KR100820039B1 - Alkylamino naphthalenyloxymethyl propenyl hydroxybenzamide derivatives having inhibitory activity against histone deacetylase, method for the preparation thereof, and anticancer composition comprising the same - Google Patents

Alkylamino naphthalenyloxymethyl propenyl hydroxybenzamide derivatives having inhibitory activity against histone deacetylase, method for the preparation thereof, and anticancer composition comprising the same Download PDF

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KR100820039B1
KR100820039B1 KR1020060109436A KR20060109436A KR100820039B1 KR 100820039 B1 KR100820039 B1 KR 100820039B1 KR 1020060109436 A KR1020060109436 A KR 1020060109436A KR 20060109436 A KR20060109436 A KR 20060109436A KR 100820039 B1 KR100820039 B1 KR 100820039B1
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methyl
yloxy
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naphthalen
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이철해
정희정
김재학
정원장
조중명
노성구
현영란
이철순
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한국화학연구원
크리스탈지노믹스(주)
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Priority to EP07833799.5A priority patent/EP2089354A4/en
Priority to EP15153308.0A priority patent/EP2913322A3/en
Priority to PCT/KR2007/005491 priority patent/WO2008054154A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/22—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
    • C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
    • C07C217/16—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring not being further substituted
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/21—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to an acyclic carbon atom of an unsaturated carbon skeleton containing rings other than six-membered aromatic rings

Abstract

An alkylamino naphthalenyloxymethyl propenyl hydroxybenzamide derivative is provided to obtain a pharmaceutical composition having an anti-cancer effect by inhibiting activity of histone deacetylase, inducing differentiation of tumor cells and inhibiting growth of tumor cells. An alkylamino naphthalenyloxymethyl propenyl hydroxybenzamide derivative is represented by the following formula 1. In formula 1, R1 is H or a C1-C3 alkyl; R2 is a C1-C6 alkyl non-substituted or substituted with a substituent selected from the group consisting of di-C1-C3 alkylamino, C1-C4 alkylpyrrolidinyl, morpholinyl, imidazolyl, methoxy and thiophenyl, a C1-C6 alkyl substituted with hydroxyphenyl, di-C1-C3 alkylaminophenyl, methoxyphenyl or trifluoromethoxyphenyl, pyrrolidine non-substituted or substituted with C1-C3 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl C1-C3 alkyl, benzyl or C3-C8 cycloalkylcarbonyl, piperidine substituted with a C3-C8 cycloalkyl or C1-C6 alkyl, or a C3-C8 cycloalkyl, with the proviso that when R1 is H or CH3, R2 is not non-substituted C1-C2 alkyl and morpholinyl-substituted C1-C2 alkyl.

Description

히스톤 디아세틸라제 저해활성을 갖는 알킬아미노 나프탈렌일옥시메틸 프로페닐 하이드록시벤즈아마이드 유도체, 이의 제조방법 및 이를 유효성분으로 하는 항암제용 약학 조성물{ALKYLAMINO NAPHTHALENYLOXYMETHYL PROPENYL HYDROXYBENZAMIDE DERIVATIVES HAVING INHIBITORY ACTIVITY AGAINST HISTONE DEACETYLASE, METHOD FOR THE PREPARATION THEREOF, AND ANTICANCER COMPOSITION COMPRISING THE SAME}Alkylamino naphthalenyloxymethyl propenyl hydroxybenzamide derivatives having histone deacetylase inhibitory activity, preparation method thereof, and pharmaceutical composition for anticancer agent using the same as an active ingredient TECHNICAL FIELD THE PREPARATION THEREOF, AND ANTICANCER COMPOSITION COMPRISING THE SAME}

본 발명은 히스톤 디아세틸라제의 효소활성을 효과적으로 억제하는 신규한 알킬아미노 나프탈렌일옥시메틸 프로페닐 하이드록시벤즈아마이드 유도체 또는 이의 약학적으로 허용가능한 염, 이의 제조방법 및 이를 유효성분으로 하는 항암제용 약학 조성물에 관한 것이다.The present invention is a novel alkylamino naphthalenyloxymethyl propenyl hydroxybenzamide derivative or pharmaceutically acceptable salt thereof, which effectively inhibits the enzymatic activity of histone deacetylase, a preparation method thereof, and a pharmaceutical for anticancer drug using the same To a composition.

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 아세틸전 이효소(acetyltransferases) (HATs) 및 히스톤 디아세틸라제(histone deacetylase)(HDACs)에 의해 안정하게 조절된다. 상기 효소들은 히스톤의 아미노 말단에 존재하는 라이신 잔기(H4의 경우 4개)의 양전하를 아세틸화로 중화시켜 전사활성을 유도하거나, 탈아세틸화시켜 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 or the cell division cycle, and is associated with histone acetyltransferases (HATs) and histone deacetylases (histones). deacetylases (HDACs). These enzymes neutralize the positive charges of lysine residues (four for H4) at the amino terminus of histones by acetylation to induce transcriptional activity, or deacetylate them to give charge again to inhibit transcription, thereby acetylating the levels of histones. Induction of equilibrium is known 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(문헌[Lin RJ, et. al. Oncogene 20: 7204 (2001)]; 및 [Zelent A, et. al. Oncogene 20: 7186 (2001)]참조). 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 (see Lin RJ, et. Al. Oncogene 20: 7204 (2001); and Zeent 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(문헌[Munster PN, et. al. Cancer research 61: 8492 (2001)]; 및 [Han JW, et. al. Cancer research 60: 6068 (2000)]참조).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. (See Munster PN, et. Al. Cancer research 61: 8492 (2001); and 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(문헌[Yoshida M, et. al. Cancer Research 47: 3688 (1987)]; [Yoshida M & Beppu T Exp. Cell Res. 177: 122 (1988)]; 및 [Yoshida M, et. al. J of Biol. Chem. 265: 17174 (1990)]참조). 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); and 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, 알킬아미노 나프탈렌일옥시메틸 프로펜일 하이드록시벤즈아마이드 유도체가 히스톤 디아세틸라제 활성을 효과적으로 저해하여 매우 강력한 세포증식 억제력을 갖는다는 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 find an HDAC inhibitor compound, and found that the alkylamino naphthalenyloxymethyl propenyl hydroxybenzamide derivative effectively inhibits histone deacetylase activity and thus has a very strong cell proliferation inhibitory effect. The present invention has been completed by discovering and confirming that they can be usefully used for the treatment of cancer.

따라서, 본 발명의 목적은 히스톤 디아세틸라제의 효소활성을 효과적으로 저해함으로써 종양세포의 증식을 억제하는, 신규한 알킬아미노 나프탈렌일옥시메틸 프로페닐 하이드록시벤즈아마이드 유도체 또는 이의 약학적으로 허용가능한 염, 및 이의 제조방법을 제공하는 것이다. Accordingly, an object of the present invention is a novel alkylaminonaphthalenyloxymethyl propenyl hydroxybenzamide derivative which inhibits the proliferation of tumor cells by effectively inhibiting the enzymatic activity of histone deacetylase. Or a pharmaceutically acceptable salt thereof, and a method for preparing the same.

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 알킬아미노 나프탈렌일옥시메틸 프로페닐 하이드록시벤즈아마이드 유도체 및 그의 약학적으로 허용 가능한 염을 제공한다:In order to achieve the above object, the present invention provides an alkylamino naphthalenyloxymethyl propenyl hydroxybenzamide derivative of the formula (1) and a pharmaceutically acceptable salt thereof:

<화학식 1><Formula 1>

Figure 112006081424267-pat00002
Figure 112006081424267-pat00002

상기 식에서, Where

R1은 수소 또는 C1-3 알킬이고;R 1 is hydrogen or C 1-3 alkyl;

R2는 다이 C1-3 알킬 아미노, C1-3 알킬 피롤리디닐, 몰포리닐, 이미다졸일, 메톡시, 및 티오페닐로 이루어진 군으로부터 선택된 치환기로 치환되거나 치환되지 않은 C1-6 알킬; 하이드록시페닐, 다이 C1-3 알킬 아미노 페닐, 메톡시페닐 또는 트리플루오로메톡시페닐로 치환된 C1-6 알킬; C1-3 알킬, C3-8 사이클로알킬, C3-8 사이클로알킬C1-3 알킬, 벤질 또는 C3-8사이클로알킬카보닐로 치환되거나 치환되지 않은 피롤리딘; C3-8 사이클로알킬 또는 C1-6 알킬로 치환된 피페리딘; 또는 C3-8 사이클로알킬이다. R 2 is C 1-6 unsubstituted or substituted with a substituent selected from the group consisting of di C 1-3 alkyl amino, C 1-3 alkyl pyrrolidinyl, morpholinyl, imidazolyl, methoxy, and thiophenyl Alkyl; C 1-6 alkyl substituted with hydroxyphenyl, di C 1-3 alkyl amino phenyl, methoxyphenyl or trifluoromethoxyphenyl; Pyrrolidine unsubstituted or substituted with C 1-3 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkylC 1-3 alkyl, benzyl or C 3-8 cycloalkylcarbonyl; Piperidine substituted with C 3-8 cycloalkyl or C 1-6 alkyl; Or C 3-8 cycloalkyl.

또한, 본 발명은 상기 화학식 1의 알킬아미노 나프탈렌일옥시메틸 프로페닐 하이드록시벤즈아마이드 유도체의 제조방법을 제공한다.In addition, the present invention provides a method for preparing alkylamino naphthalenyloxymethyl propenyl hydroxybenzamide derivative of Chemical Formula 1 .

또한, 본 발명은 상기 화학식 1의 알킬아미노 나프탈렌일옥시메틸 프로페닐 하이드록시벤즈아마이드 또는 그의 약학적으로 허용가능한 염을 유효성분으로 하는 항암제용 약학 조성물을 제공한다.The present invention also provides a pharmaceutical composition for the anti-cancer agent for the alkyl amino naphthalene-yloxymethyl-propenyl-hydroxy-benzamide or a pharmaceutically acceptable salt thereof of formula (I) as an active ingredient.

아울러, 본 발명은 상기 화학식 1의 알킬아미노 나프탈렌일옥시메틸 프로페닐 하이드록시벤즈아마이드 또는 그의 약학적으로 허용가능한 염을 유효성분으로 하는 히스톤 디아세틸라제의 효소활성 저해제를 제공한다.In addition, the present invention provides an alkylamino naphthalene-yloxymethyl-propenyl-hydroxy-benzamide or histone deacetylase inhibitors of the enzyme activity to a pharmacologically acceptable salt thereof as an active ingredient of formula (I).

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

본 발명에 따른 화학식 1의 알킬아미노 나프탈렌옥시메틸 프로페닐 하이드록시벤즈아마이드 유도체의 바람직한 화합물로는, Preferred compounds of the alkylamino naphthaleneoxymethyl propenyl hydroxybenzamide derivative of the general formula (1) according to the present invention,

(Z)-4-(3-(1-에틸피페리딘-4-일아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)-N-하이드록시벤즈아마이드;(Z) -4- (3- (1-ethylpiperidin-4-ylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) -N -hydroxybenzamide ;

(Z)-4-(3-(1-에틸피롤리딘-3-일아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)-N-하이드록시벤즈아마이드;(Z) -4- (3- (1-ethylpyrrolidin-3-ylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) -N -hydroxybenzamide ;

(Z)-N-하이드록시-4-(3-(나프탈렌-1-일옥시)-2-((4-(트라이플루오로메톡시)벤질아미노)메틸)프로프-1-엔일)벤즈아마이드;(Z) -N -hydroxy-4- (3- (naphthalen-1-yloxy) -2-((4- (trifluoromethoxy) benzylamino) methyl) prop-1-enyl) benzamide;

(Z)-3-(3-(4-(하이드록시카바모일)페닐)-2-((나프탈렌-1-일옥시)메틸)알릴아미노)피롤리딘-1-카복실산-t-뷰틸에스터;(Z) -3- (3- (4- (hydroxycarbamoyl) phenyl) -2-((naphthalen-1-yloxy) methyl) allylamino) pyrrolidine-1-carboxylic acid-t-butylester;

(Z)-N-하이드록시-4-(3-(나프탈렌-1-일옥시)-2-((피롤리딘-3-일아미노)메틸)프로프-1-엔일)벤즈아마이드;(Z) -N -hydroxy-4- (3- (naphthalen-1-yloxy) -2-((pyrrolidin-3-ylamino) methyl) prop-1-enyl) benzamide;

(Z)-4-(3-(1-(사이클로헥실카보닐)피롤리딘-3-일아미노)-2-((나프탈렌-1-일 옥시)메틸)프로프-1-엔일)-N-하이드록시벤즈아마이드;(Z) -4- (3- (1- (cyclohexylcarbonyl) pyrrolidin-3-ylamino) -2-((naphthalen-1-yl oxy) methyl) prop-1-enyl) -N Hydroxybenzamide;

(Z)-4-(3-(1-사이클로펜틸피페리딘-4-일아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)-N-하이드록시벤즈아마이드;(Z) -4- (3- (1-cyclopentylpiperidin-4-ylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) -N -hydroxybenz Amides;

(Z)-4-(3-(1-(사이클로헥실메틸)피롤리딘-3-일아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)-N-하이드록시벤즈아마이드;(Z) -4- (3- (1- ( cyclohexylmethyl) pyrrolidin-3-ylamino) -2 - ((naphthalen-1-yloxy) methyl) prop-1-enyl) - N - Hydroxybenzamide;

(Z)-4-(3-(1-벤질피롤리딘-3-일아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)-N-하이드록시벤즈아마이드;(Z) -4- (3- (1-benzylpyrrolidin-3-ylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) -N -hydroxybenzamide ;

(Z)-4-(3-(1-사이클로프로필피페리딘-4-일아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)-N-하이드록시벤즈아마이드;(Z) -4- (3- (1-cyclopropylpiperidin-4-ylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) -N -hydroxybenz Amides;

(Z)-4-(3-(1-사이클로프로필피롤리딘-3-일아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)-N-하이드록시벤즈아마이드;(Z) -4- (3- (1-cyclopropylpyrrolidin-3-ylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) -N -hydroxybenz Amides;

(Z)-4-(3-(1-사이클로헥실피롤리딘-3-일아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)-N-하이드록시벤즈아마이드;(Z) -4- (3- (1-cyclohexylpyrrolidin-3-ylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) -N-hydroxybenz Amides;

(Z)-4-(3-(에틸(2-몰포리노에틸)아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)-N-하이드록시벤즈아마이드;(Z) -4- (3- (ethyl (2-morpholinoethyl) amino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) -N -hydroxybenzamide;

(Z)-N-하이드록시-4-(3-(1-메톡시프로판-2-일아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)벤즈아마이드;(Z) -N -hydroxy-4- (3- (1-methoxypropan-2-ylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzamide;

(Z)-N-하이드록시-4-(3-(2-(1-메틸피롤리딘-2-일)에틸아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔닐)벤즈아마이드;(Z) -N -hydroxy-4- (3- (2- (1-methylpyrrolidin-2-yl) ethylamino) -2-((naphthalen-1-yloxy) methyl) prop-1 -Enyl) benzamide;

(Z)-N-하이드록시-4-(3-(1-아이소프로필피페리딘-4-일아미노)-2-((나프탈렌- 1-일옥시)메틸)프로프-1-엔닐)벤즈아마이드;(Z) -N -hydroxy-4- (3- (1-isopropylpiperidin-4-ylamino) -2-((naphthalene-1-yloxy) methyl) prop-1-enyl) benz Amides;

(Z)-4-(3-(3-(1H-이미다졸-1-일)프로필아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)-N-하이드록시벤즈아마이드;(Z) -4- (3- (3- (1H-imidazol-1-yl) propylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) -N -hydr Oxybenzamide;

(Z)-N-하이드록시-4-(3-(4-하이드록시페네틸아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)벤즈아마이드;(Z) -N -hydroxy-4- (3- (4-hydroxyphenethylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzamide;

(Z)-4-(3-(3-(다이메틸아미노)-2,2-다이메틸프로필아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)-N-하이드록시벤즈아마이드;(Z) -4- (3- (3- (dimethylamino) -2,2-dimethylpropylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) -N Hydroxybenzamide;

(Z)-4-(3-(2-(다이아이소프로필아미노)에틸아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)-N-하이드록시벤즈아마이드;(Z) -4- (3- (2- (diisopropylamino) ethylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) -N -hydroxybenzamide;

(Z)-N-하이드록시-4-(3-(2-메톡시에틸아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)벤즈아마이드;(Z) -N -hydroxy-4- (3- (2-methoxyethylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzamide;

(Z)-4-(3-(사이클로헥실아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)-N-하이드록시벤즈아마이드;(Z) -4- (3- (cyclohexylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) -N -hydroxybenzamide;

(Z)-N-하이드록시-4-(3-(나프탈렌-1-일옥시)-2-((티오펜-2-일 메틸아미노)메틸)프로프-1-엔일)벤즈아마이드;(Z) -N -hydroxy-4- (3- (naphthalen-1-yloxy) -2-((thiophen-2-yl methylamino) methyl) prop-1-enyl) benzamide;

(Z)-N-하이드록시-4-(3-(4-메톡시페네틸아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)벤즈아마이드; 및(Z) -N -hydroxy-4- (3- (4-methoxyphenethylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzamide; And

(Z)-4-(3-(4-(다이메틸아미노)벤질아미노))-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)-N-하이드록시벤즈아마이드를 예로 들 수 있다.(Z) -4- (3- (4- (dimethylamino) benzylamino))-2-((naphthalen-1-yloxy) methyl) prop-1-enyl) -N -hydroxybenzamide For example.

본 발명에 따른 화학식 1의 화합물은 무기산 또는 유기산으로부터 유도된 약 학적으로 허용가능한 염의 형태로 사용될 수 있으며, 바람직한 염으로는 염산, 브롬화수소산, 황산, 인산, 질산, 아세트산, 글리콜산, 락트산, 피루브산, 말론산, 석신산, 글루타르산, 푸마르산, 말산, 만델산, 타르타르산, 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 may be used in the form of a pharmaceutically acceptable salt derived from an inorganic acid or an organic acid. Preferred salts include 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, methane Salts, such as a sulfonic acid, benzene sulfonic acid, and toluene sulfonic acid, are mentioned.

또한, 본 발명은 상기 화학식 1의 알킬아미노 나프탈렌옥시메틸 프로페닐 하이드록시벤즈아마이드 유도체의 제조방법을 제공한다. The present invention also provides a method for preparing the alkylamino naphthaleneoxymethyl propenyl hydroxybenzamide derivative of the formula (1).

본 발명에 따른 제조방법은, Manufacturing method according to the invention,

1) 하기 화학식 2의 화합물을 1,4-다이아자비사이클로[2,2,2]옥탄(DABCO) 존재하에서 알킬아크릴레이트와 반응시켜 하기 화학식 3의 화합물을 제조하는 단계;1) reacting with an alkyl acrylate in the presence of 1,4-diamine ratio bicyclo [2,2,2] octane (DABCO) a compound of formula 2 to prepare a compound of formula (3);

2) 화학식 3의 화합물을 유기용매 중에서 삼브롬화인(PBr3)과 반응시켜 화학식 4의 화합물을 제조하는 단계;2) preparing a compound of formula 4 to the compound of formula (III) to phosphorus tribromide (PBr 3) reacting in an organic solvent;

3) 화학식 4의 화합물을 1-나프탈렌올과 반응시켜 화학식 5의 화합물로 전환시키는 단계;3) reacting the compound of formula 4 with 1-naphthalenol to convert the compound of formula 5 ;

4) 화학식 5의 화합물을 트라이플루오로아세트산(TFA)으로 가수분해 반응시켜 카복시프로페닐 벤조산메틸에스터를 제조한 후, 에틸클로로포메이트(ECC)로 처리하고 환원제로 환원시켜 화학식 6의 화합물을 제조하는 단계;4) The compound of formula 5 is hydrolyzed with trifluoroacetic acid (TFA) to prepare carboxypropenyl benzoate methyl ester, and then treated with ethylchloroformate (ECC) and reduced with a reducing agent to prepare a compound of formula 6 Making;

5) 화학식 6의 화합물을 비극성 용매에 녹인 후 트라이페닐포스핀(PPh3)과 테트라브로모메탄 (CBr4)을 첨가하고 브롬화 반응시켜 화학식 7의 화합물을 제조하는 단계;5) dissolving the compound of Formula 6 in a nonpolar solvent, and then adding triphenylphosphine (PPh 3 ) and tetrabromomethane (CBr 4 ) and bromination to prepare a compound of Formula 7 ;

6) 화학식 7의 화합물을 아민 (R1R2NH)과 반응시켜 화학식 8의 화합물을 제조하는 단계;6) reacting a compound of Formula 7 with an amine (R 1 R 2 NH) to prepare a compound of Formula 8 ;

7) 화학식 8의 화합물을 무기염기 처리에 의해 가수분해 반응시켜 화학식 9의 화합물을 제조하는 단계;7) hydrolyzing the compound of Formula 8 by inorganic base treatment to prepare a compound of Formula 9 ;

8) 화학식 9의 화합물을 유기용매 중에서 N-하이드록시-6-트라이플루오로 벤조트라이아졸(FOBt) 및 1-에틸-3-(3-다이메틸아미노프로필)카바다이이마이드·염산염(EDC·HCl)의 존재 하에 테트라하이드로-2H-피란-2-일 옥시아민(THPONH2)과 아실화 반응시켜 화학식 10의 화합물을 제조하는 단계; 및8) a compound of formula (9) in an organic solvent N - hydroxy-6-trifluoromethyl benzotriazole (FOBt) and 1-ethyl-3- (3-dimethylaminopropyl) carbazole dayiyi polyimide hydrochloride (EDC · HCl Acylation with tetrahydro-2H-pyran-2-yl oxyamine (THPONH 2 ) in the presence of) to prepare a compound of formula 10 ; And

9) 화학식 10의 화합물을 수용성 무기산 또는 유기산으로 처리하여 테트라하이드로-2H-피란-2-일옥시 보호기를 제거하는 단계를 포함한다:9) treating the compound of Formula 10 with a water soluble inorganic or organic acid to remove the tetrahydro-2H-pyran-2-yloxy protecting group:

Figure 112006081424267-pat00003
Figure 112006081424267-pat00003

Figure 112006081424267-pat00004
Figure 112006081424267-pat00004

Figure 112006081424267-pat00005
Figure 112006081424267-pat00005

Figure 112006081424267-pat00006
Figure 112006081424267-pat00006

Figure 112006081424267-pat00007
Figure 112006081424267-pat00007

Figure 112006081424267-pat00008
Figure 112006081424267-pat00008

Figure 112006081424267-pat00009
Figure 112006081424267-pat00009

Figure 112006081424267-pat00010
Figure 112006081424267-pat00010

Figure 112006081424267-pat00011
Figure 112006081424267-pat00011

Figure 112006081424267-pat00012
Figure 112006081424267-pat00012

상기 식들에서, R1, 및 R2는 각각 상기 화학식 1에서 정의한 바와 같다.In the above formula, R 1 and R 2 are as defined in the formula (1), respectively.

상기 제조방법은 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 112006081424267-pat00013
Figure 112006081424267-pat00013

상기 식에서, R1, 및 R2는 각각 상기 화학식 1에서 정의한 바와 같다.Wherein R 1 and R 2 are the same as defined in Chemical Formula 1, respectively.

단계 1)에서는 베일리스 힐만 반응에 의해 알데하이드와 알킬아크릴레이트가 DABCO 존재하에서 반응하여 알콕시카보닐 하이드록시 알릴 화합물이 생성되는데, 알킬아크릴레이트로는 에틸아크릴레이트, 아이소뷰틸아크릴레이트, t-뷰틸아크릴레이트 등이 사용될 수 있다.In step 1), an aldehyde and an alkyl acrylate are reacted in the presence of DABCO by a Baileys Hillman reaction to produce an alkoxycarbonyl hydroxy allyl compound. As alkyl acrylate, ethyl acrylate, isobutyl acrylate and t -butyl acrylate are produced. And the like can be used.

단계 2)의 반응은 유기용매로 에틸에테르, 테트라하이드로퓨란, 다이클로로메탄 또는 다이클로로에탄 등을 사용하고 빙냉하에서 이루어지는 것이 바람직하다.The reaction of step 2) is preferably performed under ice cooling using ethyl ether, tetrahydrofuran, dichloromethane or dichloroethane as an organic solvent.

단계 3)의 반응은 유기용매 중에서 유기염기 또는 무기염기 존재하에서 이루어지는 것이 바람직한데, 유기용매로는 아세톤, 아세토나이트릴, 다이클로로메탄 또는 테트라하이드로퓨란 등이 사용될 수 있고, 유기염기로는 트라이에틸아민, 다이아이소프로필에틸아민 또는 피리딘 등이, 무기염기로는 탄산칼륨, 중탄산나트륨 또는 탄산나트륨 등이 사용될 수 있다.The reaction of step 3) is preferably carried out in the presence of an organic base or an inorganic base in an organic solvent. As the organic solvent, acetone, acetonitrile, dichloromethane or tetrahydrofuran may be used. As the amine, diisopropylethylamine or pyridine, and the inorganic base, potassium carbonate, sodium bicarbonate, sodium carbonate and the like can be used.

단계 4)에서 ECC와의 반응은 테트라하이드로퓨란, 1,4-다이옥산, 다이클로로메탄, 또는 클로로폼 등과 같은 용매를 사용하여 빙냉하에서 이루어지고, 환원제로서 소듐보로하이드라이드, 소듐사이아노보로하이드라이드, 또는 리튬보로하이드라이드를 넣고 물을 적가하면서 이루어지는 것이 바람직하다.The reaction with ECC in step 4) is carried out under ice-cooling using a solvent such as tetrahydrofuran, 1,4-dioxane, dichloromethane, or chloroform, and as a reducing agent sodium borohydride, sodium cyanoborohydride It is preferable to add a lide or lithium borohydride and add water dropwise.

단계 5)의 브롬화 반응에서 비극성 용매로는 다이클로로메탄, 클로로폼, 테트라하이드로퓨란, 다이클로로에탄 등이 사용될 수 있다.In the bromination reaction of step 5), dichloromethane, chloroform, tetrahydrofuran, dichloroethane and the like may be used.

단계 6)의 아민 반응은 유기용매 중에서 유기염기 또는 무기염기를 사용하여 이루어지는데, 유기용매로는 N,N-다이메틸포름아마이드, 아세톤, 아세토나이트릴, 다이클로로메탄 또는 테트라하이드로퓨란 등이 사용될 수 있고, 유기염기로는 트라이에틸아민, 다이아이소프로필에틸아민 또는 피리딘 등이, 무기염기로는 탄산칼륨, 중탄산나트륨 또는 탄산나트륨 등이 사용될 수 있다.The amine reaction of step 6) is performed using an organic base or an inorganic base in an organic solvent. As the organic solvent, N, N-dimethylformamide, acetone, acetonitrile, dichloromethane or tetrahydrofuran may be used. As the organic base, triethylamine, diisopropylethylamine or pyridine may be used, and as the inorganic base, potassium carbonate, sodium bicarbonate or sodium carbonate may be used.

단계 7)의 가수분해 반응은 알콜 수용액 또는 테트라하이드로퓨란 수용액 중에서 무기염기를 사용하여 이루어지는데, 알콜 수용액으로는 메탄올, 에탄올, 아이소프로판올, n-뷰탄올, t-뷰탄올 수용액 등이 사용될 수 있고, 무기염기로는 수산화리튬, 수산화나트륨, 수산화칼륨 등이 사용될 수 있다.The hydrolysis reaction of step 7) is performed using an inorganic base in an aqueous alcohol solution or an aqueous tetrahydrofuran solution. As the aqueous alcohol solution, methanol, ethanol, isopropanol, n-butanol, t-butanol aqueous solution, etc. may be used. As the inorganic base, lithium hydroxide, sodium hydroxide, potassium hydroxide and the like can be used.

단계 8)에서 사용가능한 유기용매로는 N,N-다이메틸폼아마이드, 다이메틸설폭사이드, 테트라하이드로퓨란 또는 다이클로로메탄 등을 예로 들 수 있다.Examples of the organic solvent usable in step 8) include N, N -dimethylformamide, dimethylsulfoxide, tetrahydrofuran or dichloromethane.

단계 9)는 메탄올, 다이클로로메탄, 다이클로로에탄, 벤젠, 및 톨루엔 등의 유기용매 중에서 수행되며, 수용성 무기산으로는 염산, 황산, 또는 인산 등을 사용할 수 있고, 유기산으로는 트라이플루오로아세트산, 아세트산, 또는 시트르산 등을 사용할 수 있다.Step 9) is performed in organic solvents such as methanol, dichloromethane, dichloroethane, benzene, and toluene, and hydrochloric acid, sulfuric acid, or phosphoric acid may be used as the water-soluble inorganic acid, and trifluoroacetic acid, Acetic acid, citric acid, etc. can be used.

또한, 상기 화학식 1의 화합물에서 R1이 수소인 경우에 해당하는 본 발명의 또 다른 제조방법은,In addition, another manufacturing method of the present invention corresponding to the case where R 1 in the compound of Formula 1 is hydrogen,

1) 하기 화학식 7의 화합물을 1차 아민(R2NH2)과 반응시켜 하기 화학식 11의 화합물을 제조하는 단계;1) preparing a compound of Formula 11 by reacting a compound of Formula 7 with a primary amine (R 2 NH 2 );

2) 화학식 11의 화합물을 비극성 용매에 녹이고 t-뷰틸 다이카보네이트를 이용하여 아민을 보호하여 하기 화학식 12의 화합물을 제조하는 단계;2) dissolving the compound of Formula 11 in a nonpolar solvent and protecting the amine with t -butyl dicarbonate to prepare a compound of Formula 12 ;

3) 화학식 12의 화합물을 무기염기 처리에 의해 가수분해 반응시켜 하기 화 학식 13의 화합물을 제조하는 단계; 3) hydrolyzing the compound of Formula 12 by inorganic base treatment to prepare a compound of Formula 13 ;

4) 화학식 13의 화합물을 유기용매 중에서 N-하이드록시-6-트라이플루오로 벤조트라이아졸(FOBt) 및 1-에틸-3-(3-다이메틸아미노프로필)카바다이이마이드·염산염(EDC·HCl)의 존재하에 테트라하이드로-2H-피란-2-일 옥시아민(THPONH2)과 아실화 반응시켜 화합식 14의 화합물을 제조하는 단계; 및4) a compound of formula 13 in an organic solvent N - hydroxy-6-trifluoromethyl benzotriazole (FOBt) and 1-ethyl-3- (3-dimethylaminopropyl) carbazole dayiyi polyimide hydrochloride (EDC · HCl Acylation with tetrahydro-2H-pyran-2-yl oxyamine (THPONH 2 ) in the presence of a) to prepare a compound of Formula 14 ; And

5) 화학식 14의 화합물을 수용성 무기산 또는 유기산으로 처리하여 테트라하이드로-2H-피란-2-일옥시기(-OTPH)와 t-뷰톡시카보닐기(Boc-)를 제거하는 단계를 포함한다.5) treating the compound of Formula 14 with a water-soluble inorganic or organic acid to remove the tetrahydro-2H-pyran-2-yloxy group (-OTPH) and t -butoxycarbonyl group (Boc-).

<화학식 7><Formula 7>

Figure 112006081424267-pat00014
Figure 112006081424267-pat00014

Figure 112006081424267-pat00015
Figure 112006081424267-pat00016
Figure 112006081424267-pat00015
Figure 112006081424267-pat00016

Figure 112006081424267-pat00017
Figure 112006081424267-pat00017

Figure 112006081424267-pat00018
Figure 112006081424267-pat00018

Figure 112006081424267-pat00019
Figure 112006081424267-pat00019

상기 식들에서, R2는 상기 화학식 1에서 정의한 바와 같다. In the above formula , R 2 is as defined in formula (I) .

상기 제조방법은 하기 반응식 2로 나타내어질 수 있으며, 이를 단계별로 설명하면 다음과 같다. The preparation method may be represented by the following Scheme 2 , which will be described below step by step.

Figure 112006081424267-pat00020
Figure 112006081424267-pat00020

상기 식에서, R2는 상기 화학식 1에서 정의한 바와 같다.Wherein R 2 is as defined in Formula 1 above.

단계 1)의 반응은 유기용매 중에서 유기염기 또는 무기염기를 사용하여 이루어지는데, 용매로는 아세톤, 아세토나이트릴, 다이클로로메탄 또는 테트라하이드로퓨란 등이 사용될 수 있고, 유기염기로는 트라이에틸아민, 다이아이소프로필에틸아민 또는 피리딘 등이, 무기염기로는 탄산칼륨, 중탄산나트륨 또는 탄산나트륨 등이 사용될 수 있다.The reaction of step 1) is performed using an organic base or an inorganic base in an organic solvent, and acetone, acetonitrile, dichloromethane or tetrahydrofuran may be used as a solvent, and triethylamine, Diisopropylethylamine or pyridine or the like may be used as the inorganic base such as potassium carbonate, sodium bicarbonate or sodium carbonate.

단계 2)는 비극성 용매 중에서 유기염기와 촉매를 사용하여 이루어지는데, 비극성 용매로는 다이클로로메탄, 클로로폼, 테트라하이드로퓨란, 1,4-다이옥산 또는 다이클로로에탄 등이 사용될 수 있고, 유기염기로는 트라이에틸아민, 다이아이소프로필에틸아민, 또는 피리딘 등이 사용될 수 있으며, 이 반응은 촉매로서 4-다이메틸아미노피리딘(DMAP)을 사용하는 것이 바람직하다.Step 2) is performed using an organic base and a catalyst in a non-polar solvent, and dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane or dichloroethane may be used as the non-polar solvent. Triethylamine, diisopropylethylamine, pyridine and the like can be used, and this reaction preferably uses 4-dimethylaminopyridine (DMAP) as a catalyst.

단계 3)의 가수분해 반응은 알콜 수용액 또는 테트라하이드로퓨란 수용액 중에서 이루어지는 것이 바람직하며, 이때 알콜 수용액으로는 메탄올, 에탄올, 아이소프로판올, N-뷰탄올, t-뷰탄올 수용액 등이 사용될 수 있고, 또한, 바람직한 무기염기로는 수산화리튬, 수산화나트륨, 수산화칼륨 등이 사용될 수 있다. The hydrolysis reaction of step 3) is preferably carried out in an aqueous alcohol solution or an aqueous tetrahydrofuran solution, wherein the aqueous alcohol solution may be methanol, ethanol, isopropanol, N-butanol, t-butanol aqueous solution, or the like. As the preferred inorganic base, lithium hydroxide, sodium hydroxide, potassium hydroxide and the like can be used.

단계 4)에서 사용가능한 유기용매로는 N,N-다이메틸폼아마이드, 다이메틸설폭사이드, 테트라하이드로퓨란 또는 다이클로로메탄 등을 예로 들 수 있다.Examples of the organic solvent usable in step 4) include N, N -dimethylformamide, dimethylsulfoxide, tetrahydrofuran or dichloromethane.

단계 5)에서 사용가능한 유기용매로는 메탄올, 다이클로로메탄, 다이클로로에탄, 벤젠, 및 톨루엔 등이 있고, 수용성 무기산으로는 염산, 황산, 또는 인산 등을 사용할 수 있으며, 유기산으로는 트라이플루오로아세트산, 아세트산, 또는 시트르산 등을 사용할 수 있다.Organic solvents that can be used in step 5) include methanol, dichloromethane, dichloroethane, benzene, toluene, and the like. As the water-soluble inorganic acid, hydrochloric acid, sulfuric acid, or phosphoric acid may be used. Acetic acid, acetic acid, citric acid and the like can be used.

상기 화학식 1의 화합물의 제조에 출발물질로 사용되는 화학식 2의 화합물은 통상적인 방법으로 용이하게 제조가능하고, 필요하면 상업적으로 시판되는 것을 구입하여 사용할 수도 있다.The compound of formula (2) used as a starting material for the preparation of the compound of formula (1 ) can be easily prepared by conventional methods, and if necessary, a commercially available one can be purchased and used.

이와 같이 제조된, 본 발명의 화학식 1의 알킬아미노 나프탈렌일옥시메틸 프 로페닐 하이드록시벤즈아마이드 유도체는 히스톤 디아세틸라제의 효소활성을 효과적으로 저해하여 종양세포의 말기 분화를 선택적으로 유도함으로써 이들 종양세포의 증식을 억제하고, 궁극적으로는 암을 치료할 수 있다. The alkylamino naphthalenyloxymethyl propenyl hydroxybenzamide derivatives of the formula (1) of the present invention prepared as described above effectively inhibit the enzymatic activity of histone deacetylase to selectively induce terminal differentiation of tumor cells. Inhibit the proliferation of cancer and ultimately treat cancer.

따라서, 본 발명의 화학식 1의 알킬아미노 나프탈렌일옥시메틸 프로페닐 하이드록시벤즈아마이드 유도체는 히스톤 디아세틸라제의 효소활성 저해제로 유용하게 사용될 수 있다.Therefore, the alkylamino naphthalenyloxymethyl propenyl hydroxybenzamide derivative of the general formula (1) of the present invention can be usefully used as an inhibitor of enzymatic activity of histone deacetylase.

또한, 본 발명은 화학식 1의 화합물 또는 그의 약학적으로 허용가능한 염을 유효성분으로 하는 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 or a pharmaceutically acceptable salt thereof as an active ingredient. 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 카복시메틸셀룰로즈 및/또는 폴리비닐피롤리딘과 같은 결합제를 함유할 수 있으며, 경우에 따라 전분, 한천, 알긴산 또는 그의 나트륨염과 같은 붕해제 또는 비등 혼합물 및/또는 흡수제, 착색제, 향미제, 및 감미제를 함유할 수 있다. 또한, 비경구 투여용 제형의 대표 적인 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, colorants, flavoring agents, and sweetening agents. Also representative of parenteral formulations 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. Hereinafter, the present invention will be described in more detail by the following Preparation Examples and Examples.

하기 제조예 및 실시예는 본 발명을 예시하기 위한 것일 뿐, 본 발명의 범위가 이들만으로 한정되는 것은 아니다.The following Preparation Examples and Examples are only for illustrating the present invention, but the scope of the present invention is not limited thereto.

제조예 1: Preparation Example 1: tt -뷰틸 3-하이드록시-2-메틸렌-3-[4-(메톡시카보닐)페닐]프로파네이트 (화학식 3의 화합물)-Butyl 3-hydroxy-2-methylene-3- [4- (methoxycarbonyl) phenyl] propanoate (compound of formula 3)

4-(메톡시카보닐) 벤즈알데하이드(3.3 g, 20 mM), t-뷰틸아크릴레이트(3.5 ㎖, 24 mM) 및 1,4-다이아자비사이클로[2,2,2]옥탄(449㎎, 4 mM)을 실온의 밀폐된 용기에서 5일간 교반하였다. 반응 혼합물을 다이에틸에테르로 추출하여 2 N 염산용액, 물 및 중조로 세척하고 무수 황산나트륨으로 건조시킨 후 여과, 감압 증류하 여 농축한 다음 실리카겔 컬럼 크로마토그래피로 정제하여 흰색 고체의 표제화합물 4.2 g(수율 73％)을 얻었다.4- (methoxycarbonyl) benzaldehyde (3.3 g, 20 mM), t -butylacrylate (3.5 mL, 24 mM) and 1,4-diazabicyclo [2,2,2] octane (449 mg, 4 mM) was stirred for 5 days in a closed vessel at room temperature. The reaction mixture was extracted with diethyl ether, washed with 2N hydrochloric acid solution, water and sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, distilled under reduced pressure, concentrated under reduced pressure, and purified by silica gel column chromatography to give 4.2 g of the title compound as a white solid. Yield 73%) was obtained.

1H NMR (300 MHz, CDCl3) δ1.40 (s, 9H), 3.28 (m, 1H), 3.91 (s, 3H), 5.53 (d, 1H, J=5.2 Hz), 5.71 (s, 1H), 6.27 (s, 1H), 7.45 (d, 2H, J=8.0 Hz), 7.81 (d, 2H, J=8.0 Hz); 1 H NMR (300 MHz, CDCl 3 ) δ 1.40 (s, 9H), 3.28 (m, 1H), 3.91 (s, 3H), 5.53 (d, 1H, J = 5.2 Hz), 5.71 (s, 1H ), 6.27 (s, 1 H), 7.45 (d, 2H, J = 8.0 Hz), 7.81 (d, 2H, J = 8.0 Hz);

MS (EI, 70 eV) m/z 292(M+), 283, 255, 241, 227, 201, 189, 179, 150, 135; MS (EI, 70 eV) m / z 292 (M + ), 283, 255, 241, 227, 201, 189, 179, 150, 135;

융점: 70℃Melting point: 70 ℃

제조예 2: 4-(3-브로모-2-t-뷰톡시카보닐프로페닐)-벤조산 메틸에스터 (화학식 4의 화합물)Preparation Example 2 4- (3-Bromo-2-t-butoxycarbonylpropenyl) -benzoic acid methyl ester (Compound 4)

상기 제조예 1에서 제조된 t-뷰틸-3-하이드록시-2-메틸렌-3-(4-메톡시카보닐페닐)-프로파네이트(994㎎ 3.4 mM)를 에틸에테르(10㎖)에 녹이고 0℃로 냉각한 후 삼브롬화인(0.35㎖ 3.74 mM)을 천천히 적가하고 실온에서 1시간 동안 교반시켰다. 반응이 종결되면 반응 혼합물을 얼음물에 부어 에틸에테르로 추출하고 유기층을 소금물로 세척한 후 무수 황산마그네슘으로 건조시켰다. 이로부터 얻은 건조물을 여과, 감압 증류하여 용매를 제거하였고 남은 잔사를 실리카겔 컬럼 크로마토그래피로 정제하여 연두색 고체의 표제화합물 943㎎(수율 71 ％)을 얻었다. T -Butyl-3-hydroxy-2-methylene-3- (4-methoxycarbonylphenyl) -propane (994 mg 3.4 mM) prepared in Preparation Example 1 was dissolved in ethyl ether (10 ml). After cooling to 0 ° C., phosphorus tribromide (0.35 mL 3.74 mM) was slowly added dropwise and stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was poured into iced water, extracted with ethyl ether, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The dried product was filtered, distilled under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography to obtain 943 mg (yield 71%) of the title compound as a light green solid.

1H NMR (300 MHz, CDCl3) δ1.40 (S, 9H, OCH3), 3.88 (S, 3H, OCH3), 3.97 (S, 2H, CH2), 7.41 (d, 2H J=8.4 Hz, ArH), 7.50 (s, 1H), 7.91 (d, 2H, J=8.4 Hz, ArH); 1 H NMR (300 MHz, CDCl 3 ) δ 1.40 (S, 9H, OCH 3), 3.88 (S, 3H, OCH 3), 3.97 (S, 2H, CH 2), 7.41 (d, 2H J = 8.4 Hz, ArH ), 7.50 (s, 1 H), 7.91 (d, 2H, J = 8.4 Hz, ArH);

MS (EI, 70eV) m/z 355 (M+), 338, 296, 278, 259, 219, 187, 143, 115MS (EI, 70 eV) m / z 355 (M + ), 338, 296, 278, 259, 219, 187, 143, 115

융점: 78℃Melting point: 78 ℃

제조예 3: 4-[2-Preparation Example 3 4- [2- tt -뷰톡시카보닐-3-(나프탈렌-1-일옥시)-프로페닐]-벤조산 메틸에스터 (화학식 5의 화합물)Butoxycarbonyl-3- (naphthalen-1-yloxy) -propenyl] -benzoic acid methyl ester (compound of formula 5)

제조예 2에서 제조된 4-(3-브로모-2-t-뷰톡시카보닐프로페닐)-벤조산 메틸에스터(355㎎, 1 mM)를 아세톤(5 ㎖)에 녹이고 탄산칼륨(207㎎, 1.50 mM)과 1-나프탈렌올(144㎎, 1 mM)을 가한 후 3시간 동안 가열 환류시켰다. 반응이 종결되면 반응 혼합물을 상온으로 냉각시킨 후 여과하여 용매를 제거하였고 남은 잔사를 실리카겔 컬럼 크로마토그래피로 정제하여 흰색 고체의 표제화합물 438㎎(수율 99％)을 얻었다.4- (3-Bromo-2-t-butoxycarbonylpropenyl) -benzoic acid methyl ester (355 mg, 1 mM) prepared in Preparation Example 2 was dissolved in acetone (5 mL), and potassium carbonate (207 mg, 1.50 mM) and 1-naphthalenol (144 mg, 1 mM) were added and heated to reflux for 3 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered to remove the solvent, and the remaining residue was purified by silica gel column chromatography to obtain 438 mg (yield 99%) of the title compound as a white solid.

1H NMR (200 MHz, CDCl3) δ1.49 (S, 9H, CH3), 3.89 (S, 3H, OCH3), 4.96 (S, 2H, CH2), 6.84 (d, 1H J=7.33 Hz, ArH), 7.53 (m, 5H, ArH), 7.89 (m, 1H, ArH), 8.01 (m, 3H, ArH), 8.24 (m, 3H, ArH) 1 H NMR (200 MHz, CDCl 3 ) δ 1.49 (S, 9H, CH 3), 3.89 (S, 3H, OCH 3), 4.96 (S, 2H, CH 2), 6.84 (d, 1H J = 7.33 Hz, ArH ), 7.53 (m, 5H, ArH), 7.89 (m, 1H, ArH), 8.01 (m, 3H, ArH), 8.24 (m, 3H, ArH)

제조예 4: 4-[2-하이드록시메틸-3-(나프탈렌-1-일옥시)-프로페닐]-벤조산 메틸에스터(화학식 6의 화합물)Preparation Example 4 4- [2-hydroxymethyl-3- (naphthalen-1-yloxy) -propenyl] -benzoic acid methyl ester (compound of formula 6)

상기 제조예 3에서 제조된 4-(2-카복시-3-(나프탈렌-1-일옥시)-프로페닐)-벤조산 메틸에스터(2 g, 5.52 mM)를 테트라하이드로퓨란(30 ㎖)에 녹이고, 0℃에서 트라이에틸아민(1.15 ㎖, 8.27 mM)과 에틸클로로포메이트(0.792 ㎖, 8.279 mM)를 천천히 적가하여 1시간 동안 교반하였다. 상기 반응 혼합물에 소듐보로하이드라이드(1.462㎎, 38.64 mM)와 증류수(10 ㎖)를 순차적으로 천천히 가하여 상온에서 2.5시간 동안 교반하였다. 1 N 염산수용액을 사용하여 반응 혼합물의 pH를 2로 조절한 후 에틸아세트산으로 추출하였다. 이로부터 얻은 유기층을 포화 중조와 소금물로 세척한 후 황산마그네슘으로 건조시키고 여과하여 얻은 잔사를 실리카겔 컬럼 크로마토그래피로 정제하여 흰색 고체의 표제화합물 1.58㎎(수율 82％)을 얻었다.4- (2-carboxy-3- (naphthalen-1-yloxy) -propenyl) -benzoic acid methyl ester (2 g, 5.52 mM) prepared in Preparation Example 3 was dissolved in tetrahydrofuran (30 ml), Triethylamine (1.15 mL, 8.27 mM) and ethylchloroformate (0.792 mL, 8.279 mM) were slowly added dropwise at 0 ° C. and stirred for 1 hour. Sodium borohydride (1.462 mg, 38.64 mM) and distilled water (10 mL) were slowly added to the reaction mixture, followed by stirring at room temperature for 2.5 hours. The pH of the reaction mixture was adjusted to 2 using 1 N aqueous hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, and filtered. The residue was purified by silica gel column chromatography to obtain 1.58 mg (yield 82%) of the title compound as a white solid.

1H NMR (200 MHz, CDCl3) δ3.89 (S, 3H, OCH3), 4.55 (S, 2H, CH2), 4.88 (S, 2H , CH2), 6.71 (d, 1H J=7.5Hz, ArH), 6.96 (S, 1H, CH), 7.28-7.54 (m, 6H, ArH), 7.83 (m, 1H, ArH), 8.03 (d, 2H J=8.1 Hz, ArH), 8.30 (m, 1H, ArH) 1 H NMR (200 MHz, CDCl 3 ) δ 3.89 (S, 3H, OCH 3), 4.55 (S, 2H, CH 2), 4.88 (S, 2H, CH 2), 6.71 (d, 1H J = 7.5 Hz, ArH ), 6.96 (S, 1H, CH), 7.28-7.54 (m, 6H, ArH), 7.83 (m, 1H, ArH), 8.03 (d, 2H J = 8.1 Hz, ArH), 8.30 (m, 1H, ArH)

제조예 5: 4-[2-브로모메틸-3-(나프탈렌-1-일옥시)-프로페닐]-벤조산 메틸에스터 (화학식 7의 화합물)Preparation Example 5 4- [2-Bromomethyl-3- (naphthalen-1-yloxy) -propenyl] -benzoic acid methyl ester (Compound 7)

상기 제조예 4에서 제조된 4-[2-하이드록시메틸-3-(나프탈렌-1-일옥시)-프로페닐]-벤조산 메틸에스터(1.57 g, 4.52 mM)를 다이클로로메탄(15 ㎖)에 녹인 후 트 라이페닐포스핀(1.78 g, 6.79 mM)을 가하고 0℃로 냉각시킨 다음 테트라브로모메탄(2.25 g, 6.79 mM)을 첨가하고 6시간 동안 교반하였다. 감압하에 용매를 제거한 후 실리카겔 컬럼 크로마토그래피로 정제하여 흰색 고체의 표제화합물 1.36 g(수율 73％)을 얻었다.4- [2-hydroxymethyl-3- (naphthalen-1-yloxy) -propenyl] -benzoic acid methyl ester (1.57 g, 4.52 mM) prepared in Preparation Example 4 was added to dichloromethane (15 ml). After dissolving, triphenylphosphine (1.78 g, 6.79 mM) was added and cooled to 0 ° C., then tetrabromomethane (2.25 g, 6.79 mM) was added and stirred for 6 hours. After removing the solvent under reduced pressure, the residue was purified by silica gel column chromatography to obtain 1.36 g (yield 73%) of the title compound as a white solid.

1H NMR (200 MHz, CDCl3) δ3.91 (S, 3H, OCH3), 4.42 (S, 2H, CH2), 4.98 (S, 2H, CH2), 6.71 (d, 1H J=7.5 Hz, ArH), 7.05 (S, 1H, CH), 7.27-7.56 (m, 6H, ArH), 7.83 (m, 1H, ArH), 8.03 (d, 2H J=8.1 Hz, ArH), 8.30 (m, 1H, ArH) 1 H NMR (200 MHz, CDCl 3 ) δ3.91 (S, 3H, OCH 3), 4.42 (S, 2H, CH 2), 4.98 (S, 2H, CH 2), 6.71 (d, 1H J = 7.5 Hz, ArH ), 7.05 (S, 1H, CH), 7.27-7.56 (m, 6H, ArH), 7.83 (m, 1H, ArH), 8.03 (d, 2H J = 8.1 Hz, ArH), 8.30 (m, 1H, ArH)

제조예 6에 들어가기 앞서 화학식 8의 화합물들을 만들기 위한 아민(R1R2NH) 화합물들은 상업적으로 시판되는 것을 구입해서 사용할 수도 있고 통상적인 방법으로 용이하게 제조하여 사용할 수도 있다. Prior to entering Preparation Example 6, the amine (R 1 R 2 NH) compounds for preparing the compounds of Formula 8 may be purchased commercially available or may be easily prepared and used by conventional methods.

상기 아민 화합물 중 C1-6 알킬로 치환된 피페리딘 또는 피롤리딘으로 치환된 화합물들은 예를 들면, 하기 반응식 3에서와 같이 제조할 수 있다. Among the amine compounds, piperidine substituted with C 1-6 alkyl or compound substituted with pyrrolidine may be prepared, for example, as in Scheme 3 below.

Figure 112006081424267-pat00021
Figure 112006081424267-pat00021

상기 식에서 R은 C1-6 알킬이다. Wherein R is C 1-6 alkyl.

또한, 아민 화합물들의 제조예는 아래에 상세하게 설명하였다. In addition, the preparation examples of the amine compounds are described in detail below.

제조예 i: Preparation Example i: tt -부틸 1-벤질피페리딘-4-일카바메이트(화학식 15의 화합물)-Butyl 1-benzylpiperidin-4-ylcarbamate (compound of formula 15)

250㎖ 반응 용기에 출발 물질 1-벤질피페리딘-4-아민(3g, 15.8mml)을 1M 수산화나트륨 수용액 (35.8㎖)과 t-부탄올(32㎖)에 녹여 교반시키면서 t-부틸 다이카 보네이트((tBoc)2O; 3.79g, 17.38mmol)를 가한 다음, 실온에서 12시간 반응한 후 에틸 아세테이트로 2번 추출하고 0.1N 염산 수용액과 소금물로 씻어주었다. 남은 유기층은 무수 황산나트륨으로 건조시킨 후 여과, 감압 증류하여 농축한 다음 실리카겔 컬럼 크로마토그래피로 정제하여 흰색 고체의 표제 화합물 3.801g (82.8％)을 얻었다.In a 250 ml reaction vessel, the starting material 1-benzylpiperidin-4-amine (3 g, 15.8 mmol) was dissolved in 1 M aqueous sodium hydroxide solution (35.8 ml) and t -butanol (32 ml) and stirred with t -butyl dicarbo. Nate (( t Boc) 2 O; 3.79 g, 17.38 mmol) was added, followed by reaction at room temperature for 12 hours, extracted twice with ethyl acetate, and washed with 0.1N aqueous hydrochloric acid solution and brine. The remaining organic layer was dried over anhydrous sodium sulfate, filtered, distilled under reduced pressure, concentrated, and then purified by silica gel column chromatography to obtain 3.801 g (82.8%) of the title compound as a white solid.

1H-NMR (200MHz, CDCl3) δ 1.38(s, 9H), 1.86-2.33(m, 4H), 2.70(m, 2H), 3.40(m, 2H), 3.57(br, 1H), 4.12(s, 2H), 7.43(m, 3H), 7.55(m, 2H) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.38 (s, 9H), 1.86-2.33 (m, 4H), 2.70 (m, 2H), 3.40 (m, 2H), 3.57 (br, 1H), 4.12 ( s, 2H), 7.43 (m, 3H), 7.55 (m, 2H)

LC/MS(M+H): 291LC / MS (M + H): 291

제조예Production Example iiii : : tt -부틸 피페리딘-4--Butyl piperidine-4- 일카바메이트Ilcarbamate (화학식 16의 화합물)(Compound of formula 16)

100㎖ 반응 용기에 상기 제조예 i에서 제조한 t-부틸-1-벤질피페리딘-4-일카바메이트 (3.801g, 13.1mmol)를 26㎖의 메탄올에 녹인 후 촉매 량의 10% 활성 팔라듐/카본를 넣고 수소 하에서 반응시켰다. 12시간 후 반응종결을 확인하고 셀라이트 페드로 여과하여 활성 팔라듐/카본을 제거하고 용매를 감압 증류하여 제거하였다. 반응 혼합물을 실리카겔 칼럼 크로마토그래피 방법으로 정제하여 목적화합물(2.64g)을 99%의 수율로 얻었다. Prepared in Preparation Example i in a 100 ml reaction vessel t -Butyl-1-benzylpiperidin-4-ylcarbamate (3.801 g, 13.1 mmol) was dissolved in 26 ml of methanol, and then a catalytic amount of 10% active palladium / carbon was added and reacted under hydrogen. After 12 hours, the reaction was terminated, filtered through Celite Ped to remove active palladium / carbon, and the solvent was distilled off under reduced pressure. The reaction mixture was purified by silica gel column chromatography to obtain the target compound (2.64 g) in 99% yield.

1H-NMR (200MHz, CD3OD) δ 1.36(s, 9H), 1.84-2.36(m, 4H), 2.74(m, 2H), 3.42(m, 2H), 3.60(br, 1H) 1 H-NMR (200 MHz, CD 3 OD) δ 1.36 (s, 9H), 1.84-2.36 (m, 4H), 2.74 (m, 2H), 3.42 (m, 2H), 3.60 (br, 1H)

LC/MS(M+H): 201LC / MS (M + H): 201

제조예 iii: Preparation Example iii: tt -부틸 1-R-피페리딘-4-일카바메이트(화학식 17의 화합물)-Butyl 1-R-piperidin-4-ylcarbamate (compound of Formula 17)

(iii-1) (iii-1) tt -부틸 1-아이소프로필피페리딘-4-일카바메이트(17a)-Butyl 1-isopropylpiperidin-4-ylcarbamate (17a)

방법 A: 100㎖ 반응 용기에 상기 제조예 ii에서 제조한 t-부틸 피페리딘-4-일카바메이트 (3g, 15mmol)를 메탄올(30㎖)에 녹여 교반하면서 아세톤 (7.70㎖, 105mmol)과 아세트산(0.45㎖, 7.5mmol)을 넣은 후 소듐시아노보로하이드라이드(NaCNBH3; 1.885㎎, 30mmol)를 4번에 걸쳐 적가하여 18시간 반응시켰다. 반응 종결을 확인 한 후 얼음물을 넣고 교반시킨 다음 에틸아세테이트로 추출하고 중조와 소금물로 씻어준 후, 남은 유기층은 무수 황산나트륨으로 건조시킨 후 여과, 감압 증류하여 농축한 다음 실리카겔 컬럼 크로마토그래피로 정제하여 흰색 고체의 표제 화합물 2.644g (17a, 73.3％)을 얻었다.Method A: prepared in Preparation Example ii in a 100 ml reaction vessel. t -butyl piperidin-4-ylcarbamate (3g, 15mmol) was dissolved in methanol (30ml) and acetone (7.70ml, 105mmol) and acetic acid (0.45ml, 7.5mmol) were added, followed by sodium cyanoborohydride (NaCNBH 3 ; 1.885mg, 30mmol). It was added dropwise four times and reacted for 18 hours. After confirming the completion of the reaction, add iced water, stir, extract with ethyl acetate and wash with sodium bicarbonate and brine. The remaining organic layer was dried over anhydrous sodium sulfate, filtered, distilled under reduced pressure, concentrated and purified by silica gel column chromatography. 2.644 g (17a, 73.3%) of the title compound were obtained as a solid.

1H-NMR (200MHz, CDCl3) δ 1.36(d, J=7.0Hz, 6H), 1.44(s, 9H), 2.00(m, 2H), 2.17(m, 2H), 2.94(m, 2H), 3.38(m, 3H), 3.69(m, 1H), 4.92(br, 1H) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.36 (d, J = 7.0 Hz, 6H), 1.44 (s, 9H), 2.00 (m, 2H), 2.17 (m, 2H), 2.94 (m, 2H) , 3.38 (m, 3 H), 3.69 (m, 1 H), 4.92 (br, 1 H)

LC/MS(M+H): 243LC / MS (M + H): 243

(iii-2) (iii-2) tt -부틸 1-사이클로프로필피페리딘-4-일카바메이트 (17b)-Butyl 1-cyclopropylpiperidin-4-ylcarbamate (17b)

아민치환기로서 아세톤 대신 브로모사이클로프로판을 사용한 것을 제외하고는 상기 (iii-1)과 동일한 방법으로 연한 노란색 오일 형태의 목적화합물 0.716g (17b, 60%)을 얻었다. 0.716 g (17b, 60%) of the target compound in the form of a pale yellow oil was obtained in the same manner as in (iii-1), except that bromocyclopropane was used instead of acetone as the amine substituent.

1H-NMR (200MHz, CDCl3) δ 0.44(m, 4H), 1.31(m, 2H), 1.47(s, 9H), 1.58(m, 1H), 1.90(m, 2H), 2.29(m, 2H), 2.94(m, 2H), 3.49(br, 1H), 4.42(br, 1H) 1 H-NMR (200 MHz, CDCl 3 ) δ 0.44 (m, 4H), 1.31 (m, 2H), 1.47 (s, 9H), 1.58 (m, 1H), 1.90 (m, 2H), 2.29 (m, 2H), 2.94 (m, 2H), 3.49 (br, 1H), 4.42 (br, 1H)

LC/MS(M+H): 241LC / MS (M + H): 241

(iii-3) (iii-3) tt -부틸 1-사이클로펜틸피페리딘-4-일카바메이트(17c) -Butyl 1-cyclopentylpiperidin-4-ylcarbamate (17c)

아민치환기로서 아세톤 대신 브로모사이클로펜탄을 사용한 것을 제외하고는 상기 (iii-1)과 동일한 방법으로 연한 노란색 오일 형태의 목적화합물 1.16g (17c, 86%)을 얻었다. 1.16 g (17c, 86%) of the target compound in the form of a pale yellow oil was obtained in the same manner as in (iii-1), except that bromocyclopentane was used instead of acetone as the amine substituent.

1H-NMR (200MHz, CDCl3) δ 1.45(s, 9H), 1.50-1.80(m, 8H), 1.81-2.18(m, 6H), 2.50(m, 1H), 2.94(m, 2H), 3.48(br, 1H), 4.41(br, 1H) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.45 (s, 9H), 1.50-1.80 (m, 8H), 1.81-2.18 (m, 6H), 2.50 (m, 1H), 2.94 (m, 2H), 3.48 (br, 1 H), 4.41 (br, 1 H)

LC/MS(M+H): 269LC / MS (M + H): 269

(iii-4) (iii-4) tt -부틸 1-메틸피페리딘-4-일카바메이트(17d)-Butyl 1-methylpiperidin-4-ylcarbamate (17d)

아민치환기로서 아세톤 대신 아이오도메탄을 사용한 것을 제외하고는 상기 (iii-1)과 동일한 방법으로 연한 노란색 오일 형태의 목적화합물 1.43g (17d, 79.4%)을 얻었다. In the same manner as in (iii-1), except that iodomethane was used instead of acetone as the amine substituent. 1.43 g (17d, 79.4%) of the title compound in the form of a light yellow oil were obtained.

1H-NMR (200MHz, CDCl3) δ 1.44(s, 9H), 1.45(m, 2H), 1.92(m, 2H), 2.07(m, 2H), 2.27(s, 3H), 2.74(m, 2H), 3.44(br, 1H), 4.43(br, 1H) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.44 (s, 9H), 1.45 (m, 2H), 1.92 (m, 2H), 2.07 (m, 2H), 2.27 (s, 3H), 2.74 (m, 2H), 3.44 (br, 1H), 4.43 (br, 1H)

LC/MS(M+H): 215LC / MS (M + H): 215

(iii-5) (iii-5) tt -부틸 1-에틸피페리딘-4-일카바메이트(17e)-Butyl 1-ethylpiperidin-4-ylcarbamate (17e)

방법 B: 25㎖ 반응 플라스크에 제조예 ii에서 제조한 t-부틸피페리딘-4-일카바메이트 (1.5g, 7.49mmol)를 0℃에서 19㎖의 N,N-다이메틸포름아마이드에 녹여 교반하면서 탄산칼륨 (2.07g, 14.98mmol, 2당량)과 아이오도에탄(0.60㎖, 7.49mmol, 1당량)을 첨가하고 0℃에서 실온으로 올려 4시간 반응시켰다. 반응 완결을 확인하고 용매를 감압 증류하여 남은 여액을 에틸에스테르로 추출하고 유기층을 포화 중조와 소금물로 세척한 다음 무수 황산마그네슘으로 건조 후 감압하에서 농축하였다. 얻어진 반응혼합물를 실리카겔 컬럼 크로마토그래피 방법으로 정제하여 연노란색의 오일형태의 목적 화합물(17e, 1.337g)을 78%의 수율로 얻었다. Method B: The t-butylpiperidin-4-ylcarbamate (1.5 g, 7.49 mmol) prepared in Preparation Example ii was dissolved in 19 ml of N, N-dimethylformamide at 0 ° C. in a 25 ml reaction flask. Potassium carbonate (2.07 g, 14.98 mmol, 2 equiv) and iodoethane (0.60 mL, 7.49 mmol, 1 equiv) were added while stirring, and the mixture was reacted for 4 hours at room temperature at 0 deg. After completion of the reaction, the solvent was distilled off under reduced pressure, and the remaining filtrate was extracted with ethyl ester. The organic layer was washed with saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained reaction mixture was purified by silica gel column chromatography to give the title compound (17e, 1.337 g) as light yellow oil in 78% yield.

1H-NMR (200MHz, CDCl3) δ 1.10(t, J=7.4Hz, 3H), 1.43(m, 2H), 1.47(s, 9H), 1.99(m, 4H), 2.40(q, J=7.2Hz, 2H), 2.85(m, 2H), 3.47(br, 1H), 4.43(br, 1H) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.10 (t, J = 7.4 Hz, 3H), 1.43 (m, 2H), 1.47 (s, 9H), 1.99 (m, 4H), 2.40 (q, J = 7.2 Hz, 2H), 2.85 (m, 2H), 3.47 (br, 1H), 4.43 (br, 1H)

LC/MS(M+H): 229LC / MS (M + H): 229

제조예 iv: 1-R-피페리딘-4-아민 (화학식 18의 화합물)Preparation Example iv: 1-R-Piperidin-4-amine (Compound 18)

(iv-1) 1-아이소프로필피페리딘-4-아민(18a)(iv-1) 1-isopropylpiperidin-4-amine (18a)

250㎖ 반응 용기에 상기 제조예 (iii-1)에서 제조한 t-부틸 1-아이소프로필 피페리딘-4-일카바메이트 (17a) (2.64g, 10.9mmol)를 메탄올(20㎖)에 녹여 교반하면서 트라이플루오로아세트산 (TFA; 4.06㎖, 54.5mmol, 5당량)을 천천히 적가한 후 18시간 반응시켰다. 반응 종결을 확인한 후 감압 증류하여 농축한 다음 클로로폼(CHCl3)으로 세 번 공비 감압 증류하고 2N 수산화칼륨 수용액 (20㎖)으로 염기화한 다음, 클로로폼(CHCl3)으로 3회 추출하고 소금물로 씻고 건조 후 여과하고 감압증류하여 노란색 오일형태의 표제 화합물 1.229g (18a, 79.3％)을 얻었다.In a 250 mL reaction vessel, t-butyl 1-isopropyl piperidin-4-ylcarbamate (17a) (2.64 g, 10.9 mmol) prepared in Preparation Example (iii-1) was dissolved in methanol (20 mL). Trifluoroacetic acid (TFA; 4.06 mL, 54.5 mmol, 5 equivalents) was slowly added dropwise while stirring, followed by reaction for 18 hours. After confirming the completion of the reaction, the mixture was distilled under reduced pressure, concentrated, and then azeotropically distilled three times with chloroform (CHCl 3 ), basified with 2N aqueous potassium hydroxide solution (20 mL), extracted three times with chloroform (CHCl 3 ), and brine. The mixture was washed with water, dried, filtered and distilled under reduced pressure to obtain 1.229 g (18a, 79.3%) of the title compound as a yellow oil.

1H-NMR (200MHz, CDCl3) δ 1.02(d, J=6.6Hz, 6H), 1.38(m, 2H), 1.56(br, 2H), 1.80(d, J=11.8Hz, 2H), 2.17(m, 2H), 2.71(m, 2H), 2.80(m, 2H) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.02 (d, J = 6.6 Hz, 6H), 1.38 (m, 2H), 1.56 (br, 2H), 1.80 (d, J = 11.8 Hz, 2H), 2.17 (m, 2H), 2.71 (m, 2H), 2.80 (m, 2H)

LC/MS(M+H): 143LC / MS (M + H): 143

(iv-2) 1-사이클로프로필피페리딘-4-아민(18b)(iv-2) 1-cyclopropylpiperidin-4-amine (18b)

상기 제조예 (iii-2)에서 제조한 화합물 (716㎎, 2.98mmol)을 출발물질로 사용하는 것을 제외하고 상기 (iv-1)과 동일한 방법으로 연한 노란색 오일 형태의 목적화합물 286㎎ (18b, 75%)을 얻었다. In the same manner as in (iv-1), except that the compound (716 mg, 2.98 mmol) prepared in Preparation Example (iii-2) was used as a starting material. 286 mg (18b, 75%) of the title compound was obtained as a pale yellow oil.

1H-NMR (200MHz, CDCl3) δ 0.44(m, 4H), 1.33(m, 2H), 1.52(m, 1H), 1.76(m, 2H), 2.20(m, 2H), 2.66(m, 1H), 3.00(m, 2H) 1 H-NMR (200 MHz, CDCl 3 ) δ 0.44 (m, 4H), 1.33 (m, 2H), 1.52 (m, 1H), 1.76 (m, 2H), 2.20 (m, 2H), 2.66 (m, 1H), 3.00 (m, 2H)

LC/MS(M+H): 141LC / MS (M + H): 141

(iv-3) 1-사이클로펜틸피페리딘-4-아민(18c)(iv-3) 1-cyclopentylpiperidin-4-amine (18c)

상기 제조예 (iii-3)에서 제조한 화합물 (1.16g, 4.3mmol)을 출발물질로 사용하는 것을 제외하고 상기 (iv-1)과 동일한 방법으로 연한 노란색 오일 형태의 목적화합물 689㎎ (18c, 95%)을 얻었다. In the same manner as in (iv-1), except that the compound (1.16 g, 4.3 mmol) prepared in Preparation Example (iii-3) was used as a starting material. 689 mg (18c, 95%) of the title compound was obtained as a light yellow oil.

1H-NMR (200MHz, CDCl3) δ 1.50-1.80(m, 8H), 1.81-2.18(m, 6H), 2.50(m, 2H), 2.74(m, 2H) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.50-1.80 (m, 8H), 1.81-2.18 (m, 6H), 2.50 (m, 2H), 2.74 (m, 2H)

LC/MS(M+H): 169LC / MS (M + H): 169

(iv-4) 1-메틸피페리딘-4-아민(18d)(iv-4) 1-methylpiperidin-4-amine (18d)

상기 제조예 (iii-4)에서 제조한 화합물 (1.80g, 8.4mmol)을 출발물질로 사용하는 것을 제외하고 상기 (iv-1)과 동일한 방법으로 연한 노란색 오일 형태의 목적화합물 820㎎ (18d, 86%)을 얻었다. Except for using the compound (1.80g, 8.4mmol) prepared in Preparation Example (iii-4) as a starting material, the target compound in light yellow oil form 820 mg (18d, 86%).

1H-NMR (200MHz, CDCl3) δ 1.37(m, 2H), 1.78(m, 2H), 1.99(m, 2H), 2.27(s, 3H), 2.70(m, 1H), 2.81(m, 2H) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.37 (m, 2H), 1.78 (m, 2H), 1.99 (m, 2H), 2.27 (s, 3H), 2.70 (m, 1H), 2.81 (m, 2H)

LC/MS(M+H): 115LC / MS (M + H): 115

(iv-5) 1-에틸피페리딘-4-아민(18e)(iv-5) 1-ethylpiperidin-4-amine (18e)

상기 제조예 (iii-5)에서 제조한 화합물 (1.34g, 5.86mmol)을 출발물질로 사 용하는 것을 제외하고 상기 (iv-1)과 동일한 방법으로 연한 노란색 오일 형태의 목적화합물 672㎎ (18e, 89%)을 얻었다. 672 mg (18e) of the target compound as a pale yellow oil, in the same manner as in (iv-1), except that the compound (1.34 g, 5.86 mmol) prepared in Preparation Example (iii-5) was used as a starting material. , 89%).

1H-NMR (200MHz, CDCl3) δ 1.08(t, J=7.2hz, 3H), 1.37(m, 2H), 1.81-2.08(m, 4H), 2.37(q, J=7.2Hz, 2H), 2.65(m, 1H), 2.87(m, 2H) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.08 (t, J = 7.2 hz, 3H), 1.37 (m, 2H), 1.81-2.08 (m, 4H), 2.37 (q, J = 7.2 Hz, 2H) , 2.65 (m, 1 H), 2.87 (m, 2 H)

LC/MS(M+H): 129LC / MS (M + H): 129

제조예 v: Preparation example v: tt -부틸 1-벤질피롤리딘-3-일카바메이트 (화학식 19의 화합물) -Butyl 1-benzylpyrrolidin-3-ylcarbamate (compound of formula 19)

500㎖ 반응 용기에 1-벤질피롤리딘-4-아민 (10g, 57mmol)을 3M 수산화나트륨 수용액 (21㎖)과 t-부탄올(114㎖)에 녹여 교반시키면서 t-부틸 다이카보네이트((tBoc)2O; 13.07g, 59.9mmol)를 가한 다음, 실온에서 12시간 반응시킨 후 에틸아세테이트로 2번 추출하고 0.1N 염산 수용액과 소금물로 씻어주었다. 남은 유기층은 무수 황산나트륨으로 건조시킨 후 여과, 감압 증류하여 농축한 다음, 실리카겔 컬럼 크로마토그래피로 정제하여 흰색 고체의 표제 화합물 15.25g (19, 97％)을 얻었다.In a 500 ml reaction vessel, 1-benzylpyrrolidin-4-amine (10 g, 57 mmol) was dissolved in 3M aqueous sodium hydroxide solution (21 ml) and t -butanol (114 ml) and stirred with t -butyl dicarbonate (( t Boc ) 2 O; 13.07 g, 59.9 mmol) was added thereto, followed by reaction at room temperature for 12 hours, followed by extraction twice with ethyl acetate and washing with 0.1N aqueous hydrochloric acid solution and brine. The remaining organic layer was dried over anhydrous sodium sulfate, filtered, distilled under reduced pressure, concentrated, and then purified by silica gel column chromatography to obtain 15.25 g (19, 97%) of the title compound as a white solid.

1H-NMR (200MHz, CDCl3) δ 1.43(s, 9H), 2.27(m, 2H), 2.57(m, 3H), 2.75(m, 1H), 3.59(s, 2H), 4.16(br, 1H), 4.85(br, 1H), 7.30(m, 5H) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.43 (s, 9H), 2.27 (m, 2H), 2.57 (m, 3H), 2.75 (m, 1H), 3.59 (s, 2H), 4.16 (br, 1H), 4.85 (br, 1H), 7.30 (m, 5H)

LC/MS(M+H): 277LC / MS (M + H): 277

제조예 vi: Preparation Example vi: tt -부틸 피롤리딘-3-일카바메이트 (화학식 20의 화합물)-Butyl pyrrolidin-3-ylcarbamate (compound of formula 20)

100㎖ 반응 용기에 상기 제조예 v에서 제조한 t-부틸 1-벤질피롤리딘-3-일카바메이트 (19, 15.75g, 57.0mmol)를 114㎖의 메탄올과 테트라부틸퓨란(4: 1)에 녹인 후, 촉매 량의 10% 활성 팔라듐/카본를 넣고 수소 하에서 반응시켰다. 12시간 후 반응종결을 확인하고 셀라이트 페드로 여과하여 활성 팔라듐/카본을 제거하고 용매를 감압 증류하여 제거하였다. 반응 혼합물을 실리카겔 칼럼 크로마토그래피 방법으로 정제하여 목적화합물(20, 9.51g)을 99%의 수율로 얻었다. In a 100 ml reaction vessel, t-butyl 1-benzylpyrrolidin-3-ylcarbamate (19, 15.75 g, 57.0 mmol) prepared in Preparation Example V was charged with 114 ml of methanol and tetrabutylfuran (4: 1). After dissolving in, a catalytic amount of 10% active palladium / carbon was added and reacted under hydrogen. After 12 hours, the reaction was terminated, filtered through Celite Ped to remove active palladium / carbon, and the solvent was distilled off under reduced pressure. The reaction mixture was purified by silica gel column chromatography to obtain the target compound (20, 9.51 g) in 99% yield.

1H-NMR (200MHz, CDCl3) δ 1.41(s, 9H), 2.26(m, 2H), 2.55(m, 3H), 2.74(m, 1H), 4.84(br, 1H), 1 H-NMR (200 MHz, CDCl 3 ) δ 1.41 (s, 9H), 2.26 (m, 2H), 2.55 (m, 3H), 2.74 (m, 1H), 4.84 (br, 1H),

LC/MS(M+H): 187LC / MS (M + H): 187

제조예 vii: Preparation Example vii: tt -부틸 1-R-피롤리딘-3-일카바메이트(화학식 21의 화합물)-Butyl 1-R-pyrrolidin-3-ylcarbamate (compound of formula 21)

(vii-1) (vii-1) tt -부틸 1-아이소프로필피롤리딘-3-일카바메이트 (21a)-Butyl 1-isopropylpyrrolidin-3-ylcarbamate (21a)

방법 A: 250㎖ 반응 용기에 상기 제조예 vi에서 제조한 t-부틸 피롤리딘-3-일카바메이트 (1.24g, 6.7mmol)를 메탄올(14㎖)에 녹여 교반하면서 아세톤(3.44㎖, 46.9mmol)과 아세트산(0.19㎖, 3.35mmol)을 넣은 후 소듐시아노보로하이드라이드(NaCNBH3; 842㎖, 13.4mmol)를 4번에 걸쳐 적가하여 18시간 반응시켰다. 반응 종결을 확인한 후 얼음물을 넣고 교반시킨 다음 에틸아세테이트로 추출하고 중조와 소금물로 씻어준 후, 남은 유기층은 무수 황산나트륨으로 건조시킨 후 여과, 감압 증류하여 농축한 다음 실리카겔 컬럼 크로마토그래피로 정제하여 흰색 고체의 표제 화합물 897㎎ (21a, 58％)을 얻었다.Method A: Prepared in Preparation Example vi above in a 250 ml reaction vessel. t -butyl pyrrolidin-3-ylcarbamate (1.24g, 6.7mmol) was dissolved in methanol (14ml) and stirred with acetone (3.44ml, 46.9mmol) and acetic acid (0.19ml, 3.35mmol), followed by sodium cyanoborohydride (NaCNBH 3 ; 842ml, 13.4 mmol) was added dropwise four times and reacted for 18 hours. After confirming the completion of the reaction, add ice water, stir, extract with ethyl acetate and wash with sodium bicarbonate and brine. The remaining organic layer was dried over anhydrous sodium sulfate, filtered, distilled under reduced pressure and concentrated by silica gel column chromatography to obtain white solid. 897 mg (21a, 58%) of the title compound were obtained.

1H-NMR (200MHz, CDCl3) δ 1.40(d, J=6.6Hz, 6Hz), 1.44(s, 9H), 2.12(m, 1H), 2.48(m, 1H), 3.27(m, 1H), 3.39(m, 3H), 3.57(m, 1H), 4.38(m, 1H), 5.41(m, 1H) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.40 (d, J = 6.6 Hz, 6 Hz), 1.44 (s, 9H), 2.12 (m, 1H), 2.48 (m, 1H), 3.27 (m, 1H) , 3.39 (m, 3H), 3.57 (m, 1H), 4.38 (m, 1H), 5.41 (m, 1H)

LC/MS(M+H): 229LC / MS (M + H): 229

(vii-2) (vii-2) tt -부틸 1-사이클로프로필피롤리딘-3-일카바메이트(21b)-Butyl 1-cyclopropylpyrrolidin-3-ylcarbamate (21b)

아민치환기로서 아세톤 대신 브로모사이클로프로판을 사용한 것을 제외하고는 상기 (vii-1)과 동일한 방법으로 연한 노란색 오일 형태의 목적화합물 7.17 g (21b, 59%)을 얻었다. In the same manner as in (vii-1), except that bromocyclopropane was used instead of acetone as the amine substituent. 7.17 g (21b, 59%) of the title compound in the form of a light yellow oil were obtained.

1H-NMR (200MHz, CDCl3) δ 0.40(m, 4H), 1.44(s, 9H), 1.60(m, 2H), 2.19(m, 1H), 2.57(m, 2H), 2.81(m, 2H), 4.14(br, 1H), 4.80(br, 1H) 1 H-NMR (200 MHz, CDCl 3 ) δ 0.40 (m, 4H), 1.44 (s, 9H), 1.60 (m, 2H), 2.19 (m, 1H), 2.57 (m, 2H), 2.81 (m, 2H), 4.14 (br, 1H), 4.80 (br, 1H)

LC/MS(M+H): 227LC / MS (M + H): 227

(vii-3) (vii-3) tt -부틸 1-사이클로헥실피롤리딘-3-일카바메이트(21c)-Butyl 1-cyclohexylpyrrolidin-3-ylcarbamate (21c)

아민치환기로서 아세톤 대신 사이클로헥사논을 사용한 것을 제외하고는 상기 (vii-1)과 동일한 방법으로 연한 노란색 오일 형태의 목적화합물 1.103 g (21c, 77%)을 얻었다. In the same manner as in (vii-1), except that cyclohexanone was used instead of acetone as the amine substituent. 1.103 g (21c, 77%) of the title compound in the form of a light yellow oil were obtained.

1H-NMR (200MHz, CDCl3) δ 1.23(m, 2H), 1.41(m, 2H), 1.46(s, 9H), 1.78(m, 2H), 1.89(m, 2H), 2.06(m, 3H), 2.44(m, 1H), 2.76(m, 1H), 3.04(m, 1H), 3.24(m, 2H), 3.49(m, 1H), 4.34(m, 1H), 5.33(m, 1H) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.23 (m, 2H), 1.41 (m, 2H), 1.46 (s, 9H), 1.78 (m, 2H), 1.89 (m, 2H), 2.06 (m, 3H), 2.44 (m, 1H), 2.76 (m, 1H), 3.04 (m, 1H), 3.24 (m, 2H), 3.49 (m, 1H), 4.34 (m, 1H), 5.33 (m, 1H) )

LC/MS(M+H): 269LC / MS (M + H): 269

(vii-4) (vii-4) tt -부틸 1-에틸피롤리딘-3-일카바메이트(21d)-Butyl 1-ethylpyrrolidin-3-ylcarbamate (21d)

방법 B: 100㎖ 반응 플라스크에 상기 제조예 vi에서 제조한 t-부틸 피롤리딘-3-일카바메이트 (1.5g, 8.05mmol)를 0℃에서 20㎖의 N,N-다이메틸포름아마이드에 녹여 교반하면서 탄산칼륨(K2CO3; 2.23g, 16.1mmol, 2당량)과 아이오도에탄(0.64㎖, 8.05mmol, 1당량)을 첨가하고 0℃에서 실온으로 올려 12시간 반응시켰다. 반응 완결을 확인하고 용매를 감압 증류하여 남은 여액을 에틸에스테르로 추출하고 유기층을 포화 중조와 소금물로 세척한 다음 무수 황산마그네슘으로 건조 후 감압하에서 농축하였다. 얻어진 반응혼합물을 실리카겔 컬럼 크로마토그래피 방법으로 정제하여 연노란색의 오일형태의 목적 화합물(21d, 1.13g)을 66%의 수율로 얻었다. Method B: t-butyl pyrrolidin-3-ylcarbamate (1.5 g, 8.05 mmol) prepared in Preparation Example vi was added to a 100 ml reaction flask. Potassium carbonate (K 2 CO 3 ; 2.23 g, 16.1 mmol, 2 equiv) and iodoethane (0.64 mL, 8.05 mmol, 1 equiv) were dissolved in 20 mL of N, N -dimethylformamide at 0 ° C while stirring. The mixture was added and reacted at room temperature at 0 ° C for 12 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the remaining filtrate was extracted with ethyl ester. The organic layer was washed with saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting reaction mixture was purified by silica gel column chromatography to give the title compound (21d, 1.13 g) as a pale yellow oil in a yield of 66%.

1H-NMR (200MHz, CDCl3) δ 1.10(t, J=7.4Hz, 3H), 1.44(s, 9H), 1.69(m, 1H), 2.27(m, 2H), 2.48(q, J=7.0Hz, 2H), 2.57(m, 1H), 2.81(m, 1H), 4.16(br, 1H), 4.86(br, 1H) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.10 (t, J = 7.4 Hz, 3H), 1.44 (s, 9H), 1.69 (m, 1H), 2.27 (m, 2H), 2.48 (q, J = 7.0 Hz, 2H), 2.57 (m, 1H), 2.81 (m, 1H), 4.16 (br, 1H), 4.86 (br, 1H)

LC/MS(M+H): 215LC / MS (M + H): 215

(vii-5) (vii-5) tt -부틸 1-(사이클로헥산카보닐)피롤리딘-3-일카바메이트(21e)-Butyl 1- (cyclohexanecarbonyl) pyrrolidin-3-ylcarbamate (21e)

방법 C: 50㎖ 반응 플라스크에 상기 제조예 vi에서 제조한 t-부틸 피롤리딘-3-일카바메이트 (1g, 5.4mmol)를 0℃에서 14㎖의 다이클로로메탄에 녹여 교반하면서 트라이에틸아민(0.83㎖, 5.94mmol, 1.1당량)과 사이클로헥실카보닐 클로라이드 (0.79㎖, 5.94mmol, 1.1당량)를 첨가하고 0℃에서 실온으로 올려 4시간 반응시켰다. 반응 완결을 확인하고 용매를 감압 증류하여 남은 여액을 다이클로로메탄로 추출하고 유기층을 포화 중조와 소금물로 세척한 다음 무수 황산마그네슘으로 건조 후 감압하에서 농축하였다. 얻어진 반응혼합물를 실리카겔 컬럼 크로마토그래피 방법으로 정제하여 연노란색의 오일형태의 목적 화합물(21e, 1.57g)을 98%의 수율로 얻었다. Method C: 50 ml reaction flask was prepared with t-butyl pyrrolidin-3-ylcarbamate (1 g, 5.4 mmol) prepared in Preparation Example vi above. Dissolve in 14 ml of dichloromethane at 0 ° C. and add triethylamine (0.83 ml, 5.94 mmol, 1.1 equiv) and cyclohexylcarbonyl chloride (0.79 mL, 5.94 mmol, 1.1 equiv) to room temperature at 0 ° C. The reaction was carried out for 4 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the remaining filtrate was extracted with dichloromethane. The organic layer was washed with saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained reaction mixture was purified by silica gel column chromatography to give the title compound (21e, 1.57 g) as a pale yellow oil in a yield of 98%.

1H-NMR (200MHz, CDCl3) δ 1.26(m, 4H), 1.46(s, 9H), 1.79(m, 6H), 1.98(m, 1H), 2.08-2.49(m, 2H), 3.39(m, 1H), 3.59(m, 2H), 3.73(m, 1H), 4.22(m, 1H), 4.63(m, 1H) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.26 (m, 4H), 1.46 (s, 9H), 1.79 (m, 6H), 1.98 (m, 1H), 2.08-2.49 (m, 2H), 3.39 ( m, 1H), 3.59 (m, 2H), 3.73 (m, 1H), 4.22 (m, 1H), 4.63 (m, 1H)

LC/MS(M+H): 297LC / MS (M + H): 297

제조예 viii: 1-R-피롤리딘-3-아민(화학식 22의 화합물)Preparation viii: 1-R-pyrrolidin-3-amine (compound of formula 22)

(viii-1) 1-아이소프로필피롤리딘-3-아민(22a)(viii-1) 1-isopropylpyrrolidin-3-amine (22a)

50㎖ 반응 용기에 상기 제조예 (vii-1)에서 제조한 t-부틸 1-아이소프로필피 롤리딘-3-일카바메이트(21a, 0.897g, 3.9mmol)를 다이클로로메탄(10㎖)에 녹여 교반하면서 트라이플루오로아세트산 (TFA; 1.45㎖, 1.95mmol, 5당량)을 천천히 적가한 후 18시간 반응시켰다. 반응 종결을 확인한 후 감압 증류하여 농축한 다음 클로로폼으로 세 번 공비 감압 증류하고 2N 수산화칼륨 수용액 20㎖로 염기화한 다음, 클로로폼으로 3회 추출하고 소금물로 씻고 건조 후 여과하여 감압증류하여 노란색 오일형태의 표제 화합물 433㎎ (22a, 86％)을 얻었다.In a 50 ml reaction vessel, t-butyl 1-isopropylpyrrolidin-3-ylcarbamate (21a, 0.897 g, 3.9 mmol) prepared in Preparation Example (vii-1) was added. It was dissolved in dichloromethane (10 mL) and slowly added dropwise trifluoroacetic acid (TFA; 1.45 mL, 1.95 mmol, 5 equiv.) While reacting for 18 hours. After confirming the completion of the reaction, the mixture was distilled under reduced pressure, concentrated, and then azeotropically distilled three times with chloroform, basified with 20 ml of 2N potassium hydroxide aqueous solution, extracted three times with chloroform, washed with brine, dried, filtered and distilled under reduced pressure. 433 mg (22a, 86%) of the title compound in the form of an oil was obtained.

1H-NMR (200MHz, CDCl3) δ 1.38(d, J=6.6Hz, 6Hz), 2.11(m, 1H), 2.47(m, 1H), 3.15(m, 1H), 3.29(m, 4H), 3.57(m, 1H) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.38 (d, J = 6.6 Hz, 6 Hz), 2.11 (m, 1H), 2.47 (m, 1H), 3.15 (m, 1H), 3.29 (m, 4H) , 3.57 (m, 1 H)

LC/MS(M+H): 129LC / MS (M + H): 129

(viii-2) 1-사이클로프로필피롤리딘-3-아민(22b)(viii-2) 1-cyclopropylpyrrolidin-3-amine (22b)

상기 제조예 (vii-2)에서 제조한 화합물 (1.129g, 5.27mmol)을 출발물질로 사용하는 것을 제외하고 상기 (viii-1)과 동일한 방법으로 연한 노란색 오일 형태의 목적화합물 477㎎ (22b, 79%)을 얻었다. Except for using the compound (1.129g, 5.27mmol) prepared in Preparation Example (vii-2) as a starting material, the target compound in the form of light yellow oil 477 mg (22b, 79%).

1H-NMR (200MHz, CDCl3) δ 0.41(m, 4H), 1.55(m, 2H), 2.16(m, 1H), 2.40(m, 1H), 2.68(m, 1H), 2.80(m, 1H), 2.93(m, 1H), 3.47(m, 1H) 1 H-NMR (200 MHz, CDCl 3 ) δ 0.41 (m, 4H), 1.55 (m, 2H), 2.16 (m, 1H), 2.40 (m, 1H), 2.68 (m, 1H), 2.80 (m, 1H), 2.93 (m, 1H), 3.47 (m, 1H)

LC/MS(M+H): 127LC / MS (M + H): 127

(viii-3) 1-사이클로핵실피롤리딘-3-아민(22c)(viii-3) 1-cyclonucleosilpyrrolidine-3-amine (22c)

상기 제조예 (vii-3)에서 제조한 화합물 (1.10g, 4.11mmol)을 출발물질로 사용하는 것을 제외하고 상기 (viii-1)과 동일한 방법으로 연한 노란색 오일 형태의 목적화합물 513㎎ (22c, 74%)을 얻었다. Except for using the compound (1.10g, 4.11mmol) prepared in Preparation Example (vii-3) as a starting material, the target compound in light yellow oil form in the same manner as in (viii-1) 513 mg (22c, 74%).

1H-NMR (200MHz, CDCl3) δ 1.19(m, 4H), 1.39-1.62(m, 4H), 1.72(m, 1H), 1.93(m, 3H), 2.14(m, 1H), 2.31(m, 1H), 2.58-2.78(m, 2H), 2.85(m, 1H), 3.47(m, 1H) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.19 (m, 4H), 1.39-1.62 (m, 4H), 1.72 (m, 1H), 1.93 (m, 3H), 2.14 (m, 1H), 2.31 ( m, 1H), 2.58-2.78 (m, 2H), 2.85 (m, 1H), 3.47 (m, 1H)

LC/MS(M+H): 169LC / MS (M + H): 169

(viii-4) 1-에틸피롤리딘-3-아민(22d)(viii-4) 1-ethylpyrrolidin-3-amine (22d)

상기 제조예 (vii-4)에서 제조한 화합물 (1.129g, 5.27mmol)을 출발물질로 사용하는 것을 제외하고 상기 (viii-1)과 동일한 방법으로 연한 노란색 오일 형태의 목적화합물 477㎎ (22d, 79%)을 얻었다. Except for using the compound (1.129g, 5.27mmol) prepared in Preparation Example (vii-4) as a starting material, the target compound in the form of light yellow oil 477 mg (22d, 79%).

1H-NMR (200MHz, CDCl3) δ 1.13(t, J=7.2hz, 3H), 1.51(m, 2H), 2.31(m, 2H), 2.47(m, 3H), 2.73(m, 1H), 3.54(m, 1H) 1 H-NMR (200MHz, CDCl 3 ) δ 1.13 (t, J = 7.2hz, 3H), 1.51 (m, 2H), 2.31 (m, 2H), 2.47 (m, 3H), 2.73 (m, 1H) , 3.54 (m, 1 H)

LC/MS(M+H): 115LC / MS (M + H): 115

(viii-5) (3-아미노피롤리딘-1-일)(사이클로헥실)메탄논(22e)(viii-5) (3-aminopyrrolidin-1-yl) (cyclohexyl) methanone (22e)

상기 제조예 (vii-5)에서 제조한 화합물 (1.57g, 5.3mmol)을 출발물질로 사 용하는 것을 제외하고 상기 (viii-1)과 동일한 방법으로 연한 노란색 오일 형태의 목적화합물 1.51g (22e, 99%)을 얻었다. 1.51 g (22e) of the target compound as a pale yellow oil, in the same manner as in (viii-1), except that the compound (1.57 g, 5.3 mmol) prepared in Preparation Example (vii-5) was used as a starting material. , 99%).

1H-NMR (200MHz, CDCl3) δ 1.26(m, 4H), 1.79(m, 6H), 1.98(m, 1H), 2.08-2.49(m, 2H), 3.39(m, 1H), 3.59(m, 2H), 3.73(m, 1H) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.26 (m, 4H), 1.79 (m, 6H), 1.98 (m, 1H), 2.08-2.49 (m, 2H), 3.39 (m, 1H), 3.59 ( m, 2H), 3.73 (m, 1H)

LC/MS(M+H): 197LC / MS (M + H): 197

제조예 6: 화학식 8의 화합물의 제조Preparation Example 6 Preparation of Compound of Formula 8

(6-1) (Z)-메틸 4-(3-(1-에틸피페리딘-4-일아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔닐)벤조에이트(8a)(6-1) (Z) -methyl 4- (3- (1-ethylpiperidin-4-ylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzo Eight (8a)

100㎖ 반응 플라스크에 4-[2-브로모메틸-3-(나프탈렌-1-일옥시)-프로페닐]-벤조산 메틸에스터(412㎎, 1mmol)를 0℃에서 2.5㎖의 N,N-다이메틸포름아마이드에 녹여 교반하면서 트라이에틸아민(0.17㎖, 1.2mmol, 1.2eq)과 1-에틸피페리딘-4-아민(128㎖, 1.0mmol, 1.0당량)을 첨가하고 0℃에서 실온으로 올려 4시간 반응시켰다. 반응 완결을 확인하고 용매를 감압 증류하여 남은 여액을 에틸에스테르로 추출하고 유기층을 포화 중조와 소금물로 세척한 다음 무수 황산마그네슘으로 건조 후 감압하에서 농축하였다. 얻어진 반응혼합물를 실리카겔 컬럼 크로마토그래피 방법으로 정제하여 연노란색의 오일형태의 목적 화합물(8a, 211㎎)을 46%의 수율로 얻었다. In a 100 ml reaction flask, 4- [2-bromomethyl-3- (naphthalen-1-yloxy) -propenyl] -benzoic acid methyl ester (412 mg, 1 mmol) was added 2.5 ml of N, N-di at 0 ° C. Dissolve in methylformamide and add triethylamine (0.17 mL, 1.2 mmol, 1.2 eq) and 1-ethylpiperidin-4-amine (128 mL, 1.0 mmol, 1.0 equiv.) To room temperature at 0 ° C. with stirring. The reaction was carried out for 4 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the remaining filtrate was extracted with ethyl ester. The organic layer was washed with saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained reaction mixture was purified by silica gel column chromatography to give the title compound (8a, 211 mg) in light yellow oil form in 46% yield.

1H-NMR (200MHz, CDCl3) δ 1.29(m, 5H), 1.72(m, 4H), 2.63(m, 3H), 2.96(m, 2H), 3.63(s, 2H), 3.91(s, 3H), 4.87(s, 2H), 6.70(s, J=7.8Hz, 1H), 6.89(s, 1H), 7.28-7.57(m, 6H), 7.80(m, 1H), 7.99(d, J=8.2Hz, 2H), 8.22(m, 1H) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.29 (m, 5H), 1.72 (m, 4H), 2.63 (m, 3H), 2.96 (m, 2H), 3.63 (s, 2H), 3.91 (s, 3H), 4.87 (s, 2H), 6.70 (s, J = 7.8 Hz, 1H), 6.89 (s, 1H), 7.28-7.57 (m, 6H), 7.80 (m, 1H), 7.99 (d, J) = 8.2 Hz, 2H), 8.22 (m, 1H)

LC/MS(M+H): 459LC / MS (M + H): 459

(6-2) ((Z)-메틸 4-(3-(1-에틸피롤리딘-3-일아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔닐)벤조에이트(8b)(6-2) ((Z) -methyl 4- (3- (1-ethylpyrrolidin-3-ylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) Benzoate (8b)

아민으로서 1-에틸피페리딘-4-아민 대신 1-에틸피롤리딘-3-아민을 사용한 것을 제외하고는 상기 (6-1)과 동일한 방법으로 연한 노란색 오일 형태의 목적화합물 160㎎ (8b, 36%)을 얻었다. In the same manner as in (6-1), except that 1-ethylpyrrolidin-3-amine was used instead of 1-ethylpiperidin-4-amine as the amine. 160 mg (8b, 36%) of the title compound was obtained as a pale yellow oil.

1H-NMR (200MHz, CDCl3) δ 1.26(t, J=7.8Hz, 3H), 1.81(m, 2H), 2.32(m, 2H), 2.86(q, J=7.2Hz, 2H), 3.15(m, 2H), 3.49(s, 2H), 3.60(m, 1H), 3.90(s, 3H), 4.86(s, 2H), 6.69(d, J=7.5Hz, 1H), 6.90(s, 1H), 7.28-7.52(m, 6H), 7.80(d, J=7.2Hz, 1H), 7.98(d, J=8.1Hz, 2H), 8.22(d, J=7.2Hz, 1H) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.26 (t, J = 7.8 Hz, 3H), 1.81 (m, 2H), 2.32 (m, 2H), 2.86 (q, J = 7.2 Hz, 2H), 3.15 (m, 2H), 3.49 (s, 2H), 3.60 (m, 1H), 3.90 (s, 3H), 4.86 (s, 2H), 6.69 (d, J = 7.5 Hz, 1H), 6.90 (s, 1H), 7.28-7.52 (m, 6H), 7.80 (d, J = 7.2 Hz, 1H), 7.98 (d, J = 8.1 Hz, 2H), 8.22 (d, J = 7.2 Hz, 1H)

LC/MS(M+H): 445LC / MS (M + H): 445

(6-3) (Z)-메틸 4-(2-((4-(트라이플루오로메톡시)벤질아미노)메틸)-3-(나프탈렌-1-일옥시)프로프-1-엔일)벤조에이트(8c)(6-3) (Z) -methyl 4- (2-((4- (trifluoromethoxy) benzylamino) methyl) -3- (naphthalen-1-yloxy) prop-1-enyl) benzoate (8c)

아민으로서 1-에틸피페리딘-4-아민 대신 4-(트라이플루오로메톡시)벤질아민을 사용한 것을 제외하고는 상기 (6-1)과 동일한 방법으로 연한 노란색 오일 형태의 목적화합물 421㎎ (8c, 92%)을 얻었다. 421 mg (8c) of the target compound as a pale yellow oil in the same manner as in (6-1), except that 4- (trifluoromethoxy) benzylamine was used instead of 1-ethylpiperidin-4-amine as the amine. , 92%).

TLC (EtOAc/Hex = 1/4) Rf 0.20TLC (EtOAc / Hex = 1/4) Rf 0.20

1H-NMR (300 MHz, CDCl3) δ 3.65(s, 2H), 3.86(s, 2H), 3.89(s, 3H), 4.86(s, 2H), 6.69(d, J=7.4Hz, 1H), 6.89(s, 1H), 7.10(d, J=7.6Hz, 2H), 7.25-7.50 (m, 8H), 7.79(d, J=7.4Hz, 1H), 7.96(d, J=7.8Hz, 2H), 8.18(d, J=7.4Hz, 1H) 1 H-NMR (300 MHz, CDCl 3 ) δ 3.65 (s, 2H), 3.86 (s, 2H), 3.89 (s, 3H), 4.86 (s, 2H), 6.69 (d, J = 7.4Hz, 1H ), 6.89 (s, 1H), 7.10 (d, J = 7.6 Hz, 2H), 7.25-7.50 (m, 8H), 7.79 (d, J = 7.4 Hz, 1H), 7.96 (d, J = 7.8 Hz , 2H), 8.18 (d, J = 7.4 Hz, 1H)

LC/MS(M+H): 506LC / MS (M + H): 506

(6-4) (Z)-(6-4) (Z)- tt -부틸 3-(3-(4-(메톡시카보닐)페닐)-2-((나프탈렌-1-일옥시)메틸)알릴아미노)피롤리딘-1-카복시레이트(8d)-Butyl 3- (3- (4- (methoxycarbonyl) phenyl) -2-((naphthalen-1-yloxy) methyl) allylamino) pyrrolidine-1-carboxylate (8d)

아민으로서 1-에틸피페리딘-4-아민 대신 4-(메톡시카보닐)페닐아민을 사용한 것을 제외하고는 상기 (6-1)과 동일한 방법으로 연한 노란색 오일 형태의 목적화합물 466㎎ (8d, 98%)을 얻었다. 466 mg (8d) of the target compound as a pale yellow oil in the same manner as in (6-1), except that 4- (methoxycarbonyl) phenylamine was used instead of 1-ethylpiperidin-4-amine as the amine. , 98%).

TLC (MeOH/MC = 1/12) Rf 0.45TLC (MeOH / MC = 1/12) Rf 0.45

1H NMR (300 MHz, CDCl3) δ 1.44(s, 9H), 1.60-1.74(m, 2H), 2.01-2.07 (q, J=7.4Hz, 1H), 2.86(d, J=7.6Hz, 2H), 3.10(m, 1H), 3.35-3.63(m, 3H), 3.88(s, 3H), 4.84(s, 2H), 6.68(d, J=7.4Hz, 1H), 6.88(s, 1H), 7.26-7.50(m, 6H), 7.78(t, J=7.8Hz, 1H), 7.96(d, J=7.6Hz, 2H), 8.23(d, J=7.6Hz, 1H)1 H NMR (300 MHz, CDCl 3 ) δ 1.44 (s, 9H), 1.60-1.74 (m, 2H), 2.01-2.07 (q, J = 7.4Hz, 1H), 2.86 (d, J = 7.6Hz, 2H ), 3.10 (m, 1H), 3.35-3.63 (m, 3H), 3.88 (s, 3H), 4.84 (s, 2H), 6.68 (d, J = 7.4 Hz, 1H), 6.88 (s, 1H) , 7.26-7.50 (m, 6H), 7.78 (t, J = 7.8 Hz, 1H), 7.96 (d, J = 7.6 Hz, 2H), 8.23 (d, J = 7.6 Hz, 1H)

LC/MS(M+H): 517LC / MS (M + H): 517

(6-5) (Z)-메틸 4-(3-(1-(사이클로헥산카보닐)피롤리딘-3-일아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)벤조에이트(8e)(6-5) (Z) -methyl 4- (3- (1- (cyclohexanecarbonyl) pyrrolidin-3-ylamino) -2-((naphthalen-1-yloxy) methyl) prop- 1-enyl) benzoate (8e)

아민으로서 1-에틸피페리딘-4-아민 대신 1-(사이클로헥산카보닐)피롤리딘-3-아민을 사용한 것을 제외하고는 상기 (6-1)과 동일한 방법으로 연한 노란색 오일 형태의 목적화합물 401㎎ (8e, 79%)을 얻었다. Except for using 1- (cyclohexanecarbonyl) pyrrolidine-3-amine as the amine instead of 1-ethylpiperidin-4-amine, the purpose of the pale yellow oil form in the same manner as in (6-1) above. Compound 401 mg (8e, 79%) was obtained.

TLC (MeOH/MC = 1/12) Rf 0.25TLC (MeOH / MC = 1/12) Rf 0.25

1H-NMR (300 MHz, CDCl3) δ 1.23(m, 5H), 1.43(m, 5H), 2.09(q, J=7.4Hz, 3H), 3.58(m, 4H), 3.87(d, J=7.4Hz, 3H), 4.81(t, J=7.4Hz, 3H), 4.93(s, 2H), 6.71(s, 1H), 6.77(d, J=7.6Hz, 1H), 7.31(m, 2H), 7.46(m, 4H), 7.82(d, J=7.6Hz, 2H), 7.94(dd, J = 7.8, 7.8 Hz, 1H), 8.22(d, J = 7.6 Hz, 1H) 1 H-NMR (300 MHz, CDCl 3 ) δ 1.23 (m, 5H), 1.43 (m, 5H), 2.09 (q, J = 7.4 Hz, 3H), 3.58 (m, 4H), 3.87 (d, J = 7.4 Hz, 3H), 4.81 (t, J = 7.4 Hz, 3H), 4.93 (s, 2H), 6.71 (s, 1H), 6.77 (d, J = 7.6 Hz, 1H), 7.31 (m, 2H) ), 7.46 (m, 4H), 7.82 (d, J = 7.6 Hz, 2H), 7.94 (dd, J = 7.8, 7.8 Hz, 1H), 8.22 (d, J = 7.6 Hz, 1H)

LC/MS(M+H): 527LC / MS (M + H): 527

(6-6) (Z)-메틸 4-(3-(1-사이클로펜틸피페리딘-4-일아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)벤조에이트(8f)(6-6) (Z) -methyl 4- (3- (1-cyclopentylpiperidin-4-ylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) Benzoate (8f)

아민으로서 1-에틸피페리딘-4-아민 대신 1-사이클로펜틸피페리딘-4아민을 사용한 것을 제외하고는 상기 (6-1)과 동일한 방법으로 연한 노란색 오일 형태의 목적화합물 433㎎ (8f, 86%)을 얻었다. 433 mg (8f) of the target compound as a pale yellow oil in the same manner as in (6-1), except that 1-cyclopentylpiperidin-4amine was used instead of 1-ethylpiperidin-4-amine as the amine. , 86%).

TLC (MeOH/MC = 1/6) Rf 0.40TLC (MeOH / MC = 1/6) Rf 0.40

1H-NMR (300 MHz, CDCl3) δ 1.39(m, 9H), 2.47(s, 1H), 3.45(s, 1H), 3.57(m, 6H), 3.86(s, 3H), 4.63(s, 2H), 4.90(s, 2H), 5.29(s, 1H), 6.74(d, J=7.4Hz, 1H), 7.27(s, 1H), 7.48(m, 5H), 7.64(s, 1H), 7.83(t, J=7.8Hz, 1H), 7.93(d, J= 7.8Hz, 2H), 8.09(t, J=7.6Hz, 1H) 1 H-NMR (300 MHz, CDCl 3 ) δ 1.39 (m, 9H), 2.47 (s, 1H), 3.45 (s, 1H), 3.57 (m, 6H), 3.86 (s, 3H), 4.63 (s , 2H), 4.90 (s, 2H), 5.29 (s, 1H), 6.74 (d, J = 7.4 Hz, 1H), 7.27 (s, 1H), 7.48 (m, 5H), 7.64 (s, 1H) , 7.83 (t, J = 7.8 Hz, 1H), 7.93 (d, J = 7.8 Hz, 2H), 8.09 (t, J = 7.6 Hz, 1H)

LC/MS(M+H): 499LC / MS (M + H): 499

(6-7) (Z)-메틸 4-(3-(1-(사이클로헥실메틸)피롤리딘-3-일아미노)-2-((나프탈렌-1-일옥시)메틸프로프-1-엔일)벤조에이트(8g)(6-7) (Z) -methyl 4- (3- (1- (cyclohexylmethyl) pyrrolidin-3-ylamino) -2-((naphthalen-1-yloxy) methylprop-1- Nyl) Benzoate (8 g)

아민으로서 1-에틸피페리딘-4-아민 대신 1-(사이클로헥실메틸)피롤리딘-3-아민을 사용한 것을 제외하고는 상기 (6-1)과 동일한 방법으로 연한 노란색 오일 형태의 목적화합물 477㎎ (8g, 90%)을 얻었다. Except for using 1- (cyclohexylmethyl) pyrrolidine-3-amine instead of 1-ethylpiperidin-4-amine as the amine, the target compound in the form of a pale yellow oil in the same manner as in (6-1). 477 mg (8 g, 90%) were obtained.

TLC (MeOH/MC = 1/6) Rf 0.80TLC (MeOH / MC = 1/6) Rf 0.80

1H-NMR (300 MHz, CDCl3) δ 0.83(m, 3H), 1.07-1.33(m, 4H), 1.60(m, 5H), 2.02(d, J=7.6Hz, 2H), 2.17(m, 5H), 3.46-3.63(m, 2H), 3.89(s, 3H), 4.57(s, 1H), 4.79(m, 2H), 6.69(d, J=7.4Hz, 1H), 6.86(t, J=7.6Hz, 2H), 7.18-7.48(m, 5H), 7.83(d, J=7.8Hz, 2H), 7.95(d, J=7.6Hz, 1H), 8.26(d, J=7.6Hz, 1H) 1 H-NMR (300 MHz, CDCl 3 ) δ 0.83 (m, 3H), 1.07-1.33 (m, 4H), 1.60 (m, 5H), 2.02 (d, J = 7.6 Hz, 2H), 2.17 (m , 5H), 3.46-3.63 (m, 2H), 3.89 (s, 3H), 4.57 (s, 1H), 4.79 (m, 2H), 6.69 (d, J = 7.4 Hz, 1H), 6.86 (t, J = 7.6 Hz, 2H), 7.18-7.48 (m, 5H), 7.83 (d, J = 7.8 Hz, 2H), 7.95 (d, J = 7.6 Hz, 1H), 8.26 (d, J = 7.6 Hz, 1H)

LC/MS(M+H): 513LC / MS (M + H): 513

(6-8) (Z)-메틸 4-(3-(1-벤질피롤리딘-3-일아미노)-2-((나프탈렌-1-일옥시)메틸프로프-1-엔일)벤조에이트(8h)(6-8) (Z) -methyl 4- (3- (1-benzylpyrrolidin-3-ylamino) -2-((naphthalen-1-yloxy) methylprop-1-enyl) benzoate (8h)

아민으로서 1-에틸피페리딘-4-아민 대신 1-벤질피롤리딘-3-아민을 사용한 것을 제외하고는 상기 (6-1)과 동일한 방법으로 연한 노란색 오일 형태의 목적화합물 485㎎ (8h, 94%)을 얻었다. 485 mg (8h) of the target compound as a pale yellow oil in the same manner as in (6-1), except that 1-benzylpyrrolidin-3-amine was used instead of 1-ethylpiperidin-4-amine as the amine. , 94%).

TLC (MeOH/MC = 1/12) Rf 0.25TLC (MeOH / MC = 1/12) Rf 0.25

1H-NMR (300 MHz, CDCl3) δ 1.61(t, J=7.6Hz, 1H), 2.15(m, 2H), 2.41(q, J=7.6Hz, 1H), 2.51(d, J=7.6Hz, 1H), 2.64(d, J=7.6Hz, 1H), 2.73(m, 1H), 3.39-(m, 1H), 3.55(m, 3H), 3.85(s, 3H), 4.81(s, 2H), 6.66(d, J=7.6Hz, 1H), 6.85(s, 1H), 7.35(m, 6H), 7.47(m, 5H), 7.76(t, J=7.8Hz, 1H), 7.94(d, J=7.6Hz, 2H), 8.23(d, J=7.6Hz, 1H) 1 H-NMR (300 MHz, CDCl 3 ) δ 1.61 (t, J = 7.6 Hz, 1H), 2.15 (m, 2H), 2.41 (q, J = 7.6 Hz, 1H), 2.51 (d, J = 7.6 Hz, 1H), 2.64 (d, J = 7.6Hz, 1H), 2.73 (m, 1H), 3.39- (m, 1H), 3.55 (m, 3H), 3.85 (s, 3H), 4.81 (s, 2H), 6.66 (d, J = 7.6 Hz, 1H), 6.85 (s, 1H), 7.35 (m, 6H), 7.47 (m, 5H), 7.76 (t, J = 7.8 Hz, 1H), 7.94 ( d, J = 7.6 Hz, 2H), 8.23 (d, J = 7.6 Hz, 1H)

LC/MS(M+H): 507LC / MS (M + H): 507

(6-9) (Z)-메틸 4-(3-(1-사이클로프로필피페리딘-4-일아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)벤조에이트(8i)(6-9) (Z) -methyl 4- (3- (1-cyclopropylpiperidin-4-ylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) Benzoate (8i)

아민으로서 1-에틸피페리딘-4-아민 대신 1-사이클로프로필피페리딘-4-아민을 사용한 것을 제외하고는 상기 (6-1)과 동일한 방법으로 연한 노란색 오일 형태의 목적화합물 320㎎ (8i, 30%)을 얻었다. 320 mg of the target compound as a pale yellow oil in the same manner as in (6-1), except that 1-cyclopropylpiperidin-4-amine was used instead of 1-ethylpiperidin-4-amine as the amine. 8i, 30%).

수율 30 % Yield 30%

TLC (MeOH/MC = 1/6) Rf 0.55TLC (MeOH / MC = 1/6) Rf 0.55

1H-NMR (300 MHz, CDCl3) δ 0.47(m, 2H), 1.47(m, 3H), 1.64(t, J=7.4Hz, 3H), 2.32(m, 1H), 2.57(s, 1H), 3.04(q, J=7.4Hz, 1H), 3.25(m, 1H), 3.62(m, 4H), 3.87(s, 3H), 4.86(s, 2H), 6.69(d, J=7.4Hz, 1H), 6.96(s, 1H), 7.27-7.50 (m, 4H), 7.78(d, J=7.4Hz, 1H), 7.95(t, J=7.4Hz, 4H), 8.21(d, J=7.6Hz, 1H) 1 H-NMR (300 MHz, CDCl 3 ) δ 0.47 (m, 2H), 1.47 (m, 3H), 1.64 (t, J = 7.4 Hz, 3H), 2.32 (m, 1H), 2.57 (s, 1H ), 3.04 (q, J = 7.4 Hz, 1H), 3.25 (m, 1H), 3.62 (m, 4H), 3.87 (s, 3H), 4.86 (s, 2H), 6.69 (d, J = 7.4 Hz , 1H), 6.96 (s, 1H), 7.27-7.50 (m, 4H), 7.78 (d, J = 7.4Hz, 1H), 7.95 (t, J = 7.4Hz, 4H), 8.21 (d, J = 7.6 Hz, 1H)

(6-10) (Z)-메틸 4-(3-(1-사이클로프로필피롤리딘-3-일아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)벤조에이트(8j)(6-10) (Z) -methyl 4- (3- (1-cyclopropylpyrrolidin-3-ylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) Benzoate (8j)

아민으로서 1-에틸피페리딘-4-아민 대신 1-사이클로프로필피롤리딘-3-아민을 사용한 것을 제외하고는 상기 (6-1)과 동일한 방법으로 연한 노란색 오일 형태의 목적화합물 394㎎ (8j, 60%)을 얻었다. 394 mg of the target compound as a pale yellow oil in the same manner as in (6-1), except that 1-cyclopropylpyrrolidin-3-amine was used instead of 1-ethylpiperidin-4-amine as the amine. 8j, 60%).

TLC (MeOH/MC = 1/12) Rf 0.80TLC (MeOH / MC = 1/12) Rf 0.80

1H-NMR (300 MHz, CDCl3) δ 0.38(m, 3H), 1.56(q, J=7.6Hz, 2H), 2.11(m, 2H), 2.51(q, J=7.6Hz, 1H), 2.87(m, 3H), 3.41(d, J=7.6Hz, 1H), 3.59s, 2H), 3.88(s, 3H), 4.83(s, 2H), 6.69(d, J=7.6 Hz, 1H), 6.87(s, 1H), 7.28-7.50 (m, 4H), 7.78(d, J=7.8Hz, 1H), 7.95(m, 4H), 8.24(d, J=7.6Hz, 1H) 1 H-NMR (300 MHz, CDCl 3 ) δ 0.38 (m, 3H), 1.56 (q, J = 7.6 Hz, 2H), 2.11 (m, 2H), 2.51 (q, J = 7.6 Hz, 1H), 2.87 (m, 3H), 3.41 (d, J = 7.6 Hz, 1H), 3.59 s, 2H, 3.88 (s, 3H), 4.83 (s, 2H), 6.69 (d, J = 7.6 Hz, 1H) , 6.87 (s, 1H), 7.28-7.50 (m, 4H), 7.78 (d, J = 7.8 Hz, 1H), 7.95 (m, 4H), 8.24 (d, J = 7.6 Hz, 1H)

(6-11) (Z)-메틸 4-(3-(1-사이클로헥실피롤리딘-3-일아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)벤조에이트(8k)(6-11) (Z) -methyl 4- (3- (1-cyclohexylpyrrolidin-3-ylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) Benzoate (8k)

아민으로서 1-에틸피페리딘-4-아민 대신 1-사이클로헥실피롤리딘-3-아민을 사용한 것을 제외하고는 상기 (6-1)과 동일한 방법으로 연한 노란색 오일 형태의 목적화합물 463㎎ (8k, 95%)을 얻었다. 463 mg of the target compound in light yellow oil form in the same manner as in (6-1), except that 1-cyclohexylpyrrolidin-3-amine was used instead of 1-ethylpiperidin-4-amine as the amine. 8k, 95%).

TLC (MeOH/MC = 1/12) Rf 0.20TLC (MeOH / MC = 1/12) Rf 0.20

1H-NMR (300 MHz, CDCl3) δ 1.17(m, 4H), 1.62 (m, 4H), 1.71(s, 2H), 2.16(m, 3H), 2.43(q, J=7.8Hz, 1H), 2.64(m, 2H), 2.87(m, 1H), 3.40(d, J=7.8Hz, 1H), 3.59(s, 2H), 3.88(s, 3H), 4.84(s, 2H), 6.68(d, J=7.4Hz, 1H), 6.87(s, 1H), 7.26-7.50(m, 6H), 7.78(d, J=7.8Hz, 1H), 7.96(d, J=7.6Hz, 2H), 8.24(d, J=7.6Hz, 1H) 1 H-NMR (300 MHz, CDCl 3 ) δ 1.17 (m, 4H), 1.62 (m, 4H), 1.71 (s, 2H), 2.16 (m, 3H), 2.43 (q, J = 7.8 Hz, 1H ), 2.64 (m, 2H), 2.87 (m, 1H), 3.40 (d, J = 7.8 Hz, 1H), 3.59 (s, 2H), 3.88 (s, 3H), 4.84 (s, 2H), 6.68 (d, J = 7.4 Hz, 1H), 6.87 (s, 1H), 7.26-7.50 (m, 6H), 7.78 (d, J = 7.8 Hz, 1H), 7.96 (d, J = 7.6 Hz, 2H) , 8.24 (d, J = 7.6 Hz, 1H)

(6-12) (Z)-메틸 4-(3-(에틸(2-몰포리노에틸)아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)벤조에이트(8l)(6-12) (Z) -methyl 4- (3- (ethyl (2-morpholinoethyl) amino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzoate ( 8l)

아민으로서 1-에틸피페리딘-4-아민 대신 에틸(2-몰포리노에틸)아민을 사용한 것을 제외하고는 상기 (6-1)과 동일한 방법으로 연한 노란색 오일 형태의 목적화합물 401㎎ (8l, 69%)을 얻었다. 401 mg (8 l, 8 g, 8 g of a target compound as a pale yellow oil) in the same manner as in (6-1), except that ethyl (2-morpholinoethyl) amine was used instead of 1-ethyl piperidin-4-amine as an amine. 69%).

TLC (MeOH/MC = 1/9) Rf 0.90TLC (MeOH / MC = 1/9) Rf 0.90

1H-NMR (300 MHz, CDCl3) δ 1.01(m, 3H), 1.80(m, 1H), 2.32(m, 6H), 2.51(m, 3H), 3.42(s, 2H), 3.54(m, 4H), 3.85(s, 3H), 4.84(s, 2H), 6.73(d, J=7.4Hz, 1H), 6.90(s, 1H), 7.30-7.56(m, 6H), 7.84(d, J=7.8Hz, 1H), 7.97(d, J=7.8Hz, 2H), 8.30(d, J=7.6Hz, 1H) 1 H-NMR (300 MHz, CDCl 3 ) δ 1.01 (m, 3H), 1.80 (m, 1H), 2.32 (m, 6H), 2.51 (m, 3H), 3.42 (s, 2H), 3.54 (m , 4H), 3.85 (s, 3H), 4.84 (s, 2H), 6.73 (d, J = 7.4 Hz, 1H), 6.90 (s, 1H), 7.30-7.56 (m, 6H), 7.84 (d, J = 7.8Hz, 1H), 7.97 (d, J = 7.8Hz, 2H), 8.30 (d, J = 7.6Hz, 1H)

(6-13) (Z)-메틸 4-(3-(1-메톡시프로판-2-일아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)벤조에이트(8m)(6-13) (Z) -methyl 4- (3- (1-methoxypropan-2-ylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzoate (8m)

아민으로서 1-에틸피페리딘-4-아민 대신 1-메톡시프로판-2-아민을 사용한 것을 제외하고는 상기 (6-1)과 동일한 방법으로 연한 노란색 오일 형태의 목적화합물 240㎎ (8m, 57%)을 얻었다. 240 mg (8m, 8 mg, 8 mg, 8 mg, of the title compound as a pale yellow oil, in the same manner as in (6-1), except that 1-methoxypropan-2-amine was used instead of 1-ethylpiperidin-4-amine as the amine). 57%).

1H-NMR (200MHz, CDCl3) δ 1.08(d, J=6.4Hz, 3H), 3.07(m, 1H), 3.30(m, 2H), 3.34(s, 3H), 3.64(dd, J=15.8Hz, 14.4Hz, 2H), 3.92(s, 3H), 4.87(s, 2H), 6.71(d, J=7.4Hz, 1H), 6.92(s, 1H), 7.27-7.57(m, 6H), 7.81(m, 1H), 7.98(d, J=8.2Hz, 2H), 8.30(m, 1H) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.08 (d, J = 6.4 Hz, 3H), 3.07 (m, 1H), 3.30 (m, 2H), 3.34 (s, 3H), 3.64 (dd, J = 15.8 Hz, 14.4 Hz, 2H), 3.92 (s, 3H), 4.87 (s, 2H), 6.71 (d, J = 7.4 Hz, 1H), 6.92 (s, 1H), 7.27-7.57 (m, 6H) , 7.81 (m, 1H), 7.98 (d, J = 8.2 Hz, 2H), 8.30 (m, 1H)

LC/MS(M+H): 420LC / MS (M + H): 420

제조예 7 : 화학식 9의 화합물의 제조Preparation Example 7 Preparation of Compound of Formula 9

(7-1) (Z)-4-(3-(1-에틸피페리딘-4-일아미노)-2-((나프탈렌-1-일옥시) 메틸)프로프 -1-엔닐)벤조산(9a)(7-1) (Z) -4- (3- (1-ethylpiperidin-4-ylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzoic acid ( 9a)

100㎖ 반응용기에 상기 제조예 (6-1)에서 제조한 (Z)-메틸 4-(3-(1-에틸피페리딘-4-일아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔닐)벤조에이트 (8a; 211㎎, 0.46 mmol)를 1.2㎖의 테트라하이드로퓨란에 녹여 교반하였다. 리튬하이드록사이드 · 일수화물(58㎎, 1.35mmol, 3aq)을 0.4㎖의 물에 녹여 가한 다음, 실온에서 약 12시간동안 교반하였다. 반응 완결을 확인한 후 에틸아세테이트로 물 층을 씻어 준 후 6노르말 염산 수용액을 이용하여 산성화(PH=4)하였다. 여액을 감압증류하고 에틸아세테이트로 2번 추출하였다. 유기층을 소금물로 씻어주고 마그네슘 설페이트로 건조시킨 후 여과하여 용매를 감압 증류하여 제거하였다. 남은 잔사를 실리카겔 칼럼 크로마토그래피로 정제하여 연한 노란색 거품형태의 목적화합물 200㎎(9a, 98%)을 얻었다.(Z) -methyl 4- (3- (1-ethylpiperidin-4-ylamino) -2-((naphthalen-1-yloxy) prepared in Preparation Example (6-1) in a 100 ml reaction vessel. ) Methyl) prop-1-enyl) benzoate (8a; 211 mg, 0.46 mmol) was dissolved in 1.2 ml of tetrahydrofuran and stirred. Lithium hydroxide monohydrate (58 mg, 1.35 mmol, 3aq) was dissolved in 0.4 ml of water, and then stirred at room temperature for about 12 hours. After confirming the completion of the reaction, wash the water layer with ethyl acetate Acidification (PH = 4) using 6-normal hydrochloric acid aqueous solution. The filtrate was distilled under reduced pressure and extracted twice with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and the solvent was distilled off under reduced pressure. The remaining residue was purified by silica gel column chromatography to obtain 200 mg (9a, 98%) of the title compound as a pale yellow foam.

TLC (MeOH/MC = 1/6) Rf 0.25TLC (MeOH / MC = 1/6) Rf 0.25

(7-2) (Z)-4-(3-(1-에틸피롤리딘-3-일아미노)-2-((나프탈렌-1-일옥시) 메틸)프로프-1-엔닐)벤조산(9b)(7-2) (Z) -4- (3- (1-ethylpyrrolidin-3-ylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzoic acid ( 9b)

출발물질로서 상기 제조예 (6-2)에서 제조한 화합물을 사용한 것을 제외하고는 상기 (7-1)과 동일한 방법으로 연한 노란색 거품 형태의 목적화합물 149㎎ (9b, 96%)을 얻었다. 149 mg (9b, 96%) of the target compound in the form of a pale yellow foam was obtained in the same manner as in (7-1), except that the compound prepared in Preparation Example (6-2) was used as the starting material.

TLC (MeOH/MC = 1/6) Rf 0.40TLC (MeOH / MC = 1/6) Rf 0.40

(7-3) (Z)-4-(2-((4-(트라이플루오로메톡시)벤질아미노)메틸)-3-(나프탈렌-1-일옥시)프로프-1-엔일)벤조산(9c)(7-3) (Z) -4- (2-((4- (trifluoromethoxy) benzylamino) methyl) -3- (naphthalen-1-yloxy) prop-1-enyl) benzoic acid (9c )

출발물질로서 상기 제조예 (6-3)에서 제조한 화합물을 사용한 것을 제외하고는 상기 (7-1)과 동일한 방법으로 연한 노란색 거품 형태의 목적화합물 164㎎ (9c, 100%)을 얻었다. 164 mg (9c, 100%) of the target compound in the form of a pale yellow foam was obtained in the same manner as in (7-1), except that the compound prepared in Preparation Example (6-3) was used as the starting material.

TLC (MeOH/MC = 1/6) Rf 0.25TLC (MeOH / MC = 1/6) Rf 0.25

1H-NMR (300 MHz, CD3OD) δ 4.10(s, 2H), 4.37(s, 2H), 4.98(s, 2H), 6.75(d, J=7.4Hz, 1H), 7.21 (s, 1H), 7.28(q, J = 7.6 Hz, 3H), 7.36-7.48(m, 5H), 7.57(d, J=7.8Hz, 2H), 7.77(d, J=7.4Hz, 1H), 7.97(d, J=7.8Hz, 2H), 8.06(d, J=7.4Hz, 1H) 1 H-NMR (300 MHz, CD 3 OD) δ 4.10 (s, 2H), 4.37 (s, 2H), 4.98 (s, 2H), 6.75 (d, J = 7.4 Hz, 1H), 7.21 (s, 1H), 7.28 (q, J = 7.6 Hz, 3H), 7.36-7.48 (m, 5H), 7.57 (d, J = 7.8 Hz, 2H), 7.77 (d, J = 7.4 Hz, 1H), 7.97 ( d, J = 7.8 Hz, 2H), 8.06 (d, J = 7.4 Hz, 1H)

LC/MS(M+H): 492LC / MS (M + H): 492

(7-4) (Z)-4-(3-(1-((7-4) (Z) -4- (3- (1- ( tt -부톡시카보닐)피롤리딘-3-일아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)벤조산(9d)-Butoxycarbonyl) pyrrolidin-3-ylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzoic acid (9d)

출발물질로서 상기 제조예 (6-4)에서 제조한 화합물을 사용한 것을 제외하고는 상기 (7-1)과 동일한 방법으로 연한 노란색 거품 형태의 목적화합물 201㎎ (9d, 98%)을 얻었다. 201 mg (9d, 98%) of the target compound in the form of a pale yellow foam was obtained in the same manner as in (7-1), except that the compound prepared in Preparation Example (6-4) was used as the starting material.

TLC (MeOH/MC = 1/6) Rf 0.45TLC (MeOH / MC = 1/6) Rf 0.45

(7-5) (Z)-4-(3-(1-(사이클로헥산카보닐)피롤리딘-3-일아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)벤조산(9e)(7-5) (Z) -4- (3- (1- (cyclohexanecarbonyl) pyrrolidin-3-ylamino) -2-((naphthalen-1-yloxy) methyl) prop-1 -Enyl) benzoic acid (9e)

출발물질로서 상기 제조예 (6-5)에서 제조한 화합물을 사용한 것을 제외하고는 상기 (7-1)과 동일한 방법으로 연한 노란색 거품 형태의 목적화합물 144㎎ (9e, 87%)을 얻었다.144 mg (9e, 87%) of the target compound in the form of a pale yellow foam was obtained in the same manner as in (7-1), except that the compound prepared in Preparation Example (6-5) was used as the starting material.

TLC (MeOH/MC = 1/6) Rf 0.15TLC (MeOH / MC = 1/6) Rf 0.15

(7-6) (Z)-4-(3-(1-사이클로펜틸피페리딘-4-일아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)벤조산(9f)(7-6) (Z) -4- (3- (1-cyclopentylpiperidin-4-ylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzoic acid (9f)

출발물질로서 상기 제조예 (6-6)에서 제조한 화합물을 사용한 것을 제외하고는 상기 (7-1)과 동일한 방법으로 연한 노란색 거품 형태의 목적화합물 96㎎ (9f, 16%)을 얻었다.96 mg (9f, 16%) of the target compound in the form of a pale yellow foam was obtained in the same manner as in (7-1), except that the compound prepared in Preparation Example (6-6) was used as the starting material.

TLC (MeOH/MC = 1/6) Rf 0.20TLC (MeOH / MC = 1/6) Rf 0.20

(7-7) (Z)-4-(3-(1-(사이클로헥실메틸)피롤리딘-3-일아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)벤조산(9g)(7-7) (Z) -4- (3- (1- (cyclohexylmethyl) pyrrolidin-3-ylamino) -2-((naphthalen-1-yloxy) methyl) prop-1- Nyl) benzoic acid (9 g)

출발물질로서 상기 제조예 (6-7)에서 제조한 화합물을 사용한 것을 제외하고는 상기 (7-1)과 동일한 방법으로 연한 노란색 거품 형태의 목적화합물 125㎎ (9g, 42%)을 얻었다.125 mg (9 g, 42%) of the target compound in the form of a pale yellow foam was obtained in the same manner as in (7-1), except that the compound prepared in Preparation Example (6-7) was used as the starting material.

TLC (MeOH/MC = 1/6) Rf 0.45TLC (MeOH / MC = 1/6) Rf 0.45

(7-8) (Z)-4-(3-(1-벤질피롤리딘-3-일아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)벤조산(9h)(7-8) (Z) -4- (3- (1-benzylpyrrolidin-3-ylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzoic acid ( 9h)

출발물질로서 상기 제조예 (6-8)에서 제조한 화합물을 사용한 것을 제외하고는 상기 (7-1)과 동일한 방법으로 연한 노란색 거품 형태의 목적화합물 232㎎ (9h, 96%)을 얻었다. 232 mg (9h, 96%) of the title compound in the form of a pale yellow foam was obtained in the same manner as in (7-1), except that the compound prepared in Preparation Example (6-8) was used as the starting material.

TLC (MeOH/MC = 1/6) Rf 0.45TLC (MeOH / MC = 1/6) Rf 0.45

(7-9) (Z)-4-(3-(1-사이클로프로필피페리딘-4-일아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)벤조산(9i)(7-9) (Z) -4- (3- (1-cyclopropylpiperidin-4-ylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzoic acid (9i)

출발물질로서 상기 제조예 (6-9)에서 제조한 화합물을 사용한 것을 제외하고는 상기 (7-1)과 동일한 방법으로 연한 노란색 거품 형태의 목적화합물 250㎎ (9i, 100%)을 얻었다. 250 mg (9i, 100%) of the title compound was obtained in the same manner as in (7-1), except that the compound prepared in Preparation Example (6-9) was used as a starting material.

TLC (MeOH/MC = 1/6) Rf 0.30TLC (MeOH / MC = 1/6) Rf 0.30

(7-10) (Z)-4-(3-(1-사이클로프로필피롤리딘-3-일아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)벤조산(9j)(7-10) (Z) -4- (3- (1-cyclopropylpyrrolidin-3-ylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzoic acid (9j)

출발물질로서 상기 제조예 (6-10)에서 제조한 화합물을 사용한 것을 제외하고는 상기 (7-1)과 동일한 방법으로 연한 노란색 거품 형태의 목적화합물 198㎎ (9j, 67%)을 얻었다. Except for using the compound prepared in Preparation Example (6-10) as a starting material in the same manner as in the above (7-1) to give a 198 mg (9j, 67%) of the target compound in the form of light yellow foam.

TLC (MeOH/MC = 1/6) Rf 0.45TLC (MeOH / MC = 1/6) Rf 0.45

(7-11) (Z)-4-(3-(1-사이클로헥실피롤리딘-3-일아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)벤조산(9k)(7-11) (Z) -4- (3- (1-cyclohexylpyrrolidin-3-ylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzoic acid (9k)

출발물질로서 상기 제조예 (6-11)에서 제조한 화합물을 사용한 것을 제외하고는 상기 (7-1)과 동일한 방법으로 연한 노란색 거품 형태의 목적화합물 160㎎ (9k, 67%)을 얻었다. 160 mg (9k, 67%) of the target compound in the form of a pale yellow foam was obtained in the same manner as in (7-1), except that the compound prepared in Preparation Example (6-11) was used as a starting material.

TLC (MeOH/MC = 1/6) Rf 0.30TLC (MeOH / MC = 1/6) Rf 0.30

(7-12) (Z)-4-(3-(에틸(2-몰포리노에틸)아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)벤조산(9l)(7-12) (Z) -4- (3- (ethyl (2-morpholinoethyl) amino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzoic acid (9l)

출발물질로서 상기 제조예 (6-12)에서 제조한 화합물을 사용한 것을 제외하고는 상기 (7-1)과 동일한 방법으로 연한 노란색 거품 형태의 목적화합물 201㎎ (9l, 100%)을 얻었다. 201 mg (9l, 100%) of the title compound in the form of a pale yellow foam was obtained in the same manner as in (7-1), except that the compound prepared in Preparation Example (6-12) was used as the starting material.

TLC (MeOH/MC = 1/9) Rf 0.35TLC (MeOH / MC = 1/9) Rf 0.35

(7-13) (Z)-4-(3-(1-메톡시프로판-2-일아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)벤조산(9m)(7-13) (Z) -4- (3- (1-methoxypropan-2-ylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzoic acid (9m )

출발물질로서 상기 제조예 (6-13)에서 제조한 화합물을 사용한 것을 제외하고는 상기 (7-1)과 동일한 방법으로 연한 노란색 거품 형태의 목적화합물 210 ㎎(9m, 89%)을 얻었다.210 mg (9m, 89%) of the target compound in the form of a pale yellow foam was obtained in the same manner as in (7-1), except that the compound prepared in Preparation Example (6-13) was used as a starting material.

1H-NMR (200MHz, CDCl3) δ 1.34(d, J=6.4Hz, 3H), 3.17(s, 3H), 3.48(m, 1H), 3.54(s, 2H), 3.91(dd, J=16.4Hz, 13.6Hz, 2H), 4.94(s, 2H), 6.62(d, J=7.8Hz, 1H), 7.08(s, 1H), 7.13(d, J=8.2Hz, 2H), 7.31(m, 2H), 7.45(m, 2H), 7.73(m, 1H), 7.79(d, J=8.2Hz, 2H), 8.23(m, 1H) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.34 (d, J = 6.4 Hz, 3H), 3.17 (s, 3H), 3.48 (m, 1H), 3.54 (s, 2H), 3.91 (dd, J = 16.4Hz, 13.6Hz, 2H), 4.94 (s, 2H), 6.62 (d, J = 7.8Hz, 1H), 7.08 (s, 1H), 7.13 (d, J = 8.2Hz, 2H), 7.31 (m , 2H), 7.45 (m, 2H), 7.73 (m, 1H), 7.79 (d, J = 8.2 Hz, 2H), 8.23 (m, 1H)

LC/MS(M+H): 406LC / MS (M + H): 406

제조예 8 : 화합식 10의 화합물의 제조 Preparation Example 8 Preparation of Compound of Formula 10

(8-1) (Z)-4-(3-(1-에틸피페리딘-4-일아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔닐)-N-(테트라하이드로-2H-피란-2-일옥시)벤즈아마이드(10a)(8-1) (Z) -4- (3- (1-ethylpiperidin-4-ylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) -N (Tetrahydro-2H-pyran-2-yloxy) benzamide (10a)

50㎖ 반응용기에 출발물질로서 상기 제조예 (7-1)에서 제조한 화합물 (9a; 205㎎, 0.46mmol, 1당량)을 2.3㎖의 N,N-다이메틸포르말에 녹여 교반하면서 N-하이드록시-6-트리플루오로 벤조트리아졸(FOBt; 104㎎, 0.51mmol, 1.1당량), 1-에틸-3-(3-다이메틸아미노프로필)카바다이이마이드·염산염(EDC·HCl; 114㎎, 0.60mmol, 1.3eq), 테트라하이드로-2H-피란-2-일 옥시아민(THPONH2; 81㎎, 0.64mmol, 1.5eq) 및 트라이에틸아민 (0.19㎖, 1.38mmol, 3당량)을 0℃에서 각각 첨가하고 상온에서 12시간 동안 교반시켰다. 반응이 종결되면 10% 탄산칼륨 수용액(20㎖)을 가하고 에틸아세테이트(EA(20㎖)×3)로 추출한 후, 유기층을 포화 중조와 소금물로 세척한 다음 무수 황산마그네슘으로 건조 후 감압하에서 농축하고 얻어진 잔사를 실리카겔 컬럼 크로마토그래피 방법으로 정제하여 짙은 노란색 거품형태의 표제 화합물 143㎎(10a, 41.3％)을 얻었다.With stirring and dissolved in dimethyl formal N - a; (205㎎, 0.46mmol, 1 eq. 9a), N, N of 2.3㎖ - as a starting material in the reaction vessel 50㎖ the compound prepared in Preparative Example 7-1 Hydroxy-6-trifluoro benzotriazole (FOBt; 104 mg, 0.51 mmol, 1.1 equiv), 1-ethyl-3- (3-dimethylaminopropyl) carbaimide hydrochloride (EDCHCl; 114 mg , 0.60 mmol, 1.3 eq), tetrahydro-2H-pyran-2-yl oxyamine (THPONH 2 ; 81 mg, 0.64 mmol, 1.5 eq) and triethylamine (0.19 mL, 1.38 mmol, 3 equiv) at 0 ° C. Each was added and stirred at room temperature for 12 hours. After the reaction was completed, 10% aqueous potassium carbonate solution (20 ml) was added, extracted with ethyl acetate (EA (20 ml) × 3), 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 143 mg (10a, 41.3%) of the title compound as a dark yellow foam.

1H-NMR (200MHz, CDCl3) δ 1.07(t, J=7.2Hz, 3H), 1.45(m, 2H), 1.59(m, 4H), 1.80-2.08(m, 6H), 2.37(q, J=7.2Hz, 2H), 2.58(m, 1H), 2.87(m, 2H), 3.60(m, 1H), 3.65(s, 2H), 3.97(m, 1H), 4.81(s, 2H), 5.05(m, 1H), 6.70(d, J=7.5Hz, 1H), 6.87(s, 1H), 7.37(m, 3H), 7.48(m, 4H), 7.67(d, J=8.4Hz, 2H), 7.79(d, J=7.2Hz, 1H), 8.23(d, J=7.5Hz, 1H) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.07 (t, J = 7.2 Hz, 3H), 1.45 (m, 2H), 1.59 (m, 4H), 1.80-2.08 (m, 6H), 2.37 (q, J = 7.2 Hz, 2H), 2.58 (m, 1H), 2.87 (m, 2H), 3.60 (m, 1H), 3.65 (s, 2H), 3.97 (m, 1H), 4.81 (s, 2H), 5.05 (m, 1H), 6.70 (d, J = 7.5Hz, 1H), 6.87 (s, 1H), 7.37 (m, 3H), 7.48 (m, 4H), 7.67 (d, J = 8.4Hz, 2H ), 7.79 (d, J = 7.2 Hz, 1H), 8.23 (d, J = 7.5 Hz, 1H)

LC/MS(M+H): 544LC / MS (M + H): 544

(8-2) (Z)-4-(3-(1-에틸피롤리딘-3-일아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔닐)-N-(테트라하이드로-2H-피란-2-일옥시)벤즈아마이드(10b)(8-2) (Z) -4- (3- (1-ethylpyrrolidin-3-ylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) -N -(Tetrahydro-2H-pyran-2-yloxy) benzamide (10b)

출발물질로서 상기 제조예 (7-2)에서 제조한 화합물을 사용한 것을 제외하고는 상기 (8-1)과 동일한 방법으로 사용하여 연한 노란색 거품 형태의 목적화합물 120㎎ (10b, 64%)을 얻었다. 120 mg (10b, 64%) of the target compound in the form of a pale yellow foam was obtained in the same manner as in (8-1), except that the compound prepared in Preparation Example (7-2) was used as the starting material. .

1H-NMR (200MHz, CDCl3) δ 1.28(t, J=7.8Hz, 3H), 1.55-2.02(m, 8H), 2.26(m, 2H), 2.84(q, J=7.2Hz, 2H), 3.16(m, 2H), 3.49(s, 2H), 3.63(m, 2H), 3.98(m, 1H), 4.84(s, 2H), 5.06(m, 1H), 6.70(d, J=7.8Hz, 1H), 6.88(s, 1H), 7.27-7.54(m, 6H), 7.70(d, J=8.1Hz, 2H), 7.80(d, J=7.2Hz, 1H), 8.21(d, J=7.2Hz, 1H) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.28 (t, J = 7.8 Hz, 3H), 1.55-2.02 (m, 8H), 2.26 (m, 2H), 2.84 (q, J = 7.2 Hz, 2H) , 3.16 (m, 2H), 3.49 (s, 2H), 3.63 (m, 2H), 3.98 (m, 1H), 4.84 (s, 2H), 5.06 (m, 1H), 6.70 (d, J = 7.8 Hz, 1H), 6.88 (s, 1H), 7.27-7.54 (m, 6H), 7.70 (d, J = 8.1 Hz, 2H), 7.80 (d, J = 7.2 Hz, 1H), 8.21 (d, J = 7.2 Hz, 1H)

LC/MS(M+H): 530LC / MS (M + H): 530

(8-3) (Z)-4-(2-((4-(트라이플루오로메톡시)벤질아미노)메틸)-3-(나프탈렌-1-일옥시)프로프-1-엔일)-N-(테트라하이드로-2H-피란-2-일옥시)벤즈아마이드(10c)(8-3) (Z) -4- (2-((4- (trifluoromethoxy) benzylamino) methyl) -3- (naphthalen-1-yloxy) prop-1-enyl) -N- (Tetrahydro-2H-pyran-2-yloxy) benzamide (10c)

출발물질로서 상기 제조예 (7-3)에서 제조한 화합물을 사용한 것을 제외하고는 상기 (8-1)과 동일한 방법으로 사용하여 연한 노란색 거품 형태의 목적화합물 189㎎ (10c, 99%)을 얻었다. 189 mg (10c, 99%) of the title compound was obtained in the same manner as in (8-1), except that the compound prepared in Preparation Example (7-3) was used as a starting material. .

TLC (MeOH/MC = 1/6) Rf 0.70TLC (MeOH / MC = 1/6) Rf 0.70

1H-NMR (300 MHz, CDCl3) δ 0.88 (m, 2H), 1.03(m, 2H), 1.25-1.43(m, 4H), 3.61(s, 2H), 3.89(s, 2H), 4.83(s, 2H), 5.05(s, 1H), 6.69(d, J=7.4Hz, 1H), 6.88(s, 1H), 7.11(d, J=7.6Hz, 2H), 7.26-7.52(m, 4H), 7.68(d, J=7.4Hz, 2H), 7.79(d, J=7.8Hz, 1H), 8.17(d, J=7.4Hz, 1H) 1 H-NMR (300 MHz, CDCl 3 ) δ 0.88 (m, 2H), 1.03 (m, 2H), 1.25-1.43 (m, 4H), 3.61 (s, 2H), 3.89 (s, 2H), 4.83 (s, 2H), 5.05 (s, 1H), 6.69 (d, J = 7.4 Hz, 1H), 6.88 (s, 1H), 7.11 (d, J = 7.6 Hz, 2H), 7.26-7.52 (m, 4H), 7.68 (d, J = 7.4 Hz, 2H), 7.79 (d, J = 7.8 Hz, 1H), 8.17 (d, J = 7.4 Hz, 1H)

LC/MS(M+H): 591LC / MS (M + H): 591

(8-4) (Z)-(8-4) (Z)- tt -부틸 3-(2-((나프탈렌-1-일옥시)메틸)-3-(4-(테트라하이드로-2H-피란-2-일옥시카바모일)페닐)알릴아미노)피롤리딘-1-카복시레이트(10d)-Butyl 3- (2-((naphthalen-1-yloxy) methyl) -3- (4- (tetrahydro-2H-pyran-2-yloxycarbamoyl) phenyl) allylamino) pyrrolidine-1- Carboxylate (10d)

출발물질로서 상기 제조예 (7-4)에서 제조한 화합물을 사용한 것을 제외하고는 상기 (8-1)과 동일한 방법으로 사용하여 연한 노란색 거품 형태의 목적화합물 184㎎ (10d, 90%)을 얻었다.184 mg (10d, 90%) of the title compound was obtained in the same manner as in (8-1), except that the compound prepared in Preparation Example (7-4) was used as a starting material. .

TLC (MeOH/MC = 1/6) Rf 0.80TLC (MeOH / MC = 1/6) Rf 0.80

1H-NMR (300 MHz, CDCl3) δ 1.43(s, 9H), 1.58-1.84(m, 4H), 2.01(q, J=7.4Hz, 1H), 2.86(d, J=7.6Hz, 8H), 3.40-3.62 (m, 3H), 3.94(t, J=7.8Hz, 1H), 4.81(s, 2H), 5.05(s, 1H), 6.68(d, J=7.4Hz, 1H), 6.86(s, 1H), 7.26-7.50 (m, 5H), 7.69-7.71(d, J=7.8Hz, 2H), 7.76(d, J=7.6Hz, 1H), 7.99(s, 1H), 8.21(d, J=7.8Hz, 1H) 1 H-NMR (300 MHz, CDCl 3 ) δ 1.43 (s, 9H), 1.58-1.84 (m, 4H), 2.01 (q, J = 7.4 Hz, 1H), 2.86 (d, J = 7.6 Hz, 8H ), 3.40-3.62 (m, 3H), 3.94 (t, J = 7.8 Hz, 1H), 4.81 (s, 2H), 5.05 (s, 1H), 6.68 (d, J = 7.4 Hz, 1H), 6.86 (s, 1H), 7.26-7.50 (m, 5H), 7.69-7.71 (d, J = 7.8 Hz, 2H), 7.76 (d, J = 7.6 Hz, 1H), 7.99 (s, 1H), 8.21 ( d, J = 7.8 Hz, 1H)

LC/MS(M+H): 602LC / MS (M + H): 602

(8-5) (Z)-4-(3-(1-(사이클로헥산카보닐)피롤리딘-3-일아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)-N-(테트라하이드로-2H-피란-2-일옥시)벤즈아마이드(10e)(8-5) (Z) -4- (3- (1- (cyclohexanecarbonyl) pyrrolidin-3-ylamino) -2-((naphthalen-1-yloxy) methyl) prop-1 -Enyl) -N- (tetrahydro-2H-pyran-2-yloxy) benzamide (10e)

출발물질로서 상기 제조예 (7-5)에서 제조한 화합물을 사용한 것을 제외하고는 상기 (8-1)과 동일한 방법으로 사용하여 연한 노란색 거품 형태의 목적화합물 170㎎ (10e, 89%)을 얻었다.170 mg (10e, 89%) of the title compound was obtained in the same manner as in (8-1), except that the compound prepared in Preparation Example (7-5) was used as a starting material. .

수율 89 % Yield 89%

TLC (MeOH/MC = 1/6) Rf 0.55TLC (MeOH / MC = 1/6) Rf 0.55

1H NMR (300 MHz, CDCl3) δ 1.19(m, 3H), 1.45-1.82(m, 8H), 1.86-2.03(m, 2H), 2.83(m, 6H), 3.38(m, 1H), 3.54(m, 7H), 3.97(t, J=7.8Hz, 1H), 4.79(d, J=7.8Hz, 2H), 5.06(s, 1H), 6.68(d, J=7.8 Hz, 1H), 6.81(d, J=7.6Hz, 1H), 7.32(m, 3H), 7.48(m, 2H), 7.73(q, J=7.8Hz, 3H), 7.96(s, 1H), 8.20(d, J=7.6Hz, 1H)1 H NMR (300 MHz, CDCl 3 ) δ 1.19 (m, 3H), 1.45-1.82 (m, 8H), 1.86-2.03 (m, 2H), 2.83 (m, 6H), 3.38 (m, 1H), 3.54 (m, 7H), 3.97 (t, J = 7.8 Hz, 1H), 4.79 (d, J = 7.8 Hz, 2H), 5.06 (s, 1H), 6.68 (d, J = 7.8 Hz, 1H), 6.81 (d, J = 7.6 Hz, 1H), 7.32 (m, 3H), 7.48 (m, 2H), 7.73 (q, J = 7.8 Hz, 3H), 7.96 (s, 1H), 8.20 (d, J = 7.6 Hz, 1H)

LC/MS(M+H): 612LC / MS (M + H): 612

(8-6) (Z)-4-(3-(1-사이클로펜틸피페리딘-4-일아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔닐)-N-(테트라하이드로-2H-피란-2-일옥시)벤즈아마이드(10f)(8-6) (Z) -4- (3- (1-cyclopentylpiperidin-4-ylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl)- N- (tetrahydro-2H-pyran-2-yloxy) benzamide (10f)

출발물질로서 상기 제조예 (7-6)에서 제조한 화합물을 사용한 것을 제외하고는 상기 (8-1)과 동일한 방법으로 사용하여 연한 노란색 거품 형태의 목적화합물 122㎎ (10f, 54%)을 얻었다.122 mg (10f, 54%) of the title compound was obtained in the same manner as in (8-1), except that the compound prepared in Preparation Example (7-6) was used as a starting material. .

TLC (MeOH/MC = 1/6) Rf 0.45TLC (MeOH / MC = 1/6) Rf 0.45

1H NMR (300 MHz, CDCl3) δ 1.40(m, 9H), 1.59(m, 9H), 2.46(m, 3H), 2.94(m, 3H), 3.64(s, 3H), 3.93(m, 1H), 4.81(s, 2H), 5.05(s, 1H), 6.69(d, J=7.4Hz, 1H), 6.87(s, 1H), 7.26(m, 3H), 7.42(m, 3H), 7.67(d, J=7.8Hz, 2H), 7.79(d, J=7.8Hz, 1H), 8.22(d, J=7.6Hz, 1H)1 H NMR (300 MHz, CDCl 3 ) δ 1.40 (m, 9H), 1.59 (m, 9H), 2.46 (m, 3H), 2.94 (m, 3H), 3.64 (s, 3H), 3.93 (m, 1H ), 4.81 (s, 2H), 5.05 (s, 1H), 6.69 (d, J = 7.4 Hz, 1H), 6.87 (s, 1H), 7.26 (m, 3H), 7.42 (m, 3H), 7.67 (d, J = 7.8 Hz, 2H), 7.79 (d, J = 7.8 Hz, 1H), 8.22 (d, J = 7.6 Hz, 1H)

LC/MS(M+H): 584LC / MS (M + H): 584

(8-7) (Z)-4-(3-(1-(사이클로메틸)피롤리딘-3-일아미노)-2-((나프탈렌-1-일옥시)메틸프로프-1-엔일)-N-(테트라하이드로-2H-피란-2-일옥시)벤즈아마이드(10g)(8-7) (Z) -4- (3- (1- (cyclomethyl) pyrrolidin-3-ylamino) -2-((naphthalen-1-yloxy) methylprop-1-enyl) -N- (tetrahydro-2H-pyran-2-yloxy) benzamide (10 g)

출발물질로서 상기 제조예 (7-7)에서 제조한 화합물을 사용한 것을 제외하고는 상기 (8-1)과 동일한 방법으로 사용하여 연한 노란색 거품 형태의 목적화합물 204㎎ (10g, 93%)을 얻었다. 204 mg (10 g, 93%) of the title compound was obtained in the same manner as in (8-1), except that the compound prepared in Preparation Example (7-7) was used as the starting material. .

TLC (MeOH/MC = 1/6) Rf 0.55TLC (MeOH / MC = 1/6) Rf 0.55

1H NMR (300 MHz, CDCl3) δ 0.83(m, 3H), 1.14(m, 4H), 1.30(m, 2H), 1.59-1.85(m, 5H), 2.16(m, 5H), 2.23(m, 1H), 2.41(d, J=7.6Hz, 2H), 2.61(s, 1H), 2.94(s, 2H), 3.42(d, J=7.4Hz, 1H), 3.63(s, 3H), 3.88(m, 1H), 4.80(s, 2H), 5.04(s, 1H), 6.68(d, J=7. Hz, 1H), 6.85(s, 1H), 7.26-7.50(m, 6H), 7.67(d, J=7.8Hz, 2H), 7.78(s, 1H), 8.22(d, J=7.6Hz, 1H)1 H NMR (300 MHz, CDCl 3 ) δ 0.83 (m, 3H), 1.14 (m, 4H), 1.30 (m, 2H), 1.59-1.85 (m, 5H), 2.16 (m, 5H), 2.23 (m , 1H), 2.41 (d, J = 7.6 Hz, 2H), 2.61 (s, 1H), 2.94 (s, 2H), 3.42 (d, J = 7.4 Hz, 1H), 3.63 (s, 3H), 3.88 (m, 1H), 4.80 (s, 2H), 5.04 (s, 1H), 6.68 (d, J = 7.Hz, 1H), 6.85 (s, 1H), 7.26-7.50 (m, 6H), 7.67 (d, J = 7.8Hz, 2H), 7.78 (s, 1H), 8.22 (d, J = 7.6Hz, 1H)

LC/MS(M+H): 598LC / MS (M + H): 598

(8-8) (Z)-4-(3-(1-벤질피롤리딘-3-일아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)-N-(테트라하이드로-2H-피란-2-일옥시)벤즈아마이드(10h)(8-8) (Z) -4- (3- (1-benzylpyrrolidin-3-ylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) -N -(Tetrahydro-2H-pyran-2-yloxy) benzamide (10h)

출발물질로서 상기 제조예 (7-8)에서 제조한 화합물을 사용한 것을 제외하고는 상기 (8-1)과 동일한 방법으로 사용하여 연한 노란색 거품 형태의 목적화합물 196㎎ (10h, 90%)을 얻었다.Except for using the compound prepared in Preparation Example (7-8) as a starting material in the same manner as in the above (8-1) to obtain the target compound 196 mg (10h, 90%) in the form of a pale yellow foam. .

TLC (MeOH/MC = 1/6) Rf 0.60TLC (MeOH / MC = 1/6) Rf 0.60

1H NMR (300 MHz, CDCl3) δ 1.21(m, 1H), 1.56(d, J=7.6Hz, 3H), 1.79(m, 2H), 2.03(m, 2H), 2.40(d, J=7.6Hz, 4H), 2.73(q, J=7.6Hz, 2H), 3.54(m, 4H), 3.90(s, 1H), 4.77(s, 2H), 5.03(s, 1H), 6.66(d, J=7.6Hz, 1H), 6.81(s, 1H), 7.18(m, 8H), 7.40-7.48(m, 3H), 7.65(d, J=7.8Hz, 2H), 7.77(d, J=7.6Hz, 1H), 8.20(d, J=7.6Hz, 1H)1 H NMR (300 MHz, CDCl 3 ) δ 1.21 (m, 1H), 1.56 (d, J = 7.6 Hz, 3H), 1.79 (m, 2H), 2.03 (m, 2H), 2.40 (d, J = 7.6 Hz, 4H), 2.73 (q, J = 7.6 Hz, 2H), 3.54 (m, 4H), 3.90 (s, 1H), 4.77 (s, 2H), 5.03 (s, 1H), 6.66 (d, J = 7.6 Hz, 1H), 6.81 (s, 1H), 7.18 (m, 8H), 7.40-7.48 (m, 3H), 7.65 (d, J = 7.8 Hz, 2H), 7.77 (d, J = 7.6 Hz , 1H), 8.20 (d, J = 7.6 Hz, 1H)

LC/MS(M+H): 592LC / MS (M + H): 592

(8-9) (Z)-4-(3-(1-사이클로프로필피페리딘-4-일아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)-N-(테트라하이드로-2H-피란-2-일옥시)벤즈아마이드(10i)(8-9) (Z) -4- (3- (1-cyclopropylpiperidin-4-ylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl)- N- (tetrahydro-2H-pyran-2-yloxy) benzamide (10i)

출발물질로서 상기 제조예 (7-9)에서 제조한 화합물을 사용한 것을 제외하고는 상기 (8-1)과 동일한 방법으로 사용하여 연한 노란색 거품 형태의 목적화합물 92㎎ (10i, 43%)을 얻었다.92 mg (10i, 43%) of the title compound was obtained in the same manner as in (8-1), except that the compound prepared in Preparation Example (7-9) was used as a starting material. .

TLC (MeOH/MC = 1/6) Rf 0.40TLC (MeOH / MC = 1/6) Rf 0.40

1H-NMR (300 MHz, CDCl3) δ 0.41(m, 4H), 1.36(m, 3H), 1.52(m, 3H), 1.80(m, 4H), 2.27(m, 2H), 2.59(d, J=7.4Hz, 1H), 2.96(t, J=7.6Hz, 2H), 3.64(m, 4H), 3.97(s, 1H), 4.81(s, 2H), 5.04(s, 1H), 6.69(d, J=7.4Hz, 1H), 6.87(s, 1H), 7.26-7.50 (m, 6H), 7.67(d, J=7.4Hz, 2H), 7.79(d, J=7.4Hz, 1H), 8.22(d, J=7.6Hz, 1H) 1 H-NMR (300 MHz, CDCl 3 ) δ 0.41 (m, 4H), 1.36 (m, 3H), 1.52 (m, 3H), 1.80 (m, 4H), 2.27 (m, 2H), 2.59 (d , J = 7.4Hz, 1H), 2.96 (t, J = 7.6Hz, 2H), 3.64 (m, 4H), 3.97 (s, 1H), 4.81 (s, 2H), 5.04 (s, 1H), 6.69 (d, J = 7.4Hz, 1H), 6.87 (s, 1H), 7.26-7.50 (m, 6H), 7.67 (d, J = 7.4Hz, 2H), 7.79 (d, J = 7.4Hz, 1H) , 8.22 (d, J = 7.6 Hz, 1H)

(8-10) (Z)-4-(3-(1-사이클로프로필피롤리딘-3-일아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)-N-(테트라하이드로-2H-피란-2-일옥시)벤즈아마이드(10j)(8-10) (Z) -4- (3- (1-cyclopropylpyrrolidin-3-ylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl)- N- (tetrahydro-2H-pyran-2-yloxy) benzamide (10j)

출발물질로서 상기 제조예 (7-10)에서 제조한 화합물을 사용한 것을 제외하고는 상기 (8-1)과 동일한 방법으로 사용하여 연한 노란색 거품 형태의 목적화합물 244㎎ (10j, 100%)을 얻었다.244 mg (10j, 100%) of the title compound was obtained in the same manner as in (8-1), except that the compound prepared in Preparation Example (7-10) was used as a starting material. .

TLC (MeOH/MC = 1/6) Rf 0.60TLC (MeOH / MC = 1/6) Rf 0.60

1H-NMR (300 MHz, CDCl3) δ 0.41 (m, 4H), 1.59(t, J=7.6Hz, 2H), 1.81(m, 2H), 2.16(m, 3H), 2.53(m, 4H), 2.87(m, 2H), 3.42(m, 1H), 3.58(m, 3H), 3.80(m, 1H), 4.80(s, 2H), 5.05(s, 1H), 6.69(d, J=7.6Hz, 1H), 6.85(s, 1H), 7.26-7.50 (m, 6H), 7.67(d, J=7.8Hz, 2H), 7.77(d, J=7.6Hz, 1H), 8.23(d, J=7.6Hz, 1H) 1 H-NMR (300 MHz, CDCl 3 ) δ 0.41 (m, 4H), 1.59 (t, J = 7.6 Hz, 2H), 1.81 (m, 2H), 2.16 (m, 3H), 2.53 (m, 4H ), 2.87 (m, 2H), 3.42 (m, 1H), 3.58 (m, 3H), 3.80 (m, 1H), 4.80 (s, 2H), 5.05 (s, 1H), 6.69 (d, J = 7.6 Hz, 1H), 6.85 (s, 1H), 7.26-7.50 (m, 6H), 7.67 (d, J = 7.8 Hz, 2H), 7.77 (d, J = 7.6 Hz, 1H), 8.23 (d, J = 7.6Hz, 1H)

(8-11) (Z)-4-(3-(1-사이클로헥실피롤리딘-3-일아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)-N-(테트라하이드로-2H-피란-2-일옥시)벤즈아마이드(10k)(8-11) (Z) -4- (3- (1-cyclohexylpyrrolidin-3-ylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl)- N- (tetrahydro-2H-pyran-2-yloxy) benzamide (10k)

출발물질로서 상기 제조예 (7-11)에서 제조한 화합물을 사용한 것을 제외하고는 상기 (8-1)과 동일한 방법으로 사용하여 연한 노란색 거품 형태의 목적화합물 146㎎ (10k, 77%)을 얻었다. 146 mg (10k, 77%) of the title compound was obtained in the same manner as in (8-1), except that the compound prepared in Preparation Example (7-11) was used as a starting material. .

TLC (MeOH/MC = 1/6) Rf 0.60TLC (MeOH / MC = 1/6) Rf 0.60

1H-NMR (300 MHz, CDCl3) δ 1.25 (m, 5H), 1.57(m, 5H), 1.79(m, 7H), 2.11 (s, 1H), 2.38(q, J=7.8Hz, 1H), 2.59(q, J=7.8Hz, 2H), 2.85(q, J=7.8Hz, 1H), 3.40(m, 2H), 3.57(m, 3H), 3.96(s, 1H), 4.79(s, 2H), 5.03(s, 1H), 6.67(d, J=7.4Hz, 1H), 6.84(s, 1H), 7.26(m, 3H), 7.49 (m, 3H), 7.66(d, J=7.8Hz, 2H), 7.78(d, J=7.6Hz, 1H), 8.23(d, J=7.6Hz, 1H) 1 H-NMR (300 MHz, CDCl 3 ) δ 1.25 (m, 5H), 1.57 (m, 5H), 1.79 (m, 7H), 2.11 (s, 1H), 2.38 (q, J = 7.8 Hz, 1H ), 2.59 (q, J = 7.8 Hz, 2H), 2.85 (q, J = 7.8 Hz, 1H), 3.40 (m, 2H), 3.57 (m, 3H), 3.96 (s, 1H), 4.79 (s , 2H), 5.03 (s, 1H), 6.67 (d, J = 7.4Hz, 1H), 6.84 (s, 1H), 7.26 (m, 3H), 7.49 (m, 3H), 7.66 (d, J = 7.8 Hz, 2H), 7.78 (d, J = 7.6 Hz, 1H), 8.23 (d, J = 7.6 Hz, 1H)

(8-12) (Z)-4-(3-(에틸(2-몰포리노에틸)아미노)-2-((나프탈렌-1-일옥시메틸)프로프 -1-엔일)-N-(테트라하이드로-2H-피란-2-일옥시)벤즈아마이드(10l)(8-12) (Z) -4- (3- (ethyl (2-morpholinoethyl) amino) -2-((naphthalen-1-yloxymethyl) prop-1-enyl) -N- (tetra Hydro-2H-pyran-2-yloxy) benzamide (10l)

출발물질로서 상기 제조예 (7-12)에서 제조한 화합물을 사용한 것을 제외하고는 상기 (8-1)과 동일한 방법으로 사용하여 연한 노란색 거품 형태의 목적화합물 186㎎ (10l, 93%)을 얻었다.186 mg (10l, 93%) of the title compound was obtained in the same manner as in (8-1), except that the compound prepared in Preparation Example (7-12) was used as a starting material. .

TLC (MeOH/MC = 1/6) Rf 0.30TLC (MeOH / MC = 1/6) Rf 0.30

1H-NMR (300 MHz, CDCl3) δ 0.99(m, 3H), 1.25(s, 1H), 2.30(m, 5H), 2.57(m, 5H), 2.86(m, 4H), 3.39(s, 2H), 3.57(m, 6H), 3.93(m, 1H), 4.79(s, 2H), 5.04(s, 1H), 6.71 (d, J=7.4Hz, 1H), 6.85(s, 1H), 7.26-7.49(m, 5H), 7.67(d, J=7.8Hz, 2H), 7.78(t, J=7.8Hz, 1H), 8.00(s, 1H), 8.23(d, J=7.6 Hz, 1H) 1 H-NMR (300 MHz, CDCl 3 ) δ 0.99 (m, 3H), 1.25 (s, 1H), 2.30 (m, 5H), 2.57 (m, 5H), 2.86 (m, 4H), 3.39 (s , 2H), 3.57 (m, 6H), 3.93 (m, 1H), 4.79 (s, 2H), 5.04 (s, 1H), 6.71 (d, J = 7.4 Hz, 1H), 6.85 (s, 1H) , 7.26-7.49 (m, 5H), 7.67 (d, J = 7.8 Hz, 2H), 7.78 (t, J = 7.8 Hz, 1H), 8.00 (s, 1H), 8.23 (d, J = 7.6 Hz, 1H)

(8-13) (Z)-4-(3-(1-메톡시프로판-2-일아미노)-(2-((나프탈렌-1-일옥시)메틸)-3-(4-(테트라하이드로-2H-피란-2-일옥시카바모일)페닐)아릴)카바메이트(10m)(8-13) (Z) -4- (3- (1-methoxypropan-2-ylamino)-(2-((naphthalen-1-yloxy) methyl) -3- (4- (tetrahydro -2H-pyran-2-yloxycarbamoyl) phenyl) aryl) carbamate (10m)

출발물질로서 상기 제조예 (7-13)에서 제조한 화합물을 사용한 것을 제외하고는 상기 (8-1)과 동일한 방법으로 사용하여 연한 노란색 오일형태의 표제화합물 209㎎(10m, 78.8%)을 얻었다.209 mg (10 m, 78.8%) of the title compound was obtained in the same manner as (8-1), except that the compound prepared in Preparation Example (7-13) was used as a starting material. .

1H-NMR (200MHz, CDCl3) δ 1.05(d, J=6.2Hz, 3H), 1.59(m, 4H), 1.86(m, 2H), 2.99(m, 1H), 3.27(s, 2H), 3.31(s, 3H), 3.61(d, J=17.2Hz, 13.4Hz, 2H), 3.66(m, 1H), 3.97(m, 1H), 4.82(s, 2H), 5.06(m, 1H), 6.69(d, J=7.8Hz, 1H), 6.88(s, 1H), 7.27-7.56(m, 6H), 7.67(d, J=8.2Hz, 2H), 7.78(m, 1H), 8.25(m, 1H) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.05 (d, J = 6.2 Hz, 3H), 1.59 (m, 4H), 1.86 (m, 2H), 2.99 (m, 1H), 3.27 (s, 2H) , 3.31 (s, 3H), 3.61 (d, J = 17.2Hz, 13.4Hz, 2H), 3.66 (m, 1H), 3.97 (m, 1H), 4.82 (s, 2H), 5.06 (m, 1H) , 6.69 (d, J = 7.8 Hz, 1H), 6.88 (s, 1H), 7.27-7.56 (m, 6H), 7.67 (d, J = 8.2 Hz, 2H), 7.78 (m, 1H), 8.25 ( m, 1H)

LC/MS(M+H): 505LC / MS (M + H): 505

제조예 9 : 화학식 11의 화합물의 제조 Preparation Example 9 Preparation of Compound of Formula 11

(9-1) (Z)-메틸 4-(3-(2-(1-메틸피롤리딘-2-일)에틸아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔닐)벤조에이트(11a)(9-1) (Z) -methyl 4- (3- (2- (1-methylpyrrolidin-2-yl) ethylamino) -2-((naphthalen-1-yloxy) methyl) prop- 1-enyl) benzoate (11a)

100㎖ 반응 플라스크에 4-[2-브로모메틸-3-(나프탈렌-1-일옥시)-프로페닐]-벤조산 메틸에스터(412㎎, 1mmol)를 0℃에서 5㎖의 아세토나이트릴에 녹여 교반하면서 트라이에틸아민(0.21㎖, 1.5mmol, 1.5당량)과 2-(1-메틸피롤리딘-2-일)에탄아민(R2NH2; 0.22㎖, 1.5mmol, 1.5당량)을 첨가하고 0℃에서 실온으로 올려 4시간 반응시켰다. 반응 완결을 확인하고 용매를 감압 증류하여 남은 여액을 에틸에스테르로 추출하고 유기층을 포화 중조와 소금물로 세척한 다음 무수 황산마그네슘으로 건조 후 감압하에서 농축하였다. 얻어진 반응혼합물를 실리카겔 컬럼 크로마토그래피 방법으로 정제하여 연노란색의 오일형태의 목적 화합물 220㎎ (11a, 48%)을 얻었다. Dissolve 4- [2-bromomethyl-3- (naphthalen-1-yloxy) -propenyl] -benzoic acid methyl ester (412 mg, 1 mmol) in 5 ml of acetonitrile at 0 ° C. in a 100 ml reaction flask. While stirring triethylamine (0.21 mL, 1.5 mmol, 1.5 equiv) and 2- (1-methylpyrrolidin-2-yl) ethanamine (R 2 NH 2 ; 0.22 mL, 1.5 mmol, 1.5 equiv) were added It heated up at room temperature at 0 degreeC and made it react for 4 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the remaining filtrate was extracted with ethyl ester. The organic layer was washed with saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained reaction mixture was purified by silica gel column chromatography to obtain 220 mg (11a, 48%) of the title compound as a pale yellow oil.

1H-NMR (200MHz, CDCl3) δ 1.61(m, 2H), 1.95(m, 4H), 2.25(m, 1H), 2.37(s, 3H), 2.58(m, 1H), 2.81(m, 2H), 3.22(m, 1H), 3.67(s, 2H), 3.89(s, 3H), 4.86(s, 2H), 6.71(d, J=7.4Hz, 1H), 6.91(s, 1H), 7.28-7.58(m, 6H), 7.79(m, 1H), 7.97(d, J=8.6Hz, 2H), 8.22(m, 1H) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.61 (m, 2H), 1.95 (m, 4H), 2.25 (m, 1H), 2.37 (s, 3H), 2.58 (m, 1H), 2.81 (m, 2H), 3.22 (m, 1H), 3.67 (s, 2H), 3.89 (s, 3H), 4.86 (s, 2H), 6.71 (d, J = 7.4 Hz, 1H), 6.91 (s, 1H), 7.28-7.58 (m, 6H), 7.79 (m, 1H), 7.97 (d, J = 8.6 Hz, 2H), 8.22 (m, 1H)

LC/MS(M+H): 459LC / MS (M + H): 459

(9-2) (Z)-메틸 4-(3-(1-아이소프로필피페리딘-4-일아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔닐)벤조에이트(11b)(9-2) (Z) -methyl 4- (3- (1-isopropylpiperidin-4-ylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) Benzoate (11b)

아민으로서 2-(1-메틸피롤리딘-2-일)에탄아민 대신 1-아이소프로필피페리딘-4-아민을 사용한 것을 제외하고는 상기 (9-1)과 동일한 방법으로 연한 노란색 오일 형태의 목적화합물 255㎎ (11b, 54%)을 얻었다.Light yellow oil form in the same manner as in (9-1), except that 1-isopropylpiperidin-4-amine was used instead of 2- (1-methylpyrrolidin-2-yl) ethanamine as the amine. 255 mg (11b, 54%) of the desired compound were obtained.

1H-NMR (200MHz, CDCl3) δ 1.16(d, J=6.4Hz, 6H), 1.90(m, 2H), 2.37(m, 2H), 2.73(m, 2H), 3.09(m, 4H), 3.64(s, 2H), 3.92(s, 3H), 4.89(s, 2H), 6.71(d, J=7.8Hz, 1H), 6.89(s, 1H), 7.28-7.60(m, 6H), 7.81(d, J=7.0Hz, 1H), 8.00(d, J=7.6Hz, 2H), 8.21(d, J=7.4Hz, 1H) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.16 (d, J = 6.4 Hz, 6H), 1.90 (m, 2H), 2.37 (m, 2H), 2.73 (m, 2H), 3.09 (m, 4H) , 3.64 (s, 2H), 3.92 (s, 3H), 4.89 (s, 2H), 6.71 (d, J = 7.8Hz, 1H), 6.89 (s, 1H), 7.28-7.60 (m, 6H), 7.81 (d, J = 7.0 Hz, 1H), 8.00 (d, J = 7.6 Hz, 2H), 8.21 (d, J = 7.4 Hz, 1H)

LC/MS(M+H): 473LC / MS (M + H): 473

(9-3) (Z)-메틸 4-(3-(3-(1H-이미다졸-1-일)프로필아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)벤조에이트(11c)(9-3) (Z) -methyl 4- (3- (3- (1H-imidazol-1-yl) propylamino) -2-((naphthalen-1-yloxy) methyl) prop-1- Nyl) benzoate (11c)

아민으로서 2-(1-메틸피롤리딘-2-일)에탄아민 대신 1H-이미다졸-1-프로필아민을 사용한 것을 제외하고는 상기 (9-1)과 동일한 방법으로 연한 노란색 오일 형태의 목적화합물 263㎎ (11c, 58%)을 얻었다.The purpose of the pale yellow oil form in the same manner as in (9-1), except that 1H-imidazol-1-propylamine was used instead of 2- (1-methylpyrrolidin-2-yl) ethanamine as the amine. Compound 263 mg (11c, 58%) was obtained.

1H-NMR (200MHz, CDCl3) δ 1.93(m, 2H), 2.69(t, J=6.4Hz, 2H), 3.61(s, 2H), 3.90(s, 3H), 4.00(t, J=7.0Hz, 2H), 4.85(s, 2H), 6.70(d, J=7.4Hz, 1H), 6.85(s, 2H), 7.02(s, 1H), 7.26-7.56(m, 7H), 7.85(m, 1H), 7.97(d, J=8.2Hz, 2H), 8.23(m, 1H) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.93 (m, 2H), 2.69 (t, J = 6.4 Hz, 2H), 3.61 (s, 2H), 3.90 (s, 3H), 4.00 (t, J = 7.0 Hz, 2H), 4.85 (s, 2H), 6.70 (d, J = 7.4 Hz, 1H), 6.85 (s, 2H), 7.02 (s, 1H), 7.26-7.56 (m, 7H), 7.85 ( m, 1H), 7.97 (d, J = 8.2 Hz, 2H), 8.23 (m, 1H)

LC/MS(M+H): 456LC / MS (M + H): 456

(9-4) (Z)-메틸 4-(3-(4-하이드록시펜에틸아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)벤조에이트(11d)(9-4) (Z) -methyl 4- (3- (4-hydroxyphenethylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzoate (11d)

아민으로서 2-(1-메틸피롤리딘-2-일)에탄아민 대신 4-하이드록시펜에틸아민을 사용한 것을 제외하고는 상기 (9-1)과 동일한 방법으로 연한 노란색 오일형태의 목적화합물 271㎎ (11d, 52%)을 얻었다.Except for using 4-hydroxyphenethylamine instead of 2- (1-methylpyrrolidin-2-yl) ethanamine as the amine, the target compound in the form of light yellow oil was obtained in the same manner as in (9-1). Mg (11d, 52%) was obtained.

1H-NMR (200MHz, CDCl3) δ 2.76(t, J=7.2Hz, 2H), 2.94(t, J=6.6Hz, 2H), 3.65(s, 2H), 3.89(s, 3H), 4.76(s, 2H), 6.65(m, 3H), 6.82(s, 1H), 7.01(d, J=8.4Hz, 2H), 7.31(d, J=8.0Hz, 3H), 7.49(m, 3H), 7.78(m, 1H), 7.95(d, J=8.0Hz, 2H), 8.19(m, 1H) 1 H-NMR (200 MHz, CDCl 3 ) δ 2.76 (t, J = 7.2 Hz, 2H), 2.94 (t, J = 6.6 Hz, 2H), 3.65 (s, 2H), 3.89 (s, 3H), 4.76 (s, 2H), 6.65 (m, 3H), 6.82 (s, 1H), 7.01 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.0 Hz, 3H), 7.49 (m, 3H) , 7.78 (m, 1H), 7.95 (d, J = 8.0 Hz, 2H), 8.19 (m, 1H)

LC/MS(M+H): 468LC / MS (M + H): 468

(9-5) (Z)-메틸 4-(3-(3-(다이메틸아미노)-2,2-다이메틸프로필아미노)-2-((나프탈 렌-1-일옥시)메틸)프로프-1-엔일)벤조에이트(11e)(9-5) (Z) -methyl 4- (3- (3- (dimethylamino) -2,2-dimethylpropylamino) -2-((naphthalen-1-yloxy) methyl) pro Ph-1-enyl) benzoate (11e)

아민으로서 2-(1-메틸피롤리딘-2-일)에탄아민 대신 3-다이메틸아미노-2,2-다이메틸프로필아민을 사용한 것을 제외하고는 상기 (9-1)과 동일한 방법으로 연한 노란색 오일형태의 목적화합물 328㎎ (11e, 71%)을 얻었다. It was lighter in the same manner as in (9-1), except that 3-dimethylamino-2,2-dimethylpropylamine was used instead of 2- (1-methylpyrrolidin-2-yl) ethanamine as the amine. 328 mg (11e, 71%) of the title compound in the form of a yellow oil were obtained.

1H-NMR (200MHz, CDCl3) δ 1.13(s, 6H), 2.28(s, 6H), 2.57(s, 2H), 3.04(s, 2H), 3.90(s, 3H), 3.93(s, 2H), 4.95(s, 2H), 6.75(d, J=7.4Hz, 1H), 7.18(s, 1H), 7.27-7.56(m, 6H), 7.80(m, 1H), 7.98(d, J=8.2Hz, 2H), 8.23(m, 1H) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.13 (s, 6H), 2.28 (s, 6H), 2.57 (s, 2H), 3.04 (s, 2H), 3.90 (s, 3H), 3.93 (s, 2H), 4.95 (s, 2H), 6.75 (d, J = 7.4 Hz, 1H), 7.18 (s, 1H), 7.27-7.56 (m, 6H), 7.80 (m, 1H), 7.98 (d, J) = 8.2 Hz, 2H), 8.23 (m, 1H)

LC/MS(M+H):461LC / MS (M + H): 461

(9-6) (Z)-메틸 4-(3-(2-(다이아이소프로필아미노)에틸아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)벤조에이트(11f)(9-6) (Z) -methyl 4- (3- (2- (diisopropylamino) ethylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzoate (11f)

아민으로서 2-(1-메틸피롤리딘-2-일)에탄아민 대신 2-(다이아이소프로필아미노)에틸아민을 사용한 것을 제외하고는 상기 (9-1)과 동일한 방법으로 연한 노란색 오일형태의 목적화합물 316㎎ (11f, 67%)을 얻었다.Except for using 2- (diisopropylamino) ethylamine instead of 2- (1-methylpyrrolidin-2-yl) ethanamine as an amine, it was light yellow oil type in the same manner as in (9-1). 316 mg (11f, 67%) of the title compound were obtained.

1H-NMR (200MHz, CDCl3) δ 1.29(d, J=6.6Hz, 12H), 2.95(t, J=5.8Hz, 2H), 3.22(t, J=6.4Hz, 2H), 3.45(m, 2H), 3.71(s, 2H), 3.89(s, 3H), 4.89(s, 2H), 5.30(br, 1H), 6.73(d, J=7.6Hz, 1H), 6.97(s, 1H), 7.42(m, 6H), 7.79(m, 1H), 7.96(d, J=8.4Hz, 2H), 8.22(m, 1H) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.29 (d, J = 6.6 Hz, 12H), 2.95 (t, J = 5.8 Hz, 2H), 3.22 (t, J = 6.4 Hz, 2H), 3.45 (m , 2H), 3.71 (s, 2H), 3.89 (s, 3H), 4.89 (s, 2H), 5.30 (br, 1H), 6.73 (d, J = 7.6Hz, 1H), 6.97 (s, 1H) , 7.42 (m, 6H), 7.79 (m, 1H), 7.96 (d, J = 8.4 Hz, 2H), 8.22 (m, 1H)

LC/MS(M+H): 475LC / MS (M + H): 475

(9-7) (Z)-메틸 4-(3-(2-메톡시에틸아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)벤조에이트(11h)(9-7) (Z) -methyl 4- (3- (2-methoxyethylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzoate (11h)

아민으로서 2-(1-메틸피롤리딘-2-일)에탄아민 대신 2-메톡시에틸아민을 사용한 것을 제외하고는 상기 (9-1)과 동일한 방법으로 연한 노란색 오일형태의 목적화합물 239㎎ (11h, 59%)을 얻었다.239 mg of the target compound as a pale yellow oil in the same manner as in (9-1), except that 2-methoxyethylamine was used instead of 2- (1-methylpyrrolidin-2-yl) ethanamine as the amine. (11h, 59%) was obtained.

1H-NMR (200MHz, CDCl3) δ 2.91(t, J=5.4Hz, 2H), 3.38(s, 3H), 3.56(t, J=5.4Hz, 2H), 3.68(s, 2H), 3.91(s, 3H), 4.86(s, 2H), 6.71(d, J=7.8Hz, 1H), 6.92(s, 1H), 7.27-7.56(m, 6H), 7.81(m, 1H), 7.98(d, J=8.2Hz, 2H), 8.27(m, 1H) 1 H-NMR (200 MHz, CDCl 3 ) δ 2.91 (t, J = 5.4 Hz, 2H), 3.38 (s, 3H), 3.56 (t, J = 5.4 Hz, 2H), 3.68 (s, 2H), 3.91 (s, 3H), 4.86 (s, 2H), 6.71 (d, J = 7.8 Hz, 1H), 6.92 (s, 1H), 7.27-7.56 (m, 6H), 7.81 (m, 1H), 7.98 ( d, J = 8.2 Hz, 2H), 8.27 (m, 1H)

LC/MS(M+H): 406LC / MS (M + H): 406

(9-8) (Z)-메틸 4-(3-(사이클로헥실아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)벤조에이트(11i)(9-8) (Z) -methyl 4- (3- (cyclohexylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzoate (11i)

아민으로서 2-(1-메틸피롤리딘-2-일)에탄아민 대신 3-사이클로헥실아민을 사용한 것을 제외하고는 상기 (9-1)과 동일한 방법으로 연한 노란색 오일형태의 목적화합물 300㎎ (11i, 70%)을 얻었다.300 mg of the target compound as a pale yellow oil in the same manner as in (9-1), except that 3-cyclohexylamine was used instead of 2- (1-methylpyrrolidin-2-yl) ethanamine as the amine. 11i, 70%).

1H-NMR (200MHz, CDCl3) δ 1.03-1.41(m, 4H), 1.49(m, 2H), 1.73(m, 2H), 1.92(m, 2H), 2.58(m, 1H), 3.68(s, 2H), 3.91(s, 3H), 4.86(s, 2H), 6.72(d, J=7.4Hz, 1H), 6.91(s, 1H), 7.27-7.58(m, 6H), 7.81(m, 1H), 7.98(d, J=8.2Hz, 2H), 8.26(m, 1H) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.03-1.41 (m, 4H), 1.49 (m, 2H), 1.73 (m, 2H), 1.92 (m, 2H), 2.58 (m, 1H), 3.68 ( s, 2H), 3.91 (s, 3H), 4.86 (s, 2H), 6.72 (d, J = 7.4 Hz, 1H), 6.91 (s, 1H), 7.27-7.58 (m, 6H), 7.81 (m , 1H), 7.98 (d, J = 8.2 Hz, 2H), 8.26 (m, 1H)

LC/MS(M+H): 430LC / MS (M + H): 430

(9-9) (Z)-메틸 4-(2-((4-(다이메틸아미노)벤질아미노)메틸)-3-((나프탈렌-1-일옥시프로프)-1-엔일)벤조에이트(11j)(9-9) (Z) -methyl 4- (2-((4- (dimethylamino) benzylamino) methyl) -3-((naphthalen-1-yloxyprop) -1-enyl) benzoate ( 11j)

아민으로서 2-(1-메틸피롤리딘-2-일)에탄아민 대신 4-(다이메틸아미노)벤질아민을 사용한 것을 제외하고는 상기 (9-1)과 동일한 방법으로 연한 노란색 오일 형태의 목적화합물 324㎎ (11j, 77%)을 얻었다.The purpose of the pale yellow oil form in the same manner as in (9-1), except that 4- (dimethylamino) benzylamine was used instead of 2- (1-methylpyrrolidin-2-yl) ethanamine as the amine. Compound 324 mg (11j, 77%) were obtained.

TLC (EtOAc/Hex = 1/2) Rf 0.10TLC (EtOAc / Hex = 1/2) Rf 0.10

1H-NMR (300 MHz, CDCl3) δ 3.00(s, 6H), 3.70(s, 2H), 3.80(s, 2H), 3.90(s, 3H), 4.82(s, 2H), 6.66(m, 4H), 6.90(s, 1H), 7.18-7.42(m, 7H), 7.38(m, 2H), 7.80(dd, J = 14.8, 7.4 Hz, 1H), 7.90(dd, J=14.8, 7.4 Hz, 2H), 8.21 (dd, J =14.8, 7.4 Hz, 1H) 1 H-NMR (300 MHz, CDCl 3 ) δ 3.00 (s, 6H), 3.70 (s, 2H), 3.80 (s, 2H), 3.90 (s, 3H), 4.82 (s, 2H), 6.66 (m , 4H), 6.90 (s, 1H), 7.18-7.42 (m, 7H), 7.38 (m, 2H), 7.80 (dd, J = 14.8, 7.4 Hz, 1H), 7.90 (dd, J = 14.8, 7.4 Hz, 2H), 8.21 (dd, J = 14.8, 7.4 Hz, 1H)

LC/MS(M+H): 481LC / MS (M + H): 481

(9-10) (Z)-메틸 4-(3-(나프탈렌-1-일옥시)-2-((티오펜-2-일메틸아미노)메틸)프로프-1-엔일)벤조에이트(11k)(9-10) (Z) -methyl 4- (3- (naphthalen-1-yloxy) -2-((thiophen-2-ylmethylamino) methyl) prop-1-enyl) benzoate (11k )

아민으로서 2-(1-메틸피롤리딘-2-일)에탄아민 대신 2-티오펜-2-메틸아민을 사용한 것을 제외하고는 상기 (9-1)과 동일한 방법으로 연한 노란색 오일 형태의 목적화합물 301㎎ (11k, 61%)을 얻었다.The purpose of the pale yellow oil in the same manner as in (9-1), except that 2-thiophen-2-methylamine was used instead of 2- (1-methylpyrrolidin-2-yl) ethanamine as the amine. 301 mg (11k, 61%) was obtained.

TLC (EtOAc/Hex = 1/2) Rf 0.30TLC (EtOAc / Hex = 1/2) Rf 0.30

1H-NMR (300 MHz, CDCl3) δ 3.68(s, 2H), 3.88(s, 3H), 4.08(s, 2H), 4.84(s, 2H), 6.69(d, J=7.4 Hz, 1H), 6.89(dd, J=14.4, 7.6 Hz, 3H), 7.30-7.48(m, 7H), 7.78(d, J=7.6 Hz, 1H), 7.97(t, J=7.8, 7.8 Hz, 2H), 8.20(d, J=7.6 Hz, 1H) 1 H-NMR (300 MHz, CDCl 3 ) δ 3.68 (s, 2H), 3.88 (s, 3H), 4.08 (s, 2H), 4.84 (s, 2H), 6.69 (d, J = 7.4 Hz, 1H ), 6.89 (dd, J = 14.4, 7.6 Hz, 3H), 7.30-7.48 (m, 7H), 7.78 (d, J = 7.6 Hz, 1H), 7.97 (t, J = 7.8, 7.8 Hz, 2H) , 8.20 (d, J = 7.6 Hz, 1H)

LC/MS(M+H): 444LC / MS (M + H): 444

(9-11) (Z)-메틸 4-(2-((4-메톡시펜에틸아미노)메틸)-3-(나프탈렌-1-일옥시)프로프-1-엔일)벤조에이트(11l)(9-11) (Z) -methyl 4- (2-((4-methoxyphenethylamino) methyl) -3- (naphthalen-1-yloxy) prop-1-enyl) benzoate (11 l)

아민으로서 2-(1-메틸피롤리딘-2-일)에탄아민 대신 4-메톡시펜에틸아민을 사용한 것을 제외하고는 상기 (9-1)과 동일한 방법으로 연한 노란색 오일 형태의 목적화합물 350㎎ (11l, 77%)을 얻었다.Except for using 4-methoxyphenethylamine instead of 2- (1-methylpyrrolidin-2-yl) ethanamine as the amine, the target compound in light yellow oil form was manufactured in the same manner as in (9-1). Mg (111, 77%) was obtained.

TLC (EtOAc/Hex = 2/1) Rf 0.35TLC (EtOAc / Hex = 2/1) Rf 0.35

1H NMR (300 MHz, CDCl3) δ 2.77(t, J=7.8 Hz, 2H), 2.94(t, J=7.8Hz, 2H), 3.63 (s, 2H), 3.74 (s, 3H), 3.88 (s, 3H), 4.76 (s, 2H), 6.64(d, J=7.4 Hz, 1H), 6.78(t, J=7.6 Hz, 3H), 7.09(d, J=7.8Hz, 2H), 7.24-7.50(m, 6H), 7.79(t, J=7.8Hz, 1H), 7.95(d, J=7.8 Hz, 2H), 8.21(d, J=7.6 H, 1Hz)1 H NMR (300 MHz, CDCl 3 ) δ 2.77 (t, J = 7.8 Hz, 2H), 2.94 (t, J = 7.8 Hz, 2H), 3.63 (s, 2H), 3.74 (s, 3H), 3.88 ( s, 3H), 4.76 (s, 2H), 6.64 (d, J = 7.4 Hz, 1H), 6.78 (t, J = 7.6 Hz, 3H), 7.09 (d, J = 7.8 Hz, 2H), 7.24- 7.50 (m, 6H), 7.79 (t, J = 7.8 Hz, 1H), 7.95 (d, J = 7.8 Hz, 2H), 8.21 (d, J = 7.6 H, 1 Hz)

LC/MS(M+H): 482LC / MS (M + H): 482

제조예 10 : 화학식 12의 화합물의 제조Preparation Example 10 Preparation of Compound of Formula 12

(10-1) (Z)-메틸 4-(3-((10-1) (Z) -methyl 4- (3- ( tt -부톡시카보닐(2-(1-메틸피롤리딘-2-일)에틸)아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔닐)벤조에이트(12a)-Butoxycarbonyl (2- (1-methylpyrrolidin-2-yl) ethyl) amino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzoate (12a)

100㎖ 반응 플라스크에 상기 제조예 (9-1)에서 제조한 (Z)-메틸 4-(3-(2-(1-메틸피롤리딘-2-일)에틸아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔닐)벤조에이트(11a; 220㎎, 0.48 mmol)를 0℃에서 2㎖의 다이클로로메탄에 녹여 교반하면서 트라이에틸아민(0.08㎖, 0.58mmol, 1.2당량)과 다이 t-부틸 다이카보네이트((tBoc)2O; 127㎎, 0.58mmol, 1.2당량)를 첨가하고 촉매량의 4-다이메틸아미노피리딘(DMAP; 4㎎, 0.05당량)을 가한 후 0℃에서 실온으로 올려 12시간 반응시켰다. 반응 완결을 확인하고 다이클로로메탄으로 추출하고 유기층을 포화 중조와 소금물로 세척한 다음 무수 황산마그네슘으로 건조 후 감압하에서 농축하였다. 얻어진 반응혼합물을 실리카겔 컬럼 크로마토그래피 방법으로 정제하여 연노란색의 오일형태의 목적 화합물(12a, 252㎎)을 94%의 수율로 얻었다. (Z) -methyl 4- (3- (2- (1-methylpyrrolidin-2-yl) ethylamino) -2-((naphthalene) prepared in Preparation Example (9-1) above in a 100 ml reaction flask -1-yloxy) methyl) prop-1-enyl) benzoate (11a; 220 mg, 0.48 mmol) was dissolved in 2 ml of dichloromethane at 0 ° C. with stirring and triethylamine (0.08 ml, 0.58 mmol, 1.2 equivalents) and di t -butyl dicarbonate ((tBoc) 2 O; 127 mg, 0.58 mmol, 1.2 equivalents) were added and a catalytic amount of 4-dimethylaminopyridine (DMAP; 4 mg, 0.05 equivalents) was added. The reaction was carried out at room temperature at room temperature for 12 hours. After completion of the reaction, the mixture was extracted with dichloromethane and the organic layer was washed with saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained reaction mixture was purified by silica gel column chromatography to give the title compound (12a, 252 mg) as light yellow oil in 94% yield.

1H-NMR (200MHz, CDCl3) δ 1.33(s, 9H), 1.61-2.24(m, 8H), 2.54(s, 3H), 3.36(m, 2H), 3.51(m, 1H), 3.89(s, 3H), 4.25(s, 2H), 4.75(s, 2H), 6.66(d, J=7.2Hz, 1H), 6.74(s, 1H), 7.28-7.58(m, 6H), 7.81(m, 1H), 7.96(d, J=8.4Hz, 2H), 8.24(m, 1H) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.33 (s, 9H), 1.61-2.24 (m, 8H), 2.54 (s, 3H), 3.36 (m, 2H), 3.51 (m, 1H), 3.89 ( s, 3H), 4.25 (s, 2H), 4.75 (s, 2H), 6.66 (d, J = 7.2 Hz, 1H), 6.74 (s, 1H), 7.28-7.58 (m, 6H), 7.81 (m , 1H), 7.96 (d, J = 8.4 Hz, 2H), 8.24 (m, 1H)

LC/MS(M+H): 559LC / MS (M + H): 559

(10-2) (Z)-메틸 4-(3-((10-2) (Z) -methyl 4- (3- ( tt -부톡시카보닐(1-아이소프로필피페리딘-4-일)아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔닐)벤조에이트(12b)-Butoxycarbonyl (1-isopropylpiperidin-4-yl) amino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzoate (12b)

상기 제조예 (9-2)에서 얻은 출발물질 (11b, 255㎎)을 사용하여 상기 (10-1)과 동일한 방법으로 연한 노란색 오일 형태의 목적화합물 158㎎ (12b, 52%)을 얻었다. Using the starting material (11b, 255mg) obtained in the Preparation Example (9-2), 158 mg (12b, 52%) of the target compound in the form of a pale yellow oil was obtained in the same manner as in (10-1).

1H-NMR (200MHz, CDCl3) δ 1.07(d, J=6.6Hz, 6H), 1.45(s, 9H), 1.86(m, 5H), 2.29(m, 2H), 2.79(m, 1H), 2.97(m, 2H), 3.91(s, 3H), 4.23(s, 2H), 4.77(s, 2H), 6.69(d, J=7.0Hz, 1H), 6.72(s, 1H), 7.33(d, J=8.2Hz, 3H), 7.49(m, 3H), 7.81(m, 1H), 7.96(d, J=8.2Hz, 2H), 8.28(m, 1H) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.07 (d, J = 6.6 Hz, 6H), 1.45 (s, 9H), 1.86 (m, 5H), 2.29 (m, 2H), 2.79 (m, 1H) , 2.97 (m, 2H), 3.91 (s, 3H), 4.23 (s, 2H), 4.77 (s, 2H), 6.69 (d, J = 7.0 Hz, 1H), 6.72 (s, 1H), 7.33 ( d, J = 8.2 Hz, 3H), 7.49 (m, 3H), 7.81 (m, 1H), 7.96 (d, J = 8.2 Hz, 2H), 8.28 (m, 1H)

LC/MS(M+H): 573LC / MS (M + H): 573

(10-3) (Z)-메틸 4-(3-((3-(1H-이미다졸-1-일)프로필)((10-3) (Z) -methyl 4- (3-((3- (1H-imidazol-1-yl) propyl) ( tt -부톡시카보닐)아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔닐)벤조에이트(12c)-Butoxycarbonyl) amino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzoate (12c)

상기 제조예 (9-3)에서 얻은 출발물질 (11c, 253㎎)을 사용하여 상기 (10-1)과 동일한 방법으로 연한 노란색 오일 형태의 목적화합물 174㎎ (12c, 53%)을 얻었다. Using the starting material (11c, 253mg) obtained in Preparation Example (9-3), 174 mg (12c, 53%) of the title compound in the form of light yellow oil was obtained in the same manner as in (10-1).

1H-NMR (200MHz, CDCl3) δ 1.32(s, 9H), 2.02(m, 2H), 3.31(t, J=5.6Hz, 2H), 3.89(s, 3H), 3.89(t, J=6.0Hz, 2H), 4.19(s, 2H), 4.74(s, 2H), 6.65(m, 2H), 6.85(s, 1H), 7.03(s, 1H), 7.26-7.56(m, 7H), 7.79(m, 1H), 7.96(d, J=8.2Hz, 2H), 8.21(m, 1H) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.32 (s, 9H), 2.02 (m, 2H), 3.31 (t, J = 5.6 Hz, 2H), 3.89 (s, 3H), 3.89 (t, J = 6.0 Hz, 2H), 4.19 (s, 2H), 4.74 (s, 2H), 6.65 (m, 2H), 6.85 (s, 1H), 7.03 (s, 1H), 7.26-7.56 (m, 7H), 7.79 (m, 1H), 7.96 (d, J = 8.2 Hz, 2H), 8.21 (m, 1H)

LC/MS(M+H): 556LC / MS (M + H): 556

(10-4) (Z)-메틸 4-(3-((10-4) (Z) -methyl 4- (3- ( tt -부톡시카보닐(4-하이드록시펜에틸)아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔닐)벤조에이트(12d)-Butoxycarbonyl (4-hydroxyphenethyl) amino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzoate (12d)

상기 제조예 (9-4)에서 얻은 출발물질 (11d, 271㎎)을 사용하여 상기 (10-1)과 동일한 방법으로 연한 노란색 오일형태의 목적화합물 32㎎(12d, 12%)을 얻었다.Using starting material (11d, 271mg) obtained in Preparation Example (9-4), 32 mg (12d, 12%) of the title compound in the form of light yellow oil were obtained in the same manner as in (10-1).

1H-NMR (200MHz, CDCl3) δ 1.56(s, 9H), 2.81(t, J=6.2Hz, 2H), 2.96(t, J=6.6Hz, 2H), 3.64(s, 2H), 3.89(s, 3H), 4.78(s, 2H), 6.67(d, J=7.2Hz, 1H), 6.83(s, 1H), 7.03(d, J=8.4Hz, 2H), 7.17(d, J=8.6Hz, 2H), 7.33(m, 3H), 7.46(m, 3H), 7.79(m, 1H), 7.95(d, J=8.0Hz, 2H), 8.23(m, 1H) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.56 (s, 9H), 2.81 (t, J = 6.2 Hz, 2H), 2.96 (t, J = 6.6 Hz, 2H), 3.64 (s, 2H), 3.89 (s, 3H), 4.78 (s, 2H), 6.67 (d, J = 7.2 Hz, 1H), 6.83 (s, 1H), 7.03 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 8.6 Hz, 2H), 7.33 (m, 3H), 7.46 (m, 3H), 7.79 (m, 1H), 7.95 (d, J = 8.0 Hz, 2H), 8.23 (m, 1H)

LC/MS(M+H): 568LC / MS (M + H): 568

(10-5) (Z)-메틸 4-(3-((10-5) (Z) -methyl 4- (3- ( tt -부톡시카보닐(3-(다이메틸아미노)-2,2-다이메틸프로필)아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔닐)벤조에이트(12e)-Butoxycarbonyl (3- (dimethylamino) -2,2-dimethylpropyl) amino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzoate (12e)

상기 제조예 (9-5)에서 얻은 출발물질 (11e, 328㎎)을 사용하여 상기 (10-1)과 동일한 방법으로 연한 노란색 오일형태의 목적화합물 148㎎(12e, 37%)을 얻었다.Using the starting material (11e, 328mg) obtained in the Preparation Example (9-5), 148 mg (12e, 37%) of the title compound was obtained as a pale yellow oil, in the same manner as in (10-1).

1H-NMR (200MHz, CDCl3) δ 0.97(s, 6H), 1.39(s, 9H), 2.13(s, 2H), 2.25(s, 6H), 3.28(s, 2H), 3.91(s, 3H), 4.35(s, 2H), 4.75(s, 2H), 6.65(s, 1H), 6.67(d, J=7.6Hz, 1H), 7.28-7.59(m, 6H), 7.81(m, 1H), 7.98(d, J=7.8Hz, 2H), 8.29(m, 1H) 1 H-NMR (200 MHz, CDCl 3 ) δ 0.97 (s, 6H), 1.39 (s, 9H), 2.13 (s, 2H), 2.25 (s, 6H), 3.28 (s, 2H), 3.91 (s, 3H), 4.35 (s, 2H), 4.75 (s, 2H), 6.65 (s, 1H), 6.67 (d, J = 7.6Hz, 1H), 7.28-7.59 (m, 6H), 7.81 (m, 1H ), 7.98 (d, J = 7.8 Hz, 2H), 8.29 (m, 1H)

LC/MS(M+H): 561LC / MS (M + H): 561

(10-6) (Z)-메틸 4-(3-((10-6) (Z) -methyl 4- (3- ( tt -부톡시카보닐(2-(다이아이소프로필아미노)에틸)아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔닐)벤조에이트(12f)-Butoxycarbonyl (2- (diisopropylamino) ethyl) amino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzoate (12f)

상기 제조예 (9-6)에서 얻은 출발물질 (11f, 316㎎)을 사용하여 상기 (10-1)과 동일한 방법으로 연한 노란색 오일형태의 목적화합물 277㎎(12f, 72%)을 얻었다. Using starting material (11f, 316mg) obtained in Preparation Example (9-6), 277 mg (12f, 72%) of the title compound was obtained as a pale yellow oil, in the same manner as in (10-1).

1H-NMR (200MHz, CDCl3) δ 1.27(d, J=6.4Hz, 12H), 1.39(s, 9H), 2.64(t, J=5.8Hz, 2H), 3.34(t, J=6.4Hz, 2H), 3.45(m, 2H), 3.71(s, 2H), 3.91(s, 3H), 4.89(s, 2H), 6.73(d, J=7.6Hz, 1H), 6.97(s, 1H), 7.42(m, 6H), 7.79(m, 1H), 7.96(d, J=8.4Hz, 2H), 8.22(m, 1H) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.27 (d, J = 6.4 Hz, 12H), 1.39 (s, 9H), 2.64 (t, J = 5.8 Hz, 2H), 3.34 (t, J = 6.4 Hz , 2H), 3.45 (m, 2H), 3.71 (s, 2H), 3.91 (s, 3H), 4.89 (s, 2H), 6.73 (d, J = 7.6 Hz, 1H), 6.97 (s, 1H) , 7.42 (m, 6H), 7.79 (m, 1H), 7.96 (d, J = 8.4 Hz, 2H), 8.22 (m, 1H)

LC/MS(M+H): 575LC / MS (M + H): 575

(10-7) (Z)-메틸 4-(3-((10-7) (Z) -methyl 4- (3- ( tt -부톡시카보닐(2-메톡시에틸)아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔닐)벤조에이트(12g)-Butoxycarbonyl (2-methoxyethyl) amino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzoate (12 g)

상기 제조예 (9-7)에서 얻은 출발물질 (11g, 239㎎)을 사용하여 상기 (10-1)과 동일한 방법으로 연한 노란색 오일형태의 목적화합물 262㎎(12g, 88%)을 얻었다. Using the starting material (11 g, 239 mg) obtained in Preparation Example (9-7), 262 mg (12 g, 88%) of the title compound in the form of light yellow oil were obtained in the same manner as in (10-1).

1H-NMR (200MHz, CDCl3) δ 1.36(s, 9H), 3.35(s, 3H), 3.56(s, 4H), 3.91(s, 3H), 4.37(s, 2H), 4.75(s, 2H), 6.68(m, 2H), 7.27-7.57(m, 6H), 7.81(m, 1H), 7.97(d, J=7.8Hz, 2H), 8.27(m, 1H) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.36 (s, 9H), 3.35 (s, 3H), 3.56 (s, 4H), 3.91 (s, 3H), 4.37 (s, 2H), 4.75 (s, 2H), 6.68 (m, 2H), 7.27-7.57 (m, 6H), 7.81 (m, 1H), 7.97 (d, J = 7.8 Hz, 2H), 8.27 (m, 1H)

LC/MS(M+H): 506LC / MS (M + H): 506

(10-8) (Z)-메틸 4-(3-((10-8) (Z) -methyl 4- (3- ( tt -부톡시카보닐(사이클로헥실)아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔닐)벤조에이트(12h)-Butoxycarbonyl (cyclohexyl) amino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzoate (12h)

상기 제조예 (9-8)에서 얻은 출발물질 (11h, 300㎎)을 사용하여 상기 (10-1)과 동일한 방법으로 연한 노란색 오일형태의 목적화합물 289㎎(12h, 94%)을 얻었다. Using the starting material (11h, 300mg) obtained in Preparation Example (9-8), 289 mg (12h, 94%) of the title compound was obtained as a pale yellow oil, in the same manner as in (10-1).

1H-NMR (200MHz, CDCl3) δ 1.02-1.44(m, 4H), 1.36(s, 9H),1.45(m, 2H), 1.71(m, 2H), 1.91(m, 2H), 2.59(m, 1H), 3.67(s, 2H), 3.91(s, 3H), 4.86(s, 2H), 6.72(d, J=7.4Hz, 1H), 6.88(s, 1H), 7.26-7.54(m, 6H), 7.80(m, 1H), 7.97(d, J=8.2Hz, 2H), 8.22(m, 1H) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.02-1.44 (m, 4H), 1.36 (s, 9H), 1.45 (m, 2H), 1.71 (m, 2H), 1.91 (m, 2H), 2.59 ( m, 1H), 3.67 (s, 2H), 3.91 (s, 3H), 4.86 (s, 2H), 6.72 (d, J = 7.4 Hz, 1H), 6.88 (s, 1H), 7.26-7.54 (m , 6H), 7.80 (m, 1H), 7.97 (d, J = 8.2 Hz, 2H), 8.22 (m, 1H)

LC/MS(M+H): 530LC / MS (M + H): 530

(10-9) (Z)-메틸 4-(3-((10-9) (Z) -methyl 4- (3- ( tt -부톡시카보닐(4-(다이메틸아미노)벤질)아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1엔일)벤조에이트(12i)-Butoxycarbonyl (4- (dimethylamino) benzyl) amino) -2-((naphthalen-1-yloxy) methyl) prop-1enyl) benzoate (12i)

상기 제조예 (9-9)에서 얻은 출발물질 (11i, 210㎎)을 사용하여 상기 (10-1)과 동일한 방법으로 연한 노란색 오일형태의 목적화합물 181㎎(12i, 51%)을 얻었다. Using the starting material (11i, 210mg) obtained in the Preparation Example (9-9), 181 mg (12i, 51%) of the target compound in the form of a pale yellow oil was obtained in the same manner as in (10-1).

TLC (EtOAc/Hex = 1/4) Rf 0.20TLC (EtOAc / Hex = 1/4) Rf 0.20

1H-NMR (300 MHz, CDCl3) δ 1.36(s, 9H), 2.91(s, 6H), 3.87(d, J=14.8Hz, 3H), 4.15(s, 2H), 4.45(s, 2H), 4.70(s, 2H), 6.64(t, J = 14.8, 7.4 Hz, 4H), 7.11(d, J = 14.8, 7.4 Hz, 1H), 7.23-7.50 (m, 7H), 7.78(d, J = 14.8, 7.4 Hz, 1H), 7.95(d, J = 14.8, 7.4 Hz, 2H), 8.23(d, J = 14.8, 7.4 Hz, 1H) 1 H-NMR (300 MHz, CDCl 3 ) δ 1.36 (s, 9H), 2.91 (s, 6H), 3.87 (d, J = 14.8 Hz, 3H), 4.15 (s, 2H), 4.45 (s, 2H ), 4.70 (s, 2H), 6.64 (t, J = 14.8, 7.4 Hz, 4H), 7.11 (d, J = 14.8, 7.4 Hz, 1H), 7.23-7.50 (m, 7H), 7.78 (d, J = 14.8, 7.4 Hz, 1H), 7.95 (d, J = 14.8, 7.4 Hz, 2H), 8.23 (d, J = 14.8, 7.4 Hz, 1H)

LC/MS(M+H): 581LC / MS (M + H): 581

(10-10) (Z)-메틸 4-(2-(((10-10) (Z) -methyl 4- (2-(( tt -부톡시카보닐(티오펜-2-일메틸)아미노)-2-(나프탈렌-1-일옥시)메틸)프로프-1-엔일)벤조에이트(12j)-Butoxycarbonyl (thiophen-2-ylmethyl) amino) -2- (naphthalen-1-yloxy) methyl) prop-1-enyl) benzoate (12j)

상기 제조예 (9-10)에서 얻은 출발물질 (11j, 180㎎)을 사용하여 상기 (10-1)과 동일한 방법으로 연한 노란색 오일형태의 목적화합물 162㎎(12j, 55%)을 얻었다.Using the starting material (11j, 180mg) obtained in the Preparation Example (9-10), 162 mg (12j, 55%) of the title compound was obtained as a pale yellow oil, in the same manner as in (10-1).

TLC (EtOAc/Hex = 1/4) Rf 0.70TLC (EtOAc / Hex = 1/4) Rf 0.70

1H NMR (300 MHz, CDCl3) δ 1.37(s, 9H), 3.88(s, 3H), 4.26(s, 2H), 4.67(s, 2H), 4.73(s, 2H), 6.65(d, J=7.4Hz, 2H), 6.88(d, J=7.6Hz, 2H), 7.20-7.50(m, 7H), 7.79(d, J=7.6 Hz, 1H), 7.96(d, J=7.8 Hz, 2H), 8.24(d, J=7.6 H, 1Hz)1 H NMR (300 MHz, CDCl 3 ) δ 1.37 (s, 9H), 3.88 (s, 3H), 4.26 (s, 2H), 4.67 (s, 2H), 4.73 (s, 2H), 6.65 (d, J = 7.4 Hz, 2H), 6.88 (d, J = 7.6 Hz, 2H), 7.20-7.50 (m, 7H), 7.79 (d, J = 7.6 Hz, 1H), 7.96 (d, J = 7.8 Hz, 2H ), 8.24 (d, J = 7.6 H, 1 Hz)

LC/MS(M+H): 544LC / MS (M + H): 544

(10-11) (Z)-메틸 4-(2-(((10-11) (Z) -methyl 4- (2-(( tt -부톡시카보닐(4-메톡시펜에틸)아미노)-2-(나프탈렌-1-일옥시)메틸)프로프-1-엔일)벤조에이트(12k)-Butoxycarbonyl (4-methoxyphenethyl) amino) -2- (naphthalen-1-yloxy) methyl) prop-1-enyl) benzoate (12k)

상기 제조예 (9-11)에서 얻은 출발물질 (11k, 262㎎)을 사용하여 상기 (10-1)과 동일한 방법으로 연한 노란색 오일형태의 목적화합물 255㎎(12k, 75%)을 얻었다.The starting material (11k, 262mg) obtained in Preparation Example (9-11) was used to obtain 255 mg (12k, 75%) of the title compound as a pale yellow oil in the same manner as in (10-1).

TLC (EtOAc/Hex = 1/4) Rf 0.50TLC (EtOAc / Hex = 1/4) Rf 0.50

1H-NMR (300 MHz, CDCl3) δ 1.35(s, 9H), 2.80(s, 2H), 3.48(s, 2H), 3.75(s, 3H), 3.88(s, 3H), 4.15(m, 2H), 4.71(s, 2H), 6.66(s, 1H), 6.78(d, J=7.4Hz, 2H), 7.05(s, 2H), 7.25-7.51(m, 7H), 7.79(t, J=7.8Hz, 1H), 7.95(d, J=7.4Hz, 2H), 8.23(d, J=7.6Hz, 1H) 1 H-NMR (300 MHz, CDCl 3 ) δ 1.35 (s, 9H), 2.80 (s, 2H), 3.48 (s, 2H), 3.75 (s, 3H), 3.88 (s, 3H), 4.15 (m , 2H), 4.71 (s, 2H), 6.66 (s, 1H), 6.78 (d, J = 7.4 Hz, 2H), 7.05 (s, 2H), 7.25-7.51 (m, 7H), 7.79 (t, J = 7.8Hz, 1H), 7.95 (d, J = 7.4Hz, 2H), 8.23 (d, J = 7.6Hz, 1H)

LC/MS(M+H): 582LC / MS (M + H): 582

제조예 11 : 화학식 13의 화합물의 제조Preparation Example 11 Preparation of Compound of Formula 13

(11-1) (Z)-4-(3-((11-1) (Z) -4- (3- ( tt -부톡시카보닐(2-(1-메틸피롤리딘-2-일)에틸)아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔닐)벤조산(13a)-Butoxycarbonyl (2- (1-methylpyrrolidin-2-yl) ethyl) amino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzoic acid (13a)

100㎖ 반응용기에 상기 제조예 (10-1)에서 제조한 (Z)-메틸 4-(3-(t-부톡시카보닐(2-(1-메틸피롤리딘-2-일)에틸)아미노)-2-((나프탈렌-1-일옥시)메틸)프로프- 1-엔닐)벤조에이트 (12a; 252㎎, 0.45 mmol)을 1.2㎖의 테트라하이드로퓨란에 녹여 교반하였다. 리튬하이드록사이드 · 일수화물(57㎎, 1.35mmol, 3당량)을 0.4㎖의 물에 녹여 가한 다음, 실온에서 약 12시간동안 교반하였다. 반응 완결을 확인한 후 에틸아세테이트로 물 층을 씻어 준 후 6노르말 염산 수용액을 이용하여 산성화(PH=4)하였다. 여액을 감압증류하고 에틸아세테이트로 2번 추출하였다. 유기층을 소금물로 씻어주고 마그네슘 설페이트로 건조시킨 후 여과하여 용매를 감압 증류하여 제거하였다. 남은 잔사를 실리카겔 칼럼 크로마토그래피로 정제하여 연한 노란색 거품형태의 목적화합물 245㎎(13a, 100%)을 얻었다.(Z) -methyl 4- (3- ( t -butoxycarbonyl (2- (1-methylpyrrolidin-2-yl) ethyl) ethyl) prepared in Preparation Example (10-1) in a 100 ml reaction vessel. Amino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzoate (12a; 252 mg, 0.45 mmol) was dissolved in 1.2 ml of tetrahydrofuran and stirred. Lithium hydroxide monohydrate (57 mg, 1.35 mmol, 3 equiv) was dissolved in 0.4 ml of water, and then stirred at room temperature for about 12 hours. After confirming the completion of the reaction, wash the water layer with ethyl acetate Acidification (PH = 4) using 6-normal hydrochloric acid aqueous solution. The filtrate was distilled under reduced pressure and extracted twice with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and the solvent was distilled off under reduced pressure. The remaining residue was purified by silica gel column chromatography to obtain 245 mg (13a, 100%) of the title compound as a pale yellow foam.

(11-2) (Z)-4-(3-((11-2) (Z) -4- (3- ( tt -부톡시카보닐(1-아이소프로필피페리딘-4-일)아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔닐)벤조산(13b)-Butoxycarbonyl (1-isopropylpiperidin-4-yl) amino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzoic acid (13b)

상기 제조예 (10-2)에서 얻은 출발물질 (12b, 158㎎)을 사용하여 상기 (11-1)과 동일한 방법으로 연한 노란색 거품 형태의 목적화합물 145㎎(13b, 93%)을 얻었다.Using the starting material (12b, 158mg) obtained in the Preparation Example (10-2), 145 mg (13b, 93%) of the target compound in the form of a pale yellow foam was obtained in the same manner as in (11-1).

(11-3) (Z)-4-(3-((3-(1H-이미다졸-1-일)프로필)((11-3) (Z) -4- (3-((3- (1H-imidazol-1-yl) propyl) ( tt -부톡시카보닐)아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)벤조산(13c)-Butoxycarbonyl) amino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzoic acid (13c)

상기 제조예 (10-3)에서 얻은 출발물질 (12c, 174㎎)을 사용하여 상기 (11-1)과 동일한 방법으로 연한 노란색 거품 형태의 목적화합물 167㎎(13c, 100%)을 얻었다.Using the starting material (12c, 174mg) obtained in Preparation Example (10-3), 167 mg (13c, 100%) of the target compound in the form of a pale yellow foam was obtained in the same manner as in (11-1).

1H-NMR (200MHz, CD3OD) δ 1.30(s, 9H), 2.10(m, 2H), 3.36(t, J=5.8Hz, 2H), 4.14(t, J=6.2Hz, 2H), 4.23(s, 2H), 4.73(s, 2H), 6.70(m, 3H), 7.10(br, 1H), 7.29(m, 4H), 7.46(m, 3H), 7.77(m, 1H), 7.97(d, J=8.2Hz, 2H), 8.21(m, 1H), 8.92(br, 1H) 1 H-NMR (200 MHz, CD 3 OD) δ 1.30 (s, 9H), 2.10 (m, 2H), 3.36 (t, J = 5.8 Hz, 2H), 4.14 (t, J = 6.2 Hz, 2H), 4.23 (s, 2H), 4.73 (s, 2H), 6.70 (m, 3H), 7.10 (br, 1H), 7.29 (m, 4H), 7.46 (m, 3H), 7.77 (m, 1H), 7.97 (d, J = 8.2 Hz, 2H), 8.21 (m, 1H), 8.92 (br, 1H)

LC/MS(M+H): 542LC / MS (M + H): 542

(11-4) (Z)-4-(3-((11-4) (Z) -4- (3- ( tt -부톡시카르보닐(4-하이드록시펜에틸)아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)벤조산(13d)-Butoxycarbonyl (4-hydroxyphenethyl) amino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzoic acid (13d)

상기 제조예 (10-4)에서 얻은 출발물질 (12d, 32㎎)을 사용하여 상기 (11-1)과 동일한 방법으로 연한 노란색 거품형태의 목적화합물 31㎎(13d, 100%)을 얻었다.Using starting material (12d, 32mg) obtained in Preparation Example (10-4), 31 mg (13d, 100%) of the target compound in the form of a pale yellow foam was obtained in the same manner as in (11-1).

1H-NMR (200MHz, CD3OD) δ 1.36(s, 9H), 2.79(t, J=4.8Hz, 2H), 3.49(t, J=4.4Hz, 2H), 4.13(s, 2H), 4.72(s, 2H), 6.69(m, 4H), 6.75(d, J=8.0Hz, 2H), 7.27-7.57(m, 6H), 7.79(m, 1H), 7.99(d, J=7.8Hz, 2H), 8.21(m, 1H) 1 H-NMR (200 MHz, CD 3 OD) δ 1.36 (s, 9H), 2.79 (t, J = 4.8 Hz, 2H), 3.49 (t, J = 4.4 Hz, 2H), 4.13 (s, 2H), 4.72 (s, 2H), 6.69 (m, 4H), 6.75 (d, J = 8.0Hz, 2H), 7.27-7.57 (m, 6H), 7.79 (m, 1H), 7.99 (d, J = 7.8Hz , 2H), 8.21 (m, 1H)

LC/MS(M+H): 554LC / MS (M + H): 554

(11-5) (Z)-4-(3-((11-5) (Z) -4- (3- ( tt -부톡시카보닐(3-(다이메틸아미노)-2,2-다이메틸프로필)아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)벤조산(13e)Butoxycarbonyl (3- (dimethylamino) -2,2-dimethylpropyl) amino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzoic acid (13e)

상기 제조예 (10-5)에서 얻은 출발물질 (12e, 148㎎)을 사용하여 상기 (11-1)과 동일한 방법으로 연한 노란색 거품형태의 목적화합물 142㎎(13e, 100%)을 얻었다.Using the starting material (12e, 148mg) obtained in the Preparation Example (10-5), 142 mg (13e, 100%) of the title compound in the form of a pale yellow foam was obtained in the same manner as in (11-1).

1H-NMR (200MHz, CDCl3) δ 1.28(s, 6H), 1.36(s, 9H), 2.84(s, 6H), 2.95(s, 2H), 3.33(s, 2H), 4.30(s, 2H), 4.77(s, 2H), 6.60(s, 1H), 6.63(d, J=7.4Hz, 1H), 7.26-7.56(m, 6H), 7.81(m, 1H), 8.00(d, J=8.2Hz, 2H), 8.21(m, 1H) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.28 (s, 6H), 1.36 (s, 9H), 2.84 (s, 6H), 2.95 (s, 2H), 3.33 (s, 2H), 4.30 (s, 2H), 4.77 (s, 2H), 6.60 (s, 1H), 6.63 (d, J = 7.4 Hz, 1H), 7.26-7.56 (m, 6H), 7.81 (m, 1H), 8.00 (d, J = 8.2 Hz, 2H), 8.21 (m, 1H)

LC/MS(M+H): 547LC / MS (M + H): 547

(11-6) (Z)-4-(3-((11-6) (Z) -4- (3- ( tt -부톡시카보닐(2-(다이아이소프로필아미노)에틸)아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)벤조산(13f)-Butoxycarbonyl (2- (diisopropylamino) ethyl) amino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzoic acid (13f)

상기 제조예 (10-6)에서 얻은 출발물질 (12f, 277㎎)을 사용하여 상기 (11-1)과 동일한 방법으로 연한 노란색 거품형태의 목적화합물 267㎎(13f, 100%)을 얻었다. Using starting material (12f, 277mg) obtained in Preparation Example (10-6), 267 mg (13f, 100%) of the title compound was obtained as a pale yellow foam, in the same manner as in (11-1).

1H-NMR (200MHz, CDCl3) δ 1.26(br, 12H), 1.44(s, 9H), 3.16(m, 2H), 3.54(m, 2H), 3.97(m, 2H), 4.14(s, 2H), 4.32(s, 2H), 6.68(d, J=7.4Hz, 1H), 6.88(s, 1H), 7.40(m, 6H), 7.77(m, 1H), 7.90(d, J=8.0Hz, 2H), 8.22(m, 1H) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.26 (br, 12H), 1.44 (s, 9H), 3.16 (m, 2H), 3.54 (m, 2H), 3.97 (m, 2H), 4.14 (s, 2H), 4.32 (s, 2H), 6.68 (d, J = 7.4Hz, 1H), 6.88 (s, 1H), 7.40 (m, 6H), 7.77 (m, 1H), 7.90 (d, J = 8.0 Hz, 2H), 8.22 (m, 1H)

LC/MS(M+H): 561LC / MS (M + H): 561

(11-7) (Z)-4-(3-((11-7) (Z) -4- (3- ( tt -부톡시카보닐(2-메톡시에틸)아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)벤조산(13g)-Butoxycarbonyl (2-methoxyethyl) amino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzoic acid (13 g)

상기 제조예 (10-7)에서 얻은 출발물질 (12g, 262㎎)을 사용하여 상기 (11-1)과 동일한 방법으로 연한 노란색 거품형태의 목적화합물 225㎎(13g, 89%)을 얻었다. Using the starting material (12 g, 262 mg) obtained in Preparation Example (10-7), 225 mg (13 g, 89%) of the target compound in the form of a pale yellow foam was obtained in the same manner as in (11-1).

1H-NMR (200MHz, CDCl3) δ 1.36(s, 9H), 3.35(s, 3H), 3.58(s, 4H), 4.37(s, 2H), 4.76(s, 2H), 6.70(m, 2H), 7.27-7.56(m, 6H), 7.80(m, 1H), 8.02(d, J=8.2Hz, 2H), 8.27(m, 1H) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.36 (s, 9H), 3.35 (s, 3H), 3.58 (s, 4H), 4.37 (s, 2H), 4.76 (s, 2H), 6.70 (m, 2H), 7.27-7.56 (m, 6H), 7.80 (m, 1H), 8.02 (d, J = 8.2 Hz, 2H), 8.27 (m, 1H)

LC/MS(M+H): 492LC / MS (M + H): 492

(11-8) (Z)-4-(3-((11-8) (Z) -4- (3- ( tt -부톡시카보닐(사이클로헥실)아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)벤조산(13h)-Butoxycarbonyl (cyclohexyl) amino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzoic acid (13h)

상기 제조예 (10-8)에서 얻은 출발물질 (12h, 289㎎)을 사용하여 상기 (11-1)과 동일한 방법으로 연한 노란색 거품형태의 목적화합물 81㎎(13h, 23%)을 얻었다. Using starting material (12h, 289mg) obtained in Preparation Example (10-8), 81 mg (13h, 23%) of the target compound in the form of a pale yellow foam was obtained in the same manner as in (11-1).

1H-NMR (200MHz, CDCl3) δ 1.35(m, 4H), 1.46(s, 9H), 1.67(m, 2H), 1.80(m, 4H), 4.03(m, 1H), 4.17(s, 2H), 4.80(s, 2H), 6.69(d, J=7.8Hz, 1H), 6.73(s, 1H), 7.27-7.58(m, 6H), 7.82(m, 1H), 8.02(d, J=8.6Hz, 2H), 8.28(m, 1H) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.35 (m, 4H), 1.46 (s, 9H), 1.67 (m, 2H), 1.80 (m, 4H), 4.03 (m, 1H), 4.17 (s, 2H), 4.80 (s, 2H), 6.69 (d, J = 7.8Hz, 1H), 6.73 (s, 1H), 7.27-7.58 (m, 6H), 7.82 (m, 1H), 8.02 (d, J = 8.6 Hz, 2H), 8.28 (m, 1H)

LC/MS(M+H): 516LC / MS (M + H): 516

(11-9) (Z)-4-(3-(((11-9) (Z) -4- (3-(( tt -부톡시카보닐(4-다이메틸아미노)벤질)아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)벤조산(13i)-Butoxycarbonyl (4-dimethylamino) benzyl) amino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzoic acid (13i)

상기 제조예 (10-9)에서 얻은 출발물질 (12i, 181㎎)을 사용하여 상기 (11-1)과 동일한 방법으로 연한 노란색 거품형태의 목적화합물 176㎎(13i, 99%)을 얻었다. Using the starting material (12i, 181 mg) obtained in the Preparation Example (10-9), 176 mg (13i, 99%) of the target compound in the form of a pale yellow foam was obtained in the same manner as in (11-1).

TLC (EtOAC) Rf 0.20TLC (EtOAC) Rf 0.20

(11-10) (Z)-4-(3-((11-10) (Z) -4- (3- ( tt -부톡시카보닐(티오펜-2-일메틸)아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)벤조산(13j)-Butoxycarbonyl (thiophen-2-ylmethyl) amino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzoic acid (13j)

상기 제조예 (10-10)에서 얻은 출발물질 (12j, 162㎎)을 사용하여 상기 (11-1)과 동일한 방법으로 연한 노란색 거품형태의 목적화합물 156㎎(13j, 99%)을 얻었다. Using the starting material (12j, 162mg) obtained in the Preparation Example (10-10), 156 mg (13j, 99%) of the title compound was obtained as a pale yellow foam, in the same manner as in (11-1).

TLC (EtOAC) Rf 0.80TLC (EtOAC) Rf 0.80

(11-11) (Z)-4-(3-((11-11) (Z) -4- (3- ( tt -부톡시카보닐(4-메톡시펜에틸)아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)벤조산(13k)-Butoxycarbonyl (4-methoxyphenethyl) amino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzoic acid (13k)

상기 제조예 (10-11)에서 얻은 출발물질 (12k, 255㎎)을 사용하여 상기 (11-1)과 동일한 방법으로 연한 노란색 거품형태의 목적화합물 228㎎(13k, 93%)을 얻었다. Using the starting material (12k, 255mg) obtained in the Preparation Example (10-11), 228 mg (13k, 93%) of the target compound in the form of a pale yellow foam was obtained in the same manner as in (11-1).

TLC (EtOAC) Rf 0.80TLC (EtOAC) Rf 0.80

1H-NMR (300 MHz, CD3OD) δ 1.17(s, 9H), 2.68(s, 2H), 3.22(s, 2H), 3.44(s, 3H), 4.02(s, 2H), 4.80(s, 2H), 6.59-6.69(m, 4H), 6.92(d, J=7.4Hz, 2H), 7.18(t, J=7.8 Hz, 1H), 7.29-7.41(m, 5H), 7.69(d, J=7.8Hz, 1H), 7.85(d, J=7.4Hz, 2H), 8.09(d, J=7.6Hz, 1H) 1 H-NMR (300 MHz, CD 3 OD) δ 1.17 (s, 9H), 2.68 (s, 2H), 3.22 (s, 2H), 3.44 (s, 3H), 4.02 (s, 2H), 4.80 ( s, 2H), 6.59-6.69 (m, 4H), 6.92 (d, J = 7.4 Hz, 2H), 7.18 (t, J = 7.8 Hz, 1H), 7.29-7.41 (m, 5H), 7.69 (d , J = 7.8Hz, 1H), 7.85 (d, J = 7.4Hz, 2H), 8.09 (d, J = 7.6Hz, 1H)

제조예 12 : 화학식 14의 화합물의 제조Preparation Example 12 Preparation of Compound of Formula 14

(12-1) (Z)-(12-1) (Z)- tt -부틸 2-(1-메틸피롤리딘-2-일)에틸(2-((나프탈렌-1-일옥시))-3-(4-(테트라하이드로-2H-피란-2-일옥시카바모일)페닐)알릴)카바메이트(14a)-Butyl 2- (1-methylpyrrolidin-2-yl) ethyl (2-((naphthalen-1-yloxy))-3- (4- (tetrahydro-2H-pyran-2-yloxycarbamoyl ) Phenyl) allyl) carbamate (14a)

100㎖ 반응용기에 상기 제조예 (11-1)에서 제조한 (Z)-4-(3-(t-부톡시카보닐(2-(1-메틸피롤리딘-2-일)에틸)아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔닐)벤조산(13a; 305㎎, 0.56mmol, 1당량)을 3㎖의 N,N-다이메틸포르말에 녹여 교반하면서 N-하이드록시-6-트리플루오로 벤조트리아졸(FOBt; 126㎎, 0.62mmol, 1.1당량), 1-에틸-3-(3-다이메틸아미노프로필)카바다이이마이드·염산염(EDC·HCl; 140㎎, 0.73mmol, 1.3당량), 테트라하이드로-2H-피란-2-일옥시아민(THPONH2; 99㎎, 0.84mmol, 1.5당량) 및 트라이에틸아민 (0.12㎖, 0.84mmol, 1.5당량)을 0℃에서 각각 첨가하고 상온에서 12시간 동안 교반시켰다. 반응이 종결되면 10% 탄산칼륨 수용액을 가하고 에틸아세테이트로 추출한 후, 유기층을 포화 중조와 소금물로 세척한 다음 무수 황산마그네슘으로 건조 후 감압하에서 농축하고 얻어진 잔사를 실리카겔 컬럼 크로마토그래피 방법으로 정제하여 짙은 노란색 거품형태의 표제 화합물 170㎎(14a, 46％)을 얻었다.(Z) -4- (3- ( t -butoxycarbonyl (2- (1-methylpyrrolidin-2-yl) ethyl) amino prepared in Preparation Example (11-1) in a 100 ml reaction vessel ) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzoic acid (13a; 305 mg, 0.56 mmol, 1 equiv) is dissolved in 3 ml of N, N -dimethyl formal and stirred N -hydroxy-6-trifluoro benzotriazole (FOBt; 126 mg, 0.62 mmol, 1.1 equiv), 1-ethyl-3- (3-dimethylaminopropyl) carbaimide hydrochloride (EDC-HCl) ; 140㎎, 0.73mmol, 1.3 equiv.), tetrahydro -2H- blood is oxy-2-yl amine (THPONH 2; 99㎎, 0.84mmol, 1.5 eq) and triethylamine (0.12㎖, 0.84mmol, 1.5 eq. ) Were added at 0 ° C. and stirred at room temperature for 12 hours. After the reaction was completed, 10% aqueous potassium carbonate solution was added and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give a dark yellow color. 170 mg (14a, 46%) of the title compound in the foam form was obtained.

1H-NMR (200MHz, CDCl3) δ 1.36(s, 9H), 1.41-2.12(m, 14H), 2.22(m, 1H), 2.36(s, 3H), 3.18(m, 1H), 3.35(m, 2H), 3.62(m, 1H), 3.99(m, 1H), 4.26(s, 2H), 4.74(s, 2H), 5.08(m, 1H), 6.68(d, J=9.4Hz, 1H), 6.73(s, 1H), 7.29-7.55(m, 6H), 7.69(d, J=7.8Hz, 2H), 7.80(m, 1H), 8.28(m, 1H) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.36 (s, 9H), 1.41-2.12 (m, 14H), 2.22 (m, 1H), 2.36 (s, 3H), 3.18 (m, 1H), 3.35 ( m, 2H), 3.62 (m, 1H), 3.99 (m, 1H), 4.26 (s, 2H), 4.74 (s, 2H), 5.08 (m, 1H), 6.68 (d, J = 9.4 Hz, 1H ), 6.73 (s, 1H), 7.29-7.55 (m, 6H), 7.69 (d, J = 7.8 Hz, 2H), 7.80 (m, 1H), 8.28 (m, 1H)

LC/MS(M+H): 644LC / MS (M + H): 644

(12-2) (Z)-(12-2) (Z)- tt -부틸 1-아이소프로필피페리딘-4-일(2-((나프탈렌-1-일옥시)메틸)-3-(4-(테트라하이드로-2H-피란-2-일옥시카바모일)페닐)알릴)카바메이트(14b)-Butyl 1-isopropylpiperidin-4-yl (2-((naphthalen-1-yloxy) methyl) -3- (4- (tetrahydro-2H-pyran-2-yloxycarbamoyl) phenyl) Allyl) carbamate (14b)

상기 제조예 (11-2)에서 얻은 출발물질 (13b, 145㎎)을 사용하여 상기 (12-1)과 동일한 방법으로 연한 노란색 거품 형태의 목적화합물 122㎎ (14b, 73%)을 얻었다.122 mg (14b, 73%) of the title compound as a pale yellow foam was obtained using the starting material (13b, 145 mg) obtained in Preparation Example (11-2).

1H-NMR (200MHz, CDCl3) δ 1.12(d, J=6.6Hz, 6H), 1.43(s, 9H), 1.61(m, 3H), 1.86(m, 7H), 2.06(m, 2H), 2.37(m, 2H), 3.61(m, 1H), 3.98(m, 1H), 4.23(s, 2H), 4.74(s, 2H), 5.07(m, 1H), 6.68(d, J=7.4Hz, 2H), 7.33(m, 3H), 7.48(m, 3H), 7.68(d, J=8.6Hz, 2H), 7.80(m, 1H), 8.27(m, 1H) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.12 (d, J = 6.6 Hz, 6H), 1.43 (s, 9H), 1.61 (m, 3H), 1.86 (m, 7H), 2.06 (m, 2H) , 2.37 (m, 2H), 3.61 (m, 1H), 3.98 (m, 1H), 4.23 (s, 2H), 4.74 (s, 2H), 5.07 (m, 1H), 6.68 (d, J = 7.4 Hz, 2H), 7.33 (m, 3H), 7.48 (m, 3H), 7.68 (d, J = 8.6 Hz, 2H), 7.80 (m, 1H), 8.27 (m, 1H)

LC/MS(M+H): 658LC / MS (M + H): 658

(12-3) (Z)-(12-3) (Z)- tt -부틸 3-(1H-이미다졸-1-일)프로필(2-((나프탈렌-1-일옥시)메틸)-3-(4-(테트라하이드로-2H-피란-2-일옥시카바모일)페닐)아릴)카바메이트 (14c) 합성-Butyl 3- (1H-imidazol-1-yl) propyl (2-((naphthalen-1-yloxy) methyl) -3- (4- (tetrahydro-2H-pyran-2-yloxycarbamoyl) Phenyl) aryl) carbamate (14c) synthesis

상기 제조예 (11-3)에서 얻은 출발물질 (13c, 176㎎)을 사용하여 상기 (12-1)과 동일한 방법으로 연한 노란색 거품 형태의 목적화합물 205㎎ (14c, 99%)을 얻었다.Using the starting material (13c, 176 mg) obtained in the Preparation Example (11-3), 205 mg (14c, 99%) of the target compound in the form of a pale yellow foam was obtained in the same manner as in (12-1).

1H-NMR (200MHz, CDCl3) δ 1.34(s,9H), 1.61(m, 4H), 1.88(m, 2H), 2.05(m, 2H), 3.33(t, J=7.0Hz, 2H), 3.64(m, 1H), 3.91(t, J=6.8hz, 2H), 3.95(m, 1H), 4.21(s, 2H), 4.73(s, 2H), 5.08(m, 1H0, 6.66(d, J=7.6Hz, 2H), 6.88(s, 1H), 7.05(s, 1H), 7.27-7.59(m, 7H), 7.70(d, J=8.2Hz, 2H), 7.82(m, 1H), 8.21(m, 1H) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.34 (s, 9H), 1.61 (m, 4H), 1.88 (m, 2H), 2.05 (m, 2H), 3.33 (t, J = 7.0 Hz, 2H) , 3.64 (m, 1H), 3.91 (t, J = 6.8hz, 2H), 3.95 (m, 1H), 4.21 (s, 2H), 4.73 (s, 2H), 5.08 (m, 1H0, 6.66 (d , J = 7.6Hz, 2H), 6.88 (s, 1H), 7.05 (s, 1H), 7.27-7.59 (m, 7H), 7.70 (d, J = 8.2Hz, 2H), 7.82 (m, 1H) , 8.21 (m, 1 H)

LC/MS(M+H): 641LC / MS (M + H): 641

(12-4) (Z)-(12-4) (Z)- tt -부틸 4-하이드록시펜에틸(2-((나프탈렌-1-일옥시)메틸)-3-(4-(테트라하이드로-2H-피란-2-일옥시카바모일)페닐)아릴)카바메이트(14d)-Butyl 4-hydroxyphenethyl (2-((naphthalen-1-yloxy) methyl) -3- (4- (tetrahydro-2H-pyran-2-yloxycarbamoyl) phenyl) aryl) carbamate ( 14d)

상기 제조예 (11-4)에서 얻은 출발물질(13d, 31㎎)을 사용하여 상기 (12-1)과 동일한 방법으로 연한 노란색 오일형태의 표제화합물 36㎎(14d, 98%)을 얻었다.Starting material (13d, 31 mg) obtained in Preparation Example (11-4) was used to obtain 36 mg (14d, 98%) of the title compound as a pale yellow oil in the same manner as in (12-1).

1H-NMR (200MHz, CDCl3) δ 1.35(s, 9H), 1.61(m, 4H), 1.85(,m 2H), 2.34(m, 2H), 3.22(m, 2H), 3.27(s, 2H), 3.60(m, 1H), 3.93(m, 1H), 4.68(s, 2H), 5.06(m, 1H), 6.74(m, 4H), 6.98(m, 2H), 7.31(m, 3H), 7.49(m, 3H), 7.66(d, J=7.6Hz, 2H), 7.79(m, 1H), 8.16(m, 1H) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.35 (s, 9H), 1.61 (m, 4H), 1.85 (, m 2H), 2.34 (m, 2H), 3.22 (m, 2H), 3.27 (s, 2H), 3.60 (m, 1H), 3.93 (m, 1H), 4.68 (s, 2H), 5.06 (m, 1H), 6.74 (m, 4H), 6.98 (m, 2H), 7.31 (m, 3H) ), 7.49 (m, 3H), 7.66 (d, J = 7.6 Hz, 2H), 7.79 (m, 1H), 8.16 (m, 1H)

LC/MS(M+H): 653LC / MS (M + H): 653

(12-5) (Z)-(12-5) (Z)- tt -부틸 3-(다이메틸아미노)-2,2-다이메틸프로필(2-((나프탈렌-1-일옥시)메틸)-3-(4-(테트라하이드로-2H-피란-2-일옥시카바모일)페닐)아릴)카바메이트(14e)-Butyl 3- (dimethylamino) -2,2-dimethylpropyl (2-((naphthalen-1-yloxy) methyl) -3- (4- (tetrahydro-2H-pyran-2-yloxycarba Moyl) phenyl) aryl) carbamate (14e)

상기 제조예 (11-5)에서 얻은 출발물질(13e, 159㎎)을 사용하여 상기 (12-1)과 동일한 방법으로 연한 노란색 오일형태의 표제화합물 187㎎(14e, 100%)을 얻었다.Using the starting material (13e, 159mg) obtained in the Preparation Example (11-5), 187 mg (14e, 100%) of the title compound was obtained as a pale yellow oil, in the same manner as in (12-1).

1H-NMR (200MHz, CDCl3) δ 0.96(s, 6H), 1.39(s, 9H), 1.61(m, 4H), 1.88(m, 2H), 2.24(s, 2H), 3.28(s, 2H), 3.67(m, 1H), 3.99(m, 1H), 4.35(s, 2H), 4.73(s, 2H), 5.08(m, 1H), 6.63(s, 1H), 6.67(d, J=8.0Hz, 1H), 7.27-7.57(m, 6H), 7.69(d, J=8.2Hz, 2H), 7.80(m, 1H), 8.28(m, 1H) 1 H-NMR (200 MHz, CDCl 3 ) δ 0.96 (s, 6H), 1.39 (s, 9H), 1.61 (m, 4H), 1.88 (m, 2H), 2.24 (s, 2H), 3.28 (s, 2H), 3.67 (m, 1H), 3.99 (m, 1H), 4.35 (s, 2H), 4.73 (s, 2H), 5.08 (m, 1H), 6.63 (s, 1H), 6.67 (d, J) = 8.0 Hz, 1H), 7.27-7.57 (m, 6H), 7.69 (d, J = 8.2 Hz, 2H), 7.80 (m, 1H), 8.28 (m, 1H)

LC/MS(M+H): 646LC / MS (M + H): 646

(12-6) (Z)-(12-6) (Z)- tt -부틸 2-(다이아이소프로필아미노)에틸(2-((나프탈렌-1-일옥시)메틸)-3-(4-(테트라하이드로-2H-피란-2-일옥시카바모일)페닐)아릴)카바메이트(14f)-Butyl 2- (diisopropylamino) ethyl (2-((naphthalen-1-yloxy) methyl) -3- (4- (tetrahydro-2H-pyran-2-yloxycarbamoyl) phenyl) aryl) Carbamate (14f)

상기 제조예 (11-6)에서 얻은 출발물질(13f, 267㎎)을 사용하여 상기 (12-1)과 동일한 방법으로 연한 노란색 오일형태의 표제화합물 317㎎(14f, 100%)을 얻었다.Using the starting material (13f, 267 mg) obtained in the Preparation Example (11-6) to give the title compound in the light yellow oil form 317 mg (14f, 100%) in the same manner as in (12-1).

1H-NMR (200MHz, CDCl3) δ 0.99(d, J=6.6Hz, 12H), 1.36(s, 9H), 1.61(m, 4H), 1.86(m, 2H), 2.61(t, J=7.0Hz, 2H), 3.29(t, J=6.4Hz, 2H), 3.67(m, 1H), 3.98(m, 1H), 4.31(s, 2H), 4.72(s, 2H), 5.07(m, 1H), 6.71(m, 2H), 7.29-7.58(m, 6H), 7.68(d, J=8.2Hz, 2H). 7.80(d, J=7.0Hz, 1H), 8.26(d, J=7.4Hz, 1H) 1 H-NMR (200 MHz, CDCl 3 ) δ 0.99 (d, J = 6.6 Hz, 12H), 1.36 (s, 9H), 1.61 (m, 4H), 1.86 (m, 2H), 2.61 (t, J = 7.0 Hz, 2H), 3.29 (t, J = 6.4 Hz, 2H), 3.67 (m, 1H), 3.98 (m, 1H), 4.31 (s, 2H), 4.72 (s, 2H), 5.07 (m, 1H), 6.71 (m, 2H), 7.29-7.58 (m, 6H), 7.68 (d, J = 8.2 Hz, 2H). 7.80 (d, J = 7.0 Hz, 1H), 8.26 (d, J = 7.4 Hz, 1H)

LC/MS(M+H): 660LC / MS (M + H): 660

(12-7) (Z)-(12-7) (Z)- tt -부틸 2-메톡시에틸(2-((나프탈렌-1-일옥시)메틸)-3-(4-(테트라하이드로-2H-피란-2-일옥시카바모일)페닐)아릴)카바메이트(14g)-Butyl 2-methoxyethyl (2-((naphthalen-1-yloxy) methyl) -3- (4- (tetrahydro-2H-pyran-2-yloxycarbamoyl) phenyl) aryl) carbamate (14 g )

상기 제조예 (11-7)에서 얻은 출발물질(13g, 225㎎)을 사용하여 상기 (12-1)과 동일한 방법으로 연한 노란색 오일형태의 표제화합물 274㎎(14g, 100%)을 얻었다.274 mg (14 g, 100%) of the title compound as a pale yellow oil was obtained in the same manner as in (12-1), using the starting material (13 g, 225 mg) obtained in Preparation Example (11-7).

1H-NMR (200MHz, CDCl3) δ 1.33(s,9H), 1.59(m, 4H), 1.85(m, 2H), 3.33(s, 3H), 3.53(s. 4H), 3.59(m, 1H), 3.91(m, 1H), 4.33(s, 2H), 4.71(s, 2H), 5.05(m, 1H), 6.67(m, 2H), 7.27-7.55(m, 6H), 7.66(d, J=8.0Hz, 2H), 7.78(m, 1H), 8.24(m, 1H) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.33 (s, 9H), 1.59 (m, 4H), 1.85 (m, 2H), 3.33 (s, 3H), 3.53 (s. 4H), 3.59 (m, 1H), 3.91 (m, 1H), 4.33 (s, 2H), 4.71 (s, 2H), 5.05 (m, 1H), 6.67 (m, 2H), 7.27-7.55 (m, 6H), 7.66 (d , J = 8.0 Hz, 2H), 7.78 (m, 1H), 8.24 (m, 1H)

LC/MS(M+H): 592LC / MS (M + H): 592

(12-8) (Z)-(12-8) (Z)- tt -부틸 사이클로헥실(2-((나프탈렌-1-일옥시)메틸)-3-(4-(테트라하이드로-2H-피란-2-일옥시카바모일)페닐)아릴)카바메이트(14h)-Butyl cyclohexyl (2-((naphthalen-1-yloxy) methyl) -3- (4- (tetrahydro-2H-pyran-2-yloxycarbamoyl) phenyl) aryl) carbamate (14h)

상기 제조예 (11-8)에서 얻은 출발물질(13h, 81㎎)을 사용하여 상기 (12-1)과 동일한 방법으로 연한 노란색 오일형태의 표제화합물 109㎎(14h, 98%)을 얻었다.Using the starting material (13h, 81mg) obtained in the Preparation Example (11-8) to give 109 mg (14h, 98%) of the title compound as a pale yellow oil in the same manner as in (12-1).

1H-NMR (200MHz, CDCl3) δ 1.05-1.41(m, 4H), 1.43(s, 9H), 1.59(m, 6H), 1.69-1.95(m, 6H), 2.54(m, 1H), 3.66(m, 1H), 3.97(m, 1H), 4.14(s, 2H), 4.74(s, 2H), 5.06(m, 1H), 6.68(m, 2H), 7.30(m, 3H), 7.47(m, 3H), 7.67(d, J=8.2Hz, 2H), 7.80(m, 1H), 8.26(m, 1H) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.05-1.41 (m, 4H), 1.43 (s, 9H), 1.59 (m, 6H), 1.69-1.95 (m, 6H), 2.54 (m, 1H), 3.66 (m, 1H), 3.97 (m, 1H), 4.14 (s, 2H), 4.74 (s, 2H), 5.06 (m, 1H), 6.68 (m, 2H), 7.30 (m, 3H), 7.47 (m, 3H), 7.67 (d, J = 8.2 Hz, 2H), 7.80 (m, 1H), 8.26 (m, 1H)

LC/MS(M+H): 616LC / MS (M + H): 616

(12-9) (Z)-(12-9) (Z)- tt -부틸 4-(다이메틸아미노)벤질(2-((나프탈렌-1-일옥시)메틸)-3-(4-(테 트라하이드로-2H-피란-2-일옥시카바모일)페닐)알릴)카바메이트(14i)-Butyl 4- (dimethylamino) benzyl (2-((naphthalen-1-yloxy) methyl) -3- (4- (tetrahydro-2H-pyran-2-yloxycarbamoyl) phenyl) allyl) Carbamate (14i)

상기 제조예 (11-9)에서 얻은 출발물질(13i, 176㎎)을 사용하여 상기 (12-1)과 동일한 방법으로 연한 노란색 오일형태의 표제화합물 210㎎(14i, 98%)을 얻었다.Using starting material (13i, 176mg) obtained in Preparation Example (11-9), 210 mg (14i, 98%) of the title compound was obtained as a pale yellow oil, in the same manner as in (12-1).

TLC (EtOAC) Rf 0.80TLC (EtOAC) Rf 0.80

1H NMR (300 MHz, CDCl3) δ 1.23-1.27(t, J=14.8, 7.4 Hz, 6H), 1.35(s, 9H), 1.58(s, 2H), 1.79(d, J=14.8Hz, 2H), 2.91(s, 6H), 3.93-4.15(m, 4H), 4.45(s, 2H), 4.67(s, 2H), 5.04(s, 1H), 6.63(d, J=7.4Hz, 4H), 7.10(dd, J=14.8, 7.4 Hz, 1H), 7.25-7.53(m, 7H), 7.66(d, J=14.8, 7.4Hz, 2H), 7.78(d, J=14.8, 7.4Hz, 1H), 8.21(d, J=14.8, 7.4Hz, 1H)1 H NMR (300 MHz, CDCl 3 ) δ 1.23-1.27 (t, J = 14.8, 7.4 Hz, 6H), 1.35 (s, 9H), 1.58 (s, 2H), 1.79 (d, J = 14.8 Hz, 2H ), 2.91 (s, 6H), 3.93-4.15 (m, 4H), 4.45 (s, 2H), 4.67 (s, 2H), 5.04 (s, 1H), 6.63 (d, J = 7.4 Hz, 4H) , 7.10 (dd, J = 14.8, 7.4 Hz, 1H), 7.25-7.53 (m, 7H), 7.66 (d, J = 14.8, 7.4 Hz, 2H), 7.78 (d, J = 14.8, 7.4 Hz, 1H ), 8.21 (d, J = 14.8, 7.4 Hz, 1H)

LC/MS(M+H): 616LC / MS (M + H): 616

(12-10) (Z)-(12-10) (Z)- tt -부틸 3-(4-((테트라하이드로-2H-피란-2-일옥시)카바모일)페닐)-2-((나프탈렌-1-일옥시)메틸)알릴(티오펜-2-일메틸)카바메이트(14j)-Butyl 3- (4-((tetrahydro-2H-pyran-2-yloxy) carbamoyl) phenyl) -2-((naphthalen-1-yloxy) methyl) allyl (thiophen-2-ylmethyl) Carbamate (14j)

상기 제조예 (11-10)에서 얻은 출발물질(13j, 156㎎)을 사용하여 상기 (12-1)과 동일한 방법으로 연한 노란색 오일형태의 표제화합물 194㎎(14j, 97%)을 얻었다.Using the starting material (13j, 156mg) obtained in the Preparation Example (11-10), 194 mg (14j, 97%) of the title compound was obtained as a pale yellow oil, in the same manner as in (12-1).

TLC (EtOAC) Rf 0.85TLC (EtOAC) Rf 0.85

1H-NMR (300 MHz, CDCl3) δ 1.25(s, 2H), 1.36(s, 9H), 1.58(s, 2H), 1.85(m, 2H), 3.60(s, 1H), 3.98(s, 1H), 4.25(s, 2H), 4.67-4.70(m, 4H), 5.05(s, 1H), 6.65(m, 2H), 6.88(t, J =7.6, 7.6 Hz, 2H), 7.30(m, 2H), 7.42-7.50(m, 2H), 7.69(d, J=7.4 Hz, 2H), 7.79(d, J=7.8Hz, 2H), 8.00(s, 2H), 8.23(d, J=7.6 Hz, 1H) 1 H-NMR (300 MHz, CDCl 3 ) δ 1.25 (s, 2H), 1.36 (s, 9H), 1.58 (s, 2H), 1.85 (m, 2H), 3.60 (s, 1H), 3.98 (s , 1H), 4.25 (s, 2H), 4.67-4.70 (m, 4H), 5.05 (s, 1H), 6.65 (m, 2H), 6.88 (t, J = 7.6, 7.6 Hz, 2H), 7.30 ( m, 2H), 7.42-7.50 (m, 2H), 7.69 (d, J = 7.4 Hz, 2H), 7.79 (d, J = 7.8 Hz, 2H), 8.00 (s, 2H), 8.23 (d, J = 7.6 Hz, 1H)

LC/MS(M+H): 629LC / MS (M + H): 629

(12-11) (Z)-(12-11) (Z)- tt -부틸 3-(4-((테트라하이드로-2H-피란-2-일옥시)카바모일)페닐)-2-((나프탈렌-1-일옥시)메틸)알릴(4-메톡시펜에틸)카바메이트(14k)-Butyl 3- (4-((tetrahydro-2H-pyran-2-yloxy) carbamoyl) phenyl) -2-((naphthalen-1-yloxy) methyl) allyl (4-methoxyphenethyl) carba Mate (14k)

상기 제조예 (11-11)에서 얻은 출발물질(13k, 228㎎)을 사용하여 상기 (12-1)과 동일한 방법으로 연한 노란색 오일형태의 표제화합물 283㎎(14k, 98%)을 얻었다.Using the starting material (13k, 228mg) obtained in Preparation Example (11-11), 283 mg (14k, 98%) of the title compound was obtained as a pale yellow oil, in the same manner as in (12-1).

TLC (EtOAC) Rf 0.90TLC (EtOAC) Rf 0.90

1H NMR (300 MHz, CDCl3) δ 1.34(s, 9H), 1.58(s, 3H), 1.71-1.88(m, 3H), 2.80(s, 2H), 3.45-3.50(t, J=7.4Hz, 2H), 3.59(d, J=7.4Hz, 1H), 3.75(s, 3H), 3.95(t, J=7.4Hz, 1H), 4.10(d, J=7.8Hz, 2H), 4.57(s, 2H), 5.03(s, 1H), 6.64(d, J=7.8Hz, 2H), 6.78(d, J=7.8Hz, 2H), 7.26-7.33 (m, 4H), 7.41-7.53 (m, 4H), 7.66(d, J=7.8Hz, 2H), 7.79(d, J=7.4Hz, 1H), 8.21(d, J=7.6Hz, 1H)1 H NMR (300 MHz, CDCl 3 ) δ 1.34 (s, 9H), 1.58 (s, 3H), 1.71-1.88 (m, 3H), 2.80 (s, 2H), 3.45-3.50 (t, J = 7.4 Hz , 2H), 3.59 (d, J = 7.4 Hz, 1H), 3.75 (s, 3H), 3.95 (t, J = 7.4 Hz, 1H), 4.10 (d, J = 7.8 Hz, 2H), 4.57 (s , 2H), 5.03 (s, 1H), 6.64 (d, J = 7.8Hz, 2H), 6.78 (d, J = 7.8Hz, 2H), 7.26-7.33 (m, 4H), 7.41-7.53 (m, 4H), 7.66 (d, J = 7.8 Hz, 2H), 7.79 (d, J = 7.4 Hz, 1H), 8.21 (d, J = 7.6 Hz, 1H)

LC/MS(M+H): 667LC / MS (M + H): 667

실시예 1 : (Z)-4-(3-(1-에틸피페리딘-4-일아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)-Example 1 (Z) -4- (3- (1-ethylpiperidin-4-ylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl)- NN -하이드록시벤즈아마이드(1a)Hydroxybenzamide (1a)

제조예 (8-1)에서 제조된 출발물질 (10a, 103㎎, 0.19 mmol)을 메탄올(1.5㎖)에 녹이고 트라이플루오로아세트산(0.07㎖, 0.95mmol)을 실온에서 천천히 가한 후 실온에서 8 시간동안 반응시켜 탈보호기(THP)반응을 하고 반응 종결을 확인하고 감압하에서 농축하고 얻어진 잔사를 prep. HPLC로 정제하여 연한 주황색 거품형태의 표제 화합물 37㎎ (1a, 분석용)을 얻었다.The starting material (10a, 103 mg, 0.19 mmol) prepared in Preparation Example (8-1) was dissolved in methanol (1.5 mL) and trifluoroacetic acid (0.07 mL, 0.95 mmol) was slowly added at room temperature, followed by 8 hours at room temperature. The reaction was carried out during the deprotection group (THP) reaction to confirm the completion of the reaction, and concentrated under reduced pressure. Purification by HPLC gave 37 mg (1a, analytical) of the title compound as a pale orange foam.

1H-NMR (300MHz, CD3OD) δ 1.31(t, J=7.5Hz, 3H), 2.03(m, 2H), 2.44(m, 2H), 3.01(m, 2H), 3.18(m, 3H), 3.68(m, 2H), 4.12(s, 2H), 4.96(s, 2H), 6.78(d, J=7.5Hz, 1H), 7.24(s, 1H), 7.31(t, J=8.1Hz, 1H), 7.46(m, 5H), 7.70(d, J=8.1Hz, 2H), 7.79(m, 1H), 8.18(m, 1H) 1 H-NMR (300 MHz, CD 3 OD) δ 1.31 (t, J = 7.5 Hz, 3H), 2.03 (m, 2H), 2.44 (m, 2H), 3.01 (m, 2H), 3.18 (m, 3H ), 3.68 (m, 2H), 4.12 (s, 2H), 4.96 (s, 2H), 6.78 (d, J = 7.5 Hz, 1H), 7.24 (s, 1H), 7.31 (t, J = 8.1 Hz , 1H), 7.46 (m, 5H), 7.70 (d, J = 8.1 Hz, 2H), 7.79 (m, 1H), 8.18 (m, 1H)

LC/MS(M+H): 460LC / MS (M + H): 460

실시예 2 : (Z)-4-(3-(1-에틸피롤리딘-3-일아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)-Example 2: (Z) -4- (3- (1-ethylpyrrolidin-3-ylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl)- NN -하이드록시벤즈아마이드(1b)Hydroxybenzamide (1b)

제조예 (8-2)에서 제조된 화합물을 출발물질(10b, 120㎎)로 사용하여 상기 실시예 1과 동일한 방법으로 연한 노란색 오일형태의 표제화합물 56㎎ (1b, 분석용)을 얻었다.Using the compound prepared in Preparation Example (8-2) as a starting material (10b, 120 mg), 56 mg (1b, analytical) of the title compound was obtained as a pale yellow oil, in the same manner as in Example 1.

1H-NMR (300MHz, CD3OD) δ 1.29(t, J=7.3Hz, 3H), 2.29(m, 1H), 2.60(m, 1H), 3.27(q, J=7.3Hz, 2H), 3.30(m, 2H), 3.69(m, 2H), 4.05(s, 2H), 4.21(m, 1H), 4.96(s, 2H), 6.76(d, J=7.6Hz, 1H), 7.21(s, 1H), 7.27(t, J=8.0Hz, 1H), 7.45(m, 5H), 7.69(d, J=8.2Hz, 2H), 7.78(d, J=7.0Hz, 1H), 8.17(d, J=7.1Hz, 1H) 1 H-NMR (300 MHz, CD 3 OD) δ 1.29 (t, J = 7.3 Hz, 3H), 2.29 (m, 1H), 2.60 (m, 1H), 3.27 (q, J = 7.3 Hz, 2H), 3.30 (m, 2H), 3.69 (m, 2H), 4.05 (s, 2H), 4.21 (m, 1H), 4.96 (s, 2H), 6.76 (d, J = 7.6 Hz, 1H), 7.21 (s , 1H), 7.27 (t, J = 8.0 Hz, 1H), 7.45 (m, 5H), 7.69 (d, J = 8.2 Hz, 2H), 7.78 (d, J = 7.0 Hz, 1H), 8.17 (d , J = 7.1 Hz, 1H)

LC/MS(M+H): 446LC / MS (M + H): 446

실시예 3 : (Z)-Example 3: (Z)- NN -하이드록시-4-(3-(나프탈렌-1-일옥시)-2-((4-(트라이플루오로메톡시)벤질아미노)메틸)프로프-1-엔일)벤즈아마이드(1c) -Hydroxy-4- (3- (naphthalen-1-yloxy) -2-((4- (trifluoromethoxy) benzylamino) methyl) prop-1-enyl) benzamide (1c)

제조예 (8-3)에서 제조된 화합물을 출발물질(10c, 180㎎)로 사용하여 상기 실시예 1과 동일한 방법으로 연한 노란색 오일형태의 표제화합물 92㎎ (1c, 분석용)을 얻었다. Using the compound prepared in Preparation Example (8-3) as a starting material (10c, 180 mg), 92 mg (1c, analytical) of the title compound was obtained as a pale yellow oil, in the same manner as in Example 1.

TLC (MeOH/MC = 1/6) Rf 0.45TLC (MeOH / MC = 1/6) Rf 0.45

1H-NMR (300 MHz, CD3OD) δ 4.09(s, 2H), 4.37(s, 2H), 4.94(s, 2H), 6.73(d, J=7.4Hz, 1H), 7.18(s, 1H), 7.27(t, J=7.6 Hz, 3H), 7.35-7.47(m, 5H), 7.55(d, J=7.8Hz, 2H), 7.68(d, J=7.4Hz, 2H), 7.76(d, J=7.8Hz, 1H), 8.07(d, J=7.4Hz, 1H) 1 H-NMR (300 MHz, CD 3 OD) δ 4.09 (s, 2H), 4.37 (s, 2H), 4.94 (s, 2H), 6.73 (d, J = 7.4 Hz, 1H), 7.18 (s, 1H), 7.27 (t, J = 7.6 Hz, 3H), 7.35-7.47 (m, 5H), 7.55 (d, J = 7.8 Hz, 2H), 7.68 (d, J = 7.4 Hz, 2H), 7.76 ( d, J = 7.8 Hz, 1H), 8.07 (d, J = 7.4 Hz, 1H)

LC/MS(M+H): 507LC / MS (M + H): 507

실시예 4 : (Z)-3-(3-(4-(하이드록시카바모일)페닐)-2-((나프탈렌-1-일옥시)메틸)알릴아미노)피롤리딘-1-카복실산-t-뷰틸에스터(1d) Example 4: (Z) -3- (3- (4- (hydroxycarbamoyl) phenyl) -2-((naphthalen-1-yloxy) methyl) allylamino) pyrrolidine-1-carboxylic acid-t -Butyl ester (1d)

제조예 (8-4)에서 제조된 화합물을 출발물질(10d, 180㎎)로 사용하여 상기 실시예 1과 동일한 방법으로 연한 노란색 오일형태의 표제화합물 84㎎ (1d, 분석용)을 얻었다.84 mg (1 d, analytical) of the title compound as a pale yellow oil was obtained in the same manner as in Example 1, using the compound prepared in Preparation Example (8-4) as a starting material (10 d, 180 mg).

수율 81 % Yield 81%

TLC (MeOH/MC = 1/6) Rf 0.75TLC (MeOH / MC = 1/6) Rf 0.75

1H-NMR (300 MHz, CD3OD) δ 1.37(s, 9H), 1.79-2.12(m, 2H), 3.14-3.26(m, 4H), 3.33-3.51 m, 3H), 4.61(s, 2H), 6.69(d, J=7.4Hz, 1H), 6.93(s, 1H), 7.29-7.55(m, 6H), 7.63(t, J=7.8Hz, 1H), 7.72(d, J=7.6Hz, 2H), 8.11(d, J=7.6Hz, 1H) 1 H-NMR (300 MHz, CD 3 OD) δ 1.37 (s, 9H), 1.79-2.12 (m, 2H), 3.14-3.26 (m, 4H), 3.33-3.51 m, 3H), 4.61 (s, 2H), 6.69 (d, J = 7.4 Hz, 1H), 6.93 (s, 1H), 7.29-7.55 (m, 6H), 7.63 (t, J = 7.8 Hz, 1H), 7.72 (d, J = 7.6 Hz, 2H), 8.11 (d, J = 7.6Hz, 1H)

LC/MS(M+H): 518LC / MS (M + H): 518

실시예　5 ： (Z)-Example # 5: (Z)- NN -하이드록시-4-(3-(나프탈렌-1-일옥시)-2-((피롤리딘-3-일아미노)메틸)프로프-1-엔일)벤즈아마이드 (1e)-Hydroxy-4- (3- (naphthalen-1-yloxy) -2-((pyrrolidin-3-ylamino) methyl) prop-1-enyl) benzamide (1e)

실시예 4에서 제조된 출발물질 (1d, 103㎎, 0.19 mmol)을 다이클로로메탄(1.5㎖)에 녹이고 트라이플루오로아세트산(0.07㎖, 0.95mmol)을 실온에서 천천히 가한 후 실온에서 8 시간동안 반응시켜 반응 종결을 확인하고 감압하에서 농축하고 얻어진 잔사를 prep. HPLC로 정제하여 연한 주황색 거품형태의 표제 화합물 37㎎(1e, 분석용)을 얻었다.The starting material (1d, 103 mg, 0.19 mmol) prepared in Example 4 was dissolved in dichloromethane (1.5 mL) and trifluoroacetic acid (0.07 mL, 0.95 mmol) was slowly added at room temperature, followed by reaction at room temperature for 8 hours. To confirm the completion of the reaction, and concentrated under reduced pressure. Purification by HPLC gave 37 mg (1e, Analytical) of the title compound as a pale orange foam.

TLC (MeOH/MC = 1/4) Rf 0.55TLC (MeOH / MC = 1/4) Rf 0.55

1H-NMR (300 MHz, CD3OD) δ 2.45(m, 2H), 3.33(s, 3H), 3.57-3.73 (m, 3H), 4.09(s, 1H), 4.77(s, 2H), 6.69(d, J=7.4Hz, 1H), 7.19-7.55 (m, 7H), 7.56(t, J=7.8Hz, 2H), 7.67(s, 1H), 8.11(d, J=7.6Hz, 1H) 1 H-NMR (300 MHz, CD 3 OD) δ 2.45 (m, 2H), 3.33 (s, 3H), 3.57-3.73 (m, 3H), 4.09 (s, 1H), 4.77 (s, 2H), 6.69 (d, J = 7.4Hz, 1H), 7.19-7.55 (m, 7H), 7.56 (t, J = 7.8Hz, 2H), 7.67 (s, 1H), 8.11 (d, J = 7.6Hz, 1H )

LC/MS(M+H): ４18LC / MS (M + H): 418

실시예 6 : (Z)-4-(3-(1-(사이클로헥실카보닐)피롤리딘-3-일아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)-Example 6: (Z) -4- (3- (1- (cyclohexylcarbonyl) pyrrolidin-3-ylamino) -2-((naphthalen-1-yloxy) methyl) prop-1- Yen) NN -하이드록시벤즈아마이드(1f)Hydroxybenzamide (1f)

제조예 (8-5)에서 제조된 화합물을 출발물질(10e, 160㎎)로 사용하여 상기 실시예 1과 동일한 방법으로 연한 노란색 오일형태의 표제화합물 68㎎ (1f, 분석용)을 얻었다.Using the compound prepared in Preparation Example (8-5) as a starting material (10e, 160 mg), 68 mg (1f, analytical) of the title compound was obtained as a pale yellow oil, in the same manner as in Example 1.

수율 71 % Yield 71%

TLC (MeOH/MC = 1/6) Rf 0.45TLC (MeOH / MC = 1/6) Rf 0.45

1H-NMR (300 MHz, CD3OD) δ 1.18-1.33(m, 5H), 1.63(m, 5H), 2.13-2.44(m, 3H), 3.33-3.86(m, 4H), 4.05(t, J=7.4Hz, 3H), 4.88(s, 2H), 6.77(s, 1H), 7.22(d, J=7.6Hz, 2H), 7.35-7.68 (m, 5H), 7.75(t, J=7.8Hz, 2H), 7.81 (d, J=7.6Hz, 1H), 8.18 (s, 1H) 1 H-NMR (300 MHz, CD 3 OD) δ 1.18-1.33 (m, 5H), 1.63 (m, 5H), 2.13-2.44 (m, 3H), 3.33-3.86 (m, 4H), 4.05 (t , J = 7.4 Hz, 3H), 4.88 (s, 2H), 6.77 (s, 1H), 7.22 (d, J = 7.6 Hz, 2H), 7.35-7.68 (m, 5H), 7.75 (t, J = 7.8 Hz, 2H), 7.81 (d, J = 7.6 Hz, 1H), 8.18 (s, 1H)

LC/MS(M+H): 528LC / MS (M + H): 528

실시예 7 : (Z)-4-(3-(1-사이클로펜틸피페리딘-4-일아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)-Example 7: (Z) -4- (3- (1-cyclopentylpiperidin-4-ylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl)- NN -하이드록시벤즈아마이드(1g)Hydroxybenzamide (1 g)

제조예 (8-6)에서 제조된 화합물을 출발물질(10f, 120㎎)로 사용하여 상기 실시예 1과 동일한 방법으로 연한 노란색 오일형태의 표제화합물 77㎎ (1g, 분석 용)을 얻었다.Using the compound prepared in Preparation Example (8-6) as a starting material (10f, 120 mg), 77 mg (1 g, analytical) of the title compound was obtained as a pale yellow oil, in the same manner as in Example 1.

수율 44 % Yield 44%

TLC (MeOH/MC = 1/6) Rf 0.20TLC (MeOH / MC = 1/6) Rf 0.20

1H-NMR (300 MHz, CD3OD) δ 1.64(m, 6H), 1.93(m, 4H), 2.42(s, 2H), 3.02-3.19(m, 2H), 3.29-3.73(m, 4H), 4.10(s, 2H), 4.94(s, 2H), 6.74(d, J=7.4Hz, 1H), 7.21(m, 2H), 7.40(m, 5H), 7.66(d, J=7.8Hz, 2H), 7.76(t, J=7.8Hz, 1H), 8.16(d, J=7.6Hz, 1H) 1 H-NMR (300 MHz, CD 3 OD) δ 1.64 (m, 6H), 1.93 (m, 4H), 2.42 (s, 2H), 3.02-3.19 (m, 2H), 3.29-3.73 (m, 4H ), 4.10 (s, 2H), 4.94 (s, 2H), 6.74 (d, J = 7.4 Hz, 1H), 7.21 (m, 2H), 7.40 (m, 5H), 7.66 (d, J = 7.8 Hz , 2H), 7.76 (t, J = 7.8 Hz, 1H), 8.16 (d, J = 7.6 Hz, 1H)

LC/MS(M+H): 500LC / MS (M + H): 500

실시예 8 : (Z)-4-(3-(1-(사이클로헥실메틸)피롤리딘-3-일아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)-Example 8 (Z) -4- (3- (1- (cyclohexylmethyl) pyrrolidin-3-ylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl )- NN -하이드록시벤즈아마이드(1h)Hydroxybenzamide (1 h)

제조예 (8-7)에서 제조된 화합물을 출발물질(10g, 200㎎)로 사용하여 상기 실시예 1과 동일한 방법으로 연한 노란색 오일형태의 표제화합물 121㎎ (1h, 분석용)을 얻었다.Using the compound obtained in Preparation Example (8-7) as a starting material (10 g, 200 mg), 121 mg (1 h, analytical) of the title compound in the form of a pale yellow oil was obtained in the same manner as in Example 1.

수율 64 % Yield 64%

TLC (MeOH/MC = 1/6) Rf 0.50TLC (MeOH / MC = 1/6) Rf 0.50

1H-NMR (300 MHz, CD3OD) δ 1.46(m, 2H), 1.69(m, 4H), 2.20(m, 5H), 2.63(m, 2H), 3.55(d, J=7.6Hz, 2H), 3.77(m, 4H), 4.57(s, 2H), 4.72(s, 1H), 5.48(s, 2H), 7.30(s, 1H), 7.47(m, 5H), 7.71(s, 1H), 7.81(s, 1H), 8.19(d, J=7.8Hz, 2H), 8.29(d, J=7.6Hz, 1H), 8.71(s, 1H) 1 H-NMR (300 MHz, CD 3 OD) δ 1.46 (m, 2H), 1.69 (m, 4H), 2.20 (m, 5H), 2.63 (m, 2H), 3.55 (d, J = 7.6 Hz, 2H), 3.77 (m, 4H), 4.57 (s, 2H), 4.72 (s, 1H), 5.48 (s, 2H), 7.30 (s, 1H), 7.47 (m, 5H), 7.71 (s, 1H) ), 7.81 (s, 1H), 8.19 (d, J = 7.8 Hz, 2H), 8.29 (d, J = 7.6 Hz, 1H), 8.71 (s, 1H)

LC/MS(M+H): 514LC / MS (M + H): 514

실시예 9 : (Z)-4-(3-(1-벤질피롤리딘-3-일아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)-Example 9: (Z) -4- (3- (1-benzylpyrrolidin-3-ylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl)- NN -하이드록시벤즈아마이드(1i)Hydroxybenzamide (1i)

제조예 (8-8)에서 제조된 화합물을 출발물질(10h, 180㎎)로 사용하여 상기 실시예 1과 동일한 방법으로 연한 노란색 오일형태의 표제화합물 94㎎ (1i, 분석용)을 얻었다. 94 mg (1i, Analytical) of the title compound as a pale yellow oil was obtained in the same manner as in Example 1, using the compound prepared in Preparation Example (8-8) as a starting material (10 h, 180 mg).

수율 77 % Yield 77%

TLC (MeOH/MC = 1/6) Rf 0.35TLC (MeOH / MC = 1/6) Rf 0.35

1H-NMR (300 MHz, CD3OD) δ 1.50(m, 1H), 2.20(m, 1H), 3.51(m, 4H), 3.99(s, 2H), 4.14(s, 1H), 4.28(d, J=7.8Hz, 2H), 4.91(s, 2H), 6.73(d, J=7.6Hz, 1H), 7.24(t, J=7.8Hz, 1H), 7.37-7.58 (m, 11H), 7.66(d, J=7.8Hz, 2H), 7.75(d, J=7.6Hz, 1H), 8.13(d, J=7.6Hz, 1H) 1 H-NMR (300 MHz, CD3OD) δ 1.50 (m, 1H), 2.20 (m, 1H), 3.51 (m, 4H), 3.99 (s, 2H), 4.14 (s, 1H), 4.28 (d, J = 7.8 Hz, 2H), 4.91 (s, 2H), 6.73 (d, J = 7.6 Hz, 1H), 7.24 (t, J = 7.8 Hz, 1H), 7.37-7.58 (m, 11H), 7.66 ( d, J = 7.8 Hz, 2H), 7.75 (d, J = 7.6 Hz, 1H), 8.13 (d, J = 7.6 Hz, 1H)

LC/MS(M+H): 508LC / MS (M + H): 508

실시예 10 : (Z)-4-(3-(1-사이클로프로필피페리딘-4-일아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)-Example 10: (Z) -4- (3- (1-cyclopropylpiperidin-4-ylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl)- NN -하이드록시벤즈아마이드(1j)Hydroxybenzamide (1j)

제조예 (8-9)에서 제조된 화합물을 출발물질(10i, 90㎎)로 사용하여 상기 실시예 1과 동일한 방법으로 연한 노란색 오일형태의 표제화합물 44㎎ (1j, 분석용)을 얻었다.Using the compound prepared in Preparation Example (8-9) as a starting material (10i, 90 mg), 44 mg (1j, analytical) of the title compound was obtained as a pale yellow oil, in the same manner as in Example 1.

수율 57 % Yield 57%

TLC (MeOH/MC = 1/6) Rf 0.25TLC (MeOH / MC = 1/6) Rf 0.25

1H-NMR (300 MHz, CD3OD) δ 0.47(m, 2H), 1.47(m, 3H), 1.64(t, J=7.4Hz, 3H), 2.35(m, 1H), 2.57(s, 1H), 3.04(d, J=7.4Hz, 1H), 3.25(m, 1H), 3.62(m, 4H), 4.86(s, 2H), 6.69(d, J=7.4Hz, 1H), 6.96(s, 1H), 7.27-7.50(m, 4H), 7.78(d, J=7.4Hz, 1H), 7.95(t, J=7.4Hz, 4H), 8.21(d, J=7.6Hz, 1H) 1 H-NMR (300 MHz, CD 3 OD) δ 0.47 (m, 2H), 1.47 (m, 3H), 1.64 (t, J = 7.4 Hz, 3H), 2.35 (m, 1H), 2.57 (s, 1H), 3.04 (d, J = 7.4 Hz, 1H), 3.25 (m, 1H), 3.62 (m, 4H), 4.86 (s, 2H), 6.69 (d, J = 7.4 Hz, 1H), 6.96 ( s, 1H), 7.27-7.50 (m, 4H), 7.78 (d, J = 7.4 Hz, 1H), 7.95 (t, J = 7.4 Hz, 4H), 8.21 (d, J = 7.6 Hz, 1H)

실시예 11 : (Z)-4-(3-(1-사이클로프로필피롤리딘-3-일아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)-Example 11 (Z) -4- (3- (1-cyclopropylpyrrolidin-3-ylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl)- NN -하이드록시벤즈아마이드(1k)Hydroxybenzamide (1k)

제조예 (8-10)에서 제조된 화합물을 출발물질(10j, 200㎎)로 사용하여 상기 실시예 1과 동일한 방법으로 연한 노란색 오일형태의 표제화합물 121㎎ (1k, 분석용)을 얻었다.Using the compound obtained in Preparation Example (8-10) as a starting material (10j, 200 mg), 121 mg (1k, analytical) of the title compound was obtained as a pale yellow oil, in the same manner as in Example 1.

수율 71 % Yield 71%

TLC (MeOH/MC = 1/6) Rf 0.55TLC (MeOH / MC = 1/6) Rf 0.55

1H-NMR (300 MHz, CD3OD) δ 0.40(m, 3H), 1.62(m, 2H), 2.11(m, 2H), 2.51(q, J=7.6Hz, 1H), 2.87(m, 3H), 3.41(d, J=7.6Hz, 1H), 3.59(s, 2H), 4.83(s, 2H), 6.69(d, J=7.6Hz, 1H), 6.87(s, 1H), 7.28-7.50 (m, 4H), 7.78(d, J=7.8Hz, 1H), 7.95(m, 4H), 8.24(d, J=7.6Hz, 1H) 1 H-NMR (300 MHz, CD 3 OD) δ 0.40 (m, 3H), 1.62 (m, 2H), 2.11 (m, 2H), 2.51 (q, J = 7.6 Hz, 1H), 2.87 (m, 3H), 3.41 (d, J = 7.6 Hz, 1H), 3.59 (s, 2H), 4.83 (s, 2H), 6.69 (d, J = 7.6 Hz, 1H), 6.87 (s, 1H), 7.28- 7.50 (m, 4H), 7.78 (d, J = 7.8 Hz, 1H), 7.95 (m, 4H), 8.24 (d, J = 7.6 Hz, 1H)

실시예 12 : (Z)-4-(3-(1-사이클로헥실피롤리딘-3-일아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)-Example 12 (Z) -4- (3- (1-cyclohexylpyrrolidin-3-ylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl)- NN -하이드록시벤즈아마이드(1l) Hydroxybenzamide (1 l)

제조예 (8-11)에서 제조된 화합물을 출발물질(10k, 130㎎)로 사용하여 상기 실시예 1과 동일한 방법으로 연한 노란색 오일형태의 표제화합물 68㎎ (1l, 분석용)을 얻었다.Using the compound prepared in Preparation Example (8-11) as a starting material (10k, 130mg), 68 mg (1 l, analytical) of the title compound was obtained as a pale yellow oil, in the same manner as in Example 1.

수율 55 % Yield 55%

TLC (MeOH/MC = 1/6) Rf 0.35TLC (MeOH / MC = 1/6) Rf 0.35

1H-NMR (300 MHz, CD3OD) δ 1.17(m, 4H), 1.56(m, 4H), 1.71(s, 2H), 2.11(m, 3H), 2.43(m, 1H), 2.64(m, 2H), 2.87(m, 1H), 3.40(d, J=7.8Hz, 1H), 3.59(s, 2H), 4.84(s, 2H), 6.68(d, J=7.4Hz, 1H), 6.87(s, 1H), 7.26(m, 6H), 7.78(d, J=7.8Hz, 1H), 7.96(d, J=7.6Hz, 2H), 8.24(d, J=7.6Hz, 1H) 1 H-NMR (300 MHz, CD 3 OD) δ 1.17 (m, 4H), 1.56 (m, 4H), 1.71 (s, 2H), 2.11 (m, 3H), 2.43 (m, 1H), 2.64 ( m, 2H), 2.87 (m, 1H), 3.40 (d, J = 7.8 Hz, 1H), 3.59 (s, 2H), 4.84 (s, 2H), 6.68 (d, J = 7.4 Hz, 1H), 6.87 (s, 1H), 7.26 (m, 6H), 7.78 (d, J = 7.8 Hz, 1H), 7.96 (d, J = 7.6 Hz, 2H), 8.24 (d, J = 7.6 Hz, 1H)

실시예 13 : (Z)-4-(3-(에틸(2-몰포리노에틸)아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)-Example 13: (Z) -4- (3- (ethyl (2-morpholinoethyl) amino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl)- NN -하이드록시벤즈아마이드(1m)Hydroxybenzamide (1m)

제조예 (8-12)에서 제조된 화합물을 출발물질(10l, 170㎎)로 사용하여 상기 실시예 1과 동일한 방법으로 연한 노란색 오일형태의 표제화합물 136㎎ (1m, 분석용)을 얻었다.Using the compound prepared in Preparation Example (8-12) as a starting material (10 l, 170 mg), 136 mg (1 m, analytical) of the title compound was obtained as a pale yellow oil, in the same manner as in Example 1.

수율 93 % Yield 93%

TLC (MeOH/MC = 1/6) Rf 0.25TLC (MeOH / MC = 1/6) Rf 0.25

1H-NMR (300 MHz, CD3OD) δ 1.33(t, J=7.2Hz, 3H), 3.03(s, 4H), 3.37(m, 4H), 3.61(s, 6H), 4.23(s, 2H), 4.96(s, 2H), 6.76(d, J=7.6Hz, 1H), 7.26(t, J=7.6Hz, 2H), 7.49(m, 5H), 7.65(d, J=8.2Hz, 2H), 7.80(m, 1H), 8.15(t, J=7.6Hz, 1H) 1 H-NMR (300 MHz, CD 3 OD) δ 1.33 (t, J = 7.2 Hz, 3H), 3.03 (s, 4H), 3.37 (m, 4H), 3.61 (s, 6H), 4.23 (s, 2H), 4.96 (s, 2H), 6.76 (d, J = 7.6 Hz, 1H), 7.26 (t, J = 7.6 Hz, 2H), 7.49 (m, 5H), 7.65 (d, J = 8.2 Hz, 2H), 7.80 (m, 1H), 8.15 (t, J = 7.6 Hz, 1H)

실시예 14 : (Z)-N-하이드록시-4-(3-(1-메톡시프로판-2-일아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)벤즈아마이드 (1n) Example 14 (Z) -N-hydroxy-4- (3- (1-methoxypropan-2-ylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl Benzamide (1n)

제조예 (8-13)에서 제조된 화합물을 출발물질(10m, 209㎎)로 사용하여 상기 실시예 1과 동일한 방법으로 연한 노란색 오일형태의 표제화합물 170㎎ (1n, 99%)을 얻었다.Using the compound obtained in Preparation Example (8-13) as a starting material (10m, 209 mg), 170 mg (1 n, 99%) of the title compound was obtained as a pale yellow oil, in the same manner as in Example 1.

1H-NMR (200MHz, CD3OD) δ 1.40(d, J=6.4Hz, 3H), 3.30(s, 3H), 3.53(m, 1H), 3.68(d, J=8.0Hz, 2H), 4.13(s, 2H), 5.00(s, 2H), 6.80(d, J=7.8Hz, 1H), 7.26(s, 1H), 7.34(t, J=8.0Hz, 1H), 7.49(m, 5H), 7.73(d, J=8.2Hz, 2H), 7.81(m, 1H), 8.23(m, 1H) 1 H-NMR (200 MHz, CD 3 OD) δ 1.40 (d, J = 6.4 Hz, 3H), 3.30 (s, 3H), 3.53 (m, 1H), 3.68 (d, J = 8.0 Hz, 2H), 4.13 (s, 2H), 5.00 (s, 2H), 6.80 (d, J = 7.8Hz, 1H), 7.26 (s, 1H), 7.34 (t, J = 8.0Hz, 1H), 7.49 (m, 5H ), 7.73 (d, J = 8.2 Hz, 2H), 7.81 (m, 1H), 8.23 (m, 1H)

LC/MS(M+H): 421LC / MS (M + H): 421

실시예 15 : (Z)-Example 15 (Z)- NN -하이드록시-4-(3-(2-(1-메틸피롤리딘-2-일)에틸아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔닐)벤즈아마이드(1o)-Hydroxy-4- (3- (2- (1-methylpyrrolidin-2-yl) ethylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzamide (1o)

제조예 (12-1)에서 제조된 (Z)-t-부틸 2-(1-메틸피롤리딘-2-일)에틸(2-((나프탈렌-1-일옥시)메틸)-3-(4-(테트라하이드로-2H-피란-2-일옥시카바모일)페닐)알릴)카바메이트 (14a, 170㎎, 0.26 mmol)를 메탄올(1.5㎖)에 녹이고 트라이플루오로아세트산(0.10㎖, 1.3mmol)을 실온에서 천천히 가한 후 실온에서 8 시간동안 반응시켜 탈보호기(THP)반응을 하고 반응 종결을 확인한 후, 감압 하에서 용매를 제거하고 남은 잔사를 트라이플루오로아세트산(0.10㎖) / 다이클로로메탄(1.5㎖)에 녹여서 12시간동안 교반시켰다. 반응 종결을 확인하고 감압하에서 농축하고 얻어진 잔사를 prep. HPLC로 정제하여 연한 주황색 거품형태의 표제 화합물 68㎎(1o, 58％)을 얻었다.(Z) -t -butyl 2- (1-methylpyrrolidin-2-yl) ethyl (2-((naphthalen-1-yloxy) methyl) -3- (prepared in Preparation Example (12-1) 4- (tetrahydro-2H-pyran-2-yloxycarbamoyl) phenyl) allyl) carbamate (14a, 170 mg, 0.26 mmol) was dissolved in methanol (1.5 mL) and trifluoroacetic acid (0.10 mL, 1.3 mmol) ) Was added slowly at room temperature and then reacted at room temperature for 8 hours to conduct a deprotection group (THP) reaction. After completion of the reaction, the solvent was removed under reduced pressure, and the remaining residue was separated with trifluoroacetic acid (0.10 ml) 1.5 ml) and stirred for 12 hours. Confirm the completion of the reaction, concentrate under reduced pressure and prep. Purification by HPLC gave 68 mg (1o, 58%) of the title compound as a pale orange foam.

1H-NMR (200MHz, CD3OD) δ 1.79(m, 1H), 2.04(m, 3H), 2.40(m, 2H), 2.92(s, 3H), 3.19(m, 2H), 3.34(m, 2H), 3.69(m, 1H), 4.15(s, 2H), 4.98(s, 1H), 6.80(d, J=6.2Hz, 1H), 7.26(s, 1H), 7.33(t, J+8.0Hz, 1H), 7.48(m, 5H), 7.70(d, J=8.0Hz, 2H), 7.83(m, 1H), 8.23(m, 1H) 1 H-NMR (200 MHz, CD 3 OD) δ 1.79 (m, 1H), 2.04 (m, 3H), 2.40 (m, 2H), 2.92 (s, 3H), 3.19 (m, 2H), 3.34 (m , 2H), 3.69 (m, 1H), 4.15 (s, 2H), 4.98 (s, 1H), 6.80 (d, J = 6.2 Hz, 1H), 7.26 (s, 1H), 7.33 (t, J + 8.0 Hz, 1H), 7.48 (m, 5H), 7.70 (d, J = 8.0 Hz, 2H), 7.83 (m, 1H), 8.23 (m, 1H)

LC/MS(M+H): 460LC / MS (M + H): 460

실시예 16 : (Z)-Example 16: (Z)- NN -하이드록시-4-(3-(1-아이소프로필피페리딘-4-일아미노)-2-((나 프탈렌-1-일옥시)메틸)프로프-1-엔닐)벤즈아마이드(1p)-Hydroxy-4- (3- (1-isopropylpiperidin-4-ylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzamide (1p )

제조예 (12-2)에서 제조된 화합물을 출발물질(14b, 122㎎)로 사용하여 상기 실시예 15와 동일한 방법으로 연한 노란색 오일형태의 표제화합물 55㎎ (1p, 62%)을 얻었다.55 mg (1p, 62%) of the title compound as a pale yellow oil was obtained in the same manner as in Example 15, using the compound prepared in Preparation Example (12-2) as a starting material (14b, 122 mg).

1H-NMR (200MHz, CD3OD) δ 1.34(d, J=7.0Hz, 6H), 2.17(m, 2H), 2.51(m,2H), 3.16(m,2H), 3.60(m, 4H), 4.17(s, 2H), 4.98(s, 2H), 6.77(d, J=7.2Hz, 1H), 7.27(s, 1H), 7.31(t, J=7.8Hz, 1H), 7.47(m, 5H), 7.68(d, J=8.2Hz, 2H), 7.81(m, 1H), 8.23(m, 1H) 1 H-NMR (200 MHz, CD 3 OD) δ 1.34 (d, J = 7.0 Hz, 6H), 2.17 (m, 2H), 2.51 (m, 2H), 3.16 (m, 2H), 3.60 (m, 4H ), 4.17 (s, 2H), 4.98 (s, 2H), 6.77 (d, J = 7.2 Hz, 1H), 7.27 (s, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.47 (m , 5H), 7.68 (d, J = 8.2 Hz, 2H), 7.81 (m, 1H), 8.23 (m, 1H)

LC/MS(M+H): 474LC / MS (M + H): 474

실시예 17 : (Z)-4-(3-(3-(1H-이미다졸-1-일)프로필아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)-Example 17: (Z) -4- (3- (3- (1H-imidazol-1-yl) propylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) - NN -하이드록시벤즈아마이드(1q)Hydroxybenzamide (1q)

제조예 (12-3)에서 제조된 화합물을 출발물질(14c, 205㎎)로 사용하여 상기 실시예 15와 동일한 방법으로 연한 노란색 오일형태의 표제화합물 70㎎ (1q, 47%)을 얻었다.Using the compound obtained in Preparation Example (12-3) as a starting material (14c, 205 mg), 70 mg (1q, 47%) of the title compound was obtained as a pale yellow oil, in the same manner as in Example 15.

1H-NMR (200MHz, CD3OD) δ 2.41(m,2H), 3.29(t, J=6.2Hz, 2H), 4.13(s, 2H), 4.46(t, J=6.4Hz, 2H), 4.98(s, 2H), 6.79(d, J=7.4Hz, 1H), 7.24(s, 1H), 7.33(t, J=7.4Hz, 1H), 7.48(m, 7H), 7.70(t, J=8.2Hz, 3H), 7.80(m, 1H), 8.23(m, 1H) 1 H-NMR (200 MHz, CD 3 OD) δ 2.41 (m, 2H), 3.29 (t, J = 6.2 Hz, 2H), 4.13 (s, 2H), 4.46 (t, J = 6.4 Hz, 2H), 4.98 (s, 2H), 6.79 (d, J = 7.4Hz, 1H), 7.24 (s, 1H), 7.33 (t, J = 7.4Hz, 1H), 7.48 (m, 7H), 7.70 (t, J = 8.2 Hz, 3H), 7.80 (m, 1H), 8.23 (m, 1H)

LC/MS(M+H): 457LC / MS (M + H): 457

실시예 18 : (Z)-Example 18 (Z)- NN -하이드록시-4-(3-(4-하이드록시펜에틸아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)벤즈아마이드(1r)-Hydroxy-4- (3- (4-hydroxyphenethylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzamide (1r)

제조예 (12-4)에서 제조된 화합물을 출발물질(14d, 36㎎)로 사용하여 상기 실시예 15와 동일한 방법으로 연한 노란색 오일형태의 표제화합물 18㎎ (1r, 67%)을 얻었다.18 mg (1r, 67%) of the title compound as a pale yellow oil was obtained in the same manner as in Example 15, using the compound prepared in Preparation Example (12-4) as a starting material (14d, 36 mg).

1H-NMR (200MHz, CD3OD) δ 3.00(t, J=5.8Hz, 2H), 3.37(m, 2H), 4.10(s, 2H), 4.95(s, 2H), 6.69(d, J=8.6Hz, 2H), 6.80(d, J=7.8Hz, 1H), 7.04(d, J=8.6Hz, 2H), 7.23(s, 1H), 7.34(t, J=8.2Hz, 1H), 7.48(m, 5H), 7.69(d, J=8.6Hz, 2H), 7.81(m, 1H), 8.20(m, 1H) 1 H-NMR (200 MHz, CD 3 OD) δ 3.00 (t, J = 5.8 Hz, 2H), 3.37 (m, 2H), 4.10 (s, 2H), 4.95 (s, 2H), 6.69 (d, J = 8.6 Hz, 2H), 6.80 (d, J = 7.8 Hz, 1H), 7.04 (d, J = 8.6 Hz, 2H), 7.23 (s, 1H), 7.34 (t, J = 8.2 Hz, 1H), 7.48 (m, 5H), 7.69 (d, J = 8.6 Hz, 2H), 7.81 (m, 1H), 8.20 (m, 1H)

LC/MS(M+H): 469LC / MS (M + H): 469

실시예 19 : (Z)-4-(3-(3-(다이메틸아미노)-2,2-다이메틸프로필아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)-Example 19: (Z) -4- (3- (3- (dimethylamino) -2,2-dimethylpropylamino) -2-((naphthalen-1-yloxy) methyl) prop-1- Yen) NN -하이드록시벤즈아마이드(1s)Hydroxybenzamide (1s)

제조예 (12-5)에서 제조된 화합물을 출발물질(14e, 187㎎)로 사용하여 상기 실시예 15와 동일한 방법으로 연한 노란색 오일형태의 표제화합물 65㎎ (1s, 48%)을 얻었다.65 mg (1s, 48%) of the title compound as a pale yellow oil was obtained in the same manner as in Example 15, using the compound prepared in Preparation Example (12-5) as a starting material (14e, 187 mg).

1H-NMR (200MHz, CD3OD) δ 1.29(s, 6H), 2.93(s, 6H), 3.34(s, 4H), 4.20(s, 2H), 5.00(s, 2H), 6.84(d, J=7.4Hz, 1H), 7.30(s, 1H), 7.36(t, J=7.6Hz, 1H), 7.51(m, 5H), 7.71(d, J=8.6Hz, 2H), 7.83(m, 1H), 8.23(m, 1H) 1 H-NMR (200 MHz, CD 3 OD) δ 1.29 (s, 6H), 2.93 (s, 6H), 3.34 (s, 4H), 4.20 (s, 2H), 5.00 (s, 2H), 6.84 (d , J = 7.4 Hz, 1H), 7.30 (s, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.51 (m, 5H), 7.71 (d, J = 8.6 Hz, 2H), 7.83 (m , 1H), 8.23 (m, 1H)

LC/MS(M+H): 462LC / MS (M + H): 462

실시예 20 : (Z)-4-(3-(2-(다이아이소프로필아미노)에틸아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)-Example 20: (Z) -4- (3- (2- (diisopropylamino) ethylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl)- NN -하이드록시벤즈아마이드 (1t)Hydroxybenzamide (1t)

제조예 (12-6)에서 제조된 화합물을 출발물질(14f, 317㎎)로 사용하여 상기 실시예 15와 동일한 방법으로 연한 노란색 오일형태의 표제화합물 171㎎ (1t, 75%)을 얻었다.171 mg (1t, 75%) of the title compound as a pale yellow oil was obtained in the same manner as in Example 15, using the compound prepared in Preparation Example (12-6) as a starting material (14f, 317 mg).

1H-NMR (200MHz, CD3OD) δ 1.37(d, J=6.6Hz, 12H), 3.67(m, 4H), 3.81(m, 2H), 4.23(s, 2H), 4.96(s, 2H), 6.78(d, J=7.8Hz, 1H), 7.26(s, 1H), 7.29(t, J=7.6Hz, 1H), 7.43(m, 5H), 7.63(d, J=8.0Hz, 2H), 7.76(m, 1H), 8.23(m, 1H) 1 H-NMR (200 MHz, CD 3 OD) δ 1.37 (d, J = 6.6 Hz, 12H), 3.67 (m, 4H), 3.81 (m, 2H), 4.23 (s, 2H), 4.96 (s, 2H ), 6.78 (d, J = 7.8 Hz, 1H), 7.26 (s, 1H), 7.29 (t, J = 7.6 Hz, 1H), 7.43 (m, 5H), 7.63 (d, J = 8.0 Hz, 2H ), 7.76 (m, 1 H), 8.23 (m, 1 H)

LC/MS(M+H): 476LC / MS (M + H): 476

실시예 21 : (Z)-Example 21 (Z)- NN -하이드록시-4-(3-(2-메톡시에틸아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)벤즈아마이드(1u)-Hydroxy-4- (3- (2-methoxyethylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzamide (1u)

제조예 (12-7)에서 제조된 화합물을 출발물질(14g, 274㎎)로 사용하여 상기 실시예 15와 동일한 방법으로 연한 노란색 오일형태의 표제화합물 85㎎ (1u, 45%)을 얻었다.Using the compound prepared in Preparation Example (12-7) as a starting material (14 g, 274 mg), 85 mg (1 u, 45%) of the title compound was obtained as a pale yellow oil, in the same manner as in Example 15.

1H-NMR (200MHz, CD3OD) δ 3.33(s, 3H), 3.43(t. J=4.8Hz, 2H), 3.72(t, J=4.6Hz, 2H), 4.13(s, 2H), 4.99(s, 2H), 6.82(d, J=6.8Hz, 1H), 7.25(s, 1H), 7.36(t, J=7.8Hz, 1H), 7.25(s, 1H), 7.36(t, J=7.8Hz, 1H), 7.51(m, 5H), 7.74(d, J=8.2Hz, 2H), 7.83(m, 1H), 8.23(m, 1H) 1 H-NMR (200 MHz, CD 3 OD) δ 3.33 (s, 3H), 3.43 (t. J = 4.8 Hz, 2H), 3.72 (t, J = 4.6 Hz, 2H), 4.13 (s, 2H), 4.99 (s, 2H), 6.82 (d, J = 6.8Hz, 1H), 7.25 (s, 1H), 7.36 (t, J = 7.8Hz, 1H), 7.25 (s, 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.51 (m, 5H), 7.74 (d, J = 8.2 Hz, 2H), 7.83 (m, 1H), 8.23 (m, 1H)

LC/MS(M+H): 407LC / MS (M + H): 407

실시예 22 : (Z)-4-(3-(사이클로헥실아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)-Example 22: (Z) -4- (3- (cyclohexylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl)- NN -하이드록시벤즈아마이드(1v)Hydroxybenzamide (1v)

제조예 (12-8)에서 제조된 화합물을 출발물질(14h, 98㎎)로 사용하여 상기 실시예 15와 동일한 방법으로 연한 노란색 오일형태의 표제화합물 26㎎ (1v, 37%)을 얻었다.26 mg (1v, 37%) of the title compound as a pale yellow oil was obtained in the same manner as in Example 15, using the compound prepared in Preparation Example (12-8) as a starting material (14h, 98 mg).

1H-NMR (200MHz, CD3OD) δ 1.20-1.58(m, 5H), 1.73(m, 1H), 1.92(m, 2H), 2.20(m, 2H), 3.32(m, 1H), 4.11(s, 2H), 5.00(s, 2H), 6.82(d, J=7.2Hz, 1H), 7.27(s, 1H), 7.36(t, J=6.2Hz, 1H), 7.52(m, 5H), 7.74(d, J=8.2Hz, 2H), 7.84(m, 1H), 8.23(m, 1H) 1 H-NMR (200 MHz, CD 3 OD) δ 1.20-1.58 (m, 5H), 1.73 (m, 1H), 1.92 (m, 2H), 2.20 (m, 2H), 3.32 (m, 1H), 4.11 (s, 2H), 5.00 (s, 2H), 6.82 (d, J = 7.2 Hz, 1H), 7.27 (s, 1H), 7.36 (t, J = 6.2 Hz, 1H), 7.52 (m, 5H) , 7.74 (d, J = 8.2 Hz, 2H), 7.84 (m, 1H), 8.23 (m, 1H)

LC/MS(M+H): 431LC / MS (M + H): 431

실시예 23 : (Z)-Example 23 (Z)- NN -하이드록시-4-(3-(나프탈렌-1-일옥시)-2-((티오펜-2-일 메틸아미노)메틸)프로프-1-엔일)벤즈아마이드(1w)-Hydroxy-4- (3- (naphthalen-1-yloxy) -2-((thiophen-2-yl methylamino) methyl) prop-1-enyl) benzamide (1w)

제조예 (12-9)에서 제조된 화합물을 출발물질(14i, 130㎎)로 사용하여 상기 실시예 15와 동일한 방법으로 연한 노란색 오일형태의 표제화합물 6㎎ (1w, 분석용)을 얻었다.Using the compound prepared in Preparation Example (12-9) as a starting material (14i, 130 mg), 6 mg (1 w, analytical) of the title compound was obtained as a pale yellow oil, in the same manner as in Example 15.

1H-NMR (200MHz, CD3OD) δ 4.14(s, 2H), 4.64(s, 2H), 4.98(s, 2H), 6.78(d, J=7.4Hz, 1H), 7.09(m, 1H), 7.23(s, 1H), 7.33(m, 2H), 7.48(m, 6H), 7.71(d, J=8.2Hz, 2H), 7.80(m, 1H), 8.14(m, 1H) 1 H-NMR (200 MHz, CD 3 OD) δ 4.14 (s, 2H), 4.64 (s, 2H), 4.98 (s, 2H), 6.78 (d, J = 7.4 Hz, 1H), 7.09 (m, 1H ), 7.23 (s, 1H), 7.33 (m, 2H), 7.48 (m, 6H), 7.71 (d, J = 8.2 Hz, 2H), 7.80 (m, 1H), 8.14 (m, 1H)

LC/MS(M+H): 445LC / MS (M + H): 445

실시예 24 : (Z)-Example 24 (Z)- NN -하이드록시-4-(3-(4-메톡시펜에틸아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)벤즈아마이드(1x)-Hydroxy-4- (3- (4-methoxyphenethylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzamide (1x)

제조예 (12-10)에서 제조된 화합물을 출발물질(14j, 150㎎)로 사용하여 상기 실시예 15와 동일한 방법으로 연한 노란색 오일형태의 표제화합물 20㎎ (1x, 분석용)을 얻었다.Using the compound prepared in Preparation Example (12-10) as a starting material (14j, 150 mg), 20 mg (1 ×, analytical) of the title compound was obtained as a pale yellow oil, in the same manner as in Example 15.

1H-NMR (200MHz, CD3OD) δ 3.01(t, J=7.4Hz, 2H), 3.40(t, J=6.4Hz, 2H), 3.72(s, 3H), 4.12(s, 2H), 4.95(s, 2H), 6.79(d, J=9.0Hz, 3H), 7.15(d, J=8.4Hz, 2H), 7.24(s, 1H), 7.34(t, J=7.6Hz, 1H), 7.48(m, 5H), 7.70(d, J=8.4Hz, 2H), 7.82(m, 1H), 8.21(m, 1H) 1 H-NMR (200 MHz, CD 3 OD) δ 3.01 (t, J = 7.4 Hz, 2H), 3.40 (t, J = 6.4 Hz, 2H), 3.72 (s, 3H), 4.12 (s, 2H), 4.95 (s, 2H), 6.79 (d, J = 9.0Hz, 3H), 7.15 (d, J = 8.4Hz, 2H), 7.24 (s, 1H), 7.34 (t, J = 7.6Hz, 1H), 7.48 (m, 5H), 7.70 (d, J = 8.4 Hz, 2H), 7.82 (m, 1H), 8.21 (m, 1H)

LC/MS(M+H): 483LC / MS (M + H): 483

실시예 25 : (Z)-4-(3-(4-(다이메틸아미노)벤질아미노))-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)-N-하이드록시벤즈아마이드(1y)Example 25 (Z) -4- (3- (4- (dimethylamino) benzylamino))-2-((naphthalen-1-yloxy) methyl) prop-1-enyl) -N-hydr Roxybenzamide (1y)

제조예 (12-11)에서 제조된 화합물을 출발물질(14k, 211㎎)로 사용하여 상기 실시예 15와 동일한 방법으로 연한 노란색 오일형태의 표제화합물 19㎎ (1y, 분석용)을 얻었다.Using the compound obtained in Preparation Example (12-11) as a starting material (14k, 211 mg), 19 mg (1y, analytical) of the title compound was obtained as a pale yellow oil, in the same manner as in Example 15.

1H-NMR (200MHz, CD3OD) δ 3.06(s, 6H), 4.10(s, 2H), 4.35(s, 2H), 4.97(s, 2H), 6.76(d, J=8.0Hz, 1H), 7.09(d, J=8.6Hz, 2H), 7.21(s, 1H), 7.32(t, J=8.0Hz, 1H), 7.48(m, 7H), 7.76(d, J=8.0Hz, 2H), 7.80(m, 1H), 8.12(m, 1H) 1 H-NMR (200MHz, CD 3 OD) δ 3.06 (s, 6H), 4.10 (s, 2H), 4.35 (s, 2H), 4.97 (s, 2H), 6.76 (d, J = 8.0Hz, 1H ), 7.09 (d, J = 8.6 Hz, 2H), 7.21 (s, 1H), 7.32 (t, J = 8.0 Hz, 1H), 7.48 (m, 7H), 7.76 (d, J = 8.0 Hz, 2H ), 7.80 (m, 1 H), 8.12 (m, 1 H)

LC/MS(M+H): 482LC / MS (M + H): 482

시험예 1: HDAC 활성분석Test Example 1: HDAC Activity Assay

HDAC 활성분석은 바이오몰사(BIOMOL)의 퀀티자임(Quantizyme)TM 분석 시스템에 기초하여 수행하였다. 분석은 두 단계로 이루어지는데, 제1 단계는 HDAC와 기질이 반응하는 효소반응 단계로서, 이 단계에서 HDAC 저해제를 넣어 HDAC 효소활성 저해정도를 측정하였다. 먼저, 반응 혼합물을 제조하기 위하여 96-웰 플레이트에 42 ㎕의 반응 완충용액(25 mM Tris-HCl [pH 8.0], 137 mM NaCl, 2.7 mM KCl, 1 mM MgCl2)을 첨가하고 250 μM 형광표지 라이신(Fluor de LysTM) 기질 5 ㎕를 첨가하였다. 이때, HDAC 효소활성 저해제로서 상기 실시예 1 내지 25의 화합물들을 각각 0.01, 0.1, 1, 10 및 100 μM 농도로 2.5 ㎕씩 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 트라이코스타틴 A를 넣고 실온에서 15분간 반응시켰다. 상기 형광물질로부터 355 ㎚에서 여기(excitation)되고 460 ㎚에서 방출되어 나오는 광을 형광측정용 기판 판독기(fluorometric plate reader)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 Biomolar's Quantizyme ™ assay system. The analysis consists of two steps. The first step is an enzyme reaction step in which the HDAC reacts with the substrate. In this step, an HDAC inhibitor was added to measure the degree of inhibition of HDAC enzyme activity. 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 fluorescent label. 5 μl of lysine (Fluor de Lys ™ ) substrate was added. At this time, 2.5 μl of the compounds of Examples 1 to 25 were added at 0.01, 0.1, 1, 10 and 100 μM concentrations as HDAC enzyme activity inhibitors, respectively. 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 50 μl of fluorescent labeled lysine developer (Flour de Lys TM developer) was added 2 μM tricostatin A and reacted at room temperature for 15 minutes. 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. The degree of HDAC inhibitory activity (IC 50 ) of the representative compounds prepared in the Example is shown in Table 1 below.

Figure 112006081424267-pat00022
Figure 112006081424267-pat00022

상기 표 1로부터, 본 발명에 따라 제조된 화학식 1의 알킬아미노 나프탈렌일옥시메틸 프로페닐 하이드록시벤즈아마이드 유도체 화합물들이 기존에 HDAC 저해제로 알려진 SAHA와 유사하거나 월등히 우수한 HDAC 저해활성을 나타냄을 확인하였다.From Table 1 , it was confirmed that the alkylamino naphthalenyloxymethyl propenyl hydroxybenzamide derivative compounds of the formula (1) prepared according to the present invention showed similar or superior HDAC inhibitory activity to SAHA known as HDAC inhibitor.

시험예 2: 암세포 증식 억제 효과 확인Test Example 2 Confirmation of Inhibitory Effect of Cancer Cell Proliferation

상기 실시예에서 제조된 알킬아미노 나프탈렌일옥시메틸 프로페닐 하이드록시벤즈아마이드 유도체 화합물들의 암세포 증식 억제효과를 SRB(Sulforhodamine B) 분석방법으로 측정하였다. 본 실험에서는 대장암 세포인 HCT116(한국 세포주은행, KCLB 10247)을 사용하여 암세포 증식 억제효과를 측정하였다. The cancer cell proliferation inhibitory effect of the alkylamino naphthalenyloxymethyl propenyl hydroxybenzamide derivative compounds prepared in the above example was measured by SRB (Sulforhodamine B) analysis method. In this experiment, HCT116 (Korea Cell Line Bank, KCLB 10247), a colon cancer cell, was used to measure the effect of inhibiting cancer cell proliferation.

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 시험 화합물들을 0.2, 1, 5, 25, 100 μM의 농도별로 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, test compounds were treated at concentrations of 0.2, 1, 5, 25, and 100 μM, 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% 아세트산으로 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. 시험 화합물을 처리하지 않은 세포의 흡광도를 기준으로 시험 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 test compounds were treated by concentration based on the absorbance of the cells not treated with the test 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, 시험 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, test cells were dispensed in 6-well plates at a concentration of 1.5 × 10 8 cells / well, followed by overnight culture 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 112006081424267-pat00023
Figure 112006081424267-pat00023

상기 표 2로부터, 본 발명에 따른 화학식 1의 알킬아미노 나프탈렌일옥시메틸 프로페닐 하이드록시벤즈아마이드 유도체가 암세포에서 매우 우수한 HDAC 저해활성과 암세포 증식 억제효과를 나타냄을 알 수 있다. From Table 2 , it can be seen that the alkylamino naphthalenyloxymethyl propenyl hydroxybenzamide 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 알킬아미노 나프탈렌일옥시메틸 프로페닐 하이드록시벤즈아마이드 유도체는 히스톤 디아세틸라제의 효소활성을 효과적으로 저해하여 종양세포의 말기 분화를 선택적으로 유도하고 증식을 억제하므로 항암제 또는 히스톤 디아세틸라제의 효소활성 저해제로서 유용하게 사용될 수 있다.As described above, the alkylamino naphthalenyloxymethyl propenyl hydroxybenzamide derivative of Formula 1 of the present invention effectively inhibits the enzymatic activity of histone deacetylase to selectively induce terminal differentiation of tumor cells and inhibit proliferation. Therefore, it can be usefully used as an anticancer agent or inhibitor of enzymatic activity of histone deacetylase.

Claims (28)

하기 화학식 1의 알킬아미노 나프탈렌일옥시메틸 프로페닐 하이드록시벤즈아마이드 유도체 화합물:Alkylamino naphthalenyloxymethyl propenyl hydroxybenzamide derivative compound of Formula 1 <화학식 1><Formula 1>
Figure 112007085262374-pat00024
Figure 112007085262374-pat00024
 상기 식에서, Where R1은 수소 또는 C1-3 알킬이고;R 1 is hydrogen or C 1-3 alkyl; R2는 다이 C1-3 알킬 아미노, C1-3 알킬 피롤리디닐, 몰포리닐, 이미다졸일, 메톡시, 및 티오페닐로 이루어진 군으로부터 선택된 치환기로 치환되거나 치환되지 않은 C1-6 알킬; 하이드록시페닐, 다이 C1-3 알킬 아미노 페닐, 메톡시페닐 또는 트리플루오로메톡시페닐로 치환된 C1-6 알킬; C1-3 알킬, C3-8 사이클로알킬, C3-8 사이클로알킬C1-3 알킬, 벤질 또는 C3-8사이클로알킬카보닐로 치환되거나 치환되지 않은 피롤리딘; C3-8 사이클로알킬 또는 C1-6 알킬로 치환된 피페리딘; 또는 C3-8 사이클로알킬이며, R 2 is C 1-6 unsubstituted or substituted with a substituent selected from the group consisting of di C 1-3 alkyl amino, C 1-3 alkyl pyrrolidinyl, morpholinyl, imidazolyl, methoxy, and thiophenyl Alkyl; C 1-6 alkyl substituted with hydroxyphenyl, di C 1-3 alkyl amino phenyl, methoxyphenyl or trifluoromethoxyphenyl; Pyrrolidine unsubstituted or substituted with C 1-3 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkylC 1-3 alkyl, benzyl or C 3-8 cycloalkylcarbonyl; Piperidine substituted with C 3-8 cycloalkyl or C 1-6 alkyl; Or C 3-8 cycloalkyl, 단, 치환기 R1이 수소 또는 메틸일 때, R2는 치환되지 않은 C1-2 알킬 및 몰포리닐로 치환된 C1-2 알킬이 아니다.However, when the substituents R 1, hydrogen or methyl, R 2 is not a C 1-2 alkyl substituted with C 1-2 alkyl and are unsubstituted morpholinyl. 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: (Z)-4-(3-(1-에틸피페리딘-4-일아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)-N-하이드록시벤즈아마이드;(Z) -4- (3- (1-ethylpiperidin-4-ylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) -N -hydroxybenzamide ; (Z)-4-(3-(1-에틸피롤리딘-3-일아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)-N-하이드록시벤즈아마이드;(Z) -4- (3- (1-ethylpyrrolidin-3-ylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) -N -hydroxybenzamide ; (Z)-N-하이드록시-4-(3-(나프탈렌-1-일옥시)-2-((4-(트라이플루오로메톡시)벤질아미노)메틸)프로프-1-엔일)벤즈아마이드;(Z) -N -hydroxy-4- (3- (naphthalen-1-yloxy) -2-((4- (trifluoromethoxy) benzylamino) methyl) prop-1-enyl) benzamide; (Z)-3-(3-(4-(하이드록시카바모일)페닐)-2-((나프탈렌-1-일옥시)메틸)알릴아미노)피롤리딘-1-카복실산-t-뷰틸에스터;(Z) -3- (3- (4- (hydroxycarbamoyl) phenyl) -2-((naphthalen-1-yloxy) methyl) allylamino) pyrrolidine-1-carboxylic acid-t-butylester; (Z)-N-하이드록시-4-(3-(나프탈렌-1-일옥시)-2-((피롤리딘-3-일아미노)메틸)프로프-1-엔일)벤즈아마이드;(Z) -N -hydroxy-4- (3- (naphthalen-1-yloxy) -2-((pyrrolidin-3-ylamino) methyl) prop-1-enyl) benzamide; (Z)-4-(3-(1-(사이클로헥실카보닐)피롤리딘-3-일아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)-N-하이드록시벤즈아마이드;(Z) -4- (3- (1- (cyclohexylcarbonyl) pyrrolidin-3-ylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) -N Hydroxybenzamide; (Z)-4-(3-(1-사이클로펜틸피페리딘-4-일아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)-N-하이드록시벤즈아마이드;(Z) -4- (3- (1-cyclopentylpiperidin-4-ylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) -N -hydroxybenz Amides; (Z)-4-(3-(1-(사이클로헥실메틸)피롤리딘-3-일아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)-N-하이드록시벤즈아마이드;(Z) -4- (3- (1- ( cyclohexylmethyl) pyrrolidin-3-ylamino) -2 - ((naphthalen-1-yloxy) methyl) prop-1-enyl) - N - Hydroxybenzamide; (Z)-4-(3-(1-벤질피롤리딘-3-일아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)-N-하이드록시벤즈아마이드;(Z) -4- (3- (1-benzylpyrrolidin-3-ylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) -N -hydroxybenzamide ; (Z)-4-(3-(1-사이클로프로필피페리딘-4-일아미노)-2-((나프탈렌-1-일옥시)메틸)프 로프-1-엔일)-N-하이드록시벤즈아마이드;(Z) -4- (3- (1-cyclopropylpiperidin-4-ylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) -N -hydroxybenz Amides; (Z)-4-(3-(1-사이클로프로필피롤리딘-3-일아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)-N-하이드록시벤즈아마이드;(Z) -4- (3- (1-cyclopropylpyrrolidin-3-ylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) -N -hydroxybenz Amides; (Z)-4-(3-(1-사이클로헥실피롤리딘-3-일아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)-N-하이드록시벤즈아마이드;(Z) -4- (3- (1-cyclohexylpyrrolidin-3-ylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) -N-hydroxybenz Amides; (Z)-4-(3-(에틸(2-몰포리노에틸)아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)-N-하이드록시벤즈아마이드;(Z) -4- (3- (ethyl (2-morpholinoethyl) amino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) -N -hydroxybenzamide; (Z)-N-하이드록시-4-(3-(1-메톡시프로판-2-일아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)벤즈아마이드;(Z) -N -hydroxy-4- (3- (1-methoxypropan-2-ylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzamide; (Z)-N-하이드록시-4-(3-(2-(1-메틸피롤리딘-2-일)에틸아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔닐)벤즈아마이드;(Z) -N -hydroxy-4- (3- (2- (1-methylpyrrolidin-2-yl) ethylamino) -2-((naphthalen-1-yloxy) methyl) prop-1 -Enyl) benzamide; (Z)-N-하이드록시-4-(3-(1-아이소프로필피페리딘-4-일아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔닐)벤즈아마이드;(Z) -N -hydroxy-4- (3- (1-isopropylpiperidin-4-ylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benz Amides; (Z)-4-(3-(3-(1H-이미다졸-1-일)프로필아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)-N-하이드록시벤즈아마이드;(Z) -4- (3- (3- (1H-imidazol-1-yl) propylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) -N -hydr Oxybenzamide; (Z)-N-하이드록시-4-(3-(4-하이드록시페네틸아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)벤즈아마이드;(Z) -N -hydroxy-4- (3- (4-hydroxyphenethylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzamide; (Z)-4-(3-(3-(다이메틸아미노)-2,2-다이메틸프로필아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)-N-하이드록시벤즈아마이드;(Z) -4- (3- (3- (dimethylamino) -2,2-dimethylpropylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) -N Hydroxybenzamide; (Z)-4-(3-(2-(다이아이소프로필아미노)에틸아미노)-2-((나프탈렌-1-일옥시)메틸)프 로프-1-엔일)-N-하이드록시벤즈아마이드;(Z) -4- (3- (2- (diisopropylamino) ethylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) -N -hydroxybenzamide; (Z)-N-하이드록시-4-(3-(2-메톡시에틸아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)벤즈아마이드;(Z) -N -hydroxy-4- (3- (2-methoxyethylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzamide; (Z)-4-(3-(사이클로헥실아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)-N-하이드록시벤즈아마이드;(Z) -4- (3- (cyclohexylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) -N -hydroxybenzamide; (Z)-N-하이드록시-4-(3-(나프탈렌-1-일옥시)-2-((티오펜-2-일 메틸아미노)메틸)프로프-1-엔일)벤즈아마이드;(Z) -N -hydroxy-4- (3- (naphthalen-1-yloxy) -2-((thiophen-2-yl methylamino) methyl) prop-1-enyl) benzamide; (Z)-N-하이드록시-4-(3-(4-메톡시페네틸아미노)-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)벤즈아마이드; 및(Z) -N -hydroxy-4- (3- (4-methoxyphenethylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzamide; And (Z)-4-(3-(4-(다이메틸아미노)벤질아미노))-2-((나프탈렌-1-일옥시)메틸)프로프-1-엔일)-N-하이드록시벤즈아마이드.(Z) -4- (3- (4- (dimethylamino) benzylamino))-2-((naphthalen-1-yloxy) methyl) prop-1-enyl) -N -hydroxybenzamide. 1) 하기 화학식 2의 화합물을 1,4-다이아자비사이클로[2,2,2]옥탄(DABCO) 존재하에서 알킬아크릴레이트와 반응시켜 하기 화학식 3의 화합물을 제조하는 단계;1) reacting with an alkyl acrylate in the presence of 1,4-diamine ratio bicyclo [2,2,2] octane (DABCO) a compound of formula 2 to prepare a compound of formula (3); 2) 화학식 3의 화합물을 유기용매 중에서 삼브롬화인(PBr3)과 반응시켜 화학식 4의 화합물을 제조하는 단계;2) preparing a compound of formula 4 to the compound of formula (III) to phosphorus tribromide (PBr 3) reacting in an organic solvent; 3) 화학식 4의 화합물을 1-나프탈렌올과 반응시켜 화학식 5의 화합물로 전환시키는 단계;3) reacting the compound of formula 4 with 1-naphthalenol to convert the compound of formula 5 ; 4) 화학식 5의 화합물을 트라이플루오로아세트산(TFA)으로 가수분해 반응시켜 카복 시프로페닐 벤조산메틸에스터를 제조한 후, 에틸클로로포메이트(ECC)로 처리하고 환원제로 환원시켜 화학식 6의 화합물을 제조하는 단계;4) The compound of formula 5 was hydrolyzed with trifluoroacetic acid (TFA) to prepare carboxypropenyl benzoate methyl ester, which was then treated with ethylchloroformate (ECC) and reduced with a reducing agent to obtain the compound of formula 6 Manufacturing step; 5) 화학식 6의 화합물을 비극성 용매에 녹인 후 트라이페닐포스핀(PPh3)과 테트라브로모메탄 (CBr4)을 첨가하고 브롬화 반응시켜 화학식 7의 화합물을 제조하는 단계;5) dissolving the compound of Formula 6 in a nonpolar solvent, and then adding triphenylphosphine (PPh 3 ) and tetrabromomethane (CBr 4 ) and bromination to prepare a compound of Formula 7 ; 6) 화학식 7의 화합물을 아민 (R1R2NH)과 반응시켜 화학식 8의 화합물을 제조하는 단계;6) reacting a compound of Formula 7 with an amine (R 1 R 2 NH) to prepare a compound of Formula 8 ; 7) 화학식 8의 화합물을 무기염기 처리에 의해 가수분해 반응시켜 화학식 9의 화합물을 제조하는 단계;7) hydrolyzing the compound of Formula 8 by inorganic base treatment to prepare a compound of Formula 9 ; 8) 화학식 9의 화합물을 유기용매 중에서 N-하이드록시-6-트라이플루오로 벤조트라이아졸(FOBt) 및 1-에틸-3-(3-다이메틸아미노프로필)카바다이이마이드·염산염(EDC·HCl)의 존재 하에 테트라하이드로-2H-피란-2-일 옥시아민(THPONH2)과 아실화 반응시켜 화학식 10의 화합물을 제조하는 단계; 및8) a compound of formula (9) in an organic solvent N - hydroxy-6-trifluoromethyl benzotriazole (FOBt) and 1-ethyl-3- (3-dimethylaminopropyl) carbazole dayiyi polyimide hydrochloride (EDC · HCl Acylation with tetrahydro-2H-pyran-2-yl oxyamine (THPONH 2 ) in the presence of) to prepare a compound of formula 10 ; And 9) 화학식 10의 화합물을 수용성 무기산 또는 유기산으로 처리하여 테트라하이드로-2H-피란-2-일옥시 보호기를 제거하는 단계를 포함하는, 하기 화학식 1의 알킬아미노 나프탈렌일옥시메틸 프로페닐 하이드록시벤즈아마이드 유도체의 제조방법.9) Alkylamino naphthalenyloxymethyl propenyl hydroxybenzamide of the formula (I) comprising the step of removing the tetrahydro-2H-pyran-2-yloxy protecting group by treating the compound of formula 10 with a water-soluble inorganic or organic acid Process for the preparation of derivatives. <화학식 1><Formula 1>
Figure 112006081424267-pat00025
Figure 112006081424267-pat00025
 <화학식 2><Formula 2>
Figure 112006081424267-pat00026
Figure 112006081424267-pat00026
 <화학식 3><Formula 3>
Figure 112006081424267-pat00027
Figure 112006081424267-pat00027
 <화학식 4><Formula 4>
Figure 112006081424267-pat00028
Figure 112006081424267-pat00028
 <화학식 5><Formula 5>
Figure 112006081424267-pat00029
Figure 112006081424267-pat00029
 <화학식 6><Formula 6>
Figure 112006081424267-pat00030
Figure 112006081424267-pat00030
 <화학식 7><Formula 7>
Figure 112006081424267-pat00031
Figure 112006081424267-pat00031
 <화학식 8><Formula 8>
Figure 112006081424267-pat00032
Figure 112006081424267-pat00032
 <화학식 9><Formula 9>
Figure 112006081424267-pat00033
Figure 112006081424267-pat00033
 <화학식 10><Formula 10>
Figure 112006081424267-pat00034
Figure 112006081424267-pat00034
 상기 식에서, R1, 및 R2는 제 1항에서 정의한 바와 같다.Wherein R 1 and R 2 are as defined in claim 1. 제 3항에 있어서,The method of claim 3, wherein 단계 1)의 알킬아크릴레이트가 에틸아크릴레이트, 아이소뷰틸아크릴레이트 및 t-뷰틸아크릴레이트로 구성된 군으로부터 선택되는 것을 특징으로 하는 제조방법.The alkyl acrylate of step 1) is selected from the group consisting of ethyl acrylate, isobutyl acrylate and t-butyl acrylate. 제 3항에 있어서,The method of claim 3, wherein 단계 2)의 반응이 빙냉하에서 이루어지고, 유기용매가 에틸에테르, 테트라하이드로퓨란, 다이클로로메탄 및 다이클로로에탄으로 구성된 군으로부터 선택되는 것을 특징으로 하는 제조방법.The reaction of step 2) is carried out under ice-cooling, and the organic solvent is selected from the group consisting of ethyl ether, tetrahydrofuran, dichloromethane and dichloroethane. 제 3항에 있어서,The method of claim 3, wherein 단계 3)의 반응이 유기용매 중에서 유기염기 또는 무기염기를 사용하여 이루어지는 것을 특징으로 하는 제조방법.The reaction of step 3) is characterized in that using an organic base or an inorganic base in an organic solvent. 제 6항에 있어서,The method of claim 6, 유기용매가 아세톤, 아세토나이트릴, 다이클로로메탄 및 테트라하이드로퓨란으로 구성된 군으로부터 선택되고, 유기염기가 트라이에틸아민, 다이아이소프로필에틸아민 및 피리딘으로 구성된 군으로부터 선택되고, 무기염기가 탄산칼륨, 중탄산나트륨 및 탄산나트륨으로 구성된 군으로부터 선택되는 것을 특징으로 하는 제조방법.The organic solvent is selected from the group consisting of acetone, acetonitrile, dichloromethane and tetrahydrofuran, the organic base is selected from the group consisting of triethylamine, diisopropylethylamine and pyridine, the inorganic base is potassium carbonate, A process according to claim 1, wherein the method is selected from the group consisting of sodium bicarbonate and sodium carbonate. 제 3항에 있어서,The method of claim 3, wherein 단계 4)에서 에틸클로로포메이트 처리가 용매를 사용하여 빙냉하에서 수행되고, 환원시 물을 적가하는 것을 특징으로 하는 제조방법.The ethylchloroformate treatment in step 4) is carried out under ice-cooling using a solvent, and water is added dropwise upon reduction. 제 3항에 있어서, The method of claim 3, wherein 단계 4)에서 환원제가 소듐보로하이드라이드, 소듐사이아노보로하이드라이드, 또는 리튬보로하이드라이드인 것을 특징으로 하는 제조방법.The method of claim 4, wherein the reducing agent is sodium borohydride, sodium cyanoborohydride, or lithium borohydride. 제 8항에 있어서, The method of claim 8, 용매가 테트라하이드로퓨란, 1,4-다이옥산, 다이클로로메탄 및 클로로폼으로 구성 된 군으로부터 선택되는 것을 특징으로 하는 제조방법.And the solvent is selected from the group consisting of tetrahydrofuran, 1,4-dioxane, dichloromethane and chloroform. 제 3항에 있어서, The method of claim 3, wherein 단계 5)의 비극성 용매가 다이클로로메탄, 클로로폼, 테트라하이드로퓨란 및 다이클로로에탄으로 구성된 군으로부터 선택되는 것을 특징으로 하는 제조방법.The nonpolar solvent of step 5) And dichloromethane, chloroform, tetrahydrofuran and dichloroethane. 제 3항에 있어서,The method of claim 3, wherein 단계 6)의 반응이 유기용매 중에서 유기염기 또는 무기염기를 사용하여 이루어지는 것을 특징으로 하는 제조방법.The process of step 6) characterized in that the reaction is carried out using an organic base or an inorganic base in an organic solvent. 제 12항에 있어서,The method of claim 12, 유기용매가 아세톤, 아세토나이트릴, 다이클로로메탄 및 테트라하이드로퓨란으로 구성된 군으로부터 선택되고, 유기염기가 트라이에틸아민, 다이아이소프로필에틸아민 및 피리딘으로 구성된 군으로부터 선택되고, 무기염기가 탄산칼륨, 중탄산나트륨 및 탄산나트륨으로 구성된 군으로부터 선택되는 것을 특징으로 하는 제조방법.The organic solvent is selected from the group consisting of acetone, acetonitrile, dichloromethane and tetrahydrofuran, the organic base is selected from the group consisting of triethylamine, diisopropylethylamine and pyridine, the inorganic base is potassium carbonate, A process according to claim 1, wherein the method is selected from the group consisting of sodium bicarbonate and sodium carbonate. 제 3항에 있어서, The method of claim 3, wherein 단계 7)의 가수분해 반응이 알콜 수용액 또는 테트라하이드로퓨란 수용액에서 이루어지고, 무기염기가 수산화리튬, 수산화나트륨 및 수산화칼륨으로 구성된 군으로부터 선택되는 것을 특징으로 하는 제조방법.The hydrolysis reaction of step 7) is carried out in an aqueous alcohol solution or an aqueous tetrahydrofuran solution, wherein the inorganic base is selected from the group consisting of lithium hydroxide, sodium hydroxide and potassium hydroxide. 제 14항에 있어서,The method of claim 14, 알콜 수용액이 메탄올, 에탄올, 아이소프로판올, n-뷰탄올 및 t-뷰탄올 수용액으로 구성된 군으로부터 선택되는 것을 특징으로 하는 제조방법.The aqueous alcohol solution is selected from the group consisting of methanol, ethanol, isopropanol, n-butanol and t-butanol aqueous solution. 제 3항에 있어서,The method of claim 3, wherein 단계 8)에서 유기용매가 N,N-다이메틸폼아마이드, 다이메틸설폭사이드, 테트라하이드로퓨란 및 다이클로로메탄으로 구성된 군으로부터 선택되는 것을 특징으로 하는 제조방법.The process of claim 8) wherein the organic solvent is selected from the group consisting of N, N -dimethylformamide, dimethylsulfoxide, tetrahydrofuran and dichloromethane. 제 3항에 있어서,The method of claim 3, wherein 단계 9)의 보호기 제거가 다이클로로메탄, 다이클로로에탄, 벤젠, 및 톨루엔으로 구성된 군으로부터 선택된 유기용매 중에서 수행되고, 수용성 무기산이 염산, 황산, 및 인산으로 구성된 군으로부터 선택되며, 유기산이 트라이플루오로아세트산, 아세트산, 및 시트르산으로 구성된 군으로부터 선택되는 것을 특징으로 하는 제조방법. The protecting group removal in step 9) is carried out in an organic solvent selected from the group consisting of dichloromethane, dichloroethane, benzene, and toluene, the water soluble inorganic acid is selected from the group consisting of hydrochloric acid, sulfuric acid, and phosphoric acid, and the organic acid is trifluoro A process according to claim 1, wherein the method is selected from the group consisting of roacetic acid, acetic acid, and citric acid. 1) 하기 화학식 7의 화합물을 1차 아민(R2NH2)과 반응시켜 하기 화학식 11의 화합물을 제조하는 단계;1) preparing a compound of Formula 11 by reacting a compound of Formula 7 with a primary amine (R 2 NH 2 ); 2) 화학식 11의 화합물을 비극성 용매에 녹이고 t-뷰틸 다이카보네이트를 이용하여 아민을 보호하여 하기 화학식 12의 화합물을 제조하는 단계;2) dissolving the compound of Formula 11 in a nonpolar solvent and protecting the amine with t -butyl dicarbonate to prepare a compound of Formula 12 ; 3) 화학식 12의 화합물을 무기염기 처리에 의해 가수분해 반응시켜 하기 화학식 13의 화합물을 제조하는 단계; 3) hydrolyzing the compound of Formula 12 by inorganic base treatment to prepare a compound of Formula 13 ; 4) 화학식 13의 화합물을 유기용매 중에서 N-하이드록시-6-트라이플루오로 벤조트라이아졸(FOBt) 및 1-에틸-3-(3-다이메틸아미노프로필)카바다이이마이드·염산염(EDC·HCl)의 존재하에 테트라하이드로-2H-피란-2-일 옥시아민(THPONH2)과 아실화 반응시켜 화합식 14의 화합물을 제조하는 단계; 및4) a compound of formula 13 in an organic solvent N - hydroxy-6-trifluoromethyl benzotriazole (FOBt) and 1-ethyl-3- (3-dimethylaminopropyl) carbazole dayiyi polyimide hydrochloride (EDC · HCl Acylation with tetrahydro-2H-pyran-2-yl oxyamine (THPONH 2 ) in the presence of a) to prepare a compound of Formula 14 ; And 5) 화학식 14의 화합물을 수용성 무기산 또는 유기산으로 처리하여 테트라하이드로-2H-피란-2-일옥시기(-OTPH)와 t-뷰톡시카보닐기(Boc-)를 제거하는 단계를 포함하는, 화학식 1의 알킬아미노 나프탈렌일옥시메틸 프로페닐 하이드록시벤즈아마이드 유도체에서 R1이 수소인 화합물의 제조방법.5) treating a compound of formula 14 with aqueous mineral or organic acid tetrahydro -2H- pyran comprising the step of removing the 2-yloxy group (-OTPH) and t- butoxy carbonyl (Boc-), formula (1) A method for producing a compound wherein R 1 is hydrogen in an alkylamino naphthalenyloxymethyl propenyl hydroxybenzamide derivative of. <화학식 1><Formula 1>
Figure 112007085262374-pat00040
Figure 112007085262374-pat00040
 <화학식 7><Formula 7>
Figure 112007085262374-pat00035
Figure 112007085262374-pat00035
 <화학식 11><Formula 11>
Figure 112007085262374-pat00036
Figure 112007085262374-pat00036
 <화학식 12><Formula 12>
Figure 112007085262374-pat00037
Figure 112007085262374-pat00037
 <화학식 13><Formula 13>
Figure 112007085262374-pat00038
Figure 112007085262374-pat00038
 <화학식 14><Formula 14>
Figure 112007085262374-pat00039
Figure 112007085262374-pat00039
 상기 식에서, R1은 수소이고, R2는 제 1항에서 정의한 바와 같다.Wherein R 1 is hydrogen and R 2 is as defined in claim 1. 제 18항에 있어서,The method of claim 18, 단계 1)의 반응이 유기용매 중에서 유기염기 또는 무기염기를 사용하여 이루어지는 것을 특징으로 하는 제조방법.The method of claim 1, wherein the reaction of step 1) is carried out using an organic base or an inorganic base in an organic solvent. 제 19항에 있어서,The method of claim 19, 유기용매가 아세톤, 아세토나이트릴, 다이클로로메탄 및 테트라하이드로퓨란으로 구성된 군으로부터 선택되고, 유기염기가 트라이에틸아민, 다이아이소프로필에틸아민 및 피리딘으로 구성된 군으로부터 선택되고, 무기염기가 탄산칼륨, 중탄산나트륨 및 탄산나트륨으로 구성된 군으로부터 선택되는 것을 특징으로 하는 제조방법.The organic solvent is selected from the group consisting of acetone, acetonitrile, dichloromethane and tetrahydrofuran, the organic base is selected from the group consisting of triethylamine, diisopropylethylamine and pyridine, the inorganic base is potassium carbonate, A process according to claim 1, wherein the method is selected from the group consisting of sodium bicarbonate and sodium carbonate. 제 18항에 있어서,The method of claim 18, 단계 2)의 반응이 비극성 용매 중에서 유기염기와 촉매를 사용하여 이루어지는 것을 특징으로 하는 제조방법.The reaction of step 2) is carried out using an organic base and a catalyst in a nonpolar solvent. 제 21항에 있어서,The method of claim 21, 비극성 용매가 다이클로로메탄, 클로로폼, 테트라하이드로퓨란, 1,4-다이옥산 및 다이클로로에탄으로 구성된 군으로부터 선택되고, 유기염기가 트라이에틸아민, 다이아이소프로필에틸아민 및 피리딘으로 구성된 군으로부터 선택되고, 촉매가 4-다이메틸아미노피리딘(DMAP)인 것을 것을 특징으로 하는 제조방법.The nonpolar solvent is selected from the group consisting of dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane and dichloroethane, and the organic base is selected from the group consisting of triethylamine, diisopropylethylamine and pyridine And the catalyst is 4-dimethylaminopyridine (DMAP). 제 18항에 있어서,The method of claim 18, 단계 3)의 가수분해 반응이 알콜 수용액 또는 테트라하이드로퓨란 수용액에서 이루어지고, 무기염기가 수산화리튬, 수산화나트륨 및 수산화칼륨으로 구성된 군으로부터 선택되는 것을 특징으로 하는 제조방법.The hydrolysis reaction of step 3) is carried out in an aqueous alcohol solution or tetrahydrofuran aqueous solution, characterized in that the inorganic base is selected from the group consisting of lithium hydroxide, sodium hydroxide and potassium hydroxide. 제 23항에 있어서,The method of claim 23, wherein 알콜 수용액이 메탄올, 에탄올, 아이소프로판올, n-뷰탄올 및 t-뷰탄올 수용액으로 구성된 군으로부터 선택되는 것을 특징으로 하는 제조방법.The aqueous alcohol solution is selected from the group consisting of methanol, ethanol, isopropanol, n-butanol and t-butanol aqueous solution. 제 18항에 있어서,The method of claim 18, 단계 4)에서 유기용매가 N,N-다이메틸폼아마이드, 다이메틸설폭사이드, 테트라하이드로퓨란 및 다이클로로메탄으로 구성된 군으로부터 선택되는 것을 특징으로 하는 제조방법.The process of claim 4) wherein the organic solvent is selected from the group consisting of N, N -dimethylformamide, dimethylsulfoxide, tetrahydrofuran and dichloromethane. 제 18항에 있어서,The method of claim 18, 단계 5)가 다이클로로메탄, 다이클로로에탄, 벤젠, 및 톨루엔으로 구성된 군으로부터 선택된 유기용매 중에서 이루어지고, 수용성 무기산이 염산, 황산, 및 인산 으로 구성된 군으로부터 선택되며, 유기산이 트라이플루오로아세트산, 아세트산, 및 시트르산으로 구성된 군으로부터 선택되는 것을 특징으로 하는 제조방법. Step 5) is carried out in an organic solvent selected from the group consisting of dichloromethane, dichloroethane, benzene, and toluene, the water-soluble inorganic acid is selected from the group consisting of hydrochloric acid, sulfuric acid, and phosphoric acid, the organic acid is trifluoroacetic acid, Acetic acid, and citric acid. 제 1항의 화학식 1의 알킬아미노 나프탈렌일옥시메틸 프로페닐 하이드록시벤즈아마이드 유도체 또는 그의 약학적으로 허용가능한 염을 유효성분으로 포함하는 항암제용 약학 조성물.Claim 1 of the formula alkyl-amino-naphthalene-yloxymethyl-propenyl-hydroxy-benzamide derivatives or pharmaceutical compositions for anticancer agents, including their pharmaceutically acceptable salts as an active ingredient. 삭제delete
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KR20190014822A (en) 2017-08-04 2019-02-13 중원대학교 산학협력단 Novel benzamide derivatives compounds, manufacturing method thereof, and phamaceutical composition for preventing and treating cancer containing the same
CN117004179A (en) * 2023-09-27 2023-11-07 常州宏巨电子科技有限公司 High-temperature-resistant graphene film and preparation method and application thereof
CN117004179B (en) * 2023-09-27 2023-12-05 常州宏巨电子科技有限公司 High-temperature-resistant graphene film and preparation method and application thereof

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