KR20210088789A - Novel Production Method for Aminated Azine - Google Patents

Novel Production Method for Aminated Azine Download PDF

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KR20210088789A
KR20210088789A KR1020200001367A KR20200001367A KR20210088789A KR 20210088789 A KR20210088789 A KR 20210088789A KR 1020200001367 A KR1020200001367 A KR 1020200001367A KR 20200001367 A KR20200001367 A KR 20200001367A KR 20210088789 A KR20210088789 A KR 20210088789A
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amine
substituted
tolyl
unsubstituted
quinolin
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KR102399037B1 (en
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김인수
김형식
김세건
김동은
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성균관대학교산학협력단
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Abstract

The present invention relates to a novel method for manufacturing a quadruple continuous ring compound. According to the method of the present invention, by using the novel reactivity of acetal used as a unit structure to protect an existing carbonyl group or a hydroxyl group to synthesize a molecular structure of a quadruple continuous ring drug, known as a core framework of pharmaceuticals, the method is expected to be usefully applied to various pharmaceutical chemistry and pharmaceutical process studies.

Description

아민화된 아진의 신규한 제조방법{Novel Production Method for Aminated Azine}Novel Production Method for Aminated Azine

본 발명은 아민화된 아진의 신규한 제조방법 등에 관한 것이다.The present invention relates to a novel method for preparing an aminated azine and the like.

하나 이상의 질소 원자를 함유하는 6원 방향족 화합물인 아진은 다양한 생물학적 응용에 유비쿼터스 코어 구조로 인식되어 왔다. 따라서, 치환된 아진의 합성은 의약, 농약 및 기타 화학 물질의 발달을 촉진한다는 관점에서 중요하다. 특히, 아민화된 아진은 현저한 치료 효과가 있을 가능성으로 인해 약물 개발 분야에서 관심있게 보고 있다 (도 2 참조).Aazine, a six-membered aromatic compound containing one or more nitrogen atoms, has been recognized as a ubiquitous core structure for various biological applications. Therefore, the synthesis of substituted azines is important in terms of promoting the development of medicines, pesticides and other chemicals. In particular, aminated azines are of interest in the field of drug development due to their potential to have significant therapeutic effects (see FIG. 2 ).

피리딘의 C2-아민화에 대한 연구는 1914년 Chichibabin에 의해 보고되었다. 그러나, 친핵성 방향족 치환 (SNAr)에서 아진의 매우 낮은 반응성으로 인해, 오르토-할로겐화 아진이 통상적으로 C2-아민화 반응에 사용되었다. 아진 고유의 낮은 반응성을 극복하기 위해, 외부 화학량론적 시약과 아진-N-옥 사이드의 반응이 보고되어왔다. N-산화물의 활성화를 위해 전이 금속 촉매 화된 CH 아민화 반응의 사용 또한 최근에 보고되었다.A study on the C2-amination of pyridine was reported by Chichibabin in 1914. However, due to the very low reactivity of azines in nucleophilic aromatic substitution (SNAr), ortho-halogenated azines have been commonly used for C2-amination reactions. To overcome the inherent low reactivity of azine, the reaction of azine-N-oxide with an external stoichiometric reagent has been reported. The use of transition metal catalyzed CH amination reactions for the activation of N-oxides has also been recently reported.

1,2-쌍극성 N-O 결합을 갖는 아진-N-옥사이드는 방향족 고리의 오르쏘 위치에 양전하를 비편재화하여 친핵성 첨가에 영향을 줄 수 있다. 그러나, [3 + 2] 쌍극성 고리 첨가 반응을 통한 아진-N-옥사이드의 C2-관능화 반응은 지금까지 거의 보고되지 않았다. 예를 들어, Ocone과 Makosza는 독립적으로 [3 + 2] 고리 첨가 반응을 통해 전자 결함이 높은 알켄을 갖는 피리딘-N-옥사이드의 C2-알킬화에 이어 레트로 알돌 단편화 (반응식 1)를 보고하였다.Azine-N-oxides with 1,2-dipolar N-O bonds can delocalize positive charges at ortho positions of aromatic rings, thereby affecting nucleophilic addition. However, C2-functionalization reaction of azine-N-oxide through [3 + 2] dipolar cycloaddition reaction has been rarely reported so far. For example, Ocone and Makosza independently reported retro aldol fragmentation (Scheme 1) following C2-alkylation of pyridine-N-oxide with alkenes with high electron defects via a [3 + 2] cycloaddition reaction.

최근에, Murakami는 [3 + 2]-타입 첨가환화(cycloadduct) 중간체를 통해 피리딘 N-옥사이드가 광촉매화된 오르토-알킬화를 보고하였다. 또한, 본 발명자들은 C2-알킬화된 아진을 수득하기 위해 아진-N-옥사이드의 [3 + 2] 쌍극성 고리 첨가 반응에 포스포늄 일라이드(phosphonium ylides)를 사용하였다. 아실 아자이드는 열 및 광화학 조건 하에서 Curtius 자리옮김을 통해 상응하는 이소시아네이트에 대한 합성 전구체로서 작용하였다.Recently, Murakami reported the photocatalytic ortho-alkylation of pyridine N-oxide via a [3 + 2]-type cycloadduct intermediate. In addition, the present inventors used phosphonium ylides in the [3 + 2] dipolar cycloaddition reaction of azine-N-oxide to obtain a C2-alkylated azine. Acyl azides acted as synthetic precursors to the corresponding isocyanates via Curtius translocation under thermal and photochemical conditions.

이에, 본 발명자들은 [3 + 2] 쌍극성 첨가환화 반응을 통해 아실아자이드를 사용하여 다양한 아진-N-옥사이드의 전이금속-프리-위치 선택적 C2 아민화 반응을 확인함으로써, 아진의 형성을 초래하는 복잡한 생물 활성 화합물의 아민화를 통해 아민화된 아진을 효과적으로 제공할 수 있을 것이라고 가정하고 본 발명을 완성하였다.Accordingly, the present inventors confirmed the transition metal-pre-regioselective C2 amination reaction of various azine-N-oxides using an acylazide through a [3 + 2] dipolar addition cyclization reaction, resulting in the formation of azines The present invention was completed on the assumption that it would be possible to effectively provide an aminated azine through the amination of a complex biologically active compound.

Nakao, Y. Transition-Metal-Catalyzed C-H Functionalization for the Synthesis of Substituted Pyridines. Synthesis 2011, 2011, 3209-3219Nakao, Y. Transition-Metal-Catalyzed C-H Functionalization for the Synthesis of Substituted Pyridines. Synthesis 2011, 2011, 3209-3219

따라서, 본 발명의 목적은 화학식 1 내지 화학식 3으로 표시되는 화합물, 이의 입체 이성질체, 또는 이의 약학적으로 허용가능한 염을 제공하는 것이다.Accordingly, an object of the present invention is to provide a compound represented by Formulas 1 to 3, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

또한, 본 발명의 다른 목적은 화학식 1 내지 화학식 3으로 표시되는 화합물의 제조방법을 제공하는 것이다.Another object of the present invention is to provide a method for preparing a compound represented by Chemical Formulas 1 to 3.

그러나 본 발명이 이루고자 하는 기술적 과제는 이상에서 언급한 과제에 제한되지 않으며, 언급되지 않은 또 다른 과제들은 아래의 기재로부터 당업자에게 명확하게 이해될 수 있을 것이다.However, the technical problem to be achieved by the present invention is not limited to the above-mentioned problems, and other problems not mentioned will be clearly understood by those skilled in the art from the following description.

상기 본 발명의 목적을 달성하기 위하여, 본 발명은 하기 화학식 1 내지 화학식 3으로 표시되는 화합물, 이의 입체 이성질체, 또는 이의 약학적으로 허용가능한 염을 제공한다.In order to achieve the above object of the present invention, the present invention provides a compound represented by the following Chemical Formulas 1 to 3, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[화학식 1][Formula 1]

Figure pat00001
Figure pat00001

[화학식 2][Formula 2]

Figure pat00002
Figure pat00002

[화학식 3][Formula 3]

Figure pat00003
Figure pat00003

상기 화학식 1 내지 화학식 3에 있어서,In Formulas 1 to 3,

상기 R1은 수소, 할로겐, 치환 또는 비치환된 C1-C6 알킬, 치환 또는 비치환된 C1-C6 알콕시, 아다만테인-1-일, C6-C20 아릴 또는 C6-C20 헤테로아릴이며;wherein R 1 is hydrogen, halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy, adamantane-1-yl, C 6 -C 20 aryl or C 6 -C 20 heteroaryl;

상기 R2는 치환 또는 비치환된 C1-C6 알킬, 치환 또는 비치환된 C1-C6 알콕시, C6-C20 아릴 또는 C6-C20 헤테로아릴이며;wherein R 2 is substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy, C 6 -C 20 aryl or C 6 -C 20 heteroaryl;

상기 R3 및 R4는 각각 독립적으로 수소, 할로겐, 치환 또는 비치환된 C1-C6 알킬, 치환 또는 비치환된 C1-C6 알콕시,

Figure pat00004
,
Figure pat00005
, 또는
Figure pat00006
이거나, 서로 결합하여 치환 또는 비치환된 C6-C20 아릴 또는 C6-C20 헤테로아릴 고리를 형성하며;wherein R 3 and R 4 are each independently hydrogen, halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy;
Figure pat00004
,
Figure pat00005
, or
Figure pat00006
or combine with each other to form a substituted or unsubstituted C 6 -C 20 aryl or C 6 -C 20 heteroaryl ring;

상기 X 및 Y는 각각 독립적으로 탄소, 수소, 질소, 산소, 황, 할로겐, 치환 또는 비치환된 C1-C6 알킬, 치환 또는 비치환된 C1-C6 알콕시이거나, 서로 결합하여 치환 또는 비치환된 C6-C20 아릴 또는 C6-C20 헤테로아릴 고리를 형성한다. Wherein X and Y are each independently carbon, hydrogen, nitrogen, oxygen, sulfur, halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy, or bonded to each other, substituted or form an unsubstituted C 6 -C 20 aryl or C 6 -C 20 heteroaryl ring.

또한, 본 발명은 염기 조건 하에서, 하기 화학식 4로 표시되는 화합물을 화학식 5로 표시되는 화합물과 반응시키는 단계를 포함하는, 화학식 1 내지 화학식 3으로 표시되는 화합물의 제조방법을 제공한다.In addition, the present invention provides a method for preparing a compound represented by Formulas 1 to 3, comprising reacting a compound represented by Formula 4 with a compound represented by Formula 5 under basic conditions.

[화학식 4][Formula 4]

Figure pat00007
Figure pat00007

[화학식 5][Formula 5]

Figure pat00008
Figure pat00008

상기 화학식 4 내지 화학식 5에 있어서,In Formulas 4 to 5,

상기 R1은 수소, 할로겐, 치환 또는 비치환된 C1-C6 알킬, 치환 또는 비치환된 C1-C6 알콕시, 아다만테인-1-일, C6-C20 아릴 또는 C6-C20 헤테로아릴이며;wherein R 1 is hydrogen, halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy, adamantane-1-yl, C 6 -C 20 aryl or C 6 -C 20 heteroaryl;

상기 R2는 치환 또는 비치환된 C1-C6 알킬, 치환 또는 비치환된 C1-C6 알콕시, C6-C20 아릴 또는 C6-C20 헤테로아릴이며;wherein R 2 is substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy, C 6 -C 20 aryl or C 6 -C 20 heteroaryl;

상기 R3 및 R4는 각각 독립적으로 수소, 할로겐, 치환 또는 비치환된 C1-C6 알킬, 치환 또는 비치환된 C1-C6 알콕시,

Figure pat00009
,
Figure pat00010
, 또는
Figure pat00011
이거나, 서로 결합하여 치환 또는 비치환된 C6-C20 아릴 또는 C6-C20 헤테로아릴 고리를 형성하며;wherein R 3 and R 4 are each independently hydrogen, halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy;
Figure pat00009
,
Figure pat00010
, or
Figure pat00011
or combine with each other to form a substituted or unsubstituted C 6 -C 20 aryl or C 6 -C 20 heteroaryl ring;

상기 X 및 Y는 각각 독립적으로 탄소, 수소, 질소, 산소, 황, 할로겐, 치환 또는 비치환된 C1-C6 알킬, 치환 또는 비치환된 C1-C6 알콕시이거나, 서로 결합하여 치환 또는 비치환된 C6-C20 아릴 또는 C6-C20 헤테로아릴 고리를 형성한다. Wherein X and Y are each independently carbon, hydrogen, nitrogen, oxygen, sulfur, halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy, or bonded to each other, substituted or form an unsubstituted C 6 -C 20 aryl or C 6 -C 20 heteroaryl ring.

본 발명의 일실시예에서, 상기 R1은 톨릴, 벤질, 메틸페닐, 에틸페닐, 프로필페닐, 부틸페닐, 트리플루오로메틸페닐, 디메톡시페닐, 브로모메틸페닐, 나프탈렌일, 피리딘일, 또는 아다만테인일일 수 있으나 이에 제한되는 것은 아니다.In one embodiment of the present invention, R 1 is tolyl, benzyl, methylphenyl, ethylphenyl, propylphenyl, butylphenyl, trifluoromethylphenyl, dimethoxyphenyl, bromomethylphenyl, naphthalenyl, pyridinyl, or adamantane day, but is not limited thereto.

본 발명의 다른 실시예에서, 상기 R2는 페닐, 피리딜 또는

Figure pat00012
일 수 있으나, 이에 제한되는 것은 아니다.In another embodiment of the present invention, R 2 is phenyl, pyridyl or
Figure pat00012
may be, but is not limited thereto.

본 발명의 또 다른 실시예에서, 상기 R3 및 R4는 각각 독립적으로 수소, 플루오로, 클로로, 브로모, 메틸, 메톡시,

Figure pat00013
,
Figure pat00014
, 또는
Figure pat00015
이거나, 서로 결합하여 치환 또는 비치환된 벤질, 페닐 또는 피리딘을 형성할 수 있으나, 이에 제한되는 것은 아니다.In another embodiment of the present invention, R 3 and R 4 are each independently hydrogen, fluoro, chloro, bromo, methyl, methoxy,
Figure pat00013
,
Figure pat00014
, or
Figure pat00015
or may be combined with each other to form a substituted or unsubstituted benzyl, phenyl or pyridine, but is not limited thereto.

본 발명의 또 다른 실시예에서, 상기 X 및 Y는 각각 독립적으로 질소, 치환 또는 비치환된 C1-C6 알킬이거나, 서로 결합하여 벤질고리를 형성할 수 있으나, 이에 제한되는 것은 아니다.In another embodiment of the present invention, X and Y are each independently nitrogen, a substituted or unsubstituted C 1 -C 6 alkyl, or may combine with each other to form a benzyl ring, but is not limited thereto.

본 발명의 또 다른 실시예에서, 상기 치환은 할로겐, N, O, 및 S로 이루어진 군으로부터 선택된 하나 이상으로 치환될 수 있으나, 이에 제한되는 것은 아니다. In another embodiment of the present invention, the substitution may be substituted with one or more selected from the group consisting of halogen, N, O, and S, but is not limited thereto.

본 발명의 또 다른 실시예에서, 상기 화합물은 하기 화합물들로 이루어진 군으로부터 선택되는 어느 하나일 수 있으나, 이에 제한되는 것은 아니다 :In another embodiment of the present invention, the compound may be any one selected from the group consisting of the following compounds, but is not limited thereto:

N-(p-Tol일)퀴놀린-2-아민 (3a);N-(p-Tolyl)quinolin-2-amine (3a);

6-메톡시-N-(p-톨릴)퀴놀린-2-아민 (3b);6-methoxy-N-(p-tolyl)quinolin-2-amine (3b);

6-클로로-N-(p-톨릴)퀴놀린-2-아민 (3c);6-chloro-N-(p-tolyl)quinolin-2-amine (3c);

6-플루오로-N-(p-톨릴)퀴놀린-2-아민 (3d);6-fluoro-N-(p-tolyl)quinolin-2-amine (3d);

5-플루오로-8-메톡시-N-(p-톨릴)퀴놀린-2-아민 (3e);5-fluoro-8-methoxy-N-(p-tolyl)quinolin-2-amine (3e);

4-메틸-N-(p-톨릴)퀴놀린-2-아민 (3f);4-methyl-N-(p-tolyl)quinolin-2-amine (3f);

4-클로로-N-(p-톨릴)퀴놀린-2-아민 (3g);4-chloro-N-(p-tolyl)quinolin-2-amine (3 g);

3-메틸-N-(p-톨릴)퀴놀린-2-아민 (3h);3-methyl-N-(p-tolyl)quinolin-2-amine (3h);

8-메틸-N-(p-톨릴)퀴놀린-2-아민 (3i);8-methyl-N-(p-tolyl)quinolin-2-amine (3i);

7-브로모-8-메틸-N-(p-톨릴)퀴놀린-2-아민 (3j);7-bromo-8-methyl-N-(p-tolyl)quinolin-2-amine (3j);

6-클로로-8-메틸-N-(p-톨릴)퀴놀린-2-아민 (3k);6-chloro-8-methyl-N-(p-tolyl)quinolin-2-amine (3k);

N-(p-톨릴)벤조[f]퀴놀린-3-아민 (3l);N-(p-tolyl)benzo[f]quinolin-3-amine (31);

N-(p-톨릴)페난트리딘-6-아민 (3m);N-(p-tolyl)phenanthridin-6-amine (3m);

N-(p-톨릴)-9-(트리플루오로메틸)-1,10-페난트롤린-2-아민 (3n);N-(p-tolyl)-9-(trifluoromethyl)-1,10-phenanthrolin-2-amine (3n);

4-페닐-N-(p-톨릴)피리딘-2-아민 (3o);4-phenyl-N-(p-tolyl)pyridin-2-amine (3o);

N-(p-톨릴)-[2,2'-비피리딘]-6-아민 (3p);N-(p-tolyl)-[2,2'-bipyridin]-6-amine (3p);

4,4'-디메틸-N-(p-톨릴)-[2,2'-비피리딘]-6-아민 (3q);4,4′-dimethyl-N-(p-tolyl)-[2,2′-bipyridin]-6-amine (3q);

N-(p-톨릴)퀴녹살린-2-아민 (3r);N-(p-tolyl)quinoxalin-2-amine (3r);

N-(p-톨릴)이소퀴놀린-1-아민 (3s);N-(p-tolyl)isoquinolin-1-amine (3s);

N-(p-톨릴)프탈라진-1-아민 (3t);N-(p-tolyl)phthalazin-1-amine (3t);

6-메톡시-N-페닐퀴놀린-2-아민 (4b);6-methoxy-N-phenylquinolin-2-amine (4b);

N-(4-(tert-부틸)페닐)-6-메톡시퀴놀린-2-아민 (4c);N-(4-(tert-butyl)phenyl)-6-methoxyquinolin-2-amine (4c);

6-메톡시-N-(4-(트리플루오로메틸)페닐)퀴놀린-2-아민 (4d);6-methoxy-N-(4-(trifluoromethyl)phenyl)quinolin-2-amine (4d);

6-메톡시-N-(m-톨릴)퀴놀린-2-아민 (4e);6-methoxy-N-(m-tolyl)quinolin-2-amine (4e);

N-(3,4-디메톡시페닐)-6-메톡시퀴놀린-2-아민 (4f);N-(3,4-dimethoxyphenyl)-6-methoxyquinolin-2-amine (4f);

N-(3-브로모-4-메틸페닐)-6-메톡시퀴놀린-2-아민 (4g);N-(3-bromo-4-methylphenyl)-6-methoxyquinolin-2-amine (4 g);

6-메톡시-N-(나프탈렌-2-일)퀴놀린-2-아민 (4h);6-methoxy-N-(naphthalen-2-yl)quinolin-2-amine (4h);

6-메톡시-N-(피리딘-3-일)퀴놀린-2-아민 (4i);6-methoxy-N-(pyridin-3-yl)quinolin-2-amine (4i);

N-((3S,5S,7S)-아다만테인-1-일)-6-메톡시퀴놀린-2-아민 (4j);N-((3S,5S,7S)-adamanthein-1-yl)-6-methoxyquinolin-2-amine (4j);

6-메톡시-4-((1S)-메톡시((1S,4S,5R)-5-비닐퀴누클리딘-2-일)메틸)-N-(p-톨릴)퀴놀린-2-아민 (6a);6-methoxy-4-((1S)-methoxy((1S,4S,5R)-5-vinylquinuclidin-2-yl)methyl)-N-(p-tolyl)quinolin-2-amine ( 6a);

벤조일 4-((1-(p-톨릴아미노)이소퀴놀린-5-일)설포닐)-1,4-디아제페인-1-카복실레이트 (6b);benzoyl 4-((1-(p-tolylamino)isoquinolin-5-yl)sulfonyl)-1,4-diazepain-1-carboxylate (6b);

8-((4-메틸페닐)설폰아미도)퀴놀린 N-옥사이드 (7a);8-((4-methylphenyl)sulfonamido)quinoline N-oxide (7a);

4-메틸-N-(2-(p-톨릴아미노)퀴놀린-8-일)벤젠설폰아마이드 (7b);4-methyl-N-(2-(p-tolylamino)quinolin-8-yl)benzenesulfonamide (7b);

6-메톡시-2-(5-메틸-2,3-디페닐-1H-인돌-1-일)퀴놀린 (8a);6-methoxy-2-(5-methyl-2,3-diphenyl-1H-indol-1-yl)quinoline (8a);

3-메톡시-10-메틸벤조[4,5]이미다조[1,2-a]퀴놀린 (8b); 및3-methoxy-10-methylbenzo [4,5] imidazo [1,2-a] quinoline (8b); and

3-메톡시-10-메틸-12H-퀴놀리노[2,1-b]퀴나졸린-12-원 (8c).3-Methoxy-10-methyl-12H-quinolino[2,1-b]quinazoline-12-one (8c).

본 발명의 또 다른 실시예에서, 상기 염기는 칼륨터트-부톡사이드(KO t Bu), 소듐터트-부톡사이드(NaO t Bu), 탄산칼륨(K2CO3), 메톡사이드나트륨(NaOMe), 수산화나트륨(NaOH), 트리에틸아민(Et3N), 및 실버 테트라플루오로보레이트(AgBF4)로 이루어진 군으로부터 선택된 하나 이상일 수 있으나, 이에 제한되는 것은 아니다.In another embodiment of the present invention, the base is potassium tert-butoxide (KO t Bu), sodium tert-butoxide (NaO t Bu), potassium carbonate (K 2 CO 3 ) , sodium methoxide (NaOMe), It may be at least one selected from the group consisting of sodium hydroxide (NaOH), triethylamine (Et 3 N), and silver tetrafluoroborate (AgBF 4 ), but is not limited thereto.

본 발명의 또 다른 실시예에서, 상기 반응은 1,4-다이옥세인(1,4-Dioxane), 메틸 삼차 뷰틸 에터(Methyl tert-Butyl Ether, MTBE), 아세토니트릴(Acetonitrile, MeCN), 디메틸포름아마이드(Dimethylformamide, DMF), 다이클로로에테인(Dichloroethene; DCE), 다이클로로메탄(Dichloromethane; DCM), 테트라하이드로퓨란(Tetrahydrofuran, THF), 에탄올(EtOH), 테트라플루오로에틸렌(Tetrafluoroethylene, TFE) 및 헥사플루오로 이소프로판올(Hexafluoro isopropanol, HFIP)로 이루어진 군으로부터 선택된 용매에서 이루어지는 것일 수 있으나, 이에 제한되는 것은 아니다.In another embodiment of the present invention, the reaction is 1,4-dioxane (1,4-Dioxane), methyl tert-butyl ether (Methyl tert-Butyl Ether, MTBE), acetonitrile (Acetonitrile, MeCN), dimethylform Amide (Dimethylformamide, DMF), Dichloroethene (DCE), Dichloromethane (DCM), Tetrahydrofuran (THF), Ethanol (EtOH), Tetrafluoroethylene (TFE) and Hexa It may be made in a solvent selected from the group consisting of fluoro isopropanol (Hexafluoro isopropanol, HFIP), but is not limited thereto.

본 발명은 아진-N-옥사이드와 아실 아자이드를 활용하여 단일단계 반응을 통해 목적하는 아민화된 아진 화합물을 합성함으로써, 다단계의 합성 단계가 필요하고 금속 부산물이 생성되는 기존 문제점을 해결하면서, 아민화된 아진 계열의 의약품을 효과적으로 합성할 수 있다는 장점이 있다.The present invention utilizes azine-N-oxide and acyl azide to synthesize the desired aminated azine compound through a single-step reaction, solving the existing problems of requiring a multi-step synthesis step and generating metal by-products, It has the advantage of effectively synthesizing medicinal products of the folk azine series.

또한, 본 발명의 제조방법에 따르면, 아진 내 2번 위치로의 선택적 아민화 반응을 통해 현재 의약품으로 개발 중에 있는 화합물의 효과적인 합성 및 추가적인 유도체 합성함으로써, 다양한 의약화학 및 제약 공정 연구에 유용하게 적용될 것으로 기대된다.In addition, according to the preparation method of the present invention, it can be usefully applied to various pharmaceutical chemistry and pharmaceutical process research by effectively synthesizing compounds currently under development as pharmaceuticals and synthesizing additional derivatives through selective amination to the 2nd position in azine. is expected to

도 1은 아진-N-옥사이드와 아실 아자이드를 염기 조건 하에서 반응하여 아민화된 아진 화합물을 합성하는 반응식으로서, 아실 아자이드는 반응 용기 내에서 Curtius 자리옮김 반응을 통해 이소시아네이트로 변환되고 아진-N-옥사이드와 [3+2] 고리화 첨가반응 및 탈탄산 반응을 통해 아민화된 아진으로 변환됨을 제시하는 것이다.
도 2는 현재 의약품으로 개발되어 있은 아민화된 아진 약물 분자구조를 나타낸 것이다.
도 3은 [3+2] 고리화 첨가반응을 주요 반응 메커니즘으로 하는 합성법에 관한 기존 문헌과 본 발명의 차별성 및 신규성을 나타낸 것이다.1 is a reaction scheme for synthesizing an aminated azine compound by reacting an azine-N-oxide with an acyl azide under basic conditions, wherein the acyl azide is converted into an isocyanate through a Curtius displacement reaction in a reaction vessel and azine-N This suggests that -oxide is converted to an aminated azine through [3+2] cycloaddition reaction and decarboxylation reaction.
Figure 2 shows the molecular structure of the aminated azine drug currently developed as a drug.
3 shows the differentiation and novelty of the present invention and the existing literature on a synthesis method using [3+2] cycloaddition as the main reaction mechanism.

본 발명은 하기 화학식 1 내지 화학식 3으로 표시되는 화합물, 이의 입체 이성질체, 또는 이의 약학적으로 허용가능한 염, 및 그의 제조방법을 제공한다.The present invention provides a compound represented by the following Chemical Formulas 1 to 3, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a method for preparing the same.

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

본 발명의 화학식 1 내지 화학식 3은 다음과 같다.Formulas 1 to 3 of the present invention are as follows.

[화학식 1][Formula 1]

Figure pat00016
Figure pat00016

[화학식 2][Formula 2]

Figure pat00017
Figure pat00017

[화학식 3][Formula 3]

Figure pat00018
Figure pat00018

상기 화학식 1 내지 화학식 3에 있어서,In Formulas 1 to 3,

상기 R1은 수소, 할로겐, 치환 또는 비치환된 C1-C6 알킬, 치환 또는 비치환된 C1-C6 알콕시, 아다만테인-1-일, C6-C20 아릴 또는 C6-C20 헤테로아릴이며;wherein R 1 is hydrogen, halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy, adamantane-1-yl, C 6 -C 20 aryl or C 6 -C 20 heteroaryl;

상기 R2는 치환 또는 비치환된 C1-C6 알킬, 치환 또는 비치환된 C1-C6 알콕시, C6-C20 아릴 또는 C6-C20 헤테로아릴이며;wherein R 2 is substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy, C 6 -C 20 aryl or C 6 -C 20 heteroaryl;

상기 R3 및 R4는 각각 독립적으로 수소, 할로겐, 치환 또는 비치환된 C1-C6 알킬, 치환 또는 비치환된 C1-C6 알콕시,

Figure pat00019
,
Figure pat00020
, 또는
Figure pat00021
이거나, 서로 결합하여 치환 또는 비치환된 C6-C20 아릴 또는 C6-C20 헤테로아릴 고리를 형성하며;wherein R 3 and R 4 are each independently hydrogen, halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy;
Figure pat00019
,
Figure pat00020
, or
Figure pat00021
or combine with each other to form a substituted or unsubstituted C 6 -C 20 aryl or C 6 -C 20 heteroaryl ring;

상기 X 및 Y는 각각 독립적으로 탄소, 수소, 질소, 산소, 황, 할로겐, 치환 또는 비치환된 C1-C6 알킬, 치환 또는 비치환된 C1-C6 알콕시이거나, 서로 결합하여 치환 또는 비치환된 C6-C20 아릴 또는 C6-C20 헤테로아릴 고리를 형성한다. Wherein X and Y are each independently carbon, hydrogen, nitrogen, oxygen, sulfur, halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy, or bonded to each other, substituted or form an unsubstituted C 6 -C 20 aryl or C 6 -C 20 heteroaryl ring.

다음은 본 발명에 따른 화합물들을 제조하는 여러가지 치환기의 정의를 설명한다.The following describes the definitions of the various substituents making up the compounds according to the present invention.

본 발명에서 사용된 용어 “C1-C6 알킬”은 탄소원자수 1 내지 6의 1가 알킬기를 의미한다. 이 용어는 메틸, 에틸, n-프로필, i-프로필, n-부틸, i-부틸, tert-부틸, n-헥실 등과 같은 기능기를 예로 들 수 있다. 본 발명에 기재된 알킬, 및 그 외 알킬 부분을 포함하는 치환체는 직쇄 또는 분쇄 형태를 모두 포함한다. 치환된 C1-C6 알킬은 수소원자 중 하나 이상의 수소원자가 다른 치환기로 치환된 것을 의미하는 것으로, 치환기는 제한되지는 않으나, 할로겐, N, O, S 등을 포함한다. 예를 들어 치환된 C1-C6 알킬은 트리플로오로메틸(-CF3)일 수 있다.As used herein, the term “C 1 -C 6 alkyl” refers to a monovalent alkyl group having 1 to 6 carbon atoms. The term includes functional groups such as methyl, ethyl, n -propyl, i -propyl, n -butyl, i -butyl, tert -butyl, n -hexyl and the like. The alkyl, and other alkyl moiety-containing substituents described herein include both straight-chain and comminuted forms. Substituted C 1 -C 6 alkyl means that one or more hydrogen atoms among hydrogen atoms are substituted with other substituents, and the substituents are not limited, but include halogen, N, O, S, and the like. For example a substituted C 1 -C 6 alkyl may be trifluoromethyl(—CF 3 ).

본 발명에서 사용된 용어 “C1-C6 알코올”은 탄소원자수 1 내지 6의 1가 알코올기(-R-OH)를 의미한다. 여기서 R은 메틸, 에틸, n-프로필, i-프로필, n-부틸, i-부틸, tert-부틸, n-헥실 등과 같은 기능기를 예로 들 수 있다. 본 발명에 기재된 알킬, 및 그 외 알킬 부분을 포함하는 치환체는 직쇄 또는 분쇄 형태를 모두 포함한다. 치환된 C1-C6알킬은 수소원자 중 하나 이상의 수소원자가 다른 치환기로 치환된 것을 의미하는 것으로, 여기서 치환된 C1-C6알킬은 트리플로오로메틸(-CF3)일 수 있다.As used herein, the term “C 1 -C 6 alcohol” refers to a monohydric alcohol group having 1 to 6 carbon atoms (-R-OH). Here, R may be exemplified by a functional group such as methyl, ethyl, n -propyl, i -propyl, n -butyl, i -butyl, tert -butyl, n-hexyl and the like. The alkyl, and other alkyl moiety-containing substituents described herein include both straight-chain and comminuted forms. Substituted C 1 -C 6 alkyl means that at least one hydrogen atom among hydrogen atoms is substituted with another substituent, wherein the substituted C 1 -C 6 alkyl may be trifluoromethyl (-CF 3 ).

본 발명에서 사용된 용어 “할로겐”은 플루오로(F), 클로로(Cl), 및 브로모(Br), 요오드(I) 를 포함할 수 있다.As used herein, the term “halogen” may include fluoro (F), chloro (Cl), and bromo (Br) and iodine (I).

본 발명에서 사용된 용어 “C1-C6 알콕시”는 -O-R기를 의미하며, 여기서 R은 "C1-C6알킬"을 의미한다. 바람직한 알콕시기는 예를 들면, 메톡시, 에톡시, 프로폭시, 부톡시, 페녹시 등을 포함한다.As used herein, the term “C 1 -C 6 alkoxy” refers to an —OR group, where R refers to “C 1 -C 6 alkyl”. Preferred alkoxy groups include, for example, methoxy, ethoxy, propoxy, butoxy, phenoxy and the like.

본 발명에서 사용된 용어 "C2-C6 알콕시알킬"은 2-메톡시에틸 등을 포함하는 알콕시 치환체를 갖는 알킬기를 의미하는 것이다.As used herein, the term “C 2 -C 6 alkoxyalkyl” refers to an alkyl group having an alkoxy substituent including 2-methoxyethyl and the like.

본 발명에서 사용된 용어 "C6-C20 아릴"은 단일링(예를 들면 페닐) 또는 복수의 축합링(예를 들면 나프틸)을 갖는 탄소원자수 6 내지 20의 불포화 방향족 고리화합물을 의미한다. 상기 아릴은 페닐, 나프틸, 안트릴 및 바이아릴로 이루어지는 군으로부터 선택될 수 있다.As used herein, the term "C 6 -C 20 aryl" refers to an unsaturated aromatic ring compound having 6 to 20 carbon atoms having a single ring (eg phenyl) or a plurality of condensed rings (eg naphthyl). . The aryl may be selected from the group consisting of phenyl, naphthyl, anthryl and biaryl.

본 발명에서 사용된 용어 “상기 “C6-C20 헤테로아릴”은 S, O 및 N으로부터 선택되는 1 내지 3개의 이종원자를 포함하는 아릴기로서, 다이옥솔일, 피리딜, 피리미딜, 티오페닐, 피롤릴, 퓨라닐 및 트리아졸릴로 이루어지는 군으로부터 선택될 수 있으나, 이에 제한되지 않는다. The term “C 6 -C 20 heteroaryl” used in the present invention is an aryl group containing 1 to 3 heteroatoms selected from S, O and N, dioxolyl, pyridyl, pyrimidyl, thiophenyl, It may be selected from the group consisting of pyrrolyl, furanyl and triazolyl, but is not limited thereto.

본 발명에서 사용된 용어 "C7-C20 아릴알킬"은 -(CH2)n-R로 표시되는 것으로, 여기서 R은 아릴기를 의미하는 것이며, 벤질, 펜에틸 등을 포함하는 아릴 치환체를 갖는 알킬기를 의미하는 것으로, "C6-C20아릴"은 단일링(예를 들면 페닐) 또는 복수의 축합링(예를 들면 나프틸)을 갖는 탄소원자수 6 내지 20의 불포화 방향족 고리화합물을 의미한다. 상기 아릴은 페닐, 나프틸 등을 포함한다. The term "C 7 -C 20 arylalkyl" used in the present invention is represented by -(CH 2 ) n -R, where R means an aryl group, having an aryl substituent including benzyl, phenethyl, etc. As meaning an alkyl group, "C 6 -C 20 aryl" refers to an unsaturated aromatic ring compound having 6 to 20 carbon atoms having a single ring (eg phenyl) or a plurality of condensed rings (eg naphthyl). . The aryl includes phenyl, naphthyl, and the like.

상기 화학식 1 내지 화학식 3 중 어느 하나의 화학식에 있어서,In any one of the formulas 1 to 3,

본 발명의 일실시예에서, 상기 R1은 톨릴, 벤질, 메틸페닐, 에틸페닐, 프로필페닐, 부틸페닐, 트리플루오로메틸페닐, 디메톡시페닐, 브로모메틸페닐, 나프탈렌일, 피리딘일, 또는 아다만테인일일 수 있으나 이에 제한되는 것은 아니다.In one embodiment of the present invention, R 1 is tolyl, benzyl, methylphenyl, ethylphenyl, propylphenyl, butylphenyl, trifluoromethylphenyl, dimethoxyphenyl, bromomethylphenyl, naphthalenyl, pyridinyl, or adamantane day, but is not limited thereto.

본 발명의 다른 실시예에서, 상기 R2는 페닐, 피리딜 또는

Figure pat00022
일 수 있으나, 이에 제한되는 것은 아니다.In another embodiment of the present invention, R 2 is phenyl, pyridyl or
Figure pat00022
may be, but is not limited thereto.

본 발명의 또 다른 실시예에서, 상기 R3 및 R4는 각각 독립적으로 수소, 플루오로, 클로로, 브로모, 메틸, 메톡시,

Figure pat00023
,
Figure pat00024
, 또는
Figure pat00025
이거나, 서로 결합하여 치환 또는 비치환된 벤질, 페닐 또는 피리딘을 형성할 수 있으나, 이에 제한되는 것은 아니다.In another embodiment of the present invention, R 3 and R 4 are each independently hydrogen, fluoro, chloro, bromo, methyl, methoxy,
Figure pat00023
,
Figure pat00024
, or
Figure pat00025
or may be combined with each other to form a substituted or unsubstituted benzyl, phenyl or pyridine, but is not limited thereto.

본 발명의 또 다른 실시예에서, 상기 X 및 Y는 각각 독립적으로 질소, 치환 또는 비치환된 C1-C6 알킬이거나, 서로 결합하여 벤질고리를 형성할 수 있으나, 이에 제한되는 것은 아니다.In another embodiment of the present invention, X and Y are each independently nitrogen, a substituted or unsubstituted C 1 -C 6 alkyl, or may combine with each other to form a benzyl ring, but is not limited thereto.

본 발명의 상기 화합물은 약학적으로 허용 가능한 염의 형태로 사용할 수 있으며, 염으로는 약학적으로 허용가능한 유리산(free acid)에 의해 형성된 산부가염이 유용하다.The compound of the present invention may be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful.

본 발명에서 사용되는 용어 "염"은 약학적으로 허용 가능한 유리산(free acid)에 의해 형성된 산 부가염이 유용하다. 산 부가염은 염산, 질산, 인산, 황산, 브롬화수소산, 요드화수소산, 아질산 또는 아인산과 같은 무기산류와 지방족 모노 및 디카르복실레이트, 페닐-치환된 알카노에이트, 하이드록시 알카노에이트 및 알칸디오에이트, 방향족 산류, 지방족 및 방향족 설폰산류와 같은 무독성 유기산으로부터 얻는다. 이러한 약학적으로 무독한 염류로는 설페이트, 피로설페이트, 바이설페이트, 설파이트, 바이설파이트, 니트레이트, 포스페이트, 모노하이드로겐 포스페이트, 디하이드로겐 포스페이트, 메타포스페이트, 피로포스페이트 클로라이드, 브로마이드, 아이오다이드, 플루오라이드, 아세테이트, 프로피오네이트, 데카노에이트, 카프릴레이트, 아크릴레이트, 포메이트, 이소부티레이트, 카프레이트, 헵타노에이트, 프로피올레이트, 옥살레이트, 말로네이트, 석시네이트, 수베레이트, 세바케이트, 푸마레이트, 말리에이트, 부틴-1,4-디오에이트, 헥산-1,6-디오에이트, 벤조에이트, 클로로벤조에이트, 메틸벤조에이트, 디니트로 벤조에이트, 하이드록시벤조에이트, 메톡시벤조에이트, 프탈레이트, 테레프탈레이트, 벤젠설포네이트, 톨루엔설포네이트, 클로로벤젠설포네이트, 크실렌설포네이트, 페닐아세테이트, 페닐프로피오네이트, 페닐부티레이트, 시트레이트, 락테이트, β-하이드록시부티레이트, 글리콜레이트, 말레이트, 타트레이트, 메탄설포네이트, 프로판설포네이트, 나프탈렌-1-설포네이트, 나프탈렌-2-설포네이트 또는 만델레이트를 포함한다.As used herein, the term "salt" is useful as an acid addition salt formed by a pharmaceutically acceptable free acid. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. It is obtained from non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids. Such pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, ioda. Id, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate , sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, Toxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycol late, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate or mandelate.

본 발명에 따른 산 부가염은 통상의 방법, 예를 들면, 상기 화합물을 과량의 산 수용액 중에 용해시키고, 이 염을 수혼화성 유기 용매, 예를 들면 메탄올, 에탄올, 아세톤 또는 아세토니트릴을 사용하여 침전시켜서 제조할 수 있다. 또한 이 혼합물에서 용매나 과량의 산을 증발시킨 후 건조시키거나 또는 석출된 염을 흡입 여과시켜 제조할 수도 있다.The acid addition salt according to the invention is prepared by a conventional method, for example by dissolving the compound in an aqueous solution of an excess of acid, and precipitating the salt using a water-miscible organic solvent, for example methanol, ethanol, acetone or acetonitrile It can be manufactured by It can also be prepared by evaporating the solvent or excess acid from the mixture and drying the mixture, or by suction filtration of the precipitated salt.

또한, 염기를 사용하여 약학적으로 허용 가능한 금속염을 만들 수도 있다. 알칼리 금속 또는 알칼리 토금속 염은 예를 들면, 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해하고, 비용해 화합물 염을 여과하고, 여액을 증발, 건조시켜 얻는다. 이때, 금속염으로는 나트륨, 칼륨 또는 칼슘염을 제조하는 것이 제약상 적합하다. 이에 대응하는 은염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 음염 (예, 질산은)과 반응시켜 얻는다.In addition, a pharmaceutically acceptable metal salt may be prepared using a base. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. In this case, it is pharmaceutically suitable to prepare a sodium, potassium or calcium salt as the metal salt. The corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable negative salt (eg silver nitrate).

또한, 본 발명의 화합물은 약학적으로 허용되는 염뿐만 아니라, 통상의 방법에 의해 제조될 수 있는 모든 염, 이성질체, 수화물 및 용매화물을 모두 포함한다.In addition, the compound of the present invention includes all salts, isomers, hydrates and solvates that can be prepared by conventional methods as well as pharmaceutically acceptable salts.

본 발명의 제조방법은 염기 조건 하에서 아진-N-옥사이드와 아실 아자이드를 반응시켜 아민화된 아진 화합물을 합성하는 것으로, 화합물의 합성 단계를 단축시킬 뿐만 아니라 금속 부산물 생성 문제점을 개선한 것이다. The preparation method of the present invention synthesizes an aminated azine compound by reacting an azine-N-oxide with an acyl azide under a basic condition, which not only shortens the synthesis step of the compound but also improves the metal by-product generation problem.

따라서, 본 발명은 염기 조건 하에서, 하기 화학식 4로 표시되는 화합물을 화학식 5로 표시되는 화합물과 반응시키는 단계를 포함하는, 본 발명의 화합물의 제조방법을 제공한다.Accordingly, the present invention provides a method for preparing a compound of the present invention, comprising reacting a compound represented by the following formula (4) with a compound represented by formula (5) under basic conditions.

[화학식 4][Formula 4]

Figure pat00026
Figure pat00026

[화학식 5][Formula 5]

Figure pat00027
Figure pat00027

상기 화학식 4 내지 화학식 5에 있어서,In Formulas 4 to 5,

상기 R1은 수소, 할로겐, 치환 또는 비치환된 C1-C6 알킬, 치환 또는 비치환된 C1-C6 알콕시, 아다만테인-1-일, C6-C20 아릴 또는 C6-C20 헤테로아릴이며;wherein R 1 is hydrogen, halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy, adamantane-1-yl, C 6 -C 20 aryl or C 6 -C 20 heteroaryl;

상기 R2는 치환 또는 비치환된 C1-C6 알킬, 치환 또는 비치환된 C1-C6 알콕시, C6-C20 아릴 또는 C6-C20 헤테로아릴이며;wherein R 2 is substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy, C 6 -C 20 aryl or C 6 -C 20 heteroaryl;

상기 R3 및 R4는 각각 독립적으로 수소, 할로겐, 치환 또는 비치환된 C1-C6 알킬, 치환 또는 비치환된 C1-C6 알콕시,

Figure pat00028
,
Figure pat00029
, 또는
Figure pat00030
이거나, 서로 결합하여 치환 또는 비치환된 C6-C20 아릴 또는 C6-C20 헤테로아릴 고리를 형성하며;wherein R 3 and R 4 are each independently hydrogen, halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy;
Figure pat00028
,
Figure pat00029
, or
Figure pat00030
or combine with each other to form a substituted or unsubstituted C 6 -C 20 aryl or C 6 -C 20 heteroaryl ring;

상기 X 및 Y는 각각 독립적으로 탄소, 수소, 질소, 산소, 황, 할로겐, 치환 또는 비치환된 C1-C6 알킬, 치환 또는 비치환된 C1-C6 알콕시이거나, 서로 결합하여 치환 또는 비치환된 C6-C20 아릴 또는 C6-C20 헤테로아릴 고리를 형성하며;Wherein X and Y are each independently carbon, hydrogen, nitrogen, oxygen, sulfur, halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy, or bonded to each other, substituted or form an unsubstituted C 6 -C 20 aryl or C 6 -C 20 heteroaryl ring;

상기 치환은 할로겐, N, O, 및 S로 이루어진 군으로부터 선택된 하나 이상으로 치환된다. The substitution is substituted with one or more selected from the group consisting of halogen, N, O, and S.

본 발명의 제조방법에서, 상기 염기는 칼륨터트-부톡사이드(KO t Bu), 소듐터트-부톡사이드(NaO t Bu), 탄산칼륨(K2CO3), 메톡사이드나트륨(NaOMe), 수산화나트륨(NaOH), 트리에틸아민(Et3N), 및 실버 테트라플루오로보레이트(AgBF4)로 이루어진 군으로부터 선택된 하나 이상일 수 있으나, 이에 제한되는 것은 아니다.In the preparation method of the present invention, the base is potassium tert-butoxide (KO t Bu), sodium tert-butoxide (NaO t Bu), potassium carbonate (K 2 CO 3 ) , sodium methoxide (NaOMe), sodium hydroxide (NaOH), triethylamine (Et 3 N), and silver tetrafluoroborate (AgBF 4 ) It may be at least one selected from the group consisting of, but is not limited thereto.

본 발명의 제조방법에서, 상기 반응은 유기용매 하에서 이루어 질 수 있으며, 상기 반응물질을 용해할 수 있는 것이라면 유기용매에 제한을 둘 필요는 없다. 상기 유기용매의 일례로는 1,4-다이옥세인(1,4-Dioxane), 메틸 삼차 뷰틸 에터(Methyl tert-Butyl Ether, MTBE), 아세토니트릴(Acetonitrile, MeCN), 디메틸포름아마이드(Dimethylformamide, DMF), 다이클로로에테인(Dichloroethene; DCE), 다이클로로메탄(Dichloromethane; DCM), 테트라하이드로퓨란(Tetrahydrofuran, THF), 에탄올(EtOH), 테트라플루오로에틸렌(Tetrafluoroethylene, TFE) 및 헥사플루오로 이소프로판올(Hexafluoro isopropanol, HFIP), 및 이들의 혼합물로 이루어진 군에서 선택된다.In the preparation method of the present invention, the reaction may be carried out in an organic solvent, and there is no need to limit the organic solvent as long as it can dissolve the reactant. An example of the organic solvent is 1,4-dioxane (1,4-Dioxane), methyl tert-butyl ether (Methyl tert-Butyl Ether, MTBE), acetonitrile (Acetonitrile, MeCN), dimethylformamide (Dimethylformamide, DMF) ), dichloroethene (DCE), dichloromethane (DCM), tetrahydrofuran (THF), ethanol (EtOH), tetrafluoroethylene (TFE) and hexafluoro isopropanol (Hexafluoro) isopropanol, HFIP), and mixtures thereof.

또한, 본 발명의 일 실시예에 따른 반응 온도는 이에 제한되지 않으나, 바람직하게 실온 내지 200 ℃의 범위 일 수 있다.In addition, the reaction temperature according to an embodiment of the present invention is not limited thereto, but may preferably be in the range of room temperature to 200 °C.

또한, 본 발명의 일 실시예에 따른 반응 시간은 1시간 내지 48시간일 수 있고, 바람직하게 10 내지 25시간의 범위 일 수 있다.In addition, the reaction time according to an embodiment of the present invention may be in the range of 1 hour to 48 hours, preferably in the range of 10 to 25 hours.

이하, 본 발명의 이해를 돕기 위하여 바람직한 실시예를 제시한다. 그러나 하기의 실시예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐, 하기 실시예에 의해 본 발명의 내용이 한정되는 것은 아니다.Hereinafter, preferred examples are presented to help the understanding of the present invention. However, the following examples are only provided for easier understanding of the present invention, and the contents of the present invention are not limited by the following examples.

[[ 실시예Example ]]

본 발명의 실시예에서는 별도로 언급하지 않는 한, 시판되는 시약을 추가 정제없이 사용하였다. 밀폐된 튜브(13 × 100 mm2)는 Fischer Scientific에서 구입하였고, 오븐에서 밤새 건조시킨 다음 사용 전에 실온에서 냉각시켜 사용하였으며, 박층 크로마토그래피는 Kieselgel 60F254(Merck)로 코팅된 플레이트를 사용하여 수행하였으며, 플래시 칼럼 크로마토그래피의 경우, E. Merck Kieselgel 60(230-400 메쉬)을 사용 하였다. In the examples of the present invention, unless otherwise specified, commercially available reagents were used without further purification. Sealed tubes (13 × 100 mm 2 ) were purchased from Fischer Scientific, dried in an oven overnight and then cooled to room temperature prior to use, and thin layer chromatography was performed using plates coated with Kieselgel 60F 254 (Merck). and for flash column chromatography, E. Merck Kieselgel 60 (230-400 mesh) was used.

핵 자기 공명 스펙트럼 (1H 및 13C 1H NMR)을 CDCl3, CD3OD 및 DMSO-d6 용액에서 브루커유니티 400, 500, 700 분광계에서 기록하고 화학적 이동은 ppm (parts per million)으로 기재하였다.Nuclear magnetic resonance spectra ( 1 H and 13 C 1 H NMR) were recorded on a Brukerunity 400, 500, 700 spectrometer in CDCl 3 , CD 3 OD and DMSO-d 6 solutions, and chemical shifts were measured in parts per million (ppm). described.

공명 패턴은 다음 표기법으로 기재하였다 : s (singlet), d (doublet), dd (doublet of doublets), td (triplet of doublets), t (triplet), q (quartet), and m (multiplet). 또한, 표시 br은 넓은 신호를 나타내는 데 사용하였다. 커플링 상수 (J)는 헤르츠 (Hz)로 기재하였다.Resonance patterns are described in the following notations: s (singlet), d (doublet), dd (doublet of doublets), td (triplet of doublets), t (triplet), q (quartet), and m (multiplet). In addition, the label br was used to indicate a broad signal. Coupling constants (J) are expressed in Hertz (Hz).

IR 스펙트럼은 Varian 2000 적외선 분광 광도계에서 기록되었고 cm-1로 기재하였다. 고해상도 질량 스펙트럼(HRMS)은 JEOL JMS-600 분광기를 통해 분석된 것이다.IR spectra were recorded on a Varian 2000 infrared spectrophotometer and expressed in cm −1 . High-resolution mass spectra (HRMS) were analyzed with a JEOL JMS-600 spectrometer.

실시예 1. 아실 아자이드 (3a-3n, 3r, 3s, 4b-4h, 6a 및 6b)를 사용한 아진-N-옥사이드의 아민화의 일반적인 절차Example 1. General procedure for the amination of azine-N-oxides with acyl azides (3a-3n, 3r, 3s, 4b-4h, 6a and 6b)

실온에서 공기 중에 4-메틸벤조일아자이드 (2a) (96.7 mg, 0.6 mmol, 300 mol %) 및 t-부틸 메틸 에테르 (1 mL)로 충전된 건조된 밀봉 튜브에, 반응 혼합물을 110 ℃에서 2 시간 동안 교반하고 실온으로 냉각시켰다. 이어서, 퀴놀린 N-옥사이드 (1a) (29.0 mg, 0.2 mmol, 100 mol %) 및 KOtBu (44.9 mg, 0.4 mmol, 200 mol %)를 실온에서 공기중에 반응 혼합물에 첨가하였다. 반응 혼합물을 130 ℃에서 18 시간 동안 교반하고, 실온으로 냉각시켰다. In a dried sealed tube filled with 4-methylbenzoylazide (2a ) (96.7 mg, 0.6 mmol, 300 mol %) and t-butyl methyl ether (1 mL) in air at room temperature, the reaction mixture was stirred at 110 °C for 2 It was stirred for an hour and then cooled to room temperature. Quinoline N-oxide ( 1a ) (29.0 mg, 0.2 mmol, 100 mol %) and KOtBu (44.9 mg, 0.4 mmol, 200 mol %) were then added to the reaction mixture at room temperature in air. The reaction mixture was stirred at 130 °C for 18 h and cooled to room temperature.

반응 혼합물을 셀라이트를 통해 여과하고 디클로로메탄 (10 mL)으로 세척하였다. 여액을 감압 하에 농축시켰다. 잔류물을 플래쉬 컬럼크로마토그래피 (n- 헥산 / EtOAc = 3 : 1)로 정제하여 44.5 mg의 3a를 95 % 수율로 수득하였다. 3b-3m, 3s 및 4b-4h의 잔류물을 플래쉬 컬럼 크로마토그래피 (n- 헥산 / EtOAc = 3 : 1)로 정제 하였다. 3n, 3r, 6a 및 6b의 잔류물을 플래쉬 컬럼 크로마토 그래피 (n- 헥산 / EtOAc = 1 : 1)로 정제하였다. t-부틸 메틸 에테르 (MTBE) 대신 DMF (1 mL) 용매를 사용하여 화합물 6b를 합성하였다.The reaction mixture was filtered through celite and washed with dichloromethane (10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (n-hexane / EtOAc = 3 : 1) to give 44.5 mg of 3a in 95% yield. The residues of 3b-3m, 3s and 4b-4h were purified by flash column chromatography (n-hexane/EtOAc=3:1). The residues of 3n, 3r, 6a and 6b were purified by flash column chromatography (n-hexane/EtOAc = 1:1). Compound 6b was synthesized using DMF (1 mL) solvent instead of t-butyl methyl ether (MTBE).

실시예Example 2. 아실 2. Acyl 아자이드azide (3o-3q, 3t, 4i 및 4j)를 사용한 (3o-3q, 3t, 4i and 4j) 아진Ajin -N--N- 옥사이드의of oxide 아민화의amination 일반적인 절차 general procedure

실온에서 공기 중에 아실 아자이드 (0.6mmol, 300mol %) 및 THF (1mL)가 충전된 건조된 밀봉 튜브에, 반응 혼합물을 110 ℃에서 2 시간 동안 교반하고 실온으로 냉각시켰다. 이어서, 아진 N-옥사이드 (0.2 mmol, 100 mol %)를 반응 혼합물에 첨가하고 130 ℃에서 12 시간 동안 교반한 후, 실온으로 냉각시켰다. 이어서, THF (0.25 mL) 중 KOtBu (0.25 mmol, 125 mol %)의 용액을 0 ℃에서 반응 혼합물에 적가하였다. 반응 혼합물을 실온에서 2 시간 동안 교반되도록 하였다. 반응 혼합물을 셀라이트를 통해 여과하고 디클로로메탄 (10 mL)으로 세척하였다. 여액을 감압 하에 농축시켰다. 3o-3q, 3t 및 4i의 잔류물을 플래쉬 컬럼 크로마토그래피 (n-헥산 / EtOAc = 1 : 1)로 정제하였다. 4j의 잔류물을 플래쉬 컬럼 크로마토그래피 (n-헥산 / EtOAc = 3 : 1)로 정제하였다.In a dried sealed tube filled with acyl azide (0.6mmol, 300mol%) and THF (1mL) in air at room temperature, the reaction mixture was stirred at 110°C for 2 hours and cooled to room temperature. Then, azine N-oxide (0.2 mmol, 100 mol %) was added to the reaction mixture, stirred at 130° C. for 12 hours, and then cooled to room temperature. Then, a solution of KOtBu (0.25 mmol, 125 mol %) in THF (0.25 mL) was added dropwise to the reaction mixture at 0 °C. The reaction mixture was allowed to stir at room temperature for 2 h. The reaction mixture was filtered through celite and washed with dichloromethane (10 mL). The filtrate was concentrated under reduced pressure. The residues of 3o-3q, 3t and 4i were purified by flash column chromatography (n-hexane/EtOAc = 1:1). The residue of 4j was purified by flash column chromatography (n-hexane / EtOAc = 3 : 1).

실시예Example 3. NMR 분석을 통한 신규 화합물의 구조 분석 3. Structural analysis of novel compounds through NMR analysis

3-1. N-(p-3-1. N-(p- TolylTolyl )) quinolinquinolin -2-amine (3a)-2-amine (3a)

44.5 mg (95%); 노란색 고체; mp = 102.5-103.2 ℃; 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 8.8 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.64-7.56 (m, 2H), 7.39 (d, J = 8.0 Hz, 2H), 7.29 (t, J = 7.6 Hz, 1H), 7.17 (d, J = 8.0 Hz, 2H), 6.96 (d, J = 9.2 Hz, 1H), 2.35 (s, 3H); 13C1H NMR (100 MHz, CDCl3) δ 154.6, 146.7, 138.1, 137.0, 133.4, 130.0, 129.8, 127.4, 125.8, 123.8, 123.1, 121.5, 111.2, 20.8; IR (KBr) υ 3359, 2925, 2835, 1606, 1512, 1321, 1248, 1154, 956, 788, 757 cm-1; HRMS (orbitrap, ESI) calcd for C16H15N2 [M+H]+ 235.1235, found 235.1232.44.5 mg (95%); yellow solid; mp = 102.5-103.2 °C; 1H NMR (400 MHz, CDCl 3 ) δ 7.89 (d, J = 8.8 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.64-7.56 (m, 2H), 7.39 (d, J = 8.0) Hz, 2H), 7.29 (t, J = 7.6 Hz, 1H), 7.17 (d, J = 8.0 Hz, 2H), 6.96 (d, J = 9.2 Hz, 1H), 2.35 (s, 3H); 13C1H NMR (100 MHz, CDCl 3 ) δ 154.6, 146.7, 138.1, 137.0, 133.4, 130.0, 129.8, 127.4, 125.8, 123.8, 123.1, 121.5, 111.2, 20.8; IR (KBr) υ 3359, 2925, 2835, 1606, 1512, 1321, 1248, 1154, 956, 788, 757 cm-1; HRMS (orbitrap, ESI) calcd for C 16 H 15 N 2 [M+H]+ 235.1235, found 235.1232.

3-2. 6-3-2. 6- MethoxyMethoxy -N-(p--N-(p- tolyltolyl )) quinolinquinolin -2-amine (3b)-2-amine (3b)

447.5 mg (90%); 노란색 고체; mp = 111.2-113.8 ℃; 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.37 (d, J = 8.0 Hz, 2H), 7.27-7.26 (m, 1H), 7.16 (d, J = 8.0 Hz, 2H), 6.99-6.95 (m, 2H), 6.83 (s, 1H), 3.89 (s, 3H), 2.34 (s, 3H); 13C1H NMR (100 MHz, CDCl3) δ 155.5, 153.3, 142.6, 137.5, 137.0, 132.9, 129.8, 127.5, 124.4, 121.5, 121.0, 111.5, 106.3, 55.5, 20.8; IR (KBr) υ 3401, 3196, 2998, 2918, 2850, 2731, 1601, 1572, 1509, 1459, 1394, 1348, 1317, 1262, 1226, 1159, 1112, 1030, 826, 807 cm-1; HRMS (orbitrap, ESI) calcd for C17H17N2O [M+H]+ 265.1341, found 265.13382.447.5 mg (90%); yellow solid; mp = 111.2-113.8 ° C; 1H NMR (400 MHz, CDCl 3 ) δ 7.83 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.37 (d, J = 8.0 Hz, 2H), 7.27-7.26 ( m, 1H), 7.16 (d, J = 8.0 Hz, 2H), 6.99-6.95 (m, 2H), 6.83 (s, 1H), 3.89 (s, 3H), 2.34 (s, 3H); 13C1H NMR (100 MHz, CDCl 3 ) δ 155.5, 153.3, 142.6, 137.5, 137.0, 132.9, 129.8, 127.5, 124.4, 121.5, 121.0, 111.5, 106.3, 55.5, 20.8; IR (KBr) υ 3401, 3196, 2998, 2918, 2850, 2731, 1601, 1572, 1509, 1459, 1394, 1348, 1317, 1262, 1226, 1159, 1112, 1030, 826, 807 cm-1; HRMS (orbitrap, ESI) calcd for C 17 H 17 N 2 O [M+H]+ 265.1341, found 265.13382.

3-3. 6-3-3. 6- ChloroChloro -N-(p--N-(p- tolyltolyl )) quinolinquinolin -2-amine (3c)-2-amine (3c)

39.2 mg (73%); 갈색 고체; mp = 108.1-110.2 ℃; 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.8 Hz, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.59 (s, 1H), 7.49 (d, J = 8.8 Hz, 1H), 7.40 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 6.94 (d, J = 9.2 Hz, 1H), 2.35 (s, 3H); 13C1H NMR (100 MHz, CDCl3) δ 154.9, 146.0, 137.0, 136.7, 133.4, 130.3, 129.8, 128.0, 127.9, 126.1, 124.5, 121.4, 112.2, 20.8; IR (KBr) υ 3241, 3026, 2919, 2855, 1671, 1617, 1509, 1489, 1369, 1348, 1243, 1191, 1076, 932, 878, 826, 807 cm-1; HRMS (orbitrap, ESI) calcd for C16H14ClN2 [M+H]+ 269.0845, found 269.0841.39.2 mg (73%); brown solid; mp = 108.1-110.2 °C; 1H NMR (400 MHz, CDCl 3 ) δ 7.78 (d, J = 8.8 Hz, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.59 (s, 1H), 7.49 (d, J = 8.8 Hz, 1H), 7.40 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 6.94 (d, J = 9.2 Hz, 1H), 2.35 (s, 3H); 13C1H NMR (100 MHz, CDCl 3 ) δ 154.9, 146.0, 137.0, 136.7, 133.4, 130.3, 129.8, 128.0, 127.9, 126.1, 124.5, 121.4, 112.2, 20.8; IR (KBr) υ 3241, 3026, 2919, 2855, 1671, 1617, 1509, 1489, 1369, 1348, 1243, 1191, 1076, 932, 878, 826, 807 cm-1; HRMS (orbitrap, ESI) calcd for C 16 H 14 ClN 2 [M+H]+ 269.0845, found 269.0841.

3-4. 6-3-4. 6- FluoroFluoro -N-(p--N-(p- tolyltolyl )) quinolinquinolin -2-amine (3d)-2-amine (3d)

25.7 mg (51%); 노란색 고체; mp = 105.5-107.1 ℃; 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 8.8 Hz, 1H), 7.74-7.71 (m, 1H), 7.40 (d, J = 8.0 Hz, 2H), 7.34 (t, J = 9.2 Hz, 1H), 7.28-7.26 (m, 1H), 7.17 (d, J = 8.0 Hz, 2H), 6.97 (d, J = 8.8 Hz, 1H), 2.35 (s, 3H); 13C1H NMR (100 MHz, CDCl3) δ 158.4 (d, JC-F = 241.2 Hz), 154.3 (d, JC-F = 1.3 Hz), 144.3, 137.2, 137.0 (d, JC-F = 4.5 Hz), 133.2, 129.8, 128.2 (d, JC-F = 8.4 Hz), 124.0 (d, JC-F = 9.4 Hz), 121.2, 119.2 (d, JC-F = 24.8 Hz), 112.3, 110.8 (d, JC-F = 21.7 Hz), 20.8; IR (KBr) υ 3367, 2926, 1665, 1622, 1608, 1571, 1512, 1401, 1356, 1319, 1245, 1137, 1107, 812 cm-1; HRMS (orbitrap, ESI) calcd for C16H14FN2 [M+H]+ 253.1141, found 253.1135.25.7 mg (51%); yellow solid; mp = 105.5-107.1 °C; 1H NMR (400 MHz, CDCl 3 ) δ 7.83 (d, J = 8.8 Hz, 1H), 7.74-7.71 (m, 1H), 7.40 (d, J = 8.0 Hz, 2H), 7.34 (t, J = 9.2) Hz, 1H), 7.28-7.26 (m, 1H), 7.17 (d, J = 8.0 Hz, 2H), 6.97 (d, J = 8.8 Hz, 1H), 2.35 (s, 3H); 13C1H NMR (100 MHz, CDCl 3 ) δ 158.4 (d, JC-F = 241.2 Hz), 154.3 (d, JC-F = 1.3 Hz), 144.3, 137.2, 137.0 (d, JC-F = 4.5 Hz), 133.2, 129.8, 128.2 (d, JC-F = 8.4 Hz), 124.0 (d, JC-F = 9.4 Hz), 121.2, 119.2 (d, JC-F = 24.8 Hz), 112.3, 110.8 (d, JC-F = 24.8 Hz) F = 21.7 Hz), 20.8; IR (KBr) υ 3367, 2926, 1665, 1622, 1608, 1571, 1512, 1401, 1356, 1319, 1245, 1137, 1107, 812 cm-1; HRMS (orbitrap, ESI) calcd for C 16 H 14 FN 2 [M+H]+ 253.1141, found 253.1135.

3-5. 5-Fluoro-8-methoxy-N-(p-tolyl)quinolin-2-amine (3e)3-5. 5-Fluoro-8-methoxy-N-(p-tolyl)quinolin-2-amine (3e)

31.0 mg (55%); 노란색 고체; mp = 122.5-123.7 ℃; 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 9.2 Hz, 1H), 7.25 (d, J = 7.6 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 7.10 (d, J = 8.8 Hz, 1H), 6.84 (d, J = 6.8 Hz, 2H), 4.02 (s, 3H), 2.35 (s, 3H); 13C1H NMR (100 MHz, CDCl3) δ 155.2, 152.5 (d, JC-F = 244.3 Hz), 149.7 (d, JC-F = 2.9 Hz), 139.5, 136.8, 134.0, 131.2 (d, JC-F = 4.0 Hz), 130.0, 122.2, 114.8 (d, JC-F = 17.7 Hz), 110.5 (d, JC-F = 2.2 Hz), 107.4 (d, JC-F = 9.0 Hz), 105.5 (d, JC-F = 21.1 Hz), 56.1, 20.8; IR (KBr) υ 3351, 2920, 2855, 1681, 1604, 1535, 1509, 1483, 1415, 1312, 1248, 1154, 1091, 1041, 996, 945, 806 cm-1; HRMS (orbitrap, ESI) calcd for C17H16FN2O [M+H]+ 283.1246, found 283.1245.31.0 mg (55%); yellow solid; mp = 122.5-123.7 ° C; 1H NMR (400 MHz, CDCl 3 ) δ 8.11 (d, J = 9.2 Hz, 1H), 7.25 (d, J = 7.6 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 7.10 (d, J = 8.8 Hz, 1H), 6.84 (d, J = 6.8 Hz, 2H), 4.02 (s, 3H), 2.35 (s, 3H); 13C1H NMR (100 MHz, CDCl 3 ) δ 155.2, 152.5 (d, JC-F = 244.3 Hz), 149.7 (d, JC-F = 2.9 Hz), 139.5, 136.8, 134.0, 131.2 (d, JC-F = 2.9 Hz) 4.0 Hz), 130.0, 122.2, 114.8 (d, JC-F = 17.7 Hz), 110.5 (d, JC-F = 2.2 Hz), 107.4 (d, JC-F = 9.0 Hz), 105.5 (d, JC- F = 21.1 Hz), 56.1, 20.8; IR (KBr) υ 3351, 2920, 2855, 1681, 1604, 1535, 1509, 1483, 1415, 1312, 1248, 1154, 1091, 1041, 996, 945, 806 cm-1; HRMS (orbitrap, ESI) calcd for C 17 H 16 FN 2 O [M+H]+ 283.1246, found 283.1245.

3-6. 4-Methyl-N-(p-tolyl)quinolin-2-amine (3f)3-6. 4-Methyl-N-(p-tolyl)quinolin-2-amine (3f)

22.8 mg (46%); 갈색 고체; mp = 117.5-119.2 ℃; 1H NMR (700 MHz, CDCl3) δ 7.80 (dd, J = 8.4, 1.4 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.57 (t, J = 7.0 Hz, 1H), 7.38 (d, J = 8.4 Hz, 2H), 7.30 (t, J = 7.0 Hz, 1H), 7.18 (d, J = 7.7 Hz, 2H), 6.82 (s, 1H), 2.57 (s, 3H), 2.35 (s, 3H); 13C1H NMR (175 MHz, CDCl3) δ 154.5, 147.0, 146.1, 137.2, 133.2, 129.8, 129.7, 126.5, 124.2, 123.6, 122.8, 121.6, 111.2, 20.8, 18.9; IR (KBr) υ 3405, 3059, 2919, 2853, 1605, 1511, 1474, 1447, 1394, 1327, 1246, 1193, 1130, 1034, 850, 814 cm-1; HRMS (or-bitrap, ESI) calcd for C17H17N2 [M+H]+ 249.1391, found 249.1386.22.8 mg (46%); brown solid; mp = 117.5-119.2 °C; 1H NMR (700 MHz, CDCl 3 ) δ 7.80 (dd, J = 8.4, 1.4 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.57 (t, J = 7.0 Hz, 1H), 7.38 ( d, J = 8.4 Hz, 2H), 7.30 (t, J = 7.0 Hz, 1H), 7.18 (d, J = 7.7 Hz, 2H), 6.82 (s, 1H), 2.57 (s, 3H), 2.35 ( s, 3H); 13C1H NMR (175 MHz, CDCl 3 ) δ 154.5, 147.0, 146.1, 137.2, 133.2, 129.8, 129.7, 126.5, 124.2, 123.6, 122.8, 121.6, 111.2, 20.8, 18.9; IR (KBr) υ 3405, 3059, 2919, 2853, 1605, 1511, 1474, 1447, 1394, 1327, 1246, 1193, 1130, 1034, 850, 814 cm-1; HRMS (or-bitrap, ESI) calcd for C 17 H 17 N 2 [M+H]+ 249.1391, found 249.1386.

3-7. 4-Chloro-N-(p-tolyl)quinolin-2-amine (3g) 3-7. 4-Chloro-N-(p-tolyl)quinolin-2-amine (3g)

16.7 mg (31%); 노란색 고체; mp = 109.5-110.1 ℃; 1H NMR (500 MHz, CDCl3) δ 8.03 (d, J = 8.5 Hz, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.62 (t, J = 8.0 Hz, 1H), 7.37-7.34 (m, 3H), 7.20 (d, J = 8.0 Hz, 2H), 7.07 (s, 1H), 6.88 (brs, 1H), 2.36 (s, 3H); 13C1H NMR (175 MHz, CDCl3) δ 154.6, 148.4, 143.5, 136.7, 133.9, 130.8, 130.0, 126.7, 124.0, 123.6, 122.3, 121.9, 110.7, 20.9; IR (KBr) υ 3398, 3060, 3026, 2923, 2851, 1604, 1563, 1533, 1420, 1343, 1248, 1181, 1148, 1029, 956, 869, 813, 796 cm-1; HRMS (orbitrap, ESI) calcd for C16H14ClN2 [M+H]+ 269.0845, found 269.0841.16.7 mg (31%); yellow solid; mp = 109.5-110.1 °C; 1H NMR (500 MHz, CDCl 3 ) δ 8.03 (d, J = 8.5 Hz, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.62 (t, J = 8.0 Hz, 1H), 7.37-7.34 ( m, 3H), 7.20 (d, J = 8.0 Hz, 2H), 7.07 (s, 1H), 6.88 (brs, 1H), 2.36 (s, 3H); 13C1H NMR (175 MHz, CDCl 3 ) δ 154.6, 148.4, 143.5, 136.7, 133.9, 130.8, 130.0, 126.7, 124.0, 123.6, 122.3, 121.9, 110.7, 20.9; IR (KBr) υ 3398, 3060, 3026, 2923, 2851, 1604, 1563, 1533, 1420, 1343, 1248, 1181, 1148, 1029, 956, 869, 813, 796 cm-1; HRMS (orbitrap, ESI) calcd for C 16 H 14 ClN 2 [M+H]+ 269.0845, found 269.0841.

3-8. 3-Methyl-N-(p-3-8. 3-Methyl-N-(p- tolyltolyl )) quinolinquinolin -2-amine (3h)-2-amine (3h)

13.9 mg (28%); 노란색 고체; mp = 118.9-119.8 ℃; 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 8.0 Hz, 1H), 7.74-7.72 (m, 3H), 7.59 (d, J = 8.0 Hz, 1H), 7.52 (t, J = 7.6 Hz, 1H), 7.29-7.27 (m, 1H), 7.18 (d, J = 8.0 Hz, 2H), 6.50 (brs, 1H), 2.39 (s, 3H), 2.35 (s, 3H); 13C1H NMR (100 MHz, CDCl3) δ 152.8, 146.2, 137.7, 136.4, 131.9, 129.3, 128.5, 126.6, 126.4, 124.3, 122.9, 119.9, 119.8, 20.8, 17.7; IR (KBr) υ 3449, 3303, 3026, 2921, 2853, 1735, 1660, 1629, 1570, 1547, 1473, 1433, 1351, 1309, 1251, 1111, 1007, 900, 810 cm-1; HRMS (orbitrap, ESI) calcd for C17H17N2 [M+H]+ 249.1391, found 249.1390.13.9 mg (28%); yellow solid; mp = 118.9-119.8 °C; 1H NMR (400 MHz, CDCl 3 ) δ 7.81 (d, J = 8.0 Hz, 1H), 7.74-7.72 (m, 3H), 7.59 (d, J = 8.0 Hz, 1H), 7.52 (t, J = 7.6) Hz, 1H), 7.29-7.27 (m, 1H), 7.18 (d, J = 8.0 Hz, 2H), 6.50 (brs, 1H), 2.39 (s, 3H), 2.35 (s, 3H); 13C1H NMR (100 MHz, CDCl 3 ) δ 152.8, 146.2, 137.7, 136.4, 131.9, 129.3, 128.5, 126.6, 126.4, 124.3, 122.9, 119.9, 119.8, 20.8, 17.7; IR (KBr) υ 3449, 3303, 3026, 2921, 2853, 1735, 1660, 1629, 1570, 1547, 1473, 1433, 1351, 1309, 1251, 1111, 1007, 900, 810 cm-1; HRMS (orbitrap, ESI) calcd for C 17 H 17 N 2 [M+H]+ 249.1391, found 249.1390.

3-9. 8-Methyl-N-(p-3-9. 8-Methyl-N-(p- tolyltolyl )) quinolinquinolin -2-amine (3i)-2-amine (3i)

42.2 mg (85%); 갈색 고체; mp = 127.5-129.0 ℃; 1H NMR (700 MHz, CDCl3) δ 7.87 (d, J = 9.1 Hz, 1H), 7.60 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 7.7 Hz, 1H), 7.46 (d, J = 7.0 Hz, 1H), 7.20-7.18 (m, 3H), 6.87 (d, J = 8.4 Hz, 1H), 6.68 (brs, 1H), 2.72 (s, 3H), 2.36 (s, 3H); 13C1H NMR (175 MHz, CDCl3) δ 153.3, 146.5, 137.9, 137.8, 134.5, 132.0, 129.9, 129.5, 125.2, 123.7, 122.6, 119.9, 111.5, 20.8, 18.1; IR (KBr) υ 3401, 3044, 3019, 2920, 2863, 1649, 1536, 1427, 1343, 1318, 1244, 1159, 1143, 1060, 814 cm-1; HRMS (orbitrap, ESI) calcd for C17H17N2 [M+H]+ 249.1391, found 249.1389.42.2 mg (85%); brown solid; mp = 127.5-129.0 °C; 1H NMR (700 MHz, CDCl 3 ) δ 7.87 (d, J = 9.1 Hz, 1H), 7.60 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 7.7 Hz, 1H), 7.46 (d, J = 7.0 Hz, 1H), 7.20-7.18 (m, 3H), 6.87 (d, J = 8.4 Hz, 1H), 6.68 (brs, 1H), 2.72 (s, 3H), 2.36 (s, 3H); 13C1H NMR (175 MHz, CDCl 3 ) δ 153.3, 146.5, 137.9, 137.8, 134.5, 132.0, 129.9, 129.5, 125.2, 123.7, 122.6, 119.9, 111.5, 20.8, 18.1; IR (KBr) υ 3401, 3044, 3019, 2920, 2863, 1649, 1536, 1427, 1343, 1318, 1244, 1159, 1143, 1060, 814 cm-1; HRMS (orbitrap, ESI) calcd for C 17 H 17 N 2 [M+H]+ 249.1391, found 249.1389.

3-10. 7-3-10. 7- BromoBromo -8-methyl-N-(p--8-methyl-N-(p- tolyltolyl )) quinolinquinolin -2-amine (3j)-2-amine (3j)

47.8 mg (73%); 노란색 고체; mp = 106.5-109.0 ℃; 1H NMR (700 MHz, CDCl3) δ 7.76 (d, J = 9.1 Hz, 1H), 7.61 (d, J = 2.1 Hz, 1H), 7.57-7.53 (m, 3H), 7.18 (d, J = 7.0 Hz, 1H), 6.71 (brs, 1H), 2.67 (s, 3H), 2.35 (s, 3H); 13C1H NMR (175 MHz, CDCl3) δ 153.5, 145.4, 137.5, 136.9, 136.8, 132.7, 130.4, 129.6, 127.2, 124.8, 120.1, 115.5, 112.4, 20.8, 17.9; IR (KBr) υ 3346, 3027, 2857, 2853, 1652, 1606, 1538, 1483, 1344, 1318, 1248, 1071, 862, 808, 784 cm-1; HRMS (orbitrap, ESI) calcd for C17H16BrN2 [M+H]+ 327.0496, found 327.0493.47.8 mg (73%); yellow solid; mp = 106.5-109.0 °C; 1H NMR (700 MHz, CDCl 3 ) δ 7.76 (d, J = 9.1 Hz, 1H), 7.61 (d, J = 2.1 Hz, 1H), 7.57-7.53 (m, 3H), 7.18 (d, J = 7.0) Hz, 1H), 6.71 (brs, 1H), 2.67 (s, 3H), 2.35 (s, 3H); 13C1H NMR (175 MHz, CDCl 3 ) δ 153.5, 145.4, 137.5, 136.9, 136.8, 132.7, 130.4, 129.6, 127.2, 124.8, 120.1, 115.5, 112.4, 20.8, 17.9; IR (KBr) υ 3346, 3027, 2857, 2853, 1652, 1606, 1538, 1483, 1344, 1318, 1248, 1071, 862, 808, 784 cm-1; HRMS (orbitrap, ESI) calcd for C 17 H 16 BrN 2 [M+H]+ 327.0496, found 327.0493.

3-11. 6-3-11. 6- ChloroChloro -8-methyl-N-(p--8-methyl-N-(p- tolyltolyl )) quinolinquinolin -2-amine (3k)-2-amine (3k)

47.0 mg (83%); 오렌지색 고체; mp = 137.5-139.1 ℃; 1H NMR (700 MHz, CDCl3) δ 7.76 (d, J = 9.1 Hz, 1H), 7.57 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 2.1 Hz, 1H), 7.41-7.40 (m, 1H), 7.18 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 9.1 Hz, 1H), 6.68 (brs, 1H), 2.68 (s, 3H), 2.35 (s, 3H); 13C1H NMR (175 MHz, CDCl3) δ 153.4, 145.1, 137.6, 136.8, 136.7, 132.4, 130.2, 129.6, 127.6, 124.2, 123.8, 120.1, 112.4, 20.8, 17.9; IR (KBr) υ 3410, 3027, 2920, 2854, 1703, 1661, 1654, 1533, 1342, 1317, 1148, 1071, 894, 861, 806, 783 cm-1; HRMS (orbitrap, ESI) calcd for C17H16ClN2 [M+H]+ 283.1002, found 283.1000.47.0 mg (83%); orange solid; mp = 137.5-139.1 °C; 1H NMR (700 MHz, CDCl 3 ) δ 7.76 (d, J = 9.1 Hz, 1H), 7.57 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 2.1 Hz, 1H), 7.41-7.40 ( m, 1H), 7.18 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 9.1 Hz, 1H), 6.68 (brs, 1H), 2.68 (s, 3H), 2.35 (s, 3H); 13C1H NMR (175 MHz, CDCl 3 ) δ 153.4, 145.1, 137.6, 136.8, 136.7, 132.4, 130.2, 129.6, 127.6, 124.2, 123.8, 120.1, 112.4, 20.8, 17.9; IR (KBr) υ 3410, 3027, 2920, 2854, 1703, 1661, 1654, 1533, 1342, 1317, 1148, 1071, 894, 861, 806, 783 cm-1; HRMS (orbitrap, ESI) calcd for C 17 H 16 ClN 2 [M+H]+ 283.1002, found 283.1000.

3-12. N-3-12. N- (p-Tolyl)benzo[f]quinolin(p-Tolyl)benzo[f]quinolin -3-amine (3l)-3-amine (3l)

44.4 mg (78%); 갈색 고체; mp = 205.1-206.2 ℃; 1H NMR (700 MHz, CDCl3) δ 8.68 (d, J = 9.1 Hz, 1H), 8.42 (d, J = 8.4 Hz, 1H), 7.91 (d, J = 9.1 Hz, 1H), 7.88 (d, J = 7.7 Hz, 1H), 7.76 (d, J = 9.1 Hz, 1H), 7.63-7.61 (m, 1H), 7.52 (td, J = 7.7, 0.7 Hz, 1H), 7.41 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H), 7.10 (d, J = 9.1 Hz, 1H), 6.93 (brs, 1H), 2.37 (s, 3H); 13C1H NMR (175 MHz, CDCl3) δ 155.2, 147.6, 137.5, 133.0, 132.6, 130.8, 130.2, 130.1, 129.8, 128.6, 126.9, 126.8, 125.3, 121.5, 121.2, 119.3, 109.5, 20.8; IR (KBr) υ 3411, 3053, 2907, 2838, 1617, 1606, 1573, 1509, 1467, 1402, 1321, 1240, 1180, 811 cm-1; HRMS (orbitrap, ESI) calcd for C20H17N2 [M+H]+ 285.1391, found 285.1388.44.4 mg (78%); brown solid; mp = 205.1-206.2 °C; 1H NMR (700 MHz, CDCl 3 ) δ 8.68 (d, J = 9.1 Hz, 1H), 8.42 (d, J = 8.4 Hz, 1H), 7.91 (d, J = 9.1 Hz, 1H), 7.88 (d, J = 7.7 Hz, 1H), 7.76 (d, J = 9.1 Hz, 1H), 7.63-7.61 (m, 1H), 7.52 (td, J = 7.7, 0.7 Hz, 1H), 7.41 (d, J = 8.4) Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H), 7.10 (d, J = 9.1 Hz, 1H), 6.93 (brs, 1H), 2.37 (s, 3H); 13C1H NMR (175 MHz, CDCl 3 ) δ 155.2, 147.6, 137.5, 133.0, 132.6, 130.8, 130.2, 130.1, 129.8, 128.6, 126.9, 126.8, 125.3, 121.5, 121.2, 119.3, 109.5, 20.8; IR (KBr) υ 3411, 3053, 2907, 2838, 1617, 1606, 1573, 1509, 1467, 1402, 1321, 1240, 1180, 811 cm-1; HRMS (orbitrap, ESI) calcd for C 20 H 17 N 2 [M+H]+ 285.1391, found 285.1388.

3-13. N-(p-3-13. N-(p- TolylTolyl )) phenanthridinphenanthridin -6-amine (3m)-6-amine (3m)

45.5 mg (80%); 갈색 고체; mp = 201.1-202.9 ℃; 1H NMR (400 MHz, CDCl3) δ 8.57 (d, J = 8.4 Hz, 1H), 8.38 (d, J = 8.0 Hz, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.83-7.78 (m, 2H), 7.72 (d, J = 8.0 Hz, 2H), 7.64 (t, J = 7.6 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.21 (d, J = 8.0 Hz, 2H), 2.37 (s, 3H); 13C1H NMR (100 MHz, CDCl3) δ 150.2, 143.4, 137.9, 134.2, 132.3, 130.4, 129.7, 129.4, 128.9, 127.2, 123.5, 122.9, 122.3, 121.8, 121.2, 120.5, 119.7, 20.8; IR (KBr) υ 3446, 3302, 3060, 2921, 2854, 1616, 1584, 1509, 1465, 1423, 1405, 1350, 1317, 1232, 1157, 1037, 815 cm-1; HRMS (or-bitrap, ESI) calcd for C20H17N2 [M+H]+ 285.1391, found 285.1389.45.5 mg (80%); brown solid; mp = 201.1-202.9 ° C; 1H NMR (400 MHz, CDCl 3 ) δ 8.57 (d, J = 8.4 Hz, 1H), 8.38 (d, J = 8.0 Hz, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.83-7.78 ( m, 2H), 7.72 (d, J = 8.0 Hz, 2H), 7.64 (t, J = 7.6 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.21 (d, J = 8.0 Hz, 2H), 2.37 (s, 3H); 13C1H NMR (100 MHz, CDCl 3 ) δ 150.2, 143.4, 137.9, 134.2, 132.3, 130.4, 129.7, 129.4, 128.9, 127.2, 123.5, 122.9, 122.3, 121.8, 121.2, 120.5, 119.7, 20.8; IR (KBr) υ 3446, 3302, 3060, 2921, 2854, 1616, 1584, 1509, 1465, 1423, 1405, 1350, 1317, 1232, 1157, 1037, 815 cm-1; HRMS (or-bitrap, ESI) calcd for C 20 H 17 N 2 [M+H]+ 285.1391, found 285.1389.

3-14. N-(p-3-14. N-(p- TolylTolyl )-9-()-9-( trifluoromethyltrifluoromethyl )-1,10-)-1,10- phenanthrolinphenanthrolin -2-amine (3n)-2-amine (3n)

46.0 mg (65%); 노란색 고체; mp = 212.5-213.2 ℃; 1H NMR (700 MHz, CDCl3) δ 8.37 (d, J = 8.4 Hz, 1H), 7.99 (d, J = 9.1 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 8.4 Hz, 2H), 7.21 (t, J = 8.4 Hz, 3H), 2.37 (s, 3H); 13C1H NMR (175 MHz, CDCl3) δ 156.3, 146.8 (q, JC-F = 33.9 Hz), 144.2, 137.9, 137.7, 137.0, 133.8, 130.3, 130.0, 128.6, 125.8, 123.6, 122.0, 121.9 (q, JC-F = 272.8 Hz), 121.2, 118.5 (q, JC-F = 2.3 Hz), 111.3, 20.9; IR (KBr) υ 3336, 2991, 2853, 1705, 1607, 15914, 1514, 1466, 1369, 1333, 1243, 1159, 1112, 1064, 851, 815 cm-1; HRMS (orbitrap, ESI) calcd for C20H15F3N3 [M+H]+ 354.1219, found 354.1218.46.0 mg (65%); yellow solid; mp = 212.5-213.2 ° C; 1H NMR (700 MHz, CDCl 3 ) δ 8.37 (d, J = 8.4 Hz, 1H), 7.99 (d, J = 9.1 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 8.4 Hz, 2H), 7.21 (t, J = 8.4 Hz, 3H), 2.37 (s, 3H) ; 13C1H NMR (175 MHz, CDCl 3 ) δ 156.3, 146.8 (q, JC-F = 33.9 Hz), 144.2, 137.9, 137.7, 137.0, 133.8, 130.3, 130.0, 128.6, 125.8, 123.6, 122.0, 121.9 (q, JC-F = 272.8 Hz), 121.2, 118.5 (q, JC-F = 2.3 Hz), 111.3, 20.9; IR (KBr) υ 3336, 2991, 2853, 1705, 1607, 15914, 1514, 1466, 1369, 1333, 1243, 1159, 1112, 1064, 851, 815 cm-1; HRMS (orbitrap, ESI) calcd for C 20 H 15 F 3 N 3 [M+H]+ 354.1219, found 354.1218.

3-15. 4-Phenyl-N-(p-3-15. 4-Phenyl-N-(p- tolyltolyl )) pyridinpyridin -2-amine (3o)-2-amine (3o)

18.1 mg (35%); 백색 고체; mp = 84.1-86.2 ℃; 1H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 7.56-7.55 (m, 2H), 7.46-7.41 (m, 2H), 7.26-7.23 (m, 4H), 7.17 (d, J = 8.4 Hz, 2H), 7.05 (s, 1H), 6.96 (s, 1H), 2.34 (s, 3H); 13C1H NMR (125 MHz, CDCl3) δ 156.9, 150.5, 148.3, 138.8, 137.6, 133.1, 129.9, 128.9, 128.8, 126.9, 121.5, 113.3, 105.5, 20.8; IR (KBr) υ 3392, 2855, 2803, 1655, 1558, 1522, 1451, 1333, 1322, 1188, 1111, 1025, 851 cm-1; HRMS (orbitrap, ESI) calcd for C18H17N2 [M+H]+ 261.1391, found 261.1390.18.1 mg (35%); white solid; mp = 84.1-86.2 °C; 1H NMR (400 MHz, CDCl 3 ) δ 8.19 (s, 1H), 7.56-7.55 (m, 2H), 7.46-7.41 (m, 2H), 7.26-7.23 (m, 4H), 7.17 (d, J = 8.4 Hz, 2H), 7.05 (s, 1H), 6.96 (s, 1H), 2.34 (s, 3H); 13C1H NMR (125 MHz, CDCl 3 ) δ 156.9, 150.5, 148.3, 138.8, 137.6, 133.1, 129.9, 128.9, 128.8, 126.9, 121.5, 113.3, 105.5, 20.8; IR (KBr) υ 3392, 2855, 2803, 1655, 1558, 1522, 1451, 1333, 1322, 1188, 1111, 1025, 851 cm -1 ; HRMS (orbitrap, ESI) calcd for C 18 H 17 N 2 [M+H]+ 261.1391, found 261.1390.

3-16. N-(p-3-16. N-(p- TolylTolyl )-[2,2'-)-[2,2'- bipyridinbipyridin ]-6-amine (3p)]-6-amine (3p)

26.2 mg (50%); 노란색 고체; mp = 85.0-86.8 ℃; 1H NMR (400 MHz, CDCl3) δ 8.67 (d, J = 8.4 Hz, 1H), 8.32 (d, J = 8.0 Hz, 1H), 7.82-7.79 (m, 2H), 7.61 (t, J = 8.0 Hz, 1H), 7.31-7.27 (m, 3H), 7.17 (d, J = 8.0 Hz, 2H), 6.83 (d, J = 8.4 Hz, 1H), 6.59 (brs, 1H), 2.34 (s, 3H); 13C1H NMR (100 MHz, CDCl3) δ 156.3, 155.8, 154.6, 149.1, 138.6, 137.8, 136.8, 132.5, 129.8, 123.4, 121.0, 120.8, 112.1, 108.3, 20.8; IR (KBr) υ 33947, 3310, 3054, 29250, 2852, 1596, 1581, 1564, 1511, 1454, 1428, 1342, 1296, 1247, 1156, 1100, 985, 812, 775 cm-1; HRMS (orbitrap, ESI) calcd for C17H16N3 [M+H]+ 262.1339, found 262.1338.26.2 mg (50%); yellow solid; mp = 85.0-86.8 °C; 1H NMR (400 MHz, CDCl 3 ) δ 8.67 (d, J = 8.4 Hz, 1H), 8.32 (d, J = 8.0 Hz, 1H), 7.82-7.79 (m, 2H), 7.61 (t, J = 8.0) Hz, 1H), 7.31-7.27 (m, 3H), 7.17 (d, J = 8.0 Hz, 2H), 6.83 (d, J = 8.4 Hz, 1H), 6.59 (brs, 1H), 2.34 (s, 3H) ); 13C1H NMR (100 MHz, CDCl 3 ) δ 156.3, 155.8, 154.6, 149.1, 138.6, 137.8, 136.8, 132.5, 129.8, 123.4, 121.0, 120.8, 112.1, 108.3, 20.8; IR (KBr) υ 33947, 3310, 3054, 29250, 2852, 1596, 1581, 1564, 1511, 1454, 1428, 1342, 1296, 1247, 1156, 1100, 985, 812, 775 cm-1; HRMS (orbitrap, ESI) calcd for C 17 H 16 N 3 [M+H]+ 262.1339, found 262.1338.

3-17. 4,4'-3-17. 4,4'- DimethylDimethyl -N-(p--N-(p- tolyltolyl )-[2,2'-)-[2,2'- bipyridinbipyridin ]-6-amine (3q)]-6-amine (3q)

33.1 mg (57%); 노란색 고체; mp = 102.0-103.2 ℃; 1H NMR (700 MHz, CDCl3) δ 8.61 (d, J = 4.9 Hz, 1H), 8.25 (t, J = 0.7 Hz, 1H), 7.75 (s, 1H), 7.61 (t, J = 8.0 Hz, 1H), 7.37-7.35 (m, 2H), 7.25 (d, J = 7.7 Hz, 2H), 7.19-7.18 (m, 1H), 6.51 (s, 1H), 6.65 (brs, 1H), 2.51 (s, 3H), 2.43 (s, 3H), 2.40 (s, 3H); 13C1H NMR (175 MHz, CDCl3) δ 156.1, 154.5, 149.7, 148.9, 147.8, 138.1, 132.5, 129.8, 124.3, 121.9, 121.1, 113.8, 108.4, 21.4, 21.3, 20.8; IR (KBr) υ 2923, 2854, 1597, 1563, 1513, 1453, 1404, 1291, 1186, 822 cm-1; HRMS (orbitrap, ESI) calcd for C19H20N3 [M+H]+ 290.1657, found 290.1654.33.1 mg (57%); yellow solid; mp = 102.0-103.2 °C; 1H NMR (700 MHz, CDCl 3 ) δ 8.61 (d, J = 4.9 Hz, 1H), 8.25 (t, J = 0.7 Hz, 1H), 7.75 (s, 1H), 7.61 (t, J = 8.0 Hz, 1H), 7.37-7.35 (m, 2H), 7.25 (d, J = 7.7 Hz, 2H), 7.19-7.18 (m, 1H), 6.51 (s, 1H), 6.65 (brs, 1H), 2.51 (s) , 3H), 2.43 (s, 3H), 2.40 (s, 3H); 13C1H NMR (175 MHz, CDCl 3 ) δ 156.1, 154.5, 149.7, 148.9, 147.8, 138.1, 132.5, 129.8, 124.3, 121.9, 121.1, 113.8, 108.4, 21.4, 21.3, 20.8; IR (KBr) υ 2923, 2854, 1597, 1563, 1513, 1453, 1404, 1291, 1186, 822 cm-1; HRMS (orbitrap, ESI) calcd for C 19 H 20 N 3 [M+H]+ 290.1657, found 290.1654.

3-18. N-(p-3-18. N-(p- TolylTolyl )) quinoxalinquinoxalin -2-amine (3r)-2-amine (3r)

20.3 mg (43%); 갈색 고체; mp = 167.5-170.2 ℃; 1H NMR (700 MHz, CDCl3) δ 8.42 (s, 1H), 7.91 (dd, J = 8.4, 1.4 Hz, 1H), 7.77 (dd, J = 8.4, 1.4 Hz, 1H), 7.62-7.60 (m, 1H), 7.56 (d, J = 8.4 Hz, 2H), 7.46-7.44 (m, 1H), 7.20 (d, J = 8.4 Hz, 2H), 6.90 (brs, 1H), 2.36 (s, 3H); 13C1H NMR (175 MHz, CDCl3) δ 149.6, 141.3, 138.2, 137.8, 136.4, 133.5, 130.2, 129.8, 128.8, 126.7, 125.3, 120.4, 20.8; IR (KBr) υ 3376, 1211, 3061, 2922, 2850, 1601, 1527, 1398, 1316, 1229, 1159, 1108, 1064, 1031, 831 cm-1; HRMS (orbitrap, ESI) calcd for C15H14N3 [M+H]+ 263.1187, found 263.1185.20.3 mg (43%); brown solid; mp = 167.5-170.2 °C; 1H NMR (700 MHz, CDCl 3 ) δ 8.42 (s, 1H), 7.91 (dd, J = 8.4, 1.4 Hz, 1H), 7.77 (dd, J = 8.4, 1.4 Hz, 1H), 7.62-7.60 (m) , 1H), 7.56 (d, J = 8.4 Hz, 2H), 7.46-7.44 (m, 1H), 7.20 (d, J = 8.4 Hz, 2H), 6.90 (brs, 1H), 2.36 (s, 3H) ; 13C1H NMR (175 MHz, CDCl 3 ) δ 149.6, 141.3, 138.2, 137.8, 136.4, 133.5, 130.2, 129.8, 128.8, 126.7, 125.3, 120.4, 20.8; IR (KBr) υ 3376, 1211, 3061, 2922, 2850, 1601, 1527, 1398, 1316, 1229, 1159, 1108, 1064, 1031, 831 cm-1; HRMS (orbitrap, ESI) calcd for C 15 H 14 N 3 [M+H]+ 263.1187, found 263.1185.

3-19. N-(p-3-19. N-(p- TolylTolyl )) isoquinolinisoquinolin -1-amine (3s)-1-amine (3s)

24.4 mg (52%); 갈색 고체; mp = 94.3-95.8 ℃; 1H NMR (700 MHz, CDCl3) δ 8.07 (d, J = 6.3 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.63 (t, J = 8.4 Hz, 1H), 7.54-7.51 (m, 3H), 7.17 (d, J = 8.4 Hz, 2H), 7.10 (d, J = 6.3 Hz, 2H), 7.06 (brs, 1H), 2.34 (s, 3H); 13C1H NMR (175 MHz, CDCl3) δ 152.6, 141.0, 137.7, 137.4, 132.4, 129.8, 129.5, 127.4, 126.3, 121.4, 120.8, 118.7, 113.0, 20.8; IR (KBr) υ 3297, 3049, 2917, 2851, 1709, 1624, 1595, 1509, 1393, 1321, 1230, 1143, 1057, 906, 862, 796 cm-1; HRMS (orbitrap, ESI) calcd for C16H15N2 [M+H]+ 235.1235, found 235.1231.24.4 mg (52%); brown solid; mp = 94.3-95.8 °C; 1H NMR (700 MHz, CDCl 3 ) δ 8.07 (d, J = 6.3 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.63 (t, J = 8.4 Hz, 1H), 7.54-7.51 (m, 3H), 7.17 (d, J = 8.4 Hz, 2H), 7.10 (d, J = 6.3 Hz, 2H), 7.06 (brs, 1H), 2.34 ( s, 3H); 13C1H NMR (175 MHz, CDCl 3 ) δ 152.6, 141.0, 137.7, 137.4, 132.4, 129.8, 129.5, 127.4, 126.3, 121.4, 120.8, 118.7, 113.0, 20.8; IR (KBr) υ 3297, 3049, 2917, 2851, 1709, 1624, 1595, 1509, 1393, 1321, 1230, 1143, 1057, 906, 862, 796 cm -1 ; HRMS (orbitrap, ESI) calcd for C 16 H 15 N 2 [M+H]+ 235.1235, found 235.1231.

3-20. N-(p-3-20. N-(p- TolylTolyl )) phthalazinphthalazin -1-amine (3t)-1-amine (3t)

10.4 mg (22%); 노란색 고체; mp = 102.9-105.2 ℃; 1H NMR (400 MHz, CD3OD) δ 8.94 (s, 1H), 8.41 (d, J = 8.0 Hz, 1H), 7.99-7.90 (m, 3H), 7.56 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H), 2.33 (s, 3H); 13C1H NMR (100 MHz, CD3OD) δ 154.7, 145.9, 138.8, 134.2, 133.6, 133.4, 130.2, 129.3, 128.0, 123.2, 123.0, 120.7, 20.9; IR (KBr) υ 3077, 3059, 2915, 1854, 1622, 1602, 1514, 1455, 1408, 1271, 1155, 817 cm-1; HRMS (orbitrap, ESI) calcd for C15H14N3 [M+H]+ 236.1183, found 236.1185.10.4 mg (22%); yellow solid; mp = 102.9-105.2 °C; 1H NMR (400 MHz, CDOD) δ 8.94 (s, 1H), 8.41 (d, J = 8.0 Hz, 1H), 7.99-7.90 (m, 3H), 7.56 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H), 2.33 (s, 3H); 13C1H NMR (100 MHz, CDOD) δ 154.7, 145.9, 138.8, 134.2, 133.6, 133.4, 130.2, 129.3, 128.0, 123.2, 123.0, 120.7, 20.9; IR (KBr) υ 3077, 3059, 2915, 1854, 1622, 1602, 1514, 1455, 1408, 1271, 1155, 817 cm-1; HRMS (orbitrap, ESI) calcd for C 15 H 14 N 3 [M+H]+ 236.1183, found 236.1185.

3-21. 6-3-21. 6- MethoxyMethoxy -N--N- phenylquinolinphenylquinoline -2-amine (4b)-2-amine (4b)

46.1 mg (92%); 갈색 고체; mp = 97.5-100.2 ℃; 1H NMR (700 MHz, CDCl3) δ 7.83 (d, J = 9.1 Hz, 1H), 7.72 (d, J = 9.1, Hz, 1H), 7.53 (dd, J = 8.4, 1.4 Hz, 2H), 7.35 (dd, J = 8.4, 7.0 Hz, 2H), 7.27 (dd, J = 9.1, 2.8 Hz, 1H), 7.06 (t, J = 7.0, Hz, 1H), 6.99-6.97 (m, 2H), 6.87 (brs, 1H), 3.88 (s, 3H); 13C1H NMR (175 MHz, CDCl3) δ 155.5, 152.9, 143.1, 140.5, 136.6, 129.1, 128.0, 124.6, 122.6, 121.3, 119.9, 111.9, 106.2, 55.4; IR (KBr) υ 3041, 3053, 3004, 2961, 1595, 1525, 1486, 1360, 1320, 1229, 1161, 1111, 1027, 996, 853, 829 cm-1; HRMS (orbitrap, ESI) calcd for C16H15N2O [M+H]+ 251.1184, found 251.1186.46.1 mg (92%); brown solid; mp = 97.5-100.2 °C; 1H NMR (700 MHz, CDCl 3 ) δ 7.83 (d, J = 9.1 Hz, 1H), 7.72 (d, J = 9.1, Hz, 1H), 7.53 (dd, J = 8.4, 1.4 Hz, 2H), 7.35 (dd, J = 8.4, 7.0 Hz, 2H), 7.27 (dd, J = 9.1, 2.8 Hz, 1H), 7.06 (t, J = 7.0, Hz, 1H), 6.99-6.97 (m, 2H), 6.87 (brs, 1H), 3.88 (s, 3H); 13C1H NMR (175 MHz, CDCl 3 ) δ 155.5, 152.9, 143.1, 140.5, 136.6, 129.1, 128.0, 124.6, 122.6, 121.3, 119.9, 111.9, 106.2, 55.4; IR (KBr) υ 3041, 3053, 3004, 2961, 1595, 1525, 1486, 1360, 1320, 1229, 1161, 1111, 1027, 996, 853, 829 cm-1; HRMS (orbitrap, ESI) calcd for C 16 H 15 N 2 O [M+H]+ 251.1184, found 251.1186.

3-22. N-(4-(3-22. N-(4-( terttert -Butyl)phenyl)-6--Butyl)phenyl)-6- methoxyquinolinmethoxyquinolin -2-amine (4c)-2-amine (4c)

52.1 mg (85%); 갈색 고체; mp = 187.2-190.1 ℃; 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 8.8, Hz, 1H), 7.42-7.36 (m, 4H), 7.28-7.26 (m, 1H), 7.00-6.98 (m, 1H), 3.88 (s, 3H), 1.33 (s, 9H); 13C1H NMR (100 MHz, CDCl3) δ 155.6, 153.0, 146.4, 161.8, 137.4, 137.1, 127.0, 126.1, 124.2, 121.6, 120.7, 111.6, 106.4, 55.5, 34.3, 31.4; IR (KBr) υ 3392, 2958, 2903, 2865, 1655, 1589, 1521, 1461, 1397, 1361, 1322, 1265, 1230, 1193, 1111, 1033, 831, 738 cm-1; HRMS (orbitrap, ESI) calcd for C20H23N2O [M+H]+ 307.1805, found 307.1803.52.1 mg (85%); brown solid; mp = 187.2-190.1 °C; 1H NMR (400 MHz, CDCl 3 ) δ 7.84 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 8.8, Hz, 1H), 7.42-7.36 (m, 4H), 7.28-7.26 (m, 1H), 7.00-6.98 (m, 1H), 3.88 (s, 3H), 1.33 (s, 9H); 13C1H NMR (100 MHz, CDCl 3 ) δ 155.6, 153.0, 146.4, 161.8, 137.4, 137.1, 127.0, 126.1, 124.2, 121.6, 120.7, 111.6, 106.4, 55.5, 34.3, 31.4; IR (KBr) υ 3392, 2958, 2903, 2865, 1655, 1589, 1521, 1461, 1397, 1361, 1322, 1265, 1230, 1193, 1111, 1033, 831, 738 cm-1; HRMS (orbitrap, ESI) calcd for C 20 H 23 N 2 O [M+H]+ 307.1805, found 307.1803.

3-23. 6-3-23. 6- MethoxyMethoxy -N-(4-(-N-(4-( trifluoromethyltrifluoromethyl )phenyl))phenyl) quinolinquinolin -2-amine (4d)-2-amine (4d)

24.2 mg (38%); 노란색 고체; mp = 142.9-145.1 ℃ 1H NMR (700 MHz, CDCl3) δ 7.91 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 9.1, Hz, 1H), 7.73 (d, J = 8.4, Hz, 2H), 7.58 (d, J = 8.4, Hz, 2H), 7.30 (dd, J = 9.1, 2.8 Hz, 1H), 7.02 (d, J = 2.8 Hz, 1H), 6.97 (d, J = 8.4, Hz, 1H), 3.90 (s, 3H); 13C1H NMR (175 MHz, CDCl3) δ 156.1, 151.6, 143.8, 142.6, 137.1, 128.3, 126.4 (q, JC-F = 3.3 Hz), 124.9, 124.4 (q, JC-F = 268.9 Hz), 123.5 (q, JC-F = 31.6 Hz), 121.8, 118.1, 112.7, 106.1, 55.5; IR (KBr) υ 3299, 3193, 3127, 3060, 2921, 2854, 1688, 1613, 1582, 1537, 1510, 1414, 1321, 1242, 1019, 813, 756 cm-1; HRMS (orbitrap, ESI) calcd for C17H14F3N2O [M+H]+ 319.1058, found 319.1053.24.2 mg (38%); yellow solid; mp = 142.9-145.1 °C 1H NMR (700 MHz, CDCl 3 ) δ 7.91 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 9.1, Hz, 1H), 7.73 (d, J = 8.4, Hz) , 2H), 7.58 (d, J = 8.4, Hz, 2H), 7.30 (dd, J = 9.1, 2.8 Hz, 1H), 7.02 (d, J = 2.8 Hz, 1H), 6.97 (d, J = 8.4) , Hz, 1H), 3.90 (s, 3H); 13C1H NMR (175 MHz, CDCl 3 ) δ 156.1, 151.6, 143.8, 142.6, 137.1, 128.3, 126.4 (q, JC-F = 3.3 Hz), 124.9, 124.4 (q, JC-F = 268.9 Hz), 123.5 ( q, JC-F = 31.6 Hz), 121.8, 118.1, 112.7, 106.1, 55.5; IR (KBr) υ 3299, 3193, 3127, 3060, 2921, 2854, 1688, 1613, 1582, 1537, 1510, 1414, 1321, 1242, 1019, 813, 756 cm-1; HRMS (orbitrap, ESI) calcd for C 17 H 14 F 3 N 2 O [M+H]+ 319.1058, found 319.1053.

3-24. 6-3-24. 6- MethoxyMethoxy -N-(m--N-(m- tolyltolyl )) quinolinquinolin -2-amine (4e)-2-amine (4e)

50.3 mg (95%); 노란색 고체; mp = 109.9-110.2 ℃; 1H NMR (700 MHz, CDCl3) δ 7.83 (d, J = 8.4, Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.29 (brs, 1H), 7.27 (d, J = 2.8 Hz, 1H), 7.26 (d, J = 2.8 Hz, 1H), 7.23 (t, J = 7.7 Hz, 1H), 7.00-6.99 (m, 2H), 6.89 (d, J = 7.7 Hz, 1H), 6.81 (brs, 1H), 3.89 (s, 3H), 2.36 (s, 3H); 13C1H NMR (175 MHz, CDCl3) δ 155.5, 153.0, 143.1, 140.4, 139.0, 136.7, 129.0, 128.0, 124.5, 123.6, 121.4, 120.8, 117.2, 111.9, 106.2, 55.5, 21.5; IR (KBr) υ 3394, 3046, 2995, 2922, 2853, 1697, 1571, 1538, 1331, 1263, 1113, 1031, 848, 827, 773, 687 cm-1; HRMS (orbitrap, ESI) calcd for C17H17N2O [M+H]+ 265.1341, found 265.1341.50.3 mg (95%); yellow solid; mp = 109.9-110.2 °C; 1H NMR (700 MHz, CDCl 3 ) δ 7.83 (d, J = 8.4, Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.29 (brs) , 1H), 7.27 (d, J = 2.8 Hz, 1H), 7.26 (d, J = 2.8 Hz, 1H), 7.23 (t, J = 7.7 Hz, 1H), 7.00-6.99 (m, 2H), 6.89 (d, J = 7.7 Hz, 1H), 6.81 (brs, 1H), 3.89 (s, 3H), 2.36 (s, 3H); 13C1H NMR (175 MHz, CDCl 3 ) δ 155.5, 153.0, 143.1, 140.4, 139.0, 136.7, 129.0, 128.0, 124.5, 123.6, 121.4, 120.8, 117.2, 111.9, 106.2, 55.5, 21.5; IR (KBr) υ 3394, 3046, 2995, 2922, 2853, 1697, 1571, 1538, 1331, 1263, 1113, 1031, 848, 827, 773, 687 cm-1; HRMS (orbitrap, ESI) calcd for C 17 H 17 N 2 O [M+H]+ 265.1341, found 265.1341.

3-25. N-(3,4-3-25. N-(3,4- DimethoxyphenylDimethoxyphenyl )-6-)-6- methoxyquinolinmethoxyquinolin -2-amine (4f)-2-amine (4f)

47.2 mg (76%); 노란색 고체; mp = 159.7-161.2 ℃; 1H NMR (500 MHz, CDCl3) δ 7.81 (d, J = 9.0 Hz, 1H), 7.66 (d, J = 9.0 Hz, 1H), 7.26-7.24 (m, 2H), 6.98 (d, J = 2.5 Hz, 1H), 6.94 (dd, J = 8.5, 2.5 Hz, 1H), 6.89-6.82 (m, 3H), 3.90-3.88 (m, 9H); 13C1H NMR (125 MHz, CDCl3) δ 155.4, 153.7, 149.3, 145.4, 142.8, 136.8, 133.8, 127.6, 124.3, 121.4, 113.4, 111.8, 111.5, 106.5, 106.3, 56.2, 55.9, 55.5; IR (KBr) υ 3372, 2996, 2928, 2853, 1641, 1462, 1401, 1362, 1227, 1161, 1132, 1113, 1027, 831, 743 cm-1; HRMS (or-bitrap, ESI) calcd for C18H19N2O3 [M+H]+ 311.1390, found 311.1389.47.2 mg (76%); yellow solid; mp = 159.7-161.2 ° C; 1H NMR (500 MHz, CDCl 3 ) δ 7.81 (d, J = 9.0 Hz, 1H), 7.66 (d, J = 9.0 Hz, 1H), 7.26-7.24 (m, 2H), 6.98 (d, J = 2.5) Hz, 1H), 6.94 (dd, J = 8.5, 2.5 Hz, 1H), 6.89-6.82 (m, 3H), 3.90-3.88 (m, 9H); 13C1H NMR (125 MHz, CDCl 3 ) δ 155.4, 153.7, 149.3, 145.4, 142.8, 136.8, 133.8, 127.6, 124.3, 121.4, 113.4, 111.8, 111.5, 106.5, 106.3, 56.2, 55.9, 55.5; IR (KBr) υ 3372, 2996, 2928, 2853, 1641, 1462, 1401, 1362, 1227, 1161, 1132, 1113, 1027, 831, 743 cm-1; HRMS (or-bitrap, ESI) calcd for C 18 H 19 N 2 O 3 [M+H]+ 311.1390, found 311.1389.

3-26. N-(3-3-26. N-(3- BromoBromo -4--4- methylphenylmethylphenyl )-6-)-6- methoxyquinolinmethoxyquinolin -2-amine (4g)-2-amine (4g)

55.6 mg (81%); 노란색 고체; mp = 129.1-130.1 ℃; 1H NMR (400 MHz, CDCl3) δ 7.85-7.83 (m, 2H), 7.72 (d, J = 9.2 Hz, 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.28-7.26 (m, 1H), 7.17 (d, J = 8.0 Hz, 1H), 6.99 (s, 1H), 6.90 (d, J = 8.8 Hz, 1H), 6.69 (brs, 1H), 3.89 (s, 3H), 2.36 (s, 3H); 13C1H NMR (100 MHz, CDCl3) δ 155.6, 152.4, 142.9, 139.4, 136.8, 131.6, 130.8, 128.2, 124.9, 124.6, 123.3, 121.5, 118.8, 112.0, 106.1, 55.5, 22.1; IR (KBr) υ 3406, 2923, 2853, 1617, 1566, 1539, 1422, 1393, 1229, 1161, 1113, 1032, 995, 829, 807 cm-1; HRMS (orbitrap, ESI) calcd for C17H16BrN2O [M+H]+ 343.0441, found 343.0441.55.6 mg (81%); yellow solid; mp = 129.1-130.1 °C; 1H NMR (400 MHz, CDCl 3 ) δ 7.85-7.83 (m, 2H), 7.72 (d, J = 9.2 Hz, 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.28-7.26 (m, 1H) ), 7.17 (d, J = 8.0 Hz, 1H), 6.99 (s, 1H), 6.90 (d, J = 8.8 Hz, 1H), 6.69 (brs, 1H), 3.89 (s, 3H), 2.36 (s) , 3H); 13C1H NMR (100 MHz, CDCl 3 ) δ 155.6, 152.4, 142.9, 139.4, 136.8, 131.6, 130.8, 128.2, 124.9, 124.6, 123.3, 121.5, 118.8, 112.0, 106.1, 55.5, 22.1; IR (KBr) υ 3406, 2923, 2853, 1617, 1566, 1539, 1422, 1393, 1229, 1161, 1113, 1032, 995, 829, 807 cm-1; HRMS (orbitrap, ESI) calcd for C 17 H 16 BrN 2 O [M+H]+ 343.0441, found 343.0441.

3-27. 6-3-27. 6- MethoxyMethoxy -N-(-N-( naphthalennaphthalen -2--2- ylyl )) quinolinquinolin -2-amine (4h)-2-amine (4h)

48.1 mg (80%); 갈색 고체; mp = 190.1-192.2 ℃; 1H NMR (500 MHz, CDCl3) δ 8.14 (s, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.82-7.76 (m, 4H), 7.52-7.44 (m, 2H), 7.39-7.35 (m, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.08 (d, J = 8.4 Hz, 1H), 7.02 (s, 1H), 3.90 (s, 3H); 13C1H NMR (125 MHz, CDCl3) δ 152.8, 141.2, 140.8, 136.9, 134.3, 130.0, 129.0, 127.9, 127.6, 127.1, 126.4, 124.7, 124.2, 121.6, 121.2, 121.1, 115.3, 112.1, 106.2, 55.5; IR (KBr) υ 3398, 3055, 2948, 1678, 1586, 1531, 1361, 1240, 1229, 1162, 1113, 1032, 952, 848, 831, 813 cm-1; HRMS (orbitrap, ESI) calcd for C20H17N2O [M+H]+ 301.1341, found 301.1338.48.1 mg (80%); brown solid; mp = 190.1-192.2 °C; 1H NMR (500 MHz, CDCl 3 ) δ 8.14 (s, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.82-7.76 (m, 4H), 7.52-7.44 (m, 2H), 7.39-7.35 (m, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.08 (d, J = 8.4 Hz, 1H), 7.02 (s, 1H), 3.90 (s, 3H); 13C1H NMR (125 MHz, CDCl 3 ) δ 152.8, 141.2, 140.8, 136.9, 134.3, 130.0, 129.0, 127.9, 127.6, 127.1, 126.4, 124.7, 124.2, 121.6, 121.2, 121.1, 115.3, 112.1, 106.2, 55.5; IR (KBr) υ 3398, 3055, 2948, 1678, 1586, 1531, 1361, 1240, 1229, 1162, 1113, 1032, 952, 848, 831, 813 cm-1; HRMS (orbitrap, ESI) calcd for C 20 H 17 N 2 O [M+H]+ 301.1341, found 301.1338.

3-28. 6-3-28. 6- MethoxyMethoxy -N-(-N-( pyridinpyridin -3--3- ylyl )) quinolinquinolin -2-amine (4i)-2-amine (4i)

17.6 mg (35%); 갈색 고체; mp = 167.5-170.2 ℃; 1H NMR (400 MHz, CD3OD + CDCl3) δ 8.95 (s, 1H), 8.48 (d, J = 8.4 Hz, 1H), 8.07 (s, 1H), 7.93 (d, J = 8.8 Hz, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.34 (dd, J = 8.0, 4.8 Hz, 1H), 7.23 (dd, J = 8.8, 2.8 Hz, 1H), 7.08 (d, J = 2.4 Hz, 1H), 6.97 (d, J = 8.8 Hz, 1H), 3.88 (s, 3H); 13C1H NMR (100 MHz, CD3OD+CDCl3) δ 156.9, 153.5, 143.3, 141.5, 140.2, 137.7, 128.7, 126.6, 125.7, 124.9, 124.8, 121.9, 114.6, 107.1, 55.8; IR (KBr) υ 3295, 3193, 2949, 2924, 2852, 1616, 1543, 1471, 1409, 1363, 1292, 1235, 1162, 1116, 1030, 830, 802 cm-1; HRMS (orbitrap, ESI) calcd for C15H14N3O [M+H]+ 252.1136, found 252.1135.17.6 mg (35%); brown solid; mp = 167.5-170.2 °C; 1H NMR (400 MHz, CDOD + CDCl 3 ) δ 8.95 (s, 1H), 8.48 (d, J = 8.4 Hz, 1H), 8.07 (s, 1H), 7.93 (d, J = 8.8 Hz, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.34 (dd, J = 8.0, 4.8 Hz, 1H), 7.23 (dd, J = 8.8, 2.8 Hz, 1H), 7.08 (d, J = 2.4 Hz, 1H) ), 6.97 (d, J = 8.8 Hz, 1H), 3.88 (s, 3H); 13C1H NMR (100 MHz, CD3OD+CDCl 3 ) δ 156.9, 153.5, 143.3, 141.5, 140.2, 137.7, 128.7, 126.6, 125.7, 124.9, 124.8, 121.9, 114.6, 107.1, 55.8; IR (KBr) υ 3295, 3193, 2949, 2924, 2852, 1616, 1543, 1471, 1409, 1363, 1292, 1235, 1162, 1116, 1030, 830, 802 cm-1; HRMS (orbitrap, ESI) calcd for C 15 H 14 N 3 O [M+H]+ 252.1136, found 252.1135.

3-29. N-((3-29. N-(( 3S,5S,7S3S, 5S, 7S )-)- AdamantanAdamantan -1--One- ylyl )-6-)-6- methoxyquinolinmethoxyquinolin -2-amine (4j)-2-amine (4j)

22.3 mg (36%); 노란색 고체; mp = 102.6-103.2 ℃; 1H NMR (400 MHz, CDCl3) δ 11.4 (s, 1H), 8.67 (d, J = 8.8 Hz, 1H), 8.35 (d, J = 8.8 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.42 (d, J = 9.2 Hz, 1H), 7.11 (s, 1H), 3.96 (s, 3H), 2.21 (s, 6H), 2.13 (s, 3H), 1.78-1.70 (m, 6H); 13C1H NMR (100 MHz, CDCl3) δ 160.2, 158.8, 137.1, 132.3, 125.6, 123.4, 123.1, 121.7, 105.8, 55.8, 52.2, 41.4, 36.4, 29.4; IR (KBr) υ 2899, 2842, 2107, 1665, 1618, 1545, 1457, 1376, 1244, 1185, 1026, 852 cm-1; HRMS (orbitrap, ESI) calcd for C20H25N2O [M+H]+ 309.1962, found 309.1962.22.3 mg (36%); yellow solid; mp = 102.6-103.2 °C; 1H NMR (400 MHz, CDCl 3 ) δ 11.4 (s, 1H), 8.67 (d, J = 8.8 Hz, 1H), 8.35 (d, J = 8.8 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.42 (d, J = 9.2 Hz, 1H), 7.11 (s, 1H), 3.96 (s, 3H), 2.21 (s, 6H), 2.13 (s, 3H), 1.78-1.70 (m, 6H) ); 13C1H NMR (100 MHz, CDCl 3 ) δ 160.2, 158.8, 137.1, 132.3, 125.6, 123.4, 123.1, 121.7, 105.8, 55.8, 52.2, 41.4, 36.4, 29.4; IR (KBr) υ 2899, 2842, 2107, 1665, 1618, 1545, 1457, 1376, 1244, 1185, 1026, 852 cm-1; HRMS (orbitrap, ESI) calcd for C 20 H 25 N 2 O [M+H]+ 309.1962, found 309.1962.

3-30. 6-3-30. 6- MethoxyMethoxy -4-((1S)--4-((1S)- methoxy((1S,4S,5R)methoxy((1S,4S,5R) -5--5- vinylquinuclidinvinylquinucliden -2--2- ylyl )methyl)-N-(p-tolyl)quinolin-2-amine (6a))methyl)-N-(p-tolyl)quinolin-2-amine (6a)

63.9 mg (72%); 갈색 고체; mp = 267.5-270.2 ℃; 1H NMR (500 MHz, CDCl3) δ 7.74 (d, J = 9.0 Hz, 1H), 7.42 (d, J = 8.0 Hz, 2H), 7.26-7.24 (m, 1H), 7.18-7.14 (m, 3H), 7.04 (s, 1H), 6.66 (brs, 1H), 6.09-6.02 (m, 1H), 5.09-4.98 (m, 3H), 3.89 (s, 3H), 3.33 (s, 3H), 3.30-3.28 (m, 1H), 3.02-2.88 (m, 3H), 2.81-2.75 (m, 3H), 2.34 (s, 3H), 2.26-2.21 (m, 1H), 2.04-2.00 (m, 1H), 1.74 (s, 1H), 1.52-1.46 (m, 1H), 1.16 (brs, 1H); 13C1H NMR (175 MHz, CDCl3) δ 155.4, 152.8, 146.0, 143.8, 140.8, 138.1, 131.9, 129.6, 129.0, 122.8, 120.7, 119.7, 114.3, 109.3, 102.4, 83.5, 59.4, 57.2, 55.6, 50.2, 49.6, 40.2, 28.3, 26.5, 21.2, 20.8; IR (KBr) υ 2923, 2867, 1714, 1641, 1577, 1528, 1404, 1348, 1263, 1236, 1171, 1120, 1035, 916, 815 cm-1; HRMS (orbitrap, ESI) calcd for C28H34N3O2 [M+H]+ 444.2646, found 444.2646.63.9 mg (72%); brown solid; mp = 267.5-270.2 ° C; 1H NMR (500 MHz, CDCl 3 ) δ 7.74 (d, J = 9.0 Hz, 1H), 7.42 (d, J = 8.0 Hz, 2H), 7.26-7.24 (m, 1H), 7.18-7.14 (m, 3H) ), 7.04 (s, 1H), 6.66 (brs, 1H), 6.09-6.02 (m, 1H), 5.09-4.98 (m, 3H), 3.89 (s, 3H), 3.33 (s, 3H), 3.30- 3.28 (m, 1H), 3.02-2.88 (m, 3H), 2.81-2.75 (m, 3H), 2.34 (s, 3H), 2.26-2.21 (m, 1H), 2.04-2.00 (m, 1H), 1.74 (s, 1H), 1.52-1.46 (m, 1H), 1.16 (brs, 1H); 13C1H NMR (175 MHz, CDCl 3 ) δ 155.4, 152.8, 146.0, 143.8, 140.8, 138.1, 131.9, 129.6, 129.0, 122.8, 120.7, 119.7, 114.3, 109.3, 102.4, 83.5, 59.4, 57.2, 55.6, 50.2, 49.6, 40.2, 28.3, 26.5, 21.2, 20.8; IR (KBr) υ 2923, 2867, 1714, 1641, 1577, 1528, 1404, 1348, 1263, 1236, 1171, 1120, 1035, 916, 815 cm-1; HRMS (orbitrap, ESI) calcd for C 28 H 34 N 3 O 2 [M+H]+ 444.2646, found 444.2646.

3-31. Benzyl 4-((1-(p-3-31. Benzyl 4-((1-(p- tolylaminotolylamino )) isoquinolinisoquinolin -5--5- ylyl )) sulfonylsulfonyl )-1,4-)-1,4- diazepanediazepane -1--One- carboxylatecarboxylate (6b) (6b)

63.9 mg (60%); 갈색 고체; mp = 187.1-190.6 ℃; 1H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 8.81 (d, J = 8.4 Hz, 1H), 8.24-8.21 (m, 1H), 8.09 (t, J = 5.2 Hz, 1H), 7.73-7.60 (m, 4H), 7.37-7.29 (m, 5H), 7.14 (d, J = 8.0 Hz, 2H), 5.02 (s, 2H), 3.53-3.37 (m, 8H), 2.28 (s, 3H), 1.72 (brs, 2H); 13C1H NMR (175 MHz, DMSO-d6) δ 154.8, 153.6, 143.1, 138.0, 136.8, 132.8, 131.8, 129.0, 128.7, 128.4, 127.8, 127.4, 124.8, 121.3, 119.8, 119.2, 108.1, 79.1, 66.2, 47.9, 28.8, 28.5, 20.5; IR (KBr) υ 3030, 2933, 2854, 1689, 1614, 1527, 1455, 1419, 1372, 1227, 1153, 1121, 1041, 980, 905, 810 cm-1; HRMS (orbitrap, ESI) calcd for C29H31N4O4S [M+H]+ 531.2061, found 531.2061. developed protocol. 63.9 mg (60%); brown solid; mp = 187.1-190.6 °C; 1H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 8.81 (d, J = 8.4 Hz, 1H), 8.24-8.21 (m, 1H), 8.09 (t, J = 5.2 Hz, 1H) , 7.73-7.60 (m, 4H), 7.37-7.29 (m, 5H), 7.14 (d, J = 8.0 Hz, 2H), 5.02 (s, 2H), 3.53-3.37 (m, 8H), 2.28 (s) , 3H), 1.72 (brs, 2H); 13C1H NMR (175 MHz, DMSO-d6) δ 154.8, 153.6, 143.1, 138.0, 136.8, 132.8, 131.8, 129.0, 128.7, 128.4, 127.8, 127.4, 124.8, 121.3, 119.8, 119.2, 108.1, 79.1, 66.2, 47.9 , 28.8, 28.5, 20.5; IR (KBr) υ 3030, 2933, 2854, 1689, 1614, 1527, 1455, 1419, 1372, 1227, 1153, 1121, 1041, 980, 905, 810 cm-1; HRMS (orbitrap, ESI) calcd for C 29 H 31 N 4 O 4 S [M+H]+ 531.2061, found 531.2061. developed protocol.

실시예Example 4. 그램 규모 실험 4. Gram Scale Experiments

4-메틸 벤조일 아자이드 (2a) (2.9g, 18mmol, 300mol %) 및 t-부틸 메틸 에테르 (5mL)를 실온에서 공기로 충전한 건조된 밀봉 튜브에. 반응 혼합물을 110 ℃에서 2 시간 동안 교반하고, 실온으로 냉각시켰다. 이어서, 반응 혼합물에 퀴놀린 N-옥사이드 (1a) (1.0 g, 6 mmol, 100 mol %) 및 KOtBu (1.35 g, 12 mmol, 200 mol %)를 실온에서 공기 중에서 첨가 하였다. 반응 혼합물을 130 ℃에서 18 시간 동안 교반하고, 실온으로 냉각시켰다. 반응 혼합물을 셀라이트를 통해 여과하고 디클로로 메탄 (80 mL)으로 세척하였다. 여액을 감압 하에 농축시켰다. 잔류물을 플래쉬 컬럼 크로마토그래피 (n-헥산 / EtOAc = 3 : 1)로 정제하여 86 % 수율로 1.21 g의 3a를 수득하였다.4-methyl benzoyl azide (2a) (2.9 g, 18 mmol, 300 mol %) and t-butyl methyl ether (5 mL) were charged at room temperature with air in a dry sealed tube. The reaction mixture was stirred at 110 °C for 2 h and cooled to room temperature. Then to the reaction mixture were added quinoline N-oxide (1a) (1.0 g, 6 mmol, 100 mol %) and KOtBu (1.35 g, 12 mmol, 200 mol %) at room temperature in air. The reaction mixture was stirred at 130 °C for 18 h and cooled to room temperature. The reaction mixture was filtered through celite and washed with dichloromethane (80 mL). The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (n-hexane / EtOAc = 3 : 1) to give 1.21 g of 3a in 86 % yield.

실시예Example 5. 8-((4- 5. 8-((4- MethylphenylMethylphenyl )) sulfonamidosulfonamido )) quinolinequinoline N-oxide (7a) 합성 및 구조 분석 N-oxide (7a) synthesis and structural analysis

퀴놀린 N-옥사이드 (1a) (29.0 mg, 0.2 mmol, 100 mol %)로 충전된 건조 밀봉된 튜브에, [IrCp*Cl2]2 (3.2 mg, 0.004 mmol, 2.0 mol %), AcOH (3.6 mg, 0.06 mmol, 30 mol %) 및 4-메틸 벤젠 설포닐 아자이드 (59.2 mg, 0.3 mmol, 150 mol %) 를 실온, 공기 중에서 AgNTf2 (7.8 mg, 0.02 mmol, 10 mol %) 및 DCE (0.5 mL)에 첨가하였다. 반응 혼합물을 50 ℃에서 12 시간 동안 교반하고, 실온으로 냉각시켰다. 반응 혼합물을 EtOAc (3 mL)로 희석하고 진공에서 농축시켰다. 잔류물을 플래쉬 컬럼 크로마토그래피 (n-헥산 / EtOAc = 8 : 1)로 정제하여 88 % 수율로 55.4 mg의 7a를 수득하였다.Quinoline N- oxide (1a) (29.0 mg, 0.2 mmol, 100 mol%) in a dry sealed tube charged with, [IrCp * Cl2] 2 ( 3.2 mg, 0.004 mmol, 2.0 mol%), AcOH (3.6 mg, 0.06 mmol, 30 mol %) and 4-methyl benzene sulfonyl azide (59.2 mg, 0.3 mmol, 150 mol %) were dissolved in AgNTf2 (7.8 mg, 0.02 mmol, 10 mol %) and DCE (0.5 mL) at room temperature, in air. was added to The reaction mixture was stirred at 50 °C for 12 h and cooled to room temperature. The reaction mixture was diluted with EtOAc (3 mL) and concentrated in vacuo. The residue was purified by flash column chromatography (n-hexane / EtOAc = 8 : 1) to give 55.4 mg of 7a in 88 % yield.

7a의 NMR 분석 결과는 다음과 같다 : The results of NMR analysis of 7a are as follows:

55.4 mg (88%); 갈색 고체; mp = 177.3-180.2 oC; 1H NMR (400 MHz, CDCl3)δ14.41 (s, 1H), 8.31 (d, J = 6.0 Hz, 1H), 7.87-7.83 (m, 3H), 7.45 (d, J = 8.4 Hz, 1H), 7.49-7.41 (m, 2H), 7.29-7.23 (m, 1H), 7.21 (d, J = 8.0 Hz, 2H), 2.34 (s, 3H); 13C1HNMR (100 MHz, CDCl3)δ143.6,136.9,136.6,133.7,132.3,131.0,129.5,129.1,128.9,127.3,122.2,120.8,117.8,21.4; IR (KBr) υ 3065, 2924, 1659, 1580, 1521, 1458, 1392, 1317, 1277, 1190, 1155, 1087, 889, 814, 746 cm-1; HRMS (orbitrap, ESI) calcd for C16H15N2O3S [M+H]+ 315.0803, found 315.0802.55.4 mg (88%); brown solid; mp = 177.3-180.2 o C; 1 H NMR (400 MHz, CDCl 3 )δ 14.41 (s, 1H), 8.31 (d, J = 6.0 Hz, 1H), 7.87-7.83 (m, 3H), 7.45 (d, J = 8.4 Hz, 1H) ), 7.49-7.41 (m, 2H), 7.29-7.23 (m, 1H), 7.21 (d, J = 8.0 Hz, 2H), 2.34 (s, 3H); 13 C 1 HNMR (100 MHz, CDCl 3 )δ 143.6,136.9,136.6,133.7,132.3,131.0,129.5,129.1,128.9,127.3,122.2,120.8,117.8,21.4; IR (KBr) υ 3065, 2924, 1659, 1580, 1521, 1458, 1392, 1317, 1277, 1190, 1155, 1087, 889, 814, 746 cm -1 ; HRMS (orbitrap, ESI) calcd for C 16 H 15 N 2 O 3 S [M+H] + 315.0803, found 315.0802.

실시예Example 6. 4-Methyl-N-(2-(p- 6. 4-Methyl-N-(2-(p- tolylaminotolylamino )) quinolinquinolin -8--8- ylyl )) benzenesulfonamidebenzenesulfonamide (7b) 합성 및 구조 분석 (7b) synthesis and structural analysis

4-메틸 벤조일 아자이드 (2a) (96.7 mg, 0.6 mmol, 300 mol %) 및 t- 부틸 메틸 에테르 (1 mL)를 실온에서 공기로 충전한 오븐-건조 밀봉된 튜브에, 반응 혼합물을 110 ℃에서 2 시간 동안 교반하고 실온으로 냉각시켰다. 이어서, 반응 혼합물에 8-((4-메틸페닐)설폰아미도)퀴놀린N-옥사이드 (7a) (62.9 mg, 0.2 mmol, 100 mol %) 및 KOtBu (44.9 mg, 0.4 mmol, 200 mol %) 반응 혼합물을 실온에서 공기 중에 첨가하였다. 130 ℃에서 18 시간 동안 교반하고, 실온에서 냉각시켰다. 반응 혼합물을 셀라이트를 통해 여과하고 디클로로메탄 (10 mL)으로 세척하였다. 여액은 감압하에 농축시켰다. 잔류물을 플래쉬 컬럼 크로마토그래피 (n- 헥산 / EtOAc = 1 : 1)로 정제하여 57 % 수율로 46.0 mg의 7b를 수득하였다.In an oven-dried sealed tube filled with 4-methyl benzoyl azide (2a) (96.7 mg, 0.6 mmol, 300 mol %) and t-butyl methyl ether (1 mL) with air at room temperature, the reaction mixture was placed at 110 °C. stirred for 2 h and cooled to room temperature. Then, in the reaction mixture 8-((4-methylphenyl)sulfonamido)quinolineN-oxide (7a) (62.9 mg, 0.2 mmol, 100 mol %) and KOtBu (44.9 mg, 0.4 mmol, 200 mol %) reaction mixture was added to air at room temperature. Stirred at 130 °C for 18 h and cooled to room temperature. The reaction mixture was filtered through celite and washed with dichloromethane (10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (n-hexane / EtOAc = 1:1) to give 46.0 mg of 7b in 57 % yield.

7b의 NMR 분석 결과는 다음과 같다 :The results of NMR analysis of 7b are as follows:

46.0 mg (57%); 갈색 고체; mp = 136.5-139.0 oC; 1H NMR (700 MHz, CDCl3)δ8.75 (brs, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.74-7.71 (m, 3H), 7.33 (d, J = 7.7 Hz, 2H), 7.27-7.26 (m, 1H), 7.22 (d, J = 7.7 Hz, 2H), 7.14 (t, J = 7.7 Hz, 1H), 7.10 (d, J = 7.7 Hz, 2H), 6.85 (d, J = 9.1 Hz, 1H), 6.73 (brs, 1H), 2.37 (s, 3H), 2.26 (s, 3H); 13C1HNMR (175 MHz, CDCl3)δ153.5,143.5,137.8,137.7,136.7,136.5,133.6,131.3,129.7,129.4,127.1,123.5,122.7,122.1,121.3,116.4,112.3,21.4,20.8; IR (KBr) υ 3373, 3256, 3055, 2921, 2854, 1603, 1530, 1429, 1323, 1284, 1249, 1158, 1069, 1057, 916, 811, 754 cm-1; HRMS (orbitrap,ESI) calcd for C23H22N3O2S [M+H]+ 404.1433, found 404.1433.46.0 mg (57%); brown solid; mp = 136.5-139.0 o C; 1 H NMR (700 MHz, CDCl 3 )δ8.75 (brs, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.74-7.71 (m, 3H), 7.33 (d, J = 7.7 Hz, 2H) ), 7.27-7.26 (m, 1H), 7.22 (d, J = 7.7 Hz, 2H), 7.14 (t, J = 7.7 Hz, 1H), 7.10 (d, J = 7.7 Hz, 2H), 6.85 (d) , J = 9.1 Hz, 1H), 6.73 (brs, 1H), 2.37 (s, 3H), 2.26 (s, 3H); 13 C 1 HNMR (175 MHz, CDCl 3 )δ153.5,143.5,137.8,137.7,136.7,136.5,133.6,131.3,129.7,129.4,127.1,123.5,122.7,122.1,121.3,116.4,112.3,21.4,20.8; IR (KBr) υ 3373, 3256, 3055, 2921, 2854, 1603, 1530, 1429, 1323, 1284, 1249, 1158, 1069, 1057, 916, 811, 754 cm -1 ; HRMS (orbitrap,ESI) calcd for C 23 H 22 N 3 O 2 S [M+H] + 404.1433, found 404.1433.

실시예Example 7. 6- 7. 6- MethoxyMethoxy -2-(5-methyl-2,3--2-(5-methyl-2,3- diphenyldiphenyl -1H--1H- indolindol -1--One- ylyl )) quinolinequinoline (8a) 합성 및 구조 분석 (8a) Synthesis and structural analysis

Pd(MeCN)2Cl2 (4.2 mg, 0.016 mmol, 4 mol %), CuCl2 (113.0 mg, 0.84 mmol, 210 mol %), 6-메톡시-N-(p-톨릴)퀴놀린-2-아민 (3b) (105.7 mg, 0.4 mmol, 100 mol %) 및 디페닐 아세틸렌 (106.9 mg, 0.6 mmol, 150 mol %)으로 충전된 오븐-건조된 밀봉 튜브에 N2 하에 실온에서 DMF (2 mL)를 첨가하였다. 반응 혼합물을 110 ℃에서 12 시간 동안 교반하고, 실온으로 냉각시켰다. 반응 혼합물을 EtOAc (15 mL x 3)로 추출하였다. 결합된 유기층을 염수 (10 mL x 2)로 세척하고, MgSO4 상에서 건조시키고, 여과하고 감압 하에서 농축시켰다. 잔류물을 플래시 컬럼 크로마토그래피 (n- 헥산 / EtOAc = 1 : 1)로 정제하여 79 % 수율로 69.7 mg의 8a를 수득하였다.Pd(MeCN) 2 Cl 2 (4.2 mg, 0.016 mmol, 4 mol %), CuCl 2 (113.0 mg, 0.84 mmol, 210 mol %), 6-methoxy-N-(p-tolyl)quinolin-2-amine (3b) (105.7 mg, 0.4 mmol, 100 mol %) and diphenyl acetylene (106.9 mg , 0.6 mmol, 150 mol %) was added DMF (2 mL) at room temperature under N 2 to an oven-dried sealed tube. The reaction mixture was stirred at 110 °C for 12 h and cooled to room temperature. The reaction mixture was extracted with EtOAc (15 mL×3). The combined organic layers were washed with brine (10 mL x 2), MgSO 4 dried over, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (n-hexane / EtOAc = 1:1) to give 69.7 mg of 8a in 79% yield.

8a의 NMR 분석 결과는 다음과 같다 :The results of the NMR analysis of 8a are as follows:

69.7 mg (79%); 노란색 고체; mp = 146.5-148.8 oC; 1H NMR (700 MHz, CDCl3)δ8.08 (d, J = 9.1 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.58 (s, 1H), 7.46 (d, J = 9.1 Hz, 1H), 7.42 (d, J = 7.7 Hz, 2H), 7.38 (t, J = 7.7 Hz, 2H), 7.29 (t, J = 7.0 Hz, 1H), 7.22 (d, J = 7.7 Hz, 2H), 7.19 (d, J = 6.3 Hz, 1H), 7.17-7.15 (m, 3H), 7.06 (d, J = 2.8 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 3.93 (s, 3H), 2.50 (s, 3H); 13C1HNMR (175 MHz, CDCl3)δ157.9,149.2(one carbon overlap), 143.0, 136.1, 135.9, 135.6, 134.8, 131.9, 130.9, 130.8, 130.3 (one carbon overlap), 128.6, 128.2, 128.0, 127.3, 126.0, 124.9, 122.5, 120.7, 119.1, 118.0, 111.6, 105.1, 55.5, 21.5; IR (KBr) υ 3055, 2922, 2853, 1621, 1601, 1571, 1420, 1373, 1229, 1162, 1112, 1030, 921, 832, 733 cm-1; HRMS (orbitrap,ESI) calcd for C31H25N2O [M+H]+441.1967, found 441.1964.69.7 mg (79%); yellow solid; mp = 146.5-148.8 o C; 1 H NMR (700 MHz, CDCl 3 )δ8.08 (d, J = 9.1 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.58 ( s, 1H), 7.46 (d, J = 9.1 Hz, 1H), 7.42 (d, J = 7.7 Hz, 2H), 7.38 (t, J = 7.7 Hz, 2H), 7.29 (t, J = 7.0 Hz, 1H), 7.22 (d, J = 7.7 Hz, 2H), 7.19 (d, J = 6.3 Hz, 1H), 7.17-7.15 (m, 3H), 7.06 (d, J = 2.8 Hz, 1H), 6.82 ( d, J = 8.4 Hz, 1H), 3.93 (s, 3H), 2.50 (s, 3H); 13 C 1 HNMR (175 MHz, CDCl 3 )δ157.9,149.2(one carbon overlap), 143.0, 136.1, 135.9, 135.6, 134.8, 131.9, 130.9, 130.8, 130.3 (one carbon overlap), 128.6, 128.2, 128.0, 127.3 , 126.0, 124.9, 122.5, 120.7, 119.1, 118.0, 111.6, 105.1, 55.5, 21.5; IR (KBr) υ 3055, 2922, 2853, 1621, 1601, 1571, 1420, 1373, 1229, 1162, 1112, 1030, 921, 832, 733 cm -1 ; HRMS (orbitrap,ESI) calcd for C 31 H 25 N 2 O [M+H] + 441.1967, found 441.1964.

실시예Example 8. 3- 8. 3- MethoxyMethoxy -10--10- methylbenzo[4,5]imidazomethylbenzo[4,5]imidazo [1,2-a][1,2-a] quinolinequinoline (8b) 합성 및 구조 분석 (8b) synthesis and structural analysis

세릭(IV)암모늄나이트레이트 (219.3 mg, 0.4 mmol, 200 mol %) 및 6-메톡시-N-(p-톨릴) 퀴놀린-2-아민 (3b) (52.9 mg, 0.2 mmol, 100 mol %) 으로 채워진 오븐-건조된 밀봉 튜브에 0 ℃에서 공기 하에 H2O : MeCN (5:1, 1.2 mL)을 첨가 하였다. 반응 혼합물을 실온에서 1.5 시간 동안 교반하였다. 반응 혼합물을 EtOAc (15 mL x 3)로 추출 였다. 결합된 유기층을 염수 (10 mL x 2)로 세척하고, MgSO4상에서 건조시키고, 여과하고 감압 하에서 농축시켰다. 잔류물을 플래쉬 컬럼 크로마토그래피 (n- 헥산 / EtOAc = 1 : 1)로 정제하여 82 % 수율로 43.1 mg의 8b를 수득하였다.ceric(IV)ammonium nitrate (219.3 mg, 0.4 mmol, 200 mol %) and 6-methoxy-N-(p-tolyl) quinolin-2-amine ( 3b ) (52.9 mg, 0.2 mmol, 100 mol %) H 2 O:MeCN (5:1, 1.2 mL) was added under air at 0 °C to an oven-dried sealed tube filled with The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (10 mL×2), dried over MgSO 4 , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (n-hexane / EtOAc = 1:1) to give 43.1 mg of 8b in 82% yield.

8b의 NMR 분석 결과는 다음과 같다 :The results of the NMR analysis of 8b are as follows:

43.1 mg (82%); 갈색 고체; mp = 167.1-170.2 oC; 1H NMR (400 MHz, CDCl3)δ8.45 (d, J = 9.2 Hz, 1H), 8.09 (s, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.61-7.55 (m, 2H), 7.35-7.29 (m, 2H), 7.21 (d, J = 2.4 Hz, 1H), 3.92 (s, 3H), 2.64 (s, 3H); 13C1HNMR (100 MHz, CDCl3)δ155.8,147.4,142.4,132.5,130.8,130.4,130.1,125.9,124.6,119.7,118.1,117.7,116.4,113.6,111.2,55.6,22.3; IR (KBr) υ 2938, 1688, 1660, 1595, 1563, 1535, 1479, 1422, 1254, 1168, 807, 750 cm-1; HRMS (orbitrap,ESI) calcd for C17H15N2O [M+H]+253.1179, found 263.1179.43.1 mg (82%); brown solid; mp = 167.1-170.2 o C; 1 H NMR (400 MHz, CDCl 3 )δ8.45 (d, J = 9.2 Hz, 1H), 8.09 (s, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.61-7.55 (m, 2H) ), 7.35-7.29 (m, 2H), 7.21 (d, J = 2.4 Hz, 1H), 3.92 (s, 3H), 2.64 (s, 3H); 13 C 1 HNMR (100 MHz, CDCl 3 )δ155.8,147.4,142.4,132.5,130.8,130.4,130.1,125.9,124.6,119.7,118.1,117.7,116.4,113.6,111.2,55.6,22.3; IR (KBr) υ 2938, 1688, 1660, 1595, 1563, 1535, 1479, 1422, 1254, 1168, 807, 750 cm -1 ; HRMS (orbitrap,ESI) calcd for C 17 H 15 N 2 O [M+H] + 253.1179, found 263.1179.

실시예Example 9. 3- 9. 3- MethoxyMethoxy -10-methyl-12H--10-methyl-12H- quinolino[2,1-b]quinazolinquinolino[2,1-b]quinazolin -12-one (8c) 합성 및 구조 분석-12-one (8c) synthesis and structural analysis

Pd(OAc)2 (5.0 mg, 0.02 mmol, 10 mol %), Cu (TFA)2.xH2O(114.7 mg, 0.24 mmol, 120 mol %), 6-메톡시-N-(p-톨릴)퀴놀린-2-아민 (3b) (52.9 mg, 0.2 mmol, 100 mol %)로 충전된 오븐-건조 밀봉 튜브에, 대기압 하에 톨루엔 (2 mL)을 첨가하였다. 반응 혼합물을 실온에서 교반한 후, 포름산 (60.4 μL, 1.6 mmol, 800 mol %) 및 아세트산 무수물 (151.2 μL, 1.6 mmol, 800 mol %)을 적가하였다. 반응 혼합물을 110 ℃에서 12 시간 동안 교반하고, 실온으로 냉각시켰다. 반응 혼합물을 EtOAc로 추출했다. 결합된 유기층을 염수 및 포화 NH4OH 용액으로 세척하고, MgSO4상에서 건조시키고, 여과한 뒤 감압 하에서 농축시켰다. 잔류물을 플래쉬 컬럼 크로마토그래피 (n- 헥산 / EtOAc = 2 : 1)로 정제하여 45 % 수율로 26.2 mg의 8c를 수득 하였다.Pd(OAc) 2 (5.0 mg, 0.02 mmol, 10 mol %), Cu (TFA) 2 .xH 2 O (114.7 mg, 0.24 mmol, 120 mol %), 6-methoxy-N-(p-tolyl)quinolin-2-amine To an oven-dried sealed tube filled with ( 3b ) (52.9 mg, 0.2 mmol, 100 mol %) was added toluene (2 mL) under atmospheric pressure. After the reaction mixture was stirred at room temperature, formic acid (60.4 μL, 1.6 mmol, 800 mol %) and acetic anhydride (151.2 μL, 1.6 mmol, 800 mol %) were added dropwise. The reaction mixture was stirred at 110 °C for 12 h and cooled to room temperature. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine and saturated NH 4 OH solution, dried over MgSO 4 , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (n-hexane/EtOAc=2:1) to give 26.2 mg of 8c in 45% yield.

8c의 NMR 분석 결과는 다음과 같다 :The results of the NMR analysis of 8c are as follows:

26.2 mg (45%); 노란색 고체; mp = 148.0-149.2 oC; 1H NMR (400 MHz, CDCl3)δ9.58 (d, J = 9.6 Hz, 1H), 8.22 (s, 1H), 7.66-7.61 (m, 2H), 7.51 (d, J = 9.2 Hz, 1H), 7.22 (d, J = 9.2 Hz, 1H), 7.15 (dd, J = 9.6, 2.8 Hz, 1H), 7.01 (d, J = 2.8 Hz, 1H), 3.90 (s, 3H), 2.53 (s, 3H); 13C1HNMR (100 MHz, CDCl3)δ162.8,157.1,147.0,144.3,136.3,136.1,134.6,129.5,126.6,126.1,125.9,125.5,123.4,119.6,116.1,110.7,55.5,21.5; IR (KBr) υ 3057, 2923, 2853, 1673, 1610, 1569, 1478, 1455, 1266, 1238, 1135, 1040, 862, 806 cm-1; HRMS (orbitrap,ESI) calcd for C18H15N2O2 [M+H]+ 291.1128, found 291.1125.26.2 mg (45%); yellow solid; mp = 148.0-149.2 o C; 1 H NMR (400 MHz, CDCl 3 )δ9.58 (d, J = 9.6 Hz, 1H), 8.22 (s, 1H), 7.66-7.61 (m, 2H), 7.51 (d, J = 9.2 Hz, 1H) ), 7.22 (d, J = 9.2 Hz, 1H), 7.15 (dd, J = 9.6, 2.8 Hz, 1H), 7.01 (d, J = 2.8 Hz, 1H), 3.90 (s, 3H), 2.53 (s) , 3H); 13 C 1 HNMR (100 MHz, CDCl 3 )δ 162.8,157.1,147.0,144.3,136.3,136.1,134.6,129.5,126.6,126.1,125.9,125.5,123.4,119.6,116.1,110.7,55.5,21.5; IR (KBr) υ 3057, 2923, 2853, 1673, 1610, 1569, 1478, 1455, 1266, 1238, 1135, 1040, 862, 806 cm -1 ; HRMS (orbitrap,ESI) calcd for C 18 H 15 N 2 O 2 [M+H] + 291.1128, found 291.1125.

실시예 10. 반응 조건의 최적화Example 10. Optimization of reaction conditions

퀴놀린 N-옥사이드 (1a)와 4-메틸 벤조일 아자이드 (2a) 사이의 커플링 반응을 수행함으로써 표 1에 나타낸 바와 같이 초기 반응 조건의 최적화를 수행하였다. THF에서 KOtBu (2 당량 (equiv.))의 존재하에 2a (2 당량)의 처리는 36 % 수율로 C2-아민화된 퀴놀린 3a를 수득하였다 (표 1, entry 1). 3 당량으로 2a의 로딩 증가는 74 % 수율로 3a의 생성을 유의하게 증가시켰다 (표 1, entry 2). 그러나 KOtBu의 양을 2 당량에서 3 당량으로 정가시킨 것은 3a의 수율 개선에 효과적이지 않았다 (표 1, entry 3). 베이스를 스크리닝하여 KOtBu가 이 전환에서 가장 효과적임을 알 수 있었다 (표 1, entry 4-8). KOtBu를 Lewis 산으로서 AgBF4로 교체한 결과, 원하는 생성물 3a를 5 % 수율로 제공하였다 (표 1, entry 9). entry 11에 나타낸 바와 같이, 반응 용매로서 MTBE (t-부틸 메틸 에테르)를 사용한 결과, 3a의 수율 (95 %)이 극적으로 개선되었음을 확인하였다. 대조 실험은 반응 온도가 아실 아자이드 2a를 목적하는 이소시아네이트 중간체로 전환시키는 데 중추적인 것으로 나타났으며, 이는 1a와 반응하여 생성물 3a를 제공할 수 있다 (표 1, entry 14). 마지막으로, 최적의 반응 조건 하에서 p-톨릴 이소시아네이트를 3a의 형성에 사용하였다 (표 1, entry 15). 이 결과는 이소시아네이트가 이 과정에서 잠재적인 중재제라는 것을 시사하는 것이다.Optimization of initial reaction conditions as shown in Table 1 was performed by performing a coupling reaction between quinoline N-oxide (1a) and 4-methyl benzoyl azide (2a). Treatment of 2a (2 equiv.) in the presence of KOtBu (2 equiv.) in THF gave C2-aminated quinoline 3a in 36% yield (Table 1, entry 1). Increasing the loading of 2a with 3 equivalents significantly increased the production of 3a in 74% yield (Table 1, entry 2). However, adding the amount of KOtBu from 2 equivalents to 3 equivalents was not effective in improving the yield of 3a (Table 1, entry 3). By screening the base, it was found that KOtBu was most effective in this conversion (Table 1, entry 4-8). Replacing KOtBu with AgBF 4 as Lewis acid gave the desired product 3a in 5% yield (Table 1, entry 9). As shown in entry 11, as a result of using MTBE (t-butyl methyl ether) as a reaction solvent, it was confirmed that the yield (95%) of 3a was dramatically improved. Control experiments have shown that the reaction temperature is pivotal for the conversion of acyl azide 2a to the desired isocyanate intermediate, which can react with 1a to give product 3a (Table 1, entry 14). Finally, p-tolyl isocyanate was used for the formation of 3a under optimal reaction conditions (Table 1, entry 15). These results suggest that isocyanates are potential mediators in this process.

[반응식 1][Scheme 1]

Figure pat00031
Figure pat00031

entryentry reagent (equiv.) reagent (equiv.) 2a (equiv.) 2a (equiv.) solventsolvent yield(%) b yield(%) b 1One KO t Bu (2)KO t Bu (2) 22 THFTHF 3636 22 KO t Bu (2) KO t Bu (2) 33 THFTHF 7474 33 KO t Bu (3)KO t Bu (3) 33 THFTHF 7373 44 NaO t Bu (2)NaO t Bu (2) 33 THFTHF 66 55 K2CO3 (2)K 2 CO 3 (2) 33 THFTHF tracetrace 66 NaOMe (2)NaOMe (2) 33 THFTHF 4242 77 NaOH (2)NaOH (2) 33 THFTHF tracetrace 88 Et3N (2) Et 3 N (2) 33 THFTHF tracetrace 99 AgBF4 (0.5) AgBF 4 (0.5) 33 THFTHF 55 1010 KO t Bu (2)KO t Bu (2) 33 1,4-dioxane1,4-dioxane tracetrace 1111 KOEN tt BuBu (2) (2) 33 MTBE MTBE 9595 1212 KO t Bu (2)KO t Bu (2) 33 MeCNMeCN 1717 1313 KO t Bu (2)KO t Bu (2) 33 DMFDMF tracetrace 14 c 14 c KO t Bu (2)KO t Bu (2) 33 MTBE MTBE 4343 1515 KO t Bu (2)KO t Bu (2) p-tolylNCO (3) p -tolylNCO (3) MTBE MTBE 8282

a 반응 조건 : 1a (0.2mmol), 시약 (수량 표시), 2a (수량 표시), 용매 (1mL), 압력 튜브에서 20 시간 동안 130℃에서 N2 조건. a Reaction conditions: 1a (0.2mmol), reagent (quantity indication), 2a (quantity indication), solvent (1mL), N 2 conditions at 130°C for 20 hours in a pressure tube.

b 플래시 컬럼 크로마토그래피 후 분리된 수율. b Isolated yield after flash column chromatography.

c 반응을 80 ℃에서 40 시간 동안 수행하였다. c reaction was carried out at 80 °C for 40 hours.

실시예 11. 생성 화합물의 확인Example 11. Identification of the product compound

실시예 11-1. 아진-N-옥사이드의 범위Example 11-1. Range of azine-N-oxides

[반응식 2][Scheme 2]

Figure pat00032
Figure pat00032

a 반응 조건 :1a-1t (0.2mmol), 2a (0.6mmol), KOtBu (0.4mmol), MTBE (1mL), 압력 튜브에서 20 시간 동안 130℃에서 N2 조건. a Reaction conditions: 1a-1t (0.2mmol), 2a (0.6mmol), KOtBu (0.4mmol), MTBE (1mL), N 2 conditions at 130°C for 20 h in a pressure tube.

b 플래시 컬럼 크로마토그래피 후 분리된 수율. b Isolated yield after flash column chromatography.

c 그램 규모 (1g, 6mmol) 반응. c Gram scale (1 g, 6 mmol) reaction.

d KOtBu (0.25mmol) 및 THF (1mL)를 사용. d Using KOtBu (0.25 mmol) and THF (1 mL).

e MTBE 대신에 반응 용매로서 DMF를 사용. e Use DMF as reaction solvent instead of MTBE.

f KOtBu 및 MTBE 대신 KHMDS (0.2 mmol) 및 THF를 사용. f Use KHMDS (0.2 mmol) and THF instead of KOtBu and MTBE.

최적의 반응 조건으로, 2a와의 반응에 사용된 아진-N-옥사이드 1a-1t의 범위를 조사하였다 (반응식 2). 전자-풍부 그룹 및 전자-결핍 그룹 둘 다를 갖는 C6- 치환 및 C5, C8- 치환된 퀴놀린-N-옥사이드 1b-1e는 목적하는 생성물 3b-3e를 제공하는 이 커플링 반응에서 가장 효과적인 기질임을 확인하였다. 반응을 용이하게 스케일 업하고 1 g (6 mmol) 스케일로 수행하여 3a를 86 % 수율로 제공할 수 있음을 확인하였다. C4- 치환된 퀴놀린-N-옥사이드 1f 및 1g는 현재 반응 조건 하에서 비교적 반응성이 작은 것으로 나타났다. 다만, 입체적으로 구조가 혼잡한 퀴놀린-N-옥사이드 1h가 2a와 결합하여 28 % 수율로 3h를 생성한다는 것을 확인하였다.As the optimal reaction conditions, the range of azine-N-oxide 1a-1t used in the reaction with 2a was investigated (Scheme 2). Confirming that C6-substituted and C5, C8-substituted quinoline-N-oxides 1b-1e having both electron-rich and electron-deficient groups are the most effective substrates in this coupling reaction to give the desired product 3b-3e did. It was confirmed that the reaction was easily scaled up and performed on a 1 g (6 mmol) scale to provide 3a in 86% yield. C4-substituted quinoline-N-oxides 1f and 1g were shown to be relatively less reactive under current reaction conditions. However, it was confirmed that quinoline-N-oxide 1h having a three-dimensional structure was combined with 2a to produce 3h with a yield of 28%.

최근에, 8-메틸 퀴놀린은 전이 금속 촉매 하에서 벤질 C (sp3)-H 관능화 반응에 널리 사용되어왔다. 8-메틸 퀴놀린의 적용가능성으로부터, 8-메틸-퀴놀린-N-옥사이드 1i-1k와 2a의 반응을 수행하여, 상응하는 C2-아민화된 8-메틸-퀴놀린 3i-3k를 높은 수율로 수득하였다.Recently, 8-methyl quinoline has been widely used for benzyl C(sp3)-H functionalization reactions under transition metal catalysts. From the applicability of 8-methyl quinoline, the reaction of 8-methyl-quinoline-N-oxide 1i-1k with 2a was carried out to give the corresponding C2-aminated 8-methyl-quinoline 3i-3k in high yield .

또한, 벤조[f]퀴놀린, 페난트리딘 및 1,10-페난트롤린에서 유래한 π- 연장 퀴놀린-N-옥사이드가 형질 전환에 적합함에 따라, 65-80 % 수율로 원하는 생성물인 3l-3n을 수득하였다. 또한, 반응 조건을 약간 변경하여 피리딘-N-옥사이드 1o-1q에 적용함으로써, C2 아민화된 피리딘 3o-3q를 수득하였다. 특히 비대칭 페난트롤린 3n 및 바이피리딘 3p 및 3q가 합성되었으며, 이는 금속-촉매 반응에서 두자리(bidentate) 리간드로서 용이하게 적용될 수 있었다.In addition, as the π-extended quinoline-N-oxide derived from benzo[f ]quinoline, phenanthridine and 1,10-phenanthroline is suitable for transformation, the desired product 3l-3n in 65-80% yield was obtained. In addition, by changing the reaction conditions slightly and applying to pyridine-N-oxide 1o-1q, C2 aminated pyridine 3o-3q was obtained. In particular, asymmetric phenanthrolines 3n and bipyridines 3p and 3q were synthesized, which could be easily applied as bidentate ligands in metal-catalyzed reactions.

이러한 방법은 퀴놀린- 및 피리딘-N-옥사이드에만 제한되지 않는다. 퀴녹살린, 이소퀴놀린 및 프탈라진 잔기를 함유하는 다른 아진-N-옥사이드는 표준 또는 변형된 반응 조건 하에서 3r-3t를 제공하기 위해 부위-선택적 CH 아민화 반응에 참여할 수 있음을 확인하였다.This method is not limited to quinoline- and pyridine-N-oxides. It was confirmed that quinoxaline, isoquinoline and other azine-N-oxides containing phthalazine residues can participate in site-selective CH amination reactions to give 3r-3t under standard or modified reaction conditions.

실시예 11-2. 아실 아자이드의 범위Example 11-2. Scope of acyl azide

[반응식 3][Scheme 3]

Figure pat00033
Figure pat00033

a 반응 조건 : 1b (0.2mmol), 2b-2j (0.6mmol), KOtBu (0.4mmol), MTBE (1mL), 압력 튜브에서 20 시간 동안 130℃에서 N2 조건.. a Reaction conditions: 1b (0.2mmol), 2b-2j (0.6mmol), KOtBu (0.4mmol), MTBE (1mL), N 2 conditions at 130°C for 20 h in a pressure tube.

b 플래시 컬럼 크로마토그래피 후 분리된 수율. b Isolated yield after flash column chromatography.

c KOtBu (0.25 mmol)를 사용. c Using KOtBu (0.25 mmol).

아진-N-옥사이드의 성공적인 범위를 가짐으로써, 반응식 3에 나타낸 바와 같이, 1b와의 반응에 사용되는 아실 아자이드 2b-2j의 범위를 추가로 평가 하였다. 전자가 풍부한 아실 아자이드 2b, 2c 및 2e-2g는 1b와 쉽게 결합하여 높은 수율로 C2-아민형 퀴놀린 유도체를 제공함을 확인하였다.By having a successful range of azine-N-oxides, as shown in Scheme 3, the range of acyl azides 2b-2j used for reaction with 1b was further evaluated. It was confirmed that electron-rich acyl azides 2b, 2c, and 2e-2g were easily combined with 1b to provide a C2-amine-type quinoline derivative in high yield.

그러나, 전자-결핍 아실 아자이드 2d는 현재 반응 조건 하에서 덜 반응성으로 나타났다. 이러한 결과는 커티우스(Curtius) 자리옮김 반응 중에 이소시아네이트 중간체의 부분적인 형성에 의해 뒷받침된다.However, electron-deficient acyl azide 2d appeared to be less reactive under current reaction conditions. These results are supported by the partial formation of isocyanate intermediates during the Curtius translocation reaction.

또한, 2-나프토일아자이드 (2h)로부터 CH 아민화 반응을 통해 80 % 수율로 4h를 수득 하였다. 또한, 이 반응은 반응성이 감소하더라도 헤테로시클릭 및 알킬 아실 아자이드 2i 및 2j에도 적합한 것으로 나타났다.In addition, 4h was obtained in 80% yield through CH amination reaction from 2-naphthoylazide (2h). It has also been shown that this reaction is suitable for heterocyclic and alkyl acyl azides 2i and 2j even with reduced reactivity.

실시예Example 11-3. C-H 11-3. C-H 아민화의amination 최종 단계(Last stage) Last stage

본 발명의 방법은 상업적으로 이용 가능한 N-헤테로시클릭 약물 몰-쿨의 후기 CH 아민화 반응을 허용한다 (반응식 4). 예를 들어, 퀴놀린 스캐폴드를 함유하는 퀴니딘-N-옥사이드 5a를 2a와 매끄럽게 커플링하여 6a를 72 % 수율로 수득하였다. 또한, RhoA / Rho 키나제 (ROCK) 억제제인 파수딜(fasudil)의 N-옥사이드 유도체를 C1 위치에서 선택적으로 아민화하여 60% 수율로 6b를 수득하였다.The process of the present invention allows for the late CH amination reaction of the commercially available N-heterocyclic drug Mole-Cool (Scheme 4). For example, quinidine-N-oxide 5a containing a quinoline scaffold was smoothly coupled with 2a to give 6a in 72% yield. In addition, an N-oxide derivative of fasudil, a RhoA/Rho kinase (ROCK) inhibitor, was selectively ainated at the C1 position to obtain 6b in 60% yield.

[반응식 4][Scheme 4]

Figure pat00034
Figure pat00034

실시예 11-4. 순차적 C-H 아민화Example 11-4. Sequential C-H Amination

8-아미노퀴놀린은 약물 개발에서 유비쿼터스 프레임 워크로 인식된다8-aminoquinoline is recognized as a ubiquitous framework in drug development

또한, 2,8-디아미노퀴놀린은 크레놀라닙과 같은 생물학적으로 관련된 분자에서 발견되는 중추 코어로도 알려져 있다. 개발된 프로토콜의 유용성을 강조하기 위해 퀴놀린-N-옥사이드 (1a)의 순차 CH 아민화 반응을 수행하였다. 아실 아자이드 2a를 사용하여 이리듐 (III)-촉매된 산화 환원-중성 C8-아미 네이션 및 후속적인 환원성 C2-아미네이션으로 2,8-디아미노 퀴놀린 유도체 7b를 수득하였다 (반응식 5).2,8-diaminoquinoline is also known as the central core found in biologically related molecules such as crenolanib. To highlight the usefulness of the developed protocol, sequential CH amination reactions of quinoline-N-oxide (1a) were performed. Iridium (III)-catalyzed redox-neutral C8-amination followed by reductive C2-amination using acyl azide 2a gave the 2,8-diamino quinoline derivative 7b (Scheme 5).

[반응식 5][Scheme 5]

Figure pat00035
Figure pat00035

실시예 11-5. C2-아민화된 퀴놀린의 합성 변환Example 11-5. Synthetic transformation of C2-aminated quinolines

C2-아민화된 퀴놀린의 합성 유용성을 설명하기 위해, 반응식 6에 나타낸 바와 같이, 다양한 N-헤테로 사이클의 형성에 대한 분자 간 및 분자 내 반응을 수행하였다. C2-아미노 퀴놀린 3b와 1,3-디페닐 아세틸렌 사이의 Pd (II)-촉매된 산화적 공동-결합 반응으로부터 79 % 수율로 2-(1H-인돌-1-일)퀴놀린 8a를 수득하였다.To demonstrate the synthetic utility of C2-aminated quinolines, intermolecular and intramolecular reactions to the formation of various N-hetero cycles were performed, as shown in Scheme 6. 2-(1H-indol-1-yl)quinoline 8a was obtained in 79 % yield from Pd(II)-catalyzed oxidative co-linking reaction between C2-amino quinoline 3b and 1,3-diphenyl acetylene.

흥미롭게도, 3b의 CAN-매개 분자 내 고리화에 의해 항종양제에서 발견되는 유망한 구조적 코어인 벤즈이미다조[1,2-a] 퀴놀린 8b가 82 % 수율로 수득될 수 있었다. 한편, 3b의 Pd(II)-촉매된 환형 카르보닐화를 사용하여 퀴놀리노-퀴나졸리논 유도체 8c를 45 % 수율로 수득하였다.Interestingly, by CAN-mediated intramolecular cyclization of 3b, benzimidazo[1,2-a]quinoline 8b, a promising structural core found in antitumor agents, could be obtained in 82% yield. On the other hand, the quinolino-quinazolinone derivative 8c was obtained in 45% yield using Pd(II)-catalyzed cyclic carbonylation of 3b.

[반응식 6][Scheme 6]

Figure pat00036
Figure pat00036

결론적으로, 본 발명자들은 아진-N-옥사이드와 아실 아자이드의 전이 금속이 없는 환원성 C2-아민화 반응을 개시하였다. 메카니즘 경로의 관점에서, Curtius 자리옮김 반응을 통한 아실 아자이드로부터 유도된 이소시아네이트는 극성 N-옥사이드와의 [3 + 2] 쌍극성 고리화 첨가 반응을 거쳐 아민화된 아진을 제공한다. 특히, 이 공정의 유용성은 퀴니딘 및 파수딜과 같은 복잡한 생물 활성 화합물의 최종 및 순차적 아미노화 반응을 사용하여 입증되었다. 합성된 제품을 생물 활성 N-헤테로 사이클로 직접 변환하는 것은 새로 개발된 프로토콜의 중요성을 나타내었다.In conclusion, the present inventors disclosed a transition metal-free reductive C2-amination reaction of azine-N-oxide and acyl azide. In terms of the mechanistic pathway, isocyanates derived from acyl azides via a Curtius displacement reaction undergo a [3 + 2] dipolar cycloaddition reaction with a polar N-oxide to give an aminated azine. In particular, the utility of this process has been demonstrated using the terminal and sequential amination reactions of complex biologically active compounds such as quinidine and fasudil. The direct transformation of the synthesized product into the bioactive N-hetero cycle indicated the importance of the newly developed protocol.

결론적으로, 본 발명자들은 아진-N-옥사이드와 아실 아자이드의 전이 금속이 없는 환원성 C2-아민화 반응을 개시하였다. 메카니즘 경로의 관점에서, Curtius 재배열을 통한 아실 아자이드로부터 유도된 이소시아네이트는 극성 N-옥사이드와의 [3 + 2] 쌍극성 고리화 첨가 반응을 거쳐 아민화된 아진을 제공한다.In conclusion, the present inventors disclosed a transition metal-free reductive C2-amination reaction of azine-N-oxide and acyl azide. In view of the mechanistic pathway, isocyanates derived from acyl azides via Curtius rearrangements undergo [3 + 2] dipolar cycloaddition reactions with polar N-oxides to give the aminated azines.

이 공정의 유용성은 퀴니딘 (quinidine) 및 파수딜 (fasudil)과 같은 복잡한 생물 활성 화합물의 후기 및 순차적 아미노화 반응을 사용하여 입증되었다. 합성된 제품을 생물 활성 N-헤테로 사이클로 직접 변환하는 것은 새로 개발된 프로토콜의 중요성을 시사한다.The utility of this process has been demonstrated using late and sequential amination reactions of complex bioactive compounds such as quinidine and fasudil. Direct transformation of the synthesized product into the bioactive N-heterocycle suggests the importance of the newly developed protocol.

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

Claims (6)

하기 화학식 1 내지 화학식 3으로 표시되는 화합물, 이의 입체 이성질체, 또는 이의 약학적으로 허용가능한 염:
[화학식 1]
Figure pat00037

[화학식 2]
Figure pat00038


[화학식 3]
Figure pat00039


상기 화학식 1 내지 화학식 3에 있어서,
상기 R1은 수소, 할로겐, 치환 또는 비치환된 C1-C6 알킬, 치환 또는 비치환된 C1-C6 알콕시, 아다만테인-1-일, C6-C20 아릴 또는 C6-C20 헤테로아릴이며;
상기 R2는 치환 또는 비치환된 C1-C6 알킬, 치환 또는 비치환된 C1-C6 알콕시, C6-C20 아릴 또는 C6-C20 헤테로아릴이며;
상기 R3 및 R4는 각각 독립적으로 수소, 할로겐, 치환 또는 비치환된 C1-C6 알킬, 치환 또는 비치환된 C1-C6 알콕시,
Figure pat00040
,
Figure pat00041
, 또는
Figure pat00042
이거나, 서로 결합하여 치환 또는 비치환된 C6-C20 아릴 또는 C6-C20 헤테로아릴 고리를 형성하며;
상기 X 및 Y는 각각 독립적으로 탄소, 수소, 질소, 산소, 황, 할로겐, 치환 또는 비치환된 C1-C6 알킬, 치환 또는 비치환된 C1-C6 알콕시이거나, 서로 결합하여 치환 또는 비치환된 C6-C20 아릴 또는 C6-C20 헤테로아릴 고리를 형성하며;
상기 치환은 할로겐, N, O, 및 S로 이루어진 군으로부터 선택된 하나 이상으로 치환된다.
A compound represented by the following Chemical Formulas 1 to 3, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
[Formula 1]
Figure pat00037

[Formula 2]
Figure pat00038


[Formula 3]
Figure pat00039


In Formulas 1 to 3,
wherein R 1 is hydrogen, halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy, adamantane-1-yl, C 6 -C 20 aryl or C 6 -C 20 heteroaryl;
wherein R 2 is substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy, C 6 -C 20 aryl or C 6 -C 20 heteroaryl;
wherein R 3 and R 4 are each independently hydrogen, halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy;
Figure pat00040
,
Figure pat00041
, or
Figure pat00042
or combine with each other to form a substituted or unsubstituted C 6 -C 20 aryl or C 6 -C 20 heteroaryl ring;
Wherein X and Y are each independently carbon, hydrogen, nitrogen, oxygen, sulfur, halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy, or bonded to each other, substituted or form an unsubstituted C 6 -C 20 aryl or C 6 -C 20 heteroaryl ring;
The substitution is substituted with one or more selected from the group consisting of halogen, N, O, and S.
 제1항에 있어서,
상기 R1은 톨릴, 벤질, 메틸페닐, 에틸페닐, 프로필페닐, 부틸페닐, 트리플루오로메틸페닐, 디메톡시페닐, 브로모메틸페닐, 나프탈렌일, 피리딘일, 또는 아다만테인일이며;
상기 R2는 페닐, 피리딜 또는
Figure pat00043
이며;
상기 R3 및 R4는 각각 독립적으로 수소, 플루오로, 클로로, 브로모, 메틸, 메톡시,
Figure pat00044
,
Figure pat00045
, 또는
Figure pat00046
이거나, 서로 결합하여 치환 또는 비치환된 벤질, 페닐 또는 피리딘을 형성하며;
상기 X 및 Y는 각각 독립적으로 질소, 치환 또는 비치환된 C1-C6 알킬이거나, 서로 결합하여 벤질고리를 형성하며;
상기 치환은 할로겐, N, O, 및 S로 이루어진 군으로부터 선택된 하나 이상으로 치환되는 것을 특징으로 하는, 화합물, 이의 입체 이성질체, 또는 이의 약학적으로 허용가능한 염.
According to claim 1,
wherein R 1 is tolyl, benzyl, methylphenyl, ethylphenyl, propylphenyl, butylphenyl, trifluoromethylphenyl, dimethoxyphenyl, bromomethylphenyl, naphthalenyl, pyridinyl, or adamantaneinyl;
Wherein R 2 is phenyl, pyridyl or
Figure pat00043
is;
The R 3 and R 4 are each independently hydrogen, fluoro, chloro, bromo, methyl, methoxy,
Figure pat00044
,
Figure pat00045
, or
Figure pat00046
or combine with each other to form a substituted or unsubstituted benzyl, phenyl or pyridine;
wherein X and Y are each independently nitrogen, substituted or unsubstituted C 1 -C 6 alkyl, or combine with each other to form a benzyl ring;
A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that the substitution is substituted with one or more selected from the group consisting of halogen, N, O, and S.
 제1항에 있어서,
상기 화합물은 하기 화합물들로 이루어진 군으로부터 선택되는 어느 하나인 것을 특징으로 하는, 화합물, 이의 입체 이성질체, 또는 이의 약학적으로 허용가능한 염:
N-(p-톨릴)퀴놀린-2-아민 (3a);
6-메톡시-N-(p-톨릴)퀴놀린-2-아민 (3b);
6-클로로-N-(p-톨릴)퀴놀린-2-아민 (3c);
6-플루오로-N-(p-톨릴)퀴놀린-2-아민 (3d);
5-플루오로-8-메톡시-N-(p-톨릴)퀴놀린-2-아민 (3e);
4-메틸-N-(p-톨릴)퀴놀린-2-아민 (3f);
4-클로로-N-(p-톨릴)퀴놀린-2-아민 (3g);
3-메틸-N-(p-톨릴)퀴놀린-2-아민 (3h);
8-메틸-N-(p-톨릴)퀴놀린-2-아민 (3i);
7-브로모-8-메틸-N-(p-톨릴)퀴놀린-2-아민 (3j);
6-클로로-8-메틸-N-(p-톨릴)퀴놀린-2-아민 (3k);
N-(p-톨릴)벤조[f]퀴놀린-3-아민 (3l);
N-(p-톨릴)페난트리딘-6-아민 (3m);
N-(p-톨릴)-9-(트리플루오로메틸)-1,10-페난트롤린-2-아민 (3n);
4-페닐-N-(p-톨릴)피리딘-2-아민 (3o);
N-(p-톨릴)-[2,2'-비피리딘]-6-아민 (3p);
4,4'-디메틸-N-(p-톨릴)-[2,2'-비피리딘]-6-아민 (3q);
N-(p-톨릴)퀴녹살린-2-아민 (3r);
N-(p-톨릴)이소퀴놀린-1-아민 (3s);
N-(p-톨릴)프탈라진-1-아민 (3t);
6-메톡시-N-페닐퀴놀린-2-아민 (4b);
N-(4-(tert-부틸)페닐)-6-메톡시퀴놀린-2-아민 (4c);
6-메톡시-N-(4-(트리플루오로메틸)페닐)퀴놀린-2-아민 (4d);
6-메톡시-N-(m-톨릴)퀴놀린-2-아민 (4e);
N-(3,4-디메톡시페닐)-6-메톡시퀴놀린-2-아민 (4f);
N-(3-브로모-4-메틸페닐)-6-메톡시퀴놀린-2-아민 (4g);
6-메톡시-N-(나프탈렌-2-일)퀴놀린-2-아민 (4h);
6-메톡시-N-(피리딘-3-일)퀴놀린-2-아민 (4i);
N-((3S,5S,7S)-아다만테인-1-일)-6-메톡시퀴놀린-2-아민 (4j);
6-메톡시-4-((1S)-메톡시((1S,4S,5R)-5-비닐퀴누클리딘-2-일)메틸)-N-(p-톨릴)퀴놀린-2-아민 (6a);
벤조일 4-((1-(p-톨릴아미노)이소퀴놀린-5-일)설포닐)-1,4-디아제페인-1-카복실레이트 (6b);
8-((4-메틸페닐)설폰아미도)퀴놀린 N-옥사이드 (7a);
4-메틸-N-(2-(p-톨릴아미노)퀴놀린-8-일)벤젠설폰아마이드 (7b);
6-메톡시-2-(5-메틸-2,3-디페닐-1H-인돌-1-일)퀴놀린 (8a);
3-메톡시-10-메틸벤조[4,5]이미다조[1,2-a]퀴놀린 (8b); 및
3-메톡시-10-메틸-12H-퀴놀리노[2,1-b]퀴나졸린-12-원 (8c).
According to claim 1,
The compound is characterized in that any one selected from the group consisting of the following compounds, a compound, a stereoisomer, or a pharmaceutically acceptable salt thereof:
N-(p-tolyl)quinolin-2-amine (3a);
6-methoxy-N-(p-tolyl)quinolin-2-amine (3b);
6-chloro-N-(p-tolyl)quinolin-2-amine (3c);
6-fluoro-N-(p-tolyl)quinolin-2-amine (3d);
5-fluoro-8-methoxy-N-(p-tolyl)quinolin-2-amine (3e);
4-methyl-N-(p-tolyl)quinolin-2-amine (3f);
4-chloro-N-(p-tolyl)quinolin-2-amine (3 g);
3-methyl-N-(p-tolyl)quinolin-2-amine (3h);
8-methyl-N-(p-tolyl)quinolin-2-amine (3i);
7-bromo-8-methyl-N-(p-tolyl)quinolin-2-amine (3j);
6-chloro-8-methyl-N-(p-tolyl)quinolin-2-amine (3k);
N-(p-tolyl)benzo[f]quinolin-3-amine (31);
N-(p-tolyl)phenanthridin-6-amine (3m);
N-(p-tolyl)-9-(trifluoromethyl)-1,10-phenanthrolin-2-amine (3n);
4-phenyl-N-(p-tolyl)pyridin-2-amine (3o);
N-(p-tolyl)-[2,2'-bipyridin]-6-amine (3p);
4,4′-dimethyl-N-(p-tolyl)-[2,2′-bipyridin]-6-amine (3q);
N-(p-tolyl)quinoxalin-2-amine (3r);
N-(p-tolyl)isoquinolin-1-amine (3s);
N-(p-tolyl)phthalazin-1-amine (3t);
6-methoxy-N-phenylquinolin-2-amine (4b);
N-(4-(tert-butyl)phenyl)-6-methoxyquinolin-2-amine (4c);
6-methoxy-N-(4-(trifluoromethyl)phenyl)quinolin-2-amine (4d);
6-methoxy-N-(m-tolyl)quinolin-2-amine (4e);
N-(3,4-dimethoxyphenyl)-6-methoxyquinolin-2-amine (4f);
N-(3-bromo-4-methylphenyl)-6-methoxyquinolin-2-amine (4 g);
6-methoxy-N-(naphthalen-2-yl)quinolin-2-amine (4h);
6-methoxy-N-(pyridin-3-yl)quinolin-2-amine (4i);
N-((3S,5S,7S)-adamanthein-1-yl)-6-methoxyquinolin-2-amine (4j);
6-methoxy-4-((1S)-methoxy((1S,4S,5R)-5-vinylquinuclidin-2-yl)methyl)-N-(p-tolyl)quinolin-2-amine ( 6a);
benzoyl 4-((1-(p-tolylamino)isoquinolin-5-yl)sulfonyl)-1,4-diazepain-1-carboxylate (6b);
8-((4-methylphenyl)sulfonamido)quinoline N-oxide (7a);
4-methyl-N-(2-(p-tolylamino)quinolin-8-yl)benzenesulfonamide (7b);
6-methoxy-2-(5-methyl-2,3-diphenyl-1H-indol-1-yl)quinoline (8a);
3-methoxy-10-methylbenzo [4,5] imidazo [1,2-a] quinoline (8b); and
3-Methoxy-10-methyl-12H-quinolino[2,1-b]quinazoline-12-one (8c).
 염기 조건 하에서, 하기 화학식 4로 표시되는 화합물을 화학식 5로 표시되는 화합물과 반응시키는 단계를 포함하는, 제1항의 화합물의 제조방법:
[화학식 4]
Figure pat00047

[화학식 5]
Figure pat00048

상기 화학식 4 내지 화학식 5에 있어서,
상기 R1은 수소, 할로겐, 치환 또는 비치환된 C1-C6 알킬, 치환 또는 비치환된 C1-C6 알콕시, 아다만테인-1-일, C6-C20 아릴 또는 C6-C20 헤테로아릴이며;
상기 R2는 치환 또는 비치환된 C1-C6 알킬, 치환 또는 비치환된 C1-C6 알콕시, C6-C20 아릴 또는 C6-C20 헤테로아릴이며;
상기 R3 및 R4는 각각 독립적으로 수소, 할로겐, 치환 또는 비치환된 C1-C6 알킬, 치환 또는 비치환된 C1-C6 알콕시,
Figure pat00049
,
Figure pat00050
, 또는
Figure pat00051
이거나, 서로 결합하여 치환 또는 비치환된 C6-C20 아릴 또는 C6-C20 헤테로아릴 고리를 형성하며;
상기 X 및 Y는 각각 독립적으로 탄소, 수소, 질소, 산소, 황, 할로겐, 치환 또는 비치환된 C1-C6 알킬, 치환 또는 비치환된 C1-C6 알콕시이거나, 서로 결합하여 치환 또는 비치환된 C6-C20 아릴 또는 C6-C20 헤테로아릴 고리를 형성하며;
상기 치환은 할로겐, N, O, 및 S로 이루어진 군으로부터 선택된 하나 이상으로 치환된다.
A method for preparing the compound of claim 1, comprising reacting a compound represented by the following formula (4) with a compound represented by formula (5) under basic conditions:
[Formula 4]
Figure pat00047

[Formula 5]
Figure pat00048

In Formulas 4 to 5,
wherein R 1 is hydrogen, halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy, adamantane-1-yl, C 6 -C 20 aryl or C 6 -C 20 heteroaryl;
wherein R 2 is substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy, C 6 -C 20 aryl or C 6 -C 20 heteroaryl;
wherein R 3 and R 4 are each independently hydrogen, halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy;
Figure pat00049
,
Figure pat00050
, or
Figure pat00051
or combine with each other to form a substituted or unsubstituted C 6 -C 20 aryl or C 6 -C 20 heteroaryl ring;
Wherein X and Y are each independently carbon, hydrogen, nitrogen, oxygen, sulfur, halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy, or bonded to each other, substituted or form an unsubstituted C 6 -C 20 aryl or C 6 -C 20 heteroaryl ring;
The substitution is substituted with one or more selected from the group consisting of halogen, N, O, and S.
 제4항에 있어서,
상기 염기는 칼륨터트-부톡사이드(KO t Bu), 소듐터트-부톡사이드(NaO t Bu), 탄산칼륨(K2CO3), 메톡사이드나트륨(NaOMe), 수산화나트륨(NaOH), 트리에틸아민(Et3N), 및 실버 테트라플루오로보레이트(AgBF4)로 이루어진 군으로부터 선택된 하나 이상인 것을 특징으로 하는, 제1항의 화합물의 제조방법.
5. The method of claim 4,
The base is potassium tert-butoxide (KO t Bu), sodium tert-butoxide (NaO t Bu), potassium carbonate (K 2 CO 3 ) , sodium methoxide (NaOMe), sodium hydroxide (NaOH), triethylamine (Et 3 N), and silver tetrafluoroborate (AgBF 4 ) A method for preparing the compound of claim 1, characterized in that at least one selected from the group consisting of.
 제4항에 있어서,
상기 반응은 1,4-다이옥세인(1,4-Dioxane), 메틸 삼차 뷰틸 에터(Methyl tert-Butyl Ether, MTBE), 아세토니트릴(Acetonitrile, MeCN), 디메틸포름아마이드(Dimethylformamide, DMF), 다이클로로에테인(Dichloroethene; DCE), 다이클로로메탄(Dichloromethane; DCM), 테트라하이드로퓨란(Tetrahydrofuran, THF), 에탄올(EtOH), 테트라플루오로에틸렌(Tetrafluoroethylene, TFE) 및 헥사플루오로 이소프로판올(Hexafluoro isopropanol, HFIP)로 이루어진 군으로부터 선택된 용매에서 이루어지는 것을 특징으로 하는, 제1항의 화합물의 제조방법.

5. The method of claim 4,
The reaction is 1,4-dioxane (1,4-Dioxane), methyl tert-butyl ether (Methyl tert-Butyl Ether, MTBE), acetonitrile (Acetonitrile, MeCN), dimethylformamide (Dimethylformamide, DMF), dichloro Dichloroethene (DCE), Dichloromethane (DCM), Tetrahydrofuran (THF), Ethanol (EtOH), Tetrafluoroethylene (TFE) and Hexafluoro isopropanol (HFIP) A method for preparing the compound of claim 1, characterized in that it is made in a solvent selected from the group consisting of.
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