KR100599252B1 - 1,2,4-Oxadiazolyl substituted benzoylguanidines - Google Patents

1,2,4-Oxadiazolyl substituted benzoylguanidines Download PDF

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KR100599252B1
KR100599252B1 KR1020040025050A KR20040025050A KR100599252B1 KR 100599252 B1 KR100599252 B1 KR 100599252B1 KR 1020040025050 A KR1020040025050 A KR 1020040025050A KR 20040025050 A KR20040025050 A KR 20040025050A KR 100599252 B1 KR100599252 B1 KR 100599252B1
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benzoyl
guanidine
oxadiazol
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compound
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KR20050099836A (en
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정명희
최일영
안미자
이병호
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한국화학연구원
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
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Abstract

본 발명은 심근세포의 소듐(Na+)과 프로톤(H+)의 교환을 효과적으로 억제하는 1,2,4-옥사디아졸이 치환된 벤조일구아니딘 유도체와 이 화합물의 제조방법, 그리고 상기 화합물을 심경색, 협심증 및 부정맥 등의 심혈관계 질환 치료 및 예방제로 사용하는 의약적 용도에 관한 것이다.The present invention provides a 1,2,4-oxadiazole-substituted benzoylguanidine derivative which effectively inhibits the exchange of sodium (Na + ) and proton (H + ) in cardiomyocytes, a method for preparing the compound, and the compound The present invention relates to a medicinal use for treating and preventing cardiovascular diseases such as color, angina and arrhythmia.

심경색, 허혈, 심장병, NHE-억제제, 벤조일 구아니딘, 1,2,4-옥사디아졸, Na+/H+-교환 억제Infarction, ischemia, heart disease, NHE-inhibitors, benzoyl guanidine, 1,2,4-oxadiazole, Na + / H + -inhibition

Description

1,2,4-옥사디아졸이 치환된 벤조일구아니딘 유도체{1,2,4-Oxadiazolyl substituted benzoylguanidines}Benzoylguanidine derivatives substituted with 1,2,4-oxadiazoles {1,2,4-Oxadiazolyl substituted benzoylguanidines}

본 발명은 심근세포의 소듐(Na+)과 프로톤(H+)의 교환을 효과적으로 억제하는 1,2,4-옥사디아졸이 치환된 벤조일구아니딘 유도체와 이 화합물의 제조방법, 그리고 상기 화합물을 심경색, 협심증 및 부정맥 등의 심혈관계 질환 치료 및 예방제로 사용하는 의약적 용도에 관한 것이다.The present invention provides a 1,2,4-oxadiazole-substituted benzoylguanidine derivative which effectively inhibits the exchange of sodium (Na + ) and proton (H + ) in cardiomyocytes, a method for preparing the compound, and the compound The present invention relates to a medicinal use for treating and preventing cardiovascular diseases such as color, angina and arrhythmia.

심장과 혈관은 전신에 산소와 영양분을 공급하는 기관으로, 인간이 생명을 유지하는데 핵심적인 기관이다. 그러나, 각종 원인에 의해 심혈관계에 이상이 생겨 각 조직 및 기관으로의 혈액과 산소공급이 원활치 않으면, 국소부위 조직괴사는 물론 생명에 위협을 주는 질환을 야기시키게 된다. 이러한 심혈관계 질환은 대표적인 성인병 중의 하나로서 최근에는 환자들이 증가하는 추세이지만 뚜렷한 치료약 및 예방약이 없다. 특히, 심경색으로 인한 계속되는 세포손상을 예방하기 위한 Na+/H+-교환억제 제제의 개발은 새로운 의약품 개발에 좋은 타겟(target)이 되 고 있다. The heart and blood vessels are the organs that supply oxygen and nutrients to the whole body, and are vital for human life. However, abnormalities in the cardiovascular system due to various causes, if blood and oxygen supply to each tissue and organs are not smooth, causing local tissue necrosis as well as life-threatening diseases. Such cardiovascular disease is one of the typical adult diseases, but the number of patients is increasing in recent years, but there is no obvious treatment and preventive medicine. In particular, the development of Na + / H + -exhibition preparations to prevent continued cell damage due to deep infarction has become a good target for the development of new drugs.

심혈관계 질환의 치료제로는 니트레이트(Nitrate)계 제제로 이스모(ISMO™, Schwarz 사) 등이 잘 알려져 있다. 니트레이트(Nitrate)계 제제는 관상동맥을 확장시킴으로써 심근에 산소공급을 증가시키는 약물로 치료효과는 우수하나 체위성 저혈압과 심계항진, 두통 등의 부작용으로 저혈압, 녹내장 등의 환자에 처치하는데는 제약이 있다.As a therapeutic agent for cardiovascular diseases, Ismo (ISMO ™, Schwarz) is well known as a nitrate-based preparation. Nitrate-based drugs increase the oxygen supply to the myocardium by expanding coronary arteries. The nitrate-based preparations have excellent therapeutic effect, but they are difficult to treat in patients with hypotension and glaucoma due to side effects such as postural hypotension, palpitations and headaches. have.

또한, β-차단제로 베타록(BETALOC™, ASTRA 사) 등이 잘 알려져 있다. β-차단제는 심장박동수와 심박출량을 감소시키는 약물로 치료효과는 우수하나 급격한 심장억제, 심장부전작용과 심장정지를 유발하거나 약화시키므로 울혈성 심부전 등의 환자에 처치하는데는 제약이 있다.In addition, beta-lock (BETALOC ™, ASTRA) is well known as a β-blocker. β-blocker is a drug that reduces heart rate and cardiac output. The therapeutic effect is excellent, but there is a limitation in treating patients with congestive heart failure because it causes or weakens sudden cardiac arrest, heart failure and cardiac arrest.

한편, 다수의 벤조일구아니딘 유도체가 심혈관계 질환 치료에 유효한 것으로 공지되어 있다. 예를 들면, 국제특허공개 WO 2000/17176호에는 4-아릴카보닐-1-피페라지닐기가 치환된 벤조일구아니딘 유도체가 인간 장암 세포 내에서의 Na+/H+-교환 억제활성이 우수한 것으로 공개되어 있다. 국제특허공개 WO 1997/23476호에는 헤테로싸이클릭-접합된 벤조일구아니딘 유도체가 세포내 Na+/H+-교환 억제활성이 우수한 것으로 공개되어 있다. On the other hand, many benzoylguanidine derivatives are known to be effective for treating cardiovascular diseases. For example, WO 2000/17176 discloses that benzoylguanidine derivatives substituted with 4-arylcarbonyl-1-piperazinyl groups have excellent Na + / H + -exchange inhibitory activity in human intestinal cancer cells. It is. International Patent Publication No. WO 1997/23476 discloses that heterocyclic-conjugated benzoylguanidine derivatives have excellent intracellular Na + / H + -exchange inhibitory activity.

그러나, 본 발명이 특징으로 하고 있는 1,2,4-옥사디아졸이 치환된 벤조일구아니딘 유도체는 현재까지 어떠한 문헌에도 공개된 바가 없는 신규 화합물로서, Na+/H+-교환 억제활성에 대해 보고된 바도 없다.However, 1,2,4-oxadiazole-substituted benzoylguanidine derivatives, which are characterized by the present invention, are novel compounds that have not been disclosed in any literature so far, and report on Na + / H + -exchange inhibitory activity. It has never been.

본 발명자들은 심혈관계 질환의 치료 및 예방에 유효한 신규 화합물을 합성하고자 노력하였고, 그 결과 신규 구조의 1,2,4-옥사디아졸이 치환된 벤조일구아니딘 유도체를 합성하게 되었고, 이 신규 화합물이 Na+/H+-교환 억제활성이 우수함을 확인함으로써 본 발명을 완성하게 되었다.The present inventors have tried to synthesize new compounds effective for the treatment and prevention of cardiovascular diseases, and as a result, a new structure of benzoylguanidine derivatives substituted with 1,2,4-oxadiazole having a new structure was obtained. The present invention was completed by confirming the excellent + / H + -exchange inhibitory activity.

따라서, 본 발명은 1,2,4-옥사디아졸이 치환된 벤조일구아니딘 유도체와 이의 약제학적 허용 가능한 염을 제공하는데 그 목적이 있다.Accordingly, an object of the present invention is to provide a benzoylguanidine derivative substituted with 1,2,4-oxadiazole and a pharmaceutically acceptable salt thereof.

또한, 본 발명은 상기 화학식 1로 표시되는 화합물의 제조방법을 제공하는데 다른 목적이 있다.Another object of the present invention is to provide a method for preparing a compound represented by Chemical Formula 1.

또한, 본 발명은 상기한 신규 화합물이 유효성분으로 함유되어 있어 심경색, 협심증 및 부정맥 등의 심혈관계 질환의 치료 및 예방제로서 유용한 약제 조성물을 제공하는데 또 다른 목적이 있다.
In addition, the present invention is another object to provide a pharmaceutical composition useful as a treatment and prevention of cardiovascular diseases, such as cardiac infarction, angina pectoris and arrhythmia, because the novel compound is contained as an active ingredient.

본 발명은 다음 화학식 1로 표시되는 1,2,4-옥사디아졸이 치환된 벤조일구아니딘 유도체 및 약제학적 허용 가능한 이의 염을 그 특징으로 한다.The present invention is characterized by benzoylguanidine derivatives substituted with 1,2,4-oxadiazole represented by the following formula (1) and pharmaceutically acceptable salts thereof.

Figure 112004015018597-pat00001
Figure 112004015018597-pat00001

상기 화학식 1에서, R1은 수소원자, 할로겐원자, 및 C1-C6 알킬기 중에서 선택되고; R2는 C1-C6 알킬기, 페닐기, 피리딘기, 티오펜기, 및 퀴놀린기 중에서 선택되며, 상기한 페닐기, 피리딘기, 티오펜기, 또는 퀴놀린기는 할로겐 원자, 시아노기, 및 C1-C6 알킬기 중에서 선택된 1 내지 3개의 치환체로 치환될 수 있다.In Formula 1, R 1 is selected from a hydrogen atom, a halogen atom, and a C 1 -C 6 alkyl group; R 2 is selected from a C 1 -C 6 alkyl group, a phenyl group, a pyridine group, a thiophene group, and a quinoline group, wherein the phenyl group, pyridine group, thiophene group, or quinoline group is a halogen atom, cyano group, and C 1- It may be substituted with 1 to 3 substituents selected from C 6 alkyl group.

이와 같은 본 발명을 더욱 상세히 설명하면 다음과 같다.Referring to the present invention in more detail as follows.

본 발명에 따른 상기 화학식 1로 표시되는 화합물을 구체적으로 예시하면 다음과 같다 :Specific examples of the compound represented by Formula 1 according to the present invention are as follows:

N-[2-클로로-4-(5-피리딘-3-일-[1,2,4]옥사디아졸-3-일)-벤조일]구아니딘, N- [2-chloro-4- (5-pyridin-3-yl- [1,2,4] oxadiazol-3-yl) -benzoyl] guanidine,

N-[2-클로로-4-(5-이소프로필-[1,2,4]옥사디아졸-3-일)-벤조일]구아니딘, N- [2-chloro-4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) -benzoyl] guanidine,

N-[2-클로로-4-(5-티오펜-3-일-[1,2,4]옥사디아졸-3-일)-벤조일]구아니딘, N- [2-chloro-4- (5-thiophen-3-yl- [1,2,4] oxadiazol-3-yl) -benzoyl] guanidine,

N-[4-(5-피리딘-3-일-[1,2,4]옥사디아졸-3-일)-벤조일]구아니딘, N- [4- (5-pyridin-3-yl- [1,2,4] oxadiazol-3-yl) -benzoyl] guanidine,

N-[2-메틸-4-(5-피리딘-3-일-[1,2,4]옥사디아졸-3-일)-벤조일]구아니딘, N- [2-methyl-4- (5-pyridin-3-yl- [1,2,4] oxadiazol-3-yl) -benzoyl] guanidine,

N-[4-(5-이소프로필-[1,2,4]옥사디아졸-3-일)-2-메틸벤조일]구아니딘, N- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) -2-methylbenzoyl] guanidine,

N-[2-메틸-4-(5-메틸-[1,2,4]옥사디아졸-3-일)-벤조일]구아니딘, N- [2-methyl-4- (5-methyl- [1,2,4] oxadiazol-3-yl) -benzoyl] guanidine,

N-[2-메틸-4-(5-티오펜-3-일-[1,2,4]옥사디아졸-3-일)-벤조일]구아니딘, N- [2-methyl-4- (5-thiophen-3-yl- [1,2,4] oxadiazol-3-yl) -benzoyl] guanidine,

N-[2-메틸-4-(5-페닐-[1,2,4]옥사디아졸-3-일)-벤조일]구아니딘, N- [2-methyl-4- (5-phenyl- [1,2,4] oxadiazol-3-yl) -benzoyl] guanidine,

N-[2-메틸-4-(5-퀴놀린-3-일-[1,2,4]옥사디아졸-3-일)-벤조일]구아니딘, N- [2-methyl-4- (5-quinolin-3-yl- [1,2,4] oxadiazol-3-yl) -benzoyl] guanidine,

N-{4-[5-(2-브로모페닐)-[1,2,4]옥사디아졸-3-일)-2-메틸벤조일]구아니딘, N- {4- [5- (2-bromophenyl)-[1,2,4] oxadiazol-3-yl) -2-methylbenzoyl] guanidine,

N-{4-[5-(3-브로모페닐)-[1,2,4]옥사디아졸-3-일)-2-메틸벤조일}구아니딘, N- {4- [5- (3-bromophenyl)-[1,2,4] oxadiazol-3-yl) -2-methylbenzoyl} guanidine,

N-{4-[5-(4-브로모페닐)-[1,2,4]옥사디아졸-3-일)-2-메틸벤조일}구아니딘, N- {4- [5- (4-bromophenyl)-[1,2,4] oxadiazol-3-yl) -2-methylbenzoyl} guanidine,

N-[2-메틸-4-(5-o-토릴)-[1,2,4]옥사디아졸-3-일)-벤조일}구아니딘, N- [2-methyl-4- (5- o -tolyl)-[1,2,4] oxadiazol-3-yl) -benzoyl} guanidine,

N-[2-메틸-4-(5-m-토릴)-[1,2,4]옥사디아졸-3-일)-벤조일]구아니딘, N- [2-methyl-4- (5- m -tolyl)-[1,2,4] oxadiazol-3-yl) -benzoyl] guanidine,

N-[2-메틸-4-(5-p-토릴)-[1,2,4]옥사디아졸-3-일)-벤조일]구아니딘, N- [2-methyl-4- (5- p -tolyl)-[1,2,4] oxadiazol-3-yl) -benzoyl] guanidine,

N-{4-[5-(2-시아노페닐)-[1,2,4]옥사디아졸-3-일)-2-메틸벤조일}구아니딘, N- {4- [5- (2-cyanophenyl)-[1,2,4] oxadiazol-3-yl) -2-methylbenzoyl} guanidine,

N-{4-[5-(6-클로로피리딘-3-일)-[1,2,4]옥사디아졸-3-일)-2-메틸벤조일}구아니딘, N- {4- [5- (6-chloropyridin-3-yl)-[1,2,4] oxadiazol-3-yl) -2-methylbenzoyl} guanidine,

N-{2-메틸-4-[5-(6-메틸피리딘-3-일)-[1,2,4]옥사디아졸-3-일)-벤조일}구아니딘, 또는 N- {2-methyl-4- [5- (6-methylpyridin-3-yl)-[1,2,4] oxadiazol-3-yl) -benzoyl} guanidine, or

이들의 약학적으로 허용 가능한 염을 포함할 수 있다.Pharmaceutically acceptable salts thereof.

본 발명에 따른 상기 화학식 1로 표시되는 화합물은 당해 기술분야에서 통상적인 방법에 따라 약학적으로 허용되는 산부가염을 형성할 수 있다. 그 예로는 염산, 브롬산, 인산 또는 황산 등과 같은 무기산의 염, 그리고 메틸설폰산, p-톨루엔설폰산, 포름산, 아세트산, 옥살산, 말산, 시트르산, 말레인산, 퓨마르산, 벤조산 등과 같은 유기산 염을 포함한다. 바람직하기로는 염산, 메틸설폰산, p-톨 루엔설폰산, 옥살산, 퓨마르산 및 타르타르산 중에서 선택되는 것이다.The compound represented by Chemical Formula 1 according to the present invention may form a pharmaceutically acceptable acid addition salt according to a conventional method in the art. Examples include salts of inorganic acids such as hydrochloric acid, bromic acid, phosphoric acid or sulfuric acid, and organic acid salts such as methylsulfonic acid, p -toluenesulfonic acid, formic acid, acetic acid, oxalic acid, malic acid, citric acid, maleic acid, fumaric acid, benzoic acid and the like. do. Preferably it is selected from hydrochloric acid, methylsulfonic acid, p -toluenesulfonic acid, oxalic acid, fumaric acid and tartaric acid.

한편, 본 발명은 상기 화학식 1로 표시되는 1,2,4-옥사디아졸이 치환된 벤조일구아니딘 유도체와 약학적으로 허용 가능한 이들의 염의 제조방법을 포함한다.On the other hand, the present invention includes a method for preparing benzoylguanidine derivatives substituted with 1,2,4-oxadiazole represented by Formula 1 and their pharmaceutically acceptable salts.

본 발명에 따른 상기 화학식 1로 표시되는 화합물의 제조방법은, 다음 반응식 1에 나타낸 바와 같이, 다음 화학식 2로 표시되는 4-시아노벤조산 메틸 에스테르 유도체를 출발 물질로 사용하여 하이드록실아민의 첨가반응, 유기산과의 고리화 반응, 구아니딘의 치환반응을 포함하고 있다.In the method for preparing a compound represented by Chemical Formula 1 according to the present invention, as shown in the following Scheme 1, addition reaction of hydroxylamine using 4-cyanobenzoic acid methyl ester derivative represented by the following Chemical Formula 2 as a starting material , Cyclization reaction with organic acid and substitution reaction with guanidine.

Figure 112004015018597-pat00002
Figure 112004015018597-pat00002

상기 반응식 1에서, R1과 R2는 각각 상기에서 정의한 바와 같다.In Scheme 1, R 1 and R 2 are each as defined above.

상기 반응식 1에 따른 제조방법을 보다 상세히 설명하면 다음과 같다.Hereinafter, the preparation method according to Scheme 1 will be described in more detail.

먼저, 상기 화학식 2로 표시되는 4-시아노벤조산 메틸 에스테르 유도체와 하이드록실아민 염화수소를 염기 존재 하에서 가열 환류반응하여 상기 화학식 3으로 표시되는 화합물을 합성한다. 상기 첨가반응은 통상의 유기용매를 사용하는 조 건에서 수행하며, 바람직하기로는 알콜 용매를 사용하며, 특히 바람직하기로는 에탄올 용매를 사용한다. 염기로는 통상의 유기염기 또는 무기염기를 사용할 수 있으며, 바람직하기로는 유기아민 염기를 사용하며, 특히 바람직하기로는 트리에틸아민(Et3N)을 포함하는 알킬아민을 사용한다. First, a 4-cyanobenzoic acid methyl ester derivative represented by Chemical Formula 2 and hydroxylamine hydrogen chloride are heated to reflux in the presence of a base to synthesize a compound represented by Chemical Formula 3. The addition reaction is carried out under conditions using a conventional organic solvent, preferably an alcohol solvent, and particularly preferably an ethanol solvent. Conventional organic bases or inorganic bases may be used as the base, preferably an organic amine base, and particularly preferably an alkylamine containing triethylamine (Et 3 N).

그런 다음, 상기 화학식 3으로 표시되는 화합물과 상기 화학식 4로 표시되는 유기산 화합물을 고리화 반응하여 상기 화학식 5로 표시되는 화합물을 합성한다. 상기 고리화 반응은 1-(3-디메틸아미노프로필)-3-에틸카보디이미드(이하, 'EDCI'라 함)와 4-디메틸아미노피리딘(이하, 'DMAP'라 함) 존재 하에서 수행한다. 고리화 반응에 사용되는 용매는 통상의 유기용매를 사용하는 조건에서 수행하며, 바람직하기로는 N,N-디메틸포름아마이드(DMF)를 사용하는 것이다.Then, the compound represented by Chemical Formula 5 is synthesized by cyclizing the compound represented by Chemical Formula 3 and the organic acid compound represented by Chemical Formula 4. The cyclization reaction is carried out in the presence of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (hereinafter referred to as 'EDCI') and 4-dimethylaminopyridine (hereinafter referred to as 'DMAP'). The solvent used for the cyclization reaction is carried out under the conditions using a conventional organic solvent, preferably using N , N -dimethylformamide (DMF).

그런 다음, 상기 화학식 5로 표시되는 화합물을 구아니딘으로 치환반응하여 본 발명이 목적하는 상기 화학식 1로 표시되는 1,2,4-옥사디아졸이 치환된 벤조일구아니딘 유도체를 제조한다. 상기 치환반응에 사용되는 구아니딘은, 구아니딘 염화수소를 DMF 단독용매 또는 DMF와 1,4-디옥산의 혼합용매 상에서 칼륨 tert-부톡사이드로 처리하여 유리염기(free base)로 만든 다음, 상기 화학식 5로 표시되는 화합물과의 치환반응에 사용한다.Thereafter, the compound represented by Chemical Formula 5 is substituted with guanidine to prepare a benzoylguanidine derivative substituted with 1,2,4-oxadiazole represented by Chemical Formula 1 according to the present invention. The guanidine used in the substitution reaction is treated with potassium tert -butoxide in guanidine hydrogen chloride alone or in a mixed solvent of DMF and 1,4-dioxane to form a free base, and then to Chemical Formula 5. It is used for the substitution reaction with the compound represented.

이상의 제조방법으로 합성한 상기 화학식 1로 표시되는 화합물 또는 각 반응 중간체는 추출, 재결정, 칼럼 크로마토그래피 등과 같은 통상의 방법에 의하여 분리 및 정제할 수 있다.Compounds represented by the formula (1) or each reaction intermediate synthesized by the above preparation method can be separated and purified by conventional methods such as extraction, recrystallization, column chromatography.

또한, 상기 화합물 1로 표시되는 화합물의 약학적 허용 가능한 염은 당 분야에서 널리 알려진 공지 방법에 의해 제조할 수 있는 바, 구아니딘 치환 반응 후에 산 용액으로 간단히 처리함으로써 쉽게 제조할 수 있다.In addition, the pharmaceutically acceptable salt of the compound represented by Compound 1 may be prepared by a known method well known in the art, and can be easily prepared by simply treating with an acid solution after the guanidine substitution reaction.

한편, 본 발명에 따른 상기 화학식 1로 표시되는 1,2,4-옥사디아졸이 치환된 벤조일구아니딘 유도체 및 이의 약제학적으로 허용 가능한 염은 Na+/H+-교환 억제활성이 우수하므로 심경색, 협심증 및 부정맥 등의 각종 심혈관계 질환의 치료 및 예방용 약제로서 매우 유효하다. 따라서, 본 발명은 상기 화학식 1로 표시되는 신규 화합물을 유효성분으로 하는 심혈관계 질환의 치료 및 예방용 약제 조성물을 포함한다. Meanwhile, 1,2,4-oxadiazole-substituted benzoylguanidine derivatives represented by Chemical Formula 1 and pharmaceutically acceptable salts thereof according to the present invention have excellent na + / H + -exchange inhibitory activity, which leads to deep infarction. It is very effective for the treatment and prevention of various cardiovascular diseases such as angina, angina and arrhythmia. Therefore, the present invention includes a pharmaceutical composition for the treatment and prevention of cardiovascular diseases, using the novel compound represented by Formula 1 as an active ingredient.

본 발명에 따른 약제 조성물은 상기 화학식 1로 표시되는 화합물에 통상의 무독성 약제학적으로 허용 가능한 담체, 보강제 및 부형제를 첨가하여 약제학적 분야에서 통상적인 제제 예를 들면 경구용, 주사용, 정맥주사 등 다양한 형태로 제형화하여 질환의 증상에 따라 투여경로를 적당히 할 수 있다. 경구투여에 적합한 제제는 정제, 분말제, 그래뉼제, 캡슐제 등의 고체형 제제; 용액제; 오일성 현탁제; 시럽, 엘릭시르 등과 같은 액제 등이다. 비경구 투여에 적합한 제제는 본 발명의 화합물을 수용성 또는 오일성 현탁액으로 제조하여 주사에 적합하도록 제제화한 것이다. 제제화함에 있어서는, 통상의 부형제, 결합제, 담체, 수용성 용매, 오일성 용매, 유화제, 현탁제 등이 사용될 수 있고, 그밖에도 기타 첨가제 예 를 들면 보존제, 안정제 등이 포함될 수 있다. The pharmaceutical composition according to the present invention is a conventional formulation in the pharmaceutical field, such as oral, injectable, intravenous injection, etc. by adding a conventional non-toxic pharmaceutically acceptable carrier, adjuvant and excipient to the compound represented by the formula (1) It can be formulated in various forms to suit the route of administration depending on the condition of the disease. Formulations suitable for oral administration include solid dosage forms such as tablets, powders, granules, capsules, and the like; Solution; Oily suspensions; Liquids such as syrups and elixirs. Formulations suitable for parenteral administration are those prepared by injection of the compounds of the invention into aqueous or oily suspensions. In formulating, conventional excipients, binders, carriers, water-soluble solvents, oily solvents, emulsifiers, suspending agents and the like may be used, and other additives such as preservatives, stabilizers and the like may be included.

본 발명에 따른 상기 화학식 1로 표시되는 1,2,4-옥사디아졸이 치환된 벤조일구아니딘 유도체의 인체에 대한 투여 용량은 환자의 나이, 몸무게, 성별, 투여형태, 건강상태 및 질환정도에 따라 달라질 수 있으며 일반적으로는 0.01 ∼ 200 mg/kg/day가 바람직하며 의사 또는 약사의 판단에 따라 일정시간 간격으로 1일 수회, 바람직하기로는 1회 내지 6회 분할 투여할 수 있다.The dosage of 1,2,4-oxadiazole-substituted benzoylguanidine derivatives represented by Formula 1 according to the present invention to the human body is dependent on the age, weight, sex, dosage form, health condition and degree of disease of the patient. In general, 0.01 to 200 mg / kg / day is preferable and may be divided into several times a day, preferably 1 to 6 times at regular time intervals according to the judgment of a doctor or pharmacist.

이와 같은 본 발명은 다음의 실시예에 의거하여 더욱 상세히 설명하겠는 바, 본 발명이 이에 한정되는 것은 아니다.Such a present invention will be described in more detail based on the following examples, but the present invention is not limited thereto.

실시예 1. 2-클로로-4-(N-하이드록시카밤이미도일)-벤조산 메틸 에스테르의 합성 Example 1.Synthesis of 2-chloro-4- ( N -hydroxycarbamimidoyl) -benzoic acid methyl ester

2-클로로-4-시아노벤조산 메틸 에스테르 660 mg(3.37 mmol)을 EtOH 30 mL에 용해시키고 하이드록실아민 염화수소 234.18 mg(3.37 mmol, 1.0 eq.)과 Et3N 469.71 μL(3.37 mmol, 1.0 eq.)을 넣고 3시간 가열, 환류하였다. 반응용액을 감압 증류하고 잔류물에 MeOH을 넣어 용해시킨 다음, 불용물은 여과하여 제거하였다. 유기층은 다시 감압 증류하고 잔류물을 컬럼 크로마토그래피(n-Hex.:아세톤=2:1)로 분류하여 상기 화합물의 흰색 고체 650 mg(84.4%)를 얻었다. 660 mg (3.37 mmol) of 2-chloro-4-cyanobenzoic acid methyl ester were dissolved in 30 mL of EtOH, 234.18 mg of hydroxylamine hydrogen chloride (3.37 mmol, 1.0 eq.) And Et 3 N 469.71 μL (3.37 mmol, 1.0 eq) .) Was added and the mixture was heated and refluxed for 3 hours. The reaction solution was distilled under reduced pressure, MeOH was added to the residue to dissolve it, and the insolubles were filtered off. The organic layer was again distilled under reduced pressure and the residue was purified by column chromatography (n -Hex .: acetone = 2: 1) to obtain the classification of white solid 650 mg (84.4%) of the compound.

84.4% yield(white solid); mp 142-143 ℃; IR(KBr) 3492, 3384, 1724, 1639, 1262 cm-1; 1H NMR(300 MHz, DMSO-d 6) δ 10.0(s, 1H, OH), 7.80(m, 3H, benzoyl-H), 6.02(s, 2H, NH2), 3.85(s, 3H, OCH3); 13C NMR(75 MHz, DMSO-d 6) δ 165.4(C=O), 149.1(C=N), 138.0, 132.1, 131.2, 129.8, 127.4, 124.2(benzoyl-C), 52.8(OCH3).84.4% yield (white solid); mp 142-143 ° C; IR (KBr) 3492, 3384, 1724, 1639, 1262 cm −1 ; 1 H NMR (300 MHz, DMSO- d 6 ) δ 10.0 (s, 1H, OH), 7.80 (m, 3H, benzoyl-H), 6.02 (s, 2H, NH 2 ), 3.85 (s, 3H, OCH 3 ) ; 13 C NMR (75 MHz, DMSO- d 6 ) δ 165.4 (C = O), 149.1 (C = N), 138.0, 132.1, 131.2, 129.8, 127.4, 124.2 (benzoyl-C), 52.8 (OCH 3 ).

실시예 2. 4-(N-하이드록시카밤이미도일)벤조산 메틸 에스테르의 합성 Example 2. Synthesis of 4- ( N -hydroxycarbamidomiyl) benzoic Acid Methyl Ester

4-시아노벤조산 메틸 에스테르 2.0 g(12.41 mmol)을 EtOH 50 mL에 용해시키고 하이드록실아민 염화수소 905.45 mg(13.03 mmol, 1.05 eq.)과 Et3N 1.82 mL(13.03 mmol, 1.05 eq.)을 넣고 3시간 가열, 환류하였다. 반응용액을 감압 증류하고 잔류물에 MeOH을 넣어 용해시킨 다음, 불용물은 여과하여 제거하였다. 유기층은 다시 감압 증류하고 잔류물을 컬럼 크로마토그래피(CH2Cl2:MeOH=20:1)로 분류하여 상기 화합물의 흰색 고체 1.9 g(78.8%)를 얻었다. Dissolve 2.0 g (12.41 mmol) of 4-cyanobenzoic acid methyl ester in 50 mL of EtOH, add 905.45 mg (13.03 mmol, 1.05 eq.) Of hydroxylamine hydrogen chloride and 1.82 mL (13.03 mmol, 1.05 eq.) Of Et 3 N. Heated and refluxed for 3 hours. The reaction solution was distilled under reduced pressure, MeOH was added to the residue to dissolve it, and the insolubles were filtered off. The organic layer was distilled under reduced pressure again, and the residue was partitioned by column chromatography (CH 2 Cl 2 : MeOH = 20: 1) to obtain 1.9 g (78.8%) of a white solid of the compound.

78.8% yield(white solid); mp 160-161 ℃; IR(KBr) 3504, 3395, 1716, 1648, 1288 cm-1; 1H NMR(300 MHz, DMSO-d 6) δ 9.90(s, 1H, OH), 7.94(d, 2H, benzoyl-H), 7.82(d, 2H, benzoyl-H), 5.93(s, 2H, NH2), 3.85(s, 3H, OCH3); 13C NMR(75 MHz, DMSO-d 6) δ 166.2(C=O), 150.2(C=N), 138.0, 129.9, 129.2, 128.0, 125.8(benzoyl-C), 52.4(OCH3).78.8% yield (white solid); mp 160-161 ° C; IR (KBr) 3504, 3395, 1716, 1648, 1288 cm -1 ; 1 H NMR (300 MHz, DMSO- d 6 ) δ 9.90 (s, 1H, OH), 7.94 (d, 2H, benzoyl-H), 7.82 (d, 2H, benzoyl-H), 5.93 (s, 2H, NH 2 ), 3.85 (s, 3H, OCH 3 ); 13 C NMR (75 MHz, DMSO- d 6 ) δ 166.2 (C = O), 150.2 (C = N), 138.0, 129.9, 129.2, 128.0, 125.8 (benzoyl-C), 52.4 (OCH 3 ).

실시예 3. 4-(N-하이드록시카밤이미도일)-2-메틸벤조산 메틸 에스테르의 합성 Example 3. Synthesis of 4- ( N -hydroxycarbamidoyl) -2-methylbenzoic acid methyl ester

4-시아노-2-메틸벤조산 메틸 에스테르 418 mg(2.39 mmol)을 EtOH 20 mL에 용해시키고 하이드록실아민 염화수소 174.42 mg(2.51 mmol, 1.05 eq.)과 Et3N 349.84 μL(2.51 mmol, 1.05 eq.)을 넣고 3시간 가열, 환류하였다. 반응용액을 감압 증류하고 잔류물에 MeOH을 넣어 용해시킨 다음, 불용물은 여과하여 제거하였다. 유기층은 다시 감압 증류하고 잔류물을 컬럼 크로마토그래피(CH2Cl2:MeOH=20:1)로 분류하여 상기 화합물의 흰색 고체 330 mg(66.3%)를 얻었다. 418 mg (2.39 mmol) of 4-cyano-2-methylbenzoic acid methyl ester are dissolved in 20 mL of EtOH, 174.42 mg (2.51 mmol, 1.05 eq.) Of hydroxylamine hydrogen chloride and Et 3 N 349.84 μL (2.51 mmol, 1.05 eq) .) Was added and heated to reflux for 3 hours. The reaction solution was distilled under reduced pressure, MeOH was added to the residue to dissolve it, and the insolubles were filtered off. The organic layer was distilled under reduced pressure again, and the residue was partitioned by column chromatography (CH 2 Cl 2 : MeOH = 20: 1) to obtain 330 mg (66.3%) of a white solid of the compound.

66.3% yield(white solid); mp 117-119 ℃; IR(KBr) 3496, 3387, 1708, 1636, 1268 cm-1; 1H NMR(300 MHz, DMSO-d 6) δ 9.83(s, 1H, OH), 7.80(m, 1H, benzoyl-H), 7.61(m, 2H, benzoyl-H), 5.89(s, 2H, NH2), 3.81(s, 3H, OCH3), 2.52(s, 3H, CH 3); 13C NMR(75 MHz, DMSO-d 6) δ 167.2(C=O), 150.1(C=N), 139.3, 136.8, 130.2, 129.5, 128.6, 123.1(benzoyl-C), 52.8(OCH3).66.3% yield (white solid); mp 117-119 ° C; IR (KBr) 3496, 3387, 1708, 1636, 1268 cm −1 ; 1 H NMR (300 MHz, DMSO- d 6 ) δ 9.83 (s, 1H, OH), 7.80 (m, 1H, benzoyl-H), 7.61 (m, 2H, benzoyl-H), 5.89 (s, 2H, NH 2 ), 3.81 (s, 3H, OCH 3 ), 2.52 (s, 3H, CH 3 ); 13 C NMR (75 MHz, DMSO- d 6 ) δ 167.2 (C = O), 150.1 (C = N), 139.3, 136.8, 130.2, 129.5, 128.6, 123.1 (benzoyl-C), 52.8 (OCH 3 ).

실시예 4. 2-클로로-4-(5-피리딘-3-일-[1,2,4]옥사디아졸-3-일)벤조산 메틸 에스테르의 합성 Example 4 Synthesis of 2-chloro-4- (5-pyridin-3-yl- [1,2,4] oxadiazol-3-yl) benzoic acid methyl ester

2-클로로-4-(N-하이드록시카밤이미도일)벤조산 메틸 에스테르 600 mg(2.62 mmol)에 DMF 20 mL을 넣어 용해시키고 니코틴산 322.55 mg(2.62 mmol, 1.0 eq.), EDCI 502.28 mg(2.62 mmol, 1.0 eq.), DMAP 31.76 mg(0.26 mmol, 0.1 eq.)을 넣고 실온에서 18 시간 교반한 다음, 90 ℃에서 3시간 가열하였다. 반응용액을 감압 증류하고 잔류물을 컬럼 크로마토그래피(CH2Cl2:MeOH=25:1)로 분리하여 상기 화합물의 흰색 고체 714 mg(86.3%)를 얻었다. 20 mL of DMF was dissolved in 600 mg (2.62 mmol) of 2-chloro-4- ( N -hydroxycarbamidoyl) benzoic acid methyl ester, 322.55 mg (2.62 mmol, 1.0 eq.) Of nicotinic acid, and 502.28 mg (2.62 mmol) of EDCI. , 1.0 eq.) And 31.76 mg (0.26 mmol, 0.1 eq.) Of DMAP were added and stirred at room temperature for 18 hours, followed by heating at 90 ° C. for 3 hours. The reaction solution was distilled under reduced pressure and the residue was separated by column chromatography (CH 2 Cl 2 : MeOH = 25: 1) to give 714 mg (86.3%) of a white solid of the compound.

86.3% yield(white solid); mp 138-139 ℃; IR(KBr) 3082, 2962, 1735, 1251 cm-1; 1H NMR(300 MHz, CDCl3) δ 9.43(m, 1H, pyridyl-H), 8.85(dd, 1H, pyridyl-H), 8.47(dt, 1H, pyridyl-H), 8.27(d, 1H, benzoyl-H), 8.10(dd, 1H, benzoyl-H), 7.95(d, 1H, benzoyl-H), 7.51(ddd, 1H, pyridyl-H), 3.96(s, 3H, OCH3); 13C NMR(75 MHz, CDCl3) δ 174.2(C-5), 167.3(C-3), 165.4(C=O), 153.6, 149.1, 135.3, 123.9, 120.3(pyridyl-C), 134.4, 132.3, 131.9, 130.5, 129.9, 125.4(benzoyl-C), 52.7(OCH3).86.3% yield (white solid); mp 138-139 ° C; IR (KBr) 3082, 2962, 1735, 1251 cm −1 ; 1 H NMR (300 MHz, CDCl 3 ) δ 9.43 (m, 1H, pyridyl-H), 8.85 (dd, 1H, pyridyl-H), 8.47 (dt, 1H, pyridyl-H), 8.27 (d, 1H, benzoyl- H), 8.10 (dd, 1H, benzoyl-H), 7.95 (d, 1H, benzoyl-H), 7.51 (ddd, 1H, pyridyl-H), 3.96 (s, 3H, OCH 3 ); 13 C NMR (75 MHz, CDCl 3 ) δ 174.2 (C-5), 167.3 (C-3), 165.4 (C = O), 153.6, 149.1, 135.3, 123.9, 120.3 (pyridyl-C), 134.4, 132.3 , 131.9, 130.5, 129.9, 125.4 (benzoyl-C), 52.7 (OCH 3 ).

실시예 5. 2-클로로-4-(5-이소프로필-[1,2,4]옥사디아졸-3-일)벤조산 메틸 에스테르의 합성 Example 5. Synthesis of 2-chloro-4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) benzoic acid methyl ester

2-클로로-4-(N-하이드록시카밤이미도일)벤조산 메틸 에스테르 563 mg(2.46 mmol)에 DMF 20 mL을 넣어 용해시키고 이소부티르산 239.29 μL(2.58 mmol, 1.05 eq.), EDCI 565.54 mg(2.95 mmol, 1.2 eq.), DMAP 30.54 mg(0.25 mmol, 0.1 eq.)을 넣고 실온에서 3시간 교반한 다음, 90 ℃에서 3시간 가열하였다. 반응용액을 감압 증류하고 잔류물을 컬럼 크로마토그래피(n-Hex.:EtOAc=7:1)로 분리하여 상기 화합물의 무색 액체 550 mg(79.6%)을 얻었다. Dissolve 20 mL of DMF in 563 mg (2.46 mmol) of 2-chloro-4- ( N -hydroxycarbamidoyl) benzoic acid methyl ester, dissolve 239.29 μL (2.58 mmol, 1.05 eq.) Of isobutyric acid, and 565.54 mg (2.95) of EDCI. mmol, 1.2 eq.) and DMAP 30.54 mg (0.25 mmol, 0.1 eq.) were added thereto, stirred at room temperature for 3 hours, and heated at 90 ° C. for 3 hours. It was evaporated under reduced pressure the reaction solution to separate the residue by column chromatography (n -Hex.:EtOAc=7:1) to give a colorless liquid 550 mg (79.6%) of the compound.

79.6% yield(colorless oil); IR(neat) 2980, 1738, 1292 cm-1; 1H NMR(300 MHz, CDCl3) δ 8.17(d, 1H, benzoyl-H), 8.00(dd, 1H, benzoyl-H), 7.90(d, 1H, benzoyl-H), 3.93(s, 3H, OCH3), 3.27(m, 1H, CH), 1.44(d, 6H, CH3×2); 13 C NMR(75 MHz, CDCl3) δ 184.6(C-5), 166.5(C-3), 165.6(C=O), 134.3, 131.9, 131.8, 131.1, 129.8, 125.3(benzoyl-C), 52.6(OCH3), 27.5(CH), 20.1(CH3).79.6% yield (colorless oil); IR (neat) 2980, 1738, 1292 cm −1 ; 1 H NMR (300 MHz, CDCl 3 ) δ 8.17 (d, 1H, benzoyl-H), 8.00 (dd, 1H, benzoyl-H), 7.90 (d, 1H, benzoyl-H), 3.93 (s, 3H, OCH 3 ), 3.27 (m, 1H, CH), 1.44 (d, 6H, CH 3 x 2); 13 C NMR (75 MHz, CDCl 3 ) δ 184.6 (C-5), 166.5 (C-3), 165.6 (C = O), 134.3, 131.9, 131.8, 131.1, 129.8, 125.3 (benzoyl-C), 52.6 (OCH 3 ), 27.5 (CH), 20.1 (CH 3 ).

실시예 6. 2-클로로-4-(5-티오펜-3-일-[1,2,4]옥사디아졸-3-일)벤조산 메틸 에스테르의 합성 Example 6 Synthesis of 2-chloro-4- (5-thiophen-3-yl- [1,2,4] oxadiazol-3-yl) benzoic acid methyl ester

2-클로로-4-(N-하이드록시카밤이미도일)벤조산 메틸 에스테르 1.0 g(4.37 mmol)에 DMF 20 mL을 넣어 용해시키고 3-티오펜카르복시산 588.21 mg(4.59 mmol, 1.05 eq.), EDCI 1.0 g(5.24 mmol, 1.2 eq.), DMAP 106.29 mg(0.87 mmol, 0.20 eq.)을 넣고 실온에서 3시간 교반한 다음, 90 ℃에서 3시간 가열하였다. 반응용액을 감압 증류하고 잔류물을 컬럼 크로마토그래피(n-Hex.:EtOAc=5:1)로 분리하여 상기 화합물의 흰색 고체 917 mg(65.4%)을 얻었다. Dissolve 20 mL of DMF in 1.0 g (4.37 mmol) of 2-chloro-4- ( N -hydroxycarbamidoyl) benzoic acid methyl ester, and dissolve 588.21 mg (4.59 mmol, 1.05 eq.) Of 3-thiophenecarboxylic acid, EDCI 1.0 g (5.24 mmol, 1.2 eq.) and 106.29 mg (0.87 mmol, 0.20 eq.) of DMAP were added thereto, stirred at room temperature for 3 hours, and heated at 90 ° C. for 3 hours. It was evaporated under reduced pressure the reaction solution to separate the residue by column chromatography (n -Hex.:EtOAc=5:1) to give a white solid 917 mg (65.4%) of the compound.

65.4% yield(white solid); mp 136-137 ℃; IR(KBr) 3118, 2954, 1737, 1266 cm-1; 1H NMR(300 MHz, CDCl3) δ 8.26(m, 1H, thienyl-H), 8.22(m, 1H, benzoyl-H), 8.04(m, 1H, benzoyl-H), 7.92(d, 1H, benzoyl-H), 7.71(m, 1H, thienyl-H), 7.47(dd, 1H, thienyl-H), 3.94(s, 3H, OCH3); 13C NMR(75 MHz, CDCl3) δ 172.4(C-5), 167.0(C-3), 165.5(C=O), 134.4, 132.0, 131.8, 130.9, 129.9, 125.4(benzoyl-C), 130.6, 127.7, 126.6, 125.3(thienyl-C), 52.6(OCH3). Anal. Calcd for C14H9ClN2O3S: C, 52.42; H, 2.83; N, 8.73; S, 10.00. Found: C, 52.62; H, 2.77; N, 8.83; S, 9.71.65.4% yield (white solid); mp 136-137 ° C; IR (KBr) 3118, 2954, 1737, 1266 cm −1 ; 1 H NMR (300 MHz, CDCl 3 ) δ 8.26 (m, 1H, thienyl-H), 8.22 (m, 1H, benzoyl-H), 8.04 (m, 1H, benzoyl-H), 7.92 (d, 1H, benzoyl-H), 7.71 (m, 1H, thienyl-H), 7.47 (dd, 1H, thienyl-H), 3.94 (s, 3H, OCH 3 ); 13 C NMR (75 MHz, CDCl 3 ) δ 172.4 (C-5), 167.0 (C-3), 165.5 (C = O), 134.4, 132.0, 131.8, 130.9, 129.9, 125.4 (benzoyl-C), 130.6 , 127.7, 126.6, 125.3 (thienyl-C), 52.6 (OCH 3 ). Anal. Calcd for C 14 H 9 ClN 2 O 3 S: C, 52.42; H, 2.83; N, 8.73; S, 10.00. Found: C, 52.62; H, 2.77; N, 8.83; S, 9.71.

실시예 7. 4-(5-피리딘-3-일-[1,2,4]옥사디아졸-3-일)벤조산 메틸 에스테르의 합성 Example 7. Synthesis of 4- (5-pyridin-3-yl- [1,2,4] oxadiazol-3-yl) benzoic acid methyl ester

4-(N-하이드록시카밤이미도일)벤조산 메틸 에스테르 1.50 g(7.72 mmol)을 DMF 25 mL을 넣어 용해시키고 니코틴산 950.41 mg(7.72 mmol, 1.0 eq.), EDCI 1.55 g(8.11 mmol, 1.05 eq.), DMAP 94.07 mg(0.77 mmol, 0.1 eq.)을 넣고 실온에서 3시간 교반한 다음, 90 ℃에서 3시간 가열하였다. 반응용액을 감압 증류하고 잔류물을 아세톤에서 재결정하여 상기 화합물의 흰색 고체 1.40 g(64.5%)을 얻었다. 1.50 g (7.72 mmol) of 4- ( N -hydroxycarbamidoyl) benzoic acid methyl ester was dissolved in 25 mL of DMF, and 950.41 mg (7.72 mmol, 1.0 eq.) Of nicotinic acid and 1.55 g (8.11 mmol, 1.05 eq.) Of nicotinic acid were dissolved. ), 94.07 mg (0.77 mmol, 0.1 eq.) Of DMAP was added thereto, stirred at room temperature for 3 hours, and heated at 90 ° C. for 3 hours. The reaction solution was distilled under reduced pressure and the residue was recrystallized from acetone to obtain 1.40 g (64.5%) of a white solid of the compound.

64.5% yield(white solid); mp 172-173 ℃; IR(KBr) 3011, 2956, 1718, 1612, 1280 cm-1; 1H NMR(300 MHz, CDCl3) δ 9.44(m, 1H, pyridyl-H), 8.85(dd, 1H, pyridyl-H), 8.47(dt, 1H, pyridyl-H), 8.21(m, 4H, benzoyl-H), 7.52(m, 1H, pyridyl-H), 3.97(s, 3H, OCH3); 13C NMR(75 MHz, CDCl3) δ 174.0(C-5), 168.4(C-3), 166.3(C=O), 153.5, 149.2, 135.3, 123.8, 120.5(pyridyl-C), 132.6, 130.5, 130.1, 127.5(benzoyl-C), 52.4(OCH3).64.5% yield (white solid); mp 172-173 ° C; IR (KBr) 3011, 2956, 1718, 1612, 1280 cm −1 ; 1 H NMR (300 MHz, CDCl 3 ) δ 9.44 (m, 1H, pyridyl-H), 8.85 (dd, 1H, pyridyl-H), 8.47 (dt, 1H, pyridyl-H), 8.21 (m, 4H, benzoyl-H), 7.52 (m, 1H, pyridyl-H), 3.97 (s, 3H, OCH 3 ); 13 C NMR (75 MHz, CDCl 3 ) δ 174.0 (C-5), 168.4 (C-3), 166.3 (C = O), 153.5, 149.2, 135.3, 123.8, 120.5 (pyridyl-C), 132.6, 130.5 , 130.1, 127.5 (benzoyl-C), 52.4 (OCH 3 ).

실시예 8. 2-메틸-4-(5-피리딘-3-일-[1,2,4]옥사디아졸-3-일)벤조산 메틸 에스테르의 합성 Example 8. Synthesis of 2-methyl-4- (5-pyridin-3-yl- [1,2,4] oxadiazol-3-yl) benzoic acid methyl ester

4-(N-하이드록시카밤이미도일)-2-메틸벤조산 메틸 에스테르 560 mg(2.69 mmol)을 DMF 25 mL을 넣어 용해시키고 니코틴산 364.41 mg(2.96 mmol, 1.1 eq.), EDCI 540.62 mg(2.82 mmol, 1.05 eq.), DMAP 32.99 mg(0.27 mmol, 0.1 eq.)을 넣고 실온에서 3시간 교반한 다음, 90 ℃에서 3시간 가열하였다. 반응용액을 감압 증류하고 잔류물을 컬럼 크로마토그래피(n-Hex.:EtOAc=3:1)로 분리하여 상기 화합물의 흰색 고체 570 mg(71.8%)을 얻었다. 560 mg (2.69 mmol) of 4- ( N -hydroxycarbamidoyl) -2-methylbenzoic acid methyl ester was dissolved in 25 mL of DMF, and 364.41 mg (2.96 mmol, 1.1 eq.) Of nicotinic acid and 540.62 mg (2.82 mmol) of EDCI , 1.05 eq.) And DMAP 32.99 mg (0.27 mmol, 0.1 eq.) Were added thereto, the mixture was stirred at room temperature for 3 hours, and heated at 90 ° C. for 3 hours. It was evaporated under reduced pressure the reaction solution to separate the residue by column chromatography (n -Hex.:EtOAc=3:1) to give a white solid 570 mg (71.8%) of the compound.

71.8% yield(white solid); mp 122-123 ℃; IR(KBr) 3087, 2979, 1718, 1610, 1265 cm-1; 1H NMR(300 MHz, CDCl3) δ 9.39(m, 1H, pyridyl-H), 8.80(dd, 1H, pyridyl-H), 8.41(dt, 1H, pyridyl-H), 8.00(br s, 1H, benzoyl-H), 7.97(br s, 2H, benzoyl-H), 7.47(dd, 1H, pyridyl-H), 3.88(s, 3H, OCH3), 2.64(s, 3H, CH3); 13C NMR(75 MHz, CDCl3) δ 173.8(C-5), 168.3(C-3), 167.3(C=O), 153.3, 149.1, 135.2, 123.8, 120.5(pyridyl-C), 140.9, 132.0, 131.1, 130.4, 129.3, 124.7(benzoyl-C), 52.8(OCH3), 21.7(CH3).71.8% yield (white solid); mp 122-123 ° C; IR (KBr) 3087, 2979, 1718, 1610, 1265 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ) δ 9.39 (m, 1H, pyridyl-H), 8.80 (dd, 1H, pyridyl-H), 8.41 (dt, 1H, pyridyl-H), 8.00 (br s, 1H , benzoyl-H), 7.97 (br s, 2H, benzoyl-H), 7.47 (dd, 1H, pyridyl-H), 3.88 (s, 3H, OCH 3 ), 2.64 (s, 3H, CH 3 ); 13 C NMR (75 MHz, CDCl 3 ) δ 173.8 (C-5), 168.3 (C-3), 167.3 (C = O), 153.3, 149.1, 135.2, 123.8, 120.5 (pyridyl-C), 140.9, 132.0 , 131.1, 130.4, 129.3, 124.7 (benzoyl-C), 52.8 (OCH 3 ), 21.7 (CH 3 ).

실시예 9. 4-(5-이소프로필-[1,2,4]옥사디아졸-3-일)-2-메틸벤조산 메틸 에스테르의 합성 Example 9. Synthesis of 4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) -2-methylbenzoic acid methyl ester

4-(N-하이드록시카밤이미도일)-2-메틸벤조산 메틸 에스테르 600 mg(2.88 mmol)을 DMF 25 mL을 넣어 용해시키고 이소부티르산 320.87 μL(3.46 mmol, 1.2 eq.), EDCI 578.96 mg(3.02 mmol, 1.05 eq.), DMAP 35.43 mg(0.29 mmol, 0.1 eq.)을 넣고 실온에서 3시간 교반한 다음, 90 ℃에서 3시간 가열하였다. 반응용액을 감압 증류하고 잔류물을 컬럼 크로마토그래피(n-Hex.:EtOAc=5:1)로 분리하여 상기 화합물의 흰색 고체 560 mg(74.7%)을 얻었다. 600 mg (2.88 mmol) of 4- ( N -hydroxycarbamidoyl) -2-methylbenzoic acid methyl ester was dissolved in 25 mL of DMF, and 320.87 μL (3.46 mmol, 1.2 eq.) Of isobutyric acid and 578.96 mg of EDCI (3.02) mmol, 1.05 eq.) and 35.43 mg (0.29 mmol, 0.1 eq.) of DMAP were added thereto, stirred at room temperature for 3 hours, and heated at 90 ° C. for 3 hours. It was evaporated under reduced pressure the reaction solution to separate the residue by column chromatography (n -Hex.:EtOAc=5:1) to give a white solid 560 mg (74.7%) of the compound.

74.7% yield(white solid); mp 39-40 ℃; IR(KBr) 2980, 1718, 1256 cm-1; 1H NMR(300 MHz, CDCl3) δ 7.94(m, 3H, benzoyl-H), 3.88(s, 3H, OCH3), 3.27(m, 1H, CH), 2.63(s, 3H, benzoyl-CH3), 1.44(d, 6H, CH3×2); 13C NMR(75 MHz, CDCl3) δ 184.2(C-5), 167.4(C-3, C=O), 140.8, 131.7, 131.0, 130.4, 130.0, 124.5(benzoyl-C), 52.0(OCH3), 27.5(CH), 21.6(benzoyl-CH3), 20.1(CH3 ).74.7% yield (white solid); mp 39-40 ° C; IR (KBr) 2980, 1718, 1256 cm −1 ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.94 (m, 3H, benzoyl-H), 3.88 (s, 3H, OCH 3 ), 3.27 (m, 1H, CH), 2.63 (s, 3H, benzoyl-CH 3 ), 1.44 (d, 6H, CH 3 x 2); 13 C NMR (75 MHz, CDCl 3 ) δ 184.2 (C-5), 167.4 (C-3, C = O), 140.8, 131.7, 131.0, 130.4, 130.0, 124.5 (benzoyl-C), 52.0 (OCH 3 ), 27.5 (CH), 21.6 (benzoyl-CH 3 ), 20.1 (CH 3 ).

실시예 10. 2-메틸-4-(5-메틸-[1,2,4]옥사디아졸-3-일)벤조산 메틸 에스테르의 합 성 Example 10. Synthesis of 2-methyl-4- (5-methyl- [1,2,4] oxadiazol-3-yl) benzoic acid methyl ester

4-(N-하이드록시카밤이미도일)-2-메틸벤조산 메틸 에스테르 700 mg(3.36 mmol)을 DMF 20 mL을 넣어 용해시키고 아세트산 230.70 μL(4.03 mmol, 1.2 eq.), EDCI 676.74 mg(3.53 mmol, 1.05 eq.), DMAP 41.54 mg(0.34 mmol, 0.1 eq.)을 넣고 실온에서 3시간 교반한 다음, 90 ℃에서 3시간 가열하였다. 반응용액을 감압 증류하고 잔류물을 컬럼 크로마토그래피(n-Hex.:EtOAc=5:1)로 분리하여 상기 화합물의 흰색 고체 500 mg(64.1%)을 얻었다.700 mg (3.36 mmol) of 4- ( N -hydroxycarbamidoyl) -2-methylbenzoic acid methyl ester was dissolved by adding 20 mL of DMF, acetic acid 230.70 μL (4.03 mmol, 1.2 eq.), EDCI 676.74 mg (3.53 mmol) , 1.05 eq.) And 41.54 mg (0.34 mmol, 0.1 eq.) Of DMAP were added and stirred at room temperature for 3 hours, followed by heating at 90 ° C. for 3 hours. The reaction solution was evaporated under reduced pressure and the residue was separated by column chromatography (n -Hex.:EtOAc=5:1) to give a white solid 500 mg (64.1%) of the compound.

64.1% yield(white solid); mp 92-93 ℃; IR(KBr) 3006, 2956, 1720, 1263 cm-1; 1 H NMR(300 MHz, CDCl3) δ 7.92(m, 3H, benzoyl-H), 3.88(s, 3H, OCH3), 2.63(s, 3H, benzoyl-CH3), 2.62(s, 3H, CH3); 13C NMR(75 MHz, CDCl3) δ 176.8(C-5), 167.6(C-3), 167.3(C=O), 140.8, 131.8, 131.1, 130.3, 129.7, 124.5(benzoyl-C), 52.0(OCH3), 21.6(benzoyl-CH3), 12.4(CH3).64.1% yield (white solid); mp 92-93 ° C; IR (KBr) 3006, 2956, 1720, 1263 cm −1 ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.92 (m, 3H, benzoyl-H), 3.88 (s, 3H, OCH 3 ), 2.63 (s, 3H, benzoyl-CH 3 ), 2.62 (s, 3H, CH 3 ); 13 C NMR (75 MHz, CDCl 3 ) δ 176.8 (C-5), 167.6 (C-3), 167.3 (C = O), 140.8, 131.8, 131.1, 130.3, 129.7, 124.5 (benzoyl-C), 52.0 (OCH 3 ), 21.6 (benzoyl-CH 3 ), 12.4 (CH 3 ).

실시예 11. 2-메틸-4-(5-티오펜-3-일-[1,2,4]옥사디아졸-3-일)벤조산 메틸 에스테르의 합성 Example 11.Synthesis of 2-methyl-4- (5-thiophen-3-yl- [1,2,4] oxadiazol-3-yl) benzoic acid methyl ester

4-(N-하이드록시카밤이미도일)-2-메틸벤조산 메틸 에스테르 450 mg(2.16 mmol)을 DMF 20 mL을 넣어 용해시키고 3-티오펜카르복시산 331.91 mg(2.59 mmol, 1.2 eq.), EDCI 435.18 mg(2.27 mmol, 1.05 eq.), DMAP 26.88 mg(0.22 mmol, 0.1 eq.)을 넣고 실온에서 3시간 교반한 다음, 90 ℃에서 3시간 가열하였다. 반응용액을 감압 증류하고 잔류물을 컬럼 크로마토그래피(n-Hex.:AcOEt=6:1)로 분리하여 상기 화합물의 흰색 고체 487 mg(75.1%)을 얻었다. 450 mg (2.16 mmol) of 4- ( N -hydroxycarbamidoyl) -2-methylbenzoic acid methyl ester was dissolved by adding 20 mL of DMF, and 331.91 mg (2.59 mmol, 1.2 eq.) Of 3-thiophenecarboxylic acid, EDCI 435.18 mg (2.27 mmol, 1.05 eq.) and DMAP 26.88 mg (0.22 mmol, 0.1 eq.) were added thereto, stirred at room temperature for 3 hours, and heated at 90 ° C. for 3 hours. It was evaporated under reduced pressure the reaction solution to separate the residue by column chromatography (n -Hex.:AcOEt=6:1) to give a white solid 487 mg (75.1%) of the compound.

75.1% yield(white solid); mp 123-124 ℃; 3107, 2953, 1720, 1599, 1259 cm-1; 1 H NMR(300 MHz, CDCl3) δ 8.27(dd, 1H, thienyl-H), 8.02(m, 3H, benzoyl-H), 7.74(dd, 1H, thienyl-H), 7.48(dd, 1H, thienyl-H), 3.91(s, 3H, OCH3), 2.67(s, 3H, benzoyl-CH3), 2.66(s, 3H, CH3); 13C NMR(75 MHz, CDCl3 ) δ 172.1(C-5), 168.1(C-3), 167.5(C=O), 140.9, 131.9, 131.1, 130.5, 129.8, 124.7(benzoyl-C), 130.4, 127.5, 126.6, 125.7(thienyl-C), 52.0(OCH3), 21.7(CH3).75.1% yield (white solid); mp 123-124 ° C; 3107, 2953, 1720, 1599, 1259 cm −1 ; 1 H NMR (300 MHz, CDCl 3 ) δ 8.27 (dd, 1H, thienyl-H), 8.02 (m, 3H, benzoyl-H), 7.74 (dd, 1H, thienyl-H), 7.48 (dd, 1H, thienyl-H), 3.91 (s, 3H, OCH 3 ), 2.67 (s, 3H, benzoyl-CH 3 ), 2.66 (s, 3H, CH 3 ); 13 C NMR (75 MHz, CDCl 3 ) δ 172.1 (C-5), 168.1 (C-3), 167.5 (C = O), 140.9, 131.9, 131.1, 130.5, 129.8, 124.7 (benzoyl-C), 130.4 , 127.5, 126.6, 125.7 (thienyl-C), 52.0 (OCH 3 ), 21.7 (CH 3 ).

실시예 12. 2-메틸-4-(5-페닐-[1,2,4]옥사디아졸-3-일)벤조산 메틸 에스테르의 합성 Example 12 Synthesis of 2-methyl-4- (5-phenyl- [1,2,4] oxadiazol-3-yl) benzoic acid methyl ester

4-(N-하이드록시카밤이미도일)-2-메틸벤조산 메틸 에스테르 800 mg(3.84 mmol)에 DMF 20 mL을 넣어 용해시키고 벤조산 562.97 mg(4.61 mmol, 1.2 eq.), EDCI 772.59 mg(4.03 mmol, 1.05 eq.), DMAP 46.42 mg(0.38 mmol, 0.1 eq.)을 넣고 실온에서 3시간 교반한 다음, 90 ℃에서 3시간 가열하였다. 반응용액을 감압 증류하고 잔류물을 컬럼 크로마토그래피(n-Hex.:EtOAc=8:1)로 분리하여 상기 화합물의 흰색 고체 800 mg(70.8%)을 얻었다. Dissolve 20 mL of DMF in 800 mg (3.84 mmol) of 4- ( N -hydroxycarbamidoyl) -2-methylbenzoic acid methyl ester, and dissolve 562.97 mg (4.61 mmol, 1.2 eq.) Of benzoic acid and 772.59 mg (4.03 mmol) of EDCI. , 1.05 eq.) And 46.42 mg (0.38 mmol, 0.1 eq.) Of DMAP were added and stirred at room temperature for 3 hours, followed by heating at 90 ° C. for 3 hours. It was evaporated under reduced pressure the reaction solution to separate the residue by column chromatography (n -Hex.:EtOAc=8:1) to give a white solid 800 mg (70.8%) of the compound.

70.8% yield(white solid); mp 109-110 ℃; IR(KBr) 3046 2955, 1725, 1259 cm-1; 1H NMR(300 MHz, CDCl3) δ 8.18(m, 2H, phenyl-H), 8.05(br s, 1H, benzoyl-H), 8.01(m, 2H, benzoyl-H), 7.55(m, 3H, phenyl-H), 3.90(s, 3H, OCH3), 2.67(s, 3H, CH3); 13C NMR(75 MHz, CDCl3) δ 175.9(C-5), 168.2(C-3), 167.4(C=O), 140.8, 131.8, 131.1, 130.5, 129.9, 124.7(benzoyl-C), 132.8, 129.1, 128.1, 124.1(phenyl-C), 52.0(OCH3), 21.7(CH3).70.8% yield (white solid); mp 109-110 ° C; IR (KBr) 3046 2955, 1725, 1259 cm −1 ; 1 H NMR (300 MHz, CDCl 3 ) δ 8.18 (m, 2H, phenyl-H), 8.05 (br s, 1H, benzoyl-H), 8.01 (m, 2H, benzoyl-H), 7.55 (m, 3H , phenyl-H), 3.90 (s, 3H, OCH 3 ), 2.67 (s, 3H, CH 3 ); 13 C NMR (75 MHz, CDCl 3 ) δ 175.9 (C-5), 168.2 (C-3), 167.4 (C = O), 140.8, 131.8, 131.1, 130.5, 129.9, 124.7 (benzoyl-C), 132.8 , 129.1, 128.1, 124.1 (phenyl-C), 52.0 (OCH 3 ), 21.7 (CH 3 ).

실시예 13. 2-메틸-4-(5-퀴놀린-3-일-[1,2,4]옥사디아졸-3-일)벤조산 메틸 에스테르의 합성 Example 13. Synthesis of 2-methyl-4- (5-quinolin-3-yl- [1,2,4] oxadiazol-3-yl) benzoic acid methyl ester

4-(N-하이드록시카밤이미도일)-2-메틸벤조산 메틸 에스테르 700 mg(3.36 mmol)에 DMF 20 mL을 넣어 용해시키고 3-퀴놀린카르복시산 697.88 mg(4.03 mmol, 1.2 eq.), EDCI 676.74 mg(3.53 mmol, 1.05 eq.), DMAP 41.54 mg(0.34 mmol, 0.1 eq.)을 넣고 실온에서 3시간 교반한 다음, 90 ℃에서 3.5시간 가열하였다. 반응용액을 감압 증류하고 잔류물을 벤젠에서 재결정하여 상기 화합물의 흰색 고체 900 mg(77.6%)을 얻었다. To 700 mg (3.36 mmol) of 4- ( N -hydroxycarbamidoyl) -2-methylbenzoic acid methyl ester was dissolved in 20 mL of DMF. 697.88 mg (4.03 mmol, 1.2 eq.) Of 3-quinolinecarboxylic acid and 676.74 mg of EDCI were dissolved. (3.53 mmol, 1.05 eq.) And 41.54 mg (0.34 mmol, 0.1 eq.) Of DMAP were added thereto, stirred at room temperature for 3 hours, and heated at 90 ° C. for 3.5 hours. The reaction solution was distilled under reduced pressure and the residue was recrystallized from benzene to obtain 900 mg (77.6%) of a white solid of the compound.

77.6% yield(white solid); mp 195-196 ℃; IR(KBr) 3046, 2951, 1723, 1621, 1259 cm-1; 1H NMR(300 MHz, CDCl3) δ 9.60(d, 1H, quinolyl-H), 8.94(m, 1H, quinolyl- H), 8.17(br d, 1H, quinolyl-H), 8.04(br s, 1H, benzoyl-H), 8.01(br s, 2H, benzoyl-H), 7.95(br d, 1H, quinolyl-H), 7.83(br t, 1H, quinolyl-H), 7.64(br t, 1H, quinolyl-H), 3.90(s, 3H, OCH3), 2.66(s, 3H, CH3); 13C NMR(75 MHz, CDCl3) δ 174.1(C-5), 168.4(C-3), 167.3(C=O), 140.9, 132.06, 131.1, 130.5, 129.4, 124.7(benzoyl-C), 149.6, 148.1, 136.5, 132.1, 129.7, 128.9, 128.0, 126.8, 117.3(quinolyl-C), 52.0(OCH3), 21.7(CH3).77.6% yield (white solid); mp 195-196 ° C; IR (KBr) 3046, 2951, 1723, 1621, 1259 cm −1 ; 1 H NMR (300 MHz, CDCl 3 ) δ 9.60 (d, 1H, quinolyl-H), 8.94 (m, 1H, quinolyl-H), 8.17 (br d, 1H, quinolyl-H), 8.04 (br s, 1H, benzoyl-H), 8.01 (br s, 2H, benzoyl-H), 7.95 (br d, 1H, quinolyl-H), 7.83 (br t, 1H, quinolyl-H), 7.64 (br t, 1H, quinolyl-H), 3.90 (s, 3H, OCH 3 ), 2.66 (s, 3H, CH 3 ); 13 C NMR (75 MHz, CDCl 3 ) δ 174.1 (C-5), 168.4 (C-3), 167.3 (C = O), 140.9, 132.06, 131.1, 130.5, 129.4, 124.7 (benzoyl-C), 149.6 , 148.1, 136.5, 132.1, 129.7, 128.9, 128.0, 126.8, 117.3 (quinolyl-C), 52.0 (OCH 3 ), 21.7 (CH 3 ).

실시예 14. 4-[5-(2-브로모페닐)-[1,2,4]옥사디아졸-3-일]-2-메틸벤조산 메틸 에스테르의 합성 Example 14. Synthesis of 4- [5- (2-bromophenyl)-[1,2,4] oxadiazol-3-yl] -2-methylbenzoic acid methyl ester

4-(N-하이드록시카밤이미도일)-2-메틸벤조산 메틸 에스테르 700 mg(3.36 mmol)에 DMF 20 mL을 넣어 용해시키고 2-브로모벤조산 810.11 mg(4.03 mmol, 1.2 eq.), EDCI 676.74 mg(3.53 mmol, 1.05 eq.), DMAP 41.54 mg(0.34 mmol, 0.1 eq.)을 넣고 실온에서 3시간 교반한 다음, 90 ℃에서 3시간 가열하였다. 반응용액을 감압 증류하고 잔류물을 컬럼 크로마토그래피(n-Hex.:EtOAc=5:1)로 분리하여 상기 화합물의 흰색 고체 310 mg(24.7%)을 얻었다. To 700 mg (3.36 mmol) of 4- ( N -hydroxycarbamidoyl) -2-methylbenzoic acid methyl ester was dissolved in 20 mL of DMF. 810.11 mg (4.03 mmol, 1.2 eq.) Of 2-bromobenzoic acid, EDCI 676.74 mg (3.53 mmol, 1.05 eq.) and 41.54 mg (0.34 mmol, 0.1 eq.) of DMAP were added thereto, stirred at room temperature for 3 hours, and heated at 90 ° C. for 3 hours. It was evaporated under reduced pressure the reaction solution to separate the residue by column chromatography (n -Hex.:EtOAc=5:1) to give a white solid 310 mg (24.7%) of the compound.

24.7% yield(white solid); mp 104-105 ℃; IR(KBr) 3074, 2976, 1721, 1258 cm-1; 1H NMR(300 MHz, CDCl3) δ 8.05(m, 2H, benzoyl-H, phenyl-H), 8.02(br s, 2H, benzoyl-H), 7.77(m, 1H, phenyl-H), 7.44(m, 2H, phenyl-H), 3.91(s, 3H, OCH3), 2.67(s, 3H, CH3); 13C NMR(75 MHz, CDCl3) δ 175.1(C-5), 168.0(C-3), 167.4(C=O), 140.9, 132.0, 131.1, 130.5, 129.6, 124.7(benzoyl-C), 134.8, 133.2, 132.1, 127.6, 125.5, 122.1(phenyl-C), 52.0(OCH3), 21.7(CH3).24.7% yield (white solid); mp 104-105 ° C; IR (KBr) 3074, 2976, 1721, 1258 cm <-1>; 1 H NMR (300 MHz, CDCl 3 ) δ 8.05 (m, 2H, benzoyl-H, phenyl-H), 8.02 (br s, 2H, benzoyl-H), 7.77 (m, 1H, phenyl-H), 7.44 (m, 2H, phenyl-H), 3.91 (s, 3H, OCH 3 ), 2.67 (s, 3H, CH 3 ); 13 C NMR (75 MHz, CDCl 3 ) δ 175.1 (C-5), 168.0 (C-3), 167.4 (C = O), 140.9, 132.0, 131.1, 130.5, 129.6, 124.7 (benzoyl-C), 134.8 , 133.2, 132.1, 127.6, 125.5, 122.1 (phenyl-C), 52.0 (OCH 3 ), 21.7 (CH 3 ).

실시예 15. 4-[5-(3-브로모페닐)-[1,2,4]옥사디아졸-3-일]-2-메틸벤조산 메틸 에스테르의 합성 Example 15 Synthesis of 4- [5- (3-bromophenyl)-[1,2,4] oxadiazol-3-yl] -2-methylbenzoic acid methyl ester

4-(N-하이드록시카밤이미도일)-2-메틸벤조산 메틸 에스테르 700 mg(3.36 mmol)에 DMF 20 mL을 넣어 용해시키고 3-브로모벤조산 810.11 mg(4.03 mmol, 1.2 eq.), EDCI 676.74 mg(3.53 mmol, 1.05 eq.), DMAP 41.54 mg(0.34 mmol, 0.1 eq.)을 넣고 실온에서 3시간 교반한 다음, 90 ℃에서 3시간 가열하였다. 반응용액을 감압 증류하고 잔류물을 컬럼 크로마토그래피(n-Hex.:EtOAc=5:1)로 분리하여 상기 화합물의 흰색 고체 870 mg(69.4%)을 얻었다. To 700 mg (3.36 mmol) of 4- ( N -hydroxycarbamidoyl) -2-methylbenzoic acid methyl ester was dissolved in 20 mL of DMF. 810.11 mg (4.03 mmol, 1.2 eq.) Of 3-bromobenzoic acid, EDCI 676.74 mg (3.53 mmol, 1.05 eq.) and 41.54 mg (0.34 mmol, 0.1 eq.) of DMAP were added thereto, stirred at room temperature for 3 hours, and heated at 90 ° C. for 3 hours. It was evaporated under reduced pressure the reaction solution to separate the residue by column chromatography (n -Hex.:EtOAc=5:1) to give a white solid 870 mg (69.4%) of the compound.

69.4% yield(white solid); mp 125-127 ℃; IR(KBr) 3063, 2954, 1723, 1257 cm-1; 1H NMR(300 MHz, CDCl3) δ 8.35(m, 1H, phenyl-H), 8.12(m, 1H, phenyl-H), 8.03(br s, 1H, benzoyl-H), 8.00(br s, 2H, benzoyl-H), 7.72(m, 1H, phenyl-H), 7.41(t, 1H, phenyl-H), 3.91(s, 3H, OCH3), 2.67(s, 3H, CH3); 13C NMR(75 MHz, CDCl3) δ 174.5(C-5), 168.3(C-3), 167.4(C=O), 140.9, 132.0, 131.1, 130.5, 129.6, 124.7(benzoyl-C), 135.8, 131.4, 130.7, 126.6, 125.8, 123.2(phenyl-C), 52.1(OCH3), 21.7(CH3); Anal. Calcd for C17H13BrN2 O3: C, 54.71; H, 3.51; N, 7.51. Found: C, 54.71; H, 3.34; N, 7.38.69.4% yield (white solid); mp 125-127 ° C; IR (KBr) 3063, 2954, 1723, 1257 cm −1 ; 1 H NMR (300 MHz, CDCl 3 ) δ 8.35 (m, 1H, phenyl-H), 8.12 (m, 1H, phenyl-H), 8.03 (br s, 1H, benzoyl-H), 8.00 (br s, 2H, benzoyl-H), 7.72 (m, 1H, phenyl-H), 7.41 (t, 1H, phenyl-H), 3.91 (s, 3H, OCH 3 ), 2.67 (s, 3H, CH 3 ); 13 C NMR (75 MHz, CDCl 3 ) δ 174.5 (C-5), 168.3 (C-3), 167.4 (C = O), 140.9, 132.0, 131.1, 130.5, 129.6, 124.7 (benzoyl-C), 135.8 , 131.4, 130.7, 126.6, 125.8, 123.2 (phenyl-C), 52.1 (OCH 3 ), 21.7 (CH 3 ); Anal. Calcd for C 17 H 13 BrN 2 O 3 : C, 54.71; H, 3.51; N, 7.51. Found: C, 54.71; H, 3. 34; N, 7.38.

실시예 16. 4-[5-(4-브로모페닐)-[1,2,4]옥사디아졸-3-일]-2-메틸벤조산 메틸 에스테르의 합성 Example 16 Synthesis of 4- [5- (4-bromophenyl)-[1,2,4] oxadiazol-3-yl] -2-methylbenzoic acid methyl ester

4-(N-하이드록시카밤이미도일)-2-메틸벤조산 메틸 에스테르 700 mg(3.36 mmol)에 DMF 20 mL을 넣어 용해시키고 4-브로모벤조산 810.11 mg(4.03 mmol, 1.2 eq.), EDCI 676.74 mg(3.53 mmol, 1.05 eq.), DMAP 41.54 mg(0.34 mmol, 0.1 eq.)을 넣고 실온에서 3시간 교반한 다음, 90 ℃에서 3시간 가열하였다. 반응용액을 감압 증류하고 잔류물을 컬럼 크로마토그래피(n-Hex.:EtOAc=5:1)로 분리하여 상기 화합물의 흰색 고체 900 mg(71.8%)을 얻었다. To 700 mg (3.36 mmol) of 4- ( N -hydroxycarbamidoyl) -2-methylbenzoic acid methyl ester was added 20 mL of DMF to dissolve. 810.11 mg (4.03 mmol, 1.2 eq.) Of 4-bromobenzoic acid, EDCI 676.74 mg (3.53 mmol, 1.05 eq.) and 41.54 mg (0.34 mmol, 0.1 eq.) of DMAP were added thereto, stirred at room temperature for 3 hours, and heated at 90 ° C. for 3 hours. It was evaporated under reduced pressure the reaction solution to separate the residue by column chromatography (n -Hex.:EtOAc=5:1) to give a white solid 900 mg (71.8%) of the compound.

71.8% yield(white solid); mp 145-146 ℃; IR(KBr) 3040, 2958, 1724, 1258 cm-1; 1H NMR(300 MHz, CDCl3) δ 8.02(m, 5H), 7.68(m, 2H), 3.91(s, 3H, OCH3 ), 2.66(s, 3H, CH3); 13C NMR(75 MHz, CDCl3) δ 175.1(C-5), 168.3(C-3), 167.4(C=O), 140.9, 132.0, 131.1, 130.5, 129.6, 124.7(benzoyl-C), 132.5, 129.5, 127.9, 122.9(phenyl-C), 52.0(OCH3), 21.7(CH3); Anal. Calcd for C17H 13BrN2O3: C, 54.71; H, 3.51; N, 7.51. Found: C, 54.80; H, 3.45; N, 7.44.71.8% yield (white solid); mp 145-146 ° C; IR (KBr) 3040, 2958, 1724, 1258 cm −1 ; 1 H NMR (300 MHz, CDCl 3 ) δ 8.02 (m, 5H), 7.68 (m, 2H), 3.91 (s, 3H, OCH 3 ), 2.66 (s, 3H, CH 3 ); 13 C NMR (75 MHz, CDCl 3 ) δ 175.1 (C-5), 168.3 (C-3), 167.4 (C = O), 140.9, 132.0, 131.1, 130.5, 129.6, 124.7 (benzoyl-C), 132.5 , 129.5, 127.9, 122.9 (phenyl-C), 52.0 (OCH 3 ), 21.7 (CH 3 ); Anal. Calcd for C 17 H 13 BrN 2 O 3 : C, 54.71; H, 3.51; N, 7.51. Found: C, 54.80; H, 3. 45; N, 7.44.

실시예 17. 2-메틸-4-(5-o-토릴-[1,2,4]옥사디아졸-3-일)벤조산 메틸 에스테르의 합성 Example 17 Synthesis of 2-methyl-4- (5- o -tolyl- [1,2,4] oxadiazol-3-yl) benzoic acid methyl ester

4-(N-하이드록시카밤이미도일)-2-메틸벤조산 메틸 에스테르 700 mg(3.36 mmol)에 DMF 20 mL을 넣어 용해시키고 o-톨루엔산 548.68 mg(4.03 mmol, 1.2 eq.), EDCI 676.74 mg(3.53 mmol, 1.2 eq.), DMAP 41.54 mg(0.34 mmol, 0.1 eq.)을 넣고 실온에서 3시간 교반한 다음, 90 ℃에서 3시간 가열하였다. 반응용액을 감압 증류하고 잔류물을 컬럼 크로마토그래피(n-Hex.:EtOAc=5:1)로 분리하여 상기 화합물의 흰색 고체 675 mg(65.2%)을 얻었다. To 700 mg (3.36 mmol) of 4- ( N -hydroxycarbamidoyl) -2-methylbenzoic acid methyl ester was added 20 mL of DMF to dissolve and 548.68 mg (4.03 mmol, 1.2 eq.) Of o- toluic acid, 676.74 mg of EDCI. (3.53 mmol, 1.2 eq.) And 41.54 mg (0.34 mmol, 0.1 eq.) Of DMAP were added thereto, stirred at room temperature for 3 hours, and heated at 90 ° C. for 3 hours. It was evaporated under reduced pressure the reaction solution to separate the residue by column chromatography (n -Hex.:EtOAc=5:1) to give a white solid 675 mg (65.2%) of the compound.

65.2% yield(white solid); mp 90-91 ℃; IR(KBr) 3013, 2969, 1723, 1259 cm-1; 1 H NMR(300 MHz, CDCl3) δ 8.14(m, 1H, tolyl-H), 8.05(br s, 1H, benzoyl-H), 8.01(br s, 2H, benzoyl-H), 7.46(m, 1H, tolyl-H), 7.34(m, 2H, tolyl-H), 3.91(s, 3H, OCH3), 2.76(s, 3H, tolyl-CH3), 2.67(s, 3H, benzoyl-CH 3); 13C NMR(75 MHz, CDCl3) δ 176.6(C-5), 167.8(C-3), 167.4(C=O), 140.8, 131.8, 131.1, 130.5, 130.0, 124.7(benzoyl-C), 139.1, 132.3, 131.9, 130.2, 126.3, 123.2(tolyl-C), 52.0(OCH3), 22.0(tolyl-CH3), 21.7(benzoyl-CH3); Anal. Calcd for C 18H16N2O3: C, 70.12; H, 5.23; N, 9.09. Found: C, 70.15; H, 5.33; N, 9.09.65.2% yield (white solid); mp 90-91 ° C; IR (KBr) 3013, 2969, 1723, 1259 cm <-1>; 1 H NMR (300 MHz, CDCl 3 ) δ 8.14 (m, 1H, tolyl-H), 8.05 (br s, 1H, benzoyl-H), 8.01 (br s, 2H, benzoyl-H), 7.46 (m, 1H, tolyl-H), 7.34 (m, 2H, tolyl-H), 3.91 (s, 3H, OCH 3 ), 2.76 (s, 3H, tolyl - CH 3 ), 2.67 (s, 3H, benzoyl-CH 3 ); 13 C NMR (75 MHz, CDCl 3 ) δ 176.6 (C-5), 167.8 (C-3), 167.4 (C = O), 140.8, 131.8, 131.1, 130.5, 130.0, 124.7 (benzoyl-C), 139.1 , 132.3, 131.9, 130.2, 126.3, 123.2 (tolyl-C), 52.0 (OCH 3 ), 22.0 (tolyl-CH 3 ), 21.7 (benzoyl-CH 3 ); Anal. Calcd for C 18 H 16 N 2 O 3 : C, 70.12; H, 5. 23; N, 9.09. Found: C, 70.15; H, 5. 33; N, 9.09.

실시예 18. 2-메틸-4-(5-m-토릴-[1,2,4]옥사디아졸-3-일)벤조산 메틸 에스테르의 합성 Example 18 Synthesis of 2-methyl-4- (5- m -tolyl- [1,2,4] oxadiazol-3-yl) benzoic acid methyl ester

4-(N-하이드록시카밤이미도일)-2-메틸벤조산 메틸 에스테르 700 mg(3.36 mmol)에 DMF 20 mL을 넣어 용해시키고 m-톨루엔산 548.68 mg(4.03 mmol, 1.2 eq.), EDCI 676.74 mg(3.53 mmol, 1.2 eq.), DMAP 41.54 mg(0.34 mmol, 0.1 eq.)을 넣고 실온에서 3시간 교반한 다음, 90 ℃에서 3시간 가열하였다. 반응용액을 감압 증류하고 잔류물을 컬럼 크로마토그래피(n-Hex.:EtOAc=5:1)로 분리하여 상기 화합물의 흰색 고체 730 mg(70.5%)을 얻었다. To 700 mg (3.36 mmol) of 4- ( N -hydroxycarbamidoyl) -2-methylbenzoic acid methyl ester was added 20 mL of DMF to dissolve. 548.68 mg (4.03 mmol, 1.2 eq.) Of m- toluic acid and ED 676.74 mg (3.53 mmol, 1.2 eq.) And 41.54 mg (0.34 mmol, 0.1 eq.) Of DMAP were added thereto, stirred at room temperature for 3 hours, and heated at 90 ° C. for 3 hours. It was evaporated under reduced pressure the reaction solution to separate the residue by column chromatography (n -Hex.:EtOAc=5:1) to give a white solid 730 mg (70.5%) of the compound.

70.5% yield(white solid); mp 105 ℃; IR(KBr) 3057, 2953, 1729, 1260 cm-1; 1H NMR(300 MHz, CDCl3) δ 8.01(m, 5H, benzoyl-H, tolyl-H), 7.39(m, 2H, tolyl-H), 3.90(s, 3H, OCH3), 2.67(s, 3H, benzoyl-CH3), 2.44(s, 3H, tolyl-CH3 ); 13C NMR(75 MHz, CDCl3) δ 176.1(C-5), 168.2(C-3), 167.4(CO), 140.8, 131.8, 131.1, 130.5, 129.9, 124.6(benzoyl-C), 139.0, 133.7, 129.0, 128.6, 125.3, 123.9(tolyl-C), 52.0(OCH3), 22.0(tolyl-CH3), 21.7(benzoyl-CH3); Anal. Calcd for C 18H16N2O3: C, 70.12; H, 5.23; N, 9.09. Found: C, 70.15; H, 5.25; N, 9.07.70.5% yield (white solid); mp 105 ° C; IR (KBr) 3057, 2953, 1729, 1260 cm −1 ; 1 H NMR (300 MHz, CDCl 3 ) δ 8.01 (m, 5H, benzoyl-H, tolyl-H), 7.39 (m, 2H, tolyl-H), 3.90 (s, 3H, OCH 3 ), 2.67 (s , 3H, benzoyl-CH 3 ), 2.44 (s, 3H, tolyl-CH 3 ); 13 C NMR (75 MHz, CDCl 3 ) δ 176.1 (C-5), 168.2 (C-3), 167.4 (CO), 140.8, 131.8, 131.1, 130.5, 129.9, 124.6 (benzoyl-C), 139.0, 133.7 , 129.0, 128.6, 125.3, 123.9 (tolyl-C), 52.0 (OCH 3 ), 22.0 (tolyl-CH 3 ), 21.7 (benzoyl-CH 3 ); Anal. Calcd for C 18 H 16 N 2 O 3 : C, 70.12; H, 5. 23; N, 9.09. Found: C, 70.15; H, 5. 25; N, 9.07.

실시예 19. 2-메틸-4-(5-p-토릴-[1,2,4]옥사디아졸-3-일)벤조산 메틸 에스테르의 합성 Example 19 Synthesis of 2-methyl-4- (5- p -tolyl- [1,2,4] oxadiazol-3-yl) benzoic acid methyl ester

4-(N-하이드록시카밤이미도일)-2-메틸벤조산 메틸 에스테르 700 mg(3.36 mmol)에 DMF 20 mL을 넣어 용해시키고 p-톨루엔산 548.68 mg(4.03 mmol, 1.2 eq.), EDCI 676.74 mg(3.53 mmol, 1.2 eq.), DMAP 41.54 mg(0.34 mmol, 0.1 eq.)을 넣고 실온에서 3시간 교반한 다음, 90 ℃에서 3시간 가열하였다. 반응용액을 감압 증류하고 잔류물을 컬럼 크로마토그래피(n-Hex.:EtOAc=5:1)로 분리하여 상기 화합물의 흰색 고체 620 mg(59.8%)을 얻었다.To 700 mg (3.36 mmol) of 4- ( N -hydroxycarbamidoyl) -2-methylbenzoic acid methyl ester was added 20 mL of DMF to dissolve. 548.68 mg (4.03 mmol, 1.2 eq.) Of p- toluic acid and 676.74 mg of EDCI. (3.53 mmol, 1.2 eq.) And 41.54 mg (0.34 mmol, 0.1 eq.) Of DMAP were added thereto, stirred at room temperature for 3 hours, and heated at 90 ° C. for 3 hours. It was evaporated under reduced pressure the reaction solution to separate the residue by column chromatography (n -Hex.:EtOAc=5:1) to give a white solid 620 mg (59.8%) of the compound.

59.8% yield(white solid); mp 111-112 ℃; IR(KBr) 3032, 2972, 1718. 1257 cm-1; 1H NMR(300 MHz, CDCl3) δ 8.08(d, 2H, tolyl-H), 8.04(br s, 1H, benzoyl-H), 8.00(br s, 2H, benzoyl-H), 7.33(d, 2H, tolyl-H), 3.90(s, 3H, OCH3), 2.67(s, 3H, benzoyl-CH3), 2.43(s, 3H, tolyl-CH3); 13C NMR(75 MHz, CDCl 3) δ 176.1(C-5), 168.1(C-3), 167.5(CO), 140.8, 131.8, 131.1, 130.5, 130.0, 124.7(benzoyl-C), 143.7, 129.8, 128.1, 121.3(tolyl-C), 52.0(OCH3), 21.8(tolyl-CH3), 21.7(benzoyl-CH3); Anal. Calcd for C18H16N2O3 : C, 70.12; H, 5.23; N, 9.09. Found: C, 70.27; H, 5.24; N, 9.10.59.8% yield (white solid); mp 111-112 ° C; IR (KBr) 3032, 2972, 1718 1257 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ) δ 8.08 (d, 2H, tolyl-H), 8.04 (br s, 1H, benzoyl-H), 8.00 (br s, 2H, benzoyl-H), 7.33 (d, 2H, tolyl-H), 3.90 (s, 3H, OCH 3 ), 2.67 (s, 3H, benzoyl-CH 3 ), 2.43 (s, 3H, tolyl-CH 3 ); 13 C NMR (75 MHz, CDCl 3 ) δ 176.1 (C-5), 168.1 (C-3), 167.5 (CO), 140.8, 131.8, 131.1, 130.5, 130.0, 124.7 (benzoyl-C), 143.7, 129.8 , 128.1, 121.3 (tolyl-C), 52.0 (OCH 3 ), 21.8 (tolyl-CH 3 ), 21.7 (benzoyl-CH 3 ); Anal. Calcd for C 18 H 16 N 2 O 3 : C, 70.12; H, 5. 23; N, 9.09. Found: C, 70.27; H, 5. 24; N, 9.10.

실시예 20. 4-[5-(2-시아노페닐)-[1,2,4]옥사디아졸-3-일]-2-메틸벤조산 메틸 에스테르의 합성 Example 20 Synthesis of 4- [5- (2-cyanophenyl)-[1,2,4] oxadiazol-3-yl] -2-methylbenzoic acid methyl ester

4-(N-하이드록시카밤이미도일)-2-메틸벤조산 메틸 에스테르 700 mg(3.36 mmol)에 DMF 20 mL을 넣어 용해시키고 2-시아노벤조산 592.93 mg(4.03 mmol, 1.2 eq.), EDCI 676.74 mg(3.53 mmol, 1.2 eq.), DMAP 41.54 mg(0.34 mmol, 0.1 eq.)을 넣고 실온에서 3시간 교반한 다음, 90 ℃에서 3시간 가열하였다. 반응용액을 감압 증류하고 잔류물을 컬럼 크로마토그래피(n-Hex.:EtOAc=5:1)로 분리하여 상기 화합물의 흰색 고체 800 mg(74.6%)을 얻었다.To 700 mg (3.36 mmol) of 4- ( N -hydroxycarbamidoyl) -2-methylbenzoic acid methyl ester was dissolved in 20 mL of DMF, 592.93 mg (4.03 mmol, 1.2 eq.) Of 2-cyanobenzoic acid, EDCI 676.74 mg (3.53 mmol, 1.2 eq.) and 41.54 mg (0.34 mmol, 0.1 eq.) of DMAP were added thereto, stirred at room temperature for 3 hours, and heated at 90 ° C. for 3 hours. It was evaporated under reduced pressure the reaction solution to separate the residue by column chromatography (n -Hex.:EtOAc=5:1) to give a white solid 800 mg (74.6%) of the compound.

74.6% yield(white solid); mp 169-170 ℃; IR(KBr) 3068, 2966, 2236, 1720, 1262 cm-1; 1H NMR(300 MHz, CDCl3) δ 8.52(m, 1H, phenyl-H), 8.44(dt, 1H, phenyl-H), 8.05(br s, 1H, benzoyl-H), 8.02(br s, 2H, benzoyl-H), 7.89(dt, 1H, phenyl-H), 7.70(t, 1H, phenyl-H), 3.92(s, 3H, OCH3), 2.68(s, 3H, CH3); 13C NMR(75 MHz, CDCl3) δ 173.8(C-5), 168.5(C-3), 167.3(C=O), 140.9, 132.2, 131.1, 130.5, 129.2, 124.7(benzoyl-C), 135.8, 131.9, 131.6, 130.2, 125.3, 117.4(phenyl-C), 113.8(CN), 52.1(OCH3), 21.7(CH3); Anal. Calcd for C18H13 N3O3: C, 67.71; H, 4.10; N, 13.16. Found: C, 67.86; H, 4.13; N, 13.52.74.6% yield (white solid); mp 169-170 ° C; IR (KBr) 3068, 2966, 2236, 1720, 1262 cm −1 ; 1 H NMR (300 MHz, CDCl 3 ) δ 8.52 (m, 1H, phenyl-H), 8.44 (dt, 1H, phenyl-H), 8.05 (br s, 1H, benzoyl-H), 8.02 (br s, 2H, benzoyl-H), 7.89 (dt, 1H, phenyl-H), 7.70 (t, 1H, phenyl-H), 3.92 (s, 3H, OCH 3 ), 2.68 (s, 3H, CH 3 ); 13 C NMR (75 MHz, CDCl 3 ) δ 173.8 (C-5), 168.5 (C-3), 167.3 (C = O), 140.9, 132.2, 131.1, 130.5, 129.2, 124.7 (benzoyl-C), 135.8 , 131.9, 131.6, 130.2, 125.3, 117.4 (phenyl-C), 113.8 (CN), 52.1 (OCH 3 ), 21.7 (CH 3 ); Anal. Calcd for C 18 H 13 N 3 O 3 : C, 67.71; H, 4.10; N, 13.16. Found: C, 67.86; H, 4.13; N, 13.52.

실시예 21. 4-[5-(6-클로로피리딘-3-일)-[1,2,4]옥사디아졸-3-일]-2-메틸벤조산 메틸 에스테르의 합성 Example 21. Synthesis of 4- [5- (6-chloropyridin-3-yl)-[1,2,4] oxadiazol-3-yl] -2-methylbenzoic acid methyl ester

4-(N-하이드록시카밤이미도일)-2-메틸벤조산 메틸 에스테르 700 mg(3.36 mmol)에 DMF 20 mL을 넣어 용해시키고 6-클로로니코틴산 634.97 mg(4.03 mmol, 1.2 eq.), EDCI 676.74 mg(3.53 mmol, 1.2 eq.), DMAP 41.54 mg(0.34 mmol, 0.1 eq.)을 넣고 실온에서 3시간 교반한 다음, 90 ℃에서 3시간 가열하였다. 반응용액을 감압 증류하고 잔류물을 컬럼 크로마토그래피(n-Hex.:EtOAc=5:1)로 분리하여 상기 화합물의 흰색 고체 730 mg(65.9%)을 얻었다. To 700 mg (3.36 mmol) of 4- ( N -hydroxycarbamidoyl) -2-methylbenzoic acid methyl ester was dissolved in 20 mL of DMF. 6-chloronicotinic acid 634.97 mg (4.03 mmol, 1.2 eq.), EDCI 676.74 mg (3.53 mmol, 1.2 eq.) And 41.54 mg (0.34 mmol, 0.1 eq.) Of DMAP were added thereto, stirred at room temperature for 3 hours, and heated at 90 ° C. for 3 hours. It was evaporated under reduced pressure the reaction solution to separate the residue by column chromatography (n -Hex.:EtOAc=5:1) to give a white solid 730 mg (65.9%) of the compound.

65.9% yield(white solid); mp 134-135 ℃; IR(KBr) 3090, 2951, 1726, 1252cm-1; 1H NMR(300 MHz, CDCl3) δ 9.18(d, 1H, pyridyl-H), 8.39(dd, 1H, pyridyl-H), 8.01(br s, 1H, benzoyl-H), 7.99(br s, 2H, benzoyl-H), 7.52(d, 1H, pyridyl-H), 3.90(s, 3H, OCH3), 2.66(s, 3H, CH3); 13C NMR(75 MHz, CDCl3 ) δ 173.0(C-5), 168.4(C-3), 167.3(C=O), 155.6, 149.2, 137.6, 124.9, 119.4(pyridyl-C), 140.9, 132.2, 131.1, 130.5, 129.1, 124.7(benzoyl-C), 52.1(OCH3), 21.7(CH3).65.9% yield (white solid); mp 134-135 ° C; IR (KBr) 3090, 2951, 1726, 1252 cm −1 ; 1 H NMR (300 MHz, CDCl 3 ) δ 9.18 (d, 1H, pyridyl-H), 8.39 (dd, 1H, pyridyl-H), 8.01 (br s, 1H, benzoyl-H), 7.99 (br s, 2H, benzoyl-H), 7.52 (d, 1H, pyridyl-H), 3.90 (s, 3H, OCH 3 ), 2.66 (s, 3H, CH 3 ); 13 C NMR (75 MHz, CDCl 3 ) δ 173.0 (C-5), 168.4 (C-3), 167.3 (C = O), 155.6, 149.2, 137.6, 124.9, 119.4 (pyridyl-C), 140.9, 132.2 , 131.1, 130.5, 129.1, 124.7 (benzoyl-C), 52.1 (OCH 3 ), 21.7 (CH 3 ).

실시예 22. 2-메틸-4-[5-(6-메틸피리딘-3-일)-[1,2,4]옥사디아졸-3-일]벤조산 메틸 에스테르의 합성 Example 22. Synthesis of 2-methyl-4- [5- (6-methylpyridin-3-yl)-[1,2,4] oxadiazol-3-yl] benzoic acid methyl ester

4-(N-하이드록시카밤이미도일)-2-메틸벤조산 메틸 에스테르 700 mg(3.36 mmol)에 DMF 20 mL을 넣어 용해시키고 6-메틸니코틴산 552.67 mg(4.03 mmol, 1.2 eq.), EDCI 676.74 mg(3.53 mmol, 1.2 eq.), DMAP 41.54 mg(0.34 mmol, 0.1 eq.)을 넣고 실온에서 3시간 교반한 다음, 90 ℃에서 3시간 가열하였다. 반응용액을 감압 증류하고 잔류물을 컬럼 크로마토그래피(n-Hex.:EtOAc=5:1)로 분리하여 상기 화합물의 흰색 고체 900 mg(86.6%)을 얻었다.To 700 mg (3.36 mmol) of 4- ( N -hydroxycarbamidoyl) -2-methylbenzoic acid methyl ester was added 20 mL of DMF to dissolve. 6-methylnicotinic acid 552.67 mg (4.03 mmol, 1.2 eq.), EDCI 676.74 mg (3.53 mmol, 1.2 eq.) And 41.54 mg (0.34 mmol, 0.1 eq.) Of DMAP were added thereto, stirred at room temperature for 3 hours, and heated at 90 ° C. for 3 hours. It was evaporated under reduced pressure the reaction solution to separate the residue by column chromatography (n -Hex.:EtOAc=5:1) to give a white solid 900 mg (86.6%) of the compound.

86.6% yield(white solid); mp 110-111 ℃; IR(KBr) 3059, 2945, 1716, 1257 cm-1; 1H NMR(300 MHz, CDCl3) δ 9.31(m, 1H, pyridyl-H), 8.34(dd, 1H, pyridyl-H), 8.05(br s, 1H, benzoyl-H), 8.02(br s, 2H, benzoyl-H), 7.35(d, 1H, pyridyl-H), 3.91(s, 3H, OCH3), 2.68(s, 3H, pyridyl-CH3), 2.67(s, 3H, benzoyl-CH3 ); 13C NMR(75 MHz, CDCl3) δ 174.2(C-5), 168.2(C-3), 167.4(C=O), 140.9, 132.0, 131.1, 130.5, 129.5, 124.7(benzoyl-C), 163.3, 148.6, 135.4, 123.5, 117.8(pyridyl-C), 52.0(OCH3), 24.8(pyridyl-CH3), 21.6(benzoyl-CH3).86.6% yield (white solid); mp 110-111 ° C; IR (KBr) 3059, 2945, 1716, 1257 cm −1 ; 1 H NMR (300 MHz, CDCl 3 ) δ 9.31 (m, 1H, pyridyl-H), 8.34 (dd, 1H, pyridyl-H), 8.05 (br s, 1H, benzoyl-H), 8.02 (br s, 2H, benzoyl-H), 7.35 (d, 1H, pyridyl-H), 3.91 (s, 3H, OCH 3 ), 2.68 (s, 3H, pyridyl-CH 3 ), 2.67 (s, 3H, benzoyl-CH 3 ); 13 C NMR (75 MHz, CDCl 3 ) δ 174.2 (C-5), 168.2 (C-3), 167.4 (C = O), 140.9, 132.0, 131.1, 130.5, 129.5, 124.7 (benzoyl-C), 163.3 , 148.6, 135.4, 123.5, 117.8 (pyridyl-C), 52.0 (OCH 3 ), 24.8 (pyridyl-CH 3 ), 21.6 (benzoyl-CH 3 ).

실시예 23. N-[2-클로로-4-(5-피리딘-3-일-[1,2,4]옥사디아졸-3-일)-벤조일]구아니딘의 합성 Example 23 Synthesis of N- [2-Chloro-4- (5-pyridin-3-yl- [1,2,4] oxadiazol-3-yl) -benzoyl] guanidine

질소 기류하에서 구아니딘 염화수소 207.30 mg(2.17 mmol, 1.2 eq.)에 DMF 10 mL을 넣어 용해시키고 여기에 칼륨 tert-부톡사이드 243.52 mg(2.17 mmol, 1.2 eq.)을 넣어 50 ℃에서 20분 교반하였다. 반응용액을 여과하여 불용물을 제거하고 여액을 2-클로로-4-(5-피리딘-3-일-[1,2,4]옥사디아졸-3-일)벤조산 메틸 에스테르(570 mg, 1.81 mmol)의 DMF 용액(10 mL)에 넣고 70 ℃에서 2 시간 가열하였다. 반응용액을 감압 증류하고 잔류물을 컬럼 크로마토그래피(CH2Cl2:MeOH=10:1)로 분리하여 상기 화합물의 흰색 고체 115 mg(18.5%)을 얻었다. Under nitrogen stream, 10 mL of DMF was added to 207.30 mg (2.17 mmol, 1.2 eq.) Of guanidine hydrogen chloride, and 243.52 mg (2.17 mmol, 1.2 eq.) Of potassium tert -butoxide was added thereto and stirred at 50 ° C. for 20 minutes. The reaction solution was filtered to remove insolubles and the filtrate was purified by 2-chloro-4- (5-pyridin-3-yl- [1,2,4] oxadiazol-3-yl) benzoic acid methyl ester (570 mg, 1.81). mmol) in DMF solution (10 mL) and heated at 70 ° C for 2 h. The reaction solution was distilled under reduced pressure and the residue was separated by column chromatography (CH 2 Cl 2 : MeOH = 10: 1) to give 115 mg (18.5%) of a white solid of the compound.

18.5% yield(white solid); mp 257-258 ℃; IR(KBr) 3412, 3258, 3049, 1663, 1612 cm-1; 1H NMR(300 MHz, DMSO-d 6) δ 9.34(m, 1H, pyridyl-H), 8.89(dd, 1H, pyridyl-H), 8.56(dt, 1H, pyridyl-H), 8.04(m, 3H, benzoyl-H), 7.70(dd, 1H, pyridyl-H), 6.83(br s, NH2); 13C NMR(75 MHz, DMSO-d 6) δ 176.2(C=O), 174.3(C-5), 167.3(C-3), 163.0(C=N), 154.0, 148.8, 135.9, 124.7, 120.1(pyridyl-C), 143.6, 130.8, 130.3, 128.1, 126.9, 125.6(benzoyl-C); HRMS m/z calcd for C15H11ClN 6O2(M)+ 342.0632, found 342.0625.18.5% yield (white solid); mp 257-258 ° C; IR (KBr) 3412, 3258, 3049, 1663, 1612 cm −1 ; 1 H NMR (300 MHz, DMSO- d 6 ) δ 9.34 (m, 1H, pyridyl-H), 8.89 (dd, 1H, pyridyl-H), 8.56 (dt, 1H, pyridyl-H), 8.04 (m, 3H, benzoyl-H), 7.70 (dd, 1H, pyridyl-H), 6.83 (br s, NH 2 ); 13 C NMR (75 MHz, DMSO- d 6 ) δ 176.2 (C = O), 174.3 (C-5), 167.3 (C-3), 163.0 (C = N), 154.0, 148.8, 135.9, 124.7, 120.1 (pyridyl-C), 143.6, 130.8, 130.3, 128.1, 126.9, 125.6 (benzoyl-C); HRMS m / z calcd for C 15 H 11 ClN 6 O 2 (M) + 342.0632, found 342.0625.

실시예 24. N-[2-클로로-4-(5-이소프로필-[1,2,4]-옥사디아졸-3-일)-벤조일]구아니딘 메탄설포네이트의 합성 Example 24. Synthesis of N- [2-chloro-4- (5-isopropyl- [1,2,4] -oxadiazol-3-yl) -benzoyl] guanidine methanesulfonate

질소 기류하에서 구아니딘 염화수소 299.96 mg(3.14 mmol, 2.0 eq.)에 DMF와 1,4-디옥산의 혼합용액 5 mL(1:1)을 넣어 용해시키고 여기에 칼륨 tert-부톡사이드 352.37 mg(3.14 mmol, 2.0 eq.)을 넣어 50 ℃에서 20분 교반하였다. 반응용액을 여과하여 불용물을 제거하고 여액을 2-클로로-4-(5-이소프로필-3-일-[1,2,4]옥사디아졸-3-일)벤조산 메틸 에스테르(440 mg, 1.57 mmol)의 DMF 용액(5 mL)에 넣고 70 ℃에서 18시간 가열하였다. 반응용액을 감압 증류하고 잔류물을 컬럼 크로 마토그래피(CH2Cl2:MeOH=10:1)로 분리하여 N-[2-클로로-4-(5-이소프로필-[1,2,4]옥사디아졸-3-일)-벤조일]구아니딘 300 mg(0.97 mmol)을 얻었다. 얻어진 화합물에 아세톤 5 mL을 넣어 용해시키고 메탄설폰산 75.32 μL(1.16 mmol)을 넣어 실온에서 30분 교반하였다. 생성된 화합물을 여과하여 상기 화합물의 흰색 고체 306 mg(48.3%)을 얻었다. 5 mL (1: 1) of a mixed solution of DMF and 1,4-dioxane was dissolved in 299.96 mg (3.14 mmol, 2.0 eq.) Of guanidine hydrogen chloride under nitrogen stream, and 352.37 mg (3.14 mmol) of potassium tert -butoxide was added thereto. , 2.0 eq.) Was added and stirred at 50 ° C. for 20 minutes. The reaction solution was filtered to remove insolubles and the filtrate was purified by 2-chloro-4- (5-isopropyl-3-yl- [1,2,4] oxadiazol-3-yl) benzoic acid methyl ester (440 mg, 1.57 mmol) was added to a DMF solution (5 mL) and heated at 70 ° C. for 18 hours. The reaction solution was distilled under reduced pressure, and the residue was separated by column chromatography (CH 2 Cl 2 : MeOH = 10: 1) to give N- [2-chloro-4- (5-isopropyl- [1,2,4] 300 mg (0.97 mmol) of oxadiazol-3-yl) -benzoyl] guanidine was obtained. 5 mL of acetone was added to the obtained compound, and 75.32 μL (1.16 mmol) of methanesulfonic acid was added thereto, followed by stirring at room temperature for 30 minutes. The resulting compound was filtered to give 306 mg (48.3%) of a white solid of the compound.

48.3% yield(white solid); mp 196-197 ℃; IR(KBr) 3359, 3123, 2985, 1715, 1699, 1177 cm-1; 1H NMR(300 MHz, DMSO-d 6) δ 12.0(s, 1H, SO 3H), 8.68(br s, NH2), 8.36(br s, NH2), 8.10(m, 2H, benzoyl-H), 7.91(m, 1H, benzoyl-H), 3.37(m, 1H, CH), 2.39(s, 3H, CH3SO3H), 1.38(d, 6H, CH3×2); 13C NMR(75 MHz, DMSO-d 6) δ 185.1(C-5), 166.9(C=O), 166.0(C-3), 154.6(C=N), 135.6, 131.3, 130.9, 130.6, 128.3, 126.1(benzoyl-C), 39.9(CH3SO3H), 27.1(CH), 20.0(CH3). Anal. Calcd for C14H18ClN5O5S: C, 41.64; H, 4.49; N, 17.34; S, 7.94. Found: C, 41.76; H, 4.50; N, 17.44; S, 7.83.48.3% yield (white solid); mp 196-197 ° C; IR (KBr) 3359, 3123, 2985, 1715, 1699, 1177 cm −1 ; 1 H NMR (300 MHz, DMSO- d 6 ) δ 12.0 (s, 1H, SO 3 H), 8.68 (br s, NH 2 ), 8.36 (br s, NH 2 ), 8.10 (m, 2H, benzoyl- H), 7.91 (m, 1H, benzoyl-H), 3.37 (m, 1H, CH), 2.39 (s, 3H, CH 3 SO 3 H), 1.38 (d, 6H, CH 3 x 2); 13 C NMR (75 MHz, DMSO- d 6 ) δ 185.1 (C-5), 166.9 (C = O), 166.0 (C-3), 154.6 (C = N), 135.6, 131.3, 130.9, 130.6, 128.3 , 126.1 (benzoyl-C), 39.9 (CH 3 SO 3 H), 27.1 (CH), 20.0 (CH 3 ). Anal. Calcd for C 14 H 18 ClN 5 O 5 S: C, 41.64; H, 4. 49; N, 17.34; S, 7.94. Found: C, 41.76; H, 4.50; N, 17.44; S, 7.83.

실시예 25. N-[2-클로로-4-(5-티오펜-3-일-[1,2,4]옥사디아졸-3-일)-벤조일]구아니딘 메탄설포네이트의 합성 Example 25 Synthesis of N- [2-Chloro-4- (5-thiophen-3-yl- [1,2,4] oxadiazol-3-yl) -benzoyl] guanidine methanesulfonate

질소 기류하에서 구아니딘 염화수소 447.08 mg(4.68 mmol, 2.0 eq.)에 DMF와 1,4-디옥산의 혼합용액 8 mL(1:1)을 넣어 용해시키고 여기에 칼륨 tert-부톡사이드 525.19 mg(4.68 mmol, 2.0 eq.)을 넣어 50 ℃에서 20분 교반하였다. 반응용액을 여과하여 불용물을 제거하고 여액을 2-클로로-4-(5-티오펜-3-일-[1,2,4]옥사디아졸-3-일)벤조산 메틸 에스테르(750 mg, 2.34 mmol)의 DMF 용액(10 mL)에 넣고 70 ℃에서 12시간 가열하였다. 반응용액을 감압 증류하고 잔류물을 컬럼 크로마토그래피(CH2Cl2:MeOH=10:1)로 분리하여 N-[2-클로로-4-(5-티오펜-3-일-[1,2,4]옥사디아졸-3-일)-벤조일]구아니딘 508 mg(1.46 mmol)을 얻었다. 얻어진 화합물에 아세톤 5 mL을 넣어 용해시키고 메탄설폰산 113.63 μL(1.75 mmol)을 넣어 실온에서 30분 교반하였다. 생성된 화합물을 여과하여 상기 화합물의 흰색 고체 482 mg(46.4%)을 얻었다. 8 mL (1: 1) of a mixed solution of DMF and 1,4-dioxane was dissolved in 447.08 mg (4.68 mmol, 2.0 eq.) Of guanidine hydrogen chloride under nitrogen stream, and 525.19 mg (4.68 mmol) of potassium tert -butoxide was added thereto. , 2.0 eq.) Was added and stirred at 50 ° C. for 20 minutes. The reaction solution was filtered to remove insolubles and the filtrate was purified by 2-chloro-4- (5-thiophen-3-yl- [1,2,4] oxadiazol-3-yl) benzoic acid methyl ester (750 mg, 2.34 mmol) in a DMF solution (10 mL) and heated at 70 ° C. for 12 hours. The reaction solution was evaporated under reduced pressure, and the residue was separated by column chromatography (CH 2 Cl 2 : MeOH = 10: 1) to give N- [2-chloro-4- (5-thiophen-3-yl- [1,2 , 4] oxadiazol-3-yl) -benzoyl] guanidine 508 mg (1.46 mmol) were obtained. 5 mL of acetone was added to the obtained compound, and 113.63 μL (1.75 mmol) of methanesulfonic acid was added thereto, followed by stirring at room temperature for 30 minutes. The resulting compound was filtered to give 482 mg (46.4%) of a white solid of the compound.

46.4% yield(white solid); mp 267-268 ℃; IR(KBr) 3352, 3111, 1722, 1707, 1207 cm-1; 1H NMR(300 MHz, DMSO-d 6) δ 12.1(s, 1H, SO3 H), 8.73(br s, NH2), 8.67(m, 1H, thienyl-H), 8.41(br s, NH2), 8.15(m, 2H, benzoyl-H), 7.94(m, 1H, benzoyl-H), 7.87(dd, 1H, thienyl-H), 7.73(m, 1H, thienyl-H); 13C NMR(75 MHz, DMSO-d 6 ) δ 172.6(C-5), 166.9(C=O), 166.7(C-3), 154.6(C=N), 135.7, 131.4, 130.9, 130.5, 128.4, 126.2(benzoyl-C), 132.8, 129.7, 126.5, 124.6(thienyl-C), 39.9(CH3SO3H).; Anal. Calcd for C15H14ClN5O 5S2: C, 40.59; H, 3.18; N, 15.78; S, 14.45. Found: C, 40.66; H, 3.12; N, 15.73; S, 14.24.46.4% yield (white solid); mp 267-268 ° C; IR (KBr) 3352, 3111, 1722, 1707, 1207 cm −1 ; 1 H NMR (300 MHz, DMSO- d 6 ) δ 12.1 (s, 1H, SO 3 H), 8.73 (br s, NH 2 ), 8.67 (m, 1H, thienyl-H), 8.41 (br s, NH 2 ), 8.15 (m, 2H, benzoyl-H), 7.94 (m, 1H, benzoyl-H), 7.87 (dd, 1H, thienyl-H), 7.73 (m, 1H, thienyl-H); 13 C NMR (75 MHz, DMSO- d 6 ) δ 172.6 (C-5), 166.9 (C = O), 166.7 (C-3), 154.6 (C = N), 135.7, 131.4, 130.9, 130.5, 128.4 , 126.2 (benzoyl-C), 132.8, 129.7, 126.5, 124.6 (thienyl-C), 39.9 (CH 3 SO 3 H) .; Anal. Calcd for C 15 H 14 ClN 5 O 5 S 2 : C, 40.59; H, 3.18; N, 15.78; S, 14.45. Found: C, 40.66; H, 3. 12; N, 15.73; S, 14.24.

실시예 26. N-[4-(5-피리딘-3-일-[1,2,4]옥사디아졸-3-일)-벤조일]구아니딘의 합성 Example 26. Synthesis of N- [4- (5-pyridin-3-yl- [1,2,4] oxadiazol-3-yl) -benzoyl] guanidine

질소 기류하에서 구아니딘 염화수소 204.43 mg(2.14 mmol, 2.0 eq.)에 DMF 10 mL을 넣어 용해시키고 여기에 칼륨 tert-부톡사이드 240.15 mg(2.14 mmol, 2.0 eq.)을 넣어 50 ℃에서 20분 교반하였다. 반응용액을 여과하여 불용물을 제거하고 여액을 4-(5-피리딘-3-일-[1,2,4]옥사디아졸-3-일)벤조산 메틸 에스테르(300 mg, 1.07 mmol)의 DMF 용액(5 mL)에 넣고 70 ℃에서 30분 가열하였다. 반응용액을 감압 농축하고 잔류물을 컬럼 크로마토그래피(CH2Cl2:MeOH=9:1)로 분리하여 상기 화합물의 흰색 고체 130 mg(39.4%)을 얻었다. Under nitrogen stream, 10 mL of DMF was added to 204.43 mg (2.14 mmol, 2.0 eq.) Of guanidine hydrogen chloride, and 240.15 mg (2.14 mmol, 2.0 eq.) Of potassium tert -butoxide was added thereto and stirred at 50 ° C. for 20 minutes. The reaction solution was filtered to remove insolubles and the filtrate was purified by DMF of 4- (5-pyridin-3-yl- [1,2,4] oxadiazol-3-yl) benzoic acid methyl ester (300 mg, 1.07 mmol). It was added to the solution (5 mL) and heated at 70 ° C for 30 minutes. The reaction solution was concentrated under reduced pressure and the residue was separated by column chromatography (CH 2 Cl 2 : MeOH = 9: 1) to give 130 mg (39.4%) of a white solid of the compound.

39.4% yield(white solid); mp 248-249 ℃; IR(KBr) 3448, 3348, 3155, 1603 cm-1; 1H NMR(300 MHz, DMSO-d 6) δ 9.34(m, 1H, pyridyl-H), 8.89(dd, 1H, pyridyl-H), 8.54(dt, 1H, pyridyl-H), 8.25(m, 2H, benzoyl-H), 8.12(m, 2H, benzoyl-H), 7.70(ddd, 1H, pyridyl-H); 13C NMR(75 MHz, DMSO-d 6) δ 174.9(C=O), 174.1(C-5), 168.3(C-3), 163.3(C=N), 153.9, 148.7, 135.8, 124.7, 120.2(pyridyl-C), 142.3, 129.5, 127.7, 126.8(benzoyl-C).39.4% yield (white solid); mp 248-249 ° C; IR (KBr) 3448, 3348, 3155, 1603 cm −1 ; 1 H NMR (300 MHz, DMSO- d 6 ) δ 9.34 (m, 1H, pyridyl-H), 8.89 (dd, 1H, pyridyl-H), 8.54 (dt, 1H, pyridyl-H), 8.25 (m, 2H, benzoyl-H), 8.12 (m, 2H, benzoyl-H), 7.70 (ddd, 1H, pyridyl-H); 13 C NMR (75 MHz, DMSO- d 6 ) δ 174.9 (C = O), 174.1 (C-5), 168.3 (C-3), 163.3 (C = N), 153.9, 148.7, 135.8, 124.7, 120.2 (pyridyl-C), 142.3, 129.5, 127.7, 126.8 (benzoyl-C).

실시예 27. N-[2-메틸-4-(5-피리딘-3-일-[1,2,4]옥사디아졸-3-일)-벤조일]구아니딘의 합성 Example 27. Synthesis of N- [2-methyl-4- (5-pyridin-3-yl- [1,2,4] oxadiazol-3-yl) -benzoyl] guanidine

질소 기류하에서 구아니딘 염화수소 268.59 mg(3.0 mmol, 4.0 eq.)에 DMF 와 1,4-디옥산 혼합용액 15 mL(1:1)을넣어 용해시키고 여기에 칼륨 tert-부톡사이드 336.66 mg(3.0 mmol, 4.0 eq.)을 넣어 50 ℃에서 20분 교반하였다. 반응용액을 여과하여 불용물을 제거하고 여액을 2-메틸-4-(5-피리딘-3-일-[1,2,4]-옥사디아졸-3-일)벤조산 메틸 에스테르(220 mg, 0.75 mmol)의 DMF 용액(5 mL)에 넣고 70 ℃에서 30분 가열하였다. 반응용액을 감압 농축하고 잔류물을 컬럼 크로마토그래피(CH2Cl2:MeOH=9:1)로 분리하여 상기 화합물의 흰색 고체 150 mg(62.1%)을 얻었다. 15 mL (1: 1) of DMF and 1,4-dioxane mixed solution was dissolved in 268.59 mg (3.0 mmol, 4.0 eq.) Of guanidine hydrogen chloride under nitrogen stream, and 336.66 mg (3.0 mmol, potassium tert -butoxide was added thereto. 4.0 eq.) Was added and stirred at 50 ° C. for 20 minutes. The reaction solution was filtered to remove insolubles and the filtrate was purified by 2-methyl-4- (5-pyridin-3-yl- [1,2,4] -oxadiazol-3-yl) benzoic acid methyl ester (220 mg, 0.75 mmol) in DMF solution (5 mL) and heated at 70 ° C. for 30 minutes. The reaction solution was concentrated under reduced pressure and the residue was separated by column chromatography (CH 2 Cl 2 : MeOH = 9: 1) to give 150 mg (62.1%) of a white solid of the compound.

62.1% yield(white solid); mp 235-236 ℃; IR(KBr) 3408, 3027, 1657, 1610 cm-1; 1H NMR(300 MHz, DMSO-d 6) δ 9.32(br s, 1H, pyridyl-H), 8.88(d, 1H, pyridyl-H), 8.54(dt, 1H, pyridyl-H), 7.89(m, 2H, benzoyl-H), 7.82(m, 1H, benzoyl-H), 7.69(ddd, 1H, pyridyl-H), 2.53(s, 3H, CH3); 13C NMR(75 MHz, DMSO-d 6 ) δ 178.6(C=O), 174.0(C-5), 168.3(C-3), 162.8(C=N), 153.8, 148.7, 135.8, 120.2(pyridyl-C), 143.5, 137.3, 129.6, 129.3, 125.8, 124.2(benzoyl-C), 20.8(CH3).62.1% yield (white solid); mp 235-236 ° C; IR (KBr) 3408, 3027, 1657, 1610 cm −1 ; 1 H NMR (300 MHz, DMSO- d 6 ) δ 9.32 (br s, 1H, pyridyl-H), 8.88 (d, 1H, pyridyl-H), 8.54 (dt, 1H, pyridyl-H), 7.89 (m , 2H, benzoyl-H), 7.82 (m, 1H, benzoyl-H), 7.69 (ddd, 1H, pyridyl-H), 2.53 (s, 3H, CH 3 ); 13 C NMR (75 MHz, DMSO- d 6 ) δ 178.6 (C = O), 174.0 (C-5), 168.3 (C-3), 162.8 (C = N), 153.8, 148.7, 135.8, 120.2 (pyridyl -C), 143.5, 137.3, 129.6, 129.3, 125.8, 124.2 (benzoyl-C), 20.8 (CH 3 ).

실시예 28. N-[4-(5-이소프로필-[1,2,4]옥사디아졸-3-일)-2-메틸벤조일]구아니딘 메탄설포네이트의 합성 Example 28 Synthesis of N- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) -2-methylbenzoyl] guanidine methanesulfonate

질소 기류하에서 구아니딘 염화수소 294.23 mg(3.08 mmol, 2.0 eq.)에 DMF 10 mL을 넣어 용해시키고 여기에 칼륨 tert-부톡사이드 345.64 mg(3.08 mmol, 2.0 eq.)을 넣어 50 ℃에서 20분 교반하였다. 반응용액을 여과하여 불용물을 제거하고 여액을 4-(5-이소프로필-[1,2,4]옥사디아졸-3-일)-2-메틸벤조산 메틸 에스테르 400 mg, 1.54 mmole)의 DMF 용액(5 mL)에 넣고 70 ℃에서 30분 가열하였다. 반응용액을 감압 농축하고 잔류물을 컬럼 크로마토그래피(CH2Cl2:MeOH=9:1)로 분리하여 N-[4-(5-이소프로필-[1,2,4]옥사디아졸-3-일)-2-메틸벤조일]구아니딘 170 mg(0.59 mmol)을 얻었다. 얻어진 화합물에 아세톤과 MeOH 혼합용액 5 mL(1:1)을 넣어 용해시키고 메탄설폰산 46.10 μL(0.71 mmol)을 넣어 실온에서 30분 교반하였다. 생성된 화합물을 여과하여 상기 화합물의 흰색 고체 147 mg(24.9%)을 얻었다.Under nitrogen stream, 10 mL of DMF was added to 294.23 mg (3.08 mmol, 2.0 eq.) Of guanidine hydrogen chloride, and 345.64 mg (3.08 mmol, 2.0 eq.) Of potassium tert -butoxide was added thereto and stirred at 50 ° C. for 20 minutes. The reaction solution was filtered to remove insolubles and the filtrate was purified by DMF of 4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) -2-methylbenzoic acid methyl ester 400 mg, 1.54 mmole). It was added to the solution (5 mL) and heated at 70 ° C for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was separated by column chromatography (CH 2 Cl 2 : MeOH = 9: 1) to obtain N- [4- (5-isopropyl- [1,2,4] oxadiazole-3 -Yl) -2-methylbenzoyl] guanidine 170 mg (0.59 mmol) were obtained. 5 mL (1: 1) of acetone and MeOH mixed solution were added to the obtained compound, and 46.10 μL (0.71 mmol) of methanesulfonic acid was added thereto, followed by stirring at room temperature for 30 minutes. The resulting compound was filtered to give 147 mg (24.9%) of a white solid of the compound.

24.9% yield(white solid); mp 171-172 ℃; IR(KBr) 3358, 3129, 2980, 1720, 1209 cm-1; 1H NMR(300 MHz, DMSO-d 6) δ 11.6(s, 1H, SO3 H), 8.60(br s, NH2), 8.30(br s, NH2), 7.96(m, 2H, benzoyl-H), 7.78(m, 1H, benzoyl-H), 3.37(m, 1H, CH), 2.50(s, 3H, benzoyl-CH3), 2.40(s, 3H, CH3SO3H), 1.38(d, 6H, CH3 ×2); 13C NMR(75 MHz, DMSO-d 6) δ 184.8(C-5), 169.3(C=O), 166.9(C-3) 155.0(C=N), 138.5, 135.5, 129.7, 129.4, 129.2, 124.7(benzoyl-C), 39.9(CH3SO3H), 27.1(CH), 20.0(CH 3). 19.7(benzoyl-C).24.9% yield (white solid); mp 171-172 ° C; IR (KBr) 3358, 3129, 2980, 1720, 1209 cm −1 ; 1 H NMR (300 MHz, DMSO- d 6 ) δ 11.6 (s, 1H, SO 3 H), 8.60 (br s, NH 2 ), 8.30 (br s, NH 2 ), 7.96 (m, 2H, benzoyl- H), 7.78 (m, 1H, benzoyl-H), 3.37 (m, 1H, CH), 2.50 (s, 3H, benzoyl-CH 3 ), 2.40 (s, 3H, CH 3 SO 3 H), 1.38 ( d, 6H, CH 3 x 2); 13 C NMR (75 MHz, DMSO- d 6 ) δ 184.8 (C-5), 169.3 (C = O), 166.9 (C-3) 155.0 (C = N), 138.5, 135.5, 129.7, 129.4, 129.2, 124.7 (benzoyl-C), 39.9 (CH 3 SO 3 H), 27.1 (CH), 20.0 (CH 3 ). 19.7 (benzoyl-C).

실시예 29. N-[2-메틸-4-(5-메틸-[1,2,4]옥사디아졸-3-일)-벤조일]구아니딘 메탄설포네이트의 합성 Example 29. Synthesis of N- [2-methyl-4- (5-methyl- [1,2,4] oxadiazol-3-yl) -benzoyl] guanidine methanesulfonate

질소 기류하에서 구아니딘 염화수소 657.25 mg(6.88 mmol, 4.0 eq.)에 DMF 와 1,4-디옥산 혼합용액 20 mL(1:1)을 넣어 용해시키고 여기에 칼륨 tert-부톡사이드 772.07 mg(6.88 mmol, 4.0 eq.)을 넣어 50 ℃에서 20분 교반하였다. 반응용액을 여과하여 불용물을 제거하고 여액을 2-메틸-4-(5-메틸-[1,2,4]옥사디아졸-3-일)벤조산 메틸 에스테르(400 mg, 1.72 mmole)의 DMF 용액(5 mL)에 넣고 70 ℃에서 30분 가열하였다. 반응용액을 감압 농축하고 잔류물을 컬럼 크로마토그래피(CH2Cl2:MeOH=9:1)로 분리하여 N-[2-메틸-4-(5-메틸-[1,2,4]옥사디아졸-3-일)-벤조일]구아니딘 320 mg(1.23 mmol)을 얻었다. 얻어진 화합물에 아세톤과 MeOH 혼합용액 7 mL(1:1)을 넣어 용해시키고 메탄설폰산 96.10 μL(1.48 mmol)을 넣어 실온에서 30분 교반하였다. 생성된 화합물을 여과하여 상기 화합물의 흰색 고체 297 mg(48.6%)을 얻었다.Dissolve 20 mL (1: 1) of DMF and 1,4-dioxane solution in 657.25 mg (6.88 mmol, 4.0 eq.) Of guanidine hydrogen chloride under nitrogen stream, and dissolve 772.07 mg of potassium tert -butoxide (6.88 mmol, 4.0 eq.) Was added and stirred at 50 ° C. for 20 minutes. The reaction solution was filtered to remove insolubles and the filtrate was purified by DMF of 2-methyl-4- (5-methyl- [1,2,4] oxadiazol-3-yl) benzoic acid methyl ester (400 mg, 1.72 mmole). Put in solution (5 mL) and heated at 70 ℃ 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was separated by column chromatography (CH 2 Cl 2 : MeOH = 9: 1) to give N- [2-methyl-4- (5-methyl- [1,2,4] oxadia. Zol-3-yl) -benzoyl] guanidine 320 mg (1.23 mmol) were obtained. 7 mL (1: 1) of acetone and MeOH mixed solution were added to the obtained compound, and 96.10 μL (1.48 mmol) of methanesulfonic acid was added thereto, followed by stirring at room temperature for 30 minutes. The resulting compound was filtered to give 297 mg (48.6%) of a white solid of the compound.

48.6% yield(white solid); mp 216-217 ℃; IR(KBr) 3318, 3124, 1720, 1704, 1169 cm-1; 1H NMR(300 MHz, DMSO-d 6) δ 11.5(s, 1H, SO3 H), 8.43(br s, NH2), 8.33(br s, NH2), 7.98(m, 2H, benzoyl-H), 7.78(d, 1H, benzoyl-H), 2.68(s, 3H, CH3), 2.50(benzoyl-CH3), 2.32(CH3SO3H); 13C NMR(75 MHz, DMSO- d 6) δ 178.1(C-5), 169.4(C=O), 167.1(C-3), 155.0(C=N), 138.5, 135.5, 129.7, 129.3, 129.2, 124.6(benzoyl-C), 39.9(CH3SO3H), 19.7(benzoyl-CH3), 12.3(CH3 ).48.6% yield (white solid); mp 216-217 ° C; IR (KBr) 3318, 3124, 1720, 1704, 1169 cm −1 ; 1 H NMR (300 MHz, DMSO- d 6 ) δ 11.5 (s, 1H, SO 3 H), 8.43 (br s, NH 2 ), 8.33 (br s, NH 2 ), 7.98 (m, 2H, benzoyl- H), 7.78 (d, 1H, benzoyl-H), 2.68 (s, 3H, CH 3 ), 2.50 (benzoyl-CH 3 ), 2.32 (CH 3 SO 3 H); 13 C NMR (75 MHz, DMSO- d 6 ) δ 178.1 (C-5), 169.4 (C = O), 167.1 (C-3), 155.0 (C = N), 138.5, 135.5, 129.7, 129.3, 129.2 , 124.6 (benzoyl-C), 39.9 (CH 3 SO 3 H), 19.7 (benzoyl-CH 3 ), 12.3 (CH 3 ).

실시예 30. N-[2-메틸-4-(5-티오펜-3-일-[1,2,4]옥사디아졸-3-일)-벤조일]구아니딘 메탄설포네이트의 합성 Example 30 Synthesis of N- [2-methyl-4- (5-thiophen-3-yl- [1,2,4] oxadiazol-3-yl) -benzoyl] guanidine methanesulfonate

질소 기류하에서 구아니딘 염화수소 661.07 mg(6.92 mmol, 4.0 eq.)에 DMF 와 1,4-디옥산 혼합용액 30 mL(1:1)을 넣어 용해시키고 여기에 칼륨 tert-부톡사이드 776.56 mg(6.92 mmol, 4.0 eq.)을 넣어 50 ℃에서 20분 교반하였다. 반응용액을 여과하여 불용물을 제거하고 여액을 2-메틸-4-(5-티오펜-3-일-[1,2,4]옥사디아졸-3-일)벤조산 메틸 에스테르(520 mg, 1.73 mmole)의 DMF 용액(5 mL)에 넣고 70 ℃에서 15시간 가열하였다. 반응용액을 감압 농축하고 잔류물을 컬럼 크로마토그래피(CH2Cl2:MeOH=9:1)로 분리하여 N-[2-메틸-4-(5-티오펜-3-일-[1,2,4]옥사디아졸-3-일)-벤조일]구아니딘 400 mg(1.22 mmol)을 얻었다. 얻어진 화합물에 아세톤과 MeOH 혼합용액 10 mL(1:1)을 넣어 용해시키고 메탄설폰산 94.80 μL(1.46 mmol)을 넣어 실온에서 30분 교반하였다. 생성된 화합물을 여과하여 상기 화합물의 흰색 고체 393 mg(53.6%)을 얻었다.In a nitrogen stream, 30 mL (1: 1) of a mixed solution of DMF and 1,4-dioxane was dissolved in 661.07 mg (6.92 mmol, 4.0 eq.) Of guanidine hydrogen chloride, and 776.56 mg (6.92 mmol, of potassium tert -butoxide was added thereto. 4.0 eq.) Was added and stirred at 50 ° C. for 20 minutes. The reaction solution was filtered to remove insolubles and the filtrate was purified by 2-methyl-4- (5-thiophen-3-yl- [1,2,4] oxadiazol-3-yl) benzoic acid methyl ester (520 mg, 1.73 mmole) was added to a DMF solution (5 mL) and heated at 70 ° C. for 15 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated by column chromatography (CH 2 Cl 2 : MeOH = 9: 1) to obtain N- [2-methyl-4- (5-thiophen-3-yl- [1,2 , 4] oxadiazol-3-yl) -benzoyl] guanidine 400 mg (1.22 mmol) were obtained. 10 mL (1: 1) of acetone and MeOH mixed solution were added to the obtained compound, and 94.80 μL (1.46 mmol) of methanesulfonic acid was added thereto, followed by stirring at room temperature for 30 minutes. The resulting compound was filtered to give 393 mg (53.6%) of a white solid of the compound.

53.6% yield(white solid); mp 246-247 ℃; IR(KBr) 3355, 3131, 1713, 1180 cm-1; 1H NMR(300 MHz, DMSO-d 6) δ 11.6(s, 1H, SO3H), 8.66(dd, 1H, thienyl-H), 8.64(br s, NH2), 8.33(br s, NH2), 8.02(m, 2H, benzoyl-H), 7.86(dd, 1H, thienyl-H), 7.82(m, 1H, benzoyl-H), 7.74(dd, 1H, thienyl-H), 2.52(benzoyl-CH3), 2.42(CH3SO3H); 13C NMR(75 MHz, DMSO-d 6 ) δ 172.3(C-5), 169.3(C=O), 167.5(C-3), 155.0(C=N), 138.5, 135.5, 129.7, 129.3, 129.2, 124.7(benzoyl-C), 132.6, 129.8, 126.5, 124.8(thienyl-C), 39.9(CH3SO3H), 19.7(CH3). 53.6% yield (white solid); mp 246-247 ° C; IR (KBr) 3355, 3131, 1713, 1180 cm −1 ; 1 H NMR (300 MHz, DMSO- d 6 ) δ 11.6 (s, 1H, SO 3 H), 8.66 (dd, 1H, thienyl-H), 8.64 (br s, NH 2 ), 8.33 (br s, NH 2 ), 8.02 (m, 2H, benzoyl-H), 7.86 (dd, 1H, thienyl-H), 7.82 (m, 1H, benzoyl-H), 7.74 (dd, 1H, thienyl-H), 2.52 (benzoyl -CH 3 ), 2.42 (CH 3 SO 3 H); 13 C NMR (75 MHz, DMSO- d 6 ) δ 172.3 (C-5), 169.3 (C = O), 167.5 (C-3), 155.0 (C = N), 138.5, 135.5, 129.7, 129.3, 129.2 , 124.7 (benzoyl-C), 132.6, 129.8, 126.5, 124.8 (thienyl-C), 39.9 (CH 3 SO 3 H), 19.7 (CH 3 ).

실시예 31. N-[2-메틸-4-(5-페닐-[1,2,4]옥사디아졸-3-일)-벤조일]구아니딘 메탄설포네이트의 합성 Example 31.Synthesis of N- [2-methyl-4- (5-phenyl- [1,2,4] oxadiazol-3-yl) -benzoyl] guanidine methanesulfonate

질소 기류하에서 구아니딘 염화수소 615.21 mg(6.44 mmol, 4.0 eq.)에 DMF 와 1,4-디옥산의 혼합용액 15 mL(1:1)을 넣어 용해시키고 여기에 칼륨 tert-부톡사이드 722.70 mg(6.44 mmol, 4.0 eq.)을 넣어 50 ℃에서 20분 교반하였다. 반응용액을 여과하여 불용물을 제거하고 여액을 2-메틸-4-(5-페닐-[1,2,4]옥사디아졸-3-일)벤조산 메틸 에스테르(475 mg, 1.61 mmole)의 DMF 용액(5 mL)에 넣고 70 ℃에서 30분 가열하였다. 반응용액을 감압 농축하고 잔류물을 컬럼 크로마토그래피(CH2Cl2:MeOH=9:1)로 분리하여 N-[2-메틸-4-(5-[1,2,4]옥사디아졸-3-일)-벤조일]구아니딘 390 mg(1.21 mmol)을 얻었다. 얻어진 화합물에 아세톤과 MeOH 혼합용액 5 mL(1:1)을 넣어 용해시키고 메탄설폰산 94.15 μL(1.45 mmol)을 넣어 실온에서 30분 교반하였다. 생성된 화합물을 여과하여 상기 화합물의 흰색 고체 369 mg(54.9%)을 얻었다.Dissolve 15 mL (1: 1) of DMF and 1,4-dioxane in 615.21 mg (6.44 mmol, 4.0 eq.) Of guanidine hydrogen chloride under nitrogen stream, and dissolve 722.70 mg (6.44 mmol) of potassium tert -butoxide. , 4.0 eq.) And stirred at 50 ° C. for 20 minutes. The reaction solution was filtered to remove insolubles and the filtrate was purified by DMF of 2-methyl-4- (5-phenyl- [1,2,4] oxadiazol-3-yl) benzoic acid methyl ester (475 mg, 1.61 mmole). It was added to the solution (5 mL) and heated at 70 ° C for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was separated by column chromatography (CH 2 Cl 2 : MeOH = 9: 1) to give N- [2-methyl-4- (5- [1,2,4] oxadiazole- 390 mg (1.21 mmol) of 3-yl) -benzoyl] guanidine were obtained. 5 mL (1: 1) of acetone and MeOH mixed solution were added to the obtained compound, and 94.15 μL (1.45 mmol) of methanesulfonic acid was added thereto, followed by stirring at room temperature for 30 minutes. The resulting compound was filtered to give 369 mg (54.9%) of a white solid of the compound.

54.9% yield(white solid); mp 226-228 ℃; IR(KBr) 3329, 3123, 1713, 1702, 1172 cm-1; 1H NMR(300 MHz, DMSO-d 6) δ 11.6(s, 1H, SO3 H), 8.60(br s, NH2), 8.31(br s, NH2), 8.19(d, 2H, phenyl-H), 8.05(m, 2H, benzoyl-H), 7.82(d, 1H, benzoyl-H), 7.69(m, 3H, phenyl-H), 2.53(benzoyl-CH3), 2.40(CH3SO3H); 13 C NMR(75 MHz, DMSO-d 6) δ 175.9(C-5), 169.3(C=O), 167.7(C-3), 155.0(C=N), 138.5, 135.6, 129.8, 129.2, 128.2, 124.8(benzoyl-C), 133.8, 129.15, 123.4(phenyl-C), 39.9(CH3SO3H), 20.0(CH3).54.9% yield (white solid); mp 226-228 ° C; IR (KBr) 3329, 3123, 1713, 1702, 1172 cm −1 ; 1 H NMR (300 MHz, DMSO- d 6 ) δ 11.6 (s, 1H, SO 3 H), 8.60 (br s, NH 2 ), 8.31 (br s, NH 2 ), 8.19 (d, 2H, phenyl- H), 8.05 (m, 2H, benzoyl-H), 7.82 (d, 1H, benzoyl-H), 7.69 (m, 3H, phenyl-H), 2.53 (benzoyl-CH 3 ), 2.40 (CH 3 SO 3 H); 13 C NMR (75 MHz, DMSO- d 6 ) δ 175.9 (C-5), 169.3 (C = O), 167.7 (C-3), 155.0 (C = N), 138.5, 135.6, 129.8, 129.2, 128.2 , 124.8 (benzoyl-C), 133.8, 129.15, 123.4 (phenyl-C), 39.9 (CH 3 SO 3 H), 20.0 (CH 3 ).

실시예 32. N-[2-메틸-4-(5-퀴놀린-3-일-[1,2,4]옥사디아졸-3-일)-벤조일]구아니딘의 합성 Example 32. Synthesis of N- [2-methyl-4- (5-quinolin-3-yl- [1,2,4] oxadiazol-3-yl) -benzoyl] guanidine

질소 기류하에서 구아니딘 염화수소 829.20 mg(8.68 mmol, 4.0 eq.)에 DMF 와 1,4-디옥산의 혼합용액 20 mL(1:1)을 넣어 용해시키고 여기에 칼륨 tert-부톡사이드 974.07 mg(8.68 mmol, 4.0 eq.)을 넣어 50 ℃에서 20분 교반하였다. 반응용액을 여과하여 불용물을 제거하고 여액을 2-메틸-4-(5-퀴놀린-3-일-[1,2,4]옥사디아졸-3-일)벤조산 메틸 에스테르(750 mg, 2.17 mmole)의 DMF 용액(5 mL)에 넣고 70 ℃에서 30분 가열하였다. 반응용액을 감압 농축하고 잔류물을 컬럼 크로마토그래피(CH2Cl2:MeOH=9:1)로 분리하여 상기 화합물의 흰색 고체 360 mg(44.6%)을 얻었다. Dissolve 20 mL (1: 1) of a mixed solution of DMF and 1,4-dioxane in 829.20 mg (8.68 mmol, 4.0 eq.) Of guanidine hydrogen chloride under nitrogen stream, and dissolve 974.07 mg (8.68 mmol) of potassium tert -butoxide. , 4.0 eq.) And stirred at 50 ° C. for 20 minutes. The reaction solution was filtered to remove insolubles and the filtrate was purified by 2-methyl-4- (5-quinolin-3-yl- [1,2,4] oxadiazol-3-yl) benzoic acid methyl ester (750 mg, 2.17 mmol D) solution (5 mL) and heated at 70 ° C. for 30 minutes. The reaction solution was concentrated under reduced pressure and the residue was separated by column chromatography (CH 2 Cl 2 : MeOH = 9: 1) to give 360 mg (44.6%) of a white solid of the compound.

44.6% yield(white solid); mp 221-223 ℃; IR(KBr) 3332, 3066, 1666, 1604 cm-1; 1H NMR(300 MHz, DMSO-d 6) δ 9.56(m, 1H, quinolyl-H) 9.30(m, 1H, quinolyl-H), 8.29(d, 1H, quinolyl-H), 8.16(d, 1H, quinolyl-H), 7.97(m, 3H, 벤조일-H), 7.80(m, 2H, quinolyl-H), 2.55(s, 3H, CH3); 13C NMR(75 MHz, DMSO-d 6 ) δ 178.1(C=O), 174.1(C-5), 168.3(C-3), 162.4(C=N), 149.1, 148.0, 137.0, 132.6, 129.8, 129.4, 128.3, 126.8, 117.1(quinolyl-C), 143.1, 137.3, 129.6, 129.2, 126.1, 124.2(benzoyl-C), 20.8(CH3).44.6% yield (white solid); mp 221-223 ° C; IR (KBr) 3332, 3066, 1666, 1604 cm <-1>; 1 H NMR (300 MHz, DMSO- d 6 ) δ 9.56 (m, 1H, quinolyl-H) 9.30 (m, 1H, quinolyl-H), 8.29 (d, 1H, quinolyl-H), 8.16 (d, 1H , quinolyl-H), 7.97 (m, 3H, benzoyl-H), 7.80 (m, 2H, quinolyl-H), 2.55 (s, 3H, CH 3 ); 13 C NMR (75 MHz, DMSO- d 6 ) δ 178.1 (C = O), 174.1 (C-5), 168.3 (C-3), 162.4 (C = N), 149.1, 148.0, 137.0, 132.6, 129.8 , 129.4, 128.3, 126.8, 117.1 (quinolyl-C), 143.1, 137.3, 129.6, 129.2, 126.1, 124.2 (benzoyl-C), 20.8 (CH 3 ).

실시예 33. N-{4-[5-(2-브로모페닐)-[1,2,4]옥사디아졸-3-일]-2-메틸벤조일}구아니딘 메탄설포네이트의 합성 Example 33. Synthesis of N- {4- [5- (2-bromophenyl)-[1,2,4] oxadiazol-3-yl] -2-methylbenzoyl} guanidine methanesulfonate

질소 기류하에서 구아니딘 염화수소 248.38 mg(2.60 mmol, 4.0 eq.)에 DMF 와 1,4-디옥산의 혼합용액 10 mL(1:1)을 넣어 용해시키고 여기에 칼륨 tert-부톡사이드 291.77 mg(2.60 mmol, 4.0 eq.)을 넣어 50 ℃에서 20분 교반하였다. 반응용액을 여과하여 불용물을 제거하고 여액을 4-[5-(2-브로모페닐)-[1,2,4]옥사디아졸-3-일]-2-메틸벤조산 메틸 에스테르(244 mg, 0.65 mmole)의 DMF 용액(5 mL)에 넣 고 70 ℃에서 30분 가열하였다. 반응용액을 감압 농축하고 잔류물을 컬럼 크로마토그래피(CH2Cl2:MeOH=9:1)로 분리하여 N-{4-[5-(2-브로모페닐)-[1,2,4]옥사디아졸-3-일]-2-메틸벤조일}구아니딘 160 mg(0.40 mmol)을 얻었다. 얻어진 화합물에 아세톤과 MeOH 혼합용액 5 mL(1:1)을 넣어 용해시키고 메탄설폰산 31.17 μL(0.48 mmol)을 넣어 실온에서 30분 교반하였다. 생성된 화합물을 여과하여 상기 화합물의 흰색 고체 160 mg(49.6%)을 얻었다.Dissolve 10 mL (1: 1) of a mixed solution of DMF and 1,4-dioxane in 248.38 mg (2.60 mmol, 4.0 eq.) Of guanidine hydrogen chloride under nitrogen stream, and dissolve 291.77 mg (2.60 mmol) of potassium tert -butoxide. , 4.0 eq.) And stirred at 50 ° C. for 20 minutes. The reaction solution was filtered to remove insolubles and the filtrate was purified by 4- [5- (2-bromophenyl)-[1,2,4] oxadiazol-3-yl] -2-methylbenzoic acid methyl ester (244 mg). , 0.65 mmole) was added to a DMF solution (5 mL) and heated at 70 ° C. for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was separated by column chromatography (CH 2 Cl 2 : MeOH = 9: 1), and N- {4- [5- (2-bromophenyl)-[1,2,4] 160 mg (0.40 mmol) of oxadiazol-3-yl] -2-methylbenzoyl} guanidine were obtained. 5 mL (1: 1) of acetone and MeOH mixed solution were added to the obtained compound, and 31.17 μL (0.48 mmol) of methanesulfonic acid was added thereto, followed by stirring at room temperature for 30 minutes. The resulting compound was filtered to give 160 mg (49.6%) of a white solid of the compound.

49.6% yield(white solid); mp 185-186 ℃; IR(KBr) 3374, 3085, 1711, 1592, 1203 cm-1; 1H NMR(300 MHz, DMSO-d 6) δ 11.6(s, 1H, SO3 H), 8.60(br s, NH2), 8.31(br s, NH2), 8.07(m, 3H), 7.94(m, 1H), 7.84(m, 1H), 7.64(m, 2H), 2.53(benzoyl-CH3), 2.39(CH3SO3H); 13C NMR(75 MHz, DMSO-d 6) δ 175.2(C-5), 169.3(C=O), 167.5(C-3), 155.0(C=N), 138.5, 135.8, 129.8, 129.3, 128.6, 124.9(benzoyl-C), 134.8, 134.6, 132.7, 128.9, 124.86, 121.4(tolyl-C), 39.9(CH3SO3H), 19.7(benzoyl-CH 3).49.6% yield (white solid); mp 185-186 ° C; IR (KBr) 3374, 3085, 1711, 1592, 1203 cm −1 ; 1 H NMR (300 MHz, DMSO- d 6 ) δ 11.6 (s, 1H, SO 3 H), 8.60 (br s, NH 2 ), 8.31 (br s, NH 2 ), 8.07 (m, 3H), 7.94 (m, 1H), 7.84 (m, 1H), 7.64 (m, 2H), 2.53 (benzoyl-CH 3 ), 2.39 (CH 3 SO 3 H); 13 C NMR (75 MHz, DMSO- d 6 ) δ 175.2 (C-5), 169.3 (C = O), 167.5 (C-3), 155.0 (C = N), 138.5, 135.8, 129.8, 129.3, 128.6 , 124.9 (benzoyl-C), 134.8, 134.6, 132.7, 128.9, 124.86, 121.4 (tolyl-C), 39.9 (CH 3 SO 3 H), 19.7 (benzoyl-CH 3 ).

실시예 34. N-{4-[5-(3-브로모페닐)-[1,2,4]옥사디아졸-3-일]-2-메틸벤조일}구아니딘 메탄설포네이트의 합성 Example 34. Synthesis of N- {4- [5- (3-bromophenyl)-[1,2,4] oxadiazol-3-yl] -2-methylbenzoyl} guanidine methanesulfonate

질소 기류하에서 구아니딘 염화수소 718.39 mg(7.52 mmol, 4.0 eq.)에 DMF 와 1,4-디옥산의 혼합용액 20 mL(1:1)을 넣어 용해시키고 여기에 칼륨 tert-부톡사이드 843.89 mg(7.52 mmol, 4.0 eq.)을 넣어 50 ℃에서 20분 교반하였다. 반응 용액을 여과하여 불용물을 제거하고 여액을 4-[5-(3-브로모페닐)-[1,2,4]옥사디아졸-3-일]-2-메틸벤조산 메틸 에스테르(700 mg, 1.88 mmole)의 DMF 용액(10 mL)에 넣고 70 ℃에서 30분 가열하였다. 반응용액을 감압 농축하고 잔류물을 컬럼 크로마토그래피(CH2Cl2:MeOH=9:1)로 분리하여 N-{4-[5-3-브로모페닐)-[1,2,4]옥사디아졸-3-일]-2-메틸벤조일}구아니딘 180 mg(0.45 mmol)을 얻었다. 얻어진 화합물에 아세톤과 MeOH 혼합용액 5 mL(1:1)을 넣어 용해시키고 메탄설폰산 35.06 μL(0.54 mmol)을 넣어 실온에서 30분 교반하였다. 생성된 화합물을 여과하여 상기 화합물의 흰색 고체 163 mg(17.5%)을 얻었다.Dissolve 20 mL (1: 1) of DMF and 1,4-dioxane in 718.39 mg (7.52 mmol, 4.0 eq.) Of guanidine hydrogen chloride under nitrogen stream, and dissolve 843.89 mg (7.52 mmol) of potassium tert -butoxide. , 4.0 eq.) And stirred at 50 ° C. for 20 minutes. The reaction solution was filtered to remove insolubles and the filtrate was purified by 4- [5- (3-bromophenyl)-[1,2,4] oxadiazol-3-yl] -2-methylbenzoic acid methyl ester (700 mg , 1.88 mmole) was added to a DMF solution (10 mL) and heated at 70 ° C. for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was separated by column chromatography (CH 2 Cl 2 : MeOH = 9: 1) to obtain N- {4- [5-3-bromophenyl)-[1,2,4] oxa. 180 mg (0.45 mmol) of diazol-3-yl] -2-methylbenzoyl} guanidine were obtained. 5 mL (1: 1) of acetone and MeOH mixed solution were added to the obtained compound, and 35.06 μL (0.54 mmol) of methanesulfonic acid was added thereto, followed by stirring at room temperature for 30 minutes. The resulting compound was filtered to give 163 mg (17.5%) of a white solid of the compound.

17.5% yield(white solid); mp 225-227 ℃; IR(KBr) 3338, 3129, 1711, 1598, 1219 cm-1; 1H NMR(300 MHz, DMSO-d 6) δ 11.6(s, 1H, SO3 H), 8.60(br s, NH2), 8.31(br s, NH2), 8.29(br s, 1H), 8.17(d, 1H), 8.06(m, 2H), 7.94(br d, 1H), 7.83(m, 1H), 7.61(t, 1H), 2.52(benzoyl-CH3), 2.40(CH3SO3H); 13C NMR(75 MHz, DMSO-d 6) δ 174.6(C-5), 169.3(C=O), 167.8(C-3), 155.0(C=N), 138.6, 135.7, 129.8, 129.3, 128.9, 124.8(benzoyl-C), 136.4, 132.0, 130.5, 127.2, 125.5, 122.7(tolyl-C), 39.9(CH3SO3H), 19.7(benzoyl-CH3).17.5% yield (white solid); mp 225-227 ° C; IR (KBr) 3338, 3129, 1711, 1598, 1219 cm −1 ; 1 H NMR (300 MHz, DMSO- d 6 ) δ 11.6 (s, 1H, SO 3 H), 8.60 (br s, NH 2 ), 8.31 (br s, NH 2 ), 8.29 (br s, 1H), 8.17 (d, 1H), 8.06 (m, 2H), 7.94 (br d, 1H), 7.83 (m, 1H), 7.61 (t, 1H), 2.52 (benzoyl-CH 3 ), 2.40 (CH 3 SO 3 H); 13 C NMR (75 MHz, DMSO- d 6 ) δ 174.6 (C-5), 169.3 (C = O), 167.8 (C-3), 155.0 (C = N), 138.6, 135.7, 129.8, 129.3, 128.9 , 124.8 (benzoyl-C), 136.4, 132.0, 130.5, 127.2, 125.5, 122.7 (tolyl-C), 39.9 (CH 3 SO 3 H), 19.7 (benzoyl-CH 3 ).

실시예 35. N-{4-[5-(4-브로모페닐)-[1,2,4]옥사디아졸-3-일]-2-메틸벤조일}구아니딘 메탄설포네이트의 합성 Example 35. Synthesis of N- {4- [5- (4-bromophenyl)-[1,2,4] oxadiazol-3-yl] -2-methylbenzoyl} guanidine methanesulfonate

질소 기류하에서 구아니딘 염화수소 817.74 mg(8.56 mmol, 4.0 eq.)에 DMF 와 1,4-디옥산의 혼합용액 20 mL(1:1)을 넣어 용해시키고 여기에 칼륨 tert-부톡사이드 960.60 mg(8.56 mmol, 4.0 eq.)을 넣어 50 ℃에서 20분 교반하였다. 반응용액을 여과하여 불용물을 제거하고 여액을 4-[5-(4-브로모페닐)-[1,2,4]옥사디아졸-3-일]-2-메틸벤조산 메틸 에스테르(800 mg, 2.14 mmole)의 DMF 용액(10 mL)에 넣고 70 ℃에서 30분 가열하였다. 반응용액을 감압 농축하고 잔류물을 컬럼 크로마토그래피(CH2Cl2:MeOH=9:1)로 분리하여 N-{4-[5-4-브로모페닐)-[1,2,4]옥사디아졸-3-일]-2-메틸벤조일}구아니딘 490 mg(1.22 mmol)을 얻었다. 얻어진 화합물에 아세톤과 MeOH 혼합용액 30 mL(1:1)을 넣어 용해시키고 메탄설폰산 94.80 μL(1.46 mmol)을 넣어 실온에서 30분 교반하였다. 생성된 화합물을 여과하여 상기 화합물의 흰색 고체 315 mg(29.7%)을 얻었다.Dissolve 20 mL (1: 1) of DMF and 1,4-dioxane in 817.74 mg (8.56 mmol, 4.0 eq.) Of guanidine hydrogen chloride under nitrogen stream, and dissolve 960.60 mg (8.56 mmol) of potassium tert -butoxide. , 4.0 eq.) And stirred at 50 ° C. for 20 minutes. The reaction solution was filtered to remove insolubles and the filtrate was purified by 4- [5- (4-bromophenyl)-[1,2,4] oxadiazol-3-yl] -2-methylbenzoic acid methyl ester (800 mg). , 2.14 mmole) was added to a DMF solution (10 mL) and heated at 70 ° C. for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was separated by column chromatography (CH 2 Cl 2 : MeOH = 9: 1) to obtain N- {4- [5-4-bromophenyl)-[1,2,4] oxa. Diazol-3-yl] -2-methylbenzoyl} guanidine 490 mg (1.22 mmol) was obtained. 30 mL (1: 1) of acetone and MeOH mixed solution were added to the obtained compound, and 94.80 μL (1.46 mmol) of methanesulfonic acid was added thereto, followed by stirring at room temperature for 30 minutes. The resulting compound was filtered to give 315 mg (29.7%) of a white solid of the compound.

29.7% yield(white solid); mp 246-247 ℃; IR(KBr) 3328, 3103, 1712, 1696, 1210 cm-1; 1H NMR(300 MHz, DMSO-d 6) δ 11.6(s, 1H, SO3 H), 8.60(br s, NH2), 8.31(br s, NH2), 8.04(m, 4H), 7.83(m, 3H), 2.52(benzoyl-CH3), 2.40(CH3SO 3H); 13C NMR(75 MHz, DMSO-d 6) δ 175.2(C-5), 169.3(C=O), 167.8(C-3), 155.0(C=N), 138.5, 135.7, 129.8, 129.3, 129.0, 124.8(benzoyl-C), 132.9, 130.1, 127.7, 122.6(tolyl-C), 39.9(CH3SO3H), 19.8(benzoyl-CH3).29.7% yield (white solid); mp 246-247 ° C; IR (KBr) 3328, 3103, 1712, 1696, 1210 cm −1 ; 1 H NMR (300 MHz, DMSO- d 6 ) δ 11.6 (s, 1H, SO 3 H), 8.60 (br s, NH 2 ), 8.31 (br s, NH 2 ), 8.04 (m, 4H), 7.83 (m, 3H), 2.52 (benzoyl-CH 3 ), 2.40 (CH 3 SO 3 H); 13 C NMR (75 MHz, DMSO- d 6 ) δ 175.2 (C-5), 169.3 (C = O), 167.8 (C-3), 155.0 (C = N), 138.5, 135.7, 129.8, 129.3, 129.0 , 124.8 (benzoyl-C), 132.9, 130.1, 127.7, 122.6 (tolyl-C), 39.9 (CH 3 SO 3 H), 19.8 (benzoyl-CH 3 ).

실시예 36. N-[2-메틸-4-(5-o-토릴-[1,2,4]옥사디아졸-3-일)-벤조일]구아니딘 메탄설포네이트의 합성 Example 36. Synthesis of N- [2-methyl-4- (5- o -tolyl- [1,2,4] oxadiazol-3-yl) -benzoyl] guanidine methanesulfonate

질소 기류하에서 구아니딘 염화수소 729.85 mg(7.64 mmol, 4.0 eq.)에 DMF 와 1,4-디옥산의 혼합용액 30 mL(1:1)을 넣어 용해시키고 여기에 칼륨 tert-부톡사이드 857.36 mg(7.64 mmol, 4.0 eq.)을 넣어 50 ℃에서 20분 교반하였다. 반응용액을 여과하여 불용물을 제거하고 여액을 2-메틸-4-(5-o-토릴-[1,2,4]옥사디아졸-3-일)벤조산 메틸 에스테르(590 mg, 1.91 mmole)의 DMF 용액(5 mL)에 넣고 70 ℃에서 30분 가열하였다. 반응용액을 감압 농축하고 잔류물을 컬럼 크로마토그래피(CH2Cl2:MeOH=9:1)로 분리하여 N-[2-메틸-4-(5-o-토릴-[1,2,4]옥사디아졸-3-일)-벤조일]구아니딘 500 mg(1.49 mmol)을 얻었다. 얻어진 화합물에 아세톤과 MeOH 혼합용액 10 mL(1:1)을 넣어 용해시키고 메탄설폰산 116.23μL(1.79 mmol)을 넣어 실온에서 30분 교반하였다. 생성된 화합물을 여과하여 상기 화합물의 흰색 고체 566 mg(68.7%)을 얻었다.In a nitrogen stream, 30 mL (1: 1) of a mixed solution of DMF and 1,4-dioxane was dissolved in 729.85 mg (7.64 mmol, 4.0 eq.) Of guanidine hydrogen chloride, and 857.36 mg (7.64 mmol) of potassium tert -butoxide was added thereto. , 4.0 eq.) And stirred at 50 ° C. for 20 minutes. The reaction solution was filtered to remove insolubles and the filtrate was purified by 2-methyl-4- (5- o -tolyl- [1,2,4] oxadiazol-3-yl) benzoic acid methyl ester (590 mg, 1.91 mmole). Into DMF solution (5 mL) and heated at 70 ° C. for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was separated by column chromatography (CH 2 Cl 2 : MeOH = 9: 1) to give N- [2-methyl-4- (5- o -tolyl- [1,2,4] 500 mg (1.49 mmol) of oxadiazol-3-yl) -benzoyl] guanidine were obtained. 10 mL (1: 1) of acetone and MeOH mixed solution were added to the obtained compound, and 116.23 µL (1.79 mmol) of methanesulfonic acid was added thereto, followed by stirring at room temperature for 30 minutes. The resulting compound was filtered to give 566 mg (68.7%) of a white solid of the compound.

68.7% yield(white solid); mp 210-211 ℃; IR(KBr) 3374, 3082, 1712, 1590, 1200 cm-1; 1H NMR(300 MHz, DMSO-d 6) δ 11.6(s, 1H, SO3 H), 8.60(br s, NH2), 8.33(br s, NH2), 8.05(m, 3H), 7.83(m, 1H), 7.56(m, 1H), 7.47(m, 2H), 2.70(s, 3H, tolyl-CH3), 2.52(s, 3H, benzoyl-CH3), 2.41(CH3SO3H); 13C NMR(75 MHz, DMSO-d 6) δ 176.5(C-5), 169.3(C=O), 167.3(C-3), 155.0(C=N), 138.9, 133.1, 132.2, 130.2, 122.7(tolyl-C), 138.4, 135.7, 129.7, 129.3, 126.9, 124.8(benzoyl-C), 39.9(CH3SO3H), 21.6(tolyl-CH3), 19.8(benzoyl-CH3).68.7% yield (white solid); mp 210-211 ° C; IR (KBr) 3374, 3082, 1712, 1590, 1200 cm −1 ; 1 H NMR (300 MHz, DMSO- d 6 ) δ 11.6 (s, 1H, SO 3 H), 8.60 (br s, NH 2 ), 8.33 (br s, NH 2 ), 8.05 (m, 3H), 7.83 (m, 1H), 7.56 (m, 1H), 7.47 (m, 2H), 2.70 (s, 3H, tolyl - CH 3 ), 2.52 (s, 3H, benzoyl-CH 3 ), 2.41 (CH 3 SO 3 H); 13 C NMR (75 MHz, DMSO- d 6 ) δ 176.5 (C-5), 169.3 (C = O), 167.3 (C-3), 155.0 (C = N), 138.9, 133.1, 132.2, 130.2, 122.7 (tolyl-C), 138.4, 135.7, 129.7, 129.3, 126.9, 124.8 (benzoyl-C), 39.9 (CH 3 SO 3 H), 21.6 (tolyl-CH 3 ), 19.8 (benzoyl-CH 3 ).

실시예 37. N-[2-메틸-4-(5-m-토릴-[1,2,4]옥사디아졸-3-일)-벤조일]구아니딘 메탄설포네이트의 합성 Example 37. Synthesis of N- [2-methyl-4- (5- m -tolyl- [1,2,4] oxadiazol-3-yl) -benzoyl] guanidine methanesulfonate

질소 기류하에서 구아니딘 염화수소 840.66 mg(8.80 mmol, 4.0 eq.)에 DMF 와 1,4-디옥산의 혼합용액 10 mL(1:1)을 넣어 용해시키고 여기에 칼륨 tert-부톡사이드 987.54 mg(8.80 mmol, 4.0 eq.)을 넣어 50 ℃에서 20분 교반하였다. 반응용액을 여과하여 불용물을 제거하고 여액을 2-메틸-4-(5-m-토릴-[1,2,4]옥사디아졸-3-일)벤조산 메틸 에스테르(678 mg, 2.20 mmole)의 DMF 용액(5 mL)에 넣고 70 ℃에서 30분 가열하였다. 반응용액을 감압 농축하고 잔류물을 컬럼 크로마토그래피(CH2Cl2:MeOH=9:1)로 분리하여 N-[2-메틸-4-(5-m-토릴-[1,2,4]옥사디아졸-3-일)-벤조일]구아니딘 560 mg(1.67 mmol)을 얻었다. 얻어진 화합물에 아세톤과 MeOH 혼합용액 10 mL(1:1)을 넣어 용해시키고 메탄설폰산 129.86 μL(2.00 mmol)을 넣어 실온에서 30분 교반하였다. 생성된 화합물을 여과하여 상기 화합물의 흰색 고체 648 mg(68.3%)을 얻었다.10 mL (1: 1) of a mixed solution of DMF and 1,4-dioxane was dissolved in 840.66 mg (8.80 mmol, 4.0 eq.) Of guanidine hydrogen chloride under nitrogen stream, and 987.54 mg (8.80 mmol) of potassium tert -butoxide was added thereto. , 4.0 eq.) And stirred at 50 ° C. for 20 minutes. The reaction solution was filtered to remove insolubles and the filtrate was purified by 2-methyl-4- (5- m -tolyl- [1,2,4] oxadiazol-3-yl) benzoic acid methyl ester (678 mg, 2.20 mmole). Into DMF solution (5 mL) and heated at 70 ° C. for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was separated by column chromatography (CH 2 Cl 2 : MeOH = 9: 1) to obtain N- [2-methyl-4- (5- m -tolyl- [1,2,4] 560 mg (1.67 mmol) of oxadiazol-3-yl) -benzoyl] guanidine were obtained. 10 mL (1: 1) of acetone and MeOH mixed solution were added to the obtained compound, and 129.86 μL (2.00 mmol) of methanesulfonic acid was added thereto, followed by stirring at room temperature for 30 minutes. The resulting compound was filtered to give 648 mg (68.3%) of a white solid of the compound.

68.3% yield(white solid); mp 222-223 ℃; IR(KBr) 3364, 3115, 1710, 1593, 1220 cm-1; 1H NMR(300 MHz, DMSO-d 6) δ 11.6(s, 1H, SO3 H), 8.6(br s, NH2), 8.32(br s, NH2), 8.04(m, 2H), 7.96(m, 2H), 7.82(m, 1H), 7.53(d, 2H), 2.52(s, 3H, benzoyl-CH3), 2.42(s, 3H, tolyl-CH3), 2.41(CH3SO3H); 13C NMR(75 MHz, DMSO-d 6) δ 175.2(C-5), 169.3(C=O), 167.7(C-3), 155.0(C=N), 139.4, 134.4, 129.7, 129.2, 125.3, 123.3(tolyl-C), 138.5, 135.6, 129.8, 129.3, 128.5, 124.8(benzoyl-C), 39.9(CH3SO3H), 21.0(tolyl-CH3), 19.7(benzoyl-CH3).68.3% yield (white solid); mp 222-223 ° C; IR (KBr) 3364, 3115, 1710, 1593, 1220 cm −1 ; 1 H NMR (300 MHz, DMSO- d 6 ) δ 11.6 (s, 1H, SO 3 H), 8.6 (br s, NH 2 ), 8.32 (br s, NH 2 ), 8.04 (m, 2H), 7.96 (m, 2H), 7.82 (m, 1H), 7.53 (d, 2H), 2.52 (s, 3H, benzoyl-CH 3 ), 2.42 (s, 3H, tolyl - CH 3 ), 2.41 (CH 3 SO 3 H); 13 C NMR (75 MHz, DMSO- d 6 ) δ 175.2 (C-5), 169.3 (C = O), 167.7 (C-3), 155.0 (C = N), 139.4, 134.4, 129.7, 129.2, 125.3 , 123.3 (tolyl-C), 138.5, 135.6, 129.8, 129.3, 128.5, 124.8 (benzoyl-C), 39.9 (CH 3 SO 3 H), 21.0 (tolyl-CH 3 ), 19.7 (benzoyl-CH 3 ).

실시예 38. N-[2-메틸-4-(5-p-토릴-[1,2,4]옥사디아졸-3-일)-벤조일]구아니딘 메탄설포네이트의 합성 Example 38. Synthesis of N- [2-methyl-4- (5- p -tolyl- [1,2,4] oxadiazol-3-yl) -benzoyl] guanidine methanesulfonate

질소 기류하에서 구아니딘 염화수소 680.17 mg(7.12 mmol, 4.0 eq.)에 DMF 와 1,4-디옥산의 혼합용액 10 mL(1:1)을 넣어 용해시키고 여기에 칼륨 tert-부톡사이드 799.01 mg(7.12 mmol, 4.0 eq.)을 넣어 50 ℃에서 20분 교반하였다. 반응용액을 여과하여 불용물을 제거하고 여액을 2-메틸-4-(5-p-토릴-[1,2,4]옥사디아졸-3-일)벤조산 메틸 에스테르(550 mg, 1.78 mmol)의 DMF 용액(10 mL)에 넣고 70 ℃에서 30분 가열하였다. 반응용액을 감압 농축하고 잔류물을 컬럼 크로마토그래피(CH2Cl2:MeOH=9:1)로 분리하여 N-[2-메틸-4-(5-p-토릴-[1,2,4]옥사디아졸-3-일)-벤조일]구아니딘 110 mg(0.33 mmol)을 얻었다. 얻어진 화합물에 아세톤과 MeOH 혼합용액 10 mL(1:1)을 넣어 용해시키고 메탄설폰산 25.97 μL(0.40 mmol)을 넣어 실온에서 30분 교반하였다. 생성된 화합물을 여과하여 상기 화합물의 흰색 고체 110 mg(14.3%)을 얻었다.10 mL (1: 1) of a mixed solution of DMF and 1,4-dioxane was dissolved in 680.17 mg (7.12 mmol, 4.0 eq.) Of guanidine hydrogen chloride under nitrogen stream, and 799.01 mg (7.12 mmol) of potassium tert -butoxide was added thereto. , 4.0 eq.) And stirred at 50 ° C. for 20 minutes. The reaction solution was filtered to remove insolubles and the filtrate was purified by 2-methyl-4- (5- p -tolyl- [1,2,4] oxadiazol-3-yl) benzoic acid methyl ester (550 mg, 1.78 mmol). Into DMF solution (10 mL) and heated at 70 ° C for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was separated by column chromatography (CH 2 Cl 2 : MeOH = 9: 1) to obtain N- [2-methyl-4- (5- p -tolyl- [1,2,4] 110 mg (0.33 mmol) of oxadiazol-3-yl) -benzoyl] guanidine were obtained. 10 mL (1: 1) of acetone and MeOH mixed solution were added to the obtained compound, and 25.97 μL (0.40 mmol) of methanesulfonic acid was added thereto, followed by stirring at room temperature for 30 minutes. The resulting compound was filtered to give 110 mg (14.3%) of a white solid of the compound.

14.3% yield(white solid); mp 247-248 ℃; IR(KBr) 3366, 3152, 2927, 1720, 1704, 1210 cm-1; 1H NMR(300 MHz, DMSO-d 6) δ 11.6(s, 1H, SO 3H), 8.61(br s, NH2), 8.31(br s, NH2), 8.04(m, 4H), 7.82(m, 1H), 7.46(d, 2H), 2.52(benzoyl-CH3), 2.40(s, 6H, tolyl-CH3, CH3SO3H); 13C NMR(75 MHz, DMSO- d 6) δ 176.0(C-5), 169.3(C=O), 167.6(C-3), 155.0(C=N), 144.2, 130.4, 120.7(tolyl-C), 138.5, 135.6, 129.8, 129.2, 128.2, 124.8(benzoyl-C), 39.9(CH3SO3H), 21.4(tolyl-CH 3), 20.0(benzoyl-CH3).14.3% yield (white solid); mp 247-248 ° C; IR (KBr) 3366, 3152, 2927, 1720, 1704, 1210 cm −1 ; 1 H NMR (300 MHz, DMSO- d 6 ) δ 11.6 (s, 1H, SO 3 H), 8.61 (br s, NH 2 ), 8.31 (br s, NH 2 ), 8.04 (m, 4H), 7.82 (m, 1H), 7.46 (d, 2H), 2.52 (benzoyl-CH 3 ), 2.40 (s, 6H, tolyl-CH 3 , CH 3 SO 3 H); 13 C NMR (75 MHz, DMSO- d 6 ) δ 176.0 (C-5), 169.3 (C = O), 167.6 (C-3), 155.0 (C = N), 144.2, 130.4, 120.7 (tolyl-C ), 138.5, 135.6, 129.8, 129.2, 128.2, 124.8 (benzoyl-C), 39.9 (CH 3 SO 3 H), 21.4 (tolyl-CH 3 ), 20.0 (benzoyl-CH 3 ).

실시예 39. N-{4-[5-(2-시아노페닐)-[1,2,4]옥사디아졸-3-일]-2-메틸벤조일}구아니딘 메탄설포네이트의 합성 Example 39. Synthesis of N- {4- [5- (2-cyanophenyl)-[1,2,4] oxadiazol-3-yl] -2-methylbenzoyl} guanidine methanesulfonate

질소 기류하에서 구아니딘 염화수소 779.52 mg(8.16 mmol, 4.0 eq.)에 DMF 와 1,4-디옥산의 혼합용액 10 mL(1:1)을 넣어 용해시키고 여기에 칼륨 tert-부톡사이드 915.72 mg(8.16 mmol, 4.0 eq.)을 넣어 50 ℃에서 20분 교반하였다. 반응용액을 여과하여 불용물을 제거하고 여액을 4-[5-(2-시아노페닐)-[1,2,4]옥사디아졸-3-일]-2-메틸벤조산 메틸 에스테르(650 mg, 2.04 mmol)의 DMF 용액(10 mL)에 넣고 70 ℃에서 30분 가열하였다. 반응용액을 감압 농축하고 잔류물을 컬럼 크로 마토그래피(CH2Cl2:MeOH=9:1)로 분리하여 N-{4-[5-(2-시아노-페닐)-[1,2,4]옥사디아졸-3-일]-2-메틸벤조일}구아니딘 78 mg(0.23 mmol)을 얻었다. 얻어진 화합물에 아세톤과 MeOH 혼합용액 5 mL(1:1)을 넣어 용해시키고 메탄설폰산 18.18 μL(0.28 mmol)을 넣어 실온에서 30분 교반하였다. 생성된 화합물을 여과하여 상기 화합물의 흰색 고체 66 mg(7.3%)을 얻었다.Dissolve 10 mL (1: 1) of DMF and 1,4-dioxane in 779.52 mg (8.16 mmol, 4.0 eq.) Of guanidine hydrogen chloride under nitrogen stream, and dissolve 915.72 mg (8.16 mmol) of potassium tert -butoxide. , 4.0 eq.) And stirred at 50 ° C. for 20 minutes. The reaction solution was filtered to remove insolubles and the filtrate was washed with 4- [5- (2-cyanophenyl)-[1,2,4] oxadiazol-3-yl] -2-methylbenzoic acid methyl ester (650 mg). , 2.04 mmol) in a DMF solution (10 mL) and heated at 70 ° C. for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was separated by column chromatography (CH 2 Cl 2 : MeOH = 9: 1) to obtain N- {4- [5- (2-cyano-phenyl)-[1,2, 4] oxadiazol-3-yl] -2-methylbenzoyl} guanidine 78 mg (0.23 mmol) were obtained. 5 mL (1: 1) of acetone and MeOH mixed solution were added to the obtained compound, and 18.18 μL (0.28 mmol) of methanesulfonic acid was added thereto, followed by stirring at room temperature for 30 minutes. The resulting compound was filtered to give 66 mg (7.3%) of a white solid of the compound.

7.3% yield(white solid); mp 263-264 ℃; IR(KBr) 3374, 3150, 2235, 1712, 1592, 1203 cm-1; 1H NMR(300 MHz, DMSO-d 6) δ 11.6(s, 1H, SO 3H), 8.64(m, 1H), 8.50(m, 1H), 8.22(m, 1H), 8.10(m, 2H), 7.86(m, 2H), 2.54(benzoyl-CH3), 2.33(CH3SO 3H).7.3% yield (white solid); mp 263-264 ° C; IR (KBr) 3374, 3150, 2235, 1712, 1592, 1203 cm −1 ; 1 H NMR (300 MHz, DMSO- d 6 ) δ 11.6 (s, 1H, SO 3 H), 8.64 (m, 1H), 8.50 (m, 1H), 8.22 (m, 1H), 8.10 (m, 2H ), 7.86 (m, 2H), 2.54 (benzoyl-CH 3 ), 2.33 (CH 3 SO 3 H).

실시예 40. N-{4-[5-(6-클로로피리딘-3-일)-[1,2,4]옥사디아졸-3-일]-2-메틸벤조일}구아니딘의 합성 Example 40. Synthesis of N- {4- [5- (6-chloropyridin-3-yl)-[1,2,4] oxadiazol-3-yl] -2-methylbenzoyl} guanidine

질소 기류하에서 구아니딘 염화수소 393.58 mg(4.12 mmol, 4.0 eq.)에 DMF 와 1,4-디옥산의 혼합용액 15 mL(1:1)을 넣어 용해시키고 여기에 칼륨 tert-부톡사이드 462.35 mg(4.12 mmol, 4.0 eq.)을 넣어 50 ℃에서 20분 교반하였다. 반응용액을 여과하여 불용물을 제거하고 여액을 4-[5-(6-클로로피리딘-3-일)-[1,2,4]-옥사디아졸-3-일]-2-메틸벤조산 메틸 에스테르(340 mg, 1.03 mmole)의 DMF 용액(5 mL)에 넣고 70 ℃에서 30분 가열하였다. 반응용액을 감압 농축하고 잔류물을 컬럼 크로마토그래피(CH2Cl2:MeOH=9:1)로 분리하여 상기 화합물의 흰색 고체 170 mg(46.3%)을 얻었다.Dissolve 15 mL (1: 1) of DMF and 1,4-dioxane in 393.58 mg (4.12 mmol, 4.0 eq.) Of guanidine hydrogen chloride under nitrogen stream, and dissolve 462.35 mg (4.12 mmol) of potassium tert -butoxide. , 4.0 eq.) And stirred at 50 ° C. for 20 minutes. The reaction solution was filtered to remove insolubles and the filtrate was washed with 4- [5- (6-chloropyridin-3-yl)-[1,2,4] -oxadiazol-3-yl] -2-methylbenzoate. To a DMF solution (5 mL) of ester (340 mg, 1.03 mmole) was heated at 70 ° C. for 30 minutes. The reaction solution was concentrated under reduced pressure and the residue was separated by column chromatography (CH 2 Cl 2 : MeOH = 9: 1) to give 170 mg (46.3%) of a white solid of the compound.

46.3% yield(white solid); mp 260-262 ℃; IR(KBr) 3400, 3298, 3068, 1614 cm-1; 1H NMR(300 MHz, DMSO-d 6) δ 8.85(d, 1H, pyridyl-H), 8.14(dd, 1H, pyridyl-H), 7.82(m, 3H, benzoyl-H), 6.82(d, 1H, pyridyl-H), 2.52(s, 3H, CH3); 13C NMR(75 MHz, DMSO-d 6) δ 178.0(C=O), 174.9(C-5), 167.7(C-3), 162.3(C=N), 160.4, 148.8, 136.1, 107.2, 106.0(pyridyl-C), 142.6, 137.2, 129.5, 129.3, 126.6, 124.1(benzoyl-C), 20.7(CH3).46.3% yield (white solid); mp 260-262 ° C; IR (KBr) 3400, 3298, 3068, 1614 cm −1 ; 1 H NMR (300 MHz, DMSO- d 6 ) δ 8.85 (d, 1H, pyridyl-H), 8.14 (dd, 1H, pyridyl-H), 7.82 (m, 3H, benzoyl-H), 6.82 (d, 1H, pyridyl-H), 2.52 (s, 3H, CH 3 ); 13 C NMR (75 MHz, DMSO- d 6 ) δ 178.0 (C = O), 174.9 (C-5), 167.7 (C-3), 162.3 (C = N), 160.4, 148.8, 136.1, 107.2, 106.0 (pyridyl-C), 142.6, 137.2, 129.5, 129.3, 126.6, 124.1 (benzoyl-C), 20.7 (CH 3 ).

실시예 41. N-{2-메틸-4-[5-(6-메틸피리딘-3-일)-[1,2,4]옥사디아졸-3-일]-벤조일}구아니딘의 합성 Example 41.Synthesis of N- {2-methyl-4- [5- (6-methylpyridin-3-yl)-[1,2,4] oxadiazol-3-yl] -benzoyl} guanidine

질소 기류하에서 구아니딘 염화수소 940.02 mg(9.84 mmol, 4.0 eq.)에 DMF 와 1,4-디옥산의 혼합용액 20 mL(1:1)을 넣어 용해시키고 여기에 칼륨 tert-부톡사이드 1.10 g(9.84 mmol, 4.0 eq.)을 넣어 50 ℃에서 20분 교반하였다. 반응용액을 여과하여 불용물을 제거하고 여액을 2-메틸-4-[5-(6-메틸피리딘-3-일)-[1,2,4]옥사디아졸-3-일]벤조산 메틸 에스테르(760 mg, 2.46 mmol)의 DMF 용액(10 mL)에 넣고 70 ℃에서 30분 가열하였다. 반응용액을 감압 농축하고 잔류물을 컬럼 크로마토그래피(CH2Cl2:MeOH=9:1)로 분리하여 상기 화합물의 흰색 고체 480 mg(58.0 %)을 얻었다.In a stream of nitrogen, 20 mL (1: 1) of a mixed solution of DMF and 1,4-dioxane was dissolved in 940.02 mg (9.84 mmol, 4.0 eq.) Of guanidine hydrogen chloride, and 1.10 g (9.84 mmol) of potassium tert -butoxide was added thereto. , 4.0 eq.) And stirred at 50 ° C. for 20 minutes. The reaction solution was filtered to remove insolubles and the filtrate was 2-methyl-4- [5- (6-methylpyridin-3-yl)-[1,2,4] oxadiazol-3-yl] benzoic acid methyl ester (760 mg, 2.46 mmol) was added to a DMF solution (10 mL) and heated at 70 ° C. for 30 minutes. The reaction solution was concentrated under reduced pressure and the residue was separated by column chromatography (CH 2 Cl 2 : MeOH = 9: 1) to give 480 mg (58.0%) of a white solid of the compound.

58.0% yield(white solid); mp 261-263 ℃; IR(KBr) 3412, 3296, 3067, 1683, 1618 cm-1; 1H NMR(300 MHz, DMSO-d 6) δ 9.18(m, 1H, pyridyl-H), 8.38(dd, 1H, pyridyl-H), 7.83(m, 3H, benzoyl-H), 7.52(d, 1H, pyridyl-H), 2.58(s, 3H, pyridyl-CH3), 2.52(s, 3H, benzoyl-CH3); 13C NMR(75 MHz, DMSO-d 6) δ 178.8(C=O), 174.1(C-5), 168.2(C-3), 163.3(C=N), 163.0, 148.2, 135.8, 124.0, 117.5(pyridyl-C), 143.6, 137.2, 129.6, 129.3, 125.9, 124.1(benzoyl-C), 24.6(pyridyl-CH3), 20.8(benzoyl-CH3).58.0% yield (white solid); mp 261-263 ° C; IR (KBr) 3412, 3296, 3067, 1683, 1618 cm −1 ; 1 H NMR (300 MHz, DMSO- d 6 ) δ 9.18 (m, 1H, pyridyl-H), 8.38 (dd, 1H, pyridyl-H), 7.83 (m, 3H, benzoyl-H), 7.52 (d, 1H, pyridyl-H), 2.58 (s, 3H, pyridyl-CH 3 ), 2.52 (s, 3H, benzoyl-CH 3 ); 13 C NMR (75 MHz, DMSO- d 6 ) δ 178.8 (C = O), 174.1 (C-5), 168.2 (C-3), 163.3 (C = N), 163.0, 148.2, 135.8, 124.0, 117.5 (pyridyl-C), 143.6, 137.2, 129.6, 129.3, 125.9, 124.1 (benzoyl-C), 24.6 (pyridyl-CH 3 ), 20.8 (benzoyl-CH 3 ).

다음의 제제예들은 본 발명에 따른 일반적인 약제 조성물을 설명한 것으로서, 다음 각각의 경우에서 유효성분은 상기 화학식 1로 표시되는 화합물을 나타내며, 경우에 따라서는 본 발명에 포함되는 다른 화합물과 동등한 효과 용량으로 대체할 수도 있다.The following formulation examples illustrate a general pharmaceutical composition according to the present invention, in which the active ingredient in each case represents a compound represented by Formula 1, and in some cases at an effective dose equivalent to the other compounds included in the present invention It can also be replaced.

제제예 1. 정제 Formulation Example 1 Tablet

유효성분 250 g을 락토오스 175.9 g, 감자전분 180 g 및 콜로이드성 규산 32 g과 혼합한 다음, 이 혼합물에 10% 젤라틴 용액을 첨가시킨 후 분쇄하여 14 mesh를 통과시켰다. 그리고, 건조시킨 다음 여기에 감자전분 160 g, 활석 50 g 및 스 테아린산 마그네슘 5 g을 각각 첨가하여 얻은 혼합물을 정제로 만들었다.250 g of the active ingredient was mixed with 175.9 g of lactose, 180 g of potato starch, and 32 g of colloidal silicic acid. Then, 10% gelatin solution was added to the mixture, which was ground and passed through 14 mesh. After drying, the mixture obtained by adding 160 g of potato starch, 50 g of talc and 5 g of magnesium stearate, respectively, was made into tablets.

제제예 2. 분말과 캡슐제 Formulation Example 2 Powder and Capsule

유효성분 5.0 ㎎을 체로 친 다음, 락토스 14.8 ㎎, 폴리비닐 피롤리돈 10.0 ㎎, 및 마그네슘 스테아레이트 0.2 ㎎을 혼합하여 분말제를 얻었다. 이 분말은 적당한 장치를 사용하여 단단한 No. 5 젤라틴 캡슐에 채웠다.5.0 mg of the active ingredient was sieved, and then 14.8 mg of lactose, 10.0 mg of polyvinyl pyrrolidone, and 0.2 mg of magnesium stearate were mixed to obtain a powder. This powder is prepared by using a suitable device. Filled in 5 gelatin capsules.

제제예 3. 주사제 Formulation Example 3 Injection

유효성분 100 mg을 함유시키고, 그밖에도 만니톨 180 mg, Na2HPO4·12H2 O 26 mg, 및 증류수 2974 mg을 함유시켜 주사제를 제조하였다.Injectables were prepared by containing 100 mg of active ingredient, 26 mg of mannitol, 26 mg of Na 2 HPO 4 .12H 2 O, and 2974 mg of distilled water.

[약효활성실험] Drug Activity Test

PS120/NHE1 세포를 이용한 NHE-1 억제효과 측정Determination of NHE-1 Inhibitory Effect Using PS120 / NHE1 Cells

본 발명에 따른 몇몇 화합물에 대해서는 다음과 같은 방법으로 NHE-1 억제효과 측정하였다. Some compounds according to the present invention were measured for the inhibitory effect of NHE-1 by the following method.

CCL39-derived PS120 세포에 인간 NHE-1으로 형질전환시킨 세포를 사용하였으며, 10% 우태혈청(fetal bovine serum), 1% 페니실린/스트렙토마이신(×100 용액) 및 1% L-글루타민(200 mM 용액)이 보충된 DMEM 배양액(Dulbecco's Modified Eagle's Medium, Sigma, USA)을 사용하여 세포를 배양하였다. 직경 100 mm 디 쉬에서 약 80 ∼ 90% 키운 PS120/NHE-1 세포를 트립신 처리한 후, DPBS(Dulbecco's phosphate-buffered saline)로 1회, Na-유리 완충액(138.2 mM 콜린 클로라이드, 4.9 mM KCl, 1.5 mM CaCl2·2H2O, 1.2 mM MgSO4·7H2O, 1.2 mM KH2PO4, 15 mM D-글루코스, 20 mM HEPES, at pH 7.4)로 1회 세척하였다. 이것을 원심분리하여 Na-유리 완충액과 20 mM NH4Cl 그리고 10uM BCECF-AM의 혼합액에 부유시킨 후, 37 ℃ CO2 배양기에서 30분간 배양시켰다. NH4Cl을 제거해줌으로서 세포내 산성화를 유발시키고 동시에 세포밖에 남아있는 BCECF-AM를 세척해주기 위해, PS120/NHE-1 세포를 원심분리한 후 Na-유리 완충액로 1회 세척하고, 세포수가 2.5×104 cells/10 μL 되게 부유액을 만들어 4 ℃의 암실에 보관하였다. 96-웰 플레이트에 180 μL HBS 완충액(137 mM NaCl, 4.9 mM KCl, 1.5 mM CaCl2·2H2O, 1.2 mM MgSO4 ·7H2O, 1.2 mM KH2PO4, 15 mM D-글루코스, 20 mM HEPES, at pH 7.4)와 DMSO 또는 약물(0.03 ∼ 10 μM) 10 μL 씩을 분주하여 잘 섞어준 후, 마지막으로 세포내 산성화가 유발된 PS120/NHE-1 세포를 10 μL 씩 첨가하여 교반시켰다. 세포를 첨가한 후 4분 뒤에 96-웰 플레이트용 형광분광광도계(XEMINI-XS; Molecular Device)를 사용하여 형광(Excitation 485/444 nm, Emission 535 nm)을 측정하였다. 측정된 형광값은 high-K+/nigericin technique을 이용하여 pH로 환산하였다. NH4Cl prepulse로 세포내 산성화를 유발시킨 세포는 NHE-1의 작동에 의해 세포내 산성화가 다시 정상 으로 회복되게 되는데, 이때 세포내 산성화의 회복을 50% 억제시키는 약물의 농도를 구하여(IC50 값) 약물간의 약효를 상호 비교하였다. 이상의 실험 결과는 다음 표 1에 나타내었다.CCL39-derived PS120 cells were transformed with human NHE-1 cells, 10% fetal bovine serum, 1% penicillin / streptomycin (× 100 solution) and 1% L-glutamine (200 mM solution). Cells were cultured using DMEM medium supplemented with Dulbecco's Modified Eagle's Medium, Sigma, USA. After trypsinizing PS120 / NHE-1 cells grown about 80-90% in a 100 mm diameter dish, once with Dulbecco's phosphate-buffered saline (DPBS), Na-glass buffer (138.2 mM choline chloride, 4.9 mM KCl, 1.5 mM CaCl 2 · 2H 2 O, 1.2 mM MgSO 4 · 7H 2 O, 1.2 mM KH 2 PO 4 , 15 mM D-glucose, 20 mM HEPES, at pH 7.4). This was centrifuged and suspended in a mixture of Na-glass buffer, 20 mM NH 4 Cl and 10 uM BCECF-AM, followed by incubation for 30 minutes in a 37 ° C. CO 2 incubator. PS120 / NHE-1 cells were centrifuged and washed once with Na-glass buffer to remove NH 4 Cl to induce intracellular acidification and simultaneously wash out extracellular BCECF-AM. Suspensions were made to × 10 4 cells / 10 μL and stored in the dark at 4 ℃. 180 μL HBS buffer (137 mM NaCl, 4.9 mM KCl, 1.5 mM CaCl 2 · 2H 2 O, 1.2 mM MgSO 4 · 7H 2 O, 1.2 mM KH 2 PO 4 , 15 mM D-glucose, 20 in a 96-well plate, 20 After dispensing and mixing 10 μL of DM HEPES, at pH 7.4) and DMSO or drug (0.03 to 10 μM), finally, 10 μL of PS120 / NHE-1 cells inducing intracellular acidification were added and stirred. Four minutes after the addition of the cells, fluorescence (Excitation 485/444 nm, Emission 535 nm) was measured using a fluorescence spectrophotometer (XEMINI-XS; Molecular Device) for 96-well plates. The measured fluorescence value was converted to pH using high-K + / nigericin technique. Cells that induced intracellular acidification with NH 4 Cl prepulse are restored to normal intracellular acidification by the operation of NHE-1. At this time, a concentration of a drug that inhibits the recovery of intracellular acidification by 50% is obtained (IC 50). Values) Drug efficacy was compared between drugs. The experimental results are shown in Table 1 below.

시험화합물Test compound 세포시험Cell test NHE-1 (IC50, μM)NHE-1 (IC 50 , μM) Ratio (new/caripo)Ratio (new / caripo) PS120 (IC50, μM)PS120 (IC 50 , μM) 대조군 (Cariporide)Control (Cariporide) 1.01.0 1.01.0 > 30> 30 실시예 31Example 31 0.50.5 0.70.7 > 30> 30 실시예 32Example 32 0.50.5 0.70.7 > 30> 30 실시예 33Example 33 1.01.0 1.41.4 > 30> 30 실시예 36Example 36 0.90.9 1.71.7 > 30> 30 실시예 37Example 37 0.80.8 1.51.5 > 30> 30 실시예 38Example 38 0.80.8 1.51.5 > 30> 30 실시예 39Example 39 0.40.4 0.80.8 > 30> 30 실시예 40Example 40 0.30.3 0.60.6 > 30> 30 실시예 41Example 41 0.30.3 0.60.6 > 30> 30

상기 표 1의 결과에 의하면, 본 발명에 따른 화합물은 비교물질인 캐리포라이드(cariporide)와 비교하여 NHE-1 억제효과가 우수하였고, 특히 실시예 40과 실시예 41의 화합물은 매우 우수한 효과를 나타냄을 확인할 수 있었다.According to the results of Table 1, the compound according to the present invention was superior to the NHE-1 inhibitory effect compared to the comparative material (cariporide), especially the compounds of Examples 40 and 41 have a very good effect Could be confirmed.

이상에서 살펴본 바와 같이 본 발명의 방법으로 제조되는 1,2,4-옥사디아졸이 치환된 벤조일구아니딘 유도체는 심경색과 협심증 및 부정맥 등의 심혈관 관련 치료약물에 응용될 수 있고 이미 임상 실험중에 있는 캐리포라이드(cariporide)와 비교했을 때 세포 실험에서 더욱 우수한 NHE-1 억제효과를 나타내었다. As described above, 1,2,4-oxadiazole-substituted benzoylguanidine derivatives prepared by the method of the present invention can be applied to cardiovascular related therapeutic drugs such as cardiac infarction, angina pectoris and arrhythmia, and are already in clinical trials. Cell experiments showed better NHE-1 inhibitory effects when compared to cariporide.

Claims (8)

다음 화학식 1로 표시되는 1,2,4-옥사디아졸이 치환된 벤조일구아니딘 유도체 또는 이의 약학적으로 허용 가능한 염 :A benzoylguanidine derivative substituted with 1,2,4-oxadiazole represented by the following formula (1) or a pharmaceutically acceptable salt thereof: [화학식 1][Formula 1]
Figure 112006021533420-pat00003
Figure 112006021533420-pat00003
 상기 화학식 1에서, R1은 수소원자, 할로겐원자, 및 C1-C6 알킬기 중에서 선택되고; R2는 페닐기, 피리딘기, 티오펜기, 및 퀴놀린기 중에서 선택된 방향족기를 나타내며, 상기한 페닐기, 피리딘기, 티오펜기, 및 퀴놀린기 중에서 선택된 방향족기는 할로겐 원자, 시아노기, 및 C1-C6 알킬기 중에서 선택된 1 내지 3개의 치환체로 치환될 수 있다. In Formula 1, R 1 is selected from a hydrogen atom, a halogen atom, and a C 1 -C 6 alkyl group; R 2 represents an aromatic group selected from a phenyl group, a pyridine group, a thiophene group, and a quinoline group, and the aromatic group selected from the phenyl group, pyridine group, thiophene group, and quinoline group is a halogen atom, cyano group, and C 1 -C It may be substituted with 1 to 3 substituents selected from 6 alkyl groups. 제 1 항에 있어서, 상기 화학식 1로 표시되는 화합물이 According to claim 1, wherein the compound represented by the formula (1) N-[2-클로로-4-(5-피리딘-3-일-[1,2,4]옥사디아졸-3-일)-벤조일]구아니딘, N- [2-chloro-4- (5-pyridin-3-yl- [1,2,4] oxadiazol-3-yl) -benzoyl] guanidine, N-[2-클로로-4-(5-티오펜-3-일-[1,2,4]옥사디아졸-3-일)-벤조일]구아니딘, N- [2-chloro-4- (5-thiophen-3-yl- [1,2,4] oxadiazol-3-yl) -benzoyl] guanidine, N-[4-(5-피리딘-3-일-[1,2,4]옥사디아졸-3-일)-벤조일]구아니딘, N- [4- (5-pyridin-3-yl- [1,2,4] oxadiazol-3-yl) -benzoyl] guanidine, N-[2-메틸-4-(5-피리딘-3-일-[1,2,4]옥사디아졸-3-일)-벤조일]구아니딘, N- [2-methyl-4- (5-pyridin-3-yl- [1,2,4] oxadiazol-3-yl) -benzoyl] guanidine, N-[2-메틸-4-(5-티오펜-3-일-[1,2,4]옥사디아졸-3-일)-벤조일]구아니딘, N- [2-methyl-4- (5-thiophen-3-yl- [1,2,4] oxadiazol-3-yl) -benzoyl] guanidine, N-[2-메틸-4-(5-페닐-[1,2,4]옥사디아졸-3-일)-벤조일]구아니딘, N- [2-methyl-4- (5-phenyl- [1,2,4] oxadiazol-3-yl) -benzoyl] guanidine, N-[2-메틸-4-(5-퀴놀린-3-일-[1,2,4]옥사디아졸-3-일)-벤조일]구아니딘, N- [2-methyl-4- (5-quinolin-3-yl- [1,2,4] oxadiazol-3-yl) -benzoyl] guanidine, N-{4-[5-(2-브로모페닐)-[1,2,4]옥사디아졸-3-일)-2-메틸벤조일]구아니딘, N- {4- [5- (2-bromophenyl)-[1,2,4] oxadiazol-3-yl) -2-methylbenzoyl] guanidine, N-{4-[5-(3-브로모페닐)-[1,2,4]옥사디아졸-3-일)-2-메틸벤조일}구아니딘, N- {4- [5- (3-bromophenyl)-[1,2,4] oxadiazol-3-yl) -2-methylbenzoyl} guanidine, N-{4-[5-(4-브로모페닐)-[1,2,4]옥사디아졸-3-일)-2-메틸벤조일}구아니딘, N- {4- [5- (4-bromophenyl)-[1,2,4] oxadiazol-3-yl) -2-methylbenzoyl} guanidine, N-[2-메틸-4-(5-o-토릴)-[1,2,4]옥사디아졸-3-일)-벤조일}구아니딘, N- [2-methyl-4- (5- o -tolyl)-[1,2,4] oxadiazol-3-yl) -benzoyl} guanidine, N-[2-메틸-4-(5-m-토릴)-[1,2,4]옥사디아졸-3-일)-벤조일}구아니딘, N- [2-methyl-4- (5- m -tolyl)-[1,2,4] oxadiazol-3-yl) -benzoyl} guanidine, N-[2-메틸-4-(5-p-토릴)-[1,2,4]옥사디아졸-3-일)-벤조일]구아니딘, N- [2-methyl-4- (5- p -tolyl)-[1,2,4] oxadiazol-3-yl) -benzoyl] guanidine, N-{4-[5-(2-시아노페닐)-[1,2,4]옥사디아졸-3-일)-2-메틸벤조일}구아니딘, N- {4- [5- (2-cyanophenyl)-[1,2,4] oxadiazol-3-yl) -2-methylbenzoyl} guanidine, N-{4-[5-(6-클로로피리딘-3-일)-[1,2,4]옥사디아졸-3-일)-2-메틸벤조일}구아니딘, N- {4- [5- (6-chloropyridin-3-yl)-[1,2,4] oxadiazol-3-yl) -2-methylbenzoyl} guanidine, N-{2-메틸-4-[5-(6-메틸피리딘-3-일)-[1,2,4]옥사디아졸-3-일)-벤조일}구아니딘, 및 N- {2-methyl-4- [5- (6-methylpyridin-3-yl)-[1,2,4] oxadiazol-3-yl) -benzoyl} guanidine, and 이들의 약학적으로 허용 가능한 염 중에서 선택되는 것임을 특징으로 하는 화합물.A compound characterized in that it is selected from pharmaceutically acceptable salts thereof. 제 1 항에 있어서, 상기 약학적으로 허용 가능한 염이 염산, 메틸설폰산, p-톨루엔설폰산, 옥살산, 퓨마르산, 및 타르타르산 중에서 선택된 산의 염인 것을 특징으로 하는 화합물. The compound of claim 1, wherein the pharmaceutically acceptable salt is a salt of an acid selected from hydrochloric acid, methylsulfonic acid, p -toluenesulfonic acid, oxalic acid, fumaric acid, and tartaric acid. a) 다음 화학식 2로 표시되는 4-시아노벤조산 메틸 에스테르 유도체를 하이드록실아민 염화수소과의 첨가반응하여 다음 화학식 3으로 표시되는 화합물을 합성하는 과정;a) adding a 4-cyanobenzoic acid methyl ester derivative represented by the following Chemical Formula 2 with hydroxylamine hydrogen chloride to synthesize a compound represented by the following Chemical Formula 3; b) 상기 화학식 3으로 표시되는 화합물과 다음 화학식 4로 표시되는 유기산 화합물을 고리화 반응하여 다음 화학식 5로 표시되는 화합물을 합성하는 과정; 및b) cyclizing a compound represented by Chemical Formula 3 and an organic acid compound represented by Chemical Formula 4 to synthesize a compound represented by Chemical Formula 5; And c) 상기 화학식 5로 표시되는 화합물을 구아니딘으로 치환반응하여 다음 화학식 1로 표시되는 1,2,4-옥사디아졸이 치환된 벤조일구아니딘 유도체를 합성하는 과정c) a process of synthesizing the benzoylguanidine derivative substituted with 1,2,4-oxadiazole represented by the following Chemical Formula 1 by replacing the compound represented by Chemical Formula 5 with guanidine 이 포함되는 것을 특징으로 하는 제조방법 :Manufacturing method characterized in that it includes:
Figure 112004015018597-pat00004
Figure 112004015018597-pat00004
Figure 112004015018597-pat00005
Figure 112004015018597-pat00005
Figure 112004015018597-pat00006
Figure 112004015018597-pat00006
Figure 112004015018597-pat00007
Figure 112004015018597-pat00007
 [화학식 1][Formula 1]
Figure 112004015018597-pat00008
Figure 112004015018597-pat00008
 상기 화학식에서, R1 및 R2는 각각 상기 청구항 1에서 정의한 바와 같다.In the above formula, R 1 and R 2 are as defined in claim 1, respectively. 제 4 항에 있어서, 상기 첨가반응은 알킬아민 염기의 존재 하에서 수행하는 것을 특징으로 하는 제조방법. The method according to claim 4, wherein the addition reaction is carried out in the presence of an alkylamine base. 제 4 항에 있어서, 상기 고리화 반응은 1-(3-디메틸아미노프로필)-3-에틸카 보디이미드(EDCI)와 4-디메틸아미노피리딘(DMAP)의 존재 하에서 수행하는 것을 특징으로 하는 제조방법. The method according to claim 4, wherein the cyclization reaction is carried out in the presence of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDCI) and 4-dimethylaminopyridine (DMAP). . 제 4 항에 있어서, 상기 구아니딘 치환반응에 사용되는 구아니딘은, 구아니딘 염화수소를 N,N-디메틸포름아마이드(DMF) 단독용매 또는 N,N-디메틸포름아마이드(DMF)와 1,4-디옥산의 혼합용매 상에서 칼륨 tert-부톡사이드로 처리한 유리염기(free base)인 것을 특징으로 하는 제조방법. The guanidine to be used in the guanidine substitution reaction is a guanidine hydrogen chloride of N , N -dimethylformamide (DMF) alone solvent or N , N -dimethylformamide (DMF) and 1,4-dioxane A free base treated with potassium tert -butoxide in a mixed solvent. 다음 화학식 1로 표시되는 1,2,4-옥사디아졸이 치환된 벤조일구아니딘 유도체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 것을 특징으로 하는 심경색, 협심증, 부정맥의 심혈관계 질환의 치료 및 예방용 약제 조성물 :Of cardiovascular disease of infarction, angina, arrhythmia, characterized in that it comprises a benzoylguanidine derivative substituted with 1,2,4-oxadiazole represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient Pharmaceutical compositions for treatment and prevention: [화학식 1][Formula 1]
Figure 112006021533420-pat00009
Figure 112006021533420-pat00009
 상기 화학식 1에서, R1 및 R2는 각각 상기 청구항 1에서 정의한 바와 같다.In Formula 1, R 1 and R 2 are as defined in claim 1, respectively.
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