KR970007919B1 - Novel pyridone carboxylic acid derivatives and their preparing method - Google Patents

Novel pyridone carboxylic acid derivatives and their preparing method Download PDF

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KR970007919B1
KR970007919B1 KR1019930021035A KR930021035A KR970007919B1 KR 970007919 B1 KR970007919 B1 KR 970007919B1 KR 1019930021035 A KR1019930021035 A KR 1019930021035A KR 930021035 A KR930021035 A KR 930021035A KR 970007919 B1 KR970007919 B1 KR 970007919B1
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azabicyclo
amino
dihydro
methyl
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KR940014394A (en
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김진웅
조일환
이재목
이기호
김제학
정용환
안승호
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제일제당 주식회사
김정순
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

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Abstract

Pyridone carboxyl acid derivative of general formula(I) is obtained by reacting a compound of general formula(II) with Z-N new compound and separating the product. Here, R1 is low-level alkyl group, halogen-substituted low-level alkyl group, low-level alkenyl group, cycloalkyl group or is substituted or non-substituted phenyl group. R2 is hydrogen, low-level alkyl group or amino group. A is nitrogen atom or C-X(here X is hydrogen, halogen atom or alkoxy group) and Z means group indicated as the general formula(I). In the general formula(II), Y is halogen atom and R7 is hydrogen or low-level alkyl group.

Description

신규한 피리돈 카르본산 유도체 및 그의 제조방법Novel pyridone carboxylic acid derivatives and preparation method thereof

본 발명은 우수한 항균활성을 갖는 새로운 항균물질로서 의약, 동물약, 어병약으로 사용되어질 수 있는 신규한 피리돈 카르본산 유도체와 그의 제조방법 및 그의 약리학적 제제에 관한 것이다.The present invention relates to a novel pyridone carboxylic acid derivative which can be used as a medicine, an animal medicine, a fish medicine as a new antibacterial substance having excellent antimicrobial activity, a preparation method thereof, and a pharmacological preparation thereof.

지금까지 알려진 합성 항균 유도체들 중에는 항균 활성이 높지만 경구투여시 흡수가 어려워 생체내 약효가 떨어지거나 독성이 강하여 의약으로 사용하기 어려운 것들이 많았다.Among the known synthetic antimicrobial derivatives, there are many antimicrobial activities that have high antimicrobial activity but are difficult to be absorbed during oral administration, and thus are difficult to use as drugs due to their inferior drug efficacy or strong toxicity.

본 발명들은 이러한 단점을 해결하기 위하여 뛰어난 약효를 가지고 있으면서 경구흡수가 월등히 좋은 신규한 퀴놀론계 항균제를 개발하여 본 발명을 완성하게 되었다.The present invention has completed the present invention by developing a novel quinolone-based antibacterial agent having an excellent drug in order to solve these disadvantages and excellent oral absorption.

본 발명의 화합물은 하기 일반식(I)로 표시되는 피리돈 카르본산 유도체와 그의 에스테르 및 그의 염이다.The compounds of the present invention are pyridone carboxylic acid derivatives represented by the following general formula (I), esters thereof and salts thereof.

상기 식(I)에서, R1은 저급 알킬기,하롤겐 치환 저급 알킬기, 저급 알케닐기, 사이클로 알킬기 또는 치환되었거나 치환되지 않은 페닐기를 의미하고, R2는 수소, 저급 알킬기 또는 아미노기를 의미하고, A는 질소원자 또는 C-X(여기서 X는 수소, 할로겐 원자 또는 알콕시기를 의미함)를 의미하며, Z는 하기식으로 표시되는 기를 의미한다.In formula (I), R 1 means a lower alkyl group, a lower halogen substituted lower alkyl group, a lower alkenyl group, a cycloalkyl group or a substituted or unsubstituted phenyl group, R 2 means hydrogen, a lower alkyl group or an amino group, and A Means a nitrogen atom or CX (where X means hydrogen, a halogen atom or an alkoxy group), and Z means a group represented by the following formula.

(여기서, R3, R4는 수소원자 또는 저급 알킬기를 의미하고, R5, R6는 수소, 히드록시, 알콕시, 아미노, 저급 알킬기로 치환된 아미노기를 의미하는데 둘 중 하나는 수소를 의미한다.)Where R 3 and R 4 represent a hydrogen atom or a lower alkyl group, and R 5 and R 6 represent an amino group substituted with hydrogen, hydroxy, alkoxy, amino or a lower alkyl group, one of which means hydrogen .)

본 발명에 있어서, 할로겐, 원자는 클로로, 브로모, 플루오로를 의미하고, 저급 알킬기로서는 예를 들면, 메틸, 에틸, 프로필, 이소프로필, 부틸, 이소부틸, t-부틸, 펜틸, 네오펜틸 등이 있다. 저급 알케닐기로서는 예를 들면 사이클로프로필, 사이클로부틸, 사이클로펜틸, 사이클로헥실 등이 있다. 치환기를 가져도 좋은 페닐기에 있어서 치환기의 예로서는 할로겐, 저급 알킬, 저급 알킬옥시, 할로게노 저급 알킬, 히드록시, 니트로, 아미노 등이 있다.In the present invention, halogen, atom means chloro, bromo, fluoro, and as the lower alkyl group, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, neopentyl and the like There is this. Lower alkenyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. Examples of the substituent in the phenyl group which may have a substituent include halogen, lower alkyl, lower alkyloxy, halogeno lower alkyl, hydroxy, nitro, amino and the like.

본 발명의 화합물의 염은 염산, 황산, 인산등의 무기산과의 염; 초산, 젖산, 옥살산, 숙신산, 메탄술폰산, 말레인산, 말론산, 글루콘산 등의 유기산과의 염; 아스파라긴산, 글루타민산 등의 산성 아미노산과의 염; 또는 산 식(I) 화합물의 나트륨, 칼륨, 칼슘, 마그네슘, 아연, 은 등의 금속염; 디메틸아민, 트리에틸아민, 디사이클로헥실아민, 벤질아민 등의 유기염기와의 염; 라이신, 알기닌 등의 염기성 아미노산과의 염 등이다.Salts of the compounds of the present invention include salts with inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid; Salts with organic acids such as acetic acid, lactic acid, oxalic acid, succinic acid, methanesulfonic acid, maleic acid, malonic acid and gluconic acid; Salts with acidic amino acids such as aspartic acid and glutamic acid; Or metal salts such as sodium, potassium, calcium, magnesium, zinc and silver of the acid formula (I) compound; Salts with organic bases such as dimethylamine, triethylamine, dicyclohexylamine and benzylamine; Salts with basic amino acids such as lysine and arginine.

상기 식(I)의 화합물의 에스테르는 화합물(I)의 메틸 에스테르, 에틸에스테르 등의 저급 알킬에스테르, 또는 가수분해되거나 생체내에서 용이하게 이탈되어 화합물(I)이 되는 공지의 에스테르, 예를들면 아세톡시메틸 에스테르, 피발로일옥시메틸 에스테르, 에톡시카르보닐에틸 에스테르, 콜린 에스테르, 디메틸아미노에틸 에스테르나 1-피패리디닐에틸 에스테르 등의 아미노에틸 에스테르류, 5-인다닐 에스테르, 프탈리디닐 에스테르 등을 의미한다.The ester of the compound of formula (I) is a lower alkyl ester such as methyl ester or ethyl ester of compound (I), or a known ester which is hydrolyzed or easily released in vivo to become compound (I), for example Aminoethyl esters such as acetoxymethyl ester, pivaloyloxymethyl ester, ethoxycarbonylethyl ester, choline ester, dimethylaminoethyl ester or 1-piperidinylethyl ester, 5-indanyl ester, phthalidinyl Ester and the like.

본 발명의 화합물은 또한 수화물로서도 얻어지는데 이러한 형태의 것도 당연히 본 발명의 화합물에 포함된다.The compound of the present invention is also obtained as a hydrate, which of course is included in the compound of the present invention.

본 발명의 화합물에서는, 그 7위치의 치환기에 부제탄소원자를 가지므로 광학활성체로서도 얻을 수 있으며, 이러한 광학 활성체도 본 발명의 화합물에 포함된다.In the compound of the present invention, since the substituent at the 7-position has a subsidiary carbon atom, it can also be obtained as an optically active substance, and such optically active substance is also included in the compound of the present invention.

이하, 본 발명의 화합물의 제조방법에 대하여 설명한다.Hereinafter, the manufacturing method of the compound of this invention is demonstrated.

본 발명의 화합물은 하기 일반식(II)로 표시되는 화합물과 하기 일반식(III)으로 표시되는 신규화합물을 반응시켜서 그 생성물을 통상의 방법에 의해 단리시켜서 제조할 수 있다.The compound of the present invention can be prepared by reacting a compound represented by the following general formula (II) with a novel compound represented by the following general formula (III) and isolating the product by a conventional method.

(식(II)에서 Y는 할로겐 원자를 의미하고, R7은 수소 또는 저급 알킬기를 의미하고, A, R1및 R2는 전술한 바와 같다).(In formula (II), Y means a halogen atom, R 7 means hydrogen or a lower alkyl group, and A, R 1 and R 2 are as described above).

Z-N(III)Z-N (III)

(식(III))에서, Z는 상술한 바와 같다).In formula (III), Z is as described above).

본 반응은 원료 화합물(II)와 (III)을 에탄올과 같은 알콜류, 디옥산, 테트라하이드로퓨란, 1,2-디메톡시에탄과 같은 에테르류, 벤젠, 톨루엔, 크실렌과 같은 방향족 탄화수소류, 아세토니트릴, 디메틸포름아미드, 디메틸설폭사이드, 피리딘, 물 등의 불활성 유기용매 중에서 0∼200℃의 온도에서 10분∼24시간 동안 교반시키므로써 이루어진다.This reaction is carried out with crude compounds (II) and (III), alcohols such as ethanol, dioxane, tetrahydrofuran, ethers such as 1,2-dimethoxyethane, aromatic hydrocarbons such as benzene, toluene and xylene, acetonitrile And inert organic solvents such as dimethylformamide, dimethylsulfoxide, pyridine and water at a temperature of 0 to 200 캜 for 10 minutes to 24 hours.

본 반응은 산 수용체의 존재하에 원료화합물(III)을 원료화합물(II)에 대하여 당량 또는 과량 사용하는 것이 일반적이나 원료화합물(III)을 과량 사용함으로써 산수용체의 역할을 겸하게 할 수도 있다.This reaction generally uses the equivalent or excess of the source compound (III) relative to the source compound (II) in the presence of an acid acceptor, but may also serve as an acid acceptor by using the source compound (III) in an excessive amount.

산 수용체로서는, 수산화나트륨 또는 수산화칼륨 등의 수산화물, 탄산나트륨 또는 탄산칼륨 등의 탄산염, 중탄산나트륨 또는 중탄산칼륨 등의 중탄산염, 트리에틸아민, 디메틸아닐린, N,N-디이소프로필에틸아민, 1,8-디아자바이사이클로[5.4.0]운데세-7-엔(DBU)과 같은 유기염기 등을 들 수 있다.As the acid acceptor, hydroxides such as sodium hydroxide or potassium hydroxide, carbonates such as sodium carbonate or potassium carbonate, bicarbonates such as sodium bicarbonate or potassium bicarbonate, triethylamine, dimethylaniline, N, N-diisopropylethylamine, 1,8 Organic bases such as diazabicyclo [5.4.0] undec-7-ene (DBU); and the like.

상기의 반응에서 사용되는 원료화합물(III)은 그 자체로 사용될 수 있으나, 반응에 관여하지 않는 아민기를 보호한 형태로 사용할 수도 있는데 이때에는 반응 종료후 통상의 방법에 따라 그 보호기를 제거하게 된다. 보호기로서는 반응에 의해 형성된 본 발명의 화합물의 구조를 파괴하지 않고 제거시킬 수 있는 것으로서 펩타이드, 아미노산, 헥산 또는 베타락탐계 화합물에서 통상 사용되는 보호기를 들 수 있다. 바람직한 보호기로는 예를 들면 아세틸, 트리플루오로 아세틸, 에톡시카르보닐기와 같은 가수분해성 기 또는 벤질기등이 있다.The raw material compound (III) used in the above reaction may be used by itself, but may also be used in the form of protecting the amine group not involved in the reaction. In this case, the protecting group is removed according to a conventional method after completion of the reaction. As a protecting group, what can be removed without destroying the structure of the compound of this invention formed by reaction is a protecting group normally used by a peptide, an amino acid, hexane, or a beta lactam type compound. Preferred protecting groups include, for example, hydrolyzable groups such as acetyl, trifluoro acetyl, ethoxycarbonyl groups or benzyl groups.

원료화합물(II)는 상기의 화합물로서 예를 들면 이하의 문헌에 기재된 방법에 따르거나, 그에 준하는 방법에 의해 제조된다[J. Med. Chem., 1988, 31, 503; J.Org.Chem., 1981, 46, 846; EP 0132845(1985); USP 4826987(1989); EP 0271275(1987); JP 01-028662; JP 64-16746; J. Heterocyclic Chem., 1990, 27, 1609; J. Heterocyclic Chem., 1991, 28, 541].The raw material compound (II) is prepared by the method described in the following literature or by a method similar thereto, for example, as the compound [J. Med. Chem., 1988, 31, 503; J. Org. Chem., 1981, 46, 846; EP 0132845 (1985); USP 4826987 (1989); EP 0271275 (1987); JP 01-028662; JP 64-16746; J. Heterocyclic Chem., 1990, 27, 1609; J. Heterocyclic Chem., 1991, 28, 541].

원료화합물(III)은 본 발명에서 합성한 신규 화합물인데, 그 중 한 예인 6-아미노-1-메틸-3-아자비시클로[3.2.0] 헵탄은 다음과 같은 방법에 의해 제조될 수 있다.Raw material compound (III) is a novel compound synthesized in the present invention, one of which is 6-amino-1-methyl-3-azabicyclo [3.2.0] heptane can be prepared by the following method.

(여기서, R8은 수소 또는 메틸기이다).(Wherein R 8 is hydrogen or methyl group).

즉, 공지화합물인 N-p-톨루엔술포닐-1-메틸-6-옥소-3-아자비시클로[3.2.0] 헵탄(참조 : Heterocycles, 1989, 25, 29] 을 염기 존재하에 메톡시아민 또는 히드록시 아민의 염산염과 축합 반응시켜 생성된 메톡시아민 또는 히드록시이민화합물(Ⅳ)을 환원제로 환원시키면 아미노화합물(V)가 만들어지고, 이 화합물을 산존재하에서 보호기를 제거하면 목적하는 라세미체의 [1α,5α,6β]-6-dkalsh-1-메틸-3-아자비시클로[3.2.0] 헵탄(VI)을 제조할 수 있다.That is, the known compound Np-toluenesulfonyl-1-methyl-6-oxo-3-azabicyclo [3.2.0] heptane (see Heterocycles, 1989, 25, 29) in the presence of a methoxyamine or hydroxy Reduction of the methoxyamine or hydroxyimine compound (IV) produced by condensation reaction with the hydrochloride salt of the amine with a reducing agent produces an amino compound (V), and the removal of the protecting group in the presence of the acid results in the removal of the desired racemate. [1α, 5α, 6β] -6-dkalsh-1-methyl-3-azabicyclo [3.2.0] heptanes (VI) can be prepared.

한편, 이 라세미체(VI)을 광학분할하기 위하여 아미노 화합물(V)를 N-p-톨루엔술포닐-L-페닐알라닌과 축합시켜 아마이드 화합물(Ⅶ) 및 (Ⅷ)을 합성한 후 컬럼크로마토그래피나 재결정을 통하여 각각의 광학활성 디아스테레오머(Diastereomer)를 분리한 다음 이것을 각각 산가수분해시키면 화합물(VI)의 광학이성체가 얻어진다.On the other hand, in order to optically divide the racemate (VI), the amino compound (V) is condensed with Np-toluenesulfonyl-L-phenylalanine to synthesize amide compounds (VII) and (VII), and then column chromatography or recrystallization. After separating each optically active diastereomer (Diastereomer) through the acid hydrolysis of each to obtain the optical isomer of the compound (VI).

또한, 공지 화합물인 N-p-톨루엔설포닐-1-메틸-6-옥소-3-아자비시클로[3.2.0]헵탄올을 환원제로 환원하여 알콜 화합물(IX)을 얻고, 이를 산가수분해 하면 [1α,5α,6β]-6-히드록시-1-메틸-3-아자비시클로[3.2.0] 헵탄(X)을 얻을 수 있다.In addition, Np-toluenesulfonyl-1-methyl-6-oxo-3-azabicyclo [3.2.0] heptanol, a known compound, is reduced with a reducing agent to obtain an alcohol compound (IX), which is subjected to acid hydrolysis. , 5α, 6β] -6-hydroxy-1-methyl-3-azabicyclo [3.2.0] heptane (X) can be obtained.

상기의 방법에 의해 얻어지는 본 발명의 화합물이 에스테르인 경우 그 에스테르 부분을 통상의 방법에 의해 가수분해하여 상기 일반식(I)의 화합물로 변환시킨다. 한편, 필요에 따라 상기 일반식(I)의 화합물을 통상의 방법에 의해 에스테르화하여 상기 일반식(I) 화합물의 에스테르를 만들 수 있다.When the compound of the present invention obtained by the above method is an ester, the ester moiety is hydrolyzed by a conventional method to be converted into the compound of formula (I). On the other hand, if necessary, the compound of the general formula (I) may be esterified by a conventional method to produce an ester of the compound of the general formula (I).

이상과 같이 제조된 본 발명의 화합물은 통상의 방법에 따라 단리, 정제한다. 단리, 정제조건에 있어서 염의 형태나 유리(遊離) 형태로 얻어지나 이것들은 목적에 따라 상호변환되고 목적하는 형태의 본 발명의 화합물이 제조된다.The compound of the present invention prepared as described above is isolated and purified according to a conventional method. In isolation and refining conditions, they are obtained in the form of a salt or in a free form, but these are mutually converted according to the purpose and the compound of the present invention is prepared in the desired form.

상기 일반식(I)로 표시되는 본 발명의 화합물, 그의 에스테르, 또는 그의 염은 신규 화합물이고 특히 화합물(I) 또는 그의 염은 다음 표에 나타난 바와 같이 광범위하고 강한 항균 활성을 나타낼 뿐만 아니라 그람 양성균 및 메티실린 내성균에도 강력한 항균 활성을 가지기 때문에 항균제로서의 가치가 충분하다.Compounds of the present invention, esters, or salts thereof represented by the general formula (I) are novel compounds, and in particular, compound (I) or salts thereof exhibits a wide range of strong antimicrobial activity as shown in the following table, as well as Gram-positive bacteria And because it has a strong antibacterial activity to methicillin-resistant bacteria, its value as an antimicrobial agent is sufficient.

시험관내 항균작용*1 In vitro antibacterial activity * 1

CPFX : 시프로플록사신, OFLX : 오플록사신CPFX: Ciprofloxacin, OFLX: Ofloxacin

*1 최소 발육 저지 농도(MIC : mcg/ml)는 Chemotheraphy, 29(1), 76(1981)에 기재된 방법에 준하여 측정하여 그 결과를 표중에 나타내었다.* 1 The minimum growth inhibition concentration (MIC: mcg / ml) was measured in accordance with the method described in Chemotheraphy, 29 (1), 76 (1981), and the results are shown in the table.

*2 A : Staphylococcus aureus smith* 2 A: Staphylococcus aureus smith

B : Streptococcus pyogenes C4003B: Streptococcus pyogenes C4003

C : MRSA C2208C: MRSA C2208

D : Escherichia coli A10536D: Escherichia coli A10536

E : Klebsiella pneumoniae A10031E: Klebsiella pneumoniae A10031

F : Pseudomonas aeruginosa A27853F: Pseudomonas aeruginosa A27853

화합물(I) 또는 그의 염은, 사람 또는 동물용 약은 물론 어병약, 농약, 식품의 보존제등으로서도 사용가능하다. 또 화합물(I)의 에스테르는 화합물(I)의 합성원료로서는 물론 가치 있는 것이나, 그 외에 이 화합물이 생체내에서 쉽게 화합물(I)로 변환되는 경우에는 화합물(I)과 동등한 작용효과를 발휘하므로 항균제로서 유용한 화합물이다.Compound (I) or a salt thereof can be used not only for human or animal drugs but also as a fish disease drug, pesticide, food preservative, and the like. The ester of compound (I) is, of course, valuable as a synthetic raw material of compound (I), but in addition, when this compound is easily converted into compound (I) in vivo, it exhibits the same effect as compound (I). Compounds useful as antibacterial agents.

본 발명의 화합물을 사람에게 항균제로서 사용할 경우 그의 투여량은, 연령, 체중, 증상, 투여경로 등에 따라 다르나, 하루에 5mg∼5g을 1회에서부터 수회에 걸쳐 투여할 수 있고 경로는 경구, 비경구 양쪽에 가능하다.When the compound of the present invention is used as an antimicrobial agent in humans, its dosage varies depending on age, weight, symptoms, route of administration, etc., but 5 mg to 5 g per day can be administered from one to several times, and the route is oral or parenteral. It is possible on both sides.

본 발명의 화합물은 그래도 사용해도 좋으나 통상 제제용 담체와 같이 조제하는 형태로 투여한다. 그 구체적인 예로서는 정제, 액제, 캡슐제, 과립제, 세립제, 산제, 시럽(Syrup)제, 주사제, 연고제 등이 있다.The compound of the present invention may still be used, but is usually administered in the form of a preparation for use as a carrier for the preparation. Specific examples thereof include tablets, liquids, capsules, granules, fine granules, powders, syrups, injections, ointments, and the like.

경구용 제제의 담체로서는 전분, 만니톨, 결정셀룰로오스, CMC Na, 물, 에탄올 등 제제분야에 있어서 상용되는 것으로서, 본 발명의 화합물과 반응하지 않은 물질이 사용되어진다. 주사용 담체로서는 물, 생리식염수, 글리코오스액, 수액제 등의 주사제 분야에 상응되는 담체등이 있다.As a carrier of the oral preparation, a substance which is commonly used in the preparation of starch, mannitol, crystalline cellulose, CMC Na, water, ethanol and the like, and a substance which does not react with the compound of the present invention is used. Examples of carriers for injection include carriers corresponding to the field of injections such as water, saline solution, glycos solution, and infusion solution.

또, 상기 액제 또는 연고제는, 이빈후과나 안과에서 치료의 목적으로 사용되어진다.Moreover, the said liquid preparation or ointment is used for the purpose of treatment in an aftertreatment or ophthalmology.

실시예Example

다음의 실시예는 본 발명 화합물의 제조방법을 구체적으로 설명하는 것이다.The following examples specifically illustrate the preparation of the compounds of the present invention.

참고예 1 :Reference Example 1:

[1α,5α]-6-메톡시이미노-1-메틸-2-(p-톨루엔술포닐)-3-아자비시클로[3.2.0]헵탄[1α, 5α] -6-methoxyimino-1-methyl-2- (p-toluenesulfonyl) -3-azabicyclo [3.2.0] heptane

[1α,5α]-1-메틸-6-옥소-3-(p-톨루엔술포닐)-3-아자비시클로[3.2.0]헵탄 40.0g, 메톡실아민산염 14.35g 및 피리딘 400ml의 혼합액을 실온에서 2시간 동안 교반하였다. 반응액을 감압농축하고 잔사를 에틸아세테이트 500ml에 녹여 5% 염산 수용액 200ml로 2회, 염화나트륨 포화수용액 200ml로 1회 세척한 후 무수황산마그네슘으로 건조하였다. 고체를 감압여과하여 제거하고 여액을 감압농축하여 황갈색 유상의 표제화합물 43.0g을 얻었다(수율 98%).A mixture of 40.0 g of [1α, 5α] -1-methyl-6-oxo-3- (p-toluenesulfonyl) -3-azabicyclo [3.2.0] heptane, 14.35 g of methoxylamine salt and 400 ml of pyridine was prepared at room temperature. Stirred for 2 h. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 500 ml of ethyl acetate, washed twice with 200 ml of 5% aqueous hydrochloric acid solution and once with 200 ml of saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solid was removed by filtration under reduced pressure, and the filtrate was concentrated under reduced pressure to obtain 43.0 g of a yellowish brown oily title compound (yield 98%).

1H-NMR(CDCL3)δ : 7.7(2H,d,J=8.28Hz), 7.3(2H,d,J=9.6Hz), 3.84(0.6H,s), 3.81(0.4H,s), 3.9∼2.3(7H,m), 2.4(3H,s), 1.3(3H,s) 1 H-NMR (CDCL 3 ) δ: 7.7 (2H, d, J = 8.28 Hz), 7.3 (2H, d, J = 9.6 Hz), 3.84 (0.6 H, s), 3.81 (0.4 H, s), 3.9 to 2.3 (7H, m), 2.4 (3H, s), 1.3 (3H, s)

참고예 2 :Reference Example 2:

[1α,5α,6β]-6-메틸-3-(p-톨루엔술포닐)-3-아자비시클로[3.2.0]헵탄[1α, 5α, 6β] -6-methyl-3- (p-toluenesulfonyl) -3-azabicyclo [3.2.0] heptane

NaBH4, 27.0g을 THF 150ml에 현탁시키고 트리플루오로아세트산(TEA) 55.0ml를 150ml에 용해시켜 실온에서 2시간에 걸쳐서 가하였다. 참고예 1의 표제화합물 43.0g을 THF 200ml에 용해시켜 실온에서 2시간에 걸쳐서 가한 다음 반응액을 실온에서 3시간 동안 교반하고, 물 50ml 및 40% 수산화나트륨 수용액 30ml를 가하여 5시간 동안 가열환류하였다. 반응액을 감압농축하여 THF를 제거하고 디클로로메탄 200ml로 3회 추출한 다음 유기층을 염화나트륨 포화수용액 200ml로 세척하고 무수황산나트륨으로 건조하였다. 고체를 감압여과하여 제거하고 여액을 감압농축하여 황갈색 유상을 표제화합물 39.0g을 얻었다(수율 98%).27.0 g of NaBH 4 were suspended in 150 ml of THF and 55.0 ml of trifluoroacetic acid (TEA) was dissolved in 150 ml and added at room temperature over 2 hours. 43.0 g of the title compound of Reference Example 1 was dissolved in 200 ml of THF, added over 2 hours at room temperature, and the reaction solution was stirred at room temperature for 3 hours, and 50 ml of water and 30 ml of 40% sodium hydroxide aqueous solution were added thereto. . The reaction solution was concentrated under reduced pressure to remove THF, extracted three times with 200 ml of dichloromethane, and the organic layer was washed with 200 ml of saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solid was removed by filtration under reduced pressure, and the filtrate was concentrated under reduced pressure to give 39.0 g of the title compound as a tan oil (yield 98%).

1H-NMR(CDCL3)δ : 7.7∼7.1(4H,m), 3.4∼2.0(10H,m), 2.3(3H,s), 1.3(3H,s) 1 H-NMR (CDCL 3 ) δ: 7.7 to 7.1 (4H, m), 3.4 to 2.0 (10H, m), 2.3 (3H, s), 1.3 (3H, s)

참고예 3 :Reference Example 3:

[1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄[1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptane

참고예 2의 표제화합물 5.0g 및 48% HBr 수용액 30ml의 혼액을 5시간 동안 가열환류하였다.A mixture of 5.0 g of the title compound of Reference Example 2 and 30 ml of an aqueous 48% HBr solution was heated to reflux for 5 hours.

반응액을 감압농축하여 잔사를 물 5ml에 녹이고 40% 수산화나트륨수용액 3ml를 가한 다음 클로로포름 100ml로 3회 추출하였다. 유기층을 무수황산 나트륨으로 건조하고 감압여과하여 고체를 제거한 후 감압농축하여 미황색 유상의 표제화합물 1.8g을 얻었다(수율 80%).The reaction solution was concentrated under reduced pressure, the residue was dissolved in 5 ml of water, 3 ml of 40% aqueous sodium hydroxide solution was added thereto, and then extracted three times with 100 ml of chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure to remove solids, and then concentrated under reduced pressure to obtain 1.8 g of a pale yellow oily title compound (yield 80%).

1H-NMR(CDCL3)δ : 3.5∼2.5(10H,m), 1.3∼1.1(1H,m), 1.26(3H,s) 1 H-NMR (CDCL 3 ) δ: 3.5 to 2.5 (10H, m), 1.3 to 1.1 (1H, m), 1.26 (3H, s)

참고예 4 :Reference Example 4:

[1α,5α,6β]-6-히드록시-1-메틸-3-(p-톨루엔술포닐)-3-아자비시클로[3.2.0]헵탄[1α, 5α, 6β] -6-hydroxy-1-methyl-3- (p-toluenesulfonyl) -3-azabicyclo [3.2.0] heptane

[1α,5α]-1-메틸-6-옥소-3-(p-톨루엔술포닐)-3-아자비시클로[3.2.0]헵탄 2.00g을 에탄올 30ml에 용해시키고, NaBH40.19g을 가하여 실온에서 1시간 동안 교반하였다. 반응액을 감압농축하고 잔사에 물 20ml를 가한 다음 5% 염산 수용액으로 산성화하고 실온에서 1시간 동안 교반하였다. 생성된 고체를 여과하고 물로 세척한 후 건조하여 미황색의 표제화합물 1.82g을 얻었다(수율 91%).2.00 g of [1α, 5α] -1-methyl-6-oxo-3- (p-toluenesulfonyl) -3-azabicyclo [3.2.0] heptane was dissolved in 30 ml of ethanol, 0.19 g of NaBH 4 was added to room temperature. Stirred for 1 h. The reaction solution was concentrated under reduced pressure, 20 ml of water was added to the residue, acidified with 5% aqueous hydrochloric acid solution, and the mixture was stirred at room temperature for 1 hour. The resulting solid was filtered, washed with water and dried to give 1.82 g of a pale yellow title compound (yield 91%).

1H-NMR(CDCL3)δ : 7.6∼7.1(4H,m), 4.3∼3.9(1H,m), 3.7∼1.8(8H,m),2.36(3H,s), 1.13(3H,s) 1 H-NMR (CDCL 3 ) δ: 7.6 to 7.1 (4H, m), 4.3 to 3.9 (1H, m), 3.7 to 1.8 (8H, m), 2.36 (3H, s), 1.13 (3H, s)

참고예 5 :Reference Example 5:

[1α,5α,6β]-6-히드록시-1-메틸-3-아자비시클로[3.2.0]헵탄[1α, 5α, 6β] -6-hydroxy-1-methyl-3-azabicyclo [3.2.0] heptane

참고예 4의 표제화합물 1.50g 및 48% HBr 수용액 20ml의 혼액을 5시간 동안 가열환류한 후 반응액을 감압농축하고 잔사를 물 5ml 및 40% 수산화나트륨 수용액 3ml를 가하였다. 클로로포름 50ml로 3회 추출하여 유기층을 무수황산나트륨으로 건조하고 감압여과하여 고체를 제거한 후 감압농축하여 미황색 유상의 표제화합물 0.54g을 얻었다(수율 80%).After the mixture of 1.50 g of the title compound of Reference Example 1 and 20 ml of a 48% aqueous HBr solution was heated to reflux for 5 hours, the reaction mixture was concentrated under reduced pressure, and the residue was added with 5 ml of water and 3 ml of 40% aqueous sodium hydroxide solution. The organic layer was extracted three times with 50 ml of chloroform, dried over anhydrous sodium sulfate, filtered under reduced pressure to remove solids, and concentrated under reduced pressure to give 0.54 g of a pale yellow oily title compound (yield 80%).

1H-NMR(CDCL3)δ : 4.5∼3.9(1H,m), 3.6∼1.7(9H,m), 1.2(3H,s) 1 H-NMR (CDCL 3 ) δ: 4.5 to 3.9 (1 H, m), 3.6 to 1.7 (9 H, m), 1.2 (3 H, s)

참고예 6 :Reference Example 6:

(-)-[1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄 및 (+)-[1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄(-)-[1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptane and (+)-[1α, 5α, 6β] -6-amino-1-methyl -3-azabicyclo [3.2.0] heptane

(1) [1α,5α,6β]-6-아미노-1-메틸-3-(p-톨루엔술포닐)-3-아자비시클로[3.2.0]헵탄 1.20g 및 N-(p-톨루엔술포닐)-L-페닐알라닌 1.51g을 디메틸포름아미드 30ml에 용해시키고 디에틸시아노포스포네이트 0.78ml 및 트리에틸아민 1.20ml를 가하여 실온에서 5시간 동안 교반하였다. 반응액을 에틸아세테이트 200ml로 희석하고 5% 염산 수용액 100ml로 2회, 포화 탄산수소나트륨 수용액 100ml로 2회, 물 100ml로 2회, 포화 염화나트륨 수용액 100ml로 1회 세척하고 무수 황산마그네슘으로 건조한 후 고체를 감압여과하여 제거하고 여액을 감압농축하였다. 잔사에 에탄올 20ml를 가하고 실온에서 1시간 동안 교반한 후 감압여과하여 0.67g의 백색 고체를 얻었다. 여액을 감압농축하고 실리카겔로 컬럼 크로마토그래피하여 무색의 유상물질 1.00g을 얻었다.(1) 1.20 g of [1α, 5α, 6β] -6-amino-1-methyl-3- (p-toluenesulfonyl) -3-azabicyclo [3.2.0] heptane and N- (p-toluenesulfonyl 1.51 g of) -L-phenylalanine was dissolved in 30 ml of dimethylformamide, 0.78 ml of diethylcyanophosphonate and 1.20 ml of triethylamine were added and stirred at room temperature for 5 hours. The reaction solution was diluted with 200 ml of ethyl acetate, washed twice with 100 ml of 5% aqueous hydrochloric acid solution, twice with 100 ml of saturated aqueous sodium hydrogen carbonate solution, twice with 100 ml of water, once with 100 ml of saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Under reduced pressure filtration, and the filtrate was concentrated under reduced pressure. 20 ml of ethanol was added to the residue, followed by stirring at room temperature for 1 hour, followed by filtration under reduced pressure to obtain 0.67 g of a white solid. The filtrate was concentrated under reduced pressure and column chromatography was performed on silica gel to obtain 1.00 g of a colorless oil.

(2) (1)에서 얻은 백색의 고체 0.67g 및 48% HBr 수용액 200ml의 혼액을 8시간 동안 가열환류하고 반응액을 감압농축하였다. 잔사를 물 5ml에 녹이고 40% 수산화나트륨 수용액 2ml를 가한 후 클로로포름 30ml로 3회 추출하고 유기층을 합하여 무수 황산나트륨으로 건조한 다음 고체를 감압여과하여 제거하고 감압농축하여 미황색 유상물질로서 (-)-[1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄 0.13g을 얻었다(수율 48%).(2) A mixture of 0.67 g of the white solid obtained in (1) and 200 ml of a 48% HBr aqueous solution was heated to reflux for 8 hours, and the reaction solution was concentrated under reduced pressure. The residue was dissolved in 5 ml of water, 2 ml of 40% aqueous sodium hydroxide solution was added, followed by extraction three times with 30 ml of chloroform. The organic layers were combined, dried over anhydrous sodium sulfate, the solid was filtered off under reduced pressure, concentrated under reduced pressure and concentrated as a slightly yellow oily substance (-)-[1α. 0.13 g of, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptane was obtained (yield 48%).

[α]20 D-15.2(C=1.0 MeOH)[α] 20 D -15.2 (C = 1.0 MeOH)

1H-NMR(CDCL3)δ : 3.5∼2.5(10H,m), 1.3∼1.1(1H,m), 1.26(3H,s) 1 H-NMR (CDCL 3 ) δ: 3.5 to 2.5 (10H, m), 1.3 to 1.1 (1H, m), 1.26 (3H, s)

(3) (1)에서 얻은 유상물질 1.00g 및 48% HBr 수용액 20ml의 혼액을 (2)에서와 같은 방법으로 처리하여 미황색 유상물질로서 (+)-[1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄 0.19g을 얻었다(수율 70%).(3) A mixture of 1.00 g of the oily substance obtained in (1) and 20 ml of a 48% aqueous solution of 48% HBr was treated in the same manner as in (2) to give (+)-[1α, 5α, 6β] -6-amino as a pale yellow oily substance. 0.19 g of -1-methyl-3-azabicyclo [3.2.0] heptane was obtained (yield 70%).

[α]20 D+15.0(C=1.0, MeOH)[α] 20 D +15.0 (C = 1.0, MeOH)

1H-NMR(CDCL3)δ : 3.5∼2.5(10H,m), 1.3∼1.1(1H,m), 1.26(3H,s) 1 H-NMR (CDCL 3 ) δ: 3.5 to 2.5 (10H, m), 1.3 to 1.1 (1H, m), 1.26 (3H, s)

참고예 7 :Reference Example 7:

[1α,5α]-6-메톡시이미노-3-(p-톨루엔술포닐)-3-아자비시클로[3.2.0]헵탄[1α, 5α] -6-methoxyimino-3- (p-toluenesulfonyl) -3-azabicyclo [3.2.0] heptane

[1α,5α]-6-옥소-3-(p-톨루엔술포닐)-3-아자비시클로[3.2.0]헵탄 35.5g, 메톡시아민 염산염 15.0g 및 피리딘 500ml의 혼합액을 실온에서 3시간 동안 교반하였다. 반응액을 감압농축하고 잔사를 에틸아세테이트 500ml에 녹여 5% 염산 수용액 200ml로 2회, 염화나트륨 포화 수용액 200ml로 1회 세척한 후 무수황산마그네슘으로 건조하였다. 고체를 감압여과하여 제거하고 여액을 감압농축하여 황갈색 유상을 표제화합물 39.0g을 얻었다(수율 99%).35.5 g of [1α, 5α] -6-oxo-3- (p-toluenesulfonyl) -3-azabicyclo [3.2.0] heptane, 15.0 g of methoxyamine hydrochloride and 500 ml of pyridine were mixed at room temperature for 3 hours. Stirred. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 500 ml of ethyl acetate, washed twice with 200 ml of 5% aqueous hydrochloric acid solution, and once with 200 ml of saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solid was removed by filtration under reduced pressure, and the filtrate was concentrated under reduced pressure to obtain 39.0 g of the title compound as a tan oil (yield 99%).

1H-NMR(CDCL3)δ : 7.67∼7.2(4H,dd,J=28.Hz,8.0Hz), 3.73(3H,d,J=1.2Hz), 3.6∼3.35(3H,m), 3.05∼2.4(5H,m), 2.35(3H,s). 1 H-NMR (CDCL 3 ) δ: 7.67 to 7.2 (4H, dd, J = 28.Hz, 8.0 Hz), 3.73 (3H, d, J = 1.2 Hz), 3.6 to 3.35 (3H, m), 3.05 2.4 (5H, m), 2.35 (3H, s).

참고예 8 :Reference Example 8:

[1α,5α,6β]-6-아미노-3-(p-톨루엔술포닐)-3-아자비시클로[3.2.0]헵탄[1α, 5α, 6β] -6-amino-3- (p-toluenesulfonyl) -3-azabicyclo [3.2.0] heptane

NaBH4, 20.0g을 THF 150ml에 현탁시키고 트리플루오로아세트산(TFA) 37.0ml을 THF 200ml에 용해시켜 실온에서 2시간에 걸려서 가하였다. 참고예 7의 표제화합물 25.0g을 THF 200ml에 용해시켜 실온에서 2시간에 걸쳐서 가한 다음 반응액을 실온에서 3시간 동안 교반하고, 물 50ml 및 40% 수산화나트륨 수용액 50ml를 가하여 5시간 동안 가열 환류하였다. 반응액을 감압농축하여 THF를 제거하고 디클로로메탄 200ml로 3회 추출한 다음 유기층을 염화나트륨 포화수용액 200ml로 세척하고 무수 황산나트륨으로 건조하였다. 고체를 감압여과하여 제거하고 여액을 감압농축하여 황갈색 유상의 표제화합물 21.5g을 얻었다(수율 95%).20.0 g of NaBH 4 was suspended in 150 ml of THF, and 37.0 ml of trifluoroacetic acid (TFA) was dissolved in 200 ml of THF and added at room temperature over 2 hours. 25.0 g of the title compound of Reference Example 7 was dissolved in 200 ml of THF, added at room temperature over 2 hours, and the reaction solution was stirred at room temperature for 3 hours, and 50 ml of water and 50 ml of 40% sodium hydroxide aqueous solution were added thereto, followed by heating to reflux for 5 hours. . The reaction solution was concentrated under reduced pressure to remove THF, extracted three times with 200 ml of dichloromethane, and the organic layer was washed with 200 ml of saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solid was removed by filtration under reduced pressure, and the filtrate was concentrated under reduced pressure to give 21.5 g of the titled compound as a tan oil (95% yield).

1H-NMR(CDCL3)δ : 7.7∼7.2(4H,m), 3.5∼2.0(11H,m), 2.35(3H,s). 1 H-NMR (CDCL 3 ) δ: 7.7 to 7.2 (4H, m), 3.5 to 2.0 (11H, m), 2.35 (3H, s).

참고예 9 :Reference Example 9:

[1α,5α,6β]-6-아미노-3-아자비시클로[3.2.0]헵탄[1α, 5α, 6β] -6-amino-3-azabicyclo [3.2.0] heptane

참고예 8의 표제화합물 7.0g 및 48% HBr 수용액 50ml의 혼합액을 5시간 동안 가열 환류하였다. 반응액을 감압농축하여 잔사를 물 5ml에 녹이고, 40% 수산화나트륨 수용액 3ml를 가한 다음 클로로포름 100ml로 3회 추출하였다. 유기층을 무수황산 나트륨으로 건조하고 감압여과하여 고체를 제거한 후 감압농축하여 미황색 유상의 표제화합물 2.1g을 얻었다(수율 71.3%).A mixture of 7.0 g of the title compound of Reference Example 8 and 50 ml of an 48% aqueous HBr solution was heated to reflux for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 5 ml of water. 3 ml of 40% aqueous sodium hydroxide solution was added thereto, followed by extraction three times with 100 ml of chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure to remove solids, and concentrated under reduced pressure to obtain 2.1 g of the title compound as a pale yellow oil (yield 71.3%).

1H-NMR(CDCL3)δ : 3.5∼2.4(11H,m), 1.3∼1.1(1H,m) 1 H-NMR (CDCL 3 ) δ: 3.5 to 2.4 (11 H, m), 1.3 to 1.1 (1 H, m)

참고예 10 :Reference Example 10:

[1α,5α,6β]-6-히드록시-3-(p-톨루엔술포닐)-3-아자비시클로[3.2.0]헵탄[1α, 5α, 6β] -6-hydroxy-3- (p-toluenesulfonyl) -3-azabicyclo [3.2.0] heptane

참고예 4와 동일한 방법으로 하여 표제 화합물을 92% 수율로 얻었다.In the same manner as in Reference Example 4, the title compound was obtained in 92% yield.

1H-NMR(CDCL3)δ : 7.7∼7.2(4H,m), 4.3∼3.8(1H,m), 3.6∼1.8(9H,m), 2.4(3H,s) 1 H-NMR (CDCL 3 ) δ: 7.7 to 7.2 (4H, m), 4.3 to 3.8 (1H, m), 3.6 to 1.8 (9H, m), 2.4 (3H, s)

참고예 11 :Reference Example 11:

[1α,5α,6β]-6-히드록시-3-아자비시클로[3.2.0]헵탄[1α, 5α, 6β] -6-hydroxy-3-azabicyclo [3.2.0] heptane

참고예 10의 표제화합물로 참고예 5와 동일한 방법으로 하여 표제 화합물을 90% 수율로 얻었다.The title compound of Reference Example 10 was obtained in the same manner as the Reference Example 5 to obtain the title compound in 90% yield.

1H-NMR(CDCL3)δ : 4.5∼4.0(1H,m), 3.6∼1.6(10H,m) 1 H-NMR (CDCL 3 ) δ: 4.5 to 4.0 (1H, m), 3.6 to 1.6 (10H, m)

참고예 12 :Reference Example 12:

[1α,5α]-6-메톡시이미노-5-메틸-3-(p-톨루엔술포닐)-3-아자비시클로[3.2.0]헵탄[1α, 5α] -6-methoxyimino-5-methyl-3- (p-toluenesulfonyl) -3-azabicyclo [3.2.0] heptane

[1α,5α]-5-메틸-6-옥소-3-(p-톨루엔술포닐)-3-아자비시클로[3.2.0]헵탄 20.0g, 메톡실아민7.4g 및 피리딘 300ml의 혼합액을 실온에서 3시간 동안 교반한 다음 참고예 7과 동일한 방법으로 하여 황갈색 유상의 표제화합물 18.9g을 얻었다(수율 85.6%).A mixture of 20.0 g of [1α, 5α] -5-methyl-6-oxo-3- (p-toluenesulfonyl) -3-azabicyclo [3.2.0] heptane, 7.4 g of methoxylamine and 300 ml of pyridine was stirred at room temperature. After stirring for 3 hours, 18.9 g of a tan oily title compound was obtained in the same manner as in Reference Example 7 (yield 85.6%).

1H-NMR(CDCL3)δ : 7.8∼7.2(4H,m), 3.85(3H,s), 4.0∼2.5(7H,m), 2.45(3H,s), 1.3(3H,s) 1 H-NMR (CDCL 3 ) δ: 7.8 to 7.2 (4H, m), 3.85 (3H, s), 4.0 to 2.5 (7H, m), 2.45 (3H, s), 1.3 (3H, s)

참고예 13 :Reference Example 13:

[1α,5α,6β]-6-아미노-5-메틸-3-(p-톨루엔술포닐)-3-아자비시클로[3.2.0]헵탄[1α, 5α, 6β] -6-amino-5-methyl-3- (p-toluenesulfonyl) -3-azabicyclo [3.2.0] heptane

참고예 12의 표제화합물 18.9g을 참고예 8과 같은 방법으로 하여 표제화합물 14.6g을 얻었다(수율 85%).14.6 g of the title compound of Reference Example 12 was obtained in the same manner as the Reference Example 8 to obtain 14.6 g of the title compound (yield 85%).

1H-NMR(CDCL3)δ : 7.8∼7.2(4H,m), 3.5∼2.1(10H,m), 2.4(3H,s), 1.35(3H,s) 1 H-NMR (CDCL 3 ) δ: 7.8 to 7.2 (4H, m), 3.5 to 2.1 (10H, m), 2.4 (3H, s), 1.35 (3H, s)

참고예 14 :Reference Example 14

[1α,5α,6β]-6-아미노-5-메틸-3-아자비시클로[3.2.0]헵탄[1α, 5α, 6β] -6-amino-5-methyl-3-azabicyclo [3.2.0] heptane

참고예 13의 표제화합물 11.0g을 참고예 9와 동일한 방법으로 하여 표제화합물 3.3g을 얻었다(수율 67%).In the same manner as in Reference Example 9, 11.0 g of the title compound of Reference Example 13 was obtained 3.3 g (yield 67%).

1H-NMR(CDCL3)δ : 3.7∼2.7(10H,m), 1.5∼1.2(1H,m), 1.3(3H,s) 1 H-NMR (CDCL 3 ) δ: 3.7 to 2.7 (10 H, m), 1.5 to 1.2 (1 H, m), 1.3 (3 H, s)

참고예 15 :Reference Example 15:

(-)-[1α,5α,6β]-6-아미노-3-아자비시클로[3.2.0]헵탄 및 (+)-[1α,5α,6β]-6-아미노-3-아자비시클로[3.2.0]헵탄(-)-[1α, 5α, 6β] -6-amino-3-azabicyclo [3.2.0] heptane and (+)-[1α, 5α, 6β] -6-amino-3-azabicyclo [3.2. 0] heptane

(1) 1α,5α,6β]-6-아미노-3-(p-톨루엔술포닐)-3-아자비시클로[3.2.0]헵탄 1.15g 및 N-(p-톨루엔술포닐)-L-페닐알라닌 1.51g을 디메틸포름아미드 30ml에 용해시키고, 디에틸시아노포스포네이트 0.78ml 및 트리에틸아민 1.20ml를 가하여 실온에서 5시간 동안 교반하였다. 반응액을 에틸아세테이트 200ml로 희석하고 5% 염산용액 100ml로 2회, 포화탄산수소나트륨 수용액 100ml로 2회, 물 100ml로 2회, 포화염화나트륨 수용액 100ml로 1회 세척하고 무수 황산마그네슘으로 건조한 후 고체를 감압여과하여 제거하고 여액을 감압농축하였다. 잔사에 에탄올 20ml를 가하고 실온에서 1시간 동안 교반한 후 감압여과하여 0.67g의 백색 고체를 얻었다. 그리고 여액을 감압농축하고 실리카겔로 컬럼 크로마토그래피하여 무색의 유상물질 1.00g을 얻었다.(1) 1.15 g of 1α, 5α, 6β] -6-amino-3- (p-toluenesulfonyl) -3-azabicyclo [3.2.0] heptane and N- (p-toluenesulfonyl) -L-phenylalanine 1.51 g was dissolved in 30 ml of dimethylformamide, 0.78 ml of diethylcyanophosphonate and 1.20 ml of triethylamine were added and stirred at room temperature for 5 hours. The reaction solution was diluted with 200 ml of ethyl acetate, washed twice with 100 ml of 5% hydrochloric acid solution, twice with 100 ml of saturated aqueous sodium hydrogen carbonate solution, twice with 100 ml of water, once with 100 ml of saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Under reduced pressure filtration, and the filtrate was concentrated under reduced pressure. 20 ml of ethanol was added to the residue, followed by stirring at room temperature for 1 hour, followed by filtration under reduced pressure to obtain 0.67 g of a white solid. The filtrate was concentrated under reduced pressure and column chromatography was performed on silica gel to obtain 1.00 g of a colorless oil.

(2) (1)에서 얻은 백색고체 0.67g 및 48% HBr 수용액 20ml의 혼액을 8시간 동안 가열환류하고 반응액을 감압농축하였다. 잔사를 물 5ml에 녹이고 40% 수산화나트륨 수용액 2ml를 가한 후 클로로포름 30ml로 3회 추출하고 유기층을 합하여 무수 황산나트륨으로 건조한 다음 고체를 감압여과하여 제거하고 감압농축하여 미황색 유상물질로서 (-)-[1α,5α,6β]-6-아미노-3-아자비시클로[3.2.0]헵탄 0.13g을 얻었다(수율 48%).(2) A mixture of 0.67 g of the white solid obtained in (1) and 20 ml of a 48% aqueous HBr solution was heated to reflux for 8 hours, and the reaction solution was concentrated under reduced pressure. The residue was dissolved in 5 ml of water, 2 ml of 40% aqueous sodium hydroxide solution was added, followed by extraction three times with 30 ml of chloroform. The organic layers were combined, dried over anhydrous sodium sulfate, the solid was filtered off under reduced pressure, concentrated under reduced pressure and concentrated as a slightly yellow oily substance (-)-[1α. 0.13 g of, 5α, 6β] -6-amino-3-azabicyclo [3.2.0] heptane was obtained (yield 48%).

[α]20 D-13.8(C=1.0, MeOH)[α] 20 D -13.8 (C = 1.0, MeOH)

1H-NMR(CDCL3)δ : 3.5∼1.5(12H,m) 1 H-NMR (CDCL 3 ) δ: 3.5 to 1.5 (12H, m)

(3) (1)에서 얻은 유상물질 1.00g 및 48% HBr 수용액 20ml의 혼액을 (2)에서와 같은 방법으로 처리하여 미황색 유상물질로서 (+)-[1α,5α,6β]-6-아미노-3-아자비시클로[3.2.0]헵탄 0.19g을 얻었다(수율 70%).(3) A mixture of 1.00 g of the oily substance obtained in (1) and 20 ml of a 48% aqueous solution of 48% HBr was treated in the same manner as in (2) to give (+)-[1α, 5α, 6β] -6-amino as a pale yellow oily substance. 0.19 g of 3-azabicyclo [3.2.0] heptane was obtained (yield 70%).

[α]20 D-14.0(C=1.0, MeOH)[α] 20 D -14.0 (C = 1.0, MeOH)

1H-NMR(CDCL3)δ : 3.48∼1.52(12H,m) 1 H-NMR (CDCL 3 ) δ: 3.48 to 1.52 (12H, m)

참고예 16 :Reference Example 16:

[1α,5α,6β]-1-메틸-6-(프탈이미도-1-일)-3-(p-톨루엔술포닐)-3-아자비시클로[3.2.0]헵탄[1α, 5α, 6β] -1-methyl-6- (phthalimido-1-yl) -3- (p-toluenesulfonyl) -3-azabicyclo [3.2.0] heptane

[1α,5α6α]-6-히드록시-1-메틸-3-(p-톨루엔술포닐)-3-아자비시클로[3.2.0]헵탄 7.00g, 프탈이미드 7.35g 및 트리페닐포스핀 13.09g을 THF 70ml에 용해시키고 DEAD 8.67g을 가한 후 실온에서 5시간 동안 교반하였다. 반응액을 감압농축하고 잔사를 에틸아세테이트 300ml에 녹여 5% NaOH 수용액 100ml로 3회, 5% HCl 수용액 100ml 및 NaCl 포화수용액 100ml로 차례로 세척하였다. 유기층을 무수 황산 마그네슘으로 건조하고 감압농축한후 잔사에 메탄을 소량을 가하여 실온에서 1시간 동안 교반하고 생성된 교체를 여과, 건조하여 미황색 표제화합물 3.50g을 얻었다(수율 34%).[1α, 5α6α] -6-hydroxy-1-methyl-3- (p-toluenesulfonyl) -3-azabicyclo [3.2.0] heptane 7.00 g, phthalimide 7.35 g and triphenylphosphine 13.09 g Was dissolved in 70 ml of THF, 8.67 g of DEAD was added, and stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 300 ml of ethyl acetate, and washed three times with 100 ml of 5% NaOH aqueous solution, 100 ml of 5% HCl aqueous solution, and 100 ml of saturated aqueous NaCl solution. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, a small amount of methane was added to the residue, stirred at room temperature for 1 hour, and the resulting replacement was filtered and dried to yield 3.50 g of a pale yellow title compound (yield 34%).

융점 : 180∼184℃Melting Point: 180 ~ 184 ℃

1H-NMR(CDCL3)δ : 7.9∼7.6(6H,m), 7.35(2H,d,J=8.6Hz), 4.7∼4.3(1H,m), 3.6∼2.3(7H,m), 2.45(3H,s), 1.38(3H,s) 1 H-NMR (CDCL 3 ) δ: 7.9 to 7.6 (6H, m), 7.35 (2H, d, J = 8.6 Hz), 4.7 to 4.3 (1H, m), 3.6 to 2.3 (7H, m), 2.45 (3H, s), 1.38 (3H, s)

참고예 17 :Reference Example 17:

[1α,5α,6α]-6-아미노-1-메틸-3-(p-톨루엔설포닐)-3-아자비시클로[3.2.0]헵탄[1α, 5α, 6α] -6-amino-1-methyl-3- (p-toluenesulfonyl) -3-azabicyclo [3.2.0] heptane

[1α,5α,6α]-1-메틸-6-(프탈리미도-1-일)-3-(p-톨루엔술포닐)-3-아자비시클로[3.2.0]헵탄 0.70g, 히드라진 1수화물 0.26g 및 메탄올 40ml의 혼합용액을 3시간 동안 가열환류하고 실온까지 냉각하여 고체를 여과하여 제거한다. 여액을 감압농축하고 잔사를 에틸아세테이트 30ml을 가하여 실온에서 30분간 교반한 후 고체를 여과하여 제거하고 여액을 감압농축하여 미황색 표제화합물 0.45g을 얻었다(수율 95%).[1α, 5α, 6α] -1-methyl-6- (phthalimido-1-yl) -3- (p-toluenesulfonyl) -3-azabicyclo [3.2.0] heptane 0.70 g, hydrazine monohydrate A mixed solution of 0.26 g and 40 ml of methanol was heated to reflux for 3 hours, cooled to room temperature, and the solid was filtered off. The filtrate was concentrated under reduced pressure, the residue was added with 30 ml of ethyl acetate, stirred at room temperature for 30 minutes, the solid was filtered off, and the filtrate was concentrated under reduced pressure to obtain 0.45 g of a slightly yellow title compound (yield 95%).

융점 : 70∼74℃Melting Point: 70 ~ 74 ℃

1H-NMR(CDCL3)δ : 7.7∼7.1(4H,m), 3.4(4H,m), 3.4∼2.0(10H,m), 2.3(3H,s), 1.3(3H,s) 1 H-NMR (CDCL 3 ) δ: 7.7 to 7.1 (4H, m), 3.4 (4H, m), 3.4 to 2.0 (10H, m), 2.3 (3H, s), 1.3 (3H, s)

참고예 18 :Reference Example 18:

[1α,5α,6α]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄[1α, 5α, 6α] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptane

[1α,5α,6α]-6-아미노-1-메틸-3-(p-톨루엔술포닐)-3-아자비시클로[3.2.0]헵탄 0.45g 및 48% HBr 수용액 10ml의 혼합액을 3시간 동안 가열환류하였다. 반응액을 감압농축하여 잔사를 물 5ml에 녹이고 40% 수산화나트륨 수용액 1ml을 가한 다음 클로로포름 20ml로 3회 추출하였다. 유기층을 무수 황산나트륨으로 건조하고 감압농축하여 무색 유상의 표제화합물 0.19g을 얻었다(수율 95%).A mixture of 0.45 g of [1α, 5α, 6α] -6-amino-1-methyl-3- (p-toluenesulfonyl) -3-azabicyclo [3.2.0] heptane and 10 ml of 48% HBr aqueous solution was added for 3 hours. It was heated to reflux. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 5 ml of water, 1 ml of 40% aqueous sodium hydroxide solution was added thereto, and the resultant was extracted three times with 20 ml of chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 0.19 g of a colorless oily title compound (yield 95%).

1H-NMR(CDCL3)δ : 3.5∼2.5(10H,m), 1.3∼1.1(1H,m), 1.26(3H,s) 1 H-NMR (CDCL 3 ) δ: 3.5 to 2.5 (10H, m), 1.3 to 1.1 (1H, m), 1.26 (3H, s)

참고예 19 :Reference Example 19:

[1α,5α,6β]-6-에톡시카르보닐아미노-1-메틸-3-(p-톨루엔술포닐)-3-아자비시클로[3.2.0]헵탄[1α, 5α, 6β] -6-ethoxycarbonylamino-1-methyl-3- (p-toluenesulfonyl) -3-azabicyclo [3.2.0] heptane

[1α,5α,6α]-6-아미노-1-메틸-3-(p-톨루엔술포닐)-3-아자비시클로[3.2.0]헵탄 4.53g, 트리에틸아민 2.46g 및 디클로로메탄 20ml의 혼액을 0℃까지 냉각하고 클로로에틸카르보네이트 1.93g을 적가한 후 실온에서 1시간 동안 교반하였다. 반응액을 디클로로메탄 50ml로 희석하고 5% 염산수용액 30ml로 2회, 염화나트륨 포화수용액 30ml로 1회 세척하였다. 유기층을 무수 황산 마그네슘으로 건조하고 감압농축한 후 잔사를 실리카겔로 컬럼크로마토그래피하여 무색 유상의 표제화합물 2.8g을 얻었다(수율 49%).A mixture of 4.53 g of [1α, 5α, 6α] -6-amino-1-methyl-3- (p-toluenesulfonyl) -3-azabicyclo [3.2.0] heptane, 2.46 g of triethylamine and 20 ml of dichloromethane The mixture was cooled to 0 ° C. and 1.93 g of chloroethyl carbonate was added dropwise, followed by stirring at room temperature for 1 hour. The reaction solution was diluted with 50 ml of dichloromethane and washed twice with 30 ml of 5% aqueous hydrochloric acid solution and once with 30 ml of saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel to give 2.8 g of a colorless oily title compound (yield 49%).

1H-NMR(CDCL3)δ : 7.8∼7.3(4H,m), 5.04(1H,d,J=9.45Hz), 4.5∼2.0(8H,m), 4.11(2H,q,J=7.22Hz), 2.45(3H,s), 1.25(3H,t,J=7.2Hz) 1.20(3H,s) 1 H-NMR (CDCL 3 ) δ: 7.8 to 7.3 (4H, m), 5.04 (1H, d, J = 9.45 Hz), 4.5 to 2.0 (8H, m), 4.11 (2H, q, J = 7.22 Hz ), 2.45 (3H, s), 1.25 (3H, t, J = 7.2 Hz) 1.20 (3H, s)

참고예 20 :Reference Example 20:

[1α,5α,6β]-1-메틸-6-메틸아미노-3-(p-톨루엔술포닐)-3-아자비시클로[3.2.0]헵탄[1α, 5α, 6β] -1-methyl-6-methylamino-3- (p-toluenesulfonyl) -3-azabicyclo [3.2.0] heptane

[1α,5α,6β]-6-에톡시카르보닐아미노-1-메틸-3-(p-톨루엔술포닐)-3-아자비시클로[3.2.0]헵탄 2.80g 및 THF 30ml의 혼액에 LAH 0.45g을 가하고 10분간 가열환류하였다. 반응액에 물 5ml 및 20% 수산화나트륨 수용액 5ml를 차례로 가하고 용액층을 분리하여 감압농축하였다. 잔사를 에틸아세테이트 50ml에 용해시키고 10% 염산수용액 20ml로 추출하여 수층에 20% 수산화나트륨 수용액을 적가하여 pH 12로 조정하였다. 수층을 디클로로메탄 30ml로 2회추출하고 유기층을 합하여 무수 황산나트륨으로 건조한 후 감압농축하여 미황색 유상의 표제화합물 0.85g을 얻었다(수율 36%).LAH 0.45 in a mixture of 2.80 g of [1α, 5α, 6β] -6-ethoxycarbonylamino-1-methyl-3- (p-toluenesulfonyl) -3-azabicyclo [3.2.0] heptane and 30 ml of THF g was added and heated to reflux for 10 minutes. 5 ml of water and 5 ml of 20% sodium hydroxide aqueous solution were sequentially added to the reaction solution, and the solution layer was separated and concentrated under reduced pressure. The residue was dissolved in 50 ml of ethyl acetate, extracted with 20 ml of 10% aqueous hydrochloric acid solution, and adjusted to pH 12 by dropwise adding 20% aqueous sodium hydroxide solution to the aqueous layer. The aqueous layer was extracted twice with 30 ml of dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 0.85 g of a pale yellow oily title compound (yield 36%).

1H-NMR(CDCL3)δ : 7.8∼7.3(4H,m), 3.8∼1.5(9H,m), 2.44(3H,s), 2.30(3H,s), 1.20(3H,s) 1 H-NMR (CDCL 3 ) δ: 7.8 to 7.3 (4H, m), 3.8 to 1.5 (9H, m), 2.44 (3H, s), 2.30 (3H, s), 1.20 (3H, s)

참고예 21 :Reference Example 21:

[1α,5α,6β]-1-메틸-6-메틸아미노-3-아자비시클로[3.2.0]헵탄[1α, 5α, 6β] -1-methyl-6-methylamino-3-azabicyclo [3.2.0] heptane

[1α,5α,6β]-1-메틸-6-메틸아미노-3-(p-톨루엔술포닐)-3-아자비시클로[3.2.0]헵탄 0.82g 및 48% HBr 수용액 10ml의 혼액을 1시간 동안 가열환류하였다. 반응액을 감압농축하여 잔사를 물 10ml에 녹이고 40% 수산화나트륨 수용액을 적가하여 pH 12정도로 조정한 후 클로로포름 30ml로 2회 추출하였다. 유기층을 합하여 무수 황산 나트륨으로 건조하고 감압농축하여 미황색 유상의 표제화합물 0.37g을 얻었다(수율 96%).A mixture of 0.82 g of [1α, 5α, 6β] -1-methyl-6-methylamino-3- (p-toluenesulfonyl) -3-azabicyclo [3.2.0] heptane and 10 ml of 48% HBr aqueous solution was added for 1 hour. Heated to reflux. The reaction solution was concentrated under reduced pressure, the residue was dissolved in 10 ml of water, 40% aqueous sodium hydroxide solution was added dropwise to pH 12, and extracted twice with 30 ml of chloroform. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 0.37 g of a pale yellow oily title compound (yield 96%).

1H-NMR(CDCL3)δ : 3.4∼1.5(10H,m), 2.28(3H,s), 1.25(3H,s) 1 H-NMR (CDCL 3 ) δ: 3.4 to 1.5 (10H, m), 2.28 (3H, s), 1.25 (3H, s)

실시예 1Example 1

7-([1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-1-시클로프로필-6-플루오로-1,4-디히드로-4-옥소퀴놀린-3-카르복실산7-([1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptan-3-yl) -1-cyclopropyl-6-fluoro-1,4-di Hydro-4-oxoquinoline-3-carboxylic acid

1-시클로로프로필-6,7-디플루오로-1,4-디히드로-4-옥소퀴놀린-3-카르복실산 150mg을 아세토니트릴 5ml에 현탁시키고 DBU 200mg과 [1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄 200mg을 가한 후 1시간 동안 가열환류하였다. 용매를 감압증류하여 제거하고 잔사에 5% 수용액 5ml을 가하여 실온에서 3시간 동안 교반하였다. 생성된 고체를 여과하고 물 및 에탄올로 세척한 후 건조하여 표제화합물의 염산염인 140mg의 미황색 고체를 얻었다(수율 61%).150 mg of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid is suspended in 5 ml of acetonitrile and 200 mg of DBU and [1α, 5α, 6β]- After 200 mg of 6-amino-1-methyl-3-azabicyclo [3.2.0] heptane was added, the mixture was heated to reflux for 1 hour. The solvent was distilled off under reduced pressure, and 5 ml of a 5% aqueous solution was added to the residue, followed by stirring at room temperature for 3 hours. The resulting solid was filtered, washed with water and ethanol and dried to give 140 mg of a pale yellow solid as the hydrochloride of the title compound (yield 61%).

융점 : 285∼290℃Melting Point: 285 ~ 290 ℃

1H-NMR(CDCL-d6+TFA-d)δ : 8.55(1H,s), 8.00(1H,d,J=17.4Hz), 7.24(1H,d,J=7.4Hz), 4.3∼3.5(4H,m), 3.5∼3.3(1H,m), 3.0∼2.6(2H,m), 2.3∼ 2.0(2H,m), 1.31(3H,s), 1.4∼1.0(4H,m) 1 H-NMR (CDCL-d 6 + TFA-d) δ: 8.55 (1H, s), 8.00 (1H, d, J = 17.4 Hz), 7.24 (1H, d, J = 7.4 Hz), 4.3-3.5 (4H, m), 3.5 to 3.3 (1H, m), 3.0 to 2.6 (2H, m), 2.3 to 2.0 (2H, m), 1.31 (3H, s), 1.4 to 1.0 (4H, m)

실시예 2Example 2

7-([1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-1-시클로프로필-6,8-디플루오로-1,4-디히드로-4-옥소퀴놀린-3-카르복실산7-([1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptan-3-yl) -1-cyclopropyl-6,8-difluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid

1-시클로프로필-6,7,8-트리플루오로-1,4-디히드로-4-옥소퀴놀린-3-카르복실산 140mg을 디메틸술폭시드 3ml에 현탁시키고, K2CO3100mg 및 [1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄 180mg을 가한 후, 60∼80℃에서 4시간 동안 교반하였다. 반응액을 실온까지 냉각시키고 5% 염산 수용액 3ml을 가하여 2시간 동안 교반하였다. 생성된 고체를 여과하고 THF로 세척한 후 건조하여 표제화합물의 염산염인 70mg의 미황색 고체를 얻었다(수율 33%).140 mg of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid is suspended in 3 ml of dimethyl sulfoxide, 100 mg of K 2 CO 3 and [1α] 180 mg of, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptane was added, followed by stirring at 60 to 80 ° C. for 4 hours. The reaction solution was cooled to room temperature, and 3 ml of 5% aqueous hydrochloric acid solution was added thereto, followed by stirring for 2 hours. The resulting solid was filtered, washed with THF and dried to give 70 mg of a pale yellow solid as a hydrochloride of the title compound (yield 33%).

융점 : 290∼293℃(분해)Melting Point: 290 ~ 293 ℃ (Decomposition)

1H-NMR(DMSO-d6+TFA-d)δ : 7.69(1H,s), 7.83(1H,dd,J=13.2Hz,1.96Hz ), 4.3∼3.8(2H,m), 3.8∼2.8(4H,m), 2.8∼3.0(3H,m), 1.35(3H,s), 1.3∼1.0(4H,m) 1 H-NMR (DMSO-d 6 + TFA-d) δ: 7.69 (1H, s), 7.83 (1H, dd, J = 13.2 Hz, 1.96 Hz), 4.3 to 3.8 (2H, m), 3.8 to 2.8 (4H, m), 2.8 to 3.0 (3H, m), 1.35 (3H, s), 1.3 to 1.0 (4H, m)

실시예 2Example 2

7-([1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-1-시클로프로필-6,8-디플루오로-1,4-디히드로-4-옥소퀴놀린-3-카르복실산7-([1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptan-3-yl) -1-cyclopropyl-6,8-difluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid

1-시클로프로필-6,7,8-트리플루오로-1,4-디히드로-4-옥소퀴놀린-3-카르복실산 140mg을 디메틸술폭시드 3ml에 현탁시키고, K2CO3100mg 및 [1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄 180mg을 가한 후, 60∼80℃에서 4시간 동안 교반하였다. 반응액을 실온까지 냉각시키고 5% 염산 수용액 3ml을 가하여 2시간 동안 교반하였다. 생성된 고체를 여과하고 THF로 세척한 후 건조하여 표제화합물의 염산염인 70mg의 미황색 고체를 얻었다(수율 33%).140 mg of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid is suspended in 3 ml of dimethyl sulfoxide, 100 mg of K 2 CO 3 and [1α] 180 mg of, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptane was added, followed by stirring at 60 to 80 ° C. for 4 hours. The reaction solution was cooled to room temperature, and 3 ml of 5% aqueous hydrochloric acid solution was added thereto, followed by stirring for 2 hours. The resulting solid was filtered, washed with THF and dried to give 70 mg of a pale yellow solid as a hydrochloride of the title compound (yield 33%).

융점 : 290∼293℃(분해)Melting Point: 290 ~ 293 ℃ (Decomposition)

1H-NMR(DMSO-d6+TFA-d)δ : 8.69(1H,s), 7.83(1H,dd,J=13.2Hz,1.96Hz), 4.3∼3.8(2H,m), 3.8∼2.8(4H,m), 2.8∼3.0(3H,m), 1.35(3H,s), 1.3∼1.0(4H,m) 1 H-NMR (DMSO-d 6 + TFA-d) δ: 8.69 (1H, s), 7.83 (1H, dd, J = 13.2 Hz, 1.96 Hz), 4.3 to 3.8 (2H, m), 3.8 to 2.8 (4H, m), 2.8 to 3.0 (3H, m), 1.35 (3H, s), 1.3 to 1.0 (4H, m)

실시예 3Example 3

5-아미노-7-([1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-1-시클로프로필-6,8-디플루오로-1,4-디히드로-4-옥소퀴놀린-3-카르복실산5-amino-7-([1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptan-3-yl) -1-cyclopropyl-6,8-difluoro Rho-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

5-아미노-1-시클로프로필-6,6,7-트리플루오로-1,4-디히드로-4-옥소퀴놀린-3-카르복실산 70mg을 아세토니트릴 3ml에 현탁시키고, DBU 120mg 및 [1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄 150mg을 가한 후 3시간 동안 가열환류하였다. 반응액을 실온까지 냉각시키고, 10% 염산 수용액으로 중화하여 실온에서 1시간 동안 교반하였다. 생성된 고체를 여과한 후 물로 세척하고 건조하여 황색의 표제화합물 60mg을 얻었다(수율 63%).70 mg of 5-amino-1-cyclopropyl-6,6,7-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was suspended in 3 ml of acetonitrile, 120 mg of DBU and [1α] 150 mg of, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptane was added thereto, followed by heating to reflux for 3 hours. The reaction solution was cooled to room temperature, neutralized with 10% aqueous hydrochloric acid solution, and stirred at room temperature for 1 hour. The resulting solid was filtered, washed with water and dried to give 60 mg of the title compound as a yellow color (yield 63%).

융점 : 195∼200℃(분해)Melting Point: 195 ~ 200 ℃ (Decomposition)

1H-NMR(DMSO-d6+TFA-d)δ: 8.3(1H,s), 4.1∼3.1(5H,m), 3.0∼2.52H,m), 2.4∼2.02H,m), 1.25(3H,s), 1.2∼0.9(4H,m) 1 H-NMR (DMSO-d 6 + TFA-d) δ: 8.3 (1H, s), 4.1 to 3.1 (5H, m), 3.0 to 2.52H, m), 2.4 to 2.02H, m), 1.25 ( 3H, s), 1.2 to 0.9 (4H, m)

실시예 4Example 4

7-([1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-6,8-디플루오로-1-(2,4-디플루오로페닐-1,4-디히드로-4-옥소퀴놀린-3-카르복실산7-([1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptan-3-yl) -6,8-difluoro-1- (2,4- Difluorophenyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

1-(2,4-디클루오로페닐)-6,7,8-트리플루오로-1,4-디히드로-4-옥소퀴놀린-3-카르복실산 100mg을 아세토니트릴 3ml에 현탁시키고 DBU 110mg 및 [1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄 150mg을 가한 후 2시간 동안 가열환류하였다. 반응액을 감압농축하고 잔사를 물 2ml에 녹인 후 10% 염산으로 수용액으로 중화하여 실온에서 1시간 동안 교반하였다. 생성된 고체를 여과한 후 물로 세척하고 건조하여 미황색의 표제화합물 100mg 얻었다(수율 89%).100 mg of 1- (2,4-difluorophenyl) -6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid are suspended in 3 ml of acetonitrile and DBU 110 mg And 150 mg of [1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptane were heated and refluxed for 2 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in 2 ml of water, neutralized with an aqueous solution with 10% hydrochloric acid, and stirred at room temperature for 1 hour. The resulting solid was filtered, washed with water and dried to give 100 mg of pale yellow title compound (yield 89%).

융점 : 135∼140℃Melting Point: 135 ~ 140 ℃

1H-NMR(DMSO-d6+TFA-d)δ : 8.5(1H,s), 8.0∼7.0(5H,m), 4.0∼3.0(5H,m), 2.9∼ 2.5(2H,m), 2.4∼1.9(2H,m), 1.2(3H,s) 1 H-NMR (DMSO-d 6 + TFA-d) δ: 8.5 (1H, s), 8.0 to 7.0 (5H, m), 4.0 to 3.0 (5H, m), 2.9 to 2.5 (2H, m), 2.4 to 1.9 (2H, m), 1.2 (3H, s)

실시예 5Example 5

7-([1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-1-시클로프로필-6,8-디플루오로-5-메틸-1,4-디히드로-4-옥소퀴놀린-3-카르복실산7-([1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptan-3-yl) -1-cyclopropyl-6,8-difluoro-5- Methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

1-시클로프로필-5-메틸-6,7,8-트리플루오로-1,4-디히드로-4-옥소퀴놀린-3-카르복실산 100mg을 아세토니트릴 2ml에 현탁시키고 DBU 100mg 및 [1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄 150mg을 가한 후 1시간 동안 가열 환류하였다. 반응액을 감압농축하고 잔사를 물 2ml에 녹인 후 10% 염산 수용액으로 중화하여 실온에서 1시간 동안 교반하였다. 생성된 고체를 여과하고 물로 세척한 후 건조하여 황색의 표제화합물 70mg을 얻었다(수율 47%).100 mg of 1-cyclopropyl-5-methyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid are suspended in 2 ml of acetonitrile and 100 mg of DBU and [1α, 150 mg of 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptane was added and then heated to reflux for 1 hour. The reaction solution was concentrated under reduced pressure, the residue was dissolved in 2 ml of water, neutralized with an aqueous 10% hydrochloric acid solution, and stirred at room temperature for 1 hour. The resulting solid was filtered, washed with water and dried to give 70 mg of yellow title compound (yield 47%).

융점 : 275∼280℃Melting Point: 275 ~ 280 ℃

1H-NMR(DMSO-d6+TFA-d)δ : 8.5(1H,s), 4.1∼3.5(5H,m), 3.0∼2.5(2H,m), 2.6(3H,d,J=3.0Hz), 2.3∼2.0(2H,m), 1.2(3H,s), 1.2∼0.8(4H,m) 1 H-NMR (DMSO-d 6 + TFA-d) δ: 8.5 (1H, s), 4.1 to 3.5 (5H, m), 3.0 to 2.5 (2H, m), 2.6 (3H, d, J = 3.0 Hz), 2.3 to 2.0 (2H, m), 1.2 (3H, s), 1.2 to 0.8 (4H, m)

실시예 6Example 6

7-([1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-8-클로로-1-시클로프로필-6-플루오로-1,4-디히드로-1,4-옥소퀴놀린-3-카르복실산7-([1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptan-3-yl) -8-chloro-1-cyclopropyl-6-fluoro-1 , 4-dihydro-1,4-oxoquinoline-3-carboxylic acid

8-클로로-1-시클로프로필-6,7-디플루오로-1,4-디히드로-4-옥소퀴놀린-3-카르복실산 100mg을 아세토니트릴 2ml에 현탁시키고 DBU 100mg 및 [1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄 70mg을 가하여 5시간 동안 가열환류하였다. 반응액을 감압농축하고 잔사를 물 2ml에 녹여 10% 염산 수용액으로 중화한 후 실온에서 1시간 동안 교반하였다. 생성된 고체를 여과하고 물로 세척한 후 건조하여 미황색의 표제화합물 40mg을 얻었다(수율 30%).100 mg of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid are suspended in 2 ml of acetonitrile and 100 mg of DBU and [1α, 5α, 70 mg of 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptane was added and heated to reflux for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 2 ml of water, neutralized with an aqueous 10% hydrochloric acid solution, and stirred at room temperature for 1 hour. The resulting solid was filtered, washed with water and dried to give 40 mg of pale yellow title compound (yield 30%).

융점 : 222∼225℃Melting Point: 222 ~ 225 ℃

1H-NMR(DMSO-d6+TFA-d)δ : 8.77(1H,s), 7.86(1H,d,J=12.8Hz), 4.5∼4.0(1H,m), 4.0∼3.2(4H,m), 2.9∼2.5(2H,m), 2.3∼2.0(2H,m), 1.25(3H,s), 1.1∼0.7(4H,m) 1 H-NMR (DMSO-d 6 + TFA-d) δ: 8.77 (1 H, s), 7.86 (1 H, d, J = 12.8 Hz), 4.5-4.0 (1H, m), 4.0-3.2 (4H, m), 2.9 to 2.5 (2H, m), 2.3 to 2.0 (2H, m), 1.25 (3H, s), 1.1 to 0.7 (4H, m)

실시예 7Example 7

7-([1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-1-시클로프로필-6-플루오로-1,4-디히드로-1,4-디히드로-4-옥소-1,8-나프티리딘-3-카르복실산7-([1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptan-3-yl) -1-cyclopropyl-6-fluoro-1,4-di Hydro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid

7-클로로-1-시클로프로필-6-플루오로-1,4-디히드로-4-옥소-1,8-나프티리딘-3-카르복실산 100mg을 아세토니트릴 2ml에 현탁시키고, DBU 120mg 및 [1α,5α,6β]-6-아미노-1-메틸-아자비시클로[3.2.0]헵탄 150mg을 가한 후 , 2시간 동안 가열환류하였다. 반응액을 감압농축하고 잔사를 물 2ml에 녹여 10% 염산 수용액으로 중화한 후 실온에서 1시간 동안 교반하였다. 생성된 고체를 여과하고 물로 세척한후, 건조하여 미황색의 표제화합물 100mg을 얻었다(수율 77%).100 mg of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid is suspended in 2 ml of acetonitrile, DBU 120 mg and [ 150 mg of 1α, 5α, 6β] -6-amino-1-methyl-azabicyclo [3.2.0] heptane was added and then heated to reflux for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 2 ml of water, neutralized with an aqueous 10% hydrochloric acid solution, and stirred at room temperature for 1 hour. The resulting solid was filtered, washed with water and dried to give 100 mg of pale yellow title compound (yield 77%).

융점 : >270℃Melting Point:> 270 ℃

1H-NMR(CDCl3)δ : 8.67(1H,s), 8.00(1H,d,J=12.7Hz), 4.7∼4.3(1H,m), 4.2∼3.1(6H,m), 2.7∼2.1(2H,m), 1.27(3H,s), 1.1∼0.8(4H,m) 1 H-NMR (CDCl 3 ) δ: 8.67 (1H, s), 8.00 (1H, d, J = 12.7Hz), 4.7-4.3 (1H, m), 4.2-3.1 (6H, m), 2.7-2.1 (2H, m), 1.27 (3H, s), 1.1 to 0.8 (4H, m)

실시예 8Example 8

7-([1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-1-(2,4-디플루오로페닐)-6-플루오로-1,4-디히드로-4-옥소-1,8-나프티리딘-3-카르복실산7-([1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptan-3-yl) -1- (2,4-difluorophenyl) -6- Fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid

7-클로로-1-(2,4-디플루오로페닐)-6-플루오로-1,4-디히드로-4-옥소-1,8-나프티리딘-3-카르복실산 100mg을 아세토니트릴 2ml에 현탁시키고 DBU 100mg 및 [1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄 150mg을 가한 후 2시간 동안 가열환류하였다. 반응액을 감압농축하고 잔사를 물 2ml에 녹여 10% 염산 수용액으로 중화한 후, 실온에서 1시간 동안 교반하였다. 생성된 고체를 여과하고 물로 세척한후 건조하여 미황색의 표제 화합물 110mg 얻었다(수율 88%).2ml of acetonitrile 100mg of 7-chloro-1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid Suspension was added, and 100 mg of DBU and 150 mg of [1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptane were added thereto, followed by heating to reflux for 2 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in 2 ml of water, neutralized with an aqueous 10% hydrochloric acid solution, and stirred at room temperature for 1 hour. The resulting solid was filtered, washed with water and dried to give 110 mg of pale yellow title compound (yield 88%).

융점 : 120∼125℃Melting Point: 120 ~ 125 ℃

1H-NMR(DMSO-d6+TFA-d)δ : 8.7(1H,s), 8.0(1H,d,J=12.7Hz), 7.8∼7.0(3H,m), 4.0∼3.2(4H,m), 3.1∼2.5(2H,m), 2.2∼1.8(2H,m), 1.2(3H,s) 1 H-NMR (DMSO-d 6 + TFA-d) δ: 8.7 (1H, s), 8.0 (1H, d, J = 12.7 Hz), 7.8 to 7.0 (3H, m), 4.0 to 3.2 (4H, m), 3.1 to 2.5 (2H, m), 2.2 to 1.8 (2H, m), 1.2 (3H, s)

실시예 9Example 9

7-([1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-6-플루오로-1-(4-플루오로페닐)-1,4-디히드로-4-옥소-1,8-나프티리딘-3-카르복실산7-([1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptan-3-yl) -6-fluoro-1- (4-fluorophenyl)- 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid

7-클로로-6-플루오로-1-(4-플루오로페닐)-1,4-디히드로-4-옥소-1,8-나프티리딘-3-카르복실산 60mg을 아세토니트릴 2ml에 현탁시키고 DBU 100mg 및 [1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄 100mg을 가하여 실온에서 2시간 동안 교반하였다. 반응액을 감압농축하고 잔사를 물 2ml에 녹여 10% 염산 수용액으로 중화한 후 실온에서 1시간 동안 교반하였다.60 mg of 7-chloro-6-fluoro-1- (4-fluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid is suspended in 2 ml of acetonitrile and 100 mg of DBU and 100 mg of [1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptane were added and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 2 ml of water, neutralized with an aqueous 10% hydrochloric acid solution, and stirred at room temperature for 1 hour.

생성된 고체를 여과하고 물로 세척한후 건조하여 미황색의 표제 화합물을 50mg을 얻었다(수율 67%).The resulting solid was filtered, washed with water and dried to give 50 mg of the pale yellow title compound (yield 67%).

융점 : 248∼252℃(분해)Melting Point: 248 ~ 252 ℃ (Decomposition)

1H-NMR(DMSO-d6+TFA-d)δ : 8.62(1H,s), 8.00(1H,d,J=16.0Hz), 7.8∼7.1(4H,m), 4.1∼3.2(4H,m), 3.1∼2.5(2H,m), 2.3∼1.8(2H,m), 1.23(3H,s) 1 H-NMR (DMSO-d 6 + TFA-d) δ: 8.62 (1H, s), 8.00 (1H, d, J = 16.0 Hz), 7.8 to 7.1 (4H, m), 4.1 to 3.2 (4H, m), 3.1 to 2.5 (2H, m), 2.3 to 1.8 (2H, m), 1.23 (3H, s)

실시예 10Example 10

7-([1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-1-t-부틸-6-플루오로-1,4-디히드로-4-옥소-1,8-나프티리딘-3-카르복실산7-([1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptan-3-yl) -1-t-butyl-6-fluoro-1,4- Dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid

1-t-부틸-7-클로로-6-플루오로-1,4-디히드로-4-옥소-1,8-나프티리딘-3-카르복실산 100mg을 아세토니트릴 2ml에 현탁시키고 DBU 80mg 및 [1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄 70mg을 가하여 실온에서 5시간 동안 교반하였다. 반응액을 감압농축하고 잔사를 물 2ml에 녹여 10% 염산 수용액으로 중화한 후, 실온에서 1시간 동안 교반하였다. 생성된 고체를 여과하고 물로 세척한후, 건조하여 백색의 표제화합물 60mg을 얻었다(수율 48%).100 mg of 1-t-butyl-7-chloro-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid is suspended in 2 ml of acetonitrile and 80 mg of DBU and [ 70 mg of 1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptane was added and stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in 2 ml of water, neutralized with an aqueous 10% hydrochloric acid solution, and stirred at room temperature for 1 hour. The resulting solid was filtered, washed with water and dried to give 60 mg of the title compound as a white (yield 48%).

융점 : 130∼135℃Melting Point: 130 ~ 135 ℃

1H-NMR(DMSO-d6+TFA-d)δ : 8.86(1H,s), 8.05(1H,d,J=13.0Hz), 4.5∼2.0(8H,m), 1.90(9H,s), 1.38(3H,s) 1 H-NMR (DMSO-d 6 + TFA-d) δ: 8.86 (1H, s), 8.05 (1H, d, J = 13.0 Hz), 4.5-2.0 (8H, m), 1.90 (9H, s) , 1.38 (3H, s)

실시예 11Example 11

7-([1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-1-(2,4-디플루오로페닐)-6-플루오로-5-메틸-1,4-디히드로-4-옥소-1,8-나프티리딘-3-카르복실산7-([1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptan-3-yl) -1- (2,4-difluorophenyl) -6- Fluoro-5-methyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid

7-클로로-1-(2,4-디플루오로페닐)-6-플루오로-5-메틸-1,4-디히드로-4-옥소-1,8-나프티리딘-3-카르복실산 80mg을 아세토니트릴 2ml에 현탁시키고 DBU 70mg 및 [1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄 70mg을 가하여 실온에서 4시간 동안 교반하였다. 반응액을 감압농축하고 잔사를 물 2ml에 녹여 10% 염산 수용액으로 중화한 후, 실온에서 1시간 동안 교반하였다. 생성된 고체를 여과하고 물로 세척한후, 건조하여 미황색의 표제 화합물 90mg을 얻었다(수율 91%).7-chloro-1- (2,4-difluorophenyl) -6-fluoro-5-methyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid 80 mg Was suspended in 2 ml of acetonitrile and 70 mg of DBU and 70 mg of [1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptane were added and stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in 2 ml of water, neutralized with an aqueous 10% hydrochloric acid solution, and stirred at room temperature for 1 hour. The resulting solid was filtered, washed with water and dried to give 90 mg of pale yellow title compound (yield 91%).

융점 : 110∼115℃Melting Point: 110 ~ 115 ℃

1H-NMR(DMSO-d6+TFA-d)δ : 8.6(1H,s), 7.5∼6.9(3H,m), 4.5∼2.0(10H,m), 2.8(3H,d,J=3.3Hz), 1.3(3H,s) 1 H-NMR (DMSO-d 6 + TFA-d) δ: 8.6 (1H, s), 7.5-6.9 (3H, m), 4.5-2.0 (10H, m), 2.8 (3H, d, J = 3.3 Hz), 1.3 (3H, s)

실시예 12Example 12

(+)-7-([1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-1-시클로프로필-6-플루오로-1,4-디히드로-4-옥소-1,8-나프티리딘-3-카르복실산(+)-7-([1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptan-3-yl) -1-cyclopropyl-6-fluoro-1 , 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid

7-클로로-1-시클로프로필-6-플루오로-1,4-디히드로-4-옥소-1,8-나프티리딘-3-카르복실산 400mg을 아세토니트릴 10ml에 현탁시키고 DBU 320mg 및 (-)-([1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄 300mg을 가하여 실온에서 3시간 동안 교반하였다. 생성된 고체를 여과하고 소량의 아세토니트릴로 세척한 후 건조하여 백색의 표제화합물을 400mg을 얻었다(수율 76%).400 mg of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid is suspended in 10 ml of acetonitrile and 320 mg of DBU and (- )-([1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptane 300 mg was added and stirred at room temperature for 3 hours. The resulting solid was filtered and a small amount of acetonitrile Washed with and dried to obtain 400 mg of the title compound as a white (yield 76%).

융점 : >270℃Melting Point:> 270 ℃

(α)20 D+17.2°(C=0.5,1N-NaOH)(α) 20 D + 17.2 ° (C = 0.5,1N-NaOH)

1H-NMR(CDCL3)δ : 8.67(1H,s), 8.00(1H,d,J=12.7Hz), 4.7∼4.3(1H,m), 4.2∼3.1(6H,m), 2.7∼2.1(2H,m), 1.27(3H,s) 1.1 ∼0.8(4H,m) 1 H-NMR (CDCL 3 ) δ: 8.67 (1H, s), 8.00 (1H, d, J = 12.7Hz), 4.7-4.3 (1H, m), 4.2-3.1 (6H, m), 2.7-2.1 (2H, m), 1.27 (3H, s) 1.1 to 0.8 (4H, m)

실시예 13Example 13

(-)-7-([1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-1-시클로프로필-6,8-디플루오로-1,4-디히드로-4-옥소퀴놀린-3-카르복실산(-)-7-([1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptan-3-yl) -1-cyclopropyl-6,8-difluoro Rho-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

1-시클로프로필-6,7,8-트리플루오로-1,4-디히드로-4-옥소퀴놀린-3-카르복실산 50mg을 아세토니트릴 2ml에 현탁시키고 DBU 70mg 및 (-)-[1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄 60mg을 가하여 5시간 동안 가열 환류하였다. 반응액을 감압 농축하고 잔사를 물 2ml에 녹여 진한 염산 수용액을 적당량 가하여 pH1로 조정하였다. 생성된 고체를 여과하고 이소프로필알콜로 세척한 후 건조하여 표제화합물의 염산염인 30mg의 미황색 고체를 얻었다(수율 34%).50 mg of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid are suspended in 2 ml of acetonitrile and 70 mg of DBU and (-)-[1α, 60 mg of 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptane was added and heated to reflux for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 2 ml of water and adjusted to pH 1 by adding an appropriate amount of a concentrated aqueous hydrochloric acid solution. The resulting solid was filtered, washed with isopropyl alcohol and dried to give 30 mg of a pale yellow solid as a hydrochloride of the title compound (yield 34%).

융점 : >270℃Melting Point:> 270 ℃

1H-NMR(DMSO-d6+TFA-d)δ : 8.69(1H,s), 7.83(1H,dd,J=13.2Hz,1.96(Hz), 4.3∼3.8(2H,m), 3.8∼2.8(4H,m), 2.8∼2.0(3H,m), 1.35(3H,s), 1.3∼1.0(4H,m) 1 H-NMR (DMSO-d 6 + TFA-d) δ: 8.69 (1H, s), 7.83 (1H, dd, J = 13.2 Hz, 1.96 (Hz), 4.3 to 3.8 (2H, m), 3.8 to 2.8 (4H, m), 2.8-2.0 (3H, m), 1.35 (3H, s), 1.3-1.0 (4H, m)

실시예 14Example 14

(+)-7-([1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-1-시클로프로필-6,8-디플루오로-1,4-디히드로-4-옥소퀴놀린-3-카르복실산(+)-7-([1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptan-3-yl) -1-cyclopropyl-6,8-difluoro Rho-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

1-시클로프로필-6,7,8-트리플루오로-1,4-디히드로-4-옥소퀴놀린-3-카르복실산 100mg을 아세토니트릴 2ml에 현탁시키고 DBU 130mg 및 (+)-[1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄 110mg을 가하여 3시간 동안 가열환류하였다. 반응액을 감압농축하고 잔사를 물 2ml에 녹여 진한 염산 수용액을 가하여 pH1로 조정하였다. 생성된 고체를 여과하고 이소프로필알콜로 세척한 후, 건조하여 표제화합물의 염산염인 60mg의 미황색 고체를 얻었다(수율 41%).100 mg of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid are suspended in 2 ml of acetonitrile and 130 mg of DBU and (+)-[1α, 110 mg of 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptane was added thereto, and the mixture was heated to reflux for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 2 ml of water, and concentrated hydrochloric acid was added to adjust pH to 1. The resulting solid was filtered, washed with isopropyl alcohol and dried to give 60 mg of a pale yellow solid as the hydrochloride of the title compound (yield 41%).

융점 : >270℃Melting Point:> 270 ℃

1H-NMR(DMSO-d6+TFA-d)δ : 8.69(1H,s), 7.83(1H,dd,J=13.2Hz,1.96Hz), 4.3∼3.8(2H,m), 2.8∼2.0(4H,m), 1.35(3H,s), 1.3∼1.0(4H,m) 1 H-NMR (DMSO-d 6 + TFA-d) δ: 8.69 (1H, s), 7.83 (1H, dd, J = 13.2 Hz, 1.96 Hz), 4.3 to 3.8 (2H, m), 2.8 to 2.0 (4H, m), 1.35 (3H, s), 1.3 to 1.0 (4H, m)

실시예 15Example 15

1-시클로프로필-6,8-디플루오로-7-([1α,5α,6β]-6-히드록시-1-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-1,4-디히드로-4-옥소퀴놀린-3-카르복실산1-cyclopropyl-6,8-difluoro-7-([1α, 5α, 6β] -6-hydroxy-1-methyl-3-azabicyclo [3.2.0] heptan-3-yl) -1 , 4-dihydro-4-oxoquinoline-3-carboxylic acid

1-시클로프로필-6,7,8-트리플루오로-1,4-디히드로-4-옥소퀴놀린-3-카르복실산 150mg을 아세토니트릴 3ml에 현탁시키고 DBU 160mg 및 [1α,5α,6β]-6-히드록시-1-메틸-3-아자비시클로[3.2.0]헵탄 150mg을 가하여 4시간 동안 가열 환류하였다. 반응액을 실온에서 밤새 교반하여 생성된 고체를 여파하고, 소량의 아세토니트릴로 세척 후 건조하여 백색의 표제화합물 170mg을 얻었다(수율 82%).150 mg of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid are suspended in 3 ml of acetonitrile and 160 mg of DBU and [1α, 5α, 6β] 150 mg of -6-hydroxy-1-methyl-3-azabicyclo [3.2.0] heptane was added and heated to reflux for 4 hours. The reaction solution was stirred overnight at room temperature to filter the resulting solid, washed with a small amount of acetonitrile and dried to give 170 mg of a white title compound (yield 82%).

융점 : 215∼218℃(분해)Melting Point: 215 ~ 218 ℃ (Decomposition)

1H-NMR(DMSO-d6+TFA-d)δ : 8.65(1H,s), 7.76(1H,dd,J=13.6Hz,1.9Hz), 4.5∼3.9(2H,m), 3.7∼3.1(4H,m), 2.7∼1.8(3H,m), 1.3(3H,s), 1.2∼1.0(4H,m) 1 H-NMR (DMSO-d 6 + TFA-d) δ: 8.65 (1H, s), 7.76 (1H, dd, J = 13.6 Hz, 1.9 Hz), 4.5-3.9 (2H, m), 3.7-3.1 (4H, m), 2.7 to 1.8 (3H, m), 1.3 (3H, s), 1.2 to 1.0 (4H, m)

실시예 16Example 16

1-시클로프로필-6-플루오로-7-([1α,5α,6β]-6-히드록시-1-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-1,4-디히드로-4-옥소-1,8-나프티리딘-3-카르복실산1-cyclopropyl-6-fluoro-7-([1α, 5α, 6β] -6-hydroxy-1-methyl-3-azabicyclo [3.2.0] heptan-3-yl) -1,4- Dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid

7-클로로-1-시클로프로필-6-플루오로-1,4-디히드로-4-옥소-1,8-나프티리딘-3-카르복실산 100mg을 아세토니트릴 3ml에 현탁시키고 DBU 150mg 및 [1α,5α,6β]-6-히드록시-1-메틸-3-아자비시클로[3.2.0]헵탄 130mg을 가하여 1시간 동안 가열환류하였다. 반응액을 감압농축하고 실온에서 1시간 동안 교반하였다. 생성된 고체를 여과하고 물 및 소량의 아세토니트릴로 세척한 후 건조하여 미황색의 표제화합물 70mg을 얻었다(수율 53%).100 mg of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid was suspended in 3 ml of acetonitrile and 150 mg of DBU and [1α 130 mg of, 5α, 6β] -6-hydroxy-1-methyl-3-azabicyclo [3.2.0] heptane was added and heated to reflux for 1 hour. The reaction solution was concentrated under reduced pressure and stirred at room temperature for 1 hour. The resulting solid was filtered, washed with water and a small amount of acetonitrile and dried to give 70 mg of pale yellow title compound (yield 53%).

융점 : 265℃(분해)Melting Point: 265 ° C (Decomposition)

1H-NMR(DMSO-d6+TFA-d)δ : 8.55(1H,s), 7.93(1H,d,J=13.0Hz), 4.7∼3.1(6H,m), 2.8∼2.0(3H,m), 1.32(3H,s), 1.3∼0.9(4H,m) 1 H-NMR (DMSO-d 6 + TFA-d) δ: 8.55 (1H, s), 7.93 (1H, d, J = 13.0 Hz), 4.7-3.1 (6H, m), 2.8-2.0 (3H, m), 1.32 (3H, s), 1.3 to 0.9 (4H, m)

실시예 17Example 17

(-)-7-([1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-1-시클로프로필-6,8-디플루오로-5-메틸-1,4-디히드로-4-옥소퀴놀린-3-카르복실산(-)-7-([1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptan-3-yl) -1-cyclopropyl-6,8-difluoro Rho-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

1-시클로프로필-5-메틸-6,7,8-트리플루오로-1,4-디히드로-4-옥소퀴놀린-3-카르복실산 300mg을 아세토니트릴 10ml에 현탁시키고 DBU 230mg 및 (-)-[1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄 190mg을 가하여 60℃에서 8시간 동안 교반하였다. 반응액을 감압농축하고 잔사를 물 3ml에 녹여 10% 염산 수용액으로 중화한 후 실온에서 2시간 동안 교반하였다. 생성된 고체를 여과하고 물로 세척한 후 건조하여 백색의 표제화합물 340mg을 얻었다(수율 84%).300 mg of 1-cyclopropyl-5-methyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid are suspended in 10 ml of acetonitrile and 230 mg DBU (-) 190 mg of-[1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptane was added and stirred at 60 ° C. for 8 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in 3 ml of water, neutralized with 10% aqueous hydrochloric acid solution, and stirred at room temperature for 2 hours. The resulting solid was filtered, washed with water and dried to give 340 mg of white title compound (yield 84%).

융점 : 275∼280℃Melting Point: 275 ~ 280 ℃

[α]20 D-221.2(C=0.5,DMSO)[α] 20 D -221.2 (C = 0.5, DMSO)

1H-NMR(DMSO-d6)δ : 8.64(1H,s), 4.3∼2.0(9H,m), 2.71(3H,d,J=3.15Hz), 1.33(3H,s), 1.2∼0.9(4H,m) 1 H-NMR (DMSO-d 6 ) δ: 8.64 (1H, s), 4.3-2.0 (9H, m), 2.71 (3H, d, J = 3.15Hz), 1.33 (3H, s), 1.2-0.9 (4H, m)

실시예 18Example 18

(-)-5-아미노-7-([1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-1-시클로프로필-6,8-디플루오로-1,4-디히드로-4-옥소퀴놀린-3-카르복실산(-)-5-amino-7-([1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptan-3-yl) -1-cyclopropyl-6, 8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

5-아미노-1-시클로프로필-6,7,8-트리플루오로-1,4-디히드로-4-옥소퀴놀린-3-카르복실산 300mg을 DMSO 3ml에 현탁시키고 (-)-[1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄 190mg을 가하여 60℃에서 5시간 동안 교반하였다. 반응액을 실온까지 냉각시키고 물 10ml을 가하여 2시간 동안 교반한 다음, 생성된 고체를 여과하고 물로 세척한 후 건조하여 황색의 표제화합물 340mg을 얻었다(수율 83%).300 mg of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid are suspended in 3 ml of DMSO and (-)-[1α, 190 mg of 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptane was added and stirred at 60 ° C for 5 hours. The reaction solution was cooled to room temperature, 10 ml of water was added thereto, stirred for 2 hours, and the resulting solid was filtered, washed with water and dried to give 340 mg of the title compound (yield 83%).

융점 : 196∼200℃(분해)Melting Point: 196 ~ 200 ℃ (Decomposition)

[α]20 D-280.6(C=0.5,DMSO)[α] 20 D -280.6 (C = 0.5, DMSO)

1H-NMR(DMSO-d6)δ : 8.49(1H,s), 7.19(2H,s), 4.3∼2.0(9H,m), 1.34(3H,s), 1.3∼0.8(4H,m) 1 H-NMR (DMSO-d 6 ) δ: 8.49 (1H, s), 7.19 (2H, s), 4.3-2.0 (9H, m), 1.34 (3H, s), 1.3-0.8 (4H, m)

실시예 19Example 19

(-)-7-([1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-1-t-부틸-6-플루오로-1,4-디히드로-4-옥소-1,8-나프티리딘-3-카르복실산(-)-7-([1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptan-3-yl) -1-t-butyl-6-fluoro- 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid

1-t-부틸-7-클로로-6-플루오로-1,4-디히드로-4-옥소-1,8-나프티리딘-3-카르복실산 300mg을 아세토니트릴 5ml에 현탁시키고 DBU 200mg 및 (-)-[1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄 150mg을 가하여 70℃에서 2시간 동안 교반하였다. 반응액을 실온까지 냉각시키고 감압농축하여 잔사를 물 3ml에 녹인 후, 5% 염산 수용액으로 중화하고 실온에서 2시간 동안 교반하였다. 생성된 고체를 여과하고 물로 세척한 후, 건조하여 미황색의 표제화합물 260mg을 얻었다(수율 67%).300 mg of 1-t-butyl-7-chloro-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid are suspended in 5 ml of acetonitrile and 200 mg of DBU and ( 150 mg of-)-[1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptane was added and stirred at 70 ° C. for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, the residue was dissolved in 3 ml of water, neutralized with 5% aqueous hydrochloric acid solution, and stirred at room temperature for 2 hours. The resulting solid was filtered, washed with water and dried to give 260 mg of pale yellow title compound (yield 67%).

융점 : 134∼138℃Melting Point: 134 ~ 138 ℃

[α]20 D-20.4(C=0.5,DMSO)[α] 20 D -20.4 (C = 0.5, DMSO)

1H-NMR(DMSO-d6)δ : 8.87(1H,s), 8.06(1H,d,J=12.9Hz), 4.5∼2.0(8H,m), 1.90(9H,s), 1.39(3H,s) 1 H-NMR (DMSO-d 6 ) δ: 8.87 (1H, s), 8.06 (1H, d, J = 12.9Hz), 4.5-2.0 (8H, m), 1.90 (9H, s), 1.39 (3H , s)

실시예 20Example 20

(-)-7-([1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-8-클로로-1-시클로프로필-6-플루오로-1,4-디히드로-4-옥소퀴놀린-3-카르복실산(-)-7-([1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptan-3-yl) -8-chloro-1-cyclopropyl-6- Fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

8-클로로-1-시클로프로필-6,7-디플루오로-1,4-디히드로-4-옥소퀴놀린-3-카르복실산 300mg을 아세토니트릴 4ml에 현탁시키고 DBU 190mg 및 (-)-[1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄 150mg을 가하여 50℃에서 3시간 동안 교반하였다. 반응액을 실온에서 하릇밤 동안 교반한후, 생성된 고체를 여과하고 소량의 아세토니트릴로 세척한 후 건조하여 백색의 표제화합물 290mg을 얻었다(수율 71%).300 mg of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid are suspended in 4 ml of acetonitrile and 190 mg of DBU and (-)-[ 150 mg of 1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptane was added and stirred at 50 ° C. for 3 hours. The reaction solution was stirred overnight at room temperature, and the resulting solid was filtered, washed with a small amount of acetonitrile and dried to give 290 mg of a white title compound (yield 71%).

융점 : 222∼228℃Melting Point: 222 ~ 228 ℃

[α]D 20-111.2(C=0.5, DMSO)[α] D 20 -111.2 (C = 0.5, DMSO)

1H-NMR(DMSO-d6)δ : 8.77(1H,s), 7.88(1H,d,J=12.8Hz), 4.5∼4.0(1H,m), 4.0∼3.2(4H,m), 2.9∼2.5(2H,m), 2.3∼2.0(2H,m), 1.25(3H,s), 1.0∼0.7(4H,m) 1 H-NMR (DMSO-d 6 ) δ: 8.77 (1H, s), 7.88 (1H, d, J = 12.8 Hz), 4.5 to 4.0 (1H, m), 4.0 to 3.2 (4H, m), 2.9 -2.5 (2H, m), 2.3-2.0 (2H, m), 1.25 (3H, s), 1.0-0.7 (4H, m)

실시예 21Example 21

(-)-7-([1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-1-(2,4-디플루오로페닐)-6-플루오로-1,4-디히드로-4-옥소-1,8-나프티리딘-3-카르복실산(-)-7-([1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptan-3-yl) -1- (2,4-difluorophenyl ) -6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid

7-클로로-1-(2,4-디플루오로페닐)-6-플루오로-1,4-디히드로-4-옥소-1,8-나프티리딘-3-카르복실산 200mg을 아세토니트릴 2ml에 현탁시키고 DBU 140mg 및 (-)-[1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄 140mg을 가하여 실온에서 12시간 동안 교반하였다. 반응액을 감압농축하고 잔사를물 3ml에 녹여 5% 염산 수용액으로 중화한 다음 실온에서 2시간 동안 교반하였다. 생성된 고체를 여과하고 물로 세척한 후 건조하여 백색의 표제화합물 210mg을 얻었다(수율 84%).200 ml of 7-chloro-1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid 2 ml of acetonitrile Suspension was added and 140 mg of DBU and 140 mg of (-)-[1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptane were added and stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 3 ml of water, neutralized with 5% aqueous hydrochloric acid, and then stirred at room temperature for 2 hours. The resulting solid was filtered, washed with water and dried to give 210 mg of white title compound (yield 84%).

융점 : 123∼127℃Melting Point: 123 ~ 127 ℃

[α]D 20-17.0(C=0.5, DMSO)[α] D 20 -17.0 (C = 0.5, DMSO)

1H-NMR(DMSO-d6+TFA-d)δ : 8.7(1H,s), 8.0(1H,d,J=12.7Hz), 7.8∼7.0(3H,m), 4.0∼3.2(4H,m), 3.1∼2.5(2H,m), 2.2∼1.8(2H,m), 1.2(3H,s) 1 H-NMR (DMSO-d 6 + TFA-d) δ: 8.7 (1H, s), 8.0 (1H, d, J = 12.7 Hz), 7.8 to 7.0 (3H, m), 4.0 to 3.2 (4H, m), 3.1 to 2.5 (2H, m), 2.2 to 1.8 (2H, m), 1.2 (3H, s)

실시예 22Example 22

(-)-7-([1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-6-플루오로-1-(4-플루오로페닐)-1,4-디히드로-4-옥소-1,8-나프티리딘-3-카르복실산(-)-7-([1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptan-3-yl) -6-fluoro-1- (4-fluoro Rophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid

7-클로로-6-플루오로-1-(4-플루오로페닐)-1,4-디히드로-4-옥소-1,8-나프티리딘-3-카르복실산 200mg을 아세토니트릴 2ml에 현탁시키고 DBU 140mg 및 (-)-[1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄 140mg을 가하여 실온에서 12시간 동안 교반하였다. 반응액을 감압농축하고 잔사를 물 3ml에 녹여 5% 염산 수용액으로 중화한 후 실온에서 2시간 동안 교반하였다. 생성된 고체를 여과하고 물로 세척한 후 건조하여 백색의 표제화합물 140mg을 얻었다(수율 56%).200 mg of 7-chloro-6-fluoro-1- (4-fluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid is suspended in 2 ml of acetonitrile and 140 mg of DBU and 140 mg of (−)-[1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptane were added and stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in 3 ml of water, neutralized with 5% aqueous hydrochloric acid solution, and stirred at room temperature for 2 hours. The resulting solid was filtered, washed with water and dried to give 140 mg of white title compound (yield 56%).

융점 : 250∼253℃Melting Point: 250 ~ 253 ℃

[α]D 20-37.6℃(C=0.5, DMSO)[α] D 20 -37.6 ° C (C = 0.5, DMSO)

1H-NMR(DMSO-d6+TFA-d)δ : 8.6(1H,s), 8.0(1H,d,J=16.0Hz), 7.8∼7.1(4H,m), 4.1∼3.2(4H,m), 3.1∼2.5(2H,m), 2.3∼1.8(2H,m), 1.2(3H,s) 1 H-NMR (DMSO-d 6 + TFA-d) δ: 8.6 (1H, s), 8.0 (1H, d, J = 16.0 Hz), 7.8 to 7.1 (4H, m), 4.1 to 3.2 (4H, m), 3.1 to 2.5 (2H, m), 2.3 to 1.8 (2H, m), 1.2 (3H, s)

실시예 23Example 23

7-([1α,5α,6β]-6-아미노-5-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-6,8-디플루오로-1,4-디히드로-4-옥소퀴놀린-3-카르복실산7-([1α, 5α, 6β] -6-amino-5-methyl-3-azabicyclo [3.2.0] heptan-3-yl) -6,8-difluoro-1,4-dihydro- 4-oxoquinoline-3-carboxylic acid

1-시클로프로필-1,4-디히드로-6,7,8-트리플루오로-4-옥소-3-퀴놀린카르복실산 120mg을 아세토니트릴 10ml에 현탁시키고 DBU 100mg과 [1α,5α,6β]-6-아미노-5-메틸-3-아자비시클로[3.2.0]헵탄 150mg을 가하였다. 80℃에서 10시간 동안 환류시킨 후 실온으로 냉각하여 하룻밤 방치하였다. 생성된 고체를 감압여과하고 이소프로필에테르로 세척한 후 건조하여 목적화합물 90mg을 얻었다(수율 55%).120 mg of 1-cyclopropyl-1,4-dihydro-6,7,8-trifluoro-4-oxo-3-quinolinecarboxylic acid are suspended in 10 ml of acetonitrile and 100 mg of DBU and [1α, 5α, 6β] 150 mg of -6-amino-5-methyl-3-azabicyclo [3.2.0] heptane was added. After refluxing at 80 ° C. for 10 hours, the mixture was cooled to room temperature and left overnight. The resulting solid was filtered under reduced pressure, washed with isopropyl ether and dried to obtain 90 mg of the target compound (yield 55%).

융점 : 235∼240℃(분해)Melting Point: 235 ~ 240 ℃ (Decomposition)

1H-NMR(DMSO-d6+TFA-d)δ : 8.68(1H,s), 8.08(2H,bs), 7.81(1H,dd,J=2Hz,12Hz), 4.2∼3.5(6H,m), 3.0∼2.5(1H,m), 2.0∼1.6(2H,m), 1 H-NMR (DMSO-d 6 + TFA-d) δ: 8.68 (1H, s), 8.08 (2H, bs), 7.81 (1H, dd, J = 2 Hz, 12 Hz), 4.2-3.5 (6 H, m ), 3.0 to 2.5 (1H, m), 2.0 to 1.6 (2H, m),

1.4(3H,s), 1.2∼0.9(4H,m)1.4 (3H, s), 1.2 to 0.9 (4H, m)

실시예 24Example 24

7-([1α,5α,6β]-6-아미노-5-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-6-플루오로-1-(4-플루오로페닐)-1,4-디히드로-4-옥소-1,8-나프티리딘-3-카르복실산7-([1α, 5α, 6β] -6-amino-5-methyl-3-azabicyclo [3.2.0] heptan-3-yl) -6-fluoro-1- (4-fluorophenyl)- 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid

7-클로로-1,4-디히드로-1-(4-플루오로페닐)-6-플루오로-4-옥소-1,8-나프티리딘-3-카르복실산 200mg을 아세토니트릴 5ml에 현탁시키고 DBU 110mg과 [1α,5α,6β]-6-아미노-5-메틸-3-아자비시클로[3.2.0]헵탄 100mg을 가하였다. 실온에서 1시간 교반한 후 감압하에 용매를 제거하고 증류수를 2ml가한 다음 10% 염산 수용액으로 중화시켰다. 반응용액을 실온에서 2시간 교반시킨 후 생성된 고체를 여과하고 소량의 증류수와 이소프로필에테르로 차례로 세척한 다음 건조시켜 목적화합물 220mg을 얻었다(수율 79%).200 mg of 7-chloro-1,4-dihydro-1- (4-fluorophenyl) -6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid is suspended in 5 ml of acetonitrile and 110 mg of DBU and 100 mg of [1α, 5α, 6β] -6-amino-5-methyl-3-azabicyclo [3.2.0] heptane were added. After stirring for 1 hour at room temperature, the solvent was removed under reduced pressure, 2 ml of distilled water was added, and then neutralized with an aqueous 10% hydrochloric acid solution. The reaction solution was stirred at room temperature for 2 hours, and the resulting solid was filtered, washed with a small amount of distilled water and isopropyl ether, and dried to obtain 220 mg of the target compound (yield 79%).

융점 : 253∼255℃(분해)Melting Point: 253 ~ 255 ℃ (Decomposition)

1H-NMR(DMSO-d6+TFA-d)δ : 8.63(1H,s), 8.05(1H,d,J=12.9Hz), 7.6∼7.3(4H,m), 4.4∼4.1(1H,m), 3.70∼3.05(4H,m), 2.5∼2.1(2H,m), 1.7∼1.3(1H,m), 1.22(3H,s) 1 H-NMR (DMSO-d 6 + TFA-d) δ: 8.63 (1H, s), 8.05 (1H, d, J = 12.9 Hz), 7.6 to 7.3 (4H, m), 4.4 to 4.1 (1H, m), 3.70 to 3.05 (4H, m), 2.5 to 2.1 (2H, m), 1.7 to 1.3 (1H, m), 1.22 (3H, s)

실시예 25Example 25

8-클로로-1-시클로프로필-7-([1α,5α,6β]-6-아미노-5-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-6-플루오로-1,4-디히드로-4-옥소-3-퀴놀린카르복실산8-chloro-1-cyclopropyl-7-([1α, 5α, 6β] -6-amino-5-methyl-3-azabicyclo [3.2.0] heptan-3-yl) -6-fluoro-1 , 4-dihydro-4-oxo-3-quinolinecarboxylic acid

8-클로로-1-시클로프로필-6,7-디플루오로-1,4-디히드로-4-옥소-3-퀴놀린카르복실산 200mg을 아세토니트릴 5ml에 현탁시킨 후 DBU 130mg과 [1α,5α,6β]-6-아미노-5-메틸-3-아자비시클로[3.2.0]헵탄 100mg을 가하였다. 80℃에서 4시간 동안 환류한 다음 감압하에 용매를 제거하고 증류수를 3ml 가하였다. 반응용액을 5% 염산 수용액으로 중화시켜 생성된 고체를 감압여과하고 증류수와 이소프로필에테르로 세척한 후 건조시켜 목적한 화합물 140mg을 얻었다(수율 54%).After 200 mg of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was suspended in 5 ml of acetonitrile, 130 mg of DBU and [1α, 5α 100 mg of, 6β] -6-amino-5-methyl-3-azabicyclo [3.2.0] heptane was added. After refluxing at 80 ° C. for 4 hours, the solvent was removed under reduced pressure and 3 ml of distilled water was added. The reaction solution was neutralized with 5% aqueous hydrochloric acid, and the resulting solid was filtered under reduced pressure, washed with distilled water and isopropyl ether, and dried to obtain 140 mg of the target compound (yield 54%).

융점 : 175∼178℃Melting Point: 175 ~ 178 ℃

1H-NMR(DMSO-d6+TFA-d)δ : 8.85(1H,s), 7.91(1H,d,J=12.8Hz), 4.5∼4.3(1H,m), 3.9∼3.7(1H,m), 3.6∼3,0(4H,m), 2.5∼2.3(2H,m), 2.0∼1.8(1H,m), 1.34(3H,s), 1.1∼0.9(4H,m) 1 H-NMR (DMSO-d 6 + TFA-d) δ: 8.85 (1H, s), 7.91 (1H, d, J = 12.8 Hz), 4.5-4.3 (1H, m), 3.9-3.7 (1H, m), 3.6 to 3,0 (4H, m), 2.5 to 2.3 (2H, m), 2.0 to 1.8 (1H, m), 1.34 (3H, s), 1.1 to 0.9 (4H, m)

실시예 26Example 26

7-([1α,5α,6β]-6-아미노-5-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-1-시클로프로필-6-플루오로-1,4-디히드로-4-옥소-1,8-나프티리딘-3-카르복실산7-([1α, 5α, 6β] -6-amino-5-methyl-3-azabicyclo [3.2.0] heptan-3-yl) -1-cyclopropyl-6-fluoro-1,4-di Hydro-4-oxo-1,8-naphthyridine-3-carboxylic acid

7-클로로-1-시클로프로필-1,4-디히드로-6-플루오로-4-옥소-1,8-나프티리딘-3-카르복실산 180mg을 아세토니트릴 5ml에 녹이고 DBU 130mg과 [1α,5α,6β]-6-아미노-5-메틸-3-아자비시클로[3.2.0]헵탄 100mg을 가하였다. 반응용액을 50℃에서 1.5시간 동안 교반한 후 실온으로 냉각시켜 생성된 고체를 여과하고 이소프로필알콜로 세척한 다음 건조시켜 목적한 화합물 200mg을 얻었다(수율 84%).180 mg of 7-chloro-1-cyclopropyl-1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid was dissolved in 5 ml of acetonitrile and 130 mg of DBU and [1α, 100 mg of 5α, 6β] -6-amino-5-methyl-3-azabicyclo [3.2.0] heptane was added. The reaction solution was stirred at 50 ° C. for 1.5 hours and then cooled to room temperature. The resulting solid was filtered, washed with isopropyl alcohol and dried to give the desired compound 200 mg (yield 84%).

융점 : 265∼270℃(분해)Melting Point: 265 ~ 270 ℃ (Decomposition)

1H-NMR(DMSO-d6+TFA-d)δ : 8.55(1H,s), 7.94(1H,d,J=12.9Hz), 4.5∼4.3(1H,m), 4.1∼3.8(1H,m), 3.7∼3.3(4H,m), 2.7∼2.4(2H,m), 1.9∼1.6(1H,m), 1.37(3H,s), 1.3∼1.1(4H,m) 1 H-NMR (DMSO-d 6 + TFA-d) δ: 8.55 (1H, s), 7.94 (1H, d, J = 12.9 Hz), 4.5-4.3 (1H, m), 4.1-3.8 (1H, m), 3.7 to 3.3 (4H, m), 2.7 to 2.4 (2H, m), 1.9 to 1.6 (1H, m), 1.37 (3H, s), 1.3 to 1.1 (4H, m)

실시예 27Example 27

1-(2,4-디플루오로페닐)-7-([1α,5α,6β]-아미노-5-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-6-플루오로-1,4-디히드로-4-옥소-1,8-나프티리딘-3-카르복실산1- (2,4-difluorophenyl) -7-([1α, 5α, 6β] -amino-5-methyl-3-azabicyclo [3.2.0] heptan-3-yl) -6-fluoro -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid

7-클로로-1-(2,4-디플루오로페닐)-1,4-디히드로-6-플루오로-4-옥소-1,8-나프티리딘-3-카르복실산 200mg을 아세토니트릴 5ml에 현탁시키고 DBU 110mg과 [1α,5α,6β]-6-아미노-5-메틸-3-아자비시클로[3.2.0]헵탄 100mg을 가하였다. 반응용액을 30∼40℃에서 1시간 교반한 후 용매를 감압하에 모두 제거하고 증류수를 2ml 가하였다. 5% 염산 용액을 사용하여 용액의 pH를 6∼7로 맞춘 다음 반응용액을 빙욕하에 30분간 교반하였다. 생성된 고체를 여과하고 소량의 증류수와 이소프로필에테르로 차례로 세척하고 건조시켜 목적한 화합물을 220mg 얻었다(수율 88%).200 ml of 7-chloro-1- (2,4-difluorophenyl) -1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid 5 ml of acetonitrile Suspension was added and 110 mg of DBU and 100 mg of [1α, 5α, 6β] -6-amino-5-methyl-3-azabicyclo [3.2.0] heptane were added thereto. After the reaction solution was stirred at 30 to 40 ° C. for 1 hour, all solvents were removed under reduced pressure, and 2 ml of distilled water was added. The pH of the solution was adjusted to 6-7 with 5% hydrochloric acid solution and the reaction solution was stirred for 30 minutes under an ice bath. The resulting solid was filtered, washed sequentially with a small amount of distilled water and isopropyl ether, and dried to obtain 220 mg of the target compound (yield 88%).

융점 : 110∼115℃Melting Point: 110 ~ 115 ℃

1H-NMR(DMSO-d6+TFA-d)δ : 8.80(1H,s), 8.08(1H,d,J=12.7Hz), 7.9∼7.2(3H,m), 4.2∼4.0(1H,m), 3.6∼3.1(4H,m), 2.7∼2.3(2H,m), 1.8∼1.5(1H,m), 1.27(3H,s) 1 H-NMR (DMSO-d 6 + TFA-d) δ: 8.80 (1H, s), 8.08 (1H, d, J = 12.7 Hz), 7.9-7.2 (3H, m), 4.2-4.0 (1H, m), 3.6 to 3.1 (4H, m), 2.7 to 2.3 (2H, m), 1.8 to 1.5 (1H, m), 1.27 (3H, s)

실시예 28Example 28

(-)-7-([1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-1-(2,4-디플루오로페닐)-1,4-디히드로-6-플루오로-5-메틸-4-옥소-1,8-나프티리딘-3-카르복실산(-)-7-([1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptan-3-yl) -1- (2,4-difluorophenyl ) -1,4-dihydro-6-fluoro-5-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid

7-클로로-1-(2,4-디플루오로페닐)-1,4-디히드로-6-플루오로-5-메틸-4-옥소-1,8-나프티리딘-3-카르복실산 100mg을 아세토니트릴 4ml에 현탁시키고 DBU 80mg과 (-)-[1α,5α,6β]-6-아미노-5-메틸-3-아자비시클로[3.2.0]헵탄 70mg을 가하였다. 50℃에서 3시간 동안 교반시킨 후 아세토니트릴을 감압하에 제거하고 증류수를 1ml 가한 다음 5% 염산 수용액으로 중화시켰다. 생성된 고체를 이소프로필에테르로 세척한 다음 건조시켜 목적한 화합물 100mg을 얻었다(수율 80.6%).100 mg of 7-chloro-1- (2,4-difluorophenyl) -1,4-dihydro-6-fluoro-5-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid Was suspended in 4 ml of acetonitrile and 80 mg of DBU and 70 mg of (-)-[1α, 5α, 6β] -6-amino-5-methyl-3-azabicyclo [3.2.0] heptane were added. After stirring at 50 ° C. for 3 hours, acetonitrile was removed under reduced pressure, 1 ml of distilled water was added, and then neutralized with 5% aqueous hydrochloric acid solution. The resulting solid was washed with isopropyl ether and dried to give 100 mg of the desired compound (yield 80.6%).

융점 : 113∼115℃Melting Point: 113 ~ 115 ℃

1H-NMR(CDCl3)δ : 8.6(1H,s), 7.6∼6.8(3H,m), 4.5∼2.0(10H,m), 2.8(3H,d,J=3.2Hz), 1.3(3H,s) 1 H-NMR (CDCl 3 ) δ: 8.6 (1H, s), 7.6-6.8 (3H, m), 4.5-2.0 (10H, m), 2.8 (3H, d, J = 3.2Hz), 1.3 (3H , s)

실시예 29Example 29

1-시클로프로필-7-([1α,5α,6β]-6-히드록시-3-아자비시클로[3.2.0]헵탄-3-일)-6,8-디플루오로-1,4-디히드로-4-옥소-3-퀴놀린카르복실산1-cyclopropyl-7-([1α, 5α, 6β] -6-hydroxy-3-azabicyclo [3.2.0] heptan-3-yl) -6,8-difluoro-1,4-di Hydro-4-oxo-3-quinolinecarboxylic acid

1-시클로프로필-6,7,8-트리플루오로-1,4-디히드로-4-옥소-3-퀴놀린카르복실산 250mg을 디메틸설폭시드 5ml에 현탁시키고, [1α,5α,6β]-6-히드록시-3-아자비시클로[3.2.0]헵탄 250mg을 가한 후 60∼80℃에서 8시간 동안 환류시켰다. 반응물을 실온으로 냉각시킨 후 5ml의 증류수를 붓고 생성된 고체를 여과하였다. 여과한 생성물을 이소프로필 알콜로 세척한 후 건조하여 목적화합물 280mg을 얻었다(수율 84.3%).250 mg of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are suspended in 5 ml of dimethylsulfoxide, [1α, 5α, 6β]- 250 mg of 6-hydroxy-3-azabicyclo [3.2.0] heptane was added and then refluxed at 60 to 80 ° C. for 8 hours. After the reaction was cooled to room temperature, 5 ml of distilled water was poured and the resulting solid was filtered. The filtered product was washed with isopropyl alcohol and dried to give 280 mg of the target compound (yield 84.3%).

융점 : 235∼240℃Melting Point: 235 ~ 240 ℃

1H-NMR(DMSO-d6+TFA-d)δ : 8.26(1H,s), 7.71(1H,dd,J=2.0Hz,J=12.Hz), 4.8∼4.4(3H,m), 3.9∼3.3(4H,m), 3.2∼2.85(1H,m), 2.8∼2.2(2H,m), 1.9∼1.5(1H,m), 1.4∼1.05(4H,d,J=6.2Hz) 1 H-NMR (DMSO-d 6 + TFA-d) δ: 8.26 (1H, s), 7.71 (1H, dd, J = 2.0 Hz, J = 12.Hz), 4.8-4.4 (3H, m), 3.9 to 3.3 (4H, m), 3.2 to 2.85 (1H, m), 2.8 to 2.2 (2H, m), 1.9 to 1.5 (1H, m), 1.4 to 1.05 (4H, d, J = 6.2 Hz)

실시예 30Example 30

5-아미노-1-시클로프로필-7-([1α,5α,6β]-6-히드록시-3-아자비시클로[3.2.0]헵탄-3-일)-6,8-디플루오로-1,4-디히드로-4-옥소-3-퀴놀린카르복실산5-amino-1-cyclopropyl-7-([1α, 5α, 6β] -6-hydroxy-3-azabicyclo [3.2.0] heptan-3-yl) -6,8-difluoro-1 , 4-dihydro-4-oxo-3-quinolinecarboxylic acid

5-아미노-1-시클로프로필-6,7,8-트리플루오로-1,4-디히드로-4-옥소-3-퀴놀린카르복실산 300mg을 디메틸설폭시드 5ml에 현탁시키고, [1α,5α,6β]-6-히드록시-3-아자비시클로[3.2.0]헵탄 250mg을 가한 후 90℃에서 5시간 동안 환류시켰다. 반응물을 실온으로 냉각한 후 5ml의 증류수를 부어서 생성된 고체를 여과하였다. 여과한 생성물을 이소프로필 알콜로 세척하고 건조하여 목적화합물 150mg을 얻었다(수율 38%).300 mg of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are suspended in 5 ml of dimethylsulfoxide, [1α, 5α 250 mg of, 6β] -6-hydroxy-3-azabicyclo [3.2.0] heptane was added and refluxed at 90 ° C. for 5 hours. After the reaction was cooled to room temperature, 5 ml of distilled water was poured to filter the resulting solid. The filtered product was washed with isopropyl alcohol and dried to give 150 mg of the target compound (yield 38%).

융점 : 220℃(분해)Melting Point: 220 ℃ (Decomposition)

1H-NMR(DMSO-d6+TFA-d)δ : 8.48(1H,s), 4.4∼3.8(3H,m), 3.8∼2.8(5H,m), 2.6∼2.2(2H,m), 1.9∼1.5(1H,m), 1.3∼0.9(4H,m) 1 H-NMR (DMSO-d 6 + TFA-d) δ: 8.48 (1H, s), 4.4 to 3.8 (3H, m), 3.8 to 2.8 (5H, m), 2.6 to 2.2 (2H, m), 1.9 to 1.5 (1H, m), 1.3 to 0.9 (4H, m)

실시예 31Example 31

1-시클로프로필-7-([1α,5α,6β]-6-히드록시-3-아자비시클로[3.2.0]헵탄-3-일)-6,8-디플루오로-1,4-디히드로-5-메틸-4-옥소-3-퀴놀린카르복실산1-cyclopropyl-7-([1α, 5α, 6β] -6-hydroxy-3-azabicyclo [3.2.0] heptan-3-yl) -6,8-difluoro-1,4-di Hydro-5-methyl-4-oxo-3-quinolinecarboxylic acid

1-시클로프로필-1,4-디히드로-5-메틸-6,7,8-트리플루오로-4-옥소-3-퀴놀린카르복실산 110mg을 아세토니트릴 3ml에 현탁시키고 DBU 100mg 및 [1α,5α,6β]-6-히드록시-3-아자비시클로[3.2.0]헵탄 100mg을 가한 후 1시간 동안 가열 환류시켰다. 반응액을 실온에서 5시간 동안 방치하여 생성된 고체를 여과하고 이소프로필에테르로 세척한 후 건조하여 목적화합물 100mg을 얻었다(수율 69%).110 mg of 1-cyclopropyl-1,4-dihydro-5-methyl-6,7,8-trifluoro-4-oxo-3-quinolinecarboxylic acid were suspended in 3 ml of acetonitrile and 100 mg and [1α, 100 mg of 5α, 6β] -6-hydroxy-3-azabicyclo [3.2.0] heptane was added and then heated to reflux for 1 hour. The reaction solution was left at room temperature for 5 hours, and the resulting solid was filtered, washed with isopropyl ether, and dried to obtain 100 mg of the target compound (yield 69%).

융점 : 190∼200℃(분해)Melting Point: 190 ~ 200 ℃ (Decomposition)

1H-NMR(DMSO-d6+TFA-d)δ : 8.61(1H,s), 4.5∼3.84(3H,m), 3.80∼3.25(4H,m), 3.20∼2.85(1H,m), 2.77(3H,dd,J=3.12Hz,J=1.41Hz), 2.65∼2.1(2H,m), 1.80∼1.35(1H,m), 1.32∼1.0(4H,m) 1 H-NMR (DMSO-d 6 + TFA-d) δ: 8.61 (1H, s), 4.5 to 3.74 (3H, m), 3.80 to 3.25 (4H, m), 3.20 to 2.85 (1H, m), 2.77 (3H, dd, J = 3.12 Hz, J = 1.41 Hz), 2.65 to 2.1 (2H, m), 1.80 to 1.35 (1H, m), 1.32 to 1.0 (4H, m)

실시예 32Example 32

1-시클로프로필-7-([1α,5α,6β]-6-아미노-3-아자비시클로[3.2.0]헵탄-3-일)-6,8-디플루오로-1,4-디히드로-5-메틸-4-옥소-3-퀴놀린카르복실산1-cyclopropyl-7-([1α, 5α, 6β] -6-amino-3-azabicyclo [3.2.0] heptan-3-yl) -6,8-difluoro-1,4-dihydro -5-Methyl-4-oxo-3-quinolinecarboxylic acid

1-시클로프로필-1,4-디히드로-5-메틸-6,7,8-트리플루오로-4-옥소-3-퀴놀린카르복실산 200mg을 아세토니트릴 5ml에 현탁시키고 DBU 153mg 과 [1α,5α,6β]-6-아미노-3-아자비시클로[3.2.0]헵탄 230mg을 가한 후 100℃에서 6시간 동안 가열 환류시켰다. 실온으로 냉각한 후 아세토니트릴을 감압농축한 후 증류수를 10ml 넣고 10% 염산 용액으로 중화하여 생성된 고체를 여과하였다. 여과한 생성물을 약간의 증류수와 이소프로필에테르로 차례로 세척한 후 건조하여 목적화합물 120mg을 얻었다(수율 46%).200 mg of 1-cyclopropyl-1,4-dihydro-5-methyl-6,7,8-trifluoro-4-oxo-3-quinolinecarboxylic acid were suspended in 5 ml of acetonitrile and 153 mg of DBU and [1α, 230 mg of 5α, 6β] -6-amino-3-azabicyclo [3.2.0] heptane was added and heated to reflux at 100 ° C. for 6 hours. After cooling to room temperature, acetonitrile was concentrated under reduced pressure, 10 ml of distilled water was added, and the solid formed by neutralizing with a 10% hydrochloric acid solution was filtered. The filtered product was washed sequentially with some distilled water and isopropyl ether and dried to obtain 120 mg of the target compound (yield 46%).

융점 : 260℃Melting Point: 260 ℃

1H-NMR(DMSO-d6+TFA-d)δ : 8.67(1H,s), 8.5∼7.7(2H,bs), 4.3∼3.5(6H,m), 3.5∼2.8(3H,m), 2.74(3H,d,J=3.2Hz), 2.2∼1.7(1H,m), 1.3∼1.1(4H,m) 1 H-NMR (DMSO-d 6 + TFA-d) δ: 8.67 (1H, s), 8.5 to 7.7 (2H, bs), 4.3 to 3.5 (6H, m), 3.5 to 2.8 (3H, m), 2.74 (3H, d, J = 3.2 Hz), 2.2 to 1.7 (1H, m), 1.3 to 1.1 (4H, m)

실시예 33Example 33

1-시클로프로필-7-([1α,5α,6β]-6-아미노-3-아자비시클로[3.2.0]헵탄-3-일)-6,8-디플루오로-1,4-디히드로-4-옥소-3-퀴놀린카르복실산1-cyclopropyl-7-([1α, 5α, 6β] -6-amino-3-azabicyclo [3.2.0] heptan-3-yl) -6,8-difluoro-1,4-dihydro 4-oxo-3-quinolinecarboxylic acid

1-시클로프로필-1,4-디히드로-4-옥소-6,7,8-트리플루오로-3-퀴놀린카르복실산 200mg을 아세토니트릴 6ml에 현탁시키고 DBU 160mg과 [1α,5α,6β]-6-아미노-3-아자비시클로[3.2.0]헵탄 240mg을 넣은 후 80℃에서 10시간 동안 가열 환류시켰다. 실온으로 냉각한 후 아세토니트릴을 감압농축하고 증류수를 5ml 넣고, 10% 염산 용액으로 중화하여 생성된 고체를 감압여과한 하였다. 여과한 생성물을 약간의 증류수와 이소프로필알콜로 차례로 세척한 후 건조하여 목적화합물 160mg을 얻었다(수율 60%).200 mg of 1-cyclopropyl-1,4-dihydro-4-oxo-6,7,8-trifluoro-3-quinolinecarboxylic acid are suspended in 6 ml of acetonitrile and 160 mg of DBU and [1α, 5α, 6β] 240 mg of -6-amino-3-azabicyclo [3.2.0] heptane was added thereto, followed by heating to reflux at 80 ° C. for 10 hours. After cooling to room temperature, acetonitrile was concentrated under reduced pressure, 5 ml of distilled water was added, and the resulting solid was neutralized with 10% hydrochloric acid solution and filtered under reduced pressure. The filtered product was washed with distilled water and isopropyl alcohol in that order and dried to obtain 160 mg of the target compound (yield 60%).

융점 : 240℃Melting Point: 240 ℃

1H-NMR(DMSO-d6+TFA-d)δ : 8.71(1H,s), 3.4∼7.8(2H,bs), 7.86(1H,dd,J=2Hz,12Hz), 4.4∼3.4(6H,m), 3.4∼2.6(3H,m), 2.1∼1.6(1H,m), 1.4∼1.1(4H,m) 1 H-NMR (DMSO-d 6 + TFA-d) δ: 8.71 (1H, s), 3.4 to 7.8 (2H, bs), 7.86 (1H, dd, J = 2 Hz, 12 Hz), 4.4 to 3.4 (6H , m), 3.4 to 2.6 (3H, m), 2.1 to 1.6 (1H, m), 1.4 to 1.1 (4H, m)

실시예 34Example 34

5-아미노-1-시클로프로필-7-([1α,5α,6β]-6-아미노-3-아자비시클로[3.2.0]헵탄-3-일)-6,8-디플루오로-1,4-디히드로-4-옥소-3-퀴놀린카르복실산, 염산염5-amino-1-cyclopropyl-7-([1α, 5α, 6β] -6-amino-3-azabicyclo [3.2.0] heptan-3-yl) -6,8-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid, hydrochloride

5-아미노-1-시클로프로필-1,4-디히드로-4-옥소-6,7,8-트리플루오로-3-퀴놀린카르복실산 180mg을 디메틸설폭시드 2.2ml에 현탁시키고, [1α,5α,6β]-6-아미노-3-아자비시클로[3.2.0]헵탄 270mg을 넣은 후 80℃에서 5시간 동안 환류시켰다. 실온으로 냉각한 후 증류수 5ml을 넣고 10% 염산 용액으로 pH 1-2를 맞춘 후 여과하고 이소프로필 알콜로 세척하였다. 생성된 고체를 메틸알콜 20ml에 넣고 가열해서 녹인 후 냉장고에서 24시간 방치하여 다시 얻어진 연황색 고체를 감압여과하고 이소프로필 알콜로 세척한 후 50℃에서 감압 건조하여 목적한 화합물 130mg을 얻었다(수율 50%).180 mg of 5-amino-1-cyclopropyl-1,4-dihydro-4-oxo-6,7,8-trifluoro-3-quinolinecarboxylic acid are suspended in 2.2 ml of dimethylsulfoxide, [1α, 270 mg of 5α, 6β] -6-amino-3-azabicyclo [3.2.0] heptane was added thereto, and the mixture was refluxed at 80 ° C. for 5 hours. After cooling to room temperature, 5 ml of distilled water was added, the pH was adjusted to 1-2 with 10% hydrochloric acid solution, filtered, and washed with isopropyl alcohol. The resulting solid was dissolved in 20 ml of methyl alcohol, heated, dissolved, and left to stand in a refrigerator for 24 hours. The resulting pale yellow solid was filtered under reduced pressure, washed with isopropyl alcohol, and dried under reduced pressure at 50 ° C. to obtain 130 mg of the desired compound (yield 50). %).

융점 : 243∼245℃(분해)Melting Point: 243 ~ 245 ℃ (Decomposition)

1H-NMR(DMSO-d6+TFA-d)δ : 8.48(1H,s), 8.1(2H,bs), 4.3∼3.3(7H,m), 3.2∼2.7(3H,m), 1.2∼0.9(4H,m) 1 H-NMR (DMSO-d 6 + TFA-d) δ: 8.48 (1H, s), 8.1 (2H, bs), 4.3-3.3 (7H, m), 3.2-2.7 (3H, m), 1.2- 0.9 (4H, m)

실시예 35Example 35

1-시클로프로필-7-([1α,5α,6β]-6-히드록시-3-아자비시클로[3.2.0]헵탄-3-일)-6-플루오로-1,4-디히드로-4-옥소-1,8-나프티리딘-3-카르복실산1-cyclopropyl-7-([1α, 5α, 6β] -6-hydroxy-3-azabicyclo [3.2.0] heptan-3-yl) -6-fluoro-1,4-dihydro-4 Oxo-1,8-naphthyridine-3-carboxylic acid

7-클로로-1-시클로프로필-1,4-디히드로-6-플루오로-4-옥소-1,8-나프티리딘-3-카르복실산 200mg을 아세토니트릴 5ml에 현탁시키고 DBU 150mg과 [1α,5α,6β]-6-히드록시-3-아자비시클로[3.2.0]헵탄 260mg을 넣은 후 80℃에서 30분 동안 환류시켰다. 아세토니트릴을 감압농축한 후 증류수를 5ml 붓고 5% 염산 용액으로 중화하여 생성된 고체를 감압여과하였다. 이것을 건조하여 목적한 화합물 160mg을 얻었다(수율 63%).200 mg of 7-chloro-1-cyclopropyl-1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid is suspended in 5 ml of acetonitrile and 150 mg of DBU and [1α] 260 mg of, 5α, 6β] -6-hydroxy-3-azabicyclo [3.2.0] heptane was added thereto, and the mixture was refluxed at 80 ° C. for 30 minutes. The acetonitrile was concentrated under reduced pressure, 5 ml of distilled water was poured and neutralized with a 5% hydrochloric acid solution, and the resulting solid was filtered under reduced pressure. This was dried to obtain 160 mg of the target compound (yield 63%).

융점 : 243℃Melting Point: 243 ℃

1H-NMR(DMSO-d6+TFA-d)δ : 8.57(1H,s), 7.96(1H,d,J=13.0Hz), 4.7∼4.05(3H,m), 4.0∼3.4(5H,m), 3.2∼3.0(1H,m), 2.7∼2.5(2H,m), 1.2∼1.0(4H,m) 1 H-NMR (DMSO-d 6 + TFA-d) δ: 8.57 (1H, s), 7.96 (1H, d, J = 13.0 Hz), 4.7 to 4.05 (3H, m), 4.0 to 3.4 (5H, m), 3.2 to 3.0 (1H, m), 2.7 to 2.5 (2H, m), 1.2 to 1.0 (4H, m)

실시예 36Example 36

1-시클로프로필-7-([1α,5α,6β]-6-아미노-3-아자비시클로[3.2.0]헵탄-3-일)-6-플루오로-1,4-디히드로-4-옥소-1,8-나프티리딘-3-카르복실산1-cyclopropyl-7-([1α, 5α, 6β] -6-amino-3-azabicyclo [3.2.0] heptan-3-yl) -6-fluoro-1,4-dihydro-4- Oxo-1,8-naphthyridine-3-carboxylic acid

7-클로로-1-시클로프로필-1,4-디히드로-6-플루오로-4-옥소-1,8-나프티리딘-3-카르복실산 100mg을 아세토니트릴 4ml에 현탁시키고 DBU 90mg과 [1α,5α,6β]-6-아미노-3-아자비시클로[3.2.0]헵탄 110mg을 넣었다. 반응용액을 80℃에서 1시간 환류한 후 실온으로 냉각하여 하룻밤 방치시켰다. 생성된 고체를 여과하고 이소프로필에테르 세척한 후 건조시켜 목적한 화합물 70mg을 얻었다(수율 55%).100 mg of 7-chloro-1-cyclopropyl-1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid is suspended in 4 ml of acetonitrile and 90 mg of DBU and [1α 110 mg of, 5α, 6β] -6-amino-3-azabicyclo [3.2.0] heptane was added thereto. The reaction solution was refluxed at 80 ° C. for 1 hour, cooled to room temperature and left overnight. The resulting solid was filtered, washed with isopropyl ether and dried to give 70 mg of the desired compound (yield 55%).

융점 : 242℃(분해)Melting Point: 242 ° C (Decomposition)

1H-NMR(DMSO-d6+TFA-d)δ : 8.60(1H,s), 8.2(2H,bs), 8.00(1H,d,J=13.0Hz), 4.6∼2.0(8H,m), 2.6∼2.4(1H,m), 2.0∼1.8(1H,m), 1.2∼0.95(4H,m) 1 H-NMR (DMSO-d 6 + TFA-d) δ: 8.60 (1H, s), 8.2 (2H, bs), 8.00 (1H, d, J = 13.0 Hz), 4.6-2.0 (8H, m) , 2.6 to 2.4 (1H, m), 2.0 to 1.8 (1H, m), 1.2 to 0.95 (4H, m)

실시예 37Example 37

7-([1α,5α,6β]-6-아미노-3-아자비시클로[3.2.0]헵탄-3-일)-1-(2,4-디플루오로페닐)-1,4-디히드로-6-플루오로-4-옥소-1,8-나프티리딘-3-카르복실산7-([1α, 5α, 6β] -6-amino-3-azabicyclo [3.2.0] heptan-3-yl) -1- (2,4-difluorophenyl) -1,4-dihydro -6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid

7-클로로-1-(2,4-디플루오로페닐)-1,4-디히드로-6-플루오로-4-옥소-1,8-나프티리딘-3-카르복실산 260mg을 아세토니트릴 4ml에 현탁시키고 DBU 280mg 과 [1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄 260mg을 넣었다. 반응액을 80℃에서 12시간 동안 환류시키고, 실온으로 냉각하여 하룻밤 동안 방치시켰다. 생성된 고체를 여과하고 이소프로필에테르로 세척한 후 건조시켜 목적한 화합물 156mg을 얻었다(수율 49.5%).260 mg of 7-chloro-1- (2,4-difluorophenyl) -1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid 4 ml of acetonitrile It was suspended in 280 mg of DBU and 260 mg of [1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptane. The reaction was refluxed at 80 ° C. for 12 hours, cooled to room temperature and left overnight. The resulting solid was filtered, washed with isopropyl ether and dried to give 156 mg of the desired compound (yield 49.5%).

융점 : 200℃Melting Point: 200 ℃

1H-NMR(DMSO-d6+TFA-d)δ : 8.83(1H,s), 8.14(1H,d,J=13.0Hz), 8.2∼7.3(3H,m), 4.5∼2.7(8H,m), 2.4∼1.6(1H,m) 1 H-NMR (DMSO-d 6 + TFA-d) δ: 8.83 (1H, s), 8.14 (1H, d, J = 13.0 Hz), 8.2-7.3 (3H, m), 4.5-2.7 (8H, m), 2.4 to 1.6 (1H, m)

실시예 38Example 38

7-([1α,5α,6β]-6-아미노-3-아자비시클로[3.2.0]헵탄-3-일)-1,4-디히드로-6-플루오로-1-(4-플루오로페닐)-4-옥소-1,8-나프티리딘-3-카르복실산7-([1α, 5α, 6β] -6-amino-3-azabicyclo [3.2.0] heptan-3-yl) -1,4-dihydro-6-fluoro-1- (4-fluoro Phenyl) -4-oxo-1,8-naphthyridine-3-carboxylic acid

7-클로로-1,4-디히드로-6-플루오로-1-(4-플루오로페닐)-4-옥소-1,8-나프티리딘-3-카르복실산 200mg을 아세토니트릴 5ml에 현탁시키고 DBU 110mg 과 [1α,5α,6β]-6-아미노-3-아자비시클로[3.2.0]헵탄 80mg을 넣었다. 실온에서 5시간 동안 교반한 후 아세토니트릴을 감압 농축하였다. 반응용액에 증류수를 2ml 넣고, 10% 염산 용액으로 pH 6-7을 맞추었다. 실온에서 하룻밤 방치시킨 후 여과하고 소량의 증류수와 이소프로필에테르로 차례로 세척하여 건조시켜 목적한 화합물을 200mg 얻었다(수율 82%).200 mg of 7-chloro-1,4-dihydro-6-fluoro-1- (4-fluorophenyl) -4-oxo-1,8-naphthyridine-3-carboxylic acid is suspended in 5 ml of acetonitrile and 110 mg of DBU and 80 mg of [1α, 5α, 6β] -6-amino-3-azabicyclo [3.2.0] heptane were added. After stirring for 5 hours at room temperature, acetonitrile was concentrated under reduced pressure. 2 ml of distilled water was added to the reaction solution, and the pH was adjusted to 6-7 with 10% hydrochloric acid solution. It was left at room temperature overnight, filtered, washed sequentially with a small amount of distilled water and isopropyl ether, and dried to obtain 200 mg of the target compound (yield 82%).

융점 : 275∼277℃(분해)Melting Point: 275 ~ 277 ℃ (Decomposition)

1H-NMR(DMSO-d6+TFA-d)δ : 8.65(1H,s), 8.14(H,d,J=12.8Hz), 7.8∼7.3(4H,m), 4.3∼1.5(9H,m) 1 H-NMR (DMSO-d 6 + TFA-d) δ: 8.65 (1H, s), 8.14 (H, d, J = 12.8 Hz), 7.8-7.3 (4H, m), 4.3-1.5 (9H, m)

실시예 39Example 39

7-([1α,5α,6β]-6-아미노-3-아자비시클로[3.2.0]헵탄-3-일)-8-클로로-1-시클로프로필-6-플루오로-1,4-디히드로-4-옥소-3-퀴놀린카르복실산7-([1α, 5α, 6β] -6-amino-3-azabicyclo [3.2.0] heptan-3-yl) -8-chloro-1-cyclopropyl-6-fluoro-1,4-di Hydro-4-oxo-3-quinolinecarboxylic acid

8-클로로-1-시클로프로필-6,7-디플루오로-1,4-디히드로-4-옥소-3-퀴놀린카르복실산 200mg을 아세토니트릴 3ml에 현탁시키고 DBU 140mg과 [1α,5α,6β]-6-아미노-3-아자비시클로[3.2.0]헵탄 100mg을 넣었다. 반응용액을 80℃에서 6시간 동안 환류한 후 실온으로 냉각하고 감압하여 용매를 제거하고, 이에 증류수를 3ml을 붓고 5% 염산 용액으로 중화시켰다. 생성된 고체를 여과하고 여과한 고체를 다시 3ml의 에틸알콜에 넣고 가열해서 모두 녹였다. 녹인 용액을 냉장고에서 12시간 방치한 후 생성된 고체를 감압여과하고 이소프로필알콜로 세척한 후 건조시켜 목적한 화합물을 80mg 얻었다(수율 31%).200 mg of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are suspended in 3 ml of acetonitrile and 140 mg of DBU and [1α, 5α, 100 mg of 6β] -6-amino-3-azabicyclo [3.2.0] heptane was added thereto. The reaction solution was refluxed at 80 ° C. for 6 hours, cooled to room temperature, and removed under reduced pressure, and then, 3 ml of distilled water was poured and neutralized with a 5% hydrochloric acid solution. The produced solid was filtered and the filtered solid was put in 3 ml of ethyl alcohol and heated to dissolve all. The dissolved solution was left in a refrigerator for 12 hours, and the resulting solid was filtered under reduced pressure, washed with isopropyl alcohol, and dried to obtain 80 mg of the target compound (yield 31%).

융점 : 205∼207℃(분해)Melting Point: 205 ~ 207 ℃ (Decomposition)

1H-NMR(DMSO-d6+TFA-d)δ : 9.20(1H,s), 8.2(1H,d,J=12.8Hz), 4.8∼4.2(1H,m), 4.2∼3.6(4H,m), 3.5∼2.8(3H,m), 2.4∼2.0(2H,m), 1.3∼1.1(4H,m) 1 H-NMR (DMSO-d 6 + TFA-d) δ: 9.20 (1H, s), 8.2 (1H, d, J = 12.8 Hz), 4.8-4.2 (1H, m), 4.2-3.6 (4H, m), 3.5 to 2.8 (3H, m), 2.4 to 2.0 (2H, m), 1.3 to 1.1 (4H, m)

실시예 40Example 40

7-([1α,5α,6β]-6-아미노-3-아자비시클로[3.2.0]헵탄-3-일)-1-(2,4-디플루오로페닐)-1,4-디히드로-6-플루오로-5-메틸-4-옥소-1,8-나프티리딘-3-카르복실산7-([1α, 5α, 6β] -6-amino-3-azabicyclo [3.2.0] heptan-3-yl) -1- (2,4-difluorophenyl) -1,4-dihydro -6-Fluoro-5-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid

7-클로로-1-(2,4-디플루오로페닐)-1,4-디히드로-6-플루오로-5-메틸-4-옥소-1,8-나프티리딘-3-카르복실산 130mg을 아세토니트릴 4ml에 현탁시키고 DBU 70mg과 [1α,5α,6β]-6-아미노-3-아자비시클로[3.2.0]헵탄 80mg을 넣었다. 반응용액을 50℃에서 3시간 동안 교반한 후 아세토니트릴을 감압농축하고 증류수를 2ml 부은 다음 5% 염산 용액으로 중화시켰다. 생성된 고체를 감압여과하여 소량의 증류수와 이소프로필에테르로 차례로 세척하였다. 이를 건조시켜 목적한 화합물 120mg을 얻었다(수율 77%).130 mg of 7-chloro-1- (2,4-difluorophenyl) -1,4-dihydro-6-fluoro-5-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid Was suspended in 4 ml of acetonitrile and 70 mg of DBU and 80 mg of [1α, 5α, 6β] -6-amino-3-azabicyclo [3.2.0] heptane were added thereto. After the reaction solution was stirred at 50 ° C. for 3 hours, acetonitrile was concentrated under reduced pressure, 2 ml of distilled water was poured out, and neutralized with 5% hydrochloric acid solution. The resulting solid was filtered under reduced pressure and washed sequentially with a small amount of distilled water and isopropyl ether. This was dried to give 120 mg of the desired compound (yield 77%).

융점 : 130∼135℃(분해)Melting Point: 130 ~ 135 ℃ (Decomposition)

1H-NMR(DMSO-d6+TFA-d)δ : 8.76(1H,s), 8.10(1H,d,J=12.8Hz), 7.85∼7.17(3H,m), 4.2∼4.0(1H,m), 3.8∼3.3(4H,m), 3.2∼2.9(2H,m), 2.75(3H,d,J=3.36Hz), 2.35∼2.0(1H,m), 1.75∼1.5(1H,m) 1 H-NMR (DMSO-d 6 + TFA-d) δ: 8.76 (1H, s), 8.10 (1H, d, J = 12.8 Hz), 7.85 to 7.17 (3H, m), 4.2 to 4.0 (1H, m), 3.8 to 3.3 (4H, m), 3.2 to 2.9 (2H, m), 2.75 (3H, d, J = 3.36 Hz), 2.35 to 2.0 (1H, m), 1.75 to 1.5 (1H, m)

실시예 41Example 41

(-)-7-([1α,5α,6β]-6-아미노-3-아자비시클로[3.2.0]헵탄-3-일)-1(2,4-디플루오로페닐)-1,4-디히드로-6-플루오로-4-옥소-1,8-나프티리딘-3-카르복실산(-)-7-([1α, 5α, 6β] -6-amino-3-azabicyclo [3.2.0] heptan-3-yl) -1 (2,4-difluorophenyl) -1,4 -Dihydro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid

7-클로로-1-(2,4-디플루오로페닐)-1,4-디히드로-6-플루오로-4-옥소-1,8-나프티리딘-3-카르복실산 180mg을 아세토니트릴 5ml에 현탁시키고 DBU 100mg과 (-)-[1α,5α,6β]-6-아미노-3-아자비시클로[3.2.0]헵탄 80mg을 넣은 후 50℃에서 2시간 교반시켰다. 실시예 37에서와 같은 방법으로 하여 목적화합물 80mg을 얻었다(수율 37%).180 ml of 7-chloro-1- (2,4-difluorophenyl) -1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid 5 ml of acetonitrile Suspension was added, and 100 mg of DBU and 80 mg of (-)-[1α, 5α, 6β] -6-amino-3-azabicyclo [3.2.0] heptane were added thereto, followed by stirring at 50 ° C for 2 hours. In the same manner as in Example 37, 80 mg of the target compound was obtained (yield 37%).

융점 : 200℃Melting Point: 200 ℃

1H-NMR(DMSO-d6+TFA-d)δ : 8.83(1H,s), 8.13(1H,d), 8.3∼7.25(3H,m), 4.6∼4.1(1H,m), 3.8∼3.3(4H,m), 3.2∼2.9(2H,m), 2.4∼2.0(1H,m), 1.6∼1.4(1H,m) 1 H-NMR (DMSO-d 6 + TFA-d) δ: 8.83 (1H, s), 8.13 (1H, d), 8.3 to 7.25 (3H, m), 4.6 to 4.1 (1H, m), 3.8 to 3.3 (4H, m), 3.2-2.9 (2H, m), 2.4-2.0 (1H, m), 1.6-1.4 (1H, m)

실시예 42Example 42

7-([1α,5α,6β]-6-아미노-3-아자비시클로[3.2.0]헵탄-3-일)-1-(tert-부틸)-6-플루오로-1,4-디히드로-4-옥소-1,8-나프티리딘-3-카르복실산7-([1α, 5α, 6β] -6-amino-3-azabicyclo [3.2.0] heptan-3-yl) -1- (tert-butyl) -6-fluoro-1,4-dihydro 4-oxo-1,8-naphthyridine-3-carboxylic acid

1-(tert-부틸)-7-클로로-1,4-디히드로-6-플루오로-4-옥소-1,8-나프티리딘-3-카르복실산 200mg을 아세토니트릴 3ml에 현탁시키고 DBU 130mg과 [1α,5α,6β]-6-아미노-3-아자비시클로[3.2.0]헵탄을 넣었다. 70℃에서 1시간 환류시킨 후 실시예 39과 같은 방법으로 목적한 화합물 100mg을 얻었다(수율 40%).200 mg of 1- (tert-butyl) -7-chloro-1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid are suspended in 3 ml of acetonitrile and 130 mg of DBU And [1α, 5α, 6β] -6-amino-3-azabicyclo [3.2.0] heptane. After refluxing at 70 ° C. for 1 hour, the target compound 100 mg was obtained in the same manner as in Example 39 (yield 40%).

융점 : 235∼233℃Melting Point: 235 ~ 233 ℃

1H-NMR(DMSO-d6+TFA-d)δ : 8.86(1H,s), 8.02(1H,d,J=12.8Hz), 4.3∼4.15(1H,m), 3.83∼3.63(4H,m), 3.12∼3.0(2H,m), 2.54∼2.25(2H,m), 1.89(9H,s) 1 H-NMR (DMSO-d 6 + TFA-d) δ: 8.86 (1H, s), 8.02 (1H, d, J = 12.8 Hz), 4.3-4.15 (1H, m), 3.83-3.63 (4H, m), 3.12 to 3.0 (2H, m), 2.54 to 2.25 (2H, m), 1.89 (9H, s)

실시예 43Example 43

(-)-7-([1α,5α,6β]-6-아미노-3-아자비시클로[3.2.0]헵탄-3-일)-1시클로프로필-1,4-디히드로-6-플루오로-5-메틸-1,8-나프티리딘-3-카르복실산(-)-7-([1α, 5α, 6β] -6-amino-3-azabicyclo [3.2.0] heptan-3-yl) -1cyclopropyl-1,4-dihydro-6-fluoro -5-Methyl-1,8-naphthyridine-3-carboxylic acid

7-클로로-1-시클로프로필-1,4-디히드로-6-플루오로-5-메틸-1,8-나프티리딘-3-카르복실산 140mg을 아세토니트릴 4ml에 현탁시키고 DBU 100mg과 (-)-[1α,5α,6β]-6-아미노-3-아자비시클로[3.2.0]헵탄 80mg을 넣었다. 실온에서 24시간 교반시키고 실시예 39과 같은 방법으로 하여 목적한 화합물 80mg을 얻었다(수율 45%).140 mg of 7-chloro-1-cyclopropyl-1,4-dihydro-6-fluoro-5-methyl-1,8-naphthyridine-3-carboxylic acid is suspended in 4 ml of acetonitrile and 100 mg of DBU (- 80 mg of)-[1α, 5α, 6β] -6-amino-3-azabicyclo [3.2.0] heptane was added. It stirred at room temperature for 24 hours, and obtained the target compound 80 mg by the same method as Example 39 (yield 45%).

융점 : 140∼145℃Melting Point: 140 ~ 145 ℃

1H-NMR(DMSO-d6+TFA-d)δ : 8.72(1H,s), 4.5∼4.2(1H,m), 4.10∼3.90(1H,m), 3.7∼3.3(4H,m), 2.75(3H,d,J=3.2Hz), 2.7∼2.4(2H,m), 1.9∼1.6(2H,m), 1.3∼1.1(4H,m) 1 H-NMR (DMSO-d 6 + TFA-d) δ: 8.72 (1H, s), 4.5 to 4.2 (1H, m), 4.10 to 3.90 (1H, m), 3.7 to 3.3 (4H, m), 2.75 (3H, d, J = 3.2 Hz), 2.7 to 2.4 (2H, m), 1.9 to 1.6 (2H, m), 1.3 to 1.1 (4H, m)

실시예 44Example 44

7-([1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-1-시클로프로필-6-플루오로-8-메톡시-1,4-디히드로-4-옥소퀴놀린-3-카르복실산7-([1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptan-3-yl) -1-cyclopropyl-6-fluoro-8-methoxy- 1,4-dihydro-4-oxoquinoline-3-carboxylic acid

1-시클로프로필-6,7-디플루오로-8-메톡시-1,4-디히드로-4-옥소퀴놀린-3-카르복실산 100mg [1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄 120mg을 DMSO 2ml에 가하고 80-90℃로 2시간 동안 가열하였다. 반응액에 물 5ml를 가하고 5% 염산용액으로 pH 7로 조정하여 클로로포름 30ml로 2회 추출하였다. 클로로포름층을 감압농축하여 잔사에 물 및 에탄올을 소량 가하고 실온에서 1시간 동안 교반한 후 생성된 고체를 여과, 건조하여 백색의 표제화합물 20mg을 얻었다(수율 15%).1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 100 mg [1α, 5α, 6β] -6-amino-1- 120 mg of methyl-3-azabicyclo [3.2.0] heptane was added to 2 ml of DMSO and heated to 80-90 ° C. for 2 hours. To the reaction solution was added 5 ml of water, adjusted to pH 7 with 5% hydrochloric acid solution, and extracted twice with 30 ml of chloroform. The chloroform layer was concentrated under reduced pressure, and a small amount of water and ethanol were added to the residue, followed by stirring at room temperature for 1 hour. The resulting solid was filtered and dried to obtain 20 mg of the title compound as a white (yield 15%).

융점 : 195∼200℃Melting Point: 195 ~ 200 ℃

1H-NMR(DMSO-d6+TFA)δ : 8.73(1H,s), 7.77(1H,d,J=14.2Hz), 4.3∼1.9(9H,m), 3.65(3H,s), 1.35(3H,s), 1.4∼0.7(4H,m) 1 H-NMR (DMSO-d 6 + TFA) δ: 8.73 (1H, s), 7.77 (1H, d, J = 14.2 Hz), 4.3-1.9 (9H, m), 3.65 (3H, s), 1.35 (3H, s), 1.4 to 0.7 (4H, m)

실시예 45Example 45

7-([1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-1-시클로프로필-6-플루오로-1,4-디히드로-4-옥소-1,8-나프티리딘-3-카르복실산7-([1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptan-3-yl) -1-cyclopropyl-6-fluoro-1,4-di Hydro-4-oxo-1,8-naphthyridine-3-carboxylic acid

7-클로로-1-시클로프로필-6-플루오로-1,4-디히드로-4-옥소-1,8-나프티리딘-3-카르복실산 95mg을 아세토니트릴 3ml에 현탁시키고 DBU 100mg 및 [1α,5α,6α]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄 93mg을 가한 후 실온에서 3시간 동안 교반하였다. 반응액을 감압농축하고 잔사를 물에 녹여 5%-HCl 용액으로 중화한 후 생성된 고체를 여과하고 건조하여 미황색의 표제화합물 98mg을 얻었다(수율 78%).95 mg of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid are suspended in 3 ml of acetonitrile and 100 mg of DBU and [1α 93 mg of, 5α, 6α] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptane was added and stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in water and neutralized with 5% -HCl solution. The resulting solid was filtered and dried to give 98 mg of a pale yellow title compound (yield 78%).

융점 : 237∼240℃(분해)Melting Point: 237 ~ 240 ℃ (Decomposition)

1H-NMR(DMSO-d6+TFA)δ : 8.52(1H,s), 7.94(1H,d,J=12.8Hz), 4.3-3.4(6H,m), 2.9∼2.7(1H,m), 2.5∼2.0(2H,m), 1.37(3H,s), 1.3∼1.0(4H,m) 1 H-NMR (DMSO-d 6 + TFA) δ: 8.52 (1H, s), 7.94 (1H, d, J = 12.8Hz), 4.3-3.4 (6H, m), 2.9-2.7 (1H, m) , 2.5 to 2.0 (2H, m), 1.37 (3H, s), 1.3 to 1.0 (4H, m)

실시예 46Example 46

8-클로로-1-시클로프로필-6-플루오로-7-([1α,5α,6β]-1-메틸-6-메틸아미노-3-아자비시클로[3.2.0]헵탄-3-일)-1,4-디히드로-4-옥소퀴놀린-3-카르복실산8-chloro-1-cyclopropyl-6-fluoro-7-([1α, 5α, 6β] -1-methyl-6-methylamino-3-azabicyclo [3.2.0] heptan-3-yl)- 1,4-dihydro-4-oxoquinoline-3-carboxylic acid

8-클로로-1-시클로프로필-6,7-디플루오로-1,4-디히드로-4-옥소퀴놀린-3-카르복실산 100mg을 아세토니트릴 2ml에 현탁시키고 DBU 60mg 및 아세토니트릴 1ml에 용해시킨 [1α,5α,6β]-1-메틸-6-메틸아미노-3-아자비시클로[3.2.0]헵탄 60mg을 가한 후 18시간 동안 가열 환류하였다. 반응액을 감압농축하여 잔사를 물 3ml에 녹이고 5% 염산용액으로 pH 7로 조정한 후 냉장고에서 밤새 방치하였다. 생성된 고체를 여과하고 소량의 물 및 에테르로 세척한 후 건조하여 황색의 표제화합물 30mg을 얻었다(수율 21%).100 mg of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid are suspended in 2 ml of acetonitrile and dissolved in 60 mg of DBU and 1 ml of acetonitrile. 60 mg of [1α, 5α, 6β] -1-methyl-6-methylamino-3-azabicyclo [3.2.0] heptane was added and heated to reflux for 18 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in 3 ml of water, adjusted to pH 7 with 5% hydrochloric acid solution, and left to stand overnight in a refrigerator. The resulting solid was filtered, washed with a little water and ether and dried to give 30 mg of yellow title compound (yield 21%).

융점 : 250∼255℃Melting Point: 250 ~ 255 ℃

1H-NMR(DMSO-d6+TFA)δ : 8.87(1H,s), 7.94(1H,d,J=12.8Hz), 4.6~4.2(1H,m), 4.0∼2.0(8H,m), 2.46(3H,s), 1.36(3H,m), 1.3∼0.8(4H,m) 1 H-NMR (DMSO-d 6 + TFA) δ: 8.87 (1H, s), 7.94 (1H, d, J = 12.8 Hz), 4.6-4.2 (1H, m), 4.0-2.0 (8H, m) , 2.46 (3H, s), 1.36 (3H, m), 1.3 to 0.8 (4H, m)

실시예 47Example 47

1-시클로프로필-6,8-디플루오로-7-([1α,5α,6β]-1-메틸-6-메틸아미노-3-아자비시클로[3.2.0]헵탄-3-일)-1,4-디히드로-4-옥소퀴놀린-3-카르복실산1-cyclopropyl-6,8-difluoro-7-([1α, 5α, 6β] -1-methyl-6-methylamino-3-azabicyclo [3.2.0] heptan-3-yl) -1 , 4-dihydro-4-oxoquinoline-3-carboxylic acid

1-시클로프로필-6,7,8-트리플루오로-1,4-디히드로-4-옥소퀴놀린-3-카르복실산 100mg을 아세토니트릴 2ml에 현탁시키고 DBU 60mg 및 아세토니트릴 1ml에 용해시킨 [1α,5α,6β]-1-메틸-6-메틸아미노-3-아자비시클로[3.2.0]헵탄 60mg을 가한 후 18시간 동안 가열 환류하였다. 생성된 고체를 여과하고 소량의 아세토니트릴로 세척한 후 건조하여 백색의 표제화합물 65mg을 얻었다(수율 46%).100 mg of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was suspended in 2 ml of acetonitrile and dissolved in 60 mg of DBU and 1 ml of acetonitrile [ 60 mg of 1α, 5α, 6β] -1-methyl-6-methylamino-3-azabicyclo [3.2.0] heptane was added and then heated to reflux for 18 hours. The resulting solid was filtered, washed with a small amount of acetonitrile and dried to give 65 mg of a white title compound (yield 46%).

융점 : 260∼265℃(분해)Melting Point: 260 ~ 265 ℃ (Decomposition)

1H-NMR(DMSO-d6+TFA)δ:8.64(1H,s),7.78(1H,dd,J=13.6Hz,1.84Hz), 4.2∼2.0(9H,m), 2.50(3H,s), 1.32(3H,s), 13∼0.9(4H,m) 1 H-NMR (DMSO-d 6 + TFA) δ: 8.64 (1H, s), 7.78 (1H, dd, J = 13.6Hz, 1.84Hz), 4.2-2.0 (9H, m), 2.50 (3H, s ), 1.32 (3H, s), 13-0.9 (4H, m)

실시예 48Example 48

1-시클로프로필-6-플루오로-7-([1α,5α,6β]-1-메틸-6-메틸아미노-3-아자비시클로[3.2.0]헵탄-3-일)-1,4-디히드로-4-옥소-1,8-나프티리딘-3-카르복실산1-cyclopropyl-6-fluoro-7-([1α, 5α, 6β] -1-methyl-6-methylamino-3-azabicyclo [3.2.0] heptan-3-yl) -1,4- Dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid

7-클로로-1-시클로프로필-6-플루오로-1,4-디히드로-4-옥소-1,8-나프티리딘-3-카르복실산 100mg을 아세토니트릴 2ml에 현탁시키고 DBU 60mg 및 [1α,5α,6β]-1-메틸-6-메틸아미노-3-아자비시클로[3.2.0]헵탄 60mg을 가한 후 실온에서 2시간 동안 교반하였다. 생성된 고체를 여과하고 소량의 아세토니트릴로 세척한 후 건조하여 백색의 표제화합물 102mg을 얻었다(수율 74%).100 mg of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid was suspended in 2 ml of acetonitrile and 60 mg and [1α] 60 mg of, 5α, 6β] -1-methyl-6-methylamino-3-azabicyclo [3.2.0] heptane was added, followed by stirring at room temperature for 2 hours. The resulting solid was filtered, washed with a little acetonitrile and dried to give 102 mg of a white title compound (yield 74%).

융점 : 245∼250℃(분해)Melting Point: 245 ~ 250 ℃ (Decomposition)

1H-NMR(DMSO-d6+TFA)δ : 8.58(1H,s), 8.01(1H,d,J=12.8Hz), 4.5∼1.9(9H,m), 2.49(3H,s), 1.37(3H,s), 1.3∼0.9(4H,m) 1 H-NMR (DMSO-d 6 + TFA) δ: 8.58 (1H, s), 8.01 (1H, d, J = 12.8 Hz), 4.5-1.9 (9H, m), 2.49 (3H, s), 1.37 (3H, s), 1.3 to 0.9 (4H, m)

실시예 49Example 49

7-([1α,5α,6α]-6-아미노-3-아자비시클로[3.2.0]헵탄-3-일)-1-시클로프로필-6-플루오로-1,4-디히드로-4-옥소-1,8-나프티리딘-3-카르복실산7-([1α, 5α, 6α] -6-amino-3-azabicyclo [3.2.0] heptan-3-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4- Oxo-1,8-naphthyridine-3-carboxylic acid

7-클로로-1-시클로프로필-6-플루오로-1,4-디히드로-4-옥소-1,8-나프티리딘-3-카르복실산 140mg을 아세토니트릴 5ml에 현탁시키고 DBU 140mg 및 [1α,5α,6α]-6-아미노-3-아자비시클로[3.2.0]헵탄 70mg을 가한 후 실온에서 2시간 동안 교반하였다. 고체를 여과하고 소량의 아세토니트릴로 세척한 후 에탄올로 재결정하여 백색 분말상의 표제화합물 120mg을 얻었다(수율 68%).140 mg of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid is suspended in 5 ml of acetonitrile and 140 mg and [1α] 70 mg of, 5α, 6α] -6-amino-3-azabicyclo [3.2.0] heptane was added and stirred at room temperature for 2 hours. The solid was filtered, washed with a small amount of acetonitrile and recrystallized with ethanol to obtain 120 mg of the title compound as a white powder (yield 68%).

융점 : 225∼230℃Melting Point: 225 ~ 230 ℃

1H-NMR(DMSO-d6+TFA)δ:8.54(1H,s),8.17(2H,brs),7.95(1H,d,J=12.8Hz), 4.5∼1.8(10H,m), 1.2∼1.0(4H,m) 1 H-NMR (DMSO-d 6 + TFA) δ: 8.54 (1H, s), 8.17 (2H, brs), 7.95 (1H, d, J = 12.8 Hz), 4.5-1.8 (10H, m), 1.2 1.0 (4H, m)

실시예 50Example 50

7-([1α,5α,6α]-6-아미노-3-아자비시클로[3.2.0]헵탄-3-일)-1-시클로프로필-6,8-디플루오로-1,4-디히드로-4-옥소퀴놀린-3-카르복실산7-([1α, 5α, 6α] -6-amino-3-azabicyclo [3.2.0] heptan-3-yl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro 4-oxoquinoline-3-carboxylic acid

1-시클로프로필-6,7,8-트리플루오로-1,4-디히드로-4-옥소퀴놀린-3-카르복실산 100mg을 아세토니트릴 4ml에 현탁시키고 [1α,5α,6α]-6-아미노-3-아자비시클로[3.2.0]헵탄 60mg 및 DBU 60mg을 가한 후 2시간 동안 가열환류하였다. 반응액을 실온으로 냉각하여 1시간 동안 교반한 후 생성된 고체를 여과하고 아세토니트릴로 세척한 다음 건조하여 백색의 표제화합물 90mg을 얻었다(수율 69%).100 mg of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid are suspended in 4 ml of acetonitrile and [1α, 5α, 6α] -6- 60 mg of amino-3-azabicyclo [3.2.0] heptanes and 60 mg of DBU were added and then heated to reflux for 2 hours. The reaction solution was cooled to room temperature, stirred for 1 hour, and the resulting solid was filtered, washed with acetonitrile and dried to give 90 mg of the title compound as a white (yield 69%).

융점 : 250℃(분해)Melting Point: 250 ℃ (Decomposition)

1H-NMR(DMSO-d6+TFA)δ:8.63(1H,s),8.16(2H,brs),7.75(1H,dd,J=12.8Hz,1.44Hz), 4.3-1.8(10H,m), 1.2-1.0(4H,m) 1 H-NMR (DMSO-d 6 + TFA) δ: 8.63 (1H, s), 8.16 (2H, brs), 7.75 (1H, dd, J = 12.8Hz, 1.44Hz), 4.3-1.8 (10H, m ), 1.2-1.0 (4H, m)

Claims (53)

다음 일반식(Ⅰ)로 표시되는 피리돈 카르본산 유도체와 그의 에스테르 및 그의 염.The pyridone carboxylic acid derivative represented by the following general formula (I), its ester, and its salt. 상기 식(Ⅰ)에서, R1은 저급 알킬기, 할로겐 치환 저급 알킬기, 저급 알케닐기, 사이클로알킬기 또는 치환되거나 치환되지 않은 페닐기를 의미하고, R2는 수소, 아미노기 또는 저급 알킬기를 의미하고, A는 질소원자 또는 C-X(여기서 X는 수소, 할로겐 원자 또는 알콕시기를 의미함)를 의미하며, Z는 다음식으로 표시되는 기를 나타낸다.In formula (I), R 1 means lower alkyl group, halogen substituted lower alkyl group, lower alkenyl group, cycloalkyl group or substituted or unsubstituted phenyl group, R 2 means hydrogen, amino group or lower alkyl group, and A is A nitrogen atom or CX (where X means hydrogen, a halogen atom or an alkoxy group), and Z represents a group represented by the following formula. (상기 식에서 R3, R4는 수소원자 또는 저급 알킬기를 의미하고, R5, R6는 수소, 히드록시, 알콕시, 아미노, 저급 알킬기로 치환된 아미노기를 의미하는데 둘중 하나는 수소를 의미한다).(Wherein R 3 , R 4 means a hydrogen atom or a lower alkyl group, R 5 , R 6 means an amino group substituted with hydrogen, hydroxy, alkoxy, amino, a lower alkyl group, one of which means hydrogen) . 제1항에 있어서, 화합물은 7-([1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-1-시클로프로필-6-플루오로-1,4-디히드로-4-옥소퀴놀린-3-카르복실산인 것을 특징으로 하는 피리돈카르본산 화합물과 그의 염.The compound of claim 1, wherein the compound is 7-([1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptan-3-yl) -1-cyclopropyl-6- Pyridonecarboxylic acid compound and its salt, characterized in that it is fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. 제1항에 있어서, 화합물은 7-([1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-1-시클로프로필-6,8-디플루오로-1,4-디히드로-4-옥소퀴놀린-3-카르복실산인 것을 특징으로 하는 피리돈카르본산 화합물과 그의 염.The compound of claim 1, wherein the compound is 7-([1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptan-3-yl) -1-cyclopropyl-6, A pyridonecarboxylic acid compound and salt thereof characterized by being 8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. 제1항에 있어서, 화합물은 5-아미노-7-([1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-1-시클로프로필-6,8-디플루오로-1,4-디히드로-4-옥소퀴놀린-3-카르복실산인 것을 특징으로 하는 피리돈카르본산 화합물과 그의 염.The compound of claim 1, wherein the compound is 5-amino-7-([1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptan-3-yl) -1-cyclo A pyridonecarboxylic acid compound and its salt, which are propyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. 제1항에 있어서, 화합물은 7-([1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-6,8-디플루오로-1-(2,4-디플루오로페닐)-1,4-디히드로-4-옥소퀴놀린-3-카르복실산인 것을 특징으로 하는 피리돈카르본산 화합물과 그의 염.The compound of claim 1, wherein the compound is 7-([1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptan-3-yl) -6,8-difluoro Pyridonecarboxylic acid compound and its salt characterized by the fact that it is -1- (2,4-difluorophenyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid. 제1항에 있어서, 화합물은 7-([1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-1-시클로프로필-6,8-디플루오로-5-메틸-1,4-디히드로-4-옥소퀴놀린-3-카르복실산인 것을 특징으로 하는 피리돈카르본산 화합물과 그의 염.The compound of claim 1, wherein the compound is 7-([1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptan-3-yl) -1-cyclopropyl-6, A pyridonecarboxylic acid compound and salt thereof characterized by being 8-difluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. 제1항에 있어서, 화합물은 7-([1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-8-클로로-1-시클로프로필-6-플루오로-1,4-디히드로-4-옥소퀴놀린-3-카르복실산인 것을 특징으로 하는 피리돈카르본산 화합물과 그의 염.The compound of claim 1, wherein the compound is 7-([1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptan-3-yl) -8-chloro-1-cyclo A pyridonecarboxylic acid compound and its salt, characterized in that it is propyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. 제1항에 있어서, 화합물은 7-([1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-1-시클로프로필-6-플루오로-1,4-디히드로-4-옥소-1,8-나프티리딘-3-카르복실산인 것을 특징으로 하는 피리돈카르본산 화합물과 그의 염.The compound of claim 1, wherein the compound is 7-([1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptan-3-yl) -1-cyclopropyl-6- Pyridonecarboxylic acid compound and salt thereof characterized by being fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid. 제1항에 있어서, 화합물은 7-([1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-1-(2,4-디플루오로페닐)-6-플루오로-1,4-디히드로-4-옥소-1,8-나프티리딘-3-카르복실산인 것을 특징으로 하는 피리돈카르본산 화합물과 그의 염.The compound of claim 1, wherein the compound is 7-([1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptan-3-yl) -1- (2,4- Difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid. A pyridonecarboxylic acid compound and salt thereof. 제1항에 있어서, 화합물은 7-([1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-6-플루오로-1-(4-플루오로페닐)-1,4-디히드로-4-옥소-1,8-나프티리딘-3-카르복실산인 것을 특징으로 하는 피리돈카르본산 화합물과 그의 염.The compound of claim 1, wherein the compound is 7-([1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptan-3-yl) -6-fluoro-1- (4-fluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid. A pyridonecarboxylic acid compound and salt thereof. 제1항에 있어서, 화합물은 7-([1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-1-t-부틸-6-플루오로-1,4-디히드로-4-옥소-1,8-나프티리딘-3-카르복실산인 것을 특징으로 하는 피리돈카르본산 화합물과 그의 염.The compound of claim 1, wherein the compound is 7-([1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptan-3-yl) -1-t-butyl-6 -Pyrodon-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, The pyridonecarboxylic acid compound and its salt. 제1항에 있어서, 화합물은 7-([1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-1-(2,4-디플루오로페닐)-6-플루오로-5-메틸-1,4-디히드로-4-옥소-1,8-나프티리딘-3-카르복실산인 것을 특징으로 하는 피리돈카르본산 화합물과 그의 염.The compound of claim 1, wherein the compound is 7-([1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptan-3-yl) -1- (2,4- Difluorophenyl) -6-fluoro-5-methyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid and a salt thereof . 제1항에 있어서, 화합물은 (+)-7-([1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-1-시클로프로필-6-플루오로-1,4-디히드로-4-옥소-1,8-나프티리딘-3-카르복실산인 것을 특징으로 하는 피리돈카르본산 화합물과 그의 염.The compound of claim 1, wherein the compound is (+)-7-([1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptan-3-yl) -1-cyclo A pyridonecarboxylic acid compound and salt thereof, which is propyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid. 제1항에 있어서, 화합물은 (-)-7-([1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-1-시클로프로필-6,8-디플루오로-1,4-디히드로-4-옥소퀴놀린-3-카르복실산인 것을 특징으로 하는 피리돈카르본산 화합물과 그의 염.The compound of claim 1, wherein the compound is (-)-7-([1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptan-3-yl) -1-cyclo A pyridonecarboxylic acid compound and its salt, which are propyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. 제1항에 있어서, 화합물은 (+)-7-([1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-1-시클로프로필-6,8-디플루오로-1,4-디히드로-4-옥소퀴놀린-3-카르복실산인 것을 특징으로 하는 피리돈카르본산 화합물과 그의 염.The compound of claim 1, wherein the compound is (+)-7-([1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptan-3-yl) -1-cyclo A pyridonecarboxylic acid compound and its salt, which are propyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. 제1항에 있어서, 화합물은 1-시클로프로필-6,8-디플루오로-7-([1α,5α,6β]-6-히드록시-1-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-1,4-디히드로-4-옥소퀴놀린-3-카르복실산인 것을 특징으로 하는 피리돈카르본산 화합물과 그의 염.The compound of claim 1, wherein the compound is 1-cyclopropyl-6,8-difluoro-7-([1α, 5α, 6β] -6-hydroxy-1-methyl-3-azabicyclo [3.2.0] Heptane-3-yl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, The pyridonecarboxylic acid compound and its salt. 제1항에 있어서, 화합물은 1-시클로프로필-6-플루오로-7-([1α,5α,6β]-6-히드록시-1-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-1,4-디히드로-4-옥소-1,8-나프티리딘-3-카르복실산인 것을 특징으로 하는 피리돈카르본산 화합물과 그의 염.The compound of claim 1, wherein the compound is 1-cyclopropyl-6-fluoro-7-([1α, 5α, 6β] -6-hydroxy-1-methyl-3-azabicyclo [3.2.0] heptan-3 -Yl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid; a pyridonecarboxylic acid compound and salt thereof. 제1항에 있어서, 화합물은 (-)-7-([1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-1-시클로프로필-6,8-디플루오로-5-메틸-1,4-디히드로-4-옥소퀴놀린-3-카르복실산인 것을 특징으로 하는 피리돈카르본산 화합물과 그의 염.The compound of claim 1, wherein the compound is (-)-7-([1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptan-3-yl) -1-cyclo A pyridonecarboxylic acid compound and salt thereof, which is propyl-6,8-difluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. 제1항에 있어서, 화합물은 (-)-5-아미노-7-([1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-1-시클로프로필-6,8-디플루오로-1,4-디히드로-4-옥소퀴놀린-3-카르복실산인 것을 특징으로 하는 피리돈카르본산 화합물과 그의 염.The compound of claim 1, wherein the compound is (-)-5-amino-7-([1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptan-3-yl) It is a 1-cyclopropyl-6,8-difluoro- 1,4-dihydro-4-oxoquinoline-3-carboxylic acid, The pyridonecarboxylic acid compound and its salt. 제1항에 있어서, 화합물은 (-)-7-([1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-1-t-부틸-6-플루오로-1,4-디히드로-4-옥소-1,8-나프티리딘-3-카르복실산인 것을 특징으로 하는 피리돈카르본산 화합물과 그의 염.The compound of claim 1, wherein the compound is (-)-7-([1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptan-3-yl) -1-t It is -butyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, The pyridonecarboxylic-acid compound and its salt. 제1항에 있어서, 화합물은 (-)-7-([1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-8-클로로-1-시클로프로필-6-플루오로-1,4-디히드로-4-옥소퀴놀린-3-카르복실산인 것을 특징으로 하는 피리돈카르본산 화합물과 그의 염.The compound of claim 1, wherein the compound is (-)-7-([1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptan-3-yl) -8-chloro It is a 1-cyclopropyl-6-fluoro- 1, 4- dihydro-4- oxoquinoline-3-carboxylic acid, The pyridonecarboxylic acid compound and its salt. 제1항에 있어서, 화합물은 (-)-7-([1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-1-(2,4-디플루오로페닐)-6-플루오로-1,4-디히드로-4-옥소-1,8-나프티리딘-3-카르복실산인 것을 특징으로 하는 피리돈카르본산 화합물과 그의 염.The compound of claim 1, wherein the compound is selected from (-)-7-([1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptan-3-yl) -1- ( 2,4-difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid and a salt thereof . 제1항에 있어서, 화합물은 (-)-7-([1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-6-플루오로-1-(4-플루오로페닐)-1,4-디히드로-4-옥소-1,8-나프티리딘-3-카르복실산인 것을 특징으로 하는 피리돈카르본산 화합물과 그의 염.The compound of claim 1, wherein the compound is (-)-7-([1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptan-3-yl) -6-fluoro Pyridonecarboxylic acid compound and its salt characterized by the above-mentioned rho-1- (4-fluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid. 제1항에 있어서, 화합물은 7-([1α,5α,6β]-6-아미노-5-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-6,8-디플루오로-1,4-디히드로-4-옥소퀴놀린-3-카르복실산인 것을 특징으로 하는 피리돈카르본산 화합물과 그의 염.The compound of claim 1, wherein the compound is 7-([1α, 5α, 6β] -6-amino-5-methyl-3-azabicyclo [3.2.0] heptan-3-yl) -6,8-difluoro Pyridonecarboxylic acid compound and its salt characterized by -1,4-dihydro-4-oxoquinoline-3-carboxylic acid. 제1항에 있어서, 화합물은 7-([1α,5α,6β]-6-아미노-5-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-6-플루오로-1-(4-플루오로페닐)-1,4-디히드로-4-옥소-1,8-나프티리딘-3-카르복실산인 것을 특징으로 하는 피리돈카르본산 화합물과 그의 염.The compound of claim 1, wherein the compound is 7-([1α, 5α, 6β] -6-amino-5-methyl-3-azabicyclo [3.2.0] heptan-3-yl) -6-fluoro-1- (4-fluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid. A pyridonecarboxylic acid compound and salt thereof. 제1항에 있어서, 화합물은 8-클로로-1-시클로프로필-7-([1α,5α,6β]-6-아미노-5-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-6-플루오로-1,4-디히드로-4-옥소-3-퀴놀린카르복실산인 것을 특징으로 하는 피리돈카르본산 화합물과 그의 염.The compound of claim 1, wherein the compound is 8-chloro-1-cyclopropyl-7-([1α, 5α, 6β] -6-amino-5-methyl-3-azabicyclo [3.2.0] heptan-3-yl ) -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, and a pyridonecarboxylic acid compound and its salt. 제1항에 있어서, 화합물은 7-([1α,5α,6β]-6-아미노-5-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-1-시클로프로필-6-플루오로-1,4-디히드로-4-옥소-1,8-나프티리딘-3-카르복실산인 것을 특징으로 하는 피리돈카르본산 화합물과 그의 염.The compound of claim 1, wherein the compound is 7-([1α, 5α, 6β] -6-amino-5-methyl-3-azabicyclo [3.2.0] heptan-3-yl) -1-cyclopropyl-6- Pyridonecarboxylic acid compound and salt thereof characterized by being fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid. 제1항에 있어서, 화합물은 1-(2,4-디플루오로페닐)-7-([1α,5α,6β]-아미노-5-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-6-플루오로-1,4-디히드로-4-옥소-1,8-나프티리딘-3-카르복실산인 것을 특징으로 하는 피리돈카르본산 화합물과 그의 염.The compound of claim 1, wherein the compound is 1- (2,4-difluorophenyl) -7-([1α, 5α, 6β] -amino-5-methyl-3-azabicyclo [3.2.0] heptan-3 -Yl) -6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid. A pyridonecarboxylic acid compound and salt thereof. 제1항에 있어서, 화합물은 (-)-7-([1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-1-(2,4-디플루오로페닐)-1,4-디히드로-6-플루오로-5-메틸-4-옥소-1,8-나프티리딘-3-카르복실산인 것을 특징으로 하는 피리돈카르본산 화합물과 그의 염.The compound of claim 1, wherein the compound is selected from (-)-7-([1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptan-3-yl) -1- ( Pyridonecarboxylic acid, characterized in that 2,4-difluorophenyl) -1,4-dihydro-6-fluoro-5-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid Compounds and their salts. 제1항에 있어서, 화합물은 1-시클로프로필-7-([1α,5α,6β]-6-히드록시-3-아자비시클로[3.2.0]헵탄-3-일)-6,8-디플루오로-1,4-디히드로-4-옥소-3-퀴놀린카르복실산인 것을 특징으로 하는 피리돈카르본산 화합물과 그의 염.The compound of claim 1, wherein the compound is 1-cyclopropyl-7-([1α, 5α, 6β] -6-hydroxy-3-azabicyclo [3.2.0] heptan-3-yl) -6,8-di Pyridonecarboxylic acid compound and its salt characterized by being fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid. 제1항에 있어서, 화합물은 5-아미노-1-시클로프로필-7-([1α,5α,6β]-6-히드록시-3-아자비시클로[3.2.0]헵탄-3-일)-6,8-디플루오로-1,4-디히드로-4-옥소-3-퀴놀린카르복실산인 것을 특징으로 하는 피리돈카르본산 화합물과 그의 염.The compound of claim 1, wherein the compound is 5-amino-1-cyclopropyl-7-([1α, 5α, 6β] -6-hydroxy-3-azabicyclo [3.2.0] heptan-3-yl) -6 And 8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid. A pyridonecarboxylic acid compound and salt thereof. 제1항에 있어서, 화합물은 1-시클로프로필-7-([1α,5α,6β]-6-히드록시-3-아자비시클로[3.2.0]헵탄-3-일)-6,8-디플루오로-1,4-디히드로-5-메틸-4-옥소-3-퀴놀린카르복실산인 것을 특징으로 하는 피리돈카르본산 화합물과 그의 염.The compound of claim 1, wherein the compound is 1-cyclopropyl-7-([1α, 5α, 6β] -6-hydroxy-3-azabicyclo [3.2.0] heptan-3-yl) -6,8-di Pyridonecarboxylic acid compound and its salt, characterized in that it is fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid. 제1항에 있어서, 화합물은 1-시클로프로필-7-([1α,5α,6β]-6-아미노-3-아자비시클로[3.2.0]헵탄-3-일)-6,8-디플루오로-1,4-디히드로-5-메틸-4-옥소-3-퀴놀린카르복실산인 것을 특징으로 하는 피리돈카르본산 화합물과 그의 염.The compound of claim 1, wherein the compound is 1-cyclopropyl-7-([1α, 5α, 6β] -6-amino-3-azabicyclo [3.2.0] heptan-3-yl) -6,8-difluoro Rho-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, The pyridonecarboxylic acid compound and its salt. 제1항에 있어서, 화합물은 1-시클로프로필-7-([1α,5α,6β]-6-아미노-3-아자비시클로[3.2.0]헵탄-3-일)-6,8-디플루오로-1,4-디히드로-4-옥소-3-퀴놀린카르복실산인 것을 특징으로 하는 피리돈카르본산 화합물과 그의 염.The compound of claim 1, wherein the compound is 1-cyclopropyl-7-([1α, 5α, 6β] -6-amino-3-azabicyclo [3.2.0] heptan-3-yl) -6,8-difluoro Rhod-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and a pyridonecarboxylic acid compound and its salt. 제1항에 있어서, 화합물은 5-아미노-1-시클로프로필-7-([1α,5α,6β]-6-아미노-3-아자비시클로[3.2.0]헵탄-3-일)-6,8-디플루오로-1,4-디히드로-4-옥소-3-퀴놀린카르복실산인 것을 특징으로 하는 피리돈카르본산 화합물과 그의 염.The compound of claim 1, wherein the compound is 5-amino-1-cyclopropyl-7-([1α, 5α, 6β] -6-amino-3-azabicyclo [3.2.0] heptan-3-yl) -6, A pyridonecarboxylic acid compound and salt thereof characterized by being 8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid. 제1항에 있어서, 화합물은 1-시클로프로필-7-([1α,5α,6β]-6-히드록시-3-아자비시클로[3.2.0]헵탄-3-일)-6-플루오로-1,4-디히드로-4-옥소-1,8-나프티리딘-3-퀴놀린카르복실산인 것을 특징으로 하는 피리돈카르본산 화합물과 그의 염.The compound of claim 1, wherein the compound is 1-cyclopropyl-7-([1α, 5α, 6β] -6-hydroxy-3-azabicyclo [3.2.0] heptan-3-yl) -6-fluoro- A pyridonecarboxylic acid compound and salt thereof, which is 1,4-dihydro-4-oxo-1,8-naphthyridine-3-quinolinecarboxylic acid. 제1항에 있어서, 화합물은 1-시클로프로필-7-([1α,5α,6β]-6-아미노-3-아자비시클로[3.2.0]헵탄-3-일)-6-플루오로-1,4-디히드로-4-옥소-1,8-나프티리딘-3-카르복실산인 것을 특징으로 하는 피리돈카르본산 화합물과 그의 염.The compound of claim 1, wherein the compound is 1-cyclopropyl-7-([1α, 5α, 6β] -6-amino-3-azabicyclo [3.2.0] heptan-3-yl) -6-fluoro-1 And 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid. A pyridonecarboxylic acid compound and salt thereof. 제1항에 있어서, 화합물은 7-([1α,5α,6β]-6-아미노-3-아자비시클로[3.2.0]헵탄-3-일)-1-(2,4-디플루오로페닐)-1,4-디히드로-6-플루오로-4-옥소-1,8-나프티리딘-3-카르복실산인 것을 특징으로 하는 피리돈카르본산 화합물과 그의 염.The compound of claim 1, wherein the compound is 7-([1α, 5α, 6β] -6-amino-3-azabicyclo [3.2.0] heptan-3-yl) -1- (2,4-difluorophenyl ) -1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid. A pyridonecarboxylic acid compound and salt thereof. 제1항에 있어서, 화합물은 7-([1α,5α,6β]-6-아미노-3-아자비시클로[3.2.0]헵탄-3-일)-1,4-디히드로-6-플루오로-1-(4-플루오로페닐)-4-옥소-1,8-나프티리딘-3-카르복실산인 것을 특징으로 하는 피리돈카르본산 화합물과 그의 염.The compound of claim 1, wherein the compound is 7-([1α, 5α, 6β] -6-amino-3-azabicyclo [3.2.0] heptan-3-yl) -1,4-dihydro-6-fluoro Pyridonecarboxylic acid compound and its salt characterized by the fact that it is -1- (4-fluorophenyl) -4-oxo-1,8-naphthyridine-3-carboxylic acid. 제1항에 있어서, 화합물은 7-([1α,5α,6β]-6-아미노-3-아자비시클로[3.2.0]헵탄-3-일)-8-클로로-1-시클로프로필-6-플루오로-1,4-디히드로-4-옥소-3-퀴놀린카르복실산인 것을 특징으로 하는 피리돈카르본산 화합물과 그의 염.The compound of claim 1, wherein the compound is 7-([1α, 5α, 6β] -6-amino-3-azabicyclo [3.2.0] heptan-3-yl) -8-chloro-1-cyclopropyl-6- Pyridonecarboxylic acid compound and its salt characterized by being fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid. 제1항에 있어서, 화합물은 7-([1α,5α,6β]-6-아미노-3-아자비시클로[3.2.0]헵탄-3-일)-1-(2,4-디플루오로페닐)-1,4-디히드로-6-플루오로-5-메틸-4-옥소-1,8-나프티리딘-3-카르복실산인 것을 특징으로 하는 피리돈카르본산 화합물과 그의 염.The compound of claim 1, wherein the compound is 7-([1α, 5α, 6β] -6-amino-3-azabicyclo [3.2.0] heptan-3-yl) -1- (2,4-difluorophenyl ) -1,4-dihydro-6-fluoro-5-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid. A pyridonecarboxylic acid compound and salt thereof. 제1항에 있어서, 화합물은 (-)-7-([1α,5α,6β]-6-아미노-3-아자비시클로[3.2.0]헵탄-3-일)-1-(2,4-디플루오로페닐)-1,4-디히드로-6-플루오로-4-옥소-1,8-나프티리딘-3-카르복실산인 것을 특징으로 하는 피리돈카르본산 화합물과 그의 염.The compound of claim 1, wherein the compound is (-)-7-([1α, 5α, 6β] -6-amino-3-azabicyclo [3.2.0] heptan-3-yl) -1- (2,4- Difluorophenyl) -1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid. A pyridonecarboxylic acid compound and salt thereof. 제1항에 있어서, 화합물은 7-([1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-1-(tert-부틸)-6-플루오로-1,4-디히드로-4-옥소-1,8-나프티리딘-3-카르복실산인 것을 특징으로 하는 피리돈카르본산 화합물과 그의 염.The compound of claim 1, wherein the compound is 7-([1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptan-3-yl) -1- (tert-butyl) Pyridonecarboxylic acid compound and salt thereof, wherein the compound is -6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid. 제1항에 있어서, 화합물은 (-)-7-([1α,5α,6β]-6-아미노-3-아자비시클로[3.2.0]헵탄-3-일)-1-시클로프로필-1,4-디히드로-6-플루오로-5-메틸-1,8-나프티리딘-3-카르복실산인 것을 특징으로 하는 피리돈카르본산 화합물과 그의 염.The compound of claim 1, wherein the compound is selected from (-)-7-([1α, 5α, 6β] -6-amino-3-azabicyclo [3.2.0] heptan-3-yl) -1-cyclopropyl-1, A pyridonecarboxylic acid compound and salt thereof, which is 4-dihydro-6-fluoro-5-methyl-1,8-naphthyridine-3-carboxylic acid. 제1항에 있어서, 화합물은 7-([1α,5α,6β]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-1-시클로프로필-6-플루오로-8-메톡시-1,4-디히드로-4-옥소퀴놀린-3-카르복실산인 것을 특징으로 하는 피리돈카르본산 화합물과 그의 염.The compound of claim 1, wherein the compound is 7-([1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptan-3-yl) -1-cyclopropyl-6- Pyridonecarboxylic acid compound and its salt, characterized in that it is fluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. 제1항에 있어서, 화합물은 7-([1α,5α,6α]-6-아미노-1-메틸-3-아자비시클로[3.2.0]헵탄-3-일)-1-시클로프로필-6-플루오로-1,4-디히드로-4-옥소-1,8-나프티리딘-3-카르복실산인 것을 특징으로 하는 피리돈카르본산 화합물과 그의 염.The compound of claim 1, wherein the compound is 7-([1α, 5α, 6α] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptan-3-yl) -1-cyclopropyl-6- Pyridonecarboxylic acid compound and salt thereof characterized by being fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid. 제1항에 있어서, 화합물은 8-클로로-1-시클로프로필-6-플루오로-7-([1α,5α,6β]-1-메틸-6-메틸아미노-3-아자비시클로[3.2.0]헵탄-3-일)-1,4-디히드로-4-옥소퀴놀린-3-카르복실산인 것을 특징으로 하는 피리돈카르본산 화합물과 그의 염.The compound of claim 1, wherein the compound is 8-chloro-1-cyclopropyl-6-fluoro-7-([1α, 5α, 6β] -1-methyl-6-methylamino-3-azabicyclo [3.2.0 ] Heptan-3-yl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, and a pyridonecarboxylic acid compound and its salt. 제1항에 있어서, 화합물은 1-시클로프로필-6,8-디플루오로-7-([1α,5α,6β]-1-메틸-6-메틸아미노-3-아자비시클로[3.2.0]헵탄-3-일)-1,4-디히드로-4-옥소퀴놀린-3-카르복실산인 것을 특징으로 하는 피리돈카르본산 화합물과 그의 염.The compound of claim 1, wherein the compound is 1-cyclopropyl-6,8-difluoro-7-([1α, 5α, 6β] -1-methyl-6-methylamino-3-azabicyclo [3.2.0] Heptane-3-yl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, The pyridonecarboxylic acid compound and its salt. 제1항에 있어서, 화합물은 1-시클로프로필-6-플루오로-7-([1α,5α,6β]-1-메틸-6-메틸아미노-3-아자비시클로[3.2.0]헵탄-3-일)-1,4-디히드로-4-옥소-1,8-나프티리딘-3-카르복실산인 것을 특징으로 하는 피리돈카르본산 화합물과 그의 염.The compound of claim 1, wherein the compound is 1-cyclopropyl-6-fluoro-7-([1α, 5α, 6β] -1-methyl-6-methylamino-3-azabicyclo [3.2.0] heptan-3 -Yl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid; a pyridonecarboxylic acid compound and salt thereof. 제1항에 있어서, 화합물은 7-([1α,5α,6α]-6-아미노-3-아자비시클로[3.2.0]헵탄-3-일)-1-시클로프로필-6-플루오로-1,4-디히드로-4-옥소-1,8-나프티리딘-3-카르복실산인 것을 특징으로 하는 피리돈카르본산 화합물과 그의 염.The compound of claim 1, wherein the compound is 7-([1α, 5α, 6α] -6-amino-3-azabicyclo [3.2.0] heptan-3-yl) -1-cyclopropyl-6-fluoro-1 And 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid. A pyridonecarboxylic acid compound and salt thereof. 제1항에 있어서, 화합물은 7-([1α,5α,6α]-6-아미노-3-아자비시클로[3.2.0]헵탄-3-일)-1-시클로프로필-6,8-디플루오로-1,4-디히드로-4-옥소퀴놀린-3-카르복실산인 것을 특징으로 하는 피리돈카르본산 화합물과 그의 염.The compound of claim 1, wherein the compound is 7-([1α, 5α, 6α] -6-amino-3-azabicyclo [3.2.0] heptan-3-yl) -1-cyclopropyl-6,8-difluoro Rhod-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and a pyridonecarboxylic acid compound and its salt. 다음 일반식(Ⅱ)로 표시되는 화합물과 다음 일반식(Ⅲ)으로 표시되는 화합물 또는 그의 산부가염을 불활성 유기용매 중에서 축합반응시켜 다음 일반식(Ⅰ)로 표시되는 피리돈카르본산 유도체를 제조하는 방법.To prepare a pyridonecarboxylic acid derivative represented by the following general formula (I) by condensation reaction of a compound represented by the following general formula (II) and a compound represented by the following general formula (III) or an acid addition salt thereof in an inert organic solvent Way. Z-H(Ⅲ)Z-H (Ⅲ) 상기 식에서, R1은 저급 알킬기, 할로겐 치환 저급 알킬기, 저급 알케닐기, 사이클로 알킬기 또는 치환되거나 치환되지 않은 페닐기를 의미하고, R2는 수소, 아미노기 또는 저급 알킬기를 의미하고, A는 질소원자 또는 C-X(여기서 X는 수소, 할로겐 원자 또는 알콕시기를 의미함)을 의미하며, R7은 수소 또는 저급 알킬기를 의미하며, Y는 할로겐 원자를 의미하며, Z는 다음 식으로 표시되는 기를 나타낸다.Wherein R 1 means lower alkyl group, halogen substituted lower alkyl group, lower alkenyl group, cycloalkyl group or substituted or unsubstituted phenyl group, R 2 means hydrogen, amino group or lower alkyl group, A is nitrogen atom or CX (Where X means hydrogen, a halogen atom or an alkoxy group), R 7 means hydrogen or a lower alkyl group, Y means a halogen atom, and Z represents a group represented by the following formula. (여기서, R3, R4는 수소원자 또는 저급 알킬기를 의미하고, R5, R6는 수소, 히드록시, 알콕시, 아미노, 저급 알킬기로 치환된 아미노기를 의미하는데 둘중 하나는 수소를 의미한다.)Wherein R 3 and R 4 refer to a hydrogen atom or a lower alkyl group, and R 5 and R 6 refer to an amino group substituted with hydrogen, hydroxy, alkoxy, amino or a lower alkyl group, one of which means hydrogen. ) 제52항에 있어서, 상기 일반식(Ⅱ)의 R7이 저급 알킬인 경우 일반식(Ⅱ)로 표시되는 화합물과 일반식(Ⅲ)으로 표시되는 화합물 또는 그의 산부가염을 불활성 유기용매 중에서 축합반응시킨 후 가수분해시키는 과정을 더 포함하는 것을 특징으로 하는 방법.53. The condensation reaction according to claim 52, wherein when R 7 of the general formula (II) is lower alkyl, the compound represented by the general formula (II) and the compound represented by the general formula (III) or acid addition salt thereof are condensed in an inert organic solvent. And further comprising the step of hydrolysis.
KR1019930021035A 1992-12-30 1993-10-11 Novel pyridone carboxylic acid derivatives and their preparing method KR970007919B1 (en)

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