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KR100696139B1 - Alkyl carbamoyl naphthalenyloxy octenoyl hydroxyamide derivative having histone deacetylase inhibitory activity and preparation method thereof - Google Patents

Alkyl carbamoyl naphthalenyloxy octenoyl hydroxyamide derivative having histone deacetylase inhibitory activity and preparation method thereof Download PDF

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KR100696139B1
KR100696139B1 KR1020050103693A KR20050103693A KR100696139B1 KR 100696139 B1 KR100696139 B1 KR 100696139B1 KR 1020050103693 A KR1020050103693 A KR 1020050103693A KR 20050103693 A KR20050103693 A KR 20050103693A KR 100696139 B1 KR100696139 B1 KR 100696139B1
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naphthalen
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이철해
정희정
김재학
정원장
조중명
노성구
이태규
신동규
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한국화학연구원
크리스탈지노믹스(주)
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Priority to CA002628040A priority patent/CA2628040A1/en
Priority to EP06812321A priority patent/EP1945606A4/en
Priority to CN2006800407666A priority patent/CN101300226B/en
Priority to BRPI0618131-7A priority patent/BRPI0618131A2/en
Priority to JP2008538811A priority patent/JP2009513697A/en
Priority to PCT/KR2006/004482 priority patent/WO2007052938A1/en
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Abstract

본 발명은 하기 화학식 1의 알킬카바모일 나프탈렌일옥시 옥테노일 하이드록시아마이드 유도체(alkylcarbamoyl naphthalenyloxy octenoylhydroxyamide derivatives), 이의 제조방법 및 이를 유효성분으로 하는 항암제용 약학 조성물에 관한 것으로, 본 발명의 알킬카바모일 나프탈렌일옥시 옥테노일 하이드록시아마이드 유도체는 히스톤 디아세틸라제의 효소활성을 효과적으로 저해하며 종양세포의 증식을 억제하는데 유용하게 사용될 수 있다.The present invention relates to alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide derivatives of the general formula (1), a method for preparing the same, and a pharmaceutical composition for an anticancer agent using the same as an active ingredient, wherein the alkylcarbamoyl naphthalene of the present invention Iloxy octenoyl hydroxyamide derivatives effectively inhibit the enzymatic activity of histone deacetylase and can be usefully used to inhibit the proliferation of tumor cells.

<화학식 1><Formula 1>

Figure 112005062761854-pat00001
Figure 112005062761854-pat00001

상기 식에서,Where

R1은 각각 독립적으로 C1-3알킬, 하이드록시C1-2알킬, 할로C1-2알킬, 피페리디닐, 몰포리닐, 사이아노메틸, 피페라지닐, 다이C1-2알킬아미노C1-2알킬, 다이C1-2알킬아미노C1-2알킬, 피페리디닐C1-2알킬, 몰포리노C1-2알킬, 피페라지노C1-2알킬, 피롤리디닐, C1-2알킬피롤리디닐로 구성된 군으로부터 선택된 하나 이상의 치환체로 치환되거나 치환되지 않은 C1-2알킬이고, Each R 1 is independently C 1-3 alkyl, hydroxyC 1-2 alkyl, haloC 1-2 alkyl, piperidinyl, morpholinyl, cyanomethyl, piperazinyl, diC 1-2 alkylamino C 1-2 alkyl, diC 1-2 alkylaminoC 1-2 alkyl, piperidinylC 1-2 alkyl, morpholinoC 1-2 alkyl, piperazinoC 1-2 alkyl, pyrrolidinyl, C and C 1-2 alkyl optionally substituted with one or more substituents selected from the group consisting of 1-2-alkyl-pyrrolidinyl,

R2는 수소 또는 메틸이다.R 2 is hydrogen or methyl.

Description

히스톤 디아세틸라제 저해활성을 갖는 알킬카바모일 나프탈렌일옥시 옥테노일 하이드록시아마이드 유도체 및 그의 제조방법 {ALKYLCARBAMOYL NAPHTHALENYLOXYOCTENOYLHYDROXYAMIDE DERIVATIVES HAVING INHIBITORY ACTIVITY AGAINST HISTONE DEACETYLASE AND PREPARATION THEREOF}Alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide derivatives having a histone deacetylase inhibitory activity and a method for preparing the same

본 발명은 히스톤 디아세틸라제의 효소활성을 효과적으로 억제하는 신규한 알킬카바모일 나프탈렌일옥시 옥테노일 하이드록시아마이드 유도체, 이의 제조 방법 및 이를 유효성분으로 하는 항암제용 조성물에 관한 것이다. The present invention relates to a novel alkyl carbamoyl naphthalenyloxy octenoyl hydroxyamide derivative that effectively inhibits the enzymatic activity of histone deacetylase, a preparation method thereof, and an anticancer composition comprising the same as an active ingredient.

히스톤은 진핵세포의 핵내 DNA와 결합하고 있는 염기성 단백질로서 히스톤의 각 분자 중 특정 위치의 라이신 잔기의 아미노기에 가역적인 아세틸화가 일어난다. 이러한 히스톤의 아세틸화 반응은 염색질(chromatin)의 고차구조 형성이나 세포분열주기 등과 관계가 있어서 유전자 정보의 발현조절에 관여하며, 히스톤 아세틸전이효소(acetyltransferases) (HATs) 및 히스톤 디아세틸라제(HDACs)에 의해 안정하게 조절된다. 상기 효소들은 히스톤의 아미노 말단에 존재하는 라이신 잔기(H4의 경우 4개)의 양전하를 아세틸화로 중화시켜 전사활성을 유도하거나, 탈아세틸화시 켜 다시 전하를 부여하여 전사를 억제함으로써 히스톤의 아세틸화 수준의 평형을 유도하여 전사 수준에서 유전자 발현을 조절하는 것으로 알려져 있다. Histones are basic proteins that bind to the nucleus DNA of eukaryotic cells and undergo reversible acetylation of the amino groups of lysine residues at specific positions in each molecule of histones. The acetylation of histones is involved in the regulation of the expression of genetic information, which is related to the formation of higher levels of chromatin and the cell division cycle, and histone acetyltransferases (HATs) and histone deacetylases (HDACs). It is controlled stably by These enzymes neutralize the positive charges of lysine residues (four in the case of H4) at the amino terminus of histones by acetylation to induce transcriptional activity, or deacetylation to give charge again to inhibit transcription, thereby acetylating histones. It is known to induce levels of equilibrium to regulate gene expression at the level of transcription.

HDAC는 저산소증, 저포도당, 세포 암화 등 열악한 환경조건에서 고 발현되어 세포증식 억제인자의 발현을 저해함으로써 세포증식을 촉진시키는 역할을 하는 것이 최근 밝혀지면서 세포의 암화 및 분화를 조절하는데 있어 중요한 인자로 인식되고 있다. 즉, 염색질의 높은 아세틸화 상태가 세포의 증식을 억제하고 분화를 촉진한다면 HDAC는 히스톤의 탈아세틸화를 통해 세포증식을 유도하는데 결정적인 역할을 한다. 이와 같은 사실은 HDAC 억제인자(inhibitor)를 처리하면 세포의 증식이나 혈관신생이 억제되는 결과로써 뒷받침된다. HDAC has been shown to play a role in promoting cell proliferation by inhibiting the expression of cell proliferation inhibitors by being highly expressed in poor environmental conditions such as hypoxia, low glucose and cell carcinogenesis. It is recognized. In other words, if high acetylation of chromatin inhibits cell proliferation and promotes differentiation, HDAC plays a crucial role in inducing cell proliferation through deacetylation of histones. This is supported by the treatment of HDAC inhibitors as a result of inhibition of cell proliferation and angiogenesis.

HDAC 활성의 이상과 암 생성과의 관련성을 가장 잘 보여주고 있는 것이 급성 전골수성 백혈병(acute promyelocytic leukemia, APL)의 경우인데, 비정상적인 히스톤 탈아세틸화의 조절이 급성 백혈병이 생기게 하는 중요한 원인 중의 하나라고 알려져 있다(Lin RJ, et. al. Oncogene 20: 7204, 2001; Zelent A, et. al. Oncogene 20: 7186, 2001). 그러므로, HDAC 활성의 비정상적인 조절에 의하여 일어나는 종양단백질(oncoprotein)의 부적절한 전사 억제와 염색질 구조에서의 이상이 정상적인 세포 분화에 영향을 미쳐 암 형성을 유도하게 된다. 따라서, HDAC는 유전자 발현의 억제인자로서 뿐만 아니라 새로운 항암제 개발의 표적분자로서 매우 중요한 연구대상이 되고 있으며, HDAC 저해제는 암세포의 증식을 억제시키는 획기적인 항암제로 개발될 가능성이 매우 높다.Acute promyelocytic leukemia (APL) is one of the most important causes of the development of acute leukemia. Known (Lin RJ, et. Al. Oncogene 20: 7204, 2001; Zelent A, et. Al. Oncogene 20: 7186, 2001). Therefore, improper transcription inhibition and abnormality in chromatin structure of oncoproteins caused by abnormal regulation of HDAC activity affects normal cell differentiation, leading to cancer formation. Therefore, HDAC has become a very important research subject not only as an inhibitor of gene expression but also as a target molecule for the development of a new anticancer agent, and the HDAC inhibitor is very likely to be developed as a breakthrough anticancer agent that inhibits the proliferation of cancer cells.

최근 들어 염색질 리모델링을 이용한 항암제 연구가 시작되었고, SAHA 또는 아피시딘(apicidin)과 같은 HDAC 억제인자를 처리할 경우 암세포의 증식이 억제되고 분화가 유도된다는 연구결과가 발표되면서 항암제의 개발이 더욱 활발히 진행되고 있다(Munster PN, et. al. Cancer research 61: 8492, 2001; Han JW, et. al. Cancer research 60: 6068, 2000).In recent years, the development of anticancer drugs using chromatin remodeling has been started, and the development of anticancer drugs has been more active with the results of studies that treatment of HDAC inhibitors such as SAHA or apicidin inhibits the proliferation and differentiation of cancer cells. (Munster PN, et. Al. Cancer research 61: 8492, 2001; Han JW, et. Al. Cancer research 60: 6068, 2000).

HDAC 저해제로 최초 사용된 화합물은 n-뷰티레이트(n-butyrate)로, 이 물질은 현재도 대장암의 치료에 적용되고 있을 뿐만 아니라 HDAC 효소 저해제로 생화학과 분자생물학 실험에 사용되고 있다. 그러나, n-뷰티레이트는 그 유효농도가 밀리몰(milimolar, mM) 수준으로 높아 세포내 다른 효소나 세포골격, 세포막 등에 영향을 미치는 등 HDAC 기능 해석에 적합하지 않은 성질을 가지고 있어 보다 선택적이고 약효가 우수한 HDAC 저해제의 개발이 요구되고 있다. 1988년 일본 동경대학의 요시다(M. Yoshida)와 테루히코(B. Teruhiko)는 프렌드 쥐 적백혈병(Friend murine erythroleukemia, MEL) 세포의 분화를 유도하고 동물세포의 증식을 저지하는 활성물질로 트리코스타틴 A(trichostatin A, TSA)를 발견하고, 이의 세포내 표적분자가 HDAC임을 밝혔다(Yoshida M, et. al. Cancer Research 47: 3688, 1987; Yoshida M & Beppu T Exp. Cell Res. 177: 122, 1988; Yoshida M, et. al. J of Biol. Chem. 265: 17174, 1990). The first compound used as an HDAC inhibitor is n-butyrate, which is currently used in the treatment of colorectal cancer as well as in biochemical and molecular biology experiments as an HDAC enzyme inhibitor. However, the effective concentration of n-butyrate is in the level of milimolar (mM), which is not suitable for the analysis of HDAC functions such as affecting other enzymes, cytoskeleton, and cell membranes in the cell. There is a need for the development of good HDAC inhibitors. In 1988, M. Yoshida and B. Teruhiko of the University of Tokyo, Japan, induce the differentiation of Friend murine erythroleukemia (MEL) cells and inhibit the proliferation of animal cells. (trichostatin A, TSA) and found that its intracellular target molecule was HDAC (Yoshida M, et. al. Cancer Research 47: 3688, 1987; Yoshida M & Beppu T Exp. Cell Res. 177: 122, 1988 Yoshida M, et. Al. J of Biol. Chem. 265: 17174, 1990).

따라서, 미래형 항암제로 간주되는 HDAC 억제제 화합물의 발굴에 대한 필요성이 매우 증가되고 있는 실정이다. 이에, 본 발명자들은 HDAC 억제제 화합물을 발굴하기 위해 예의 연구 노력한 결과, 알킬카바모일 나프탈렌일옥시 옥테노일 하이드록시아마이드 유도체가 히스톤 디아세틸라제 활성을 효과적으로 저해하여 매우 강력한 세포증식 억제력을 갖는 다는 사실을 발견하고 이들이 암의 치료에 유용하게 사용될 수 있음을 확인함으로써 본 발명을 완성하였다. Therefore, the need for the discovery of HDAC inhibitor compounds considered to be anticancer drugs of the future is very increasing. Accordingly, the present inventors have diligently researched to discover HDAC inhibitor compounds, and found that alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide derivatives effectively inhibit histone deacetylase activity and thus have very strong cell proliferation inhibitory ability. The present invention was completed by confirming that they can be usefully used for the treatment of cancer.

따라서, 본 발명의 목적은 히스톤 디아세틸라제의 효소활성을 효과적으로 저해함으로써 종양 세포의 증식을 억제하는, 신규한 화합물 및 이의 제조방법을 제공하는 것이다.  It is therefore an object of the present invention to provide novel compounds and methods for their preparation which inhibit the proliferation of tumor cells by effectively inhibiting the enzymatic activity of histone deacetylases.

본 발명의 다른 목적은 상기 화합물을 유효성분으로 함유하는 항암제용 약학 조성물을 제공하는 것이다.Another object of the present invention to provide a pharmaceutical composition for anticancer drugs containing the compound as an active ingredient.

본 발명의 또 다른 목적은 상기 화합물을 유효성분으로 함유하는 히스톤 디아세틸라제의 효소활성 저해제를 제공하는 것이다.Still another object of the present invention is to provide an enzyme activity inhibitor of histone deacetylase containing the compound as an active ingredient.

상기 목적을 달성하기 위하여, 본 발명은 하기 화학식 1의 알킬카바모일 나프탈렌일옥시 옥테노일 하이드록시아마이드 유도체 및 약학적으로 허용가능한 그의 염을 제공한다:In order to achieve the above object, the present invention provides an alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide derivative of the formula (1) and a pharmaceutically acceptable salt thereof:

<화학식 1><Formula 1>

Figure 112005062761854-pat00002
Figure 112005062761854-pat00002

상기 식에서,Where

R1은 각각 독립적으로 C1-3알킬, 하이드록시C1-2알킬, 할로C1-2알킬, 피페리디닐, 몰포리닐, 사이아노메틸, 피페라지닐, 다이C1-2알킬아미노C1-2알킬, 다이C1-2알킬아미노C1-2알킬, 피페리디닐C1-2알킬, 몰포리노C1-2알킬, 피페라지노C1-2알킬, 피롤리디닐, C1-2알킬피롤리디닐로 구성된 군으로부터 선택된 하나 이상의 치환체로 치환되거나 치환되지 않은 C1-2알킬이고, Each R 1 is independently C 1-3 alkyl, hydroxyC 1-2 alkyl, haloC 1-2 alkyl, piperidinyl, morpholinyl, cyanomethyl, piperazinyl, diC 1-2 alkylamino C 1-2 alkyl, diC 1-2 alkylaminoC 1-2 alkyl, piperidinylC 1-2 alkyl, morpholinoC 1-2 alkyl, piperazinoC 1-2 alkyl, pyrrolidinyl, C and C 1-2 alkyl optionally substituted with one or more substituents selected from the group consisting of 1-2-alkyl-pyrrolidinyl,

R2는 수소 또는 메틸이다.R 2 is hydrogen or methyl.

또한, 본 발명은 상기 화학식 1의 알킬카바모일 나프탈렌일옥시 옥테노일 하이드록시아마이드 유도체의 제조방법을 제공한다.In addition, the present invention provides a method for preparing alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide derivative of Chemical Formula 1.

또한, 본 발명은 상기 화학식 1의 알킬카바모일 나프탈렌일옥시 옥테노일 하이드록시아마이드 유도체 또는 그의 약학적으로 허용가능한 염을 유효성분으로 하는 항암제용 약학 조성물을 제공한다. The present invention also provides a pharmaceutical composition for an anticancer agent comprising the alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide derivative of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

아울러, 본 발명은 상기 화학식 1의 알킬카바모일 나프탈렌일옥시 옥테노일 하이드록시아마이드 유도체 또는 그의 약학적으로 허용가능한 염을 유효성분으로 하는 히스톤 디아세틸라제의 효소활성 저해제를 제공한다. In addition, the present invention provides an enzyme activity inhibitor of histone deacetylase having the alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide derivative of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

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

본 발명에 따른 화학식 1의 알킬카바모일 나프탈렌일옥시 옥테노일 하이드록시아마이드 유도체로서 바람직한 화합물로는Preferred compounds as alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide derivatives of the general formula (1) according to the present invention

(E)-N8-하이드록시-N1,N1-다이메틸-2-((나프탈렌-1-일 옥시)메틸)옥텐다이아마이드,(E) -N8-hydroxy-N1, N1-dimethyl-2-((naphthalen-1-yl oxy) methyl) octendiamide,

(E)-N1-(2-(다이메틸아미노)에틸)-N8-하이드록시-2-((나프탈렌-1-일 옥시)메틸)옥텐다이아마이드,(E) -N1- (2- (dimethylamino) ethyl) -N8-hydroxy-2-((naphthalen-1-yl oxy) methyl) octendiamide,

(E)-N1-(2-(다이메틸아미노)에틸)-N8-하이드록시-N1-메틸-2-((나프탈렌-1-일 옥시)메틸)옥텐다이아마이드,(E) -N1- (2- (dimethylamino) ethyl) -N8-hydroxy-N1-methyl-2-((naphthalen-1-yl oxy) methyl) octendiamide,

(E)-N1-(2-(다이에틸아미노)에틸)-N8-하이드록시-2-((나프탈렌-1-일 옥시)메틸)옥텐다이아마이드,(E) -N1- (2- (diethylamino) ethyl) -N8-hydroxy-2-((naphthalen-1-yl oxy) methyl) octendiamide,

(E)-N1-(2-(다이에틸아미노)에틸)-N8-하이드록시-N1-메틸-2-((나프탈렌-1-일 옥시)메틸)옥텐다이아마이드,(E) -N1- (2- (diethylamino) ethyl) -N8-hydroxy-N1-methyl-2-((naphthalen-1-yl oxy) methyl) octendiamide,

(E)-N8-하이드록시-2-((나프탈렌-1-일 옥시)메틸)-N1-(2-(피롤리딘-1-일)에틸)옥텐다이아마이드,(E) -N8-hydroxy-2-((naphthalen-1-yl oxy) methyl) -N1- (2- (pyrrolidin-1-yl) ethyl) octendiamide,

(E)-N8-하이드록시-2-((나프탈렌-1-일 옥시)메틸)-N1-(2-(피페리딘-1-일)에틸)옥텐다이아마이드,(E) -N8-hydroxy-2-((naphthalen-1-yl oxy) methyl) -N1- (2- (piperidin-1-yl) ethyl) octendiamide,

(E)-N8-하이드록시-N1-(2-몰포리노에틸)-2-((나프탈렌-1-일 옥시)메틸)옥텐다이아마이드,(E) -N8-hydroxy-N1- (2-morpholinoethyl) -2-((naphthalen-1-yl oxy) methyl) octenamide,

(E)-N-하이드록시-8-(4-메틸피페라진-1-일)-7-((나프탈렌-1-일 옥시)메틸)-8-옥소옥텐아마이드,(E) -N-hydroxy-8- (4-methylpiperazin-1-yl) -7-((naphthalen-1-yl oxy) methyl) -8-oxooctenamide,

(E)-N8-하이드록시-N1-(2-(4-메틸피페라진-1-일)에틸)-2-((나프탈렌-1-일 옥시)메틸)옥텐다이아마이드,(E) -N8-hydroxy-N1- (2- (4-methylpiperazin-1-yl) ethyl) -2-((naphthalen-1-yl oxy) methyl) octendiamide,

(E)-N1-(사이아노메틸)-N8-하이드록시-N1-메틸-2-((나프탈렌-1-일 옥시)메틸)옥텐다이아마이드,(E) -N1- (cyanomethyl) -N8-hydroxy-N1-methyl-2-((naphthalen-1-yl oxy) methyl) octenamide,

(E)-N8-하이드록시-N1-(2-하이드록시에틸)-N1-메틸-2-((나프탈렌-1-일 옥시)메틸)옥텐다이아마이드,(E) -N8-hydroxy-N1- (2-hydroxyethyl) -N1-methyl-2-((naphthalen-1-yl oxy) methyl) octenamide,

(E)-N8-하이드록시-N1-메틸-N1-(1-메틸피롤리딘-3-일)-2-((나프탈렌-1-일 옥시)메틸)옥텐다이아마이드,(E) -N8-hydroxy-N1-methyl-N1- (1-methylpyrrolidin-3-yl) -2-((naphthalen-1-yl oxy) methyl) octendiamide,

(E)-N1-(3-(다이메틸아미노)프로필)-N8-하이드록시-2-((나프탈렌-1-일 옥시)메틸)옥텐다이아마이드, 및(E) -N1- (3- (dimethylamino) propyl) -N8-hydroxy-2-((naphthalen-1-yl oxy) methyl) octendiamide, and

(E)-N-하이드록시-8-몰포리노-7-((나프탈렌-1-일 옥시)메틸)-8-옥소옥텐다이아마이드를 예로 들 수 있다.(E) -N-hydroxy-8-morpholino-7-((naphthalen-1-yl oxy) methyl) -8-oxooctendiiamide is exemplified.

본 발명에 따른 화학식 1의 화합물은 무기산 또는 유기산으로부터 유도된 약학적으로 허용가능한 염의 형태로 사용될 수 있으며, 바람직한 염으로는 염산, 브롬화수소산, 황산, 인산, 질산, 아세트산, 글리콜산, 락트산, 피루브산, 말론산, 석신산, 글루타르산, 푸마르산, 말산, 만델산, 타타르산, 시트르산, 아스코빈산, 팔미트산, 말레인산, 하이드록시말레인산, 벤조산, 하이드록시벤조산, 페닐아세트산, 신남산, 살리실산, 메탄설폰산, 벤젠설폰산, 톨루엔설폰산 등의 염을 들 수 있다.The compound of formula 1 according to the present invention can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids, with preferred salts being hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid , Malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, Salts, such as methanesulfonic acid, benzene sulfonic acid, and toluene sulfonic acid, are mentioned.

또한, 본 발명은 상기 화학식 1의 알킬카바모일 나프탈렌일옥시 옥테노일 하 이드록시아마이드 유도체의 제조방법을 제공한다.The present invention also provides a method for preparing alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide derivative of Chemical Formula 1.

본 발명에 따른 제조방법은 Manufacturing method according to the invention

1) 하기 화학식 2의 화합물을 황산으로 처리한 후, 피리디늄 클로로클로메이트(PCC)와 반응시켜 하기 화학식 3의 화합물을 제조하는 단계;1) treating the compound of Formula 2 with sulfuric acid, and then reacting with pyridinium chlorochloromate (PCC) to prepare a compound of Formula 3;

2) 화학식 3의 화합물을 1,4-다이아자비사이클로[2,2,2]옥탄 (DABCO) 존재하에서 알킬아크릴레이트와 베일리스 힐만 (Baylis Hillman) 반응을 수행하여 하기 화학식 4의 화합물을 제조하는 단계;2) preparing a compound of formula 4 by performing a Baylis Hillman reaction with an alkyl acrylate in the presence of 1,4-diazabicyclo [2,2,2] octane (DABCO) ;

3) 화학식 4의 화합물을 삼브롬화인(PBr3)과 반응시켜 하기 화학식 5의 화합물을 제조하는 단계;3) reacting a compound of Formula 4 with phosphorus tribromide (PBr 3 ) to prepare a compound of Formula 5;

4) 화학식 5의 화합물을 1-나프탈렌알콜과 반응시켜 하기 화학식 6의 화합물을 제조하는 단계;4) reacting the compound of Formula 5 with 1-naphthalene alcohol to prepare a compound of Formula 6;

5) 화학식 6의 화합물을 무기산 또는 유기산으로 가수분해하여 하기 화학식 7의 화합물을 제조하는 단계;5) preparing a compound of formula 7 by hydrolyzing the compound of formula 6 with an inorganic acid or an organic acid;

6) 화학식 7의 화합물을 알킬아민(R1R2NH)과 아실화 반응시켜 하기 화학식 8의 화합물을 제조하는 단계;6) acylating the compound of Formula 7 with an alkylamine (R 1 R 2 NH) to prepare a compound of Formula 8;

7) 화학식 8의 화합물을 무기염기 처리에 의해 가수분해시켜 하기 화학식 9의 화합물을 제조하는 단계; 및7) hydrolyzing the compound of formula 8 by inorganic base treatment to prepare a compound of formula 9; And

8) 화학식 9의 화합물을 테트라하이드로피란일옥시아민(NH2OTHP)과 아실화 반응시켜 화학식 10의 화합물을 제조하는 단계; 및8) acylating a compound of Formula 9 with tetrahydropyranyloxyamine (NH 2 OTHP) to prepare a compound of Formula 10; And

9) 화학식 10을 트라이플루오로아세트산(TFA)과 반응시켜 테트라하이드로피란일기를 제거하는 탈보호기 반응을 수행하는 단계를 포함한다.9) reacting Formula 10 with trifluoroacetic acid (TFA) to perform a deprotection group reaction to remove the tetrahydropyranyl group.

Figure 112005062761854-pat00003
Figure 112005062761854-pat00003

Figure 112005062761854-pat00004
Figure 112005062761854-pat00004

Figure 112005062761854-pat00005
Figure 112005062761854-pat00005

Figure 112005062761854-pat00006
Figure 112005062761854-pat00006

Figure 112005062761854-pat00007
Figure 112005062761854-pat00007

Figure 112005062761854-pat00008
Figure 112005062761854-pat00008

Figure 112005062761854-pat00009
Figure 112005062761854-pat00009

Figure 112005062761854-pat00010
Figure 112005062761854-pat00010

Figure 112005062761854-pat00011
Figure 112005062761854-pat00011

Figure 112005062761854-pat00012
Figure 112005062761854-pat00012

상기 식들에서, R1과 R2는 상기 화학식 1에서 정의한 바와 같고, Y는 C1-4 알킬기이다.In the above formula, R 1 and R 2 are as defined in Formula 1, Y is a C 1-4 alkyl group.

상기 제조 방법은 하기 반응식 1로 나타내어질 수 있으며, 이를 단계별로 설명하면 다음과 같다.The preparation method may be represented by the following Scheme 1, which will be described below step by step.

Figure 112005062761854-pat00013
Figure 112005062761854-pat00013

상기 식에서, R1, R2는 상기 화학식 1에서 정의한 바와 같고, Y는 C1-4 알킬기이다.Wherein R 1 and R 2 are as defined in Formula 1, and Y is a C 1-4 alkyl group.

단계 1)은 ε-카프로락톤(화학식 2)을 메탄올에 녹인 후 진한 황산 처리하여 6-하이드록시-헥사노산 메틸에스터를 얻은 다음, 이를 피리디늄 클로로클로메이트(PCC)가 용해된 용매에 첨가한 후 2시간 동안 반응시켜 6-옥소-헥사노산 메틸에스터화합물 (화학식 3)을 제조하는 단계이며, 용매로는 다이클로로메탄, 테트라하이드로퓨란, 다이클로로에탄 등을 사용할 수 있다.Step 1) is obtained by dissolving ε-caprolactone (Formula 2) in methanol and treating with concentrated sulfuric acid to obtain 6-hydroxy-hexanoic acid methyl ester, which is added to a solvent containing pyridinium chlorochloromate (PCC). After the reaction for 2 hours to prepare a 6-oxo-hexanoic acid methyl ester compound (Formula 3), as a solvent may be used dichloromethane, tetrahydrofuran, dichloroethane and the like.

단계 2)는 상기 6-옥소-헥사노산 메틸에스터(화학식 3)를 1,4-다이아자바이 사이클로[2,2,2]옥탄(DABCO) 존재하에 C1-4알킬아크릴레이트와 0 ~ 25 ℃에서 5 내지 7일간 베일리스 힐만 반응을 수행하여 하이드록시 화합물(화학식 4)을 제조하는 단계로, 알킬아크릴레이트로서 에틸아크릴레이트, 아이소뷰틸아크릴레이트 또는 t-뷰틸아크릴레이트가 사용될 수 있다.Step 2) the 6-oxo-hexanoic acid methyl ester (Formula 3) in the presence of 1,4-diazabicyclo [2,2,2] octane (DABCO) with C 1-4 alkyl acrylate and 0 ~ 25 ℃ In a step of preparing a hydroxy compound (Formula 4) by performing a Baileys Hillman reaction for 5 to 7 days at, ethyl acrylate, isobutyl acrylate or t-butyl acrylate may be used as the alkyl acrylate.

단계 3)은 상기 하이드록시 화합물(화학식 4)을 유기 용매중에서 브롬화물과 반응시켜 브로모 화합물(화학식 5)로 전환시키는 단계로, 유기 용매로는 에틸에테르, 다이클로로메탄, 하이드로퓨란 등이 사용될 수 있으며, 브롬화물로는 삼브롬화인(PBr3), 사브롬화탄소(CBr4), N-브로모석신산(NBS) 등을 예로 들 수 있다. Step 3) converts the hydroxy compound (Formula 4) into a bromo compound (Formula 5) by reacting with a bromide in an organic solvent, ethyl ether, dichloromethane, hydrofuran, etc. are used as the organic solvent. Examples of the bromide include phosphorus tribromide (PBr 3 ), carbon tetrabromide (CBr 4 ), and N-bromosuccinic acid (NBS).

단계 4)는 상기 브로모 화합물(화학식 5)을 탄산칼륨, 중탄산나트륨 또는 탄산나트륨 존재하에 아세톤, 아세토나이트릴 등에서 1-나프탈렌알콜과 반응시켜 1-나프탈렌알콜 화합물(화학식 6)을 제조하는 단계이다.Step 4) is a step of preparing the 1-naphthalene alcohol compound (Formula 6) by reacting the bromo compound (Formula 5) with 1-naphthalene alcohol in acetone, acetonitrile, etc. in the presence of potassium carbonate, sodium bicarbonate or sodium carbonate.

단계 5)는 상기 1-나프탈렌알콜 화합물(화학식 6)을 다이클로로메탄, 테트라하이드로퓨란 또는 N,N-다이메틸폼아마이드 등과 같은 용매 중에서 무기산 또는 유기산과 에스터 가수분해 반응시켜 유기산 화합물(화학식 7)로 전환시키는 단계로, 무기산으로는 염산, 황산, 인산 등을, 유기산으로는 트라이플루오로아세트산(TFA) 등을 예로 들 수 있다.In step 5), the 1-naphthalene alcohol compound (Formula 6) is subjected to ester hydrolysis reaction with an inorganic acid or an organic acid in a solvent such as dichloromethane, tetrahydrofuran or N, N -dimethylformamide , and the like. In the step of converting to hydrochloric acid, hydrochloric acid, sulfuric acid, phosphoric acid, etc. may be used as the inorganic acid, and trifluoroacetic acid (TFA) may be mentioned as the organic acid.

단계 6)은 상기 유기산 화합물(화학식 7)을 알킬아민(R1R2NH)과 아실화 반응시켜 알킬아마이드(화학식 8)를 제조하는 단계로, 이때, 아실화 반응은 비양성자성 용매 중에서 아실화제를 촉매로 사용하여 효과적으로 수행될 수 있는데, 비양성자 성 용매로는 다이메틸폼아마이드. 다이메틸설폭사이드, 테트라하이드로퓨란 등이 사용될 수 있고, 아실화제로는 N-메탄설포닐옥시-6-트라이플루오로 벤조트라이아졸(FMS), N-하이드록시-6-트라이플루오로 벤조트라이아졸 (FOBT), 1-(3-다이에틸아미노프로필)-3-에틸카보다이이미드 염산염 (EDC.HCl) 등이 사용될 수 있다. Step 6) is an acylation reaction of the organic acid compound (Formula 7) with alkylamine (R 1 R 2 NH) to prepare an alkylamide (Formula 8), wherein the acylation reaction is acyl in an aprotic solvent The agent can be effectively carried out using a catalyst as aprotic solvent, such as dimethylformamide. Dimethylsulfoxide, tetrahydrofuran and the like can be used, and the acylating agent is N-methanesulfonyloxy-6-trifluoro benzotriazole (FMS), N-hydroxy-6-trifluoro benzotriazole. (FOBT), 1- (3-diethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC.HCl) and the like can be used.

단계 7)은 상기 알킬아마이드 화합물(화학식 8)을 수용성 알콜 또는 테트라하이드로퓨란 중에서 무기염으로 가수분해시켜 유기산 화합물(화학식 9)을 제조하는 단계이다. 이때, 무기염으로는 수산화나트륨 또는 수산화리튬이 사용될 수 있다.Step 7) is a step of hydrolyzing the alkylamide compound (Formula 8) with an inorganic salt in a water-soluble alcohol or tetrahydrofuran to prepare an organic acid compound (Formula 9). At this time, sodium hydroxide or lithium hydroxide may be used as the inorganic salt.

단계 8)은 상기 유기산 화합물(화학식 9)을 유기용매 중에서 테트라하이드로피란일옥시아민 (NH2OTHP)과 아실화 반응시켜 화학식 10의 화합물을 제조하는 단계로, 아실화 반응은 N-하이드록시-6-트라이플루오로 벤조트라이아졸(FOBT)과 1-(3-다이에틸아미노프로필)-3-에틸카보다이이미드 염산염(EDC.HCl) 존재하에 이루어지며, 이때 유기 용매로는 N,N-다이메틸폼아마이드, 다이메틸설폭사이드, 테트라하이드로퓨란 또는 다이클로로메탄 등이 사용될 수 있다.Step 8) is an acylation reaction of the organic acid compound (Formula 9) with tetrahydropyranyloxyamine (NH 2 OTHP) in an organic solvent to prepare a compound of Formula 10, the acylation reaction is N-hydroxy- 6-trifluoro benzotriazole (FOBT) and 1- (3-diethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC.HCl) in the presence of N, N-di Methylformamide, dimethylsulfoxide, tetrahydrofuran or dichloromethane and the like can be used.

단계 9)는 화학식 10을 용매중에서 트라이플루오로아세트산(TFA)과 반응시켜 테트라하이드로피란일기를 제거하는 탈보호 반응단계로서, 용매로는 메탄올, 에탄올, 테트라하이드로퓨란 또는 다이클로로메탄 등이 사용될 수 있다.Step 9) is a deprotection step of removing tetrahydropyranyl group by reacting Chemical Formula 10 with trifluoroacetic acid (TFA) in a solvent. As a solvent, methanol, ethanol, tetrahydrofuran or dichloromethane may be used. have.

상기 화학식 1의 화합물의 제조에 출발물질로 사용되는 화학식 2의 화합물은 상업적으로 시판되는 것을 구입하여 사용할 수도 있다.The compound of Formula 2 used as a starting material in the preparation of the compound of Formula 1 may be purchased commercially available.

이와 같이 제조된, 본 발명의 화학식 1의 알킬카바모일 나프탈렌일옥시 옥테노일 하이드록시아마이드 유도체는 히스톤 디아세틸라제의 효소활성을 효과적으로 저해하여 암 세포 증식의 억제 및 치료효과를 나타낼 수 있으며, 종양세포의 말기 분화를 선택적으로 유도함으로써 이들 종양세포의 증식을 억제한다.As described above, the alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide derivative of the formula (1) of the present invention can effectively inhibit the enzymatic activity of histone deacetylase, thereby exhibiting cancer cell proliferation inhibition and therapeutic effect, tumor cells It selectively inhibits proliferation of these tumor cells by selectively inducing terminal differentiation.

따라서, 본 발명의 화학식 1의 알킬카바모일 나프탈렌일옥시 옥테노일 하이드록시아마이드 유도체는 히스톤 디아세틸라제의 효소활성 저해제로 유용하게 사용될 수 있다.Therefore, the alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide derivative of the formula (1) of the present invention can be usefully used as an inhibitor of the enzymatic activity of histone deacetylase.

또한, 본 발명은 화학식 1의 화합물을 유효성분으로 하고 약제학적으로 허용가능한 담체를 포함하는 항암제용 약학 조성물을 제공한다. 본 발명의 약학 조성물에는 유효성분인 화학식 1의 화합물이 조성물의 총중량을 기준으로 하여 0.1 내지 75 중량％, 바람직하게는 1 내지 50 중량％의 양으로 함유될 수 있다. The present invention also provides a pharmaceutical composition for an anticancer agent comprising the compound of formula 1 as an active ingredient and a pharmaceutically acceptable carrier. The pharmaceutical composition of the present invention may contain the compound of formula 1 as an active ingredient in an amount of 0.1 to 75% by weight, preferably 1 to 50% by weight, based on the total weight of the composition.

본 발명의 약학 조성물은 다양한 경구 또는 비경구 투여 형태로 제형화할 수 있다. 경구 투여용 제형으로는 예를 들면 정제, 환제, 경·연질 캅셀제, 액제, 현탁제, 유화제, 시럽제, 과립제 등이 있는데, 이들 제형은 유효성분 이외에 희석제(예: 락토즈, 덱스트로즈, 수크로즈, 만니톨, 솔비톨, 셀룰로즈 및/또는 글리신), 활택제(예: 실리카, 탈크, 스테아르산 및 그의 마그네슘 또는 칼슘염 및/또는 폴리에틸렌글리콜)를 함유하고 있다. 정제는 또한 마그네슘 알루미늄 실리케이트, 전분 페이스트, 젤라틴, 트라가칸스, 메틸셀룰로즈, 나트륨 카르복시메틸셀룰로즈 및/또는 폴리비닐피롤리딘과 같은 결합제를 함유할 수 있으며, 경우에 따라 전분, 한천, 알긴산 또는 그의 나트륨염과 같은 붕해제 또는 비등 혼합물 및/또는 흡수제, 착색 제, 향미제, 및 감미제를 함유할 수 있다. 또한, 비경구 투여용 제형의 대표적인 것은 주사용 제형으로 등장성 수용액 또는 현탁액이 바람직하다.The pharmaceutical compositions of the invention can be formulated in a variety of oral or parenteral dosage forms. Formulations for oral administration include, for example, tablets, pills, hard and soft capsules, solutions, suspensions, emulsifiers, syrups, and granules. These formulations may contain diluents (e.g., lactose, dextrose, water, etc.) in addition to the active ingredients. Cross, mannitol, sorbitol, cellulose and / or glycine), lubricants such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols. Tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine, optionally starch, agar, alginic acid or its Disintegrating or boiling mixtures such as sodium salts and / or absorbents, coloring agents, flavoring agents, and sweetening agents. Also representative of formulations for parenteral administration are injectable formulations, preferably aqueous isotonic solutions or suspensions.

상기 조성물은 멸균되고/되거나 방부제, 안정화제, 수화제 또는 유화 촉진제, 삼투압 조절을 위한 염 및/또는 완충제 등의 보조제 및 기타 치료학적으로 유용한 물질을 함유할 수 있으며, 통상적인 혼합, 과립화 또는 코팅방법에 따라 제제화할 수 있다.The composition may contain sterile and / or auxiliaries such as preservatives, stabilizers, hydrating or emulsifying accelerators, salts and / or buffers for controlling osmotic pressure and other therapeutically useful materials, and may be mixed, granulated or coated conventionally. It can be formulated according to the method.

유효성분으로서 화학식 1의 화합물은 사람을 포함하는 포유동물에 대해 하루에 2.5 내지 100 ㎎/㎏ 체중, 바람직하게는 5 내지 60 ㎎/㎏ 체중의 양으로 1일 1회 또는 분할하여 경구 또는 비경구적 경로를 통해 투여될 수 있다. As an active ingredient, the compound of formula 1 may be orally or parenterally administered once daily or divided into an amount of 2.5 to 100 mg / kg body weight, preferably 5 to 60 mg / kg body weight, for a mammal including a human. It can be administered via the route.

이하, 하기 제조예 및 실시예에 의하여 본 발명을 더욱 상세하게 설명하고자 한다. 단, 하기 제조예 및 실시예는 본 발명을 예시하기 위한 것일 뿐 본 발명의 범위가 이들만으로 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail by the following Preparation Examples and Examples. However, the following Preparation Examples and Examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

제조예 1 : 6-하이드록시-헥사노산 메틸 에스터Preparation Example 1 6-hydroxyhexanoic acid methyl ester

ε-카프로락톤(12.50 g, 109.51 mM)을 메탄올(125 ml)에 녹인 후 황산용액(1 ml, 0.01 mM)을 천천히 가한 뒤 상온에서 이틀 동안 교반하였다. 반응이 종결되면 감압, 농축하여 메탄올을 제거한 후 냉수를 넣고 에틸에테르로 추출한 다음, 포화 중조 용액 및 소금물로 세척 후 감압, 농축하였고, 이렇게 얻어진 잔사를 컬럼 크로마토그래피(용리제: 에틸초산/노르말 헥산 = 1/2)로 정제하여 표제 화합물 10.18 g(수율 64%)을 얻었다.ε-caprolactone (12.50 g, 109.51 mM) was dissolved in methanol (125 ml), and sulfuric acid solution (1 ml, 0.01 mM) was slowly added, followed by stirring at room temperature for two days. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, concentrated to remove methanol, extracted with cold water, extracted with ethyl ether, washed with saturated sodium bicarbonate solution and brine, and concentrated under reduced pressure. The residue thus obtained was purified by column chromatography (eluent: ethyl acetate / normal hexane). = 1/2) to give 10.18 g (64% yield) of the title compound.

1H NMR (200 MHz, CDCl3) δ1.23 (m, 2H, CH2), 1.33~1.42 (m, 4H, CH2CH2), 1.44~1.74 (t, 4H, CH2CH2), 3.66 (s, 3H, OCH3). 1 H NMR (200 MHz, CDCl 3 ) δ1.23 (m, 2H, CH 2 ), 1.33 to 1.42 (m, 4H, CH 2 CH 2 ), 1.44 to 1.74 (t, 4H, CH 2 CH 2 ), 3.66 (s, 3 H, OCH 3 ).

제조예 2 : 6-옥소-헥사노산 메틸 에스터(화학식 3의 화합물)의 제조Preparation Example 2 Preparation of 6-Oxo-hexanoic Acid Methyl Ester (Compound of Formula 3)

피리디늄 클로로클로메이트(16.27 g, 75.48 mM)를 디크로로메탄 (140 ml)에 녹인 후, 상기 제조예 1에서 얻은 6-하이드록시-헥사노산 메틸 에스터(10.03 g, 68.61 mM)를 디크로로메탄 (20 ml)에 녹여서 30분간 적가한 뒤 25 내지 30℃에서 2시간 동안 교반시켰다. 반응이 종결되면 반응 혼합물을 에틸에테르로 희석시킨 후 실리카겔을 깔고 여과, 감압 및 농축하고, 얻어진 잔사를 컬럼 크로마토그래피(용리제: 에틸초산/노르말 헥산 = 1/4)로 정제하여 표제 화합물 5.77 g(수율 59%)을 얻었다.Pyridinium chlorochloromate (16.27 g, 75.48 mM) was converted to dichloromethane. After dissolving in (140 ml), 6-hydroxy-hexanoic acid methyl ester (10.03 g, 68.61 mM) obtained in Preparation Example 1 was added dropwise to dichloromethane (20 ml) for 30 minutes, and then 25 to 30 ° C. Stirred for 2 h. At the end of the reaction, the reaction mixture was diluted with ethyl ether, filtered over silica gel, filtered, reduced pressure and concentrated, and the residue was purified by column chromatography (eluent: ethyl acetate / normal hexane = 1/4) to give 5.77 g of the title compound. (Yield 59%) was obtained.

1H NMR (200 MHz, CDCl3) δ1.66 (m, 4H, CH2CH2), 2.33 (m, 2H, CH2), 2.46 (m, 2H, CH2), 3.66 (s, 3H, OCH3), 9.74 (S, 1H, CH). 1 H NMR (200 MHz, CDCl 3 ) δ 1.66 (m, 4H, CH 2 CH 2 ), 2.33 (m, 2H, CH 2 ), 2.46 (m, 2H, CH 2 ), 3.66 (s, 3H, OCH 3 ), 9.74 (S, 1 H, CH).

제조예 3 : 3-하이드록시-2-메틸렌-다이노난산 1-t-뷰틸 에스터 9-메틸에스터(화학식 4의 화합물)의 제조Preparation Example 3 Preparation of 3-hydroxy-2-methylene-dinonanoic acid 1-t-butyl ester 9-methylester (compound of Formula 4)

상기 제조예 2에서 얻은 6-옥소-헥사노산 메틸에스터(20 g, 168.72 mM)을 물 과 다이옥산(1:1)의 혼합액 (100 mL)에 녹인 후 아크릴산 t-뷰틸 에스터(60.96 ml, 461.17 mM)를 가하고, 여기에 물과 다이옥산(1:1) (63 mL)에 녹인 1,4-디아자비사이클로[2,2,2]옥탄 (DABCO)(15.56 g, 138.72 mM)의 용액을 천천히 가한 다음 7일 동안 교반하였다. 반응이 종결되면, 반응 혼합물에 얼음물을 가하고, 에틸에테르로 추출하고, 이 추출물을 2N 염산 용액, 포화 중조 용액 및 소금물로 세척한 후, 건조 및 감압농축하였다. 얻어진 잔사를 컬럼 크로마토그래피(용리제: 에틸초산/노르말 헥산 = 1/9)로 정제하여 표제 화합물 21.7 g(수율 57%)을 얻었다.6-oxo-hexanoic acid methyl ester (20 g, 168.72 mM) obtained in Preparation Example 2 was dissolved in a mixed solution (100 mL) of water and dioxane (1: 1), followed by acrylic acid t-butyl ester (60.96 ml, 461.17 mM). ) Was added slowly to a solution of 1,4-diazabicyclo [2,2,2] octane (DABCO) (15.56 g, 138.72 mM) dissolved in water and dioxane (1: 1) (63 mL). Stir for the next 7 days. When the reaction was completed, ice water was added to the reaction mixture, extracted with ethyl ether, and the extract was washed with 2N hydrochloric acid solution, saturated sodium bicarbonate solution and brine, dried and concentrated under reduced pressure. The obtained residue was purified by column chromatography (eluent: ethyl acetate / normal hexane = 1/9) to give 21.7 g (yield 57%) of the title compound.

1H NMR (200 MHz, CDCl3) δ1.46 (m, 2H, CH2), 1.47 (S, 9H, 3CH3), 1.62 (m, 4H, CH2CH2), 2.96 (m, 4H, CH2CH2), 3.64 (s, 3H, OCH3), 5.67 (s, 1H, CH), 6.09 (s, 1H, CH). 1 H NMR (200 MHz, CDCl 3 ) δ 1.46 (m, 2H, CH 2 ), 1.47 (S, 9H, 3CH 3 ), 1.62 (m, 4H, CH 2 CH 2 ), 2.96 (m, 4H, CH 2 CH 2 ), 3.64 (s, 3H, OCH 3 ), 5.67 (s, 1H, CH), 6.09 (s, 1H, CH).

제조예 4 : 2-브로모메틸-2-다이옥텐산 1-t-뷰틸 에스터 8-메틸에스터(화학식 5의 화합물)의 제조Preparation Example 4 Preparation of 2-Bromomethyl-2-dioctenoic Acid 1-t-Butyl Ester 8-Methyl Ester (Compound 5)

상기 제조예 3에서 합성된 3-하이드록시-2-메틸렌-다이노난산 1-t-뷰틸 에스터 9-메틸에스터(10,40 g, 38.20 mM)를 에틸에테르 (100 ml)에 녹이고 0℃로 냉각시켰다. 여기에 삼브롬화인(3.93 ml, 42.02 mM)을 천천히 가하고 실온에서 1시간 동안 교반하였다. 반응이 종결되면 상기 반응 혼합물을 -10℃로 냉각하여 얼음물을 가한 다음, 에틸에테르로 추출하였다. 이로부터 얻은 추출물을 소금물로 세척한 후 건조(MgSO4) 및 여과하고 감압 하에 용매를 제거하였다. 남은 잔사를 실리카겔 컬럼 크로마토그래피(용리제: 에틸초산/노르말 헥산 = 1/9)로 정제하여 표제 화합물 6.30 g(수율 49%)을 얻었다.3-hydroxy-2-methylene-dinonanoic acid 1-t-butyl ester 9-methyl ester (10,40 g, 38.20 mM) synthesized in Preparation Example 3 was dissolved in ethyl ether (100 ml) and cooled to 0 ° C. I was. Phosphorous tribromide (3.93 ml, 42.02 mM) was slowly added thereto and stirred at room temperature for 1 hour. When the reaction was completed, the reaction mixture was cooled to -10 ℃ to add ice water, and then extracted with ethyl ether. The extract obtained was washed with brine, dried (MgSO 4 ), filtered and the solvent was removed under reduced pressure. The remaining residue was purified by silica gel column chromatography (eluent: ethyl acetate / normal hexane = 1/9) to give 6.30 g (yield 49%) of the title compound.

1H NMR (200 MHz, CDCl3) δ1.50 (s, 9H, CH3), 1.65 (m, 4H, CH2), 2.30 (m, 4H, CH2), 3.66 (s, 3H, OCH3), 4.27 (s, 2H, CH2), 6.82 (m, 1H, CH). 1 H NMR (200 MHz, CDCl 3 ) δ1.50 (s, 9H, CH 3 ), 1.65 (m, 4H, CH 2 ), 2.30 (m, 4H, CH 2 ), 3.66 (s, 3H, OCH 3 ), 4.27 (s, 2H, CH 2 ), 6.82 (m, 1H, CH).

제조예 5 : 2-(나프탈렌-1-일 옥시메틸)-2-다이옥텐산 1-t-뷰틸 에스터 8-메틸에스터(화학식 6의 화합물)의 제조Preparation Example 5 Preparation of 2- (naphthalen-1-yl oxymethyl) -2-dioctenoic acid 1-t-butyl ester 8-methylester (compound of formula 6)

상기 제조예 4에서 합성된 2-브로모메틸-2-다이옥텐산 1-t-뷰틸 에스터 8-메틸에스터(11.2 g 33.41 mM)를 아세톤(50 ml)에 녹인 후, 탄산칼륨(6.93 g 50.11 mM) 및 1-나프탈렌올(5.30 g 36.75 mM)을 가하고 3시간 동안 끓였다. 반응이 종결되면 반응 혼합물을 상온에서 감압하여 용매를 제거하였고 남은 잔사를 실리카겔 컬럼 크로마토그래피(용리제: 에틸초산/노르말 헥산 = 1/15)로 정제하여 흰색 고체의 표제 화합물 11.5 g(수율 86%)을 얻었다. 2-bromomethyl-2-dioctenoic acid 1-t-butyl ester 8-methyl ester (11.2 g 33.41 mM) synthesized in Preparation Example 4 was dissolved in acetone (50 ml), and then potassium carbonate (6.93 g 50.11 mM). ) And 1-naphthalenol (5.30 g 36.75 mM) were added and boiled for 3 hours. At the end of the reaction, the reaction mixture was dried under reduced pressure at room temperature to remove the solvent, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / normal hexane = 1/15) to give 11.5 g of the title compound as a white solid (yield 86%). )

1H NMR (200 MHz, CDCl3) δ1.45 (s, 9H, CH3), 1.65 (m, 4H, CH2), 2.30 (m, 4H, CH2), 3.62 (s, 3H, OCH3), 4.80 (s, 2H, CH2), 6.64 (m, 1H, ArH), 6.98 (m, 1H, CH), 7.40 (m, 4H, ArH), 7.77 (m, 1H, ArH), 8.19 (m, 1H, ArH). 1 H NMR (200 MHz, CDCl 3 ) δ 1.45 (s, 9H, CH 3 ), 1.65 (m, 4H, CH 2 ), 2.30 (m, 4H, CH 2 ), 3.62 (s, 3H, OCH 3 ), 4.80 (s, 2H, CH 2 ), 6.64 (m, 1H, ArH), 6.98 (m, 1H, CH), 7.40 (m, 4H, ArH), 7.77 (m, 1H, ArH), 8.19 ( m, 1H, ArH).

제조예 6 : 2-(나프탈렌-1-일 옥시메틸)-2-다이옥텐산 8-메틸에스터(화학식 7의 화 합물)의 제조Preparation Example 6 Preparation of 2- (naphthalen-1-yl oxymethyl) -2-dioctenoic acid 8-methylester (compound of formula 7)

상기 제조예 5에서 합성된 2-(나프탈렌-1-일 옥시메틸)-2-다이옥텐산 1-t-뷰틸 에스터 8-메틸에스터(5.00 g 12.55 mM)를 다이클로로메탄(60 ml)에 녹인 후, 트라이플루오로아세트산(6.77 ml, 87.83 mM)을 0℃에서 천천히 가하고 실온에서 7시간 동안 반응시켰다. 반응이 종결되면 반응 혼합물을 상온에서 감압하여 용매를 제거하였고, 남은 잔사를 실리카겔 컬럼 크로마토그래피(용리제: 에틸초산/노르말 헥산 = 1/4)로 정제하여 표제 화합물 2.08 g(수율 48%)을 얻었다. 2- (naphthalen-1-yl oxymethyl) -2-dioctenoic acid 1-t-butyl ester 8-methyl ester (5.00 g 12.55 mM) synthesized in Preparation Example 5 was dissolved in dichloromethane (60 ml). , Trifluoroacetic acid (6.77 ml, 87.83 mM) was slowly added at 0 ° C. and reacted at room temperature for 7 hours. At the end of the reaction, the reaction mixture was dried under reduced pressure at room temperature to remove the solvent, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / normal hexane = 1/4) to give 2.08 g (48% yield) of the title compound. Got it.

1H NMR (200 MHz, CDCl3) δ1.46 (m, 2H, CH2), 1.59 (m, 2H, CH2), 2.26 (t, 2H, J = 7.1 Hz, CH2), 2.43 (q, 2H, J = 14.9, 7.5 Hz, CH2), 3.62 (s, 3H, OCH3), 4.94 (s, 2H, CH2), 6.89 (d, 1H, J = 7.3 Hz, CH), 7.27~7.47 (m, 5H, ArH), 7.80 (dd, 1H, J = 7.3, 1.7 Hz, ArH), 8.20 (t, 1H, J = 7.1, 1.7 Hz, ArH). 1 H NMR (200 MHz, CDCl 3 ) δ 1.46 (m, 2H, CH 2 ), 1.59 (m, 2H, CH 2 ), 2.26 (t, 2H, J = 7.1 Hz, CH 2 ), 2.43 (q , 2H, J = 14.9, 7.5 Hz, CH 2 ), 3.62 (s, 3H, OCH 3 ), 4.94 (s, 2H, CH 2 ), 6.89 (d, 1H, J = 7.3 Hz, CH), 7.27 ~ 7.47 (m, 5H, ArH), 7.80 (dd, 1H, J = 7.3, 1.7 Hz, ArH), 8.20 (t, 1H, J = 7.1, 1.7 Hz, ArH).

실시예 1 : (E)-N8-하이드록시-N1,N1-다이메틸-2-((나프탈렌-1-일 옥시)메틸)옥텐다이아마이드(화학식 1의 화합물)의 제조Example 1 Preparation of (E) -N8-hydroxy-N1, N1-dimethyl-2-((naphthalen-1-yl oxy) methyl) octenamide (compound of Formula 1)

(1-1) : (E)-8-(다이메틸아미노)-7-((나프탈렌-1-일 옥시)메틸)-8-옥소-6-옥텐산 메틸에스터(화학식 8의 화합물)의 제조(1-1): Preparation of (E) -8- (dimethylamino) -7-((naphthalen-1-yl oxy) methyl) -8-oxo-6-octenate methyl ester (compound of formula 8)

상기 제조예 6에서 얻은 2-(나프탈렌-1-일 옥시메틸)-2-다이옥텐산 8-메틸에스터 (423 mg, 1.24 mM)를 다이메틸폼아마이드(4 ml)에 녹이고 0℃로 냉각한 후, 트라이에틸아민(520 ㎕, 3.72 mM) 및 N-메탄설포닐옥시-6-트라이플루오로 벤조트라 이아졸(418 mg, 1.49 mM)을 가하고 0℃에서 30분 동안 교반하였다. 여기에 다이메틸아민염산염(111 mg, 1.36 mM)을 천천히 가하고 실온에서 1시간 동안 교반하였다. 반응이 종결되면 반응 혼합물을 실온으로 냉각하여 얼음물을 가하여 초산에틸로 추출한 후 1N 염산용액, 중조 및 소금물로 세척하였다. 그 후 추출물을 무수 황산마그네슘으로 건조 및 여과하고 감압 하에 용매를 제거하였고 남은 잔사를 실리카겔 컬럼 크로마토그래피로 정제(용리제: 에틸초산/노르말 헥산 = 2/1)하여 노란색 고체의 표제 화합물 437 mg(수율 95%)을 얻었다. 2- (naphthalen-1-yl oxymethyl) -2-dioctenoic acid 8-methylester (423 mg, 1.24 mM) obtained in Preparation Example 6 was dissolved in dimethylformamide (4 ml) and cooled to 0 ° C. , Triethylamine (520 μl, 3.72 mM) and N-methanesulfonyloxy-6-trifluoro benzotriazole (418 mg, 1.49 mM) were added and stirred at 0 ° C. for 30 minutes. Dimethylamine hydrochloride (111 mg, 1.36 mM) was slowly added thereto and stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was cooled to room temperature, iced water was added, extracted with ethyl acetate, and washed with 1N hydrochloric acid solution, sodium bicarbonate and brine. The extract was then dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / normal hexane = 2/1) to give 437 mg of the title compound as a yellow solid ( Yield 95%).

1H NMR (300 MHz, CDCl3) δ1.46 (m, 2H, CH2), 1.59 (m, 2H, CH2), 2.43 (q, 4H, J = 14.9, 7.5 Hz, CH2), 3.02 (s, 6H, N(CH3)2), 3.63 (s, 3H, OCH3), 4.95 (s, 2H, CH2), 5.84 (t, 1H, J = 14.8, 6.5 Hz, CH), 6.85 (d, 1H, J = 7.4 Hz, ArH), 7.36~7.47 (m, 4H, ArH), 7.79 (t, 1H, J = 9.0, 1.4 Hz, ArH), 8.10 (t, 1H, J = 8.8, 7.5 Hz, ArH). 1 H NMR (300 MHz, CDCl 3 ) δ 1.46 (m, 2H, CH 2 ), 1.59 (m, 2H, CH 2 ), 2.43 (q, 4H, J = 14.9, 7.5 Hz, CH 2 ), 3.02 ( s, 6H, N (CH 3 ) 2 ), 3.63 (s, 3H, OCH 3 ), 4.95 (s, 2H, CH 2 ), 5.84 (t, 1H, J = 14.8, 6.5 Hz, CH), 6.85 ( d, 1H, J = 7.4 Hz, ArH), 7.36-7.47 (m, 4H, ArH), 7.79 (t, 1H, J = 9.0, 1.4 Hz, ArH), 8.10 (t, 1H, J = 8.8, 7.5 Hz, ArH).

(1-2) : (E)-8-(다이메틸아미노)-7-((나프탈렌-1-일 옥시)메틸)-8-옥소-6-옥텐산 (화학식 9의 화합물)의 제조(1-2): Preparation of (E) -8- (dimethylamino) -7-((naphthalen-1-yl oxy) methyl) -8-oxo-6-octenic acid (compound of formula 9)

상기 실시예 (1-1)에서 얻은 (E)-8-(다이메틸아미노)-7-((나프탈렌-1-일 옥시)메틸)-8-옥소-6-옥텐산 메틸에스터(437 mg, 1.18 mM)를 30% 에탄올 수용액(4 ml)에 용해시켰다. 여기에 일수 수산화리튬(248 mg, 5.90 mM) 및 테트라하이드로퓨란(4 ml)을 가하고 상온에서 10분 동안 교반하고 50℃에서 3시간 동안 다시 교반하 였다. 반응이 종결되면 실온으로 냉각하여 얼음물을 가하고 감압 하에 용매를 제거하였다. 이를 다시 5℃로 냉각하여 2N 염산용액으로 약산성화(pH 4)한 후 여과하고 무수 황산마그네슘으로 건조하여 흰색 고체의 표제 화합물 413 mg(수율 99%)을 얻었다.(E) -8- (dimethylamino) -7-((naphthalen-1-yl oxy) methyl) -8-oxo-6-octenate methyl ester (437 mg, obtained in the above Example (1-1), 1.18 mM) was dissolved in 30% aqueous ethanol solution (4 ml). Lithium hydroxide (248 mg, 5.90 mM) and tetrahydrofuran (4 ml) were added thereto, and the resultant was stirred at room temperature for 10 minutes and stirred at 50 ° C. for 3 hours. After the reaction was completed, the mixture was cooled to room temperature, ice water was added, and the solvent was removed under reduced pressure. The mixture was cooled to 5 ° C., slightly acidified with 2N hydrochloric acid solution (pH 4), filtered, and dried over anhydrous magnesium sulfate to obtain 413 mg (yield 99%) of the title compound as a white solid.

(1-3) : (E)-N8-하이드록시-N1,N1-다이메틸-2-((나프탈렌-1-일 옥시)메틸)옥텐다이아마이드(화학식 1의 화합물)의 제조(1-3): Preparation of (E) -N8-hydroxy-N1, N1-dimethyl-2-((naphthalen-1-yl oxy) methyl) octenamide (compound of Formula 1)

상기 실시예 (1-2)에서 얻은 (E)-8-(다이메틸아미노)-7-((나프탈렌-1-일 옥시)메틸)-8-옥소-6-옥텐산 (413 mg, 1.16 mM)을 다이메틸폼아마이드 (4 ml)에 녹이고 0℃로 냉각한 후, 트라이에틸아민 (240 μL, 1.74 mM) 및 N-메탄설포닐옥시-6-트라이플루오로 벤조트라이아졸 (391 mg, 1.39 mM)을 가하고 0℃에서 20분간 교반한 다음, N-t-뷰틸다이메틸실릴옥시아민 (256 mg, 1.74 mM)을 가하고 실온에서 1시간 교반하였다. 반응이 종결되면 실온으로 냉각하여 얼음물을 가하고 초산에틸로 추출하여 중조로 세척한 후 무수 황산나트륨으로 건조 및 여과하고 감압 하에 용매를 제거하고, 남은 잔사를 실리카겔 컬럼 크로마토그래피로 정제하여 하얀색 고체의 표제 화합물 280 mg(수율 65%)을 얻었다.(E) -8- (dimethylamino) -7-((naphthalen-1-yl oxy) methyl) -8-oxo-6-octenic acid (413 mg, 1.16 mM) obtained in Example (1-2) above ) Was dissolved in dimethylformamide (4 ml) and cooled to 0 ° C., then triethylamine (240 μL, 1.74 mM) and N-methanesulfonyloxy-6-trifluoro benzotriazole (391 mg, 1.39 mM) and stirred at 0 ° C. for 20 minutes, then Nt-butyldimethylsilyloxyamine (256 mg, 1.74 mM) was added and stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was cooled to room temperature, added with ice water, extracted with ethyl acetate, washed with sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure, and the remaining residue was purified by silica gel column chromatography to give the title compound as a white solid. 280 mg (65% yield) were obtained.

1H NMR (300 MHz, MeOH-d4) δ1.46 (m, 2H, CH2), 1.59 (m, 2H, CH2), 2.43 (q, 4H, J = 14.9, 7.4 Hz, CH2), 3.02 (s, 6H, N(CH3)2), 4.94 (s, 2H, CH2), 5.84 (t, 1H, J = 14.8, 6.5 Hz, CH), 6.85 (d, 1H, J = 7.4 Hz, ArH), 7.36~7.47 (m, 4H, ArH), 7.79 (d, 1H, J = 7.4 Hz, ArH), 8.10 (d, 1H, J = 7.4 Hz, ArH). 1 H NMR (300 MHz, MeOH-d 4 ) δ 1.46 (m, 2H, CH 2 ), 1.59 (m, 2H, CH 2 ), 2.43 (q, 4H, J = 14.9, 7.4 Hz, CH 2 ), 3.02 (s, 6H, N (CH 3 ) 2 ), 4.94 (s, 2H, CH 2 ), 5.84 (t, 1H, J = 14.8, 6.5 Hz, CH), 6.85 (d, 1H, J = 7.4 Hz , ArH), 7.36-7.47 (m, 4H, ArH), 7.79 (d, 1H, J = 7.4 Hz, ArH), 8.10 (d, 1H, J = 7.4 Hz, ArH).

실시예 2 : (E)-N1-(2-(다이메틸아미노)에틸)-N8-하이드록시-2-((나프탈렌-1-일 옥시)메틸)옥텐다이아마이드Example 2: (E) -N1- (2- (dimethylamino) ethyl) -N8-hydroxy-2-((naphthalen-1-yl oxy) methyl) octendiamide

(2-1) : (E)-8-(2-(다이메틸아미노)에틸아미노)-7-((나프탈렌-1-일 옥시)메틸)-8-옥소-6-옥텐산 메틸에스터(2-1): (E) -8- (2- (dimethylamino) ethylamino) -7-((naphthalen-1-yl oxy) methyl) -8-oxo-6-octenic acid methyl ester

상기 제조예 6에서 얻은 2-(나프탈렌-1-일 옥시메틸)-2-다이옥텐산 8-메틸에스터를 출발물질로 하여 상기 실시예 (1-1)과 동일한 방법으로 표제 화합물 428 mg(수율 86%)을 얻었다.428 mg of the title compound (yield 86) in the same manner as in Example (1-1) using 2- (naphthalen-1-yl oxymethyl) -2-dioctenoic acid 8-methylester obtained in Preparation Example 6 as a starting material. %) Was obtained.

1H NMR (300 MHz, CDCl3) δ1.51 (m, 2H, CH2), 1.63 (m, 2H, CH2), 2.03 (s, 6H, N(CH3)2), 2.23 (m, 4H, CH2CH2), 2.38 (m, 2H, CH2), 2.37 (q, 1H, J = 11.1, 5.7 Hz, CH2), 3.62 (s, 3H, OCH3), 4.92 (s, 2H, CH2), 6.85 (t, 1H, J = 15.3, 7.6 Hz, CH), 6.91 (d, 1H, J = 7.0 Hz, ArH), 7.44 (m, 4H, ArH), 7.78 (dd, 1H, J = 6.8, 1.8 Hz, ArH), 8.20 (t, 1H, J = 9.3, 7.5 Hz, ArH). 1 H NMR (300 MHz, CDCl 3 ) δ 1.51 (m, 2H, CH 2 ), 1.63 (m, 2H, CH 2 ), 2.03 (s, 6H, N (CH 3 ) 2 ), 2.23 (m, 4H , CH 2 CH 2 ), 2.38 (m, 2H, CH 2 ), 2.37 (q, 1H, J = 11.1, 5.7 Hz, CH 2 ), 3.62 (s, 3H, OCH 3 ), 4.92 (s, 2H, CH 2 ), 6.85 (t, 1H, J = 15.3, 7.6 Hz, CH), 6.91 (d, 1H, J = 7.0 Hz, ArH), 7.44 (m, 4H, ArH), 7.78 (dd, 1H, J) = 6.8, 1.8 Hz, ArH), 8.20 (t, 1H, J = 9.3, 7.5 Hz, ArH).

(2-2) : (E)-8-(2-(다이메틸아미노)에틸아미노)-7-((나프탈렌-1-일 옥시)메틸)-8-옥소-6-옥텐산(2-2): (E) -8- (2- (dimethylamino) ethylamino) -7-((naphthalen-1-yl oxy) methyl) -8-oxo-6-octenic acid

상기 (2-1)에서 얻은 화합물을 출발물질로 하여 상기 실시예 (1-2)와 동일한 방법으로 표제 화합물 335 mg(수율 81%)을 얻었다.Using the compound obtained in the above (2-1) as a starting material, 335 mg (yield 81%) of the title compound were obtained in the same manner as the Example (1-2).

1H NMR (300 MHz, MeOH-d4) δ1.52 (m, 2H, CH2), 1.64 (m, 2H, CH2), 2.20 (m, 2H, CH2), 2.27 (s, 6H, N(CH3)2), 2.38 (m, 2H, CH2), 2.55 (m, 2H, CH2), 3.42 (m, 2H, CH2), 4.97 (s, 2H, CH2), 6.67 (s, 1H, CH), 6.99 (t, 1H, J = 7.0, 1.8 Hz, ArH), 7.41 (m, 4H, ArH), 7.77 (d, 1H, J = 7.0, 1.8 Hz, ArH), 8.14 (d, 1H, J = 7.2 Hz, ArH). 1 H NMR (300 MHz, MeOH-d 4 ) δ 1.52 (m, 2H, CH 2 ), 1.64 (m, 2H, CH 2 ), 2.20 (m, 2H, CH 2 ), 2.27 (s, 6H, N (CH 3 ) 2 ), 2.38 (m, 2H, CH 2 ), 2.55 (m, 2H, CH 2 ), 3.42 (m, 2H, CH 2 ), 4.97 (s, 2H, CH 2 ), 6.67 (s , 1H, CH), 6.99 (t, 1H, J = 7.0, 1.8 Hz, ArH), 7.41 (m, 4H, ArH), 7.77 (d, 1H, J = 7.0, 1.8 Hz, ArH), 8.14 (d , 1H, J = 7.2 Hz, ArH).

(2-3) : (E)-N1-(2-(다이메틸아미노)에틸)-N8-하이드록시-2-((나프탈렌-1-일 옥시)메틸)옥텐다이아마이드(2-3): (E) -N1- (2- (dimethylamino) ethyl) -N8-hydroxy-2-((naphthalen-1-yl oxy) methyl) octendiamide

상기 (2-2)에서 얻은 화합물을 출발물질로 하여 상기 실시예 (1-3)과 동일한 방법으로 표제 화합물 134 mg(수율 88%)을 합성하였다.Using the compound obtained in the above (2-2) as a starting material, 134 mg (yield 88%) of the title compound were synthesized in the same manner as in Example (1-3).

1H NMR (200 MHz, MeOH-d4) δ1.58 (m, 4H, CH2CH2), 2.40 (m, 2H, CH2), 2.82 (s, 6H, N(CH3)2), 3.30 (m, 4H, CH2CH2), 3.62 (m, 2H, CH2), 5.01 (s, 2H, CH2), 6.70 (t, 1H, J = 15.2, 7.4 Hz, CH), 7.04 (d, 1H, J = 1.2 Hz, ArH), 7.44 (m, 4H, ArH), 7.81 (m, 1H,ArH), 8.19 (m, ArH). 1 H NMR (200 MHz, MeOH-d 4 ) δ 1.58 (m, 4H, CH 2 CH 2 ), 2.40 (m, 2H, CH 2 ), 2.82 (s, 6H, N (CH 3 ) 2 ), 3.30 (m, 4H, CH 2 CH 2 ), 3.62 (m, 2H, CH 2 ), 5.01 (s, 2H, CH 2 ), 6.70 (t, 1H, J = 15.2, 7.4 Hz, CH), 7.04 (d , 1H, J = 1.2 Hz, ArH), 7.44 (m, 4H, ArH), 7.81 (m, 1H, ArH), 8.19 (m, ArH).

실시예 3 : (E)-N1-(2-(다이메틸아미노)에틸)-N8-하이드록시-N1-메틸-2-((나프탈렌-1-일 옥시)메틸)옥텐다이아마이드Example 3: (E) -N1- (2- (dimethylamino) ethyl) -N8-hydroxy-N1-methyl-2-((naphthalen-1-yl oxy) methyl) octendiamide

(3-1) : (E)- 8-((2-(다이메틸아미노)에틸)(메틸)아미노)-7-((나프탈렌-1-일 옥시) 메틸)-8-옥소-6-옥텐산 메틸에스터(3-1): (E) -8-((2- (dimethylamino) ethyl) (methyl) amino) -7-((naphthalen-1-yloxy) methyl) -8-oxo-6-ox Tenic Acid Methyl Ester

상기 제조예 6에서 얻은 2-(나프탈렌-1-일 옥시메틸)-2-다이옥텐산 8-메틸에스터를 출발물질로 하여 상기 실시예 (1-1)과 동일한 방법으로 표제 화합물 351 mg(수율 77%)을 얻었다.351 mg of the title compound (yield 77) in the same manner as in Example (1-1) using 2- (naphthalen-1-yl oxymethyl) -2-dioctenoic acid 8-methylester obtained in Preparation Example 6 as a starting material. %) Was obtained.

1H NMR (200 MHz, CDCl3) δ1.6 (m, 4H, CH2CH2), 2.2 (m, 8H, CH2CH2CH2CH2), 3.05 (s, 3H, NCH3), 3.55 (m, 2H, CH2), 3.70 (s, 3H, OCH3), 5.00 (s, 2H, PhCH2), 5.80 (s, 1H, CH), 6.89 (d, 1H, J = 1.4 Hz, ArH), 7.48 (m, 4H, ArH), 7.80 (dd, 1H, J = 6.0, 2.0 Hz, ArH), 8.20 (m, 1H, ArH). 1 H NMR (200 MHz, CDCl 3 ) δ 1.6 (m, 4H, CH 2 CH 2 ), 2.2 (m, 8H, CH 2 CH 2 CH 2 CH 2 ), 3.05 (s, 3H, NCH 3 ), 3.55 (m, 2H, CH 2 ), 3.70 (s, 3H, OCH 3 ), 5.00 (s, 2H, PhCH 2 ), 5.80 (s, 1H, CH), 6.89 (d, 1H, J = 1.4 Hz, ArH ), 7.48 (m, 4H, ArH), 7.80 (dd, 1H, J = 6.0, 2.0 Hz, ArH), 8.20 (m, 1H, ArH).

(3-2) : (E)- 8-((2-(다이메틸아미노)에틸)(메틸)아미노)-7-((나프탈렌-1-일 옥시)메틸)-8-옥소-6-옥텐산(3-2): (E) -8-((2- (dimethylamino) ethyl) (methyl) amino) -7-((naphthalen-1-yl oxy) methyl) -8-oxo-6-ox Tensan

상기 (3-1)에서 얻은 화합물을 출발물질로 하여 상기 실시예 (1-2)와 동일한 방법으로 표제 화합물 224 mg(수율 92%)을 얻었다.Using the compound obtained in the above (3-1) as a starting material, 224 mg (yield 92%) of the title compound were obtained in the same manner as the Example (1-2).

1H NMR (200 MHz, MeOH-d4) δ1.6 (m, 4H, CH2CH2), 2.4 (m, 6H, CH2CH2CH2), 2.50 (m, 4H, CH2CH2), 2.80 (m, 2H, CH2), 3.01 (s, 3H, NCH3), 3.29 (m, 1H, CH), 3.65 (m, 1H, CH), 4.95 (s, 2H, PhCH2), 6.00 (m, 1H, CH), 7.00 (t, 1H, J = 16.6, 9.4 Hz, ArH), 7.46 (m, 4H, ArH), 7.82 (m, 1H, ArH), 8.18 (m, 1H, ArH). 1 H NMR (200 MHz, MeOH-d 4 ) δ 1.6 (m, 4H, CH 2 CH 2 ), 2.4 (m, 6H, CH 2 CH 2 CH 2 ), 2.50 (m, 4H, CH 2 CH 2 ) , 2.80 (m, 2H, CH 2 ), 3.01 (s, 3H, NCH 3 ), 3.29 (m, 1H, CH), 3.65 (m, 1H, CH), 4.95 (s, 2H, PhCH 2 ), 6.00 (m, 1H, CH), 7.00 (t, 1H, J = 16.6, 9.4 Hz, ArH), 7.46 (m, 4H, ArH), 7.82 (m, 1H, ArH), 8.18 (m, 1H, ArH) .

(3-3) : (E)-N1-(2-(다이메틸아미노)에틸)-N8-하이드록시-N1-메틸-2-((나프탈렌-1-일 옥시)메틸)옥텐다이아마이드(3-3): (E) -N1- (2- (dimethylamino) ethyl) -N8-hydroxy-N1-methyl-2-((naphthalen-1-yl oxy) methyl) octendiamide

상기 (3-2)에서 얻은 화합물을 출발물질로 하여 상기 실시예 (1-3)과 동일한 방법으로 표제 화합물 155 mg(수율 68%)을 합성하였다.Using the compound obtained in the above (3-2) as a starting material, 155 mg (yield 68%) of the title compound were synthesized in the same manner as in Example (1-3).

1H NMR (200 MHz, MeOH-d4) δ1.48 (m, 2H, CH2), 1.58 (m, 2H, CH2), 2.4 (m, 6H, CH2CH2CH2), 2.49 (m, 4H, CH2CH2), 2.81 (m, 2H, CH2), 3.02 (s, 3H, NCH3), 3.28 (m, 1H, CH), 3.64 (m, 1H, CH), 4.95 (s, 2H, PhCH2), 6.02 (m, 1H, CH), 7.00 (d, 1H, J = 8.2 Hz, ArH), 7.44 (m, 4H, ArH), 7.80 (m, 1H, ArH), 8.17 (m, 1H, ArH). 1 H NMR (200 MHz, MeOH-d 4 ) δ 1.48 (m, 2H, CH 2 ), 1.58 (m, 2H, CH 2 ), 2.4 (m, 6H, CH 2 CH 2 CH 2 ), 2.49 (m , 4H, CH 2 CH 2 ), 2.81 (m, 2H, CH 2 ), 3.02 (s, 3H, NCH 3 ), 3.28 (m, 1H, CH), 3.64 (m, 1H, CH), 4.95 (s , 2H, PhCH 2 ), 6.02 (m, 1H, CH), 7.00 (d, 1H, J = 8.2 Hz, ArH), 7.44 (m, 4H, ArH), 7.80 (m, 1H, ArH), 8.17 ( m, 1H, ArH).

실시예 4 : (E)-N1-(2-(다이에틸아미노)에틸)-N8-하이드록시-2-((나프탈렌-1-일 옥시)메틸)옥텐다이아마이드Example 4: (E) -N1- (2- (diethylamino) ethyl) -N8-hydroxy-2-((naphthalen-1-yl oxy) methyl) octendiamide

(4-1) : (E)-8-(2-(다이에틸아미노)에틸아미노)-7-((나프탈렌-1-일 옥시)메틸)-8-옥소-6-옥텐산 메틸에스터(4-1): (E) -8- (2- (diethylamino) ethylamino) -7-((naphthalen-1-yl oxy) methyl) -8-oxo-6-octenic acid methyl ester

상기 제조예 6에서 얻은 2-(나프탈렌-1-일 옥시메틸)-2-다이옥텐산 8-메틸에스터를 출발물질로 하여 상기 실시예 (1-1)과 동일한 방법으로 표제 화합물 164 mg(수율 37%)을 합성하였다.164 mg (yield 37) of the title compound in the same manner as in Example (1-1) using 2- (naphthalen-1-yl oxymethyl) -2-dioctenoic acid 8-methylester obtained in Preparation Example 6 as a starting material. %) Was synthesized.

1H NMR (200 MHz, CDCl3) δ1.24 (m, 6H, CH2CH2CH2), 1.60 (m, 4H, CH2CH2), 2.14 (t, 2H, J = 14,2, 7.4 Hz, CH2), 2.40 (m, 2H, CH2), 3.14 (m, 6H, CH2CH2CH2), 3.50 (s, 2H, CH2), 3.86 (s, 3H, OCH3), 5.02 (s, 2H, CH2), 6.73 (t, 1H, J = 14.6, 7.2 Hz, CH), 7.01 (d, 1H, J = 7.4 Hz, ArH), 7.40 (m, 4H, ArH), 7.76 (d, 1H, J = 7.4 Hz, ArH), 8.18 (dd, 1H, J = 7.4, 2.8 Hz, ArH). 1 H NMR (200 MHz, CDCl 3 ) δ 1.24 (m, 6H, CH 2 CH 2 CH 2 ), 1.60 (m, 4H, CH 2 CH 2 ), 2.14 (t, 2H, J = 14,2, 7.4 Hz, CH 2 ), 2.40 (m, 2H, CH 2 ), 3.14 (m, 6H, CH 2 CH 2 CH 2 ), 3.50 (s, 2H, CH 2 ), 3.86 (s, 3H, OCH 3 ), 5.02 (s, 2H, CH 2 ), 6.73 (t, 1H, J = 14.6, 7.2 Hz, CH), 7.01 (d, 1H, J = 7.4 Hz, ArH), 7.40 (m, 4H, ArH), 7.76 (d, 1H, J = 7.4 Hz, ArH), 8.18 (dd, 1H, J = 7.4, 2.8 Hz, ArH).

(4-2) : (E)-8-(2-(다이에틸아미노)에틸아미노)-7-((나프탈렌-1-일 옥시)메틸)-8-옥소-6-옥텐산(4-2): (E) -8- (2- (diethylamino) ethylamino) -7-((naphthalen-1-yl oxy) methyl) -8-oxo-6-octenic acid

상기 (4-1)에서 얻은 화합물을 출발물질로 하여 상기 실시예 (1-2)와 동일한 방법으로 표제 화합물 130 mg(수율 81%)을 합성하였다.Using the compound obtained in the above (4-1) as a starting material, 130 mg (yield 81%) of the title compound were synthesized in the same manner as in Example (1-2).

1H NMR (200 MHz, MeOH-d4) δ1.24 (m, 6H, CH2CH2CH2), 1.60 (m, 4H, CH2CH2), 2.12 (m, 2H, JCH2), 2.36 (m, 2H, CH2), 3.14 (m, 6H, CH2CH2CH2), 3.50 (s, 2H, CH2), 5.01 (s, 2H, CH2), 6.72 (d, 1H, J = 7.4 Hz, CH), 7.02 (d, 1H, J = 7.4 Hz, ArH), 7.40 (m, 4H, ArH), 7.80 (dd, 1H, J = 7.6, 1.8 Hz, ArH), 8.16 (d, 1H, J = 7.2 Hz, ArH). 1 H NMR (200 MHz, MeOH-d 4 ) δ 1.24 (m, 6H, CH 2 CH 2 CH 2 ), 1.60 (m, 4H, CH 2 CH 2 ), 2.12 (m, 2H, JCH 2 ), 2.36 (m, 2H, CH 2 ), 3.14 (m, 6H, CH 2 CH 2 CH 2 ), 3.50 (s, 2H, CH 2 ), 5.01 (s, 2H, CH 2 ), 6.72 (d, 1H, J = 7.4 Hz, CH), 7.02 (d, 1H, J = 7.4 Hz, ArH), 7.40 (m, 4H, ArH), 7.80 (dd, 1H, J = 7.6, 1.8 Hz, ArH), 8.16 (d, 1H, J = 7.2 Hz, ArH).

(4-3) : (E)-N1-(2-(다이에틸아미노)에틸)-2-((나프탈렌-1-일 옥시)메틸)-N8-(테트라하이드로-2H-피란-2-일옥시)옥텐다이아마이드(4-3): (E) -N1- (2- (diethylamino) ethyl) -2-((naphthalen-1-yl oxy) methyl) -N8- (tetrahydro-2H-pyran-2-yljade Octene amide

상기 실시예 (4-2)에서 얻은 (E)-8-(2-(다이에틸아미노)에틸아미노)-7-((나 프탈렌-1-일 옥시)메틸)-8-옥소-6-옥텐산(311 ㎎, 0.71 mM)을 다이메틸폼아마이드(3 ㎖)에 녹이고 트라이에틸아민(150 ㎕, 1.07 mM)을 가한 후, 0℃로 냉각한 다음, 여기에 N-하이드록시-6-트라이플루오로 벤조트라이아졸(159 ㎎, 0.78 mM), 1-(3-다이에틸아미노프로필)-3-에틸카보다이이미드염산염(177 ㎎, 0.92 mM)과 테트라하이드로피란일옥시아민(125 ㎎, 1.07 mM)을 가하여 상온에서 18시간 동안 교반시켰다. 반응이 종결되면 반응 혼합물에 얼음물을 가하고 에틸초산으로 추출한 후, 유기층을 포화 중조와 소금물로 세척한 다음 무수 황산마그네슘으로 건조 후 감압 하에서 농축하였다. 얻어진 잔사를 실리카겔 컬럼 크로마토그래피 방법으로 정제하여 표제 화합물 320 mg(수율 87%)을 얻었다.(E) -8- (2- (diethylamino) ethylamino) -7-((naphthalen-1-yl oxy) methyl) -8-oxo-6- obtained in Example (4-2) above Octenoic acid (311 mg, 0.71 mM) was dissolved in dimethylformamide (3 mL), triethylamine (150 μl, 1.07 mM) was added, cooled to 0 ° C., and then N-hydroxy-6- Trifluoro benzotriazole (159 mg, 0.78 mM), 1- (3-diethylaminopropyl) -3-ethylcarbodiimide hydrochloride (177 mg, 0.92 mM) and tetrahydropyranyloxyamine (125 mg, 1.07 mM) was added and stirred at room temperature for 18 hours. After the reaction was completed, ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 320 mg (87%) of the title compound.

1H NMR (200 MHz, MeOH-d4) δ0.80 (m, 6H, CH2CH2CH2), 1.80 (m, 12H, CH2CH2CH2CH2), 2.10 (s, 1H, CH2), 2.35 (m, 6H, CH3CH3), 2.58 (m, 2H, CH2), 3.40 (m, 2H, CH2), 3.60 (m, 1H, CH), 3.94 (m, 1H, CH), 4.96 (s, 2H, CH2), 6.80 (d, 1H, J = 7.4 Hz, CH), 6.98 (d, 1H, J = 6.8 Hz, ArH), 7.42 (m, 4H, ArH), 7.80 (m, 1H, ArH), 8.21 (dd, 1H, J = 12.6, 6.4 Hz, ArH). 1 H NMR (200 MHz, MeOH-d 4 ) δ 0.80 (m, 6H, CH 2 CH 2 CH 2 ), 1.80 (m, 12H, CH 2 CH 2 CH 2 CH 2 ), 2.10 (s, 1H, CH 2 ), 2.35 (m, 6H, CH 3 CH 3 ), 2.58 (m, 2H, CH 2 ), 3.40 (m, 2H, CH 2 ), 3.60 (m, 1H, CH), 3.94 (m, 1H, CH), 4.96 (s, 2H, CH 2 ), 6.80 (d, 1H, J = 7.4 Hz, CH), 6.98 (d, 1H, J = 6.8 Hz, ArH), 7.42 (m, 4H, ArH), 7.80 (m, 1H, ArH), 8.21 (dd, 1H, J = 12.6, 6.4 Hz, ArH).

(4-4) : (E)-N1-(2-(다이에틸아미노)에틸)-N8-하이드록시-2-((나프탈렌-1-일 옥시)메틸)옥텐다이아마이드(4-4): (E) -N1- (2- (diethylamino) ethyl) -N8-hydroxy-2-((naphthalen-1-yl oxy) methyl) octendiamide

상기 실시예 (4-4)에서 얻은 (E)-N1-(2-(다이에틸아미노)에틸)-2-((나프탈렌-1-일 옥시)메틸)-N8-(테트라하이드로-2H-피란-2-일옥시)옥텐다이아마이드(320 mg, 0.62 mM)를 다이클로로메탄(10 ml)에 녹인 후, 트라이플루오로아세트산(0.46 ml, 6.20 mM)을 0℃에서 천천히 가하여 실온에서 18시간 동안 반응시켰다. 반응이 종결되면 반응 혼합물을 상온에서 감압 하여 용매를 제거하고 남은 잔사를 실리카겔 컬럼 크로마토그래피(용리제: 메틸알콜/다이클로로메탄 = 1/9)로 정제하여 표제 화합물 261 mg(수율 95%)을 얻었다. (E) -N1- (2- (diethylamino) ethyl) -2-((naphthalen-1-yl oxy) methyl) -N8- (tetrahydro-2H-pyran obtained in the above Example (4-4) 2-yloxy) octendiamide (320 mg, 0.62 mM) was dissolved in dichloromethane (10 ml), then trifluoroacetic acid (0.46 ml, 6.20 mM) was added slowly at 0 ° C. for 18 hours at room temperature. Reacted. At the end of the reaction, the reaction mixture was decompressed at room temperature to remove the solvent, and the residue was purified by silica gel column chromatography (eluent: methyl alcohol / dichloromethane = 1/9) to give 261 mg (95% yield) of the title compound. Got it.

1H NMR (200 MHz, MeOH-d4) δ1.24 (m, 6H, CH2CH2CH2), 1.60 (m, 4H, CH2CH2), 2.14 (t, 2H, J = 13,8, 7.0 Hz, CH2), 2.40 (q, 2H, J = 14.4, 7.0 Hz, CH2), 3.12 (m, 6H, CH2CH2CH2), 3.51 (s, 2H, CH2), 5.02 (s, 2H, CH2), 6.73 (t, 1H, J = 14.8, 7.4 Hz, CH), 7.02 (d, 1H, J = 6.4 Hz, ArH), 7.41 (m, 4H, ArH), 7.80 (dd, 1H, J = 5.6, 2.0 Hz, ArH), 8.18 (dd, 1H, J = 7.0, 3.8 Hz, ArH). 1 H NMR (200 MHz, MeOH-d 4 ) δ 1.24 (m, 6H, CH 2 CH 2 CH 2 ), 1.60 (m, 4H, CH 2 CH 2 ), 2.14 (t, 2H, J = 13,8 , 7.0 Hz, CH 2 ), 2.40 (q, 2H, J = 14.4, 7.0 Hz, CH 2 ), 3.12 (m, 6H, CH 2 CH 2 CH 2 ), 3.51 (s, 2H, CH 2 ), 5.02 (s, 2H, CH 2 ), 6.73 (t, 1H, J = 14.8, 7.4 Hz, CH), 7.02 (d, 1H, J = 6.4 Hz, ArH), 7.41 (m, 4H, ArH), 7.80 ( dd, 1H, J = 5.6, 2.0 Hz, ArH), 8.18 (dd, 1H, J = 7.0, 3.8 Hz, ArH).

실시예 5 : (E)-N1-(2-(다이에틸아미노)에틸)-N8-하이드록시-N1-메틸-2-((나프탈렌-1-일 옥시)메틸)옥텐다이아마이드Example 5 (E) -N1- (2- (Diethylamino) ethyl) -N8-hydroxy-N1-methyl-2-((naphthalen-1-yl oxy) methyl) octendiamide

(5-1) : (E)-8-((2-(다이에틸아미노)에틸)(메틸)아미노)-7-((나프탈렌-1-일 옥시)메틸)-8-옥소-6-옥텐산 메틸에스터 ( 5-1): (E) -8-((2- (diethylamino) ethyl) (methyl) amino) -7-((naphthalen-1-yl oxy) methyl) -8-oxo-6-ox Tenic Acid Methyl Ester

상기 제조예 6에서 얻은 2-(나프탈렌-1-일 옥시메틸)-2-다이옥텐산 8-메틸에스터를 출발물질로 하여 상기 실시예 (1-1)과 동일한 방법으로 표제 화합물 483 mg(수율71%)을 합성하였다.483 mg of the title compound (yield 71) in the same manner as in Example (1-1) using 2- (naphthalen-1-yl oxymethyl) -2-dioctenoic acid 8-methylester obtained in Preparation Example 6 as a starting material. %) Was synthesized.

1H NMR (300 MHz, CDCl3) δ1.11 (m, 6H, CH2CH2CH2), 1.40 (m, 2H, CH2), 1.65 (m, 2H, CH2), 2.28 (m, 8H, CH2CH2CH3CH3), 2.90 (s, 2H, CH2), 3.00 (s, 3H, NCH3), 3.57 (s, 2H, CH2), 3.66 (s, 3H, OCH3), 4.93 (s, 2H, CH2), 6.85 (d, 1H, J = 7.8 Hz, CH), 6.99 (m, 1H, ArH), 7.41 (m, 4H, ArH), 7.75 (m, 1H, ArH), 8.14 (m, 1H, NH), 8.17 (m, 1H, ArH). 1 H NMR (300 MHz, CDCl 3 ) δ 1.11 (m, 6H, CH 2 CH 2 CH 2 ), 1.40 (m, 2H, CH 2 ), 1.65 (m, 2H, CH 2 ), 2.28 (m, 8H , CH 2 CH 2 CH 3 CH 3 ), 2.90 (s, 2H, CH 2 ), 3.00 (s, 3H, NCH 3 ), 3.57 (s, 2H, CH 2 ), 3.66 (s, 3H, OCH 3 ) , 4.93 (s, 2H, CH 2 ), 6.85 (d, 1H, J = 7.8 Hz, CH), 6.99 (m, 1H, ArH), 7.41 (m, 4H, ArH), 7.75 (m, 1H, ArH ), 8.14 (m, 1H, NH), 8.17 (m, 1H, ArH).

(5-2) : (E)-8-((2-(다이에틸아미노)에틸)(메틸)아미노)-7-((나프탈렌-1-일 옥시)메틸)-8-옥소-6-옥텐산(5-2): (E) -8-((2- (diethylamino) ethyl) (methyl) amino) -7-((naphthalen-1-yl oxy) methyl) -8-oxo-6-ox Tensan

상기 (5-1)의 화합물을 출발물질로 하여 상기 실시예 (1-2)와 동일한 방법으로 표제 화합물 300 mg(수율 65 %)을 합성하였다.Using the compound of (5-1) as a starting material, 300 mg (yield 65%) of the title compound were synthesized in the same manner as in Example (1-2).

1H NMR (300 MHz, MeOH-d4) δ1.05 (m, 6H, CH2CH2CH2), 1.38 (m, 2H, CH2), 1.50 (m, 2H, CH2), 2.17 (m, 4H, CH2CH2), 2.99 (m, 6H, CH3CH3), 3.16 (s, 3H, NCH3), 3.60 (m, 2H, CH2), 4.87 (s, 2H, CH2), 5.86 (d, 1H, J = 7.4 Hz, CH), 6.82 (d, 1H, J = 7.4 Hz, ArH), 7.28 (m, 4H, ArH), 7.64 (t, 1H, J = 9.4, 6.1 Hz, ArH), 7.92 (d, 1H, J = 9.7 Hz, ArH). 1 H NMR (300 MHz, MeOH-d 4 ) δ 1.05 (m, 6H, CH 2 CH 2 CH 2 ), 1.38 (m, 2H, CH 2 ), 1.50 (m, 2H, CH 2 ), 2.17 (m , 4H, CH 2 CH 2 ), 2.99 (m, 6H, CH 3 CH 3 ), 3.16 (s, 3H, NCH 3 ), 3.60 (m, 2H, CH 2 ), 4.87 (s, 2H, CH 2 ) , 5.86 (d, 1H, J = 7.4 Hz, CH), 6.82 (d, 1H, J = 7.4 Hz, ArH), 7.28 (m, 4H, ArH), 7.64 (t, 1H, J = 9.4, 6.1 Hz , ArH), 7.92 (d, 1H, J = 9.7 Hz, ArH).

(5-3) : (E)-N1-(2-(다이에틸아미노)에틸)-2-((나프탈렌-1-일 옥시)메틸)-N8-(테트 라하이드로-2H-피란-2-일옥시)-2-옥텐다이아마이드(5-3): (E) -N1- (2- (diethylamino) ethyl) -2-((naphthalen-1-yl oxy) methyl) -N8- (tetrahydro-2H-pyran-2- Yloxy) -2-octenamide

상기 (5-2)에서 얻은 화합물을 출발물질로 하여 상기 실시예 (4-3)과 동일한 방법으로 표제 화합물 320 mg(수율 87%)을 합성하였다.Using the compound obtained in the above (5-2) as a starting material, 320 mg (yield 87%) of the title compound were synthesized in the same manner as in Example (4-3).

1H NMR (300 MHz, MeOH-d4) δ1.00 (m, 6H, CH2CH2CH2), 1.54 (m, 4H, CH2CH2), 1.73 (m, 8H, CH2CH2CH2CH2), 2.14 (d, 2H, J = 7.0 Hz, CH2), 2.36 (d, 2H, J = 7.4 Hz, CH2), 2.58 (d, 2H, J = 6.8 Hz, CH2), 3.07 (m, 6H, CH3CH3), 3.32 (s, 3H, NCH3), 3.55 (m, 2H, CH2), 3.98 (m, 1H, CH), 5.05 (s, 2H, CH2), 5.94 (m, 1H, CH), 7.01 (d, 1H, J = 7.4 Hz, ArH), 7.48 (m, 4H, ArH), 7.82 (t, 1H, J = 9.1, 2.0 Hz, ArH), 8.11 (dd, 1H, J = 7.4, 2.3 Hz, ArH). 1 H NMR (300 MHz, MeOH-d 4 ) δ 1.00 (m, 6H, CH 2 CH 2 CH 2 ), 1.54 (m, 4H, CH 2 CH 2 ), 1.73 (m, 8H, CH 2 CH 2 CH 2 CH 2 ), 2.14 (d, 2H, J = 7.0 Hz, CH 2 ), 2.36 (d, 2H, J = 7.4 Hz, CH 2 ), 2.58 (d, 2H, J = 6.8 Hz, CH 2 ), 3.07 (m, 6H, CH 3 CH 3 ), 3.32 (s, 3H, NCH 3 ), 3.55 (m, 2H, CH 2 ), 3.98 (m, 1H, CH), 5.05 (s, 2H, CH 2 ) , 5.94 (m, 1H, CH), 7.01 (d, 1H, J = 7.4 Hz, ArH), 7.48 (m, 4H, ArH), 7.82 (t, 1H, J = 9.1, 2.0 Hz, ArH), 8.11 (dd, 1H, J = 7.4, 2.3 Hz, ArH).

(5-4) : (E)-N1-(2-(다이에틸아미노)에틸)-N8-하이드록시-N1-메틸-2-((나프탈렌-1-일 옥시)메틸)옥텐다이아마이드(5-4): (E) -N1- (2- (diethylamino) ethyl) -N8-hydroxy-N1-methyl-2-((naphthalen-1-yl oxy) methyl) octendiamide

상기 (5-3)에서 얻은 화합물을 출발물질로 하여 상기 실시예 (4-4)와 동일한 방법으로 표제 화합물 285 mg(수율 93%)을 합성하였다.Using the compound obtained in the above (5-3) as a starting material, 285 mg (yield 93%) of the title compound were synthesized in the same manner as in Example (4-4).

1H NMR (300 MHz, MeOH-d4) δ1.10 (m, 6H, CH2CH2CH2), 1.13 (m, 2H, CH2), 1.58 (m, 2H, CH2), 2.02 (t, 2H, J = 14.1, 7.0 Hz, CH2), 2.28 (d, 2H, J = 7.2 Hz, CH2), 3.07 (m, 6H, CH3CH3), 3.21 (s, 3H, NCH3), 3.64 (m, 2H, CH2), 4.96 (s, 2H, CH2), 5.93 (s, 1H, CH), 6.90 (d, 1H, J = 7.2 Hz, ArH), 7.36 (m, 4H, ArH), 7.71 (dd, 1H, J = 8.0, 3.7 Hz, ArH), 7.98 (d, 1H, J = 9.4 Hz, ArH); MS (LC, 70 eV) m/z 456 (M+1), 382. 1 H NMR (300 MHz, MeOH-d 4 ) δ 1.10 (m, 6H, CH 2 CH 2 CH 2 ), 1.13 (m, 2H, CH 2 ), 1.58 (m, 2H, CH 2 ), 2.02 (t , 2H, J = 14.1, 7.0 Hz, CH 2 ), 2.28 (d, 2H, J = 7.2 Hz, CH 2 ), 3.07 (m, 6H, CH 3 CH 3 ), 3.21 (s, 3H, NCH 3 ) , 3.64 (m, 2H, CH 2 ), 4.96 (s, 2H, CH 2 ), 5.93 (s, 1H, CH), 6.90 (d, 1H, J = 7.2 Hz, ArH), 7.36 (m, 4H, ArH), 7.71 (dd, 1H, J = 8.0, 3.7 Hz, ArH), 7.98 (d, 1H, J = 9.4 Hz, ArH); MS (LC, 70 eV) m / z 456 (M + l), 382.

실시예 6 : (E)-N8-하이드록시-2-((나프탈렌-1-일 옥시)메틸)-N1-(2-(피롤리딘-1-일)에틸)옥텐다이아마이드Example 6: (E) -N8-hydroxy-2-((naphthalen-1-yl oxy) methyl) -N1- (2- (pyrrolidin-1-yl) ethyl) octendiamide

(6-1) : (E)-7-((나프탈렌-1-일 옥시)메틸)-8-옥소-8-(2-(피롤리딘-1-일)에틸아미노)-6-옥텐산 메틸에스터(6-1): (E) -7-((naphthalen-1-yl oxy) methyl) -8-oxo-8- (2- (pyrrolidin-1-yl) ethylamino) -6-octenic acid Methyl ester

상기 제조예 6에서 얻은 2-(나프탈렌-1-일 옥시메틸)-2-다이옥텐산 8-메틸에스터를 출발물질로 하여 상기 실시예 (1-1)과 동일한 방법으로 표제 화합물 74 mg(수율 29%)을 합성하였다.74 mg of the title compound (yield 29) in the same manner as in Example (1-1) using 2- (naphthalen-1-yl oxymethyl) -2-dioctenoic acid 8-methylester obtained in Preparation Example 6 as a starting material %) Was synthesized.

1H NMR (200 MHz, CDCl3) δ1.50 (d, 2H, J = 7.4 Hz, CH2), 1.62 (d, 2H, J = 7.4 Hz, CH2), 1.89 (m, 4H, CH2), 2.09 (m, 2H, CH2), 2.35 (m, 2H, CH2), 3.13 (m, 5H, CHCH2CH2), 3.32 (s, 1H, CH), 3.58 (t, 2H, J = 12.1, 6.1 Hz, CH2), 3.96 (s, 3H, OCH3), 4.96 (s, 2H, CH2), 6.80 (d, 1H, J = 7.4 Hz, CH), 6.98 (d, 1H, J = 7.4 Hz, ArH), 7.45 (m, 4H, ArH), 7.80 (m, 1H, ArH), 8.21 (m, 1H, ArH). 1 H NMR (200 MHz, CDCl 3 ) δ 1.50 (d, 2H, J = 7.4 Hz, CH 2 ), 1.62 (d, 2H, J = 7.4 Hz, CH 2 ), 1.89 (m, 4H, CH 2 ) , 2.09 (m, 2H, CH 2 ), 2.35 (m, 2H, CH 2 ), 3.13 (m, 5H, CHCH 2 CH 2 ), 3.32 (s, 1H, CH), 3.58 (t, 2H, J = 12.1, 6.1 Hz, CH 2 ), 3.96 (s, 3H, OCH 3 ), 4.96 (s, 2H, CH 2 ), 6.80 (d, 1H, J = 7.4 Hz, CH), 6.98 (d, 1H, J = 7.4 Hz, ArH), 7.45 (m, 4H, ArH), 7.80 (m, 1H, ArH), 8.21 (m, 1H, ArH).

(6-2) : (E)-7-((나프탈렌-1-일 옥시)메틸)-8-옥소-8-(2-(피롤리딘-1-일)에틸아미 노)-6-옥텐산(6-2): (E) -7-((naphthalen-1-yl oxy) methyl) -8-oxo-8- (2- (pyrrolidin-1-yl) ethylamino) -6-jade Tensan

상기 (6-1)에서 얻은 화합물을 출발물질로 하여 상기 실시예 (1-2)와 동일한 방법으로 표제 화합물 69 mg(수율 96%)을 합성하였다.Using the compound obtained in the above (6-1) as a starting material, 69 mg (yield 96%) of the title compound were synthesized in the same manner as in Example (1-2).

1H NMR (200 MHz, MeOH-d4) δ1.50 (d, 2H, J = 7.2 Hz, CH2), 1.60 (d, 2H, J = 7.2 Hz, CH2), 1.88 (m, 4H, CH2), 2.08 (m, 2H, CH2), 2.34 (m, 2H, CH2), 3.14 (m, 5H, CHCH2CH2), 3.34 (s, 1H, CH), 3.58 (t, 2H, J = 12.1, 6.1 Hz, CH2), 4.96 (s, 2H, CH2), 6.80 (d, 1H, J = 7.0 Hz, CH), 6.98 (d, 1H, J = 7.2 Hz, ArH), 7.45 (m, 4H, ArH), 7.80 (m, 1H, ArH), 8.21 (m, 1H, ArH). 1 H NMR (200 MHz, MeOH-d 4 ) δ 1.50 (d, 2H, J = 7.2 Hz, CH 2 ), 1.60 (d, 2H, J = 7.2 Hz, CH 2 ), 1.88 (m, 4H, CH 2 ), 2.08 (m, 2H, CH 2 ), 2.34 (m, 2H, CH 2 ), 3.14 (m, 5H, CHCH 2 CH 2 ), 3.34 (s, 1H, CH), 3.58 (t, 2H, J = 12.1, 6.1 Hz, CH 2 ), 4.96 (s, 2H, CH 2 ), 6.80 (d, 1H, J = 7.0 Hz, CH), 6.98 (d, 1H, J = 7.2 Hz, ArH), 7.45 (m, 4H, ArH), 7.80 (m, 1H, ArH), 8.21 (m, 1H, ArH).

(6-3) : (E)-2-((나프탈렌-1-일 옥시)메틸)-N1-(2-(피롤리딘-1-일)에틸)-N8-(테트라하이드로-2H-피란-2-일옥시)옥텐다이아마이드(6-3): (E) -2-((naphthalen-1-yl oxy) methyl) -N1- (2- (pyrrolidin-1-yl) ethyl) -N8- (tetrahydro-2H-pyran 2-yloxy) octenamide

상기 (6-2)에서 얻은 화합물을 출발물질로 하여 상기 실시예 (4-3)과 동일한 방법으로 표제 화합물 87 mg(수율 85%)을 얻었다.Using the compound obtained in the above (6-2) as a starting material, 87 mg (yield 85%) of the title compound were obtained in the same manner as the Example (4-3).

1H NMR (200 MHz, MeOH-d4) δ1.50 (m, 8H, CH2CH2CH2CH2), 1.80 (m, 4H, CH2CH2), 2.01 (m, 2H, CH2), 2.40 (m, 4H, CH2CH2), 2.59 (m, 5H, CHCH2CH2), 2.78 (m, 2H, CH2), 3.50 (m, 3H, CHCH2), 3.90 (s, 1H, CH), 4.96 (s, 2H, CH2), 6.80 (d, 1H, J = 7.2 Hz, CH), 6.98 (d, 1H, J = 7.4 Hz, ArH), 7.45 (m, 4H, ArH), 7.80 (m, 1H, ArH), 8.21 (m, 1H, ArH). 1 H NMR (200 MHz, MeOH-d 4 ) δ 1.50 (m, 8H, CH 2 CH 2 CH 2 CH 2 ), 1.80 (m, 4H, CH 2 CH 2 ), 2.01 (m, 2H, CH 2 ) , 2.40 (m, 4H, CH 2 CH 2 ), 2.59 (m, 5H, CHCH 2 CH 2 ), 2.78 (m, 2H, CH 2 ), 3.50 (m, 3H, CHCH 2 ), 3.90 (s, 1H , CH), 4.96 (s, 2H, CH 2 ), 6.80 (d, 1H, J = 7.2 Hz, CH), 6.98 (d, 1H, J = 7.4 Hz, ArH), 7.45 (m, 4H, ArH) , 7.80 (m, 1H, ArH), 8.21 (m, 1H, ArH).

(6-4) : (E)-N8-하이드록시-2-((나프탈렌-1-일 옥시)메틸)-N1-(2-(피롤리딘-1-일)에틸)옥텐다이아마이드(6-4): (E) -N8-hydroxy-2-((naphthalen-1-yl oxy) methyl) -N1- (2- (pyrrolidin-1-yl) ethyl) octendiamide

상기 (6-3)에서 얻은 화합물을 출발물질로 하여 상기 실시예 (4-4)와 동일한 방법으로 표제 화합물 72 mg(수율 84%)을 얻었다.Using the compound obtained in the above (6-3) as a starting material, 72 mg (yield 84%) of the title compound were obtained in the same manner as the Example (4-4).

1H NMR (300 MHz, MeOH-d4) δ1.51 (d, 2H, J = 7.0 Hz, CH2), 1.62 (d, 2H, J = 7.9 Hz, CH2), 1.89 (m, 4H, CH2), 2.09 (m, 2H, CH2), 2.35 (m, 2H, CH2), 3.13 (m, 5H, CHCH2CH2), 3.32 (s, 1H, CH), 3.58 (t, 2H, J = 12.1, 6.1 Hz, CH2), 5.01 (s, 2H, CH2), 6.70 (s, 1H, CH), 7.00 (d, 1H, J = 7.2 Hz, ArH), 7.45 (m, 4H, ArH), 7.80 (t, 1H, J = 8.4, 1.8 Hz, ArH), 8.12 (t, 1H, J = 9.4, 7.5 Hz, ArH); MS (LC, 70 eV) m/z 440 (M+1), 425, 328, 313, 242, 210, 192. 1 H NMR (300 MHz, MeOH-d 4 ) δ 1.51 (d, 2H, J = 7.0 Hz, CH 2 ), 1.62 (d, 2H, J = 7.9 Hz, CH 2 ), 1.89 (m, 4H, CH 2 ), 2.09 (m, 2H, CH 2 ), 2.35 (m, 2H, CH 2 ), 3.13 (m, 5H, CHCH 2 CH 2 ), 3.32 (s, 1H, CH), 3.58 (t, 2H, J = 12.1, 6.1 Hz, CH 2 ), 5.01 (s, 2H, CH 2 ), 6.70 (s, 1H, CH), 7.00 (d, 1H, J = 7.2 Hz, ArH), 7.45 (m, 4H, ArH), 7.80 (t, 1H, J = 8.4, 1.8 Hz, ArH), 8.12 (t, 1H, J = 9.4, 7.5 Hz, ArH); MS (LC, 70 eV) m / z 440 (M + l), 425, 328, 313, 242, 210, 192.

실시예 7 : (E)-N8-하이드록시-2-((나프탈렌-1-일 옥시)메틸)-N1-(2-(피페리딘-1-일)에틸)옥텐다이아마이드Example 7: (E) -N8-hydroxy-2-((naphthalen-1-yl oxy) methyl) -N1- (2- (piperidin-1-yl) ethyl) octendiamide

(7-1) : (E)-7-((나프탈렌-1-일 옥시)메틸)-8-옥소-8-(2-(피페리딘-1-일)에틸아미노)-6-옥텐산 메틸에스터(7-1): (E) -7-((naphthalen-1-yl oxy) methyl) -8-oxo-8- (2- (piperidin-1-yl) ethylamino) -6-octenic acid Methyl ester

상기 제조예 6에서 얻은 2-(나프탈렌-1-일 옥시메틸)-2-다이옥텐산 8-메틸에 스터를 출발물질로 하여 상기 실시예 (1-1)과 동일한 방법으로 표제 화합물 290 mg(수율 94%)을 합성하였다.290 mg of the title compound (yield) in the same manner as in Example (1-1) using 2- (naphthalen-1-yl oxymethyl) -2-dioctenoic acid 8-methyl ester obtained in Preparation Example 6 as a starting material. 94%) was synthesized.

1H NMR (200 MHz, CDCl3) δ1.10 (m, 2H, CH2), 1.21 (m, 2H, CH2), 1.60 (m, 4H, CH2), 2.01 (m, 2H, CH2), 2.21 (m, 5H, CHCH2CH2), 2.38 (m, 5H, CHCH2CH2), 3.41 (t, 2H, J = 11.4, 5.8 Hz, CH), 3.65 (s, 3H, OCH2), 4.95 (s, 2H, CH2), 6.81 (d, 1H, J = 7.8 Hz, CH), 6.95 (d, 1H, J = 7.0 Hz, ArH), 7.10 (brs, 1H, NH), 7.45 (m, 4H, ArH), 7.80 (q, 1H, J = 5.8, 2.4 Hz, ArH), 8.21 (dd, 1H, J = 7.0, 3.4 Hz, ArH). 1 H NMR (200 MHz, CDCl 3 ) δ 1.10 (m, 2H, CH 2 ), 1.21 (m, 2H, CH 2 ), 1.60 (m, 4H, CH 2 ), 2.01 (m, 2H, CH 2 ) , 2.21 (m, 5H, CHCH 2 CH 2 ), 2.38 (m, 5H, CHCH 2 CH 2 ), 3.41 (t, 2H, J = 11.4, 5.8 Hz, CH), 3.65 (s, 3H, OCH 2 ) , 4.95 (s, 2H, CH 2 ), 6.81 (d, 1H, J = 7.8 Hz, CH), 6.95 (d, 1H, J = 7.0 Hz, ArH), 7.10 (brs, 1H, NH), 7.45 ( m, 4H, ArH), 7.80 (q, 1H, J = 5.8, 2.4 Hz, ArH), 8.21 (dd, 1H, J = 7.0, 3.4 Hz, ArH).

(7-2) : (E)-7-((나프탈렌-1-일 옥시)메틸)-8-옥소-8-(2-(피페리딘-1-일)에틸아미노)-6-옥텐산(7-2): (E) -7-((naphthalen-1-yl oxy) methyl) -8-oxo-8- (2- (piperidin-1-yl) ethylamino) -6-octenic acid

상기 (7-1)에서 얻은 화합물을 출발물질로 하여 상기 실시예 (1-2)와 동일한 방법으로 표제 화합물 256 mg(수율 94%)을 합성하였다.Using the compound obtained in the above (7-1) as a starting material, 256 mg (yield 94%) of the title compound were synthesized in the same manner as in Example (1-2).

1H NMR (300 MHz, MeOH-d4) δ1.44 (m, 4H, CH2CH2), 1.64 (m, 2H, CH2), 2.12 (m, 2H, CH2), 2.26 (m, 2H, CH2), 3.08 (m, 10H, CH2CH2CH2CH2CH2), 3.51 (d, 2H, J = 6.0 Hz, CH), 4.91 (s, 2H, CH2), 6.61 (s, 1H, CH), 6.91 (d, 1H, J = 6.2 Hz, ArH), 7.31 (m, 4H, ArH), 7.68 (dd, 1H, J = 6.8, 3.4 Hz, ArH), 8.00 (dd, 1H, J = 7.0, 3.4 Hz, ArH). 1 H NMR (300 MHz, MeOH-d 4 ) δ 1.44 (m, 4H, CH 2 CH 2 ), 1.64 (m, 2H, CH 2 ), 2.12 (m, 2H, CH 2 ), 2.26 (m, 2H , CH 2 ), 3.08 (m, 10H, CH 2 CH 2 CH 2 CH 2 CH 2 ), 3.51 (d, 2H, J = 6.0 Hz, CH), 4.91 (s, 2H, CH 2 ), 6.61 (s , 1H, CH), 6.91 (d, 1H, J = 6.2 Hz, ArH), 7.31 (m, 4H, ArH), 7.68 (dd, 1H, J = 6.8, 3.4 Hz, ArH), 8.00 (dd, 1H , J = 7.0, 3.4 Hz, ArH).

(7-3) : (E)-2-((나프탈렌-1-일 옥시)메틸)-N1-(2-(피페리딘-1-일)에틸)-N8-(테트라하이드로-2H-피란-2-일옥시)옥텐다이아마이드(7-3): (E) -2-((naphthalen-1-yl oxy) methyl) -N1- (2- (piperidin-1-yl) ethyl) -N8- (tetrahydro-2H-pyran 2-yloxy) octenamide

상기 (7-2)에서 얻은 화합물을 출발물질로 하여 상기 실시예 (4-3)과 동일한 방법으로 표제 화합물 288 mg(수율 91%)을 얻었다.Using the compound obtained in the above (7-2) as a starting material, 288 mg (yield 91%) of the title compound were obtained in the same manner as the Example (4-3).

1H NMR (300 MHz, MeOH-d4) δ1.42 (m, 2H, CH2), 1.45 (m, 4H, CH2CH2), 1.60 (m, 8H, CH2CH2CH2CH2), 2.09 (s, 2H, CH2), 2.29 (m, 10H, CH2CH2CH2CH2CH2), 3.21 (m, 2H, CH2), 3.47 (m, 2H, CH2), 3.89 (t, 1H, J = 7.2 Hz, CH), 4.90 (s, 2H, CH2), 6.50 (s, 1H, CH), 6.90 (d, 1H, J = 7.2 Hz, ArH), 7.33 (m, 4H, ArH), 7.70 (t, 1H, J = 9.0, 1.4 Hz, ArH), 8.02 (d, 1H, J = 8.2 Hz, ArH). 1 H NMR (300 MHz, MeOH-d 4 ) δ 1.42 (m, 2H, CH 2 ), 1.45 (m, 4H, CH 2 CH 2 ), 1.60 (m, 8H, CH 2 CH 2 CH 2 CH 2 ) , 2.09 (s, 2H, CH 2 ), 2.29 (m, 10H, CH 2 CH 2 CH 2 CH 2 CH 2 ), 3.21 (m, 2H, CH 2 ), 3.47 (m, 2H, CH 2 ), 3.89 (t, 1H, J = 7.2 Hz, CH), 4.90 (s, 2H, CH 2 ), 6.50 (s, 1H, CH), 6.90 (d, 1H, J = 7.2 Hz, ArH), 7.33 (m, 4H, ArH), 7.70 (t, 1H, J = 9.0, 1.4 Hz, ArH), 8.02 (d, 1H, J = 8.2 Hz, ArH).

(7-4) : (E)-N8-하이드록시-2-((나프탈렌-1-일 옥시)메틸)-N1-(2-(피페리딘-1-일)에틸)옥텐다이아마이드(7-4): (E) -N8-hydroxy-2-((naphthalen-1-yl oxy) methyl) -N1- (2- (piperidin-1-yl) ethyl) octendiamide

상기 (7-3)에서 얻은 화합물을 출발물질로 하여 상기 실시예 (4-4)와 동일한 방법으로 표제 화합물 213 mg(수율 94%)을 얻었다.Using the compound obtained in the above (7-3) as a starting material, 213 mg (yield 94%) of the title compound were obtained in the same manner as the Example (4-4).

1H NMR (300 MHz, MeOH-d4) δ1.41 (m, 4H, CH2CH2), 1.65 (m, 4H, CH2CH2), 2.10 (t, 2H, J = 14.3, 7.0 Hz, CH2), 2.41 (d, 2H, J = 7.2 Hz, CH2), 2.89 (m, 2H, CH2), 3.22 (t, 2H, J = 11.8, 5.9 Hz, CH), 3.32 (m, 2H, CH2), 3.52 (d, 2H, J = 11.8 Hz, CH2), 3.65 (t, J = 11.8, 5.8 Hz, 2H, CH2), 5.04 (s, 2H, CH2), 6.70 (s, 1H, CH), 7.05 (t, 1H, J = 7.3, 1.0 Hz, ArH), 7.45 (m, 4H, ArH), 7.83 (d, 1H, J = 7.2 Hz, ArH), 8.13 (d, 1H, J = 7.2 Hz, ArH). 1 H NMR (300 MHz, MeOH-d 4 ) δ 1.41 (m, 4H, CH 2 CH 2 ), 1.65 (m, 4H, CH 2 CH 2 ), 2.10 (t, 2H, J = 14.3, 7.0 Hz, CH 2 ), 2.41 (d, 2H, J = 7.2 Hz, CH 2 ), 2.89 (m, 2H, CH 2 ), 3.22 (t, 2H, J = 11.8, 5.9 Hz, CH), 3.32 (m, 2H , CH 2 ), 3.52 (d, 2H, J = 11.8 Hz, CH 2 ), 3.65 (t, J = 11.8, 5.8 Hz, 2H, CH 2 ), 5.04 (s, 2H, CH 2 ), 6.70 (s , 1H, CH), 7.05 (t, 1H, J = 7.3, 1.0 Hz, ArH), 7.45 (m, 4H, ArH), 7.83 (d, 1H, J = 7.2 Hz, ArH), 8.13 (d, 1H , J = 7.2 Hz, ArH).

실시예 8 : (E)-N8-하이드록시-N1-(2-몰포리노에틸)-2-((나프탈렌-1-일 옥시)메틸)옥텐다이아마이드Example 8 (E) -N8-hydroxy-N1- (2-morpholinoethyl) -2-((naphthalen-1-yl oxy) methyl) octendiamide

(8-1) : (E)-8-(2-몰포리노에틸아미노)-7-((나프탈렌-1-일 옥시)메틸)-8-옥소-6-옥텐산 메틸에스터(8-1): (E) -8- (2-morpholinoethylamino) -7-((naphthalen-1-yl oxy) methyl) -8-oxo-6-octenic acid methyl ester

상기 제조예 6에서 얻은 2-(나프탈렌-1-일 옥시메틸)-2-다이옥텐산 8-메틸에스터를 출발물질로 하여 상기 실시예 (1-1)과 동일한 방법으로 표제 화합물 266 mg(수율 91%)을 합성하였다.266 mg of the title compound (yield 91) in the same manner as in Example (1-1) using 2- (naphthalen-1-yl oxymethyl) -2-dioctenoic acid 8-methylester obtained in Preparation Example 6 as a starting material. %) Was synthesized.

1H NMR (200 MHz, CDCl3) δ1.45 (m, 2H, CH2), 1.64 (m, 2H, CH2), 2.20 (m, 4H, CH2CH2), 2.25 (m, 4H, CH2CH2), 2.40 (m, 2H, CH2), 3.07 (t, 2H, J = 8.6, 4.2 Hz, CH), 3.42 (t, 2H, J = 10.6, 5.4 Hz, CH2), 3.61 (s, 3H, OCH3), 4.89 (s, 2H, CH2), 6.90 (s, 1H, CH), 6.94 (d, 1H, J = 7.8 Hz, ArH), 7.45 (m, 4H, ArH), 7.82 (dd, 1H, J = 7.8, 2.4 Hz, ArH), 8.19 (dd, 1H, J = 7.8, 2.8 Hz, ArH). 1 H NMR (200 MHz, CDCl 3 ) δ 1.45 (m, 2H, CH 2 ), 1.64 (m, 2H, CH 2 ), 2.20 (m, 4H, CH 2 CH 2 ), 2.25 (m, 4H, CH 2 CH 2 ), 2.40 (m, 2H, CH 2 ), 3.07 (t, 2H, J = 8.6, 4.2 Hz, CH), 3.42 (t, 2H, J = 10.6, 5.4 Hz, CH 2 ), 3.61 ( s, 3H, OCH 3 ), 4.89 (s, 2H, CH 2 ), 6.90 (s, 1H, CH), 6.94 (d, 1H, J = 7.8 Hz, ArH), 7.45 (m, 4H, ArH), 7.82 (dd, 1H, J = 7.8, 2.4 Hz, ArH), 8.19 (dd, 1H, J = 7.8, 2.8 Hz, ArH).

(8-2) : (E)-8-(2-몰포리노에틸아미노)-7-((나프탈렌-1-일 옥시)메틸)-8-옥소-6-옥텐산(8-2): (E) -8- (2-morpholinoethylamino) -7-((naphthalen-1-yl oxy) methyl) -8-oxo-6-octenic acid

상기 (8-1)에서 얻은 화합물을 출발물질로 하여 상기 실시예 (1-2)와 동일한 방법으로 표제 화합물 250 mg(수율 96%)을 합성하였다.Using the compound obtained in the above (8-1) as a starting material, 250 mg (yield 96%) of the title compound were synthesized in the same manner as in Example (1-2).

1H NMR (300 MHz, MeOH-d4) δ1.50 (m, 2H, CH2), 1.62 (m, 2H, CH2), 2.24 (m, 4H, CH2CH2), 2.38 (m, 4H, CH2CH2), 2.58 (m, 2H, CH2), 3.32 (q, 2H, J = 3.1, 1.5 Hz, CH), 3.43 (m, 4H, CH2CH2), 4.96 (s, 2H, CH2), 6.71 (s, 1H, CH), 7.01 (d, 1H, J = 7.3 Hz, ArH), 7.43 (m, 4H, ArH), 7.80 (t, 1H, J = 7.1, 5.5 Hz, ArH), 8.19 (d, 1H, J = 7.6 Hz, ArH); MS (LC, 70 eV) m/z 416 (M+1), 403, 346, 313, 298, 204, 102. 1 H NMR (300 MHz, MeOH-d 4 ) δ 1.50 (m, 2H, CH 2 ), 1.62 (m, 2H, CH 2 ), 2.24 (m, 4H, CH 2 CH 2 ), 2.38 (m, 4H , CH 2 CH 2 ), 2.58 (m, 2H, CH 2 ), 3.32 (q, 2H, J = 3.1, 1.5 Hz, CH), 3.43 (m, 4H, CH 2 CH 2 ), 4.96 (s, 2H , CH 2 ), 6.71 (s, 1H, CH), 7.01 (d, 1H, J = 7.3 Hz, ArH), 7.43 (m, 4H, ArH), 7.80 (t, 1H, J = 7.1, 5.5 Hz, ArH), 8.19 (d, 1H, J = 7.6 Hz, ArH); MS (LC, 70 eV) m / z 416 (M + l), 403, 346, 313, 298, 204, 102.

(8-3) : (E)-N8-하이드록시-N1-(2-몰포리노에틸)-2-((나프탈렌-1-일 옥시)메틸)옥텐다이아마이드(8-3): (E) -N8-hydroxy-N1- (2-morpholinoethyl) -2-((naphthalen-1-yl oxy) methyl) octendiamide

상기 (8-2)에서 얻은 화합물을 출발물질로 하여 상기 실시예 (1-3)와 동일한 방법으로 표제 화합물 155 mg(수율 90%)를 합성하였다.Using the compound obtained in the above (8-2) as a starting material, 155 mg (yield 90%) of the title compound were synthesized in the same manner as in Example (1-3).

1H NMR (300 MHz, MeOH-d4) δ1.48 (m, 2H, CH2), 1.59 (m, 2H, CH2), 2.25 (m, 4H, CH2CH2), 2.38 (m, 4H, CH2CH2), 2.56 (m, 2H, CH2), 3.30 (d, 2H, J = 7.5 Hz, CH), 3.42 (m, 4H, CH2CH2), 5.01 (s, 2H, CH2), 6.78 (s, 1H, CH), 7.00 (d, 1H, J = 7.4 Hz, ArH), 7.45 (m, 4H, ArH), 7.78 (d, 1H, J = 7.4 Hz, ArH), 8.14 (d, 1H, J = 7.6 Hz, ArH); MS (LC, 70 eV) m/z 416 (M+1), 403, 346, 313, 298, 204, 102. 1 H NMR (300 MHz, MeOH-d 4 ) δ 1.48 (m, 2H, CH 2 ), 1.59 (m, 2H, CH 2 ), 2.25 (m, 4H, CH 2 CH 2 ), 2.38 (m, 4H , CH 2 CH 2 ), 2.56 (m, 2H, CH 2 ), 3.30 (d, 2H, J = 7.5 Hz, CH), 3.42 (m, 4H, CH 2 CH 2 ), 5.01 (s, 2H, CH 2 ), 6.78 (s, 1H, CH), 7.00 (d, 1H, J = 7.4 Hz, ArH), 7.45 (m, 4H, ArH), 7.78 (d, 1H, J = 7.4 Hz, ArH), 8.14 (d, 1H, J = 7.6 Hz, ArH); MS (LC, 70 eV) m / z 416 (M + l), 403, 346, 313, 298, 204, 102.

실시예 9 : (E)-N-하이드록시-8-(4-메틸피페라진-1-일)-7-((나프탈렌-1-일 옥시)메틸)-8-옥소옥텐아마이드Example 9: (E) -N-hydroxy-8- (4-methylpiperazin-1-yl) -7-((naphthalen-1-yl oxy) methyl) -8-oxooctenamide

(9-1) : (E)-8-(4-메틸피페라진-1-일)-7-((나프탈렌-1-일 옥시)메틸)-8-옥소-6-옥텐산 메틸에스터(9-1): (E) -8- (4-methylpiperazin-1-yl) -7-((naphthalen-1-yl oxy) methyl) -8-oxo-6-octenic acid methyl ester

상기 제조예 6에서 얻은 2-(나프탈렌-1-일 옥시메틸)-2-다이옥텐산 8-메틸에스터를 출발물질로 하여 상기 실시예 (1-1)과 동일한 방법으로 표제 화합물 175 mg(수율 41%)을 합성하였다.175 mg of the title compound (yield 41) in the same manner as in Example (1-1) using 2- (naphthalen-1-yl oxymethyl) -2-dioctenoic acid 8-methylester obtained in Preparation Example 6 as a starting material. %) Was synthesized.

1H NMR (300 MHz, CDCl3) δ1.46 (m, 2H, CH2), 1.53 (m, 2H, CH2), 2.17 (m, 4H, CH2CH2), 2.34 (m, 8H, CH2CH2CH2CH2), 3.64 (s, 3H, NCH3), 3.75 (s, 3H, OCH3), 4.98 (s, 2H, CH2), 5.78 (t, 1H, J = 15.0, 7.5 Hz, CH), 6.84 (d, 1H, J = 7.5 Hz, ArH), 7.44 (m, 4H, ArH), 7.79 (t, 1H, J = 8.7, 1.2 Hz, ArH), 8.13 (d, 1H, J = 7.8 Hz, ArH). 1 H NMR (300 MHz, CDCl 3 ) δ 1.46 (m, 2H, CH 2 ), 1.53 (m, 2H, CH 2 ), 2.17 (m, 4H, CH 2 CH 2 ), 2.34 (m, 8H, CH 2 CH 2 CH 2 CH 2 ), 3.64 (s, 3H, NCH 3 ), 3.75 (s, 3H, OCH 3 ), 4.98 (s, 2H, CH 2 ), 5.78 (t, 1H, J = 15.0, 7.5 Hz, CH), 6.84 (d, 1H, J = 7.5 Hz, ArH), 7.44 (m, 4H, ArH), 7.79 (t, 1H, J = 8.7, 1.2 Hz, ArH), 8.13 (d, 1H, J = 7.8 Hz, ArH).

(9-2) : (E)-8-(4-메틸피페라진-1-일)-7-((나프탈렌-1-일 옥시)메틸)-8-옥소-6-옥 텐산(9-2): (E) -8- (4-methylpiperazin-1-yl) -7-((naphthalen-1-yl oxy) methyl) -8-oxo-6-octenic acid

상기 (9-1)에서 얻은 화합물을 출발물질로 하여 상기 실시예 (1-2)와 동일한 방법으로 표제 화합물 168 mg(수율 100%)을 합성하였다.Using the compound obtained in the above (9-1) as a starting material, 168 mg (yield 100%) of the title compound were synthesized in the same manner as in Example (1-2).

1H NMR (300 MHz, MeOH-d4) δ1.55 (m, 2H, CH2), 1.68 (m, 2H, CH2), 2.32 (m, 11H, CHCH2CH2CH2CH2CH2), 3.31 (m, 1H, CH), 3.66 (s, 3H, NCH3), 5.09 (s, 2H, CH2), 5.92 (s, 1H, CH), 6.97 (dd, 1H, J = 6.5, 6.5 Hz, ArH), 7.46 (m, 4H, ArH), 7.81 (d, 1H, J = 7.8 Hz, ArH), 8.16 (d, 1H, J = 7.8 Hz, ArH). 1 H NMR (300 MHz, MeOH-d 4 ) δ 1.55 (m, 2H, CH 2 ), 1.68 (m, 2H, CH 2 ), 2.32 (m, 11H, CHCH 2 CH 2 CH 2 CH 2 CH 2 ) , 3.31 (m, 1H, CH), 3.66 (s, 3H, NCH 3 ), 5.09 (s, 2H, CH 2 ), 5.92 (s, 1H, CH), 6.97 (dd, 1H, J = 6.5, 6.5 Hz, ArH), 7.46 (m, 4H, ArH), 7.81 (d, 1H, J = 7.8 Hz, ArH), 8.16 (d, 1H, J = 7.8 Hz, ArH).

(9-3) : (E)-8-(4-메틸피페라진-1-일)-7-((나프탈렌-1-일 옥시)메틸)-8-옥소-N-(테트라하이드로-2H-피란-2-일옥시)-6-옥텐아마이드(9-3): (E) -8- (4-methylpiperazin-1-yl) -7-((naphthalen-1-yl oxy) methyl) -8-oxo-N- (tetrahydro-2H- Pyran-2-yloxy) -6-octenamide

상기 (9-2)에서 얻은 화합물을 출발물질로 하여 상기 실시예 (4-3)과 동일한 방법으로 표제 화합물 317 mg(수율 83%)을 합성하였다.Using the compound obtained in the above (9-2) as a starting material, 317 mg (yield 83%) of the title compound was synthesized in the same manner as in Example (4-3).

1H NMR (300 MHz, MeOH-d4) δ1.54 (m, 4H, CH2CH2), 1.72 (m, 4H, CH2CH2), 2.17 (m, 8H, CH2CH2CH2CH2), 2.37 (m, 6H, CH2CH2CH2), 3.32 (q, 2H, J = 3.2, 1.6 Hz, CH2), 3.57 (s, 3H, NCH3), 3,92 (m, 1H, CH), 5.08 (s, 2H, CH2), 5.86 (s, 1H, CH), 6.96 (d, 1H, J = 7.3 Hz, ArH), 7.45 (m, 4H, ArH), 7.80 (d, 1H, J = 7.3 Hz, ArH), 8.14 (d, 1H, J = 7.3 Hz, ArH). 1 H NMR (300 MHz, MeOH-d 4 ) δ 1.54 (m, 4H, CH 2 CH 2 ), 1.72 (m, 4H, CH 2 CH 2 ), 2.17 (m, 8H, CH 2 CH 2 CH 2 CH 2 ), 2.37 (m, 6H, CH 2 CH 2 CH 2 ), 3.32 (q, 2H, J = 3.2, 1.6 Hz, CH 2 ), 3.57 (s, 3H, NCH 3 ), 3,92 (m, 1H, CH), 5.08 (s, 2H, CH 2 ), 5.86 (s, 1H, CH), 6.96 (d, 1H, J = 7.3 Hz, ArH), 7.45 (m, 4H, ArH), 7.80 (d , 1H, J = 7.3 Hz, ArH), 8.14 (d, 1H, J = 7.3 Hz, ArH).

(9-4) : (E)-N-하이드록시-8-(4-메틸피페라진-1-일)-7-((나프탈렌-1-일 옥시)메틸)-8-옥소옥텐아마이드(9-4): (E) -N-hydroxy-8- (4-methylpiperazin-1-yl) -7-((naphthalen-1-yl oxy) methyl) -8-oxooctenamide

상기 (9-3)에서 얻은 화합물을 출발물질로 하여 상기 실시예 (4-4)와 동일한 방법으로 표제 화합물 287 mg(수율 92%)을 합성하였다.Using the compound obtained in the above (9-3) as a starting material, 287 mg (yield 92%) of the title compound were synthesized in the same manner as in Example (4-4).

1H NMR (300 MHz, MeOH-d4) δ1.52 (m, 2H, CH2), 1.57 (m, 2H, CH2), 2.13 (t, 2H, J = 14.3, 7.1 Hz, CH2), 2.37 (q, 2H, J = 14.4, 7.1 Hz, CH2), 2.61 (m, 4H, CH2CH2), 3.32 (m, 2H, CH2), 3.76 (m, 2H, CH2), 3.80 (s, 3H, NCH3), 5.10 (s, 2H, CH2), 5.96 (s, 1H, CH), 6.97 (d, 1H, J = 7.3 Hz, ArH), 7.47 (m, 4H, ArH), 7.83 (t, 1H, J = 9.1, 4.0 Hz, ArH), 8.13 (t, 1H, J = 9.2, 5.1 Hz, ArH); MS (LC, 70 eV) m/z 426 (M+1), 407, 325, 293, 281, 265, 149, 102. 1 H NMR (300 MHz, MeOH-d 4 ) δ 1.52 (m, 2H, CH 2 ), 1.57 (m, 2H, CH 2 ), 2.13 (t, 2H, J = 14.3, 7.1 Hz, CH 2 ), 2.37 (q, 2H, J = 14.4, 7.1 Hz, CH 2 ), 2.61 (m, 4H, CH 2 CH 2 ), 3.32 (m, 2H, CH 2 ), 3.76 (m, 2H, CH 2 ), 3.80 (s, 3H, NCH 3 ), 5.10 (s, 2H, CH 2 ), 5.96 (s, 1H, CH), 6.97 (d, 1H, J = 7.3 Hz, ArH), 7.47 (m, 4H, ArH) , 7.83 (t, 1H, J = 9.1, 4.0 Hz, ArH), 8.13 (t, 1H, J = 9.2, 5.1 Hz, ArH); MS (LC, 70 eV) m / z 426 (M + l), 407, 325, 293, 281, 265, 149, 102.

실시예 10 : (E)-N8-하이드록시-N1-(2-(4-메틸피페라진-1-일)에틸)-2-((나프탈렌-1-일 옥시)메틸)옥텐다이아마이드Example 10: (E) -N8-hydroxy-N1- (2- (4-methylpiperazin-1-yl) ethyl) -2-((naphthalen-1-yl oxy) methyl) octendiamide

(10-1) : (E)-8-(2-(4-메틸피페라진-1-일)에틸아미노)-7-((나프탈렌-1-일 옥시)메틸)-8-옥소-6-옥텐산 메틸에스터(10-1): (E) -8- (2- (4-methylpiperazin-1-yl) ethylamino) -7-((naphthalen-1-yl oxy) methyl) -8-oxo-6- Octenoic Acid Methyl Ester

상기 제조예 6에서 얻은 2-(나프탈렌-1-일 옥시메틸)-2-다이옥텐산 8-메틸에스터를 출발물질로 하여 상기 실시예 (1-1)과 동일한 방법으로 표제 화합물 225 mg(수율 48%)을 합성하였다.225 mg (yield 48) of the title compound in the same manner as in Example (1-1) using 2- (naphthalen-1-yl oxymethyl) -2-dioctenoic acid 8-methylester obtained in Preparation Example 6 as a starting material. %) Was synthesized.

1H NMR (300 MHz, CDCl3) δ1.53 (m, 2H, CH2), 1.66 (m, 4H, CH2CH2), 1.92 (m, 4H, CH2CH2), 2.31 (m, 8H, CH2CH2CH2CH2), 2.42 (s, 3H, NCH3), 3.40 (q, 2H, J = 10.5, 5.4 Hz, CH2), 3.63 (s, 3H, OCH3), 4.87 (s, 2H, CH2), 6.95 (dd, 1H, J = 15.6, 7.8 Hz, CH), 7.05 (s, 1H, ArH), 7.45 (m, 4H, ArH), 7.80 (dd, 1H, J = 6.9, 1.8 Hz, ArH), 8.19 (t, 1H, J = 9.6, 7.8 Hz, ArH). 1 H NMR (300 MHz, CDCl 3 ) δ 1.53 (m, 2H, CH 2 ), 1.66 (m, 4H, CH 2 CH 2 ), 1.92 (m, 4H, CH 2 CH 2 ), 2.31 (m, 8H , CH 2 CH 2 CH 2 CH 2 ), 2.42 (s, 3H, NCH 3 ), 3.40 (q, 2H, J = 10.5, 5.4 Hz, CH 2 ), 3.63 (s, 3H, OCH 3 ), 4.87 ( s, 2H, CH 2 ), 6.95 (dd, 1H, J = 15.6, 7.8 Hz, CH), 7.05 (s, 1H, ArH), 7.45 (m, 4H, ArH), 7.80 (dd, 1H, J = 6.9, 1.8 Hz, ArH), 8.19 (t, 1H, J = 9.6, 7.8 Hz, ArH).

(10-2) : (E)-8-(2-(4-메틸피페라진-1-일)에틸아미노)-7-((나프탈렌-1-일 옥시)메틸)-8-옥소-6-옥텐산(10-2): (E) -8- (2- (4-methylpiperazin-1-yl) ethylamino) -7-((naphthalen-1-yl oxy) methyl) -8-oxo-6- Octenic acid

상기 (10-1)에서 얻은 화합물을 출발물질로 하여 상기 실시예 (1-2)와 동일한 방법으로 표제 화합물 157 mg(수율 76%)을 합성하였다.Using the compound obtained in the above (10-1) as a starting material, 157 mg (yield 76%) of the title compound were synthesized in the same manner as in Example (1-2).

1H NMR (300 MHz, MeOH-d4) δ1.24 (s, 1H, CH), 1.54 (m, 4H, CH2CH2), 2.20 (m, 4H, CH2CH2), 2.29 (m, 4H, CH2CH2), 2.51 (m, 4H, CH2CH2), 3.05 (m, 1H, CH), 3.24 (s, 3H, NCH3), 3.34 (m, 2H, CH2), 4.94 (s, 2H, CH2), 6.69 (s, 1H, CH), 7.01 (dd, 1H, J = 7.2, 1.0 Hz, ArH), 7.42 (m, 4H, ArH), 7.75 (d, 1H, J = 7.2 Hz, ArH), 8.08 (d, 1H, J = 1.7 Hz, ArH). 1 H NMR (300 MHz, MeOH-d 4 ) δ 1.24 (s, 1H, CH), 1.54 (m, 4H, CH 2 CH 2 ), 2.20 (m, 4H, CH 2 CH 2 ), 2.29 (m, 4H, CH 2 CH 2 ), 2.51 (m, 4H, CH 2 CH 2 ), 3.05 (m, 1H, CH), 3.24 (s, 3H, NCH 3 ), 3.34 (m, 2H, CH 2 ), 4.94 (s, 2H, CH 2 ), 6.69 (s, 1H, CH), 7.01 (dd, 1H, J = 7.2, 1.0 Hz, ArH), 7.42 (m, 4H, ArH), 7.75 (d, 1H, J = 7.2 Hz, ArH), 8.08 (d, 1H, J = 1.7 Hz, ArH).

(10-3) : (E)-N1-(2-(4-메틸피페라진-1-일)에틸)-2-((나프탈렌-1-일 옥시)메틸)- N8-(테트라하이드로-2H-피란-2-일옥시)-2-옥텐다이아마이드(10-3): (E) -N1- (2- (4-methylpiperazin-1-yl) ethyl) -2-((naphthalen-1-yl oxy) methyl) -N8- (tetrahydro-2H -Pyran-2-yloxy) -2-octendiamide

상기 (10-2)에서 얻은 화합물을 출발물질로 하여 상기 실시예 (4-3)과 동일한 방법으로 표제 화합물 137 mg(수율 54%)을 합성하였다.Using the compound obtained in the above (10-2) as a starting material, 137 mg (yield 54%) of the title compound were synthesized in the same manner as in Example (4-3).

1H NMR (300 MHz, MeOH-d4) δ1.54 (m, 4H, CH2CH2), 1.64 (m, 6H, CHCH2CH2), 2.11 (m, 5H, CHCH2CH2), 2.41 (m, 8H, CH2CH2CH2CH2), 3.27 (s, 3H, NCH3), 3.34 (m, 3H, CHCH2), 3.50 (m, 2H, CH2), 3.85 (t, 1H, J = 7.2, 1.8 Hz, CH), 4.96 (s, 2H, CH2), 6.70 (s, 1H, CH), 7.01 (d, 1H, J = 7.2 Hz, ArH), 7.43 (m, 4H, ArH), 7.79 (dd, 1H, J = 6.6, 1.7 Hz, ArH), 8.10 (t, 1H, J = 8.9, 7.2 Hz, ArH). 1 H NMR (300 MHz, MeOH-d 4 ) δ 1.54 (m, 4H, CH 2 CH 2 ), 1.64 (m, 6H, CHCH 2 CH 2 ), 2.11 (m, 5H, CHCH 2 CH 2 ), 2.41 (m, 8H, CH 2 CH 2 CH 2 CH 2 ), 3.27 (s, 3H, NCH 3 ), 3.34 (m, 3H, CHCH 2 ), 3.50 (m, 2H, CH 2 ), 3.85 (t, 1H , J = 7.2, 1.8 Hz, CH), 4.96 (s, 2H, CH 2 ), 6.70 (s, 1H, CH), 7.01 (d, 1H, J = 7.2 Hz, ArH), 7.43 (m, 4H, ArH), 7.79 (dd, 1H, J = 6.6, 1.7 Hz, ArH), 8.10 (t, 1H, J = 8.9, 7.2 Hz, ArH).

(10-4) : (E)-N8-하이드록시-N1-(2-(4-메틸피페라진-1-일)에틸)-2-((나프탈렌-1-일 옥시)메틸)옥텐다이아마이드(10-4): (E) -N8-hydroxy-N1- (2- (4-methylpiperazin-1-yl) ethyl) -2-((naphthalen-1-yl oxy) methyl) octendiamide

상기 (10-3)에서 얻은 화합물을 출발물질로 하여 상기 실시예 (4-4)와 동일한 방법으로 표제 화합물 118 mg(수율 76%)을 합성하였다.Using the compound obtained in the above (10-3) as a starting material, 118 mg (yield 76%) of the title compound were synthesized in the same manner as in Example (4-4).

1H NMR (300 MHz, MeOH-d4) δ1.53 (d, 2H, J = 7.7 Hz, CH2), 1.65 (d, 2H, J = 7.0 Hz, CH2), 2.10 (t, 2H, J = 14.3, 7.0 Hz, CH2), 2.39 (t, 2H, J = 14.2, 7.3 Hz, CH2), 2.72 (d, 2H, J = 8.2 Hz, CH2), 2.95 (d, 2H, J = 5.4 Hz, CH2), 3.12 (m, 6H, CH2CH2CH2), 3.32 (s, 3H, NCH3), 3.56 (t, 2H, J = 11.2, 5.6 Hz, CH2), 5.02 (s, 2H, CH2), 6.75 (t, 1H, J = 15.0, 7.2 Hz, CH), 7.05 (d, 1H, J = 7.2 Hz, ArH), 7.46 (m, 4H, ArH), 7.82 (d, 1H, J = 7.5 Hz, ArH), 8.14 (d, 1H, J = 8.5 Hz, ArH). 1 H NMR (300 MHz, MeOH-d 4 ) δ 1.53 (d, 2H, J = 7.7 Hz, CH 2 ), 1.65 (d, 2H, J = 7.0 Hz, CH 2 ), 2.10 (t, 2H, J = 14.3, 7.0 Hz, CH 2 ), 2.39 (t, 2H, J = 14.2, 7.3 Hz, CH 2 ), 2.72 (d, 2H, J = 8.2 Hz, CH 2 ), 2.95 (d, 2H, J = 5.4 Hz, CH 2 ), 3.12 (m, 6H, CH 2 CH 2 CH 2 ), 3.32 (s, 3H, NCH 3 ), 3.56 (t, 2H, J = 11.2, 5.6 Hz, CH 2 ), 5.02 ( s, 2H, CH 2 ), 6.75 (t, 1H, J = 15.0, 7.2 Hz, CH), 7.05 (d, 1H, J = 7.2 Hz, ArH), 7.46 (m, 4H, ArH), 7.82 (d , 1H, J = 7.5 Hz, ArH), 8.14 (d, 1H, J = 8.5 Hz, ArH).

실시예 11 : (E)-N1-(사이아노메틸)-N8-하이드록시-N1-메틸-2-((나프탈렌-1-일 옥시)메틸)옥텐다이아마이드Example 11 (E) -N1- (Cyanomethyl) -N8-hydroxy-N1-methyl-2-((naphthalen-1-yl oxy) methyl) octendiamide

(11-1) : (E)-8-((사이아노메틸)(사이아노메틸)아미노)-7-((나프탈렌-1-일 옥시)메틸)-8-옥소-6-옥텐산 메틸에스터(11-1): (E) -8-((cyanomethyl) (cyanomethyl) amino) -7-((naphthalen-1-yl oxy) methyl) -8-oxo-6-octenic acid methyl ester

상기 제조예 6에서 얻은 2-(나프탈렌-1-일 옥시메틸)-2-다이옥텐산 8-메틸에스터를 출발물질로 하여 상기 실시예 (1-1)과 동일한 방법으로 표제 화합물 299 mg(수율 76%)을 합성하였다.299 mg of the title compound (yield 76) in the same manner as in Example (1-1) using 2- (naphthalen-1-yl oxymethyl) -2-dioctenoic acid 8-methylester obtained in Preparation Example 6 as a starting material. %) Was synthesized.

1H NMR (200 MHz, CDCl3) δ1.35 (m, 2H, CH2), 1.60 (m, 2H, CH2), 2.31 (m, 4H, CH2CH2), 3.11 (s, 3H, NCH3), 3.67 (s, 3H, OCH3), 4.38 (s, 2H, CH2), 4.97 (s, 2H, CH2), 5.98 (s, 1H, CH), 6.85 (d, 1H, J = 4.6 Hz, ArH), 7.37 (t, 1H, J = 10.6, 5.2 Hz, ArH), 7.47 (m, 3H, ArH), 7.79 (dd, 1H, J = 6.2, 1.4 Hz, ArH), 8.06 (d, 1H, J = 4.6 Hz, ArH). 1 H NMR (200 MHz, CDCl 3 ) δ 1.35 (m, 2H, CH 2 ), 1.60 (m, 2H, CH 2 ), 2.31 (m, 4H, CH 2 CH 2 ), 3.11 (s, 3H, NCH 3 ), 3.67 (s, 3H, OCH 3 ), 4.38 (s, 2H, CH 2 ), 4.97 (s, 2H, CH 2 ), 5.98 (s, 1H, CH), 6.85 (d, 1H, J = 4.6 Hz, ArH), 7.37 (t, 1H, J = 10.6, 5.2 Hz, ArH), 7.47 (m, 3H, ArH), 7.79 (dd, 1H, J = 6.2, 1.4 Hz, ArH), 8.06 (d , 1H, J = 4.6 Hz, ArH).

(11-2) : (E)-8-((사이아노메틸)(사이아노메틸)아미노)-7-((나프탈렌-1-일 옥시)메 틸)-8-옥소-6-옥텐산(11-2): (E) -8-((cyanomethyl) (cyanomethyl) amino) -7-((naphthalen-1-yl oxy) methyl) -8-oxo-6-octenic acid

상기 (11-1)에서 얻은 화합물을 출발물질로 하여 상기 실시예 (1-2)와 동일한 방법으로 표제 화합물 250 mg(수율 84%)을 합성하였다.Using the compound obtained in the above (11-1) as a starting material, 250 mg (yield 84%) of the title compound were synthesized in the same manner as in Example (1-2).

1H NMR (300 MHz, MeOH-d4) δ1.37 (m, 2H, CH2), 1.61 (m, 2H, CH2), 2.31 (m, 4H, CH2CH2), 3.31 (s, 3H, NCH3), 4.16 (d, 2H, J = 8.5 Hz, CH2), 5.01 (s, 2H, CH2), 6.21 (m, 1H, CH), 6.98 (d, 1H, J = 7.0 Hz, ArH), 7.44 (m, 4H, ArH), 7.81 (t, 1H, J = 8.8, 2.8 Hz, ArH), 8.13 (d, 1H, J = 13.6 Hz, ArH). 1 H NMR (300 MHz, MeOH-d 4 ) δ 1.37 (m, 2H, CH 2 ), 1.61 (m, 2H, CH 2 ), 2.31 (m, 4H, CH 2 CH 2 ), 3.31 (s, 3H , NCH 3 ), 4.16 (d, 2H, J = 8.5 Hz, CH 2 ), 5.01 (s, 2H, CH 2 ), 6.21 (m, 1H, CH), 6.98 (d, 1H, J = 7.0 Hz, ArH), 7.44 (m, 4H, ArH), 7.81 (t, 1H, J = 8.8, 2.8 Hz, ArH), 8.13 (d, 1H, J = 13.6 Hz, ArH).

(11-3) : (E)-N1-(사이아노메틸)-N1-메틸-2-((나프탈렌-1-일 옥시)메틸)-N8-(테트라하이드로-2H-피란-2-일옥시)-2-옥텐다이아마이드(11-3): (E) -N1- (Cyanomethyl) -N1-methyl-2-((naphthalen-1-yl oxy) methyl) -N8- (tetrahydro-2H-pyran-2-yloxy ) -2-octenamide

상기 (11-2)에서 얻은 화합물을 출발물질로 하여 상기 실시예 (4-3)과 동일한 방법으로 표제 화합물 222 mg(수율 64%)을 합성하였다.Using the compound obtained in the above (11-2) as a starting material, 222 mg (yield 64%) of the title compound were synthesized in the same manner as in Example (4-3).

1H NMR (300 MHz, MeOH-d4) δ1.48 (m, 4H, CH2CH2), 1.71 (m, 4H, CH2CH2), 1.92 (m, 4H, CH2CH2), 2.32 (m, 4H, CH2CH2), 3.21 (s, 3H, NCH3), 3.73 (t, 1H, J = 7.2 Hz, CH2), 4.39 (s, 2H, CH2), 5.06 (s, 2H, CH2), 6.18 (m, 1H, CH), 7.20 (d, 1H, J = 7.0 Hz, ArH), 7.64 (m, 4H, ArH), 8.09 (dd, 1H, J = 14.8, 7.2 Hz, ArH), 8.13 (m, 1H, ArH). 1 H NMR (300 MHz, MeOH-d 4 ) δ 1.48 (m, 4H, CH 2 CH 2 ), 1.71 (m, 4H, CH 2 CH 2 ), 1.92 (m, 4H, CH 2 CH 2 ), 2.32 (m, 4H, CH 2 CH 2 ), 3.21 (s, 3H, NCH 3 ), 3.73 (t, 1H, J = 7.2 Hz, CH 2 ), 4.39 (s, 2H, CH 2 ), 5.06 (s, 2H, CH 2 ), 6.18 (m, 1H, CH), 7.20 (d, 1H, J = 7.0 Hz, ArH), 7.64 (m, 4H, ArH), 8.09 (dd, 1H, J = 14.8, 7.2 Hz , ArH), 8.13 (m, 1H, ArH).

(11-4) : (E)-N1-(사이아노메틸)-N8-하이드록시-N1-메틸-2-((나프탈렌-1-일 옥시)메틸)옥텐다이아마이드(11-4): (E) -N1- (Cyanomethyl) -N8-hydroxy-N1-methyl-2-((naphthalen-1-yl oxy) methyl) octendiamide

상기 (11-3)에서 얻은 화합물을 출발물질로 하여 상기 실시예 (4-4)와 동일한 방법으로 표제 화합물 170 mg(수율 75%)을 합성하였다.Using the compound obtained in the above (11-3) as a starting material, 170 mg (yield 75%) of the title compound were synthesized in the same manner as in Example (4-4).

1H NMR (300 MHz, MeOH-d4) δ1.34 (d, 2H, J = 7.7 Hz, CH2), 1.50 (d, 2H, J = 6.7 Hz, CH2), 1.89 (d, 2H, J = 7.2 Hz, CH2), 2.25 (q, 2H, J = 16.2, 7.9 Hz, CH2), 3.20 (s, 3H, NCH3), 3.91 (d, 2H, J = 7.6 Hz, CH2), 4.98 (s, 2H, CH2), 5.98 (d, 1H, J = 14.7 Hz, CH), 6.86 (d, 1H, J = 6.7 Hz, ArH), 7.35 (m, 4H, ArH), 7.56 (t, 1H, J = 9.1, 3.4 Hz, ArH), 7.98 (m, 1H, ArH). 1 H NMR (300 MHz, MeOH-d 4 ) δ 1.34 (d, 2H, J = 7.7 Hz, CH 2 ), 1.50 (d, 2H, J = 6.7 Hz, CH 2 ), 1.89 (d, 2H, J = 7.2 Hz, CH 2 ), 2.25 (q, 2H, J = 16.2, 7.9 Hz, CH 2 ), 3.20 (s, 3H, NCH 3 ), 3.91 (d, 2H, J = 7.6 Hz, CH 2 ), 4.98 (s, 2H, CH 2 ), 5.98 (d, 1H, J = 14.7 Hz, CH), 6.86 (d, 1H, J = 6.7 Hz, ArH), 7.35 (m, 4H, ArH), 7.56 (t , 1H, J = 9.1, 3.4 Hz, ArH), 7.98 (m, 1H, ArH).

실시예 12 : (E)-N8-하이드록시-N1-(2-하이드록시에틸)-N1-메틸-2-((나프탈렌-1-일 옥시)메틸)옥텐다이아마이드Example 12: (E) -N8-hydroxy-N1- (2-hydroxyethyl) -N1-methyl-2-((naphthalen-1-yl oxy) methyl) octendiamide

(12-1) : (E)-8-((2-하이드록시에틸)(메틸)아미노)-7-((나프탈렌-1-일 옥시)메틸)-8-옥소-6-옥텐산 메틸에스터(12-1): (E) -8-((2-hydroxyethyl) (methyl) amino) -7-((naphthalen-1-yl oxy) methyl) -8-oxo-6-octenic acid methyl ester

상기 제조예 6에서 얻은 2-(나프탈렌-1-일 옥시메틸)-2-다이옥텐산 8-메틸에스터를 출발물질로 하여 상기 실시예 (1-1)과 동일한 방법으로 표제 화합물 366 mg(수율 93%)을 합성하였다.Using the 2- (naphthalen-1-yl oxymethyl) -2-dioctenoic acid 8-methyl ester obtained in Preparation Example 6 as a starting material, 366 mg of the title compound was obtained in the same manner as in Example (1-1). %) Was synthesized.

1H NMR (300 MHz, CDCl3) δ1.51 (m, 2H, CH2), 1.68 (m, 2H, CH2), 2.29 (m, 4H, CH2CH2), 3.08 (s, 3H, NCH3), 3.66 (m, 4H, CH2CH2), 3.81 (S, 3H, OCH3), 4.96 (s, 2H, CH2), 6.86 (d, 1H, J = 7.0 Hz, CH), 7.26 (s, 1H, ArH), 7.44 (m, 4H, ArH), 7.77 (d, 1H, J = 7.2 Hz, ArH), 8.15 (d, 1H, J = 7.2 Hz, ArH). 1 H NMR (300 MHz, CDCl 3 ) δ 1.51 (m, 2H, CH 2 ), 1.68 (m, 2H, CH 2 ), 2.29 (m, 4H, CH 2 CH 2 ), 3.08 (s, 3H, NCH 3 ), 3.66 (m, 4H, CH 2 CH 2 ), 3.81 (S, 3H, OCH 3 ), 4.96 (s, 2H, CH 2 ), 6.86 (d, 1H, J = 7.0 Hz, CH), 7.26 (s, 1H, ArH), 7.44 (m, 4H, ArH), 7.77 (d, 1H, J = 7.2 Hz, ArH), 8.15 (d, 1H, J = 7.2 Hz, ArH).

(12-2) : (E)-8-((2-하이드록시에틸)(메틸)아미노)-7-((나프탈렌-1-일 옥시)메틸)-8-옥소-6-옥텐산(12-2): (E) -8-((2-hydroxyethyl) (methyl) amino) -7-((naphthalen-1-yl oxy) methyl) -8-oxo-6-octenic acid

상기 (12-1)에서 얻은 화합물을 출발물질로 하여 상기 실시예 (1-2)와 동일한 방법으로 표제 화합물 320 mg(수율 88%)을 합성하였다.Using the compound obtained in the above (12-1) as a starting material, 320 mg (yield 88%) of the title compound were synthesized in the same manner as in Example (1-2).

1H NMR (300 MHz, MeOH-d4) δ1.30 (m, 4H, CH2CH2), 2.08 (m, 4H, CH2CH2), 3.07 (s, 3H, NCH3), 3.09 (m, 4H, CH2CH2), 4.74 (s, 2H, CH2), 6.77 (t, 1H, J = 7.2, 1.2 Hz, CH), 6.95 (s, 1H, ArH), 7.20 (m, 4H, ArH), 7.56 (t, 1H, J = 7.0, 1.9 Hz, ArH), 7.90 (d, 1H, J = 7.2 Hz, ArH). 1 H NMR (300 MHz, MeOH-d 4 ) δ 1.30 (m, 4H, CH 2 CH 2 ), 2.08 (m, 4H, CH 2 CH 2 ), 3.07 (s, 3H, NCH 3 ), 3.09 (m , 4H, CH 2 CH 2 ), 4.74 (s, 2H, CH 2 ), 6.77 (t, 1H, J = 7.2, 1.2 Hz, CH), 6.95 (s, 1H, ArH), 7.20 (m, 4H, ArH), 7.56 (t, 1H, J = 7.0, 1.9 Hz, ArH), 7.90 (d, 1H, J = 7.2 Hz, ArH).

(12-3) : (E)-N8-하이드록시-N1-(2-하이드록시에틸)-N1-메틸-2-((나프탈렌-1-일 옥시)메틸)옥텐다이아마이드(12-3): (E) -N8-hydroxy-N1- (2-hydroxyethyl) -N1-methyl-2-((naphthalen-1-yl oxy) methyl) octendiamide

상기 (12-2)에서 얻은 화합물을 출발물질로 하여 상기 실시예 (1-3)과 동일한 방법으로 표제 화합물 262 mg(수율 90%)을 합성하였다.Using the compound obtained in the above (12-2) as a starting material, 262 mg (yield 90%) of the title compound were synthesized in the same manner as in Example (1-3).

1H NMR (300 MHz, MeOH-d4) δ1.32 (m, 4H, CH2CH2), 2.06 (m, 4H, CH2CH2), 3.08 (s, 3H, NCH3), 3.13 (m, 4H, CH2CH2), 4.92 (s, 2H, CH2), 6.78 (t, 1H, J = 7.4, 1.8 Hz, CH), 6.92 (s, 1H, ArH), 7.28 (m, 4H, ArH), 7.56 (d, 1H, J = 7.4 Hz, ArH), 7.88 (d, 1H, J = 7.4 Hz, ArH); MS (LC, 70 eV) m/z 448 (M+1), 305, 204. 1 H NMR (300 MHz, MeOH-d 4 ) δ 1.32 (m, 4H, CH 2 CH 2 ), 2.06 (m, 4H, CH 2 CH 2 ), 3.08 (s, 3H, NCH 3 ), 3.13 (m , 4H, CH 2 CH 2 ), 4.92 (s, 2H, CH 2 ), 6.78 (t, 1H, J = 7.4, 1.8 Hz, CH), 6.92 (s, 1H, ArH), 7.28 (m, 4H, ArH), 7.56 (d, 1H, J = 7.4 Hz, ArH), 7.88 (d, 1H, J = 7.4 Hz, ArH); MS (LC, 70 eV) m / z 448 (M + l), 305, 204.

실시예 13 : (E)-N8-하이드록시-N1-메틸-N1-(1-메틸피롤리딘-3-일)-2-((나프탈렌-1-일 옥시)메틸)옥텐다이아마이드Example 13: (E) -N8-hydroxy-N1-methyl-N1- (1-methylpyrrolidin-3-yl) -2-((naphthalen-1-yl oxy) methyl) octendiamide

(13-1) : (E)-8-(메틸(1-메틸피롤리딘-3-일)아미노)-7-((나프탈렌-1-일 옥시)메틸)-8-옥소-6-옥텐산 메틸에스터(13-1): (E) -8- (methyl (1-methylpyrrolidin-3-yl) amino) -7-((naphthalen-1-yl oxy) methyl) -8-oxo-6-ox Tenic Acid Methyl Ester

상기 제조예 6에서 얻은 2-(나프탈렌-1-일 옥시메틸)-2-다이옥텐산 8-메틸에스터를 출발물질로 하여 상기 실시예 (1-1)과 동일한 방법으로 표제 화합물 355 mg(수율 91%)을 합성하였다.355 mg (yield 91 of the title compound) in the same manner as in Example (1-1) using 2- (naphthalen-1-yl oxymethyl) -2-dioctenoic acid 8-methylester obtained in Preparation Example 6 as a starting material. %) Was synthesized.

1H NMR (200 MHz, CDCl3) δ1.42 (m, 4H, CH2CH2), 1.80 (m, 4H, CH2CH2), 2.20 (m, 4H, CH2CH2), 2.98 (s, 3H, NCH3), 3.61 (s, 3H, NCH3), 3.80 (s, 3H, OCH3), 4.82 (s, 2H, CH2), 4.96 (s, 2H, CH2), 5.81 (m, 1H, CH), 6.82 (m, 1H, ArH), 7.45 (m, 4H, ArH), 7.80 (m, 1H, ArH), 8.15 (m, 1H, ArH). 1 H NMR (200 MHz, CDCl 3 ) δ 1.42 (m, 4H, CH 2 CH 2 ), 1.80 (m, 4H, CH 2 CH 2 ), 2.20 (m, 4H, CH 2 CH 2 ), 2.98 (s , 3H, NCH 3 ), 3.61 (s, 3H, NCH 3 ), 3.80 (s, 3H, OCH 3 ), 4.82 (s, 2H, CH 2 ), 4.96 (s, 2H, CH 2 ), 5.81 (m , 1H, CH), 6.82 (m, 1H, ArH), 7.45 (m, 4H, ArH), 7.80 (m, 1H, ArH), 8.15 (m, 1H, ArH).

(13-2) : (E)-8-(메틸(1-메틸피롤리딘-3-일)아미노)-7-((나프탈렌-1-일 옥시)메틸)-8-옥소-6-옥텐산(13-2): (E) -8- (methyl (1-methylpyrrolidin-3-yl) amino) -7-((naphthalen-1-yl oxy) methyl) -8-oxo-6-ox Tensan

상기 (13-1)에서 얻은 화합물을 출발물질로 하여 상기 실시예 (1-2)와 동일한 방법으로 표제 화합물 320 mg(수율 86%)을 합성하였다.Using the compound obtained in the above (13-1) as a starting material, 320 mg (yield 86%) of the title compound were synthesized in the same manner as in Example (1-2).

1H NMR (300 MHz, MeOH-d4) δ1.42 (m, 4H, CH2CH2), 1.76 (m, 4H, CH2CH2), 2.22 (m, 4H, CH2CH2), 2.88 (s, 3H, NCH3), 3.58 (s, 3H, NCH3), 4.80 (s, 2H, CH2), 4.99 (s, 2H, CH2), 5.84 (m, 1H, CH), 6.80 (m, 1H, ArH), 7.44 (m, 4H, ArH), 7.80 (m, 1H, ArH), 8.12 (m, 1H, ArH). 1 H NMR (300 MHz, MeOH-d 4 ) δ 1.42 (m, 4H, CH 2 CH 2 ), 1.76 (m, 4H, CH 2 CH 2 ), 2.22 (m, 4H, CH 2 CH 2 ), 2.88 (s, 3H, NCH 3 ), 3.58 (s, 3H, NCH 3 ), 4.80 (s, 2H, CH 2 ), 4.99 (s, 2H, CH 2 ), 5.84 (m, 1H, CH), 6.80 ( m, 1H, ArH), 7.44 (m, 4H, ArH), 7.80 (m, 1H, ArH), 8.12 (m, 1H, ArH).

(13-3) : (E)-N8-하이드록시-N1-메틸-N1-(1-메틸피롤리딘-3-일)-2-((나프탈렌-1-일 옥시)메틸)옥텐다이아마이드(13-3): (E) -N8-hydroxy-N1-methyl-N1- (1-methylpyrrolidin-3-yl) -2-((naphthalen-1-yl oxy) methyl) octendiamide

상기 (13-2)에서 얻은 화합물을 출발물질로 하여 상기 실시예 (1-3)과 동일한 방법으로 표제 화합물 188 mg(수율 41%)을 합성하였다.Using the compound obtained in the above (13-2) as a starting material, 188 mg (yield 41%) of the title compound were synthesized in the same manner as in Example (1-3).

1H NMR (300 MHz, MeOH-d4) δ1.42 (m, 4H, CH2CH2), 1.80 (m, 4H, CH2CH2), 2.20 (m, 4H, CH2CH2), 2.98 (s, 3H, NCH3), 3.60 (s, 3H, NCH3), 3.80 (s, 3H, OCH2), 5.00 (s, 2H, CH2), 4.96 (s, 2H, CH2), 5.82 (m, 1H, CH), 6.84 (m, 1H, ArH), 7.44 (m, 4H, ArH), 7.78 (m, 1H, ArH), 8.14 (m, 1H, ArH). 1 H NMR (300 MHz, MeOH-d 4 ) δ 1.42 (m, 4H, CH 2 CH 2 ), 1.80 (m, 4H, CH 2 CH 2 ), 2.20 (m, 4H, CH 2 CH 2 ), 2.98 (s, 3H, NCH 3 ), 3.60 (s, 3H, NCH 3 ), 3.80 (s, 3H, OCH 2 ), 5.00 (s, 2H, CH 2 ), 4.96 (s, 2H, CH 2 ), 5.82 (m, 1H, CH), 6.84 (m, 1H, ArH), 7.44 (m, 4H, ArH), 7.78 (m, 1H, ArH), 8.14 (m, 1H, ArH).

실시예 14 : (E)-N1-(3-(다이메틸아미노)프로필)-N8-하이드록시-2-((나프탈렌-1-일 옥시)메틸)옥텐다이아마이드Example 14 (E) -N1- (3- (dimethylamino) propyl) -N8-hydroxy-2-((naphthalen-1-yl oxy) methyl) octendiamide

(14-1) : (E)-7-(3-(다이메틸아미노)프로필카바모일)-8-(나프탈렌-1-일 옥시)옥텐산 메틸에스터(14-1): (E) -7- (3- (dimethylamino) propylcarbamoyl) -8- (naphthalen-1-yl oxy) octenic acid methyl ester

상기 제조예 6에서 얻은 2-(나프탈렌-1-일 옥시메틸)-2-다이옥텐산 8-메틸에스터를 출발물질로 하여 상기 실시예 (1-1)과 동일한 방법으로 표제 화합물 467 mg(수율 73%)을 합성하였다.467 mg of the title compound (yield 73) in the same manner as in Example (1-1) using 2- (naphthalen-1-yl oxymethyl) -2-dioctenoic acid 8-methylester obtained in Preparation Example 6 as a starting material. %) Was synthesized.

1H NMR (200 MHz, CDCl3) δ1.45 (m, 2H, CH2), 1.64 (m, 4H, CH2CH2), 2.01 (s, 6H, N(CH3)2), 2.25 (m, 6H, CH2CH2CH2), 3.40 (m, 2H, CH2), 3.60 (s, 3H, OCH3), 4.96 (s, 2H, CH2), 6.81 (t, 1H, J = 15.4, 7.8 Hz, CH), 6.94 (t, 1H, J = 7.4, 6.2 Hz, ArH), 7.43 (m, 4H, ArH), 7.79 (m, 1H, ArH), 8.19 (dd, 1H, J = 6.8, 3.6 Hz, ArH). 1 H NMR (200 MHz, CDCl 3 ) δ 1.45 (m, 2H, CH 2 ), 1.64 (m, 4H, CH 2 CH 2 ), 2.01 (s, 6H, N (CH 3 ) 2 ), 2.25 (m , 6H, CH 2 CH 2 CH 2 ), 3.40 (m, 2H, CH 2 ), 3.60 (s, 3H, OCH 3 ), 4.96 (s, 2H, CH 2 ), 6.81 (t, 1H, J = 15.4 , 7.8 Hz, CH), 6.94 (t, 1H, J = 7.4, 6.2 Hz, ArH), 7.43 (m, 4H, ArH), 7.79 (m, 1H, ArH), 8.19 (dd, 1H, J = 6.8 , 3.6 Hz, ArH).

(14-2) : (E)-7-(3-(다이메틸아미노)프로필카바모일)-8-(나프탈렌-1-일 옥시)옥텐산(14-2): (E) -7- (3- (dimethylamino) propylcarbamoyl) -8- (naphthalen-1-yl oxy) octenic acid

상기 (14-1)에서 얻은 화합물을 출발물질로 하여 상기 실시예 (1-2)와 동일한 방법으로 표제 화합물 154 mg(수율 83%)을 합성하였다.Using the compound obtained in the above (14-1) as a starting material, 154 mg (yield 83%) of the title compound was synthesized in the same manner as in Example (1-2).

1H NMR (300 MHz, MeOH-d4) δ1.30 (m, 2H, CH2), 1.64 (d, 2H, J = 6.9 Hz, CH2), 1.94 (m, 2H, CH2), 2.27 (t, 2H, J = 14.2, 7.0 Hz, CH2), 2.39 (d, 2H, J = 7.2 Hz, CH2), 2.74 (s, 6H, N(CH3)2), 3.03 (t, 2H, J = 15.0, 7.2 Hz, CH2), 3.33 (m, 2H, CH2), 5.05 (s, 2H, CH2), 6.66 (s, 1H, CH), 7.03 (dd, 1H, J = 7.2, 1.2 Hz, ArH), 7.46 (m, 4H, ArH), 7.80 (d, 1H, J = 6.9 Hz, ArH), 8.14 (d, 1H, J = 7.0 Hz, ArH). 1 H NMR (300 MHz, MeOH-d 4 ) δ 1.30 (m, 2H, CH 2 ), 1.64 (d, 2H, J = 6.9 Hz, CH 2 ), 1.94 (m, 2H, CH 2 ), 2.27 ( t, 2H, J = 14.2, 7.0 Hz, CH 2 ), 2.39 (d, 2H, J = 7.2 Hz, CH 2 ), 2.74 (s, 6H, N (CH 3 ) 2 ), 3.03 (t, 2H, J = 15.0, 7.2 Hz, CH 2 ), 3.33 (m, 2H, CH 2 ), 5.05 (s, 2H, CH 2 ), 6.66 (s, 1H, CH), 7.03 (dd, 1H, J = 7.2, 1.2 Hz, ArH), 7.46 (m, 4H, ArH), 7.80 (d, 1H, J = 6.9 Hz, ArH), 8.14 (d, 1H, J = 7.0 Hz, ArH).

(14-3) : (E)-N1-(3-(다이메틸아미노)프로필)-2-((나프탈렌-1-일 옥시)메틸)-N8-(테트라하이드로-2H-피란-2-일옥시)옥텐다이아마이드(14-3): (E) -N1- (3- (dimethylamino) propyl) -2-((naphthalen-1-yl oxy) methyl) -N8- (tetrahydro-2H-pyran-2-yljade Octene amide

상기 (14-2)에서 얻은 화합물을 출발물질로 하여 상기 실시예 (4-3)과 동일한 방법으로 표제 화합물 160 mg(수율 89%)을 합성하였다.Using the compound obtained in the above (14-2) as a starting material, 160 mg (yield 89%) of the title compound were synthesized in the same manner as in Example (4-3).

1H NMR (200 MHz, MeOH-d4) δ1.59 (m, 13H, CHCH2CH2CH2CH2CH2CH2), 1.90 (s, 6H, N(CH3)2), 2.23 (m, 6H, CH2CH2CH2), 3.41 (q, 2H, J = 11.8, 6.2 Hz, CH2), 3.61 (m, 1H, CH), 3.91 (m, 1H, CH), 4.87 (s, 2H, CH2), 6.82 (d, 1H, J = 7.4 Hz, CH), 6.89 (d, 1H, J = 6.8 Hz, ArH), 7.44 (m, 4H, ArH), 7.79 (dd, 1H, J = 5.2, 3.2 Hz, ArH), 8.16 (t, 1H, J = 9.4, 6.4 Hz, ArH). 1 H NMR (200 MHz, MeOH-d 4 ) δ 1.59 (m, 13H, CHCH 2 CH 2 CH 2 CH 2 CH 2 CH 2 ), 1.90 (s, 6H, N (CH 3 ) 2 ), 2.23 (m , 6H, CH 2 CH 2 CH 2 ), 3.41 (q, 2H, J = 11.8, 6.2 Hz, CH 2 ), 3.61 (m, 1H, CH), 3.91 (m, 1H, CH), 4.87 (s, 2H, CH 2 ), 6.82 (d, 1H, J = 7.4 Hz, CH), 6.89 (d, 1H, J = 6.8 Hz, ArH), 7.44 (m, 4H, ArH), 7.79 (dd, 1H, J = 5.2, 3.2 Hz, ArH), 8.16 (t, 1H, J = 9.4, 6.4 Hz, ArH).

(14-4) : (E)-N1-(3-(다이메틸아미노)프로필)-N8-하이드록시-2-((나프탈렌-1-일 옥시)메틸)옥텐다이아마이드(14-4): (E) -N1- (3- (dimethylamino) propyl) -N8-hydroxy-2-((naphthalen-1-yl oxy) methyl) octendiamide

상기 (14-3)에서 얻은 화합물을 출발물질로 하여 상기 실시예 (4-4)와 동일 한 방법으로 표제 화합물 142 mg(수율 92%)을 합성하였다.Using the compound obtained in the above (14-3) as a starting material, 142 mg (yield 92%) of the title compound were synthesized in the same manner as in Example (4-4).

1H NMR (300 MHz, MeOH-d4) δ1.52 (t, 2H, J = 7.5, 4.1 Hz, CH2), 1.64 (d, 2H, J = 7.1 Hz, CH2), 1.92 (t, 2H, J = 13.8, 7.5 Hz, CH2), 2.10 (t, 1H, J = 14.2, 7.0 Hz, CH2), 2.37 (d, 2H, J = 7.2 Hz, CH2), 2.72 (s, 6H, N(CH3)2), 3.01 (t, 2H, J = 14.8, 7.3 Hz, CH2), 3.35 (m, 3H, CHCH2), 5.03 (s, 2H, CH2), 6.62 (t, 1H, J = 15.0, 7.5 Hz, CH), 7.02 (d, 1H, J = 7.1 Hz, ArH), 7.46 (m, 4H, ArH), 7.80 (dd, 1H, J = 6.2, 1.9 Hz, ArH), 8.14 (t, 1H, J = 8.9, 6.9 Hz, ArH); MS (LC, 70 eV) m/z 429 (M+1), 413, 301, 256, 224. 1 H NMR (300 MHz, MeOH-d 4 ) δ 1.52 (t, 2H, J = 7.5, 4.1 Hz, CH 2 ), 1.64 (d, 2H, J = 7.1 Hz, CH 2 ), 1.92 (t, 2H , J = 13.8, 7.5 Hz, CH 2 ), 2.10 (t, 1H, J = 14.2, 7.0 Hz, CH 2 ), 2.37 (d, 2H, J = 7.2 Hz, CH 2 ), 2.72 (s, 6H, N (CH 3 ) 2 ), 3.01 (t, 2H, J = 14.8, 7.3 Hz, CH 2 ), 3.35 (m, 3H, CHCH 2 ), 5.03 (s, 2H, CH 2 ), 6.62 (t, 1H , J = 15.0, 7.5 Hz, CH), 7.02 (d, 1H, J = 7.1 Hz, ArH), 7.46 (m, 4H, ArH), 7.80 (dd, 1H, J = 6.2, 1.9 Hz, ArH), 8.14 (t, 1 H, J = 8.9, 6.9 Hz, ArH); MS (LC, 70 eV) m / z 429 (M + l), 413, 301, 256, 224.

실시예 15 : (E)-N-하이드록시-8-몰포리노-7-((나프탈렌-1-일 옥시)메틸)-8-옥소옥텐다이아마이드Example 15 (E) -N-hydroxy-8-morpholino-7-((naphthalen-1-yl oxy) methyl) -8-oxooctenamide

(15-1) : (E)-8-몰포리노-7-((나프탈렌-1-일 옥시)메틸)-8-옥소옥텐산 메틸에스터(15-1): (E) -8-morpholino-7-((naphthalen-1-yl oxy) methyl) -8-oxooctenic acid methyl ester

상기 제조예 6에서 얻은 2-(나프탈렌-1-일 옥시메틸)-2-다이옥텐산 8-메틸에스터를 출발물질로 하여 상기 실시예 (1-1)과 동일한 방법으로 표제 화합물 416 mg(수율 67%)을 합성하였다.416 mg (yield 67) of the title compound in the same manner as in Example (1-1) using 2- (naphthalen-1-yl oxymethyl) -2-dioctenoic acid 8-methylester obtained in Preparation Example 6 as a starting material. %) Was synthesized.

1H NMR (200 MHz, CDCl3) δ1.45 (m, 2H, CH2), 1.63 (m, 2H, CH2), 2.25 (m, 4H, CH2CH2), 3.60 (m, 8H, CH2CH2CH2CH2), 3.71 (s, 3H, OCH3), 5.01 (s, 2H, CH2), 5.82 (t, 1H, J = 15.0, 7.8 Hz, CH), 6.84 (dd, 1H, J = 7.2, 1.2 Hz, ArH), 7.46 (m, 4H, ArH), 7.79 (m, 1H, ArH), 8.13 (dd, 1H, J = 4.0, 3.2 Hz, ArH). 1 H NMR (200 MHz, CDCl 3 ) δ 1.45 (m, 2H, CH 2 ), 1.63 (m, 2H, CH 2 ), 2.25 (m, 4H, CH 2 CH 2 ), 3.60 (m, 8H, CH 2 CH 2 CH 2 CH 2 ), 3.71 (s, 3H, OCH 3 ), 5.01 (s, 2H, CH 2 ), 5.82 (t, 1H, J = 15.0, 7.8 Hz, CH), 6.84 (dd, 1H , J = 7.2, 1.2 Hz, ArH), 7.46 (m, 4H, ArH), 7.79 (m, 1H, ArH), 8.13 (dd, 1H, J = 4.0, 3.2 Hz, ArH).

(15-2) : (E)-8-몰포리노-7-((나프탈렌-1-일 옥시)메틸)-8-옥소옥텐산(15-2): (E) -8-morpholino-7-((naphthalen-1-yl oxy) methyl) -8-oxooctenic acid

상기 (15-1)에서 얻은 화합물을 출발물질로 하여 상기 실시예 (1-2)와 동일한 방법으로 표제 화합물 85 mg(수율 89%)을 합성하였다.Using the compound obtained in the above (15-1) as a starting material, 85 mg (yield 89%) of the title compound were synthesized in the same manner as in Example (1-2).

1H NMR (300 MHz, MeOH-d4) δ1.45 (m, 2H, CH2), 1.63 (m, 2H, CH2), 2.24 (m, 4H, CH2CH2), 3.58 (m, 8H, CH2CH2CH2CH2), 5.02 (s, 2H, CH2), 5.86 (t, 1H, J = 15.2, 7.6 Hz, CH), 6.82 (dd, 1H, J = 7.4, 1.2 Hz, ArH), 7.45 (m, 4H, ArH), 7.80 (d, 1H, J = 7.4 Hz, ArH), 8.13 (t, 1H, J = 7.4, 3.4 Hz, ArH). 1 H NMR (300 MHz, MeOH-d 4 ) δ 1.45 (m, 2H, CH 2 ), 1.63 (m, 2H, CH 2 ), 2.24 (m, 4H, CH 2 CH 2 ), 3.58 (m, 8H , CH 2 CH 2 CH 2 CH 2 ), 5.02 (s, 2H, CH 2 ), 5.86 (t, 1H, J = 15.2, 7.6 Hz, CH), 6.82 (dd, 1H, J = 7.4, 1.2 Hz, ArH), 7.45 (m, 4H, ArH), 7.80 (d, 1H, J = 7.4 Hz, ArH), 8.13 (t, 1H, J = 7.4, 3.4 Hz, ArH).

(15-3) : (E)-8-몰포리노-7-((나프탈렌-1-일 옥시)메틸)-8-옥소-N-(테트라하이드로-2H-피란-2-일옥시)옥텐아마이드(15-3): (E) -8-morpholino-7-((naphthalen-1-yl oxy) methyl) -8-oxo-N- (tetrahydro-2H-pyran-2-yloxy) octenamide

상기 (15-2)에서 얻은 화합물을 출발물질로 하여 상기 실시예 (4-3)와 동일한 방법으로 표제 화합물 92 mg(수율 88%)을 합성하였다.Using the compound obtained in the above (15-2) as a starting material, 92 mg (yield 88%) of the title compound were synthesized in the same manner as in Example (4-3).

1H NMR (200 MHz, MeOH-d4) δ1.54 (m, 5H, CHCH2CH2), 1.68 (m, 4H, CH2CH2), 2.18 (m, 2H, CH2), 2.40 (m, 2H, CH2), 3.25 (m, 5H, CHCH2CH2), 3.59 (m, 6H, CH2CH2CH2), 3.99 (m, 1H, CH), 5.08 (s, 2H, CH2), 5.90 (t, 1H, J = 15.0, 7.6 Hz, CH), 6.97 (t, 1H, J = 7.0, 5.8 Hz, ArH), 7.48 (m, 4H, ArH), 7.91 (dd, 1H, J = 12.6, 3.0 Hz, ArH), 8.13 (t, 1H, J = 7.0, 4.0 Hz, ArH). 1 H NMR (200 MHz, MeOH-d 4 ) δ 1.54 (m, 5H, CHCH 2 CH 2 ), 1.68 (m, 4H, CH 2 CH 2 ), 2.18 (m, 2H, CH 2 ), 2.40 (m , 2H, CH 2 ), 3.25 (m, 5H, CHCH 2 CH 2 ), 3.59 (m, 6H, CH 2 CH 2 CH 2 ), 3.99 (m, 1H, CH), 5.08 (s, 2H, CH 2 ), 5.90 (t, 1H, J = 15.0, 7.6 Hz, CH), 6.97 (t, 1H, J = 7.0, 5.8 Hz, ArH), 7.48 (m, 4H, ArH), 7.91 (dd, 1H, J) = 12.6, 3.0 Hz, ArH), 8.13 (t, 1H, J = 7.0, 4.0 Hz, ArH).

(15-4) : (E)-N-하이드록시-8-몰포리노-7-((나프탈렌-1-일 옥시)메틸)-8-옥소옥텐다이아마이드(15-4): (E) -N-hydroxy-8-morpholino-7-((naphthalen-1-yl oxy) methyl) -8-oxooctendiamide

상기 (15-3)에서 얻은 화합물을 출발물질로 하여 상기 실시예 (4-4)와 동일한 방법으로 표제 화합물 64 mg(수율 72%)을 합성하였다.Using the compound obtained in the above (15-3) as a starting material, 64 mg (yield 72%) of the title compound were synthesized in the same manner as in Example (4-4).

1H NMR (300 MHz, MeOH-d4) δ1.53 (s, 2H, CH2), 1.68 (m, 2H, CH2), 2.13 (t, 2H, J = 14.1, 7.0 Hz, CH2), 2.35 (q, 2H, J = 14.6, 7.3 Hz, CH2), 3.33 (m, 2H, CH2), 3.53 (m, 6H, CH2CH2CH2), 5.06 (s, 2H, ArH), 5.86 (t, 1H, J = 14.9, 7.4 Hz, CH), 6.97 (t, 1H, J = 7.2, 2.4 Hz, ArH), 7.45 (m, 4H, ArH), 7.80 (dd, 1H, J = 5.6, 2.6 Hz, ArH), 8.13 (dd, 1H, J = 6.2, 2.6 Hz, ArH); MS (LC, 70 eV) m/z 413 (M+1), 380, 309, 293, 265, 236, 149, 121. 1 H NMR (300 MHz, MeOH-d 4 ) δ 1.53 (s, 2H, CH 2 ), 1.68 (m, 2H, CH 2 ), 2.13 (t, 2H, J = 14.1, 7.0 Hz, CH 2 ), 2.35 (q, 2H, J = 14.6, 7.3 Hz, CH 2 ), 3.33 (m, 2H, CH 2 ), 3.53 (m, 6H, CH 2 CH 2 CH 2 ), 5.06 (s, 2H, ArH), 5.86 (t, 1H, J = 14.9, 7.4 Hz, CH), 6.97 (t, 1H, J = 7.2, 2.4 Hz, ArH), 7.45 (m, 4H, ArH), 7.80 (dd, 1H, J = 5.6 , 2.6 Hz, ArH), 8.13 (dd, 1H, J = 6.2, 2.6 Hz, ArH); MS (LC, 70 eV) m / z 413 (M + l), 380, 309, 293, 265, 236, 149, 121.

실시예 16 : (E)-N8-하이드록시-N1-(6-(4-메틸피페라진-1-일)피리딘-3-일)-2-((나프탈렌-1-일 옥시)메틸)옥텐다이아마이드Example 16: (E) -N8-hydroxy-N1- (6- (4-methylpiperazin-1-yl) pyridin-3-yl) -2-((naphthalen-1-yl oxy) methyl) octene Damide

(16-1) : (E)-8-(6-(4-메틸피페라진-1-일)피리딘-3-일아미노)-7-((나프탈렌-1-일 옥시)메틸)-8-옥소-6-옥텐산 메틸에스터(16-1): (E) -8- (6- (4-methylpiperazin-1-yl) pyridin-3-ylamino) -7-((naphthalen-1-yl oxy) methyl) -8- Oxo-6-octenate methyl ester

상기 제조예 6에서 얻은 2-(나프탈렌-1-일 옥시메틸)-2-다이옥텐산 8-메틸에 스터를 출발물질로 하여 상기 실시예 (1-1)과 동일한 방법으로 표제 화합물 216 mg(수율 37%)을 합성하였다.216 mg of the title compound (yield) in the same manner as in Example (1-1) using 2- (naphthalen-1-yl oxymethyl) -2-dioctenoic acid 8-methyl ester obtained in Preparation Example 6 as a starting material 37%) was synthesized.

1H NMR (300 MHz, MeOH-d4) δ1.47 (m, 2H), 1.67 ( , 2H), 1.88 (m, 2H), 2.37 (t, 2H), 2.93 (s, 3H), 3.34 (m, 4H), 3.61 (s, 3H), 3.79 (br, 4H), 4.34 (t, 1H), 4.58 (d, 1H), 6.91 (d, 1H), 7.42 (m, 3H), 7.51 (d, 1H), 7.86 (m, 1H), 7.91 (m, 2H), 8.06 (s, 1H), 8.11 (m, 1H), 8.39 (s, 1H); MS (LC, 70 eV) m/z 517 (M+1). 1 H NMR (300 MHz, MeOH-d 4 ) δ 1.47 (m, 2H), 1.67 (, 2H), 1.88 (m, 2H), 2.37 (t, 2H), 2.93 (s, 3H), 3.34 (m , 4H), 3.61 (s, 3H), 3.79 (br, 4H), 4.34 (t, 1H), 4.58 (d, 1H), 6.91 (d, 1H), 7.42 (m, 3H), 7.51 (d, 1H), 7.86 (m, 1H), 7.91 (m, 2H), 8.06 (s, 1H), 8.11 (m, 1H), 8.39 (s, 1H); MS (LC, 70 eV) m / z 517 (M + l).

(16-2) : (E)-8-(6-(4-메틸피페라진-1-일)피리딘-3-일아미노)-7-((나프탈렌-1-일 옥시)메틸)-8-옥소-6-옥텐산(16-2): (E) -8- (6- (4-methylpiperazin-1-yl) pyridin-3-ylamino) -7-((naphthalen-1-yl oxy) methyl) -8- Oxo-6-octenic acid

상기 (16-1)에서 얻은 화합물을 출발물질로 하여 상기 실시예 (1-2)와 동일한 방법으로 표제 화합물 249 mg(수율 94%)을 합성하였다.Using the compound obtained in the above (16-1) as a starting material, 249 mg (yield 94%) of the title compound were synthesized in the same manner as in Example (1-2).

1H NMR (300 MHz, MeOH-d4) δ1.45 (m, 2H), 1,67 (m, 2H), 2.30 (t, 2H), 2.94 (s, 3H), 3.33 (m, 4H), 3.83 (br, 4H), 4.45 (t, 1H), 4.56 (d, 1H), 7.03 (d, 1H), 7.41 (m, 4H), 7.76 (m, 2H), 7.92 (d, 1H), 8.12 (m, 2H), 8.49 (s, 1H); MS (LC, 70 eV) m/z 503 (M+1). 1 H NMR (300 MHz, MeOH-d 4 ) δ 1.45 (m, 2H), 1,67 (m, 2H), 2.30 (t, 2H), 2.94 (s, 3H), 3.33 (m, 4H), 3.83 (br, 4H), 4.45 (t, 1H), 4.56 (d, 1H), 7.03 (d, 1H), 7.41 (m, 4H), 7.76 (m, 2H), 7.92 (d, 1H), 8.12 (m, 2 H), 8.49 (s, 1 H); MS (LC, 70 eV) m / z 503 (M + l).

(16-3) : (E)-N8-하이드록시-N1-(6-(4-메틸피페라진-1-일)피리딘-3-일)-2-((나프탈 렌-1-일 옥시)메틸)옥텐다이아마이드(16-3): (E) -N8-hydroxy-N1- (6- (4-methylpiperazin-1-yl) pyridin-3-yl) -2-((naphthalen-1-yl oxy Methyl) octenamide

상기 (16-2)에서 얻은 화합물을 출발물질로 하여 상기 실시예 (1-3)과 동일한 방법으로 표제 화합물 132 mg(수율 72%)을 합성하였다.Using the compound obtained in the above (16-2) as a starting material, 132 mg (yield 72%) of the title compound was synthesized in the same manner as in Example (1-3).

1H NMR (300 MHz, MeOH-d4) δ1.45 (m, 2H), 1,67 (m, 2H), 2.11 (t, 2H), 2.94 (s, 3H), 3.33 (m, 4H), 3.83 (br, 4H), 4.45 (t, 1H), 4.56 (d, 1H), 7.03 (d, 1H), 7.41 (m, 4H), 7.76 (m, 2H), 7.92 (d, 1H), 8.12 (m, 2H), 8.49 (s, 1H); MS (LC, 70 eV) m/z 518 (M+1). 1 H NMR (300 MHz, MeOH-d 4 ) δ 1.45 (m, 2H), 1,67 (m, 2H), 2.11 (t, 2H), 2.94 (s, 3H), 3.33 (m, 4H), 3.83 (br, 4H), 4.45 (t, 1H), 4.56 (d, 1H), 7.03 (d, 1H), 7.41 (m, 4H), 7.76 (m, 2H), 7.92 (d, 1H), 8.12 (m, 2 H), 8.49 (s, 1 H); MS (LC, 70 eV) m / z 518 (M + l).

실시예 17 : (E)-N1-(6-(2-몰포리노에틸마이노)피리딘-3일)-N8-하이드록시-2-((나프탈렌-1-일 옥시)메틸)옥텐다이아마이드Example 17: (E) -N1- (6- (2-morpholinoethylmino) pyridin-3yl) -N8-hydroxy-2-((naphthalen-1-yl oxy) methyl) octendiamide

(17-1) : (E)-7-(6-(2-몰포리노에틸마이노)피리딘-3일카바모일)-8-(나프탈렌-1-일 옥시)-6-옥텐산 메틸에스터(17-1): (E) -7- (6- (2-morpholinoethylmino) pyridin-3ylcarbamoyl) -8- (naphthalen-1-yl oxy) -6-octenic acid methyl ester

상기 제조예 6에서 얻은 2-(나프탈렌-1-일 옥시메틸)-2-다이옥텐산 8-메틸에스터를 출발물질로 하여 상기 실시예 (1-1)과 동일한 방법으로 표제 화합물 350 mg(수율 64%)을 합성하였다.350 mg (yield 64) of the title compound in the same manner as in Example (1-1) using 2- (naphthalen-1-yl oxymethyl) -2-dioctenoic acid 8-methylester obtained in Preparation Example 6 as a starting material. %) Was synthesized.

1H NMR (300 MHz, MeOH-d4) δ1.45 (m, 2H), 1.63 (m, 2H), 1.91 (m, 2H), 2.29 (t, 2H), 2.88 (m, 6H), 3.52 (t, 2H), 3.69 (s, 3H), 3.81 (m, 4H), 4.34 (t, 1H), 4.78 (d, 1H), 6.60 (d, 1H), 7.42 (m, 6H), 7.66 (d, 1H), 7.74 (m, 1H), 8.12 (m, 1H), 8.24 (s, 1H); MS (LC, 70 eV) m/z 547 (M+1). 1 H NMR (300 MHz, MeOH-d 4 ) δ 1.45 (m, 2H), 1.63 (m, 2H), 1.91 (m, 2H), 2.29 (t, 2H), 2.88 (m, 6H), 3.52 ( t, 2H), 3.69 (s, 3H), 3.81 (m, 4H), 4.34 (t, 1H), 4.78 (d, 1H), 6.60 (d, 1H), 7.42 (m, 6H), 7.66 (d , 1H), 7.74 (m, 1 H), 8.12 (m, 1 H), 8.24 (s, 1 H); MS (LC, 70 eV) m / z 547 (M + l).

(17-2) : (E)-7-(6-(2-몰포리노에틸마이노)피리딘-3일카바모일)-8-(나프탈렌-1-일 옥시)-6-옥텐산(17-2): (E) -7- (6- (2-morpholinoethylmino) pyridin-3 ylcarbamoyl) -8- (naphthalen-1-yl oxy) -6-octenic acid

상기 (17-1)에서 얻은 화합물을 출발물질로 하여 상기 실시예 (1-2)와 동일한 방법으로 표제 화합물 207 mg(수율 87%)을 합성하였다.Using the compound obtained in the above (17-1) as a starting material, 207 mg (yield 87%) of the title compound were synthesized in the same manner as in Example (1-2).

1H NMR (300 MHz, MeOH-d4) δ1.45 (m, 2H), 1.63 (m, 2H), 1.91 (m, 2H), 2.29 (t, 2H), 2.88 (m, 6H), 3.52 (t, 2H), 3.81 (m, 4H), 4.34 (t, 1H), 4.78 (d, 1H), 6.60 (d, 1H), 7.42 (m, 6H), 7.66 (d, 1H), 7.74 (m, 1H), 8.12 (m, 1H), 8.24 (s, 1H); MS (LC, 70 eV) m/z 533 (M+1). 1 H NMR (300 MHz, MeOH-d 4 ) δ 1.45 (m, 2H), 1.63 (m, 2H), 1.91 (m, 2H), 2.29 (t, 2H), 2.88 (m, 6H), 3.52 ( t, 2H), 3.81 (m, 4H), 4.34 (t, 1H), 4.78 (d, 1H), 6.60 (d, 1H), 7.42 (m, 6H), 7.66 (d, 1H), 7.74 (m , 1H), 8.12 (m, 1 H), 8.24 (s, 1 H); MS (LC, 70 eV) m / z 533 (M + l).

(17-3) : (E)-N1-(6-(2-몰포리노에틸마이노)피리딘-3일)-N8-하이드록시-2-((나프탈렌-1-일 옥시)메틸)옥텐다이아마이드(17-3): (E) -N1- (6- (2-morpholinoethylmino) pyridin-3yl) -N8-hydroxy-2-((naphthalen-1-yl oxy) methyl) octendi Amide

상기 (17-2)에서 얻은 화합물을 출발물질로 하여 상기 실시예 (1-3)과 동일한 방법으로 표제 화합물 171 mg(수율 48%)을 합성하였다.Using the compound obtained in the above (17-2) as a starting material, 171 mg (yield 48%) of the title compound was synthesized in the same manner as in Example (1-3).

1H NMR (300 MHz, DMSO-d6) δ1.39 (m, 2H), 1.54 (m, 2H), 1.78 (m, 2H), 1.96 (t, 2H), 3.35 (m, 6H), 3.69 (m, 2H), 3.85 (m, 4H), 4.38 (t,1H), 4.52 (d, 1H), 6.87 (d, 1H), 7.45 (m, 6H), 7.82 (m, 2H), 8.03 (m, 1H), 8.38 (s, 1H), 10.07 (s, 1H), 10.39 (s, 1H); MS (LC, 70 eV) m/z 548 (M+1). 1 H NMR (300 MHz, DMSO-d 6 ) δ 1.39 (m, 2H), 1.54 (m, 2H), 1.78 (m, 2H), 1.96 (t, 2H), 3.35 (m, 6H), 3.69 ( m, 2H), 3.85 (m, 4H), 4.38 (t, 1H), 4.52 (d, 1H), 6.87 (d, 1H), 7.45 (m, 6H), 7.82 (m, 2H), 8.03 (m , 1H), 8.38 (s, 1 H), 10.07 (s, 1 H), 10.39 (s, 1 H); MS (LC, 70 eV) m / z 548 (M + l).

실시예 18 : (E)-N1-(6-(다이메틸아미노)피리딘-3-일)-N8-하이드록시-2-((나프탈렌-1-일 옥시)메틸)옥텐다이아마이드Example 18: (E) -N1- (6- (dimethylamino) pyridin-3-yl) -N8-hydroxy-2-((naphthalen-1-yl oxy) methyl) octendiamide

(18-1) : (E)-7-(6-(다이메틸아미노)피리딘-3-일카바모일)-8-(나프탈렌-1-일 옥시)-6-옥텐산 메틸에스터(18-1): (E) -7- (6- (dimethylamino) pyridin-3-ylcarbamoyl) -8- (naphthalen-1-yl oxy) -6-octenic acid methyl ester

상기 제조예 6에서 얻은 2-(나프탈렌-1-일 옥시메틸)-2-다이옥텐산 8-메틸에스터를 출발물질로 하여 상기 실시예 (1-1)과 동일한 방법으로 표제 화합물 256 mg(수율 63%)을 합성하였다.256 mg of the title compound (yield 63) in the same manner as in Example (1-1) using 2- (naphthalen-1-yl oxymethyl) -2-dioctenoic acid 8-methylester obtained in Preparation Example 6 as a starting material %) Was synthesized.

1H NMR (300 MHz, CDCl3) δ1.64 (m, 4H), 2.36 (m, 4H), 3.07 (s, 6H), 3.68 (s, 3H), 5.06 (s, 2H), 6.52 (d, 1H), 6.98 (m, 2H), 7.44 (t, 1H), 7.53 (m, 3H), 7.87 (m, 2H), 8.11 (d, 1H), 8.27 (m, 1H); MS (LC, 70 eV) m/z 462 (M+1). 1 H NMR (300 MHz, CDCl 3 ) δ 1.64 (m, 4H), 2.36 (m, 4H), 3.07 (s, 6H), 3.68 (s, 3H), 5.06 (s, 2H), 6.52 (d, 1H), 6.98 (m, 2H), 7.44 (t, 1H), 7.53 (m, 3H), 7.87 (m, 2H), 8.11 (d, 1H), 8.27 (m, 1H); MS (LC, 70 eV) m / z 462 (M + l).

(18-2) : (E)-7-(6-(다이메틸아미노)피리딘-3-일카바모일)-8-(나프탈렌-1-일 옥시)-6-옥텐산(18-2): (E) -7- (6- (dimethylamino) pyridin-3-ylcarbamoyl) -8- (naphthalen-1-yl oxy) -6-octenic acid

상기 (18-1)에서 얻은 화합물을 출발물질로 하여 상기 실시예 (1-2)와 동일한 방법으로 표제 화합물 190 mg(수율 76%)을 합성하였다.Using the compound obtained in the above (18-1) as a starting material, 190 mg (yield 76%) of the title compound were synthesized in the same manner as in Example (1-2).

1H NMR (300 MHz, MeOH-d4) δ1.61 (m, 4H), 2.28 (t, 2H), 2.44 (q, 2H), 3.08 (s, 6H), 5.12 (s, 2H), 6.71 (m, 2H), 7.05 (d, 1H), 7.44 (m, 4H), 7.79 (m, 2H), 8.23 (m, 2H); MS (LC, 70 eV) m/z 448 (M+1). 1 H NMR (300 MHz, MeOH-d 4 ) δ 1.61 (m, 4H), 2.28 (t, 2H), 2.44 (q, 2H), 3.08 (s, 6H), 5.12 (s, 2H), 6.71 ( m, 2H), 7.05 (d, 1H), 7.44 (m, 4H), 7.79 (m, 2H), 8.23 (m, 2H); MS (LC, 70 eV) m / z 448 (M + l).

(18-3) : (E)-N1-(6-(다이메틸아미노)피리딘-3-일)-N8-하이드록시-2-((나프탈렌-1-일 옥시)메틸)옥텐다이아마이드(18-3): (E) -N1- (6- (dimethylamino) pyridin-3-yl) -N8-hydroxy-2-((naphthalen-1-yl oxy) methyl) octendiamide

상기 (18-2)에서 얻은 화합물을 출발물질로 하여 상기 실시예 (1-3)과 동일한 방법으로 표제 화합물 90 mg(수율 46%)을 합성하였다.Using the compound obtained in the above (18-2) as a starting material, 90 mg (yield 46%) of the title compound was synthesized in the same manner as in Example (1-3).

1H NMR (300 MHz, MeOH-d4) δ1.66 (m, 4H), 2.11 (t, 2H), 2.43 (q, 2H), 3.06 (s, 6H), 5.10 (s, 2H), 6.68 (m, 2H), 7.07 (d, 1H), 7.44 (m, 4H), 7.78 (m, 2H), 8.20 (m, 2H); MS (LC, 70 eV) m/z 463 (M+1). 1 H NMR (300 MHz, MeOH-d 4 ) δ 1.66 (m, 4H), 2.11 (t, 2H), 2.43 (q, 2H), 3.06 (s, 6H), 5.10 (s, 2H), 6.68 ( m, 2H), 7.07 (d, 1H), 7.44 (m, 4H), 7.78 (m, 2H), 8.20 (m, 2H); MS (LC, 70 eV) m / z 463 (M + l).

실시예 19 : (E)-N1-(6-(2-(다이메틸아미노)에틸아미노)피리딘-3-일)-N8-하이드록시-2-((나프탈렌-1-일 옥시)메틸)옥텐다이아마이드Example 19: (E) -N1- (6- (2- (dimethylamino) ethylamino) pyridin-3-yl) -N8-hydroxy-2-((naphthalen-1-yl oxy) methyl) octene Damide

(19-1) : (E)-8-(6-(2-(다이메틸아미노)에틸아미노)피리딘-3-일아미노)-7-((나프탈렌-1-일 옥시)메틸)-8-옥소-6-옥텐산 메틸에스터(19-1): (E) -8- (6- (2- (dimethylamino) ethylamino) pyridin-3-ylamino) -7-((naphthalen-1-yl oxy) methyl) -8- Oxo-6-octenate methyl ester

상기 제조예 6에서 얻은 2-(나프탈렌-1-일 옥시메틸)-2-다이옥텐산 8-메틸에스터를 출발물질로 하여 상기 실시예 (1-1)과 동일한 방법으로 표제 화합물 307 mg(수율 31%)을 합성하였다.307 mg of the title compound (yield 31) in the same manner as in Example (1-1) using 2- (naphthalen-1-yl oxymethyl) -2-dioctenoic acid 8-methylester obtained in Preparation Example 6 as a starting material. %) Was synthesized.

1H NMR (300 MHz, CDCl3) δ1.65 (m, 4H), 2.08 (m, 2H), 2.31 (s, 6H), 2.38 (m, 2H), 2.59 (t, 2H), 3.35 (q, 2H), 3.67 (s, 3H), 5.06 (s, 2H), 6.44 (d, 1H), 7.03 (m, 2H), 7.45 (t, 1H), 7.53 (m, 3H), 7.75 (dd, 1H), 7.85 (dd, 1H), 8.06 (d, 1H), 8.24 (m, 2H); MS (LC, 70 eV) m/z 505 (M+1). 1 H NMR (300 MHz, CDCl 3 ) δ 1.65 (m, 4H), 2.08 (m, 2H), 2.31 (s, 6H), 2.38 (m, 2H), 2.59 (t, 2H), 3.35 (q, 2H), 3.67 (s, 3H), 5.06 (s, 2H), 6.44 (d, 1H), 7.03 (m, 2H), 7.45 (t, 1H), 7.53 (m, 3H), 7.75 (dd, 1H ), 7.85 (dd, 1 H), 8.06 (d, 1 H), 8.24 (m, 2 H); MS (LC, 70 eV) m / z 505 (M + l).

(19-2) : (E)-8-(6-(2-(다이메틸아미노)에틸아미노)피리딘-3-일아미노)-7-((나프탈렌-1-일 옥시)메틸)-8-옥소-6-옥텐산(19-2): (E) -8- (6- (2- (dimethylamino) ethylamino) pyridin-3-ylamino) -7-((naphthalen-1-yl oxy) methyl) -8- Oxo-6-octenic acid

상기 (19-1)에서 얻은 화합물을 출발물질로 하여 상기 실시예 (1-2)와 동일한 방법으로 표제 화합물 226 mg(수율 75%)을 합성하였다.Using the compound obtained in the above (19-1) as a starting material, 226 mg (yield 75%) of the title compound were synthesized in the same manner as in Example (1-2).

1H NMR (300 MHz, MeOH-d4) δ1.64 (m, 4H), 2.27 (t, 2H), 2.47 (m, 2H), 2.91 (s, 6H), 3.28 (q, 2H), 3.65 (t, 2H), 5.11 (s, 2H), 6.66 (d, 1H), 6.72 (t, 1H), 7.08 (d, 1H), 7.44 (m, 4H), 7.67 (dd, 1H), 7.78 (dd, 1H), 8.15 (dd, 1H), 8.29 (m, 1H); MS (LC, 70 eV) m/z 491 (M+1). 1 H NMR (300 MHz, MeOH-d 4 ) δ 1.64 (m, 4H), 2.27 (t, 2H), 2.47 (m, 2H), 2.91 (s, 6H), 3.28 (q, 2H), 3.65 ( t, 2H), 5.11 (s, 2H), 6.66 (d, 1H), 6.72 (t, 1H), 7.08 (d, 1H), 7.44 (m, 4H), 7.67 (dd, 1H), 7.78 (dd , 1H), 8.15 (dd, 1H), 8.29 (m, 1H); MS (LC, 70 eV) m / z 491 (M + l).

(19-3) : (E)-N1-(6-(2-(다이메틸아미노)에틸아미노)피리딘-3-일)-N8-하이드록시-2-((나프탈렌-1-일 옥시)메틸)옥텐다이아마이드(19-3): (E) -N1- (6- (2- (dimethylamino) ethylamino) pyridin-3-yl) -N8-hydroxy-2-((naphthalen-1-yl oxy) methyl Octenedamide

상기 (19-2)에서 얻은 화합물을 출발물질로 하여 상기 실시예 (1-3)과 동일한 방법으로 표제 화합물 11 mg(수율 5%)을 합성하였다.Using the compound obtained in the above (19-2) as a starting material, 11 mg (yield 5%) of the title compound were synthesized in the same manner as in Example (1-3).

1H NMR (300 MHz, MeOH-d4) δ1.64 (m, 4H), 2.11 (t, 2H), 2.50 (s, 6H), 2.52 (m, 2H), 2.83 (t, 2H), 4.11 (t, 2H), 5.13 (s, 2H), 6.78 (m, 1H), 7.06 (d, 1H), 7.45 (m, 4H), 7.58 (dd, 1H), 7.78 (dd, 1H), 8.06 (dd, 1H), 8.13 (d, 1H), 8.74 (d, 1H); MS (LC, 70 eV) m/z 506 (M+1). 1 H NMR (300 MHz, MeOH-d 4 ) δ 1.64 (m, 4H), 2.11 (t, 2H), 2.50 (s, 6H), 2.52 (m, 2H), 2.83 (t, 2H), 4.11 ( t, 2H), 5.13 (s, 2H), 6.78 (m, 1H), 7.06 (d, 1H), 7.45 (m, 4H), 7.58 (dd, 1H), 7.78 (dd, 1H), 8.06 (dd , 1H), 8.13 (d, 1H), 8.74 (d, 1H); MS (LC, 70 eV) m / z 506 (M + l).

실시예 20 : (E)-N8-하이드록시-N1-(6-메톡시피리딘-3-일)-2-((나프탈렌-1-일옥시)메틸)옥텐다이아마이드Example 20 (E) -N8-hydroxy-N1- (6-methoxypyridin-3-yl) -2-((naphthalen-1-yloxy) methyl) octenamide

(20-1) : 7-(6-메톡시-피리딘-3-일카바모일)-8-(나프탈렌-1-일아미노)-6-옥텐산 메틸에스터(20-1): 7- (6-methoxy-pyridin-3-ylcarbamoyl) -8- (naphthalen-1-ylamino) -6-octenic acid methyl ester

상기 제조예 6에서 얻은 2-(나프탈렌-1-일 옥시메틸)-2-다이옥텐산 8-메틸에스터를 출발물질로 하여 상기 실시예 (1-1)과 동일한 방법으로 표제 화합물 1.67 g(수율 42%)을 합성하였다.1.67 g (yield 42) of the title compound in the same manner as in Example (1-1) using 2- (naphthalen-1-yl oxymethyl) -2-dioctenoic acid 8-methylester obtained in Preparation Example 6 as a starting material. %) Was synthesized.

1H NMR (300 MHz, CDCl3) δ1.54~1.73 (m, 4H), 2.29~2.37 (m, 4H), 3.63 (S, 3H), 3.85 (S, 3H), 6.65 (m, 1H), 6.82~6.98 (m, 2H), 7.39~7.52 (m, 4H), 7.81~7.91 (m, 3H), 8.10 (m, 1H), 9.29 (S, 1H). 1 H NMR (300 MHz, CDCl 3 ) δ 1.54-1.73 (m, 4H), 2.29-2.37 (m, 4H), 3.63 (S, 3H), 3.85 (S, 3H), 6.65 (m, 1H), 6.82-6.98 (m, 2H), 7.39-7.52 (m, 4H), 7.81-7.91 (m, 3H), 8.10 (m, 1H), 9.29 (S, 1H).

(20-2) : 7-(6-메톡시-피리딘-3-일카바모일)-8-(나프탈렌-1-일아미노)-6-옥텐산(20-2): 7- (6-methoxy-pyridin-3-ylcarbamoyl) -8- (naphthalen-1-ylamino) -6-octenic acid

상기 (20-1)에서 얻은 화합물을 출발물질로 하여 상기 실시예 (1-2)와 동일 한 방법으로 표제 화합물 670 mg(수율 40%)을 합성하였다.Using the compound obtained in (20-1) as a starting material, 670 mg (yield 40%) of the title compound were synthesized in the same manner as in Example (1-2).

(20-3) : (E)-N8-하이드록시-N1-(6-메톡시피리딘-3-일)-2-((나프탈렌-1-일옥시)메틸)옥텐다이아마이드(20-3): (E) -N8-hydroxy-N1- (6-methoxypyridin-3-yl) -2-((naphthalen-1-yloxy) methyl) octenamide

상기 (20-2)에서 얻은 화합물을 출발물질로 하여 상기 실시예 (1-3)과 동일한 방법으로 표제 화합물 482 mg(수율 69%)을 합성하였다.Using the compound obtained in the above (20-2) as a starting material, 482 mg (yield 69%) of the title compound was synthesized in the same manner as in Example (1-3).

1H NMR (300 MHz, MeOH-d4) δ1.45~1.59 (m, 4H), 1.97 (m, 2H), 2.40 (m, 2H), 3.80 (S, 3H), 4.17 (S, 2H), 6.15 (S, 1H), 6.55 (m, 2H), 6.78 (d, J = 9.0 Hz, 1H), 7.13(d, J = 7.7 Hz, 1H), 7.24~7.41 (m, 3H), 7.74 (d, J = 8.8 Hz, 1H), 7.91 (m, 1H), 8.10 (S, 1H), 8.38 (S, 1H), 9.84 (S, 1H), 10.37 (S, 1H). 1 H NMR (300 MHz, MeOH-d 4 ) δ 1.45-1.59 (m, 4H), 1.97 (m, 2H), 2.40 (m, 2H), 3.80 (S, 3H), 4.17 (S, 2H), 6.15 (S, 1H), 6.55 (m, 2H), 6.78 (d, J = 9.0 Hz, 1H), 7.13 (d, J = 7.7 Hz, 1H), 7.24-7.41 (m, 3H), 7.74 (d , J = 8.8 Hz, 1H), 7.91 (m, 1H), 8.10 (S, 1H), 8.38 (S, 1H), 9.84 (S, 1H), 10.37 (S, 1H).

시험예 1Test Example 1

HDAC 활성분석은 바이오몰사(BIOMOL) 퀀티자임 (Quantizyme)TM 분석 시스템에 기초하여 수행하였다. 분석은 두 단계로 이루어지는데, 제 1 단계는 HDAC와 기질이 반응하는 효소반응 단계로서, 이 단계에서 HDAC 저해제를 넣어 HDAC 효소활성 저해를 측정하였다. 먼저, 반응 혼합물을 제조하기 위하여 96-웰 플레이트에 반응 완충용액(25 mM Tris-HCl [pH 8.0], 137 mM NaCl, 2.7 mM KCl, 1 mM MgCl2)을 42 ㎕ 첨가하고 250 μM Fluor de LysTM 기질을 5 ㎕ 첨가하였다. 이때, HDAC 효소활성 저 해제로서 상기 실시예 1 내지 20의 화합물들을 각각 0.01, 0.1, 1, 10, 100 uM 농도로 2.5 ㎕ 첨가하였다. HDAC 효소원으로는 HeLa 세포핵 추출물(nuclear extract)을 사용하였는데, 최종 농도가 100 nM이 되도록 HeLa 세포핵 추출물(10 μM)을 0.5 ㎕ 첨가하였고 1시간 동안 효소반응을 수행하였다. 이어지는 제2 단계는 검출단계로서, 50 ㎕ 형광표지 라이신 디벨로퍼(Flour de LysTM developer)에 2 μM 트리코스타틴 A를 넣고 실온에서 15분 정도 반응시켰다. 상기 형광물질로부터 355 ㎚에서 여기 (excitation)되고 460 ㎚에서 방출되어 나오는 광을 형광측정용 기판 판독기(fluorometric plate reader로 detection)로 검출하였다. 이때, 효소활성이 높을수록 460 ㎚에서 방출되어 나오는 형광도가 커지게 되고, HDAC 저해제가 포함되지지 않은 경우와 포함된 경우에서 검출된 형광도를 비교하여 HDAC 저해효과를 측정하였다. 이때, 대조군으로는 기존에 HDAC 저해제로 알려진 SAHA(Biomol)를 동일한 농도로 사용하였다HDAC activity assays were performed based on the BIOMOL Quantizyme ™ assay system. The analysis consists of two steps. The first step is an enzyme reaction in which HDAC reacts with a substrate. In this step, the inhibition of HDAC enzyme activity was measured by adding an HDAC inhibitor. First, 42 μl of reaction buffer (25 mM Tris-HCl [pH 8.0], 137 mM NaCl, 2.7 mM KCl, 1 mM MgCl 2 ) was added to a 96-well plate to prepare a reaction mixture, and 250 μM Fluor de Lys. 5 μl TM substrate was added. At this time, 2.5 μl of the compounds of Examples 1 to 20 were added at 0.01, 0.1, 1, 10, and 100 uM concentrations as HDAC enzymatic inhibitors. HeLa nuclear extract (nuclear extract) was used as the HDAC enzyme source, 0.5 μl of HeLa nuclear extract (10 μM) was added so that the final concentration was 100 nM and the enzyme reaction was performed for 1 hour. The second step was a detection step, in which 2 μM tricostatin A was added to a 50 μl fluorescent label lysine developer (Flour de Lys ™ developer) and reacted for 15 minutes at room temperature. Light excited from the fluorescent material at 355 nm and emitted at 460 nm was detected by a fluorometric plate reader. In this case, the higher the enzyme activity, the greater the fluorescence emitted at 460 nm, and the HDAC inhibitory effect was measured by comparing the fluorescence detected in the case with and without the HDAC inhibitor. At this time, SAHA (Biomol), which is known as an HDAC inhibitor, was used as a control at the same concentration.

상기 실시예에서 제조된 대표적 화합물들의 HDAC 저해활성(IC50) 정도를 하기 표 1에 나타내었다.HDAC inhibitory activity (IC 50 ) degree of the representative compounds prepared in the above Example is shown in Table 1 below.

Figure 112005062761854-pat00014
Figure 112005062761854-pat00014

상기 표 1로부터, 본 발명에 따라 제조된 화학식 1의 알킬카바모일 나프탈렌일옥시 옥테노일 하이드록시아마이드 유도체 화합물들이 기존에 HDAC 저해제로 알려진 SAHA보다 월등히 우수한 HDAC 저해활성을 나타냄을 확인하였다.From Table 1, it was confirmed that the alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide derivative compounds prepared according to the present invention showed significantly superior HDAC inhibitory activity than SAHA known as HDAC inhibitors.

시험예 2Test Example 2

상기 실시예에서 제조된 알킬카바모일 나프탈렌일옥시 옥테노일 하이드록시아마이드 유도체 화합물들의 암세포 증식을 억제하는 효과를 SRB (Sulforhodamine B) 분석 방법으로 측정하였다. 본 실험 예에서는 자궁경부암 세포인 HeLa 세포(한국 세포주 은행, KCLB 10002)와 대장암 세포인 HCT116 세포(한국 세포주 은행, KCLB 10247)를 사용하여 암세포 증식 억제효과를 측정하였다. The effect of inhibiting cancer cell proliferation of the alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide derivative compounds prepared in the above example was measured by SRB (Sulforhodamine B) analysis method. In this experiment, HeLa cells (Korea Cell Line Bank, KCLB 10002), which are cervical cancer cells, and HCT116 cells (Korea Cell Line Bank, KCLB 10247), which were colorectal cancer cells, were used to measure cancer cell proliferation inhibitory effects.

우선, 단세포로 분리된 암세포들의 수를 세어 96-웰 플레이트의 한 웰당 1×103 내지 3×103 세포수가 되도록 세포를 분주하였다. 5 % CO2 농도와 37℃를 유지하는 세포 배양기에서 24시간 동안 암세포를 배양하였다. 암세포 배양이 완료되면 시료 화합물들을 농도별0.2, 1, 5, 25, 100 uM로 처리한 후 48시간 동안 세포 배양기에서 이를 배양하였다. 암세포 억제효과는 암세포 배양 후 세포 기질내의 단백질을 SRB로 염색한 후에 화합물을 처리하지 않은 암세포에서의 단백질 양과 화합물을 농도 별로 처리한 암세포에서의 단백질 양을 비교함으로써 측정하였다. First, the cells were separated by counting the number of cancer cells separated into single cells so that the number of cells was 1 × 10 3 to 3 × 10 3 cells per well of a 96-well plate. Cancer cells were cultured for 24 hours in a cell incubator maintained at 5% CO 2 concentration and 37 ℃. When cancer cell culture was completed, the sample compounds were treated with concentrations of 0.2, 1, 5, 25, and 100 uM, and then cultured in a cell incubator for 48 hours. The inhibitory effect of cancer cells was measured by comparing the amount of protein in cancer cells treated with compound and the concentration of protein in cancer cells treated with compound after staining protein in cell substrate with SRB after cancer cell culture.

구체적으로, 배양 완료 후, 배지를 제거하고 세포를 PBS(pH 7.4)로 3회 정도 세척하였다. 여기에 50% TCA(Trichloroacetic acid) 냉각용액 50 ㎕/웰을 첨가한 후, 4℃에서 1시간 동안 세포를 고정시켰다. 세포 고정 후, 증류수로 5회 세척하고 공기 중에서 건조시켰다. Specifically, after completion of the culture, the medium was removed and the cells were washed three times with PBS (pH 7.4). 50 μl / well of 50% TCA (Trichloroacetic acid) cooling solution was added thereto, and the cells were fixed at 4 ° C. for 1 hour. After cell fixation, the cells were washed 5 times with distilled water and dried in air.

1% 아세트산(acetic acid)으로 제조된 0.4% SRB 용액 50 ㎕를 각 웰에 첨가한 후, 실온에서 1시간 정도 염색하였다. 1시간 후에 1% 아세트산으로 5회 정도 세척한 후 공기 중에서 건조시켰다. 여기에 10 mM Tris-HCl(pH 10.5) 150 ㎕/웰을 첨가한 후, 540 ㎚에서 흡광도를 측정하였다. 시료 화합물을 처리하지 않은 세포의 흡광도를 기준으로 시료 화합물들이 농도별로 처리된 경우, 감소하는 흡광도의 정도를 측정하였고 암세포의 증식을 50% 억제하는 화합물의 농도를 IC50(μM)으로 결정하였고, 그 결과를 하기 표 2에 나타내었다. 50 [mu] l of 0.4% SRB solution prepared with 1% acetic acid was added to each well and stained for 1 hour at room temperature. After 1 hour, washed 5 times with 1% acetic acid and dried in air. 150 μl / well of 10 mM Tris-HCl (pH 10.5) was added thereto, and the absorbance was measured at 540 nm. When the sample compounds were treated by concentration based on the absorbance of the cells without the sample compound, the degree of decreasing absorbance was measured, and the concentration of the compound that inhibits the proliferation of cancer cells by 50% was determined as IC 50 (μM), The results are shown in Table 2 below.

한편, HDAC 억제제를 암세포에 처리하면 히스톤 디아세틸화(histone deacetylation)가 저해되고, 아세틸화된 히스톤의 양이 증가하게 되는데, 본 발명의 화합물 처리 후 이와 같이 증가된 아세틸-히스톤(acetyl-histone)의 양을 측정하기 위하여 웨스턴 블럿팅을 수행하였다. On the other hand, treatment of cancer cells with HDAC inhibitors inhibits histone deacetylation and increases the amount of acetylated histones. Thus, the increased acetyl-histone after treatment with the compound of the present invention. Western blotting was performed to determine the amount of.

우선, 자궁경부암 세포인 HeLa 세포를 6-웰 플레이트에 1.5×108 세포/웰의 농도로 분주한 후, 5% CO2 농도와 37℃를 유지하는 세포 배양기에서 밤새 배양하였다. HDAC 억제제로서의 효능을 스크리닝하기 위하여 각 시험 화합물들과 대조군인 SAHA를 10 μM 농도로 첨가한 후, 24시간 동안 37℃, 5% CO2 세포 배양기에서 세포를 배양하였다.First, cervical cancer cells HeLa cells were dispensed in a 6-well plate at a concentration of 1.5 × 10 8 cells / well, and then cultured overnight in a cell incubator maintained at 5% CO 2 concentration and 37 ° C. In order to screen for efficacy as HDAC inhibitors, each test compound and a control SAHA were added at a concentration of 10 μM, followed by culturing the cells in a 37 ° C., 5% CO 2 cell incubator for 24 hours.

화합물이 첨가된 상태에서 배양된 세포를 수확하고 이들로부터 핵을 분리해 내기 위하여 분획(fractionation)을 수행하였다. 저장액에서 세포를 부풀린 후 세포를 냉동시키고 해동시키는 과정을 반복하여 세포를 파괴한 후 1,300 rpm에서 5분간 원심분리하여 핵만을 분리하였다. 이로부터 얻어진 핵은 단백질 추출물(protein extract)을 얻기 위하여 용해 완충용액(20 mM HEPES(pH7.9), 25% 글리세롤, 420 mM KCl, 1.5 mM MgCl2, 0.2 mM EDTA)에 용해(lysis)시켰다. 웨스턴 블럿팅을 수행하기 위하여, SDS-PAGE를 걸어 단백질들을 크기 별로 분리한 후 막에 전이시켰고, 이 후의 과정은 통상적인 웨스턴 블럿팅 방법에 따라 수행하였다. 항-아세틸 히스톤 H4 항체(Anti-acetyl histone H4 antibody, Upstate, USA)를 사용하여 아세틸화된 히스톤 H4의 양을 측정하였다. SAHA 및 시험 화합물의 처리시 증가된 히스톤 H4의 양을 비교하여 본 발명에 따른 화합물의 HDAC 저해제로서의 효능을 평가하였고, 그 결과를 하기 표 2에 나타내었다.Cells cultured with the compound added were harvested and fractionation was performed to separate the nuclei from them. After inflating the cells in the stock solution, the cells were repeatedly frozen and thawed to destroy the cells, followed by centrifugation at 1,300 rpm for 5 minutes to separate only the nuclei. The resulting nuclei were lysed in lysis buffer (20 mM HEPES (pH7.9), 25% glycerol, 420 mM KCl, 1.5 mM MgCl 2 , 0.2 mM EDTA) to obtain a protein extract. . In order to perform western blotting, the proteins were separated by size by SDS-PAGE and transferred to the membrane, and the subsequent procedure was performed according to a conventional western blotting method. Anti-acetyl histone H4 antibody (Upstate, USA) was used to measure the amount of acetylated histone H4. The efficacy of the compounds according to the invention as HDAC inhibitors was evaluated by comparing the amount of increased histone H4 upon treatment of SAHA and test compounds, the results are shown in Table 2 below.

Figure 112005062761854-pat00015
Figure 112005062761854-pat00015

상기 표 2로부터, 본 발명에 따른 화학식 1의 알킬카바모일 나프탈렌일옥시 옥테노일 하이드록시아마이드 유도체가 암세포에서 매우 우수한 HDAC 저해활성과 암세포 증식 억제 효과를 나타냄을 알 수 있다. From Table 2, it can be seen that the alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide derivative of Formula 1 according to the present invention shows very good HDAC inhibitory activity and cancer cell proliferation inhibitory effect in cancer cells.

상기에서 살펴본 바와 같이 본 발명의 화학식 1의 알킬카바모일 나프탈렌일옥시 옥테노일 하이드록시아마이드 유도체는 히스톤 디아세틸라제의 효소활성을 효과적으로 저해하여 종양세포의 말기 분화를 선택적으로 유도하고 증식을 억제하므 로, 항암제 또는 히스톤 디아세틸라제의 효소활성 저해제로서 유용하게 사용될 수 있다.As described above, the alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide derivative of Formula 1 effectively inhibits the enzymatic activity of histone deacetylase to selectively induce terminal differentiation and inhibit proliferation of tumor cells. It can be usefully used as an enzyme activity inhibitor of anticancer agent or histone deacetylase.

Claims (15)

하기 화학식 1의 알킬카바모일 나프탈렌일옥시 옥테노일 하이드록시아마이드 유도체 화합물:Alkyl carbamoyl naphthalenyloxy octenoyl hydroxyamide derivative compound of Formula 1 <화학식 1><Formula 1>
Figure 112005062761854-pat00016
Figure 112005062761854-pat00016
 상기 식에서, Where R1은 각각 독립적으로 C1-3알킬, 하이드록시C1-2알킬, 할로C1-2알킬, 피페리디닐, 몰포리닐, 사이아노메틸, 피페라지닐, 다이C1-2알킬아미노C1-2알킬, 다이C1-2알킬아미노C1-2알킬, 피페리디닐C1-2알킬, 몰포리노C1-2알킬, 피페라지노C1-2알킬, 피롤리디닐, C1-2알킬피롤리디닐로 구성된 군으로부터 선택된 하나 이상의 치환체로 치환되거나 치환되지 않은 C1-2알킬이고, Each R 1 is independently C 1-3 alkyl, hydroxyC 1-2 alkyl, haloC 1-2 alkyl, piperidinyl, morpholinyl, cyanomethyl, piperazinyl, diC 1-2 alkylamino C 1-2 alkyl, diC 1-2 alkylaminoC 1-2 alkyl, piperidinylC 1-2 alkyl, morpholinoC 1-2 alkyl, piperazinoC 1-2 alkyl, pyrrolidinyl, C and C 1-2 alkyl optionally substituted with one or more substituents selected from the group consisting of 1-2-alkyl-pyrrolidinyl, R2는 수소 또는 메틸이다.R 2 is hydrogen or methyl. 제 1항에 있어서,The method of claim 1, 하기 화합물들로 구성된 군으로부터 선택되는 것을 특징으로 하는 화합물:A compound selected from the group consisting of: (E)-N8-하이드록시-N1,N1-다이메틸-2-((나프탈렌-1-일 옥시)메틸)옥텐다이아마이드,(E) -N8-hydroxy-N1, N1-dimethyl-2-((naphthalen-1-yl oxy) methyl) octendiamide, (E)-N1-(2-(다이메틸아미노)에틸)-N8-하이드록시-2-((나프탈렌-1-일 옥시)메틸)옥텐다이아마이드,(E) -N1- (2- (dimethylamino) ethyl) -N8-hydroxy-2-((naphthalen-1-yl oxy) methyl) octendiamide, (E)-N1-(2-(다이메틸아미노)에틸)-N8-하이드록시-N1-메틸-2-((나프탈렌-1-일 옥시)메틸)옥텐다이아마이드,(E) -N1- (2- (dimethylamino) ethyl) -N8-hydroxy-N1-methyl-2-((naphthalen-1-yl oxy) methyl) octendiamide, (E)-N1-(2-(다이에틸아미노)에틸)-N8-하이드록시-2-((나프탈렌-1-일 옥시)메틸)옥텐다이아마이드,(E) -N1- (2- (diethylamino) ethyl) -N8-hydroxy-2-((naphthalen-1-yl oxy) methyl) octendiamide, (E)-N1-(2-(다이에틸아미노)에틸)-N8-하이드록시-N1-메틸-2-((나프탈렌-1-일 옥시)메틸)옥텐다이아마이드,(E) -N1- (2- (diethylamino) ethyl) -N8-hydroxy-N1-methyl-2-((naphthalen-1-yl oxy) methyl) octendiamide, (E)-N8-하이드록시-2-((나프탈렌-1-일 옥시)메틸)-N1-(2-(피롤리딘-1-일)에틸)옥텐다이아마이드,(E) -N8-hydroxy-2-((naphthalen-1-yl oxy) methyl) -N1- (2- (pyrrolidin-1-yl) ethyl) octendiamide, (E)-N8-하이드록시-2-((나프탈렌-1-일 옥시)메틸)-N1-(2-(피페리딘-1-일)에틸)옥텐다이아마이드,(E) -N8-hydroxy-2-((naphthalen-1-yl oxy) methyl) -N1- (2- (piperidin-1-yl) ethyl) octendiamide, (E)-N8-하이드록시-N1-(2-몰포리노에틸)-2-((나프탈렌-1-일 옥시)메틸)옥텐다이아마이드,(E) -N8-hydroxy-N1- (2-morpholinoethyl) -2-((naphthalen-1-yl oxy) methyl) octenamide, (E)-N-하이드록시-8-(4-메틸피페라진-1-일)-7-((나프탈렌-1-일 옥시)메틸)-8-옥소옥텐아마이드,(E) -N-hydroxy-8- (4-methylpiperazin-1-yl) -7-((naphthalen-1-yl oxy) methyl) -8-oxooctenamide, (E)-N8-하이드록시-N1-(2-(4-메틸피페라진-1-일)에틸)-2-((나프탈렌-1-일 옥시)메틸)옥텐다이아마이드,(E) -N8-hydroxy-N1- (2- (4-methylpiperazin-1-yl) ethyl) -2-((naphthalen-1-yl oxy) methyl) octendiamide, (E)-N1-(사이아노메틸)-N8-하이드록시-N1-메틸-2-((나프탈렌-1-일 옥시)메틸)옥텐다이아마이드,(E) -N1- (cyanomethyl) -N8-hydroxy-N1-methyl-2-((naphthalen-1-yl oxy) methyl) octenamide, (E)-N8-하이드록시-N1-(2-하이드록시에틸)-N1-메틸-2-((나프탈렌-1-일 옥시)메틸)옥텐다이아마이드,(E) -N8-hydroxy-N1- (2-hydroxyethyl) -N1-methyl-2-((naphthalen-1-yl oxy) methyl) octenamide, (E)-N8-하이드록시-N1-메틸-N1-(1-메틸피롤리딘-3-일)-2-((나프탈렌-1-일 옥시)메틸)옥텐다이아마이드,(E) -N8-hydroxy-N1-methyl-N1- (1-methylpyrrolidin-3-yl) -2-((naphthalen-1-yl oxy) methyl) octendiamide, (E)-N1-(3-(다이메틸아미노)프로필)-N8-하이드록시-2-((나프탈렌-1-일 옥시)메틸)옥텐다이아마이드, 및(E) -N1- (3- (dimethylamino) propyl) -N8-hydroxy-2-((naphthalen-1-yl oxy) methyl) octendiamide, and (E)-N-하이드록시-8-몰포리노-7-((나프탈렌-1-일 옥시)메틸)-8-옥소옥텐다이아마이드 유도체(E) -N-hydroxy-8-morpholino-7-((naphthalen-1-yl oxy) methyl) -8-oxooctenamideamide derivative 1) 하기 화학식 2의 화합물을 황산 처리한 후, 피리디늄 클로로클로메이트(PCC)와 반응시켜 하기 화학식 3의 화합물을 제조하는 단계;1) treating the compound of Formula 2 with sulfuric acid and then reacting with pyridinium chlorochloromate (PCC) to produce a compound of Formula 3; 2) 화학식 3의 화합물을 1,4-다이아자비사이클로[2,2,2]옥탄 (DABCO) 존재하에서 알킬아크릴레이트와 베일리스 힐만 (Baylis Hillman) 반응을 수행하여 하기 화학식 4의 화합물을 제조하는 단계;2) preparing a compound of formula 4 by performing a Baylis Hillman reaction with an alkyl acrylate in the presence of 1,4-diazabicyclo [2,2,2] octane (DABCO) ; 3) 화학식 4의 화합물을 삼브롬화인(PBr3)과 반응시켜 하기 화학식 5의 화합물을 제조하는 단계;3) reacting a compound of Formula 4 with phosphorus tribromide (PBr 3 ) to prepare a compound of Formula 5; 4) 화학식 5의 화합물을 1-나프탈렌알콜과 반응시켜 하기 화학식 6의 화합물 을 제조하는 단계;4) reacting the compound of Formula 5 with 1-naphthalene alcohol to prepare a compound of Formula 6; 5) 화학식 6의 화합물을 무기산 또는 유기산으로 가수분해하여 하기 화학식 7의 화합물을 제조하는 단계;5) preparing a compound of formula 7 by hydrolyzing the compound of formula 6 with an inorganic acid or an organic acid; 6) 화학식 7의 화합물을 알킬아민(R1R2NH)과 아실화 반응시켜 하기 화학식 8의 화합물을 제조하는 단계;6) acylating the compound of Formula 7 with an alkylamine (R 1 R 2 NH) to prepare a compound of Formula 8; 7) 화학식 8의 화합물을 무기염기 처리에 의해 가수분해시켜 하기 화학식 9의 화합물을 제조하는 단계; 및7) hydrolyzing the compound of formula 8 by inorganic base treatment to prepare a compound of formula 9; And 8) 화학식 9의 화합물을 테트라하이드로피란일옥시아민(NH2OTHP)과 아실화 반응시켜 화학식 10의 화합물을 제조하는 단계; 및8) acylating a compound of Formula 9 with tetrahydropyranyloxyamine (NH 2 OTHP) to prepare a compound of Formula 10; And 9) 화학식 10을 트라이플루오로아세트산(TFA)과 반응시켜 테트라하이드로피란일기를 제거하는 탈보호기 반응을 수행하는 단계를 포함하는, 화학식 1의 알킬카바모일 나프탈렌일옥시 옥테노일 하이드록시아마이드 유도체의 제조방법:9) Preparation of alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide derivatives comprising the step of reacting formula 10 with trifluoroacetic acid (TFA) to perform a deprotection group reaction to remove tetrahydropyranyl groups Way: <화학식 1><Formula 1>
Figure 112005062761854-pat00017
Figure 112005062761854-pat00017
 <화학식 2><Formula 2>
Figure 112005062761854-pat00018
Figure 112005062761854-pat00018
 <화학식 3><Formula 3>
Figure 112005062761854-pat00019
Figure 112005062761854-pat00019
 <화학식 4><Formula 4>
Figure 112005062761854-pat00020
Figure 112005062761854-pat00020
 <화학식 5><Formula 5>
Figure 112005062761854-pat00021
Figure 112005062761854-pat00021
 <화학식 6><Formula 6>
Figure 112005062761854-pat00022
Figure 112005062761854-pat00022
 <화학식 7><Formula 7>
Figure 112005062761854-pat00023
Figure 112005062761854-pat00023
 <화학식 8><Formula 8>
Figure 112005062761854-pat00024
Figure 112005062761854-pat00024
 <화학식 9><Formula 9>
Figure 112005062761854-pat00025
Figure 112005062761854-pat00025
 <화학식 10><Formula 10>
Figure 112005062761854-pat00026
Figure 112005062761854-pat00026
 상기 식에서, R1과 R2는 제1항에서 정의한 바와 같고, Y는 C1-4 알킬기이다.Wherein R 1 and R 2 are as defined in claim 1 and Y is a C 1-4 alkyl group. 제 3항에 있어서, The method of claim 3, 단계 2)의 알킬아크릴레이트가 에틸아크릴레이트, 아이소뷰틸아크릴레이트 및 t-뷰틸아크릴레이트로 구성된 군으로부터 선택되는 것을 특징으로 하는 제조방법.The alkyl acrylate of step 2) is selected from the group consisting of ethyl acrylate, isobutyl acrylate and t-butyl acrylate. 제 3항에 있어서, The method of claim 3, 단계 4)의 반응이 탄산칼륨, 중탄산나트륨 또는 탄산나트륨 존재하에 아세톤 또는 아세토나이트릴 중에서 이루어지는 것을 특징으로 하는 제조방법.A process according to claim 4, wherein the reaction of step 4) takes place in acetone or acetonitrile in the presence of potassium carbonate, sodium bicarbonate or sodium carbonate. 제 3항에 있어서, The method of claim 3, 단계 5)의 가수분해 반응이 다이클로로메탄, 테트라하이드로퓨란 또는 N,N-다이메틸폼아마이드 중에서 이루어지는 것을 특징으로 하는 제조방법.The hydrolysis reaction of step 5) is carried out in dichloromethane, tetrahydrofuran or N, N -dimethylformamide. 제 3항에 있어서, The method of claim 3, 단계 5)의 무기산이 염산, 황산, 인산 등으로 구성된 군으로부터 선택되고, 유기산이 트라이플루오로아세트산(TFA)인 것을 특징으로 하는 제조방법.The inorganic acid of step 5) is selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid and the like, and the organic acid is trifluoroacetic acid (TFA). 제 3항에 있어서, The method of claim 3, 단계 6)의 아실화 반응이 비양자성 용매 중에서 아실화제를 촉매로 사용하여 이루어지는 것을 특징으로 하는 제조방법.And the acylation reaction of step 6) is carried out using an acylating agent as a catalyst in an aprotic solvent. 제 8항에 있어서, The method of claim 8, 비양자성 용매가 다이메틸폼아마이드, 다이메틸설폭사이드, 테트라하이드로퓨란 및 다이클로로메탄으로 구성된 군으로부터 선택되고, 아실화제가 N-메탄설포닐옥시-6-트라이플루오로 벤조트라이아졸(FMS), N-하이드록시-6-트라이플루오로 벤조트라이아졸(FOBT), 1-(3-다이에틸아미노프로필)-3-에틸카보다이이미드 염산염 (EDC.HCl) 으로 구성된 군으로부터 선택되는 것을 특징으로 하는 제조방법.The aprotic solvent is selected from the group consisting of dimethylformamide, dimethylsulfoxide, tetrahydrofuran and dichloromethane, the acylating agent is N-methanesulfonyloxy-6-trifluoro benzotriazole (FMS), N-hydroxy-6-trifluoro benzotriazole (FOBT), 1- (3-diethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC.HCl), characterized in that Manufacturing method. 제 3항에 있어서, The method of claim 3, 단계 7)의 가수분해 반응이 수용성 알콜 또는 테트라하이드로퓨란 중에서 이루어지는 것을 특징으로 하는 제조방법.The hydrolysis reaction of step 7) is carried out in a water-soluble alcohol or tetrahydrofuran. 제 3항에 있어서, The method of claim 3, 단계 7)의 무기염기가 수산화나트륨 또는 수산화리튬인 것을 특징으로 하는 제조방법.The inorganic base of step 7) characterized in that the sodium hydroxide or lithium hydroxide. 제 3항에 있어서, The method of claim 3, 단계 8)의 아실화 반응이 N-하이드록시-6-트라이플루오로 벤조트라이아졸(FOBT)과 1-(3-다이에틸아미노프로필)-3-에틸카보다이이미드염산염(EDC.HCl) 존재하에서 수행되는 것을 특징으로 하는 방법.Acylation reaction of step 8) in the presence of N-hydroxy-6-trifluoro benzotriazole (FOBT) and 1- (3-diethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC.HCl) Characterized in that it is carried out. 제 3항에 있어서, The method of claim 3, 단계 10)의 탈보호기 반응이 메탄올, 에탄올, 테트라하이드로퓨란 또는 다이클로로메탄 중에서 수행되는 것을 특징으로 하는 방법.The deprotection group reaction of step 10) is carried out in methanol, ethanol, tetrahydrofuran or dichloromethane. 제 1항의 화학식 1의 알킬카바모일 나프탈렌일옥시 옥테노일 하이드록시아마이드 유도체 또는 그의 약학적으로 허용가능한 염을 유효성분으로 하는 항암제용 약학 조성물.The pharmaceutical composition for an anticancer agent comprising the alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide derivative of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 삭제delete
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KR100814092B1 (en) 2006-11-03 2008-03-14 한국화학연구원 Alkyl carbamoyl naphthalenyloxy octenoyl hydroxyamide derivatives having histone deacetylase inhibitory activity, preparation method thereof, and pharmaceutical composition for anticancer agent comprising the same as an active ingredient
KR101388596B1 (en) * 2008-12-11 2014-04-24 대한민국 Histone deacetylase inhibitor that reactivates hiv-1 proviruses from latently hiv-infected cells
WO2018230829A1 (en) * 2017-06-15 2018-12-20 크리스탈지노믹스(주) Pharmaceutically acceptable salt of alkylcarbamoyl naphthalenyloxy octenoylhydroxyamide or of derivative thereof and method for preparing same
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