KR20230163603A - Pharmaceutical composition comprising phenylpropine derivative for use in preventing or treating cancer as an active ingredient - Google Patents

Pharmaceutical composition comprising phenylpropine derivative for use in preventing or treating cancer as an active ingredient Download PDF

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KR20230163603A
KR20230163603A KR1020220062613A KR20220062613A KR20230163603A KR 20230163603 A KR20230163603 A KR 20230163603A KR 1020220062613 A KR1020220062613 A KR 1020220062613A KR 20220062613 A KR20220062613 A KR 20220062613A KR 20230163603 A KR20230163603 A KR 20230163603A
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prop
amino
ethyl
biphenyl
phenyl
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KR1020220062613A
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Korean (ko)
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임춘영
민상현
김남희
황희종
오배준
홍은미
우서연
한예리
도현주
장태호
이슬
김남두
이지영
유지훈
이하연
김영규
박상욱
신선혜
차은주
황지선
서창훈
염영일
이동철
박경찬
김차연
구한
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재단법인 대구경북첨단의료산업진흥재단
한국생명공학연구원
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Priority to KR1020220062613A priority Critical patent/KR20230163603A/en
Priority to PCT/KR2023/006799 priority patent/WO2023229295A1/en
Publication of KR20230163603A publication Critical patent/KR20230163603A/en

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Abstract

본 발명은 페닐프로핀 유도체 및 이를 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물에 관한 것으로, 본 명세서에 기재된 페닐프로핀 유도체는 종양 증식 및 전이억제 기전에 관여하는 ACC 저해활성을 확인하여 암의 예방 또는 치료에 유용할 것으로 기대된다.The present invention relates to a phenylpropine derivative and a pharmaceutical composition for the prevention or treatment of cancer containing the same as an active ingredient. The phenylpropine derivative described herein has confirmed ACC inhibitory activity, which is involved in tumor proliferation and metastasis inhibition mechanisms. Therefore, it is expected to be useful in preventing or treating cancer.

Description

페닐프로핀 유도체를 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물{Pharmaceutical composition comprising phenylpropine derivative for use in preventing or treating cancer as an active ingredient}Pharmaceutical composition comprising phenylpropine derivative for use in preventing or treating cancer as an active ingredient}

본 발명은 페닐프로핀 유도체 및 이를 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물에 관한 것이다.The present invention relates to a phenylpropine derivative and a pharmaceutical composition for the prevention or treatment of cancer containing the same as an active ingredient.

간암은 국내에서 발병률은 6위이며, 전체 암중에서 사망률은 2위로, 발생률과 사망률이 높으며 폐나 뼈로 전이가 빠른 암이다. 또한, 간암 수술환자의 70%가 5 년 이내에 다시 재발하는 높은 재발률을 보이고 있으며 재발한 간암의 치료 예후 또한 좋지 않다. 이 때문에 간암세포의 사멸 및 증식 억제를 효과적으로 유도할 수 있는 의약의 개발이 필요하다.Liver cancer ranks 6th in incidence in Korea and 2nd in mortality among all cancers. It is a cancer with a high incidence and mortality rate and rapid metastasis to the lungs and bones. In addition, 70% of liver cancer surgery patients have a high recurrence rate, with recurrence within 5 years, and the treatment prognosis for relapsed liver cancer is also poor. For this reason, there is a need for the development of drugs that can effectively induce death and inhibition of proliferation of liver cancer cells.

암세포는 대사작용을 통해 증식한다. 지질(lipid)은 에너지 저장소 역할 외에 새롭게 합성되는 막의 building block을 제공하는 역할을 한다. 암세포의 지질대사 작용에 특정 변이가 일어남이 최근 많은 연구를 통해 증명되고 있으며 발암 신호의 활성에 의해 지질대사 효소의 발현과 활성에 변화가 생긴다고 보고되어 있다. 이러한 사실은 지질대사에 연관된 단백질이 암 치료를 위한 훌륭한 화학요법 표적으로 이용될 수 있음을 시사한다. Cancer cells proliferate through metabolism. In addition to serving as energy storage, lipids also serve as building blocks for newly synthesized membranes. It has been proven through many recent studies that specific mutations occur in the lipid metabolism of cancer cells, and it has been reported that changes in the expression and activity of lipid metabolism enzymes occur due to the activation of oncogenic signals. This fact suggests that proteins involved in lipid metabolism can be used as excellent chemotherapy targets for cancer treatment.

acetyl-CoA 카복실화효소 (acetyl-CoA carboxylase, ACC)는 지방산 합성에서의 속도-제한 효소로 암세포 내에서는 Acetyl-CoA Carboxylase (ACC)가 인산화되어 비활성화되면, 지질(lipid) 합성을 억제하고 베타-산화(β-oxidation)가 촉진됨으로 에너지 대사가 조절된다. 이러한 에너지 대사 조절은 암세포의 증식과 전이에 영향을 미친다(WANG, Chao, et al. Expert Review of Anticancer Therapy, 2015, 15.6: 667-676). Acetyl-CoA carboxylase (ACC) is the rate-limiting enzyme in fatty acid synthesis. When Acetyl-CoA Carboxylase (ACC) is phosphorylated and inactivated in cancer cells, it inhibits lipid synthesis and beta- Energy metabolism is regulated by promoting oxidation (β-oxidation). This regulation of energy metabolism affects the proliferation and metastasis of cancer cells (WANG, Chao, et al. Expert Review of Anticancer Therapy, 2015, 15.6: 667-676).

특히 지질 대사의 중심 기관인 간에서 Acetyl-CoA Carboxylase (ACC)와 같은 효소들을 비활성화시켜서 간 내부의 지방 합성을 감소시킴으로써 암 성장과 진행을 억제시키는 것은 새로운 항-대사 치료제의 개발의 유용한 타깃으로 연구되고 있다. In particular, inhibiting cancer growth and progression by reducing fat synthesis within the liver by inactivating enzymes such as Acetyl-CoA Carboxylase (ACC) in the liver, the central organ of lipid metabolism, is being studied as a useful target for the development of new anti-metabolic treatments. there is.

이에, 본 발명자들은 본 명세서의 페닐프로핀 유도체가 인간 간암세포주에서 암세포의 증식 억제에 관여하는 지방산 합성에서의 속도-제한 효소인 Acetyl-CoA Carboxylase (ACC)의 저해 활성하는 것을 확인하고 본 발명을 완성하였다.Accordingly, the present inventors confirmed that the phenylpropine derivative of the present specification has an inhibitory activity on Acetyl-CoA Carboxylase (ACC), a rate-limiting enzyme in fatty acid synthesis involved in inhibiting the proliferation of cancer cells in human liver cancer cell lines, and proposed the present invention. Completed.

본 발명의 목적은 페닐프로핀 유도체를 제공하는 데 있다.The object of the present invention is to provide phenylpropine derivatives.

본 발명의 다른 목적은 신규한 암의 예방 또는 치료용 약학적 조성물을 제공하는 데 있다.Another object of the present invention is to provide a novel pharmaceutical composition for preventing or treating cancer.

본 발명의 다른 목적은 신규한 암의 예방 또는 개선용 건강기능식품 조성물을 제공하는 데 있다.Another object of the present invention is to provide a novel health functional food composition for preventing or improving cancer.

상기 목적을 달성하기 위하여,In order to achieve the above purpose,

본 발명은 하기 화학식 1로 표시되는 화합물, 이의 입체이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염을 제공한다.The present invention provides a compound represented by the following formula (1), a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[화학식 1][Formula 1]

An-L-BA n -LB

상기 화학식 1에서,In Formula 1,

n는 1 또는 2이고;n is 1 or 2;

A는 비치환이거나 치환된 C6아릴 또는 6원자헤테로아릴이고,A is unsubstituted or substituted C6 aryl or 6-membered heteroaryl,

상기 치환된 C6아릴 또는 6원자헤테로아릴은 할로겐, 히드록시, 6원자헤테로사이클로알킬, C1-C10알킬설포닐, C1-C10알킬옥시카보닐, 카르복시 및 설폰아미드로 이루어진 군에서 선택되는 하나이상으로 치환되거나, 또는 인접하는 두 개의 원자에 치환되어 5-6원자의 비치환된 헤테로사이클을 형성하고;The substituted C6 aryl or 6-membered heteroaryl is at least one selected from the group consisting of halogen, hydroxy, 6-membered heterocycloalkyl, C1-C10 alkylsulfonyl, C1-C10 alkyloxycarbonyl, carboxy, and sulfonamide. is substituted, or is substituted on two adjacent atoms to form an unsubstituted heterocycle of 5-6 atoms;

L은 -CHR1-, -CHCH2- 또는 -CH2CH2-이고,L is -CHR 1 -, -CHCH 2 - or -CH 2 CH 2 -,

여기서, 상기 R1은 수소 또는 C1-C10알킬이고;Here, R 1 is hydrogen or C1-C10 alkyl;

B는 -NR2X, -NX2 또는-OX이고,B is -NR 2 X, -NX 2 or -OX,

여기서, 상기 R2는 수소 또는 C1-C10알킬이고;Here, R 2 is hydrogen or C1-C10 alkyl;

상기 X는 이고,The X above is ego,

여기서, 상기 R3는 수소 또는 옥소(=O)이고;Here, R 3 is hydrogen or oxo (=O);

R4는 비치환이거나 치환된 C1-C10알킬, C1-C10알콕시, 6원자헤테로사이클로알킬, C6아릴 또는 6원자헤테로아릴이고,R 4 is unsubstituted or substituted C1-C10 alkyl, C1-C10 alkoxy, 6-membered heterocycloalkyl, C6-aryl or 6-membered heteroaryl,

상기 치환된 C1-C10알킬, C1-C10알콕시, 6원자헤테로사이클로알킬, C6아릴 또는 6원자헤테로아릴은 비치환이거나 히드록시 및 C6아릴로 이루어진 군에서 선택되는 하나이상으로 치환된 C1-C10알킬, 비치환이거나 하나이상의 할로겐으로 치환된 C1-C10알킬카보닐, 할로겐, 히드록시, Boc(tert-부틸옥시카보닐), 비치환이거나 C1-C10알콕시로 치환된 C1-C10알콕시, C6아릴옥시 및 C6아릴카보닐로 이루어진 군에서 선택되는 하나이상으로 치환된다.The substituted C1-C10 alkyl, C1-C10 alkoxy, 6-membered heterocycloalkyl, C6 aryl or 6-membered heteroaryl is unsubstituted or substituted C1-C10 alkyl with one or more selected from the group consisting of hydroxy and C6 aryl. , C1-C10 alkyl carbonyl, unsubstituted or substituted with one or more halogens, halogen, hydroxy, Boc (tert-butyloxycarbonyl), C1-C10 alkoxy unsubstituted or substituted with C1-C10 alkoxy, C6 aryloxy. and C6 arylcarbonyl.

다른 측면에서, 본 발명은 상기 화학식 1로 표시되는 화합물, 이의 입체이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물을 제공한다.In another aspect, the present invention provides a pharmaceutical composition for the prevention or treatment of cancer containing the compound represented by Formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. do.

또 다른 측면에서, 본 발명은 상기 화학식 1로 표시되는 화합물, 이의 광학이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 암의 예방 또는 개선용 건강기능식품 조성물을 제공한다.In another aspect, the present invention provides a health functional food composition for preventing or improving cancer containing the compound represented by Formula 1, an optical isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. provides.

본 명세서에 기재된 화학식 1로 표시되는 화합물은 종양 증식 및 전이억제 기전에 관여하는 ACC 저해활성을 확인하여 암의 예방 또는 치료에 유용할 것으로 기대된다.The compound represented by Formula 1 described herein is expected to be useful in the prevention or treatment of cancer by confirming the ACC inhibitory activity involved in tumor proliferation and metastasis inhibition mechanisms.

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

한편, 본 발명의 실시 형태는 여러 가지 다른 형태로 변형될 수 있으며, 본 발명의 범위가 이하 설명하는 실시 형태로 한정되는 것은 아니다. 또한, 본 발명의 실시 형태는 당해 기술분야에서 평균적인 지식을 가진 자에게 본 발명을 더욱 완전하게 설명하기 위해서 제공되는 것이다.Meanwhile, the embodiments of the present invention may be modified into various other forms, and the scope of the present invention is not limited to the embodiments described below. Additionally, the embodiments of the present invention are provided to more completely explain the present invention to those with average knowledge in the relevant technical field.

나아가, 명세서 전체에서 어떤 구성요소를 "포함"한다는 것은 특별히 반대되는 기재가 없는 한 다른 구성요소를 제외하는 것이 아니라 다른 구성요소를 더 포함할 수 있다는 것을 의미한다.Furthermore, “including” a certain element throughout the specification means that other elements may be further included, rather than excluding other elements, unless specifically stated to the contrary.

용어 "알킬렌", “알케닐” 또는 "알킬"은, 달리 명시되지 않는 한, 직쇄 또는 분지쇄의 탄화수소 잔기를 포함한다. 예를 들어, "C1-C5알킬"은 1 내지 5개 탄소로 골격이 이루어진 알킬을 의미한다. 구체적으로 C1-C5알킬은 메틸, 에틸, n-프로필, i-프로필, n-부틸, i-부틸, t-부틸, n-펜틸, i-펜틸, t-펜틸, sec-펜틸, 네오펜틸 등을 포함할 수 있다.The terms “alkylene”, “alkenyl” or “alkyl” include straight or branched chain hydrocarbon moieties, unless otherwise specified. For example, “C1-C5alkyl” means alkyl with a skeleton of 1 to 5 carbons. Specifically, C1-C5 alkyl is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, sec-pentyl, neopentyl, etc. may include.

용어 “사이클로알킬”은, 달리 명시되지 않는 한, 탄소 원자를 포함하는 카보사이클릭 기를 포함한다. 예를 들어, "C3-C8 사이클로알킬"은 3 내지 8개 탄소로 골격이 이루어진 사이클로알킬을 의미한다. 구체적으로 C3-C8 사이클로알킬 은 사이클로프로필, 사이클로부틸, 사이클로펜틸, 사이클로헥실 등을 포함할 수 있다.The term “cycloalkyl,” unless otherwise specified, includes carbocyclic groups containing carbon atoms. For example, “C3-C8 cycloalkyl” means cycloalkyl with a skeleton of 3 to 8 carbons. Specifically, C3-C8 cycloalkyl may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

용어 “헤테로사이클”은, 완전 포화된 헤테로사이클로알킬이거나 부분적으로 불포화된 헤테로사이클로알킬 및 헤테로아릴을 포함한다.The term “heterocycle” includes fully saturated or partially unsaturated heterocycloalkyl and heteroaryl.

용어 “헤테로사이클로알킬”은, 달리 명시되지 않는 한, N, O 또는 S로부터 선택되는 1, 2, 3 또는 4개의 헤테로원자를 포함하는 1 내지 3개의 고리로 이루어진 1가 포화 잔기를 포함한다. 2 또는 3개의 고리는 다리형(bridged), 융합형(fused) 또는 나선형(spiro) 헤테로사이클로알킬을 포함할 수 있다.The term “heterocycloalkyl”, unless otherwise specified, includes monovalent saturated moieties consisting of 1 to 3 rings containing 1, 2, 3 or 4 heteroatoms selected from N, O or S. Two or three rings may contain bridged, fused or spiro heterocycloalkyls.

용어 “헤테로아릴”은, 달리 명시되지 않는 한, N, O 또는 S로부터 선택되는 1, 2 또는 3개의 고리 헤테로원자를 함유하는 하나 이상의 방향족고리를 갖는 단일 고리 또는 2 또는 3개의 융합 고리의 방향족 라디칼을 포함할 수 있다.The term “heteroaryl”, unless otherwise specified, refers to an aromatic ring having one or more aromatic rings containing 1, 2 or 3 ring heteroatoms selected from N, O or S or an aromatic ring of 2 or 3 fused rings. May contain radicals.

본 발명의 일 실시 형태는,One embodiment of the present invention is,

하기 화학식 1로 표시되는 화합물, 이의 입체이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염을 제공한다.Provided is a compound represented by the following formula (1), a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[화학식 1][Formula 1]

An-L-BA n -LB

상기 화학식 1에서,In Formula 1,

n는 1 또는 2이고;n is 1 or 2;

A는 비치환이거나 치환된 C6아릴 또는 6원자헤테로아릴이고,A is unsubstituted or substituted C6 aryl or 6-membered heteroaryl,

상기 치환된 C6아릴 또는 6원자헤테로아릴은 할로겐, 히드록시, 6원자헤테로사이클로알킬, C1-C10알킬설포닐, C1-C10알킬옥시카보닐, 카르복시 및 설폰아미드로 이루어진 군에서 선택되는 하나이상으로 치환되거나, 또는 인접하는 두 개의 원자에 치환되어 5-6원자의 비치환된 헤테로사이클을 형성하고;The substituted C6 aryl or 6-membered heteroaryl is at least one selected from the group consisting of halogen, hydroxy, 6-membered heterocycloalkyl, C1-C10 alkylsulfonyl, C1-C10 alkyloxycarbonyl, carboxy, and sulfonamide. is substituted, or is substituted on two adjacent atoms to form an unsubstituted heterocycle of 5-6 atoms;

L은 -CHR1-, -CHCH2- 또는 -CH2CH2-이고,L is -CHR 1 -, -CHCH 2 - or -CH 2 CH 2 -,

여기서, 상기 R1은 수소 또는 C1-C10알킬이고;Here, R 1 is hydrogen or C1-C10 alkyl;

B는 -NR2X, -NX2 또는-OX이고,B is -NR 2 X, -NX 2 or -OX,

여기서, 상기 R2는 수소 또는 C1-C10알킬이고;Here, R 2 is hydrogen or C1-C10 alkyl;

상기 X는 이고,The X above is ego,

여기서, 상기 R3는 수소 또는 옥소(=O)이고;Here, R 3 is hydrogen or oxo (=O);

R4는 비치환이거나 치환된 C1-C10알킬, C1-C10알콕시, 6원자헤테로사이클로알킬, C6아릴 또는 6원자헤테로아릴이고,R 4 is unsubstituted or substituted C1-C10 alkyl, C1-C10 alkoxy, 6-membered heterocycloalkyl, C6-aryl or 6-membered heteroaryl,

상기 치환된 C1-C10알킬, C1-C10알콕시, 6원자헤테로사이클로알킬, C6아릴 또는 6원자헤테로아릴은 비치환이거나 히드록시 및 C6아릴로 이루어진 군에서 선택되는 하나이상으로 치환된 C1-C10알킬, 비치환이거나 하나이상의 할로겐으로 치환된 C1-C10알킬카보닐, 할로겐, 히드록시, Boc(tert-부틸옥시카보닐), 비치환이거나 C1-C10알콕시로 치환된 C1-C10알콕시, C6아릴옥시 및 C6아릴카보닐로 이루어진 군에서 선택되는 하나이상으로 치환된다.The substituted C1-C10 alkyl, C1-C10 alkoxy, 6-membered heterocycloalkyl, C6 aryl or 6-membered heteroaryl is unsubstituted or substituted C1-C10 alkyl with one or more selected from the group consisting of hydroxy and C6 aryl. , C1-C10 alkyl carbonyl, unsubstituted or substituted with one or more halogens, halogen, hydroxy, Boc (tert-butyloxycarbonyl), C1-C10 alkoxy unsubstituted or substituted with C1-C10 alkoxy, C6 aryloxy. and C6 arylcarbonyl.

본 발명의 일 실시 형태는,One embodiment of the present invention,

상기 화학식 1에서,In Formula 1,

n는 1 또는 2이고;n is 1 or 2;

A는 비치환이거나 치환된 C6아릴 또는 N을 포함하는 6원자헤테로아릴이고,A is unsubstituted or substituted C6 aryl or 6-membered heteroaryl containing N,

상기 치환된 C6아릴 또는 N을 포함하는 6원자헤테로아릴은 할로겐, 히드록시, 6원자헤테로사이클로알킬, C1-C5알킬설포닐, C1-C5알킬옥시카보닐, 카르복시 및 설폰아미드로 이루어진 군에서 선택되는 하나이상으로 치환되거나, 또는 인접하는 두 개의 원자에 치환되어 두 개의 O를 포함하는 5원자의 비치환된 헤테로사이클을 형성하고;The substituted C6 aryl or 6-membered heteroaryl containing N is selected from the group consisting of halogen, hydroxy, 6-membered heterocycloalkyl, C1-C5 alkylsulfonyl, C1-C5 alkyloxycarbonyl, carboxy, and sulfonamide. is substituted with one or more atoms, or is substituted on two adjacent atoms to form a 5-atom unsubstituted heterocycle containing two O's;

L은 -CHR1-, -CHCH2- 또는 -CH2CH2-이고,L is -CHR 1 -, -CHCH 2 - or -CH 2 CH 2 -,

여기서, 상기 R1은 수소 또는 C1-C5알킬이고;Here, R 1 is hydrogen or C1-C5 alkyl;

B는 -NR2X, -NX2 또는-OX이고,B is -NR 2 X, -NX 2 or -OX,

여기서, 상기 R2는 수소 또는 C1-C5알킬이고;Here, R 2 is hydrogen or C1-C5 alkyl;

상기 X는 이고,The X above is ego,

여기서, 상기 R3는 수소 또는 옥소(=O)이고;Here, R 3 is hydrogen or oxo (=O);

R4는 비치환이거나 치환된 C1-C5알킬, C1-C5알콕시, 6원자헤테로사이클로알킬, C6아릴 또는 6원자헤테로아릴이고,R 4 is unsubstituted or substituted C1-C5alkyl, C1-C5alkoxy, 6-membered heterocycloalkyl, C6aryl or 6-membered heteroaryl,

상기 치환된 C1-C5알킬, C1-C5알콕시, 6원자헤테로사이클로알킬, C6아릴 또는 6원자헤테로아릴은 비치환이거나 히드록시 및 C6아릴로 이루어진 군에서 선택되는 하나이상으로 치환된 C1-C5알킬, 비치환이거나 하나이상의 할로겐으로 치환된 C1-C5알킬카보닐, 할로겐, 히드록시, Boc(tert-부틸옥시카보닐), 비치환이거나 C1-C5알콕시로 치환된 C1-C5알콕시, C6아릴옥시 및 C6아릴카보닐로 이루어진 군에서 선택되는 하나이상으로 치환되는 것을 특징으로 하는, 화합물, 이의 입체이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염을 제공한다.The substituted C1-C5 alkyl, C1-C5 alkoxy, 6-membered heterocycloalkyl, C6 aryl or 6-membered heteroaryl is unsubstituted or substituted C1-C5 alkyl with one or more selected from the group consisting of hydroxy and C6 aryl. , C1-C5 alkylcarbonyl, unsubstituted or substituted with one or more halogens, halogen, hydroxy, Boc (tert-butyloxycarbonyl), C1-C5 alkoxy, unsubstituted or substituted with C1-C5 alkoxy, C6 aryloxy. and C6 arylcarbonyl, and a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

본 발명의 일 실시 형태는,One embodiment of the present invention,

상기 화학식 1에서,In Formula 1,

n는 1 또는 2이고;n is 1 or 2;

A는 비치환이거나 페닐 또는 피리딘이고,A is unsubstituted or phenyl or pyridine,

상기 치환된 페닐 또는 피리딘은 Cl, 히드록시, 몰포린, 메틸설포닐, 메틸옥시카보닐, 카르복시 및 설폰아미드로 이루어진 군에서 선택되는 하나이상으로 치환되거나, 또는 인접하는 두 개의 원자에 치환되어 1,3-디옥솔을 형성하고;The substituted phenyl or pyridine is substituted with one or more selected from the group consisting of Cl, hydroxy, morpholine, methylsulfonyl, methyloxycarbonyl, carboxy and sulfonamide, or is substituted on two adjacent atoms to give 1 , forming 3-dioxole;

L은 -CHR1-, -CHCH2- 또는 -CH2CH2-이고,L is -CHR 1 -, -CHCH 2 - or -CH 2 CH 2 -,

여기서, 상기 R1은 수소 또는 메틸이고;Here, R 1 is hydrogen or methyl;

B는 -NR2X, -NX2 또는-OX이고,B is -NR 2 X, -NX 2 or -OX,

여기서, 상기 R2는 수소 또는 메틸이고;Here, R 2 is hydrogen or methyl;

상기 X는 이고,The X above is ego,

여기서, 상기 R3는 수소 또는 옥소(=O)이고;Here, R 3 is hydrogen or oxo (=O);

R4는 비치환이거나 치환된 메틸, 메톡시, 피페라진, 몰포린, 페닐, 피리딘 또는 피리미딘이고,R 4 is unsubstituted or substituted methyl, methoxy, piperazine, morpholine, phenyl, pyridine or pyrimidine,

상기 치환된 메틸, 메톡시, 피페라진, 몰포린, 페닐, 피리딘 또는 피리미딘은 비치환이거나 히드록시 및 페닐로 이루어진 군에서 선택되는 하나이상으로 치환된 메틸, 비치환이거나 하나이상의 F으로 치환된 메틸카보닐, F, 이소프로필, 히드록시, Boc(tert-부틸옥시카보닐), 메톡시, 메톡시로 치환된 메톡시, 페닐옥시 및 페닐카보닐로 이루어진 군에서 선택되는 하나이상으로 치환되는 것을 특징으로 하는, 화합물, 이의 입체이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염을 제공한다.The substituted methyl, methoxy, piperazine, morpholine, phenyl, pyridine or pyrimidine is unsubstituted or substituted with one or more methyl selected from the group consisting of hydroxy and phenyl, unsubstituted or substituted with one or more F. Substituted with one or more selected from the group consisting of methylcarbonyl, F, isopropyl, hydroxy, Boc (tert-butyloxycarbonyl), methoxy, methoxy substituted with methoxy, phenyloxy and phenylcarbonyl A compound, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof is provided.

본 발명의 일 실시 형태는,One embodiment of the present invention,

상기 화학식 1에서,In Formula 1,

A는 , , , , , , , , , 또는 이고;A is , , , , , , , , , or ego;

R4는 , , , , , , , , , , , , , , , , , , , , 또는 인 것을 특징으로 하는, 화합물, 이의 입체이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염을 제공한다.R 4 is , , , , , , , , , , , , , , , , , , , , or It provides a compound, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, which is characterized in that:

본 발명의 일 실시 형태는,One embodiment of the present invention,

상기 화학식 1로 표시되는 화합물은 하기 화합물 군으로부터 선택되는 어느 하나인 화합물, 이의 입체이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염을 제공한다.The compound represented by Formula 1 provides any one compound selected from the following compound group, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

<1> 4-(2-(비스(3-페닐프로프-2-인-1-일)아미노)에틸)벤젠설폰아미드;<1> 4-(2-(bis(3-phenylprop-2-yn-1-yl)amino)ethyl)benzenesulfonamide;

<2> 3-페닐-N-(4-설파모일페네틸)프로피올아미드;<2> 3-phenyl-N-(4-sulfamoylphenethyl)propiolamide;

<3> 4-(2-((3-(4-(트리플루오로메틸)페닐)프로프-2-인-1-일)아미노)에틸)벤젠설폰아미드;<3> 4-(2-((3-(4-(trifluoromethyl)phenyl)prop-2-yn-1-yl)amino)ethyl)benzenesulfonamide;

<4> 4-(2-((3-페닐프로프-2-인-1-일)아미노)에틸)벤젠설폰아미드;<4> 4-(2-((3-phenylprop-2-yn-1-yl)amino)ethyl)benzenesulfonamide;

<5> 4-(2-((3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)벤젠설폰아미드;<5> 4-(2-((3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)benzenesulfonamide;

<6> 4-(2-(메틸(3-페닐프로프-2-인-1-일)아미노)에틸)벤젠설폰아미드;<6> 4-(2-(methyl(3-phenylprop-2-yn-1-yl)amino)ethyl)benzenesulfonamide;

<7> 4-(2-(비스(3-(4-메톡시페닐)프로프-2-인-1-일)아미노)에틸)벤젠설폰아미드;<7> 4-(2-(bis(3-(4-methoxyphenyl)prop-2-yn-1-yl)amino)ethyl)benzenesulfonamide;

<8> 4-(2-((3-(4-메톡시페닐)프로프-2-인-1-일)아미노)에틸)벤젠설폰아미드;<8> 4-(2-((3-(4-methoxyphenyl)prop-2-yn-1-yl)amino)ethyl)benzenesulfonamide;

<9> 3-([1,1'-비페닐]-4-일)-N-페네틸프로프-2-인-1-아민;<9> 3-([1,1'-biphenyl]-4-yl)-N-phenethylprop-2-yn-1-amine;

<10> 4-(((3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)메틸)벤젠설폰아미드;<10> 4-(((3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)methyl)benzenesulfonamide;

<11> 4-((비스(3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)메틸)벤젠설폰아미드;<11> 4-((bis(3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)methyl)benzenesulfonamide;

<12> 3-([1,1'-비페닐]-4-일)-N-(4-클로로펜에틸)프로프-2-인-1-아민;<12> 3-([1,1'-biphenyl]-4-yl)-N-(4-chlorophenethyl)prop-2-yn-1-amine;

<13> 3-([1,1'-바이페닐]-4-일)-N-(3-([1,1'-바이페닐]-4-일)프로프-2-인-1-일)-N-(4-클로로페네틸)프로프-2-인-1-아민;<13> 3-([1,1'-biphenyl]-4-yl)-N-(3-([1,1'-biphenyl]-4-yl)prop-2-yne-1- 1)-N-(4-chlorophenethyl)prop-2-yn-1-amine;

<14> 4-(2-((3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)페놀;<14> 4-(2-((3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)phenol;

<15> 4-(2-(비스(3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)페놀;<15> 4-(2-(bis(3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)phenol;

<16> 3-([1,1'-비페닐]-4-일)-N-(2-(벤조[d][1,3]디옥솔-5-일)에틸)프로프-2-인-1-아민;<16> 3-([1,1'-biphenyl]-4-yl)-N-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)prop-2- phosphorus-1-amine;

<17> 3-([1,1'-바이페닐]-4-일)-N-(3-([1,1'-바이페닐]-4-일)프로프-2-인-1-일)-N-(2-(벤조[d][1,3]디옥솔-5-일)에틸)프로프-2-인-1-아민;<17> 3-([1,1'-biphenyl]-4-yl)-N-(3-([1,1'-biphenyl]-4-yl)prop-2-yne-1- 1)-N-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)prop-2-yn-1-amine;

<18> 3-([1,1'-비페닐]-4-일)-N-(2,2-디페닐에틸)프로프-2-인-1-아민;<18> 3-([1,1'-biphenyl]-4-yl)-N-(2,2-diphenylethyl)prop-2-yn-1-amine;

<19> 3-([1,1'-바이페닐]-4-일)-N-(3-([1,1'-바이페닐]-4-일)프로프-2-인-1-일)-N-(2,2-디페닐에틸)프로프-2-인-1-아민;<19> 3-([1,1'-biphenyl]-4-yl)-N-(3-([1,1'-biphenyl]-4-yl)prop-2-yne-1- 1)-N-(2,2-diphenylethyl)prop-2-yn-1-amine;

<20> 3-([1,1'-비페닐]-4-일)-N-(4-모르폴리노펜에틸)프로프-2-인-1-아민;<20> 3-([1,1'-biphenyl]-4-yl)-N-(4-morpholinophenethyl)prop-2-yn-1-amine;

<21> 3-([1,1'-바이페닐]-4-일)-N-(3-([1,1'-바이페닐]-4-일)프로프-2-인-1-일)-N-(4-모르폴리노펜에틸)프로프-2-인-1-아민;<21> 3-([1,1'-biphenyl]-4-yl)-N-(3-([1,1'-biphenyl]-4-yl)prop-2-yne-1- 1)-N-(4-morpholinophenethyl)prop-2-yn-1-amine;

<22> 2-(1-((3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)-4-클로로페놀;<22> 2-(1-((3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)-4-chlorophenol;

<23> 4-클로로-2-(1-((3-(4-메톡시페닐)프로프-2-인-1-일)아미노)에틸)페놀;<23> 4-chloro-2-(1-((3-(4-methoxyphenyl)prop-2-yn-1-yl)amino)ethyl)phenol;

<24> 4-(2-((3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)(메틸)아미노)에틸)벤젠설폰아미드;<24> 4-(2-((3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)(methyl)amino)ethyl)benzenesulfonamide;

<25> 3-([1,1'-비페닐]-4-일)-N-(4-(메틸설포닐)페네틸)프로프-2-인-1-아민;<25> 3-([1,1'-biphenyl]-4-yl)-N-(4-(methylsulfonyl)phenethyl)prop-2-yn-1-amine;

<26> 3-([1,1'-바이페닐]-4-일)-N-(3-([1,1'-바이페닐]-4-일)프로프-2-인-1-일)-N-(4-(메틸설포닐)페네틸)프로프-2-인-1-아민;<26> 3-([1,1'-biphenyl]-4-yl)-N-(3-([1,1'-biphenyl]-4-yl)prop-2-yne-1- 1)-N-(4-(methylsulfonyl)phenethyl)prop-2-yn-1-amine;

<27> 메틸 4-(2-((3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)벤조에이트;<27> Methyl 4-(2-((3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)benzoate;

<28> 메틸 4-(2-(비스(3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)벤조에이트;<28> Methyl 4-(2-(bis(3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)benzoate;

<29> 4-(2-((3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)벤조산;<29> 4-(2-((3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)benzoic acid;

<30> 4-(2-(비스(3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)벤조산;<30> 4-(2-(bis(3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)benzoic acid;

<31> 4-(2-((3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)(메틸)아미노)에틸)페놀;<31> 4-(2-((3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)(methyl)amino)ethyl)phenol;

<32> 4-(1-((3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)옥시)에틸)-3,5-디클로로피리딘;<32> 4-(1-((3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)oxy)ethyl)-3,5-dichloropyridine;

<33> 4-클로로-2-(1-((3-(4-메톡시페닐)프로프-2-인-1-일)(메틸)아미노)에틸)페놀;<33> 4-chloro-2-(1-((3-(4-methoxyphenyl)prop-2-yn-1-yl)(methyl)amino)ethyl)phenol;

<34> tert-부틸 4-(4-(3-((4-히드록시페네틸)아미노)프로프-1-인-1-일)페닐)피페라진-1-카르복실레이트;<34> tert-Butyl 4-(4-(3-((4-hydroxyphenethyl)amino)prop-1-yn-1-yl)phenyl)piperazine-1-carboxylate;

<35> tert-부틸 4-(4-(3-((1-(5-클로로-2-히드록시페닐)에틸)아미노)프로프-1-인-1-일)페닐)피페라진-1-카르복실레이트;<35> tert-Butyl 4-(4-(3-((1-(5-chloro-2-hydroxyphenyl)ethyl)amino)prop-1-yn-1-yl)phenyl)piperazine-1 -carboxylate;

<36> 4-(2-((3-(4-(피페라진-1-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀;<36> 4-(2-((3-(4-(piperazin-1-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol;

<37> 4-클로로-2-(1-((3-(4-(피페라진-1-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀;<37> 4-chloro-2-(1-((3-(4-(piperazin-1-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol;

<38> 4-(2-((3-(4-모르폴리노페닐)프로프-2-인-1-일)아미노)에틸)페놀;<38> 4-(2-((3-(4-morpholinophenyl)prop-2-yn-1-yl)amino)ethyl)phenol;

<39> 4-클로로-2-(1-((3-(4-모르폴리노페닐)프로프-2-인-1-일)아미노)에틸)페놀;<39> 4-chloro-2-(1-((3-(4-morpholinophenyl)prop-2-yn-1-yl)amino)ethyl)phenol;

<40> 4-(2-((3-(4-(4-메틸피페라진-1-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀;<40> 4-(2-((3-(4-(4-methylpiperazin-1-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol;

<41> 4-클로로-2-(1-((3-(4-(4-메틸피페라진-1-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀;<41> 4-chloro-2-(1-((3-(4-(4-methylpiperazin-1-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol;

<42> 4-(2-((3-(4-(피리딘-4-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀;<42> 4-(2-((3-(4-(pyridin-4-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol;

<43> 4-클로로-2-(1-((3-(4-(피리딘-4-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀;<43> 4-chloro-2-(1-((3-(4-(pyridin-4-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol;

<44> 4-(2-((3-(4'-메톡시-[1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)페놀;<44> 4-(2-((3-(4'-methoxy-[1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)phenol;

<45> 4-클로로-2-(1-((3-(4'-메톡시-[1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)페놀;<45> 4-Chloro-2-(1-((3-(4'-methoxy-[1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino) ethyl)phenol;

<46> 4-(2-((3-(4'-(메톡시메톡시)-[1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)페놀;<46> 4-(2-((3-(4'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino) ethyl)phenol;

<47> 4-클로로-2-(1-((3-(4'-(메톡시메톡시)-[1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)페놀;<47> 4-Chloro-2-(1-((3-(4'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)prop-2-yne-1- 1) amino) ethyl) phenol;

<48> 4-(2-((3-(4-(피리딘-3-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀;<48> 4-(2-((3-(4-(pyridin-3-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol;

<49> 4-클로로-2-(1-((3-(4-(피리딘-3-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀;<49> 4-Chloro-2-(1-((3-(4-(pyridin-3-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol;

<50> 4-(2-((3-(4-(피리딘-2-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀;<50> 4-(2-((3-(4-(pyridin-2-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol;

<51> 4-클로로-2-(1-((3-(4-(피리딘-2-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀;<51> 4-chloro-2-(1-((3-(4-(pyridin-2-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol;

<52> 4'-(3-((4-히드록시페네틸)아미노)프로프-1-인-1-일)-[1,1'-비페닐]-4-올;<52> 4'-(3-((4-hydroxyphenethyl)amino)prop-1-yn-1-yl)-[1,1'-biphenyl]-4-ol;

<53> 4'-(3-((1-(5-클로로-2-히드록시페닐)에틸)아미노)프로프-1-인-1-일)-[1,1'-비페닐]-4-올;<53> 4'-(3-((1-(5-chloro-2-hydroxyphenyl)ethyl)amino)prop-1-yn-1-yl)-[1,1'-biphenyl]- 4-all;

<54> 4-(2-((3-(4-(피리미딘-2-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀;<54> 4-(2-((3-(4-(pyrimidin-2-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol;

<55> 4-클로로-2-(1-((3-(4-(피리미딘-2-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀;<55> 4-Chloro-2-(1-((3-(4-(pyrimidin-2-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol;

<56> 4-(2-((3-(4'-페녹시-[1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)페놀;<56> 4-(2-((3-(4'-phenoxy-[1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)phenol;

<57> 4-클로로-2-(1-((3-(4'-페녹시-[1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)페놀;<57> 4-Chloro-2-(1-((3-(4'-phenoxy-[1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino) ethyl)phenol;

<58> 4-(2-((3-(4-(피리미딘-5-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀;<58> 4-(2-((3-(4-(pyrimidin-5-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol;

<59> 4-클로로-2-(1-((3-(4-(피리미딘-5-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀;<59> 4-Chloro-2-(1-((3-(4-(pyrimidin-5-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol;

<60> 4-(2-((3-(4-(4-이소프로필피페라진-1-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀;<60> 4-(2-((3-(4-(4-isopropylpiperazin-1-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol;

<61> 1-(4-(4-(3-((4-히드록시펜에틸)아미노)프로프-1-인-1-일)페닐)피페라진-1-일)에탄-1-온;<61> 1-(4-(4-(3-((4-hydroxyphenethyl)amino)prop-1-yn-1-yl)phenyl)piperazin-1-yl)ethan-1-one ;

<62> 2,2,2-트리플루오로-1-(4-(4-(3-((4-히드록시펜에틸)아미노)프로프-1-인-1-일)페닐)피페라진-1-일)에탄-1-온;<62> 2,2,2-trifluoro-1-(4-(4-(3-((4-hydroxyphenethyl)amino)prop-1-yn-1-yl)phenyl)piperazine -1-yl)ethan-1-one;

<63> 4-(2-((3-(4'-(히드록시(페닐)메틸)-[1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)페놀;<63> 4-(2-((3-(4'-(hydroxy(phenyl)methyl)-[1,1'-biphenyl]-4-yl)prop-2-yn-1-yl) amino)ethyl)phenol;

<64> ((((4-히드록시페네틸)아잔디일)비스(프로프-1-인-3,1-디일))비스([1,1'-비페닐]-4',4-디일))비스(페닐메탄온);<64> ((((4-hydroxyphenethyl)azanediyl)bis(prop-1-yn-3,1-diyl))bis([1,1'-biphenyl]-4',4 -diyl))bis(phenylmethanone);

<65> (4'-(3-((4-히드록시페네틸)아미노)프로프-1-인-1-일)-[1,1'-비페닐]-4-일)(페닐)메탄온;<65> (4'-(3-((4-hydroxyphenethyl)amino)prop-1-yn-1-yl)-[1,1'-biphenyl]-4-yl)(phenyl) methanone;

<66> 4-(2-((3-(4'-페녹시-[1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)벤젠설폰아미드;<66> 4-(2-((3-(4'-phenoxy-[1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)benzenesulfone amides;

<67> 4-(2-((3-(4'-(메톡시메톡시)-[1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)벤젠설폰아미드;<67> 4-(2-((3-(4'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino) ethyl)benzenesulfonamide;

<68> 4-(2-((3-(4-(4-벤질피페라진-1-일)페닐)프로프-2-인-1-일)아미노)에틸)벤젠설폰아미드; 및<68> 4-(2-((3-(4-(4-benzylpiperazin-1-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)benzenesulfonamide; and

<69> 4-(2-((3-(4-(4-벤질피페라진-1-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀.<69> 4-(2-((3-(4-(4-benzylpiperazin-1-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol.

본 발명의 일 실시 형태는,One embodiment of the present invention,

상기 화학식 1로 표시되는 화합물, 이의 입체이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는, 암의 예방 또는 치료용 약학적 조성물을 제공한다.Provided is a pharmaceutical composition for preventing or treating cancer, containing the compound represented by Formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

상기 암은 폐암, 비-소세포 폐암(NSCL), 기관지 폐포 세포 폐암, 난소암, 대장암, 흑색종, 위암, 위장관암, 간암, 골암, 췌장암, 피부암, 두경부암, 피부 또는 안구 흑색종, 자궁암, 직장암, 결장암, 유방암, 자궁 육종, 나팔관 암종, 내궁내막 암종, 자궁경부 암종, 질 암종, 외음부 암종, 식도암, 후두암, 소장암, 갑상선암, 부갑상선암, 연조직의 육종, 요도암, 음경암, 전립선암, 다발성 골수종, 만성 또는 급성 백혈병 중 어느 하나인 것 일 수 있고, 바람직하게 간암일 수 있다.These cancers include lung cancer, non-small cell lung cancer (NSCL), bronchoalveolar cell lung cancer, ovarian cancer, colorectal cancer, melanoma, stomach cancer, gastrointestinal cancer, liver cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or eye melanoma, and uterine cancer. , rectal cancer, colon cancer, breast cancer, uterine sarcoma, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, esophagus cancer, laryngeal cancer, small intestine cancer, thyroid cancer, parathyroid cancer, sarcoma of soft tissue, urethral cancer, penile cancer, prostate cancer It may be any one of cancer, multiple myeloma, chronic or acute leukemia, and preferably liver cancer.

본 발명의 일 실시 형태는,One embodiment of the present invention,

상기 화학식 1로 표시되는 화합물, 이의 입체이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는,Containing the compound represented by Formula 1 above, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient,

ACC 과활성화로 인한 질환의 예방 또는 치료용 약학적 조성물을 제공한다.A pharmaceutical composition for preventing or treating diseases caused by ACC hyperactivation is provided.

본 발명에 있어서, 용어 "유효성분으로 함유하는"이란, 암의 예방, 개선, 또는 치료의 효과를 가져오는 용량 범위로 함유하는 것을 의미하고, 중증도 및 제형에 따라 용량 범위는 변할 수 있으며, 적용 횟수도 적용 대상의 연령, 체중 및 체질에 따라 변할 수 있다. In the present invention, the term "containing as an active ingredient" means containing in a dosage range that brings about the effect of preventing, improving, or treating cancer, and the dosage range may vary depending on the severity and formulation, and application. The number of times may vary depending on the age, weight, and constitution of the subject.

본 발명의 상기 약학적 조성물은 약학적으로 유효한 양으로 투여한다.The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount.

본 발명에 있어서, 용어 "약학적으로 유효한 양"이란, 의학적 치료 또는 개선에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효 용량 수준은 개체 종류 및 중증도, 연령, 성별, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출 비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 예를 들어, 0.001 mg/kg 내지 100 mg/kg, 0.01 mg/kg 내지 10 mg/kg 또는 0.1 mg/kg 내지 1 mg/kg의 유효한 양이 포함된다. 본 발명의 약학적 조성물의 양적 상한은 당업자가 적절한 범위 내에서 선택하여 실시할 수 있다.In the present invention, the term "pharmaceutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment or improvement, and the effective dose level is determined by the type and severity of the individual, age, It can be determined based on factors including gender, drug activity, sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment, concurrently used drugs, and other factors well known in the medical field. For example, effective amounts of 0.001 mg/kg to 100 mg/kg, 0.01 mg/kg to 10 mg/kg, or 0.1 mg/kg to 1 mg/kg are included. The upper quantitative limit of the pharmaceutical composition of the present invention can be selected and implemented by a person skilled in the art within an appropriate range.

본 발명에 따른 약학적 조성물은 유효량의 화학식 1로 표시되는 화합물을 단독으로 포함하거나 하나 이상의 약학적으로 허용되는 담체, 부형제 또는 희석제를 포함할 수 있다.The pharmaceutical composition according to the present invention may contain an effective amount of the compound represented by Formula 1 alone or may include one or more pharmaceutically acceptable carriers, excipients, or diluents.

상기 약학적으로 허용되는 담체, 부형제 또는 희석제는 생리학적으로 허용되고 인간에게 투여될 때, 통상적으로 위장 장애, 현기증과 같은 알레르기 반응 또는 이와 유사한 반응을 일으키지 않는 물질을 말한다. 상기 담체, 부형제 및 희석제의 예로는, 락토즈, 덱스트로즈, 수크로즈, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 폴리비닐피롤리돈, 물, 메틸하이드록시벤조에이트, 프로필하이드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있으며, 이에 제한되는 것은 아니다. 또한, 충진제, 항응집제, 윤활제, 습윤제, 향료, 유화제 및 방부제 등을 추가로 포함할 수 있다.The pharmaceutically acceptable carrier, excipient, or diluent refers to a substance that is physiologically acceptable and does not typically cause gastrointestinal upset, allergic reactions such as dizziness, or similar reactions when administered to humans. Examples of the carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, Examples include, but are not limited to, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. In addition, fillers, anti-coagulants, lubricants, wetting agents, fragrances, emulsifiers and preservatives may be additionally included.

상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염은 임상 투여시에 경구 및 비경구의 여러 가지 제형으로 투여될 수 있다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 하나 이상의 화합물에 적어도 하나 이상의 부형제 예를 들면, 전분, 탄산칼슘, 수크로오스 (sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 스테아린산 마그네슘, 탈크 등과 같은 윤활제들도 사용된다. 경구투여를 위한 액상제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제가 포함된다. 비수성용제, 현탁용제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테로 등이 사용될 수 있다.The compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be administered in various oral and parenteral dosage forms during clinical administration. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc. These solid preparations contain one or more compounds and at least one excipient, such as starch, calcium carbonate, sucrose, or lactose ( It is prepared by mixing lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, oral solutions, emulsions, and syrups. In addition to the commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. there is. Preparations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, and emulsions. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable esters such as ethyl oleate.

상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 유효 성분으로 하는 약학적 조성물은 비경구 투여할 수 있으며, 비경구 투여는 피하주사, 정맥주사, 근육 내 주사 또는 흉부 내 주사를 주입하는 방법에 의한다. A pharmaceutical composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient can be administered parenterally, and parenteral administration can be done by subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection. It depends on how you do it.

이때, 비경구 투여용 제형으로 제제화하기 위하여 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 안정제 또는 완충제와 함께 물에 혼합하여 용액 또는 현탁액으로 제조하고, 이를 앰플 또는 바이알 단위 투여형으로 제조할 수 있다. 상기 조성물은 멸균되고/되거나 방부제, 안정화제, 수화제 또는 유화 촉진제, 삼투압 조절을 위한 염 및/또는 완충제 등의 보조제, 및 기타 치료적으로 유용한 물질을 함유할 수 있으며, 통상적인 방법인 혼합, 과립화 또는 코팅 방법에 따라 제제화할 수 있다.At this time, in order to formulate a formulation for parenteral administration, the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is mixed with water along with a stabilizer or buffer to prepare a solution or suspension, which is administered in ampoule or vial unit dosage form. It can be manufactured with The composition may be sterilized and/or contain auxiliaries such as preservatives, stabilizers, wetting agents or emulsification accelerators, salts and/or buffers for adjusting osmotic pressure, and other therapeutically useful substances, and may be mixed, granulated, etc. using conventional methods. It can be formulated according to the coating or coating method.

본 발명에 있어서, 용어 "예방"이란, 본 발명의 약학적 조성물, 건강기능식품을 암의 투병중이지 않은 개체에게 투여, 섭취 또는 적용하여 암의 증세를 억제 또는 차단함으로써, 암의 증세가 사전에 발생되지 않도록 하는 것을 의미한다.In the present invention, the term "prevention" refers to the prevention of cancer symptoms in advance by suppressing or blocking the symptoms of cancer by administering, ingesting, or applying the pharmaceutical composition or health functional food of the present invention to an individual who is not suffering from cancer. This means preventing it from occurring.

본 발명에 있어서, 용어 "치료"란, 본 발명의 약학적 조성물을 암 투병중인 개체에게 투여한 결과로서 암의 증세 완치는 물론 암의 증세 부분적 완치, 호전 및 경감을 포함한다.In the present invention, the term "treatment" includes complete cure of cancer symptoms as well as partial cure, improvement, and relief of cancer symptoms as a result of administering the pharmaceutical composition of the present invention to an individual suffering from cancer.

나아가, 상기 화학식 1로 표시되는 화합물은 이의 약학적으로 허용가능한 염뿐만 아니라, 이로부터 제조될 수 있는 이성질체, 용매화물, 수화물 등의 형태로 사용될 수 있다.Furthermore, the compound represented by Formula 1 can be used not only in the form of its pharmaceutically acceptable salt, but also in the form of isomers, solvates, hydrates, etc. that can be prepared therefrom.

용어 "이성질체(isomer)"는 동일한 화학식 또는 분자식을 가지지만 구조적 또는 입체적으로 다른 본 발명의 화합물 또는 그것의 염을 의미한다. 이러한 이성질체에는 호변이성질체(tautomer) 등의 구조이성질체와, 입체이성질체(stereoisomer)가 있으며, 입체이성질체에는 비대칭 탄소 중심을 가지는 R 또는 S 이성질체(광학 이성질체, enantiomer), 기하이성질체(트랜스, 시스) 등이 모두 포함된다. 본 발명에서는 상기 화학식 1로 표시되는 화합물의 모든 입체이성질체 및 그것의 혼합물들 역시 본 발명의 범위에 포함된다.The term “isomer” refers to a compound of the present invention or a salt thereof that has the same chemical or molecular formula but is structurally or sterically different. These isomers include structural isomers such as tautomers and stereoisomers, and stereoisomers include R or S isomers (optical isomers, enantiomers) and geometric isomers (trans, cis) with an asymmetric carbon center. Everything is included. In the present invention, all stereoisomers of the compound represented by Formula 1 and mixtures thereof are also included within the scope of the present invention.

용어 "수화물(hydrate)"은 비공유적 분자간력(non-covalent intermolecular force)에 의해 결합된 화학양론적(stoichiometric) 또는 비화학양론적(non-stoichiometric) 량의 물을 포함하고 있는 본 발명의 화합물 또는 그것의 염을 의미한다. 본 발명의 상기 화학식 1로 표시되는 화합물의 수화물은 비공유적 분자간 힘으로 결합되는 화학양론적 또는 비화학양론적 양의 물을 포함할 수 있다. 상기 수화물은 1당량 이상, 바람직하게는, 1당량 내지 5당량의 물을 함유할 수 있다. 이러한 수화물은 물 또는 물을 함유하는 용매로부터 본 발명의 상기 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이들의 약제학적으로 허용 가능한 염을 결정화시켜 제조될 수 있다.The term “hydrate” refers to a compound of the present invention containing a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. or its salt. The hydrate of the compound represented by Formula 1 of the present invention may contain a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. The hydrate may contain more than 1 equivalent of water, preferably 1 to 5 equivalents of water. Such hydrates can be prepared by crystallizing the compound represented by Formula 1 of the present invention, an isomer thereof, or a pharmaceutically acceptable salt thereof from water or a solvent containing water.

용어 "용매화물(solvate)"은 비공유적 분자간력에 의해 결합된 화학양론적 또는 비화학양론적 양의 용매를 포함하고 있는 본 발명의 화합물 또는 그것의 염을 의미한다. 그에 관한 바람직한 용매들로는 휘발성, 비독성, 및/또는 인간에게 투여되기에 적합한 용매들이 있다.The term “solvate” refers to a compound of the invention or a salt thereof containing a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Preferred solvents therefor are solvents that are volatile, non-toxic, and/or suitable for administration to humans.

본 발명의 상기 화학식 1로 표시되는 화합물은 약학적으로 허용가능한 염의 형태로 사용할 수 있으며, 염으로는 약학적으로 허용가능한 유리산(free acid)에 의해 형성된 산 부가염이 유용하다. 산 부가염은 염산, 질산, 인산, 황산, 브롬화수소산, 요드화수소산, 아질산, 아인산 등과 같은 무기산류, 지방족 모노 및 디카복실레이트, 페닐-치환된 알카노에이트, 하이드록시 알카노에이트 및 알칸디오에이트, 방향족 산류, 지방족 및 방향족 설폰산류 등과 같은 무독성 유기산, 트리플루오로아세트산, 아세테이트, 안식향산, 구연산, 젖산, 말레인산, 글루콘산, 메탄설폰산, 4-톨루엔설폰산, 주석산, 푸마르산 등과 같은 유기산으로부터 얻는다. 이러한 약학적으로 무독한 염의 종류로는 설페이트, 피로설페이트, 바이설페이트, 설파이트, 바이설파이트, 니트레이트, 포스페이트, 모노하이드로겐 포스페이트, 디하이드로겐 포스페이트, 메타포스페이트, 피로포스페이트 클로라이드, 브로마이드, 아이오다이드, 플루오라이드, 아세테이트, 프로피오네이트, 데카노에이트, 카프릴레이트, 아크릴레이트, 포메이트, 이소부티레이트, 카프레이트, 헵타노에이트, 프로피올레이트, 옥살레이트, 말로네이트, 석시네이트, 수베레이트, 세바케이트, 푸마레이트, 말리에이트, 부틴-1,4-디오에이트, 헥산-1,6-디오에이트, 벤조에이트, 클로로벤조에이트, 메틸벤조에이트, 디니트로 벤조에이트, 하이드록시벤조에이트, 메톡시벤조에이트, 프탈레이트, 테레프탈레이트, 벤젠설포네이트, 톨루엔설포네이트, 클로로벤젠설포네이트, 크실렌설포네이트, 페닐아세테이트, 페닐프로피오네이트, 페닐부티레이트, 시트레이트, 락테이트, β하이드록시부티레이트, 글리콜레이트, 말레이트, 타트레이트, 메탄설포네이트, 프로판설포네이트, 나프탈렌-1-설포네이트, 나프탈렌-2-설포네이트, 만델레이트 등을 포함한다.The compound represented by Formula 1 of the present invention can be used in the form of a pharmaceutically acceptable salt, and an acid addition salt formed by a pharmaceutically acceptable free acid is useful as the salt. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, etc., aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanedio acids. Non-toxic organic acids such as ate, aromatic acids, aliphatic and aromatic sulfonic acids, organic acids such as trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, etc. get These pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and nitrate. Odide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, sube. Latex, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycol Includes nitrate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, etc.

본 발명에 따른 산 부가염은 통상의 방법으로 제조할 수 있으며, 예를 들면 화학식 1의 유도체를 메탄올, 에탄올, 아세톤, 메틸렌클로라이드, 아세토니트릴 등과 같은 유기용매에 녹이고 유기산 또는 무기산을 가하여 생성된 침전물을 여과, 건조시켜 제조하거나, 용매와 과량의 산을 감압 증류한 후 건조시켜 유기용매 하에서 결정화시켜서 제조할 수 있다.The acid addition salt according to the present invention can be prepared by conventional methods, for example, the precipitate produced by dissolving the derivative of Formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc. and adding an organic acid or inorganic acid. It can be prepared by filtering and drying, or by distilling the solvent and excess acid under reduced pressure, drying it, and crystallizing it in an organic solvent.

또한, 상기 화학식 1로 표시되는 화합물, 이의 입체이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물은 개별 치료제로 투여하거나, 사용중인 다른 치료제와 병용투여하여 사용할 수 있으며, 병용투여함으로써 효과를 증진시킬 수 있다.In addition, a pharmaceutical composition for the prevention or treatment of cancer containing the compound represented by Formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient may be administered as an individual therapeutic agent, or It can be used in combination with other treatments in use, and the effect can be enhanced by combined administration.

본 발명의 일 실시 형태는,One embodiment of the present invention,

상기 화학식 1로 표시되는 화합물, 이의 입체이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 암의 예방 또는 개선용 건강기능식품 조성물을 제공한다.Provided is a health functional food composition for preventing or improving cancer containing the compound represented by Formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

본 발명에 있어서, 용어 “개선”이란, 본 발명의 약학적 조성물, 식품 조성물을 암 투병 개체에게 투여, 섭취 또는 적용하여 암의 증세 경감 또는 완화를 포함하는 의미이다.In the present invention, the term “improvement” means reducing or alleviating cancer symptoms by administering, ingesting, or applying the pharmaceutical composition or food composition of the present invention to a cancer-stricken individual.

용어 "건강기능식품"은 건강기능식품에 관한 법률에 따른 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 제조 및 가공한 식품을 의미하며, 용어 “기능성” 이라 함은, 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건 용도에 유용한 효과를 얻을 목적으로 섭취하는 것을 의미한다. 이와 같이 하여 얻어지는 본 발명의 건강기능식품 또는 건강보조식품은, 일상적으로 섭취하는 것이 가능하기 때문에 매우 유용하다.The term “health functional food” refers to food manufactured and processed using raw materials or ingredients with functionality useful to the human body in accordance with the Health Functional Food Act, and the term “functional” refers to food that is related to the structure and function of the human body. It means ingestion for the purpose of controlling nutrients or obtaining useful health effects such as physiological effects. The health functional food or health supplement food of the present invention obtained in this way is very useful because it can be consumed on a daily basis.

상기 식품의 종류에는 특별한 제한이 없으며, 통상적인 의미에서의 건강기능식품을 모두 포함한다.There are no particular restrictions on the type of food, and it includes all health functional foods in the conventional sense.

본 발명의 약학적 조성물 및 건강기능식품에서 언급된 사항은 서로 모순되지 않는 한 동일하게 적용된다.Matters mentioned in the pharmaceutical composition and health functional food of the present invention apply equally unless they contradict each other.

본 발명의 일 실시형태는, 본 명세서에 기재된 화학식 1로 표시되는 화합물, 이의 입체이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염을 필요한 대상에게 투여하는 단계를 포함하는 암의 예방 또는 치료 방법(method)을 제공한다.One embodiment of the present invention is a method for preventing cancer, comprising administering to a subject in need a compound represented by Formula 1 described herein, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof. Or provide a treatment method.

본 발명의 일 실시형태는, 암의 예방 또는 치료에 사용하기 위한 약제(medicament) 제조에 사용하기 위한 본 명세서에 기재된 화학식 1로 표시되는 화합물, 이의 입체이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염의 용도(use)를 제공한다.One embodiment of the present invention is a compound represented by Formula 1 described herein for use in the manufacture of a medicament for use in the prevention or treatment of cancer, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutical thereof. Provides an acceptable use of salt.

상기 방법 또는 용도에 있어서, 전술한 약학적 조성물에 대한 상세한 설명이 적용될 수 있다.For the above method or use, the detailed description of the pharmaceutical composition described above may be applied.

이하, 본 발명을 실시예 및 실험예에 의해 상세히 설명한다.Hereinafter, the present invention will be described in detail through examples and experimental examples.

단, 하기 실시예 및 실험예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 제조예, 실시예 및 실험예에 한정되는 것은 아니다.However, the following examples and experimental examples are merely illustrative of the present invention, and the content of the present invention is not limited to the following production examples, examples, and experimental examples.

<분석 및 정제 조건><Analysis and purification conditions>

1. HPLC 분석 조건 (A)1. HPLC analysis conditions (A)

기기명: ShimadzuDevice name: Shimadzu

컬럼: YMC-pack pro C18, 150x4.6mm I.D., 5 μm, 40℃Column: YMC-pack pro C18, 150x4.6mm I.D., 5 μm, 40℃

이동상: 5% ->100% 아세토나이트릴/H2O + 0.1% 트리플루오로아세트산, Mobile phase: 5% -> 100% acetonitrile/H 2 O + 0.1% trifluoroacetic acid,

분석시간 : 9분, 유속 : 1ml/minAnalysis time: 9 minutes, flow rate: 1ml/min

UV detector: 254nmUV detector: 254nm

2. HPLC 분석 조건 (B)2. HPLC analysis conditions (B)

기기명: Thermo Scientific Ultimate 3000RSLCDevice Name: Thermo Scientific Ultimate 3000RSLC

컬럼: Kinetex® 2.6 μM 비페닐 100Å, 100x2.1mm Column: Kinetex® 2.6 μM biphenyl 100Å, 100x2.1mm

이동상: 5% ->100% 아세토나이트릴/H2O + 0.1% 트리플루오로아세트산, Mobile phase: 5% -> 100% acetonitrile/H 2 O + 0.1% trifluoroacetic acid,

분석시간 : 8분, 유속 : 0.7ml/minAnalysis time: 8 minutes, flow rate: 0.7ml/min

UV detector: 254nmUV detector: 254nm

3. LC-MS 분석 조건3. LC-MS analysis conditions

기기명: Shimadzu LCMS-2020Device name: Shimadzu LCMS-2020

컬럼: ACE Excel2 C18, 75x2.1 mmColumn: ACE Excel2 C18, 75x2.1 mm

이동상: 아세토나이트릴/H2O + 0.1% 트리플루오로아세트산Mobile phase: Acetonitrile/H 2 O + 0.1% trifluoroacetic acid

유속 : 1mL/minFlow rate: 1mL/min

UV detector: 254nmUV detector: 254nm

4. MPLC 정제 조건4. MPLC purification conditions

기기명: CombiFlash®Rf+Device name: CombiFlash®Rf+

UV detector: 254nmUV detector: 254nm

5. Prep-HPLC 정제 조건5. Prep-HPLC purification conditions

기기명: Gilson GX-281, 321 pump, UV/VIS-155Device name: Gilson GX-281, 321 pump, UV/VIS-155

컬럼: Luna® 10 μM C18 (2) 100 Å, 250x21.2 mmColumn: Luna® 10 μM C18 (2) 100 Å, 250x21.2 mm

이동상: 아세토나이트릴/ 0.1% 트리플루오로아세트산 H2OMobile phase: Acetonitrile/0.1% trifluoroacetic acid H 2 O

유속 : 15mL/minFlow rate: 15mL/min

UV detector: 254nmUV detector: 254nm

6. 6. 1One H NMR분석 조건H NMR analysis conditions

기기명: Bruker Avance (400 MHz)Device name: Bruker Avance (400 MHz)

<실시예 1> 4-(2-(비스(3-페닐프로프-2-인-1-일)아미노)에틸)벤젠설폰아미드의 제조<Example 1> Preparation of 4-(2-(bis(3-phenylprop-2-yn-1-yl)amino)ethyl)benzenesulfonamide

4-(2-아미노에틸)벤젠술폰아미드(402 mg, 2.01 mmol)를 디클로로에탄에 용해시킨 뒤, 상온에서 3-페닐프로피올알데히드(0.082 ml, 0.66 mmol), 아세트산 (0.115 ml, 2.01 mmol)을 첨가하였다. 0 ℃에서 30분동안 교반한 뒤, 소듐트리아세톡시보로하이드라이드(284 mg, 1.34 mmol)을 천천히 첨가하였다. 상온에서 30분동안 교반한 뒤, 탄산수소나트륨 수용액을 적가하여 반응을 종결시키고 디클로로메탄으로 희석시키고 물과 소금물로 씻어주었다. 추출한 유기층은 무수 황산나트륨으로 건조 및 여과한 다음 감압 농축하였다. 얻어진 잔사를 실리카겔 크로마토그래피법(0~50% 에틸아세테이트/헥산)으로 분리 및 정제하여, 목적화합물 4-(2-(비스(3-페닐프로프-2-인-1-일)아미노)에틸)벤젠설폰아미드 (200 mg, 70%, 갈색 고체)를 수득하였다.4-(2-Aminoethyl)benzenesulfonamide (402 mg, 2.01 mmol) was dissolved in dichloroethane, then 3-phenylpropialdehyde (0.082 ml, 0.66 mmol) and acetic acid (0.115 ml, 2.01 mmol) were added at room temperature. was added. After stirring at 0°C for 30 minutes, sodium triacetoxyborohydride (284 mg, 1.34 mmol) was slowly added. After stirring at room temperature for 30 minutes, the reaction was terminated by adding aqueous sodium bicarbonate solution dropwise, diluted with dichloromethane, and washed with water and salt water. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0~50% ethyl acetate/hexane) to produce the target compound 4-(2-(bis(3-phenylprop-2-yn-1-yl)amino)ethyl. )Benzenesulfonamide (200 mg, 70%, brown solid) was obtained.

1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 8.4 Hz, 2H), 7.44 - 7.39 (m, 6H), 7.33 - 7.28 (m, 6H), 4.74 (s, 2H), 3.76 (s, 4H), 3.02 - 2.93 (m, 4H); LCMS, m/z 429[M+H]+ 1 H NMR (400 MHz, CDCl 3 ) δ 7.84 (d, J = 8.4 Hz, 2H), 7.44 - 7.39 (m, 6H), 7.33 - 7.28 (m, 6H), 4.74 (s, 2H), 3.76 ( s, 4H), 3.02 - 2.93 (m, 4H); LCMS, m/z 429[M+H] +

<실시예 2> 3-페닐-N-(4-설파모일페네틸)프로피올아미드의 제조<Example 2> Preparation of 3-phenyl-N-(4-sulfamoylphenethyl)propiolamide

4-(2-아미노에틸)벤젠술폰아미드(401 mg, 2.00 mmol)를 디메틸포름아미드에 용해시킨 뒤, 상온에서 3-페닐프로피올산(307 mg, 2.10 mmol), EDCI(576mg, 3mmol), HOBt(368 mg, 2.40 mmol), DIPEA(1.07 ml, 6.00 mmol)을 첨가하였다. 상온에서 15시간동안 교반한 뒤, 증류수를 적가하여 반응을 종결시키고 에틸아세테이트로 희석시키고 물로 씻어주었다. 추출한 유기층은 무수 황산나트륨으로 건조 및 여과한 다음 감압 농축하였다. 얻어진 잔사를 실리카겔 크로마토그래피법(0~40% 에틸아세테이트/헥산)으로 분리 및 정제하여, 목적화합물 3-페닐-N-(4-설파모일페네틸)프로피올아미드(450 mg, 68%, 갈색 고체)를 수득하였다.4-(2-Aminoethyl)benzenesulfonamide (401 mg, 2.00 mmol) was dissolved in dimethylformamide, and then 3-phenylpropiolic acid (307 mg, 2.10 mmol), EDCI (576 mg, 3 mmol), and HOBt were added at room temperature. (368 mg, 2.40 mmol) and DIPEA (1.07 ml, 6.00 mmol) were added. After stirring at room temperature for 15 hours, distilled water was added dropwise to terminate the reaction, diluted with ethyl acetate, and washed with water. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0~40% ethyl acetate/hexane), and the target compound 3-phenyl-N-(4-sulfamoylphenethyl)propiolamide (450 mg, 68%, brown) was obtained. solid) was obtained.

1H NMR (400 MHz, DMSO-d6) δ 8.90 (t, J = 5.7 Hz, 1H), 7.75 (d, J = 8.3 Hz, 2H), 7.58 - 7.55 (m, 2H), 7.52 - 7.41 (m, 5H), 7.30 (s, 2H), 2.85 (t, J = 7.2 Hz, 2H), other CH2 overlapped in solvent peak.; LCMS, m/z 329[M+H]+ 1H NMR (400 MHz, DMSO-d 6 ) δ 8.90 (t, J = 5.7 Hz, 1H), 7.75 (d, J = 8.3 Hz, 2H), 7.58 - 7.55 (m, 2H), 7.52 - 7.41 ( m, 5H), 7.30 (s, 2H), 2.85 (t, J = 7.2 Hz, 2H), other CH 2 overlapped in solvent peak.; LCMS, m/z 329[M+H] +

<실시예 3> 4-(2-((3-(4-(트리플루오로메틸)페닐)프로프-2-인-1-일)아미노)에틸)벤젠설폰아미드의 제조<Example 3> Preparation of 4-(2-((3-(4-(trifluoromethyl)phenyl)prop-2-yn-1-yl)amino)ethyl)benzenesulfonamide

4-(2-아미노에틸)벤젠술폰아미드(201 mg, 1 mmol)를 디메틸포름아미드에 용해시킨 뒤, 상온에서 1-(3-브로모프로프-1-인-1-일)-4-(트리플루오로메틸)벤젠(88 mg, 0.33 mmol)를 첨가한뒤, 5분동안 교반한다. 그리고, DIPEA(0.088 mL, 0.502 mmol)을 첨가하였다. 상온에서 15시간동안 교반한 뒤, 물을 첨가하여 반응을 종결시킨 후, 에틸아세테이트로 희석시키고 물로 씻어주었다. 추출한 유기층은 무수 황산나트륨으로 건조 및 여과한 다음 감압 농축하였다. 얻어진 잔사를 실리카겔 크로마토그래피법(0~50% 에틸아세테이트/헥산)으로 분리 및 정제하여, 목적화합물 4-(2-((3-(4-(트리플루오로메틸)페닐)프로프-2-인-1-일)아미노)에틸)벤젠설폰아미드(70 mg, 55%, 노란색 고체)를 수득하였다.4-(2-Aminoethyl)benzenesulfonamide (201 mg, 1 mmol) was dissolved in dimethylformamide and then dissolved in 1-(3-bromoprop-1-yn-1-yl)-4-( Trifluoromethyl)benzene (88 mg, 0.33 mmol) was added and stirred for 5 minutes. Then, DIPEA (0.088 mL, 0.502 mmol) was added. After stirring at room temperature for 15 hours, the reaction was terminated by adding water, then diluted with ethyl acetate and washed with water. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0~50% ethyl acetate/hexane) to obtain the target compound 4-(2-((3-(4-(trifluoromethyl)phenyl)prop-2- Yin-1-yl)amino)ethyl)benzenesulfonamide (70 mg, 55%, yellow solid) was obtained.

1H NMR (400 MHz, CD3OD) δ 7.85 (d, J = 8.2 Hz, 2H), 7.65 (d, J = 8.2 Hz, 2H), 7.59 (d, J = 8.2 Hz, 2H), 7.45 (d, J = 8.2 Hz, 2H), 3.70 (s, 2H), 3.06 - 2.93 (m, 4H); LCMS, m/z 383[M+H]+ 1 H NMR (400 MHz, CD 3 OD) δ 7.85 (d, J = 8.2 Hz, 2H), 7.65 (d, J = 8.2 Hz, 2H), 7.59 (d, J = 8.2 Hz, 2H), 7.45 ( d, J = 8.2 Hz, 2H), 3.70 (s, 2H), 3.06 - 2.93 (m, 4H); LCMS, m/z 383[M+H] +

<실시예 4> 4-(2-((3-페닐프로프-2-인-1-일)아미노)에틸)벤젠설폰아미드의 제조<Example 4> Preparation of 4-(2-((3-phenylprop-2-yn-1-yl)amino)ethyl)benzenesulfonamide

상기 실시예 3과 유사한 방법으로 목적화합물 4-(2-((3-페닐프로프-2-인-1-일)아미노)에틸)벤젠설폰아미드를 수득하였다.The target compound 4-(2-((3-phenylprop-2-yn-1-yl)amino)ethyl)benzenesulfonamide was obtained in a similar manner to Example 3.

1H NMR (400 MHz, CD3OD) δ 7.85 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 7.42 - 7.38 (m, 2H), 7.34 - 7.31 (m, 3H), 3.66 (s, 2H), 3.08 - 3.01 (m, 2H), 2.96 - 2.91 (m, 2H); LCMS, m/z 315[M+H]+ 1 H NMR (400 MHz, CD 3 OD) δ 7.85 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 7.42 - 7.38 (m, 2H), 7.34 - 7.31 (m , 3H), 3.66 (s, 2H), 3.08 - 3.01 (m, 2H), 2.96 - 2.91 (m, 2H); LCMS, m/z 315[M+H] +

<실시예 5> 4-(2-((3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)벤젠설폰아미드의 제조<Example 5> Preparation of 4-(2-((3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)benzenesulfonamide

상기 실시예 3과 유사한 방법으로 목적화합물 4-(2-((3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)벤젠설폰아미드를 수득하였다.In a manner similar to Example 3, the target compound 4-(2-((3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)benzene Sulfonamide was obtained.

1H NMR (400 MHz, CD3OD) δ 7.86 (d, J = 8.4 Hz, 2H), 7.64 - 7.60 (m, 4H), 7.49 - 7.43 (m, 6H), 7.38 - 7.34 (m, 1H), 4.60 (s, 1H), 3.68 (s, 2H), 3.07 - 3.03 (m, 2H), 2.98 - 2.93 (m, 2H); LCMS, m/z 391[M+H]+ 1 H NMR (400 MHz, CD 3 OD) δ 7.86 (d, J = 8.4 Hz, 2H), 7.64 - 7.60 (m, 4H), 7.49 - 7.43 (m, 6H), 7.38 - 7.34 (m, 1H) , 4.60 (s, 1H), 3.68 (s, 2H), 3.07 - 3.03 (m, 2H), 2.98 - 2.93 (m, 2H); LCMS, m/z 391[M+H] +

<실시예 6> 4-(2-(메틸(3-페닐프로프-2-인-1-일)아미노)에틸)벤젠설폰아미드의 제조<Example 6> Preparation of 4-(2-(methyl(3-phenylprop-2-yn-1-yl)amino)ethyl)benzenesulfonamide

N-메틸-3-페닐프로프-2-인-1-아민(43 mg, 0.30 mmol)를 디메틸포름아미드에 용해시킨 뒤, 상온에서 4-(2-요오도에틸)벤젠술폰아미드(31 mg, 0.100 mmol), DIPEA(0.026 ml, 0.150 mmol)을 첨가하였다. 60 ℃로 가열하고 15시간 동안 가열 교반한 뒤, 증류수를 첨가하여 반응을 종결시키고 에틸아세테이트로 희석시키고 물로 씻어주었다. 추출한 유기층은 무수 황산나트륨으로 건조 및 여과한 다음 감압 농축하였다. 얻어진 잔사를 실리카겔 크로마토그래피법(0~40% 에틸아세테이트/헥산)으로 분리 및 정제하여, 목적화합물 4-(2-(메틸(3-페닐프로프-2-인-1-일)아미노)에틸)벤젠설폰아미드(15 mg, 46%, 노란색 고체)를 수득하였다.N-methyl-3-phenylprop-2-yn-1-amine (43 mg, 0.30 mmol) was dissolved in dimethylformamide and then 4-(2-iodoethyl)benzenesulfonamide (31 mg) at room temperature. , 0.100 mmol), and DIPEA (0.026 ml, 0.150 mmol) were added. After heating to 60°C and heating and stirring for 15 hours, the reaction was terminated by adding distilled water, diluted with ethyl acetate, and washed with water. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0-40% ethyl acetate/hexane) to produce the target compound 4-(2-(methyl(3-phenylprop-2-yn-1-yl)amino)ethyl. ) Benzenesulfonamide (15 mg, 46%, yellow solid) was obtained.

1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 8.4 Hz, 2H), 7.43 - 7.35 (m, 4H), 7.31 - 7.28 (m, 3H), 4.88 (s, 2H), 3.61 (s, 2H), 2.91 - 2.87 (m, 2H), 2.80 - 2.93 (m, 2H), 2.43 (s, 3H); LCMS, m/z 329[M+H]+ 1 H NMR (400 MHz, CDCl 3 ) δ 7.84 (d, J = 8.4 Hz, 2H), 7.43 - 7.35 (m, 4H), 7.31 - 7.28 (m, 3H), 4.88 (s, 2H), 3.61 ( s, 2H), 2.91 - 2.87 (m, 2H), 2.80 - 2.93 (m, 2H), 2.43 (s, 3H); LCMS, m/z 329[M+H] +

<실시예 7> 4-(2-(비스(3-(4-메톡시페닐)프로프-2-인-1-일)아미노)에틸)벤젠설폰아미드의 제조<Example 7> Preparation of 4-(2-(bis(3-(4-methoxyphenyl)prop-2-yn-1-yl)amino)ethyl)benzenesulfonamide

상기 실시예 1과 유사한 방법으로 목적화합물 4-(2-(비스(3-(4-메톡시페닐)프로프-2-인-1-일)아미노)에틸)벤젠설폰아미드를 수득하였다.The target compound 4-(2-(bis(3-(4-methoxyphenyl)prop-2-yn-1-yl)amino)ethyl)benzenesulfonamide was obtained in a similar manner to Example 1.

1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 7.38 - 7.34 (m, 4H), 6.85 - 6.81 (m, 4H), 4.74 (s, 2H), 3.81 (s, 6H), 3.74 (s, 4H), 2.96 (s, 4H); LCMS, m/z 489[M+H]+ 1 H NMR (400 MHz, CDCl 3 ) δ 7.83 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 7.38 - 7.34 (m, 4H), 6.85 - 6.81 (m, 4H), 4.74 (s, 2H), 3.81 (s, 6H), 3.74 (s, 4H), 2.96 (s, 4H); LCMS, m/z 489[M+H] +

<실시예 8> 4-(2-((3-(4-메톡시페닐)프로프-2-인-1-일)아미노)에틸)벤젠설폰아미드의 제조<Example 8> Preparation of 4-(2-((3-(4-methoxyphenyl)prop-2-yn-1-yl)amino)ethyl)benzenesulfonamide

상기 실시예 3과 유사한 방법으로 목적화합물 4-(2-((3-(4-메톡시페닐)프로프-2-인-1-일)아미노)에틸)벤젠설폰아미드를 수득하였다.The target compound 4-(2-((3-(4-methoxyphenyl)prop-2-yn-1-yl)amino)ethyl)benzenesulfonamide was obtained in a similar manner to Example 3.

1H NMR (400 MHz, CDCl3) δ 7.87 - 7.84 (m, 2H), 7.40 (d, J = 8.4 Hz, 2H), 7.35 - 7.31 (m, 2H), 6.84 - 6.80 (m, 2H), 4.80 (s, 2H), 3.80 (s, 3H), 3.65 (s, 2H), 3.06 (t, J = 6.8 Hz, 2H), 2.96 - 2.90 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.87 - 7.84 (m, 2H), 7.40 (d, J = 8.4 Hz, 2H), 7.35 - 7.31 (m, 2H), 6.84 - 6.80 (m, 2H), 4.80 (s, 2H), 3.80 (s, 3H), 3.65 (s, 2H), 3.06 (t, J = 6.8 Hz, 2H), 2.96 - 2.90 (m, 2H).

<실시예 9> 3-([1,1'-비페닐]-4-일)-N-페네틸프로프-2-인-1-아민의 제조<Example 9> Preparation of 3-([1,1'-biphenyl]-4-yl)-N-phenethylprop-2-yn-1-amine

상기 실시예 3과 유사한 방법으로 목적화합물 3-([1,1'-비페닐]-4-일)-N-페네틸프로프-2-인-1-아민을 수득하였다.The target compound 3-([1,1'-biphenyl]-4-yl)-N-phenethylprop-2-yn-1-amine was obtained in a similar manner to Example 3.

1H NMR (400MHz, CDCl3) δ 8.46 (d, J = 8.3 Hz, 1H), 8.34 (s, 1H), 8.13 (d, J =7.5 Hz, 1H), 8.09 (d, J =8.3 Hz, 1H), 7.96 (d, J =8.1 Hz, 1H), 5.24 (brs, 2H, NH2), 4.48 (s, 2H), 4.11 (s, 3H), 3.25 (s, 3H); LCMS, m/z 312[M+H]+ 1H NMR (400MHz, CDCl3) δ 8.46 (d, J = 8.3 Hz, 1H), 8.34 (s, 1H), 8.13 (d, J =7.5 Hz, 1H), 8.09 (d, J =8.3 Hz, 1H ), 7.96 (d, J =8.1 Hz, 1H), 5.24 (brs, 2H, NH2), 4.48 (s, 2H), 4.11 (s, 3H), 3.25 (s, 3H); LCMS, m/z 312[M+H] +

<실시예 10> 4-(((3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)메틸)벤젠설폰아미드의 제조<Example 10> Preparation of 4-(((3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)methyl)benzenesulfonamide

상기 실시예 3과 유사한 방법으로 목적화합물 4-(((3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)메틸)벤젠설폰아미드를 수득하였다.In a manner similar to Example 3, the target compound 4-(((3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)methyl)benzenesulfonamide was obtained.

1H NMR (400MHz, CDCl3) δ 7.91 (d, J = 8.4 Hz, 2H), 7.60 - 7.55 (m, 6H), 7.51 - 7.43 (4H), 7.39-7.35 (m, 1H), 4.79 (s, 2H), 4.05 (s, 2H), 3.68 (s, 2H); LCMS, m/z 489[M]+ 1H NMR (400MHz, CDCl3) δ 7.91 (d, J = 8.4 Hz, 2H), 7.60 - 7.55 (m, 6H), 7.51 - 7.43 (4H), 7.39-7.35 (m, 1H), 4.79 (s, 2H), 4.05 (s, 2H), 3.68 (s, 2H); LCMS, m/z 489[M] +

<실시예 11> 4-((비스(3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)메틸)벤젠설폰아미드의 제조<Example 11> Preparation of 4-((bis(3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)methyl)benzenesulfonamide

상기 실시예 3과 유사한 방법으로 목적화합물 4-((비스(3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)메틸)벤젠설폰아미드를 수득하였다.In a manner similar to Example 3, the target compound 4-((bis(3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)methyl)benzenesulfone The amide was obtained.

1H NMR (400MHz, CDCl3) δ 7.92 (d, J = 7.9 Hz, 2H), 7.63 (d, J = 8.0 Hz, 2H), 7.59 - 7.51 (m, 12H), 7.47 - 7.43 (m, 4H), 7.38 - 7.34 (m, 2H), 4.64 (s, 2H), 3.95 (s, 2H), 3.74 (s, 4H); LCMS, m/z 567[M+H]+ 1H NMR (400MHz, CDCl3) δ 7.92 (d, J = 7.9 Hz, 2H), 7.63 (d, J = 8.0 Hz, 2H), 7.59 - 7.51 (m, 12H), 7.47 - 7.43 (m, 4H) , 7.38 - 7.34 (m, 2H), 4.64 (s, 2H), 3.95 (s, 2H), 3.74 (s, 4H); LCMS, m/z 567[M+H] +

<실시예 12> 3-([1,1'-비페닐]-4-일)-N-(4-클로로펜에틸)프로프-2-인-1-아민의 제조<Example 12> Preparation of 3-([1,1'-biphenyl]-4-yl)-N-(4-chlorophenethyl)prop-2-yn-1-amine

상기 실시예 3과 유사한 방법으로 목적화합물 3-([1,1'-비페닐]-4-일)-N-(4-클로로펜에틸)프로프-2-인-1-아민을 수득하였다.The target compound 3-([1,1'-biphenyl]-4-yl)-N-(4-chlorophenethyl)prop-2-yn-1-amine was obtained in a similar manner to Example 3. .

1H NMR (400MHz, CDCl3) δ 7.59 - 7.52 (m, 4H), 7.48 - 7.42 (m, 4H), 7.37 - 7.33 (m, 1H), 7.29 -7.26 (m, 2H), 7.20 - 7.16 (m, 2H), 3.68 (s, 2H), 3.04 (t, J = 7.1 Hz, 2H), 2.83 (t, J = 7.0 Hz, 2H); LCMS, m/z 346[M+H]+ 1H NMR (400MHz, CDCl3) δ 7.59 - 7.52 (m, 4H), 7.48 - 7.42 (m, 4H), 7.37 - 7.33 (m, 1H), 7.29 -7.26 (m, 2H), 7.20 - 7.16 (m , 2H), 3.68 (s, 2H), 3.04 (t, J = 7.1 Hz, 2H), 2.83 (t, J = 7.0 Hz, 2H); LCMS, m/z 346[M+H] +

<실시예 13> 3-([1,1'-바이페닐]-4-일)-N-(3-([1,1'-바이페닐]-4-일)프로프-2-인-1-일)-N-(4-클로로페네틸)프로프-2-인-1-아민의 제조<Example 13> 3-([1,1'-biphenyl]-4-yl)-N-(3-([1,1'-biphenyl]-4-yl)prop-2-yne- Preparation of 1-yl)-N-(4-chlorophenethyl)prop-2-yn-1-amine

상기 실시예 3과 유사한 방법으로 목적화합물 3-([1,1'-바이페닐]-4-일)-N-(3-([1,1'-바이페닐]-4-일)프로프-2-인-1-일)-N-(4-클로로페네틸)프로프-2-인-1-아민을 수득하였다.In a similar manner to Example 3, the target compound 3-([1,1'-biphenyl]-4-yl)-N-(3-([1,1'-biphenyl]-4-yl)prop -2-yn-1-yl)-N-(4-chlorophenethyl)prop-2-yn-1-amine was obtained.

1H NMR (400MHz, CDCl3) δ 7.59 - 7.57 (m, 4H), 7.55 - 7.46 (m, 8H), 7.46 - 7.42 (m, 4H), 7.38 -7.34 (m, 2H), 7.27 - 7.25 (m, 2H), 7.22 - 7.20 (m, 2H), 3.81 (s, 4H), 2.99 - 2.95 (m, 2H), 2.91 - 2.86 (m, 2H); LCMS, m/z 536[M+H]+ 1H NMR (400MHz, CDCl3) δ 7.59 - 7.57 (m, 4H), 7.55 - 7.46 (m, 8H), 7.46 - 7.42 (m, 4H), 7.38 -7.34 (m, 2H), 7.27 - 7.25 (m) , 2H), 7.22 - 7.20 (m, 2H), 3.81 (s, 4H), 2.99 - 2.95 (m, 2H), 2.91 - 2.86 (m, 2H); LCMS, m/z 536[M+H] +

<실시예 14> 4-(2-((3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)페놀의 제조<Example 14> Preparation of 4-(2-((3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)phenol

상기 실시예 3과 유사한 방법으로 목적화합물 4-(2-((3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)페놀을 수득하였다.In a manner similar to Example 3, the target compound 4-(2-((3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)phenol was obtained.

1H NMR (400MHz, CDCl3) δ 7.59 - 7.56 (m, 2H), 7.55 - 7.52 (m, 2H), 7.48 - 7.42 (m, 4H), 7.37 -7.33 (m, 1H), 7.12 - 7.09 (m, 2H), 6.78 - 6.75 (m, 2H), 3.68 (s, 2H), 3.03 (t, J = 7.0 Hz, 2H), 2.80 (t, J = 7.0 Hz, 2H); LCMS, m/z 328[M+H]+ 1H NMR (400MHz, CDCl3) δ 7.59 - 7.56 (m, 2H), 7.55 - 7.52 (m, 2H), 7.48 - 7.42 (m, 4H), 7.37 -7.33 (m, 1H), 7.12 - 7.09 (m , 2H), 6.78 - 6.75 (m, 2H), 3.68 (s, 2H), 3.03 (t, J = 7.0 Hz, 2H), 2.80 (t, J = 7.0 Hz, 2H); LCMS, m/z 328[M+H] +

<실시예 15> 4-(2-(비스(3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)페놀의 제조<Example 15> Preparation of 4-(2-(bis(3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)phenol

상기 실시예 3과 유사한 방법으로 목적화합물 4-(2-(비스(3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)페놀을 수득하였다.In a similar manner to Example 3, the target compound 4-(2-(bis(3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl) Phenol was obtained.

1H NMR (400MHz, CDCl3) δ 7.59 - 7.57 (m, 4H), 7.55 - 7.50 (m, 8H), 7.46 - 7.42 (m, 4H), 7.38 -7.34 (m, 2H), 7.15 - 7.13 (m, 2H), 6.78 - 6.76 (m, 2H), 5.00 (s, 1H), 3.82 (s, 4H), 2.97 - 2.93 (m, 2H), 2.87 - 2.83 (m, 2H); LCMS, m/z 518[M+H]+ 1H NMR (400MHz, CDCl3) δ 7.59 - 7.57 (m, 4H), 7.55 - 7.50 (m, 8H), 7.46 - 7.42 (m, 4H), 7.38 -7.34 (m, 2H), 7.15 - 7.13 (m) , 2H), 6.78 - 6.76 (m, 2H), 5.00 (s, 1H), 3.82 (s, 4H), 2.97 - 2.93 (m, 2H), 2.87 - 2.83 (m, 2H); LCMS, m/z 518[M+H] +

<실시예 16> 3-([1,1'-비페닐]-4-일)-N-(2-(벤조[d][1,3]디옥솔-5-일)에틸)프로프-2-인-1-아민의 제조<Example 16> 3-([1,1'-biphenyl]-4-yl)-N-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)prop- Preparation of 2-phospho-1-amine

상기 실시예 3과 유사한 방법으로 목적화합물 3-([1,1'-비페닐]-4-일)-N-(2-(벤조[d][1,3]디옥솔-5-일)에틸)프로프-2-인-1-아민을 수득하였다.In a similar manner to Example 3, the target compound 3-([1,1'-biphenyl]-4-yl)-N-(2-(benzo[d][1,3]dioxol-5-yl) Ethyl)prop-2-yn-1-amine was obtained.

1H NMR (400MHz, CDCl3) δ 7.59 - 7.56 (m, 2H), 7.55 - 7.52 (m, 2H), 7.49 - 7.42 (m, 4H), 7.37 -7.33 (m, 1H), 6.76 - 6.68 (m, 3H), 5.93 (s, 2H), 3.68 (s, 2H), 3.01 (t, J = 7.0 Hz, 2H), 2.79 (t, J = 7.0 Hz, 2H); LCMS, m/z 356[M+H]+ 1H NMR (400MHz, CDCl3) δ 7.59 - 7.56 (m, 2H), 7.55 - 7.52 (m, 2H), 7.49 - 7.42 (m, 4H), 7.37 -7.33 (m, 1H), 6.76 - 6.68 (m , 3H), 5.93 (s, 2H), 3.68 (s, 2H), 3.01 (t, J = 7.0 Hz, 2H), 2.79 (t, J = 7.0 Hz, 2H); LCMS, m/z 356[M+H] +

<실시예 17> 3-([1,1'-바이페닐]-4-일)-N-(3-([1,1'-바이페닐]-4-일)프로프-2-인-1-일)-N-(2-(벤조[d][1,3]디옥솔-5-일)에틸)프로프-2-인-1-아민의 제조<Example 17> 3-([1,1'-biphenyl]-4-yl)-N-(3-([1,1'-biphenyl]-4-yl)prop-2-yne- Preparation of 1-yl)-N-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)prop-2-yn-1-amine

상기 실시예 3과 유사한 방법으로 목적화합물 3-([1,1'-바이페닐]-4-일)-N-(3-([1,1'-바이페닐]-4-일)프로프-2-인-1-일)-N-(2-(벤조[d][1,3]디옥솔-5-일)에틸)프로프-2-인-1-아민을 수득하였다.In a similar manner to Example 3, the target compound 3-([1,1'-biphenyl]-4-yl)-N-(3-([1,1'-biphenyl]-4-yl)prop -2-yn-1-yl)-N-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)prop-2-yn-1-amine was obtained.

1H NMR (400MHz, CDCl3) δ 7.59 - 7.56 (m, 4H), 7.55 - 7.50 (m, 8H), 7.46 - 7.42 (m, 4H), 7.37 -7.33 (m, 2H), 6.78 - 6.73 (m, 3H), 5.92 (s, 2H), 3.81 (s, 4H), 2.97 - 2.93 (m, 2H), 2.86 - 2.82 (m, 2H); LCMS, m/z 546[M+H]+ 1H NMR (400MHz, CDCl3) δ 7.59 - 7.56 (m, 4H), 7.55 - 7.50 (m, 8H), 7.46 - 7.42 (m, 4H), 7.37 -7.33 (m, 2H), 6.78 - 6.73 (m) , 3H), 5.92 (s, 2H), 3.81 (s, 4H), 2.97 - 2.93 (m, 2H), 2.86 - 2.82 (m, 2H); LCMS, m/z 546[M+H] +

<실시예 18> 3-([1,1'-비페닐]-4-일)-N-(2,2-디페닐에틸)프로프-2-인-1-아민의 제조<Example 18> Preparation of 3-([1,1'-biphenyl]-4-yl)-N-(2,2-diphenylethyl)prop-2-yn-1-amine

상기 실시예 3과 유사한 방법으로 목적화합물 3-([1,1'-비페닐]-4-일)-N-(2,2-디페닐에틸)프로프-2-인-1-아민을 수득하였다.The target compound 3-([1,1'-biphenyl]-4-yl)-N-(2,2-diphenylethyl)prop-2-yn-1-amine was prepared in a manner similar to Example 3 above. Obtained.

1H NMR (400MHz, CDCl3) δ 7.60 - 7.53 (m, 4H), 7.50 - 7.42 (m, 4H), 7.38 - 7.29 (m, 9H), 7.23 -7.19 (m, 2H), 4.25 (t, J = 7.7 Hz, 1H), 3.69 (s, 2H), 3.42 (d, J = 7.7 Hz, 2H); LCMS, m/z 388[M+H]+ 1H NMR (400MHz, CDCl3) δ 7.60 - 7.53 (m, 4H), 7.50 - 7.42 (m, 4H), 7.38 - 7.29 (m, 9H), 7.23 -7.19 (m, 2H), 4.25 (t, J = 7.7 Hz, 1H), 3.69 (s, 2H), 3.42 (d, J = 7.7 Hz, 2H); LCMS, m/z 388[M+H] +

<실시예 19> 3-([1,1'-바이페닐]-4-일)-N-(3-([1,1'-바이페닐]-4-일)프로프-2-인-1-일)-N-(2,2-디페닐에틸)프로프-2-인-1-아민의 제조<Example 19> 3-([1,1'-biphenyl]-4-yl)-N-(3-([1,1'-biphenyl]-4-yl)prop-2-yne- Preparation of 1-yl)-N-(2,2-diphenylethyl)prop-2-yn-1-amine

상기 실시예 3과 유사한 방법으로 목적화합물 3-([1,1'-바이페닐]-4-일)-N-(3-([1,1'-바이페닐]-4-일)프로프-2-인-1-일)-N-(2,2-디페닐에틸)프로프-2-인-1-아민을 수득하였다.In a similar manner to Example 3, the target compound 3-([1,1'-biphenyl]-4-yl)-N-(3-([1,1'-biphenyl]-4-yl)prop -2-yn-1-yl)-N-(2,2-diphenylethyl)prop-2-yn-1-amine was obtained.

1H NMR (400MHz, CDCl3) δ 7.59 - 7.56 (m, 4H), 7.55 - 7.49 (m, 8H), 7.46 - 7.42 (m, 4H), 7.38 -7.27 (m, 10H), 7.22 - 7.18 (m, 2H), 4.34 (t, J = 7.8 Hz, 1H), 3.75 (s, 4H), 3.40 (d, J = 7.9 Hz, 2H); LCMS, m/z 578[M+H]+ 1H NMR (400MHz, CDCl3) δ 7.59 - 7.56 (m, 4H), 7.55 - 7.49 (m, 8H), 7.46 - 7.42 (m, 4H), 7.38 -7.27 (m, 10H), 7.22 - 7.18 (m , 2H), 4.34 (t, J = 7.8 Hz, 1H), 3.75 (s, 4H), 3.40 (d, J = 7.9 Hz, 2H); LCMS, m/z 578[M+H] +

<실시예 20> 3-([1,1'-비페닐]-4-일)-N-(4-모르폴리노펜에틸)프로프-2-인-1-아민의 제조<Example 20> Preparation of 3-([1,1'-biphenyl]-4-yl)-N-(4-morpholinophenethyl)prop-2-yn-1-amine

상기 실시예 3과 유사한 방법으로 목적화합물 3-([1,1'-비페닐]-4-일)-N-(4-모르폴리노펜에틸)프로프-2-인-1-아민을 수득하였다.The target compound 3-([1,1'-biphenyl]-4-yl)-N-(4-morpholinophenethyl)prop-2-yn-1-amine was obtained in a similar manner to Example 3. did.

1H NMR (400MHz, CDCl3) δ 7.58 (d, J = 8.6 Hz, 2H), 7.53 (d, J = 8.3 Hz, 2H), 7.48 - 7.42 (m, 4H), 7.35 (t, J = 7.4 Hz, 1H), 7.16 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 3.86 (t, J = 4.8 Hz, 4H), 3.67 (s, 2H), 3.13 (t, J = 4.8 Hz, 4H), 3.02 (t, J = 7.0 Hz, 2H), 2.80 (t, J = 7.0 Hz, 2H); LCMS, m/z 397[M+H]+ 1 H NMR (400MHz, CDCl3) δ 7.58 (d, J = 8.6 Hz, 2H), 7.53 (d, J = 8.3 Hz, 2H), 7.48 - 7.42 (m, 4H), 7.35 (t, J = 7.4 Hz) , 1H), 7.16 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 3.86 (t, J = 4.8 Hz, 4H), 3.67 (s, 2H), 3.13 (t , J = 4.8 Hz, 4H), 3.02 (t, J = 7.0 Hz, 2H), 2.80 (t, J = 7.0 Hz, 2H); LCMS, m/z 397[M+H] +

<실시예 21> 3-([1,1'-바이페닐]-4-일)-N-(3-([1,1'-바이페닐]-4-일)프로프-2-인-1-일)-N-(4-모르폴리노펜에틸)프로프-2-인-1-아민의 제조<Example 21> 3-([1,1'-biphenyl]-4-yl)-N-(3-([1,1'-biphenyl]-4-yl)prop-2-yne- Preparation of 1-yl)-N-(4-morpholinophenethyl)prop-2-yn-1-amine

상기 실시예 3과 유사한 방법으로 목적화합물 3-([1,1'-바이페닐]-4-일)-N-(3-([1,1'-바이페닐]-4-일)프로프-2-인-1-일)-N-(4-모르폴리노펜에틸)프로프-2-인-1-아민을 수득하였다.In a similar manner to Example 3, the target compound 3-([1,1'-biphenyl]-4-yl)-N-(3-([1,1'-biphenyl]-4-yl)prop -2-yn-1-yl)-N-(4-morpholinophenethyl)prop-2-yn-1-amine was obtained.

1H NMR (400MHz, CDCl3) δ 7.58 (d, J = 8.6 Hz, 4H), 7.55 - 7.50 (m, 8H), 7.46 - 7.42 (m, 4H), 7.37 - 7.35 (m, 2H), 7.19 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 3.85 (t, J = 4.8 Hz, 4H), 3.82 (s, 4H), 3.12 (t, J = 4.8 Hz, 4H), 2.97 - 2.93 (m, 2H), 2.87 - 2.83 (m, 2H); LCMS, m/z 587[M+H]+ 1H NMR (400MHz, CDCl3) δ 7.58 (d, J = 8.6 Hz, 4H), 7.55 - 7.50 (m, 8H), 7.46 - 7.42 (m, 4H), 7.37 - 7.35 (m, 2H), 7.19 ( d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 3.85 (t, J = 4.8 Hz, 4H), 3.82 (s, 4H), 3.12 (t, J = 4.8 Hz, 4H), 2.97 - 2.93 (m, 2H), 2.87 - 2.83 (m, 2H); LCMS, m/z 587[M+H] +

<실시예 22> 2-(1-((3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)-4-클로로페놀의 제조<Example 22> 2-(1-((3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)-4-chlorophenol manufacturing

단계 1 : 2-(1-아미노에틸)-4-클로로페놀의 제조Step 1: Preparation of 2-(1-aminoethyl)-4-chlorophenol

1-(5-클로로-2-하이드록시페닐)에타논(341 mg, 2 mmol)을 7N 암모니아(메탄올 혼합용액)(4 mL, 28 mmol)에 직접 용해시킨 뒤, 상온에서 15시간동안 교반하였다. 혼합물을 감압 농축하여, 목적화합물 4-클로로-2-(1-이미노에틸)페놀(330 mg, 97%, 노란색 고체)을 수득하였다. 1-(5-Chloro-2-hydroxyphenyl)ethanone (341 mg, 2 mmol) was directly dissolved in 7N ammonia (methanol mixed solution) (4 mL, 28 mmol) and stirred at room temperature for 15 hours. . The mixture was concentrated under reduced pressure to obtain the target compound, 4-chloro-2-(1-iminoethyl)phenol (330 mg, 97%, yellow solid).

앞서 얻어진 4-클로로-2-(1-이미노에틸)페놀(156 mg, 0.92 mmol)을 테트라하이드로퓨란에 용해시킨 뒤, Ti(OiPr)4 (0.323 ml, 1.10 mmol)을 첨가하였다. 상온에서 30분 동안 교반한 뒤, 1M BH3(테트라하이드로퓨란 혼합용액)(1.2 mL, 1.2 mmol)을 5분동안 천천히 적가하였다. 1시간동안 교반한 뒤, 1M HCl 수용액(3 mL)을 천천히 첨가하고 1시간동안 교반하였다. 그리고 과포화 탄산수소나트륨 수용액(10 mL)를 첨가하고 30분동안 교반하였다. 혼합물을 셀라이트에 여과한 후, 여과된 잔사를 에틸아세테이트로 추출하였다. 유기층의 잔류물은 무수 황산나트륨으로 건조 및 여과한 다음 감압 농축하여, 목적화합물 2-(1-아미노에틸)-4-클로로페놀 (150 mg, 91%, 노란색 고체)을 수득하였다.The previously obtained 4-chloro-2-(1-iminoethyl)phenol (156 mg, 0.92 mmol) was dissolved in tetrahydrofuran, and then Ti(OiPr) 4 (0.323 ml, 1.10 mmol) was added. After stirring at room temperature for 30 minutes, 1M BH3 (tetrahydrofuran mixed solution) (1.2 mL, 1.2 mmol) was slowly added dropwise over 5 minutes. After stirring for 1 hour, 1M HCl aqueous solution (3 mL) was slowly added and stirred for 1 hour. Then, supersaturated aqueous sodium bicarbonate solution (10 mL) was added and stirred for 30 minutes. The mixture was filtered through Celite, and the filtered residue was extracted with ethyl acetate. The residue of the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target compound 2-(1-aminoethyl)-4-chlorophenol (150 mg, 91%, yellow solid).

단계 2 : 2-(1-((3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)-4-클로로페놀의 제조Step 2: Preparation of 2-(1-((3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)-4-chlorophenol

상기 실시예 3과 유사한 방법으로 목적화합물 2-(1-((3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)-4-클로로페놀을 수득하였다. In a similar manner to Example 3, the target compound 2-(1-((3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)- 4-chlorophenol was obtained.

1H NMR (400 MHz, CDCl3) δ 11.0 (s, 1H), 7.60 - 7.54 (m, 4H), 7.50 - 7.41 (m, 4H), 7.11 (d of d, J = 2.6 Hz, 8.6 Hz, 1H), 7.00 (d, J = 2.6 Hz, 1H), 6.76 (d, J = 8.6 Hz, 1H), 4.24 (q, J = 6.7 Hz, 1H), 3.75 (d, J = 17.2 Hz, 1H), 3.53 (d, J = 17.2 Hz, 1H), 1.49 (d, J = 6.7 Hz, 3H); LCMS, m/z 362[M+H]+ 1 H NMR (400 MHz, CDCl 3 ) δ 11.0 (s, 1H), 7.60 - 7.54 (m, 4H), 7.50 - 7.41 (m, 4H), 7.11 (d of d, J = 2.6 Hz, 8.6 Hz, 1H), 7.00 (d, J = 2.6 Hz, 1H), 6.76 (d, J = 8.6 Hz, 1H), 4.24 (q, J = 6.7 Hz, 1H), 3.75 (d, J = 17.2 Hz, 1H) , 3.53 (d, J = 17.2 Hz, 1H), 1.49 (d, J = 6.7 Hz, 3H); LCMS, m/z 362[M+H] +

<실시예 23> 4-클로로-2-(1-((3-(4-메톡시페닐)프로프-2-인-1-일)아미노)에틸)페놀의 제조<Example 23> Preparation of 4-chloro-2-(1-((3-(4-methoxyphenyl)prop-2-yn-1-yl)amino)ethyl)phenol

상기 실시예 22와 유사한 방법으로 목적화합물 4-클로로-2-(1-((3-(4-메톡시페닐)프로프-2-인-1-일)아미노)에틸)페놀을 수득하였다. The target compound 4-chloro-2-(1-((3-(4-methoxyphenyl)prop-2-yn-1-yl)amino)ethyl)phenol was obtained in a similar manner to Example 22.

1H NMR (400 MHz, CDCl3) δ 7.37 - 7.33 (m, 2H), 7.10 (d of d, J = 2.6 Hz, 8.6 Hz, 1H), 6.99 (d, J = 2.6 Hz, 1H), 6.86 - 6.82 (m, 2H), 6.75 (d, J = 8.7 Hz, 1H), 4.21 (q, J = 6.8 Hz, 1H), 3.81 (s, 3H), 3.70 (d, J = 17.3 Hz, 1H), 3.47 (d, J = 17.3 Hz, 1H), 1.46 (d, J = 6.8 Hz, 3H); LCMS, m/z 316[M+H]+ 1 H NMR (400 MHz, CDCl 3 ) δ 7.37 - 7.33 (m, 2H), 7.10 (d of d, J = 2.6 Hz, 8.6 Hz, 1H), 6.99 (d, J = 2.6 Hz, 1H), 6.86 - 6.82 (m, 2H), 6.75 (d, J = 8.7 Hz, 1H), 4.21 (q, J = 6.8 Hz, 1H), 3.81 (s, 3H), 3.70 (d, J = 17.3 Hz, 1H) , 3.47 (d, J = 17.3 Hz, 1H), 1.46 (d, J = 6.8 Hz, 3H); LCMS, m/z 316[M+H] +

<실시예 24> 4-(2-((3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)(메틸)아미노)에틸)벤젠설폰아미드의 제조<Example 24> 4-(2-((3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)(methyl)amino)ethyl)benzenesulfonamide manufacture of

상기 실시예 6과 유사한 방법으로 목적화합물 4-(2-((3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)(메틸)아미노)에틸)벤젠설폰아미드를 수득하였다.In a similar manner to Example 6, the target compound 4-(2-((3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)(methyl)amino) Ethyl)benzenesulfonamide was obtained.

1H NMR (400 MHz, CD3OD) δ 7.87 - 7.83 (m, 2H), 7.65- 7.60 (m, 4H), 7.52 - 7.43 (m, 6H), 7.38- 7.34 (m, 1H), 3.68 (s, 2H), 2.97 - 2.94 (m, 2H), 2.87 - 2.83 (m, 2H), 2.49 (s, 3H); LCMS, m/z 405[M+H]+ 1 H NMR (400 MHz, CD 3 OD) δ 7.87 - 7.83 (m, 2H), 7.65 - 7.60 (m, 4H), 7.52 - 7.43 (m, 6H), 7.38 - 7.34 (m, 1H), 3.68 ( s, 2H), 2.97 - 2.94 (m, 2H), 2.87 - 2.83 (m, 2H), 2.49 (s, 3H); LCMS, m/z 405[M+H] +

<실시예 25> 3-([1,1'-비페닐]-4-일)-N-(4-(메틸설포닐)페네틸)프로프-2-인-1-아민의 제조<Example 25> Preparation of 3-([1,1'-biphenyl]-4-yl)-N-(4-(methylsulfonyl)phenethyl)prop-2-yn-1-amine

상기 실시예 3과 유사한 방법으로 목적화합물 3-([1,1'-비페닐]-4-일)-N-(4-(메틸설포닐)페네틸)프로프-2-인-1-아민을 수득하였다. In a similar manner to Example 3, the target compound 3-([1,1'-biphenyl]-4-yl)-N-(4-(methylsulfonyl)phenethyl)prop-2-yne-1- The amine was obtained.

1H NMR (400MHz, CDCl3) δ 7.88 (d, J = 8.4 Hz, 2H), 7.59 - 7.53 (m, 4H), 7.48 - 7.42 (m, 6H), 7.38 - 7.34 (m, 1H), 3.70 (s, 2H), 3.10 (t, J = 7.0 Hz, 2H), 3.04 (s, 3H), 2.96 (t, J = 7.0 Hz, 2H); LCMS, m/z 390[M+H]+ 1 H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.4 Hz, 2H), 7.59 - 7.53 (m, 4H), 7.48 - 7.42 (m, 6H), 7.38 - 7.34 (m, 1H), 3.70 ( s, 2H), 3.10 (t, J = 7.0 Hz, 2H), 3.04 (s, 3H), 2.96 (t, J = 7.0 Hz, 2H); LCMS, m/z 390[M+H] +

<실시예 26> 3-([1,1'-바이페닐]-4-일)-N-(3-([1,1'-바이페닐]-4-일)프로프-2-인-1-일)-N-(4-(메틸설포닐)페네틸)프로프-2-인-1-아민의 제조<Example 26> 3-([1,1'-biphenyl]-4-yl)-N-(3-([1,1'-biphenyl]-4-yl)prop-2-yne- Preparation of 1-yl)-N-(4-(methylsulfonyl)phenethyl)prop-2-yn-1-amine

상기 실시예 3과 유사한 방법으로 목적화합물 3-([1,1'-바이페닐]-4-일)-N-(3-([1,1'-바이페닐]-4-일)프로프-2-인-1-일)-N-(4-(메틸설포닐)페네틸)프로프-2-인-1-아민을 수득하였다.In a similar manner to Example 3, the target compound 3-([1,1'-biphenyl]-4-yl)-N-(3-([1,1'-biphenyl]-4-yl)prop -2-yn-1-yl)-N-(4-(methylsulfonyl)phenethyl)prop-2-yn-1-amine was obtained.

1H NMR (400MHz, CDCl3) δ 7.99 - 7.97 (m, 2H), 7.59 - 7.57 (m, 4H), 7.55 - 7.49 (m, 8H), 7.46 - 7.42 (m, 4H), 7.38 - 7.34 (m, 4H), 3.81 (s, 4H), 3.03 (s, 7H); LCMS, m/z 580[M+H]+ 1H NMR (400MHz, CDCl3) δ 7.99 - 7.97 (m, 2H), 7.59 - 7.57 (m, 4H), 7.55 - 7.49 (m, 8H), 7.46 - 7.42 (m, 4H), 7.38 - 7.34 (m) , 4H), 3.81 (s, 4H), 3.03 (s, 7H); LCMS, m/z 580[M+H] +

<실시예 27> 메틸 4-(2-((3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)벤조에이트의 제조<Example 27> Preparation of methyl 4-(2-((3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)benzoate

상기 실시예 3과 유사한 방법으로 목적화합물 메틸 4-(2-((3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)벤조에이트를 수득하였다.In a similar manner to Example 3, the target compound methyl 4-(2-((3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl) Benzoate was obtained.

1H NMR (400MHz, CDCl3) δ 7.94 (d, J = 8.1 Hz, 2H), 7.52 - 7.40 (m, 8H), 7.36 (d, J = 7.2 Hz, 1H), 7.24 (d, J = 8.3 Hz, 2H), 4.01 (s, 2H), 3.86 (s, 3H), 3.36 (t, J = 8.1 Hz, 2H), 3.11 (t, J = 8.1 Hz, 2H); LCMS, m/z 370[M+H]+ 1 H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 8.1 Hz, 2H), 7.52 - 7.40 (m, 8H), 7.36 (d, J = 7.2 Hz, 1H), 7.24 (d, J = 8.3 Hz) , 2H), 4.01 (s, 2H), 3.86 (s, 3H), 3.36 (t, J = 8.1 Hz, 2H), 3.11 (t, J = 8.1 Hz, 2H); LCMS, m/z 370[M+H] +

<실시예 28> 메틸 4-(2-(비스(3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)벤조에이트의 제조<Example 28> Preparation of methyl 4-(2-(bis(3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)benzoate

상기 실시예 3과 유사한 방법으로 목적화합물 메틸 4-(2-(비스(3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)벤조에이트를 수득하였다.In a similar manner to Example 3, the target compound methyl 4-(2-(bis(3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl ) Benzoate was obtained.

1H NMR (400MHz, CDCl3) δ 7.98 (d, J = 8.3 Hz, 2H), 7.59 - 7.57 (m, 4H), 7.55 - 7.49 (m, 8H), 7.46 - 7.42 (m, 4H), 7.38 - 7.34 (m, 4H), 3.90 (s, 3H), 3.82 (s, 4H), 3.03 - 2.96 (m, 4H); LCMS, m/z 560[M+H]+ 1 H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 8.3 Hz, 2H), 7.59 - 7.57 (m, 4H), 7.55 - 7.49 (m, 8H), 7.46 - 7.42 (m, 4H), 7.38 - 7.34 (m, 4H), 3.90 (s, 3H), 3.82 (s, 4H), 3.03 - 2.96 (m, 4H); LCMS, m/z 560[M+H] +

<실시예 29> 4-(2-((3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)벤조산의 제조<Example 29> Preparation of 4-(2-((3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)benzoic acid

상기 실시예 27에서 제조한 화합물 메틸 4-(2-((3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)벤조에이트(100 mg, 0.27 mmol)를 테트라하이드로퓨란에 용해시킨 뒤, 1M 수산화리튬 수용액(0.8 mL, 0.812 mmol)을 첨가하였다. 50 ℃에서 15시간동안 교반한 뒤, 1M HCl 수용액을 첨가하여 반응을 종결시켰다. 혼합물을 에틸아세테이트로 희석시킨 뒤, 물과 소금물로 씻어 주었다. 유기층의 잔류물은 무수 황산나트륨으로 건조 및 여과한 다음 감압 농축하였다. 얻어진 잔사를 실리카겔 크로마토그래피법으로 분리 및 정제하여, 목적화합물 4-(2-((3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)벤조산(20 mg, 20%, 흰색 고체)을 수득하였다.Compound methyl 4-(2-((3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)benzoate prepared in Example 27 (100 mg, 0.27 mmol) was dissolved in tetrahydrofuran, and then 1M lithium hydroxide aqueous solution (0.8 mL, 0.812 mmol) was added. After stirring at 50°C for 15 hours, the reaction was terminated by adding 1M HCl aqueous solution. The mixture was diluted with ethyl acetate and washed with water and salt water. The residue of the organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography, and the target compound 4-(2-((3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl) Amino)ethyl)benzoic acid (20 mg, 20%, white solid) was obtained.

1H NMR (400MHz, MeOD) δ 8.05 (dd, J = 8.3, 1.8 Hz, 2H), 7.70 - 7.65 (m, 4H), 7.60 (d, J = 8.5 Hz, 2H), 7.50 - 7.45 (m, 4H), 7.41 - 7.37 (m, 1H), 4.25 (s, 2H), 3.49 (t, J = 7.9 Hz, 2H), 3.15 (t, J = 7.7 Hz, 2H); LCMS, m/z 356[M+H]+ 1 H NMR (400 MHz, MeOD) δ 8.05 (dd, J = 8.3, 1.8 Hz, 2H), 7.70 - 7.65 (m, 4H), 7.60 (d, J = 8.5 Hz, 2H), 7.50 - 7.45 (m, 4H), 7.41 - 7.37 (m, 1H), 4.25 (s, 2H), 3.49 (t, J = 7.9 Hz, 2H), 3.15 (t, J = 7.7 Hz, 2H); LCMS, m/z 356[M+H] +

<실시예 30> 4-(2-(비스(3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)벤조산의 제조<Example 30> Preparation of 4-(2-(bis(3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)benzoic acid

상기 실시예 29와 유사한 방법으로 목적화합물 4-(2-(비스(3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)벤조산을 수득하였다.In a similar manner to Example 29, the target compound 4-(2-(bis(3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl) Benzoic acid was obtained.

1H NMR (400MHz, CDCl3) δ 8.03 (d, J = 8.1 Hz, 2H), 7.59 - 7.50 (m, 12H), 7.46 - 7.34 (m, 9H), 4.04 (s, 4H), 3.25 - 3.23 (m, 2H), 3.12 - 3.08 (m, 2H); LCMS, m/z 546[M+H]+ 1H NMR (400MHz, CDCl3) δ 8.03 (d, J = 8.1 Hz, 2H), 7.59 - 7.50 (m, 12H), 7.46 - 7.34 (m, 9H), 4.04 (s, 4H), 3.25 - 3.23 ( m, 2H), 3.12 - 3.08 (m, 2H); LCMS, m/z 546[M+H] +

<실시예 31> 4-(2-((3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)(메틸)아미노)에틸)페놀의 제조<Example 31> Preparation of 4-(2-((3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)(methyl)amino)ethyl)phenol

상기 실시예 14에서 제조한 4-(2-((3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)페놀(33 mg, 0.10 mmol)을 테트라하이드로퓨란에 용해시킨 뒤, 파라포름알데하이드(12 mg, 0.40 mmol), 소듐트리아세톡시보로하이드라이드(106 mg, 0.50 mmol), 아세트산(0.035 mL, 0.60 mmol)을 첨가하였다. 60 ℃에서 2시간동안 교반한 뒤, 증류수를 첨가하여 반응을 종결시킨 후, 에틸아세테이트에 희석시키고 물로 씻어주었다. 유기층의 잔류물은 무수 황산나트륨으로 건조 및 여과한 다음 감압 농축하였다. 얻어진 잔사를 실리카겔 크로마토그래피법(0~70% 에틸아세테이트/헥산)으로 분리 및 정제하여, 목적화합물 4-(2-((3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)(메틸)아미노)에틸)페놀(20 mg, 60%, 흰색 고체)을 수득하였다.4-(2-((3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)phenol (33 mg) prepared in Example 14 , 0.10 mmol) was dissolved in tetrahydrofuran, then paraformaldehyde (12 mg, 0.40 mmol), sodium triacetoxyborohydride (106 mg, 0.50 mmol), and acetic acid (0.035 mL, 0.60 mmol) were added. . After stirring at 60°C for 2 hours, the reaction was terminated by adding distilled water, then diluted with ethyl acetate and washed with water. The residue of the organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0~70% ethyl acetate/hexane) to produce the target compound 4-(2-((3-([1,1'-biphenyl]-4-yl)pro. P-2-yn-1-yl)(methyl)amino)ethyl)phenol (20 mg, 60%, white solid) was obtained.

1H NMR (400 MHz, CD3OD) δ 7.70 - 7.60 (m, 6H), 7.49 - 7.45 (m, 2H), 7.41 - 7.37 (m, 1H), 7.17 (d, J = 8.4 Hz, 2H), 6.81 - 6.76 (m, 2H), 4.34 (s, 2H), 3.45 (broad s, 2H), 3.03 - 3.00 (m, 5H); LCMS, m/z 342[M+H]+ 1 H NMR (400 MHz, CD 3 OD) δ 7.70 - 7.60 (m, 6H), 7.49 - 7.45 (m, 2H), 7.41 - 7.37 (m, 1H), 7.17 (d, J = 8.4 Hz, 2H) , 6.81 - 6.76 (m, 2H), 4.34 (s, 2H), 3.45 (broad s, 2H), 3.03 - 3.00 (m, 5H); LCMS, m/z 342[M+H] +

<실시예 32> 4-(1-((3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)옥시)에틸)-3,5-디클로로피리딘의 제조<Example 32> 4-(1-((3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)oxy)ethyl)-3,5-dichloro Preparation of pyridine

1-(3,5-디클로로피리딘-4-일)에탄올(160 mg, 0.83 mmol)을 테트라하이드로퓨란에 용해시킨 뒤, 0 ℃에서 60% 소듐하이드라이드(30 mg, 1.25 mmol)를 천천히 첨가하였다. 20분동안 교반한 뒤, 4-(3-브로모프로피-1-닐)-1,1'-바이페닐(0.339 g, 1.25 mmol)을 첨가하였다. 상온에서 15시간동안 교반한 뒤, 염화암모늄 수용액을 첨가하여 반응을 종결시킨다. 에틸아세테이트로 희석시키고 물로 씻어주었다. 추출한 유기층은 무수 황산나트륨으로 건조 및 여과한 다음 감압 농축하였다. 얻어진 잔사를 실리카겔 크로마토그래피법(0~10% 에틸아세테이트/헥산)으로 분리 및 정제하여, 목적화합물 4-(1-((3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)옥시)에틸)-3,5-디클로로피리딘(142 mg, 44%, 무색 액체)을 수득하였다.1-(3,5-dichloropyridin-4-yl)ethanol (160 mg, 0.83 mmol) was dissolved in tetrahydrofuran, and then 60% sodium hydride (30 mg, 1.25 mmol) was slowly added at 0°C. . After stirring for 20 minutes, 4-(3-bromopropy-1-yl)-1,1'-biphenyl (0.339 g, 1.25 mmol) was added. After stirring at room temperature for 15 hours, the reaction is terminated by adding ammonium chloride aqueous solution. It was diluted with ethyl acetate and washed with water. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0~10% ethyl acetate/hexane) to produce the target compound 4-(1-((3-([1,1'-biphenyl]-4-yl)pro. Pro-2-yn-1-yl)oxy)ethyl)-3,5-dichloropyridine (142 mg, 44%, colorless liquid) was obtained.

1H NMR (400MHz, CDCl3) δ 8.47 (s, 2H), 7.59 - 7.53 (m, 4H), 7.46 - 7.43 (m, 4H), 7.38 - 7.34 (m, 1H), 5.58 (1, J = 6.8 Hz, 1H), 4.42 (d, J = 16.0 Hz, 1H), 4.18 (d, J = 16.0 Hz, 1H), 1.64 (d. J = 6.8 Hz, 3H); LCMS, m/z 382[M+H]+ 1H NMR (400MHz, CDCl3) δ 8.47 (s, 2H), 7.59 - 7.53 (m, 4H), 7.46 - 7.43 (m, 4H), 7.38 - 7.34 (m, 1H), 5.58 (1, J = 6.8 Hz, 1H), 4.42 (d. J = 16.0 Hz, 1H), 4.18 (d. J = 16.0 Hz, 1H), 1.64 (d. J = 6.8 Hz, 3H); LCMS, m/z 382[M+H] +

<실시예 33> 4-클로로-2-(1-((3-(4-메톡시페닐)프로프-2-인-1-일)(메틸)아미노)에틸)페놀의 제조<Example 33> Preparation of 4-chloro-2-(1-((3-(4-methoxyphenyl)prop-2-yn-1-yl)(methyl)amino)ethyl)phenol

상기 실시예 31과 유사한 방법으로 목적화합물 4-클로로-2-(1-((3-(4-메톡시페닐)프로프-2-인-1-일)(메틸)아미노)에틸)페놀을 수득하였다.The target compound 4-chloro-2-(1-((3-(4-methoxyphenyl)prop-2-yn-1-yl)(methyl)amino)ethyl)phenol was prepared in a manner similar to Example 31. Obtained.

1H NMR (400 MHz, CDCl3) δ 11.0 (s, 1H), 7.40 - 7.36 (m, 2H), 7.09 (d of d, J = 2.6 Hz, 8.6 Hz, 1H), 6.99 (d, J = 2.6 Hz, 1H), 6.87 - 6.83 (m, 2H), 6.76 (d, J = 8.6 Hz, 1H), 3.84 (q, J = 6.7 Hz, 1H), 3.82 (s, 3H), 3.75 (d, J = 17.2 Hz, 1H), 3.59 (d, J = 17.2 Hz, 1H), 2.45 (s, 3H), 1.44 (d, J = 6.7 Hz, 3H); LCMS, m/z 330[M+H]+ 1 H NMR (400 MHz, CDCl 3 ) δ 11.0 (s, 1H), 7.40 - 7.36 (m, 2H), 7.09 (d of d, J = 2.6 Hz, 8.6 Hz, 1H), 6.99 (d, J = 2.6 Hz, 1H), 6.87 - 6.83 (m, 2H), 6.76 (d, J = 8.6 Hz, 1H), 3.84 (q, J = 6.7 Hz, 1H), 3.82 (s, 3H), 3.75 (d, J = 17.2 Hz, 1H), 3.59 (d, J = 17.2 Hz, 1H), 2.45 (s, 3H), 1.44 (d, J = 6.7 Hz, 3H); LCMS, m/z 330[M+H] +

<실시예 34> tert-부틸 4-(4-(3-((4-히드록시페네틸)아미노)프로프-1-인-1-일)페닐)피페라진-1-카르복실레이트의 제조<Example 34> Preparation of tert-butyl 4-(4-(3-((4-hydroxyphenethyl)amino)prop-1-yn-1-yl)phenyl)piperazine-1-carboxylate

단계 1 : tert-부틸 4-(4-브로모페닐)피페라진-1-카르복실레이트의 제조Step 1: Preparation of tert-butyl 4-(4-bromophenyl)piperazine-1-carboxylate

1-(4-브로모페닐)피페라진(1 g, 4.15 mmol)을 디클로로메탄에 용해시킨 뒤, 상온에서 디-tert-부틸 디카보네이트(1.35 g, 6.22 mmol), DMAP(152 mg, 1.24 mmol), 트리에틸아민(1.15 mL, 8.3 mmol)을 첨가하였다. 상온에서 1시간 동안 교반하였다. 반응 종결 후, 혼합물을 감압 농축하였다. 얻어진 잔사를 실리카겔 크로마토그래피법(0~10% 에틸아세테이트/헥산)으로 분리 및 정제하여, 목적화합물 tert-부틸 4-(4-브로모페닐)피페라진-1-카르복실레이트(0.72 g, 50%, 흰색 고체)를 수득하였다.1-(4-bromophenyl)piperazine (1 g, 4.15 mmol) was dissolved in dichloromethane, then di-tert-butyl dicarbonate (1.35 g, 6.22 mmol) and DMAP (152 mg, 1.24 mmol) were added at room temperature. ), triethylamine (1.15 mL, 8.3 mmol) was added. It was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0~10% ethyl acetate/hexane), and the target compound tert-butyl 4-(4-bromophenyl)piperazine-1-carboxylate (0.72 g, 50% %, white solid) was obtained.

단계 2 : tert-부틸 4-(4-(3-히드록시프로프-1-인-1-일)페닐)피페라진-1-카르복실레이트의 제조Step 2: Preparation of tert-butyl 4-(4-(3-hydroxyprop-1-yn-1-yl)phenyl)piperazine-1-carboxylate

상기 단계 1에서 제조한 화합물 tert-부틸 4-(4-브로모페닐)피페라진-1-카르복실레이트(0.72 g, 2.11 mmol)을 피롤리딘에 용해시킨 뒤, 상온에서 Pd(PPh3)4(36 mg, 0.12 mmol), 프로파질알코올(0.48 mL, 8.44 mmol)을 첨가하였다. 질소 풍선을 이용하여 반응 혼합물을 탈기한 다음 상온에서 30분동안 교반하였다. 그 다음 120 °C로 가열하여 8시간 동안 가열 교반하였다. 반응 종결 후, 혼합물을 상온으로 식힌 뒤 셀라이트에 여과한 다음 감압 농축하였다. 얻어진 잔사는 에틸 아세테이트에 희석시키고 물과 소금물로 씻어주었다. 유기층의 잔류물은 무수 황산나트륨으로 건조 및 여과한 다음 감압 농축하였다. 얻어진 잔사를 실리카겔 크로마토그래피법(0~30% 에틸아세테이트/헥산)으로 분리 및 정제하여, 목적화합물 tert-부틸 4-(4-(3-히드록시프로프-1-인-1-일)페닐)피페라진-1-카르복실레이트 (0.34 g, 51%, 노란색 고체)를 수득하였다. The compound tert-butyl 4-(4-bromophenyl)piperazine-1-carboxylate (0.72 g, 2.11 mmol) prepared in step 1 was dissolved in pyrrolidine and then dissolved in Pd(PPh 3 ) at room temperature. 4 (36 mg, 0.12 mmol) and propargyl alcohol (0.48 mL, 8.44 mmol) were added. The reaction mixture was degassed using a nitrogen balloon and then stirred at room temperature for 30 minutes. It was then heated to 120 °C and heated and stirred for 8 hours. After completion of the reaction, the mixture was cooled to room temperature, filtered through Celite, and then concentrated under reduced pressure. The obtained residue was diluted in ethyl acetate and washed with water and salt water. The residue of the organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0~30% ethyl acetate/hexane) to produce the target compound tert-butyl 4-(4-(3-hydroxyprop-1-yn-1-yl)phenyl. ) Piperazine-1-carboxylate (0.34 g, 51%, yellow solid) was obtained.

단계 3 : tert-부틸 4-(4-(3-옥소프로프-1-인-1-일)페닐)피페라진-1-카르복실레이트의 제조Step 3: Preparation of tert-butyl 4-(4-(3-oxoprop-1-yn-1-yl)phenyl)piperazine-1-carboxylate

상기 단계 2에서 제조한 화합물 tert-부틸 4-(4-(3-히드록시프로프-1-인-1-일)페닐)피페라진-1-카르복실레이트(342 mg, 1.00 mmol)을 디클로로메탄에 용해시킨 뒤, 0 °C에서 DMP(550 mg, 1.29 mmol)을 천천히 첨가하였다. 0 °C에서 30분 동안 교반하였다. 반응이 종결된 후, 디클로로메탄으로 희석시키고 물과 소금물로 씻어주었다. 유기층의 잔류물은 무수 황산나트륨으로 건조 및 여과한 다음 감압 농축하였다. 얻어진 잔사를 실리카겔 크로마토그래피법(0~30% 에틸아세테이트/헥산)으로 분리 및 정제하여, 목적화합물 tert-부틸 4-(4-(3-옥소프로프-1-인-1-일)페닐)피페라진-1-카르복실레이트(199 mg, 58%, 노란색 고체)를 제조하였다.The compound tert-butyl 4-(4-(3-hydroxyprop-1-yn-1-yl)phenyl)piperazine-1-carboxylate (342 mg, 1.00 mmol) prepared in step 2 was dissolved in dichloro. After dissolving in methane, DMP (550 mg, 1.29 mmol) was slowly added at 0 °C. Stirred for 30 minutes at 0 °C. After the reaction was completed, it was diluted with dichloromethane and washed with water and salt water. The residue of the organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0-30% ethyl acetate/hexane), and the target compound tert-butyl 4-(4-(3-oxoprop-1-yn-1-yl)phenyl) was obtained. Piperazine-1-carboxylate (199 mg, 58%, yellow solid) was prepared.

단계 4 : tert-부틸 4-(4-(3-((4-히드록시페네틸)아미노)프로프-1-인-1-일)페닐)피페라진-1-카르복실레이트의 제조Step 4: Preparation of tert-butyl 4-(4-(3-((4-hydroxyphenethyl)amino)prop-1-yn-1-yl)phenyl)piperazine-1-carboxylate

상기 단계 3에서 제조한 화합물 tert-부틸 4-(4-(3-옥소프로프-1-인-1-일)페닐)피페라진-1-카르복실레이트 (100 mg, 0.31 mmol)을 메탄올에 용해시킨 뒤, 4-(2-아미노에틸)페놀(65 mg, 0.47 mmol)을 상온에서 첨가하였다. 상온에서 1시간동안 교반한 뒤, 0 ℃에서 소듐보로하이드라이드(36 mg, 0.95 mmol)을 천천히 첨가하였다. 30분동안 교반한 뒤, 증류수를 적가하여 반응을 종결시키고 에틸아세테이트로 추출하고 증류수로 씻어주었다. 추출한 유기층은 무수 황산나트륨으로 건조 및 여과한 다음 감압 농축하였다. 얻어진 잔사를 실리카겔 크로마토그래피법(0~5% 메탄올/디클로로메탄)으로 분리 및 정제하여, 목적화합물 tert-부틸 4-(4-(3-((4-히드록시페네틸)아미노)프로프-1-인-1-일)페닐)피페라진-1-카르복실레이트 (74 mg, 53%, 흰색 고체)을 수득하였다. The compound tert-butyl 4-(4-(3-oxoprop-1-yn-1-yl)phenyl)piperazine-1-carboxylate (100 mg, 0.31 mmol) prepared in step 3 was added to methanol. After dissolution, 4-(2-aminoethyl)phenol (65 mg, 0.47 mmol) was added at room temperature. After stirring at room temperature for 1 hour, sodium borohydride (36 mg, 0.95 mmol) was slowly added at 0°C. After stirring for 30 minutes, distilled water was added dropwise to terminate the reaction, extracted with ethyl acetate, and washed with distilled water. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0~5% methanol/dichloromethane), and the target compound tert-butyl 4-(4-(3-((4-hydroxyphenethyl)amino)prop- 1-In-1-yl)phenyl)piperazine-1-carboxylate (74 mg, 53%, white solid) was obtained.

1H NMR (400 MHz, CDCl3) δ 7.30 (d, J = 8.9 Hz, 2H), 7.10 (d, J = 8.5 Hz, 2H), 6.81 (d, J = 8.9 Hz, 2H), 6.76 (d, J = 8.5 Hz, 2H), 3.63 (s, 2H), 3.60 - 3.52 (m, 4H), 3.19 - 3.12 (m, 4H), 2.99 (t, J = 7.1 Hz, 2H), 2.78 (t, J = 7.1 Hz, 2H), 1.48 (s, 9H); LCMS, m/z 436[M+H]+ 1H NMR (400 MHz, CDCl3) δ 7.30 (d, J = 8.9 Hz, 2H), 7.10 (d, J = 8.5 Hz, 2H), 6.81 (d, J = 8.9 Hz, 2H), 6.76 (d, J = 8.5 Hz, 2H), 3.63 (s, 2H), 3.60 - 3.52 (m, 4H), 3.19 - 3.12 (m, 4H), 2.99 (t, J = 7.1 Hz, 2H), 2.78 (t, J = 7.1 Hz, 2H), 1.48 (s, 9H); LCMS, m/z 436[M+H] +

<실시예 35> tert-부틸 4-(4-(3-((1-(5-클로로-2-히드록시페닐)에틸)아미노)프로프-1-인-1-일)페닐)피페라진-1-카르복실레이트의 제조<Example 35> tert-Butyl 4-(4-(3-((1-(5-chloro-2-hydroxyphenyl)ethyl)amino)prop-1-yn-1-yl)phenyl)piperazine -Preparation of 1-carboxylate

상기 실시예 34의 단계 3에서 제조한 화합물 tert-부틸 4-(4-(3-옥소프로프-1-인-1-일)페닐)피페라진-1-카르복실레이트(99 mg, 0.31 mmol)을 메탄올에 용해시킨 뒤, 2-(1-아미노에틸)-4-클로로페놀(108 mg, 0.63 mmol)을 상온에서 첨가하였다. 아세틱에시드를 두방울 첨가한 뒤, 0 ℃에서 소듐싸이아노보로하이드라이드(59 mg, 0.94 mmol)을 천천히 첨가하였다. 30분 동안 교반한 뒤, 증류수를 적가하여 반응을 종결시키고 에틸아세테이트로 추출하고 증류수로 씻어주었다. 추출한 유기층은 무수 황산나트륨으로 건조 및 여과한 다음 감압 농축하였다. 얻어진 잔사를 실리카겔 크로마토그래피법(0~30% 에틸아세테이트/헥산)으로 분리 및 정제하여, 목적화합물 tert-부틸 4-(4-(3-((1-(5-클로로-2-히드록시페닐)에틸)아미노)프로프-1-인-1-일)페닐)피페라진-1-카르복실레이트(47 mg, 31%, 흰색 고체)를 수득하였다. Compound tert-butyl 4-(4-(3-oxoprop-1-yn-1-yl)phenyl)piperazine-1-carboxylate prepared in step 3 of Example 34 (99 mg, 0.31 mmol) ) was dissolved in methanol, and then 2-(1-aminoethyl)-4-chlorophenol (108 mg, 0.63 mmol) was added at room temperature. After adding two drops of acetic acid, sodium cyanoborohydride (59 mg, 0.94 mmol) was slowly added at 0°C. After stirring for 30 minutes, distilled water was added dropwise to terminate the reaction, extracted with ethyl acetate, and washed with distilled water. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0~30% ethyl acetate/hexane) to produce the target compound tert-butyl 4-(4-(3-((1-(5-chloro-2-hydroxyphenyl) )Ethyl)amino)prop-1-yn-1-yl)phenyl)piperazine-1-carboxylate (47 mg, 31%, white solid) was obtained.

1H NMR (400 MHz, CDCl3) δ 7.32 (d, J = 8.4 Hz, 2H), 7.10 (d, J = 8.6 Hz, 1H), 6.98 (s, 1H), 6.83 (d, J = 8.4 Hz, 2H), 6.75 (d, J = 8.6 Hz, 1H), 4.22 (q, J = 6.8 Hz, 1H), 3.71 (d, J = 17.2 Hz, 1H), 3.64 - 3.50 (m, 4H), 3.47 (d, J = 17.2 Hz, 1H), 3.24 - 3.08 (m, 4H), 1.50 - 1,40 (m, 12H); LCMS, m/z 471[M+H]+ 1H NMR (400 MHz, CDCl3) δ 7.32 (d, J = 8.4 Hz, 2H), 7.10 (d, J = 8.6 Hz, 1H), 6.98 (s, 1H), 6.83 (d, J = 8.4 Hz, 2H), 6.75 (d, J = 8.6 Hz, 1H), 4.22 (q, J = 6.8 Hz, 1H), 3.71 (d, J = 17.2 Hz, 1H), 3.64 - 3.50 (m, 4H), 3.47 ( d, J = 17.2 Hz, 1H), 3.24 - 3.08 (m, 4H), 1.50 - 1,40 (m, 12H); LCMS, m/z 471[M+H] +

<실시예 36> 4-(2-((3-(4-(피페라진-1-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀의 제조<Example 36> Preparation of 4-(2-((3-(4-(piperazin-1-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol

상기 실시예 34에서 제조한 화합물 tert-부틸 4-(4-(3-((4-히드록시페네틸)아미노)프로프-1-인-1-일)페닐)피페라진-1-카르복실레이트(40 mg, 0.09 mmol)을 디클로로메탄에 용해시킨 뒤, 트리플루오로아세틱에시드(0.5 mL, 6.49 mmol)을 0 ℃에서 적가하였다. 2시간 동안 교반한 뒤, 탄산수소나트륨 수용액를 적가하여 반응을 종결시키고 디클로로메탄:메탄올(3:1)혼합용액으로 추출하고 증류수로 씻어주었다. 추출한 유기층은 무수 황산나트륨으로 건조 및 여과한 다음 감압 농축하였다. 얻어진 잔사를 실리카겔 크로마토그래피법(0~5% 메탄올혼합용액(암모니아수1%)/디클로로메탄)으로 분리 및 정제하여, 목적화합물 4-(2-((3-(4-(피페라진-1-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀(6 mg, 19%, 흰색 고체)을 수득하였다. Compound prepared in Example 34 tert-butyl 4-(4-(3-((4-hydroxyphenethyl)amino)prop-1-yn-1-yl)phenyl)piperazine-1-carboxyl After dissolved in dichloromethane (40 mg, 0.09 mmol), trifluoroacetic acid (0.5 mL, 6.49 mmol) was added dropwise at 0°C. After stirring for 2 hours, the reaction was terminated by adding aqueous sodium bicarbonate solution dropwise, extracted with a dichloromethane:methanol (3:1) mixed solution, and washed with distilled water. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0~5% methanol mixed solution (1% ammonia water)/dichloromethane) to produce the target compound 4-(2-((3-(4-(piperazine-1- Y)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol (6 mg, 19%, white solid) was obtained.

1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 9.1 Hz, 2H), 7.05 (d, J = 8.5 Hz, 2H), 6.85 (d, J = 9.1 Hz, 2H), 6.73 (d, J = 8.5 Hz, 2H), 3.37 - 3.27 (m, 4H), 3.10 (t, J = 6.6 Hz, 2H), 3.05 - 2.97 (m, 5H), 2.97 - 2.83 (m, 2H), 2.79 - 2.62 (m, 2H); LCMS, m/z 354 [M+H2O]+ 1H NMR (400 MHz, CDCl 3 ) δ 7.86 (d, J = 9.1 Hz, 2H), 7.05 (d, J = 8.5 Hz, 2H), 6.85 (d, J = 9.1 Hz, 2H), 6.73 (d) , J = 8.5 Hz, 2H), 3.37 - 3.27 (m, 4H), 3.10 (t, J = 6.6 Hz, 2H), 3.05 - 2.97 (m, 5H), 2.97 - 2.83 (m, 2H), 2.79 - 2.62 (m, 2H); LCMS, m/z 354 [M+H 2 O] +

<실시예 37> 4-클로로-2-(1-((3-(4-(피페라진-1-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀의 제조<Example 37> Preparation of 4-chloro-2-(1-((3-(4-(piperazin-1-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol

상기 실시예 35에서 제조한 화합물 tert-부틸 4-(4-(3-((1-(5-클로로-2-히드록시페닐)에틸)아미노)프로프-1-인-1-일)페닐)피페라진-1-카르복실레이트(40 mg, 0.08 mmol)을 디클로로메탄에 용해시킨 뒤, 트리플루오로아세틱에시드(0.5 mL, 6.49 mmol)을 0 ℃에서 적가하였다. 2시간 동안 교반한 뒤, 탄산수소나트륨 수용액를 적가하여 반응을 종결시키고 디클로로메탄:메탄올(3:1)혼합용액으로 추출하고 증류수로 씻어주었다. 추출한 유기층은 무수 황산나트륨으로 건조 및 여과한 다음 감압 농축하였다. 얻어진 잔사를 실리카겔 크로마토그래피법(0~5% 메탄올혼합용액(암모니아수1%)/디클로로메탄)으로 분리 및 정제하여, 목적화합물 4-클로로-2-(1-((3-(4-(피페라진-1-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀(15 mg, 47%, 흰색 고체)을 수득하였다. Compound tert-butyl 4-(4-(3-((1-(5-chloro-2-hydroxyphenyl)ethyl)amino)prop-1-yn-1-yl)phenyl prepared in Example 35 ) Piperazine-1-carboxylate (40 mg, 0.08 mmol) was dissolved in dichloromethane, and then trifluoroacetic acid (0.5 mL, 6.49 mmol) was added dropwise at 0°C. After stirring for 2 hours, the reaction was terminated by adding aqueous sodium bicarbonate solution dropwise, extracted with a dichloromethane:methanol (3:1) mixed solution, and washed with distilled water. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0~5% methanol mixed solution (1% ammonia water)/dichloromethane), and the target compound 4-chloro-2-(1-((3-(4-(Pipe) was obtained. Razin-1-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol (15 mg, 47%, white solid) was obtained.

1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 9.1 Hz, 2H), 7.07 (dd, J = 8.6, 2.6 Hz, 1H), 6.95 (d, J = 2.6 Hz, 1H), 6.86 (d, J = 9.1 Hz, 2H), 6.71 (d, J = 8.6 Hz, 1H), 3.93 (q, J = 6.7 Hz, 1H), 3.33 (dd, J = 6.1, 4.1 Hz, 4H), 3.18 - 3.06 (m, 3H), 3.02 (dd, J = 6.1, 4.1 Hz, 4H), 2.83 - 2.79 (m, 1H), 1.44 (d, J = 6.7 Hz, 3H); LCMS, m/z 388[M+H]+ 1H NMR (400 MHz, CDCl 3 ) δ 7.85 (d, J = 9.1 Hz, 2H), 7.07 (dd, J = 8.6, 2.6 Hz, 1H), 6.95 (d, J = 2.6 Hz, 1H), 6.86 (d, J = 9.1 Hz, 2H), 6.71 (d, J = 8.6 Hz, 1H), 3.93 (q, J = 6.7 Hz, 1H), 3.33 (dd, J = 6.1, 4.1 Hz, 4H), 3.18 - 3.06 (m, 3H), 3.02 (dd, J = 6.1, 4.1 Hz, 4H), 2.83 - 2.79 (m, 1H), 1.44 (d, J = 6.7 Hz, 3H); LCMS, m/z 388[M+H] +

<실시예 38> 4-(2-((3-(4-모르폴리노페닐)프로프-2-인-1-일)아미노)에틸)페놀의 제조<Example 38> Preparation of 4-(2-((3-(4-morpholinophenyl)prop-2-yn-1-yl)amino)ethyl)phenol

단계 1 : 3-(4-모르폴리노페닐)프로프-2-인-1-올의 제조Step 1: Preparation of 3-(4-morpholinophenyl)prop-2-yn-1-ol

4-(4-브로모페닐)모르폴린(1.5 g, 6.20 mmol)을 피롤리딘에 용해시킨 뒤, 상온에서 Pd(PPh3)4(89 mg, 0.31 mmol), 프로파질알코올(0.89 mL, 15.49 mmol)을 첨가하였다. 질소 풍선을 이용하여 반응 혼합물을 탈기한 다음 상온에서 30분 교반하였다. 그 다음 100 °C로 가열하여 6시간 동안 가열 교반하였다. 반응 종결 후, 혼합물을 상온으로 식힌 뒤 셀라이트에 여과한 다음 감압 농축하였다. 얻어진 잔사는 에틸 아세테이트에 희석시키고 물과 소금물로 씻어주었다. 유기층의 잔류물은 무수 황산나트륨으로 건조 및 여과한 다음 감압 농축하였다. 얻어진 잔사를 실리카겔 크로마토그래피법(0~30% 에틸아세테이트/헥산)으로 분리 및 정제하여, 목적화합물 3-(4-모르폴리노페닐)프로프-2-인-1-올(0.74 g, 34%, 노란색 고체)을 수득하였다. 4-(4-bromophenyl)morpholine (1.5 g, 6.20 mmol) was dissolved in pyrrolidine, then Pd(PPh 3 ) 4 (89 mg, 0.31 mmol) and propargyl alcohol (0.89 mL, 15.49 mmol) was added. The reaction mixture was degassed using a nitrogen balloon and then stirred at room temperature for 30 minutes. It was then heated to 100 °C and heated and stirred for 6 hours. After completion of the reaction, the mixture was cooled to room temperature, filtered through Celite, and then concentrated under reduced pressure. The obtained residue was diluted in ethyl acetate and washed with water and salt water. The residue of the organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0~30% ethyl acetate/hexane), and the target compound 3-(4-morpholinophenyl)prop-2-yn-1-ol (0.74 g, 34 g) was obtained. %, yellow solid) was obtained.

단계 2 : 3-(4-모르폴리노페닐)프로피올알데히드의 제조Step 2: Preparation of 3-(4-morpholinophenyl)propiolaldehyde

상기 단계 1에서 제조한 화합물 3-(4-모르폴리노페닐)프로프-2-인-1-올(100 mg, 0.46 mmol)을 디클로로메탄에 용해시킨 뒤, 0 °C에서 DMP(234 mg, 0.55 mmol)을 천천히 첨가하였다. 30분 후, 상온으로 반응 혼합물을 식히고 1시간동안 교반하였다. 반응이 종결된 후, 디클로로메탄으로 희석시키고 물과 소금물로 씻어주었다. 유기층의 잔류물은 무수 황산나트륨으로 건조 및 여과한 다음 감압 농축하였다. 얻어진 잔사를 실리카겔 크로마토그래피법(0~30% 에틸아세테이트/헥산)으로 분리 및 정제하여, 목적화합물 3-(4-모르폴리노페닐)프로피올알데히드(55 mg, 55%, 노란색 고체)를 제조하였다.Compound 3-(4-morpholinophenyl)prop-2-yn-1-ol (100 mg, 0.46 mmol) prepared in step 1 was dissolved in dichloromethane, and then dissolved in DMP (234 mg) at 0 °C. , 0.55 mmol) was added slowly. After 30 minutes, the reaction mixture was cooled to room temperature and stirred for 1 hour. After the reaction was completed, it was diluted with dichloromethane and washed with water and salt water. The residue of the organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0-30% ethyl acetate/hexane) to prepare the target compound 3-(4-morpholinophenyl)propiolaldehyde (55 mg, 55%, yellow solid). did.

단계 3 : 4-(2-((3-(4-모르폴리노페닐)프로프-2-인-1-일)아미노)에틸)페놀의 제조Step 3: Preparation of 4-(2-((3-(4-morpholinophenyl)prop-2-yn-1-yl)amino)ethyl)phenol

상기 단계 2에서 제조한 화합물 3-(4-모르폴리노페닐)프로피올알데히드(55 mg, 0.25 mmol)을 메탄올에 용해시킨 뒤, 4-(2-아미노에틸)페놀(42 mg, 0.30 mmol)을 상온에서 첨가하였다. 상온에서 1시간동안 교반한 뒤, 0 ℃에서 소듐보로하이드라이드(29 mg, 0.76 mmol)을 천천히 첨가하였다. 30분동안 교반한 뒤, 증류수를 적가하여 반응을 종결시키고 에틸아에세테이트로 추출하고 증류수로 씻어주었다. 추출한 유기층은 무수 황산나트륨으로 건조 및 여과한 다음 감압 농축하였다. 얻어진 잔사를 실리카겔 크로마토그래피법(0~10% 메탄올/디클로로메탄)으로 분리 및 정제하여, 목적화합물 4-(2-((3-(4-모르폴리노페닐)프로프-2-인-1-일)아미노)에틸)페놀(40 mg, 46%, 노란색 고체)을 수득하였다. Compound 3-(4-morpholinophenyl)propiolaldehyde (55 mg, 0.25 mmol) prepared in step 2 was dissolved in methanol, and then 4-(2-aminoethyl)phenol (42 mg, 0.30 mmol) was added at room temperature. After stirring at room temperature for 1 hour, sodium borohydride (29 mg, 0.76 mmol) was slowly added at 0°C. After stirring for 30 minutes, distilled water was added dropwise to terminate the reaction, extracted with ethyl acetate, and washed with distilled water. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0~10% methanol/dichloromethane) to produce the target compound 4-(2-((3-(4-morpholinophenyl)prop-2-yn-1 -yl)amino)ethyl)phenol (40 mg, 46%, yellow solid) was obtained.

1H NMR (400 MHz, DMSO) δ 9.12 (s, 1H), 7.24 (d, J = 8.8 Hz, 2H), 7.00 (d, J = 8.4 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 6.66 (d, J = 8.4 Hz, 2H), 3.76 - 3.66 (m, 4H), 3.52 (s, 2H), 3.18 - 3.08 (m, 4H), 2.77 (t, J = 7.4 Hz, 1H), 2.60 (t, J = 7.4 Hz, 1H); 337 [M+H]+ 1H NMR (400 MHz, DMSO) δ 9.12 (s, 1H), 7.24 (d, J = 8.8 Hz, 2H), 7.00 (d, J = 8.4 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 6.66 (d, J = 8.4 Hz, 2H), 3.76 - 3.66 (m, 4H), 3.52 (s, 2H), 3.18 - 3.08 (m, 4H), 2.77 (t, J = 7.4 Hz, 1H) ), 2.60 (t, J = 7.4 Hz, 1H); 337 [M+H] +

<실시예 39> 4-클로로-2-(1-((3-(4-모르폴리노페닐)프로프-2-인-1-일)아미노)에틸)페놀의 제조<Example 39> Preparation of 4-chloro-2-(1-((3-(4-morpholinophenyl)prop-2-yn-1-yl)amino)ethyl)phenol

상기 실시예 38의 단계 2에서 제조한 화합물 3-(4-모르폴리노페닐)프로피올알데히드(50 mg, 0.23 mmol)을 메탄올에 용해시킨 뒤, 2-(1-아미노에틸)-4-클로로페놀(96 mg, 0.55 mmol)을 상온에서 첨가하였다. 아세틱에시드를 두방울 첨가한 뒤, 0 ℃에서 소듐싸이아노보로하이드라이드(43 mg, 0.69 mmol)을 천천히 첨가하였다. 30분동안 교반한 뒤, 증류수를 적가하여 반응을 종결시키고 에틸아에세테이트로 추출하고 증류수로 씻어주었다. 추출한 유기층은 무수 황산나트륨으로 건조 및 여과한 다음 감압 농축하였다. 얻어진 잔사를 실리카겔 크로마토그래피법(0~10% 메탄올/디클로로메탄)으로 분리 및 정제하여, 목적화합물 4-클로로-2-(1-((3-(4-모르폴리노페닐)프로프-2-인-1-일)아미노)에틸)페놀(37 mg, 42%, 흰색 고체)을 수득하였다. Compound 3-(4-morpholinophenyl)propiolaldehyde (50 mg, 0.23 mmol) prepared in step 2 of Example 38 was dissolved in methanol and then dissolved in 2-(1-aminoethyl)-4-chloro. Phenol (96 mg, 0.55 mmol) was added at room temperature. After adding two drops of acetic acid, sodium cyanoborohydride (43 mg, 0.69 mmol) was slowly added at 0°C. After stirring for 30 minutes, distilled water was added dropwise to terminate the reaction, extracted with ethyl acetate, and washed with distilled water. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0~10% methanol/dichloromethane) to produce the target compound 4-chloro-2-(1-((3-(4-morpholinophenyl)prop-2 -In-1-yl)amino)ethyl)phenol (37 mg, 42%, white solid) was obtained.

1H NMR (400 MHz, DMSO) δ 7.25 (d, J = 8.8 Hz, 2H), 7.20 (d, J = 2.7 Hz, 1H), 7.08 (dd, J = 8.6, 2.7 Hz, 1H), 6.90 (d, J = 8.8 Hz, 2H), 6.72 (d, J = 8.6 Hz, 1H), 4.17 (q, J = 6.6 Hz, 1H), 3.78 - 3.67 (m, 4H), 3.52 (d, J = 17.1 Hz, 2H), 3.21 - 3.10 (m, 4H), 1.28 (d, J = 6.6 Hz, 3H); LCMS, m/z 371[M+H]+ 1H NMR (400 MHz, DMSO) δ 7.25 (d, J = 8.8 Hz, 2H), 7.20 (d, J = 2.7 Hz, 1H), 7.08 (dd, J = 8.6, 2.7 Hz, 1H), 6.90 ( d, J = 8.8 Hz, 2H), 6.72 (d, J = 8.6 Hz, 1H), 4.17 (q, J = 6.6 Hz, 1H), 3.78 - 3.67 (m, 4H), 3.52 (d, J = 17.1 Hz, 2H), 3.21 - 3.10 (m, 4H), 1.28 (d, J = 6.6 Hz, 3H); LCMS, m/z 371[M+H] +

<실시예 40> 4-(2-((3-(4-(4-메틸피페라진-1-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀의 제조<Example 40> Preparation of 4-(2-((3-(4-(4-methylpiperazin-1-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol

상기 실시예 38과 유사한 방법으로 목적화합물 4-(2-((3-(4-(4-메틸피페라진-1-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀을 수득하였다.In a similar manner to Example 38, the target compound 4-(2-((3-(4-(4-methylpiperazin-1-yl)phenyl)prop-2-yn-1-yl)amino)ethyl) Phenol was obtained.

1H NMR (400 MHz, CDCl3) δ 7.28 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 8.0 Hz, 2H), 6.80 (d, J = 8.4 Hz, 2H), 6.72 (d, J = 8.0 Hz, 2H), 3.63 (s, 2H), 3.31 - 3.18 (m, 4H), 3.00 (t, J = 6.9 Hz, 2H), 2.78 (t, J = 6.9 Hz, 2H), 2.64 - 2.54 (m, 4H), 2.36 (s, 3H); LCMS, m/z 350[M+H]+ 1H NMR (400 MHz, CDCl3) δ 7.28 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 8.0 Hz, 2H), 6.80 (d, J = 8.4 Hz, 2H), 6.72 (d, J = 8.0 Hz, 2H), 3.63 (s, 2H), 3.31 - 3.18 (m, 4H), 3.00 (t, J = 6.9 Hz, 2H), 2.78 (t, J = 6.9 Hz, 2H), 2.64 - 2.54 (m, 4H), 2.36 (s, 3H); LCMS, m/z 350[M+H] +

<실시예 41> 4-클로로-2-(1-((3-(4-(4-메틸피페라진-1-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀의 제조<Example 41> 4-Chloro-2-(1-((3-(4-(4-methylpiperazin-1-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol manufacture of

상기 실시예 39과 유사한 방법으로 목적화합물 4-클로로-2-(1-((3-(4-(4-메틸피페라진-1-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀을 수득하였다.In a similar manner to Example 39, the target compound 4-chloro-2-(1-((3-(4-(4-methylpiperazin-1-yl)phenyl)prop-2-yn-1-yl) Amino)ethyl)phenol was obtained.

1H NMR (400 MHz, CDCl3) δ 7.31 (d, J = 8.7 Hz, 2H), 7.10 (dd, J = 8.5, 2.5 Hz, 1H), 6.98 (d, J = 2.5 Hz, 1H), 6.84 (d, J = 8.7 Hz, 2H), 6.75 (d, J = 8.5 Hz, 1H), 4.22 (q, J = 6.6 Hz, 1H), 3.71 (d, J = 17.3 Hz, 1H), 3.49 (d, J = 17.3 Hz, 1H), 3.34 - 3.19 (m, 4H), 2.64 - 2.51 (m, 4H), 2.35 (s, 3H), 1.47 (d, J = 6.6 Hz, 3H); LCMS, m/z 384[M+H]+ 1H NMR (400 MHz, CDCl3) δ 7.31 (d, J = 8.7 Hz, 2H), 7.10 (dd, J = 8.5, 2.5 Hz, 1H), 6.98 (d, J = 2.5 Hz, 1H), 6.84 ( d, J = 8.7 Hz, 2H), 6.75 (d, J = 8.5 Hz, 1H), 4.22 (q, J = 6.6 Hz, 1H), 3.71 (d, J = 17.3 Hz, 1H), 3.49 (d, J = 17.3 Hz, 1H), 3.34 - 3.19 (m, 4H), 2.64 - 2.51 (m, 4H), 2.35 (s, 3H), 1.47 (d, J = 6.6 Hz, 3H); LCMS, m/z 384[M+H] +

<실시예 42> 4-(2-((3-(4-(피리딘-4-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀의 제조<Example 42> Preparation of 4-(2-((3-(4-(pyridin-4-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol

상기 실시예 38과 유사한 방법으로 목적화합물 4-(2-((3-(4-(피리딘-4-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀을 수득하였다.The target compound 4-(2-((3-(4-(pyridin-4-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol was obtained in a similar manner to Example 38. .

1H NMR (400 MHz, CDCl3) δ 8.66 (dd, J = 4.6, 1.6 Hz, 2H), 7.58 (d, J = 8.4 Hz, 2H), 7.55 - 7.46 (m, 4H), 7.11 (d, J = 8.4 Hz, 2H), 6.78 (d, J = 8.5 Hz, 2H), 3.68 (s, 2H), 3.02 (t, J = 7.0 Hz, 2H), 2.80 (t, J = 7.0 Hz, 2H); LCMS, m/z 329[M+H]+ 1H NMR (400 MHz, CDCl3) δ 8.66 (dd, J = 4.6, 1.6 Hz, 2H), 7.58 (d, J = 8.4 Hz, 2H), 7.55 - 7.46 (m, 4H), 7.11 (d, J = 8.4 Hz, 2H), 6.78 (d, J = 8.5 Hz, 2H), 3.68 (s, 2H), 3.02 (t, J = 7.0 Hz, 2H), 2.80 (t, J = 7.0 Hz, 2H); LCMS, m/z 329[M+H] +

<실시예 43> 4-클로로-2-(1-((3-(4-(피리딘-4-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀의 제조<Example 43> Preparation of 4-chloro-2-(1-((3-(4-(pyridin-4-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol

상기 실시예 39와 유사한 방법으로 목적화합물 4-클로로-2-(1-((3-(4-(피리딘-4-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀을 수득하였다.In a similar manner to Example 39, the target compound 4-chloro-2-(1-((3-(4-(pyridin-4-yl)phenyl)prop-2-yn-1-yl)amino)ethyl) Phenol was obtained.

1H NMR (400 MHz, CDCl3) δ 10.91 (s, 1H), 8.68 (dd, J = 4.5, 1.6 Hz, 2H), 7.65 - 7.56 (m, 2H), 7.57 - 7.46 (m, 4H), 7.12 (dd, J = 8.6, 2.6 Hz, 1H), 7.00 (d, J = 2.6 Hz, 1H), 6.77 (d, J = 8.6 Hz, 1H), 4.23 (q, J = 6.7 Hz, 1H), 3.76 (d, J = 17.4 Hz, 1H), 3.53 (d, J = 17.4 Hz, 1H), 1.50 (d, J = 6.7 Hz, 3H); LCMS, m/z 363[M+H]+ 1H NMR (400 MHz, CDCl3) δ 10.91 (s, 1H), 8.68 (dd, J = 4.5, 1.6 Hz, 2H), 7.65 - 7.56 (m, 2H), 7.57 - 7.46 (m, 4H), 7.12 (dd, J = 8.6, 2.6 Hz, 1H), 7.00 (d, J = 2.6 Hz, 1H), 6.77 (d, J = 8.6 Hz, 1H), 4.23 (q, J = 6.7 Hz, 1H), 3.76 (d, J = 17.4 Hz, 1H), 3.53 (d, J = 17.4 Hz, 1H), 1.50 (d, J = 6.7 Hz, 3H); LCMS, m/z 363[M+H] +

<실시예 44> 4-(2-((3-(4'-메톡시-[1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)페놀의 제조<Example 44> 4-(2-((3-(4'-methoxy-[1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl) Manufacture of phenol

상기 실시예 38과 유사한 방법으로 목적화합물 4-(2-((3-(4'-메톡시-[1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)페놀을 수득하였다.In a similar manner to Example 38, the target compound 4-(2-((3-(4'-methoxy-[1,1'-biphenyl]-4-yl)prop-2-yn-1-yl )Amino)ethyl)phenol was obtained.

1H NMR (400 MHz, CDCl3) δ 7.55 - 7.41 (m, 6H), 7.11 (d, J = 8.5 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 6.77 (d, J = 8.5 Hz, 2H), 3.85 (s, 3H), 3.67 (s, 2H), 3.02 (t, J = 7.0 Hz, 2H), 2.80 (t, J = 7.0 Hz, 2H); LCMS, m/z 358[M+H]+ 1H NMR (400 MHz, CDCl3) δ 7.55 - 7.41 (m, 6H), 7.11 (d, J = 8.5 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 6.77 (d, J = 8.5 Hz, 2H), 3.85 (s, 3H), 3.67 (s, 2H), 3.02 (t, J = 7.0 Hz, 2H), 2.80 (t, J = 7.0 Hz, 2H); LCMS, m/z 358[M+H] +

<실시예 45> 4-클로로-2-(1-((3-(4'-메톡시-[1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)페놀의 제조<Example 45> 4-Chloro-2-(1-((3-(4'-methoxy-[1,1'-biphenyl]-4-yl)prop-2-yn-1-yl) Production of amino)ethyl)phenol

상기 실시예 39와 유사한 방법으로 목적화합물 4-클로로-2-(1-((3-(4'-메톡시-[1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)페놀을 수득하였다.In a similar manner to Example 39, the target compound 4-chloro-2-(1-((3-(4'-methoxy-[1,1'-biphenyl]-4-yl)prop-2-yne -1-yl)amino)ethyl)phenol was obtained.

1H NMR (400 MHz, CDCl3) δ 7.56 - 7.49 (m, 4H), 7.46 (d, J = 8.4 Hz, 2H), 7.11 (dd, J = 8.6, 2.6 Hz, 1H), 7.00 - 6.95 (m, 3H), 6.76 (d, J = 8.6 Hz, 1H), 4.24 (q, J = 6.7 Hz, 1H), 3.85 (s, 3H), 3.74 (d, J = 17.3 Hz, 1H), 3.51 (d, J = 17.3 Hz, 1H), 1.49 (d, J = 6.7 Hz, 3H); LCMS, m/z 392[M+H]+ 1 H NMR (400 MHz, CDCl3) δ 7.56 - 7.49 (m, 4H), 7.46 (d, J = 8.4 Hz, 2H), 7.11 (dd, J = 8.6, 2.6 Hz, 1H), 7.00 - 6.95 (m , 3H), 6.76 (d, J = 8.6 Hz, 1H), 4.24 (q, J = 6.7 Hz, 1H), 3.85 (s, 3H), 3.74 (d, J = 17.3 Hz, 1H), 3.51 (d , J = 17.3 Hz, 1H), 1.49 (d, J = 6.7 Hz, 3H); LCMS, m/z 392[M+H] +

<실시예 46> 4-(2-((3-(4'-(메톡시메톡시)-[1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)페놀의 제조<Example 46> 4-(2-((3-(4'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)prop-2-yn-1-yl) Production of amino)ethyl)phenol

단계 1 : 4-브로모-4'-(메톡시메톡시)-1,1'-비페닐의 제조Step 1: Preparation of 4-bromo-4'-(methoxymethoxy)-1,1'-biphenyl

4'-브로모-[1,1'-비페닐]-4-올(1 g, 4.01 mmol)을 테트라하이드로퓨란에 용해시킨 뒤, 0 °C에서 60wt% 수소화나트륨(0.48 g, 20.06 mmol)을 천천히 첨가하였다. 1시간 동안 교반한 뒤, MOMCl(0.64 g, 8.03 mmol)을 천천히 적가하였다. 1시간 동안 교반한 뒤, 혼합물에 증류수를 적가하여 반응을 종결시킨 뒤, 디클로로메탄으로 추출하고 소금물로 씻어주었다. 추출한 유기층은 무수 황산나트륨으로 건조 및 여과하고 감압 농축하였다. 얻어진 잔사를 실리카겔 크로마토그래피법(0~10% 에틸아세테이트/헥산)으로 분리 및 정제하여, 목적화합물(0.52 g, 45%, 흰색 고체)을 수득하였다.4'-Bromo-[1,1'-biphenyl]-4-ol (1 g, 4.01 mmol) was dissolved in tetrahydrofuran and then dissolved in 60 wt% sodium hydride (0.48 g, 20.06 mmol) at 0 °C. was added slowly. After stirring for 1 hour, MOMCl (0.64 g, 8.03 mmol) was slowly added dropwise. After stirring for 1 hour, distilled water was added dropwise to the mixture to terminate the reaction, extracted with dichloromethane, and washed with salt water. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0-10% ethyl acetate/hexane) to obtain the target compound (0.52 g, 45%, white solid).

단계 2 : 3-(4'-(메톡시메톡시)-[1,1'-비페닐]-4-일)프로프-2-인-1-올의 제조Step 2: Preparation of 3-(4'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)prop-2-yn-1-ol

상기 단계 1에서 제조한 화합물 4-브로모-4'-(메톡시메톡시)-1,1'-비페닐(0.3 g, 1.02 mmol)을 피롤리딘에 용해시킨 뒤, 상온에서 Pd(PPh3)4(17 mg, 0.06 mmol), 프로파질알코올(0.23 mL, 4.09 mmol)을 첨가하였다. 질소 풍선을 이용하여 반응 혼합물을 탈기한 다음 상온에서 30분 교반하였다. 그 다음 100 °C로 가열하여 3시간 동안 가열 교반하였다. 반응 종결 후, 혼합물을 상온으로 식힌 뒤 셀라이트에 여과한 다음 감압 농축하였다. 얻어진 잔사는 에틸 아세테이트에 희석시키고 물과 소금물로 씻어주었다. 유기층의 잔류물은 무수 황산나트륨으로 건조 및 여과한 다음 감압 농축하였다. 얻어진 잔사를 실리카겔 크로마토그래피법(0~30% 에틸아세테이트/헥산)으로 분리 및 정제하여, 목적화합물(0.19 g, 69%, 흰색 고체)을 수득하였다.Compound 4-bromo-4'-(methoxymethoxy)-1,1'-biphenyl (0.3 g, 1.02 mmol) prepared in step 1 was dissolved in pyrrolidine and then dissolved in Pd(PPh) at room temperature. 3 ) 4 (17 mg, 0.06 mmol) and propargyl alcohol (0.23 mL, 4.09 mmol) were added. The reaction mixture was degassed using a nitrogen balloon and then stirred at room temperature for 30 minutes. It was then heated to 100 °C and heated and stirred for 3 hours. After completion of the reaction, the mixture was cooled to room temperature, filtered through Celite, and then concentrated under reduced pressure. The obtained residue was diluted in ethyl acetate and washed with water and salt water. The residue of the organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0-30% ethyl acetate/hexane) to obtain the target compound (0.19 g, 69%, white solid).

단계 3 : 3-(4'-(메톡시메톡시)-[1,1'-비페닐]-4-일)프로피올알데히드의 제조Step 3: Preparation of 3-(4'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)propiolaldehyde

상기 단계 2에서 제조한 화합물 3-(4'-(메톡시메톡시)-[1,1'-비페닐]-4-일)프로프-2-인-1-올(192 mg, 0.71 mmol)을 디클로로메탄에 용해시킨 뒤, 0 °C에서 DMP(607 mg, 1.43 mmol)을 천천히 첨가하였다. 0 °C에서 30분 동안 교반하고 반응이 종결된 후, 디클로로메탄으로 희석시키고 물과 소금물로 씻어주었다. 유기층의 잔류물은 무수 황산나트륨으로 건조 및 여과한 다음 감압 농축하였다. 얻어진 잔사를 실리카겔 크로마토그래피법(0~20% 에틸아세테이트/헥산)으로 분리 및 정제하여, 목적화합물(161 mg, 84%, 흰색 고체)을 제조하였다.Compound 3-(4'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)prop-2-yn-1-ol (192 mg, 0.71 mmol) prepared in step 2 above. ) was dissolved in dichloromethane, and then DMP (607 mg, 1.43 mmol) was slowly added at 0 °C. After stirring at 0 °C for 30 minutes and the reaction was completed, it was diluted with dichloromethane and washed with water and salt water. The residue of the organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0-20% ethyl acetate/hexane) to prepare the target compound (161 mg, 84%, white solid).

단계 4 : 4-(2-((3-(4'-(메톡시메톡시)-[1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)페놀의 제조Step 4: 4-(2-((3-(4'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino) Manufacture of ethyl)phenol

상기 단계 3에서 제조한 화합물 3-(4'-(메톡시메톡시)-[1,1'-비페닐]-4-일)프로피올알데히드(50 mg, 0.18 mmol)을 메탄올에 용해시킨 뒤, 4-(2-아미노에틸)페놀(38 mg, 0.28 mmol)을 상온에서 첨가하였다. 상온에서 1시간동안 교반한 뒤, 0 ℃에서 소듐보로하이드라이드(21 mg, 0.56 mmol)을 천천히 첨가하였다. 30분동안 교반한 뒤, 증류수를 적가하여 반응을 종결시키고 에틸아세테이트로 추출하고 증류수로 씻어주었다. 추출한 유기층은 무수 황산나트륨으로 건조 및 여과한 다음 감압 농축하였다. 얻어진 잔사를 실리카겔 크로마토그래피법(0~50% 에틸아세테이트/헥산)으로 분리 및 정제하여, 목적화합물 4-(2-((3-(4'-(메톡시메톡시)-[1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)페놀(63 mg, 87%, 노란색 고체)을 수득하였다. Compound 3-(4'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)propiolaldehyde (50 mg, 0.18 mmol) prepared in step 3 was dissolved in methanol. , 4-(2-aminoethyl)phenol (38 mg, 0.28 mmol) was added at room temperature. After stirring at room temperature for 1 hour, sodium borohydride (21 mg, 0.56 mmol) was slowly added at 0°C. After stirring for 30 minutes, distilled water was added dropwise to terminate the reaction, extracted with ethyl acetate, and washed with distilled water. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0~50% ethyl acetate/hexane) to produce the target compound 4-(2-((3-(4'-(methoxymethoxy)-[1,1' -Biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)phenol (63 mg, 87%, yellow solid) was obtained.

1H NMR (400 MHz, CDCl3) δ 7.57 - 7.37 (m, 6H), 7.11 (d, J = 8.5 Hz, 4H), 6.77 (d, J = 8.4 Hz, 2H), 5.22 (s, 2H), 3.67 (s, 2H), 3.50 (s, 3H), 3.02 (t, J = 7.0 Hz, 2H), 2.80 (t, J = 7.0 Hz, 2H); LCMS, m/z 388[M+H]+ 1 H NMR (400 MHz, CDCl3) δ 7.57 - 7.37 (m, 6H), 7.11 (d, J = 8.5 Hz, 4H), 6.77 (d, J = 8.4 Hz, 2H), 5.22 (s, 2H), 3.67 (s, 2H), 3.50 (s, 3H), 3.02 (t, J = 7.0 Hz, 2H), 2.80 (t, J = 7.0 Hz, 2H); LCMS, m/z 388[M+H] +

<실시예 47> 4-클로로-2-(1-((3-(4'-(메톡시메톡시)-[1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)페놀의 제조<Example 47> 4-Chloro-2-(1-((3-(4'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)prop-2-yne- Preparation of 1-yl)amino)ethyl)phenol

상기 실시예 46의 단계 3에서 제조한 화합물 3-(4'-(메톡시메톡시)-[1,1'-비페닐]-4-일)프로피올알데히드(50 mg, 0.18 mmol)을 메탄올에 용해시킨 뒤, 2-(1-아미노에틸)-4-클로로페놀(32 mg, 0.18 mmol), 소듐보로하이드라이드(21 mg, 0.56 mmol)을 0 ℃에서 천천히 첨가하였다. 30분 동안 교반한 뒤, 증류수를 적가하여 반응을 종결시키고 디클로로메탄으로 추출하고 증류수로 씻어주었다. 추출한 유기층은 무수 황산나트륨으로 건조 및 여과한 다음 감압 농축하였다. 얻어진 잔사를 실리카겔 크로마토그래피법(0~20% 에틸아세테이트/헥산)으로 분리 및 정제하여, 목적화합물 4-클로로-2-(1-((3-(4'-(메톡시메톡시)-[1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)페놀(79 mg, 100%, 무색 끈적한 액체)을 수득하였다. Compound 3-(4'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)propiolaldehyde (50 mg, 0.18 mmol) prepared in step 3 of Example 46 was mixed with methanol. After dissolving in , 2-(1-aminoethyl)-4-chlorophenol (32 mg, 0.18 mmol) and sodium borohydride (21 mg, 0.56 mmol) were slowly added at 0°C. After stirring for 30 minutes, distilled water was added dropwise to terminate the reaction, extracted with dichloromethane, and washed with distilled water. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0~20% ethyl acetate/hexane) to produce the target compound 4-chloro-2-(1-((3-(4'-(methoxymethoxy)-[ 1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)phenol (79 mg, 100%, colorless sticky liquid) was obtained.

1H NMR (400 MHz, CDCl3) δ 7.55 - 7.50 (m, 4H), 7.46 (d, J = 8.5 Hz, 2H), 7.17 - 7.07 (m, 3H), 7.00 (d, J = 2.6 Hz, 1H), 6.76 (d, J = 8.6 Hz, 1H), 5.30 (s, 1H), 5.22 (s, 2H), 4.24 (q, J = 6.7 Hz, 1H), 3.75 (d, J = 17.4 Hz, 1H), 3.56 - 3.46 (m, 4H), 1.49 (d, J = 6.7 Hz, 3H); LCMS, m/z 422[M+H]+ 1H NMR (400 MHz, CDCl3) δ 7.55 - 7.50 (m, 4H), 7.46 (d, J = 8.5 Hz, 2H), 7.17 - 7.07 (m, 3H), 7.00 (d, J = 2.6 Hz, 1H) ), 6.76 (d, J = 8.6 Hz, 1H), 5.30 (s, 1H), 5.22 (s, 2H), 4.24 (q, J = 6.7 Hz, 1H), 3.75 (d, J = 17.4 Hz, 1H) ), 3.56 - 3.46 (m, 4H), 1.49 (d, J = 6.7 Hz, 3H); LCMS, m/z 422[M+H] +

<실시예 48> 4-(2-((3-(4-(피리딘-3-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀의 제조<Example 48> Preparation of 4-(2-((3-(4-(pyridin-3-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol

상기 실시예 38과 유사한 방법으로 목적화합물 4-(2-((3-(4-(피리딘-3-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀을 수득하였다.The target compound 4-(2-((3-(4-(pyridin-3-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol was obtained in a similar manner to Example 38. .

1H NMR (400 MHz, CDCl3) δ 8.84 (d, J = 1.8 Hz, 1H), 8.60 (dd, J = 4.8, 1.5 Hz, 1H), 7.92 - 7.83 (m, 1H), 7.59 - 7.46 (m, 4H), 7.38 (dd, J = 7.9, 4.8 Hz, 1H), 7.11 (d, J = 8.4 Hz, 2H), 6.78 (d, J = 8.4 Hz, 2H), 3.69 (s, 2H), 3.04 (t, J = 7.0 Hz, 2H), 2.81 (t, J = 7.0 Hz, 2H); LCMS, m/z 329[M+H]+ 1H NMR (400 MHz, CDCl3) δ 8.84 (d, J = 1.8 Hz, 1H), 8.60 (dd, J = 4.8, 1.5 Hz, 1H), 7.92 - 7.83 (m, 1H), 7.59 - 7.46 (m , 4H), 7.38 (dd, J = 7.9, 4.8 Hz, 1H), 7.11 (d, J = 8.4 Hz, 2H), 6.78 (d, J = 8.4 Hz, 2H), 3.69 (s, 2H), 3.04 (t, J = 7.0 Hz, 2H), 2.81 (t, J = 7.0 Hz, 2H); LCMS, m/z 329[M+H] +

<실시예 49> 4-클로로-2-(1-((3-(4-(피리딘-3-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀의 제조<Example 49> Preparation of 4-chloro-2-(1-((3-(4-(pyridin-3-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol

상기 실시예 39와 유사한 방법으로 목적화합물 4-클로로-2-(1-((3-(4-(피리딘-3-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀을 수득하였다.In a similar manner to Example 39, the target compound 4-chloro-2-(1-((3-(4-(pyridin-3-yl)phenyl)prop-2-yn-1-yl)amino)ethyl) Phenol was obtained.

1H NMR (400 MHz, CDCl3) δ 8.85 (d, J = 2.1 Hz, 1H), 8.61 (d, J = 4.8 Hz, 1H), 7.88 (d, J = 7.9 Hz, 1H), 7.57 - 7.52 (m, 4H), 7.38 (dd, J = 8.0, 4.8 Hz, 1H), 7.11 (dd, J = 8.7, 2.6 Hz, 1H), 7.00 (d, J = 2.6 Hz, 1H), 6.77 (d, J = 8.7 Hz, 1H), 4.23 (q, J = 6.7 Hz, 1H), 3.76 (d, J = 17.4 Hz, 1H), 3.53 (d, J = 17.4 Hz, 1H), 1.50 (d, J = 6.7 Hz, 3H); LCMS, m/z 363[M+H]+ 1H NMR (400 MHz, CDCl3) δ 8.85 (d, J = 2.1 Hz, 1H), 8.61 (d, J = 4.8 Hz, 1H), 7.88 (d, J = 7.9 Hz, 1H), 7.57 - 7.52 ( m, 4H), 7.38 (dd, J = 8.0, 4.8 Hz, 1H), 7.11 (dd, J = 8.7, 2.6 Hz, 1H), 7.00 (d, J = 2.6 Hz, 1H), 6.77 (d, J = 8.7 Hz, 1H), 4.23 (q, J = 6.7 Hz, 1H), 3.76 (d, J = 17.4 Hz, 1H), 3.53 (d, J = 17.4 Hz, 1H), 1.50 (d, J = 6.7 Hz, 3H); LCMS, m/z 363[M+H] +

<실시예 50> 4-(2-((3-(4-(피리딘-2-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀의 제조<Example 50> Preparation of 4-(2-((3-(4-(pyridin-2-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol

상기 실시예 38과 유사한 방법으로 목적화합물 4-(2-((3-(4-(피리딘-2-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀을 수득하였다.The target compound 4-(2-((3-(4-(pyridin-2-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol was obtained in a similar manner to Example 38. .

1H NMR (400 MHz, CDCl3) δ 8.69 (d, J = 4.8 Hz, 1H), 7.94 (d, J = 8.1 Hz, 2H), 7.76 - 7.71 (m, 2H), 7.50 (d, J = 8.1 Hz, 2H), 7.25 - 7.23 (m, 1H), 7.11 (d, J = 8.3 Hz, 2H), 6.77 (d, J = 8.3 Hz, 2H), 3.68 (s, 2H), 3.02 (t, J = 7.0 Hz, 2H), 2.80 (t, J = 7.0 Hz, 2H); LCMS, m/z 329[M+H]+ 1H NMR (400 MHz, CDCl3) δ 8.69 (d, J = 4.8 Hz, 1H), 7.94 (d, J = 8.1 Hz, 2H), 7.76 - 7.71 (m, 2H), 7.50 (d, J = 8.1 Hz, 2H), 7.25 - 7.23 (m, 1H), 7.11 (d, J = 8.3 Hz, 2H), 6.77 (d, J = 8.3 Hz, 2H), 3.68 (s, 2H), 3.02 (t, J = 7.0 Hz, 2H), 2.80 (t, J = 7.0 Hz, 2H); LCMS, m/z 329[M+H] +

<실시예 51> 4-클로로-2-(1-((3-(4-(피리딘-2-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀의 제조<Example 51> Preparation of 4-chloro-2-(1-((3-(4-(pyridin-2-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol

상기 실시예 39와 유사한 방법으로 목적화합물 4-클로로-2-(1-((3-(4-(피리딘-2-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀을 수득하였다.In a similar manner to Example 39, the target compound 4-chloro-2-(1-((3-(4-(pyridin-2-yl)phenyl)prop-2-yn-1-yl)amino)ethyl) Phenol was obtained.

1H NMR (400 MHz, CDCl3) δ 8.70 (d, J = 4.4 Hz, 1H), 7.98 (d, J = 8.5 Hz, 2H), 7.82 - 7.70 (m, 2H), 7.53 (d, J = 8.5 Hz, 2H), 7.27 - 7.24 (m, 1H), 7.11 (dd, J = 8.6, 2.6 Hz, 1H), 7.01 (d, J = 2.6 Hz, 1H), 6.77 (d, J = 8.6 Hz, 1H), 4.24 (q, J = 6.7 Hz, 1H), 3.76 (d, J = 17.4 Hz, 1H), 3.53 (d, J = 17.4 Hz, 1H), 1.50 (d, J = 6.8 Hz, 3H); LCMS, m/z 363[M+H]+ 1H NMR (400 MHz, CDCl 3 ) δ 8.70 (d, J = 4.4 Hz, 1H), 7.98 (d, J = 8.5 Hz, 2H), 7.82 - 7.70 (m, 2H), 7.53 (d, J = 8.5 Hz, 2H), 7.27 - 7.24 (m, 1H), 7.11 (dd, J = 8.6, 2.6 Hz, 1H), 7.01 (d, J = 2.6 Hz, 1H), 6.77 (d, J = 8.6 Hz, 1H), 4.24 (q, J = 6.7 Hz, 1H), 3.76 (d, J = 17.4 Hz, 1H), 3.53 (d, J = 17.4 Hz, 1H), 1.50 (d, J = 6.8 Hz, 3H) ; LCMS, m/z 363[M+H] +

<실시예 52> 4'-(3-((4-히드록시페네틸)아미노)프로프-1-인-1-일)-[1,1'-비페닐]-4-올의 제조<Example 52> Preparation of 4'-(3-((4-hydroxyphenethyl)amino)prop-1-yn-1-yl)-[1,1'-biphenyl]-4-ol

상기 실시예 46에서 제조한 화합물 4-(2-((3-(4'-(메톡시메톡시)-[1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)페놀(30 mg, 0.07 mmol)을 아이소프로판올에 용해시킨 뒤, 4M 염산 혼합용액(다이옥세인)(0.5 mL, 2.09 mmol)을 상온에서 적가하였다. 1시간 30분 동안 교반한 뒤, 탄산수소나트륨 수용액를 적가하여 반응을 종결시키고 디클로로메탄으로 추출하고 증류수로 씻어주었다. 추출한 유기층은 무수 황산나트륨으로 건조 및 여과한 다음 감압 농축하여, 목적화합물 4'-(3-((4-히드록시페네틸)아미노)프로프-1-인-1-일)-[1,1'-비페닐]-4-올(26 mg, 98%, 노란색 고체)을 수득하였다. Compound 4-(2-((3-(4'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)prop-2-yne-1 prepared in Example 46 -yl)amino)ethyl)phenol (30 mg, 0.07 mmol) was dissolved in isopropanol, and then 4M hydrochloric acid mixed solution (dioxane) (0.5 mL, 2.09 mmol) was added dropwise at room temperature. After stirring for 1 hour and 30 minutes, aqueous sodium bicarbonate solution was added dropwise to terminate the reaction, extracted with dichloromethane, and washed with distilled water. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to obtain the target compound 4'-(3-((4-hydroxyphenethyl)amino)prop-1-yn-1-yl)-[1,1. '-Biphenyl]-4-ol (26 mg, 98%, yellow solid) was obtained.

1H NMR (400 MHz, MeOD) δ 7.54 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.7 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 7.09 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 6.75 (d, J = 8.4 Hz, 2H), 3.65 (s, 2H), 2.96 (t, J = 7.4 Hz, 2H), 2.77 (t, J = 7.4 Hz, 2H); LCMS, m/z 344[M+H]+ 1H NMR (400 MHz, MeOD) δ 7.54 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.7 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 7.09 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 6.75 (d, J = 8.4 Hz, 2H), 3.65 (s, 2H), 2.96 (t, J = 7.4 Hz, 2H) , 2.77 (t, J = 7.4 Hz, 2H); LCMS, m/z 344[M+H] +

<실시예 53> 4'-(3-((1-(5-클로로-2-히드록시페닐)에틸)아미노)프로프-1-인-1-일)-[1,1'-비페닐]-4-올의 제조<Example 53> 4'-(3-((1-(5-chloro-2-hydroxyphenyl)ethyl)amino)prop-1-yn-1-yl)-[1,1'-biphenyl Preparation of ]-4-ol

상기 실시예 47에서 제조한 화합물 4-클로로-2-(1-((3-(4'-(메톡시메톡시)-[1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)페놀(68 mg, 0.16 mmol)을 아이소프로판올에 용해시킨 뒤, 4M 염산 혼합용액(다이옥세인)(0.5 mL, 2.09 mmol)을 상온에서 적가하였다. 1시간 30분 동안 교반한 뒤, 탄산수소나트륨 수용액를 적가하여 반응을 종결시키고 디클로로메탄으로 추출하고 증류수로 씻어주었다. 추출한 유기층은 무수 황산나트륨으로 건조 및 여과한 다음 감압 농축하여, 목적화합물 4'-(3-((1-(5-클로로-2-히드록시페닐)에틸)아미노)프로프-1-인-1-일)-[1,1'-비페닐]-4-올(40 mg, 67%, 흰색 고체)을 수득하였다. Compound 4-chloro-2-(1-((3-(4'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)prop-2 prepared in Example 47 -In-1-yl)amino)ethyl)phenol (68 mg, 0.16 mmol) was dissolved in isopropanol, and then 4M hydrochloric acid mixed solution (dioxane) (0.5 mL, 2.09 mmol) was added dropwise at room temperature. After stirring for 1 hour and 30 minutes, aqueous sodium bicarbonate solution was added dropwise to terminate the reaction, extracted with dichloromethane, and washed with distilled water. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to produce the target compound 4'-(3-((1-(5-chloro-2-hydroxyphenyl)ethyl)amino)prop-1-yn-1. -I)-[1,1'-biphenyl]-4-ol (40 mg, 67%, white solid) was obtained.

1H NMR (400 MHz, MeOD) δ 7.54 (d, J = 8.4 Hz, 2H), 7.51 - 7.46 (m, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.16 - 7.05 (m, 2H), 6.92 - 6.84 (m, 2H), 6.74 (d, J = 8.6 Hz, 1H), 4.26 (q, J = 6.7 Hz, 1H), 3.66 (d, J = 17.1 Hz, 1H), 3.48 (d, J = 17.1 Hz, 1H), 1.45 (d, J = 6.7 Hz, 3H); LCMS, m/z 378[M+H]+ 1 H NMR (400 MHz, MeOD) δ 7.54 (d, J = 8.4 Hz, 2H), 7.51 - 7.46 (m, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.16 - 7.05 (m, 2H) ), 6.92 - 6.84 (m, 2H), 6.74 (d, J = 8.6 Hz, 1H), 4.26 (q, J = 6.7 Hz, 1H), 3.66 (d, J = 17.1 Hz, 1H), 3.48 (d , J = 17.1 Hz, 1H), 1.45 (d, J = 6.7 Hz, 3H); LCMS, m/z 378[M+H] +

<실시예 54> 4-(2-((3-(4-(피리미딘-2-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀의 제조<Example 54> Preparation of 4-(2-((3-(4-(pyrimidin-2-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol

상기 실시예 38과 유사한 방법으로 목적화합물 4-(2-((3-(4-(피리미딘-2-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀을 수득하였다.The target compound 4-(2-((3-(4-(pyrimidin-2-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol was obtained in a similar manner to Example 38. did.

1H NMR (400 MHz, CDCl3) δ 8.81 (d, J = 4.8 Hz, 2H), 8.39 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.19 (dd, J = 4.8 Hz, 1H), 7.11 (d, J = 8.4 Hz, 2H), 6.77 (d, J = 8.4 Hz, 2H), 3.69 (s, 2H), 3.03 (t, J = 7.0 Hz, 2H), 2.80 (t, J = 7.0 Hz, 2H); LCMS, m/z 330[M+H]+ 1H NMR (400 MHz, CDCl3) δ 8.81 (d, J = 4.8 Hz, 2H), 8.39 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.19 (dd, J = 4.8 Hz, 1H), 7.11 (d, J = 8.4 Hz, 2H), 6.77 (d, J = 8.4 Hz, 2H), 3.69 (s, 2H), 3.03 (t, J = 7.0 Hz, 2H) , 2.80 (t, J = 7.0 Hz, 2H); LCMS, m/z 330[M+H] +

<실시예 55> 4-클로로-2-(1-((3-(4-(피리미딘-2-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀의 제조<Example 55> Preparation of 4-chloro-2-(1-((3-(4-(pyrimidin-2-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol

상기 실시예 39와 유사한 방법으로 목적화합물 4-클로로-2-(1-((3-(4-(피리미딘-2-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀을 수득하였다.In a manner similar to Example 39, the target compound 4-chloro-2-(1-((3-(4-(pyrimidin-2-yl)phenyl)prop-2-yn-1-yl)amino)ethyl ) Phenol was obtained.

1H NMR (400 MHz, CDCl3) δ 8.82 (d, J = 4.8 Hz, 2H), 8.42 (d, J = 8.3 Hz, 2H), 7.54 (d, J = 8.3 Hz, 2H), 7.21 (dd, J = 4.8 Hz, 1H), 7.11 (dd, J = 8.5, 2.4 Hz, 1H), 7.01 (d, J = 2.4 Hz, 1H), 6.77 (d, J = 8.5 Hz, 1H), 4.24 (q, J = 7.0 Hz, 1H), 3.77 (d, J = 17.4 Hz, 2H), 3.53 (d, J = 17.4 Hz, 2H), 1.50 (d, J = 7.0 Hz, 3H); LCMS, m/z 364[M+H]+ 1H NMR (400 MHz, CDCl3) δ 8.82 (d, J = 4.8 Hz, 2H), 8.42 (d, J = 8.3 Hz, 2H), 7.54 (d, J = 8.3 Hz, 2H), 7.21 (dd, J = 4.8 Hz, 1H), 7.11 (dd, J = 8.5, 2.4 Hz, 1H), 7.01 (d, J = 2.4 Hz, 1H), 6.77 (d, J = 8.5 Hz, 1H), 4.24 (q, J = 7.0 Hz, 1H), 3.77 (d, J = 17.4 Hz, 2H), 3.53 (d, J = 17.4 Hz, 2H), 1.50 (d, J = 7.0 Hz, 3H); LCMS, m/z 364[M+H] +

<실시예 56> 4-(2-((3-(4'-페녹시-[1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)페놀의 제조<Example 56> 4-(2-((3-(4'-phenoxy-[1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl) Manufacture of phenol

단계 1 : 4-브로모-4'-페녹시-1,1'-비페닐의 제조Step 1: Preparation of 4-bromo-4'-phenoxy-1,1'-biphenyl

4'-브로모-[1,1'-비페닐]-4-올(0.5 g, 2.00 mmol)을 1,4-다이옥세인에 용해시킨 뒤, 상온에서 아이오도벤젠(0.44 Ml, 4.01 mmol), Cs2CO3(1.3 g, 4.01 mmol), CuI(38 mg, 0.20 mmol), 2-(다이메틸아미노)아세틱에시드(83 mg, 0.80 mmol)을 첨가하였다. 질소 풍선을 이용하여 반응 혼합물을 탈기한 다음 상온에서 30분 교반하였다. 그 다음 110 °C로 가열하여 22시간 동안 가열 교반하였다. 반응 종결 후, 혼합물을 상온으로 식힌 뒤 셀라이트에 여과한 다음 감압 농축하였다. 얻어진 잔사는 디클로로메탄에 희석시키고 물과 소금물로 씻어주었다. 유기층의 잔류물은 무수 황산나트륨으로 건조 및 여과한 다음 감압 농축하였다. 얻어진 잔사를 실리카겔 크로마토그래피법(0~10% 에틸아세테이트/헥산)으로 분리 및 정제하여, 목적화합물 4-브로모-4'-페녹시-1,1'-비페닐(0.43 g, 66%, 흰색 고체)을 수득하였다.4'-Bromo-[1,1'-biphenyl]-4-ol (0.5 g, 2.00 mmol) was dissolved in 1,4-dioxane, and then iodobenzene (0.44 Ml, 4.01 mmol) was dissolved at room temperature. , Cs2CO3 (1.3 g, 4.01 mmol), CuI (38 mg, 0.20 mmol), and 2-(dimethylamino)acetic acid (83 mg, 0.80 mmol) were added. The reaction mixture was degassed using a nitrogen balloon and then stirred at room temperature for 30 minutes. It was then heated to 110 °C and heated and stirred for 22 hours. After completion of the reaction, the mixture was cooled to room temperature, filtered through Celite, and then concentrated under reduced pressure. The obtained residue was diluted in dichloromethane and washed with water and salt water. The residue of the organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0-10% ethyl acetate/hexane) to obtain the target compound 4-bromo-4'-phenoxy-1,1'-biphenyl (0.43 g, 66%, A white solid) was obtained.

단계 2 : 3-(4'-페녹시-[1,1'-비페닐]-4-일)프로프-2-인-1-올의 제조Step 2: Preparation of 3-(4'-phenoxy-[1,1'-biphenyl]-4-yl)prop-2-yn-1-ol

상기 단계 1에서 제조한 화합물 4-브로모-4'-페녹시-1,1'-비페닐(0.43 g, 1.33 mmol)을 피롤리딘에 용해시킨 뒤, 상온에서 Pd(PPh3)4(23 mg, 0.08 mmol), 프로파질알코올(0.30 mL, 5.34 mmol)을 첨가하였다. 질소 풍선을 이용하여 반응 혼합물을 탈기한 다음 상온에서 30분 교반하였다. 그 다음 100 °C로 가열하여 1시간 동안 가열 교반하였다. 반응 종결 후, 혼합물을 상온으로 식힌 뒤 셀라이트에 여과한 다음 감압 농축하였다. 얻어진 잔사는 디클로로메탄에 희석시키고 물과 소금물로 씻어주었다. 유기층의 잔류물은 무수 황산나트륨으로 건조 및 여과한 다음 감압 농축하였다. 얻어진 잔사를 실리카겔 크로마토그래피법(0~40% 에틸아세테이트/헥산)으로 분리 및 정제하여, 목적화합물 3-(4'-페녹시-[1,1'-비페닐]-4-일)프로프-2-인-1-올(0.30 g, 76%, 노란색 고체)을 수득하였다.Compound 4-bromo-4'-phenoxy-1,1'-biphenyl (0.43 g, 1.33 mmol) prepared in step 1 was dissolved in pyrrolidine and then dissolved in Pd(PPh 3 ) 4 ( 23 mg, 0.08 mmol) and propargyl alcohol (0.30 mL, 5.34 mmol) were added. The reaction mixture was degassed using a nitrogen balloon and then stirred at room temperature for 30 minutes. Then, it was heated to 100 °C and heated and stirred for 1 hour. After completion of the reaction, the mixture was cooled to room temperature, filtered through Celite, and then concentrated under reduced pressure. The obtained residue was diluted in dichloromethane and washed with water and salt water. The residue of the organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0~40% ethyl acetate/hexane) to produce the target compound 3-(4'-phenoxy-[1,1'-biphenyl]-4-yl)prop. -2-yn-1-ol (0.30 g, 76%, yellow solid) was obtained.

단계 3 : 3-(4'-페녹시-[1,1'-비페닐]-4-일)프로피올알데히드의 제조Step 3: Preparation of 3-(4'-phenoxy-[1,1'-biphenyl]-4-yl)propiolaldehyde

상기 단계 2에서 제조한 화합물 3-(4'-페녹시-[1,1'-비페닐]-4-일)프로프-2-인-1-올(0.30 g, 1.01 mmol)을 디클로로메탄에 용해시킨 뒤, 0 °C에서 DMP(0.64 g, 1.52 mmol)을 천천히 첨가하였다. 0 °C에서 1시간 30분 동안 교반하고 반응이 종결된 후, 디클로로메탄으로 희석시키고 물과 소금물로 씻어주었다. 유기층의 잔류물은 무수 황산나트륨으로 건조 및 여과한 다음 감압 농축하였다. 얻어진 잔사를 실리카겔 크로마토그래피법(0~25% 에틸아세테이트/헥산)으로 분리 및 정제하여, 목적화합물 3-(4'-페녹시-[1,1'-비페닐]-4-일)프로피올알데히드(0.24 g, 80%, 노란색 고체)을 제조하였다.Compound 3-(4'-phenoxy-[1,1'-biphenyl]-4-yl)prop-2-yn-1-ol (0.30 g, 1.01 mmol) prepared in step 2 was dissolved in dichloromethane. After dissolving in , DMP (0.64 g, 1.52 mmol) was slowly added at 0 °C. It was stirred at 0 °C for 1 hour and 30 minutes, and after the reaction was completed, it was diluted with dichloromethane and washed with water and salt water. The residue of the organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0~25% ethyl acetate/hexane) to produce the target compound 3-(4'-phenoxy-[1,1'-biphenyl]-4-yl)propiol. The aldehyde (0.24 g, 80%, yellow solid) was prepared.

단계 4 : 4-(2-((3-(4'-페녹시-[1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)페놀의 제조Step 4: 4-(2-((3-(4'-phenoxy-[1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)phenol manufacturing

상기 단계 3에서 제조한 화합물 3-(4'-페녹시-[1,1'-비페닐]-4-일)프로피올알데히드(50 mg, 0.16 mmol)을 메탄올에 용해시킨 뒤, 4-(2-아미노에틸)페놀(34 mg, 0.25 mmol)을 상온에서 첨가하였다. 상온에서 1시간동안 교반한 뒤, 0 ℃에서 소듐보로하이드라이드(19 mg, 0.50 mmol)을 천천히 첨가하였다. 30분동안 교반한 뒤, 증류수를 적가하여 반응을 종결시키고 디클로로메탄으로 추출하고 증류수로 씻어주었다. 추출한 유기층은 무수 황산나트륨으로 건조 및 여과한 다음 감압 농축하였다. 얻어진 잔사를 실리카겔 크로마토그래피법(0~5% 메탄올/디클로로메탄)으로 분리 및 정제하여, 목적화합물 4-(2-((3-(4'-페녹시-[1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)페놀(55 mg, 80%, 갈색 고체)을 수득하였다. Compound 3-(4'-phenoxy-[1,1'-biphenyl]-4-yl)propiolaldehyde (50 mg, 0.16 mmol) prepared in step 3 was dissolved in methanol, and then 4-( 2-Aminoethyl)phenol (34 mg, 0.25 mmol) was added at room temperature. After stirring at room temperature for 1 hour, sodium borohydride (19 mg, 0.50 mmol) was slowly added at 0°C. After stirring for 30 minutes, distilled water was added dropwise to terminate the reaction, extracted with dichloromethane, and washed with distilled water. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0~5% methanol/dichloromethane) to obtain the target compound 4-(2-((3-(4'-phenoxy-[1,1'-biphenyl] -4-yl)prop-2-yn-1-yl)amino)ethyl)phenol (55 mg, 80%, brown solid) was obtained.

1H NMR (400 MHz, CDCl3) δ 7.55 - 7.44 (m, 6H), 7.39 - 7.32 (m, 2H), 7.17 - 7.00 (m, 7H), 6.77 (d, J = 8.4 Hz, 2H), 3.67 (s, 2H), 3.02 (t, J = 7.0 Hz, 2H), 2.80 (t, J = 7.0 Hz, 2H); LCMS, m/z 420[M+H]+ 1 H NMR (400 MHz, CDCl3) δ 7.55 - 7.44 (m, 6H), 7.39 - 7.32 (m, 2H), 7.17 - 7.00 (m, 7H), 6.77 (d, J = 8.4 Hz, 2H), 3.67 (s, 2H), 3.02 (t, J = 7.0 Hz, 2H), 2.80 (t, J = 7.0 Hz, 2H); LCMS, m/z 420[M+H] +

<실시예 57> 4-클로로-2-(1-((3-(4'-페녹시-[1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)페놀의 제조<Example 57> 4-Chloro-2-(1-((3-(4'-phenoxy-[1,1'-biphenyl]-4-yl)prop-2-yn-1-yl) Production of amino)ethyl)phenol

상기 실시예 56의 단계 3에서 제조한 화합물 3-(4'-페녹시-[1,1'-비페닐]-4-일)프로피올알데히드(50 mg, 0.16 mmol)을 메탄올에 용해시킨 뒤, 2-(1-아미노에틸)-4-클로로페놀(43 mg, 0.25 mmol), 소듐보로하이드라이드(19 mg, 0.50 mmol)을 0 ℃에서 천천히 첨가하였다. 30분 동안 교반한 뒤, 증류수를 적가하여 반응을 종결시키고 디클로로메탄으로 추출하고 증류수로 씻어주었다. 추출한 유기층은 무수 황산나트륨으로 건조 및 여과한 다음 감압 농축하였다. 얻어진 잔사를 실리카겔 크로마토그래피법(0~25% 에틸아세테이트/헥산)으로 분리 및 정제하여, 목적화합물 4-클로로-2-(1-((3-(4'-페녹시-[1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)페놀(65 mg, 85%, 무색 끈적한 액체)을 수득하였다. Compound 3-(4'-phenoxy-[1,1'-biphenyl]-4-yl)propiolaldehyde (50 mg, 0.16 mmol) prepared in step 3 of Example 56 was dissolved in methanol. , 2-(1-aminoethyl)-4-chlorophenol (43 mg, 0.25 mmol), and sodium borohydride (19 mg, 0.50 mmol) were added slowly at 0°C. After stirring for 30 minutes, distilled water was added dropwise to terminate the reaction, extracted with dichloromethane, and washed with distilled water. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0~25% ethyl acetate/hexane) to produce the target compound 4-chloro-2-(1-((3-(4'-phenoxy-[1,1' -Biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)phenol (65 mg, 85%, colorless sticky liquid) was obtained.

1H NMR (400 MHz, CDCl3) δ 7.60 - 7.50 (m, 4H), 7.51 - 7.45 (m, 2H), 7.40 - 7.33 (m, 2H), 7.19 - 7.04 (m, 6H), 7.00 (d, J = 2.6 Hz, 1H), 6.77 (d, J = 8.6 Hz, 1H), 4.24 (q, J = 6.7 Hz, 1H), 3.75 (d, J = 17.4 Hz, 1H), 3.52 (d, J = 17.4 Hz, 1H), 1.49 (d, J = 6.7 Hz, 3H); LCMS, m/z 454[M+H]+ 1 H NMR (400 MHz, CDCl3) δ 7.60 - 7.50 (m, 4H), 7.51 - 7.45 (m, 2H), 7.40 - 7.33 (m, 2H), 7.19 - 7.04 (m, 6H), 7.00 (d, J = 2.6 Hz, 1H), 6.77 (d, J = 8.6 Hz, 1H), 4.24 (q, J = 6.7 Hz, 1H), 3.75 (d, J = 17.4 Hz, 1H), 3.52 (d, J = 17.4 Hz, 1H), 1.49 (d, J = 6.7 Hz, 3H); LCMS, m/z 454[M+H] +

<실시예 58> 4-(2-((3-(4-(피리미딘-5-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀의 제조<Example 58> Preparation of 4-(2-((3-(4-(pyrimidin-5-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol

상기 실시예 38과 유사한 방법으로 목적화합물 4-(2-((3-(4-(피리미딘-5-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀을 수득하였다.The target compound 4-(2-((3-(4-(pyrimidin-5-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol was obtained in a similar manner to Example 38. did.

1H NMR (400 MHz, CDCl3) δ 9.21 (s, 1H), 8.95 (s, 2H), 7.55 - 7.52 (m, 4H), 7.11 (d, J = 8.5 Hz, 2H), 6.78 (d, J = 8.5 Hz, 2H), 3.68 (s, 2H), 3.02 (t, J = 7.0 Hz, 2H), 2.80 (t, J = 7.0 Hz, 2H); LCMS, m/z 330[M+H]+ 1H NMR (400 MHz, CDCl3) δ 9.21 (s, 1H), 8.95 (s, 2H), 7.55 - 7.52 (m, 4H), 7.11 (d, J = 8.5 Hz, 2H), 6.78 (d, J = 8.5 Hz, 2H), 3.68 (s, 2H), 3.02 (t, J = 7.0 Hz, 2H), 2.80 (t, J = 7.0 Hz, 2H); LCMS, m/z 330[M+H] +

<실시예 59> 4-클로로-2-(1-((3-(4-(피리미딘-5-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀의 제조<Example 59> Preparation of 4-chloro-2-(1-((3-(4-(pyrimidin-5-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol

상기 실시예 39와 유사한 방법으로 목적화합물 4-클로로-2-(1-((3-(4-(피리미딘-5-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀을 수득하였다.In a similar manner to Example 39, the target compound 4-chloro-2-(1-((3-(4-(pyrimidin-5-yl)phenyl)prop-2-yn-1-yl)amino)ethyl ) Phenol was obtained.

1H NMR (400 MHz, CDCl3) δ 9.22 (s, 1H), 8.96 (s, 2H), 7.56 (s, 4H), 7.12 (dd, J = 8.6, 2.6 Hz, 1H), 7.00 (d, J = 2.6 Hz, 1H), 6.77 (d, J = 8.6 Hz, 1H), 4.22 (q, J = 6.7 Hz, 1H), 3.77 (d, J = 17.4 Hz, 1H), 3.54 (d, J = 17.4 Hz, 1H), 1.50 (d, J = 6.7 Hz, 3H); LCMS, m/z 364[M+H]+ 1H NMR (400 MHz, CDCl3) δ 9.22 (s, 1H), 8.96 (s, 2H), 7.56 (s, 4H), 7.12 (dd, J = 8.6, 2.6 Hz, 1H), 7.00 (d, J = 2.6 Hz, 1H), 6.77 (d, J = 8.6 Hz, 1H), 4.22 (q, J = 6.7 Hz, 1H), 3.77 (d, J = 17.4 Hz, 1H), 3.54 (d, J = 17.4 Hz, 1H), 1.50 (d, J = 6.7 Hz, 3H); LCMS, m/z 364[M+H] +

<실시예 60> 4-(2-((3-(4-(4-이소프로필피페라진-1-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀의 제조<Example 60> Preparation of 4-(2-((3-(4-(4-isopropylpiperazin-1-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol

단계 1 : 1-(4-브로모페닐)-4-이소프로필피페라진의 제조Step 1: Preparation of 1-(4-bromophenyl)-4-isopropylpiperazine

1-(4-브로모페닐)피페라진(0.5 g, 2.07 mmol)을 아세토나이트릴에 용해시킨 뒤, 상온에서 2-아이오도프로판(0.84 g, 4.98 mmol), 탄산칼륨(0.57 g, 4.15 mmol)을 첨가하였다. 65 °C로 가열하여 3시간 30분 동안 교반한 뒤, 혼합물에 증류수를 적가하여 반응을 종결시킨 뒤, 디클로로메탄으로 추출하고 소금물로 씻어주었다. 추출한 유기층은 무수 황산나트륨으로 건조 및 여과하고 감압 농축하였다. 얻어진 잔사를 실리카겔 크로마토그래피법(0~70% 에틸아세테이트 혼합용액(1% 트리에틸아민)/헥산)으로 분리 및 정제하여, 목적화합물 1-(4-브로모페닐)-4-이소프로필피페라진(0.50 g, 87%, 흰색 고체)을 수득하였다.1-(4-bromophenyl)piperazine (0.5 g, 2.07 mmol) was dissolved in acetonitrile, and then 2-iodopropane (0.84 g, 4.98 mmol) and potassium carbonate (0.57 g, 4.15 mmol) were dissolved in acetonitrile. ) was added. After heating to 65 °C and stirring for 3 hours and 30 minutes, distilled water was added dropwise to the mixture to terminate the reaction, followed by extraction with dichloromethane and washing with salt water. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0~70% ethyl acetate mixed solution (1% triethylamine)/hexane) to produce the target compound 1-(4-bromophenyl)-4-isopropylpiperazine. (0.50 g, 87%, white solid) was obtained.

단계 2 : 3-(4-(4-이소프로필피페라진-1-일)페닐)프로프-2-인-1-올의 제조Step 2: Preparation of 3-(4-(4-isopropylpiperazin-1-yl)phenyl)prop-2-yn-1-ol

상기 단계 1에서 제조한 화합물 1-(4-브로모페닐)-4-이소프로필피페라진(0.50 g, 1.79 mmol)을 피롤리딘에 용해시킨 뒤, 상온에서 Pd(PPh3)4(31 mg, 0.10 mmol), 프로파질알코올(0.41 mL, 7.17 mmol)을 첨가하였다. 질소 풍선을 이용하여 반응 혼합물을 탈기한 다음 상온에서 30분 교반하였다. 그 다음 110 °C로 가열하여 3시간 동안 가열 교반하였다. 반응 종결 후, 혼합물을 상온으로 식힌 뒤 셀라이트에 여과한 다음 감압 농축하였다. 얻어진 잔사는 에틸 아세테이트에 희석시키고 물과 소금물로 씻어주었다. 유기층의 잔류물은 무수 황산나트륨으로 건조 및 여과한 다음 감압 농축하였다. 얻어진 잔사를 실리카겔 크로마토그래피법(0~5% 메탄올/디클로로메탄)으로 분리 및 정제하여, 목적화합물 3-(4-(4-이소프로필피페라진-1-일)페닐)프로프-2-인-1-올(0.16 g, 36%, 흰색 고체)을 수득하였다. Compound 1-(4-bromophenyl)-4-isopropylpiperazine (0.50 g, 1.79 mmol) prepared in step 1 was dissolved in pyrrolidine, and then added to Pd(PPh 3 ) 4 (31 mg) at room temperature. , 0.10 mmol) and propargyl alcohol (0.41 mL, 7.17 mmol) were added. The reaction mixture was degassed using a nitrogen balloon and then stirred at room temperature for 30 minutes. It was then heated to 110 °C and heated and stirred for 3 hours. After completion of the reaction, the mixture was cooled to room temperature, filtered through Celite, and then concentrated under reduced pressure. The obtained residue was diluted in ethyl acetate and washed with water and salt water. The residue of the organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0~5% methanol/dichloromethane) to produce the target compound 3-(4-(4-isopropylpiperazin-1-yl)phenyl)prop-2-yne. -1-ol (0.16 g, 36%, white solid) was obtained.

단계 3 : 3-(4-(4-이소프로필피페라진-1-일)페닐)프로피올알데히드의 제조Step 3: Preparation of 3-(4-(4-isopropylpiperazin-1-yl)phenyl)propiolaldehyde

상기 단계 2에서 제조한 화합물 3-(4-(4-이소프로필피페라진-1-일)페닐)프로프-2-인-1-올(168 mg, 0.65 mmol)을 디클로로메탄에 용해시킨 뒤, 0 °C에서 DMP(414 mg, 0.97 mmol)을 천천히 첨가하였다. 0 °C에서 30분 동안 교반하고 반응이 종결된 후, 디클로로메탄으로 희석시키고 물과 소금물로 씻어주었다. 유기층의 잔류물은 무수 황산나트륨으로 건조 및 여과한 다음 감압 농축하였다. 얻어진 잔사를 실리카겔 크로마토그래피법(0~5% 메탄올/디클로로메탄)으로 분리 및 정제하여, 목적화합물 3-(4-(4-이소프로필피페라진-1-일)페닐)프로피올알데히드(107 mg, 64%, 노란색 고체)을 제조하였다.Compound 3-(4-(4-isopropylpiperazin-1-yl)phenyl)prop-2-yn-1-ol (168 mg, 0.65 mmol) prepared in step 2 was dissolved in dichloromethane. , DMP (414 mg, 0.97 mmol) was added slowly at 0 °C. After stirring at 0 °C for 30 minutes and the reaction was completed, it was diluted with dichloromethane and washed with water and salt water. The residue of the organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0~5% methanol/dichloromethane), and the target compound 3-(4-(4-isopropylpiperazin-1-yl)phenyl)propialdehyde (107 mg) was obtained. , 64%, yellow solid) was prepared.

단계 4 : 4-(2-((3-(4-(4-이소프로필피페라진-1-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀의 제조Step 4: Preparation of 4-(2-((3-(4-(4-isopropylpiperazin-1-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol

상기 단계 3에서 제조한 화합물 3-(4-(4-이소프로필피페라진-1-일)페닐)프로피올알데히드(50 mg, 0.19 mmol)을 메탄올에 용해시킨 뒤, 4-(2-아미노에틸)페놀(40 mg, 0.29 mmol), 소듐보로하이드라이드(22 mg, 0.58 mmol)을 천천히 첨가하였다. 30분동안 교반한 뒤, 증류수를 적가하여 반응을 종결시키고 디클로로메탄으로 추출하고 증류수로 씻어주었다. 추출한 유기층은 무수 황산나트륨으로 건조 및 여과한 다음 감압 농축하였다. 얻어진 잔사를 실리카겔 크로마토그래피법(0~100% 에틸아세테이트 혼합용액(1% 트리에틸아민)/헥산)으로 분리 및 정제하여, 목적화합물 4-(2-((3-(4-(4-이소프로필피페라진-1-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀(25 mg, 34%, 흰색 고체)을 수득하였다. Compound 3-(4-(4-isopropylpiperazin-1-yl)phenyl)propiolaldehyde (50 mg, 0.19 mmol) prepared in step 3 was dissolved in methanol, and then dissolved in 4-(2-aminoethyl). ) Phenol (40 mg, 0.29 mmol) and sodium borohydride (22 mg, 0.58 mmol) were added slowly. After stirring for 30 minutes, distilled water was added dropwise to terminate the reaction, extracted with dichloromethane, and washed with distilled water. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0~100% ethyl acetate mixed solution (1% triethylamine)/hexane), and the target compound 4-(2-((3-(4-(4-iso) Propylpiperazin-1-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol (25 mg, 34%, white solid) was obtained.

1H NMR (400 MHz, CDCl3) δ 7.29 (d, J = 8.7 Hz, 2H), 7.09 (d, J = 8.4 Hz, 2H), 6.82 (d, J = 8.7 Hz, 2H), 6.75 (d, J = 8.4 Hz, 2H), 3.63 (s, 2H), 3.29 - 3.17 (m, 4H), 2.99 (t, J = 7.1 Hz, 2H), 2.78 (t, J = 7.1 Hz, 2H), 2.74 (q, J = 6.5 Hz, 1H), 2.70 - 2.64 (m, 4H), 1.09 (d, J = 6.5 Hz, 6H); LCMS, m/z 374[M+H]+ 1H NMR (400 MHz, CDCl3) δ 7.29 (d, J = 8.7 Hz, 2H), 7.09 (d, J = 8.4 Hz, 2H), 6.82 (d, J = 8.7 Hz, 2H), 6.75 (d, J = 8.4 Hz, 2H), 3.63 (s, 2H), 3.29 - 3.17 (m, 4H), 2.99 (t, J = 7.1 Hz, 2H), 2.78 (t, J = 7.1 Hz, 2H), 2.74 ( q, J = 6.5 Hz, 1H), 2.70 - 2.64 (m, 4H), 1.09 (d, J = 6.5 Hz, 6H); LCMS, m/z 374[M+H] +

<실시예 61> 1-(4-(4-(3-((4-히드록시펜에틸)아미노)프로프-1-인-1-일)페닐)피페라진-1-일)에탄-1-온의 제조<Example 61> 1-(4-(4-(3-((4-hydroxyphenethyl)amino)prop-1-yn-1-yl)phenyl)piperazin-1-yl)ethane-1 -manufacture of

단계 1 : 1-(4-(4-브로모페닐)피페라진-1-일)에탄-1-온의 제조Step 1: Preparation of 1-(4-(4-bromophenyl)piperazin-1-yl)ethan-1-one

1-(4-브로모페닐)피페라진(0.5 g, 2.07 mmol)을 디클로로메탄에 용해시킨 뒤, 0 °C에서 아세틸클로라이드(0.29 g, 3.73 mmol), 트리에틸아민(0.57 mL, 4.15 mmol)을 첨가하였다. 1시간 동안 교반한 뒤, 혼합물에 증류수를 적가하여 반응을 종결시킨 뒤, 디클로로메탄으로 추출하고 소금물로 씻어주었다. 추출한 유기층은 무수 황산나트륨으로 건조 및 여과하고 감압 농축하여, 목적화합물 1-(4-(4-브로모페닐)피페라진-1-일)에탄-1-온(0.56 g, 96%, 흰색 고체)을 수득하였다.1-(4-Bromophenyl)piperazine (0.5 g, 2.07 mmol) was dissolved in dichloromethane, and then acetylchloride (0.29 g, 3.73 mmol) and triethylamine (0.57 mL, 4.15 mmol) were added at 0 °C. was added. After stirring for 1 hour, distilled water was added dropwise to the mixture to terminate the reaction, extracted with dichloromethane, and washed with salt water. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target compound 1-(4-(4-bromophenyl)piperazin-1-yl)ethan-1-one (0.56 g, 96%, white solid). was obtained.

단계 2 : 1-(4-(4-(3-히드록시프로프-1-인-1-일)페닐)피페라진-1-일)에탄-1-온의 제조Step 2: Preparation of 1-(4-(4-(3-hydroxyprop-1-yn-1-yl)phenyl)piperazin-1-yl)ethan-1-one

상기 단계 1에서 제조한 화합물 1-(4-(4-브로모페닐)피페라진-1-일)에탄-1-온(0.56 g, 1.98 mmol)을 피롤리딘에 용해시킨 뒤, 상온에서 Pd(PPh3)4(34 mg, 0.11 mmol), 프로파질알코올(0.45 mL, 7.94 mmol)을 첨가하였다. 질소 풍선을 이용하여 반응 혼합물을 탈기한 다음 상온에서 30분 교반하였다. 그 다음 100 °C로 가열하여 5시간 동안 가열 교반하였다. 반응 종결 후, 혼합물을 상온으로 식힌 뒤 셀라이트에 여과한 다음 감압 농축하였다. 얻어진 잔사는 에틸 아세테이트에 희석시키고 물과 소금물로 씻어주었다. 유기층의 잔류물은 무수 황산나트륨으로 건조 및 여과한 다음 감압 농축하였다. 얻어진 잔사를 실리카겔 크로마토그래피법(0~5% 메탄올/디클로로메탄)으로 분리 및 정제하여, 목적화합물 1-(4-(4-(3-히드록시프로프-1-인-1-일)페닐)피페라진-1-일)에탄-1-온(0.14 g, 28%, 갈색 고체)을 수득하였다. Compound 1-(4-(4-bromophenyl)piperazin-1-yl)ethan-1-one (0.56 g, 1.98 mmol) prepared in step 1 was dissolved in pyrrolidine, and then dissolved in Pd at room temperature. (PPh 3 ) 4 (34 mg, 0.11 mmol) and propargyl alcohol (0.45 mL, 7.94 mmol) were added. The reaction mixture was degassed using a nitrogen balloon and then stirred at room temperature for 30 minutes. It was then heated to 100 °C and heated and stirred for 5 hours. After completion of the reaction, the mixture was cooled to room temperature, filtered through Celite, and then concentrated under reduced pressure. The obtained residue was diluted in ethyl acetate and washed with water and salt water. The residue of the organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0~5% methanol/dichloromethane) to produce the target compound 1-(4-(4-(3-hydroxyprop-1-yn-1-yl)phenyl. )piperazin-1-yl)ethan-1-one (0.14 g, 28%, brown solid) was obtained.

단계 3 : 3-(4'-(메톡시메톡시)-[1,1'-비페닐]-4-일)프로피올알데히드의 제조Step 3: Preparation of 3-(4'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)propiolaldehyde

상기 단계 2에서 제조한 화합물 1-(4-(4-(3-히드록시프로프-1-인-1-일)페닐)피페라진-1-일)에탄-1-온(145 mg, 0.56 mmol)을 디클로로메탄에 용해시킨 뒤, 0 °C에서 DMP(357 mg, 0.84 mmol)을 천천히 첨가하였다. 0 °C에서 3시간 동안 교반하고 반응이 종결된 후, 디클로로메탄으로 희석시키고 물과 소금물로 씻어주었다. 유기층의 잔류물은 무수 황산나트륨으로 건조 및 여과한 다음 감압 농축하였다. 얻어진 잔사를 실리카겔 크로마토그래피법(0~5% 메탄올/디클로로메탄)으로 분리 및 정제하여, 목적화합물 3-(4'-(메톡시메톡시)-[1,1'-비페닐]-4-일)프로피올알데히드(100 mg, 69%, 갈색 고체)을 제조하였다.Compound 1-(4-(4-(3-hydroxyprop-1-yn-1-yl)phenyl)piperazin-1-yl)ethan-1-one (145 mg, 0.56 mg) prepared in step 2 above. mmol) was dissolved in dichloromethane, and then DMP (357 mg, 0.84 mmol) was slowly added at 0 °C. After stirring at 0 °C for 3 hours and the reaction was completed, it was diluted with dichloromethane and washed with water and salt water. The residue of the organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0~5% methanol/dichloromethane), and the target compound 3-(4'-(methoxymethoxy)-[1,1'-biphenyl]-4- 1) Propionaldehyde (100 mg, 69%, brown solid) was prepared.

단계 4 : 1-(4-(4-(3-((4-히드록시펜에틸)아미노)프로프-1-인-1-일)페닐)피페라진-1-일)에탄-1-온의 제조Step 4: 1-(4-(4-(3-((4-hydroxyphenethyl)amino)prop-1-yn-1-yl)phenyl)piperazin-1-yl)ethan-1-one manufacture of

상기 단계 3에서 제조한 화합물 3-(4'-(메톡시메톡시)-[1,1'-비페닐]-4-일)프로피올알데히드(100 mg, 0.39 mmol)을 메탄올에 용해시킨 뒤, 4-(2-아미노에틸)페놀(80 mg, 0.58 mmol), 소듐보로하이드라이드(21 mg, 0.56 mmol)을 천천히 첨가하였다. 30분동안 교반한 뒤, 증류수를 적가하여 반응을 종결시키고 디클로로메탄으로 추출하고 증류수로 씻어주었다. 추출한 유기층은 무수 황산나트륨으로 건조 및 여과한 다음 감압 농축하였다. 얻어진 잔사를 실리카겔 크로마토그래피법(0~5% 메탄올/디클로로메탄)으로 분리 및 정제하여, 목적화합물 1-(4-(4-(3-((4-히드록시펜에틸)아미노)프로프-1-인-1-일)페닐)피페라진-1-일)에탄-1-온(35 mg, 23%, 노란색 고체)을 수득하였다. Compound 3-(4'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)propiol aldehyde (100 mg, 0.39 mmol) prepared in step 3 was dissolved in methanol. , 4-(2-aminoethyl)phenol (80 mg, 0.58 mmol), and sodium borohydride (21 mg, 0.56 mmol) were slowly added. After stirring for 30 minutes, distilled water was added dropwise to terminate the reaction, extracted with dichloromethane, and washed with distilled water. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0~5% methanol/dichloromethane) to produce the target compound 1-(4-(4-(3-((4-hydroxyphenethyl)amino)prop- 1-yn-1-yl)phenyl)piperazin-1-yl)ethan-1-one (35 mg, 23%, yellow solid) was obtained.

1H NMR (400 MHz, CDCl3) δ 7.29 (d, J = 8.7 Hz, 2H), 7.09 (d, J = 8.4 Hz, 2H), 6.82 (d, J = 8.7 Hz, 2H), 6.75 (d, J = 8.4 Hz, 2H), 3.63 (s, 2H), 3.29 - 3.17 (m, 4H), 2.99 (t, J = 7.1 Hz, 2H), 2.78 (t, J = 7.1 Hz, 2H), 2.74 (q, J = 6.5 Hz, 1H), 2.70 - 2.64 (m, 4H), 1.09 (d, J = 6.5 Hz, 6H); LCMS, m/z 378[M+H]+ 1H NMR (400 MHz, CDCl3) δ 7.29 (d, J = 8.7 Hz, 2H), 7.09 (d, J = 8.4 Hz, 2H), 6.82 (d, J = 8.7 Hz, 2H), 6.75 (d, J = 8.4 Hz, 2H), 3.63 (s, 2H), 3.29 - 3.17 (m, 4H), 2.99 (t, J = 7.1 Hz, 2H), 2.78 (t, J = 7.1 Hz, 2H), 2.74 ( q, J = 6.5 Hz, 1H), 2.70 - 2.64 (m, 4H), 1.09 (d, J = 6.5 Hz, 6H); LCMS, m/z 378[M+H] +

<실시예 62> 2,2,2-트리플루오로-1-(4-(4-(3-((4-히드록시펜에틸)아미노)프로프-1-인-1-일)페닐)피페라진-1-일)에탄-1-온의 제조<Example 62> 2,2,2-trifluoro-1-(4-(4-(3-((4-hydroxyphenethyl)amino)prop-1-yn-1-yl)phenyl) Preparation of piperazin-1-yl)ethan-1-one

단계 1 : tert-부틸 (3-(4-(4-아세틸피페라진-1-일)페닐)프로프-2-인-1-일)(4-히드록시펜에틸)카르바메이트의 제조Step 1: Preparation of tert-butyl (3-(4-(4-acetylpiperazin-1-yl)phenyl)prop-2-yn-1-yl)(4-hydroxyphenethyl)carbamate

상기 실시예 61에서 제조한 화합물 1-(4-(4-(3-((4-히드록시펜에틸)아미노)프로프-1-인-1-일)페닐)피페라진-1-일)에탄-1-온(80 mg, 0.21 mmol)을 디클로로메탄에 용해시킨 뒤, 상온에서 디-tert-부틸 디카보네이트(55 mg, 0.25 mmol), 트리에틸아민(44 μL, 0.31 mmol)을 첨가하였다. 30분동안 교반하고 감압 농축하였다. 얻어진 잔사를 실리카겔 크로마토그래피법(0~50% 에틸아세테이트/헥산)으로 분리 및 정제하여, 목적화합물 tert-부틸 (3-(4-(4-아세틸피페라진-1-일)페닐)프로프-2-인-1-일)(4-히드록시펜에틸)카르바메이트(51 mg, 50%, 흰색 고체)을 수득하였다.Compound 1-(4-(4-(3-((4-hydroxyphenethyl)amino)prop-1-yn-1-yl)phenyl)piperazin-1-yl) prepared in Example 61 Ethane-1-one (80 mg, 0.21 mmol) was dissolved in dichloromethane, and then di-tert-butyl dicarbonate (55 mg, 0.25 mmol) and triethylamine (44 μL, 0.31 mmol) were added at room temperature. . The mixture was stirred for 30 minutes and concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0~50% ethyl acetate/hexane) to produce the target compound tert-butyl (3-(4-(4-acetylpiperazin-1-yl)phenyl)prop- 2-yn-1-yl)(4-hydroxyphenethyl)carbamate (51 mg, 50%, white solid) was obtained.

단계 2 : tert-부틸 (4-히드록시펜에틸)(3-(4-(피페라진-1-일)페닐)프로프-2-인-1-일)카르바메이트의 제조Step 2: Preparation of tert-butyl (4-hydroxyphenethyl)(3-(4-(piperazin-1-yl)phenyl)prop-2-yn-1-yl)carbamate

상기 단계 1에서 제조한 화합물 tert-부틸 (3-(4-(4-아세틸피페라진-1-일)페닐)프로프-2-인-1-일)(4-히드록시펜에틸)카르바메이트(51 mg, 0.10 mmol)을 에탄올에 용해시킨 뒤, 상온에서 2M 소듐하이드록사이드(0.32 mL, 0.64 mmol)을 첨가하였다. 80 °C로 가열하여 24시간 동안 가열 교반하였다. 반응 종결 후, 혼합물을 상온으로 식히고 염화암모늄 수용액으로 반응을 종결시켰다. 혼합물을 디클로로메탄에 희석시키고 물과 소금물로 씻어주었다. 유기층의 잔류물은 무수 황산나트륨으로 건조 및 여과한 다음 감압 농축하여, 목적화합물 tert-부틸 (4-히드록시펜에틸)(3-(4-(피페라진-1-일)페닐)프로프-2-인-1-일)카르바메이트(45 mg, 97%, 흰색 고체)을 수득하였다.Compound prepared in step 1 above tert-butyl (3-(4-(4-acetylpiperazin-1-yl)phenyl)prop-2-yn-1-yl)(4-hydroxyphenethyl)carba Mate (51 mg, 0.10 mmol) was dissolved in ethanol, and 2M sodium hydroxide (0.32 mL, 0.64 mmol) was added at room temperature. It was heated to 80 °C and stirred for 24 hours. After completion of the reaction, the mixture was cooled to room temperature and the reaction was terminated with an aqueous ammonium chloride solution. The mixture was diluted in dichloromethane and washed with water and salt water. The residue of the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target compound, tert-butyl (4-hydroxyphenethyl) (3- (4- (piperazin-1-yl) phenyl) prop-2. -In-1-yl)carbamate (45 mg, 97%, white solid) was obtained.

단계 3 : tert-부틸 (4-히드록시펜에틸)(3-(4-(4-(2,2,2-트리플루오로아세틸)피페라진-1-일)페닐)프로프-2-인-1-일)카르바메이트의 제조Step 3: tert-Butyl (4-hydroxyphenethyl)(3-(4-(4-(2,2,2-trifluoroacetyl)piperazin-1-yl)phenyl)prop-2-yne -1-day) Preparation of carbamate

상기 단계 2에서 제조한 화합물 tert-부틸 (4-히드록시펜에틸)(3-(4-(피페라진-1-일)페닐)프로프-2-인-1-일)카르바메이트(45 mg, 0.10 mmol)을 디클로로메탄에 용해시킨 뒤, 0 °C에서 2,2,2-트리플루오로아세트산 무수물 (29 μL, 0.20 mmol), 트리에틸아민(29 μL, 0.20 mmol)을 천천히 첨가하였다. 0 °C에서 30분 동안 교반하고 반응이 종결된 후, 에틸아세테이트으로 희석시키고 증류수과 소금물로 씻어주었다. 유기층의 잔류물은 무수 황산나트륨으로 건조 및 여과한 다음 감압 농축하였다. 얻어진 잔사를 실리카겔 크로마토그래피법(0~30% 에틸아세테이트/헥산)으로 분리 및 정제하여, 목적화합물 tert-부틸 (4-히드록시펜에틸)(3-(4-(4-(2,2,2-트리플루오로아세틸)피페라진-1-일)페닐)프로프-2-인-1-일)카르바메이트(50 mg, 91%, 붉은색 고체)을 제조하였다.Compound tert-butyl (4-hydroxyphenethyl) (3- (4- (piperazin-1-yl) phenyl) prop-2-yn-1-yl) carbamate (45) prepared in step 2 above mg, 0.10 mmol) was dissolved in dichloromethane, and then 2,2,2-trifluoroacetic anhydride (29 μL, 0.20 mmol) and triethylamine (29 μL, 0.20 mmol) were slowly added at 0 °C. . It was stirred at 0 °C for 30 minutes and after the reaction was completed, it was diluted with ethyl acetate and washed with distilled water and salt water. The residue of the organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0~30% ethyl acetate/hexane), and the target compound tert-butyl (4-hydroxyphenethyl) (3-(4-(4-(2,2, 2-Trifluoroacetyl)piperazin-1-yl)phenyl)prop-2-yn-1-yl)carbamate (50 mg, 91%, red solid) was prepared.

단계 4 : 2,2,2-트리플루오로-1-(4-(4-(3-((4-히드록시펜에틸)아미노)프로프-1-인-1-일)페닐)피페라진-1-일)에탄-1-온의 제조Step 4: 2,2,2-trifluoro-1-(4-(4-(3-((4-hydroxyphenethyl)amino)prop-1-yn-1-yl)phenyl)piperazine -1-day) Preparation of ethane-1-one

상기 단계 3에서 제조한 화합물 tert-부틸 (4-히드록시펜에틸)(3-(4-(4-(2,2,2-트리플루오로아세틸)피페라진-1-일)페닐)프로프-2-인-1-일)카르바메이트(50 mg, 0.09 mmol)을 디클로로메탄에 용해시킨 뒤, 0 ℃에서 트리플루오로아세틱에시드(100 μL, 1.29 mmol)을 첨가하였다. 0 ℃에서 1시간동안 교반한 뒤, 반응이 종결되면 디클롤로메탄으로 추출하고 증류수와 소금물로 씻어주었다. 추출한 유기층은 무수 황산나트륨으로 건조 및 여과한 다음 감압 농축하였다. 얻어진 잔사를 실리카겔 크로마토그래피법(0~5% 메탄올/디클로로메탄)으로 분리 및 정제하여, 목적화합물 2,2,2-트리플루오로-1-(4-(4-(3-((4-히드록시펜에틸)아미노)프로프-1-인-1-일)페닐)피페라진-1-일)에탄-1-온(7 mg, 17%, 노란색 끈적한 고체)을 수득하였다. Compound tert-butyl (4-hydroxyphenethyl) (3- (4- (4- (2,2,2-trifluoroacetyl) piperazin-1-yl) phenyl) prop prepared in step 3 above -2-In-1-yl)carbamate (50 mg, 0.09 mmol) was dissolved in dichloromethane, and then trifluoroacetic acid (100 μL, 1.29 mmol) was added at 0°C. After stirring at 0°C for 1 hour, when the reaction was completed, it was extracted with dichloromethane and washed with distilled water and salt water. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0~5% methanol/dichloromethane), and the target compound 2,2,2-trifluoro-1-(4-(4-(3-((4- Hydroxyphenethyl)amino)prop-1-yn-1-yl)phenyl)piperazin-1-yl)ethan-1-one (7 mg, 17%, yellow sticky solid) was obtained.

1H NMR (400 MHz, CDCl3) δ 7.32 (d, J = 8.6 Hz, 2H), 7.08 (d, J = 8.3 Hz, 2H), 6.82 (d, J = 8.6 Hz, 2H), 6.74 (d, J = 8.3 Hz, 2H), 3.86 - 3.80 (m, 2H), 3.79 - 3.72 (m, 2H), 3.64 (s, 2H), 3.31 - 3.20 (m, 4H), 3.01 (t, J = 7.0 Hz, 1H), 2.79 (t, J = 7.0 Hz, 1H); LCMS, m/z 432[M+H]+ 1H NMR (400 MHz, CDCl3) δ 7.32 (d, J = 8.6 Hz, 2H), 7.08 (d, J = 8.3 Hz, 2H), 6.82 (d, J = 8.6 Hz, 2H), 6.74 (d, J = 8.3 Hz, 2H), 3.86 - 3.80 (m, 2H), 3.79 - 3.72 (m, 2H), 3.64 (s, 2H), 3.31 - 3.20 (m, 4H), 3.01 (t, J = 7.0 Hz) , 1H), 2.79 (t, J = 7.0 Hz, 1H); LCMS, m/z 432[M+H] +

<실시예 63> 4-(2-((3-(4'-(히드록시(페닐)메틸)-[1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)페놀의 제조<Example 63> 4-(2-((3-(4'-(hydroxy(phenyl)methyl)-[1,1'-biphenyl]-4-yl)prop-2-yn-1- Production of 1) amino) ethyl) phenol

단계 1 : (4'-(3-히드록시-1-프로핀-1-일)-(1,1'-비페닐)-4-일)(페닐)메타논의 제조Step 1: Preparation of (4'-(3-hydroxy-1-propyn-1-yl)-(1,1'-biphenyl)-4-yl)(phenyl)methanone

(4'-브로모-(1,1'-비페닐)-4-일)(페닐)메타논 (1 g, 2.97 mmol)을 피롤리돈에 용해시킨 뒤 질소 풍선을 이용하여 반응 혼합물을 탈기한 다음 Pd(PPh3)4 (51 mg, 0.178 mmol)을 첨가하였다. 이후 질소 풍선을 이용하여 반응 혼합물을 탈기한 뒤 프로파질알코올 (0.68 mL, 11.86 mmol)을 첨가하였다. 그 다음 100 °C로 가열하여 1시간 동안 가열 교반하였다. 반응 종결 후, 혼합물을 상온으로 식힌 뒤 셀라이트에 여과한 다음 감압 농축하였다. 얻어진 잔사는 디클로로메탄으로 희석시키고 물과 소금물로 씻어주었다. 유기층의 잔류물은 무수 황산나트륨으로 건조 및 여과한 다음 감압 농축하였다. 얻어진 잔사를 실리카겔 크로마토그래피법 (0~50% 에틸아세테이트/헥산)으로 분리 및 정제하여, 목적화합물 (0.45 g, 49%, 노란색 고체)을 수득하였다.(4'-Bromo-(1,1'-biphenyl)-4-yl)(phenyl)methanone (1 g, 2.97 mmol) was dissolved in pyrrolidone and the reaction mixture was degassed using a nitrogen balloon. Then, Pd(PPh 3 ) 4 (51 mg, 0.178 mmol) was added. Afterwards, the reaction mixture was degassed using a nitrogen balloon, and then propargyl alcohol (0.68 mL, 11.86 mmol) was added. Then, it was heated to 100 °C and heated and stirred for 1 hour. After completion of the reaction, the mixture was cooled to room temperature, filtered through Celite, and then concentrated under reduced pressure. The obtained residue was diluted with dichloromethane and washed with water and salt water. The residue of the organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0-50% ethyl acetate/hexane) to obtain the target compound (0.45 g, 49%, yellow solid).

단계 2 : 3-(4'-벤조일-(1,1'-비페닐)-4-일)프로피올알데히드의 제조Step 2: Preparation of 3-(4'-benzoyl-(1,1'-biphenyl)-4-yl)propiolaldehyde

상기 단계 1에서 제조한 화합물 (4'-(3-히드록시-1-프로핀-1-일)-(1,1'-비페닐)-4-일)(페닐)메타논 (0.45 g, 1.45 mmol)을 디클로로메탄에 용해시킨 뒤, 0 °C에서 Dess-martin periodinane (0.92 g, 2.17 mmol)을 첨가하였다. 이후 반응 혼합물을 1.5시간 동안 교반하였다. 반응 종결 후, 디클로로메탄으로 희석시키고 물과 소금물로 씻어주었다. 유기층의 잔류물은 무수 황산나트륨으로 건조 및 여과한 다음 감압 농축하였다. 얻어진 잔사를 실리카겔 크로마토그래피법 (0~25% 에틸아세테이트/헥산)으로 분리 및 정제하여, 목적화합물 (0.32 g, 71%, 흰색 고체)을 수득하였다.Compound (4'-(3-hydroxy-1-propyn-1-yl)-(1,1'-biphenyl)-4-yl)(phenyl)methanone (0.45 g, 1.45 mmol) was dissolved in dichloromethane, and then Dess-martin periodinane (0.92 g, 2.17 mmol) was added at 0 °C. The reaction mixture was then stirred for 1.5 hours. After completion of the reaction, it was diluted with dichloromethane and washed with water and salt water. The residue of the organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0-25% ethyl acetate/hexane) to obtain the target compound (0.32 g, 71%, white solid).

단계 3 : 4-(2-((3-(4'-(히드록시(페닐)메틸)-[1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)페놀의 제조Step 3: 4-(2-((3-(4'-(hydroxy(phenyl)methyl)-[1,1'-biphenyl]-4-yl)prop-2-yn-1-yl) Production of amino)ethyl)phenol

상기 단계 2에서 제조한 화합물 3-(4'-벤조일-(1,1'-비페닐)-4-일)프로피올알데히드 (40 mg, 0.129 mmol)를 메탄올에 용해시킨 뒤, 0 °C에서 4-(2-아미노에틸)페놀 (26.5 mg, 0.193 mmol)을 첨가하였다. 이후, 소듐보로하이드라이드 (9.75 mg, 0.258 mmol)을 0 ℃에서 천천히 첨가하였다. 1시간 동안 교반한 뒤, 증류수를 첨가하여 반응을 종결시키고 디클로로메탄으로 추출하고 증류수로 씻어주었다. 추출한 유기층은 무수 황산나트륨으로 건조 및 여과한 다음 감압 농축하였다. 얻어진 잔사를 실리카겔 크로마토그래피법 (0~70% 에틸아세테이트/헥산)으로 분리 및 정제하여, 목적화합물 4-(2-((3-(4'-(히드록시(페닐)메틸)-[1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)페놀 (29.4 mg, 49%, 노란색 고체)을 수득하였다.Compound 3-(4'-benzoyl-(1,1'-biphenyl)-4-yl)propiolaldehyde (40 mg, 0.129 mmol) prepared in step 2 was dissolved in methanol and then dissolved in methanol at 0 °C. 4-(2-Aminoethyl)phenol (26.5 mg, 0.193 mmol) was added. Afterwards, sodium borohydride (9.75 mg, 0.258 mmol) was added slowly at 0°C. After stirring for 1 hour, the reaction was terminated by adding distilled water, extracted with dichloromethane, and washed with distilled water. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0~70% ethyl acetate/hexane) to produce the target compound 4-(2-((3-(4'-(hydroxy(phenyl)methyl)-[1, 1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)phenol (29.4 mg, 49%, yellow solid) was obtained.

1H NMR (400 MHz, MeOD) δ 7.58-7.55 (m, 4H), 7.44 (d, J = 8.28 Hz, 4H), 7.39 (d, J = 7.32 Hz, 2H), 7.31 (t, J = 7.32 Hz, 2H), 7.24-7.20 (m, 1H), 7.05 (d, J = 8.4 Hz, 2H), 6.74-6.71 (m, 2H), 5.81 (s, 1H), 3.63 (s, 2H), 2.93 (t, J = 7.16 Hz, 2H), 2.74 (t, J = 7.64 Hz, 2H); LCMS, m/z 434[M+H]+ 1H NMR (400 MHz, MeOD) δ 7.58-7.55 (m, 4H), 7.44 (d, J = 8.28 Hz, 4H), 7.39 (d, J = 7.32 Hz, 2H), 7.31 (t, J = 7.32 Hz, 2H), 7.24-7.20 (m, 1H), 7.05 (d, J = 8.4 Hz, 2H), 6.74-6.71 (m, 2H), 5.81 (s, 1H), 3.63 (s, 2H), 2.93 (t, J = 7.16 Hz, 2H), 2.74 (t, J = 7.64 Hz, 2H); LCMS, m/z 434[M+H] +

<실시예 64> ((((4-히드록시페네틸)아잔디일)비스(프로프-1-인-3,1-디일))비스([1,1'-비페닐]-4',4-디일))비스(페닐메탄온)의 제조<Example 64> ((((4-hydroxyphenethyl)azanediyl)bis(prop-1-yn-3,1-diyl))bis([1,1'-biphenyl]-4' , 4-diyl)) Preparation of bis(phenylmethanone)

상기 실시예 63 단계 2에서 제조한 화합물 3-(4'-벤조일-(1,1'-비페닐)-4-일)프로피올알데히드 (20 mg, 0.064 mmol)와 4-(2-아미노에틸)페놀 (13.26 mg, 0.097 mmol)을 디클로로에탄에 용해시킨 뒤, 아세트산 (5.8 mg, 0.097 mmol)과 소듐트리아세톡시보로하이드라이드 (27.3 mg, 0.129 mmol)을 천천히 첨가하였다. 상온에서 30분동안 교반한 뒤, 탄산수소나트륨 수용액을 첨가하여 반응을 종결시키고 디클로로메탄으로 희석시킨 다음 물과 소금물로 씻어주었다. 추출한 유기층은 무수 황산나트륨으로 건조 및 여과한 다음 감압 농축하였다. 얻어진 잔사를 실리카겔 크로마토그래피법(0~50% 에틸아세테이트/헥산)으로 분리 및 정제하여, 목적화합물 ((((4-히드록시페네틸)아잔디일)비스(프로프-1-인-3,1-디일))비스([1,1'-비페닐]-4',4-디일))비스(페닐메탄온) (12.9 mg, 28%, 노란색 고체)을 수득하였다.Compound 3-(4'-benzoyl-(1,1'-biphenyl)-4-yl)propiolaldehyde (20 mg, 0.064 mmol) and 4-(2-aminoethyl) prepared in Step 2 of Example 63 ) Phenol (13.26 mg, 0.097 mmol) was dissolved in dichloroethane, and then acetic acid (5.8 mg, 0.097 mmol) and sodium triacetoxyborohydride (27.3 mg, 0.129 mmol) were slowly added. After stirring at room temperature for 30 minutes, the reaction was terminated by adding aqueous sodium bicarbonate solution, diluted with dichloromethane, and washed with water and salt water. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0~50% ethyl acetate/hexane) to obtain the target compound ((((4-hydroxyphenethyl)azanediyl)bis(prop-1-yne-3) ,1-diyl))bis([1,1'-biphenyl]-4',4-diyl))bis(phenylmethanone) (12.9 mg, 28%, yellow solid) was obtained.

1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 8.28 Hz, 4H), 7.83 (d, J = 7.2 Hz, 4H), 7.69 (d, J = 8.28 Hz, 4H), 7.62-7.48 (m, 14H), 7.14 (d, J = 8.4 Hz, 2H), 6.79 (d, J = 8.4 Hz, 2H), 5.20 (br-s, 1H), 3.83 (s, 4H), 2.97-2.84 (m, 4H); LCMS, m/z 726[M+H]+ 1H NMR (400 MHz, CDCl 3 ) δ 7.89 (d, J = 8.28 Hz, 4H), 7.83 (d, J = 7.2 Hz, 4H), 7.69 (d, J = 8.28 Hz, 4H), 7.62-7.48 (m, 14H), 7.14 (d, J = 8.4 Hz, 2H), 6.79 (d, J = 8.4 Hz, 2H), 5.20 (br-s, 1H), 3.83 (s, 4H), 2.97-2.84 ( m, 4H); LCMS, m/z 726[M+H] +

<실시예 65> (4'-(3-((4-히드록시페네틸)아미노)프로프-1-인-1-일)-[1,1'-비페닐]-4-일)(페닐)메탄온의 제조<Example 65> (4'-(3-((4-hydroxyphenethyl)amino)prop-1-yn-1-yl)-[1,1'-biphenyl]-4-yl)( Preparation of phenyl)methanone

상기 실시예 63 단계 2에서 제조한 화합물 3-(4'-벤조일-(1,1'-비페닐)-4-일)프로피올알데히드 (50 mg, 0.161 mmol)와 4-(2-아미노에틸)페놀 (111 mg, 0.806 mmol)을 메탄올에 용해시킨 뒤, 1시간동안 교반하였다. 이후 소듐시아노보로하이드라이드 (30.4 mg, 0.48 mmol)를 첨가한 뒤 2시간 동안 교반하였다. 반응이 종결된 후, 탄산수소나트륨 수용액을 첨가하여 반응을 종결시키고 디클로로메탄으로 희석시킨 다음 물과 소금물로 씻어주었다. 추출한 유기층은 무수 황산나트륨으로 건조 및 여과한 다음 감압 농축하였다. 얻어진 잔사를 실리카겔 크로마토그래피법(0~50% 에틸아세테이트/헥산)으로 분리 및 정제하여, 목적화합물 (4'-(3-((4-히드록시페네틸)아미노)프로프-1-인-1-일)-[1,1'-비페닐]-4-일)(페닐)메탄온(8.6 mg, 12%, 노란색 고체)을 수득하였다.Compound 3-(4'-benzoyl-(1,1'-biphenyl)-4-yl)propiolaldehyde (50 mg, 0.161 mmol) prepared in Step 2 of Example 63 and 4-(2-aminoethyl) ) Phenol (111 mg, 0.806 mmol) was dissolved in methanol and stirred for 1 hour. Afterwards, sodium cyanoborohydride (30.4 mg, 0.48 mmol) was added and stirred for 2 hours. After the reaction was completed, an aqueous solution of sodium bicarbonate was added to terminate the reaction, diluted with dichloromethane, and then washed with water and salt water. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0~50% ethyl acetate/hexane) to produce the target compound (4'-(3-((4-hydroxyphenethyl)amino)prop-1-yne- 1-yl)-[1,1'-biphenyl]-4-yl)(phenyl)methanone (8.6 mg, 12%, yellow solid) was obtained.

1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.32 Hz, 2H), 7.83 (d, J = 7.08 Hz, 2H), 7.68 (d, J = 8.32 Hz, 2H), 7.60-7.57 (m, 3H), 7.52-7.48 (m, 4H), 7.09 (d, J = 8.36 Hz, 2H), 6.77 (d, J = 8.4 Hz, 2H), 3.69 (s, 2H), 3.04 (t, J = 7.0 Hz, 2H), 2.81 (t, J = 6.84 Hz, 2H); LCMS, m/z 432[M+H]+ 1H NMR (400 MHz, CDCl 3 ) δ 7.88 (d, J = 8.32 Hz, 2H), 7.83 (d, J = 7.08 Hz, 2H), 7.68 (d, J = 8.32 Hz, 2H), 7.60-7.57 (m, 3H), 7.52-7.48 (m, 4H), 7.09 (d, J = 8.36 Hz, 2H), 6.77 (d, J = 8.4 Hz, 2H), 3.69 (s, 2H), 3.04 (t, J = 7.0 Hz, 2H), 2.81 (t, J = 6.84 Hz, 2H); LCMS, m/z 432[M+H] +

<실시예 66> 4-(2-((3-(4'-페녹시-[1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)벤젠설폰아미드의 제조<Example 66> 4-(2-((3-(4'-phenoxy-[1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl) Preparation of benzenesulfonamide

상기 실시예 56 단계 3에서 제조한 화합물 3-(4'-페녹시-[1,1'-비페닐]-4-일)프로피올알데히드(25 mg, 0.08 mmol)을 메탄올에 용해시킨 뒤, 4-(2-아미노에틸)벤젠술폰아미드(25 mg, 0.12 mmol), 소듐보로하이드라이드(9 mg, 0.25 mmol)을 0 ℃에서 천천히 첨가하였다. 2시간 동안 교반한 뒤, 증류수를 적가하여 반응을 종결시키고 디클로로메탄으로 추출하고 증류수로 씻어주었다. 추출한 유기층은 무수 황산나트륨으로 건조 및 여과한 다음 감압 농축하였다. 얻어진 잔사를 실리카겔 크로마토그래피법(0~5% 메탄올/디클로로메탄)으로 분리 및 정제하여, 목적화합물 4-(2-((3-(4'-페녹시-[1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)벤젠설폰아미드(32 mg, 79%, 흰색 고체)을 수득하였다. Compound 3-(4'-phenoxy-[1,1'-biphenyl]-4-yl)propiolaldehyde (25 mg, 0.08 mmol) prepared in step 3 of Example 56 was dissolved in methanol, 4-(2-Aminoethyl)benzenesulfonamide (25 mg, 0.12 mmol) and sodium borohydride (9 mg, 0.25 mmol) were added slowly at 0°C. After stirring for 2 hours, distilled water was added dropwise to terminate the reaction, extracted with dichloromethane, and washed with distilled water. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0~5% methanol/dichloromethane) to obtain the target compound 4-(2-((3-(4'-phenoxy-[1,1'-biphenyl] -4-yl)prop-2-yn-1-yl)amino)ethyl)benzenesulfonamide (32 mg, 79%, white solid) was obtained.

1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 8.3 Hz, 2H), 7.58 - 7.30 (m, 9H), 7.13 (dd, J = 7.4 Hz, 1H), 7.10 - 7.05 (m, 4H), 4.74 (s, 2H), 3.69 (s, 2H), 3.09 (t, J = 7.0 Hz, 2H), 2.94 (t, J = 7.0 Hz, 2H); LCMS, m/z 483[M+H]+ 1 H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 8.3 Hz, 2H), 7.58 - 7.30 (m, 9H), 7.13 (dd, J = 7.4 Hz, 1H), 7.10 - 7.05 (m, 4H) ), 4.74 (s, 2H), 3.69 (s, 2H), 3.09 (t, J = 7.0 Hz, 2H), 2.94 (t, J = 7.0 Hz, 2H); LCMS, m/z 483[M+H] +

<실시예 67> 4-(2-((3-(4'-(메톡시메톡시)-[1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)벤젠설폰아미드의 제조<Example 67> 4-(2-((3-(4'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)prop-2-yn-1-yl) Preparation of amino) ethyl) benzenesulfonamide

상기 실시예 66과 유사한 방법으로 목적화합물 4-(2-((3-(4'-(메톡시메톡시)-[1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)벤젠설폰아미드를 수득하였다. In a similar manner to Example 66, the target compound 4-(2-((3-(4'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)prop-2-yne -1-yl)amino)ethyl)benzenesulfonamide was obtained.

1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 8.3 Hz, 2H), 7.52 - 7.40 (m, 8H), 7.11 (d, J = 8.8 Hz, 2H), 5.22 (s, 2H), 4.73 (s, 2H), 3.69 (s, 2H), 3.50 (s, 3H), 3.08 (t, J = 7.0 Hz, 2H), 2.94 (t, J = 7.0 Hz, 2H); LCMS, m/z 451[M+H]+ 1 H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 8.3 Hz, 2H), 7.52 - 7.40 (m, 8H), 7.11 (d, J = 8.8 Hz, 2H), 5.22 (s, 2H), 4.73 (s, 2H), 3.69 (s, 2H), 3.50 (s, 3H), 3.08 (t, J = 7.0 Hz, 2H), 2.94 (t, J = 7.0 Hz, 2H); LCMS, m/z 451[M+H] +

<실시예 68> 4-(2-((3-(4-(4-벤질피페라진-1-일)페닐)프로프-2-인-1-일)아미노)에틸)벤젠설폰아미드의 제조<Example 68> Preparation of 4-(2-((3-(4-(4-benzylpiperazin-1-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)benzenesulfonamide

단계 1 : 1-벤질-4-(4-브로모페닐)피페라진의 제조Step 1: Preparation of 1-benzyl-4-(4-bromophenyl)piperazine

1-(4-브로모페닐)피페라진(1 g, 4.01 mmol)을 테트라하이드로퓨란에 용해시킨 뒤, 상온에서 벤질브로마이드(0.54 mL, 4.56 mmol), 탄산칼륨(1.14 g, 8.29 mmol)을 첨가하였다. 상온에서 3시간 동안 교반한 뒤, 혼합물에 증류수를 적가하여 반응을 종결시킨 뒤, 디클로로메탄으로 추출하고 소금물로 씻어주었다. 추출한 유기층은 무수 황산나트륨으로 건조 및 여과하고 감압 농축하였다. 얻어진 잔사를 실리카겔 크로마토그래피법(0~10% 에틸아세테이트/헥산)으로 분리 및 정제하여, 목적화합물(1.05 g, 76%, 흰색 고체)을 수득하였다.1-(4-bromophenyl)piperazine (1 g, 4.01 mmol) was dissolved in tetrahydrofuran, and benzyl bromide (0.54 mL, 4.56 mmol) and potassium carbonate (1.14 g, 8.29 mmol) were added at room temperature. did. After stirring at room temperature for 3 hours, distilled water was added dropwise to the mixture to terminate the reaction, extracted with dichloromethane, and washed with salt water. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0-10% ethyl acetate/hexane) to obtain the target compound (1.05 g, 76%, white solid).

단계 2 : 3-(4-(4-벤질피페라진-1-일)페닐)프로프-2-인-1-올의 제조Step 2: Preparation of 3-(4-(4-benzylpiperazin-1-yl)phenyl)prop-2-yn-1-ol

상기 단계 1에서 제조한 화합물 1-벤질-4-(4-브로모페닐)피페라진(1.05 g, 3.17 mmol)을 피롤리딘에 용해시킨 뒤, 상온에서 Pd(PPh3)4(220 mg, 0.19 mmol), 프로파질알코올(0.54 mL, 9.51 mmol)을 첨가하였다. 질소 풍선을 이용하여 반응 혼합물을 탈기한 다음 상온에서 30분 교반하였다. 그 다음 100 °C로 가열하여 2시간 동안 가열 교반하였다. 반응 종결 후, 혼합물을 상온으로 식힌 뒤 셀라이트에 여과한 다음 감압 농축하였다. 얻어진 잔사는 디클로로메탄으로 희석시키고 물과 소금물로 씻어주었다. 유기층의 잔류물은 무수 황산나트륨으로 건조 및 여과한 다음 감압 농축하였다. 얻어진 잔사를 실리카겔 크로마토그래피법(0~50% 에틸아세테이트/헥산)으로 분리 및 정제하여, 목적화합물(0.4 g, 41%, 노란색 고체)을 수득하였다. Compound 1-benzyl-4-(4-bromophenyl)piperazine (1.05 g, 3.17 mmol) prepared in step 1 was dissolved in pyrrolidine, and then added to Pd(PPh 3 ) 4 (220 mg, 0.19 mmol) and propargyl alcohol (0.54 mL, 9.51 mmol) were added. The reaction mixture was degassed using a nitrogen balloon and then stirred at room temperature for 30 minutes. It was then heated to 100 °C and heated and stirred for 2 hours. After completion of the reaction, the mixture was cooled to room temperature, filtered through Celite, and then concentrated under reduced pressure. The obtained residue was diluted with dichloromethane and washed with water and salt water. The residue of the organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0-50% ethyl acetate/hexane) to obtain the target compound (0.4 g, 41%, yellow solid).

단계 3 : 3-(4-(4-벤질피페라진-1-일)페닐)프로피올알데히드의 제조Step 3: Preparation of 3-(4-(4-benzylpiperazin-1-yl)phenyl)propiolaldehyde

상기 단계 2에서 제조한 화합물 3-(4-(4-벤질피페라진-1-일)페닐)프로피올알데히드(0.4 g, 1.30 mmol)을 디클로로메탄에 용해시킨 뒤, 0 °C에서 DMP(0.66 g, 1.56 mmol)을 천천히 첨가하였다. 상온에서 2시간 동안 교반하고 반응이 종결 후, 디클로로메탄으로 희석시키고 물과 소금물로 씻어주었다. 유기층의 잔류물은 무수 황산나트륨으로 건조 및 여과한 다음 감압 농축하였다. 얻어진 잔사를 실리카겔 크로마토그래피법(0~30% 에틸아세테이트/헥산)으로 분리 및 정제하여, 목적화합물(198 mg, 49%, 노란색 끈적한 고체)을 제조하였다.Compound 3-(4-(4-benzylpiperazin-1-yl)phenyl)propiolaldehyde (0.4 g, 1.30 mmol) prepared in step 2 was dissolved in dichloromethane and then dissolved in DMP (0.66) at 0 °C. g, 1.56 mmol) was added slowly. It was stirred at room temperature for 2 hours, and after the reaction was completed, it was diluted with dichloromethane and washed with water and salt water. The residue of the organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0-30% ethyl acetate/hexane) to prepare the target compound (198 mg, 49%, yellow sticky solid).

단계 4 : 4-(2-((3-(4-(4-벤질피페라진-1-일)페닐)프로프-2-인-1-일)아미노)에틸)벤젠설폰아미드의 제조Step 4: Preparation of 4-(2-((3-(4-(4-benzylpiperazin-1-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)benzenesulfonamide

상기 단계 3에서 제조한 화합물 3-(4-(4-벤질피페라진-1-일)페닐)프로피올알데히드(50 mg, 0.16 mmol)을 메탄올에 용해시킨 뒤, 4-(2-아미노에틸)벤젠술폰아미드(49 mg, 0.24 mmol), 소듐보로하이드라이드(18 mg, 0.49 mmol)을 0 ℃에서 천천히 첨가하였다. 30분 동안 교반한 뒤, 증류수를 적가하여 반응을 종결시키고 디클로로메탄으로 추출하고 증류수로 씻어주었다. 추출한 유기층은 무수 황산나트륨으로 건조 및 여과한 다음 감압 농축하였다. 얻어진 잔사를 실리카겔 크로마토그래피법(0~5% 메탄올/디클로로메탄)으로 분리 및 정제하여, 목적화합물 4-(2-((3-(4-(4-벤질피페라진-1-일)페닐)프로프-2-인-1-일)아미노)에틸)벤젠설폰아미드(17 mg, 21%, 흰색 고체)을 수득하였다.Compound 3-(4-(4-benzylpiperazin-1-yl)phenyl)propiolaldehyde (50 mg, 0.16 mmol) prepared in step 3 was dissolved in methanol, and then dissolved in 4-(2-aminoethyl) Benzenesulfonamide (49 mg, 0.24 mmol) and sodium borohydride (18 mg, 0.49 mmol) were added slowly at 0°C. After stirring for 30 minutes, distilled water was added dropwise to terminate the reaction, extracted with dichloromethane, and washed with distilled water. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0~5% methanol/dichloromethane) to obtain the target compound 4-(2-((3-(4-(4-benzylpiperazin-1-yl)phenyl) Prop-2-yn-1-yl)amino)ethyl)benzenesulfonamide (17 mg, 21%, white solid) was obtained.

1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 8.3 Hz, 2H), 7.39 (d, J = 8.3 Hz, 2H), 7.37 - 7.26 (m, 7H), 6.81 (d, J = 8.8 Hz, 2H), 4.72 (s, 2H), 3.64 (s, 2H), 3.56 (s, 2H), 3.26 - 3.15 (m, 4H), 3.05 (t, J = 7.0 Hz, 2H), 2.92 (t, J = 7.0 Hz, 2H), 2.65 - 2.55 (m, 4H); LCMS, m/z 389[M+H]+ 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 8.3 Hz, 2H), 7.39 (d, J = 8.3 Hz, 2H), 7.37 - 7.26 (m, 7H), 6.81 (d, J = 8.8 Hz, 2H), 4.72 (s, 2H), 3.64 (s, 2H), 3.56 (s, 2H), 3.26 - 3.15 (m, 4H), 3.05 (t, J = 7.0 Hz, 2H), 2.92 (t , J = 7.0 Hz, 2H), 2.65 - 2.55 (m, 4H); LCMS, m/z 389[M+H] +

<실시예 69> 4-(2-((3-(4-(4-벤질피페라진-1-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀의 제조<Example 69> Preparation of 4-(2-((3-(4-(4-benzylpiperazin-1-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol

상기 실시예 68과 유사한 방법으로 목적화합물 4-(2-((3-(4-(4-벤질피페라진-1-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀을 수득하였다.In a similar manner to Example 68, the target compound 4-(2-((3-(4-(4-benzylpiperazin-1-yl)phenyl)prop-2-yn-1-yl)amino)ethyl) Phenol was obtained.

1H NMR (400 MHz, CDCl3) δ 7.38 - 7.26 (m, 7H), 7.08 (d, J = 8.3 Hz, 2H), 6.80 (d, J = 8.8 Hz, 2H), 6.74 (d, J = 8.3 Hz, 2H), 3.63 (s, 2H), 3.56 (s, 2H), 3.26 - 3.16 (m, 4H), 2.99 (t, J = 7.0 Hz, 2H), 2.78 (t, J = 7.0 Hz, 2H), 2.62 - 2.55 (m, 4H); LCMS, m/z 426[M+H]+ 1 H NMR (400 MHz, CDCl3) δ 7.38 - 7.26 (m, 7H), 7.08 (d, J = 8.3 Hz, 2H), 6.80 (d, J = 8.8 Hz, 2H), 6.74 (d, J = 8.3 Hz, 2H), 3.63 (s, 2H), 3.56 (s, 2H), 3.26 - 3.16 (m, 4H), 2.99 (t, J = 7.0 Hz, 2H), 2.78 (t, J = 7.0 Hz, 2H) ), 2.62 - 2.55 (m, 4H); LCMS, m/z 426[M+H] +

실시예 1 내지 실시예 69의 화합물구조 및 화합물명은 하기 표 1과 같다.The compound structures and compound names of Examples 1 to 69 are shown in Table 1 below.

실시예Example 화합물 구조compound structure 화합물명Compound name 1One 4-(2-(비스(3-페닐프로프-2-인-1-일)아미노)에틸)벤젠설폰아미드4-(2-(bis(3-phenylprop-2-yn-1-yl)amino)ethyl)benzenesulfonamide 22 3-페닐-N-(4-설파모일페네틸)프로피올아미드3-phenyl-N-(4-sulfamoylphenethyl)propiolamide 33 4-(2-((3-(4-(트리플루오로메틸)페닐)프로프-2-인-1-일)아미노)에틸)벤젠설폰아미드4-(2-((3-(4-(trifluoromethyl)phenyl)prop-2-yn-1-yl)amino)ethyl)benzenesulfonamide 44 4-(2-((3-페닐프로프-2-인-1-일)아미노)에틸)벤젠설폰아미드4-(2-((3-phenylprop-2-yn-1-yl)amino)ethyl)benzenesulfonamide 55 4-(2-((3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)벤젠설폰아미드4-(2-((3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)benzenesulfonamide 66 4-(2-(메틸(3-페닐프로프-2-인-1-일)아미노)에틸)벤젠설폰아미드4-(2-(methyl(3-phenylprop-2-yn-1-yl)amino)ethyl)benzenesulfonamide 77 4-(2-(비스(3-(4-메톡시페닐)프로프-2-인-1-일)아미노)에틸)벤젠설폰아미드4-(2-(bis(3-(4-methoxyphenyl)prop-2-yn-1-yl)amino)ethyl)benzenesulfonamide 88 4-(2-((3-(4-메톡시페닐)프로프-2-인-1-일)아미노)에틸)벤젠설폰아미드4-(2-((3-(4-methoxyphenyl)prop-2-yn-1-yl)amino)ethyl)benzenesulfonamide 99 3-([1,1'-비페닐]-4-일)-N-페네틸프로프-2-인-1-아민3-([1,1'-biphenyl]-4-yl)-N-phenethylprop-2-yn-1-amine 1010 4-(((3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)메틸)벤젠설폰아미드4-(((3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)methyl)benzenesulfonamide 1111 4-((비스(3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)메틸)벤젠설폰아미드4-((bis(3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)methyl)benzenesulfonamide 1212 3-([1,1'-비페닐]-4-일)-N-(4-클로로펜에틸)프로프-2-인-1-아민3-([1,1'-biphenyl]-4-yl)-N-(4-chlorophenethyl)prop-2-yn-1-amine 1313 3-([1,1'-바이페닐]-4-일)-N-(3-([1,1'-바이페닐]-4-일)프로프-2-인-1-일)-N-(4-클로로페네틸)프로프-2-인-1-아민3-([1,1'-biphenyl]-4-yl)-N-(3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)- N-(4-chlorophenethyl)prop-2-yn-1-amine 1414 4-(2-((3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)페놀4-(2-((3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)phenol 1515 4-(2-(비스(3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)페놀4-(2-(bis(3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)phenol 1616 3-([1,1'-비페닐]-4-일)-N-(2-(벤조[d][1,3]디옥솔-5-일)에틸)프로프-2-인-1-아민3-([1,1'-biphenyl]-4-yl)-N-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)prop-2-yne-1 -Amine 1717 3-([1,1'-바이페닐]-4-일)-N-(3-([1,1'-바이페닐]-4-일)프로프-2-인-1-일)-N-(2-(벤조[d][1,3]디옥솔-5-일)에틸)프로프-2-인-1-아민3-([1,1'-biphenyl]-4-yl)-N-(3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)- N-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)prop-2-yn-1-amine 1818 3-([1,1'-비페닐]-4-일)-N-(2,2-디페닐에틸)프로프-2-인-1-아민3-([1,1'-biphenyl]-4-yl)-N-(2,2-diphenylethyl)prop-2-yn-1-amine 1919 3-([1,1'-바이페닐]-4-일)-N-(3-([1,1'-바이페닐]-4-일)프로프-2-인-1-일)-N-(2,2-디페닐에틸)프로프-2-인-1-아민3-([1,1'-biphenyl]-4-yl)-N-(3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)- N-(2,2-diphenylethyl)prop-2-yn-1-amine 2020 3-([1,1'-비페닐]-4-일)-N-(4-모르폴리노펜에틸)프로프-2-인-1-아민3-([1,1'-biphenyl]-4-yl)-N-(4-morpholinophenethyl)prop-2-yn-1-amine 2121 3-([1,1'-바이페닐]-4-일)-N-(3-([1,1'-바이페닐]-4-일)프로프-2-인-1-일)-N-(4-모르폴리노펜에틸)프로프-2-인-1-아민3-([1,1'-biphenyl]-4-yl)-N-(3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)- N-(4-morpholinophenethyl)prop-2-yn-1-amine 2222 2-(1-((3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)-4-클로로페놀2-(1-((3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)-4-chlorophenol 2323 4-클로로-2-(1-((3-(4-메톡시페닐)프로프-2-인-1-일)아미노)에틸)페놀4-chloro-2-(1-((3-(4-methoxyphenyl)prop-2-yn-1-yl)amino)ethyl)phenol 2424 4-(2-((3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)(메틸)아미노)에틸)벤젠설폰아미드4-(2-((3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)(methyl)amino)ethyl)benzenesulfonamide 2525 3-([1,1'-비페닐]-4-일)-N-(4-(메틸설포닐)페네틸)프로프-2-인-1-아민3-([1,1'-biphenyl]-4-yl)-N-(4-(methylsulfonyl)phenethyl)prop-2-yn-1-amine 2626 3-([1,1'-바이페닐]-4-일)-N-(3-([1,1'-바이페닐]-4-일)프로프-2-인-1-일)-N-(4-(메틸설포닐)페네틸)프로프-2-인-1-아민3-([1,1'-biphenyl]-4-yl)-N-(3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)- N-(4-(methylsulfonyl)phenethyl)prop-2-yn-1-amine 2727 메틸 4-(2-((3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)벤조에이트Methyl 4-(2-((3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)benzoate 2828 메틸 4-(2-(비스(3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)벤조에이트Methyl 4-(2-(bis(3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)benzoate 2929 4-(2-((3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)벤조산4-(2-((3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)benzoic acid 3030 4-(2-(비스(3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)벤조산4-(2-(bis(3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)benzoic acid 3131 4-(2-((3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)(메틸)아미노)에틸)페놀4-(2-((3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)(methyl)amino)ethyl)phenol 3232 4-(1-((3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)옥시)에틸)-3,5-디클로로피리딘4-(1-((3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)oxy)ethyl)-3,5-dichloropyridine 3333 4-클로로-2-(1-((3-(4-메톡시페닐)프로프-2-인-1-일)(메틸)아미노)에틸)페놀4-chloro-2-(1-((3-(4-methoxyphenyl)prop-2-yn-1-yl)(methyl)amino)ethyl)phenol 3434 tert-부틸 4-(4-(3-((4-히드록시페네틸)아미노)프로프-1-인-1-일)페닐)피페라진-1-카르복실레이트tert-Butyl 4-(4-(3-((4-hydroxyphenethyl)amino)prop-1-yn-1-yl)phenyl)piperazine-1-carboxylate 3535 tert-부틸 4-(4-(3-((1-(5-클로로-2-히드록시페닐)에틸)아미노)프로프-1-인-1-일)페닐)피페라진-1-카르복실레이트tert-Butyl 4-(4-(3-((1-(5-chloro-2-hydroxyphenyl)ethyl)amino)prop-1-yn-1-yl)phenyl)piperazine-1-carboxyl rate 3636 4-(2-((3-(4-(피페라진-1-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀4-(2-((3-(4-(piperazin-1-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol 3737 4-클로로-2-(1-((3-(4-(피페라진-1-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀4-chloro-2-(1-((3-(4-(piperazin-1-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol 3838 4-(2-((3-(4-모르폴리노페닐)프로프-2-인-1-일)아미노)에틸)페놀4-(2-((3-(4-morpholinophenyl)prop-2-yn-1-yl)amino)ethyl)phenol 3939 4-클로로-2-(1-((3-(4-모르폴리노페닐)프로프-2-인-1-일)아미노)에틸)페놀4-chloro-2-(1-((3-(4-morpholinophenyl)prop-2-yn-1-yl)amino)ethyl)phenol 4040 4-(2-((3-(4-(4-메틸피페라진-1-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀4-(2-((3-(4-(4-methylpiperazin-1-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol 4141 4-클로로-2-(1-((3-(4-(4-메틸피페라진-1-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀4-chloro-2-(1-((3-(4-(4-methylpiperazin-1-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol 4242 4-(2-((3-(4-(피리딘-4-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀4-(2-((3-(4-(pyridin-4-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol 4343 4-클로로-2-(1-((3-(4-(피리딘-4-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀4-chloro-2-(1-((3-(4-(pyridin-4-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol 4444 4-(2-((3-(4'-메톡시-[1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)페놀4-(2-((3-(4'-methoxy-[1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)phenol 4545 4-클로로-2-(1-((3-(4'-메톡시-[1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)페놀4-chloro-2-(1-((3-(4'-methoxy-[1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)phenol 4646 4-(2-((3-(4'-(메톡시메톡시)-[1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)페놀4-(2-((3-(4'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)phenol 4747 4-클로로-2-(1-((3-(4'-(메톡시메톡시)-[1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)페놀4-chloro-2-(1-((3-(4'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino )ethyl)phenol 4848 4-(2-((3-(4-(피리딘-3-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀4-(2-((3-(4-(pyridin-3-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol 4949 4-클로로-2-(1-((3-(4-(피리딘-3-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀4-chloro-2-(1-((3-(4-(pyridin-3-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol 5050 4-(2-((3-(4-(피리딘-2-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀4-(2-((3-(4-(pyridin-2-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol 5151 4-클로로-2-(1-((3-(4-(피리딘-2-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀4-chloro-2-(1-((3-(4-(pyridin-2-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol 5252 4'-(3-((4-히드록시페네틸)아미노)프로프-1-인-1-일)-[1,1'-비페닐]-4-올4'-(3-((4-hydroxyphenethyl)amino)prop-1-yn-1-yl)-[1,1'-biphenyl]-4-ol 5353 4'-(3-((1-(5-클로로-2-히드록시페닐)에틸)아미노)프로프-1-인-1-일)-[1,1'-비페닐]-4-올4'-(3-((1-(5-chloro-2-hydroxyphenyl)ethyl)amino)prop-1-yn-1-yl)-[1,1'-biphenyl]-4-ol 5454 4-(2-((3-(4-(피리미딘-2-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀4-(2-((3-(4-(pyrimidin-2-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol 5555 4-클로로-2-(1-((3-(4-(피리미딘-2-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀4-chloro-2-(1-((3-(4-(pyrimidin-2-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol 5656 4-(2-((3-(4'-페녹시-[1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)페놀4-(2-((3-(4'-phenoxy-[1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)phenol 5757 4-클로로-2-(1-((3-(4'-페녹시-[1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)페놀4-chloro-2-(1-((3-(4'-phenoxy-[1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)phenol 5858 4-(2-((3-(4-(피리미딘-5-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀4-(2-((3-(4-(pyrimidin-5-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol 5959 4-클로로-2-(1-((3-(4-(피리미딘-5-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀4-chloro-2-(1-((3-(4-(pyrimidin-5-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol 6060 4-(2-((3-(4-(4-이소프로필피페라진-1-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀4-(2-((3-(4-(4-isopropylpiperazin-1-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol 6161 1-(4-(4-(3-((4-히드록시펜에틸)아미노)프로프-1-인-1-일)페닐)피페라진-1-일)에탄-1-온1-(4-(4-(3-((4-hydroxyphenethyl)amino)prop-1-yn-1-yl)phenyl)piperazin-1-yl)ethan-1-one 6262 2,2,2-트리플루오로-1-(4-(4-(3-((4-히드록시펜에틸)아미노)프로프-1-인-1-일)페닐)피페라진-1-일)에탄-1-온2,2,2-trifluoro-1-(4-(4-(3-((4-hydroxyphenethyl)amino)prop-1-yn-1-yl)phenyl)piperazine-1- 1) Ethane-1-one 6363 4-(2-((3-(4'-(히드록시(페닐)메틸)-[1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)페놀4-(2-((3-(4'-(hydroxy(phenyl)methyl)-[1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl )phenol 6464 ((((4-히드록시페네틸)아잔디일)비스(프로프-1-인-3,1-디일))비스([1,1'-비페닐]-4',4-디일))비스(페닐메탄온)((((4-hydroxyphenethyl)azanediyl)bis(prop-1-yne-3,1-diyl))bis([1,1'-biphenyl]-4',4-diyl) )bis(phenylmethanone) 6565 (4'-(3-((4-히드록시페네틸)아미노)프로프-1-인-1-일)-[1,1'-비페닐]-4-일)(페닐)메탄온(4'-(3-((4-hydroxyphenethyl)amino)prop-1-yn-1-yl)-[1,1'-biphenyl]-4-yl)(phenyl)methanone 6666 4-(2-((3-(4'-페녹시-[1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)벤젠설폰아미드4-(2-((3-(4'-phenoxy-[1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)benzenesulfonamide 6767 4-(2-((3-(4'-(메톡시메톡시)-[1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)벤젠설폰아미드4-(2-((3-(4'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)benzene Sulfonamide 6868 4-(2-((3-(4-(4-벤질피페라진-1-일)페닐)프로프-2-인-1-일)아미노)에틸)벤젠설폰아미드4-(2-((3-(4-(4-benzylpiperazin-1-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)benzenesulfonamide 6969 4-(2-((3-(4-(4-벤질피페라진-1-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀4-(2-((3-(4-(4-benzylpiperazin-1-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol

<실험예 1> Huh7 간암세포주에서 p-ACC 활성 및 암세포의 성장 억제 평가<Experimental Example 1> Evaluation of p-ACC activity and growth inhibition of cancer cells in Huh7 liver cancer cell line

1-1. 실험방법1-1. Experiment method

Huh7 간암세포주는 ATCC에서 입수하여 37 ℃, 5 % CO2 및 100 % 습도의 환경에서 10 % 소태아 혈청 (FBS; HyClone, AUS)을 함유하는 완전 DMEM 배지 (Hyclone, UT, USA)에서 배양하였다. 세포를 개별 세포주의 배가 시간 (doubling time)에 따라 200,000 세포/웰의 도금 밀도로 6-웰 마이크로타이터 플레이트에 접종하였다. 약물 첨가 전까지 24 시간 동안 배양한 후 본 발명의 화합물을 10 μM 농도로 각 웰에 첨가하고, 대조군으로는 0.1 % DMSO를 처리한 군을 사용하여 배양액을 37 ℃ 에서 1 시간 동안 배양하였다. 본 발명의 화합물 처리에 따른 간암세포의 증식 억제능에 관여하는 지방산 합성효소의 저해 활성을 확인하기 위해 지방산 합성에서의 속도-제한 효소인 Acetyl-CoA Carboxylase (ACC) 와 phosphorylated ACC (p-ACC)의 단백질 발현 정도를 웨스턴블럿 방법을 통해 비교하였다.Huh7 liver cancer cell line was obtained from ATCC and cultured in complete DMEM medium (Hyclone, UT, USA) containing 10% fetal bovine serum (FBS; HyClone, AUS) in an environment of 37°C, 5% CO 2 and 100% humidity. . Cells were seeded in 6-well microtiter plates at a plating density of 200,000 cells/well, depending on the doubling time of the individual cell lines. After culturing for 24 hours before drug addition, the compound of the present invention was added to each well at a concentration of 10 μM, and a group treated with 0.1% DMSO was used as a control group, and the culture was incubated at 37°C for 1 hour. Acetyl-CoA Carboxylase (ACC) and phosphorylated ACC (p-ACC), which are rate-limiting enzymes in fatty acid synthesis, were tested to confirm the inhibitory activity of fatty acid synthase, which is involved in the inhibition of proliferation of liver cancer cells by treatment with the compound of the present invention. Protein expression levels were compared using Western blot method.

전체 세포 용해물은 50 mM Tris-HCl 외에 150 mM 염화나트륨, 1.0 % IGEPAL CA-630 (NP-40), 0.5 % 나트륨 데옥시콜레이트 (sodium deoxycholate), 0.1 % 나트륨 도데실 설페이트 (sodium dodecyl sulfate), 프로테아제 억제제 및 포스파타아제 억제제의 혼합제를 함유하는 RIPA 완충액 (pH 8.0)을 이용하여 균질화 하였다. 단백질을 정량화 하기 위해 BCA 단백질분석 Kit (Thermo Fisher, IL, USA)가 사용되었다. 단백질을 SDS-PAGE로 분석하고 Polyvinylidene difluoride (PVDF) 막 (Merck Millipore, MA, USA)으로 옮겼다. 막은 실온에서 1 시간 동안 5 % BSA에서 블락되었으며, 표시된 항체와 함께 밤새 4 ℃에서 배양했다. 그 후 막을 실온에서 10분씩 3회 TBS-T로 세척한 후, 실온에서 1 시간 30분 동안 겨자무과산화효소(horseradish peroxidase)-결합 2 차 항체와 함께 배양하였다. 배양 후, 막을 실온에서 1 시간 동안 TBS-T로 세척하여 enhanced chemiluminescence detection system (ECL)을 이용하여 확인하였다. 면역반응성 단백질 밴드 이미지를 스캔하여 시각적 밀도를 컴퓨터 소프트웨어 (ImageJ software, version 1.37, Wayne Rasband, NIH, Bethesda, MD)를 사용하여 정량화 하였다.Whole cell lysates were supplemented with 150 mM sodium chloride, 1.0% IGEPAL CA-630 (NP-40), 0.5% sodium deoxycholate, 0.1% sodium dodecyl sulfate, in addition to 50 mM Tris-HCl. Homogenization was performed using RIPA buffer (pH 8.0) containing a mixture of protease inhibitors and phosphatase inhibitors. The BCA Protein Analysis Kit (Thermo Fisher, IL, USA) was used to quantify proteins. Proteins were resolved by SDS-PAGE and transferred to polyvinylidene difluoride (PVDF) membrane (Merck Millipore, MA, USA). Membranes were blocked in 5% BSA for 1 h at room temperature and incubated with the indicated antibodies overnight at 4 °C. Afterwards, the membrane was washed with TBS-T three times for 10 minutes each at room temperature, and then incubated with horseradish peroxidase-conjugated secondary antibody for 1 hour and 30 minutes at room temperature. After incubation, the membrane was washed with TBS-T for 1 hour at room temperature and confirmed using an enhanced chemiluminescence detection system (ECL). Immunoreactive protein band images were scanned and visual density was quantified using computer software (ImageJ software, version 1.37, Wayne Rasband, NIH, Bethesda, MD).

1-2. 결과1-2. result

표 2과 같이 본 발명의 화합물들을 간암 세포 Huh7 모델에 처리하였을 경우 지방산 합성에서의 속도-제한 효소인 Acetyl-CoA Carboxylase (ACC)의 활성억제 정도를 phosphorylated ACC (p-ACC)의 인산화 단백질 발현 정도로 확인하였으며, 이를 수치화하여 지방산 합성 효소 저해능을 평가하였다. 본 발명의 화합물을 10 μM 농도로 처리하여 얻은 효소 저해능에 대한 결과를 대조군 대비 발현 변화값 (fold change)으로 계산하여 보고하였다. 여기서는 높은 숫자일수록 더 강한 히트를 나타내며, 발현 변화값 (fold change)이 20배 이상인 기준을 만족하는 화합물군;S, 10배 이상인 기준을 만족하는 화합물군;A, 4배 이상인 기준을 만족하는 화합물군;B, 2배 이상인 기준을 만족하는 화합물군;C, 1.2배 이상인 기준을 만족하는 화합물군;D 와 1.2배 미만인 기준을 만족하는 화합물군;E로 구분하여 평가하였다(S≥ 20, A≥ 10, B≥ 4, C≥ 2, D≥ 1.2, E< 1.2). 본 발명의 화합물, 특히 상기 나타낸 실시예 화합물 34, 35, 43, 56, 65의 5종은 발현 변화값이 20배 이상으로 강력한 저해 활성을 나타낸다.As shown in Table 2, when the compounds of the present invention were treated with the liver cancer cell Huh7 model, the degree of inhibition of the activity of Acetyl-CoA Carboxylase (ACC), the rate-limiting enzyme in fatty acid synthesis, was determined by the degree of phosphorylated protein expression of phosphorylated ACC (p-ACC). This was confirmed, and the fatty acid synthesis enzyme inhibitory ability was evaluated by quantifying this. The results of enzyme inhibition ability obtained by treating the compound of the present invention at a concentration of 10 μM were reported by calculating the expression change (fold change) compared to the control group. Here, the higher the number, the stronger the hit, and the group of compounds that meet the criteria for expression change (fold change) of 20 times or more; S, the group of compounds that meet the criteria of 10 times or more; A, the compounds that meet the criteria of 4 times or more Group: B, a group of compounds satisfying the criteria of 2 times or more; C, a group of compounds satisfying the criteria of 1.2 times or more; D and a group of compounds satisfying the criteria of less than 1.2 times; E were evaluated separately (S ≥ 20, A ≥ 10, B≥ 4, C≥ 2, D≥ 1.2, E< 1.2). The compounds of the present invention, especially the five examples compounds 34, 35, 43, 56, and 65 shown above, exhibit strong inhibitory activity with an expression change value of 20 times or more.

간암을 비롯한 다양한 암의 진행에 지질 대사 과정의 교란이 관여하는 것으로 알려져 있으며, 이는 지방 합성에서의 조절 이상으로 결국 암의 성장과 진행을 촉진한다는 것을 의미한다. 본 발명의 화합물들을 간암 세포 Huh7 모델에 처리하였을 경우 지질 대사 과정에서 지질 합성을 촉진시키면서 동시에 기존 지방의 산화를 억제하는 Acetyl-CoA Carboxylase (ACC)를 비활성화시킴으로써 간 내부의 지방 합성을 감소시키게 되고 간암 세포에서 종양 수준의 에너지대사를 조절하여 종양의 증식 및 전이 억제에 기여하는 것으로 보여진다.It is known that disturbances in the lipid metabolism process are involved in the progression of various cancers, including liver cancer, which means that dysregulation in fat synthesis ultimately promotes the growth and progression of cancer. When the compounds of the present invention are treated with the liver cancer cell Huh7 model, they promote lipid synthesis during lipid metabolism and at the same time inactivate Acetyl-CoA Carboxylase (ACC), which inhibits oxidation of existing fat, thereby reducing fat synthesis within the liver and liver cancer. It appears to contribute to the inhibition of tumor proliferation and metastasis by regulating energy metabolism at the tumor level in cells.

실시예Example p-ACC activityp-ACC activity 실시예Example p-ACC activityp-ACC activity 실시예Example p-ACC activityp-ACC activity 1One EE 2424 EE 4747 CC 22 EE 2525 CC 4848 CC 33 EE 2626 CC 4949 CC 44 EE 2727 EE 5050 CC 55 CC 2828 EE 5151 AA 66 EE 2929 EE 5252 DD 77 EE 3030 EE 5353 DD 88 EE 3131 DD 5454 DD 99 EE 3232 CC 5555 AA 1010 EE 3333 EE 5656 SS 1111 EE 3434 SS 5757 EE 1212 EE 3535 SS 5858 BB 1313 EE 3636 DD 5959 BB 1414 CC 3737 DD 6060 AA 1515 EE 3838 DD 6161 AA 1616 CC 3939 CC 6262 AA 1717 BB 4040 DD 6363 AA 1818 EE 4141 DD 6464 EE 1919 EE 4242 AA 6565 SS 2020 DD 4343 SS 6666 AA 2121 EE 4444 AA 6767 AA 2222 EE 4545 AA 6868 AA 2323 EE 4646 BB 6969 AA

<실험예 2> Huh7 간암세포주가 이식된 이종이식 동물 모델에서 p-AMPK 활성 및 암의 크기 평가<Experimental Example 2> Evaluation of p-AMPK activity and cancer size in a xenograft animal model transplanted with Huh7 liver cancer cell line

Huh-7 (human, hepatocarcinoma) 세포를 DMEM 배지 (10 %FBS, 10 % P/S)를 이용하여 15cm dish에 배양한 이후 4 X 106 cells/animal로 matrigel과 함께 100 ul 용량을 7주령 BALB/C 마우스 (Orient bio., Busan, Korea) 오른쪽 둔부에 이식하였다. 암세포 투여 후 종양의 크기가 300 mm3 이상 자랐을 때, 용매 대조군 (Control)과 시험물질군 (본 발명의 실시예 18화합물)의 2 그룹으로 나누었다.Huh-7 (human, hepatocarcinoma) cells were cultured in a 15cm dish using DMEM medium (10% FBS, 10% P/S) , then 4 /C mouse (Orient bio., Busan, Korea) was transplanted into the right hip. When the size of the tumor grew to more than 300 mm 3 after administration of the cancer cells, it was divided into two groups: the solvent control group (Control) and the test substance group (Example 18 compound of the present invention).

본 발명의 실시예 18화합물 (10 mg/kg, 체중) 및 용매 (5 % NMP, 5 % DMSO, 10 % Cremophor EL, 30 % PEG, 50 % water)를 총 3주간 15회 복강 투여하였다. 암세포를 이식한 후, 투여를 시작하였을 때를 기준으로 2회/주 다음과 같은 방법으로 종양의 부피 {종양의 부피 (mm3) = [(종양의 장경) X (종양의 단경)2]/2}를 측정하여 하기 표 3에 나타내었다.Example 18 Compound of the present invention (10 mg/kg, body weight) and solvent (5% NMP, 5% DMSO, 10% Cremophor EL, 30% PEG, 50% water) were administered intraperitoneally 15 times for a total of 3 weeks. After transplanting cancer cells, 2 times/week based on the start of administration, the tumor volume is calculated in the following manner {tumor volume (mm 3 ) = [( longer diameter of tumor) 2} was measured and shown in Table 3 below.

또한, Huh7 간암세포주가 이식된 이종이식 동물 모델에서 본 발명의 실시예 18 화합물의 투여로 인한 종양 형성 억제 기전을 확인하고자 종양 조직에서 단백질을 추출하여 실험에 이용하였다. 세포모델에서의 검증과 동일하게 종양 증식 및 전이 억제 기전에 관여하는 p-AMPK의 발현 정도를 측정하여 하기 표 3에 나타내었다(ND = Not Determinded).In addition, to confirm the mechanism of suppressing tumor formation caused by administration of the compound of Example 18 of the present invention in a xenograft animal model transplanted with the Huh7 liver cancer cell line, proteins were extracted from tumor tissue and used in experiments. In the same manner as verification in the cell model, the expression level of p-AMPK, which is involved in tumor proliferation and metastasis inhibition mechanisms, was measured and shown in Table 3 below (ND = Not Determined).

이종이식 동물모델((Huh7, 10mpk, IP)Xenograft animal model ((Huh7, 10mpk, IP) p-AMPK activity (배수)p-AMPK activity (multiple) 암 크기 감소(%)Cancer size reduction (%) 대조군control group 1One 0%0% 실시예 14Example 14 NDN.D. 55.31%/37.64%/47.67%55.31%/37.64%/47.67% 실시예 56Example 56 19.3819.38 39.52%39.52%

상기 실시예 14의 암 크기 감소 실험은 3번 반복 실험 하였으며, 그 결과 암의 크기가 55.31%, 37.64%, 47.67% 감소하는 것을 확인하였다.The cancer size reduction experiment of Example 14 was repeated three times, and as a result, it was confirmed that the cancer size was reduced by 55.31%, 37.64%, and 47.67%.

Claims (10)

하기 화학식 1로 표시되는 화합물, 이의 입체이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염:
[화학식 1]
An-L-B
상기 화학식 1에서,
n는 1 또는 2이고;
A는 비치환이거나 치환된 C6아릴 또는 6원자헤테로아릴이고,
상기 치환된 C6아릴 또는 6원자헤테로아릴은 할로겐, 히드록시, 6원자헤테로사이클로알킬, C1-C10알킬설포닐, C1-C10알킬옥시카보닐, 카르복시 및 설폰아미드로 이루어진 군에서 선택되는 하나이상으로 치환되거나, 또는 인접하는 두 개의 원자에 치환되어 5-6원자의 비치환된 헤테로사이클을 형성하고;
L은 -CHR1-, -CHCH2- 또는 -CH2CH2-이고,
여기서, 상기 R1은 수소 또는 C1-C10알킬이고;
B는 -NR2X, -NX2 또는-OX이고,
여기서, 상기 R2는 수소 또는 C1-C10알킬이고;
상기 X는 이고,
여기서, 상기 R3는 수소 또는 옥소(=O)이고;
R4는 비치환이거나 치환된 C1-C10알킬, C1-C10알콕시, 6원자헤테로사이클로알킬, C6아릴 또는 6원자헤테로아릴이고,
상기 치환된 C1-C10알킬, C1-C10알콕시, 6원자헤테로사이클로알킬, C6아릴 또는 6원자헤테로아릴은 비치환이거나 히드록시 및 C6아릴로 이루어진 군에서 선택되는 하나이상으로 치환된 C1-C10알킬, 비치환이거나 하나이상의 할로겐으로 치환된 C1-C10알킬카보닐, 할로겐, 히드록시, Boc(tert-부틸옥시카보닐), 비치환이거나 C1-C10알콕시로 치환된 C1-C10알콕시, C6아릴옥시 및 C6아릴카보닐로 이루어진 군에서 선택되는 하나이상으로 치환된다.
A compound represented by the following formula (1), a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof:
[Formula 1]
A n -LB
In Formula 1,
n is 1 or 2;
A is unsubstituted or substituted C6 aryl or 6-membered heteroaryl,
The substituted C6 aryl or 6-membered heteroaryl is at least one selected from the group consisting of halogen, hydroxy, 6-membered heterocycloalkyl, C1-C10 alkylsulfonyl, C1-C10 alkyloxycarbonyl, carboxy, and sulfonamide. is substituted, or is substituted on two adjacent atoms to form an unsubstituted heterocycle of 5-6 atoms;
L is -CHR 1 -, -CHCH 2 - or -CH 2 CH 2 -,
Here, R 1 is hydrogen or C1-C10 alkyl;
B is -NR 2 X, -NX 2 or -OX,
Here, R 2 is hydrogen or C1-C10 alkyl;
The X above is ego,
Here, R 3 is hydrogen or oxo (=O);
R 4 is unsubstituted or substituted C1-C10 alkyl, C1-C10 alkoxy, 6-membered heterocycloalkyl, C6-aryl or 6-membered heteroaryl,
The substituted C1-C10 alkyl, C1-C10 alkoxy, 6-membered heterocycloalkyl, C6 aryl or 6-membered heteroaryl is unsubstituted or substituted C1-C10 alkyl with one or more selected from the group consisting of hydroxy and C6 aryl. , C1-C10 alkyl carbonyl, unsubstituted or substituted with one or more halogens, halogen, hydroxy, Boc (tert-butyloxycarbonyl), C1-C10 alkoxy unsubstituted or substituted with C1-C10 alkoxy, C6 aryloxy. and C6 arylcarbonyl.
 제1항에 있어서,
n는 1 또는 2이고;
A는 비치환이거나 치환된 C6아릴 또는 N을 포함하는 6원자헤테로아릴이고,
상기 치환된 C6아릴 또는 N을 포함하는 6원자헤테로아릴은 할로겐, 히드록시, 6원자헤테로사이클로알킬, C1-C5알킬설포닐, C1-C5알킬옥시카보닐, 카르복시 및 설폰아미드로 이루어진 군에서 선택되는 하나이상으로 치환되거나, 또는 인접하는 두 개의 원자에 치환되어 두 개의 O를 포함하는 5원자의 비치환된 헤테로사이클을 형성하고;
L은 -CHR1-, -CHCH2- 또는 -CH2CH2-이고,
여기서, 상기 R1은 수소 또는 C1-C5알킬이고;
B는 -NR2X, -NX2 또는-OX이고,
여기서, 상기 R2는 수소 또는 C1-C5알킬이고;
상기 X는 이고,
여기서, 상기 R3는 수소 또는 옥소(=O)이고;
R4는 비치환이거나 치환된 C1-C5알킬, C1-C5알콕시, 6원자헤테로사이클로알킬, C6아릴 또는 6원자헤테로아릴이고,
상기 치환된 C1-C5알킬, C1-C5알콕시, 6원자헤테로사이클로알킬, C6아릴 또는 6원자헤테로아릴은 비치환이거나 히드록시 및 C6아릴로 이루어진 군에서 선택되는 하나이상으로 치환된 C1-C5알킬, 비치환이거나 하나이상의 할로겐으로 치환된 C1-C5알킬카보닐, 할로겐, 히드록시, Boc(tert-부틸옥시카보닐), 비치환이거나 C1-C5알콕시로 치환된 C1-C5알콕시, C6아릴옥시 및 C6아릴카보닐로 이루어진 군에서 선택되는 하나이상으로 치환되는 것을 특징으로 하는, 화합물, 이의 입체이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염.
According to paragraph 1,
n is 1 or 2;
A is unsubstituted or substituted C6 aryl or 6-membered heteroaryl containing N,
The substituted C6 aryl or 6-membered heteroaryl containing N is selected from the group consisting of halogen, hydroxy, 6-membered heterocycloalkyl, C1-C5 alkylsulfonyl, C1-C5 alkyloxycarbonyl, carboxy, and sulfonamide. is substituted with one or more atoms, or is substituted on two adjacent atoms to form a 5-atom unsubstituted heterocycle containing two O's;
L is -CHR 1 -, -CHCH 2 - or -CH 2 CH 2 -,
Here, R 1 is hydrogen or C1-C5 alkyl;
B is -NR 2 X, -NX 2 or -OX,
Here, R 2 is hydrogen or C1-C5 alkyl;
The X above is ego,
Here, R 3 is hydrogen or oxo (=O);
R 4 is unsubstituted or substituted C1-C5alkyl, C1-C5alkoxy, 6-membered heterocycloalkyl, C6aryl or 6-membered heteroaryl,
The substituted C1-C5 alkyl, C1-C5 alkoxy, 6-membered heterocycloalkyl, C6 aryl or 6-membered heteroaryl is unsubstituted or substituted C1-C5 alkyl with one or more selected from the group consisting of hydroxy and C6 aryl. , C1-C5 alkylcarbonyl, unsubstituted or substituted with one or more halogens, halogen, hydroxy, Boc (tert-butyloxycarbonyl), C1-C5 alkoxy, unsubstituted or substituted with C1-C5 alkoxy, C6 aryloxy. A compound, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, characterized in that it is substituted with one or more selected from the group consisting of C6 arylcarbonyl.
 제1항에 있어서,
n는 1 또는 2이고;
A는 비치환이거나 페닐 또는 피리딘이고,
상기 치환된 페닐 또는 피리딘은 Cl, 히드록시, 몰포린, 메틸설포닐, 메틸옥시카보닐, 카르복시 및 설폰아미드로 이루어진 군에서 선택되는 하나이상으로 치환되거나, 또는 인접하는 두 개의 원자에 치환되어 1,3-디옥솔을 형성하고;
L은 -CHR1-, -CHCH2- 또는 -CH2CH2-이고,
여기서, 상기 R1은 수소 또는 메틸이고;
B는 -NR2X, -NX2 또는-OX이고,
여기서, 상기 R2는 수소 또는 메틸이고;
상기 X는 이고,
여기서, 상기 R3는 수소 또는 옥소(=O)이고;
R4는 비치환이거나 치환된 메틸, 메톡시, 피페라진, 몰포린, 페닐, 피리딘 또는 피리미딘이고,
상기 치환된 메틸, 메톡시, 피페라진, 몰포린, 페닐, 피리딘 또는 피리미딘은 비치환이거나 히드록시 및 페닐로 이루어진 군에서 선택되는 하나이상으로 치환된 메틸, 비치환이거나 하나이상의 F으로 치환된 메틸카보닐, F, 이소프로필, 히드록시, Boc(tert-부틸옥시카보닐), 메톡시, 메톡시로 치환된 메톡시, 페닐옥시 및 페닐카보닐로 이루어진 군에서 선택되는 하나이상으로 치환되는 것을 특징으로 하는, 화합물, 이의 입체이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염.
According to paragraph 1,
n is 1 or 2;
A is unsubstituted or phenyl or pyridine,
The substituted phenyl or pyridine is substituted with one or more selected from the group consisting of Cl, hydroxy, morpholine, methylsulfonyl, methyloxycarbonyl, carboxy and sulfonamide, or is substituted on two adjacent atoms to give 1 , forming 3-dioxole;
L is -CHR 1 -, -CHCH 2 - or -CH 2 CH 2 -,
Here, R 1 is hydrogen or methyl;
B is -NR 2 X, -NX 2 or -OX,
Here, R 2 is hydrogen or methyl;
The X above is ego,
Here, R 3 is hydrogen or oxo (=O);
R 4 is unsubstituted or substituted methyl, methoxy, piperazine, morpholine, phenyl, pyridine or pyrimidine,
The substituted methyl, methoxy, piperazine, morpholine, phenyl, pyridine or pyrimidine is unsubstituted or substituted with one or more methyl selected from the group consisting of hydroxy and phenyl, unsubstituted or substituted with one or more F. Substituted with one or more selected from the group consisting of methylcarbonyl, F, isopropyl, hydroxy, Boc (tert-butyloxycarbonyl), methoxy, methoxy substituted with methoxy, phenyloxy and phenylcarbonyl A compound, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.
 제1항에 있어서,
A는 , , , , , , , , , 또는 이고;
R4는 , , , , , , , , , , , , , , , , , , , , 또는 인 것을 특징으로 하는, 화합물, 이의 입체이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염.
According to paragraph 1,
A is , , , , , , , , , or ego;
R 4 is , , , , , , , , , , , , , , , , , , , , or A compound, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, characterized in that.
 제1항에 있어서,
상기 화학식 1로 표시되는 화합물은 하기 화합물 군으로부터 선택되는 어느 하나인 화합물, 이의 입체이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염:
<1> 4-(2-(비스(3-페닐프로프-2-인-1-일)아미노)에틸)벤젠설폰아미드;
<2> 3-페닐-N-(4-설파모일페네틸)프로피올아미드;
<3> 4-(2-((3-(4-(트리플루오로메틸)페닐)프로프-2-인-1-일)아미노)에틸)벤젠설폰아미드;
<4> 4-(2-((3-페닐프로프-2-인-1-일)아미노)에틸)벤젠설폰아미드;
<5> 4-(2-((3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)벤젠설폰아미드;
<6> 4-(2-(메틸(3-페닐프로프-2-인-1-일)아미노)에틸)벤젠설폰아미드;
<7> 4-(2-(비스(3-(4-메톡시페닐)프로프-2-인-1-일)아미노)에틸)벤젠설폰아미드;
<8> 4-(2-((3-(4-메톡시페닐)프로프-2-인-1-일)아미노)에틸)벤젠설폰아미드;
<9> 3-([1,1'-비페닐]-4-일)-N-페네틸프로프-2-인-1-아민;
<10> 4-(((3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)메틸)벤젠설폰아미드;
<11> 4-((비스(3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)메틸)벤젠설폰아미드;
<12> 3-([1,1'-비페닐]-4-일)-N-(4-클로로펜에틸)프로프-2-인-1-아민;
<13> 3-([1,1'-바이페닐]-4-일)-N-(3-([1,1'-바이페닐]-4-일)프로프-2-인-1-일)-N-(4-클로로페네틸)프로프-2-인-1-아민;
<14> 4-(2-((3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)페놀;
<15> 4-(2-(비스(3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)페놀;
<16> 3-([1,1'-비페닐]-4-일)-N-(2-(벤조[d][1,3]디옥솔-5-일)에틸)프로프-2-인-1-아민;
<17> 3-([1,1'-바이페닐]-4-일)-N-(3-([1,1'-바이페닐]-4-일)프로프-2-인-1-일)-N-(2-(벤조[d][1,3]디옥솔-5-일)에틸)프로프-2-인-1-아민;
<18> 3-([1,1'-비페닐]-4-일)-N-(2,2-디페닐에틸)프로프-2-인-1-아민;
<19> 3-([1,1'-바이페닐]-4-일)-N-(3-([1,1'-바이페닐]-4-일)프로프-2-인-1-일)-N-(2,2-디페닐에틸)프로프-2-인-1-아민;
<20> 3-([1,1'-비페닐]-4-일)-N-(4-모르폴리노펜에틸)프로프-2-인-1-아민;
<21> 3-([1,1'-바이페닐]-4-일)-N-(3-([1,1'-바이페닐]-4-일)프로프-2-인-1-일)-N-(4-모르폴리노펜에틸)프로프-2-인-1-아민;
<22> 2-(1-((3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)-4-클로로페놀;
<23> 4-클로로-2-(1-((3-(4-메톡시페닐)프로프-2-인-1-일)아미노)에틸)페놀;
<24> 4-(2-((3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)(메틸)아미노)에틸)벤젠설폰아미드;
<25> 3-([1,1'-비페닐]-4-일)-N-(4-(메틸설포닐)페네틸)프로프-2-인-1-아민;
<26> 3-([1,1'-바이페닐]-4-일)-N-(3-([1,1'-바이페닐]-4-일)프로프-2-인-1-일)-N-(4-(메틸설포닐)페네틸)프로프-2-인-1-아민;
<27> 메틸 4-(2-((3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)벤조에이트;
<28> 메틸 4-(2-(비스(3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)벤조에이트;
<29> 4-(2-((3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)벤조산;
<30> 4-(2-(비스(3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)벤조산;
<31> 4-(2-((3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)(메틸)아미노)에틸)페놀;
<32> 4-(1-((3-([1,1'-비페닐]-4-일)프로프-2-인-1-일)옥시)에틸)-3,5-디클로로피리딘;
<33> 4-클로로-2-(1-((3-(4-메톡시페닐)프로프-2-인-1-일)(메틸)아미노)에틸)페놀;
<34> tert-부틸 4-(4-(3-((4-히드록시페네틸)아미노)프로프-1-인-1-일)페닐)피페라진-1-카르복실레이트;
<35> tert-부틸 4-(4-(3-((1-(5-클로로-2-히드록시페닐)에틸)아미노)프로프-1-인-1-일)페닐)피페라진-1-카르복실레이트;
<36> 4-(2-((3-(4-(피페라진-1-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀;
<37> 4-클로로-2-(1-((3-(4-(피페라진-1-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀;
<38> 4-(2-((3-(4-모르폴리노페닐)프로프-2-인-1-일)아미노)에틸)페놀;
<39> 4-클로로-2-(1-((3-(4-모르폴리노페닐)프로프-2-인-1-일)아미노)에틸)페놀;
<40> 4-(2-((3-(4-(4-메틸피페라진-1-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀;
<41> 4-클로로-2-(1-((3-(4-(4-메틸피페라진-1-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀;
<42> 4-(2-((3-(4-(피리딘-4-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀;
<43> 4-클로로-2-(1-((3-(4-(피리딘-4-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀;
<44> 4-(2-((3-(4'-메톡시-[1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)페놀;
<45> 4-클로로-2-(1-((3-(4'-메톡시-[1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)페놀;
<46> 4-(2-((3-(4'-(메톡시메톡시)-[1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)페놀;
<47> 4-클로로-2-(1-((3-(4'-(메톡시메톡시)-[1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)페놀;
<48> 4-(2-((3-(4-(피리딘-3-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀;
<49> 4-클로로-2-(1-((3-(4-(피리딘-3-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀;
<50> 4-(2-((3-(4-(피리딘-2-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀;
<51> 4-클로로-2-(1-((3-(4-(피리딘-2-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀;
<52> 4'-(3-((4-히드록시페네틸)아미노)프로프-1-인-1-일)-[1,1'-비페닐]-4-올;
<53> 4'-(3-((1-(5-클로로-2-히드록시페닐)에틸)아미노)프로프-1-인-1-일)-[1,1'-비페닐]-4-올;
<54> 4-(2-((3-(4-(피리미딘-2-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀;
<55> 4-클로로-2-(1-((3-(4-(피리미딘-2-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀;
<56> 4-(2-((3-(4'-페녹시-[1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)페놀;
<57> 4-클로로-2-(1-((3-(4'-페녹시-[1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)페놀;
<58> 4-(2-((3-(4-(피리미딘-5-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀;
<59> 4-클로로-2-(1-((3-(4-(피리미딘-5-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀;
<60> 4-(2-((3-(4-(4-이소프로필피페라진-1-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀;
<61> 1-(4-(4-(3-((4-히드록시펜에틸)아미노)프로프-1-인-1-일)페닐)피페라진-1-일)에탄-1-온;
<62> 2,2,2-트리플루오로-1-(4-(4-(3-((4-히드록시펜에틸)아미노)프로프-1-인-1-일)페닐)피페라진-1-일)에탄-1-온;
<63> 4-(2-((3-(4'-(히드록시(페닐)메틸)-[1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)페놀;
<64> ((((4-히드록시페네틸)아잔디일)비스(프로프-1-인-3,1-디일))비스([1,1'-비페닐]-4',4-디일))비스(페닐메탄온);
<65> (4'-(3-((4-히드록시페네틸)아미노)프로프-1-인-1-일)-[1,1'-비페닐]-4-일)(페닐)메탄온;
<66> 4-(2-((3-(4'-페녹시-[1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)벤젠설폰아미드;
<67> 4-(2-((3-(4'-(메톡시메톡시)-[1,1'-비페닐]-4-일)프로프-2-인-1-일)아미노)에틸)벤젠설폰아미드;
<68> 4-(2-((3-(4-(4-벤질피페라진-1-일)페닐)프로프-2-인-1-일)아미노)에틸)벤젠설폰아미드; 및
<69> 4-(2-((3-(4-(4-벤질피페라진-1-일)페닐)프로프-2-인-1-일)아미노)에틸)페놀.According to paragraph 1,
The compound represented by Formula 1 is any one compound selected from the following compound group, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof:
<1>4-(2-(bis(3-phenylprop-2-yn-1-yl)amino)ethyl)benzenesulfonamide;
<2>3-phenyl-N-(4-sulfamoylphenethyl)propiolamide;
<3>4-(2-((3-(4-(trifluoromethyl)phenyl)prop-2-yn-1-yl)amino)ethyl)benzenesulfonamide;
<4>4-(2-((3-phenylprop-2-yn-1-yl)amino)ethyl)benzenesulfonamide;
<5>4-(2-((3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)benzenesulfonamide;
<6>4-(2-(methyl(3-phenylprop-2-yn-1-yl)amino)ethyl)benzenesulfonamide;
<7>4-(2-(bis(3-(4-methoxyphenyl)prop-2-yn-1-yl)amino)ethyl)benzenesulfonamide;
<8>4-(2-((3-(4-methoxyphenyl)prop-2-yn-1-yl)amino)ethyl)benzenesulfonamide;
<9>3-([1,1'-biphenyl]-4-yl)-N-phenethylprop-2-yn-1-amine;
<10>4-(((3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)methyl)benzenesulfonamide;
<11>4-((bis(3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)methyl)benzenesulfonamide;
<12>3-([1,1'-biphenyl]-4-yl)-N-(4-chlorophenethyl)prop-2-yn-1-amine;
<13>3-([1,1'-biphenyl]-4-yl)-N-(3-([1,1'-biphenyl]-4-yl)prop-2-yne-1-1)-N-(4-chlorophenethyl)prop-2-yn-1-amine;
<14>4-(2-((3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)phenol;
<15>4-(2-(bis(3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)phenol;
<16>3-([1,1'-biphenyl]-4-yl)-N-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)prop-2-phosphorus-1-amine;
<17>3-([1,1'-biphenyl]-4-yl)-N-(3-([1,1'-biphenyl]-4-yl)prop-2-yne-1-1)-N-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)prop-2-yn-1-amine;
<18>3-([1,1'-biphenyl]-4-yl)-N-(2,2-diphenylethyl)prop-2-yn-1-amine;
<19>3-([1,1'-biphenyl]-4-yl)-N-(3-([1,1'-biphenyl]-4-yl)prop-2-yne-1-1)-N-(2,2-diphenylethyl)prop-2-yn-1-amine;
<20>3-([1,1'-biphenyl]-4-yl)-N-(4-morpholinophenethyl)prop-2-yn-1-amine;
<21>3-([1,1'-biphenyl]-4-yl)-N-(3-([1,1'-biphenyl]-4-yl)prop-2-yne-1-1)-N-(4-morpholinophenethyl)prop-2-yn-1-amine;
<22>2-(1-((3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)-4-chlorophenol;
<23>4-chloro-2-(1-((3-(4-methoxyphenyl)prop-2-yn-1-yl)amino)ethyl)phenol;
<24>4-(2-((3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)(methyl)amino)ethyl)benzenesulfonamide;
<25>3-([1,1'-biphenyl]-4-yl)-N-(4-(methylsulfonyl)phenethyl)prop-2-yn-1-amine;
<26>3-([1,1'-biphenyl]-4-yl)-N-(3-([1,1'-biphenyl]-4-yl)prop-2-yne-1-1)-N-(4-(methylsulfonyl)phenethyl)prop-2-yn-1-amine;
<27> Methyl 4-(2-((3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)benzoate;
<28> Methyl 4-(2-(bis(3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)benzoate;
<29>4-(2-((3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)benzoicacid;
<30>4-(2-(bis(3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)benzoicacid;
<31>4-(2-((3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)(methyl)amino)ethyl)phenol;
<32>4-(1-((3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)oxy)ethyl)-3,5-dichloropyridine;
<33>4-chloro-2-(1-((3-(4-methoxyphenyl)prop-2-yn-1-yl)(methyl)amino)ethyl)phenol;
<34> tert-Butyl 4-(4-(3-((4-hydroxyphenethyl)amino)prop-1-yn-1-yl)phenyl)piperazine-1-carboxylate;
<35> tert-Butyl 4-(4-(3-((1-(5-chloro-2-hydroxyphenyl)ethyl)amino)prop-1-yn-1-yl)phenyl)piperazine-1 -carboxylate;
<36>4-(2-((3-(4-(piperazin-1-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol;
<37>4-chloro-2-(1-((3-(4-(piperazin-1-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol;
<38>4-(2-((3-(4-morpholinophenyl)prop-2-yn-1-yl)amino)ethyl)phenol;
<39>4-chloro-2-(1-((3-(4-morpholinophenyl)prop-2-yn-1-yl)amino)ethyl)phenol;
<40>4-(2-((3-(4-(4-methylpiperazin-1-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol;
<41>4-chloro-2-(1-((3-(4-(4-methylpiperazin-1-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol;
<42>4-(2-((3-(4-(pyridin-4-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol;
<43>4-chloro-2-(1-((3-(4-(pyridin-4-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol;
<44>4-(2-((3-(4'-methoxy-[1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)phenol;
<45>4-Chloro-2-(1-((3-(4'-methoxy-[1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)phenol;
<46>4-(2-((3-(4'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)phenol;
<47>4-Chloro-2-(1-((3-(4'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)prop-2-yne-1- 1) amino) ethyl) phenol;
<48>4-(2-((3-(4-(pyridin-3-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol;
<49>4-Chloro-2-(1-((3-(4-(pyridin-3-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol;
<50>4-(2-((3-(4-(pyridin-2-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol;
<51>4-chloro-2-(1-((3-(4-(pyridin-2-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol;
<52>4'-(3-((4-hydroxyphenethyl)amino)prop-1-yn-1-yl)-[1,1'-biphenyl]-4-ol;
<53>4'-(3-((1-(5-chloro-2-hydroxyphenyl)ethyl)amino)prop-1-yn-1-yl)-[1,1'-biphenyl]-4-all;
<54>4-(2-((3-(4-(pyrimidin-2-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol;
<55>4-Chloro-2-(1-((3-(4-(pyrimidin-2-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol;
<56>4-(2-((3-(4'-phenoxy-[1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)phenol;
<57>4-Chloro-2-(1-((3-(4'-phenoxy-[1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)phenol;
<58>4-(2-((3-(4-(pyrimidin-5-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol;
<59>4-Chloro-2-(1-((3-(4-(pyrimidin-5-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol;
<60>4-(2-((3-(4-(4-isopropylpiperazin-1-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol;
<61>1-(4-(4-(3-((4-hydroxyphenethyl)amino)prop-1-yn-1-yl)phenyl)piperazin-1-yl)ethan-1-one;
<62> 2,2,2-trifluoro-1-(4-(4-(3-((4-hydroxyphenethyl)amino)prop-1-yn-1-yl)phenyl)piperazine -1-yl)ethan-1-one;
<63>4-(2-((3-(4'-(hydroxy(phenyl)methyl)-[1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)phenol;
<64>((((4-hydroxyphenethyl)azanediyl)bis(prop-1-yn-3,1-diyl))bis([1,1'-biphenyl]-4',4-diyl))bis(phenylmethanone);
<65>(4'-(3-((4-hydroxyphenethyl)amino)prop-1-yn-1-yl)-[1,1'-biphenyl]-4-yl)(phenyl)methanone;
<66>4-(2-((3-(4'-phenoxy-[1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)benzenesulfoneamides;
<67>4-(2-((3-(4'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)benzenesulfonamide;
<68>4-(2-((3-(4-(4-benzylpiperazin-1-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)benzenesulfonamide; and
<69> 4-(2-((3-(4-(4-benzylpiperazin-1-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol. 제1항의 화학식 1로 표시되는 화합물, 이의 입체이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는, 암의 예방 또는 치료용 약학적 조성물.
A pharmaceutical composition for the prevention or treatment of cancer, containing the compound represented by Formula 1 of claim 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
 제1항의 화학식 1로 표시되는 화합물, 이의 입체이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는,
ACC 과활성화로 인한 질환의 예방 또는 치료용 약학적 조성물.
Containing the compound represented by the formula 1 of claim 1, its stereoisomer, its solvate, its hydrate, or its pharmaceutically acceptable salt as an active ingredient,
Pharmaceutical composition for preventing or treating diseases caused by ACC hyperactivation.
 제6항에 있어서,
상기 암은 폐암, 비-소세포 폐암(NSCL), 기관지 폐포 세포 폐암, 난소암, 대장암, 흑색종, 위암, 위장관암, 간암, 골암, 췌장암, 피부암, 두경부암, 피부 또는 안구 흑색종, 자궁암, 직장암, 결장암, 유방암, 자궁 육종, 나팔관 암종, 내궁내막 암종, 자궁경부 암종, 질 암종, 외음부 암종, 식도암, 후두암, 소장암, 갑상선암, 부갑상선암, 연조직의 육종, 요도암, 음경암, 전립선암, 다발성 골수종, 만성 또는 급성 백혈병 중 어느 하나인 것인 암의 예방 또는 치료용 약학적 조성물.
According to clause 6,
These cancers include lung cancer, non-small cell lung cancer (NSCL), bronchoalveolar cell lung cancer, ovarian cancer, colorectal cancer, melanoma, stomach cancer, gastrointestinal cancer, liver cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or eye melanoma, and uterine cancer. , rectal cancer, colon cancer, breast cancer, uterine sarcoma, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, esophagus cancer, laryngeal cancer, small intestine cancer, thyroid cancer, parathyroid cancer, sarcoma of soft tissue, urethral cancer, penile cancer, prostate cancer A pharmaceutical composition for preventing or treating cancer, which is any one of cancer, multiple myeloma, chronic or acute leukemia.
 제8항에 있어서,
상기 암은 간암인 약학적 조성물.According to clause 8,
A pharmaceutical composition wherein the cancer is liver cancer. 제1항의 화학식 1로 표시되는 화합물, 이의 입체이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 암의 예방 또는 개선용 건강기능식품 조성물.

A health functional food composition for preventing or improving cancer containing the compound represented by Formula 1 of claim 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
KR1020220062613A 2022-05-23 2022-05-23 Pharmaceutical composition comprising phenylpropine derivative for use in preventing or treating cancer as an active ingredient KR20230163603A (en)

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