KR19990062439A - Panesyl transferase inhibitor having a pyrrole structure and its preparation method - Google Patents

Panesyl transferase inhibitor having a pyrrole structure and its preparation method Download PDF

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KR19990062439A
KR19990062439A KR1019980024423A KR19980024423A KR19990062439A KR 19990062439 A KR19990062439 A KR 19990062439A KR 1019980024423 A KR1019980024423 A KR 1019980024423A KR 19980024423 A KR19980024423 A KR 19980024423A KR 19990062439 A KR19990062439 A KR 19990062439A
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South Korea
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methyl
pyrrole
imidazol
naphthalen
formula
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KR1019980024423A
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Korean (ko)
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이현일
고종성
정원희
이진호
김종현
신유승
노성구
안인애
박기원
문경덕
곽태환
정현호
최태생
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성재갑
주식회사 엘지화학
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Priority to KR1019980035652A priority Critical patent/KR100381216B1/en
Priority to JP2000523207A priority patent/JP3548118B2/en
Priority to EP98959231A priority patent/EP1045846B1/en
Priority to DE69814167T priority patent/DE69814167T2/en
Priority to AT98959231T priority patent/ATE239014T1/en
Priority to PL98340729A priority patent/PL340729A1/en
Priority to ES98959231T priority patent/ES2193590T3/en
Priority to US09/554,646 priority patent/US6268363B1/en
Priority to IL13547398A priority patent/IL135473A0/en
Priority to NZ504013A priority patent/NZ504013A/en
Priority to PCT/KR1998/000377 priority patent/WO1999028315A1/en
Priority to CNB988114976A priority patent/CN1188407C/en
Priority to HU0004238A priority patent/HUP0004238A3/en
Priority to AU15083/99A priority patent/AU731272B2/en
Priority to RU2000116633/04A priority patent/RU2179975C1/en
Priority to CA002310629A priority patent/CA2310629A1/en
Priority to IDW20000933A priority patent/ID24175A/en
Priority to BR9815423-0A priority patent/BR9815423A/en
Priority to IN3585DE1998 priority patent/IN192478B/en
Priority to TW087119691A priority patent/TW436487B/en
Priority to ARP980106048A priority patent/AR017700A1/en
Publication of KR19990062439A publication Critical patent/KR19990062439A/en
Priority to IS5451A priority patent/IS5451A/en
Priority to US09/813,437 priority patent/US6518429B2/en
Priority to JP2001307368A priority patent/JP2002161092A/en
Priority to US10/005,262 priority patent/US6472526B1/en

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    • 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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

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

Abstract

본 발명은 피롤구조를 포함하며 파네실 전이효소를 억제할 수 있는 하기 화학식 1의 화합물, 그의 제조방법 및 이 화합물을 제조하는데 유용하게 사용되는 중간체에 관한 것이다 :The present invention relates to a compound of the formula (1) including a pyrrole structure and capable of inhibiting farnesyl transferase, a method for preparing the same, and an intermediate useful for preparing the compound.

상기식에서 A, n1, B, C, D 및 X 는 명세서에 정의된 바와 같다.Wherein A, n 1 , B, C, D and X are as defined in the specification.

Description

피롤구조를 갖는 파네실 전이효소 억제제 및 그의 제조방법Panesyl transferase inhibitor having a pyrrole structure and its preparation method

본 발명은 피롤구조를 포함하며 파네실 전이효소를 억제할 수 있는 하기 화학식 1의 화합물, 그의 약제학적으로 허용되는 염 또는 이성체에 관한 것이다 :The present invention relates to a compound of formula (I), a pharmaceutically acceptable salt or isomer thereof, which comprises a pyrrole structure and is capable of inhibiting farnesyl transferase:

화학식 1Formula 1

상기식에서In the above formula

n1은 1 내지 4의 정수를 나타내고,n 1 represents an integer of 1 to 4,

X 는 O 또는 S를 나타내며,X represents O or S,

A 는 수소; C3-C7사이클로알킬 또는 저급알콕시에 의해 치환되거나 비치환된 직쇄 또는 측쇄의 C1-C10알킬; 또는 할로겐, 시아노, 니트로, 하이드록시카보닐, 아미노카보닐, 아미노티오카보닐, 저급알콕시, 페녹시 또는 저급알킬에 의해 치환되거나 비치환된 벤질을 나타내고,A is hydrogen; Straight or branched C 1 -C 10 alkyl unsubstituted or substituted by C 3 -C 7 cycloalkyl or lower alkoxy; Or benzyl unsubstituted or substituted by halogen, cyano, nitro, hydroxycarbonyl, aminocarbonyl, aminothiocarbonyl, lower alkoxy, phenoxy or lower alkyl,

B 는 수소; 또는 하이드록시, 머캅토, 저급알콕시, 저급알킬티오 또는 아릴에 의해 치환되거나 비치환된 저급알킬을 나타내며,B is hydrogen; Or lower alkyl unsubstituted or substituted by hydroxy, mercapto, lower alkoxy, lower alkylthio or aryl,

C 는 아릴에 의해 치환되거나 비치환된 저급알킬을 나타내거나; 하기 구조식의 그룹중 선택된 어느 하나를 나타내고,C represents lower alkyl unsubstituted or substituted by aryl; Any one selected from the group of structural formulas

,,, , , ,

, ,

여기에서 R1및 R2는 각각 독립적으로 수소, 저급알킬, 저급알콕시, 할로겐, 시아노, 하이드록시카보닐, 아미노카보닐, 아미노티오카보닐, 하이드록시, 페닐 또는 페녹시를 나타내며,Wherein R 1 and R 2 each independently represent hydrogen, lower alkyl, lower alkoxy, halogen, cyano, hydroxycarbonyl, aminocarbonyl, aminothiocarbonyl, hydroxy, phenyl or phenoxy,

D 는 아미노산 잔기 또는 아미노산 잔기의 저급알킬에스테르를 나타내거나; 하기 구조식의 그룹중 선택된 어느 하나를 나타내고,D represents an amino acid residue or lower alkyl ester of an amino acid residue; Any one selected from the group of structural formulas

,,,, , , , ,

, ,

여기에서From here

R3및 R4는 각각 독립적으로 수소; 할로겐; 하이드록시; 시아노; 저급알킬; 저급알콕시; 알콕시알킬; 알킬티오; 알킬설포닐; 알킬티오알킬; 알킬티오알킬옥시; 아릴; 또는 아릴에 의해 치환된 옥시, 티오, 설포닐 또는 저급알킬을 나타내며,R 3 and R 4 are each independently hydrogen; halogen; Hydroxy; Cyano; Lower alkyl; Lower alkoxy; Alkoxyalkyl; Alkylthio; Alkylsulfonyl; Alkylthioalkyl; Alkylthioalkyloxy; Aryl; Or oxy, thio, sulfonyl or lower alkyl substituted by aryl,

Y 는 O, S, SO2, C=O, C=S를 나타내거나, 저급알킬 또는 하이드록시에 의해 치환되거나 비치환된 CH2또는 NH 를 나타내고,Y represents O, S, SO 2 , C═O, C═S, or CH 2 or NH unsubstituted or substituted by lower alkyl or hydroxy,

n2는 1 내지 3 의 정수를 나타내며,n 2 represents an integer of 1 to 3,

R5및 R6은 각각 독립적으로 수소; 아릴; 아릴 또는 시아노아릴에 의해 치환되거나 비치환된 저급알킬; 또는을 나타내고, 여기에서 n3는 2 내지 4의 정수를 나타내며, Z 는 O, S 또는 SO2를 나타내고, R7은 수소 또는 저급알킬을 나타낸다.R 5 and R 6 are each independently hydrogen; Aryl; Lower alkyl unsubstituted or substituted by aryl or cyanoaryl; or Wherein n 3 represents an integer of 2 to 4, Z represents O, S or SO 2 , and R 7 represents hydrogen or lower alkyl.

특히, 본 발명에 따른 화합물은 지금까지 알려진 파네실전이효소 억제제와는 상이한 특이구조를 갖고 있을 뿐아니라 티올기도 전혀 포함하지 않고 있다.In particular, the compound according to the present invention not only has a specific structure different from the farnesyltransferase inhibitors known to date, but also contains no thiol groups at all.

본 발명에는 또한, 상기 화학식 1의 화합물을 제조하는 방법도 포함되어 있으며, 이 화합물을 제조하는 과정에서 유용하게 사용될 수 있는 중간체도 포함되어 있다. 따라서, 이들 제조방법 및 중간체 화합물도 본 발명의 대상이다.The present invention also includes a method for preparing the compound of Formula 1, and also includes an intermediate that can be usefully used in the preparation of the compound. Accordingly, these preparation methods and intermediate compounds are also subject of the present invention.

Ras 단백질은 세포의 성장과 분화에 중요한 역할을 하는 21kDa의 단백질로서 구아닌 뉴클레오타이드와 결합하며, 구아노신 트리포스페이트(GTP)를 구아노신 디포스페이트(GDP)로 가수분해하는 효소이다. 또한, 세포 내에서 특이적인 GTPase 회로를 조절하는 분자스위치로도 작용하는 것으로 알려져 있다(참조: Bourne,H.R., Sanders,D.A., McCormick, F.Nature1991, 349, 117).Ras protein is a 21kDa protein that plays an important role in cell growth and differentiation. It binds to guanine nucleotides and hydrolyzes guanosine triphosphate (GTP) to guanosine diphosphate (GDP). It is also known to act as a molecular switch that regulates specific GTPase circuits in cells (Bourne, HR, Sanders, DA, McCormick, F. Nature 1991, 349, 117).

Ras 단백질은 포유동물세포에서 3 가지의 Ras 유전자에 의해 아미노산 188개의 K-Ras-4B 또는 189개의 H-Ras, K-ras-4A 및 N-Ras로 생성된다. 이 단백질의 12, 13, 61번 위치에 있는 아미노산은 GTP의 인산기와 근접하여 있어, 이 아미노산 잔기들은 GTP의 가수분해에 관여하는 물분자의 공간적 위치에 영향을 미침으로써 GTPase 활성에 영향을 미친다. 인체에서 암이 발생한 경우, 이 위치의 아미노산에 돌연변이가 관찰되는데, 이 돌연변이가 결국 Ras 단백질 고유의 GTPase 활성을 저해하여 GTP 결합상태를 지속시킴으로써 비정상적인 성장신호를 지속적으로 전달하여 발암성을 나타내는 것으로 알려져 있다. 이와 같이 발암성인 Ras 유전자는 특이적으로 췌장암, 방광암, 폐암 및 피부암등에 밀접한 관련이 있는 것으로 알려져 있으며(참조: Bos,J.L.,Cancer Res., 1989, 49, 4682), Ras 단백질은 혈관평활근(vascular smooth muscle) 세포의 성장에도 관여한다고 보고되어 있어 동맥경화 및 당뇨병과도 밀접한 관련이 있는 것으로 생각되고 있다(참조: JP H7-112930 호).Ras protein is produced by mammalian cells by three Ras genes as amino acids 188 K-Ras-4B or 189 H-Ras, K-ras-4A and N-Ras. The amino acids at positions 12, 13, and 61 of the protein are in close proximity to the phosphate groups of GTP, and these amino acid residues affect GTPase activity by affecting the spatial position of water molecules involved in the hydrolysis of GTP. When cancer occurs in the human body, mutations in amino acids at this position are observed, which eventually inhibits Ras protein's intrinsic GTPase activity and maintains GTP binding status, which is known to show carcinogenicity by continuously transmitting abnormal growth signals. have. Such a carcinogenic Ras gene is known to be closely related to pancreatic cancer, bladder cancer, lung cancer and skin cancer (see Bos, JL, Cancer Res ., 1989, 49, 4682). It has been reported to be involved in the growth of smooth muscle cells, and is thought to be closely related to atherosclerosis and diabetes mellitus (JP JP H7-112930).

Ras 단백질이 생물학적으로 활성화 상태에 있기 위해서는 세포막 내에 부착되어야 하는데 이를 위해서는 Ras 파네실 전이효소, Ras 단백질 카복시 말단의 3 개 AAX 펩타이드 절단효소, 메틸 전이효소 및 팔미토일 전이효소에 의한 단백질 전이 후의 탄소말단의 변형이 요구된다. 이중 첫번째 단계인 파네실화는 파네실 전이효소(FTase)에 의해 이루어진다. 파네실 전이효소의 기질은 Ras 단백질의 카복시 말단에 있는 CA1A2X라는 네개의 펩타이드이며, 여기서 A1 및 A2는 전기적 부하를 띄지 않는 지방족 아미노산이고 X는 메티오닌, 알라닌 또는 세린등이다. 파네실 반응은 시스테인에 일어나 황에테르 결합을 형성시키며, H-Ras와 N-Ras의 경우에는 카복시 말단 근처의 또 다른 시스테인에 팔미토일화가 일어난다. 파네실화의 결과로 Ras 단백질은 친소성이 증가되어 세포막 내에 부착하게되며, 파네실화된 Ras 단백질은 카복시 말단으로 부터 연이어 3개의 AAX 펩타이드가 절단효소에 의해 제거되고 메틸화되어 파네실기가 세포막 내의 지질층 또는 다른 수용체와 결합하는 것을 용이하게 해주는 것으로 알려져 있다. 한편, K-Ras-4B는 H-Ras, N-Ras와는 달리 팔미토일화에 필요한 시스테인 대신 폴리베이직(Poly basic) 도메인이라 불리는 여러개의 라이신이 배열된 부위를 가지고 있으며, 이를 통해 세포막내의 음이온성 지질과의 결합이 용이하게 되는 것으로 알려져있다. Ras 단백질이 세포막내에 잘 부착하기 위해서는 모든 변형 단계가 필요하나, Ras 단백질의 활성화에는 파네실화만으로도 충분한 것으로 알려져 있으므로 이 파네실화를 차단함으로써 돌연변이에 의한 Ras 발암성을 억제하기 위한 연구가 활발히 진행되고 있다(참조: Buss, J.E.et al.,Chemistry Biology, 1995, 2, 787).In order for the Ras protein to be biologically active, it must be attached to the cell membrane. This requires a carbon term after protein transfer by Ras farnesyl transferase, three AAX peptide cleavage enzymes at the Ras protein carboxy terminus, methyl transferase and palmitoyl transferase. The modification of is required. The first step, panesylation, is achieved by farnesyl transferase (FTase). The substrate of the farnesyl transferase is four peptides, CA1A2X, at the carboxy terminus of the Ras protein, where A1 and A2 are aliphatic amino acids with no electrical load and X is methionine, alanine or serine. The farnesyl reaction occurs on cysteine to form sulfur ether bonds, and in the case of H-Ras and N-Ras, palmitoylation occurs at another cysteine near the carboxy terminus. As a result of the panesylation, the Ras protein increases in affinity and adheres to the cell membrane. The panesylated Ras protein is subsequently removed from the carboxy terminus by three AAX peptides removed and methylated so that the panesyl group is formed in the lipid layer or in the cell membrane. It is known to facilitate binding with other receptors. On the other hand, unlike H-Ras and N-Ras, K-Ras-4B has a site where several lysines, called poly basic domains, are arranged in place of cysteine required for palmitoylation. It is known that binding to lipids is facilitated. In order for Ras protein to adhere well to the cell membrane, all modification steps are required. However, the activation of Ras protein is known to be sufficient for panicylation alone. Therefore, studies are being actively conducted to inhibit Ras carcinogenicity by mutation by blocking this panicylation. (Bus, JE et al ., Chemistry Biology , 1995, 2, 787).

그간의 연구결과, Ras로 형질전환된 세포에서 파네실 전이효소를 저해했을때 세포의 성장이 저해되는 것으로 관찰되었으며, 또한 Ras에 의해 변형된 세포형질을 개선하는 것으로 나타났다.Previous studies have shown that inhibition of farnesyl transferase in Ras-transformed cells inhibits cell growth and improves the cell morphology modified by Ras.

실제로 파네실 전이효소의 몇몇 저해제들은 Ras 발암성 유전인자의 세포내 프레닐기에 의한 반응을 선택적으로 저해하는 것으로 밝혀졌다(참조: Kohl,N.E.et al, Proc. Natl. Acad. Sci. USA., 91, 9141(1994); Kohl, N.E.et al., Nature Medicine, 1, 792(1995)). 개발된 파네실 전이효소 저해제로는 시스테인 티올(thiol)기를 함유하며 CAAX와 유사한 구조를 갖는 펩타이드 변형체 및 이를 개선한 저해제(참조: US Patent No. 5,141,851 호; Kohl,N.E.et al., Science260, 1934(1993); Grahamet al.,PCT/US95/12224), 페닐기로 변형된 펩타이드(참조: Sebti, S.M.,J. Biol. Chem.270, 26802, 1995), 향정신성 의약품 골격구조중 벤조디아제핀을 펩타이드의 turn 모사구조로 활용한 변형체(James,G.L.et al.,Science,260, 1937, 1993), 펩타이드 구조에서 벗어나 트리사이클릭 유기 화합물을 골격으로한 저해제(참조: Bishop W.R.et al.,J. Biol. Chem.,270, 30611, 1995)를 들 수 있다. 또한, 파네실 전이효소가 프레닐기를 전이시키는 작용기전이 전자 친화적 치환반응 (Electrophilic Displacement)이므로 반응의 트랜지션 상태(transition state)에 양성부하를 요구함에 착안하여 프레닐기에 트랜지션 상태의 양성 부하를 연결시킨 새로운 형태의 저해제가 제시되었다(참조: Poulter, C.D.et al., J. Am. Chem. Soc., 118, 8761, 1996).Indeed, several inhibitors of farnesyl transferase have been shown to selectively inhibit the response of Ras oncogenic genes to intracellular prenyl groups (see Kohl, NE et al, Proc. Natl. Acad. Sci. USA , 91, 9141 (1994); Kohl, NE et al., Nature Medicine , 1, 792 (1995). The developed farnesyl transferase inhibitors include peptide variants containing cysteine thiol groups and similar structures to CAAX, and inhibitors that improve them (see US Patent No. 5,141,851; Kohl, NE et al., Science 260, 1934 (1993); Graham et al., PCT / US95 / 12224), peptides modified with phenyl groups (Sebti, SM, J. Biol. Chem. 270, 26802, 1995), benzodiazepines in the psychotropic pharmaceutical framework Variant (James, GL et al. , Science, 260, 1937, 1993), which was used as a turn simulation structure of the inhibitor, and inhibitors based on tricyclic organic compounds from the peptide structure (Bishop WR et al. , J. Biol. Chem., 270, 30611, 1995). In addition, since the mechanism by which Panesyl transferase transfers a prenyl group is an electrophilic displacement reaction, it is considered that a positive load is required in the transition state of the reaction, thereby linking the positive load of the transition state to the prenyl group. New types of inhibitors have been proposed (Poulter, CD et al., J. Am. Chem. Soc ., 118, 8761, 1996).

그러나, 많은 경우의 인체암에서 K-Ras 활성화가 주요 원인으로 작용하며, 지금까지 개발된 대부분의 프레닐 전이효소 저해제들은 K-Ras를 활성화시킨다. 따라서, K-Ras에 의해 형질전환된 세포의 성장저해 정도가 H-Ras, N-Ras에 의해 형질전환된 세포의 성장저해에 비해 떨어지므로 K-Ras 활성을 효과적으로 저해할 수 있는 새로운 저해제의 연구가 주목을 받고 있다.However, K-Ras activation is a major cause in many cases of human cancer, and most prenyl transferase inhibitors developed to date activate K-Ras. Therefore, the inhibition of growth of cells transformed by K-Ras is lower than the growth inhibition of cells transformed by H-Ras and N-Ras, so the study of novel inhibitors that can effectively inhibit K-Ras activity Is getting attention.

이에 본 발명자들은 K-Ras 기질에 대한 효소활성 저해능 및 세포내 K-Ras 프레닐화 저해능을 평가할 수 있는 새로운 평가체계를 확립하여 이를 활용함으로써 K-Ras 뿐만 아니라 H-Ras, N-Ras 기질의 파네실화를 저해하는 신규한 화합물을 합성하고 그 저해능을 평가하였다. 그 결과, 본 발명자들은 상기 화학식 1의 화합물이 본 발명의 소기 목적에 부합되어 이들이 항암제로서 유용하게 사용될 수 있음을 발견하고 본 발명을 완성하게 되었다.Therefore, the present inventors established a new evaluation system for evaluating the enzyme activity inhibitory ability against K-Ras substrate and the inhibitory activity of intracellular K-Ras prenylation, and utilizing the same, thereby identifying the K-Ras as well as H-Ras and N-Ras substrates. Novel compounds that inhibit misfire were synthesized and their inhibitory ability evaluated. As a result, the present inventors have found that the compound of Formula 1 meets the intended purpose of the present invention and that they can be usefully used as an anticancer agent.

따라서, 본 발명은 우수한 항암효과를 갖는 화학식 1의 화합물, 그의 제조방법 및 이 화합물의 제조과정에서 유용하게 사용될 수 있는 중간체에 관한 것이다.Accordingly, the present invention relates to a compound of formula (1) having excellent anticancer effect, a preparation method thereof, and an intermediate that can be usefully used in the preparation of the compound.

본 발명은 피롤구조를 포함하며 파네실 전이효소를 억제할 수 있는 하기 화학식 1의 화합물, 그의 약제학적으로 허용되는 염 또는 이성체에 관한 것이다 :The present invention relates to a compound of formula (I), a pharmaceutically acceptable salt or isomer thereof, which comprises a pyrrole structure and is capable of inhibiting farnesyl transferase:

화학식 1Formula 1

상기식에서In the above formula

n1은 1 내지 4의 정수를 나타내고,n 1 represents an integer of 1 to 4,

X 는 O 또는 S를 나타내며,X represents O or S,

A 는 수소; C3-C7사이클로알킬 또는 저급알콕시에 의해 치환되거나 비치환된 직쇄 또는 측쇄의 C1-C10알킬; 또는 할로겐, 시아노, 니트로, 하이드록시카보닐, 아미노카보닐, 아미노티오카보닐, 저급알콕시, 페녹시 또는 저급알킬에 의해 치환되거나 비치환된 벤질을 나타내고,A is hydrogen; Straight or branched C 1 -C 10 alkyl unsubstituted or substituted by C 3 -C 7 cycloalkyl or lower alkoxy; Or benzyl unsubstituted or substituted by halogen, cyano, nitro, hydroxycarbonyl, aminocarbonyl, aminothiocarbonyl, lower alkoxy, phenoxy or lower alkyl,

B 는 수소; 또는 하이드록시, 머캅토, 저급알콕시, 저급알킬티오 또는 아릴에 의해 치환되거나 비치환된 저급알킬을 나타내며,B is hydrogen; Or lower alkyl unsubstituted or substituted by hydroxy, mercapto, lower alkoxy, lower alkylthio or aryl,

C 는 아릴에 의해 치환되거나 비치환된 저급알킬을 나타내거나; 하기 구조식의 그룹중 선택된 어느 하나를 나타내고,C represents lower alkyl unsubstituted or substituted by aryl; Any one selected from the group of structural formulas

,,, , , ,

, ,

여기에서 R1및 R2는 각각 독립적으로 수소, 저급알킬, 저급알콕시, 할로겐, 시아노, 하이드록시카보닐, 아미노카보닐, 아미노티오카보닐, 하이드록시, 페닐 또는 페녹시를 나타내며,Wherein R 1 and R 2 each independently represent hydrogen, lower alkyl, lower alkoxy, halogen, cyano, hydroxycarbonyl, aminocarbonyl, aminothiocarbonyl, hydroxy, phenyl or phenoxy,

D 는 아미노산 잔기 또는 아미노산 잔기의 저급알킬에스테르를 나타내거나; 하기 구조식의 그룹중 선택된 어느 하나를 나타내고,D represents an amino acid residue or lower alkyl ester of an amino acid residue; Any one selected from the group of structural formulas

,,,, , , , ,

, ,

여기에서From here

R3및 R4는 각각 독립적으로 수소; 할로겐; 하이드록시; 시아노; 저급알킬; 저급알콕시; 알콕시알킬; 알킬티오; 알킬설포닐; 알킬티오알킬; 알킬티오알킬옥시; 아릴; 또는 아릴에 의해 치환된 옥시, 티오, 설포닐 또는 저급알킬을 나타내며,R 3 and R 4 are each independently hydrogen; halogen; Hydroxy; Cyano; Lower alkyl; Lower alkoxy; Alkoxyalkyl; Alkylthio; Alkylsulfonyl; Alkylthioalkyl; Alkylthioalkyloxy; Aryl; Or oxy, thio, sulfonyl or lower alkyl substituted by aryl,

Y 는 O, S, SO2, C=O, C=S를 나타내거나, 저급알킬 또는 하이드록시에 의해 치환되거나 비치환된 CH2또는 NH 를 나타내고,Y represents O, S, SO 2 , C═O, C═S, or CH 2 or NH unsubstituted or substituted by lower alkyl or hydroxy,

n2는 1 내지 3 의 정수를 나타내며,n 2 represents an integer of 1 to 3,

R5및 R6은 각각 독립적으로 수소; 아릴; 아릴 또는 시아노아릴에 의해 치환되거나 비치환된 저급알킬; 또는을 나타내고, 여기에서 n3는 2 내지 4의 정수를 나타내며, Z 는 O, S 또는 SO2를 나타내고, R7은 수소 또는 저급알킬을 나타낸다.R 5 and R 6 are each independently hydrogen; Aryl; Lower alkyl unsubstituted or substituted by aryl or cyanoaryl; or Wherein n 3 represents an integer of 2 to 4, Z represents O, S or SO 2 , and R 7 represents hydrogen or lower alkyl.

상기 화학식 1의 화합물에 대한 치환기 정의에서 용어 저급알킬은 메틸, 에틸, 이소프로필, 이소부틸, t-부틸 등과 같은 탄소수 1 내지 4의 직쇄 또는 측쇄알킬을 의미한다.In the substituent definition for the compound of Formula 1, the term lower alkyl means straight or branched chain alkyl having 1 to 4 carbon atoms such as methyl, ethyl, isopropyl, isobutyl, t-butyl and the like.

본 발명에 따른 화합물은 비대칭탄소 중심을 가질 수 있으며, 따라서 R 또는 S 이성체, 라세미체, 또는 이들의 혼합물로 존재할 수 있다. 따라서, 본 발명의 범위에는 이들 각각의 이성체 및 이들의 혼합물이 포함된다.The compounds according to the invention may have asymmetric carbon centers and therefore may exist in R or S isomers, racemates, or mixtures thereof. Accordingly, the scope of the present invention includes each of these isomers and mixtures thereof.

우수한 항암효과를 나타내는 상기 화학식 1의 화합물중에서도 바람직한 화합물은Among the compounds of Formula 1, which show excellent anticancer effects, preferred compounds are

n1은 1 내지 3의 정수를 나타내고,n 1 represents an integer of 1 to 3,

X 는 O 또는 S를 나타내며,X represents O or S,

A 는 수소, C5-C6사이클로알킬 또는 저급알콕시에 의해 치환되거나 비치환된 직쇄 또는 측쇄의 C1-C10알킬, 4-브로보벤질, 또는 4-시아노벤질을 나타내고,A represents straight or branched C 1 -C 10 alkyl, 4-brobobenzyl, or 4-cyanobenzyl unsubstituted or substituted by hydrogen, C 5 -C 6 cycloalkyl or lower alkoxy,

B 는 수소, 저급알킬, 또는 벤질을 나타내며,B represents hydrogen, lower alkyl, or benzyl,

C 는 하기 구조식의 그룹중 선택된 어느 하나를 나타내고,C represents any one selected from the group of the following structural formulas,

,,, , , ,

여기에서 R1및 R2는 각각 독립적으로 수소 또는 저급알킬을 나타내며,Wherein R 1 and R 2 each independently represent hydrogen or lower alkyl,

D 는 메티오닌 또는 루신 잔기 또는 이들 아미노산 잔기의 저급알킬에스테르를 나타내거나; 하기 구조식의 그룹중 선택된 어느 하나를 나타내고,D represents a methionine or leucine residue or a lower alkylester of these amino acid residues; Any one selected from the group of structural formulas

,,,, , , , ,

여기에서From here

R3및 R4는 각각 독립적으로 수소; 할로겐; 시아노; 저급알킬; 저급알콕시; 알킬티오알킬; 알킬티오알킬옥시; 페닐; 또는 페닐에 의해 치환된 옥시 또는 저급알킬을 나타내며,R 3 and R 4 are each independently hydrogen; halogen; Cyano; Lower alkyl; Lower alkoxy; Alkylthioalkyl; Alkylthioalkyloxy; Phenyl; Or oxy or lower alkyl substituted by phenyl,

Y 는 O, S, SO2, C=O 를 나타내거나, 저급알킬 또는 하이드록시에 의해 치환되거나 비치환된 CH2또는 NH 를 나타내고,Y represents O, S, SO 2 , C═O, or CH 2 or NH unsubstituted or substituted by lower alkyl or hydroxy,

n2는 1 또는 2를 나타내며,n 2 represents 1 or 2,

R5및 R6은 각각 독립적으로 수소; 페닐; 페닐 또는 4-시아노페닐에 의해 치환되거나 비치환된 저급알킬; 또는 하이드록시 또는 저급알콕시에 의해 치환된 C2-C4직쇄알킬을 나타낸다.R 5 and R 6 are each independently hydrogen; Phenyl; Lower alkyl unsubstituted or substituted by phenyl or 4-cyanophenyl; Or C 2 -C 4 straight alkyl substituted by hydroxy or lower alkoxy.

본 발명에 따른 화학식 1 화합물의 대표적인 예는 하기 표 1a 내지 1i 에 나타낸 바와 같다.Representative examples of the compound of formula 1 according to the present invention are as shown in Tables 1a to 1i below.

화합물 번호Compound number 화합물 구조Compound structure 화합물 번호Compound number 화합물 구조Compound structure 1One 22 33 44 55 66 77 88 99 1010

1111 1212 1313 1414 1515 1616 1717 1818 1919 2020

2121 2222 2323 2424 2525 2626 2727 2828 2929 3030

3131 3232 3333 3434 3535 3636 3737 3838 3939 4040

4141 4242 4343 4444 4545 4646 4747 4848 4949 5050

5151 5252 5353 5454 5555 5656 5757 5858 5959 6060

6161 6262 6363 6464 6565 6666 6767 6868 6969 7070

7171 7272 7373 7474 7575 7676 7777 7878 7979 8080

8181 8282 8383 8484 8585

본 발명에 따른 화학식 1의 화합물은 (a) 하기 화학식 2의 화합물을 용매중에서 염기의 존재하에 하기 화학식 3의 화합물과 반응시킨 후 트리플루오로아세트산의 존재하에 트리틸 보호기를 제거하여 하기 화학식 1a의 화합물을 제조하거나; (b) 하기 화학식 4의 화합물을 용매중에서 염기의 존재하에 화학식 3의 화합물과 반응시켜 하기 화학식 1b의 화합물을 제조하거나; (c) 하기 화학식 5의 화합물을 용매중에서 염기의 존재하에 하기 화학식 3의 화합물과 반응시키고 트리플루오로아세트산의 존재하에 트리틸 보호기를 제거하여 하기 화학식 6의 화합물을 제조한 다음 수첨반응을 수행하여 하기 화학식 1c의 화합물을 제조하거나; (d) 하기 화학식 7의 화합물을 가수분해시켜 하기 화학식 8의 화합물을 제조한 다음, 이를 하기 화학식 9의 화합물과 커플링제의 존재하에 커플링시켜 하기 화학식 1d의 화합물을 제조하거나; (e) 하기 화학식 1e 화합물의 카보닐그룹을 황화제 존재하에 티오카보닐그룹으로 전환시켜 하기 화학식 1f의 화합물을 제조함을 특징으로하여 수득할 수 있으며, 이러한 화학식 1 화합물의 제조방법도 또한 본 발명의 목적이다.Compound (1) according to the present invention is (a) reacting a compound of formula (2) with a compound of formula (3) in the presence of a base in a solvent and then removing a trityl protecting group in the presence of trifluoroacetic acid To prepare a compound; (b) reacting a compound of formula 4 with a compound of formula 3 in the presence of a base in a solvent to prepare a compound of formula 1b; (c) reacting a compound of formula 5 with a compound of formula 3 in a solvent in the presence of a base and removing a trityl protecting group in the presence of trifluoroacetic acid to produce a compound of formula 6, followed by hydrogenation To prepare a compound of formula 1c; (d) hydrolyzing the compound of Formula 7 to prepare a compound of Formula 8, and then coupling the compound of Formula 9 with a compound of Formula 9 in the presence of a coupling agent to prepare a compound of Formula 1d; (e) converting a carbonyl group of a compound of formula 1e to a thiocarbonyl group in the presence of a sulfiding agent to obtain a compound of formula 1f, which is also obtained. It is an object of the invention.

그러나, 본 발명에 따른 화합물의 제조방법이 하기에 설명하는 것으로만 한정되는 것은 아니며, 본 명세서에 기재되거나 선행문헌에 개시된 여러 가지 합성방법을 임의로 조합함으로써 용이하게 제조할 수 있고, 이러한 조합은 본 발명이 속하는 기술 분야의 당업자에게 범용화된 통상의 기술이다.However, the preparation method of the compound according to the present invention is not limited to the following description, and can be easily prepared by arbitrarily combining various synthesis methods described in this specification or disclosed in the prior literature, and such combinations are It is a common technique generalized to those skilled in the art to which the invention belongs.

상기식에서In the above formula

A, n1, B, C, D, R5, R6는 앞에서 정의한 바와 같고,A, n 1 , B, C, D, R 5 , R 6 are as defined above,

A' 는 A 와 동일하나, 단 수소는 제외되며,A 'is the same as A, except hydrogen

Tr 은 트리틸을 나타낸다.Tr represents trityl.

상기 본 발명에 따른 방법에서 화학식 1d의 화합물을 제조하는데 중간체로 사용된 화학식 8의 화합물은 그 자체로 신규한 화합물이므로, 본 발명은 또한 화학식 8의 중간체 화합물을 제공함도 목적으로 한다.The compounds of formula (8) used as intermediates in the preparation of the compounds of formula (1d) in the process according to the invention are themselves novel compounds, and the present invention also aims to provide intermediate compounds of formula (8).

본 발명에 따른 화학식 1의 화합물을 제조하는 상기 방법 (a) 내지 (e)에서 용매로는 반응에 불활성인 용매중 어느 것이라도 사용할 수 있으나, 바람직하게는 디메틸포름아미드, 디메틸아세트아미드, 에탄올, 물, 메틸렌클로라이드, 테트라하이드로푸란 및 N-메틸피롤리디논 중에서 선택된 1 종 이상을 사용한다. 염기로는 수소화나트륨, 수산화칼륨, 탄산칼륨, 포타슘 t-부톡사이드, 소듐비스(트리메틸실릴)아미드 및 포타슘비스(트리메틸실릴)아미드 중에서 선택된 1 종 이상을 사용할 수 있고, 특히 바람직하게는 수소화나트륨 또는 수산화칼륨을 사용한다.In the above methods (a) to (e) of preparing the compound of formula 1 according to the present invention, any solvent which is inert to the reaction may be used. Preferably, dimethylformamide, dimethylacetamide, ethanol, At least one selected from water, methylene chloride, tetrahydrofuran and N-methylpyrrolidinone is used. The base may be one or more selected from sodium hydride, potassium hydroxide, potassium carbonate, potassium t-butoxide, sodium bis (trimethylsilyl) amide and potassium bis (trimethylsilyl) amide, and particularly preferably sodium hydride or Potassium hydroxide is used.

화학식 8 화합물과 화학식 9 화합물의 반응에서 커플링제로는 디사이클로헥실카르보디이미드(DCC), 1-에틸-3-(3-디메틸아미노프로필)카르보디이미드(EDC)등의 카르보디이미드류와 실리콘 테트라클로라이드 등의 무기탈수제 중에서 선택된 1 종 이상을 1-하이드록시벤조트리아졸과 혼합된 상태로 사용할 수 있다. 특히 바람직하게는 1-(3-디메틸아미노프로필)-3-에틸카보디이미드 하이드로클로라이드(EDC) 및 1-하이드록시벤조트리아졸 수화물의 존재하에 반응시킨다.In the reaction between the compound of Formula 8 and compound of Formula 9, as coupling agent, carbodiimide such as dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC) One or more selected from inorganic dehydrating agents such as silicon tetrachloride can be used in a mixed state with 1-hydroxybenzotriazole. Particular preference is given to reacting in the presence of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and 1-hydroxybenzotriazole hydrate.

화학식 1e의 화합물로부터 화학식 1f의 화합물을 제조하는데 사용할 수 있는 황화제로는 2,4-비스(페닐티오)-1,3-디티아-2,4-디포스파탄-2,4-디설파이드, 로웨슨 시약(Lawesson's Reagent) 또는 P4S10을 들 수 있으며, 이중에서도 2,4-비스(페닐티오)-1,3-디티아-2,4-디포스파탄-2,4-디설파이드를 가장 바람직하게 사용한다.Sulfurizing agents that can be used to prepare the compound of formula 1f from the compound of formula 1e include 2,4-bis (phenylthio) -1,3-dithia-2,4-diphosphatane-2,4-disulfide, Wesson's Reagent or P 4 S 10 , including 2,4-bis (phenylthio) -1,3-dithia-2,4-diphosphatane-2,4-disulfide. It is preferably used.

본 발명에 따른 방법에서 출발물질로 사용된 화합물들은 하기 반응식 1 내지 4 에 도시된 방법에 따라 제조할 수 있다.Compounds used as starting materials in the process according to the invention can be prepared according to the methods shown in Schemes 1-4.

먼저, 화학식 2의 화합물은 하기 반응식 1에 나타낸 바와 같이 보호기화 반응 및 할로겐화 반응을 거쳐 제조할 수 있다.First, the compound of Formula 2 may be prepared through a protecting group reaction and a halogenation reaction as shown in Scheme 1 below.

화학식 4의 화합물에서 A'가 4-시아노벤질인 화합물은 하기 반응식 2a에 도시한 바에 따라 보호기화, 아세틸화, 커플링, 탈보호기화 및 할로겐화 반응을 거쳐 합성할 수 있으며, A' 가 C3-C7사이클로알킬 또는 저급알콕시에 의해 치환되거나 비치환된 직쇄 또는 측쇄의 C1-C10알킬을 나타내거나, 할로겐에 의해 치환되거나 비치환된 벤질을 나타내는 화합물은 하기 반응식 2b에 도시한 바에 따라 폐환, 탈황 및 할로겐화 반응을 거쳐 합성할 수 있다.In the compound of Formula 4, A 'is 4-cyanobenzyl, and the compound may be synthesized through protecting group, acetylation, coupling, deprotection group and halogenation reaction as shown in Scheme 2a, wherein A' is C Compounds representing straight or branched C 1 -C 10 alkyl unsubstituted or substituted by 3 -C 7 cycloalkyl or lower alkoxy, or benzyl unsubstituted or substituted by halogen, are shown in Scheme 2b below. Therefore, it can be synthesized through ring closure, desulfurization and halogenation.

상기 반응식 2b에서In Scheme 2b

A 는 C3-C7사이클로알킬 또는 저급알콕시에 의해 치환되거나 비치환된 직쇄 또는 측쇄의 C1-C10알킬을 나타내거나, 할로겐에 의해 치환되거나 비치환된 벤질을 나타낸다.A represents straight or branched C 1 -C 10 alkyl unsubstituted or substituted by C 3 -C 7 cycloalkyl or lower alkoxy, or benzyl unsubstituted or substituted by halogen.

화학식 5의 화합물은 하기 반응식 3에 도시한 바에 따라 에스테르화, 보호기화, 환원 및 할로겐화 반응을 거쳐 합성할 수 있다.The compound of Formula 5 may be synthesized through esterification, protecting group, reduction and halogenation reaction as shown in Scheme 3 below.

상기 반응식 3에서In Scheme 3 above

DIBAL 은 디이소부틸알루미늄하이드리드를 나타낸다.DIBAL stands for diisobutylaluminum hydride.

한편, 화학식 3의 화합물은 1-나프탈데히드로부터 하기 반응식 4a 또는 4b 에 도시한 방법에 따라 합성할 수 있다.Meanwhile, the compound of Formula 3 may be synthesized according to the method shown in Scheme 4a or 4b below from 1-naphthaldehydro.

상기 반응식 4a 및 4b에서In Schemes 4a and 4b

Ar 은 페닐, 피롤, 티에닐, 나프틸 등의 방향족 그룹을 나타내고,Ar represents an aromatic group such as phenyl, pyrrole, thienyl, naphthyl,

TosMIC 는 토실메틸이소시아나이드를 나타낸다.TosMIC stands for tosylmethyl isocyanide.

또한, 화학식 7의 화합물은 상기 반응식 4b에 나타낸 방법과 반응식 2a 및 2b에 나타낸 방법을 적절히 주합함으로써 용이하게 제조할 수 있다.In addition, the compound of formula (7) can be easily prepared by appropriately combining the method shown in Scheme 4b and the method shown in Schemes 2a and 2b.

본 발명, 특히 상기 설명한 제조방법들을 하기 제조예, 실시예 및 실험예에 의거하여 보다 구체적으로 설명한다. 그러나, 이들 제조예, 실시예 및 실험예는 본 발명에 대한 이해를 돕기위한 것일 뿐, 어떤 의미로든 본 발명의 범위가 이들에 의해 한정되는 것은 아니다.The present invention, in particular the production methods described above will be described in more detail based on the following Preparation Examples, Examples and Experimental Examples. However, these preparation examples, examples and experimental examples are only intended to help the understanding of the present invention, and the scope of the present invention in any sense is not limited thereto.

제조예 1: 4-클로로메틸-1-트리틸-1H-이미다졸 하이드로클로라이드의 합성Preparation Example 1 Synthesis of 4-chloromethyl-1-trityl-1H-imidazole hydrochloride

1-1) 4-하이드록시메틸-1-트리틸-1H-이미다졸의 제조1-1) Preparation of 4-hydroxymethyl-1-trityl-1H-imidazole

하이드록시메틸이미다졸 하이드로클로라이드 3.99g(29.6 밀리몰)을 디메틸포름아미드 30㎖와 트리에틸아민 10㎖의 혼합물에 녹인 후, 여기에 트리페닐메틸 클로라이드 9.35g(33.5 밀리몰)을 디메틸포름아미드 110㎖에 용해시킨 용액을 서서히 가하였다. 2시간 후, 반응액에 얼음물 500㎖를 가하고, 생성된 고체를 수득하였다. 이 고체를 디옥산으로 재결정하여 표제화합물 8.82g(수율 87%)을 수득하였다.3.99 g (29.6 mmol) of hydroxymethylimidazole hydrochloride was dissolved in a mixture of 30 ml of dimethylformamide and 10 ml of triethylamine, and then 9.35 g (33.5 mmol) of triphenylmethyl chloride was added to 110 ml of dimethylformamide. The solution dissolved in was slowly added. After 2 hours, 500 ml of ice water was added to the reaction solution, and the resulting solid was obtained. This solid was recrystallized from dioxane to give 8.82 g (87% yield) of the title compound.

융점: 227-229℃Melting Point: 227-229 ℃

1-2) 4-클로로메틸-1-트리틸-1H-이미다졸 하이드로클로라이드의 제조1-2) Preparation of 4-chloromethyl-1-trityl-1H-imidazole hydrochloride

제조예 1-1)에서 수득한 화합물 1.50g(4.41 밀리몰)을 클로로포름 50㎖에 녹인 다음, 0℃에서 티오닐클로라이드 0.94㎖(13.2 밀리몰)을 서서히 가하고 상온에서 2 시간동안 교반하였다. 감압하에 유기용매를 제거하여 표제화합물 1.66g(4.20 밀리몰, 수율 95%)을 수득하였으며, 이 화합물은 정제하지 않고 바로 다음 반응에 사용하였다.1.50 g (4.41 mmol) of the compound obtained in Preparation Example 1-1) was dissolved in 50 mL of chloroform, and then 0.94 mL (13.2 mmol) of thionyl chloride was slowly added at 0 ° C. and stirred at room temperature for 2 hours. The organic solvent was removed under reduced pressure to yield 1.66 g (4.20 mmol, 95% yield) of the title compound which was used for the next reaction without purification.

제조예 2: 4-(5-클로로메틸-1H-이미다졸-1-일메틸)벤조니트릴 하이드로클로라이드의 합성Preparation Example 2 Synthesis of 4- (5-chloromethyl-1H-imidazol-1-ylmethyl) benzonitrile Hydrochloride

2-1) (4-아세톡시메틸-1-트리틸)이미다졸의 제조2-1) Preparation of (4-acetoxymethyl-1-trityl) imidazole

피리딘 100㎖에 제조예 1-1)에서 수득한 화합물 5.00g(14.7 밀리몰)을 가하고 아세트산무수물 1.65g(16.2 밀리몰)을 가한 다음, 상온에서 24 시간동안 교반하였다. 반응액을 감압증류하여 피리딘을 제거하고 잔류물을 에틸아세테이트 200㎖에 녹인 다음, 소금물 100㎖로 세척해주었다. 유기용매를 감압증류하여 제거한 후, 칼럼 크로마토그래피(용리제: 디클로로메탄/메탄올=20/1, v/v)를 실시하여 표제화합물 5.22g(13.7 밀리몰, 수율 93%)을 수득하였다.To 100 ml of pyridine was added 5.00 g (14.7 mmol) of the compound obtained in Preparation Example 1-1, 1.65 g (16.2 mmol) of acetic anhydride was added thereto, followed by stirring at room temperature for 24 hours. The reaction solution was distilled under reduced pressure to remove pyridine, and the residue was dissolved in 200 ml of ethyl acetate and washed with 100 ml of brine. After distilling off the organic solvent under reduced pressure, column chromatography (eluent: dichloromethane / methanol = 20/1, v / v) was carried out to obtain 5.22 g (13.7 mmol, 93% yield) of the title compound.

1H NMR(CDCl3) δ 2.01(s, 3H), 4.95(s, 2H), 6.88(s, 1H), 7.08(s, 5H), 7.27(s, 10H), 7.45 (s, 1H). 1 H NMR (CDCl 3 ) δ 2.01 (s, 3H), 4.95 (s, 2H), 6.88 (s, 1H), 7.08 (s, 5H), 7.27 (s, 10H), 7.45 (s, 1H).

2-2) 4-(4-아세톡시메틸-1-트리틸-1H-이미다졸-3-일메틸)벤조니트릴 브로마이드의 제조2-2) Preparation of 4- (4-acetoxymethyl-1-trityl-1H-imidazol-3-ylmethyl) benzonitrile bromide

제조예 2-1)에서 수득한 화합물 5.00g(13.1 밀리몰)을 디클로로메탄 20㎖에 녹이고, 4-시아노벤질브로마이드 2.82g(14.4 밀리몰)을 가한 다음, 상온에서 60 시간동안 교반하였다. 유기용매를 감압증류하여 제거하고 잔류물에 대해 칼럼 크로마토그래피(용리제: 디클로로메탄/메탄올=5/1, v/v)를 실시하여 표제화합물 5.31g (9.17 밀리몰, 수율 70%)을 수득하였다.5.00 g (13.1 mmol) of the compound obtained in Preparation Example 2-1) was dissolved in 20 ml of dichloromethane, and 2.82 g (14.4 mmol) of 4-cyanobenzylbromide was added thereto, followed by stirring at room temperature for 60 hours. The organic solvent was removed by distillation under reduced pressure and the residue was subjected to column chromatography (eluent: dichloromethane / methanol = 5/1, v / v) to give 5.31 g (9.17 mmol, 70% yield) of the title compound. .

1H NMR(CDCl3+ CD3OD) δ 1.95(s, 3H), 4.95(s, 2H), 5.45(s, 2H), 7.11- 7.40(m, 18H), 7.65(d, 2H), 8.21(s, 1H). 1 H NMR (CDCl 3 + CD 3 OD) δ 1.95 (s, 3H), 4.95 (s, 2H), 5.45 (s, 2H), 7.11- 7.40 (m, 18H), 7.65 (d, 2H), 8.21 (s, 1 H).

2-3) 4-(5-아세톡시메틸-1H-이미다졸-1-일메틸)벤조니트릴의 제조2-3) Preparation of 4- (5-acetoxymethyl-1H-imidazol-1-ylmethyl) benzonitrile

제조예 2-2)에서 수득한 화합물 9.10g(15.7 밀리몰)을 디클로로메탄 500㎖에 녹인 후, 0℃에서 트리플루오로아세트산 6.06㎖(78.7 밀리몰) 및 트리에틸실란 12.5㎖(78.7 밀리몰)를 서서히 가하고 상온에서 1시간동안 교반하였다. 유기용매를 감압증류하여 제거하고, K2CO3포화 수용액으로 pH를 10으로 맞춘 다음, 에틸아세테이트 300㎖로 추출하였다. 유기용매를 감압증류하여 제거하고 잔류물에 대해 에틸아세테이트를 용리제로 하는 칼럼 크로마토그래피를 실시하여 표제화합물 3.60 g(14.1 밀리몰, 수율 90%)을 수득하였다.9.10 g (15.7 mmol) of the compound obtained in Preparation Example 2-2) was dissolved in 500 ml of dichloromethane, and then 6.06 ml (78.7 mmol) of trifluoroacetic acid and 12.5 ml (78.7 mmol) of triethylsilane were slowly added at 0 ° C. It was added and stirred at room temperature for 1 hour. The organic solvent was removed by distillation under reduced pressure, the pH was adjusted to 10 with a saturated aqueous K 2 CO 3 solution, and extracted with 300 ml of ethyl acetate. The organic solvent was removed by distillation under reduced pressure, and the residue was subjected to column chromatography using ethyl acetate as an eluent to obtain 3.60 g (14.1 mmol, 90% yield) of the title compound.

1H NMR(CDCl3) δ 1.90(s, 3H), 4.97(s, 2H), 5.25(s, 2H), 7.14(d, 2H), 7.21(d, 1H), 7.67(s, 1H), 7.75(d, 2H) 1 H NMR (CDCl 3 ) δ 1.90 (s, 3H), 4.97 (s, 2H), 5.25 (s, 2H), 7.14 (d, 2H), 7.21 (d, 1H), 7.67 (s, 1H), 7.75 (d, 2 H)

2-4) 4-(5-하이드록시메틸-1H-이미다졸-1-일메틸)벤조니트릴의 제조2-4) Preparation of 4- (5-hydroxymethyl-1H-imidazol-1-ylmethyl) benzonitrile

제조예 2-3)에서 수득한 화합물 4.20g(16.5 밀리몰)을 메탄올 200㎖에 녹인 후, K2CO34.50g(32.9 밀리몰)을 가한 다음, 상온에서 20분동안 교반하였다. 유기 용매를 감압증류하여 제거하고 에틸아세테이트 300㎖로 추출한 다음, 칼럼 크로마토그래피(용리제: 디클로로메탄/메탄올=10/1, v/v)를 수행하여 표제화합물 3.19g (15.0 밀리몰, 수율 91%)을 수득하였다.4.20 g (16.5 mmol) of the compound obtained in Preparation Example 2-3) was dissolved in 200 ml of methanol, and then 4.50 g (32.9 mmol) of K 2 CO 3 was added thereto, followed by stirring at room temperature for 20 minutes. The organic solvent was removed by distillation under reduced pressure, extracted with 300 ml of ethyl acetate, and then subjected to column chromatography (eluent: dichloromethane / methanol = 10/1, v / v) to give 3.19 g (15.0 mmol, 91% yield) of the title compound. ) Was obtained.

1H NMR(CDCl3+ CD3OD) δ 4.28(s, 2H), 5.18(s, 2H), 6.84(s, 1H), 7.12(d, 2H), 7.42(s, 1H), 7.55(d, 2H) 1 H NMR (CDCl 3 + CD 3 OD) δ 4.28 (s, 2H), 5.18 (s, 2H), 6.84 (s, 1H), 7.12 (d, 2H), 7.42 (s, 1H), 7.55 (d , 2H)

2-5) 4-(5-클로로메틸-1H-이미다졸-1-일메틸)벤조니트릴 하이드로클로라이드의 제조2-5) Preparation of 4- (5-chloromethyl-1H-imidazol-1-ylmethyl) benzonitrile hydrochloride

제조예 2-4)에서 수득한 화합물 3.00g(14.1 밀리몰)을 클로로포름 40㎖에 녹인 후, 0℃에서 티오닐클로라이드 5.02㎖(70.5 밀리몰)를 서서히 가하고 상온에서 2시간동안 교반하였다. 유기용매를 감압하에 제거하여 표제화합물 3.50g(13.1 밀리몰, 수율 93%)을 수득하였다. 이 화합물은 정제하지 않고 바로 반응에 사용하였다.3.00 g (14.1 mmol) of the compound obtained in Preparation Example 2-4) was dissolved in 40 mL of chloroform, and then 5.02 mL (70.5 mmol) of thionyl chloride was slowly added at 0 ° C., and stirred at room temperature for 2 hours. The organic solvent was removed under reduced pressure to yield 3.50 g (13.1 mmol, yield 93%) of the title compound. This compound was used directly in the reaction without purification.

제조예 3: 4-(3-클로로-1-프로페닐)-1-트리틸-1H-이미다졸의 합성Preparation Example 3 Synthesis of 4- (3-chloro-1-propenyl) -1-trityl-1H-imidazole

3-1) 메틸 3-(1H-이미다졸-4-일)아크릴레이트의 제조3-1) Preparation of methyl 3- (1H-imidazol-4-yl) acrylate

3-(1H-이미다졸-4-일)아크릴산 500mg(3.62 밀리몰)을 메탄올릭 HCl 20㎖에 가하고 10시간동안 상온에서 교반하였다. 감압하에 용매를 제거하고 디클로로메탄 30㎖를 가한 다음, NaHCO3포화 수용액, 소금물, 물로 차례로 세척해주었다. 유기층을 무수 마그네슘설페이트로 건조시키고 농축시켜 표제화합물 510mg(3.35 밀리몰, 수율 93%)을 수득하였다. 이 화합물은 정제하지 않고 다음 반응에 사용하였다.500 mg (3.62 mmol) of 3- (1H-imidazol-4-yl) acrylic acid were added to 20 ml of methanolic HCl and stirred at room temperature for 10 hours. The solvent was removed under reduced pressure, and 30 ml of dichloromethane was added, followed by washing with saturated aqueous NaHCO 3 solution, brine and water. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give 510 mg (3.35 mmol, 93% yield) of the title compound. This compound was used in the next reaction without purification.

3-2) 메틸 3-(1-트리틸-1H-이미다졸-4-일)아크릴레이트3-2) Methyl 3- (1-trityl-1H-imidazol-4-yl) acrylate

제조예 3-1)에서 수득한 화합물 350mg(2.30 밀리몰)과 트리페닐메틸클로라이드 705mg(2.53 밀리몰)을 디메틸포름아미드 10㎖에 녹인 후 트리에틸아민 350㎕ (2.53 밀리몰)를 첨가하였다. 2시간 후에 얼음물 100㎖를 가하고 생성된 고체를 여과한 다음, 디에틸에테르, 헥산으로 세척하고 건조시켜 표제화합물 810mg(2.05 밀리몰, 수율 87%)을 수득하였다.350 mg (2.30 mmol) of the compound obtained in Preparation Example 3-1) and 705 mg (2.53 mmol) of triphenylmethyl chloride were dissolved in 10 ml of dimethylformamide, and 350 µl (2.53 mmol) of triethylamine was added thereto. After 2 hours, 100 ml of ice water was added, and the resulting solid was filtered, washed with diethyl ether, hexane and dried to give 810 mg (2.05 mmol, 87% yield) of the title compound.

1H NMR(CDCl3) δ 3.75(s, 3H), 6.35(d, 1H), 7.05-7.50(m, 18H) 1 H NMR (CDCl 3 ) δ 3.75 (s, 3H), 6.35 (d, 1H), 7.05-7.50 (m, 18H)

3-3) 1-(1-트리틸-1H-이미다졸-4-일)프로펜-3-올의 제조3-3) Preparation of 1- (1-trityl-1H-imidazol-4-yl) propen-3-ol

제조예 3-2)에서 수득한 화합물 800mg(2.03 밀리몰)을 무수 디클로로메탄 20㎖에 가하고 -78℃로 냉각시킨 후 디이소부틸알루미늄하이드라이드 6.1㎖(1M 헥산 용액)를 첨가하였다. 온도를 천천히 상온으로 올리고 물 2㎖를 가하여 반응을 중지시켰다. 1N NaOH 3㎖를 첨가하고 다시 물 2㎖를 가한 후 셀라이트를 통해 여과하였다. 여액의 유기층을 분리하고 물층을 디클로로메탄으로 추출하여 합한 후 무수 마그네슘설페이트로 건조시켰다. 감압하에 유기용매를 제거하고 잔류물에 대해 칼럼 크로마토그래피(용리제: 디클로로메탄/메탄올=20/1, v/v)를 수행하여 표제화합물 671mg(1.83 밀리몰, 수율 90%)을 수득하였다.800 mg (2.03 mmol) of the compound obtained in Preparation Example 3-2) were added to 20 ml of anhydrous dichloromethane, cooled to −78 ° C., and 6.1 ml (1M hexane solution) of diisobutyl aluminum hydride was added thereto. The temperature was slowly raised to room temperature and 2 ml of water was added to stop the reaction. 3 ml of 1N NaOH was added, followed by 2 ml of water, followed by filtration through celite. The organic layer of the filtrate was separated, the water layer was extracted with dichloromethane, combined and dried over anhydrous magnesium sulfate. The organic solvent was removed under reduced pressure and column chromatography (eluent: dichloromethane / methanol = 20/1, v / v) was performed on the residue to give 671 mg (1.83 mmol, 90% yield) of the title compound.

1H NMR(CDCl3) δ 4.25(s, 2H), 6.45(s, 2H), 6.78(s, 1H), 7.10-7.50(m, 16H) 1 H NMR (CDCl 3 ) δ 4.25 (s, 2H), 6.45 (s, 2H), 6.78 (s, 1H), 7.10-7.50 (m, 16H)

3-4) 4-(3-클로로프로페닐)-1-트리틸-1H-이미다졸의 제조3-4) Preparation of 4- (3-chloropropenyl) -1-trityl-1H-imidazole

제조예 3-3)에서 수득한 화합물 650mg(1.77 밀리몰)을 클로로포름 10㎖에 가하고 0℃에서 티오닐클로라이드 135㎕(1.9 밀리몰)를 가한 다음 상온에서 2시간 동안 교반하였다. 유기용매를 감압증류하여 제거하고, 잔류물을 에틸아세테이트 10 ㎖에 녹였다. NaHCO3포화 수용액으로 세척해준 다음 유기용매를 감압증류하여 표제화합물 647mg(1.68 밀리몰, 수율 95%)을 수득하였다.650 mg (1.77 mmol) of the compound obtained in Preparation Example 3-3) were added to 10 ml of chloroform, and 135 µl (1.9 mmol) of thionyl chloride was added at 0 ° C., followed by stirring at room temperature for 2 hours. The organic solvent was removed by distillation under reduced pressure, and the residue was dissolved in 10 ml of ethyl acetate. After washing with saturated aqueous NaHCO 3 solution, the organic solvent was distilled under reduced pressure to obtain 647 mg (1.68 mmol, yield 95%) of the title compound.

1H NMR(CDCl3) δ 4.22(d, 2H), 6.40-6.55(m, 2H), 6.81(s, 1H), 7.10-7.50 (m, 16H) 1 H NMR (CDCl 3 ) δ 4.22 (d, 2H), 6.40-6.55 (m, 2H), 6.81 (s, 1H), 7.10-7.50 (m, 16H)

제조예 4: 5-클로로메틸-1-메틸이미다졸 하이드로클로라이드의 합성Preparation Example 4 Synthesis of 5-Chloromethyl-1-methylimidazole Hydrochloride

4-1) 5-하이드록시메틸-1-메틸이미다졸의 제조4-1) Preparation of 5-hydroxymethyl-1-methylimidazole

디하이드록시아세톤과 메틸아민 하이드로클로라이드를 출발물질로하여 문헌(참조: J.M.Dener, L-H Zhang, H. Rapoport,J. Org. Chem., 1993, 58, 1159)에 기재된 방법대로 실시하여 32% 수율로 표제화합물을 수득하였다.Starting with dihydroxyacetone and methylamine hydrochloride as starting materials (JMDener, LH Zhang, H. Rapoport, J. Org. Chem. , 1993, 58, 1159) in 32% yield The title compound was obtained.

1H NMR(CDCl3) δ 3.67(s, 3H), 4.58(s, 2H), 5.37(brs, 1H), 6.76(s, 1H), 7.32(s, 1H) 1 H NMR (CDCl 3 ) δ 3.67 (s, 3H), 4.58 (s, 2H), 5.37 (brs, 1H), 6.76 (s, 1H), 7.32 (s, 1H)

4-2) 5-클로로메틸-1-메틸이미다졸 하이드로클로라이드의 제조4-2) Preparation of 5-chloromethyl-1-methylimidazole hydrochloride

제조예 4-1)에서 수득한 화합물을 출발물질로 사용하는 점을 제외하고는 제조예 1-2)에서와 유사하게 실시하여 95% 수율로 표제화합물을 수득하였다.Except for using the compound obtained in Preparation Example 4-1) as a starting material, the title compound was obtained in the 95% yield in the same manner as in Preparation Example 1-2).

제조예 5: 1-(4-브로모벤질)-5-클로로메틸이미다졸 하이드로클로라이드 의 합성Preparation Example 5 Synthesis of 1- (4-bromobenzyl) -5-chloromethylimidazole hydrochloride

5-1) 1-(4-브로모벤질)-5-하이드록시메틸이미다졸의 제조5-1) Preparation of 1- (4-bromobenzyl) -5-hydroxymethylimidazole

디하이드록시아세톤과 4-브로모벤질아민 하이드로클로라이드를 출발물질로하여 제조예 4-1)에서와 유사한 반응을 수행함으로써 50% 수율로 표제화합물을 수득하였다.The title compound was obtained in 50% yield by carrying out a similar reaction as in Preparation Example 4-1) using dihydroxyacetone and 4-bromobenzylamine hydrochloride as starting materials.

1H NMR(CDCl3+CD3OD) δ 4.46(s, 2H), 5.26(s, 2H), 7.00(s, 1H), 7.07(d, 2H), 7.50(d, 2H), 7.65(s, 1H) 1 H NMR (CDCl 3 + CD 3 OD) δ 4.46 (s, 2H), 5.26 (s, 2H), 7.00 (s, 1H), 7.07 (d, 2H), 7.50 (d, 2H), 7.65 (s , 1H)

5-2) 1-(4-브로모벤질)-5-클로로메틸이미다졸 하이드로클로라이드의 제조5-2) Preparation of 1- (4-bromobenzyl) -5-chloromethylimidazole hydrochloride

제조예 5-1)에서 수득한 화합물을 출발물질로 사용하는 점을 제외하고는 제조예 1-2)에서와 유사하게 실시하여 96% 수율로 표제화합물을 수득하였다. 이 화합물을 정제하지 않고 바로 다음 반응에 사용하였다.Except for using the compound obtained in Preparation Example 5-1) as a starting material, to give the title compound in 96% yield in the same manner as in Preparation Example 1-2). This compound was used directly in the next reaction without purification.

제조예 6: 5-클로로메틸-1-이소부틸이미다졸 하이드로클로라이드의 합성Preparation Example 6 Synthesis of 5-chloromethyl-1-isobutylimidazole hydrochloride

6-1) 5-하이드록시메틸-1-이소부틸이미다졸의 제조6-1) Preparation of 5-hydroxymethyl-1-isobutylimidazole

디하이드록시아세톤과 이소부틸아민 하이드로클로라이드를 출발물질로하여 제조예 4-1)에서와 유사한 반응을 수행함으로써 45%의 수율로 표제화합물을 수득하였다.The title compound was obtained in a yield of 45% by carrying out a similar reaction as in Preparation Example 4-1) using dihydroxyacetone and isobutylamine hydrochloride as starting materials.

1H NMR(CDCl3) δ 0.90(d, 6H), 1.76(m, 1H), 3.62(d, 2H), 4.24(brs, 1H), 4.60(s, 2H), 6.85(s, 1H), 7.45(s, 1H) 1 H NMR (CDCl 3 ) δ 0.90 (d, 6H), 1.76 (m, 1H), 3.62 (d, 2H), 4.24 (brs, 1H), 4.60 (s, 2H), 6.85 (s, 1H), 7.45 (s, 1 H)

FAB (M+H): 155FAB (M + H): 155

6-2) 5-클로로메틸-1-이소부틸이미다졸 하이드로클로라이드의 제조6-2) Preparation of 5-chloromethyl-1-isobutylimidazole hydrochloride

제조예 6-1)에서 수득한 화합물을 출발물질로 사용하는 점을 제외하고는 제조예 1-2)에서와 유사하게 실시하여 95% 수율로 표제화합물을 수득하였다.Except for using the compound obtained in Preparation Example 6-1) as a starting material, the title compound was obtained in the same manner as in Preparation Example 1-2) in 95% yield.

제조예 7: 5-클로로메틸-1-사이클로헥실메틸이미다졸 하이드로클로라이드의 합성Preparation Example 7 Synthesis of 5-chloromethyl-1-cyclohexylmethylimidazole hydrochloride

7-1) 5-하이드록시메틸-1-사이클로헥실메틸이미다졸의 제조7-1) Preparation of 5-hydroxymethyl-1-cyclohexylmethylimidazole

디하이드록시아세톤과 사이클로헥실메틸아민 하이드로클로라이드를 출발물질로하여 제조예 4-1)에서와 유사한 반응을 수행함으로써 45% 수율로 표제화합물을 수득하였다.The title compound was obtained in 45% yield by carrying out a similar reaction as in Preparation Example 4-1) using dihydroxyacetone and cyclohexylmethylamine hydrochloride as starting materials.

1H NMR(CDCl3) δ 0.94(m, 2H), 1.16(m, 3H), 1.50-1.70(m, 6H), 3.65(d, 2H), 4.24(brs, 1H), 4.60(s, 2H), 6.85(s, 1H), 7.45(s, 1H) 1 H NMR (CDCl 3 ) δ 0.94 (m, 2H), 1.16 (m, 3H), 1.50-1.70 (m, 6H), 3.65 (d, 2H), 4.24 (brs, 1H), 4.60 (s, 2H ), 6.85 (s, 1 H), 7.45 (s, 1 H)

FAB (M+H): 195FAB (M + H): 195

7-2) 5-클로로메틸-1-사이클로헥실메틸이미다졸 하이드로클로라이드의 제조7-2) Preparation of 5-chloromethyl-1-cyclohexylmethylimidazole hydrochloride

제조예 7-1)에서 수득한 화합물을 출발물질로 사용하는 점을 제외하고는 제조예 1-2)에서와 유사하게 실시하여 95% 수율로 표제화합물을 수득하였다.The title compound was obtained in 95% yield in the same manner as in Preparation Example 1-2) except that the compound obtained in Preparation Example 7-1) was used as a starting material.

제조예 8: 5-클로로메틸-1-펜틸이미다졸 하이드로클로라이드의 합성Preparation Example 8 Synthesis of 5-chloromethyl-1-pentylimidazole hydrochloride

8-1) 5-하이드록시메틸-1-펜틸이미다졸의 제조8-1) Preparation of 5-hydroxymethyl-1-pentylimidazole

디하이드록시아세톤과 펜틸아민 하이드로클로라이드를 출발물질로하여 제조예 4-1)에서와 유사한 반응을 수행함으로써 50% 수율로 표제화합물을 수득하였다.The title compound was obtained in 50% yield by carrying out a similar reaction as in Preparation Example 4-1) using dihydroxyacetone and pentylamine hydrochloride as starting materials.

1H NMR(CDCl3) δ 0.90(t, 3H), 1.08(brs, 2H), 1.30(m, 4H), 1.45(m, 2H), 3.64(t, 2H), 4.24(brs, 1H), 4.60(s, 2H), 6.84(s, 1H), 7.44(s, 1H) 1 H NMR (CDCl 3 ) δ 0.90 (t, 3H), 1.08 (brs, 2H), 1.30 (m, 4H), 1.45 (m, 2H), 3.64 (t, 2H), 4.24 (brs, 1H), 4.60 (s, 2H), 6.84 (s, 1H), 7.44 (s, 1H)

FAB (M+H): 169FAB (M + H): 169

8-2) 5-클로로메틸-1-펜틸이미다졸 하이드로클로라이드의 제조8-2) Preparation of 5-chloromethyl-1-pentylimidazole hydrochloride

제조예 8-1)에서 수득한 화합물을 출발물질로 사용하는 점을 제외하고는 제조예 1-2)에서와 유사하게 실시하여 90% 수율로 표제화합물을 수득하였다.Except for using the compound obtained in Preparation Example 8-1) as a starting material, to give the title compound in 90% yield in the same manner as in Preparation Example 1-2).

제조예 9: 5-클로로메틸-1-옥틸이미다졸 하이드로클로라이드의 합성Preparation Example 9 Synthesis of 5-chloromethyl-1-octylimidazole hydrochloride

9-1) 5-하이드록시메틸-1-옥틸이미다졸의 제조9-1) Preparation of 5-hydroxymethyl-1-octylimidazole

디하이드록시아세톤과 옥틸아민 하이드로클로라이드를 출발물질로하여 제조예 4-1)에서와 유사한 반응을 수행함으로써 52% 수율로 표제화합물을 수득하였다.The title compound was obtained in 52% yield by carrying out a similar reaction as in Preparation Example 4-1) using dihydroxyacetone and octylamine hydrochloride as starting materials.

1H NMR(CDCl3) δ 0.88(t, 3H), 1.18(brs, 2H), 1.30(brs, 10H), 1.42(m, 2H), 3.67(t, 2H), 4.23(brs, 1H), 4.60(s, 2H), 6.84(s, 1H), 7.44(s, 1H) 1 H NMR (CDCl 3 ) δ 0.88 (t, 3H), 1.18 (brs, 2H), 1.30 (brs, 10H), 1.42 (m, 2H), 3.67 (t, 2H), 4.23 (brs, 1H), 4.60 (s, 2H), 6.84 (s, 1H), 7.44 (s, 1H)

FAB (M+H): 211FAB (M + H): 211

9-2) 5-클로로메틸-1-옥틸이미다졸 하이드로클로라이드의 제조9-2) Preparation of 5-chloromethyl-1-octylimidazole hydrochloride

제조예 9-1)에서 수득한 화합물을 출발물질로 사용하는 점을 제외하고는 제조예 1-2)에서와 유사하게 실시하여 93% 수율로 표제화합물을 수득하였다.The title compound was obtained in 93% yield in the same manner as in Preparation Example 1-2) except that the compound obtained in Preparation Example 9-1) was used as a starting material.

제조예 10: 5-클로로메틸-1-데실이미다졸 하이드로클로라이드의 합성Preparation Example 10 Synthesis of 5-chloromethyl-1-decylimidazole hydrochloride

10-1) 5-하이드록시메틸-1-데실이미다졸의 제조10-1) Preparation of 5-hydroxymethyl-1-decylimidazole

디하이드록시아세톤과 데실아민 하이드로클로라이드를 출발물질로하여 제조예 4-1)에서 유사한 반응을 수행함으로써 52% 수율로 표제화합물을 수득하였다.The title compound was obtained in 52% yield by carrying out a similar reaction in Preparation Example 4-1) using dihydroxyacetone and decylamine hydrochloride as starting materials.

1H NMR(CDCl3) δ 0.88(t, 3H), 1.04(brs, 2H), 1.30(brs, 14H), 1.42(m, 2H), 3.68(t, 2H), 4.23(brs, 1H), 4.60(s, 2H), 6.84(s, 1H), 7.44(s, 1H) 1 H NMR (CDCl 3 ) δ 0.88 (t, 3H), 1.04 (brs, 2H), 1.30 (brs, 14H), 1.42 (m, 2H), 3.68 (t, 2H), 4.23 (brs, 1H), 4.60 (s, 2H), 6.84 (s, 1H), 7.44 (s, 1H)

FAB (M+H): 239FAB (M + H): 239

10-2) 5-클로로메틸-1-데실이미다졸 하이드로클로라이드의 제조10-2) Preparation of 5-chloromethyl-1-decylimidazole hydrochloride

제조예 10-1)에서 수득한 화합물을 출발물질로 사용하는 점을 제외하고는 제조예 1-2)에서와 유사하게 실시하여 93% 수율로 표제화합물을 수득하였다.The title compound was obtained in 93% yield in the same manner as in Preparation Example 1-2) except for using the compound obtained in Preparation Example 10-1) as a starting material.

제조예 11: 5-클로로메틸-1-(3-메틸)부틸이미다졸 하이드로클로라이드의 합성Preparation Example 11 Synthesis of 5-chloromethyl-1- (3-methyl) butylimidazole hydrochloride

11-1) 5-하이드록시메틸-1-(3-메틸)부틸이미다졸의 제조11-1) Preparation of 5-hydroxymethyl-1- (3-methyl) butylimidazole

디하이드록시아세톤과 이소아밀아민 하이드로클로라이드를 출발물질로하여 제조예 4-1)에서와 유사한 반응을 수행함으로써 52% 수율로 표제화합물을 수득하였다.The title compound was obtained in 52% yield by carrying out a similar reaction as in Preparation Example 4-1) using dihydroxyacetone and isoamylamine hydrochloride as starting materials.

1H NMR(CDCl3) δ 0.90(d, 6H), 1.32(m, 2H), 1.65(m, 1H), 3.67(t, 2H), 4.23(brs, 1H), 4.60(s, 2H), 6.84(s, 1H), 7.44(s, 1H) 1 H NMR (CDCl 3 ) δ 0.90 (d, 6H), 1.32 (m, 2H), 1.65 (m, 1H), 3.67 (t, 2H), 4.23 (brs, 1H), 4.60 (s, 2H), 6.84 (s, 1 H), 7.44 (s, 1 H)

FAB (M+H): 169FAB (M + H): 169

11-2) 5-클로로메틸-1-(3-메틸)부틸이미다졸 하이드로클로라이드의 제조11-2) Preparation of 5-chloromethyl-1- (3-methyl) butylimidazole hydrochloride

제조예 11-1)에서 수득한 화합물을 출발물질로 사용하는 점을 제외하고는 제조예 1-2)에서와 유사하게 실시하여 93% 수율로 표제화합물을 수득하였다.The title compound was obtained in 93% yield in the same manner as in Preparation Example 1-2) except for using the compound obtained in Preparation Example 11-1) as a starting material.

제조예 12: 5-클로로메틸-1-(2-메톡시)에틸이미다졸 하이드로클로라이드의 합성Preparation Example 12 Synthesis of 5-chloromethyl-1- (2-methoxy) ethylimidazole hydrochloride

12-1) 5-하이드록시메틸-1-(2-메톡시)에틸이미다졸의 제조12-1) Preparation of 5-hydroxymethyl-1- (2-methoxy) ethylimidazole

디하이드록시아세톤과 2-메톡시에틸아민 하이드로클로라이드를 출발물질로하여 제조예 4-1)에서 유사한 반응을 수행함으로써 60% 수율로 표제화합물을 수득하였다.The title compound was obtained in 60% yield by performing a similar reaction in Preparation Example 4-1) using dihydroxyacetone and 2-methoxyethylamine hydrochloride as starting materials.

1H NMR(CDCl3) δ 3.38(s, 3H), 3.42(t, 2H), 3.65(t, 2H), 4.23(brs, 1H), 4.60(s, 2H), 6.84(s, 1H), 7.44(s, 1H) 1 H NMR (CDCl 3 ) δ 3.38 (s, 3H), 3.42 (t, 2H), 3.65 (t, 2H), 4.23 (brs, 1H), 4.60 (s, 2H), 6.84 (s, 1H), 7.44 (s, 1 H)

FAB (M+H): 157FAB (M + H): 157

12-2) 5-클로로메틸-1-(2-메톡시)에틸이미다졸 하이드로클로라이드의 제조12-2) Preparation of 5-chloromethyl-1- (2-methoxy) ethylimidazole hydrochloride

제조예 12-1)에서 수득한 화합물을 출발물질로 사용하는 점을 제외하고는 제조예 1-2)에서와 유사하게 실시하여 93% 수율로 표제화합물을 수득하였다.The title compound was obtained in 93% yield in the same manner as in Preparation Example 1-2) except that the compound obtained in Preparation Example 12-1) was used as a starting material.

제조예 13: 5-클로로메틸-1-(3-메톡시)프로필이미다졸 하이드로클로라이드의 합성Preparation Example 13 Synthesis of 5-chloromethyl-1- (3-methoxy) propylimidazole hydrochloride

13-1) 5-하이드록시메틸-1-(3-메톡시)프로필이미다졸의 제조13-1) Preparation of 5-hydroxymethyl-1- (3-methoxy) propylimidazole

디하이드록시아세톤과 3-메톡시프로필아민 하이드로클로라이드를 출발물질로하여 제조예 4-1)에서와 유사한 반응을 수행함으로써 61% 수율로 표제화합물을 수득하였다.The title compound was obtained in 61% yield by carrying out a similar reaction as in Preparation Example 4-1) using dihydroxyacetone and 3-methoxypropylamine hydrochloride as starting materials.

1H NMR(CDCl3) δ 1.72(m, 2H), 3.32(s, 3H), 3.46(t, 2H), 3.63(t, 2H), 4.23(brs, 1H), 4.60(s, 2H), 6.84(s, 1H), 7.44(s, 1H) 1 H NMR (CDCl 3 ) δ 1.72 (m, 2H), 3.32 (s, 3H), 3.46 (t, 2H), 3.63 (t, 2H), 4.23 (brs, 1H), 4.60 (s, 2H), 6.84 (s, 1 H), 7.44 (s, 1 H)

FAB (M+H): 171FAB (M + H): 171

13-2) 5-클로로메틸-1-(3-메톡시)프로필이미다졸 하이드로클로라이드의 제조13-2) Preparation of 5-chloromethyl-1- (3-methoxy) propylimidazole hydrochloride

제조예 13-1)에서 수득한 화합물을 출발물질로 사용하는 점을 제외하고는 제조예 1-2)에서와 유사하게 실시하여 90% 수율로 표제화합물을 수득하였다.Except for using the compound obtained in Preparation Example 13-1) as a starting material, the title compound was obtained in the same manner as in Preparation Example 1-2) in 90% yield.

제조예 14: 5-클로로메틸-1-(3-에톡시)프로필이미다졸 하이드로클로라이드의 합성Preparation Example 14 Synthesis of 5-chloromethyl-1- (3-ethoxy) propylimidazole hydrochloride

14-1) 5-하이드록시메틸-1-(3-에톡시)프로필이미다졸의 제조14-1) Preparation of 5-hydroxymethyl-1- (3-ethoxy) propylimidazole

디하이드록시아세톤과 3-에톡시프로필아민 하이드로클로라이드를 출발물질로하여 제조예 4-1)에서와 유사한 반응을 수행함으로써 61% 수율로 표제화합물을 수득하였다.The title compound was obtained in 61% yield by carrying out a similar reaction as in Preparation Example 4-1) using dihydroxyacetone and 3-ethoxypropylamine hydrochloride as starting materials.

1H NMR(CDCl3) δ 1.20(t, 3H), 1.72(m, 2H), 3.50(s, 4H), 3.63(t, 2H), 4.23(brs, 1H), 4.60(s, 2H), 6.84(s, 1H), 7.44(s, 1H) 1 H NMR (CDCl 3 ) δ 1.20 (t, 3H), 1.72 (m, 2H), 3.50 (s, 4H), 3.63 (t, 2H), 4.23 (brs, 1H), 4.60 (s, 2H), 6.84 (s, 1 H), 7.44 (s, 1 H)

FAB (M+H): 185FAB (M + H): 185

14-2) 5-클로로메틸-1-(3-에톡시)프로필이미다졸 하이드로클로라이드의 제조14-2) Preparation of 5-chloromethyl-1- (3-ethoxy) propylimidazole hydrochloride

제조예 14-1)에서 수득한 화합물을 출발물질로 사용하는 점을 제외하고는 제조예 1-2)에서와 유사하게 실시하여 90% 수율로 표제화합물을 수득하였다.Except for using the compound obtained in Preparation Example 14-1) as a starting material, the title compound was obtained in a 90% yield in the same manner as in Preparation Example 1-2).

제조예 15: 5-클로로메틸-1-(3-이소프로폭시)프로필이미다졸 하이드로클로라이드의 합성Preparation Example 15 Synthesis of 5-chloromethyl-1- (3-isopropoxy) propylimidazole hydrochloride

15-1) 5-하이드록시메틸-1-(3-이소프로폭시)프로필이미다졸의 제조15-1) Preparation of 5-hydroxymethyl-1- (3-isopropoxy) propylimidazole

디하이드록시아세톤과 3-이소프로폭시프로필아민 하이드로클로라이드를 출발물질로하여 제조예 4-1)에서와 유사한 반응을 수행함으로써 61% 수율로 표제화합물을 수득하였다.The title compound was obtained in 61% yield by carrying out a similar reaction as in Preparation Example 4-1) using dihydroxyacetone and 3-isopropoxypropylamine hydrochloride as starting materials.

1H NMR(CDCl3) δ 1.15(d, 6H), 1.71(m, 2H), 3.45-3.55(m, 3H), 3.63(t, 2H), 4.23(brs, 1H), 4.60(s, 2H), 6.84(s, 1H), 7.44(s, 1H) 1 H NMR (CDCl 3 ) δ 1.15 (d, 6H), 1.71 (m, 2H), 3.45-3.55 (m, 3H), 3.63 (t, 2H), 4.23 (brs, 1H), 4.60 (s, 2H ), 6.84 (s, 1 H), 7.44 (s, 1 H)

FAB (M+H): 199FAB (M + H): 199

15-2) 5-클로로메틸-1-(3-이소프로폭시)프로필이미다졸 하이드로클로라이드의 제조15-2) Preparation of 5-chloromethyl-1- (3-isopropoxy) propylimidazole hydrochloride

제조예 15-1)에서 수득한 화합물을 출발물질로 사용하는 점을 제외하고는 제조예 1-2)에서와 유사하게 실시하여 90% 수율로 표제화합물을 수득하였다.Except for using the compound obtained in Preparation Example 15-1) as a starting material, the title compound was obtained in the same manner as in Preparation Example 1-2) in 90% yield.

실시예 1: 1-(1H-이미다졸-4-일)메틸-4-(나프탈렌-1-일)-3-(티오펜-2-일)카보닐-1H-피롤(1)의 합성Example 1 Synthesis of 1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -3- (thiophen-2-yl) carbonyl-1H-pyrrole (1)

1-1) 3-(나프탈렌-1-일)-1-(티오펜-2-일)-프로프-2-엔-1-온의 제조1-1) Preparation of 3- (naphthalen-1-yl) -1- (thiophen-2-yl) -prop-2-en-1-one

1-나프탈데히드 3.12g(20 밀리몰) 및 2-아세틸티오펜 2.52g(20 밀리몰)을 메탄올 20㎖에 녹이고 수산화나트륨 800mg(20 밀리몰)을 천천히 가하였다. 상온에서 8시간동안 반응시킨 후 생성된 고체를 여과하여 건조시켰다. 1N 염산을 사용하여 여액의 pH를 4-6 으로 조절한 후 에틸아세테이트로 추출하였다. 감압하에 유기용매를 제거하고 칼럼 크로마토그라피(용리제: 헥산/에틸아세테이트=4/1, v/v)를 수행하여 여과된 고체와 함께 표제화합물 4.23g(16 밀리몰, 수율 80%)을 수득하였다.3.12 g (20 mmol) of 1-naphthalaldehyde and 2.52 g (20 mmol) of 2-acetylthiophene were dissolved in 20 mL of methanol and 800 mg (20 mmol) of sodium hydroxide were slowly added. After reacting for 8 hours at room temperature, the resulting solid was filtered and dried. The pH of the filtrate was adjusted to 4-6 with 1N hydrochloric acid and extracted with ethyl acetate. The organic solvent was removed under reduced pressure and column chromatography (eluent: hexane / ethyl acetate = 4/1, v / v) was carried out to obtain 4.23 g (16 mmol, 80% yield) of the title compound together with the filtered solid. .

1H NMR(CDCl3) δ 7.13-7.31(m, 2H), 7.55-7.70(m, 3H), 7.70(d, 1H), 7.85-7.90(m, 4H), 8.28(d, 1H), 8.70(d, 1H) 1 H NMR (CDCl 3 ) δ 7.13-7.31 (m, 2H), 7.55-7.70 (m, 3H), 7.70 (d, 1H), 7.85-7.90 (m, 4H), 8.28 (d, 1H), 8.70 (d, 1H)

1-2) 4-(나프탈렌-1-일)-3-(티오펜-2-일)카보닐-1H-피롤의 제조1-2) Preparation of 4- (naphthalen-1-yl) -3- (thiophen-2-yl) carbonyl-1H-pyrrole

실시예 1-1)에서 수득한 화합물 2.64g(9.99 밀리몰)과 토실메틸이소시아나이드 2.35g(12.0 밀리몰)을 테트라하이드로푸란 30㎖에 용해시켰다. 여기에 포타슘 t-부톡사이드 1.35g(12.0 밀리몰)을 천천히 첨가하고 30분간 환류시켰다. 용매를 감압하에 제거하고 물 15㎖ 및 에틸아세테이트 20㎖를 가하여 잘 흔들어준 후 생성된 고체를 여과하였다. 디에틸에테르로 세척해준 다음 건조시켜 표제화합물 1.97 g(6.48 밀리몰, 수율 65%)을 수득하였다.2.64 g (9.99 mmol) of the compound obtained in Example 1-1) and 2.35 g (12.0 mmol) of tosylmethyl isocyanide were dissolved in 30 ml of tetrahydrofuran. To this was slowly added 1.35 g (12.0 mmol) of potassium t-butoxide and refluxed for 30 minutes. The solvent was removed under reduced pressure, 15 ml of water and 20 ml of ethyl acetate were added thereto, the mixture was shaken well, and the resulting solid was filtered. Washed with diethyl ether and dried to give 1.97 g (6.48 mmol, 65% yield) of the title compound.

1H NMR(CDCl3) δ 6.90(s, 1H), 7.12(s, 1H), 7.20-7.45(m, 4H), 7.55(s, 1H), 7.61(s, 1H), 7.70-8.00(m, 4H), 11.4(s, 1H) 1 H NMR (CDCl 3 ) δ 6.90 (s, 1H), 7.12 (s, 1H), 7.20-7.45 (m, 4H), 7.55 (s, 1H), 7.61 (s, 1H), 7.70-8.00 (m , 4H), 11.4 (s, 1H)

1-3) 4-(나프탈렌-1-일)-3-(티오펜-2-일)카보닐-1-(1-트리틸-1H-이미다졸-4-일)메틸-1H-피롤의 제조1-3) 4- (naphthalen-1-yl) -3- (thiophen-2-yl) carbonyl-1- (1-trityl-1H-imidazol-4-yl) methyl-1H-pyrrole Produce

실시예 1-2)에서 수득한 화합물 200mg(0.99밀리몰)을 디메틸포름아미드 5㎖에 녹이고 0℃에서 수소화나트륨(50%) 95mg(4.0밀리몰)을 가한 후 5분간 교반하였다. 반응액에 제조예 1-2)에서 수득한 화합물 391mg(0.99밀리몰)을 첨가하고 상온에서 5시간동안 교반하였다. 용매를 감압증류하여 제거한 다음, 에틸아세테이트로 추출하였다. 추출액을 무수 마그네슘설페이트로 건조시키고 농축시킨 후, 칼럼 크로마토그라피(용리제: 헥산/에틸아세테이트=1/3, v/v)를 수행하여 표제화합물 205mg(0.33밀리몰, 수율 33%)을 수득하였다.200 mg (0.99 mmol) of the compound obtained in Example 1-2) was dissolved in 5 ml of dimethylformamide, 95 mg (4.0 mmol) of sodium hydride (50%) was added at 0 ° C., and the mixture was stirred for 5 minutes. 391 mg (0.99 mmol) of the compound obtained in Preparation Example 1-2) was added to the reaction solution, and the mixture was stirred at room temperature for 5 hours. The solvent was removed by distillation under reduced pressure, and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated, followed by column chromatography (eluent: hexane / ethyl acetate = 1/3, v / v) to give 205 mg (0.33 mmol, 33% yield) of the title compound.

1H NMR(CDCl3) δ 5.02(s, 2H), 6.75(s, 1H), 6.79(s, 1H), 6.86(t, 1H), 7.10-7.52(m, 23H), 7.71(d, 1H), 7.78(d, 1H), 7.89(d, 1H) 1 H NMR (CDCl 3 ) δ 5.02 (s, 2H), 6.75 (s, 1H), 6.79 (s, 1H), 6.86 (t, 1H), 7.10-7.52 (m, 23H), 7.71 (d, 1H ), 7.78 (d, 1 H), 7.89 (d, 1 H)

1-4) 1-(1H-이미다졸-4-일)메틸-4-(나프탈렌-1-일)-3-(티오펜-2-일)카보닐-1H-피롤의 제조1-4) Preparation of 1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -3- (thiophen-2-yl) carbonyl-1H-pyrrole

실시예 1-3)에서 수득한 화합물 190mg(0.304 밀리몰)을 트리플루오로아세트산/디클로로메탄의 혼합액(0.5㎖/0.5㎖)에 녹이고 상온에서 2시간동안 교반하였다. 유기용매를 감압하에 제거하고 에틸아세테이트 10㎖에 녹인 후 포화 Na2CO3수용액과 물로 세척해주었다. 무수 마그네슘 설페이트로 건조시키고 농축시킨 후, 칼럼 크로마토그라피(용리제: 에틸아세테이트)를 수행하여 표제화합물 103mg(0.269 밀리몰, 수율 88%)을 수득하였다.190 mg (0.304 mmol) of the compound obtained in Example 1-3) were dissolved in a mixed solution of trifluoroacetic acid / dichloromethane (0.5 mL / 0.5 mL) and stirred at room temperature for 2 hours. The organic solvent was removed under reduced pressure, dissolved in 10 ml of ethyl acetate, and washed with saturated Na 2 CO 3 aqueous solution and water. After drying over anhydrous magnesium sulfate and concentration, column chromatography (eluent: ethyl acetate) was performed to give 103 mg (0.269 mmol, 88% yield) of the title compound.

1H NMR(CDCl3) δ 4.87(s, 2H), 6.55(s, 1H), 6.72(s, 1H), 6.88(t, 1H), 7.11-7.34(m, 7H), 7.50-7.67(m, 3H), 7.83(d, 1H) 1 H NMR (CDCl 3 ) δ 4.87 (s, 2H), 6.55 (s, 1H), 6.72 (s, 1H), 6.88 (t, 1H), 7.11-7.34 (m, 7H), 7.50-7.67 (m , 3H), 7.83 (d, 1H)

FAB MS: 384(M+1)FAB MS: 384 (M + 1)

실시예 2 내지 29:Examples 2 to 29:

실시예 1과 유사한 방법으로 반응을 수행하여 하기 표 2a 내지 2c 에 열거한 화합물들을 수득하였다.The reaction was carried out in a similar manner to Example 1 to obtain the compounds listed in Tables 2A to 2C.

화합물번호Compound number 1H NMR(CDCl3) δ 1 H NMR (CDCl 3 ) δ FAB MS (M+1)FAB MS (M + 1) 22 4.85(s, 2H), 6.51(s, 1H), 6.67(s, 1H), 7.06(s, 1H), 7.14(s, 1H), 7.21-7.32(m, 7H), 7.61-7.74(m, 3H), 7.82(d, 1H)4.85 (s, 2H), 6.51 (s, 1H), 6.67 (s, 1H), 7.06 (s, 1H), 7.14 (s, 1H), 7.21-7.32 (m, 7H), 7.61-7.74 (m, 3H), 7.82 (d, 1H) 384384 33 4.95(s, 2H), 6.58(s, 1H), 6.76(s, 1H), 7.13-7.35(m, 9H), 7.61- 7.68(m, 4H), 7.91(d, 1H)4.95 (s, 2H), 6.58 (s, 1H), 6.76 (s, 1H), 7.13-7.35 (m, 9H), 7.61-7.68 (m, 4H), 7.91 (d, 1H) 378378 44 4.92(s, 2H), 6.61(s, 1H), 6.70(s, 1H), 7.02(d, 2H), 7.17-7.35(m, 9H), 7.62(d, 1H), 7.70(d, 1H), 7.95(d, 1H)4.92 (s, 2H), 6.61 (s, 1H), 6.70 (s, 1H), 7.02 (d, 2H), 7.17-7.35 (m, 9H), 7.62 (d, 1H), 7.70 (d, 1H) , 7.95 (d, 1 H) 456456 55 5.03(s, 2H), 6.76(s, 1H), 6.85(s, 1H), 7.07(t, 1H), 7.34-7.54(m, 9H), 7.72-7.79(m, 3H), 7.94(d, 1H)5.03 (s, 2H), 6.76 (s, 1H), 6.85 (s, 1H), 7.07 (t, 1H), 7.34-7.54 (m, 9H), 7.72-7.79 (m, 3H), 7.94 (d, 1H) 456456 66 5.00(s, 2H), 6.72(s, 1H), 6.77(s, 1H), 7.21-7.38(m, 11H), 7.62 (d, 1H), 7.70(d, 1H), 7.78(d, 1H)5.00 (s, 2H), 6.72 (s, 1H), 6.77 (s, 1H), 7.21-7.38 (m, 11H), 7.62 (d, 1H), 7.70 (d, 1H), 7.78 (d, 1H) 456456 77 2.23(s, 3H), 5.02(s, 2H), 6.74-7.10(m, 5H), 7.17-7.50(m, 8H), 7.65(d, 1H), 7.71(d, 1H), 7.86(d, 1H)2.23 (s, 3H), 5.02 (s, 2H), 6.74-7.10 (m, 5H), 7.17-7.50 (m, 8H), 7.65 (d, 1H), 7.71 (d, 1H), 7.86 (d, 1H) 392392 88 (CDCl3+CD3OD) 2.05(s, 3H), 5.09(s, 2H), 6.84(s, 1H), 6.99-7.05(m, 8H), 7.23-7.36(m, 3H), 7.70(d, 1H), 7.86(d, 1H)(CDCl 3 + CD 3 OD) 2.05 (s, 3H), 5.09 (s, 2H), 6.84 (s, 1H), 6.99-7.05 (m, 8H), 7.23-7.36 (m, 3H), 7.70 (d , 1H), 7.86 (d, 1H) 392392 99 2.21(s, 3H), 4.92(s, 2H), 6.62(s, 1H), 6.83(s, 1H), 7.14-7.35(m, 8H), 7.61-7.73(m, 5H), 7.88(d, 1H)2.21 (s, 3H), 4.92 (s, 2H), 6.62 (s, 1H), 6.83 (s, 1H), 7.14-7.35 (m, 8H), 7.61-7.73 (m, 5H), 7.88 (d, 1H) 392392 1010 3.66(s, 3H), 5.04(s, 2H), 6.85(s, 1H), 6.82(d, 1H), 6.90(m, 1H), 7.12-7.17(m, 2H), 7.26-7.36(m, 8H), 7.67(t, 1H), 7.74(d, 1H), 7.93(d, 1H)3.66 (s, 3H), 5.04 (s, 2H), 6.85 (s, 1H), 6.82 (d, 1H), 6.90 (m, 1H), 7.12-7.17 (m, 2H), 7.26-7.36 (m, 8H), 7.67 (t, 1H), 7.74 (d, 1H), 7.93 (d, 1H) 408408 1111 3.75(s, 3H), 5.02(s, 2H), 6.71(m, 3H), 6.80(t, 1H), 7.20-7.35(m, 6H), 7.60-7.75(m, 4H), 7.91(d, 1H)3.75 (s, 3H), 5.02 (s, 2H), 6.71 (m, 3H), 6.80 (t, 1H), 7.20-7.35 (m, 6H), 7.60-7.75 (m, 4H), 7.91 (d, 1H) 408408 1212 4.83(s, 2H), 6.51(s, 1H), 6.63(s, 1H), 6.85(m, 1H), 7.03-7.29(m, 10H), 7.61-7.69(m, 2H), 7.83(d, 1H)4.83 (s, 2H), 6.51 (s, 1H), 6.63 (s, 1H), 6.85 (m, 1H), 7.03-7.29 (m, 10H), 7.61-7.69 (m, 2H), 7.83 (d, 1H) 412412

1313 5.01(s, 2H), 6.72(s, 1H), 6.77(s, 1H), 7.22-7.35(m, 11H), 7.61- 7.80(m, 3H)5.01 (s, 2H), 6.72 (s, 1H), 6.77 (s, 1H), 7.22-7.35 (m, 11H), 7.61-7.80 (m, 3H) 412412 1414 4.82(s, 2H), 6.63(s, 1H), 6.72(s, 1H), 7.02-7.24(m, 10H), 7.56- 7.70(m, 3H)4.82 (s, 2H), 6.63 (s, 1H), 6.72 (s, 1H), 7.02-7.24 (m, 10H), 7.56- 7.70 (m, 3H) 446446 1515 4.91(s, 2H), 6.65(s, 1H), 6.77(m, 1H), 7.20-7.31(m, 7H), 7.61(m, 3H), 7.81(d, 1H)4.91 (s, 2H), 6.65 (s, 1H), 6.77 (m, 1H), 7.20-7.31 (m, 7H), 7.61 (m, 3H), 7.81 (d, 1H) 396396 1616 4.92(s, 2H), 6.45(m, 1H), 6.71(m, 2H), 7.20-7.32(m, 9H), 7.63- 7.77(m, 3H)4.92 (s, 2H), 6.45 (m, 1H), 6.71 (m, 2H), 7.20-7.32 (m, 9H), 7.63-7.77 (m, 3H) 414414 1717 5.09(s, 2H), 6.80-7.20(m, 4H), 7.15-7.35(m, 4H), 7.40(d, 1H), 7.45-7.50(m, 3H), 7.60(m, 1H), 7.65(d, 1H), 7.75(d, 1H)5.09 (s, 2H), 6.80-7.20 (m, 4H), 7.15-7.35 (m, 4H), 7.40 (d, 1H), 7.45-7.50 (m, 3H), 7.60 (m, 1H), 7.65 ( d, 1H), 7.75 (d, 1H) 403403 1818 1.87(s, 3H), 3.55(s, 2H), 5.07(s, 2H), 6.84(s, 2H), 7.08(d, 2H), 7.28-7.48(m, 6H), 7.57(d, 2H), 7.63(t, 1H), 7.71(d, 1H), 7.90(d, 1H)1.87 (s, 3H), 3.55 (s, 2H), 5.07 (s, 2H), 6.84 (s, 2H), 7.08 (d, 2H), 7.28-7.48 (m, 6H), 7.57 (d, 2H) , 7.63 (t, 1H), 7.71 (d, 1H), 7.90 (d, 1H) 438438 1919 2.03(s, 3H), 2.74(m, 2H), 2.91(m, 2H), 5.00(s, 2H), 6.67(s, 1H), 7.02(d, 2H), 7.14-7.43(m, 11H), 7.72-7.89(m, 3H)2.03 (s, 3H), 2.74 (m, 2H), 2.91 (m, 2H), 5.00 (s, 2H), 6.67 (s, 1H), 7.02 (d, 2H), 7.14-7.43 (m, 11H) , 7.72-7.89 (m, 3H) 452452 2020 1.98(s, 3H), 2.75(t, 2H), 3.90(t, 2H), 4.85(s, 2H), 6.60-6.72(m, 4H), 7.11-7.45(m, 9H), 7.68-7.82(m, 3H)1.98 (s, 3H), 2.75 (t, 2H), 3.90 (t, 2H), 4.85 (s, 2H), 6.60-6.72 (m, 4H), 7.11-7.45 (m, 9H), 7.68-7.82 ( m, 3H) 468468 2121 2.01(s, 3H), 3.61(s, 2H), 4.98(s, 2H), 6.61(s, 2H), 6.74(m, 2H), 7.10-7.48(m, 10H), 7.71-7.88(m, 3H)2.01 (s, 3H), 3.61 (s, 2H), 4.98 (s, 2H), 6.61 (s, 2H), 6.74 (m, 2H), 7.10-7.48 (m, 10H), 7.71-7.88 (m, 3H) 438438 2222 4.92(s, 2H), 6.62(s, 1H), 6.70(s, 1H), 7.12-7.27(m, 14H), 7.53- 7.62(m, 4H), 7.81(d, 1H)4.92 (s, 2H), 6.62 (s, 1H), 6.70 (s, 1H), 7.12-7.27 (m, 14H), 7.53- 7.62 (m, 4H), 7.81 (d, 1H) 454454 2323 4.97(s, 2H), 6.87(d, 1H), 7.15-7.46(m, 15H), 7.55-7.73(m, 4H), 7.86(m, 1H)4.97 (s, 2H), 6.87 (d, 1H), 7.15-7.46 (m, 15H), 7.55-7.73 (m, 4H), 7.86 (m, 1H) 454454 2424 5.10(s, 2H), 6.70(t, 2H), 6.80-6.95(m, 4H), 7.15(t, 1H), 7.21-7.45(m, 7H), 7.50(t, 1H), 7.60(d, 2H), 7.71(d, 1H), 7.75- 7.80(m, 2H), 7.91(m, 1H)5.10 (s, 2H), 6.70 (t, 2H), 6.80-6.95 (m, 4H), 7.15 (t, 1H), 7.21-7.45 (m, 7H), 7.50 (t, 1H), 7.60 (d, 2H), 7.71 (d, 1H), 7.75-7.80 (m, 2H), 7.91 (m, 1H) 470470 2525 3.82(s, 2H), 4.95(s, 2H), 6.57(s, 1H), 6.63(s, 1H), 6.92(d, 2H), 7.04(d, 2H), 7.20-7.32(m, 10H), 7.51-7.68(m, 4H), 7.82(d, 1H)3.82 (s, 2H), 4.95 (s, 2H), 6.57 (s, 1H), 6.63 (s, 1H), 6.92 (d, 2H), 7.04 (d, 2H), 7.20-7.32 (m, 10H) , 7.51-7.68 (m, 4H), 7.82 (d, 1H) 468468

2626 4.82(s, 2H), 6.41(s, 1H), 6.70(s, 1H), 6.95(s, 1H), 7.16-7.32(m, 9H), 7.51(d, 1H), 7.59(d, 1H), 7.67(m, 3H), 7.90(d, 1H), 8.05(d, 1H)4.82 (s, 2H), 6.41 (s, 1H), 6.70 (s, 1H), 6.95 (s, 1H), 7.16-7.32 (m, 9H), 7.51 (d, 1H), 7.59 (d, 1H) , 7.67 (m, 3H), 7.90 (d, 1H), 8.05 (d, 1H) 428428 2727 2.38(s, 3H), 3.65(s, 3H), 4.91(s, 2H), 6.69(s, 1H), 6.97(d, 1H), 7.00(t, 1H), 7.04(d, 1H), 7.10-7.16(m, 3H), 7.19(d, 1H), 7.34(s, 1H), 7.42(s, 1H), 7.57(d, 1H), 7.67(s, 2H)2.38 (s, 3H), 3.65 (s, 3H), 4.91 (s, 2H), 6.69 (s, 1H), 6.97 (d, 1H), 7.00 (t, 1H), 7.04 (d, 1H), 7.10 -7.16 (m, 3H), 7.19 (d, 1H), 7.34 (s, 1H), 7.42 (s, 1H), 7.57 (d, 1H), 7.67 (s, 2H) 395395 2828 0.61(t, 3H), 1.02(m, 2H), 1.25(m, 2H), 2.31(m, 1H), 2.47(m, 1H), 5.05(s, 2H), 6.57(s, 1H), 6.63(s, 1H), 6.80(d, 1H), 6.87(s, 1H), 7.22-7.35(m, 7H), 7.61-7.72(m, 3H)0.61 (t, 3H), 1.02 (m, 2H), 1.25 (m, 2H), 2.31 (m, 1H), 2.47 (m, 1H), 5.05 (s, 2H), 6.57 (s, 1H), 6.63 (s, 1H), 6.80 (d, 1H), 6.87 (s, 1H), 7.22-7.35 (m, 7H), 7.61-7.72 (m, 3H) 502502 2929 3.71(d, 1H), 3.85(d, 1H), 4.85(s, 2H), 6.61(s, 1H), 6.73(d, 1H), 6.92-7.41(m, 14H), 7.62-7.73(m, 3H)3.71 (d, 1H), 3.85 (d, 1H), 4.85 (s, 2H), 6.61 (s, 1H), 6.73 (d, 1H), 6.92-7.41 (m, 14H), 7.62-7.73 (m, 3H) 536536

실시예 30: 1-[1-(4-시아노벤질)-1H-이미다졸-5-일]메틸-4-(나프탈렌-1-일)-3-(티오펜-2-일)카보닐-1H-피롤(30)의 합성Example 30 1- [1- (4-cyanobenzyl) -1H-imidazol-5-yl] methyl-4- (naphthalen-1-yl) -3- (thiophen-2-yl) carbonyl Synthesis of -1H-pyrrole (30)

제조예 2-5)에서 수득한 화합물 80mg(0.3밀리몰)과 실시예 1-2)에서 수득한 화합물 90mg(0.3밀리몰)을 디메틸포름아미드 2㎖에 녹이고 60% 수소화나트륨 36mg을 가한 후 2시간 동안 교반하였다. 용매를 감압증류하여 제거하고 칼럼 크로마토그래피(용리제: 디클로로메탄/메탄올=10/1, v/v)를 수행하여 표제화합물 83mg(0.17밀리몰, 수율 56%)을 수득하였다.80 mg (0.3 mmol) of the compound obtained in Preparation Example 2-5) and 90 mg (0.3 mmol) of the compound obtained in Example 1-2) were dissolved in 2 ml of dimethylformamide and 36 mg of 60% sodium hydride was added for 2 hours. Stirred. The solvent was removed by distillation under reduced pressure and column chromatography (eluent: dichloromethane / methanol = 10/1, v / v) was performed to obtain 83 mg (0.17 mmol, yield 56%) of the title compound.

1H NMR(CDCl3) δ 5.02(s, 2H), 5.08(s, 1H), 6.73(s, 1H), 6.85(s, 1H), 7.03(t, 1H), 7.32-7.45(m, 11H), 7.63(s, 1H), 7.75(d, 1H), 7.82(d, 1H), 8.02 (d, 1H) 1 H NMR (CDCl 3 ) δ 5.02 (s, 2H), 5.08 (s, 1H), 6.73 (s, 1H), 6.85 (s, 1H), 7.03 (t, 1H), 7.32-7.45 (m, 11H ), 7.63 (s, 1H), 7.75 (d, 1H), 7.82 (d, 1H), 8.02 (d, 1H)

FAB MS : 499 (M+1)FAB MS: 499 (M + 1)

실시예 31 내지 34:Examples 31 to 34:

실시예 30과 유사한 방법으로 반응을 수행하여 하기 표 3에 열거한 화합물들을 수득하였다.The reaction was carried out in a similar manner to Example 30 to obtain the compounds listed in Table 3 below.

화합물번호Compound number 1H NMR(CDCl3) δ 1 H NMR (CDCl 3 ) δ FAB MS (M+1)FAB MS (M + 1) 3131 4.82(s, 2H), 5.12(s, 1H), 6.30(s, 1H), 6.41(s, 1H), 6.77-7.08(m, 12H), 7.31-7.46(m, 3H), 7.68(d, 1H)4.82 (s, 2H), 5.12 (s, 1H), 6.30 (s, 1H), 6.41 (s, 1H), 6.77-7.08 (m, 12H), 7.31-7.46 (m, 3H), 7.68 (d, 1H) 499499 3232 5.00(s, 2H), 5.05(s, 2H), 6.76(s, 1H), 6.82(s, 1H), 7.23-7.40(m, 12H), 7.63(d, 2H), 7.72(d, 1H), 7.90(d, 1H)5.00 (s, 2H), 5.05 (s, 2H), 6.76 (s, 1H), 6.82 (s, 1H), 7.23-7.40 (m, 12H), 7.63 (d, 2H), 7.72 (d, 1H) , 7.90 (d, 1 H) 493493 3333 5.02(s, 2H), 5.08(s, 2H), 6.65(s, 1H), 6.78(s, 1H), 6.98(t, 1H), 7.23-7.42(m, 12H), 7.65-7.73(m, 3H), 7.82(d, 1H)5.02 (s, 2H), 5.08 (s, 2H), 6.65 (s, 1H), 6.78 (s, 1H), 6.98 (t, 1H), 7.23-7.42 (m, 12H), 7.65-7.73 (m, 3H), 7.82 (d, 1H) 571571 3434 5.03(s, 2H), 5.10(s, 2H), 6.78(s, 1H), 6.87(s, 1H), 7.32-7.45(m, 12H), 7.74(d, 3H), 7.81(d, 1H), 7.88(d, 1H)5.03 (s, 2H), 5.10 (s, 2H), 6.78 (s, 1H), 6.87 (s, 1H), 7.32-7.45 (m, 12H), 7.74 (d, 3H), 7.81 (d, 1H) , 7.88 (d, 1 H) 571571

실시예 35: 3-(4-플루오로벤조일)-1-(1-메틸-1H-이미다졸-4-일)메틸-4-(나프탈렌-1-일)-1H-피롤(35)의 합성Example 35 Synthesis of 3- (4-fluorobenzoyl) -1- (1-methyl-1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -1H-pyrrole (35)

3-(4-플루오로벤조일)-4-(나프탈렌-1-일)-1H-피롤 및 제조예 4-2)에서 수득한 화합물을 사용하는 점을 제외하고는 실시예 1-3)에서와 동일하게 실시하여 75% 수율로 표제화합물을 수득하였다.In Examples 1-3) except that 3- (4-fluorobenzoyl) -4- (naphthalen-1-yl) -1H-pyrrole and the compound obtained in Preparation Example 4-2) are used; In the same manner, the title compound was obtained in 75% yield.

1H NMR(CDCl3) δ 3.42(s, 3H), 5.01(s, 2H), 6.73(m, 3H), 7.11(s, 1H), 7.24-7.57(m, 8H), 7.67-7.75(m, 2H) 1 H NMR (CDCl 3 ) δ 3.42 (s, 3H), 5.01 (s, 2H), 6.73 (m, 3H), 7.11 (s, 1H), 7.24-7.57 (m, 8H), 7.67-7.75 (m , 2H)

FAB MS (M+1): 410FAB MS (M + 1): 410

실시예 36: 1-(1-메틸-1H-이미다졸-4-일)메틸-4-(나프탈렌-1-일)-3-(4-페녹시벤조일)-1H-피롤(36)의 합성Example 36 Synthesis of 1- (1-methyl-1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -3- (4-phenoxybenzoyl) -1H-pyrrole (36)

4-(나프탈렌-1-일)-3-(4-페녹시벤조일)-1H-피롤 및 제조예 4-2)에서 수득한 화합물을 사용하는 점을 제외하고는 실시예 1-3)에서와 동일하게 실시하여 70% 수율로 표제화합물을 수득하였다.In Examples 1-3) except that 4- (naphthalen-1-yl) -3- (4-phenoxybenzoyl) -1H-pyrrole and the compound obtained in Preparation Example 4-2) are used; In the same manner, the title compound was obtained in 70% yield.

1H NMR(CDCl3) δ 3.52(s, 3H), 5.12(s, 2H), 6.63(d, 2H), 6.76(d, 1H), 6.85(d, 2H), 7.12(t, 1H), 7.20(s, 1H), 7.28-7.40(m, 7H), 7.51(d, 2H), 7.68(d, 2H), 7.74(d, 1H), 7.83(d, 1H) 1 H NMR (CDCl 3 ) δ 3.52 (s, 3H), 5.12 (s, 2H), 6.63 (d, 2H), 6.76 (d, 1H), 6.85 (d, 2H), 7.12 (t, 1H), 7.20 (s, 1H), 7.28-7.40 (m, 7H), 7.51 (d, 2H), 7.68 (d, 2H), 7.74 (d, 1H), 7.83 (d, 1H)

FAB MS (M+1): 484FAB MS (M + 1): 484

실시예 37: (S)-1-(1H-이미다졸-4-일)메틸-3-[N-(1-메톡시카보닐-3-메틸티오)프로필]카바모일-4-(나프탈렌-1-일)-1H-피롤(37)의 합성Example 37: (S) -1- (1H-imidazol-4-yl) methyl-3- [N- (1-methoxycarbonyl-3-methylthio) propyl] carbamoyl-4- (naphthalene- Synthesis of 1-yl) -1H-pyrrole (37)

37-1) 에틸 3-(나프탈렌-1-일)아크릴레이트의 제조37-1) Preparation of ethyl 3- (naphthalen-1-yl) acrylate

트리에틸포스포노아세테이트 22.4g(0.10 몰)을 테트라하이드로푸란 500㎖에 녹인 후 포타슘 t-부톡사이드 12.4g(1.1 몰)을 서서히 첨가하였다. 이 용액에 1-나프탈데히드 15.6g(0.10 몰)을 테트라하이드로푸란 20㎖에 녹여 서서히 가한 후 8 시간동안 교반하였다. 유기용매를 감압증류하여 제거한 후 에틸아세테이트에 녹이고 물로 2번 세척해주었다. 무수 마그네슘설페이트로 건조시키고 농축시킨 후 칼럼 크로마토그라피(용리제: 헥산/에틸아세테이트=95/5, v/v)를 수행하여 표제화합물 20.3g(0.090 몰, 수율 90%)을 수득하였다.22.4 g (0.10 mol) of triethylphosphonoacetate was dissolved in 500 ml of tetrahydrofuran, and then 12.4 g (1.1 mol) of potassium t-butoxide was added slowly. 15.6 g (0.10 mol) of 1-naphthalaldehyde was dissolved in 20 ml of tetrahydrofuran and slowly added to the solution, followed by stirring for 8 hours. The organic solvent was removed by distillation under reduced pressure, and then dissolved in ethyl acetate and washed twice with water. After drying over anhydrous magnesium sulfate and concentration, column chromatography (eluent: hexane / ethyl acetate = 95/5, v / v) was carried out to give 20.3 g (0.090 mol, 90% yield) of the title compound.

1H NMR(CDCl3) δ 1.42(t, 3H), 4.30(q, 2H), 6.50(d, 1H), 7.40-7.60(m, 3H), 7.73(d, 1H), 7.82(m, 2H), 8.20(d, 1H), 8.50(d, 1H) 1 H NMR (CDCl 3 ) δ 1.42 (t, 3H), 4.30 (q, 2H), 6.50 (d, 1H), 7.40-7.60 (m, 3H), 7.73 (d, 1H), 7.82 (m, 2H ), 8.20 (d, 1 H), 8.50 (d, 1 H)

37-2) 3-에톡시카보닐-4-(나프탈렌-1-일)-1H-피롤의 제조37-2) Preparation of 3-ethoxycarbonyl-4- (naphthalen-1-yl) -1H-pyrrole

실시예 37-1)에서 수득한 에틸 3-(나프탈렌-1-일)아크릴레이트 500mg(1.89 밀리몰)과 토실메틸이소시아나이드 368mg(1.89 밀리몰)을 테트라하이드로푸란 10㎖ 에 녹였다. 여기에 포타슘 t-부톡사이드 255mg(2.27 밀리몰)의 테트라하이드로푸란(10㎖)용액을 천천히 첨가하고 30분간 환류시켰다. 반응액에 물 10㎖를 가하여 반응을 중지시키고 감압하에 용매를 제거하였다. 디에틸에테르로 추출하고 소금물로 세척해준 후 무수 마그네슘설페이트로 건조시켰다. 용매를 감압하에 제거한 다음, 칼럼 크로마토그래피(용리제: 에틸아세테이트/헥산=1/3, v/v)를 수행하여 표제화합물 385mg(1.45 밀리몰, 수율 77%)을 수득하였다.500 mg (1.89 mmol) of ethyl 3- (naphthalen-1-yl) acrylate obtained in Example 37-1) and 368 mg (1.89 mmol) of tosylmethyl isocyanide were dissolved in 10 ml of tetrahydrofuran. To this was slowly added 255 mg (2.27 mmol) of tetrahydrofuran (10 mL) solution of potassium t-butoxide and refluxed for 30 minutes. 10 ml of water was added to the reaction mixture to stop the reaction, and the solvent was removed under reduced pressure. Extracted with diethyl ether, washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and then column chromatography (eluent: ethyl acetate / hexane = 1/3, v / v) was carried out to give 385 mg (1.45 mmol, 77% yield) of the title compound.

1H NMR(CDCl3) δ 0.86(t, 3H), 4.02(q, 2H), 6.81(s, 1H), 7.48-7.61(m, 5H), 7.90-7.97(m, 3H), 8.92(s, 1H) 1 H NMR (CDCl 3 ) δ 0.86 (t, 3H), 4.02 (q, 2H), 6.81 (s, 1H), 7.48-7.61 (m, 5H), 7.90-7.97 (m, 3H), 8.92 (s , 1H)

37-3) 3-에톡시카보닐-1-(1H-이미다졸-4-일)메틸-4-(나프탈렌-1-일)-1H-피롤의 제조37-3) Preparation of 3-ethoxycarbonyl-1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -1H-pyrrole

실시예 37-2)에서 수득한 화합물 및 제조예 1-2)에서 수득한 화합물로부터 실시예 1-3) 및 1-4)의 방법을 이용하여 39% 수율로 표제화합물을 수득하였다.The title compound was obtained in 39% yield using the method of Examples 1-3) and 1-4) from the compound obtained in Example 37-2) and the compound obtained in Preparation Example 1-2).

1H NMR(CDCl3) δ 1.11(t, 3H), 4.20(q, 2H), 5.05(s, 2H), 6.78(s, 1H), 6.89(s, 1H), 7.38-7.49(m, 6H), 7.85-7.97(m, 3H) 1 H NMR (CDCl 3 ) δ 1.11 (t, 3H), 4.20 (q, 2H), 5.05 (s, 2H), 6.78 (s, 1H), 6.89 (s, 1H), 7.38-7.49 (m, 6H ), 7.85-7.97 (m, 3H)

37-4) 3-하이드록시카보닐-1-(1H-이미다졸-4-일)메틸-4-(나프탈렌-1-일)-1H-피롤의 제조37-4) Preparation of 3-hydroxycarbonyl-1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -1H-pyrrole

실시예 37-3)에서 수득한 화합물 220mg(0.64 밀리몰)을 50% 에탄올 5㎖에 녹이고 수산화칼륨 216mg(3.8 밀리몰)을 적가한 후 7 시간동안 환류시켰다. 반응액을 상온으로 냉각시킨 후 pH 를 4-5로 맞추고 에틸아세테이트로 추출하였다. 무수 소듐설페이트로 건조시키고 감압하에 용매를 제거하여 표제화합물 162mg(0.51 밀리몰, 수율 80%)을 수득하였다. 이 화합물은 정제하지 않고 다음 반응에 사용하였다.220 mg (0.64 mmol) of the compound obtained in Example 37-3) was dissolved in 5 ml of 50% ethanol, and 216 mg (3.8 mmol) of potassium hydroxide was added dropwise to reflux for 7 hours. After cooling the reaction solution to room temperature, the pH was adjusted to 4-5 and extracted with ethyl acetate. Drying over anhydrous sodium sulfate and removal of the solvent under reduced pressure yielded 162 mg (0.51 mmol, yield 80%) of the title compound. This compound was used in the next reaction without purification.

1H NMR(CD3OD + CDCl3) δ 5.01(s, 2H), 6.82(s, 1H), 6.87(s, 1H), 7.42- 7.70(m, 7H), 7.82-7.89(m, 3H) 1 H NMR (CD 3 OD + CDCl 3 ) δ 5.01 (s, 2H), 6.82 (s, 1H), 6.87 (s, 1H), 7.42-7.70 (m, 7H), 7.82-7.89 (m, 3H)

37-5) (S)-1-(1H-이미다졸-4-일)메틸-3-[N-(1-메톡시카보닐-3-메틸티오)프로필]카바모일-4-(나프탈렌-1-일)-1H-피롤의 제조37-5) (S) -1- (1H-imidazol-4-yl) methyl-3- [N- (1-methoxycarbonyl-3-methylthio) propyl] carbamoyl-4- (naphthalene- Preparation of 1-yl) -1H-pyrrole

실시예 37-4)에서 수득한 화합물 200mg(0.60 밀리몰)을 디메틸포름아미드 2㎖에 녹이고 EDC 150mg(0.78 밀리몰) 및 HOBT 105mg(0.78밀리몰)을 가한 다음 0℃에서 5분간 교반하였다. 반응액에 L-메티오닌 메틸에스테르 120mg(0.60밀리몰)을 가하고 실온에서 5시간동안 교반하였다. 용매를 감압하에 제거하고 NaHCO3포화 수용액 10㎖를 가한 후 에틸아세테이트로 추출하였다. 소금물과 물로 세척해주고 무수 소듐설페이트로 건조시킨 후 농축시켰다. 잔류물에 대해 칼럼 크로마토그래피(용리제: 디클로로메탄/메탄올=20/1, v/v)를 수행하여 표제화합물 104mg (0.225 밀리몰, 수율 37%)을 수득하였다.200 mg (0.60 mmol) of the compound obtained in Example 37-4) was dissolved in 2 ml of dimethylformamide, 150 mg (0.78 mmol) of EDC and 105 mg (0.78 mmol) of HOBT were added, followed by stirring at 0 ° C. for 5 minutes. 120 mg (0.60 mmol) of L-methionine methyl ester was added to the reaction solution, and the mixture was stirred at room temperature for 5 hours. The solvent was removed under reduced pressure, 10 ml of saturated aqueous NaHCO 3 solution was added, and the mixture was extracted with ethyl acetate. Washed with brine and water, dried over anhydrous sodium sulfate and concentrated. Column chromatography on the residue (eluent: dichloromethane / methanol = 20/1, v / v) gave 104 mg (0.225 mmol, 37% yield) of the title compound.

1H NMR(CDCl3) δ 1.21(m, 1H), 1.55(m, 3H), 1.80(s, 3H), 3.42(s, 3H), 4.43(m, 1H), 5.05(s, 2H), 5.60(d, 1H), 6.71(s, 1H), 6.95(s, 1H), 7.21-7.45(m, 7H), 7.75-7.87(m, 3H) 1 H NMR (CDCl 3 ) δ 1.21 (m, 1H), 1.55 (m, 3H), 1.80 (s, 3H), 3.42 (s, 3H), 4.43 (m, 1H), 5.05 (s, 2H), 5.60 (d, 1H), 6.71 (s, 1H), 6.95 (s, 1H), 7.21-7.45 (m, 7H), 7.75-7.87 (m, 3H)

FAB MS : 463 (M+1)FAB MS: 463 (M + 1)

실시예 38: (S)-3-[N-(1-하이드록시카보닐-3-메틸티오)프로필]카바모일-1-(1H-이미다졸-4-일)메틸-4-(나프탈렌-1-일)-1H-피롤(38)의 합성Example 38: (S) -3- [N- (1-hydroxycarbonyl-3-methylthio) propyl] carbamoyl-1- (1H-imidazol-4-yl) methyl-4- (naphthalene- Synthesis of 1-yl) -1H-pyrrole (38)

실시예 37-5)에서 수득한 화합물 70mg(0.15 밀리몰)을 테트라하이드로푸란/메탄올/물(3/2/1, v/v/v)의 혼합용매 2㎖에 녹이고 수산화리튬 10mg(0.18 밀리몰)을 가한 다음, 4시간동안 상온에서 교반하였다. 용매를 감압하에 제거하여 표제화합물의 리튬염 68mg(0.15 밀리몰, 수율 99.7%)을 수득하였다.70 mg (0.15 mmol) of the compound obtained in Example 37-5) was dissolved in 2 ml of a mixed solvent of tetrahydrofuran / methanol / water (3/2/1, v / v / v), and 10 mg (0.18 mmol) of lithium hydroxide. After the addition, the mixture was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure to give 68 mg (0.15 mmol, yield 99.7%) of the lithium salt of the title compound.

1H NMR(CD3OD + CDCl3) δ 1.25(m, 1H), 1.49(m, 3H), 1.85(s, 3H), 4.41 (m, 1H), 5.11(s, 2H), 5.58(d, 1H), 6.70(s, 1H), 6.89(s, 1H), 7.15-7.38(m, 7H), 7.76-7.81(m, 3H) 1 H NMR (CD 3 OD + CDCl 3 ) δ 1.25 (m, 1H), 1.49 (m, 3H), 1.85 (s, 3H), 4.41 (m, 1H), 5.11 (s, 2H), 5.58 (d , 1H), 6.70 (s, 1H), 6.89 (s, 1H), 7.15-7.38 (m, 7H), 7.76-7.81 (m, 3H)

FAB MS : 449 (M+1)FAB MS: 449 (M + 1)

실시예 39 내지 55:Examples 39-55:

실시예 37과 유사한 방법으로 반응을 수행하여 하기 표 4a 및 4b에 열거한 화합물들을 수득하였다.The reaction was carried out in a similar manner to Example 37 to obtain the compounds listed in Tables 4A and 4B below.

화합물번호Compound number 1H NMR(CDCl3) δ 1 H NMR (CDCl 3 ) δ FAB MS (M+1)FAB MS (M + 1) 3939 5.02(s, 2H), 6.69(d, 2H), 6.77(s, 1H), 6.92-7.18(m, 5H), 7.40- 7.58(m, 6H), 7.75-7.87(m, 4H)5.02 (s, 2H), 6.69 (d, 2H), 6.77 (s, 1H), 6.92-7.18 (m, 5H), 7.40-7.58 (m, 6H), 7.75-7.87 (m, 4H) 393393 4040 4.06(d, 2H), 5.01(s, 2H), 5.57(t, 1H), 6.46(d, 1H), 6.71(s, 1H), 6.83(s, 1H), 6.92-7.05(m, 3H), 7.42-7.55(m, 7H), 7.74-7.81(m, 3H)4.06 (d, 2H), 5.01 (s, 2H), 5.57 (t, 1H), 6.46 (d, 1H), 6.71 (s, 1H), 6.83 (s, 1H), 6.92-7.05 (m, 3H) , 7.42-7.55 (m, 7H), 7.74-7.81 (m, 3H) 407407 4141 0.45(brs, 2H), 1.22(brs, 4H), 2.95(brs, 2H), 3.37(brs, 2H), 5.04(s, 2H), 6.65(s, 1H), 6.92(s, 1H), 7.08(s, 1H), 7.31-7.45(m, 6H), 7.72(d, 1H), 7.82(d, 1H), 8.12 (d, 1H)0.45 (brs, 2H), 1.22 (brs, 4H), 2.95 (brs, 2H), 3.37 (brs, 2H), 5.04 (s, 2H), 6.65 (s, 1H), 6.92 (s, 1H), 7.08 (s, 1H), 7.31-7.45 (m, 6H), 7.72 (d, 1H), 7.82 (d, 1H), 8.12 (d, 1H) 385385 4242 2.32(brs, 2H), 2.22(brs, 2H), 3.23(brs, 2H), 3.65(brs, 2H), 5.06(s, 2H), 6.72(s, 1H), 6.95(s, 1H), 7.12(s, 1H), 7.31- 7.48(m, 6H), 7.81(d, 1H), 7.85(d, 1H), 8.11(d, 1H)2.32 (brs, 2H), 2.22 (brs, 2H), 3.23 (brs, 2H), 3.65 (brs, 2H), 5.06 (s, 2H), 6.72 (s, 1H), 6.95 (s, 1H), 7.12 (s, 1H), 7.31-7.48 (m, 6H), 7.81 (d, 1H), 7.85 (d, 1H), 8.11 (d, 1H) 387387 4343 1.41(brs, 2H), 2.86-3.25(m, 6H), 4.97(s, 2H), 6.68(s, 1H), 6.85(s, 1H), 7.06(s, 1H), 7.21-7.35(m, 6H), 7.72(d, 1H), 7.78(d, 1H), 7.95(d, 1H)1.41 (brs, 2H), 2.86-3.25 (m, 6H), 4.97 (s, 2H), 6.68 (s, 1H), 6.85 (s, 1H), 7.06 (s, 1H), 7.21-7.35 (m, 6H), 7.72 (d, 1H), 7.78 (d, 1H), 7.95 (d, 1H) 403403 4444 2.04(brs, 4H), 3.62(brs, 4H), 5.03(s, 2H), 6.91(d, 2H), 7.22- 7.48(m, 7H), 7.81-7.88(m, 2H), 8.02(m, 1H)2.04 (brs, 4H), 3.62 (brs, 4H), 5.03 (s, 2H), 6.91 (d, 2H), 7.22- 7.48 (m, 7H), 7.81-7.88 (m, 2H), 8.02 (m, 1H) 435435 4545 1.46(brs, 2H), 2.21(brs, 2H), 3.14(brs, 4H), 5.11(s, 2H), 6.88 (s, 1H), 7.02(s, 1H), 7.11(s, 1H), 7.32-7.51(m, 5H), 7.62(s, 1H), 7.72-7.80(m, 2H), 8.05(d, 1H)1.46 (brs, 2H), 2.21 (brs, 2H), 3.14 (brs, 4H), 5.11 (s, 2H), 6.88 (s, 1H), 7.02 (s, 1H), 7.11 (s, 1H), 7.32 -7.51 (m, 5H), 7.62 (s, 1H), 7.72-7.80 (m, 2H), 8.05 (d, 1H) 386386 4646 (CDCl3+ CD3OD) 2.05(s, 3H), 3.33(brs, 8H), 5.13(s, 2H), 6.90(s, 1H), 7.06(s, 1H), 7.21(s, 1H), 7.30-7.55(m, 4H), 7.64(s, 1H), 7.81(s, 1H), 7.88(d, 1H), 8.06(d, 1H)(CDCl 3 + CD 3 OD) 2.05 (s, 3H), 3.33 (brs, 8H), 5.13 (s, 2H), 6.90 (s, 1H), 7.06 (s, 1H), 7.21 (s, 1H), 7.30-7.55 (m, 4H), 7.64 (s, 1H), 7.81 (s, 1H), 7.88 (d, 1H), 8.06 (d, 1H) 400400 4747 2.62(brs, 2H), 3.15(brs, 2H), 3.86(brs, 1H), 4.35(brs, 1H), 5.06(s, 2H), 6.83(s, 1H), 6.90(s, 1H), 7.15-7.60(m, 6H), 7.73(d, 1H), 7.82(d, 1H), 8.06(d, 1H)2.62 (brs, 2H), 3.15 (brs, 2H), 3.86 (brs, 1H), 4.35 (brs, 1H), 5.06 (s, 2H), 6.83 (s, 1H), 6.90 (s, 1H), 7.15 -7.60 (m, 6H), 7.73 (d, 1H), 7.82 (d, 1H), 8.06 (d, 1H) 389389 4848 0.22(m, 1H), 0.63(m, 1H), 0.83(m, 1H), 1.24(m, 1H), 2.61(brs, 2H), 3.24(brs, 2H), 3.65(brs, 1H), 4.94(s, 2H), 6.71(s, 1H), 6.84(s, 1H), 6.94(s, 1H), 7.24-7.42(m, 6H), 7.62-7.70(m, 2H), 7.94(d, 1H)0.22 (m, 1H), 0.63 (m, 1H), 0.83 (m, 1H), 1.24 (m, 1H), 2.61 (brs, 2H), 3.24 (brs, 2H), 3.65 (brs, 1H), 4.94 (s, 2H), 6.71 (s, 1H), 6.84 (s, 1H), 6.94 (s, 1H), 7.24-7.42 (m, 6H), 7.62-7.70 (m, 2H), 7.94 (d, 1H) ) 401401

4949 1.37(brs, 2H), 1.96(brs, 2H), 3.52(brs, 4H), 5.21(s, 2H), 7.08(s, 1H), 7.20(s, 1H), 7.37(s, 1H), 7.54(m, 5H), 7.70(s, 1H), 7.94(m, 2H), 8.23(d, 1H)1.37 (brs, 2H), 1.96 (brs, 2H), 3.52 (brs, 4H), 5.21 (s, 2H), 7.08 (s, 1H), 7.20 (s, 1H), 7.37 (s, 1H), 7.54 (m, 5H), 7.70 (s, 1H), 7.94 (m, 2H), 8.23 (d, 1H) 399399 5050 2.12(brs, 2H), 3.02(brs, 2H), 4.98(s, 2H), 5.24(m, 1H), 6.82(s, 1H), 7.03(s, 1H), 7.20-7.34(m, 6H), 7.62-7.71(m, 3H), 7.93(d, 1H)2.12 (brs, 2H), 3.02 (brs, 2H), 4.98 (s, 2H), 5.24 (m, 1H), 6.82 (s, 1H), 7.03 (s, 1H), 7.20-7.34 (m, 6H) , 7.62-7.71 (m, 3H), 7.93 (d, 1H) 361361 5151 2.24(brs, 2H), 3.04(brs, 4H), 3.11(s, 3H), 5.03(s, 2H), 6.77(s, 1H), 6.89(s, 1H), 7.14-7.31(m, 6H), 7.56-7.63(m, 3H), 7.87(d, 1H)2.24 (brs, 2H), 3.04 (brs, 4H), 3.11 (s, 3H), 5.03 (s, 2H), 6.77 (s, 1H), 6.89 (s, 1H), 7.14-7.31 (m, 6H) , 7.56-7.63 (m, 3H), 7.87 (d, 1H) 375375 5252 2.51(m, 2H), 3.10(s, 3H), 3.21(m, 2H), 3.47(s, 3H), 5.05(s, 2H), 6.68(s, 1H), 7.05-7.48(m, 7H), 7.74-7.85(m, 2H), 8.09(d, 1H)2.51 (m, 2H), 3.10 (s, 3H), 3.21 (m, 2H), 3.47 (s, 3H), 5.05 (s, 2H), 6.68 (s, 1H), 7.05-7.48 (m, 7H) , 7.74-7.85 (m, 2H), 8.09 (d, 1H) 389389 5353 2.58-3.50(brs, 8H), 5.16(s, 2H), 6.98(d, 1H), 7.08(s, 1H), 7.20-7.27(m, 2H), 7.47(t, 1H), 7.67(s, 1H), 7.71(t, 1H), 8.08(d, 1H), 8.15(d, 1H), 8.80(d, 1H)2.58-3.50 (brs, 8H), 5.16 (s, 2H), 6.98 (d, 1H), 7.08 (s, 1H), 7.20-7.27 (m, 2H), 7.47 (t, 1H), 7.67 (s, 1H), 7.71 (t, 1H), 8.08 (d, 1H), 8.15 (d, 1H), 8.80 (d, 1H) 388388 5454 3.40(m, 4H), 3.70-4.45(brs, 8H), 3.11(s, 3H), 5.18(s, 2H), 6.98(d, 1H), 7.12(s, 1H), 7.17-7.22(m, 2H), 7.25(d, 1H), 7.30(d, 1H), 7.35(t, 1H), 7.62(d, 1H), 7.90(s, 1H)3.40 (m, 4H), 3.70-4.45 (brs, 8H), 3.11 (s, 3H), 5.18 (s, 2H), 6.98 (d, 1H), 7.12 (s, 1H), 7.17-7.22 (m, 2H), 7.25 (d, 1H), 7.30 (d, 1H), 7.35 (t, 1H), 7.62 (d, 1H), 7.90 (s, 1H) 413413 5555 (CD3OD) 3.86(s, 2H), 4.83(s, 2H), 5.58(t, 1H), 6.37(d, 1H), 6.52(s, 2H), 6.81(s, 1H), 7.05-7.35(m, 9H), 7.51(d, 1H), 7.54(d, 1H), 7.58(d, 1H)(CD 3 OD) 3.86 (s, 2H), 4.83 (s, 2H), 5.58 (t, 1H), 6.37 (d, 1H), 6.52 (s, 2H), 6.81 (s, 1H), 7.05-7.35 (m, 9H), 7.51 (d, 1H), 7.54 (d, 1H), 7.58 (d, 1H) 432432

실시예 56: 1-(1-메틸-1H-이미다졸-5-일)메틸-3-(모폴린-4-일)카보닐-4-(나프탈렌-1-일)-1H-피롤(56)의 합성Example 56 1- (1-Methyl-1H-imidazol-5-yl) methyl-3- (morpholin-4-yl) carbonyl-4- (naphthalen-1-yl) -1H-pyrrole (56 ) Synthesis

실시예 42에서 수득한 화합물에 제조예 1-1)에서와 같이 트리틸 보호기를 도입한 후, 메틸요오다이드를 사용하여 제조예 2-2) 및 2-3)과 유사하게 실시함으로써 55% 수율로 표제화합물을 수득하였다.55% by introducing a trityl protecting group to the compound obtained in Example 42 as in Preparation Example 1-1, and then using methyl iodide in a similar manner to Preparation Examples 2-2) and 2-3) The title compound was obtained in yield.

1H NMR(CDCl3) δ 2.80-3.45(m, 8H), 3.58(s, 3H), 5.19(s, 2H), 6.75(d, 1H), 7.18(d, 1H), 7.21(s, 1H), 7.35(d, 1H), 7.40-7.50(m, 3H), 7.72(d, 1H), 8.03(d, 1H) 1 H NMR (CDCl 3 ) δ 2.80-3.45 (m, 8H), 3.58 (s, 3H), 5.19 (s, 2H), 6.75 (d, 1H), 7.18 (d, 1H), 7.21 (s, 1H ), 7.35 (d, 1H), 7.40-7.50 (m, 3H), 7.72 (d, 1H), 8.03 (d, 1H)

FAB MS : 401 (M+1)FAB MS: 401 (M + 1)

실시예 57: (S)-1-[1-(4-시아노벤질)-1H-이미다졸-5-일]메틸-3-[N-(1-메톡시카보닐-3-메틸티오)프로필]카바모일-4-(나프탈렌-1-일)-1H-피롤(57)의 합성Example 57: (S) -1- [1- (4-cyanobenzyl) -1H-imidazol-5-yl] methyl-3- [N- (1-methoxycarbonyl-3-methylthio) Propyl] Synthesis of Carbamoyl-4- (naphthalen-1-yl) -1H-pyrrole (57)

57-1) 1-[1-(4-시아노벤질)-1H-이미다졸-5-일메틸]-3-하이드록시카보닐-4-(나프탈렌-1-일)-1H-피롤의 제조57-1) Preparation of 1- [1- (4-cyanobenzyl) -1H-imidazol-5-ylmethyl] -3-hydroxycarbonyl-4- (naphthalen-1-yl) -1H-pyrrole

실시예 37-2)에서 수득한 화합물과 제조예 2-5)에서 수득한 화합물로부터 실시예 30 및 실시예 37-4)의 방법을 차례로 실시하여 75% 수율로 표제화합물을 수득하였다.From the compound obtained in Example 37-2) and the compound obtained in Preparation Example 2-5), the methods of Example 30 and Example 37-4) were carried out in order to obtain the title compound in 75% yield.

1H NMR(CDCl3+ CD3OD) δ 5.02(s, 2H), 5.10(s, 2H), 6.76(s, 1H), 7.07(m, 2H), 7.25-7.82(m, 12H) 1 H NMR (CDCl 3 + CD 3 OD) δ 5.02 (s, 2H), 5.10 (s, 2H), 6.76 (s, 1H), 7.07 (m, 2H), 7.25-7.82 (m, 12H)

57-2) (S)-1-[1-(4-시아노벤질)-1H-이미다졸-5-일]메틸-3-[N-(1-메톡시카보닐-3-메틸티오)프로필]카바모일-4-(나프탈렌-1-일)-1H-피롤의 제조57-2) (S) -1- [1- (4-cyanobenzyl) -1H-imidazol-5-yl] methyl-3- [N- (1-methoxycarbonyl-3-methylthio) Propyl] Preparation of Carbamoyl-4- (naphthalen-1-yl) -1H-pyrrole

실시예 57-1)에서 수득한 화합물을 사용하는 점을 제외하고는 실시예 37-5)와 동일하게 실시하여 35% 수율로 표제화합물을 수득하였다Except for using the compound obtained in Example 57-1), the title compound was obtained in the same manner as in Example 37-5) in 35% yield.

1H NMR(CDCl3) δ 1.85(s, 3H), 2.04(m, 1H), 2.13(m, 1H), 2.42(t, 2H), 3.61(s, 3H), 4.83(m, 1H), 5.02(s, 2H), 5.11(s, 2H), 6.63(s, 1H), 7.01(d, 2H), 7.13(d, 1H), 7.22-7.43(m, 7H), 7.65-7.92(m, 4H) 1 H NMR (CDCl 3 ) δ 1.85 (s, 3H), 2.04 (m, 1H), 2.13 (m, 1H), 2.42 (t, 2H), 3.61 (s, 3H), 4.83 (m, 1H), 5.02 (s, 2H), 5.11 (s, 2H), 6.63 (s, 1H), 7.01 (d, 2H), 7.13 (d, 1H), 7.22-7.43 (m, 7H), 7.65-7.92 (m, 4H)

FAB MS : 578 (M+1)FAB MS: 578 (M + 1)

실시예 58: (S)-1-[1-(4-시아노벤질)-1H-이미다졸-5-일]메틸-3-[N-(1-하이드록시카보닐-3-메틸티오)프로필]카바모일-4-(나프탈렌-1-일)-1H-피롤(58)의 합성Example 58: (S) -1- [1- (4-cyanobenzyl) -1H-imidazol-5-yl] methyl-3- [N- (1-hydroxycarbonyl-3-methylthio) Propyl] Synthesis of Carbamoyl-4- (naphthalen-1-yl) -1H-pyrrole (58)

실시예 57-2)에서 수득한 화합물로부터 실시예 38에서와 유사하게 실시하여 96% 수율로 표제화합물의 리튬염을 수득하였다.From the compound obtained in Example 57-2), a lithium salt of the title compound was obtained in 96% yield in the same manner as in Example 38.

1H NMR(CDCl3+ CD3OD) δ 1.82(s, 3H), 2.00(m, 1H), 2.11(m, 1H), 2.36(t, 2H), 4.82(m, 1H), 4.89(s, 2H), 5.02(s, 2H), 6.49(s, 1H), 6.88(d, 2H), 7.11(d, 1H), 7.17-7.32(m, 7H), 7.62-7.83(m, 4H) 1 H NMR (CDCl 3 + CD 3 OD) δ 1.82 (s, 3H), 2.00 (m, 1H), 2.11 (m, 1H), 2.36 (t, 2H), 4.82 (m, 1H), 4.89 (s , 2H), 5.02 (s, 2H), 6.49 (s, 1H), 6.88 (d, 2H), 7.11 (d, 1H), 7.17-7.32 (m, 7H), 7.62-7.83 (m, 4H)

FAB MS : 564(M+1)FAB MS: 564 (M + 1)

실시예 59 및 60:Examples 59 and 60:

실시예 57 및 58과 유사한 방법으로 반응을 수행하여 하기 표 5에 열거한 화합물들을 수득하였다.The reaction was carried out in a similar manner to Examples 57 and 58 to afford the compounds listed in Table 5 below.

화합물번호Compound number 1H NMR δ 1 H NMR δ FAB MS (M+1)FAB MS (M + 1) 5959 (CDCl3) 0.67(d, 3H), 0.78(d, 3H), 0.82(m, 1H), 0.90(m, 1H), 1.10(m, 1H), 3.52(s, 3H), 4.32(m, 1H), 5.02(s, 2H), 5.17(s, 2H), 6.72(s, 1H), 6.83(s, 1H), 7.23-7.34(m, 3H), 7.41-7.92(m, 10H)(CDCl 3 ) 0.67 (d, 3H), 0.78 (d, 3H), 0.82 (m, 1H), 0.90 (m, 1H), 1.10 (m, 1H), 3.52 (s, 3H), 4.32 (m, 1H), 5.02 (s, 2H), 5.17 (s, 2H), 6.72 (s, 1H), 6.83 (s, 1H), 7.23-7.34 (m, 3H), 7.41-7.92 (m, 10H) 560560 6060 (CDCl3+ CD3OD) 0.62(d, 3H), 0.71(d, 3H), 0.79(m, 1H), 0.88(m, 1H), 0.98(m, 1H), 4.12(m, 1H), 4.97(s, 2H), 5.08(s, 2H), 6.77(s, 1H), 6.82(s, 1H), 7.14-7.30(m, 4H), 7.38-7.84(m, 9H)(CDCl 3 + CD 3 OD) 0.62 (d, 3H), 0.71 (d, 3H), 0.79 (m, 1H), 0.88 (m, 1H), 0.98 (m, 1H), 4.12 (m, 1H), 4.97 (s, 2H), 5.08 (s, 2H), 6.77 (s, 1H), 6.82 (s, 1H), 7.14-7.30 (m, 4H), 7.38-7.84 (m, 9H) 546546

실시예 61 및 62:Examples 61 and 62:

실시예 58과 유사한 방법으로 반응을 수행하여 하기 표 6에 열거한 화합물들을 수득하였다.The reaction was carried out in a similar manner to Example 58 to obtain the compounds listed in Table 6 below.

화합물번호Compound number 1H NMR (CDCl3) δ 1 H NMR (CDCl 3 ) δ FAB MS (M+1)FAB MS (M + 1) 6161 1.95(brs, 2H), 2.33(brs, 1H), 2.95(brs, 5H), 4.93(s, 2H), 5.05 (s, 2H), 6.62(s, 1H), 7.05(s, 1H), 7.11(d, 2H), 7.28(m, 2H), 7.51(m, 3H), 7.63(m, 3H), 7.81-7.88(m, 2H), 7.95(d, 1H)1.95 (brs, 2H), 2.33 (brs, 1H), 2.95 (brs, 5H), 4.93 (s, 2H), 5.05 (s, 2H), 6.62 (s, 1H), 7.05 (s, 1H), 7.11 (d, 2H), 7.28 (m, 2H), 7.51 (m, 3H), 7.63 (m, 3H), 7.81-7.88 (m, 2H), 7.95 (d, 1H) 502502 6262 1.12(brs, 2H), 1.88(brs, 2H), 1.90(s, 3H), 2.95(brs, 2H), 3.34 (brs, 2H), 4.97(s, 2H), 5.07(s, 2H), 6.60(s, 1H), 7.02(s, 1H), 7.10(d, 2H), 7.29(m, 2H), 7.46(m, 3H), 7.60(m, 3H), 7.80(d, 1H), 7.85(d, 1H), 7.97(d, 1H)1.12 (brs, 2H), 1.88 (brs, 2H), 1.90 (s, 3H), 2.95 (brs, 2H), 3.34 (brs, 2H), 4.97 (s, 2H), 5.07 (s, 2H), 6.60 (s, 1H), 7.02 (s, 1H), 7.10 (d, 2H), 7.29 (m, 2H), 7.46 (m, 3H), 7.60 (m, 3H), 7.80 (d, 1H), 7.85 ( d, 1H), 7.97 (d, 1H) 515515

실시예 63: 1-[2-(1H-이미다졸-1-일)에틸]-3-(모폴린-4-일)카보닐-4-(나프탈렌-1-일)-1H-피롤(63)의 합성Example 63 1- [2- (1H-imidazol-1-yl) ethyl] -3- (morpholin-4-yl) carbonyl-4- (naphthalen-1-yl) -1H-pyrrole (63 ) Synthesis

63-1) 2-(1H-이미다졸-1-일)에틸 p-토실레이트의 제조63-1) Preparation of 2- (1H-imidazol-1-yl) ethyl p-tosylate

2-(1H-이미다졸-1-일)에탄올 0.24g(2.41 밀리몰)과 토실클로라이드 0.55g (2.88 밀리몰)을 디클로로메탄 20㎖에 녹이고 0℃에서 트리에틸아민 0.67㎖를 서서히 첨가한 후 상온에서 4시간동안 교반하였다. 감압하에 유기용매를 제거한 후 에틸아세테이트 10㎖에 녹이고, 1N 염산수용액, 중탄산나트륨 포화수용액, 소금물을 사용하여 차례로 세척해주었다. 무수 마그네슘설페이트로 건조시킨 후 농축시켰다. 잔류물에 대해 칼럼 크로마토그래피(용리제: 디클로로메탄/메탄올=20/1, v/v)를 수행하여 표제화합물 0.30g(1.13 밀리몰, 수율 47%)을 수득하였다.0.24 g (2.41 mmol) of 2- (1H-imidazol-1-yl) ethanol and 0.55 g (2.88 mmol) of tosyl chloride were dissolved in 20 ml of dichloromethane, and 0.67 ml of triethylamine was slowly added at 0 ° C, and then at room temperature. Stir for 4 hours. After removing the organic solvent under reduced pressure, it was dissolved in 10 ml of ethyl acetate, and washed sequentially with 1N aqueous hydrochloric acid solution, saturated aqueous sodium bicarbonate solution and brine. It was dried over anhydrous magnesium sulfate and then concentrated. Column chromatography (eluent: dichloromethane / methanol = 20/1, v / v) on the residue gave 0.30 g (1.13 mmol, 47% yield) of the title compound.

1H NMR(CDCl3) δ 2.42(s, 3H), 4.17-4.28(m, 4H), 6.88(s, 1H), 6.99(s, 1H), 7.29(d, 2H), 7.45(s, 1H), 7.64(d, 2H) 1 H NMR (CDCl 3 ) δ 2.42 (s, 3H), 4.17-4.28 (m, 4H), 6.88 (s, 1H), 6.99 (s, 1H), 7.29 (d, 2H), 7.45 (s, 1H ), 7.64 (d, 2 H)

63-2) 3-하이드록시카보닐-4-(나프탈렌-1-일)-1H-피롤의 제조63-2) Preparation of 3-hydroxycarbonyl-4- (naphthalen-1-yl) -1H-pyrrole

실시예 37-2)에서 수득한 화합물을 실시예 37-4)의 방법으로 가수분해하여 80% 수율로 표제화합물을 수득하였다.The compound obtained in Example 37-2) was hydrolyzed by the method of Example 37-4) to give the title compound in 80% yield.

1H NMR (CDCl3+ CD3OD) δ 7.12(m, 3H), 7.20-7.31(m, 3H), 7.50(d, 1H), 7.68(d, 1H), 7.76(d, 1H) 1 H NMR (CDCl 3 + CD 3 OD) δ 7.12 (m, 3H), 7.20-7.31 (m, 3H), 7.50 (d, 1H), 7.68 (d, 1H), 7.76 (d, 1H)

63-3) 3-(모폴린-4-일)카보닐-4-(나프탈렌-1-일)-1H-피롤의 제조63-3) Preparation of 3- (morpholin-4-yl) carbonyl-4- (naphthalen-1-yl) -1H-pyrrole

실시예 63-2)에서 수득한 화합물과 모폴린으로부터 실시예 37-5)의 방법에 따라 실시하여 99% 수율로 표제화합물을 수득하였다.The title compound was obtained in 99% yield from the compound obtained in Example 63-2) and the morpholine by the method of Example 37-5).

1H NMR (CDCl3) δ 2.68-3.62(brs, 8H), 6.88(s, 1H), 7.20(s, 1H), 7.30-7.62(m, 4H), 7.78(d, 1H), 7.85(d, 1H), 8.08(d, 1H), 10.34(s, 1H) 1 H NMR (CDCl 3 ) δ 2.68-3.62 (brs, 8H), 6.88 (s, 1H), 7.20 (s, 1H), 7.30-7.62 (m, 4H), 7.78 (d, 1H), 7.85 (d , 1H), 8.08 (d, 1H), 10.34 (s, 1H)

63-4) 1-[2-(1H-이미다졸-1-일)에틸]-3-(모폴린-4-일)카보닐-4-(나프탈렌-1-일)-1H-피롤의 제조63-4) Preparation of 1- [2- (1H-imidazol-1-yl) ethyl] -3- (morpholin-4-yl) carbonyl-4- (naphthalen-1-yl) -1H-pyrrole

실시예 63-1)에서 수득한 화합물과 실시예 63-3)에서 수득한 화합물을 실시예 1-3)의 방법에 따라 반응시켜 51% 수율로 표제화합물을 수득하였다.The compound obtained in Example 63-1) and the compound obtained in Example 63-3) were reacted according to the method of Example 1-3) to obtain the title compound in 51% yield.

1H NMR (CDCl3) δ 2.20-3.72(brs, 12H), 7.20(s, 1H), 7.40-7.55(m, 8H), 7.82(d, 1H), 7.88(d, 1H), 8.05(d, 1H) 1 H NMR (CDCl 3 ) δ 2.20-3.72 (brs, 12H), 7.20 (s, 1H), 7.40-7.55 (m, 8H), 7.82 (d, 1H), 7.88 (d, 1H), 8.05 (d , 1H)

FAB MS : 401 (M+1)FAB MS: 401 (M + 1)

실시예 64: (S)-1-[3-(1H-이미다졸-4-일)프로필]-3-[N-(1-메톡시카보닐-3-메틸티오)프로필]카바모일-4-(나프탈렌-1-일)-1H-피롤(64)의 합성Example 64: (S) -1- [3- (1H-imidazol-4-yl) propyl] -3- [N- (1-methoxycarbonyl-3-methylthio) propyl] carbamoyl-4 Synthesis of-(naphthalen-1-yl) -1H-pyrrole (64)

64-1) 3-에톡시카보닐-4-(나프탈렌-1-일)-1-[3-(1-트리틸-1H-이미다졸-4-일)알릴]-1H-피롤의 제조64-1) Preparation of 3-ethoxycarbonyl-4- (naphthalen-1-yl) -1- [3- (1-trityl-1H-imidazol-4-yl) allyl] -1H-pyrrole

실시예 37-2)에서 수득한 화합물과 제조예 3-4)에서 수득한 화합물을 실시예1-3)의 방법에 따라 반응시켜 85% 수율로 표제화합물을 수득하였다.The compound obtained in Example 37-2) and the compound obtained in Preparation Example 3-4) were reacted according to the method of Example 1-3) to obtain the title compound in 85% yield.

1H NMR (CDCl3) δ 0.82(t, 3H), 3.95(q, 2H), 4.67(s, 2H), 6.23(d, 1H), 6.47(m, 1H), 6.63(s, 1H), 7.02(s, 1H), 7.25-7.81(m, 24H) 1 H NMR (CDCl 3 ) δ 0.82 (t, 3H), 3.95 (q, 2H), 4.67 (s, 2H), 6.23 (d, 1H), 6.47 (m, 1H), 6.63 (s, 1H), 7.02 (s, 1H), 7.25-7.81 (m, 24H)

64-2) 3-에톡시카보닐-4-(나프탈렌-1-일)-1-[3-(1-트리틸-1H-이미다졸-4-일)프로필]-1H-피롤의 제조64-2) Preparation of 3-ethoxycarbonyl-4- (naphthalen-1-yl) -1- [3- (1-trityl-1H-imidazol-4-yl) propyl] -1H-pyrrole

실시예 64-1)에서 수득한 화합물 300mg(0.49 밀리몰)을 메탄올 2㎖에 녹이고 Pd/C를 촉매량 가한 후 수소대기하에서 1시간동안 교반하였다. 여과하여 촉매를 제거하고 감압하에 용매를 제거하였다. 잔류물에 대해 칼럼 크로마토그래피(용리제: 디클로로메탄/메탄올=98/2, v/v)를 수행하여 표제화합물 246mg(0.40 밀리몰, 수율 82%)을 수득하였다.300 mg (0.49 mmol) of the compound obtained in Example 64-1) was dissolved in 2 ml of methanol, and a catalytic amount of Pd / C was added, followed by stirring for 1 hour under hydrogen atmosphere. The catalyst was removed by filtration to remove the solvent under reduced pressure. Column chromatography on the residue (eluent: dichloromethane / methanol = 98/2, v / v) gave 246 mg (0.40 mmol, yield 82%) of the title compound.

1H NMR (CDCl3) δ 0.92(t, 3H), 2.22(m, 2H), 2.73(t, 2H), 4.01(m, 4H), 6.70(s, 1H), 6.82(s, 1H), 7.32-7.73(m, 21H), 7.91(m, 3H) 1 H NMR (CDCl 3 ) δ 0.92 (t, 3H), 2.22 (m, 2H), 2.73 (t, 2H), 4.01 (m, 4H), 6.70 (s, 1H), 6.82 (s, 1H), 7.32-7.73 (m, 21 H), 7.91 (m, 3 H)

64-3) (S)-1-[3-(1H-이미다졸-4-일)프로필]-3-[N-(1-메톡시카보닐-3-메틸티오)프로필]카바모일-4-(나프탈렌-1-일)-1H-피롤의 제조64-3) (S) -1- [3- (1H-imidazol-4-yl) propyl] -3- [N- (1-methoxycarbonyl-3-methylthio) propyl] carbamoyl-4 Preparation of-(naphthalen-1-yl) -1H-pyrrole

실시예 64-2)에서 수득한 화합물에 대해 실시예 1-4) 및 37-4)의 방법을 차례로 실시하여 트리틸기를 제거하고 가수분해를 수행한 다음, (L)-메티오닌 메틸에스테르와 실시예 37-5)의 방법으로 반응을 실시하여 29% 수율로 표제화합물을 수득하였다.The compounds obtained in Example 64-2) were sequentially subjected to the methods of Examples 1-4) and 37-4) to remove trityl groups and subjected to hydrolysis, followed by (L) -methionine methyl ester. Example 37-5) was carried out to give the title compound in 29% yield.

1H NMR (CDCl3) δ 1.65(m, 2H), 1.90(s, 3H), 2.12(m, 2H), 2.31(m, 2H), 2.73(m, 2H), 3.54(s, 3H), 4.02(m, 2H), 4.56(m, 1H), 5.77(d, 1H), 6.72(s, 1H), 6.90(s, 1H), 7.42-7.67(m, 7H), 7.82-8.01(m, 5H) 1 H NMR (CDCl 3 ) δ 1.65 (m, 2H), 1.90 (s, 3H), 2.12 (m, 2H), 2.31 (m, 2H), 2.73 (m, 2H), 3.54 (s, 3H), 4.02 (m, 2H), 4.56 (m, 1H), 5.77 (d, 1H), 6.72 (s, 1H), 6.90 (s, 1H), 7.42-7.67 (m, 7H), 7.82-8.01 (m, 5H)

FAB MS : 491(M+1)FAB MS: 491 (M + 1)

실시예 65: (S)-3-[N-(1-하이드록시카보닐-3-메틸티오)프로필]카바모일-1-[3-(1H-이미다졸-4-일)프로필]-4-(나프탈렌-1-일)-1H-피롤(65)의 합성Example 65: (S) -3- [N- (1-hydroxycarbonyl-3-methylthio) propyl] carbamoyl-1- [3- (1H-imidazol-4-yl) propyl] -4 Synthesis of-(naphthalen-1-yl) -1H-pyrrole (65)

실시예 64-3)에서 수득한 화합물을 사용하는 점을 제외하고는 실시예 38에서와 동일하게 실시하여 95% 수율로 표제화합물을 수득하였다.The title compound was obtained in 95% yield as in Example 38, except that the compound obtained in Example 64-3) was used.

1H NMR (CDCl3) δ 1.57(m, 2H), 1.88(s, 3H), 2.08(m, 2H), 2.29(m, 2H), 2.77(m, 2H), 4.12(m, 2H), 4.49(m, 1H), 5.69(d, 1H), 6.77(s, 1H), 6.92(s, 1H), 7.34-7.58(m, 7H), 7.80-7.89(m, 5H) 1 H NMR (CDCl 3 ) δ 1.57 (m, 2H), 1.88 (s, 3H), 2.08 (m, 2H), 2.29 (m, 2H), 2.77 (m, 2H), 4.12 (m, 2H), 4.49 (m, 1H), 5.69 (d, 1H), 6.77 (s, 1H), 6.92 (s, 1H), 7.34-7.58 (m, 7H), 7.80-7.89 (m, 5H)

FAB MS : 477(M+1)FAB MS: 477 (M + 1)

실시예 66: 1-[3-(1H-이미다졸-4-일)프로필]-3-(모폴린-4-일)카보닐-4-(나프탈렌-1-일)-1H-피롤(66)의 합성Example 66 1- [3- (1H-imidazol-4-yl) propyl] -3- (morpholin-4-yl) carbonyl-4- (naphthalen-1-yl) -1H-pyrrole (66 ) Synthesis

실시예 64-2)에서 수득한 화합물에 대해 모폴린을 사용하는 것을 제외하고는 실시예 64-3)과 동일한 방법을 적용하여 42% 수율로 표제화합물을 수득하였다.The title compound was obtained in 42% yield using the same method as Example 64-3) except for using morpholine for the compound obtained in Example 64-2).

1H NMR (CDCl3) δ 2.16(m, 2H), 2.35(brs, 2H), 2.63(m, 2H), 2.80-3.50(brs, 6H), 3.54(s, 3H), 3.96(m, 2H), 6.74(d, 1H), 6.76(s, 1H), 7.07(s, 1H), 7.33(t, 1H), 7.36-7.50(m, 4H), 7.76(d, 1H), 7.84(d, 1H), 8.08(d, 1H) 1 H NMR (CDCl 3 ) δ 2.16 (m, 2H), 2.35 (brs, 2H), 2.63 (m, 2H), 2.80-3.50 (brs, 6H), 3.54 (s, 3H), 3.96 (m, 2H ), 6.74 (d, 1H), 6.76 (s, 1H), 7.07 (s, 1H), 7.33 (t, 1H), 7.36-7.50 (m, 4H), 7.76 (d, 1H), 7.84 (d, 1H), 8.08 (d, 1H)

FAB MS : 415(M+1)FAB MS: 415 (M + 1)

실시예 67: 1-[1-(4-시아노벤질)-1H-이미다졸-5-일]메틸-3-[N-(2-메톡시에틸)-N-메틸]카바모일-4-(나프탈렌-1-일)-1H-피롤(67)의 합성Example 67 1- [1- (4-cyanobenzyl) -1H-imidazol-5-yl] methyl-3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- Synthesis of (naphthalen-1-yl) -1H-pyrrole (67)

67-1) 3-[N-(2-메톡시에틸)-N-메틸]카바모일-4-(나프탈렌-1-일)-1H-피롤의 제조67-1) Preparation of 3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- (naphthalen-1-yl) -1H-pyrrole

실시예 63-2)에서 수득한 화합물 100㎎(0.42 밀리몰)과 N-(2-메톡시에틸)-N-메틸아민 38㎎(0.4 밀리몰)을 사용하여 실시예 37-5)에서와 유사한 방법으로 반응을 수행하여 표제화합물 110㎎(0.35 밀리몰, 수율 85%)을 수득하였다.Similar method as in Example 37-5) using 100 mg (0.42 mmol) of the compound obtained in Example 63-2) and 38 mg (0.4 mmol) of N- (2-methoxyethyl) -N-methylamine The reaction was carried out to give 110 mg (0.35 mmol, 85% yield) of the title compound.

1H NMR (CDCl3) δ 2.21(s, 3H), 2.64(brs, 1H), 2.75(brs, 1H), 3.02(s, 3H), 3.13(brs, 1H), 3.32(brs, 1H), 6.72(s, 1H), 7.05(m, 2H), 7.21(m, 2H), 7.54(m, 1H), 7.78(m, 2H), 8.04(d, 1H), 8.78(brs, 1H) 1 H NMR (CDCl 3 ) δ 2.21 (s, 3H), 2.64 (brs, 1H), 2.75 (brs, 1H), 3.02 (s, 3H), 3.13 (brs, 1H), 3.32 (brs, 1H), 6.72 (s, 1H), 7.05 (m, 2H), 7.21 (m, 2H), 7.54 (m, 1H), 7.78 (m, 2H), 8.04 (d, 1H), 8.78 (brs, 1H)

67-2) 1-[1-(4-시아노벤질)-1H-이미다졸-5-일]메틸-3-[N-(2-메톡시에틸)-N-메틸]카바모일-4-(나프탈렌-1-일)-1H-피롤의 제조67-2) 1- [1- (4-cyanobenzyl) -1H-imidazol-5-yl] methyl-3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- Preparation of (Naphthalen-1-yl) -1H-pyrrole

실시예 67-1)에서 수득한 화합물 98㎎(0.32 밀리몰)과 제조예 2-5)에서 수득한 화합물 85㎎(0.32 밀리몰)을 사용하여 실시예 1-3)과 유사한 방법으로 반응을 수행하여 표제화합물 115㎎(0.23 밀리몰, 수율 72%)을 수득하였다.The reaction was carried out in a similar manner to Example 1-3) using 98 mg (0.32 mmol) of the compound obtained in Example 67-1) and 85 mg (0.32 mmol) of the compound obtained in Preparation Example 2-5). 115 mg (0.23 mmol, 72% yield) of the title compound were obtained.

1H NMR (CDCl3) δ 2.41(s, 3H), 2.75(brs, 2H), 3.07(s, 3H), 3.17(brs, 1H), 3.32(brs, 1H), 4.91(s, 2H), 5.11(s, 2H), 6.71(s, 1H), 7.05(s, 1H), 7.17(d, 1H), 7.40-7.68(m, 9H), 7.78(d, 1H), 7.88(d, 1H), 8.06(d, 1H) 1 H NMR (CDCl 3 ) δ 2.41 (s, 3H), 2.75 (brs, 2H), 3.07 (s, 3H), 3.17 (brs, 1H), 3.32 (brs, 1H), 4.91 (s, 2H), 5.11 (s, 2H), 6.71 (s, 1H), 7.05 (s, 1H), 7.17 (d, 1H), 7.40-7.68 (m, 9H), 7.78 (d, 1H), 7.88 (d, 1H) , 8.06 (d, 1 H)

FAB MS : 504 (M+1)FAB MS: 504 (M + 1)

실시예 68: 1-[1-(4-브로모벤질)-1H-이미다졸-5-일]메틸-3-[N-(2-메톡시에틸)-N-메틸]카바모일-4-(나프탈렌-1-일)-1H-피롤(68)의 합성Example 68: 1- [1- (4-bromobenzyl) -1H-imidazol-5-yl] methyl-3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- Synthesis of (naphthalen-1-yl) -1H-pyrrole (68)

실시예 67-1)에서 수득한 화합물 105㎎(0.29 밀리몰)과 제조예 5-2)에서 수득한 화합물 78㎎(0.29 밀리몰)을 사용하여 실시예 1-3)과 유사한 방법으로 반응을 수행하여 표제화합물 121㎎(0.21 밀리몰, 수율 75%)을 수득하였다.The reaction was carried out in a similar manner to Example 1-3) using 105 mg (0.29 mmol) of the compound obtained in Example 67-1) and 78 mg (0.29 mmol) of the compound obtained in Preparation Example 5-2). 121 mg (0.21 mmol, Yield 75%) of the title compound were obtained.

1H NMR (CDCl3) δ 2.37(s, 3H), 2.72(brs, 2H), 3.04(s, 3H), 3.15(brs, 1H), 3.31(brs, 1H), 4.95(s, 2H), 5.10(s, 2H), 6.67(s, 1H), 7.11(s, 1H), 7.23-7.65(m, 10H), 7.81(d, 1H), 7.89(d, 1H), 8.02(d, 1H) 1 H NMR (CDCl 3 ) δ 2.37 (s, 3H), 2.72 (brs, 2H), 3.04 (s, 3H), 3.15 (brs, 1H), 3.31 (brs, 1H), 4.95 (s, 2H), 5.10 (s, 2H), 6.67 (s, 1H), 7.11 (s, 1H), 7.23-7.65 (m, 10H), 7.81 (d, 1H), 7.89 (d, 1H), 8.02 (d, 1H)

FAB MS : 557 (M+1)FAB MS: 557 (M + 1)

실시예 69: 1-[1-(4-브로모벤질)-1H-이미다졸-5-일]메틸-3-(모폴린-4-일)카보닐-4-(나프탈렌-1-일)-1H-피롤(69)의 합성Example 69 1- [1- (4-bromobenzyl) -1H-imidazol-5-yl] methyl-3- (morpholin-4-yl) carbonyl-4- (naphthalen-1-yl) Synthesis of -1H-pyrrole (69)

실시예 63-3)에서 수득한 화합물 100㎎(0.33 밀리몰)과 제조예 5-2)에서 수득한 화합물 105㎎(0.33 밀리몰)을 사용하여 실시예 1-3)과 유사한 방법으로 반응을 수행하여 표제화합물 130㎎(0.23 밀리몰, 수율 71%)을 수득하였다.The reaction was carried out in a similar manner to Example 1-3) using 100 mg (0.33 mmol) of the compound obtained in Example 63-3) and 105 mg (0.33 mmol) of the compound obtained in Preparation Example 5-2). 130 mg (0.23 mmol, 71% yield) of the title compound were obtained.

1H NMR (CDCl3) δ 2.04(brs, 2H), 2.25(brs, 1H), 3.03(brs, 5H), 4.93(s, 2H), 5.07(s, 2H), 6.62(s, 1H), 7.10(m, 3H), 7.29(m, 2H), 7.41(m, 3H), 7.60(m, 3H), 7.81(d, 1H), 7.89(d, 1H), 8.01(d, 1H) 1 H NMR (CDCl 3 ) δ 2.04 (brs, 2H), 2.25 (brs, 1H), 3.03 (brs, 5H), 4.93 (s, 2H), 5.07 (s, 2H), 6.62 (s, 1H), 7.10 (m, 3H), 7.29 (m, 2H), 7.41 (m, 3H), 7.60 (m, 3H), 7.81 (d, 1H), 7.89 (d, 1H), 8.01 (d, 1H)

FAB MS : 555 (M+1)FAB MS: 555 (M + 1)

실시예 70: 1-[1-(4-시아노벤질)-1H-이미다졸-5-일]메틸-3-(모폴린-4-일)티오카보닐-4-(나프탈렌-1-일)-1H-피롤(70)의 합성Example 70 1- [1- (4-cyanobenzyl) -1H-imidazol-5-yl] methyl-3- (morpholin-4-yl) thiocarbonyl-4- (naphthalen-1-yl Synthesis of) -1H-pyrrole 70

실시예 61에서 수득한 화합물 20㎎(0.04 밀리몰)과 2,4-비스(페닐티오)-1,3-디티아-2,4-디포스파탄-2,4-디설파이드 18㎎을 테트라하이드로푸란 1㎖에 녹인 후 상온에서 3시간동안 교반하였다. 반응액에 포화 중탄산나트륨 수용액 2㎖를 가하고 에틸아세테이트로 추출하였다. 무수 소듐설페이트로 건조시키고 감압하에 유기용매를 제거하였다. 잔류물을 칼럼 크로마토그래피(용리제: 디클로로메탄/메탄올=9/1, v/v)로 정제하여 표제화합물 9㎎(0.017 밀리몰, 수율 43%)을 수득하였다.20 mg (0.04 mmol) of the compound obtained in Example 61 and 18 mg of 2,4-bis (phenylthio) -1,3-dithia-2,4-diphosphatane-2,4-disulfide were tetrahydrofuran. It was dissolved in 1ml and stirred at room temperature for 3 hours. 2 ml of saturated aqueous sodium bicarbonate solution was added to the reaction solution, which was then extracted with ethyl acetate. Dry over anhydrous sodium sulfate and remove the organic solvent under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol = 9/1, v / v) to give 9 mg (0.017 mmol, yield 43%) of the title compound.

1H NMR (CDCl3) δ 1.88(brs, 2H), 2.64(brs, 6H), 4.86(s, 2H), 5.01(s, 2H), 6.67(s, 1H), 7.14(m, 3H), 7.26-7.58(m, 8H), 7.81(m, 2H), 8.03(d, 1H) 1 H NMR (CDCl 3 ) δ 1.88 (brs, 2H), 2.64 (brs, 6H), 4.86 (s, 2H), 5.01 (s, 2H), 6.67 (s, 1H), 7.14 (m, 3H), 7.26-7.58 (m, 8H), 7.81 (m, 2H), 8.03 (d, 1H)

FAB MS : 518 (M+1)FAB MS: 518 (M + 1)

실시예 71: 3-[N-(2-메톡시에틸)-N-메틸]카바모일-1-(1-메틸-1H-이미다졸-5-일)메틸-4-(나프탈렌-1-일)-1H-피롤(71)의 합성Example 71: 3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-1- (1-methyl-1H-imidazol-5-yl) methyl-4- (naphthalen-1-yl Synthesis of) -1H-pyrrole (71)

71-1) 4-(나프탈렌-1-일)-1H-피롤-3-카복실산의 제조71-1) Preparation of 4- (naphthalen-1-yl) -1H-pyrrole-3-carboxylic acid

실시예 37-2)의 화합물 2.64g(10 밀리몰)을 50% 에탄올 50㎖에 녹이고 수산화칼륨 2.24g(40 밀리몰)을 가한 후 7 시간동안 환류시켰다. 반응액을 상온으로 냉각시킨후 pH를 4-5로 조절하고 에틸아세테이트로 추출하였다. 무수 황산나트륨상에서 건조시키고, 감압하에 용매를 제거하여 표제화합물 1.62g(8.1 밀리몰; 수율 81%)을 수득하였다. 이 화합물은 정제하지 않고 다음 반응에 사용하였다.2.64 g (10 mmol) of the compound of Example 37-2) were dissolved in 50 mL of 50% ethanol, and 2.24 g (40 mmol) of potassium hydroxide was added and refluxed for 7 hours. After cooling the reaction solution to room temperature, the pH was adjusted to 4-5 and extracted with ethyl acetate. Dry over anhydrous sodium sulfate and remove the solvent under reduced pressure to afford 1.62 g (8.1 mmol; yield 81%) of the title compound. This compound was used in the next reaction without purification.

1H NMR(CDCl3) δ 6.60(s, 1H), 7.32-7.49(m, 5H), 7.54(s, 1H), 7.84(m, 2H), 9.92(s, 1H) 1 H NMR (CDCl 3 ) δ 6.60 (s, 1H), 7.32-7.49 (m, 5H), 7.54 (s, 1H), 7.84 (m, 2H), 9.92 (s, 1H)

FAB (M+H): 236FAB (M + H): 236

71-2) 3-[N-(2-메톡시에틸)-N-메틸]카바모일-4-(나프탈렌-1-일)-1H-피롤의 제조71-2) Preparation of 3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- (naphthalen-1-yl) -1H-pyrrole

실시예 71-1)에서 수득한 화합물 234㎎(1 밀리몰)을 디메틸포름아미드 2㎖에 용해시키고 EDC 230㎎(1.2 밀리몰), 트리에틸아민 101㎎(1 밀리몰)과 HOBT 162㎎ (1.7 밀리몰)을 넣어준 뒤 0℃에서 5분간 교반하였다. 여기에 N-(2-메톡시에틸)-N-메틸아민 하이드로클로라이드 124㎎(1 밀리몰)을 넣고 실온에서 5시간동안 교반하였다. 용매를 감압하에 제거하고 포화 탄산칼륨 수용액 10㎖를 넣은 후 에틸아세테이트 20㎖로 추출하고, 1N 염산 수용액 10㎖로 세척해주었다. 계속하여 소금물과 물로 세척해주고 무수 황산나트륨상에서 건조시킨 후 농축하여 표제화합물 246㎎(0.8 밀리몰)을 수득하였다.234 mg (1 mmol) of the compound obtained in Example 71-1) was dissolved in 2 ml of dimethylformamide, 230 mg (1.2 mmol) EDC, 101 mg (1 mmol) triethylamine, and 162 mg (1.7 mmol) HOBT. After the addition was stirred for 5 minutes at 0 ℃. 124 mg (1 mmol) of N- (2-methoxyethyl) -N-methylamine hydrochloride was added thereto, followed by stirring at room temperature for 5 hours. The solvent was removed under reduced pressure, 10 mL of saturated potassium carbonate solution was added thereto, followed by extraction with 20 mL of ethyl acetate, followed by washing with 10 mL of 1N hydrochloric acid solution. Then washed with brine and water, dried over anhydrous sodium sulfate and concentrated to give 246 mg (0.8 mmol) of the title compound.

1H NMR(CDCl3) δ 2.46(s, 2H), 2.80-3.40(m, 7H), 3.40(s, 1H), 6.80(s, 1H), 7.00(s, 1H), 7.42(m, 4H), 7.73(d, 1H), 7.81(d, 1H), 8.17(d, 1H), 10.66 (s, 1H) 1 H NMR (CDCl 3 ) δ 2.46 (s, 2H), 2.80-3.40 (m, 7H), 3.40 (s, 1H), 6.80 (s, 1H), 7.00 (s, 1H), 7.42 (m, 4H ), 7.73 (d, 1H), 7.81 (d, 1H), 8.17 (d, 1H), 10.66 (s, 1H)

FAB (M+H): 309FAB (M + H): 309

71-3) 1-(1-메틸-1H-이미다졸-5-일)메틸-3-[N-(2-메톡시에틸)-N-메틸]카바모일-4-(나프탈렌-1-일)-1H-피롤의 제조71-3) 1- (1-methyl-1H-imidazol-5-yl) methyl-3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- (naphthalen-1-yl Preparation of 1H-pyrrole

실시예 71-2)에서 수득한 화합물 618㎎(2.0 밀리몰)을 디메틸포름아미드 10㎖에 녹이고 0℃에서 수소화나트륨(60%) 264㎎(6.6 밀리몰)을 가한후 5분간 교반하였다. 여기에 5-클로로메틸-1-메틸이미다졸 하이드로클로라이드 367㎎(2.2 밀리몰)을 첨가하고 상온에서 5시간동안 교반하였다. 용매를 감압증류하여 제거한후 물 10㎖를 첨가하고 에틸아세테이트 20㎖로 2회 추출하였다. 무수 황산나트륨 상에서 건조시키고 농축시킨 후 실리카겔 칼럼 크로마토그래피(용리제:디클로로메탄/메탄올=90/10, v/v)를 실시하여 표제화합물 644㎎(수율 80%)을 수득하였다.618 mg (2.0 mmol) of the compound obtained in Example 71-2) was dissolved in 10 ml of dimethylformamide, and 264 mg (6.6 mmol) of sodium hydride (60%) was added at 0 ° C, followed by stirring for 5 minutes. To this was added 367 mg (2.2 mmol) of 5-chloromethyl-1-methylimidazole hydrochloride and stirred at room temperature for 5 hours. After distilling off the solvent under reduced pressure, 10 ml of water was added thereto and extracted twice with 20 ml of ethyl acetate. After drying over anhydrous sodium sulfate and concentration, silica gel column chromatography (eluent: dichloromethane / methanol = 90/10, v / v) was carried out to give 644 mg (yield 80%) of the title compound.

1H NMR(CDCl3) δ 2.42(s, 2H), 2.71(m, 1H), 3.10(brs, 6H), 3.30(brs, 1H), 3.50(s, 3H), 5.09(s, 2H), 6.70(s, 1H), 7.05(s, 1H), 7.15(s, 1H), 7.30-7.49 (m, 4H), 7.72(d, 1H), 7.84(d, 2H), 8.08(d, 1H) 1 H NMR (CDCl 3 ) δ 2.42 (s, 2H), 2.71 (m, 1H), 3.10 (brs, 6H), 3.30 (brs, 1H), 3.50 (s, 3H), 5.09 (s, 2H), 6.70 (s, 1H), 7.05 (s, 1H), 7.15 (s, 1H), 7.30-7.49 (m, 4H), 7.72 (d, 1H), 7.84 (d, 2H), 8.08 (d, 1H)

FAB (M+H): 403FAB (M + H): 403

실시예 72: 1-(1-이소부틸-1H-이미다졸-5-일)메틸-3-[N-(2-메톡시에틸)-N-메틸]카바모일-4-(나프탈렌-1-일)-1H-피롤(72)의 합성Example 72: 1- (1-isobutyl-1H-imidazol-5-yl) methyl-3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- (naphthalene-1- Synthesis of I) -1H-pyrrole 72

실시예 71-2)에서 수득한 화합물 618㎎(2.0 밀리몰)을 디메틸포름아미드 10㎖에 녹이고 0℃에서 수소화나트륨(60%) 264㎎(6.6 밀리몰)을 가한 후 5분간 교반하였다. 여기에 제조예 6-2)에서 수득한 화합물 459㎎(2.2 밀리몰)을 첨가하고 상온에서 5시간동안 교반하였다. 용매를 감압증류하여 제거한후 물 10㎖를 첨가하고 에틸아세테이트 20㎖로 2회 추출하였다. 무수 황산나트륨 상에서 건조시키고 농축시킨후 실리카겔 칼럼 크로마토그래피(용리제:디클로로메탄/메탄올=90/10, v/v)를 실시하여 표제화합물 667㎎(수율 75%)을 수득하였다.618 mg (2.0 mmol) of the compound obtained in Example 71-2) was dissolved in 10 ml of dimethylformamide, and 264 mg (6.6 mmol) of sodium hydride (60%) was added at 0 ° C, followed by stirring for 5 minutes. To this was added 459 mg (2.2 mmol) of the compound obtained in Preparation Example 6-2) and stirred at room temperature for 5 hours. After distilling off the solvent under reduced pressure, 10 ml of water was added thereto and extracted twice with 20 ml of ethyl acetate. After drying over anhydrous sodium sulfate and concentration, silica gel column chromatography (eluent: dichloromethane / methanol = 90/10, v / v) was carried out to give 667 mg (yield 75%) of the title compound.

1H NMR(CDCl3) δ 0.90(d, 6H), 1.75(m, 1H), 2.41(brs, 2H), 2.72(brs, 1H), 3.01(brs, 6H), 3.32(brs, 1H), 3.62(d, 2H), 5.13(s, 2H), 6.72(s, 1H), 7.09(s, 1H), 7.19(s, 1H), 7.30-7.49(m, 4H), 7.78(d, 1H), 7.84(d, 2H), 8.08 d, 1H) 1 H NMR (CDCl 3 ) δ 0.90 (d, 6H), 1.75 (m, 1H), 2.41 (brs, 2H), 2.72 (brs, 1H), 3.01 (brs, 6H), 3.32 (brs, 1H), 3.62 (d, 2H), 5.13 (s, 2H), 6.72 (s, 1H), 7.09 (s, 1H), 7.19 (s, 1H), 7.30-7.49 (m, 4H), 7.78 (d, 1H) , 7.84 (d, 2 H), 8.08 d, 1 H)

FAB (M+H): 445FAB (M + H): 445

실시예 73: 1-(1-사이클로헥실메틸-1H-이미다졸-5-일)메틸-3-[N-(2-메톡시에틸)-N-메틸]카바모일-4-(나프탈렌-1-일)-1H-피롤(73)의 합성Example 73: 1- (1-cyclohexylmethyl-1H-imidazol-5-yl) methyl-3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- (naphthalene-1 Synthesis of -yl) -1H-pyrrole (73)

실시예 71-2)에서 수득한 화합물 618㎎(2.0 밀리몰)을 디메틸포름아미드 10 ㎖에 녹이고 0℃에서 수소화나트륨(60%) 264㎎(6.6 밀리몰)을 가한후 5분간 교반하였다. 여기에 제조예 7-2)에서 수득한 화합물 647㎎(2.2 밀리몰)을 첨가하고 상온에서 5시간동안 교반하였다. 용매를 감압증류하여 제거한후 물 10㎖를 첨가하고 에틸아세테이트 20㎖로 2회 추출하였다. 무수 황산나트륨 상에서 건조시키고 농축시킨후 실리카겔 칼럼 크로마토그래피(용리제:디클로로메탄/메탄올=90/10, v/v)를 실시하여 표제화합물 726㎎(수율 75%)을 수득하였다.618 mg (2.0 mmol) of the compound obtained in Example 71-2) was dissolved in 10 ml of dimethylformamide, and 264 mg (6.6 mmol) of sodium hydride (60%) was added at 0 ° C, followed by stirring for 5 minutes. To this was added 647 mg (2.2 mmol) of the compound obtained in Preparation Example 2-2 and stirred at room temperature for 5 hours. After distilling off the solvent under reduced pressure, 10 ml of water was added thereto and extracted twice with 20 ml of ethyl acetate. After drying over anhydrous sodium sulfate and concentration, silica gel column chromatography (eluent: dichloromethane / methanol = 90/10, v / v) was carried out to give 726 mg (yield 75%) of the title compound.

1H NMR(CDCl3) δ 0.87(m, 2H), 1.12(m, 3H), 1.30(brs, 1H), 1.40-1.80(m, 5H), 2.41(brs, 2H), 2.72(brs, 1H), 3.01(brs, 6H), 3.32(brs, 1H), 3.63(d, 2H), 5.09(s, 2H), 6.72(s, 1H), 7.09(s, 1H), 7.19(s, 1H), 7.25(s, 1H), 7.30-7.49 (m, 3H), 7.78(d, 1H), 7.83(d, 2H), 8.08(d, 1H) 1 H NMR (CDCl 3 ) δ 0.87 (m, 2H), 1.12 (m, 3H), 1.30 (brs, 1H), 1.40-1.80 (m, 5H), 2.41 (brs, 2H), 2.72 (brs, 1H ), 3.01 (brs, 6H), 3.32 (brs, 1H), 3.63 (d, 2H), 5.09 (s, 2H), 6.72 (s, 1H), 7.09 (s, 1H), 7.19 (s, 1H) , 7.25 (s, 1H), 7.30-7.49 (m, 3H), 7.78 (d, 1H), 7.83 (d, 2H), 8.08 (d, 1H)

FAB (M+H): 485FAB (M + H): 485

실시예 74: 3-[N-(2-메톡시에틸)-N-메틸]카바모일-4-(나프탈렌-1-일)- 1-(1-펜틸-1H-이미다졸-5-일)메틸-1H-피롤(74)의 합성Example 74: 3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- (naphthalen-1-yl) -1- (1-pentyl-1H-imidazol-5-yl) Synthesis of Methyl-1H-pyrrole (74)

실시예 71-2)에서 수득한 화합물 618㎎(2.0 밀리몰)을 디메틸포름아미드 10 ㎖ 에 녹이고 0℃에서 수소화나트륨(60%) 264㎎(6.6 밀리몰)을 가한후 5분간 교반하였다. 여기에 제조예 8-2)에서 수득한 화합물 429㎎(2.2 밀리몰)을 첨가하고 상온에서 5시간동안 교반하였다. 용매를 감압증류하여 제거한 후 물 10㎖를 첨가하고 에틸아세테이트 20㎖로 2회 추출하였다. 무수 황산나트륨 상에서 건조시키고 농축시킨후 실리카겔 칼럼 크로마토그래피(용리제:디클로로메탄/메탄올=90/10, v/ v)를 실시하여 표제화합물 714㎎(수율 78%)을 수득하였다.618 mg (2.0 mmol) of the compound obtained in Example 71-2) was dissolved in 10 ml of dimethylformamide, and 264 mg (6.6 mmol) of sodium hydride (60%) was added at 0 ° C, followed by stirring for 5 minutes. To this was added 429 mg (2.2 mmol) of the compound obtained in Preparation Example 8-2) and stirred at room temperature for 5 hours. After distilling off the solvent under reduced pressure, 10 ml of water was added thereto and extracted twice with 20 ml of ethyl acetate. After drying over anhydrous sodium sulfate and concentration, silica gel column chromatography (eluent: dichloromethane / methanol = 90/10, v / v) was carried out to give 714 mg (yield 78%) of the title compound.

1H NMR(CDCl3) δ 0.90(t, 3H), 1.08(brs, 2H), 1.30(m, 2H), 1.45(m, 2H), 2.41(brs, 2H), 2.72(brs, 1H), 3.01(brs, 6H), 3.32(brs, 1H), 3.63(t, 2H), 5.09 (s, 2H), 6.72(s, 1H), 7.09(s, 1H), 7.19(s, 1H), 7.25(s, 1H), 7.30-7.49(m, 3H), 7.78(d, 1H), 7.83(d, 2H), 8.08(d, 1H) 1 H NMR (CDCl 3 ) δ 0.90 (t, 3H), 1.08 (brs, 2H), 1.30 (m, 2H), 1.45 (m, 2H), 2.41 (brs, 2H), 2.72 (brs, 1H), 3.01 (brs, 6H), 3.32 (brs, 1H), 3.63 (t, 2H), 5.09 (s, 2H), 6.72 (s, 1H), 7.09 (s, 1H), 7.19 (s, 1H), 7.25 (s, 1H), 7.30-7.49 (m, 3H), 7.78 (d, 1H), 7.83 (d, 2H), 8.08 (d, 1H)

FAB (M+H): 459FAB (M + H): 459

실시예 75: 3-[N-(2-메톡시에틸)-N-메틸]카바모일-4-(나프탈렌-1-일)- 1-(1-옥틸-1H-이미다졸-5-일)메틸-1H-피롤(75)의 합성Example 75: 3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- (naphthalen-1-yl) -1- (1-octyl-1H-imidazol-5-yl) Synthesis of Methyl-1H-pyrrole (75)

실시예 71-2)에서 수득한 화합물 618㎎(2.0 밀리몰)을 디메틸포름아미드 10 ㎖에 녹이고 0℃에서 수소화나트륨(60%) 264㎎(6.6 밀리몰)을 가한후 5분간 교반하였다. 여기에 제조예 9-2)에서 수득한 화합물 508㎎(2.2 밀리몰)을 첨가하고 상온에서 5시간동안 교반하였다. 용매를 감압증류하여 제거한 후 물 10㎖를 첨가하고 에틸아세테이트 20㎖로 2회 추출하였다. 무수 황산나트륨상에서 건조시키고 농축시킨 후 실리카겔 칼럼 크로마토그래피(용리제:디클로로메탄/메탄올=90/10, v/v)를 실시하여 표제화합물 760㎎(수율 76%)을 수득하였다.618 mg (2.0 mmol) of the compound obtained in Example 71-2) was dissolved in 10 ml of dimethylformamide, and 264 mg (6.6 mmol) of sodium hydride (60%) was added at 0 ° C, followed by stirring for 5 minutes. To this was added 508 mg (2.2 mmol) of the compound obtained in Preparation Example 9-2 and stirred at room temperature for 5 hours. After distilling off the solvent under reduced pressure, 10 ml of water was added thereto and extracted twice with 20 ml of ethyl acetate. After drying over anhydrous sodium sulfate and concentration, silica gel column chromatography (eluent: dichloromethane / methanol = 90/10, v / v) was carried out to give 760 mg (yield 76%) of the title compound.

1H NMR(CDCl3) δ 0.87(t, 3H), 1.17(brs, 2H), 1.30(brs, 10H), 1.44(m, 2H), 2.41(brs, 2H), 2.72(brs, 1H), 3.01(brs, 6H), 3.32(brs, 1H), 3.62(t, 2H), 5.09(s, 2H), 6.72(s, 1H), 7.09(s, 1H), 7.19(s, 1H), 7.25(s, 1H), 7.30-7.49 (m, 3H), 7.78(d, 1H), 7.83(d, 2H), 8.08(d, 1H) 1 H NMR (CDCl 3 ) δ 0.87 (t, 3H), 1.17 (brs, 2H), 1.30 (brs, 10H), 1.44 (m, 2H), 2.41 (brs, 2H), 2.72 (brs, 1H), 3.01 (brs, 6H), 3.32 (brs, 1H), 3.62 (t, 2H), 5.09 (s, 2H), 6.72 (s, 1H), 7.09 (s, 1H), 7.19 (s, 1H), 7.25 (s, 1H), 7.30-7.49 (m, 3H), 7.78 (d, 1H), 7.83 (d, 2H), 8.08 (d, 1H)

FAB (M+H): 501FAB (M + H): 501

실시예 76: 1-(1-데실-1H-이미다졸-5-일)메틸-3-[N-(2-메톡시에틸)-N-메틸]카바모일-4-(나프탈렌-1-일)-1H-피롤(76)의 합성Example 76: 1- (1-decyl-1H-imidazol-5-yl) methyl-3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- (naphthalen-1-yl Synthesis of) -1H-pyrrole (76)

실시예 71-2)에서 수득한 화합물 618㎎(2.0 밀리몰)을 디메틸포름아미드 10 ㎖에 녹이고 0℃에서 수소화나트륨(60%) 264㎎(6.6 밀리몰)을 가한 후 5분간 교반하였다. 여기에 제조예 10-2)에서 수득한 화합물 567㎎(2.2 밀리몰)을 첨가하고 상온에서 5시간동안 교반하였다. 용매를 감압증류하여 제거한 후 물 10㎖를 첨가하고 에틸아세테이트 20㎖로 2회 추출하였다. 무수 황산나트륨상에서 건조시키고 농축시킨 후 실리카겔 칼럼 크로마토그래피(용리제:디클로로메탄/메탄올=90/10, v/ v)를 실시하여 표제화합물 667㎎(수율 75%)을 수득하였다.618 mg (2.0 mmol) of the compound obtained in Example 71-2) was dissolved in 10 ml of dimethylformamide, and 264 mg (6.6 mmol) of sodium hydride (60%) was added at 0 ° C, followed by stirring for 5 minutes. To this was added 567 mg (2.2 mmol) of the compound obtained in Preparation Example 10-2) and stirred at room temperature for 5 hours. After distilling off the solvent under reduced pressure, 10 ml of water was added thereto and extracted twice with 20 ml of ethyl acetate. After drying over anhydrous sodium sulfate and concentration, silica gel column chromatography (eluent: dichloromethane / methanol = 90/10, v / v) was carried out to give 667 mg (yield 75%) of the title compound.

1H NMR(CDCl3) δ 0.87(t, 3H), 1.17(brs, 2H), 1.30(brs, 14H), 1.44(m, 2H), 2.41(brs, 2H), 2.72(brs, 1H), 3.01(brs, 6H), 3.32(brs, 1H), 3.62(t, 2H), 5.09(s, 2H), 6.72(s, 1H), 7.09(s, 1H), 7.19(s, 1H), 7.25(s, 1H), 7.30-7.49 (m, 3H), 7.78(d, 1H), 7.83(d, 2H), 8.08(d, 1H) 1 H NMR (CDCl 3 ) δ 0.87 (t, 3H), 1.17 (brs, 2H), 1.30 (brs, 14H), 1.44 (m, 2H), 2.41 (brs, 2H), 2.72 (brs, 1H), 3.01 (brs, 6H), 3.32 (brs, 1H), 3.62 (t, 2H), 5.09 (s, 2H), 6.72 (s, 1H), 7.09 (s, 1H), 7.19 (s, 1H), 7.25 (s, 1H), 7.30-7.49 (m, 3H), 7.78 (d, 1H), 7.83 (d, 2H), 8.08 (d, 1H)

FAB (M+H): 529FAB (M + H): 529

실시예 77: 3-[N-(2-메톡시에틸)-N-메틸]카바모일-1-[1-(3-메틸부틸)- 1H-이미다졸-5-일]메틸-4-(나프탈렌-1-일)-1H-피롤(77)의 합성Example 77: 3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-1- [1- (3-methylbutyl) -1H-imidazol-5-yl] methyl-4- ( Synthesis of naphthalen-1-yl) -1H-pyrrole (77)

실시예 71-2)에서 수득한 화합물 618㎎(2.0 밀리몰)을 디메틸포름아미드 10 ㎖에 녹이고 0℃에서 수소화나트륨(60%) 264㎎(6.6 밀리몰)을 가한 후 5분간 교반하였다. 여기에 제조예 11-2)에서 수득한 화합물 429㎎(2.2 밀리몰)을 첨가하고 상온에서 5시간동안 교반하였다. 용매를 감압증류하여 제거한 후 물 10㎖를 첨가하고 에틸아세테이트 20㎖로 2회 추출하였다. 무수 황산나트륨상에서 건조시키고 농축시킨 후 실리카겔 칼럼 크로마토그래피(용리제:디클로로메탄/메탄올=90/10, v/ v)를 실시하여 표제화합물 667㎎(수율 75%)을 수득하였다.618 mg (2.0 mmol) of the compound obtained in Example 71-2) was dissolved in 10 ml of dimethylformamide, and 264 mg (6.6 mmol) of sodium hydride (60%) was added at 0 ° C, followed by stirring for 5 minutes. To this was added 429 mg (2.2 mmol) of the compound obtained in Preparation Example 11-2) and stirred at room temperature for 5 hours. After distilling off the solvent under reduced pressure, 10 ml of water was added thereto and extracted twice with 20 ml of ethyl acetate. After drying over anhydrous sodium sulfate and concentration, silica gel column chromatography (eluent: dichloromethane / methanol = 90/10, v / v) was carried out to give 667 mg (yield 75%) of the title compound.

1H NMR(CDCl3) δ 0.91(d, 6H), 1.31(q, 2H), 1.67(m, 1H), 2.41(brs, 2H), 2.72(brs, 1H), 3.01(brs, 6H), 3.32(brs, 1H), 3.62(t, 2H), 5.09(s, 2H), 6.72 (s, 1H), 7.09(s, 1H), 7.19(s, 1H), 7.25(s, 1H), 7.30-7.49(m, 3H), 7.78(d, 1H), 7.83(d, 2H), 8.08(d, 1H) 1 H NMR (CDCl 3 ) δ 0.91 (d, 6H), 1.31 (q, 2H), 1.67 (m, 1H), 2.41 (brs, 2H), 2.72 (brs, 1H), 3.01 (brs, 6H), 3.32 (brs, 1H), 3.62 (t, 2H), 5.09 (s, 2H), 6.72 (s, 1H), 7.09 (s, 1H), 7.19 (s, 1H), 7.25 (s, 1H), 7.30 -7.49 (m, 3H), 7.78 (d, 1H), 7.83 (d, 2H), 8.08 (d, 1H)

FAB (M+H): 459FAB (M + H): 459

실시예 78: 1-[1-(2-메톡시에틸)-1H-이미다졸-5-일]메틸-3-[N-(2-메톡시에틸)-N-메틸]카바모일-4-(나프탈렌-1-일)-1H-피롤(78)의 합성Example 78: 1- [1- (2-methoxyethyl) -1H-imidazol-5-yl] methyl-3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- Synthesis of (naphthalen-1-yl) -1H-pyrrole (78)

실시예 71-2)에서 수득한 화합물 618㎎(2.0 밀리몰)을 디메틸포름아미드 10 ㎖에 녹이고 0℃에서 수소화나트륨(60%) 264㎎(6.6 밀리몰)을 가한 후 5분간 교반하였다. 여기에 제조예 12-2)에서 수득한 화합물 429㎎(2.2 밀리몰)을 첨가하고 상온에서 5시간동안 교반하였다. 용매를 감압증류하여 제거한 후 물 10㎖를 첨가하고 에틸아세테이트 20㎖로 2회 추출하였다. 무수 황산나트륨상에서 건조시키고 농축시킨 후 실리카겔 칼럼 크로마토그래피(용리제:디클로로메탄/메탄올=90/10, v/ v)를 실시하여 표제화합물 667㎎(수율 75%)을 수득하였다.618 mg (2.0 mmol) of the compound obtained in Example 71-2) was dissolved in 10 ml of dimethylformamide, and 264 mg (6.6 mmol) of sodium hydride (60%) was added at 0 ° C, followed by stirring for 5 minutes. To this was added 429 mg (2.2 mmol) of the compound obtained in Preparation Example 12-2) and stirred at room temperature for 5 hours. After distilling off the solvent under reduced pressure, 10 ml of water was added thereto and extracted twice with 20 ml of ethyl acetate. After drying over anhydrous sodium sulfate and concentration, silica gel column chromatography (eluent: dichloromethane / methanol = 90/10, v / v) was carried out to give 667 mg (yield 75%) of the title compound.

1H NMR(CDCl3) δ 2.41(brs, 2H), 2.72(brs, 1H), 3.01(brs, 6H), 3.32(brs, 1H), 3.37(s, 3H), 3.45(t, 2H), 3.63(t, 2H), 5.09(s, 2H), 6.72(s, 1H), 7.09 (s, 1H), 7.19(s, 1H), 7.25(s, 1H), 7.30-7.49(m, 3H), 7.78(d, 1H), 7.83(d, 2H), 8.08(d, 1H) 1 H NMR (CDCl 3 ) δ 2.41 (brs, 2H), 2.72 (brs, 1H), 3.01 (brs, 6H), 3.32 (brs, 1H), 3.37 (s, 3H), 3.45 (t, 2H), 3.63 (t, 2H), 5.09 (s, 2H), 6.72 (s, 1H), 7.09 (s, 1H), 7.19 (s, 1H), 7.25 (s, 1H), 7.30-7.49 (m, 3H) , 7.78 (d, 1H), 7.83 (d, 2H), 8.08 (d, 1H)

FAB (M+H): 431FAB (M + H): 431

실시예 79: 3-[N-(2-메톡시에틸)-N-메틸]카바모일-1-[1-(3-메톡시프로필)-1H-이미다졸-5-일]메틸-4-(나프탈렌-1-일)-1H-피롤(79)의 합성Example 79: 3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-1- [1- (3-methoxypropyl) -1H-imidazol-5-yl] methyl-4- Synthesis of (naphthalen-1-yl) -1H-pyrrole (79)

실시예 71-2)에서 수득한 화합물 618㎎(2.0 밀리몰)을 디메틸포름아미드 10 ㎖에 녹이고 0℃에서 수소화나트륨(60%) 264㎎(6.6 밀리몰)을 가한후 5분간 교반하였다. 여기에 제조예 13-2)에서 수득한 화합물 459㎎(2.2 밀리몰)을 첨가하고 상온에서 5시간동안 교반하였다. 용매를 감압증류하여 제거한 후 물 10㎖를 첨가하고 에틸아세테이트 20㎖로 2회 추출하였다. 무수 황산나트륨상에서 건조시키고 농축시킨 후 실리카겔 칼럼 크로마토그래피(용리제:디클로로메탄/메탄올=90/10, v/ v)를 실시하여 표제화합물 683㎎(수율 70%)을 수득하였다.618 mg (2.0 mmol) of the compound obtained in Example 71-2) was dissolved in 10 ml of dimethylformamide, and 264 mg (6.6 mmol) of sodium hydride (60%) was added at 0 ° C, followed by stirring for 5 minutes. 459 mg (2.2 mmol) of the compound obtained in Preparation Example 13-2 was added thereto, and the resultant was stirred at room temperature for 5 hours. After distilling off the solvent under reduced pressure, 10 ml of water was added thereto and extracted twice with 20 ml of ethyl acetate. After drying over anhydrous sodium sulfate and concentration, silica gel column chromatography (eluent: dichloromethane / methanol = 90/10, v / v) was carried out to give 683 mg (yield 70%) of the title compound.

1H NMR(CDCl3) δ 1.71(m, 2H), 2.41(brs, 2H), 2.72(brs, 1H), 3.01(brs, 6H), 3.31(s, 3H), 3.32(brs, 1H), 3.48(t, 2H), 3.63(t, 2H), 5.09(s, 2H), 6.72 (s, 1H), 7.09(s, 1H), 7.19(s, 1H), 7.25(s, 1H), 7.30-7.49(m, 3H), 7.78(d, 1H), 7.83(d, 2H), 8.08(d, 1H) 1 H NMR (CDCl 3 ) δ 1.71 (m, 2H), 2.41 (brs, 2H), 2.72 (brs, 1H), 3.01 (brs, 6H), 3.31 (s, 3H), 3.32 (brs, 1H), 3.48 (t, 2H), 3.63 (t, 2H), 5.09 (s, 2H), 6.72 (s, 1H), 7.09 (s, 1H), 7.19 (s, 1H), 7.25 (s, 1H), 7.30 -7.49 (m, 3H), 7.78 (d, 1H), 7.83 (d, 2H), 8.08 (d, 1H)

FAB (M+H): 445FAB (M + H): 445

실시예 80: 1-[1-(3-에톡시프로필)-1H-이미다졸-5-일]메틸-3-[N-(2-메톡시에틸)-N-메틸]카바모일-4-(나프탈렌-1-일)-1H-피롤(80)의 합성Example 80: 1- [1- (3-ethoxypropyl) -1H-imidazol-5-yl] methyl-3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- Synthesis of (naphthalen-1-yl) -1H-pyrrole (80)

실시예 71-2)에서 수득한 화합물 618㎎(2.0 밀리몰)을 디메틸포름아미드 10 ㎖에 녹이고 0℃에서 수소화나트륨(60%) 264㎎(6.6 밀리몰)을 가한후 5분간 교반하였다. 여기에 제조예 14-2)에서 수득한 화합물 459㎎(2.2 밀리몰)을 첨가하고 상온에서 5시간동안 교반하였다. 용매를 감압증류하여 제거한 후 물 10㎖를 첨가하고 에틸아세테이트 20㎖로 2회 추출하였다. 무수 황산나트륨상에서 건조시키고 농축시킨 후 실리카겔 칼럼 크로마토그래피(용리제: 디클로로메탄/메탄올=90/10, v/v)를 실시하여 표제화합물 712㎎(수율 71%)을 수득하였다.618 mg (2.0 mmol) of the compound obtained in Example 71-2) was dissolved in 10 ml of dimethylformamide, and 264 mg (6.6 mmol) of sodium hydride (60%) was added at 0 ° C, followed by stirring for 5 minutes. 459 mg (2.2 mmol) of the compound obtained in Preparation Example 14-2 was added thereto, and the resultant was stirred at room temperature for 5 hours. After distilling off the solvent under reduced pressure, 10 ml of water was added thereto and extracted twice with 20 ml of ethyl acetate. After drying over anhydrous sodium sulfate and concentration, silica gel column chromatography (eluent: dichloromethane / methanol = 90/10, v / v) was carried out to give 712 mg (yield 71%) of the title compound.

1H NMR(CDCl3) δ 1.20(t, 3H), 1.70(m, 2H), 2.41(brs, 2H), 2.72(brs, 1H), 3.01(brs, 6H), 3.32(brs, 1H), 3.50(m, 4H), 3.63(t, 2H), 5.09(s, 2H), 6.72(s, 1H), 7.09(s, 1H), 7.19(s, 1H), 7.25(s, 1H), 7.30-7.49(m, 3H), 7.78(d, 1H), 7.83(d, 2H), 8.08(d, 1H) 1 H NMR (CDCl 3 ) δ 1.20 (t, 3H), 1.70 (m, 2H), 2.41 (brs, 2H), 2.72 (brs, 1H), 3.01 (brs, 6H), 3.32 (brs, 1H), 3.50 (m, 4H), 3.63 (t, 2H), 5.09 (s, 2H), 6.72 (s, 1H), 7.09 (s, 1H), 7.19 (s, 1H), 7.25 (s, 1H), 7.30 -7.49 (m, 3H), 7.78 (d, 1H), 7.83 (d, 2H), 8.08 (d, 1H)

FAB (M+H): 457FAB (M + H): 457

실시예 81: 1-[1-(3-이소프로폭시프로필)-1H-이미다졸-5-일]메틸-3-[N- (2-메톡시에틸)-N-메틸]카바모일-4-(나프탈렌-1-일)-1H-피롤(81)의 합성Example 81 1- [1- (3-isopropoxypropyl) -1H-imidazol-5-yl] methyl-3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4 Synthesis of-(naphthalen-1-yl) -1H-pyrrole (81)

실시예 71-2)에서 수득한 화합물 618㎎(2.0 밀리몰)을 디메틸포름아미드 10 ㎖에 녹이고 0℃에서 수소화나트륨(60%) 264㎎(6.6 밀리몰)을 가한후 5분간 교반하였다. 여기에 제조예 15-2)에서 수득한 화합물 459㎎(2.2 밀리몰)을 첨가하고 상온에서 5시간동안 교반하였다. 용매를 감압증류하여 제거한 후 물 10㎖를 첨가하고 에틸아세테이트 20㎖로 2회 추출하였다. 무수 황산나트륨상에서 건조시키고 농축시킨 후 실리카겔 칼럼 크로마토그래피(용리제: 디클로로메탄/메탄올=90/10, v/ v)를 실시하여 표제화합물 751㎎(수율 73%)을 수득하였다.618 mg (2.0 mmol) of the compound obtained in Example 71-2) was dissolved in 10 ml of dimethylformamide, and 264 mg (6.6 mmol) of sodium hydride (60%) was added at 0 ° C, followed by stirring for 5 minutes. 459 mg (2.2 mmol) of the compound obtained in Preparation Example 15-2 was added thereto, and the resultant was stirred at room temperature for 5 hours. After distilling off the solvent under reduced pressure, 10 ml of water was added thereto and extracted twice with 20 ml of ethyl acetate. After drying over anhydrous sodium sulfate and concentration, silica gel column chromatography (eluent: dichloromethane / methanol = 90/10, v / v) was carried out to give 751 mg (yield 73%) of the title compound.

1H NMR(CDCl3) δ 1.16(d, 6H), 1.70(m, 2H), 2.41(brs, 2H), 2.72(brs, 1H), 3.01(brs, 6H), 3.32(brs, 1H), 3.45-3.55(m, 3H), 3.63(t, 2H), 5.09(s, 2H), 6.72(s, 1H), 7.09(s, 1H), 7.19(s, 1H), 7.25(s, 1H), 7.30-7.49(m, 3H), 7.78 (d, 1H), 7.83(d, 2H), 8.08(d, 1H) 1 H NMR (CDCl 3 ) δ 1.16 (d, 6H), 1.70 (m, 2H), 2.41 (brs, 2H), 2.72 (brs, 1H), 3.01 (brs, 6H), 3.32 (brs, 1H), 3.45-3.55 (m, 3H), 3.63 (t, 2H), 5.09 (s, 2H), 6.72 (s, 1H), 7.09 (s, 1H), 7.19 (s, 1H), 7.25 (s, 1H) , 7.30-7.49 (m, 3H), 7.78 (d, 1H), 7.83 (d, 2H), 8.08 (d, 1H)

FAB (M+H): 469FAB (M + H): 469

실시예 82: 1-[1-(4-브로모벤질)-1H-이미다졸-5-일]메틸-3-[4-메틸피페라진-1-일]카보닐-4-(나프탈렌-1-일)-1H-피롤의 합성Example 82: 1- [1- (4-bromobenzyl) -1H-imidazol-5-yl] methyl-3- [4-methylpiperazin-1-yl] carbonyl-4- (naphthalene-1 Synthesis of -yl) -1H-pyrrole

82-1) 3-[4-메틸피페라진-1-일]카보닐-4-(나프탈렌)-1H-피롤의 제조82-1) Preparation of 3- [4-methylpiperazin-1-yl] carbonyl-4- (naphthalene) -1H-pyrrole

실시예 63-2)에서 수득한 화합물과 4-메틸피페라진으로부터 실시예 37-5)의 방법에 따라 실시하여 90% 수율로 표제화합물을 수득하였다.The title compound was obtained in 90% yield from the compound obtained in Example 63-2) and 4-methylpiperazine according to the method of Example 37-5).

1H NMR (CDCl3) δ 1.15(br, 2H), 1.87(br, 2H), 1.92(s, 3H), 2.96(br, 2H), 3.41(br, 2H), 6.83(s, 1H), 7.09(s, 1H), 7.36-7.42(m, 4H), 7.73(d, 1H), 7.75 (d, 1H), 8.10(d, 1H), 10.52(s, 1H) 1 H NMR (CDCl 3 ) δ 1.15 (br, 2H), 1.87 (br, 2H), 1.92 (s, 3H), 2.96 (br, 2H), 3.41 (br, 2H), 6.83 (s, 1H), 7.09 (s, 1H), 7.36-7.42 (m, 4H), 7.73 (d, 1H), 7.75 (d, 1H), 8.10 (d, 1H), 10.52 (s, 1H)

FAB(M+H): 320FAB (M + H): 320

82-2) 1-[1-(4-브로모벤질)-1H-이미다졸-5-일]메틸-3-[4-메틸피페라진-1- 일]카보닐-4-(나프탈렌-1-일)-1H-피롤의 제조82-2) 1- [1- (4-bromobenzyl) -1H-imidazol-5-yl] methyl-3- [4-methylpiperazin-1-yl] carbonyl-4- (naphthalene-1 Preparation of -yl) -1H-pyrrole

실시예 82-1)에서 수득한 화합물 64㎎(0.2 밀리몰)을 디메틸포름아미드 2㎖ 에 녹이고 0℃에서 수소화나트륨 26㎎(0.66 밀리몰)을 가한후 5분간 교반하였다. 여기에 제조예 5-2)에서 수득한 화합물 66㎎(0.22 밀리몰)을 첨가하고 상온에서 5시간동안 교반하였다. 용매를 감압증류하여 제거한 후 물 10㎖를 첨가하고 에틸아세테이트 10㎖로 2회 추출하였다. 무수 황산나트륨상에서 건조시키고 농축시킨 후 실리카겔 칼럼 크로마토그래피(용리제: 디클로로메탄/메탄올=90/10, v/v)를 실시하여 표제화합물 91㎎(수율 80%)을 수득하였다.64 mg (0.2 mmol) of the compound obtained in Example 82-1) was dissolved in 2 ml of dimethylformamide, and 26 mg (0.66 mmol) of sodium hydride was added at 0 ° C., followed by stirring for 5 minutes. To this was added 66 mg (0.22 mmol) of the compound obtained in Preparation Example 5-2) and stirred at room temperature for 5 hours. After distilling off the solvent under reduced pressure, 10 ml of water was added thereto and extracted twice with 10 ml of ethyl acetate. After drying over anhydrous sodium sulfate and concentration, silica gel column chromatography (eluent: dichloromethane / methanol = 90/10, v / v) was carried out to give 91 mg (yield 80%) of the title compound.

1H NMR (CDCl3) δ 1.15(br, 2H), 1.77(br, 2H), 1.86(s, 3H), 2.82(br, 2H), 3.28(br, 2H), 4.87(s, 2H), 3.88(s, 2H), 6.55(s, 1H), 6.79(d, 2H), 6.97(s, 1H), 7.16(s, 1H), 7.36(d, 1H), 7.36-7.39(m, 5H), 7.50(s, 1H), 7.71(d, 1H), 7.79(d, 1H), 7.93(d, 1H) 1 H NMR (CDCl 3 ) δ 1.15 (br, 2H), 1.77 (br, 2H), 1.86 (s, 3H), 2.82 (br, 2H), 3.28 (br, 2H), 4.87 (s, 2H), 3.88 (s, 2H), 6.55 (s, 1H), 6.79 (d, 2H), 6.97 (s, 1H), 7.16 (s, 1H), 7.36 (d, 1H), 7.36-7.39 (m, 5H) , 7.50 (s, 1H), 7.71 (d, 1H), 7.79 (d, 1H), 7.93 (d, 1H)

FAB(M+H): 569FAB (M + H): 569

실시예 83: 1-[1-(4-클로로벤질)-1H-이미다졸-5-일]메틸-3-[4-메틸피페라진-1-일]카보닐-4-(나프탈렌-1-일)-1H-피롤(83)의 합성Example 83 1- [1- (4-chlorobenzyl) -1H-imidazol-5-yl] methyl-3- [4-methylpiperazin-1-yl] carbonyl-4- (naphthalene-1- Synthesis of 1) -1H-pyrrole (83)

실시예 82-1)에서 수득한 화합물 64㎎(0.2 밀리몰)을 디메틸포름아미드 2㎖에 녹이고 0℃에서 수소화나트륨 26㎎(0.66 밀리몰)을 가한 후 5분간 교반하였다. 여기에 제조예 5에서와 유사한 반응을 수행하므로써 수득한 1-(4-클로로벤질)-5-클로로메틸이미다졸 하이드로클로라이드 55㎎(0.22 밀리몰)을 첨가하고 상온에서 5시간동안 교반하였다. 용매를 감압증류하여 제거한 후 물 10㎖를 첨가하고 에틸아세테이트 10㎖로 2회 추출하였다. 무수 황산나트륨상에서 건조시키고 농축시킨 후 실리카겔 칼럼 크로마토그래피(용리제: 디클로로메탄/메탄올=90/10, v/v)를 실시하여 표제화합물 77㎎(수율 57%)을 수득하였다.64 mg (0.2 mmol) of the compound obtained in Example 82-1) was dissolved in 2 ml of dimethylformamide, and 26 mg (0.66 mmol) of sodium hydride was added at 0 ° C., followed by stirring for 5 minutes. To this was added 55 mg (0.22 mmol) of 1- (4-chlorobenzyl) -5-chloromethylimidazole hydrochloride obtained by carrying out a similar reaction as in Preparation Example 5, and stirred at room temperature for 5 hours. After distilling off the solvent under reduced pressure, 10 ml of water was added thereto and extracted twice with 10 ml of ethyl acetate. After drying over anhydrous sodium sulfate and concentration, silica gel column chromatography (eluent: dichloromethane / methanol = 90/10, v / v) was carried out to give 77 mg (yield 57%) of the title compound.

1H NMR (CDCl3) δ 1.15(br, 2H), 1.77(br, 2H), 1.86(s, 3H), 2.82(br, 2H), 3.28(br, 2H), 4.92(s, 2H), 4.95(s, 2H), 6.60(s, 1H), 6.91(d, 2H), 6.01(s, 1H), 7.22(s, 1H), 7.26-7.36(m, 3H), 7.36-7.48(m, 2H), 7.56(s, 1H), 7.77(d, 1H), 7.82(d, 1H), 7.93(d, 1H) 1 H NMR (CDCl 3 ) δ 1.15 (br, 2H), 1.77 (br, 2H), 1.86 (s, 3H), 2.82 (br, 2H), 3.28 (br, 2H), 4.92 (s, 2H), 4.95 (s, 2H), 6.60 (s, 1H), 6.91 (d, 2H), 6.01 (s, 1H), 7.22 (s, 1H), 7.26-7.36 (m, 3H), 7.36-7.48 (m, 2H), 7.56 (s, 1H), 7.77 (d, 1H), 7.82 (d, 1H), 7.93 (d, 1H)

FAB(M+H): 523.5FAB (M + H): 523.5

실시예 84: 1-[1-(4-플루오로벤질)-1H-이미다졸-5-일]메틸-3-[N-(2-메톡시에틸)-N-메틸]카바모일-4-(나프탈렌-1-일)-1H-피롤(84)의 합성Example 84 1- [1- (4-fluorobenzyl) -1H-imidazol-5-yl] methyl-3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- Synthesis of (naphthalen-1-yl) -1H-pyrrole (84)

실시예 71-2)에서 수득한 화합물 62㎎(0.2 밀리몰)을 디메틸포름아미드 2㎖에 녹이고 0℃에서 수소화나트륨 26㎎(0.66 밀리몰)을 가한후 5분간 교반하였다. 여기에 제조예 5)에서와 유사한 반응을 수행하므로써 수득한 1-(4-플루오로벤질)-5-클로로메틸이미다졸 하이드로클로라이드 51㎎(0.22 밀리몰)을 첨가하고 상온에서 5시간동안 교반하였다. 용매를 감압증류하여 제거한 후 물 10㎖를 첨가하고 에틸아세테이트 10㎖로 2회 추출하였다. 무수 황산나트륨상에서 건조시키고 농축시킨 후 실리카겔 칼럼 크로마토그래피(용리제: 디클로로메탄/메탄올=90/10, v/v)를 실시하여 표제화합물 77㎎(수율 80%)을 수득하였다.62 mg (0.2 mmol) of the compound obtained in Example 71-2) was dissolved in 2 ml of dimethylformamide, and 26 mg (0.66 mmol) of sodium hydride was added at 0 ° C, followed by stirring for 5 minutes. To this was added 51 mg (0.22 mmol) of 1- (4-fluorobenzyl) -5-chloromethylimidazole hydrochloride obtained by carrying out a similar reaction as in Preparation Example 5), followed by stirring at room temperature for 5 hours. . After distilling off the solvent under reduced pressure, 10 ml of water was added thereto and extracted twice with 10 ml of ethyl acetate. After drying over anhydrous sodium sulfate and concentration, silica gel column chromatography (eluent: dichloromethane / methanol = 90/10, v / v) was carried out to give 77 mg (yield 80%) of the title compound.

1H NMR(CDCl3) δ 2.12(br, 3H), 2.72(br, 1H), 3.00-3.20(m, 5H), 3.32(s, 1H), 4.97(s, 2H), 3.98(s, 2H), 6.64(s, 1H), 6.95-7.10(m, 5H), 7.21(s, 1H), 7.33(m, 1H), 7.40-7.51(m, 3H), 7.66(s, 1H), 7.74(d, 1H), 7.81(d, 1H), 8.08(d, 1H) 1 H NMR (CDCl 3 ) δ 2.12 (br, 3H), 2.72 (br, 1H), 3.00-3.20 (m, 5H), 3.32 (s, 1H), 4.97 (s, 2H), 3.98 (s, 2H ), 6.64 (s, 1H), 6.95-7.10 (m, 5H), 7.21 (s, 1H), 7.33 (m, 1H), 7.40-7.51 (m, 3H), 7.66 (s, 1H), 7.74 ( d, 1H), 7.81 (d, 1H), 8.08 (d, 1H)

FAB(M+H):497FAB (M + H): 497

실시예 85: 1-[1-(4-플루오로벤질)-1H-이미다졸-5-일]메틸-3-[4-메틸피페라진-1-일]카보닐-4-(나프탈렌-1-일)-1H-피롤(85)의 합성Example 85: 1- [1- (4-fluorobenzyl) -1H-imidazol-5-yl] methyl-3- [4-methylpiperazin-1-yl] carbonyl-4- (naphthalene-1 Synthesis of -yl) -1H-pyrrole (85)

실시예 82-1)에서 수득한 화합물 64㎎(0.2 밀리몰)을 디메틸포름아미드 2㎖에 녹이고 0℃에서 수소화나트륨 26㎎(0.66 밀리몰)을 가한후 5분간 교반하였다. 여기에 제조예 5)에서와 유사한 반응을 수행하므로써 수득한 1-(4-플루오로벤질)-5-클로로메틸이미다졸 하이드로클로라이드 51㎎(0.22 밀리몰)을 첨가하고 상온에서 5시간동안 교반하였다. 용매를 감압증류하여 제거한 후 물 10㎖를 첨가하고 에틸아세테이트 10㎖로 2회 추출하였다. 무수 황산나트륨상에서 건조시키고 농축시킨 후 실리카겔 칼럼 크로마토그래피(용리제: 디클로로메탄/메탄올=90/10, v/v)를 실시하여 표제화합물 79㎎(수율 80%)을 수득하였다.64 mg (0.2 mmol) of the compound obtained in Example 82-1) was dissolved in 2 ml of dimethylformamide, and 26 mg (0.66 mmol) of sodium hydride was added at 0 ° C, followed by stirring for 5 minutes. To this was added 51 mg (0.22 mmol) of 1- (4-fluorobenzyl) -5-chloromethylimidazole hydrochloride obtained by carrying out a similar reaction as in Preparation Example 5), followed by stirring at room temperature for 5 hours. . After distilling off the solvent under reduced pressure, 10 ml of water was added thereto and extracted twice with 10 ml of ethyl acetate. After drying over anhydrous sodium sulfate and concentration, silica gel column chromatography (eluent: dichloromethane / methanol = 90/10, v / v) was carried out to give 79 mg (yield 80%) of the title compound.

1H NMR (CDCl3) δ 1.15(br, 2H), 1.77(br, 2H), 1.86(s, 3H), 2.82(br, 2H), 3.28(br, 2H), 4.92(s, 2H), 4.97(s, 2H), 6.60(s, 1H), 6.93(d, 2H), 6.01(s, 1H), 7.22(s, 1H), 7.25-7.36(m, 3H), 7.36-7.47(m, 2H), 7.57(s, 1H), 7.78(d, 1H), 7.82(d, 1H), 7.93(d, 1H) 1 H NMR (CDCl 3 ) δ 1.15 (br, 2H), 1.77 (br, 2H), 1.86 (s, 3H), 2.82 (br, 2H), 3.28 (br, 2H), 4.92 (s, 2H), 4.97 (s, 2H), 6.60 (s, 1H), 6.93 (d, 2H), 6.01 (s, 1H), 7.22 (s, 1H), 7.25-7.36 (m, 3H), 7.36-7.47 (m, 2H), 7.57 (s, 1H), 7.78 (d, 1H), 7.82 (d, 1H), 7.93 (d, 1H)

FAB(M+H):507FAB (M + H): 507

실험예 1: Ras 파네실 전이효소 억제능 분석Experimental Example 1: Analysis of Ras farnesyl transferase inhibitory activity

본 실험에서는 폼프리아노 등의 방법(참조: Pompliano et al., Biochemistry 31, 3800, 1992)의 개선된 방법을 이용하였다. 즉, 유전자 재조합 기술에 의해 제조된 Ras 파네실 전이효소를 사용하였으며, 기질로는 H-Ras(H-Ras-CVLS)와 K-Ras의 카복시말단에 존재하는 다염기성 라이신 도메인을 치환시킨 H-Ras와의 결합단백질(참조: 대한민국 특허출원 제97-14409 호)을 기보고된 방법(참조: Chung et al., Bichimica et Biophysica Acta 1129, 278, 1992)에 따라 정제하여 사용하였다.In this experiment, the improved method of Pompiano et al. (Pompliano et al., Biochemistry 31, 3800, 1992) was used. In other words, Ras farnesyl transferase prepared by genetic recombination technology was used, and H-Ras (H-Ras-CVLS) as a substrate and H- which substituted the polybasic lysine domain at the carboxy terminus of K-Ras The binding protein with Ras (see Korean Patent Application No. 97-14409) was purified and used according to the previously reported method (Chung et al., Bichimica et Biophysica Acta 1129, 278, 1992).

효소 반응은 염화칼륨 25mM, 염화마그네슘 25mM, 디티티(DTT) 10mM 및 염화아연 50μM을 함유하는 50㎕의 50mM 소듐히피스 완충용액중에서 수행하였으며, Ras 기질 단백질 1.5μM, 트리튬-파네실 피로 포스페이트 0.15μM 및 파네실 전이효소 4.5nM이 사용되었다. 파네실 전이효소를 첨가하고 37℃에서 30분간 반응을 지속시킨 후 1M 염산을 함유한 에탄올 용액 1㎖를 첨가하여 반응을 정지시켰다. 생성된 침전물을 필터바인딩을 위한 호퍼 하베스터(호퍼 #FH 225V)를 사용하여 GF/B 필터에 흡착시킨후, 에탄올을 사용하여 세척하고, 건조시킨 필터의 방사능을 LKB 베타 카운터를 사용하여 측정하였다. 효소의 역가검정은 Ras 기질 단백질과 파네실 효소의 농도가 정량적 역가관계를 나타내는 기질 불포화 상태에서 측정되었으며, 본 발명에 따라 합성된 화합물은 디메틸설폭사이드(DMSO) 용매에 용해시켜 전체 반응액의 5% 이내로 첨가하여 효소 저해능을 평가하였다. 효소 저해능은 시험화합물이 없는 상태에서 Ras 기질 단백질에 도입된 파네실량에 대해 시험화합물 존재하에 측정된 파네실 도입량을 백분율로 표시하였으며, 50%의 효소활성을 저해하는 농도를 각 시험화합물의 IC50으로 결정하였다. 시험화합물의 선택적 저해능을 평가하기 위한 제라닐제라닐 전이효소는 샤버 등의 방법(참조: Schaberet al. J. Biol Chem.,265, 14701, 1990)을 변형하여 소뇌로부터 정제하여 사용하였으며, 파네실 전이효소 반응과 유사한 조건에서 제라닐제라닐 전이효소의 특이적 기질인 제라닐 제라닐 피로 포스페이트와 Ras-CVIL 기질 단백질을 사용하여 실험을 수행하였다. 실험결과는 하기 표 7a 내지 7d에 나타내었다.Enzyme reactions were carried out in 50 μl of 50 mM sodium hippies buffer containing 25 mM potassium chloride, 25 mM magnesium chloride, 10 mM Diti (DTT) and 50 μM zinc chloride, 1.5 μM Ras substrate protein, 0.15 μM tritium-panesyl pyrophosphate And farnesyl transferase 4.5 nM was used. The reaction was stopped by the addition of farnesyl transferase and the reaction was continued at 37 ° C. for 30 minutes, followed by the addition of 1 ml of ethanol solution containing 1 M hydrochloric acid. The resulting precipitate was adsorbed onto a GF / B filter using a hopper harvester (Hopper #FH 225V) for filter binding, washed with ethanol and the radioactivity of the dried filter was measured using an LKB beta counter. The enzyme titer was measured in the state of substrate unsaturation where the concentration of Ras substrate protein and panesyl enzyme showed a quantitative titer relationship. The enzyme inhibition was assessed by addition within%. The enzyme inhibitory activity was expressed as a percentage of the amount of farnesyl introduced in the presence of the test compound relative to the amount of farnesyl introduced into the Ras substrate protein in the absence of the test compound, and the concentration that inhibited the enzyme activity of 50% was determined by IC 50 of each test compound. Determined. Geranylgeranyl transferase for evaluating the selective inhibitory activity of the test compound was used after purification from the cerebellum by modifying the method of Shaver et al. (Schaber et al. J. Biol Chem., 265, 14701, 1990) Experiments were performed using geranyl geranyl pyrophosphate and Ras-CVIL substrate protein, which are specific substrates of geranylgeranyl transferase under conditions similar to the real transferase reaction. The experimental results are shown in Tables 7a to 7d below.

실험예 2: 세포내 Ras 파네실 전이효소의 억제효능 분석Experimental Example 2 Analysis of Inhibitory Effect of Intracellular Ras Farnesyl Transferase

본 실험에서는 돌연변이에 의해 형질전환 활성을 갖는 C-Harvey-Ras 단백질을 발현하는 Rat2 세포주 및 K-Ras 카복시 말단의 다염기성 라이신 도메인으로 치환된 H-Ras 결합 단백질로 형질전환된 Rat2 세포주(참조: 대한민국 특허출원 제97-14409 호)를 사용하였으며, 실험은 드크루 등의 방법(참조: Declue. J. E. et al., Cancer Research, 51, 712, 1991)을 변형시켜 다음과 같이 수행하였다.In this experiment, a rat2 cell line expressing a C-Harvey-Ras protein having a transforming activity by mutation and a Rat2 cell line transformed with an H-Ras binding protein substituted with a polybasic lysine domain at the K-Ras carboxy terminus (see: Korean Patent Application No. 97-14409) was used, and the experiment was performed by modifying the method of Decrue et al.

형질전환된 Rat2 섬유아세포(fibroblast) 세포주를 60㎜ 세포배양 디쉬에 디쉬당 3x105세포의 밀도로 분주하여 37℃ 세포배양기에서 48시간동안 배양함으로써 50%이상의 밀도로 성장시킨 후 시험화합물로 처리하였다. 이때 시험화합물의 용매로는 디메틸설폭사이드(DMSO)를 사용하였으며, 대조군과 시험군 모두 디메틸설폭사이드 농도를 1%로 사용하였다. 시험화합물로 처리한 지 4시간이 경과한 후에 배지 1㎖당 150μCi의 방사성동위원소[35S]로 표지된 메티오닌을 첨가하고 20시간동안 배양한 후 생리적 식염수로 세포를 세척하였다. 냉각된 세포 용해 완충용액(염화마그네슘 5mM, 디티티 1mM, NP40 1%, EDTA 1mM, PMSF 1mM, 루펩틴 2μM, 펩스타틴에이 2μM 및 안티페인 2μM을 포함하는 소듐히피스 완충용액 50mM) 1㎖를 가하여 세포를 용해시킨 후, 세포가 용해되어있는 상등액을 고속원심분리(12,000g x 5분)에 의해 수득하였다. 상등액의 방사성 동위원소 표지량을 측정하여 면역침전 반응시 정량적 결과를 얻을수 있도록 표준화하였다. 그 후, 반응액에 Ras 단백질에 특이적 결합을 하는 단일클론항체, Y13-259(참조: Furth, M.E.et al., J. Virol., 43, 294, 1982)를 가하고 4℃에서 15시간동안 반응시켰다. 이 용액에 다시 고트에서 유래된 쥐의 면역글로블린에 대한 항체가 결합된 Protein A-아가로즈 현탁액을 가하여 1시간동안 4℃에서 반응시킨 후 면역반응 침전물로부터 비특이적 결합물을 제거하기 위해 완충용액(염화나트륨 50mM, 소듐 디옥시콜레이트 0.5%, NP40 0.5% 및 SDS 0.1%를 포함하는 트리스 클로라이드 50mM 완충용액)으로 세척하였다. 전기영동 방법을 사용하여 침전물을 분석하기 위해, 침전물을 전기영동 시료 완충액에 가하여 끓인 후 13.5%의 SDS 폴리아크릴아미드 겔을 사용하여 전기영동을 수행하였다. 전기영동후 겔을 고정시키고 건조시킨 후 X-ray 필름에 감광시켜 현상인화하였다. 세포내 Ras 파네실 전이효소의 억제효능은 Ras 단백질의 파네실이 결합된 밴드와 결합되지 않은 밴드의 강도를 측정하여 파네실 결합이 50% 저해된 시험화합물의 농도(IC50)로 나타내었다. 하기 표 7a 내지 7d 에는 본 발명에 따른 대표적인 화합물들의 억제효능을 나타내었다. 여기서 IC50은 실험예 1을 수행한 결과 얻어진 데이터이고 CIC50은 실험예 2를 수행한 결과 얻어진 데이터이다.The transformed rat2 fibroblast cell line was seeded at a density of 3 × 10 5 cells per dish in a 60 mm cell culture dish, grown to a density of 50% or more by incubating for 48 hours in a 37 ° C. cell culture medium, and then treated with a test compound. . At this time, dimethyl sulfoxide (DMSO) was used as a solvent of the test compound, and dimethyl sulfoxide concentration was used as 1% in both the control group and the test group. After 4 hours of treatment with the test compound, methionine labeled with 150 μCi of radioisotope [35S] per 1 ml of medium was added and incubated for 20 hours, and the cells were washed with physiological saline. 1 ml of cooled cell lysis buffer (Magnesium chloride 5 mM, Dity 1 mM, NP40 1%, EDTA 1 mM, PMSF 1 mM, Lupetin 2 μM, Peptstatin A 2 μM and 50 μM Sodium Hippies buffer solution 2 μM) After the addition of the cells to lysate, the supernatant in which the cells were lysed was obtained by high-speed centrifugation (12,000 gx 5 minutes). The radioisotope labeling amount of the supernatant was measured and normalized to obtain quantitative results in the immunoprecipitation reaction. Subsequently, a monoclonal antibody, Y13-259 (see Furth, ME et al., J. Virol. , 43, 294, 1982), which specifically binds to Ras protein, was added to the reaction solution at Reacted. To this solution was added a protein A-agarose suspension bound to an immunoglobulin antibody from a goth-derived mouse and reacted at 4 ° C for 1 hour, followed by a buffer solution (sodium chloride) to remove the nonspecific binding substance from the immunoreactive precipitate. 50 mM, sodium dioxycholate 0.5%, NP40 0.5% and SDS 0.1% SDS). In order to analyze the precipitate using the electrophoretic method, the precipitate was added to the electrophoretic sample buffer and boiled, followed by electrophoresis using 13.5% SDS polyacrylamide gel. After electrophoresis, the gel was fixed, dried, and then subjected to photo printing by exposing to an X-ray film. The inhibitory effect of intracellular Ras farnesyl transferase was expressed as the concentration of test compound (IC 50 ) in which the farnesyl binding was inhibited by measuring the intensity of the non-bound bands of the farnesyl bound band of the Ras protein. Tables 7a to 7d below show the inhibitory effects of representative compounds according to the invention. Here, IC 50 is data obtained by performing Experimental Example 1 and CIC 50 is data obtained by performing Experimental Example 2.

화합물번호Compound number H-Ras IC50(μM)H-Ras IC 50 (μM) H-Ras CIC50(μM)H-Ras CIC 50 (μM) K-Ras IC50(μM)K-Ras IC 50 (μM) K-Ras CIC50(μM)K-Ras CIC 50 (μM) 1One 0.250.25 1-501-50 0.1-100.1-10 10-10010-100 22 0.130.13 1-501-50 0.1-100.1-10 10-10010-100 33 0.120.12 1-501-50 0.1-100.1-10 10-10010-100 44 0.090.09 1-501-50 0.1-100.1-10 10-10010-100 55 0.150.15 1-501-50 1010 10-10010-100 66 0.030.03 0.70.7 0.4850.485 ＜20<20 77 0.150.15 1-501-50 0.1-100.1-10 10-10010-100 88 0.270.27 1-501-50 0.1-100.1-10 10-10010-100 99 0.070.07 1-501-50 0.1-100.1-10 10-10010-100 1010 0.30.3 1-501-50 0.1-100.1-10 10-10010-100 1111 0.390.39 1-501-50 0.1-100.1-10 10-10010-100 1212 0.060.06 1-501-50 0.1-100.1-10 10-10010-100 1313 0.040.04 1-501-50 0.1-100.1-10 10-10010-100 1414 0.0380.038 1-501-50 0.1-100.1-10 10-10010-100 1515 0.0250.025 1-501-50 0.1-100.1-10 10-10010-100 1616 0.570.57 1-501-50 0.1-100.1-10 10-10010-100 1717 0.20.2 1-501-50 0.1-100.1-10 10-10010-100 1818 0.740.74 1-501-50 0.1-100.1-10 10-10010-100 1919 0.0680.068 1-501-50 0.1-100.1-10 10-10010-100 2020 0.230.23 1-501-50 0.1-100.1-10 10-10010-100 2121 0.160.16 1-501-50 0.1-100.1-10 10-10010-100 2222 0.420.42 1-501-50 0.1-100.1-10 10-10010-100

2323 0.120.12 1-501-50 0.1-100.1-10 10-10010-100 2424 0.020.02 33 0.1-100.1-10 ＞50＞ 50 2525 0.120.12 1-501-50 0.1-100.1-10 10-10010-100 2626 0.550.55 1-501-50 0.1-100.1-10 10-10010-100 2727 0.210.21 1-501-50 0.1-100.1-10 10-10010-100 2828 0.120.12 1-501-50 0.1-100.1-10 10-10010-100 2929 0.050.05 1-501-50 0.1-100.1-10 10-10010-100 3030 0.0020.002 0.20.2 0.020.02 ＞10＞ 10 3131 0.010.01 0.1-10.1-1 0.01-0.10.01-0.1 10-10010-100 3232 0.0050.005 0.20.2 0.160.16 2020 3333 0.0040.004 0.1-10.1-1 0.1-100.1-10 10-10010-100 3434 0.0040.004 0.10.1 0.120.12 2020 3535 0.00450.0045 0.10.1 0.20.2 10-10010-100 3636 0.0050.005 0.10.1 0.10.1 ＞50＞ 50 3737 8.218.21 1-501-50 0.1-100.1-10 10-10010-100 3838 0.680.68 1-501-50 0.1-100.1-10 10-10010-100 3939 0.40.4 1-501-50 0.1-100.1-10 10-10010-100 4040 0.260.26 1-501-50 18.518.5 10-10010-100 4141 0.720.72 1-501-50 1.831.83 10-10010-100 4242 0.030.03 44 0.1-100.1-10 ＞50＞ 50 4343 0.030.03 22 0.1-100.1-10 ＞50＞ 50 4444 0.060.06 1-501-50 0.1-100.1-10 10-10010-100 4545 0.60.6 1-501-50 0.1-100.1-10 10-10010-100

4646 0.0140.014 1One 0.1-100.1-10 10-10010-100 4747 0.04250.0425 1-501-50 0.1-100.1-10 10-10010-100 4848 2.152.15 1-501-50 0.1-100.1-10 10-10010-100 4949 0.070.07 1-501-50 0.1-100.1-10 10-10010-100 5050 0.320.32 1-501-50 0.1-100.1-10 10-10010-100 5151 0.20.2 1-501-50 0.1-100.1-10 10-10010-100 5252 0.00070.0007 0.01-0.10.01-0.1 0.1-10.1-1 10-5010-50 5353 0.230.23 1-501-50 1-101-10 10-10010-100 5454 1212 10-10010-100 10-10010-100 10-10010-100 5555 0.90-0.90.90-0.9 1-501-50 0.1-100.1-10 10-10010-100 5656 0.00300.0030 0.10.1 0.10.1 ＞50＞ 50 5757 1.81.8 ＞1＞ 1 0.1-100.1-10 ＞20＞ 20 5858 0.010.01 ＞5＞ 5 0.80.8 ＞50＞ 50 5959 0.450.45 1-501-50 2222 ＞50＞ 50 6060 0.0640.064 0.1-100.1-10 1.71.7 10-10010-100 6161 0.00050.0005 ＜0.05<0.05 0.0060.006 ＜10<10 6262 0.00040.0004 0.050.05 0.090.09 ＞50＞ 50 6363 0.90.9 1-501-50 10-10010-100 10-10010-100 6464 1010 1-501-50 0.1-100.1-10 10-10010-100 6565 0.260.26 1-501-50 0.1-100.1-10 10-10010-100 6666 8.68.6 1-501-50 1-501-50 10-10010-100 6767 0.00060.0006 0.0080.008 0.00150.0015 1010 6868 0.0020.002 0.030.03 0.0020.002 44

6969 0.0040.004 0.0150.015 0.0060.006 1010 7070 0.0040.004 ＜0.1<0.1 ＜0.1<0.1 10-10010-100 7171 0.0010.001 0.0150.015 0.1000.100 ＜100<100 7272 0.0020.002 0.0250.025 0.0350.035 ＜50<50 7373 0.0040.004 0.0300.030 0.0620.062 ＜50<50 7474 -- -- -- ＜50<50 7575 -- -- -- ＜40<40 7676 -- -- -- ＜30<30 7777 -- -- -- ＜20<20 7878 -- -- -- ＜40<40 7979 -- -- -- ＜30<30 8080 -- -- -- ＜40<40 8181 -- -- -- ＜20<20 8282 0.0020.002 0.0060.006 0.0040.004 44 8383 0.0010.001 0.0120.012 0.0040.004 55 8484 0.0020.002 0.0150.015 0.0050.005 55 8585 0.0020.002 0.0100.010 0.0100.010 55

Claims (5)

하기 화학식 1의 화합물, 그의 약제학적으로 허용되는 염 또는 이성체 :A compound of Formula 1, a pharmaceutically acceptable salt or isomer thereof: 화학식 1Formula 1 상기식에서In the above formula n1은 1 내지 4의 정수를 나타내고,n 1 represents an integer of 1 to 4, X 는 O 또는 S를 나타내며,X represents O or S, A 는 수소; C3-C7사이클로알킬 또는 저급알콕시에 의해 치환되거나 비치환된 직쇄 또는 측쇄의 C1-C10알킬; 또는 할로겐, 시아노, 니트로, 하이드록시카보닐, 아미노카보닐, 아미노티오카보닐, 저급알콕시, 페녹시 또는 저급알킬에 의해 치환되거나 비치환된 벤질을 나타내고,A is hydrogen; Straight or branched C 1 -C 10 alkyl unsubstituted or substituted by C 3 -C 7 cycloalkyl or lower alkoxy; Or benzyl unsubstituted or substituted by halogen, cyano, nitro, hydroxycarbonyl, aminocarbonyl, aminothiocarbonyl, lower alkoxy, phenoxy or lower alkyl, B 는 수소; 또는 하이드록시, 머캅토, 저급알콕시, 저급알킬티오 또는 아릴에 의해 치환되거나 비치환된 저급알킬을 나타내며,B is hydrogen; Or lower alkyl unsubstituted or substituted by hydroxy, mercapto, lower alkoxy, lower alkylthio or aryl, C 는 아릴에 의해 치환되거나 비치환된 저급알킬을 나타내거나; 하기 구조식의 그룹중 선택된 어느 하나를 나타내고,C represents lower alkyl unsubstituted or substituted by aryl; Any one selected from the group of structural formulas ,,, , , , , , 여기에서 R1및 R2는 각각 독립적으로 수소, 저급알킬, 저급알콕시, 할로겐, 시아노, 하이드록시카보닐, 아미노카보닐, 아미노티오카보닐, 하이드록시, 페닐 또는 페녹시를 나타내며,Wherein R 1 and R 2 each independently represent hydrogen, lower alkyl, lower alkoxy, halogen, cyano, hydroxycarbonyl, aminocarbonyl, aminothiocarbonyl, hydroxy, phenyl or phenoxy, D 는 아미노산 잔기 또는 아미노산 잔기의 저급알킬에스테르를 나타내거나; 하기 구조식의 그룹중 선택된 어느 하나를 나타내고,D represents an amino acid residue or lower alkyl ester of an amino acid residue; Any one selected from the group of structural formulas ,,,, , , , , , , 여기에서From here R3및 R4는 각각 독립적으로 수소; 할로겐; 하이드록시; 시아노; 저급알킬; 저급알콕시; 알콕시알킬; 알킬티오; 알킬설포닐; 알킬티오알킬; 알킬티오알킬옥시; 아릴; 또는 아릴에 의해 치환된 옥시, 티오, 설포닐 또는 저급알킬을 나타내며,R 3 and R 4 are each independently hydrogen; halogen; Hydroxy; Cyano; Lower alkyl; Lower alkoxy; Alkoxyalkyl; Alkylthio; Alkylsulfonyl; Alkylthioalkyl; Alkylthioalkyloxy; Aryl; Or oxy, thio, sulfonyl or lower alkyl substituted by aryl, Y 는 O, S, SO2, C=O, C=S를 나타내거나, 저급알킬 또는 하이드록시에 의해 치환되거나 비치환된 CH2또는 NH 를 나타내고,Y represents O, S, SO 2 , C═O, C═S, or CH 2 or NH unsubstituted or substituted by lower alkyl or hydroxy, n2는 1 내지 3 의 정수를 나타내며,n 2 represents an integer of 1 to 3, R5및 R6은 각각 독립적으로 수소; 아릴; 아릴 또는 시아노아릴에 의해 치환되거나 비치환된 저급알킬; 또는을 나타내고, 여기에서 n3는 2 내지 4의 정수를 나타내며, Z 는 O, S 또는 SO2를 나타내고, R7은 수소 또는 저급알킬을 나타낸다.R 5 and R 6 are each independently hydrogen; Aryl; Lower alkyl unsubstituted or substituted by aryl or cyanoaryl; or Wherein n 3 represents an integer of 2 to 4, Z represents O, S or SO 2 , and R 7 represents hydrogen or lower alkyl. 제 1 항에 있어서,The method of claim 1, n1은 1 내지 3의 정수를 나타내고,n 1 represents an integer of 1 to 3, X 는 O 또는 S를 나타내며,X represents O or S, A 는 수소, C5-C6사이클로알킬 또는 저급알콕시에 의해 치환되거나 비치환된 직쇄 또는 측쇄의 C1-C10알킬, 4-브로보벤질, 또는 4-시아노벤질을 나타내고,A represents straight or branched C 1 -C 10 alkyl, 4-brobobenzyl, or 4-cyanobenzyl unsubstituted or substituted by hydrogen, C 5 -C 6 cycloalkyl or lower alkoxy, B 는 수소, 저급알킬, 또는 벤질을 나타내며,B represents hydrogen, lower alkyl, or benzyl, C 는 하기 구조식의 그룹중 선택된 어느 하나를 나타내고,C represents any one selected from the group of the following structural formulas, ,,, , , , 여기에서 R1및 R2는 각각 독립적으로 수소 또는 저급알킬을 나타내며,Wherein R 1 and R 2 each independently represent hydrogen or lower alkyl, D 는 메티오닌 또는 루신 잔기 또는 이들 아미노산 잔기의 저급알킬에스테르를 나타내거나; 하기 구조식의 그룹중 선택된 어느 하나를 나타내고,D represents a methionine or leucine residue or a lower alkylester of these amino acid residues; Any one selected from the group of structural formulas ,,,, , , , , 여기에서From here R3및 R4는 각각 독립적으로 수소; 할로겐; 시아노; 저급알킬; 저급알콕시; 알킬티오알킬; 알킬티오알킬옥시; 페닐; 또는 페닐에 의해 치환된 옥시 또는 저급알킬을 나타내며,R 3 and R 4 are each independently hydrogen; halogen; Cyano; Lower alkyl; Lower alkoxy; Alkylthioalkyl; Alkylthioalkyloxy; Phenyl; Or oxy or lower alkyl substituted by phenyl, Y 는 O, S, SO2, C=O 를 나타내거나, 저급알킬 또는 하이드록시에 의해 치환되거나 비치환된 CH2또는 NH 를 나타내고,Y represents O, S, SO 2 , C═O, or CH 2 or NH unsubstituted or substituted by lower alkyl or hydroxy, n2는 1 또는 2를 나타내며,n 2 represents 1 or 2, R5및 R6은 각각 독립적으로 수소; 페닐; 페닐 또는 4-시아노페닐에 의해 치환되거나 비치환된 저급알킬; 또는 하이드록시 또는 저급알콕시에 의해 치환된 C2-C4직쇄알킬을 나타내는 화합물.R 5 and R 6 are each independently hydrogen; Phenyl; Lower alkyl unsubstituted or substituted by phenyl or 4-cyanophenyl; Or C 2 -C 4 linear alkyl substituted by hydroxy or lower alkoxy. 제 2 항에 있어서,The method of claim 2, 1-(1H-이미다졸-4-일)메틸-4-(나프탈렌-1-일)-3-(티오펜-2-일)카보닐-1H-피롤(1),1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -3- (thiophen-2-yl) carbonyl-1H-pyrrole (1), 1-(1H-이미다졸-4-일)메틸-4-(나프탈렌-1-일)-3-(티오펜-3-일)카보닐-1H-피롤(2),1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -3- (thiophen-3-yl) carbonyl-1H-pyrrole (2), 3-벤조일-1-(1H-이미다졸-4-일)메틸-4-(나프탈렌-1-일)-1H-피롤(3),3-benzoyl-1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -1H-pyrrole (3), 3-(2-브로모벤조일)-1-(1H-이미다졸-4-일)메틸-4-(나프탈렌-1-일)-1H-피롤(4),3- (2-bromobenzoyl) -1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -1H-pyrrole (4), 3-(3-브로모벤조일)-1-(1H-이미다졸-4-일)메틸-4-(나프탈렌-1-일)-1H-피롤(5),3- (3-bromobenzoyl) -1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -1H-pyrrole (5), 3-(4-브로모벤조일)-1-(1H-이미다졸-4-일)메틸-4-(나프탈렌-1-일)-1H-피롤(6),3- (4-bromobenzoyl) -1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -1H-pyrrole (6), 1-(1H-이미다졸-4-일)메틸-3-(2-메틸벤조일)-4-(나프탈렌-1-일)-1H-피롤(7),1- (1H-imidazol-4-yl) methyl-3- (2-methylbenzoyl) -4- (naphthalen-1-yl) -1H-pyrrole (7), 1-(1H-이미다졸-4-일)메틸-3-(3-메틸벤조일)-4-(나프탈렌-1-일)-1H-피롤(8),1- (1H-imidazol-4-yl) methyl-3- (3-methylbenzoyl) -4- (naphthalen-1-yl) -1H-pyrrole (8), 1-(1H-이미다졸-4-일)메틸-3-(4-메틸벤조일)-4-(나프탈렌-1-일)-1H-피롤(9),1- (1H-imidazol-4-yl) methyl-3- (4-methylbenzoyl) -4- (naphthalen-1-yl) -1H-pyrrole (9), 1-(1H-이미다졸-4-일)메틸-3-(3-메톡시벤조일)-4-(나프탈렌-1-일)-1H-피롤 (10),1- (1H-imidazol-4-yl) methyl-3- (3-methoxybenzoyl) -4- (naphthalen-1-yl) -1H-pyrrole (10), 1-(1H-이미다졸-4-일)메틸-3-(4-메톡시벤조일)-4-(나프탈렌-1-일)-1H-피롤 (11),1- (1H-imidazol-4-yl) methyl-3- (4-methoxybenzoyl) -4- (naphthalen-1-yl) -1H-pyrrole (11), 3-(2-클로로벤조일)-1-(1H-이미다졸-4-일)메틸-4-(나프탈렌-1-일)-1H-피롤 (12),3- (2-chlorobenzoyl) -1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -1H-pyrrole (12), 3-(4-클로로벤조일)-1-(1H-이미다졸-4-일)메틸-4-(나프탈렌-1-일)-1H-피롤 (13),3- (4-chlorobenzoyl) -1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -1H-pyrrole (13), 3-(2,4-디클로로벤조일)-1-(1H-이미다졸-4-일)메틸-4-(나프탈렌-1-일)-1H-피롤 (14),3- (2,4-dichlorobenzoyl) -1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -1H-pyrrole (14), 3-(4-플루오로벤조일)-1-(1H-이미다졸-4-일)메틸-4-(나프탈렌-1-일)-1H-피롤 (15),3- (4-fluorobenzoyl) -1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -1H-pyrrole (15), 3-(2,4-디플루오로벤조일)-1-(1H-이미다졸-4-일)메틸-4-(나프탈렌-1-일)-1H-피롤 (16),3- (2,4-difluorobenzoyl) -1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -1H-pyrrole (16), 3-(4-시아노벤조일)-1-(1H-이미다졸-4-일)메틸-4-(나프탈렌-1-일)-1H-피롤 (17),3- (4-cyanobenzoyl) -1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -1H-pyrrole (17), 1-(1H-이미다졸-4-일)메틸-3-(4-메틸티오메틸벤조일)-4-(나프탈렌-1-일)-1H-피롤(18),1- (1H-imidazol-4-yl) methyl-3- (4-methylthiomethylbenzoyl) -4- (naphthalen-1-yl) -1H-pyrrole (18), 1-(1H-이미다졸-4-일)메틸-3-[4-(2-메틸티오에틸)벤조일]-4-(나프탈렌-1-일)-1H-피롤(19),1- (1H-imidazol-4-yl) methyl-3- [4- (2-methylthioethyl) benzoyl] -4- (naphthalen-1-yl) -1H-pyrrole (19), 1-(1H-이미다졸-4-일)메틸-3-[4-(2-메틸티오에톡시)벤조일]-4-(나프탈렌-1-일)-1H-피롤(20),1- (1H-imidazol-4-yl) methyl-3- [4- (2-methylthioethoxy) benzoyl] -4- (naphthalen-1-yl) -1H-pyrrole (20), 1-(1H-이미다졸-4-일)메틸-3-(3-메틸티오메틸벤조일)-4-(나프탈렌-1-일)-1H-피롤(21),1- (1H-imidazol-4-yl) methyl-3- (3-methylthiomethylbenzoyl) -4- (naphthalen-1-yl) -1H-pyrrole (21), 1-(1H-이미다졸-4-일)메틸-4-(나프탈렌-1-일)-3-(3-페닐벤조일)-1H-피롤(22),1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -3- (3-phenylbenzoyl) -1H-pyrrole (22), 1-(1H-이미다졸-4-일)메틸-4-(나프탈렌-1-일)-3-(4-페닐벤조일)-1H-피롤(23),1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -3- (4-phenylbenzoyl) -1H-pyrrole (23), 1-(1H-이미다졸-4-일)메틸-4-(나프탈렌-1-일)-3-(4-페녹시벤조일)-1H-피롤 (24),1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -3- (4-phenoxybenzoyl) -1H-pyrrole (24), 3-(4-벤질벤조일)-1-(1H-이미다졸-4-일)메틸-4-(나프탈렌-1-일)-1H-피롤(25),3- (4-benzylbenzoyl) -1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -1H-pyrrole (25), 1-(1H-이미다졸-4-일)메틸-4-(나프탈렌-1-일)-3-(나프탈렌-1-일)카보닐-1H-피롤(26),1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -3- (naphthalen-1-yl) carbonyl-1H-pyrrole (26), 1-(1H-이미다졸-4-일)메틸-3-(4-메틸벤조일)-4-(1-메틸인돌-3-일)-1H-피롤 (27),1- (1H-imidazol-4-yl) methyl-3- (4-methylbenzoyl) -4- (1-methylindol-3-yl) -1H-pyrrole (27), 5-n-부틸-3-(2,4-디클로로벤조일)-1-(1H-이미다졸-4-일)메틸-4-(나프탈렌-1-일)-1H-피롤(28),5-n-butyl-3- (2,4-dichlorobenzoyl) -1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -1H-pyrrole (28), 5-벤질-3-(2,4-디클로로벤조일)-1-(1H-이미다졸-4-일)메틸-4-(나프탈렌-1-일)-1H-피롤(29),5-benzyl-3- (2,4-dichlorobenzoyl) -1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -1H-pyrrole (29), 1-[1-(4-시아노벤질)-1H-이미다졸-5-일]메틸-4-(나프탈렌-1-일)-3-(티오펜-2-일)카보닐-1H-피롤(30),1- [1- (4-cyanobenzyl) -1H-imidazol-5-yl] methyl-4- (naphthalen-1-yl) -3- (thiophen-2-yl) carbonyl-1H-pyrrole 30, 1-[1-(4-시아노벤질)-1H-이미다졸-5-일]메틸-4-(나프탈렌-1-일)-3-(티오펜-3-일)카보닐-1H-피롤(31),1- [1- (4-cyanobenzyl) -1H-imidazol-5-yl] methyl-4- (naphthalen-1-yl) -3- (thiophen-3-yl) carbonyl-1H-pyrrole (31), 3-벤조일-1-[1-(4-시아노벤질)-1H-이미다졸-5-일]메틸-4-(나프탈렌-1-일)-1H-피롤(32),3-benzoyl-1- [1- (4-cyanobenzyl) -1H-imidazol-5-yl] methyl-4- (naphthalen-1-yl) -1H-pyrrole (32), 3-(3-브로모벤조일)-1-[1-(4-시아노벤질)-1H-이미다졸-5-일]메틸-4-(나프탈렌-1-일)-1H-피롤(33),3- (3-bromobenzoyl) -1- [1- (4-cyanobenzyl) -1H-imidazol-5-yl] methyl-4- (naphthalen-1-yl) -1H-pyrrole (33) , 3-(4-브로모벤조일)-1-[1-(4-시아노벤질)-1H-이미다졸-5-일]메틸-4-(나프탈렌-1-일)-1H-피롤(34),3- (4-bromobenzoyl) -1- [1- (4-cyanobenzyl) -1H-imidazol-5-yl] methyl-4- (naphthalen-1-yl) -1H-pyrrole (34) , 3-(4-플루오로벤조일)-1-(1-메틸-1H-이미다졸-4-일)메틸-4-(나프탈렌-1-일)-1H-피롤(35),3- (4-fluorobenzoyl) -1- (1-methyl-1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -1H-pyrrole (35), 1-(1-메틸-1H-이미다졸-4-일)메틸-4-(나프탈렌-1-일)-3-(4-페녹시벤조일)-1H-피롤(36),1- (1-methyl-1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -3- (4-phenoxybenzoyl) -1H-pyrrole (36), (S)-1-(1H-이미다졸-4-일)메틸-3-[N-(1-메톡시카보닐-3-메틸티오)프로필]카바모일-4-(나프탈렌-1-일)-1H-피롤(37),(S) -1- (1H-imidazol-4-yl) methyl-3- [N- (1-methoxycarbonyl-3-methylthio) propyl] carbamoyl-4- (naphthalen-1-yl) -1H-pyrrole (37), (S)-3-[N-(1-하이드록시카보닐-3-메틸티오)프로필]카바모일-1-(1H-이미다졸-4-일)메틸-4-(나프탈렌-1-일)-1H-피롤(38),(S) -3- [N- (1-hydroxycarbonyl-3-methylthio) propyl] carbamoyl-1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -1H-pyrrole (38), 1-(1H-이미다졸-4-일)메틸-4-(나프탈렌-1-일)-3-(N-페닐)카바모일-1H-피롤 (39),1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -3- (N-phenyl) carbamoyl-1H-pyrrole (39), 3-(N-벤질)카바모일-1-(1H-이미다졸-4-일)메틸-4-(나프탈렌-1-일)-1H-피롤 (40),3- (N-benzyl) carbamoyl-1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -1H-pyrrole (40), 1-(1H-이미다졸-4-일)메틸-4-(나프탈렌-1-일)-3-(피페리딘-1-일)카보닐-1H-피롤(41),1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -3- (piperidin-1-yl) carbonyl-1H-pyrrole (41), 1-(1H-이미다졸-4-일)메틸-3-(모폴린-4-일)카보닐-4-(나프탈렌-1-일)-1H-피롤(42),1- (1H-imidazol-4-yl) methyl-3- (morpholin-4-yl) carbonyl-4- (naphthalen-1-yl) -1H-pyrrole (42), 1-(1H-이미다졸-4-일)메틸-4-(나프탈렌-1-일)-3-(티아모폴린-4-일)카보닐-1H-피롤(43),1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -3- (thiamorpholin-4-yl) carbonyl-1H-pyrrole (43), 3-(1,1-디옥소티아모폴린-4-일)카보닐-1-(1H-이미다졸-4-일)메틸-4-(나프탈렌-1-일)-1H-피롤(44),3- (1,1-dioxothiamorpholin-4-yl) carbonyl-1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -1H-pyrrole (44) , 1-(1H-이미다졸-4-일)메틸-4-(나프탈렌-1-일)-3-(피페라진-1-일)카보닐-1H-피롤(45),1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -3- (piperazin-1-yl) carbonyl-1H-pyrrole (45), 1-(1H-이미다졸-4-일)메틸-3-(4-메틸피페라진-1-일)카보닐-4-(나프탈렌-1-일)-1H-피롤(46),1- (1H-imidazol-4-yl) methyl-3- (4-methylpiperazin-1-yl) carbonyl-4- (naphthalen-1-yl) -1H-pyrrole (46), 1-(1H-이미다졸-4-일)메틸-4-(나프탈렌-1-일)-3-(티아졸리딘-3-일)카보닐-1H-피롤(47),1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -3- (thiazolidin-3-yl) carbonyl-1H-pyrrole (47), 3-(4-하이드록시피페리딘-1-일)카보닐-1-(1H-이미다졸-4-일)메틸-4-(나프탈렌-1-일)-1H-피롤(48),3- (4-hydroxypiperidin-1-yl) carbonyl-1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -1H-pyrrole (48), 1-(1H-이미다졸-4-일)메틸-4-(나프탈렌-1-일)-3-(4-옥소피페리딘-1-일)카보닐-1H-피롤(49),1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -3- (4-oxopiperidin-1-yl) carbonyl-1H-pyrrole (49), 3-[N-(2-하이드록시에틸)]카바모일-1-(1H-이미다졸-4-일)메틸-4-(나프탈렌-1-일)-1H-피롤(50),3- [N- (2-hydroxyethyl)] carbamoyl-1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -1H-pyrrole (50), 3-[N-(2-하이드록시에틸)-N-메틸]카바모일-1-(1H-이미다졸-4-일)메틸-4-(나프탈렌-1-일)-1H-피롤(51),3- [N- (2-hydroxyethyl) -N-methyl] carbamoyl-1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -1H-pyrrole (51) , 1-(1H-이미다졸-4-일)메틸-3-[N-(2-메톡시에틸)-N-메틸]카바모일-4-(나프탈렌-1-일)-1H-피롤(52),1- (1H-imidazol-4-yl) methyl-3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- (naphthalen-1-yl) -1H-pyrrole (52) , 1-(1H-이미다졸-4-일)메틸-3-(모폴린-4-일)카보닐-4-(퀴놀린-4-일)-1H-피롤 (53),1- (1H-imidazol-4-yl) methyl-3- (morpholin-4-yl) carbonyl-4- (quinolin-4-yl) -1H-pyrrole (53), 4-(1,2-디하이드로아세나프탈렌-5-일)-1-(1H-이미다졸-4-일)메틸-3-(모폴린-4-일)카보닐-1H-피롤(54),4- (1,2-dihydroacenaphthalen-5-yl) -1- (1H-imidazol-4-yl) methyl-3- (morpholin-4-yl) carbonyl-1H-pyrrole (54) , 3-[N-(4-시아노벤질)]카바모일-1-(1H-이미다졸-4-일)메틸-4-(나프탈렌-1-일)-1H-피롤(55),3- [N- (4-cyanobenzyl)] carbamoyl-1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -1H-pyrrole (55), 1-(1-메틸-1H-이미다졸-5-일)메틸-3-(모폴린-4-일)카보닐-4-(나프탈렌-1-일)-1H-피롤(56),1- (1-methyl-1H-imidazol-5-yl) methyl-3- (morpholin-4-yl) carbonyl-4- (naphthalen-1-yl) -1H-pyrrole (56), (S)-1-[1-(4-시아노벤질)-1H-이미다졸-5-일]메틸-3-[N-(1-메톡시카보닐-3-메틸티오)프로필]카바모일-4-(나프탈렌-1-일)-1H-피롤(57),(S) -1- [1- (4-cyanobenzyl) -1H-imidazol-5-yl] methyl-3- [N- (1-methoxycarbonyl-3-methylthio) propyl] carbamoyl -4- (naphthalen-1-yl) -1 H-pyrrole (57), (S)-1-[1-(4-시아노벤질)-1H-이미다졸-5-일]메틸-3-[N-(1-하이드록시카보닐-3-메틸티오)프로필]카바모일-4-(나프탈렌-1-일)-1H-피롤(58),(S) -1- [1- (4-cyanobenzyl) -1H-imidazol-5-yl] methyl-3- [N- (1-hydroxycarbonyl-3-methylthio) propyl] carbamoyl -4- (naphthalen-l-yl) -lH-pyrrole (58), (S)-1-[1-(4-시아노벤질)-1H-이미다졸-5-일]메틸-3-[N-(1-메톡시카보닐-3-메틸)부틸]카바모일-4-(나프탈렌-1-일)-1H-피롤(59),(S) -1- [1- (4-cyanobenzyl) -1H-imidazol-5-yl] methyl-3- [N- (1-methoxycarbonyl-3-methyl) butyl] carbamoyl- 4- (naphthalen-1-yl) -1H-pyrrole (59), (S)-1-[1-(4-시아노벤질)-1H-이미다졸-5-일]메틸-3-[N-(1-하이드록시카보닐-3-메틸)부틸]카바모일-4-(나프탈렌-1-일)-1H-피롤(60),(S) -1- [1- (4-cyanobenzyl) -1H-imidazol-5-yl] methyl-3- [N- (1-hydroxycarbonyl-3-methyl) butyl] carbamoyl- 4- (naphthalen-1-yl) -1H-pyrrole (60), 1-[1-(4-시아노벤질)-1H-이미다졸-5-일]메틸-3-(모폴린-4-일)카보닐-4-(나프탈렌-1-일)-1H-피롤(61),1- [1- (4-cyanobenzyl) -1H-imidazol-5-yl] methyl-3- (morpholin-4-yl) carbonyl-4- (naphthalen-1-yl) -1H-pyrrole 61, 1-[1-(4-시아노벤질)-1H-이미다졸-5-일]메틸-3-(4-메틸피페라진-1-일)카보닐-4-(나프탈렌-1-일)-1H-피롤(62),1- [1- (4-cyanobenzyl) -1H-imidazol-5-yl] methyl-3- (4-methylpiperazin-1-yl) carbonyl-4- (naphthalen-1-yl)- 1 H-pyrrole 62, 1-[2-(1H-이미다졸-1-일)에틸]-3-(모폴린-4-일)카보닐-4-(나프탈렌-1-일)-1H-피롤(63),1- [2- (1H-imidazol-1-yl) ethyl] -3- (morpholin-4-yl) carbonyl-4- (naphthalen-1-yl) -1H-pyrrole (63), (S)-1-[3-(1H-이미다졸-4-일)프로필]-3-[N-(1-메톡시카보닐-3-메틸티오)프로필]카바모일-4-(나프탈렌-1-일)-1H-피롤(64),(S) -1- [3- (1H-imidazol-4-yl) propyl] -3- [N- (1-methoxycarbonyl-3-methylthio) propyl] carbamoyl-4- (naphthalene- 1-day) -1H-pyrrole (64), (S)-3-[N-(1-하이드록시카보닐-3-메틸티오)프로필]카바모일-1-[3-(1H-이미다졸-4-일)프로필]-4-(나프탈렌-1-일)-1H-피롤(65),(S) -3- [N- (1-hydroxycarbonyl-3-methylthio) propyl] carbamoyl-1- [3- (1H-imidazol-4-yl) propyl] -4- (naphthalene- 1-day) -1H-pyrrole 65, 1-[3-(1H-이미다졸-4-일)프로필]-3-(모폴린-4-일)카보닐-4-(나프탈렌-1-일)-1H-피롤(66),1- [3- (1H-imidazol-4-yl) propyl] -3- (morpholin-4-yl) carbonyl-4- (naphthalen-1-yl) -1H-pyrrole (66), 1-[1-(4-시아노벤질)-1H-이미다졸-5-일]메틸-3-[N-(2-메톡시에틸)-N-메틸]카바모일-4-(나프탈렌-1-일)-1H-피롤(67),1- [1- (4-cyanobenzyl) -1H-imidazol-5-yl] methyl-3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- (naphthalene-1 -Yl) -1H-pyrrole (67), 1-[1-(4-브로모벤질)-1H-이미다졸-5-일]메틸-3-[N-(2-메톡시에틸)-N-메틸]카바모일-4-(나프탈렌-1-일)-1H-피롤(68),1- [1- (4-bromobenzyl) -1H-imidazol-5-yl] methyl-3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- (naphthalene-1 -Yl) -1H-pyrrole (68), 1-[1-(4-브로모벤질)-1H-이미다졸-5-일]메틸-3-(모폴린-4-일)카보닐-4-(나프탈렌-1-일)-1H-피롤(69),1- [1- (4-bromobenzyl) -1H-imidazol-5-yl] methyl-3- (morpholin-4-yl) carbonyl-4- (naphthalen-1-yl) -1H-pyrrole 69, 1-[1-(4-시아노벤질)-1H-이미다졸-5-일]메틸-3-(모폴린-4-일)티오카보닐-4-(나프탈렌-1-일)-1H-피롤(70),1- [1- (4-cyanobenzyl) -1H-imidazol-5-yl] methyl-3- (morpholin-4-yl) thiocarbonyl-4- (naphthalen-1-yl) -1H- Pyrrole 70, 3-[N-(2-메톡시에틸)-N-메틸]카바모일-1-(1-메틸-1H-이미다졸-5-일)메틸-4- (나프탈렌-1-일)-1H-피롤(71),3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-1- (1-methyl-1H-imidazol-5-yl) methyl-4- (naphthalen-1-yl) -1H- Pyrrole (71), 1-(1-이소부틸-1H-이미다졸-5-일)메틸-3-[N-(2-메톡시에틸)-N-메틸]카바모일-4-(나프탈렌-1-일)-1H-피롤(72),1- (1-isobutyl-1H-imidazol-5-yl) methyl-3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- (naphthalen-1-yl) -1H Pyrrole 72, 1-(1-사이클로헥실메틸-1H-이미다졸-5-일)메틸-3-[N-(2-메톡시에틸)-N-메틸]카바모일-4-(나프탈렌-1-일)-1H-피롤(73),1- (1-cyclohexylmethyl-1H-imidazol-5-yl) methyl-3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- (naphthalen-1-yl)- 1 H-pyrrole (73), 3-[N-(2-메톡시에틸)-N-메틸]카바모일-4-(나프탈렌-1-일)-1-(1-펜틸-1H-이미다졸-5-일)메틸-1H-피롤(74),3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- (naphthalen-1-yl) -1- (1-pentyl-1H-imidazol-5-yl) methyl-1H- Pyrrole (74), 3-[N-(2-메톡시에틸)-N-메틸]카바모일-4-(나프탈렌-1-일)-1-(1-옥틸-1H-이미다졸-5-일)메틸-1H-피롤(75),3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- (naphthalen-1-yl) -1- (1-octyl-1H-imidazol-5-yl) methyl-1H- Pyrrole (75), 1-(1-데실-1H-이미다졸-5-일)메틸-3-[N-(2-메톡시에틸)-N-메틸]카바모일-4- (나프탈렌-1-일)-1H-피롤(76),1- (1-decyl-1H-imidazol-5-yl) methyl-3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- (naphthalen-1-yl) -1H- Pyrrole (76), 3-[N-(2-메톡시에틸)-N-메틸]카바모일-1-[1-(3-메틸부틸)-1H-이미다졸-5-일]메틸-4-(나프탈렌-1-일)-1H-피롤(77),3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-1- [1- (3-methylbutyl) -1H-imidazol-5-yl] methyl-4- (naphthalene-1- 1) -1H-pyrrole (77), 1-[1-(2-메톡시에틸)-1H-이미다졸-5-일]메틸-3-[N-(2-메톡시에틸)-N-메틸]카바모일-4-(나프탈렌-1-일)-1H-피롤(78),1- [1- (2-methoxyethyl) -1H-imidazol-5-yl] methyl-3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- (naphthalene-1 -Yl) -1H-pyrrole (78), 3-[N-(2-메톡시에틸)-N-메틸]카바모일-1-[1-(3-메톡시프로필)-1H-이미다졸-5-일]메틸-4-(나프탈렌-1-일)-1H-피롤(79),3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-1- [1- (3-methoxypropyl) -1H-imidazol-5-yl] methyl-4- (naphthalene-1 -Yl) -1H-pyrrole (79), 1-[1-(3-에톡시프로필)-1H-이미다졸-5-일]메틸-3-[N-(2-메톡시에틸)-N-메틸]카바모일-4-(나프탈렌-1-일)-1H-피롤(80),1- [1- (3-ethoxypropyl) -1H-imidazol-5-yl] methyl-3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- (naphthalene-1 -Yl) -1H-pyrrole (80), 1-[1-(3-이소프로폭시프로필)-1H-이미다졸-5-일]메틸-3-[N-(2-메톡시에틸)-N-메틸]카바모일-4-(나프탈렌-1-일)-1H-피롤(81),1- [1- (3-Isopropoxypropyl) -1H-imidazol-5-yl] methyl-3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- (naphthalene- 1-day) -1H-pyrrole (81), 1-[1-(4-브로모벤질)-1H-이미다졸-5-일]메틸-3-[4-메틸피페라진-1-일]카보닐-4-(나프탈렌-1-일)-1H-피롤(82),1- [1- (4-bromobenzyl) -1H-imidazol-5-yl] methyl-3- [4-methylpiperazin-1-yl] carbonyl-4- (naphthalen-1-yl)- 1H-pyrrole 82, 1-[1-(4-클로로벤질)-1H-이미다졸-5-일]메틸-3-[4-메틸피페라진-1-일]카보닐-4-(나프탈렌-1-일)-1H-피롤(83),1- [1- (4-chlorobenzyl) -1H-imidazol-5-yl] methyl-3- [4-methylpiperazin-1-yl] carbonyl-4- (naphthalen-1-yl) -1H Pyrrole 83, 1-[1-(4-플루오로벤질)-1H-이미다졸-5-일]메틸-3-[N-(2-메톡시에틸)-N-메틸]카바모일-4-(나프탈렌-1-일)-1H-피롤(84), 또는1- [1- (4-fluorobenzyl) -1H-imidazol-5-yl] methyl-3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- (naphthalene-1 -Yl) -1H-pyrrole 84, or 1-[1-(4-플루오로벤질)-1H-이미다졸-5-일]메틸-3-[4-메틸피페라진-1-일]카보닐-4-(나프탈렌-1-일)-1H-피롤(85)인 화합물.1- [1- (4-fluorobenzyl) -1H-imidazol-5-yl] methyl-3- [4-methylpiperazin-1-yl] carbonyl-4- (naphthalen-1-yl)- 1 H-pyrrole (85). (a) 하기 화학식 2의 화합물을 용매중에서 염기의 존재하에 하기 화학식 3의 화합물과 반응시킨 후 트리플루오로아세트산의 존재하에 보호기를 제거하여 하기 화학식 1a의 화합물을 제조하거나; (b) 하기 화학식 4의 화합물을 용매중에서 염기의 존재하에 화학식 3의 화합물과 반응시켜 하기 화학식 1b의 화합물을 제조하거나; (c) 하기 화학식 5의 화합물을 용매중에서 염기의 존재하에 하기 화학식 3의 화합물과 반응시키고 트리플루오로아세트산의 존재하에 보호기를 제거하여 하기 화학식 6의 화합물을 제조한 다음 수첨반응을 수행하여 하기 화학식 1c의 화합물을 제조하거나; (d) 하기 화학식 7의 화합물을 가수분해시켜 하기 화학식 8의 화합물을 제조한 다음 하기 화학식 9의 화합물과 커플링제의 존재하에 커플링시켜 하기 화학식 1d의 화합물을 제조하거나; (e) 하기 화학식 1e 화합물의 카보닐그룹을 황화제 존재하에 티오카보닐그룹으로 전환시켜 하기 화학식 1f의 화합물을 제조함을 특징으로하여 제 1 항에 정의된 화학식 1의 화합물을 제조하는 방법 :(a) reacting a compound of formula 2 with a compound of formula 3 in a solvent in the presence of a base and then removing a protecting group in the presence of trifluoroacetic acid to prepare a compound of formula 1a; (b) reacting a compound of formula 4 with a compound of formula 3 in the presence of a base in a solvent to prepare a compound of formula 1b; (c) reacting a compound of formula 5 with a compound of formula 3 in a solvent in the presence of a base and removing a protecting group in the presence of trifluoroacetic acid to produce a compound of formula 6, followed by hydrogenation; To prepare the compound of 1c; (d) hydrolyzing the compound of Formula 7 to prepare a compound of Formula 8, and then coupling the compound of Formula 9 with a coupling agent in the presence of a coupling agent to prepare a compound of Formula 1d; (e) A process for preparing the compound of formula 1 as defined in claim 1, characterized by converting the carbonyl group of the compound of formula 1e to a thiocarbonyl group in the presence of a sulfiding agent 화학식 2Formula 2 화학식 3Formula 3 화학식 1aFormula 1a 화학식 4Formula 4 화학식 1bFormula 1b 화학식 5Formula 5 화학식 6Formula 6 화학식 1cFormula 1c 화학식 7Formula 7 화학식 8Formula 8 화학식 9Formula 9 화학식 1dFormula 1d 화학식 1eFormula 1e 화학식 1fFormula 1f 상기식에서In the above formula A, n1, B, C, D, R5, R6는 제 1 항에서 정의한 바와 같고,A, n 1 , B, C, D, R 5 , R 6 are as defined in claim 1, A' 는 A 와 동일하나, 단 수소는 제외되며,A 'is the same as A, except hydrogen Tr 은 트리틸을 나타낸다.Tr represents trityl. 하기 화학식 8의 화합물 :A compound of formula 화학식 8Formula 8 상기식에서 A, n1, B 및 C 는 제 1 항에서 정의한 바와 같다.Wherein A, n 1 , B and C are as defined in claim 1.
KR1019980024423A 1997-11-28 1998-06-26 Panesyl transferase inhibitor having a pyrrole structure and its preparation method KR19990062439A (en)

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RU2000116633/04A RU2179975C1 (en) 1997-11-28 1998-11-25 Derivatives of imidazole eliciting inhibitory activity with respect to farnesyltransferase, method of their synthesis, intermediate compounds, pharmaceutical composition
AU15083/99A AU731272B2 (en) 1997-11-28 1998-11-25 Imidazole derivatives having an inhibitory activity for farnesyl transferase and process for preparation thereof
AT98959231T ATE239014T1 (en) 1997-11-28 1998-11-25 IMIDAZOLE DERIVATIVES WITH FARNESYL TRANSFERASE INHIBITING PROPERTIES AND METHOD FOR THE PRODUCTION THEREOF
EP98959231A EP1045846B1 (en) 1997-11-28 1998-11-25 Imidazole derivatives having an inhibitory activity for farnesyl transferase and process for preparation thereof
ES98959231T ES2193590T3 (en) 1997-11-28 1998-11-25 IMIDAZOL DERIVATIVES THAT HAVE INHIBITORY ACTIVITY AGAINST FARNESIL TRANSFERASA AND PROCEDURE FOR THE PREPARATION OF THE SAME.
US09/554,646 US6268363B1 (en) 1997-11-28 1998-11-25 Imidazole derivatives having an inhibitory activity for farnesyl transferase and process for preparation thereof
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NZ504013A NZ504013A (en) 1997-11-28 1998-11-25 Imidazole derivatives having an inhibitory activity for farnesyl transferase and process for preparation thereof
PCT/KR1998/000377 WO1999028315A1 (en) 1997-11-28 1998-11-25 Imidazole derivatives having an inhibitory activity for farnesyl transferase and process for preparation thereof
JP2000523207A JP3548118B2 (en) 1997-11-28 1998-11-25 Imidazole derivatives having farnesyl transferase inhibitory activity and method for producing the same
HU0004238A HUP0004238A3 (en) 1997-11-28 1998-11-25 Imidazole derivatives having an inhibitory activity for farnesyl transferase, process for preparation thereof and pharmaceutical compositions containing them
DE69814167T DE69814167T2 (en) 1997-11-28 1998-11-25 IMIDAZOLE DERIVATIVES WITH FARNESYL TRANSFERASE INHIBITING PROPERTIES AND METHOD FOR THE PRODUCTION THEREOF
PL98340729A PL340729A1 (en) 1997-11-28 1998-11-25 Imidazolic derivatives exhibiting inhibitive activity in respect to pharnesil transferase and method of obtaining them
IL13547398A IL135473A0 (en) 1997-11-28 1998-11-25 Imidazole derivatives having an inhibitory activity for farnesyl transferase and process for preparation thereof
IDW20000933A ID24175A (en) 1997-11-28 1998-11-25 IMIDAZOL DRIVINGS WHICH HAVE A LIVING ACTIVITY FOR FARNESIL TRANSFERASE AND THE PROCESS OF MAKING IT
BR9815423-0A BR9815423A (en) 1997-11-28 1998-11-25 Compound derived from imidazole, process for preparing an imidazole derivative, and pharmaceutical composition.
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KR20010077400A (en) * 2000-02-02 2001-08-17 성재갑 Anticancer agents by combination of Ftase inhibitor(LB42908) and other anticancer drugs
KR100395300B1 (en) * 1999-08-11 2003-08-27 주식회사 엘지생명과학 Pyrrole derivatives useful for inhibition of farnesyl transferase and process for preparation thereof

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* Cited by examiner, † Cited by third party
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KR100395300B1 (en) * 1999-08-11 2003-08-27 주식회사 엘지생명과학 Pyrrole derivatives useful for inhibition of farnesyl transferase and process for preparation thereof
KR20010077400A (en) * 2000-02-02 2001-08-17 성재갑 Anticancer agents by combination of Ftase inhibitor(LB42908) and other anticancer drugs

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