KR20230127844A - Novel compound having anticancer and use thereof - Google Patents

Novel compound having anticancer and use thereof Download PDF

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KR20230127844A
KR20230127844A KR1020220092975A KR20220092975A KR20230127844A KR 20230127844 A KR20230127844 A KR 20230127844A KR 1020220092975 A KR1020220092975 A KR 1020220092975A KR 20220092975 A KR20220092975 A KR 20220092975A KR 20230127844 A KR20230127844 A KR 20230127844A
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cancer
amino
compound
ethoxy
dioxopiperidin
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서영호
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계명대학교 산학협력단
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Abstract

본 발명은 항암 활성을 갖는 신규 화합물 및 이의 용도에 관한 것으로, 신규화합물은 E3 리가아제 리간드인 포말리도마이드(pomalidomide) 및 HSF1 억제제인 KRIBB11을 링커로 연결 및 합성한 화합물이고, 상기 신규 화합물은 HSF1 발현을 억제하여 HSF1이 과발현되어 발생하는 다양한 암종에서의 치료 효과를 나타 낼 수 있다.The present invention relates to a novel compound having anticancer activity and its use, wherein the novel compound is a compound synthesized by linking pomalidomide, an E3 ligase ligand, and KRIBB11, an HSF1 inhibitor, with a linker, and the novel compound is HSF1 By suppressing its expression, it can exhibit therapeutic effects in various carcinomas caused by overexpression of HSF1.

Description

항암 활성을 갖는 신규 화합물 및 이의 용도{NOVEL COMPOUND HAVING ANTICANCER AND USE THEREOF}Novel compounds with anticancer activity and their uses {NOVEL COMPOUND HAVING ANTICANCER AND USE THEREOF}

본 발명은 항암 활성을 갖는 신규 화합물 및 이의 용도를 제공한다.The present invention provides novel compounds with anti-cancer activity and uses thereof.

암은 전 세계적으로 질병률 및 사망률의 지속적인 주요 원인 중 하나로, 2020년 천만 명의 사망자를 기록했다. 암은 막대한 경제적 영향을 미치고 있는데, 이는 큰 인명 손실과 더불어 증가하고 있다. 기존의 전통적인 항암화학요법, 표적치료제 및 면역치료제는 심각한 부작용, 독성, 치료요법에 대한 내성 및 통제 불가능한 면역계의 과도한 활성 등의 단점이 많다. 따라서, 암을 퇴치하기 위한 새로운 전략이 의학적으로 계속적으로 연구되고 있다.Cancer continues to be one of the leading causes of morbidity and mortality worldwide, accounting for 10 million deaths in 2020. Cancer has a huge economic impact, which is growing with great loss of life. Existing traditional anti-cancer chemotherapy, targeted therapy, and immunotherapy have many disadvantages such as serious side effects, toxicity, resistance to therapy, and excessive activation of the immune system that cannot be controlled. Therefore, new strategies for combating cancer are continuously being studied medically.

HSF1 (heat shock factor 1)은 단백질 독성 스트레스에 대한 전사 반응의 마스터 조절자이며, 방사선 요법 및 온열 요법을 포함한 항암 요법의 효과적인 약물의 표적이 된다. HSF1은 전립선암, 췌장암, 유방암, 결장직장암, 림프종, 흑색종 및 구강암 등 많은 암 유형에서 과활성 또는 과발현되는 것으로 알려져 있고, HSF1의 활성화는 본질적으로 치료 결과에 영향을 미치는 다양한 열 충격 단백질의 과발현을 초래한다. HSF1에 의한 열충격 단백질의 과발현은 암 치료에 사용되는 화학요법, 방사선 요법 및 저체온 요법에 대한 내성의 주요 원인으로 알려져 있는데, HSF1이 다양한 암 화학 요법 치료의 개발 및 낮은 예후에서 중요한 요인으로 밝혀졌지만 HSF1의 효과적인 억제제는 개발이 더디며, 현재까지 보고된 대부분의 HSF1 억제제는 HSF1을 직접적으로 억제하기 보다는 HSF1에서 높은 신호 교란을 통한 간접적인 억제제이다. 따라서, HSF1을 직접적으로 억제하는 억제제 개발이 여전히 필요한 실정이다.Heat shock factor 1 (HSF1) is a master regulator of the transcriptional response to proteotoxic stress and is a target for effective anticancer therapies, including radiation therapy and hyperthermia. HSF1 is known to be overactive or overexpressed in many cancer types, including prostate cancer, pancreatic cancer, breast cancer, colorectal cancer, lymphoma, melanoma, and oral cancer. causes Overexpression of heat shock protein by HSF1 is known to be a major cause of resistance to chemotherapy, radiation therapy and hypothermia used in cancer treatment. Although HSF1 has been found to be an important factor in the development of various cancer chemotherapy treatments and poor prognosis, HSF1 Effective inhibitors of HSF1 have been slow to develop, and most of the HSF1 inhibitors reported so far are indirect inhibitors through high signal perturbation in HSF1 rather than directly inhibiting HSF1. Therefore, there is still a need to develop inhibitors that directly inhibit HSF1.

1. 대한민국 공개특허 10-2021-0025061호.1. Republic of Korea Patent Publication No. 10-2021-0025061.

본 발명의 목적은 신규 화합물 및 이를 함유하는 암 질환 예방 또는 치료용 약학 조성물 및 건강기능식품 조성물을 제공하는 데에 있다.An object of the present invention is to provide a novel compound and a pharmaceutical composition and health functional food composition for preventing or treating cancer disease containing the same.

본 발명의 또 다른 목적은 상기 신규화합물을 함유하는 HSF1 (heat shock factor 1) 또는 열충격단백질 (heat shock protein) 발현 억제용 시약 조성물 및 이를 이용한 억제방법을 제공하는 데에 있다.Another object of the present invention is to provide a reagent composition for inhibiting heat shock factor 1 (HSF1) or heat shock protein expression containing the novel compound and a method for suppressing the same.

상기 목적을 달성하기 위하여, 본 발명은 하기 화학식 A로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 제공한다.In order to achieve the above object, the present invention provides a compound represented by Formula A or a pharmaceutically acceptable salt thereof.

[화학식 A][Formula A]

이때, 상기 L은 에스터기 또는 아마이드기를 하나 이상 포함하거나 포함하지 않는 (C4 내지 C18)알킬 일 수 있다.In this case, the L may be (C4 to C18) alkyl with or without one or more ester groups or amide groups.

또한, 본 발명은 상기 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 암 질환 예방 또는 치료용 약학 조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for preventing or treating cancer disease containing the compound or a pharmaceutically acceptable salt thereof as an active ingredient.

또한, 본 발명은 상기 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 암 질환 예방 또는 개선용 건강기능식품 조성물을 제공한다.In addition, the present invention provides a health functional food composition for preventing or improving cancer disease containing the compound or a pharmaceutically acceptable salt thereof as an active ingredient.

또한, 본 발명은 상기 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 HSF1 (heat shock factor 1) 또는 열충격단백질 (heat shock protein) 발현 억제용 시약 조성물을 제공한다.In addition, the present invention provides a reagent composition for inhibiting heat shock factor 1 (HSF1) or heat shock protein expression containing the compound or a pharmaceutically acceptable salt thereof as an active ingredient.

또한, 본 발명은 상기 화합물 또는 이의 약학적으로 허용 가능한 염을 투여하는 단계를 포함하는 HSF1 (heat shock factor 1) 또는 열충격단백질 (heat shock protein) 발현 억제방법을 제공한다.In addition, the present invention provides a method for inhibiting the expression of heat shock factor 1 (HSF1) or heat shock protein, comprising administering the compound or a pharmaceutically acceptable salt thereof.

본 발명은 항암 활성을 갖는 신규 화합물 및 이의 용도에 관한 것으로, 프로테오솜 매개 단백질 분해를 이용하고 천연 단백질 분해 시스템을 동원하여 암성 단백질을 선택적으로 분해하며, 구체적으로, 상기 신규 화합물은 HSF1 발현을 억제하여 HSF1이 과발현되어 발생하는 다양한 암종에서의 치료 효과를 나타내어, 치료제 나 치료방법 등에 널리 이용될 수 있다.The present invention relates to a novel compound having anticancer activity and its use, wherein the novel compound selectively degrades cancer proteins by using proteosome-mediated proteolysis and recruiting a natural proteolytic system, and specifically, the novel compound inhibits HSF1 expression. Inhibiting HSF1 to show therapeutic effects in various carcinomas caused by overexpression, it can be widely used for therapeutic agents or treatment methods.

도 1은 HSF1 (heat shock factor 1)이 있는 KRIBB11의 도킹상태 및 신규 화합물 설계 모식도를 나타낸다.
도 2는 KRIBB11 유사체 합성 모식도를 나타낸다.
도 3은 포말리도마이드 (pomalidomide) 합성 모식도를 나타낸다.
도 4는 상기 신규 화합물에서 KRIBB11 유사체 및 포말리도마이드를 연결하는 링커 (linker)의 합성 모식도를 나타낸다.
도 5는 상기 신규 화합물 합성 모식도를 나타낸다.
도 6은 N-(6-클로로-3-나이트로피리딘-2-일)-1H-인다졸-5-아민 [N-(6-chloro-3-nitropyridin-2-yl)-1H-indazol-5-amine] (이하, 화합물 3이라함)의 1H 스펙트럼을 나타낸다.
도 7은 N 6-(4-아미노부틸)-N 2-(1H-인다졸-5-일)-3-나이트로피리딘-2,6-디아민 [N 6-(4-aminobutyl)-N 2-(1H-indazol-5-yl)-3-nitropyridine-2,6-diamine] (이하, 화합물 4라함)의 1H 스펙트럼을 나타낸다.
도 8은 tert-부틸 (2,6-디옥소피페리딘-3-일)카르바메이트 [tert-butyl (2,6-dioxopiperidin-3-yl)carbamate] (이하, 화합물 6이라함)의 1H 스펙트럼을 나타낸다.
도 9는 2,6-디옥소피페리딘-3-아미니움 [2,6-dioxopiperidin-3-aminium] (이하, 화합물 7이라함)의 1H 스펙트럼을 나타낸다.
도 10은 2-(2,6-디옥소피페리딘-3-yl)-4-플루오로아이소인돌린-1,3-디온 [2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione] (이하, 화합물 9a라함)의 1H 스펙트럼을 나타낸다.
도 11은 2-(2,6-디옥소피페리딘-3-일)-4-나이트로아이소인돌린-1,3-디온 [2-(2,6-dioxopiperidin-3-yl)-4-nitroisoindoline-1,3-dione] (이하, 화합물 9b라함)의 1H 스펙트럼을 나타낸다.
도 12는 4-아미노-2-(2,6-디옥소피페리딘-3-일)아이소인돌린-1,3-디온 [4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione] (이하, 화합물 9c라함)의 1H 스펙트럼을 나타낸다.
도 13은 tert-부틸 (3-(2-(2-(3-아미노프로폭시)에톡시)에톡시)ㅊ프로필)카르바메이트 [tert-butyl (3-(2-(2-(3-aminopropoxy)ethoxy)ethoxy)propyl)carbamate] (이하, 화합물 10b라함)의 1H 스펙트럼을 나타낸다.
도 14는 tert-부틸 (3-(2-(2-(3-((2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소아이소인돌린-4-일)아미노)프로폭시)에톡시)에톡시)프로필)카르바메이트 [tert-butyl (3-(2-(2-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propoxy)ethoxy)ethoxy)propyl)carbamate] (이하, 화합물 12a라함)의 1H 스펙트럼을 나타낸다.
도 15는 4-((3-(2-(2-(3-아미노프로폭시)에톡시)에톡시)프로필)아미노)-2-(2,6-디옥소피페리딘-3-일)아이소인돌린-1,3-디온 [4-((3-(2-(2-(3-aminopropoxy)ethoxy)ethoxy)propyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione] (이하, 화합물 12b라함)의 1H 스펙트럼을 나타낸다.
도 16은 tert-부틸 (1-클로로-2-옥소-7,10,13-트리옥사-3-아자헥사데칸-16-일)카르바메이트 [tert-butyl (1-chloro-2-oxo-7,10,13-trioxa-3-azahexadecan-16-yl)carbamate] (이하, 화합물 11이라함)의 1H 스펙트럼을 나타낸다.
도 17은 tert-부틸 (1-((2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소아이소인돌린-4-일)아미노)-2-옥소-7,10,13-트리옥사-3-아자헥사데칸-16-일)카르바메이트 [tert-butyl (1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-2-oxo-7,10,13-trioxa-3-azahexadecan-16-yl)carbamate] (이하, 화합물 13a라함)의 1H 스펙트럼을 나타낸다.
도 18은 N-(3-(2-(2-(3-아미노프로폭시)에톡시)에톡시)프로필)-2-((2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소아이소인돌린-4-일)아미노)아세트아마이드 [N-(3-(2-(2-(3-aminopropoxy)ethoxy)ethoxy)propyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetamide] (이하, 화합물 13b라함)의 1H 스펙트럼을 나타낸다.
도 19는 4-((4-((6-((1H-인다졸-5-일)아미노)-5-나이트로피리딘-2-일)아미노)부틸)아미노)-2-(2,6-디옥소피페리딘-3-일)아이소인돌린-1,3-디온 [4-((4-((6-((1H-indazol-5-yl)amino)-5-nitropyridin-2-yl)amino)butyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione] (이하, 화합물 14라함)의 1H 스펙트럼을 나타낸다.
도 20은 화합물 14의 13C 스펙트럼을 나타낸다.
도 21은 4-((3-(2-(2-(3-((6-((1H-인다졸-5-일)아미노)-5-나이트로피리딘-2-일)아미노)프로폭시)에톡시)에톡시)프로필)아미노)-2-(2,6-디옥소피페리딘-3-일)아이소인돌린-1,3-디온 [4-((3-(2-(2-(3-((6-((1H-indazol-5-yl)amino)-5-nitropyridin-2-yl)amino)propoxy)ethoxy)ethoxy)propyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione] (이하, 화합물 15라함)의 1H 스펙트럼을 나타낸다.
도 22는 화합물 15의 13C 스펙트럼을 나타낸다.
도 23은 N-(3-(2-(2-(3-((6-((1H-인다졸-5-일)아미노)-5-나이트로피리딘-2-일)아미노)프록폭시)에톡시)에톡시)프로필)-2-((2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소아이소인돌린-4-일)아미노)아세트아마이드 [N-(3-(2-(2-(3-((6-((1H-indazol-5-yl)amino)-5-nitropyridin-2-yl)amino)propoxy)ethoxy)ethoxy)propyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetamide] (이하, 화합물 16이라함)의 1H 스펙트럼을 나타낸다.
도 24는 화합물 16의 13C 스펙트럼을 나타낸다.
도 25는 삼중 음성 유방암 세포인 MDA-MB-231의 세포 생존율에 대한 화합물 14 내지 16의 효과를 확인한 시험 결과를 나타낸다.
도 26은 HSF1 (heat shock factor 1)에 대한 화합물 14 내지 16의 단백질 분해 효과를 확인한 시험 결과를 나타낸다.Figure 1 shows the docking state of KRIBB11 with HSF1 (heat shock factor 1) and a schematic diagram of novel compound design.
Figure 2 shows a schematic diagram of KRIBB11 analog synthesis.
3 shows a schematic diagram of the synthesis of pomalidomide.
Figure 4 shows a schematic diagram of the synthesis of a linker connecting the KRIBB11 analog and pomalidomide in the novel compound.
5 shows a schematic diagram of the synthesis of the novel compound.
6 is N- (6-chloro-3-nitropyridin-2-yl)-1 H -indazol-5-amine [ N- (6-chloro-3-nitropyridin-2-yl)-1 H- indazol-5-amine] (hereinafter, referred to as compound 3 ).
7 is N 6 -(4-aminobutyl) -N 2 -(1 H -indazol-5-yl)-3-nitropyridine-2,6-diamine [ N 6 -(4-aminobutyl)- N 2- (1 H -indazol-5-yl)-3-nitropyridine-2,6-diamine] (hereinafter referred to as compound 4 ).
8 is 1 of tert -butyl (2,6-dioxopiperidin-3-yl)carbamate [ tert -butyl (2,6-dioxopiperidin-3-yl)carbamate] (hereinafter referred to as Compound 6). Shows the H spectrum.
9 shows the 1 H spectrum of 2,6-dioxopiperidin-3-aminium [2,6-dioxopiperidin-3-aminium] (hereinafter referred to as Compound 7).
10 is 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione [2-(2,6-dioxopiperidin-3-yl)-4- fluoroisoindoline-1,3-dione] ( hereinafter referred to as compound 9a).
11 shows 2-(2,6-dioxopiperidin-3-yl)-4-nitroisoindoline-1,3-dione [2-(2,6-dioxopiperidin-3-yl)-4- nitroisoindoline-1,3-dione] (hereinafter referred to as Compound 9b).
12 is 4-amino-2- (2,6-dioxopiperidin-3-yl) isoindoline-1,3-dione [4-amino-2- (2,6-dioxopiperidin-3-yl) isoindoline-1,3-dione] (hereinafter referred to as Compound 9c).
13 is tert -butyl (3- (2- (2- (3-aminopropoxy) ethoxy) ethoxy) propyl) carbamate [ tert -butyl (3- (2- (2- (3- aminopropoxy)ethoxy)ethoxy)propyl)carbamate] ( hereinafter referred to as compound 10b).
14 is tert -butyl (3-(2-(2-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl )amino)propoxy)ethoxy)ethoxy)propyl)carbamate [ tert -butyl (3-(2-(2-(3-((2-(2,6-dioxopiperidin-3-yl)-1 ,3-dioxoisoindolin-4-yl)amino)propoxy)ethoxy)ethoxy)propyl)carbamate] (hereinafter referred to as compound 12a ).
15 is 4-((3-(2-(2-(3-aminopropoxy)ethoxy)ethoxy)propyl)amino)-2-(2,6-dioxopiperidin-3-yl)ai Soindoline-1,3-dione [4-((3-(2-(2-(3-aminopropoxy)ethoxy)ethoxy)propyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione] (hereinafter referred to as compound 12b).
16 is tert -butyl (1-chloro-2-oxo-7,10,13-trioxa-3-azahexadecan-16-yl)carbamate [ tert -butyl (1-chloro-2-oxo- 7,10,13-trioxa-3-azahexadecan-16-yl)carbamate] (hereinafter referred to as compound 11 ).
17 is tert -butyl (1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-2-oxo-7 ,10,13-trioxa-3-azahexadecane-16-yl)carbamate [ tert -butyl (1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin- 4-yl)amino)-2-oxo-7,10,13-trioxa-3-azahexadecan-16-yl)carbamate] (hereinafter referred to as Compound 13a ).
18 is N- (3-(2-(2-(3-aminopropoxy)ethoxy)ethoxy)propyl)-2-((2-(2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-4-yl)amino)acetamide [ N- (3-(2-(2-(3-aminopropoxy)ethoxy)ethoxy)propyl)-2-((2-( 2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetamide] (hereinafter referred to as Compound 13b) shows a 1 H spectrum.
19 shows 4-((4-((6-((1H-indazol-5-yl)amino)-5-nitropyridin-2-yl)amino)butyl)amino)-2-(2,6 -dioxopiperidin-3-yl)isoindoline-1,3-dione [4-((4-((6-((1H-indazol-5-yl)amino)-5-nitropyridin-2-yl )amino)butyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione] (hereinafter referred to as compound 14 ).
20 shows the 13 C spectrum of compound 14.
21 is 4-((3-(2-(2-(3-((6-((1H-indazol-5-yl)amino)-5-nitropyridin-2-yl)amino)propoxy )ethoxy)ethoxy)propyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [4-((3-(2-(2-) (3-((6-((1H-indazol-5-yl)amino)-5-nitropyridin-2-yl)amino)propoxy)ethoxy)ethoxy)propyl)amino)-2-(2,6-dioxopiperidin- 3-yl)isoindoline-1,3-dione] (hereinafter referred to as compound 15).
22 shows the 13 C spectrum of compound 15.
23 is N-(3-(2-(2-(3-((6-((1H-indazol-5-yl)amino)-5-nitropyridin-2-yl)amino)propoxy) Ethoxy)ethoxy)propyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetamide [N -(3-(2-(2-(3-((6-((1H-indazol-5-yl)amino)-5-nitropyridin-2-yl)amino)propoxy)ethoxy)ethoxy)propyl)-2 1 H spectrum of -((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetamide] (hereinafter referred to as Compound 16) is shown.
24 shows the 13 C spectrum of compound 16.
25 shows test results confirming the effects of compounds 14 to 16 on the cell viability of triple negative breast cancer cells, MDA-MB-231.
26 shows test results confirming the proteolytic effect of compounds 14 to 16 on heat shock factor 1 (HSF1).

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

본 발명자들은 HSF1 (heat shock factor 1)은 전립선암, 췌장암, 유방암, 결장직장암, 림프종, 흑색종 및 구강암 등 많은 암 유형에서 과활성 또는 과발현되어 나타나는 것으로, 신규 화합물을 통해, HSF1의 효과적인 억제효과로 인하여 항암효과를 나타낼 수 있는 본 발명을 완성하였다.The present inventors found that heat shock factor 1 (HSF1) is overactive or overexpressed in many cancer types such as prostate cancer, pancreatic cancer, breast cancer, colorectal cancer, lymphoma, melanoma, and oral cancer. Due to this, the present invention, which can exhibit anticancer effects, was completed.

본 발명은 하기 화학식 A로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 제공한다.The present invention provides a compound represented by Formula A below or a pharmaceutically acceptable salt thereof.

[화학식 A][Formula A]

이때, 상기 L은 에스터기 또는 아마이드기를 하나 이상 포함하거나 포함하지 않는 (C4 내지 C18)알킬 일 수 있고, 바람직하게 상기 L은 에스터기를 2 내지 4개 포함하거나 포함하지 않는 (C4 내지 C12)알킬 일 수 있다.In this case, L may be a (C4 to C18)alkyl group with or without one or more ester groups or amide groups, and preferably L is a (C4 to C12)alkyl group with or without 2 to 4 ester groups. can

상기 화합물은 하기 화합물 14 내지 16일 수 있다.The compound may be the following compounds 14 to 16.

(화합물 14) 4-((4-((6-((1H-인다졸-5-일)아미노)-5-나이트로피리딘-2-일)아미노)부틸)아미노)-2-(2,6-디옥소피페리딘-3-일)아이소인돌린-1,3-디온 [4-((4-((6-((1H-indazol-5-yl)amino)-5-nitropyridin-2-yl)amino)butyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione];(Compound 14) 4-((4-((6-((1H-indazol-5-yl)amino)-5-nitropyridin-2-yl)amino)butyl)amino)-2-(2, 6-dioxopiperidin-3-yl)isoindoline-1,3-dione [4-((4-((6-((1H-indazol-5-yl)amino)-5-nitropyridin-2- yl)amino)butyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione];

(화합물 15) 4-((3-(2-(2-(3-((6-((1H-인다졸-5-일)아미노)-5-나이트로피리딘-2-일)아미노)프로폭시)에톡시)에톡시)프로필)아미노)-2-(2,6-디옥소피페리딘-3-일)아이소인돌린-1,3-디온 [4-((3-(2-(2-(3-((6-((1H-indazol-5-yl)amino)-5-nitropyridin-2-yl)amino)propoxy)ethoxy)ethoxy)propyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione]; 및(Compound 15) 4-((3-(2-(2-(3-((6-((1H-indazol-5-yl)amino)-5-nitropyridin-2-yl)amino)pro Poxy)ethoxy)ethoxy)propyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [4-((3-(2-(2 -(3-((6-((1H-indazol-5-yl)amino)-5-nitropyridin-2-yl)amino)propoxy)ethoxy)ethoxy)propyl)amino)-2-(2,6-dioxopiperidin -3-yl)isoindoline-1,3-dione]; and

(화합물 16) N-(3-(2-(2-(3-((6-((1H-인다졸-5-일)아미노)-5-나이트로피리딘-2-일)아미노)프록폭시)에톡시)에톡시)프로필)-2-((2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소아이소인돌린-4-일)아미노)아세트아마이드 [N-(3-(2-(2-(3-((6-((1H-indazol-5-yl)amino)-5-nitropyridin-2-yl)amino)propoxy)ethoxy)ethoxy)propyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetamide].(Compound 16) N-(3-(2-(2-(3-((6-((1H-indazol-5-yl)amino)-5-nitropyridin-2-yl)amino)propoxy )ethoxy)ethoxy)propyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetamide [ N-(3-(2-(2-(3-((6-((1H-indazol-5-yl)amino)-5-nitropyridin-2-yl)amino)propoxy)ethoxy)ethoxy)propyl)- 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetamide].

또한, 본 발명은 상기 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 암 질환 예방 또는 치료용 약학 조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for preventing or treating cancer disease containing the compound or a pharmaceutically acceptable salt thereof as an active ingredient.

상기 암 질환은 HSF1 (heat shock factor 1) 또는 열충격단백질 (heat shock protein) 활성에 의해 발생하는 암 질환 일 수 있다.The cancer disease may be a cancer disease caused by heat shock factor 1 (HSF1) or heat shock protein activity.

상기 암 질환은 유방암, 삼중음성유방암 (TNBC), 자궁경부암, 폐암, 췌장암, 결장암, 골암, 피부암, 피부 또는 안구내 흑색종, 자궁암, 난소암, 직장암, 위암, 항문부근암, 결장암, 나팔관암종, 자궁내막암종, 질암, 음문암, 호지킨병(Hodgkin's disease), 식도암, 소장암, 내분비선암, 갑상선암, 부갑상선암, 부신암, 연조직 육종, 요도암, 음경암, 전립선암, 만성 또는 급성 백혈병, 림프구 림프종, 방광암, 신장 또는 수뇨관 암, 중추신경계 종양, 1차 CNS 림프종, 척수 종양, 뇌간 신경교종 및 뇌하수체 선종으로 이루어진 군에서 선택된 어느 하나 일 수 있으나, 이에 한정되는 것은 아니다.The cancer disease is breast cancer, triple negative breast cancer (TNBC), cervical cancer, lung cancer, pancreatic cancer, colon cancer, bone cancer, skin cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, stomach cancer, near anus cancer, colon cancer, fallopian tube carcinoma , endometrial carcinoma, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia , lymphocytic lymphoma, bladder cancer, renal or ureteral cancer, central nervous system tumor, primary CNS lymphoma, spinal cord tumor, brainstem glioma, and pituitary adenoma, but may be any one selected from the group consisting of, but is not limited thereto.

본 발명의 다른 구체예에서, 약학 조성물은 약학 조성물의 제조에 통상적으로 사용하는 적절한 담체, 부형제, 붕해제, 감미제, 피복제, 팽창제, 윤활제, 활택제, 향미제, 항산화제, 완충액, 정균제, 희석제, 분산제, 계면활성제, 결합제 및 윤활제로 이루어진 군에서 선택되는 하나 이상의 첨가제를 추가로 포함할 수 있다.In another embodiment of the present invention, the pharmaceutical composition is a suitable carrier, excipient, disintegrant, sweetener, coating agent, swelling agent, lubricant, lubricant, flavoring agent, antioxidant, buffer, bacteriostatic agent, One or more additives selected from the group consisting of diluents, dispersants, surfactants, binders and lubricants may be further included.

구체적으로 담체, 부형제 및 희석제는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 사용할 수 있으며, 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 조성물에 적어도 하나 이상의 부형제, 예를 들면, 전분, 칼슘카보네이트, 수크로스 또는 락토오스, 젤라틴 등을 섞어 조제할 수 있다. 또한 단순한 부형제 이외에 마그네슘 스티레이트, 탈크 같은 윤활제들도 사용할 수 있다. 경구를 위한 액상제제로는 현탁제, 내용액제, 유제, 시럽제 등이 있으며 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제, 좌제 등이 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜, 폴리에틸렌 글리콜, 올리브오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기재로는 위텝솔 (witepsol), 마크로골, 트윈 (tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다.Specifically, carriers, excipients and diluents are lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline Cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil may be used, and solid dosage forms for oral administration include tablets, pills, powders, granules, and capsules. These solid preparations may be prepared by mixing at least one or more excipients, for example, starch, calcium carbonate, sucrose or lactose, gelatin, etc., with the composition. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Liquid preparations for oral administration include suspensions, solutions for oral use, emulsions, syrups, and the like, and various excipients such as wetting agents, sweeteners, aromatics, and preservatives may be included in addition to commonly used simple diluents such as water and liquid paraffin. Preparations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, suppositories, and the like. Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspensions. As a base material of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin paper, glycerogeratin and the like may be used.

본 발명의 일실시예에 따르면, 상기 약학 조성물은 정맥내, 동맥내, 복강내, 근육내, 동맥내, 복강내, 흉골내, 경피, 비측내, 흡입, 국소, 직장, 경구, 안구내 또는 피내 경로를 통해 통상적인 방식으로 대상체로 투여할 수 있다.According to one embodiment of the present invention, the pharmaceutical composition is intravenous, intraarterial, intraperitoneal, intramuscular, intraarterial, intraperitoneal, intrasternal, transdermal, intranasal, inhalational, topical, rectal, oral, intraocular or It can be administered to a subject in a conventional manner via the intradermal route.

본 발명에 따른 유효성분의 투여량은 대상체의 상태 및 체중, 질환의 종류 및 정도, 약물 형태, 투여경로 및 기간에 따라 달라질 수 있으며 당업자에 의해 적절하게 선택될 수 있고, 1일 투여량이 0.01 mg/kg 내지 200 mg/kg, 바람직하게는 0.1 mg/kg 내지 200 mg/kg, 보다 바람직하게는 0.1 mg/kg 내지 100 mg/kg 일 수 있다. 투여는 하루에 한번 투여할 수도 있고 수회로 나누어 투여할 수도 있으며, 이에 의해 본 발명의 범위가 제한되는 것은 아니다.The dosage of the active ingredient according to the present invention may vary depending on the condition and weight of the subject, the type and severity of the disease, the drug type, the route and duration of administration, and may be appropriately selected by a person skilled in the art, and the daily dosage is 0.01 mg. /kg to 200 mg/kg, preferably 0.1 mg/kg to 200 mg/kg, and more preferably 0.1 mg/kg to 100 mg/kg. Administration may be administered once a day or divided into several times, and the scope of the present invention is not limited thereby.

또한, 본 발명은 상기 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 암 질환 예방 또는 개선용 건강기능식품 조성물을 제공한다.In addition, the present invention provides a health functional food composition for preventing or improving cancer disease containing the compound or a pharmaceutically acceptable salt thereof as an active ingredient.

상기 건강기능식품은 여러 가지 영양제, 비타민, 광물 (전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제 (치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다.The health functional food includes various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, colorants and enhancers (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts, It may contain organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonation agents used in carbonated beverages, and the like.

그밖에 천연 과일 주스, 합성 과일 주스 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 또한, 건강기능식품 조성물은 육류, 소세지, 빵, 초콜릿, 캔디류, 스넥류, 과자류, 피자, 라면, 껌류, 아이스크림류, 스프, 음료수, 차, 기능수, 드링크제, 알코올 및 비타민 복합제 중 어느 하나의 형태일 수 있다.In addition, it may contain fruit flesh for the production of natural fruit juice, synthetic fruit juice and vegetable beverages. These components may be used independently or in combination. In addition, the health functional food composition is any one form of meat, sausage, bread, chocolate, candy, snack, confectionery, pizza, ramen, gum, ice cream, soup, beverage, tea, functional water, drink, alcohol and vitamin complex can be

또한, 상기 건강기능식품은 식품첨가물을 추가로 포함할 수 있으며, "식품첨가물"로서의 적합 여부는 다른 규정이 없는 한 식품의약품안전청에 승인된 식품첨가물공전의 총칙 및 일반 시험법 등에 따라 해당 품목에 관한 규격 및 기준에 의하여 판정한다.In addition, the health functional food may additionally contain food additives, and the suitability as a "food additive" is determined according to the general rules of the Food Additive Code and general test methods approved by the Korea Food and Drug Administration unless otherwise specified. It is judged according to the relevant standards and standards.

상기 "식품첨가물공전"에 수재된 품목으로 예를 들어, 케톤류, 글리신, 구연산칼륨, 니코틴산, 계피산 등의 화학적 합성품, 감색소, 감초추출물, 결정셀룰로오스, 고랭색소, 구아검 등의 천연첨가물, L-글루타민산나트륨 제제, 면류 첨가 알칼리제, 보존료제제, 타르색소 제제 등의 혼합 제제류 등을 들 수 있다.Examples of items listed in the “Food Additives Codex” include, for example, chemical synthetic products such as ketones, glycine, potassium citrate, nicotinic acid, and cinnamic acid, natural additives such as dark pigment, licorice extract, crystalline cellulose, goreng pigment, guar gum, L -Mixed preparations such as sodium glutamate preparations, noodle-added alkali preparations, preservative preparations, tar color preparations, and the like.

이때, 건강기능식품을 제조하는 과정에서 식품에 첨가되는 유효성분은 필요에 따라 그 함량을 적절히 가감할 수 있으며, 바람직하게는 식품 100 중량부에 1 중량부 내지 90 중량부 포함되도록 첨가될 수 있다.At this time, the content of the active ingredient added to the food in the process of manufacturing the health functional food may be appropriately increased or decreased as necessary, and preferably may be added so that 1 part by weight to 90 parts by weight is included in 100 parts by weight of the food. .

또한, 본 발명은 상기 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 HSF1 (heat shock factor 1) 또는 열충격단백질 (heat shock protein) 발현 억제용 시약 조성물을 제공한다.In addition, the present invention provides a reagent composition for inhibiting heat shock factor 1 (HSF1) or heat shock protein expression containing the compound or a pharmaceutically acceptable salt thereof as an active ingredient.

또한, 본 발명은 상기 화합물 또는 이의 약학적으로 허용 가능한 염을 투여하는 단계를 포함하는 HSF1 (heat shock factor 1) 또는 열충격단백질 (heat shock protein) 발현 억제방법을 제공한다.In addition, the present invention provides a method for inhibiting the expression of heat shock factor 1 (HSF1) or heat shock protein, comprising administering the compound or a pharmaceutically acceptable salt thereof.

이하, 본 발명의 이해를 돕기 위하여 실시예 등을 들어 상세하게 설명하기로 한다. 다만 하기의 실시예 등은 본 발명의 내용을 예시하는 것일 뿐 본 발명의 범위가 하기 실시예 등에 한정되는 것은 아니다. 본 발명의 실시예 등은 당업계에서 평균적인 지식을 가진 자에게 본 발명을 보다 완전하게 설명하기 위해 제공되는 것이다.Hereinafter, examples and the like will be described in detail to aid understanding of the present invention. However, the following examples are merely illustrative of the content of the present invention, and the scope of the present invention is not limited to the following examples. Examples of the present invention and the like are provided to more completely explain the present invention to those skilled in the art.

[실험예 1] 시험 준비 [Experimental Example 1] Test preparation

모든 시약 및 용매는 상업적 공급업체로부터 구입하여 추가 정제 없이 사용하였다. 습기에 민감한 화합물을 다루는 모든 실험은 아르곤 분위기에서 수행되었다. 회전 증발기를 이용하여 감압조건에서 농축 또는 용매 제거를 수행하였다. 분석 박층 크로마토그래피는 미리 코팅된 실리카겔 F254 TLC 플레이트 (E, Merck)의 UV광 하에서 시각화하거나, 요오드를 사용한 염색에 의해 수행되었다. 컬럼 크로마토그래피 (Column chromatography) 및 중압 액체 크로마토그래피 (medium pressure liquid chromatography; MPLC)는 실리카 (Merck Silica Gel 40-63m)에서 수행하거나 미리 포장된 실리카겔 카트리지가 있는 바이오테이지 (Biotage) SP1 플래시 정제 시스템을 사용하여 수행하였다. NMR 분석은 JNM-ECZ500R (500MHz; Jeol Resonance)을 사용하여 수행하였다. 화학적 이동은 백만분율 (δ)로 보고되고, 샘플 용매의 중수소 잠금 신호가 사용되었으며 커플링 상수 (J)는 헤르츠 (Hz)로 표시되었다. 분할 패턴 약어는 다음과 같다: s, 일중항; d, 이중항; t, 삼중항; q, 사중항; dd, 이중항의 이중항; td, 이중항의 삼중항; m, 다중항. 모든 최종 화합물의 순도는 VP-ODS C18 컬럼 (4.6 mm x 250 mm, 5 μm , Shimadzu)이 장착된 이중 펌프 Shimadzu LC-6AD 시스템으로 수행된 분석 HPLC에 의해 95 % 이상으로 확인되었다. LC-QTOF-MS 분석은 Agilent 1290 Infinity LC (Agilent Technologies, Palo Alto, CA, USA)를 갖춘 Agilent 6530 Accurate-Mass Q-TOF LC/MS 시스템을 사용하여 수행되었다. 가드 컬럼과 분석 컬럼은 각각 Zorbax SB-C8 (3.5 μm, 2.1 x 30 mm, Agilent Technologies)과 Zorbax SB-Aq (1.8 μm, 2.1 x 100 mm, Agilent Technologies)였고, 40 ℃를 유지하였다. 이동상은 물에 희석된 0.1 % 포름산(formic acid) (이하, 이동상 A라함)과 (B) 아세토니트릴 (acetonitrile)에 희석된 0.1 % 포름산 (formic acid) (이하, 이동상 B라함)으로 구성되었다. 구배 조건 (gradient conditions)은 다음과 같다: 400 μL/min의 유속에서 1) 0-30분, 이동상 B 부피율 1-20 %; 2) 30-40분, 이동상 B 부피율 20-90 %; 3) 40-45분, 이동상 B 부피율 90 %; 4) 45-47분, 이동상 B 부피율 90-1 %; 5) 47-52분, 이동상 B 부피율 1 %. MS 시스템은 양이온 및 음이온화 모드에서 ESI를 사용하여 작동되었다. 두 이온화 모드에 대한 QTOF-MS 시스템의 최적화된 조건은 다음과 같다: 건조 가스 온도, 300 ℃; 건조 가스 흐름, 10 L/min; 분무 압력, 45 psi; 차단 가스 온도, 350 ℃; 차단 가스 흐름, 10 L/min; 모세관 전압, 3500 V; 노즐 전압, 0 V; 단편화기 전압, 175 V; 스키머 전압, 65 V. 질량 범위는 50-1700 m/z이고 스캔 속도는 MS 및 MS/MS 분석 모두에 대해 2.00 spectra/sec이었다.All reagents and solvents were purchased from commercial suppliers and used without further purification. All experiments dealing with moisture-sensitive compounds were performed in an argon atmosphere. Concentration or solvent removal was performed under reduced pressure using a rotary evaporator. Analytical thin layer chromatography was performed either by visualization under UV light on pre-coated silica gel F254 TLC plates (E, Merck) or by staining with iodine. Column chromatography and medium pressure liquid chromatography (MPLC) are performed on silica (Merck Silica Gel 40-63m) or using a Biotage SP1 flash purification system with pre-packaged silica gel cartridges. was performed using NMR analysis was performed using a JNM-ECZ500R (500 MHz; Jeol Resonance). Chemical shifts are reported in parts per million (δ), the deuterium locking signal of the sample solvent was used and coupling constants (J) were expressed in hertz (Hz). Split pattern abbreviations are: s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; td, triplet of doublets; m, multinomial. The purity of all final compounds was confirmed to be greater than 95% by analytical HPLC performed on a dual pump Shimadzu LC-6AD system equipped with a VP-ODS C18 column (4.6 mm x 250 mm, 5 μm, Shimadzu). LC-QTOF-MS analysis was performed using an Agilent 6530 Accurate-Mass Q-TOF LC/MS system with an Agilent 1290 Infinity LC (Agilent Technologies, Palo Alto, CA, USA). The guard and analytical columns were Zorbax SB-C8 (3.5 μm, 2.1 x 30 mm, Agilent Technologies) and Zorbax SB-Aq (1.8 μm, 2.1 x 100 mm, Agilent Technologies), respectively, and maintained at 40 °C. The mobile phase consisted of 0.1% formic acid diluted in water (hereinafter referred to as mobile phase A) and (B) 0.1% formic acid diluted in acetonitrile (hereinafter referred to as mobile phase B). The gradient conditions were as follows: 1) 0-30 min at a flow rate of 400 μL/min, mobile phase B volume fraction 1-20%; 2) 30-40 minutes, mobile phase B volume fraction 20-90%; 3) 40-45 minutes, 90% by volume of mobile phase B; 4) 45-47 minutes, 90-1% by volume of mobile phase B; 5) 47-52 min, mobile phase B 1% by volume. The MS system was operated using the ESI in both positive and negative ionization modes. The optimized conditions of the QTOF-MS system for both ionization modes were as follows: dry gas temperature, 300 °C; dry gas flow, 10 L/min; spray pressure, 45 psi; shut-off gas temperature, 350 °C; Shut-off gas flow, 10 L/min; capillary voltage, 3500 V; nozzle voltage, 0 V; Fragmenter voltage, 175 V; Skimmer voltage, 65 V. The mass range was 50-1700 m/z and the scan rate was 2.00 spectra/sec for both MS and MS/MS analyses.

[실험예 2] 화합물 합성 [Experimental Example 2] Compound synthesis

(1) KRIBB11 유사체 (화합물 4)의 합성 (도 2)(1) Synthesis of KRIBB11 analogue (Compound 4) (Fig. 2)

1) 화합물 3 합성 1) Synthesis of Compound 3

에탄올 15 ml에 2,6-디클로로니트로피리딘 (2,6-dichloronitropyridine, 0.5 g, 2.59 mmol), 5-아미노인다졸 (5-aminoindazole, 0.36 g, 2.72 mmol) 및 트리에틸아민 (triethylamine, 0.4 ml, 2.85 mmol)을 첨가하였다. 첨가된 반응 혼합물을 5시간 동안 90 ℃에서 환류시켰다. 반응 종료 후, 얻어진 고체를 여과하고, 메탄올로 세척한 후, 진공 건조하여 화합물 3을 80.7 % 수율로 얻었다. 2,6-dichloronitropyridine (0.5 g, 2.59 mmol), 5-aminoindazole (5-aminoindazole, 0.36 g, 2.72 mmol) and triethylamine (0.4 ml) in 15 ml of ethanol. , 2.85 mmol) was added. The added reaction mixture was refluxed at 90 °C for 5 hours. After completion of the reaction, the obtained solid was filtered, washed with methanol, and vacuum dried to obtain Compound 3 in a yield of 80.7%.

-1H-NMR (500 MHz, DMSO-D6)δ10.22(s,1H),8.54(d,J=8.6Hz,1H),8.09(s,1H),7.92(d,J=1.7Hz,1H),7.56(d,J=9.2Hz,1H),7.44(dd,J=8.6,1.7Hz,1H),6.95(d,J=8.6Hz,1H) (도 6).- 1 H-NMR (500 MHz, DMSO-D 6 )δ 10.22 (s, 1H), 8.54 (d, J = 8.6Hz, 1H), 8.09 (s, 1H), 7.92 (d, J = 1.7Hz , 1H), 7.56 (d, J = 9.2 Hz, 1H), 7.44 (dd, J = 8.6, 1.7 Hz, 1H), 6.95 (d, J = 8.6 Hz, 1H) (Fig. 6).

2) 화합물 4 합성2) Compound 4 synthesis

상기 화합물 3 (0.289 g, 1 mmol)을 25 ml 아세토니트릴 (acetonitrile)에 용해시키고 1,4-디아미노부탄 (1,4-diaminobutane, 0.44 ml, 5 mmol)을 첨가하였다. 반응 혼합물을 실온에서 14시간 동안 교반하였다. 반응 완료 후, 아세토니트릴을 증발시키고, 잔류물을 1N 수산화나트륨 (NaOH)과 에틸 아세테이트 (ethyl acetate) 사이에 분배하였다. 유기층을 황산나트륨 (sodium sulfate)으로 건조시키고, 진공에서 증발시켜 화합물 4를 70.3 % 수율로 얻었다.The compound 3 (0.289 g, 1 mmol) was dissolved in 25 ml acetonitrile and 1,4-diaminobutane (1,4-diaminobutane, 0.44 ml, 5 mmol) was added. The reaction mixture was stirred at room temperature for 14 hours. After completion of the reaction, acetonitrile was evaporated and the residue was partitioned between 1N sodium hydroxide (NaOH) and ethyl acetate. The organic layer was dried over sodium sulfate and evaporated in vacuo to give compound 4 in 70.3% yield.

-1H-NMR (500 MHz, DMSO-D6)δ10.94(s,1H),8.20(s,1H),8.07(d,J=9.2Hz,1H),8.04(s,1H),7.53(s,2H),6.09(d,J=9.7Hz,1H),3.30(t,J=7.4Hz,2H),2.48(d,J=6.9Hz,2H),1.53(t,J=7.4Hz,2H),1.33(t,J=7.4Hz,2H) (도 7).- 1 H-NMR (500 MHz, DMSO-D 6 )δ 10.94 (s, 1H), 8.20 (s, 1H), 8.07 (d, J = 9.2Hz, 1H), 8.04 (s, 1H), 7.53 (s,2H),6.09(d,J=9.7Hz,1H),3.30(t,J=7.4Hz,2H),2.48(d,J=6.9Hz,2H),1.53(t,J=7.4Hz ,2H),1.33(t,J=7.4Hz,2H) (FIG. 7).

(3) E-3 리가제 리간드 (화합물 9a 및 화합물 9c)의 합성 (도 3)(3) Synthesis of E-3 ligase ligand (Compound 9a and Compound 9c) (FIG. 3)

1) 화합물 6 합성1) Compound 6 synthesis

무수 THF (21.5 mL)에 용해된 N-Boc-L-아스파라긴 (N-Boc-L-asparagine, 2 g, 8.61 mmol), CDI (1.39 g, 8.61 mmol) 및 촉매량의 4-DMAP의 혼합물을 교반하고, 76 ℃에서 48시간동안 가열하여 환류 하였다. 반응 종료 후, 혼합물을 여과하고 고체를 THF로 세척하여 화합물 6을 73 % 수율로 무색 고체형태로 얻었다.A mixture of N-Boc-L-asparagine (2 g, 8.61 mmol), CDI (1.39 g, 8.61 mmol) and a catalytic amount of 4-DMAP dissolved in anhydrous THF (21.5 mL) was stirred. and heated to reflux at 76 °C for 48 hours. After completion of the reaction, the mixture was filtered and the solid was washed with THF to obtain Compound 6 in the form of a colorless solid in a yield of 73%.

-1H-NMR (500 MHz, DMSO-D6) 10.77 (s, 1H), 7.15 (d, J = 8.6 Hz, 1H), 4.20-4.25 (m, 1H), 2.71 (dt, J = 17.8, 6.3 Hz, 1H), 2.46 (t, J = 3.7 Hz, 1H), 1.87-1.94 (m, 2H), and 1.40 (s, 9H) (도 8).-1H-NMR (500 MHz, DMSO-D6) 10.77 (s, 1H), 7.15 (d, J = 8.6 Hz, 1H), 4.20-4.25 (m, 1H), 2.71 (dt, J = 17.8, 6.3 Hz , 1H), 2.46 (t, J = 3.7 Hz, 1H), 1.87–1.94 (m, 2H), and 1.40 (s, 9H) (Fig. 8).

2) 화합물 7 합성2) Synthesis of Compound 7

상기 화합물 6 (1.54 g, 6.75 mmol)을 TFA (7.8 mL, 101.25 mmol)에 용해시키고 30분 동안 교반하였다. 과량의 산은 진공에서 제거하였고, 결과물을 진공 하에 건조시켜 정량적 수율로 회백색 고체형태의 화합물 7을 얻었다.The above compound 6 (1.54 g, 6.75 mmol) was dissolved in TFA (7.8 mL, 101.25 mmol) and stirred for 30 min. Excess acid was removed in vacuo, and the resultant was dried in vacuo to give Compound 7 as an off-white solid in quantitative yield.

-1H-NMR (500 MHz, DMSO-D6)δ11.25(s,1H),8.58(s,3H),4.21(d,J=8.6Hz,1H),2.67-2.75(m,1H),2.59(dt,J=15.3,2.3Hz,1H),2.14-2.19(m,1H),2.02(td,J=13.0,4.8Hz,1H) (도 9).- 1 H-NMR (500 MHz, DMSO-D 6 )δ 11.25 (s, 1H), 8.58 (s, 3H), 4.21 (d, J = 8.6Hz, 1H), 2.67-2.75 (m, 1H) , 2.59 (dt, J = 15.3, 2.3 Hz, 1 H), 2.14-2.19 (m, 1 H), 2.02 (td, J = 13.0, 4.8 Hz, 1 H) (FIG. 9).

3) 화합물 9a 합성3) Synthesis of Compound 9a

3-플루오로프탈산 무수물 (3-fluorophthalic anhydride, 1.25 g, 7.5 mmol), 상기 화합물 7 (1.14 g, 5 mmol) 및 빙초산 (20mL) 중의 아세트산나트륨 (sodium acetate, 0.50 g, 6.0 mmol) 용액의 혼합물을 140 ℃에서 18시간 동안 환류시켰다. 냉각 후, 이를 물 (100mL)에 붓고 형성된 고체를 여과에 의해 수집하고, 물 및 석유 에테르로 세척하였다. 보라색 고체를 진공에서 추가로 건조시켜 화합물 9a를 91 % 수율로 얻었다.A mixture of 3-fluorophthalic anhydride (1.25 g, 7.5 mmol), compound 7 above (1.14 g, 5 mmol), and a solution of sodium acetate (0.50 g, 6.0 mmol) in glacial acetic acid (20 mL) was refluxed at 140 °C for 18 hours. After cooling, it was poured into water (100 mL) and the solid formed was collected by filtration, washed with water and petroleum ether. The purple solid was further dried in vacuo to give compound 9a in 91% yield.

-1H-NMR (500 MHz, DMSO-D6)δ11.17(s,1H),7.95(td,J=7.9,4.0Hz,1H),7.79(d,J=7.4Hz,1H),7.74(t,J=8.9Hz,1H),5.16(dd,J=12.9,5.4Hz,1H),2.85-2.91(m,1H),2.58-2.63(m,1H),2.52(t,J=2.0Hz,1H),2.04-2.07(m,1H) (도 10).- 1 H-NMR (500 MHz, DMSO-D 6 )δ 11.17 (s, 1H), 7.95 (td, J = 7.9, 4.0 Hz, 1H), 7.79 (d, J = 7.4 Hz, 1H), 7.74 (t,J=8.9Hz,1H),5.16(dd,J=12.9,5.4Hz,1H),2.85-2.91(m,1H),2.58-2.63(m,1H),2.52(t,J=2.0 Hz, 1H), 2.04-2.07 (m, 1H) (FIG. 10).

4) 화합물 9b 합성4) Synthesis of compound 9b

36 mL의 빙초산 및 무수 아세트산나트륨 (anhydrous sodium acetate) (0.308 g, 3.75 mmol)의 혼합물을 화합물 7 (0.57 g, 2.5 mmol)의 3-니트로프탈산 무수물 (3-nitrophthalic anhydride)(0.58g, 3mmol)에 첨가하였다. 반응 혼합물을 140 ℃에서 18시간 동안 가열하였다. 반응 완료 후, 반응 혼합물을 실온으로 냉각하고, 물을 반응 혼합물에 첨가하고, 추가로 30분 동안 교반하였다. 고체를 여과하고 물로 세척하였다. 생성물을 진공 하에 건조시켜 화합물 9b를 44.5 %의 수율로 얻었다.3-nitrophthalic anhydride (3-nitrophthalic anhydride) (0.58 g, 3 mmol) of compound 7 (0.57 g, 2.5 mmol) was added to a mixture of glacial acetic acid and sodium acetate (0.308 g, 3.75 mmol) in 36 mL. added to. The reaction mixture was heated at 140 °C for 18 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, water was added to the reaction mixture, and stirred for an additional 30 minutes. The solid was filtered and washed with water. The product was dried under vacuum to obtain compound 9b in a yield of 44.5%.

-1H-NMR (500 MHz, DMSO-D6)δ11.18(s,1H),8.35(d,J=7.4Hz,1H),8.24(d,J=6.9Hz,1H),8.12(t,J=7.7Hz,1H),5.20(dd,J=12.9,5.4Hz,1H),2.85-2.92(m,1H),2.54-2.63(m,1H),2.52-2.54(m,1H),2.05-2.10(m,1H) (도 11). - 1 H-NMR (500 MHz, DMSO-D 6 )δ 11.18 (s, 1H), 8.35 (d, J = 7.4Hz, 1H), 8.24 (d, J = 6.9Hz, 1H), 8.12 (t ,J=7.7Hz,1H),5.20(dd,J=12.9,5.4Hz,1H),2.85-2.92(m,1H),2.54-2.63(m,1H),2.52-2.54(m,1H), 2.05-2.10 (m, 1H) (FIG. 11).

5) 화합물 9c 합성5) Synthesis of Compound 9c

아세톤에 용해된 화합물 9b (0.61 g, 2.02 mmol)의 혼합물에 촉매량의 10 % Pd/C (0.24 g, 0.66 mmol)를 첨가하였다. 이 혼합물을 수소 기체 하에 실온에서 72시간 동안 교반하였다. 그 다음, 혼합물을 여과하여 팔라듐을 제거하고, 아세톤을 증발시켜 화합물 9c를 90.8 %의 수율로 얻었다.To a mixture of compound 9b (0.61 g, 2.02 mmol) dissolved in acetone was added a catalytic amount of 10% Pd/C (0.24 g, 0.66 mmol). This mixture was stirred at room temperature under hydrogen gas for 72 hours. Then, the mixture was filtered to remove palladium, and acetone was evaporated to obtain compound 9c in a yield of 90.8%.

-1H-NMR (500 MHz, DMSO-D6)δ11.10(s,1H),7.47(dd,J=8.3,7.2Hz,1H),7.01(t,J=7.4Hz,2H),6.53(s,2H),5.05(dd,J=12.9,5.4Hz,1H),2.84-2.89(m,1H),2.52-2.60(m,2H),2.02(td,J=6.4,2.1Hz,1H) (도 12).- 1H -NMR (500 MHz, DMSO-D 6 )δ11.10(s,1H),7.47(dd,J=8.3,7.2Hz,1H),7.01(t,J=7.4Hz,2H),6.53 (s,2H),5.05(dd,J=12.9,5.4Hz,1H),2.84-2.89(m,1H),2.52-2.60(m,2H),2.02(td,J=6.4,2.1Hz,1H ) (FIG. 12).

(4) 링커 (linker; 화합물 12b 및 13b)의 합성 (도 4)(4) Synthesis of Linker (Compounds 12b and 13b) (FIG. 4)

1) 화합물 10b 합성1) Synthesis of compound 10b

무수 디클로로메탄 (15 mL; 이하, DCM이라함)에 용해된 4,7,10-트리옥사-1,13-트리데칸디아민 (4,7,10-trioxa-1,13-tridecanediamine, 1.0 g, 4.5 mmol) 용액을 DCM (22.5 ml) 중 Boc2O (0.164 g,0.75 mmol)및 TEA (0.627 mL, 4.5 mmol)로 처리하였다. 반응물을 실온에서 4시간 동안 교반하였다. 생성된 황색 오일을 컬럼 크로마토그래피로 정제하여 화합물 10b를 51.5 % 수율로 얻었다.1.0 g of 4,7,10-trioxa-1,13-tridecanediamine dissolved in anhydrous dichloromethane (15 mL; hereinafter referred to as DCM) 4.5 mmol) solution was treated with Boc 2 O (0.164 g, 0.75 mmol) and TEA (0.627 mL, 4.5 mmol) in DCM (22.5 ml). The reaction was stirred at room temperature for 4 hours. The resulting yellow oil was purified by column chromatography to obtain compound 10b in a yield of 51.5%.

-1H-NMR (500 MHz, CDCl3)δ5.26(s,1H),3.51-3.53(m,4H),3.46-3.49(m,4H),3.41-3.45(m,4H),3.09(q,J=6.1Hz,2H),2.69(t,J=6.6Hz,2H),2.47(s,2H),1.63(td,J=13.0,6.7Hz,4H),1.31(s,9H) (도 13).- 1 H-NMR (500 MHz, CDCl 3 ) δ 5.26 (s, 1H), 3.51-3.53 (m, 4H), 3.46-3.49 (m, 4H), 3.41-3.45 (m, 4H), 3.09 ( q,J=6.1Hz,2H),2.69(t,J=6.6Hz,2H),2.47(s,2H),1.63(td,J=13.0,6.7Hz,4H),1.31(s,9H) ( Figure 13).

2) 화합물 12a 합성2) Synthesis of Compound 12a

DMF (2 mL)에 용해된 화합물 10b (0.2 g, 0.7 mmol) 및 화합물 9a (0.14 g, 0.8 mmol)의 용액을 90 ℃에서 12시간 동안 DIPEA (0.18 g, 1.4 mmol)로 처리하였다. 처리한 반응 혼합물을 물에 붓고, 에틸아세테이트 (EtOAc)로 추출하였다. 혼합한 유기상을 건조시키고 감압하에 농축시켰다. 조 생성물을 정제하여 화합물 12a를 40 % 수율로 얻었다.A solution of compound 10b (0.2 g, 0.7 mmol) and compound 9a (0.14 g, 0.8 mmol) in DMF (2 mL) was treated with DIPEA (0.18 g, 1.4 mmol) at 90 °C for 12 h. The treated reaction mixture was poured into water and extracted with ethyl acetate (EtOAc). The combined organic phases were dried and concentrated under reduced pressure. The crude product was purified to obtain compound 12a in 40% yield.

-1H-NMR (500 MHz, CDCl3)δ8.41(s,1H),7.48(dd,J=8.6,7.4Hz,1H),7.07(d,J=6.9Hz,1H),6.92(d,J=8.6Hz,1H),6.43(s,1H),4.99(s,1H),4.90(q,J=5.7Hz,1H),3.57-3.69(m,11H),3.52(t,J=6.0Hz,2H),3.39(q,J=6.1Hz,2H),3.21(q,J=5.9Hz,2H),2.69-2.89(m,4H),2.09-2.14(m,1H),1.89-1.94(m,2H),1.71-1.76(m,2H),1.42(s,9H) (도 14).- 1H -NMR (500 MHz, CDCl 3 )δ 8.41 (s, 1H), 7.48 (dd, J = 8.6, 7.4Hz, 1H), 7.07 (d, J = 6.9Hz, 1H), 6.92 (d ,J=8.6Hz,1H),6.43(s,1H),4.99(s,1H),4.90(q,J=5.7Hz,1H),3.57-3.69(m,11H),3.52(t,J= 6.0Hz,2H),3.39(q,J=6.1Hz,2H),3.21(q,J=5.9Hz,2H),2.69-2.89(m,4H),2.09-2.14(m,1H),1.89- 1.94 (m, 2H), 1.71-1.76 (m, 2H), 1.42 (s, 9H) (FIG. 14).

3) 화합물 12b 합성3) Synthesis of compound 12b

화합물 12a (0.154 g, 0.267 mmol)를 TFA (0.78 mL, 10.13 mmol)에 용해시키고 30분 동안 교반하였다. 과량의 산을 진공에서 제거하고, 생성된 생성물을 진공 하에 건조시켜 12b를 정량적 수율로 얻었다.Compound 12a (0.154 g, 0.267 mmol) was dissolved in TFA (0.78 mL, 10.13 mmol) and stirred for 30 min. Excess acid was removed in vacuo and the resulting product was dried under vacuum to give 12b in quantitative yield.

-1H-NMR (500 MHz, CDCl3)δ9.45(s,1H),7.60(t,J=8.0Hz,1H),7.28(d,J=7.4Hz,1H),7.15(d,J=8.0Hz,1H),7.01(s,2H),5.29(s,1H),5.01(dd,J=12.6,5.2Hz,1H),3.63-3.72(m,13H),3.45(t,J=6.0Hz,2H),3.24(q,J=5.2Hz,2H),3.10(s,1H),2.98(s,1H),2.89(s,1H),2.72-2.83(m,2H),2.17-2.19(m,1H),1.94(dt,J=26.7,5.3Hz,4H) (도 15).- 1H -NMR (500 MHz, CDCl 3 )δ9.45(s,1H),7.60(t,J=8.0Hz,1H),7.28(d,J=7.4Hz,1H),7.15(d,J =8.0Hz,1H),7.01(s,2H),5.29(s,1H),5.01(dd,J=12.6,5.2Hz,1H),3.63-3.72(m,13H),3.45(t,J= 6.0Hz,2H),3.24(q,J=5.2Hz,2H),3.10(s,1H),2.98(s,1H),2.89(s,1H),2.72-2.83(m,2H),2.17- 2.19 (m, 1H), 1.94 (dt, J = 26.7, 5.3 Hz, 4H) (FIG. 15).

4) 화합물 11 합성4) Synthesis of Compound 11

THF (2 mL)에 용해된 화합물 10b (0.2 g, 0.7 mmol)의 용액을 DIPEA (0.18 g, 1.4 mmol)로 처리하고, 6시간 동안 교반하여 화합물 11을 44.5 % 조수율로 생성하고 추가 정제 없이 사용하였다.A solution of compound 10b (0.2 g, 0.7 mmol) dissolved in THF (2 mL) was treated with DIPEA (0.18 g, 1.4 mmol) and stirred for 6 h to yield compound 11 in 44.5% crude yield without further purification. used

-1H-NMR (500 MHz, CDCl3)δ5.22-4.71(1H),4.02(d,J=1.7Hz,2H),3.57-3.67(m,10H),3.53(td,J=6.0,1.7CDCl3Hz,2H),3.43(q,J=5.9Hz,2H),3.21(d,J=4.0Hz,2H),1.86(s,1H),1.83(q,J=5.9Hz,3H),1.75(t,J=6.3Hz,2H),1.43(d,J=2.3Hz,9H) (도 16).- 1H -NMR (500 MHz, CDCl 3 )δ 5.22-4.71 (1H), 4.02 (d, J = 1.7Hz, 2H), 3.57-3.67 (m, 10H), 3.53 (td, J = 6.0, 1.7CDCl3Hz,2H),3.43(q,J=5.9Hz,2H),3.21(d,J=4.0Hz,2H),1.86(s,1H),1.83(q,J=5.9Hz,3H),1.75 (t, J = 6.3 Hz, 2H), 1.43 (d, J = 2.3 Hz, 9H) (FIG. 16).

5) 화합물 13a 합성5) Synthesis of Compound 13a

아세토니트릴 (acetonitrile, 2 mL)에 용해된 화합물 11 (0.14 g, 0.8 mmol) 및 클로로아세틸 클로라이드 (chloroacetyl chloride, 0.108 g, 0.96 mmol)를 실온에서 3시간 동안 탄산세슘 (cesium carbonate, 0.18 g, 1.4 mmol)으로 처리하였다. 반응 혼합물을 여과하고 감압 하에서 용매를 제거하였다. 조 생성물을 컬럼으로 정제하여 화합물 13a를 33 % 수율로 얻었다.Compound 11 (0.14 g, 0.8 mmol) and chloroacetyl chloride (0.108 g, 0.96 mmol) dissolved in acetonitrile (acetonitrile, 2 mL) were mixed with cesium carbonate (0.18 g, 1.4 g) at room temperature for 3 hours. mmol). The reaction mixture was filtered and the solvent was removed under reduced pressure. The crude product was purified by column to obtain compound 13a in 33% yield.

-1H-NMR (500 MHz, CDCl3)δ7.38(dd,J=8.6,7.4Hz,1H),7.09(d,J=6.9Hz,1H),6.87(d,J=8.0Hz,1H),6.73(s,1H),5.03(q,J=5.9Hz,1H),4.46(dd,J=22.6,15.8Hz,2H),3.60-3.62(m,5H),3.55-3.57(m,5H),3.49-3.53(m,5H),3.35(dd,J=10.0,6.0Hz,2H),3.17(t,J=6.6Hz,2H),2.92-2.97(m,1H),2.83-2.86(m,1H),2.69(dd,J=12.3,4.3Hz,1H),2.15(t,J=1.7Hz,1H),1.71-1.78(m,4H),1.41(d,J=5.2Hz,10H) (도 17).- 1H -NMR (500 MHz, CDCl 3 )δ 7.38(dd,J=8.6,7.4Hz,1H),7.09(d,J=6.9Hz,1H),6.87(d,J=8.0Hz,1H) ),6.73(s,1H),5.03(q,J=5.9Hz,1H),4.46(dd,J=22.6,15.8Hz,2H),3.60-3.62(m,5H),3.55-3.57(m, 5H),3.49-3.53(m,5H),3.35(dd,J=10.0,6.0Hz,2H),3.17(t,J=6.6Hz,2H),2.92-2.97(m,1H),2.83-2.86 (m,1H),2.69(dd,J=12.3,4.3Hz,1H),2.15(t,J=1.7Hz,1H),1.71-1.78(m,4H),1.41(d,J=5.2Hz, 10H) (FIG. 17).

6) 화합물 13b 합성6) Synthesis of compound 13b

화합물 13a (0.2 g, 0.31 mmol)를 TFA (0.78 mL, 10.13 mmol)에 용해시키고 30분 동안 교반하였다. 과량의 산을 진공에서 제거하고, 생성된 생성물을 진공 하에 건조시켜 화합물 13b를 정량적 수율로 얻었다.Compound 13a (0.2 g, 0.31 mmol) was dissolved in TFA (0.78 mL, 10.13 mmol) and stirred for 30 min. Excess acid was removed in vacuo and the resulting product was dried under vacuum to give compound 13b in quantitative yield.

-1H-NMR (500 MHz, CH3OD)δ7.45(dd,J=8.3,7.2Hz,1H),7.04(d,J=6.9Hz,1H),6.99(d,J=8.6Hz,1H),5.18(dd,J=12.9,5.4Hz,1H),4.44(d,J=7.4Hz,2H),3.60-3.66(m,10H),3.56-3.58(m,2H),3.49(t,J=6.0Hz,2H),3.28-3.29(m,2H),3.09(t,J=6.3Hz,3H),2.86-2.99(m,4H),1.91(dd,J=6.3,5.2Hz,2H),1.76(t,J=6.3Hz,2H) (도 18).- 1 H-NMR (500 MHz, CH 3 OD) δ 7.45 (dd, J = 8.3, 7.2 Hz, 1H), 7.04 (d, J = 6.9 Hz, 1H), 6.99 (d, J = 8.6 Hz, 1H),5.18(dd,J=12.9,5.4Hz,1H),4.44(d,J=7.4Hz,2H),3.60-3.66(m,10H),3.56-3.58(m,2H),3.49(t ,J=6.0Hz,2H),3.28-3.29(m,2H),3.09(t,J=6.3Hz,3H),2.86-2.99(m,4H),1.91(dd,J=6.3,5.2Hz, 2H), 1.76 (t, J = 6.3 Hz, 2H) (FIG. 18).

(5) 프로탁 (PROTACS; 화합물 14 내지 화합물 16) 합성 (도 5)(5) Synthesis of PROTACS (Compounds 14 to 16) (FIG. 5)

1) 화합물 14 합성1) Synthesis of Compound 14

1.5 ml DMF에 용해된 화합물 4 (0.02 g, 0.07 mmol) 및 화합물 9a (0.024 g, 0.07 mmol)의 혼합물을 DIPEA (0.03 ml, 0.14 mmol)와 함께 첨가하였다. 반응 혼합물을 90 ℃에서 48시간 동안 환류시켰다. DMF를 증발로 제거하고, 조물질을 MPLC로 정제하여 화합물 14를 58 % 수율로 얻었다.A mixture of compound 4 (0.02 g, 0.07 mmol) and compound 9a (0.024 g, 0.07 mmol) dissolved in 1.5 ml DMF was added along with DIPEA (0.03 ml, 0.14 mmol). The reaction mixture was refluxed at 90 °C for 48 hours. DMF was removed by evaporation, and the crude material was purified by MPLC to give compound 14 in 58% yield.

- 1H-NMR (500 MHz, ACETONE-D6)δ12.24(s,1H),10.96(s,1H),9.98(s,1H),8.26(s,1H),8.11(d,J=9.2Hz,1H),8.02(s,1H),7.58(dd,J=11.7,8.9Hz,2H),7.48(q,J=7.4Hz,2H),6.96(dd,J=22.6,7.7Hz,2H),6.36(s,1H),6.10(d,J=9.2Hz,1H),5.06(q,J=6.1Hz,1H),3.53(d,J=5.7Hz,2H),3.30(d,J=6.3Hz,2H),2.91-2.98(m,4H),2.71-2.79(m,2H),2.16-2.21(m,1H),1.73(s,4H).13C-NMR(126MHz,ACETONE-D6)δ172.74,170.36,170.26,168.22,161.61,153.33,147.61,138.72,136.86,135.95,134.63,133.51,132.57,124.43,124.29,119.40,117.45,114.27,111.27,110.75,103.27,49.80,42.64,41.92,31.96,27.3023.38ESIMS(m/z) ;598.2148[M+H]+ (도 19 및 도 20). - 1 H-NMR (500 MHz, ACETONE-D 6 )δ 12.24 (s, 1H), 10.96 (s, 1H), 9.98 (s, 1H), 8.26 (s, 1H), 8.11 (d, J = 9.2Hz,1H),8.02(s,1H),7.58(dd,J=11.7,8.9Hz,2H),7.48(q,J=7.4Hz,2H),6.96(dd,J=22.6,7.7Hz, 2H),6.36(s,1H),6.10(d,J=9.2Hz,1H),5.06(q,J=6.1Hz,1H),3.53(d,J=5.7Hz,2H),3.30(d, J=6.3Hz,2H),2.91-2.98(m,4H),2.71-2.79(m,2H),2.16-2.21(m,1H),1.73(s,4H). 13 C-NMR(126MHz,ACETONE- D6 )δ172.74,170.36,170.26,168.22,161.61,153.33,147.61,138.72,136.86,135.95,134.63,133.51,132.57,124.43,1 24.29,119.40,117.45,114.27,111.27, 110.75,103.27,49.80,42.64,41.92,31.96,27.3023.38ESIMS(m/z); 598.2148[M+H] + (FIGS. 19 and 20) .

2) 화합물 15 합성2) Synthesis of Compound 15

20 ml 아세토나이트릴에 용해된 화합물 3 (0.039 g, 0.12 mmol) 및 화합물 12b (0.09 g, 0.18 mmol)의 혼합물을 TEA (0.05 ml, 0.36 mmol)와 함께 첨가하였다. 첨가된 반응 혼합물을 실온에서 24시간 동안 교반하였다. 아세토나이트릴을 증발로 제거하고, 조물질을 MPLC로 정제하여 화합물 15를 47 % 수율로 얻었다.A mixture of compound 3 (0.039 g, 0.12 mmol) and compound 12b (0.09 g, 0.18 mmol) dissolved in 20 ml acetonitrile was added along with TEA (0.05 ml, 0.36 mmol). The added reaction mixture was stirred at room temperature for 24 hours. Acetonitrile was removed by evaporation, and the crude material was purified by MPLC to obtain compound 15 in 47% yield.

-1H-NMR (500 MHz, ACETONE-D6)δ12.23(s,1H),10.99(s,1H),9.97(s,1H),8.30(s,1H),8.06-8.10(m,2H),7.49-7.60(m,3H),7.37(s,1H),6.99(dd,J=26.1,7.7Hz,2H),6.56(t,J=5.4Hz,1H),6.10(d,J=9.2Hz,1H),5.05(q,J=6.1Hz,1H),3.37-3.63(m,16H),2.90-2.95(m,3H),2.72-2.79(m,2H),2.16-2.20(m,1H),1.83-1.88(m,4H).13C-NMR(126MHz,ACETONE-D6)δ172.75,170.37,170.14,168.25,161.54,153.21,147.73,136.85,135.85,134.69,124.22,117.45,113.99,111.12,103.39,71.13,71.09,71.05,70.86,69.46,49.78,40.88,23.39ESIMS(m/z) ;730.29[M+H]+ (도 21 및 도 22).- 1H -NMR (500 MHz, ACETONE-D 6 )δ 12.23 (s, 1H), 10.99 (s, 1H), 9.97 (s, 1H), 8.30 (s, 1H), 8.06-8.10 (m, 2H),7.49-7.60(m,3H),7.37(s,1H),6.99(dd,J=26.1,7.7Hz,2H),6.56(t,J=5.4Hz,1H),6.10(d,J =9.2Hz,1H),5.05(q,J=6.1Hz,1H),3.37-3.63(m,16H),2.90-2.95(m,3H),2.72-2.79(m,2H),2.16-2.20( m, 1H), 1.83-1.88 (m, 4H). 13 C-NMR(126MHz,ACETONE- D6 )δ172.75,170.37,170.14,168.25,161.54,153.21,147.73,136.85,135.85,134.69,124.22,117.45,113.99,111.12,1 03.39,71.13,71.09,71.05,70.86, 69.46, 49.78, 40.88, 23.39ESIMS (m/z); 730.29[M+H]+ (FIGS. 21 and 22).

3) 화합물 16 합성3) Synthesis of Compound 16

20 ml 아세토나이트릴에 용해된 화합물 3 (0.056 g, 0.19 mmol) 및 화합물 13b (0.118 g, 0.22 mmol)의 혼합물을 TEA (0.03 ml, 0.23 mmol)와 함께 첨가하였다. 반응 혼합물을 실온에서 18시간 동안 교반하였다. 아세토나이트릴을 증발로 제거하고 조물질을 MPLC로 정제하여 화합물 16을 38 % 수율로 얻었다.A mixture of compound 3 (0.056 g, 0.19 mmol) and compound 13b (0.118 g, 0.22 mmol) dissolved in 20 ml acetonitrile was added along with TEA (0.03 ml, 0.23 mmol). The reaction mixture was stirred at room temperature for 18 hours. Acetonitrile was removed by evaporation and the crude material was purified by MPLC to obtain compound 16 in 38% yield.

-1H-NMR (500 MHz, ACETONE-D6)δ12.33(s,0H),11.00(s,1H),8.28(s,1H),8.11(d,J=9.2Hz,1H),7.45-7.63(m,4H),7.26(d,J=14.9Hz,1H),7.05(dd,J=13.7,8.0Hz,2H),6.20(d,J=7.4Hz,2H),6.12(d,J=9.2Hz,1H),5.15(dd,J=12.9,5.4Hz,1H),4.40(s,2H),3.42-3.61(m,14H),3.25(tt,J=20.4,6.7Hz,2H),3.05(ddd,J=18.3,13.2,4.6Hz,1H),2.77-2.90(m,2H),2.19-2.24(m,1H),1.66-1.72(m,2H).13C-NMR(126MHz,ACETONE-D6)δ171.92,170.27,169.85,168.26,167.23,161.63,153.31,147.75,136.28,135.83,134.61,133.35,132.60,124.29,122.34,122.28,119.31,114.08,112.25,110.83,110.59,103.49,71.06,71.03,70.82,70.70,69.46,69.20,50.32,41.26,37.38,22.54.ESIMS(m/z) ;787.31[M+H]+ (도 23 및 도 24).- 1 H-NMR (500 MHz, ACETONE-D 6 )δ 12.33 (s, 0H), 11.00 (s, 1H), 8.28 (s, 1H), 8.11 (d, J = 9.2Hz, 1H), 7.45 -7.63(m,4H),7.26(d,J=14.9Hz,1H),7.05(dd,J=13.7,8.0Hz,2H),6.20(d,J=7.4Hz,2H),6.12(d, J=9.2Hz,1H),5.15(dd,J=12.9,5.4Hz,1H),4.40(s,2H),3.42-3.61(m,14H),3.25(tt,J=20.4,6.7Hz,2H) ), 3.05 (ddd, J = 18.3, 13.2, 4.6Hz, 1H), 2.77-2.90 (m, 2H), 2.19-2.24 (m, 1H), 1.66-1.72 (m, 2H). 13 C-NMR(126MHz,ACETONE- D6 )δ171.92,170.27,169.85,168.26,167.23,161.63,153.31,147.75,136.28,135.83,134.61,133.35,132.60,124.29,1 22.34,122.28,119.31,114.08,112.25, 110.83, 110.59, 103.49, 71.06, 71.03, 70.82, 70.70, 69.46, 69.20, 50.32, 41.26, 37.38, 22.54. ESIMS (m/z); 787.31 [M+H] + (Figs. 23 and 24).

[실험예 3] 도킹 연구[Experimental Example 3] Docking Study

HSF1 (PDB 코드: 5d5U)의 X선 결정 구조의 3D 좌표와 함께 KRIBB11의 인 실리코 도킹은 스크립스 연구소 (Scripps Research Institute)의 분자 그래픽스 실험실 (Molecular Graphics Laboratory)에서 다운로드한 오토독 4.2 (AutoDock 4.2) 프로그램을 사용하여 수행되었다. 해당 프로그램이 라마르크 버전의 유전 알고리즘을 사용하여 알려진 또는 예측된 결합 부위 내부의 리간드의 포즈 (pose)를 생성하는 유전 알고리즘을 사용하기 때문인데, 여기서 In situ 최적화 후 분자에 의해 채택된 형태의 변화가 후대에서 후속 포즈 (pose)로서 사용된다. 수행된 도킹 실험에서 오토독(AutoDock) 제품군의 도구를 사용하여 KRIBB11과 함께 HSF1의 X선 구조에 Gasteiger 전하를 배치하였다. 50x50x50 포인트 및 0.375 Å 간격의 선명도를 갖는 HDAC 효소의 기질 결합 포켓에 집중된 격자 상자가 리간드 도킹 실험을 위해 선택되었다. 도킹 매개변수는 모집단 크기를 150으로 설정하고 세대 수를 27,000으로, 평가 횟수를 2,500,000으로 설정하는 것으로 구성되었으며, 도킹 실행 횟수는 100으로 설정되었고, 각 도킹 실행의 그룹화에 대한 제곱 평균 허용오차의 컷오프는 1 Å이었다. 화합물 KRIBB11이 있는 HSF1의 도킹 포즈는 도 1에서 묘사되어 있으며, 그림의 렌더링은 파이몰 (PyMol, DeLanoScientific)을 사용하여 생성되었다.In silico docking of KRIBB11 with the 3D coordinates of the X-ray crystal structure of HSF1 (PDB code: 5d5U) was performed using the AutoDock 4.2 program downloaded from the Molecular Graphics Laboratory at Scripps Research Institute. was performed using This is because the program uses a Lamarck version of a genetic algorithm to generate the pose of the ligand inside the known or predicted binding site, where the change in conformation adopted by the molecule after in situ optimization is It is used as a follow-up pose in later generations. In the docking experiments performed, Gasteiger charges were placed on the X-ray structure of HSF1 together with KRIBB11 using tools from the AutoDock family. A lattice box centered on the substrate-binding pocket of the HDAC enzyme with sharpness of 50 × 50 × 50 points and spacing of 0.375 Å was chosen for the ligand docking experiments. Docking parameters consisted of setting the population size to 150, the number of generations to 27,000 and the number of evaluations to 2,500,000, the number of docking runs to be set to 100, and the cutoff of root mean square tolerance for grouping of each docking run was 1 Å. The docking pose of HSF1 with compound KRIBB11 is depicted in Figure 1, and a rendering of the figure was created using PyMol (DeLanoScientific).

[실험예 4] 세포 배양 및 재료 [Experimental Example 4] Cell culture and materials

삼중 음성 유방암 세포 MDA-MB-231을 DMEM 고포도당 (high glucose)에서 성장시키고, 스트렙토마이신 (500 mg/mL), 페니실린 (100 units/mL) 및 10 % FBS로 보충했다. 세포는 5% 이산화탄소로 가습된 대기에서 37 ℃에서 합류될 때까지 성장하였다. HSF1 (1:1000; rabbit anti-human mAb; cat. no. 12972) 및 β-액틴(1:1000; rabbit anti-human mAb; cat. no. 4970)에 대한 항체는 Cell Signaling Technology(미국 베벌리, MA)에서 구입했다.Triple negative breast cancer cells MDA-MB-231 were grown in DMEM high glucose and supplemented with streptomycin (500 mg/mL), penicillin (100 units/mL) and 10% FBS. Cells were grown to confluence at 37 °C in a humidified atmosphere with 5% carbon dioxide. Antibodies against HSF1 (1:1000; rabbit anti-human mAb; cat. no. 12972) and β-actin (1:1000; rabbit anti-human mAb; cat. no. 4970) were purchased from Cell Signaling Technology (Beverly, USA). MA) was purchased.

[실험예 5] MTS 색도 측정[Experimental Example 5] MTS chromaticity measurement

MDA-MB-231 세포는 투명한 96-웰 플레이트에서 웰 당 2x103 세포로 시딩되었고, 중간 부피는 100 μL로 가져왔고, 세포는 하룻밤 동안 부착할 수 있었다. 그런 다음 37 ℃에서 24시간 동안 표시된 농도의 화합물 14, 15 또는 16으로 세포를 배양하였다. Promega Cell Titer 96 Aquid One Solution 세포 증식 분석을 사용하여 세포 생존성을 측정하였다. 490 nm에서의 흡광도는 Tecan Infinite F200 Pro 플레이트 리더에서 판독되었으며, 값은 DMSO에서만 배양된 세포로부터의 흡광도 백분율로 표현되었다.MDA-MB-231 cells were seeded at 2x10 3 cells per well in a clear 96-well plate, the medium volume was brought to 100 μL, and cells were allowed to adhere overnight. Cells were then incubated with the indicated concentrations of compound 14, 15 or 16 at 37 °C for 24 hours. Cell viability was measured using the Promega Cell Titer 96 Aquid One Solution Cell Proliferation Assay. Absorbance at 490 nm was read on a Tecan Infinite F200 Pro plate reader and values were expressed as a percentage of absorbance from cells cultured in DMSO only.

[실험예 6] 웨스턴 블랏[Experimental Example 6] Western blot

세포는 100mm 배양접시 (1 x 106 cells/dish)에 씨앗을 뿌리고 밤새 부착할 수 있도록 했다. 화합물을 다양한 농도로 첨가하여 24시간 동안 세포를 배양하였으며, 비교를 위하여 24시간 동안 DMSO (0.5 %)로 세포를 배양하였다. 셀은 차가운 용해 완충제 (23 mM Tris-HCl pH 7.6, 130 mM NaCl, 1 % NP-40, 1 % 디옥시콜산나트륨, 0.1 % SDS)에서 채취하였으며, 용해물 (Lysate)을 PVDF 막 (Bio-Rad)으로 분리하였다. 막은 TBST에서 5 % 탈지 우유로 막은 다음 해당 항체 (HSF-1 또는 β-액틴)로 배양되었다. 겨자무과산화효소 (horseradish peroxidase)에 결합된 적절한 2차 항체의 결합 후, 단백질은 제조사 (GE healthcare, Chicago, IL, USA)의 지침에 따라 ECL 화학발광을 통해 시각화되었다.Cells were seeded in 100 mm culture dishes (1 x 10 6 cells/dish) and allowed to attach overnight. Cells were cultured for 24 hours by adding compounds at various concentrations, and cells were cultured with DMSO (0.5%) for 24 hours for comparison. Cells were harvested in cold lysis buffer (23 mM Tris-HCl pH 7.6, 130 mM NaCl, 1% NP-40, 1% sodium deoxycholate, 0.1% SDS), and lysates were transferred to PVDF membranes (Bio- Rad). Membranes were blocked with 5% skim milk in TBST and then incubated with the corresponding antibodies (HSF-1 or β-actin). After binding of an appropriate secondary antibody coupled to horseradish peroxidase, proteins were visualized by ECL chemiluminescence according to the manufacturer's instructions (GE healthcare, Chicago, IL, USA).

[실시예 1] 신규화합물 처리에 따른 암 세포주 생존율 확인[Example 1] Confirmation of survival rate of cancer cell lines according to treatment with novel compounds

상기 실험예 2에서 얻어진 화합물 14 내지 화합물 16을 사용하여 삼중 음성 유방암(TNBC) 세포주인 MDA-MB-231의 세포 생존율을 확인하는 시험을 하였다. 그 결과, 도 25에 따를 때, 화합물 14 내지 화합물 16은 MDA-MB-231 유방암 세포의 성장을 화합물 14 내지 화합물 16이 각각 10 내지 27 % 저해시키는 것을 확인했다.A test was performed to confirm the cell viability of MDA-MB-231, a triple negative breast cancer (TNBC) cell line, using Compounds 14 to 16 obtained in Experimental Example 2. As a result, according to FIG. 25 , it was confirmed that Compounds 14 to 16 inhibited the growth of MDA-MB-231 breast cancer cells by 10 to 27%, respectively.

[실시예 2] HSF1 단백질의 웨스턴 블롯 분석[Example 2] Western blot analysis of HSF1 protein

HSF1에 대한 화합물 14 내지 화합물 16의 단백질 분해 효과를 웨스턴 블롯 시험을 통해 추가로 평가하였다. 그 결과, 도 26에 따를 때, 웨스턴 블롯 데이터는 화합물 14 내지 화합물 16에서 HSF1분해를 나타내는 것을 확인할 수 있었다.The proteolytic effects of compounds 14 to 16 on HSF1 were further evaluated by Western blot test. As a result, according to FIG. 26, it was confirmed that Western blot data showed HSF1 degradation in compounds 14 to 16.

전술한 본 발명의 설명은 예시를 위한 것이며, 본 발명이 속하는 기술 분야의 통상의 지식을 가진 자는 본 발명의 기술적 사상이나 필수적인 특징을 변경하지 않고서 다른 구체적인 형태로 쉽게 변형이 가능하다는 것을 이해할 수 있을 것이다. 그러므로 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적이 아닌 것으로 이해해야만 한다. The above description of the present invention is for illustrative purposes, and those skilled in the art can understand that it can be easily modified into other specific forms without changing the technical spirit or essential features of the present invention. will be. Therefore, the embodiments described above should be understood as illustrative in all respects and not limiting.

본 발명의 범위는 후술하는 청구범위에 의하여 나타내어지며, 청구범위의 의미 및 범위 그리고 그 균등 개념으로부터 도출되는 모든 변경 또는 변형된 형태가 본 발명의 범위에 포함되는 것으로 해석되어야 한다.The scope of the present invention is indicated by the following claims, and all changes or modifications derived from the meaning and scope of the claims and equivalent concepts should be interpreted as being included in the scope of the present invention.

Claims (9)

하기 화학식 A로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염:
[화학식 A]

상기 L은 에스터기 또는 아마이드기를 하나 이상 포함하거나 포함하지 않는 (C4 내지 C18)알킬임. A compound represented by Formula A or a pharmaceutically acceptable salt thereof:
[Formula A]

Wherein L is a (C4 to C18)alkyl with or without one or more ester groups or amide groups. 청구항 1에 있어서, 상기 L은 에스터기를 2 내지 4개 포함하거나 포함하지 않는 (C4 내지 C12)알킬인 것을 특징으로 하는 화합물 또는 이의 약학적으로 허용가능한 염. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein L is (C4 to C12)alkyl with or without 2 to 4 ester groups. 청구항 1에 있어서, 상기 화합물은 하기 화합물 14 내지 16인 것을 특징으로 하는 화합물 또는 이의 약학적으로 허용가능한 염:
(화합물 14) 4-((4-((6-((1H-인다졸-5-일)아미노)-5-나이트로피리딘-2-일)아미노)부틸)아미노)-2-(2,6-디옥소피페리딘-3-일)아이소인돌린-1,3-디온 [4-((4-((6-((1H-indazol-5-yl)amino)-5-nitropyridin-2-yl)amino)butyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione];
(화합물 15) 4-((3-(2-(2-(3-((6-((1H-인다졸-5-일)아미노)-5-나이트로피리딘-2-일)아미노)프로폭시)에톡시)에톡시)프로필)아미노)-2-(2,6-디옥소피페리딘-3-일)아이소인돌린-1,3-디온 [4-((3-(2-(2-(3-((6-((1H-indazol-5-yl)amino)-5-nitropyridin-2-yl)amino)propoxy)ethoxy)ethoxy)propyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione]; 및
(화합물 16) N-(3-(2-(2-(3-((6-((1H-인다졸-5-일)아미노)-5-나이트로피리딘-2-일)아미노)프록폭시)에톡시)에톡시)프로필)-2-((2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소아이소인돌린-4-일)아미노)아세트아마이드 [N-(3-(2-(2-(3-((6-((1H-indazol-5-yl)amino)-5-nitropyridin-2-yl)amino)propoxy)ethoxy)ethoxy)propyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetamide].The method according to claim 1, wherein the compound is characterized in that the following compounds 14 to 16, or a pharmaceutically acceptable salt thereof:
(Compound 14) 4-((4-((6-((1H-indazol-5-yl)amino)-5-nitropyridin-2-yl)amino)butyl)amino)-2-(2, 6-dioxopiperidin-3-yl)isoindoline-1,3-dione [4-((4-((6-((1H-indazol-5-yl)amino)-5-nitropyridin-2- yl)amino)butyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione];
(Compound 15) 4-((3-(2-(2-(3-((6-((1H-indazol-5-yl)amino)-5-nitropyridin-2-yl)amino)pro Poxy)ethoxy)ethoxy)propyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [4-((3-(2-(2 -(3-((6-((1H-indazol-5-yl)amino)-5-nitropyridin-2-yl)amino)propoxy)ethoxy)ethoxy)propyl)amino)-2-(2,6-dioxopiperidin -3-yl)isoindoline-1,3-dione]; and
(Compound 16) N-(3-(2-(2-(3-((6-((1H-indazol-5-yl)amino)-5-nitropyridin-2-yl)amino)propoxy )ethoxy)ethoxy)propyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetamide [ N-(3-(2-(2-(3-((6-((1H-indazol-5-yl)amino)-5-nitropyridin-2-yl)amino)propoxy)ethoxy)ethoxy)propyl)- 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetamide]. 청구항 1의 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 암 질환 예방 또는 치료용 약학 조성물.A pharmaceutical composition for preventing or treating cancer containing the compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 청구항 4에 있어서, 상기 암 질환은 HSF1 (heat shock factor 1) 또는 열충격단백질 (heat shock protein) 활성에 의해 발생하는 암 질환인 것을 특징으로 하는 약학 조성물.The pharmaceutical composition according to claim 4, wherein the cancer disease is a cancer disease caused by heat shock factor 1 (HSF1) or heat shock protein activity. 청구항 4에 있어서, 상기 암 질환은 유방암, 삼중음성유방암 (TNBC), 자궁경부암, 폐암, 췌장암, 결장암, 골암, 피부암, 피부 또는 안구내 흑색종, 자궁암, 난소암, 직장암, 위암, 항문부근암, 결장암, 나팔관암종, 자궁내막암종, 질암, 음문암, 호지킨병(Hodgkin's disease), 식도암, 소장암, 내분비선암, 갑상선암, 부갑상선암, 부신암, 연조직 육종, 요도암, 음경암, 전립선암, 만성 또는 급성 백혈병, 림프구 림프종, 방광암, 신장 또는 수뇨관 암, 중추신경계 종양, 1차 CNS 림프종, 척수 종양, 뇌간 신경교종 및 뇌하수체 선종으로 이루어진 군에서 선택된 어느 하나인 것을 특징으로 하는 약학 조성물. The method according to claim 4, wherein the cancer disease is breast cancer, triple negative breast cancer (TNBC), cervical cancer, lung cancer, pancreatic cancer, colon cancer, bone cancer, skin cancer, skin or intraocular melanoma, cervical cancer, ovarian cancer, rectal cancer, stomach cancer, or proximal anal cancer , colon cancer, fallopian tube carcinoma, endometrial carcinoma, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer , A pharmaceutical composition, characterized in that any one selected from the group consisting of chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureteral cancer, central nervous system tumor, primary CNS lymphoma, spinal cord tumor, brainstem glioma, and pituitary adenoma. 청구항 1의 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 암 질환 예방 또는 개선용 건강기능식품 조성물.A health functional food composition for preventing or improving cancer disease, containing the compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 청구항 1의 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 HSF1 (heat shock factor 1) 또는 열충격단백질 (heat shock protein) 발현 억제용 시약 조성물.A reagent composition for inhibiting the expression of heat shock factor 1 (HSF1) or heat shock protein, containing the compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 청구항 1의 화합물 또는 이의 약학적으로 허용 가능한 염을 투여하는 단계를 포함하는 HSF1 (heat shock factor 1) 또는 열충격단백질 (heat shock protein) 발현 억제방법.A method for suppressing heat shock factor 1 (HSF1) or heat shock protein expression comprising administering the compound of claim 1 or a pharmaceutically acceptable salt thereof.
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