KR100584811B1 - N,n-dimethylaminophenyl octanoic acid hydroxyamide derivatives with inhibitory activity against histone deacetylase and method for the preparation thereof - Google Patents

N,n-dimethylaminophenyl octanoic acid hydroxyamide derivatives with inhibitory activity against histone deacetylase and method for the preparation thereof Download PDF

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KR100584811B1
KR100584811B1 KR1020040084428A KR20040084428A KR100584811B1 KR 100584811 B1 KR100584811 B1 KR 100584811B1 KR 1020040084428 A KR1020040084428 A KR 1020040084428A KR 20040084428 A KR20040084428 A KR 20040084428A KR 100584811 B1 KR100584811 B1 KR 100584811B1
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phenyl
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이철해
정희정
김성곤
김재학
전미애
성태현
조중명
노성구
이태규
현영란
신동규
이준희
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C239/00—Compounds containing nitrogen-to-halogen bonds; Hydroxylamino compounds or ethers or esters thereof
    • C07C239/08—Hydroxylamino compounds or their ethers or esters
    • C07C239/14—Hydroxylamino compounds or their ethers or esters having nitrogen atoms of hydroxylamino groups further bound to carbon atoms of hydrocarbon radicals substituted by doubly-bound oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/22—Separation; Purification; Stabilisation; Use of additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C239/00—Compounds containing nitrogen-to-halogen bonds; Hydroxylamino compounds or ethers or esters thereof
    • C07C239/08—Hydroxylamino compounds or their ethers or esters
    • C07C239/16—Hydroxylamino compounds or their ethers or esters having nitrogen atoms of hydroxylamino groups further bound to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups

Abstract

본 발명은 하기 화학식 1로 표시되는 신규한 N,N-다이메틸아미노페닐 옥타노산 하이드록시아마이드 유도체 화합물, 이의 거울상 이성질체 또는 이의 약학적으로 허용가능한 염, 이의 제조방법 및 이를 함유하는 항암 조성물에 관한 것으로, 본 발명에 따른 화학식 1의 신규 화합물은 항암제로서 유용하게 사용될 수 있다.The present invention relates to a novel N, N-dimethylaminophenyl octanoic acid hydroxyamide derivative compound represented by the following Chemical Formula 1 , an enantiomer thereof or a pharmaceutically acceptable salt thereof, a preparation method thereof, and an anticancer composition containing the same As a novel compound of formula 1 according to the present invention, it can be usefully used as an anticancer agent.

<화학식 1><Formula 1>

Figure 112004047982053-pat00001
Figure 112004047982053-pat00001

상기 식에서,Where

R은 치환되거나 비치환된 하이드록시메틸기, 아릴아미노메틸기, 아릴아마이드기, C1-5 알킬아마이드기, 헤테로아릴아마이드기이고, 상기에서 헤테로아릴은 고리 중에 질소, 황 또는 산소를 포함하며, 피페라진, 트라이아졸, 티아졸, 벤조티아졸, 다이벤조퓨란, 피리딘, 퀴놀린, 또는 이소퀴놀린이다.R is a substituted or unsubstituted hydroxymethyl group, arylaminomethyl group, arylamide group, C 1-5 alkylamide group, heteroarylamide group, wherein heteroaryl includes nitrogen, sulfur or oxygen in the ring, Razin, triazole, thiazole, benzothiazole, dibenzofuran, pyridine, quinoline, or isoquinoline.

Description

히스톤 디아세틸라제 저해활성을 갖는 Ｎ,Ｎ-다이메틸아미노페닐 옥타노산 하이드록시아마이드 유도체 및 이의 제조방법 {N,N-DIMETHYLAMINOPHENYL OCTANOIC ACID HYDROXYAMIDE DERIVATIVES WITH INHIBITORY ACTIVITY AGAINST HISTONE DEACETYLASE AND METHOD FOR THE PREPARATION THEREOF}N, N-DIMETHYLAMINOPHENYL OCTANOIC ACID HYDROXYAMIDE DERIVATIVES WITH INHIBITORY ACTIVITY AGAINST HISTONE DEACETYLASE AND METHOD FOR THE PREPARATION

본 발명은 히스톤 디아세틸라제의 저해활성을 가져 암의 진행을 효과적으로 억제하는 N,N-다이메틸아미노페닐 옥타노산 하이드록시아마이드 유도체 화합물, 이의 거울상 이성질체 또는 이의 약학적으로 허용가능한 염, 이의 제조방법 및 이를 함유하는 약학적 조성물에 관한 것이다.The present invention provides an N, N-dimethylaminophenyl octanoic acid hydroxyamide derivative compound having an inhibitory activity of histone deacetylase, effectively inhibiting cancer progression, an enantiomer thereof or a pharmaceutically acceptable salt thereof, and a method of preparing the same. And pharmaceutical compositions containing the same.

히스톤 디아세틸라제 (histone deacetylase, HDAC)는 암 치료제의 표적 단백질로서 체내에서 세포증식, 세포성장주기 조절, 분화, 암 형성 등의 중요한 세포활동에 관여하는 효소이다. 상기 효소는 기능적으로 히스톤의 N-말단 쪽 라이신 꼬리의 아미노기에 존재하는 아세틸기를 제거하는 역할을 한다. Histone deacetylase (HDAC) is a target protein of cancer drugs and is an enzyme involved in important cellular activities such as cell proliferation, cell growth cycle regulation, differentiation and cancer formation in the body. The enzyme functions to remove the acetyl group present in the amino group of the lysine tail on the N-terminal side of the histone.

HDAC의 기질로 작용하는 히스톤은 진핵세포의 핵내 DNA와 결합하고 있는 염기성 단백질로서 히스톤의 각 분자 중 특정 위치의 라이신 잔기의 아미노기에 가역 적인 아세틸화가 일어난다. 이러한 히스톤의 아세틸화 반응은 염색질 (chromatin)의 고차구조 형성이나 세포분열주기 등과 관계가 있어서 비히스톤 단백질과 함께 유전자 정보의 발현조절에 관여하는 것으로 생각되고 있다.Histone, which acts as a substrate of HDAC, is a basic protein that binds to DNA in eukaryotic nuclei, and reversible acetylation occurs in the amino group of lysine residues at specific positions in each molecule of histone. These histone acetylation reactions are associated with the formation of higher levels of chromatin, cell division cycles, and the like, and are thought to be involved in the regulation of gene information expression with nonhistone proteins.

진핵세포 DNA는 히스톤이라는 8각체 (octamer) (H1b, H1b, H3, H4) 염기성 단백질에 2번 감겨 있으면서 (총 146염기) 좁은 핵내 공간에 압축되어 저장되어 있고, 이와 같이 압축된 DNA를 유전정보로 활용하기 위해서는 압축을 다시 풀어야만 한다. 이를 위해 세포에는 염색질의 구조를 변형, 조절할 수 있는 기전이 있을 것이라 예상되어 왔으며, 최근의 연구를 통해 뉴클레오좀 (nucleosome) 구조를 변형하여 전사인자와 DNA와의 접근을 촉진시키는 SWI/SNF, RSC, NURF, NRD 등과 같은 염색질 재형성 인자 (chromatin remodeling factor), 히스톤의 아세틸화 상태를 조절하는 히스톤 아세틸전이효소 (acetyltransferases) (HATs)와 히스톤 디아세틸라제 (HDACs)가 중요한 조절인자로 작용함이 밝혀졌다. 특히, 이들 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.Eukaryotic DNA is wound twice in a octamer (H1b, H1b, H3, H4) basic protein called histones (total 146 bases), and is compressed and stored in a narrow nucleus space. In order to use it, you have to decompress it again. To this end, cells have been expected to have a mechanism for modifying and regulating chromatin structure. Recent studies have suggested that SWI / SNF, RSC, which modifies the nucleosome structure, facilitates access to transcription factors and DNA. , Chromatin remodeling factors such as NURF and NRD, histone acetyltransferases (HATs) and histone deacetylases (HDACs) that regulate histone acetylation, act as important regulators. Turned out. In particular, 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 recharge to inhibit transcription, thereby inhibiting transcription. It is known to regulate gene expression at the transcriptional level by inducing equilibrium levels of evolution.

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 촉 진한다면 HDAC는 히스톤의 탈아세틸화를 통해 증식을 유도하는데 결정적인 역할을 할 것이다. 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 will play a crucial role in inducing proliferation through deacetylation of histones. This fact 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 (참조: Lin R. J. et. al. Oncogene 20: 7204, 2001; Zelent A. et. al. Oncogene 20: 7186, 2001). 그러므로, HDAC 활성의 비정상적인 조절에 의하여 일어나는 종양단백질 (oncoprotein)의 부적절한 전사 억제와 염색질 구조에서의 이상이 정상적인 세포 분화에 영향을 미쳐 암 형성을 유도하게 된다. 따라서, HDAC는 유전자 발현의 억제인자로서 뿐만 아니라 새로운 항암제 개발의 표적분자로서 매우 중요한 연구대상이 되고 있으며, HDAC 저해제는 암세포의 증식을 억제시키는 획기적인 항암제로 개발될 가능성이 매우 높다.Acute promyelocytic leukemia (APL) is one of the most important causes of the development of acute leukemia. Known (Lin RJ et. Al. Oncogene 20: 7204, 2001; Zelent A. et. Al. Oncogene 20: 7186, 2001). Therefore, improper transcription inhibition and abnormality in chromatin structure of oncoprotein caused by abnormal regulation of HDAC activity affect normal cell differentiation and induce 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.

그 동안 항암제 연구는 세포신호전달 저해, 세포주기조절, 그리고 혈관형성억제의 세 분야에 집중되어 있었다. 그러나, 최근 들어 염색질 리모델링을 이용한 항암제 연구가 시작되었고, SAHA (suberanilohydroxamic acid) 또는 아피시딘 (apicidin)과 같은 HDAC 억제인자를 처리할 경우 암세포의 증식이 억제되고 분화가 유도된다는 연구결과가 발표되면서 항암제의 개발이 더욱 활발히 진행되고 있다 (참조: Munster P. N. et. al. Cancer research 61: 8492, 2001; Han J. W. et. al. Cancer research 60: 6068, 2000).Anticancer drug research has focused on three areas: cell signaling inhibition, cell cycle regulation, and angiogenesis inhibition. Recently, however, studies of anticancer drugs using chromatin remodeling have begun, and studies showing that treatment of HDAC inhibitors such as SAHA (suberanilohydroxamic acid) or apicidin inhibits the proliferation and differentiation of cancer cells. The development of anticancer agents is more active (Munster PN et.al. Cancer research 61: 8492, 2001; Han JW et.al. Cancer research 60: 6068, 2000).

HDAC 저해제로 최초 사용된 화합물은 n-부티레이트 (n-butyrate)로, 이 물질은 현재도 대장암의 치료에 적용되고 있을 뿐만 아니라 HDAC 효소 저해제로 생화학과 분자생물학 실험에 사용되고 있다. 그러나, n-부티레이트는 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 나노몰 (nanomolar, nM) 수준에서 유도하고 동물세포의 증식을 G1 및 G2기에서 저지하는 활성물질로 트라이코스타틴 A (trichostatin A, TSA)를 발견하고, 이의 세포내 표적분자가 HDAC임을 밝힌 바 있으나 (참조: Yoshida M. et. al. Cancer research 47:3688, 1987; Yoshida M. & Beppu T. Exp Cell Res 177:122, 1988; Yoshida M. et. al. J of Biol. Chem. 265:17174, 1990), 계속해서 미래형 항암제로 간주되는 HDAC 억제제 화합물의 발굴에 대한 필요성이 매우 증가되고 있는 실정이다.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 biochemistry and molecular biology experiments as an HDAC enzyme inhibitor. However, the effective concentration of n-butyrate is in the level of millimolar (millimolar), which is not suitable for the analysis of HDAC function such as affecting other enzymes, cytoskeleton, and cell membrane in the cell. There is a need for the development of HDAC inhibitors. In 1988, M. Yoshida and B. Teruhiko of the University of Tokyo, Japan, induced the differentiation of friend murine erythroleukemia (MEL) cells at the nanomolar (nM) level and proliferated the animal cells. Trichostatin A (TSA) was detected as an active substance that inhibits G1 and G2 phases, and it has been shown that its intracellular target molecule is HDAC (see Yoshida M. et. Al. Cancer research 47: 3688, 1987; Yoshida M. & Beppu T. Exp Cell Res 177: 122, 1988; Yoshida M. et.al. J of Biol. Chem. 265: 17174, 1990), HDAC inhibitor compounds continually considered future anticancer agents The need for excavation is increasing very much.

이에, 본 발명자들은 HDAC 억제제 화합물을 개발하기 위해 예의 연구 노력한 결과, 화학식 1로 표시되는 N,N-다이메틸아미노페닐 옥타노산 하이드록시아마이드 유도체가 매우 강력한 세포증식 억제력을 갖는 사실을 발견하고 이들이 암의 치료에 유용하게 사용될 수 있음을 확인함으로써 본 발명을 완성하였다.Accordingly, the present inventors have made diligent research efforts to develop HDAC inhibitor compounds, and found that the N, N-dimethylaminophenyl octanoic acid hydroxyamide derivative represented by Formula 1 has a very strong cell proliferation inhibitory ability and The present invention has been completed by confirming that it can be usefully used for the treatment of.

본 발명의 목적은 히스톤 디아세틸라제의 효소활성을 효과적으로 억제함으로써 종양세포의 증식을 억제하는, 화학식 1의 N,N-다이메틸아미노페닐 옥타노산 하이드록시아마이드 유도체 화합물, 이의 거울상 이성질체 또는 이의 약학적으로 허용가능한 염 및 이의 제조방법을 제공하는 것이다.It is an object of the present invention to inhibit the proliferation of tumor cells by effectively inhibiting the enzymatic activity of histone deacetylase, N, N-dimethylaminophenyl octanoic acid hydroxyamide derivative compound of formula (1 ), an enantiomer thereof or a pharmaceutical thereof To provide an acceptable salt and a method for preparing the same.

본 발명의 또 다른 목적은 화학식 1의 N,N-다이메틸아미노페닐 옥타노산 하이드록시아마이드 유도체 화합물, 이의 거울상 이성질체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 항암제 또는 히스톤 디아세틸라제의 효소활성으로 유발되는 질환의 예방 및 치료제를 제공하는 것이다.
Still another object of the present invention is to provide an anticancer agent or histone deacetylase containing N, N-dimethylaminophenyl octanoic acid hydroxyamide derivative compound of Formula 1 , an enantiomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient. It is to provide a preventive and therapeutic agent for diseases caused by enzymatic activity.

상기 목적을 달성하기 위하여, 본 발명은 하기 화학식 1의 N,N-다이메틸아미노페닐 옥타노산 하이드록시아마이드 유도체 및 이의 제조방법을 제공한다:In order to achieve the above object, the present invention provides a N, N-dimethylaminophenyl octanoic acid hydroxyamide derivative of the general formula (1) and a method for preparing the same:

Figure 112004047982053-pat00002
Figure 112004047982053-pat00002

상기 식에서,Where

R은 치환되거나 비치환된 하이드록시메틸기, 아릴아미노메틸기, 아릴아마이드기, C1-5 알킬아마이드기, 헤테로아릴아마이드기이고, 상기에서 헤테로아릴은 고 리 중에 질소, 황 또는 산소를 포함하며, 피페라진, 트라이아졸, 티아졸, 벤조티아졸, 다이벤조퓨란, 피리딘, 퀴놀린, 또는 이소퀴놀린이다.R is a substituted or unsubstituted hydroxymethyl group, arylaminomethyl group, arylamide group, C 1-5 alkylamide group, heteroarylamide group, wherein heteroaryl includes nitrogen, sulfur or oxygen in the ring, Piperazine, triazole, thiazole, benzothiazole, dibenzofuran, pyridine, quinoline, or isoquinoline.

또한, 본 발명은 유효량의 화학식 1의 N,N-다이메틸아미노페닐 옥타노산 하이드록시아마이드 유도체를 활성성분으로 함유하고 약학적으로 허용가능한 담체를 포함하는 항암제 조성물을 제공한다.The present invention also provides an anticancer composition comprising an effective amount of N, N-dimethylaminophenyl octanoic acid hydroxyamide derivative of Formula 1 as an active ingredient and a pharmaceutically acceptable carrier.

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

본 발명의 화학식 1의 화합물중 바람직한 것들은 하기 화학식 1a 또는 1b로 표시되는 것들이다.Preferred among the compounds of the formula (1) of the present invention are those represented by the following formula (1a) or ( 1b ).

Figure 112004047982053-pat00003
Figure 112004047982053-pat00003

Figure 112004047982053-pat00004
Figure 112004047982053-pat00004

본 발명에 따른 화학식 1의 화합물중 더욱 바람직한 것들은 하기에 기재된 바와 같다:Further preferred of the compounds of formula 1 according to the invention are as described below:

(S)-7-(4-다이메틸아미노-페닐)-8-하이드록시-옥타-2,4-디에노산 하이드록시아마이드;(S) -7- (4-dimethylamino-phenyl) -8-hydroxy-octa-2,4-dienoic acid hydroxyamide;

(S)-7-(4-다이메틸아미노-페닐)-8-하이드록시-옥타노산 하이드록시아마이드;(S) -7- (4-dimethylamino-phenyl) -8-hydroxy-octanoic acid hydroxyamide;

(S)-7-(4-다이메틸아미노-페닐)-8-페닐아미노-옥타-2,4-디에노산 하이드록시아마이드;(S) -7- (4-dimethylamino-phenyl) -8-phenylamino-octa-2,4-dienoic acid hydroxyamide;

(S)-7-(4-다이메틸아미노-페닐)-8-페닐아미노-옥타노산 하이드록시아마이드;(S) -7- (4-dimethylamino-phenyl) -8-phenylamino-octanoic acid hydroxyamide;

(S)-8-(3-벤질옥소-페닐아미노)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디에노산 하이드록시아마이드;(S) -8- (3-benzyloxo-phenylamino) -7- (4-dimethylamino-phenyl) -octa-2,4-dienoic acid hydroxyamide;

(S)-7-(4-다이메틸아미노-페닐)-8-(3-하이드록시-페닐아미노)-옥타노산 하이드록시아마이드;(S) -7- (4-dimethylamino-phenyl) -8- (3-hydroxy-phenylamino) -octanoic acid hydroxyamide;

(S)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 하이드록시아마이드 8-페닐아마이드;(S) -7- (4-dimethylamino-phenyl) -octa-2,4-dienodioic acid hydroxyamide 8-phenylamide;

(S)-2-(4-다이메틸아미노-페닐)-옥타노산 8-하이드록시아마이드 1-페닐아마이드;(S) -2- (4-dimethylamino-phenyl) -octanoic acid 8-hydroxyamide 1-phenylamide;

(S)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 8-[(3-벤질옥소-페닐)-아마이드] 1-하이드록시아마이드;(S) -7- (4-dimethylamino-phenyl) -octa-2,4-dienodioic acid 8-[(3-benzyloxo-phenyl) -amide] 1-hydroxyamide;

(S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-[(3-하이드록시-페닐)-아마이드]; (S) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 1-[(3-hydroxy-phenyl) -amide];

(S)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-하이드록시아마이드 8-나프탈렌-1-일아마이드;(S) -7- (4-dimethylamino-phenyl) -octa-2,4-dienodioic acid 1-hydroxyamide 8-naphthalen-1-ylamide;

(S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 8-나프탈렌-1-일아마이드;(S) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 8-naphthalen-1-ylamide;

(S)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-하이드록시아마이드 8-퀴놀린-6-일아마이드;(S) -7- (4-dimethylamino-phenyl) -octa-2,4-dienodioic acid 1-hydroxyamide 8-quinolin-6-ylamide;

(S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-퀴놀린-6-일아마이드;(S) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 1-quinolin-6-ylamide;

(S)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-하이드록시아마이드 8-퀴놀린-8-일아마이드; (S) -7- (4-dimethylamino-phenyl) -octa-2,4-dienodioic acid 1-hydroxyamide 8-quinolin-8-ylamide;

(S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-퀴놀린-8-일아마이드;(S) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 1-quinolin-8-ylamide;

(S)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-하이드록시아마이드 8-[(3-메톡시-페닐)-아마이드];(S) -7- (4-dimethylamino-phenyl) -octa-2,4-dienodioic acid 1-hydroxyamide 8-[(3-methoxy-phenyl) -amide];

(S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-[(3-메톡시-페닐)-아마이드]-8-일아마이드;(S) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 1-[(3-methoxy-phenyl) -amide] -8-ylamide;

(S)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 8-[(3,4-다이메톡시-페닐)-아마이드] 1-하이드록시아마이드;(S) -7- (4-dimethylamino-phenyl) -octa-2,4-dienodioic acid 8-[(3,4-dimethoxy-phenyl) -amide] 1-hydroxyamide;

(S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-[(3,4-다이메톡시-페닐)-아마이드]-8-일아마이드;(S) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 1-[(3,4-dimethoxy-phenyl) -amide] -8-ylamide;

(S)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-하이드록시아마이드 3-퀴놀린-8-일아마이드;(S) -7- (4-dimethylamino-phenyl) -octa-2,4-dienodioic acid 1-hydroxyamide 3-quinolin-8-ylamide;

(S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-퀴놀린-3-일아마이드;(S) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 1-quinolin-3-ylamide;

(S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-피리딘-4-일아마이드;(S) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 1-pyridin-4-ylamide;

(S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 1-[(4-다이메틸아미노-페닐)-아마이드] 8-하이드록시아마이드;(S) -2- (4-dimethylamino-phenyl) -octanedioic acid 1-[(4-dimethylamino-phenyl) -amide] 8-hydroxyamide;

(S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-피리딘-3-일아마이드;(S) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 1-pyridin-3-ylamide;

(S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-[(5-하이드록시-나프탈렌-1-일)-아마이드];(S) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 1-[(5-hydroxy-naphthalen-1-yl) -amide];

(S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-{[2-(1H-인돌-3-일)-에틸]-아마이드};(S) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 1-{[2- (1H-indol-3-yl) -ethyl] -amide};

(S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-[(6-메톡시-퀴놀린-3-일)-아마이드];(S) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 1-[(6-methoxy-quinolin-3-yl) -amide];

(S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 1-[(4'-시아노-바이페닐-4-일)-아마이드] 8-하이드록시아마이드;(S) -2- (4-dimethylamino-phenyl) -octanedioic acid 1-[(4'-cyano-biphenyl-4-yl) -amide] 8-hydroxyamide;

(S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-[(1H-인다졸-6-일)-아마이드];(S) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 1-[(1H-indazol-6-yl) -amide];

(S)-7-(4-다이메틸아미노-페닐)-8-옥소-8-(4-페닐-피페라진-1일)-옥타노산 하이드록시아마이드;(S) -7- (4-dimethylamino-phenyl) -8-oxo-8- (4-phenyl-piperazin-1yl) -octanoic acid hydroxyamide;

(S)-2-(4-다이메틸아미노-페닐)-옥타노산 8-하이드록시아마이드 1-[(6-메톡시-벤조사이아졸-2-일)-아마이드];(S) -2- (4-dimethylamino-phenyl) -octanoic acid 8-hydroxyamide 1-[(6-methoxy-benzothiazol-2-yl) -amide];

(S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-[(2-메틸-퀴놀린-4-일)-아마이드];(S) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 1-[(2-methyl-quinolin-4-yl) -amide];

(S)-8-(3,4-디하이드로-1H-이소퀴놀린-2-일)-7-(4-다이메틸아미노-페닐)-8-옥소-옥타노산 하이드록시아마이드; (S) -8- (3,4-dihydro-1H-isoquinolin-2-yl) -7- (4-dimethylamino-phenyl) -8-oxo-octanoic acid hydroxyamide;

(S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-[(피리딘-3-일메틸)-아마이드];(S) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 1-[(pyridin-3-ylmethyl) -amide];

(S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 1-[(3-벤질옥시-페닐)-아마이드] 8-하이드록시아마이드;(S) -2- (4-dimethylamino-phenyl) -octanedioic acid 1-[(3-benzyloxy-phenyl) -amide] 8-hydroxyamide;

(S)-8-(1,3-디하이드로-이소인돌-2-일)-7-(4-다이메틸아미노-페닐)-8-옥소-옥타노산 하이드록시아마이드;(S) -8- (1,3-dihydro-isoindol-2-yl) -7- (4-dimethylamino-phenyl) -8-oxo-octanoic acid hydroxyamide;

(S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 1-[(9-에틸-9H-카바졸-3-일)-아마이드 ] 8-하이드록시아마이드;(S) -2- (4-dimethylamino-phenyl) -octanedioic acid 1-[(9-ethyl-9H-carbazol-3-yl) -amide] 8-hydroxyamide;

(S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-[(피리딘-4-일메틸)-아마이드];(S) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 1-[(pyridin-4-ylmethyl) -amide];

(S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-[(5-메틸설파닐-1H-[1,2,4]트라이아졸-3-일)-아마이드];(S) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 1-[(5-methylsulfanyl-1H- [1,2,4] triazol-3-yl) Amide];

(R)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 하이드록시아마이드 8-페닐아마이드;(R) -7- (4-dimethylamino-phenyl) -octa-2,4-dienodioic acid hydroxyamide 8-phenylamide;

(R)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 8-[(3-벤질옥소-페닐)-아마이드] 1-하이드록시아마이드;(R) -7- (4-dimethylamino-phenyl) -octa-2,4-dienodioic acid 8-[(3-benzyloxo-phenyl) -amide] 1-hydroxyamide;

(R)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-하이드록시아마이드 8-나프탈렌-1-일아마이드;(R) -7- (4-dimethylamino-phenyl) -octa-2,4-dienodioic acid 1-hydroxyamide 8-naphthalen-1-ylamide;

(R)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 8-나프탈렌-1-일아마이드;(R) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 8-naphthalen-1-ylamide;

(R)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-하이드록시아마이드 8-퀴놀린-8-일아마이드;(R) -7- (4-dimethylamino-phenyl) -octa-2,4-dienodioic acid 1-hydroxyamide 8-quinolin-8-ylamide;

(R)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-퀴놀린-8-일아마이드;(R) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 1-quinolin-8-ylamide;

(R)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-하이드록시아마이드 3-퀴놀린-8-일아마이드;(R) -7- (4-dimethylamino-phenyl) -octa-2,4-dienodioic acid 1-hydroxyamide 3-quinolin-8-ylamide;

(R)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-하이드록시아마이드 8-[(3-메톡시-페닐)-아마이드]; 및(R) -7- (4-dimethylamino-phenyl) -octa-2,4-dienodioic acid 1-hydroxyamide 8-[(3-methoxy-phenyl) -amide]; And

(R)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 8-[(3,4-다이메톡시-페닐)-아마이드] 1-하이드록시아마이드.(R) -7- (4-Dimethylamino-phenyl) -octa-2,4-dienedioic acid 8-[(3,4-dimethoxy-phenyl) -amide] 1-hydroxyamide.

본 발명에 따른 화학식 1의 화합물은 거울상 이성질체를 포함하며, 무기 또는 유기산으로부터 유도된 약학적으로 허용가능한 염의 형태로도 사용될 수 있다. 바람직한 염으로는 염산, 브롬화수소산, 황산, 인산, 질산, 아세트산, 글리콜산, 락트산, 피루빅산, 말론산, 숙신산, 글루타르산, 푸마르산, 말산, 만델산, 타르타 르산, 시트르산, 아스코르빈산, 팔미트산, 말레인산, 히드록시말레인산, 벤조산, 하이드록시벤조산, 페닐아세트산, 신남산, 살리실산, 메탄설폰산, 벤젠설폰산, 톨루엔설폰산 등의 염을 들 수 있다.Compounds of formula (1) according to the invention comprise enantiomers and may also be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids. 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 Salts such as hydrochloric acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid.

화학식 1에서 R이 하이드록시메틸기인 경우의 화합물들은 하기 반응식 1로 표시되는 합성 경로에 따라 제조될 수 있다. Compounds when R in the formula (1) is a hydroxymethyl group can be prepared according to the synthetic route represented by Scheme 1 .

Figure 112004047982053-pat00005
Figure 112004047982053-pat00005

상기 식에서, R은 하이드록시메틸기이다.Wherein R is a hydroxymethyl group.

상기 반응식 1은 다음과 같은 단계를 포함한다: Scheme 1 includes the following steps:

1) 4-옥소부테노산 메틸에스터(화합물 3)를 반응촉매로서 (2R,5R)- 또는 (2S,5S)-5-벤질-2-t-부틸-3-메틸이미다졸리딘-4-온의 존재하에서 N,N-다이메틸아닐린과 반응시켜 (S)-2-(4-다이메틸아미노-페닐)-4-옥소-부티르산 메틸 에스터 (화합물 4)를 제조하는 단계 (참조: MacMillan, D. W. C. et. al. J. Am. Chem. Soc. 124: 7894, 2002);1) (2R, 5R)-or (2S, 5S) -5-benzyl-2-t-butyl-3-methylimidazolidine-4- as a reaction catalyst using 4-oxobutenoic acid methyl ester (Compound 3) Reacting with N, N-dimethylaniline in the presence of one to prepare (S) -2- (4-dimethylamino-phenyl) -4-oxo-butyric acid methyl ester (Compound 4) (see MacMillan, DWC et al. J. Am. Chem. Soc. 124: 7894, 2002);

2) 화합물 4를 4-(디에톡시-포스포릴)-부트-2-에노산 에틸 에스터와 반응시켜 (S)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-에틸 에스터 8-메틸 에스터 (화합물 5)를 얻는 단계;2) Compound 4 was reacted with 4- (diethoxy-phosphoryl) -but-2-enoic acid ethyl ester to give (S) -7- (4-dimethylamino-phenyl) -octa-2,4-dienoic acid Obtaining 1-ethyl ester 8-methyl ester (Compound 5);

3) 화합물 5를 염산으로 처리하여 (S)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-에틸 에스터 (화합물 6)로 전환시키는 단계;3) treating Compound 5 with hydrochloric acid to convert (S) -7- (4-dimethylamino-phenyl) -octa-2,4-dienoic acid 1-ethyl ester (Compound 6);

4) 화합물 6을 에틸클로로포메이트 (ECC)로 처리하고, 소듐보로하이드라이드 (NaBH4)로 환원시켜 (S)-7-(4-다이메틸아미노-페닐)-8-하이드록시-옥타-2,4-디에노산 1-에틸 에스터 (화합물 7)를 얻는 단계;4) Treatment of compound 6 with ethylchloroformate (ECC) and reduction with sodium borohydride (NaBH 4 ) to give (S) -7- (4-dimethylamino-phenyl) -8-hydroxy-octa Obtaining -2,4-dienoic acid 1-ethyl ester (Compound 7);

5) 화합물 7을 염산으로 처리하여 (S)-7-(4-다이메틸아미노-페닐)-8-하이드록시-옥타-2,4-디에노산 (화합물 8)로 전환시키는 단계;5) treating Compound 7 with hydrochloric acid to convert to (S) -7- (4-dimethylamino-phenyl) -8-hydroxy-octa-2,4-dienoic acid (Compound 8);

6) 화합물 8을 t-뷰틸다이메틸실릴옥시아민 (NH2OTBS)과 아실화 반응시킨 후 트라이플루오로아세트산으로 t-뷰틸다이메틸실릴기를 제거함으로써 화학식 1b의 화합물을 제조하는 단계; 및6) preparing a compound of Formula 1b by acylating compound 8 with t-butyldimethylsilyloxyamine (NH 2 OTBS) and then removing t-butyldimethylsilyl group with trifluoroacetic acid; And

7) 화학식 1b의 화합물을 수소압력하에서 팔라듐/카본과 반응시켜 화학식 1a의 화합물을 제조하는 단계.7) reacting a compound of Formula 1b with palladium / carbon under hydrogen pressure to produce a compound of Formula 1a .

상기에서, 단계 1)에서는 클로로폼을 용매로 사용하는 것이 바람직하다.In the above, in step 1), it is preferable to use chloroform as a solvent.

단계 2)의 반응은 수산화리튬 존재하에서 테트라하이드로퓨란을 용매로 사용하여 이루어지는 것이 바람직하다.The reaction of step 2) is preferably carried out using tetrahydrofuran as a solvent in the presence of lithium hydroxide.

단계 3) 및 5)의 반응은 아세톤을 용매로 사용하여 이루어지는 것이 바람직 하다.The reaction of steps 3) and 5) is preferably carried out using acetone as a solvent.

단계 4)에서 에틸클로로포메이트의 처리는 테트라하이드로퓨란을 용매로 사용하여 빙냉하에서 이루어지는 것이 바람직하다.The treatment of ethylchloroformate in step 4) is preferably carried out under ice cooling using tetrahydrofuran as a solvent.

단계 6)의 반응은 N-메탄설포닐옥시-6-트라이플루오로 벤조트라이아졸 (FMS)존재하에서 N,N-다이메틸폼아마이드 또는 테트라하이드로퓨란을 용매로 사용하여 이루어지는 것이 바람직하다.The reaction of step 6) is preferably carried out using N, N-dimethylformamide or tetrahydrofuran as solvent in the presence of N-methanesulfonyloxy-6-trifluoro benzotriazole (FMS).

단계 7)에서는 알콜 수용액, 예를 들어 메탄올, 에탄올 또는 이소프로판올을 용매로 사용하는 것이 바람직하다.In step 7) preference is given to using an aqueous alcohol solution, for example methanol, ethanol or isopropanol as solvent.

화학식 1에서 R이 C1-5 알킬아미노메틸, 아릴아미노메틸 또는 헤테로아릴아미노메틸인 경우의 화합물들은 하기 반응식 2로 표시되는 합성 경로에 따라 제조될 수 있다. Compounds when R in Formula 1 is C 1-5 alkylaminomethyl, arylaminomethyl or heteroarylaminomethyl can be prepared according to the synthetic route represented by the following Scheme 2 .

Figure 112004047982053-pat00006
Figure 112004047982053-pat00006

상기 식에서, R은 C1-5 알킬아미노메틸, 아릴아미노메틸 또는 헤테로아릴아미노메틸이며, R'는 아릴이다.Wherein R is C 1-5 alkylaminomethyl, arylaminomethyl or heteroarylaminomethyl, and R 'is aryl.

상기 반응식 2는 다음과 같은 단계를 포함한다: Scheme 2 includes the following steps:

1) (S)-7-(4-다이메틸아미노-페닐)-8-하이드록시-옥타-2,4-디에노산 1-에틸 에스터 (화합물 7)를 다이메틸설폭사이드의 존재하에 옥사릴클로라이드와 반응시켜 (S)-7-(4-다이메틸아미노-페닐)-8-옥소-옥타-2,4-디에노산 1-에틸 에스터 (화합물 9)를 얻는 단계;1) (S) -7- (4-dimethylamino-phenyl) -8-hydroxy-octa-2,4-dienoic acid 1-ethyl ester (Compound 7) in the presence of dimethylsulfoxide Reacting with (S) -7- (4-dimethylamino-phenyl) -8-oxo-octa-2,4-dienoic acid 1-ethyl ester (Compound 9);

2) 화합물 9를 빙초산과 소듐 트라이아세톡시보로하이드라이드 (NaBH(OAc)3) 존재하에서 아민 화합물과 반응시켜 (S)-7-(4-다이메틸아미노-페닐)-8-아릴아미노-옥타-2,4-디에노산 1-에틸 에스터 (화합물 10)를 제조하는 단계;2) Compound 9 was reacted with an amine compound in the presence of glacial acetic acid and sodium triacetoxyborohydride (NaBH (OAc) 3 ) to give (S) -7- (4-dimethylamino-phenyl) -8-arylamino- Preparing octa-2,4-dienoic acid 1-ethyl ester (Compound 10);

3) 화합물 10을 무기염기로 처리하여 유기산 (화합물 11)으로 전환시키는 단계; 3) treating compound 10 with an inorganic base to convert it to an organic acid (compound 11);

4) 화합물 11을 t-뷰틸다이메틸실릴옥시아민 (NH2OTBS)과 아실화 반응시킨 후 수용성 무기산으로 t-뷰틸다이메틸실릴기를 제거함으로써 화학식 1b의 화합물을 제조하는 단계; 및4) preparing a compound of formula 1b by acylating compound 11 with t-butyldimethylsilyloxyamine (NH 2 OTBS) and then removing the t-butyldimethylsilyl group with a water-soluble inorganic acid; And

5) 화학식 2의 화합물을 수소압력하에서 팔라듐/카본과 반응시켜 화학식 1a의 화합물을 제조하는 단계.5) preparing a compound of formula 1a by reacting a compound of formula 2 with palladium / carbon under hydrogen pressure.

상기에서, 단계 1) 및 2)의 반응은 다이클로로메탄을 용매로 사용하여 이루어지는 것이 바람직하다.In the above, the reaction of steps 1) and 2) is preferably carried out using dichloromethane as a solvent.

단계 3)의 반응은 알콜 수용액을 용매로 사용하여 테트라하이드로퓨란 존재하에서 이루어지며, 무기염기로는 수산화리튬 또는 수산화나트륨이 사용된다.The reaction of step 3) is carried out in the presence of tetrahydrofuran using an aqueous alcohol solution as a solvent, and lithium or sodium hydroxide is used as the inorganic base.

단계 4)의 반응은 N-메탄설포닐옥시-6-트라이플루오로 벤조트라이아졸 (FMS)존재하에서 N,N-다이메틸폼아마이드 또는 테트라하이드로퓨란을 용매로 사용하여 이루어지며, 수용성 무기산으로는 염산 또는 황산을 사용하는 것이 바람직하다.The reaction of step 4) is carried out using N, N-dimethylformamide or tetrahydrofuran as solvent in the presence of N-methanesulfonyloxy-6-trifluoro benzotriazole (FMS). Preference is given to using hydrochloric acid or sulfuric acid.

단계 5)의 반응은 알콜 수용액, 바람직하게는 메탄올, 에탄올 또는 이소프로판올을 용매로 사용한다.The reaction of step 5) uses an aqueous alcohol solution, preferably methanol, ethanol or isopropanol as solvent.

화학식 1에서 R이 C1-5 알킬아마이드기, 아릴아마이드기 또는 헤테로아릴아마이드기인 경우의 화합물들은 하기 반응식 3으로 표시되는 합성 경로에 따라 제조될 수 있다. When R of compound are C 1-5 alkyl amide group, aryl amide group or a heteroaryl group amide group in formula (1) may be prepared according to the synthesis route represented by Scheme 3.

Figure 112004047982053-pat00007
Figure 112004047982053-pat00007

상기 식에서, R은 C1-5 알킬아마이드기, 아릴아마이드기 또는 헤테로아릴아마이드기이며, R'는 C1-5 알킬, 아릴 또는 헤테로아릴이다.Wherein R is a C 1-5 alkylamide group, arylamide group or heteroarylamide group, and R 'is C 1-5 alkyl, aryl or heteroaryl.

상기 반응식 3은 다음과 같은 단계를 포함한다: Scheme 3 includes the following steps:

1) (S)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-에틸 에스터 (화합물 6)를 아민 화합물과 반응시켜 (S)-7-(4-다이메틸아미노-페닐)-8-아릴카바모일-헵타-2,4-디엔디오산 1-에틸 에스터 (화합물 12)를 제조하는 단계;1) (S) -7- (4-dimethylamino-phenyl) -octa-2,4-dienoic acid 1-ethyl ester (Compound 6) is reacted with an amine compound to give (S) -7- (4-di Preparing methylamino-phenyl) -8-arylcarbamoyl-hepta-2,4-dienoic acid 1-ethyl ester (Compound 12);

2) 화합물 12를 염산으로 처리하여 (S)-7-(4-다이메틸아미노-페닐)-7-아릴카바모일-헵타-2,4-디엔디오산 (화합물 13)로 전환시키는 단계;2) treating Compound 12 with hydrochloric acid to convert (S) -7- (4-dimethylamino-phenyl) -7-arylcarbamoyl-hepta-2,4-dienoic acid (Compound 13);

3) 화합물 13을 t-뷰틸다이메틸실릴옥시아민 (NH2OTBS)과 아실화 반응시킨 후 수용성 무기산으로 t-뷰틸다이메틸실릴기를 제거함으로써 화학식 1b의 화합물을 제조하는 단계; 및,3) preparing a compound of formula 1b by acylating compound 13 with t-butyldimethylsilyloxyamine (NH 2 OTBS) and then removing the t-butyldimethylsilyl group with a water-soluble inorganic acid; And,

4) 화학식 1b의 화합물을 수소압력하에서 팔라듐/카본과 반응시켜 화학식 1a의 화합물을 제조하는 단계.4) preparing a compound of formula 1a by reacting the compound of formula 1b with palladium / carbon under hydrogen pressure.

상기에서, 단계 1) 및 3)의 반응은 N-메탄설포닐옥시-6-트라이플루오로 벤조트라이아졸 (FMS) 존재하에서 N,N-다이메틸폼아마이드 또는 테트라하이드로퓨란을 용매로 사용하여 이루어지는 것이 바람직하다.In the above, the reactions of steps 1) and 3) consist of using N, N-dimethylformamide or tetrahydrofuran as solvent in the presence of N-methanesulfonyloxy-6-trifluoro benzotriazole (FMS). It is preferable.

단계 1)에서 아민화합물로는 C1-5 알킬아민, 아릴아민 또는 헤테로아릴아민이 바람직하다.The amine compound in step 1) is preferably C 1-5 alkylamine, arylamine or heteroarylamine.

단계 2)의 반응은 아세톤을 용매로 사용하여 이루어지는 것이 바람직하다.The reaction of step 2) is preferably carried out using acetone as a solvent.

단계 3)에서, 수용성 무기산으로는 염산 또는 황산을 사용하는 것이 바람직하다.In step 3), it is preferable to use hydrochloric acid or sulfuric acid as the water-soluble inorganic acid.

단계 4)에서는 알콜 수용액, 바람직하게는 메탄올, 에탄올 또는 이소프로판 올을 용매로 사용한다.In step 4) an aqueous alcohol solution, preferably methanol, ethanol or isopropanol is used as the solvent.

다른 방법으로, R이 C1-5 알킬아마이드기, 아릴아마이드기 또는 헤테로아릴아마이드기인 화학식 1a의 화합물은 하기 반응식 4로 표시되는 경로에 따라 제조할 수도 있다.Alternatively, the compound of Formula 1a , wherein R is a C 1-5 alkylamide group, arylamide group or heteroarylamide group, may be prepared according to the route represented by Scheme 4 below.

Figure 112004047982053-pat00008
Figure 112004047982053-pat00008

상기 식에서, R은 C1-5 알킬아마이드기, 아릴아마이드기 또는 헤테로아릴아마이드기이며, R'는 C1-5 알킬, 아릴 또는 헤테로아릴이다.Wherein R is a C 1-5 alkylamide group, arylamide group or heteroarylamide group, and R 'is C 1-5 alkyl, aryl or heteroaryl.

상기 반응식 4는 다음과 같은 단계를 포함한다: Scheme 4 includes the following steps:

1)화합물 12를 수소압력하에서 팔라듐/카본과 반응시켜 (S)-7-(4-다이메틸아미노-페닐)-7-아릴카바모일-헵타노산 에틸에스터 (화합물 14)로 전환시키는 단계;1) reacting compound 12 with palladium / carbon under hydrogen pressure to convert to (S) -7- (4-dimethylamino-phenyl) -7-arylcarbamoyl-heptanoic acid ethyl ester (Compound 14);

2) 화합물 14를 무기염기로 처리하여 유기산 (화합물 15)으로 전환시키는 단계; 및2) treating Compound 14 with an inorganic base to convert it to an organic acid (Compound 15); And

3) 화합물 15를 t-뷰틸다이메틸실릴옥시아민 (NH2OTBS)과 아실화 반응시킨 후 수용성 무기산으로 t-뷰틸다이메틸실릴기를 제거함으로써 화학식 1a의 화합물을 제조하는 단계.3) preparing a compound of Formula 1a by acylating compound 15 with t-butyldimethylsilyloxyamine (NH 2 OTBS) and then removing the t-butyldimethylsilyl group with a water-soluble inorganic acid.

상기에서, 단계 1)에서는 알콜 수용액, 바람직하게는 메탄올, 에탄올 또는 이소프로판올을 용매로 사용한다.In the above, step 1) uses an aqueous alcohol solution, preferably methanol, ethanol or isopropanol as a solvent.

단계 2)에서는 무기 염기로서 수산화나트륨(NaOH) 또는 수산화리튬을 사용하는 것이 바람직하다.In step 2), it is preferable to use sodium hydroxide (NaOH) or lithium hydroxide as the inorganic base.

단계 3)의 반응은 N-메탄설포닐옥시-6-트라이플루오로 벤조트라이아졸 (FMS) 존재하에서 N,N-다이메틸폼아마이드 또는 테트라하이드로퓨란을 용매로 사용하여 이루어지며, 수용성 무기산으로서 염산 또는 황산을 사용하는 것이 바람직하다.The reaction of step 3) is carried out using N, N-dimethylformamide or tetrahydrofuran as solvent in the presence of N-methanesulfonyloxy-6-trifluoro benzotriazole (FMS) and hydrochloric acid as a water-soluble inorganic acid. Or sulfuric acid is preferred.

또 다른 방법으로, R이 C1-5 알킬아마이드기, 아릴아마이드기 또는 헤테로아릴아마이드기인 화학식 1a의 화합물은 하기 반응식 5로 표시되는 경로에 따라 제조할 수도 있다.In another method, the compound of Formula 1a , wherein R is a C 1-5 alkylamide group, arylamide group, or heteroarylamide group, may be prepared according to the route represented by Scheme 5 below.

Figure 112004047982053-pat00009
Figure 112004047982053-pat00009

상기 식에서, R은 C1-5 알킬아마이드기, 아릴아마이드기 또는 헤테로아릴아마 이드기이며, R'는 C1-5 알킬, 아릴 또는 헤테로아릴이다.Wherein R is a C 1-5 alkylamide group, arylamide group or heteroarylamide group, and R 'is C 1-5 alkyl, aryl or heteroaryl.

상기 반응식 5는 다음과 같은 단계를 포함한다: Scheme 5 includes the following steps:

1)화합물 6을 수소압력하에서 팔라듐/카본과 반응시켜 (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-에틸 에스터 (화합물 16)로 전환시키는 단계;1) reacting compound 6 with palladium / carbon under hydrogen pressure to convert to (S) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-ethyl ester (Compound 16);

2) 화합물 16을 아민 화합물과 반응시켜 (S)-7-(4-다이메틸아미노-페닐)-7-아릴카바모일-헵타노산 에틸 에스터 (화합물 14)를 제조하는 단계;2) reacting compound 16 with an amine compound to produce (S) -7- (4-dimethylamino-phenyl) -7-arylcarbamoyl-heptanoic acid ethyl ester (Compound 14);

3) 화합물 14를 무기염기로 처리하여 유기산 (화합물 15)으로 전환시키는 단계; 및3) treating Compound 14 with an inorganic base to convert it to an organic acid (Compound 15); And

4) 화합물 15를 t-뷰틸다이메틸실릴옥시아민 (NH2OTBS)과 아실화 반응시킨 후 수용성 무기산으로 t-뷰틸다이메틸실릴기를 제거함으로써 화학식 1a의 화합물을 제조하는 단계.4) preparing a compound of Formula 1a by acylating a compound 15 with t-butyldimethylsilyloxyamine (NH 2 OTBS) and then removing the t-butyldimethylsilyl group with a water-soluble inorganic acid.

상기에서, 단계 1)의 반응은 알콜 수용액, 바람직하게는 메탄올, 에탄올 또는 이소프로판올을 용매로 사용하여 이루어지며, 아민화합물로는 C1-5 알킬아민, 아릴아민 또는 헤테로아릴아민을 사용하는 것이 바람직하다.In the above, the reaction of step 1) is carried out using an aqueous alcohol solution, preferably methanol, ethanol or isopropanol as a solvent, and it is preferable to use C 1-5 alkylamine, arylamine or heteroarylamine as the amine compound. Do.

단계 2)에서는 N,N-다이메틸폼아마이드를 용매로 사용한다.In step 2), N, N-dimethylformamide is used as the solvent.

단계 3)에서는 무기 염기로서 수산화나트륨(NaOH) 또는 수산화리튬을 사용하는 것이 바람직하다.In step 3), it is preferable to use sodium hydroxide (NaOH) or lithium hydroxide as the inorganic base.

단계 4)에서는 N-메탄설포닐옥시-6-트라이플루오로 벤조트라이아졸 (FMS) 존재하에서 N,N-다이메틸폼아마이드 또는 테트라하이드로퓨란을 용매로 사용하여 이 루어지며, 수용성 무기산으로는 염산 또는 황산을 사용하는 것이 바람직하다.In step 4), N, N-dimethylformamide or tetrahydrofuran is used as a solvent in the presence of N-methanesulfonyloxy-6-trifluoro benzotriazole (FMS). Or sulfuric acid is preferred.

이와 같이 제조된, 본 발명의 화학식 1의 N,N-다이메틸아미노페닐 옥타노산 하이드록시아마이드 유도체 또는 이의 약학적으로 허용가능한 염은 히스톤 디아세틸라제의 효소활성을 효과적으로 억제하여 종양세포의 말기 분화를 선택적으로 유도함으로써 이들 종양세포의 증식을 억제한다.The thus produced, N, N- dimethylamino-phenyl octanoic acid hydroxy amide derivative or a pharmaceutically acceptable salt thereof of the general formula (I) of the present invention is to effectively inhibit the enzyme activity of histone deacetylase end-stage differentiation of tumor cells It selectively inhibits the proliferation of these tumor cells.

따라서, 본 발명에서는 활성성분으로 화학식 1의 화합물 또는 이의 약학적으로 허용가능한 염 및 약학적으로 허용가능한 담체를 포함하는 항암제용 약학 조성물을 제공한다. 본 발명의 약학 조성물에는 활성성분인 화학식 1의 화합물이 조성물의 총중량을 기준으로 하여 0.1 내지 75 중량％, 바람직하게는 1 내지 50 중량％의 양으로 함유될 수 있다.Accordingly, the present invention provides a pharmaceutical composition for an anticancer agent comprising the compound of formula 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier 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 카르복시메틸셀룰로즈 및/또는 폴리비닐피롤리딘과 같은 결합제를 함유할 수 있으며, 경우에 따라 전분, 한천, 알긴산 또는 그의 나트륨염과 같은 붕해제 또는 비등 혼합물 및/또는 흡수제, 착색제, 향미제, 및 감미제를 함유할 수 있다. 또한, 비경구 투여용 제형의 대표적인 것은 주사용 제형으로 등장성 수용액 또는 현탁액이 바람직하다.The pharmaceutical compositions of the invention can be formulated in a variety of oral or parenteral dosage forms. Formulations for oral administration include, for example, tablets, pills, hard and soft capsules, solutions, suspensions, emulsifiers, syrups, and granules. These formulations may contain diluents (e.g., lactose, dextrose, water, etc.) in addition to the active ingredients. Cross, mannitol, sorbitol, cellulose and / or glycine), lubricants such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethyleneglycols. 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 formulations for parenteral administration are injectable formulations, preferably aqueous isotonic solutions or suspensions.

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

유효성분으로서 화학식 1의 화합물은 사람을 포함하는 포유동물에 대해 하루에 2.5 내지 100 ㎎/㎏ 체중, 바람직하게는 5 내지 60 ㎎/㎏ 체중의 양으로 1일 1회 또는 분할하여 경구 또는 비경구적 경로를 통해 투여할 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, per day for mammals including humans. Administration can be by route.

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

제조예 1: (S)-2-(4-다이메틸아미노-페닐)-4-옥소-부티르산 메틸 에스터 (4) Preparation Example 1 (S) -2- (4-dimethylamino-phenyl) -4-oxo-butyric acid methyl ester (4)

100 ml 플라스크에 4-옥소부테노산 메틸에스터 (4.0 g, 35 mmol), 반응 촉매로서 (2R,5R)-5-벤질-2-t-부틸-3-메틸이미다졸리딘-4-온(861 mg, 3.5 mmol), 클로로폼 (35 ml), HCl (1,4-디옥산중의 4N 용액, 0.875 ml, 3.5 mmol)을 넣고 교반하면서 N,N-다이메틸아닐린 (5.3 ml, 42 mmol)을 서서히 적가하였다. 반응물을 상온에서 12시간 동안 교반시킨 후 포화 중조로 반응을 종결하였다. 반응생성물을 다 이클로로메탄으로 추출하고, 소금물로 세척하고, 무수황산나트륨으로 건조한 다음 여과 및 감압 농축한 후 실리카겔 컬럼 크로마토그래피법으로 정제하여 노란색 고체의 표제 화합물 (70％ 수율, 94％ 거울상선택성)을 얻었다 .In a 100 ml flask, 4-oxobutenoic acid methyl ester (4.0 g, 35 mmol), as a reaction catalyst, (2R, 5R) -5-benzyl-2-t-butyl-3-methylimidazolidin-4-one ( 861 mg, 3.5 mmol), chloroform (35 ml), HCl (4N solution in 1,4-dioxane, 0.875 ml, 3.5 mmol) were added and stirred with N, N-dimethylaniline (5.3 ml, 42 mmol) Was slowly added dropwise. The reaction was stirred at room temperature for 12 hours and then terminated with saturated sodium bicarbonate. The reaction product was extracted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure and purified by silica gel column chromatography to give the title compound as a yellow solid (70% yield, 94% enantioselectivity). ).

1H NMR (300 MHz, CDCl3) : δ 9.77 (s, 1H), 7.14 (d, J = 7.1 Hz, 2H), 6.68 (d, J = 7.6 Hz, 2H), 4.03 (dd, J = 4.7, 9.9 Hz, 1H), 3.66 (s, 3H), 3.35 (dd, J = 9.9, 18.7 Hz, 1H), 2.93 (s, 6H), 2.77 (dd, J = 4.8, 18.3 Hz, 1H) 1 H NMR (300 MHz, CDCl 3 ): δ 9.77 (s, 1H), 7.14 (d, J = 7.1 Hz, 2H), 6.68 (d, J = 7.6 Hz, 2H), 4.03 (dd, J = 4.7 , 9.9 Hz, 1H), 3.66 (s, 3H), 3.35 (dd, J = 9.9, 18.7 Hz, 1H), 2.93 (s, 6H), 2.77 (dd, J = 4.8, 18.3 Hz, 1H)

[α]D = +152.3 (c=1, CHCl3)[α] D = +152.3 (c = 1, CHCl 3 )

제조예 2: (S)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-에틸 에스터 8-메틸 에스터Preparation Example 2 (S) -7- (4-dimethylamino-phenyl) -octa-2,4-dienodioic acid 1-ethyl ester 8-methyl ester (5)(5)

제조예 1에서 얻은 (S)-2-(4-다이메틸아미노-페닐)-4-옥소-부티르산 메틸 에스터 (4) (1.18 g, 5.0 mmol)을 테트라하이드로퓨란 (25 ml)에 녹이고, 4Å 분자체 (7.5 g), 4-(디에톡시-포스포릴)-부트-2-에노산 에틸 에스터 (1.63 g, 6.5 mmol), 수산화리튬 (270 mg, 6.5 mmol)을 가하고 6시간 동안 교반 환류시켰다. 반응이 종결되면 반응생성물을 실온으로 냉각한 후 여과하여 불용성 고체를 제거하고, 여액은 농축시킨 후 실리카겔 컬럼 크로마토그래피법로 정제하여 노란색의 표제 화합물 (72％)을 얻었다.(S) -2- (4-dimethylamino-phenyl) -4-oxo-butyric acid methyl ester (4) (1.18 g, 5.0 mmol) obtained in Preparation Example 1 was dissolved in tetrahydrofuran (25 ml), and Molecular sieve (7.5 g), 4- (diethoxy-phosphoryl) -but-2-enoic acid ethyl ester (1.63 g, 6.5 mmol) and lithium hydroxide (270 mg, 6.5 mmol) were added and stirred at reflux for 6 hours. . After completion of the reaction, the reaction product was cooled to room temperature, filtered to remove insoluble solids, and the filtrate was concentrated and purified by silica gel column chromatography to obtain the title compound (72%) as yellow.

1H NMR (200 MHz, CDCl3) : δ 7.15-7.25 (m, 1H), 7.13 (d, J = 8.6 Hz, 2H), 6.67 (d, J = 8.6 Hz, 2H), 5.82-6.27 (m, 2H), 5.76 (d, J = 15.6 Hz, 1H), 4.17 (q, J = 7.0 Hz, 2H), 3.63 (s, 3H), 3.51-3.62(m, 1H), 2.93 (s, 6H), 2.55-2.91 (m, 2H), 1.27(t, J = 7.0 Hz, 3H) 1 H NMR (200 MHz, CDCl 3 ): δ 7.15-7.25 (m, 1H), 7.13 (d, J = 8.6 Hz, 2H), 6.67 (d, J = 8.6 Hz, 2H), 5.82-6.27 (m , 2H), 5.76 (d, J = 15.6 Hz, 1H), 4.17 (q, J = 7.0 Hz, 2H), 3.63 (s, 3H), 3.51-3.62 (m, 1H), 2.93 (s, 6H) , 2.55-2.91 (m, 2H), 1.27 (t, J = 7.0 Hz, 3H)

제조예 3: (S)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-에틸 에스터 (6)Preparation Example 3: (S) -7- (4-dimethylamino-phenyl) -octa-2,4-dienodioic acid 1-ethyl ester (6)

제조예 2에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-에틸 에스터 8-메틸 에스터 (5) (1.21 g, 4.0 mmol)을 아세톤에 녹이고, 5 N 염산 용액 (4.0 ml)을 가한 후 15 시간 동안 교반 환류시켰다. 반응이 종결되면 반응생성물을 실온으로 냉각하고 감압하에 용매를 제거하고, 2N 수산화나트륨으로 중화한 후(pH=4.5), 에틸아세에이트로 추출하고, 무수황산나트륨으로의 건조, 여과 및 감압농축한 후 실리카겔 컬럼 크로마토그래피법으로 정제하여 표제 화합물 (60％)을 얻었다. (S) -7- (4-dimethylamino-phenyl) -octa-2,4-dienoic acid 1-ethyl ester 8-methyl ester (5) (1.21 g, 4.0 mmol) obtained in Production Example 2 was added to acetone. It was dissolved, 5 N hydrochloric acid solution (4.0 ml) was added, followed by stirring under reflux for 15 hours. At the end of the reaction, the reaction product was cooled to room temperature, the solvent was removed under reduced pressure, neutralized with 2N sodium hydroxide (pH = 4.5), extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel column chromatography gave the title compound (60%).

1H NMR (200 MHz, CDCl3) : δ 7.10-7.28 (m, 1H), 7.13 (d, J = 8.2 Hz, 2H), 6.69 (d, J = 8.2 Hz, 2H), 5.82-6.26 (m, 2H), 5.78 (d, J = 22.8 Hz, 1H), 4.17 (q, J = 7.2 Hz, 2H), 3.51-3.72(m, 1H), 2.92 (s, 6H), 2.52-3.03 (m, 2H), 1.27(t, J = 7.2 Hz, 3H) 1 H NMR (200 MHz, CDCl 3 ): δ 7.10-7.28 (m, 1H), 7.13 (d, J = 8.2 Hz, 2H), 6.69 (d, J = 8.2 Hz, 2H), 5.82-6.26 (m , 2H), 5.78 (d, J = 22.8 Hz, 1H), 4.17 (q, J = 7.2 Hz, 2H), 3.51-3.72 (m, 1H), 2.92 (s, 6H), 2.52-3.03 (m, 2H), 1.27 (t, J = 7.2 Hz, 3H)

제조예 4: (S)-7-(4-다이메틸아미노-페닐)-8-하이드록시-옥타-2,4-디에노 산 1-에틸 에스터 (7)Preparation Example 4 (S) -7- (4-dimethylamino-phenyl) -8-hydroxy-octa-2,4-dienoic acid 1-ethyl ester (7)

제조예 3에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-에틸 에스터 (6) (365 mg, 1.15 mmol)를 테트라하이드로퓨란 (15 ml)에 녹이고, 0℃에서 트라이에틸아민 (0.32 ml, 2.30 mmol)과 에틸클로로포메이트 (0.17 ml, 1.85 mmol)을 가한 후 1시간 동안 교반하였다. 이 반응물에 소듐보로하이드라이드(261 mg, 6.90 mmol)을 가하고 물(6 ml)를 서서히 가한 후 상온에서 2시간 동안 교반하였다. 반응이 종결되면 1N 염산용액으로 중화한 후(pH=4.5), 에틸아세에이트로 추출하고, 소금물로 세척하고, 무수황산나트륨으로 건조하고, 감압농축한 후 실리카겔 컬럼 크로마토그래피법으로 정제하여 표제 화합물 (92％)을 얻었다.(S) -7- (4-dimethylamino-phenyl) -octa-2,4-dienoic acid 1-ethyl ester (6) (365 mg, 1.15 mmol) obtained in Production Example 3 was diluted with tetrahydrofuran (15 ml). ), Triethylamine (0.32 ml, 2.30 mmol) and ethylchloroformate (0.17 ml, 1.85 mmol) were added at 0 ° C. and stirred for 1 hour. Sodium borohydride (261 mg, 6.90 mmol) was added to the reaction, and water (6 ml) was added slowly, followed by stirring at room temperature for 2 hours. After completion of the reaction, the mixture was neutralized with 1N hydrochloric acid solution (pH = 4.5), extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography to obtain the title compound ( 92%) was obtained.

1H NMR (200 MHz, CDCl3) : δ 7.10-7.26 (m, 1H), 7.05 (d, J = 8.4 Hz, 2H), 6.70 (d, J = 8.4 Hz, 2H), 5.87-6.23 (m, 2H), 5.78 (d, J = 15.4 Hz, 1H), 4.17 (q, J = 6.8 Hz, 2H), 3.69 (d, J = 7.0 Hz, 2H), 2.93 (s, 6H), 2.37-2.88 (m, 3H), 1.27(t, J = 6.8 Hz, 3H) 1 H NMR (200 MHz, CDCl 3 ): δ 7.10-7.26 (m, 1H), 7.05 (d, J = 8.4 Hz, 2H), 6.70 (d, J = 8.4 Hz, 2H), 5.87-6.23 (m , 2H), 5.78 (d, J = 15.4 Hz, 1H), 4.17 (q, J = 6.8 Hz, 2H), 3.69 (d, J = 7.0 Hz, 2H), 2.93 (s, 6H), 2.37-2.88 (m, 3H), 1.27 (t, J = 6.8 Hz, 3H)

제조예 5: (S)-7-(4-다이메틸아미노-페닐)-8-옥소-옥타-2,4-디에노산 1-에틸 에스터 (9)Preparation Example 5 (S) -7- (4-Dimethylamino-phenyl) -8-oxo-octa-2,4-dienoic acid 1-ethyl ester (9)

다이클로로메탄 (1.0 ml)에 옥사릴클로라이드 (0.035 ml, 0.39 mmol)을 가하고, -78℃에서 다이메틸설폭사이드 (0.056 ml, 0.79 mmol)을 가한 후 10분 동안 교반하여 얻은 용액에 다이클로로메탄 (1.5 ml)중의 제조예 4에서 얻은 (S)-7-(4-다 이메틸아미노-페닐)-8-하이드록시-옥타-2,4-디에노산 1-에틸 에스터 (7) (100 mg, 0.33 mmol)의 용액을 서서히 첨가하여 30 분 동안 교반한 다음, 트라이에틸아민 (0.20 ml, 1.45 mmol)을 가한 후 반응 온도를 0℃로 올려 30 분 동안 교반하였다. 포화 염화암모니아 용액으로 반응을 종결시킨 후, 반응생성물을 에틸아세테이트로 추출하고, 소금물로 세척하고, 무수황산나트륨으로 건조, 여과 및 감압농축한 후 실리카겔 컬럼 크로마토그래피법으로 정제하여 표제 화합물 (70％)을 얻었다.Oxalylchloride in dichloromethane (1.0 ml) (0.035 ml, 0.39 mmol) was added and dimethylsulfoxide (0.056 ml, 0.79 mmol) was added at -78 ° C and stirred for 10 minutes to a solution obtained in Preparation Example 4 in dichloromethane (1.5 ml) ( S) -7- (4-Dimethylamino-phenyl) -8-hydroxy-octa-2,4-dienoic acid 1-ethyl ester (7) (100 mg, 0.33 mmol) was added slowly to 30 After stirring for 3 minutes, triethylamine (0.20 ml, 1.45 mmol) was added and the reaction temperature was raised to 0 ° C. and stirred for 30 minutes. After completion of the reaction with saturated ammonia chloride solution, the reaction product was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and purified by silica gel column chromatography to obtain the title compound (70%). Got.

1H NMR (200 MHz, CDCl3) : δ 9.63 (d, J = 1.2 Hz, 1H), 7.06-7.26 (m, 1H), 7.00 (d, J = 9.0 Hz, 2H), 6.71 (d, J = 9.0 Hz, 2H), 5.89-6.23 (m, 2H), 5.78 (d, J = 15.4 Hz, 1H), 4.18 (q, J = 7.4 Hz, 2H), 3.53 (t, J = 6.4 Hz, 1H), 2.95 (s, 6H), 2.47-2.84 (m, 2H), 1.27(t, J = 7.4 Hz, 3H) 1 H NMR (200 MHz, CDCl 3 ): δ 9.63 (d, J = 1.2 Hz, 1H), 7.06-7.26 (m, 1H), 7.00 (d, J = 9.0 Hz, 2H), 6.71 (d, J = 9.0 Hz, 2H), 5.89-6.23 (m, 2H), 5.78 (d, J = 15.4 Hz, 1H), 4.18 (q, J = 7.4 Hz, 2H), 3.53 (t, J = 6.4 Hz, 1H ), 2.95 (s, 6H), 2.47-2.84 (m, 2H), 1.27 (t, J = 7.4 Hz, 3H)

제조예 6: (S)-7-(4-다이메틸아미노-페닐)-옥탄디오산 8-에틸 에스터 (16)Preparation Example 6 (S) -7- (4-dimethylamino-phenyl) -octanedioic acid 8-ethyl ester (16)

제조예 3에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-에틸 에스터 (6) (1.0 g)을 메탄올 (1 ml)에 녹이고, 10％ Pd/C (100 mg)을 가한 후, 반응물을 상온에서 수소 압력하에 1 시간 동안 교반하였다. 반응이 종결되면 불용성 고체를 여과 및 제거하고, 여액은 감압농축한 후 실리카겔 컬럼 크로마토그래피법으로 정제하여 표제화합물 (90％)을 얻었다.(S) -7- (4-dimethylamino-phenyl) -octa-2,4-dienoic acid 1-ethyl ester (6) (1.0 g) obtained in Preparation Example 3 was dissolved in methanol (1 ml), and After addition of% Pd / C (100 mg), the reaction was stirred at room temperature under hydrogen pressure for 1 hour. After the reaction was completed, the insoluble solid was filtered and removed, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the title compound (90%).

1H NMR (200 MHz, CDCl3) : δ 7.13 (d, J = 8.2 Hz, 2H), 6.69 (d, J = 8.2 Hz, 2H), 4.19 (q, J = 7.2 Hz, 2H), 3.54-3.72(m, 1H), 2.92 (s, 6H), 1.32-2.22 (m, 10H), 1.26(t, J = 7.2 Hz, 3H) 1 H NMR (200 MHz, CDCl 3 ): δ 7.13 (d, J = 8.2 Hz, 2H), 6.69 (d, J = 8.2 Hz, 2H), 4.19 (q, J = 7.2 Hz, 2H), 3.54- 3.72 (m, 1H), 2.92 (s, 6H), 1.32-2.22 (m, 10H), 1.26 (t, J = 7.2 Hz, 3H)

실시예 1: (S)-7-(4-다이메틸아미노-페닐)-8-하이드록시-옥타-2,4-디에노산 하이드록시아마이드Example 1: (S) -7- (4-dimethylamino-phenyl) -8-hydroxy-octa-2,4-dienoic acid hydroxyamide

단계 1: (S)-7-(4-다이메틸아미노-페닐)-8-하이드록시-옥타-2,4-디에노산Step 1: (S) -7- (4-dimethylamino-phenyl) -8-hydroxy-octa-2,4-dienoic acid

제조예 4에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-8-하이드록시-옥타-2,4-디에노산 1-에틸 에스터 (7) (1.10 g, 4.0 mmol)를 아세톤에 녹이고, 5 N 염산 용액 (4.0 ml)을 가한 후 48 시간 동안 교반 환류시켰다. 반응이 종결되면, 반응생성물을 실온으로 냉각하고 감압하에 용매를 제거하고, 2N 수산화나트륨으로 중화한 후(pH=4.5), 에틸아세에이트로 추출하고, 무수황산나트륨으로 건조, 여과 및 감압 농축한 후 실리카겔 컬럼 크로마토그래피법으로 정제하여 표제 화합물 (66％)을 얻었다.(S) -7- (4-dimethylamino-phenyl) -8-hydroxy-octa-2,4-dienoic acid 1-ethyl ester (7) (1.10 g, 4.0 mmol) obtained in Production Example 4 was prepared with acetone. It was dissolved in and 5N hydrochloric acid solution (4.0 ml) was added, followed by stirring under reflux for 48 hours. After the reaction was completed, the reaction product was cooled to room temperature, the solvent was removed under reduced pressure, neutralized with 2N sodium hydroxide (pH = 4.5), extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel column chromatography gave the title compound (66%).

1H NMR (200 MHz, CDCl3) : δ 7.16-7.29 (m, 1H), 6.72 (d, J = 9.0 Hz, 2H), 6.65 (s, 1H), 6.72 (d, J = 9.0 Hz, 2H), 5.97-6.215 (m, 2H), 5.72 (d, J = 15.0 Hz, 1H), 3.62 (d, J = 6.6 Hz, 2H), 2.92 (s, 6H), 2.40-2.85 (m, 3H) 1 H NMR (200 MHz, CDCl 3 ): δ 7.16-7.29 (m, 1H), 6.72 (d, J = 9.0 Hz, 2H), 6.65 (s, 1H), 6.72 (d, J = 9.0 Hz, 2H ), 5.97-6.215 (m, 2H), 5.72 (d, J = 15.0 Hz, 1H), 3.62 (d, J = 6.6 Hz, 2H), 2.92 (s, 6H), 2.40-2.85 (m, 3H)

단계 2: (S)-7-(4-다이메틸아미노-페닐)-8-하이드록시-옥타-2,4-디에노산 하이드록시아마이드Step 2: (S) -7- (4-dimethylamino-phenyl) -8-hydroxy-octa-2,4-dienoic acid hydroxyamide

상기 단계 1에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-8-하이드록시-옥타- 2,4-디에노산 (35 mg, 0.11 mmol)을 다이메틸폼아마이드 (2 ml)에 녹이고 0℃에서 트라이에틸아민 (0.023 ml, 0.17 mmol), N-메탄설포닐옥시-6-트라이플루오로 벤조트라이아졸 (37 mg, 0.13 mmol)를 가한 후 30분 동안 교반하였다. 반응물에 t-뷰틸다이메틸실릴옥시아민 (19 mg, 0.13 mmol)을 가하고 실온에서 2 시간 교반한 후 물을 가해 반응을 종결하였다. 반응생성물을 에틸아세테이트로 추출하고, 무수황산나트륨으로 건조, 여과 및 감압 농축한 후 다이클로로메탄 (2 ml)에 녹이고, 트라이플루오로아세트산 (0.017 ml, 0.22 mmol)으로 처리하고, 다시 상온에서 1 시간 동안 교반한 후 포화 중조로 반응을 종결하였다. 최종 생성물을 에틸아세테이트로 추출하고, 건조 (무수황산나트륨), 여과, 감압 농축한 후 실리카겔 컬럼 크로마토그래피법으로 정제하여 표제화합물 (22％)을 얻었다.(S) -7- (4-dimethylamino-phenyl) -8-hydroxy-octa-2,4-dienoic acid (35 mg, 0.11 mmol) obtained in step 1 was added to dimethylformamide (2 ml). It was dissolved in and triethylamine (0.023 ml, 0.17 mmol), N- methanesulfonyloxy-6-trifluoro benzotriazole (37 mg, 0.13 mmol) at 0 ℃ and stirred for 30 minutes. T-Butyldimethylsilyloxyamine (19 mg, 0.13 mmol) was added to the reaction, stirred at room temperature for 2 hours, and water was added to terminate the reaction. The reaction product was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, dissolved in dichloromethane (2 ml), treated with trifluoroacetic acid (0.017 ml, 0.22 mmol), and again at room temperature for 1 hour. After stirring, the reaction was terminated by saturated sodium bicarbonate. The final product was extracted with ethyl acetate, dried (sodium sulfate anhydride), filtered, concentrated under reduced pressure and purified by silica gel column chromatography to obtain the title compound (22%).

1H NMR (200 MHz, CD3OD) : δ 6.97-7.12 (m, 3H), 6.70 (d, J = 8.8 Hz, 2H), 5.87-6.21 (m, 2H), 5.78 (d, J = 15.2 Hz, 1H), 3.62 (d, J = 7.8 Hz, 2H), 2.87 (s, 6H), 2.37-2.884 (m, 3H) 1 H NMR (200 MHz, CD 3 OD): δ 6.97-7.12 (m, 3H), 6.70 (d, J = 8.8 Hz, 2H), 5.87-6.21 (m, 2H), 5.78 (d, J = 15.2 Hz, 1H), 3.62 (d, J = 7.8 Hz, 2H), 2.87 (s, 6H), 2.37-2.884 (m, 3H)

실시예 2: (S)-7-(4-다이메틸아미노-페닐)-8-하이드록시-옥타노산 하이드록시아마이드Example 2: (S) -7- (4-dimethylamino-phenyl) -8-hydroxy-octanoic acid hydroxyamide

실시예 1에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-8-하이드록시-옥타-2,4-디에노산 하이드록시아마이드 (20 mg)를 메탄올 (1 ml)에 녹이고, 10％ Pd/C (4 mg)을 가한 후, 상온에서 수소 압력하에 1 시간 동안 교반하였다. 반응이 종결되 면 불용성 고체를 여과 및 제거하고, 여액은 감압 농축한 후 실리카겔 컬럼 크로마토그래피법으로 정제하여 표제화합물 (45％)을 얻었다.(S) -7- (4-dimethylamino-phenyl) -8-hydroxy-octa-2,4-dienoic acid hydroxyamide (20 mg) obtained in Example 1 was dissolved in methanol (1 ml), 10% Pd / C (4 mg) was added, followed by stirring at room temperature under hydrogen pressure for 1 hour. When the reaction was completed, the insoluble solid was filtered and removed, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the title compound (45%).

1H NMR (300 MHz, CD3OD) : δ 7.07 (d, J = 8.7 Hz, 2H), 6.79 (d, J = 8.7 Hz, 2H), 3.62 (d, J = 7.82 Hz, 2H), 2.91 (s, 6H), 1.19-2.64 (m, 11H) 1 H NMR (300 MHz, CD 3 OD): δ 7.07 (d, J = 8.7 Hz, 2H), 6.79 (d, J = 8.7 Hz, 2H), 3.62 (d, J = 7.82 Hz, 2H), 2.91 (s, 6H), 1.19-2.64 (m, 11H)

실시예 3: (S)-7-(4-다이메틸아미노-페닐메틸)-8-페닐아미노-옥타-2,4-디에노산 하이드록시아마이드Example 3: (S) -7- (4-dimethylamino-phenylmethyl) -8-phenylamino-octa-2,4-dienoic acid hydroxyamide

단계 1: (S)-7-(4-다이메틸아미노-페닐)-8-페닐아미노-옥타-2,4-디에노산 에틸 에스터Step 1: (S) -7- (4-dimethylamino-phenyl) -8-phenylamino-octa-2,4-dienoic acid ethyl ester

제조예 5에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-8-옥소-옥타-2,4-디에노산 1-에틸 에스터 (9) (135 mg, 0.45 mmol) 및 아민화합물로서 아닐린 (0.059 ml, 0.59 mmol)을 1,2-다이클로로메탄 ( 3 ml)에 녹이고, 상온에서 빙초산 (0.043 ml, 0.68 mmol)과 소듐 트라이아세톡시보로하이드라이드 (138, 0.59 mmol)을 가한 후 1시간 30 분 동안 교반하였다. 포화중조로 반응을 종결시킨 후, 반응생성물을 다이클로로메탄으로 추출하고, 소금물로 세척하고, 무수황산나트륨으로 건조, 여과 및 감압농축한 후 실리카겔 컬럼 크로마토그래피법으로 정제하여 표제 화합물 (53％)을 얻었다.(S) -7- (4-dimethylamino-phenyl) -8-oxo-octa-2,4-dienoic acid 1-ethyl ester (9) (135 mg, 0.45 mmol) obtained in Production Example 5 and an amine compound As aniline (0.059 ml, 0.59 mmol) was dissolved in 1,2-dichloromethane (3 ml), glacial acetic acid (0.043 ml, 0.68 mmol) and sodium triacetoxyborohydride at room temperature. (138, 0.59 mmol) was added and the mixture was stirred for 1 hour 30 minutes. After completion of the reaction by saturated sodium bicarbonate, the reaction product was extracted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and purified by silica gel column chromatography to obtain the title compound (53%). Got it.

1H NMR (200 MHz, CDCl3) : δ 7.06-7.38 (m, 6H), 6.56-6.77 (m, 4H), 5.82-6.27 (m, 2H), 5.78 (d, J = 15.4 Hz, 1H), 4.20 (q, J = 7.4 Hz, 2H), 3.08-3.61 (m, 3H), 2.97 (s, 6H), 2.47-2.84 (m, 2H), 1.30(t, J = 7.4 Hz, 3H) 1 H NMR (200 MHz, CDCl 3 ): δ 7.06-7.38 (m, 6H), 6.56-6.77 (m, 4H), 5.82-6.27 (m, 2H), 5.78 (d, J = 15.4 Hz, 1H) , 4.20 (q, J = 7.4 Hz, 2H), 3.08-3.61 (m, 3H), 2.97 (s, 6H), 2.47-2.84 (m, 2H), 1.30 (t, J = 7.4 Hz, 3H)

단계 2: (S)-7-(4-다이메틸아미노-페닐)-8-페닐아미노-옥타-2,4-디에노산 Step 2: ( S) -7- (4-dimethylamino-phenyl) -8-phenylamino-octa-2,4-dienoic acid

상기 단계 1에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-8-페닐아미노-옥타-2,4-디에노산 에틸 에스터 (100 mg, 0.26 mmol)를 테트라하이드로퓨란 (2.5 ml)과 메탄올 (2.5 ml)에 녹이고, 1N 수산화나트륨 (1.3 ml)을 가한 후 상온에서 12 시간 동안 교반하였다. 반응생성물을 1N 염산 용액으로 중화한 후(pH=4.5), 에틸 아세테이트로 추출하고, 무수황산나트륨으로 건조, 여과 및 감압농축한 후 실리카겔 컬럼 크로마토그래피법으로 정제하여 표제 화합물 (55％)을 얻었다.(S) -7- (4-dimethylamino-phenyl) -8-phenylamino-octa-2,4-dienoic acid ethyl ester (100 mg, 0.26 mmol) obtained in step 1 was added with tetrahydrofuran (2.5 ml). ) And methanol (2.5 ml), 1N sodium hydroxide (1.3 ml) was added thereto, followed by stirring at room temperature for 12 hours. The reaction product was neutralized with 1N hydrochloric acid solution (pH = 4.5), extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and purified by silica gel column chromatography to obtain the title compound (55%).

1H NMR (200 MHz, CDCl3) : δ 7.94 (brs, 1H), 7.04-7.38 (m, 5H), 6.56-6.77 (m, 5H), 6.00-6.28 (m, 2H), 5.78 (d, J = 15.4 Hz, 1H), 2.98-3.48 (m, 3H), 2.99 (s, 6H), 2.52-2.62 (m, 2H) 1 H NMR (200 MHz, CDCl 3 ): δ 7.94 (brs, 1H), 7.04-7.38 (m, 5H), 6.56-6.77 (m, 5H), 6.00-6.28 (m, 2H), 5.78 (d, J = 15.4 Hz, 1H), 2.98-3.48 (m, 3H), 2.99 (s, 6H), 2.52-2.62 (m, 2H)

단계 3: (S)-7-(4-다이메틸아미노-페닐)-8-페닐아미노-옥타-2,4-디에노산 하이드록시아마이드Step 3: (S) -7- (4-dimethylamino-phenyl) -8-phenylamino-octa-2,4-dienoic acid hydroxyamide

출발물질로 상기 단계 2에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-8-페닐아미노-옥타-2,4-디에노산을 사용하는 것을 제외하고는 실시예 1의 단계 2와 동일한 방법으로 표제 화합물 (61％)을 얻었다.Step 2 of Example 1, except using (S) -7- (4-dimethylamino-phenyl) -8-phenylamino-octa-2,4-dienoic acid obtained in Step 2 above as starting material In the same manner as the title compound (61%) was obtained.

1H NMR (200 MHz, CD3OD) : δ 7.03-7.18 (m, 5H), 6.54-6.78 (m, 5H), 5.52-6.21 (m, 3H), 3.16-3.53 (m, 3H), 2.87 (s, 6H), 2.43-2.84 (m, 2H) 1 H NMR (200 MHz, CD 3 OD): δ 7.03-7.18 (m, 5H), 6.54-6.78 (m, 5H), 5.52-6.21 (m, 3H), 3.16-3.53 (m, 3H), 2.87 (s, 6H), 2.43-2.84 (m, 2H)

실시예 4: (S)-7-(4-다이메틸아미노-페닐)-8-페닐아미노-옥타노산 하이드록시아마이드Example 4: (S) -7- (4-dimethylamino-phenyl) -8-phenylamino-octanoic acid hydroxyamide

출발물질로 실시예 3에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-8-페닐아미노-옥타-2,4-디에노산 하이드록시아마이드를 사용하는 것을 제외하고는 실시예 2와 동일한 방법으로 표제 화합물 (56％)을 얻었다.Example 2, except using (S) -7- (4-dimethylamino-phenyl) -8-phenylamino-octa-2,4-dienoic acid hydroxyamide obtained in Example 3 as starting material In the same manner as the title compound (56%) was obtained.

1H NMR (300 MHz, CD3OD) : δ 6.34-6.98 (m, 9H), 2.90-3.26 (m, 2H), 2.88 (s, 6H), 1.08-2.69 (m, 11H) 1 H NMR (300 MHz, CD 3 OD): δ 6.34-6.98 (m, 9H), 2.90-3.26 (m, 2H), 2.88 (s, 6H), 1.08-2.69 (m, 11H)

실시예 5: (S)-8-(3-벤질옥소-페닐아미노)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디에노산 하이드록시아마이드Example 5: (S) -8- (3-benzyloxo-phenylamino) -7- (4-dimethylamino-phenyl) -octa-2,4-dienoic acid hydroxyamide

단계 1: (S)-8-(3-벤질옥소-페닐아미노)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디에노산 에틸 에스터Step 1: (S) -8- (3-benzyloxo-phenylamino) -7- (4-dimethylamino-phenyl) -octa-2,4-dienoic acid ethyl ester

아민 화합물로서 3-벤질옥소-페닐아민을 사용하는 것을 제외하고는 실시예 3의 단계 1과 동일한 방법으로 표제 화합물 (48％)을 얻었다.The title compound (48%) was obtained by the same method as Step 1 of Example 3, except using 3-benzyloxo-phenylamine as the amine compound.

1H NMR (200 MHz, CDCl3) : δ 7.01-7.45 (m, 8H), 6.65-6.77 (m, 3H), 5.92-6.35 (m, 5H), 5.77 (d, J = 15.6 Hz, 1H), 5.01 (s, 2H), 4.20 (q, J = 7.2 Hz, 2H), 3.02-3.43 (m, 3H), 2.95 (s, 6H), 2.48-2.60 (m, 2H), 1.27(t, J = 7.2 Hz, 3H) 1 H NMR (200 MHz, CDCl 3 ): δ 7.01-7.45 (m, 8H), 6.65-6.77 (m, 3H), 5.92-6.35 (m, 5H), 5.77 (d, J = 15.6 Hz, 1H) , 5.01 (s, 2H), 4.20 (q, J = 7.2 Hz, 2H), 3.02-3.43 (m, 3H), 2.95 (s, 6H), 2.48-2.60 (m, 2H), 1.27 (t, J = 7.2 Hz, 3H)

단계 2: (S)-8-(3-벤질옥소-페닐아미노)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디에노산Step 2: (S) -8- (3-benzyloxo-phenylamino) -7- (4-dimethylamino-phenyl) -octa-2,4-dienoic acid

출발물질로 상기 단계 1에서 얻은 (S)-8-(3-벤질옥소-페닐아미노)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디에노산 에틸 에스터을 사용하는 것을 제외하고는 실시예 3의 단계 2과 동일한 방법으로 표제 화합물 (66％)을 얻었다.Except for using (S) -8- (3-benzyloxo-phenylamino) -7- (4-dimethylamino-phenyl) -octa-2,4-dienoic acid ethyl ester obtained in step 1 as starting material In the same manner as in Step 2 of Example 3, the title compound (66%) was obtained.

1H NMR (200 MHz, CDCl3) : δ 7.16-7.29 (m, 1H), 6.72 (d, J = 9.0 Hz, 2H), 6.65 (s, 1H), 6.72 (d, J = 9.0 Hz, 2H), 5.97-6.215 (m, 2H), 5.72 (d, J = 15.0 Hz, 1H), 3.62 (d, J = 6.6 Hz, 2H), 2.92 (s, 6H), 2.40-2.85 (m, 3H) 1 H NMR (200 MHz, CDCl 3 ): δ 7.16-7.29 (m, 1H), 6.72 (d, J = 9.0 Hz, 2H), 6.65 (s, 1H), 6.72 (d, J = 9.0 Hz, 2H ), 5.97-6.215 (m, 2H), 5.72 (d, J = 15.0 Hz, 1H), 3.62 (d, J = 6.6 Hz, 2H), 2.92 (s, 6H), 2.40-2.85 (m, 3H)

단계 3: (S)-8-(3-벤질옥소-페닐아미노)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디에노산 하이드록시아마이드Step 3: (S) -8- (3-benzyloxo-phenylamino) -7- (4-dimethylamino-phenyl) -octa-2,4-dienoic acid hydroxyamide

출발물질로 상기 단계 2에서 얻은 (S)-8-(3-벤질옥소-페닐아미노)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디에노산을 사용하는 것을 제외하고는 실시예 1의 단계 2와 동일한 방법으로 표제 화합물 (50％)을 얻었다.Except for using (S) -8- (3-benzyloxo-phenylamino) -7- (4-dimethylamino-phenyl) -octa-2,4-dienoic acid obtained in step 2 as starting material Obtained the title compound (50%) in the same manner as in Step 2 of Example 1.

1H NMR (200 MHz, CD3OD) : δ 6.95-7.38 (m, 9H), 6.73 (d, J = 9.0 Hz, 2H), 5.47-6.27 (m, 6H), 4.98 (s, 2H), 3.06-3.48 (m, 3H), 2.87 (s, 6H), 2.40-2.83 (m, 2H) 1 H NMR (200 MHz, CD 3 OD): δ 6.95-7.38 (m, 9H), 6.73 (d, J = 9.0 Hz, 2H), 5.47-6.27 (m, 6H), 4.98 (s, 2H), 3.06-3.48 (m, 3H), 2.87 (s, 6H), 2.40-2.83 (m, 2H)

실시예 6: (S)-7-(4-다이메틸아미노-페닐)-8-(3-벤질옥소-페닐아미노)-옥타노산 하이드록시아마이드Example 6: (S) -7- (4-dimethylamino-phenyl) -8- (3-benzyloxo-phenylamino) -octanoic acid hydroxyamide

출발물질로 실시예 5에서 얻은 (S)-8-(3-벤질옥소-페닐아미노)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디에노산 하이드록시아마이드를 사용하는 것을 제외하고는 실시예 2와 동일한 방법으로 표제 화합물 (68％)을 얻었다.Using (S) -8- (3-benzyloxo-phenylamino) -7- (4-dimethylamino-phenyl) -octa-2,4-dienoic acid hydroxyamide obtained in Example 5 as starting material A title compound (68%) was obtained by the same method as Example 2 except for the above.

1H NMR (200 MHz, CD3OD) : δ 6.64-7.31 (m, 6H), 5.96-6.16 (m, 2H), 4.91 (s, 2H), 3.06-3.48 (m, 3H), 2.95-3.21 (m, 2H), 2.78 (s, 6H), 1.08-2.63 (m, 11H) 1 H NMR (200 MHz, CD 3 OD): δ 6.64-7.31 (m, 6H), 5.96-6.16 (m, 2H), 4.91 (s, 2H), 3.06-3.48 (m, 3H), 2.95-3.21 (m, 2H), 2.78 (s, 6H), 1.08-2.63 (m, 11H)

실시예 7: (S)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 하이드록시아마이드 8-페닐아마이드Example 7: (S) -7- (4-dimethylamino-phenyl) -octa-2,4-dienodioic acid hydroxyamide 8-phenylamide

단계 1: (S)-7-(4-다이메틸아미노-페닐)-7-페닐카바모일-헵타-2,4-디에노산 1-에틸 에스터Step 1: (S) -7- (4-dimethylamino-phenyl) -7-phenylcarbamoyl-hepta-2,4-dienoic acid 1-ethyl ester

제조예 3에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-에틸 에스터 (6) (190 mg, 0.60 mmol)을 다이메틸폼아마이드 (6 ml)에 녹이고 0℃에서 트라이에틸아민 (0.11 ml, 0.78 mmol), N-메탄설포닐옥시-6-트라이플루오로 벤조트라이아졸 (202 mg, 0.72 mmol)를 가한 후 30분 교반하였다. 여기에, 아민 화합물로서 아닐린 (0.066 ml, 0.72 mmol)을 가하고 실온에서 3 시간 교반한 후 물을 가해 반응을 종결하였다. 반응생성물을 에틸아세테이트로 추출하고, 소금물로 세척하고, 무수황산나트륨으로 건조, 여과 및 감압농축한 후 실리카겔 컬럼 크로마토그래피법으로 정제하여 노란색의 표제 화합물 (92％)을 얻었다.(S) -7- (4-dimethylamino-phenyl) -octa-2,4-dienoic acid 1-ethyl ester (6) (190 mg, 0.60 mmol) obtained in Preparation Example 3 was prepared using dimethylformamide (6 ml) and triethylamine (0.11 ml, 0.78 mmol) and N-methanesulfonyloxy-6-trifluoro benzotriazole (202 mg, 0.72 mmol) were added at 0 ° C. and stirred for 30 minutes. To this, aniline (0.066 ml, 0.72 mmol) was added as an amine compound, stirred at room temperature for 3 hours, and water was added to terminate the reaction. The reaction product was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and purified by silica gel column chromatography to obtain the title compound (92%) as yellow.

1H NMR (200 MHz, CDCl3) : δ 7.01-7.48 (m, 8H), 6.71 (d, J = 9.0 Hz, 2H), 5.92-6.28 (m, 2H), 5.78 (d, J = 15.4 Hz, 1H), 4.17 (q, J = 7.2 Hz, 2H), 3.49-3.62(m, 1H), 2.95 (s, 6H), 2.59-3.15 (m, 2H), 1.26(t, J = 7.2 Hz, 3H) 1 H NMR (200 MHz, CDCl 3 ): δ 7.01-7.48 (m, 8H), 6.71 (d, J = 9.0 Hz, 2H), 5.92-6.28 (m, 2H), 5.78 (d, J = 15.4 Hz , 1H), 4.17 (q, J = 7.2 Hz, 2H), 3.49-3.62 (m, 1H), 2.95 (s, 6H), 2.59-3.15 (m, 2H), 1.26 (t, J = 7.2 Hz, 3H)

단계 2: (S)-7-(4-다이메틸아미노-페닐)-7-페닐카바모일-헵타-2,4-디에노산 Step 2: (S) -7- (4-dimethylamino-phenyl) -7-phenylcarbamoyl-hepta-2,4-dienoic acid

출발물질로 상기 단계 1에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-7-페닐카바모일-헵타-2,4-디에노산 1-에틸 에스터를 사용하는 것을 제외하고는 실시예 1의 단계 1과 동일한 방법으로 표제 화합물 (74％)을 얻었다.Except for using (S) -7- (4-dimethylamino-phenyl) -7-phenylcarbamoyl-hepta-2,4-dienoic acid 1-ethyl ester obtained in step 1 as starting material In the same manner as in Step 1 of Example 1, the title compound (74%) was obtained.

1H NMR (200 MHz, CDCl3) : δ 6.95-7.40 (m, 8H), 6.65 (d, J = 9.0 Hz, 2H), 5.89-6.22 (m, 2H), 5.78 (d, J = 15.4 Hz, 1H), 3.43-3.57(m, 1H), 2.87 (s, 6H), 2.54-3.15 (m, 2H) 1 H NMR (200 MHz, CDCl 3 ): δ 6.95-7.40 (m, 8H), 6.65 (d, J = 9.0 Hz, 2H), 5.89-6.22 (m, 2H), 5.78 (d, J = 15.4 Hz , 1H), 3.43-3.57 (m, 1H), 2.87 (s, 6H), 2.54-3.15 (m, 2H)

단계 3: (S)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 하이드록시 아마이드 8-페닐아마이드Step 3: (S) -7- (4-dimethylamino-phenyl) -octa-2,4-dienodioic acid hydroxy amide 8-phenylamide

출발물질로 상기 단계 2에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-7-페닐카바모일-헵타-2,4-디에노산을 사용하는 것을 제외하고는 실시예 1의 단계 2와 동일한 방법으로 표제 화합물 (72％)을 얻었다.Step of Example 1, except using (S) -7- (4-dimethylamino-phenyl) -7-phenylcarbamoyl-hepta-2,4-dienoic acid obtained as a starting material In the same manner as 2, the title compound (72%) was obtained.

1H NMR (200 MHz, DMSO-d6) : δ 10. 60 (brs, 1H), 10.07 (s, 1H), 7.56 (d, J = 8.2 Hz, 2H), 6.87-7.28 (m, 6H), 6.71 (d, J = 8.2 Hz, 2H), 5.89-6.30 (m, 2H), 5.78 (d, J = 15.4 Hz, 1H), 3.52-3.70(m, 1H), 2.82 (s, 6H), 2.37-3.89 (m, 2H) 1 H NMR (200 MHz, DMSO-d 6 ): δ 10.60 (brs, 1H), 10.07 (s, 1H), 7.56 (d, J = 8.2 Hz, 2H), 6.87-7.28 (m, 6H) , 6.71 (d, J = 8.2 Hz, 2H), 5.89-6.30 (m, 2H), 5.78 (d, J = 15.4 Hz, 1H), 3.52-3.70 (m, 1H), 2.82 (s, 6H), 2.37-3.89 (m, 2H)

실시예 8: (S)-2-(4-다이메틸아미노-페닐)-옥타노산 8-하이드록시아마이드 1-페닐아마이드Example 8: (S) -2- (4-dimethylamino-phenyl) -octanoic acid 8-hydroxyamide 1-phenylamide

출발물질로 실시예 7에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 하이드록시아마이드 8-페닐아마이드를 사용하는 것을 제외하고는 실시예 2와 동일한 방법으로 표제 화합물 (70％)을 얻었다.Example 2, except that (S) -7- (4-dimethylamino-phenyl) -octa-2,4-dienoic acid hydroxyamide 8-phenylamide obtained in Example 7 was used as a starting material. In the same manner the title compound (70%) was obtained.

1H NMR (200 MHz, CD3OD) : δ 7.50 (d, J = 8.6 Hz, 2H), 7.01-7.30 (m, 5H), 6.73 (d, J = 8.6 Hz, 2H), 3.52 (t, J = 7.8 Hz, 1H), 2.88 (s, 6H), 1.20-2.10 (m, 10H) 1 H NMR (200 MHz, CD 3 OD): δ 7.50 (d, J = 8.6 Hz, 2H), 7.01-7.30 (m, 5H), 6.73 (d, J = 8.6 Hz, 2H), 3.52 (t, J = 7.8 Hz, 1H), 2.88 (s, 6H), 1.20-2.10 (m, 10H)

실시예 9: (S)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 8-[(3-벤 질옥소-페닐)-아마이드] 1-하이드록시아마이드 Example 9: (S) -7- (4-Dimethylamino-phenyl) -octa-2,4-dienodioic acid 8-[(3-benzyl oxo-phenyl) -amide] 1-hydroxyamide

단계 1: (S)-7-(3-벤질옥소-페닐카바모일)-7-(4-다이메틸아미노-페닐)-헵타-2,4-디에노산 에틸 에스터 Step 1: (S) -7- (3-benzyloxo-phenylcarbamoyl) -7- (4-dimethylamino-phenyl) -hepta-2,4-dienoic acid ethyl ester

아민 화합물로서 3-벤질옥소-페닐아민을 사용하는 것을 제외하고는 실시예 7의 단계 1과 동일한 방법으로 표제 화합물 (75％)을 얻었다.The title compound (75%) was obtained by the same method as Step 1 of Example 7, except that 3-benzyloxo-phenylamine was used as the amine compound.

1H NMR (200 MHz, CDCl3) : δ 6.98-7.40 (m, 8H), 6.69 (d, J = 9.0 Hz, 2H), 5.89-6.22 (m, 2H), 5.78 (d, J = 15.4 Hz, 1H), 4.17 (q, J = 7.2 Hz, 2H), 3.43-3.57(m, 1H), 2.87 (s, 6H), 2.54-3.15 (m, 2H), 1.26(t, J = 7.2 Hz, 3H) 1 H NMR (200 MHz, CDCl 3 ): δ 6.98-7.40 (m, 8H), 6.69 (d, J = 9.0 Hz, 2H), 5.89-6.22 (m, 2H), 5.78 (d, J = 15.4 Hz , 1H), 4.17 (q, J = 7.2 Hz, 2H), 3.43-3.57 (m, 1H), 2.87 (s, 6H), 2.54-3.15 (m, 2H), 1.26 (t, J = 7.2 Hz, 3H)

단계 2: (S)-7-(3-벤질옥소-페닐카바모일)-7-(4-다이메틸아미노-페닐)-헵타-2,4-디에노산Step 2: (S) -7- (3-benzyloxo-phenylcarbamoyl) -7- (4-dimethylamino-phenyl) -hepta-2,4-dienoic acid

출발물질로 상기 단계 1에서 얻은 (S)-7-(3-벤질옥소-페닐카바모일)-7-(4-다이메틸아미노-페닐)-헵타-2,4-디에노산 에틸 에스터를 사용하는 것을 제외하고는 실시예 1의 단계 1과 동일한 방법으로 표제 화합물 (62％)을 얻었다.Using (S) -7- (3-benzyloxo-phenylcarbamoyl) -7- (4-dimethylamino-phenyl) -hepta-2,4-dienoic acid ethyl ester obtained in step 1 as starting material Except for the title compound (62%) in the same manner as in Step 1 of Example 1.

1H NMR (200 MHz, CDCl3) : δ 7.09-7.38 (m, 10H), 6.64-6.87 (m, 4H), 5.98-6.28 (m, 2H), 5.75 (d, J = 15.4 Hz, 1H), 5.00 (s, 2H), 3.52 (t, J = 8.2 Hz, 1H), 2.94 (s, 6H), 2.60-3.14 (m, 2H) 1 H NMR (200 MHz, CDCl 3 ): δ 7.09-7.38 (m, 10H), 6.64-6.87 (m, 4H), 5.98-6.28 (m, 2H), 5.75 (d, J = 15.4 Hz, 1H) , 5.00 (s, 2H), 3.52 (t, J = 8.2 Hz, 1H), 2.94 (s, 6H), 2.60-3.14 (m, 2H)

단계 3: (S)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 8-[(3-벤질 옥소-페닐)-아마이드] 1-하이드록시아마이드Step 3: (S) -7- (4-Dimethylamino-phenyl) -octa-2,4-dienedioic acid 8-[(3-benzyl oxo-phenyl) -amide] 1-hydroxyamide

출발물질로 상기 단계 2에서 얻은 (S)-7-(3-벤질옥소-페닐카바모일)-7-(4-다이메틸아미노-페닐)-헵타-2,4-디에노산을 사용하는 것을 제외하고는 실시예 1의 단계 2와 동일한 방법으로 표제 화합물 (54％)을 얻었다.Except for using (S) -7- (3-benzyloxo-phenylcarbamoyl) -7- (4-dimethylamino-phenyl) -hepta-2,4-dienoic acid obtained in step 2 as starting material In the same manner as in Step 2 of Example 1, the title compound (54%) was obtained.

1H NMR (200 MHz, DMSO-d6) : δ 10. 62 (brs, 1H), 10.09 (s, 1H), 6.63-7.49 (m, 14H), 5.88-6.29 (m, 2H), 5.78 (d, J = 15.4 Hz, 1H), 5.02 (s, 2H), 3.53-3.70(m, 1H), 2.82 (s, 6H), 2.35-3.87 (m, 2H) 1 H NMR (200 MHz, DMSO-d 6 ): δ 10.62 (brs, 1H), 10.09 (s, 1H), 6.63-7.49 (m, 14H), 5.88-6.29 (m, 2H), 5.78 ( d, J = 15.4 Hz, 1H), 5.02 (s, 2H), 3.53-3.70 (m, 1H), 2.82 (s, 6H), 2.35-3.87 (m, 2H)

실시예 10: (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-[(3-하이드록시-페닐)-아마이드] Example 10: (S) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 1-[(3-hydroxy-phenyl) -amide]

출발물질로 실시예 9에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 8-[(3-벤질옥소-페닐)-아마이드] 1-하이드록시아마이드를 사용하는 것을 제외하고는 실시예 2와 동일한 방법으로 표제 화합물 (54％)을 얻었다.(S) -7- (4-dimethylamino-phenyl) -octa-2,4-dienoic acid 8-[(3-benzyloxo-phenyl) -amide] 1-hydroxy obtained as a starting material in Example 9 The title compound (54%) was obtained by the same method as Example 2 except using an amide.

11H NMR (200 MHz, CD3OD) : δ 6.48-7.25 (m, 8H), 3.49 (t, J = 7.6 Hz, 1H), 2.88 (s, 6H), 1.25-2.09 (m, 10H) 1 1H NMR (200 MHz, CD 3 OD): δ 6.48-7.25 (m, 8H), 3.49 (t, J = 7.6 Hz, 1H), 2.88 (s, 6H), 1.25-2.09 (m, 10H)

실시예 11: (S)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-하이드록시아마이드 8-나프탈렌-1-일아마이드 Example 11: (S) -7- (4-dimethylamino-phenyl) -octa-2,4-dienodioic acid 1-hydroxyamide 8-naphthalen-1-ylamide

단계 1: (S)-7-(4-다이메틸아미노-페닐)-7-(나프틸렌-1-일카바모일)-헵타-2,4-디에노산 에틸 에스터 Step 1: (S) -7- (4-dimethylamino-phenyl) -7- (naphthylene-1-ylcarbamoyl) -hepta-2,4-dienoic acid ethyl ester

아민화합물로서 1-아미노나프탈렌을 사용하는 것을 제외하고는 실시예 7의 단계 1과 동일한 방법으로 표제 화합물 (85％)을 얻었다.The title compound (85%) was obtained in the same manner as in Step 1 of Example 7, except that 1-aminonaphthalene was used as the amine compound.

1H NMR (200 MHz, CDCl3) : δ 8.16 (s, 1H), 7.11-7.82 (m, 10H), 6.70 (d, J = 8.6 Hz, 2H), 5.88-6.27 (m, 2H), 5.75 (d, J = 15.1 Hz, 1H), 4.17 (q, J = 7.4 Hz, 2H), 3.59 (t, J = 7.2 Hz, 1H), 2.94 (s, 6H), 2.60-3.17 (m, 2H), 1.27 (t, J = 7.2 Hz, 3H) 1 H NMR (200 MHz, CDCl 3 ): δ 8.16 (s, 1H), 7.11-7.82 (m, 10H), 6.70 (d, J = 8.6 Hz, 2H), 5.88-6.27 (m, 2H), 5.75 (d, J = 15.1 Hz, 1H), 4.17 (q, J = 7.4 Hz, 2H), 3.59 (t, J = 7.2 Hz, 1H), 2.94 (s, 6H), 2.60-3.17 (m, 2H) , 1.27 (t, J = 7.2 Hz, 3H)

단계 2: (S)-7-(4-다이메틸아미노-페닐)-7-(나프틸렌-1-일카바모일)-헵타-2,4-디에노산Step 2: (S) -7- (4-dimethylamino-phenyl) -7- (naphthylene-1-ylcarbamoyl) -hepta-2,4-dienoic acid

출발물질로 상기 단계 1에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-7-(나프틸렌-1-일카바모일)-헵타-2,4-디에노산 에틸 에스터를 사용하는 것을 제외하고는 실시예 1의 단계 1과 동일한 방법으로 표제 화합물 (76％)을 얻었다.Using (S) -7- (4-dimethylamino-phenyl) -7- (naphthylene-1-ylcarbamoyl) -hepta-2,4-dienoic acid ethyl ester obtained in step 1 as starting material A title compound (76%) was obtained by the same method as Step 1 of Example 1, except that.

1H NMR (200 MHz, CDCl3) : δ 8.14 (s, 1H), 7.17-7.75 (m, 10H), 6.72 (d, J = 8.2 Hz, 2H), 5.98-6.29 (m, 2H), 5.74 (d, J = 15.4 Hz, 1H), 3.52-3.64 (m, 1H), 2.95 (s, 6H), 2.61-3.19 (m, 2H) 1 H NMR (200 MHz, CDCl 3 ): δ 8.14 (s, 1H), 7.17-7.75 (m, 10H), 6.72 (d, J = 8.2 Hz, 2H), 5.98-6.29 (m, 2H), 5.74 (d, J = 15.4 Hz, 1H), 3.52-3.64 (m, 1H), 2.95 (s, 6H), 2.61-3.19 (m, 2H)

단계 3: (S)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-하이드록시아마이드 8-나프탈렌-1-일아마이드Step 3: (S) -7- (4-dimethylamino-phenyl) -octa-2,4-dienodioic acid 1-hydroxyamide 8-naphthalen-1-ylamide

출발물질로 상기 단계 2에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-7-(나프틸렌-1-일카바모일)-헵타-2,4-디에노산을 사용하는 것을 제외하고는 실시예 1의 단계 2와 동일한 방법으로 표제 화합물 (64％)을 얻었다.Except using (S) -7- (4-dimethylamino-phenyl) -7- (naphthylene-1-ylcarbamoyl) -hepta-2,4-dienoic acid obtained in step 2 as starting material In the same manner as in Step 2 of Example 1, the title compound (64%) was obtained.

1H NMR (300 MHz, DMSO-d6) : δ 1.32 (m, 4H), 1.50 (m, 2H), 1.65(m, 1H), 1.94 (t, J = 7.2 Hz, 2H), 2.04 (m, 1H), 2.87 (s, 6H), 3.80 (t, J = 6.6 Hz, 1H), 6.74 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.49 (m, 3H), 7.61 (d, J = 7.5 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.93 (d, J = 7.5 Hz, 2H), 8.65 (s, 1H), 9.95 (s, 1H), 10.33 (s, 1H) 1 H NMR (300 MHz, DMSO-d 6 ): δ 1.32 (m, 4H), 1.50 (m, 2H), 1.65 (m, 1H), 1.94 (t, J = 7.2 Hz, 2H), 2.04 (m , 1H), 2.87 (s, 6H), 3.80 (t, J = 6.6 Hz, 1H), 6.74 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.49 (m , 3H), 7.61 (d, J = 7.5 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.93 (d, J = 7.5 Hz, 2H), 8.65 (s, 1H), 9.95 (s , 1H), 10.33 (s, 1H)

실시예 12: (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 8-나프탈렌-1-일아마이드Example 12: (S) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 8-naphthalen-1-ylamide

출발물질로 실시예 11에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-하이드록시아마이드 8-나프탈렌-1-일아마이드를 사용하는 것을 제외하고는 실시예 2와 동일한 방법으로 표제 화합물 (65％)을 얻었다.Except for using (S) -7- (4-dimethylamino-phenyl) -octa-2,4-dienoic acid 1-hydroxyamide 8-naphthalen-1-ylamide obtained in Example 11 as a starting material. In the same manner as in Example 2, the title compound (65%) was obtained.

1H NMR (300 MHz, DMSO-d6) : δ 1.32 (m, 4H), 1.50 (m, 2H), 1.65(m, 1H), 1.94 (t, J = 7.2 Hz, 2H), 2.04 (m, 1H), 2.87 (s, 6H), 3.80 (t, J = 6.6 Hz, 1H), 6.74 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.49 (m, 3H), 7.61 (d, J = 7.5 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.93 (d, J = 7.5 Hz, 2H), 8.65 (s, 1H), 9.95 (s, 1H), 10.33 (s, 1H) 1 H NMR (300 MHz, DMSO-d 6 ): δ 1.32 (m, 4H), 1.50 (m, 2H), 1.65 (m, 1H), 1.94 (t, J = 7.2 Hz, 2H), 2.04 (m , 1H), 2.87 (s, 6H), 3.80 (t, J = 6.6 Hz, 1H), 6.74 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.49 (m , 3H), 7.61 (d, J = 7.5 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.93 (d, J = 7.5 Hz, 2H), 8.65 (s, 1H), 9.95 (s , 1H), 10.33 (s, 1H)

실시예 13: (S)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-하이드록시아마이드 8-퀴놀린-6-일아마이드 Example 13: (S) -7- (4-dimethylamino-phenyl) -octa-2,4-dienodioic acid 1-hydroxyamide 8-quinolin-6-ylamide

단계 1: (S)-7-(4-다이메틸아미노-페닐)-7-(퀴놀린-6-일카바모일)-헵타-2,4-디에노산 에틸 에스터 Step 1: (S) -7- (4-dimethylamino-phenyl) -7- (quinolin-6-ylcarbamoyl) -hepta-2,4-dienoic acid ethyl ester

아민 화합물로서 6-아미노퀴놀린을 사용하는 것을 제외하고는 실시예 7의 단계 1과 동일한 방법으로 표제 화합물 (45％)을 얻었다. The title compound (45%) was obtained by the same method as Step 1 of Example 7, except for using 6-aminoquinoline as the amine compound.

1H NMR (200 MHz, CDCl3) : δ 8.15 (s, 1H), 7.09-7.82 (m, 10H), 6.72 (d, J = 8.6 Hz, 2H), 5.88-6.27 (m, 2H), 5.74 (d, J = 15.1 Hz, 1H), 4.17 (q, J = 7.4 Hz, 2H), 3.58 (t, J = 7.2 Hz, 1H), 2.92 (s, 6H), 2.60-3.19 (m, 2H), 1.27 (t, J = 7.2 Hz, 3H) 1 H NMR (200 MHz, CDCl 3 ): δ 8.15 (s, 1H), 7.09-7.82 (m, 10H), 6.72 (d, J = 8.6 Hz, 2H), 5.88-6.27 (m, 2H), 5.74 (d, J = 15.1 Hz, 1H), 4.17 (q, J = 7.4 Hz, 2H), 3.58 (t, J = 7.2 Hz, 1H), 2.92 (s, 6H), 2.60-3.19 (m, 2H) , 1.27 (t, J = 7.2 Hz, 3H)

단계 2: (S)-7-(4-다이메틸아미노-페닐)-7-(퀴놀린-6-일카바모일)-헵타-2,4-디에노산Step 2: (S) -7- (4-dimethylamino-phenyl) -7- (quinolin-6-ylcarbamoyl) -hepta-2,4-dienoic acid

출발물질로 상기 단계 1에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-7-(퀴놀린-6-일카바모일)-헵타-2,4-디에노산 에틸 에스터를 사용하는 것을 제외하고는 실시예 1의 단계 1과 동일한 방법으로 표제 화합물 (30％)을 얻었다.Using (S) -7- (4-dimethylamino-phenyl) -7- (quinolin-6-ylcarbamoyl) -hepta-2,4-dienoic acid ethyl ester obtained as a starting material The title compound (30%) was obtained by the same method as Step 1 of Example 1, except.

1H NMR (300 MHz, CDCl3) : δ 2.66 (m, 1H), 2.91 (s, 6H), 3.08 (m, 1H), 3.61 (t, J = 7.5 Hz, 1H), 5.81 (d, J = 15.1 Hz, 1H), 6.07 (m, 1H), 6.22 (m, 1H), 6.70 (d, J = 8.6 Hz, 2H), 7.20 (d, J = 8.9 Hz, 2H), 7.30 (m, 2H), 7.90 (d, J = 9.0 Hz, 1H), 8.01 (d, J = 8.1 Hz, 1H), 8.12 (s, 1H), 8.26 (s, 1H), 8.67 (s, 1H) 1 H NMR (300 MHz, CDCl 3 ): δ 2.66 (m, 1H), 2.91 (s, 6H), 3.08 (m, 1H), 3.61 (t, J = 7.5 Hz, 1H), 5.81 (d, J = 15.1 Hz, 1H), 6.07 (m, 1H), 6.22 (m, 1H), 6.70 (d, J = 8.6 Hz, 2H), 7.20 (d, J = 8.9 Hz, 2H), 7.30 (m, 2H ), 7.90 (d, J = 9.0 Hz, 1H), 8.01 (d, J = 8.1 Hz, 1H), 8.12 (s, 1H), 8.26 (s, 1H), 8.67 (s, 1H)

단계 3: (S)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-하이드록시아마이드 8-퀴놀린-6-일아마이드 Step 3: (S) -7- (4-Dimethylamino-phenyl) -octa-2,4-dienodioic acid 1-hydroxyamide 8-quinolin-6-ylamide

출발물질로 상기 단계 2에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-7-(퀴놀린-6-일카바모일)-헵타-2,4-디에노산을 사용하는 것을 제외하고는 실시예 1의 단계 2와 동일한 방법으로 표제 화합물 (45％)을 얻었다.Except for using (S) -7- (4-dimethylamino-phenyl) -7- (quinolin-6-ylcarbamoyl) -hepta-2,4-dienoic acid obtained in step 2 as starting material Obtained the title compound (45%) in the same manner as in Step 2 of Example 1.

1H NMR (300 MHz, DMSO-d6) : δ 2.55 (m, 1H), 2.80 (s, 6H), 2.88(m, 1H), 3.62 (m, 1H), 5.69 (d, J = 15.0 Hz, 1H), 6.13 (m, 1H), 6.69 (m, 1H), 6.68 (d, J = 8.7 Hz, 2H), 6.99 (m, 1H), 7.20 (d, J = 8.7 Hz, 2H), 7.39 (q, J = 4.5 Hz, 1H), 7.67 (d, J = 9.2 Hz, 1H), 7.85 (d, J = 9.2 Hz, 2H), 8.18 (d, J = 8.7 Hz, 1H), 8.22 (s, 1H), 8.63 (s, 1H) 1 H NMR (300 MHz, DMSO-d 6 ): δ 2.55 (m, 1H), 2.80 (s, 6H), 2.88 (m, 1H), 3.62 (m, 1H), 5.69 (d, J = 15.0 Hz , 1H), 6.13 (m, 1H), 6.69 (m, 1H), 6.68 (d, J = 8.7 Hz, 2H), 6.99 (m, 1H), 7.20 (d, J = 8.7 Hz, 2H), 7.39 (q, J = 4.5 Hz, 1H), 7.67 (d, J = 9.2 Hz, 1H), 7.85 (d, J = 9.2 Hz, 2H), 8.18 (d, J = 8.7 Hz, 1H), 8.22 (s , 1H), 8.63 (s, 1H)

실시예 14: (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-퀴놀린-6-일아마이드Example 14 (S) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 1-quinolin-6-ylamide

출발물질로 실시예 13에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-하이드록시아마이드 8-퀴놀린-6-일아마이드를 사용하는 것을 제외하고는 실시예 2와 동일한 방법으로 표제 화합물 (45％)을 얻었다.Except for using (S) -7- (4-dimethylamino-phenyl) -octa-2,4-dienoic acid 1-hydroxyamide 8-quinolin-6-ylamide obtained in Example 13 as starting material In the same manner as in Example 2, the title compound (45%) was obtained.

1H NMR (300 MHz, DMSO-d6) : δ 1.33 (m, 4H), 1.63 (m, 3H), 2.05 (m, 3H), 2.90 (s, 6H), 3.80 (m, 1H), 6.53 (m, 2H), 6.74 (m, 3H), 6.87 (m, 2H), 7.25 (m, 3H) 1 H NMR (300 MHz, DMSO-d 6 ): δ 1.33 (m, 4H), 1.63 (m, 3H), 2.05 (m, 3H), 2.90 (s, 6H), 3.80 (m, 1H), 6.53 (m, 2H), 6.74 (m, 3H), 6.87 (m, 2H), 7.25 (m, 3H)

실시예 15: (S)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-하이드록시아마이드 8-퀴놀린-8-일아마이드 Example 15 (S) -7- (4-Dimethylamino-phenyl) -octa-2,4-dienoic acid 1-hydroxyamide 8-quinolin-8-ylamide

단계 1: (S)-7-(4-다이메틸아미노-페닐)-7-(퀴놀린-8-일카바모일)-헵타-2,4-디에노산 에틸 에스터 Step 1: (S) -7- (4-dimethylamino-phenyl) -7- (quinolin-8-ylcarbamoyl) -hepta-2,4-dienoic acid ethyl ester

아민 화합물로서 8-아미노퀴놀린을 사용하는 것을 제외하고는 실시예 7의 단계 1과 동일한 방법으로 표제 화합물 (55％)을 얻었다.The title compound (55%) was obtained by the same method as Step 1 of Example 7, except for using 8-aminoquinoline as the amine compound.

1H NMR (300 MHz, CDCl3) : δ 9.87 (s, 1H), 8.75 (m, 2H), 8.11 (d, J = 8.1 Hz, 1H), 7.41 (m, 6H), 6.75 (d, J = 8.4 Hz, 2H), 6.22 (m, 2H), 5.78 (d, J = 15.3 Hz, 1H), 4.17 (q, J = 7.4 Hz, 2H), 3.73 (t, J = 7.5 Hz, 1H), 3.12 (m, 1H), 2.93 (s, 6H), 2.78 (m, 1H), 1.27 (t, J = 7.3 Hz, 3H) 1 H NMR (300 MHz, CDCl 3 ): δ 9.87 (s, 1H), 8.75 (m, 2H), 8.11 (d, J = 8.1 Hz, 1H), 7.41 (m, 6H), 6.75 (d, J = 8.4 Hz, 2H), 6.22 (m, 2H), 5.78 (d, J = 15.3 Hz, 1H), 4.17 (q, J = 7.4 Hz, 2H), 3.73 (t, J = 7.5 Hz, 1H), 3.12 (m, 1H), 2.93 (s, 6H), 2.78 (m, 1H), 1.27 (t, J = 7.3 Hz, 3H)

단계 2: (S)-7-(4-다이메틸아미노-페닐)-7-(퀴놀린-8-일카바모일)-헵타-2,4-디에노산Step 2: (S) -7- (4-dimethylamino-phenyl) -7- (quinolin-8-ylcarbamoyl) -hepta-2,4-dienoic acid

출발물질로 상기 단계 1에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-7-(퀴놀린-8-일카바모일)-헵타-2,4-디에노산 에틸 에스터를 사용하는 것을 제외하고는 실시예 1의 단계 1과 동일한 방법으로 표제 화합물 (46％)을 얻었다.Using (S) -7- (4-dimethylamino-phenyl) -7- (quinolin-8-ylcarbamoyl) -hepta-2,4-dienoic acid ethyl ester obtained as a starting material The title compound (46%) was obtained by the same method as Step 1 of Example 1, except.

1H NMR (300 MHz, MeOD-d4) : δ 8.64 (s, 1H), 8.48 (d, J = 8.0 Hz, 1H), 8.11 (d, J = 8.1 Hz, 1H), 7.39 (m, 3H),7.19 (d, J = 8.2 Hz, 2H), 7.00 (m, 1H), 6.67 (d, J = 8.4 Hz, 2H), 6.17 (m, 1H), 6.02 (m, 1H), 5.63 (d, J = 15.3 Hz, 1H), 3.79 (t, J = 7.6 Hz, 1H), 2.92 (m, 1H), 2.76 (s, 6H), 2.60 (m, 1H) 1 H NMR (300 MHz, MeOD-d 4 ): δ 8.64 (s, 1H), 8.48 (d, J = 8.0 Hz, 1H), 8.11 (d, J = 8.1 Hz, 1H), 7.39 (m, 3H ), 7.19 (d, J = 8.2 Hz, 2H), 7.00 (m, 1H), 6.67 (d, J = 8.4 Hz, 2H), 6.17 (m, 1H), 6.02 (m, 1H), 5.63 (d , J = 15.3 Hz, 1H), 3.79 (t, J = 7.6 Hz, 1H), 2.92 (m, 1H), 2.76 (s, 6H), 2.60 (m, 1H)

단계 3: (S)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-하이드록시아마이드 8-퀴놀린-8-일아마이드 Step 3: (S) -7- (4-Dimethylamino-phenyl) -octa-2,4-dienodioic acid 1-hydroxyamide 8-quinolin-8-ylamide

출발물질로 상기 단계 2에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-7-(퀴놀린-8-일카바모일)-헵타-2,4-디에노산을 사용하는 것을 제외하고는 실시예 1의 단계 2와 동일한 방법으로 표제 화합물 (15％)을 얻었다.Except for using (S) -7- (4-dimethylamino-phenyl) -7- (quinolin-8-ylcarbamoyl) -hepta-2,4-dienoic acid obtained in step 2 as starting material Obtained the title compound (15%) in the same manner as in Step 2 of Example 1.

1H NMR (300 MHz, MeOD-d4) : δ 8.81 (s, 1H), 8.64 (d, J =7.6 Hz, 1H), 8.29 (d, J = 8.1 Hz, 1H), 7.55 (m, 3H), 7.34 (d, J = 8.6 Hz, 2H), 6.29(m, 1H), 6.13 (m, 1H), 5.78 (d, J = 14.9 Hz, 1H), 3.93 (m, 1H), 3.09 (m, 1H), 2.93 (s, 6H), 2.76 (m, 1H) 1 H NMR (300 MHz, MeOD-d 4 ): δ 8.81 (s, 1H), 8.64 (d, J = 7.6 Hz, 1H), 8.29 (d, J = 8.1 Hz, 1H), 7.55 (m, 3H ), 7.34 (d, J = 8.6 Hz, 2H), 6.29 (m, 1H), 6.13 (m, 1H), 5.78 (d, J = 14.9 Hz, 1H), 3.93 (m, 1H), 3.09 (m , 1H), 2.93 (s, 6H), 2.76 (m, 1H)

실시예 16: (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마 이드 1-퀴놀린-8-일아마이드Example 16: (S) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 1-quinolin-8-ylamide

출발물질로 실시예 15에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-하이드록시아마이드 8-퀴놀린-8-일아마이드를 사용하는 것을 제외하고는 실시예 2와 동일한 방법으로 표제 화합물 (70％)을 얻었다.Except for using (S) -7- (4-dimethylamino-phenyl) -octa-2,4-dienoic acid 1-hydroxyamide 8-quinolin-8-ylamide obtained in Example 15 as starting material In the same manner as in Example 2, the title compound (70%) was obtained.

1H NMR (300 MHz, MeOD-d4) : δ 8.92 (s, 1H), 8.74 (d, J =7.5 Hz, 1H), 8.40 (d, J = 7.1 Hz, 1H), 7.55 (m, 3H), 7.64 (m, 3H), 6.94(d, J = 8.5 Hz, 2H), 3.69 (m, 1H), 3.03 (s, 6H), 2.21 (m, 3H), 1.95 (m, 1H), 1.76 (m, 2H), 1.39 (m, 4H) 1 H NMR (300 MHz, MeOD-d 4 ): δ 8.92 (s, 1H), 8.74 (d, J = 7.5 Hz, 1H), 8.40 (d, J = 7.1 Hz, 1H), 7.55 (m, 3H ), 7.64 (m, 3H), 6.94 (d, J = 8.5 Hz, 2H), 3.69 (m, 1H), 3.03 (s, 6H), 2.21 (m, 3H), 1.95 (m, 1H), 1.76 (m, 2H), 1.39 (m, 4H)

실시예 17: (S)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-하이드록시아마이드 8-[(3-메톡시-페닐)-아마이드]Example 17: (S) -7- (4-Dimethylamino-phenyl) -octa-2,4-dienoic acid 1-hydroxyamide 8-[(3-methoxy-phenyl) -amide]

단계 1: (S)-7-(4-다이메틸아미노-페닐)-7-(3-메톡시-페닐카바모일)-헵타-2,4-디에노산 에틸 에스터Step 1: (S) -7- (4-dimethylamino-phenyl) -7- (3-methoxy-phenylcarbamoyl) -hepta-2,4-dienoic acid ethyl ester

아민화합물로서 3-메톡시아닐린을 사용하는 것을 제외하고는 실시예 7의 단계 1과 동일한 방법으로 표제 화합물 (85％)을 얻었다.The title compound (85%) was obtained by the same method as Step 1 of Example 7, except that 3-methoxyaniline was used as the amine compound.

1H NMR (300 MHz, CDCl3) : δ 7.15 (m, 4H), 6.86 (m, 4H), 6.27 (m, 3H), 5.77 (d, J = 15.3 Hz, 1H), 4.17 (q, J = 7.4 Hz, 2H), 3.75 (s, 3H), 3.52 (t, J = 7.1 Hz, 1H), 2.98 (m, 1H), 2.94 (s, 6H), 2.75 (m, 1H), 1.27 (t, J = 7.2 Hz, 3H) 1 H NMR (300 MHz, CDCl 3 ): δ 7.15 (m, 4H), 6.86 (m, 4H), 6.27 (m, 3H), 5.77 (d, J = 15.3 Hz, 1H), 4.17 (q, J = 7.4 Hz, 2H), 3.75 (s, 3H), 3.52 (t, J = 7.1 Hz, 1H), 2.98 (m, 1H), 2.94 (s, 6H), 2.75 (m, 1H), 1.27 (t , J = 7.2 Hz, 3H)

단계 2: (S)-7-(4-다이메틸아미노-페닐)-7-(3-메톡시-페닐카바모일)-헵타-2,4-디에노산 Step 2: (S) -7- (4-dimethylamino-phenyl) -7- (3-methoxy-phenylcarbamoyl) -hepta-2,4-dienoic acid

출발물질로 상기 단계 1에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-7-(3-메톡시-페닐카바모일)-헵타-2,4-디에노산 에틸 에스터를 사용하는 것을 제외하고는 실시예 1의 단계 1과 동일한 방법으로 표제 화합물 (59％)을 얻었다.Using (S) -7- (4-dimethylamino-phenyl) -7- (3-methoxy-phenylcarbamoyl) -hepta-2,4-dienoic acid ethyl ester obtained in step 1 as starting material Except for the title compound (59%) in the same manner as in Step 1 of Example 1.

1H NMR (300 MHz, MeOD-d4) : δ 7.24 (m, 5H), 7.04 (d, J = 8.1 Hz, 1H),6.78 (d, J = 8.8 Hz, 2H), 6.65 (d, J = 8.0 Hz, 1H), 6.30 (m, 1H), 6.10 (m, 1H), 5.80 (d, J = 15.3 Hz, 1H), 3.78 (s, 3H), 3.66 (t, J = 7.1 Hz, 1H), 2.94 (m, 1H), 2.90 (s, 6H), 2.65 (m, 1H) 1 H NMR (300 MHz, MeOD-d 4 ): δ 7.24 (m, 5H), 7.04 (d, J = 8.1 Hz, 1H), 6.78 (d, J = 8.8 Hz, 2H), 6.65 (d, J = 8.0 Hz, 1H), 6.30 (m, 1H), 6.10 (m, 1H), 5.80 (d, J = 15.3 Hz, 1H), 3.78 (s, 3H), 3.66 (t, J = 7.1 Hz, 1H ), 2.94 (m, 1H), 2.90 (s, 6H), 2.65 (m, 1H)

단계 3: (S)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-하이드록시아마이드 8-[(3-메톡시-페닐)-아마이드] Step 3: (S) -7- (4-Dimethylamino-phenyl) -octa-2,4-dienodioic acid 1-hydroxyamide 8-[(3-methoxy-phenyl) -amide]

출발물질로 상기 단계 2에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-7-(3-메톡시-페닐카바모일)-헵타-2,4-디에노산을 사용하는 것을 제외하고는 실시예 1의 단계 2와 동일한 방법으로 표제 화합물 (10％)을 얻었다.Except for using (S) -7- (4-dimethylamino-phenyl) -7- (3-methoxy-phenylcarbamoyl) -hepta-2,4-dienoic acid obtained in step 2 as starting material In the same manner as in Step 2 of Example 1, the title compound (10%) was obtained.

1H NMR (300 MHz, MeOD-d4) : δ 7.53 (bs, 1H), 7.16 (m, 3H), 6.99 (m, 1H), 6.88 (d, J = 8.7 Hz, 1H), 6.77 (d, J = 8.7 Hz, 1H), 6.67 (d, J = 8.1 Hz, 2H), 6.15 (m, 1H), 5.97 (m, 1H), 5.69 (d, J = 15.3 Hz, 1H), 3.69 (s, 3H), 3.51 (t, J = 7.5 Hz, 1H), 2.85 (m, 1H), 2.80 (s, 6H), 2.49 (m, 1H) 1 H NMR (300 MHz, MeOD-d 4 ): δ 7.53 (bs, 1H), 7.16 (m, 3H), 6.99 (m, 1H), 6.88 (d, J = 8.7 Hz, 1H), 6.77 (d , J = 8.7 Hz, 1H), 6.67 (d, J = 8.1 Hz, 2H), 6.15 (m, 1H), 5.97 (m, 1H), 5.69 (d, J = 15.3 Hz, 1H), 3.69 (s , 3H), 3.51 (t, J = 7.5 Hz, 1H), 2.85 (m, 1H), 2.80 (s, 6H), 2.49 (m, 1H)

실시예 18: (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-[(3-메톡시-페닐)-아마이드]-8-일아마이드Example 18: (S) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 1-[(3-methoxy-phenyl) -amide] -8-ylamide

출발물질로 실시예 17에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 8-[(3-메톡시-페닐)-아마이드] 1-하이드록시아마이드를 사용하는 것을 제외하고는 실시예 2와 동일한 방법으로 표제 화합물 (75％)을 얻었다.(S) -7- (4-Dimethylamino-phenyl) -octa-2,4-dienoic acid 8-[(3-methoxy-phenyl) -amide] 1-hydroxy obtained as a starting material in Example 17 The title compound (75%) was obtained by the same method as Example 2 except for using an amide.

1H NMR (300 MHz, MeOD-d4) : δ 7.19 (m, 3H), 6.92 (m, 2H), 6.79 (d, J = 8.7 Hz, 1H), 6.69(d, J = 8.8 Hz, 2H), 3.69 (s, 3H), 3.41 (t, J = 7.0 Hz, 1H), 2.82 (s, 6H), 2.09 (m, 3H), 1.53 (m, 3H), 1.22 (m, 4H) 1 H NMR (300 MHz, MeOD-d 4 ): δ 7.19 (m, 3H), 6.92 (m, 2H), 6.79 (d, J = 8.7 Hz, 1H), 6.69 (d, J = 8.8 Hz, 2H ), 3.69 (s, 3H), 3.41 (t, J = 7.0 Hz, 1H), 2.82 (s, 6H), 2.09 (m, 3H), 1.53 (m, 3H), 1.22 (m, 4H)

실시예 19: (S)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 8-[(3,4-다이메톡시-페닐)-아마이드] 1-하이드록시아마이드Example 19: (S) -7- (4-Dimethylamino-phenyl) -octa-2,4-dienodioic acid 8-[(3,4-dimethoxy-phenyl) -amide] 1-hydroxyamide

단계 1: (S)-7-(3,4-다이메톡시-페닐카바모일)-7-(4-다이메틸아미노-페닐)-헵타-2,4-디에노산 에틸 에스터 Step 1: (S) -7- (3,4-Dimethoxy-phenylcarbamoyl) -7- (4-dimethylamino-phenyl) -hepta-2,4-dienoic acid ethyl ester

아민 화합물로서 3,4-다이메톡시아닐린을 사용하는 것을 제외하고는 실시예 7의 단계 1과 동일한 방법으로 표제 화합물 (83％)을 얻었다. The title compound (83%) was obtained by the same method as Step 1 of Example 7, except that 3,4-dimethoxyaniline was used as the amine compound.

1H NMR (300 MHz, CDCl3) : δ 7.25 (m, 3H), 6.77 (m, 5H), 6.19 (m, 1H), 6.06 (m, 1H), 5.78 (d, J = 15.3 Hz, 1H), 4.19 (q, J = 7.2 Hz, 2H), 3.85 (s, 3H), 3.83 (s, 3H), 3.53 (t, J = 6.6 Hz, 1H), 3.05 (m, 1H), 2.96 (s, 6H), 2.70 (m, 1H), 1.28 (t, J = 8.4 Hz, 3H) 1 H NMR (300 MHz, CDCl 3 ): δ 7.25 (m, 3H), 6.77 (m, 5H), 6.19 (m, 1H), 6.06 (m, 1H), 5.78 (d, J = 15.3 Hz, 1H ), 4.19 (q, J = 7.2 Hz, 2H), 3.85 (s, 3H), 3.83 (s, 3H), 3.53 (t, J = 6.6 Hz, 1H), 3.05 (m, 1H), 2.96 (s , 6H), 2.70 (m, 1H), 1.28 (t, J = 8.4 Hz, 3H)

단계 2: (S)-7-(3,4-다이메톡시-페닐카바모일)-7-(4-다이메틸아미노-페닐)-헵타-2,4-디에노산 Step 2: (S) -7- (3,4-dimethoxy-phenylcarbamoyl) -7- (4-dimethylamino-phenyl) -hepta-2,4-dienoic acid

출발물질로 상기 단계 1에서 얻은 (S)-7-(3,4-다이메톡시-페닐카바모일)-7-(4-다이메틸아미노-페닐)-헵타-2,4-디에노산 에틸 에스터를 사용하는 것을 제외하고는 실시예 1의 단계 1과 동일한 방법으로 표제 화합물 (36％)을 얻었다.(S) -7- (3,4-Dimethoxy-phenylcarbamoyl) -7- (4-dimethylamino-phenyl) -hepta-2,4-dienoic acid ethyl ester obtained in step 1 as a starting material The title compound (36%) was obtained by the same method as Step 1 of Example 1 except for using.

1H NMR (300 MHz, MeOD-d4) : δ 7.12 (m, 4H), 6.88 (d, J = 8.7 Hz, 1H), 6.76 (d, J = 8.7 Hz, 1H), 6.67 (d, J = 8.4 Hz, 2H), 6.19 (m, 1H), 5.99 (m, 1H), 5.69(d, J = 15.3 Hz, 1H), 3.68 (s, 6H), 3.52 (t, J = 7.8 Hz, 1H), 2.83 (m, 1H), 2.57 (s, 6H), 2.52 (m, 1H) 1 H NMR (300 MHz, MeOD-d 4 ): δ 7.12 (m, 4H), 6.88 (d, J = 8.7 Hz, 1H), 6.76 (d, J = 8.7 Hz, 1H), 6.67 (d, J = 8.4 Hz, 2H), 6.19 (m, 1H), 5.99 (m, 1H), 5.69 (d, J = 15.3 Hz, 1H), 3.68 (s, 6H), 3.52 (t, J = 7.8 Hz, 1H ), 2.83 (m, 1H), 2.57 (s, 6H), 2.52 (m, 1H)

단계 3: (S)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 8-[(3,4-다이메톡시-페닐)-아마이드] 1-하이드록시아마이드Step 3: (S) -7- (4-Dimethylamino-phenyl) -octa-2,4-dienedioic acid 8-[(3,4-dimethoxy-phenyl) -amide] 1-hydroxyamide

출발물질로 상기 단계 2에서 얻은 (S)-7-(3,4-다이메톡시-페닐카바모일)-7-(4-다이메틸아미노-페닐)-헵타-2,4-디에노산을 사용하는 것을 제외하고는 실시예 1의 단계 2와 동일한 방법으로 표제 화합물 (11％)을 얻었다.(S) -7- (3,4-Dimethoxy-phenylcarbamoyl) -7- (4-dimethylamino-phenyl) -hepta-2,4-dienoic acid obtained in Step 2 was used as a starting material. The title compound (11%) was obtained in the same manner as in Step 2 of Example 1, except that.

1H NMR (300 MHz, MeOD-d4) : δ 7.34 (d, J = 8.5 Hz, 3H), 7.21(m, 1H), 7.08 (m, 1H), 6.97 (d, J = 8.7 Hz, 1H), 6.88 (d, J = 8.6 Hz, 2H), 6.36 (m, 1H), 6.19 (m, 1H), 5.90 (d, J = 15.6 Hz, 1H), 3.90 (s, 6H), 3.72 (m, 1H), 3.02 (m, 1H), 3.00 (s, 6H), 2.72 (m, 1H) 1 H NMR (300 MHz, MeOD-d 4 ): δ 7.34 (d, J = 8.5 Hz, 3H), 7.21 (m, 1H), 7.08 (m, 1H), 6.97 (d, J = 8.7 Hz, 1H ), 6.88 (d, J = 8.6 Hz, 2H), 6.36 (m, 1H), 6.19 (m, 1H), 5.90 (d, J = 15.6 Hz, 1H), 3.90 (s, 6H), 3.72 (m , 1H), 3.02 (m, 1H), 3.00 (s, 6H), 2.72 (m, 1H)

실시예 20: (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-[(3,4-다이메톡시-페닐)-아마이드]-8-일아마이드Example 20: (S) -2- (4-Dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 1-[(3,4-dimethoxy-phenyl) -amide] -8-ylamide

단계 1: Step 1:

출발물질로 실시예 19에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 8-[(3,4-다이메톡시-페닐)-아마이드] 1-하이드록시아마이드를 사용하는 것을 제외하고는 실시예 2와 동일한 방법으로 표제 화합물 (75％)을 얻었다.(S) -7- (4-Dimethylamino-phenyl) -octa-2,4-dienedioic acid 8-[(3,4-dimethoxy-phenyl) -amide] obtained as a starting material in Example 19 1 The title compound (75%) was obtained by the same method as Example 2 except for using hydroxyamide.

1H NMR (300 MHz, MeOD-d4) : δ 7.19 (m, 3H), 6.92 (m, 1H), 6.79 (d, J = 8.7 Hz, 1H), 6.69(d, J = 8.8 Hz, 2H), 3.73 (s, 3H), 3.71 (s, 3H), 3.41 (t, J = 7.0 Hz, 1H), 2.82 (s, 6H), 2.08 (m, 3H), 1.53 (m, 3H), 1.23 (m, 4H) 1 H NMR (300 MHz, MeOD-d 4 ): δ 7.19 (m, 3H), 6.92 (m, 1H), 6.79 (d, J = 8.7 Hz, 1H), 6.69 (d, J = 8.8 Hz, 2H ), 3.73 (s, 3H), 3.71 (s, 3H), 3.41 (t, J = 7.0 Hz, 1H), 2.82 (s, 6H), 2.08 (m, 3H), 1.53 (m, 3H), 1.23 (m, 4H)

실시예 21: (S)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-하이드록시아마이드 3-퀴놀린-8-일아마이드 Example 21: (S) -7- (4-dimethylamino-phenyl) -octa-2,4-dienodioic acid 1-hydroxyamide 3-quinolin-8-ylamide

단계 1: (S)-7-(4-다이메틸아미노-페닐)-7-(퀴놀린-3-일카바모일)-헵타-2,4-디에노산 에틸 에스터 Step 1: (S) -7- (4-dimethylamino-phenyl) -7- (quinolin-3-ylcarbamoyl) -hepta-2,4-dienoic acid ethyl ester

아민 화합물로서 3-아미노퀴놀린을 사용하는 것을 제외하고는 실시예 7의 단계 1과 동일한 방법으로 표제 화합물 (49％)을 얻었다.The title compound (49%) was obtained by the same method as Step 1 of Example 7, except for using 3-aminoquinoline as the amine compound.

1H NMR (300 MHz, CDCl3) : δ 8.73 (s, 1H), 8.57 (s, 1H), 8.00 (d, J =8.1 Hz, 1H), 7.775 (d, J =8.1 Hz, 1H), 7.57 (m, 2H), 7.18 (m, 3H), 6.74 (d, J = 8.7 Hz, 2H), 6.22 (m, 1H), 6.07 (m, 1H), 5.79 (d, J = 15.6 Hz, 1H), 4.18 (q, J = 7.4 Hz, 2H), 3.65 (t, J = 7.2 Hz, 1H), 3.08 (m, 1H), 2.94 (s, 6H), 2.74 (m, 1H), 1.28 (t, J = 7.2 Hz, 3H) 1 H NMR (300 MHz, CDCl 3 ): δ 8.73 (s, 1H), 8.57 (s, 1H), 8.00 (d, J = 8.1 Hz, 1H), 7.775 (d, J = 8.1 Hz, 1H), 7.57 (m, 2H), 7.18 (m, 3H), 6.74 (d, J = 8.7 Hz, 2H), 6.22 (m, 1H), 6.07 (m, 1H), 5.79 (d, J = 15.6 Hz, 1H ), 4.18 (q, J = 7.4 Hz, 2H), 3.65 (t, J = 7.2 Hz, 1H), 3.08 (m, 1H), 2.94 (s, 6H), 2.74 (m, 1H), 1.28 (t , J = 7.2 Hz, 3H)

단계 2: (S)-7-(4-다이메틸아미노-페닐)-7-(퀴놀린-3-일카바모일)-헵타-2,4-디에노산Step 2: (S) -7- (4-dimethylamino-phenyl) -7- (quinolin-3-ylcarbamoyl) -hepta-2,4-dienoic acid

출발물질로 상기 단계 1에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-7-(퀴놀린-3-일카바모일)-헵타-2,4-디에노산 에틸 에스터를 사용하는 것을 제외하고는 실시예 1의 단계 1과 동일한 방법으로 표제 화합물 (35％)을 얻었다.Using (S) -7- (4-dimethylamino-phenyl) -7- (quinolin-3-ylcarbamoyl) -hepta-2,4-dienoic acid ethyl ester obtained in step 1 above as starting material The title compound (35%) was obtained by the same method as Step 1 of Example 1, except.

1H NMR (300 MHz, MeOD-d4) : δ 8.87 (s, 1H), 8.68 (s, 1H), 7.97(m, 1H), 7.67 (m, 1H), 7.43 (m, 1H), 7.18 (m, 4H), 6.77 (d, J = 8.8 Hz, 2H), 6.22 (m, 1H), 6.10 (m, 1H), 5.80 (d, J = 15.3 Hz, 1H), 3.57 (t, J = 7.7 Hz, 1H), 2.91 (s, 6H), 2.86 (m, 1H), 2.61 (m, 1H) 1 H NMR (300 MHz, MeOD-d 4 ): δ 8.87 (s, 1H), 8.68 (s, 1H), 7.97 (m, 1H), 7.67 (m, 1H), 7.43 (m, 1H), 7.18 (m, 4H), 6.77 (d, J = 8.8 Hz, 2H), 6.22 (m, 1H), 6.10 (m, 1H), 5.80 (d, J = 15.3 Hz, 1H), 3.57 (t, J = 7.7 Hz, 1H), 2.91 (s, 6H), 2.86 (m, 1H), 2.61 (m, 1H)

단계 3: (S)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-하이드록 시아마이드 8-퀴놀린-8-일아마이드Step 3: (S) -7- (4-Dimethylamino-phenyl) -octa-2,4-dienedioic acid 1-hydroxy cyanide 8-quinolin-8-ylamide

출발물질로 상기 단계 2에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-7-(퀴놀린-8-일카바모일)-헵타-2,4-디에노산을 사용하는 것을 제외하고는 실시예 1의 단계 2와 동일한 방법으로 표제 화합물 (34％)을 얻었다.Except for using (S) -7- (4-dimethylamino-phenyl) -7- (quinolin-8-ylcarbamoyl) -hepta-2,4-dienoic acid obtained in step 2 as starting material Obtained the title compound (34%) in the same manner as in Step 2 of Example 1.

1H NMR (300 MHz, MeOD-d4) : δ 8.84 (s, 1H), 8.62 (s, 1H), 7.97(m, 1H), 7.67 (m, 1H), 7.45 (m, 1H), 7.13 (m, 4H), 6.77 (d, J = 8.8 Hz, 2H), 6.24 (m, 1H), 6.12 (m, 1H), 5.83 (d, J = 15.3 Hz, 1H), 3.57 (m, 1H), 2.93 (s, 6H), 2.86 (m, 1H), 2.61 (m, 1H) 1 H NMR (300 MHz, MeOD-d 4 ): δ 8.84 (s, 1H), 8.62 (s, 1H), 7.97 (m, 1H), 7.67 (m, 1H), 7.45 (m, 1H), 7.13 (m, 4H), 6.77 (d, J = 8.8 Hz, 2H), 6.24 (m, 1H), 6.12 (m, 1H), 5.83 (d, J = 15.3 Hz, 1H), 3.57 (m, 1H) , 2.93 (s, 6H), 2.86 (m, 1H), 2.61 (m, 1H)

실시예 22: (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-퀴놀린-3-일아마이드Example 22: (S) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 1-quinolin-3-ylamide

단계 1: (S)-7-(4-다이메틸아미노-페닐)-7-(퀴놀린-3-일카바모일)-헵타-2,4-디에노산 에틸 에스터Step 1: (S) -7- (4-dimethylamino-phenyl) -7- (quinolin-3-ylcarbamoyl) -hepta-2,4-dienoic acid ethyl ester

아민 화합물로서 3-아미노퀴놀린을 사용하는 것을 제외하고는 실시예 7의 단계 1과 동일한 방법으로 표제 화합물 (49％)을 얻었다.The title compound (49%) was obtained by the same method as Step 1 of Example 7, except for using 3-aminoquinoline as the amine compound.

1H NMR (300 MHz, CDCl3) : δ 8.73 (s, 1H), 8.57 (s, 1H), 8.00 (d, J =8.1 Hz, 1H), 7.775 (d, J =8.1 Hz, 1H), 7.57 (m, 2H), 7.18 (m, 3H), 6.74 (d, J = 8.7 Hz, 2H), 6.22 (m, 1H), 6.07 (m, 1H), 5.79 (d, J = 15.6 Hz, 1H), 4.18 (q, J = 7.4 Hz, 2H), 3.65 (t, J = 7.2 Hz, 1H), 3.08 (m, 1H), 2.94 (s, 6H), 2.74 (m, 1H), 1.28 (t, J = 7.2 Hz, 3H) 1 H NMR (300 MHz, CDCl 3 ): δ 8.73 (s, 1H), 8.57 (s, 1H), 8.00 (d, J = 8.1 Hz, 1H), 7.775 (d, J = 8.1 Hz, 1H), 7.57 (m, 2H), 7.18 (m, 3H), 6.74 (d, J = 8.7 Hz, 2H), 6.22 (m, 1H), 6.07 (m, 1H), 5.79 (d, J = 15.6 Hz, 1H ), 4.18 (q, J = 7.4 Hz, 2H), 3.65 (t, J = 7.2 Hz, 1H), 3.08 (m, 1H), 2.94 (s, 6H), 2.74 (m, 1H), 1.28 (t , J = 7.2 Hz, 3H)

단계 2: (S)-7-(4-다이메틸아미노-페닐)-7-(퀴놀린-3-일카바모일)-헵타노산 에틸 에스터Step 2: (S) -7- (4-dimethylamino-phenyl) -7- (quinolin-3-ylcarbamoyl) -heptanoic acid ethyl ester

출발물질로 상기 단계 1에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-7-(퀴놀린-3-일카바모일)-헵타-2,4-디에노산 에틸 에스터를 사용하는 것을 제외하고는 실시예 2와 동일한 방법으로 표제 화합물 (40％)을 얻었다.Using (S) -7- (4-dimethylamino-phenyl) -7- (quinolin-3-ylcarbamoyl) -hepta-2,4-dienoic acid ethyl ester obtained in step 1 above as starting material The title compound (40%) was obtained by the same method as the Example 2 except for the above.

1H NMR (300 MHz, CDCl3) : δ 1.22 (t, J = 7.2 Hz, 3H), 1.33 (m, 4H), 1.53 (m, 3H), 1.75 (m, 1H), 2.25 (m, 2H), 3.50 (m, 1H), 4.09 (q, J = 7.2 Hz, 2H), 6.45 (d, J = 7.8 Hz, 1H), 7.62 (m, 2H), 7.74 (d, J = 8.7 Hz, 2H), 8.01 (m, 3H), 8.22 (d, J = 8.7 Hz, 2H) 1 H NMR (300 MHz, CDCl 3 ): δ 1.22 (t, J = 7.2 Hz, 3H), 1.33 (m, 4H), 1.53 (m, 3H), 1.75 (m, 1H), 2.25 (m, 2H ), 3.50 (m, 1H), 4.09 (q, J = 7.2 Hz, 2H), 6.45 (d, J = 7.8 Hz, 1H), 7.62 (m, 2H), 7.74 (d, J = 8.7 Hz, 2H ), 8.01 (m, 3H), 8.22 (d, J = 8.7 Hz, 2H)

단계 3: (S)-7-(4-다이메틸아미노-페닐)-7-(퀴놀린-3-일카바모일)-헵타노산 Step 3: (S) -7- (4-dimethylamino-phenyl) -7- (quinolin-3-ylcarbamoyl) -heptanoic acid

출발물질로 상기 단계 2에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-7-(퀴놀린-3-일카바모일)-헵타노산 에틸 에스터를 사용하는 것을 제외하고는 실시예 3의 단계 2와 동일한 방법으로 표제 화합물 (95％)을 얻었다.Example 3, except using (S) -7- (4-dimethylamino-phenyl) -7- (quinolin-3-ylcarbamoyl) -heptanoic acid ethyl ester obtained as a starting material The title compound (95%) was obtained in the same manner as in step 2 of.

1H NMR (300 MHz, CDCl3) : δ 1.24 (m, 4H), 1.55 (m, 2H), 1.60 (m, 1H), 2.10 (m, 1H), 2.29 (m, 2H), 3.31 (m, 1H), 6.47 (d, J = 7.8 Hz, 1H), 6.67 (m, 4H), 6.99 (m, 5H) 1 H NMR (300 MHz, CDCl 3 ): δ 1.24 (m, 4H), 1.55 (m, 2H), 1.60 (m, 1H), 2.10 (m, 1H), 2.29 (m, 2H), 3.31 (m , 1H), 6.47 (d, J = 7.8 Hz, 1H), 6.67 (m, 4H), 6.99 (m, 5H)

단계 4: (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-퀴놀린-3-일아마이드Step 4: (S) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 1-quinolin-3-ylamide

출발물질로 상기 단계 3에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-7-(퀴놀린-3-일카바모일)-헵타노산을 사용하는 것을 제외하고는 실시예 1의 단계 2와 동일한 방법으로 표제 화합물 (95％)을 얻었다.Step of Example 1, except using (S) -7- (4-dimethylamino-phenyl) -7- (quinolin-3-ylcarbamoyl) -heptanoic acid obtained in step 3 above as starting material In the same manner as 2, the title compound (95%) was obtained.

1H NMR (300 MHz, DMSO-d6) : δ 1.32 (m, 4H), 1.50 (m, 2H), 1.65(m, 1H), 1.94 (t, J = 7.2 Hz, 2H), 2.04 (m, 1H), 2.87 (s, 6H), 3.80 (t, J = 6.6 Hz, 1H), 6.74 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.49 (m, 3H), 7.61 (d, J = 7.5 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.93 (d, J = 7.5 Hz, 2H), 8.65 (s, 1H), 9.95 (s, 1H), 10.33 (s, 1H) 1 H NMR (300 MHz, DMSO-d 6 ): δ 1.32 (m, 4H), 1.50 (m, 2H), 1.65 (m, 1H), 1.94 (t, J = 7.2 Hz, 2H), 2.04 (m , 1H), 2.87 (s, 6H), 3.80 (t, J = 6.6 Hz, 1H), 6.74 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.49 (m , 3H), 7.61 (d, J = 7.5 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.93 (d, J = 7.5 Hz, 2H), 8.65 (s, 1H), 9.95 (s , 1H), 10.33 (s, 1H)

실시예 23: (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-피리딘-4-일아마이드 Example 23 (S) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 1-pyridin-4-ylamide

단계 1: (S)-7-(4-다이메틸아미노-페닐)-7-(피리딘-4-일카바모일)-헵타-2,4-디에노산 에틸 에스터Step 1: (S) -7- (4-dimethylamino-phenyl) -7- (pyridin-4-ylcarbamoyl) -hepta-2,4-dienoic acid ethyl ester

아민 화합물로서 4-아미노피리딘을 사용하는 것을 제외하고는 실시예 7의 단계 1과 동일한 방법으로 표제 화합물 (78％)을 얻었다.The title compound (78%) was obtained by the same method as Step 1 of Example 7, except that 4-aminopyridine was used as the amine compound.

1H NMR (300 MHz, CDCl3) : δ 1.34 (m, 4H), 1.63 (m, 2H), 1.81 (m, 1H), 2.21 (m, 1H), 2.33 (t, J = 6.9 Hz, 2H), 2.94 (s, 6H), 3.49 (t, J = 7.5 Hz, 1H), 6.73 (d, J = 8.6 Hz, 2H), 7.23 (m, 3H), 7.91 (s, 1H), 8.26 (m, 2H), 8.47 (s, 1H) 1 H NMR (300 MHz, CDCl 3 ): δ 1.34 (m, 4H), 1.63 (m, 2H), 1.81 (m, 1H), 2.21 (m, 1H), 2.33 (t, J = 6.9 Hz, 2H ), 2.94 (s, 6H), 3.49 (t, J = 7.5 Hz, 1H), 6.73 (d, J = 8.6 Hz, 2H), 7.23 (m, 3H), 7.91 (s, 1H), 8.26 (m , 2H), 8.47 (s, 1H)

단계 2: (S)-7-(4-다이메틸아미노-페닐)-7-(피리딘-4-일카바모일)-헵타노산 에틸 에스터Step 2: (S) -7- (4-dimethylamino-phenyl) -7- (pyridin-4-ylcarbamoyl) -heptanoic acid ethyl ester

출발물질로 상기 단계 1에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-7-(피리딘-4-일카바모일)-헵타-2,4-디에노산 에틸 에스터를 사용하는 것을 제외하고는 실시예 2와 동일한 방법으로 표제 화합물 (81％)을 얻었다.Using (S) -7- (4-dimethylamino-phenyl) -7- (pyridin-4-ylcarbamoyl) -hepta-2,4-dienoic acid ethyl ester obtained in step 1 as starting material A title compound (81%) was obtained in the same manner as in Example 2 except for the following.

1H NMR (300 MHz, CDCl3) : δ 1.24 (t, J = 7.2 Hz, 3H), 1.31 (m, 4H), 1.50 (m, 2H), 1.80 (m, 1H), 2.21 (m, 3H), 2.95 (s, 6H), 3.35 (m, 1H), 4.11 (q, J = 7.2 Hz, 2H), 5.80 (m, 1H), 6.71 (d, J = 8.4 Hz, 2H), 7.04 (d, J = 6.0 Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H), 8.47 (d, J = 5.8 Hz, 2H) 1 H NMR (300 MHz, CDCl 3 ): δ 1.24 (t, J = 7.2 Hz, 3H), 1.31 (m, 4H), 1.50 (m, 2H), 1.80 (m, 1H), 2.21 (m, 3H ), 2.95 (s, 6H), 3.35 (m, 1H), 4.11 (q, J = 7.2 Hz, 2H), 5.80 (m, 1H), 6.71 (d, J = 8.4 Hz, 2H), 7.04 (d , J = 6.0 Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H), 8.47 (d, J = 5.8 Hz, 2H)

단계 3: (S)-7-(4-다이메틸아미노-페닐)-7-(피리딘-4-일카바모일)-헵타노산 Step 3: (S) -7- (4-dimethylamino-phenyl) -7- (pyridin-4-ylcarbamoyl) -heptanoic acid

출발물질로 상기 단계 2에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-7-(피리딘-4-일카바모일)-헵타노산 에틸 에스터를 사용하는 것을 제외하고는 실시예 3의 단 계 2와 동일한 방법으로 표제 화합물 (67％)을 얻었다.Example 3 except using (S) -7- (4-dimethylamino-phenyl) -7- (pyridin-4-ylcarbamoyl) -heptanoic acid ethyl ester obtained as a starting material The title compound (67%) was obtained in the same manner as Step 2 of.

1H NMR (300 MHz, CDCl3) : δ 1.24 (t, J = 7.2 Hz, 3H), 1.31 (m, 4H), 1.50 (m, 2H), 1.80 (m, 1H), 2.21 (m, 3H), 2.95 (s, 6H), 3.35 (m, 1H), 4.11 (q, J = 7.2 Hz, 2H), 5.80 (m, 1H), 6.71 (d, J = 8.4 Hz, 2H), 7.04 (d, J = 6.0 Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H), 8.47 (d, J = 5.8 Hz, 2H) 1 H NMR (300 MHz, CDCl 3 ): δ 1.24 (t, J = 7.2 Hz, 3H), 1.31 (m, 4H), 1.50 (m, 2H), 1.80 (m, 1H), 2.21 (m, 3H ), 2.95 (s, 6H), 3.35 (m, 1H), 4.11 (q, J = 7.2 Hz, 2H), 5.80 (m, 1H), 6.71 (d, J = 8.4 Hz, 2H), 7.04 (d , J = 6.0 Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H), 8.47 (d, J = 5.8 Hz, 2H)

단계 4: (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-피리딘-4-일아마이드Step 4: (S) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 1-pyridin-4-ylamide

출발물질로 상기 단계 3에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-7-(피리딘-4-일카바모일)-헵타노산을 사용하는 것을 제외하고는 실시예 1의 단계 2와 동일한 방법으로 표제 화합물 (67％)을 얻었다.Step of Example 1, except using (S) -7- (4-dimethylamino-phenyl) -7- (pyridin-4-ylcarbamoyl) -heptanoic acid obtained in step 3 above as starting material In the same manner as 2, the title compound (67%) was obtained.

1H NMR (300 MHz, DMSO-d6) : δ 1.32 (m, 4H), 1.50 (m, 2H), 1.65(m, 1H), 1.94 (t, J = 7.2 Hz, 2H), 2.04 (m, 1H), 2.87 (s, 6H), 3.80 (t, J = 6.6 Hz, 1H), 6.74 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.49 (m, 3H), 7.61 (d, J = 7.5 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.93 (d, J = 7.5 Hz, 2H), 8.65 (s, 1H), 9.95 (s, 1H), 10.33 (s, 1H) 1 H NMR (300 MHz, DMSO-d 6 ): δ 1.32 (m, 4H), 1.50 (m, 2H), 1.65 (m, 1H), 1.94 (t, J = 7.2 Hz, 2H), 2.04 (m , 1H), 2.87 (s, 6H), 3.80 (t, J = 6.6 Hz, 1H), 6.74 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.49 (m , 3H), 7.61 (d, J = 7.5 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.93 (d, J = 7.5 Hz, 2H), 8.65 (s, 1H), 9.95 (s , 1H), 10.33 (s, 1H)

실시예 24: (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 1-[(4-다이메틸아미노-페닐)-아마이드] 8-하이드록시아마이드Example 24: (S) -2- (4-Dimethylamino-phenyl) -octanedioic acid 1-[(4-dimethylamino-phenyl) -amide] 8-hydroxyamide

단계 1: (S)-7-(4-다이메틸아미노-페닐)-7-(4-다이메틸아미노-페닐카바모일)-헵타-2,4-디에노산 에틸 에스터Step 1: (S) -7- (4-dimethylamino-phenyl) -7- (4-dimethylamino-phenylcarbamoyl) -hepta-2,4-dienoic acid ethyl ester

아민화합물로서 N,N-다이메틸-1,4-페닐렌디아민을 사용하는 것을 제외하고는 실시예 7의 단계 1과 동일한 방법으로 표제 화합물 (90％)을 얻었다.The title compound (90%) was obtained by the same method as Step 1 of Example 7, except for using N, N-dimethyl-1,4-phenylenediamine as the amine compound.

1H NMR (200 MHz, CDCl3) : δ 1.34 (m, 4H), 1.63 (m, 2H), 1.81 (m, 1H), 2.21 (m, 1H), 2.33 (t, J = 6.9 Hz, 2H), 2.94 (s, 6H), 3.49 (t, J = 7.5 Hz, 1H), 6.73 (d, J = 8.6 Hz, 2H), 7.23 (m, 3H), 7.91 (s, 1H), 8.26 (m, 2H), 8.47 (s, 1H) 1 H NMR (200 MHz, CDCl 3 ): δ 1.34 (m, 4H), 1.63 (m, 2H), 1.81 (m, 1H), 2.21 (m, 1H), 2.33 (t, J = 6.9 Hz, 2H ), 2.94 (s, 6H), 3.49 (t, J = 7.5 Hz, 1H), 6.73 (d, J = 8.6 Hz, 2H), 7.23 (m, 3H), 7.91 (s, 1H), 8.26 (m , 2H), 8.47 (s, 1H)

단계 2: (S)-7-(4-다이메틸아미노-페닐)-7-(4-다이메틸아미노-페닐카바모일)-헵타노산 에틸 에스터Step 2: (S) -7- (4-dimethylamino-phenyl) -7- (4-dimethylamino-phenylcarbamoyl) -heptanoic acid ethyl ester

출발물질로 상기 단계 1에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-7-(4-다이메틸아미노-페닐카바모일)-헵타-2,4-디에노산 에틸 에스터를 사용하는 것을 제외하고는 실시예 2와 동일한 방법으로 표제 화합물 (78％)을 얻었다.(S) -7- (4-dimethylamino-phenyl) -7- (4-dimethylamino-phenylcarbamoyl) -hepta-2,4-dienoic acid ethyl ester obtained in step 1 was used as a starting material. The title compound (78%) was obtained in the same manner as in Example 2 except for the following procedure.

1H NMR (300 MHz, CDCl3) : δ 1.24 (t, J = 7.2 Hz, 3H), 1.30 (m, 4H), 1.59 (m, 2H), 1.69 (m, 1H), 2.25 (m, 3H), 2.95 (s, 6H), 3.36 (m, 1H), 4.11 (q, J = 7.2 Hz, 2H), 6.70 (m, 4H), 6.97 (s, 1H), 7.20 (m, 4H) 1 H NMR (300 MHz, CDCl 3 ): δ 1.24 (t, J = 7.2 Hz, 3H), 1.30 (m, 4H), 1.59 (m, 2H), 1.69 (m, 1H), 2.25 (m, 3H ), 2.95 (s, 6H), 3.36 (m, 1H), 4.11 (q, J = 7.2 Hz, 2H), 6.70 (m, 4H), 6.97 (s, 1H), 7.20 (m, 4H)

단계 3: (S)-7-(4-다이메틸아미노-페닐)-7-(4-다이메틸아미노-페닐카바모 일)-헵타노산Step 3: (S) -7- (4-dimethylamino-phenyl) -7- (4-dimethylamino-phenylcarbamoyl) -heptanoic acid

출발물질로 상기 단계 2에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-7-(4-다이메틸아미노-페닐카바모일)-헵타노산 에틸 에스터를 사용하는 것을 제외하고는 실시예 3의 단계 2와 동일한 방법으로 표제 화합물 (23％)을 얻었다.Except for using (S) -7- (4-dimethylamino-phenyl) -7- (4-dimethylamino-phenylcarbamoyl) -heptanoic acid ethyl ester obtained in step 2 as starting material In the same manner as in Step 2 of Example 3, the title compound (23%) was obtained.

1H NMR (300 MHz, CDCl3) : δ 1.28 (m, 4H), 1.61 (m, 2H), 1.77 (m, 1H), 2.28 (m, 3H), 2.95 (s, 6H), 3.36 (m, 1H), 6.66 (d, J = 9.0 Hz, 2H), 6.74 (d, J = 8.7 Hz, 2H), 6.94 (s, 1H), 7.15 (d, J = 9.0 Hz, 2H), 7.27 (d, J = 8.7 Hz, 2H) 1 H NMR (300 MHz, CDCl 3 ): δ 1.28 (m, 4H), 1.61 (m, 2H), 1.77 (m, 1H), 2.28 (m, 3H), 2.95 (s, 6H), 3.36 (m , 1H), 6.66 (d, J = 9.0 Hz, 2H), 6.74 (d, J = 8.7 Hz, 2H), 6.94 (s, 1H), 7.15 (d, J = 9.0 Hz, 2H), 7.27 (d , J = 8.7 Hz, 2H)

단계 4: (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 1-[(4-다이메틸아미노-페닐)-아마이드] 8-하이드록시아마이드Step 4: (S) -2- (4-dimethylamino-phenyl) -octanedioic acid 1-[(4-dimethylamino-phenyl) -amide] 8-hydroxyamide

출발물질로 상기 단계 3에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-7-(4-다이메틸아미노-페닐카바모일)-헵타노산을 사용하는 것을 제외하고는 실시예 1의 단계 2와 동일한 방법으로 표제 화합물 (23％)을 얻었다.Example 1, except that (S) -7- (4-dimethylamino-phenyl) -7- (4-dimethylamino-phenylcarbamoyl) -heptanoic acid obtained in Step 3 was used as a starting material. The title compound (23%) was obtained in the same manner as in Step 2 of.

1H NMR (300 MHz, DMSO-d6) : δ 1.32 (m, 4H), 1.50 (m, 2H), 1.65(m, 1H), 1.94 (t, J = 7.2 Hz, 2H), 2.04 (m, 1H), 2.87 (s, 6H), 3.80 (t, J = 6.6 Hz, 1H), 6.74 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.49 (m, 3H), 7.61 (d, J = 7.5 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.93 (d, J = 7.5 Hz, 2H), 8.65 (s, 1H), 9.95 (s, 1H), 10.33 (s, 1H) 1 H NMR (300 MHz, DMSO-d 6 ): δ 1.32 (m, 4H), 1.50 (m, 2H), 1.65 (m, 1H), 1.94 (t, J = 7.2 Hz, 2H), 2.04 (m , 1H), 2.87 (s, 6H), 3.80 (t, J = 6.6 Hz, 1H), 6.74 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.49 (m , 3H), 7.61 (d, J = 7.5 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.93 (d, J = 7.5 Hz, 2H), 8.65 (s, 1H), 9.95 (s , 1H), 10.33 (s, 1H)

실시예 25: (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-피리딘-3-일아마이드 Example 25 (S) -2- (4-Dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 1-pyridin-3-ylamide

단계 1: (S)-7-(4-다이메틸아미노-페닐)-7-(피리딘-3-일카바모일)-헵타-2,4-디에노산 에틸 에스터Step 1: (S) -7- (4-dimethylamino-phenyl) -7- (pyridin-3-ylcarbamoyl) -hepta-2,4-dienoic acid ethyl ester

아민 화합물로서 3-아미노피리딘을 사용하는 것을 제외하고는 실시예 7의 단계 1과 동일한 방법으로 표제 화합물 (70％)을 얻었다.The title compound (70%) was obtained by the same method as Step 1 of Example 7, except that 3-aminopyridine was used as the amine compound.

1H NMR (300 MHz, CDCl3) : δ 1.34 (m, 4H), 1.63 (m, 2H), 1.81 (m, 1H), 2.21 (m, 1H), 2.33 (t, J = 6.4 Hz, 2H), 2.94 (s, 6H), 3.49 (t, J = 7.4 Hz, 1H), 6.73 (d, J = 8.4 Hz, 2H), 7.25 (m, 3H), 7.95 (s, 1H), 8.26 (m, 2H), 8.47 (s, 1H) 1 H NMR (300 MHz, CDCl 3 ): δ 1.34 (m, 4H), 1.63 (m, 2H), 1.81 (m, 1H), 2.21 (m, 1H), 2.33 (t, J = 6.4 Hz, 2H ), 2.94 (s, 6H), 3.49 (t, J = 7.4 Hz, 1H), 6.73 (d, J = 8.4 Hz, 2H), 7.25 (m, 3H), 7.95 (s, 1H), 8.26 (m , 2H), 8.47 (s, 1H)

단계 2: (S)-7-(4-다이메틸아미노-페닐)-7-(피리딘-3-일카바모일)-헵타노산 에틸 에스터Step 2: (S) -7- (4-dimethylamino-phenyl) -7- (pyridin-3-ylcarbamoyl) -heptanoic acid ethyl ester

출발물질로 상기 단계 1에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-7-(피리딘-3-일카바모일)-헵타-2,4-디에노산 에틸 에스터를 사용하는 것을 제외하고는 실시예 2와 동일한 방법으로 표제 화합물 (75％)을 얻었다.Using (S) -7- (4-dimethylamino-phenyl) -7- (pyridin-3-ylcarbamoyl) -hepta-2,4-dienoic acid ethyl ester obtained in step 1 as starting material A title compound (75%) was obtained in the same manner as in Example 2 except for the following.

1H NMR (300 MHz, CDCl3) : δ 1.23 (t, J = 7.2 Hz, 3H), 1.33 (m, 4H), 1.59 (m, 2H), 1.80 (m, 1H), 2.23 (m, 3H), 2.95 (s, 6H), 3.40 (m, 1H), 4.11 (q, J = 7.2 Hz, 2H), 6.73 (d, J = 8.5 Hz, 2H), 7.19 (m, 3H), 7.40 (s, 1H), 8.13 (m, 1H), 8.28 (m, 1H), 8.40 (s, 1H) 1 H NMR (300 MHz, CDCl 3 ): δ 1.23 (t, J = 7.2 Hz, 3H), 1.33 (m, 4H), 1.59 (m, 2H), 1.80 (m, 1H), 2.23 (m, 3H ), 2.95 (s, 6H), 3.40 (m, 1H), 4.11 (q, J = 7.2 Hz, 2H), 6.73 (d, J = 8.5 Hz, 2H), 7.19 (m, 3H), 7.40 (s , 1H), 8.13 (m, 1H), 8.28 (m, 1H), 8.40 (s, 1H)

단계 3: (S)-7-(4-다이메틸아미노-페닐)-7-(피리딘-3-일카바모일)-헵타노산 Step 3: (S) -7- (4-dimethylamino-phenyl) -7- (pyridin-3-ylcarbamoyl) -heptanoic acid

출발물질로 상기 단계 2에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-7-(피리딘-3-일카바모일)-헵타노산 에틸 에스터를 사용하는 것을 제외하고는 실시예 3의 단계 2와 동일한 방법으로 표제 화합물 (77％)을 얻었다.Example 3, except using (S) -7- (4-dimethylamino-phenyl) -7- (pyridin-3-ylcarbamoyl) -heptanoic acid ethyl ester obtained as a starting material The title compound (77%) was obtained in the same manner as in Step 2.

1H NMR (300 MHz, CDCl3) : δ 1.34 (m, 4H), 1.63 (m, 2H), 1.81 (m, 1H), 2.21 (m, 1H), 2.33 (t, J = 6.9 Hz, 2H), 2.94 (s, 6H), 3.49 (t, J = 7.5 Hz, 1H), 6.73 (d, J = 8.6 Hz, 2H), 7.23 (m, 3H), 7.91 (s, 1H), 8.26 (m, 2H), 8.47 (s, 1H) 1 H NMR (300 MHz, CDCl 3 ): δ 1.34 (m, 4H), 1.63 (m, 2H), 1.81 (m, 1H), 2.21 (m, 1H), 2.33 (t, J = 6.9 Hz, 2H ), 2.94 (s, 6H), 3.49 (t, J = 7.5 Hz, 1H), 6.73 (d, J = 8.6 Hz, 2H), 7.23 (m, 3H), 7.91 (s, 1H), 8.26 (m , 2H), 8.47 (s, 1H)

단계 4: (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-피리딘-3-일아마이드Step 4: (S) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 1-pyridin-3-ylamide

출발물질로 상기 단계 3에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-7-(피리딘-3-일카바모일)-헵타노산을 사용하는 것을 제외하고는 실시예 1의 단계 2와 동일한 방법으로 표제 화합물 (77％)을 얻었다.Step of Example 1, except using (S) -7- (4-dimethylamino-phenyl) -7- (pyridin-3-ylcarbamoyl) -heptanoic acid obtained in step 3 above as starting material In the same manner as 2, the title compound (77%) was obtained.

1H NMR (300 MHz, DMSO-d6) : δ 1.32 (m, 4H), 1.50 (m, 2H), 1.65(m, 1H), 1.94 (t, J = 7.2 Hz, 2H), 2.04 (m, 1H), 2.87 (s, 6H), 3.80 (t, J = 6.6 Hz, 1H), 6.74 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.49 (m, 3H), 7.61 (d, J = 7.5 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.93 (d, J = 7.5 Hz, 2H), 8.65 (s, 1H), 9.95 (s, 1H), 10.33 (s, 1H) 1 H NMR (300 MHz, DMSO-d 6 ): δ 1.32 (m, 4H), 1.50 (m, 2H), 1.65 (m, 1H), 1.94 (t, J = 7.2 Hz, 2H), 2.04 (m , 1H), 2.87 (s, 6H), 3.80 (t, J = 6.6 Hz, 1H), 6.74 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.49 (m , 3H), 7.61 (d, J = 7.5 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.93 (d, J = 7.5 Hz, 2H), 8.65 (s, 1H), 9.95 (s , 1H), 10.33 (s, 1H)

실시예 26: (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-[(5-하이드록시-나프탈렌-1-일)-아마이드] Example 26: (S) -2- (4-Dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 1-[(5-hydroxy-naphthalen-1-yl) -amide]

단계 1: (S)-7-(4-다이메틸아미노-페닐)-7-(5-하이드록시-나프탈렌-1-일카바모일)-헵타-2,4-디에노산 에틸 에스터Step 1: (S) -7- (4-dimethylamino-phenyl) -7- (5-hydroxy-naphthalen-1-ylcarbamoyl) -hepta-2,4-dienoic acid ethyl ester

아민 화합물로서 5-아미노-1-나프톨을 사용하는 것을 제외하고는 실시예 7의 단계 1과 동일한 방법으로 표제 화합물 (94％)을 얻었다.The title compound (94%) was obtained by the same method as Step 1 of Example 7, except that 5-amino-1-naphthol was used as the amine compound.

1H NMR (300 MHz, CDCl3) : δ 1.33 (m, 4H), 1.67 (m, 2H), 1.82 (m, 1H), 2.21 (m, 1H), 2.33 (t, J = 6.4 Hz, 2H), 2.94 (s, 6H), 3.49 (t, J = 7.4 Hz, 1H), 6.73 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 8.4 Hz, 1H), 7.12 (m, 2H), 7.42 (m, 4H), 7.67 (d, J = 8.6 Hz, 1H) 1 H NMR (300 MHz, CDCl 3 ): δ 1.33 (m, 4H), 1.67 (m, 2H), 1.82 (m, 1H), 2.21 (m, 1H), 2.33 (t, J = 6.4 Hz, 2H ), 2.94 (s, 6H), 3.49 (t, J = 7.4 Hz, 1H), 6.73 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 8.4 Hz, 1H), 7.12 (m, 2H ), 7.42 (m, 4H), 7.67 (d, J = 8.6 Hz, 1H)

단계 2: (S)-7-(4-다이메틸아미노-페닐)-7-(5-하이드록시-나프탈렌-1-일카바모일)-헵타노산 에틸 에스터Step 2: (S) -7- (4-dimethylamino-phenyl) -7- (5-hydroxy-naphthalen-1-ylcarbamoyl) -heptanoic acid ethyl ester

출발물질로 상기 단계 1에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-7-(5-하이 드록시-나프탈렌-1-일카바모일)-헵타-2,4-디에노산 에틸 에스터를 사용하는 것을 제외하고는 실시예 2와 동일한 방법으로 표제 화합물 (80％)을 얻었다.(S) -7- (4-dimethylamino-phenyl) -7- (5-hydroxy-naphthalen-1-ylcarbamoyl) -hepta-2,4-dienoic acid obtained in step 1 as starting material The title compound (80%) was obtained by the same method as Example 2 except using ethyl ester.

1H NMR (300 MHz, CDCl3) : δ 1.25 (t, J = 7.2 Hz, 3H), 1.42 (m, 4H), 1.63 (m, 2H), 1.90 (m, 1H), 2.23 (m, 3H), 2.97 (s, 6H), 3.82 (m, 1H), 4.13 (q, J = 7.2 Hz, 2H), 6.79 (m, 3H), 6.99 (d, J = 8.4 Hz, 1H), 7.15 (m, 2H), 7.38 (m, 4H), 7.65 (d, J = 8.6 Hz, 1H) 1 H NMR (300 MHz, CDCl 3 ): δ 1.25 (t, J = 7.2 Hz, 3H), 1.42 (m, 4H), 1.63 (m, 2H), 1.90 (m, 1H), 2.23 (m, 3H ), 2.97 (s, 6H), 3.82 (m, 1H), 4.13 (q, J = 7.2 Hz, 2H), 6.79 (m, 3H), 6.99 (d, J = 8.4 Hz, 1H), 7.15 (m , 2H), 7.38 (m, 4H), 7.65 (d, J = 8.6 Hz, 1H)

단계 3: (S)-7-(4-다이메틸아미노-페닐)-7-(5-하이드록시-나프탈렌-1-일카바모일)-헵타노산 Step 3: (S) -7- (4-dimethylamino-phenyl) -7- (5-hydroxy-naphthalen-1-ylcarbamoyl) -heptanoic acid

출발물질로 상기 단계 2에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-7-(5-하이드록시-나프탈렌-1-일카바모일)-헵타노산 에틸 에스터를 사용하는 것을 제외하고는 실시예 3의 단계 2와 동일한 방법으로 표제 화합물 (80％)을 얻었다.Except for using (S) -7- (4-dimethylamino-phenyl) -7- (5-hydroxy-naphthalen-1-ylcarbamoyl) -heptanoic acid ethyl ester obtained in step 2 as starting material In the same manner as in Step 2 of Example 3, the title compound (80%) was obtained.

1H NMR (300 MHz, CDCl3) : δ 1.28 (m, 4H), 1.61 (m, 2H), 1.75 (m, 1H), 2.05 (m, 1H), 2.31 (t, J = 7.3 Hz, 2H), 2.92 (s, 6H), 3.44 (t, J = 7.6 Hz, 1H), 6.72 (d, J = 8.7 Hz, 2H), 6.82 (m, 2H), 7.19 (d, J = 8.7 Hz, 2H), 7.30 (m, 3H), 7.41 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H) 1 H NMR (300 MHz, CDCl 3 ): δ 1.28 (m, 4H), 1.61 (m, 2H), 1.75 (m, 1H), 2.05 (m, 1H), 2.31 (t, J = 7.3 Hz, 2H ), 2.92 (s, 6H), 3.44 (t, J = 7.6 Hz, 1H), 6.72 (d, J = 8.7 Hz, 2H), 6.82 (m, 2H), 7.19 (d, J = 8.7 Hz, 2H ), 7.30 (m, 3H), 7.41 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H)

단계 4: (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-[(5-하이드록시-나프탈렌-1-일)-아마이드] Step 4: (S) -2- (4-Dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 1-[(5-hydroxy-naphthalen-1-yl) -amide]

출발물질로 상기 단계 3에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-7-(5-하이드록시-나프탈렌-1-일카바모일)-헵타노산을 사용하는 것을 제외하고는 실시예 1의 단계 2와 동일한 방법으로 표제 화합물 (80％)을 얻었다.Except for using (S) -7- (4-dimethylamino-phenyl) -7- (5-hydroxy-naphthalen-1-ylcarbamoyl) -heptanoic acid obtained in step 3 above as starting material In the same manner as in Step 2 of Example 1, the title compound (80%) was obtained.

1H NMR (300 MHz, DMSO-d6) : δ 1.32 (m, 4H), 1.50 (m, 2H), 1.65(m, 1H), 1.94 (t, J = 7.2 Hz, 2H), 2.04 (m, 1H), 2.87 (s, 6H), 3.80 (t, J = 6.6 Hz, 1H), 6.74 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.49 (m, 3H), 7.61 (d, J = 7.5 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.93 (d, J = 7.5 Hz, 2H), 8.65 (s, 1H), 9.95 (s, 1H), 10.33 (s, 1H) 1 H NMR (300 MHz, DMSO-d 6 ): δ 1.32 (m, 4H), 1.50 (m, 2H), 1.65 (m, 1H), 1.94 (t, J = 7.2 Hz, 2H), 2.04 (m , 1H), 2.87 (s, 6H), 3.80 (t, J = 6.6 Hz, 1H), 6.74 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.49 (m , 3H), 7.61 (d, J = 7.5 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.93 (d, J = 7.5 Hz, 2H), 8.65 (s, 1H), 9.95 (s , 1H), 10.33 (s, 1H)

실시예 27: (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-{[2-(1H-인돌-3-일)-에틸]-아마이드} Example 27: (S) -2- (4-Dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 1-{[2- (1H-indol-3-yl) -ethyl] -amide}

단계 1: (S)-7-(4-다이메틸아미노-페닐)-7-[2-(1H-인돌-3-일)-에틸카바모일]-헵타-2,4-디에노산 에틸 에스터Step 1: (S) -7- (4-Dimethylamino-phenyl) -7- [2- (1H-indol-3-yl) -ethylcarbamoyl] -hepta-2,4-dienoic acid ethyl ester

아민 화합물로서 트립타민을 사용하는 것을 제외하고는 실시예 7의 단계 1과 동일한 방법으로 표제 화합물 (74％)을 얻었다.The title compound (74%) was obtained by the same method as Step 1 of Example 7, except for using tryptamine as the amine compound.

1H NMR (300 MHz, CDCl3) : δ1.25 (t, J = 7.2 Hz, 3H), 1.28 (m, 4H), 1.61 (m, 2H), 1.75 (m, 1H), 2.05 (m, 1H), 2.31 (t, J = 7.3 Hz, 2H), 2.92 (s, 6H), 3.44 (t, J = 7.6 Hz, 1H), 4.13 (q, J = 7.2 Hz, 2H), 6.72 (d, J = 8.7 Hz, 2H), 6.82 (m, 2H), 7.19 (d, J = 8.7 Hz, 2H), 7.30 (m, 3H), 7.41 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H) 1 H NMR (300 MHz, CDCl 3 ): δ 1.25 (t, J = 7.2 Hz, 3H), 1.28 (m, 4H), 1.61 (m, 2H), 1.75 (m, 1H), 2.05 (m, 1H), 2.31 (t, J = 7.3 Hz, 2H), 2.92 (s, 6H), 3.44 (t, J = 7.6 Hz, 1H), 4.13 (q, J = 7.2 Hz, 2H), 6.72 (d, J = 8.7 Hz, 2H), 6.82 (m, 2H), 7.19 (d, J = 8.7 Hz, 2H), 7.30 (m, 3H), 7.41 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H)

단계 2: (S)-7-(4-다이메틸아미노-페닐)-7-[2-(1H-인돌-3-일)-에틸카바모일]-헵타노산 에틸 에스터Step 2: (S) -7- (4-dimethylamino-phenyl) -7- [2- (1H-indol-3-yl) -ethylcarbamoyl] -heptanoic acid ethyl ester

출발물질로 상기 단계 1에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-7-[2-(1H-인돌-3-일)-에틸카바모일)-헵타-2,4-디에노산 에틸 에스터를 사용하는 것을 제외하고는 실시예 2와 동일한 방법으로 표제 화합물 (94％)을 얻었다.(S) -7- (4-dimethylamino-phenyl) -7- [2- (1H-indol-3-yl) -ethylcarbamoyl) -hepta-2,4- as a starting material The title compound (94%) was obtained in the same manner as in Example 2 except for using dienoic acid ethyl ester.

1H NMR (300 MHz, CDCl3) : δ1.25 (t, J = 7.2 Hz, 3H), 1.28 (m, 4H), 1.61 (m, 2H), 1.75 (m, 1H), 2.05 (m, 1H), 2.31 (t, J = 7.3 Hz, 2H), 2.92 (s, 6H), 3.44 (t, J = 7.6 Hz, 1H), 4.13 (q, J = 7.2 Hz, 2H), 6.72 (d, J = 8.7 Hz, 2H), 6.82 (m, 2H), 7.19 (d, J = 8.7 Hz, 2H), 7.30 (m, 3H), 7.41 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H) 1 H NMR (300 MHz, CDCl 3 ): δ 1.25 (t, J = 7.2 Hz, 3H), 1.28 (m, 4H), 1.61 (m, 2H), 1.75 (m, 1H), 2.05 (m, 1H), 2.31 (t, J = 7.3 Hz, 2H), 2.92 (s, 6H), 3.44 (t, J = 7.6 Hz, 1H), 4.13 (q, J = 7.2 Hz, 2H), 6.72 (d, J = 8.7 Hz, 2H), 6.82 (m, 2H), 7.19 (d, J = 8.7 Hz, 2H), 7.30 (m, 3H), 7.41 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H)

단계 3: (S)-7-(4-다이메틸아미노-페닐)-7-[2-(1H-인돌-3-일)-에틸카바모일]-헵타노산 Step 3: (S) -7- (4-Dimethylamino-phenyl) -7- [2- (1H-indol-3-yl) -ethylcarbamoyl] -heptanoic acid

출발물질로 상기 단계 2에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-7-[2-(1H-인돌-3-일)-에틸카바모일]-헵타노산 에틸 에스터를 사용하는 것을 제외하고는 실시예 3의 단계 2와 동일한 방법으로 표제 화합물 (93％)을 얻었다.(S) -7- (4-Dimethylamino-phenyl) -7- [2- (1H-indol-3-yl) -ethylcarbamoyl] -heptanoic acid ethyl ester obtained as a starting material was used. The title compound (93%) was obtained in the same manner as in Step 2 of Example 3, except that.

1H NMR (300 MHz, CDCl3) : δ 1.28 (m, 4H), 1.61 (m, 2H), 1.75 (m, 1H), 2.05 (m, 1H), 2.31 (t, J = 7.3 Hz, 2H), 2.92 (s, 6H), 3.44 (t, J = 7.6 Hz, 1H), 6.72 (d, J = 8.7 Hz, 2H), 6.82 (m, 2H), 7.19 (d, J = 8.7 Hz, 2H), 7.30 (m, 3H), 7.41 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H) 1 H NMR (300 MHz, CDCl 3 ): δ 1.28 (m, 4H), 1.61 (m, 2H), 1.75 (m, 1H), 2.05 (m, 1H), 2.31 (t, J = 7.3 Hz, 2H ), 2.92 (s, 6H), 3.44 (t, J = 7.6 Hz, 1H), 6.72 (d, J = 8.7 Hz, 2H), 6.82 (m, 2H), 7.19 (d, J = 8.7 Hz, 2H ), 7.30 (m, 3H), 7.41 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H)

단계 4: (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-{[2-(1H-인돌-3-일)-에틸]-아마이드} Step 4: (S) -2- (4-Dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 1-{[2- (1H-indol-3-yl) -ethyl] -amide}

출발물질로 상기 단계 3에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-7-[2-(1H-인돌-3-일)-에틸카바모일]-헵타노산을 사용하는 것을 제외하고는 실시예 1의 단계 2와 동일한 방법으로 표제 화합물 (93％)을 얻었다.Using (S) -7- (4-dimethylamino-phenyl) -7- [2- (1H-indol-3-yl) -ethylcarbamoyl] -heptanoic acid obtained in step 3 above as starting material Except for Step 2 of Example 1, the title compound (93%) was obtained.

1H NMR (300 MHz, DMSO-d6) : δ 1.32 (m, 4H), 1.50 (m, 2H), 1.65(m, 1H), 1.94 (t, J = 7.2 Hz, 2H), 2.04 (m, 1H), 2.87 (s, 6H), 3.80 (t, J = 6.6 Hz, 1H), 6.74 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.49 (m, 3H), 7.61 (d, J = 7.5 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.93 (d, J = 7.5 Hz, 2H), 8.65 (s, 1H), 9.95 (s, 1H), 10.33 (s, 1H) 1 H NMR (300 MHz, DMSO-d 6 ): δ 1.32 (m, 4H), 1.50 (m, 2H), 1.65 (m, 1H), 1.94 (t, J = 7.2 Hz, 2H), 2.04 (m , 1H), 2.87 (s, 6H), 3.80 (t, J = 6.6 Hz, 1H), 6.74 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.49 (m , 3H), 7.61 (d, J = 7.5 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.93 (d, J = 7.5 Hz, 2H), 8.65 (s, 1H), 9.95 (s , 1H), 10.33 (s, 1H)

실시예 28: (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-[(6-메톡시-퀴놀린-3-일)-아마이드]Example 28: (S) -2- (4-Dimethylamino-phenyl) -octanodioic acid 8-hydroxyamide 1-[(6-methoxy-quinolin-3-yl) -amide]

단계 1: (S)-7-(4-다이메틸아미노-페닐)-7-(6-메톡시-퀴놀린-3-일카바모일)-헵타-2,4-디에노산 에틸 에스터Step 1: (S) -7- (4-dimethylamino-phenyl) -7- (6-methoxy-quinolin-3-ylcarbamoyl) -hepta-2,4-dienoic acid ethyl ester

아민 화합물로서 3-아미노 6-메톡시퀴놀린을 사용하는 것을 제외하고는 실시예 7의 단계 1과 동일한 방법으로 표제 화합물 (48％)을 얻었다.The title compound (48%) was obtained by the same method as Step 1 of Example 7, except that 3-amino 6-methoxyquinoline was used as the amine compound.

1H NMR (300 MHz, CDCl3) : δ 8.71 (s, 1H), 8.57 (s, 1H), 8.04 (d, J =8.1 Hz, 1H), 7.75 (d, J =8.1 Hz, 1H), 7.57 (m, 2H), 7.18 (m, 2H), 6.74 (d, J = 8.7 Hz, 2H), 6.22 (m, 1H), 6.07 (m, 1H), 5.79 (d, J = 15.6 Hz, 1H), 4.18 (q, J = 7.4 Hz, 2H), 3.75 (s, 3H), 3.65 (m, 1H), 3.08 (m, 1H), 2.94 (s, 6H), 2.74 (m, 1H), 1.28 (t, J = 7.2 Hz, 3H) 1 H NMR (300 MHz, CDCl 3 ): δ 8.71 (s, 1H), 8.57 (s, 1H), 8.04 (d, J = 8.1 Hz, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.57 (m, 2H), 7.18 (m, 2H), 6.74 (d, J = 8.7 Hz, 2H), 6.22 (m, 1H), 6.07 (m, 1H), 5.79 (d, J = 15.6 Hz, 1H ), 4.18 (q, J = 7.4 Hz, 2H), 3.75 (s, 3H), 3.65 (m, 1H), 3.08 (m, 1H), 2.94 (s, 6H), 2.74 (m, 1H), 1.28 (t, J = 7.2 Hz, 3H)

단계 2: (S)-7-(4-다이메틸아미노-페닐)-7-(6-메톡시-퀴놀린-3-일카바모일)-헵타노산 에틸 에스터Step 2: (S) -7- (4-dimethylamino-phenyl) -7- (6-methoxy-quinolin-3-ylcarbamoyl) -heptanoic acid ethyl ester

출발물질로 상기 단계 1에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-7-(6-메톡시-퀴놀린-3-일카바모일)-헵타-2,4-디에노산 에틸 에스터를 사용하는 것을 제외하고는 실시예 2와 동일한 방법으로 표제 화합물 (76％)을 얻었다.(S) -7- (4-dimethylamino-phenyl) -7- (6-methoxy - quinolin-3-ylcarbamoyl) -hepta-2,4-dienoic acid ethyl obtained in step 1 as starting material The title compound (76%) was obtained in the same manner as in Example 2 except using the ester.

1H NMR (300 MHz, CDCl3) : δ 1.23 (t, J = 7.2 Hz, 3H), 1.33 (m, 4H), 1.53 (m, 3H), 1.75 (m, 1H), 2.25 (m, 2H), 3.50 (m, 1H), 3.75 (s, 3H), 4.09 (q, J = 7.2 Hz, 2H), 6.45 (d, J = 7.8 Hz, 1H), 7.02 (m, 4H), 7.10 (m, 2H), 7.80 (m, 1H), 8.01 (m, 1H) 1 H NMR (300 MHz, CDCl 3 ): δ 1.23 (t, J = 7.2 Hz, 3H), 1.33 (m, 4H), 1.53 (m, 3H), 1.75 (m, 1H), 2.25 (m, 2H ), 3.50 (m, 1H), 3.75 (s, 3H), 4.09 (q, J = 7.2 Hz, 2H), 6.45 (d, J = 7.8 Hz, 1H), 7.02 (m, 4H), 7.10 (m , 2H), 7.80 (m, 1H), 8.01 (m, 1H)

단계 3: (S)-7-(4-다이메틸아미노-페닐)-7-(6-메톡시-퀴놀린-3-일카바모 일)-헵타노산 Step 3: (S) -7- (4-Dimethylamino-phenyl) -7- (6-methoxy-quinolin-3-ylcarbamoyl) -heptanoic acid

출발물질로 상기 단계 2에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-7-(6-메톡시-퀴놀린-3-일카바모일)-헵타노산 에틸 에스터를 사용하는 것을 제외하고는 실시예 3의 단계 2와 동일한 방법으로 표제 화합물 (47％)을 얻었다.Except for using (S) -7- (4-dimethylamino-phenyl) -7- (6-methoxy - quinolin-3-ylcarbamoyl) -heptanoic acid ethyl ester obtained in step 2 as starting material In the same manner as in Step 2 of Example 3, the title compound (47%) was obtained.

1H NMR (300 MHz, CDCl3) : δ 1.29 (m, 4H), 1.53 (m, 3H), 1.71 (m, 1H), 2.25 (m, 2H), 3.48 (m, 1H), 3.75 (s, 3H), 6.45 (d, J = 7.8 Hz, 1H), 7.02 (m, 4H), 7.10 (m, 2H), 7.90 (m, 1H), 8.05 (m, 1H) 1 H NMR (300 MHz, CDCl 3 ): δ 1.29 (m, 4H), 1.53 (m, 3H), 1.71 (m, 1H), 2.25 (m, 2H), 3.48 (m, 1H), 3.75 (s , 3H), 6.45 (d, J = 7.8 Hz, 1H), 7.02 (m, 4H), 7.10 (m, 2H), 7.90 (m, 1H), 8.05 (m, 1H)

단계 4: (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-[(6-메톡시-퀴놀린-3-일)-아마이드]Step 4: (S) -2- (4-Dimethylamino-phenyl) -octanodioic acid 8-hydroxyamide 1-[(6-methoxy-quinolin-3-yl) -amide]

출발물질로 상기 단계 3에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-7-(6-메톡시-퀴놀린-3-일카바모일)-헵타노산을 사용하는 것을 제외하고는 실시예 1의 단계 2와 동일한 방법으로 표제 화합물 (47％)을 얻었다.Except for using (S) -7- (4-dimethylamino-phenyl) -7- (6-methoxy-quinolin-3-ylcarbamoyl) -heptanoic acid obtained in step 3 above as starting material The title compound (47%) was obtained by the same method as Step 2 of Example 1.

1H NMR (300 MHz, DMSO-d6) : δ 1.32 (m, 4H), 1.50 (m, 2H), 1.65(m, 1H), 1.94 (t, J = 7.2 Hz, 2H), 2.04 (m, 1H), 2.87 (s, 6H), 3.80 (t, J = 6.6 Hz, 1H), 6.74 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.49 (m, 3H), 7.61 (d, J = 7.5 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.93 (d, J = 7.5 Hz, 2H), 8.65 (s, 1H), 9.95 (s, 1H), 10.33 (s, 1H) 1 H NMR (300 MHz, DMSO-d 6 ): δ 1.32 (m, 4H), 1.50 (m, 2H), 1.65 (m, 1H), 1.94 (t, J = 7.2 Hz, 2H), 2.04 (m , 1H), 2.87 (s, 6H), 3.80 (t, J = 6.6 Hz, 1H), 6.74 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.49 (m , 3H), 7.61 (d, J = 7.5 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.93 (d, J = 7.5 Hz, 2H), 8.65 (s, 1H), 9.95 (s , 1H), 10.33 (s, 1H)

실시예 29: (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 1-[(4'-시아노-바이페닐-4-일)-아마이드] 8-하이드록시아마이드 Example 29: (S) -2- (4-Dimethylamino-phenyl) -octanedioic acid 1-[(4'-cyano-biphenyl-4-yl) -amide] 8-hydroxyamide

단계 1: (S)-7-(4'-시아노-바이페닐-4-일)-7-(4-다이메틸아미노-페닐)-헵타-2,4-디에노산 에틸 에스터Step 1: (S) -7- (4'-cyano-biphenyl-4-yl) -7- (4-dimethylamino-phenyl) -hepta-2,4-dienoic acid ethyl ester

아민 화합물로서 4'-아미노-바이페닐-4-카보나트릴을 사용하는 것을 제외하고는 실시예 7의 단계 1과 동일한 방법으로 표제 화합물 (67％)을 얻었다.The title compound (67%) was obtained by the same method as Step 1 of Example 7, except for using 4'-amino-biphenyl-4-carbonatryl as the amine compound.

1H NMR (300 MHz, CDCl3) : δ1.30 (t, J = 7.2 Hz, 3H), 2.51 (m, 1H), 2.78 (m, 1H), 2.96 (s, 6H), 3.75 (t, J = 7.6 Hz, 1H), 4.13 (q, J = 7.2 Hz, 2H), 5.72 (d, J = 15.3 Hz, 1H), 6.08 (m, 1H), 6.20 (m, 1H), 6.68 (d, J = 8.5 Hz, 2H), 6.99 (d, J = 8.5 Hz, 2H), 7.65 (m, 8H), 8.01 (s, 1H) 1 H NMR (300 MHz, CDCl 3 ): δ 1.30 (t, J = 7.2 Hz, 3H), 2.51 (m, 1H), 2.78 (m, 1H), 2.96 (s, 6H), 3.75 (t, J = 7.6 Hz, 1H), 4.13 (q, J = 7.2 Hz, 2H), 5.72 (d, J = 15.3 Hz, 1H), 6.08 (m, 1H), 6.20 (m, 1H), 6.68 (d, J = 8.5 Hz, 2H), 6.99 (d, J = 8.5 Hz, 2H), 7.65 (m, 8H), 8.01 (s, 1H)

단계 2: (S)-7-(4'-시아노-바이페닐-4-일)-7-(4-다이메틸아미노-페닐)-헵타노산 에틸 에스터Step 2: (S) -7- (4'-cyano-biphenyl-4-yl) -7- (4-dimethylamino-phenyl) -heptanoic acid ethyl ester

출발물질로 상기 단계 1에서 얻은 (S)-7-(4'-시아노-바이페닐-4-일)-7-(4-다이메틸아미노-페닐)-헵타-2,4-디에노산 에틸 에스터를 사용하는 것을 제외하고는 실시예 2와 동일한 방법으로 표제 화합물 (69％)을 얻었다.(S) -7- (4'-cyano-biphenyl-4-yl) -7- (4-dimethylamino-phenyl) -hepta-2,4-dienoic acid ethyl obtained in step 1 as starting material The title compound (69%) was obtained in the same manner as in Example 2 except using the ester.

1H NMR (300 MHz, CDCl3) : δ1.30 (m, 7H), 1.60 (m, 2H), 2.12 (m, 3H), 2.98 (s, 6H), 3.84 (m, 1H), 4.10 (q, J = 7.2 Hz, 2H), 6.65 (d, J = 8.5 Hz, 2H), 6.98 (d, J = 8.5 Hz, 2H), 7.70 (m, 8H), 8.01 (s, 1H) 1 H NMR (300 MHz, CDCl 3 ): δ 1.30 (m, 7H), 1.60 (m, 2H), 2.12 (m, 3H), 2.98 (s, 6H), 3.84 (m, 1H), 4.10 ( q, J = 7.2 Hz, 2H), 6.65 (d, J = 8.5 Hz, 2H), 6.98 (d, J = 8.5 Hz, 2H), 7.70 (m, 8H), 8.01 (s, 1H)

단계 3: (S)-7-(4'-시아노-바이페닐-4-일)-7-(4-다이메틸아미노-페닐)-헵타노산 Step 3: (S) -7- (4′-cyano-biphenyl-4-yl) -7- (4-dimethylamino-phenyl) -heptanoic acid

출발물질로 상기 단계 2에서 얻은 (S)-7-(4'-시아노-바이페닐-4-일)-7-(4-다이메틸아미노-페닐)-헵타노산 에틸 에스터를 사용하는 것을 제외하고는 실시예 3의 단계 2와 동일한 방법으로 표제 화합물 (33％)을 얻었다.Except using (S) -7- (4'-cyano-biphenyl-4-yl) -7- (4-dimethylamino-phenyl) -heptanoic acid ethyl ester obtained in step 2 as starting material In the same manner as in Step 2 of Example 3, the title compound (33%) was obtained.

1H NMR (300 MHz, CDCl3) : δ1.29 (m, 4H), 1.56 (m, 2H), 2.78 (m, 3H), 2.98 (s, 6H), 3.84 (m, 1H), 6.65 (d, J = 8.5 Hz, 2H), 6.98 (d, J = 8.5 Hz, 2H), 7.75 (m, 8H), 8.05 (s, 1H) 1 H NMR (300 MHz, CDCl 3 ): δ 1.29 (m, 4H), 1.56 (m, 2H), 2.78 (m, 3H), 2.98 (s, 6H), 3.84 (m, 1H), 6.65 ( d, J = 8.5 Hz, 2H), 6.98 (d, J = 8.5 Hz, 2H), 7.75 (m, 8H), 8.05 (s, 1H)

단계 4: (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 1-[(4'-시아노-바이페닐-4-일)-아마이드] 8-하이드록시아마이드 Step 4: (S) -2- (4-Dimethylamino-phenyl) -octanedioic acid 1-[(4'-cyano-biphenyl-4-yl) -amide] 8-hydroxyamide

출발물질로 상기 단계 3에서 얻은 (S)-7-(4'-시아노-바이페닐-4-일)-7-(4-다이메틸아미노-페닐)-헵타노산을 사용하는 것을 제외하고는 실시예 1의 단계 2와 동일한 방법으로 표제 화합물 (33％)을 얻었다.Except for using (S) -7- (4'-cyano-biphenyl-4-yl) -7- (4-dimethylamino-phenyl) -heptanoic acid obtained in step 3 above as starting material The title compound (33%) was obtained by the same method as Step 2 of Example 1.

1H NMR (300 MHz, DMSO-d6) : δ 1.32 (m, 4H), 1.50 (m, 2H), 1.65(m, 1H), 1.94 (t, J = 7.2 Hz, 2H), 2.04 (m, 1H), 2.87 (s, 6H), 3.80 (t, J = 6.6 Hz, 1H), 6.74 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.49 (m, 3H), 7.61 (d, J = 7.5 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.93 (d, J = 7.5 Hz, 2H), 8.65 (s, 1H), 9.95 (s, 1H), 10.33 (s, 1H) 1 H NMR (300 MHz, DMSO-d 6 ): δ 1.32 (m, 4H), 1.50 (m, 2H), 1.65 (m, 1H), 1.94 (t, J = 7.2 Hz, 2H), 2.04 (m , 1H), 2.87 (s, 6H), 3.80 (t, J = 6.6 Hz, 1H), 6.74 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.49 (m , 3H), 7.61 (d, J = 7.5 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.93 (d, J = 7.5 Hz, 2H), 8.65 (s, 1H), 9.95 (s , 1H), 10.33 (s, 1H)

실시예 30: (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-[(1H-인다졸-6-일)-아마이드] Example 30: (S) -2- (4-Dimethylamino-phenyl) -octanodioic acid 8-hydroxyamide 1-[(1H-indazol-6-yl) -amide]

단계 1: (S)-7-(4-다이메틸아미노-페닐)-7-(1H-인다졸-6-일카바모일)-헵타노산 에틸 에스터Step 1: (S) -7- (4-dimethylamino-phenyl) -7- (1H-indazol-6-ylcarbamoyl) -heptanoic acid ethyl ester

출발물질로 제조예 6에서 얻은 (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-에틸 에스터과 1H-인다졸-6-일아민 (16)을 사용하는 것을 제외하고는 실시예 7의 단계 1과 동일한 방법으로 표제 화합물 (45％)을 얻었다. Except for using (S) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-ethyl ester and 1H-indazol-6-ylamine (16) obtained in Preparation Example 6 as starting materials. The title compound (45%) was obtained by the same method as Step 1 of Example 7.

1H NMR (300 MHz, CDCl3) : δ 1.26 (t, J = 7.2 Hz, 3H), 1.31 (m, 4H), 1.60 (m, 2H), 1.83 (m, 1H), 2.30 (m, 3H), 2.98 (s, 6H), 3.42 (m, 1H), 4.15 (q, J = 7.2 Hz, 2H), 6.78 (d, J = 8.6 Hz, 2H), 7.29 (m, 4H), 7.99 (s, 1H) 1 H NMR (300 MHz, CDCl 3 ): δ 1.26 (t, J = 7.2 Hz, 3H), 1.31 (m, 4H), 1.60 (m, 2H), 1.83 (m, 1H), 2.30 (m, 3H ), 2.98 (s, 6H), 3.42 (m, 1H), 4.15 (q, J = 7.2 Hz, 2H), 6.78 (d, J = 8.6 Hz, 2H), 7.29 (m, 4H), 7.99 (s , 1H)

단계 2: (S)-7-(4-다이메틸아미노-페닐)-7-(1H-인다졸-6-일카바모일)-헵타노산 Step 2: (S) -7- (4-dimethylamino-phenyl) -7- (1H-indazol-6-ylcarbamoyl) -heptanoic acid

출발물질로 상기 단계 1에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-7-(1H-인다졸-6-일카바모일)-헵타노산 에틸 에스터를 사용하는 것을 제외하고는 실시예 3의 단계 2와 동일한 방법으로 표제 화합물 (75％)을 얻었다.Except for using (S) -7- ( 4-dimethylamino-phenyl ) -7- (1H-indazol-6-ylcarbamoyl) -heptanoic acid ethyl ester obtained as a starting material The title compound (75%) was obtained in the same manner as Step 2 of Example 3.

1H NMR (300 MHz, CDCl3) : δ 1.31 (m, 4H), 1.60 (m, 2H), 1.83 (m, 1H), 2.30 (m, 3H), 2.98 (s, 6H), 3.42 (m, 1H), 6.78 (d, J = 8.6 Hz, 2H), 7.29 (m, 4H), 7.99 (s, 1H) 1 H NMR (300 MHz, CDCl 3 ): δ 1.31 (m, 4H), 1.60 (m, 2H), 1.83 (m, 1H), 2.30 (m, 3H), 2.98 (s, 6H), 3.42 (m , 1H), 6.78 (d, J = 8.6 Hz, 2H), 7.29 (m, 4H), 7.99 (s, 1H)

단계 3: (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-[(1H-인다졸-6-일)-아마이드] Step 3: (S) -2- (4-Dimethylamino-phenyl) -octanodioic acid 8-hydroxyamide 1-[(1H-indazol-6-yl) -amide]

출발물질로 상기 단계 2에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-7-(1H-인다졸-6-일카바모일)-헵타노산을 사용하는 것을 제외하고는 실시예 1의 단계 2와 동일한 방법으로 표제 화합물 (44％)을 얻었다.Except for using (S) -7- (4-dimethylamino-phenyl) -7- (1H-indazol-6-ylcarbamoyl) -heptanoic acid obtained in Step 2 as starting material The title compound (44%) was obtained in the same manner as in step 2 of 1.

1H NMR (300 MHz, DMSO-d6) : δ 1.24 (m, 4H), 1.46 (m, 2H), 1.63 (m, 1H), 1.94 (m, 3H), 2.85 (s, 6H), 3.54 (m, 1H), 6.70 (d, J = 8.7 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H), 7.34 (m, 2H), 7.47 (m, 1H), 7.58 (m, 1H), 7.93 (s, 1H), 8.64 (s, 1H), 10.06 (s, 1H), 10.31 (s, 1H) 1 H NMR (300 MHz, DMSO-d 6 ): δ 1.24 (m, 4H), 1.46 (m, 2H), 1.63 (m, 1H), 1.94 (m, 3H), 2.85 (s, 6H), 3.54 (m, 1H), 6.70 (d, J = 8.7 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H), 7.34 (m, 2H), 7.47 (m, 1H), 7.58 (m, 1H) , 7.93 (s, 1H), 8.64 (s, 1H), 10.06 (s, 1H), 10.31 (s, 1H)

실시예 31: (S)-7-(4-다이메틸아미노-페닐)-8-옥소-8-(4-페닐-피페라진-1일)-옥타노산 하이드록시아마이드Example 31: (S) -7- (4-Dimethylamino-phenyl) -8-oxo-8- (4-phenyl-piperazin-1yl) -octanoic acid hydroxyamide

단계 1: (S)-7-(4-다이메틸아미노-페닐)-8-옥소-8-(4-페닐-피페라진-1일)-옥타노산 에틸 에스터Step 1: (S) -7- (4-dimethylamino-phenyl) -8-oxo-8- (4-phenyl-piperazin-1 yl) -octanoic acid ethyl ester

출발물질로 제조예 6에서 얻은 (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-에틸 에스터 (16) 및 1-페닐-피페라진을 사용하는 것을 제외하고는 실시예 7의 단계 1과 동일한 방법으로 표제 화합물 (67％)을 얻었다. Except for using (S) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-ethyl ester (16) and 1-phenyl-piperazine obtained from Preparation Example 6 as starting materials The title compound (67%) was obtained by the same method as Step 1 of 7.

1H NMR (300 MHz, CDCl3) : δ 1.25 (t, J = 7.2 Hz, 3H), 1.30 (m, 4H), 1.62 (m, 3H), 2.08 (m, 1H), 2.28 (t, J = 7.6 Hz, 2H), 2.62 (m, 1H), 2.94 (s, 6H), 3.13 (m, 3H), 3.60 (m, 4H), 3.97 (m, 1H), 4.10 (q, J = 7.2 Hz, 2H), 6.70 (d, J = 8.8 Hz, 2H), 6.88 (m, 3H), 7.14 (d, J = 8.4 Hz, 2H), 7.26 (m, 2H) 1 H NMR (300 MHz, CDCl 3 ): δ 1.25 (t, J = 7.2 Hz, 3H), 1.30 (m, 4H), 1.62 (m, 3H), 2.08 (m, 1H), 2.28 (t, J = 7.6 Hz, 2H), 2.62 (m, 1H), 2.94 (s, 6H), 3.13 (m, 3H), 3.60 (m, 4H), 3.97 (m, 1H), 4.10 (q, J = 7.2 Hz , 2H), 6.70 (d, J = 8.8 Hz, 2H), 6.88 (m, 3H), 7.14 (d, J = 8.4 Hz, 2H), 7.26 (m, 2H)

단계 2: (S)-7-(4-다이메틸아미노-페닐)-8-옥소-8-(4-페닐-피페라진-1일)-옥타노산Step 2: (S) -7- (4-dimethylamino-phenyl) -8-oxo-8- (4-phenyl-piperazin-1 yl) -octanoic acid

출발물질로 상기 단계 1에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-8-옥소-8-(4-페닐-피페라진-1일)-옥타노산 에틸 에스터를 사용하는 것을 제외하고는 실시예 3의 단계 2와 동일한 방법으로 표제 화합물 (89％)을 얻었다.Using (S) -7- (4-dimethylamino-phenyl) -8-oxo-8- (4-phenyl-piperazin-1yl) -octanoic acid ethyl ester obtained in step 1 above as starting material Except for the title compound (89%) in the same manner as in Step 2 of Example 3.

1H NMR (300 MHz, CDCl3) : δ 1.30 (m, 4H), 1.62 (m, 3H), 2.08 (m, 1H), 2.28 (t, J = 7.6 Hz, 2H), 2.62 (m, 1H), 2.94 (s, 6H), 3.13 (m, 3H), 3.60 (m, 4H), 3.97 (m, 1H), 6.70 (d, J = 8.8 Hz, 2H), 6.88 (m, 3H), 7.14 (d, J = 8.4 Hz, 2H), 7.26 (m, 2H) 1 H NMR (300 MHz, CDCl 3 ): δ 1.30 (m, 4H), 1.62 (m, 3H), 2.08 (m, 1H), 2.28 (t, J = 7.6 Hz, 2H), 2.62 (m, 1H ), 2.94 (s, 6H), 3.13 (m, 3H), 3.60 (m, 4H), 3.97 (m, 1H), 6.70 (d, J = 8.8 Hz, 2H), 6.88 (m, 3H), 7.14 (d, J = 8.4 Hz, 2H), 7.26 (m, 2H)

단계 3: (S)-7-(4-다이메틸아미노-페닐)-8-옥소-8-(4-페닐-피페라진-1일)-옥타노산 하이드록시아마이드Step 3: (S) -7- (4-Dimethylamino-phenyl) -8-oxo-8- (4-phenyl-piperazin-1yl) -octanoic acid hydroxyamide

출발물질로 상기 단계 2에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-8-옥소-8-(4-페닐-피페라진-1일)-옥타노산을 사용하는 것을 제외하고는 실시예 1의 단계 2와 동일한 방법으로 표제 화합물 (67％)을 얻었다.Except for using (S) -7- (4-dimethylamino-phenyl) -8-oxo-8- (4-phenyl-piperazin-1yl) -octanoic acid obtained in step 2 as starting material Obtained the title compound (67%) in the same manner as in Step 2 of Example 1.

1H NMR (300 MHz, DMSO-d6) : δ 1.33 (m, 4H), 1.54 (m, 3H), 2.00 (m, 3H), 2.74 (m, 1H), 2.94 (s, 6H), 3.02 (m, 1H), 3.16 (m, 2H), 3.59 (m, 1H), 3.70 (m, 3H), 3.91 (m, 1H), 6.77 (d, J = 8.4 Hz, 2H), 6.88 (t, J = 7.2 Hz, 1H), 6.99 (d, J = 73.2 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 7.29 (t, J = 8.1 Hz, 2H), 8.74 (s, 1H), 10.41 (s, 1H) 1 H NMR (300 MHz, DMSO-d 6 ): δ 1.33 (m, 4H), 1.54 (m, 3H), 2.00 (m, 3H), 2.74 (m, 1H), 2.94 (s, 6H), 3.02 (m, 1H), 3.16 (m, 2H), 3.59 (m, 1H), 3.70 (m, 3H), 3.91 (m, 1H), 6.77 (d, J = 8.4 Hz, 2H), 6.88 (t, J = 7.2 Hz, 1H), 6.99 (d, J = 73.2 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 7.29 (t, J = 8.1 Hz, 2H), 8.74 (s, 1H) , 10.41 (s, 1H)

실시예 32: (S)-2-(4-다이메틸아미노-페닐)-옥타노산 8-하이드록시아마이드 1-[(6-메톡시-벤조사이아졸-2-일)-아마이드]Example 32: (S) -2- (4-Dimethylamino-phenyl) -octanoic acid 8-hydroxyamide 1-[(6-methoxy-benzothiazol-2-yl) -amide]

단계 1: (S)-7-(4-다이메틸아미노-페닐)-7-(6-메톡시-벤조사이아졸-2-일카바모일)-헵타노산 에틸 에스터Step 1: (S) -7- (4-dimethylamino-phenyl) -7- (6-methoxy-benzothiazol-2-ylcarbamoyl) -heptanoic acid ethyl ester

출발물질로 제조예 6에서 얻은 (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-에틸 에스터 (16) 및 6-메톡시-벤조사이아졸-2-일아민을 사용하는 것을 제외하고는 실시예 7의 단계 1과 동일한 방법으로 표제 화합물 (34％)을 얻었다. (S) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-ethyl ester (16) and 6-methoxy-benzothiazol-2-ylamine obtained in Preparation Example 6 were used as starting materials. The title compound (34%) was obtained in the same manner as in Step 1 of Example 7, except that.

1H NMR (300 MHz, CDCl3) : δ 1.18 (m, 7H), 1.50 (m, 2H), 1.73 (m, 1H), 2.16 (m, 3H), 2.85 (s, 6H), 3.40 (m, 1H), 3.79 (s, 3H), 4.04 (q, J = 7.2 Hz, 2H), 6.58 (d, J = 8.7 Hz, 2H), 6.93 (m, 3H), 7.21 (m, 1H), 7.52 (d, J = 8.9 Hz, 1H) 1 H NMR (300 MHz, CDCl 3 ): δ 1.18 (m, 7H), 1.50 (m, 2H), 1.73 (m, 1H), 2.16 (m, 3H), 2.85 (s, 6H), 3.40 (m , 1H), 3.79 (s, 3H), 4.04 (q, J = 7.2 Hz, 2H), 6.58 (d, J = 8.7 Hz, 2H), 6.93 (m, 3H), 7.21 (m, 1H), 7.52 (d, J = 8.9 Hz, 1H)

단계 2: (S)-7-(4-다이메틸아미노-페닐)-7-(6-메톡시-벤조사이아졸-2-일카 바모일)-헵타노산 Step 2: (S) -7- (4-dimethylamino-phenyl) -7- (6-methoxy-benzothiazol-2-ylcarbamoyl) -heptanoic acid

출발물질로 상기 단계 1에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-7-(6-메톡시-벤조사이아졸-2-일카바모일)-헵타노산 에틸 에스터를 사용하는 것을 제외하고는 실시예 3의 단계 2와 동일한 방법으로 표제 화합물 (88％)을 얻었다.Using (S) -7- (4-dimethylamino-phenyl) -7- (6-methoxy-benzothiazol-2-ylcarbamoyl) -heptanoic acid ethyl ester obtained in step 1 as starting material A title compound (88%) was obtained by the same method as Step 2 of Example 3, except that.

1H NMR (300 MHz, CDCl3) : δ 1.18 (m, 4H), 1.50 (m, 2H), 1.73 (m, 1H), 2.16 (m, 3H), 2.85 (s, 6H), 3.40 (m, 1H), 3.79 (s, 3H), 6.58 (d, J = 8.7 Hz, 2H), 6.93 (m, 3H), 7.21 (m, 1H), 7.52 (d, J = 8.9 Hz, 1H) 1 H NMR (300 MHz, CDCl 3 ): δ 1.18 (m, 4H), 1.50 (m, 2H), 1.73 (m, 1H), 2.16 (m, 3H), 2.85 (s, 6H), 3.40 (m , 1H), 3.79 (s, 3H), 6.58 (d, J = 8.7 Hz, 2H), 6.93 (m, 3H), 7.21 (m, 1H), 7.52 (d, J = 8.9 Hz, 1H)

단계 3: (S)-2-(4-다이메틸아미노-페닐)-옥타노산 8-하이드록시아마이드 1-[(6-메톡시-벤조사이아졸-2-일)-아마이드]Step 3: (S) -2- (4-Dimethylamino-phenyl) -octanoic acid 8-hydroxyamide 1-[(6-methoxy-benzothiazol-2-yl) -amide]

출발물질로 상기 단계 2에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-7-(6-메톡시-벤조사이아졸-2-일카바모일)-헵타노산을 사용하는 것을 제외하고는 실시예 1의 단계 2와 동일한 방법으로 표제 화합물 (61％)을 얻었다.Except for using (S) -7- (4-dimethylamino-phenyl) -7- (6-methoxy-benzothiazol-2-ylcarbamoyl) -heptanoic acid obtained in step 2 as starting material In the same manner as in Step 2 of Example 1, the title compound (61%) was obtained.

1H NMR (300 MHz, DMSO-d6) : δ 1.19 (m, 4H), 1.55 (m, 2H), 1.73 (m, 1H), 2.16 (m, 3H), 2.87 (s, 6H), 3.40 (m, 1H), 3.79 (s, 3H), 6.59 (d, J = 8.7 Hz, 2H), 6.923 (m, 3H), 7.21 (m, 1H), 7.57 (d, J = 8.9 Hz, 1H), 8.75 (s, 1H), 10.43 (s, 1H) 1 H NMR (300 MHz, DMSO-d 6 ): δ 1.19 (m, 4H), 1.55 (m, 2H), 1.73 (m, 1H), 2.16 (m, 3H), 2.87 (s, 6H), 3.40 (m, 1H), 3.79 (s, 3H), 6.59 (d, J = 8.7 Hz, 2H), 6.923 (m, 3H), 7.21 (m, 1H), 7.57 (d, J = 8.9 Hz, 1H) , 8.75 (s, 1H), 10.43 (s, 1H)

실시예 33: (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마 이드 1-[(2-메틸-퀴놀린-4-일)-아마이드]Example 33: (S) -2- (4-Dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 1-[(2-methyl-quinolin-4-yl) -amide]

단계 1: (S)-7-(4-다이메틸아미노-페닐)-7-(2-메틸-퀴놀린-4-일카바모일)-헵타노산 에틸 에스터Step 1: (S) -7- (4-dimethylamino-phenyl) -7- (2-methyl-quinolin-4-ylcarbamoyl) -heptanoic acid ethyl ester

출발물질로 제조예 6에서 얻은 (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-에틸 에스터 (16) 및 2-메틸-퀴놀린-4-일아민을 사용하는 것을 제외하고는 실시예 7의 단계 1과 동일한 방법으로 표제 화합물 (40％)을 얻었다. Except for using (S) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-ethyl ester (16) and 2-methyl-quinolin-4-ylamine obtained in Preparation Example 6 as starting materials. The title compound (40%) was obtained in the same manner as Step 1 of Example 7.

1H NMR (300 MHz, CDCl3) : δ 1.24 (t, J = 7.2 Hz, 3H), 1.38 (m, 4H), 1.60 (m, 2H), 1.95 (m, 1H), 2.28 (m, 3H), 2.69 (s, 3H), 2.99 (s, 6H), 3.60 (m, 1H), 4.11 (q, J = 7.2 Hz, 2H), 6.80 (d, J = 8.4 Hz, 2H), 7.22 (m, 5H), 7.60 (m, 1H), 7.95 (s, 1H), 8.20 (s, 1H) 1 H NMR (300 MHz, CDCl 3 ): δ 1.24 (t, J = 7.2 Hz, 3H), 1.38 (m, 4H), 1.60 (m, 2H), 1.95 (m, 1H), 2.28 (m, 3H ), 2.69 (s, 3H), 2.99 (s, 6H), 3.60 (m, 1H), 4.11 (q, J = 7.2 Hz, 2H), 6.80 (d, J = 8.4 Hz, 2H), 7.22 (m , 5H), 7.60 (m, 1H), 7.95 (s, 1H), 8.20 (s, 1H)

단계 2: (S)-7-(4-다이메틸아미노-페닐)-7-(2-메틸-퀴놀린-4-일카바모일)-헵타노산Step 2: (S) -7- (4-dimethylamino-phenyl) -7- (2-methyl-quinolin-4-ylcarbamoyl) -heptanoic acid

출발물질로 상기 단계 1에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-7-(2-메틸-퀴놀린-4-일카바모일)-헵타노산 에틸 에스터를 사용하는 것을 제외하고는 실시예 3의 단계 2와 동일한 방법으로 표제 화합물 (91％)을 얻었다.(S) -7- (4-dimethylamino-phenyl) -7- (2-methyl-quinolin-4-ylcarbamoyl) -heptanoic acid obtained in step 1 as a starting material The title compound (91%) was obtained by the same method as Step 2 of Example 3, except using ethyl ester.

1H NMR (300 MHz, CDCl3) : δ 1.38 (m, 4H), 1.60 (m, 2H), 1.95 (m, 1H), 2.28 (m, 3H), 2.69 (s, 3H), 2.99 (s, 6H), 3.60 (m, 1H), 6.80 (d, J = 8.4 Hz, 2H), 7.22 (m, 5H), 7.60 (m, 1H), 7.95 (s, 1H), 8.20 (s, 1H) 1 H NMR (300 MHz, CDCl 3 ): δ 1.38 (m, 4H), 1.60 (m, 2H), 1.95 (m, 1H), 2.28 (m, 3H), 2.69 (s, 3H), 2.99 (s , 6H), 3.60 (m, 1H), 6.80 (d, J = 8.4 Hz, 2H), 7.22 (m, 5H), 7.60 (m, 1H), 7.95 (s, 1H), 8.20 (s, 1H)

단계 3: (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-[(2-메틸-퀴놀린-4-일)-아마이드]Step 3: (S) -2- (4-Dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 1-[(2-methyl-quinolin-4-yl) -amide]

출발물질로 상기 단계 2에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-7-(2-메틸-퀴놀린-4-일카바모일)-헵타노산을 사용하는 것을 제외하고는 실시예 1의 단계 2와 동일한 방법으로 표제 화합물 (54％)을 얻었다.Except for using (S) -7- (4-dimethylamino-phenyl) -7- (2-methyl-quinolin-4-ylcarbamoyl) -heptanoic acid obtained in step 2 as starting material The title compound (54%) was obtained by the same method as Step 2 of Example 1.

1H NMR (300 MHz, DMSO-d6) : δ 1.39 (m, 4H), 1.65 (m, 2H), 1.95 (m, 1H), 2.28 (m, 3H), 2.69 (s, 3H), 2.99 (s, 6H), 3.60 (m, 1H), 6.82 (d, J = 8.4 Hz, 2H), 7.22 (m, 5H), 7.63 (m, 1H), 7.97 (s, 1H), 8.20 (s, 1H), 8.75 (s, 1H), 10.43 (s, 1H) 1 H NMR (300 MHz, DMSO-d 6 ): δ 1.39 (m, 4H), 1.65 (m, 2H), 1.95 (m, 1H), 2.28 (m, 3H), 2.69 (s, 3H), 2.99 (s, 6H), 3.60 (m, 1H), 6.82 (d, J = 8.4 Hz, 2H), 7.22 (m, 5H), 7.63 (m, 1H), 7.97 (s, 1H), 8.20 (s, 1H), 8.75 (s, 1H), 10.43 (s, 1H)

실시예 34: (S)-8-(3,4-디하이드로-1H-이소퀴놀린-2-일)-7-(4-다이메틸아미노-페닐)-8-옥소-옥타노산 하이드록시아마이드Example 34: (S) -8- (3,4-Dihydro-1H-isoquinolin-2-yl) -7- (4-dimethylamino-phenyl) -8-oxo-octanoic acid hydroxyamide

단계 1: (S)-8-(3,4-디하이드로-1H-이소퀴놀린-2-일)-7-(4-다이메틸아미노-페닐)-8-옥소-옥타노산 에틸 에스터Step 1: (S) -8- (3,4-Dihydro-1 H-isoquinolin-2-yl) -7- (4-dimethylamino-phenyl) -8-oxo-octanoic acid ethyl ester

출발물질로 제조예 6에서 얻은 (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-에틸 에스터 (16) 및 1,2,3,4-테트라하이드로-이소퀴놀린을 사용하는 것을 제외하고는 실시예 7의 단계 1과 동일한 방법으로 표제 화합물 (35％)을 얻었다.1H NMR (300 MHz, CDCl3) : δ 1.25 (t, J = 7.2 Hz, 3H), 1.32 (m, 4H), 1.60 (m, 2H), 1.79 (m, 1H), 2.05 (m, 1H), 2.21 (m, 2H), 2.46 (m, 1H), 2.76 (m, 1H), 3.60 (m, 3H), 4.10 (q, J = 7.2 Hz, 2H), 4.78 (s, 2H), 6.70 (d, J = 8.4 Hz, 2H), 7.19 (m, 6H) (S) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-ethyl ester (16) and 1,2,3,4-tetrahydro-isoquinoline obtained in Preparation Example 6 were used as starting materials. The title compound (35%) was obtained in the same manner as in Step 1 of Example 7, except that. 1 H NMR (300 MHz, CDCl 3 ): δ 1.25 (t, J = 7.2 Hz, 3H), 1.32 (m, 4H), 1.60 (m, 2H), 1.79 (m, 1H), 2.05 (m, 1H ), 2.21 (m, 2H), 2.46 (m, 1H), 2.76 (m, 1H), 3.60 (m, 3H), 4.10 (q, J = 7.2 Hz, 2H), 4.78 (s, 2H), 6.70 (d, J = 8.4 Hz, 2H), 7.19 (m, 6H)

단계 2: (S)-8-(3,4-디하이드로-1H-이소퀴놀린-2-일)-7-(4-다이메틸아미노-페닐)-8-옥소-옥타노산Step 2: (S) -8- (3,4-Dihydro-1 H-isoquinolin-2-yl) -7- (4-dimethylamino-phenyl) -8-oxo-octanoic acid

출발물질로 상기 단계 1에서 얻은 (S)-8-(3,4-디하이드로-1H-이소퀴놀린-2-일)-7-(4-다이메틸아미노-페닐)-8-옥소-옥타노산 에틸 에스터를 사용하는 것을 제외하고는 실시예 3의 단계 2와 동일한 방법으로 표제 화합물 (88％)을 얻었다. 1H NMR (300 MHz, CDCl3) : δ 1.32 (m, 4H), 1.60 (m, 2H), 1.79 (m, 1H), 2.05 (m, 1H), 2.21 (m, 2H), 2.46 (m, 1H), 2.76 (m, 1H), 3.60 (m, 3H), 4.78 (s, 2H), 6.70 (d, J = 8.4 Hz, 2H), 7.19 (m, 6H)(S) -8- (3,4-dihydro-1H-isoquinolin-2-yl) -7- (4-dimethylamino-phenyl) -8-oxo-octanoic acid obtained in step 1 as a starting material The title compound (88%) was obtained by the same method as Step 2 of Example 3, except using ethyl ester. 1 H NMR (300 MHz, CDCl 3 ): δ 1.32 (m, 4H), 1.60 (m, 2H), 1.79 (m, 1H), 2.05 (m, 1H), 2.21 (m, 2H), 2.46 (m , 1H), 2.76 (m, 1H), 3.60 (m, 3H), 4.78 (s, 2H), 6.70 (d, J = 8.4 Hz, 2H), 7.19 (m, 6H)

단계 3: (S)-8-(3,4-디하이드로-1H-이소퀴놀린-2-일)-7-(4-다이메틸아미노-페닐)-8-옥소-옥타노산 하이드록시아마이드Step 3: (S) -8- (3,4-Dihydro-1 H-isoquinolin-2-yl) -7- (4-dimethylamino-phenyl) -8-oxo-octanoic acid hydroxyamide

출발물질로 상기 단계 2에서 얻은 (S)-8-(3,4-디하이드로-1H-이소퀴놀린-2-일)-7-(4-다이메틸아미노-페닐)-8-옥소-옥타노산을 사용하는 것을 제외하고는 실시예 1의 단계 2와 동일한 방법으로 표제 화합물 (77％)을 얻었다.(S) -8- (3,4-dihydro-1H-isoquinolin-2-yl) -7- (4-dimethylamino-phenyl) -8-oxo-octanoic acid obtained in step 2 as a starting material The title compound (77%) was obtained by the same method as Step 2 of Example 1, except for using.

1H NMR (300 MHz, DMSO-d6) : δ 1.34 (m, 4H), 1.60 (m, 2H), 1.95 (m, 1H), 2.28 (m, 3H), 2.63 (s, 3H), 2.99 (s, 6H), 3.62 (m, 1H), 6.82 (d, J = 8.4 Hz, 2H), 7.24 (m, 5H), 7.63 (m, 1H), 7.95 (s, 1H), 8.20 (s, 1H), 8.78 (s, 1H), 10.41 (s, 1H) 1 H NMR (300 MHz, DMSO-d 6 ): δ 1.34 (m, 4H), 1.60 (m, 2H), 1.95 (m, 1H), 2.28 (m, 3H), 2.63 (s, 3H), 2.99 (s, 6H), 3.62 (m, 1H), 6.82 (d, J = 8.4 Hz, 2H), 7.24 (m, 5H), 7.63 (m, 1H), 7.95 (s, 1H), 8.20 (s, 1H), 8.78 (s, 1H), 10.41 (s, 1H)

실시예 35: (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-[(피리딘-3-일메틸)-아마이드]Example 35: (S) -2- (4-Dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 1-[(pyridin-3-ylmethyl) -amide]

단계 1: (S)-7-(4-다이메틸아미노-페닐)-7-[(피리딘-3-일메틸)-카바모일]-헵타노산 에틸 에스터Step 1: (S) -7- (4-Dimethylamino-phenyl) -7-[(pyridin-3-ylmethyl) -carbamoyl] -heptanoic acid ethyl ester

출발물질로 제조예 6에서 얻은 (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-에틸 에스터 (16) 및 C-피리딘-3-일-메틸아민을 사용하는 것을 제외하고는 실시예 7의 단계 1과 동일한 방법으로 표제 화합물 (68％)을 얻었다. Except for using (S) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-ethyl ester (16) and C -pyridin-3-yl-methylamine obtained in Preparation Example 6 as starting materials. In the same manner as in Step 1 of Example 7, the title compound (68%) was obtained.

1H NMR (300 MHz, CDCl3) : δ 1.27 (t, J = 7.2 Hz, 3H), 1.30 (m, 4H), 1.59 (m, 2H), 1.75 (m, 1H), 2.20 (m, 3H), 2.93 (s, 6H), 3.27 (m, 1H), 4.10 (q, J = 7.2 Hz, 2H), 4.39 (d, J = 6.2 Hz, 2H), 5.80 (m, 1H), 6.68 (d, J = 8.4 Hz, 2H), 7.15 (m, 3H), 7.49 (m, 1H), 8.48 (m, 1H) 1 H NMR (300 MHz, CDCl 3 ): δ 1.27 (t, J = 7.2 Hz, 3H), 1.30 (m, 4H), 1.59 (m, 2H), 1.75 (m, 1H), 2.20 (m, 3H ), 2.93 (s, 6H), 3.27 (m, 1H), 4.10 (q, J = 7.2 Hz, 2H), 4.39 (d, J = 6.2 Hz, 2H), 5.80 (m, 1H), 6.68 (d , J = 8.4 Hz, 2H), 7.15 (m, 3H), 7.49 (m, 1H), 8.48 (m, 1H)

단계 2: (S)-7-(4-다이메틸아미노-페닐)-7-[(피리딘-3-일메틸)-카바모일]-헵타노산 Step 2: (S) -7- (4-dimethylamino-phenyl) -7-[(pyridin-3-ylmethyl) -carbamoyl] -heptanoic acid

출발물질로 상기 단계 1에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-7-[(피리 딘-3-일메틸)-카바모일]-헵타노산 에틸 에스터를 사용하는 것을 제외하고는 실시예 3의 단계 2와 동일한 방법으로 표제 화합물 (89％)을 얻었다.Except for using (S) -7- (4-dimethylamino-phenyl) -7-[(pyridin-3-ylmethyl) -carbamoyl] -heptanoic acid ethyl ester obtained in step 1 as starting material In the same manner as in Step 2 of Example 3, the title compound (89%) was obtained.

1H NMR (300 MHz, CDCl3) : δ 1.30 (m, 4H), 1.59 (m, 2H), 1.75 (m, 1H), 2.20 (m, 3H), 2.93 (s, 6H), 3.27 (m, 1H), 4.39 (d, J = 6.2 Hz, 2H), 5.80 (m, 1H), 6.68 (d, J = 8.4 Hz, 2H), 7.15 (m, 3H), 7.49 (m, 1H), 8.48 (m, 1H) 1 H NMR (300 MHz, CDCl 3 ): δ 1.30 (m, 4H), 1.59 (m, 2H), 1.75 (m, 1H), 2.20 (m, 3H), 2.93 (s, 6H), 3.27 (m , 1H), 4.39 (d, J = 6.2 Hz, 2H), 5.80 (m, 1H), 6.68 (d, J = 8.4 Hz, 2H), 7.15 (m, 3H), 7.49 (m, 1H), 8.48 (m, 1 H)

단계 3: (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-[(피리딘-3-일메틸)-아마이드]Step 3: (S) -2- (4-Dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 1-[(pyridin-3-ylmethyl) -amide]

출발물질로 상기 단계 2에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-7-[(피리딘-3-일메틸)-카바모일]-헵타노산을 사용하는 것을 제외하고는 실시예 1의 단계 2와 동일한 방법으로 표제 화합물 (42％)을 얻었다. Except for using (S) -7- (4-dimethylamino-phenyl) -7-[(pyridin-3-ylmethyl) -carbamoyl] -heptanoic acid obtained in step 2 as starting material The title compound (42%) was obtained by the same method as Step 2 of Example 1.

1H NMR (300 MHz, DMSO-d6) : δ 1.31 (m, 4H), 1.59 (m, 2H), 1.78 (m, 1H), 2.20 (m, 3H), 2.93 (s, 6H), 3.27 (m, 1H), 4.34 (d, J = 6.2 Hz, 2H), 5.80 (m, 1H), 6.67 (d, J = 8.4 Hz, 2H), 7.15 (m, 3H), 7.49 (m, 1H), 8.48 (m, 1H), 8.77 (s, 1H), 10.45 (s, 1H) 1 H NMR (300 MHz, DMSO-d 6 ): δ 1.31 (m, 4H), 1.59 (m, 2H), 1.78 (m, 1H), 2.20 (m, 3H), 2.93 (s, 6H), 3.27 (m, 1H), 4.34 (d, J = 6.2 Hz, 2H), 5.80 (m, 1H), 6.67 (d, J = 8.4 Hz, 2H), 7.15 (m, 3H), 7.49 (m, 1H) , 8.48 (m, 1H), 8.77 (s, 1H), 10.45 (s, 1H)

실시예 36: (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 1-[(3-벤질옥시-페닐)-아마이드] 8-하이드록시아마이드 Example 36: (S) -2- (4-dimethylamino-phenyl) -octanedioic acid 1-[(3-benzyloxy-phenyl) -amide] 8-hydroxyamide

단계 1: (S)-7-(3-벤질옥시-페닐카바모일)-7-(4-다이메틸아미노-페닐)-헵 타노산 에틸 에스터Step 1: (S) -7- (3-benzyloxy-phenylcarbamoyl) -7- (4-dimethylamino-phenyl) -heptanoic acid ethyl ester

출발물질로 제조예 6에서 얻은 (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-에틸 에스터 (16) 및 3-벤질옥시-페닐아민을 사용하는 것을 제외하고는 실시예 7의 단계 1과 동일한 방법으로 표제 화합물 (56％)을 얻었다. Except for using (S) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-ethyl ester (16) and 3-benzyloxy-phenylamine obtained in Preparation Example 6 as starting materials. The title compound (56%) was obtained by the same method as Step 1 of Example 7.

1H NMR (300 MHz, CDCl3) : δ 1.28 (m, 7H), 1.61 (m, 2H), 1.80 (m, 1H), 2.20 (m, 3H), 2.97 (s, 6H), 3.40 (m, 1H), 4.10 (q, J = 7.2 Hz, 2H), 5.04 (s, 2H), 6.35 (m, 1H), 6.40 (m, 1H), 6.75 (d, J = 8.4 Hz, 2H), 6.88 (m, 1H), 7.15 (m, 3H), 7.20 (m, 5H) 1 H NMR (300 MHz, CDCl 3 ): δ 1.28 (m, 7H), 1.61 (m, 2H), 1.80 (m, 1H), 2.20 (m, 3H), 2.97 (s, 6H), 3.40 (m , 1H), 4.10 (q, J = 7.2 Hz, 2H), 5.04 (s, 2H), 6.35 (m, 1H), 6.40 (m, 1H), 6.75 (d, J = 8.4 Hz, 2H), 6.88 (m, 1H), 7.15 (m, 3H), 7.20 (m, 5H)

단계 2: (S)-7-(3-벤질옥시-페닐카바모일)-7-(4-다이메틸아미노-페닐)-헵타노산Step 2: (S) -7- (3-benzyloxy-phenylcarbamoyl) -7- (4-dimethylamino-phenyl) -heptanoic acid

출발물질로 상기 단계 1에서 얻은 (S)-7-(3-벤질옥시-페닐카바모일)-7-(4-다이메틸아미노-페닐)-헵타노산 에틸 에스터를 사용하는 것을 제외하고는 실시예 3의 단계 2와 동일한 방법으로 표제 화합물 (77％)을 얻었다.Except for using (S) -7- (3-benzyloxy-phenylcarbamoyl) -7- (4-dimethylamino-phenyl) -heptanoic acid ethyl ester obtained in step 1 as starting material The title compound (77%) was obtained by the same method as Step 2 of 3.

1H NMR (300 MHz, CDCl3) : δ 1.28 (m, 4H), 1.61 (m, 2H), 1.80 (m, 1H), 2.20 (m, 3H), 2.97 (s, 6H), 3.40 (m, 1H), 5.04 (s, 2H), 6.35 (m, 1H), 6.40 (m, 1H), 6.75 (d, J = 8.4 Hz, 2H), 6.88 (m, 1H), 7.15 (m, 3H), 7.20 (m, 5H) 1 H NMR (300 MHz, CDCl 3 ): δ 1.28 (m, 4H), 1.61 (m, 2H), 1.80 (m, 1H), 2.20 (m, 3H), 2.97 (s, 6H), 3.40 (m , 1H), 5.04 (s, 2H), 6.35 (m, 1H), 6.40 (m, 1H), 6.75 (d, J = 8.4 Hz, 2H), 6.88 (m, 1H), 7.15 (m, 3H) , 7.20 (m, 5H)

단계 3: (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 1-[(3-벤질옥시-페닐 )-아마이드] 8-하이드록시아마이드 Step 3: (S) -2- (4-Dimethylamino-phenyl) -octanedioic acid 1-[(3-benzyloxy-phenyl) -amide] 8-hydroxyamide

출발물질로 상기 단계 2에서 얻은 (S)-7-(3-벤질옥시-페닐카바모일)-7-(4-다이메틸아미노-페닐)-헵타노산을 사용하는 것을 제외하고는 실시예 1의 단계 2와 동일한 방법으로 표제 화합물 (33％)을 얻었다.Example 1, except that (S) -7- (3-benzyloxy-phenylcarbamoyl) -7- (4-dimethylamino-phenyl) -heptanoic acid obtained in Step 2 was used as a starting material. The title compound (33%) was obtained in the same manner as in step 2.

1H NMR (300 MHz, DMSO-d6) : δ 1.28 (m, 4H), 1.62 (m, 2H), 1.85 (m, 1H), 2.20 (m, 3H), 2.97 (s, 6H), 3.42 (m, 1H), 5.04 (s, 2H), 6.35 (m, 1H), 6.42 (m, 1H), 6.77 (d, J = 8.4 Hz, 2H), 6.88 (m, 1H), 7.17 (m, 3H), 7.24 (m, 5H), 8.77 (s, 1H), 10.47 (s, 1H) 1 H NMR (300 MHz, DMSO-d 6 ): δ 1.28 (m, 4H), 1.62 (m, 2H), 1.85 (m, 1H), 2.20 (m, 3H), 2.97 (s, 6H), 3.42 (m, 1H), 5.04 (s, 2H), 6.35 (m, 1H), 6.42 (m, 1H), 6.77 (d, J = 8.4 Hz, 2H), 6.88 (m, 1H), 7.17 (m, 3H), 7.24 (m, 5H), 8.77 (s, 1H), 10.47 (s, 1H)

실시예 37: (S)-8-(1,3-디하이드로-이소인돌-2-일)-7-(4-다이메틸아미노-페닐)-8-옥소-옥타노산 하이드록시아마이드 Example 37: (S) -8- (1,3-dihydro-isoindol-2-yl) -7- (4-dimethylamino-phenyl) -8-oxo-octanoic acid hydroxyamide

단계 1: (S)-8-(1,3-디하이드로-이소인돌-2-일)-7-(4-다이메틸아미노-페닐)-8-옥소-옥타노산 에틸 에스터Step 1: (S) -8- (1,3-dihydro-isoindol-2-yl) -7- (4-dimethylamino-phenyl) -8-oxo-octanoic acid ethyl ester

출발물질로 제조예 6에서 얻은 (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-에틸 에스터 (16) 및 2,3-디하이드로-1-H-이소인돌을 사용하는 것을 제외하고는 실시예 7의 단계 1과 동일한 방법으로 표제 화합물 (66％)을 얻었다. (S) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-ethyl ester (16) and 2,3-dihydro-1-H-isoindole obtained in Preparation Example 6 were used as starting materials. The title compound (66%) was obtained in the same manner as in Step 1 of Example 7, except that.

1H NMR (300 MHz, CDCl3) : δ 1.25 (t, J = 7.2 Hz, 3H), 1.31 (m, 4H), 1.62 (m, 3H), 2.19 (m, 3H), 2.93 (s, 6H), 3.22 (m, 3H), 4.10 (q, J = 7.2 Hz, 2H), 4.31 (m, 1H), 4.71 (m, 1H), 6.70 (d, J = 8.4 Hz, 2H), 7.19 (m, 6H) 1 H NMR (300 MHz, CDCl 3 ): δ 1.25 (t, J = 7.2 Hz, 3H), 1.31 (m, 4H), 1.62 (m, 3H), 2.19 (m, 3H), 2.93 (s, 6H ), 3.22 (m, 3H), 4.10 (q, J = 7.2 Hz, 2H), 4.31 (m, 1H), 4.71 (m, 1H), 6.70 (d, J = 8.4 Hz, 2H), 7.19 (m , 6H)

단계 2: (S)-8-(1,3-디하이드로-이소인돌-2-일)-7-(4-다이메틸아미노-페닐)-8-옥소-옥타노산Step 2: (S) -8- (1,3-dihydro-isoindol-2-yl) -7- (4-dimethylamino-phenyl) -8-oxo-octanoic acid

출발물질로 상기 단계 1에서 얻은 (S)-8-(1,3-디하이드로-이소인돌-2-일)-7-(4-다이메틸아미노-페닐)-8-옥소-옥타노산 에틸 에스터를 사용하는 것을 제외하고는 실시예 3의 단계 2와 동일한 방법으로 표제 화합물 (79％)을 얻었다.(S) -8- (1,3-dihydro-isoindol-2-yl) -7- (4-dimethylamino-phenyl) -8-oxo-octanoic acid ethyl ester obtained in step 1 as a starting material The title compound (79%) was obtained by the same method as Step 2 of Example 3, except for using.

1H NMR (300 MHz, CDCl3) : δ 1.31 (m, 4H), 1.62 (m, 3H), 2.19 (m, 3H), 2.93 (s, 6H), 3.22 (m, 3H), 4.31 (m, 1H), 4.71 (m, 1H), 6.70 (d, J = 8.4 Hz, 2H), 7.19 (m, 6H) 1 H NMR (300 MHz, CDCl 3 ): δ 1.31 (m, 4H), 1.62 (m, 3H), 2.19 (m, 3H), 2.93 (s, 6H), 3.22 (m, 3H), 4.31 (m , 1H), 4.71 (m, 1H), 6.70 (d, J = 8.4 Hz, 2H), 7.19 (m, 6H)

단계 3: (S)-8-(1,3-디하이드로-이소인돌-2-일)-7-(4-다이메틸아미노-페닐)-8-옥소-옥타노산 8-하이드록시아마이드 Step 3: (S) -8- (1,3-Dihydro-isoindol-2-yl) -7- (4-dimethylamino-phenyl) -8-oxo-octanoic acid 8-hydroxyamide

출발물질로 상기 단계 2에서 얻은 (S)-8-(1,3-디하이드로-이소인돌-2-일)-7-(4-다이메틸아미노-페닐)-8-옥소-옥타노산을 사용하는 것을 제외하고는 실시예 1의 단계 2와 동일한 방법으로 표제 화합물 (25％)을 얻었다.Using (S) -8- (1,3-dihydro-isoindol-2-yl) -7- (4-dimethylamino-phenyl) -8-oxo-octanoic acid obtained in step 2 as starting material The title compound (25%) was obtained in the same manner as in Step 2 of Example 1, except that.

1H NMR (300 MHz, DMSO-d6) : δ 1.33 (m, 4H), 1.60 (m, 3H), 2.19 (m, 3H), 2.93 (s, 6H), 3.22 (m, 3H), 4.35 (m, 1H), 4.70 (m, 1H), 6.70 (d, J = 8.4 Hz, 2H), 7.19 (m, 6H), 8.74 (s, 1H), 10.43 (s, 1H) 1 H NMR (300 MHz, DMSO-d 6 ): δ 1.33 (m, 4H), 1.60 (m, 3H), 2.19 (m, 3H), 2.93 (s, 6H), 3.22 (m, 3H), 4.35 (m, 1H), 4.70 (m, 1H), 6.70 (d, J = 8.4 Hz, 2H), 7.19 (m, 6H), 8.74 (s, 1H), 10.43 (s, 1H)

실시예 38: (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 1-[(9-에틸-9H-카바졸-3-일)-아마이드] 8-하이드록시아마이드 Example 38: (S) -2- (4-Dimethylamino-phenyl) -octanedioic acid 1-[(9-ethyl-9H-carbazol-3-yl) -amide] 8-hydroxyamide

단계 1: (S)-7-(4-다이메틸아미노-페닐)-7-(9-에틸-9H-카바졸-3-일카바모일)-헵타노산 에틸 에스터 Step 1: (S) -7- (4-dimethylamino-phenyl) -7- (9-ethyl-9H-carbazol-3-ylcarbamoyl) -heptanoic acid ethyl ester

출발물질로 제조예 6에서 얻은 (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-에틸 에스터 (16) 및 9-에틸-9H-카바졸-3-일아민을 사용하는 것을 제외하고는 실시예 7의 단계 1과 동일한 방법으로 표제 화합물 (33％)을 얻었다.(S) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-ethyl ester (16) obtained in Preparation Example 6 as a starting material, and The title compound (33%) was obtained by the same method as Step 1 of Example 7, except for using 9-ethyl-9H-carbazol-3-ylamine.

1H NMR (300 MHz, CDCl3) : δ 1.24 (t, J = 7.2 Hz, 3H), 1.19 (m, 7H), 1.60 (m, 2H), 1.88 (m, 1H), 2.28 (m, 3H), 2.97 (s, 6H), 3.45 (m, 1H), 4.13 (q, J = 7.2 Hz, 2H), 4.33 (q, J = 7.2 Hz, 2H), 6.78 (d, J = 8.4 Hz, 2H), 6.91 (m, 1H), 7.22 (m, 4H), 7.40 (m, 3H), 8.01 (t, J = 7.6 Hz, 1H), 8.25 (s, 1H) 1 H NMR (300 MHz, CDCl 3 ): δ 1.24 (t, J = 7.2 Hz, 3H), 1.19 (m, 7H), 1.60 (m, 2H), 1.88 (m, 1H), 2.28 (m, 3H ), 2.97 (s, 6H), 3.45 (m, 1H), 4.13 (q, J = 7.2 Hz, 2H), 4.33 (q, J = 7.2 Hz, 2H), 6.78 (d, J = 8.4 Hz, 2H ), 6.91 (m, 1H), 7.22 (m, 4H), 7.40 (m, 3H), 8.01 (t, J = 7.6 Hz, 1H), 8.25 (s, 1H)

단계 2: (S)-7-(4-다이메틸아미노-페닐)-7-(9-에틸-9H-카바졸-3-일카바모일)-헵타노산 Step 2: (S) -7- (4-dimethylamino-phenyl) -7- (9-ethyl-9H-carbazol-3-ylcarbamoyl) -heptanoic acid

출발물질로 상기 단계 1에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-7-(9-에틸-9H-카바졸-3-일카바모일)-헵타노산 에틸 에스터를 사용하는 것을 제외하고는 실시예 3의 단계 2와 동일한 방법으로 표제 화합물 (67％)을 얻었다.Using (S) -7- (4-dimethylamino-phenyl) -7- (9-ethyl-9H-carbazol-3-ylcarbamoyl) -heptanoic acid ethyl ester obtained in step 1 above as starting material A title compound (67%) was obtained by the same method as Step 2 of Example 3, except that.

1H NMR (300 MHz, CDCl3) : δ 1.19 (m, 7H), 1.60 (m, 2H), 1.88 (m, 1H), 2.28 (m, 3H), 2.97 (s, 6H), 3.45 (m, 1H), 4.33 (q, J = 7.2 Hz, 2H), 6.78 (d, J = 8.4 Hz, 2H), 6.91 (m, 1H), 7.22 (m, 4H), 7.40 (m, 3H), 8.01 (t, J = 7.6 Hz, 1H), 8.25 (s, 1H) 1 H NMR (300 MHz, CDCl 3 ): δ 1.19 (m, 7H), 1.60 (m, 2H), 1.88 (m, 1H), 2.28 (m, 3H), 2.97 (s, 6H), 3.45 (m , 1H), 4.33 (q, J = 7.2 Hz, 2H), 6.78 (d, J = 8.4 Hz, 2H), 6.91 (m, 1H), 7.22 (m, 4H), 7.40 (m, 3H), 8.01 (t, J = 7.6 Hz, 1H), 8.25 (s, 1H)

단계 3: (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 1-[(9-에틸-9H-카바졸-3-일)-아마이드 ] 8-하이드록시아마이드 Step 3: (S) -2- (4-Dimethylamino-phenyl) -octanodioic acid 1-[(9-ethyl-9H-carbazol-3-yl) -amide] 8-hydroxyamide

출발물질로 상기 단계 2에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-7-(9-에틸-9H-카바졸-3-일카바모일)-헵타노산을 사용하는 것을 제외하고는 실시예 1의 단계 2와 동일한 방법으로 표제 화합물 (32％)을 얻었다.Except for using (S) -7- (4-dimethylamino-phenyl) -7- (9-ethyl-9H-carbazol-3-ylcarbamoyl) -heptanoic acid obtained in step 2 as starting material In the same manner as in Step 2 of Example 1, the title compound (32%) was obtained.

1H NMR (300 MHz, DMSO-d6) : δ 1.23 (m, 7H), 1.65 (m, 2H), 1.88 (m, 1H), 2.28 (m, 3H), 2.95 (s, 6H), 3.47 (m, 1H), 4.33 (q, J = 7.2 Hz, 2H), 6.78 (d, J = 8.4 Hz, 2H), 6.92 (m, 1H), 7.22 (m, 4H), 7.40 (m, 3H), 8.05 (t, J = 7.6 Hz, 1H), 8.26 (s, 1H), 8.75 (s, 1H), 10.43 (s, 1H) 1 H NMR (300 MHz, DMSO-d 6 ): δ 1.23 (m, 7H), 1.65 (m, 2H), 1.88 (m, 1H), 2.28 (m, 3H), 2.95 (s, 6H), 3.47 (m, 1H), 4.33 (q, J = 7.2 Hz, 2H), 6.78 (d, J = 8.4 Hz, 2H), 6.92 (m, 1H), 7.22 (m, 4H), 7.40 (m, 3H) , 8.05 (t, J = 7.6 Hz, 1H), 8.26 (s, 1H), 8.75 (s, 1H), 10.43 (s, 1H)

실시예 39: (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-[(피리딘-4-일메틸)-아마이드] Example 39: (S) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 1-[(pyridin-4-ylmethyl) -amide]

단계 1: (S)-7-(4-다이메틸아미노-페닐)-7-[(피리딘-4-일메틸)-카바모일]-헵타노산 에틸 에스터Step 1: (S) -7- (4-dimethylamino-phenyl) -7-[(pyridin-4-ylmethyl) -carbamoyl] -heptanoic acid ethyl ester

출발물질로 제조예 6에서 얻은 (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-에틸 에스터 (16) 및 C-피리딘-4-일-메틸아민을 사용하는 것을 제외하고는 실시 예 7의 단계 1과 동일한 방법으로 표제 화합물 (45％)을 얻었다. Except for using (S) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-ethyl ester (16) and C-pyridin-4-yl-methylamine obtained in Preparation Example 6 as starting materials. The title compound (45%) was obtained in the same manner as in Step 1 of Example 7.

1H NMR (300 MHz, CDCl3) : δ 1.26 (t, J = 7.2 Hz, 3H), 1.31 (m, 4H), 1.59 (m, 2H), 1.72 (m, 1H), 2.20 (m, 3H), 2.93 (s, 6H), 3.22 (m, 1H), 4.10 (q, J = 7.2 Hz, 2H), 4.39 (d, J = 6.2 Hz, 2H), 5.80 (m, 1H), 6.68 (d, J = 8.4 Hz, 2H), 7.14 (m, 3H), 7.47 (m, 1H), 8.48 (m, 1H) 1 H NMR (300 MHz, CDCl 3 ): δ 1.26 (t, J = 7.2 Hz, 3H), 1.31 (m, 4H), 1.59 (m, 2H), 1.72 (m, 1H), 2.20 (m, 3H ), 2.93 (s, 6H), 3.22 (m, 1H), 4.10 (q, J = 7.2 Hz, 2H), 4.39 (d, J = 6.2 Hz, 2H), 5.80 (m, 1H), 6.68 (d , J = 8.4 Hz, 2H), 7.14 (m, 3H), 7.47 (m, 1H), 8.48 (m, 1H)

단계 2: (S)-7-(4-다이메틸아미노-페닐)-7-[(피리딘-4-일메틸)-카바모일]-헵타노산 Step 2: (S) -7- (4-dimethylamino-phenyl) -7-[(pyridin-4-ylmethyl) -carbamoyl] -heptanoic acid

출발물질로 상기 단계 1에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-7-[(피리딘-4-일메틸)-카바모일]-헵타노산 에틸 에스터를 사용하는 것을 제외하고는 실시예 3의 단계 2와 동일한 방법으로 표제 화합물 (89％)을 얻었다. Except for using (S) -7- (4-dimethylamino-phenyl) -7-[(pyridin-4-ylmethyl) -carbamoyl] -heptanoic acid ethyl ester obtained in step 1 as starting material Obtained the title compound (89%) in the same manner as in Step 2 of Example 3.

1H NMR (300 MHz, CDCl3) : δ 1.31 (m, 4H), 1.59 (m, 2H), 1.72 (m, 1H), 2.20 (m, 3H), 2.93 (s, 6H), 3.22 (m, 1H), 4.39 (d, J = 6.2 Hz, 2H), 5.80 (m, 1H), 6.68 (d, J = 8.4 Hz, 2H), 7.14 (m, 3H), 7.47 (m, 1H), 8.48 (m, 1H) 1 H NMR (300 MHz, CDCl 3 ): δ 1.31 (m, 4H), 1.59 (m, 2H), 1.72 (m, 1H), 2.20 (m, 3H), 2.93 (s, 6H), 3.22 (m , 1H), 4.39 (d, J = 6.2 Hz, 2H), 5.80 (m, 1H), 6.68 (d, J = 8.4 Hz, 2H), 7.14 (m, 3H), 7.47 (m, 1H), 8.48 (m, 1 H)

단계 3: (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-[(피리딘-4-일메틸)-아마이드] Step 3: (S) -2- (4-Dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 1-[(pyridin-4-ylmethyl) -amide]

출발물질로 (S)-7-(4-다이메틸아미노-페닐)-7-[(피리딘-4-일메틸)-카바모일]-헵타노산을 사용하는 것을 제외하고는 실시예 1의 단계 2와 동일한 방법으로 표 제 화합물 (55％)을 얻었다.Step 2 of Example 1, except using (S) -7- (4-dimethylamino-phenyl) -7-[(pyridin-4-ylmethyl) -carbamoyl] -heptanoic acid as starting material In the same manner as the title compound (55%) was obtained.

1H NMR (300 MHz, DMSO-d6) : δ 1.34 (m, 4H), 1.59 (m, 2H), 1.75 (m, 1H), 2.20 (m, 3H), 2.93 (s, 6H), 3.22 (m, 1H), 4.39 (d, J = 6.2 Hz, 2H), 5.82 (m, 1H), 6.68 (d, J = 8.4 Hz, 2H), 7.14 (m, 3H), 7.47 (m, 1H), 8.48 (m, 1H), 8.85 (s, 1H), 10.42 (s, 1H) 1 H NMR (300 MHz, DMSO-d 6 ): δ 1.34 (m, 4H), 1.59 (m, 2H), 1.75 (m, 1H), 2.20 (m, 3H), 2.93 (s, 6H), 3.22 (m, 1H), 4.39 (d, J = 6.2 Hz, 2H), 5.82 (m, 1H), 6.68 (d, J = 8.4 Hz, 2H), 7.14 (m, 3H), 7.47 (m, 1H) , 8.48 (m, 1H), 8.85 (s, 1H), 10.42 (s, 1H)

실시예 40: (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-[(5-메틸설파닐-1H-[1,2,4]트라이아졸-3-일)-아마이드] Example 40: (S) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 1-[(5-methylsulfanyl-1H- [1,2,4] triazole- 3-day) -amide]

단계 1: (S)-7-(4-다이메틸아미노-페닐)-7-(5-메틸설파닐-1H-[1,2,4]트라이아졸-3-일카바모일]-헵타노산 에틸 에스터Step 1: (S) -7- (4-dimethylamino-phenyl) -7- (5-methylsulfanyl-1H- [1,2,4] triazol-3-ylcarbamoyl] -heptanoic acid ethyl Ester

출발물질로 제조예 6에서 얻은 (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-에틸 에스터 (16) 및 5-메틸설파닐-1H-[1,2,4]트라이아졸-3-일아민을 사용하는 것을 제외하고는 실시예 7의 단계 1과 동일한 방법으로 표제 화합물 (23％)을 얻었다. (S) -2- (4-Dimethylamino-phenyl) -octanedioic acid 8-ethyl ester (16) and 5-methylsulfanyl-1H- [1,2,4] obtained as starting materials The title compound (23%) was obtained by the same method as Step 1 of Example 7, except using triazol-3-ylamine.

1H NMR (300 MHz, CDCl3) : δ 1.24 (t, J = 7.2 Hz, 3H), 1.25 (m, 4H), 1.58 (m, 2H), 1.80 (m, 1H), 2.10 (m, 1H), 2.25 (t, J = 7.4 Hz, 2H), 2.54 (s, 3H), 2.92 (s, 6H), 4.12 (q, J = 7.2 Hz, 2H), 4.60 (t, J = 7.8 Hz, 1H), 6.31 (m, 2H), 6.64 (d, J = 8.4 Hz, 2H), 7.21 (s, 1H) 1 H NMR (300 MHz, CDCl 3 ): δ 1.24 (t, J = 7.2 Hz, 3H), 1.25 (m, 4H), 1.58 (m, 2H), 1.80 (m, 1H), 2.10 (m, 1H ), 2.25 (t, J = 7.4 Hz, 2H), 2.54 (s, 3H), 2.92 (s, 6H), 4.12 (q, J = 7.2 Hz, 2H), 4.60 (t, J = 7.8 Hz, 1H ), 6.31 (m, 2H), 6.64 (d, J = 8.4 Hz, 2H), 7.21 (s, 1H)

단계 2: (S)-7-(4-다이메틸아미노-페닐)-7-(5-메틸설파닐-1H-[1,2,4]트라이아졸-3-일카바모일]-헵타노산 Step 2: (S) -7- (4-dimethylamino-phenyl) -7- (5-methylsulfanyl-1H- [1,2,4] triazol-3-ylcarbamoyl] -heptanoic acid

출발물질로 상기 단계 1에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-7-(5-메틸설파닐-1H-[1,2,4]트라이아졸-3-일카바모일]-헵타노산 에틸 에스터를 사용하는 것을 제외하고는 실시예 3의 단계 2와 동일한 방법으로 표제 화합물 (65％)을 얻었다.(S) -7- (4-dimethylamino-phenyl) -7- (5-methylsulfanyl-1H- [1,2,4] triazol-3-ylcarbamoyl obtained in step 1 as starting material The title compound (65%) was obtained by the same method as Step 2 of Example 3, except for using] -heptanoic acid ethyl ester.

1H NMR (300 MHz, CDCl3) : δ 1.26 (m, 4H), 1.58 (m, 2H), 1.81 (m, 1H), 2.10 (m, 1H), 2.25 (t, J = 7.4 Hz, 2H), 2.54 (s, 3H), 2.94 (s, 6H), 4.60 (t, J = 7.8 Hz, 1H), 6.31 (m, 2H), 6.64 (d, J = 8.4 Hz, 2H), 7.21 (s, 1H) 1 H NMR (300 MHz, CDCl 3 ): δ 1.26 (m, 4H), 1.58 (m, 2H), 1.81 (m, 1H), 2.10 (m, 1H), 2.25 (t, J = 7.4 Hz, 2H ), 2.54 (s, 3H), 2.94 (s, 6H), 4.60 (t, J = 7.8 Hz, 1H), 6.31 (m, 2H), 6.64 (d, J = 8.4 Hz, 2H), 7.21 (s , 1H)

단계 3: (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-[(5-메틸설파닐-1H-[1,2,4]트라이아졸-3-일)-아마이드] Step 3: (S) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 1-[(5-methylsulfanyl-1H- [1,2,4] triazole-3 -Work)-amide]

출발물질로 상기 단계 2에서 얻은 (S)-7-(4-다이메틸아미노-페닐)-7-(5-메틸설파닐-1H-[1,2,4]트라이아졸-3-일카바모일]-헵타노산을 사용하는 것을 제외하고는 실시예 1의 단계 2와 동일한 방법으로 표제 화합물 (34％)을 얻었다.(S) -7- (4-dimethylamino-phenyl) -7- (5-methylsulfanyl-1H- [1,2,4] triazol-3-ylcarbamoyl obtained in step 2 as starting material The title compound (34%) was obtained by the same method as Step 2 of Example 1, except for using] -heptanoic acid.

1H NMR (300 MHz, DMSO-d6) : δ 1.21 (m, 4H), 1.57 (m, 2H), 1.81 (m, 1H), 2.10 (m, 1H), 2.22 (t, J = 7.4 Hz, 2H), 2.54 (s, 3H), 2.95 (s, 6H), 4.60 (t, J = 7.8 Hz, 1H), 6.31 (m, 2H), 6.66 (d, J = 8.4 Hz, 2H), 7.21 (s, 1H), 8.84 (s, 1H), 10.47 (s, 1H) 1 H NMR (300 MHz, DMSO-d 6 ): δ 1.21 (m, 4H), 1.57 (m, 2H), 1.81 (m, 1H), 2.10 (m, 1H), 2.22 (t, J = 7.4 Hz , 2H), 2.54 (s, 3H), 2.95 (s, 6H), 4.60 (t, J = 7.8 Hz, 1H), 6.31 (m, 2H), 6.66 (d, J = 8.4 Hz, 2H), 7.21 (s, 1H), 8.84 (s, 1H), 10.47 (s, 1H)

실시예 41: (R)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 하이드록시아마이드 8-페닐아마이드Example 41: (R) -7- (4-dimethylamino-phenyl) -octa-2,4-dienodioic acid hydroxyamide 8-phenylamide

단계 1: (R)-2-(4-다이메틸아미노-페닐)-4-옥소-부티르산 메틸 에스터Step 1: (R) -2- (4-dimethylamino-phenyl) -4-oxo-butyric acid methyl ester

반응촉매로 (2S,5S)-5-벤질-2-t-부틸-3-메틸이미다졸리딘-4-온을 사용하는 것을 제외하고는 제조예 1과 동일한 방법으로 표제 화합물 (72％ 수율, 94％ 거울상선택성)을 얻었다The title compound (72% yield) in the same manner as in Preparation Example 1, except that (2S, 5S) -5-benzyl-2-t-butyl-3-methylimidazolidin-4-one was used as the reaction catalyst. , 94% enantioselectivity) was obtained.

1H NMR (300 MHz, CDCl3) : δ 9.77 (s, 1H), 7.14 (d, J = 7.1 Hz, 2H), 6.68 (d, J = 7.6 Hz, 2H), 4.03 (dd, J = 4.7, 9.9 Hz, 1H), 3.66 (s, 3H), 3.35 (dd, J = 9.9, 18.7 Hz, 1H), 2.93 (s, 6H), 2.77 (dd, J = 4.8, 18.3 Hz, 1H) 1 H NMR (300 MHz, CDCl 3 ): δ 9.77 (s, 1H), 7.14 (d, J = 7.1 Hz, 2H), 6.68 (d, J = 7.6 Hz, 2H), 4.03 (dd, J = 4.7 , 9.9 Hz, 1H), 3.66 (s, 3H), 3.35 (dd, J = 9.9, 18.7 Hz, 1H), 2.93 (s, 6H), 2.77 (dd, J = 4.8, 18.3 Hz, 1H)

[α]D = -152.3 (c=1, CHCl3)[α] D = -152.3 (c = 1, CHCl 3 )

단계 2: (R)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-에틸 에스터 8-메틸 에스터Step 2: (R) -7- (4-dimethylamino-phenyl) -octa-2,4-dienodioic acid 1-ethyl ester 8-methyl ester

출발물질로 상기 단계 1에서 얻은 (R)-2-(4-다이메틸아미노-페닐)-4-옥소-부티르산 메틸 에스터를 사용하는 것을 제외하고는 제조예 2와 동일한 방법으로 표제 화합물 (74％)을 얻었다.The title compound (74%) in the same manner as in Preparation Example 2, except that (R) -2- (4-dimethylamino-phenyl) -4-oxo-butyric acid methyl ester obtained in Step 1 was used as a starting material. )

1H NMR (200 MHz, CDCl3) : δ 7.15-7.25 (m, 1H), 7.13 (d, J = 8.6 Hz, 2H), 6.67 (d, J = 8.6 Hz, 2H), 5.82-6.27 (m, 2H), 5.76 (d, J = 15.6 Hz, 1H), 4.17 (q, J = 7.0 Hz, 2H), 3.63 (s, 3H), 3.51-3.62(m, 1H), 2.93 (s, 6H), 2.55-2.91 (m, 2H), 1.27(t, J = 7.0 Hz, 3H) 1 H NMR (200 MHz, CDCl 3 ): δ 7.15-7.25 (m, 1H), 7.13 (d, J = 8.6 Hz, 2H), 6.67 (d, J = 8.6 Hz, 2H), 5.82-6.27 (m , 2H), 5.76 (d, J = 15.6 Hz, 1H), 4.17 (q, J = 7.0 Hz, 2H), 3.63 (s, 3H), 3.51-3.62 (m, 1H), 2.93 (s, 6H) , 2.55-2.91 (m, 2H), 1.27 (t, J = 7.0 Hz, 3H)

단계 3: (R)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-에틸 에스터 (6)Step 3: (R) -7- (4-dimethylamino-phenyl) -octa-2,4-dienodioic acid 1-ethyl ester (6)

출발물질로 상기 단계 2에서 얻은 (R)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-에틸 에스터 8-메틸 에스터를 사용하는 것을 제외하고는 제조예 3과 동일한 방법으로 표제 화합물 (60％)을 얻었다.Preparation Example 3, except that (R) -7- (4-dimethylamino-phenyl) -octa-2,4-dienoic acid 1-ethyl ester 8-methyl ester obtained in step 2 was used as a starting material In the same manner as the title compound (60%) was obtained.

1H NMR (200 MHz, CDCl3) : δ 7.10-7.28 (m, 1H), 7.13 (d, J = 8.2 Hz, 2H), 6.69 (d, J = 8.2 Hz, 2H), 5.82-6.26 (m, 2H), 5.78 (d, J = 22.8 Hz, 1H), 4.17 (q, J = 7.2 Hz, 2H), 3.51-3.72(m, 1H), 2.92 (s, 6H), 2.52-3.03 (m, 2H), 1.27(t, J = 7.2 Hz, 3H) 1 H NMR (200 MHz, CDCl 3 ): δ 7.10-7.28 (m, 1H), 7.13 (d, J = 8.2 Hz, 2H), 6.69 (d, J = 8.2 Hz, 2H), 5.82-6.26 (m , 2H), 5.78 (d, J = 22.8 Hz, 1H), 4.17 (q, J = 7.2 Hz, 2H), 3.51-3.72 (m, 1H), 2.92 (s, 6H), 2.52-3.03 (m, 2H), 1.27 (t, J = 7.2 Hz, 3H)

단계 4: (R)-7-(4-다이메틸아미노-페닐)-7-페닐카바모일-헵타-2,4-디에노산 1-에틸 에스터 Step 4: (R) -7- (4-dimethylamino-phenyl) -7-phenylcarbamoyl-hepta-2,4-dienoic acid 1-ethyl ester

출발물질로 상기 단계 3에서 얻은 (R)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-에틸 에스터를 사용하는 것을 제외하고는 실시예 7의 단계 1과 동일한 방법으로 표제 화합물 (90％)을 얻었다. Step 1 of Example 7 except that (R) -7- (4-dimethylamino-phenyl) -octa-2,4-dienoic acid 1-ethyl ester obtained in step 3 above was used as starting material. In the same manner the title compound (90%) was obtained.

1H NMR (200 MHz, CDCl3) : δ 7.01-7.48 (m, 8H), 6.71 (d, J = 9.0 Hz, 2H), 5.92-6.28 (m, 2H), 5.78 (d, J = 15.4 Hz, 1H), 4.17 (q, J = 7.2 Hz, 2H), 3.49-3.62(m, 1H), 2.95 (s, 6H), 2.59-3.15 (m, 2H), 1.26(t, J = 7.2 Hz, 3H) 1 H NMR (200 MHz, CDCl 3 ): δ 7.01-7.48 (m, 8H), 6.71 (d, J = 9.0 Hz, 2H), 5.92-6.28 (m, 2H), 5.78 (d, J = 15.4 Hz , 1H), 4.17 (q, J = 7.2 Hz, 2H), 3.49-3.62 (m, 1H), 2.95 (s, 6H), 2.59-3.15 (m, 2H), 1.26 (t, J = 7.2 Hz, 3H)

단계 5: (R)-7-(4-다이메틸아미노-페닐)-7-페닐카바모일-헵타-2,4-디에노산 Step 5: (R) -7- (4-Dimethylamino-phenyl) -7-phenylcarbamoyl-hepta-2,4-dienoic acid

출발물질로 상기 단계 4에서 얻은 (R)-7-(4-다이메틸아미노-페닐)-7-페닐카바모일-헵타-2,4-디에노산 1-에틸 에스터를 사용하는 것을 제외하고는 실시예 1의 단계 1과 동일한 방법으로 표제 화합물 (74％)을 얻었다.Except for using (R) -7- (4-dimethylamino-phenyl) -7-phenylcarbamoyl-hepta-2,4-dienoic acid 1-ethyl ester obtained as a starting material In the same manner as in Step 1 of Example 1, the title compound (74%) was obtained.

1H NMR (200 MHz, CDCl3) : δ 6.95-7.40 (m, 8H), 6.65 (d, J = 9.0 Hz, 2H), 5.89-6.22 (m, 2H), 5.78 (d, J = 15.4 Hz, 1H), 3.43-3.57(m, 1H), 2.87 (s, 6H), 2.54-3.15 (m, 2H) 1 H NMR (200 MHz, CDCl 3 ): δ 6.95-7.40 (m, 8H), 6.65 (d, J = 9.0 Hz, 2H), 5.89-6.22 (m, 2H), 5.78 (d, J = 15.4 Hz , 1H), 3.43-3.57 (m, 1H), 2.87 (s, 6H), 2.54-3.15 (m, 2H)

단계 6: (R)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 하이드록시아마이드 8-페닐아마이드Step 6: (R) -7- (4-dimethylamino-phenyl) -octa-2,4-dienodioic acid hydroxyamide 8-phenylamide

출발물질로 상기 단계 5에서 얻은 (R)-7-(4-다이메틸아미노-페닐)-7-페닐카바모일-헵타-2,4-디에노산을 사용하는 것을 제외하고는 실시예 1의 단계 2와 동일한 방법으로 표제 화합물 (70％)을 얻었다.Step of Example 1, except using (R) -7- (4-dimethylamino-phenyl) -7-phenylcarbamoyl-hepta-2,4-dienoic acid obtained in Step 5 above as starting material In the same manner as 2, the title compound (70%) was obtained.

1H NMR (200 MHz, DMSO-d6) : δ 10. 60 (brs, 1H), 10.07 (s, 1H), 7.56 (d, J = 8.2 Hz, 2H), 6.87-7.28 (m, 6H), 6.71 (d, J = 8.2 Hz, 2H), 5.89-6.30 (m, 2H), 5.78 (d, J = 15.4 Hz, 1H), 3.52-3.70(m, 1H), 2.82 (s, 6H), 2.37-3.89 (m, 2H)] 1 H NMR (200 MHz, DMSO-d 6 ): δ 10.60 (brs, 1H), 10.07 (s, 1H), 7.56 (d, J = 8.2 Hz, 2H), 6.87-7.28 (m, 6H) , 6.71 (d, J = 8.2 Hz, 2H), 5.89-6.30 (m, 2H), 5.78 (d, J = 15.4 Hz, 1H), 3.52-3.70 (m, 1H), 2.82 (s, 6H), 2.37-3.89 (m, 2H)]

실시예 42: (R)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 8-[(3-벤질옥소-페닐)-아마이드] 1-하이드록시아마이드 Example 42: (R) -7- (4-Dimethylamino-phenyl) -octa-2,4-dienodioic acid 8-[(3-benzyloxo-phenyl) -amide] 1-hydroxyamide

단계 1: (R)-7-(3-벤질옥소-페닐카바모일)-7-(4-다이메틸아미노-페닐)-헵타-2,4-디에노산 에틸 에스터 Step 1: (R) -7- (3-benzyloxo-phenylcarbamoyl) -7- (4-dimethylamino-phenyl) -hepta-2,4-dienoic acid ethyl ester

출발물질로 실시예 41의 단계 3에서 얻은 (R)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-에틸 에스터 및 3-벤질옥소-페닐아민을 사용하는 것을 제외하고는 실시예 7의 단계 1과 동일한 방법으로 표제 화합물 (70％)을 얻었다. Using (R) -7- (4-dimethylamino-phenyl) -octa-2,4-dienoic acid 1-ethyl ester and 3-benzyloxo-phenylamine obtained in step 3 of Example 41 as starting materials Except for the title compound (70%) in the same manner as in Step 1 of Example 7.

1H NMR (200 MHz, CDCl3) : δ 6.98-7.40 (m, 8H), 6.69 (d, J = 9.0 Hz, 2H), 5.89-6.22 (m, 2H), 5.78 (d, J = 15.4 Hz, 1H), 4.17 (q, J = 7.2 Hz, 2H), 3.43-3.57(m, 1H), 2.87 (s, 6H), 2.54-3.15 (m, 2H), 1.26(t, J = 7.2 Hz, 3H) 1 H NMR (200 MHz, CDCl 3 ): δ 6.98-7.40 (m, 8H), 6.69 (d, J = 9.0 Hz, 2H), 5.89-6.22 (m, 2H), 5.78 (d, J = 15.4 Hz , 1H), 4.17 (q, J = 7.2 Hz, 2H), 3.43-3.57 (m, 1H), 2.87 (s, 6H), 2.54-3.15 (m, 2H), 1.26 (t, J = 7.2 Hz, 3H)

단계 2: (R)-7-(3-벤질옥소-페닐카바모일)-7-(4-다이메틸아미노-페닐)-헵타-2,4-디에노산Step 2: (R) -7- (3-benzyloxo-phenylcarbamoyl) -7- (4-dimethylamino-phenyl) -hepta-2,4-dienoic acid

출발물질로 상기 단계 1에서 얻은 (R)-7-(3-벤질옥소-페닐카바모일)-7-(4-다 이메틸아미노-페닐)-헵타-2,4-디에노산 에틸 에스터를 사용하는 것을 제외하고는 실시예 1의 단계 1과 동일한 방법으로 표제 화합물 (65％)을 얻었다.Using (R) -7- (3-benzyloxo-phenylcarbamoyl) -7- (4-dimethylamino-phenyl) -hepta-2,4-dienoic acid ethyl ester obtained in step 1 above as starting material The title compound (65%) was obtained by the same method as Step 1 of Example 1, except that.

1H NMR (200 MHz, CDCl3) : δ 7.09-7.38 (m, 10H), 6.64-6.87 (m, 4H), 5.98-6.28 (m, 2H), 5.75 (d, J = 15.4 Hz, 1H), 5.00 (s, 2H), 3.52 (t, J = 8.2 Hz, 1H), 2.94 (s, 6H), 2.60-3.14 (m, 2H) 1 H NMR (200 MHz, CDCl 3 ): δ 7.09-7.38 (m, 10H), 6.64-6.87 (m, 4H), 5.98-6.28 (m, 2H), 5.75 (d, J = 15.4 Hz, 1H) , 5.00 (s, 2H), 3.52 (t, J = 8.2 Hz, 1H), 2.94 (s, 6H), 2.60-3.14 (m, 2H)

단계 3: (R)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 8-[(3-벤질옥소-페닐)-아마이드] 1-하이드록시아마이드 Step 3: (R) -7- (4-Dimethylamino-phenyl) -octa-2,4-dienodioic acid 8-[(3-benzyloxo-phenyl) -amide] 1-hydroxyamide

출발물질로 상기 단계 2에서 얻은 (R)-7-(3-벤질옥소-페닐카바모일)-7-(4-다이메틸아미노-페닐)-헵타-2,4-디에노산을 사용하는 것을 제외하고는 실시예 1의 단계 2와 동일한 방법으로 표제 화합물 (54％)을 얻었다.Except for using (R) -7- (3-benzyloxo-phenylcarbamoyl) -7- (4-dimethylamino-phenyl) -hepta-2,4-dienoic acid obtained in step 2 as starting material In the same manner as in Step 2 of Example 1, the title compound (54%) was obtained.

1H NMR (200 MHz, DMSO-d6) : δ 10. 62 (brs, 1H), 10.09 (s, 1H), 6.63-7.49 (m, 14H), 5.88-6.29 (m, 2H), 5.78 (d, J = 15.4 Hz, 1H), 5.02 (s, 2H), 3.53-3.70(m, 1H), 2.82 (s, 6H), 2.35-3.87 (m, 2H) 1 H NMR (200 MHz, DMSO-d 6 ): δ 10.62 (brs, 1H), 10.09 (s, 1H), 6.63-7.49 (m, 14H), 5.88-6.29 (m, 2H), 5.78 ( d, J = 15.4 Hz, 1H), 5.02 (s, 2H), 3.53-3.70 (m, 1H), 2.82 (s, 6H), 2.35-3.87 (m, 2H)

실시예 43: (R)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-하이드록시아마이드 8-나프탈렌-1-일아마이드 Example 43: (R) -7- (4-dimethylamino-phenyl) -octa-2,4-dienedioic acid 1-hydroxyamide 8-naphthalen-1-ylamide

단계 1: (R)-7-(4-다이메틸아미노-페닐)-7-(나프틸렌-1-일카바모일)-헵타-2,4-디에노산 에틸 에스터 Step 1: (R) -7- (4-dimethylamino-phenyl) -7- (naphthylene-1-ylcarbamoyl) -hepta-2,4-dienoic acid ethyl ester

출발물질로 실시예 41의 단계 3에서 얻은 (R)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-에틸 에스터 및 1-아미노나프탈렌을 사용하는 것을 제외하고는 실시예 7의 단계 1과 동일한 방법으로 표제 화합물 (85％)을 얻었다. Except for using (R) -7- (4-dimethylamino-phenyl) -octa-2,4-dienoic acid 1-ethyl ester and 1-aminonaphthalene obtained in Step 3 of Example 41 as starting materials Obtained the title compound (85%) in the same manner as in Step 1 of Example 7.

1H NMR (200 MHz, CDCl3) : δ 8.16 (s, 1H), 7.11-7.82 (m, 10H), 6.70 (d, J = 8.6 Hz, 2H), 5.88-6.27 (m, 2H), 5.75 (d, J = 15.1 Hz, 1H), 4.17 (q, J = 7.4 Hz, 2H), 3.59 (t, J = 7.2 Hz, 1H), 2.94 (s, 6H), 2.60-3.17 (m, 2H), 1.27 (t, J = 7.2 Hz, 3H) 1 H NMR (200 MHz, CDCl 3 ): δ 8.16 (s, 1H), 7.11-7.82 (m, 10H), 6.70 (d, J = 8.6 Hz, 2H), 5.88-6.27 (m, 2H), 5.75 (d, J = 15.1 Hz, 1H), 4.17 (q, J = 7.4 Hz, 2H), 3.59 (t, J = 7.2 Hz, 1H), 2.94 (s, 6H), 2.60-3.17 (m, 2H) , 1.27 (t, J = 7.2 Hz, 3H)

단계 2: (R)-7-(4-다이메틸아미노-페닐)-7-(나프틸렌-1-일카바모일)-헵타-2,4-디에노산Step 2: (R) -7- (4-dimethylamino-phenyl) -7- (naphthylene-1-ylcarbamoyl) -hepta-2,4-dienoic acid

출발물질로 상기 단계 1에서 얻은 (R)-7-(4-다이메틸아미노-페닐)-7-(나프틸렌-1-일카바모일)-헵타-2,4-디에노산 에틸 에스터를 사용하는 것을 제외하고는 실시예 1의 단계 1과 동일한 방법으로 표제 화합물 (77％)을 얻었다.Using (R) -7- (4-dimethylamino-phenyl) -7- (naphthylene-1-ylcarbamoyl) -hepta-2,4-dienoic acid ethyl ester obtained in step 1 as starting material Except for the title compound (77%) in the same manner as in Step 1 of Example 1.

1H NMR (200 MHz, CDCl3) : δ 8.14 (s, 1H), 7.17-7.75 (m, 10H), 6.72 (d, J = 8.2 Hz, 2H), 5.98-6.29 (m, 2H), 5.74 (d, J = 15.4 Hz, 1H), 3.52-3.64 (m, 1H), 2.95 (s, 6H), 2.61-3.19 (m, 2H) 1 H NMR (200 MHz, CDCl 3 ): δ 8.14 (s, 1H), 7.17-7.75 (m, 10H), 6.72 (d, J = 8.2 Hz, 2H), 5.98-6.29 (m, 2H), 5.74 (d, J = 15.4 Hz, 1H), 3.52-3.64 (m, 1H), 2.95 (s, 6H), 2.61-3.19 (m, 2H)

단계 3: (R)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-하이드록시아마이드 8-나프탈렌-1-일아마이드Step 3: (R) -7- (4-dimethylamino-phenyl) -octa-2,4-dienodioic acid 1-hydroxyamide 8-naphthalen-1-ylamide

출발물질로 상기 단계 2에서 얻은 (R)-7-(4-다이메틸아미노-페닐)-7-(나프틸렌-1-일카바모일)-헵타-2,4-디에노산을 사용하는 것을 제외하고는 실시예 1의 단계 2와 동일한 방법으로 표제 화합물 (63％)을 얻었다.Except for using (R) -7- (4-dimethylamino-phenyl) -7- (naphthylene-1-ylcarbamoyl) -hepta-2,4-dienoic acid obtained in step 2 as starting material In the same manner as in Step 2 of Example 1, the title compound (63%) was obtained.

1H NMR (300 MHz, DMSO-d6) : δ 1.32 (m, 4H), 1.50 (m, 2H), 1.65(m, 1H), 1.94 (t, J = 7.2 Hz, 2H), 2.04 (m, 1H), 2.87 (s, 6H), 3.80 (t, J = 6.6 Hz, 1H), 6.74 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.49 (m, 3H), 7.61 (d, J = 7.5 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.93 (d, J = 7.5 Hz, 2H), 8.65 (s, 1H), 9.95 (s, 1H), 10.33 (s, 1H) 1 H NMR (300 MHz, DMSO-d 6 ): δ 1.32 (m, 4H), 1.50 (m, 2H), 1.65 (m, 1H), 1.94 (t, J = 7.2 Hz, 2H), 2.04 (m , 1H), 2.87 (s, 6H), 3.80 (t, J = 6.6 Hz, 1H), 6.74 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.49 (m , 3H), 7.61 (d, J = 7.5 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.93 (d, J = 7.5 Hz, 2H), 8.65 (s, 1H), 9.95 (s , 1H), 10.33 (s, 1H)

실시예 44: (R)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 8-나프탈렌-1-일아마이드Example 44 (R) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 8-naphthalen-1-ylamide

출발물질로 실시예 43에서 얻은 (R)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-하이드록시아마이드 8-나프탈렌-1-일아마이드를 사용하는 것을 제외하고는 실시예 2와 동일한 방법으로 표제 화합물 (70％)을 얻었다.Except for using (R) -7- (4-dimethylamino-phenyl) -octa-2,4-dienoic acid 1-hydroxyamide 8-naphthalen-1-ylamide obtained in Example 43 as a starting material. In the same manner as in Example 2, the title compound (70%) was obtained.

1H NMR (300 MHz, DMSO-d6) : δ 1.32 (m, 4H), 1.50 (m, 2H), 1.65(m, 1H), 1.94 (t, J = 7.2 Hz, 2H), 2.04 (m, 1H), 2.87 (s, 6H), 3.80 (t, J = 6.6 Hz, 1H), 6.74 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.49 (m, 3H), 7.61 (d, J = 7.5 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.93 (d, J = 7.5 Hz, 2H), 8.65 (s, 1H), 9.95 (s, 1H), 10.33 (s, 1H) 1 H NMR (300 MHz, DMSO-d 6 ): δ 1.32 (m, 4H), 1.50 (m, 2H), 1.65 (m, 1H), 1.94 (t, J = 7.2 Hz, 2H), 2.04 (m , 1H), 2.87 (s, 6H), 3.80 (t, J = 6.6 Hz, 1H), 6.74 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.49 (m , 3H), 7.61 (d, J = 7.5 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.93 (d, J = 7.5 Hz, 2H), 8.65 (s, 1H), 9.95 (s , 1H), 10.33 (s, 1H)

실시예 45: (R)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-하이드록시아마이드 8-퀴놀린-8-일아마이드 Example 45: (R) -7- (4-dimethylamino-phenyl) -octa-2,4-dienodioic acid 1-hydroxyamide 8-quinolin-8-ylamide

단계 1: (R)-7-(4-다이메틸아미노-페닐)-7-(퀴놀린-8-일카바모일)-헵타-2,4-디에노산 에틸 에스터 Step 1: (R) -7- (4-dimethylamino-phenyl) -7- (quinolin-8-ylcarbamoyl) -hepta-2,4-dienoic acid ethyl ester

출발물질로 실시예 41의 단계 3에서 얻은 (R)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-에틸 에스터 및 8-아미노퀴놀린을 사용하는 것을 제외하고는 실시예 7의 단계 1과 동일한 방법으로 표제 화합물 (57％)을 얻었다. Except for using (R) -7- (4-dimethylamino-phenyl) -octa-2,4-dienoic acid 1-ethyl ester and 8-aminoquinoline obtained in Step 3 of Example 41 as starting materials Obtained the title compound (57%) in the same manner as in Step 1 of Example 7.

1H NMR (300 MHz, CDCl3) : δ 9.87 (s, 1H), 8.75 (m, 2H), 8.11 (d, J = 8.1 Hz, 1H), 7.41 (m, 6H), 6.75 (d, J = 8.4 Hz, 2H), 6.22 (m, 2H), 5.78 (d, J = 15.3 Hz, 1H), 4.17 (q, J = 7.4 Hz, 2H), 3.73 (t, J = 7.5 Hz, 1H), 3.12 (m, 1H), 2.93 (s, 6H), 2.78 (m, 1H), 1.27 (t, J = 7.3 Hz, 3H) 1 H NMR (300 MHz, CDCl 3 ): δ 9.87 (s, 1H), 8.75 (m, 2H), 8.11 (d, J = 8.1 Hz, 1H), 7.41 (m, 6H), 6.75 (d, J = 8.4 Hz, 2H), 6.22 (m, 2H), 5.78 (d, J = 15.3 Hz, 1H), 4.17 (q, J = 7.4 Hz, 2H), 3.73 (t, J = 7.5 Hz, 1H), 3.12 (m, 1H), 2.93 (s, 6H), 2.78 (m, 1H), 1.27 (t, J = 7.3 Hz, 3H)

단계 2: (R)-7-(4-다이메틸아미노-페닐)-7-(퀴놀린-8-일카바모일)-헵타-2,4-디에노산Step 2: (R) -7- (4-dimethylamino-phenyl) -7- (quinolin-8-ylcarbamoyl) -hepta-2,4-dienoic acid

출발물질로 상기 단계 1에서 얻은 (R)-7-(4-다이메틸아미노-페닐)-7-(퀴놀린-8-일카바모일)-헵타-2,4-디에노산 에틸 에스터를 사용하는 것을 제외하고는 실시예 1의 단계 1과 동일한 방법으로 표제 화합물 (46％)을 얻었다.Using (R) -7- (4-dimethylamino-phenyl) -7- (quinolin-8-ylcarbamoyl) -hepta-2,4-dienoic acid ethyl ester obtained as a starting material The title compound (46%) was obtained by the same method as Step 1 of Example 1, except.

1H NMR (300 MHz, MeOD-d4) : δ 8.64 (s, 1H), 8.48 (d, J = 8.0 Hz, 1H), 8.11 (d, J = 8.1 Hz, 1H), 7.39 (m, 3H),7.19 (d, J = 8.2 Hz, 2H), 7.00 (m, 1H), 6.67 (d, J = 8.4 Hz, 2H), 6.17 (m, 1H), 6.02 (m, 1H), 5.63 (d, J = 15.3 Hz, 1H), 3.79 (t, J = 7.6 Hz, 1H), 2.92 (m, 1H), 2.76 (s, 6H), 2.60 (m, 1H) 1 H NMR (300 MHz, MeOD-d 4 ): δ 8.64 (s, 1H), 8.48 (d, J = 8.0 Hz, 1H), 8.11 (d, J = 8.1 Hz, 1H), 7.39 (m, 3H ), 7.19 (d, J = 8.2 Hz, 2H), 7.00 (m, 1H), 6.67 (d, J = 8.4 Hz, 2H), 6.17 (m, 1H), 6.02 (m, 1H), 5.63 (d , J = 15.3 Hz, 1H), 3.79 (t, J = 7.6 Hz, 1H), 2.92 (m, 1H), 2.76 (s, 6H), 2.60 (m, 1H)

단계 3: (R)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-하이드록시아마이드 8-퀴놀린-8-일아마이드 Step 3: (R) -7- (4-dimethylamino-phenyl) -octa-2,4-dienodioic acid 1-hydroxyamide 8-quinolin-8-ylamide

출발물질로 상기 단계 2에서 얻은 (R)-7-(4-다이메틸아미노-페닐)-7-(퀴놀린-8-일카바모일)-헵타-2,4-디에노산을 사용하는 것을 제외하고는 실시예 1의 단계 2와 동일한 방법으로 표제 화합물 (21％)을 얻었다.Except for using (R) -7- (4-dimethylamino-phenyl) -7- (quinolin-8-ylcarbamoyl) -hepta-2,4-dienoic acid obtained as the starting material in step 2 above. Obtained the title compound (21%) in the same manner as in Step 2 of Example 1.

1H NMR (300 MHz, MeOD-d4) : δ 8.81 (s, 1H), 8.64 (d, J =7.6 Hz, 1H), 8.29 (d, J = 8.1 Hz, 1H), 7.55 (m, 3H), 7.34 (d, J = 8.6 Hz, 2H), 6.29(m, 1H), 6.13 (m, 1H), 5.78 (d, J = 14.9 Hz, 1H), 3.93 (m, 1H), 3.09 (m, 1H), 2.93 (s, 6H), 2.76 (m, 1H) 1 H NMR (300 MHz, MeOD-d 4 ): δ 8.81 (s, 1H), 8.64 (d, J = 7.6 Hz, 1H), 8.29 (d, J = 8.1 Hz, 1H), 7.55 (m, 3H ), 7.34 (d, J = 8.6 Hz, 2H), 6.29 (m, 1H), 6.13 (m, 1H), 5.78 (d, J = 14.9 Hz, 1H), 3.93 (m, 1H), 3.09 (m , 1H), 2.93 (s, 6H), 2.76 (m, 1H)

실시예 46: (R)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-퀴놀린-8-일아마이드Example 46: (R) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 1-quinolin-8-ylamide

출발물질로 실시예 45에서 얻은 (R)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-하이드록시아마이드 8-퀴놀린-8-일아마이드를 사용하는 것을 제외하고는 실시예 2와 동일한 방법으로 표제 화합물 (70％)을 얻었다.Except for using (R) -7- (4-dimethylamino-phenyl) -octa-2,4-dienoic acid 1-hydroxyamide 8-quinolin-8-ylamide obtained in Example 45 as a starting material. In the same manner as in Example 2, the title compound (70%) was obtained.

1H NMR (300 MHz, MeOD-d4) : δ 8.92 (s, 1H), 8.74 (d, J =7.5 Hz, 1H), 8.40 (d, J = 7.1 Hz, 1H), 7.55 (m, 3H), 7.64 (m, 3H), 6.94(d, J = 8.5 Hz, 2H), 3.69 (m, 1H), 3.03 (s, 6H), 2.21 (m, 3H), 1.95 (m, 1H), 1.76 (m, 2H), 1.39 (m, 4H) 1 H NMR (300 MHz, MeOD-d 4 ): δ 8.92 (s, 1H), 8.74 (d, J = 7.5 Hz, 1H), 8.40 (d, J = 7.1 Hz, 1H), 7.55 (m, 3H ), 7.64 (m, 3H), 6.94 (d, J = 8.5 Hz, 2H), 3.69 (m, 1H), 3.03 (s, 6H), 2.21 (m, 3H), 1.95 (m, 1H), 1.76 (m, 2H), 1.39 (m, 4H)

실시예 47: (R)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-하이드록시아마이드 3-퀴놀린-8-일아마이드 Example 47 (R) -7- (4-dimethylamino-phenyl) -octa-2,4-dienodioic acid 1-hydroxyamide 3-quinolin-8-ylamide

단계 1: (R)-7-(4-다이메틸아미노-페닐)-7-(퀴놀린-3-일카바모일)-헵타-2,4-디에노산 에틸 에스터 Step 1: (R) -7- (4-dimethylamino-phenyl) -7- (quinolin-3-ylcarbamoyl) -hepta-2,4-dienoic acid ethyl ester

출발물질로 실시예 41의 단계 3에서 얻은 (R)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-에틸 에스터 및 3-아미노퀴놀린을 사용하는 것을 제외하고는 실시예 7의 단계 1과 동일한 방법으로 표제 화합물 (49％)을 얻었다. Except for using (R) -7- (4-dimethylamino-phenyl) -octa-2,4-dienoic acid 1-ethyl ester and 3-aminoquinoline obtained in Step 3 of Example 41 as starting materials Obtained the title compound (49%) in the same manner as in Step 1 of Example 7.

1H NMR (300 MHz, CDCl3) : δ 8.73 (s, 1H), 8.57 (s, 1H), 8.00 (d, J =8.1 Hz, 1H), 7.775 (d, J =8.1 Hz, 1H), 7.57 (m, 2H), 7.18 (m, 3H), 6.74 (d, J = 8.7 Hz, 2H), 6.22 (m, 1H), 6.07 (m, 1H), 5.79 (d, J = 15.6 Hz, 1H), 4.18 (q, J = 7.4 Hz, 2H), 3.65 (t, J = 7.2 Hz, 1H), 3.08 (m, 1H), 2.94 (s, 6H), 2.74 (m, 1H), 1.28 (t, J = 7.2 Hz, 3H) 1 H NMR (300 MHz, CDCl 3 ): δ 8.73 (s, 1H), 8.57 (s, 1H), 8.00 (d, J = 8.1 Hz, 1H), 7.775 (d, J = 8.1 Hz, 1H), 7.57 (m, 2H), 7.18 (m, 3H), 6.74 (d, J = 8.7 Hz, 2H), 6.22 (m, 1H), 6.07 (m, 1H), 5.79 (d, J = 15.6 Hz, 1H ), 4.18 (q, J = 7.4 Hz, 2H), 3.65 (t, J = 7.2 Hz, 1H), 3.08 (m, 1H), 2.94 (s, 6H), 2.74 (m, 1H), 1.28 (t , J = 7.2 Hz, 3H)

단계 2: (R)-7-(4-다이메틸아미노-페닐)-7-(퀴놀린-3-일카바모일)-헵타-2,4-디에노산Step 2: (R) -7- (4-dimethylamino-phenyl) -7- (quinolin-3-ylcarbamoyl) -hepta-2,4-dienoic acid

출발물질로 상기 단계 1에서 얻은 (R)-7-(4-다이메틸아미노-페닐)-7-(퀴놀린-3-일카바모일)-헵타-2,4-디에노산 에틸 에스터를 사용하는 것을 제외하고는 실시예 1의 단계 1과 동일한 방법으로 표제 화합물 (33％)을 얻었다.Using (R) -7- (4-dimethylamino-phenyl) -7- (quinolin-3-ylcarbamoyl) -hepta-2,4-dienoic acid ethyl ester obtained in step 1 as starting material The title compound (33%) was obtained by the same method as Step 1 of Example 1, except.

1H NMR (300 MHz, MeOD-d4) : δ 8.87 (s, 1H), 8.68 (s, 1H), 7.97(m, 1H), 7.67 (m, 1H), 7.43 (m, 1H), 7.18 (m, 4H), 6.77 (d, J = 8.8 Hz, 2H), 6.22 (m, 1H), 6.10 (m, 1H), 5.80 (d, J = 15.3 Hz, 1H), 3.57 (t, J = 7.7 Hz, 1H), 2.91 (s, 6H), 2.86 (m, 1H), 2.61 (m, 1H) 1 H NMR (300 MHz, MeOD-d 4 ): δ 8.87 (s, 1H), 8.68 (s, 1H), 7.97 (m, 1H), 7.67 (m, 1H), 7.43 (m, 1H), 7.18 (m, 4H), 6.77 (d, J = 8.8 Hz, 2H), 6.22 (m, 1H), 6.10 (m, 1H), 5.80 (d, J = 15.3 Hz, 1H), 3.57 (t, J = 7.7 Hz, 1H), 2.91 (s, 6H), 2.86 (m, 1H), 2.61 (m, 1H)

단계 3: (R)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-하이드록시아마이드 8-퀴놀린-8-일아마이드 Step 3: (R) -7- (4-dimethylamino-phenyl) -octa-2,4-dienodioic acid 1-hydroxyamide 8-quinolin-8-ylamide

출발물질로 상기 단계 2에서 얻은 (R)-7-(4-다이메틸아미노-페닐)-7-(퀴놀린-8-일카바모일)-헵타-2,4-디에노산을 사용하는 것을 제외하고는 실시예 1의 단계 2와 동일한 방법으로 표제 화합물 (34％)을 얻었다.Except for using (R) -7- (4-dimethylamino-phenyl) -7- (quinolin-8-ylcarbamoyl) -hepta-2,4-dienoic acid obtained as the starting material in step 2 above. Obtained the title compound (34%) in the same manner as in Step 2 of Example 1.

1H NMR (300 MHz, MeOD-d4) : δ 8.84 (s, 1H), 8.62 (s, 1H), 7.97(m, 1H), 7.67 (m, 1H), 7.45 (m, 1H), 7.13 (m, 4H), 6.77 (d, J = 8.8 Hz, 2H), 6.24 (m, 1H), 6.12 (m, 1H), 5.83 (d, J = 15.3 Hz, 1H), 3.57 (m, 1H), 2.93 (s, 6H), 2.86 (m, 1H), 2.61 (m, 1H) 1 H NMR (300 MHz, MeOD-d 4 ): δ 8.84 (s, 1H), 8.62 (s, 1H), 7.97 (m, 1H), 7.67 (m, 1H), 7.45 (m, 1H), 7.13 (m, 4H), 6.77 (d, J = 8.8 Hz, 2H), 6.24 (m, 1H), 6.12 (m, 1H), 5.83 (d, J = 15.3 Hz, 1H), 3.57 (m, 1H) , 2.93 (s, 6H), 2.86 (m, 1H), 2.61 (m, 1H)

실시예 48: (R)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-하이드 록시아마이드 8-[(3-메톡시-페닐)-아마이드] Example 48: (R) -7- (4-Dimethylamino-phenyl) -octa-2,4-dienodioic acid 1-hydroxycamide 8-[(3-methoxy-phenyl) -amide]

단계 1: (R)-7-(4-다이메틸아미노-페닐)-7-(3-메톡시-페닐카바모일)-헵타-2,4-디에노산 에틸 에스터 Step 1: (R) -7- (4-dimethylamino-phenyl) -7- (3-methoxy-phenylcarbamoyl) -hepta-2,4-dienoic acid ethyl ester

출발물질로 실시예 41의 단계 3에서 얻은 (R)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-에틸 에스터 및 3-메톡시아닐린을 사용하는 것을 제외하고는 실시예 7의 단계 1과 동일한 방법으로 표제 화합물 (85％)을 얻었다. Except using (R) -7- (4-dimethylamino-phenyl) -octa-2,4-dienoic acid 1-ethyl ester and 3-methoxyaniline obtained in step 3 of Example 41 as starting material In the same manner as in Step 1 of Example 7, the title compound (85%) was obtained.

1H NMR (300 MHz, CDCl3) : δ 7.15 (m, 4H), 6.86 (m, 4H), 6.27 (m, 3H), 5.77 (d, J = 15.3 Hz, 1H), 4.17 (q, J = 7.4 Hz, 2H), 3.75 (s, 3H), 3.52 (t, J = 7.1 Hz, 1H), 2.98 (m, 1H), 2.94 (s, 6H), 2.75 (m, 1H), 1.27 (t, J = 7.2 Hz, 3H) 1 H NMR (300 MHz, CDCl 3 ): δ 7.15 (m, 4H), 6.86 (m, 4H), 6.27 (m, 3H), 5.77 (d, J = 15.3 Hz, 1H), 4.17 (q, J = 7.4 Hz, 2H), 3.75 (s, 3H), 3.52 (t, J = 7.1 Hz, 1H), 2.98 (m, 1H), 2.94 (s, 6H), 2.75 (m, 1H), 1.27 (t , J = 7.2 Hz, 3H)

단계 2: (R)-7-(4-다이메틸아미노-페닐)-7-(3-메톡시-페닐카바모일)-헵타-2,4-디에노산 Step 2: (R) -7- (4-dimethylamino-phenyl) -7- (3-methoxy-phenylcarbamoyl) -hepta-2,4-dienoic acid

출발물질로 상기 단계 1에서 얻은 (R)-7-(4-다이메틸아미노-페닐)-7-(3-메톡시-페닐카바모일)-헵타-2,4-디에노산 에틸 에스터를 사용하는 것을 제외하고는 실시예 1의 단계 1과 동일한 방법으로 표제 화합물 (59％)을 얻었다.Using (R) -7- (4-dimethylamino-phenyl) -7- (3-methoxy-phenylcarbamoyl) -hepta-2,4-dienoic acid ethyl ester obtained in step 1 as starting material Except for the title compound (59%) in the same manner as in Step 1 of Example 1.

1H NMR (300 MHz, MeOD-d4) : δ 7.24 (m, 5H), 7.04 (d, J = 8.1 Hz, 1H),6.78 (d, J = 8.8 Hz, 2H), 6.65 (d, J = 8.0 Hz, 1H), 6.30 (m, 1H), 6.10 (m, 1H), 5.80 (d, J = 15.3 Hz, 1H), 3.78 (s, 3H), 3.66 (t, J = 7.1 Hz, 1H), 2.94 (m, 1H), 2.90 (s, 6H), 2.65 (m, 1H) 1 H NMR (300 MHz, MeOD-d 4 ): δ 7.24 (m, 5H), 7.04 (d, J = 8.1 Hz, 1H), 6.78 (d, J = 8.8 Hz, 2H), 6.65 (d, J = 8.0 Hz, 1H), 6.30 (m, 1H), 6.10 (m, 1H), 5.80 (d, J = 15.3 Hz, 1H), 3.78 (s, 3H), 3.66 (t, J = 7.1 Hz, 1H ), 2.94 (m, 1H), 2.90 (s, 6H), 2.65 (m, 1H)

단계 3: (R)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-하이드록시아마이드 8-[(3-메톡시-페닐)-아마이드] Step 3: (R) -7- (4-Dimethylamino-phenyl) -octa-2,4-dienodioic acid 1-hydroxyamide 8-[(3-methoxy-phenyl) -amide]

출발물질로 상기 단계 2에서 얻은 (R)-7-(4-다이메틸아미노-페닐)-7-(3-메톡시-페닐카바모일)-헵타-2,4-디에노산을 사용하는 것을 제외하고는 실시예 1의 단계 2와 동일한 방법으로 표제 화합물 (10％)을 얻었다.Except for using (R) -7- (4-dimethylamino-phenyl) -7- (3-methoxy-phenylcarbamoyl) -hepta-2,4-dienoic acid obtained in step 2 as starting material In the same manner as in Step 2 of Example 1, the title compound (10%) was obtained.

1H NMR (300 MHz, MeOD-d4) : δ 7.53 (bs, 1H), 7.16 (m, 3H), 6.99 (m, 1H), 6.88 (d, J = 8.7 Hz, 1H), 6.77 (d, J = 8.7 Hz, 1H), 6.67 (d, J = 8.1 Hz, 2H), 6.15 (m, 1H), 5.97 (m, 1H), 5.69 (d, J = 15.3 Hz, 1H), 3.69 (s, 3H), 3.51 (t, J = 7.5 Hz, 1H), 2.85 (m, 1H), 2.80 (s, 6H), 2.49 (m, 1H) 1 H NMR (300 MHz, MeOD-d 4 ): δ 7.53 (bs, 1H), 7.16 (m, 3H), 6.99 (m, 1H), 6.88 (d, J = 8.7 Hz, 1H), 6.77 (d , J = 8.7 Hz, 1H), 6.67 (d, J = 8.1 Hz, 2H), 6.15 (m, 1H), 5.97 (m, 1H), 5.69 (d, J = 15.3 Hz, 1H), 3.69 (s , 3H), 3.51 (t, J = 7.5 Hz, 1H), 2.85 (m, 1H), 2.80 (s, 6H), 2.49 (m, 1H)

실시예 49: (R)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 8-[(3,4-다이메톡시-페닐)-아마이드] 1-하이드록시아마이드Example 49: (R) -7- (4-Dimethylamino-phenyl) -octa-2,4-dienedioic acid 8-[(3,4-dimethoxy-phenyl) -amide] 1-hydroxyamide

단계 1: (R)-7-(3,4-다이메톡시-페닐카바모일)-7-(4-다이메틸아미노-페닐)-헵타-2,4-디에노산 에틸 에스터 Step 1: (R) -7- (3,4-Dimethoxy-phenylcarbamoyl) -7- (4-dimethylamino-phenyl) -hepta-2,4-dienoic acid ethyl ester

출발물질로 실시예 41의 단계 3에서 얻은 (R)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-에틸 에스터 및 3,4-다이메톡시아닐린을 사용하는 것을 제외하고는 실시예 7의 단계 1과 동일한 방법으로 표제 화합물 (83％)을 얻었다. (R) -7- (4-dimethylamino-phenyl) -octa-2,4-dienoic acid 1-ethyl ester and 3,4-dimethoxyaniline obtained in step 3 of Example 41 were used as starting materials. The title compound (83%) was obtained in the same manner as in Step 1 of Example 7, except that.

1H NMR (300 MHz, CDCl3) : δ 7.25 (m, 3H), 6.77 (m, 5H), 6.19 (m, 1H), 6.06 (m, 1H), 5.78 (d, J = 15.3 Hz, 1H), 4.19 (q, J = 7.2 Hz, 2H), 3.85 (s, 3H), 3.83 (s, 3H), 3.53 (t, J = 6.6 Hz, 1H), 3.05 (m, 1H), 2.96 (s, 6H), 2.70 (m, 1H), 1.28 (t, J = 8.4 Hz, 3H) 1 H NMR (300 MHz, CDCl 3 ): δ 7.25 (m, 3H), 6.77 (m, 5H), 6.19 (m, 1H), 6.06 (m, 1H), 5.78 (d, J = 15.3 Hz, 1H ), 4.19 (q, J = 7.2 Hz, 2H), 3.85 (s, 3H), 3.83 (s, 3H), 3.53 (t, J = 6.6 Hz, 1H), 3.05 (m, 1H), 2.96 (s , 6H), 2.70 (m, 1H), 1.28 (t, J = 8.4 Hz, 3H)

단계 2: (R)-7-(3,4-다이메톡시-페닐카바모일)-7-(4-다이메틸아미노-페닐)-헵타-2,4-디에노산 Step 2: (R) -7- (3,4-dimethoxy-phenylcarbamoyl) -7- (4-dimethylamino-phenyl) -hepta-2,4-dienoic acid

출발물질로 상기 단계 1에서 얻은 (R)-7-(3,4-다이메톡시-페닐카바모일)-7-(4-다이메틸아미노-페닐)-헵타-2,4-디에노산 에틸 에스터를 사용하는 것을 제외하고는 실시예 1의 단계 1과 동일한 방법으로 표제 화합물 (36％)을 얻었다.(R) -7- (3,4-dimethoxy-phenylcarbamoyl) -7- (4-dimethylamino-phenyl) -hepta-2,4-dienoic acid ethyl ester obtained in step 1 as a starting material The title compound (36%) was obtained by the same method as Step 1 of Example 1 except for using.

1H NMR (300 MHz, MeOD-d4) : δ 7.12 (m, 4H), 6.88 (d, J = 8.7 Hz, 1H), 6.76 (d, J = 8.7 Hz, 1H), 6.67 (d, J = 8.4 Hz, 2H), 6.19 (m, 1H), 5.99 (m, 1H), 5.69(d, J = 15.3 Hz, 1H), 3.68 (s, 6H), 3.52 (t, J = 7.8 Hz, 1H), 2.83 (m, 1H), 2.57 (s, 6H), 2.52 (m, 1H) 1 H NMR (300 MHz, MeOD-d 4 ): δ 7.12 (m, 4H), 6.88 (d, J = 8.7 Hz, 1H), 6.76 (d, J = 8.7 Hz, 1H), 6.67 (d, J = 8.4 Hz, 2H), 6.19 (m, 1H), 5.99 (m, 1H), 5.69 (d, J = 15.3 Hz, 1H), 3.68 (s, 6H), 3.52 (t, J = 7.8 Hz, 1H ), 2.83 (m, 1H), 2.57 (s, 6H), 2.52 (m, 1H)

단계 3: (R)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 8-[(3,4-다이메톡시-페닐)-아마이드] 1-하이드록시아마이드Step 3: (R) -7- (4-Dimethylamino-phenyl) -octa-2,4-dienedioic acid 8-[(3,4-dimethoxy-phenyl) -amide] 1-hydroxyamide

출발물질로 상기 단계 2에서 얻은 (R)-7-(3,4-다이메톡시-페닐카바모일)-7-(4-다이메틸아미노-페닐)-헵타-2,4-디에노산을 사용하는 것을 제외하고는 실시예 1 의 단계 2와 동일한 방법으로 표제 화합물 (11％)을 얻었다.(R) -7- (3,4-Dimethoxy-phenylcarbamoyl) -7- (4-dimethylamino-phenyl) -hepta-2,4-dienoic acid obtained in Step 2 was used as a starting material. The title compound (11%) was obtained in the same manner as in Step 2 of Example 1, except that.

1H NMR (300 MHz, MeOD-d4) : δ 7.34 (d, J = 8.5 Hz, 3H), 7.21(m, 1H), 7.08 (m, 1H), 6.97 (d, J = 8.7 Hz, 1H), 6.88 (d, J = 8.6 Hz, 2H), 6.36 (m, 1H), 6.19 (m, 1H), 5.90 (d, J = 15.6 Hz, 1H), 3.90 (s, 6H), 3.72 (m, 1H), 3.02 (m, 1H), 3.00 (s, 6H), 2.72 (m, 1H) 1 H NMR (300 MHz, MeOD-d 4 ): δ 7.34 (d, J = 8.5 Hz, 3H), 7.21 (m, 1H), 7.08 (m, 1H), 6.97 (d, J = 8.7 Hz, 1H ), 6.88 (d, J = 8.6 Hz, 2H), 6.36 (m, 1H), 6.19 (m, 1H), 5.90 (d, J = 15.6 Hz, 1H), 3.90 (s, 6H), 3.72 (m , 1H), 3.02 (m, 1H), 3.00 (s, 6H), 2.72 (m, 1H)

시험예 1Test Example 1

HDAC 활성분석은 바이오물 (BIOMOL) 퀸티자임 (Quantizyme)TM 분석 시스템에 기초하여 수행하였다. 분석은 두 단계로 이루어지는데, 제 1 단계는 HDAC와 기질이 반응하는 효소반응 단계로서, 이 단계에서 HDAC 저해제를 넣어 HDAC 효소활성 저해를 측정하였다. 먼저, 반응 혼합물을 제조하기 위하여 96웰 플레이트에 반응 완충용액 (25 mM Tris-HCl [pH 8.0], 137 mM NaCl, 2.7 mM KCl, 1 mM MgCl2)을 42 ㎕ 첨가하고 250 μM Fluor de LysTM 기질을 5 ㎕ 첨가하였다. 이때, 효소저해제로서 원하는 농도(구체적으로 0.01 내지 1 μM/㎖)의 상기 실시예에서 제조된 화합물들을 2.5㎕ 첨가하였다. 비교군으로서 SAHA를 제조하여 사용하였다. 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. 이어, 제 2 단계는 검출단계로서, 50 ㎕ Flour de LysTM 디벨로 퍼(developer)에 2 μM 트라이코스타틴 a를 넣고 실온에서 15분 정도 반응시켰다. 상기 플루오로포어로부터 355 ㎚에서 여기 (excitation)되고 460 ㎚에서 방출되어 나오는 광을 형광측정용 기판 판독기 (fluorometric plate reader로 detection)로 검출하였다. 이때, 효소활성이 높을수록 460 ㎚에서 방출되어 나오는 형광도가 커지게 되고, HDAC 저해제가 들어있지 않은 경우와 들어 있는 경우에서 검출된 형광도를 비교하여 HDAC 저해효과를 측정하였다.HDAC activity assays were performed based on the BioOMOL Quintizyme ™ Assay System. The analysis consists of two steps. The first step is an enzyme reaction in which HDAC reacts with a substrate. In this step, the inhibition of HDAC enzyme activity was measured by adding an HDAC inhibitor. First, 42 μl of reaction buffer (25 mM Tris-HCl [pH 8.0], 137 mM NaCl, 2.7 mM KCl, 1 mM MgCl 2 ) was added to a 96 well plate to prepare a reaction mixture, and 250 μM Fluor de Lys ™ was added. 5 μl of substrate was added. At this time, 2.5 [mu] l of the compounds prepared in the above example at the desired concentration (specifically 0.01 to 1 [mu] M / ml) was added as an enzyme inhibitor. SAHA was prepared and used as a comparative group. 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. Subsequently, the second step was a detection step, and 2 μM tricostatin a was added to 50 μl Flour de Lys ™ developer (reveloper) and reacted for 15 minutes at room temperature. Light excited from the fluoropores at 355 nm and emitted at 460 nm was detected by detection with 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.

상기 실시예에서 제조된 대표적 화합물들의 HDAC 저해농도를 하기 표 1에 나타내었다 The HDAC inhibitory concentrations of the representative compounds prepared in the Examples are shown in Table 1 below.

Figure 112004047982053-pat00010
Figure 112004047982053-pat00010

상기 표 1로부터, 본 발명에 따른 화학식 1의 N,N-다이메틸아미노페닐 옥타노산 하이드록시아마이드 유도체가 매우 우수한 HDAC 저해활성을 나타냄을 알 수 있다.From Table 1 , it can be seen that the N, N-dimethylaminophenyl octanoic acid hydroxyamide derivative of the formula (1) according to the present invention shows very good HDAC inhibitory activity.

상기에서 살펴본 바와 같이, 본 발명의 화학식 1의 N,N-다이메틸아미노페닐 옥타노산 하이드록시아마이드 유도체는 히스톤 디아세틸라제의 활성을 효과적으로 억제하여 종양세포의 말기 분화를 선택적으로 유도함으로써 이들 종양세포의 증식을 억제하므로, 항암제로서 유용하게 사용될 수 있다.As described above, the N, N-dimethylaminophenyl octanoic acid hydroxyamide derivative of the general formula (1) of the present invention effectively inhibits histone deacetylase activity and selectively induces terminal differentiation of tumor cells. Since it suppresses the proliferation of, it can be usefully used as an anticancer agent.

Claims (28)

하기 화학식 1의 N,N-다이메틸아미노페닐 옥타노산 하이드록시아마이드 유도체 화합물, 이의 거울상 이성질체 또는 이의 약학적으로 허용가능한 염:N, N-dimethylaminophenyl octanoic acid hydroxyamide derivative compound of Formula 1 , an enantiomer thereof or a pharmaceutically acceptable salt thereof: <화학식 1><Formula 1>
Figure 112004047982053-pat00011
Figure 112004047982053-pat00011
 상기 식에서, Where R은 치환되거나 비치환된 하이드록시메틸기, 아릴아미노메틸기, 아릴아마이드기, C1-5 알킬아마이드기, 헤테로아릴아마이드기이고, 상기에서 헤테로아릴은 고리 중에 질소, 황 또는 산소를 포함하며, 피페라진, 트라이아졸, 티아졸, 벤조티아졸, 다이벤조퓨란, 피리딘, 퀴놀린, 또는 이소퀴놀린이다.R is a substituted or unsubstituted hydroxymethyl group, arylaminomethyl group, arylamide group, C 1-5 alkylamide group, heteroarylamide group, wherein heteroaryl includes nitrogen, sulfur or oxygen in the ring, Razin, triazole, thiazole, benzothiazole, dibenzofuran, pyridine, quinoline, or isoquinoline. 제 1항에 있어서, The method of claim 1, 하기 화합물로 구성된 군으로부터 선택되는 것을 특징으로 하는 화합물, 이의 거울상 이성질체 또는 이의 약학적으로 허용가능한 염.A compound, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of the following compounds. (S)-7-(4-다이메틸아미노-페닐)-8-하이드록시-옥타-2,4-디에노산 하이드록시아마이드;(S) -7- (4-dimethylamino-phenyl) -8-hydroxy-octa-2,4-dienoic acid hydroxyamide; (S)-7-(4-다이메틸아미노-페닐)-8-하이드록시-옥타노산 하이드록시아마이드;(S) -7- (4-dimethylamino-phenyl) -8-hydroxy-octanoic acid hydroxyamide; (S)-7-(4-다이메틸아미노-페닐)-8-페닐아미노-옥타-2,4-디에노산 하이드록시아마이드;(S) -7- (4-dimethylamino-phenyl) -8-phenylamino-octa-2,4-dienoic acid hydroxyamide; (S)-7-(4-다이메틸아미노-페닐)-8-페닐아미노-옥타노산 하이드록시아마이드;(S) -7- (4-dimethylamino-phenyl) -8-phenylamino-octanoic acid hydroxyamide; (S)-8-(3-벤질옥소-페닐아미노)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디에노산 하이드록시아마이드;(S) -8- (3-benzyloxo-phenylamino) -7- (4-dimethylamino-phenyl) -octa-2,4-dienoic acid hydroxyamide; (S)-7-(4-다이메틸아미노-페닐)-8-(3-하이드록시-페닐아미노)-옥타노산 하이드록시아마이드;(S) -7- (4-dimethylamino-phenyl) -8- (3-hydroxy-phenylamino) -octanoic acid hydroxyamide; (S)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 하이드록시아마이드 8-페닐아마이드;(S) -7- (4-dimethylamino-phenyl) -octa-2,4-dienodioic acid hydroxyamide 8-phenylamide; (S)-2-(4-다이메틸아미노-페닐)-옥타노산 8-하이드록시아마이드 1-페닐아마이드;(S) -2- (4-dimethylamino-phenyl) -octanoic acid 8-hydroxyamide 1-phenylamide; (S)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 8-[(3-벤질옥소-페닐)-아마이드] 1-하이드록시아마이드;(S) -7- (4-dimethylamino-phenyl) -octa-2,4-dienodioic acid 8-[(3-benzyloxo-phenyl) -amide] 1-hydroxyamide; (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-[(3-하이드록시-페닐)-아마이드]; (S) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 1-[(3-hydroxy-phenyl) -amide]; (S)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-하이드록시아마이드 8-나프탈렌-1-일아마이드;(S) -7- (4-dimethylamino-phenyl) -octa-2,4-dienodioic acid 1-hydroxyamide 8-naphthalen-1-ylamide; (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 8-나프탈렌-1-일아마이드;(S) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 8-naphthalen-1-ylamide; (S)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-하이드록시아마이드 8-퀴놀린-6-일아마이드;(S) -7- (4-dimethylamino-phenyl) -octa-2,4-dienodioic acid 1-hydroxyamide 8-quinolin-6-ylamide; (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-퀴놀린-6-일아마이드;(S) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 1-quinolin-6-ylamide; (S)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-하이드록시아마이드 8-퀴놀린-8-일아마이드; (S) -7- (4-dimethylamino-phenyl) -octa-2,4-dienodioic acid 1-hydroxyamide 8-quinolin-8-ylamide; (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-퀴놀린-8-일아마이드;(S) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 1-quinolin-8-ylamide; (S)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-하이드록시아마이드 8-[(3-메톡시-페닐)-아마이드];(S) -7- (4-dimethylamino-phenyl) -octa-2,4-dienodioic acid 1-hydroxyamide 8-[(3-methoxy-phenyl) -amide]; (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-[(3-메톡시-페닐)-아마이드]-8-일아마이드;(S) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 1-[(3-methoxy-phenyl) -amide] -8-ylamide; (S)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 8-[(3,4-다이메톡시-페닐)-아마이드] 1-하이드록시아마이드;(S) -7- (4-dimethylamino-phenyl) -octa-2,4-dienodioic acid 8-[(3,4-dimethoxy-phenyl) -amide] 1-hydroxyamide; (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-[(3,4-다이메톡시-페닐)-아마이드]-8-일아마이드;(S) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 1-[(3,4-dimethoxy-phenyl) -amide] -8-ylamide; (S)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-하이드록시아마이드 3-퀴놀린-8-일아마이드;(S) -7- (4-dimethylamino-phenyl) -octa-2,4-dienodioic acid 1-hydroxyamide 3-quinolin-8-ylamide; (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-퀴놀린-3-일아마이드;(S) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 1-quinolin-3-ylamide; (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-피리딘- 4-일아마이드;(S) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 1-pyridine-4-ylamide; (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 1-[(4-다이메틸아미노-페닐)-아마이드] 8-하이드록시아마이드;(S) -2- (4-dimethylamino-phenyl) -octanedioic acid 1-[(4-dimethylamino-phenyl) -amide] 8-hydroxyamide; (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-피리딘-3-일아마이드;(S) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 1-pyridin-3-ylamide; (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-[(5-하이드록시-나프탈렌-1-일)-아마이드];(S) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 1-[(5-hydroxy-naphthalen-1-yl) -amide]; (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-{[2-(1H-인돌-3-일)-에틸]-아마이드};(S) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 1-{[2- (1H-indol-3-yl) -ethyl] -amide}; (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-[(6-메톡시-퀴놀린-3-일)-아마이드];(S) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 1-[(6-methoxy-quinolin-3-yl) -amide]; (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 1-[(4'-시아노-바이페닐-4-일)-아마이드] 8-하이드록시아마이드;(S) -2- (4-dimethylamino-phenyl) -octanedioic acid 1-[(4'-cyano-biphenyl-4-yl) -amide] 8-hydroxyamide; (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-[(1H-인다졸-6-일)-아마이드];(S) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 1-[(1H-indazol-6-yl) -amide]; (S)-7-(4-다이메틸아미노-페닐)-8-옥소-8-(4-페닐-피페라진-1일)-옥타노산 하이드록시아마이드;(S) -7- (4-dimethylamino-phenyl) -8-oxo-8- (4-phenyl-piperazin-1yl) -octanoic acid hydroxyamide; (S)-2-(4-다이메틸아미노-페닐)-옥타노산 8-하이드록시아마이드 1-[(6-메톡시-벤조사이아졸-2-일)-아마이드];(S) -2- (4-dimethylamino-phenyl) -octanoic acid 8-hydroxyamide 1-[(6-methoxy-benzothiazol-2-yl) -amide]; (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-[(2-메 틸-퀴놀린-4-일)-아마이드];(S) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 1-[(2-methyl-quinolin-4-yl) -amide]; (S)-8-(3,4-디하이드로-1H-이소퀴놀린-2-일)-7-(4-다이메틸아미노-페닐)-8-옥소-옥타노산 하이드록시아마이드; (S) -8- (3,4-dihydro-1H-isoquinolin-2-yl) -7- (4-dimethylamino-phenyl) -8-oxo-octanoic acid hydroxyamide; (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-[(피리딘-3-일메틸)-아마이드];(S) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 1-[(pyridin-3-ylmethyl) -amide]; (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 1-[(3-벤질옥시-페닐)-아마이드] 8-하이드록시아마이드;(S) -2- (4-dimethylamino-phenyl) -octanedioic acid 1-[(3-benzyloxy-phenyl) -amide] 8-hydroxyamide; (S)-8-(1,3-디하이드로-이소인돌-2-일)-7-(4-다이메틸아미노-페닐)-8-옥소-옥타노산 하이드록시아마이드;(S) -8- (1,3-dihydro-isoindol-2-yl) -7- (4-dimethylamino-phenyl) -8-oxo-octanoic acid hydroxyamide; (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 1-[(9-에틸-9H-카바졸-3-일)-아마이드 ] 8-하이드록시아마이드;(S) -2- (4-dimethylamino-phenyl) -octanedioic acid 1-[(9-ethyl-9H-carbazol-3-yl) -amide] 8-hydroxyamide; (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-[(피리딘-4-일메틸)-아마이드];(S) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 1-[(pyridin-4-ylmethyl) -amide]; (S)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-[(5-메틸설파닐-1H-[1,2,4]트라이아졸-3-일)-아마이드];(S) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 1-[(5-methylsulfanyl-1H- [1,2,4] triazol-3-yl) Amide]; (R)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 하이드록시아마이드 8-페닐아마이드;(R) -7- (4-dimethylamino-phenyl) -octa-2,4-dienodioic acid hydroxyamide 8-phenylamide; (R)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 8-[(3-벤질옥소-페닐)-아마이드] 1-하이드록시아마이드;(R) -7- (4-dimethylamino-phenyl) -octa-2,4-dienodioic acid 8-[(3-benzyloxo-phenyl) -amide] 1-hydroxyamide; (R)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-하이드록시아마이드 8-나프탈렌-1-일아마이드;(R) -7- (4-dimethylamino-phenyl) -octa-2,4-dienodioic acid 1-hydroxyamide 8-naphthalen-1-ylamide; (R)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 8-나프탈렌-1-일아마이드;(R) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 8-naphthalen-1-ylamide; (R)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-하이드록시아마이드 8-퀴놀린-8-일아마이드;(R) -7- (4-dimethylamino-phenyl) -octa-2,4-dienodioic acid 1-hydroxyamide 8-quinolin-8-ylamide; (R)-2-(4-다이메틸아미노-페닐)-옥탄디오산 8-하이드록시아마이드 1-퀴놀린-8-일아마이드;(R) -2- (4-dimethylamino-phenyl) -octanedioic acid 8-hydroxyamide 1-quinolin-8-ylamide; (R)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-하이드록시아마이드 3-퀴놀린-8-일아마이드;(R) -7- (4-dimethylamino-phenyl) -octa-2,4-dienodioic acid 1-hydroxyamide 3-quinolin-8-ylamide; (R)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 1-하이드록시아마이드 8-[(3-메톡시-페닐)-아마이드]; 및(R) -7- (4-dimethylamino-phenyl) -octa-2,4-dienodioic acid 1-hydroxyamide 8-[(3-methoxy-phenyl) -amide]; And (R)-7-(4-다이메틸아미노-페닐)-옥타-2,4-디엔디오산 8-[(3,4-다이메톡시-페닐)-아마이드] 1-하이드록시아마이드.(R) -7- (4-Dimethylamino-phenyl) -octa-2,4-dienedioic acid 8-[(3,4-dimethoxy-phenyl) -amide] 1-hydroxyamide. 1) 화학식 3의 화합물을 (2R,5R)- 또는 (2S,5S)-5-벤질-2-t-부틸-3-메틸이미다졸리딘-4-온의 존재하에서 N,N-다이메틸아닐린과 반응시켜 화학식 4의 화합물을 제조하는 단계;1) a compound of formula 3 (2R, 5R) - or (2S, 5S) -5- benzyl -2-t- butyl-3-methylimidazole in the presence of a jolly-4-one N, N- dimethyl Reacting with aniline to prepare a compound of formula 4 ; 2) 화학식 4의 화합물을 4-(디에톡시-포스포릴)-부트-2-에노산 에틸 에스터와 반응시켜 화학식 5의 화합물을 제조하는 단계;2) reacting the compound of formula 4 with 4- (diethoxy-phosphoryl) -but-2-enoic acid ethyl ester to prepare a compound of formula 5 ; 3) 화학식 5의 화합물을 염산으로 처리하여 화학식 6의 화합물을 제조하는 단계;3) treating the compound of Formula 5 with hydrochloric acid to produce a compound of Formula 6 ; 4) 화학식 6의 화합물을 에틸클로로포메이트 (ECC)로 처리하고, 소듐보로하이드라이드 (NaBH4)로 환원시켜 화학식 7의 화합물을 제조하는 단계;4) treating the compound of Formula 6 with ethylchloroformate (ECC) and reducing it with sodium borohydride (NaBH 4 ) to prepare a compound of Formula 7 ; 5) 화학식 7의 화합물을 염산으로 처리하여 화학식 8의 화합물을 제조하는 단계;5) treating the compound of Formula 7 with hydrochloric acid to prepare a compound of Formula 8 ; 6) 화학식 8의 화합물을 t-뷰틸다이메틸실릴옥시아민 (NH2OTBS)과 아실화 반응시킨 후 트라이플루오로아세트산으로 t-뷰틸다이메틸실릴기를 제거하여 화학식 1b의 화합물을 제조하는 단계; 및6) acylating a compound of Formula 8 with t-butyldimethylsilyloxyamine (NH 2 OTBS) and then removing t-butyldimethylsilyl group with trifluoroacetic acid to prepare a compound of Formula 1b ; And 7) 화학식 1b의 화합물을 수소압력하에서 팔라듐/카본과 반응시키는 단계를 포함하는, 화학식 1a의 화합물의 제조방법;7) a process for preparing a compound of formula 1a comprising reacting a compound of formula 1b with palladium / carbon under hydrogen pressure; <화학식 1a><Formula 1a>
Figure 112004047982053-pat00012
Figure 112004047982053-pat00012
 <화학식 1b><Formula 1b>
Figure 112004047982053-pat00013
Figure 112004047982053-pat00013
Figure 112004047982053-pat00014
Figure 112004047982053-pat00014
Figure 112004047982053-pat00015
Figure 112004047982053-pat00015
Figure 112004047982053-pat00016
Figure 112004047982053-pat00016
Figure 112004047982053-pat00017
Figure 112004047982053-pat00017
Figure 112004047982053-pat00018
Figure 112004047982053-pat00018
Figure 112004047982053-pat00019
Figure 112004047982053-pat00019
 상기 식에서, R은 하이드록시메틸기이다.Wherein R is a hydroxymethyl group. 제 3항에 있어서,The method of claim 3, wherein 단계 1)의 반응이 클로로폼을 용매로 사용하여 이루어지는 것을 특징으로 하는 방법.The reaction of step 1) is carried out using chloroform as a solvent. 제 3항에 있어서,The method of claim 3, wherein 단계 2)의 반응이 수산화리튬 존재하에서 테트라하이드로퓨란을 용매로 사용하여 이루어지는 것을 특징으로 하는 방법.The reaction of step 2) is carried out using tetrahydrofuran as a solvent in the presence of lithium hydroxide. 제 3항에 있어서,The method of claim 3, wherein 단계 3) 및 5)의 반응이 아세톤을 용매로 사용하여 이루어지는 것을 특징으로 하는 방법.The reaction of steps 3) and 5) using acetone as solvent. 제 3항에 있어서,The method of claim 3, wherein 단계 4)에서 에틸클로로포메이트의 처리가 테트라하이드로퓨란을 용매로 사용하여 빙냉하에서 이루어지는 것을 특징으로 하는 방법.Treatment of ethylchloroformate in step 4) is carried out under ice cooling using tetrahydrofuran as a solvent. 제 3항에 있어서,The method of claim 3, wherein 단계 6)의 반응이 N-메탄설포닐옥시-6-트라이플루오로 벤조트라이아졸 (FMS)존재하에서 N,N-다이메틸폼아마이드 또는 테트라하이드로퓨란을 용매로 사용하여 이루어지는 것을 특징으로 하는 방법.The reaction of step 6) is carried out using N, N-dimethylformamide or tetrahydrofuran as solvent in the presence of N-methanesulfonyloxy-6-trifluoro benzotriazole (FMS). 제 3항에 있어서,The method of claim 3, wherein 단계 7)의 반응이 알코올 수용액을 용매로 사용하여 이루어지는 것을 특징으로 하는 방법.The reaction of step 7) is carried out using an aqueous alcohol solution as a solvent. 1) 화학식 7의 화합물을 다이메틸설폭사이드의 존재하에서 옥사릴클로라이드와 반응시켜 화학식 9의 화합물을 제조하는 단계;1) reacting a compound of Formula 7 with oxarylyl chloride in the presence of dimethyl sulfoxide to prepare a compound of Formula 9 ; 2) 화학식 9의 화합물을 빙초산과 소듐 트라이아세톡시보로하이드라이드 (NaBH(OAc)3) 존재하에서 아민 화합물과 반응시켜 화학식 10의 화합물을 제조하는 단계;2) is reacted with an amine compound in the hydride (NaBH (OAc) 3) the presence of a compound of formula 9 with glacial acetic acid and sodium tri-acetoxy time signal to obtain a compound of formula (10); 3) 화학식 10의 화합물을 무기염기로 처리하여 화학식 11의 화합물로 전환시키는 단계; 3) treating the compound of Formula 10 with an inorganic base to convert it to a compound of Formula 11 ; 4) 화학식 11의 화합물을 t-뷰틸다이메틸실릴옥시아민 (NH2OTBS)과 아실화 반응시킨 후 수용성 무기산으로 t-뷰틸다이메틸실릴기를 제거하여 화학식 1b의 화합물을 제조하는 단계; 및,4) acylating the compound of Formula 11 with t-butyldimethylsilyloxyamine (NH 2 OTBS) and removing the t-butyldimethylsilyl group with a water-soluble inorganic acid to prepare a compound of Formula 1b ; And, 5) 화학식 1b의 화합물을 수소압력하에서 팔라듐/카본과 반응시키는 단계를 포함하는, 화학식 1a의 화합물의 제조방법:5) A process for preparing a compound of Formula 1a comprising reacting a compound of Formula 1b with palladium / carbon under hydrogen pressure: <화학식 1a><Formula 1a>
Figure 112004047982053-pat00020
Figure 112004047982053-pat00020
 <화학식 1b><Formula 1b>
Figure 112004047982053-pat00021
Figure 112004047982053-pat00021
 <화학식 7><Formula 7>
Figure 112004047982053-pat00022
Figure 112004047982053-pat00022
Figure 112004047982053-pat00023
Figure 112004047982053-pat00023
Figure 112004047982053-pat00024
Figure 112004047982053-pat00024
Figure 112004047982053-pat00025
Figure 112004047982053-pat00025
 상기 식에서, Where R은 C1-5 알킬아미노메틸, 아릴아미노메틸 또는 헤테로아릴아미노메틸이며, R'는 아릴이다.R is C 1-5 alkylaminomethyl, arylaminomethyl or heteroarylaminomethyl, and R 'is aryl. 제 10항에 있어서, The method of claim 10, 단계 1) 및 2)의 반응이 다이클로로메탄을 용매로 사용하여 이루어지는 것을 특징으로 하는 방법.The reaction of steps 1) and 2) using dichloromethane as solvent. 제 10항에 있어서, The method of claim 10, 단계 3)의 반응이 알콜 수용액을 용매로 사용하여 테트라하이드로퓨란 존재하에서 이루어지고, 무기염기가 수산화리튬 또는 수산화나트륨인 것을 특징으로 하는 방법.The reaction of step 3) is carried out in the presence of tetrahydrofuran using an aqueous solution of alcohol as a solvent, characterized in that the inorganic base is lithium hydroxide or sodium hydroxide. 제 10항에 있어서,The method of claim 10, 단계 4)의 반응이 N-메탄설포닐옥시-6-트라이플루오로 벤조트라이아졸 (FMS)존재하에서 N,N-다이메틸폼아마이드 또는 테트라하이드로퓨란을 용매로 사용하여 이루어지며, 수용성 무기산으로는 염산 또는 황산을 사용하는 것을 특징으로 하는 방법.The reaction of step 4) is carried out using N, N-dimethylformamide or tetrahydrofuran as solvent in the presence of N-methanesulfonyloxy-6-trifluoro benzotriazole (FMS). Hydrochloric or sulfuric acid. 제 10항에 있어서,The method of claim 10, 단계 5)의 반응이 알코올 수용액을 용매로 사용하여 이루어지는 것을 특징으로 하는 방법.The reaction of step 5) is carried out using an aqueous alcohol solution as a solvent. 1) 화학식 6의 화합물을 아민 화합물과 반응시켜 화학식 12의 화합물을 제조하는 단계;1) reacting a compound of Formula 6 with an amine compound to produce a compound of Formula 12 ; 2) 화학식 12의 화합물을 염산으로 처리하여 화학식 13의 화합물로 전환시키는 단계;2) treating the compound of Formula 12 with hydrochloric acid to convert the compound of Formula 12 to a compound of Formula 13 ; 3) 화학식 13의 화합물을 t-뷰틸다이메틸실릴옥시아민 (NH2OTBS)과 아실화 반응시킨 후 t-뷰틸다이메틸실릴기를 제거하여 화학식 1b의 화합물을 제조하는 단계; 및 3) acylating the compound of Formula 13 with t-butyldimethylsilyloxyamine (NH 2 OTBS) to remove the t-butyldimethylsilyl group to prepare a compound of Formula 1b ; And 4) 화학식 1b의 화합물을 수소압력하에서 팔라듐/카본과 반응시키는 단계를 포함하는 화학식 1a의 화합물의 제조방법:4) A process for preparing a compound of Formula 1a comprising reacting a compound of Formula 1b with palladium / carbon under hydrogen pressure: <화학식 1a><Formula 1a>
Figure 112004047982053-pat00026
Figure 112004047982053-pat00026
 <화학식 1b><Formula 1b>
Figure 112004047982053-pat00027
Figure 112004047982053-pat00027
 <화학식 6><Formula 6>
Figure 112004047982053-pat00028
Figure 112004047982053-pat00028
Figure 112004047982053-pat00029
Figure 112004047982053-pat00029
Figure 112004047982053-pat00030
Figure 112004047982053-pat00030
 상기 식에서, Where R은 C1-5 알킬아마이드기, 아릴아마이드기 또는 헤테로아릴아마이드기이며, R'는 C1-5 알킬, 아릴 또는 헤테로아릴이다.R is a C 1-5 alkylamide group, arylamide group or heteroarylamide group, and R 'is C 1-5 alkyl, aryl or heteroaryl. 제 15항에 있어서, The method of claim 15, 단계 1) 및 3)의 반응이 N-메탄설포닐옥시-6-트라이플루오로 벤조트라이아졸 (FMS) 존재하에서 N,N-다이메틸폼아마이드 또는 테트라하이드로퓨란을 용매로 사용하여 이루어지며, 단계 3)에서 수용성 무기산으로 염산 또는 황산을 사용하는 것을 특징으로 하는 방법.The reaction of steps 1) and 3) is carried out using N, N-dimethylformamide or tetrahydrofuran as solvent in the presence of N-methanesulfonyloxy-6-trifluoro benzotriazole (FMS), step A hydrochloric acid or sulfuric acid is used as the water-soluble inorganic acid in 3). 제 15항에 있어서,The method of claim 15, 단계 2)의 반응이 아세톤을 용매로 사용하여 이루어지는 것을 특징으로 하는 방법.The reaction of step 2) is carried out using acetone as a solvent. 제 15항에 있어서,The method of claim 15, 단계 4)의 반응이 알코올 수용액을 용매로 사용하여 이루어지는 것을 특징으로 하는 방법.The reaction of step 4) is carried out using an aqueous alcohol solution as a solvent. 1)화학식 12의 화합물을 수소압력하에서 팔라듐/카본과 반응시켜 화학식 14의 화합물을 제조하는 단계;1) preparing a compound of formula 14 by reacting a compound of formula 12 with palladium / carbon under hydrogen pressure; 2) 화학식 14의 화합물을 무기염기로 처리하여 화학식 15의 화합물로 전환시키는 단계; 및2) treating the compound of Formula 14 with an inorganic base to convert it to a compound of Formula 15 ; And 3) 화학식 15의 화합물을 t-뷰틸다이메틸실릴옥시아민 (NH2OTBS)과 아실화 반응시킨 후 수용성 무기산으로 t-뷰틸다이메틸실릴기를 제거하는 단계를 포함하는, 화학식 1a의 화합물의 제조방법.3) The method for producing a compound of the formula 1a, which comprises removing a compound of formula 15 t- butyldibenzo silyloxy methyl amine (NH 2 OTBS) and a water-soluble inorganic acid after acylation t- view methyl silyl groups butyldibenzo . <화학식 1a><Formula 1a>
Figure 112004047982053-pat00031
Figure 112004047982053-pat00031
 <화학식 12><Formula 12>
Figure 112004047982053-pat00032
Figure 112004047982053-pat00032
Figure 112004047982053-pat00033
Figure 112004047982053-pat00033
Figure 112004047982053-pat00034
Figure 112004047982053-pat00034
 상기 식에서, Where R은 C1-5 알킬아마이드기, 아릴아마이드기 또는 헤테로아릴아마이드기이며, R'는 C1-5 알킬, 아릴 또는 헤테로아릴이다.R is a C 1-5 alkylamide group, arylamide group or heteroarylamide group, and R 'is C 1-5 alkyl, aryl or heteroaryl. 제 19항에 있어서,The method of claim 19, 단계 1)의 반응이 알코올 수용액을 용매로 사용하여 이루어지는 것을 특징으로 하는 방법.The reaction of step 1) is carried out using an aqueous alcohol solution as a solvent. 제 19항에 있어서, The method of claim 19, 단계 2)에서 무기 염기로서 수산화나트륨 또는 수산화리튬이 사용되는 것을 특징으로 하는 방법.Sodium hydroxide or lithium hydroxide is used as the inorganic base in step 2). 제 19항에 있어서, The method of claim 19, 단계 3)의 반응이 N-메탄설포닐옥시-6-트라이플루오로 벤조트라이아졸 (FMS) 존재 하에서 N,N-다이메틸폼아마이드 또는 테트라하이드로퓨란을 용매로 사용하여 이루어지며, 수용성 무기산으로서 염산 또는 황산을 사용하는 것을 특징으로 하는 방법.The reaction of step 3) is carried out using N, N-dimethylformamide or tetrahydrofuran as solvent in the presence of N-methanesulfonyloxy-6-trifluoro benzotriazole (FMS) and hydrochloric acid as a water-soluble inorganic acid. Or sulfuric acid. 1) 화학식 6의 화합물을 수소압력하에서 팔라듐/카본과 반응시켜 화학식 16의 화합물을 제조하는 단계;1) preparing a compound of formula 16 by reacting a compound of formula 6 with palladium / carbon under hydrogen pressure; 2) 화학식 16의 화합물을 아민 화합물과 반응시켜 화학식 14의 화합물을 제조하는 단계;2) reacting a compound of Formula 16 with an amine compound to produce a compound of Formula 14 ; 3) 화학식 14의 화합물을 무기염기로 처리하여 화학식 15의 화합물로 전환시키는 단계; 및3) treating the compound of Formula 14 with an inorganic base to convert it to a compound of Formula 15 ; And 4) 화학식 15의 화합물을 t-뷰틸다이메틸실릴옥시아민 (NH2OTBS)과 아실화 반응시킨 후 t-뷰틸다이메틸실릴기를 제거하는 단계를 포함하는, 화학식 1a의 화합물의 제조방법:4) A method for preparing a compound of Formula 1a comprising acylation of a compound of Formula 15 with t-butyldimethylsilyloxyamine (NH 2 OTBS) and then removing the t-butyldimethylsilyl group: <화학식 1a><Formula 1a>
Figure 112004047982053-pat00035
Figure 112004047982053-pat00035
 <화학식 6><Formula 6>
Figure 112004047982053-pat00036
Figure 112004047982053-pat00036
 <화학식 14><Formula 14>
Figure 112004047982053-pat00037
Figure 112004047982053-pat00037
 <화학식 15><Formula 15>
Figure 112004047982053-pat00038
Figure 112004047982053-pat00038
Figure 112004047982053-pat00039
Figure 112004047982053-pat00039
 상기 식에서, Where R은 C1-5 알킬아마이드기, 아릴아마이드기 또는 헤테로아릴아마이드기이며, R'는 C1-5 알킬, 아릴 또는 헤테로아릴이다.R is a C 1-5 alkylamide group, arylamide group or heteroarylamide group, and R 'is C 1-5 alkyl, aryl or heteroaryl. 제 23항에 있어서,The method of claim 23, wherein 단계 1)의 반응이 알코올 수용액을 용매로 사용하여 이루어지는 것을 특징으로 하는 방법.The reaction of step 1) is carried out using an aqueous alcohol solution as a solvent. 제 23항에 있어서,The method of claim 23, wherein 단계 2)의 반응이 N,N-다이메틸폼아마이드를 용매로 사용하여 이루어지는 것을 특 징으로 하는 방법.A process characterized in that the reaction of step 2) is carried out using N, N-dimethylformamide as a solvent. 제 23항에 있어서, The method of claim 23, wherein 단계 3)에서 무기 염기로서 수산화나트륨 또는 수산화리튬이 사용되는 것을 특징으로 하는 방법.Sodium hydroxide or lithium hydroxide is used as the inorganic base in step 3). 제 23항에 있어서, The method of claim 23, wherein 단계 4)의 반응이 N-메탄설포닐옥시-6-트라이플루오로 벤조트라이아졸 (FMS) 존재하에서 N,N-다이메틸폼아마이드 또는 테트라하이드로퓨란을 용매로 사용하여 이루어지며, 수용성 무기산으로 염산 또는 황산이 사용되는 것을 특징으로 하는 방법.The reaction of step 4) is carried out using N, N-dimethylformamide or tetrahydrofuran as solvent in the presence of N-methanesulfonyloxy-6-trifluoro benzotriazole (FMS), hydrochloric acid as a water-soluble inorganic acid. Or sulfuric acid is used. 활성성분으로서 제 1항에 따른 N,N-다이메틸아미노페닐 옥타노산 하이드록시아마이드 유도체 화합물, 이의 거울상 이성질체 또는 이의 약학적으로 허용가능한 염 및 약제학적으로 허용 가능한 담체를 포함하는 암 치료용 약학 조성물.A pharmaceutical composition for treating cancer comprising the N, N-dimethylaminophenyl octanoic acid hydroxyamide derivative compound according to claim 1, an enantiomer thereof or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier as an active ingredient. .
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US20020115826A1 (en) 2000-03-24 2002-08-22 Daniel Delorme Inhibitors of histone deacetylase
US20030152557A1 (en) 2001-01-12 2003-08-14 Besterman Jeffrey M. Methods for inhibiting histone deacetylase-4
US20040002506A1 (en) 1999-09-08 2004-01-01 Sloan Kettering Institute For Cancer Research Novel class of cytodifferentiating agents and histone deacetylase inhibitors, and methods of use thereof

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* Cited by examiner, † Cited by third party
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US20040002506A1 (en) 1999-09-08 2004-01-01 Sloan Kettering Institute For Cancer Research Novel class of cytodifferentiating agents and histone deacetylase inhibitors, and methods of use thereof
US20020115826A1 (en) 2000-03-24 2002-08-22 Daniel Delorme Inhibitors of histone deacetylase
US20030152557A1 (en) 2001-01-12 2003-08-14 Besterman Jeffrey M. Methods for inhibiting histone deacetylase-4

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