KR920008165B1

KR920008165B1 - 2,5-dihydro-1h-pyrrolo|3,4,c¨ pyridine derivatives and the preparation process thereof

Info

Publication number: KR920008165B1
Application number: KR1019900011885A
Authority: KR
Inventors: 김완주; 박태호; 김문환; 송복주
Original assignee: 재단법인 한국화학연구소; 채영복
Priority date: 1990-08-02
Filing date: 1990-08-02
Publication date: 1992-09-24
Also published as: KR920004384A

Abstract

Quinolne derivs. of formula (I) and their pharmaceutically acceptable salts are prepd.by condensing a pyridine deriv. of formula (II) and a quinoline carboxylic acid deriv. of formula (III) in the presence (or absence) of a solvent, at room temp. - 200 deg.C for 2-16 hrs. In the formulas, Z1, Z2 nd Z3 each = H, C1-3 alkyl, halogen, cyano, amino, hydroxy, C1-3 alkylamine or alkoxy; R1= ethyl or cyclopropyl; R2 and R3=H,F,Br or Cl; X=N, methyne or fluoromethyne, The cpds. (I) are useful as an antibacterial agent.

Description

2, 5-dihydro-1H-pyrrolo [3.4.C.] pyridine derivative having an antimicrobial activity and a method of preparing the same

본 발명은 2, 5-디히드로-1H-피롤로[3.4.C]피리딘 유도체를 갖는 신규한 퀴놀론계 항균제와 그의 제조방법에 관한 것으로서, 특히, 다음 구조식(Ⅱ)로 표시되는 피리딘 유도체를 퀴놀론 모핵의 7번 위치에 도입시키므로써 항균 스펙트럼 우수한 항균작용 및 약리대사 성능을 갖는 다음 구조식 (Ⅰ)로 표시되는 신규한 퀴놀론계 항균제에 관한 것이다.The present invention relates to a novel quinolone antibacterial agent having a 2,5-dihydro-1H-pyrrolo [3.4.C] pyridine derivative and a preparation method thereof. In particular, the pyridine derivative represented by the following structural formula (II) Antimicrobial spectrum by introducing at the position 7 of the mother core relates to a novel quinolone antibacterial agent represented by the following structural formula (I) having excellent antibacterial action and pharmacological metabolism performance.

상기 식에서, R₁은 에틸 또는 사이클로프로필기이고, R₂와 R₃는 각각 수소원자, 아미노기 또는 할로겐원소이며 X는 질소원자, 메틴(CH)기, 플루오르메닌(CF)기, 클로로메틴(CCl)기, 또는 에틴(CCH₂)기이고, Z₁, Z₂ 및 Z₃는 각각 수소원자, 탄소수 1 내지 3의 저급알킬기 또는 불소, 브롬, 염소와 같은 할로겐원소, 아미노기, 탄소수 1 내지 3의 저급알킬기가 하나 또는 두개 치환된 아미노기, 히드록시기, 티오히드록시기, 탄소소 1 내지 3의 저급알킬기의 알콕시 또는 티오알콕시기, 니트로기 또는 시아노기이다.Wherein R 'is an ethyl or cyclopropyl group, R2 and R₃ are each a hydrogen atom, an amino group or a halogen element and X is a nitrogen atom, a methine (CH) group, a fluormenine (CF) group, a chloromethine (CCl) group, Or an ethine (CCH ₂ ) group, Z₁, Z₂ and Z₃ each represent a hydrogen atom, a lower alkyl group having 1 to 3 carbon atoms or a halogen element such as fluorine, bromine or chlorine, an amino group or a lower alkyl group having 1 to 3 carbon atoms Substituted amino group, hydroxy group, thiohydroxy group, alkoxy or thioalkoxy group, nitro group or cyano group of lower alkyl group having 1 to 3 carbon atoms.

1963년 날리딕식산이 요도염치료제로 소개된 이래로 보다 뛰어난 항균력과 광범위한 항균스펙트럼을 갖는 퀴놀린계 항균제를 발명하기 위해 많은 연구가 진행되어졌다. 그 결과로 노르플록사신(Norflo-xacin), 에녹사신(Enoxacin), 시프로폴록사신 (Ciorofloxacin) 및 오플록사신(Ofloxcin)이 개발되어 현재 시판되고 있으며, 이들은 모두 피페라진기를 갖고 있는 것을 그 특징으로 하고 있다.Since nalidic acid was introduced as a urethritis treatment in 1963, much research has been conducted to invent a quinoline-based antimicrobial agent having superior antimicrobial activity and broad antimicrobial spectrum. As a result, norflo-xacin, Enoxacin, Cirofloxacin and Ofloxcin have been developed and are commercially available, all of which have piperazine groups. I am doing it.

최근에는 피롤리딘기를 갖는 퀴놀린계 항균제들이 많이 개발되어 그램양성균에 대한 항균력은 현저히 향상되었으나 그램음성균에 대한 항균력은 그들에 미치지 못하였다. 최근 일본 카네보(Kanebo)사에서 발표한 보고에서는 항균력에 향상 뿐만 아니라 급성독성을 줄이는 방면으로의 연구도 진행된어, 피페라진기를 갖는 퀴놀린계 항균제에 있어서 피페라진기의 4번 아민 대신에 N-히드록시아민기를 갖는 피페리진기를 도입시키므로써 항균제의 급성독성이 현저히 감소되고 항균력은 그대로 유지되며 생체내 항균력 시험에서도 항균력이 월등히 증가되는 것을 확인하였다.Recently, many quinoline-based antimicrobial agents having pyrrolidine groups have been developed, and the antimicrobial activity against Gram-positive bacteria was remarkably improved, but the antimicrobial activity against Gram-negative bacteria did not reach them. In a recent report published by Kanebo, Japan, not only improved antimicrobial activity but also studies to reduce acute toxicity. In the quinoline antibacterial agent having piperazine group, N- instead of piperazine group 4 amine was used. By introducing a piperizine group having a hydroxyamine group, the acute toxicity of the antimicrobial agent was significantly reduced, and the antimicrobial activity was maintained as it was.

이에 본 발명은 2, 5-디히드로-1H-피롤로[3.4.C]피리딘 유도체를 퀴놀론 모핵의 7번 위치에 도입시키므로써 그램양성균과 그램음성균등 모든 병균에 대하여 우수한 항균력과 넓은 항균 스펙트럼을 갖는 신규한 퀴놀론계 항균제와 그를 제조하는 방법을 제공하는데 목적이 있다.Therefore, the present invention introduces a 2, 5-dihydro-1H-pyrrolo [3.4.C] pyridine derivative at position 7 of the quinolone mother nucleus to provide excellent antimicrobial activity and broad antimicrobial spectrum against all gram positive bacteria and gram negative bacteria. It is an object to provide a novel quinolone-based antimicrobial agent having and a method for producing the same.

이하 본 발명을 상세히 설명하면 다음과 같다.Hereinafter, the present invention will be described in detail.

본 발명은 상기 구조식(Ⅰ)로 표시되는 퀴놀론계 항균제 및 약제학적으로 허용가능한 그의 염인 것이다.The present invention is a quinolone antibacterial agent represented by the above formula (I) and a pharmaceutically acceptable salt thereof.

또한, 본 발명은 다음 구조식(Ⅱ)로 표시되는 피리딘 유도체와 다음 구조식(Ⅲ)으로 표시되는 퀴놀린카르복실산 유도체를 용매 존재하에 또는 용매를 사용하지 않고 실욘 내지 200℃의 온도에서 염기 존재하에 2 내지 16시간 동안 반응시켜 되는 것임을 특징으로 하는 상기 구조식(Ⅰ)로 표시되는 퀴놀론계 항균제의 제조방법인 것이다.The present invention also provides a pyridine derivative represented by the following structural formula (II) and a quinolinecarboxylic acid derivative represented by the following structural formula (III) in the presence of a solvent or in the presence of a base at a temperature of from Silyon to 200 ° C without using a solvent. It is a method for producing a quinolone antibacterial agent represented by the structural formula (I), characterized in that the reaction for 16 to 16 hours.

상기 식에서, R₁내지 R₃, Z₁내지 Z₃ 및 X는 상기와 같고, R₄는 불소, 브롬, 염소와 같은 할로겐 원자 또는 술포닐기이다.Wherein R 'to R < 3 >, Z' to Z < 3 > and X are as described above, and R 'is a halogen atom or sulfonyl group such as fluorine, bromine or chlorine.

또한, 본 발명은 유효성분으로서 상기 구조식(Ⅰ)로 표시되는 퀴놀린계 항균제를 적어도 1종 이상 함유하는 것을 특징으로 하는 항균제 조상물인 것이다.Moreover, this invention is an antimicrobial ancestor characterized by containing at least 1 or more types of quinoline antimicrobial agents represented by said structural formula (I) as an active ingredient.

이와 같은 본 발명을 더욱 상세하게 설명하면 다음과 같다.The present invention will be described in more detail as follows.

본 발명은 상기 구조식(Ⅰ)로 표시되는 신규한 퀴놀론계 유도체로서, 다음 반응식에서 보는 바와 같이다음 구조식(Ⅱ)로 표시되는 피리딘 유도체와 다음 구조식(Ⅲ)으로 표시되는 화합물을 축합반응시켜 얻어지게 된다.The present invention is a novel quinolone derivative represented by the above structural formula (I), and is obtained by condensation reaction of a pyridine derivative represented by the following structural formula (II) and a compound represented by the following structural formula (III) as shown in the following reaction formula. do.

상기 식에서, R₁, R₂, R₃, R₄, X, Z₁, Z₂ 및 Z₃는 상술한 바와 동일하다.Wherein R ', R2, R3, R', X, Z ', Z2 and Z3 are the same as described above.

즉, 상기 구조식(Ⅱ)로 표시되는 피리딘 유도체와 상기 구조식(Ⅲ)으로 표시되는 퀴놀린 카르복실산 유도체를 용매 존재 또는 비존재하에 반응시킨 후, 여기에 적당한 염기를 첨가하고 실온 내지 200℃의 온도에서 2 내지 16시간 동안 교반시켜주면 다음 구조식(Ⅰ)로 표시되는 신규한 퀴놀론계 항균제를 제조하는 되는데, 상기 반응에서 사용되는 용매로는 아세토니트릴, 디메틸포름아미드(DMF), 디메틸술폭사이드(DMSO), 피리딘 또는 헥사메틸포스포아미드(HMPA)등이 바람직하며, 염기로는 가성소다, 탄산소다, 탄산칼륨, 탄산나트륨 등의 무기염기와 트리에틸아민, 디이소프로필에틸아민, 피리딘, 푸티딘, N, N-디메틸아닐린, N, N-디메틸아미노피리딘, 1, 8-디아자비시클로 [5.4.0]운데크-7-엔(DBU), 1, 5-디아자비시클로[4.3.0]노넨-5(DBN), 1, 4-디아자비시클로[2.2.2]옥탄(DABCO)등의 유기염기를 사용하는 것이 바람직하다.That is, after reacting the pyridine derivative represented by the structural formula (II) and the quinoline carboxylic acid derivative represented by the structural formula (III) in the presence or absence of a solvent, an appropriate base is added thereto and a temperature of room temperature to 200 ° C. After stirring for 2 to 16 hours to prepare a novel quinolone antibacterial agent represented by the following structural formula (I), the solvent used in the reaction is acetonitrile, dimethylformamide (DMF), dimethyl sulfoxide (DMSO ), Pyridine or hexamethylphosphoramide (HMPA) and the like, and bases include inorganic bases such as caustic soda, sodium carbonate, potassium carbonate and sodium carbonate, triethylamine, diisopropylethylamine, pyridine, putidine, N, N-dimethylaniline, N, N-dimethylaminopyridine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4.3.0] nonene -5 (DBN), 1,4-diazabicyclo [2.2.2] octane ( It is preferable to use organic bases, such as DABCO).

한편, 상기 구조식(Ⅱ)로 표시되는 피리딘 유도체들은 공지의 방법 즉, S. C.shama법(JCS. Perkin I. 1972, 2485), K. A. Watana-be법 (JOC, 54, 220, 1983) 및 S. A. Gadnar법(JOC. 26, 468, 1961)등을 이용하거나, 또는 다음과 같은 반응메카니즘에 의해서 제조될 수 있다.On the other hand, the pyridine derivatives represented by the structural formula (II) are known methods, that is, the SCshama method (JCS. Perkin I. 1972, 2485), the KA Watana-be method (JOC, 54, 220, 1983) and the SA Gadnar method (JOC. 26, 468, 1961) and the like, or by the following reaction mechanism.

상기 식에서, Z₁, Z₂ 및 Z₃는 상술한 바와 동일하고, R₅와 R₆는 각각 브롬이나 염소같은 할로겐 원자, 메실옥시기 또는 토실옥시기이며, R₇는 토실기, 벤질기, 디벤질기, 트리틸기, 에톡시카르보닐기 또는 t-부록시카르보닐기이다.Wherein Z 식, Z₂ and Z₃ are the same as described above, and R ₅ and R ₆ are each halogen atom such as bromine or chlorine, mesyloxy group or tosyloxy group, and R ₇ is tosyl group, benzyl group, dibenzyl group , A trityl group, an ethoxycarbonyl group or a t-butoxycarbonyl group.

상기 반응식에서, 상기 구조식(Ⅳ)로 표시되는 화합물을 포스 포러스옥시클로라이드, 티오틸클로라이드, 삼브롬화인, 또는 오염화인 등으로 할로겐화시키거나 메탄술포닐클로라이드나 톨루엔술포닐 클로라이드 등으로 메실화 또는 토실화 반응시켜 상기 구조식(Ⅴ)로 표시되는 화합물을 제조한 후, 일반적인 아민의 보호기를 갖고 있는 아민을 소디움히드리드와 같은 염기존재하에서 상기 일반식(Ⅴ)의 화합물과 반응시켜 상기 일반식(Ⅵ)의 화합물을 얻은 다음. 이것은 산 또는 알카리 가수분해시키거나 또는 일반적인 탈보호 반응시키게 되면 상기 일반식(Ⅰ)로 표시되는 화합물을 얻게 된다.In the above scheme, the compound represented by the above formula (IV) is halogenated with phosphorus oxychloride, thiothyl chloride, phosphorus tribromide or phosphorus pentachloride, or mesylated or soiled with methanesulfonyl chloride or toluenesulfonyl chloride or the like. The compound represented by Structural Formula (V) was prepared by a silylation reaction, and then the amine having a protecting group of a general amine was reacted with the compound of Formula (V) in the presence of a base such as sodium hydride. ) Compound. This gives an compound represented by the general formula (I) by acid or alkali hydrolysis or general deprotection reaction.

본 발명에서 화합물의 구조는 합성방법, 원소분석, 질량분석, 적외선 분광분석 및 핵자기공명 스펙트럼으로 확인되었다.In the present invention, the structure of the compound was confirmed by synthesis method, elemental analysis, mass spectrometry, infrared spectroscopy and nuclear magnetic resonance spectra.

이하 본 발명을 실시예에 의거하여 더욱 상세히 설명하면 다음과 같다.Hereinafter, the present invention will be described in more detail with reference to Examples.

[참고예 1 : 3, 4-디메톡시카르보닐 피리딘의 제조][Reference Example 1: Preparation of 3, 4-dimethoxycarbonyl pyridine]

3, 4-피리딘 디카르복실산(97%) 25g을 염화수소로 포화된 메탄올 500㎖에 넣고 10시간 동안 환륙시켰다. 이어서, 감압하에 메탄올로 증류시키고 핵산 : 에틸아세테이트(1 : 1)로 실리카겔 관크로마토그래피시켜 순수한 상기 목적화합물 22g을 얻었다.25 g of 3,4-pyridine dicarboxylic acid (97%) was added to 500 ml of methanol saturated with hydrogen chloride and refluxed for 10 hours. Subsequently, distilled with methanol under reduced pressure and silica gel column chromatography with nucleic acid: ethyl acetate (1: 1) gave 22 g of the target compound as pure.

원소분석Elemental analysis

이론치(%) : C; 55.39, H; 4.65, N; 7.18Theoretical value (%): C; 55.39, H; 4.65, N; 7.18

실측치(%) : C; 55.20, H; 4.55, N; 7.25Found (%): C; 55.20, H; 4.55, N; 7.25

H NMR(CDCl₃) δ(ppm) : 3.95(6H, s), 7.51(1H, d), 8.84(1H, d), 9.03 (1H, s).H NMR (CDCl 3) δ (ppm): 3.95 (6H, s), 7.51 (1H, d), 8.84 (1H, d), 9.03 (1H, s).

[참고예 2 : 3, 4-디히도록시메틸 피리딘의 제조][Reference Example 2: Preparation of 3,4-dihydroxygylmethyl pyridine]

3, 4-피리딘 디카르복실산 메틸에스테르 22g을 에틸에테르 200㎖에 녹인 용액을, 건조된 에틸에테르 300㎖에 리튬알루미늄 히드리드 10g을 현탁시킨 용액에다 0℃에서 적가시켰다. 이 혼합용액을 상온에서 3시간 동안 교반시키후 0℃에서 물 30㎖를 서서히 첨가시킨 다음, 상온에서 5시간 동안 잘 교반하고 셀라이트를 통하여 고체를 여과시켰다. 그 여액을 감암증류한 후 클로로포름 : 메탄올(10 : 1)로 시릴카겔 관크로마토그래피하여 순수한 상기 목적화합물 11.9g을 얻었다.A solution of 22 g of 3,4-pyridine dicarboxylic acid methyl ester in 200 ml of ethyl ether was added dropwise to 0 ml at a solution of 10 g of lithium aluminum hydride in 300 ml of dried ethyl ether. The mixed solution was stirred at room temperature for 3 hours, and then 30 ml of water was slowly added at 0 ° C., then stirred well at room temperature for 5 hours, and the solid was filtered through celite. The filtrate was distilled under reduced pressure and then subjected to Cyrilka gel column chromatography with chloroform: methanol (10: 1) to obtain 11.9 g of the pure target compound.

원소분석 :Elemental Analysis:

이론치(%) : C; 60.43. H; 6.52, N; 1.07Theoretical value (%): C; 60.43. H; 6.52, N; 1.07

실측치(%) : C; 60.12, H; 6.43, N; 10.11Found (%): C; 60.12, H; 6.43, N; 10.11

¹H NMR(CDCl₃+DMSO-d₆)δ(ppm) : 4.58(2H, d), 4.67(2H, d), 5.13 (1H, s), 5.30(1H, d), 7.45(1H, d), 8.45(1H, d), 8.48(1H, s). ¹ H NMR (CDCl ₃ + DMSO-d ₆ ) δ (ppm): 4.58 (2H, d), 4.67 (2H, d), 5.13 (1H, s), 5.30 (1H, d), 7.45 (1H, d ), 8.45 (1 H, d), 8.48 (1 H, s).

[참고에 3 : 3, 4-디클로로메틸피리딘 염산염의 제조][Preparation of 3: 3,4-dichloromethylpyridine hydrochloride]

3, 4-디히드록시메틸피리딘 11.0g을 티오닐클로라이드 20㎖에 첨가 시키고 0℃의 온도에서 2시간 동안 반응시킨 후, 티오닐클로라이드를 감압증발시켜 황색 고체상태의 상기 목적화합물 14g을 얻었다.After adding 11.0 g of 3,4-dihydroxymethylpyridine to 20 ml of thionyl chloride and reacting for 2 hours at a temperature of 0 ° C., thionyl chloride was evaporated under reduced pressure to obtain 14 g of the target compound as a yellow solid.

원소분석Elemental analysis

이론치(%) : C; 39.56, H; 3.79, N; 6.59Theoretical value (%): C; 39.56, H; 3.79, N; 6.59

실측치(%) : C; 39.21, H; 3.73, N; 6.55Found (%): C; 39.21, H; 3.73, N; 6.55

¹H NMR(CDCl₃+DMSO-d₆)δ(ppm) : 5.10(2H, s), 5.15(2H, s), 8.15 (1H, d), 8.95(1H, d), 9.11(1H, s). ¹ H NMR (CDCl ₃ + DMSO-d ₆ ) δ (ppm): 5.10 (2H, s), 5.15 (2H, s), 8.15 (1H, d), 8.95 (1H, d), 9.11 (1H, s ).

[실시예 1]Example 1

2, 3-디히드로-2-p-톨루엔술포닐-1H-피롤로[3.4.C]피리딘의 제조Preparation of 2, 3-dihydro-2-p-toluenesulfonyl-1H-pyrrolo [3.4.C] pyridine

(1) 2, 3, 디히드로-1-P-톨루엔술포닐-1H-피롤로-[3.4.C]피리딘의 제조(1) Preparation of 2, 3, dihydro-1-P-toluenesulfonyl-1H-pyrrolo- [3.4.C] pyridine

건조된 피메틸포름아미드 50㎖에 55% 소디움히드리드 0.9g을 현탁시킨 후, p-톨루엔술포닐아미드 3.5g을 건조된 디메틸포름아미드 20㎖에 용해시킨 다음, 여기에다 상기 반응혼합물을 2시간 동안에 걸쳐 서서히 적가시켰다. 이것을 상온에서 1시간 동안 더 교반시킨 후, 승온시키고 65 내지 70℃의 온도를 유지하면서 다시 1시간 동안 교반시켰다. 별도로 3, 4-디클로로메틸피리딘 염산염 2g을 건조된 디메틸포름아미드 30㎖에 용해시킨 후, 60 내지 70℃의 온도에서 상기 반응혼합물에 적가시킨 같은 온도에서 3시간 동안 교반시키고 물 20㎖를 투입시켜 감압하에 용매를 증발시킨 후, 다시 물 20㎖를 넣고 소금으로 포화시키고 에틸아세테이트 100㎖로 추출하였다. 이어서, 상기 반응혼합물을 무수황산마그네슘으로 건조시킨 수 감압증류하고 핵산 : 에틸아세테이트 (1 : 2)로 실리카겔 관크로마토그래피하여 순수한 상기 목적화합물 1.8g을 얻었다.After suspending 0.9 g of 55% sodium hydride in 50 ml of dried fimethylformamide, 3.5 g of p-toluenesulfonylamide was dissolved in 20 ml of dried dimethylformamide, and the reaction mixture was added thereto for 2 hours. Slowly dropwise over. This was further stirred at room temperature for 1 hour, and then stirred for another hour while raising the temperature and maintaining the temperature of 65 to 70 ℃. Separately, 2 g of 3,4-dichloromethylpyridine hydrochloride was dissolved in 30 ml of dried dimethylformamide, and then stirred at the same temperature added dropwise to the reaction mixture at a temperature of 60 to 70 ° C. for 3 hours, and 20 ml of water was added thereto. After evaporating the solvent under reduced pressure, 20 ml of water was added thereto, saturated with salt, and extracted with 100 ml of ethyl acetate. Subsequently, the reaction mixture was dried over anhydrous magnesium sulfate, dried under reduced pressure, and purified by silica gel column chromatography with nucleic acid: ethyl acetate (1: 2) to obtain pure 1.8 g of the target compound.

원소분석Elemental analysis

이론치(%) : C; 61.30, H; 5.14, N; 10.21Theoretical value (%): C; 61.30, H; 5.14, N; 10.21

실측치(%) : C; 16.11, H; 5.10, N; 10.30Found (%): C; 16.11, H; 5.10, N; 10.30

¹H NMR(CDCl₃)δ(ppm) : 2.45(3H, s), 4.65∼6.48(4H, d), 7.15(1H, d), 7.35(2H, d), 7.7892H, d), 8.4891H, d), 8.49(1H, s). ¹ H NMR (CDCl ₃ ) δ (ppm): 2.45 (3H, s), 4.65 to 6.68 (4H, d), 7.15 (1H, d), 7.35 (2H, d), 7.7892H, d), 8.4891H , d), 8.49 (1 H, s).

(2) 2, 3-디히드로-1H-피롤로[3.4.C]피리딘 히드로브로마이드의 제조(2) Preparation of 2, 3-dihydro-1H-pyrrolo [3.4.C] pyridine hydrobromide

2, 3-디히드로-2p-톨루엔술포닐-1H-피롤로[3.4.C]피리딘 1.6g을 48%브롬화수소산 20㎖에 투입시킨 후, 여기에 페놀 1.75g프로피온산 9.18㎖를 첨가하고 48시간 동안 환류시켰다. 이 반응용액에서 용매를 감압증발시킨 후, 물 50㎖를 투입하고 추출한 다음. 물층을 다시 농출시킨 후, 냉장고에 방치하여 백색침전의 상기 목적화합물 1.23g을 얻었다.1.6 g of 2,3-dihydro-2p-toluenesulfonyl-1H-pyrrolo [3.4.C] pyridine was added to 20 ml of 48% hydrobromic acid, and then 1.18 g of phenol 1.75 g propionic acid was added thereto for 48 hours. At reflux. After evaporating the solvent under reduced pressure in this reaction solution, 50 ml of water was added and extracted. The aqueous layer was concentrated again, and left in a refrigerator to obtain 1.23 g of the target compound of white precipitate.

원소분석Elemental analysis

이론치(%) : C; 29.81, H; 3.58, N; 9.93Theoretical value (%): C; 29.81, H; 3.58, N; 9.93

실측치(%) : C; 29.75, H; 3.51, N; 9.91Found (%): C; 29.75, H; 3.51, N; 9.91

¹H NMR(F₃COOD+DMSO-d₆+CDCl₃)δ(ppm) : 5.24(4H, d), 8.20(1H, d), 8.90(1H, d), 9.02(1H, s). ¹ H NMR (F ₃ COOD + DMSO-d ₆ + CDCl ₃ ) δ (ppm): 5.24 (4H, d), 8.20 (1H, d), 8.90 (1H, d), 9.02 (1H, s).

[실시예 2]Example 2

7-메톡시-6-메틸-2, 3-디히드로-1H-피롤로[3.4.C]피리딘 디히드로클로라이드의 제조Preparation of 7-methoxy-6-methyl-2, 3-dihydro-1H-pyrrolo [3.4.C] pyridine dihydrochloride

2-벤조일-7-메톡시-6-메틸-2, 3-디히드로-1H-피롤로[3.4.C]피리딘 2.95g 을 5% 가성소다 11㎖와 에타올 18㎖의 혼합용액에 첨가시키고 3시간 동안 가열시킨 다음 냉각하고, 여기에 진한 염산 4.75㎖를 투입하여 중화시켰다. 이어서 에탄올을 감압증류시킨 후, 진한 염산 2㎖와 물 4㎖로 다시 산성화시킨 다음 침전물은 여과해내고 이 여액에 5%을 첨가하고 물을 증발시킨 후, 뜨거운 에탄올 4㎖로 용해시킨 다음 여과시켰다. 이것을 에탄올 3㎖로 세척하면 여액을 농축시킨 후, 다시 물 5㎖를 투입하여 용해시킨 다음 활성탄으로 처리했다. 여기에 진한 염산 2.1㎖를 침전물을 여과한 후 에탄올 세척 및 건조시켜 상기 목적화합물 2.1g을 얻었다.2.95 g of 2-benzoyl-7-methoxy-6-methyl-2 and 3-dihydro-1H-pyrrolo [3.4.C] pyridine were added to a mixed solution of 11 ml of 5% caustic soda and 18 ml of ethanol. The mixture was heated for 3 hours, cooled, and neutralized by adding 4.75 ml of concentrated hydrochloric acid. The ethanol was then distilled under reduced pressure, acidified again with 2 ml of concentrated hydrochloric acid and 4 ml of water, and the precipitate was filtered off, 5% was added to the filtrate, the water was evaporated, dissolved in 4 ml of hot ethanol and filtered. . When this was washed with 3 ml of ethanol, the filtrate was concentrated, and 5 ml of water was added again to dissolve it, and then treated with activated carbon. The precipitate was filtered with 2.1 ml of concentrated hydrochloric acid, washed with ethanol and dried to obtain 2.1 g of the target compound.

원소분석Elemental analysis

이론치(%) : C; 45.59, H; 5.95, N; 11.81Theoretical value (%): C; 45.59, H; 5.95, N; 11.81

실측치(%) : C; 45.47, H; 5.83, N; 11.92Found (%): C; 45.47, H; 5.83, N; 11.92

[실시예 3]Example 3

6-메틸-2, 3-디히드로-1H-피로로[3.4.C]피리딘 디히드로클로라이드의 제조Preparation of 6-methyl-2, 3-dihydro-1H-pyrrolo [3.4.C] pyridine dihydrochloride

2-에톡시카르보닐-6-메틸-2, 3-디히드로-1H-피롤로[3.4.C]피리딘 1g을 진한 염산 10㎖에 첨가시키고 12시간 동안 환류시킨 다음, 이 반응혼합물과 동일한 양의 물로 희석시켰다. 이어서, 활성탄을 여과하여 그 여액을 감압증류시켰다. 이때 생성된 고체를 에탄올 10㎖에 현탁시킨 후, 여과하여 다시 에탄올 5㎖로 세척 및 건조시켜 상기 목적화합물 1.1g을 얻었다.1 g of 2-ethoxycarbonyl-6-methyl-2, 3-dihydro-1H-pyrrolo [3.4.C] pyridine was added to 10 ml of concentrated hydrochloric acid and refluxed for 12 hours, and then the same amount as the reaction mixture. Diluted with water. Subsequently, activated carbon was filtered and the filtrate was distilled under reduced pressure. The resulting solid was suspended in 10 ml of ethanol, filtered, washed again with 5 ml of ethanol and dried to obtain 1.1 g of the target compound.

원소분석Elemental analysis

이론치(%) : C; 46.40, H; 5.84, N; 13.58Theoretical value (%): C; 46.40, H; 5.84, N; 13.58

실측치(%) : C; 46.10, H; 5.75, N; 13.49Found (%): C; 46.10, H; 5.75, N; 13.49

¹H NMR(CF₃COOD+DMSO-d₆+CDCl₃)δ(ppm) : 2.71(3H, s), 5.23(2H, s), 5.24(2H, s), 8.51(1H, s). ¹ H NMR (CF ₃ COOD + DMSO-d ₆ + CDCl ₃ ) δ (ppm): 2.71 (3H, s), 5.23 (2H, s), 5.24 (2H, s), 8.51 (1H, s).

[실시예 4]Example 4

7-히드록시-2, 3-디히드로-1H피롤로[3.4.C]피리딘 디히드로클로라이드의 제조Preparation of 7-hydroxy-2, 3-dihydro-1Hpyrrolo [3.4.C] pyridine dihydrochloride

2-벤조일-7-히드록시-2, 3-디히드로-1H-피클로[3.4.C]피리딘 디히드로클로라이드 1g을 5N 염산용액 8㎖에 첨가시키고 5시간 동안 환류시킨 다음, 이 반응혼합물을 냉각하여 벤조익산을 여과해내고, 여액을 활성탄으로 처리한 후 농축시켰다. 이때 생성된 고체를 여과시킨 다음 알코올로 세척 및 건조하여 상기 목적화합물을 0.6g을 얻었다.1 g of 2-benzoyl-7-hydroxy-2, 3-dihydro-1H-piclo [3.4.C] pyridine dihydrochloride was added to 8 ml of 5N hydrochloric acid solution and refluxed for 5 hours, and then the reaction mixture was After cooling, the benzoic acid was filtered off, and the filtrate was concentrated with activated carbon. At this time, the resulting solid was filtered, washed with alcohol and dried to obtain 0.6g of the target compound.

원소분석Elemental analysis

이론치(%) : C; 40.21, H; 4.82, N; 13.40Theoretical value (%): C; 40.21, H; 4.82, N; 13.40

실측치(%) : C; 40.01, H; 4.86, N; 13.51Found (%): C; 40.01, H; 4.86, N; 13.51

¹H NMR(CF₃COOD+DMSO-d₆+CDCl₃)δ(ppm) : 5.12(2H, s), 5.14(2H, s), 8.53(1H, s), 8.60(1H, s). ¹ H NMR (CF ₃ COOD + DMSO-d ₆ + CDCl ₃ ) δ (ppm): 5.12 (2H, s), 5.14 (2H, s), 8.53 (1H, s), 8.60 (1H, s).

[실시예 5]Example 5

6-메틸-7-클로로-2, 3-디히드로-1H-피롤로[3.4.C]피리딘 디히드로클로라이드의 제조Preparation of 6-methyl-7-chloro-2, 3-dihydro-1H-pyrrolo [3.4.C] pyridine dihydrochloride

2-에톡시카르보닐-6-메틸-7-클로로-2, 3-디히드로-1H-피롤로[3.4.C]피리딘 모노하이드레이트 1.2g을 진한 염산 10㎖에 첨가시키고 30시간 동안 환류시킨 다음, 이 반응혼합물과 동량의 물로 희석시키고 활성탄으로 여과했다. 이어서, 여액을 감압증류시키고 담황색의 고체를 찬 에탄올 10㎖에 현탁시킨 다음 여과하여 얻어진 고체를 다시 찬 에탄올 5㎖로 세척 및 건조시켜 상기 목적화합물 1.0g을 얻었다.1.2 g of 2-ethoxycarbonyl-6-methyl-7-chloro-2, 3-dihydro-1H-pyrrolo [3.4.C] pyridine monohydrate were added to 10 ml of concentrated hydrochloric acid and refluxed for 30 hours. The reaction mixture was diluted with the same amount of water and filtered over activated carbon. Subsequently, the filtrate was distilled under reduced pressure, and the pale yellow solid was suspended in 10 ml of cold ethanol, and the solid obtained by filtration was washed with 5 ml of cold ethanol and dried to obtain 1.0 g of the target compound.

원소분석Elemental analysis

이론치(%) : C; 39.78, H; 4.59, N; 11.60Theoretical value (%): C; 39.78, H; 4.59, N; 11.60

실측치(%) : C; 39.61, H; 4.51, N; 11.51Found (%): C; 39.61, H; 4.51, N; 11.51

¹H NMR(CF₃COOD+DMSO-d₆+CDCl₃) δ(ppm) : 2.73(3H, s), 5.27(2H, s), 5.29(2H, s), 8.53(1H, s). ¹ H NMR (CF ₃ COOD + DMSO-d ₆ + CDCl ₃ ) δ (ppm): 2.73 (3H, s), 5.27 (2H, s), 5.29 (2H, s), 8.53 (1H, s).

[실시예 6]Example 6

7-클로로-2, 3-디히드로-1H-피롤로[3.4.C]피리딘 디히드로클로라이드의 제조Preparation of 7-chloro-2, 3-dihydro-1H-pyrrolo [3.4.C] pyridine dihydrochloride

2-에톡시카르보닐-7-클로로-2, 3-디히드로-1H-피롤로[3.4.C]피리딘 0.23g을 진한 염산 2.5㎖에 첨가시키고 48시간 동안 가열시킨 다음, 이때 얻어진 황색용액을 물 3.0㎖로 희석시킨 다음 감압증류 시켰다. 이때 얻어진 잔사를 에테르 3.0㎖로 현탁하고 여과시킨 결과, 담황색 고체의 상기 목적화합물 0.2g을 얻었다.0.23 g of 2-ethoxycarbonyl-7-chloro-2,3-dihydro-1H-pyrrolo [3.4.C] pyridine was added to 2.5 ml of concentrated hydrochloric acid and heated for 48 hours, and then the yellow solution obtained was Diluted with 3.0ml of water and distilled under reduced pressure. The obtained residue was suspended with 3.0 ml of ether and filtered to obtain 0.2 g of the target compound as a pale yellow solid.

원소분석Elemental analysis

이론치(%) : C; 36.95, H; 3.99, N; 12.31Theoretical value (%): C; 36.95, H; 3.99, N; 12.31

실측치(%) : C; 36.81, H; 3.91, N; 12.25Found (%): C; 36.81, H; 3.91, N; 12.25

¹H NMR(CF₃COOD+DMSO-d₆+CDCl₃) δ(ppm) : 5.13(2H, s), 5.15(2H, s), 8.51(1H, s), 8.76(1H, s). ¹ H NMR (CF ₃ COOD + DMSO-d ₆ + CDCl ₃ ) δ (ppm): 5.13 (2H, s), 5.15 (2H, s), 8.51 (1H, s), 8.76 (1H, s).

[실시예 7]Example 7

7-아미노-6-메틸-2, 3-디히드로-1H-피롤로[3.4.C]피리딘 디히드로클로라이드의 제조Preparation of 7-amino-6-methyl-2, 3-dihydro-1H-pyrrolo [3.4.C] pyridine dihydrochloride

리튬알루미늄 히드리드 4.0g을 테트라히드로퓨란 200㎖에 첨가하여 질소를 통과시킨 다음, 3-아미노-5-아미노메틸-2-메틸-아이소니코틴산이 감마락탐 1.8g을 테트라하이드로퓨란 350㎖에 용해시킨 것을 상기 혼합물에 서서히 적가시켰다. 이 반응혼합물을 65℃의 온도에서 7시간 동안 환류시킨 다음 실온에서 하릇밤 동안 방치시킨 후, 테트라히드로퓨란 100㎖에 물 8㎖을 혼합시킨 용액을 상기 반응용액에 투입하여 과량의 리튬알루미늄 히드리드를 용해시키고 여과하였다. 이때 얻어진 여액을 진한 염산 10㎖로 산성화시키고 냉장고에 방치시켜 생성된 침전물을 소량의 물에 용해시킨 후, 염산/에테르의 혼합용액으로 처리하여 재침전시켰다. 이와 같은 과정을 되풀이 하여 순수한 상기 목적화합물 0.6g을 얻었다.4.0 g of lithium aluminum hydride was added to 200 ml of tetrahydrofuran, passed through nitrogen, and 3-amino-5-aminomethyl-2-methyl-isonicotinic acid dissolved 1.8 g of gammalactam in 350 ml of tetrahydrofuran. Was slowly added dropwise to the mixture. The reaction mixture was refluxed at a temperature of 65 ° C. for 7 hours and then left at room temperature overnight. Then, a solution of 8 ml of water mixed with 100 ml of tetrahydrofuran was added to the reaction solution to excess lithium aluminum hydride. Was dissolved and filtered. The filtrate thus obtained was acidified with 10 ml of concentrated hydrochloric acid and left in a refrigerator to dissolve the resulting precipitate in a small amount of water, followed by reprecipitation by treatment with a mixed solution of hydrochloric acid / ether. This procedure was repeated to obtain 0.6 g of the pure target compound.

원소분석Elemental analysis

이론치(%) : C; 37.16, H; 5.49, N; 16.25Theoretical value (%): C; 37.16, H; 5.49, N; 16.25

실측치(%) : C; 36.95, H; 5.41, N; 16.11Found (%): C; 36.95, H; 5.41, N; 16.11

¹H NMR(CF₃COOD+DMSO-d₆+CDCl₃) δ(ppm) : 5.15(2H, s), 8.51(1H, s). ¹ H NMR (CF ₃ COOD + DMSO-d ₆ + CDCl ₃ ) δ (ppm): 5.15 (2H, s), 8.51 (1H, s).

[실시예 8]Example 8

7-브로모-6-메틸-2, 3-디히드로-1H-피롤로[3.4.C]피리딘 디히드로클로라이드의 제조Preparation of 7-bromo-6-methyl-2, 3-dihydro-1H-pyrrolo [3.4.C] pyridine dihydrochloride

7-브로모-6-메틸-2, 3-디히드로-1H-피롤로[3.4.C]피리딘 0.86g을 4.5N 가성소다 3㎖ 및 에탄올 3.5㎖에 첨가시키고 3시간 동안 환류시킨 다음, 이 반응혼합물을 냉각시킨 후, 침전물은 여과해내고 여액은 진한 염산 1.25㎖로 산성화시켜 활성탄으로 처리했다. 이어서 용매를 감압증발시켜 얻어진 고체를 에탄올로 세척시킨 후, 소디움 메톡사이드 0.264g을 에탄올 5㎖에 투입시킨 것을 상기 반응혼합물에 첨가하고 실온에서 1시간 동안 교반시켰다. 이것을 30분동안 환류시켜 여과하고 그 여액을 냉각시킨 후, 염화수소기체를 통과시킨 결과, 상기 모적화합물 0.7g을 얻었다.0.86 g of 7-bromo-6-methyl-2, 3-dihydro-1H-pyrrolo [3.4.C] pyridine was added to 3 ml of 4.5 N caustic soda and 3.5 ml of ethanol and refluxed for 3 hours. After cooling the reaction mixture, the precipitate was filtered off and the filtrate was acidified with 1.25 ml of concentrated hydrochloric acid and treated with activated carbon. Subsequently, the solid obtained by evaporation of the solvent under reduced pressure was washed with ethanol, and 0.264 g of sodium methoxide was added to 5 ml of ethanol to the reaction mixture and stirred at room temperature for 1 hour. The mixture was refluxed for 30 minutes, filtered, and the filtrate was cooled and passed through a hydrogen chloride gas. As a result, 0.7 g of the parent compound was obtained.

원소분석Elemental analysis

이론치(%) : C; 33.60, H; 3.68, N; 9.79Theoretical value (%): C; 33.60, H; 3.68, N; 9.79

실측치(%) : C; 33.10, H; 3.79, N; 9.67Found (%): C; 33.10, H; 3.79, N; 9.67

¹H NMR(CF₃COOD+DMSO-d₆+CDCl₃)δ(ppm) : 2.71(3H, s), 5.16(2H, s), 5.18(2H, s), 8.51(1H, s). ¹ H NMR (CF ₃ COOD + DMSO-d ₆ + CDCl ₃ ) δ (ppm): 2.71 (3H, s), 5.16 (2H, s), 5.18 (2H, s), 8.51 (1H, s).

[실시예 9]Example 9

7-아미노-2, 3-디히드로-1H-피롤로[3.4.C]피리딘 트리히드로클로라이드의 제조Preparation of 7-amino-2, 3-dihydro-1H-pyrrolo [3.4.C] pyridine trihydrochloride

7-아미노-N-벤질-2, 3-디히드로-1H-피롤로[3.4.C]피리딘 1g을 에탄올 50㎖에 용해시킨 후, 여기에 10% Pd/c 1.1g을 첨가시키고 다시 6시간 동안 301bs의 수소를 투입시켰다. 이어서 촉매를 여과해내고 물로 세척시킨 다음, 그 세척액과 여액을 수집하고 여기에다 진한염산 2㎖를 첨가시킨 후, 감압증류 및 건조시킨 결과, 상기 목적화합물 0.5g을 얻었다.After dissolving 1 g of 7-amino-N-benzyl-2, 3-dihydro-1H-pyrrolo [3.4.C] pyridine in 50 ml of ethanol, 1.1 g of 10% Pd / c was added thereto, followed by another 6 hours. 301bs of hydrogen was added. Subsequently, the catalyst was filtered off, washed with water, the washed solution and the filtrate were collected, and 2 ml of concentrated hydrochloric acid was added thereto, followed by distillation under reduced pressure and drying to obtain 0.5 g of the target compound.

원소분석Elemental analysis

이론치(%) : C; 34.38, H; 4.95, N; 17.18Theoretical value (%): C; 34.38, H; 4.95, N; 17.18

실측치(%) : C; 34.21, H; 4.81, N; 17.11Found (%): C; 34.21, H; 4.81, N; 17.11

¹H NMR(CF₃COOD+DMSO-d₆)δ(ppm) : 5.09(2H, s), 5.12(2H, s), 8.51(1H, s), 8.58(1H, s). ¹ H NMR (CF ₃ COOD + DMSO-d ₆ ) δ (ppm): 5.09 (2H, s), 5.12 (2H, s), 8.51 (1H, s), 8.58 (1H, s).

[실시예 10]Example 10

7-메틸아미노-2, 3-디히드로-1H-피롤로[3.4.C]피리딘 트리히드로클로라이드의 제조Preparation of 7-methylamino-2, 3-dihydro-1H-pyrrolo [3.4.C] pyridine trihydrochloride

7-메틸아미노-N-벤질-2, 3-디히드로-1H-피롤로[3.4.C]피리딘 1g을 에탄올 30㎖에 용해시킨 다음, 10% Pd/c 1.05g을 첨가시킨 후, 여기에 301bs의 수소가스를 6시간 동안에 걸쳐 첨가시켰다. 이어서 촉매를 여과해내고 물로 세척시킨 후, 진한 염산 2㎖를 첨가시켜 감압증류 및 건조시킨 결과, 상기 목적화합 물 0.6g을 얻었다.1 g of 7-methylamino-N-benzyl-2, 3-dihydro-1H-pyrrolo [3.4.C] pyridine was dissolved in 30 ml of ethanol, and then 1.05 g of 10% Pd / c was added thereto. 301bs of hydrogen gas was added over 6 hours. Subsequently, the catalyst was filtered off, washed with water, distilled under reduced pressure and dried by adding 2 ml of concentrated hydrochloric acid, and 0.6 g of the target compound was obtained.

원소분석Elemental analysis

이론치(%) : C; 37.16, H; 5.46, N; 16.25Theoretical value (%): C; 37.16, H; 5.46, N; 16.25

실측치(%) : C; 37.10, H; 5.39, N; 16.15Found (%): C; 37.10, H; 5.39, N; 16.15

¹H NMR(CF₃COOD+DMSO-d₆)δ(ppm) : 5.41(2H, s), 5.16(2H, s), 8.56(1H, s). ¹ H NMR (CF ₃ COOD + DMSO-d ₆ ) δ (ppm): 5.41 (2H, s), 5.16 (2H, s), 8.56 (1H, s).

[실시예 11]Example 11

6-아미노-7-시아노-2, 3-디히드로-1H-피롤로[3.4.C]피리딘 트리히드로클로라이드의 제조Preparation of 6-amino-7-cyano-2, 3-dihydro-1H-pyrrolo [3.4.C] pyridine trihydrochloride

6-아미노-2-t-부톡시카르보닐-7-시아노-2, 3-디히드로-1H-피롤로[3. 4.C.]피리딘 1g 및 티오페놀 0.4㎖를 20% 히드로클로라이드/메탄올 용액 10㎖에 첨가시키고 실온에서 3시간 동안 교반시킨 다음, 감압하에 용매를 증류시킨 후, 에틸에테르와 아세토니트릴로 세척 및 건조시켜 상기 목적화합물 0.91g 얻었다.6-amino-2-t-butoxycarbonyl-7-cyano-2, 3-dihydro-1H-pyrrolo [3. 4.C.] 1 g of pyridine and 0.4 ml of thiophenol were added to 10 ml of a 20% hydrochloride / methanol solution, stirred at room temperature for 3 hours, the solvent was distilled off under reduced pressure, washed with ethyl ether and acetonitrile and It dried and obtained 0.91g of the target compounds.

원소분석Elemental analysis

이론치(%) : C; 35.65, H; 4.11, N; 20.78Theoretical value (%): C; 35.65, H; 4.11, N; 20.78

실측치(%) : C; 35.59, H; 4.07, N; 20.84Found (%): C; 35.59, H; 4.07, N; 20.84

¹H NMR(CF₃COOD+DMSO-d₆)δ(ppm) : 5.16(2H, s), 5.17(2H, s), 8.53(1H, s). ¹ H NMR (CF ₃ COOD + DMSO-d ₆ ) δ (ppm): 5.16 (2H, s), 5.17 (2H, s), 8.53 (1H, s).

[실시예 12]Example 12

4-아미노-7-시아노-2, 3-디히드로-1H-피롤로[3.4.C]피리딘 트리히드로클로라이드의 제조Preparation of 4-amino-7-cyano-2, 3-dihydro-1H-pyrrolo [3.4.C] pyridine trihydrochloride

4-아미노-2-t-부톡시카르보닐-7-시아노-2, 3-디히드로-1H-피롤로[3. 4.C]피리딘 1g 및 티오페놀 0.4㎖를 20% 히드로클로라이드/메탄올 용액 10㎖에 첨가시키고 실온에서 3시간 동안 교반시킨 다음, 용매를 감압증류시켰다. 이어서 에틸에테르와 아세토니트릴로 세척 및 건조시켜 상기 목적화합물 0.9g을 얻었다.4-amino-2-t-butoxycarbonyl-7-cyano-2, 3-dihydro-1H-pyrrolo [3. 4.C] 1 g of pyridine and 0.4 ml of thiophenol were added to 10 ml of a 20% hydrochloride / methanol solution, stirred at room temperature for 3 hours, and the solvent was distilled under reduced pressure. Subsequently, 0.9 g of the target compound was obtained by washing and drying with ethyl ether and acetonitrile.

원소분석Elemental analysis

실측치(%) : C; 35.61, H; 4.02, N; 20.86Found (%): C; 35.61, H; 4.02, N; 20.86

[실시예 13]Example 13

1-시클로프로필-7[2, 3]-디히드로-1H-피롤로[3.4.C]피리딘-6, 8-디플루오르-1, 4-디히드로-4-옥소-3-퀴놀린카르복실산의 제조1-cyclopropyl-7 [2, 3] -dihydro-1H-pyrrolo [3.4.C] pyridine-6, 8-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid Manufacture

2, 3-디히드로-1H-피롤로[3.4.C]피리딘 디히드로브로마이드 0.2g을 무수아세토니트릴 2㎖에 첨가시킨 후, 여기에 DBU 0.23㎖를 투입하여 용해시킨 다음 1-시클로프로필-6, 7, 8-트리플루오르-1, 4-디히드로-4-옥소-3-퀴놀린카르복실산 0.18g을 첨가하고 5시간 동안 환류시켰다. 이 반응용액을 0℃로 냉각하여 침전물을 여과한 후 아세토니트릴 5㎖와 물5㎖로 세척 및 건조시켜 상기 목적화합물 0.16g을 얻었다.0.2 g of 2,3-dihydro-1H-pyrrolo [3.4.C] pyridine dihydrobromide was added to 2 ml of anhydrous acetonitrile, and 0.23 ml of DBU was added thereto to dissolve it, followed by 1-cyclopropyl-6. 0.18 g of 7, 8-trifluor-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid was added and refluxed for 5 hours. The reaction solution was cooled to 0 ° C., the precipitate was filtered, washed with 5 ml of acetonitrile and 5 ml of water and dried to obtain 0.16 g of the target compound.

원소분석Elemental analysis

이론치(%) : C; 62.66, H; 3.94, N; 10.96Theoretical value (%): C; 62.66, H; 3.94, N; 10.96

실측치(%) : C; 62.61, H; 3.91, N; 10.92Found (%): C; 62.61, H; 3.91, N; 10.92

¹H NMR(CDCl₃)δ(ppm) : 1.10∼1.32(4H, m), 4.01(1H, m), 5.21(4H, m), 7.30(1H, d), 7.93(1H, d), 8.56(1H, d), 8.62(1H, s), 8.78(1H, s). ¹ H NMR (CDCl ₃ ) δ (ppm): 1.10 to 1.32 (4H, m), 4.01 (1H, m), 5.21 (4H, m), 7.30 (1H, d), 7.93 (1H, d), 8.56 (1H, d), 8.62 (1H, s), 8.78 (1H, s).

[실시예 14]Example 14

1-시클로프로필-7-[2, 3-디히드로-1H-피롤로[3.4.C]피리딘-2-일]-6 -플로오르-1, 4-디히드로-옥소-1, 8-나프티리딘-3-카르복실산의 제조1-cyclopropyl-7- [2,3-dihydro-1H-pyrrolo [3.4.C] pyridin-2-yl] -6-floor-1, 4-dihydro-oxo-1, 8-naphti Preparation of Ridine-3-carboxylic Acid

2, 3-디히드로-1H-피롤로[3.4.C]피리딘 디히드로브로마이드 0.2g을 무수아세토니트릴 2㎖에 첨가시킨 후, 여기에 DBU 0.23㎖을 투입하여 용해시킨 다음 1-시클로프로필-6-플루오르-7-클로로-1, 4-디히드로-4-옥소-1, 8-나프티리딘-3-카르복실산 0.21g을 첨가했다. 이 반응혼합물을 5시간 동안 환류시킨 다음 상기 실시예 13에서와 동일한 방법으로 처리한 결과, 상기 목적화합물 0.21g을 얻었다.0.2 g of 2,3-dihydro-1H-pyrrolo [3.4.C] pyridine dihydrobromide was added to 2 ml of anhydrous acetonitrile, and 0.23 ml of DBU was added thereto to dissolve it, followed by 1-cyclopropyl-6. 0.21 g of -fluoro-7-chloro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid was added. The reaction mixture was refluxed for 5 hours and then treated in the same manner as in Example 13 to obtain 0.21 g of the target compound.

원소분석Elemental analysis

이론치(%) : C; 62.29, H; 4.13, N; 15.29Theoretical value (%): C; 62.29, H; 4.13, N; 15.29

실측치(%) : C; 62.11, H; 4.10, N; 15.23Found (%): C; 62.11, H; 4.10, N; 15.23

¹H NMR(CDCl₃)δ(ppm) : 1.10∼1.30(4H, m), 4.01(1H, m), 5.20(4H, d), 7.85(1H, d), 7.85(1H, d), 7.30(1H, d), 8.55(1H, d), 8.60(1H, s), 8.75(1H, s). ¹ H NMR (CDCl ₃ ) δ (ppm): 1.10 to 1.30 (4H, m), 4.01 (1H, m), 5.20 (4H, d), 7.85 (1H, d), 7.85 (1H, d), 7.30 (1H, d), 8.55 (1H, d), 8.60 (1H, s), 8.75 (1H, s).

[실시예 15]Example 15

7-[(2, 3-디히드로-1H-피롤로[3.4.C]피리딘)-2-일]-1에틸-6-플루올-1, 4-디히드로-4-옥소-3-퀴놀린카르복실산의 제조7-[(2,3-dihydro-1H-pyrrolo [3.4.C] pyridin) -2-yl] -1ethyl-6-fluol-1, 4-dihydro-4-oxo-3-quinoline Preparation of Carboxylic Acids

2, 3-디히드로-1H-피롤로[3.4.C]피리딘 디히드로브로마이드 0.2g을 무수아세토니트릴 3㎖에 첨가시킨 후, 여기서 DBU 0.26㎖를 투입하여 용해시킨 다음 1-에틸-6, 7-티플루오르-1, 4-디히드로-4-옥소-3-퀴놀린카르복실산 0.2ig을 첨가하고 8시간 동안 환류시켰다. 이 반응혼합물을 상기 실시예 13에서와 동일한 방법으로 실시한 결과, 상기 목적화합물 0.22g을 얻었다.0.2 g of 2,3-dihydro-1H-pyrrolo [3.4.C] pyridine dihydrobromide was added to 3 ml of anhydrous acetonitrile, where 0.26 ml of DBU was added and dissolved, followed by 1-ethyl-6, 7 0.2 ig of -Tifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was added and refluxed for 8 hours. As a result of this reaction mixture in the same manner as in Example 13, 0.22 g of the target compound was obtained.

원소분석Elemental analysis

이론치(%) : C:64.59, H; 4.56, N; 11.89Theoretical (%): C: 64.59, H; 4.56, N; 11.89

실측치(%) : C; 64.51, H; 4.52, N; 12.01Found (%): C; 64.51, H; 4.52, N; 12.01

¹H NMR(CDCl3)δ(ppm) : 1.35(3H, t), 3.60(2H, q), 5.20(4H, d), 7.50(1H, d), 7.30(1H, d), 7.29(1H, d), 8.55(1H, d), 8.61(1H, s), 8.78(1H, s). ¹ H NMR (CDCl 3) δ (ppm): 1.35 (3H, t), 3.60 (2H, q), 5.20 (4H, d), 7.50 (1H, d), 7.30 (1H, d), 7.29 (1H, d), 8.55 (1 H, d), 8.61 (1 H, s), 8.78 (1 H, s).

[실시예 16]Example 16

7-[7-클로로-6-메틸-2, 3-디히드로-1H-피로로[3.4.C]피리딘-2-일]-1-시클로프로필-6, 8-디플루오르-1, 4-디히드로-4-옥소-3-퀴놀린 카르복실산의 제조7- [7-chloro-6-methyl-2, 3-dihydro-1H-pyrrolo [3.4.C] pyridin-2-yl] -1-cyclopropyl-6, 8-difluoro-1, 4- Preparation of Dihydro-4-oxo-3-quinoline Carboxylic Acid

7-클로로-6-메틸-2, 3-디히드로-1H-피롤로[3.4.C]피리딘 이염산염 0.1g을 무수아세토니트릴 2㎖에 첨가시킨 후, 여기에 DBU 0.16㎖를 넣어 용해시킨 다음 1-시클로프로필-6, 7, 8-트리플루오르-1, 4-디히드로-4-옥소-3-퀴놀린카르복실산 0.11g을 투입시켰다. 이어서 상기 반응혼합물을 5시간 동안 환류시킨 다음. 실시예 13과 같은 방법으로 처리하여 상기 목적화합물 0.11g을 얻었다.0.1 g of 7-chloro-6-methyl-2, 3-dihydro-1H-pyrrolo [3.4.C] pyridine dihydrochloride was added to 2 ml of anhydrous acetonitrile, and then dissolved in 0.16 ml of DBU. 0.11 g of 1-cyclopropyl-6, 7, 8-trifluor-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid was added thereto. The reaction mixture was then refluxed for 5 hours. 0.11 g of the title compound was obtained in the same manner as in Example 13.

원소분석Elemental analysis

이론치(%) : C; 65.71, H; 4.20, N; 10.95Theoretical value (%): C; 65.71, H; 4.20, N; 10.95

실측치(%) : C; 65.63, H; 4.05, N; 10.82Found (%): C; 65.63, H; 4.05, N; 10.82

¹H NMR(CDCl₃)δ(ppm) : 1.10∼1.30(4H, m), 4.01(1H, m), 4.80(2H, m), 5.10(2H, s), 7.85(1H, d), 8.50(1H, s), 8.75(1H, s). ¹ H NMR (CDCl ₃ ) δ (ppm): 1.10 to 1.30 (4H, m), 4.01 (1H, m), 4.80 (2H, m), 5.10 (2H, s), 7.85 (1H, d), 8.50 (1 H, s), 8.75 (1 H, s).

[실시예 17]Example 17

7-[7-클로로-6-메틸-2, 3-디히드로-1H-피롤로[3.4.C]피리딘-2-일]-1-에틸-6-플루오르-1, 4-디하이드로-4-옥소-3-퀴놀린 카르복실산의 제조7- [7-chloro-6-methyl-2, 3-dihydro-1H-pyrrolo [3.4.C] pyridin-2-yl] -1-ethyl-6-fluor-1, 4-dihydro-4 -Oxo-3-quinoline Carboxylic Acid

7-클로로-6-메틸-2, 3-디히드로-1H-피롤로[3.4.C]피리딘 이염산염 0.2g을 무수아세토니아세토니트릴 3㎖에 첨가시킨 후, 여기에 DBU 0.35㎖를 넣어 용해시킨 다음 1-에틸-6, 7-티플루오르-1, 4-디히드로-4-옥소-3-퀴놀린카르복실산 0.21g을 투입시키고 5시간 동안 환류시켰다. 이어서, 상기 실시예 13과 같은 방법으로 처리하여 상기 목적화합물 0.12g을 얻었다.0.2 g of 7-chloro-6-methyl-2 and 3-dihydro-1H-pyrrolo [3.4.C] pyridine dihydrochloride were added to 3 ml of anhydrous acetonitrile nitrile, and 0.35 ml of DBU was added thereto to dissolve. Then, 0.21 g of 1-ethyl-6, 7-thifluoro-1, and 4-dihydro-4-oxo-3-quinolinecarboxylic acid were added thereto, and the mixture was refluxed for 5 hours. Subsequently, 0.12 g of the target compound was obtained by the same method as in Example 13.

원소분석Elemental analysis

이론치(%) : C; 67.89, H; 4.84, N; 11.88Theoretical value (%): C; 67.89, H; 4.84, N; 11.88

실측치(%) : C; 67.11, H; 4.89, N; 11.75Found (%): C; 67.11, H; 4.89, N; 11.75

¹H NMR(CDCl3) δ(ppm) : 1.30(3H, t), 2.50(3H, s), 3.60(2H, q), 4.82(2H, s), 5.12(2H, s), 7.50(1H, d), 7.75((1H, d), 8.52(1H, s), 8.78(1H, s). ¹ H NMR (CDCl 3) δ (ppm): 1.30 (3H, t), 2.50 (3H, s), 3.60 (2H, q), 4.82 (2H, s), 5.12 (2H, s), 7.50 (1H, d), 7.75 ((1 H, d), 8.52 (1 H, s), 8.78 (1 H, s).

[실시예 18]Example 18

7-[7-클로로-6-메틸-2, 3-디히드로-1H-피롤로[3.4.C]피리딘-2-일]-1-시클로프로필-6-플루오르-1, 4-디히드로-4-옥소-1, 8-나프티리딘-3-퀴놀린카르복실산의 제조7- [7-chloro-6-methyl-2, 3-dihydro-1H-pyrrolo [3.4.C] pyridin-2-yl] -1-cyclopropyl-6-fluor-1, 4-dihydro- Preparation of 4-oxo-1,8-naphthyridine-3-quinolinecarboxylic acid

7-클로로-6-메틸-2, 3-디히드로-1H-피롤로[3.4.C]피리딘 이염산염 0.2g을 무수아세트니트릴 3㎖에 첨가시킨 후, 여기에 DBU 0.38㎖를 넣어 용해시킨 다음 1-시클로프로필-6-플루오르-7-클로로-1, 4-디히드로-4-옥소-1, 8-나프티리딘3-퀴놀린카르복실산 0.19g을 투입하고 5시간 동안 환류시켰다. 이어서 상기 실시예 13과 같은 방법으로처리한 결과, 상기 목적화학물 0.22g을 얻었다.0.2 g of 7-chloro-6-methyl-2 and 3-dihydro-1H-pyrrolo [3.4.C] pyridine dihydrochloride were added to 3 ml of anhydrous acetonitrile, and 0.38 ml of DBU was added thereto to dissolve. 0.19 g of 1-cyclopropyl-6-fluoro-7-chloro-1, 4-dihydro-4-oxo-1, 8-naphthyridine3-quinolinecarboxylic acid was added and refluxed for 5 hours. Subsequently, the same procedure as in Example 13 was carried out to obtain 0.22 g of the target chemical.

원소분석Elemental analysis

계산치(%) : C; 57.91, H; 3.89, N; 13.42Calculated (%): C; 57.91, H; 3.89, N; 13.42

실측치(%) : C; 57.95, H; 3.77, N; 13.42Found (%): C; 57.95, H; 3.77, N; 13.42

¹H NMR(CDCl3) δ(ppm) : 1.10∼1.32(4H, m), 2.50(3H, s), 4.02(1H, m), 4.75(2H, s), 5.15(2H, s), 7.70(1H, d), 8.50(1H, s), 8.75(1H, s) ¹ H NMR (CDCl 3) δ (ppm): 1.10 to 1.32 (4H, m), 2.50 (3H, s), 4.02 (1H, m), 4.75 (2H, s), 5.15 (2H, s), 7.70 ( 1H, d), 8.50 (1H, s), 8.75 (1H, s)

[실시예 19]Example 19

7-[7-아미노-2, 3-디히드로-1H-피롤로[3.4.C]피리딘-2-일]-1-시클로프로필-6, 8-디플루오프-1, 4-디히드로-4-옥소-3-퀴놀린 카르복실산의 제조7- [7-amino-2, 3-dihydro-1H-pyrrolo [3.4.C] pyridin-2-yl] -1-cyclopropyl-6, 8-difluoro-1, 4-dihydro- Preparation of 4-oxo-3-quinoline carboxylic acid

7-아미노-2, 3-디히드로-1H-피롤로[3.4.C]피리딘 트리히드로 클로라이드 0.2g을 무수아세토니트릴 3㎖에 첨가시킨 후, 여기에 DBU 0.35㎖를 용해시킨 다음 1-시클로프로필-6, 7, 8-트리플루오르-1, 4-디히드로-4-옥소-3-퀴놀린카르복실산 0.18g을 투입하고 5시간 동안 환류시켰다. 이어서, 상기 실시예 13과 같은 방법으로 처리한 결과, 상기 목적화합물을 0.17g을 얻었다.0.2 g of 7-amino-2,3-dihydro-1H-pyrrolo [3.4.C] pyridine trihydrochloride was added to 3 ml of anhydrous acetonitrile, and then 0.35 ml of DBU was dissolved therein, followed by 1-cyclopropyl 0.18 g of -6, 7, 8-trifluor-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid was added and refluxed for 5 hours. Subsequently, 0.17 g of the target compound was obtained as a result of treatment in the same manner as in Example 13.

원소분석Elemental analysis

계산치(%) : C; 60.30, H; 4.05, N; 14.06Calculated (%): C; 60.30, H; 4.05, N; 14.06

실측치(%) : C; 60.12, H; 4.01, N; 14.11Found (%): C; 60.12, H; 4.01, N; 14.11

¹H NMR(DMSO-d6) δ(ppm) : 1.10∼1.30(4H, m), 4.02(1H, m), 4.50(2H, s), 4.75(2H, s), 7.90(1H, d), 8.32(1H, s), 8.57(1H, s), 8.78(1H, s). ¹ H NMR (DMSO-d6) δ (ppm): 1.10 to 1.30 (4H, m), 4.02 (1H, m), 4.50 (2H, s), 4.75 (2H, s), 7.90 (1H, d), 8.32 (1 H, s), 8.57 (1 H, s), 8.78 (1 H, s).

[실시예 20]Example 20

7-[7-아미노-2, 3-디히드로-1H-피롤로[3.4.C]피리딘-2-일]-1-시클로프로필-6-플루오르-1, 4-디히드로-4-옥소-1, 8-나프티리딘-3-퀴놀린 카르복실산의 제조7- [7-amino-2, 3-dihydro-1H-pyrrolo [3.4.C] pyridin-2-yl] -1-cyclopropyl-6-fluor-1, 4-dihydro-4-oxo- Preparation of 1,8-naphthyridine-3-quinoline carboxylic acid

7-아미노-2, 3-디히드로-1H-피롤로[3.4.C]피리딘 트리히드로 클로라이드 0.2g을 무수아세토니트릴 3㎖에 첨가시킨 후, 여기에 DBU 0.4㎖를 넣어 용해시킨 다음 1-시클로프로필-6-플루오르-7-클로로-1, 4-디히드로-4-옥소-1, 8-나프티리딘-3-퀴놀린카르복실산 0.21g을 투입하고 5시간 동안 환류시켰다. 이어서, 상기 실시예 13과 같은 방법으로 처리하여 상기 목적화합물 0.17을 얻었다.0.2 g of 7-amino-2,3-dihydro-1H-pyrrolo [3.4.C] pyridine trihydrochloride was added to 3 ml of anhydrous acetonitrile, and 0.4 ml of DBU was dissolved therein to dissolve 1-cyclone. 0.21 g of propyl-6-fluoro-7-chloro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-quinolinecarboxylic acid was added and refluxed for 5 hours. Subsequently, the same procedure as in Example 13 was carried out to obtain 0.17 of the target compound.

원소분석Elemental analysis

계산치(%) : C; 59.84, H; 4.23, N; 18.36Calculated (%): C; 59.84, H; 4.23, N; 18.36

실측치(%) : C; 59.81, H; 4.19, N; 18.23Found (%): C; 59.81, H; 4.19, N; 18.23

¹H NMR(DMSO-d6)δ(ppm) : 1.10∼1.30(4H, m), 3.95(1H, m), 4.55(2H, s), 4.86(2H, s), 7.70(1H, d), 8.30(1H, s), 8.55(1H, s), 8.75(1H, s). ¹ H NMR (DMSO-d 6) δ (ppm): 1.10 to 1.30 (4H, m), 3.95 (1H, m), 4.55 (2H, s), 4.86 (2H, s), 7.70 (1H, d), 8.30 (1 H, s), 8.55 (1 H, s), 8.75 (1 H, s).

[실시예 21]Example 21

7-[7-아미노-2, 3-디히드로-1H-피롤로[3.4.C]피리딘-2-일]-1-에틸-6-플루오루-1, 4-디히드로-4-옥소-3-퀴놀린카르복실산의 제조7- [7-amino-2, 3-dihydro-1H-pyrrolo [3.4.C] pyridin-2-yl] -1-ethyl-6-fluorolu-1, 4-dihydro-4-oxo- Preparation of 3-Quinolinecarboxylic Acid

7-아미노-2, 3-디히드로-1H-피롤로[3.4.C]피리딘 트리히드로 클로라이드 0.2g을 무수아세토니트릴 3㎖을 첨가시킨 후, 여기에 DBU 0.36㎖를 넣어 용해시킨 다음 1-에틸-6, 7-디플루오르-1, 4-디히드로-4-옥소-3-카르복실산 0.19g를 투입하고 5시간 동안 환류시켰다. 이어서, 상기 실시예 13과 같은 방법으로 처리한 결과, 상기 목적화합물 0.22g을 얻었다.0.2 g of 7-amino-2,3-dihydro-1H-pyrrolo [3.4.C] pyridine trihydrochloride was added to 3 ml of anhydrous acetonitrile, and then dissolved in 0.36 ml of DBU. 0.19 g of -6, 7-difluoro-1, 4-dihydro-4-oxo-3-carboxylic acid was added and refluxed for 5 hours. Subsequently, the same procedure as in Example 13 was carried out to obtain 0.22 g of the target compound.

원소분석Elemental analysis

계산치(%) : C; 61.95, H; 4.65, N; 15.21Calculated (%): C; 61.95, H; 4.65, N; 15.21

실측치(%) : C; 62.10, H; 4.71, N; 16.10Found (%): C; 62.10, H; 4.71, N; 16.10

¹H MR(MSO-d6)δ(ppm) : 1.35(3H, t), 3.60(2H, q), 4.50(2H, s), 4.75(2H, s), 7.65(1H, d)7.90(1H, d), 8.32(1H, s), 8.56(1H, s), 8.75(1H, s). ¹ H MR (MSO-d6) δ (ppm): 1.35 (3H, t), 3.60 (2H, q), 4.50 (2H, s), 4.75 (2H, s), 7.65 (1H, d) 7.90 (1H , d), 8.32 (1H, s), 8.56 (1H, s), 8.75 (1H, s).

[실시예 22]Example 22

7-[7-아미노-6-메틸-2, 3-티히드로-1H-피롤로[3.4.C]피리딘-2-일]-1-시클로프로필-6, 8-디플루오르-1, 4-디히드로-4-옥소-3-퀴놀린카르복실산의 제조7- [7-amino-6-methyl-2, 3-thihydro-1H-pyrrolo [3.4.C] pyridin-2-yl] -1-cyclopropyl-6, 8-difluoro-1, 4- Preparation of Dihydro-4-oxo-3-quinolinecarboxylic Acid

7-아미노-6-메틸-2, 3-디히드로-1H-피롤로[3.4.C]피리딘 트리히드로클로라이드 0.2g을 무수아세토니트릴 3㎖에 첨가시킨 후, 여기에 DBU 0.38㎖를 넣어 용해시킨 다음, 1-시클로프로필-6, 7, 8-트리플루오르-1, 4-디히드로-4-옥소-3-퀴놀린카르복실산 0.19g을 투입하고 5시간 동안 환류시켰다. 이어서, 상기 실시예 13과 같은 방법으로 처리한 결과, 상기 목적화합물 0.19g을 얻었다.0.2 g of 7-amino-6-methyl-2 and 3-dihydro-1H-pyrrolo [3.4.C] pyridine trihydrochloride were added to 3 ml of anhydrous acetonitrile, and 0.38 ml of DBU was added thereto to dissolve. Next, 0.19 g of 1-cyclopropyl-6, 7, 8-trifluor-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid was added thereto, and the mixture was refluxed for 5 hours. Subsequently, the resultant was treated in the same manner as in Example 13 to obtain 0.19 g of the target compound.

원소분석Elemental analysis

계산치(%) : C; 61.16, H; 4.39, N; 13, 59Calculated (%): C; 61.16, H; 4.39, N; 13, 59

실측치(%) : C; 61.11, H; 4.32, N; 13.51Found (%): C; 61.11, H; 4.32, N; 13.51

¹H NMR(DMSO-d6 δ(ppm) : 1.12∼1.32(4H, m), 2.50(3H, s), 4.01(1H, m), 4.68(2H, s), 4.82(2H, s), 7.91(1H, d), 8.45(1H, s), 8.75(1H, s). ¹ H NMR (DMSO-d6 δ (ppm): 1.12 to 1.32 (4H, m), 2.50 (3H, s), 4.01 (1H, m), 4.68 (2H, s), 4.82 (2H, s), 7.91 (1H, d), 8.45 (1H, s), 8.75 (1H, s).

[실시예 23]Example 23

7-[7-아미노6-메틸-2, 3-디히드로-1H-피롤로-[3.4.C]피리딘-2-일]-1-시클로프로필-6-풀루오르-1, 4-디히드로-4-옥소-1, 8-나프티리딘-3-퀴놀린카르복실산의 제조7- [7-amino6-methyl-2, 3-dihydro-1H-pyrrolo- [3.4.C] pyridin-2-yl] -1-cyclopropyl-6-pulluor-1, 4-dihydro Preparation of 4-oxo-1,8-naphthyridine-3-quinolinecarboxylic acid

7-아미노-6-메틸-2, 3-디히드로-1H-피롤로[3.4.C]피리딘 트리히드로라이드 0.2g을 무수아세토니드릴 3㎖에 첨가시킨 후, 여기에 DBU 0.26㎖를 넣어 용해시킨 다음, 1-시클로포로필-6-플루오로-7-클로로-1, 4-디히드로-4-옥소-1, 8-나프티리딘 3-퀴놀린카르복실산 0.21g을 투입하고 5시간 동안 환류시켰다. 실시예 13과 같은 방법으로 처리한 결과, 하여 상기 목저화합물 0.17g을 얻었다.0.2 g of 7-amino-6-methyl-2 and 3-dihydro-1H-pyrrolo [3.4.C] pyridine trihydrolide were added to 3 ml of anhydrous acetonitrile, and 0.26 ml of DBU was added thereto to dissolve. Then, 0.21 g of 1-cycloporophyl-6-fluoro-7-chloro-1, 4-dihydro-4-oxo-1, 8-naphthyridine 3-quinolinecarboxylic acid was added and refluxed for 5 hours. I was. As a result of treatment in the same manner as in Example 13, 0.17 g of the wood compound was obtained.

원소분석Elemental analysis

계산치(%) : C; 60.60, H; 4.83, N; 17, 67Calculated (%): C; 60.60, H; 4.83, N; 17, 67

실측치(%) : C; 60.11, H; 4.79, N; 17.59Found (%): C; 60.11, H; 4.79, N; 17.59

¹H NMR(DMSO-d6) δ(ppm) : 1.10∼1.32(4H, m), 2.51(3H, s), 4.02(1H, m), 4.65(2H, s), 4.90(2H, s), 7.70(1H, d), 8.20(1H, s), 8.80(1H, s). ¹ H NMR (DMSO-d6) δ (ppm): 1.10-1.32 (4H, m), 2.51 (3H, s), 4.02 (1H, m), 4.65 (2H, s), 4.90 (2H, s), 7.70 (1 H, d), 8.20 (1 H, s), 8.80 (1 H, s).

[실시예 24]Example 24

7-[7-아미노-6-메틸-2, 3-디히드로-1H-피로로-[3.4.C]피리딘-2-일]-1- 에틸-6-플루오르-1, 4, -디히드로-4-옥소-3-퀴놀린카르복실산의 제조7- [7-amino-6-methyl-2, 3-dihydro-1H-pyrrolo- [3.4.C] pyridin-2-yl] -1- ethyl-6-fluor-1, 4, -dihydro Preparation of 4-oxo-3-quinolinecarboxylic acid

7-아니노-6-메틸-2, 3-디히드로-1H-피롤로[3.4.C]피리딘 디히드로클로라이드 0.2g을 무수아세트나트릴 3㎖에 첨가시킨 후,여기에 DBU 0.36㎖를 넣어 용해시킨 다음 1-에틸-6, 7-디플루오르-1, 4-디히드로-4-옥소-3-퀴놀린카르복실산 0.19g을 투입하고 5시간 동안 환류시켰다, 이어서, 상기 실시예 13과 같은 방법으로 처리한 결과, 상기 목적화합물 0.17g을 얻었다.0.2 g of 7-anino-6-methyl-2, 3-dihydro-1H-pyrrolo [3.4.C] pyridine dihydrochloride was added to 3 ml of anhydrous acetnatrile, and 0.36 ml of DBU was added thereto. After dissolving, 0.19 g of 1-ethyl-6, 7-difluoro-1, and 4-dihydro-4-oxo-3-quinolinecarboxylic acid were added thereto, and the mixture was refluxed for 5 hours, followed by the same procedure as in Example 13 above. As a result of treatment, 0.17 g of the target compound was obtained.

원소분석Elemental analysis

계산치(%) : C; 62.82, H; 5.01, N; 14.65Calculated (%): C; 62.82, H; 5.01, N; 14.65

실측치(%) : C; 62.71, H; 5.09, N; 14.55Found (%): C; 62.71, H; 5.09, N; 14.55

¹H NMR(DMSO-d6) δ(ppm) : 1.25(3H, t), 2.51(3H, s), 3.60(2H, q), 4.55(2H, s), 4.75(2H, s), 7.56(1H, d), 7.80(1H, d), 8.51(1H, s), 8.85(1H, S). ¹ H NMR (DMSO-d6) δ (ppm): 1.25 (3H, t), 2.51 (3H, s), 3.60 (2H, q), 4.55 (2H, s), 4.75 (2H, s), 7.56 ( 1H, d), 7.80 (1H, d), 8.51 (1H, s), 8.85 (1H, S).

[실시예 25]Example 25

7-[4-클로로-2, 3-디히드로-1H-피롤로[3.4.C]피리딘-2-일]-1-시클로프로필-6, 8-디플루오르-1, 4, -디히드로-4-옥소-3-퀴놀린카르복실산의 제조7- [4-chloro-2, 3-dihydro-1H-pyrrolo [3.4.C] pyridin-2-yl] -1-cyclopropyl-6, 8-difluoro-1, 4, -dihydro- Preparation of 4-oxo-3-quinolinecarboxylic acid

4-클로로-2, 3-디히드로-1H-피롤로[3.4.C]피리딘 디히드로클로라이드 0.2g을 무수아세토니트릴 3㎖에 첨가시킨 후,여기에 DBU 0.25㎖를 넣어 용해시킨 다음 1-시클로프로필-6, 7, 8-트리플루오르-1, 4-디하이드로-4-옥소-3-퀴놀린카르복실산 0.19g을 투입하고 5시간 동안 환류시켰다. 이어서, 상기 실시예 13과 같은 방법으로 처리한 결과, 상기 목적화합물 0.21g을 얻었다.0.2 g of 4-chloro-2,3-dihydro-1H-pyrrolo [3.4.C] pyridine dihydrochloride was added to 3 ml of anhydrous acetonitrile, and then 0.25 ml of DBU was dissolved therein, followed by 1-cyclo 0.19 g of propyl-6, 7, 8-trifluor-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid was added and refluxed for 5 hours. Subsequently, the resultant was treated in the same manner as in Example 13 to obtain 0.21 g of the target compound.

원소분석Elemental analysis

계산치(%) : C; 57.50, H; 3.31, N; 10.05Calculated (%): C; 57.50, H; 3.31, N; 10.05

실측치(%) : C; 57.10, H; 3.31, N; 10.05Found (%): C; 57.10, H; 3.31, N; 10.05

¹H NMR(CDCl3) δ(ppm) : 1.10∼1.30(4H, m), 4.01(1H, m), 4.75(2H, S), 5.25(2H, s), 7.90(1H, d), 8.60(1H, D), 8.75(1H, S). ¹ H NMR (CDCl 3) δ (ppm): 1.10 to 1.30 (4H, m), 4.01 (1H, m), 4.75 (2H, S), 5.25 (2H, s), 7.90 (1H, d), 8.60 ( 1 H, D), 8.75 (1 H, S).

[실시예 26]Example 26

7-[4-클로로-2, 3디히드로-1H-피롤로[3.4.C]피리딘-2-일]-1-시클로프로필-6-플루오르-1, 4-디히드로-4-옥소-1, 8-나프티리딘-3-퀸놀리카르복실산의 제조7- [4-chloro-2,3dihydro-1H-pyrrolo [3.4.C] pyridin-2-yl] -1-cyclopropyl-6-fluor-1, 4-dihydro-4-oxo-1 , 8-naphthyridine-3-quinolicarboxylic acid

4-클로로-2, 3-디히드로-1H-피롤로[3.4.C]피리딘 디히드로클로라이드0.2g을 무수아세토니트릴 3㎖에 첨가시킨 후, 여기에 DBU 0.26㎖를 넣어 용해시킨 다음 1-시클로프로필-6-플루오르-7-클로로-1, 4-디히드로-4-옥소-1, 8-나프티리딘-3-퀴놀린카르복실산 0.21g을 투입하고 5시간 동안 환류시켰다. 이어서, 상기 실시예 13과 같은 방법으로 처리한 결과, 상기 목적화합물 0.31g을 얻었다.0.2 g of 4-chloro-2,3-dihydro-1H-pyrrolo [3.4.C] pyridine dihydrochloride was added to 3 ml of anhydrous acetonitrile, and 0.26 ml of DBU was added thereto to dissolve and then 1-cyclone. 0.21 g of propyl-6-fluoro-7-chloro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-quinolinecarboxylic acid was added and refluxed for 5 hours. Subsequently, 0.31 g of the target compound was obtained as a result of treatment in the same manner as in Example 13.

원소분석Elemental analysis

계산치(%) : C; 56.94, H; 3.52, N; 13.98Calculated (%): C; 56.94, H; 3.52, N; 13.98

실측치(%) : C; 56.85, H; 3.55, N; 13.91Found (%): C; 56.85, H; 3.55, N; 13.91

¹H NMR(CDCl3) δ(ppm) : 1.10∼1.30(4H, m), 4.03(1H, m), 4.78(2H, s), 5.21(2H, s), 7.70(1H, d), 7.35(1H, d), 8.50(1H, d), 8.80(1H, s). ¹ H NMR (CDCl 3) δ (ppm): 1.10 to 1.30 (4H, m), 4.03 (1H, m), 4.78 (2H, s), 5.21 (2H, s), 7.70 (1H, d), 7.35 ( 1H, d), 8.50 (1H, d), 8.80 (1H, s).

[실시예 27]Example 27

7-[4-클로로-2, 3-디히드로-1H-피롤로[3.4.C]피리딘-2-일]-1-에틸-6-플루오르-1, 4, -디히드로-4-옥소-3-퀴놀린카르복실산의 제조7- [4-chloro-2, 3-dihydro-1H-pyrrolo [3.4.C] pyridin-2-yl] -1-ethyl-6-fluor-1, 4, -dihydro-4-oxo- Preparation of 3-Quinolinecarboxylic Acid

4-클로로-2, 3-디히드로-1H-피롤로[3.4.C]피리딘 디히드로클 로라이드 0.2g을 무수아세토니트릴 3㎖에 첨가시킨 후, 여기에 DBU 0.26㎖를 넣어 용해시킨 다음, 1-에틸-6, 7-디플루오르-1, 4-디히드로-4-옥소-3-퀴놀린카르복실산 0.19g을 투입하고 10시간 동안 환류시켰다. 이어서, 상기 실시예 13과 같은 방법으로 처리한 결과, 상기 목적화합물 0.19g을 얻었다.0.2 g of 4-chloro-2,3-dihydro-1H-pyrrolo [3.4.C] pyridine dihydrochloride were added to 3 ml of anhydrous acetonitrile, and 0.26 ml of DBU was added thereto to dissolve it. 0.19 g of 1-ethyl-6, 7-difluoro-1 and 4-dihydro-4-oxo-3-quinolinecarboxylic acid were added and refluxed for 10 hours. Subsequently, the resultant was treated in the same manner as in Example 13 to obtain 0.19 g of the target compound.

원소분석Elemental analysis

계산치(%) : C; 58.85 H; 3.89, N; 10.84Calculated (%): C; 58.85 H; 3.89, N; 10.84

실측치(%) : C; 58.81, H; 3.81, N; 10.79Found (%): C; 58.81, H; 3.81, N; 10.79

¹H NMR(CDCl3) δ(ppm) : 11.35(3H, t), 3.80(2H, q), 4.70(2H, s), 5.21(2H, s), 7.35(1H, d), 7.55(1H, d), 7.85(1H, d), 8.50(1H, d), 8.90(1H, s). ¹ H NMR (CDCl 3) δ (ppm): 11.35 (3H, t), 3.80 (2H, q), 4.70 (2H, s), 5.21 (2H, s), 7.35 (1H, d), 7.55 (1H, d), 7.85 (1 H, d), 8.50 (1 H, d), 8.90 (1 H, s).

[실시예 28]Example 28

7-[7-클로로-2, 3-디히드로-1H-피롤로-[3.4.C]피리딘-2-일]-6, 8디플루오르-1, 4-디히드로-4-옥소-3- 카르복실산의 제조7- [7-chloro-2, 3-dihydro-1H-pyrrolo- [3.4.C] pyridin-2-yl] -6, 8difluoro-1, 4-dihydro-4-oxo-3- Preparation of Carboxylic Acids

7-클로로-2, 3-디히드로-1H-피롤로[3.4.C]피리딘 디히드로클로라이드 0.2g을 무수아세토니트릴3㎖에 넣고 DBU 0.24㎖를 넣어 용해시킨 다음 1-시클로프로필-6, 7, 8-프리프루오르-1, 4-디히드로-4-옥소-3-퀴놀린카르복실산 0.18g을 투입하고 6시간 동안 환류시켰다. 이어서, 상기 실시예 13과 같은 방법으로 처리한 결과, 상기 목적화합물 0.18g을 얻었다.0.2 g of 7-chloro-2,3-dihydro-1H-pyrrolo [3.4.C] pyridine dihydrochloride was added to 3 ml of anhydrous acetonitrile, 0.24 ml of DBU was dissolved, and then 1-cyclopropyl-6, 7 , 8-prefluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid 0.18g was added and refluxed for 6 hours. Subsequently, the same process as in Example 13 was carried out to obtain 0.18 g of the target compound.

원소분석Elemental analysis

계산치(%) : C; 57.59, H; 3.38, N; 10.06Calculated (%): C; 57.59, H; 3.38, N; 10.06

실측치(%) : C; 57.11, H; 3.32, N; 10.01Found (%): C; 57.11, H; 3.32, N; 10.01

¹H NMR(CDCl3)δ(ppm) : 1.10∼1.32(4H, m), 4.01(1H, m), 4.75(2H, s), 5.15(2H, s), 7.95(1H, d), 8.50(1H, s), 8.61(1H, s), 8.75(1H, S). ¹ H NMR (CDCl 3) δ (ppm): 1.10 to 1.32 (4H, m), 4.01 (1H, m), 4.75 (2H, s), 5.15 (2H, s), 7.95 (1H, d), 8.50 ( 1 H, s), 8.61 (1 H, s), 8.75 (1 H, S).

[실시예 29]Example 29

7-[7-클로로-2, 3-디히드로-1H-피롤로[3.4.C]피리딘-2-일]-1-시클로프로필-6-플루오르-1, 4-디히드로-4-옥소-1, 8-나프티리딘-3-카르복실산의 제조7- [7-chloro-2, 3-dihydro-1H-pyrrolo [3.4.C] pyridin-2-yl] -1-cyclopropyl-6-fluor-1, 4-dihydro-4-oxo- Preparation of 1,8-naphthyridine-3-carboxylic acid

7-클로로-2, 3-디히드로-1H-피롤로[3.4.C]피리딘 디히드로클로라이드 0.2g을 무수아세토니트릴 3㎖에 첨가시킨 후, 여기에 DBU 0.25㎖를 넣어 용해시킨 다음 1-시클로프로필-6-플루오르-7-클로로-1, 4-디히드로-4-옥소-1, 8-나프티리딘-3-카르복실산 0.18g을 투입하고 3시간 동안 환류시켰다. 이어서, 상기 실시예 13과 같은 방법으로 처리한 결과, 상기 목적화합물 0.23g을 얻었다.0.2 g of 7-chloro-2,3-dihydro-1H-pyrrolo [3.4.C] pyridine dihydrochloride was added to 3 ml of anhydrous acetonitrile, and then 0.25 ml of DBU was dissolved therein, followed by 1-cyclo 0.18 g of propyl-6-fluoro-7-chloro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid was added and refluxed for 3 hours. Subsequently, 0.23 g of the target compound was obtained as a result of treatment in the same manner as in Example 13.

[원소분서][Element element]

계산치(%) : C; 59.64, H; 3.52, N; 13.98Calculated (%): C; 59.64, H; 3.52, N; 13.98

실측치(%) : C; 56.90 H; 3.48, N; 13.85Found (%): C; 56.90 H; 3.48, N; 13.85

¹H NMR(CDCl3) δ(ppm) : 1.10∼1.30(4H, m), 4.01(1H, m), 4.80(2H, s), 5.20(2H, s), 7.65(1H, d), 8.55(1H, s), 8.56(1H, s). ¹ H NMR (CDCl 3) δ (ppm): 1.10 to 1.30 (4H, m), 4.01 (1H, m), 4.80 (2H, s), 5.20 (2H, s), 7.65 (1H, d), 8.55 ( 1 H, s), 8.56 (1 H, s).

[실시예 30]Example 30

7-[7-클로로-2, 3-디히드로-1H-피롤로-[3.4.C]피리딘-2-일]-에틸-6-플루오르 -1, 4-디히드로-4-옥소-3-카르복실산의 제조7- [7-chloro-2, 3-dihydro-1H-pyrrolo- [3.4.C] pyridin-2-yl] -ethyl-6-fluor-1, 4-dihydro-4-oxo-3- Preparation of Carboxylic Acids

7-클로로-2, 3-디히드로-1H-피롤로-[3.4.C]피리딘 디히드로클로라이 0.2g을 무수아세토니트릴 3㎖에 첨가시킨 후, 여기에 DBU 0.25㎖를 넣어 용해시킨 다음 1-에틸-6, 6-디플루오르-1, 4-디히드로-4-옥소-3-퀴놀린카르복실산-0.19g을 투입하고 8시간 동안 환류시켰다. 이어서, 상기 실시예 13과 같은 방법으로 처리한 결과, 상기 목적화합물 0.22g을 얻었다.0.2 g of 7-chloro-2,3-dihydro-1H-pyrrolo- [3.4.C] pyridine dihydrochlorai was added to 3 ml of anhydrous acetonitrile, and then 0.25 ml of DBU was dissolved therein, followed by 1 -Ethyl-6, 6-difluor-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid-0.19 g were added and refluxed for 8 hours. Subsequently, the same procedure as in Example 13 was carried out to obtain 0.22 g of the target compound.

원소분석Elemental analysis

계산치(%) : C; 67.16, H; 4.45, N; 12.37Calculated (%): C; 67.16, H; 4.45, N; 12.37

실측치(%) : C; 67.11, H; 4.41, N; 12.32Found (%): C; 67.11, H; 4.41, N; 12.32

¹H NMR(CDCl3) δ : 1.30(3H, t), 3.65(2H, q), 4.86(2H, s), 5.20(2H, s), 7.57(1H, d), 7.82(1H, d), 8.65(1H, s), 8.61(1H, s), 8.87(1H, s). ¹ H NMR (CDCl3) δ: 1.30 (3H, t), 3.65 (2H, q), 4.86 (2H, s), 5.20 (2H, s), 7.57 (1H, d), 7.82 (1H, d), 8.65 (1 H, s), 8.61 (1 H, s), 8.87 (1 H, s).

[실시예 31]Example 31

7-[7-히드록시-2, 3-디히드로-1H-피롤로[3.4.C]피리딘-2-일]-6-플루오르-1, 4-디히드로-4-옥소-3-퀴놀린카르복실산의 제조7- [7-hydroxy-2, 3-dihydro-1H-pyrrolo [3.4.C] pyridin-2-yl] -6-fluor-1, 4-dihydro-4-oxo-3-quinolinecar Preparation of Acids

7-히드록시-2, 3-디히드로-1H-피롤로[3.4.C]피리딘 디히드로 클로라이드 0.2g을 무수아세토니트릴 3㎖에 첨가시킨 후, 여기에 DBU 0.26㎖를 넣어 용해시킨 다음 1-에틸-6, 7-디플루오르-1, 4-디히드로-4-옥소-3-카르복실산 0.21g을 투입하고 10시간 동안 환류시켰다. 이어서, 상기 실시예 13과 같은 방법으로 처리한 결과, 상기 목적화합물 0.22g을 얻었다.0.2 g of 7-hydroxy-2,3-dihydro-1H-pyrrolo [3.4.C] pyridine dihydrochloride was added to 3 ml of anhydrous acetonitrile, and 0.26 ml of DBU was dissolved therein, followed by 1- 0.21 g of ethyl-6, 7-difluor-1, 4-dihydro-4-oxo-3-carboxylic acid was added and refluxed for 10 hours. Subsequently, the same procedure as in Example 13 was carried out to obtain 0.22 g of the target compound.

원소분석Elemental analysis

계산치(%) : C; 61.79, H; 4.37, N; 11.38Calculated (%): C; 61.79, H; 4.37, N; 11.38

실측치(%) : C; 61.71, H; 4.32, N; 11.32Found (%): C; 61.71, H; 4.32, N; 11.32

¹H NMR(CDCl3) δ : 1.45(3H, t), 3.90(2H, q), 4.75(2H, s), 4.95(2H, s), 7.55(1H, d), 7.90(1H, d), 8.50(1H, s), 8.61(1H, s), 8.75(1H, s). ¹ H NMR (CDCl 3) δ: 1.45 (3H, t), 3.90 (2H, q), 4.75 (2H, s), 4.95 (2H, s), 7.55 (1H, d), 7.90 (1H, d), 8.50 (1 H, s), 8.61 (1 H, s), 8.75 (1 H, s).

[실시예 32]Example 32

1-시클로프로필-7-[7-히드록시-2.3-디히드로-1H-피롤로[3.4.C]피리딘-2-일]-6-플루오르-1, 4-디히드로-4-옥소-1, 8-나프티리딘-3-카르복실산의 제조1-cyclopropyl-7- [7-hydroxy-2.3-dihydro-1H-pyrrolo [3.4.C] pyridin-2-yl] -6-fluor-1, 4-dihydro-4-oxo-1 , Preparation of 8-naphthyridine-3-carboxylic acid

7-히드록시-2, 3-디히드로-1H-피롤로[3.4.C]피리딘 디히드로 클로라이드 0.2g을 무수아세토니트릴 3㎖에 첨가시킨 후, 여기에DBU 0.26㎖를 넣어 용해시킨 다음 1-시클로프로피-6-플루오르-7-클로로-1, 4-디히드로-4-옥소-1, 8-나프티리딘-3-카르복실산 0.19g을 투입하고 3시간 동안 환류시켰다. 이어서, 상기 실시예 13과 같은 방법으로 처리한 결과, 상기 목적화합물 0.91g을 얻었다.0.2 g of 7-hydroxy-2,3-dihydro-1H-pyrrolo [3.4.C] pyridine dihydrochloride was added to 3 ml of anhydrous acetonitrile, followed by dissolving 0.26 ml of DBU, followed by 1- 0.19 g of cyclopropy-6-fluoro-7-chloro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid was added and refluxed for 3 hours. Subsequently, 0.91 g of the target compound was obtained as a result of treatment in the same manner as in Example 13.

원소분석Elemental analysis

계산치(%) : C; 59.69, H; 3.95, N; 14.65Calculated (%): C; 59.69, H; 3.95, N; 14.65

실측치(%) : C; 59.61, H; 3.90, N; 14.68Found (%): C; 59.61, H; 3.90, N; 14.68

¹H NMR(DMSO-d₆δ : 1.11∼1.32(4H, m), 4.02(1H, m), 4.80(2H, s), 4.85 (2H, s), 7.75(1H, d), 8.01(1H, s), 8.31(1H, s), 8.75(1H, s). ¹ H NMR (DMSO-d ₆ δ: 1.11 to 1.32 (4H, m), 4.02 (1H, m), 4.80 (2H, s), 4.85 (2H, s), 7.75 (1H, d), 8.01 (1H , s), 8.31 (1H, s), 8.75 (1H, s).

[실시예 33]Example 33

1-시클로프로필-7-[7-히드록시-2, 3-디히드로-1H-피롤로[3.4.C]피리딘-2-일 ]-6, 8-디플루오르-1, 4-디히드로-4-옥소-3-퀴놀린카르복실산의 제조1-cyclopropyl-7- [7-hydroxy-2, 3-dihydro-1H-pyrrolo [3.4.C] pyridin-2-yl] -6, 8-difluoro-1, 4-dihydro- Preparation of 4-oxo-3-quinolinecarboxylic acid

7-히드록시-2, 3-디히드로-1H-피롤로[3.4.C]피리딘 디히드로클로라이드 0.2g을 무수아세토니트릴 2㎖에 첨가시킨 후, 여기에 DBU 023㎖를 넣어 용해시킨 다음 1-시클로프로필-6, 7, 8-트리플루오르-1, 4-디히드로-4-옥소-3-퀴놀린-카르복실산 0.18g을 투입하고 6시간 동안 환류시켰다. 이어서, 상기 실시예 13과 같은 방법으로 처리한 결과, 상기 목적화합물 0.20g을 얻었다.0.2 g of 7-hydroxy-2,3-dihydro-1H-pyrrolo [3.4.C] pyridine dihydrochloride was added to 2 ml of anhydrous acetonitrile, and then 023 ml of DBU was dissolved therein, followed by 1- 0.18 g of cyclopropyl-6, 7, 8-trifluor-1, 4-dihydro-4-oxo-3-quinoline-carboxylic acid was added and refluxed for 6 hours. Subsequently, 0.20 g of the target compound was obtained as a result of treatment in the same manner as in Example 13.

원소분석Elemental analysis

계산치(%) : C; 60.16, H; 3.79, N; 10.52Calculated (%): C; 60.16, H; 3.79, N; 10.52

실측치(%) : C; 60.11, H; 3.72, N; 10.48Found (%): C; 60.11, H; 3.72, N; 10.48

¹H NMR(CDCl3) δ : 1.10∼1.30(4H, m), 4.02(1H, m), 4.70(2H, s), 4.85(2H, s), 7.93(1H, d), 8.01(1H, s), 8.51(1H, s), 8.75(1H, s). ¹ H NMR (CDCl 3) δ: 1.10 to 1.30 (4H, m), 4.02 (1H, m), 4.70 (2H, s), 4.85 (2H, s), 7.93 (1H, d), 8.01 (1H, s ), 8.51 (1H, s), 8.75 (1H, s).

[실시예 34]Example 34

1-시클로프로필-7-[7-메틸아니노-2, 3-디히드로-1H-피롤도[3.4.C]피리딘-2-일-]-6, 8-디플루오르-1, 4-디히드로-4-옥소-3-카르복실산의 제조1-cyclopropyl-7- [7-methylanino-2, 3-dihydro-1H-pyrraldo [3.4.C] pyridin-2-yl-]-6, 8-difluoro-1, 4-di Preparation of Hydro-4-oxo-3-carboxylic Acid

7-메틸아미노-2, 3-디히드로-1H-피리롤[3.4.C]피리딘 트리히드로클로라이드 0.2g을 무수아세토니트릴 3㎖에 첨가시킨 후, 여기 DABCO 0.38㎖를 넣어 용해시킨 다음 1-시클로프로필-6, 7, 8-트리플루오르-1, 4-디히드로-4-옥소-3-퀴놀린카르복실산 0.21g을 투입하고 10시간 동안 환류시켰다. 이어서, 상기 실시예 13과 같은 방법으로 처리한 결과, 상기 목적화합물 0.19g을 얻었다.0.2 g of 7-methylamino-2,3-dihydro-1H-pyrrole [3.4.C] pyridine trihydrochloride was added to 3 ml of anhydrous acetonitrile, and 0.38 ml of DABCO was dissolved therein, followed by 1-cyclo 0.21 g of propyl-6, 7, 8-trifluor-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid was added and refluxed for 10 hours. Subsequently, the resultant was treated in the same manner as in Example 13 to obtain 0.19 g of the target compound.

원소분석Elemental analysis

계산치(%) : C; 61.16, H; 4.40, N; 13.58Calculated (%): C; 61.16, H; 4.40, N; 13.58

실측치(%) : C; 61.11, H; 4.32, N; 13.52Found (%): C; 61.11, H; 4.32, N; 13.52

¹H NMR(DMSO-d6) δ : 1.12∼1.32(4H, m), .3.15(3h, S0, 4.01(1H, m), 4.60(2h, s). 4.80(2H, s), 7.91(1H, d), 8.51(H, d), 8.60(1H, s), 8.75(1H, d). ¹ H NMR (DMSO-d6) δ: 1.12 to 1.32 (4H, m), .3.15 (3h, S0, 4.01 (1H, m), 4.60 (2h, s) .4.80 (2H, s), 7.91 (1H , d), 8.51 (H, d), 8.60 (1H, s), 8.75 (1H, d).

[실시예 35]Example 35

1-시클로프로필-7-[7-메틸아미노-2, 4-디히드로-1H-피롤로[3.4.C]피리딘-2-일]-6-플루오르-1, 4-디히드로-4-옥소-1, 8-나프티리딘-3-카르복실산의 제조1-cyclopropyl-7- [7-methylamino-2, 4-dihydro-1H-pyrrolo [3.4.C] pyridin-2-yl] -6-fluoro-1, 4-dihydro-4-oxo Preparation of -1,8-naphthyridine-3-carboxylic acid

7-메틸아미노-2, 3-디히드로-1H-피롤로[3.4.C]피리딘 트리히드르클로라이드 0.2g을 무수아세토니트릴 3㎖에 첨가시킨 후, 여기에 DABCO 0.36㎖를 넣어 용해시킨 다음 1-시클로프로필-6-플루오로-7-클로로-1, 4-디히드로-4-옥소-1, 8-나프티리딘-3-퀴놀린 카르복실산 0.21g을 투입하고 3시간 동안 환류시켰다. 이어서, 상기 실시예 13과 같은 방법으로 처리한 결과, 상기 목적화합물 0.22g을 얻었다.0.2 g of 7-methylamino-2,3-dihydro-1H-pyrrolo [3.4.C] pyridine trihydrchloride was added to 3 ml of anhydrous acetonitrile, and 0.36 ml of DABCO was dissolved thereinto 1 0.21 g of -cyclopropyl-6-fluoro-7-chloro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-quinoline carboxylic acid was added and refluxed for 3 hours. Subsequently, the same procedure as in Example 13 was carried out to obtain 0.22 g of the target compound.

원소분석Elemental analysis

계산치(%) : C; 60.76, H; 4.59, N; 17.71Calculated (%): C; 60.76, H; 4.59, N; 17.71

실측치(%) : C; 60.68, H; 4.53, N; 17.65Found (%): C; 60.68, H; 4.53, N; 17.65

¹H NMR(DMSO-d6) δ : 1.11∼1.32(4H, m), 3.20(1H, m), 4.01(1H, m), 4.55(2H, s), 4, 75(2H, s), 7.72(1H, s), 8.45(1H, s), 8.52(1H, s). ¹ H NMR (DMSO-d6) δ: 1.11 to 1.32 (4H, m), 3.20 (1H, m), 4.01 (1H, m), 4.55 (2H, s), 4, 75 (2H, s), 7.72 (1H, s), 8.45 (1H, s), 8.52 (1H, s).

[실시예 36]Example 36

1-에틸-7-[메틸아미노-2, 3-디히드로-1H-피롤리[3.4.C]피리딘-2-일]-6-플루오르-1, 4-디히드로-4-옥소-3-퀴놀린카르복실산의 제조1-ethyl-7- [methylamino-2, 3-dihydro-1H-pyrroli [3.4.C] pyridin-2-yl] -6-fluor-1, 4-dihydro-4-oxo-3- Preparation of Quinolinecarboxylic Acid

7-메틸아미노-2, 3-디히드로-1H-피롤로[3.4.C]피리딘 트리히드로클로라이드 0.2g을 무수아세트니트릴 3㎖에 첨가시킨 후, 여기에 DBU 0.38㎖를 넣어 용해시킨 다음, 1-에틸-6, 7-디플루오르-1, 4-디히드로-4-옥소-3-퀴놀린복실산 0.19g을 투입하고 10시간 동안 환류시켰다. 이어서, 상기 실시예 13과 같은 방법으로 처리한 결과, 상기 목적화합물 0.19g을 얻었다.0.2 g of 7-methylamino-2,3-dihydro-1H-pyrrolo [3.4.C] pyridine trihydrochloride was added to 3 ml of anhydrous acetonitrile, and 0.38 ml of DBU was dissolved therein, followed by 1 0.19 g of -ethyl-6, 7-difluoro-1 and 4-dihydro-4-oxo-3-quinoline acid were added and refluxed for 10 hours. Subsequently, the resultant was treated in the same manner as in Example 13 to obtain 0.19 g of the target compound.

원소분석Elemental analysis

실측치(%) : C; 72.75, H; 5.04, N; 14.01Found (%): C; 72.75, H; 5.04, N; 14.01

¹H NMR(DMSO-d6) δ : 1.35(3H, t), 3.25(3H, s), 3.85(2H, q), 4.55(2H, s), 4.85(2H, s), 7.56(1H, d), 7.80(1H, d), 8.51(1H, s), 8.55(1H, s), 8.85(1H, s). ¹ H NMR (DMSO-d6) δ: 1.35 (3H, t), 3.25 (3H, s), 3.85 (2H, q), 4.55 (2H, s), 4.85 (2H, s), 7.56 (1H, d ), 7.80 (1 H, d), 8.51 (1 H, s), 8.55 (1 H, s), 8.85 (1 H, s).

[실시예 37]Example 37

1-시클로프로필-7-[7-메톡시-6-메틸- 2, 3-디히드로-1H-피롤로[3.4.C]피리딘-2-일]-6, 8-디플루오르-1, 4-디히드로-4-옥소-3-퀴놀린카르복실산의 제조1-cyclopropyl-7- [7-methoxy-6-methyl-2, 3-dihydro-1H-pyrrolo [3.4.C] pyridin-2-yl] -6, 8-difluoro-1, 4 Preparation of -dihydro-4-oxo-3-quinolinecarboxylic acid

7-메톡시-6-메틸-2, 3-디히드로-1H-피롤로[3.4.C]피리딘 디히드로클로라이드 0.2g을 무수아세토니트릴 3㎖에 첨가시킨 후, 여기에 DBU 0.25㎖를 넣어 용해시킨 다음 1-시클로프로필-6, 7, 8-트리플루오르-1, 4-디히드로-4-옥소-3-퀴놀린카르복실산 0.21g을 넣고 6시간 동안 환류시켰다. 이어서, 상기 실시예 13과 같은 방법으로 처리한 결과, 상기 목적화합물 0.21g을 얻었다.0.2 g of 7-methoxy-6-methyl-2 and 3-dihydro-1H-pyrrolo [3.4.C] pyridine dihydrochloride were added to 3 ml of anhydrous acetonitrile, and 0.25 ml of DBU was added thereto to dissolve. Then, 1-cyclopropyl-6, 7, 8-trifluoro-1 and 4-dihydro-4-oxo-3-quinolinecarboxylic acid 0.21g was added and refluxed for 6 hours. Subsequently, the resultant was treated in the same manner as in Example 13 to obtain 0.21 g of the target compound.

원소분석Elemental analysis

계산치(%) : C; 61.83, H; 4.48, N; 9.83Calculated (%): C; 61.83, H; 4.48, N; 9.83

실측치(%) : C; 61.75, H; 4.41, N; 9.92Found (%): C; 61.75, H; 4.41, N; 9.92

¹H NMR(DMSO-d6) δ : 1.12∼1.31(4H, m), 2.52(3H, s), 3.95(3H, s), 4.03(1H, m), 4.45(2H, s), 4.75(2H, s), 7.95(1H, d), 8.56(1H, s), 8.85(1H, s). ¹ H NMR (DMSO-d6) δ: 1.12-1.31 (4H, m), 2.52 (3H, s), 3.95 (3H, s), 4.03 (1H, m), 4.45 (2H, s), 4.75 (2H , s), 7.95 (1 H, d), 8.56 (1 H, s), 8.85 (1 H, s).

[실시예 38]Example 38

1-시클로프로필-7-[6-메틸-2, 3-디히드로-1H-피롤로[3.4.C]피리딘-2-일]-6, 8-디플루오르-1, 4-디히드로-4-옥소-3-퀴놀린카르복실산의 제조1-cyclopropyl-7- [6-methyl-2, 3-dihydro-1H-pyrrolo [3.4.C] pyridin-2-yl] -6, 8-difluoro-1, 4-dihydro-4 Preparation of -oxo-3-quinolinecarboxylic acid

6-메틸-2, 3-디히드로-1H-피롤로[3.4.C]피리딘 디히드로클로라이드 0.25g을 무수아세토니트릴 4㎖에 첨가시킨 후, 여기서 DBU 0.35㎖를 넣어 용해시킨 다음 1-시클로프로필-6, 7, 8-트리플루오르-1, 4-디히드로-4-옥소-3-퀴놀린-카르복실산 0.28g을 투입하고 5시간 동안 환류시켰다. 이어서, 상기 실시예 13과 같은 방법으로 처리한 결과, 상기 목적화합물 0.29g을 얻었다.0.25 g of 6-methyl-2,3-dihydro-1H-pyrrolo [3.4.C] pyridine dihydrochloride was added to 4 ml of anhydrous acetonitrile, where 0.35 ml of DBU was added to dissolve and then 1-cyclopropyl 0.28 g of -6, 7, 8-trifluor-1, 4-dihydro-4-oxo-3-quinoline-carboxylic acid was added and refluxed for 5 hours. Subsequently, the resultant was treated in the same manner as in Example 13 to obtain 0.29 g of the target compound.

원소분석Elemental analysis

계산치(%) : C; 63.48 , H; 4.31, N; 10.57Calculated (%): C; 63.48, H; 4.31, N; 10.57

실측치(%) : C; 63.21, H; 4.19, N; 10.64Found (%): C; 63.21, H; 4.19, N; 10.64

¹H NMR(CDCl3) δ : 1.12∼1.30(4H, m0, 2.51(3H, m0, 4.02(1H, m), 4.50 (2H, s), 4.80(2H, s), 7.50(12H, s), 7.90(1H, s), 8.50(1H, s), 8.75(1H, s). ¹ H NMR (CDCl 3) δ: 1.12 to 1.30 (4H, m0, 2.51 (3H, m0, 4.02 (1H, m), 4.50 (2H, s), 4.80 (2H, s), 7.50 (12H, s), 7.90 (1 H, s), 8.50 (1 H, s), 8.75 (1 H, s).

[실시예 39]Example 39

1-시클로프로필7-[7-브로모-6-메틸-2, 3-디히드로 -1H-피롤로[3.4.C]피리딘-2-일]-6, 8-디플로오르 -1, 4-디히드로-4-옥소-3-카를복실산의 제조1-cyclopropyl7- [7-bromo-6-methyl-2, 3-dihydro-1H-pyrrolo [3.4.C] pyridin-2-yl] -6, 8-difluoro-1, 4 Preparation of -dihydro-4-oxo-3-carboxylic acid

7-브로모-6-메틸-2, 3-디히드로-1H-피롤로[3.4.C]리리딘 디히드로클로라이드 0.2g을 무수아세니트릴 3㎖에 첨가시킨 후, 여기에 DABCO 0.24㎖를 넣어 용해시킨 다음 1-시클로프로필-6, 7, 8-트리플로오로-1, 4-디히드로-4-옥소-3-퀴놀린카르복실산 0.17g을 투입하고 6시간 동안 환류시켰다. 이어서, 상기 실시예 13과 같은 방법으로 처리한 결과, 상기 목적화합물 0.19g을 얻었다.0.2 g of 7-bromo-6-methyl-2, 3-dihydro-1H-pyrrolo [3.4.C] riridine dihydrochloride was added to 3 ml of anhydrous acetonitrile, and 0.24 ml of DABCO was added thereto. After dissolution, 0.17 g of 1-cyclopropyl-6, 7, 8-trifluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid was added thereto, and the mixture was refluxed for 6 hours. Subsequently, the resultant was treated in the same manner as in Example 13 to obtain 0.19 g of the target compound.

원소분석Elemental analysis

계산치(%) : C; 52.96, H; 3.39, N; 8.82Calculated (%): C; 52.96, H; 3.39, N; 8.82

실측치(%) : C; 52.75, H; 3.43, N; 8.75Found (%): C; 52.75, H; 3.43, N; 8.75

¹H NMR(CDCl3) δ : 1.0∼1.32(4H, m), 2.50(4H, M), 2.50(3H, s), 4.02(1H, m), 4.50(2H, s), 4.78(2H, s), 7.85(1H, d), 8.54(1H, s), 8.79(1H, s). ¹ H NMR (CDCl 3) δ: 1.0 to 1.32 (4H, m), 2.50 (4H, M), 2.50 (3H, s), 4.02 (1H, m), 4.50 (2H, s), 4.78 (2H, s ), 7.85 (1 H, d), 8.54 (1 H, s), 8.79 (1 H, s).

[실시예 40]Example 40

1-시클로프로필-7-[4-아미노-2, 3-디히드로-1H-피롤로[3.4.C]피리딘-2-일]-6.8-디플루오로-1.4-디히드로-4-옥소-3-퀴놀린카를복실산의 제조1-cyclopropyl-7- [4-amino-2, 3-dihydro-1H-pyrrolo [3.4.C] pyridin-2-yl] -6.8-difluoro-1.4-dihydro-4-oxo- Preparation of 3-quinoline carboxylic acid

4-아미노-7-시아노-2, 3-디히드로-1H-피롤로[3.4.C]피리딘 디히드로클로라이드 0.2g을 무수아세토니트릴 3㎖에 첨가시킨 후, 여기에 디이소프로필에틸아민 0.4㎖를 넣어 용해시킨 다음 1-시클로프로필-6, 7, 8-트리플루오로-1, 4-디히드로-4-옥소-3-퀴놀린카르복실산 0.21g을 투입하고 5시간 동안 환류시켰다. 이어서, 상기 실시예 13과 같은 방법으로 처리한 결과, 상기 목적화합물 0.21g을 얻었다.0.2 g of 4-amino-7-cyano-2,3-dihydro-1H-pyrrolo [3.4.C] pyridine dihydrochloride was added to 3 ml of anhydrous acetonitrile, followed by diisopropylethylamine 0.4 After adding ㎖ to dissolve, 0.21 g of 1-cyclopropyl-6, 7, 8-trifluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid was added and refluxed for 5 hours. Subsequently, the resultant was treated in the same manner as in Example 13 to obtain 0.21 g of the target compound.

원소분석Elemental analysis

계산치(%) : C; 59.58, H; 3.57, N; 16.54Calculated (%): C; 59.58, H; 3.57, N; 16.54

실측치(%) : C; 59.51, H; 3.52, N; 16.51Found (%): C; 59.51, H; 3.52, N; 16.51

¹H NMR(DMSO-d6) δ : 1.10∼1.30(4H, m), 4.02(1H, m), 4.40(2H, s), 4.60(2H, s), 7.93(1H, d), 8.15(1H, s), 8.75(1H, s). ¹ H NMR (DMSO-d6) δ: 1.10 to 1.30 (4H, m), 4.02 (1H, m), 4.40 (2H, s), 4.60 (2H, s), 7.93 (1H, d), 8.15 (1H , s), 8.75 (1 H, s).

[실시예 41]Example 41

7-[4-아미노-7-시아노-2, 3-디히드로-1H-피롤로[3.4.C]피리딘-2-일]-1-시클로프로필-6-플루오르-1, 4-디히드로-4-옥소-1, 8-나프티리딘-3-카르복실산의 제조7- [4-amino-7-cyano-2, 3-dihydro-1 H-pyrrolo [3.4.C] pyridin-2-yl]-1 -cyclopropyl-6-fluoro-1, 4-dihydro Preparation of 4-oxo-1,8-naphthyridine-3-carboxylic acid

4-아미노-7-시아노-2, 3-디히드로-1H-피롤로[3.4.C]피리딘 트리히드로클로라이드 0.2g을 무수아세토니트릴 3㎖에 첨가시킨 후, 여기 디이소프로필에틸아민 0.36㎖를 넣어 용해시킨 다음 1-시클로프로필-6-플루오로-7-클로로-1, 4-디히드로-4-옥소-1, 8-나프티리딘-3-카르복실산 0.21g을 투입하고 3시간 동안 환류시켰다. 이어서, 상기 실시예 13과 같은 방법으로 처리한 결과, 상기 목적화합물 0.21g을 얻었다.0.2 g of 4-amino-7-cyano-2,3-dihydro-1H-pyrrolo [3.4.C] pyridine trihydrochloride was added to 3 ml of anhydrous acetonitrile, followed by 0.36 ml of diisopropylethylamine. To dissolve and add 0.21 g of 1-cyclopropyl-6-fluoro-7-chloro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid and for 3 hours. It was refluxed. Subsequently, the resultant was treated in the same manner as in Example 13 to obtain 0.21 g of the target compound.

원소분석Elemental analysis

계산치(%) : C; 59.31, H; 3.72, N; 20.68Calculated (%): C; 59.31, H; 3.72, N; 20.68

실측치(%) : C; 59.05, H; 3.68, N; 20.59Found (%): C; 59.05, H; 3.68, N; 20.59

¹H NMR(DMSO-d6) δ : 1.12∼1.30(4H, m), 4.00(1H, m), 4.50(2H, s), 4.70(2H, s), 7.80(1H, d), 8.40(1H, s), 8.70(1H, s). ¹ H NMR (DMSO-d6) δ: 1.12 to 1.30 (4H, m), 4.00 (1H, m), 4.50 (2H, s), 4.70 (2H, s), 7.80 (1H, d), 8.40 (1H , s), 8.70 (1 H, s).

[실시예 42]Example 42

7-[4-아미노-7-시아노-2, 3-디히드로-1H-피롤로[3.4.C]피리딘-2-일]-1-에틸-6-플루오르-1, 4, -디히드로-4-옥소-3-퀴놀린카르복실산의 제조7- [4-amino-7-cyano-2, 3-dihydro-1 H-pyrrolo [3.4.C] pyridin-2-yl] -1-ethyl-6-fluor-1, 4, -dihydro Preparation of 4-oxo-3-quinolinecarboxylic acid

4-아미노-7-시아노-2, 3-디히드로-1H-피롤로[3.4.C]피리딘 트리히드로클로라이드 0.2g을 무수아세토니트릴 3㎖에 첨가시킨 후, 여기에 DBU 0.30㎖를 넣어 용해시킨 다음 1-에틸-디플루오로-1, 4-디히드로-4-옥소-3-퀴놀리카르복실산 0.19g을 투입하고 8시간 동안 환류시켰다. 이어서, 상기 실시예 13과 같은 방법으로 처리한 결과, 상기 목적화합물 0.22g을 얻었다.0.2 g of 4-amino-7-cyano-2,3-dihydro-1H-pyrrolo [3.4.C] pyridine trihydrochloride was added to 3 ml of anhydrous acetonitrile, and 0.30 ml of DBU was added thereto to dissolve. Then, 0.19 g of 1-ethyl-difluoro-1 and 4-dihydro-4-oxo-3-quinolicarboxylic acid were added and refluxed for 8 hours. Subsequently, the same procedure as in Example 13 was carried out to obtain 0.22 g of the target compound.

원소분석Elemental analysis

계산치(%) : C; 61.07, H; 4.10, N; 17.80Calculated (%): C; 61.07, H; 4.10, N; 17.80

실측치(%) : C; 61.01, H; 4.15, N; 17.75Found (%): C; 61.01, H; 4.15, N; 17.75

¹H NMR(DMSO-d6) δ : 1.40(3H, t), 3.85(2H, q), 4.51(2H, s), 4.72(2H, s), 7.60(1H, d). 7.85(1H, d), 8.51(1H, s), 8.80(1H, s). ¹ H NMR (DMSO-d6) δ: 1.40 (3H, t), 3.85 (2H, q), 4.51 (2H, s), 4.72 (2H, s), 7.60 (1H, d). 7.85 (1 H, d), 8.51 (1 H, s), 8.80 (1 H, s).

[실시예 43]Example 43

7-[6-아미노-7-시아노-2, 3-디히드로-1H-피롤로[3.4.C]피리딘-2-일]-1-시클로프로필-6, 8-디플루오르-1, 4-디히드로-4-옥소-3-퀴놀린카르복실산의 제조7- [6-amino-7-cyano-2, 3-dihydro-1 H-pyrrolo [3.4.C] pyridin-2-yl]-1 -cyclopropyl-6, 8-difluoro-1, 4 Preparation of -dihydro-4-oxo-3-quinolinecarboxylic acid

6-아미노-7-시아노-2, 3-디히드로-1H-피롤로[3.4.C]피리딘 트리히드로클로라이드 0.2g을 무수아세토니트릴 2㎖에 첨가시킨 후, DBU 0.36㎖를 넣어 용해시킨 다음 1-시클로프로필-6, 7, 8-트리플루오르-1, 4-디히드로-4-옥소-3-퀴놀린카르복실산 0.18g을 투입하고 5시간 동안 환류시켰다. 이어서, 상기 실시예 13과 같은 방법으로 처리한 결과, 상기 목적 화합물 0.17g을 얻었다.0.2 g of 6-amino-7-cyano-2,3-dihydro-1H-pyrrolo [3.4.C] pyridine trihydrochloride was added to 2 ml of anhydrous acetonitrile, and then dissolved in 0.36 ml of DBU. 0.18 g of 1-cyclopropyl-6, 7, 8-trifluor-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid was added and refluxed for 5 hours. Subsequently, the same process as in Example 13 was carried out to obtain 0.17 g of the target compound.

원소분석Elemental analysis

실측치(%) : C; 59.72, H; 3.57, N; 16, 72Found (%): C; 59.72, H; 3.57, N; 16, 72

¹H NMR(DMSO-d6) δ : 1.09∼1.31(4H, m), 4.03(1H, m), 4.60(2H, s), 4.80(2H, s), 7.90(1H, d), 8.68(1H, s), 8.79(1H, d). ¹ H NMR (DMSO-d6) δ: 1.09-1.31 (4H, m), 4.03 (1H, m), 4.60 (2H, s), 4.80 (2H, s), 7.90 (1H, d), 8.68 (1H , s), 8.79 (1 H, d).

[실시예 44]Example 44

7-[6-아미노-7-시아노-2, 3-디히드로-1H-피롤로[3.4.C]피리딘-2-일]-1시클로프로필-6-플루오르-1, 4-디히드로-4-옥소-1, 8-나프티리딘-3-카르복실산의 제조7- [6-Amino-7-cyano-2, 3-dihydro-1 H-pyrrolo [3.4.C] pyridin-2-yl] -1 cyclopropyl-6-fluor-1, 4-dihydro- Preparation of 4-oxo-1, 8-naphthyridine-3-carboxylic acid

6-아미노-7-시아노-2, 3-디히드로-1H-피롤로[3.4.C]피리딘 트리히드로클로라이드 0.2g을 무수아세토니트릴 3㎖에 첨가시킨 후, 여기에 DUB 0.37㎖를 넣어 용해시킨 다음 1-시클로프로필-6-플루오르-7-클로로-1, 4-디히드로-4-옥소-1, 8-나프티리딘-3-카르복실산 0.21g을 투입하고 3시간 동안 환류시켰다. 이어서, 상기 실시예 13과 같은 방법으로 처리한 결과, 상기 목적화합물 0.21g을 얻었다.0.2 g of 6-amino-7-cyano-2,3-dihydro-1H-pyrrolo [3.4.C] pyridine trihydrochloride was added to 3 ml of anhydrous acetonitrile, and 0.37 ml of DUB was added thereto to dissolve. Then, 0.21 g of 1-cyclopropyl-6-fluoro-7-chloro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid was added and refluxed for 3 hours. Subsequently, the resultant was treated in the same manner as in Example 13 to obtain 0.21 g of the target compound.

원소분석Elemental analysis

계산치(%) : C; 59.11, H; 3.72, N; 20.68Calculated (%): C; 59.11, H; 3.72, N; 20.68

실측치(%) : C; 58.85, H; 3.63, N; 20.53Found (%): C; 58.85, H; 3.63, N; 20.53

¹H NMR(DMSO-d6) δ : 1.11∼1.30(4H, m), 4.02(1H, m), 4.51(2H, m), 4.71(2H, s), 7.65(1H, d), 8.55(1H, s), 8.75(1H, s). ¹ H NMR (DMSO-d6) δ: 1.11 to 1.30 (4H, m), 4.02 (1H, m), 4.51 (2H, m), 4.71 (2H, s), 7.65 (1H, d), 8.55 (1H , s), 8.75 (1 H, s).

[실시예 45]Example 45

7-[6-아미노-7-시아노-2, 3-디히드로-1H-피롤로-[3.4.C]피리딘-2-일]-1에틸-6-플루오로-1, 4-디히드로-4-옥소-3-퀴놀린카르복실산의 제조7- [6-amino-7-cyano-2, 3-dihydro-1 H-pyrrolo- [3.4.C] pyridin-2-yl] -1 ethyl-6-fluoro-1, 4-dihydro Preparation of 4-oxo-3-quinolinecarboxylic acid

6-아미노-7-시아노-2, 3-디히드르-1H-피롤로[3.4.C]피리딘 트리히드로클로라이드 0.2g을 무수아세토니트릴 3㎖에 첨가시킨 후, DBU 0.37㎖를 넣어 용해시킨 다음 1-에틸-6, 7-디플루오르-1, 4-디히드로-4-옥소-3-퀴놀린카르복실산 0.19g을 투입하고 6시간 동안 환류시켰다. 이어서, 상기 실시예 13과 같은 방법으로 처리한 결과, 상기 목적화합물을 0.21g을 얻었다.0.2 g of 6-amino-7-cyano-2,3-dihydr-1H-pyrrolo [3.4.C] pyridine trihydrochloride was added to 3 ml of anhydrous acetonitrile, and then dissolved in 0.37 ml of DBU. 0.19 g of 1-ethyl-6, 7-difluoro-1 and 4-dihydro-4-oxo-3-quinolinecarboxylic acid were added and refluxed for 6 hours. Subsequently, 0.21 g of the target compound was obtained as a result of treatment in the same manner as in Example 13.

원소분석Elemental analysis

계산치(%) : C; 61.07, H; 17.80, N; 4.10Calculated (%): C; 61.07, H; 17.80, N; 4.10

실측치(%) : C; 61.01, H; 17.75, N; 4.15Found (%): C; 61.01, H; 17.75, N; 4.15

¹H NMR(DMSO-d6) δ : 1.35(3H, t), 3.65(2H, q), 4.45(2H, s), 4.80(2H, s), 7.55(1H, d), 7.70(1H, d), 8.51(1H, s), 8.75(1H, s). ¹ H NMR (DMSO-d6) δ: 1.35 (3H, t), 3.65 (2H, q), 4.45 (2H, s), 4.80 (2H, s), 7.55 (1H, d), 7.70 (1H, d ), 8.51 (1H, s), 8.75 (1H, s).

[표 1]TABLE 1

시험관내 항균력 시험In vitro antibacterial activity test

Ⅰ 실시예 13의 화합물 Ⅱ 실시예 14의 화합물 Ⅲ 실시예 18의 화합물I Compound of Example 13 II Compound of Example 14 III Compound of Example 18

Ⅳ 실시예 19의 화합물 Ⅴ 실시예 26의 화합물 Ⅵ 실시예 34의 화합물IV Compounds of Example 19 V Compounds of Example 26 VI Compounds of Example 34

시험관내 항균력 시험In vitro antibacterial activity test

상기 실시예들에 의해 제조된 본 발명에 따른 퀴놀론계 유도체들의 항균작용을 뮬러-힌톤 한천(Muller-Hinton agar)를 사용하여 2배수 아가 회석에 의한 한천배지희석법에 의거하여 시험한 결과를 상기 표 1에 나타내었다.Table 1 shows the results of the antibacterial activity of the quinolone derivatives prepared according to the present invention based on the agar medium dilution method by double-fold agar lime using Muller-Hinton agar. 1 is shown.

이때. 균의 접종은 약 10P⁷균체 형성단의/㎖를 포함하며, 균의 성장은 시프록사신을 표준물질로 사용하여 37℃에서 약18시간 경과된 후에 관찰하였다.At this time. The inoculation of the bacterium comprises about 10P ⁷ cell formation stage / ml, and the growth of the bacterium was observed after about 18 hours at 37 ° C using ciproxacin as a reference material.

Claims

Quinolone-based antimicrobial agents represented by the following structural formula (I) and pharmaceutically acceptable salts thereof.

Wherein Z ₁ , Z ₂ and Z ₃ are each a hydrogen atom or a lower alkyl group having 1 to 3 carbon atoms. A halogen element such as fluorine, bromine or chlorine, a cyano group, an amino group, a hydroxy group, an alkylamine group having an alkyl group having 1 to 3 carbon atoms or an alkoxy group. R ₁ is an ethyl or cyclopropyl group, R ₂ and R ₃ are each a hydrogen atom, a halogen atom such as fluorine, bromine or chlorine, and X is a nitrogen atom, a methine group or a fluoromethine group.

The pyridine derivative represented by the following structural formula (II) and the quinolinecarboxylic acid derivative represented by the following structural formula (III) are reacted for 21 to 16 hours in the presence of a base in a solvent or without a solvent at a temperature of room temperature to 200 ° C. Method for producing a quinoline-based antimicrobial agent represented by the following structural formula (I) characterized in that.

Wherein Z ₁ , Z ₂ and Z ₃ each have a hydrogen atom or a lower alkyl group of 1 to 3 carbon atoms, a halogen element such as fluorine or bromine or chlorine, a cyano group, an amino group, a hydroxy group or a lower alkyl group of 1 to 3 carbon atoms An alkylamine or an alcohol group, R ₁ is an ethyl group or a cyclopropyl group, R ₂ and R ₃ are each a hydrogen atom, a halogen atom such as fluorine, bromine or chlorine, and X is a nitrogen atom, a methine group or a fluoromethine group to be.