KR100401283B1 - Ras-mutant cell growth inhibitor anidine derivatives - Google Patents

Ras-mutant cell growth inhibitor anidine derivatives Download PDF

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KR100401283B1
KR100401283B1 KR10-1998-0028069A KR19980028069A KR100401283B1 KR 100401283 B1 KR100401283 B1 KR 100401283B1 KR 19980028069 A KR19980028069 A KR 19980028069A KR 100401283 B1 KR100401283 B1 KR 100401283B1
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amino
methylpentylamine
acetyl
imidazol
amidino
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KR10-1998-0028069A
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KR20000008315A (en
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이봉용
김재규
이춘호
이정훈
황순호
이원희
정영환
박유회
심재영
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주식회사유한양행
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/02—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C211/09—Diamines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

본 발명은 하기 일반식 (I)로 표시되는 신규의 구아니딘 유도체 및 이들의 무독성염, 이들의 제조방법 및 이들을 유효성분으로 함유하는 라스(Ras) 변이세포 성장억제 조싱물에 관한 것이다.The present invention relates to novel guanidine derivatives represented by the following general formula (I), nontoxic salts thereof, their preparation methods, and Ras mutant cell growth inhibitory preparations containing them as active ingredients.

상기에서 X는 피리딜 또는 치환기를 갖거나 갖지않는 페닐이고, R1및 R2는 각각 수소, 시아노, 메톡시, 직쇄상 또는 분지상의 C1- C6알킬, 시클로알킬, 2 - 프로페닐, t-부톡시카보닐, 피리딜-N-옥시드, 4-메틸벤젠술포닐, 메탄술포닐, 치환기를 갖거나 갖지않는 페닐 또는 피리딜, 벤질, 또는 페닐에틸이다.Wherein X is pyridyl or phenyl with or without substituents, R 1 and R 2 are each hydrogen, cyano, methoxy, straight or branched C 1 -C 6 alkyl, cycloalkyl, 2-pro Phenyl, t-butoxycarbonyl, pyridyl-N-oxide, 4-methylbenzenesulfonyl, methanesulfonyl, phenyl with or without substituents, pyridyl, benzyl, or phenylethyl.

Description

라스(Ras) 변이세포 성장억제 구아니딘 유도체Ras Mutant Cell Growth Inhibition Guanidine Derivatives

본 발명은 신규의 구아니딘 유도체 및 이들의 무독성염에 관한 것으로, 더욱 상세하게는 하기 일반식 (I)로 표시되는 신규의 구아니딘 유도체 및 이들의 무독성염, 이들의 제조방법 및 이들을 유효성분으로 함유하는 라스(Ras) 변이세포 성장억제 조성물에 관한 것이다.The present invention relates to novel guanidine derivatives and their non-toxic salts, and more particularly, to novel guanidine derivatives represented by the following general formula (I) and their non-toxic salts, their preparation methods, and their containing as active ingredients Ras (Ras) mutant cell growth inhibitory composition.

상기에서 X는 피리딜 또는 치환기를 갖거나 갖지않는 페닐이고, R1및 R2는 각각 수소, 시아노, 메톡시, 직쇄상 또는 분지상의 C1- C6알킬, 시클로알킬, 2-프로페닐, t-부톡시카보닐, 피리딜-N-옥시드, 4-메틸벤젠술포닐, 메탄술포닐, 치환기를 갖거나 갖지않는 페닐 또는 피리딜, 벤질, 또는 페닐에틸이다.Wherein X is pyridyl or phenyl with or without substituents and R 1 and R 2 are each hydrogen, cyano, methoxy, straight or branched C 1 -C 6 alkyl, cycloalkyl, 2-pro Phenyl, t-butoxycarbonyl, pyridyl-N-oxide, 4-methylbenzenesulfonyl, methanesulfonyl, phenyl with or without substituents, pyridyl, benzyl, or phenylethyl.

최근에 파르네실 트랜스퍼라제 저해제 기전을 이용한 새로운 항암제의 개발에 대한 연구가 보고된 바 있다(J. Med, Chem., 40, 2921(1997)) 예를들어, 라스단백질의 카복실산 잔기와 유사한 구조를 갖는 Cys-Val-Phe-Met이 파르네실 단백질 트랜스퍼라제 (Farnesyl protein transferase, 이하 "FPT"라 한다.)의 저해제로 작용한다고 개시된 바 있다(J. Biol. Chem., 266, 15575, 1991; A. M. Garcia et al., J.Biol. Chem., 268, 18415, 1993; S. L. Graham et al., J, Med. Chem., 37, 725, 1994).Recently, studies on the development of new anticancer agents using the farnesyl transferase inhibitor mechanism have been reported (J. Med, Chem., 40, 2921 (1997)). For example, a structure similar to the carboxylic acid residue of the las protein has been reported. Cys-Val-Phe-Met has been disclosed to act as an inhibitor of Farnesyl protein transferase (hereinafter referred to as "FPT") (J. Biol. Chem., 266, 15575, 1991; AM Garcia et al., J. Biol. Chem., 268, 18415, 1993; SL Graham et al., J, Med. Chem., 37, 725, 1994).

이러한 보고에 근거하여 Cys-Ile-Phe-Met를 기본구조로 하여 다수의 유도체들이 개발중에 있다. 대표적으로는 Phe-Met 부위를 방향족알킬아민으로 대체한 화합물이 제라닐제라닐 단백질 트랜스퍼라제 (Geranylgcranyl protein transferase, 이하 "GGPT"라 한다.)에 비하여 FPT를 선택적으로 억제한다는 보고가 있고 (S. J.Desolms et al., J. Med, Chem., 38, 3967, 1995), 시스테인과 트랜스-3(S)-에틸프롤린에 아미노메틸나프탈렌을 결합시킨 카보실아미드 화합물이 FPT에 대해 억제력을 나타낸다고 개시한 바 있으며 (WO9606609, 1996), 시스테인을 이미다졸에틸기로 변환시킨 유사펩타이드 화합물들도 FPT 저해효과를 갖는 것으로 보고되고 있다 (J.H. Hunt et al., J. Med. chem., 39, 353, 1996; WO9610035, 1996; WO9610034, 1996;WO9609836, 1996), 이 밖에 Cys-Ile-Phe-Met의 시스테인을 p-시아노벤질이미다졸아세테이트로, 페닐알라닌을 N-나프틸메틸로 변환한 화합물이 FPT에 대해 억제력을 갖는다고 보고하고 있다 (WO9639173, 1996).Based on these reports, a number of derivatives are under development based on Cys-Ile-Phe-Met. Typically, compounds that replace the Phe-Met moiety with an aromatic alkylamine have been reported to selectively inhibit FPT compared to Geranylgcranyl protein transferase (hereinafter referred to as "GGPT") (SJ Desolms). et al., J. Med, Chem., 38, 3967, 1995), discloses that carbosylamide compounds that bind aminomethylnaphthalene to cysteine and trans-3 (S) -ethylproline exhibit inhibitory activity against FPT. (WO9606609, 1996), similar peptide compounds obtained by converting cysteine to imidazole ethyl groups have also been reported to have FPT inhibitory effects (JH Hunt et al., J. Med. Chem., 39, 353, 1996; WO9610035). , 1996; WO9610034, 1996; WO9609836, 1996), and other compounds in which cysteine of Cys-Ile-Phe-Met was converted to p-cyanobenzylimidazoleacetate and phenylalanine to N-naphthylmethyl for FPT Reported to have restraint (W 09639173, 1996).

그러나, 대부분의 FPT 저해제들은 실제로 대부분의 인체 암에서 발견되는 K-라스 변이세포내에서는 파르네실화를 효과적으로 억제하지 못한다고 최근에 보고된 바 있다. 즉, 인체암 세포에서 가장 발견빈도가 높은 K-라스B는 FPT 저해제에 의해라스단백질의 파르네실화가 억제되면, 대신 GGPT (특히, GGPT-1)에 의하여 프레닐화됨으로써 라스단백질의 활성을 유지한다고 최근에 보고되었다. (J. Biol. Chem. 270, 6221, 1995 ; J Biol, Chem. 272, 14459, 1997).However, it has recently been reported that most FPT inhibitors do not effectively inhibit farnesylation in K-Ras mutant cells found in most human cancers. In other words, K-RasB, which is most frequently found in human cancer cells, is inhibited by FPT inhibitors of farnesylation of Ras protein, but instead prenylated by GGPT (especially GGPT-1) to maintain Ras protein activity. Recently it was reported. (J. Biol. Chem. 270, 6221, 1995; J Biol, Chem. 272, 14459, 1997).

이에 본 발명자들은 K-라스 변이세포내에서 K-라스 단백질의 프레닐화를 억제함으로써 암세포의 성장을 억제하는 항암제를 개발하고자 연구를 거듭한 결과, 일반식(I)의 구아니딘 유도체가 효과적으로 K-라스 단백질의 프레닐화를 억제할 뿐 아니라 라스 변이세포 자체의 성장도 억제할 수 있다는 것을 발견하여 본 발명을 완성하게 되었다.Therefore, the present inventors have conducted research to develop an anticancer agent that inhibits the growth of cancer cells by inhibiting the prenylation of K-Ras protein in K-Ras mutant cells. As a result, the guanidine derivative of Formula (I) effectively The present invention was completed by discovering that not only the prenylation of proteins but also the growth of Lars mutant cells themselves can be inhibited.

이하, 본 발명을 상세히 설명하면 다음과 같다.Hereinafter, the present invention will be described in detail.

본 발명은 K-라스 단백질의 프레닐화 억제효과 및 라스변이세포 성장억제효과를 갖는 신규의 구아니딘 유도체 및 이들의 무독성염을 제공하는 것을 목적으로 한다.It is an object of the present invention to provide novel guanidine derivatives and nontoxic salts thereof, which have a prenylation inhibitory effect of K-ras protein and a las mutant cell growth inhibitory effect.

또한, 본 발명의 목적은 상기 구아니딘 유도체 및 이들의 무독성명의 제조방법을 제공하는 것을 포함한다.It is also an object of the present invention to provide a process for producing the guanidine derivatives and their nontoxic names.

또한, 본 발명의 목적은 상기 구아니딘 유도체 및 이들의 무독성염을 유효성분으로 함유하는 라스변이세포 성장억제 조성물을 제공하는 것을 포함한다.It is also an object of the present invention to provide a las mutant cell growth inhibition composition containing the guanidine derivatives and nontoxic salts thereof as an active ingredient.

이하, 본 발명을 더욱 상세히 설명한다.Hereinafter, the present invention will be described in more detail.

본 발명은 하기 일반식 (I)로 표시되는 신규의 구아니딘 유도체 및 이들의약제학적으로 허용가능한 무독성염을 포함한다.The present invention includes novel guanidine derivatives represented by the following general formula (I) and their pharmaceutically acceptable non-toxic salts.

상기에서 X는 피리딜 또는 치환기를 갖거나 갖지않는 페닐이고, R1및 R2는 각각 수소, 시아노, 메톡시, 직쇄상 또는 분지상의 C1- C6알킬, 시클로알킬, 2-프로페닐, t-부톡시카보닐, 피리딜-N-옥시드, 4-메틸벤젠술포닐, 메탄술포닐, 치환기를 갖거나 갖지않는 페닐 또는 피리딜, 벤질, 또는 페닐에틸이다.Wherein X is pyridyl or phenyl with or without substituents, R 1 and R 2 are each hydrogen, cyano, methoxy, straight or branched C 1 -C 6 alkyl, cycloalkyl, 2-propenyl , t-butoxycarbonyl, pyridyl-N-oxide, 4-methylbenzenesulfonyl, methanesulfonyl, phenyl with or without substituents, pyridyl, benzyl, or phenylethyl.

본 발명에 따른 구아니딘 유도체는 약제학적으로 허용가능한 염의 형태일 수 있으며, 그 염으로는 항암제 분야에서 통상적으로 사용가능한 무독성염, 예를들면, 무기산 또는 유기산으로부터 생성된 염의 형태일 수 있다. 이러한 통상적인 무독성 염에는 염산, 브롬화수소산, 황산, 설팜산, 인산, 질산 등과 같은 무기산으로 부터 유도된 염 및 아세트산, 프로피온산, 숙신산, 글리콜산, 스테아르산, 말레산, 하이드록시말레산, 페닐아세트산, 글루탐산, 벤조산, 살리실산, 설파닐산, 2-아세톡시-벤조산, 푸마르산, 톨루엔설폰산, 메탄설폰산, 에탄설폰산, 옥살산, 트리플루오로아세트산과 같은 유기산으로부터 제조된 염등을 포함한다.The guanidine derivatives according to the present invention may be in the form of pharmaceutically acceptable salts, which may be in the form of non-toxic salts commonly used in the field of anticancer agents, for example salts formed from inorganic or organic acids. Such conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid and the like and acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, maleic acid, hydroxymaleic acid, phenylacetic acid Salts prepared from organic acids such as glutamic acid, benzoic acid, salicylic acid, sulfanic acid, 2-acetoxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, oxalic acid, trifluoroacetic acid, and the like.

상기 본 발명에 따른 화합물중에서 보다 바람직한 화합물의 예를들면 다음과 같다.Examples of the more preferable compound among the compounds according to the present invention are as follows.

N-[N'-시아노-N"-(4-메톡시페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(4-methoxyphenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-시아노-N"-(피리딘-3-일)아미디노]-N-(2,3-디를로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(pyridin-3-yl) amidino] -N- (2,3-dilobenzyl) -2 (S)-{[1- (4-cya Nobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-시아노-N"-(2-메틸티오피리딘-5-일)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(2-methylthiopyridin-5-yl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4- Cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-시아노-N"-(4-메틸페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(4-methylphenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H -Imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-시아노-N"-(3-클로로페닐)아미디노]-N-(2,3-디플로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(3-chlorophenyl) amidino] -N- (2,3-difluorobenzyl) -2 (S)-{[1- (4-cyanobenzyl ) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-시아노-N"-(4-메틸티오페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(4-methylthiophenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-시아노-N"-(4-디메틸아미노페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(4-dimethylaminophenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-시아노-N"-(2-메톡시피리딘-5-일)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(2-methoxypyridin-5-yl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4- Cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-시아노-N"-(페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(phenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imid Dazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-시아노-N"-(벤질)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(benzyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imide Dazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-시아노-N"-(페닐에틸)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(phenylethyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H- Imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-시아노-N"-(4-클로로페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(4-chlorophenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl)- 1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-시아노-N"-(4-플루오로페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(4-fluorophenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-시아노-N"-(3-플루오로페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(3-fluorophenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-시아노-N"-(메틸)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(methyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imid Dazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-시아노-N"-(에틸)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(ethyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) 1H-imidazole -5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-시아노-N"-(n-프로필)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(n-propyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H -Imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-시아노-N"-(n-부틸)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(n-butyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H -Imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-시아노-N"-(n-펜틸)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(n-pentyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H -Imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-시아노-N"-(t-부틸)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(t-butyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H -Imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-시아노-N"-(이소부틸)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(isobutyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H- Imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-시아노-N"-(2-프로페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(2-propenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl)- 1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-시아노-N"-(시클로프로필)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(cyclopropyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H- Imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

H-[N'-시아노-N"-(시클로펜틸)아미디노]-N-(2,3-디플로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,H- [N'-cyano-N "-(cyclopentyl) amidino] -N- (2,3-difluorobenzyl) -2 (S)-{[1- (4-cyanobenzyl)- 1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-시아노-N"-(4-니트로페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(4-nitrophenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl)- 1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-시아노-N"-(시클로헥실)아미디노]-N-(2,3-디플로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(cyclohexyl) amidino] -N- (2,3-difluorobenzyl) -2 (S)-{[1- (4-cyanobenzyl)- 1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-시아노-N"-(2-플루오로페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(2-fluorophenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-시아노-N"-(3-트리플루오로메틸페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(3-trifluoromethylphenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl ) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-시아노-N"-(3-메틸페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(3-methylphenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H -Imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-시아노-N"-(2-메톡시페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(2-methoxyphenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-시아노-N"-(피리딘-4-일)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(pyridin-4-yl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-시아노-N"-(피리딘-1-N-옥시드-3-일)아미디노]-N-(2,3-디클로로벤질)-2(S){[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(pyridin-1-N-oxide-3-yl) amidino] -N- (2,3-dichlorobenzyl) -2 (S) {[1- ( 4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-시아노-N"-(4-아미노페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(4-aminophenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl)- 1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-시아노-N"-(4-메톡시페닐)아미디노]-N-(2-클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(4-methoxyphenyl) amidino] -N- (2-chlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H -Imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-시아노-N"-(4-메톡시페닐)아미디노]-N-(2,3-디를루오로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸벤질아민,N- [N'-cyano-N "-(4-methoxyphenyl) amidino] -N- (2,3-diluorobenzyl) -2 (S)-{[1- (4-cya Nobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylbenzylamine,

N-[N'-시아노-N"-(4-메톡시페닐)아미디노]1-N-(3-클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(4-methoxyphenyl) amidino] 1-N- (3-chlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl)- 1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-시아노-N"-(2-메톡시피리딘-5-일)아미디노]-N-(3-클로로벤질)-2(S)-{{1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(2-methoxypyridin-5-yl) amidino] -N- (3-chlorobenzyl) -2 (S)-{{1- (4-cyano Benzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-시아노-N"-(4-메톡시페닐)아미디노]-N-(2-트리플루오로메틸벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(4-methoxyphenyl) amidino] -N- (2-trifluoromethylbenzyl) -2 (S)-{[1- (4-cyanobenzyl ) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-시아노-N"-(2-메톡시피리딜-5-일)아미디노]-N-(2-트리플루오로메틸벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸벤질아민,N- [N'-cyano-N "-(2-methoxypyridyl-5-yl) amidino] -N- (2-trifluoromethylbenzyl) -2 (S)-{[1- ( 4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylbenzylamine,

N-[N'-시아노-N"-(4-메톡시페닐)아미디노]-N-(2-메닐벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸 아민,N- [N'-cyano-N "-(4-methoxyphenyl) amidino] -N- (2-menylbenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H -Imidazol-5-yl] acetyl} amino-3 (S) -methylpentyl amine,

N-[N'-시아노-N"-(2-메톡시피리딘-5-일)아미디노]-N-(2-메틸벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(2-methoxypyridin-5-yl) amidino] -N- (2-methylbenzyl) -2 (S)-{[1- (4-cyano Benzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-시아노-N"-(4-메톡시페닐)아미디노]-N-[(피리딘-2-일)메틸]-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(4-methoxyphenyl) amidino] -N-[(pyridin-2-yl) methyl] -2 (S)-{[1- (4-cyano Benzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-시아노-N"-(2-메톡시피리딘-5-일)아미디노]-N-[(피리딘-2-일)메틸]-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(2-methoxypyridin-5-yl) amidino] -N-[(pyridin-2-yl) methyl] -2 (S)-{[1- ( 4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-시아노-N"-(4-메톡시페닐)아미디노]-N-(3-플루오로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(4-methoxyphenyl) amidino] -N- (3-fluorobenzyl) -2 (S)-{[1- (4-cyanobenzyl)- 1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-시아노-N"-(2-메톡시피리딘-5-일)아미디노]-N-(3-플루오로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(2-methoxypyridin-5-yl) amidino] -N- (3-fluorobenzyl) -2 (S)-{[1- (4-cya Nobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-시아노-N"-(4-메톡시페닐)아미디노]-N-(3-트리플루오르메틸벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(4-methoxyphenyl) amidino] -N- (3-trifluoromethylbenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-시아노-N"-(2-메톡시피리딘-5-일)아미디노]-N-(3-트리플루오로메틸벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(2-methoxypyridin-5-yl) amidino] -N- (3-trifluoromethylbenzyl) -2 (S)-{[1- (4 -Cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-시아노-N"-(4-메톡시페닐)아미디노]-N-(3-메톡시카보닐벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(4-methoxyphenyl) amidino] -N- (3-methoxycarbonylbenzyl) -2 (S)-{[1- (4-cyanobenzyl ) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-시아노-N"-(3-플루오로페닐)아미디노]-N-(3-메톡시카보닐벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(3-fluorophenyl) amidino] -N- (3-methoxycarbonylbenzyl) -2 (S)-{[1- (4-cyanobenzyl ) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-시아노-N"-(4-메톡시페닐)아미디노]-N-(3-카복시벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민 염산염,N- [N'-cyano-N "-(4-methoxyphenyl) amidino] -N- (3-carboxybenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H -Imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine hydrochloride,

N-[N'-시아노-N"-(3-플루오로페닐)아미디노]-N-(3-카복시벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민 염산염,N- [N'-cyano-N "-(3-fluorophenyl) amidino] -N- (3-carboxybenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H -Imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine hydrochloride,

N-[N'-시아노-N"-(4-메톡시페닐)아미디노]-N-(4-메톡시카보닐벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(4-methoxyphenyl) amidino] -N- (4-methoxycarbonylbenzyl) -2 (S)-{[1- (4-cyanobenzyl ) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-시아노-N"-(3-플루오로페닐)아미디노]-N-(4-메톡시카보닐벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(3-fluorophenyl) amidino] -N- (4-methoxycarbonylbenzyl) -2 (S)-{[1- (4-cyanobenzyl ) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-시아노-N"-(4-메톡시페닐)아미디노]-N-(4-카복시벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민 염산염,N- [N'-cyano-N "-(4-methoxyphenyl) amidino] -N- (4-carboxybenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H -Imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine hydrochloride,

N-[N'-시아노-N"-(3-플루오로페닐)아미디노]-N-(4-카복시벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민 염산염,N- [N'-cyano-N "-(3-fluorophenyl) amidino] -N- (4-carboxybenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H -Imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine hydrochloride,

N-[N'-(t-부톡시카보닐)-N"-(4-메톡시페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N '-(t-butoxycarbonyl) -N "-(4-methoxyphenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- ( 4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-(4-메톡시페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N '-(4-methoxyphenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazole- 5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N',N"-(디-t-부톡시카보닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N ', N "-(di-t-butoxycarbonyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-(아미디노)-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민 트리플루오로아세트산염,N- (amidino) -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 ( S) -methylpentylamine trifluoroacetic acid salt,

N-[N'-(t-부톡시카보닐)-N"-(이소부틸)아미디노]-N-(2,3-디플로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N '-(t-butoxycarbonyl) -N "-(isobutyl) amidino] -N- (2,3-difluorobenzyl) -2 (S)-{[1- (4 -Cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-(이소부틸)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민 트리플루오로아세트산염,N- [N '-(isobutyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl ] Acetyl} amino-3 (S) -methylpentylamine trifluoroacetic acid salt,

N-[N'-(2-메톡시페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민 트리플루오로아세트산염,N- [N '-(2-methoxyphenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1Himidazole-5 -Yl] acetyl} amino-3 (S) -methylpentylamine trifluoroacetic acid salt,

N-[N'-메틸-N"-(4-메톡시페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-methyl-N "-(4-methoxyphenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl)- 1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-메톡시-N"-(4-메톡시페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-methoxy-N "-(4-methoxyphenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-메톡시-N"-(2-플루오로페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-methoxy-N "-(2-fluorophenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-메톡시-N"-(3-플루오로페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-methoxy-N "-(3-fluorophenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-메톡시-N"-(2-메톡시피리딘-5-일)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-methoxy-N "-(2-methoxypyridin-5-yl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4- Cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-메톡시-N"-(페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-methoxy-N "-(phenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imid Dazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-메톡시-N"-(4-메톡시페닐)아미디노]-N-(2-트리플루오로메틸벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-methoxy-N "-(4-methoxyphenyl) amidino] -N- (2-trifluoromethylbenzyl) -2 (S)-{[1- (4-cyanobenzyl ) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-메톡시-N"-(4-메톡시페닐)아미디노]-N-(2-메틸벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-methoxy-N "-(4-methoxyphenyl) amidino] -N- (2-methylbenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H -Imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-메톡시-N"-(4-메톡시페닐)아미디노]-N-[(피리딘-2-일)메틸)]-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-methoxy-N "-(4-methoxyphenyl) amidino] -N-[(pyridin-2-yl) methyl)]-{[1- (4-cyanobenzyl) -1H -Imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-메톡시-N"-(4-메톡시페닐)아미디노]-N-(3-플루오로벤질)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-methoxy-N "-(4-methoxyphenyl) amidino] -N- (3-fluorobenzyl)-{[1- (4-cyanobenzyl) -1 H-imidazole- 5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-메톡시-N"-(4-메톡시페닐)아미디노]-N-[(3-트리플루오로메틸)벤질]-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-methoxy-N "-(4-methoxyphenyl) amidino] -N-[(3-trifluoromethyl) benzyl]-{[1- (4-cyanobenzyl) -1H -Imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-(4-메톡시페닐)-N"-(메탄술포닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N '-(4-methoxyphenyl) -N "-(methanesulfonyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-sia Nobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-메틸-N"-(4-메틸벤젠술포닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-methyl-N "-(4-methylbenzenesulfonyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-(메탄술포닐)-N"-이소부틸아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N '-(methanesulfonyl) -N "-isobutylamidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H -Imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine,

N-[N'-(메탄숙포닐)-N"-(3-플루오로페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민.N- [N '-(methanesulfonyl) -N "-(3-fluorophenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-sia Nobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine.

본 발명은 일반식(I)로 표시되는 구아니딘 유도체 및 그의 무독성 염의 제조 방법을 포함한다. 이들 유도체의 제조방법을 반응식으로 표시하면 다음과 같다.The present invention includes a process for producing guanidine derivatives represented by general formula (I) and nontoxic salts thereof. The preparation method of these derivatives is represented as follows.

반응식 -1Scheme -1

상기 반응식-1에서 X, R1, 및 R2는 상기 정의와 동일하다.In Scheme-1, X, R 1 , and R 2 are the same as defined above.

상기 반응식-1에 따라 일반식(II)의 화합물을 일반식(III)의 화합물 또는 그의 금속염과 커플링화제(coupling reagent)존재하에서 반응시키면, 일반식(I)의 화합물을 제조할 수 있다.According to Scheme 1, a compound of Formula (I) can be prepared by reacting a compound of Formula (II) with a compound of Formula (III) or a metal salt thereof in the presence of a coupling reagent.

일반식(II)의 화합물은 본 발명자들이 1997년 9월 11일 출원한 특허출원(대한민국 출원번호 제97-46796호)에서 개시한 방법에 의해 제조할 수 있으며, R1및 R2로 치환환 일반식(III)의 티오우레아 유도체는 공지의 제조방법에 따라 치환 티오우레아로 부터 결합반응을 통하여 제조하거나 (Syn, Commun., 23, 1443, 1993 및 Tetrahedron Lett., 33, 5933, 1992), 치환-이소티오시아네이트에 시안아민, 메틸아민, 메톡실아민, 메틸술폰아민 또는 벤젠술폰아민을 각각 부가반응을 통하여 제조할 수 있다(Tetrahedron Lett., 30, 7313, 1989).The compound of formula (II) may be prepared by the method disclosed in the patent application filed on September 11, 1997 by the present inventors (Korean Application No. 97-46796), and substituted with R 1 and R 2 . Thiourea derivatives of the general formula (III) are prepared by a coupling reaction from a substituted thiourea according to a known preparation method (Syn, Commun., 23, 1443, 1993 and Tetrahedron Lett., 33, 5933, 1992), Cyanamine, methylamine, methoxylamine, methylsulfonamine or benzenesulfonamine can be prepared in the substituted-isothiocyanate by addition reaction (Tetrahedron Lett., 30, 7313, 1989).

상기 반응에서 사용될 수 있는 용매로는 디메틸포름아미드, 디클로로메탄, 또는 이들의 혼합용매 등의 유기용매가 바람직하며, 일반식(III)의 화합물의 금속염으로는 나트륨, 칼륨, 칼슘등과 같이 티오우레아와 염을 생성할 수 있는 통상적인 금속염을 사용할 수 있다. 또한, 상기 반응에 사용될 수 있는 커플링화제(coupling reagent)로는 염화수은, 염화구리, 2-클로로-1-메틸피리디니윰요오드, 또는 디알킬카보디이미드 등이 모두 가능하나, 염화수은 또는 디알킬카보디이미드가 더욱 바람직하다.As a solvent that can be used in the reaction, an organic solvent such as dimethylformamide, dichloromethane, or a mixed solvent thereof is preferable, and as the metal salt of the compound of formula (III), thiourea such as sodium, potassium, calcium, etc. Conventional metal salts that can form and salts can be used. In addition, as a coupling reagent that may be used in the reaction, mercury chloride, copper chloride, 2-chloro-1-methylpyridinium iodine, dialkylcarbodiimide, and the like may be used. Alkyl carbodiimide is more preferred.

상기 반응식-1 이외에도, 하기 반응식-2와 같이 구아니딘 형성반응을 먼저수행한 다음, 1-(4-시아노벤질)-1H-이미다졸-5-일아세트산을 반응시켜 일반식(I)의 화합물을 제조할 수 있다.In addition to the above Scheme-1, a guanidine formation reaction is first performed as in Scheme-2, followed by reacting 1- (4-cyanobenzyl) -1H-imidazol-5-ylacetic acid to the compound of formula (I). Can be prepared.

반응식-2Scheme-2

상기 반응식-2에서 X, R1, 및 R2는 상기 정의와 동일하며, Boc는 통상의 아미노 보호기이다.In Scheme-2, X, R 1 , and R 2 are the same as defined above, and Boc is a common amino protecting group.

상기 반응식-2와 같이, 일반식(IV)의 화합물을 일반식(III)의 화합물 또는 그의 금속염과 커플링화제(coupling reagent)존재하에서 반응시켜 일반식(V)의 화합물을 제조한 다음, 일반식(V)의 화합물에 1-(4-시아노벤질)-1H-이미다졸-5-일아세트산을 반응시켜 일반식(I)의 화합물을 제조할 수 있다.As in Scheme-2, a compound of Formula (IV) is reacted with a compound of Formula (III) or a metal salt thereof in the presence of a coupling reagent to prepare a compound of Formula (V), and then Compound of formula (I) may be prepared by reacting 1- (4-cyanobenzyl) -1H-imidazol-5-ylacetic acid with a compound of formula (V).

구아니딘 형성반응을 수행하여 일반식(V)의 화합물을 제조하는 단계는 상기 반응식-1에서 나타낸 바와 동일한 조건으로 수행할 수 있으며, 다음 단계인 아미드결합형성반응은 적절한 커플링화제 존재하에서 1-(4-시아노벤질)-1H-이미다졸-5-일아세트산을 반응시켜 제조할 수 있고, 커플링화제로는 상기에서 사용된 커플링화제를 사용할 수 있다.The step of preparing the compound of formula (V) by performing the guanidine forming reaction may be carried out under the same conditions as shown in Scheme 1, and the next step, the amide bond forming reaction is carried out in the presence of a suitable coupling agent 1- ( It can be prepared by reacting 4-cyanobenzyl) -1H-imidazol-5-ylacetic acid, and the coupling agent used above may be used as the coupling agent.

본 발명에 따른 화합물의 약제학적으로 허용가능한 무독성 염은 염기성 잔기를 함유하는 본 발명의 화합물로부터 통상적인 방법으로 제조할 수 있다. 일반적으로, 염은 유기염기를 화학량론적 양 또는 과량의 목적하는 염-형성 무기산 또는 유기산과 적합한 용매 또는 용매들의 다양한 배합물중에서 반응시켜 제조할 수 있다.Pharmaceutically acceptable non-toxic salts of the compounds according to the invention can be prepared by conventional methods from compounds of the invention containing basic moieties. In general, salts can be prepared by reacting an organic base with a stoichiometric amount or excess of the desired salt-forming inorganic or organic acid in a variety of suitable solvents or solvents.

본 발명은 일반식(I)의 구아니딘 유도체 및 이들의 무독성염을 유효성분으로 함유하고 약제학적으로 허용가능한 담체를 함유하는 라스변이세포 성장억제 조성물을 포함한다. 본 발명에 따른 조성물은 락토즈, 옥수수전분 등의 부형제, 마그네슘 스테아레이트 등의 윤활제, 공지되어 사용가능한 유화제, 현탁제, 완충제, 등장화제 등을 포함할 수 있으며, 경우에 따라 감미제 및/또는 향미제를 포함할 수 있다.The present invention includes a las mutant cell growth inhibitory composition containing a guanidine derivative of formula (I) and a nontoxic salt thereof as an active ingredient and a pharmaceutically acceptable carrier. The composition according to the invention may comprise excipients such as lactose, corn starch, lubricants such as magnesium stearate, emulsifiers, suspending agents, buffers, isotonic agents and the like which are well known and can be used, and in some cases sweetening and / or flavoring It may include the agent.

본 발명에 따른 조성물은 경구투여하거나, 정맥내, 복강내, 피하, 직장 및 국소 투여를 포함한 비경구 투여를 실시할 수 있다. 즉, 본 발명에 따른 조성물은 정제 또는 캡슐제 형태로, 또는 수성용제 또는 현탁제로서 투여할 수 있다. 경구용 정제의 경우 통상 사용되는 담체에는 락토즈 및 옥수수 전분이 포함되고, 마그네슘 스테아레이트와 같은 윤활제를 통상 가할 수 있다. 캡슐제 형태의 경우 유용한 희석제로서 락토즈 및 건조 옥수수 분말을 포함할 수 있다. 경구용으로 수성 현탁제가 필요할 경우 활성성분을 유화제 및 현탁제를 포함할 수 있다. 경우에 따라 특정 감미제 및/또는 향미제를 가할 수 있다. 근육내, 복강내, 피하 및 정맥내 투여의 경우, 통상 활성 성분의 멸균 용액을 제조하고, 용액의 pH를 적합하게 조절할 수 있는 완충제로 포함할 수 있으며, 정맥내 투여의 경우 용질의 총 농도는 제제에 등장성이 부여되도록 조절할 수 있는 등장화제를 포함할 수 있다. 또한, 본 발명에 따른 조성물은 pH가 7.4인 염수와 같은 약제학적으로 허용되는 담체를 포함하는 수용액제의 형태가 될 수 있으며, 용액제의 형태로 국소적으로 환자의 근육내 혈류에도입할 수 있다.The composition according to the invention can be administered orally or parenterally, including intravenous, intraperitoneal, subcutaneous, rectal and topical administration. That is, the composition according to the present invention can be administered in the form of tablets or capsules, or as an aqueous solvent or suspending agent. In the case of oral tablets, carriers commonly used include lactose and corn starch, and lubricants such as magnesium stearate can usually be added. Useful diluents for capsule form may include lactose and dry corn powder. If an aqueous suspension is required for oral use, the active ingredient may include emulsifiers and suspensions. If desired, certain sweetening and / or flavoring agents may be added. For intramuscular, intraperitoneal, subcutaneous and intravenous administration, a sterile solution of the active ingredient is usually prepared and may be included as a buffer to suitably adjust the pH of the solution. For intravenous administration, the total concentration of the solute is It may include isotonic agents that can be adjusted to impart isotonicity to the formulation. In addition, the composition according to the present invention may be in the form of an aqueous solution containing a pharmaceutically acceptable carrier such as saline having a pH of 7.4, and may be locally introduced into the patient's intramuscular blood flow in the form of a solution. have.

본 발명에 따른 화합물은 K-라스 단백질의 프레닐화 및 라스변이세포의 성장을 효과적으로 억제함으로써 결장암, 직장암, 췌장암, 또는 골수성 백혈병 등의 암환자에게 투여될 수 있으며, 그 투여용량은 통상 각 환자의 연령, 체중 및 환자의 증상에 따라 일반적으로 변화시킬 수 있는 용량, 예를들어 1일 약 0.1mg/kg 내지 약 20mg/kg, 바람직하게는 1일 0.5mg/kg 내지 약 10mg/kg, 으로 투여될 수 있다.The compound according to the present invention can be administered to cancer patients such as colon cancer, rectal cancer, pancreatic cancer, or myeloid leukemia by effectively inhibiting the prenylation of K-ras protein and the growth of las mutant cells. Doses that can generally vary depending on age, weight and symptoms of the patient, such as from about 0.1 mg / kg to about 20 mg / kg per day, preferably from 0.5 mg / kg to about 10 mg / kg per day Can be.

이하, 본 발명을 실시예를 통하여 더욱 상세히 설명한다. 그러나, 이것이 본 발명의 범위를 제한하는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to Examples. However, this does not limit the scope of the invention.

참조예 1. 1-(4-시아노벤질)-1H-이미다졸-5-일아세트산 염산염의 제조Reference Example 1. Preparation of 1- (4-cyanobenzyl) -1H-imidazol-5-monoacetic acid hydrochloride

<단계 1> 1H-이미다졸-4-일아세트산 메틸 에스테르 염산염<Step 1> 1H-imidazol-4-ylacetic acid methyl ester hydrochloride

4-이미다졸아세트산 염산염 (10 g, 61.5 mmol)의 메탄올 (200 ml) 용액에 염산가스를 포화시켰다. 이 용액을 실온에서 18시간동안 방치한 후 용매를 감압 농축하여 흰색 고체의 표제화합물 (11.6 g)을 제조하였다.Hydrochloric acid gas was saturated in a methanol (200 ml) solution of 4-imidazoleacetic acid hydrochloride (10 g, 61.5 mmol). After leaving this solution at room temperature for 18 hours, the solvent was concentrated under reduced pressure to give the title compound (11.6 g) as a white solid.

<단계 2> 1-(트리페닐메틸)-1H-이미다졸-4-일아세트산 메틸에스테르<Step 2> 1- (triphenylmethyl) -1H-imidazol-4-ylacetic acid methyl ester

1H-이미다졸-4-일아세트산 메틸에스테르 염산염 (11.6 g, 65.6 mmol)의 디클로로메탄 (350 ml)와 디메틸포름아미드 (50 ml) 현탁액에 트리에틸아민 (27.4 ml, 196.6 mmol)과 트리페닐메틸클로라이드 (21.9 g, 78.6 mmol)를 가한 후 15시간동안 교반하였다. 반응혼합물을 물과 포화 소금물로 세척하고 유기층을 무수 마그네슘술페이트로 건조한 후 감압 농축한 잔사를 실리카겔 관 크로마토그라피로 정제하여 흰색 고체의 표제화합물 (7.4 g)을 제조하였다.Triethylamine (27.4 ml, 196.6 mmol) and triphenylmethyl in a suspension of dichloromethane (350 ml) and dimethylformamide (50 ml) of 1H-imidazol-4-ylacetic acid methylester hydrochloride (11.6 g, 65.6 mmol). Chloride (21.9 g, 78.6 mmol) was added and stirred for 15 h. The reaction mixture was washed with water and saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the residue was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (7.4 g) as a white solid.

<단계 3> 1-(4-시아노벤질)-1H-이미다졸-5-일아세트산 메틸에스테르<Step 3> 1- (4-cyanobenzyl) -1H-imidazol-5-ylacetic acid methyl ester

1-(트리페닐메틸)-1H-이미다졸-4-일아세트산 메틸에스테르 (1.43 g, 3.74 mmol)의 아세토니트릴 (30 ml) 용매에 4-시아노벤질브로마이드 (0.81 g, 4.11 mmol)를 가한 후 24시간동안 65 ℃로 가온 교반하였다. 반응용액을 실온으로 식히고 용매를 감압 농축하여 제거한 후 잔사를 메탄올 (50 ml)에 용해하여 1시간동안 환류 교반하였다. 10 ml 용액이 되도록 감압 농축하고 메탄올에서 결정화하여 흰색 고체상의 표제화합물 (0.89 g, 93 %)을 제조하였다.4-cyanobenzylbromide (0.81 g, 4.11 mmol) was added to acetonitrile (30 ml) solvent of 1- (triphenylmethyl) -1H-imidazol-4-ylacetic acid methylester (1.43 g, 3.74 mmol). After stirring for 24 hours warmed to 65 ℃. The reaction solution was cooled to room temperature, the solvent was concentrated under reduced pressure, and then the residue was dissolved in methanol (50 ml) and stirred at reflux for 1 hour. Concentration under reduced pressure to a 10 ml solution and crystallization in methanol to give the title compound (0.89 g, 93%) as a white solid.

<단계 4> 1-(4-시아노벤질)-1H-이미다졸-5-일아세트산 염산염Step 4 1- (4-cyanobenzyl) -1H-imidazol-5-ylacetic acid hydrochloride

1-(4-시아노벤질)-1H-이미다졸-5-일아세트산 메틸에스테르 (0.86 g, 3.37 mmol)를 1 N 염산 수용액 (10 ml)에 녹이고 4시간동안 60 ℃로 가온 교반하였다. 이 용액을 감압 농축하여 흰색 고체의 표제화합물 (0.76 g, 90 %)을 제조하였다.1- (4-cyanobenzyl) -1H-imidazol-5-ylacetic acid methylester (0.86 g, 3.37 mmol) was dissolved in 1N aqueous hydrochloric acid solution (10 ml) and stirred at 60 ° C. for 4 hours. The solution was concentrated under reduced pressure to give the title compound (0.76 g, 90%) as a white solid.

참조예 2. N-t-부톡시카보닐-L-이소루이신 알데히드의 제조Reference Example 2 Preparation of N-t-Butoxycarbonyl-L-Isoleucine Aldehyde

<단계 1> N-t-부톡시카보닐-L-이소루이신-N'-메톡시-N'-메틸아미드<Step 1> N-t-butoxycarbonyl-L-isoleucine-N'-methoxy-N'-methylamide

N,O-디메틸히드록실아민 염산염 (6.1 g, 62.5 mmol)의 디클로로메탄 (60 ml)현탁액에 N-메틸몰포린 (7.6 ml, 69.1 mmol)을 -10 ℃ 에서 적가하고 -10 ℃ 에서 방치하였다. 다른 용기에 N-t-부톡시카보닐-L-이소루이신 (15 g, 62.4 mmol)을 디클로로메탄 (300 ml)에 녹이고 온도를 -20 ℃ 로 냉각한 후, N-메틸몰포린 (7.6 ml, 69.1 mmol)과 이소부틸클로로포르메이트 (8.1 ml, 62.4 mmol)를 -20 ℃를 유지시키며 적가하였다. 5분 후, 이 혼합물에 앞서서 제조한 N,O-디메틸히드록실아민 용액을 적가하고 상온에서 철야로 교반하였다. 반응 혼합물에 물 (100 ml)을 넣고 에틸아세테이트 (100 m X 3)로 추출하였다. 추출한 유기층을 물 (100 ml x 2)과 포화소금물(100 ml)로 세척한 후 무수 마그네슘술페이트로 탈수하고 감압 농축하였다. 잔사를 실리카겔 관 크로마토그라피로 정제하여 유상의 표제화합물 (15.1 g, 89 %)을 제조하였다.To a dichloromethane (60 ml) suspension of N, O-dimethylhydroxylamine hydrochloride (6.1 g, 62.5 mmol) was added dropwise N-methylmorpholine (7.6 ml, 69.1 mmol) at −10 ° C. and left at −10 ° C. . In another vessel Nt-butoxycarbonyl-L-isorucin (15 g, 62.4 mmol) was dissolved in dichloromethane (300 ml) and the temperature was cooled to -20 ° C, followed by N-methylmorpholine (7.6 ml, 69.1 mmol) and isobutylchloroformate (8.1 ml, 62.4 mmol) were added dropwise maintaining -20 ° C. After 5 minutes, the N, O-dimethylhydroxylamine solution prepared before this mixture was added dropwise and stirred overnight at room temperature. Water (100 ml) was added to the reaction mixture, which was then extracted with ethyl acetate (100 m X 3). The extracted organic layer was washed with water (100 ml x 2) and saturated brine (100 ml), dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (15.1 g, 89%) as an oil.

<단계 2) N-t-부톡시카보닐-L-이소루이신 알데히드Step 2) N-t-butoxycarbonyl-L-isoleucine aldehyde

리튬알루미늄 히드라이드 (2.4 g, 54.7 mmol)를 무수 테트라히드로푸란 (300ml)에 현탁시킨 용액을 -45 ℃ 로 냉각시키고,N-t-부톡시카보닐-L-이소루이신-N'-메톡시-N'-메틸아미드 (15 g, 54.7 mmol)를 무수 테트라히드로푸란 (30 ml)에 용해시켜 반응액의 온도가 -45 ℃ 에서 -35 ℃ 사이가 되도록 유지하면서 소량씩 적가하였다. 적가 완결 후, 5 ℃ 가 되도록 유지한 다음 다시 반응 용액을 -35 ℃로 냉각시키고 포타슘비술페이트 수용액 (12.7 g, 35 ml)을 적가하였다. 적가 후 냉각용기를 제거하여 온도를 상온으로 유지하고 1시간 교반한 후 셀라이트를 가하여 알루미늄염을 포집시켜 여과하고 에틸아세테이트로 세척하였다. 여과한 유기층을 증류수로 세척하고 무수 마그네슘술페이트로 탈수한 후 용매를 감압 농축하여 유상의 표제화합물 (8.2 g, 69 %)을 제조하였다.The solution in which lithium aluminum hydride (2.4 g, 54.7 mmol) was suspended in anhydrous tetrahydrofuran (300 ml) was cooled to -45 ° C, and Nt-butoxycarbonyl-L-isoleucine-N'-methoxy- N'-methylamide (15 g, 54.7 mmol) was dissolved in anhydrous tetrahydrofuran (30 ml) and added dropwise in small portions while maintaining the temperature of the reaction solution between -45 ° C and -35 ° C. After completion of the dropwise addition, the solution was maintained at 5 ° C., and then the reaction solution was cooled to −35 ° C. and aqueous potassium bisulfate solution (12.7 g, 35 ml) was added dropwise. After dropping, the cooling vessel was removed, the temperature was maintained at room temperature, and stirred for 1 hour. Then, celite was added, the aluminum salt was collected, filtered, and washed with ethyl acetate. The filtered organic layer was washed with distilled water, dehydrated with anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure to give an oily title compound (8.2 g, 69%).

참조예 3. N-시아노-N'-(4-메톡시페닐)티오우레아 나트륨염의 제조Reference Example 3. Preparation of N-cyano-N '-(4-methoxyphenyl) thiourea sodium salt

4-메톡시페닐이소티오시아네이트 (6.0 g, 36.3 mmol)과 시안아미드(1.53 g, 36.1 mmol)을 에탄올 (100 ml)에 녹인후에, 에톡시나트륨 에탄올용액(2.68 M, 13.6ml, 36.3 mmol)을 가하였다. 반응 혼합물을 30분동안 환류 교반 시킨후에 감압 증류 농축하고, 잔사에 에테르 (200 ml)를 처리하여 생성된 고체를 여과하여 표제 화합물 (6.17 g, 74 %)을 수득하였다.After dissolving 4-methoxyphenylisothiocyanate (6.0 g, 36.3 mmol) and cyanamide (1.53 g, 36.1 mmol) in ethanol (100 ml), ethoxysodium ethanol solution (2.68 M, 13.6 ml, 36.3 mmol) ) Was added. The reaction mixture was stirred under reflux for 30 minutes, concentrated under reduced pressure, and the residue was treated with ether (200 ml) to filter the resulting solid, to give the title compound (6.17 g, 74%).

참조예 4 - 32. 참조예 3 과 동일한 제조방법으로 치환-이소티오시아네이트와 시안아미드로부터 상응하는 각각의 N-시아노-N'-(치환)티오우레아 나트륨염의 표제화합물을 제조하였다.Reference Examples 4-32. The title compound of the corresponding N-cyano-N '-(substituted) thiourea sodium salt was prepared from substituted-isothiocyanate and cyanamide in the same manner as in Reference Example 3.

참조예 4. N-(4-클로로페닐)-N'-시아노-티오우레아 나트륨염Reference Example 4. N- (4-Chlorophenyl) -N'-cyano-thiourea sodium salt

참조예 5. N-(4-플루오로페닐)-N'-시아노-티오우레아 나트륨염Reference Example 5. N- (4-Fluorophenyl) -N'-cyano-thiourea sodium salt

참조예 6. N-(3-플루오로페닐)-N'-시아노-티오우레아 나트륨염Reference Example 6.N- (3-fluorophenyl) -N'-cyano-thiourea sodium salt

참조예 7. N-(2-메톡시피리딘-5-일)-N'-시아노-티오우레아 나트륨염Reference Example 7.N- (2-methoxypyridin-5-yl) -N'-cyano-thiourea sodium salt

참조예 8. N-(시클로프로필)-N'-시아노-티오우레아 나트륨염Reference Example 8. N- (Cyclopropyl) -N'-cyano-thiourea sodium salt

참조예 9. N-(4-디메틸아미노페닐)-N'-시아노-티오우레아 나트륨염Reference Example 9.N- (4-dimethylaminophenyl) -N'-cyano-thiourea sodium salt

참조예 10. N-(시클로펜틸)-N'-시아노-티오우레아 나트륨염Reference Example 10 N- (cyclopentyl) -N'-cyano-thiourea sodium salt

참조에 11. N-(2-프로페닐)-N'-시아노-티오우레아 니-트륨염11.N- (2-propenyl) -N'-cyano-thioureani-thridium salts for reference

참조예 12. N-(이소부틸)-N'-시아노-티오우레아 나트륨염Reference Example 12 N- (Isobutyl) -N'-Cyano-thiourea Sodium Salt

참조예 13. N-(피리딘-3-일)-N'-시아노-티오우레아 나트륨염Reference Example 13. N- (Pyridin-3-yl) -N'-cyano-thiourea sodium salt

1H)1H)

참조예 14. N-페닐-N'-시아노-티오우레아 나트륨염Reference Example 14. N-phenyl-N'-cyano-thiourea sodium salt

참조예 15. N-(t-부틸)-N'-시아노-티오우레아 나트륨염Reference Example 15 N- (t-butyl) -N'-Cyano-thiourea Sodium Salt

참조예 16. N-메틸-N'-시아노-티오우레아 나트륨염Reference Example 16 N-Methyl-N'-Cyano-thiourea Sodium Salt

참조예 17. N-(4-니트로페닐)-N'-시아노-티오우레아 나트륨염Reference Example 17 N- (4-nitrophenyl) -N'-cyano-thiourea sodium salt

참조예 18. N-(2-메틸티오피리딘-5-일)-N'-시아노-티오우레아 나트륨염Reference Example 18 N- (2-methylthiopyridin-5-yl) -N'-cyano-thiourea sodium salt

참조예 19. N-에틸-N'-시아노-티오우레아 나트륨염Reference Example 19 N-ethyl-N'-cyano-thiourea sodium salt

참조예 20. N-시클로헥실-N'-시아노-티오우레아 나트륨염Reference Example 20 N-Cyclohexyl-N'-Cyano-thiourea Sodium Salt

참조예 21. N-(2-플루오로페닐)-N'-시아노-티오우레아 나트륨염Reference Example 21 N- (2-fluorophenyl) -N'-cyano-thiourea sodium salt

참조예 22. N-(n-프로필)-N'-시아노-티오우레아 나트륨염Reference Example 22 N- (n-propyl) -N'-Cyano-thiourea Sodium Salt

참조예 23. N-(n-부틸)-N'-시아노-티오우레아 나트륨염Reference Example 23 N- (n-Butyl) -N'-Cyano-thiourea Sodium Salt

참조예 24. N-(n-펜틸)-N'-시아노-티오우레아 나트륨염Reference Example 24 N- (n-pentyl) -N'-cyano-thiourea sodium salt

참조예 25. N-(3-트리플루오로메틸페닐)-N'-시아노-티오우레아 나트륨염Reference Example 25 N- (3-trifluoromethylphenyl) -N'-cyano-thiourea sodium salt

참조예 26. N-(3-메틸페닐)-N'-시아노-티오우레아 나트륨염Reference Example 26 N- (3-Methylphenyl) -N'-Cyano-thiourea Sodium Salt

참조예 27 N-(2-메톡시페닐)-N'-시아노-티오우레아 나트륨염Reference Example 27 N- (2-methoxyphenyl) -N'-cyano-thiourea sodium salt

참조예 28. N-벤질-N'-시아노-티오우레아 나트륨염Reference Example 28 N-benzyl-N'-cyano-thiourea sodium salt

참조예 29. N-(4-메틸페닐)-N'-시아노-티오우레아 나트륨염Reference Example 29 N- (4-methylphenyl) -N'-cyano-thiourea sodium salt

참조예 30. N-(4-클로로페닐)-N'-시아노-티오우레아 나트륨염Reference Example 30 N- (4-Chlorophenyl) -N'-cyano-thiourea sodium salt

참조예 31. N-(4-메틸티오페닐)-N'-시아노-티오우레아 나트륨염Reference Example 31 N- (4-methylthiophenyl) -N'-cyano-thiourea sodium salt

참조예 32. N-페닐에틸-N'-시아노-티오우레아 나트륨염Reference Example 32 N-phenylethyl-N'-cyano-thiourea sodium salt

참조예 33. N, N'-비스-t-부톡시카르보닐-티오우레아Reference Example 33 N, N'-bis-t-butoxycarbonyl-thiourea

티오우레아 (114 g, 15 mmol)을 무수 테트라히드로푸란 (300 ml)에 녹인 후에 0 ℃로 냉각한 다음에 수소나트륨 (2.7 g, 60 %, 68 mmol)을 천천히 가하고 상온에서 약 20분 동안 교반하였다. 이반응 혼합물을 다시 0 ℃로 냉각하고 디-t-부틸디카보닐레이트 (7.2 g, 33 mmol)을 가하고 약 30분후에 상온에서 2시간 동안 교반하였다. 반응 혼합물에 포화 중조 수용액 (20 ml)를 적가후에 에틸아세테이트 (50 ml x 2)로 추출하고, 유기 추출물을 탈수 및 감압 증류 농축한 후에, 잔사에 이소프로필 에테르를 처리하여 생성된 흰색 고체를 여과하여 표제화합물 (3.5 g)을 수득하였다.Thiourea (114 g, 15 mmol) was dissolved in anhydrous tetrahydrofuran (300 ml), cooled to 0 ° C., and sodium hydrogen (2.7 g, 60%, 68 mmol) was slowly added and stirred at room temperature for about 20 minutes. It was. The reaction mixture was cooled to 0 ° C. again and di-t-butyldicarbonylate (7.2 g, 33 mmol) was added and stirred for about 2 hours at room temperature after about 30 minutes. Saturated aqueous sodium bicarbonate solution (20 ml) was added dropwise to the reaction mixture, followed by extraction with ethyl acetate (50 ml x 2). The organic extract was dehydrated and concentrated under reduced pressure, and then the residue was treated with isopropyl ether to filter the resulting white solid. To give the title compound (3.5 g).

참조예 34 - 36 참조예 33과 동일한 제조방법으로 치환-티오우레아로부터 상응하는 각각의 N-t-부톡시카르보닐-N'-(치환)티오우레아의 표제화합물을 제조하였다.Reference Examples 34-36 The title compound of the corresponding respective N-t-butoxycarbonyl-N '-(substituted) thioureas was prepared from substituted-thioureas in the same preparation as in Reference Example 33.

참조예 34. N-(t-부특시카보닐)-N'-이소부틸-티오우레아REFERENCE EXAMPLE 34 N- (t-butoxycarbonyl) -N'-isobutyl-thiourea

참조예 35. N-(t-부톡시카보닐)-N'-(2-메톡시페닐)-티오우레아Reference Example 35 N- (t-butoxycarbonyl) -N '-(2-methoxyphenyl) -thiourea

참조예 36. N-(t-부톡시카보닐)-N'-(4-메톡시페닐)-티오우레아Reference Example 36 N- (t-butoxycarbonyl) -N '-(4-methoxyphenyl) -thiourea

참조예 37. N-메털-N'-(4-메톡시페닐)-티오우레아Reference Example 37 N-Metal-N '-(4-methoxyphenyl) -thiourea

4-메톡시페닐이소티오시아네이트 (1.8 g, 10.9 mmol)를 클로로포름 (50 ml)에 녹인 후에 메틸아민 수용액 (40 %, 20 mmol)을 천천히 가하고 상온에서 약 20분 동안 교반하였다. 이반응 혼합물을 상온에서 1시간 동안 교반한 다음에 유기층을 물로 세척하고, 건조 및 감압 증류 농축하여 생성된 흰색 고체를 여과하여 표제화합물 (2.0 g)을 수득하였다.4-methoxyphenylisothiocyanate (1.8 g, 10.9 mmol) was dissolved in chloroform (50 ml), and then aqueous methylamine solution (40%, 20 mmol) was slowly added and stirred at room temperature for about 20 minutes. The reaction mixture was stirred at room temperature for 1 hour, then the organic layer was washed with water, dried and concentrated under reduced pressure, and the resulting white solid was filtered to give the title compound (2.0 g).

참조예 38. N-메톡시-N'-페닐-티오우레아Reference Example 38 N-methoxy-N'-phenyl-thiourea

페닐이소티오시아네이트 (0.68 g, 5 mmol)와 메톡실아민 염산염 수용액 (1.5ml, 25 %, 5 mmol)을 에탄올 (50 ml)에 녹인 후에 에톡시나트륨 에탄올 용액 (2.68 M, 5 mmol)을 천천히 가하고 상온에서 4시간동안 교반하였다. 이 반응혼합물에 물(20 ml)를 넣고, 디클로로메탄 (50 ml X 3)으로 추출, 탈수 및 감압 증류 농축하여 생성된 흰색 고체를 여과하여 표제화합물 (0.9 g)을 수득하였다.Dissolve phenylisothiocyanate (0.68 g, 5 mmol) and aqueous methoxylamine hydrochloride solution (1.5 ml, 25%, 5 mmol) in ethanol (50 ml), and then add ethoxysodium ethanol solution (2.68 M, 5 mmol). Slowly added and stirred at room temperature for 4 hours. Water (20 ml) was added to the reaction mixture, followed by extraction with dichloromethane (50 ml X 3), dehydration, and distillation under reduced pressure. The resulting white solid was filtered to obtain the title compound (0.9 g).

참조예 39 - 41. 참조예 38과 동일한 제조방법으로 치환-이소티오시아네이트로부터 상응하는 각각의 N-메톡시-N'-(치환)-티오우레아의 표제화합물을 제조하였다.Reference Examples 39-41. The title compound of the respective corresponding N-methoxy-N '-(substituted) -thioureas was prepared from substituted-isothiocyanates by the same preparation method as Reference Example 38.

참조예 39. N-메톡시-N'-(2-플루오로페닐)-티오우레아Reference Example 39 N-methoxy-N '-(2-fluorophenyl) -thiourea

참조예 40. N-메톡시-N'-(3-플루오로페닐)-티오우레아Reference Example 40 N-methoxy-N '-(3-fluorophenyl) -thiourea

참조예 41. N-메톡시-N'-(4-메톡시페닐)-티오우레아Reference Example 41 N-methoxy-N '-(4-methoxyphenyl) -thiourea

참조예 42. N-메탄술포닐-N'-이소부틸-티오우레아Reference Example 42 N-methanesulfonyl-N'-isobutyl-thiourea

이소부틸이소티오시아네이트 (1.15 g, 10 mmol)과 메탄술폰아미드 (0.95 g, 10 mmol)을 에탄올 (50 ml)에 녹인 후에 에톡시나트륨 에탄올 용액 (2.68 M, 10 mmol)을 천천히 가하고 30분 동안 환류 교반을 계속한다. 이반응 혼합물을 식힌후에 디클로로메탄 (100 ml)으로 희석하고, 1N-염산 수용액으로 중성화하고 유기층을 분리, 건조 및 감압 증류 농축하여 생성된 흰색 고체를 여과하여 표제화합물 (0.5 g)을 수득하였다.Isobutylisothiocyanate (1.15 g, 10 mmol) and methanesulfonamide (0.95 g, 10 mmol) were dissolved in ethanol (50 ml), then ethoxysodium ethanol solution (2.68 M, 10 mmol) was added slowly and 30 minutes Continue reflux stirring for a while. The reaction mixture was cooled, diluted with dichloromethane (100 ml), neutralized with 1N aqueous hydrochloric acid solution, the organic layer was separated, dried and concentrated under reduced pressure, and the resulting white solid was filtered to give the title compound (0.5 g).

참조예 43. - 45. 참조예 42와 동일한 제조방법으로 치환-이소티오시아네이트와 치환 술폰아미드로부터 상응하는 각각의 N-치환술포닐-N'-치환-티오우레아의 표제화합물을 제조하였다.Reference Examples 43. 45. The title compound of the corresponding N-substituted sulfonyl-N'-substituted-thioureas was prepared from the substituted-isothiocyanate and substituted sulfonamides in the same manner as in Reference Example 42.

참조예 43. N-메탄술포닐-N'-(3-플루오로페닐)-티오우레아Reference Example 43 N-Methanesulfonyl-N '-(3-fluorophenyl) -thiourea

참조예 44. N-메탄술포닐-N'-(4-메톡시페닐)-티오우레아Reference Example 44 N-Methanesulfonyl-N '-(4-methoxyphenyl) -thiourea

참조예 45. N-메틸-N'-(4-메틸벤젠술포닐)-티오우레아Reference Example 45 N-Methyl-N '-(4-methylbenzenesulfonyl) -thiourea

실시예 1. N-[N'-시아노-N''-(4-메톡시페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 1. N- [N'-cyano-N ''-(4-methoxyphenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4 -Cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

<단계 1> N-(2,3-디클로로벤질)-2(S)-(t-부톡시카보닐)아미노-3(S)-메틸펜틸아민<Step 1> N- (2,3-dichlorobenzyl) -2 (S)-(t-butoxycarbonyl) amino-3 (S) -methylpentylamine

참조예 2에서 제조한 N-(t-부톡시카보닐)-L-이소루이신 알데히드 (4.52 g, 21.0 mmol)를 메탄올 (20 ml)에 녹이고 2,3-디클로로벤질아민 (3.70 ml, 21.0 mmol), 포타슘아세톡시드 (1.03 g, 10.5 mmol)와 3A 분자체 (molecular sieves, 5 g)를 가하였다. 이 혼합용액에 소디움시아노보로하이드라이드 용액 (25.2 ml, 1M테트라히드로푸란)을 적가한 후 실온에서 철야 교반하였다. 반응 혼합물의 침전물을 여과하고 여액을 감압 농축하였다. 이 농축물에 물 (30 ml)을 가하고 에틸아세테이트 (50ml)로 추출한 후, 무수 마그네슘술페이트로 탈수하고 용매를 감압 농축하였다. 잔사를 실리카겔 관 크로마토그라피 (에틸아세테이트 / n-헥산 = 1 / 3)로 정제하여 노란 유상의 표제화합물 (5.0 g, 63 %)을 제조하였다.N- (t-butoxycarbonyl) -L-isorucin aldehyde (4.52 g, 21.0 mmol) prepared in Reference Example 2 was dissolved in methanol (20 ml) and 2,3-dichlorobenzylamine (3.70 ml, 21.0 mmol), potassium acetoxide (1.03 g, 10.5 mmol) and 3A molecular sieves (molecular sieves, 5 g) were added. A sodium cyanoborohydride solution (25.2 ml, 1M tetrahydrofuran) was added dropwise to this mixed solution, followed by stirring overnight at room temperature. The precipitate of the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. To the concentrate was added water (30 ml), extracted with ethyl acetate (50 ml), dehydrated with anhydrous magnesium sulfate and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1/3) to give the title compound (5.0 g, 63%) as a yellow oil.

<단계 2> N-(2,3-디클로로벤질)-N-(9-플루오레닐메틸옥시카보닐)-2(S)-(t-부톡시카보닐)아미노-3(S)-메틸펜틸아민Step 2 N- (2,3-dichlorobenzyl) -N- (9-fluorenylmethyloxycarbonyl) -2 (S)-(t-butoxycarbonyl) amino-3 (S) -methyl Pentylamine

N-(2,3-디클로로벤질)-2(S)-(t-부톡시카보닐)아미노-3(S)-메틸펜틸아민 (2.79 g, 7.39 mmol)을 디클로로메탄 (15 ml)에 녹이고 트리에틸아민 (1.24 ml, 8.86mmol)을 적가하였다. 이 반응 혼합액을 0 ℃로 냉각하고 9-플루오레닐메틸클로로포르메이트 (2.29 g, 8,86 mmol)를 디클로로메탄 (5 ml)에 녹인 용액을 적가하였다. 반응용액을 상온에서 철야 교반한 후 디클로로메탄 (20 ml)을 가하고, 5% 염산 수용액, 포화 중조수용액과 포화 소금수용액으로 각각 세척하였다. 유기층을 무수 마그네슘술페이트로 탈수하고 용매를 감압 농축하였다. 잔사를 실리카겔 관 크로마토그라피 (에틸아세테이트 / n-헥산 = 1 / 5)로 정제하여 흰 거품상의 표제화합물(2.42 g, 55 %)을 제조하였다.N- (2,3-dichlorobenzyl) -2 (S)-(t-butoxycarbonyl) amino-3 (S) -methylpentylamine (2.79 g, 7.39 mmol) was dissolved in dichloromethane (15 ml) Triethylamine (1.24 ml, 8.86 mmol) was added dropwise. The reaction mixture was cooled to 0 ° C. and a solution of 9-fluorenylmethylchloroformate (2.29 g, 8,86 mmol) in dichloromethane (5 ml) was added dropwise. After stirring the reaction solution at room temperature overnight, dichloromethane (20 ml) was added, and the mixture was washed with 5% aqueous hydrochloric acid solution, saturated sodium bicarbonate solution and saturated aqueous salt solution, respectively. The organic layer was dehydrated with anhydrous magnesium sulfate and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1/5) to obtain the title compound (2.42 g, 55%) in the form of a white foam.

<단계 3> N-(2,3-디클로로벤질)-N-(9-플루오레닐메틸옥시카보닐)-2(S)-아미노-3(S)-메틸펜틸아민 트리플루오로아세트산염<Step 3> N- (2,3-dichlorobenzyl) -N- (9-fluorenylmethyloxycarbonyl) -2 (S) -amino-3 (S) -methylpentylamine trifluoroacetic acid salt

N-(2,3-디클로로벤질)-N-(9-플루오레닐메틸옥시카보닐)-2(S)-(t-부톡시카보닐)아미노-3(S)-메틸펜틸아민 (2.42 g, 4.03 mmol)을 디클로로메탄 (50 ml)에 녹이고 트리플루오로아세트산 (10 ml)을 적가하였다. 반응 용액을 2시간동안 교반 후 용액을 감압 농축하여 유상의 표제화합물을 제조하여 더 이상의 정제없이 다음반응에 이용하였다.N- (2,3-dichlorobenzyl) -N- (9-fluorenylmethyloxycarbonyl) -2 (S)-(t-butoxycarbonyl) amino-3 (S) -methylpentylamine (2.42 g, 4.03 mmol) was dissolved in dichloromethane (50 ml) and trifluoroacetic acid (10 ml) was added dropwise. After stirring the reaction solution for 2 hours, the solution was concentrated under reduced pressure to prepare an oily title compound, which was used in the next reaction without further purification.

<단계 4> N-(2,3-디클로로벤질)-N-(9-플루오레닐메틸옥시카보닐)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Step 4 N- (2,3-dichlorobenzyl) -N- (9-fluorenylmethyloxycarbonyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazole -5-yl] acetyl} amino-3 (S) -methylpentylamine

참조예 1. 에서 제조한 1-(4-시아노벤질)-1H-이미다졸-5-일아세트산 염산염(1.23 g, 4,43 mmol)을 무수 디클로로메탄/디메틸포름아미드 (25 ml/25 ml) 용액에 녹이고 1-히드록시벤조트리아졸 (817 mg, 6.05 mmol), 1-에틸-3-(3-디메틸아미노프로필)카보디이미드 (927 mg, 4,84 mmol)와 트리에틸아민 (1.85 ml, 13.3 mmol)을 적가하였다. 반응 혼합용액에 <단계 3>에서 제조한 N-(2,3-디클로로벤질)-N-(9-플루오레닐메틸옥시카보닐)-2(S)-아미노-3(S)-메틸펜틸아민 트리플루오로아세트산염(2.47 g, 4.03 mmol)을 적가하였다. 반응 혼합물을 실온에서 철야로 교반한 후 물을 가하고 유기층을 추출하였다. 유기 추출물을 무수 마그네슘술페이트로 건조하고 감압 농축한 후 실리카겔 관 크로마토그라피 (디클로로메탄 / 메탄올 = 9 / 1)로 정제하여 흰 거품상의 표제화합물 (2.56 g, 88 %)을 제조하였다.1- (4-cyanobenzyl) -1H-imidazol-5-ylacetic acid hydrochloride (1.23 g, 4,43 mmol) prepared in Reference Example 1 was dissolved in anhydrous dichloromethane / dimethylformamide (25 ml / 25 ml). ) Dissolved in solution, 1-hydroxybenzotriazole (817 mg, 6.05 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (927 mg, 4,84 mmol) and triethylamine (1.85 ml, 13.3 mmol) was added dropwise. N- (2,3-dichlorobenzyl) -N- (9-fluorenylmethyloxycarbonyl) -2 (S) -amino-3 (S) -methylpentyl prepared in <Step 3> in the reaction mixture solution Amine trifluoroacetic acid salt (2.47 g, 4.03 mmol) was added dropwise. The reaction mixture was stirred overnight at room temperature, then water was added and the organic layer was extracted. The organic extract was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol = 9/1) to give the title compound (2.56 g, 88%) as a white foam.

<단계 5> N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Step 5 N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S)- Methylpentylamine

N-(2,3-디클로로벤질)-N-(9-플루오레닐메틸옥시카보닐)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민 (2.56 g, 3.55 mmol)을 디메틸포름아미드 (8 ml) 에 녹이고 피페리딘 (4 ml)를 가하였다. 반응용액을 실온에서 4 시간동안 교반한 후 용매를 감압 농축하고 실리카겔 관 크로마토그라피 (디클로로메탄 / 메탄올 = 9 / 1)로 정제하여 흰 거품상의 표제화합물 (1.43 g, 81 %)을 제조하였다.N- (2,3-dichlorobenzyl) -N- (9-fluorenylmethyloxycarbonyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl ] Acetyl} amino-3 (S) -methylpentylamine (2.56 g, 3.55 mmol) was dissolved in dimethylformamide (8 ml) and piperidine (4 ml) was added. After stirring the reaction solution at room temperature for 4 hours, the solvent was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 9/1) to give the title compound (1.43 g, 81%) as a white foam.

<단계 6> N-[N'-시아노-N"-(4-메톡시페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민<Step 6> N- [N'-cyano-N "-(4-methoxyphenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4- Cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민 (3.0 g, 6.02 mmol)과 N-시아노-N'-(4-메톡시페닐)티오우레아 나트륨염 (4.14 g, 18.06 mmol)을 디메틸포름아미드 (100 ml) 에 녹인 후 1-에틸-3-(3-디메틸아미노프로필)카보디이미드 염산염 (3.46 g, 18.06 mmol)을 가하고 실온에서 12시간동안 교반하였다. 반응 혼합물에 에틸아세테이트 (200 ml)를 가하고 물 (200 ml)과 포화 소금 수용액 (200 ml)으로 각 2회씩 세척하였다. 유기층을 무수소듐술페이트로 탈수시킨 후 감압 농축하였다. 잔사를 실리카겔 관 크로마토그라피로 정제하고, 에틸아세테이트와 디에틸에테르를 사용하여 고체화하고 진공펌프에서 건조시켜 흰 고체상의 표제 화합물 (1.6 g, 40 %)을 제조하였다.N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine ( 3.0 g, 6.02 mmol) and N-cyano-N '-(4-methoxyphenyl) thiourea sodium salt (4.14 g, 18.06 mmol) were dissolved in dimethylformamide (100 ml) and then 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (3.46 g, 18.06 mmol) was added and stirred at room temperature for 12 hours. Ethyl acetate (200 ml) was added to the reaction mixture, and the mixture was washed twice with water (200 ml) and saturated aqueous salt solution (200 ml). The organic layer was dehydrated with anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, solidified using ethyl acetate and diethyl ether and dried in a vacuum pump to give the title compound (1.6 g, 40%) as a white solid.

또한, 상기에서 제조한 표제화합물(220mg)을 3N-염산 에틸아세테이트 용액(5ml)에 녹이고 30분간 교반한 후, 이 용액에 이소프로필에테르(30ml)을 가하여 고체를 생성시킨 다음, 이를 여과하여 표제화합물의 염산염(230mg)을 제조하였다.In addition, the title compound (220 mg) prepared above was dissolved in 3N-ethyl acetate hydrochloride solution (5 ml), stirred for 30 minutes, and isopropyl ether (30 ml) was added to the solution to form a solid, which was then filtered and titled. Hydrochloride (230 mg) of the compound was prepared.

또한, 상기에서 제조한 표제화합물(200mg)을 에틸아세테이트(5ml)에 녹이고 메탄술포닉산(100mg)을 상온에서 가하고 30분간 교반한 후, 이 용액에 이소프로필에테르(30ml)을 가하여 고체를 생성시킨 다음, 이를 여과하여 표제화합물의 메탄술포닉산염(170mg)을 제조하였다.In addition, the title compound (200 mg) prepared above was dissolved in ethyl acetate (5 ml), methane sulfonic acid (100 mg) was added at room temperature, stirred for 30 minutes, and then isopropyl ether (30 ml) was added to the solution to form a solid. Next, it was filtered to prepare methanesulphonic acid salt (170 mg) of the title compound.

실시예 2 - 31. N-(2,3-디클로로벤질)-2(S)-{[(1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민을 출발물질로하여 각각의 N-시아노-N'-(치환)-티오우레아 나트륨염과 실시예 1 의 <단계 6> 의 공정과 동일한 제조방법으로 상응하는 구아니딘 유도체를 제조하였다.Examples 2-31. N- (2,3-dichlorobenzyl) -2 (S)-{[(1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 ( S) -Methylpentylamine was used as a starting material, and each N-cyano-N '-(substituted) -thiourea sodium salt and the corresponding guanidine derivative were prepared by the same preparation method as in <Step 6> of Example 1. Prepared.

실시예 2. N-[N'-시아노-N"-(피리딘-3-일)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 2. N- [N'-cyano-N "-(pyridin-3-yl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4- Cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

실시예 3. N-[N'-시아노-N"-(2-메틸티오피리딘-5-일)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 3. N- [N'-cyano-N "-(2-methylthiopyridin-5-yl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1 -(4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

실시예 4. N-[N'-시아노-N"-(4-메틸페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 4. N- [N'-cyano-N "-(4-methylphenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyano Benzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

실시예 5. N-[N'-시아노-N"-(3-클로로페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}]아미노-3(S)-메틸펜틸아민Example 5. N- [N'-cyano-N "-(3-chlorophenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cya Nobenzyl) -1H-imidazol-5-yl] acetyl}] amino-3 (S) -methylpentylamine

실시예 6. N-[N'-시아노-N"-(4-메틸티오페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 6. N- [N'-cyano-N "-(4-methylthiophenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4- Cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

실시예 7. N-[N'-시아노-N"-(4-디메틸아미노페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 7.N- [N'-cyano-N "-(4-dimethylaminophenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4- Cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

실시예 8. N-[N'-시아노-N"-(2-메톡시피리딘-5-일)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 8. N- [N'-cyano-N "-(2-methoxypyridin-5-yl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1 -(4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

실시예 9. N-[N'-시아노-N"-(페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 9.N- [N'-cyano-N "-(phenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

실시예 10. N-[N'-시아노-N"-(벤질)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 10. N- [N'-cyano-N "-(benzyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

실시예 11. N-[N'-시아노-N"-(페닐에틸)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 11. N- [N'-cyano-N "-(phenylethyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl ) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

실시예 12. N-[N'-시아노-N"-(4-클로로페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 12.N- [N'-cyano-N "-(4-chlorophenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cya Nobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

실시예 13, N-[N'-시아노-N"-(4-플루오로페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 13, N- [N'-cyano-N "-(4-fluorophenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4- Cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

실시예 14. N-[N'-시아노-N"-(3-플루오로페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 14. N- [N'-cyano-N "-(3-fluorophenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4- Cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

실시예 15. N-[N'-시아노-N"-(메틸)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 15 N- [N'-cyano-N "-(methyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

실시예 16. N-[N'-시아노-N"-(에틸)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 16. N- [N'-cyano-N "-(ethyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

실시예 17 N-[N'-시아노-N"-(n-프로필)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 17 N- [N'-cyano-N "-(n-propyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl ) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

실시예 18. N-[N'-시아노-N"-(n-부틸)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 18.N- [N'-cyano-N "-(n-butyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyano Benzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

실시예 19. N-[N'-시아노-N"-(n-펜틸)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 19. N- [N'-cyano-N "-(n-pentyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyano Benzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

실시예 20. N-[N'-시아노-N"-(t-부틸)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 20 N- [N'-cyano-N "-(t-butyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyano Benzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

실시예 21. N-[N'-시아노-N"-(이소부틸)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 21.N- [N'-cyano-N "-(isobutyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl ) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

실시예 22. N-[N'-시아노-N"-(2-프로페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 22. N- [N'-cyano-N "-(2-propenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cya Nobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

실시예 23. N-[N'-시아노-N"-(시클로프로필)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 23. N- [N'-cyano-N "-(cyclopropyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl ) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

실시예 24. N-[N'-시아노-N"-(시클로펜틸)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 24 N- [N'-cyano-N "-(cyclopentyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl ) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

실시예 25, N-[N'-시아노-N"-(4-니트로페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 25, N- [N'-cyano-N "-(4-nitrophenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cya Nobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

실시예 26, N-[N'-시아노-N"-(시클로헥실)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 26, N- [N'-cyano-N "-(cyclohexyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl ) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

실시예 27. N-[N'-시아노-N"-(2-플루오로페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 27. N- [N'-cyano-N "-(2-fluorophenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4- Cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

실시예 28, N-[N'-시아노-N"-(3-트리플루오로메틸페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 28, N- [N'-cyano-N "-(3-trifluoromethylphenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4 -Cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

실시예 29. N-[N'-시아노-N"-(3-메틸페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 29. N- [N'-cyano-N "-(3-methylphenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyano Benzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

실시예 30. N-[N'-시아노-N"-(2-메톡시페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 30. N- [N'-cyano-N "-(2-methoxyphenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4- Cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

실시예 31. N-[N'-시아노-N"-(피리딘-4-일)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 31.N- [N'-cyano-N "-(pyridin-4-yl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4- Cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

실시예 32. N-[N'-시아노-N"-(피리딘-1-N-옥시드-3-일)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 32. N- [N'-cyano-N "-(pyridin-1-N-oxide-3-yl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)- {[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

실시예 2에서 제조한 N-[N'-시아노-N"-(피리딘-3-일)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민(70 mg, 0.109 mmol)을 무수 디클로로메탄 (10 ml)에 녹인 뒤, m-클로로퍼벤조익산 (60 mg, 0.327 mmol)를 0 ℃에서 가하였다. 반응 용액을 상온에서 2시간동안 교반한 뒤, 반응 용액에 디클로로메탄 (100 ml)을 가하여 희석하고 포화 중조와 소금물로 세척하였다. 유기용액을 무수 소디윰술페이트로 탈수하고 감압 농축하여 얻어진 유상의 화합물을 실리카겔 관 크로마토그라피를 통하여 표제의 화합물을 노란 고체 (40 mg)로 수득하였다.N- [N'-cyano-N "-(pyridin-3-yl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- ( 4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine (70 mg, 0.109 mmol) was dissolved in anhydrous dichloromethane (10 ml) and then m-chloro Roperbenzoic acid (60 mg, 0.327 mmol) was added at 0 ° C. The reaction solution was stirred at room temperature for 2 hours, after which dichloromethane (100 ml) was added and diluted with saturated sodium bicarbonate and brine. The organic solution was dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound as a yellow solid (40 mg) through silica gel column chromatography.

실시예 33. N-[N'-시아노-N"-(4-아미노페닐)아미디노]-N-(2,3-디를로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 33. N- [N'-cyano-N "-(4-aminophenyl) amidino] -N- (2,3-dilobenzyl) -2 (S)-{[1- ( 4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

실시예 25에서 제조한 N-[N'-시아노-N"-(4-니트로페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민 (70mg)을 포화 중조 수용액과 아세톤 (1 ml/2 ml) 용액에 교반시키며 소디윰히드로설파이트 (209 mg)을 가하였다. 반응 혼합액을 40 ℃로 가온하여 1시간 동안 교반하였다. 그런 뒤, 반응액을 상온으로 냉각하고 디클로로메탄(100 ml)으로 희석하였다. 유기층을 증류수로 세척하고 무수 소디윰술페이트로 건조하고 감압농축하였다. 실리카겔 관 크로마토그라피를 통하여 표제의 화합물을 고체 (30 mg)로 수득하였다.N- [N'-cyano-N "-(4-nitrophenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4 prepared in Example 25 -Cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine (70 mg) was stirred in saturated aqueous sodium bicarbonate solution and acetone (1 ml / 2 ml) solution. Sulphite (209 mg) was added The reaction mixture was warmed to 40 ° C. and stirred for 1 h The reaction was then cooled to room temperature and diluted with dichloromethane (100 ml) The organic layer was washed with distilled water and It was dried over anhydrous sodium sulfate and concentrated under reduced pressure through silica gel column chromatography to obtain the title compound as a solid (30 mg).

실시예 34. N-[N'-시아노-N"-(4-메톡시페닐)아미디노]-N-(2-클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 34. N- [N'-cyano-N "-(4-methoxyphenyl) amidino] -N- (2-chlorobenzyl) -2 (S)-{[1- (4-cyano Benzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

<단계 1> N-(2-클로로벤질)-2(S)-(t-부톡시카보닐)아미노-3(S)-메틸펜틸아민Step 1 N- (2-chlorobenzyl) -2 (S)-(t-butoxycarbonyl) amino-3 (S) -methylpentylamine

참조예 2. 에서 제조한 N-t-부톡시카보닐-L-이소루이신 알데히드 (1.5 g, 6.97 mmol)와 2-클로로벤질아민 (0.99 g, 6.97 mmol)을 출발물질로 사용하여 실시예 1. 의 <단계 1>과 동일한 방법으로 유상의 표제화합물 (0.81 g)을 제조하였다.Example 1 using Nt-butoxycarbonyl-L-isorucin aldehyde (1.5 g, 6.97 mmol) and 2-chlorobenzylamine (0.99 g, 6.97 mmol) prepared in Reference Example 2. In the same manner as in <Step 1>, the title compound (0.81 g) in oil phase was prepared.

<단계 2> N-(2-클로로벤질)-N-(9-플루오레닐메틸옥시카보닐)-2(S)-(t-부톡시카보닐)아미노-3(S)-메틸펜틸아민Step 2 N- (2-chlorobenzyl) -N- (9-fluorenylmethyloxycarbonyl) -2 (S)-(t-butoxycarbonyl) amino-3 (S) -methylpentylamine

N-(2-클로로벤질)-2(S)-(t-부톡시카보닐)아미노-3(S)-메틸펜틸아민 (0.5 g, 1.48 mmol)과 9-플루오레닐메틸클로로포르메이트 (0.46 g, 1.78 mmol)를 출발물질로 사용하여 실시예 1. 의 <단계 2>와 동일한 방법으로 흰 거품상의 표제화합물 (0.45 g)을 제조하였다.N- (2-chlorobenzyl) -2 (S)-(t-butoxycarbonyl) amino-3 (S) -methylpentylamine (0.5 g, 1.48 mmol) and 9-fluorenylmethylchloroformate ( 0.46 g, 1.78 mmol) was used as a starting material, and the title compound (0.45 g) was prepared in the same manner as in <Step 2> of Example 1.

<단계 3> N-(2-클로로벤질)-N-(9-플루오레닐메틸옥시카보닐)-2(S)-아미노-3(S)-메틸펜틸아민 트리플루오로아세트산염Step 3 N- (2-chlorobenzyl) -N- (9-fluorenylmethyloxycarbonyl) -2 (S) -amino-3 (S) -methylpentylamine trifluoroacetic acid salt

N-(2-클로로벤질)-N-(9-플루오레닐메틸옥시카보닐)-2(S)-(t-부톡시카보닐)아미노-3(S)-메틸펜틸아민 (0.45 g)과 트리플루오로아세트산 (10 ml)을 사용하여 실시예 1. 의 <단계 3>과 동일한 방법으로 유상의 표제화합물을 제조하여 더 이상의 정제없이 다음반응에 이용하였다.N- (2-chlorobenzyl) -N- (9-fluorenylmethyloxycarbonyl) -2 (S)-(t-butoxycarbonyl) amino-3 (S) -methylpentylamine (0.45 g) Using trifluoroacetic acid (10 ml) in the same manner as in <Step 3> of Example 1. An oily title compound was prepared and used in the next reaction without further purification.

<단계 4> N-(2-클로로벤질)-N-(9-플루오레닐메틸옥시카보닐)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Step 4 N- (2-chlorobenzyl) -N- (9-fluorenylmethyloxycarbonyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazole-5 -Yl] acetyl} amino-3 (S) -methylpentylamine

참조예 2. 에서 제조한 1-(4-시아노벤질)-1H-이미다졸-5-일아세트산 염산염(0.33 g)과 N-(2-클로로벤질)-N-(9-플루오레닐메틸옥시카보닐)-2(S)-아미노-3(S)-메틸펜틸아민 트리플루오로아세트산염 (0.35 g)을 출발물질로 사용하여 실시예 1 의 <단계 4>와 동일한 방법으로 표제화합물 (0.4 g)을 제조하였다.1- (4-cyanobenzyl) -1H-imidazol-5-ylacetic acid hydrochloride (0.33 g) and N- (2-chlorobenzyl) -N- (9-fluorenylmethyl prepared in Reference Example 2. Using the oxycarbonyl) -2 (S) -amino-3 (S) -methylpentylamine trifluoroacetic acid salt (0.35 g) as starting material, the title compound ( 0.4 g) was prepared.

<단계 5> N-(2-클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Step 5 N- (2-chlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1 H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentyl Amine

N-(2-클로로벤질)-N-(9-플루오레닐메틸옥시카보닐)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민 (0.4 g)을 사용하여 실시예 1. 의 <단계 5>와 동일한 방법으로 노란 거품상의 표제화합물 (0.3 g)을 제조하였다.N- (2-chlorobenzyl) -N- (9-fluorenylmethyloxycarbonyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl } A yellow foamy title compound (0.3 g) was prepared in the same manner as in <Step 5> of Example 1 using amino-3 (S) -methylpentylamine (0.4 g).

<단계 6> N-[N'-시아노-N"-(4-메톡시페닐)아미디노]-N-(2-클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민<Step 6> N- [N'-cyano-N "-(4-methoxyphenyl) amidino] -N- (2-chlorobenzyl) -2 (S)-{[1- (4-cyano Benzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

N-(2-클로로벤질)-2(S)-[(1-(4-시아노벤질)-1H-이미다졸-5-일)아세틸]아미노-3(S)-메틸펜틸아민 (27 mg, 0.058 mmol)과 N-시아노-N-(4-메톡시페닐)티오우레아 나트륨염(16 mg, 0.070 mmol) 그리고 1-에틸-3-(3-디메틸아미노프로필)카보디이미드 염산염 (14 mg, 0.070 mmol)를 출발물질로 사용하여 실시예 1. 의 <단계 6>과 동일한 방법으로 표제의 화합물 (18 mg, 49 %)을 수득하였다.N- (2-chlorobenzyl) -2 (S)-[(1- (4-cyanobenzyl) -1H-imidazol-5-yl) acetyl] amino-3 (S) -methylpentylamine (27 mg , 0.058 mmol) and N-cyano-N- (4-methoxyphenyl) thiourea sodium salt (16 mg, 0.070 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (14 mg, 0.070 mmol) was used as starting material to obtain the title compound (18 mg, 49%) in the same manner as in <Step 6> of Example 1.

실시예 35. N-[N'-시아노-N"-(4-메톡시페닐)아미디노]-N-(2,3-디플루오로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸벤질아민Example 35. N- [N'-cyano-N "-(4-methoxyphenyl) amidino] -N- (2,3-difluorobenzyl) -2 (S)-{[1- ( 4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylbenzylamine

<단계 1> N-(2,3-디플루오로벤질)-2(S)-(t-부톡시카보닐)아미노-3(S)-메틸펜틸아민<Step 1> N- (2,3-difluorobenzyl) -2 (S)-(t-butoxycarbonyl) amino-3 (S) -methylpentylamine

참조예 2. 에서 제조한 N-t-부톡시카보닐-L-이소루이신 알데히드 (4.52 g, 21.0 mmol)와 2,3-디플루오로벤질아민 (3.5 g)을 출발물질로 사용하여 실시예 1. 의 <단계 1>과 동일한 방법으로 유상의 표제화합물 (4.8 g)을 제조하였다.Example 1 using Nt-butoxycarbonyl-L-isorucin aldehyde (4.52 g, 21.0 mmol) and 2,3-difluorobenzylamine (3.5 g) prepared in Reference Example 2 as starting materials In the same manner as in <Step 1> of the title compound (4.8 g) was prepared.

<단계 2> N-(2,3-디플루오로벤질)-N-(9-플루오레닐메틸옥시카보닐)-2(S)-(t-부톡시카보닐)아미노-3(S)-메틸펜틸아민Step 2 N- (2,3-difluorobenzyl) -N- (9-fluorenylmethyloxycarbonyl) -2 (S)-(t-butoxycarbonyl) amino-3 (S) Methylpentylamine

N-(2,3-디플루오로벤질)-2(S)-(t-부톡시카보닐)아미노-3(S)-메틸펜틸아민(2.6 g 7.4 mmol)과 9-플루오레닐메틸클로로포르메이트 (2.3 g, 8.9 mmol)를 출발물질로 사용하여 실시예 1. 의 <단계 2>와 동일한 방법으로 흰 거품상의 표제화합물 (2.3 g)을 제조하였다.N- (2,3-difluorobenzyl) -2 (S)-(t-butoxycarbonyl) amino-3 (S) -methylpentylamine (2.6 g 7.4 mmol) and 9-fluorenylmethylchloro Using formate (2.3 g, 8.9 mmol) as a starting material, the title compound (2.3 g) was prepared in the same manner as in <Step 2> of Example 1.

<단계 3> N-(2,3-디플루오로벤질)-N-(9-플루오레닐메틸옥시카보닐)-2(S)-아미노-3(S)-메틸펜틸아민 트리플루오로아세트산염Step 3 N- (2,3-difluorobenzyl) -N- (9-fluorenylmethyloxycarbonyl) -2 (S) -amino-3 (S) -methylpentylamine trifluoroacetic acid salt

N-(2,3-디플루오로벤질)-N-(9-플루오레닐메틸옥시카보닐)-2(S)-(t-부톡시카보닐)아미노-3(S)-메틸필틸아민 (2.0 g)과 트리플루오로 아세트산 (10 ml)을 사용하여 실시예 1. 의 <단계 3>과 동일한 방법으로 유상의 표제화합물을 제조하여 더 이상의 정제없이 다음반응에 이용하였다.N- (2,3-difluorobenzyl) -N- (9-fluorenylmethyloxycarbonyl) -2 (S)-(t-butoxycarbonyl) amino-3 (S) -methylfiltylamine (2.0 g) and trifluoro acetic acid (10 ml) were used to prepare the title compound as an oil in the same manner as in <Step 3> of Example 1. It was used for the next reaction without further purification.

<단계 4> N-(2,3-디플루오로벤질)-N-(9-플루오레닐메틸옥시카보닐)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메털펜틸아민<Step 4> N- (2,3-difluorobenzyl) -N- (9-fluorenylmethyloxycarbonyl) -2 (S)-{[1- (4-cyanobenzyl) -1H- Imidazol-5-yl] acetyl} amino-3 (S) -metalpentylamine

참조예 1. 에서 제조한 1-(4-시아노벤질)-1H-이미다졸-5-일아세트산 염산염(1.32 g)과 N-(2,3-디플루오로벤질)-N-(9-플루오레닐메틸옥시카보닐)-2(S)-아미노3(S)-메틸펜틸아민 트리플루오로아세트산염 (1.5 g)을 출발물질로 사용하여 실시예 1. 의 <단계 4>와 동일한 방법으로 표제화합물 (1.45 g)을 제조하였다.Reference Example 1 1- (4-cyanobenzyl) -1H-imidazol-5-ylacetic acid hydrochloride (1.32 g) and N- (2,3-difluorobenzyl) -N- (9- Fluorenylmethyloxycarbonyl) -2 (S) -amino3 (S) -methylpentylamine trifluoroacetic acid salt (1.5 g) was used as the starting material, and the same method as in <Step 4> of Example 1. To give the title compound (1.45 g).

<단계 5> N-(2,3-디플루오로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Step 5 N- (2,3-difluorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1 H-imidazol-5-yl] acetyl} amino-3 (S ) -Methylpentylamine

N-(2,3-디플루오로벤질)-N-(9-플루오레닐메틸옥시카보닐)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민 (1.3 g)을 사용하여 실시예 1. 의 <단계 5>와 동일한 방법으로 노란 거품상의 표제화합물 (1.0 g)을 제조하였다.N- (2,3-difluorobenzyl) -N- (9-fluorenylmethyloxycarbonyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazole-5 -Il] acetyl} amino-3 (S) -methylpentylamine (1.3 g) was used to prepare the title compound (1.0 g) as a yellow foam in the same manner as in <Step 5> of Example 1.

<단계 6> N-[N'-시아노-N"-(4-메톡시페닐)아미디노]-N-(2,3-디플루오로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸벤질아민<Step 6> N- [N'-cyano-N "-(4-methoxyphenyl) amidino] -N- (2,3-difluorobenzyl) -2 (S)-{[1- ( 4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylbenzylamine

N-(2,3-디플루오로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸]아미노-3(S)-메틸펜틸아민(29 mg, 0.062 mmol)과 N-시아노-N'-(4-메톡시페닐)티오우레아 나트륨염(17 mg, 0.075 mmol) 그리고 1-에틸-3-(3-디메틸아미노프로필)카보디이미드 염산염(15 mg, 0.075 mmol)을 출발물질로 사용하여 실시예 1. 의 <단계 6>과 동일한 방법으로 표제의 화합물 (16 mg, 40 %)을 수득하였다.N- (2,3-difluorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl] amino-3 (S) -methylpentyl Amine (29 mg, 0.062 mmol) with N-cyano-N '-(4-methoxyphenyl) thiourea sodium salt (17 mg, 0.075 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) Using the bodyimide hydrochloride (15 mg, 0.075 mmol) as starting material, the title compound (16 mg, 40%) was obtained by the same method as <Step 6> of Example 1.

실시예 36. N-[N'-시아노-N"-(4-메톡시페닐)아미디노]-N-(3-클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 36. N- [N'-cyano-N "-(4-methoxyphenyl) amidino] -N- (3-chlorobenzyl) -2 (S)-{[1- (4-cyano Benzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

<단계 1> N-(3-클로로벤질)-2(S)-(t-부톡시카보닐)아미노-3(S)-메틸펜틸아민<Step 1> N- (3-chlorobenzyl) -2 (S)-(t-butoxycarbonyl) amino-3 (S) -methylpentylamine

참조예 2. 에서 제조한 N-t-부톡시카보닐-L-이소루이신 알데히드 (0.9 g)와 3-클로로벤질아민 (0.7 g)을 출발물질로 사용하여 실시예 1. 의 <단계 1>과 동일한 방법으로 유상의 표제화합물 (1.0 g)을 제조하였다.<Step 1> of Example 1 using Nt-butoxycarbonyl-L-isorucin aldehyde (0.9 g) and 3-chlorobenzylamine (0.7 g) prepared in Reference Example 2 as starting materials In the same manner to give the oily title compound (1.0 g).

<단계 2> N-(3-클로로벤질)-N-(9-플루오레닐메틸옥시카보닐)-2(S)-(f-부톡시카보닐)아미노-3(S)-메틸펜틸아민Step 2 N- (3-chlorobenzyl) -N- (9-fluorenylmethyloxycarbonyl) -2 (S)-(f-butoxycarbonyl) amino-3 (S) -methylpentylamine

N-(3-클로로벤질)-2(S)-(t-부톡시카보닐)아미노-3(S)-메틸펜틸아민 (1.0 g)과 9-플루오레닐메틸클로로포르메이트 (0.9 g)를 출발물질로 사용하여 실시예 1. 의 <단계 2>와 동일한 방법으로 흰 거품상의 표제화합물 (1.1 g)을 제조하였다.N- (3-chlorobenzyl) -2 (S)-(t-butoxycarbonyl) amino-3 (S) -methylpentylamine (1.0 g) and 9-fluorenylmethylchloroformate (0.9 g) Using the product as a starting material, the title compound (1.1 g) was prepared in the same manner as in <Step 2> of Example 1.

<단계 3> N-(3-클로로벤질)-N-(9-플루오레닐메틸옥시카보닐)-2(S)-아미노-3(S)-메틸펜틸아민 트리플루오로아세트산염<Step 3> N- (3-chlorobenzyl) -N- (9-fluorenylmethyloxycarbonyl) -2 (S) -amino-3 (S) -methylpentylamine trifluoroacetic acid salt

N-(3-클로로벤질)-N-(9-플루오레닐메틸옥시카보닐)-2(S)-(t-부톡시카보닐)아미노-3(S)-메틸펜틸아민 (1.1 g)과 트리플루오로아세트산 (5 ml)을 사용하여 실시예 1. 의 <단계 3>과 동일한 방법으로 유상의 표제화합물 (0.8 g)을 제조하여 더이상의 정제없이 다음반응에 이용하였다.N- (3-chlorobenzyl) -N- (9-fluorenylmethyloxycarbonyl) -2 (S)-(t-butoxycarbonyl) amino-3 (S) -methylpentylamine (1.1 g) Using trifluoroacetic acid (5 ml) in the same manner as in <Step 3> of Example 1. An oily title compound (0.8 g) was prepared and used in the next reaction without further purification.

<단계 4> N-(3-클로로벤질)-N-(9-플루오레닐메틸옥시카보닐)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Step 4 N- (3-chlorobenzyl) -N- (9-fluorenylmethyloxycarbonyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazole-5 -Yl] acetyl} amino-3 (S) -methylpentylamine

참조예 1. 에서 제조한 1-(4-시아노벤질)-1H-이미다졸-5-일아세트산 염산염(0.42 g)과 N-(3-클로로벤질)-N-(9-플루오레닐메틸옥시카보닐)-2(S)-아미노-3(S)-메틸펜틸아민 트리플루오로아세트산염 (0.52 g)을 출발물질로 사용하여 실시예 1. 의 <단계 4>와 동일한 방법으로 표제화합물 (0.75 g)을 제조하였다.Reference Example 1 1- (4-cyanobenzyl) -1H-imidazol-5-ylacetic acid hydrochloride (0.42 g) and N- (3-chlorobenzyl) -N- (9-fluorenylmethyl Title compound in the same manner as in <Step 4> of Example 1, using oxycarbonyl) -2 (S) -amino-3 (S) -methylpentylamine trifluoroacetate (0.52 g) as a starting material. (0.75 g) was prepared.

<단계 5> N-(3-클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Step 5 N- (3-chlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1 H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentyl Amine

N-(3-클로로벤질)-N-(9-플루오레닐메틸옥시카보닐)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민 (0.75 g)을 사용하여 실시예 1. 의 <단계 5>와 동일한 방법으로 노란 거품상의 표제화합물 (0.55 g)을 제조하였다.N- (3-chlorobenzyl) -N- (9-fluorenylmethyloxycarbonyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl } A yellow foamy title compound (0.55 g) was prepared in the same manner as in <Step 5> of Example 1 using amino-3 (S) -methylpentylamine (0.75 g).

<단계 6> N-[N'-시아노-N"-(4-메톡시페닐)아미디노]-N-(3-클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민<Step 6> N- [N'-cyano-N "-(4-methoxyphenyl) amidino] -N- (3-chlorobenzyl) -2 (S)-{[1- (4-cyano Benzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

N-(3-클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민 (95 mg, 0.205 mmol)과 N-시아노-N'-(4-메톡시페닐) 티오우레아 나트륨임 (56 mg, 0.246 mmol) 그리고 1-에틸-3-(3-디메틸아미노프로필)카보디이미드 염산염(47 mg, 0.266 mmol)를 출발물질로 사용하여 실시예 1. 의 <단계 6>과 동일한 방법으로 표제화합물 (83 mg, 64 %)을 제조하였다.N- (3-Chlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine (95 mg , 0.205 mmol) and N-cyano-N '-(4-methoxyphenyl) thiourea sodium (56 mg, 0.246 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride ( 47 mg, 0.266 mmol) was used as the starting material to prepare the title compound (83 mg, 64%) in the same manner as in <Step 6> of Example 1.

실시예 37. N-[N'-시아노-N"-(2-메톡시-피리딘-5-일)아미디노]-N-(3-클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 37. N- [N'-cyano-N "-(2-methoxy-pyridin-5-yl) amidino] -N- (3-chlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

실시예 36. 의 <단계 5>에서 제조한 N-(3-클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민 (110 mg, 0.237 mmol)과 N-시아노-N-(2-메톡시피리딘-5-일)티오우레아 나트륨염 (66 mg, 0.284 mmol)그리고 1-에틸-3-(3-디메틸아미노프로필)카보디이미드 염산염(55 mg, 0.284 mmol)을 출발물질로 사용하여 실시예 1. 의 <단계 6>과 동일한 방법으로 표제화합물 (40 mg, 27%)을 제조하였다.Example 36. N- (3-chlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino prepared in <Step 5> of -3 (S) -methylpentylamine (110 mg, 0.237 mmol) and N-cyano-N- (2-methoxypyridin-5-yl) thiourea sodium salt (66 mg, 0.284 mmol) and 1-ethyl Using the 3- (3-dimethylaminopropyl) carbodiimide hydrochloride (55 mg, 0.284 mmol) as starting material, the title compound (40 mg, 27%) was prepared in the same manner as in <Step 6> of Example 1. Prepared.

실시예 38, N-[N'-시아노-N"-(4-메톡시페닐)아미디노]-N-(2-트리플루오로메틸벤질)-2(S)-[[1-(4-시아노벤질)-1H-이미다졸-5-일)아세틸]아미노-3(S)-메틸펜틸 아민Example 38, N- [N'-cyano-N "-(4-methoxyphenyl) amidino] -N- (2-trifluoromethylbenzyl) -2 (S)-[[1- (4 -Cyanobenzyl) -1H-imidazol-5-yl) acetyl] amino-3 (S) -methylpentyl amine

<단계 1> N-(2-트리플루오로메틸벤질)-2(S)-(t-부톡시카보닐)아미노-3(S)-메틸펜틸아민<Step 1> N- (2-trifluoromethylbenzyl) -2 (S)-(t-butoxycarbonyl) amino-3 (S) -methylpentylamine

참조예 2. 에서 제조한 N-t-부톡시카보닐-L-이소루이신 알데히드 (4.52 g)와 2-트리플루오로메틸벤질아민 (3.9 g)을 출발물질로 사용하여 실시예 1. 의 <단계 1>과 동일한 방법으로 유상의 표제화합물 (4,9 g)을 제조하였다.<Step of Example 1 using Nt-butoxycarbonyl-L-isoleucine aldehyde (4.52 g) and 2-trifluoromethylbenzylamine (3.9 g) prepared in Reference Example 2 as starting materials. In the same manner as 1>, the title compound (4,9 g) in oil phase was prepared.

<단계 2> N-(2-트리플루오로메틸벤질)-N-(9-플루오레닐메틸옥시카보닐)-2(S)-(t-부톡시카보닐)아미노-3(S)-메틸펜틸아민<Step 2> N- (2-trifluoromethylbenzyl) -N- (9-fluorenylmethyloxycarbonyl) -2 (S)-(t-butoxycarbonyl) amino-3 (S)- Methylpentylamine

N-(2-트리플루오로메틸벤질)-2(S)-(t-부톡시카보닐)아미노-3(S)-메틸펜틸아민 (0.80 g, 2.14 mmol)과 9-플루오레닐메틸클로로포르메이트 (0.66 g, 2.56 mmol)를 출발물질로 사용하여 실시예 1. 의 <단계 2>와 동일한 방법으로 흰 거품상의 표제화합물 (1.2 g)을 제조하였다.N- (2-trifluoromethylbenzyl) -2 (S)-(t-butoxycarbonyl) amino-3 (S) -methylpentylamine (0.80 g, 2.14 mmol) and 9-fluorenylmethylchloro Using formate (0.66 g, 2.56 mmol) as a starting material, the title compound (1.2 g) was prepared in the same manner as in <Step 2> of Example 1.

<단계 3> N-(2-트리플루오로메틸벤질)-N-(9-플루오레닐메틸옥시카보닐)-2(S)-아미노-3(S)-메틸펜틸아민 트리플루오로아세트산염<Step 3> N- (2-trifluoromethylbenzyl) -N- (9-fluorenylmethyloxycarbonyl) -2 (S) -amino-3 (S) -methylpentylamine trifluoroacetic acid salt

N-(2-트리플루오로메틸벤질)-N-(9-플루오레닐메틸옥시카보닐)-2(S)-(t-부톡시카보닐)아미노-3(S)-메틸꿴틸아민 (1.0 g)과 트리플루오로 아세트산 (5 ml)을 사용하여 실시예 1. 의 <단계 3>과 동일한 방법으로 유상의 표제화합물을 제조하여 더 이상의 정제없이 다음반응에 이용하였다.N- (2-Trifluoromethylbenzyl) -N- (9-fluorenylmethyloxycarbonyl) -2 (S)-(t-butoxycarbonyl) amino-3 (S) -methylpentylamine ( 1.0 g) and trifluoro acetic acid (5 ml) were used to prepare the title compound as an oil in the same manner as in <Step 3> of Example 1. It was used for the next reaction without further purification.

<단계 4> N-(2-트리플루오로메틸벤질)-N-(9-플루오레닐메틸옥시카보닐)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민<Step 4> N- (2-trifluoromethylbenzyl) -N- (9-fluorenylmethyloxycarbonyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-already Dazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

참조예 1. 에서 제조한 1-(4-시아노벤질)-1H-이미다졸-5-일아세트산 염산염(0.61 g, 2.18 mmol)과 N-(2-트리플루오로메틸벤질)-N-(9-플루오레닐메틸옥시카보닐)-2(S)-아미노-3(S)-메틸펜틸아민 트리플루오로아세트산염 (1.0 g)을 출발물질로 사용하여 실시예 1. 의 <단계 4>와 동일한 방법으로 표제화합물 (0.7 g)을제조하였다.Reference Example 1. 1- (4-cyanobenzyl) -1H-imidazol-5-ylacetic acid hydrochloride (0.61 g, 2.18 mmol) and N- (2-trifluoromethylbenzyl) -N- ( <Step 4 of Example 1> using 9-fluorenylmethyloxycarbonyl) -2 (S) -amino-3 (S) -methylpentylamine trifluoroacetic acid salt (1.0 g) as starting material In the same manner as the title compound (0.7 g) was prepared.

<단계 5> N-(2-트리플루오로메틸벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Step 5 N- (2-trifluoromethylbenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1 H-imidazol-5-yl] acetyl} amino-3 (S) Methylpentylamine

N-(2-트리플루오로메틸벤질)-N-(9-플루오레닐메틸옥시카보닐)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민 (1.0 g)을 사용하여 실시예 1. 의 <단계 5>와 동일한 방법으로 노란 거품상의 표제화합물 (0.65 g)을 제조하였다.N- (2-trifluoromethylbenzyl) -N- (9-fluorenylmethyloxycarbonyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazole-5- The title compound (0.65 g) in the yellow foam was prepared in the same manner as in <Step 5> of Example 1 using il] acetyl} amino-3 (S) -methylpentylamine (1.0 g).

<단계 6> N-[N'-시아노-N"-(4-메톡시페닐)아미디노]-N-(2-트리플루오로메틸벤질)-2(S)-[(1-(4-시아노벤질)-1H-이미다졸-5-일)아세틸]아미노-3(S)-메틸펜틸 아민<Step 6> N- [N'-cyano-N "-(4-methoxyphenyl) amidino] -N- (2-trifluoromethylbenzyl) -2 (S)-[(1- (4 -Cyanobenzyl) -1H-imidazol-5-yl) acetyl] amino-3 (S) -methylpentyl amine

N-(2-트리플루오로메틸벤질)-2(S)-[(1-(4-시아노벤질)-1H-이미다졸-5-일)아세틸]아미노-3(S)-메틸펜틸아민 (104 mg, 0.209 mmol)과 N-시아노-N'-(4-메톡시페닐)티오우레아 나트륨염 (58 mg, 0.251 mmol) 그리고 1-에틸-3-(3-디메틸아미노프로필)카보디이미드 염산염 (48 mg, 0.251 mmol)를 출발물질로 사용하여 실시예 1. 의 <단계 6>과 동일한 방법으로 표제화합물 (50 mg, 36 %)을 제조하였다.N- (2-Trifluoromethylbenzyl) -2 (S)-[(1- (4-cyanobenzyl) -1H-imidazol-5-yl) acetyl] amino-3 (S) -methylpentylamine (104 mg, 0.209 mmol) and N-cyano-N '-(4-methoxyphenyl) thiourea sodium salt (58 mg, 0.251 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodi The title compound (50 mg, 36%) was prepared in the same manner as in <Step 6> of Example 1, using mid hydrochloride (48 mg, 0.251 mmol) as a starting material.

실시예 39. N-[N'-시아노-N"-(2-메톡시피리딘-5-일)아미디노]-N-(2-트리플루오로메틸벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸벤질아민Example 39. N- [N'-cyano-N "-(2-methoxypyridin-5-yl) amidino] -N- (2-trifluoromethylbenzyl) -2 (S)-{[ 1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylbenzylamine

실시예 38, 의 <단계 5>에서 제조한 N-(2-트리플루오로메틸벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민(120 mg, 0.241 mmol)과 N-시아노-N'-(2-메톡시피리딘-5-일)티오우레아 나트륨염(67 mg, 0.289 mmol) 그리고 1-에틸-3-(3-디메틸아미노프로필)카보디이미드 염산염(56 mg, 0.289 mmol)를 출발물질로 사용하여 실시예 1. 의 <단계 6>과 동일한 방법으로 표제화합물 (44 mg, 27 %)을 제조하였다.Example 38, N- (2-trifluoromethylbenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] prepared in <step 5> of Acetyl} amino-3 (S) -methylpentylamine (120 mg, 0.241 mmol) and N-cyano-N '-(2-methoxypyridin-5-yl) thiourea sodium salt (67 mg, 0.289 mmol) And using the 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (56 mg, 0.289 mmol) as the starting material in the same manner as in <Step 6> of Example 1. 27%) was prepared.

실시예 40. N-[N'-시아노-N"-(4-메톡시페닐)아미디노]-N-[2-(메틸)벤질]-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 40. N- [N'-cyano-N "-(4-methoxyphenyl) amidino] -N- [2- (methyl) benzyl] -2 (S)-{[1- (4- Cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

<단계 1> N-(2-메틸벤질)-2(S)-(t-부톡시카보닐)아미노-3(S)-메틸펜틸아민<Step 1> N- (2-methylbenzyl) -2 (S)-(t-butoxycarbonyl) amino-3 (S) -methylpentylamine

참조예 2. 에서 제조한 N-t-부톡시카보닐-L-이소루이신 알데히드 (4.52 g)와 2-메틸벤질아민 (3.7 g)을 출발물질로 사용하여 실시예 1 의 <단계 1>과 동일한 방법으로 유상의 표제화합물 (5.8 g)을 제조하였다.The same as <Step 1> of Example 1 using Nt-butoxycarbonyl-L-isorucin aldehyde (4.52 g) and 2-methylbenzylamine (3.7 g) prepared in Reference Example 2 as starting materials. The title compound (5.8 g) was prepared by the method.

<단계 2> N-(2-메틸벤질)-N-(9-플루오레닐메틸옥시카보닐)-2(S)-(t-부톡시카보닐)아미노-3(S)-메틸펜틸아민<Step 2> N- (2-methylbenzyl) -N- (9-fluorenylmethyloxycarbonyl) -2 (S)-(t-butoxycarbonyl) amino-3 (S) -methylpentylamine

N-(2-메틸벤질)-2(S)-(t-부톡시카보닐)아미노-3(S)-메틸펜틸아민 (0.52 g, 1.62 mmol)과 9-플루오레닐메틸클로로포르메이트 (0.50 g, 1.95 mmol)를 출발물질로 사용하여 실시예 1. 의 <단계 2>와 동일한 방법으로 거품상의 표제화합물 (0.8g)을 제조하였다.N- (2-methylbenzyl) -2 (S)-(t-butoxycarbonyl) amino-3 (S) -methylpentylamine (0.52 g, 1.62 mmol) and 9-fluorenylmethylchloroformate ( 0.50 g, 1.95 mmol) was used as a starting material to prepare a foamy title compound (0.8 g) in the same manner as in <Step 2> of Example 1.

<단계 3> N-(2-메틸벤질)-N-(9-플루오레닐메틸옥시카보닐)-2(S)-아미노-3(S)-메틸펜틸아민<Step 3> N- (2-methylbenzyl) -N- (9-fluorenylmethyloxycarbonyl) -2 (S) -amino-3 (S) -methylpentylamine

N-(2-메틸벤질)-N-(9-플루오레닐메틸옥시카보닐)-2(S)-(t-부톡시카보닐)아미노-3(S)-메틸펜틸아민 (0.8 g)과 트리플루오로아세트산 (5 ml)을 사용하여 실시예 1. 의 <단계 3>과 동일한 방법으로 유상의 표제화합물 (0.55 g)을 제조하여 더 이상의 정제없이 다음반응에 이용하였다.N- (2-methylbenzyl) -N- (9-fluorenylmethyloxycarbonyl) -2 (S)-(t-butoxycarbonyl) amino-3 (S) -methylpentylamine (0.8 g) Using trifluoroacetic acid (5 ml) in the same manner as in <Step 3> of Example 1. An oily title compound (0.55 g) was prepared in the next reaction without further purification.

<단계 4> N-(2-메틸벤질)-N-(9-플루오레닐메틸옥시카보닐)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민<Step 4> N- (2-methylbenzyl) -N- (9-fluorenylmethyloxycarbonyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazole-5 -Yl] acetyl} amino-3 (S) -methylpentylamine

참조예 1. 에서 제조한 1-(4-시아노벤질)-1H-이미다졸-5-일아세트산 염산염(0.42 g)과 N-(2-메틸벤질)-N-(9-플루오레닐메틸옥시카보닐)-2(S)-아미노-3(S)-메틸펜틸아민 (0.55 g)을 출발물질로 사용하여 실시예 1. 의 <단계 4>와 동일한 방법으로 표제화합물 (0.90 g)을 제조하였다.Reference Example 1 1- (4-cyanobenzyl) -1H-imidazol-5-ylacetic acid hydrochloride (0.42 g) and N- (2-methylbenzyl) -N- (9-fluorenylmethyl The title compound (0.90 g) was prepared in the same manner as in <Step 4> of Example 1. using oxycarbonyl) -2 (S) -amino-3 (S) -methylpentylamine (0.55 g) as a starting material. Prepared.

<단계 5> N-(2-메틸벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Step 5 N- (2-methylbenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentyl Amine

N-(2-메틸벤질)-N-(9-플루오레닐메틸옥시카보닐)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민 (0.90 g)을 사용하여 실시예 1 의 <단계 5>와 동일한 방법으로 유상의 표제화합물 (0.50 g)을 제조하였다.N- (2-methylbenzyl) -N- (9-fluorenylmethyloxycarbonyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl } The title compound (0.50 g) in oily phase was prepared in the same manner as in <Step 5> of Example 1 using amino-3 (S) -methylpentylamine (0.90 g).

<단계 6> N-[N'-시아노-N"-(4-메톡시페닐)아미디노]-N-(2-메틸벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민<Step 6> N- [N'-cyano-N "-(4-methoxyphenyl) amidino] -N- (2-methylbenzyl) -2 (S)-{[1- (4-cyano Benzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

N-(2-메틸벤질)-2(S)-[(1-(4-시아노벤질)-1H-이미다졸-5-일)아세틸]아미노-3(S)-메틸펜틸아민 (100 mg, 0.23 mmol)과 N-시아노-N'-(4-메톡시페닐)티오우레아나트륨염 (62 mg, 0.27 mmol) 그리고 1-에틸-3-(3-디메틸아미노프로필)카보디이미드 염산염 (52 mg, 0.27 mmol)를 출발물질로 사용하여 실시예 1. 의 <단계 6>과 동일한 방법으로 표제의 화합물 (110 mg)을 수득하였다.N- (2-methylbenzyl) -2 (S)-[(1- (4-cyanobenzyl) -1H-imidazol-5-yl) acetyl] amino-3 (S) -methylpentylamine (100 mg , 0.23 mmol) and N-cyano-N '-(4-methoxyphenyl) thiourea sodium salt (62 mg, 0.27 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride ( 52 mg, 0.27 mmol) was used as starting material to obtain the title compound (110 mg) in the same manner as in <Step 6> of Example 1.

실시예 41. N-[N'-시아노-N"-(2-메톡시피리딘-5-일)아미디노]-N-[2-(메틸)벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 41.N- [N'-cyano-N "-(2-methoxypyridin-5-yl) amidino] -N- [2- (methyl) benzyl) -2 (S)-{[1 -(4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

실시예 40. 의 <단계 5>에서 제조한 N-(2-메틸벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민 (100 mg, 0.23 mmol)과 N-시아노-N-(2-메톡시-피리딘-5-일)티오우레아 나트륨염 (62 mg, 0.27 mmol) 그리고 1-에틸-3-(3-디메틸아미노프로필)카보디이미드 염산염 (52 mg, 0.27 mmol)를 출발물질로 사용하여 실시예 1. 의 <단계 6>과 동일한 방법으로 표제의 화합물 (90 mg)을 수득하였다.Example 40. N- (2-methylbenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino prepared in <Step 5> of -3 (S) -methylpentylamine (100 mg, 0.23 mmol) with N-cyano-N- (2-methoxy-pyridin-5-yl) thiourea sodium salt (62 mg, 0.27 mmol) and 1- Using the ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (52 mg, 0.27 mmol) as starting material, the title compound (90 mg) was obtained by the same method as <Step 6> of Example 1. It was.

실시예 42. N-[N'-시아노-N"-(4-메톡시페닐)아미디노]-N-[(피리딘-2-일)메틸]-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 42. N- [N'-cyano-N "-(4-methoxyphenyl) amidino] -N-[(pyridin-2-yl) methyl] -2 (S)-{[1- ( 4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

<단계 1> N-[(피리딘-2-일)메틸]-2(S)-(t-부톡시카보닐)아미노-3(S)-메틸펜틸아민<Step 1> N-[(pyridin-2-yl) methyl] -2 (S)-(t-butoxycarbonyl) amino-3 (S) -methylpentylamine

참조예 2. 에서 제조한 N-t-부톡시카보닐-L-이소루이신 알데히드 (4.52 g)와 (피리딘-2-일)메틸아민 (4.0 g)을 출발물질로 사용하여 실시예 1 의 <단계 1>과 동일한 방법으로 유상의 표제화합물 (4.2 g)을 제조하였다.<Step of Example 1 using Nt-butoxycarbonyl-L-isorucin aldehyde (4.52 g) and (pyridin-2-yl) methylamine (4.0 g) prepared in Reference Example 2 as starting materials. In the same manner as 1>, the title compound (4.2 g) was prepared.

<단계 2> N-[(피리딘-2-일)메틸]-N-(9-플루오레닐메틸옥시카보닐)-2(S)-(t-부톡시카보닐)아미노-3(S)-메틸펜틸아민<Step 2> N-[(pyridin-2-yl) methyl] -N- (9-fluorenylmethyloxycarbonyl) -2 (S)-(t-butoxycarbonyl) amino-3 (S) Methylpentylamine

N-[(피리딘-2-일)메틸]-2(S)-(t-부톡시카보닐)아미노-3(S)-메틸펜틸아민 (0.85 g, 2.76 mmol)과 9-플루오레닐메틸클로로포르메이트 (0.86 g, 3.32 mmol)를 출발물질로 사용하여 실시예 1. 의 <단계 2>와 동일한 방법으로 유상의표제화합물(1.1 g)을 제조하였다.N-[(pyridin-2-yl) methyl] -2 (S)-(t-butoxycarbonyl) amino-3 (S) -methylpentylamine (0.85 g, 2.76 mmol) and 9-fluorenylmethyl Using chloroformate (0.86 g, 3.32 mmol) as a starting material, an oily title compound (1.1 g) was prepared in the same manner as in <Step 2> of Example 1.

<단계 3> N-[(피리딘-2-일)메틸]-N-(9-플루오레닐메틸옥시카보닐)-2(S)-아미노-3(S)-메틸펜틸아민<Step 3> N-[(pyridin-2-yl) methyl] -N- (9-fluorenylmethyloxycarbonyl) -2 (S) -amino-3 (S) -methylpentylamine

N-[(피리딘-2-일)메틸]-N-(9-플루오레닐메틸옥시카보닐)-2(S)-(t-부톡시카보닐)아미노-3(S)-메틸펜틸아민 (0.8 g)과 트리플루오로아세트산 (5 ml)을 사용하여 실시예 1. 의 <단계 3>과 동일한 방법으로 유상의 표제화합물 (0.85 g)을 제조하여 더 이상의 정제없이 다음반응에 이용하였다.N-[(pyridin-2-yl) methyl] -N- (9-fluorenylmethyloxycarbonyl) -2 (S)-(t-butoxycarbonyl) amino-3 (S) -methylpentylamine (0.8 g) and trifluoroacetic acid (5 ml) were used to prepare the title compound (0.85 g) as an oil in the same manner as in <Step 3> of Example 1. The residue was used for the next reaction without further purification.

<단계 4> N-[(피리딘-2-일)메틸]-N-(9-플루오레닐메틸옥시카보닐)-2(S)-{[1- (4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민<Step 4> N-[(pyridin-2-yl) methyl] -N- (9-fluorenylmethyloxycarbonyl) -2 (S)-{[1- (4-cyanobenzyl) -1H- Imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

참조예 1. 에서 제조한 1-(4-시아노벤질)-1H-이미다졸-5-일아세트산 염산염 (0.66 g, 2.38 mmol)과 N-[(피리딘-2-일)메틸]-N-(9-플루오레닐메틸옥시카보닐)-2(S)-아미노-3(S)-메틸펜틸아민 (0.85 g, 1.98 mmol)을 출발물질로 사용하여 실시예 1. 의 <단계 4>와 동일한 방법으로 표제화합물 (0.85 g)을 제조하였다.1- (4-cyanobenzyl) -1H-imidazol-5-ylacetic acid hydrochloride (0.66 g, 2.38 mmol) and N-[(pyridin-2-yl) methyl] -N- prepared in Reference Example 1. <Step 4> of Example 1 using (9-fluorenylmethyloxycarbonyl) -2 (S) -amino-3 (S) -methylpentylamine (0.85 g, 1.98 mmol) as a starting material In the same manner, the title compound (0.85 g) was prepared.

<단계 5> N-[(피리딘-2-일)메틸]-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Step 5 N-[(pyridin-2-yl) methyl] -2 (S)-{[1- (4-cyanobenzyl) -1 H-imidazol-5-yl] acetyl} amino-3 (S ) -Methylpentylamine

N-[(피리딘-2-일)메틸]-N-(9-플루오레닐메틸옥시카보닐)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틴아민 (0.85 g)을 사용하여 실시예 1. 의 <단계 5>와 동일한 방법으로 흰색 무정형의 표제화합물 (0.52 g)을 제조하였다.N-[(pyridin-2-yl) methyl] -N- (9-fluorenylmethyloxycarbonyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazole-5 The white amorphous title compound (0.52 g) was prepared in the same manner as in <Step 5> of Example 1 using -yl] acetyl} amino-3 (S) -methylpentynamine (0.85 g).

<단계 6> N-[N'-시아노-N"-(4-메톡시페닐)아미디노]-N-[(피리딘-2-일)메틸]-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸벤질아민<Step 6> N- [N'-cyano-N "-(4-methoxyphenyl) amidino] -N-[(pyridin-2-yl) methyl] -2 (S)-{[1- ( 4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylbenzylamine

N-[(피리딘-2-일)메틸]-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민 (100 mg, 0.23 mmol)과 N-시아노-N-(4-메톡시페닐)티오우레아 나트륨염 (64 mg, 0.28 mmol) 그리고 1-에틸-3-(3-디메틸아미노프로필)카보디이미드 염산염 (53 mg, 0.28 mmol)를 출발물질로 사용하여 실시예 1. 의 <단계6>과 동일한 방법으로 표제의 화합물 (130 mg)을 수득하였다.N-[(pyridin-2-yl) methyl] -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentyl Amine (100 mg, 0.23 mmol) with N-cyano-N- (4-methoxyphenyl) thiourea sodium salt (64 mg, 0.28 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodi Mid hydrochloride (53 mg, 0.28 mmol) was used as starting material to obtain the title compound (130 mg) in the same manner as in <Step 6> of Example 1.

실시예 43. N-[N'-시아노-N"-(2-메톡시피리딘-5-일)아미디노]-N-[(피리딘-2-일)메틸]-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸 아민Example 43. N- [N'-cyano-N "-(2-methoxypyridin-5-yl) amidino] -N-[(pyridin-2-yl) methyl] -2 (S)-{ [1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentyl amine

실시예 42. 의 <단계 5>에서 제조한 N-[(피리딘-2-일)메틸]-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민 (100 mg, 0.23 mmol)과 N-시아노-N'-(2-메톡시-피리딘-5-일)티오우레아 나트륨염 (64 mg, 0.28 mmol) 그리고 1-에틸-3-(3-디메틸아미노프로필)카보디이미드 염산염 (53 mg, 0.28 mmol)를 출발물질로 사용하여 실시예 1. 의 <단계 6>과 동일한 방법으로 표제의 화합물 (110 mg)을 수득하였다.Example 42 N-[(pyridin-2-yl) methyl] -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl prepared in <step 5> of ] Acetyl} amino-3 (S) -methylpentylamine (100 mg, 0.23 mmol) and N-cyano-N '-(2-methoxy-pyridin-5-yl) thiourea sodium salt (64 mg, 0.28 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (53 mg, 0.28 mmol) as starting materials in the same manner as in <Step 6> of Example 1. 110 mg) was obtained.

실시예 44. N-[N'-시아노-N"-(4-메폭시페닐)아미디노]-N-(3-플루오로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 44. N- [N'-cyano-N "-(4-methoxyphenyl) amidino] -N- (3-fluorobenzyl) -2 (S)-{[1- (4-cya Nobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

<단계 1> N-(3-플루오로벤질)-2(S)-(t-부톡시카보닐)아미노-3(S)-메틸펜틸아민Step 1 N- (3-fluorobenzyl) -2 (S)-(t-butoxycarbonyl) amino-3 (S) -methylpentylamine

참조예 2. 에서 제조한 N-t-부톡시카보닐-L-이소루이신 알데히드 (4.52 g)와 3-플루오로벤질아민 (3.5 g)을 출발물질로 사용하여 실시예 1. 의 <단계 1>과 동일한 방법으로 유상의 표제화합물 (5.6 g)을 제조하였다.<Step 1> of Example 1 using Nt-butoxycarbonyl-L-isorucin aldehyde (4.52 g) and 3-fluorobenzylamine (3.5 g) prepared in Reference Example 2 as starting materials. In the same manner as the title compound (5.6 g) was prepared.

<단계 2> N-(3-플루오로벤질)-N-(9-플루오레닐메틸옥시카보닐)-2(S)-(t-부톡시카보닐)아미노-3(S)-메틸펜틸아민Step 2 N- (3-fluorobenzyl) -N- (9-fluorenylmethyloxycarbonyl) -2 (S)-(t-butoxycarbonyl) amino-3 (S) -methylpentyl Amine

N-(3-플루오로벤질)-2(S)-(t-부톡시카보닐)아미노-3(S)-메틸펜틸아민 (0.70 g, 2.16 mmol)과 9-플루오레닐메틸클로로포르메이트 (0.67 g, 2.59 mmol)를 출발물질로 사용하여 실시예 1. 의 <단계 2>와 동일한 방법으로 오일상의 표제화합물(1.0 g)을 제조하였다.N- (3-fluorobenzyl) -2 (S)-(t-butoxycarbonyl) amino-3 (S) -methylpentylamine (0.70 g, 2.16 mmol) and 9-fluorenylmethylchloroformate (0.67 g, 2.59 mmol) was used as a starting material to prepare the title compound (1.0 g) in oily phase in the same manner as in <Step 2> of Example 1.

<단계 3> N-(3-플루오로벤질)-N-(9-플루오레닐메틸옥시카보닐)-2(S)-아미노- 3(S)-메틸펜틸아민Step 3 N- (3-fluorobenzyl) -N- (9-fluorenylmethyloxycarbonyl) -2 (S) -amino-3 (S) -methylpentylamine

N-(3-플루오로벤질)-N-(9-플루오레닐메틸옥시카보닐)-2(S)-(t-부톡시카보닐)아미노-3(S)-메틸펜틸아민 (1.0 g)과 트리플루오로 아세트산 (3 ml)을 사용하여 실시예 1. 의 <단계 3>과 동일한 방법으로 유상의 표제화합물 (1.0 g)을 제조하여 더 이상의 정제없이 다음반응에 이용하였다.N- (3-fluorobenzyl) -N- (9-fluorenylmethyloxycarbonyl) -2 (S)-(t-butoxycarbonyl) amino-3 (S) -methylpentylamine (1.0 g ) And trifluoro acetic acid (3 ml) were used to prepare the title compound (1.0 g) as an oil in the same manner as in <Step 3> of Example 1. The residue was used for the next reaction without further purification.

<단계 4> N-(3-플루오로벤질)-N-(9-플루오레닐메틸옥시카보닐)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민<Step 4> N- (3-fluorobenzyl) -N- (9-fluorenylmethyloxycarbonyl) -2 (S)-{[1- (4-cyanobenzyl) -1 H-imidazole- 5-yl] acetyl} amino-3 (S) -methylpentylamine

참조예 1 에서 제조한 1-(4-시아노벤질)-1H-이미다졸-5-일아세트산 염산염 (0.60 g, 2.15 mmol)과 N-(3-플루오로벤질)-N-(9-플루오레닐메틸옥시카보닐)-2(S)-아미노-3(S)-메틸펜틸아민 (0.80 g, 1.80 mmol)을 출발물질로 사용하여 실시예 1.의 <단계 4>와 동일한 방법으로 표제화합물 (0.95 g)을 제조하였다.1- (4-cyanobenzyl) -1H-imidazol-5-ylacetic acid hydrochloride (0.60 g, 2.15 mmol) and N- (3-fluorobenzyl) -N- (9-flu prepared in Reference Example 1 Titled in the same manner as in <Step 4> of Example 1, using orenylmethyloxycarbonyl) -2 (S) -amino-3 (S) -methylpentylamine (0.80 g, 1.80 mmol) as starting material Compound (0.95 g) was prepared.

<단계 5) N-(3-플루오로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Step 5) N- (3-Fluorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1 H-imidazol-5-yl] acetyl} amino-3 (S) -methyl Pentylamine

N-(3-플루오로벤질)-N-(9-플루오레닐메틸옥시카보닐)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민 (0.95 g)을 사용하여 실시예 1. 의 <단계 5>와 동일한 방법으로 유상의 표제화합물 (0.62 g)을 제조하였다.N- (3-fluorobenzyl) -N- (9-fluorenylmethyloxycarbonyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] An oily title compound (0.62 g) was prepared in the same manner as in <Step 5> of Example 1 using acetyl} amino-3 (S) -methylpentylamine (0.95 g).

<단계 6> N-[N'-시아노-N"-(4-메톡시페닐)아미디노]-N-(3-플루오로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민<Step 6> N- [N'-cyano-N "-(4-methoxyphenyl) amidino] -N- (3-fluorobenzyl) -2 (S)-{[1- (4-cya Nobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

N-(3-플루오르벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민 (100 mg, 0.22 mmol)과 N-시아노-N'-(4-메톡시페닐)티오우레아 나트륨염 (62 mg, 0.27 mmol) 그리고 1-에틸-3-(3-디메틸아미노프로필)카보디이미드 염산염 (52 mg, 0.27 mmol)를 출발물질로 사용하여 실시예 1. 의 <단계 6>과 동일한 방법으로 표제의 화합물 (100 mg)을 수득하였다.N- (3-fluorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine (100 mg , 0.22 mmol) and N-cyano-N '-(4-methoxyphenyl) thiourea sodium salt (62 mg, 0.27 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride ( 52 mg, 0.27 mmol) was used as starting material to obtain the title compound (100 mg) in the same manner as in <Step 6> of Example 1.

실시예 45. N-[N'-시아노-N"-(2-메톡시피리딘-5-일)아미디노]-N-(3-플루오로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸 아민Example 45. N- [N'-cyano-N "-(2-methoxypyridin-5-yl) amidino] -N- (3-fluorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentyl amine

실시예 44. 의 <단계 5>에서 제조한 N-(3-플루오로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민 (100 mg, 0.22 mmol)과 N-시아노-N'-(2-메톡시피리딘-5-일)티오우레아 나트륨염 (62 mg, 0.27 mmol)그리고 1-에틸-3-(3-디메틸아미노프로필)카보디이미드 염산염 (51 mg, 0.27 mmol)를 출발물질로 사용하여 실시예 1 의 <단계 6>과 동일한 방법으로 표제의 화합물(100 mg)을 수득하였다.Example 44. N- (3-fluorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} prepared in <step 5> of Amino-3 (S) -methylpentylamine (100 mg, 0.22 mmol) and N-cyano-N '-(2-methoxypyridin-5-yl) thiourea sodium salt (62 mg, 0.27 mmol) and 1 Obtained the title compound (100 mg) in the same manner as in <Step 6> of Example 1, using -ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (51 mg, 0.27 mmol) as a starting material. It was.

실시예 46. N-[N'-시아노-N"-(4-메톡시페닐)아미디노]-N-[(3-트리플루오로메틸)벤질]-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 46. N- [N'-cyano-N "-(4-methoxyphenyl) amidino] -N-[(3-trifluoromethyl) benzyl] -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

<단계 1> N-[(3-트리플루오로메틸)벤질]-2(S)-(t-부톡시카보닐)아미노-3(S)-메틸펜틸아민<Step 1> N-[(3-trifluoromethyl) benzyl] -2 (S)-(t-butoxycarbonyl) amino-3 (S) -methylpentylamine

참조예 2. 에서 제조한 N-t-부톡시카보닐-L-이소루이신 알데히드 (4.52 g)와 (3-트리플루오로메틸)벤질아민 (3.7 g)을 출발물질로 사용하여 실시예 1. 의 <단계 1>과 동일한 방법으로 유상의 표제화합물 (5.1 g)을 제조하였다.Example 1 using Nt-butoxycarbonyl-L-isorucin aldehyde (4.52 g) and (3-trifluoromethyl) benzylamine (3.7 g) prepared in Reference Example 2 as a starting material. In the same manner as in <Step 1>, the oily title compound (5.1 g) was prepared.

<단계 2> N-[(3-트리플루오로메틸)벤질]-N-(9-플루오레닐메틸옥시카보닐)-2(S)-(t-부톡시카보닐)아미노-3(S)-메틸펜틸아민Step 2 N-[(3-trifluoromethyl) benzyl] -N- (9-fluorenylmethyloxycarbonyl) -2 (S)-(t-butoxycarbonyl) amino-3 (S ) -Methylpentylamine

N-[(3-트리플루오로메틸)벤질]-2(S)-(t-부톡시카보닐)아미노-3(S)-메틸펜틸아민 (0.80 g, 2.14 mmol)과 9-플루오레닐메틸클로로포르메이트 (0.66 g, 2.56 mmol)를 출발물질로 사용하여 실시예 1. 의 <단계 2>와 통일한 방법으로 오일상의 표제화합물 (1.0 g)을 제조하였다.N-[(3-trifluoromethyl) benzyl] -2 (S)-(t-butoxycarbonyl) amino-3 (S) -methylpentylamine (0.80 g, 2.14 mmol) and 9-fluorenyl The title compound (1.0 g) in oil phase was prepared in the same manner as in <Step 2> of Example 1. using methylchloroformate (0.66 g, 2.56 mmol) as a starting material.

<단계 3> N-[(3-트리플루오로메틸)벤질]-N-(9-플루오레닐메틸옥시카보닐)-2(S)-아미노-3(S)-메틸펜틸아민Step 3 N-[(3-trifluoromethyl) benzyl] -N- (9-fluorenylmethyloxycarbonyl) -2 (S) -amino-3 (S) -methylpentylamine

N-[(3-트리플루오로메틸)벤질]-N-(9-플루오레닐메틸옥시카보닐)-2(S)-(t-부톡시카보닐)아미노-3(S)-메틸펜틸아민 (1.0 g)과 트리플루오로아세트산 (3 ml)을 사용하여 실시예 1. 의 <단계 3>과 동일한 방법으로 유상의 표제화합물 (0.9 g)을 제조하여 더 이상의 정제없이 다음 반응에 이용하였다.N-[(3-trifluoromethyl) benzyl] -N- (9-fluorenylmethyloxycarbonyl) -2 (S)-(t-butoxycarbonyl) amino-3 (S) -methylpentyl Using the amine (1.0 g) and trifluoroacetic acid (3 ml) in the same manner as in <Step 3> of Example 1. An oily title compound (0.9 g) was prepared and used in the next reaction without further purification. .

<단계 4> N-[(3-트리플루오로메틸)벤질]-N-(9-플루오레닐메틸옥시카보닐)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민N-[(3-trifluoromethyl) benzyl] -N- (9-fluorenylmethyloxycarbonyl) -2 (S)-{[1- (4-cyanobenzyl) -1H -Imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

참조예 1. 에서 제조한 1-(4-시아노벤질)-1H-이미다졸-5-일아세트산 염산염(0.61 g, 2.18 mmol)과 N-[(3-트리플루오로메틸)벤질]-N-(9-플루오레닐메틸옥시카보닐)-2(S)-아미노-3(S)-메틸펜틸아민 (0.90 g, 1.82 mmol)을 출발물질로 사용하여 실시예 1 의 <단계 4>와 동일한 방법으로 표제화합물 (1.0 g)을 제조하였다.1- (4-cyanobenzyl) -1H-imidazol-5-ylacetic acid hydrochloride (0.61 g, 2.18 mmol) and N-[(3-trifluoromethyl) benzyl] -N prepared in Reference Example 1. -(9-fluorenylmethyloxycarbonyl) -2 (S) -amino-3 (S) -methylpentylamine (0.90 g, 1.82 mmol) as a starting material In the same manner, the title compound (1.0 g) was prepared.

<단계 5> N-[(3-트리플루오로메틸)벤질]-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Step 5 N-[(3-trifluoromethyl) benzyl] -2 (S)-{[1- (4-cyanobenzyl) -1 H-imidazol-5-yl] acetyl} amino-3 ( S) -methylpentylamine

N-[(3-트리플루오로메틸)벤질]-N-(9-플루오레닐메틸옥시카보닐)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민(1.0 g)을 사용하여 실시예 1. 의 <단계 5>와 동일한 방법으로 오일상의 표제화합물(0.60 g)을 제조하였다.N-[(3-trifluoromethyl) benzyl] -N- (9-fluorenylmethyloxycarbonyl) -2 (S)-{[1- (4-cyanobenzyl) -1 H-imidazole- The title compound (0.60 g) in oil phase was prepared in the same manner as in <Step 5> of Example 1 using 5-yl] acetyl} amino-3 (S) -methylpentylamine (1.0 g).

<단계 6> N-[N'-시아노-N"-(4-메톡시페닐)아미디노]-N-[(3-트리플루오로메틸)벤질]-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸벤질아민<Step 6> N- [N'-cyano-N "-(4-methoxyphenyl) amidino] -N-[(3-trifluoromethyl) benzyl] -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylbenzylamine

N-[(3-트리플루오르메틸)벤질]-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민 (100 mg, 0.20 mmol)과 N-시아노-N'-(4-메톡시페닐)티오우레아 나트륨염 (55 mg, 0.24 mmol) 그리고 1-에틸-3-(3-디메틸아미노프로필)카보디이미드 염산염 (46 mg, 0.24 mmol)을 출발물질로 사용하여 실시예 1, 의 <단계 6>과 동일한 방법으로 표제의 화합물 (100 mg)을 수득하였다.N-[(3-trifluoromethyl) benzyl] -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentyl Amine (100 mg, 0.20 mmol) with N-cyano-N '-(4-methoxyphenyl) thiourea sodium salt (55 mg, 0.24 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) car Body title compound (100 mg) was obtained by the same method as <Step 6> of Example 1, using bodiimide hydrochloride (46 mg, 0.24 mmol) as a starting material.

실시예 47 N-[N'-시아노-N"-(2-메톡시피리딘-5-일)아미디노]-N-[(3-트리플루오로메틸)벤질]-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 47 N- [N'-cyano-N "-(2-methoxypyridin-5-yl) amidino] -N-[(3-trifluoromethyl) benzyl] -2 (S)-{ [1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

실시예 46. 의 <단계 5>에서 제조한 N-[(3-트리플루오로메틸)벤질]-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민(100 mg, 0.20 mmol)과 N-시아노-N'-(2-메톡시피리딘-5-일)티오우레아 나트륨염(56 mg, 0.24 mmol) 그리고 1-에틸-3-(3-디메필아미노프로필)카보디이미드 염산염(46 mg, 0.24 mmol)을 출발물질로 사용하여 실시예 1. 의 <단계 6>과 동일한 방법으로 표제의 화합물 (80 mg)을 수득하였다.Example 46 N-[(3-trifluoromethyl) benzyl] -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazole-5- prepared in <step 5> of Il] acetyl} amino-3 (S) -methylpentylamine (100 mg, 0.20 mmol) and N-cyano-N '-(2-methoxypyridin-5-yl) thiourea sodium salt (56 mg, 0.24 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (46 mg, 0.24 mmol) were used as starting materials in the same manner as in <Step 6> of Example 1. (80 mg) was obtained.

실시예 48. N-[N'-시아노-N"-(4-메톡시페닐)아미디노]-N-(3-메톡시카보닐벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 48. N- [N'-cyano-N "-(4-methoxyphenyl) amidino] -N- (3-methoxycarbonylbenzyl) -2 (S)-{[1- (4 -Cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

<단계 1> N-(3-메톡시카보닐벤질)-2(S)-(t-부톡시카보닐)아미노-3(S)-메틸펜틸아민<Step 1> N- (3-methoxycarbonylbenzyl) -2 (S)-(t-butoxycarbonyl) amino-3 (S) -methylpentylamine

참조예 2. 에서 제조한 N-t-부톡시카보닐-L-이소루이신 알데히드 (3.82 g)와3-메톡시카보닐벤질아민 (1.96 g)을 출발 물질로 사용하여 실시예 1. 의 <단계 1>과 동일한 방법으로 표제화합물 (1.53 g, 35 %)을 제조하였다.<Step of Example 1 using Nt-butoxycarbonyl-L-isorucin aldehyde (3.82 g) and 3-methoxycarbonylbenzylamine (1.96 g) prepared in Reference Example 2 as starting materials The title compound (1.53 g, 35%) was prepared in the same manner as 1>.

<단계 2> N-(3-메톡시카보닐벤질)-N-(9-플루오레닐메틸옥시카보닐)-2(S)-(t-부톡시카보닐)아미노-3(S)-메틸펜틸아민<Step 2> N- (3-methoxycarbonylbenzyl) -N- (9-fluorenylmethyloxycarbonyl) -2 (S)-(t-butoxycarbonyl) amino-3 (S)- Methylpentylamine

<단계 1>에서 제조한 N-(3-메톡시카보닐벤질)-2(S)-(f-부톡시카보닐)아미노-3(S)-메틸펜틸아민 (1.53 g)을 출발 물질로 사용하여 실시예 1. 의 <단계 2>과 동일한 방법으로 표제화합물 (1.72 g, 70 %)을 제조하였다.N- (3-methoxycarbonylbenzyl) -2 (S)-(f-butoxycarbonyl) amino-3 (S) -methylpentylamine (1.53 g) prepared in <Step 1> was used as starting material. The title compound (1.72 g, 70%) was prepared in the same manner as in <Step 2> of Example 1.

<단계 3> N-(3-메톡시카보닐벤질)-N-(9-플루오레닐메틸옥시카보닐)-2(S)-아미노-3(S)-메틸펜틸아민<Step 3> N- (3-methoxycarbonylbenzyl) -N- (9-fluorenylmethyloxycarbonyl) -2 (S) -amino-3 (S) -methylpentylamine

<단계 2>에서 제조한 N-(3-메톡시카보닐벤질)-N-(9-플루오레닐메틸옥시카보닐)-2(S)-(t-부톡시카보닐)아미노-3(S)-메틸펜틸아민 (171 g, 2.91 mmol)을 디클로로메탄 (20 ml)에 녹이고 트리플루오로아세트산 (10 ml)을 적가하였다. 반응 용액을 2시간동안 교반 후 용액을 감압 농축하고 에틸아세테이트 (100 ml)로 희석한 후에 중조와 소금물로 세척하고 유기층을 건조 및 감압 농축하여 표제화합물을 제조하여 더 이상의 정제없이 다음 반응에 이용하였다.N- (3-methoxycarbonylbenzyl) -N- (9-fluorenylmethyloxycarbonyl) -2 (S)-(t-butoxycarbonyl) amino-3 (prepared in step 2) S) -Methylpentylamine (171 g, 2.91 mmol) was dissolved in dichloromethane (20 ml) and trifluoroacetic acid (10 ml) was added dropwise. After stirring the reaction solution for 2 hours, the solution was concentrated under reduced pressure, diluted with ethyl acetate (100 ml), washed with sodium bicarbonate and brine, the organic layer was dried and concentrated under reduced pressure to obtain the title compound, which was used in the next reaction without further purification. .

<단계 4> N-(3-메톡시카보닐벤질)-N-(9-플루오레닐메틸옥시카보닐)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민<Step 4> N- (3-methoxycarbonylbenzyl) -N- (9-fluorenylmethyloxycarbonyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imid Dazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

<단계 3>에서 제조한 N-(3-메톡시카보닐벤질)-N-(9-플루오레닐메틸옥시카보닐)-2(S)-아미노-3(S)-메틸펜틸아민 (1.71 mmol)을 출발 물질로 사용하여 실시예 1. 의 <단계 4>와 동일한 방법으로 표제화합물 (1.05 g. 51 %)을 제조하였다.N- (3-methoxycarbonylbenzyl) -N- (9-fluorenylmethyloxycarbonyl) -2 (S) -amino-3 (S) -methylpentylamine (1.71) prepared in <Step 3>. mmol) was used as a starting material to prepare the title compound (1.05 g. 51%) in the same manner as in <Step 4> of Example 1.

<단계 5> N-(3-메톡시카보닐벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Step 5 N- (3-methoxycarbonylbenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) Methylpentylamine

<단계 4>에서 제조한 N-(3-메톡시카보닐벤질)-N-(9-플루오레닐메틸옥시카보닐)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민 (1.05 g)을 출발 물질로 사용하여 실시예 1. 의 <단계 5>와 동일한 방법으로 표제화합물 (1.05 g, 51 %)을 제조하였다.N- (3-methoxycarbonylbenzyl) -N- (9-fluorenylmethyloxycarbonyl) -2 (S)-{[1- (4-cyanobenzyl)-prepared in <Step 4>- 1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine (1.05 g) was used as starting material in the same manner as in <Step 5> of Example 1. The title compound (1.05 g, 51%) was prepared.

<단계 6> N-[N'-시아노-N"-(4-메톡시페닐)아미디노]-N-(3-메톡시카보닐벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민<Step 6> N- [N'-cyano-N "-(4-methoxyphenyl) amidino] -N- (3-methoxycarbonylbenzyl) -2 (S)-{[1- (4 -Cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

<단계 5>에서 제조한 N-(3-메톡시카보닐벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민 (95 mg, 0.195 mmol)과 N-시아노-N'-(4-메독시페닐)티오우레아 나트륨염 (59 mg, 0.272 mmol)을 출발 물질로 사용하여 실시예 1. 의 <단계 6>와 동일한 방법으로 표제화합물 (82 mg, 64%)을 제조하였다.N- (3-methoxycarbonylbenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 prepared in <Step 5> Example 1 using (S) -methylpentylamine (95 mg, 0.195 mmol) and N-cyano-N '-(4-medoxyphenyl) thiourea sodium salt (59 mg, 0.272 mmol) as starting material The title compound (82 mg, 64%) was prepared in the same manner as in <Step 6>.

실시예 49. N-[N'-시아노-N"-(3-플루오로페닐)아미디노]-N-(3-메특시카보닐벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 49. N- [N'-cyano-N "-(3-fluorophenyl) amidino] -N- (3-mesotoxycarbonylbenzyl) -2 (S)-{[1- (4 -Cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

실시예 48. 의 <단계 5>에서 제조한 N-(3-메톡시카보닐벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민 (95 mg, 0.195 mmol)과 N-시아노-N'-(3-플루오르페닐)티오우레아 나트륨염 (59 mg, 0.275 mmol)을 출발 물질로 사용하여 실시예 1. 의 <단계 6>과 동일한 방법으로 표제화합물(80 mg, 63 %)을 제조하였다.Example 48 N- (3-methoxycarbonylbenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] prepared in <step 5> of Acetyl} amino-3 (S) -methylpentylamine (95 mg, 0.195 mmol) and N-cyano-N '-(3-fluorophenyl) thiourea sodium salt (59 mg, 0.275 mmol) were used as starting materials To obtain the title compound (80 mg, 63%) in the same manner as in <Step 6> of Example 1.

실시예 50. N-[N'-시아노-N"-(4-메톡시페닐)아미디노]-N-(3-카복시벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민염산염Example 50. N- [N'-cyano-N "-(4-methoxyphenyl) amidino] -N- (3-carboxybenzyl) -2 (S)-{[1- (4-cyano Benzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine hydrochloride

실시예 48. 의 N-[N'-시아노-N"-(4-메톡시페닐)아미디노]-N-(3-메톡시카보닐벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민 (30 mg, 0.045 mmol)을 에탄올 (1.5 ml)에 녹인후에 1 M 리튬히드록시드(2ml, 2 mmol)을 가하고 상온에서 3 시간동안 교반한다. 반응혼합물을 1 N 염산 수용액을가하고 에틸아세테이트로 추출 및 감압 증류하고 생성된 고체를 여과하여 표제화합물 (14 mg, 48 %)을 수득하였다.Example 48. N- [N'-cyano-N "-(4-methoxyphenyl) amidino] -N- (3-methoxycarbonylbenzyl) -2 (S)-{[1- ( 4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine (30 mg, 0.045 mmol) in ethanol (1.5 ml), followed by 1 M lithium hydroxide. (2 ml, 2 mmol) was added and stirred at room temperature for 3 hours The reaction mixture was added with 1 N aqueous hydrochloric acid solution, extracted with ethyl acetate and distilled under reduced pressure, and the resulting solid was filtered to give the title compound (14 mg, 48%). It was.

실시예 51. N-[N'-시아노-N"-(3-플루오로페닐)아미디노]-N-(3-카복시벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민염산염Example 51. N- [N'-cyano-N "-(3-fluorophenyl) amidino] -N- (3-carboxybenzyl) -2 (S)-{[1- (4-cyano Benzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine hydrochloride

실시예 49. 의 N-[N'-시아노-N"-(3-플루오로페닐)아미디노]-N-(3-메톡시카보닐벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민 (30 mg)을 출발 물질로 사용하여 실시예 50 과 동일한 방법으로 표제화합물(24 mg, 82 %)을 제조하였다.Example 49. N- [N'-cyano-N "-(3-fluorophenyl) amidino] -N- (3-methoxycarbonylbenzyl) -2 (S)-{[1- ( 4-Cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine (30 mg) was used as starting material in the same manner as in Example 50 for the title compound (24 mg). , 82%) was prepared.

실시예 52. N-[N'-시아노-N"-(4-메톡시페닐)아미디노]-N-(4-메톡시카보닐벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 52. N- [N'-cyano-N "-(4-methoxyphenyl) amidino] -N- (4-methoxycarbonylbenzyl) -2 (S)-{[1- (4 -Cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

<단계 1> N-(4-메톡시카보닐벤질)-2(S)-(t-부톡시카보닐)아미노-3(S)-메틸펜틸아민<Step 1> N- (4-methoxycarbonylbenzyl) -2 (S)-(t-butoxycarbonyl) amino-3 (S) -methylpentylamine

참조예 2. 에서 제조한 N-t-부톡시카보닐-L-이소루이신 알데히드 (3.82 g, 17.8 mmol)와 4-메톡시카르보닐벤질아민 (1.96 g, 11.9 mmol)을 출발 물질로 사용하여 실시예 1. 의 <단계 1>과 동일한 방법으로 표제화합물 (2.71 g, 63 %)을 제조하였다.Nt-butoxycarbonyl-L-isorucin aldehyde (3.82 g, 17.8 mmol) and 4-methoxycarbonylbenzylamine (1.96 g, 11.9 mmol) prepared in Reference Example 2 were used as starting materials. The title compound (2.71 g, 63%) was prepared in the same manner as in <Step 1> of Example 1.

<단계 2> N-(4-메톡시카보닐벤질)-N-(9-플루오레닐메틸옥시카보닐)-2(S)-(t-부톡시카보닐)아미노-3(S)-메틸펜틸아민<Step 2> N- (4-methoxycarbonylbenzyl) -N- (9-fluorenylmethyloxycarbonyl) -2 (S)-(t-butoxycarbonyl) amino-3 (S)- Methylpentylamine

<단계 1>에서 제조한 N-(4-메톡시카보닐벤질)-2(S)-(t-부톡시카보닐)아미노-3(S)-메틸펜틸아민 (1.53 g)을 출발 물질로 사용하여 실시예 1. 의 <단계 2>와 동일한 방법으로 표제화합물 (1.72 g, 70 %)을 제조하였다.N- (4-methoxycarbonylbenzyl) -2 (S)-(t-butoxycarbonyl) amino-3 (S) -methylpentylamine (1.53 g) prepared in <Step 1> was used as starting material. To obtain the title compound (1.72 g, 70%) in the same manner as in <Step 2> of Example 1.

<단계 3> N-(4-메톡시카보닐벤질)-N-(9-플루오레닐메틸옥시카보닐)-2(S)-아미노-3(S)-메틸펜틸아민<Step 3> N- (4-methoxycarbonylbenzyl) -N- (9-fluorenylmethyloxycarbonyl) -2 (S) -amino-3 (S) -methylpentylamine

<단계 2>에서 제조한 N-(4-메톡시카보닐벤질)-N-(9-플루오레닐메틸옥시카보닐)-2(S)-(t-부톡시카보닐)아미노-3(S)-메틸펜틸아민 (3.39 g)을 출발 물질로 사용하여 실시예 48. 의 <단계 3>과 동일한 방법으로 표제화합물을 제조하여 더 이상의 정제없이 다음 반응에 이용하였다.N- (4-methoxycarbonylbenzyl) -N- (9-fluorenylmethyloxycarbonyl) -2 (S)-(t-butoxycarbonyl) amino-3 (prepared in step 2) The title compound was prepared in the same manner as in <Step 3> of Example 48. using S) -methylpentylamine (3.39 g) as starting material, and used in the next reaction without further purification.

<단계 4> N-(4-메톡시카보닐벤질)-N-(9-플루오레닐메틸옥시카보닐)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민<Step 4> N- (4-methoxycarbonylbenzyl) -N- (9-fluorenylmethyloxycarbonyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imid Dazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

<단계 3>에서 제조한 N-(4-메톡시카보닐벤질)-N-(9-플루오레닐메틸옥시카보닐)-2(S)-아미노-3(S)-메틸펜틸아민 (1.61 g)을 출발 물질로 사용하여 실시예 1.의 <단계 4>와 동일한 방법으로 표제화합물 (3.35 g, 81 %)을 제조하였다.N- (4-methoxycarbonylbenzyl) -N- (9-fluorenylmethyloxycarbonyl) -2 (S) -amino-3 (S) -methylpentylamine (1.61) prepared in <Step 3>. g) was used as a starting material to prepare the title compound (3.35 g, 81%) in the same manner as in <Step 4> of Example 1.

<단계 5> N-(4-메톡시카보닐벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Step 5 N- (4-methoxycarbonylbenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) Methylpentylamine

<단계 4>에서 제조한 N-(4-메톡시카보닐벤질)-N-(9-플루오레닐메틸옥시카보닐)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민(3.35 g)을 출발 물질로 사용하여 실시예 1. 의 <단계 5>와 동일한 방법으로 표제화합물 (2.00 g, 86 %)을 제조하였다.N- (4-methoxycarbonylbenzyl) -N- (9-fluorenylmethyloxycarbonyl) -2 (S)-{[1- (4-cyanobenzyl)-prepared in <Step 4>- 1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine (3.35 g) as starting material in the same manner as in <Step 5> of Example 1. The title compound (2.00 g, 86%) was prepared.

<단계 6> N-[N'-시아노-N"-(4-메톡시페닐)아미디노]-N-(4-메톡시카보닐벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민<Step 6> N- [N'-cyano-N "-(4-methoxyphenyl) amidino] -N- (4-methoxycarbonylbenzyl) -2 (S)-{[1- (4 -Cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

<단계 5>에서 제조한 N-(4-메톡시카보닐벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민 (196 mg, 0.402 mmol)과 N-시아노-N'-(4-메톡시페닐)티오우레아 나트륨염 (118mg, 0.544 mmol)을 출발 물질로 사용하여 실시예 1. 의 <단계 6>와 동일한 방법으로 표제화합물 (142 mg, 54%)을 제조하였다.N- (4-methoxycarbonylbenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 prepared in <Step 5> Example 1 using (S) -methylpentylamine (196 mg, 0.402 mmol) and N-cyano-N '-(4-methoxyphenyl) thiourea sodium salt (118 mg, 0.544 mmol) as starting materials The title compound (142 mg, 54%) was prepared in the same manner as in <Step 6>.

실시예 53. N-[N'-시아노-N"-(3-플루오로페닐)아미디노]-N-(4-메톡시카보닐벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 53. N- [N'-cyano-N "-(3-fluorophenyl) amidino] -N- (4-methoxycarbonylbenzyl) -2 (S)-{[1- (4 -Cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

실시예 52, 의 <단계 5>에서 제조한 N-(4-메톡시카보닐벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민 (221 mg, 0.453 mmol)과 N-시아노-N'-(3-플루오로페닐)티오우레아 나트륨염 (118 mg, 0.544mmol)을 출발 물질로 사용하여 실시예 1. 의 <단계 6>과 동일한 방법으로 표제화합물 (171 mg, 58 %)을 제조하였다.Example 52, N- (4-methoxycarbonylbenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] prepared in <step 5> of Acetyl} amino-3 (S) -methylpentylamine (221 mg, 0.453 mmol) and N-cyano-N '-(3-fluorophenyl) thiourea sodium salt (118 mg, 0.544 mmol) as starting materials To obtain the title compound (171 mg, 58%) in the same manner as in <Step 6> of Example 1.

설시예 54. N-[N'-시아노-N"-(4-메톡시페닐)아미디노]-N-(4-카복시벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민염산염Example 54. N- [N'-cyano-N "-(4-methoxyphenyl) amidino] -N- (4-carboxybenzyl) -2 (S)-{[1- (4-cyano Benzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine hydrochloride

실시예 52. 의 N-[N'-시아노-N"-(4-메폭시페닐)아미디노]-N-(4-메톡시카보닐벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민 (85 mg)을 출발 물질로 사용하여 실시예 50. 과 동일한 방법으로 표제화합물(25mg, 30 %)을 제조하였다.Example 52. N- [N'-cyano-N "-(4-methoxyphenyl) amidino] -N- (4-methoxycarbonylbenzyl) -2 (S)-{[1- ( 4-Cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine (85 mg) was used as starting material in the same manner as in Example 50. , 30%) was prepared.

실시예 55. N-[N'-시아노-N"-(3-플루오로페닐)아미디노]-N-(4-카복시벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민염산염Example 55. N- [N'-cyano-N "-(3-fluorophenyl) amidino] -N- (4-carboxybenzyl) -2 (S)-{[1- (4-cyano Benzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine hydrochloride

실시예 53. 의 N-[N'-시아노-N"-(3-플루오로페닐)아미디노]-N-(4-매톡시카보닐벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민 (53 mg)을 출발 물질로 사용하여 실시예 50. 과 동일한 방법으로 표제화합물(53 mg, 48 %)을 제조하였다.Example 53. N- [N'-cyano-N "-(3-fluorophenyl) amidino] -N- (4-methoxycarbonylbenzyl) -2 (S)-{[1- ( 4-Cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine (53 mg) was used as starting material in the same manner as in Example 50. mg, 48%) was prepared.

실시예 56. N-[N'-(t-부톡시카보닐)-N"-(4-메톡시페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 56. N- [N '-(t-butoxycarbonyl) -N "-(4-methoxyphenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{ [1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

실시예 1. 의 <단계 5> 에서 제조한 N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민 (120 mg, 0.24 mmol), N-부톡시카보닐-N'-(4-메톡시페닐)티오우레아 (68 mg, 0.26 mmol), 그리고 트리에틸아민 (0.11 ml, 0.79 mmol)을 디메틸포름아미드 (2 ml) 에 녹인 후 염화수은 (62 mg, 0.26 mmol)를 가하고 실온에서 20분간 교반하였다. 반응 혼합물에 에틸아세테이트 (20 ml)를 가하고 셀라이트를 사용하여 걸러낸 후에 물 (50 ml)과 포화소금물 (50 ml)으로 각 2회씩 세척하였다. 유기층을 무수 소듐설페이트로 탈수시킨 후 감압 농축하였다. 잔사를 실리카겔 관 크로마토그라피 (디클로로메탄/메탄올 =20/1)로 정제하여 흰 거품상의 표제 화합물 (30 mg, 17 %)을 수득하였다.Example 1 N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl prepared in <Step 5> of } Amino-3 (S) -methylpentylamine (120 mg, 0.24 mmol), N-butoxycarbonyl-N '-(4-methoxyphenyl) thiourea (68 mg, 0.26 mmol), and triethylamine (0.11 ml, 0.79 mmol) was dissolved in dimethylformamide (2 ml), and mercury chloride (62 mg, 0.26 mmol) was added thereto, and the mixture was stirred at room temperature for 20 minutes. Ethyl acetate (20 ml) was added to the reaction mixture, which was filtered using Celite and washed twice with water (50 ml) and saturated brine (50 ml). The organic layer was dehydrated with anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20/1) to give the title compound (30 mg, 17%) as a white foam.

실시예 57. N-[N'-(4-메톡시페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 57. N- [N '-(4-methoxyphenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H -Imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

실시예 56. 의 N-[N'-(t-부톡시카보닐)-N"-(4-메톡시페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민 (28 mg)을 디클로로메탄 (7 ml)에 녹인 후 트리플루오로아세트산 (3 ml)를 가하고 실온에서 1시간 동안 교반하였다. 반응 혼합물을 농축한 후 포화 중조 수용액 (50 ml)를 가하고 디클로로메탄 (30 ml x 2)으로 추출하였다. 유기층을물 (50 ml)과 포화 소금 수용액 (50 ml) 으로 각 2회씩 세척하고 무수 소듐술페이트로 탈수시킨 후 감압 농축하여 흰 거품상의 표제 화합물 (15 mg, 62 %)을 제조하였다.Example 56. N- [N '-(t-butoxycarbonyl) -N "-(4-methoxyphenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)- {[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine (28 mg) was dissolved in dichloromethane (7 ml) and then trifluoro Acetic acid (3 ml) was added and stirred at room temperature for 1 hour The reaction mixture was concentrated and saturated aqueous sodium bicarbonate solution (50 ml) was added and extracted with dichloromethane (30 ml x 2) The organic layer was extracted with water (50 ml). The solution was washed twice with saturated aqueous salt solution (50 ml), dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (15 mg, 62%) as a white foam.

실시예 58. N-[N',N"-(디-t-부톡시카보닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 58. N- [N ', N "-(di-t-butoxycarbonyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4- Cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

실시예 1. 의 <단계 5> 에서 제조한 N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민 (30 mg, 0.06mmol)과 N,N-디-(t-부톡시카보닐)티오우레아 (18 mg, 0.07 mmol)를 출발물질로 사용하여 실시예 56 의 제조방법과 동일한 방법으로 표제화합물 (25 mg, 56 %)을 제조하였다.Example 1 N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl prepared in <Step 5> of Example using amino-3 (S) -methylpentylamine (30 mg, 0.06 mmol) and N, N-di- (t-butoxycarbonyl) thiourea (18 mg, 0.07 mmol) as starting material The title compound (25 mg, 56%) was prepared in the same manner as in 56.

실시예 59. N-(아미디노)-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민 트리플루오로아세트산염Example 59. N- (amidino) -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} Amino-3 (S) -methylpentylamine trifluoroacetic acid salt

실시예 58. 의 N-[N',N"-(디-t-부톡시카보닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민(24 mg)을 디글로로메탄 (7 ml) 에 녹인 후 트리플루오로아세트산 (3 ml)를 가하고 실온에서 1시간동안 교반하였다. 반응 혼합물을 농축한 후 진공 펌프에서 건조시켜노란 거품상의 표제 화합물 (18 mg, 85 %)을 제조하였다.Example 58. N- [N ', N "-(di-t-butoxycarbonyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4 -Cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine (24 mg) was dissolved in diglomethane (7 ml) followed by trifluoroacetic acid (3 ml ) And stirred for 1 h at rt The reaction mixture was concentrated and dried in a vacuum pump to give the title compound (18 mg, 85%) as a yellow foam.

실시예 60. N-[N'-(t-부톡시카보닐)-N"-(이소부틸)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 60. N- [N '-(t-butoxycarbonyl) -N "-(isobutyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

실시예 1. 의 <단계 5> 에서 제조한 N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민 (100 mg, 0.2 mmol)과 N-부톡시카보닐-N'-(이소부틸)티오우레아 (48 mg, 0.22 mmol)를 출발물질로 사용하여 실시예 56 의 제조방법과 동일한 방법으로 표제화합물 (55 mg, 39 %)을 제조하였다.Example 1 N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl prepared in <Step 5> of Example using amino-3 (S) -methylpentylamine (100 mg, 0.2 mmol) and N-butoxycarbonyl-N '-(isobutyl) thiourea (48 mg, 0.22 mmol) as starting material The title compound (55 mg, 39%) was prepared in the same manner as in 56.

실시예 61, N-[N'-(이소부틸)아미디노]-N-(2,3-디글로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민 트리플루오로아세트산염Example 61, N- [N '-(isobutyl) amidino] -N- (2,3-diglobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H- Imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine trifluoroacetic acid salt

실시예 60. 의 N-[N'-(t-부톡시카보닐)-N"-(이소부틸)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민 (41 mg, 0.06 mol)을 출발물질로 사용하여 실시예 59 과 동일한 제조 방법으로 표제화합물 (33 mg, 80 %)을 제조하였다.Example 60. N- [N '-(t-butoxycarbonyl) -N "-(isobutyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1 The same preparation as in Example 59 using-(4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine (41 mg, 0.06 mol) as starting material The title compound (33 mg, 80%) was prepared.

실시예 62. N-[N'-(2-메톡시페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민 트리플루오로아세트산염Example 62. N- [N '-(2-methoxyphenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H -Imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine trifluoroacetic acid salt

<단계 1> N-[N'-(t-부톡시카보닐)-N'-(2-메톡시페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민<Step 1> N- [N '-(t-butoxycarbonyl) -N'-(2-methoxyphenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{ [1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

실시예 1. 의 <단계 5> 에서 제조한 N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민 (100 mg, 0.2 mmol)과 N-(t-부톡시카보닐)-N'-(2-메톡시페닐)티오우레아 (62 mg, 0.22 mmol)를 출발물질로 사용하여 실시예 56 과 동일한 제조방법으로 표제화합물 (100 mg, 67 %)을 제조하였다.Example 1 N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl prepared in <Step 5> of } Amino-3 (S) -methylpentylamine (100 mg, 0.2 mmol) and N- (t-butoxycarbonyl) -N '-(2-methoxyphenyl) thiourea (62 mg, 0.22 mmol) Using the starting material was the title compound (100 mg, 67%) in the same manner as in Example 56.

<단계 2> N-[N'-(2-메톡시페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민 트리플루오로아세트산염<Step 2> N- [N '-(2-methoxyphenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H -Imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine trifluoroacetic acid salt

상기의 <단계 1>에서 제조한 N-[N'-(t-부톡시카보닐)-N'-(2-메톡시페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민 (100 mg)을 출발물질로 사용하여 실시예 59와 동일한 제조 방법으로 표제화합물 (100 mg, 98 %)을 제조하였다.N- [N '-(t-butoxycarbonyl) -N'-(2-methoxyphenyl) amidino] -N- (2,3-dichlorobenzyl) -2 prepared in <Step 1> above Example 59 using (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine (100 mg) as starting material In the same manner as the preparation of the title compound (100 mg, 98%) was prepared.

실시예 63. N-[N'-메틸-N"-(4-메톡시페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 63. N- [N'-Methyl-N "-(4-methoxyphenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-sia Nobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

실시예 1 의 <단계 5> 에서 제조한 N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민 (100 mg, 0.2 mmol)과 N-메틸-N'-(4-메톡시페닐)티오우레아 (84 mg, 0.4 mmol)와 1-에틸-3-(3-디메틸아미노프로필)카보디이미드 염산염 (77 mg, 0.4 mmol)을 출발물질로 사용하여 실시예 1. 의 <단계 6>과 동일한 제조방법으로 표제화합물 (21 mg, 16 %)을 제조하였다.N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} prepared in <Step 5> of Example 1} Amino-3 (S) -methylpentylamine (100 mg, 0.2 mmol) and N-methyl-N '-(4-methoxyphenyl) thiourea (84 mg, 0.4 mmol) and 1-ethyl-3- (3 The title compound (21 mg, 16%) was prepared in the same manner as in <Step 6> of Example 1. using -dimethylaminopropyl) carbodiimide hydrochloride (77 mg, 0.4 mmol) as a starting material.

실시예 64. N-[N'-메톡시-N"-(4-메톡시페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 64. N- [N'-methoxy-N "-(4-methoxyphenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4- Cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

<단계 1> N-[N'-메톡시-N"-(4-메톡시페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-(t-부톡시카보닐)아미노-3(S)-메틸펜틸아민<Step 1> N- [N'-methoxy-N "-(4-methoxyphenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-(t-butoxycarbonyl Amino-3 (S) -methylpentylamine

실시예1의 <단계 1>에서 제조한 N-(2,3-디클로로벤질)-2(S)-(t-부톡시카보닐)아미노-3(S)-메틸펜틸아민(112mg, 0.3mmol), N-메톡시-N'-(4-메톡시페닐)티오우레아(70mg), 트리에틸아민(0.14ml)을 디메틸포름아미드(2ml)에 녹인 후, 머큐리클로라이드(77mg, 0.33mmol)을 가하고 실온에서 12시간동안 교반하였다. 반응혼합물에 에틸아세테이트(20ml)를 가하고 여과하였다. 여과유기층을 물로 세척하고 무수 소듐술페이트로 탈수하고 감압농축하였다. 생성된 잔사를 실리카겔 크로마토그라피를 통하여 분리정제하여 표제화합물(114mg, 69%)을 제조하였다.N- (2,3-dichlorobenzyl) -2 (S)-(t-butoxycarbonyl) amino-3 (S) -methylpentylamine (112 mg, 0.3 mmol) prepared in <Step 1> of Example 1 ), N-methoxy-N '-(4-methoxyphenyl) thiourea (70 mg) and triethylamine (0.14 ml) were dissolved in dimethylformamide (2 ml), followed by mercuric chloride (77 mg, 0.33 mmol). It was added and stirred at room temperature for 12 hours. Ethyl acetate (20 ml) was added to the reaction mixture and the mixture was filtered. The filtered organic layer was washed with water, dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was separated and purified through silica gel chromatography to obtain the title compound (114 mg, 69%).

<단계 2> N-[N'-메톡시-N"-(4-메톡시페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민<Step 2> N- [N'-methoxy-N "-(4-methoxyphenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4- Cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

<단계 1>에서 제조한 N-[N'-메톡시-N"-(4-메톡시페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-(t-부톡시카보닐)아미노-3(S)-메틸펜틸아민(114mg, 0.21mmol)을 30% 트리플루오로아세트산 용액(5ml)에 녹인후 1시간동안 교반하였다. 반응혼합물을 농축하고 잔사를 디클로로메탄(50ml)에 다시 녹인 용액을 포화중조 수용액과 물로 세척하고 무수 소듐술페이트로 탈수하고 감압농축하였다. 이 잔사를 더 이상의 정제과정없이 참조예 1에서 제조한 1-(4-시아노벤질)-1H-이미다졸-5-일 아세트산염산염(69mg)을 실시예1의 <단계 4>와 동일한 방법으로 반응시켜 표제화합물(15mg)을제조하였다.N- [N'-methoxy-N "-(4-methoxyphenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-(t-part prepared in <Step 1>) Oxycarbonyl) amino-3 (S) -methylpentylamine (114 mg, 0.21 mmol) was dissolved in 30% trifluoroacetic acid solution (5 ml) and stirred for 1 hour The reaction mixture was concentrated and the residue was diluted with dichloromethane ( The solution, which was dissolved in 50 ml), was washed with saturated aqueous sodium bicarbonate solution and water, dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by 1- (4-cyanobenzyl) -1H prepared in Reference Example 1 without further purification. -Imidazol-5-yl acetate hydrochloride (69 mg) was reacted in the same manner as in <Step 4> of Example 1 to prepare the title compound (15 mg).

실시예 65. - 68. 실시예 1. 의 <단계 5> 에서 제조한 N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민(57 mg, 0.11 mmol)을 출발물질로 사용하여 N-메톡시 -N'-(치환)티오우레아 (0.17 mmol)와 실시예 56 의 제조방법과 동일한 방법으로 목적 화합물을 제조하였다.Example 65. 68. N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-Imime prepared in <step 5> of Example 1. Dazol-5-yl] acetyl} amino-3 (S) -methylpentylamine (57 mg, 0.11 mmol) with N-methoxy-N '-(substituted) thiourea (0.17 mmol) as starting material The target compound was prepared in the same manner as in the preparation method of Example 56.

실시예 65. N-[N'-메톡시-N"-(2-플루오로페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 65. N- [N'-methoxy-N "-(2-fluorophenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4- Cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

실시예 66. N-[N'-메톡시-N"-(3-플루오로페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[(1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 66. N- [N'-methoxy-N "-(3-fluorophenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[(1- (4 -Cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

실시예 67. N-[N'-메폭시-N"-(2-메톡시피리딘-5-일)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 67. N- [N'-Mepoxy-N "-(2-methoxypyridin-5-yl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1 -(4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

실시예 68. N-[N'-메톡시-N"-(페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 68. N- [N'-methoxy-N "-(phenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

실시예 69. N-[N'-메톡시-N"-(4-메톡시페닐)아미디노]-N-(2-트리플루오로메틸벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 69. N- [N'-methoxy-N "-(4-methoxyphenyl) amidino] -N- (2-trifluoromethylbenzyl) -2 (S)-{[1- (4 -Cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

실시예 38. 의 <단계 5>에서 제조한 N-(2-트리플루오로메틸벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민(125 mg, 0.251 mmol)과 N-메톡시-N'-(4-메톡시페닐)티오우레아 (64 mg, 0.30 mmol)를 출발물질로하여 실시예 56의 제조방법과 동일한 방법으로 목적 화합물을 제조하였다.Example 38. N- (2-trifluoromethylbenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] prepared in <Step 5> of Acetyl} amino-3 (S) -methylpentylamine (125 mg, 0.251 mmol) and N-methoxy-N '-(4-methoxyphenyl) thiourea (64 mg, 0.30 mmol) were used as starting materials. The target compound was prepared in the same manner as in the preparation method of Example 56.

실시예 70. N-[N'-메톡시-N"-(4-메톡시페닐)아미디노]-N-(2-메틸벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 70. N- [N'-methoxy-N "-(4-methoxyphenyl) amidino] -N- (2-methylbenzyl) -2 (S)-{[1- (4-cyano Benzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

실시예 40. 의 <단계 5>에서 제조한 N-(2-메틸벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민 (0.11 g, 0.25 mmol)과 N-메톡시-N'-(4-메톡시페닐)티오우레아 (63 mg, 0.30 mmol)를 출발물질로하여 실시예 56의 제조방법과 동일한 방법으로 목적 화합물 (60 mg)을 제조하였다.Example 40. N- (2-methylbenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino prepared in <Step 5> of -3 (S) -methylpentylamine (0.11 g, 0.25 mmol) and N-methoxy-N '-(4-methoxyphenyl) thiourea (63 mg, 0.30 mmol) were used as starting materials. The target compound (60 mg) was prepared by the same method as the preparation method.

실시예 71. N-[N'-메톡시-N"-(4-메톡시페닐)아미디노]-N-[(피리딘-2-일)메틸)]-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 71.N- [N'-methoxy-N "-(4-methoxyphenyl) amidino] -N-[(pyridin-2-yl) methyl)]-{[1- (4-cyano Benzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

실시예 42. 의 <단계 5>에서 제조한 N-[(피리딘-2-일)메틸)]-2(S)-{[1-(4시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민 (0.1 g, 0.23 mmol)과 N-매독시-N'-(4-메톡시페닐)티오우레아 (59 mg, 0.28 mmol)를 출발물질로하여 실시예 56의 제조방법과 동일한 방법으로 목적 화합물 (80 mg)을 제조하였다.Example 42 N-[(pyridin-2-yl) methyl)]-2 (S)-{[1- (4cyanobenzyl) -1H-imidazol-5-yl prepared in <step 5> of ] Acetyl} amino-3 (S) -methylpentylamine (0.1 g, 0.23 mmol) and N-Madoxi-N '-(4-methoxyphenyl) thiourea (59 mg, 0.28 mmol) as starting materials The target compound (80 mg) was prepared by the same method as the preparation method of Example 56.

실시예 72. N-[N'-메톡시-N"-(4-메톡시페닐)아미디노]-N-(3-플루오로벤질)-{[1-(4시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 72. N- [N'-methoxy-N "-(4-methoxyphenyl) amidino] -N- (3-fluorobenzyl)-{[1- (4cyanobenzyl) -1H- Imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

실시예 44. 의 <단계 5>에서 제조한 N-(3-플루오로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민 (0.13 g, 0.29 mmol)과 N-메톡시-N'-(4-메톡시페닐)티오우레아 (74 mg, 0.35 mmol)를 출발물질로하여 실시예 56의 제조방법과 동일한 방법으로 목적 화합물 (80 mg)을 제조하였다.Example 44. N- (3-fluorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} prepared in <step 5> of Example 56 starting with amino-3 (S) -methylpentylamine (0.13 g, 0.29 mmol) and N-methoxy-N '-(4-methoxyphenyl) thiourea (74 mg, 0.35 mmol) In the same manner as in the preparation of target compound (80 mg) was prepared.

실시예 73. N-[N'-메톡시-N"- (4-메톡시페닐)아미디노]-N-[(3-트리플루오로메틸)벤질]-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 73. N- [N'-methoxy-N "-(4-methoxyphenyl) amidino] -N-[(3-trifluoromethyl) benzyl]-{[1- (4-cyano Benzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

실시예 46. 의 <단계 5>에서 제조한 N-[(3-트리플루오로메틸)벤질]-2(S)-[(1-(4-시아노벤질)-1H-이미다졸-5-일)아세틸]아미노-3(S)-메틸펜틸아민(0.12 g, 0.29 mmol)과 N-메톡시-N'-(4-메톡시페닐)티오우레아 (61 mg, 0.29 mmol)를 출발물질로하여 실시예 56의 제조방법과 동일한 방법으로 목적 화합물 (70 mg)을 제조하였다.Example 46 N-[(3-trifluoromethyl) benzyl] -2 (S)-[(1- (4-cyanobenzyl) -1H-imidazole-5- prepared in <step 5> of Il) acetyl] amino-3 (S) -methylpentylamine (0.12 g, 0.29 mmol) and N-methoxy-N '-(4-methoxyphenyl) thiourea (61 mg, 0.29 mmol) as starting materials The target compound (70 mg) was prepared by the same method as the preparation method of Example 56.

실시예 74. N-[N'-(4-메톡시페닐)-N"-(메탄술포닐)아미디노]-N-(2,3-디클로로벤질)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 74. N- [N '-(4-methoxyphenyl) -N "-(methanesulfonyl) amidino] -N- (2,3-dichlorobenzyl)-{[1- (4-cyano Benzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

<단계 1> N-[N'-(4-메톡시페닐)-N"-(메탄술포닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-(t-부톡시카보닐)아미노-3(S)-메틸펜틸아민<Step 1> N- [N '-(4-methoxyphenyl) -N "-(methanesulfonyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-(t-part Methoxycarbonyl) amino-3 (S) -methylpentylamine

실시예1의 <단계 1>에서 제조한 N-(2,3-디클로로벤질)-2(S)-(t-부톡시카보닐)아미노-3(S)-메틸펜틸아민(85mg, 0.23mmol)가 N-메탄술포닐-N'-(4-메폭시페닐)티오우레아(117mg)을 디메틸포름아미드(2ml)에 녹인 후, 1-에틸-3-(3-디메틸아미노프로필)카보디이미드 염산염(87mg, 0.45mmol)을 가하고 실온에서 12시간동안 교반하였다. 반응혼합물에 에틸아세테이트(20ml)를 가하고 유기층을 물로 세척하고 무수소듐술페이트로 탈수하고 감압농축하였다. 생성된 잔사를 실리카겔 크로마토그라피를 통하여 분리정제하여 표제화합물(80mg, 59%)을 제조하였다.N- (2,3-dichlorobenzyl) -2 (S)-(t-butoxycarbonyl) amino-3 (S) -methylpentylamine (85 mg, 0.23 mmol) prepared in <Step 1> of Example 1 ) Dissolves N-methanesulfonyl-N '-(4-methoxyphenyl) thiourea (117 mg) in dimethylformamide (2 ml) and then 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide Hydrochloride (87 mg, 0.45 mmol) was added and stirred at room temperature for 12 hours. Ethyl acetate (20 ml) was added to the reaction mixture, the organic layer was washed with water, dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was separated and purified through silica gel chromatography to obtain the title compound (80 mg, 59%).

<단계 2> N-[N'-(4-메톡시페닐)-N"-(메탄술포닐)아미디노]-N-(2,3-디클로로벤질)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민<Step 2> N- [N '-(4-methoxyphenyl) -N "-(methanesulfonyl) amidino] -N- (2,3-dichlorobenzyl)-{[1- (4-cyano Benzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

<단계 1>에서 제조한 N-[N'-(4-메톡시페닐)-N"-(메탄술포닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-(t-부톡시카보닐)아미노-3(S)-메틸펜틸아민(80mg,0.13mmol)을 30% 트리플루오로아세트산 용액(5ml)에 녹인후 1시간동안 교반하였다. 반응혼합물을 농축하고 잔사를 디클로로메탄(50ml)에 다시 녹인 용액을 포화중조 수용액과 물로 세척하고 무수 소듐술페이트로 탈수하고 감압농축하였다. 이 잔사를 참조예 1에서 제조한 1-(4-시아노벤질)-1H-이미다졸-5-일 아세트산 염산염(69mg)을 실시예1의 <단계 4>와 동일한 방법으로 반응시켜 표제화합물(15mg)을 제조하였다.N- [N '-(4-methoxyphenyl) -N "-(methanesulfonyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-(prepared in <Step 1> t-butoxycarbonyl) amino-3 (S) -methylpentylamine (80 mg, 0.13 mmol) was dissolved in 30% trifluoroacetic acid solution (5 ml) and stirred for 1 hour The reaction mixture was concentrated and the residue was The solution redissolved in dichloromethane (50ml) was washed with a saturated aqueous sodium bicarbonate solution and water, dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure. The title compound (15 mg) was prepared by reacting dazol-5-yl acetate hydrochloride (69 mg) in the same manner as in <Step 4> of Example 1.

실시예 75, - 77. 실시예 1. 의 <단계 5>에서 제조한 N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민(85 mg, 0.23 mmol)을 출발물질로 사용하여 N-(치환술포닐)-N'-(치환)티오우레아(0.45 mmol)와 실시예 56의 제조방법과 동일한 방법으로 목적 화합물을 제조하였다.Examples 75,-77. N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imide prepared in <Step 5> of Example 1. Dazol-5-yl] acetyl} amino-3 (S) -methylpentylamine (85 mg, 0.23 mmol) using N- (substituted sulfonyl) -N '-(substituted) thiourea (0.45 mmol) as starting material And the target compound was prepared in the same manner as in the preparation method of Example 56.

실시예 75. N-[N'-메틸-N"-(4-메틸벤젠술포닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 75. N- [N'-Methyl-N "-(4-methylbenzenesulfonyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4- Cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

실시예 76. N-[N'-이소부틸-N"-(메탄술포닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 76. N- [N'-isobutyl-N "-(methanesulfonyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyano Benzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

실시예 77. N-[N'-(3-플루오로페닐)-N"-(메탄술포닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민Example 77. N- [N '-(3-fluorophenyl) -N "-(methanesulfonyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine

시험예 1. K-라스로 형질변환된 세포주에 대한 증식억제 시험Test Example 1 Proliferation Inhibition Test for Cell Line Transformed with K-Lass

생쥐의 섬유아세포주인 NIH 3T3 (ATCC CRL-1658)를 K-라스로 형질변환 시킨 세포 100개씩을 100 ㎕ 배지[10 % FBS (fetal bovine serum)가 포함된 DMEM (Dulbecco's modified Eagle's medium)]에 부유시켜 96 웰 플레이트 (well plate)에 분주하고, 37 ℃ 5 % CO2하에서 24시간 동안 배양하였다.100 cells transformed with mouse fibroblast NIH 3T3 (ATCC CRL-1658) with K-Lass were suspended in 100 μl medium [Dulbecco's modified Eagle's medium (DMEM) containing 10% FBS (fetal bovine serum)]. The aliquots were aliquoted into 96 well plates and incubated at 37 ° C. 5% CO 2 for 24 hours.

실시예에서 제조한 화합물을 배지에 용해시켜 적절한 농도의 시료를 제조한 다음, 이들 시료를 세포가 있는 웰 (well)에 100 ㎕씩 첨가하고, 대조군 웰 (well)에는 화합물이 포함되지 않은 배지만을 100 ㎕ 첨가하여 37 ℃, 5 % CO2하에서 120시간 동안 배양하였다.After dissolving the compound prepared in Example in a medium to prepare a sample of the appropriate concentration, these samples are added to the well containing the cells 100 μl, and the control well (well) only the medium does not contain the compound 100 μl was added and incubated for 120 hours at 37 ° C. and 5% CO 2 .

배양후 0.1 mg의 3-(4,5-디메틸치아졸-2-일)-2,5-디페닐-2H-테트라졸리움브로마이드 (MTT)를 모든 웰 (well)에 가해 주고 다시 37 ℃, 5 % CO2하에서 4 시간 동안 배양한 다음, 배지를 완전히 제거하고 0.4N 염산-이소프로필 알콜 혼합액을 100 ㎕씩 가한 후 가볍게 3 분간 진탕하였다. 마이크로프랫트 리더 (microplate reader, DL1000, Dynatech Laboratories Co.)로 570 nm에서 흡광도를 측정하였으며, 이를 근거로하여 세포성장을 50 % 억제하는 농도 (TC50)를 구하였다. 본 발명에 따른 화합물 중에서 보다 바람직한 화합물들에 대한 결과는 표 1. 과 같다.After incubation, 0.1 mg of 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyl-2H-tetrazolium bromide (MTT) was added to all wells. After incubating for 4 hours under% CO 2 , the medium was completely removed, 100 μl of 0.4N hydrochloric acid-isopropyl alcohol mixture was added thereto, and the mixture was shaken gently for 3 minutes. Absorbance was measured at 570 nm with a microplate reader (DL1000, Dynatech Laboratories Co.) and based on this, a concentration (TC 50 ) that inhibits cell growth by 50% was obtained. Results for more preferred compounds among the compounds according to the invention are shown in Table 1.

표1. K-라스로 형질변환된 세포주에 대한 증식억제 효과Table 1. Antiproliferative Effect on Cell Lines Transformed with K-Ras

(표1 계속)(Continued Table 1)

상기 표1 의 결과로부터 본 발명에 따른 일반식(I)의 화합물은 매우 우수한 라스변이세포 증식억제효과를 가지고 있음을 확인할 수 있다.From the results of Table 1, the compound of formula (I) according to the present invention can be confirmed that it has a very excellent Ras mutant cell proliferation inhibitory effect.

시험예 2. FPTase 효소에 대한 억제시험Test Example 2 Inhibition Test for FPTase Enzyme

파르네실화 단백질 트랜스퍼라제는 소의 뇌로부터 FPLC와 gel filtration을 이용하여 부분정제하여 사용하였다. 기질로는 대장균에서 발현 및 정제된 인체 재조합 K-라스4B(His6) 단백질을 사용하였고, FPT에 대한 프레닐 잔기 공여체로는3H로 표지된 파르네실 피로포스페이트 (FPP)를 사용하였다. 반응 용액은 50 mM N-(2-히드록시에틸)피페라진-N'-(2-에탄술포닉산) (HEPES), 5 mM-MgCl2, 10 μM ZnCl2, 5 mM 디티오쓰레이톨 (dithiothreitol), 0.2 % n-옥틸-베타-D-글루코피라노시드 조성물로 제조하였으며, 0.6 μg의 K-라스4B(His6) 단백질과 0.15 μCi의 [3H]FPP를 혼합한 후, 실시예의 화합물을 99.9 % 에탄올에 용해하여 가하였다. 여기에 FPT 1.5 μg을 첨가하고 멸균된 증류수로 50 μl의 부피가 되도록 제조하였다. 반응은 37 ℃에서 1시간동안 수행하고, 4 % 소디움도데실술페이트 (SDS)를 90 μl 및 30 % 트리클로로아세트산 (TCA)을 90 μl씩 차례로 가하여 종결하였다. 반응 용액을 얼음에서 60분간 방치한 후 침전된 단백질을 유리섬유 필터가 장착된 96 well multiscreen Instruments (Millipore 회사)에서 거르고, 4 % SDS와 6 % TCA가 포함된 수용액으로 세척하였다. 세척된 유리섬유 필터에 액체섬광계수기용 혼합액을 각각 5 ml 가한 후 액체섬광 계수기 (Beckman 5801)로 유리섬유 필터에 걸러진 반응 생성물의 방사선량을 측정하였다. 대조군의 방사전량을 100 %로 설정한 후 화합물 처리군의 상대적 방사선량을 백분율 (%)로 환산하여 억제도를 계산하였고, 이를 Litchfield-Wilcoxon 방법으로 IC50값을 구하였다. 본 발명에 따른 화합물 중에서 보다 바람직한 화합물들에 대한 결과는 표 2. 와 같다.Farnesylated protein transferase was partially purified from bovine brain using FPLC and gel filtration. Human recombinant K-ras4B (His6) protein expressed and purified in Escherichia coli was used as a substrate, and farnesyl pyrophosphate (FPP) labeled with 3 H was used as a prenyl residue donor for FPT. The reaction solution is 50 mM N- (2-hydroxyethyl) piperazine-N '-(2-ethanesulphonic acid) (HEPES), 5 mM-MgCl 2 , 10 μM ZnCl 2 , 5 mM dithiothreitol ), 0.2% n-octyl-beta-D-glucopyranoside composition, 0.6 μg of K-Ras4B (His6) protein and 0.15 μCi [ 3 H] FPP were mixed, and then the compound of Example Dissolved in 99.9% ethanol and added. 1.5 μg of FPT was added thereto and prepared to have a volume of 50 μl with sterile distilled water. The reaction was carried out at 37 ° C. for 1 hour and terminated by adding 90 μl of 4% sodium dodecyl sulfate (SDS) and 90 μl of 30% trichloroacetic acid (TCA) in turn. After the reaction solution was left on ice for 60 minutes, the precipitated protein was filtered by 96 well multiscreen Instruments (Millipore) equipped with a glass fiber filter, and washed with an aqueous solution containing 4% SDS and 6% TCA. 5 ml of the liquid scintillation counter mixed solution was added to the washed glass fiber filters, and the radiation dose of the reaction product filtered through the glass fiber filters was measured with a liquid scintillation counter (Beckman 5801). After setting the amount of radioactivity of the control group to 100%, the inhibition was calculated by converting the relative radiation dose of the compound treated group into a percentage (%), and the IC 50 value was obtained by Litchfield-Wilcoxon method. Results for more preferred compounds among the compounds according to the invention are shown in Table 2.

표 2. FPTase 효소에 대한 억제 효과Table 2. Inhibitory Effects on FPTase Enzymes

상기 표2. 의 결과로부터 본 발명에 따른 일반식(I)의 화합물들은 FPTase 효소에 대한 억제효과가 우수함을 확인할 수 있다.Table 2 above. From the results of the compounds of formula (I) according to the invention it can be confirmed that the inhibitory effect on the FPTase enzyme.

시험예 3. 라스-가공 (ras-processing) 억제시험Test Example 3 Ras-Processing Inhibition Test

인체 K-라스4B 유전자로 형질 변환된 생쥐의 섬유아 세포주를 6-well 배양 접시에서 105개의 세포가 되도록 배양한 다음, 화합물들을 10 μM 농도가 되도록 첨가하고 48 시간 동안 계속 배양하였다. 배양된 세포는 세포용해 완충용액 (Lysis buffer, 1×PBS(phosphate buffer saline), 1% Triton X-100, protease inhibitor) 1 ml에 부유시키고, 4 ℃에서 세포를 용해한 다음, Pan-ras 항체결합 아가로스(Y13,259)를 10 μl 첨가하고 다시 4 ℃에서 2시간 동안 회전시키면서 반응시켰다. 면역 침전된 단백질을 15 % SDS-아크릴아미드 전기영동에서 분리하고, Hybond-ECL 막 (Amersham Corp.)에 고착시킨 다음, 단백질이 고착된 막은 일차 항체로 항-K-라스 항체를 결합시키고, ECL kit (Amersham Corp.)를 사용하여 면역적 검출 (immunodetection) 수행하였다. 15% SDS-아크릴아미드 전기영동에서 비가공된 K-라스는 프레닐화된 K-라스 단백질보다 느리게 움직이므로 세포에 처리된 저해제에 의한 FPTase의 억제 정도를 관찰할 수 있다. 또한 이 방법은 세포내에 존재하는 K-라스 단백질의 정상 상태 농도를 비교분석 할 수 있다. 본 발명에 따른 화합물 중에서 보다 바람직한 화합물들에 대한 결과는 표 3. 과 같다.Fibroblast cell lines of mice transformed with the human K-Ras4B gene were cultured to 105 cells in a 6-well culture dish, and then the compounds were added to a concentration of 10 μM and continued incubation for 48 hours. The cultured cells were suspended in 1 ml of Lysis buffer (Lysis buffer, 1 × PBS (phosphate buffer saline), 1% Triton X-100, protease inhibitor), and the cells were lysed at 4 ° C., followed by Pan-ras antibody binding. 10 μl of agarose (Y13,259) was added and reacted while rotating at 4 ° C. for 2 hours. Immunoprecipitated proteins were separated by 15% SDS-acrylamide electrophoresis, fixed on a Hybond-ECL membrane (Amersham Corp.), and the protein-fixed membrane bound the anti-K-ras antibody with the primary antibody, and the ECL Immunodetection was performed using the kit (Amersham Corp.). In 15% SDS-acrylamide electrophoresis, the unprocessed K-Ras moved slower than the prenylated K-Ras protein, so the degree of inhibition of FPTase by the cell treated inhibitors can be observed. In addition, this method can compare and analyze the steady-state concentration of K-Ras protein in cells. Results for more preferred compounds among the compounds according to the invention are shown in Table 3.

표 3. K-라스4B에 대한 라스-가공 억제 효과Table 3. Lars-process inhibitory effect on K-Ras4B

상기 표3 의 결과로부터 본 발명에 따른 일반신(I)의 화합물은 K-라스4B에 대한 우수한 라스-가공 억제 효과를 가지고 있음을 확인 할 수 있다.From the results of Table 3, it can be seen that the compound of general (I) according to the present invention has excellent lath-processing inhibitory effect on K-ras 4B.

Claims (5)

하기 일반식 (I)로 표시되는 신규의 구아니딘 유도체 및 이들의 무독성염New guanidine derivatives represented by the following general formula (I) and nontoxic salts thereof 상기에서 X는 피리딜; 또는 메틸, 하나 또는 그 이상의 할로겐, 메톡시카보닐, 카복시 또는 트리플루오르메틸로 치환되거나 비치환된 페닐이고, R1및 R2는 각 각 수소; 시아노; 메톡시; 직쇄상 또는 분지상의 C1-C6 알킬; 시클로알킬; 2-프로페닐; t-부톡시카보닐; 피리딜-N-옥시드; 4-메틸벤젠술포닐; 메탄술포닐; 메틸, 메톡시, 니트로, 아시노, 할로겐, 메틸티오, 리메틸아미노 또는 트리플루오르메틸로 치환되거나 비치환된페닐; 메톡시 또는 메틸티오로 치환되거나 비치환된 피리딜; 벤질; 또는 페닐에틸이다.X is pyridyl; Or phenyl unsubstituted or substituted with methyl, one or more halogen, methoxycarbonyl, carboxy or trifluoromethyl, R 1 and R 2 are each hydrogen; Cyano; Methoxy; Straight or branched C 1 -C 6 alkyl; Cycloalkyl; 2-propenyl; t-butoxycarbonyl; Pyridyl-N-oxide; 4-methylbenzenesulfonyl; Methanesulfonyl; Phenyl unsubstituted or substituted with methyl, methoxy, nitro, acino, halogen, methylthio, dimethylamino or trifluoromethyl; Pyridyl unsubstituted or substituted with methoxy or methylthio; benzyl; Or phenylethyl. 제1항에 있어서, N-[N'-시아노-N''-(4-메독시페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,The compound of claim 1, wherein N- [N'-cyano-N ''-(4-medoxyphenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-시아노-N''(피리딘-3-일)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N '' (pyridin-3-yl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-시아노-N"- (2-메틸티오피리딘-5-일)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(2-methylthiopyridin-5-yl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4- Cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-시아노-N"-(4-메틸페닐]아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(4-methylphenyl] amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H -Imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-시아노-N"-(3-클로로페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(3-chlorophenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl)- 1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-시아노-N"-(4-메틸티오페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(4-methylthiophenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-시아노-N"-(4-디메틸아미노페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(4-dimethylaminophenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-시아노-N"-(2-메톡시피리딘-5-일)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(2-methoxypyridin-5-yl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1 (4-sia Nobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-시아노-N"-(페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(phenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imid Dazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-시아노-N"-(벤질)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(benzyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imide Dazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-시아노-N"-(페닐에틸)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(phenylethyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H- Imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-시아노-N"-(4-클로로페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1- (4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(4-chlorophenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl)- 1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-시아노-N"-(4-플루오고페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(4-fluorophenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-시아노-N"-(3-플루오로페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(3-fluorophenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-시아노-N"-(메틸)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(methyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imid Dazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-시아그-N"-(에틸)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyag-N "-(ethyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imide Dazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-시아노-N"-(n-프로필)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(n-propyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H -Imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-시아노-N"-(n-부틸)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질) 1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(n-butyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) 1H- Imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-시아노-N"-(n-펜틸)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(n-pentyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[-(4-cyanobenzyl) -1H- Imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-시아노-N"-(t-부틸)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(t-butyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H -Imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-시아노-N"-(이소부틸)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(isobutyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H- Imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-시아노-N"-(2-프로페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(2-propenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl)- 1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-시아노-N"-(시클로프로필)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(cyclopropyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H- Imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-시아노-N"-(시클로펜틸)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(cyclopentyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H- Imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-시아노-N"-(4-니트로페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(4-nitrophenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl)- 1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-시아노-N"-(시클로헥실)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(cyclohexyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H- Imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-시아노-N"-(2-플루오로페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(2-fluorophenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-시아노-N"-(3-트리플루오로메틸페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(3-trifluoromethylphenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl ) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-시아노-N"-(3-메틸페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(3-methylphenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H -Imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-시아노-N"-(2-메톡시페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(2-methoxyphenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-시아노-N"-(피리딘-4-일)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(pyridin-4-yl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-시아노-N"-(피리딘-1-N-옥시드-3-일)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(pyridin-1-N-oxide-3-yl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-시아노-N"-(4-아미노페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(4-aminophenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl)- 1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-시아노-N"-(4-메톡시페닐)아미디노]-N-(2-클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(4-methoxyphenyl) amidino] -N- (2-chlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H -Imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-시아노-N"-(4-메톡시페닐)아미디노]-N-(2,3-디플루오로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸벤질아민,N- [N'-cyano-N "-(4-methoxyphenyl) amidino] -N- (2,3-difluorobenzyl) -2 (S)-{[1- (4-cyano Benzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylbenzylamine, N-[N'-시아노-N"-(4-메톡시페닐)아미디노]-N-(3-클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(4-methoxyphenyl) amidino] -N- (3-chlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H -Imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-시아노-N"-(2-메톡시피리딘-5-일)아미디노]-N-(3-클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(2-methoxypyridin-5-yl) amidino] -N- (3-chlorobenzyl) -2 (S)-{[1- (4-cyano Benzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-시아노-N"-(4-메톡시페닐)아미디노]-N-(2-트리플루오로메틸벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(4-methoxyphenyl) amidino] -N- (2-trifluoromethylbenzyl) -2 (S)-{[1- (4-cyanobenzyl ) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-시아노-N"-(2-메톡시피리딘-5-일)아미디노]-N-(2-트리플루오로메틸벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틴}아미노-3(S)-메틸벤질아민,N- [N'-cyano-N "-(2-methoxypyridin-5-yl) amidino] -N- (2-trifluoromethylbenzyl) -2 (S)-{[1- (4 -Cyanobenzyl) -1H-imidazol-5-yl] acetin} amino-3 (S) -methylbenzylamine, N-[N'-시아노-N"-(4-메톡시페닐)아미디노]-N-(2-메틸벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸 아민,N- [N'-cyano-N "-(4-methoxyphenyl) amidino] -N- (2-methylbenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H -Imidazol-5-yl] acetyl} amino-3 (S) -methylpentyl amine, N-[N'-시아노-N"-(2-메톡시피리딘-5-일)아미디노]-N-(2-메틸벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(2-methoxypyridin-5-yl) amidino] -N- (2-methylbenzyl) -2 (S)-{[1- (4-cyano Benzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-시아노-N"-(4-메톡시폐닐)아미디노]-N-[(피리딘-2-일)메틸]-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(4-methoxypentyl) amidino] -N-[(pyridin-2-yl) methyl] -2 (S)-{[1- (4-cyano Benzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-시아노-N"-(2-메톡시피리딘-5-일)아미디노]-N-[(피리딘-2-일)메틸]-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(2-methoxypyridin-5-yl) amidino] -N-[(pyridin-2-yl) methyl] -2 (S)-{[1- ( 4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-시아노-N"-(4-메톡시페닐)아미디노]-N-(3-플루오로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(4-methoxyphenyl) amidino] -N- (3-fluorobenzyl) -2 (S)-{[1- (4-cyanobenzyl)- 1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-시아노-N"-(2-메톡시피리딘-5-일)아미디노]-N-(3-플루오로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(2-methoxypyridin-5-yl) amidino] -N- (3-fluorobenzyl) -2 (S)-{[1- (4-cya Nobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-시아노-N"-(4-메톡시페닐)아미디노]-N-(3-트리플루오르메틸벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(4-methoxyphenyl) amidino] -N- (3-trifluoromethylbenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-시아노-N"-(2-메톡시피리딘-5-일)아미디노]-N-(3-트리플루오로메틸벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미디졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(2-methoxypyridin-5-yl) amidino] -N- (3-trifluoromethylbenzyl) -2 (S)-{[1- (4 -Cyanobenzyl) -1H-imidizol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-시아노-N"-(4-메톡시페닐)아미디노]-N-(3-메톡시카보닐벤질)-2(2)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(4-methoxyphenyl) amidino] -N- (3-methoxycarbonylbenzyl) -2 (2)-{[1- (4-cyanobenzyl ) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-시아노-N"-(3-플루오로페닐)아미디노]-N-(3-메톡시카보닐벤질)-2(S)-{[1-(4시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(3-fluorophenyl) amidino] -N- (3-methoxycarbonylbenzyl) -2 (S)-{[1- (4cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-시아노-N"-(4-메톡시페닐)아미디노]-N-(3-카복시벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(4-methoxyphenyl) amidino] -N- (3-carboxybenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H -Imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-시아노-N"-(3-플루오로페닐)아미디노]-N-(3-카복시벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(3-fluorophenyl) amidino] -N- (3-carboxybenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H -Imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-시아노-N"-(4-메톡시페닐)아미디노]-N-(4-메톡시카보닐벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(4-methoxyphenyl) amidino] -N- (4-methoxycarbonylbenzyl) -2 (S)-{[1- (4-cyanobenzyl ) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-시아노-N"-(3-플루오로페닐)아미디노]-N-(4-메톡시카보닐벤질)-2(S)-{1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(3-fluorophenyl) amidino] -N- (4-methoxycarbonylbenzyl) -2 (S)-{1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-시아노-N"-(4-메톡시페닐)아미디노]-N-(4-카복시벤질)-2(S)-{1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(4-methoxyphenyl) amidino] -N- (4-carboxybenzyl) -2 (S)-{1- (4-cyanobenzyl) -1H- Imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-시아노-N"-(3-플루오로페닐)아미디노]-N-(4-카복시벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-cyano-N "-(3-fluorophenyl) amidino] -N- (4-carboxybenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H -Imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-(t-부톡시카보닐)-N"-(4-메톡시페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N '-(t-butoxycarbonyl) -N "-(4-methoxyphenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- ( 4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-(4-메톡시페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N '-(4-methoxyphenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazole- 5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N',N"-(디-t-부톡시카보닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N ', N "-(di-t-butoxycarbonyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-(아미디노)-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- (amidino) -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 ( S) -methylpentylamine, N-[N'-(t-부톡시카보닐)-N"-(이소부틸)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N '-(t-butoxycarbonyl) -N "-(isobutyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-sia Nobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-(이소부틸)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N '-(isobutyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl ] Acetyl} amino-3 (S) -methylpentylamine, N-[N'-(2-메톡시페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N '-(2-methoxyphenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazole- 5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-메틸-N"-(4-메톡시페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-methyl-N "-(4-methoxyphenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl)- 1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-메톡시-N"-(4-메톡시페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-methoxy-N "-(4-methoxyphenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-메톡시-N"-(2-플루오로페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-methoxy-N "-(2-fluorophenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-메톡시-N"-(3-플루오로페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-methoxy-N "-(3-fluorophenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-메톡시-N"-(2-메톡시피리딘-5-일)아미디노]-N-(2,3-디클로로벤짙)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-methoxy-N "-(2-methoxypyridin-5-yl) amidino] -N- (2,3-dichlorobenzine) -2 (S)-{[1- (4- Cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-메톡시-N"-(페닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-methoxy-N "-(phenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H-imid Dazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-메톡시-N"-(4-메톡시페닐)아미디노]-N-(2-트리플루오로메틸벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-methoxy-N "-(4-methoxyphenyl) amidino] -N- (2-trifluoromethylbenzyl) -2 (S)-{[1- (4-cyanobenzyl ) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-메톡시-N"-(4-메톡시페닐)아미디노]-N-(2-메틸벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-methoxy-N "-(4-methoxyphenyl) amidino] -N- (2-methylbenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H -Imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-메톡시-N"-(4-메톡시페닐)아미디노]-N-[(피리딘-2-일)메틸)]-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-methoxy-N "-(4-methoxyphenyl) amidino] -N-[(pyridin-2-yl) methyl)]-{[1- (4-cyanobenzyl) -1H -Imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-메톡시-N"-(4-메톡시페닐)아미디노]-N-(3-플루오로벤질)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-methoxy-N "-(4-methoxyphenyl) amidino] -N- (3-fluorobenzyl)-{[1- (4-cyanobenzyl) -1 H-imidazole- 5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-메톡시-N"-(4-메톡시페닐)아미디노]-N-[(3-트리플루오로메틸)벤질]-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-methoxy-N "-(4-methoxyphenyl) amidino] -N-[(3-trifluoromethyl) benzyl]-{[1- (4-cyanobenzyl) -1H -Imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-(4-메톡시페닐)-N"-(메탄술포닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N '-(4-methoxyphenyl) -N "-(methanesulfonyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-sia Nobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-메틸-N"-(4-메틱벤젠술포닐)아미디노]-N-(2,3-디클로로벤질)-2(S)-[[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민,N- [N'-methyl-N "-(4-maticbenzenesulfonyl) amidino] -N- (2,3-dichlorobenzyl) -2 (S)-[[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, N-[N'-(메탄술포닐)-N"-이소부틸아미디노]-N-(2,3-디클로로벤질)-2(S)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민, 및N- [N '-(methanesulfonyl) -N "-isobutylamidino] -N- (2,3-dichlorobenzyl) -2 (S)-{[1- (4-cyanobenzyl) -1H -Imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine, and N-[N'-(메탄술포닐)-N"-(3-플푸오로페닐)아미디노]-N-(2,3-디클로로벤질)-2(2)-{[1-(4-시아노벤질)-1H-이미다졸-5-일]아세틸}아미노-3(S)-메틸펜틸아민으로 구성된 군으로부터 선택된 것을 특징으로 하는 구아니딘 유도체 또는 이들의 무독성염.N- [N '-(methanesulfonyl) -N "-(3-flufuophenyl) amidino] -N- (2,3-dichlorobenzyl) -2 (2)-{[1- (4-sia Nobenzyl) -1H-imidazol-5-yl] acetyl} amino-3 (S) -methylpentylamine. Guanidine derivatives or non-toxic salts thereof. 일반식(II)의 화합물을 일반식(III)의 화합물 또는 그의 금속염과 커플링화제(coupling reagent)존재하에서 반응시키는 것을 특징으로 하는 일반식 (I)의 화합물의 제조방법.A method for producing a compound of formula (I), wherein the compound of formula (II) is reacted with a compound of formula (III) or a metal salt thereof in the presence of a coupling reagent. 상기에서 X, R1, 및 R2는 제1항에서 정의한 바와 동일하다.In the above, X, R 1 and R 2 are the same as defined in claim 1. 일반식(IV)의 화합물을 일반식(III)의 화합물 또는 그의 금속염과 커플링화제(coupling reagent)존재하에서 반응시켜 일반식(V)의 화합물을 제조한 다음, 일반식(V)의 화합물에 1-(4-시아노벤질)-1H-이미다졸-5-일아세트산을 반응시키는 것을 특징으로 하는 일반식 (I)의 화합물의 제조방법.A compound of formula (IV) is reacted with a compound of formula (III) or a metal salt thereof in the presence of a coupling reagent to prepare a compound of formula (V), and then to a compound of formula (V). A process for preparing a compound of formula (I) characterized by reacting 1- (4-cyanobenzyl) -1H-imidazol-5-ylacetic acid. 상기에서 X, R1, 및 R2는 제1항에서 정의한 바와 동일하며, Boc는 통상의 아미노 보호기이다.In the above, X, R 1 , and R 2 are the same as defined in claim 1 , and Boc is a common amino protecting group. 하기 일반식 (I)로 표시되는 구아니딘 유도체 또는 이들의 무독성염을 유효성분으로 함유하고 약제학적으_로 허용가능한 담체를 함유하는 라스변이세포 성장억제 조생물.Ras mutant cell growth inhibitory microorganisms containing a guanidine derivative represented by the following general formula (I) or a nontoxic salt thereof as an active ingredient and a pharmaceutically acceptable carrier. 상기에서 X, R1, 및 R2는 제1항에서 정의한 바와 동일하다.In the above, X, R 1 and R 2 are the same as defined in claim 1.
KR10-1998-0028069A 1998-07-13 1998-07-13 Ras-mutant cell growth inhibitor anidine derivatives KR100401283B1 (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5892664A (en) * 1981-11-27 1983-06-02 Tokawa Tetsuo Preparation of imidazole derivative
EP0113570A1 (en) * 1982-12-20 1984-07-18 Merck & Co. Inc. 5-(Amino or substituted amino) imidazoles
KR930011491A (en) * 1991-11-28 1993-06-24 정용문 Digital Early Tracking Loop Circuit

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5892664A (en) * 1981-11-27 1983-06-02 Tokawa Tetsuo Preparation of imidazole derivative
EP0113570A1 (en) * 1982-12-20 1984-07-18 Merck & Co. Inc. 5-(Amino or substituted amino) imidazoles
KR930011491A (en) * 1991-11-28 1993-06-24 정용문 Digital Early Tracking Loop Circuit

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