KR20230147351A - Quinoxaline carboxamide derivatives and pharmaceutical composition for prevention or treatment of glioblastoma containing the same as an active ingredient - Google Patents

Quinoxaline carboxamide derivatives and pharmaceutical composition for prevention or treatment of glioblastoma containing the same as an active ingredient Download PDF

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KR20230147351A
KR20230147351A KR1020220046259A KR20220046259A KR20230147351A KR 20230147351 A KR20230147351 A KR 20230147351A KR 1020220046259 A KR1020220046259 A KR 1020220046259A KR 20220046259 A KR20220046259 A KR 20220046259A KR 20230147351 A KR20230147351 A KR 20230147351A
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pyrrolidin
carboxamide
quinoxalin
biphenyl
ethoxy
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전문국
송진숙
김성환
이주연
채종학
김은혜
안서현
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한국화학연구원
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Abstract

본 발명은 하기 화학식 1로 표시되는 퀴녹살린 카르복스아마이드 유도체, 이의 이성질체 또는 이의 약학적으로 허용가능한 염을 제공한다.
본 발명에 따른 화학식 1의 퀴녹살린 카르복스아마이드 유도체는 우수한 교모세포종 성장 저해 활성 효과를 가지므로, 교모세포종의 예방 또는 치료에 유용하게 사용될 수 있다.
또한 본 발명에 따른 퀴녹살린 카르복스아마이드 유도체, 이의 이성질체 또는 이의 약학적으로 허용가능한 염은 화학 항암제, 면역 항암제 및 표적 치료제 등의 화학요법 또는 방사선 요법과의 병용을 통해 교모세포종의 예방 또는 치료에 유용하게 사용될 수 있다.
[화학식 1]
The present invention provides a quinoxaline carboxamide derivative represented by the following formula (1), an isomer thereof, or a pharmaceutically acceptable salt thereof.
The quinoxaline carboxamide derivative of Formula 1 according to the present invention has excellent glioblastoma growth inhibitory activity and can be usefully used in the prevention or treatment of glioblastoma.
In addition, quinoxaline carboxamide derivatives, isomers thereof, or pharmaceutically acceptable salts thereof according to the present invention can be used in combination with chemotherapy or radiation therapy such as chemical anticancer agents, immune anticancer agents, and targeted treatments for the prevention or treatment of glioblastoma. It can be useful.
[Formula 1]

Description

퀴녹살린 카르복스아마이드 유도체 및 이를 유효성분으로 포함하는 교모세포종의 예방 또는 치료용 약학적 조성물{Quinoxaline carboxamide derivatives and pharmaceutical composition for prevention or treatment of glioblastoma containing the same as an active ingredient}Quinoxaline carboxamide derivatives and pharmaceutical composition for prevention or treatment of glioblastoma containing the same as an active ingredient {Quinoxaline carboxamide derivatives and pharmaceutical composition for prevention or treatment of glioblastoma containing the same as an active ingredient}

본 발명은 퀴녹살린 카르복스아마이드 유도체, 이의 이성질체 또는 이의 약학적으로 허용가능한 염, 이의 제조방법 및 이를 유효성분으로 함유하는 교모세포종의 예방 또는 치료용 약학적 조성물에 관한 것이다.The present invention relates to a quinoxaline carboxamide derivative, an isomer thereof or a pharmaceutically acceptable salt thereof, a method for producing the same, and a pharmaceutical composition for the prevention or treatment of glioblastoma containing the same as an active ingredient.

신경교종(glioma)은 원발성 뇌종양을 일컫는 일반적인 용어로서, 기원 세포에 따라 성상세포종(astrocytoma), 역형성별아교세포종(anaplastic astrocytoma), 및 교모세포종(glioblastoma)과 같은 성상세포 종양(astrocytic tumor), 뇌실막종(ependymoma), 희돌기교종(oligodendroglioma), 교모 혼성종(mixed glioma) 등으로 분류된다. 신경교종은 중추신경계에서 가장 흔히 발생하는 종양으로서, 원발성 악성 뇌종양의 거의 80%를 차지한다. 교모세포종(또는 다형아교모세포종(glioblastoma multiforme, GBM))은 원발성 성상세포 종양 중 가장 악성이면서 흔한 유형으로서, 성인 뇌종양의 60% 이상을 차지한다. 교모세포종은 십만명당 3.2명의 발병률을 보이고, 예후가 매우 좋지 않은 치명적인 질환으로서 다양한 치료법에도 불구하고 환자들은 보통 진단 이후 대략 14-15개월 중간값 생존기간을 보여준다. 세계보건기구는 신경교종을 등급 I에서 IV로 분류하는데 교모세포종은 가장 악성으로서 등급 IV로 지정되어 있다 (ACS Chemical Neuroscience 2020 11 2962-2977).Glioma is a general term for a primary brain tumor. Depending on the cell of origin, it can be an astrocytic tumor such as astrocytoma, anaplastic astrocytoma, and glioblastoma, or ependymal tumor. It is classified into ependymoma, oligodendroglioma, and mixed glioma. Glioma is the most common tumor in the central nervous system, accounting for nearly 80% of primary malignant brain tumors. Glioblastoma (or glioblastoma multiforme, GBM) is the most malignant and common type of primary astrocytic tumor, accounting for more than 60% of adult brain tumors. Glioblastoma is a fatal disease with an incidence of 3.2 cases per 100,000 people and a very poor prognosis. Despite various treatments, patients usually have a median survival time of approximately 14-15 months after diagnosis. The World Health Organization classifies gliomas from grades I to IV, with glioblastoma being the most malignant and designated grade IV (ACS Chemical Neuroscience 2020 11 2962-2977).

교모세포종에 대한 표준적인 치료는 수술을 통한 절제, 방사선요법, 및 화학요법으로 이루어진다. 수술을 통한 절제 및 방사선요법/테모졸로마이드(temozolomide, TMZ)를 이용한 화학요법의 병행은 무진행 생존기간과 전체 생존기간을 다소 늘려줌에도 불구하고 내성으로 인해 재발이 일어나며 재발시 치료 옵션이 제한적이다 (Frontiers in Oncology 2019 9 963). 최근에 종양 치료 전기장(tumor treating fields, Optune)이 신규 진단 환자와 재발환자에 대해, 그리고 베바시주맙(bevacizumab, Avastin)이 재발환자에 대해 미국 FDA에 의해 승인되었으나, 교모세포종에 대한 미충족 의학적 수요는 여전하며 치료제 개발을 위한 노력들이 계속적으로 진행되고 있다 (BMC Biomedical Engineering 2021 3 7). Standard treatment for glioblastoma consists of surgical resection, radiation therapy, and chemotherapy. Although the combination of surgical resection and radiotherapy/chemotherapy using temozolomide (TMZ) slightly increases progression-free survival and overall survival, recurrence occurs due to resistance, and treatment options are limited in case of recurrence. (Frontiers in Oncology 2019 9 963). Recently, tumor treating fields (Optune) have been approved by the US FDA for newly diagnosed and relapsed patients, and bevacizumab (Avastin) has been approved by the US FDA for relapsed patients, but there is an unmet medical need for glioblastoma. remains the same, and efforts to develop treatments are continuing (BMC Biomedical Engineering 2021 3 7).

이에, 본 발명자들은 효능과 안전성이 보장되는 교모세포종의 예방 또는 치료용 약학적 조성물 개발을 위한 노력을 통해, 교모세포종 암세포 성장 억제 활성을 가지는 신규한 퀴녹살린 카르복스아마이드 유도체 및 이의 약학적으로 허용가능한 염을 제조하고, 그를 유효성분으로 함유하는 교모세포종의 예방 또는 치료용 약학적 조성물을 제공함으로써, 본 발명을 완성하였다.Accordingly, through efforts to develop a pharmaceutical composition for the prevention or treatment of glioblastoma with guaranteed efficacy and safety, the present inventors have developed a novel quinoxaline carboxamide derivative with glioblastoma cancer cell growth inhibitory activity and a pharmaceutically acceptable derivative thereof. The present invention was completed by preparing a possible salt and providing a pharmaceutical composition for preventing or treating glioblastoma containing it as an active ingredient.

본 발명의 목적은 퀴녹살린 카르복스아마이드 유도체 또는 이의 약학적으로 허용가능한 염을 제공하는 데 있다.The object of the present invention is to provide quinoxaline carboxamide derivatives or pharmaceutically acceptable salts thereof.

본 발명의 다른 목적은 상기 퀴녹살린 카르복스아마이드 또는 이의 약학적으로 허용가능한 염의 제조방법을 제공하는 데 있다.Another object of the present invention is to provide a method for producing the quinoxaline carboxamide or a pharmaceutically acceptable salt thereof.

본 발명의 또 다른 목적은 상기 퀴녹살린 카르복스아마이드 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 교모세포종의 예방 또는 치료용 약학적 조성물을 제공하는 데 있다.Another object of the present invention is to provide a pharmaceutical composition for preventing or treating glioblastoma containing the quinoxaline carboxamide or a pharmaceutically acceptable salt thereof as an active ingredient.

본 발명의 다른 목적은 상기 퀴녹살린 카르복스아마이드 또는 이의 약학적으로 허용가능한 염 및 항암 요법제를 포함하는 교모세포종의 예방 또는 치료용 약학적 조성물을 제공하는 데 있다.Another object of the present invention is to provide a pharmaceutical composition for preventing or treating glioblastoma, comprising the quinoxaline carboxamide or a pharmaceutically acceptable salt thereof and an anticancer therapeutic agent.

본 발명자들은 교모세포종 암세포 성장 억제 활성을 갖는 퀴녹살린 카르복스아마이드 유도체 화합물을 발견하고, 이를 교모세포종을 예방 또는 치료하는데 사용함으로써 본 발명을 완성하였다.The present inventors discovered a quinoxaline carboxamide derivative compound with glioblastoma cancer cell growth inhibitory activity and completed the present invention by using it to prevent or treat glioblastoma.

본 출원에서 사용한 용어는 단지 특정한 실시예를 설명하기 위해 사용된 것으로서 본 발명을 한정하려는 의도가 아니다. 단수의 표현은 문맥상 명백하게 다르게 뜻하지 않는 한, 복수의 표현을 포함한다. 본 출원에서, “포함하다” 또는 “가지다” 등의 용어는 명에서 상에 기재된 특징, 단계, 구조 또는 이들을 조합한 것이 존재함을 지정하려는 것이지, 하나 또는 그 이상의 다른 특징들이나 단계, 구조 또는 이들을 조합한 것들의 존재 또는 부가 가능성을 미리 배제하지 않는 것으로 이해되어야 한다.The terms used in this application are only used to describe specific embodiments and are not intended to limit the invention. Singular expressions include plural expressions unless the context clearly dictates otherwise. In this application, terms such as “comprise” or “have” are intended to designate the presence of the features, steps, structures, or combinations thereof described above in the name, but are intended to indicate the presence of one or more other features, steps, structures, or these. It should be understood that the existence or addition of combinations is not excluded in advance.

다르게 정의하지 않는 한, 기술적이거나 과학적인 용어를 포함해서 여기서 사용되는 모든 용어들은 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자에 의해 일반적으로 이해되는 것과 동일한 의미를 가지고 있다. 일반적으로 사용되는 사전에 정의되어 있는 것과 같은 용어들은 관련 기술의 문맥상 가지는 의미와 일치하는 의미를 가지는 것으로 해석되어야 하며, 본 출원에서 명백하게 정의하지 않는 한, 이상적이거나 과도하게 형식적인 의미로 해석되지 않는다.Unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meaning as generally understood by a person of ordinary skill in the technical field to which the present invention pertains. Terms defined in commonly used dictionaries should be interpreted as having a meaning consistent with the meaning in the context of the related technology, and unless clearly defined in the present application, should not be interpreted in an ideal or excessively formal sense. No.

본 발명에서, "Cx-Cy"는 탄소수가 x개 내지 y개를 가짐을 의미하는 것이다.In the present invention, “Cx-Cy” means having x to y carbon atoms.

본 발명에서, "알킬"는 선형(또는 직쇄형, linear) 포화탄화수소기 또는 분지형(또는 측쇄형, branched) 포화탄화수소기를 의미하는 것으로, 메틸, 에틸, n-프로필, 이소프로필, n-부틸, sec-부틸, 이소부틸, tert-부틸, n-펜틸, n-헥실, n-헵틸 등을 포함한다.In the present invention, “alkyl” refers to a linear (or linear) saturated hydrocarbon group or a branched (or branched) saturated hydrocarbon group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl. , sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, etc.

본 발명에서, "할로겐 원자"는 주기율표에서 17족 원소를 의미하는 것으로, F, Cl, Br 및 I로 이루어진 군으로부터 선택되는 것이다.In the present invention, “halogen atom” refers to a group 17 element in the periodic table, and is selected from the group consisting of F, Cl, Br, and I.

본 발명에서 “할로알킬”은 알킬기의 말단의 CH3의 H 중 하나 이상이 할로겐 원자로 치환된 구조를 포함하는 것이다.In the present invention, “haloalkyl” includes a structure in which at least one H of CH 3 at the end of the alkyl group is substituted with a halogen atom.

퀴녹살린 유도체 화합물Quinoxaline derivative compounds

상기 목적을 달성하기 위하여, 본 발명은 하기 화학식 1로 표시되는 퀴녹살린 카르복스아마이드 유도체, 이의 이성질체 또는 이의 약학적으로 허용가능한 염을 제공한다.In order to achieve the above object, the present invention provides a quinoxaline carboxamide derivative represented by the following formula (1), an isomer thereof, or a pharmaceutically acceptable salt thereof.

[화학식 1][Formula 1]

상기 화학식 1에서,In Formula 1,

NR1R2는 또는 또는 이고, NR 1 R 2 is or or ego,

OR3는 또는 또는 이고;OR 3 is or or ego;

R4는 수소 원자, -O-C1-C6 알킬, C1-C6 알킬, 할로겐 원자, -CN, 또는 C1-C6 할로알킬이다. R 4 is a hydrogen atom, -OC 1 -C 6 alkyl, C 1 -C 6 alkyl, a halogen atom, -CN, or C 1 -C 6 haloalkyl.

본 발명에 따른 화학식 1로 표시되는 퀴녹살린 카르복스아마이드 유도체, 이의 이성질체 또는 이의 약학적으로 허용가능한 염은 하기에 화합물 1 내지 59 및 62 내지 67로 나타내는 화합물로 이루어진 군으로부터 선택된 화합물을 포함할 수 있다.The quinoxaline carboxamide derivative represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof according to the present invention may include a compound selected from the group consisting of compounds represented by compounds 1 to 59 and 62 to 67 below. there is.

1) 4'-메톡시-N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;1) 4'-methoxy- N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1 ,1'-biphenyl]-4-carboxamide;

2) 3'-메톡시-N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;2) 3'-methoxy- N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1 ,1'-biphenyl]-4-carboxamide;

3) 2'-메톡시-N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;3) 2'-methoxy- N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1 ,1'-biphenyl]-4-carboxamide;

4) 4'-메틸-N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;4) 4'-methyl- N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;

5) 3'-메틸-N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;5) 3'-methyl- N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;

6) 2'-메틸-N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;6) 2'-methyl- N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;

7) 4'-플루오르-N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;7) 4'-fluoro- N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;

8) 3'-플루오르-N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;8) 3'-fluoro- N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;

9) 2'-플루오르-N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;9) 2'-fluoro- N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;

10) 4'-클로로-N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;10) 4'-chloro- N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;

11) 3'-클로로-N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;11) 3'-chloro- N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;

12) 2'-클로로-N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;12) 2'-chloro- N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;

13) 4'-시아노-N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;13) 4'-cyano- N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1 ,1'-biphenyl]-4-carboxamide;

14) 3'-시아노-N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;14) 3'-Cyano- N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1 ,1'-biphenyl]-4-carboxamide;

15) N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-4'-(트리플루오르메틸)-[1,1'-바이페닐]-4-카르복스아마이드;15) N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-4'-(trifluoromethyl) -[1,1'-biphenyl]-4-carboxamide;

16) N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-3'-(트리플루오르메틸)-[1,1'-바이페닐]-4-카르복스아마이드;16) N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-3'-(trifluoromethyl) -[1,1'-biphenyl]-4-carboxamide;

17) N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-2'-(트리플루오르메틸)-[1,1'-바이페닐]-4-카르복스아마이드;17) N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-2'-(trifluoromethyl) -[1,1'-biphenyl]-4-carboxamide;

18) N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;18) N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1,1'-biphenyl ]-4-carboxamide;

19) N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-4'-메톡시-[1,1'-바이페닐]-4-카르복스아마이드;19) N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-4'-methoxy-[1,1'- biphenyl]-4-carboxamide;

20) N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-3'-메톡시-[1,1'-바이페닐]-4-카르복스아마이드;20) N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-3'-methoxy-[1,1'- biphenyl]-4-carboxamide;

21) N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-2'-메톡시-[1,1'-바이페닐]-4-카르복스아마이드;21) N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-2'-methoxy-[1,1'- biphenyl]-4-carboxamide;

22) N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-4'-메틸-[1,1'-바이페닐]-4-카르복스아마이드;22) N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-4'-methyl-[1,1'-bi phenyl]-4-carboxamide;

23) N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-3'-메틸-[1,1'-바이페닐]-4-카르복스아마이드;23) N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-3'-methyl-[1,1'-bi phenyl]-4-carboxamide;

24) N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-2'-메틸-[1,1'-바이페닐]-4-카르복스아마이드;24) N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-2'-methyl-[1,1'-bi phenyl]-4-carboxamide;

25) N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-4'-플루오르-[1,1'-바이페닐]-4-카르복스아마이드;25) N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-4'-fluoro-[1,1'-bi phenyl]-4-carboxamide;

26) N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-3'-플루오르-[1,1'-바이페닐]-4-카르복스아마이드;26) N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-3'-fluoro-[1,1'-bi phenyl]-4-carboxamide;

27) N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-2'-플루오르-[1,1'-바이페닐]-4-카르복스아마이드;27) N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-2'-fluoro-[1,1'-bi phenyl]-4-carboxamide;

28) 4'-클로로-N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;28) 4'-Chloro- N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1,1'-bi phenyl]-4-carboxamide;

29) 3'-클로로-N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;29) 3'-Chloro- N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1,1'-bi phenyl]-4-carboxamide;

30) 2'-클로로-N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;30) 2'-chloro- N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1,1'-bi phenyl]-4-carboxamide;

31) 4'-시아노-N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;31) 4'-Cyano- N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1,1'- biphenyl]-4-carboxamide;

32) 3'-시아노-N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;32) 3'-Cyano- N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1,1'- biphenyl]-4-carboxamide;

33) N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-4'-(트리플루오르메틸)-[1,1'-바이페닐]-4-카르복스아마이드;33) N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-4'-(trifluoromethyl)-[1, 1'-biphenyl]-4-carboxamide;

34) N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-3'-(트리플루오르메틸)-[1,1'-바이페닐]-4-카르복스아마이드;34) N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-3'-(trifluoromethyl)-[1, 1'-biphenyl]-4-carboxamide;

35) N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-2'-(트리플루오르메틸)-[1,1'-바이페닐]-4-카르복스아마이드;35) N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-2'-(trifluoromethyl)-[1, 1'-biphenyl]-4-carboxamide;

36) N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;36) N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1,1'-biphenyl]-4- carboxamide;

37) 4'-메톡시-N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;37) 4'-methoxy- N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1 ,1'-biphenyl]-4-carboxamide;

38) 3'-메톡시-N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;38) 3'-methoxy- N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1 ,1'-biphenyl]-4-carboxamide;

39) 2'-메톡시-N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;39) 2'-methoxy- N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1 ,1'-biphenyl]-4-carboxamide;

40) 4'-메틸-N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;40) 4'-methyl- N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;

41) 3'-메틸-N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;41) 3'-methyl- N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;

42) 2'-메틸-N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;42) 2'-methyl- N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;

43) 4'-플루오르-N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;43) 4'-fluoro- N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;

44) 3'-플루오르-N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;44) 3'-fluoro- N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;

45) 2'-플루오르-N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;45) 2'-fluoro- N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;

46) 4'-클로로-N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;46) 4'-chloro- N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;

47) 3'-클로로-N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;47) 3'-chloro- N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;

48) 2'-클로로-N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;48) 2'-chloro- N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;

49) 4'-시아노-N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;49) 4'-cyano- N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1 ,1'-biphenyl]-4-carboxamide;

50) 3'-시아노-N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;50) 3'-Cyano- N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1 ,1'-biphenyl]-4-carboxamide;

51) N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-4'-(트리플루오르메틸)-[1,1'-바이페닐]-4-카르복스아마이드;51) N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-4'-(trifluoromethyl) -[1,1'-biphenyl]-4-carboxamide;

52) N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-3'-(트리플루오르메틸)-[1,1'-바이페닐]-4-카르복스아마이드;52) N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-3'-(trifluoromethyl) -[1,1'-biphenyl]-4-carboxamide;

53) N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-2'-(트리플루오르메틸)-[1,1'-바이페닐]-4-카르복스아마이드;53) N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-2'-(trifluoromethyl) -[1,1'-biphenyl]-4-carboxamide;

54) N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;54) N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1,1'-biphenyl ]-4-carboxamide;

55) 4'-메톡시-N-(3-(피페리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;55) 4'-methoxy- N -(3-(piperidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1 ,1'-biphenyl]-4-carboxamide;

56) 4'-플루오르-N-(3-(피페리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;56) 4'-fluoro- N -(3-(piperidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;

57) N-(2-(2-(다이메틸아미노)에톡시)-3-(피페리딘-1-일)퀴녹살린-6-일)-4'-메톡시-[1,1'-바이페닐]-4-카르복스아마이드;57) N -(2-(2-(dimethylamino)ethoxy)-3-(piperidin-1-yl)quinoxalin-6-yl)-4'-methoxy-[1,1'- biphenyl]-4-carboxamide;

58) N-(2-(2-(다이메틸아미노)에톡시)-3-(피페리딘-1-일)퀴녹살린-6-일)-4'-플루오르-[1,1'-바이페닐]-4-카르복스아마이드;58) N -(2-(2-(dimethylamino)ethoxy)-3-(piperidin-1-yl)quinoxalin-6-yl)-4'-fluoro-[1,1'-bi phenyl]-4-carboxamide;

59) 3'-시아노-N-(2-(2-(다이메틸아미노)에톡시)-3-(피페리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;59) 3'-Cyano- N -(2-(2-(dimethylamino)ethoxy)-3-(piperidin-1-yl)quinoxalin-6-yl)-[1,1'- biphenyl]-4-carboxamide;

62) N-(3-(벤질(메틸)아미노)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-4'-메톡시-[1,1'-바이페닐]-4-카르복스아마이드;62) N -(3-(benzyl(methyl)amino)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-4'-methoxy-[1,1 '-biphenyl]-4-carboxamide;

63) N-(3-(벤질(메틸)아미노)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-4'-플루오르-[1,1'-바이페닐]-4-카르복스아마이드;63) N -(3-(benzyl(methyl)amino)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-4'-fluoro-[1,1'-Biphenyl]-4-carboxamide;

64) N-(3-(벤질(메틸)아미노)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-3'-시아노-[1,1'-바이페닐]-4-카르복스아마이드;64) N -(3-(benzyl(methyl)amino)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-3'-cyano-[1,1 '-biphenyl]-4-carboxamide;

65) N-(3-(벤질(메틸)아미노)-2-(2-(다이메틸아미노)에톡시)퀴녹살린-6-일)-4'-플루오르-[1,1'-바이페닐]-4-카르복스아마이드;65) N -(3-(benzyl(methyl)amino)-2-(2-(dimethylamino)ethoxy)quinoxalin-6-yl)-4'-fluoro-[1,1'-biphenyl] -4-carboxamide;

66) N-(3-(벤질(메틸)아미노)-2-(2-(다이메틸아미노)에톡시)퀴녹살린-6-일)-3'-시아노-[1,1'-바이페닐]-4-카르복스아마이드;66) N -(3-(benzyl(methyl)amino)-2-(2-(dimethylamino)ethoxy)quinoxalin-6-yl)-3'-cyano-[1,1'-biphenyl ]-4-carboxamide;

67) N-(3-(벤질(메틸)아미노)-2-((1-메틸피페리딘-4-일)옥시)퀴녹살린-6-일)-4'-메톡시-[1,1'-바이페닐]-4-카르복스아마이드.67) N -(3-(benzyl(methyl)amino)-2-((1-methylpiperidin-4-yl)oxy)quinoxalin-6-yl)-4'-methoxy-[1,1 '-Biphenyl]-4-carboxamide.

본 발명의 상기 화학식 1로 표시되는 퀴녹살린 카르복스아마이드 유도체는 이의 이성질체 또는 이의 약학적으로 허용가능한 염뿐만 아니라, 통상의 방법에 의해 제조될 수 있는 모든 염, 이성질체, 수화물 및 용매화물을 모두 포함한다.The quinoxaline carboxamide derivative represented by Formula 1 of the present invention includes not only isomers or pharmaceutically acceptable salts thereof, but also all salts, isomers, hydrates and solvates that can be prepared by conventional methods. do.

본 발명에서, “약학적으로 허용가능”이란, 생리학적으로 허용되고 인간에게 투여될 때, 통상적으로 위장 장애, 현기증과 같은 알레르기 반응 또는 이와 유사한 반응을 일으키지 않고 이 분야의 통상의 지식을 가진 자가 의약제제 제조 시 통상적으로 사용되는 것을 의미할 수 있다.In the present invention, “pharmaceutically acceptable” means that it is physiologically acceptable and does not usually cause allergic reactions such as gastrointestinal disorders, dizziness, or similar reactions when administered to humans, and that a person skilled in the art will It may mean something commonly used in the manufacture of pharmaceutical preparations.

본 발명에서 사용되는 용어, “염”은 약학적으로 허용가능한 유리산(free acid)에 의해 형성된 산부가염이 유용하다. 약학적으로 허용가능한 염이란 표현은 환자에게 비교적 비독성이고 무해한 유효작용을 갖는 농도로서 이 염에 기인한 부작용이 화학식 1의 염기 화합물의 이로운 효능을 떨어뜨리지 않는 화학식 1의 염기 화합물의 어떠한 유기 또는 무기 부가염을 의미한다. 이들 염은 유리산으로는 무기산과 유기산을 사용할 수 있으며, 무기산으로는 염산, 브롬산, 질산, 황산, 과염소산, 인산 등을 사용할 수 있고, 유기산으로는 구연산, 초산, 젖산, 말레산, 푸마린산, 글루콘산, 메탄설폰산, 글리콘산, 숙신산, 타타르산, 갈룩투론산, 엠본산, 글루탐산, 아스파르트산, 옥살산, (D) 또는 (L) 말산, 말레산, 메테인설폰산, 에테인설폰산, 4-톨루엔술폰산, 살리실산, 시트르산, 벤조산 또는 말론산 등을 사용할 수 있다. 또한, 이들 염은 알칼리 금속염(나트륨염, 칼륨염 등) 및 알칼리 토금속염(칼슘염, 마그네슘염 등) 등을 포함한다. 예를 들면, 산부가염으로는 아세테이트, 아스파테이트, 벤즈에이트, 베실레이트, 바이카보네이트/카보네이트, 바이설페이트/설페이트, 보레이트, 캄실레이트, 시트레이트, 에디실레이트, 에실레이트, 포메이트, 퓨마레이트, 글루셉테이트, 글루코네이트, 글루큐로네이트, 헥사플루오로포스페이트, 하이벤제이트, 하이드로클로라이드/클로라이드, 하이드로브로마이드/브로마이드, 하이드로요오디드/요오디드, 이세티오네이트, 락테이트, 말레이트, 말리에이트, 말로네이트, 메실레이트, 메틸설페이트, 나프틸레이트, 2-나프실레이트, 니코티네이트, 나이트레이트, 오로테이트, 옥살레이트, 팔미테이트, 파모에이트, 포스페이트/수소 포스페이트/이수소 포스페이트, 사카레이트, 스테아레이트, 석시네이트, 타르트레이트, 토실레이트, 트리플루오로아세테이트, 알루미늄, 알기닌, 벤자틴, 칼슘, 콜린, 디에틸아민, 디올아민, 글라이신, 라이신, 마그네슘, 메글루민, 올아민, 칼륨, 나트륨, 트로메타민, 아연염 등이 포함될 수 있으며, 이들 중 하이드로클로라이드 또는 트리플루오로아세테이트가 바람직하다.The term “salt” used in the present invention refers to an acid addition salt formed by a pharmaceutically acceptable free acid. The expression “pharmaceutically acceptable salt” refers to any organic or organic salt of the base compound of Formula 1 where side effects due to the salt do not reduce the beneficial effects of the base compound of Formula 1, at a concentration that is relatively non-toxic and harmless to the patient and has an effective effect. It means inorganic addition salt. For these salts, inorganic acids and organic acids can be used as free acids. Hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, perchloric acid, and phosphoric acid can be used as inorganic acids, and citric acid, acetic acid, lactic acid, maleic acid, and fumarine can be used as organic acids. Acids, gluconic acid, methanesulfonic acid, glyconic acid, succinic acid, tartaric acid, galacturonic acid, embonic acid, glutamic acid, aspartic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, ethane sulfuric acid Fonic acid, 4-toluenesulfonic acid, salicylic acid, citric acid, benzoic acid, or malonic acid can be used. Additionally, these salts include alkali metal salts (sodium salts, potassium salts, etc.) and alkaline earth metal salts (calcium salts, magnesium salts, etc.). For example, acid addition salts include acetate, aspartate, benzate, besylate, bicarbonate/carbonate, bisulfate/sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, Gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, mally. ate, malonate, mesylate, methyl sulfate, naphthylate, 2-naphsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharide Latex, stearate, succinate, tartrate, tosylate, trifluoroacetate, aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, Potassium, sodium, tromethamine, zinc salt, etc. may be included, and among these, hydrochloride or trifluoroacetate is preferable.

본 발명에 따른 부가염은 통상의 방법으로 제조할 수 있으며, 예를 들면 화학식 1의 화합물을 수혼화성 유기용매, 예를 들면 아세톤, 메탄올, 에탄올, 또는 아세토니트릴 등에 녹이고 과량의 유기산을 가하거나 무기산의 산 수용액의 가한 후 침전시키거나 결정화시켜서 제조할 수 있다. 이어서 이 혼합물에서 용매나 과량의 산을 증발시킨 후 건조시켜서 부가염을 얻거나 또는 석출된 염을 흡인 여과시켜 제조할 수 있다.The addition salt according to the present invention can be prepared by conventional methods. For example, the compound of Formula 1 is dissolved in a water-miscible organic solvent, such as acetone, methanol, ethanol, or acetonitrile, and an excess amount of organic acid is added or inorganic acid. It can be manufactured by adding an aqueous acid solution and then precipitating or crystallizing it. Then, the solvent or excess acid in this mixture is evaporated and dried to obtain an addition salt, or the precipitated salt can be prepared by suction filtration.

본 발명에서 “이성질체”는 “입체 이성질제(stereoisomer)” 또는 “광학 이성질체(enantiomer)”를 포함하되, 입체 이성질체는 부분입체 이성질체(diastereomer) 각각 또는 이들의 혼합물을 포함할 수 있고, 광학 이성질체는 거울상 이성질체 각각 뿐만 아니라 거울상 이성질체의 혼합물 및 라세미체까지 모두 포함한다.In the present invention, “isomers” include “stereoisomers” or “enantiomers,” and stereoisomers may include diastereomers individually or mixtures thereof, and optical isomers may include diastereomers, respectively, or mixtures thereof. It includes not only individual enantiomers, but also mixtures and racemates of enantiomers.

본 발명의 “수화물”은 퀴녹살린 카르복스아마이드 유도체 또는 이의 약학적으로 허용가능한 염이 물이 비공유적으로 분자간 힘으로 결합되어 있는 것으로 화학양론적 또는 비화학양론적의 양의 물을 포함하는 것일 수 있다. 구체적으로는, 상기 수화물은 활성성분 1 몰을 기준으로 물을 약 0.25몰 내지 약 10몰 비로 포함할 수 있으며, 보다 구체적으로는 약 0.5몰, 약 1.5몰, 약 2몰, 약 2.5몰, 약 3몰 등을 포함할 수 있으며, 이에 한정되는 것은 아니다.“Hydrate” of the present invention refers to a quinoxaline carboxamide derivative or a pharmaceutically acceptable salt thereof containing water in a stoichiometric or non-stoichiometric amount in which water is non-covalently bound by intermolecular forces. You can. Specifically, the hydrate may contain water in a ratio of about 0.25 mole to about 10 mole based on 1 mole of the active ingredient, and more specifically, about 0.5 mole, about 1.5 mole, about 2 mole, about 2.5 mole, about It may include 3 moles, etc., but is not limited thereto.

본 발명의 “용매화물”은 퀴녹살린 카르복스아마이드 유도체 또는 이의 약학적으로 허용가능한 염이 물이 아닌 용매가 분자간 힘으로 결합되어 있는 것으로 화학양론적 또는 비화학양론적의 양의 물을 포함하는 것일 수 있다. 구체적으로는, 상기 수화물은 활성성분 1 몰을 기준으로 물을 약 0.25몰 내지 약 10몰 비로 포함할 수 있으며, 보다 구체적으로는 약 0.5몰, 약 1.5몰, 약 2몰, 약 2.5몰, 약 3몰, 약 5몰 등을 포함할 수 있으며, 이에 한정되는 것은 아니다.“Solvate” of the present invention is a quinoxaline carboxamide derivative or a pharmaceutically acceptable salt thereof that is bound to a solvent other than water by intermolecular forces and contains a stoichiometric or non-stoichiometric amount of water. It may be. Specifically, the hydrate may contain water in a ratio of about 0.25 mole to about 10 mole based on 1 mole of the active ingredient, and more specifically, about 0.5 mole, about 1.5 mole, about 2 mole, about 2.5 mole, about It may include 3 moles, about 5 moles, etc., but is not limited thereto.

퀴녹살린 카르복스아마이드 유도체 화합물의 제조방법Method for producing quinoxaline carboxamide derivative compounds

본 발명은 하기 반응식 1에 나타난 바와 같은 퀴녹살린 카르복스아마이드 유도체 화합물의 제조방법을 제공한다.The present invention provides a method for producing quinoxaline carboxamide derivative compounds as shown in Scheme 1 below.

구체적으로 본 발명은 (A-1) 화학식 2의 화합물과 R3OH을 반응시켜 화학식 3의 화합물을 제조하는 단계;Specifically, the present invention includes the steps of (A-1) reacting a compound of Formula 2 with R 3 OH to prepare a compound of Formula 3;

(A-2) 상기 단계 A-1에서 제조된 화학식 3의 화합물을 화학식 4의 바이페닐카르복실산과 반응시켜 화학식 1의 화합물을 제조하는 단계;를 포함하는 퀴녹살린 카르복스아마이드 유도체, 이의 이성질체 또는 이의 염의 제조방법을 제공한다.(A-2) reacting the compound of formula 3 prepared in step A-1 with the biphenylcarboxylic acid of formula 4 to prepare a compound of formula 1; a quinoxaline carboxamide derivative, an isomer thereof, or A method for producing salts thereof is provided.

[반응식 1][Scheme 1]

상기 반응식 1에서, 상기 R1, R2, R3, 및 R4는 본 발명에 따라 상기 화학식 1에서 정의한 바와 같으며, 이하에서 본 발명에 따른 제조방법을 단계별로 상세히 설명한다. In Scheme 1, R 1 , R 2 , R 3 , and R 4 are as defined in Formula 1 according to the present invention, and the preparation method according to the present invention will be described step by step in detail below.

(단계 A-1)(Step A-1)

본 발명에 따른 상기 단계 A-1은 출발물질인 화학식 2의 화합물과 R3OH을 염기의 존재하에서 반응시켜 R3O기를 도입하여 화학식 3의 화합물을 제조하는 단계이다. 화학식 2의 화합물은 기존 문헌(Tetrahedron Letters 2005 46 4979-4983)에 기술된 방법으로 얻을 수 있다.Step A-1 according to the present invention is a step of preparing a compound of Formula 3 by reacting the starting material, the compound of Formula 2, with R 3 OH in the presence of a base to introduce an R 3 O group. The compound of Formula 2 can be obtained by the method described in existing literature (Tetrahedron Letters 2005 46 4979-4983).

일례로, 테트라하이드로퓨란(THF) 용매 내에서 R3OH를 염기의 일종인 소디움 하이드라이드(NaH)로 처리한 뒤 상기 화학식 2의 화합물을 더하는 방식으로 R3O기를 도입할 수 있다.For example, an R 3 O group can be introduced by treating R 3 OH with sodium hydride (NaH), a type of base, in a tetrahydrofuran (THF) solvent and then adding the compound of Formula 2 above.

(단계 A-2)(Step A-2)

본 발명에 따른 상기 단계 A-2는 상기 단계 A-1에서 제조된 화학식 3의 화합물과 화학식 4의 바이페닐카르복실산을 아마이드 커플링 시약의 존재하에서 반응시켜 화학식 1의 화합물을 제조하는 단계로, 상기 단계 A-2의 반응은 아마이드 커플링 반응으로 통상적으로 알려진 반응이다.Step A-2 according to the present invention is a step of preparing a compound of Formula 1 by reacting the compound of Formula 3 prepared in Step A-1 with the biphenylcarboxylic acid of Formula 4 in the presence of an amide coupling reagent. , the reaction of step A-2 is a reaction commonly known as an amide coupling reaction.

일례로, 다이클로로메탄(DCM)/N,N-다이메틸포름아마이드(DMF) 혼합용매 내에서 1-에틸-3-(3′-다이메틸아미노프로필)카르보다이이마이드(EDC) 존재하에서 화학식 3의 화합물과 화학식 4의 바이페닐카르복실산을 커플링하여 화학식 1의 화합물을 제조할 수 있다.For example, in the presence of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (EDC) in a dichloromethane (DCM)/ N , N -dimethylformamide (DMF) mixed solvent, the formula The compound of Formula 1 can be prepared by coupling the compound of Formula 3 with the biphenylcarboxylic acid of Formula 4.

본 발명에 따른 화학식 1로 표시되는 화합물의 제조방법에 있어서, 바람직한 양태로 하기 본 발명의 실시예 1 내지 실시예 67의 제조방법을 들 수 있고, 이로부터 해당 분야의 당업자가 통상 수행할 수 있는 변경 또는 수정의 범위도 본 발명의 제조방법에 포함된다.In the method for producing a compound represented by Formula 1 according to the present invention, preferred embodiments include the production methods of Examples 1 to 67 of the present invention, which can be commonly performed by those skilled in the art. The scope of change or modification is also included in the manufacturing method of the present invention.

본 발명의 퀴녹살린 카르복스아마이드 유도체 화합물을 포함하는 조성물, 이의 용도 및 이를 이용한 치료방법, 병용 치료방법Composition containing the quinoxaline carboxamide derivative compound of the present invention, its use, treatment method using the same, and combination treatment method

본 발명의 일 측면에 있어서, 본 발명은 하기 화학식 1로 표시되는 퀴녹살린 카르복스아마이드 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 교모세포종의 예방 또는 치료용 약학적 조성물을 제공한다. In one aspect of the present invention, the present invention provides a pharmaceutical composition for preventing or treating glioblastoma containing a quinoxaline carboxamide derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient: .

[화학식 1][Formula 1]

상기 화학식 1에서,In Formula 1,

NR1R2는 또는 또는 또는 이고, NR 1 R 2 is or or or ego,

OR3는 또는 또는 이고;OR 3 is or or ego;

R4는 수소 원자, -O-C1-C6 알킬, C1-C6 알킬, 할로겐 원자, -CN, 또는 C1-C6 할로알킬이다. R 4 is a hydrogen atom, -OC 1 -C 6 alkyl, C 1 -C 6 alkyl, a halogen atom, -CN, or C 1 -C 6 haloalkyl.

본 발명에 따른 약학적 조성물에 함유되는, 화학식 1로 표시되는 퀴녹살린 카르복스아마이드 유도체, 이의 이성질체 또는 이의 약학적으로 허용가능한 염은 하기에 화합물 1 내지 67로 나타내는 화합물로 이루어진 군으로부터 선택된 화합물을 포함할 수 있다.The quinoxaline carboxamide derivative represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof contained in the pharmaceutical composition according to the present invention is a compound selected from the group consisting of compounds represented by compounds 1 to 67 below. It can be included.

1) 4'-메톡시-N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;1) 4'-methoxy- N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1 ,1'-biphenyl]-4-carboxamide;

2) 3'-메톡시-N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;2) 3'-methoxy- N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1 ,1'-biphenyl]-4-carboxamide;

3) 2'-메톡시-N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;3) 2'-methoxy- N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1 ,1'-biphenyl]-4-carboxamide;

4) 4'-메틸-N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;4) 4'-methyl- N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;

5) 3'-메틸-N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;5) 3'-methyl- N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;

6) 2'-메틸-N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;6) 2'-methyl- N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;

7) 4'-플루오르-N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;7) 4'-fluoro- N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;

8) 3'-플루오르-N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;8) 3'-fluoro- N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;

9) 2'-플루오르-N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;9) 2'-fluoro- N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;

10) 4'-클로로-N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;10) 4'-chloro- N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;

11) 3'-클로로-N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;11) 3'-chloro- N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;

12) 2'-클로로-N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;12) 2'-chloro- N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;

13) 4'-시아노-N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;13) 4'-cyano- N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1 ,1'-biphenyl]-4-carboxamide;

14) 3'-시아노-N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;14) 3'-Cyano- N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1 ,1'-biphenyl]-4-carboxamide;

15) N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-4'-(트리플루오르메틸)-[1,1'-바이페닐]-4-카르복스아마이드;15) N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-4'-(trifluoromethyl) -[1,1'-biphenyl]-4-carboxamide;

16) N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-3'-(트리플루오르메틸)-[1,1'-바이페닐]-4-카르복스아마이드;16) N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-3'-(trifluoromethyl) -[1,1'-biphenyl]-4-carboxamide;

17) N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-2'-(트리플루오르메틸)-[1,1'-바이페닐]-4-카르복스아마이드;17) N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-2'-(trifluoromethyl) -[1,1'-biphenyl]-4-carboxamide;

18) N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;18) N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1,1'-biphenyl ]-4-carboxamide;

19) N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-4'-메톡시-[1,1'-바이페닐]-4-카르복스아마이드;19) N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-4'-methoxy-[1,1'- biphenyl]-4-carboxamide;

20) N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-3'-메톡시-[1,1'-바이페닐]-4-카르복스아마이드;20) N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-3'-methoxy-[1,1'- biphenyl]-4-carboxamide;

21) N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-2'-메톡시-[1,1'-바이페닐]-4-카르복스아마이드;21) N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-2'-methoxy-[1,1'- biphenyl]-4-carboxamide;

22) N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-4'-메틸-[1,1'-바이페닐]-4-카르복스아마이드;22) N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-4'-methyl-[1,1'-bi phenyl]-4-carboxamide;

23) N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-3'-메틸-[1,1'-바이페닐]-4-카르복스아마이드;23) N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-3'-methyl-[1,1'-bi phenyl]-4-carboxamide;

24) N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-2'-메틸-[1,1'-바이페닐]-4-카르복스아마이드;24) N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-2'-methyl-[1,1'-bi phenyl]-4-carboxamide;

25) N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-4'-플루오르-[1,1'-바이페닐]-4-카르복스아마이드;25) N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-4'-fluoro-[1,1'-bi phenyl]-4-carboxamide;

26) N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-3'-플루오르-[1,1'-바이페닐]-4-카르복스아마이드;26) N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-3'-fluoro-[1,1'-bi phenyl]-4-carboxamide;

27) N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-2'-플루오르-[1,1'-바이페닐]-4-카르복스아마이드;27) N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-2'-fluoro-[1,1'-bi phenyl]-4-carboxamide;

28) 4'-클로로-N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;28) 4'-Chloro- N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1,1'-bi phenyl]-4-carboxamide;

29) 3'-클로로-N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;29) 3'-Chloro- N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1,1'-bi phenyl]-4-carboxamide;

30) 2'-클로로-N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;30) 2'-chloro- N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1,1'-bi phenyl]-4-carboxamide;

31) 4'-시아노-N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;31) 4'-Cyano- N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1,1'- biphenyl]-4-carboxamide;

32) 3'-시아노-N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;32) 3'-Cyano- N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1,1'- biphenyl]-4-carboxamide;

33) N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-4'-(트리플루오르메틸)-[1,1'-바이페닐]-4-카르복스아마이드;33) N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-4'-(trifluoromethyl)-[1, 1'-biphenyl]-4-carboxamide;

34) N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-3'-(트리플루오르메틸)-[1,1'-바이페닐]-4-카르복스아마이드;34) N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-3'-(trifluoromethyl)-[1, 1'-biphenyl]-4-carboxamide;

35) N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-2'-(트리플루오르메틸)-[1,1'-바이페닐]-4-카르복스아마이드;35) N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-2'-(trifluoromethyl)-[1, 1'-biphenyl]-4-carboxamide;

36) N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;36) N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1,1'-biphenyl]-4- carboxamide;

37) 4'-메톡시-N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;37) 4'-methoxy- N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1 ,1'-biphenyl]-4-carboxamide;

38) 3'-메톡시-N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;38) 3'-methoxy- N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1 ,1'-biphenyl]-4-carboxamide;

39) 2'-메톡시-N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;39) 2'-methoxy- N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1 ,1'-biphenyl]-4-carboxamide;

40) 4'-메틸-N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;40) 4'-methyl- N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;

41) 3'-메틸-N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;41) 3'-methyl- N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;

42) 2'-메틸-N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;42) 2'-methyl- N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;

43) 4'-플루오르-N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;43) 4'-fluoro- N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;

44) 3'-플루오르-N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;44) 3'-fluoro- N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;

45) 2'-플루오르-N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;45) 2'-fluoro- N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;

46) 4'-클로로-N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;46) 4'-chloro- N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;

47) 3'-클로로-N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;47) 3'-chloro- N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;

48) 2'-클로로-N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;48) 2'-chloro- N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;

49) 4'-시아노-N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;49) 4'-cyano- N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1 ,1'-biphenyl]-4-carboxamide;

50) 3'-시아노-N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;50) 3'-Cyano- N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1 ,1'-biphenyl]-4-carboxamide;

51) N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-4'-(트리플루오르메틸)-[1,1'-바이페닐]-4-카르복스아마이드;51) N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-4'-(trifluoromethyl) -[1,1'-biphenyl]-4-carboxamide;

52) N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-3'-(트리플루오르메틸)-[1,1'-바이페닐]-4-카르복스아마이드;52) N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-3'-(trifluoromethyl) -[1,1'-biphenyl]-4-carboxamide;

53) N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-2'-(트리플루오르메틸)-[1,1'-바이페닐]-4-카르복스아마이드;53) N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-2'-(trifluoromethyl) -[1,1'-biphenyl]-4-carboxamide;

54) N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;54) N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1,1'-biphenyl ]-4-carboxamide;

55) 4'-메톡시-N-(3-(피페리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;55) 4'-methoxy- N -(3-(piperidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1 ,1'-biphenyl]-4-carboxamide;

56) 4'-플루오르-N-(3-(피페리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;56) 4'-fluoro- N -(3-(piperidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;

57) N-(2-(2-(다이메틸아미노)에톡시)-3-(피페리딘-1-일)퀴녹살린-6-일)-4'-메톡시-[1,1'-바이페닐]-4-카르복스아마이드;57) N -(2-(2-(dimethylamino)ethoxy)-3-(piperidin-1-yl)quinoxalin-6-yl)-4'-methoxy-[1,1'- biphenyl]-4-carboxamide;

58) N-(2-(2-(다이메틸아미노)에톡시)-3-(피페리딘-1-일)퀴녹살린-6-일)-4'-플루오르-[1,1'-바이페닐]-4-카르복스아마이드;58) N -(2-(2-(dimethylamino)ethoxy)-3-(piperidin-1-yl)quinoxalin-6-yl)-4'-fluoro-[1,1'-bi phenyl]-4-carboxamide;

59) 3'-시아노-N-(2-(2-(다이메틸아미노)에톡시)-3-(피페리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;59) 3'-Cyano- N -(2-(2-(dimethylamino)ethoxy)-3-(piperidin-1-yl)quinoxalin-6-yl)-[1,1'- biphenyl]-4-carboxamide;

60) N-(3-(다이에틸아미노)-2-(2-(다이메틸아미노)에톡시)퀴녹살린-6-일)-4'-메톡시-[1,1'-바이페닐]-4-카르복스아마이드;60) N -(3-(diethylamino)-2-(2-(dimethylamino)ethoxy)quinoxalin-6-yl)-4'-methoxy-[1,1'-biphenyl]- 4-carboxamide;

61) 3'-시아노-N-(3-(다이에틸아미노)-2-(2-(다이메틸아미노)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;61) 3'-Cyano- N -(3-(diethylamino)-2-(2-(dimethylamino)ethoxy)quinoxalin-6-yl)-[1,1'-biphenyl]- 4-carboxamide;

62) N-(3-(벤질(메틸)아미노)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-4'-메톡시-[1,1'-바이페닐]-4-카르복스아마이드;62) N -(3-(benzyl(methyl)amino)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-4'-methoxy-[1,1 '-biphenyl]-4-carboxamide;

63) N-(3-(벤질(메틸)아미노)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-4'-플루오르-[1,1'-바이페닐]-4-카르복스아마이드;63) N -(3-(benzyl(methyl)amino)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-4'-fluoro-[1,1'-Biphenyl]-4-carboxamide;

64) N-(3-(벤질(메틸)아미노)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-3'-시아노-[1,1'-바이페닐]-4-카르복스아마이드;64) N -(3-(benzyl(methyl)amino)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-3'-cyano-[1,1 '-biphenyl]-4-carboxamide;

65) N-(3-(벤질(메틸)아미노)-2-(2-(다이메틸아미노)에톡시)퀴녹살린-6-일)-4'-플루오르-[1,1'-바이페닐]-4-카르복스아마이드;65) N -(3-(benzyl(methyl)amino)-2-(2-(dimethylamino)ethoxy)quinoxalin-6-yl)-4'-fluoro-[1,1'-biphenyl] -4-carboxamide;

66) N-(3-(벤질(메틸)아미노)-2-(2-(다이메틸아미노)에톡시)퀴녹살린-6-일)-3'-시아노-[1,1'-바이페닐]-4-카르복스아마이드;66) N -(3-(benzyl(methyl)amino)-2-(2-(dimethylamino)ethoxy)quinoxalin-6-yl)-3'-cyano-[1,1'-biphenyl ]-4-carboxamide;

67) N-(3-(벤질(메틸)아미노)-2-((1-메틸피페리딘-4-일)옥시)퀴녹살린-6-일)-4'-메톡시-[1,1'-바이페닐]-4-카르복스아마이드.67) N -(3-(benzyl(methyl)amino)-2-((1-methylpiperidin-4-yl)oxy)quinoxalin-6-yl)-4'-methoxy-[1,1 '-Biphenyl]-4-carboxamide.

본 발명의 약학적 조성물은 교모세포종 암세포 성장을 억제함으로써 교모세포종의 예방 또는 치료에 현저한 효과를 보인다.The pharmaceutical composition of the present invention shows a significant effect in preventing or treating glioblastoma by inhibiting the growth of glioblastoma cancer cells.

상기 약학적으로 허용가능한 염은 앞서 본 발명의 퀴녹살린 카르복스아마이드 유도체의 허용되는 염에서 설명한 바와 같다.The pharmaceutically acceptable salt is the same as previously described in the section on acceptable salts of quinoxaline carboxamide derivatives of the present invention.

본 발명에서 용어, 예방이란 본 발명에 따른 약학적 조성물의 투여에 의해 교모세포종 암세포의 성장을 억제, 교모세포종의 발병을 억제시키거나 지연시키는 모든 행위를 의미한다.In the present invention, the term prevention refers to all actions that inhibit the growth of glioblastoma cancer cells and inhibit or delay the onset of glioblastoma by administering the pharmaceutical composition according to the present invention.

본 발명에서 용어, 치료란 본 발명에 따른 약학적 조성물의 투여에 의해 교모세포종에 대한 증세가 호전되거나 이롭게 변경되는 모든 행위를 의미한다.In the present invention, the term treatment refers to any action in which symptoms of glioblastoma are improved or beneficially changed by administration of the pharmaceutical composition according to the present invention.

본 발명의 약학적 조성물은 유효성분 이외에 약학적으로 허용되는 담체를 포함할 수 있다. 이때, 약학적으로 허용되는 담체는 제제 시에 통상적으로 이용되는 것으로서, 약학적으로 허용가능한 담체는 식염수, 멸균수, 링거액, 완충 식염수, 덱스트로즈 용액, 말토 덱스트린 용액, 글리세롤, 에탄올 및 이들 성분 중 1 성분 이상을 혼합하여 사용할 수 있으며, 필요에 따라 항산화제, 완충액, 정균제 등 다른 통상의 첨가제를 첨가할 수 있다. 또한 희석제, 분산제, 계면활성제, 결합제 및 윤활제를 부가적으로 첨가하여 수용액, 현탁액, 유탁액 등과 같은 주사용 제형, 환약, 캡슐, 과립 또는 정제로 제제화할 수 있다. 따라서, 본 발명의 조성물은 패치제, 액제, 환약, 캡슐, 과립, 정제, 좌제 등일 수 있다. 이들 제제는 당 분야에서 제제화에 사용되는 통상의 방법 또는 Remington's Pharmaceutical Science(최근판), Mack Publishing Company, Easton PA 에 개시되어 있는 방법으로 제조될 수 있으며 각 질환에 따라 또는 성분에 따라 다양한 제제로 제제화될 수 있다.The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier in addition to the active ingredient. At this time, pharmaceutically acceptable carriers are those commonly used in formulations, and pharmaceutically acceptable carriers include saline solution, sterile water, Ringer's solution, buffered saline solution, dextrose solution, maltodextrin solution, glycerol, ethanol, and these components. One or more of the ingredients can be mixed and used, and other common additives such as antioxidants, buffers, and bacteriostatic agents can be added as needed. In addition, diluents, dispersants, surfactants, binders, and lubricants can be additionally added to formulate injectable formulations such as aqueous solutions, suspensions, emulsions, etc., pills, capsules, granules, or tablets. Accordingly, the composition of the present invention may be a patch, solution, pill, capsule, granule, tablet, suppository, etc. These preparations can be manufactured by conventional methods used for formulation in the art or by methods disclosed in Remington's Pharmaceutical Science (recent edition), Mack Publishing Company, Easton PA, and are formulated into various preparations depending on each disease or ingredient. It can be.

본 발명의 약학적 조성물은 목적하는 방법에 따라 경구 투여하거나 비경구투여(예를 들어, 정맥 내, 피하, 복강 내 또는 국소에 적용) 형태로 제제화되어 투여될 수 있으며, 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 시간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다.The pharmaceutical composition of the present invention can be formulated and administered in the form of oral administration or parenteral administration (e.g., intravenous, subcutaneous, intraperitoneal, or topically applied) according to the desired method, and the dosage depends on the patient's condition. It varies depending on body weight, disease severity, drug type, administration route and time, but may be appropriately selected by a person skilled in the art.

경구 투여용 제형으로는 예를 들면 정제, 환제, 경/연질 캅셀제, 액제, 현탁제, 유화제, 시럽제, 과립제, 엘릭시르제 등이 있는데, 이들 제형은 유효성분 이외에 희석제(예: 락토즈, 덱스트로즈, 수크로즈, 만니톨, 솔비톨, 셀룰로즈 및/ 또는 글리신), 활택제(예: 실리카, 탈크, 스테아르산 및 그의 마그네슘 또는 칼슘염 및/또는 폴리에틸렌 글리콜)를 함유하고 있다. 정제는 또한 마그네슘 알루미늄 실리케이트, 전분 페이스트, 젤라틴, 메틸셀룰로즈, 나트륨 카복시메틸셀룰로즈 및/또는 폴리비닐피롤리딘과 같은 결합제를 함유할 수 있으며, 경우에 따라 전분, 한천, 알긴산 또는 그의 나트륨 염과 같은 붕해제 또는 비등 혼합물 및/또는 흡수제, 착색제, 향미제, 및 감미제를 함유할 수 있다.Dosage forms for oral administration include, for example, tablets, pills, hard/soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, etc. These dosage forms contain diluents (e.g. lactose, dextrin) in addition to the active ingredient. rose, sucrose, mannitol, sorbitol, cellulose and/or glycine), lubricants (e.g. silica, talc, stearic acid and its magnesium or calcium salts and/or polyethylene glycol). The tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine, and optionally, starch, agar, alginic acid or its sodium salt. It may contain disintegrants or effervescent mixtures and/or absorbents, colorants, flavoring agents, and sweeteners.

상기 화학식 1로 표시되는 유도체를 유효성분으로 하는 약학 조성물은 비경구 투여할 수 있으며, 비경구 투여는 피하주사, 정맥주사, 근육 내 주사 또는 흉부 내 주사를 주입하는 방법에 의한다. A pharmaceutical composition containing the derivative represented by Formula 1 as an active ingredient can be administered parenterally, and parenteral administration is performed by subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.

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

본 발명의 약학적 조성물은 약학적으로 유효한 양으로 투여한다. 본 발명에 있어서 약학적으로 유효한 양은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효용량 수준은 환자의 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명에 다른 약학적 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 종래의 치료제와는 순차적 또는 동시에 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. 상기한 요소들을 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 당업자에 의해 용이하게 결정될 수 있다.The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. In the present invention, a pharmaceutically effective amount refers to an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level refers to the type and severity of the patient's disease, the activity of the drug, and the It can be determined based on factors including sensitivity, time of administration, route of administration and excretion rate, duration of treatment, concurrently used drugs, and other factors well known in the medical field. The pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiple times. Considering all of the above factors, it is important to administer an amount that can achieve maximum effect with the minimum amount without side effects, and this can be easily determined by a person skilled in the art.

구체적으로 본 발명의 약학적 조성물의 유효량은 환자의 연령, 성별, 상태, 체중, 체내에 활성 성분의 흡수도, 불활성율 및 배설속도, 질병종류, 병용되는 약물에 따라 달라질 수 있으며, 일반적으로는 몸무게가 70 ㎏인 성인 환자를 기준으로 할 때, 일반적으로 0.1-1,000 ㎎/일이며, 바람직하게는 1-500 ㎎/일이며, 의사 또는 약사의 판단에 따라 일정시간 간격으로 1일 1회 내지 수회로 분할 투여할 수도 있다. 그러나 투여 경로, 비만의 중증도, 성별, 체중, 연령 등에 따라서 증감될 수 있으므로 상기 투여량이 어떠한 방법으로도 본 발명의 범위를 한정하는 것은 아니다.Specifically, the effective amount of the pharmaceutical composition of the present invention may vary depending on the patient's age, gender, condition, weight, absorption of the active ingredient in the body, inactivation rate and excretion rate, type of disease, and concomitant drug. In general, Based on an adult patient weighing 70 kg, the dosage is generally 0.1-1,000 mg/day, preferably 1-500 mg/day, once a day at regular intervals depending on the judgment of the doctor or pharmacist. It may be administered in several divided doses. However, since it may increase or decrease depending on the route of administration, severity of obesity, gender, weight, age, etc., the above dosage does not limit the scope of the present invention in any way.

본 발명의 다른 일 측면에 있어서, 본 발명의 화학식 1로 표시되는 퀴녹살린 카르복스아마이드 유도체 또는 이의 약학적으로 허용가능한 염; 및 항암 요법제;를 포함하는 교모세포종의 예방 또는 치료용 약학적 조성물을 제공한다.In another aspect of the present invention, the quinoxaline carboxamide derivative represented by Formula 1 of the present invention or a pharmaceutically acceptable salt thereof; It provides a pharmaceutical composition for preventing or treating glioblastoma, including an anti-cancer therapy agent.

본 발명에 따른 약학적 조성물에 함유되는, 화학식 1로 표시되는 퀴녹살린 카르복스아마이드 유도체, 이의 이성질체 또는 이의 약학적으로 허용가능한 염은 상기에 화합물 1 내지 67로 나타내는 화합물로 이루어진 군으로부터 선택된 화합물을 포함할 수 있다.The quinoxaline carboxamide derivative represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof contained in the pharmaceutical composition according to the present invention is a compound selected from the group consisting of the compounds represented by compounds 1 to 67 above. It can be included.

바람직하게는, 본 발명은 상기 퀴녹살린 카르복스아마이드 유도체 또는 이의 약학적으로 허용가능한 염; 및 항암 요법제;가 동시에, 개별적으로 또는 순차적으로 병용하여 투여되는 약학적 조성물을 제공한다.Preferably, the present invention relates to the quinoxaline carboxamide derivative or a pharmaceutically acceptable salt thereof; and an anti-cancer therapy agent; provided is a pharmaceutical composition administered in combination simultaneously, individually, or sequentially.

상기 항암 요법제는 화학 요법 및 방사선 요법 등일 수 있으며, 화학 요법은 의약 분야에서 통상적으로 알려진 바와 같이, 항암제를 사용하여 암을 치료하는 것으로 전신에 퍼져있는 암세포에 작용하는 전신적인 치료 방법을 의미할 수 있으며, 화학 요법은 단독으로 사용되기도 하지만, 완치(cure)를 위한 적극적인 치료 방법으로 사용될 경우에는 치료의 효과를 높이기 위하여 외과 수술 요법이나 방사선 치료요법과 함께 사용될 수 있다.The anti-cancer treatment agent may be chemotherapy, radiation therapy, etc., and as commonly known in the medical field, chemotherapy refers to a systemic treatment method that treats cancer using anti-cancer drugs and acts on cancer cells spread throughout the body. Chemotherapy may be used alone, but when used as an active treatment method for cure, it may be used together with surgery or radiation therapy to increase the effectiveness of treatment.

본 발명에서, 상기 화학 요법에서 사용될 수 있는 항암제는 DNA 손상 물질과 같은 화학 항암제, 면역 항암제 및 표적 치료제 등을 사용한 것일 수 있다.In the present invention, the anticancer agent that can be used in the chemotherapy may be a chemical anticancer agent such as a DNA damaging agent, an immunological anticancer agent, and a targeted therapeutic agent.

구체적으로 화학 항암제는 DNA에 직접 결합하여 DNA 분자 자체를 파괴하고 DNA의 동일 나선 혹은 이중 나선 구조에 손상을 주어 암세포의 성장, 분열 및 분화를 막는 알킬화제 약물, 주로 염기쌍 사이에 끼어들어 DNA 나선을 풀어 항암 작용을 하는 항암성 항생물질, 정상세포의 DNA복제에 필요한 대사물질들과 유사한 구조를 가짐에 따라 DNA와 RNA의 구성 성분인 퓨린 (Purine)과 피리미딘(Pyrimidine)의 생합성 효소에 정상 대사물질들과 경쟁적으로 결합하여 그 작용을 방해하여 항암작용을 하는 대사 길항제 및 스테로이드계 기능적 작용을 하거나 길항작용, 에스트로겐이나 프로게스테론 같은 호르몬에 의존해서 성장하는 암세포에 연료 공급선을 차단함으로써 항암 작용을 하는 호르몬제 등일 수 있다.Specifically, chemical anti-cancer drugs are alkylating agents that bind directly to DNA, destroying the DNA molecule itself and damaging the same-helix or double-helix structure of DNA to prevent the growth, division, and differentiation of cancer cells. They are mainly alkylating agents that intervene between base pairs to unwind the DNA helix. An anticancer antibiotic with anticancer activity. It has a similar structure to the metabolites required for DNA replication in normal cells, and is a normal metabolite for the biosynthetic enzymes of purine and pyrimidine, components of DNA and RNA. Metabolic antagonists and steroids, which have anti-cancer effects by competitively binding with and interfering with their actions, have a functional action or antagonism, and have anti-cancer effects by blocking the fuel supply line to cancer cells that grow dependent on hormones such as estrogen or progesterone. It may be, etc.

보다 구체적으로, 상기 알킬화제는 스플라틴(Cisplatin), 카보플라틴(Carboplatin), 옥살리플라틴(Oxaliplatin), 메클로레타민(Mechlorethamine, nitrogen mustard), 사이클로포스파마이드(Cyclophosphamide), 이포스파마이드(Ifosfamide), 멜팔란(Melphalan), 클로람부실(Chlorambucil), 티오테파(Thiotepa), 알트레타민(Altretamine), 프로카바진(Procarbazine), 부설판(Busulfan), 카무스틴(Carmustine, BCNU), 로무스틴(Lomustine, CCNU) 및 다카바진(Dacarbazine,DTIC) 등일 수 있으며, 이에 한정되는 것은 아니다.More specifically, the alkylating agent includes Cisplatin, Carboplatin, Oxaliplatin, Mechlorethamine (nitrogen mustard), Cyclophosphamide, and Ifosfamide. , Melphalan, Chlorambucil, Thiotepa, Altretamine, Procarbazine, Busulfan, Carmustine (BCNU), Lomustine (Lomustine, CCNU) and Dacarbazine (DTIC), etc., but are not limited thereto.

상기 항암성 항생물질은 닥티노마이신(Dactinomycin), 독소루비신(Doxorubicin), 다우노루비신(Daunorubicin), 마이토마이신(Mitomycin), 블레오마이신(Bleomycin) 등일 수 있으며, 이에 한정되는 것은 아니다.The anticancer antibiotic may include Dactinomycin, Doxorubicin, Daunorubicin, Mitomycin, Bleomycin, etc., but is not limited thereto.

또한, 상기 대사 길항제는 펜토스타틴(Pentostatin), 6-메르캅토퓨린(6-Mercaptopurine), 6-티오구아닌(6-Thioguanine), 아자티오프린(Azathioprine), 2-클로로디옥시아데노신(2-Chlorodeoxyadenosine), 히드록시우레아(Hydroxyurea), 메토트렉세이트(Methotrexate), 5-플루오로우라실(5-Fluorouracil), 카페시타빈(Capecitabine), 사이타라빈(Cytarabine), 아자시티딘(Azacitidine), 젬시타빈(Gemcitabine), 플루다라빈 포스페이트(Fludarabine phosphate), 아스파라기나제(Asparaginase), 페메트렉시드(Pemetrexed) 등일 수 있으며, 이에 한정되는 것은 아니다.In addition, the metabolic antagonists include Pentostatin, 6-Mercaptopurine, 6-Thioguanine, Azathioprine, and 2-Chlorodeoxyadenosine. ), Hydroxyurea, Methotrexate, 5-Fluorouracil, Capecitabine, Cytarabine, Azacitidine, Gemcitabine ), Fludarabine phosphate, Asparaginase, Pemetrexed, etc., but is not limited thereto.

또한 상기 호르몬제는 마이토테인(Mitotane), 아미노글루테티미드(Aminoglutethimide) 등의 아로마타제(aromatase) 억제제, 프레드니손(Prednisone), 프레드니솔론(Prednisolone) 등을 포함하는 부신피질 스테로이드 호르몬, 프로게스틴(Progestin), 에스트로겐(Estrogen), 안드로겐(Androgen) 등을 포함하는 성호르몬, 타목시펜(tamoxifen) 등을 포함하는 항에스트로겐 약물, 플루타마이드(Flutamide) 등을 포함하는 항안드로젠 약물, 루프로라이드(Leuprolide) 등을 포함하는 생식선자극 호르몬 방출(Gonadotropine-releasing) 호르몬 유사물질 등을 포함할 수 있으며, 여기에 한정되는 것은 아니다.In addition, the hormonal agents include aromatase inhibitors such as Mitotane and Aminoglutethimide, corticosteroid hormones including Prednisone and Prednisolone, and progestins. , sex hormones including estrogen and androgens, anti-estrogen drugs including tamoxifen, anti-androgen drugs including flutamide, leuprolide, etc. It may include, but is not limited to, gonadotropine-releasing hormone-like substances including.

또한, 천연 물질로는 세포의 유사분열 중에 염색체 분리에 필요한 미세소관에 결합하여 그 구성 성분인 튜불린을 파괴하여 세포분열을 중지시켜 항암작용을 나타내는 빈블라스틴(Vinblastine), 빈크리스틴(Vincristine), 비노렐빈(Vinorelvine)와 같은 빈카알칼로이드(Vinca Alkaloid); 세포분열 중에 미세소관의 작용을 방해하여 염색체 분리가 일어나지 않도록 항암 작용하는 파클리탁셀(Paclitaxel), 도세탁셀(Docetaxel) 등을 포함하는 탁센(Taxane)계 물질 등을 포함할 수 있으나, 본 발명의 범위가 여기에 한정되는 것은 아니며, 항암 분야에서 통상적으로 사용되는 항암제를 제한 없이 사용할 수 있다.In addition, natural substances include Vinblastine and Vincristine, which exhibit anticancer effects by binding to microtubules necessary for chromosome separation during cell mitosis and destroying tubulin, a component thereof, thereby stopping cell division. , Vinca Alkaloids such as Vinorelvine; Taxane-based substances, including Paclitaxel and Docetaxel, which have anti-cancer properties by interfering with the action of microtubules during cell division to prevent chromosome separation, may be included, but the scope of the present invention is herein. It is not limited to this, and anticancer agents commonly used in the anticancer field can be used without limitation.

본 발명에 있어서, 상기 면역 항암제는 인공 면역 단백질을 체내에 주입하여 면역체계를 자극함으로써 면역세포가 선택적으로 암세포만을 공격하도록 유도하는 치료약제로서, 면역관문억제제, 면역세포치료제 및 항암바이러스치료제 등을 포함할 수 있으며, 이에 한정되는 것은 아니다.In the present invention, the immune anti-cancer agent is a therapeutic agent that induces immune cells to selectively attack only cancer cells by injecting artificial immune proteins into the body to stimulate the immune system, and includes immune checkpoint inhibitors, immune cell therapies, anti-cancer virus treatments, etc. It may include, but is not limited to this.

본 발명에 있어서, 상기 표적 치료제는 암의 성장과 발암에 관여하는 특별한 분자의 활동을 방해하여 암이 성장하고 퍼지는 것을 막는 약제로서, 신호전달경로 억제제(Signal Transduction Pathway Inhibitor), 신생혈관생성 억제제(Angiogenesis Inhibitors) 및 혈관내피세포 성장인자(VEGF, Vascular Endothelial Growth Factor) 억제제 등을 포함할 수 있다.In the present invention, the targeted therapeutic agent is a drug that prevents cancer from growing and spreading by interfering with the activity of special molecules involved in cancer growth and carcinogenesis, and includes a signal transduction pathway inhibitor, an angiogenesis inhibitor ( Angiogenesis Inhibitors) and Vascular Endothelial Growth Factor (VEGF) inhibitors.

또한, 본 발명에 있어서, 방사선 요법은 방사선이 발생되는 장치 혹은 방사성 동위원소를 이용하여 고에너지 방사선을 조사하여 암세포를 직접 죽이거나 암세포가 주변으로 증식하는 것을 막기 위한 암 치료 방법 중 하나로, 해당 기술분야에서 통상적으로 사용되는 방법으로 방사선 요법을 수행할 수 있다.In addition, in the present invention, radiation therapy is one of the cancer treatment methods for directly killing cancer cells or preventing cancer cells from proliferating in the surrounding area by irradiating high-energy radiation using a device that generates radiation or radioactive isotopes. Radiation therapy can be performed using methods commonly used in the field.

또한, 본 발명은 상기 퀴녹살린 카르복스아마이드 유도체 또는 이의 약학적으로 허용가능한 염을 개체에 투여하여 교모세포종 암세포의 성장을 억제하는 방법을 제공한다.Additionally, the present invention provides a method of inhibiting the growth of glioblastoma cancer cells by administering the quinoxaline carboxamide derivative or a pharmaceutically acceptable salt thereof to a subject.

본 발명에서 “개체”란 질병의 치료가 있어야 하는 대상을 의미하고, 보다 구체적으로는, 인간 또는 비-인간인 영장류, 생쥐(mouse), 개, 고양이, 말, 소 등의 포유류를 의미한다.In the present invention, “individual” refers to a subject whose disease needs to be treated, and more specifically, refers to a mammal such as a human or non-human primate, mouse, dog, cat, horse, or cow.

본 발명의 교모세포종의 예방 또는 치료 방법은 상기 퀴녹살린 카르복스아마이드 유도체 또는 이의 약학적으로 허용가능한 염을 투여함으로써, 징후의 발현 전에 질병 그 자체를 다룰 뿐만 아니라, 이의 징후를 저해하거나 피하는 것을 또한 포함한다. 질환의 관리에 있어서, 특정 활성 성분의 예방적 또는 치료학적 용량은 질병 또는 상태의 본성(nature)과 심각도, 그리고 활성 성분이 투여되는 경로에 따라 다양할 것이다. 용량 및 용량의 빈도는 개별 환자의 연령, 체중 및 반응에 따라 다양할 것이다. 적합한 용량 용법은 이러한 인자를 당연히 고려하는 이 분야의 통상의 지식을 가진 자에 의해 쉽게 선택될 수 있다. 또한, 본 발명의 교모세포종의 예방 또는 치료 방법은 상기 화학식 1로 표시되는 화합물과 함께 질환 치료에 도움이 되는 추가적인 활성 제제의 치료학적으로 유효한 양의 투여를 더 포함할 수 있으며, 추가적인 활성제제는 상기 퀴녹살린 카르복스아마이드 유도체 또는 이의 약학적으로 허용가능한 염과 함께 시너지 효과 또는 보조적 효과를 나타낼 수 있다.The method for preventing or treating glioblastoma of the present invention not only treats the disease itself before the onset of symptoms, but also inhibits or avoids the symptoms, by administering the quinoxaline carboxamide derivative or a pharmaceutically acceptable salt thereof. Includes. In the management of disease, the prophylactic or therapeutic dosage of a particular active ingredient will vary depending on the nature and severity of the disease or condition and the route by which the active ingredient is administered. Dosage and frequency of dosage will vary depending on the age, weight, and response of the individual patient. A suitable dosage regimen can be easily selected by one of ordinary skill in the art taking these factors into account. In addition, the method for preventing or treating glioblastoma of the present invention may further include administration of a therapeutically effective amount of an additional active agent helpful in treating the disease along with the compound represented by Formula 1, and the additional active agent is It may exhibit a synergistic or auxiliary effect with the quinoxaline carboxamide derivative or a pharmaceutically acceptable salt thereof.

본 발명은 또한 교모세포종의 치료용 약제의 제조를 위한 상기 화학식 I 로 표시되는 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용가능한 염의 용도를 제공하고자 한다. 약제의 제조를 위한 상기 퀴녹살린 카르복스아마이드 유도체 또는 이의 약학적으로 허용가능한 염은 허용되는 보조제, 희석제, 담체 등을 혼합할 수 있으며, 기타 활성제제와 함께 복합 제제로제조되어 활성 성분들의 상승 작용을 가질 수 있다.The present invention also seeks to provide the use of the compound represented by formula (I), its stereoisomer, or its pharmaceutically acceptable salt for the production of a medicament for the treatment of glioblastoma. The quinoxaline carboxamide derivative or a pharmaceutically acceptable salt thereof for the preparation of a drug can be mixed with acceptable auxiliaries, diluents, carriers, etc., and is prepared as a complex preparation with other active agents to achieve synergistic effect of the active ingredients. You can have

본 발명의 용도, 조성물, 치료 방법에서 언급된 사항은 서로 모순되지 않는 한 동일하게 적용된다.Matters mentioned in the uses, compositions, and treatment methods of the present invention apply equally unless they contradict each other.

이밖에 본 명세서에서 사용된 용어들과 약어들은 달리 정의되지 않는 한, 그 본래의 의미를 갖는다.In addition, terms and abbreviations used in this specification have their original meanings unless otherwise defined.

본 발명에 따른 화학식 1의 퀴녹살린 카르복스아마이드 유도체는 우수한 교모세포종 암세포의 성장 저해 활성 효과를 가지므로, 암세포가 비정상적인 증식을 보이는 상태인 교모세포종의 예방 또는 치료에 유용하게 사용될 수 있다. The quinoxaline carboxamide derivative of Formula 1 according to the present invention has an excellent growth inhibitory effect on glioblastoma cancer cells, so it can be usefully used in the prevention or treatment of glioblastoma, a condition in which cancer cells show abnormal proliferation.

또한 본 발명에 따른 퀴녹살린 카르복스아마이드 유도체는 화학 항암제, 면역 항암제 및 표적 치료제 등의 화학요법 또는 방사선 요법과의 병용을 통해 교모세포종의 예방 또는 치료에 유용하게 사용될 수 있다.In addition, the quinoxaline carboxamide derivative according to the present invention can be usefully used in the prevention or treatment of glioblastoma through combination with chemotherapy or radiotherapy such as chemical anticancer agents, immune anticancer agents, and targeted therapeutic agents.

이하, 본 발명을 실시예, 실험예, 및 제제예에 의하여 상세히 설명한다. Hereinafter, the present invention will be described in detail through examples, experimental examples, and formulation examples.

단, 하기 실시예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실시예에 한정되는 것은 아니다.However, the following examples only illustrate the present invention, and the content of the present invention is not limited to the following examples.

<실시예 1> 4'-메톡시-<Example 1> 4'-methoxy- NN -(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드 제조-(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1,1'-biphenyl]-4 -Manufacture of carboxamide

단계 1: 3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-아민 제조Step 1: Preparation of 3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-amine

실온에서 60% 소디움 하이드라이드(332 mg, 8.28 mmol)와 1-(2-하이드록시에틸)피롤리딘(888 μL, 7.59 mmol)를 테트라하이드로퓨란에 혼합한 뒤 테트라하이드로퓨란(30 mL)에 녹인 2-클로로-3-(피롤리딘-1-일)퀴녹살린-6-아민(1.72 g, 6.90 mmol)을 더하고 60시간 동안 교반하였다 (중간에 추가적으로 60% 소디움 하이드라이드 1.2 당량과 1-(2-하이드록시에틸)피롤리딘 1 당량을 더했다). 반응혼합물에 암모니움 클로라이드 포화 수용액을 더하고 다이클로로메탄으로 추출한 뒤 다이클로로메탄 층을 마그네슘 설페이트로 건조하였다. 용매를 감압하에서 제거한 다음 남은 잔류물에 대해 실리카겔 관 크로마토그래피(다이클로로메탄 : 메탄올 = 20 : 1)를 수행하여 목적화합물(12.0 g, 89%)을 얻었다. Mix 60% sodium hydride (332 mg, 8.28 mmol) and 1-(2-hydroxyethyl)pyrrolidine (888 μL, 7.59 mmol) in tetrahydrofuran at room temperature and then add in tetrahydrofuran (30 mL). Dissolved 2-chloro-3-(pyrrolidin-1-yl)quinoxalin-6-amine (1.72 g, 6.90 mmol) was added and stirred for 60 hours (additionally 1.2 equivalents of 60% sodium hydride and 1- (1 equivalent of (2-hydroxyethyl)pyrrolidine was added). A saturated aqueous solution of ammonium chloride was added to the reaction mixture, extracted with dichloromethane, and the dichloromethane layer was dried over magnesium sulfate. The solvent was removed under reduced pressure, and the remaining residue was subjected to silica gel column chromatography (dichloromethane : methanol = 20 : 1) to obtain the target compound (12.0 g, 89%).

1H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 8.5 Hz, 1H), 6.85 (d, J = 2.5 Hz, 1H), 6.68 (dd, J = 8.5, 2.5 Hz, 1H), 4.54 (t, J = 6.4 Hz, 2H), 3.81 (m, 4H), 3.72 (br s, 2H), 2.93 (t, J = 6.4 Hz, 2H), 2.62 (m, 4H), 1.93 (m, 4H), 1.80 (p, J = 3.1 Hz, 4H); MS (ESI) m/z 328 ([M+H]+). 1H NMR (400 MHz, CDCl 3 ) δ 7.39 (d, J = 8.5 Hz, 1H), 6.85 (d, J = 2.5 Hz, 1H), 6.68 (dd, J = 8.5, 2.5 Hz, 1H), 4.54 (t, J = 6.4 Hz, 2H), 3.81 (m, 4H), 3.72 (br s, 2H), 2.93 (t, J = 6.4 Hz, 2H), 2.62 (m, 4H), 1.93 (m, 4H) ), 1.80 (p, J = 3.1 Hz, 4H); MS (ESI) m/z 328 ([M+H] + ).

단계 2: 4'-메톡시-Step 2: 4'-methoxy- NN -(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드 제조-(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1,1'-biphenyl]-4 -Manufacture of carboxamide

실온에서 3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-아민(30 mg, 0.092 mmol), 4'-메톡시-[1,1'-바이페닐]-4-카르복실산(25 mg, 0.11 mmol), 및 1-에틸-3-(3′-다이메틸아미노프로필)카르보다이이마이드(21 mg, 0.11 mmol)를 다이클로로메탄/N,N-다이메틸포름아마이드(2 mL/2 mL)에 더한 뒤 60시간 동안 교반하였다 (중간에 추가적으로 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 1.2 당량과 1-에틸-3-(3′-다이메틸아미노프로필)카르보다이이마이드 1.2 당량을 더했다). 용매를 감압하에서 제거한 다음 남은 잔류물에 대해 실리카겔 관 크로마토그래피(다이클로로메탄 : 메탄올 = 15 : 1)를 수행하여 목적 화합물(19 mg, 39%)을 얻었다.3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-amine (30 mg, 0.092 mmol), 4'-methoxy at room temperature. -[1,1'-biphenyl]-4-carboxylic acid (25 mg, 0.11 mmol), and 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide (21 mg, 0.11 mmol) ) was added to dichloromethane/ N , N -dimethylformamide (2 mL/2 mL) and stirred for 60 hours (4'-methoxy-[1,1'-biphenyl]-4 was added in the middle) -1.2 equivalents of carboxylic acid and 1.2 equivalents of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide were added). The solvent was removed under reduced pressure, and the remaining residue was subjected to silica gel column chromatography (dichloromethane : methanol = 15 : 1) to obtain the target compound (19 mg, 39%).

1H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 7.93 (d, J = 8.0 Hz, 2H), 7.85 (d, J = 2.2 Hz, 1H), 7.66 (m, 2H), 7.61 (d, J = 2.2 Hz, 1H), 7.57 (d, J = 8.0 Hz, 3H), 7.00 (d, J = 8.7 Hz, 2H), 4.60 (t, J = 6.3 Hz, 2H), 3.86 (s, 3H), 3.83 (m, 4H), 2.97 (t, J = 6.3 Hz, 2H), 2.65 (m, 4H), 1.94 (m, 4H), 1.81 (m, 4H); MS (ESI) m/z 538 ([M+H]+). 1H NMR (400 MHz, CDCl 3 ) δ 8.00 (s, 1H), 7.93 (d, J = 8.0 Hz, 2H), 7.85 (d, J = 2.2 Hz, 1H), 7.66 (m, 2H), 7.61 (d, J = 2.2 Hz, 1H), 7.57 (d, J = 8.0 Hz, 3H), 7.00 (d, J = 8.7 Hz, 2H), 4.60 (t, J = 6.3 Hz, 2H), 3.86 (s) , 3H), 3.83 (m, 4H), 2.97 (t, J = 6.3 Hz, 2H), 2.65 (m, 4H), 1.94 (m, 4H), 1.81 (m, 4H); MS (ESI) m/z 538 ([M+H] + ).

<실시예 2> 3'-메톡시-<Example 2> 3'-methoxy- NN -(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드 제조-(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1,1'-biphenyl]-4 -Manufacture of carboxamide

상기 실시예 1의 단계 2와 동일한 방법으로 수행하되, 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 대신에 3'-메톡시-[1,1'-바이페닐]-4-카르복실산(25 mg, 0.11 mmol)을 사용하여 목적 화합물(35 mg, 71%)을 얻었다. Carry out in the same manner as step 2 of Example 1, except that instead of 4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, 3'-methoxy-[1,1'-bi The target compound (35 mg, 71%) was obtained using phenyl]-4-carboxylic acid (25 mg, 0.11 mmol).

1H NMR (400 MHz CDCl3) δ 7.96 (d, J = 8.2 Hz, 3H), 7.86 (d, J = 2.2 Hz, 1H), 7.70 (d, J = 8.0 Hz, 2H), 7.62 (dd, J = 8.7, 2.2 Hz, 1H), 7.57 (d, J = 8.7 Hz, 1H), 7.39 (t, J = 7.9 Hz, 1H), 7.22 (d, J = 7.6 Hz, 1H), 7.16 (t, J = 2.1 Hz, 1H), 6.95 (dd, J = 8.0, 2.5 Hz, 1H), 4.63 (t, J = 6.2 Hz, 2H), 3.89 (s, 3H), 3.84 (m, 4H), 3.01 (t, J = 6.2 Hz, 2H), 2.69 (m, 4H), 1.96 (m, 4H), 1.84 (m, 4H); MS (ESI) m/z 538 ([M+H]+). 1H NMR (400 MHz CDCl 3 ) δ 7.96 (d, J = 8.2 Hz, 3H), 7.86 (d, J = 2.2 Hz, 1H), 7.70 (d, J = 8.0 Hz, 2H), 7.62 (dd, J = 8.7, 2.2 Hz, 1H), 7.57 (d, J = 8.7 Hz, 1H), 7.39 (t, J = 7.9 Hz, 1H), 7.22 (d, J = 7.6 Hz, 1H), 7.16 (t, J = 2.1 Hz, 1H), 6.95 (dd, J = 8.0, 2.5 Hz, 1H), 4.63 (t, J = 6.2 Hz, 2H), 3.89 (s, 3H), 3.84 (m, 4H), 3.01 ( t, J = 6.2 Hz, 2H), 2.69 (m, 4H), 1.96 (m, 4H), 1.84 (m, 4H); MS (ESI) m/z 538 ([M+H] + ).

<실시예 3> 2'-메톡시-<Example 3> 2'-methoxy- NN -(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드 제조-(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1,1'-biphenyl]-4 -Manufacture of carboxamide

상기 실시예 1의 단계 2와 동일한 방법으로 수행하되, 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 대신에 2'-메톡시-[1,1'-바이페닐]-4-카르복실산(25 mg, 0.11 mmol)을 사용하여 목적 화합물(29 mg, 59%)을 얻었다. Carry out in the same manner as step 2 of Example 1, except that instead of 4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, 2'-methoxy-[1,1'-bi The target compound (29 mg, 59%) was obtained using phenyl]-4-carboxylic acid (25 mg, 0.11 mmol).

1H NMR (400 MHz CDCl3) δ 7.93 (d, J = 8.3 Hz, 3H), 7.85 (d, J = 2.3 Hz, 1H), 7.66 (d, J = 8.3 Hz, 2H), 7.62 (dd, J = 8.7, 2.3 Hz, 1H), 7.58 (d, J = 8.7 Hz, 1H), 7.37 (m, 2H), 7.06 (td, J = 7.7, 1.0 Hz, 1H), 7.01 (dd, J = 8.2, 1.0 Hz, 1H), 4.62 (t, J = 6.3 Hz, 2H), 3.85 (m, 4H), 3.84 (s, 3H), 2.99 (t, J = 6.3 Hz, 2H), 2.66 (m , 4H), 95 (m, 4H), 1.82 (m, 4H); MS (ESI) m/z 538 ([M+H]+). 1H NMR (400 MHz CDCl 3 ) δ 7.93 (d, J = 8.3 Hz, 3H), 7.85 (d, J = 2.3 Hz, 1H), 7.66 (d, J = 8.3 Hz, 2H), 7.62 (dd, J = 8.7, 2.3 Hz, 1H), 7.58 (d, J = 8.7 Hz, 1H), 7.37 (m, 2H), 7.06 (td, J = 7.7, 1.0 Hz, 1H), 7.01 (dd, J = 8.2 , 1.0 Hz, 1H), 4.62 (t, J = 6.3 Hz, 2H), 3.85 (m, 4H), 3.84 (s, 3H), 2.99 (t, J = 6.3 Hz, 2H), 2.66 (m, 4H) ), 95 (m, 4H), 1.82 (m, 4H); MS (ESI) m/z 538 ([M+H] + ).

<실시예 4> 4'-메틸-<Example 4> 4'-methyl- NN -(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드 제조-(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1,1'-biphenyl]-4 -Manufacture of carboxamide

상기 실시예 1의 단계 2와 동일한 방법으로 수행하되, 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 대신에 4'-메틸-[1,1'-바이페닐]-4-카르복실산(35 mg, 0.17 mmol)을 사용하여 목적 화합물(27 mg, 57%)을 얻었다. Carry out in the same manner as step 2 of Example 1, except that instead of 4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, 4'-methyl-[1,1'-biphenyl ]-4-Carboxylic acid (35 mg, 0.17 mmol) was used to obtain the target compound (27 mg, 57%).

1H NMR (400 MHz CDCl3) δ 7.95 (d, J = 8.4 Hz, 2H), 7.91 (s, 1H), 7.85 (d, J = 2.2 Hz, 1H), 7.70 (d, J = 8.3 Hz, 2H), 7.62 (dd, J = 8.7, 2.3 Hz, 1H), 7.58 (d, J = 8.7 Hz, 1H), 7.54 (d, J = 8.1 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 4.62 (t, J = 6.3 Hz, 2H), 3.85 (m, 4H), 2.99 (t, J = 6.3 Hz, 2H), 2.67 (m, 4H), 2.42 (s, 3H), 1.96 (m, 4H), 1.82 (m, 4H); MS (ESI) m/z 522 ([M+H]+). 1H NMR (400 MHz CDCl 3 ) δ 7.95 (d, J = 8.4 Hz, 2H), 7.91 (s, 1H), 7.85 (d, J = 2.2 Hz, 1H), 7.70 (d, J = 8.3 Hz, 2H), 7.62 (dd, J = 8.7, 2.3 Hz, 1H), 7.58 (d, J = 8.7 Hz, 1H), 7.54 (d, J = 8.1 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 4.62 (t, J = 6.3 Hz, 2H), 3.85 (m, 4H), 2.99 (t, J = 6.3 Hz, 2H), 2.67 (m, 4H), 2.42 (s, 3H), 1.96 ( m, 4H), 1.82 (m, 4H); MS (ESI) m/z 522 ([M+H] + ).

<실시예 5> 3'-메틸-<Example 5> 3'-methyl- NN -(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드 제조-(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1,1'-biphenyl]-4 -Manufacture of carboxamide

상기 실시예 1의 단계 2와 동일한 방법으로 수행하되, 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 대신에 3'-메틸-[1,1'-바이페닐]-4-카르복실산(35 mg, 0.17 mmol)을 사용하여 목적 화합물(30 mg, 63%)을 얻었다. Carry out in the same manner as step 2 of Example 1, except that instead of 4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, 3'-methyl-[1,1'-biphenyl ]-4-Carboxylic acid (35 mg, 0.17 mmol) was used to obtain the target compound (30 mg, 63%).

1H NMR (400 MHz CDCl3) δ 8.12 (s, 1H), 7.98 (d, J = 8.3 Hz, 2H), 7.91 (d, J = 2.3 Hz, 1H), 7.70 (d, J = 8.3 Hz, 2H), 7.63 (dd, J = 8.7, 2.4 Hz, 1H), 7.54 (d, J = 8.7 Hz, 1H), 7.43 (d, J = 8.5 Hz, 2H), 7.36 (t, J = 7.5 Hz, 1H), 7.22 (d, J = 7.5 Hz, 1H), 4.79 (d, J = 6.0 Hz, 2H), 3.79 (m, 4H), 3.29 (m, 2H), 3.03 (m, 4H), 2.44 (s, 3H), 2.00 (m, 4H), 1.95 (m, 4H); MS (ESI) m/z 522 ([M+H]+). 1H NMR (400 MHz CDCl 3 ) δ 8.12 (s, 1H), 7.98 (d, J = 8.3 Hz, 2H), 7.91 (d, J = 2.3 Hz, 1H), 7.70 (d, J = 8.3 Hz, 2H), 7.63 (dd, J = 8.7, 2.4 Hz, 1H), 7.54 (d, J = 8.7 Hz, 1H), 7.43 (d, J = 8.5 Hz, 2H), 7.36 (t, J = 7.5 Hz, 1H), 7.22 (d, J = 7.5 Hz, 1H), 4.79 (d, J = 6.0 Hz, 2H), 3.79 (m, 4H), 3.29 (m, 2H), 3.03 (m, 4H), 2.44 ( s, 3H), 2.00 (m, 4H), 1.95 (m, 4H); MS (ESI) m/z 522 ([M+H] + ).

<실시예 6> 2'-메틸-<Example 6> 2'-methyl- NN -(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드 제조-(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1,1'-biphenyl]-4 -Manufacture of carboxamide

상기 실시예 1의 단계 2와 동일한 방법으로 수행하되, 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 대신에 2'-메틸-[1,1'-바이페닐]-4-카르복실산(35 mg, 0.17 mmol)을 사용하여 목적 화합물(31 mg, 65%)을 얻었다. Carry out in the same manner as step 2 of Example 1, except that instead of 4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, 2'-methyl-[1,1'-biphenyl ]-4-Carboxylic acid (35 mg, 0.17 mmol) was used to obtain the target compound (31 mg, 65%).

1H NMR (400 MHz CDCl3) δ 7.99 (d, J = 8.1 Hz, 2H), 7.94 (d, J = 2.3 Hz, 1H), 7.62 (dd, J = 8.7, 2.3 Hz, 1H), 7.52 (d, J = 8.7 Hz, 1H), 7.45 (d, J = 8.1 Hz, 2H), 7.25 (m,5H), 4.82 (t, J = 5.8 Hz, 2H), 3.76 (m, 4H), 3.37 (m, 2H), 3.15 (m, 4H), 2.28 (s, 3H), 2.04 (m, 4H), 1.94 (m, 4H); MS (ESI) m/z 522 ([M+H]+). 1H NMR (400 MHz CDCl 3 ) δ 7.99 (d, J = 8.1 Hz, 2H), 7.94 (d, J = 2.3 Hz, 1H), 7.62 (dd, J = 8.7, 2.3 Hz, 1H), 7.52 ( d, J = 8.7 Hz, 1H), 7.45 (d, J = 8.1 Hz, 2H), 7.25 (m,5H), 4.82 (t, J = 5.8 Hz, 2H), 3.76 (m, 4H), 3.37 ( m, 2H), 3.15 (m, 4H), 2.28 (s, 3H), 2.04 (m, 4H), 1.94 (m, 4H); MS (ESI) m/z 522 ([M+H] + ).

<실시예 7> 4'-플루오르-<Example 7> 4'-fluorine- NN -(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드 제조-(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1,1'-biphenyl]-4 -Manufacture of carboxamide

상기 실시예 1의 단계 2와 동일한 방법으로 수행하되, 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 대신에 4'-플루오르-[1,1'-바이페닐]-4-카르복실산(48 mg, 0.22 mmol)을 사용하여 목적 화합물(35 mg, 73%)을 얻었다. Carry out in the same manner as step 2 of Example 1, except that instead of 4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, 4'-fluoro-[1,1'-biphenyl ]-4-Carboxylic acid (48 mg, 0.22 mmol) was used to obtain the target compound (35 mg, 73%).

1H NMR (400 MHz CDCl3) δ 7.96 (d, J = 8.1 Hz, 2H), 7.91 (s, 1H), 7.85 (d, J = 2.2 Hz, 1H), 7.67 (d, J = 8.1 Hz, 2H), 7.63 (m, 1H), 7.60 (d, J = 5.9 Hz, 2H), 7.58 (d, J = 5.9 Hz, 1H), 7.17 (t, J = 8.6 Hz, 2H), 4.62 (t, J = 6.3 Hz, 2H), 3.85 (m, 4H), 2.99 (t, J = 6.3 Hz, 2H), 2.67 (m, 4H), 1.96 (m, 4H), 1.83 (m, 4H); MS (ESI) m/z 526 ([M+H]+). 1H NMR (400 MHz CDCl 3 ) δ 7.96 (d, J = 8.1 Hz, 2H), 7.91 (s, 1H), 7.85 (d, J = 2.2 Hz, 1H), 7.67 (d, J = 8.1 Hz, 2H), 7.63 (m, 1H), 7.60 (d, J = 5.9 Hz, 2H), 7.58 (d, J = 5.9 Hz, 1H), 7.17 (t, J = 8.6 Hz, 2H), 4.62 (t, J = 6.3 Hz, 2H), 3.85 (m, 4H), 2.99 (t, J = 6.3 Hz, 2H), 2.67 (m, 4H), 1.96 (m, 4H), 1.83 (m, 4H); MS (ESI) m/z 526 ([M+H] + ).

<실시예 8> 3'-플루오르-<Example 8> 3'-fluorine- NN -(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드 제조-(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1,1'-biphenyl]-4 -Manufacture of carboxamide

상기 실시예 1의 단계 2와 동일한 방법으로 수행하되, 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 대신에 3'-플루오르-[1,1'-바이페닐]-4-카르복실산(48 mg, 0.22 mmol)을 사용하여 목적 화합물(33 mg, 69%)을 얻었다. Carry out in the same manner as step 2 of Example 1, except that instead of 4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, 3'-fluoro-[1,1'-biphenyl ]-4-Carboxylic acid (48 mg, 0.22 mmol) was used to obtain the target compound (33 mg, 69%).

1H NMR (400 MHz CDCl3) δ 7.98 (d, J = 8.3 Hz, 2H), 7.93 (s, 1H), 7.87 (d, J = 2.2 Hz, 1H), 7.71 (d, J = 8.3 Hz, 2H), 7.63 (m, 1H), 7.58 (d, J = 8.7 Hz, 1H), 7.45 (m, 1H), 7.42 (m, 1H), 7.34 (d, J = 10.2 Hz, 1H), 7.10 (t, J = 7.9 Hz, 1H), 4.73 (s, 2H), 3.83 (m, 4H), 2.99 (m, 6H), 1.96 (m, 4H), 1.93 (m, 4H); MS (ESI) m/z 526 ([M+H]+). 1H NMR (400 MHz CDCl 3 ) δ 7.98 (d, J = 8.3 Hz, 2H), 7.93 (s, 1H), 7.87 (d, J = 2.2 Hz, 1H), 7.71 (d, J = 8.3 Hz, 2H), 7.63 (m, 1H), 7.58 (d, J = 8.7 Hz, 1H), 7.45 (m, 1H), 7.42 (m, 1H), 7.34 (d, J = 10.2 Hz, 1H), 7.10 ( t, J = 7.9 Hz, 1H), 4.73 (s, 2H), 3.83 (m, 4H), 2.99 (m, 6H), 1.96 (m, 4H), 1.93 (m, 4H); MS (ESI) m/z 526 ([M+H] + ).

<실시예 9> 2'-플루오르-<Example 9> 2'-fluorine- NN -(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드 제조-(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1,1'-biphenyl]-4 -Manufacture of carboxamide

상기 실시예 1의 단계 5와 동일한 방법으로 수행하되, 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 대신에 2'-플루오르-[1,1'-바이페닐]-4-카르복실산(48 mg, 0.22 mmol)을 사용하여 목적 화합물(35 mg, 75%)을 얻었다. Carry out in the same manner as step 5 of Example 1, except that instead of 4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, 2'-fluoro-[1,1'-biphenyl ]-4-Carboxylic acid (48 mg, 0.22 mmol) was used to obtain the target compound (35 mg, 75%).

1H NMR (400 MHz CDCl3) δ 8.06 (d, J = 2.5 Hz, 2H), 8.04 (s, 1H), 7.71 (d, J = 8.2 Hz, 2H), 7.56 (s, 2H), 7.54 (s, 1H), 7.43 (m, 1H), 7.30 (t, J = 7.5 Hz, 1H), 7.24 (dd, J = 11.0, 8.2 Hz, 1H), 4.74 (t, J = 5.6 Hz, 2H), 3.86 (m, 4H), 3.40 (t, J = 5.6 Hz, 2H), 3.09 (m, 4H), 1.99 (m,8H); MS (ESI) m/z 526 ([M+H]+). 1H NMR (400 MHz CDCl 3 ) δ 8.06 (d, J = 2.5 Hz, 2H), 8.04 (s, 1H), 7.71 (d, J = 8.2 Hz, 2H), 7.56 (s, 2H), 7.54 ( s, 1H), 7.43 (m, 1H), 7.30 (t, J = 7.5 Hz, 1H), 7.24 (dd, J = 11.0, 8.2 Hz, 1H), 4.74 (t, J = 5.6 Hz, 2H), 3.86 (m, 4H), 3.40 (t, J = 5.6 Hz, 2H), 3.09 (m, 4H), 1.99 (m,8H); MS (ESI) m/z 526 ([M+H] + ).

<실시예 10> 4'-클로로-<Example 10> 4'-chloro- NN -(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드 제조-(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1,1'-biphenyl]-4 -Manufacture of carboxamide

상기 실시예 1의 단계 2와 동일한 방법으로 수행하되, 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 대신에 4'-클로로-[1,1'-바이페닐]-4-카르복실산(51 mg, 0.22 mmol)을 사용하여 목적 화합물(37 mg, 75%)을 얻었다. Carry out in the same manner as step 2 of Example 1, except that instead of 4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, 4'-chloro-[1,1'-biphenyl ]-4-Carboxylic acid (51 mg, 0.22 mmol) was used to obtain the target compound (37 mg, 75%).

1H NMR (400 MHz CDCl3) δ 8.06 (d, J = 3.0 Hz, 2H), 8.03 (s, 1H), 7.78 (d, J = 8.3 Hz, 2H), 7.69 (d, J = 8.5 Hz, 2H), 7.57 (s, 2H), 7.49 (d, J = 8.4 Hz, 2H), 4.80 (t, J = 5.4 Hz, 2H), 3.87 (m, 4H), 3.57 (t, J = 5.4 Hz, 2H), 3.28 (m, 4H), 2.04 (m, 4H), 2.00 (m, 4H); MS (ESI) m/z 542 ([M+H]+). 1H NMR (400 MHz CDCl 3 ) δ 8.06 (d, J = 3.0 Hz, 2H), 8.03 (s, 1H), 7.78 (d, J = 8.3 Hz, 2H), 7.69 (d, J = 8.5 Hz, 2H), 7.57 (s, 2H), 7.49 (d, J = 8.4 Hz, 2H), 4.80 (t, J = 5.4 Hz, 2H), 3.87 ( m , 4H), 3.57 (t, J = 5.4 Hz, 2H), 3.28 (m, 4H), 2.04 (m, 4H), 2.00 (m, 4H); MS (ESI) m/z 542 ([M+H] + ).

<실시예 11> 3'-클로로-<Example 11> 3'-chloro- NN -(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드 제조-(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1,1'-biphenyl]-4 -Manufacture of carboxamide

상기 실시예 1의 단계 2와 동일한 방법으로 수행하되, 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 대신에 3'-클로로-[1,1'-바이페닐]-4-카르복실산(51 mg, 0.22 mmol)를 사용하여 목적 화합물(36 mg, 73%)을 얻었다. Carry out in the same manner as step 2 of Example 1, except that instead of 4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, 3'-chloro-[1,1'-biphenyl ]-4-Carboxylic acid (51 mg, 0.22 mmol) was used to obtain the target compound (36 mg, 73%).

1H NMR (400 MHz CDCl3) δ 8.07 (s, 1H), 8.04 (m, 2H), 7.78 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 1.9 Hz, 1H), 7.63 (m, 1H), 7.57 (d, J = 2.5 Hz, 2H), 7.48 (t, J = 7.8 Hz, 1H), 7.41 (dt, J = 8.3, 1.5 Hz, 1H), 4.83 (t, J = 5.3 Hz, 2H), 3.86 (m, 4H), 3.68 (t, J = 5.3 Hz, 2H), 3.41 (m, 4H), 2.10 (m, 4H), 2.00 (m, 4H); MS (ESI) m/z 542 ([M+H]+). 1H NMR (400 MHz CDCl 3 ) δ 8.07 (s, 1H), 8.04 (m, 2H), 7.78 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 1.9 Hz, 1H), 7.63 ( m, 1H), 7.57 (d, J = 2.5 Hz, 2H), 7.48 (t, J = 7.8 Hz, 1H), 7.41 (dt, J = 8.3, 1.5 Hz, 1H), 4.83 (t, J = 5.3) Hz, 2H), 3.86 (m, 4H), 3.68 (t, J = 5.3 Hz, 2H), 3.41 (m, 4H), 2.10 (m, 4H), 2.00 (m, 4H); MS (ESI) m/z 542 ([M+H] + ).

<실시예 12> 2'-클로로-<Example 12> 2'-chloro- NN -(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드 제조-(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1,1'-biphenyl]-4 -Manufacture of carboxamide

상기 실시예 1의 단계 2와 동일한 방법으로 수행하되, 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 대신에 2'-클로로-[1,1'-바이페닐]-4-카르복실산(51 mg, 0.22 mmol)을 사용하여 목적 화합물(38 mg, 77%)을 얻었다. Carry out in the same manner as step 2 of Example 1, except that instead of 4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, 2'-chloro-[1,1'-biphenyl ]-4-Carboxylic acid (51 mg, 0.22 mmol) was used to obtain the target compound (38 mg, 77%).

1H NMR (400 MHz CDCl3) δ 8.06 (d, J = 2.1 Hz, 1H), 8.02 (d, J = 8.1 Hz, 2H), 7.58 (d, J = 8.1 Hz, 2H), 7.56 (d, J = 2.0 Hz, 1H), 7.53 (d, J = 8.7 Hz, 2H), 7.42 (m, 2H), 7.37 (dd, J = 8.2, 3.8 Hz, 1H), 4.75 (t, J = 5.6 Hz, 2H), 3.85 (m, 4H), 3.45 (t, J = 5.9 Hz, 2H), 3.16 (m, 4H), 1.99 (m, 8H); MS (ESI) m/z 542 ([M+H]+). 1H NMR (400 MHz CDCl 3 ) δ 8.06 (d, J = 2.1 Hz, 1H), 8.02 (d, J = 8.1 Hz, 2H), 7.58 (d, J = 8.1 Hz, 2H), 7.56 (d, J = 2.0 Hz, 1H), 7.53 (d, J = 8.7 Hz, 2H), 7.42 (m, 2H), 7.37 (dd, J = 8.2, 3.8 Hz, 1H), 4.75 (t, J = 5.6 Hz, 2H), 3.85 (m, 4H), 3.45 (t, J = 5.9 Hz, 2H), 3.16 (m, 4H), 1.99 (m, 8H); MS (ESI) m/z 542 ([M+H] + ).

<실시예 13> 4'-시아노-<Example 13> 4'-Cyano- NN -(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드 제조-(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1,1'-biphenyl]-4 -Manufacture of carboxamide

상기 실시예 1의 단계 2와 동일한 방법으로 수행하되, 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 대신에 4'-시아노-[1,1'-바이페닐]-4-카르복실산(49 mg, 0.22 mmol)을 사용하여 목적 화합물(37 mg, 76%)을 얻었다. Carry out in the same manner as step 2 of Example 1, except that instead of 4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, 4'-cyano-[1,1'-bi The target compound (37 mg, 76%) was obtained using phenyl]-4-carboxylic acid (49 mg, 0.22 mmol).

1H NMR (400 MHz CDCl3) δ 8.01 (d, J = 8.4 Hz, 2H), 7.96 (s, 1H), 7.86 (d, J = 2.0 Hz, 1H), 7.77 (d, J = 8.4 Hz, 2H), 7.72 (dd, J = 6.3, 2.2 Hz, 3H), 7.70 (d, J = 1.6 Hz, 1H), 7.59 (m, 2H), 4.63 (t, J = 6.2 Hz, 2H), 3.84 (m, 4H), 3.49 (m, 2H), 3.00 (t, J = 6.2 Hz, 2H), 2.68 (m, 4H), 1.96 (m, 4H), 1.83 (m, 4H); MS (ESI) m/z 533 ([M+H]+). 1H NMR (400 MHz CDCl 3 ) δ 8.01 (d, J = 8.4 Hz, 2H), 7.96 (s, 1H), 7.86 (d, J = 2.0 Hz, 1H), 7.77 (d, J = 8.4 Hz, 2H), 7.72 (dd, J = 6.3, 2.2 Hz, 3H), 7.70 (d, J = 1.6 Hz, 1H), 7.59 (m, 2H), 4.63 (t, J = 6.2 Hz, 2H), 3.84 ( m, 4H), 3.49 (m, 2H), 3.00 (t, J = 6.2 Hz, 2H), 2.68 (m, 4H), 1.96 (m, 4H), 1.83 (m, 4H); MS (ESI) m/z 533 ([M+H] + ).

<실시예 14> 3'-시아노-<Example 14> 3'-Cyano- NN -(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드 제조-(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1,1'-biphenyl]-4 -Manufacture of carboxamide

상기 실시예 1의 단계 5와 동일한 방법으로 수행하되, 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 대신에 3'-시아노-[1,1'-바이페닐]-4-카르복실산(49 mg, 0.22 mmol)을 사용하여 목적 화합물(36 mg, 74%)을 얻었다. Carry out in the same manner as step 5 of Example 1, except that instead of 4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, 3'-cyano-[1,1'-bi The target compound (36 mg, 74%) was obtained using phenyl]-4-carboxylic acid (49 mg, 0.22 mmol).

1H NMR (400 MHz CDCl3) δ 8.02 (s, 1H), 7.99 (d, J = 2.7 Hz, 2H), 7.89 (m, 2H), 7.84 (s, 1H), 7.69 (m, 3H), 7.60 (d, J = 9.1 Hz, 2H), 7.56 (dd, J = 7.1, 2.8 Hz, 1H), 4.64 (t, J = 6.2 Hz, 2H), 3.84 (m, 4H), 3.02 (t, J = 6.2 Hz, 2H), 2.71 (m, 4H), 1.94 (m, 4H), 1.84 (m, 4H); MS (ESI) m/z 533 ([M+H]+). 1H NMR (400 MHz CDCl 3 ) δ 8.02 (s, 1H), 7.99 (d, J = 2.7 Hz, 2H), 7.89 (m, 2H), 7.84 (s, 1H), 7.69 (m, 3H), 7.60 (d, J = 9.1 Hz, 2H), 7.56 (dd, J = 7.1, 2.8 Hz, 1H), 4.64 (t, J = 6.2 Hz, 2H), 3.84 (m, 4H), 3.02 (t, J = 6.2 Hz, 2H), 2.71 (m, 4H), 1.94 (m, 4H), 1.84 (m, 4H); MS (ESI) m/z 533 ([M+H] + ).

<실시예 15> <Example 15> NN -(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-4'-(트리플루오르메틸)-[1,1'-바이페닐]-4-카르복스아마이드 제조-(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-4'-(trifluoromethyl)-[1 ,1'-Biphenyl]-4-carboxamide production

상기 실시예 1의 단계 2와 동일한 방법으로 수행하되, 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 대신에 4'-(트리플루오르메틸)-[1,1'-바이페닐]-4-카르복실산(59 mg, 0.22 mmol)을 사용하여 목적 화합물(37 mg, 70%)을 얻었다. Carry out in the same manner as step 2 of Example 1, except that instead of 4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, 4'-(trifluoromethyl)-[1,1 The target compound (37 mg, 70%) was obtained using '-biphenyl]-4-carboxylic acid (59 mg, 0.22 mmol).

1H NMR (400 MHz Methanol-d 4) δ 8.08 (d, J = 8.4 Hz, 3H), 7.90 (d, J = 8.2 Hz, 2H), 7.85 (d, J = 8.2 Hz, 2H), 7.79 (d, J = 8.2 Hz, 2H), 7.57 (s, 2H), 4.80 (t, J = 5.4 Hz, 2H), 3.87 (m, 4H), 3.56 (t, J = 5.4 Hz, 2H), 3.26 (m, 4H), 2.06 (m, 4H), 2.01 (m, 4H); MS (ESI) m/z 576 ([M+H]+). 1H NMR (400 MHz Methanol- d 4 ) δ 8.08 (d, J = 8.4 Hz, 3H), 7.90 (d, J = 8.2 Hz, 2H), 7.85 (d, J = 8.2 Hz, 2H), 7.79 ( d, J = 8.2 Hz, 2H), 7.57 (s, 2H), 4.80 (t, J = 5.4 Hz, 2H), 3.87 (m, 4H), 3.56 (t, J = 5.4 Hz, 2H), 3.26 ( m, 4H), 2.06 (m, 4H), 2.01 (m, 4H); MS (ESI) m/z 576 ([M+H] + ).

<실시예 16> <Example 16> NN -(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-3'-(트리플루오르메틸)-[1,1'-바이페닐]-4-카르복스아마이드 제조-(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-3'-(trifluoromethyl)-[1 ,1'-Biphenyl]-4-carboxamide production

상기 실시예 1의 단계 2와 동일한 방법으로 수행하되, 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 대신에 3'-(트리플루오르메틸)-[1,1'-바이페닐]-4-카르복실산(59 mg, 0.22 mmol)을 사용하여 목적 화합물(40 mg, 76%)을 얻었다. Carry out in the same manner as step 2 of Example 1, except that instead of 4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, 3'-(trifluoromethyl)-[1,1 The target compound (40 mg, 76%) was obtained using '-biphenyl]-4-carboxylic acid (59 mg, 0.22 mmol).

1H NMR (400 MHz Methanol-d 4) δ 8.09 (s, 1H), 8.07 (s, 2H), 7.96 (s, 2H), 7.82 (d, J = 8.3 Hz, 2H), 7.70 (m, 2H), 7.57 (m, 2H), 4.84 (m, 2H), 3.85 (m, 4H), 3.74 (t, J = 5.2 Hz, 2H), 3.48 (s, 4H), 2.12 (m, 4H), 2.99 (m, 4H); MS (ESI) m/z 576 ([M+H]+). 1H NMR (400 MHz Methanol- d 4 ) δ 8.09 (s, 1H), 8.07 (s, 2H), 7.96 (s, 2H), 7.82 (d, J = 8.3 Hz, 2H), 7.70 (m, 2H) ), 7.57 (m, 2H), 4.84 (m, 2H), 3.85 (m, 4H), 3.74 (t, J = 5.2 Hz, 2H), 3.48 (s, 4H), 2.12 (m, 4H), 2.99 (m, 4H); MS (ESI) m/z 576 ([M+H] + ).

<실시예 17> <Example 17> NN -(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-2'-(트리플루오르메틸)-[1,1'-바이페닐]-4-카르복스아마이드 제조-(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-2'-(trifluoromethyl)-[1 ,1'-Biphenyl]-4-carboxamide production

상기 실시예 1의 단계 5와 동일한 방법으로 수행하되, 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 대신에 2'-(트리플루오르메틸)-[1,1'-바이페닐]-4-카르복실산(59 mg, 0.22 mmol)을 사용하여 목적 화합물(33 mg, 63%)을 얻었다. Carry out in the same manner as step 5 of Example 1, except that instead of 4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, 2'-(trifluoromethyl)-[1,1 The target compound (33 mg, 63%) was obtained using '-biphenyl]-4-carboxylic acid (59 mg, 0.22 mmol).

1H NMR (400 MHz Methanol-d 4) δ 8.07 (d, J = 2.1 Hz, 1H), 8.01 (d, J = 8.1 Hz, 2H), 7.82 (d, J = 7.8 Hz, 1H), 7.69 (t, J = 7.5 Hz, 1H), 7.61 (d, J = 6.7 Hz, 1H), 7.58 (d, J = 2.2 Hz, 1H), 7.55 (d, J = 8.7 Hz, 1H), 7.48 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 7.6 Hz, 1H), 4.83 (d, J = 5.4 Hz, 2H), 3.85 (m, 4H), 3.72 (t, J = 5.2 Hz, 2H), 3.46 (m, 4H), 2.10 (m, 4H), 2.00 (m, 4H); MS (ESI) m/z 576 ([M+H]+). 1H NMR (400 MHz Methanol- d 4 ) δ 8.07 (d, J = 2.1 Hz, 1H), 8.01 (d, J = 8.1 Hz, 2H), 7.82 (d, J = 7.8 Hz, 1H), 7.69 ( t, J = 7.5 Hz, 1H), 7.61 (d, J = 6.7 Hz, 1H), 7.58 (d, J = 2.2 Hz, 1H), 7.55 (d, J = 8.7 Hz, 1H), 7.48 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 7.6 Hz, 1H), 4.83 (d, J = 5.4 Hz, 2H), 3.85 (m, 4H), 3.72 (t, J = 5.2 Hz, 2H) , 3.46 (m, 4H), 2.10 (m, 4H), 2.00 (m, 4H); MS (ESI) m/z 576 ([M+H] + ).

<실시예 18> <Example 18> NN -(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드 제조-(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1,1'-biphenyl]-4 -Manufacture of carboxamide

상기 실시예 1의 단계 2와 동일한 방법으로 수행하되, 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 대신에 [1,1'-바이페닐]-4-카르복실산(22 mg, 0.11 mmol)을 사용하여 목적 화합물(24 mg, 52%)을 얻었다. Carry out in the same manner as step 2 of Example 1, except that instead of 4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, [1,1'-biphenyl]-4-carboxylic acid The target compound (24 mg, 52%) was obtained using boxylic acid (22 mg, 0.11 mmol).

1H NMR (400 MHz CDCl3) δ 7.96 (d, J = 8.3 Hz, 3H), 7.86 (d, J = 2.2 Hz, 1H), 7.71 (d, J = 8.3 Hz, 2H), 7.63 (m, 3H), 7.58 (d, J = 8.7 Hz, 1H), 7.48 (t, J = 7.3 Hz, 2H), 7.40 (t, J = 7.3 Hz, 1H), 4.61 (t, J = 6.3 Hz, 2H), 3.84 (m, 4H), 2.98 (t, J = 6.3 Hz, 2H), 2.65 (m, 4H), 1.95 (m, 4H), 182 (m, 4H); MS (ESI) m/z 508 ([M+H]+). 1H NMR (400 MHz CDCl 3 ) δ 7.96 (d, J = 8.3 Hz, 3H), 7.86 (d, J = 2.2 Hz, 1H), 7.71 (d, J = 8.3 Hz, 2H), 7.63 (m, 3H), 7.58 (d, J = 8.7 Hz, 1H), 7.48 (t, J = 7.3 Hz, 2H), 7.40 (t, J = 7.3 Hz, 1H), 4.61 (t, J = 6.3 Hz, 2H) , 3.84 (m, 4H), 2.98 (t, J = 6.3 Hz, 2H), 2.65 (m, 4H), 1.95 (m, 4H), 182 (m, 4H); MS (ESI) m/z 508 ([M+H] + ).

<실시예 19> <Example 19> NN -(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-4'-메톡시-[1,1'-바이페닐]-4-카르복스아마이드 제조-(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-4'-methoxy-[1,1'-biphenyl] -4-Carboxamide production

단계 1: 2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-아민 제조Step 1: Preparation of 2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-amine

실온에서 60% 소디움 하이드라이드(438 mg, 10.9 mmol)와 2-다이메틸아미노에탄올 (1.00 mL, 10.0 mmol)를 테트라하이드로퓨란에 혼합한 뒤 테트라하이드로퓨란(30 mL)에 녹인 2-클로로-3-(피롤리딘-1-일)퀴녹살린-6-아민(2.27 g, 9.12 mmol)을 더하고 30시간 동안 교반하였다 (중간에 추가적으로 60% 소디움 하이드라이드 1.2 당량과 2-다이메틸아미노에탄올 1 당량을 더했다). 반응혼합물에 암모니움 클로라이드 포화 수용액을 더하고 다이클로로메탄으로 추출한 뒤 다이클로로메탄 층을 마그네슘 설페이트로 건조하였다. 용매를 감압하에서 제거한 다음 남은 잔류물에 대해 실리카겔 관 크로마토그래피(다이클로로메탄 : 메탄올 = 30 : 1)를 수행하여 목적화합물(2.56 g, 93%)을 얻었다. 60% sodium hydride (438 mg, 10.9 mmol) and 2-dimethylaminoethanol (1.00 mL, 10.0 mmol) were mixed in tetrahydrofuran at room temperature, and then 2-chloro-3 dissolved in tetrahydrofuran (30 mL). -(pyrrolidin-1-yl)quinoxalin-6-amine (2.27 g, 9.12 mmol) was added and stirred for 30 hours (1.2 equivalents of 60% sodium hydride and 1 equivalent of 2-dimethylaminoethanol were added in the middle) was added). A saturated aqueous solution of ammonium chloride was added to the reaction mixture, extracted with dichloromethane, and the dichloromethane layer was dried over magnesium sulfate. The solvent was removed under reduced pressure, and the remaining residue was subjected to silica gel column chromatography (dichloromethane : methanol = 30 : 1) to obtain the target compound (2.56 g, 93%).

1H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 8.5 Hz, 1H), 6.85 (d, J = 2.5 Hz, 1H), 6.68 (dd, J = 8.5, 2.5 Hz, 1H), 4.50 (t, J = 6.0 Hz, 2H), 3.81 (m, 4H), 3.73 (br s, 2H), 2.76 (t, J = 6.0 Hz, 2H), 2.33 (s, 6H), 1.93 (m, 4H); MS (ESI) m/z 302 ([M+H]+). 1H NMR (400 MHz, CDCl 3 ) δ 7.39 (d, J = 8.5 Hz, 1H), 6.85 (d, J = 2.5 Hz, 1H), 6.68 (dd, J = 8.5, 2.5 Hz, 1H), 4.50 (t, J = 6.0 Hz, 2H), 3.81 (m, 4H), 3.73 (br s, 2H), 2.76 (t, J = 6.0 Hz, 2H), 2.33 (s, 6H), 1.93 (m, 4H) ); MS (ESI) m/z 302 ([M+H] + ).

단계 2: Step 2: NN -(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-4'-메톡시-[1,1'-바이페닐]-4-카르복스아마이드 제조-(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-4'-methoxy-[1,1'-biphenyl] -4-Carboxamide production

실온에서 2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-아민(30 mg, 0.099 mmol), 4'-메톡시-[1,1'-바이페닐]-4-카르복실산(27 mg, 0.12 mmol), 및 1-에틸-3-(3′-다이메틸아미노프로필)카르보다이이마이드(23 mg, 0.12 mmol)를 다이클로로메탄/N,N-다이메틸포름아마이드(1 mL/1 mL)에 더한 뒤 36시간 동안 교반하였다 (중간에 추가적으로 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 1.2 당량과 1-에틸-3-(3′-다이메틸아미노프로필)카르보다이이마이드 1.2 당량을 더했다). 용매를 감압하에서 제거한 다음 남은 잔류물에 대해 실리카겔 관 크로마토그래피(다이클로로메탄 : 메탄올 = 20 : 1)를 수행하여 목적 화합물(26 mg, 51%)을 얻었다.2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-amine (30 mg, 0.099 mmol), 4'-methoxy-[1, 1'-Biphenyl]-4-carboxylic acid (27 mg, 0.12 mmol), and 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide (23 mg, 0.12 mmol) were reacted with dichloro. Methane/ N , N -dimethylformamide (1 mL/1 mL) was added and stirred for 36 hours (4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid was added in the middle) 1.2 equivalents and 1.2 equivalents of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide were added). The solvent was removed under reduced pressure, and the remaining residue was subjected to silica gel column chromatography (dichloromethane : methanol = 20 : 1) to obtain the target compound (26 mg, 51%).

1H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 7.93 (d, J = 8.2 Hz, 2H), 7.85 (d, J = 2.3 Hz, 1H), 7.64 (m, 3H), 7.57 (d, J = 8.5 Hz, 3H), 7.00 (d, J = 8.5 Hz, 2H), 4.56 (t, J = 5.9 Hz, 2H), 3.86 (s, 3H), 3.83 (m, 4H), 2.80 (t, J = 5.9 Hz, 2H), 2.36 (s, 6H), 1.94 (m, 4H); MS (ESI) m/z 512 ([M+H]+). 1H NMR (400 MHz, CDCl 3 ) δ 8.00 (s, 1H), 7.93 (d, J = 8.2 Hz, 2H), 7.85 (d, J = 2.3 Hz, 1H), 7.64 (m, 3H), 7.57 (d, J = 8.5 Hz, 3H), 7.00 (d, J = 8.5 Hz, 2H), 4.56 (t, J = 5.9 Hz, 2H), 3.86 (s, 3H), 3.83 (m, 4H), 2.80 (t, J = 5.9 Hz, 2H), 2.36 (s, 6H), 1.94 (m, 4H); MS (ESI) m/z 512 ([M+H] + ).

<실시예 20> <Example 20> NN -(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-3'-메톡시-[1,1'-바이페닐]-4-카르복스아마이드 제조-(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-3'-methoxy-[1,1'-biphenyl] -4-Carboxamide production

상기 실시예 19의 단계 2와 동일한 방법으로 수행하되, 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 대신에 3'-메톡시-[1,1'-바이페닐]-4-카르복실산(27 mg, 0.12 mmol)을 사용하여 목적 화합물(30 mg, 59%)을 얻었다. Carry out in the same manner as step 2 of Example 19, except that instead of 4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, 3'-methoxy-[1,1'-bi The target compound (30 mg, 59%) was obtained using phenyl]-4-carboxylic acid (27 mg, 0.12 mmol).

1H NMR (400 MHz CDCl3) δ 7.98 (s, 1H), 7.95 (d, J = 8.0 Hz, 2H), 7.86 (d, J = 2.3 Hz, 1H), 7.69 (d, J = 8.0 Hz, 2H), 7.62 (dd, J = 8.6, 2.3 Hz, 1H), 7.57 (d, J = 8.6 Hz, 1H), 7.39 (t, J = 7.9 Hz, 1H), 7.22 (m, 1H), 7.15 (t, J = 2.1 Hz, 1H), 6.95 (dd, J = 8.2, 2.5 Hz, 1H), 4.57 (t, J = 5.9 Hz, 2H), 3.88 (s, 3H), 3.83 (m, 4H), 2.81 (t, J = 5.9 Hz, 2H), 2.37 (s, 6H), 1.94 (m, 4H); MS (ESI) m/z 512 ([M+H]+). 1H NMR (400 MHz CDCl 3 ) δ 7.98 (s, 1H), 7.95 (d, J = 8.0 Hz, 2H), 7.86 (d, J = 2.3 Hz, 1H), 7.69 (d, J = 8.0 Hz, 2H), 7.62 (dd, J = 8.6, 2.3 Hz, 1H), 7.57 (d, J = 8.6 Hz, 1H), 7.39 (t, J = 7.9 Hz, 1H), 7.22 (m, 1H), 7.15 ( t, J = 2.1 Hz, 1H), 6.95 (dd, J = 8.2, 2.5 Hz, 1H), 4.57 (t, J = 5.9 Hz, 2H), 3.88 (s, 3H), 3.83 (m, 4H), 2.81 (t, J = 5.9 Hz, 2H), 2.37 (s, 6H), 1.94 (m, 4H); MS (ESI) m/z 512 ([M+H] + ).

<실시예 21> <Example 21> NN -(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-2'-메톡시-[1,1'-바이페닐]-4-카르복스아마이드 제조-(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-2'-methoxy-[1,1'-biphenyl] -4-Carboxamide production

상기 실시예 19의 단계 2와 동일한 방법으로 수행하되, 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 대신에 2'-메톡시-[1,1'-바이페닐]-4-카르복실산(27 mg, 0.12 mmol)을 사용하여 목적 화합물(22 mg, 43%)을 얻었다. Carry out in the same manner as step 2 of Example 19, except that instead of 4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, 2'-methoxy-[1,1'-bi The target compound (22 mg, 43%) was obtained using phenyl]-4-carboxylic acid (27 mg, 0.12 mmol).

1H NMR (400 MHz CDCl3) δ 7.93 (d, J = 8.2 Hz, 3H), 7.84 (d, J = 2.3 Hz, 1H), 7.66 (d, J = 8.1 Hz, 2H), 7.62 (m, 1H), 7.58 (d, J = 8.8 Hz, 1H), 7.37 (m, 2H), 7.06 (t, J = 7.4 Hz, 1H), 7.02 (d, J = 8.2 Hz, 1H), 4.57 (t, J = 5.9 Hz, 2H), 3.85 (m, 4H), 3.84 (s, 3H), 2.80 (t, J = 5.9 Hz, 2H), 2.36 (s, 6H), 1.96 (m, 4H); MS (ESI) m/z 512 ([M+H]+). 1H NMR (400 MHz CDCl 3 ) δ 7.93 (d, J = 8.2 Hz, 3H), 7.84 (d, J = 2.3 Hz, 1H), 7.66 (d, J = 8.1 Hz, 2H), 7.62 (m, 1H), 7.58 (d, J = 8.8 Hz, 1H), 7.37 (m, 2H), 7.06 (t, J = 7.4 Hz, 1H), 7.02 (d, J = 8.2 Hz, 1H), 4.57 (t, J = 5.9 Hz, 2H), 3.85 (m, 4H), 3.84 (s, 3H), 2.80 (t, J = 5.9 Hz, 2H), 2.36 (s, 6H), 1.96 (m, 4H); MS (ESI) m/z 512 ([M+H] + ).

<실시예 22> <Example 22> NN -(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-4'-메틸-[1,1'-바이페닐]-4-카르복스아마이드 제조-(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-4'-methyl-[1,1'-biphenyl]- 4-Carboxamide production

상기 실시예 19의 단계 2와 동일한 방법으로 수행하되, 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 대신에 4'-메틸-[1,1'-바이페닐]-4-카르복실산(38 mg, 0.18 mmol)을 사용하여 목적 화합물(24 mg, 49%)을 얻었다. Carry out in the same manner as step 2 of Example 19, except that instead of 4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, 4'-methyl-[1,1'-biphenyl ]-4-Carboxylic acid (38 mg, 0.18 mmol) was used to obtain the target compound (24 mg, 49%).

1H NMR (400 MHz CDCl3) δ 7.96 (m, 2H), 7.93 (s, 1H), 7.85 (d, J = 2.3 Hz, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.62 (dd, J = 8.7, 2.3 Hz, 1H), 7.57 (d, J = 8.7 Hz, 1H), 7.53 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 4.57 (t, J = 5.9 Hz, 2H), 3.84 (m, 4H), 2.80 (t, J = 5.9 Hz, 2H), 2.41 (s, 3H), 2.36 (s, 6H), 1.95 (m, 4H); MS (ESI) m/z 496 ([M+H]+). 1H NMR (400 MHz CDCl 3 ) δ 7.96 (m, 2H), 7.93 (s, 1H), 7.85 (d, J = 2.3 Hz, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.62 ( dd, J = 8.7, 2.3 Hz, 1H), 7.57 (d, J = 8.7 Hz, 1H), 7.53 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 4.57 ( t, J = 5.9 Hz, 2H), 3.84 (m, 4H), 2.80 (t, J = 5.9 Hz, 2H), 2.41 (s, 3H), 2.36 (s, 6H), 1.95 (m, 4H); MS (ESI) m/z 496 ([M+H] + ).

<실시예 23> <Example 23> NN -(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-3'-메틸-[1,1'-바이페닐]-4-카르복스아마이드 제조-(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-3'-methyl-[1,1'-biphenyl]- 4-Carboxamide production

상기 실시예 19의 단계 2와 동일한 방법으로 수행하되, 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 대신에 3'-메틸-[1,1'-바이페닐]-4-카르복실산(38 mg, 0.18 mmol)을 사용하여 목적 화합물(26 mg, 53%)을 얻었다. Carry out in the same manner as step 2 of Example 19, except that instead of 4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, 3'-methyl-[1,1'-biphenyl ]-4-Carboxylic acid (38 mg, 0.18 mmol) was used to obtain the target compound (26 mg, 53%).

1H NMR (400 MHz CDCl3) δ 8.04 (m, 1H), 7.95 (d, J = 8.2 Hz, 2H), 7.87 (d, J = 2.3 Hz, 1H), 7.69 (d, J = 8.2 Hz, 2H), 7.62 (dd, J = 8.7, 2.3 Hz, 1H), 7.56 (d, J = 8.7 Hz, 1H), 7.43 (d, J = 8.6 Hz, 2H), 7.36 (t, J = 7.5 Hz, 1H), 7.21 (d, J = 7.5 Hz, 1H), 4.61 (t, J = 5.9 Hz, 2H), 3.82 (m, 4H), 2.88 (t, J = 5.9 Hz, 2H), 2.44 (s, 3H), 2.42 (s, 6H), 1.94 (m, 4H); MS (ESI) m/z 496 ([M+H]+). 1H NMR (400 MHz CDCl 3 ) δ 8.04 (m, 1H), 7.95 (d, J = 8.2 Hz, 2H), 7.87 (d, J = 2.3 Hz, 1H), 7.69 (d, J = 8.2 Hz, 2H), 7.62 (dd, J = 8.7, 2.3 Hz, 1H), 7.56 (d, J = 8.7 Hz, 1H), 7.43 (d, J = 8.6 Hz, 2H), 7.36 (t, J = 7.5 Hz, 1H), 7.21 (d, J = 7.5 Hz, 1H), 4.61 (t, J = 5.9 Hz, 2H), 3.82 (m, 4H), 2.88 (t, J = 5.9 Hz, 2H), 2.44 (s, 3H), 2.42 (s, 6H), 1.94 (m, 4H); MS (ESI) m/z 496 ([M+H] + ).

<실시예 24> <Example 24> NN -(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-2'-메틸-[1,1'-바이페닐]-4-카르복스아마이드 제조-(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-2'-methyl-[1,1'-biphenyl]- 4-Carboxamide production

상기 실시예 19의 단계 2와 동일한 방법으로 수행하되, 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 대신에 2'-메틸-[1,1'-바이페닐]-4-카르복실산(38 mg, 0.18 mmol)을 사용하여 목적 화합물(32 mg, 65%)을 얻었다. Carry out in the same manner as step 2 of Example 19, except that instead of 4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, 2'-methyl-[1,1'-biphenyl ]-4-Carboxylic acid (38 mg, 0.18 mmol) was used to obtain the target compound (32 mg, 65%).

1H NMR (400 MHz CDCl3) δ 7.98 (s, 1H), 7.94 (d, J = 8.0 Hz, 2H), 7.88 (d, J = 2.2 Hz, 1H), 7.62 (dd, J = 8.7, 2.3 Hz, 1H), 7.57 (d, J = 8.7 Hz, 1H), 7.45 (d, J = 8.0 Hz, 2H), 7.31 (m, 2H), 7.27 (m, 1H), 7.24 (d, J = 6.9 Hz, 1H), 4.62 (t, J = 5.9 Hz, 2H), 3.83 (m, 4H), 2.88 (t, J = 5.9 Hz, 2H), 2.42 (s, 6H), 2.29 (s, 3H), 1.95 (m, 4H); MS (ESI) m/z 496 ([M+H]+). 1H NMR (400 MHz CDCl 3 ) δ 7.98 (s, 1H), 7.94 (d, J = 8.0 Hz, 2H), 7.88 (d, J = 2.2 Hz, 1H), 7.62 (dd, J = 8.7, 2.3 Hz, 1H), 7.57 (d, J = 8.7 Hz, 1H), 7.45 (d, J = 8.0 Hz, 2H), 7.31 (m, 2H), 7.27 (m, 1H), 7.24 (d, J = 6.9 Hz, 1H), 4.62 (t, J = 5.9 Hz, 2H), 3.83 (m, 4H), 2.88 (t, J = 5.9 Hz, 2H), 2.42 (s, 6H), 2.29 (s, 3H), 1.95 (m, 4H); MS (ESI) m/z 496 ([M+H] + ).

<실시예 25> <Example 25> NN -(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-4'-플루오르-[1,1'-바이페닐]-4-카르복스아마이드 제조-(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-4'-fluoro-[1,1'-biphenyl]- 4-Carboxamide production

상기 실시예 19의 단계 2와 동일한 방법으로 수행하되, 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 대신에 4'-플루오르-[1,1'-바이페닐]-4-카르복실산(52 mg, 0.24 mmol)을 사용하여 목적 화합물(27 mg, 54%)을 얻었다. Carry out in the same manner as step 2 of Example 19, except that instead of 4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, 4'-fluoro-[1,1'-biphenyl ]-4-Carboxylic acid (52 mg, 0.24 mmol) was used to obtain the target compound (27 mg, 54%).

1H NMR (400 MHz CDCl3) δ 7.96 (d, J = 8.3 Hz, 3H), 7.86 (d, J = 2.3 Hz, 1H), 7.65 (d, J = 8.3 Hz, 2H), 7.62 (m, 2H), 7.58 (m, 2H), 7.16 (t, J = 8.6 Hz, 2H), 4.60 (t, J = 5.9 Hz, 2H), 3.83 (m, 4H), 2.85 (t, J = 5.9 Hz, 2H), 2.40 (s, 6H), 1.95 (m, 4H); MS (ESI) m/z 500 ([M+H]+). 1H NMR (400 MHz CDCl 3 ) δ 7.96 (d, J = 8.3 Hz, 3H), 7.86 (d, J = 2.3 Hz, 1H), 7.65 (d, J = 8.3 Hz, 2H), 7.62 (m, 2H), 7.58 (m, 2H), 7.16 (t, J = 8.6 Hz, 2H), 4.60 (t, J = 5.9 Hz, 2H), 3.83 (m, 4H), 2.85 (t, J = 5.9 Hz, 2H), 2.40 (s, 6H), 1.95 (m, 4H); MS (ESI) m/z 500 ([M+H] + ).

<실시예 26> <Example 26> NN -(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-3'-플루오르-[1,1'-바이페닐]-4-카르복스아마이드 제조-(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-3'-fluoro-[1,1'-biphenyl]- 4-Carboxamide production

상기 실시예 19의 단계 2와 동일한 방법으로 수행하되, 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 대신에 3'-플루오르-[1,1'-바이페닐]-4-카르복실산(52 mg, 0.24 mmol)을 사용하여 목적 화합물(29 mg, 58%)을 얻었다. Carry out in the same manner as step 2 of Example 19, except that instead of 4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, 3'-fluoro-[1,1'-biphenyl ]-4-Carboxylic acid (52 mg, 0.24 mmol) was used to obtain the target compound (29 mg, 58%).

1H NMR (400 MHz CDCl3) δ 8.97 (m, 3H), 7.86 (d, J = 2.3 Hz, 1H), 7.69 (d, J = 8.1 Hz, 2H), 7.62 (dd, J = 8.7, 2.3 Hz, 1H), 7.57 (d, J = 8.7 Hz, 1H), 7.45 (m, 1H), 7.41 (d, J = 7.2 Hz, 1H), 7.32 (m, 1H), 7.10 (m, 1H), 4.61 (t, J = 5.9 Hz, 2H), 3.84 (m, 4H), 2.86 (t, J = 5.9 Hz, 2H), 2.41 (s, 6H), 1.95 (m, 4H); MS (ESI) m/z 500 ([M+H]+). 1H NMR (400 MHz CDCl 3 ) δ 8.97 (m, 3H), 7.86 (d, J = 2.3 Hz, 1H), 7.69 (d, J = 8.1 Hz, 2H), 7.62 (dd, J = 8.7, 2.3 Hz, 1H), 7.57 (d, J = 8.7 Hz, 1H), 7.45 (m, 1H), 7.41 (d, J = 7.2 Hz, 1H), 7.32 (m, 1H), 7.10 (m, 1H), 4.61 (t, J = 5.9 Hz, 2H), 3.84 (m, 4H), 2.86 (t, J = 5.9 Hz, 2H), 2.41 (s, 6H), 1.95 (m, 4H); MS (ESI) m/z 500 ([M+H] + ).

<실시예 27> <Example 27> NN -(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-2'-플루오르-[1,1'-바이페닐]-4-카르복스아마이드 제조-(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-2'-fluoro-[1,1'-biphenyl]- 4-Carboxamide production

상기 실시예 19의 단계 2와 동일한 방법으로 수행하되, 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 대신에 2'-플루오르-[1,1'-바이페닐]-4-카르복실산(52 mg, 0.24 mmol)을 사용하여 목적 화합물(35 mg, 70%)을 얻었다. Carry out in the same manner as step 2 of Example 19, except that instead of 4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, 2'-fluoro-[1,1'-biphenyl ]-4-Carboxylic acid (52 mg, 0.24 mmol) was used to obtain the target compound (35 mg, 70%).

1H NMR (400 MHz CDCl3) δ 7.96 (d, J = 8.1 Hz, 3H), 7.86 (d, J = 2.2 Hz, 1H), 7.68 (m, 2H), 7.62 (dd, J = 8.7, 2.2 Hz, 1H), 7.57 (d, J = 8.7 Hz, 1H), 7.47 (td, J = 7.7, 1.8 Hz, 1H), 7.37 (m, 1H), 7.23 (m, 1H), 7.17 (m, 1H), 4.56 (t, J = 5.9 Hz, 2H), 3.84 (m, 4H), 2.79 (t, J = 5.9 Hz, 2H), 2.36 (s, 6H), 1.95 (m, 4H); MS (ESI) m/z 500 ([M+H]+). 1H NMR (400 MHz CDCl 3 ) δ 7.96 (d, J = 8.1 Hz, 3H), 7.86 (d, J = 2.2 Hz, 1H), 7.68 (m, 2H), 7.62 (dd, J = 8.7, 2.2 Hz, 1H), 7.57 (d, J = 8.7 Hz, 1H), 7.47 (td, J = 7.7, 1.8 Hz, 1H), 7.37 (m, 1H), 7.23 (m, 1H), 7.17 (m, 1H) ), 4.56 (t, J = 5.9 Hz, 2H), 3.84 (m, 4H), 2.79 (t, J = 5.9 Hz, 2H), 2.36 (s, 6H), 1.95 (m, 4H); MS (ESI) m/z 500 ([M+H] + ).

<실시예 28> 4'-클로로-<Example 28> 4'-chloro- NN -(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드 제조-(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1,1'-biphenyl]-4-carboxamide manufacturing

상기 실시예 19의 단계 2와 동일한 방법으로 수행하되, 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 대신에 4'-클로로-[1,1'-바이페닐]-4-카르복실산(56 mg, 0.24 mmol)을 사용하여 목적 화합물(31 mg, 60%)을 얻었다. Carry out in the same manner as step 2 of Example 19, except that instead of 4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, 4'-chloro-[1,1'-biphenyl ]-4-Carboxylic acid (56 mg, 0.24 mmol) was used to obtain the target compound (31 mg, 60%).

1H NMR (400 MHz CDCl3) δ 7.97 (d, J = 5.1 Hz, 2H), 7.95 (s, 1H), 7.85 (d, J = 2.3 Hz, 1H), 7.66 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 2.3 Hz, 1H), 7.58 (s, 1H), 7.55 (d, J = 6.3 Hz, 1H), 7.54 (s, 1H), 7.44 (d, J = 8.5 Hz, 2H), 4.59 (t, J = 5.9 Hz, 2H), 3.83 (m, 4H), 2.85 (t, J = 5.9 Hz, 2H), 2.40 (s, 6H), 1.94 (m, 4H); MS (ESI) m/z 516 ([M+H]+). 1H NMR (400 MHz CDCl 3 ) δ 7.97 (d, J = 5.1 Hz, 2H), 7.95 (s, 1H), 7.85 (d, J = 2.3 Hz, 1H), 7.66 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 2.3 Hz, 1H), 7.58 (s, 1H), 7.55 (d, J = 6.3 Hz, 1H), 7.54 (s, 1H), 7.44 (d, J = 8.5 Hz, 2H), 4.59 (t, J = 5.9 Hz, 2H), 3.83 (m, 4H), 2.85 (t, J = 5.9 Hz, 2H), 2.40 (s, 6H), 1.94 (m, 4H); MS (ESI) m/z 516 ([M+H] + ).

<실시예 29> 3'-클로로-<Example 29> 3'-Chloro- NN -(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드 제조-(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1,1'-biphenyl]-4-carboxamide manufacturing

상기 실시예 19의 단계 2와 동일한 방법으로 수행하되, 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 대신에 3'-클로로-[1,1'-바이페닐]-4-카르복실산(56 mg, 0.24 mmol)을 사용하여 목적 화합물(23 mg, 45%)을 얻었다. Carry out in the same manner as step 2 of Example 19, except that instead of 4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, 3'-chloro-[1,1'-biphenyl ]-4-Carboxylic acid (56 mg, 0.24 mmol) was used to obtain the target compound (23 mg, 45%).

1H NMR (400 MHz CDCl3) δ 8.03 (s, 1H), 7.96 (d, J = 8.3 Hz, 2H), 7.87 (s, 1H), 7.66 (d, J = 8.3 Hz, 2H), 7.61 (d, J = 11.5 Hz, 2H), 7.56 (d, J = 8.6 Hz, 1H), 7.49 (dd, J = 7.2, 1.7 Hz, 1H), 7.40 (s, 1H), 7.37 (m, 1H), 4.58 (t, J = 6.1 Hz, 2H), 3.82 (m, 4H), 2.85 (t, J = 6.1 Hz, 2H), 2.39 (s, 6H), 1.94 (m, 4H); MS (ESI) m/z 516 ([M+H]+). 1H NMR (400 MHz CDCl 3 ) δ 8.03 (s, 1H), 7.96 (d, J = 8.3 Hz, 2H), 7.87 (s, 1H), 7.66 (d, J = 8.3 Hz, 2H), 7.61 ( d, J = 11.5 Hz, 2H), 7.56 (d, J = 8.6 Hz, 1H), 7.49 (dd, J = 7.2, 1.7 Hz, 1H), 7.40 (s, 1H), 7.37 (m, 1H), 4.58 (t, J = 6.1 Hz, 2H), 3.82 (m, 4H), 2.85 (t, J = 6.1 Hz, 2H), 2.39 (s, 6H), 1.94 (m, 4H); MS (ESI) m/z 516 ([M+H] + ).

<실시예 30> 2'-클로로-<Example 30> 2'-chloro- NN -(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드 제조-(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1,1'-biphenyl]-4-carboxamide manufacturing

상기 실시예 19의 단계 2와 동일한 방법으로 수행하되, 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 대신에 2'-클로로-[1,1'-바이페닐]-4-카르복실산(56 mg, 0.24 mmol)을 사용하여 목적 화합물(24 mg, 47%)을 얻었다. Carry out in the same manner as step 2 of Example 19, except that instead of 4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, 2'-chloro-[1,1'-biphenyl ]-4-Carboxylic acid (56 mg, 0.24 mmol) was used to obtain the target compound (24 mg, 47%).

1H NMR (400 MHz CDCl3) δ 8.12 (s, 1H), 7.96 (d, J = 7.9 Hz, 2H), 7.89 (s, 1H), 7.61 (dd, J = 8.7, 2.3 Hz, 1H), 7.57 (d, J = 3.3 Hz, 1H), 7.54 (m, 2H), 7.49 (d, J = 7.6 Hz, 1H), 7.34 (s, 2H), 7.31 (d, J = 5.1 Hz, 1H), 4.63 (t, J = 5.8 Hz, 2H), 3.81 (m, 4H), 2.93 (t, J = 5.8 Hz, 2H), 2.45 (s, 6H), 1.93 (m,4H); MS (ESI) m/z 516 ([M+H]+). 1H NMR (400 MHz CDCl 3 ) δ 8.12 (s, 1H), 7.96 (d, J = 7.9 Hz, 2H), 7.89 (s, 1H), 7.61 (dd, J = 8.7, 2.3 Hz, 1H), 7.57 (d, J = 3.3 Hz, 1H), 7.54 ( m , 2H), 7.49 (d, J = 7.6 Hz, 1H), 7.34 (s, 2H), 7.31 (d, J = 5.1 Hz, 1H), 4.63 (t, J = 5.8 Hz, 2H), 3.81 (m, 4H), 2.93 (t, J = 5.8 Hz, 2H), 2.45 (s, 6H), 1.93 (m, 4H); MS (ESI) m/z 516 ([M+H] + ).

<실시예 31> 4'-시아노-<Example 31> 4'-Cyano- NN -(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드 제조-(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1,1'-biphenyl]-4-carboxamide manufacturing

상기 실시예 19의 단계 2와 동일한 방법으로 수행하되, 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 대신에 4'-시아노-[1,1'-바이페닐]-4-카르복실산(53 mg, 0.24 mmol)을 사용하여 목적 화합물(23 mg, 46%)을 얻었다. Carry out in the same manner as step 2 of Example 19, except that instead of 4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, 4'-cyano-[1,1'-bi The target compound (23 mg, 46%) was obtained using phenyl]-4-carboxylic acid (53 mg, 0.24 mmol).

1H NMR (400 MHz CDCl3) δ 8.14 (s, 1H), 7.98 (d, J = 8.1 Hz, 2H), 7.87 (d, J = 2.2 Hz, 1H), 7.74 (s, 1H), 7.72 (d, J = 5.9 Hz, 1H), 7.68 (d, J = 8.9 Hz, 3H), 7.65 (s, 1H), 7.60 (dd, J = 8.7, 2.3 Hz, 1H), 7.55 (d, J = 8.7 Hz, 1H), 4.57 (t, J = 5.9 Hz, 2H), 3.81 (m, 4H), 2.83 (t, J = 5.9 Hz, 2H), 2.38 (s, 6H), 1.93 (m, 4H); MS (ESI) m/z 507 ([M+H]+). 1H NMR (400 MHz CDCl 3 ) δ 8.14 (s, 1H), 7.98 (d, J = 8.1 Hz, 2H), 7.87 (d, J = 2.2 Hz, 1H), 7.74 (s, 1H), 7.72 ( d, J = 5.9 Hz, 1H), 7.68 (d, J = 8.9 Hz, 3H), 7.65 (s, 1H), 7.60 (dd, J = 8.7, 2.3 Hz, 1H), 7.55 (d, J = 8.7 Hz, 1H), 4.57 (t, J = 5.9 Hz, 2H), 3.81 (m, 4H), 2.83 (t, J = 5.9 Hz, 2H), 2.38 (s, 6H), 1.93 (m, 4H); MS (ESI) m/z 507 ([M+H] + ).

<실시예 32> 3'-시아노-<Example 32> 3'-Cyano- NN -(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드 제조-(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1,1'-biphenyl]-4-carboxamide manufacturing

상기 실시예 19의 단계 2와 동일한 방법으로 수행하되, 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 대신에 3'-시아노-[1,1'-바이페닐]-4-카르복실산(53 mg, 0.24 mmol)을 사용하여 목적 화합물(26 mg, 52%)을 얻었다. Carry out in the same manner as step 2 of Example 19, except that instead of 4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, 3'-cyano-[1,1'-bi The target compound (26 mg, 52%) was obtained using phenyl]-4-carboxylic acid (53 mg, 0.24 mmol).

1H NMR (400 MHz CDCl3) δ 8.05 (s, 1H), 7.99 (d, J = 7.8 Hz, 2H), 7.87 (d, J = 3.8 Hz, 2H), 7.83 (d, J = 7.8 Hz, 1H), 7.67 (m, 3H), 7.58 (t, J = 7.6 Hz, 3H), 4.56 (t, J = 6.0 Hz, 2H), 3.82( m, 4H), 2.80 (t, J = 6.0 Hz, 2H), 2.36 (s, 6H), 1.94 (m, 4H); MS (ESI) m/z 507 ([M+H]+). 1H NMR (400 MHz CDCl 3 ) δ 8.05 (s, 1H), 7.99 (d, J = 7.8 Hz, 2H), 7.87 (d, J = 3.8 Hz, 2H), 7.83 (d, J = 7.8 Hz, 1H), 7.67 (m, 3H), 7.58 (t, J = 7.6 Hz, 3H), 4.56 (t, J = 6.0 Hz, 2H), 3.82 (m, 4H), 2.80 (t, J = 6.0 Hz, 2H), 2.36 (s, 6H), 1.94 (m, 4H); MS (ESI) m/z 507 ([M+H] + ).

<실시예 33> <Example 33> NN -(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-4'-(트리플루오르메틸)-[1,1'-바이페닐]-4-카르복스아마이드 제조-(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-4'-(trifluoromethyl)-[1,1'- Biphenyl]-4-carboxamide production

상기 실시예 19의 단계 2와 동일한 방법으로 수행하되, 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 대신에 4'-(트리플루오르메틸)-[1,1'-바이페닐]-4-카르복실산(64 mg, 0.24 mmol)을 사용하여 목적 화합물(28 mg, 51%)을 얻었다. Carry out in the same manner as step 2 of Example 19, except that instead of 4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, 4'-(trifluoromethyl)-[1,1 The target compound (28 mg, 51%) was obtained using '-biphenyl]-4-carboxylic acid (64 mg, 0.24 mmol).

1H NMR (400 MHz CDCl3) δ 8.05 (m, 2H), 7.99 (s, 1H), 7.87 (d, J = 2.2 Hz, 1H), 7.73 (s, 5H), 7.70 (s, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.57 (d, J = 8.5 Hz, 1H), 4.60 (t, J = 5.9 Hz, 2H), 3.84 (m, 4H), 2.86 (d, J = 5.9 Hz, 2H), 2.40 (s, 6H), 1.95 (m, 4H); MS (ESI) m/z 550 ([M+H]+). 1H NMR (400 MHz CDCl 3 ) δ 8.05 (m, 2H), 7.99 (s, 1H), 7.87 (d, J = 2.2 Hz, 1H), 7.73 (s, 5H), 7.70 (s, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.57 (d, J = 8.5 Hz, 1H), 4.60 (t, J = 5.9 Hz, 2H), 3.84 (m, 4H), 2.86 (d, J = 5.9 Hz, 2H), 2.40 (s, 6H), 1.95 (m, 4H); MS (ESI) m/z 550 ([M+H] + ).

<실시예 34> <Example 34> NN -(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-3'-(트리플루오르메틸)-[1,1'-바이페닐]-4-카르복스아마이드 제조-(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-3'-(trifluoromethyl)-[1,1'- Biphenyl]-4-carboxamide production

상기 실시예 19의 단계 2와 동일한 방법으로 수행하되, 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 대신에 3'-(트리플루오르메틸)-[1,1'-바이페닐]-4-카르복실산(64 mg, 0.24 mmol)을 사용하여 목적 화합물(25 mg, 46%)을 얻었다. Carry out in the same manner as step 2 of Example 19, except that instead of 4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, 3'-(trifluoromethyl)-[1,1 The target compound (25 mg, 46%) was obtained using '-biphenyl]-4-carboxylic acid (64 mg, 0.24 mmol).

1H NMR (400 MHz CDCl3) δ 8.26 (m, 1H), 8.02 (d, J = 8.3 Hz, 2H), 7.91 (d, J = 2.3 Hz, 1H), 7.85 (s, 1H), 7.79 (d, J = 7.6 Hz, 1H), 7.69 (dd, J = 8.3, 2.1 Hz, 2H), 7.66 (s, 1H), 7.62 (d, J = 9.5 Hz, 1H), 7.61 (s, 1H), 7.57 (d, J = 7.7 Hz, 1H), 7.53 (dd, J = 8.7, 2.4 Hz, 1H), 4.67 (m, 2H), 3.78 (m, 4H), 3.04 (t, J = 5.8 Hz, 2H), 2.54 (s, 6H), 1.93 (m, 4H); MS (ESI) m/z 550 ([M+H]+). 1H NMR (400 MHz CDCl 3 ) δ 8.26 (m, 1H), 8.02 (d, J = 8.3 Hz, 2H), 7.91 (d, J = 2.3 Hz, 1H), 7.85 (s, 1H), 7.79 ( d, J = 7.6 Hz, 1H), 7.69 (dd, J = 8.3, 2.1 Hz, 2H), 7.66 (s, 1H), 7.62 (d, J = 9.5 Hz, 1H), 7.61 (s, 1H), 7.57 (d, J = 7.7 Hz, 1H), 7.53 (dd, J = 8.7, 2.4 Hz, 1H), 4.67 (m, 2H), 3.78 (m, 4H), 3.04 (t, J = 5.8 Hz, 2H) ), 2.54 (s, 6H), 1.93 (m, 4H); MS (ESI) m/z 550 ([M+H] + ).

<실시예 35> <Example 35> NN -(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-2'-(트리플루오르메틸)-[1,1'-바이페닐]-4-카르복스아마이드 제조-(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-2'-(trifluoromethyl)-[1,1'- Biphenyl]-4-carboxamide production

상기 실시예 19의 단계 2와 동일한 방법으로 수행하되, 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 대신에 2'-(트리플루오르메틸)-[1,1'-바이페닐]-4-카르복실산(64 mg, 0.24 mmol)을 사용하여 목적 화합물(28 mg, 51%)을 얻었다. Carry out in the same manner as step 2 of Example 19, except that instead of 4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, 2'-(trifluoromethyl)-[1,1 The target compound (28 mg, 51%) was obtained using '-biphenyl]-4-carboxylic acid (64 mg, 0.24 mmol).

1H NMR (400 MHz Methanol-d 4) δ 8.06 (d, J = 2.1 Hz, 1H), 8.01 (d, J = 8.4 Hz, 2H), 7.82 (d, J = 6.6 Hz, 1H), 7.68 (t, J = 7.2 Hz, 1H), 7.60 (d, J = 7.9 Hz, 1H), 7.55 (m, 2H), 7.47 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 7.6 Hz, 1H), 4.74 (t, J = 5.4 Hz, 2H), 3.84 (m, 4H), 3.35 (t, J = 5.4 Hz, 2H), 2.75 (s, 6H), 1.98 (m, 4H); MS (ESI) m/z 550 ([M+H]+). 1H NMR (400 MHz Methanol- d 4 ) δ 8.06 (d, J = 2.1 Hz, 1H), 8.01 (d, J = 8.4 Hz, 2H), 7.82 (d, J = 6.6 Hz, 1H), 7.68 ( t, J = 7.2 Hz, 1H), 7.60 (d, J = 7.9 Hz, 1H), 7.55 (m, 2H), 7.47 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 7.6 Hz, 1H), 4.74 (t, J = 5.4 Hz, 2H), 3.84 (m, 4H), 3.35 (t, J = 5.4 Hz, 2H), 2.75 (s, 6H), 1.98 (m, 4H); MS (ESI) m/z 550 ([M+H] + ).

<실시예 36> <Example 36> NN -(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드 제조-(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1,1'-biphenyl]-4-carboxamide manufacturing

상기 실시예 19의 단계 2와 동일한 방법으로 수행하되, 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 대신에 [1,1'-바이페닐]-4-카르복실산(24 mg, 0.12 mmol)을 사용하여 목적 화합물(29 mg, 66%)을 얻었다. Carry out in the same manner as step 2 of Example 19, except that instead of 4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, [1,1'-biphenyl]-4-carboxylic acid The target compound (29 mg, 66%) was obtained using boxylic acid (24 mg, 0.12 mmol).

1H NMR (400 MHz CDCl3) δ 7.99 (s, 1H), 7.96 (d, J = 8.0 Hz, 2H), 7.86 (d, J = 2.3 Hz, 1H), 7.70 (d, J = 8.0 Hz, 2H), 7.63 (m, 3H), 7.58 (d, J = 8.7 Hz, 1H), 7.48 (t, J = 7.4 Hz, 2H), 7.40 (t, J = 7.4 Hz, 1H), 4.57 (t, J = 5.9 Hz, 2H), 3.84 (m, 4H), 2.80 (t, J = 5.9 Hz, 2H), 2.36 (s, 6H), 1.94 (m, 4H); MS (ESI) m/z 482 ([M+H]+). 1H NMR (400 MHz CDCl 3 ) δ 7.99 (s, 1H), 7.96 (d, J = 8.0 Hz, 2H), 7.86 (d, J = 2.3 Hz, 1H), 7.70 (d, J = 8.0 Hz, 2H), 7.63 (m, 3H), 7.58 (d, J = 8.7 Hz, 1H), 7.48 (t, J = 7.4 Hz, 2H), 7.40 (t, J = 7.4 Hz, 1H), 4.57 (t, J = 5.9 Hz, 2H), 3.84 (m, 4H), 2.80 (t, J = 5.9 Hz, 2H), 2.36 (s, 6H), 1.94 (m, 4H); MS (ESI) m/z 482 ([M+H] + ).

<실시예 37> 4'-메톡시-<Example 37> 4'-methoxy- NN -(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드 제조-(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1,1'-biphenyl]-4 -Manufacture of carboxamide

단계 1: 2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-아민 제조Step 1: Preparation of 2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-amine

실온에서 60% 소디움 하이드라이드(438 mg, 10.9 mmol)와 1-메틸-4-피페리딘올(1.18 mL, 10.0 mmol)를 테트라하이드로퓨란에 혼합한 뒤 테트라하이드로퓨란(30 mL)에 녹인 2-클로로-3-(피롤리딘-1-일)퀴녹살린-6-아민(2.27 g, 9.12 mmol)을 더하고 36시간 동안 교반하였다 (중간에 추가적으로 60% 소디움 하이드라이드 1.2 당량과 2-다이메틸아미노에탄올 1 당량을 더했다). 반응혼합물에 암모니움 클로라이드 포화 수용액을 더하고 다이클로로메탄으로 추출한 뒤 다이클로로메탄 층을 마그네슘 설페이트로 건조하였다. 용매를 감압하에서 제거한 다음 남은 잔류물에 대해 실리카겔 관 크로마토그래피(다이클로로메탄 : 메탄올 = 20 : 1)를 수행하여 목적화합물(2.16 g, 72%)을 얻었다. 60% sodium hydride (438 mg, 10.9 mmol) and 1-methyl-4-piperidinol (1.18 mL, 10.0 mmol) were mixed in tetrahydrofuran at room temperature and then dissolved in tetrahydrofuran (30 mL). Chloro-3-(pyrrolidin-1-yl)quinoxalin-6-amine (2.27 g, 9.12 mmol) was added and stirred for 36 hours (additionally 1.2 equivalents of 60% sodium hydride and 2-dimethylamino 1 equivalent of ethanol was added). A saturated aqueous solution of ammonium chloride was added to the reaction mixture, extracted with dichloromethane, and the dichloromethane layer was dried over magnesium sulfate. The solvent was removed under reduced pressure, and the remaining residue was subjected to silica gel column chromatography (dichloromethane : methanol = 20 : 1) to obtain the target compound (2.16 g, 72%).

1H NMR (400 MHz, CDCl3) δ 7.36 (d, J = 8.5 Hz, 1H), 6.84 (d, J = 2.5 Hz, 1H), 6.67 (dd, J = 8.5, 2.5 Hz, 1H), 5.30 (m,1H) 3.92 (m, 4H), 3.72 (s, 2H), 2.66 (br s, 2H), 2.41 (s, 2H), 2.33 (s, 3H), 2.13 (m, 2H), 1.94 (m, 4H), 1.91 (d, J = 6.4 Hz, 2H); MS (ESI) m/z 328 ([M+H]+). 1H NMR (400 MHz, CDCl 3 ) δ 7.36 (d, J = 8.5 Hz, 1H), 6.84 (d, J = 2.5 Hz, 1H), 6.67 (dd, J = 8.5, 2.5 Hz, 1H), 5.30 (m,1H) 3.92 (m, 4H), 3.72 (s, 2H), 2.66 (br s, 2H), 2.41 (s, 2H), 2.33 (s, 3H), 2.13 (m, 2H), 1.94 ( m, 4H), 1.91 (d, J = 6.4 Hz, 2H); MS (ESI) m/z 328 ([M+H] + ).

단계 2: 4'-메톡시-Step 2: 4'-methoxy- NN -(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드 제조-(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1,1'-biphenyl]-4 -Manufacture of carboxamide

실온에서 2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-아민(30 mg, 0.092 mmol), 4'-메톡시-[1,1'-바이페닐]-4-카르복실산(25 mg, 0.11 mmol), 및 1-에틸-3-(3′-다이메틸아미노프로필)카르보다이이마이드(23 mg, 0.12 mmol)를 다이클로로메탄/N,N-다이메틸포름아마이드(1 mL/1 mL)에 더한 뒤 36시간 동안 교반하였다 (중간에 추가적으로 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 1.2 당량과 1-에틸-3-(3′-다이메틸아미노프로필)카르보다이이마이드 1.2 당량을 더했다). 용매를 감압하에서 제거한 다음 남은 잔류물에 대해 실리카겔 관 크로마토그래피(다이클로로메탄 : 메탄올 = 15 : 1)를 수행하여 목적 화합물(19 mg, 37%)을 얻었다.2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-amine (30 mg, 0.092 mmol), 4'-methoxy -[1,1'-biphenyl]-4-carboxylic acid (25 mg, 0.11 mmol), and 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide (23 mg, 0.12 mmol) ) was added to dichloromethane/ N , N -dimethylformamide (1 mL/1 mL) and stirred for 36 hours (4'-methoxy-[1,1'-biphenyl]-4 was added in the middle) -1.2 equivalents of carboxylic acid and 1.2 equivalents of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide were added). The solvent was removed under reduced pressure, and the remaining residue was subjected to silica gel column chromatography (dichloromethane : methanol = 15 : 1) to obtain the target compound (19 mg, 37%).

1H NMR (400 MHz, CDCl3) δ 7.97 (s, 1H), 7.93 (d, J = 8.0 Hz, 2H), 7.84 (d, J = 2.3 Hz, 1H), 7.66 (d, J = 8.0 Hz, 2H), 7.58 (m, 3H), 7.53 (m, 1H), 7.00 (d, J = 8.8 Hz, 2H), 5.36 (m, 1H), 3.87 (s, 3H), 3.84 (m, 4H), 2.72 (m, 2H), 2.49 (m, 2H), 2.38 (s, 3H), 2.19 (m, 2H), 1.99 (m, 2H), 1.95 (m, 4H); MS (ESI) m/z 538 ([M+H]+). 1H NMR (400 MHz, CDCl 3 ) δ 7.97 (s, 1H), 7.93 (d, J = 8.0 Hz, 2H), 7.84 (d, J = 2.3 Hz, 1H), 7.66 (d, J = 8.0 Hz) , 2H), 7.58 (m, 3H), 7.53 (m, 1H), 7.00 (d, J = 8.8 Hz, 2H), 5.36 (m, 1H), 3.87 (s, 3H), 3.84 (m, 4H) , 2.72 (m, 2H), 2.49 (m, 2H), 2.38 (s, 3H), 2.19 (m, 2H), 1.99 (m, 2H), 1.95 (m, 4H); MS (ESI) m/z 538 ([M+H] + ).

<실시예 38> 3'-메톡시-<Example 38> 3'-methoxy- NN -(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드 제조-(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1,1'-biphenyl]-4 -Manufacture of carboxamide

상기 실시예 37의 단계 2와 동일한 방법으로 수행하되, 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 대신에 3'-메톡시-[1,1'-바이페닐]-4-카르복실산(25 mg, 0.11 mmol)을 사용하여 목적 화합물(34 mg, 67%)을 얻었다. Carry out in the same manner as step 2 of Example 37, except that instead of 4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, 3'-methoxy-[1,1'-bi The target compound (34 mg, 67%) was obtained using phenyl]-4-carboxylic acid (25 mg, 0.11 mmol).

1H NMR (400 MHz CDCl3) δ 8.01 (s, 1H), 7.95 (d, J = 7.9 Hz, 2H), 7.86 (d, J = 2.3 Hz, 1H), 7.69 (d, J = 7.9 Hz, 2H), 7.62 (dd, J = 8.7, 2.3 Hz, 1H), 7.54 (d, J = 8.7 Hz, 1H), 7.39 (t, J = 7.8 Hz, 1H), 7.21 (d, J = 7.8, 1H), 7.15 (s, 1H), 6.94 (dd, J = 8.3, 2.5 Hz, 1H), 5.38 (m, 1H), 3.88 (s, 3H), 3.83 (m, 4H), 2.75 (m, 2H), 2.53 (m, 2H), 2.40 (s, 3H), 2.22 (m, 2H), 2.02 (m, 2H), 1.95 (m, 4H); MS (ESI) m/z 538 ([M+H]+). 1H NMR (400 MHz CDCl 3 ) δ 8.01 (s, 1H), 7.95 (d, J = 7.9 Hz, 2H), 7.86 (d, J = 2.3 Hz, 1H), 7.69 (d, J = 7.9 Hz, 2H), 7.62 (dd, J = 8.7, 2.3 Hz, 1H), 7.54 (d, J = 8.7 Hz, 1H), 7.39 (t, J = 7.8 Hz, 1H), 7.21 (d, J = 7.8, 1H) ), 7.15 (s, 1H), 6.94 (dd, J = 8.3, 2.5 Hz, 1H), 5.38 (m, 1H), 3.88 (s, 3H), 3.83 (m, 4H), 2.75 (m, 2H) , 2.53 (m, 2H), 2.40 (s, 3H), 2.22 (m, 2H), 2.02 (m, 2H), 1.95 (m, 4H); MS (ESI) m/z 538 ([M+H] + ).

<실시예 39> 2'-메톡시-<Example 39> 2'-methoxy- NN -(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드 제조-(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1,1'-biphenyl]-4 -Manufacture of carboxamide

상기 실시예 37의 단계 2와 동일한 방법으로 수행하되, 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 대신에 2'-메톡시-[1,1'-바이페닐]-4-카르복실산(25 mg, 0.11 mmol)을 사용하여 목적 화합물(33 mg, 65%)을 얻었다. Carry out in the same manner as step 2 of Example 37, except that instead of 4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, 2'-methoxy-[1,1'-bi The target compound (33 mg, 65%) was obtained using phenyl]-4-carboxylic acid (25 mg, 0.11 mmol).

1H NMR (400 MHz CDCl3) δ 7.98 (s, 1H), 7.93 (d, J = 8.2 Hz, 2H), 7.85 (d, J = 2.4 Hz, 1H), 7.66 (d, J = 8.3 Hz, 2H), 7.61 (s, 1H), 7.54 (d, J = 8.7 Hz, 1H), 7.36 (m, 2H), 7.06 (td, J = 7.5, 1.1 Hz, 1H), 7.01 (d, J = 8.7 Hz, 1H), 5.39 (m, 1H), 3.83 (m, 7H), 2.78 (m, 2H), 2.57 (m, 2H), 2.43 (s, 3H), 2.23 (m, 2H), 2.02 (m, 2H), 1.95 (m, 4H); MS (ESI) m/z 538 ([M+H]+). 1H NMR (400 MHz CDCl 3 ) δ 7.98 (s, 1H), 7.93 (d, J = 8.2 Hz, 2H), 7.85 (d, J = 2.4 Hz, 1H), 7.66 (d, J = 8.3 Hz, 2H), 7.61 (s, 1H), 7.54 (d, J = 8.7 Hz, 1H), 7.36 (m, 2H), 7.06 (td, J = 7.5, 1.1 Hz, 1H), 7.01 (d, J = 8.7 Hz, 1H), 5.39 (m, 1H), 3.83 (m, 7H), 2.78 (m, 2H), 2.57 (m, 2H), 2.43 (s, 3H), 2.23 (m, 2H), 2.02 (m) , 2H), 1.95 (m, 4H); MS (ESI) m/z 538 ([M+H] + ).

<실시예 40> 4'-메틸-<Example 40> 4'-methyl- NN -(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드 제조-(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1,1'-biphenyl]-4 -Manufacture of carboxamide

상기 실시예 37의 단계 2와 동일한 방법으로 수행하되, 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 대신에 4'-메틸-[1,1'-바이페닐]-4-카르복실산(35 mg, 0.17 mmol)을 사용하여 목적 화합물(27 mg, 57%)을 얻었다. Carry out in the same manner as step 2 of Example 37, except that instead of 4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, 4'-methyl-[1,1'-biphenyl ]-4-Carboxylic acid (35 mg, 0.17 mmol) was used to obtain the target compound (27 mg, 57%).

1H NMR (400 MHz CDCl3) δ 7.97 (s, 1H), 7.95 (m, 2H), 7.88 (s, 1H), 7.71 (d, J = 8.2 Hz, 2H), 7.63 (m, 1H), 7.56 (d, J = 4.1 Hz, 1H), 7.54 (d, J = 3.3 Hz, 2H), 7.29 (d, J = 7.9 Hz, 2H), 5.44 (m, 1H), 3.83 (m, 4H), 2.89 (m, 2H), 2.74 (m, 2H), 2.53 (m, 3H), 2.42 (s, 3H), 2.33 (m, 2H), 2.14 (m, 2H), 1.97 (m, 4H); MS (ESI) m/z 522 ([M+H]+). 1H NMR (400 MHz CDCl 3 ) δ 7.97 (s, 1H), 7.95 (m, 2H), 7.88 (s, 1H), 7.71 (d, J = 8.2 Hz, 2H), 7.63 (m, 1H), 7.56 (d, J = 4.1 Hz, 1H), 7.54 (d, J = 3.3 Hz, 2H), 7.29 (d, J = 7.9 Hz, 2H), 5.44 (m, 1H), 3.83 (m, 4H), 2.89 (m, 2H), 2.74 (m, 2H), 2.53 (m, 3H), 2.42 (s, 3H), 2.33 (m, 2H), 2.14 (m, 2H), 1.97 (m, 4H); MS (ESI) m/z 522 ([M+H] + ).

<실시예 41> 3'-메틸-<Example 41> 3'-methyl- NN -(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드 제조-(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1,1'-biphenyl]-4 -Manufacture of carboxamide

상기 실시예 37의 단계 2와 동일한 방법으로 수행하되, 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 대신에 3'-메틸-[1,1'-바이페닐]-4-카르복실산(35 mg, 0.17 mmol)을 사용하여 목적 화합물(29 mg, 61%)을 얻었다. Carry out in the same manner as step 2 of Example 37, except that instead of 4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, 3'-methyl-[1,1'-biphenyl ]-4-Carboxylic acid (35 mg, 0.17 mmol) was used to obtain the target compound (29 mg, 61%).

1H NMR (400 MHz CDCl3) δ 7.96 (d, J = 8.4 Hz, 3H), 7.87 (s, 1H), 7.71 (d, J = 8.3 Hz, 2H), 7.65 - 7.60 (m, 1H), 7.55 (d, J = 8.7 Hz, 1H), 7.44 (d, J = 8.3 Hz, 2H), 7.37 (t, J = 7.5 Hz, 1H), 7.22 (d, J = 7.6 Hz, 1H), 5.43 (m, 1H), 3.84 (m, 4H), 2.90 (m, 2H), 2.70 (m, 2H), 2.51 (s, 3H), 2.45 (s, 3H), 2.31 (m, 2H), 2.12 (m, 2H), 1.97 (m, 5H); MS (ESI) m/z 522 ([M+H]+). 1 H NMR (400 MHz CDCl 3 ) δ 7.96 (d, J = 8.4 Hz, 3H), 7.87 (s, 1H), 7.71 (d, J = 8.3 Hz, 2H), 7.65 - 7.60 (m, 1H), 7.55 (d, J = 8.7 Hz, 1H), 7.44 (d, J = 8.3 Hz, 2H), 7.37 (t, J = 7.5 Hz, 1H), 7.22 (d, J = 7.6 Hz, 1H), 5.43 ( m, 1H), 3.84 (m, 4H), 2.90 (m, 2H), 2.70 (m, 2H), 2.51 (s, 3H), 2.45 (s, 3H), 2.31 (m, 2H), 2.12 (m) , 2H), 1.97 (m, 5H); MS (ESI) m/z 522 ([M+H] + ).

<실시예 42> 2'-메틸-<Example 42> 2'-methyl- NN -(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드 제조-(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1,1'-biphenyl]-4 -Manufacture of carboxamide

상기 실시예 37의 단계 2와 동일한 방법으로 수행하되, 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 대신에 2'-메틸-[1,1'-바이페닐]-4-카르복실산(35 mg, 0.17 mmol)을 사용하여 목적 화합물(37 mg, 77%)을 얻었다. Carry out in the same manner as step 2 of Example 37, except that instead of 4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, 2'-methyl-[1,1'-biphenyl ]-4-Carboxylic acid (35 mg, 0.17 mmol) was used to obtain the target compound (37 mg, 77%).

1H NMR (400 MHz CDCl3) δ 8.31 (s, 1H), 7.99 (d, J = 8.3 Hz, 3H), 7.61 (dd, J = 8.8, 2.3 Hz, 1H), 7.50 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 8.3 Hz, 2H), 7.29 (m, 2H), 7.25 (s, 1H), 7.21 (m, 1H), 5.43 (m, 1H), 3.79 (m, 4H), 3.10 (m, 4H), 2.72 (s, 3H), 2.48 (m, 2H), 2.29 (m, 2H), 2.28 (s, 3H), 1.94 (m, 4H); MS (ESI) m/z 522 ([M+H]+). 1H NMR (400 MHz CDCl 3 ) δ 8.31 (s, 1H), 7.99 (d, J = 8.3 Hz, 3H), 7.61 (dd, J = 8.8, 2.3 Hz, 1H), 7.50 (d, J = 8.8) Hz, 1H), 7.44 (d, J = 8.3 Hz, 2H), 7.29 (m, 2H), 7.25 (s, 1H), 7.21 (m, 1H), 5.43 (m, 1H), 3.79 (m, 4H) ), 3.10 (m, 4H), 2.72 (s, 3H), 2.48 (m, 2H), 2.29 (m, 2H), 2.28 (s, 3H), 1.94 (m, 4H); MS (ESI) m/z 522 ([M+H] + ).

<실시예 43> 4'-플루오르-<Example 43> 4'-fluorine- NN -(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드 제조-(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1,1'-biphenyl]-4 -Manufacture of carboxamide

상기 실시예 37의 단계 2와 동일한 방법으로 수행하되, 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 대신에 4'-플루오르-[1,1'-바이페닐]-4-카르복실산(48 mg, 0.22 mmol)을 사용하여 목적 화합물(32 mg, 67%)을 얻었다. Carry out in the same manner as step 2 of Example 37, except that instead of 4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, 4'-fluoro-[1,1'-biphenyl ]-4-Carboxylic acid (48 mg, 0.22 mmol) was used to obtain the target compound (32 mg, 67%).

1H NMR (400 MHz Methanol-d 4) δ 8.05 (m, 2H), 8.01 (s, 1H), 7.75 (s, 1H), 7.70 (m, 3H), 7.55 (dd, J = 8.7, 2.2 Hz, 1H), 7.51 (d, J = 8.7 Hz, 1H), 7.20 (t, J = 8.7 Hz, 2H), 5.50 (m, 1H), 3.85 (m, 4H), 3.28 (m, 4H), 2.85 (s, 3H), 2.33 (m, 2H), 2.24 (m, 2H), 2.00 (m, 4H); MS (ESI) m/z 526 ([M+H]+). 1 H NMR (400 MHz Methanol- d 4 ) δ 8.05 (m, 2H), 8.01 (s, 1H), 7.75 (s, 1H), 7.70 (m, 3H), 7.55 (dd, J = 8.7, 2.2 Hz , 1H), 7.51 (d, J = 8.7 Hz, 1H), 7.20 (t, J = 8.7 Hz, 2H), 5.50 (m, 1H), 3.85 (m, 4H), 3.28 (m, 4H), 2.85 (s, 3H), 2.33 (m, 2H), 2.24 (m, 2H), 2.00 (m, 4H); MS (ESI) m/z 526 ([M+H] + ).

<실시예 44> 3'-플루오르-<Example 44> 3'-fluorine- NN -(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드 제조-(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1,1'-biphenyl]-4 -Manufacture of carboxamide

상기 실시예 37의 단계 2와 동일한 방법으로 수행하되, 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 대신에 3'-플루오르-[1,1'-바이페닐]-4-카르복실산(48 mg, 0.22 mmol)을 사용하여 목적 화합물(35 mg, 73%)을 얻었다. Carry out in the same manner as step 2 of Example 37, except that instead of 4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, 3'-fluoro-[1,1'-biphenyl ]-4-Carboxylic acid (48 mg, 0.22 mmol) was used to obtain the target compound (35 mg, 73%).

1H NMR (400 MHz CDCl3) δ 8.41 (s, 1H), 8.02 (t, J = 10.4 Hz, 3H), 7.67 (d, J = 8.4 Hz, 2H), 7.63 (m, 1H), 7.50 (d, J = 8.7 Hz, 1H), 7.42 (m, 1H), 7.39 (d, J = 7.3 Hz, 1H), 7.30 (d, J = 9.8 Hz, 1H), 7.08 (tt, J = 7.6, 2.2 Hz, 1H), 5.43 (s, 1H), 3.77 (m, 4H), 3.12 (m, 4H), 2.73 (s, 3H), 2.49 (m, 2H), 2.31 (m, 2H), 1.93 (m, 4H); MS (ESI) m/z 526 ([M+H]+). 1H NMR (400 MHz CDCl 3 ) δ 8.41 (s, 1H), 8.02 (t, J = 10.4 Hz, 3H), 7.67 (d, J = 8.4 Hz, 2H), 7.63 (m, 1H), 7.50 ( d, J = 8.7 Hz, 1H), 7.42 (m, 1H), 7.39 (d, J = 7.3 Hz, 1H), 7.30 (d, J = 9.8 Hz, 1H), 7.08 (tt, J = 7.6, 2.2 Hz, 1H), 5.43 (s, 1H), 3.77 (m, 4H), 3.12 (m, 4H), 2.73 (s, 3H), 2.49 (m, 2H), 2.31 (m, 2H), 1.93 (m) , 4H); MS (ESI) m/z 526 ([M+H] + ).

<실시예 45> 2'-플루오르-<Example 45> 2'-fluorine- NN -(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드 제조-(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1,1'-biphenyl]-4 -Manufacture of carboxamide

상기 실시예 37의 단계 2와 동일한 방법으로 수행하되, 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 대신에 2'-플루오르-[1,1'-바이페닐]-4-카르복실산(48 mg, 0.22 mmol)을 사용하여 목적 화합물(41 mg, 78%)을 얻었다. Carry out in the same manner as step 2 of Example 37, except that instead of 4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, 2'-fluoro-[1,1'-biphenyl ]-4-Carboxylic acid (48 mg, 0.22 mmol) was used to obtain the target compound (41 mg, 78%).

1H NMR (400 MHz CDCl3) δ 8.24 (s, 1H), 8.01 (d, J = 8.2 Hz, 2H), 7.96 (s, 1H), 7.68 (d, J = 6.7 Hz, 2H), 7.62 (dd, J = 8.7, 2.5 Hz, 1H), 7.52 (d, J = 8.7 Hz, 1H), 7.47 (td, J = 7.7, 1.8 Hz, 1H), 7.37 (m, 1H), 7.23 (d, J = 7.0 Hz, 1H), 7.18 (m, 1H), 5.46 (m, 1H), 3.80 (m, 4H), 3.09 (m, 4H), 2.70 (s, 3H), 2.48 (m, 2H), 2.30 (m, 2H), 1.95 (m, 4H); MS (ESI) m/z 526 ([M+H]+). 1H NMR (400 MHz CDCl 3 ) δ 8.24 (s, 1H), 8.01 (d, J = 8.2 Hz, 2H), 7.96 (s, 1H), 7.68 (d, J = 6.7 Hz, 2H), 7.62 ( dd, J = 8.7, 2.5 Hz, 1H), 7.52 (d, J = 8.7 Hz, 1H), 7.47 (td, J = 7.7, 1.8 Hz, 1H), 7.37 (m, 1H), 7.23 (d, J = 7.0 Hz, 1H), 7.18 (m, 1H), 5.46 (m, 1H), 3.80 (m, 4H), 3.09 (m, 4H), 2.70 (s, 3H), 2.48 (m, 2H), 2.30 (m, 2H), 1.95 (m, 4H); MS (ESI) m/z 526 ([M+H] + ).

<실시예 46> 4'-클로로-<Example 46> 4'-chloro- NN -(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드 제조-(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1,1'-biphenyl]-4 -Manufacture of carboxamide

상기 실시예 37의 단계 2와 동일한 방법으로 수행하되, 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 대신에 4'-클로로-[1,1'-바이페닐]-4-카르복실산(48 mg, 0.22 mmol)을 사용하여 목적 화합물(37 mg, 75%)을 얻었다. Carry out in the same manner as step 2 of Example 37, except that instead of 4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, 4'-chloro-[1,1'-biphenyl ]-4-Carboxylic acid (48 mg, 0.22 mmol) was used to obtain the target compound (37 mg, 75%).

1H NMR (400 MHz Methanol-d 4) δ 8.04 (d, J = 7.9 Hz, 3H), 7.77 (d, J = 8.0 Hz, 2H), 7.68 (m, 2H), 7.56 (d, J = 9.5 Hz, 1H), 7.52 (d, J = 8.8 Hz, 1H), 7.48 (d, J = 8.4 Hz, 2H), 5.52 (m, 1H), 3.87 (m, 4H), 3.30 (m, 4H), 2.87 (s, 3H), 2.35 (m, 2H), 2.26 (m, 2H), 2.01 (m, 4H); MS (ESI) m/z 542 ([M+H]+). 1H NMR (400 MHz Methanol- d 4 ) δ 8.04 (d, J = 7.9 Hz, 3H), 7.77 (d, J = 8.0 Hz, 2H), 7.68 (m, 2H), 7.56 (d, J = 9.5) Hz, 1H), 7.52 (d, J = 8.8 Hz, 1H), 7.48 (d, J = 8.4 Hz, 2H), 5.52 ( m , 1H), 3.87 (m, 4H), 3.30 (m, 4H), 2.87 (s, 3H), 2.35 (m, 2H), 2.26 (m, 2H), 2.01 (m, 4H); MS (ESI) m/z 542 ([M+H] + ).

<실시예 47> 3'-클로로-<Example 47> 3'-Chloro- NN -(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드 제조-(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1,1'-biphenyl]-4 -Manufacture of carboxamide

상기 실시예 37의 단계 2와 동일한 방법으로 수행하되, 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 대신에 3'-클로로-[1,1'-바이페닐]-4-카르복실산(48 mg, 0.22 mmol)을 사용하여 목적 화합물(33 mg, 67%)을 얻었다. Carry out in the same manner as step 2 of Example 37, except that instead of 4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, 3'-chloro-[1,1'-biphenyl ]-4-Carboxylic acid (48 mg, 0.22 mmol) was used to obtain the target compound (33 mg, 67%).

1H NMR (400 MHz CDCl3) δ 8.58 (m, 1H), 8.04 (d, J = 8.0 Hz, 2H), 8.01 (s, 1H), 7.64 (m, 3H), 7.57 (d, J = 2.1 Hz, 1H), 7.47 (m, 2H), 7.39 (d, J = 7.9 Hz, 1H), 7.34 (d, J = 9.2 Hz, 1H), 5.38 (m, 1H), 3.75 (m, 4H), 3.09 (m, 4H), 2.71 (s, 3H), 2.45 (m, 2H), 2.28 (m, 2H), 1.92 (m, 4H); MS (ESI) m/z 542 ([M+H]+). 1H NMR (400 MHz CDCl 3 ) δ 8.58 (m, 1H), 8.04 (d, J = 8.0 Hz, 2H), 8.01 (s, 1H), 7.64 (m, 3H), 7.57 (d, J = 2.1 Hz, 1H), 7.47 (m, 2H), 7.39 (d, J = 7.9 Hz, 1H), 7.34 (d, J = 9.2 Hz, 1H), 5.38 (m, 1H), 3.75 (m, 4H), 3.09 (m, 4H), 2.71 (s, 3H), 2.45 (m, 2H), 2.28 (m, 2H), 1.92 (m, 4H); MS (ESI) m/z 542 ([M+H] + ).

<실시예 48> 2'-클로로-<Example 48> 2'-chloro- NN -(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드 제조-(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1,1'-biphenyl]-4 -Manufacture of carboxamide

상기 실시예 37의 단계 2와 동일한 방법으로 수행하되, 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 대신에 2'-클로로-[1,1'-바이페닐]-4-카르복실산(48 mg, 0.22 mmol)을 사용하여 목적 화합물(30 mg, 60%)을 얻었다. Carry out in the same manner as step 2 of Example 37, except that instead of 4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, 2'-chloro-[1,1'-biphenyl ]-4-Carboxylic acid (48 mg, 0.22 mmol) was used to obtain the target compound (30 mg, 60%).

1H NMR (400 MHz CDCl3) δ 8.48 (s, 1H), 8.02 (d, J = 8.1 Hz, 2H), 7.99 (s, 1H), 7.61 (dd, J = 8.7, 2.4 Hz, 1H), 7.55 (d, J = 8.2 Hz, 2H), 7.48 (m, 2H), 7.34 (s, 1H), 7.32 (d, J = 7.1 Hz, 2H), 5.40 (m, 1H), 3.78 (m, 4H), 3.10 (m, 4H), 2.71 (s, 3H), 2.46 (m, 2H), 2.28 (m, 2H), 1.92 (m, 4H); MS (ESI) m/z 542 ([M+H]+). 1H NMR (400 MHz CDCl 3 ) δ 8.48 (s, 1H), 8.02 (d, J = 8.1 Hz, 2H), 7.99 (s, 1H), 7.61 (dd, J = 8.7, 2.4 Hz, 1H), 7.55 (d, J = 8.2 Hz, 2H), 7.48 (m, 2H), 7.34 (s, 1H), 7.32 (d, J = 7.1 Hz, 2H), 5.40 (m, 1H), 3.78 (m, 4H) ), 3.10 (m, 4H), 2.71 (s, 3H), 2.46 (m, 2H), 2.28 (m, 2H), 1.92 (m, 4H); MS (ESI) m/z 542 ([M+H] + ).

<실시예 49> 4'-시아노-<Example 49> 4'-Cyano- NN -(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드 제조-(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1,1'-biphenyl]-4 -Manufacture of carboxamide

상기 실시예 37의 단계 2와 동일한 방법으로 수행하되, 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 대신에 4'-시아노-[1,1'-바이페닐]-4-카르복실산(49 mg, 0.22 mmol)을 사용하여 목적 화합물(40 mg, 82%)을 얻었다. Carry out in the same manner as step 2 of Example 37, except that instead of 4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, 4'-cyano-[1,1'-bi The target compound (40 mg, 82%) was obtained using phenyl]-4-carboxylic acid (49 mg, 0.22 mmol).

1H NMR (400 MHz CDCl3) δ 8.07 (s, 1H), 7.99 (d, J = 8.0 Hz, 2H), 7.86 (d, J = 2.3 Hz, 1H), 7.74 (d, J = 8.2 Hz, 2H), 7.72 - 7.65 (m, 4H), 7.60 (dd, J = 8.7, 2.4 Hz, 1H), 7.53 (d, J = 8.7 Hz, 1H), 5.36 (m, 1H), 3.84 (m, 4H), 2.72 (m, 2H), 2.49 (m, 2H), 2.38 (s, 3H), 2.20 (m , 2H), 1.97 (m, 2H), 1.94 (m, 4H); MS (ESI) m/z 533 ([M+H]+). 1H NMR (400 MHz CDCl 3 ) δ 8.07 (s, 1H), 7.99 (d, J = 8.0 Hz, 2H), 7.86 (d, J = 2.3 Hz, 1H), 7.74 (d, J = 8.2 Hz, 2H), 7.72 - 7.65 (m, 4H), 7.60 (dd, J = 8.7, 2.4 Hz, 1H), 7.53 (d, J = 8.7 Hz, 1H), 5.36 (m, 1H), 3.84 (m, 4H) ), 2.72 (m, 2H), 2.49 (m, 2H), 2.38 (s, 3H), 2.20 (m, 2H), 1.97 (m, 2H), 1.94 (m, 4H); MS (ESI) m/z 533 ([M+H] + ).

<실시예 50> 3'-시아노-<Example 50> 3'-Cyano- NN -(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드 제조-(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1,1'-biphenyl]-4 -Manufacture of carboxamide

상기 실시예 37의 단계 2와 동일한 방법으로 수행하되, 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 대신에 3'-시아노-[1,1'-바이페닐]-4-카르복실산(49 mg, 0.22 mmol)을 사용하여 목적 화합물(22 mg, 45%)을 얻었다. Carry out in the same manner as step 2 of Example 37, except that instead of 4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, 3'-cyano-[1,1'-bi The target compound (22 mg, 45%) was obtained using phenyl]-4-carboxylic acid (49 mg, 0.22 mmol).

1H NMR (400 MHz CDCl3) δ 8.08 (s, 1H), 7.97 (d, J = 7.9 Hz, 2H), 7.87 (m, 2H), 7.82 (d, J = 7.8 Hz, 1H), 7.67 (d, J = 7.7 Hz, 1H), 7.63 (d, J = 8.1 Hz, 2H), 7.59 (s, 1H), 7.56 (d, J = 7.9 Hz, 1H), 7.53 (d, J = 8.7 Hz, 1H), 5.34 (m, 1H), 3.83 (m, 4H), 2.68 (m, 2H), 2.42 (m, 2H), 2.34 (s, 3H), 2.14 (m, 2H), 1.93 (m, 6H); MS (ESI) m/z 533 ([M+H]+). 1H NMR (400 MHz CDCl 3 ) δ 8.08 (s, 1H), 7.97 (d, J = 7.9 Hz, 2H), 7.87 (m, 2H), 7.82 (d, J = 7.8 Hz, 1H), 7.67 ( d, J = 7.7 Hz, 1H), 7.63 (d, J = 8.1 Hz, 2H), 7.59 (s, 1H), 7.56 (d, J = 7.9 Hz, 1H), 7.53 (d, J = 8.7 Hz, 1H), 5.34 (m, 1H), 3.83 (m, 4H), 2.68 (m, 2H), 2.42 (m, 2H), 2.34 (s, 3H), 2.14 (m, 2H), 1.93 (m, 6H) ); MS (ESI) m/z 533 ([M+H] + ).

<실시예 51> <Example 51> NN -(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-4'-(트리플루오르메틸)-[1,1'-바이페닐]-4-카르복스아마이드 제조-(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-4'-(trifluoromethyl)-[1 ,1'-Biphenyl]-4-carboxamide production

상기 실시예 37의 단계 2와 동일한 방법으로 수행하되, 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 대신에 4'-(트리플루오르메틸)-[1,1'-바이페닐]-4-카르복실산(59 mg, 0.22 mmol)을 사용하여 목적 화합물(26 mg, 49%)을 얻었다. Carry out in the same manner as step 2 of Example 37, except that instead of 4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, 4'-(trifluoromethyl)-[1,1 The target compound (26 mg, 49%) was obtained using '-biphenyl]-4-carboxylic acid (59 mg, 0.22 mmol).

1H NMR (400 MHz Methanol-d 4) δ 8.05 (m, 3H), 7.86 (d, J = 8.1 Hz, 2H), 7.81 (d, J = 8.1 Hz, 2H), 7.75 (d, J = 8.2 Hz, 2H), 7.55 (dd, J = 8.7, 2.2 Hz, 1H), 7.50 (d, J = 8.7 Hz, 1H), 5.50 (m, 1H), 3.84 (m, 4H), 3.34 (m, 4H), 2.89 (s, 3H), 2.35 (m, 2H), 2.27 (m, 2H), 1.99 (m, 4H); MS (ESI) m/z 576 ([M+H]+). 1 H NMR (400 MHz Methanol- d 4 ) δ 8.05 (m, 3H), 7.86 (d, J = 8.1 Hz, 2H), 7.81 (d, J = 8.1 Hz, 2H), 7.75 (d, J = 8.2) Hz, 2H), 7.55 (dd, J = 8.7, 2.2 Hz, 1H), 7.50 (d, J = 8.7 Hz, 1H), 5.50 (m, 1H), 3.84 (m, 4H), 3.34 (m, 4H) ), 2.89 (s, 3H), 2.35 (m, 2H), 2.27 (m, 2H), 1.99 (m, 4H); MS (ESI) m/z 576 ([M+H] + ).

<실시예 52> <Example 52> NN -(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-3'-(트리플루오르메틸)-[1,1'-바이페닐]-4-카르복스아마이드 제조-(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-3'-(trifluoromethyl)-[1 ,1'-Biphenyl]-4-carboxamide production

상기 실시예 37의 단계 2와 동일한 방법으로 수행하되, 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 대신에 3'-(트리플루오르메틸)-[1,1'-바이페닐]-4-카르복실산(59 mg, 0.22 mmol)을 사용하여 목적 화합물(36 mg, 68%)을 얻었다. Carry out in the same manner as step 2 of Example 37, except that instead of 4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, 3'-(trifluoromethyl)-[1,1 The target compound (36 mg, 68%) was obtained using '-biphenyl]-4-carboxylic acid (59 mg, 0.22 mmol).

1H NMR (400 MHz CDCl3) δ 8.75 (s, 1H), 8.10 (d, J = 8.4 Hz, 2H), 8.04 (s, 1H), 7.83 (s, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.68 (d, J = 8.5 Hz, 2H), 7.63 (d, J = 8.2 Hz, 2H), 7.56 (t, J = 7.1 Hz, 1H), 7.46 (dd, J = 8.8, 3.2 Hz, 1H), 5.36 (m, 1H), 3.74 (m, 4H), 3.12 (m, 4H), 2.73 (s, 3H), 2.46 (m, 2H), 2.28 (m, 2H), 1.91 (m, 4H); MS (ESI) m/z 576 ([M+H]+). 1H NMR (400 MHz CDCl 3 ) δ 8.75 (s, 1H), 8.10 (d, J = 8.4 Hz, 2H), 8.04 (s, 1H), 7.83 (s, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.68 (d, J = 8.5 Hz, 2H), 7.63 (d, J = 8.2 Hz, 2H), 7.56 (t, J = 7.1 Hz, 1H), 7.46 (dd, J = 8.8, 3.2 Hz, 1H), 5.36 (m, 1H), 3.74 (m, 4H), 3.12 (m, 4H), 2.73 (s, 3H), 2.46 (m, 2H), 2.28 (m, 2H), 1.91 (m) , 4H); MS (ESI) m/z 576 ([M+H] + ).

<실시예 53> <Example 53> NN -(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-2'-(트리플루오르메틸)-[1,1'-바이페닐]-4-카르복스아마이드 제조-(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-2'-(trifluoromethyl)-[1 ,1'-Biphenyl]-4-carboxamide production

상기 실시예 37의 단계 2와 동일한 방법으로 수행하되, 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 대신에 2'-(트리플루오르메틸)-[1,1'-바이페닐]-4-카르복실산(59 mg, 0.22 mmol)을 사용하여 목적 화합물(23 mg, 44%)을 얻었다. Carry out in the same manner as step 2 of Example 37, except that instead of 4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, 2'-(trifluoromethyl)-[1,1 The target compound (23 mg, 44%) was obtained using '-biphenyl]-4-carboxylic acid (59 mg, 0.22 mmol).

1H NMR (400 MHz Methanol-d 4) δ 8.06 (d, J = 2.3 Hz, 1H), 8.01 (d, J = 8.1 Hz, 2H), 7.82 (d, J = 7.8 Hz, 1H), 7.69 (t, J = 7.5 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.56 (dd, J = 8.9, 2.1 Hz, 1H), 7.51 (d, J = 8.7 Hz, 1H), 7.47 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 7.6 Hz, 1H), 5.49 (m, 1H), 3.87 (m, 4H), 3.27 (m, 4H), 2.84 (s, 3H), 2.34 (m, 2H), 2.25 (m, 2H), 1.99 (m, 4H); MS (ESI) m/z 576 ([M+H]+). 1H NMR (400 MHz Methanol- d 4 ) δ 8.06 (d, J = 2.3 Hz, 1H), 8.01 (d, J = 8.1 Hz, 2H), 7.82 (d, J = 7.8 Hz, 1H), 7.69 ( t, J = 7.5 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.56 (dd, J = 8.9, 2.1 Hz, 1H), 7.51 (d, J = 8.7 Hz, 1H), 7.47 ( d, J = 8.0 Hz, 2H), 7.41 (d, J = 7.6 Hz, 1H), 5.49 (m, 1H), 3.87 (m, 4H), 3.27 (m, 4H), 2.84 (s, 3H), 2.34 (m, 2H), 2.25 (m, 2H), 1.99 (m, 4H); MS (ESI) m/z 576 ([M+H] + ).

<실시예 54> <Example 54> NN -(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드 제조-(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1,1'-biphenyl]-4 -Manufacture of carboxamide

상기 실시예 37의 단계 2와 동일한 방법으로 수행하되, 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 대신에 [1,1'-바이페닐]-4-카르복실산(22 mg, 0.11 mmol)을 사용하여 목적 화합물(31 mg, 67%)을 얻었다. Carry out in the same manner as step 2 of Example 37, except that instead of 4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, [1,1'-biphenyl]-4-carboxylic acid The target compound (31 mg, 67%) was obtained using boxylic acid (22 mg, 0.11 mmol).

1H NMR (400 MHz CDCl3) δ 7.96 (d, J = 8.0 Hz, 3H), 7.85 (d, J = 2.3 Hz, 1H), 7.70 (d, J = 7.7 Hz, 2H), 7.63 (d, J = 7.4 Hz, 3H), 7.55 (d, J = 8.7 Hz, 1H), 7.48 (t, J = 7.5 Hz, 2H), 7.40 (t, J = 7.4 Hz, 1H), 5.36 (m, 1H), 3.84 (m, 4H), 2.69 (m, 2H), 2.44 (m, 2H), 2.36 (s, 3H), 2.17 (m, 2H), 1.95 (m, 6H); MS (ESI) m/z 508 ([M+H]+). 1H NMR (400 MHz CDCl 3 ) δ 7.96 (d, J = 8.0 Hz, 3H), 7.85 (d, J = 2.3 Hz, 1H), 7.70 (d, J = 7.7 Hz, 2H), 7.63 (d, J = 7.4 Hz, 3H), 7.55 (d, J = 8.7 Hz, 1H), 7.48 (t, J = 7.5 Hz, 2H), 7.40 (t, J = 7.4 Hz, 1H), 5.36 (m, 1H) , 3.84 (m, 4H), 2.69 (m, 2H), 2.44 (m, 2H), 2.36 (s, 3H), 2.17 (m, 2H), 1.95 (m, 6H); MS (ESI) m/z 508 ([M+H] + ).

<실시예 55> 4'-메톡시-<Example 55> 4'-methoxy- NN -(3-(피페리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드 제조-(3-(piperidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1,1'-biphenyl]-4 -Manufacture of carboxamide

단계 1: 3-(피페리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-아민 제조Step 1: Preparation of 3-(piperidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-amine

실온에서 60% 소디움 하이드라이드(14 mg, 0.36 mmol)와 1-(2-하이드록시에틸)피롤리딘(38 μL, 0.33 mmol)를 테트라하이드로퓨란(1 mL)에 혼합한 뒤 테트라하이드로퓨란(2 mL)에 녹인 2-클로로-3-(피페리딘-1-일)퀴녹살린-6-아민(78 mg, 0.30 mmol)을 더하고 48시간 동안 교반하였다 (중간에 추가적으로 60% 소디움 하이드라이드 1.2 당량과 1-(2-하이드록시에틸)피롤리딘 1 당량을 더했다). 반응혼합물에 암모니움 클로라이드 포화 수용액을 더하고 다이클로로메탄으로 추출한 뒤 다이클로로메탄 층을 마그네슘 설페이트로 건조하였다. 용매를 감압하에서 제거한 다음 남은 잔류물에 대해 실리카겔 관 크로마토그래피(다이클로로메탄 : 메탄올 = 20 : 1)를 수행하여 목적화합물(77 mg, 82%)을 얻었다. 60% sodium hydride (14 mg, 0.36 mmol) and 1-(2-hydroxyethyl)pyrrolidine (38 μL, 0.33 mmol) were mixed in tetrahydrofuran (1 mL) at room temperature and then added to tetrahydrofuran ( 2-Chloro-3-(piperidin-1-yl)quinoxalin-6-amine (78 mg, 0.30 mmol) dissolved in 2 mL) was added and stirred for 48 hours (additionally 60% sodium hydride 1.2 in the middle). equivalent and 1 equivalent of 1-(2-hydroxyethyl)pyrrolidine were added). A saturated aqueous solution of ammonium chloride was added to the reaction mixture, extracted with dichloromethane, and the dichloromethane layer was dried over magnesium sulfate. The solvent was removed under reduced pressure, and the remaining residue was subjected to silica gel column chromatography (dichloromethane : methanol = 20 : 1) to obtain the target compound (77 mg, 82%).

1H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 8.6 Hz, 1H), 6.92 (d, J = 2.5 Hz, 1H), 6.79 (dd, J = 8.6, 2.5 Hz, 1H), 4.60 (t, J = 6.0 Hz, 2H), 3.78 (br s, 2H), 3.58 (m, 4H), 2.98 (t, J = 6.0 Hz, 2H), 2.68 (m, 4H), 1.81 (m, 4H), 1.69 (m, 6H); MS (ESI) m/z 342 ([M+H]+). 1H NMR (400 MHz, CDCl 3 ) δ 7.45 (d, J = 8.6 Hz, 1H), 6.92 (d, J = 2.5 Hz, 1H), 6.79 (dd, J = 8.6, 2.5 Hz, 1H), 4.60 (t, J = 6.0 Hz, 2H), 3.78 (br s, 2H), 3.58 (m, 4H), 2.98 (t, J = 6.0 Hz, 2H), 2.68 (m, 4H), 1.81 (m, 4H) ), 1.69 (m, 6H); MS (ESI) m/z 342 ([M+H] + ).

단계 2: 4'-메톡시-Step 2: 4'-methoxy- NN -(3-(피페리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드 제조-(3-(piperidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1,1'-biphenyl]-4 -Manufacture of carboxamide

실온에서 3-(피페리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-아민(20 mg, 0.059 mmol), 4'-메톡시-[1,1'-바이페닐]-4-카르복실산(19 mg, 0.064 mmol), 및 1-에틸-3-(3′-다이메틸아미노프로필)카르보다이이마이드(34 mg, 0.17 mmol)를 다이클로로메탄/N,N-다이메틸포름아마이드(1.5 mL/0.5 mL)에 더한 뒤 48시간 동안 교반하였다. 용매를 감압하에서 제거한 다음 남은 잔류물에 대해 실리카겔 관 크로마토그래피(다이클로로메탄 : 메탄올 = 19 : 1)를 수행하여 목적 화합물(10 mg, 31%)을 얻었다.3-(piperidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-amine (20 mg, 0.059 mmol), 4'-methoxy -[1,1'-biphenyl]-4-carboxylic acid (19 mg, 0.064 mmol), and 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide (34 mg, 0.17 mmol) ) was added to dichloromethane/ N , N -dimethylformamide (1.5 mL/0.5 mL) and stirred for 48 hours. The solvent was removed under reduced pressure, and the remaining residue was subjected to silica gel column chromatography (dichloromethane : methanol = 19 : 1) to obtain the target compound (10 mg, 31%).

1H NMR (400 MHz, CDCl3) δ 7.97 (m, 2H), 7.66 (m, 4H), 7.26 (s, 3H), 7.02 (m, 2H), 4.66 (m, 1H), 3.88 (s, 2H), 3.66 (s, 3H), 3.03 (s, 1H), 2.70 (s, 2H), 1.83 (s, 4H), 1.71 (s, 5H), 1.25 (s, 2H); MS (ESI) m/z 552 ([M+H]+). 1 H NMR (400 MHz, CDCl 3 ) δ 7.97 (m, 2H), 7.66 (m, 4H), 7.26 (s, 3H), 7.02 (m, 2H), 4.66 (m, 1H), 3.88 (s, 2H), 3.66 (s, 3H), 3.03 (s, 1H), 2.70 (s, 2H), 1.83 (s, 4H), 1.71 (s, 5H), 1.25 (s, 2H); MS (ESI) m/z 552 ([M+H] + ).

<실시예 56> 4'-플루오르-<Example 56> 4'-fluorine- NN -(3-(피페리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드 제조-(3-(piperidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1,1'-biphenyl]-4 -Manufacture of carboxamide

상기 실시예 55의 단계 2와 동일한 방법으로 수행하되, 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 대신에 4'-플루오르-[1,1'-바이페닐]-4-카르복실산(14 mg, 0.064 mmol)을 사용하여 목적 화합물(7.7 mg, 24%)을 얻었다. Carry out in the same manner as step 2 of Example 55, except that instead of 4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, 4'-fluoro-[1,1'-biphenyl ]-4-Carboxylic acid (14 mg, 0.064 mmol) was used to obtain the target compound (7.7 mg, 24%).

1H NMR (400 MHz CDCl3) δ 8.05 (m, 3H), 7.68 (m, 4H), 7.26 (s, 1H), 7.15 (m, 2H), 4.79 (s, 1H), 3.63 (s, 3H), 3.25 (s, 1H), 2.98 (m, 3H), 2.89 (s, 1H), 2.02 (m, 2H), 1.69 (s, 3H), 1.25 (s, 2H); MS (ESI) m/z 540 ([M+H]+). 1H NMR (400 MHz CDCl 3 ) δ 8.05 (m, 3H), 7.68 (m, 4H), 7.26 (s, 1H), 7.15 (m, 2H), 4.79 (s, 1H), 3.63 (s, 3H) ), 3.25 (s, 1H), 2.98 (m, 3H), 2.89 (s, 1H), 2.02 (m, 2H), 1.69 (s, 3H), 1.25 (s, 2H); MS (ESI) m/z 540 ([M+H] + ).

<실시예 57> <Example 57> NN -(2-(2-(다이메틸아미노)에톡시)-3-(피페리딘-1-일)퀴녹살린-6-일)-4'-메톡시-[1,1'-바이페닐]-4-카르복스아마이드 제조-(2-(2-(dimethylamino)ethoxy)-3-(piperidin-1-yl)quinoxalin-6-yl)-4'-methoxy-[1,1'-biphenyl] -4-Carboxamide production

단계 1: 2-(2-(다이메틸아미노)에톡시)-3-(피페리딘-1-일)퀴녹살린-6-아민 제조Step 1: Preparation of 2-(2-(dimethylamino)ethoxy)-3-(piperidin-1-yl)quinoxalin-6-amine

실온에서 60% 소디움 하이드라이드(14 mg, 0.36 mmol)와 2-다이메틸아미노에탄올(33 μL, 0.33 mmol)를 테트라하이드로퓨란(1 mL)에 혼합한 뒤 테트라하이드로퓨란(2 mL)에 녹인 2-클로로-3-(피페리딘-1-일)퀴녹살린-6-아민(78 mg, 0.30 mmol)을 더하고 48시간 동안 교반하였다 (중간에 추가적으로 60% 소디움 하이드라이드 1.2 당량과 2-다이메틸아미노에탄올 1 당량을 더했다). 반응혼합물에 암모니움 클로라이드 포화 수용액을 더하고 다이클로로메탄으로 추출한 뒤 다이클로로메탄 층을 마그네슘 설페이트로 건조하였다. 용매를 감압하에서 제거한 다음 남은 잔류물에 대해 실리카겔 관 크로마토그래피(다이클로로메탄 : 메탄올 = 20 : 1)를 수행하여 목적화합물(73 mg, 84%)을 얻었다. 60% sodium hydride (14 mg, 0.36 mmol) and 2-dimethylaminoethanol (33 μL, 0.33 mmol) were mixed in tetrahydrofuran (1 mL) at room temperature, and then dissolved in tetrahydrofuran (2 mL). -Chloro-3-(piperidin-1-yl)quinoxalin-6-amine (78 mg, 0.30 mmol) was added and stirred for 48 hours (additionally 1.2 equivalents of 60% sodium hydride and 2-dimethyl 1 equivalent of aminoethanol was added). A saturated aqueous solution of ammonium chloride was added to the reaction mixture, extracted with dichloromethane, and the dichloromethane layer was dried over magnesium sulfate. The solvent was removed under reduced pressure, and the remaining residue was subjected to silica gel column chromatography (dichloromethane : methanol = 20 : 1) to obtain the target compound (73 mg, 84%).

1H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 8.6 Hz, 1H), 6.92 (d, J = 2.5 Hz, 1H), 6.79 (dd, J = 8.6, 2.5 Hz,, 1H), 4.54 (t, J = 5.9 Hz, 2H), 3.78 (br s, 2H), 3.58 (m, 4H), 2.78 (t, J = 5.9 Hz, 2H), 2.35 (s, 6H), 1.69 (m, 6H); MS (ESI) m/z 316 ([M+H]+). 1 H NMR (400 MHz, CDCl 3 ) δ 7.45 (d, J = 8.6 Hz, 1H), 6.92 (d, J = 2.5 Hz, 1H), 6.79 (dd, J = 8.6, 2.5 Hz,, 1H), 4.54 (t, J = 5.9 Hz, 2H), 3.78 (br s, 2H), 3.58 (m, 4H), 2.78 (t, J = 5.9 Hz, 2H), 2.35 (s, 6H), 1.69 (m, 6H); MS (ESI) m/z 316 ([M+H] + ).

단계 2: Step 2: NN -(2-(2-(다이메틸아미노)에톡시)-3-(피페리딘-1-일)퀴녹살린-6-일)-4'-메톡시-[1,1'-바이페닐]-4-카르복스아마이드 제조-(2-(2-(dimethylamino)ethoxy)-3-(piperidin-1-yl)quinoxalin-6-yl)-4'-methoxy-[1,1'-biphenyl] -4-Carboxamide production

실온에서 2-(2-(다이메틸아미노)에톡시)-3-(피페리딘-1-일)퀴녹살린-6-아민(15 mg, 0.048 mmol), 4'-메톡시-[1,1'-바이페닐]-4-카르복실산(19 mg, 0.053 mmol), 및 1-에틸-3-(3′-다이메틸아미노프로필)카르보다이이마이드(34 mg, 0.17 mmol)를 다이클로로메탄/N,N-다이메틸포름아마이드(1.5 mL/0.5 mL)에 더한 뒤 48시간 동안 교반하였다. 용매를 감압하에서 제거한 다음 남은 잔류물에 대해 실리카겔 관 크로마토그래피(다이클로로메탄 : 메탄올 = 19 : 1)를 수행하여 목적 화합물(3.2 mg, 13%)을 얻었다.2-(2-(dimethylamino)ethoxy)-3-(piperidin-1-yl)quinoxalin-6-amine (15 mg, 0.048 mmol), 4'-methoxy-[1, 1'-Biphenyl]-4-carboxylic acid (19 mg, 0.053 mmol), and 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide (34 mg, 0.17 mmol) were reacted with dichloro. Methane/ N , N -dimethylformamide (1.5 mL/0.5 mL) was added and stirred for 48 hours. The solvent was removed under reduced pressure, and the remaining residue was subjected to silica gel column chromatography (dichloromethane : methanol = 19 : 1) to obtain the target compound (3.2 mg, 13%).

1H NMR (400 MHz, CDCl3) δ 7.95 (m, 2H), 7.64 (m, 3H), 7.26 (s, 3H), 7.01 (m, 1H), 4.61 (s, 1H), 3.88 (s, 2H), 3.66 (s, 3H), 2.39 (s, 3H), 1.70 (s, 4H), 1.25 (s, 3H); MS (ESI) m/z 526 ([M+H]+). 1 H NMR (400 MHz, CDCl 3 ) δ 7.95 (m, 2H), 7.64 (m, 3H), 7.26 (s, 3H), 7.01 (m, 1H), 4.61 (s, 1H), 3.88 (s, 2H), 3.66 (s, 3H), 2.39 (s, 3H), 1.70 (s, 4H), 1.25 (s, 3H); MS (ESI) m/z 526 ([M+H] + ).

<실시예 58> <Example 58> NN -(2-(2-(다이메틸아미노)에톡시)-3-(피페리딘-1-일)퀴녹살린-6-일)-4'-플루오르-[1,1'-바이페닐]-4-카르복스아마이드 제조-(2-(2-(dimethylamino)ethoxy)-3-(piperidin-1-yl)quinoxalin-6-yl)-4'-fluoro-[1,1'-biphenyl]- 4-Carboxamide production

상기 실시예 57의 단계 2와 동일한 방법으로 수행하되, 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 대신에 4'-플루오르-[1,1'-바이페닐]-4-카르복실산(14 mg, 0.064 mmol)을 사용하여 목적 화합물(2.5 mg, 10%)을 얻었다. Carry out in the same manner as step 2 of Example 57, except that instead of 4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, 4'-fluoro-[1,1'-biphenyl ]-4-Carboxylic acid (14 mg, 0.064 mmol) was used to obtain the target compound (2.5 mg, 10%).

1H NMR (400 MHz CDCl3) δ 8.03 (m, 1H), 7.62 (m, 4H), 7.52 (m, 1H), 7.26 (s, 3H), 7.17 (m, 1H), 3.63 (s, 1H), 2.96 (s, 1H), 2.89 (s, 1H), 2.65 (s, 1H), 1.71 (s, 2H), 1.25 (s, 5H), 0.87 (m, 2H); MS (ESI) m/z 514 ([M+H]+). 1H NMR (400 MHz CDCl 3 ) δ 8.03 (m, 1H), 7.62 (m, 4H), 7.52 (m, 1H), 7.26 (s, 3H), 7.17 (m, 1H), 3.63 (s, 1H) ), 2.96 (s, 1H), 2.89 (s, 1H), 2.65 (s, 1H), 1.71 (s, 2H), 1.25 (s, 5H), 0.87 (m, 2H); MS (ESI) m/z 514 ([M+H] + ).

<실시예 59> 3'-시아노-<Example 59> 3'-Cyano- NN -(2-(2-(다이메틸아미노)에톡시)-3-(피페리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드 제조-(2-(2-(dimethylamino)ethoxy)-3-(piperidin-1-yl)quinoxalin-6-yl)-[1,1'-biphenyl]-4-carboxamide manufacturing

상기 실시예 57의 단계 2와 동일한 방법으로 수행하되, 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 대신에 3'-시아노-[1,1'-바이페닐]-4-카르복실산(14 mg, 0.053 mmol)을 사용하여 목적 화합물(6 mg, 24%)을 얻었다. Carry out in the same manner as step 2 of Example 57, except that instead of 4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, 3'-cyano-[1,1'-bi The target compound (6 mg, 24%) was obtained using phenyl]-4-carboxylic acid (14 mg, 0.053 mmol).

1H NMR (400 MHz CDCl3) δ 8.02 (m, 2H), 7.87 (m, 2H), 7.66 (m, 5H), 7.26 (s, 1H), 4.73 (s, 1H), 3,64 (s, 2H), 3.06 (s, 1H), 2.96 (s, 1H), 2.55 (s, 3H), 1.70 (4H), 1.25 (s, 5H), 0.87 (m, 2H); MS (ESI) m/z 521 ([M+H]+). 1 H NMR (400 MHz CDCl 3 ) δ 8.02 (m, 2H), 7.87 (m, 2H), 7.66 (m, 5H), 7.26 (s, 1H), 4.73 (s, 1H), 3,64 (s) , 2H), 3.06 (s, 1H), 2.96 (s, 1H), 2.55 (s, 3H), 1.70 (4H), 1.25 (s, 5H), 0.87 (m, 2H); MS (ESI) m/z 521 ([M+H] + ).

<실시예 60> <Example 60> NN -(3-(다이에틸아미노)-2-(2-(다이메틸아미노)에톡시)퀴녹살린-6-일)-4'-메톡시-[1,1'-바이페닐]-4-카르복스아마이드 제조-(3-(diethylamino)-2-(2-(dimethylamino)ethoxy)quinoxalin-6-yl)-4'-methoxy-[1,1'-biphenyl]-4-car Voxamide manufacturing

단계 1: 3-(2-(다이메틸아미노)에톡시)-Step 1: 3-(2-(dimethylamino)ethoxy)- NN 22 ,, NN 22 -다이에틸퀴녹살린-2,7-다이아민 제조-Manufacture of diethylquinoxaline-2,7-diamine

실온에서 60% 소디움 하이드라이드(13 mg, 0.33 mmol)와 2-다이메틸아미노에탄올(30 μL, 0.30 mmol)를 테트라하이드로퓨란(1 mL)에 혼합한 뒤 테트라하이드로퓨란(2 mL)에 녹인 3-클로로-N 2,N 2-다이에틸퀴녹살린-2,7-다이아민(69 mg, 0.28 mmol)을 더하고 48시간 동안 교반하였다 (중간에 추가적으로 60% 소디움 하이드라이드 1.2 당량과 2-다이메틸아미노에탄올 1 당량을 더했다). 반응혼합물에 암모니움 클로라이드 포화 수용액을 더하고 다이클로로메탄으로 추출한 뒤 다이클로로메탄 층을 마그네슘 설페이트로 건조하였다. 용매를 감압하에서 제거한 다음 남은 잔류물에 대해 실리카겔 관 크로마토그래피(다이클로로메탄 : 메탄올 = 20 : 1)를 수행하여 목적화합물(61 mg, 73%)을 얻었다. 60% sodium hydride (13 mg, 0.33 mmol) and 2-dimethylaminoethanol (30 μL, 0.30 mmol) were mixed in tetrahydrofuran (1 mL) at room temperature, and then dissolved in tetrahydrofuran (2 mL). -Chloro- N 2 , N 2 -diethylquinoxaline-2,7-diamine (69 mg, 0.28 mmol) was added and stirred for 48 hours (additionally 1.2 equivalents of 60% sodium hydride and 2-dimethyl 1 equivalent of aminoethanol was added). A saturated aqueous solution of ammonium chloride was added to the reaction mixture, extracted with dichloromethane, and the dichloromethane layer was dried over magnesium sulfate. The solvent was removed under reduced pressure, and the remaining residue was subjected to silica gel column chromatography (dichloromethane : methanol = 20 : 1) to obtain the target compound (61 mg, 73%).

1H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 8.6 Hz, 1H), 6.86 (d, J = 2.0 Hz, 1H), 6.72 (dd, J = 8.6, 2.0 Hz, 1H), 4.52 (t, J = 6.1 Hz, 2H), 3.73 (br s, 2H), 3.65 (q, J = 6.9 Hz, 4H), 2.76 (t, J = 6.1 Hz, 2H), 2.33 (s, 6H), 1.24 (t, J = 6.9 Hz, 6H); MS (ESI) m/z 304 ([M+H]+). 1H NMR (400 MHz, CDCl 3 ) δ 7.41 (d, J = 8.6 Hz, 1H), 6.86 (d, J = 2.0 Hz, 1H), 6.72 (dd, J = 8.6, 2.0 Hz, 1H), 4.52 (t, J = 6.1 Hz, 2H), 3.73 (br s, 2H), 3.65 (q, J = 6.9 Hz, 4H), 2.76 (t, J = 6.1 Hz, 2H), 2.33 (s, 6H), 1.24 (t, J = 6.9 Hz, 6H); MS (ESI) m/z 304 ([M+H] + ).

단계 2: Step 2: NN -(3-(다이에틸아미노)-2-(2-(다이메틸아미노)에톡시)퀴녹살린-6-일)-4'-메톡시-[1,1'-바이페닐]-4-카르복스아마이드 제조-(3-(diethylamino)-2-(2-(dimethylamino)ethoxy)quinoxalin-6-yl)-4'-methoxy-[1,1'-biphenyl]-4-car Voxamide manufacturing

실온에서 3-(2-(다이메틸아미노)에톡시)-N 2,N 2-다이에틸퀴녹살린-2,7-다이아민(15 mg, 0.049 mmol), 4'-메톡시-[1,1'-바이페닐]-4-카르복실산(12 mg, 0.054 mmol), 및 1-에틸-3-(3′-다이메틸아미노프로필)카르보다이이마이드(28 mg, 0.15 mmol)를 다이클로로메탄/N,N-다이메틸포름아마이드(1.5 mL/0.5 mL)에 더한 뒤 48시간 동안 교반하였다. 용매를 감압하에서 제거한 다음 남은 잔류물에 대해 실리카겔 관 크로마토그래피(다이클로로메탄 : 메탄올 = 19 : 1)를 수행하여 목적 화합물(5.2 mg, 21%)을 얻었다.3-(2-(dimethylamino)ethoxy)- N 2 , N 2 -diethylquinoxaline-2,7-diamine (15 mg, 0.049 mmol), 4'-methoxy-[1, 1'-Biphenyl]-4-carboxylic acid (12 mg, 0.054 mmol), and 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide (28 mg, 0.15 mmol) were reacted with dichloromethylamine. Methane/ N , N -dimethylformamide (1.5 mL/0.5 mL) was added and stirred for 48 hours. The solvent was removed under reduced pressure, and the remaining residue was subjected to silica gel column chromatography (dichloromethane : methanol = 19 : 1) to obtain the target compound (5.2 mg, 21%).

1H NMR (400 MHz, CDCl3) δ 7.95 (m, 1H), 7.59 (s, 2H), 7.26(1H), 7.02 (m, 1H), 4.55 (m, 1H), 3.87 (m, 1H), 3.66 (m, 2H), 2.79 (s, 1H), 2.36 (s, 3H), 1.26 (m, 6H); MS (ESI) m/z 514 ([M+H]+). 1 H NMR (400 MHz, CDCl 3 ) δ 7.95 (m, 1H), 7.59 (s, 2H), 7.26 (1H), 7.02 (m, 1H), 4.55 (m, 1H), 3.87 (m, 1H) , 3.66 (m, 2H), 2.79 (s, 1H), 2.36 (s, 3H), 1.26 (m, 6H); MS (ESI) m/z 514 ([M+H] + ).

<실시예 61> 3'-시아노-<Example 61> 3'-Cyano- NN -(3-(다이에틸아미노)-2-(2-(다이메틸아미노)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드 제조-(3-(diethylamino)-2-(2-(dimethylamino)ethoxy)quinoxalin-6-yl)-[1,1'-biphenyl]-4-carboxamide production

상기 실시예 60의 단계 2와 동일한 방법으로 수행하되, 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 대신에 3'-시아노-[1,1'-바이페닐]-4-카르복실산(7.2 mg, 0.054 mmol)을 사용하여 목적 화합물(9 mg, 36%)을 얻었다. Carry out in the same manner as step 2 of Example 60, except that instead of 4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, 3'-cyano-[1,1'-bi The target compound (9 mg, 36%) was obtained using phenyl]-4-carboxylic acid (7.2 mg, 0.054 mmol).

1H NMR (400 MHz CDCl3) δ 8.03 (m, 1H), 7.89 (m, 1H), 7.71 (m, 1H), 7.66 (m, 1H), 7.26 (s, 4H), 5.30 (s, 2H), 4.57 (m, 1H), 3.66 (m, 3H), 2.82 (s, 1H), 2.36 (s, 3H), 1.26 (m, 6H); MS (ESI) m/z 509 ([M+H]+). 1H NMR (400 MHz CDCl 3 ) δ 8.03 (m, 1H), 7.89 (m, 1H), 7.71 (m, 1H), 7.66 (m, 1H), 7.26 (s, 4H), 5.30 (s, 2H) ), 4.57 (m, 1H), 3.66 (m, 3H), 2.82 (s, 1H), 2.36 (s, 3H), 1.26 (m, 6H); MS (ESI) m/z 509 ([M+H] + ).

<실시예 62> <Example 62> NN -(3-(벤질(메틸)아미노)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-4'-메톡시-[1,1'-바이페닐]-4-카르복스아마이드 제조-(3-(benzyl(methyl)amino)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-4'-methoxy-[1,1'-bi Phenyl]-4-carboxamide production

단계 1: Step 1: NN 22 -벤질--benzyl- NN 22 -메틸-3-(2-(피롤리딘-1-일)에톡시)퀴녹살린-2,7-다이아민 제조-Methyl-3-(2-(pyrrolidin-1-yl)ethoxy)quinoxaline-2,7-diamine production

실온에서 60% 소디움 하이드라이드(14 mg, 0.35 mmol)와 1-(2-하이드록시에틸)피롤리딘(37 μL, 0.32 mmol)를 테트라하이드로퓨란(1 mL)에 혼합한 뒤 테트라하이드로퓨란(2 mL)에 녹인 N 2-벤질-3-클로로-N 2-메틸퀴녹살린-2,7-다이아민(87 mg, 0.29 mmol)을 더하고 72시간 동안 교반하였다 (중간에 추가적으로 60% 소디움 하이드라이드 1.2 당량과 2-다이메틸아미노에탄올 1 당량을 더했다). 반응혼합물에 암모니움 클로라이드 포화 수용액을 더하고 다이클로로메탄으로 추출한 뒤 다이클로로메탄 층을 마그네슘 설페이트로 건조하였다. 용매를 감압하에서 제거한 다음 남은 잔류물에 대해 실리카겔 관 크로마토그래피(다이클로로메탄 : 메탄올 = 20 : 1)를 수행하여 목적화합물(85 mg, 78%)을 얻었다. 60% sodium hydride (14 mg, 0.35 mmol) and 1-(2-hydroxyethyl)pyrrolidine (37 μL, 0.32 mmol) were mixed in tetrahydrofuran (1 mL) at room temperature and then added to tetrahydrofuran ( N 2 -benzyl-3-chloro- N 2 -methylquinoxaline-2,7-diamine (87 mg, 0.29 mmol) dissolved in 2 mL) was added and stirred for 72 hours (additionally 60% sodium hydride in the middle) 1.2 equivalents and 1 equivalent of 2-dimethylaminoethanol were added). A saturated aqueous solution of ammonium chloride was added to the reaction mixture, extracted with dichloromethane, and the dichloromethane layer was dried over magnesium sulfate. The solvent was removed under reduced pressure, and the remaining residue was subjected to silica gel column chromatography (dichloromethane : methanol = 20 : 1) to obtain the target compound (85 mg, 78%).

1H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 8.6 Hz, 1H), 7.30 (m, 5H), 6.91 (d, J = 2.5 Hz, 1H), 6.78 (dd, J = 8.6, 2.5 Hz, 1H), 4.87 (s, 2H), 4.56 (t, J = 6.1 Hz, 2H), 3.77 (br s, 2H), 3.10 (s, 3H), 2.80 (t, J = 6.1 Hz, 2H), 2.53 (m, 4H), 1.73 (m, 4H); MS (ESI) m/z 378 ([M+H]+). 1H NMR (400 MHz, CDCl 3 ) δ 7.46 (d, J = 8.6 Hz, 1H), 7.30 (m, 5H), 6.91 (d, J = 2.5 Hz, 1H), 6.78 (dd, J = 8.6, 2.5 Hz, 1H), 4.87 (s, 2H), 4.56 (t, J = 6.1 Hz, 2H), 3.77 (br s, 2H), 3.10 (s, 3H), 2.80 (t, J = 6.1 Hz, 2H) ), 2.53 (m, 4H), 1.73 (m, 4H); MS (ESI) m/z 378 ([M+H] + ).

단계 2: Step 2: NN -(3-(벤질(메틸)아미노)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-4'-메톡시-[1,1'-바이페닐]-4-카르복스아마이드 제조-(3-(benzyl(methyl)amino)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-4'-methoxy-[1,1'-bi Phenyl]-4-carboxamide production

실온에서 N 2-벤질-N 2-메틸-3-(2-(피롤리딘-1-일)에톡시)퀴녹살린-2,7-다이아민(25 mg, 0.066 mmol), 4'-메톡시-[1,1'-바이페닐]-4-카르복실산(17 mg, 0.073 mmol), 및 1-에틸-3-(3′-다이메틸아미노프로필)카르보다이이마이드(38 mg, 0.20 mmol)를 다이클로로메탄/N,N-다이메틸포름아마이드(1.5 mL/0.5 mL)에 더한 뒤 48시간 동안 교반하였다. 용매를 감압하에서 제거한 다음 남은 잔류물에 대해 실리카겔 관 크로마토그래피(다이클로로메탄 : 메탄올 = 19 : 1)를 수행하여 목적 화합물(17 mg, 44%)을 얻었다. N 2 -benzyl- N 2 -methyl-3-(2-(pyrrolidin-1-yl)ethoxy)quinoxaline-2,7-diamine (25 mg, 0.066 mmol), 4'-methyl at room temperature. Toxy-[1,1'-biphenyl]-4-carboxylic acid (17 mg, 0.073 mmol), and 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide (38 mg, 0.20 mg) mmol) was added to dichloromethane/ N , N -dimethylformamide (1.5 mL/0.5 mL) and stirred for 48 hours. The solvent was removed under reduced pressure, and the remaining residue was subjected to silica gel column chromatography (dichloromethane : methanol = 19 : 1) to obtain the target compound (17 mg, 44%).

1H NMR (400 MHz, CDCl3) δ 7.97 (m, 2H), 7.67 (m, 3H), 7.34 (m, 5H), 7.02 (s, 1H), 4.91 (s, 1H), 4.86 (s, 1H), 4.59 (m, 2H), 3.87 (s, 2H), 3.13 (m, 3H), 2.86 (m, 2H), 2.56 (s, 4H), 1.75 (s, 4H), 1.25 (s, 2H); MS (ESI) m/z 588 ([M+H]+). 1 H NMR (400 MHz, CDCl 3 ) δ 7.97 (m, 2H), 7.67 (m, 3H), 7.34 (m, 5H), 7.02 (s, 1H), 4.91 (s, 1H), 4.86 (s, 1H), 4.59 (m, 2H), 3.87 (s, 2H), 3.13 (m, 3H), 2.86 (m, 2H), 2.56 (s, 4H), 1.75 (s, 4H), 1.25 (s, 2H) ); MS (ESI) m/z 588 ([M+H] + ).

<실시예 63> <Example 63> NN -(3-(벤질(메틸)아미노)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-4'-플루오르-[1,1'-바이페닐]-4-카르복스아마이드 제조-(3-(benzyl(methyl)amino)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-4'-fluoro-[1,1'-biphenyl ]-4-Carboxamide production

상기 실시예 62의 단계 2와 동일한 방법으로 수행하되, 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 대신에 4'-플루오르-[1,1'-바이페닐]-4-카르복실산(16 mg, 0.073 mmol)을 사용하여 목적 화합물(20 mg, 53%)을 얻었다. Carry out in the same manner as step 2 of Example 62, except that instead of 4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, 4'-fluoro-[1,1'-biphenyl ]-4-Carboxylic acid (16 mg, 0.073 mmol) was used to obtain the target compound (20 mg, 53%).

1H NMR (400 MHz CDCl3) δ 8.24 (s, 1H), 8.03 (m, 5H), 7.19 (m, 12H), 4.83 (m, 4H), 3.65 (s, 6H), 3.18 (m, 5H), 2.99 (s, 5H), 2.04 (s, 1H), 1.91 (s, 4H), 1.25 (s, 10H), 0.84 (4H); MS (ESI) m/z 576 ([M+H]+). 1 H NMR (400 MHz CDCl 3 ) δ 8.24 (s, 1H), 8.03 (m, 5H), 7.19 (m, 12H), 4.83 (m, 4H), 3.65 (s, 6H), 3.18 (m, 5H) ), 2.99 (s, 5H), 2.04 (s, 1H), 1.91 (s, 4H), 1.25 (s, 10H), 0.84 (4H); MS (ESI) m/z 576 ([M+H] + ).

<실시예 64> <Example 64> NN -(3-(벤질(메틸)아미노)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-3'-시아노-[1,1'-바이페닐]-4-카르복스아마이드 제조-(3-(benzyl(methyl)amino)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-3'-cyano-[1,1'-bi Phenyl]-4-carboxamide production

상기 실시예 62의 단계 2와 동일한 방법으로 수행하되, 4'-메톡시-[1,1'-바이페닐]-4-카르복실산 대신에 3'-시아노-[1,1'-바이페닐]-4-카르복실산(16 mg, 0.073 mmol)을 사용하여 목적 화합물(14 mg, 36%)을 얻었다. Carry out in the same manner as step 2 of Example 62, except that instead of 4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, 3'-cyano-[1,1'-bi The target compound (14 mg, 36%) was obtained using phenyl]-4-carboxylic acid (16 mg, 0.073 mmol).

1H NMR (400 MHz CDCl3) δ 7.91 (m, 2H), 7.68 (m, 1H), 7.67 (m, 4H), 7.30 (m, 4H), 5.30 (s, 1H), 4.90 (s, 1H), 4.67 (s, 1H), 3.16 (s, 2H), 2.95 (s, 1H), 2.69 (s, 2H), 1.80 (s, 2H), 1.25 (s, 2H), 0.86 (m, 1H); MS (ESI) m/z 583 ([M+H]+). 1 H NMR (400 MHz CDCl 3 ) δ 7.91 (m, 2H), 7.68 (m, 1H), 7.67 (m, 4H), 7.30 (m, 4H), 5.30 (s, 1H), 4.90 (s, 1H) ), 4.67 (s, 1H), 3.16 (s, 2H), 2.95 (s, 1H), 2.69 (s, 2H), 1.80 (s, 2H), 1.25 (s, 2H), 0.86 (m, 1H) ; MS (ESI) m/z 583 ([M+H] + ).

<실시예 65> <Example 65> NN -(3-(벤질(메틸)아미노)-2-(2-(다이메틸아미노)에톡시)퀴녹살린-6-일)-4'-플루오르-[1,1'-바이페닐]-4-카르복스아마이드 제조-(3-(benzyl(methyl)amino)-2-(2-(dimethylamino)ethoxy)quinoxalin-6-yl)-4'-fluoro-[1,1'-biphenyl]-4- Carboxamide manufacturing

단계 1: Step 1: NN 22 -벤질-3-(2-(다이메틸아미노)에톡시)--Benzyl-3-(2-(dimethylamino)ethoxy)- NN 22 -메틸퀴녹살린-2,7-다이아민 제조-Methylquinoxaline-2,7-diamine production

실온에서 60% 소디움 하이드라이드(14 mg, 0.35 mmol)와 2-다이메틸아미노에탄올(32 μL, 0.32 mmol)를 테트라하이드로퓨란(1 mL)에 혼합한 뒤 테트라하이드로퓨란(2 mL)에 녹인 N 2-벤질-3-클로로-N 2-메틸퀴녹살린-2,7-다이아민(87 mg, 0.29 mmol)을 더하고 72시간 동안 교반하였다 (중간에 추가적으로 60% 소디움 하이드라이드 1.2 당량과 2-다이메틸아미노에탄올 1 당량을 더했다). 반응혼합물에 암모니움 클로라이드 포화 수용액을 더하고 다이클로로메탄으로 추출한 뒤 다이클로로메탄 층을 마그네슘 설페이트로 건조하였다. 용매를 감압하에서 제거한 다음 남은 잔류물에 대해 실리카겔 관 크로마토그래피(다이클로로메탄 : 메탄올 = 20 : 1)를 수행하여 목적화합물(82 mg, 81%)을 얻었다. After mixing 60% sodium hydride (14 mg, 0.35 mmol) and 2-dimethylaminoethanol (32 μL, 0.32 mmol) in tetrahydrofuran (1 mL) at room temperature, N dissolved in tetrahydrofuran (2 mL) 2 -Benzyl-3-chloro- N 2 -methylquinoxaline-2,7-diamine (87 mg, 0.29 mmol) was added and stirred for 72 hours (additionally 1.2 equivalents of 60% sodium hydride and 2-diamine were added) 1 equivalent of methylaminoethanol was added). A saturated aqueous solution of ammonium chloride was added to the reaction mixture, extracted with dichloromethane, and the dichloromethane layer was dried over magnesium sulfate. The solvent was removed under reduced pressure, and the remaining residue was subjected to silica gel column chromatography (dichloromethane : methanol = 20 : 1) to obtain the target compound (82 mg, 81%).

1H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 8.6 Hz, 1H), 7.31 (m, 5H), 6.91 (d, J = 2.4 Hz, 1H), 6.78 (dd, J = 8.6, 2.4 Hz, 1H), 4.86 (s, 2H), 4.51 (t, J = 6.0 Hz, 2H), 3.77 (br s, 2H), 3.11 (s, 3H), 2.61 (t, J = 6.0 Hz, 2H), 2.23 (s, 6H); MS (ESI) m/z 352 ([M+H]+). 1H NMR (400 MHz, CDCl 3 ) δ 7.46 (d, J = 8.6 Hz, 1H), 7.31 (m, 5H), 6.91 (d, J = 2.4 Hz, 1H), 6.78 (dd, J = 8.6, 2.4 Hz, 1H), 4.86 (s, 2H), 4.51 (t, J = 6.0 Hz, 2H), 3.77 (br s, 2H), 3.11 (s, 3H), 2.61 (t, J = 6.0 Hz, 2H) ), 2.23 (s, 6H); MS (ESI) m/z 352 ([M+H] + ).

단계 2: Step 2: NN -(3-(벤질(메틸)아미노)-2-(2-(다이메틸아미노)에톡시)퀴녹살린-6-일)-4'-플루오르-[1,1'-바이페닐]-4-카르복스아마이드 제조-(3-(benzyl(methyl)amino)-2-(2-(dimethylamino)ethoxy)quinoxalin-6-yl)-4'-fluoro-[1,1'-biphenyl]-4- Carboxamide manufacturing

실온에서 N 2-벤질-3-(2-(다이메틸아미노)에톡시)-N 2-메틸퀴녹살린-2,7-다이아민(25 mg, 0.066 mmol), 4'-플루오르-[1,1'-바이페닐]-4-카르복실산(17 mg, 0.073 mmol), 및 1-에틸-3-(3′-다이메틸아미노프로필)카르보다이이마이드(32 mg, 0.17 mmol)를 다이클로로메탄/N,N-다이메틸포름아마이드(1.5 mL/0.5 mL)에 더한 뒤 48시간 동안 교반하였다. 용매를 감압하에서 제거한 다음 남은 잔류물에 대해 실리카겔 관 크로마토그래피(다이클로로메탄 : 메탄올 = 19 : 1)를 수행하여 목적 화합물(25 mg, 69%)을 얻었다. N 2 -benzyl-3-(2-(dimethylamino)ethoxy)- N 2 -methylquinoxaline-2,7-diamine (25 mg, 0.066 mmol), 4'-fluoro-[1, 1'-Biphenyl]-4-carboxylic acid (17 mg, 0.073 mmol), and 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide (32 mg, 0.17 mmol) were reacted with dichloromethylamine. Methane/ N , N -dimethylformamide (1.5 mL/0.5 mL) was added and stirred for 48 hours. The solvent was removed under reduced pressure, and the remaining residue was subjected to silica gel column chromatography (dichloromethane : methanol = 19 : 1) to obtain the target compound (25 mg, 69%).

1H NMR (400 MHz, CDCl3) δ 8.07 (m, 1H), 7.99 (m, 2H), 7.61 (m, 2H), 7.65 (m, 3H), 7.57 (s, 3H), 7.33 (s, 2H), 6.92 (m, 2H), 4.86 (m, 1H), 4.65 (m, 1H), 3.13 (m, 2H), 2.89 (s, 2H), 2.39 (s, 4H), 1.25 (s, 3H), 0.84 (s, 2H); MS (ESI) m/z 550 ([M+H]+). 1 H NMR (400 MHz, CDCl 3 ) δ 8.07 (m, 1H), 7.99 (m, 2H), 7.61 (m, 2H), 7.65 (m, 3H), 7.57 (s, 3H), 7.33 (s, 2H), 6.92 (m, 2H), 4.86 (m, 1H), 4.65 (m, 1H), 3.13 (m, 2H), 2.89 (s, 2H), 2.39 (s, 4H), 1.25 (s, 3H) ), 0.84 (s, 2H); MS (ESI) m/z 550 ([M+H] + ).

<실시예 66> <Example 66> NN -(3-(벤질(메틸)아미노)-2-(2-(다이메틸아미노)에톡시)퀴녹살린-6-일)-3'-시아노-[1,1'-바이페닐]-4-카르복스아마이드 제조-(3-(benzyl(methyl)amino)-2-(2-(dimethylamino)ethoxy)quinoxalin-6-yl)-3'-cyano-[1,1'-biphenyl]-4 -Manufacture of carboxamide

상기 실시예 65의 단계 2와 동일한 방법으로 수행하되, 4'-플루오르-[1,1'-바이페닐]-4-카르복실산 대신에 3'-시아노-[1,1'-바이페닐]-4-카르복실산(18 mg, 0.078 mmol)을 사용하여 목적 화합물(24 mg, 65%)을 얻었다. Carry out in the same manner as step 2 of Example 65, except that instead of 4'-fluoro-[1,1'-biphenyl]-4-carboxylic acid, 3'-cyano-[1,1'-biphenyl ]-4-Carboxylic acid (18 mg, 0.078 mmol) was used to obtain the target compound (24 mg, 65%).

1H NMR (400 MHz CDCl3) δ 8.02 (m, 3H), 7.89 (m, 1H), 7.68 (m, 3H), 7.34 (s, 2H), 7.26 (s, 2H), 4.88 (m, 1H), 4.60 (s, 1H), 3.17 (s, 2H), 2.92 (m, 7H), 2.72 (s, 1H), 2.31 (s, 3H), 1.25 (s, 3H), 0.84 (s, 1H); MS (ESI) m/z 557 ([M+H]+). 1H NMR (400 MHz CDCl 3 ) δ 8.02 (m, 3H), 7.89 (m, 1H), 7.68 (m, 3H), 7.34 (s, 2H), 7.26 (s, 2H), 4.88 (m, 1H) ), 4.60 (s, 1H), 3.17 (s, 2H), 2.92 (m, 7H), 2.72 (s, 1H), 2.31 (s, 3H), 1.25 (s, 3H), 0.84 (s, 1H) ; MS (ESI) m/z 557 ([M+H] + ).

<실시예 67> <Example 67> NN -(3-(벤질(메틸)아미노)-2-((1-메틸피페리딘-4-일)옥시)퀴녹살린-6-일)-4'-메톡시-[1,1'-바이페닐]-4-카르복스아마이드 제조-(3-(benzyl(methyl)amino)-2-((1-methylpiperidin-4-yl)oxy)quinoxalin-6-yl)-4'-methoxy-[1,1'-bi Phenyl]-4-carboxamide production

단계 1: Step 1: NN 22 -벤질--benzyl- NN 22 -메틸-3-((1-메틸피페리딘-4-일)옥시)퀴녹살린-2,7-다이아민 제조-Methyl-3-((1-methylpiperidin-4-yl)oxy)quinoxaline-2,7-diamine manufactured

실온에서 60% 소디움 하이드라이드(14 mg, 0.35 mmol)와 1-메틸-4-피페리딘올(37 μL, 0.32 mmol)를 테트라하이드로퓨란(1 mL)에 혼합한 뒤 테트라하이드로퓨란(2 mL)에 녹인 N 2-벤질-3-클로로-N 2-메틸퀴녹살린-2,7-다이아민(87 mg, 0.29 mmol)을 더하고 72시간 동안 교반하였다 (중간에 추가적으로 60% 소디움 하이드라이드 1.2 당량과 2-다이메틸아미노에탄올 1 당량을 더했다). 반응혼합물에 암모니움 클로라이드 포화 수용액을 더하고 다이클로로메탄으로 추출한 뒤 다이클로로메탄 층을 마그네슘 설페이트로 건조하였다. 용매를 감압하에서 제거한 다음 남은 잔류물에 대해 실리카겔 관 크로마토그래피(다이클로로메탄 : 메탄올 = 20 : 1)를 수행하여 목적화합물(31 mg, 28%)을 얻었다. Mix 60% sodium hydride (14 mg, 0.35 mmol) and 1-methyl-4-piperidinol (37 μL, 0.32 mmol) in tetrahydrofuran (1 mL) at room temperature, then add tetrahydrofuran (2 mL). N 2 -benzyl-3-chloro- N 2 -methylquinoxaline-2,7-diamine (87 mg, 0.29 mmol) dissolved in was added and stirred for 72 hours (additionally 1.2 equivalents of 60% sodium hydride and 1 equivalent of 2-dimethylaminoethanol was added). A saturated aqueous solution of ammonium chloride was added to the reaction mixture, extracted with dichloromethane, and the dichloromethane layer was dried over magnesium sulfate. The solvent was removed under reduced pressure, and the remaining residue was subjected to silica gel column chromatography (dichloromethane : methanol = 20 : 1) to obtain the target compound (31 mg, 28%).

1H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 8.6 Hz, 1H), 7.33 (m, 5H), 6.91 (s, 1H), 6.77 (d, J = 8.6 Hz, 1H), 5.32 (s, 1H), 4.86 (s, 2H), 3.76 (br s, 2H), 3.11 (s, 3H), 2.47 (m , 2H), 2.32 (m, 2H), 2.23 (s, 3H), 2.06 (m, 2H), 1.82 (m, 2H); MS (ESI) m/z 378 ([M+H]+). 1H NMR (400 MHz, CDCl 3 ) δ 7.43 (d, J = 8.6 Hz, 1H), 7.33 (m, 5H), 6.91 (s, 1H), 6.77 (d, J = 8.6 Hz, 1H), 5.32 (s, 1H), 4.86 (s, 2H), 3.76 (br s, 2H), 3.11 (s, 3H), 2.47 (m, 2H), 2.32 (m, 2H), 2.23 (s, 3H), 2.06 (m, 2H), 1.82 (m, 2H); MS (ESI) m/z 378 ([M+H] + ).

단계 2: Step 2: NN -(3-(벤질(메틸)아미노)-2-((1-메틸피페리딘-4-일)옥시)퀴녹살린-6-일)-4'-메톡시-[1,1'-바이페닐]-4-카르복스아마이드 제조-(3-(benzyl(methyl)amino)-2-((1-methylpiperidin-4-yl)oxy)quinoxalin-6-yl)-4'-methoxy-[1,1'-bi Phenyl]-4-carboxamide production

실온에서 N 2-벤질-N 2-메틸-3-((1-메틸피페리딘-4-일)옥시)퀴녹살린-2,7-다이아민(8 mg, 0.02 mmol), 4'-메톡시-[1,1'-바이페닐]-4-카르복실산(5.3 mg, 0.023 mmol), 및 1-에틸-3-(3′-다이메틸아미노프로필)카르보다이이마이드(12 mg, 0.063 mmol)를 다이클로로메탄/N,N-다이메틸포름아마이드(1.5 mL/0.5 mL)에 더한 뒤 48시간 동안 교반하였다. 용매를 감압하에서 제거한 다음 남은 잔류물에 대해 실리카겔 관 크로마토그래피(다이클로로메탄 : 메탄올 = 19 : 1)를 수행하여 목적 화합물(3 mg, 26%)을 얻었다. N 2 -benzyl- N 2 -methyl-3-((1-methylpiperidin-4-yl)oxy)quinoxaline-2,7-diamine (8 mg, 0.02 mmol), 4'-methyl at room temperature. Toxy-[1,1'-biphenyl]-4-carboxylic acid (5.3 mg, 0.023 mmol), and 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide (12 mg, 0.063) mmol) was added to dichloromethane/ N , N -dimethylformamide (1.5 mL/0.5 mL) and stirred for 48 hours. The solvent was removed under reduced pressure, and the remaining residue was subjected to silica gel column chromatography (dichloromethane : methanol = 19 : 1) to obtain the target compound (3 mg, 26%).

1H NMR (400 MHz, CDCl3) δ 7.26 (s, 4H), 4.89 (s, 1H), 3.66 (s, 1H), 2.02 (m, 4H), 1.57 (m, 7H), 1.25 (s 30H), 0.86 (9H), 0.35 (s, 9H); MS (ESI) m/z 588 ([M+H]+). 1 H NMR (400 MHz, CDCl 3 ) δ 7.26 (s, 4H), 4.89 (s, 1H), 3.66 (s, 1H), 2.02 (m, 4H), 1.57 (m, 7H), 1.25 (s 30H) ), 0.86 (9H), 0.35 (s, 9H); MS (ESI) m/z 588 ([M+H] + ).

상기 실시예 1 내지 67에서 제조된 화합물들의 구조를 확인하기 위하여 최종 화합물들을 1H NMR 스펙트럼과 질량분석 스펙트럼으로 분석하였으며, 하기 표 1에 구조와 함께 질량분석 결과를 기재하였다.In order to confirm the structures of the compounds prepared in Examples 1 to 67, the final compounds were analyzed with 1 H NMR spectra and mass spectrometry spectra, and the structures and mass spectrometry results are listed in Table 1 below.

[표 1][Table 1]

<실험예 1> 교모세포종의 일종인 T98G 세포 성장 저해 확인 실험<Experimental Example 1> Experiment to confirm growth inhibition of T98G cells, a type of glioblastoma

T98G 세포를 96웰 플레이트에 웰당 4,000개 세포로 배양하여 하루 안정화시키고, 화합물의 최종 농도가 1, 10 μM가 되도록 세포에 처리하였다. 화합물이 처리된 세포는 3일간 배양하고, CCK-8 시약을 활용하여 세포 생존율을 측정하였다. GI50 측정은 10 μM부터 1/2씩 희석하여 9개 농도로 화합물을 처리하여 확보한 세포 생존율을 통해 계산하였다. T98G cells were cultured in a 96-well plate at 4,000 cells per well and stabilized for one day, and the cells were treated so that the final concentration of the compound was 1 and 10 μM. Cells treated with the compound were cultured for 3 days, and cell viability was measured using CCK-8 reagent. GI 50 measurement was calculated from the cell viability obtained by treating the compounds at 9 concentrations starting from 10 μM and diluting them by 1/2.

본 발명 실시예 1 내지 67에 따라 제조된 화합물에 대한 % 성장 또는 GI50을 하기 표 2에 나타내었다.The % growth or GI 50 for the compounds prepared according to Examples 1 to 67 of the present invention are shown in Table 2 below.

[표 2][Table 2]

상기 표 2에 나타난 바와 같이, 본 발명에 따라 제조된 퀴녹살린 카르복스아마이드 유도체 화합물은 10 μM에서의 우수한 성장 저해 활성 또는 GI50 값이 단단위 μM 이하로 우수한 T98G 세포 성장 저해 활성을 갖는 것으로 나타났다. 특히, 실시예 19, 32, 43 및 57에 따라 제조된 화합물은 1 μM 미만의 GI50 값을 가지는 것으로 나타나 T98G 세포 성장 저해 활성이 현저히 우수한 것을 확인할 수 있었다.As shown in Table 2, the quinoxaline carboxamide derivative compound prepared according to the present invention was shown to have excellent growth inhibitory activity at 10 μM or excellent T98G cell growth inhibitory activity with a GI 50 value of less than one unit μM. . In particular, the compounds prepared according to Examples 19, 32, 43, and 57 were found to have a GI 50 value of less than 1 μM, and were confirmed to have significantly excellent T98G cell growth inhibitory activity.

따라서 본 발명의 실시예에 나타낸 화합물들은 우수한 T98G 세포 성장 저해 활성 효과를 나타냄에 따라 암세포가 비정상적인 증식을 보이는 상태인 교모세포종의 예방 또는 치료에 유용하게 사용될 수 있다. Therefore, the compounds shown in the examples of the present invention exhibit excellent T98G cell growth inhibitory activity and can be usefully used in the prevention or treatment of glioblastoma, a condition in which cancer cells exhibit abnormal proliferation.

한편, 본 발명에 따른 상기 화학식 1로 표시되는 퀴녹살린 카르복스아마이드 유도체는 목적에 따라 여러 형태로 제제화가 가능하다. 하기는 본 발명에 따른 상기 화학식 1로 표시되는 화합물을 활성성분으로 함유시킨 몇몇 제제화 방법을 예시한 것으로 본 발명이 이에 한정되는 것은 아니다.Meanwhile, the quinoxaline carboxamide derivative represented by Formula 1 according to the present invention can be formulated in various forms depending on the purpose. The following illustrates several formulation methods containing the compound represented by Formula 1 as an active ingredient according to the present invention, but the present invention is not limited thereto.

<제제예 1> 산제의 제조<Formulation Example 1> Preparation of powder

상기의 성분을 혼합하고 기밀포에 충진하여 산제를 제조하였다.The above ingredients were mixed and filled into an airtight bubble to prepare a powder.

또한, 상기 실시예 1의 퀴녹살린 카르복스아마이드 유도체 대신에 실시예 2 내지 67에 따라 제조된 화합물 중 하나 이상을 사용하여 산제를 제조할 수 있다.Additionally, a powder can be prepared using one or more of the compounds prepared according to Examples 2 to 67 instead of the quinoxaline carboxamide derivative of Example 1.

<제제예 2> 정제의 제조<Formulation Example 2> Preparation of tablets

상기의 성분을 혼합한 후, 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조하였다.After mixing the above ingredients, tablets were manufactured by tableting according to a conventional tablet manufacturing method.

또한, 상기 실시예 1의 퀴녹살린 카르복스아마이드 유도체 대신에 실시예 2 내지 67에 따라 제조된 화합물 중 하나 이상을 사용하여 정제를 제조할 수 있다.Additionally, tablets can be manufactured using one or more of the compounds prepared according to Examples 2 to 67 instead of the quinoxaline carboxamide derivative of Example 1.

<제제예 3> 캡슐제의 제조<Formulation Example 3> Preparation of capsules

상기의 성분을 혼합한 후, 통상의 캡슐제의 제조방법에 따라서 젤라틴 캡슐에 충전하여 캡슐제를 제조하였다.After mixing the above ingredients, a capsule was prepared by filling a gelatin capsule according to a typical capsule manufacturing method.

또한, 상기 실시예 1의 퀴녹살린 카르복스아마이드 유도체 대신에 실시예 2 내지 67에 따라 제조된 화합물 중 하나 이상을 사용하여 캡슐제를 제조할 수 있다.Additionally, capsules can be prepared using one or more of the compounds prepared according to Examples 2 to 67 instead of the quinoxaline carboxamide derivative of Example 1.

<제제예 4> 주사제의 제조<Formulation Example 4> Preparation of injection

통상적인 주사제의 제조방법에 따라, 상기 성분들을 제시된 함량으로 함유시켜 주사제를 제조하였다.According to a typical manufacturing method for injectables, an injectable was prepared by containing the above ingredients in the indicated amounts.

또한, 상기 실시예 1의 퀴녹살린 카르복스아마이드 유도체 대신에 실시예 2 내지 67에 따라 제조된 화합물 중 하나 이상을 사용하여 주사제를 제조할 수 있다.Additionally, an injection can be prepared using one or more of the compounds prepared according to Examples 2 to 67 instead of the quinoxaline carboxamide derivative of Example 1.

상기에서는 본 발명의 바람직한 실시예를 참조하여 설명하였지만, 해당 기술 분야의 숙련된 당업자는 하기의 특허 청구 범위에 기재된 본 발명의 사상 및 영역으로부터 벗어나지 않는 범위 내에서 본 발명을 다양하게 수정 및 변경시킬 수 있음을 이해할 수 있을 것이다.Although the present invention has been described above with reference to preferred embodiments, those skilled in the art can make various modifications and changes to the present invention without departing from the spirit and scope of the present invention as set forth in the following patent claims. You will understand that it is possible.

Claims (14)

하기 화학식 1로 표시되는 퀴녹살린 카르복스아마이드 유도체, 이의 이성질체 또는 이의 약학적으로 허용가능한 염:
[화학식 1]

상기 화학식 1에서,
NR1R2는 또는 또는 이고,
OR3는 또는 또는 이고;
R4는 수소 원자, -O-C1-C6 알킬, C1-C6 알킬, 할로겐 원자, -CN, 또는 C1-C6 할로알킬이다. A quinoxaline carboxamide derivative represented by the following formula (1), an isomer thereof, or a pharmaceutically acceptable salt thereof:
[Formula 1]

In Formula 1,
NR 1 R 2 is or or ego,
OR 3 is or or ego;
R 4 is a hydrogen atom, -OC 1 -C 6 alkyl, C 1 -C 6 alkyl, a halogen atom, -CN, or C 1 -C 6 haloalkyl. 제1항에 있어서,
상기 화학식 1로 표시되는 퀴녹살린 카르복스아마이드 유도체는 하기에 화합물 1 내지 59 및 62 내지 67로 나타내는 화합물로 이루어진 군으로부터 선택된 것인, 퀴녹살린 카르복스아마이드 유도체, 이의 이성질체 또는 이의 약학적으로 허용가능한 염:
1) 4'-메톡시-N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
2) 3'-메톡시-N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
3) 2'-메톡시-N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
4) 4'-메틸-N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
5) 3'-메틸-N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
6) 2'-메틸-N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
7) 4'-플루오르-N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
8) 3'-플루오르-N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
9) 2'-플루오르-N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
10) 4'-클로로-N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
11) 3'-클로로-N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
12) 2'-클로로-N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
13) 4'-시아노-N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
14) 3'-시아노-N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
15) N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-4'-(트리플루오르메틸)-[1,1'-바이페닐]-4-카르복스아마이드;
16) N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-3'-(트리플루오르메틸)-[1,1'-바이페닐]-4-카르복스아마이드;
17) N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-2'-(트리플루오르메틸)-[1,1'-바이페닐]-4-카르복스아마이드;
18) N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
19) N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-4'-메톡시-[1,1'-바이페닐]-4-카르복스아마이드;
20) N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-3'-메톡시-[1,1'-바이페닐]-4-카르복스아마이드;
21) N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-2'-메톡시-[1,1'-바이페닐]-4-카르복스아마이드;
22) N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-4'-메틸-[1,1'-바이페닐]-4-카르복스아마이드;
23) N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-3'-메틸-[1,1'-바이페닐]-4-카르복스아마이드;
24) N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-2'-메틸-[1,1'-바이페닐]-4-카르복스아마이드;
25) N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-4'-플루오르-[1,1'-바이페닐]-4-카르복스아마이드;
26) N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-3'-플루오르-[1,1'-바이페닐]-4-카르복스아마이드;
27) N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-2'-플루오르-[1,1'-바이페닐]-4-카르복스아마이드;
28) 4'-클로로-N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
29) 3'-클로로-N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
30) 2'-클로로-N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
31) 4'-시아노-N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
32) 3'-시아노-N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
33) N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-4'-(트리플루오르메틸)-[1,1'-바이페닐]-4-카르복스아마이드;
34) N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-3'-(트리플루오르메틸)-[1,1'-바이페닐]-4-카르복스아마이드;
35) N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-2'-(트리플루오르메틸)-[1,1'-바이페닐]-4-카르복스아마이드;
36) N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
37) 4'-메톡시-N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
38) 3'-메톡시-N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
39) 2'-메톡시-N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
40) 4'-메틸-N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
41) 3'-메틸-N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
42) 2'-메틸-N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
43) 4'-플루오르-N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
44) 3'-플루오르-N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
45) 2'-플루오르-N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
46) 4'-클로로-N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
47) 3'-클로로-N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
48) 2'-클로로-N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
49) 4'-시아노-N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
50) 3'-시아노-N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
51) N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-4'-(트리플루오르메틸)-[1,1'-바이페닐]-4-카르복스아마이드;
52) N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-3'-(트리플루오르메틸)-[1,1'-바이페닐]-4-카르복스아마이드;
53) N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-2'-(트리플루오르메틸)-[1,1'-바이페닐]-4-카르복스아마이드;
54) N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
55) 4'-메톡시-N-(3-(피페리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
56) 4'-플루오르-N-(3-(피페리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
57) N-(2-(2-(다이메틸아미노)에톡시)-3-(피페리딘-1-일)퀴녹살린-6-일)-4'-메톡시-[1,1'-바이페닐]-4-카르복스아마이드;
58) N-(2-(2-(다이메틸아미노)에톡시)-3-(피페리딘-1-일)퀴녹살린-6-일)-4'-플루오르-[1,1'-바이페닐]-4-카르복스아마이드;
59) 3'-시아노-N-(2-(2-(다이메틸아미노)에톡시)-3-(피페리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
62) N-(3-(벤질(메틸)아미노)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-4'-메톡시-[1,1'-바이페닐]-4-카르복스아마이드;
63) N-(3-(벤질(메틸)아미노)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-4'-플루오르-[1,1'-바이페닐]-4-카르복스아마이드;
64) N-(3-(벤질(메틸)아미노)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-3'-시아노-[1,1'-바이페닐]-4-카르복스아마이드;
65) N-(3-(벤질(메틸)아미노)-2-(2-(다이메틸아미노)에톡시)퀴녹살린-6-일)-4'-플루오르-[1,1'-바이페닐]-4-카르복스아마이드;
66) N-(3-(벤질(메틸)아미노)-2-(2-(다이메틸아미노)에톡시)퀴녹살린-6-일)-3'-시아노-[1,1'-바이페닐]-4-카르복스아마이드;
67) N-(3-(벤질(메틸)아미노)-2-((1-메틸피페리딘-4-일)옥시)퀴녹살린-6-일)-4'-메톡시-[1,1'-바이페닐]-4-카르복스아마이드.According to paragraph 1,
The quinoxaline carboxamide derivative represented by Formula 1 is a quinoxaline carboxamide derivative selected from the group consisting of compounds represented by compounds 1 to 59 and 62 to 67, an isomer thereof, or a pharmaceutically acceptable derivative thereof. salt:
1) 4'-methoxy- N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1 ,1'-biphenyl]-4-carboxamide;
2) 3'-methoxy- N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1 ,1'-biphenyl]-4-carboxamide;
3) 2'-methoxy- N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1 ,1'-biphenyl]-4-carboxamide;
4) 4'-methyl- N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;
5) 3'-methyl- N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;
6) 2'-methyl- N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;
7) 4'-fluoro- N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;
8) 3'-fluoro- N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;
9) 2'-fluoro- N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;
10) 4'-chloro- N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;
11) 3'-chloro- N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;
12) 2'-chloro- N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;
13) 4'-cyano- N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1 ,1'-biphenyl]-4-carboxamide;
14) 3'-Cyano- N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1 ,1'-biphenyl]-4-carboxamide;
15) N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-4'-(trifluoromethyl) -[1,1'-biphenyl]-4-carboxamide;
16) N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-3'-(trifluoromethyl) -[1,1'-biphenyl]-4-carboxamide;
17) N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-2'-(trifluoromethyl) -[1,1'-biphenyl]-4-carboxamide;
18) N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1,1'-biphenyl ]-4-carboxamide;
19) N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-4'-methoxy-[1,1'- biphenyl]-4-carboxamide;
20) N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-3'-methoxy-[1,1'- biphenyl]-4-carboxamide;
21) N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-2'-methoxy-[1,1'- biphenyl]-4-carboxamide;
22) N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-4'-methyl-[1,1'-bi phenyl]-4-carboxamide;
23) N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-3'-methyl-[1,1'-bi phenyl]-4-carboxamide;
24) N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-2'-methyl-[1,1'-bi phenyl]-4-carboxamide;
25) N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-4'-fluoro-[1,1'-bi phenyl]-4-carboxamide;
26) N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-3'-fluoro-[1,1'-bi phenyl]-4-carboxamide;
27) N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-2'-fluoro-[1,1'-bi phenyl]-4-carboxamide;
28) 4'-Chloro- N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1,1'-bi phenyl]-4-carboxamide;
29) 3'-Chloro- N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1,1'-bi phenyl]-4-carboxamide;
30) 2'-chloro- N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1,1'-bi phenyl]-4-carboxamide;
31) 4'-Cyano- N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1,1'- biphenyl]-4-carboxamide;
32) 3'-Cyano- N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1,1'- biphenyl]-4-carboxamide;
33) N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-4'-(trifluoromethyl)-[1, 1'-biphenyl]-4-carboxamide;
34) N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-3'-(trifluoromethyl)-[1, 1'-biphenyl]-4-carboxamide;
35) N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-2'-(trifluoromethyl)-[1, 1'-biphenyl]-4-carboxamide;
36) N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1,1'-biphenyl]-4- carboxamide;
37) 4'-methoxy- N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1 ,1'-biphenyl]-4-carboxamide;
38) 3'-methoxy- N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1 ,1'-biphenyl]-4-carboxamide;
39) 2'-methoxy- N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1 ,1'-biphenyl]-4-carboxamide;
40) 4'-methyl- N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;
41) 3'-methyl- N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;
42) 2'-methyl- N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;
43) 4'-fluoro- N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;
44) 3'-fluoro- N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;
45) 2'-fluoro- N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;
46) 4'-chloro- N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;
47) 3'-chloro- N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;
48) 2'-chloro- N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;
49) 4'-cyano- N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1 ,1'-biphenyl]-4-carboxamide;
50) 3'-Cyano- N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1 ,1'-biphenyl]-4-carboxamide;
51) N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-4'-(trifluoromethyl) -[1,1'-biphenyl]-4-carboxamide;
52) N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-3'-(trifluoromethyl) -[1,1'-biphenyl]-4-carboxamide;
53) N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-2'-(trifluoromethyl) -[1,1'-biphenyl]-4-carboxamide;
54) N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1,1'-biphenyl ]-4-carboxamide;
55) 4'-methoxy- N -(3-(piperidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1 ,1'-biphenyl]-4-carboxamide;
56) 4'-fluoro- N -(3-(piperidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;
57) N -(2-(2-(dimethylamino)ethoxy)-3-(piperidin-1-yl)quinoxalin-6-yl)-4'-methoxy-[1,1'- biphenyl]-4-carboxamide;
58) N -(2-(2-(dimethylamino)ethoxy)-3-(piperidin-1-yl)quinoxalin-6-yl)-4'-fluoro-[1,1'-bi phenyl]-4-carboxamide;
59) 3'-Cyano- N -(2-(2-(dimethylamino)ethoxy)-3-(piperidin-1-yl)quinoxalin-6-yl)-[1,1'- biphenyl]-4-carboxamide;
62) N -(3-(benzyl(methyl)amino)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-4'-methoxy-[1,1 '-biphenyl]-4-carboxamide;
63) N -(3-(benzyl(methyl)amino)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-4'-fluoro-[1,1'-Biphenyl]-4-carboxamide;
64) N -(3-(benzyl(methyl)amino)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-3'-cyano-[1,1 '-biphenyl]-4-carboxamide;
65) N -(3-(benzyl(methyl)amino)-2-(2-(dimethylamino)ethoxy)quinoxalin-6-yl)-4'-fluoro-[1,1'-biphenyl] -4-carboxamide;
66) N -(3-(benzyl(methyl)amino)-2-(2-(dimethylamino)ethoxy)quinoxalin-6-yl)-3'-cyano-[1,1'-biphenyl ]-4-carboxamide;
67) N -(3-(benzyl(methyl)amino)-2-((1-methylpiperidin-4-yl)oxy)quinoxalin-6-yl)-4'-methoxy-[1,1 '-Biphenyl]-4-carboxamide. (A-1) 화학식 2의 화합물과 R3OH을 반응시켜 화학식 3의 화합물을 제조하는 단계;
(A-2) 상기 단계 A-1에서 제조된 화학식 3의 화합물을 화학식 4의 바이페닐카르복실산과 반응시켜 화학식 1의 화합물을 제조하는 단계;를 포함하는 퀴녹살린 카르복스아마이드 유도체, 이의 이성질체 또는 이의 약학적으로 허용가능한 염의 제조방법:
[반응식 1]

상기 반응식 1에서, 상기 R1, R2, R3, 및 R4는 제1항의 화학식 1에서 정의한 바와 같다. (A-1) preparing a compound of Formula 3 by reacting a compound of Formula 2 with R 3 OH;
(A-2) reacting the compound of formula 3 prepared in step A-1 with the biphenylcarboxylic acid of formula 4 to prepare a compound of formula 1; a quinoxaline carboxamide derivative, an isomer thereof, or Method for preparing pharmaceutically acceptable salts thereof:
[Scheme 1]

In Scheme 1, R 1 , R 2 , R 3 , and R 4 are as defined in Formula 1 of claim 1. 제3항에 있어서,
상기 단계 (A-1)는, 염기 존재 하에 반응이 수행되는 것인, 퀴녹살린 카르복스아마이드 유도체, 이의 이성질체 또는 이의 약학적으로 허용가능한 염의 제조방법.According to paragraph 3,
The step (A-1) is a method for producing a quinoxaline carboxamide derivative, an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein the reaction is performed in the presence of a base. 제3항에 있어서,
상기 단계 (A-2)는, 아마이드 커플링 시약의 존재 하에 반응이 수행되는 것인, 퀴녹살린 카르복스아마이드 유도체, 이의 이성질체 또는 이의 약학적으로 허용가능한 염의 제조방법.According to paragraph 3,
The step (A-2) is a method for producing a quinoxaline carboxamide derivative, an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein the reaction is performed in the presence of an amide coupling reagent. 하기 화학식 1로 표시되는 퀴녹살린 카르복스아마이드 유도체, 이의 이성질체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 교모세포종의 예방 또는 치료용 약학적 조성물:
[화학식 1]

상기 화학식 1에서,
NR1R2는 또는 또는 또는 이고,
OR3는 또는 또는 이고;
R4는 수소 원자, -O-C1-C6 알킬, C1-C6 알킬, 할로겐 원자, -CN, 또는 C1-C6 할로알킬이다. A pharmaceutical composition for the prevention or treatment of glioblastoma comprising a quinoxaline carboxamide derivative represented by the following formula (1), an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient:
[Formula 1]

In Formula 1,
NR 1 R 2 is or or or ego,
OR 3 is or or ego;
R 4 is a hydrogen atom, -OC 1 -C 6 alkyl, C 1 -C 6 alkyl, a halogen atom, -CN, or C 1 -C 6 haloalkyl. 제6항에 있어서,
상기 화학식 1로 표시되는 퀴녹살린 카르복스아마이드 유도체는 하기에 화합물 1 내지 67로 나타내는 화합물로 이루어진 군으로부터 선택된 것인, 퀴녹살린 카르복스아마이드 유도체, 이의 이성질체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 교모세포종의 예방 또는 치료용 약학적 조성물:
1) 4'-메톡시-N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
2) 3'-메톡시-N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
3) 2'-메톡시-N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
4) 4'-메틸-N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
5) 3'-메틸-N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
6) 2'-메틸-N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
7) 4'-플루오르-N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
8) 3'-플루오르-N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
9) 2'-플루오르-N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
10) 4'-클로로-N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
11) 3'-클로로-N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
12) 2'-클로로-N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
13) 4'-시아노-N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
14) 3'-시아노-N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
15) N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-4'-(트리플루오르메틸)-[1,1'-바이페닐]-4-카르복스아마이드;
16) N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-3'-(트리플루오르메틸)-[1,1'-바이페닐]-4-카르복스아마이드;
17) N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-2'-(트리플루오르메틸)-[1,1'-바이페닐]-4-카르복스아마이드;
18) N-(3-(피롤리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
19) N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-4'-메톡시-[1,1'-바이페닐]-4-카르복스아마이드;
20) N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-3'-메톡시-[1,1'-바이페닐]-4-카르복스아마이드;
21) N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-2'-메톡시-[1,1'-바이페닐]-4-카르복스아마이드;
22) N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-4'-메틸-[1,1'-바이페닐]-4-카르복스아마이드;
23) N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-3'-메틸-[1,1'-바이페닐]-4-카르복스아마이드;
24) N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-2'-메틸-[1,1'-바이페닐]-4-카르복스아마이드;
25) N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-4'-플루오르-[1,1'-바이페닐]-4-카르복스아마이드;
26) N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-3'-플루오르-[1,1'-바이페닐]-4-카르복스아마이드;
27) N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-2'-플루오르-[1,1'-바이페닐]-4-카르복스아마이드;
28) 4'-클로로-N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
29) 3'-클로로-N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
30) 2'-클로로-N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
31) 4'-시아노-N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
32) 3'-시아노-N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
33) N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-4'-(트리플루오르메틸)-[1,1'-바이페닐]-4-카르복스아마이드;
34) N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-3'-(트리플루오르메틸)-[1,1'-바이페닐]-4-카르복스아마이드;
35) N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-2'-(트리플루오르메틸)-[1,1'-바이페닐]-4-카르복스아마이드;
36) N-(2-(2-(다이메틸아미노)에톡시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
37) 4'-메톡시-N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
38) 3'-메톡시-N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
39) 2'-메톡시-N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
40) 4'-메틸-N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
41) 3'-메틸-N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
42) 2'-메틸-N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
43) 4'-플루오르-N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
44) 3'-플루오르-N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
45) 2'-플루오르-N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
46) 4'-클로로-N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
47) 3'-클로로-N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
48) 2'-클로로-N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
49) 4'-시아노-N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
50) 3'-시아노-N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
51) N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-4'-(트리플루오르메틸)-[1,1'-바이페닐]-4-카르복스아마이드;
52) N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-3'-(트리플루오르메틸)-[1,1'-바이페닐]-4-카르복스아마이드;
53) N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-2'-(트리플루오르메틸)-[1,1'-바이페닐]-4-카르복스아마이드;
54) N-(2-((1-메틸피페리딘-4-일)옥시)-3-(피롤리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
55) 4'-메톡시-N-(3-(피페리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
56) 4'-플루오르-N-(3-(피페리딘-1-일)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
57) N-(2-(2-(다이메틸아미노)에톡시)-3-(피페리딘-1-일)퀴녹살린-6-일)-4'-메톡시-[1,1'-바이페닐]-4-카르복스아마이드;
58) N-(2-(2-(다이메틸아미노)에톡시)-3-(피페리딘-1-일)퀴녹살린-6-일)-4'-플루오르-[1,1'-바이페닐]-4-카르복스아마이드;
59) 3'-시아노-N-(2-(2-(다이메틸아미노)에톡시)-3-(피페리딘-1-일)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
60) N-(3-(다이에틸아미노)-2-(2-(다이메틸아미노)에톡시)퀴녹살린-6-일)-4'-메톡시-[1,1'-바이페닐]-4-카르복스아마이드;
61) 3'-시아노-N-(3-(다이에틸아미노)-2-(2-(다이메틸아미노)에톡시)퀴녹살린-6-일)-[1,1'-바이페닐]-4-카르복스아마이드;
62) N-(3-(벤질(메틸)아미노)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-4'-메톡시-[1,1'-바이페닐]-4-카르복스아마이드;
63) N-(3-(벤질(메틸)아미노)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-4'-플루오르-[1,1'-바이페닐]-4-카르복스아마이드;
64) N-(3-(벤질(메틸)아미노)-2-(2-(피롤리딘-1-일)에톡시)퀴녹살린-6-일)-3'-시아노-[1,1'-바이페닐]-4-카르복스아마이드;
65) N-(3-(벤질(메틸)아미노)-2-(2-(다이메틸아미노)에톡시)퀴녹살린-6-일)-4'-플루오르-[1,1'-바이페닐]-4-카르복스아마이드;
66) N-(3-(벤질(메틸)아미노)-2-(2-(다이메틸아미노)에톡시)퀴녹살린-6-일)-3'-시아노-[1,1'-바이페닐]-4-카르복스아마이드;
67) N-(3-(벤질(메틸)아미노)-2-((1-메틸피페리딘-4-일)옥시)퀴녹살린-6-일)-4'-메톡시-[1,1'-바이페닐]-4-카르복스아마이드.According to clause 6,
The quinoxaline carboxamide derivative represented by the above formula (1) is a quinoxaline carboxamide derivative selected from the group consisting of compounds represented by compounds 1 to 67, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. Pharmaceutical composition for preventing or treating glioblastoma comprising:
1) 4'-methoxy- N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1 ,1'-biphenyl]-4-carboxamide;
2) 3'-methoxy- N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1 ,1'-biphenyl]-4-carboxamide;
3) 2'-methoxy- N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1 ,1'-biphenyl]-4-carboxamide;
4) 4'-methyl- N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;
5) 3'-methyl- N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;
6) 2'-methyl- N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;
7) 4'-fluoro- N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;
8) 3'-fluoro- N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;
9) 2'-fluoro- N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;
10) 4'-chloro- N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;
11) 3'-chloro- N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;
12) 2'-chloro- N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;
13) 4'-cyano- N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1 ,1'-biphenyl]-4-carboxamide;
14) 3'-Cyano- N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1 ,1'-biphenyl]-4-carboxamide;
15) N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-4'-(trifluoromethyl) -[1,1'-biphenyl]-4-carboxamide;
16) N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-3'-(trifluoromethyl) -[1,1'-biphenyl]-4-carboxamide;
17) N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-2'-(trifluoromethyl) -[1,1'-biphenyl]-4-carboxamide;
18) N -(3-(pyrrolidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1,1'-biphenyl ]-4-carboxamide;
19) N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-4'-methoxy-[1,1'- biphenyl]-4-carboxamide;
20) N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-3'-methoxy-[1,1'- biphenyl]-4-carboxamide;
21) N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-2'-methoxy-[1,1'- biphenyl]-4-carboxamide;
22) N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-4'-methyl-[1,1'-bi phenyl]-4-carboxamide;
23) N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-3'-methyl-[1,1'-bi phenyl]-4-carboxamide;
24) N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-2'-methyl-[1,1'-bi phenyl]-4-carboxamide;
25) N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-4'-fluoro-[1,1'-bi phenyl]-4-carboxamide;
26) N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-3'-fluoro-[1,1'-bi phenyl]-4-carboxamide;
27) N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-2'-fluoro-[1,1'-bi phenyl]-4-carboxamide;
28) 4'-Chloro- N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1,1'-bi phenyl]-4-carboxamide;
29) 3'-Chloro- N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1,1'-bi phenyl]-4-carboxamide;
30) 2'-chloro- N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1,1'-bi phenyl]-4-carboxamide;
31) 4'-Cyano- N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1,1'- biphenyl]-4-carboxamide;
32) 3'-Cyano- N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1,1'- biphenyl]-4-carboxamide;
33) N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-4'-(trifluoromethyl)-[1, 1'-biphenyl]-4-carboxamide;
34) N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-3'-(trifluoromethyl)-[1, 1'-biphenyl]-4-carboxamide;
35) N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-2'-(trifluoromethyl)-[1, 1'-biphenyl]-4-carboxamide;
36) N -(2-(2-(dimethylamino)ethoxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1,1'-biphenyl]-4- carboxamide;
37) 4'-methoxy- N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1 ,1'-biphenyl]-4-carboxamide;
38) 3'-methoxy- N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1 ,1'-biphenyl]-4-carboxamide;
39) 2'-methoxy- N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1 ,1'-biphenyl]-4-carboxamide;
40) 4'-methyl- N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;
41) 3'-methyl- N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;
42) 2'-methyl- N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;
43) 4'-fluoro- N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;
44) 3'-fluoro- N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;
45) 2'-fluoro- N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;
46) 4'-chloro- N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;
47) 3'-chloro- N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;
48) 2'-chloro- N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;
49) 4'-cyano- N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1 ,1'-biphenyl]-4-carboxamide;
50) 3'-Cyano- N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1 ,1'-biphenyl]-4-carboxamide;
51) N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-4'-(trifluoromethyl) -[1,1'-biphenyl]-4-carboxamide;
52) N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-3'-(trifluoromethyl) -[1,1'-biphenyl]-4-carboxamide;
53) N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-2'-(trifluoromethyl) -[1,1'-biphenyl]-4-carboxamide;
54) N -(2-((1-methylpiperidin-4-yl)oxy)-3-(pyrrolidin-1-yl)quinoxalin-6-yl)-[1,1'-biphenyl ]-4-carboxamide;
55) 4'-methoxy- N -(3-(piperidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1 ,1'-biphenyl]-4-carboxamide;
56) 4'-fluoro- N -(3-(piperidin-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-[1, 1'-biphenyl]-4-carboxamide;
57) N -(2-(2-(dimethylamino)ethoxy)-3-(piperidin-1-yl)quinoxalin-6-yl)-4'-methoxy-[1,1'- biphenyl]-4-carboxamide;
58) N -(2-(2-(dimethylamino)ethoxy)-3-(piperidin-1-yl)quinoxalin-6-yl)-4'-fluoro-[1,1'-bi phenyl]-4-carboxamide;
59) 3'-Cyano- N -(2-(2-(dimethylamino)ethoxy)-3-(piperidin-1-yl)quinoxalin-6-yl)-[1,1'- biphenyl]-4-carboxamide;
60) N -(3-(diethylamino)-2-(2-(dimethylamino)ethoxy)quinoxalin-6-yl)-4'-methoxy-[1,1'-biphenyl]- 4-carboxamide;
61) 3'-Cyano- N -(3-(diethylamino)-2-(2-(dimethylamino)ethoxy)quinoxalin-6-yl)-[1,1'-biphenyl]- 4-carboxamide;
62) N -(3-(benzyl(methyl)amino)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-4'-methoxy-[1,1 '-biphenyl]-4-carboxamide;
63) N -(3-(benzyl(methyl)amino)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-4'-fluoro-[1,1'-Biphenyl]-4-carboxamide;
64) N -(3-(benzyl(methyl)amino)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoxalin-6-yl)-3'-cyano-[1,1 '-biphenyl]-4-carboxamide;
65) N -(3-(benzyl(methyl)amino)-2-(2-(dimethylamino)ethoxy)quinoxalin-6-yl)-4'-fluoro-[1,1'-biphenyl] -4-carboxamide;
66) N -(3-(benzyl(methyl)amino)-2-(2-(dimethylamino)ethoxy)quinoxalin-6-yl)-3'-cyano-[1,1'-biphenyl ]-4-carboxamide;
67) N -(3-(benzyl(methyl)amino)-2-((1-methylpiperidin-4-yl)oxy)quinoxalin-6-yl)-4'-methoxy-[1,1 '-Biphenyl]-4-carboxamide. 하기 화학식 1로 표시되는 퀴녹살린 카르복스아마이드 유도체, 이의 이성질체 또는 이의 약학적으로 허용가능한 염; 및 항암 요법제;를 포함하는 교모세포종의 예방 또는 치료용 약학적 조성물:
[화학식 1]

상기 화학식 1에서,
NR1R2는 또는 또는 또는 이고,
OR3는 또는 또는 이고;
R4는 수소 원자, -O-C1-C6 알킬, C1-C6 알킬, 할로겐 원자, -CN, 또는 C1-C6 할로알킬이다.A quinoxaline carboxamide derivative represented by the following formula (1), an isomer thereof, or a pharmaceutically acceptable salt thereof; A pharmaceutical composition for preventing or treating glioblastoma, comprising:
[Formula 1]

In Formula 1,
NR 1 R 2 is or or or ego,
OR 3 is or or ego;
R 4 is a hydrogen atom, -OC 1 -C 6 alkyl, C 1 -C 6 alkyl, a halogen atom, -CN, or C 1 -C 6 haloalkyl. 제8항에 있어서,
상기 피라졸로피리미딘 설폰아마이드 유도체, 이의 이성질체 또는 이의 약학적으로 허용가능한 염; 및 항암 요법제;가 동시에, 개별적으로 또는 순차적으로 병용하여 투여되는 것인, 약학적 조성물.According to clause 8,
The above pyrazolopyrimidine sulfonamide derivatives, isomers thereof, or pharmaceutically acceptable salts thereof; and an anti-cancer therapy agent; a pharmaceutical composition that is administered simultaneously, individually or sequentially in combination. 제9항에 있어서,
상기 항암 요법제는 화학 요법 및 방사선 요법 중에서 선택된 1종 이상인 것인, 약학적 조성물. According to clause 9,
A pharmaceutical composition, wherein the anti-cancer therapy agent is at least one selected from chemotherapy and radiotherapy. 제10항에 있어서,
상기 화학 요법은 화학 항암제, 면역 항암제, 및 표적 치료제 중에서 선택된 1종 이상을 사용하는 것인, 약학적 조성물. According to clause 10,
A pharmaceutical composition, wherein the chemotherapy uses one or more types selected from chemical anticancer agents, immune anticancer agents, and targeted therapeutic agents. 제11항에 있어서,
상기 화학 항암제는 알킬화제(alkylating agent), 항암성 항생물질(antitumor antibiotics), 대사 길항제(antimetabolite), 호르몬제 및 천연 약물을 포함하는 것인, 약학적 조성물. According to clause 11,
A pharmaceutical composition wherein the chemical anticancer agent includes an alkylating agent, antitumor antibiotics, antimetabolite, hormone, and natural drug. 제11항에 있어서,
상기 면역 항암제는 면역관문억제제, 면역세포치료제 및 항암바이러스치료제로 이루어진 군으로부터 선택되는 1종 이상인 것인, 약학적 조성물.According to clause 11,
A pharmaceutical composition, wherein the immune anti-cancer agent is at least one selected from the group consisting of immune checkpoint inhibitors, immune cell therapy agents, and anti-cancer virus therapy agents. 제11항에 있어서,
상기 표적 치료제는 신호전달경로 억제제(Signal Transduction Pathway Inhibitor), 신생혈관생성 억제제(Angiogenesis Inhibitors) 및 혈관내피세포 성장인자(VEGF, Vascular Endothelial Growth Factor) 억제제를 포함하는 것인, 약학적 조성물.
According to clause 11,
A pharmaceutical composition wherein the targeted therapeutic agent includes a signal transduction pathway inhibitor, an angiogenesis inhibitor, and a vascular endothelial growth factor (VEGF) inhibitor.
KR1020220046259A 2022-04-14 2022-04-14 Quinoxaline carboxamide derivatives and pharmaceutical composition for prevention or treatment of glioblastoma containing the same as an active ingredient KR20230147351A (en)

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