KR100889839B1 - 2-sustituted aminoalkylenyloxy-3-substitutedphenylethynyl quinoxaline derivatives - Google Patents

2-sustituted aminoalkylenyloxy-3-substitutedphenylethynyl quinoxaline derivatives Download PDF

Info

Publication number
KR100889839B1
KR100889839B1 KR1020070096340A KR20070096340A KR100889839B1 KR 100889839 B1 KR100889839 B1 KR 100889839B1 KR 1020070096340 A KR1020070096340 A KR 1020070096340A KR 20070096340 A KR20070096340 A KR 20070096340A KR 100889839 B1 KR100889839 B1 KR 100889839B1
Authority
KR
South Korea
Prior art keywords
substituted
formula
group
alkyl group
aliphatic
Prior art date
Application number
KR1020070096340A
Other languages
Korean (ko)
Inventor
공영대
전문국
황순희
동미숙
이상범
강경호
오칠환
Original Assignee
한국화학연구원
고려대학교 산학협력단
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 한국화학연구원, 고려대학교 산학협력단 filed Critical 한국화학연구원
Priority to KR1020070096340A priority Critical patent/KR100889839B1/en
Application granted granted Critical
Publication of KR100889839B1 publication Critical patent/KR100889839B1/en

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/44—Benzopyrazines with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

Provided is a 2-substituted aminoalkylenyloxy-3-substituted phenylethynyl quinoxaline derivative, capable of suppressing expression of a WNT gene and proliferation of a cancer cell. A 2-substituted aminoalkylenyloxy-3-substituted phenylethynyl quinoxaline derivative is represented by the formula 1. In the formula 1, Y and Z is independently a hydrogen atom, halogen atom, C1-C8 alkyl group, or a C1-C8 alkoxy group; and R shows -X-Het. or -X-NR1R2, in which X is a C1-C8 alkylene group or a C2-C8 alkylene oxyalkylene group, and R1 and R2 is independently a hydrogen atom, C1-C8 alkyl group, or a pentagon or heptagon hetero group in which a hetero atom selected from another nitrogen atom or an oxygen atom with the nitrogen boned to the R1 and R2 is included.

Description

신규 2-치환아미노알킬레닐옥시-3-치환페닐에티닐 퀴녹살린 유도체 {2-Sustituted aminoalkylenyloxy-3-substitutedphenylethynyl quinoxaline derivatives} New 2-substituted aminoalkylenyloxy-3-substituted phenylethynyl quinoxaline derivatives {2-Sustituted aminoalkylenyloxy-3-substitutedphenylethynyl quinoxaline derivatives}

본 발명은 암세포 증식억제 활성과 WNT 유전자 발현 억제 활성을 가지는 신규 2-치환아미노알킬레닐옥시-3-치환페닐에티닐 퀴녹살린 유도체와 약제학적으로 허용 가능한 이의 염, 이 화합물의 제조방법, 그리고 이 화합물의 항암제로서의 용도에 관한 것이다.The present invention provides a novel 2-substituted aminoalkylenyloxy-3-substituted phenylethynyl quinoxaline derivative having a cancer cell proliferation inhibitory activity and WNT gene expression inhibitory activity, a pharmaceutically acceptable salt thereof, a method for preparing the compound, and It relates to the use of the compound as an anticancer agent.

일반적으로 항암 치료제로 사용되는 물질들은 상당한 독성을 지니고 있으며, 암 세포만을 선택적으로 제거하지 못하므로, 암의 발생 후 이의 치료뿐 아니라, 암의 발생을 예방하기 위한 독성이 적고 효과적인 항암제의 개발이 절실히 필요하다.In general, the substances used as anticancer drugs have considerable toxicity, and since they do not selectively remove only cancer cells, there is an urgent need for development of a low-toxic and effective anticancer agent to prevent cancer as well as treatment after cancer. need.

'항암제'라 함은 악성종양을 치료하기 위해 사용하는 방법들 중 수술이나 방사선 요법을 제외한 화학요법제를 총칭하는 것으로, 주로 핵산의 합성을 저해하여 항암활성을 나타내는 물질이 대부분이다. 화학요법제는 크게 대사 길항 제(antimetabolites), 알킬화제(alkylating agents), 유사분열억제제(antimitotic drugs), 호르몬제(hormones) 등으로 분류된다. 암세포의 증식에 필요한 대사과정을 저해하는 대사길항제로는 엽산 유도체(methotrexate), 퓨린 유도체(6-mercaptopurine, 6-thioguanine), 피리미딘 유도체(5-fluorouracil, Cytarabine) 등이 있다. DNA의 구아닌 등에 알킬기를 도입하여 DNA의 구조를 변형시키고 사슬을 절단시켜 항암효과를 나타내는 알킬화제로는 니트로겐 머스타드계 화합물(chlorambucil, cyclophosphamide), 에틸렌이민계 화합물(thiotepa), 알킬설포네이트계 화합물(busulfan), 니트로소우레아계 화합물(carmustine), 트리아젠계 화합물(dacarbazine)이 있다. 분열시기 특이성 약물로서 유사분열을 차단하여 세포분열을 억제하는 유사분열억제제에는 악티노마이신 D(actinomycin D), 독소루비신, 블레오마이신, 미토마이신과 같은 항암성항암제, 빈크리스틴, 빈블라스틴과 같은 식물알칼로이드, 탁산환을 포함하는 유사분열 저해제인 탁소이드 등이 포함된다. 이외에 부신피질호르몬이나 프로게스테론과 같은 호르몬제와 시스플라틴 같은 백금함유 화합물이 항암제로서 사용되고 있다. The term "anticancer agent" refers to chemotherapeutic agents other than surgery or radiation therapy among the methods used to treat malignant tumors, and most of them show anticancer activity by inhibiting the synthesis of nucleic acids. Chemotherapeutic agents are broadly classified into antimetabolites, alkylating agents, antimitotic drugs, and hormones. Metabolic antagonists that inhibit metabolic processes necessary for the proliferation of cancer cells include folate derivatives (methotrexate), purine derivatives (6-mercaptopurine, 6-thioguanine), and pyrimidine derivatives (5-fluorouracil, Cytarabine). Alkylating agents that introduce an alkyl group to DNA guanine, modify the structure of the DNA, and cut the chains to exhibit anticancer effects include nitrogen mustard compounds (chlorambucil, cyclophosphamide), ethyleneimine compounds (thiotepa), and alkylsulfonate compounds ( busulfan), nitrosourea compounds (carmustine), triazane compounds (dacarbazine). Mitosis inhibitors that inhibit mitosis by blocking mitosis as anti-mitotic drugs include plant drugs such as actinomycin D, doxorubicin, bleomycin, and anticancer drugs such as mitomycin, vincristine, and vinblastine. Alkaloids, taxoids including mitosis inhibitors including taxane rings, and the like. In addition, hormones such as corticosteroids and progesterone and platinum-containing compounds such as cisplatin are used as anticancer agents.

그러나 화학요법제의 가장 큰 문제는 약제 내성으로, 항암제에 의한 초기의 성공적인 반응에도 불구하고 결국에는 치료가 실패하게 되는 주요 요인이다. However, the biggest problem with chemotherapeutic agents is drug resistance, which, despite the initial successful response by anticancer drugs, is the main factor that eventually causes the treatment to fail.

이에 따라 약제 내성을 감소시킬 수 있는 새로운 작용점의 항암제 개발이 절실히 요구되는 바, WNT 관련 작용점이 새로운 항암 치료제 개발의 한 방법으로 대두되고 있으며, WNT를 저해하는 물질은 암세포에 선택적인 새로운 항암제로서 작용하는 것으로 보고되어 있다. [Nick Barker and Hans Clevers; Nature, 2006, 5, 997-1014]Accordingly, there is an urgent need for the development of new anticancer drugs that can reduce drug resistance. WNT-related action points are emerging as a way of developing new anticancer drugs, and WNT-inhibiting agents act as new anticancer drugs selective to cancer cells. It is reported. Nick Barker and Hans Clevers; Nature , 2006 , 5, 997-1014]

WNT는 세포막에 존재하는 Frizzled(Fzd) 수용체와 LRP를 함유하는 수용체 복합체와 결합하여 Dvl-Fzd 복합체를 형성하고, CK1γ에 의한 LRP 인산화를 유발시키며, 또한 세포막으로 액신(axin)이 이동하여 세포내에서 LRP와 액신(Axin)이 결합하는 것을 촉진한다. 이러한 과정은 액신(Axin)과 결합된 GSK3β, 및 β-카테닌 등을 해리시켜 자유 β-카테닌이 세포 내에 축적되며, 이것이 핵 내로 침투하여 TCF를 활성화시켜서 세포증식을 일으키게 되는 원인이 된다. 따라서 WNT가 세포막에 존재하는 Fzd-LRP 수용체 복합체와의 결합을 저해하게 되면, β-카테닌에 의한 세포 증식을 억제할 수 있기 때문에 그것에 의해 매개되는 세포증식 경로들을 차단할 것이므로 효과적인 항암제 개발을 기대할 수 있다. [Nico Janssens et. al., Investigational New Drugs, 2006]WNT binds to the receptor complex containing the Frizzled (Fzd) receptor and LRP in the cell membrane to form a Dvl-Fzd complex, induces LRP phosphorylation by CK1γ, and also transfers axin to the cell membrane to intracellularly. Promotes the binding of LRP and Axin. This process dissociates GSK3β, and β-catenin, which are associated with Axin, and free β-catenin accumulates in the cell, which causes the cells to penetrate into the nucleus and activate TCF to cause cell proliferation. Therefore, if WNT inhibits the binding of the Fzd-LRP receptor complex present in the cell membrane, it can inhibit cell proliferation by β-catenin, and thus block the cell proliferation pathways mediated by it. Therefore, anticancer drug development can be expected. . Nico Janssens et. al., I nvestigational New Drugs , 2006 ]

이러한 맥락에서 WNT에 대한 유기저분자 저해제 발굴 및 항암제로서의 개발을 위한 노력들이 진행되어 왔으며, 그 결과 천연물(ZTM000990, PKF118-744 등) 및 일부의 합성화합물(ICG-001, PNU-74654 등)이 보고되었으나, 아직까지 발표된 자료에 의하면 약물성 화학 구조식을 가진 유효물질은 거의 보고된 바 없다.In this context, efforts have been made to discover organic small molecule inhibitors against WNT and develop them as anticancer agents. As a result, natural products (ZTM000990, PKF118-744, etc.) and some synthetic compounds (ICG-001, PNU-74654, etc.) However, according to published data, few active substances with pharmacological chemical formulas have been reported.

한편, 본 발명에 따른 2-치환아미노알킬레닐옥시-3-치환페닐에티닐 퀴녹살린 유도체는 관련 선행 특허에서 공개된 바 없는 신규 구조의 화합물로서, 암세포 증식억제 및 WNT 억제 활성을 가지므로 암 치료제로서 활용될 수 있다.Meanwhile, the 2-substituted aminoalkylenyloxy-3-substituted phenylethynyl quinoxaline derivatives according to the present invention are compounds having a novel structure that have not been disclosed in the related prior patents, and have cancer cell proliferation inhibitory and WNT inhibitory activity, and thus are effective for treating cancer. It can be utilized as.

따라서, 본 발명은 신규의 2-치환아미노알킬레닐옥시-3-치환페닐에티닐 퀴녹살린 유도체를 제공하는데 그 목적이 있다. Accordingly, an object of the present invention is to provide a novel 2-substituted aminoalkylenyloxy-3-substituted phenylethynyl quinoxaline derivative.

또한, 본 발명은 상기한 신규 화합물을 제조하는 방법을 제공하는데 다른 목적이 있다. It is another object of the present invention to provide a method for preparing the above-mentioned novel compound.

또한, 본 발명은 상기한 신규 화합물이 암세포 증식억제 및 WNT 유전자 발현 억제 활성을 가지므로, 이 신규 화합물을 항암제로 사용하는 의약적 용도를 제공하는데 또 다른 목적이 있다. In addition, the present invention has a further object to provide a pharmaceutical use using the novel compound as an anticancer agent, since the novel compound has cancer cell proliferation inhibitory activity and WNT gene expression inhibitory activity.

본 발명은 우수한 WNT 유전자 발현 억제 활성을 가지는 하기 화학식 1로 표시되는 2-치환아미노알킬레닐옥시-3-치환페닐에티닐 퀴녹살린 유도체를 그 특징으로 한다. The present invention is characterized by a 2-substituted aminoalkylenyloxy-3-substituted phenylethynyl quinoxaline derivative represented by the following formula (1) having excellent WNT gene expression inhibitory activity.

[화학식 1][Formula 1]

Figure 112007068645505-pat00002
Figure 112007068645505-pat00002

상기 화학식 1에서, In Chemical Formula 1,

Y 및 Z는 각각 수소원자, 할로겐원자, C1-C8 알킬기 및 C1-C8 알콕시기를 나타 내고; R은 -X-NR1R2, 또는 -X-Het.를 나타내고; X는 C1-C8 알킬렌기 또는 C2-C8 알킬렌옥시알킬렌기를 나타내고; R1 및 R2는 각각 수소원자, 또는 C1-C8 알킬기이거나, 또는 R1 및 R2가 결합된 N과 함께 또는 또다른 헤테로원자를 추가로 포함시켜 헤테로원자가 1 내지 3개 포함된 5각형 내지 7각형의 지방족 헤테로고리를 형성할 수 있고, 또한 지방족 헤테로고리 내의 질소원자는 C1-C8 알킬으로 치환될 수 있고; Het.는 N 또는 O의 헤테로원자가 1 내지 3개 포함된 5각형 내지 7각형의 지방족 또는 방향족 헤테로고리를 나타내고, 또한 지방족 헤테로고리 내의 질소원자는 수소원자 또는 C1-C8 알킬기로 치환될 수 있다.Y and Z are each a hydrogen atom, a halogen atom, C 1 -C 8 Alkyl group and C 1 -C 8 Represents an alkoxy group; R represents -X-NR 1 R 2 , or -X-Het .; X is C 1 -C 8 Alkylene group or C 2 -C 8 An alkyleneoxyalkylene group; R 1 and R 2 are each a hydrogen atom, or a C 1 -C 8 alkyl group, or together with N to which R 1 and R 2 are bonded, or further including another heteroatom, containing 1 to 3 heteroatoms; Aliphatic heterocycles of the hexagonal form may be formed, and the nitrogen atom in the aliphatic heterocycle may be substituted with C 1 -C 8 alkyl; Het. Represents a pentagonal to pentagonal aliphatic or aromatic heterocycle containing 1 to 3 heteroatoms of N or O, and the nitrogen atom in the aliphatic heterocycle may be substituted with a hydrogen atom or a C 1 -C 8 alkyl group. .

또한, 본 발명에 따른 상기 화학식 1로 표시되는 화합물은 용매화물(예를 들면 수화물)의 형태로도 존재할 수 있다.In addition, the compound represented by Chemical Formula 1 according to the present invention may also exist in the form of a solvate (for example, a hydrate).

또한, 본 발명에 따른 상기 화학식 1로 표시되는 화합물은 하나 또는 그 이상의 비대칭 중심을 가질 수 있고, 이러한 화합물의 경우 거울상 이성질체 또는 부분입체이성질체가 존재할 수 있다. 따라서, 본 발명은 각 이성질체 또는 이들 이성질체 혼합물을 포함한다.In addition, the compound represented by Formula 1 according to the present invention may have one or more asymmetric centers, and in the case of such compounds, enantiomers or diastereomers may be present. Accordingly, the present invention includes each isomer or a mixture of these isomers.

본 발명에 따른 화합물을 정의하는데 이용된 각 치환기에 대해 보다 구체적으로 설명하면 다음과 같다.The substituents used to define the compounds according to the present invention are described in more detail as follows.

본 발명에서의 '할로겐 원자'라 함은 불소, 염소, 브롬, 요오드원자를 의미한다.In the present invention, the term "halogen atom" means a fluorine, chlorine, bromine or iodine atom.

본 발명에서의 'C1-C8의 알킬기'라 함은 메틸, 에틸, n-프로필, i-프로필, 싸이클로프로필, n-부틸, i-부틸, t-부틸, 싸이클로부틸, 싸이클로프로필메틸, n-펜틸, i-펜틸, 네오펜틸, t-펜틸, 싸이클로펜틸, 싸이클로부틸메틸, n-헥실, i-헥실, 싸이클로헥실, 싸이클로펜틸메틸, 헵틸, 싸이클로헥실메틸, 옥틸 등을 포함하는 1개에서 8개까지의 탄소원자를 가지는 직쇄, 분쇄 또는 고리형의 지방족 포화 탄화수소기를 의미한다. In the present invention, the alkyl group of C 1 -C 8 is methyl, ethyl, n -propyl, i -propyl, cyclopropyl, n -butyl, i -butyl, t -butyl, cyclobutyl, cyclopropylmethyl, 1 containing n -pentyl, i -pentyl, neopentyl, t -pentyl, cyclopentyl, cyclobutylmethyl, n -hexyl, i -hexyl, cyclohexyl, cyclopentylmethyl, heptyl, cyclohexylmethyl, octyl and the like Or a straight chain, pulverized or cyclic aliphatic saturated hydrocarbon group having up to 8 carbon atoms.

본 발명에서의 'C1-C8의 알콕시기'라 함은 메톡시, 에톡시, n-프로폭시, i-프로폭시, n-부톡시, i-부톡시, t-부톡시 등을 포함하는 것으로, C1-C8의 알킬기에서 선택된 치환체에 의해 수소원자가 치환된 하이드록시기를 의미한다. In the present invention, the term "C 1 -C 8 alkoxy group" includes methoxy, ethoxy, n -propoxy, i -propoxy, n -butoxy, i -butoxy, t -butoxy and the like. By that, it means a hydroxy group in which a hydrogen atom is substituted by a substituent selected from a C 1 -C 8 alkyl group.

본 발명에서의 'C1-C8의 알킬렌기'라 함은 메틸렌, 에틸렌, 트라이메틸렌, 프로필렌, 테트라메틸렌 등을 포함하는 1개에서 8개까지의 탄소원자를 가지는 직쇄 또는 분쇄형 탄화수소기이다. In the present invention, the "C 1 -C 8 alkylene group" is a straight or pulverized hydrocarbon group having 1 to 8 carbon atoms including methylene, ethylene, trimethylene, propylene, tetramethylene and the like.

본 발명에서의 '헤테로고리'라 함은 R1 및 R2가 결합된 N 단독 또는 N, O, S 중에서 선택된 또다른 헤테로원자를 추가로 포함하여 형성된 5각형 내지 8각형의 지방족 또는 방향족 탄화수소 고리기를 의미한다. 구체적으로, 본 발명에서의 '헤테로고리'는 피롤리딘, 피페리딘, 몰포린, 피페라진 중에서 선택된 지방족 헤테 로고리이거나, 또는 피롤, 피라졸, 이미다졸, 트라이아졸, 옥사졸, 아이소옥사졸, 옥사다이아졸, 피리딘, 피리다진, 피리미딘, 피라진 중에서 선택된 방향족 헤테로고리가 포함된다. In the present invention, the term "heterocycle" refers to a pentagonal to octagonal aliphatic or aromatic hydrocarbon ring formed by additionally N containing R 1 and R 2 or another hetero atom selected from N, O, and S. Means a flag. Specifically, the 'heterocyclic' in the present invention is an aliphatic hete logori selected from pyrrolidine, piperidine, morpholine, piperazine, or pyrrole, pyrazole, imidazole, triazole, oxazole, isoocta Aromatic heterocycles selected from solazole, oxadiazole, pyridine, pyridazine, pyrimidine, pyrazine.

본 발명이 특징으로 하는 상기 화학식 1로 표시되는 2-치환아미노알킬레닐옥시-3-치환페닐에티닐 퀴녹살린 유도체에 있어, 바람직하기로는 Y 및 Z는 각각 수소원자, 할로겐원자, C1-C6 알킬기 및 C1-C6 알콕시기를 나타내고; R은 -X-NR1R2, 또는 -X-Het.를 나타내고; X는 C1-C6 알킬렌기 또는 C2-C6 알킬렌옥시알킬렌기를 나타내고; R1 및 R2는 각각 수소원자, 또는 C1-C8 알킬기이거나, 또는 R1 및 R2가 결합된 N과 함께 또는 또다른 헤테로원자를 추가로 포함시켜 함께 결합하여 피롤리딘, 피페리딘, 몰포린, 및 피페라진 중에서 선택된 지방족 헤테로고리를 형성할 수 있고; Het.는 피롤리딘, 피페리딘, 몰포린, 피페라진, 피롤, 피라졸, 이미다졸, 트라이아졸, 옥사졸, 아이소옥사졸, 옥사다이아졸, 피리딘, 피리다진, 피리미딘, 및 피라진 중에서 선택된 지방족 또는 방향족 헤테로고리를 나타내고; 상기한 지방족 헤테로고리를 구성하는 질소원자가 수소원자 또는 C1-C6 알킬기로 치환된 화합물의 경우이다.In the 2-substituted aminoalkylenyloxy-3-substituted phenylethynyl quinoxaline derivative represented by the formula (1) characterized by the present invention, preferably Y and Z are each a hydrogen atom, a halogen atom, C 1 -C A 6 alkyl group and a C 1 -C 6 alkoxy group; R represents -X-NR 1 R 2 , or -X-Het .; X is C 1 -C 6 Alkylene group or C 2 -C 6 An alkyleneoxyalkylene group; R 1 and R 2 are each a hydrogen atom or a C 1 -C 8 alkyl group, or R 1 And R 2 together with N to which it is attached or further including another heteroatom, may be bonded together to form an aliphatic heterocycle selected from pyrrolidine, piperidine, morpholine, and piperazine; Het. Is selected from pyrrolidine, piperidine, morpholine, piperazine, pyrrole, pyrazole, imidazole, triazole, oxazole, isoxazole, oxadiazole, pyridine, pyridazine, pyrimidine, and pyrazine Represent selected aliphatic or aromatic heterocycles; This is the case where the nitrogen atom constituting the aliphatic heterocycle is substituted with a hydrogen atom or a C 1 -C 6 alkyl group.

상기 화학식 1로 표시되는 2-치환아미노알킬레닐옥시-3-치환페닐에티닐 퀴녹살린 유도체에 있어, 보다 바람직하기로는 Y 및 Z는 각각 수소, 염소, 불소, 메틸, 에틸, n-프로필, i-프로필, n-부틸, i-부틸, t-부틸, 메톡시, 에톡시, n-프로폭시, i-프로폭시, n-부톡시, i-부톡시, 또는 t-부톡시를 나타내고; R은 다이메틸아미노에틸렌, 다이에틸아미노에틸렌, 다이메틸아미노프로필렌, 다이에틸아미노프로필렌, 다이메틸아미노아이소프로필렌, 다이에틸아미노아이소프로필렌, 다이메틸아미노에틸렌옥시에틸렌, 다이에틸아미노에틸렌옥시에틸렌, 다이메틸아미노에틸렌옥시프로필렌, 다이에틸아미노에틸렌옥시프로필렌, 다이메틸아미노에틸렌옥시아이소프로필렌, 다이에틸아미노에틸렌옥시아이소프로필렌, 피롤리딜에틸렌, 피롤리딜프로필렌, 피롤리딜아이소프로필렌, 피페리딜에틸렌, 피페리딜프로필렌, 피페리딜아이소프로필렌, 몰포릴에틸렌, 몰포릴프로필렌, 몰포릴아이소프로필렌, 피롤일에틸렌, 피롤일프로필렌, 피롤일아이소프로필렌, 피리딜에틸렌, 피리딜프로필렌, 또는 피리딜아이소프로필렌을 나타내고; 상기한 피롤리딜, 피페리딜 및 몰포릴 중에서 선택된 지방족 헤테로고리를 구성하는 질소원자는 수소 또는 메틸, 에틸, n-프로필, i-프로필, n-부틸, i-부틸 및 t-부틸 중에서 선택된 알킬기로 치환된 화합물의 경우이다.In the 2-substituted aminoalkylenyloxy-3-substituted phenylethynyl quinoxaline derivative represented by the formula (1), more preferably Y and Z are each hydrogen, chlorine, fluorine, methyl, ethyl, n -propyl, i -Propyl, n -butyl, i -butyl, t -butyl, methoxy, ethoxy, n -propoxy, i -propoxy, n -butoxy, i -butoxy, or t -butoxy; R is dimethylaminoethylene, diethylaminoethylene, dimethylaminopropylene, diethylaminopropylene, dimethylaminoisopropylene, diethylaminoisopropylene, dimethylaminoethyleneoxyethylene, diethylaminoethyleneoxyethylene, dimethyl Aminoethyleneoxypropylene, diethylaminoethyleneoxypropylene, dimethylaminoethyleneoxyisopropylene, diethylaminoethyleneoxyisopropylene, pyrrolidylethylene, pyrrolidylpropylene, pyrrolidylisopropylene, piperidylethylene, blood Ferridylpropylene, piperidylisopropylene, morpholinyl ethylene, morpholyl propylene, morpholyl isopropylene, pyrrolylethylene, pyrroleyl propylene, pyrrolyl isopropylene, pyridylethylene, pyridyl propylene, or pyridyl isopropylene Represent; The nitrogen atom constituting the aliphatic heterocycle selected from the above pyrrolidyl, piperidyl and morpholyl is hydrogen or an alkyl group selected from methyl, ethyl, n -propyl, i -propyl, n -butyl, i -butyl and t -butyl In the case of compounds substituted with.

한편, 본 발명은 상기 화학식 1로 표시되는 화합물의 제조방법을 포함한다. 본 발명에 따른 제조방법은 하기 반응식 1에 나타낸 바와 같은 두 단계 제조과정을 포함하여 이루어진다 :On the other hand, the present invention includes a method for producing a compound represented by the formula (1). The preparation method according to the present invention comprises a two step preparation process as shown in Scheme 1 below:

하기 화학식 2로 표시되는 2,3-다이클로로퀴녹살린과 하기 화학식 3으로 표시되는 에티닐기 공여시약을 소노가쉬라 반응(Sonogashira reaction)시켜 하기 화학식 4로 표시되는 화합물을 제조하는 과정; 및Preparing a compound represented by the following Chemical Formula 4 by performing a Sonogashira reaction between 2,3-dichloroquinoxaline represented by the following Chemical Formula 2 and an ethynyl group donating reagent represented by the following Chemical Formula 3; And

하기 화학식 4로 표시되는 에티닐 화합물을 하기 화학식 5로 표시되는 알콜 화합물과 염기의 존재 하에서 반응시켜 하기 화학식 1로 표시되는 2-치환아미노알킬레닐옥시-3-치환페닐에티닐 퀴녹살린 유도체를 제조하는 과정.The ethynyl compound represented by the following formula (4) is reacted with an alcohol compound represented by the following formula (5) in the presence of a base to prepare a 2-substituted aminoalkylenyloxy-3-substituted phenylethynyl quinoxaline derivative represented by the following formula (1). Process.

Figure 112007068645505-pat00003
Figure 112007068645505-pat00003

상기 반응식 1에서, R, Y, 및 Z는 각각 상기에서 정의한 바와 같다. In Scheme 1, R, Y, and Z are as defined above, respectively.

상기 반응식 1에 따른 본 발명의 제조방법을 보다 상세히 설명하면 다음과 같다. Referring to the production method of the present invention according to Scheme 1 in more detail as follows.

상기 반응식 1에 따른 첫 번째 제조과정에서 사용되는 상기 화학식 3으로 표시되는 에티닐기 공여시약은 상기 화학식 2로 표시되는 2,3-다이클로로퀴녹살린에 대하여 1.0 내지 1.5 몰당량을 사용하는 것이 좋으며, 바람직하게는 1.0 내지 1.1 몰당량을 사용하는 것이다. 또한, 본 발명의 첫 번째 제조과정에 적용되는 '소노가쉬라 반응(Sonogashira reaction)에서 요구되는 조건'이라 함은 통상적인 팔라듐 시약, 통상적인 리간드, 통상적인 구리시약, 통상적인 무기 염기 또는 유기 염기로 이루어진다. 상기한 소노가쉬라 반응은 통상의 용매, 예를 들면 톨루엔, 테트라하이드로퓨란, 다이옥산, 다이메톡시에탄, 다이클로로메탄, 아세토나이트라일, 다이메틸포름아마이드, 물 등을 사용한다. 반응온도는 0 ℃ 내지 용매의 비점 범위, 바람직하게는 실온 내지 100 ℃ 범위를 유지하는 것이 좋고, 반응시간은 1 내지 48시간, 바람직하게는 2 내지 24시간 동안 반응시킨다. The ethynyl group donating reagent represented by Chemical Formula 3 used in the first preparation process according to Scheme 1 may use 1.0 to 1.5 molar equivalents to 2,3-dichloroquinoxaline represented by Chemical Formula 2, Preferably from 1.0 to 1.1 molar equivalents. In addition, the 'conditions required for the Sonogashira reaction' applied to the first manufacturing process of the present invention refers to conventional palladium reagents, conventional ligands, conventional copper reagents, conventional inorganic bases or organic bases. Is made of. The sonogashira reaction uses a common solvent such as toluene, tetrahydrofuran, dioxane, dimethoxyethane, dichloromethane, acetonitrile, dimethylformamide, water and the like. The reaction temperature is preferably maintained in the boiling range of 0 ° C. to the solvent, preferably in the range of room temperature to 100 ° C., and the reaction time is reacted for 1 to 48 hours, preferably 2 to 24 hours.

상기 반응식 1에 따르는 두 번째 제조과정은 통상의 유기용매, 예를 들면 테트라하이드로퓨란, 다이클로로메탄, 아세토니트릴, 다이메틸포름아마이드 등을 사 용하여 수행한다. 반응온도는 0 ℃ 내지 용매의 비점 범위, 바람직하게는 실온 내지 100 ℃ 범위를 유지하는 것이 좋다. 반응시간은 1 내지 48시간, 바람직하게는 3 내지 24시간 동안 반응시킨다. 상기 화학식 5로 표시되는 알콜 화합물은 상기 화학식 4로 표시되는 에티닐 화합물에 대해서 1.0 내지 1.5 몰당량을 사용하는 것이 좋으며, 바람직하게는 1.0 내지 1.1 몰당량을 사용하는 것이다. 또한, 이 반응은 통상의 유기 또는 무기 염기 존재 하에서 수행하는 것이 바람직하며, 예를 들면 수소화나트륨, 수소화칼륨, 수산화나트륨, 수산화칼륨, 탄산나트륨, 탄산칼륨, 탄산세슘, 탄산수소나트륨, 탄산수소칼륨, 트라이에틸아민, 피리딘, DBU 등을 들 수 있다.The second preparation process according to Scheme 1 is carried out using a conventional organic solvent, for example, tetrahydrofuran, dichloromethane, acetonitrile, dimethylformamide and the like. The reaction temperature is preferably maintained in the boiling point range of 0 ° C to the solvent, preferably in the range of room temperature to 100 ° C. The reaction time is 1 to 48 hours, preferably 3 to 24 hours. The alcohol compound represented by Chemical Formula 5 may preferably use 1.0 to 1.5 molar equivalents with respect to the ethynyl compound represented by Chemical Formula 4, and preferably 1.0 to 1.1 molar equivalents. In addition, this reaction is preferably carried out in the presence of a conventional organic or inorganic base, for example, sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, Triethylamine, pyridine, DBU and the like.

본 발명에 따른 제조방법을 수행하여 얻어진 상기 화학식 1로 표시되는 화합물들의 생성여부를 확인하기 위하여, 상기한 두 번째 제조과정을 수행한 후에 다중 컬럼크로마토그래피 장비(Quad3+; 미국 Biotage사 제품)로 분리 정제하였으며, NMR 및 Mass 스펙트럼으로 화학구조를 분석하였다.In order to confirm the production of the compound represented by Chemical Formula 1 obtained by performing the preparation method according to the present invention, after performing the above-mentioned second manufacturing process, multi-column chromatography equipment (Quad 3+ ; manufactured by Biotage, USA) It was isolated and purified, and the chemical structure was analyzed by NMR and Mass spectra.

한편, 본 발명에 따른 상기 화학식 1로 표시되는 화합물은 암세포의 성장을 억제하는 활성 및 WNT 유전자 발현을 억제하는 활성이 우수하여 암 치료 및 예방제로 유용하게 사용될 수 있다. On the other hand, the compound represented by the formula (1) according to the present invention is excellent in activity to inhibit the growth of cancer cells and WNT gene expression can be usefully used as a cancer treatment and prevention agent.

따라서, 본 발명은 상기 화학식 1로 표시되는 2-치환아미노알킬레닐옥시-3-치환페닐에티닐퀴녹살린 유도체 또는 약제학적으로 허용 가능한 이들의 염이 유효성분으로 함유되어 있는 이상 세포 증식으로 유발되는 각종 암의 예방 및 치료제로 유효한 약제조성물을 포함한다. Therefore, the present invention is induced by cell proliferation as long as the 2-substituted aminoalkylenyloxy-3-substituted phenylethynylquinoxaline derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof is contained as an active ingredient. Contains pharmaceutical compositions effective for the prevention and treatment of various cancers.

본 발명에서의 약제학적으로 허용 가능한 염은 당해 기술 분야에서 통상적인 방법에 의해 제조될 수 있는 것으로, 예를 들면 염산, 브롬산, 황산, 황산수소나트륨, 인산, 질산, 탄산 등과 같은 무기산과의 염, 개미산, 초산, 프로피온산, 옥살산, 석신산, 벤조산, 시트르산, 말레인산, 말론산, 타르타르산, 글루콘산, 락트산, 게스티스산, 푸마르산, 락토비온산, 살리실릭산, 또는 아세틸살리실릭산(아스피린)과 같은 유기산과의 염, 글리신, 알라닌, 바닐린, 이소루신, 세린, 시스테인, 시스틴, 아스파라진산, 글루타민, 리진, 아르기닌, 타이로신, 프롤린 등과 같은 아미노산과의 염, 메탄설폰산, 에탄설폰산, 벤젠설폰산, 톨루엔설폰산 등과 같은 설폰산과의 염, 나트륨, 칼륨 등의 알칼리금속과의 반응에 의한 금속염, 또는 암모늄 이온과의 염 등을 포함한다. Pharmaceutically acceptable salts in the present invention may be prepared by conventional methods in the art, for example, with inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid, sodium hydrogen sulfate, phosphoric acid, nitric acid, carbonic acid, and the like. Salts, formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, benzoic acid, citric acid, maleic acid, malonic acid, tartaric acid, gluconic acid, lactic acid, gestyic acid, fumaric acid, lactobionic acid, salicylic acid, or acetylsalicylic acid (aspirin Salts with organic acids such as), salts with amino acids such as glycine, alanine, vanillin, isoleucine, serine, cysteine, cystine, aspartic acid, glutamine, lysine, arginine, tyrosine, proline, methanesulfonic acid, ethanesulfonic acid And salts with sulfonic acids such as benzenesulfonic acid and toluenesulfonic acid, metal salts by reaction with alkali metals such as sodium and potassium, salts with ammonium ions and the like.

또한, 본 발명의 약제 조성물은 상기 화학식 1로 표시되는 화합물 또는 약제학적으로 허용 가능한 이들의 염에 통상의 무독성 약제학적으로 허용 가능한 담체, 보강제 및 부형제 등을 첨가하여 약제학적 분야에서 통상적인 제제 예를 들면 정제, 캅셀제, 트로키제, 액제, 현탁제 등의 경구 투여용 제제 또는 비경구 투여용 제제로 제조하여, 여러 종류의 종양 예방과 치료에 사용될 수 있다. In addition, the pharmaceutical composition of the present invention is a conventional formulation in the pharmaceutical field by adding a conventional non-toxic pharmaceutically acceptable carrier, adjuvant and excipient to the compound represented by the formula (1) or pharmaceutically acceptable salts thereof For example, it may be prepared by oral or parenteral administration such as tablets, capsules, troches, solutions, suspensions, and the like, and may be used for the prevention and treatment of various types of tumors.

본 발명의 약제 조성물에 사용될 수 있는 부형제로는 감미제, 결합제, 용해제, 용해보조제, 습윤제, 유화제, 등장화제, 흡착제, 붕해제, 산화방지제, 방부제, 활탁제, 충진제, 방향제 등이 포함될 수 있다. 예를 들면 락토스, 덱스트로스, 슈크로스, 만니톨, 솔비톨, 셀룰로오스, 글라이신, 실리카, 탈크, 스테아린산, 스 테린, 마그네슘 스테아린산염, 마그네슘 알루미늄 규산염, 녹말, 젤라틴, 트라가칸트 고무, 알지닌산, 소디움 알진산염, 메틸셀룰로오스, 소디움 카르복실메틸셀룰로오스, 아가, 물, 에탄올, 폴리에틸렌글리콜, 폴리비닐피롤리돈, 염화나트륨, 염화칼슘, 오렌지 엣센스, 딸기 엣센스, 바닐라 향 등을 들 수 있다. Excipients that may be used in the pharmaceutical compositions of the present invention may include sweeteners, binders, solubilizers, solubilizers, wetting agents, emulsifiers, isotonic agents, adsorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, fragrances and the like. For example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, stearin, magnesium stearate, magnesium aluminum silicate, starch, gelatin, tragacanth rubber, arginine acid, sodium Alginate, methyl cellulose, sodium carboxymethyl cellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor and the like.

또한, 본 발명에 따른 화학식 1로 표시되는 화합물의 인체에 대한 투여용량은 환자의 나이, 몸무게, 성별, 투여형태, 건강상태 및 질병정도에 따라 달라질 수 있으며, 몸무게가 70 kg인 성인환자를 기준으로 할 때 일반적으로 1일 0.01 mg 내지 5000 mg이며, 의사 또는 약사의 판단에 따라 일정 시간간격으로 1일 1회 내지 수회로 분할 투여할 수도 있다. In addition, the dosage of the compound represented by Formula 1 according to the present invention to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, based on an adult patient with a weight of 70 kg In general, 0.01 mg to 5000 mg per day, and may be dividedly administered once to several times a day at regular intervals according to the judgment of a doctor or pharmacist.

이상에서 설명한 바와 같은 본 발명은 다음의 실시예 및 실험예에 의거하여 더욱 상세히 설명하겠는 바, 본 발명이 이에 한정되는 것은 아니다. The present invention as described above will be described in more detail based on the following Examples and Experimental Examples, but the present invention is not limited thereto.

[실시예] 화합물의 합성Example Synthesis of Compound

실시예 1. 2-(N,N-디메틸)아미노에틸레닐옥시-3-페닐에티닐퀴녹살린의 합성 (화합물번호 1) Example 1.Synthesis of 2- ( N, N- dimethyl) aminoethylenyloxy-3-phenylethynylquinoxaline (Compound No. 1)

a) 2-클로로-3-페닐에티닐퀴녹살린의 합성a) Synthesis of 2-chloro-3-phenylethynylquinoxaline

상온에서 2,3-다이클로로퀴녹살린(3.33 g, 16.6 mmol)과 페닐아세틸린(1.83 mL, 16.7 mmol)을 아세토나이트라일(80 mL)에 녹인 후, 트라이에틸아민(20 mL), 팔 라듐(Ⅱ) 아세테이트(260 mg), 요오드화구리(I)(400 mg), 및 트라이페닐포스핀(360 mg)을 첨가하였다. 반응 혼합물을 60 ℃에서 2 시간 동안 교반한 뒤, 상온까지 식힌 다음 감압 농축하여 얻어진 잔류물에 물을 더하고, 다이클로로메탄으로 추출한 다음, 마그네슘 설페이트로 건조하고 감압 농축하였다. 얻어진 잔류물을 실리카겔 칼럼 상에서 크로마토그래피하였다. 헥산과 에틸아세테이트 혼합용매(3 : 1, v/v)로 용출해서 상기 표제화합물인 2-클로로-3-페닐에티닐퀴녹살린(2.71 g, 62%)을 얻었다. 2,3-dichloroquinoxaline (3.33 g, 16.6 mmol) and phenylacetyline (1.83 mL, 16.7 mmol) were dissolved in acetonitrile (80 mL) at room temperature, followed by triethylamine (20 mL) and palladium. (II) Acetate (260 mg), copper iodide (I) (400 mg), and triphenylphosphine (360 mg) were added. The reaction mixture was stirred at 60 ° C. for 2 hours, cooled to room temperature, concentrated under reduced pressure, water was added, extracted with dichloromethane, dried over magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on a silica gel column. Elution with a mixed solvent of hexane and ethyl acetate (3: 1, v / v) afforded the title compound 2-chloro-3-phenylethynylquinoxaline (2.71 g, 62%).

b) 2-(b) 2- ( N,N-N, N- 디메틸)아미노에틸레닐옥시-3-페닐에티닐퀴녹살린의 합성Synthesis of dimethyl) aminoethylenyloxy-3-phenylethynylquinoxaline

상온에서 N,N-디메틸에틸알코올(10 μL, 0.12 mmol)과 60% 수소화나트륨(6 mg, 0.15 mmol)을 테트라하이드로퓨란(2 mL)에서 20분간 교반한 뒤, 2-클로로-3-페닐에티닐퀴녹살린(30 mg, 0.097 mmol)을 첨가하였다. 같은 온도에서 10시간 동안 교반한 뒤 반응물을 감압 농축하여 얻어진 잔류물을 실리카겔 칼럼 상에서 크로마토그래피하였다. 헥산과 에틸아세테이트 혼합용매(3:1, v/v)로 용출해서 상기 표제화합물(화합물번호 1)인 2-(N,N-디메틸)아미노에틸레닐옥시-3-페닐에티닐퀴녹살린(24 mg, 72%)을 얻었다.At room temperature, N, N- dimethylethyl alcohol (10 μL, 0.12 mmol) and 60% sodium hydride (6 mg, 0.15 mmol) were stirred in tetrahydrofuran (2 mL) for 20 minutes, followed by 2-chloro-3-phenyl. Ethinylquinoxaline (30 mg, 0.097 mmol) was added. After stirring for 10 hours at the same temperature, the residue was concentrated under reduced pressure and the residue was chromatographed on a silica gel column. Elution with hexane and ethyl acetate mixed solvents (3: 1, v / v) yielded 2- ( N, N- dimethyl) aminoethylenyloxy-3-phenylethynylquinoxaline (24) as the title compound (Compound No. 1). mg, 72%).

1H NMR(500 MHz, CDCl3) δ 5.66(s, 2H), 7.39-7.46(m, 6H), 7.60-7.67(m, 5H), 8.18(m, 1H), 8.98(m, 1H); MS(ESI) m/z 338([M+H]+). 1 H NMR (500 MHz, CDCl 3 ) δ 5.66 (s, 2H), 7.39-7.46 (m, 6H), 7.60-7.67 (m, 5H), 8.18 (m, 1H), 8.98 (m, 1H); MS (ESI) m / z 338 ([M + H] + ).

상기 실시예에 따른 제조방법으로 합성된 화합물들의 구조와 분석 데이타를 다음 표 1에 정리하여 나타내었다.The structure and analysis data of the compounds synthesized by the preparation method according to the above embodiment are shown in Table 1 below.

1H NMR 스펙트럼은 Bruker Avance 500 MHz에 기록되었고, 화학적 시프트(δ)는 내부 표준으로서 트리메틸실란(TMS)과 관계있는 ppm으로 기록되었다. 모든 표본은 다른 방법으로 명시되지 않았다면, DMSO-d 6 및 CDCl3에서 용해시켰다. MS 데이터는 Waters사의 Mass 모델에서 기록되었다. 1 H NMR spectra were recorded at Bruker Avance 500 MHz and chemical shifts ( δ ) were recorded in ppm relative to trimethylsilane (TMS) as an internal standard. All samples were dissolved in DMSO- d 6 and CDCl 3 unless otherwise specified. MS data were recorded in a Mass model from Waters.

Figure 112007068645505-pat00004
Figure 112007068645505-pat00004

Figure 112007068645505-pat00005
Figure 112007068645505-pat00005

Figure 112007068645505-pat00006
Figure 112007068645505-pat00006

Figure 112007068645505-pat00007
Figure 112007068645505-pat00007

Figure 112007068645505-pat00008
Figure 112007068645505-pat00008

Figure 112007068645505-pat00009
Figure 112007068645505-pat00009

[[ 실험예Experimental Example ] 약리활성 실험Pharmacological activity experiment

또한, 본 발명에 따른 상기 화학식 1로 표시되는 신규 화합물들의 약리 활성을 다음의 실험예의 방법으로 실험하였다.In addition, the pharmacological activity of the novel compounds represented by Formula 1 according to the present invention was tested by the method of the following experimental example.

실험예 1. 암세포 증식억제효과 실험Experimental Example 1. Experiment of cancer cell proliferation inhibitory effect

비소폐암세포인 A549와 Wnt2 플라스미드를 영구 발현시킨 A549/Wnt2 세포를 96-well 플레이트(Falcon)에 각 well당 5000개로 분주하고, 24시간 배양기(CO2 gas 5%, 37℃)에서 배양하였다. 세포는 10% FBS가 들어간 DMEM(Dulbecco's Modified Eagle Medium, Gibco)에서 배양하였다. 24시간 후에 배지를 걷어내고 시험약물이 들어간 배지(10% FBS, DMEM)로 갈아주고 48시간 배양하였다. 배지를 걷어내고 well당 무혈청 DMEM 80 uL와 MTS 용액 (CellTiter 96 non-radioactive cell proliferation assay kit - Promega, Madison, WI, USA) 20 uL를 첨가해주었다. 플레이트를 CO2 배양기에서 90분간 발색 반응시키고 마이크로 플레이트 판독기를 이용하여 490 nm에서의 흡광도 값을 측정하였다. 각 시험약물에 대한 세포 증식 억제 효과를 하기 수학식 1의 수식으로 계산하였으며, 그 결과는 하기 표 2에 나타내었다.A549 / Wnt2 cells permanently expressing A549 and Wnt2 plasmids, which are non-pulmonary cancer cells, were dispensed in 5000-well plates in 96-well plates (Falcon) and incubated in a 24 hour incubator (5% CO 2 gas, 37 ° C). Cells were cultured in Dulbecco's Modified Eagle Medium (Gibco) with 10% FBS. After 24 hours, the medium was removed, changed to a medium containing test drug (10% FBS, DMEM), and incubated for 48 hours. The media was removed and 80 uL of serum free DMEM and 20 uL of MTS solution (CellTiter 96 non-radioactive cell proliferation assay kit-Promega, Madison, WI, USA) were added per well. The plate was color reacted for 90 minutes in a CO 2 incubator and the absorbance value at 490 nm was measured using a micro plate reader. The effect of inhibiting cell proliferation for each test drug was calculated by the formula of Equation 1 below, and the results are shown in Table 2 below.

Figure 112007068645505-pat00010
Figure 112007068645505-pat00010

이때 대조군은 비소폐암세포에 0.1% DMSO만을 첨가한 것이고, 배양액은 0.1% DMSO를 첨가한 10% FBS DMEM을 일컫는다. 약물은 최종농도를 세포에 처리시 DMSO 0.1%를 첨가하도록 DMSO에 녹여 비소폐암세포에 처리하였다. At this time, the control group was added with only 0.1% DMSO to non-pulmonary cancer cells, and the culture medium refers to 10% FBS DMEM to which 0.1% DMSO was added. The drug was dissolved in DMSO to treat non-pulmonary cancer cells so that the final concentration was added to 0.1% DMSO when the cells were treated.

Figure 112007068645505-pat00011
Figure 112007068645505-pat00011

실험예 2. WNT 경로 (β-catenin binding) 억제 효과 실험Experimental Example 2. Experimental effect of inhibiting the WNT pathway (β-catenin binding)

Wnt2를 영구 발현시킨 A549/wnt2 세포를 24-well 플레이트에, well당 10×104개로 분주하고 24시간동안 배양기(CO2 gas, 37℃)에서 배양하였다. 세포는 10% FBS가 들어간 DMEM(Dulbecco's Modified Eagle Medium, Gibco)에서 배양하였다. 24시간 후에는 트랜스펙션 키트(TransFast Transfection Reagent, promega, Madison, WI, USA)를 이용하여, 각 well당 Topflash 플라스미드 1 ug, 그리고 형질감염 효율을 확인하기 위한 pCMV β-gal 0.5 ug을 동시에 형질 감염시켰다. 24시간 후에 배지를 걷어내고 시험약물이 들어간 배지(10% FBS, DMEM)로 갈아주고 48시간 배양하였다. 48시간 후에 배지를 걷어내고 차가운 인산염 완충 생리식염수(PBS)로 씻어주고, well당 수동 세포용해 완충액(1×passive lysis buffer, Promega 사) 100 uL를 첨가한 후 15분간 세포를 용해시켰다. 그리고 세포 용해액 20 uL를 100 uL의 루시퍼라제 분석 시약(Luciferase assay system, promega 사)에 섞어주고 발광분석기(Hidex, Finland)로 10초 동안 루시퍼라제 활성을 측정하였다. β-갈락토시다제 활성은 96-well 플레이트에 β-gal 분석 완충액(100×Mg2 + 용액, 인산나트륨 (0.1M. pH 7.5) 그리고 1×ONPG, Sigma) 180 uL에 20 uL의 세포 용해액을 섞어주고 약 40분간 발색 반응시킨 뒤 마이크로 플레이트 판독기에서 520 nm에서의 흡광도 값을 측정하였다. Wnt 경로 활성도는 β-갈락토시다제 활성 값으로 루시퍼라제 활성 값을 보정해서 측정하였다.A549 / wnt2 cells permanently expressing Wnt2 were dispensed into 24-well plates at 10 × 10 4 per well and incubated for 24 hours (CO 2 gas, 37 ° C.). Cells were cultured in Dulbecco's Modified Eagle Medium (Gibco) with 10% FBS. After 24 hours, transfection kit (TransFast Transfection Reagent, promega, Madison, WI, USA) was used to simultaneously transduce 1 ug of Topflash plasmid per well and 0.5 ug of pCMV β-gal to confirm transfection efficiency. Infected. After 24 hours, the medium was removed, changed to a medium containing test drug (10% FBS, DMEM), and incubated for 48 hours. After 48 hours, the medium was removed, washed with cold phosphate buffered saline (PBS), and 100 μL of manual lysis buffer (1 × passive lysis buffer, Promega) was added per well, and the cells were lysed for 15 minutes. 20 uL of cell lysate was mixed with 100 uL of luciferase assay system (promega), and luciferase activity was measured for 10 seconds with a luminescence analyzer (Hidex, Finland). β- galactosidase activity of 96-well plates in β-gal assay buffer (100 × Mg 2 + solution, sodium phosphate (0.1M. pH 7.5) and 1 × ONPG, Sigma) was dissolved in 20 uL cells in 180 uL The solution was mixed and subjected to color reaction for about 40 minutes, and the absorbance value at 520 nm was measured in a microplate reader. Wnt pathway activity was determined by calibrating luciferase activity values with β-galactosidase activity values.

Fop flush는 Wnt 경로의 위양성(false positive) 결과를 얻는 것을 방지하기 위한 것으로 일정 수준 값이 기본적으로 나오는 것을 확인하였다. Top flush 결과는 Wnt 경로의 활성을 측정하기 위한 것으로 Wnt 경로 저해정도는 하기 수학식 2와 같은 수식으로 계산하였으며, 그 결과는 첨부도면 도 1로서 나타내었다.Fop flush is to prevent the false positive result of the Wnt path. Top flush results are for measuring the activity of the Wnt pathway and the degree of inhibition of the Wnt pathway was calculated by the following equation (2), and the results are shown in the accompanying drawings.

Figure 112007068645505-pat00012
Figure 112007068645505-pat00012

[제제화예][Formulation example]

한편, 본 발명에 따른 상기 화학식 1로 표시되는 신규 화합물은 목적에 따라 여러 형태로 제제화가 가능하다. 다음은 본 발명에 따른 상기 화학식 1로 표시되는 화합물을 활성성분으로 함유시킨 몇몇 제제화 방법을 예시한 것으로 본 발명이 이에 한정되는 것은 아니다. On the other hand, the novel compound represented by Formula 1 according to the present invention can be formulated in various forms according to the purpose. The following illustrates some formulation methods containing the compound represented by Formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.

제제 1. 정제(직접 가압) Formulation 1.Tablet (Direct Press)

활성성분 5.0 mg을 체로 친 후, 락토스 14.1 mg, 크로스포비돈 USNF 0.8 mg 및 마그네슘 스테아레이트 0.1 mg을 혼합하고 가압하여 정제로 만들었다. After sifting 5.0 mg of the active ingredient, 14.1 mg of lactose, 0.8 mg of crospovidone USNF and 0.1 mg of magnesium stearate were mixed and pressurized into tablets.

제제 2. 정제(습식 조립) Formulation 2. Tablet (Wet Granulation)

활성성분 5.0 mg을 체로 친 후, 락토스 16.0 mg과 녹말 4.0 mg을 섞었다. 폴리솔베이트 80 0.3 mg을 순수한 물에 녹인 후 이 용액의 적당량을 첨가한 다음, 미립화하였다. 건조 후에 미립을 체질한 후 콜로이달 실리콘 디옥사이드 2.7 mg 및 마그네슘 스테아레이트 2.0 mg과 섞었다. 미립을 가압하여 정제로 만들었다. After sifting 5.0 mg of the active ingredient, 16.0 mg of lactose and 4.0 mg of starch were mixed. 0.3 mg of polysorbate 80 was dissolved in pure water and then an appropriate amount of this solution was added and then atomized. After drying, the fine particles were sieved and mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The granules were pressed into tablets.

제제 3. 분말과 캡슐제 Formulation 3. Powders and Capsules

활성성분 5.0 mg을 체로 친 후에, 락토스 14.8 mg, 폴리비닐 피롤리돈 10.0 mg, 마그네슘 스테아레이트 0.2 mg와 함께 섞었다. 혼합물을 적당한 장치를 사용하여 단단한 No. 5 젤라틴 캡슐에 채웠다. After sifting 5.0 mg of active ingredient, it was mixed with 14.8 mg of lactose, 10.0 mg of polyvinyl pyrrolidone, and 0.2 mg of magnesium stearate. No. solid the mixture using a suitable device. Filled in 5 gelatin capsules.

제제 4. 주사제 Formulation 4. Injection

활성성분 100 mg을 함유시키고, 그 밖에도 만니톨 180 mg, Na2HPO4·12H2O 26 mg 및 증류수 2974 mg를 함유시켜 주사제를 제조하였다. Injectables were prepared by containing 100 mg of the active ingredient, followed by the addition of 180 mg of mannitol, 26 mg of Na 2 HPO 4 .12H 2 O and 2974 mg of distilled water.

이상의 실험예를 통하여 확인된 바와 같이, 본 발명에 따른 신규 화합물들은 우수한 항암효과를 보여주고 있으므로, 신규 항암제 개발에 유용하다. As confirmed through the above experimental examples, the novel compounds according to the present invention show excellent anticancer effects, and thus are useful for developing new anticancer agents.

도 1은 본 발명의 화합물에 대한 Wnt 유전자 발현 억제율을 나타낸 그래프이다.1 is a graph showing the Wnt gene expression inhibition rate for the compound of the present invention.

Claims (5)

하기 화학식 1로 표시되는 2-치환아미노알킬레닐옥시-3-치환페닐에티닐퀴녹살린 유도체 또는 그 약제학적으로 허용 가능한 염 :2-substituted aminoalkylenyloxy-3-substituted phenylethynylquinoxaline derivatives represented by the following formula (1) or a pharmaceutically acceptable salt thereof: [화학식 1][Formula 1]
Figure 112008074413102-pat00013
Figure 112008074413102-pat00013
 상기 화학식 1에서, In Chemical Formula 1, Y 및 Z는 각각 수소원자, 할로겐원자, C1-C8 알킬기, 또는 C1-C8 알콕시기를 나타내고; Y and Z each represent a hydrogen atom, a halogen atom, a C 1 -C 8 alkyl group, or a C 1 -C 8 alkoxy group; R은 -X-NR1R2, 또는 -X-Het.를 나타내고; R represents -X-NR 1 R 2 , or -X-Het .; X는 C1-C8 알킬렌기, 또는 C2-C8 알킬렌옥시알킬렌기를 나타내고; X represents a C 1 -C 8 alkylene group or a C 2 -C 8 alkyleneoxyalkylene group; 상기한 R1 및 R2는 각각 수소원자, 또는 C1-C8 알킬기이거나, 또는 R1 및 R2가 결합된 N과 함께 또는 추가로 N 또는 O 중에서 선택된 또다른 헤테로원자를 포함시켜 헤테로원자가 1 내지 3개 포함된 5각형 내지 7각형의 지방족 헤테로고리를 형성할 수 있고, 또한 지방족 헤테로고리 내의 질소원자는 수소원자 또는 C1-C8 알킬기로 치환될 수 있고; R 1 and R 2 are each a hydrogen atom, or a C 1 -C 8 alkyl group, or together with N to which R 1 and R 2 are bonded or including another heteroatom selected from N or O One to three pentagonal to five-membered aliphatic heterocycles may be formed, and also nitrogen atoms in the aliphatic heterocycles may be substituted with hydrogen atoms or C 1 -C 8 alkyl groups; Het.는 N 또는 O의 헤테로원자가 1 내지 3개 포함된 5각형 내지 7각형의 지방족 또는 방향족 헤테로고리를 나타내고, 또한 지방족 헤테로고리 내의 질소원자는 수소원자 또는 C1-C8 알킬기로 치환될 수 있다.Het. Represents a pentagonal to pentagonal aliphatic or aromatic heterocycle containing 1 to 3 heteroatoms of N or O, and the nitrogen atom in the aliphatic heterocycle may be substituted with a hydrogen atom or a C 1 -C 8 alkyl group. . 제 1 항에 있어서,The method of claim 1, Y 및 Z는 각각 수소원자, 할로겐원자, C1-C6 알킬기, 또는 C1-C6 알콕시기를 나타내고; Y and Z each represent a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group, or a C 1 -C 6 alkoxy group; R은 -X-NR1R2, 또는 -X-Het.를 나타내고; R represents -X-NR 1 R 2 , or -X-Het .; X는 C1-C6 알킬렌기, 또는 C2-C6 알킬렌옥시알킬렌기를 나타내고; X represents a C 1 -C 6 alkylene group or a C 2 -C 6 alkyleneoxyalkylene group; R1 및 R2는 각각 수소원자, 또는 C1-C8 알킬기이거나, 또는 R1 및 R2가 결합된 N과 함께 또는 또다른 헤테로원자를 추가로 포함하여 피롤리딘, 피페리딘, 몰포린, 및 피페라진 중에서 선택된 지방족 헤테로고리를 형성할 수 있고; R 1 and R 2 are each a hydrogen atom or a C 1 -C 8 alkyl group, or together with N to which R 1 and R 2 are bonded or further comprising another heteroatom, such as pyrrolidine, piperidine, mole An aliphatic heterocycle selected from porin and piperazine; Het.는 피롤리딘, 피페리딘, 몰포린, 피페라진, 피롤, 피라졸, 이미다졸, 트라이아졸, 옥사졸, 아이소옥사졸, 옥사다이아졸, 피리딘, 피리다진, 피리미딘, 및 피라진 중에서 선택된 지방족 또는 방향족 헤테로고리를 나타내고; Het. Is selected from pyrrolidine, piperidine, morpholine, piperazine, pyrrole, pyrazole, imidazole, triazole, oxazole, isoxazole, oxadiazole, pyridine, pyridazine, pyrimidine, and pyrazine Represent selected aliphatic or aromatic heterocycles; 상기한 지방족 헤테로고리를 구성하는 질소원자는 수소원자 또는 C1-C6 알킬기로 치환될 수 있는 것임을 특징으로 하는 화합물.The nitrogen atom constituting the aliphatic heterocycle can be substituted with a hydrogen atom or a C 1 -C 6 alkyl group. 제 1 항에 있어서,The method of claim 1, Y 및 Z는 각각 수소, 염소, 불소, 메틸, 에틸, n-프로필, i-프로필, n-부틸, i-부틸, t-부틸, 메톡시, 에톡시, n-프로폭시, i-프로폭시, n-부톡시, i-부톡시, 또는 t-부톡시를 나타내고; Y and Z are hydrogen, chlorine, fluorine, methyl, ethyl, n -propyl, i -propyl, n -butyl, i -butyl, t -butyl, methoxy, ethoxy, n -propoxy, i -propoxy , n -butoxy, i -butoxy, or t -butoxy; R은 다이메틸아미노에틸렌, 다이에틸아미노에틸렌, 다이메틸아미노프로필렌, 다이에틸아미노프로필렌, 다이메틸아미노아이소프로필렌, 다이에틸아미노아이소프로필렌, 다이메틸아미노에틸렌옥시에틸렌, 다이에틸아미노에틸렌옥시에틸렌, 다이메틸아미노에틸렌옥시프로필렌, 다이에틸아미노에틸렌옥시프로필렌, 다이메틸아미노에틸렌옥시아이소프로필렌, 다이에틸아미노에틸렌옥시아이소프로필렌, 피롤리딜에틸렌, 피롤리딜프로필렌, 피롤리딜아이소프로필렌, 피페리딜에틸렌, 피페리딜프로필렌, 피페리딜아이소프로필렌, 몰포릴에틸렌, 몰포릴프로필렌, 몰포릴아이소프로필렌, 피롤일에틸렌, 피롤일프로필렌, 피롤일아이소프로필렌, 피리딜에틸렌, 피리딜프로필렌, 또는 피리딜아이소프로필렌을 나타내고;R is dimethylaminoethylene, diethylaminoethylene, dimethylaminopropylene, diethylaminopropylene, dimethylaminoisopropylene, diethylaminoisopropylene, dimethylaminoethyleneoxyethylene, diethylaminoethyleneoxyethylene, dimethyl Aminoethyleneoxypropylene, diethylaminoethyleneoxypropylene, dimethylaminoethyleneoxyisopropylene, diethylaminoethyleneoxyisopropylene, pyrrolidylethylene, pyrrolidylpropylene, pyrrolidylisopropylene, piperidylethylene, blood Ferridylpropylene, piperidylisopropylene, morpholinyl ethylene, morpholyl propylene, morpholyl isopropylene, pyrrolylethylene, pyrroleyl propylene, pyrrolyl isopropylene, pyridylethylene, pyridyl propylene, or pyridyl isopropylene Represent; 상기한 피롤리딜, 피페리딜 및 몰포릴 중에서 선택된 지방족 헤테로고리를 구성하는 질소원자는 수소, 메틸, 에틸, n-프로필, i-프로필, n-부틸, i-부틸 및 t-부틸 중에서 선택된 치환기로 치환될 수 있는 것임을 특징으로 하는 화합물. The nitrogen atom constituting the aliphatic heterocycle selected from pyrrolidyl, piperidyl and morphoryl is a substituent selected from hydrogen, methyl, ethyl, n -propyl, i -propyl, n -butyl, i -butyl and t -butyl Compound which can be substituted by. 하기 화학식 2로 표시되는 2,3-다이클로로퀴녹살린과 화학식 3으로 표시되는 에티닐기 공여시약을 소노가쉬라 반응(Sonogashira reaction)시켜 하기 화학식 4로 표시되는 화합물을 제조하는 단계; 및Preparing a compound represented by Chemical Formula 4 by Sonogashira reaction of 2,3-dichloroquinoxaline represented by Chemical Formula 2 with an ethynyl group donating reagent represented by Chemical Formula 3; And
Figure 112007068645505-pat00014
Figure 112007068645505-pat00014
 상기 반응식에서, Y, Z는 각각 상기 청구항 1에서 정의한 바와 같고,In the above reaction scheme, Y and Z are as defined in claim 1, respectively. 하기 화학식 4로 표시되는 에티닐 화합물을 하기 화학식 5로 표시되는 알콜 화합물과 염기의 존재 하에서 반응시켜 하기 화학식 1로 표시되는 화합물을 제조하는 단계; Reacting an ethynyl compound represented by Formula 4 with an alcohol compound represented by Formula 5 in the presence of a base to prepare a compound represented by Formula 1;
Figure 112007068645505-pat00015
Figure 112007068645505-pat00015
 상기 반응식에서, Y, Z, R은 각각 상기 청구항 1에서 정의한 바와 같고,In the scheme, Y, Z, R are as defined in claim 1, respectively, 를 포함하여 이루어지는 것을 특징으로 하는 2-치환아미노알킬레닐옥시-3-치환페닐에티닐퀴녹살린 유도체의 제조방법.Method for producing a 2-substituted aminoalkylenyloxy-3-substituted phenylethynylquinoxaline derivative comprising a. 하기 화학식 1로 표시되는 2-치환아미노알킬레닐옥시-3-치환페닐에티닐 퀴녹살린 유도체 또는 그 약제학적으로 허용 가능한 염을 함유하여 이루어진 것을 특징으로 하는 암 치료 및 예방용 약제조성물 : 2-substituted aminoalkylenyloxy-3-substituted phenylethynyl quinoxaline derivative represented by the following formula (1) or a pharmaceutical composition for the treatment and prevention of cancer, characterized in that it comprises a pharmaceutically acceptable salt thereof: [화학식 1][Formula 1]
Figure 112007068645505-pat00016
Figure 112007068645505-pat00016
 상기 화학식 1에서, Y, Z, R은 각각 상기 청구항 1에서 정의한 바와 같다.In Formula 1, Y, Z, R are as defined in claim 1, respectively.
KR1020070096340A 2007-09-21 2007-09-21 2-sustituted aminoalkylenyloxy-3-substitutedphenylethynyl quinoxaline derivatives KR100889839B1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
KR1020070096340A KR100889839B1 (en) 2007-09-21 2007-09-21 2-sustituted aminoalkylenyloxy-3-substitutedphenylethynyl quinoxaline derivatives

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
KR1020070096340A KR100889839B1 (en) 2007-09-21 2007-09-21 2-sustituted aminoalkylenyloxy-3-substitutedphenylethynyl quinoxaline derivatives

Publications (1)

Publication Number Publication Date
KR100889839B1 true KR100889839B1 (en) 2009-03-20

Family

ID=40698538

Family Applications (1)

Application Number Title Priority Date Filing Date
KR1020070096340A KR100889839B1 (en) 2007-09-21 2007-09-21 2-sustituted aminoalkylenyloxy-3-substitutedphenylethynyl quinoxaline derivatives

Country Status (1)

Country Link
KR (1) KR100889839B1 (en)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05331065A (en) * 1991-12-20 1993-12-14 Asahi Chem Ind Co Ltd Agent for treatment of disease relating to serotonin nerve system
US5583227A (en) 1994-06-03 1996-12-10 Mochida Pharmaceutical Co. Ltd. Antiulcer compounds having a substituted alkynyl or quinoxaline nucleus and methods of making thereof
US20030207886A1 (en) 2000-03-17 2003-11-06 Pluecker Frank Preparation containing quinoxaline derivatives
US20050176717A1 (en) 2004-02-06 2005-08-11 Kim Kyoung S. Quinoxaline compounds and methods of using them

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05331065A (en) * 1991-12-20 1993-12-14 Asahi Chem Ind Co Ltd Agent for treatment of disease relating to serotonin nerve system
US5583227A (en) 1994-06-03 1996-12-10 Mochida Pharmaceutical Co. Ltd. Antiulcer compounds having a substituted alkynyl or quinoxaline nucleus and methods of making thereof
US20030207886A1 (en) 2000-03-17 2003-11-06 Pluecker Frank Preparation containing quinoxaline derivatives
US20050176717A1 (en) 2004-02-06 2005-08-11 Kim Kyoung S. Quinoxaline compounds and methods of using them

Similar Documents

Publication Publication Date Title
KR102075886B1 (en) Novel pyrazolo [3,4-d] pyrimidine compounds or salts thereof
KR101730933B1 (en) 5-alkynyl-pyrimidines
CN105315285B (en) 2,4 2 substitution 7H pyrrolo-es [2,3 d] pyrimidine derivatives, its preparation method and purposes pharmaceutically
KR20190092542A (en) Amine-Substituted Heterocyclic Compounds as EHMT2 Inhibitors and Methods of Use thereof
WO2009077956A2 (en) HETEROCYCLIC INHIBITORS OF AN Hh-SIGNAL CASCADE, MEDICINAL COMPOSITIONS BASED THEREON AND METHODS FOR TREATING DISEASES CAUSED BY THE ABERRANT ACTIVITY OF AN Hh-SIGNAL SYSTEM
KR20130044382A (en) Compounds and therapeutic uses thereof
KR20080052630A (en) Raf inhibitor compounds and methods of use thereof
JP2012504659A (en) Carbazole compounds and therapeutic uses of the compounds
JP2021536428A (en) Replacement indole and how to use it
CN112771046B (en) Other substituted triazoloquinoxaline derivatives
US10501466B2 (en) WDR5 inhibitors and modulators
WO2020125759A1 (en) Compound as wnt signal pathway inhibitor and medical use thereof
AU2017368286B2 (en) 3-amino-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-ones as cyclin dependent kinase inhibitors
RU2641693C2 (en) 5-(pyridine-2-ylamino)-pyrasin-2-carbonitrile compounds and their therapeutic application
US20150306070A1 (en) Use of maleimide derivatives for preventing and treating leukemia
WO2020125513A1 (en) Macrocyclic compound as cdk inhibitor, preparation method therefor, and use thereof in medicine
WO2021083328A1 (en) Polysubstituted isoindoline compounds, preparation method therefor, pharmaceutical composition thereof and use thereof
KR20220122597A (en) pharmaceutical compound
KR101035709B1 (en) 2-Sustitutedaminoalkylenyloxy-3-substitutedphenylethynyl-6-aminoquinoxaline derivatives
JPWO2019189555A1 (en) Heterocyclic compound
KR100889839B1 (en) 2-sustituted aminoalkylenyloxy-3-substitutedphenylethynyl quinoxaline derivatives
JP5337717B2 (en) Isoquinolinopyrrolopyridinone active as a kinase inhibitor
US9643968B2 (en) Fused acridine derivative and pharmaceutical composition, preparation method and use thereof
CN115843296B (en) CDK9 inhibitors and uses thereof
KR100888468B1 (en) 1'-Alkylpiperidine-4'-spiro-2-6-amido-2H-benzopyran derivatives having anticancer activity

Legal Events

Date Code Title Description
A201 Request for examination
E902 Notification of reason for refusal
E701 Decision to grant or registration of patent right
GRNT Written decision to grant
FPAY Annual fee payment

Payment date: 20120309

Year of fee payment: 4

FPAY Annual fee payment

Payment date: 20130111

Year of fee payment: 5

LAPS Lapse due to unpaid annual fee