KR102614653B1 - Novel heterocyclyl-phenyl-methylamine derivatives, preparation method thereof, and use thereof for preventing, improving, or treating multiple sclerosis - Google Patents

Novel heterocyclyl-phenyl-methylamine derivatives, preparation method thereof, and use thereof for preventing, improving, or treating multiple sclerosis Download PDF

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KR102614653B1
KR102614653B1 KR1020210074797A KR20210074797A KR102614653B1 KR 102614653 B1 KR102614653 B1 KR 102614653B1 KR 1020210074797 A KR1020210074797 A KR 1020210074797A KR 20210074797 A KR20210074797 A KR 20210074797A KR 102614653 B1 KR102614653 B1 KR 102614653B1
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azetidine
benzyl
carboxylate
ring
selenazol
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박기덕
박종현
박선준
김유원
김현정
김시원
김주신
최지원
김병은
리 엘리자
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한국과학기술연구원
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Abstract

본 발명은 일련의 신규한 헤테로사이클릴-페닐-메틸아민 유도체, 이의 제조방법 및 이의 다발성 경화증 예방, 개선 또는 치료 용도에 관한 것이다.The present invention relates to a series of novel heterocyclyl-phenyl-methylamine derivatives, methods for their preparation and their use in preventing, ameliorating or treating multiple sclerosis.

Description

신규한 헤테로사이클릴-페닐-메틸아민 유도체, 이의 제조방법 및 이의 다발성 경화증 예방, 개선, 또는 치료 용도{Novel heterocyclyl-phenyl-methylamine derivatives, preparation method thereof, and use thereof for preventing, improving, or treating multiple sclerosis}Novel heterocyclyl-phenyl-methylamine derivatives, preparation method thereof, and use it for preventing, improving, or treating multiple sclerosis sclerosis}

본 발명은 일련의 신규한 헤테로사이클릴-페닐-메틸아민 유도체, 이의 제조방법 및 이의 다발성 경화증 예방, 개선 또는 치료 용도에 관한 것이다.The present invention relates to a series of novel heterocyclyl-phenyl-methylamine derivatives, methods for their preparation and their use in preventing, ameliorating or treating multiple sclerosis.

다발성 경화증(multiple sclerosis, MS)은 전 연령층에서 발생이 가능하며, 특히 20대에서 40대 사이에서 많이 발생한다. 이는 1868년 장 마르탱 샤르코(Jean-Martin Charcot)에 의해 기술되었으며, 여성의 발병률이 남성보다 두 배 이상 높고, 동양인이나 흑인에서 보다 유럽계 백인에게서 많이 발생한다. 또한 일부 환자에게서는 부모에게 물려 받은 유전자로 인해서 발병하기도 한다. 현대 사회에서는 서구화 되는 식단으로 인해 서양인들 뿐만 아니라 동양인들에게도 발병이 증가하는 추세이다. 다발성 경화증은 중추신경계(central nervous system; CNS)의 여러 부위에서 병소가 나타날 수 있으나, 특히, 뇌와 척수, 백질, 시신경 쪽에서 주로 나타나며, 병변이 어디서 나타나는 지에 따라 서로 다른 신경학적 이상 소견을 보인다. 같은 다발성 경화증 환자라 할지라도 사람마다 모두 증상이 다르다. 보통은 염증성 탈수초가 일어나게 되면서 발생되는, 항체 및 보체 등 면역학적 인자와 연관된 만성염증성 및 탈수초 중추신경계 자가면역성 질환이다. 탈수초는 면역세포(T-cell)에 의해서 신경 쪽의 수초(myelin sheath)에 손상이 생기게 되면서 일어나는데 이때 딱지가 생기고 경화증이 일어난다. 신호를 전달하는 수초 부분에 손상을 입게 되면서 탈수초가 되면 신호를 전달하는 속도가 병소가 나타나지 않은 사람보다 훨씬 느려지게 된다. 상처가 회복이 되면서 수초가 재형성 되더라도, 신경 말단의 반응속도는 원래대로 돌아오지 않고 느린 경향을 보인다. 다발성 경화증 환자들의 증상에는 여러 유형들이 있으며 가장 흔한 일반적인 유형은 재발-완화 반복성 다발성경화증(relapsing-remitting multiple sclerosis)이다. 다발성 경화증의 주요 증상으로는 감각 및 운동 마비, 시신경 염증, 레르미테 증상(Lhemittes symptom), 복시, 우토프 징후(uhthoff's sign) 등이 있다. 환자들의 증상은 호전되고 악화되는 것을 반복하게 되며, 이로 인한 신경 손상의 축적으로 질병이 중증으로 심각해지며, 만성질환으로 이어지기도 한다. 자가반응성 CD4＋ T 세포가 혈액에서 중추 신경계로 이동하고 미엘린에 반응하며 활성화된다. CD4＋ T 세포에서 분비하는 물질 중에는 염증을 유발하는 물질도 있고 대식세포와 B 세포를 중추신경계로 들어올 수 있게 유도하는 물질도 포함한다. 항원 결정인자함유 세포를 파괴하는 자가반응성 CD8＋ T 세포도 혈액으로부터 중추신경계로 와서 스스로 복제 증식하기 위한 재활성화가 진행된다. CD4＋ T 세포와 CD8＋ T 세포를 중추 신경계로 들어오게 유도하는 대식세포는 중추신경계에 존재하는 미세아교세포와 함께 활성화를 시키고 B 세포를 활성화 시키기 위해서 BAFF(B cell activating factor belonging to the TNF family)라는 물질을 분비시킨다. 자가 면역 반응에 의해 다발성 경화증이 생성되는 것은 대식세포가 미엘린을 파괴하고 항체와 보체로 표지된 미엘린을 포식하여 없애는 전염증성 사이토카인을 생성하는 것에 기인한다.Multiple sclerosis (MS) can occur at any age, and is especially common among people in their 20s to 40s. It was described by Jean-Martin Charcot in 1868. The incidence in women is more than twice that in men, and it occurs more often in white Europeans than in Asians or blacks. In addition, some patients may develop the disease due to genes inherited from their parents. In modern society, the disease is increasing not only in Westerners but also in Asians due to westernized diets. Multiple sclerosis can cause lesions to appear in various parts of the central nervous system (CNS), but they mainly appear in the brain, spinal cord, white matter, and optic nerves, and show different neurological abnormalities depending on where the lesions appear. Even among patients with the same multiple sclerosis, symptoms are different for each person. It is a chronic inflammatory and demyelinating central nervous system autoimmune disease that is usually caused by inflammatory demyelination and is associated with immunological factors such as antibodies and complement. Demyelination occurs when the myelin sheath of the nerve is damaged by immune cells (T-cells). At this time, scabs form and sclerosis occurs. When the part of the myelin sheath that transmits signals is damaged and demyelination occurs, the speed of signal transmission becomes much slower than in people without lesions. Even if the myelin sheath is re-formed as the wound heals, the response speed of the nerve endings does not return to its original state and tends to be slow. There are several types of symptoms in patients with multiple sclerosis, the most common type being relapsing-remitting multiple sclerosis. The main symptoms of multiple sclerosis include sensory and motor paralysis, optic nerve inflammation, Lhemettes symptoms, double vision, and uhthoff's sign. Patients' symptoms repeatedly improve and worsen, and the accumulation of nerve damage causes the disease to become more severe and sometimes lead to chronic disease. Autoreactive CD4 + T cells migrate from the blood to the central nervous system, react to myelin and become activated. Among the substances secreted by CD4 + T cells, there are substances that cause inflammation and substances that induce macrophages and B cells to enter the central nervous system. Autoreactive CD8 + T cells, which destroy cells containing antigenic determinants, also come from the blood to the central nervous system and undergo reactivation to replicate and proliferate on their own. Macrophages that induce CD4 + T cells and CD8 + T cells into the central nervous system are activated together with microglia present in the central nervous system, and BAFF (B cell activating factor belonging to the TNF family) is used to activate B cells. ) secretes a substance called Multiple sclerosis is caused by an autoimmune response because macrophages destroy myelin and produce pro-inflammatory cytokines that phagocytose and destroy myelin labeled with antibodies and complement.

현재 다발성 경화증 치료제로 많이 쓰이고 있는 노바티스사(Novatis)의 FTY720(핀골리모드; fingolimod)이 있으나 가장 큰 부작용중에 하나인 서맥(bradycardia)을 유발하므로, 부작용이 없거나 적은 새로운 치료제의 개발이 요구된다. 이러한 부작용은 S1P3 수용체를 활성화 시키기 때문이라고 보고가 되었으며, 이에 새롭게 개발되는 치료제는 S1P3 수용체를 활성화 시키지 않으면서 S1P1, S1P5를 활성화시키는 전략으로 개발되고 있다. 2019년에 FDA 승인을 받은 노바티스사의 BAF312는 S1P3를 활성화 시키지 않고 S1P1과 S1P5에 우수한 활성을 보이는 치료제로 많은 기대를 받았으나 FTY720의 부작용인 서맥이 여전히 나타났다. 이들 약물의 기전은 림프구의 면역세포에 존재하는 S1P1가 중추신경계로 나가지 못하도록 S1P1 작용제로 처리하여 하향조절(down regulation)하는 것이다. 이때 S1P1 수용체는 집락을 형성하고 내포작용으로 인해 세포 내로 들어온 후 내재화를 거쳐 분해(degradation)되어 저해되는 효과를 발휘한다. 따라서 부작용이 없거나 적으면서도 치료 효과가 우수한 약물 및/또는 치료기술 개발이 절실히 필요하다.Currently, Novartis' FTY720 (fingolimod) is widely used as a treatment for multiple sclerosis, but it causes bradycardia, one of the biggest side effects, so the development of a new treatment with no or fewer side effects is required. It has been reported that these side effects are due to activating the S1P3 receptor, and accordingly, newly developed treatments are being developed with a strategy of activating S1P 1 and S1P 5 without activating the S1P3 receptor. Novartis' BAF312, which was approved by the FDA in 2019, was highly anticipated as a treatment that showed excellent activity against S1P 1 and S1P 5 without activating S1P 3 , but bradycardia, a side effect of FTY720, still appeared. The mechanism of these drugs is to down-regulate S1P 1 present in lymphocyte immune cells by treating them with S1P 1 agonists to prevent them from going out to the central nervous system. At this time, the S1P 1 receptor forms colonies, enters the cell through endocytosis, and then internalizes and undergoes degradation to exert an inhibitory effect. Therefore, there is an urgent need to develop drugs and/or treatment technologies that have no or few side effects and have excellent therapeutic effects.

이러한 배경하에서, 본 발명자들은 부작용이 적으면서 스핑고신-1-포스페이트 수용체(sphingosine-1-phosphate receptor; S1P1) 작용제로서 우수한 활성을 나타낼 수 있는 신규한 소분자 화합물을 발굴하고자 예의 연구 노력한 결과, 일련의 헤테로사이클릴-페닐-메틸아민 유도체 및 이의 염이 혈중 림프구의 수를 현저히 감소킴은 물론, 다발성 경화증 동물 모델인 EAE 마우스에서의 운동 장애 증상의 발현을 효과적으로 지연시키거나, 현저히 회복시킴을 확인하고, 본 발명을 완성하였다.Against this background, the present inventors have made extensive research efforts to discover novel small molecule compounds that can exhibit excellent activity as a sphingosine-1-phosphate receptor (S1P1) agonist with fewer side effects, and as a result, a series of It was confirmed that heterocyclyl-phenyl-methylamine derivatives and salts thereof not only significantly reduce the number of lymphocytes in the blood, but also effectively delay or significantly restore the onset of motor dysfunction symptoms in EAE mice, an animal model of multiple sclerosis. , completed the present invention.

한국등록공보 제10-1795562호,Korean Registration Gazette No. 10-1795562, 한국등록공보 제10-1781060호.Korean Registered Publication No. 10-1781060.

본 발명의 하나의 목적은 일련의 신규한 헤테로사이클릴-페닐-메틸아민 유도체, 또는 이의 약학적으로 허용 가능한 염을 제공하는 것이다.One object of the present invention is to provide a series of novel heterocyclyl-phenyl-methylamine derivatives, or pharmaceutically acceptable salts thereof.

본 발명의 다른 하나의 목적은 상기 헤테로사이클릴-페닐-메틸아민 유도체, 또는 이의 약학적으로 허용 가능한 염의 제조방법을 제공하는 것이다.Another object of the present invention is to provide a method for producing the heterocyclyl-phenyl-methylamine derivative, or a pharmaceutically acceptable salt thereof.

본 발명의 또 다른 하나의 목적은 상기 헤테로사이클릴-페닐-메틸아민 유도체, 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 다발성 경화증(multiple sclerosis; MS)의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of multiple sclerosis (MS) containing the heterocyclyl-phenyl-methylamine derivative or a pharmaceutically acceptable salt thereof as an active ingredient. is to provide.

본 발명의 또 다른 하나의 목적은 상기 약학적 조성물을 이를 필요로 하는 개체에 투여하는 단계를 포함하는 다발성 경화증의 예방 또는 치료방법을 제공하는 것이다.Another object of the present invention is to provide a method for preventing or treating multiple sclerosis, comprising administering the pharmaceutical composition to an individual in need thereof.

본 발명의 또 다른 하나의 목적은 상기 헤테로사이클릴-페닐-메틸아민 유도체, 또는 이의 식품학적으로 허용 가능한 염을 유효성분으로 포함하는 다발성 경화증의 예방 또는 개선용 식품 조성물을 제공하는 것이다.Another object of the present invention is to provide a food composition for preventing or improving multiple sclerosis containing the heterocyclyl-phenyl-methylamine derivative or a foodologically acceptable salt thereof as an active ingredient.

본 발명의 또 다른 하나의 목적은 상기 헤테로사이클릴-페닐-메틸아민 유도체, 또는 이의 사료학적으로 허용 가능한 염을 유효성분으로 포함하는 다발성 경화증의 예방 또는 개선용 사료 조성물을 제공하는 것이다.Another object of the present invention is to provide a feed composition for preventing or improving multiple sclerosis containing the heterocyclyl-phenyl-methylamine derivative or a feed-chemically acceptable salt thereof as an active ingredient.

본 발명에서 개시되는 각각의 설명 및 실시형태는 각각의 다른 설명 및 실시 형태에도 적용될 수 있다. 즉, 본 발명에서 개시된 다양한 요소들의 모든 조합이 본 발명의 범주에 속한다. 또한, 하기 기술되는 구체적인 서술에 의하여 본 발명의 범주가 제한된다고 할 수 없다.Each description and embodiment disclosed in the present invention can also be applied to each other description and embodiment. That is, all combinations of the various elements disclosed in the present invention fall within the scope of the present invention. Additionally, it cannot be said that the scope of the present invention is limited by the specific description described below.

또한, 당해 기술분야의 통상의 지식을 가진 자는 통상의 실험만을 사용하여 본 발명에 기재된 본 발명의 특정 양태에 대한 다수의 등가물을 인지하거나 확인할 수 있다. 또한, 이러한 등가물은 본 발명에 포함되는 것으로 의도된다.Additionally, those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Additionally, such equivalents are intended to be encompassed by this invention.

아울러, 본 발명의 명세서 전체에 있어서, 어떤 부분이 어떤 구성 요소를 "포함"한다고 할 때, 이는 특별히 반대되는 기재가 없는 한 다른 구성 요소를 제외하는 것이 아니라 다른 구성 요소를 더 포함할 수 있는 것을 의미한다.In addition, throughout the specification of the present invention, when a part is said to "include" a certain component, this does not mean excluding other components, but may further include other components, unless specifically stated to the contrary. it means.

이하, 본 발명을 보다 자세히 설명한다.Hereinafter, the present invention will be described in more detail.

상기 목적을 달성하기 위한, 본 발명의 제1양태는 하기 화학식 1로 표시되는 화합물, 또는 이의 약학적으로 허용 가능한 염을 제공한다:In order to achieve the above object, a first aspect of the present invention provides a compound represented by the following formula (1), or a pharmaceutically acceptable salt thereof:

[화학식 1][Formula 1]

상기 화학식 1에서,In Formula 1,

Ring 1은 셀레나졸레닐(selenazolenyl) 또는 이소사졸레닐(isoxazolenyl),Ring 1 is selenazolenyl or isoxazolenyl,

Ring 2는 C6-10 아릴, 또는 5 내지 10원 헤테로아릴,Ring 2 is C 6-10 aryl, or 5 to 10 membered heteroaryl,

R1은 수소, 시아노, 할로(겐), 히드록시, C1-6 알킬, C1-6 알콕시, 및 C1-6 할로알킬로 구성된 군으로부터 선택되는 서로 동일 또는 상이한 하나 이상의 치환기,R 1 is one or more substituents that are the same or different from each other selected from the group consisting of hydrogen, cyano, halo(gen), hydroxy, C 1-6 alkyl, C 1-6 alkoxy, and C 1-6 haloalkyl,

R2 및 R3은 각각 독립적으로 수소, C1-6 알콕시카보닐-C1-6 알킬, 또는 소디움 카르복시-C1-6 알킬이거나,R 2 and R 3 are each independently hydrogen, C 1-6 alkoxycarbonyl-C 1-6 alkyl, or sodium carboxy-C 1-6 alkyl,

R2 및 R3은 서로 연결되어 이들이 결합된 질소를 포함하여 비치환 또는 치환된 3원 내지 10원 헤테로사이클릴을 형성함.R 2 and R 3 are linked to each other to form an unsubstituted or substituted 3- to 10-membered heterocyclyl including the nitrogen to which they are bonded.

예컨대, 본 발명의 화합물은 하기 화학식 2 내지 4 중 어느 하나의 화학식으로 표시될 수 있으나, 이에 제한되지 않는다:For example, the compound of the present invention may be represented by any one of the following formulas 2 to 4, but is not limited thereto:

[화학식 2][Formula 2]

[화학식 3][Formula 3]

[화학식 4][Formula 4]

. .

예컨대, 상기 화학식 1 내지 4에서, Ring 2는 페닐, 또는 피리디닐일 수 있으나, 이에 제한되지 않는다.For example, in Formulas 1 to 4, Ring 2 may be phenyl or pyridinyl, but is not limited thereto.

예컨대, 상기 화학식 1 내지 4에서, R1은 부재, 시아노, 브로모, 클로로, 히드록시, 에틸, 프로필, tert-부틸, 메톡시, 에톡시, 이소프로폭시, 클로로메틸, 또는 트리플루오로메틸일 수 있으나, 이에 제한되지 않는다. 구체적으로, R1은 전술한 치환기들로부터 선택되는 어느 하나, 또는 서로 같거나 상이한 2개일 수 있으나, 이에 제한되지 않는다.For example, in Formulas 1 to 4, R 1 is absent, cyano, bromo, chloro, hydroxy, ethyl, propyl, tert-butyl, methoxy, ethoxy, isopropoxy, chloromethyl, or trifluoro. It may be, but is not limited to, methyl. Specifically, R 1 may be any one selected from the above-described substituents, or two of the same or different substituents, but is not limited thereto.

예컨대, 상기 화학식 1 내지 4에서, R2는 수소이고, R3은 에톡시카보닐메틸, 메톡시카보닐에틸, 소디움 카르복시메틸 또는 소디움 카르복시에틸일 수 있으나, 이에 제한되지 않는다.For example, in Formulas 1 to 4, R 2 is hydrogen, and R 3 may be ethoxycarbonylmethyl, methoxycarbonylethyl, sodium carboxymethyl, or sodium carboxyethyl, but is not limited thereto.

또는, 상기 화학식 1 내지 4에서, R2 및 R3은 서로 연결되어 이들이 결합된 질소를 포함하여 비치환 또는 카르복시, 메톡시카보닐, 에톡시카보닐, tert-부톡시카보닐 및 소디움 카르복시로 구성된 군으로부터 선택되는 하나 이상으로 치환된 아제티디닐(azetidinyl), 피롤리디닐(pyrrolidinyl), 또는 피페리디닐(piperidinyl)을 형성할 수 있으나, 이에 제한되지 않는다.Alternatively, in Formulas 1 to 4, R 2 and R 3 are connected to each other, including the nitrogen to which they are bonded, and are unsubstituted or carboxy, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, and sodium carboxy. It may form azetidinyl, pyrrolidinyl, or piperidinyl substituted with one or more selected from the group consisting of, but is not limited thereto.

구체적으로, 상기 화합물은Specifically, the compound is

1. 메틸 1-(4-(2-(4-tert-부틸페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트1. Methyl 1-(4-(2-(4-tert-butylphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

2. 소디움 1-(4-(2-(4-tert-부틸페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트2. Sodium 1-(4-(2-(4-tert-butylphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

3. 에틸 1-(4-(2-(4-tert-부틸페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트3. Ethyl 1-(4-(2-(4-tert-butylphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

4. tert-부틸 1-(4-(2-(4-tert-부틸페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트4. tert-Butyl 1-(4-(2-(4-tert-butylphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

5. 메틸 1-(4-(2-(3-이소시아노-4-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트5. Methyl 1-(4-(2-(3-isocyano-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

6. 소디움 1-(4-(2-(3-이소시아노-4-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트6. Sodium 1-(4-(2-(3-isocyano-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

7. 에틸 1-(4-(2-(3-시아노-4-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트7. Ethyl 1-(4-(2-(3-cyano-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

8. tert-부틸 1-(4-(2-(3-시아노-4-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트8. tert-Butyl 1-(4-(2-(3-cyano-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

9. 메틸 1-(4-(2-(4-이소프로폭시-3-(트리플루오로메틸)페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트9. Methyl 1-(4-(2-(4-isopropoxy-3-(trifluoromethyl)phenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

10. 1-(4-(2-(4-이소프로폭시-3-(트리플루오로메틸)페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실산10. 1-(4-(2-(4-isopropoxy-3-(trifluoromethyl)phenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylic acid

11. 에틸 1-(4-(2-(4-이소프로폭시-3-(트리플루오로메틸)페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트11. Ethyl 1-(4-(2-(4-isopropoxy-3-(trifluoromethyl)phenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

12. 메틸 1-(4-(2-(3-클로로-4-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트12. Methyl 1-(4-(2-(3-chloro-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

13. 소디움 1-(4-(2-(3-클로로-4-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트13. Sodium 1-(4-(2-(3-chloro-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

14. 메틸 1-(4-(2-(3-클로로-4-에톡시페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트14. Methyl 1-(4-(2-(3-chloro-4-ethoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

15. 소디움 1-(4-(2-(3-클로로-4-에톡시페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트15. Sodium 1-(4-(2-(3-chloro-4-ethoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

16. 메틸 1-(4-(2-(4-메톡시페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트16. Methyl 1-(4-(2-(4-methoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

17. 1-(4-(2-(4-메톡시페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실산17. 1-(4-(2-(4-methoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylic acid

18. 메틸 1-(4-(2-(4-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트18. Methyl 1-(4-(2-(4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

19. 1-(4-(2-(4-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실산19. 1-(4-(2-(4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylic acid

20. 에틸 1-(4-(2-(4-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트20. Ethyl 1-(4-(2-(4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

21. 메틸 1-(4-(2-(3-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트21. Methyl 1-(4-(2-(3-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

22. 1-(4-(2-(3-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실산22. 1-(4-(2-(3-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylic acid

23. 메틸 1-(4-(2-(2-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트23. Methyl 1-(4-(2-(2-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

24. 1-(4-(2-(2-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실산24. 1-(4-(2-(2-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylic acid

25. 에틸 1-(4-(2-(2-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트25. Ethyl 1-(4-(2-(2-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

26. 메틸 1-(4-(2-(피리딘-2-일)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트26. Methyl 1-(4-(2-(pyridin-2-yl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

27. 소디움 1-(4-(2-(피리딘-2-일)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트27. Sodium 1-(4-(2-(pyridin-2-yl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

28. 메틸 1-(4-(2-(피리딘-3-일)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트28. Methyl 1-(4-(2-(pyridin-3-yl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

29. 소디움 1-(4-(2-(피리딘-3-일)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트29. Sodium 1-(4-(2-(pyridin-3-yl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

30. 메틸 1-(4-(2-(4-tert-부틸페닐)-1,3-셀레나졸-5-일)벤질)피롤리딘-3-카르복실레이트30. Methyl 1-(4-(2-(4-tert-butylphenyl)-1,3-selenazol-5-yl)benzyl)pyrrolidine-3-carboxylate

31. 소디움 1-(4-(2-(4-tert-부틸페닐)-1,3-셀레나졸-5-일)벤질)피롤리딘-3-카르복실레이트31. Sodium 1-(4-(2-(4-tert-butylphenyl)-1,3-selenazol-5-yl)benzyl)pyrrolidine-3-carboxylate

32. 메틸 1-(4-(2-(4-tert-부틸페닐)-1,3-셀레나졸-5-일)벤질)피페리딘-4-카르복실레이트32. Methyl 1-(4-(2-(4-tert-butylphenyl)-1,3-selenazol-5-yl)benzyl)piperidine-4-carboxylate

33. 메틸 1-(4-(2-(3-클로로-4-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질)피롤리딘-3-카르복실레이트33. Methyl 1-(4-(2-(3-chloro-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)pyrrolidine-3-carboxylate

34. 소디움 1-(4-(2-(3-클로로-4-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질)피롤리딘-3-카르복실레이트34. Sodium 1-(4-(2-(3-chloro-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)pyrrolidine-3-carboxylate

35. 에틸 2-(4-(2-(3-클로로-4-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질아미노)아세테이트35. Ethyl 2-(4-(2-(3-chloro-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzylamino)acetate

36. 소디움 2-(4-(2-(3-클로로-4-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질아미노)아세테이트36. Sodium 2-(4-(2-(3-chloro-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzylamino)acetate

37. 메틸 3-(4-(2-(3-클로로-4-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질아미노)프로파노에이트37. Methyl 3-(4-(2-(3-chloro-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzylamino)propanoate

38. 소디움 3-(4-(2-(3-클로로-4-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질아미노)프로파노에이트38. Sodium 3-(4-(2-(3-chloro-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzylamino)propanoate

39. 메틸 1-(4-(5-(4-tert-부틸페닐)-1,3-셀레나졸-2-일)벤질)아제티딘-3-카르복실레이트39. Methyl 1-(4-(5-(4-tert-butylphenyl)-1,3-selenazol-2-yl)benzyl)azetidine-3-carboxylate

40. 소디움 1-(4-(5-(4-tert-부틸페닐)-1,3-셀레나졸-2-일)벤질)아제티딘-3-카르복실레이트40. Sodium 1-(4-(5-(4-tert-butylphenyl)-1,3-selenazol-2-yl)benzyl)azetidine-3-carboxylate

41. 메틸 1-(4-(5-(3-클로로-4-이소프로폭시페닐)-1,3-셀레나졸-2-일)벤질)아제티딘-3-카르복실레이트41. Methyl 1-(4-(5-(3-chloro-4-isopropoxyphenyl)-1,3-selenazol-2-yl)benzyl)azetidine-3-carboxylate

42. 소디움 1-(4-(5-(3-클로로-4-이소프로폭시페닐)-1,3-셀레나졸-2-일)벤질)아제티딘-3-카르복실레이트42. Sodium 1-(4-(5-(3-chloro-4-isopropoxyphenyl)-1,3-selenazol-2-yl)benzyl)azetidine-3-carboxylate

43. 메틸 1-(4-(5-페닐-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트43. Methyl 1-(4-(5-phenyl-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate

44. 1-(4-(5-페닐-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실산44. 1-(4-(5-phenyl-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylic acid

45. 메틸 1-(4-(5-(2-브로모페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트45. Methyl 1-(4-(5-(2-bromophenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate

46. 1-(4-(5-(2-브로모페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실산46. 1-(4-(5-(2-bromophenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylic acid

47. 메틸 1-(4-(5-(3-브로모페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트47. Methyl 1-(4-(5-(3-bromophenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate

48. 1-(4-(5-(3-브로모페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실산48. 1-(4-(5-(3-bromophenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylic acid

49. 메틸 1-(4-(5-(4-브로모페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트49. Methyl 1-(4-(5-(4-bromophenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate

50. 1-(4-(5-(4-브로모페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실산50. 1-(4-(5-(4-bromophenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylic acid

51. 1-(4-(5-(4-히드록시페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실산51. 1-(4-(5-(4-hydroxyphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylic acid

52. 메틸 1-(4-(5-(4-(클로로메틸)페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트52. Methyl 1-(4-(5-(4-(chloromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate

53. 소디움 1-(4-(5-(4-(클로로메틸)페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트53. Sodium 1-(4-(5-(4-(chloromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate

54. 메틸 1-(4-(5-(4-에틸페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트54. Methyl 1-(4-(5-(4-ethylphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate

55. 소디움 1-(4-(5-(4-에틸페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트55. Sodium 1-(4-(5-(4-ethylphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate

56. 소디움 1-(4-(5-(4-프로필페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트56. Sodium 1-(4-(5-(4-propylphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate

57. 메틸 1-(4-(5-(4-tert-부틸페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트57. Methyl 1-(4-(5-(4-tert-butylphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate

58. 소디움 1-(4-(5-(4-tert-부틸페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트58. Sodium 1-(4-(5-(4-tert-butylphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate

59. 메틸 1-(4-(5-(3-시아노-4-이소프로폭시페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트59. Methyl 1-(4-(5-(3-cyano-4-isopropoxyphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate

60. 1-(4-(5-(3-시아노-4-이소프로폭시페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실산60. 1-(4-(5-(3-cyano-4-isopropoxyphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylic acid

61. 메틸 1-(4-(5-(3-클로로-4-에톡시페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트61. Methyl 1-(4-(5-(3-chloro-4-ethoxyphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate

62. 소디움 1-(4-(5-(3-클로로-4-에톡시페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트62. Sodium 1-(4-(5-(3-chloro-4-ethoxyphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate

63. 메틸 1-(4-(5-(3-클로로-4-이소프로폭시페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트63. Methyl 1-(4-(5-(3-chloro-4-isopropoxyphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate

64. 소디움 1-(4-(5-(3-클로로-4-이소프로폭시페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트64. Sodium 1-(4-(5-(3-chloro-4-isopropoxyphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate

65. 메틸 1-(4-(5-(4-이소프로폭시-3-(트리플루오로메틸)페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트65. Methyl 1-(4-(5-(4-isopropoxy-3-(trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-car voxylate

66. 소디움 1-(4-(5-(4-이소프로폭시-3-(트리플루오로메틸)페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트66. Sodium 1-(4-(5-(4-isopropoxy-3-(trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-car voxylate

67. 메틸 1-(4-(5-(피리딘-2-일)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트67. Methyl 1-(4-(5-(pyridin-2-yl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate

68. 소디움 1-(4-(5-(피리딘-2-일)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트68. Sodium 1-(4-(5-(pyridin-2-yl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate

69. 메틸 1-(4-(5-(3-클로로-4-이소프로폭시페닐)-4,5-디하이드로이속사졸-3-일)벤질)피롤리딘-3-카르복실레이트69. Methyl 1-(4-(5-(3-chloro-4-isopropoxyphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)pyrrolidine-3-carboxylate

70. 소디움 1-(4-(5-(3-클로로-4-이소프로폭시페닐)-4,5-디하이드로이속사졸-3-일)벤질)피롤리딘-3-카르복실레이트, 또는70. Sodium 1-(4-(5-(3-chloro-4-isopropoxyphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)pyrrolidine-3-carboxylate, or

71. 소디움 1-(4-(5-(3-클로로-4-이소프로폭시페닐)-4,5-디하이드로이속사졸-3-일)벤질)피페리딘-4-카르복실레이트일 수 있으나, 이에 제한되지 않는다.71. Sodium 1-(4-(5-(3-chloro-4-isopropoxyphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)piperidine-4-carboxylate However, it is not limited to this.

본 발명의 화합물은 약학적으로 허용 가능한 염의 형태로 존재할 수 있다. 염으로는 약학적으로 허용 가능한 유리산(free acid)에 의해 형성된 산가염이 유용하다. 본 발명의 용어 "약학적으로 허용 가능한 염"이란 환자에게 비교적 비독성이고 무해한 유효작용을 갖는 농도로서 이 염에 기인한 부작용이 화학식 1로 표시되는 화합물의 이로운 효능을 저하시키지 않는 상기 화합물의 임의의 모든 유기 또는 무기 부가염을 의미한다.The compounds of the present invention may exist in the form of pharmaceutically acceptable salts. As a salt, an acid salt formed by a pharmaceutically acceptable free acid is useful. The term "pharmaceutically acceptable salt" of the present invention refers to any of the compounds at a concentration that is relatively non-toxic and harmless to patients and has an effective effect, and side effects due to the salt do not reduce the beneficial efficacy of the compound represented by Formula 1. refers to all organic or inorganic addition salts of

산부가염은 통상의 방법, 예를 들어 화합물을 과량의 산 수용액에 용해시키고, 이 염을 수혼화성 유기 용매, 예를 들어 메탄올, 에탄올, 아세톤 또는 아세토니트릴을 사용하여 침전시켜서 제조한다. 동 몰량의 화합물 및 물 중의 산 또는 알코올(예, 글리콜 모노메틸에테르)을 가열하고, 이어서 상기 혼합물을 증발시켜 건조시키거나, 또는 석출된 염을 흡인 여과시킬 수 있다.Acid addition salts are prepared by conventional methods, for example, by dissolving the compound in an excess of aqueous acid and precipitating the salt using a water-miscible organic solvent, such as methanol, ethanol, acetone or acetonitrile. Equimolar amounts of the compound and an acid or alcohol (e.g., glycol monomethyl ether) in water can be heated, and the mixture can then be evaporated to dryness, or the precipitated salt can be suction filtered.

이때, 유리산으로는 유기산과 무기산을 사용할 수 있으며, 무기산으로는 염산, 인산, 황산, 질산, 주석산 등을 사용할 수 있고 유기산으로는 메탄술폰산, p-톨루엔술폰산, 아세트산, 트리플루오로아세트산, 말레인산(maleic acid), 숙신산, 옥살산, 벤조산, 타르타르산, 푸마르산(fumaric acid), 만데르산, 프로피온산(propionic acid), 구연산(ci트리c acid), 젖산(lactic acid), 글리콜산(glycollic acid), 글루콘산(gluconic acid), 갈락투론산, 글루탐산, 글루타르산(glutaric acid), 글루쿠론산(glucuronic acid), 아스파르트산, 아스코르브산, 카본산, 바닐릭산, 요오드화수소산(hydroiodic acid) 등을 사용할 수 있으며, 이들에 제한되지 않는다.At this time, organic acids and inorganic acids can be used as free acids. Hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, etc. can be used as inorganic acids, and methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, and maleic acid can be used as organic acids. (maleic acid), succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, Gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, etc. can be used. possible, and is not limited to these.

또한, 염기를 사용하여 약학적으로 허용 가능한 금속염을 만들 수 있다. 알칼리 금속염 또는 알칼리 토금속염은, 예를 들어 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해시키고, 비용해 화합물 염을 여과한 후 여액을 증발, 건조시켜 얻는다. 이때, 금속염으로는 특히 나트륨, 칼륨, 또는 칼슘염을 제조하는 것이 제약상 적합하나 이들에 제한되는 것은 아니다. 또한 이에 대응하는 은염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 은염(예, 질산은)과 반응시켜 얻을 수 있다.Additionally, a pharmaceutically acceptable metal salt can be prepared using a base. The alkali metal salt or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and then evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare metal salts, especially sodium, potassium, or calcium salts, but is not limited to these. Additionally, the corresponding silver salt can be obtained by reacting an alkali metal or alkaline earth metal salt with an appropriate silver salt (e.g., silver nitrate).

본 발명의 화합물의 약학적으로 허용 가능한 염은, 달리 지시되지 않는 한, 상기 화학식 1의 화합물에 존재할 수 있는 산성 또는 염기성 기의 염을 포함한다. 예를 들어, 약학적으로 허용 가능한 염으로는 히드록시기의 나트륨, 칼슘 및 칼륨염 등이 포함될 수 있고, 아미노기의 기타 약학적으로 허용 가능한 염으로는 히드로브롬화물, 황산염, 수소 황산염, 인산염, 수소 인산염, 이수소 인산염, 아세테이트, 숙시네이트, 시트레이트, 타르트레이트, 락테이트, 만델레이트, 메탄술포네이트(메실레이트) 및 p-톨루엔술포네이트(토실레이트) 염 등이 있으며, 당업계에 알려진 염의 제조방법을 통하여 제조될 수 있다.Pharmaceutically acceptable salts of the compounds of the present invention include salts of acidic or basic groups that may be present in the compound of formula (1), unless otherwise indicated. For example, pharmaceutically acceptable salts may include sodium, calcium, and potassium salts of hydroxy groups, and other pharmaceutically acceptable salts of amino groups include hydrobromide, sulfate, hydrogen sulfate, phosphate, and hydrogen phosphate. , dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts, etc., and the preparation of salts known in the art. It can be manufactured through a method.

본 발명의 헤테로사이클릴-페닐-메틸아민 유도체 화합물의 염으로는 약학적으로 허용 가능한 염으로서, 헤테로사이클릴-페닐-메틸아민 유도체 화합물과 동등한 약리활성을 나타내는 헤테로사이클릴-페닐-메틸아민 유도체 화합물의 염이면 제한없이 모두 사용 가능하다.Heterocyclyl-phenyl-methylamine derivatives of the present invention The salt of the compound is a pharmaceutically acceptable salt, and any salt of a heterocyclyl-phenyl-methylamine derivative compound that exhibits pharmacological activity equivalent to that of a heterocyclyl-phenyl-methylamine derivative compound can be used without limitation.

또한, 본 발명에 따른 상기 화학식 1로 표시되는 화합물은, 이의 약학적으로 허용 가능한 염뿐만 아니라 이로부터 제조될 수 있는 가능한 수화물 등의 용매화물 및 가능한 모든 입체 이성질체를 제한없이 포함한다. 상기 화학식 1로 표시되는 화합물의 용매화물 및 입체이성질체는 당업계에 공지된 방법을 사용하여 화학식 1로 표시되는 화합물로부터 제조할 수 있다.In addition, the compound represented by Formula 1 according to the present invention includes, without limitation, not only its pharmaceutically acceptable salts, but also solvates such as possible hydrates that can be prepared therefrom, and all possible stereoisomers. Solvates and stereoisomers of the compound represented by Formula 1 can be prepared from the compound represented by Formula 1 using methods known in the art.

나아가, 본 발명에 따른 상기 화학식 1로 표시되는 화합물은 결정 형태 또는 비결정 형태로 제조될 수 있으며, 결정 형태로 제조될 경우 임의로 수화되거나 용매화될 수 있다. 본 발명에서는 상기 화학식 1로 표시되는 화합물의 화학양론적 수화물뿐만 아니라 다양한 양의 물을 함유하는 화합물이 포함될 수 있다. 본 발명에 따른 상기 화학식 1로 표시되는 화합물의 용매화물은 화학양론적 용매화물 및 비화학양론적 용매화물 모두를 포함한다.Furthermore, the compound represented by Formula 1 according to the present invention can be prepared in crystalline form or amorphous form, and when prepared in crystalline form, it can be arbitrarily hydrated or solvated. In the present invention, not only the stoichiometric hydrate of the compound represented by Formula 1, but also compounds containing various amounts of water may be included. Solvates of the compound represented by Formula 1 according to the present invention include both stoichiometric solvates and non-stoichiometric solvates.

본 발명의 제2양태는 하기 화학식 5로 표시되는 화합물의 알데하이드기를 아민화하는 단계를 포함하는, 제1항 내지 제7항 중 어느 한 항의 화합물, 또는 이의 약학적으로 허용 가능한 염의 제조방법을 제공한다:The second aspect of the present invention provides a method for producing the compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, comprising the step of amination of the aldehyde group of the compound represented by the following formula (5): do:

[화학식 5][Formula 5]

상기 화학식 1에서,In Formula 1,

Ring 1은 셀레나졸레닐(selenazolenyl) 또는 이소사졸레닐(isoxazolenyl),Ring 1 is selenazolenyl or isoxazolenyl,

Ring 2는 C6-10 아릴, 또는 5 내지 10원 헤테로아릴,Ring 2 is C 6-10 aryl, or 5 to 10 membered heteroaryl,

R1은 수소, 시아노, 할로(겐), 히드록시, C1-6 알킬, C1-6 알콕시, 및 C1-6 할로알킬로 구성된 군으로부터 선택되는 서로 동일 또는 상이한 하나 이상의 치환기임.R 1 is one or more substituents that are the same or different from each other selected from the group consisting of hydrogen, cyano, halo(gen), hydroxy, C 1-6 alkyl, C 1-6 alkoxy, and C 1-6 haloalkyl.

예컨대, 상기 화학식 5의 화합물은For example, the compound of Formula 5 is

R1-Ring 2-니트릴 또는 4-(히드록시메틸)벤조니트릴을 셀레늄 및 일산화탄소와 반응시켜 R1-Ring 2-치환된 셀레노아미드(selenoamide) 또는 4-히드록시벤조셀레노아미드를 제조하는 제a단계;R 1 -Ring 2-nitrile or 4-(hydroxymethyl)benzonitrile is reacted with selenium and carbon monoxide to produce R 1 -Ring 2-substituted selenoamide or 4-hydroxybenzoselenoamide. Step a;

이전 단계의 생성물을 2-브로모-1,1-디에톡시에탄 및 p-톨루엔술폰산과 반응시켜 5번 탄소에 Ring 2가 치환된 또는 2번 탄소에 페닐이 치환된 1,3-셀레나졸 고리를 형성하는 제b단계;The product from the previous step was reacted with 2-bromo-1,1-diethoxyethane and p-toluenesulfonic acid to produce a 1,3-selenazole ring with Ring 2 substituted at carbon 5 or phenyl substituted at carbon 2. Step b of forming;

이전 단계의 생성물의 1,3-셀레나졸 고리의 치환되지 않은 2번 탄소 또는 5번 탄소를 할로겐화하는 제c단계; 및Step c of halogenating the unsubstituted carbon 2 or carbon 5 of the 1,3-selenazole ring of the product of the previous step; and

이전 단계의 생성물을 4-포르밀페닐보론산 또는 R1-Ring 2-보론산과 반응시켜 상기 할로겐화된 2번 탄소 또는 5번 탄소에 추가적인 치환기를 도입하는 제d단계를 통해 준비될 수 있으나, 이에 제한되지 않는다.It can be prepared through the d step of reacting the product of the previous step with 4-formylphenylboronic acid or R 1 -Ring 2-boronic acid to introduce an additional substituent to the halogenated carbon 2 or carbon 5. Not limited.

예컨대, 상기 일련의 반응을 통해, 전술한 화학식 2로 표시되는 화합물 및 화학식 3의 전구체 화합물을 수득할 수 있으나, 이에 제한되지 않는다.For example, through the above series of reactions, a compound represented by the above-described formula 2 and a precursor compound of formula 3 can be obtained, but is not limited thereto.

4-(히드록시메틸)벤조니트릴을 반응물로 하여 전술한 일련의 과정을 따라 반응시킨 경우, 화학식 3의 페닐 고리 상에 포르밀기 대신에 히드록시메틸기를 포함하는 전구체 화합물을 수득할 수 있으며, 이는 제d단계 이후 페닐 고리 상의 히드록시기를 산화시키는 제e단계를 추가로 수행함으로써 화학식 3의 화합물로 전환할 수 있다. 이때, 제e단계의 반응은 피리디늄 클로로크로메이트(pyridinium chlorochromate; PCC)를 이용하여 수행할 수 있으나, 이에 제한되지 않는다.When 4-(hydroxymethyl)benzonitrile is used as a reactant and reacted according to the above-described series of processes, a precursor compound containing a hydroxymethyl group instead of a formyl group on the phenyl ring of Formula 3 can be obtained, which is After the d step, it can be converted to the compound of Formula 3 by additionally performing the e step of oxidizing the hydroxy group on the phenyl ring. At this time, the reaction in step e may be performed using pyridinium chlorochromate (PCC), but is not limited thereto.

예컨대, 화학식 5의 화합물은For example, the compound of Formula 5 is

N-히드록시-4-(히드록시메틸)벤즈이미도일 클로라이드를 트리에틸아민과 반응시켜 염산을 제거하는 제a'단계;Step a' of removing hydrochloric acid by reacting N-hydroxy-4-(hydroxymethyl)benzimidoyl chloride with triethylamine;

이전 단계의 생성물을 에테닐 치환된 R1-Ring 2와 반응시켜 (4-(5-(R1-Ring)-4,5-디하이드로이속사졸-3-일)페닐)메탄올을 제조하는 제b'단계; 및Reacting the product of the previous step with ethenyl substituted R 1 -Ring 2 to prepare (4-(5-(R 1 -Ring)-4,5-dihydroisoxazol-3-yl)phenyl)methanol. step b'; and

이전 단계의 생성물의 페닐 고리 상의 히드록시기를 산화시키는 제c'단계를 통해 준비될 수 있으나, 이에 제한되지 않는다.It may be prepared through the c'th step of oxidizing the hydroxy group on the phenyl ring of the product of the previous step, but is not limited thereto.

예컨대, 상기 일련의 반응을 통해, 전술한 화학식 4로 표시되는 화합물을 수득할 수 있으나, 이에 제한되지 않는다.For example, the compound represented by the above-mentioned formula (4) can be obtained through the above series of reactions, but is not limited thereto.

상기 구체적인 제조방법은 하나의 예시일 뿐, 본 발명의 범주가 이에 제한되는 것은 아니며, 당업계에 공지된 관련 반응을 그대로 또는 적절히 변형하여 수행할 수 있다. 나아가, 각 단계의 반응물은 시판되는 것을 구입하거나 공지의 방법으로 합성하여 사용할 수 있으나, 이에 제한되지 않는다. 또한, 본 발명의 제조방법은 생성물의 순도 및/또는 수율을 높이기 위하여, 각 단계 이후 분리 및/또는 정제하는 단계를 선택적으로 포함할 수 있으나, 이에 제한되지 않는다.The above specific preparation method is only an example, and the scope of the present invention is not limited thereto, and related reactions known in the art can be performed as is or by appropriately modifying them. Furthermore, the reactants in each step can be purchased commercially or synthesized using known methods, but are not limited thereto. In addition, the production method of the present invention may optionally include, but is not limited to, steps of separation and/or purification after each step in order to increase the purity and/or yield of the product.

본 발명의 제3양태는 상기 제1양태의 화합물, 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 다발성 경화증(multiple sclerosis; MS)의 예방 또는 치료용 약학적 조성물을 제공한다.A third aspect of the present invention provides a pharmaceutical composition for preventing or treating multiple sclerosis (MS), comprising the compound of the first aspect, or a pharmaceutically acceptable salt thereof, as an active ingredient.

본 발명의 제4양태는 상기 제3양태의 약학적 조성물을 이를 필요로 하는 개체에 투여하는 단계를 포함하는 다발성 경화증의 예방 또는 치료방법을 제공한다.A fourth aspect of the present invention provides a method for preventing or treating multiple sclerosis, comprising administering the pharmaceutical composition of the third aspect to an individual in need thereof.

본 발명의 다발성 경화증의 예방 또는 치료방법은 재활훈련과 병행할 수 있으나, 이에 제한되지 않는다.The method for preventing or treating multiple sclerosis of the present invention may be combined with rehabilitation training, but is not limited thereto.

본 발명의 용어, "제1양태의 화합물", 및 "약학적으로 허용 가능한 염"은 상기에서 설명한 바와 같다.The terms of the present invention, “compound of the first embodiment”, and “pharmaceutically acceptable salt” are as described above.

본 발명의 용어, "다발성 경화증(multiple sclerosis; MS)은 뇌 및 척수의 신경세포을 보호하는 커버(insulating covers)인 미엘린(myelin)이 손상되어 발생하는 탈수초 질환(demyelinating disease)이다. 이러한 손상은 신경계의 일부에서 신호전달능력을 저해하므로, 신체적(physical), 정신적(mental), 때로는 정신과적(psychiatric) 문제를 포함한 넓은 범위의 징후 및 증상을 유발한다. 구체적인 임상적 발현 징후는 시력 손실, 안구운동 장애(예컨대, 안구진탕), 감각 증상 (예컨대 피부의 저림, 따끔거림, 욱신거림), 힘이 없음, 경련, 운동실조, 방광장애, 및 인지 질환 정서 질환 및 발작 질환을 포함할 수 있다. 다발성 경화증은 산발적 어택(isolated attacks)으로 나타나는 재발성 형태(relapsing forms) 또는 시간에 따라 축적되는 진행성 형태(progressive forms) 등의 다양한 형태를 취할 수 있다. 어택과 어택 사이에서 증상은 완전히 사라질 수 있으나, 영구적인 신경학적 문제가 여전히 남아있을 수 있고, 특히, 질병의 진행을 수반할 수 있다. 이러한 다발성 경화증의 기저 메커니즘은 면역계에 의한 파괴 또는 미엘린 생성 세포(myelin-producing cells)의 오류에 인한 것으로 알려져 있으나, 그 발생 원인으로는 유전적 요인 및 바이러스 감염에 의한 촉발 등의 환경적 인자가 거론되고 있으나, 명확하지 않으며, 치료법 또한 알려진 바 없다.The term of the present invention, “multiple sclerosis (MS), is a demyelinating disease caused by damage to myelin, which is an insulating cover for the nerve cells of the brain and spinal cord. This damage is Because it inhibits the signal transmission ability in parts of the nervous system, it causes a wide range of signs and symptoms, including physical, mental, and sometimes psychiatric problems. Specific clinical manifestations include vision loss, eye problems, These may include motor disorders (e.g., nystagmus), sensory symptoms (e.g., numbness, tingling, or tingling of the skin), weakness, convulsions, ataxia, bladder disorders, and cognitive disorders, affective disorders, and seizure disorders. Multiple sclerosis can take a variety of forms, including relapsing forms that occur in isolated attacks or progressive forms that accumulate over time, although symptoms may disappear completely between attacks. However, permanent neurological problems may still remain and, in particular, may accompany disease progression.The underlying mechanism of multiple sclerosis is due to destruction by the immune system or errors in myelin-producing cells. Although it is known, environmental factors such as genetic factors and triggering by viral infection are mentioned as the cause, but it is not clear, and there is no known cure.

예컨대, 본 발명의 약학적 조성물은 상기 화합물을 나트륨염의 형태로 포함할 수 있으나, 이에 제한되지 않는다.For example, the pharmaceutical composition of the present invention may include the above compound in the form of a sodium salt, but is not limited thereto.

예컨대, 본 발명의 약학적 조성물의 유효성분인 상기 화학식 1로 표시되는 화합물은 스핑고신-1-포스페이트 수용체(sphingosine-1-phosphate receptor; S1P1) 조절제로 작용할 수 있다.For example, the compound represented by Formula 1, which is an active ingredient of the pharmaceutical composition of the present invention, may act as a sphingosine-1-phosphate receptor (S1P1) modulator.

본 발명의 용어, "스핑고신-1-포스페이트 수용체(sphingosine-1-phosphate receptor; S1P1)"는 지질 신호전달 분자(lipid signalling molecule) 스핑고신-1-포스페이트(S1P)의 표적인 G-단백질 결합된 수용체(G protein-coupled receptor)의 일종으로, S1P1, S1P2, S1P3, S1P4 및 S1P5로 구분되는 5개 아형 중 하나이며, 1990년에 내피세포(endothelial cell)에서 복제된 S1P 수용체 패밀리의 첫 구성원이다. 이들 아형은 다양한 조질에서 발현되며, 모두 백혈구(leukocytes)에서 가장 높은 밀도로 발견되기는 하나, 각각 상이한 세포 특이성을 갖는다. S1P1의 경우 편재하여(ubiquitously) 발현되는 것으로 알려져 있다. 이의 알려진 작용제(agonist)로는, 면역 조절제로 특히 다발성 경화증 치료에 주로 사용되고 있는, 핀골리모드(fingolimod)가 있다. 본 발명의 화합물을 포함하는 약학적 조성물은 S1P1 작용제로 작용함으로써 다발성 경화증 동물모델에서 핀골리모드와 동등 수준까지 임상 증상을 완화 및/또는 이의 발현을 지연시킬 수 있으므로, 핀골리모드를 대체하여 다발성 경화증 예방 및/또는 치료에 사용될 수 있다.As the term of the present invention, "sphingosine-1-phosphate receptor (S1P1)" refers to the G-protein binding target of the lipid signaling molecule sphingosine-1-phosphate (S1P) It is a type of G protein-coupled receptor, one of five subtypes divided into S1P1, S1P2, S1P3, S1P4, and S1P5, and the first member of the S1P receptor family cloned from endothelial cells in 1990. am. These subtypes are expressed in a variety of organisms and, although all are found in highest density in leukocytes, each has a different cell specificity. S1P1 is known to be expressed ubiquitously. Its known agonist is fingolimod, an immunomodulator mainly used in the treatment of multiple sclerosis. The pharmaceutical composition containing the compound of the present invention can relieve and/or delay the expression of clinical symptoms to the same level as fingolimod in animal models of multiple sclerosis by acting as an S1P1 agonist, and thus can replace fingolimod to treat multiple sclerosis. It can be used to prevent and/or treat sclerosis.

나아가, 본 발명의 약학적 조성물은 혈중 림프구(lymphocyte) 수를 감소시킴으로써 자가면역반응을 완화시킬 수 있다.Furthermore, the pharmaceutical composition of the present invention can alleviate autoimmune reactions by reducing the number of lymphocytes in the blood.

또한, 본 발명의 약학적 조성물은 경직, 또는 마비의 증상을 완화시킬 수 있을 뿐만 아니라, 이러한 다발성 경화증 증상의 발현을 지연시킬 수 있다.Additionally, the pharmaceutical composition of the present invention can not only alleviate symptoms of spasticity or paralysis, but also delay the onset of these multiple sclerosis symptoms.

본 발명의 용어 "예방"이란 본 발명의 약학적 조성물의 투여로 다발성 경화증의 발생, 확산 및 재발을 억제시키거나 지연시키는 모든 행위를 의미하고, "치료"란 본 발명의 약학적 조성물의 투여로 상기 질환의 증세가 호전되거나 이롭게 변경되는 모든 행위를 의미한다.The term "prevention" of the present invention refers to any action that inhibits or delays the occurrence, spread, and recurrence of multiple sclerosis by administering the pharmaceutical composition of the present invention, and the term "treatment" refers to any action that inhibits or delays the occurrence, spread, and recurrence of multiple sclerosis by administering the pharmaceutical composition of the present invention. It refers to any action that improves or changes the symptoms of the above disease to a beneficial effect.

본 발명의 구체적인 일 구현예에서, 상기 치료는 다발성 경화증의 징후의 감소 또는 완화, 상기 질병의 정도의 축소, 질병의 지연 또는 완행(slowing), 질병 상태의 일시적 완화(palliation) 또는 안정화, 및 그 외 이로운 결과를 의미할 수 있으나, 이에 제한되지 않는다.In one specific embodiment of the present invention, the treatment includes reducing or ameliorating the symptoms of multiple sclerosis, reducing the extent of the disease, delaying or slowing the disease, palliating or stabilizing the disease state, and the like. It may mean other beneficial results, but is not limited to this.

본 발명의 용어 "개체"란, 다발성 경화증이 발명하였거나 발병할 수 있는, 다발성 경화증이 의심되는 개체로서, 인간을 포함한 원숭이, 소, 말, 양, 돼지, 닭, 칠면조, 메추라기, 고양이, 개, 마우스, 쥐, 토끼 또는 기니아 피그를 포함한 모든 동물을 의미하고, 본 발명의 약학적 조성물을 이들 개체에게 투여함으로써 상기 질환을 효과적으로 예방 또는 치료할 수 있다. 또한, 본 발명의 약학적 조성물은 기존의 치료제와 병행하여 투여함으로써 시너지적인 효과를 나타낼 수 있다.The term "individual" of the present invention refers to an individual suspected of having multiple sclerosis, who has developed or may develop multiple sclerosis, and includes monkeys, cattle, horses, sheep, pigs, chickens, turkeys, quail, cats, dogs, including humans. This refers to all animals, including mice, rats, rabbits, or guinea pigs, and the disease can be effectively prevented or treated by administering the pharmaceutical composition of the present invention to these individuals. Additionally, the pharmaceutical composition of the present invention can exhibit a synergistic effect when administered in combination with existing therapeutic agents.

본 발명의 용어 "투여"란, 임의의 적절한 방법으로 환자에게 소정의 물질을 제공하는 것을 의미하며, 본 발명의 조성물의 투여 경로는 목적 조직에 도달할 수 있는 한 어떠한 일반적인 경로를 통하여 투여될 수 있다. 복강내 투여, 정맥내 투여, 근육내 투여, 피하 투여, 피내 투여, 경구 투여, 국소 투여, 비내 투여, 폐내투여, 직장내 투여될 수 있으나, 이에 제한되지는 않는다. 또한, 본 발명의 약학적 조성물은 활성 물질이 표적 세포로 이동할 수 있는 임의의 장치에 의해 투여될 수도 있다. 바람직한 투여방식 및 제제는 정맥 주사제, 피하 주사제, 피내 주사제, 근육 주사제, 점적 주사제 등이다. 주사제는 생리식염액, 링겔액 등의 수성 용제, 식물유, 고급 지방산 에스테르(예, 올레인산에칠 등), 알코올 류(예, 에탄올, 벤질알코올, 프로필렌글리콜, 글리세린 등) 등의 비수성 용제 등을 이용하여 제조할 수 있고, 변질 방지를 위한 안정화제(예, 아스코르빈산, 아황산수소나트륨, 피로아황산나트륨, BHA, 토코페롤, EDTA 등), 유화제, pH 조절을 위한 완충제, 미생물 발육을 저지하기 위한 보존제(예, 질산페닐수은, 치메로살, 염화벤잘코늄, 페놀, 크레솔, 벤질알코올 등) 등의 약학적 담체를 포함할 수 있다.The term "administration" of the present invention means providing a predetermined substance to a patient by any suitable method, and the administration route of the composition of the present invention can be administered through any general route as long as it can reach the target tissue. there is. It may be administered intraperitoneally, intravenously, intramuscularly, subcutaneously, intradermally, orally, topically, intranasally, intrapulmonaryly, or rectally, but is not limited thereto. Additionally, the pharmaceutical composition of the present invention may be administered by any device that allows the active agent to move to target cells. Preferred administration methods and formulations include intravenous injection, subcutaneous injection, intradermal injection, intramuscular injection, and drip injection. Injections include aqueous solvents such as physiological saline solution and Ringer's solution, non-aqueous solvents such as vegetable oil, higher fatty acid esters (e.g., ethyl oleate, etc.), and alcohols (e.g., ethanol, benzyl alcohol, propylene glycol, glycerin, etc.). It can be manufactured using stabilizers to prevent deterioration (e.g., ascorbic acid, sodium bisulfite, sodium pyrosulphite, BHA, tocopherol, EDTA, etc.), emulsifiers, buffers for pH adjustment, and agents to prevent microbial growth. It may contain pharmaceutical carriers such as preservatives (e.g., phenylmercuric nitrate, thimerosal, benzalkonium chloride, phenol, cresol, benzyl alcohol, etc.).

예컨대, 본 발명의 조성물은 약학적으로 허용가능한 담체, 희석제 또는 부형제를 추가로 포함할 수 있으며, 각각의 사용 목적에 맞게 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁제, 에멀젼, 시럽, 에어로졸 등의 경구 제형, 멸균 주사 용액의 주사제 등 다양한 형태로 제형화하여 사용할 수 있으며, 경구 투여하거나 정맥내, 복강내, 피하, 직장, 국소 투여 등을 포함한 다양한 경로를 통해 투여될 수 있다. 이러한 조성물에 포함될 수 있는 적합한 담체, 부형제 또는 희석제의 예로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸셀룰로즈, 미정질셀룰로스, 폴리비닐피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유 등을 들 수 있다. 또한, 본 발명의 조성물은 충전제, 항응집제, 윤활제, 습윤제, 향료, 유화제, 방부제 등을 추가로 포함할 수 있다.For example, the composition of the present invention may further include a pharmaceutically acceptable carrier, diluent, or excipient, and may be formulated into powders, granules, tablets, capsules, suspensions, emulsions, etc. according to conventional methods to suit each purpose of use. It can be formulated and used in a variety of forms, including oral formulations such as syrup and aerosol, and injections of sterile injectable solutions. It can be administered orally or through various routes including intravenous, intraperitoneal, subcutaneous, rectal, and topical administration. . Examples of suitable carriers, excipients or diluents that may be included in such compositions include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginates, gelatin, calcium phosphate, calcium silicate, Examples include cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. In addition, the composition of the present invention may further include fillers, anti-coagulants, lubricants, wetting agents, fragrances, emulsifiers, preservatives, etc.

경구 투여를 위한 고형 제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형 제제는 상기 조성물에 적어도 하나 이상의 부형제, 예를 들면 전분, 탄산칼슘, 수크로스, 락토즈, 젤라틴 등을 혼합하여 제형화한다. 또한, 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크와 같은 윤활제가 사용될 수 있다.Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations contain at least one excipient, such as starch, calcium carbonate, sucrose, lactose, gelatin, etc. Formulated by mixing. Additionally, in addition to simple excipients, lubricants such as magnesium stearate and talc may be used.

경구용 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 예시될 수 있으며, 흔히 사용되는 단순 희석제인 물, 액체 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다.Liquid preparations for oral use include suspensions, oral solutions, emulsions, and syrups. In addition to the commonly used simple diluents such as water and liquid paraffin, they may contain various excipients such as wetting agents, sweeteners, fragrances, and preservatives. You can.

비경구 투여를 위한 제제에는 멸균된 수용액제, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜, 폴리에틸렌글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔, 마크로골, 트윈61. 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다. 한편, 주사제에는 용해제, 등장화제, 현탁화제, 유화제, 안정화제, 방부제 등과 같은 종래의 첨가제가 포함될 수 있다.Preparations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, and suppositories. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate. The basis of suppositories is Wethepsol, Macrogol, and Twin 61. Cacao, laurel, glycerogeratin, etc. can be used. Meanwhile, injectables may contain conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers, preservatives, etc.

상기 제형은 통상적인 혼합, 과립화 또는 코팅 방법에 의해 제조될 수 있으며 활성 성분을 약 0.1 내지 75 중량%, 바람직하게는 약 1 내지 50 중량%의 범위에서 함유할 수 있다. 약 50 내지 70 kg의 포유동물에 대한 단위 제형은 약 10 내지 200 mg의 활성성분을 함유한다.The formulation may be prepared by conventional mixing, granulating or coating methods and may contain the active ingredient in the range of about 0.1 to 75% by weight, preferably about 1 to 50% by weight. A unit dosage form for a mammal weighing about 50 to 70 kg contains about 10 to 200 mg of active ingredient.

이때, 본 발명의 조성물은 약학적으로 유효한 양으로 투여한다. 본 발명의 용어 "약학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분하며 부작용을 일으키지 않을 정도의 양을 의미하며, 유효용량 수준은 환자의 건강상태, 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 방법, 투여 시간, 투여 경로 및 배출 비율, 치료 기간, 배합 또는 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명의 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고, 종래의 치료제와 순차적으로 또는 동시에 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. 상기한 요소들을 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 당업자에 의해 용이하게 결정될 수 있다.At this time, the composition of the present invention is administered in a pharmaceutically effective amount. The term "pharmaceutically effective amount" of the present invention refers to an amount that is sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment and does not cause side effects, and the effective dose level refers to the patient's health condition, Factors including the type of disease, severity, activity of the drug, sensitivity to the drug, method of administration, time of administration, route of administration and excretion rate, duration of treatment, drugs combined or used simultaneously, and other factors well known in the medical field. You can. The composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiple times. Considering all of the above factors, it is important to administer an amount that can achieve maximum effect with the minimum amount without side effects, and this can be easily determined by a person skilled in the art.

예컨대, 투여 경로, 질병의 중증도, 성별, 체중, 연령 등에 따라서 증감될 수 있으므로 상기 투여량이 어떠한 방법으로도 본 발명의 범위를 한정하는 것은 아니다.For example, the dosage may increase or decrease depending on the route of administration, severity of disease, gender, weight, age, etc., so the above dosage does not limit the scope of the present invention in any way.

본 발명의 화합물의 바람직한 투여량은 환자의 상태 및 체중, 질병의 정도, 약물의 형태, 투여 경로 및 기간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다. 그러나, 바람직한 효과를 위해서, 본 발명의 화합물을 1일 0.0001 내지 100 mg/kg(체중), 바람직하게는 0.001 내지 100 mg/kg(체중)으로 투여하는 것이 좋다. 투여는 1일 1회 또는 분할하여 경구 또는 비경구적 경로를 통해 투여될 수 있다.The preferred dosage of the compound of the present invention varies depending on the patient's condition and weight, degree of disease, form of drug, route and period of administration, but can be appropriately selected by a person skilled in the art. However, for desirable effects, it is recommended to administer the compound of the present invention at 0.0001 to 100 mg/kg (body weight) per day, preferably 0.001 to 100 mg/kg (body weight). Administration can be administered once a day or in divided doses via oral or parenteral routes.

본 발명의 다발성경화증 예방 또는 치료용 조성물은, 포유동물에 투여된 후 활성 성분의 신속, 지속 또는 지연된 방출을 제공할 수 있도록 당업계에 잘 알려진 방법을 사용하여 약학적 제형으로 제조될 수 있다. 제형의 제조에 있어서, 활성 성분을 담체와 함께 혼합 또는 희석하거나, 용기 형태의 담체 내에 봉입시킬 수 있다.The composition for preventing or treating multiple sclerosis of the present invention can be prepared into a pharmaceutical formulation using methods well known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a mammal. In preparing a dosage form, the active ingredient may be mixed or diluted with a carrier or encapsulated in a carrier in the form of a container.

이에 따라, 본 발명의 약학적 조성물은 약학적으로 허용가능한 담체, 희석제 또는 부형제를 추가로 포함할 수 있으며, 각각의 사용 목적에 맞게 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁제, 에멀젼, 시럽, 에어로졸 등의 경구 제형, 멸균 주사 용액의 주사제 등 다양한 형태로 제형화하여 사용할 수 있으며, 경구 투여하거나 정맥내, 복강내, 피하, 직장, 국소 투여 등을 포함한 다양한 경로를 통해 투여될 수 있다. 이러한 조성물에 포함될 수 있는 적합한 담체, 부형제 또는 희석제의 예로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸셀룰로즈, 미정질셀룰로스, 폴리비닐피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유 등을 들 수 있다. 또한, 본 발명의 조성물은 충전제, 항응집제, 윤활제, 습윤제, 향료, 유화제, 방부제 등을 추가로 포함할 수 있다.Accordingly, the pharmaceutical composition of the present invention may additionally contain a pharmaceutically acceptable carrier, diluent, or excipient, and may be prepared as powder, granule, tablet, capsule, or suspension according to a conventional method according to the respective purpose of use. It can be formulated and used in a variety of forms, including oral formulations such as emulsions, syrups, and aerosols, and injections of sterile injectable solutions, and is administered orally or through various routes including intravenous, intraperitoneal, subcutaneous, rectal, and topical administration. It can be. Examples of suitable carriers, excipients or diluents that may be included in such compositions include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginates, gelatin, calcium phosphate, calcium silicate, Examples include cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. In addition, the composition of the present invention may further include fillers, anti-coagulants, lubricants, wetting agents, fragrances, emulsifiers, preservatives, etc.

경구 투여를 위한 고형 제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형 제제는 상기 조성물에 적어도 하나 이상의 부형제, 예를 들면 전분, 탄산칼슘, 수크로스, 락토즈, 젤라틴 등을 혼합하여 제형화한다. 또한, 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크와 같은 윤활제가 사용될 수 있다.Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations contain at least one excipient, such as starch, calcium carbonate, sucrose, lactose, gelatin, etc. Formulated by mixing. Additionally, in addition to simple excipients, lubricants such as magnesium stearate and talc may be used.

경구용 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 예시될 수 있으며, 흔히 사용되는 단순 희석제인 물, 액체 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다.Liquid preparations for oral use include suspensions, oral solutions, emulsions, and syrups. In addition to the commonly used simple diluents such as water and liquid paraffin, they may contain various excipients such as wetting agents, sweeteners, fragrances, and preservatives. You can.

비경구 투여를 위한 제제에는 멸균된 수용액제, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜, 폴리에틸렌글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔, 마크로골, 트윈61. 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다. 한편, 주사제에는 용해제, 등장화제, 현탁화제, 유화제, 안정화제, 방부제 등과 같은 종래의 첨가제가 포함될 수 있다.Preparations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, and suppositories. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate. The basis of suppositories is Wethepsol, Macrogol, and Twin 61. Cacao, laurel, glycerogeratin, etc. can be used. Meanwhile, injectables may contain conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers, preservatives, etc.

상기 제형은 통상적인 혼합, 과립화 또는 코팅 방법에 의해 제조될 수 있으며 활성 성분을 약 0.1 내지 75 중량%, 바람직하게는 약 1 내지 50 중량%의 범위에서 함유할 수 있다. 약 50 내지 70 kg의 포유동물에 대한 단위 제형은 약 10 내지 200 mg의 활성성분을 함유한다.The formulation may be prepared by conventional mixing, granulating or coating methods and may contain the active ingredient in the range of about 0.1 to 75% by weight, preferably about 1 to 50% by weight. A unit dosage form for a mammal weighing about 50 to 70 kg contains about 10 to 200 mg of active ingredient.

이때, 본 발명의 조성물은 약학적으로 유효한 양으로 투여한다. 본 발명의 용어 "약학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분하며 부작용을 일으키지 않을 정도의 양을 의미하며, 유효용량 수준은 환자의 건강상태, 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 방법, 투여 시간, 투여 경로 및 배출 비율, 치료 기간, 배합 또는 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다.At this time, the composition of the present invention is administered in a pharmaceutically effective amount. The term "pharmaceutically effective amount" of the present invention refers to an amount that is sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment and does not cause side effects, and the effective dose level refers to the patient's health condition, Factors including the type of disease, severity, activity of the drug, sensitivity to the drug, method of administration, time of administration, route of administration and excretion rate, duration of treatment, drugs combined or used simultaneously, and other factors well known in the medical field. You can.

본 발명의 화합물의 바람직한 투여량은 환자의 상태 및 체중, 질병의 정도, 약물의 형태, 투여 경로 및 기간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다. 그러나, 바람직한 효과를 위해서, 본 발명의 화합물을 1일 0.0001 내지 100 mg/kg(체중), 바람직하게는 0.001 내지 100 mg/kg(체중)으로 투여하는 것이 좋다. 투여는 1일 1회 또는 분할하여 경구 또는 비경구적 경로를 통해 투여될 수 있다.The preferred dosage of the compound of the present invention varies depending on the patient's condition and weight, degree of disease, form of drug, route and period of administration, but can be appropriately selected by a person skilled in the art. However, for desirable effects, it is recommended to administer the compound of the present invention at 0.0001 to 100 mg/kg (body weight) per day, preferably 0.001 to 100 mg/kg (body weight). Administration can be administered once a day or in divided doses via oral or parenteral routes.

예컨대, 투여 경로, 질병의 중증도, 성별, 체중, 연령 등에 따라서 증감될 수 있으므로 상기 투여량이 어떠한 방법으로도 본 발명의 범위를 한정하는 것은 아니다.For example, the dosage may increase or decrease depending on the route of administration, severity of disease, gender, weight, age, etc., so the above dosage does not limit the scope of the present invention in any way.

또한 본 발명의 약학적 조성물은 다발성 경화증의 예방 및 치료를 위하여 단독으로, 또는 수술, 호르몬 치료, 약물 치료 및 생물학적 반응 조절제를 사용하는 방법들과 병용하여 사용할 수 있다. 본 발명의 목적상, 본 발명에 따른 약학적 조성물은 다발성 경화증의 치료에 통상적으로 사용되는 하나 이상의 추가적인 약물과 병용 투여될 수 있다.Additionally, the pharmaceutical composition of the present invention can be used alone or in combination with methods using surgery, hormone therapy, drug therapy, and biological response regulators for the prevention and treatment of multiple sclerosis. For the purposes of the present invention, the pharmaceutical composition according to the present invention may be administered in combination with one or more additional drugs commonly used in the treatment of multiple sclerosis.

본 발명에 따른 약학적 조성물을 다발성 경화증의 치료를 위해 투여하는 경우, 다발성 경화증의 치료 또는 예방에 효과가 있는 성분 및/또는 약제 1종 이상과 병용 및/또는 조합하여 투여할 수 있다. 이때 전술한 요소들을 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 당업자에 의해 용이하게 결정될 수 있다When the pharmaceutical composition according to the present invention is administered for the treatment of multiple sclerosis, it may be administered in combination and/or in combination with one or more ingredients and/or drugs effective in treating or preventing multiple sclerosis. At this time, it is important to take into account all of the above-mentioned factors and administer an amount that can achieve the maximum effect with the minimum amount without side effects, and this can be easily determined by a person skilled in the art.

구체적으로 상기 병용 및/또는 조합 투여는 본 발명의 화합물 또는 이의 약학적으로 허용가능한 염과 상기 하나 이상의 추가적인 약물을 각각 동시, 순차적, 또는 역순으로 투여할 수 있으며, 적절한 유효량의 조합으로 동시에 투여하거나, 각각 별도의 용기에 보관한 후 동시, 순차적 또는 역순으로 병용 투여할 수 있다.Specifically, the combination and/or combination administration may be performed by administering the compound of the present invention or a pharmaceutically acceptable salt thereof and one or more additional drugs simultaneously, sequentially, or in reverse order, respectively, and may be administered simultaneously in a combination of an appropriate effective amount. , each can be stored in separate containers and administered together simultaneously, sequentially, or in reverse order.

본 발명의 제5양태는 제1양태의 화합물, 또는 이의 식품학적으로 허용 가능한 염을 유효성분으로 포함하는 다발성 경화증의 예방 또는 개선용 식품 조성물을 제공한다.A fifth aspect of the present invention provides a food composition for preventing or improving multiple sclerosis comprising the compound of the first aspect, or a foodologically acceptable salt thereof, as an active ingredient.

상기 "다발성 경화증", 및 "예방"은 상기에서 설명한 바와 같다.The terms “multiple sclerosis” and “prevention” are as described above.

또한, 본 발명의 용어, "식품학적으로 허용 가능한 염"은 전술한 약학적으로 허용 가능한 염과 동일하게 정의될 수 있다.Additionally, the term “foodologically acceptable salt” of the present invention may be defined in the same way as the above-mentioned pharmaceutically acceptable salt.

본 발명의 "개선"은 상기 화학식 1의 화합물 또는 이의 식품학적으로 허용가능한 염을 포함하는 조성물을 이용하여 대상 질환의 의심 및 발명 개체의 증상이 호전되거나 이롭게 되는 모든 행위를 말한다.“Improvement” in the present invention refers to any action that improves or benefits the suspected disease and the symptoms of the subject of the invention using a composition containing the compound of Formula 1 or a foodologically acceptable salt thereof.

본 발명에 따른 식품 조성물은 환제, 분말, 과립, 침제, 정제, 캡슐 또는 액제 등의 형태를 포함하며, 본 발명의 조성물을 첨가할 수 있는 식품으로는, 예를 들어, 각종 식품류, 예를 들어, 음료, 껌, 차, 비타민 복합제, 건강보조 식품류 등이 있다.The food composition according to the present invention includes the form of pills, powders, granules, precipitates, tablets, capsules, or liquids. Foods to which the composition of the present invention can be added include, for example, various foods, such as , beverages, gum, tea, vitamin complexes, health supplements, etc.

본 발명의 식품 조성물에서 포함할 수 있는 필수 성분으로 상기 화학식 1의 화합물 또는 이의 식품학적으로 허용가능한 염의 함유 외에는 다른 성분에는 제한이 없으며 통상의 식품과 같이 여러 생약추출물, 식품 보조 첨가제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다.The essential ingredients that can be included in the food composition of the present invention are not limited to other ingredients other than the compound of Formula 1 or a foodologically acceptable salt thereof, and include various herbal extracts, food supplements, natural carbohydrates, etc. like ordinary foods. It may contain as an additional ingredient.

또한, 상기 식품 보조 첨가제는 당업계에 통상적인 식품 보조 첨가제, 예를 들어 향미제, 풍미제, 착색제, 충진제, 안정화제 등을 포함한다.In addition, the food auxiliary additives include food auxiliary additives common in the art, such as flavoring agents, flavors, colorants, fillers, stabilizers, etc.

상기 천연 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를 들어 말토스, 슈크로스 등; 및 폴리사카라이드, 예를 들어 덱스트린, 시클로덱스트린 등과 같은 통상적인 당, 및 자일리톨, 소르비톨, 에리트리톨 등의 당알코올이다. 상술한 것 이외에 향미제로서 천연 향미제(예를 들어 레바우디오시드 A, 글리시르히진 등) 및 합성 향미제(사카린, 아스파르탐 등)를 유리하게 사용할 수 있다.Examples of such natural carbohydrates include monosaccharides such as glucose, fructose, etc.; Disaccharides such as maltose, sucrose, etc.; and polysaccharides, such as common sugars such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. In addition to the above-mentioned flavoring agents, natural flavoring agents (e.g., rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used.

상기 외에 본 발명의 식품 조성물은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 충진제(치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산 음료에 사용되는 탄산화제 등을 함유할 수 있다. 그밖에 천연 과일쥬스 및 과일 쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다.In addition to the above, the food composition of the present invention contains various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic and natural flavors, colorants and fillers (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its It may contain salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc. In addition, it may contain pulp for the production of natural fruit juice, fruit juice drinks, and vegetable drinks. These ingredients can be used independently or in combination.

본 발명에서 상기 식품 조성물은 건강기능식품 및 건강보조식품 등을 포함한다.In the present invention, the food composition includes health functional foods and health supplements.

상기 건강 기능(성) 식품(functional food)이란, 특정보건용 식품(food for special health use, FoSHU)과 동일한 용어로, 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 제조 및/또는 가공한 식품으로서, 영양 공급 외에도 생체조절기능이 효율적으로 나타나도록 가공된 의학, 의료효과가 높은 식품을 의미한다. 여기서 "기능(성)"이라 함은 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건용도에 유용한 효과를 얻는 것을 의미한다. 이상과 같이 인체에 유용한 성분을 포함하는 식품으로서 식약처가 그 기능과 안정성을 인정한 식품을 건강기능식품이라 하며, 이외 식약처의 허가를 받지는 않았으나, 인체에 유리한 효과를 갖는 식품으로 여겨지는 것을 건강(보조)식품이라 구분한다. 본 발명의 식품은 당 업계에서 통상적으로 사용되는 방법에 의하여 제조 가능하며, 상기 제조시에는 당 업계에서 통상적으로 첨가하는 원료 및 성분을 첨가하여 제조할 수 있다. 또한 상기 식품의 제형 또한 식품으로 인정되는 제형이면 제한 없이 제조될 수 있다. 본 발명의 식품 조성물은 다양한 형태의 제형으로 제조될 수 있으며, 일반 약품과는 달리 식품을 원료로 하여 약품의 장기 복용 시 발생할 수 있는 부작용 등이 없는 장점이 있고, 휴대성이 뛰어나다.The above-mentioned health functional food (functional food) is the same term as food for special health use (FoSHU), and is a food manufactured and/or processed using raw materials or ingredients with functional properties useful to the human body. In other words, it refers to foods with high medical effects that have been processed to efficiently perform bioregulatory functions in addition to supplying nutrients. Here, “function” means adjusting nutrients to the structure and function of the human body or obtaining useful effects for health purposes, such as physiological effects. As mentioned above, foods that contain ingredients useful to the human body and whose function and safety have been recognized by the Ministry of Food and Drug Safety are called health functional foods. Other foods that have not been approved by the Ministry of Food and Drug Safety but are considered to have beneficial effects on the human body are called health functional foods. It is classified as a (supplementary) food. The food of the present invention can be manufactured by methods commonly used in the industry, and can be manufactured by adding raw materials and ingredients commonly added in the industry. Additionally, the food formulation can be manufactured without limitation as long as it is a formulation recognized as a food. The food composition of the present invention can be manufactured in various forms, and unlike general drugs, it is made from food as a raw material, so it has the advantage of not having side effects that may occur when taking the drug for a long time, and is highly portable.

본 발명의 제6양태는 제1양태의 화합물, 또는 이의 사료학적으로 허용 가능한 염을 유효성분으로 포함하는 다발성 경화증의 예방 또는 개선용 사료 조성물을 제공한다.A sixth aspect of the present invention provides a feed composition for preventing or improving multiple sclerosis comprising the compound of the first aspect, or a feedologically acceptable salt thereof, as an active ingredient.

상기 "다발성 경화증", "예방", 및 "개선"은 상기에서 설명한 바와 같다.The terms “multiple sclerosis”, “prevention”, and “improvement” are as described above.

또한, 본 발명의 용어, "사료학적으로 허용 가능한 염"은 전술한 약학적으로 허용 가능한 염과 동일하게 정의될 수 있다.In addition, the term “feedologically acceptable salt” of the present invention may be defined in the same way as the above-mentioned pharmaceutically acceptable salt.

본 발명의 용어, "사료"는 동물이 먹고, 섭취하며, 소화시키기 위한 또는 이에 적당한 임의의 천연 또는 인공 규정식, 한끼식 등 또는 상기 한끼식의 성분을 의미한다.As used herein, the term "feed" means any natural or artificial diet, meal, etc., or a component of the meal, for or suitable for eating, ingestion, and digestion by animals.

상기 사료의 종류는 특별히 제한되지 아니하며, 당해 기술 분야에서 통상적으로 사용되는 사료를 사용할 수 있다. 상기 사료의 비제한적인 예로는, 곡물류, 근과류, 식품 가공 부산물류, 조류, 섬유질류, 제약 부산물류, 유지류, 전분류, 박류 또는 곡물 부산물류 등과 같은 식물성 사료; 단백질류, 무기물류, 유지류, 광물성류, 유지류, 단세포 단백질류, 동물성 플랑크톤류 또는 음식물 등과 같은 동물성 사료를 들 수 있다. 이들은 단독으로 사용되거나 2종 이상을 혼합하여 사용될 수 있다.The type of feed is not particularly limited, and feed commonly used in the art can be used. Non-limiting examples of the feed include plant feeds such as grains, roots and fruits, food processing by-products, algae, fiber, pharmaceutical by-products, oils and fats, starches, cucurbits or grain by-products; Examples include animal feeds such as proteins, inorganic substances, fats and oils, minerals, oils and fats, single-cell proteins, zooplanktons or food. These may be used alone or in combination of two or more types.

본 발명의 사료는 분말 사료, 고형 사료, 모이스트 펠릿 사료, 드라이 펠릿 사료, EP(Extruder Pellet) 사료, 날먹이 등일 수 있으나, 이에 제한되지 않는다.The feed of the present invention may be powder feed, solid feed, moist pellet feed, dry pellet feed, EP (Extruder Pellet) feed, raw feed, etc., but is not limited thereto.

본 발명의 사료용 조성물은 품질 저하를 방지하기 위하여 첨가하는 결착제, 유화제, 보존제 등이 있을 수 있으며, 상기 사료용 조성물은 사료 첨가제를 포함할 수 있다. 효용 증대를 위하여 사료에 첨가하는 아미노산제, 비타민제, 효소제, 향미제, 비단백질태질소화합물, 규산염제, 완충제, 추출제, 올리고당 등이 있을 수 있다. 그 외에도 사료 혼합제 등을 추가로 포함할 수 있으며, 이에 제한되는 것은 아니다.The feed composition of the present invention may include binders, emulsifiers, preservatives, etc. added to prevent quality deterioration, and the feed composition may include feed additives. To increase utility, there may be amino acids, vitamins, enzymes, flavors, non-protein nitrogen compounds, silicate agents, buffers, extractants, oligosaccharides, etc. added to feed. In addition, feed mixtures, etc. may be additionally included, but are not limited thereto.

본 발명의 헤테로사이클릴-페닐-메틸아민 유도체들은 S1P1 수용체에 대한 작용제(agonist) 활성을 통해 수용체 내재화 및 혈중 림포구 수를 조절할 수 있고, 나아가, 다발성 경화증으로 인해 발생하는 증상인 반사성 상실 및 마비를 억제하며, 혈중 염증세포 감소에 우수한 효과를 나타내므로, 다발성 경화증의 예방 또는 치료에 유용하게 사용될 수 있다.Heterocyclyl-phenyl-methylamine derivatives of the present invention can regulate receptor internalization and the number of lymphocytes in the blood through agonist activity on the S1P1 receptor, and furthermore, help reduce reflex loss and paralysis, which are symptoms caused by multiple sclerosis. It inhibits and has an excellent effect in reducing inflammatory cells in the blood, so it can be usefully used in the prevention or treatment of multiple sclerosis.

도 1은 본 발명의 화합물 13, 62, 64, 또는 66 투여에 의한 정상 랫드에서 시간에 따른 말초 혈액의 림프구 수 변화를 나타낸 도이다. 도 1A 및 도 1B는 각각 본 발명의 화합물 64와 66 및 13과 62를 10 mg/kg 용량으로 경구 투여시 투여 후 시간 경과에 따른 혈중 림프구 수 변화를 투여 전 수치에 대한 백분율로 산출한 결과를 임상승인된 동일기전의 약물인 핀골리모드를 투여한 양성대조군에 대한 결과와 함께 나타내었다. 도 1C에는 비히클 또는 약물을 경구투여하고 6시간 경과 후 측정된 림프구 수를 비히클 투여 음성대조군을 기준으로 한 백분율로 나타내었다.
도 2는 설치류 다발성경화증 모델 제작과 약물의 투여 개요 및 설치류 다발성 경화증 모델에서의 본 발명의 화합물의 투여로 인한 다발성경화증 증상 완화를 나타낸 도이다. 도 2A는 일별 임상증상지수(꼬리와 다리의 마비 정도를 수치화) 변화를, 도 2B 및 2C는 도 2A로부터 그룹별 그래프의 아래 면적을 나타낸다. 도 2D는 일별 각 그룹의 체중 변화를, 도 2E는 실험 동물 모델 유도 시작일을 기준으로 각 군에서 시험 최종일에서의 체중 변화 정도를 나타낸다. 도 2F는 각 군에서 다발성 경화증 증상이 나타나는 시점 및 비율을 나타낸다. 도 2G는 화합물 13 투여에 대한 다발성 경화증 동물 모델 제작 및 약물 투여 개요와 일별 임상증상지수를, 도 2H는 각 군에서 다발성 경화증 증상이 나타나는 시점과 비율을 나타낸다.Figure 1 is a diagram showing changes in the number of peripheral blood lymphocytes over time in normal rats upon administration of compounds 13, 62, 64, or 66 of the present invention. Figures 1A and 1B show the results of calculating the change in the number of lymphocytes in the blood over time as a percentage of the value before administration when compounds 64 and 66 and 13 and 62 of the present invention were orally administered at a dose of 10 mg/kg, respectively. The results are shown together with the results of the positive control group administered fingolimod, a clinically approved drug with the same mechanism. In Figure 1C, the number of lymphocytes measured 6 hours after oral administration of vehicle or drug is expressed as a percentage based on the vehicle-administered negative control group.
Figure 2 is a diagram showing an overview of the production of a rodent multiple sclerosis model and drug administration and the relief of multiple sclerosis symptoms due to administration of the compound of the present invention in a rodent multiple sclerosis model. Figure 2A shows the daily change in clinical symptom index (quantifying the degree of paralysis of the tail and legs), and Figures 2B and 2C show the area under the graph for each group from Figure 2A. Figure 2D shows the change in body weight of each group by day, and Figure 2E shows the degree of change in body weight on the final day of the test in each group based on the start date of induction of the experimental animal model. Figure 2F shows the timing and rate at which multiple sclerosis symptoms appeared in each group. Figure 2G shows an overview of the creation of a multiple sclerosis animal model and drug administration and daily clinical symptom index for administration of compound 13, and Figure 2H shows the time and rate at which multiple sclerosis symptoms appear in each group.

이하 본 발명을 실시예를 통하여 보다 상세하게 설명한다. 그러나 이들 실시예는 본 발명을 예시적으로 설명하기 위한 것으로 본 발명의 범위가 이들 실시예에 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail through examples. However, these examples are for illustrative purposes only and the scope of the present invention is not limited to these examples.

실시예 1: 2-(고리 1)-5-페닐 치환된 1,3-셀레나졸 유도체의 제조 (화합물 1 내지 38)Example 1: Preparation of 2-(ring 1)-5-phenyl substituted 1,3-selenazole derivatives (Compounds 1 to 38)

Figure 112021066570416-pat00006
Figure 112021066570416-pat00006

실시예 2: 5-(고리 1)-2-페닐 치환된 1,3-셀레나졸 유도체의 제조 (화합물 39 내지 42)Example 2: Preparation of 5-(ring 1)-2-phenyl substituted 1,3-selenazole derivatives (Compounds 39 to 42)

Figure 112021066570416-pat00007
Figure 112021066570416-pat00007

실시예 3: 5-(고리 1)-2-페닐 치환된 4,5-디하이드로이속사졸 유도체의 제조 (화합물 43 내지 71)Example 3: Preparation of 5-(ring 1)-2-phenyl substituted 4,5-dihydroisoxazole derivatives (Compounds 43 to 71)

Figure 112021066570416-pat00008
Figure 112021066570416-pat00008

상기 실시예 1 내지 3의 반응식에 따라 화합물 1 내지 71의 화합물을 합성하였다. 수득한 화합물의 명칭, 구조식, 및 1H NMR 등의 정보를 아래에 정리하였다.Compounds 1 to 71 were synthesized according to the reaction schemes of Examples 1 to 3 above. Information such as name, structural formula, and 1 H NMR of the obtained compound is summarized below.

화합물 1. 메틸 1-(4-(2-(4-tert-부틸페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트Compound 1. Methyl 1-(4-(2-(4-tert-butylphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

Figure 112021066570416-pat00009
Figure 112021066570416-pat00009

노란 고체;yellow solid;

수율: 43%;Yield: 43%;

1H NMR (CDCl3, 400 MHz) δ 7.94 (s, selenazole ring-H), 7.81-7.83 (m, 2 ArH), 7.43-7.50 (m, 4 ArH), 7.26-7.30 (m, 2 ArH), 3.71 (s, COOCH 3 ), 3.62 (s, NCH 2 ), 3.52-3.55 (m, 2 azetidine ring-H), 3.33-3.35 (m, 3 azetidine ring-H), 1.35 (s, Ar(CH 3 ) 3 ); 1 H NMR (CDCl 3 , 400 MHz) δ 7.94 (s, selenazole ring- H ), 7.81-7.83 (m, 2ArH ), 7.43-7.50 (m, 4ArH ), 7.26-7.30 (m, 2ArH ), 3.71 (s) , COOC H 3 ), 3.62 (s, NC H 2 ), 3.52-3.55 (m, 2 azetidine ring- H ), 3.33-3.35 (m, 3 azetidine ring- H ), 1.35 (s, Ar(C H 3 ) 3 );

13C NMR (CDCl3, 100 MHz) δ 173.92 (NCSe), 173.54 (C(O)), 153.67, 145.40, 139.57, 137.87, 133.77, 132.68, 129.16, 127.35, 126.59, 125.99 (ArC), 62.98 (NCH2), 56.84 (azetidine ring-C), 51.97 (COOCH3), 34.93 (C(CH3)3), 33.97 (azetidine ring-C), 31.17 (C(CH3) 3 ). 13 C NMR (CDCl 3 , 100 MHz) δ 173.92 (N C Se), 173.54 ( C (O)), 153.67, 145.40, 139.57, 137.87, 133.77, 132.68, 129.16, 127.35, 126.59, 125.99 (Ar C ), 62. 98 (N C H 2 ) , 56.84 (azetidine ring- C ), 51.97 (COO C H 3 ), 34.93 ( C (CH 3 ) 3 ), 33.97 (azetidine ring- C ), 31.17 (C( C H 3 ) 3 ).

화합물 2. 소디움 1-(4-(2-(4-tert-부틸페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트Compound 2. Sodium 1-(4-(2-(4-tert-butylphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

Figure 112021066570416-pat00010
Figure 112021066570416-pat00010

하얀 고체;White solid;

수율: 82%;Yield: 82%;

1H NMR (CD3OD, 400 MHz) δ 8.14 (s, selenazole ring-H), 7.88 (d, J = 8.4 Hz, 2 ArH), 7.78 (d, J = 8.2 Hz, 2 ArH), 7.55-7.57 (m, 4 ArH), 4.45 (s, NCH 2 ), 4.32-4.33 (m, 4 azetidine ring-H), 3.59-3.67 (m, 1 azetidine ring-H), 1.39 (s, Ar(CH 3 ) 3 ); 1 H NMR (CD 3 OD, 400 MHz) δ 8.14 (s, selenazole ring- H ), 7.88 (d, J = 8.4 Hz, 2 Ar H ), 7.78 (d, J = 8.2 Hz, 2 Ar H ), 7.55-7.57 (m, 4 Ar) H ), 4.45 (s, NC H 2 ), 4.32-4.33 (m, 4 azetidine ring- H ), 3.59-3.67 (m, 1 azetidine ring- H ), 1.39 (s, Ar(C H 3 ) 3 ) ;

13C NMR (CD3OD, 100 MHz) δ 175.45 (NCSe), 174.18 (C(O)), 154.20, 144.41, 139.97, 135.08, 133.22, 130.53, 130.03, 127.62, 126.30, 125.86 (ArC), 57.73 (NCH2), 56.40 (azetidine ring-C), 34.43 (C(CH3)3), 33.81 (azetidine ring-C), 30.09 (C(CH3) 3 ). 13 C NMR (CD 3 OD, 100 MHz) δ 175.45 (N C Se), 174.18 ( C (O)), 154.20, 144.41, 139.97, 135.08, 133.22, 130.53, 130.03, 127.62, 126.30, 125.86 (Ar C ), 57. 73 (N C H 2 ) , 56.40 (azetidine ring- C ), 34.43 ( C (CH 3 ) 3 ), 33.81 (azetidine ring- C ), 30.09 (C( CH 3 ) 3 ).

화합물 3. 에틸 1-(4-(2-(4-tert-부틸페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트Compound 3. Ethyl 1-(4-(2-(4-tert-butylphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

Figure 112021066570416-pat00011
Figure 112021066570416-pat00011

노란 고체;yellow solid;

수율: 25%;Yield: 25%;

1H NMR (CDCl3, 400 MHz) δ 7.93 (s, selenazole ring-H), 7.82 (d, J = 8.5 Hz, 2 ArH), 7.49 (d, J = 8.1 Hz, 2 ArH), 7.44 (d, J = 8.5 Hz, 2 ArH), 7.29 (d, J = 8.2 Hz, 2ArH), 4.15 (q, 7.1 Hz, CH 2 CH3), 3.63 (s, NCH 2 ), 3.55 (br s, 2 azetidine ring-H), 3.32-3.33 (m, 3 azetidine ring-H), 1.34 (s, Ar(CH 3 ) 3 ), 1.26 (t, J = 7.1 Hz, CH2CH 3 ); 1 H NMR (CDCl 3 , 400 MHz) δ 7.93 (s, selenazole ring- H ), 7.82 (d, J = 8.5 Hz, 2 Ar H ), 7.49 (d, J = 8.1 Hz, 2 Ar H ), 7.44 (d, J = 8.5 Hz) , 2Ar H ), 7.29 (d, J = 8.2 Hz, 2Ar H ), 4.15 (q, 7.1 Hz, C H 2 CH 3 ), 3.63 (s, NC H 2 ), 3.55 (br s, 2 azetidine ring - H ), 3.32-3.33 (m, 3 azetidine ring- H ), 1.34 (s, Ar(C H 3 ) 3 ), 1.26 (t, J = 7.1 Hz, CH 2 C H 3 );

13C NMR (CDCl3, 100 MHz) δ 173.93 (NCSe), 173.11 (C(O)), 153.68, 145.40, 139.57, 137.79, 133.77, 132.68, 129.17, 127.35, 126.58, 125.99 (ArC), 62.98 (NCH2), 60.82 (CH2CH3), 56.84 (azetidine ring-C), 34.93, 34.11, 31.17 (C(CH3)3), 14.19 (CH2 CH3). 13 C NMR (CDCl 3 , 100 MHz) δ 173.93 (N C Se), 173.11 ( C (O)), 153.68, 145.40, 139.57, 137.79, 133.77, 132.68, 129.17, 127.35, 126.58, 125.99 (Ar C ), 62. 98 (N C H 2 ) , 60.82 ( CH 2 CH 3 ), 56.84 (azetidine ring- C ), 34.93, 34.11, 31.17 ( C (CH 3 ) 3 ), 14.19 (CH 2 C H 3 ).

화합물 4. tert-부틸 1-(4-(2-(4-tert-부틸페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트Compound 4. tert-Butyl 1-(4-(2-(4-tert-butylphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

Figure 112021066570416-pat00012
Figure 112021066570416-pat00012

상아색 고체;Ivory solid;

수율: 75%;Yield: 75%;

1H NMR (CDCl3, 400 MHz) δ 7.96 (s, selenazole ring-H), 7.85 (d, J = 8.3 Hz, 2 ArH), 7.46-7.53 (m, 4 ArH), 7.32 (d, J = 8.0 Hz, 2 ArH), 3.66 (s, NCH 2 ), 3.54-3.59 (m, 2 azetidine ring-H), 3.27-3.33 (m, 3 azetidine ring-H), 1.47 (s, COOC(CH 3 )3), 1.37 (s, Ar(CH 3 ) 3 ); 1 H NMR (CDCl 3 , 400 MHz) δ 7.96 (s, selenazole ring- H ), 7.85 (d, J = 8.3 Hz, 2 Ar H ), 7.46-7.53 (m, 4 Ar H) , 7.32 (d, J = 8.0 Hz, 2 Ar H ), 3.66 (s, NC H 2 ), 3.54-3.59 (m, 2 azetidine ring- H ), 3.27-3.33 (m, 3 azetidine ring- H ), 1.47 (s, COOC(C H 3 ) 3 ) , 1.37 (s, Ar(C H 3 ) 3 );

13C NMR (CDCl3, 100 MHz) δ 173.92 (NCSe), 172.41 (C(O)), 153.66, 145.40, 139.56, 137.81, 133.77, 132.68, 129.21, 127.34, 126.59, 125.99 (ArC), 80.81, 62.90 (NCH2), 56.78 (azetidine ring-C), 34.99, 34.92 (azetidine ring-C), 31.17 (COOC(CH 3 )3), 29.71 (COOC(CH3)3), 1.37 (s, Ar(CH 3 ) 3 ). 13 C NMR (CDCl 3 , 100 MHz) δ 173.92 (N C Se), 172.41 ( C (O)), 153.66, 145.40, 139.56, 137.81, 133.77, 132.68, 129.21, 127.34, 126.59, 125.99 (Ar C ), 80. 81, 62.90 (N C H 2 ), 56.78 (azetidine ring- C ), 34.99, 34.92 (azetidine ring- C ), 31.17 (COOC(C H 3 ) 3 ), 29.71 (COO C (CH 3 ) 3 ), 1.37 (s, Ar( C H 3 ) 3 ).

화합물 5. 메틸 1-(4-(2-(3-이소시아노-4-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트Compound 5. Methyl 1-(4-(2-(3-isocyano-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

Figure 112021066570416-pat00013
Figure 112021066570416-pat00013

노란 기름;yellow oil;

수율: 72%;Yield: 72%;

1H NMR (CDCl3, 400 MHz) δ 8.08 (s, selenazole ring-H), 8.07-8.02 (m, 1 ArH), 7.92 (s, 1 ArH), 7.49 (d, J = 8.1 Hz, 2 ArH), 7.33 (d, J = 7.8 Hz, 2 ArH), 7.01 (d, J = 8.9 Hz, 1 ArH), 4.72 (sept, J = 6.0 Hz, OCH(CH3)2), 3.73 (s, COOCH 3 ), 3.66 (br s, NCH 2 ), 3.58 (br s, 2 azetidine ring-H), 3.37 (br s, 3 azetidine ring-H), 1.60 (d, J = 5.9 Hz, OCH(CH 3 ) 2 ); 1 H NMR (CDCl 3 , 400 MHz) δ 8.08 (s, selenazole ring- H ), 8.07-8.02 (m, 1 Ar H ), 7.92 (s, 1 Ar H ), 7.49 (d, J = 8.1 Hz, 2 Ar H ), 7.33 ( d, J = 7.8 Hz, 2 Ar H ), 7.01 (d, J = 8.9 Hz, 1 Ar H ), 4.72 (sept, J = 6.0 Hz, OC H (CH 3 ) 2 ), 3.73 (s, COOC H 3 ), 3.66 (br s, NC H 2 ), 3.58 (br s, 2 azetidine ring- H ), 3.37 (br s, 3 azetidine ring- H ), 1.60 (d, J = 5.9 Hz, OCH(C H 3 ) 2 );

13C NMR (CDCl3, 100 MHz) δ 173.30 (NCSe), 170.86 (C(O)), 161.01, 146.21, 139.69, 137.40, 132.52, 132.28, 132.21, 129.42, 129.35, 127.49, 15.91, 113.79, 103.63 (ArC), 72.39, 62.58 (NCH2), 56.69 (azetidine ring-C), 52.11 (OCH3), 33.83 (azetidine ring-C), 21.82 (OCH(CH3)2). 13 C NMR (CDCl 3 , 100 MHz) δ 173.30 ( N 113.79, 103.63 (Ar C ), 72.39 , 62.58 (N C H 2 ), 56.69 (azetidine ring- C ), 52.11 (O C H 3 ), 33.83 (azetidine ring- C ), 21.82 (OCH( C H 3 ) 2 ).

화합물 6. 소디움 1-(4-(2-(3-이소시아노-4-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트Compound 6. Sodium 1-(4-(2-(3-isocyano-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

Figure 112021066570416-pat00014
Figure 112021066570416-pat00014

노란 고체;yellow solid;

수율: 97%;Yield: 97%;

1H NMR (CD3OD, 400 MHz) δ 8.10-8.06 (m, 3 ArH), 7.70 (d, J = 8.1 Hz, 2 ArH), 7.55 (d, J = 8.2 Hz, 2 ArH), 7.25 (d, J =8.8 Hz, 1 ArH), 4.82-4.88 (m, OCH(CH3)2), 4.46 (s, 2 NCH 2 ), 4.28-4.39 (m, 4 azetidine ring-H), 3.63-3.71 (m, 1 azetidine ring-H), 1.42 (d, J = 6.0 Hz, OCH(CH 3 ) 2 ); 1 H NMR (CD 3 OD, 400 MHz) δ 8.10-8.06 (m, 3 Ar H ), 7.70 (d, J = 8.1 Hz, 2 Ar H ), 7.55 (d, J = 8.2 Hz, 2 Ar H ), 7.25 (d, J = 8.8 Hz, 1 Ar H ), 4.82-4.88 (m, OC H (CH 3 ) 2 ), 4.46 (s, 2 NC H 2 ), 4.28-4.39 (m, 4 azetidine ring- H ), 3.63-3.71 (m , 1 azetidine ring- H ), 1.42 (d, J = 6.0 Hz, OCH(C H 3 ) 2 );

13C NMR (CD3OD, 100 MHz) δ 172.90 (NCSe), 172.10 (C(O)), 161.19, 145.13, 140.20, 134.87, 132.72, 131.47, 130.72, 129.83, 128.88, 127.63 (ArC), 115.31, 114.08, 102.82, 72.28 (OCH(CH3)2), 57.53 (NCH2), 55.71 (azetidine ring-C), 32.92 (azetidine ring-C), 20.70 (OCH(CH3)2). 13 C NMR (CD 3 OD, 100 MHz) δ 172.90 (N C Se), 172.10 ( C (O)), 161.19, 145.13, 140.20, 134.87, 132.72, 131.47, 130.72, 129.83, 128.88, 127.63 (Ar C ), 115 .31, 114.08, 102.82, 72.28 (O C H(CH 3 ) 2 ), 57.53 (N C H 2 ), 55.71 (azetidine ring- C ), 32.92 (azetidine ring- C ), 20.70 (OCH( C H 3 ) 2 ).

화합물 7. 에틸 1-(4-(2-(3-시아노-4-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트Compound 7. Ethyl 1-(4-(2-(3-cyano-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

Figure 112021066570416-pat00015
Figure 112021066570416-pat00015

상아색 기름;ivory oil;

수율: 70%;Yield: 70%;

1H NMR (CDCl3, 400 MHz) δ 8.01-8.07 (m, 2 ArH), 7.92 (s, selenazole ring H), 7.52 (d, J = 8.4 Hz, 2 ArH), 7.43 (d, J = 8.0 Hz, 2 ArH), 7.01 (d, J = 8.7 Hz, 1 ArH), 4.71-4.74 (m, OCH(CH3)2), 4.19 (q, J = 7.2 Hz, COOCH 2 CH3), 3.87-3.91 (m, 2 azetidine ring, NCH 2 ), 3.46-3.57 (m, 3 azetidine ring H), 1.42 (d, J = 6.0 Hz, OCH(CH 3 )2), 1.27 (t, J = 7.2 Hz, COOCH2CH 3 ); 1 H NMR (CDCl 3 , 400 MHz) δ 8.01-8.07 (m, 2 Ar H ), 7.92 (s, selenazole ring H ), 7.52 (d, J = 8.4 Hz, 2 Ar H ), 7.43 (d, J = 8.0 Hz, 2 Ar H) ), 7.01 (d, J = 8.7 Hz, 1 Ar H ), 4.71-4.74 (m, OC H (CH 3 ) 2 ), 4.19 (q, J = 7.2 Hz, COOC H 2 CH 3 ), 3.87-3.91 (m, 2 azetidine ring, NC H 2 ), 3.46-3.57 (m, 3 azetidine ring H ), 1.42 (d, J = 6.0 Hz, OCH(C H 3 ) 2 ), 1.27 (t, J = 7.2 Hz , COOCH 2 C H 3 );

13C NMR (CDCl3, 100 MHz) δ 172.23 (NCSe), 171.30 (C(O)), 161.06, 155.96, 145.83, 139.84, 132.29, 132.25, 129.88, 129.35, 127.70, 115.86, 113.75, 103.66, 72.40 (COOCH2CH3), 61.42 (NCH2), 55.95 (azetidine ring-C), 33.45 (azetidine ring-C), 21.81 (OCH(CH3) 2 ), 14.14 (COOCH2 CH3). 13 C NMR (CDCl 3 , 100 MHz ) δ 172.23 (N 103.66 , 72.40 (COO C H 2 CH 3 ), 61.42 (N C H 2 ), 55.95 (azetidine ring- C ), 33.45 (azetidine ring- C ), 21.81 (OCH( C H 3 ) 2 ), 14.14 (COOCH 2 C H 3 ).

화합물 8. tert-부틸 1-(4-(2-(3-시아노-4-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트Compound 8. tert-Butyl 1-(4-(2-(3-cyano-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

Figure 112021066570416-pat00016
Figure 112021066570416-pat00016

상아색 기름;ivory oil;

수율: 70%;Yield: 70%;

1H NMR (CDCl3, 400 MHz) δ 8.04-8.10 (m, 2 ArH), 7.94 (s, selenazole ring H), 7.53 (d, J = 8.0 Hz, 2 ArH), 7.39 (d, J = 7.5 Hz, 2 ArH), 7.04 (d, J = 8.9 Hz, 1 ArH), 4.72-4.78 (m, OCH(CH3)2), 3.57-3.85 (m, 2 azetidine ring, NCH 2 ), 3.23-3.33 (m, 3 azetidine ring H), 1.46-1.48 (m, C(CH 3 )3, OCH(CH 3 )2); 1 H NMR (CDCl 3 , 400 MHz) δ 8.04-8.10 (m, 2 Ar H ), 7.94 (s, selenazole ring H ), 7.53 (d, J = 8.0 Hz, 2 Ar H ), 7.39 (d, J = 7.5 Hz, 2 Ar H) ), 7.04 (d, J = 8.9 Hz, 1 Ar H ), 4.72-4.78 (m, OC H (CH 3 ) 2 ), 3.57-3.85 (m, 2 azetidine ring, NC H 2 ), 3.23-3.33 ( m, 3 azetidine ring H ), 1.46-1.48 (m, C(C H 3 ) 3 , OCH(C H 3 ) 2 );

13C NMR (CDCl3, 100 MHz) δ 172.90 (NCSe), 171.58 (C(O)), 140.04, 132.24, 129.39, 128.42, 127.48, 120.18, 119.45, 115.94, 113.81, 103.62 (ArC), 72.42, 62.79, 56.95, 34.75, 28.06 (OCH(CH3)2, 21.83 (C(CH3)3). 13 C NMR (CDCl 3 , 100 MHz) δ 172.90 (N C Se), 171.58 ( C (O)), 140.04, 132.24, 129.39, 128.42, 127.48, 120.18, 119.45, 115.94, 113.81, 103.62 (Ar C ), 72. 42, 62.79, 56.95, 34.75 , 28.06 (OCH( C H 3 ) 2 , 21.83 (C( C H 3 ) 3 ).

화합물 9. 메틸 1-(4-(2-(4-이소프로폭시-3-(트리플루오로메틸)페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트Compound 9. Methyl 1-(4-(2-(4-isopropoxy-3-(trifluoromethyl)phenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxyl rate

Figure 112021066570416-pat00017
Figure 112021066570416-pat00017

노란 고체;yellow solid;

수율: 68%;Yield: 68%;

1H NMR (CDCl3, 400 MHz) δ 8.10-8.12 (m, 1 ArH), 8.01 (d, J = 8.6 Hz, 1 ArH), 7.94 (s, selenazole ring-H), 7.51 (d, J = 8.2 Hz, 2 ArH), 7.33 (d, J = 8.2 Hz, 2 ArH), 7.06 (d, J = 8.7 Hz, ArH), 4.71-4.77 (m, OCH(CH3)2), 3.81 (s, COOCH 3 ), 3.74 (s, NCH 2 ), 3.58-3.66 (m, 2 azetidine ring H), 3.55-3.57 (m, 3 azetidine ring-H), 1.42 (d, J = 6.04 Hz, OCH(CH 3 )2); 1 H NMR (CDCl 3 , 400 MHz) δ 8.10-8.12 (m, 1 Ar H ), 8.01 (d, J = 8.6 Hz, 1 Ar H ), 7.94 (s, selenazole ring- H ), 7.51 (d, J = 8.2 Hz, 2 Ar H ), 7.33 (d, J = 8.2 Hz, 2 Ar H ), 7.06 (d, J = 8.7 Hz, Ar H ), 4.71-4.77 (m, OC H (CH 3 ) 2 ), 3.81 (s, COOC H 3 ), 3.74 (s, NC H 2 ), 3.58-3.66 (m, 2 azetidine ring H ), 3.55-3.57 (m, 3 azetidine ring- H ), 1.42 (d, J = 6.04 Hz, OCH(C H 3 ) 2 );

13C NMR (CDCl3, 100 MHz) δ 173.53 (NCSe), 172.00 (C(O)), 157.53, 145.80, 139.54, 138.10, 132.46, 131.27, 129.19, 128.56, 127.37, 125.95, 125.88, 125.07 (ArC), 121.46, 121.05, 120.64, 120.23 (q, J C-F = 41 Hz), 114.39, (ArC), 62.98 (NCH2), 56.88, 51.97, 33.99 (azetidine ring-C), 21.83 (OCH(CH3)2). 13 C NMR (CDCl 3 , ( 100 MHz) δ 173.53 (N 125.07 (Ar C ), 121.46 , 121.05 , 120.64, 120.23 (q, J CF = 41 Hz), 114.39, (Ar C ), 62.98 (N C H 2 ), 56.88, 51.97, 33.99 (azetidine ring- C ), 21.83 (OCH( C H 3 ) 2 ).

화합물 10. 1-(4-(2-(4-이소프로폭시-3-(트리플루오로메틸)페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실산Compound 10. 1-(4-(2-(4-isopropoxy-3-(trifluoromethyl)phenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylic acid

Figure 112021066570416-pat00018
Figure 112021066570416-pat00018

노란 고체;yellow solid;

수율: 59%;Yield: 59%;

1H NMR (CD3OD, 400 MHz) δ 8.05 (d, J = 2.04, 1 ArH), 8.01 (s, selenazole ring-H), 7.94 (dd, J = 2.0, 8.7 Hz, 1 ArH), 7.63 (d, J = 8.1 Hz, 2 ArH), 7.54 (d, J = 8.0 Hz, 2 ArH), 7.19 (d, J = 8.8 Hz, 1 ArH), 4.74-4.97 (m, OCH(CH3)2), 4.43 (s, 2 NCH 2 ), 4.23-4.35 (m, 4 azetidine ring-H), 3.54-3.63 (m, 1 azetidine ring-H), 1.35 (d, J = 6.0 Hz, OCH(CH 3 ) 2 ); 1 H NMR (CD 3 OD, 400 MHz) δ 8.05 (d, J = 2.04, 1 Ar H ), 8.01 (s, selenazole ring- H ), 7.94 (dd, J = 2.0, 8.7 Hz, 1 Ar H ), 7.63 (d, J = 8.1 Hz, 2 Ar H ), 7.54 (d, J = 8.0 Hz, 2 Ar H ), 7.19 (d, J = 8.8 Hz, 1 Ar H ), 4.74-4.97 (m, OC H (CH 3 ) 2 ), 4.43 (s, 2 NC H 2 ), 4.23-4.35 (m, 4 azetidine ring- H ), 3.54-3.63 (m, 1 azetidine ring- H ), 1.35 (d, J = 6.0 Hz, OCH(C H 3 ) 2 );

13C NMR (CD3OD, 100 MHz) δ 174.53 (NCSe), 173.00 (C(O)), 157.67, 144.74, 140.06, 134.73, 131.98, 130.72, 130.03, 127.88, 127.49, 124.66, 124.60 (Ar C), 127.38, 124.55, 121.98, 119.27 (q, J C-F = 283.0 Hz), 120.12, 119.81, 119.50, 119.20(q, J C-F = 30.0 Hz), 114.58 (ArC), 71.54 (OCH(CH3)2), 57.41 (NCH2), 56.03 (azetidine ring-C), 33.79 (azetidine ring-C), 20.73 (OCH(CH3)2). 13 C NMR (CD 3 OD, 100 MHz ) δ 174.53 (N Ar C ), 127.38, 124.55, 121.98 , 119.27 (q, J CF = 283.0 Hz), 120.12, 119.81, 119.50, 119.20(q, J CF = 30.0 Hz), 114.58 (Ar C ), 71.54 (O C H(CH 3 ) 2 ), 57.41 (N C H 2 ), 56.03 (azetidine ring- C ), 33.79 (azetidine ring- C ), 20.73 (OCH( C H 3 ) 2 ).

화합물 11. 에틸 1-(4-(2-(4-이소프로폭시-3-(트리플루오로메틸)페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트Compound 11. Ethyl 1-(4-(2-(4-isopropoxy-3-(trifluoromethyl)phenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxyl rate

Figure 112021066570416-pat00019
Figure 112021066570416-pat00019

상아색 기름;ivory oil;

수율: 70%;Yield: 70%;

1H NMR (CDCl3, 400 MHz) δ 8.11 (d, J = 2.0 Hz, 1 ArH), 8.01 (dd, J = 2.0, 8.6 Hz, 1 ArH), 7.95 (s, selenazole ring H), 7.53 (d, J = 8.1 Hz, 2 ArH), 7.38 (d, J = 8.0 Hz, 2 ArH), 7.07 (d, J = 8.8 Hz, 1 ArH), 4.71-4.77 (m, OCH(CH3)2), 4.21 (q, J = 7.1 Hz, COOCH 2 CH3), 3.56-3.88 (m, 2 azetidine ring, NCH 2 ), 3.41-3.47 (m, 3 azetidine ring H), 1.43 (d, J = 6.0 Hz, OCH(CH 3 )2), 1.30 (t, J = 7.2 Hz, COOCH2CH 3 ); 1 H NMR (CDCl 3 , 400 MHz) δ 8.11 (d, J = 2.0 Hz, 1 Ar H ), 8.01 (dd, J = 2.0, 8.6 Hz, 1 Ar H ), 7.95 (s, selenazole ring H ), 7.53 (d, J = 8.1 Hz, 2 Ar H ), 7.38 (d, J = 8.0 Hz, 2 Ar H ), 7.07 (d, J = 8.8 Hz, 1 Ar H ), 4.71-4.77 (m, OC H (CH 3 ) 2 ), 4.21 (q, J = 7.1 Hz, COOC H 2 CH 3 ), 3.56-3.88 (m, 2 azetidine ring, NC H 2 ), 3.41-3.47 (m, 3 azetidine ring H ), 1.43 (d, J = 6.0 Hz, OCH(C H 3 ) 2 ), 1.30 (t, J = 7.2 Hz, COOCH 2 C H 3 );

13C NMR (CDCl3, 100 MHz) δ 172.78 (NCSe), 172.16 (C(O)), 162.86, 157.56, 151.32, 145.59, 143.33, 139.67, 133.91, 133.39, 132.87, 131.30, (q, J C-F = 208.3 Hz), 129.46, 128.50, 127.48, 126.01, 125.95, 125.88, 125.84 (q, J C-F = 18.2 Hz) 114.38 (ArC), 71.73 (COOCH2CH3), 61.06 (NCH2), 56.51 (azetidine ring-C), 33.86 (azetidine ring-C), 21.83 (OCH(CH3) 2 ), 14.18 (COOCH2 CH3). 13 C NMR (CDCl 3 , 100 MHz) δ 172.78 ( N 08.3 Hz ), 129.46 , 128.50, 127.48, 126.01, 125.95, 125.88, 125.84 (q, J CF = 18.2 Hz) 114.38 (Ar C ), 71.73 (COO C H 2 CH 3 ), 61.06 (N C H 2 ), 56.51 (azetidine ring- C ), 33.86 (azetidine ring- C ), 21.83 (OCH( C H 3 ) 2 ), 14.18 (COOCH 2 C H 3 ).

화합물 12. 메틸 1-(4-(2-(3-클로로-4-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트Compound 12. Methyl 1-(4-(2-(3-chloro-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

Figure 112021066570416-pat00020
Figure 112021066570416-pat00020

노란 고체;yellow solid;

수율: 47%;Yield: 47%;

1H NMR (CD3OD, 400 MHz) δ 8.00 (s, selenazole ring-H), 7.95 (d, J = 2.2 Hz, ArH), 7.78 (dd, J = 2.2, 8.6 Hz, 2 ArH), 7.58-7.60 (m, 2 ArH), 7.35 (d, J = 8.2 Hz, 2ArH), 7.17 (d, J = 8.8 Hz, 1 ArH), 4.73-4.79 (m, OCH(CH3)2), 3.77 (s, COOCH 3 ), 3.73 (s, NCH 2 ), 3.53-3.66 (m, 2 azetidine ring H), 3.33-3.44 (m, 3 azetidine ring-H), 1.40 (d, J = 6.0 Hz, OCH(CH 3 )2); 1 H NMR (CD 3 OD, 400 MHz) δ 8.00 (s, selenazole ring- H ), 7.95 (d, J = 2.2 Hz, Ar H ), 7.78 (dd, J = 2.2, 8.6 Hz, 2 Ar H ), 7.58-7.60 (m, 2 Ar H ), 7.35 (d, J = 8.2 Hz, 2Ar H ), 7.17 (d, J = 8.8 Hz, 1 Ar H ), 4.73-4.79 (m, OC H (CH 3 ) 2 ), 3.77 (s, COOC H 3 ), 3.73 (s, NC H 2 ), 3.53-3.66 (m, 2 azetidine ring H ), 3.33-3.44 (m, 3 azetidine ring- H ), 1.40 (d, J = 6.0 Hz, OCH( C H 3 ) 2 );

13C NMR (CD3OD, 100 MHz) δ 173.42 (NCSe), 172.50 (C(O)), 155.32, 145.66, 139.01, 137.36, 132.48, 129.40, 129.35, 127.70, 126.90, 126.44, 124.08, 114.92 (ArC), 71.69 (OCH(CH3)2), 62.12 (NCH2), 56.11, 51.12, 33.54 (azetidine ring-C), 20.81 (OCH(CH3)2). 13 C NMR (CD 3 OD, 100 MHz) δ 173.42 ( N 114.92 ( ArC ) , 71.69 (O C H(CH 3 ) 2 ), 62.12 (N C H 2 ), 56.11, 51.12, 33.54 (azetidine ring- C ), 20.81 (OCH( C H 3 ) 2 ).

화합물 13. 소디움 1-(4-(2-(3-클로로-4-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트Compound 13. Sodium 1-(4-(2-(3-chloro-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

Figure 112021066570416-pat00021
Figure 112021066570416-pat00021

하얀 고체;White solid;

수율: 92%;Yield: 92%;

1H NMR (CD3OD, 400 MHz) δ 8.22 (s, selenazole ring-H), 7.96 (d, J = 2.1 Hz, 1 ArH), 7.83 (dd, J = 2.1, 8.6 Hz, 1 ArH), 7.63-7.67 (m, 2 ArH), 7.41-7.46 (m, 2 ArH), 7.29 (d, J = 8.8 Hz, 1 ArH), 4.76-4.82 (m, OCH(CH3)2), 3.98 (s, NCH 2 ), 3.77-3.83 (m, 2 azetidine ring H), 3.65-3.68 (m, 2 azetidine ring-H), 3.34-3.38 (m, azetidine ring-H), 1.34 (d, J = 6.0 Hz, OCH(CH 3 )2); 1 H NMR (CD 3 OD, 400 MHz) δ 8.22 (s, selenazole ring- H ), 7.96 (d, J = 2.1 Hz, 1 Ar H ), 7.83 (dd, J = 2.1, 8.6 Hz, 1 Ar H ), 7.63-7.67 (m, 2 Ar H ), 7.41-7.46 (m, 2 Ar H ), 7.29 (d, J = 8.8 Hz, 1 Ar H ), 4.76-4.82 (m, OC H (CH 3 ) 2 ), 3.98 (s, NC H 2 ), 3.77-3.83 (m, 2 azetidine ring H ), 3.65-3.68 (m, 2 azetidine ring- H ), 3.34-3.38 (m, azetidine ring- H ), 1.34 (d, J = 6.0 Hz, OCH(C H 3 ) 2 );

13C NMR (CD3OD, 100 MHz) δ 173.49 (NCSe), 171.46 (C(O)), 155.11, 145.48, 140.86, 133.19, 133.15, 130.53, 129.61, 127.93, 127.61, 127.44, 123.51, 116.01 (ArC), 71.94 (OCH(CH3)2), 59.69, 55.88, 33.35 (azetidine ring-C), 22.19 (OCH(CH3)2). 13 C NMR (CD 3 OD, 100 MHz) δ 173.49 ( N 116.01 ( ArC ), 71.94 ( O C H(CH 3 ) 2 ), 59.69, 55.88, 33.35 (azetidine ring- C ), 22.19 (OCH( C H 3 ) 2 ).

화합물 14. 메틸 1-(4-(2-(3-클로로-4-에톡시페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트Compound 14. Methyl 1-(4-(2-(3-chloro-4-ethoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

Figure 112021066570416-pat00022
Figure 112021066570416-pat00022

노란 고체;yellow solid;

수율: 55%;Yield: 55%;

1H NMR (CDCl3, 400 MHz) δ 7.95 (d, J = 1.7 Hz, 1 ArH), 7.92 (s, selenazole ring H), 7.49 (d, J = 8.0 Hz, 1 ArH), 7.49 (d, J = 8.0 Hz, 1 ArH), 7.31 (d, J = 7.6 Hz, 2 ArH), 6.95 (d, J = 8.6 Hz, 1 ArH), 4.17 (q, J = 6.9 Hz, OCH 2 CH3), 3.73 (s, COOCH 3 ), 3.65 (s, NCH 2 ), 3.56-3.57 (m, 2 azetidine ring H), 3.35-3.36 (m, 3 azetidine ring H), 1.51 (t, J = 6.8 Hz, OCH2CH 3 ); 1 H NMR (CDCl 3 , 400 MHz) δ 7.95 (d, J = 1.7 Hz, 1 Ar H ), 7.92 (s, selenazole ring H ), 7.49 (d, J = 8.0 Hz, 1 Ar H ), 7.49 (d, J = 8.0 Hz, 1 Ar H ), 7.31 (d, J = 7.6 Hz, 2 Ar H ), 6.95 (d, J = 8.6 Hz, 1 Ar H ), 4.17 (q, J = 6.9 Hz, OC H 2 CH 3 ), 3.73 (s, COOC H 3 ), 3.65 (s, NC H 2 ), 3.56-3.57 (m, 2 azetidine ring H ), 3.35-3.36 (m, 3 azetidine ring H ), 1.51 (t, J = 6.8 Hz, OCH 2 C H 3 );

13C NMR (CDCl3, 100 MHz) δ 173.52 (NCSe), 171.97 (C(O)), 155.97, 145.63, 139.48, 137.94, 132.51, 129.93, 129.19, 128.46, 127.34, 126.34, 123.49, 113.06 (ArC), 64.92 (OCH2CH3), 62.94 (NCH2), 56.84 (azetidine ring-C), 52.00, 33.97 (azetidine ring-C), 14.64 (OCH2 CH3). 13 C NMR (CDCl 3 , 100 MHz) δ 173.52 (N 113.06 ( ArC ), 64.92 ( O C H 2 CH 3 ), 62.94 (N C H 2 ), 56.84 (azetidine ring- C ), 52.00, 33.97 (azetidine ring- C ), 14.64 (OCH 2 C H 3 ).

화합물 15. 소디움 1-(4-(2-(3-클로로-4-에톡시페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트Compound 15. Sodium 1-(4-(2-(3-chloro-4-ethoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

Figure 112021066570416-pat00023
Figure 112021066570416-pat00023

하얀 고체;White solid;

수율: 90%;Yield: 90%;

1H NMR (CD3OD, 400 MHz) δ 8.01 (s, selenazole ring-H), 7.96 (d, J = 2.2 Hz, 1 ArH), 7.80 (dd, J = 2.2, 8.6 Hz, 1 ArH), 7.56 (d, J = 8.1 Hz, 2 ArH), 7.37 (d, J = 8.2 Hz, 2 ArH), 7.15 (d, J = 8.7 Hz, 1 ArH), 4.19 (q, J = 6.9 Hz, OCH 2 CH3), 3.73 (s, NCH 2 ), 3.59-3.67 (m, 2 azetidine ring H), 3.36-3.40 (m, 2 azetidine ring-H), 3.21-3.32 (m, 1 azetidine ring-H), 1.48 (t, J = 7.0 Hz, OCH2CH 3 ); 1 H NMR (CD 3 OD, 400 MHz) δ 8.01 (s, selenazole ring- H ), 7.96 (d, J = 2.2 Hz, 1 Ar H ), 7.80 (dd, J = 2.2, 8.6 Hz, 1 Ar H ), 7.56 (d, J = 8.1 Hz, 2 Ar H ), 7.37 (d, J = 8.2 Hz, 2 Ar H ), 7.15 (d, J = 8.7 Hz, 1 Ar H ), 4.19 (q, J = 6.9 Hz, OC H 2 CH 3 ), 3.73 (s, NC H 2 ), 3.59-3.67 (m, 2 azetidine ring- H ), 3.36-3.40 (m, 2 azetidine ring- H ), 3.21-3.32 (m, 1 azetidine ring- H ), 1.48 (t, J = 7.0 Hz, OCH 2 C H 3 );

13C NMR (CD3OD, 100 MHz) δ 179.46 (NCSe), 172.45 (C(O)), 156.19, 145.74, 138.95, 137.61, 132.37, 129.44, 127.47, 126.85, 126.59, 123.06, 113.16 (ArC), 64.66, 62.30 (OCH2CH3), 57.61, 36.51 (azetidine ring-C), 13.54 (OCH2 CH3). 13 C NMR (CD 3 OD, 100 MHz) δ 179.46 ( N Ar C ) , 64.66, 62.30 (O C H 2 CH 3 ), 57.61, 36.51 (azetidine ring- C ), 13.54 (OCH 2 C H 3 ).

화합물 16. 메틸 1-(4-(2-(4-메톡시페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트Compound 16. Methyl 1-(4-(2-(4-methoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

Figure 112021066570416-pat00024
Figure 112021066570416-pat00024

노란 고체;yellow solid;

수율: 55%;Yield: 55%;

1H NMR (CDCl3, 400 MHz) δ 7.93 (s, selenazole ring-H), 7.86 (dd, J = 2.0, 6.8 Hz, 2 ArH), 7.51 (d, J = 8.1 Hz, 2 ArH), 7.32 (d, J = 8.1 Hz, 2 ArH), 6.97 (dd, J = 6.88 Hz, 2 ArH), 3.89 (s, OCH 3 ), 3.74 (s, COOCH 3 ), 3.65 (s, NCH 2 ), 3.55-3.60 (m, 2 azetidine ring H), 3.33-3.41 (m, 3 azetidine ring-H); 1 H NMR (CDCl 3 , 400 MHz) δ 7.93 (s, selenazole ring- H ), 7.86 (dd, J = 2.0, 6.8 Hz, 2 Ar H ), 7.51 (d, J = 8.1 Hz, 2 Ar H ), 7.32 (d, J = 8.1 Hz, 2 Ar H ), 6.97 (dd, J = 6.88 Hz, 2 Ar H ), 3.89 (s, OC H 3 ), 3.74 (s, COOC H 3 ), 3.65 (s, NC H 2 ), 3.55 -3.60 (m, 2 azetidine ring- H ), 3.33-3.41 (m, 3 azetidine ring- H );

13C NMR (CDCl3, 100 MHz) δ 173.60 (NCSe), 173.54 (C(O)), 161.33, 144.83, 139.40, 137.81, 132.72, 129.49, 129.13, 128.30, 127.29, 114.37 (ArC), 63.00 (NCH2), 56.86 (azetidine ring-C), 55.44(OCH3), 51.98 (azetidine ring-C), 33.98 (azetidine ring-C). 13 C NMR (CDCl 3 , 100 MHz) δ 173.60 (N C Se), 173.54 ( C (O)), 161.33, 144.83, 139.40, 137.81, 132.72, 129.49, 129.13, 128.30, 127.29, 114.37 (Ar C ), 63. 00 (N C H 2 ) , 56.86 (azetidine ring- C ), 55.44(O C H 3 ), 51.98 (azetidine ring- C ), 33.98 (azetidine ring- C ).

화합물 17. 1-(4-(2-(4-메톡시페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실산Compound 17. 1-(4-(2-(4-methoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylic acid

Figure 112021066570416-pat00025
Figure 112021066570416-pat00025

상아색 고체;Ivory solid;

수율: 78%;Yield: 78%;

1H NMR (CD3OD, 400 MHz) δ 8.08 (s, selenazole ring- H), 7.89 (dd, J = 1.9, 6.8 Hz, 2 ArH), 7.75 (d, J = 8.2 Hz, 2 ArH), 7.53 (d, J = 8.2 Hz, 1 ArH), 7.03-7.06 (m, 2 ArH), 4.75 (s, 2 NCH 2 ), 4.26-4.28 (m, 4 azetidine ring-H), 3.89 (s, OCH 3 ), 3.50-3.59 (m, 1 azetidine ring-H); 1 H NMR (CD 3 OD, 400 MHz) δ 8.08 (s, selenazole ring- H ), 7.89 (dd, J = 1.9, 6.8 Hz, 2 Ar H ), 7.75 (d, J = 8.2 Hz, 2 Ar H ), 7.53 (d, J = 8.2 Hz, 1 Ar H ), 7.03-7.06 (m, 2 Ar H ), 4.75 (s, 2 NC H 2 ), 4.26-4.28 (m, 4 azetidine ring- H ), 3.89 (s, OC H 3 ) , 3.50-3.59 (m, 1 azetidine ring- H );

13C NMR (CD3OD, 100 MHz) δ 161.65, 140.91, 134.20, 131.42, 130.40, 129.23, 127.77, 127.32, 126.60, 115.21, 56.22, 54.61, 46.58, 29.06. 13 C NMR (CD 3 OD, 100 MHz) δ 161.65, 140.91, 134.20, 131.42, 130.40, 129.23, 127.77, 127.32, 126.60, 115.21, 56.22, 54.61, 46.58, 29.06.

화합물 18. 메틸 1-(4-(2-(4-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트Compound 18. Methyl 1-(4-(2-(4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

Figure 112021066570416-pat00026
Figure 112021066570416-pat00026

노란 고체;yellow solid;

수율: 31%;Yield: 31%;

1H NMR (CDCl3, 400 MHz) δ 7.91 (s, selenazole ring-H), 7.83 (d, J = 8.7 Hz, 2 ArH), 7.49 (d, J = 8.1 Hz, 2 ArH), 7.30 (d, J = 8.0 Hz, 2 ArH), 6.93 (d, J = 8.7 Hz, 1 ArH), 4.62 (sept, J = 6.0 Hz, OCH(CH3)2), 3.72 (s, COOCH 3 ), 3.63 (s, NCH 2 ), 3.55-3.56 (m, 2 azetidine ring-H), 3.35-3.39 (m, 3 azetidine ring-H), 1.37 (d, J = 6.0 Hz, OCH(CH 3 ) 2 ); 1 H NMR (CDCl 3 , 400 MHz) δ 7.91 (s, selenazole ring- H ), 7.83 (d, J = 8.7 Hz, 2 Ar H ), 7.49 (d, J = 8.1 Hz, 2 Ar H) , 7.30 (d, J = 8.0 Hz) , 2 Ar H ), 6.93 (d, J = 8.7 Hz, 1 Ar H ), 4.62 (sept, J = 6.0 Hz, OC H (CH 3 ) 2 ), 3.72 (s, COOC H 3 ), 3.63 (s) , NC H 2 ), 3.55-3.56 (m, 2 azetidine ring- H ), 3.35-3.39 (m, 3 azetidine ring- H ), 1.37 (d, J = 6.0 Hz, OCH(C H 3 ) 2 );

13C NMR (CDCl3, 100 MHz) δ 173.65 (NCSe), 173.53 (C(O)), 159.74, 144.67, 139.38, 137.79, 132.72, 129.12, 128.31, 115.97 (ArC), 70.04, 62.99 (NCH2), 56.86 (azetidine ring-C), 51.96 (OCH3), 33.98 (azetidine ring-C), 21.99 (OCH(CH3)2). 13 C NMR (CDCl 3 , 100 MHz) δ 173.65 (N C Se), 173.53 ( C (O)), 159.74, 144.67, 139.38, 137.79, 132.72, 129.12, 128.31, 115.97 (Ar C ), 70.04, 62.99 (N C H 2 ) , 56.86 (azetidine ring - C ), 51.96 ( OCH3 ), 33.98 (azetidine ring- C ), 21.99 (OCH( CH3 ) 2 ).

화합물 19. 1-(4-(2-(4-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실산Compound 19. 1-(4-(2-(4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylic acid

Figure 112021066570416-pat00027
Figure 112021066570416-pat00027

노란 고체;yellow solid;

수율: 94%;Yield: 94%;

1H NMR (CD3OD, 400 MHz) δ 8.07 (s, selenazole ring-H), 7.86 (d, J = 8.8 Hz, 2 ArH), 7.45 (d, J = 8.2 Hz, 2 ArH), 7.57 (d, J = 8.2 Hz, 2 ArH), 7.01 (d, J = 8.84 Hz, 2 ArH), 4.69-4.75 (m, OCH(CH3)2), 4.48 (s, 2 NCH 2 ), 4.33-4.42 (m, 4 azetidine ring-H), 3.73-3.79 (m, 1 azetidine ring-H), 1.37 (d, J = 6.0 Hz, OCH(CH 3 ) 2 ); 1 H NMR (CD 3 OD, 400 MHz) δ 8.07 (s, selenazole ring- H ), 7.86 (d, J = 8.8 Hz, 2 Ar H ), 7.45 (d, J = 8.2 Hz, 2 Ar H ), 7.57 (d, J = 8.2 Hz) , 2 Ar H ), 7.01 (d, J = 8.84 Hz, 2 Ar H ), 4.69-4.75 (m, OC H (CH 3 ) 2 ), 4.48 (s, 2 NC H 2 ), 4.33-4.42 (m , 4 azetidine ring- H ), 3.73-3.79 (m, 1 azetidine ring- H ), 1.37 (d, J = 6.0 Hz, OCH(C H 3 ) 2 );

13C NMR (DMSO-d 6 , 100 MHz) δ 173.34 (NCSe), 172.92 (C(O)), 159.97, 144.21, 140.97, 133.83, 130.88, 128.72, 127.62, 116.49 (ArC), 72.28, 55.46 (NCH2), 33.00 (azetidine ring-C), 20.21 (OCH(CH3)2). 13 C NMR (DMSO -d6 , 100 MHz) δ 173.34 (N C Se), 172.92 ( C (O)), 159.97, 144.21, 140.97, 133.83, 130.88, 128.72, 127.62, 116.49 (Ar C ), 72.28, 55.46 (N C H 2 ) , 33.00 (azetidine ring- C ), 20.21 (OCH( C H 3 ) 2 ).

화합물 20. 에틸 1-(4-(2-(4-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트Compound 20. Ethyl 1-(4-(2-(4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

Figure 112021066570416-pat00028
Figure 112021066570416-pat00028

상아색 기름;ivory oil;

수율: 70%;Yield: 70%;

1H NMR (CDCl3, 400 MHz) δ 7.92 (s, selenazole ring H), 7.84 (d, J = 8.7 Hz, 2 ArH), 7.51 (d, J = 8.1 Hz, 2 ArH), 7.34 (d, J = 8.0 Hz, 2 ArH), 6.94 (d, J = 8.8 Hz, 2 ArH), 4.64 (sept, J = 6.0 Hz, OCH(CH3)2), 4.20 (q, J = 7.1 Hz, COOCH 2 CH3), 3.84 (s, NCH 2 ), 3.63-3.69 (m, 2 azetidine ring H), 3.37-3.39 (m, 3 azetidine ring H), 1.39 (d, J = 6.0 Hz, OCH(CH 3 )2), 1.27 (t, J = 7.1 Hz, COOCH2CH 3 ); 1 H NMR (CDCl 3 , 400 MHz) δ 7.92 (s, selenazole ring H ), 7.84 (d, J = 8.7 Hz, 2 Ar H ), 7.51 (d, J = 8.1 Hz, 2 Ar H ), 7.34 (d, J = 8.0 Hz, 2 Ar H ), 6.94 (d, J = 8.8 Hz, 2 Ar H ), 4.64 (sept, J = 6.0 Hz, OC H (CH 3 ) 2 ), 4.20 (q, J = 7.1 Hz, COOC H 2 CH 3 ), 3.84 (s, NC H 2 ), 3.63-3.69 (m, 2 azetidine ring H ), 3.37-3.39 (m, 3 azetidine ring H ), 1.39 (d, J = 6.0 Hz, OCH(C H 3 ) 2 ), 1.27 (t, J = 7.1 Hz, COOCH 2 C H 3 );

13C NMR (CDCl3, 100 MHz) δ 173.78 (NCSe), 173.04 (C(O)), 159.78, 144.60, 139.45, 129.24, 129.14, 128.33, 127.34, 116.01 (ArC), 70.09 (COOCH2CH3), 60.91 (NCH2), 56.72 (azetidine ring-C), 34.02 (azetidine ring-C), 21.99 (OCH(CH3) 2 ), 14.19 (COOCH2 CH3). 13 C NMR (CDCl 3 , 100 MHz) δ 173.78 (N C Se), 173.04 ( C (O)), 159.78, 144.60, 139.45, 129.24, 129.14, 128.33, 127.34, 116.01 (Ar C ), 70.09 (COO C H 2 CH 3 ), 6 0.91 (N C H 2 ), 56.72 (azetidine ring- C ), 34.02 (azetidine ring- C ), 21.99 (OCH( C H 3 ) 2 ), 14.19 (COOCH 2 C H 3 ).

화합물 21. 메틸 1-(4-(2-(3-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트Compound 21. Methyl 1-(4-(2-(3-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

Figure 112021066570416-pat00029
Figure 112021066570416-pat00029

노란 고체;yellow solid;

수율: 56%;Yield: 56%;

1H NMR (CDCl3, 400 MHz) δ 7.97 (s, selenazole ring-H), 7.53-4.48 (m, 3 ArH), 7.45 (d, J = 7.68 Hz, 1 ArH), 7.32-7.36 (m, 3 ArH), 6.97-7.00 (m, 1 ArH), 4.65-4.71 (m, CH(CH3)2), 3.74 (s, COOCH 3 ), 3.65 (s, NCH 2 ), 3.57 (br s, 2 azetidine ring-H), 3.36-3.38 (m, 3 azetidine ring-H), 1.40 (d, J = 6.0 Hz, CH(CH 3 ) 2 ); 1 H NMR (CDCl 3 , 400 MHz) δ 7.97 (s, selenazole ring- H ), 7.53-4.48 (m, 3 Ar H ), 7.45 (d, J = 7.68 Hz, 1 Ar H ), 7.32-7.36 (m, 3 Ar H ), 6.97-7.00 (m, 1 Ar H ), 4.65-4.71 (m, C H (CH 3 ) 2 ), 3.74 (s, COOC H 3 ), 3.65 (s, NC H 2 ), 3.57 (br s, 2 azetidine ring- H ), 3.36-3.38 (m, 3 azetidine ring- H ), 1.40 (d, J = 6.0 Hz, CH(C H 3 ) 2 );

13C NMR (CDCl3, 100 MHz) δ 173.76 (NCSe), 173.54 (C(O)), 158.39, 146.01, 139.55, 138.07, 137.67, 132.56, 130.06, 129.15, 127.38, 119.44, 118.10, 113.39 (ArC), 70.15, 63.00 (NCH2), 56.88 (azetidine ring-C), 51.97, 33.99 (azetidine ring-C), 22.05 (CH(CH3)2). 13 C NMR (CDCl 3 , 100 MHz) δ 173.76 ( N 113.39 (Ar C ), 70.15 , 63.00 (N C H 2 ), 56.88 (azetidine ring- C ), 51.97, 33.99 (azetidine ring- C ), 22.05 (CH( C H 3 ) 2 ).

화합물 22. 1-(4-(2-(3-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실산Compound 22. 1-(4-(2-(3-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylic acid

Figure 112021066570416-pat00030
Figure 112021066570416-pat00030

노란 고체;yellow solid;

수율: 25%;Yield: 25%;

1H NMR (CD3OD, 400 MHz) δ 8.14 (s, selenazole ring-H), 7.77 (d, J = 8.2 Hz, 2 ArH), 7.56 (d, J = 8.2 Hz, 2 ArH), 7.47 (d, J = 8.5 Hz, 2 ArH), 7.38 (t, J = 7.8 Hz, 1 ArH), 7.05-7.07 (m, ArH), 4.68-4.74 (m, OCH(CH3)2), 4.46 (s, 2 NCH 2 ), 4.31-4.39 (m, 4 azetidine ring-H), 3.68-3.74 (m, 1 azetidine ring-H), 1.37 (d, J = 6.0 Hz, OCH(CH 3 ) 2 ); 1 H NMR (CD 3 OD, 400 MHz) δ 8.14 (s, selenazole ring- H ), 7.77 (d, J = 8.2 Hz, 2 Ar H ), 7.56 (d, J = 8.2 Hz, 2 Ar H ), 7.47 (d, J = 8.5 Hz) , 2 Ar H ), 7.38 (t, J = 7.8 Hz, 1 Ar H ), 7.05-7.07 (m, Ar H ), 4.68-4.74 (m, OC H (CH 3 ) 2 ), 4.46 (s, 2 NC H 2 ), 4.31-4.39 (m, 4 azetidine ring- H ), 3.68-3.74 (m, 1 azetidine ring- H ), 1.37 (d, J = 6.0 Hz, OCH( CH 3 ) 2 );

13C NMR (CD3OD, 100 MHz) δ 175.25 (NCSe), 172.14 (C(O)), 158.55, 144.93, 140.06, 137.08, 135.11, 130.66, 130.03, 129.65, 127.69, 127.19, 119.14, 117.98, 113.08 (ArC), 69.91, 57.60, 55.56, 32.52 (azetidine ring-C), 20.21 (OCH(CH3)2). 13 C NMR (CD 3 OD, 100 MHz) δ 175.25 ( N 117.98, 113.08 (Ar C ), 69.91 , 57.60, 55.56, 32.52 (azetidine ring- C ), 20.21 (OCH( C H 3 ) 2 ).

화합물 23. 메틸 1-(4-(2-(2-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트Compound 23. Methyl 1-(4-(2-(2-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

Figure 112021066570416-pat00031
Figure 112021066570416-pat00031

투명 기름;transparent oil;

수율: 33%;Yield: 33%;

1H NMR (CDCl3, 400 MHz) δ 8.44 (dd, J = 1.6, 7.8 Hz, 2 ArH), 8.08 (s, selenazole ring-H), 7.56 (d, J = 8.1 Hz, 2 ArH), 7.37-7.41 (m, ArH), 7.32 (d, J = 8.1 Hz, 2 ArH), 7.04-7.09 (m, 2 ArH), 4.85-4.95 (m, OCH(CH3)2), 3.73 (s, COOCH 3 ), 3.65 (s, NCH 2 ), 3.56-3.57 (m, 2 azetidine ring H), 3.35-3.39 (m, 3 azetidine ring-H), 1.56 (d, J = 6.0 Hz, CH(CH 3 ) 2 ); 1 H NMR (CDCl 3 , 400 MHz) δ 8.44 (dd, J = 1.6, 7.8 Hz, 2 Ar H ), 8.08 (s, selenazole ring- H ), 7.56 (d, J = 8.1 Hz, 2 Ar H ), 7.37-7.41 (m, Ar H ), 7.32 (d, J = 8.1 Hz, 2 Ar H ), 7.04-7.09 (m, 2 Ar H ), 4.85-4.95 (m, OC H (CH 3 ) 2 ), 3.73 (s, COOC H 3 ), 3.65 (s, NC H 2 ), 3.56-3.57 (m, 2 azetidine ring H ), 3.35-3.39 (m, 3 azetidine ring- H ), 1.56 (d, J = 6.0 Hz, CH(C H 3 ) 2 );

13C NMR (CDCl3, 100 MHz) δ 173.59 (NCSe), 165.86 (C(O)), 154.28, 145.55, 141.24, 138.18, 137.43, 133.34, 130.44, 129.11, 127.30, 125.55, 120.71, 113.06 (ArC), 71.63, 63.08 (NCH2), 56.86 (azetidine ring-C), 51.98, 34.01 (azetidine ring-C), 22.36 (CH(CH3)2). 13 C NMR (CDCl 3 , 100 MHz) δ 173.59 ( N 113.06 (Ar C ), 71.63 , 63.08 (N C H 2 ), 56.86 (azetidine ring- C ), 51.98, 34.01 (azetidine ring- C ), 22.36 (CH( C H 3 ) 2 ).

화합물 24. 1-(4-(2-(2-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실산Compound 24. 1-(4-(2-(2-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylic acid

Figure 112021066570416-pat00032
Figure 112021066570416-pat00032

노란 고체;yellow solid;

수율: 98%;Yield: 98%;

1H NMR (CD3OD, 400 MHz) δ 8.34 (dd, J = 1.6, 7.9 Hz, 2 ArH), 8.19 (s, selenazole ring-H), 7.78 (d, J = 8.2 Hz, 2 ArH), 7.55 (d, J = 8.2 Hz, 2 ArH), 7.49 (m, 1 ArH), 7.25 (d, J = 8.3 Hz, 1 ArH), 7.09 (t, J = 7.24 Hz, 1 ArH), 5.01-5.07 (m, OCH(CH3)2), 4.45 (s, 2 NCH 2 ), 4.32-4.37 (m, 4 azetidine ring-H), 3.63-3.69 (m, 1 azetidine ring-H), 1.57 (d, J = 6.0 Hz, OCH(CH 3 ) 2 ); 1 H NMR (CD 3 OD, 400 MHz) δ 8.34 (dd, J = 1.6, 7.9 Hz, 2ArH ), 8.19 (s, selenazole ring- H ), 7.78 (d, J = 8.2 Hz, 2ArH ), 7.55 (d, J = 8.2 Hz, 2 Ar H ), 7.49 (m, 1 Ar H ), 7.25 (d, J = 8.3 Hz, 1 Ar H ), 7.09 (t, J = 7.24 Hz, 1 Ar H ), 5.01-5.07 (m , OC H (CH 3 ) 2 ), 4.45 (s, 2 NC H 2 ), 4.32-4.37 (m, 4 azetidine ring- H ), 3.63-3.69 (m, 1 azetidine ring- H ), 1.57 (d, J = 6.0 Hz, OCH(C H 3 ) 2 );

13C NMR (CD3OD, 100 MHz) δ 172.84 (NCSe), 167.14 (C(O)), 154.52, 144.27, 138.45, 135.86, 131.00, 130.55, 129.23, 127.54, 126.57, 124.71, 120.39, 113.32 (ArC), 71.79, 57.74, 55.86, 32.97 (azetidine ring-C), 21.18 (OCH(CH3)2). 13 C NMR (CD 3 OD, 100 MHz) δ 172.84 ( N 113.32 (Ar C ), 71.79 , 57.74 , 55.86, 32.97 (azetidine ring- C ), 21.18 (OCH( C H 3 ) 2 ).

화합물 25. 에틸 1-(4-(2-(2-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트Compound 25. Ethyl 1-(4-(2-(2-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

Figure 112021066570416-pat00033
Figure 112021066570416-pat00033

상아색 기름;ivory oil;

수율: 70%;Yield: 70%;

1H NMR (CDCl3, 400 MHz) δ 8.43 (dd, J = 1.4, 7.7 Hz, 1 ArH), 8.09 (s, selenazole ring H), 7.58-7.60 (m, 2 ArH), 7.38-7.44 (m, 2 ArH), 7.05-7.10 (m, 1 ArH), 4.87-4.96 (m, OCH(CH3)2), 4.23 (q, J = 7.1 Hz, COOCH 2 CH3), 3.75-3.89 (m, NCH 2 ), 3.57-3.68 (m, 3 azetidine ring H), 3.43-3.49 (m, 1 azetidine ring H), 1.57 (d, J = 6.0 Hz, OCH(CH 3 )2), 1.31 (t, J = 7.1 Hz, COOCH2CH 3 ); 1 H NMR (CDCl 3 , 400 MHz) δ 8.43 (dd, J = 1.4, 7.7 Hz, 1 Ar H ), 8.09 (s, selenazole ring H ), 7.58-7.60 (m, 2 Ar H ), 7.38-7.44 (m, 2 Ar H ) , 7.05-7.10 (m, 1 Ar H ), 4.87-4.96 (m, OC H (CH 3 ) 2 ), 4.23 (q, J = 7.1 Hz, COOC H 2 CH 3 ), 3.75-3.89 (m, NC H 2 ), 3.57-3.68 (m, 3 azetidine ring H ), 3.43-3.49 (m, 1 azetidine ring H ), 1.57 (d, J = 6.0 Hz, OCH(CH 3 ) 2 ), 1.31 (t, J = 7.1 Hz, COOCH 2 C H 3 );

13C NMR (CDCl3, 100 MHz) δ 180.76 (NCSe), 168.76 (C(O)), 165.98, 161.15, 154.31, 138.36, 130.49, 129.45, 127.46, 127.32, 125.53, 120.73, 113.06 (ArC), 71.67 (COOCH2CH3), 62.21, 61.11 (NCH2), 56.35 (azetidine ring-C), 33.79 (azetidine ring-C), 29.56, 22.36 (OCH(CH3) 2 ), 14.17 (COOCH2 CH3). 13 C NMR (CDCl 3 , 100 MHz) δ 180.76 (N Ar C ) , 71.67 ( COO C H 2 CH 3 ), 62.21, 61.11 (N C H 2 ), 56.35 (azetidine ring- C ), 33.79 (azetidine ring- C ), 29.56, 22.36 (OCH( C H 3 ) 2 ), 14.17 (COOCH 2 C H 3 ).

화합물 26. 메틸 1-(4-(2-(피리딘-2-일)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트Compound 26. Methyl 1-(4-(2-(pyridin-2-yl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

Figure 112021066570416-pat00034
Figure 112021066570416-pat00034

하얀 고체;White solid;

수율: 50%;Yield: 50%;

1H NMR (CDCl3, 400 MHz) δ 8.61-8.63 (m, 1 ArH), 8.14 (d, J = 7.6 Hz, 1 ArH), 8.07 (s, 1 ArH), 7.80 (t, J = 7.3 Hz, 1 ArH), 7.56 (d, J = 7.6 Hz, 2 ArH), 7.36 (d, J = 8.0 Hz, 3 ArH), 3.72-3.74 (m, COOCH 3 , NCH 2 ), 3.66 (br s, 2 azetidine ring-H), 3.42 (br s, 3 azetidine ring-H); 1 H NMR (CDCl 3 , 400 MHz) δ 8.61-8.63 (m, 1 Ar H ), 8.14 (d, J = 7.6 Hz, 1 Ar H ), 8.07 (s, 1 Ar H ), 7.80 (t, J = 7.3 Hz, 1 Ar H) ), 7.56 (d, J = 7.6 Hz, 2 Ar H ), 7.36 (d, J = 8.0 Hz, 3 Ar H ), 3.72-3.74 (m, COOC H 3 , NC H 2 ), 3.66 (br s, 2 azetidine ring- H ), 3.42 (br s, 3 azetidine ring- H );

13C NMR (CDCl3, 100 MHz) δ 175.79, 173.27, 153.37, 149.68, 148.06, 140.46, 136.97, 133.27, 129.34, 127.51, 124.51, 118.43 (ArC), 62.51 (NCH2), 56.60 (azetidine ring-C), 52.07 (COOCH3), 33.79 (azetidine ring-C). 13 C NMR (CDCl 3 , 100 MHz) δ 175.79, 173.27, 153.37, 149.68, 148.06, 140.46, 136.97, 133.27, 129.34, 127.51, 124.51, 118.43 (Ar C ), 62.51 (N C H 2 ), 56.60 (azetidine ring- C ), 52.07 ( COO C H 3 ), 33.79 (azetidine ring- C ).

화합물 27. 소디움 1-(4-(2-(피리딘-2-일)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트Compound 27. Sodium 1-(4-(2-(pyridin-2-yl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

Figure 112021066570416-pat00035
Figure 112021066570416-pat00035

하얀 고체;White solid;

수율: 54%;Yield: 54%;

1H NMR (CD3OD, 400 MHz) δ 8.58 (d, J = 4.4 Hz, 1 ArH), 8.12-8.16 (m, 2 ArH), 7.90-7.94 (m, 1 ArH), 7.64 (d, J = 8.2 Hz, 2 ArH), 7.46-7.47 (m, 1 ArH), 7.45-7.38 (m, 2 ArH), 3.68 (s, NCH 2 ), 3.56-3.60 (m, 2 azetidine ring-H), 3.37-3.41 (m, 2 azetidine ring-H), 3.21-3.25 (m, 1 ArH); 1 H NMR (CD 3 OD, 400 MHz) δ 8.58 (d, J = 4.4 Hz, 1 Ar H ), 8.12-8.16 (m, 2 Ar H ), 7.90-7.94 (m, 1 Ar H ), 7.64 (d, J = 8.2 Hz, 2 Ar H ) Ar H ), 7.46-7.47 (m, 1 Ar H ), 7.45-7.38 (m, 2 Ar H ), 3.68 (s, NC H 2 ), 3.56-3.60 (m, 2 azetidine ring- H ), 3.37- 3.41 (m, 2 azetidine ring- H ), 3.21-3.25 (m, 1 Ar H );

13C NMR (CD3OD, 100 MHz) δ 179.57, 179.08, 175.60, 152.85, 149.57, 148.22, 139.96, 137.82 ,137.28, 132.61, 129.48, 126.97, 124.80, 118.06 (ArC), 62.31 (NCH2), 57.59 (azetidine ring-C), 36.50 (azetidine ring-C). 13 C NMR (CD 3 OD, 100 MHz) δ 179.57, 179.08, 175.60, 152.85, 149.57, 148.22, 139.96, 137.82,137.28, 132.61, 129.48, 126.97, 124.80, 118.06 (Ar C ) , 62.31 (N C H 2 ), 57.59 (azetidine ring- C ), 36.50 (azetidine ring- C ).

화합물 28. 메틸 1-(4-(2-(피리딘-3-일)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트Compound 28. Methyl 1-(4-(2-(pyridin-3-yl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

Figure 112021066570416-pat00036
Figure 112021066570416-pat00036

하얀 고체;White solid;

수율: 50%;Yield: 50%;

1H NMR (CD3OD, 400 MHz) δ 9.10 (s, pyridine-H), 8.62-8.64 (m, 1 ArH), 8.32-8.35 (m, 1 ArH), 8.14 (s, 1 ArH), 7.63 (d, J = 8.1 Hz, 2 ArH), 7.54-5.57 (m, 1 ArH), 7.38 (d, J = 8.1 Hz, 2 ArH), 3.73 (s, COOCH 3 ), 3.69 (s, NCH 2 ), 3.56-3.59 (m, 2 azetidine ring-H), 3.34-3.38 (m, 3 azetidine ring-H); 1 H NMR (CD 3 OD, 400 MHz) δ 9.10 (s, pyridine- H ), 8.62-8.64 (m, 1 Ar H ), 8.32-8.35 (m, 1 Ar H ), 8.14 (s, 1 Ar H ), 7.63 (d, J = 8.1 Hz, 2 Ar H ), 7.54-5.57 (m, 1 Ar H ), 7.38 (d, J = 8.1 Hz, 2 Ar H ), 3.73 (s, COOC H 3 ), 3.69 (s, NC H 2 ) , 3.56-3.59 (m, 2 azetidine ring- H ), 3.34-3.38 (m, 3 azetidine ring- H );

13C NMR (CD3OD, 100 MHz) δ 174.78, 171.12, 151.35, 149.04, 147.94, 141.13, 139.04, 135.84, 134.00, 136.61, 130.81, 128.52, 125.74 (ArC), 63.42 (NCH2), 57.52 (azetidine ring-C), 52.53 (COOCH3), 34.93 (azetidine ring-C). 13 C NMR (CD 3 OD, 100 MHz) δ 174.78, 171.12, 151.35, 149.04, 147.94, 141.13, 139.04, 135.84, 134.00, 136.61, 130.81, 128.52, 125.74 (Ar C ), 63.42 ( N C H 2 ), 57.52 (azetidine ring- C ), 52.53 (COO C H 3 ), 34.93 (azetidine ring- C ).

화합물 29. 소디움 1-(4-(2-(피리딘-3-일)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트Compound 29. Sodium 1-(4-(2-(pyridin-3-yl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

Figure 112021066570416-pat00037
Figure 112021066570416-pat00037

하얀 고체;White solid;

수율: 95%;Yield: 95%;

1H NMR (CD3OD, 400 MHz) δ 9.09 (s, pyridine-H), 8.61-8.62 (m, 1 ArH), 8.31-8.34 (m, 1 ArH), 8.13 (s, 1 ArH), 7.62 (d, J = 8.1 Hz, 2 ArH), 7.53-7.56 (m, 1 ArH), 7.37 (d, J = 8.1 Hz, 2 ArH), 3.65 (s, NCH 2 ), 3.52-3.56 (m, 2 azetidine ring-H), 3.33-3.37 (m, 2 azetidine ring-H), 3.16-3.22 (m, 1 ArH); 1 H NMR (CD 3 OD, 400 MHz) δ 9.09 (s, pyridine- H ), 8.61-8.62 (m, 1 Ar H ), 8.31-8.34 (m, 1 Ar H ), 8.13 (s, 1 Ar H ), 7.62 (d, J = 8.1 Hz, 2 Ar H ), 7.53-7.56 (m, 1 Ar H ), 7.37 (d, J = 8.1 Hz, 2 Ar H ), 3.65 (s, NC H 2 ), 3.52-3.56 (m, 2 azetidine ring- H ), 3.33-3.37 (m, 2 azetidine ring- H ), 3.16-3.22 (m, 1 Ar H );

13C NMR (CD3OD, 100 MHz) δ 179.62, 179.19, 169.88, 149.97, 147.84, 146.43, 139.62, 137.98, 134.60, 132.57, 132.03, 129.57, 127.10, 124.47 (ArC), 62.21 (NCH2), 57.54 (azetidine ring-C), 36.46 (azetidine ring-C). 13 C NMR (CD 3 OD, 100 MHz) δ 179.62, 179.19, 169.88, 149.97, 147.84, 146.43, 139.62, 137.98, 134.60, 132.57, 132.03, 129.57, 127.10, 124.47 (Ar C ) , 62.21 (N C H 2 ), 57.54 (azetidine ring- C ), 36.46 (azetidine ring- C ).

화합물 30. 메틸 1-(4-(2-(4-tert-부틸페닐)-1,3-셀레나졸-5-일)벤질)피롤리딘-3-카르복실레이트Compound 30. Methyl 1-(4-(2-(4-tert-butylphenyl)-1,3-selenazol-5-yl)benzyl)pyrrolidine-3-carboxylate

Figure 112021066570416-pat00038
Figure 112021066570416-pat00038

노란 고체;yellow solid;

수율: 52%;Yield: 52%;

1H NMR (CDCl3, 400 MHz) δ 7.97 (s, selenazole ring-H), 7.87 (d, J = 8.4 Hz, 2 ArH), 7.47-7.54 (m, 4 ArH), 7.37 (d, J = 8.0 Hz, 2 ArH), 3.71 (s, COOCH 3 ), 3.66 (s, NCH 2 ), 3.04-3.10 (m, 1 pyrrolidine ring-H), 2.90-2.94 (m, 1 pyrrolidine ring-H), 2.67-2.76 (m, 2 pyrrolidine ring-H), 2.55-2.59 (m, 1 pyrrolidien ring-H), 2.11-2.17 (m, 2 pyrrolidine ring-H), 1.38 (s, Ar(CH 3 ) 3 ); 1 H NMR (CDCl 3 , 400 MHz) δ 7.97 (s, selenazole ring- H ), 7.87 (d, J = 8.4 Hz, 2 Ar H ), 7.47-7.54 (m, 4 Ar H ), 7.37 (d, J = 8.0 Hz, 2 Ar H) H ), 3.71 (s, COOC H 3 ), 3.66 (s, NC H 2 ), 3.04-3.10 (m, 1 pyrrolidine ring- H ), 2.90-2.94 (m, 1 pyrrolidine ring- H ), 2.67-2.76 (m, 2 pyrrolidine ring- H ), 2.55-2.59 (m, 1 pyrrolidine ring- H ), 2.11-2.17 (m, 2 pyrrolidine ring- H ), 1.38 (s, Ar( CH 3 ) 3 );

13C NMR (CDCl3, 100 MHz) δ 175.47 (NCSe), 173.85 (C(O)), 153.65, 145.51, 139.53, 139.19, 133.53, 129.42,127.26, 126.60, 126.00 (ArC), 59.64 (NCH2), 56.67, 53.76, 51.90, 41.99, 34.93, 31.19 (Ar(CH3) 3 ), 27.69. 13 C NMR (CDCl 3 , 100 MHz) δ 175.47 (N C Se), 173.85 ( C (O)), 153.65, 145.51, 139.53, 139.19, 133.53, 129.42,127.26, 126.60, 126.00 (Ar C ), 59.64 (N C H 2 ) , 56.67 , 53.76, 51.90, 41.99, 34.93, 31.19 (Ar( C H 3 ) 3 ), 27.69.

화합물 31. 소디움 1-(4-(2-(4-tert-부틸페닐)-1,3-셀레나졸-5-일)벤질)피롤리딘-3-카르복실레이트Compound 31. Sodium 1-(4-(2-(4-tert-butylphenyl)-1,3-selenazol-5-yl)benzyl)pyrrolidine-3-carboxylate

Figure 112021066570416-pat00039
Figure 112021066570416-pat00039

하얀 고체;White solid;

수율: 95%;Yield: 95%;

1H NMR (CD3OD, 400 MHz) δ 8.01 (s, 1 selenazole ring-H), 7.83 (dd, J = 1.6, 6.7 Hz, 2 ArH), 7.58 (d, J = 8.2 Hz, 2 ArH), 7.49-7.51 (m, 2 ArH), 7.40 (d, J = 8.2 Hz, 2 ArH), 3.65 (d, J = 5.2 Hz, NCH 2 ), 2.93-3.04 (m, 2 pyrrolidine ring-H), 2.80-2.82 (m, 1 pyrrolidine ring-H), 2.62-2.66 (m, pyrrolidine ring-H), 2.48-2.55 (m, pyrrolidine ring-H), 2.04-2.12 (m, 2 pyrrolidine ring-H), 1.36 (s, Ar(CH 3 ) 3 ); 1 H NMR (CD 3 OD, 400 MHz) δ 8.01 (s, 1 selenazole ring- H ), 7.83 (dd, J = 1.6, 6.7 Hz, 2 Ar H ), 7.58 (d, J = 8.2 Hz, 2 Ar H ), 7.49-7.51 (m , 2 Ar H ), 7.40 (d, J = 8.2 Hz, 2 Ar H ), 3.65 (d, J = 5.2 Hz, NC H 2 ), 2.93-3.04 (m, 2 pyrrolidine ring- H ), 2.80-2.82 (m, 1 pyrrolidine ring- H ), 2.62-2.66 (m, pyrrolidine ring- H ), 2.48-2.55 (m, pyrrolidine ring- H ), 2.04-2.12 (m, 2 pyrrolidine ring- H ), 1.36 (s) , Ar(C H 3 ) 3 );

13C NMR (CD3OD, 100 MHz) δ 181.62 (NCSe), 174.47 (C(O)), 153.86, 145.71, 138.88, 13871, 133.33, 132.32, 129.87, 126.77, 126.23, 125.81 (ArC), 59.64 (NCH2), 57.72, 53.75, 45.16, 34.41, 30.16 (C(CH3) 3 ), 28.24. 13 C NMR (CD 3 OD, 100 MHz) δ 181.62 (N C Se), 174.47 ( C (O)), 153.86, 145.71, 138.88, 13871, 133.33, 132.32, 129.87, 126.77, 126.23, 125.81 (Ar C ), 59.6 4 (N C H 2 ) , 57.72, 53.75, 45.16, 34.41, 30.16 (C( C H 3 ) 3 ), 28.24.

화합물 32. 메틸 1-(4-(2-(4-tert-부틸페닐)-1,3-셀레나졸-5-일)벤질)피페리딘-4-카르복실레이트Compound 32. Methyl 1-(4-(2-(4-tert-butylphenyl)-1,3-selenazol-5-yl)benzyl)piperidine-4-carboxylate

Figure 112021066570416-pat00040
Figure 112021066570416-pat00040

하얀 고체;White solid;

수율: 12%;Yield: 12%;

1H NMR (CDCl3, 400 MHz) δ 7.98 (s, selenazole ring-H), 7.86 (d, J = 8.4 Hz, 2 ArH), 7.47-7.55 (m, 4 ArH), 7.38-7.39 (m, 2 ArH), 3.71 (s, COOCH 3 ), 3.55 (s, NCH 2 ), 2.89-2.91 (m, 2 piperidine ring-H), 2.34 (br s, 1 piperidine ring-H), 2.12-2.20 (m, 2 piperidine ring-H),1.83-1.91 (m, 4 piperidine ring-H), 1.60 (s, Ar(CH 3 ) 3 ); 1 H NMR (CDCl 3 , 400 MHz) δ 7.98 (s, selenazole ring- H ), 7.86 (d, J = 8.4 Hz, 2 Ar H ), 7.47-7.55 (m, 4 Ar H ), 7.38-7.39 (m, 2 Ar H ), 3.71 (s, COOC H 3 ), 3.55 (s, NC H 2 ), 2.89-2.91 (m, 2 piperidine ring- H ), 2.34 (br s, 1 piperidine ring- H ), 2.12-2.20 (m, 2 piperidine ring- H ),1.83-1.91 (m, 4 piperidine ring- H ), 1.60 (s, Ar(C H 3 ) 3 );

13C NMR (CDCl3, 100 MHz) δ 175.64 (NCSe), 173.87 (C(O)), 153.67, 145.51, 139.50, 133.77, 132.52, 129.71, 127.18, 126.58, 125.99 (ArC), 62.76 (NCH2), 52.90, 51.63, 50.98, 41.02, 34.93, 31.16 (Ar(CH3) 3 ), 28.27, 27.14. 13 C NMR (CDCl 3 , 100 MHz) δ 175.64 (N C Se), 173.87 ( C (O)), 153.67, 145.51, 139.50, 133.77, 132.52, 129.71, 127.18, 126.58, 125.99 (Ar C ), 62.76 (N C H 2 ), 52.90 , 51.63, 50.98, 41.02, 34.93, 31.16 (Ar( C H 3 ) 3 ), 28.27, 27.14.

화합물 33. 메틸 1-(4-(2-(3-클로로-4-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질)피롤리딘-3-카르복실레이트Compound 33. Methyl 1-(4-(2-(3-chloro-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)pyrrolidine-3-carboxylate

Figure 112021066570416-pat00041
Figure 112021066570416-pat00041

노란 고체;yellow solid;

수율: 47%;Yield: 47%;

1H NMR (CDCl3, 400 MHz) δ 7.92-7.89 (m, 1 ArH), 7.88 (s, 1 ArH), 7.68 (dd, J = 2.1, 8.6 Hz, 1 ArH), 7.45 (d, J = 8.0 Hz, 2 ArH), 7.32 (d, J = 8.0 Hz, ArH), 6.63 (d, J = 8.6 Hz, 1 ArH), 4.61 (sept, J = 6.0 Hz, OCH(CH3)2), 3.66 (s, COOCH 3 ), 3.61 (d, J = 3.6 Hz, NCH 2 ), 2.99-3.05 (m, 1 pyrrolidine ring H), 2.84-2.89 (m, 1 pyrrolidine ring-H), 2.54-2.70 (m, 2 pyrrolidine ring-H), 2.50-2.52 (m, 1 pyrrolidine ring-H), 2.06-2.12 (m, 2 pyrrolidine ring-H), 1.38 (d, J = 6.0 Hz, OCH(CH 3 )2); 1 H NMR (CDCl 3 , 400 MHz) δ 7.92-7.89 (m, 1 Ar H ), 7.88 (s, 1 Ar H ), 7.68 (dd, J = 2.1, 8.6 Hz, 1 Ar H ), 7.45 (d, J = 8.0 Hz, 2 Ar H ), 7.32 (d, J = 8.0 Hz, Ar H ), 6.63 (d, J = 8.6 Hz, 1 Ar H ), 4.61 (sept, J = 6.0 Hz, OC H (CH 3 ) 2 ), 3.66 (s, COOC H 3 ), 3.61 (d, J = 3.6 Hz, NC H 2 ), 2.99-3.05 (m, 1 pyrrolidine ring- H ), 2.84-2.89 (m, 1 pyrrolidine ring- H ), 2.54-2.70 (m, 2 pyrrolidine ring- H ), 2.50-2.52 (m, 1 pyrrolidine ring- H ), 2.06-2.12 (m, 2 pyrrolidine ring- H ), 1.38 (d, J = 6.0 Hz, OCH(C H 3 ) 2 );

13C NMR (CDCl3, 100 MHz) δ 175.44 (NCSe), 171.86 (C(O)), 155.17, 145.74, 139.42, 139.28, 132.32, 129.96, 129.43, 128.58, 127.22, 126.21, 124.63,115.12 (ArC), 72.11 (OCH(CH3)2), 59.60 (NCH2), 56.65, 53.76, 51.89, 41.97, 27.69 (pyrrolidine ring-C), 21.99 (OCH(CH3)2). 13 C NMR (CDCl 3 , 100 MHz) δ 175.44 (N C Se), 171.86 ( C (O)), 155.17, 145.74, 139.42, 139.28, 132.32, 129.96, 129.43, 128.58, 127.22, 126.21, 124.63,115.12 (Ar C ), 72.1 1 (O C H (CH 3 ) 2 ), 59.60 (N C H 2 ), 56.65, 53.76, 51.89, 41.97, 27.69 (pyrrolidine ring- C ), 21.99 (OCH( C H 3 ) 2 ).

화합물 34. 소디움 1-(4-(2-(3-클로로-4-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질)피롤리딘-3-카르복실레이트Compound 34. Sodium 1-(4-(2-(3-chloro-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)pyrrolidine-3-carboxylate

Figure 112021066570416-pat00042
Figure 112021066570416-pat00042

하얀 고체;White solid;

수율: 93%;Yield: 93%;

1H NMR (CD3OD, 400 MHz) δ 8.02 (s, selenazole ring-H), 7.97 (d, J = 2.2 Hz, 1 ArH), 7.80 (dd, J = 2.2, 8.6 Hz, 1 ArH), 7.60 (d, J = 8.1 Hz, 2 ArH), 7.43 (d, J = 8.1 Hz, 2 ArH), 7.18 (d, J = 8.8 Hz, 1 ArH), 4.75 (sept, J = 6.0 Hz, OCH(CH3)2), 3.64-3.72 (m, NCH 2 ), 3.03-3.08 (m, 1 pyrrolidine ring H), 2.91-2.99 (m, 1 pyrrolidine ring-H), 2.79-2.88 (m, 1 pyrrolidine ring-H), 2.60-2.65 (m, 1 pyrrolidine ring-H), 2.50-2.54 (m, 1 pyrrolidine ring-H), 2.06-2.13 (m, 2 pyrrolidine ring-H), 1.38 (d, J = 6.0 Hz, OCH(CH 3 )2); 1 H NMR (CD 3 OD, 400 MHz) δ 8.02 (s, selenazole ring- H ), 7.97 (d, J = 2.2 Hz, 1 Ar H ), 7.80 (dd, J = 2.2, 8.6 Hz, 1 Ar H ), 7.60 (d, J = 8.1 Hz, 2 Ar H ), 7.43 (d, J = 8.1 Hz, 2 Ar H ), 7.18 (d, J = 8.8 Hz, 1 Ar H ), 4.75 (sept, J = 6.0 Hz, OC H (CH 3 ) ) 2 ), 3.64-3.72 (m, NC H 2 ), 3.03-3.08 (m, 1 pyrrolidine ring H ), 2.91-2.99 (m, 1 pyrrolidine ring- H ), 2.79-2.88 (m, 1 pyrrolidine ring- H ), 2.60-2.65 (m, 1 pyrrolidine ring- H ), 2.50-2.54 (m, 1 pyrrolidine ring- H ), 2.06-2.13 (m, 2 pyrrolidine ring- H ), 1.38 (d, J = 6.0 Hz) , OCH(C H 3 ) 2 );

13C NMR (CD3OD, 100 MHz) δ 181.67 (NCSe), 172.16 (C(O)), 155.18, 145.75, 138.93, 138.63, 132.18, 129.83, 129.56, 129.34, 127.59, 126.71, 126.55, 124.02, 114.80 (ArC), 71.66 (OCH(CH3)2), 59.70 (NCH2), 57.76, 53.78, 45.13, 28.30 (pyrrolidine ring-C), 20.97 (OCH(CH3)2). 13 C NMR (CD 3 OD, 100 MHz) δ 181.67 (N Ar C ), 71.66 (O C H ( CH 3 ) 2 ), 59.70 (N C H 2 ), 57.76, 53.78, 45.13, 28.30 (pyrrolidine ring- C ), 20.97 (OCH( C H 3 ) 2 ).

화합물 35. 에틸 2-(4-(2-(3-클로로-4-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질아미노)아세테이트Compound 35. Ethyl 2-(4-(2-(3-chloro-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzylamino)acetate

Figure 112021066570416-pat00043
Figure 112021066570416-pat00043

상아색 고체;Ivory solid;

수율: 31%;Yield: 31%;

1H NMR (CDCl3, 400 MHz) δ 7.90-7.93 (m, selenazole ring-H, 1 ArH), 7.71 (dd, J = 2.2 Hz, 8.6 Hz, 2 ArH), 7.49 (d, J = 8.1 Hz, 2 ArH), 7.35 (d, J = 8.1 Hz, 2 ArH), 6.96 (d, J = 8.7 Hz, 1 ArH), 4.63 (sept, J = 6.0 Hz, OCH(CH3)2), 4.19 (q, J = 7.1 Hz, OCH 2 CH3), 3.82 (s, NCH 2 Ar), 3.41 (s, COCH 2 NH), 1.40 (d, J = 6.0 Hz, OCH(CH 3 )2) 1.27 (t, J = 7.1 Hz, OCH2CH 3 ); 1 H NMR (CDCl 3 , 400 MHz) δ 7.90-7.93 (m, selenazole ring- H , 1 Ar H ), 7.71 (dd, J = 2.2 Hz, 8.6 Hz, 2 Ar H ), 7.49 (d, J = 8.1 Hz, 2 Ar H ) , 7.35 (d, J = 8.1 Hz, 2 Ar H ), 6.96 (d, J = 8.7 Hz, 1 Ar H ), 4.63 (sept, J = 6.0 Hz, OC H (CH 3 ) 2 ), 4.19 (q , J = 7.1 Hz, OC H 2 CH 3 ), 3.82 (s, NC H 2 Ar), 3.41 (s, COC H 2 NH), 1.40 (d, J = 6.0 Hz, OCH(C H 3 ) 2 ) 1.27 (t, J = 7.1 Hz, OCH 2 C H 3 );

13C NMR (CDCl3, 100 MHz) δ 172.39 (NCSe), 172.02 (C(O)), 155.21, 145.63, 139.85, 139.49, 132.52, 129.97, 129.00, 128.66, 127.40, 126.18, 124.67, 115.17 (ArC), 72.15 (OCH(CH3)2), 60.84 (NCH2Ar), 52.85, 50.06, 21.99 (OCH(CH3)2), 14.25 (OCH2 CH3). 13 C NMR (CDCl 3 , 100 MHz) δ 172.39 ( N 115.17 ( ArC ) , 72.15 (O C H(CH 3 ) 2 ), 60.84 (N C H 2 Ar), 52.85, 50.06, 21.99 (OCH( C H 3 ) 2 ), 14.25 (OCH 2 C H 3 ).

화합물 36. 소디움 2-(4-(2-(3-클로로-4-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질아미노)아세테이트Compound 36. Sodium 2-(4-(2-(3-chloro-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzylamino)acetate

Figure 112021066570416-pat00044
Figure 112021066570416-pat00044

하얀 고체;White solid;

수율: 90%;Yield: 90%;

1H NMR (CD3OD, 400 MHz) δ 8.01 (s, selenazole ring-H), 7.96 (s, 1 ArH), 7.79 (d, J = 7.2 Hz, 1 ArH), 7.60 (d, J = 7.7 Hz, 2 ArH), 7.43 (d, J = 7.8 Hz, 2 ArH), 7.17 (d, J = 8.6 Hz, 1 ArH), 4.75 (sept, J = 6.2 Hz, OCH(CH3)2), 3.78 (s, NCH 2 Ar), 3.20 (s, COCH 2 NH), 1.40 (d, J = 6.0 Hz, OCH(CH 3 )2) 1.27 (t, J = 7.1 Hz, OCH2CH 3 ); 1 H NMR (CD 3 OD, 400 MHz) δ 8.01 (s, selenazole ring- H ), 7.96 (s, 1 Ar H ), 7.79 (d, J = 7.2 Hz, 1 Ar H ), 7.60 (d, J = 7.7 Hz, 2 Ar H ) , 7.43 (d, J = 7.8 Hz, 2 Ar H ), 7.17 (d, J = 8.6 Hz, 1 Ar H ), 4.75 (sept, J = 6.2 Hz, OC H (CH 3 ) 2 ), 3.78 (s) , NC H 2 Ar), 3.20 (s, COC H 2 NH), 1.40 (d, J = 6.0 Hz, OCH(C H 3 ) 2 ) 1.27 (t, J = 7.1 Hz, OCH 2 C H 3 );

13C NMR (CDCl3, 100 MHz) δ 177.26 (NCSe), 172.49 (C(O)), 155.28, 145.90, 139.77, 138.83, 132.11, 129.37, 129.13, 127.65, 126.90, 126.49, 124.07, 114.99 (ArC), 71.77 (OCH(CH3)2), 52.37 51.92, 20.85 (OCH(CH3)2). 13 C NMR (CDCl 3 , 100 MHz) δ 177.26 ( N 114.99 ( ArC ), 71.77 ( O C H(CH 3 ) 2 ), 52.37 51.92, 20.85 (OCH( C H 3 ) 2 ).

화합물 37. 메틸 3-(4-(2-(3-클로로-4-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질아미노)프로파노에이트Compound 37. Methyl 3-(4-(2-(3-chloro-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzylamino)propanoate

Figure 112021066570416-pat00045
Figure 112021066570416-pat00045

노란 고체;yellow solid;

수율: 41%;Yield: 41%;

1H NMR (CDCl3, 400 MHz) δ 7.91 (d, J = 2.2 Hz, 1 ArH), 7.88 (s, selenazole ring-H), 7.69 (dd, J = 2.2 Hz, 8.6 Hz, 1 ArH), 7.47 (d, J = 8.1 Hz, 2 ArH), 7.33 (d, J = 8.1 Hz, 2 ArH), 6.94 (d, J = 8.7 Hz, 1 ArH), 4.61 (sept, J = 6.0 Hz, OCH(CH3)2), 3.83 (s, NCH 2 Ar), 3.67 (s, COOCH 3 ), 2.89 (t, J = 6.4 Hz, NHCH 2 CH2COOCH3), 2.54 (t, J = 6.4 Hz, NHCH2CH 2 COOCH3), 1.39 (d, J = 6.0 Hz, OCH(CH 3 )2); 1 H NMR (CDCl 3 , 400 MHz) δ 7.91 (d, J = 2.2 Hz, 1 Ar H ), 7.88 (s, selenazole ring- H ), 7.69 (dd, J = 2.2 Hz, 8.6 Hz, 1 Ar H ), 7.47 (d, J) = 8.1 Hz, 2 Ar H ), 7.33 (d, J = 8.1 Hz, 2 Ar H ), 6.94 (d, J = 8.7 Hz, 1 Ar H ), 4.61 (sept, J = 6.0 Hz, OC H (CH 3 ) 2 ), 3.83 (s, NC H 2 Ar), 3.67 (s, COOC H 3 ), 2.89 (t, J = 6.4 Hz, NHC H 2 CH 2 COOCH 3 ), 2.54 (t, J = 6.4 Hz) , NHCH 2 C H 2 COOCH 3 ), 1.39 (d, J = 6.0 Hz, OCH(C H 3 ) 2 );

13C NMR (CDCl3, 100 MHz) δ 173.18 (NCSe), 171.91 (C(O)), 155.18, 145.71, 140.40, 139.43, 132.32, 129.96, 128.81, 128.61, 127.35, 127.15, 126.20, 124.64, 115.14 (ArC), 72.13 (OCH(CH3)2), 53.27 (NCH2Ar), 51.66, 44.39, 34.49, 21.99 (OCH(CH3)2). 13 C NMR (CDCl 3 , 100 MHz) δ 173.18 ( N 124.64, 115.14 (Ar C ), 72.13 (O C H (CH 3 ) 2 ), 53.27 (N C H 2 Ar), 51.66, 44.39, 34.49, 21.99 (OCH ( C H 3 ) 2 ).

화합물 38. 소디움 3-(4-(2-(3-클로로-4-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질아미노)프로파노에이트Compound 38. Sodium 3-(4-(2-(3-chloro-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzylamino)propanoate

Figure 112021066570416-pat00046
Figure 112021066570416-pat00046

상아색 고체;Ivory solid;

수율: 65%;Yield: 65%;

1H NMR (CD3OD, 400 MHz) δ 8.09 (s, selenazole ring-H), 7.98 (d, J = 2.2 Hz, 1 ArH), 7.83-7.81 (dd, J = 2.3 Hz, 8.6 Hz, 1 ArH), 7.74 (d, J = 8.2 Hz, 2 ArH), 7.55 (d, J = 8.1 Hz, 2 ArH), 7.19 (d, J = 8.7 Hz, 1 ArH), 4.78 (sept, J = 6.0 Hz, OCH(CH3)2), 4.22 (s, NCH 2 Ar), 3.14-3.20 (m, NHCH 2 CH2COOCH3), 2.52 (t, J = 6.4 Hz, NHCH2CH 2 COOH), 1.41 (d, J = 6.0 Hz, OCH(CH 3 )2); 1 H NMR (CD 3 OD, 400 MHz) δ 8.09 (s, selenazole ring- H ), 7.98 (d, J = 2.2 Hz, 1 Ar H ), 7.83-7.81 (dd, J = 2.3 Hz, 8.6 Hz, 1 Ar H ), 7.74 (d) , J = 8.2 Hz, 2 Ar H ), 7.55 (d, J = 8.1 Hz, 2 Ar H ), 7.19 (d, J = 8.7 Hz, 1 Ar H ), 4.78 (sept, J = 6.0 Hz, OC H (CH 3 ) 2 ), 4.22 (s, NC H 2 Ar), 3.14-3.20 (m, NHC H 2 CH 2 COOCH 3 ), 2.52 (t, J = 6.4 Hz, NHCH 2 C H 2 COOH), 1.41 (d, J = 6.0 Hz, OCH(C H 3 ) 2 );

13C NMR (CD3OD, 100 MHz) δ 173.18 (NCSe), 171.91 (C(O)), 155.18, 145.71, 140.40, 139.43, 132.32, 129.96, 128.81, 128.61, 127.35, 127.15, 126.20, 124.64, 115.14 (ArC), 72.13 (OCH(CH3)2), 53.27 (NCH2Ar), 51.66, 44.39, 34.49, 21.99 (OCH(CH3)2). 13 C NMR (CD 3 OD, 100 MHz) δ 173.18 ( N 124.64, 115.14 (Ar C ), 72.13 (O C H (CH 3 ) 2 ), 53.27 (N C H 2 Ar), 51.66, 44.39, 34.49, 21.99 (OCH ( C H 3 ) 2 ).

화합물 39. 메틸 1-(4-(5-(4-tert-부틸페닐)-1,3-셀레나졸-2-일)벤질)아제티딘-3-카르복실레이트Compound 39. Methyl 1-(4-(5-(4-tert-butylphenyl)-1,3-selenazol-2-yl)benzyl)azetidine-3-carboxylate

Figure 112021066570416-pat00047
Figure 112021066570416-pat00047

상아색 고체;Ivory solid;

수율: 65%;Yield: 65%;

1H NMR (CD3OD, 400 MHz) δ 8.09 (s, selenazole ring-H), 7.98 (d, J = 2.2 Hz, 1 ArH), 7.83-7.81 (dd, J = 2.3 Hz, 8.6 Hz, 1 ArH), 7.74 (d, J = 8.2 Hz, 2 ArH), 7.55 (d, J = 8.1 Hz, 2 ArH), 7.19 (d, J = 8.7 Hz, 1 ArH), 4.78 (sept, J = 6.0 Hz, OCH(CH3)2), 4.22 (s, NCH 2 Ar), 3.14-3.20 (m, NHCH 2 CH2COOCH3), 2.52 (t, J = 6.4 Hz, NHCH2CH 2 COOH), 1.41 (d, J = 6.0 Hz, OCH(CH 3 )2); 1 H NMR (CD 3 OD, 400 MHz) δ 8.09 (s, selenazole ring- H ), 7.98 (d, J = 2.2 Hz, 1 Ar H ), 7.83-7.81 (dd, J = 2.3 Hz, 8.6 Hz, 1 Ar H ), 7.74 (d) , J = 8.2 Hz, 2 Ar H ), 7.55 (d, J = 8.1 Hz, 2 Ar H ), 7.19 (d, J = 8.7 Hz, 1 Ar H ), 4.78 (sept, J = 6.0 Hz, OC H (CH 3 ) 2 ), 4.22 (s, NC H 2 Ar), 3.14-3.20 (m, NHC H 2 CH 2 COOCH 3 ), 2.52 (t, J = 6.4 Hz, NHCH 2 C H 2 COOH), 1.41 (d, J = 6.0 Hz, OCH(C H 3 ) 2 );

13C NMR (CD3OD, 100 MHz) δ 173.18 (NCSe), 171.91 (C(O)), 155.18, 145.71, 140.40, 139.43, 132.32, 129.96, 128.81, 128.61, 127.35, 127.15, 126.20, 124.64, 115.14 (ArC), 72.13 (OCH(CH3)2), 53.27 (NCH2Ar), 51.66, 44.39, 34.49, 21.99 (OCH(CH3)2). 13 C NMR (CD 3 OD, 100 MHz) δ 173.18 ( N 124.64, 115.14 (Ar C ), 72.13 (O C H (CH 3 ) 2 ), 53.27 (N C H 2 Ar), 51.66, 44.39, 34.49, 21.99 (OCH ( C H 3 ) 2 ).

화합물 40. 소디움 1-(4-(5-(4-tert-부틸페닐)-1,3-셀레나졸-2-일)벤질)아제티딘-3-카르복실레이트Compound 40. Sodium 1-(4-(5-(4-tert-butylphenyl)-1,3-selenazol-2-yl)benzyl)azetidine-3-carboxylate

Figure 112021066570416-pat00048
Figure 112021066570416-pat00048

하얀 고체;White solid;

수율: 87%;Yield: 87%;

1H NMR (CD3OD, 400 MHz) δ 8.03 (s, 1 selenazole ring-H), 7.91 (d, J = 8.2 Hz, 2 ArH), 7.58 (d, J = 8.4 Hz, 2 ArH), 7.44-7.49 (m, 4 ArH), 3.80 (s, NCH 2 ), 3.66-3.70 (m, 2 azetidine ring-H), 3.48-3.52 (m, 2 azetidine ring-H), 3.25-3.32 (m, 1 azetidine ring-H), 1.37 (s, Ar(CH 3 ) 3 ); 1 H NMR (CD 3 OD, 400 MHz) δ 8.03 (s, 1 selenazole ring- H ), 7.91 (d, J = 8.2 Hz, 2 Ar H ), 7.58 (d, J = 8.4 Hz, 2 Ar H ), 7.44-7.49 (m, 4 Ar H ), 3.80 (s, NC H 2 ), 3.66-3.70 (m, 2 azetidine ring- H ), 3.48-3.52 (m, 2 azetidine ring- H ), 3.25-3.32 (m, 1 azetidine ring- H) ), 1.37 (s, Ar(C H 3 ) 3 );

13C NMR (CD3OD, 100 MHz) δ 179.00 (NCSe), 151.65, 138.67, 135.34, 133.19, 130.41, 129.44, 128.51, 126.62, 126.48, 125.80, 123.76 (ArC), 57.58 (NCH2), 36.36, 34.15, 34.00, 30.35 (C(CH3)3), 22.81. 13 C NMR (CD 3 OD, 100 MHz) δ 179.00 (N C Se), 151.65, 138.67, 135.34, 133.19, 130.41, 129.44, 128.51, 126.62, 126.48, 125.80, 123.76 (Ar C ), 57.58 (N C H) 2 ), 36.36, 34.15, 34.00 , 30.35 ( C (CH 3 ) 3 ), 22.81.

화합물 41. 메틸 1-(4-(5-(3-클로로-4-이소프로폭시페닐)-1,3-셀레나졸-2-일)벤질)아제티딘-3-카르복실레이트Compound 41. Methyl 1-(4-(5-(3-chloro-4-isopropoxyphenyl)-1,3-selenazol-2-yl)benzyl)azetidine-3-carboxylate

Figure 112021066570416-pat00049
Figure 112021066570416-pat00049

노란 고체;yellow solid;

수율: 41%;Yield: 41%;

1H NMR (CDCl3, 400 MHz) δ 7.85 (s, selenazole ring-H), 7.82 (d, J = 8.2 Hz, 2 ArH), 7.56 (d, J = 2.2 Hz, 1 ArH), 7.33-7.38 (m, 3 ArH), 6.95 (d, J = 8.6 Hz, 1 ArH), 4.61-4.58 (m, OCH(CH3)2), 3.79 (s, COOCH 3 ), 3.71 (s, NCH 2 ), 3.54-3.56 (m, 2 azetidine ring H), 3.33-3.37 (m, 3 azetidine ring-H), 1.40 (d, J = 6.0 Hz, OCH(CH 3 )2); 1 H NMR (CDCl 3 , 400 MHz) δ 7.85 (s, selenazole ring- H ), 7.82 (d, J = 8.2 Hz, 2 Ar H ), 7.56 (d, J = 2.2 Hz, 1 Ar H ), 7.33-7.38 (m, 3 Ar H) H ), 6.95 (d, J = 8.6 Hz, 1 Ar H ), 4.61-4.58 (m, OC H (CH 3 ) 2 ), 3.79 (s, COOC H 3 ), 3.71 (s, NC H 2 ), 3.54-3.56 (m, 2 azetidine ring H ), 3.33-3.37 (m, 3 azetidine ring- H ), 1.40 (d, J = 6.0 Hz, OCH( CH 3 ) 2 );

13C NMR (CDCl3, 100 MHz) δ 173.52 (NCSe), 172.49 (C(O)), 153.71, 144.46, 140.08, 139.37, 135.33,132.84, 129.10, 127.20, 126.86, 126.60, 124.79, 115.97 (ArC), 72.32 (OCH(CH3)2), 63.04 (NCH2), 56.89, 51.99, 33.99 (azetidine ring-C), 22.01 (OCH(CH3)2). 13 C NMR (CDCl 3 , 100 MHz) δ 173.52 ( N 115.97 ( ArC ) , 72.32 (O C H(CH 3 ) 2 ), 63.04 (N C H 2 ), 56.89, 51.99, 33.99 (azetidine ring- C ), 22.01 (OCH( C H 3 ) 2 ).

화합물 42. 소디움 1-(4-(5-(3-클로로-4-이소프로폭시페닐)-1,3-셀레나졸-2-일)벤질)아제티딘-3-카르복실레이트Compound 42. Sodium 1-(4-(5-(3-chloro-4-isopropoxyphenyl)-1,3-selenazol-2-yl)benzyl)azetidine-3-carboxylate

Figure 112021066570416-pat00050
Figure 112021066570416-pat00050

하얀 고체;White solid;

수율: 90%;Yield: 90%;

1H NMR (DMSO-d 6, 400 MHz) δ 7.65 (d, J = 8.2 Hz, 2 ArH), 7.28-7.41 (m, 7 ArH), 5.70-5.75 (m, 1 isoxazoline ring-H), 3.75-3.80 (m, 1 isoxazoline ring-H), 3.73 (s, COOCH 3 ), 3.69 (s, NCH 2 ), 3.64 (br, 2 azetidine ring-H), 3.30-3.36 (m, 3 azetidine ring-H, 1 isoxazoline ring-H); 1H NMR (DMSO -d6 , 400 MHz) δ 7.65 (d, J = 8.2 Hz, 2 Ar H ), 7.28-7.41 (m, 7 Ar H ), 5.70-5.75 (m, 1 isoxazoline ring- H ), 3.75-3.80 (m, 1 isoxazoline ring-H) ring- H ), 3.73 (s, COOC H 3 ), 3.69 (s, NC H 2 ), 3.64 (br, 2 azetidine ring- H ), 3.30-3.36 (m, 3 azetidine ring- H , 1 isoxazoline ring- H );

13C NMR (CDCl3, 100 MHz) δ 173.49 (C(O)), 155.94 (isoxazoline ring-C), 140.97, 139.96, 128.79, 128.77, 128.37, 128.22, 126.84, 125.88 (ArC), 82.53 (isoxazoline ring-C), 62.99 (NCH2), 56.86 (azetidine ring-C), 51.99 (COOCH3), 43.21 (isoxazoline ring-C), 33.96 (azetidine ring-C). 13 C NMR (CDCl 3 , 100 MHz) δ 173.49 ( C (O)), 155.94 (isoxazoline ring- C ), 140.97, 139.96, 128.79, 128.77, 128.37, 128.22, 126.84, 125.88 (Ar C ), 82.53 (isoxazoline ring- C ), 62.99 ( N C H 2 ), 56.86 (azetidine ring- C ), 51.99 (COO C H 3 ), 43.21 (isoxazoline ring- C ), 33.96 (azetidine ring- C ).

화합물 43. 메틸 1-(4-(5-페닐-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트Compound 43. Methyl 1-(4-(5-phenyl-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate

Figure 112021066570416-pat00051
Figure 112021066570416-pat00051

투명 기름;transparent oil;

수율: 57%;Yield: 57%;

1H NMR (CDCl3, 400 MHz) δ 7.65 (d, J = 8.2 Hz, 2 ArH), 7.28-7.41 (m, 7 ArH), 5.70-5.75 (m, 1 isoxazoline ring-H), 3.75-3.80 (m, 1 isoxazoline ring-H), 3.73 (s, COOCH 3 ), 3.69 (s, NCH 2 ), 3.64 (br, 2 azetidine ring-H), 3.30-3.36 (m, 3 azetidine ring-H, 1 isoxazoline ring-H); 1 H NMR (CDCl 3 , 400 MHz) δ 7.65 (d, J = 8.2 Hz, 2 Ar H ), 7.28-7.41 (m, 7 Ar H ), 5.70-5.75 (m, 1 isoxazoline ring- H ), 3.75-3.80 (m, 1 isoxazoline ring-H) ring- H ), 3.73 (s, COOC H 3 ), 3.69 (s, NC H 2 ), 3.64 (br, 2 azetidine ring- H ), 3.30-3.36 (m, 3 azetidine ring- H , 1 isoxazoline ring- H );

13C NMR (CDCl3, 100 MHz) δ 173.49 (C(O)), 155.94 (isoxazoline ring-C), 140.97, 139.96, 128.79, 128.77, 128.37, 128.22, 126.84, 125.88 (ArC), 82.53 (isoxazoline ring-C), 62.99 (NCH2), 56.86 (azetidine ring-C), 51.99 (COOCH3), 43.21 (isoxazoline ring-C), 33.96 (azetidine ring-C); 13 C NMR (CDCl 3 , 100 MHz) δ 173.49 ( C (O)), 155.94 (isoxazoline ring- C ), 140.97, 139.96, 128.79, 128.77, 128.37, 128.22, 126.84, 125.88 (Ar C ), 82.53 (isoxazoline ring- C ), 62.99 ( N C H 2 ), 56.86 (azetidine ring- C ), 51.99 (COO C H 3 ), 43.21 (isoxazoline ring- C ), 33.96 (azetidine ring- C );

HPLC purity: 3.3 min, 96.0%;HPLC purity: 3.3 min, 96.0%;

HRMS (M + H)+ (ESI+) 351.1707 [M + H]+ (calcd for C21H22N2O3H+ 351.1709).HRMS (M + H) + (ESI + ) 351.1707 [M + H] + (calcd for C 21 H 22 N 2 O 3 H + 351.1709).

화합물 44. 1-(4-(5-페닐-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실산Compound 44. 1-(4-(5-phenyl-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylic acid

Figure 112021066570416-pat00052
Figure 112021066570416-pat00052

하얀 고체;White solid;

수율: 97%;Yield: 97%;

1H NMR (DMSO-d 6, 400 MHz) δ 12.62 (br, COOH), 7.75 (d, J = 8.2 Hz, 2 ArH), 7.65 (d, J = 8.2 Hz, 2 ArH), 7.36-7.40 (m, 4 ArH), 7.31-7.35 (m, 1 ArH), 5.73-5.77 (m, 1 isoxazoline ring-H), 4.40 (s, NCH 2 ), 4.04-4.12 (m, 4 azetidine ring H), 3.85-3.92 (m, 1 isoxazoline ring-H), 3.63-3.67 (m, 1 azetidine ring-H), 3.40-3.44 (m, 1 isoxazoline ring-H); 1H NMR (DMSO -d6 , 400 MHz) δ 12.62 (br, COO H ), 7.75 (d, J = 8.2 Hz, 2 Ar H ), 7.65 (d, J = 8.2 Hz, 2 Ar H ), 7.36-7.40 (m, 4 Ar H ) , 7.31-7.35 (m, 1 Ar H ), 5.73-5.77 (m, 1 isoxazoline ring- H ), 4.40 (s, NC H 2 ), 4.04-4.12 (m, 4 azetidine ring H ), 3.85-3.92 ( m, 1 isoxazoline ring- H ), 3.63-3.67 (m, 1 azetidine ring- H ), 3.40-3.44 (m, 1 isoxazoline ring- H );

13C NMR (DMSO-d 6, 100 MHz) δ 171.96 (C(O)), 156.62 (isoxazoline ring-C), 141.26, 133.09, 131.02, 130.39, 129.12, 128.63, 127.47, 126.67 (ArC), 82.73 (isoxazoline ring-C), 56.74 (NCH2), 54.58 (azetidine ring-C), 42.48 (isoxazoline ring-C), 32.51 (azetidine ring-C); 13 C NMR (DMSO -d6 , 100 MHz) δ 171.96 ( C (O)), 156.62 (isoxazoline ring- C ), 141.26, 133.09, 131.02, 130.39, 129.12, 128.63, 127.47, 126.67 (Ar C ), 82.73 (isoxazoline ring- C ), 56.74 ( N C H 2 ), 54.58 (azetidine ring- C ), 42.48 (isoxazoline ring- C ), 32.51 (azetidine ring- C );

HPLC purity: 3.6 min, 96.8%;HPLC purity: 3.6 min, 96.8%;

HRMS (M + H)+ (ESI+) 337.1551 [M + H]+ (calcd for C20H21N3O3H+ 337.1552).HRMS (M + H) + (ESI + ) 337.1551 [M + H] + (calcd for C 20 H 21 N 3 O 3 H + 337.1552).

화합물 45. 메틸 1-(4-(5-(2-브로모페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트Compound 45. Methyl 1-(4-(5-(2-bromophenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate

Figure 112021066570416-pat00053
Figure 112021066570416-pat00053

투명 기름;transparent oil;

수율: 28%;Yield: 28%;

1H NMR (CDCl3, 400 MHz) δ 7.64 (d, J = 8.4 Hz, 2 ArH), 7.55-7.59 (m, 2 ArH), 7.29-7.35 (m, 3 ArH), 7.15-7.20 (m, 1 ArH), 5.96-6.01 (m, 1 isoxazoline ring-H), 3.93-4.00 (m, 1 isoxazoline ring-H), 3.72 (s, COOCH 3 ), 3.71 (s, NCH 2 ), 3.52-3.64 (m, 2 azetidine ring-H), 3.33-3.36 (m, 3 azetidine ring-H), 3.17-3.23 (m, 1 isoxazoline ring-H); 1 H NMR (CDCl 3 , 400 MHz) δ 7.64 (d, J = 8.4 Hz, 2 Ar H ), 7.55-7.59 (m, 2 Ar H ), 7.29-7.35 (m, 3 Ar H ), 7.15-7.20 (m, 1 Ar H ) , 5.96-6.01 (m, 1 isoxazoline ring- H ), 3.93-4.00 (m, 1 isoxazoline ring- H ), 3.72 (s, COOC H 3 ), 3.71 (s, NC H 2 ), 3.52-3.64 (m , 2 azetidine ring- H ), 3.33-3.36 (m, 3 azetidine ring- H ), 3.17-3.23 (m, 1 isoxazoline ring- H );

13C NMR (CDCl3, 100 MHz) δ 173.48 (C(O)), 155.84 (isoxazoline ring-C), 140.65, 140.17, 132.74, 129.36, 128.75, 128.09, 127.83, 127.43, 126.88, 120.84 (ArC), 81.42 (isoxazoline ring-C), 63.00 (NCH2), 56.86 (azetidine ring-C), 51.97 (COOCH3), 42.98 (isoxazoline ring-C), 33.96 (azetidine ring-C); 13 C NMR (CDCl 3 , 100 MHz) δ 173.48 ( C (O)), 155.84 (isoxazoline ring- C ), 140.65, 140.17, 132.74, 129.36, 128.75, 128.09, 127.83, 127.43, 126.88, 120.84 (Ar C ), 81.42 (isoxazoline ring- C ), 63.00 (N C H 2 ), 56.86 (azetidine ring- C ), 51.97 (COO C H 3 ), 42.98 (isoxazoline ring- C ), 33.96 (azetidine ring- C );

HPLC purity: 5.09 min, 97.9%;HPLC purity: 5.09 min, 97.9%;

HRMS (M + H)+ (ESI+) 429.0817 [M + H]+ (calcd for C21H21BrN2O3H+ 429.0814).HRMS (M + H) + (ESI + ) 429.0817 [M + H] + (calcd for C 21 H 21 BrN 2 O 3 H + 429.0814).

화합물 46. 1-(4-(5-(2-브로모페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실산Compound 46. 1-(4-(5-(2-bromophenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylic acid

Figure 112021066570416-pat00054
Figure 112021066570416-pat00054

하얀 고체;White solid;

수율: 60%;Yield: 60%;

1H NMR (DMSO-d 6, 400 MHz) δ 7.78 (d, J = 8.0 Hz, 2 ArH), 7.69 (d, J = 8.0 Hz, 1 ArH), 7.58 (d, J = 8.4 Hz, 2 ArH), 7.45-7.46 (m, 2 ArH), 7.28-7.32 (m, 1 ArH), 5.93-5.98 (m, 1 isoxazoline ring-H), 4.40 (s, NCH 2 ), 4.12-4.14 (m, 4 azetidine ring-H), 4.01-4.05 (m, 1 isoxazoline ring-H), 3.59-3.64 (m, 1 azetidine ring-H), 3.34-3.37 (m, 1 isoxazoline ring-H); 1H NMR (DMSO -d6 , 400 MHz) δ 7.78 (d, J = 8.0 Hz, 2 Ar H ), 7.69 (d, J = 8.0 Hz, 1 Ar H ), 7.58 (d, J = 8.4 Hz, 2 Ar H ), 7.45-7.46 ( m, 2 Ar H ), 7.28-7.32 (m, 1 Ar H ), 5.93-5.98 (m, 1 isoxazoline ring- H ), 4.40 (s, NC H 2 ), 4.12-4.14 (m, 4 azetidine ring- H ), 4.01-4.05 (m, 1 isoxazoline ring- H ), 3.59-3.64 (m, 1 azetidine ring- H ), 3.34-3.37 (m, 1 isoxazoline ring- H );

13C NMR (DMSO-d 6, 100 MHz) δ 181.85, 177.21, 156.43 (isoxazoline ring-C), 140.43, 133.36, 130.99, 130.50, 130.21, 128.64, 127.69, 127.53, 121.38 (ArC), 86.90 (isoxazoline ring-C), 81.74, 56.97 (NCH2), 55.04 (azetidine ring-C), 42.34 (isoxazoline ring-C), 32.52 (azetidine ring-C); 13 C NMR (DMSO -d6 , 100 MHz) δ 181.85, 177.21, 156.43 (isoxazoline ring- C ), 140.43, 133.36, 130.99, 130.50, 130.21, 128.64, 127.69, 127.53, 121.38 (Ar C ), 86.90 (isoxazoline ring- C ), 81.74, 56.97 ( N C H 2 ), 55.04 (azetidine ring- C ), 42.34 (isoxazoline ring- C ), 32.52 (azetidine ring- C );

HPLC purity: 4.6 min, 99.3%;HPLC purity: 4.6 min, 99.3%;

HRMS (M + H)+ (ESI+) 415.0659 [M + H]+ (calcd for C20H19BrN2O3H+ 415.0657).HRMS (M + H) + (ESI + ) 415.0659 [M + H] + (calcd for C 20 H 19 BrN 2 O 3 H + 415.0657).

화합물 47. 메틸 1-(4-(5-(3-브로모페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트Compound 47. Methyl 1-(4-(5-(3-bromophenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate

Figure 112021066570416-pat00055
Figure 112021066570416-pat00055

투명 기름;transparent oil;

수율: 35%;Yield: 35%;

1H NMR (CDCl3, 400 MHz) δ 7.62 (d, J = 8.4 Hz, 2 ArH), 7.53 (s, 1 ArH), 7.42 (d, J = 7.6 Hz, 1 ArH), 7.29-7.32 (m, 3 ArH), 7.20-7.24 (m, 1 ArH), 5.65-5.69 (m, 1 isoxazoline ring-H), 3.73-3.80 (m, 1 isoxazoline ring-H), 3.70 (s, COOCH 3 ), 3.62 (s, NCH 2 ), 3.50-3.55 (m, 2 azetidine ring-H), 3.25-3.35 (m, 3 azetidine ring-H, 1 isoxazoline ring-H); 1 H NMR (CDCl 3 , 400 MHz) δ 7.62 (d, J = 8.4 Hz, 2 Ar H ), 7.53 (s, 1 Ar H ), 7.42 (d, J = 7.6 Hz, 1 Ar H ), 7.29-7.32 (m, 3 Ar H) ), 7.20-7.24 (m, 1Ar H ), 5.65-5.69 (m, 1 isoxazoline ring- H ), 3.73-3.80 (m, 1 isoxazoline ring- H ), 3.70 (s, COOC H 3 ), 3.62 ( s, NC H 2 ), 3.50-3.55 (m, 2 azetidine ring- H ), 3.25-3.35 (m, 3 azetidine ring- H , 1 isoxazoline ring- H );

13C NMR (CDCl3, 100 MHz) δ 173.47 (C(O)), 155.87 (isoxazoline ring-C), 143.39, 140.23, 131.23, 130.37, 128.85, 128.78, 128.00, 126.86, 124.43, 122.80 (ArC), 81.50 (isoxazoline ring-C), 62.97 (NCH2), 56.86 (azetidine ring-C), 51.97 (COOCH3), 43.27 (isoxazoline ring-C), 33.96 (azetidine ring-C); 13 C NMR (CDCl 3 , 100 MHz) δ 173.47 ( C (O)), 155.87 (isoxazoline ring- C ), 143.39, 140.23, 131.23, 130.37, 128.85, 128.78, 128.00, 126.86, 124.43, 122.80 (Ar C ), 81.50 (isoxazoline ring- C ), 62.97 (N C H 2 ), 56.86 (azetidine ring- C ), 51.97 (COO C H 3 ), 43.27 (isoxazoline ring- C ), 33.96 (azetidine ring- C );

HPLC purity: 4.7 min, 98.2%;HPLC purity: 4.7 min, 98.2%;

HRMS (M + H)+ (ESI+) 429.0816 [M + H]+ (calcd for C21H21BrN2O3H+ 429.0814).HRMS (M + H) + (ESI + ) 429.0816 [M + H] + (calcd for C 21 H 21 BrN 2 O 3 H + 429.0814).

화합물 48. 1-(4-(5-(3-브로모페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실산Compound 48. 1-(4-(5-(3-bromophenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylic acid

Figure 112021066570416-pat00056
Figure 112021066570416-pat00056

하얀 고체;White solid;

수율: 96%;Yield: 96%;

1H NMR (DMSO-d 6, 400 MHz) δ 7.75 (d, J = 8.0 Hz, 2 ArH), 7.66 (d, J = 8.0 Hz, 2 ArH), 7.59 (s, 1 ArH), 7.54 (d, J = 8.8 Hz, 1 ArH), 7.34-7.42 (m, 2 ArH), 5.76-5.81 (m, 1 isoxazoline ring-H), 4.42 (s, NCH 2 ), 4.08-4.12 (m, 5 azetidine ring-H), 3.86-3.93 (m, 1 isoxazoline ring-H), 3.43-3.49 (m, 1 isoxazoline ring-H); 1H NMR (DMSO -d6 , 400 MHz) δ 7.75 (d, J = 8.0 Hz, 2 Ar H ), 7.66 (d, J = 8.0 Hz, 2 Ar H ), 7.59 (s, 1 Ar H ), 7.54 (d, J = 8.8 Hz, 1 Ar H ), 7.34-7.42 (m, 2 Ar H ), 5.76-5.81 (m, 1 isoxazoline ring- H ), 4.42 (s, NC H 2 ), 4.08-4.12 (m, 5 azetidine ring- H ) , 3.86-3.93 (m, 1 isoxazoline ring- H ), 3.43-3.49 (m, 1 isoxazoline ring- H );

13C NMR (DMSO-d 6, 100 MHz) δ 171.03 (C(O)), 156.72 (isoxazoline ring-C), 144.11, 139.56, 132.05, 131.40, 131.03, 130.19, 129.31, 127.55, 125.66, 122.31 (ArC), 81.71 (isoxazoline ring-C), 54.43 (NCH2), 52.75 (azetidine ring-C), 42.54 (isoxazoline ring-C), 32.28 (azetidine ring-C); 13 C NMR (DMSO -d6 , 100 MHz) δ 171.03 ( C (O)), 156.72 (isoxazoline ring- C ), 144.11, 139.56, 132.05, 131.40, 131.03, 130.19, 129.31, 127.55, 125.66, 122.31 (Ar C ), 81.71 (isoxazoline ring- C ), 54.43 (N C H 2 ), 52.75 (azetidine ring- C ), 42.54 (isoxazoline ring- C ), 32.28 (azetidine ring- C );

HPLC purity: 5.1 min, 98.6%;HPLC purity: 5.1 min, 98.6%;

HRMS (M + H)+ (ESI+) 415.0662 [M + H]+ (calcd for C20H19BrN2O3H+ 415.0657).HRMS (M + H) + (ESI + ) 415.0662 [M + H] + (calcd for C 20 H 19 BrN 2 O 3 H + 415.0657).

화합물 49. 메틸 1-(4-(5-(4-브로모페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트Compound 49. Methyl 1-(4-(5-(4-bromophenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate

Figure 112021066570416-pat00057
Figure 112021066570416-pat00057

하얀 고체;White solid;

수율: 16%;Yield: 16%;

1H NMR (CDCl3, 400 MHz) δ 7.64 (d, J = 8.4 Hz, 2 ArH), 7.49-7.53 (m, 2 ArH), 7.36 (d, J = 10.0 Hz, 2 ArH), 7.29-7.32 (m, 2 ArH), 5.67-5.72 (m, 1 isoxazoline ring-H), 3.77-3.82 (m, 1 isoxazoline ring-H), 3.75 (s, COOCH 3 ), 3.68 (s, NCH 2 ), 3.52-3.65 (m, 2 azetidine ring-H), 3.26-3.39 (m, 3 azetidine ring-H, 1 isoxazoline ring-H); 1 H NMR (CDCl 3 , 400 MHz) δ 7.64 (d, J = 8.4 Hz, 2ArH ), 7.49-7.53 (m, 2ArH ), 7.36 (d, J = 10.0 Hz, 2ArH ), 7.29-7.32 (m, 2ArH) Ar H ), 5.67-5.72 (m, 1 isoxazoline ring- H ), 3.77-3.82 (m, 1 isoxazoline ring- H ), 3.75 (s, COOC H 3 ), 3.68 (s, NC H 2 ), 3.52- 3.65 (m, 2 azetidine ring- H ), 3.26-3.39 (m, 3 azetidine ring- H , 1 isoxazoline ring- H );

13C NMR (CDCl3, 100 MHz) δ 173.52 (C(O)), 155.91 (isoxazoline ring-C), 140.19, 140.05, 131.87, 128.80, 128.08, 127.56, 126.85, 122.11 (ArC), 81.75 (isoxazoline ring-C), 62.99 (NCH2), 56.87 (azetidine ring-C), 52.00 (COOCH3), 43.22 (isoxazoline ring-C), 33.96 (azetidine ring-C); 13 C NMR (CDCl 3 , 100 MHz) δ 173.52 ( C (O)), 155.91 (isoxazoline ring- C ), 140.19, 140.05, 131.87, 128.80, 128.08, 127.56, 126.85, 122.11 (Ar C ), 81.75 (isoxazoline ring- C ), 62.99 ( N C H 2 ), 56.87 (azetidine ring- C ), 52.00 (COO C H 3 ), 43.22 (isoxazoline ring- C ), 33.96 (azetidine ring- C );

HPLC purity: 9.1 min, 98.3%;HPLC purity: 9.1 min, 98.3%;

HRMS (M + H)+ (ESI+) 429.0817 [M + H]+ (calcd for C21H21BrN2O3H+ 429.0814).HRMS (M + H) + (ESI + ) 429.0817 [M + H] + (calcd for C 21 H 21 BrN 2 O 3 H + 429.0814).

화합물 50. 1-(4-(5-(4-브로모페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실산Compound 50. 1-(4-(5-(4-bromophenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylic acid

Figure 112021066570416-pat00058
Figure 112021066570416-pat00058

하얀 고체;White solid;

수율: 58%;Yield: 58%;

1H NMR (DMSO-d 6, 400 MHz) δ 7.58-7.63 (m, 4 ArH), 7.32-7.37 (m, 4 ArH), 5.69-5.74 (m, 1 isoxazoline ring-H), 3.81-3.96 (m, 1 isoxazoline ring-H), 3.50 (s, NCH 2 ), 3.22-3.26 (m, 2 azetidine ring-H, 1 isoxazoline ring-H), 3.04-3.07 (m, 2 azetidine ring-H), 2.74-2.78 (m, 1 azetidine ring-H); 1H NMR (DMSO -d6 , 400 MHz) δ 7.58-7.63 (m, 4 Ar H ), 7.32-7.37 (m, 4 Ar H ), 5.69-5.74 (m, 1 isoxazoline ring- H ), 3.81-3.96 (m, 1 isoxazoline ring- H) ), 3.50 (s, NC H 2 ), 3.22-3.26 (m, 2 azetidine ring- H , 1 isoxazoline ring- H ), 3.04-3.07 (m, 2 azetidine ring- H ), 2.74-2.78 (m, 1 azetidine ring- H );

13C NMR (CD3OD, 100 MHz) δ 178.90 (C(O)), 156.47, 140.34, 131.50, 129.45, 129.08, 127.64, 126.81, 121.59 (ArC, isoxazoline ring-C), 81.97, 57.12, 42.37, 35.83, 22.75; 13 C NMR (CD 3 OD, 100 MHz) δ 178.90 ( C (O)), 156.47, 140.34, 131.50, 129.45, 129.08, 127.64, 126.81, 121.59 (Ar C , isoxazoline ring- C ), 81.97, 57.12, 42.37, 3 5.83, 22.75;

HPLC purity: 4.8 min, 99.1%;HPLC purity: 4.8 min, 99.1%;

HRMS (M + H)+ (ESI+) 415.0659 [M + H]+ (calcd for C20H19BrN2O3H+ 415.0657).HRMS (M + H) + (ESI + ) 415.0659 [M + H] + (calcd for C 20 H 19 BrN 2 O 3 H + 415.0657).

화합물 51. 1-(4-(5-(4-히드록시페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실산Compound 51. 1-(4-(5-(4-hydroxyphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylic acid

Figure 112021066570416-pat00059
Figure 112021066570416-pat00059

하얀 고체;White solid;

수율: 66%;Yield: 66%;

1H NMR (DMSO-d 6, 400 MHz) δ 9.66 (s, COOH), 7.66 (d, J = 8.2 Hz, 2 ArH), 7.41 (d, J = 8.0 Hz, 2 ArH), 7.19 (d, J = 8.6 Hz, 2 ArH), 6.78 (d, J = 8.5 Hz, 2 ArH), 5.60 (t, J = 10.4 Hz, 1 isoxazoline ring-H), 3.73-3.80 (m, 3H), 3.55 (br, NCH 2 ), 3.40 (br, 1H), 3.30-3.37 (m, 3H); 1H NMR (DMSO -d6 , 400 MHz) δ 9.66 (s, COO H ), 7.66 (d, J = 8.2 Hz, 2 Ar H ), 7.41 (d, J = 8.0 Hz, 2 Ar H ), 7.19 (d, J = 8.6 Hz, 2 Ar H) Ar H ), 6.78 (d, J = 8.5 Hz, 2 Ar H ), 5.60 (t, J = 10.4 Hz, 1 isoxazoline ring- H ), 3.73-3.80 (m, 3 H ), 3.55 (br, NC H) 2 ), 3.40 (br, 1 H ), 3.30-3.37 (m, 3 H );

13C NMR (DMSO-d 6, 100 MHz) δ 158.00, 156.79, 131.03, 129.59, 129.15, 128.65, 128.24, 127.12, 115.79 (ArC, isoxazoline ring-C), 82.75 (isoxazoline ring-C), 56.29 (NCH2), 49.74 (azetidine ring-C), 42.09 (isoxazoline ring-C), 33.69 (azetidine ring-C); 13 C NMR (DMSO -d6 , 100 MHz) δ 158.00, 156.79, 131.03, 129.59, 129.15, 128.65, 128.24, 127.12, 115.79 (Ar C , isoxazoline ring- C ), 82.75 (isoxazoline ring- C ), 56.29 (N C H 2 ) , 49.74 (azetidine ring- C ), 42.09 (isoxazoline ring- C ), 33.69 (azetidine ring- C );

HPLC purity: 1.9 min, 98.6%;HPLC purity: 1.9 min, 98.6%;

HRMS (M + H)+ (ESI+) 353.1500 [M + H]+ (calcd for C20H20N2O4H+ 353.1501).HRMS (M + H) + (ESI + ) 353.1500 [M + H] + (calcd for C 20 H 20 N 2 O 4 H + 353.1501).

화합물 52. 메틸 1-(4-(5-(4-(클로로메틸)페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트Compound 52. Methyl 1-(4-(5-(4-(chloromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate

Figure 112021066570416-pat00060
Figure 112021066570416-pat00060

투명 기름;transparent oil;

수율: 23%;Yield: 23%;

1H NMR (CDCl3, 400 MHz) δ 7.64 (d, J = 8.4 Hz, 2 ArH), 7.37-7.41 (m, 4 ArH), 7.33 (d, J = 8.0 Hz, 2 ArH), 5.71-5.75 (m, 1 isoxazoline ring-H), 4.58 (s, ArCH 2 Cl), 3.75-3.81 (m, 1 isoxazoline ring-H), 3.73 (s, COOCH 3 ), 3.65 (s, NCH 2 ), 3.53-3.56 (m, 2 azetidine ring-H), 3.28-3.36 (m, 2 azetidine ring-H, 1 isoxazoline ring-H); 1 H NMR (CDCl 3 , 400 MHz) δ 7.64 (d, J = 8.4 Hz, 2 Ar H ), 7.37-7.41 (m, 4 Ar H ), 7.33 (d, J = 8.0 Hz, 2 Ar H ), 5.71-5.75 (m, 1 isoxazoline ring- H ), 4.58 (s, ArC H 2 Cl), 3.75-3.81 (m, 1 isoxazoline ring- H ), 3.73 (s, COOC H 3 ), 3.65 (s, NC H 2 ), 3.53-3.56 (m, 2 azetidine ring- H ), 3.28-3.36 (m, 2 azetidine ring- H , 1 isoxazoline ring- H );

13C NMR (CDCl3, 100 MHz) δ 173.49 (C(O)), 155.94 (isoxazoline ring-C), 141.28, 140.10, 137.47, 129.02, 128.79, 128.20, 126.84, 126.26 (ArC), 82.06 (isoxazoline ring-C), 62.97 (NCH2), 56.86 (azetidine ring-C), 51.99 (COOCH3), 45.82 (ArCH2Cl), 43.21 (isoxazoline ring-C), 33.96 (azetidine ring-C); 13 C NMR (CDCl 3 , 100 MHz) δ 173.49 ( C (O)), 155.94 (isoxazoline ring- C ), 141.28, 140.10, 137.47, 129.02, 128.79, 128.20, 126.84, 126.26 (Ar C ), 82.06 (isoxazoline ring- C ), 62.97 ( N C H 2 ), 56.86 (azetidine ring- C ), 51.99 (COO C H 3 ), 45.82 (Ar C H 2 Cl), 43.21 (isoxazoline ring- C ), 33.96 (azetidine ring- C );

HPLC purity: 10.1 min, 96.9%;HPLC purity: 10.1 min, 96.9%;

HRMS (M + H)+ (ESI+) 399.1480 [M + H]+ (calcd for C22H23ClN2O3H+ 399.1475).HRMS (M + H) + (ESI + ) 399.1480 [M + H] + (calcd for C 22 H 23 ClN 2 O 3 H + 399.1475).

화합물 53. 소디움 1-(4-(5-(4-(클로로메틸)페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트Compound 53. Sodium 1-(4-(5-(4-(chloromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate

Figure 112021066570416-pat00061
Figure 112021066570416-pat00061

하얀 고체;White solid;

수율: 45%;Yield: 45%;

1H NMR (DMSO-d 6, 400 MHz) δ 7.63 (d, J = 8.2 Hz, 2 ArH), 7.39-7.47 (m, 4 ArH), 7.32 (d, J = 8.2 Hz, 2 ArH), 5.70-5.75 (m, 1 isoxazoline ring-H), 4.77 (s, CH 2 Cl), 3.83-3.90 (1 isoxazoline ring-H), 3.49 (s, NCH 2 ), 3.40-3.42 (m, 1 isoxazoline ring-H), 3.17-3.25 (m, 2 azetidine ring-H), 3.02-3.06 (m, 2 azetidine ring-H), 2.67-2.73 (m, 1 azetidine ring-H); 1H NMR (DMSO -d6 , 400 MHz) δ 7.63 (d, J = 8.2 Hz, 2 Ar H ), 7.39-7.47 (m, 4 Ar H ), 7.32 (d, J = 8.2 Hz, 2 Ar H ), 5.70-5.75 (m, 1 isoxazoline ring- H ), 4.77 (s, CH 2 Cl), 3.83-3.90 (1 isoxazoline ring- H ), 3.49 (s, NC H 2 ), 3.40-3.42 (m, 1 isoxazoline ring- H ), 3.17 -3.25 (m, 2 azetidine ring- H ), 3.02-3.06 (m, 2 azetidine ring- H ), 2.67-2.73 (m, 1 azetidine ring- H );

13C NMR (DMSO-d 6, 100 MHz) δ 172.43 (C(O)), 156.75 (isoxazoline ring-C), 141.47, 140.02, 139.01, 129.48, 129.36, 128.48, 127.04, 126.63 (ArC), 82.32 (isoxazoline ring-C), 57.76 (NCH2), 53.12, 52.18, 46.75, 43.86, 42.51; 13 C NMR (DMSO -d6 , 100 MHz) δ 172.43 ( C (O)), 156.75 (isoxazoline ring- C ), 141.47, 140.02, 139.01, 129.48, 129.36, 128.48, 127.04, 126.63 (Ar C ), 82.32 (isoxazoline ring- C ), 57.76 ( N C H 2 ), 53.12, 52.18, 46.75, 43.86, 42.51;

HPLC purity: 5.6 min, 98.1%;HPLC purity: 5.6 min, 98.1%;

HRMS (M + H)+ (ESI+) 385.1320 [M + H]+ (calcd for C21H21ClN2O3H+ 385.1319).HRMS (M + H) + (ESI + ) 385.1320 [M + H] + (calcd for C 21 H 21 ClN 2 O 3 H + 385.1319).

화합물 54. 메틸 1-(4-(5-(4-에틸페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트Compound 54. Methyl 1-(4-(5-(4-ethylphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate

Figure 112021066570416-pat00062
Figure 112021066570416-pat00062

하얀 고체;White solid;

수율: 46%;Yield: 46%;

1H NMR (CDCl3, 400 MHz) δ 7.63 (d, J = 8.2 Hz, 2 ArH), 7.29-7.32 (m, 4 ArH), 7.19 (d, J = 8.0 Hz, 2 ArH), 5.69 (dd, J = 4.2, 10.8 Hz, 1 isoxazoline ring-H), 3.72-3.76 (m, 1 isoxazoline ring-H), 3.70 (s, COOCH 3 ), 3.62 (s, NCH 2 ), 3.50-3.55 (m, 2 azetidine ring-H), 3.29-3.35 (m, 3 azetidine ring-H, 1 isoxazoline ring-H), 2.64 (q, J = 7.6 Hz, CH 2 CH3), 1.22 (t, J = 7.6 Hz, CH2CH 3 ); 1H NMR (CDCl 3 , 400 MHz) δ 7.63 (d, J = 8.2 Hz, 2 Ar H ), 7.29-7.32 (m, 4 Ar H ), 7.19 (d, J = 8.0 Hz, 2 Ar H ), 5.69 (dd, J = 4.2, 10.8 Hz, 1 isoxazoline ring- H ), 3.72-3.76 (m, 1 isoxazoline ring- H ), 3.70 (s, COOC H 3 ), 3.62 (s, NC H 2 ), 3.50-3.55 (m, 2 azetidine ring- H ), 3.29-3.35 (m, 3 azetidine ring- H , 1 isoxazoline ring- H ), 2.64 (q, J = 7.6 Hz, CH 2 CH 3 ), 1.22 (t, J = 7.6 Hz, CH 2 C H 3 );

13C NMR (CDCl3, 100 MHz) δ 173.52 (C(O)), 155.98 (isoxazoline ring-C), 144.43, 139.96, 138.11, 128.76, 128.47, 128.24, 126.82, 125.98 (ArC), 82.57 (isoxazoline ring-C), 63.05 (NCH2), 56.89 (azetidine ring-C), 51.98 (COOCH3), 43.08 (isoxazoline ring-C), 33.99 (azetidine ring-C), 28.58 (CH2CH3), 15.57 (CH2 CH3); 13 C NMR (CDCl 3 , 100 MHz) δ 173.52 ( C (O)), 155.98 (isoxazoline ring- C ), 144.43, 139.96, 138.11, 128.76, 128.47, 128.24, 126.82, 125.98 (Ar C ), 82 .57 (isoxazoline ring- C ), 63.05 (N C H 2 ), 56.89 (azetidine ring- C ), 51.98 (COO C H 3 ), 43.08 (isoxazoline ring- C ), 33.99 (azetidine ring- C ), 28.58 ( C H 2 CH 3 ), 15.57 (CH 2 C H 3 );

HPLC purity: 4.5 min, 98.4%;HPLC purity: 4.5 min, 98.4%;

HRMS (M + H)+ (ESI+) 379.2021 [M + H]+ (calcd for C23H26N2O3H+ 379.2022).HRMS (M + H) + (ESI + ) 379.2021 [M + H] + (calcd for C 23 H 26 N 2 O 3 H + 379.2022).

화합물 55. 소디움 1-(4-(5-(4-에틸페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트Compound 55. Sodium 1-(4-(5-(4-ethylphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate

Figure 112021066570416-pat00063
Figure 112021066570416-pat00063

하얀 고체;White solid;

수율: 100%;Yield: 100%;

1H NMR (CD3OD, 400 MHz) δ 7.67 (d, J = 8.2 Hz, 2 ArH), 7.37 (d, J = 8.2 Hz, 2 ArH), 7.30 (d, J = 8.1 Hz, 2 ArH), 7.21 (d, J = 8.0 Hz, 2 ArH), 5.68 (dd, J = 8.8, 10.7 Hz, 1 isoxazoline ring-H), 3.82 (dd, J = 10.8, 17.0 Hz, 1 isoxazoline ring-H), 3.66 (s, NCH 2 ), 3.53 (t, J = 8.0 Hz, 2 azetidine ring-H), 3.32-3.37 (m, 2 azetidine ring-H, 1 isoxazoline ring-H), 3.18-3.24 (m, 1 azetidine ring-H), 2.63 (q, J = 7.6 Hz, alkyl chain-CH 2 ), 1.82 (t, J = 7.6 Hz, alkyl chain-CH 3 ); 1 H NMR (CD 3 OD, 400 MHz) δ 7.67 (d, J = 8.2 Hz, 2 Ar H ), 7.37 (d, J = 8.2 Hz, 2 Ar H ), 7.30 (d, J = 8.1 Hz, 2 Ar H ), 7.21 (d, J = 8.0 Hz, 2 Ar H ), 5.68 (dd, J = 8.8, 10.7 Hz, 1 isoxazoline ring- H ), 3.82 (dd, J = 10.8, 17.0 Hz, 1 isoxazoline ring- H ), 3.66 (s, NC H 2 ), 3.53 (t, J = 8.0 Hz, 2 azetidine ring- H ), 3.32-3.37 (m, 2) azetidine ring- H , 1 isoxazoline ring- H ), 3.18-3.24 (m, 1 azetidine ring- H ), 2.63 (q, J = 7.6 Hz, alkyl chain- CH 2 ), 1.82 (t, J = 7.6 Hz) , alkyl chain-C H 3 );

13C NMR (CD3OD, 100 MHz) δ 179.57 (C(O)), 156.75 (isoxazoline ring-C), 144.32, 139.64, 139.64, 138.11, 128.97, 127.82, 126.54, 125.81 (ArC), 82.71 (isoxazoline ring-C), 62.45 (NCH2), 57.69 (azetidine ring-C), 42.28 (isoxazoline ring-C), 36.54 (azetidine ring-C), 28.16 (CH2CH3), 14.75 (CH2 CH3); 13 C NMR (CD 3 OD, 100 MHz) δ 179.57 ( C (O)), 156.75 (isoxazoline ring- C ), 144.32, 139.64, 139.64, 138.11, 128.97, 127.82, 126.54, 125.81 (Ar C ), 82 .71 ( isoxazoline ring- C ), 62.45 (N C H 2 ), 57.69 (azetidine ring- C ), 42.28 (isoxazoline ring- C ), 36.54 (azetidine ring- C ), 28.16 ( CH 2 CH 3 ), 14.75 (CH 2 C H 3 );

HPLC purity: 5.0 min, 97.8%;HPLC purity: 5.0 min, 97.8%;

HRMS (M + H)+ (ESI+) 365.1864 [M + H]+ (calcd for C22H24N2O3H+ 365.1865).HRMS (M + H) + (ESI + ) 365.1864 [M + H] + (calcd for C 22 H 24 N 2 O 3 H + 365.1865).

화합물 56. 소디움 1-(4-(5-(4-프로필페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트Compound 56. Sodium 1-(4-(5-(4-propylphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate

Figure 112021066570416-pat00064
Figure 112021066570416-pat00064

하얀 고체;White solid;

수율: 112%;Yield: 112%;

1H NMR (CD3OD, 400 MHz) δ 7.67 (d, J = 8.3 Hz, 2 ArH), 7.37 (d, J = 8.3 Hz, 2 ArH), 7.29 (d, J = 8.1 Hz, 2 ArH), 7.19 (d, J = 8.1 Hz, 2 ArH), 5.67 (dd, J = 8.8, 10.7 Hz, 1 isoxazoline ring-H), 3.82 (dd, J = 10.8, 17.0 Hz, 1 isoxazoline ring-H), 3.65 (s, NCH 2 ), 3.53 (t, J = 8.1 Hz, 2 azetidine ring-H), 3.32-3.37 (m, 2 azetidine ring-H, 1 isoxazoline ring-H), 3.18-3.22 (m, 1 azetidine ring-H), 2.58 (t, J = 7.8 Hz, alkyl chain-CH 2 ), 1.59-1.65 (m, alkyl chain-CH 2 ), 0.92 (t, J = 7.3 Hz, alkyl chain-CH 3 ); 1 H NMR (CD 3 OD, 400 MHz) δ 7.67 (d, J = 8.3 Hz, 2 Ar H ), 7.37 (d, J = 8.3 Hz, 2 Ar H ), 7.29 (d, J = 8.1 Hz, 2 Ar H ), 7.19 (d, J = 8.1 Hz, 2 Ar H ), 5.67 (dd, J = 8.8, 10.7 Hz, 1 isoxazoline ring- H ), 3.82 (dd, J = 10.8, 17.0 Hz, 1 isoxazoline ring- H ), 3.65 (s, NC H 2 ), 3.53 (t, J = 8.1 Hz, 2 azetidine ring- H ), 3.32-3.37 (m, 2 azetidine ring- H , 1 isoxazoline ring- H ), 3.18-3.22 (m, 1 azetidine ring- H ), 2.58 (t, J = 7.8 Hz, alkyl chain- CH 2 ), 1.59-1.65 (m, alkyl chain- CH 2 ), 0.92 (t, J = 7.3 Hz, alkyl chain- CH 3 );

13C NMR (CD3OD, 100 MHz) δ 179.55 (C(O)), 156.77 (isoxazoline ring-C), 142.65, 139.66, 138.16, 128.98, 128.46, 126.54, 125.73 (ArC), 82.74 (isoxazoline ring-C), 62.47 (NCH2) 57.67 (azetidine ring-C), 42.38 (isoxazoline ring-C), 37.32 (alkyl chain-CH2), 36.54 (azetidine ring-C), 24.31 (alkyl chain-CH2), 12.67 (alkyl chain-CH3); 13 C NMR (CD 3 OD, 100 MHz) δ 179.55 ( C (O)), 156.77 (isoxazoline ring- C ), 142.65, 139.66, 138.16, 128.98, 128.46, 126.54, 125.73 (Ar C ), 82.74 (isoxazoline ring - C ), 62.47 (N C H 2 ) 57.67 (azetidine ring- C ), 42.38 (isoxazoline ring- C ), 37.32 (alkyl chain- C H 2 ), 36.54 (azetidine ring- C ), 24.31 (alkyl chain- C H 2 ), 12.67 (alkyl chain- C H 3 );

HPLC purity: 5.8 min, 99.3%;HPLC purity: 5.8 min, 99.3%;

HRMS (M + H)+ (ESI+) 379.2021 [M + H]+ (calcd for C23H26N2O3H+ 379.2022).HRMS (M + H) + (ESI + ) 379.2021 [M + H] + (calcd for C 23 H 26 N 2 O 3 H + 379.2022).

화합물 57. 메틸 1-(4-(5-(4-tert-부틸페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트Compound 57. Methyl 1-(4-(5-(4-tert-butylphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate

Figure 112021066570416-pat00065
Figure 112021066570416-pat00065

하얀 고체;White solid;

수율: 45%;Yield: 45%;

1H NMR (DMSO-d 6, 400 MHz) δ 7.64 (d, J = 7.9 Hz, 2 ArH), 7.39 (d, J = 8.2 Hz, 2 ArH), 7.32 (dd, J = 3.4, 8.3 Hz, 4 ArH), 5.71 (dd, J = 8.3, 10.9 Hz, 1 isoxazoline ring-H), 3.68-3.79 (m, 1 isoxazoline ring-H, COOCH 3 ), 3.63 (s, NCH 2 ), 3.57-3.60 (m, 1 azetidine ring-H, 1 isoxazoline ring-H), 3.39-3.42 (m, 2 azetidine ring-H), 3.21-3.36 (m, 2 azetidine ring-H), 1.28 (s, C(CH 3 ) 3 ); 1H NMR (DMSO -d6 , 400 MHz) δ 7.64 (d, J = 7.9 Hz, 2 Ar H ), 7.39 (d, J = 8.2 Hz, 2 Ar H ), 7.32 (dd, J = 3.4, 8.3 Hz, 4 Ar H ), 5.71 ( dd, J = 8.3, 10.9 Hz, 1 isoxazoline ring- H ), 3.68-3.79 (m, 1 isoxazoline ring- H , COOC H 3 ), 3.63 (s, NC H 2 ), 3.57-3.60 (m, 1 azetidine ring- H , 1 isoxazoline ring- H ), 3.39-3.42 (m, 2 azetidine ring- H ), 3.21-3.36 (m, 2 azetidine ring- H ), 1.28 (s, C(C H 3 ) 3 );

13C NMR (DMSO-d 6, 75 MHz) δ 173.33 (C(O)), 162.33, 156.74, 151.04, 138.32, 132.53, 129.58, 127.14, 126.39, 125.81 (ArC, isoxazoline ring-C), 82.31 (isoxazoline ring-C), 56.52 (azetidine ring-C), 52.19 (COOCH3), 49.06 (azetidine ring-C), 42.45 (isoxazoline ring-C), 34.74 (C(CH3)3), 33.61 (azetidine ring-C), 31.55 (C(CH3) 3 ); 13 C NMR (DMSO -d6 , 75 MHz) δ 173.33 ( C (O)), 162.33, 156.74, 151.04, 138.32, 132.53, 129.58, 127.14, 126.39, 125.81 (Ar C , isoxazoline ring- C ), 82.31 (isoxazoline ring- C ), 56.52 (azetidine ring- C ), 52.19 (COO C H 3 ), 49.06 (azetidine ring- C ), 42.45 (isoxazoline ring- C ), 34.74 ( C (CH 3 ) 3 ), 33.61 (azetidine ring- C ), 31.55 (C) ( C H 3 ) 3 );

HPLC purity: 9.8 min, 95.5%;HPLC purity: 9.8 min, 95.5%;

HRMS (M + H)+ (ESI+) 407.2336 [M + H]+ (calcd for C25H30N2O3H+ 407.2335).HRMS (M + H) + (ESI + ) 407.2336 [M + H] + (calcd for C 25 H 30 N 2 O 3 H + 407.2335).

화합물 58. 소디움 1-(4-(5-(4-tert-부틸페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트Compound 58. Sodium 1-(4-(5-(4-tert-butylphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate

Figure 112021066570416-pat00066
Figure 112021066570416-pat00066

하얀 고체;White solid;

수율: 96%;Yield: 96%;

1H NMR (DMSO-d 6, 400 MHz) δ 7.63 (d, J = 8.2 Hz, 2 ArH), 7.41 (d, J = 8.3 Hz, 2 ArH), 7.30-7.33 (m, 4 ArH), 5.65-5.69 (m, 1 isoxazoline ring-H), 3.78-3.85 (m, 1 isoxazoline ring-H), 3.50 (s, NCH 2 ), 3.36-3.40 (m, 1H), 3.25 (t, J = 7.6 Hz, 2H), 3.06 (t, J = 7.0 Hz, 2H), 2.74 (t, J = 7.7 Hz, 1H), 1.27 (s, C(CH 3 ) 3 ); 1H NMR (DMSO -d6 , 400 MHz) δ 7.63 (d, J = 8.2 Hz, 2 Ar H ), 7.41 (d, J = 8.3 Hz, 2 Ar H ), 7.30-7.33 (m, 4 Ar H ), 5.65-5.69 (m, 1 isoxazoline ring- H) ), 3.78-3.85 (m, 1 isoxazoline ring- H ), 3.50 (s, NC H 2 ), 3.36-3.40 (m, 1 H ), 3.25 (t, J = 7.6 Hz, 2 H ), 3.06 (t) , J = 7.0 Hz, 2 H ), 2.74 (t, J = 7.7 Hz, 1 H ), 1.27 (s, C(C H 3 ) 3 );

13C NMR (DMSO-d 6, 100 MHz) δ 176.87 (C(O)), 156.79 (isoxazoline ring-C), 151.01, 141.80, 138.36, 128.97, 128.16, 126.98, 126.43, 125.82 (ArC), 82.12 (isoxazoline ring-C), 63.26 (NCH2), 58.85, 37.35, 34.76, 31.57 (C(CH3) 3 ); 13 C NMR (DMSO -d6 , 100 MHz) δ 176.87 ( C (O)), 156.79 (isoxazoline ring- C ), 151.01, 141.80, 138.36, 128.97, 128.16, 126.98, 126.43, 125.82 (Ar C ), 82.12 (isoxazoline ring- C ), 63.26 ( N C H 2 ), 58.85, 37.35, 34.76, 31.57 (C( C H 3 ) 3 );

HPLC purity: 6.0 min, 99.3%;HPLC purity: 6.0 min, 99.3%;

HRMS (M + H)+ (ESI+) 393.2176 [M + H]+ (calcd for C24H28N2O3H+ 393.2178).HRMS (M + H) + (ESI + ) 393.2176 [M + H] + (calcd for C 24 H 28 N 2 O 3 H + 393.2178).

화합물 59. 메틸 1-(4-(5-(3-시아노-4-이소프로폭시페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트Compound 59. Methyl 1-(4-(5-(3-cyano-4-isopropoxyphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate

Figure 112021066570416-pat00067
Figure 112021066570416-pat00067

투명 기름;transparent oil;

수율: 54%;Yield: 54%;

1H NMR (CDCl3, 400 MHz) δ 7.63 (d, J = 8.2 Hz, 2 ArH), 7.52-7.56 (m, 2 ArH), 7.33 (d, J = 8.2 Hz, 2 ArH), 6.96 (d, J = 8.7 Hz, 1 ArH), 5.65-5.70 (m, 1 isoxazoline ring-H), 4.65 (sept, J = 6.0 Hz, OCH(CH3)2), 3.70-3.81 (m, 1 isoxazoline ring-H), 3.65 (s, COOCH 3 ), 3.54 (s, NCH 2 ), 3.31-3.37 (m, 2 azetidine ring-H), 3.24-3.30 (m, 3 azetidine ring-H, 1 isoxazoline ring-H), 1.41 (d, J = 6.0 Hz, OCH(CH 3 ) 2 ); 1 H NMR (CDCl 3 , 400 MHz) δ 7.63 (d, J = 8.2 Hz, 2 Ar H ), 7.52-7.56 (m, 2 Ar H ), 7.33 (d, J = 8.2 Hz, 2 Ar H ), 6.96 (d, J = 8.7) Hz, 1 Ar H ), 5.65-5.70 (m, 1 isoxazoline ring- H ), 4.65 (sept, J = 6.0 Hz, OC H (CH 3 ) 2 ), 3.70-3.81 (m, 1 isoxazoline ring- H ) , 3.65 (s, COOC H 3 ), 3.54 (s, NC H 2 ), 3.31-3.37 (m, 2 azetidine ring- H ), 3.24-3.30 (m, 3 azetidine ring- H , 1 isoxazoline ring- H ) , 1.41 (d, J = 6.0 Hz, OCH(C H 3 ) 2 );

13C NMR (CDCl3, 100 MHz) δ 173.48 (C(O)), 159.77, 155.99 (isoxazoline ring-C), 140.32, 133.33, 131.87, 131.40, 128.81, 127.93, 126.85, 116.32, 114.04 (ArC), 103.12, 81.09 (isoxazoline ring-C), 72.08 (OCH(CH3)2), 62.97 (NCH2), 56.86 (azetidine ring-C), 51.97 (COOCH3), 43.02 (isoxazoline ring-C), 33.95 (azetidine ring-C), 21.79 (OCH(CH3) 2 ); 13 C NMR (CDCl 3 , 100 MHz) δ 173.48 ( C (O)), 159.77, 155.99 (isoxazoline ring- C ), 140.32, 133.33, 131.87, 131.40, 128.81, 127.93, 126.85, 116.32, 114.04 (Ar C ), 103.12, 81.09 (isoxazoline ring - C ), 72.08 (O C H (CH 3 ) 2 ), 62.97 (N C H 2 ), 56.86 (azetidine ring- C ), 51.97 (COO C H 3 ), 43.02 (isoxazoline ring- C ), 33.95 ( azetidine ring- C ), 21.79 (OCH( C H 3 ) 2 );

HPLC purity: 4.3 min, 98.0%;HPLC purity: 4.3 min, 98.0%;

HRMS (M + H)+ (ESI+) 434.2080 [M + H]+ (calcd for C25H27N3O4H+ 434.2080).HRMS (M + H) + (ESI + ) 434.2080 [M + H] + (calcd for C 25 H 27 N 3 O 4 H + 434.2080).

화합물 60. 1-(4-(5-(3-시아노-4-이소프로폭시페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실산Compound 60. 1-(4-(5-(3-cyano-4-isopropoxyphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylic acid

Figure 112021066570416-pat00068
Figure 112021066570416-pat00068

하얀 고체;White solid;

수율: 64%;Yield: 64%;

1H NMR (CD3OD, 400 MHz) δ 7.84 (d, J = 8.3 Hz, 2 ArH), 7.64-7.67 (m, 2 ArH), 7.56 (d, J = 8.3 Hz, 2 ArH), 7.21-7.23 (m, 1 ArH), 5.74-5.79 (m, 1 isoxazoline ring-H), 4.76-4.91 (m, OCH(CH3)2), 4.47 (s, NCH 2 ), 4.28-4.36 (m, 4 azetidine ring-H), 3.85-3.92 (m, 1 isoxazoline ring-H), 3.61-3.69 (m, 1 azetidine ring-H), 3.32-3.44 (m, 1 isoxazoline ring-H), 1.40 (d, J = 6.0 Hz, OCH(CH 3 ) 2 ); 1 H NMR (CD 3 OD, 400 MHz) δ 7.84 (d, J = 8.3 Hz, 2 Ar H ), 7.64-7.67 (m, 2 Ar H ), 7.56 (d, J = 8.3 Hz, 2 Ar H ), 7.21-7.23 (m, 1 Ar H ), 5.74-5.79 (m, 1 isoxazoline ring- H ), 4.76-4.91 (m, OC H (CH 3 ) 2 ), 4.47 (s, NC H 2 ), 4.28-4.36 (m, 4 azetidine ring) - H ), 3.85-3.92 (m, 1 isoxazoline ring- H ), 3.61-3.69 (m, 1 azetidine ring- H ), 3.32-3.44 (m, 1 isoxazoline ring- H ), 1.40 (d, J = 6.0 Hz, OCH(C H 3 ) 2 );

13C NMR (CD3OD, 100 MHz) δ 173.04 (C(O)), 159.77, 156.27, 133.44, 132.29, 131.73, 131.15, 130.89, 130.20, 127.38, 115.84, 114.13 (ArC, isoxazoline ring-C), 102.23, 81.64 (isoxazoline ring-C), 71.85 (OCH(CH3)2), 57.65 (NCH2), 55.92 (azetidine ring-C), 41.91 (isoxazoline ring-C), 32.99 (azetidine ring-C), 20.67 (OCH(CH3) 2 ); 13 C NMR (CD 3 OD, 100 MHz) δ 173.04 ( C (O)), 159.77, 156.27, 133.44, 132.29, 131.73, 131.15, 130.89, 130.20, 127.38, 115.84, 114.13 (Ar C , isoxazoline ring- C ) , 102.23, 81.64 (isoxazoline ring- C ), 71.85 (OC H (CH 3 ) 2 ), 57.65 (N C H 2 ), 55.92 (azetidine ring- C ), 41.91 (isoxazoline ring- C ), 32.99 (azetidine ring- C ), 20.67 (OCH ( C H 3 ) 2 );

HPLC purity: 8.9 min, 96.0%;HPLC purity: 8.9 min, 96.0%;

HRMS (M + H)+ (ESI+) 420.1924 [M + H]+ (calcd for C24H25N3O4H+ 420.1923).HRMS (M + H) + (ESI + ) 420.1924 [M + H] + (calcd for C 24 H 25 N 3 O 4 H + 420.1923).

화합물 61. 메틸 1-(4-(5-(3-클로로-4-에톡시페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트Compound 61. Methyl 1-(4-(5-(3-chloro-4-ethoxyphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate

Figure 112021066570416-pat00069
Figure 112021066570416-pat00069

하얀 고체;White solid;

수율: 83%;Yield: 83%;

1H NMR (CDCl3, 400 MHz) δ 7.62 (d, J = 8.2 Hz, 2 ArH), 7.38 (d, J = 2.1 Hz, 1 ArH), 7.31 (d, J = 8.2 Hz, 2 ArH), 7.21 (dd, J = 2.1, 8.4 Hz, 1 ArH), 6.89 (d, J = 8.5 Hz, 1 ArH), 5.63 (dd, J = 8.2, 10.8 Hz, 1 isoxazoline ring-H), 4.09 (q, J = 6.9 Hz, OCH 2 CH3), 3.68-3.75 (m, 1 isoxazoline ring-H), 3.69 (s, COOCH 3 ), 3.62 (s, NCH 2 ), 3.50-3.53 (m, 2 azetidine ring-H), 3.24-3.34 (m, 3 azetidine ring-H, 1 isoxazoline ring-H), 1.45 (t, J = 7.0 Hz, OCH2CH 3 -); 1 H NMR (CDCl 3 , 400 MHz) δ 7.62 (d, J = 8.2 Hz, 2 Ar H ), 7.38 (d, J = 2.1 Hz, 1 Ar H ), 7.31 (d, J = 8.2 Hz, 2 Ar H ), 7.21 (dd, J = 2.1, 8.4 Hz, 1 Ar H ), 6.89 (d, J = 8.5 Hz, 1 Ar H ), 5.63 (dd, J = 8.2, 10.8 Hz, 1 isoxazoline ring- H ), 4.09 ( q, J = 6.9 Hz, OC H 2 CH 3 ), 3.68-3.75 (m, 1 isoxazoline ring- H ), 3.69 (s, COOC H 3 ), 3.62 (s, NC H 2 ), 3.50-3.53 (m , 2 azetidine ring- H ), 3.24-3.34 (m, 3 azetidine ring- H , 1 isoxazoline ring- H ), 1.45 (t, J = 7.0 Hz, OCH 2 C H 3 -);

13C NMR (CDCl3, 100 MHz) δ 173.51 (C(O)), 155.96 (isoxazoline ring-C), 154.37, 140.09, 133.82, 128.79, 127.93, 126.84, 125.35, 123.17, 113.39 (ArC), 81.67 (isoxazoline ring-C), 64.86 (NCH2), 63.02 (OCH2CH3), 56.87 (azetidine ring-C), 51.98 (COOCH3), 43.05 (isoxazoline ring-C), 33.96 (azetidine ring-C), 14.66 (OCH2 CH3); 13 C NMR (CDCl 3 , 100 MHz) δ 173.51 ( C (O)), 155.96 (isoxazoline ring- C ), 154.37, 140.09, 133.82, 128.79, 127.93, 126.84, 125.35, 123.17, 113.39 (Ar C ), 81.67 (iso xazoline ring- C ), 64.86 (N C H 2 ), 63.02 (O C H 2 CH 3 ), 56.87 (azetidine ring- C ), 51.98 (COO C H 3 ), 43.05 (isoxazoline ring- C ), 33.96 (azetidine ring- C ), 14.66 (OCH 2 C H 3 );

HPLC purity: 4.7 min, 98.5%;HPLC purity: 4.7 min, 98.5%;

HRMS (M + H)+ (ESI+) 429.1581 [M + H]+ (calcd for C23H25ClN2O4H+ 429.1581).HRMS (M + H) + (ESI + ) 429.1581 [M + H] + (calcd for C 23 H 25 ClN 2 O 4 H + 429.1581).

화합물 62. 소디움 1-(4-(5-(3-클로로-4-에톡시페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트Compound 62. Sodium 1-(4-(5-(3-chloro-4-ethoxyphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate

Figure 112021066570416-pat00070
Figure 112021066570416-pat00070

노란 고체;yellow solid;

수율: 86%;Yield: 86%;

1H NMR (CD3OD, 400 MHz) δ 7.67 (d, J = 8.2 Hz, 2 ArH), 7.37-7.40 (m, 3 ArH), 7.28 (dd, J = 2.1, 8.5 Hz, 1 ArH), 7.05 (d, J = 8.5 Hz, 1 ArH), 5.65 (dd, J = 8.6, 10.7 Hz, 1 isoxazoline ring-H), 4.11 (q, J = 6.9 Hz, OCH 2 CH3), 3.83 (dd, J = 10.8, 18.2 Hz, 1 isoxazoline ring-H), 3.67 (s, NCH 2 ), 3.55 (t, J = 8.0 Hz, 2 azetidine ring-H), 3.34-3.38 (m, 2 azetidine ring-H, 1 isoxazoline ring-H), 3.19-3.25 (m, 1 azetidine ring-H), 1.42 (t, J = 6.9 Hz, OCH2CH 3 -); 1 H NMR (CD 3 OD, 400 MHz) δ 7.67 (d, J = 8.2 Hz, 2 Ar H ), 7.37-7.40 (m, 3 Ar H ), 7.28 (dd, J = 2.1, 8.5 Hz, 1 Ar H ), 7.05 (d, J = 8.5 Hz, 1 Ar H ), 5.65 (dd, J = 8.6, 10.7 Hz, 1 isoxazoline ring- H ), 4.11 (q, J = 6.9 Hz, OC H 2 CH 3 ), 3.83 ( dd, J = 10.8, 18.2 Hz, 1 isoxazoline ring- H ), 3.67 (s, NC H 2 ), 3.55 (t, J = 8.0 Hz, 2 azetidine ring- H ), 3.34-3.38 (m, 2 azetidine ring) - H , 1 isoxazoline ring - H ), 3.19-3.25 (m, 1 azetidine ring - H ), 1.42 (t, J = 6.9 Hz, OCH 2 C H 3 -);

13C NMR (CD3OD, 100 MHz) δ 179.50 (C(O)), 157.55, 154.16, 133.82, 129.46, 128.15, 127.54, 126.93, 125.76, 122.41, 113.82 (ArC, isoxazoline ring-C), 81.79 (isoxazoline ring-C), 64.99 (NCH2), 61.45 (OCH2CH3), 57.27 (azetidine ring-C), 42.35 (isoxazoline ring-C), 36.09 (azetidine ring-C), 13.74 (OCH2 CH3); 13 C NMR (CD 3 OD, 100 MHz) δ 179.50 ( C (O)), 157.55, 154.16, 133.82, 129.46, 128.15, 127.54, 126.93, 125.76, 122.41, 113.82 (Ar C , isoxazoline ring- C ), 81.79 ( isoxazoline ring- C ), 64.99 (N C H 2 ), 61.45 (O C H 2 CH 3 ), 57.27 (azetidine ring- C ), 42.35 (isoxazoline ring- C ), 36.09 (azetidine ring- C ), 13.74 (OCH 2 C H 3 );

HPLC purity: 5.1 min, 95.9%;HPLC purity: 5.1 min, 95.9%;

HRMS (M + H)+ (ESI+) 415.1424 [M + H]+ (calcd for C22H23ClN2O4H+ 415.1425).HRMS (M + H) + (ESI + ) 415.1424 [M + H] + (calcd for C 22 H 23 ClN 2 O 4 H + 415.1425).

화합물 63. 메틸 1-(4-(5-(3-클로로-4-이소프로폭시페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트Compound 63. Methyl 1-(4-(5-(3-chloro-4-isopropoxyphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate

Figure 112021066570416-pat00071
Figure 112021066570416-pat00071

노란 기름;yellow oil;

수율: 44%;Yield: 44%;

1H NMR (CDCl3, 400 MHz) δ 7.61 (d, J = 8.1 Hz, 2 ArH), 7.37 (d, J = 2.0 Hz, 1 ArH), 7.30 (d, J = 8.0 Hz, 2 ArH), 7.19 (dd, J = 2.0, 8.4 Hz, 1 ArH), 6.91 (d, J = 8.4 Hz, 1 ArH), 5.61 (dd, J = 8.2, 10.8 Hz, 1 isoxazoline ring-H), 4.51-4.57 (m, OCH(CH3-)2), 3.72 (dd, J = 10.9, 16.7 Hz, 1 isoxazoline ring-H), 3.69 (s, COOCH 3 ), 3.63 (s, NCH 2 ), 3.52-3.54 (m, 2 azetidine ring-H), 3.26-3.36 (m, 1 isoxazoline ring-H, 3 azetidine ring-H), 1.35 (d, J = 6.0 Hz, OCH(CH 3 -) 2 ); 1 H NMR (CDCl 3 , 400 MHz) δ 7.61 (d, J = 8.1 Hz, 2 Ar H ), 7.37 (d, J = 2.0 Hz, 1 Ar H ), 7.30 (d, J = 8.0 Hz, 2 Ar H ), 7.19 (dd, J = 2.0, 8.4 Hz, 1 Ar H ), 6.91 (d, J = 8.4 Hz, 1 Ar H ), 5.61 (dd, J = 8.2, 10.8 Hz, 1 isoxazoline ring- H ), 4.51- 4.57 (m, OC H (CH 3 -) 2 ), 3.72 (dd, J = 10.9, 16.7 Hz, 1 isoxazoline ring- H ), 3.69 (s, COOC H 3 ), 3.63 (s, NC H 2 ), 3.52-3.54 (m, 2 azetidine ring- H ), 3.26-3.36 (m, 1 isoxazoline ring- H , 3 azetidine ring- H ), 1.35 (d, J = 6.0 Hz, OCH(C H 3 -) 2 ) ;

13C NMR (CDCl3, 100 MHz) δ 173.49 (C(O)), 156.01 (isoxazoline ring-C), 153.54, 140.09, 134.06, 128.78, 128.21, 128.05, 126.82, 125.27, 124.45, 115.97 (ArC), 81.66 (isoxazoline ring-C), 72.19 (OCH(CH3-)2), 62.98 (NCH2), 56.85 (azetidine ring-C), 51.96 (COOCH3), 42.98 (isoxazoline ring-C), 33.95 (azetidine ring-C), 21.99 (OCH(CH3-) 2 ); 13 C NMR (CDCl 3 , 100 MHz) δ 173.49 ( C (O)), 156.01 (isoxazoline ring- C ), 153.54, 140.09, 134.06, 128.78, 128.21, 128.05, 126.82, 125.27, 124.45 , 115.97 ( ArC ) , 81.66 (isoxazoline ring- C ), 72.19 (O C H (CH 3 -) 2 ), 62.98 (N C H 2 ), 56.85 (azetidine ring- C ), 51.96 (COO C H 3 ), 42.98 (isoxazoline ring - C ), 33.95 (azetidine ring- C ), 21.99 (OCH( C H 3 -) 2 );

HPLC purity: 5.3 min, 97.5%;HPLC purity: 5.3 min, 97.5%;

HRMS (M + H)+ (ESI+) 443.1740 [M + H]+ (calcd for C24H27ClN2O4H+ 443.1738).HRMS (M + H) + (ESI + ) 443.1740 [M + H] + (calcd for C 24 H 27 ClN 2 O 4 H + 443.1738).

화합물 64. 소디움 1-(4-(5-(3-클로로-4-이소프로폭시페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트Compound 64. Sodium 1-(4-(5-(3-chloro-4-isopropoxyphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate

Figure 112021066570416-pat00072
Figure 112021066570416-pat00072

하얀 고체;White solid;

수율: 98%;Yield: 98%;

1H NMR (CD3OD, 400 MHz) δ 7.69 (d, J = 8.1 Hz, 2 ArH), 7.38-7.42 (m, 3 ArH), 7.28 (dd, J = 2.1, 8.4 Hz, 1 ArH), 7.07 (d, J = 8.5 Hz, 1 ArH), 5.66 (dd, J = 8.5, 10.6 Hz, 1 isoxazoline ring-H), 4.61-4.89 (m, OCH(CH3-)2), 3.84 (dd, J = 10.8, 17.0 Hz, 1 isoxazoline ring-H), 3.67 (s, NCH 2 ), 3.54 (t, J = 8.0 Hz, 2 azetidine ring-H), 3.32-3.40 (m, 1 isoxazoline ring-H, 2 azetidine ring-H), 3.20-3.26 (m, 1 azetidine ring-H), 1.35 (d, J = 6.0 Hz, OCH(CH 3 -) 2 ); 1 H NMR (CD 3 OD, 400 MHz) δ 7.69 (d, J = 8.1 Hz, 2 Ar H ), 7.38-7.42 (m, 3 Ar H ), 7.28 (dd, J = 2.1, 8.4 Hz, 1 Ar H ), 7.07 (d, J) = 8.5 Hz, 1 Ar H ), 5.66 (dd, J = 8.5, 10.6 Hz, 1 isoxazoline ring- H ), 4.61-4.89 (m, OC H (CH 3 -) 2 ), 3.84 (dd, J = 10.8 , 17.0 Hz, 1 isoxazoline ring- H ), 3.67 (s, NC H 2 ), 3.54 (t, J = 8.0 Hz, 2 azetidine ring- H ), 3.32-3.40 (m, 1 isoxazoline ring- H , 2 azetidine ring- H ), 3.20-3.26 (m, 1 azetidine ring- H ), 1.35 (d, J = 6.0 Hz, OCH(C H 3 -) 2 );

13C NMR (CD3OD, 100 MHz) δ 179.60 (C(O)), 156.79 (isoxazoline ring-C), 153.42, 139.76, 134.15, 128.98, 128.29, 127.75, 126.57, 125.33, 123.78, 115.65 (ArC), 81.77 (isoxazoline ring-C), 71.68 (OCH(CH3-)2), 62.48 (NCH2), 57.69 (azetidine ring-C), 42.29 (isoxazoline ring-C), 36.54 (azetidine ring-C), 20.91 (OCH(CH3-) 2 ); 13 C NMR (CD 3 OD, 100 MHz) δ 179.60 ( C (O)), 156.79 (isoxazoline ring- C ), 153.42, 139.76, 134.15, 128.98, 128.29, 127.75, 126.57, 125.33, 123.78 , 115.65 (Ar C ), 81.77 (isoxazoline ring- C ), 71.68 (O C H (CH 3 -) 2 ), 62.48 (N C H 2 ), 57.69 (azetidine ring- C ), 42.29 (isoxazoline ring- C ), 36.54 (azetidine ring- C ), 20.91 (OCH( C H 3 -) 2 );

HPLC purity: 5.7 min, 98.1%;HPLC purity: 5.7 min, 98.1%;

HRMS (M + H)+ (ESI+) 429.1582 [M + H]+ (calcd for C23H25ClN2O4H+ 429.1581).HRMS (M + H) + (ESI + ) 429.1582 [M + H] + (calcd for C 23 H 25 ClN 2 O 4 H + 429.1581).

화합물 65. 메틸 1-(4-(5-(4-이소프로폭시-3-(트리플루오로메틸)페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트Compound 65. Methyl 1-(4-(5-(4-isopropoxy-3-(trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3- carboxylate

Figure 112021066570416-pat00073
Figure 112021066570416-pat00073

투명 기름;transparent oil;

수율: 35%;Yield: 35%;

1H NMR (CDCl3, 400 MHz) δ 7.62 (d, J = 8.0 Hz, 2ArH), 7.54 (s, 1 ArH), 7.48 (d, J = 8.5 Hz, 1 ArH), 7.31 (d, J = 8.0 Hz, 2 ArH), 6.98 (d, J = 8.6 Hz, 1 ArH), 5.68 (dd, J = 8.7, 10.5 Hz, 1 isoxazoline ring-H), 4.60-4.63 (m, OCH(CH3-)2), 3.74-3.77 (m, 1 isoxazoline ring-H), 3.73 (s, COOCH 3 ), 3.69 (s, NCH 2 ), 3.61-3.63 (m, 2 azetidine ring-H), 3.25-3.32 (m, 1 isoxazoline ring-H, 3 azetidine ring-H), 1.33 (d, J = 6.0 Hz, OCH(CH 3 -) 2 ); 1 H NMR (CDCl 3 , 400 MHz) δ 7.62 (d, J = 8.0 Hz, 2Ar H ), 7.54 (s, 1 Ar H ), 7.48 (d, J = 8.5 Hz, 1 Ar H ), 7.31 (d, J = 8.0 Hz, 2 Ar H ), 6.98 (d, J = 8.6 Hz, 1 Ar H ), 5.68 (dd, J = 8.7, 10.5 Hz, 1 isoxazoline ring- H ), 4.60-4.63 ( m, OC H (CH 3 -) 2 ), 3.74-3.77 (m, 1 isoxazoline ring- H ), 3.73 (s, COOC H 3 ), 3.69 (s, NC H 2 ), 3.61-3.63 (m, 2 azetidine ring- H ), 3.25-3.32 (m, 1 isoxazoline ring- H , 3 azetidine ring- H ), 1.33 (d, J = 6.0 Hz, OCH(C H 3 -) 2 );

13C NMR (CDCl3, 100 MHz) δ 173.49 (C(O)), 156.02 (isoxazoline ring-C), 140.19, 132.11, 130.69, 128.79, 128.16, 126.83 (ArC), 125.05 (q, J C-F = 4.9 Hz), 123.48 (q, J C-F = 270.8 Hz), 120.02 (q, J C-F = 30.5 Hz), 114.57 (ArC), 81.75 (isoxazoline ring-C), 71.42 (OCH(CH3-)2), 63.00 (NCH2), 56.87 (azetidine ring-C), 51.95 (COOCH3), 43.04 (isoxazoline ring-C), 33.96 (azetidine ring-C), 21.79 (OCH(CH3-) 2 ); 13 C NMR (CDCl 3 , 100 MHz) δ 173.49 ( C (O)), 156.02 (isoxazoline ring- C ), 140.19, 132.11, 130.69, 128.79, 128.16, 126.83 (Ar C ), 125.05 (q, J CF = 4.9 Hz), 123.48 (q, J CF = 270.8 Hz), 120.02 (q, J CF = 30.5 Hz), 114.57 (Ar C ), 81.75 (isoxazoline ring- C ), 71.42 (O C H (CH 3 -) 2 ), 63.00 (N C H 2 ), 56.87 (azetidine ring- C ), 51.95 (COO C H 3 ), 43.04 (isoxazoline ring- C ), 33.96 (azetidine ring- C ), 21.79 (OCH( C H 3 -) 2 );

HPLC purity: 5.1 min, 99.4%;HPLC purity: 5.1 min, 99.4%;

HRMS (M + H)+ (ESI+) 477.2006 [M + H]+ (calcd for C25H27F3N2O4H+ 477.2001).HRMS (M + H) + (ESI + ) 477.2006 [M + H] + (calcd for C 25 H 27 F 3 N 2 O 4 H + 477.2001).

화합물 66. 소디움 1-(4-(5-(4-이소프로폭시-3-(트리플루오로메틸)페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트Compound 66. Sodium 1-(4-(5-(4-isopropoxy-3-(trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3- carboxylate

Figure 112021066570416-pat00074
Figure 112021066570416-pat00074

하얀 고체;White solid;

수율: 92%;Yield: 92%;

1H NMR (CD3OD, 400 MHz) δ 7.71 (d, J = 8.1 Hz, 2 ArH), 7.55-7.57 (m, 2 ArH), 7.43 (d, J = 8.1 Hz, 2 ArH), 7.18 (d, J = 8.3 Hz, 1 ArH), 5.72 (dd, J = 8.7, 10.6 Hz, 1 isoxazoline ring-H), 4.74 (sept, J = 6.0 Hz, OCH(CH3-)2), 3.93 (s, NCH 2 ), 3.37-3.88 (m, 1 isoxazoline ring-H, 2 azetidine ring-H), 3.63-3.68 (m, 2 azetidine ring-H), 3.24-3.38 (m, 1 isoxazoline ring-H, 1 azetidine ring-H), 1.32 (d, J = 6.0 Hz, OCH(CH 3 -) 2 ); 1H NMR (CD 3 OD, 400 MHz) δ 7.71 (d, J = 8.1 Hz, 2ArH ), 7.55-7.57 (m, 2ArH ), 7.43 (d, J = 8.1 Hz, 2ArH ) , 7.18 (d, J = 8.3 Hz, 1 Ar H ), 5.72 (dd, J = 8.7, 10.6 Hz, 1 isoxazoline ring- H ), 4.74 (sept, J = 6.0 Hz, OC H (CH 3 -) 2 ), 3.93 (s, NC H 2 ), 3.37-3.88 (m, 1 isoxazoline ring- H , 2 azetidine ring- H ), 3.63-3.68 (m, 2 azetidine ring- H ), 3.24-3.38 (m, 1 isoxazoline ring- H , 1 azetidine ring- H ), 1.32 (d, J = 6.0 Hz, OCH(C H 3 -) 2 );

13C NMR (CD3OD, 100 MHz) δ 178.16 (C(O)), 156.63, 155.95, 136.92, 132.37, 130.95, 129.44, 129.19 (ArC, isoxazoline ring-C), 124.55 (q, J C-F = 5.3 Hz), 123.65 (q, J C-F = 270.0 Hz), 119.76, 119.45, 119.15, 118.85 (q, J C-F = 30.3 Hz), 114.55 (ArC), 81.93 (isoxazoline ring-C), 71.03 (OCH(CH3-)2), 60.55 (NCH2), 57.24, 42.22, 35.80, 20.74 (OCH(CH3-) 2 ); 13 C NMR (CD 3 OD, 100 MHz) δ 178.16 ( c (O)), 156.63, 155.95, 136.92, 132.37, 130.95, 129.44, 129.19 (AR C , Isoxazoline Ring- C ), 124.55 (Q, J CF = 5.3 Hz), 123.65 (Q, J CF = 270.0 Hz), 119.76, 119.45, 119.15, 118.85 (q, J CF = 30.3 Hz), 114.55 (Ar C ), 81.93 (isoxazoline ring- C ), 71.03 (O C H (CH 3 -) 2 ) , 60.55 (N C H 2 ), 57.24, 42.22, 35.80, 20.74 (OCH( C H 3 -) 2 );

HPLC purity: 3.8 min, 100%;HPLC purity: 3.8 min, 100%;

HRMS (M + H)+ (ESI+) 463.1848 [M + H]+ (calcd for C24H25F3N2O4H+ 463.1845).HRMS (M + H) + (ESI + ) 463.1848 [M + H] + (calcd for C 24 H 25 F 3 N 2 O 4 H + 463.1845).

화합물 67. 메틸 1-(4-(5-(피리딘-2-일)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트Compound 67. Methyl 1-(4-(5-(pyridin-2-yl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate

Figure 112021066570416-pat00075
Figure 112021066570416-pat00075

투명 기름;transparent oil;

수율: 46%;Yield: 46%;

1H NMR (CDCl3, 400 MHz) δ 8.57 (d, J = 4.1 Hz, 1 ArH), 7.70 (td, J = 1.7, 7.6 Hz, 1 ArH), 7.64 (d, J = 8.2 Hz, 2 ArH), 7.56 (d, J = 7.8 Hz, 1 ArH), 7.31 (d, J = 8.2 Hz, 2 ArH), 7.20-7.23, (m, 1 ArH), 5.81-5.85 (m, 1 isoxazoline ring-H), 3.78-3.85 (m, 1 isoxazoline ring-H), 3.66-3.74 (m, COOCH 3, 1 isoxazoline ring-H), 3.62 (s, NCH 2 ), 3.49-3.55 (m, 2 azetidine ring-H), 3.30-3.36 (m, 3 azetidine ring-H); 1 H NMR (CDCl 3 , 400 MHz) δ 8.57 (d, J = 4.1 Hz, 1 Ar H ), 7.70 (td, J = 1.7, 7.6 Hz, 1 Ar H ), 7.64 (d, J = 8.2 Hz, 2 Ar H ), 7.56 ( d, J = 7.8 Hz, 1 Ar H ), 7.31 (d, J = 8.2 Hz, 2 Ar H), 7.20-7.23, (m, 1 Ar H ), 5.81-5.85 (m, 1 isoxazoline ring- H ) , 3.78-3.85 (m, 1 isoxazoline ring- H ), 3.66-3.74 (m, COOC H 3, 1 isoxazoline ring- H ), 3.62 (s, NC H 2 ), 3.49-3.55 (m, 2 azetidine ring- H ), 3.30-3.36 (m, 3 azetidine ring- H );

13C NMR (CDCl3, 100 MHz) δ 173.45 (C(O)), 159.93, 156.31, 149.36, 140.00, 136.96, 128.74, 128.16, 126.93, 122.91, 120.57 (ArC, isoxazoline ring-C), 82.40 (isoxazoline ring-C), 62.95 (NCH2), 56.81 (azetidine ring-C), 51.96 (COOCH3), 41.48 (isoxazoline ring-C), 33.92 (azetidine ring-C); 13 C NMR (CDCl 3 , 100 MHz) δ 173.45 ( C (O)), 159.93, 156.31, 149.36, 140.00, 136.96, 128.74, 128.16, 126.93, 122.91, 120.57 (Ar C , isoxazoline ring- C ), 82.40 ( isoxazoline ring- C ), 62.95 (N C H 2 ), 56.81 (azetidine ring- C ), 51.96 (COO C H 3 ), 41.48 (isoxazoline ring- C ), 33.92 (azetidine ring- C );

HPLC purity: 5.1 min, 98.8%;HPLC purity: 5.1 min, 98.8%;

HRMS (M + H)+ (ESI+) 352.1661 [M + H]+ (calcd for C20H21N3O3H+ 352.1661).HRMS (M + H) + (ESI + ) 352.1661 [M + H] + (calcd for C 20 H 21 N 3 O 3 H + 352.1661).

화합물 68. 소디움 1-(4-(5-(피리딘-2-일)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트Compound 68. Sodium 1-(4-(5-(pyridin-2-yl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate

Figure 112021066570416-pat00076
Figure 112021066570416-pat00076

노란 기름;yellow oil;

수율: 53%;Yield: 53%;

1H NMR (CD3OD, 400 MHz) δ 8.90 (d, J = 5.6 Hz, 1 ArH), 8.69-8.73 (m, 1 ArH), 8.23 (d, J = 8.0 Hz, 1 ArH), 8.10 (d, J = 6.8 Hz, 1 ArH), 7.84 (d, J = 8.0 Hz, 2 ArH), 7.66-7.71, (m, 2 ArH), 6.29-6.34 (m, 1 isoxazoline ring-H), 4.20-4.61 (m, 7H), 3.37-3.89 (m, 2H), 3.32-3.33 (m, 1H); 1 H NMR (CD 3 OD, 400 MHz) δ 8.90 (d, J = 5.6 Hz, 1 Ar H ), 8.69-8.73 (m, 1 Ar H ), 8.23 (d, J = 8.0 Hz, 1 Ar H ), 8.10 (d, J = 6.8) Hz, 1 Ar H ), 7.84 (d, J = 8.0 Hz, 2 Ar H), 7.66-7.71, (m, 2 Ar H ), 6.29-6.34 (m, 1 isoxazoline ring- H ), 4.20-4.61 ( m, 7 H ), 3.37-3.89 (m, 2 H ), 3.32-3.33 (m, 1 H );

13C NMR (CD3OD, 100 MHz) δ 171.98, 171.47, 156.73, 154.70, 147.33, 141.82, 132.25 (d, J = 21.8 Hz), 130.55 (d, J = 8.2 Hz), 129.73, 127.73, 126.62, 124.85 (ArC, isoxazoline ring-C), 78.14 (isoxazoline ring-C), 57.26 (d, J = 22.8 Hz, NCH2), 55.27 (d, J = 25.6 Hz, azetidine ring-C), 41.89 (isoxazoline ring-C), 32.26 (azetidine ring-C); 13 C NMR (CD 3 OD, 100 MHz) δ 171.98, 171.47, 156.73, 154.70, 147.33, 141.82, 132.25 (d, J = 21.8 Hz), 130.55 (d, J = 8.2 Hz), 129.73, 127.73, 126.62, 1 24.85 (Ar C , isoxazoline ring- C ), 78.14 (isoxazoline ring- C ), 57.26 (d, J = 22.8 Hz, N C H 2 ), 55.27 (d, J = 25.6 Hz, azetidine ring- C ), 41.89 (isoxazoline ring- C ), 32.26 (azetidine ring- C );

HPLC purity: 5.1 min, 95.3%;HPLC purity: 5.1 min, 95.3%;

HRMS (M + H)+ (ESI+) 338.1503 [M + H]+ (calcd for C19H19N3O3H+ 338.1505).HRMS (M + H) + (ESI + ) 338.1503 [M + H] + (calcd for C 19 H 19 N 3 O 3 H + 338.1505).

화합물 69. 메틸 1-(4-(5-(3-클로로-4-이소프로폭시페닐)-4,5-디하이드로이속사졸-3-일)벤질)피롤리딘-3-카르복실레이트Compound 69. Methyl 1-(4-(5-(3-chloro-4-isopropoxyphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)pyrrolidine-3-carboxylate

Figure 112021066570416-pat00077
Figure 112021066570416-pat00077

노란 기름;yellow oil;

수율: 53%;Yield: 53%;

1H NMR (CDCl3, 400 MHz) δ 7.63 (d, J = 8.1 Hz, 2 ArH), 7.35-7.39 (m, 3 ArH), 7.21 (dd, J = 2.1, 8.4 Hz, 1 ArH), 6.92 (d, J = 8.5 Hz, 1 ArH), 5.63 (dd, J = 8.2, 10.8 Hz, 1 isoxazoline ring-H), 4.52-4.55 (m, OCH(CH3-)2), 3.73 (dd, J = 10.9, 16.6 Hz, 1 isoxazoline ring-H), 3.67 (s, OCH 3 ), 3.65 (d, J = 4.0 Hz, NCH 2 ), 3.30 (dd, J = 8.2, 16.6 Hz, 1 isoxazoling ring-H), 3.01-3.05 (m, 1 pyrrolidine ring-H), 2.87 (t, J = 9.0 Hz, 1 pyrrolidine ring-H), 2.64-2.68 (m, 2 pyrrolidine ring-H), 2.54 (q, J = 7.6 Hz, 1 pyrrolidine ring-H), 2.08-2.12 (m, 2 pyrrolidine ring-H), 1.36 (d, J = 6.0 Hz, OCH(CH 3 ) 2 ); 1 H NMR (CDCl 3 , 400 MHz) δ 7.63 (d, J = 8.1 Hz, 2 Ar H ), 7.35-7.39 (m, 3 Ar H ), 7.21 (dd, J = 2.1, 8.4 Hz, 1 Ar H ), 6.92 (d, J = 8.5 Hz, 1 Ar H ), 5.63 (dd, J = 8.2, 10.8 Hz, 1 isoxazoline ring- H ), 4.52- 4.55 (m, OC H (CH 3 -) 2 ), 3.73 (dd, J = 10.9, 16.6 Hz, 1 isoxazoline ring- H ), 3.67 (s, OC H 3 ), 3.65 (d, J = 4.0 Hz, NC H 2 ), 3.30 (dd, J = 8.2, 16.6 Hz, 1 isoxazoling ring- H ), 3.01-3.05 (m, 1 pyrrolidine ring- H ), 2.87 (t, J = 9.0 Hz, 1 pyrrolidine ring- H ) ), 2.64-2.68 (m, 2 pyrrolidine ring- H ), 2.54 (q, J = 7.6 Hz, 1 pyrrolidine ring- H ), 2.08-2.12 (m, 2 pyrrolidine ring- H ), 1.36 (d, J = 6.0 Hz, OCH(C H 3 ) 2 );

13C NMR (CDCl3, 100 MHz) δ 175.43 (C(O)), 156.01, 153.59, 141.27, 134.11, 129.09, 128.14, 128.09, 126.77, 125.24, 124.56, 116.02 (ArC, isoxazoline ring-C), 81.66 (isoxazoline ring-C), 72.25 (OCH(CH3-)2), 59.67 (NCH2), 56.63, 53.75 (pyrrolidine ring-C), 51.92 (OCH3), 43.07 (pyrrolidine ring-C), 41.97 (isoxazoline ring-C), 27.69 (pyrrolidine ring-C), 22.01 (OCH(CH3-) 2 ); 13 C NMR (CDCl 3 , 100 MHz) δ 175.43 ( C (O)), 156.01, 153.59, 141.27, 134.11, 129.09, 128.14, 128.09, 126.77, 125.24, 124.56, 116.02 (Ar C , isoxazoline ring- C ) , 81.66 (isoxazoline ring- C ) , 72.25 (OC H (CH 3 -) 2 ), 59.67 (N C H 2 ), 56.63, 53.75 (pyrrolidine ring- C ), 51.92 ( OC H 3 ), 43.07 (pyrrolidine ring- C ), 41.97 ( isoxazoline ring- C ), 27.69 (pyrrolidine ring- C ), 22.01 (OCH( C H 3 -) 2 );

HPLC purity: 5.3 min, 98.7%;HPLC purity: 5.3 min, 98.7%;

HRMS (M + H)+ (ESI+) 457.1895 [M + H]+ (calcd for C25H29ClN2O4H+ 457.1894).HRMS (M + H) + (ESI + ) 457.1895 [M + H] + (calcd for C 25 H 29 ClN 2 O 4 H + 457.1894).

화합물 70. 소디움 1-(4-(5-(3-클로로-4-이소프로폭시페닐)-4,5-디하이드로이속사졸-3-일)벤질)피롤리딘-3-카르복실레이트Compound 70. Sodium 1-(4-(5-(3-chloro-4-isopropoxyphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)pyrrolidine-3-carboxylate

Figure 112021066570416-pat00078
Figure 112021066570416-pat00078

노란 고체;yellow solid;

수율: 100%;Yield: 100%;

1H NMR (CD3OD, 400 MHz) δ 7.66 (d, J = 8.0 Hz, 2 ArH), 7.38-7.42 (m, 3 ArH), 7.25 (dd, J = 1.5, 8.4 Hz, 1 ArH), 7.04 (d, J = 8.5 Hz, 1 ArH), 5.63 (t, J = 10.2 Hz, 1 isoxazoline ring-H), 5.61-5.65 (m, OCH(CH3-)2), 3.80 (dd, J = 10.8, 17.0 Hz, 1 isoxazoline ring-H), 3.61-3.69 (m, NCH 2 ), 3.31-3.36 (m, 1 isoxazoline ring-H), 2.89-2.99 (m, 2 pyrrolidine ring-H), 2.72-2.77 (m, 1 pyrrolidine ring-H), 2.61 (t, J = 8.0 Hz, 1 pyrrolidine ring-H), 2.49 (q, J = 8.2 Hz, 1 pyrrolidine ring-H), 2.00-2.09 (m, 2 pyrrolidine ring-H), 1.31 (d, J = 6.0 Hz, OCH(CH 3 -) 2 ); 1 H NMR (CD 3 OD, 400 MHz) δ 7.66 (d, J = 8.0 Hz, 2 Ar H ), 7.38-7.42 (m, 3 Ar H ), 7.25 (dd, J = 1.5, 8.4 Hz, 1 Ar H ), 7.04 (d, J = 8.5 Hz, 1 Ar H ), 5.63 (t, J = 10.2 Hz, 1 isoxazoline ring- H ), 5.61-5.65 ( m, OC H (CH 3 -) 2 ), 3.80 (dd, J = 10.8, 17.0 Hz, 1 isoxazoline ring- H ), 3.61-3.69 (m, NC H 2 ), 3.31-3.36 (m, 1 isoxazoline ring) -H ), 2.89-2.99 (m, 2 pyrrolidine ring- H ), 2.72-2.77 (m, 1 pyrrolidine ring- H ), 2.61 (t, J = 8.0 Hz, 1 pyrrolidine ring- H ), 2.49 (q, J = 8.2 Hz, 1 pyrrolidine ring- H ), 2.00-2.09 (m, 2 pyrrolidine ring- H ), 1.31 (d, J = 6.0 Hz, OCH(C H 3 -) 2 );

13C NMR (CD3OD, 100 MHz) δ 181.64 (C(O)), 156.81, 153.42, 140.79, 134.16, 129.43, 128.19, 127.75, 126.48, 125.35, 123.78, 115.66 (ArC, isoxazoline ring-C), 81.75 (isoxazoline ring-C), 71.69 (OCH(CH3-)2), 59.73 (NCH2), 57.75, 53.78, 45.15 (pyrrolidine ring-C), 42.32 (isoxazoline ring-C), 28.26 (pyrrolidine ring-C), 20.93 (OCH(CH3-) 2 ); 13 C NMR (CD 3 OD, 100 MHz) δ 181.64 ( C (O)), 156.81, 153.42, 140.79, 134.16, 129.43, 128.19, 127.75, 126.48, 125.35, 123.78, 115.66 (Ar C , isoxazoline ring- C ) , 81.75 (isoxazoline ring- C ) , 71.69 (O C H (CH 3 -) 2 ), 59.73 (N C H 2 ), 57.75, 53.78, 45.15 (pyrrolidine ring- C ), 42.32 (isoxazoline ring- C ), 28.26 (pyrrolidine ring- C ), 20.93 (OCH( C H 3 -) 2 );

HPLC purity: 5.3 min, 98.7%;HPLC purity: 5.3 min, 98.7%;

HRMS (M + H)+ (ESI+) 443.1741 [M + H]+ (calcd for C24H27ClN2O4H+ 443.1738).HRMS (M + H) + (ESI + ) 443.1741 [M + H] + (calcd for C 24 H 27 ClN 2 O 4 H + 443.1738).

화합물 71. 소디움 1-(4-(5-(3-클로로-4-이소프로폭시페닐)-4,5-디하이드로이속사졸-3-일)벤질)피페리딘-4-카르복실레이트Compound 71. Sodium 1-(4-(5-(3-chloro-4-isopropoxyphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)piperidine-4-carboxylate

Figure 112021066570416-pat00079
Figure 112021066570416-pat00079

하얀 고체;White solid;

수율: 99%;Yield: 99%;

1H NMR (CD3OD, 400 MHz) δ 7.69 (d, J = 8.2 Hz, 2 ArH), 7.40-7.44 (m, 3 ArH), 7.28 (dd, J = 2.1, 8.4 Hz, 1 ArH), 7.08 (d, J = 8.5 Hz, 1 ArH), 5.66 (dd, J = 8.6, 10.6 Hz, 1 isoxazoline ring-H), 4.60-4.67 (m, OCH(CH3-)2), 3.84 (dd, J = 10.8, 17.0 Hz, 1 isoxazoline ring-H), 3.61 (s, NCH 2 ), 3.35-3.40 (m, 1 isoxazoline ring-H), 2.92 (d, J = 11.6 Hz, 2 piperidine ring-H), 2.10-2.20 (m, 3 piperidine ring-H), 1.86 (s, 2 piperidine ring-H), 1.73-1.80 (m, 2 piperidine ring-H), 1.33 (d, J = 6.0 Hz, OCH(CH 3 -) 2 ); 1 H NMR (CD 3 OD, 400 MHz) δ 7.69 (d, J = 8.2 Hz, 2 Ar H ), 7.40-7.44 (m, 3 Ar H ), 7.28 (dd, J = 2.1, 8.4 Hz, 1 Ar H ), 7.08 (d, J = 8.5 Hz, 1 Ar H ), 5.66 (dd, J = 8.6, 10.6 Hz, 1 isoxazoline ring- H ), 4.60-4.67 (m, OC H (CH 3 -) 2 ), 3.84 ( dd, J = 10.8, 17.0 Hz, 1 isoxazoline ring- H ), 3.61 (s, NC H 2 ), 3.35-3.40 (m, 1 isoxazoline ring- H ), 2.92 (d, J = 11.6 Hz, 2 piperidine ring- H ), 2.10-2.20 (m, 3 piperidine ring- H ), 1.86 (s, 2 piperidine ring- H ), 1.73-1.80 (m, 2 piperidine ring- H ), 1.33 (d, J = 6.0 Hz, OCH(C H 3 -) 2 );

13C NMR (CD3OD, 100 MHz) δ 207.53 (C(O)), 156.81 (isoxazoline ring-C), 153.57, 141.36, 134.28, 129.94, 127.75, 126.45, 125.29, 123.79, 115.65, 113.63 (ArC), 81.81 (isoxazoline ring-C), 71.67 (OCH(CH3-)2), 62.15 (NCH2), 53.05 (piperidine ring-C), 42.29 (isoxazoline ring-C), 28.62 (piperidine ring-C), 20.86 (OCH(CH3-) 2 ); 13 C NMR (CD 3 OD, 100 MHz) δ 207.53 ( C (O)), 156.81 (isoxazoline ring- C ), 153.57, 141.36, 134.28, 129.94, 127.75, 126.45, 125.29, 123.79, 115.65 , 113.63 (Ar C ), 81.81 (isoxazoline ring- C ), 71.67 (O C H (CH 3 -) 2 ), 62.15 (N C H 2 ), 53.05 (piperidine ring- C ), 42.29 (isoxazoline ring- C ), 28.62 (piperidine ring- C ), 20.86 (OCH( C H 3 -) 2 );

HPLC purity: 4.9 min, 98.3%;HPLC purity: 4.9 min, 98.3%;

HRMS (M + H)+ (ESI+) 457.1896 [M + H]+ (calcd for C25H29ClN2O4H+ 457.1894).HRMS (M + H) + (ESI + ) 457.1896 [M + H] + (calcd for C 25 H 29 ClN 2 O 4 H + 457.1894).

실험예 1: S1PExperimental Example 1: S1P 1One 작용제(agonist) 활성 검증 Verification of agonist activity

상기 실시예 1 내지 3에 따라 합성한 화합물 1 내지 71을 대상으로 S1P1 활성에 대한 효과를 확인하고자, 세포기반 평가 시스템을 이용한 in vitro 어세이를 실시하고, 그 결과를 표 1에 나타내었다.To confirm the effect on S1P 1 activity of compounds 1 to 71 synthesized according to Examples 1 to 3, an in vitro assay was performed using a cell-based evaluation system, and the results are shown in Table 1.

기능적 길항제(functional antagonist)의 효능을 분석하기 위하여, GPCR 활성화 후 일어나는 베타-어레스틴(β-arrestin)을 통한 수용체의 내재화(internalization) 정도를 측정할 수 있는 2가지 S1P1 과발현 세포주를 이용하였다. S1P1 수영체 활성화 후 수용체의 세포 내부 말단으로 베타-어레스틴의 모임 정도를 측정하는 세포주와 S1P1 수용체 활성화 후 발생하는 내재화에 의해 엔도솜을 이루는 정도를 측정하는 세포주를 사용하였으며, 이상의 모든 세포주 및 이하 실시예에서 사용되는 재료는 Eurofins의 DiscoverX에서 구입하였다.To analyze the efficacy of a functional antagonist, two S1P 1 overexpressing cell lines were used to measure the degree of internalization of the receptor through β-arrestin that occurs after GPCR activation. A cell line that measures the degree of gathering of beta-arrestin to the intracellular end of the receptor after activation of the S1P 1 receptor and a cell line that measures the degree of formation of endosomes by internalization that occurs after activation of the S1P 1 receptor were used. All cell lines above were used. and materials used in the examples below were purchased from DiscoverX of Eurofins.

본 발명의 화합물들의 S1P1 수용체 활성 검증은 각 제조업자에서 제공된 방법을 따라 수행하였으며, 화합물의 처리 농도에 따른 발광(luminescence) 정도를 측정하여 절반의 활성을 보이는 농도인 EC50 값을 산출하였다. 구체적으로, 세포주를 어세이용 배지에 1.0×104 cell/well의 밀도로 분주하여 인큐베이터에서 하루 동안 배양한 후, 세포 용해 및 발광 기질을 첨가하여 발광을 측정하였다. 산출된 2가지 EC50 값을 하기 표 1에 나타내었다. 71종 화합물 중 우수한 활성을 보인 화합물 13, 62, 64 및 66을 이후 추가적인 실험예에 사용하였다.Verification of the S1P 1 receptor activity of the compounds of the present invention was performed according to the method provided by each manufacturer, and the degree of luminescence according to the treatment concentration of the compound was measured to calculate the EC 50 value, which is the concentration showing half the activity. Specifically, the cell line was dispensed into the assay medium at a density of 1.0 The two calculated EC 50 values are shown in Table 1 below. Among the 71 types of compounds, compounds 13, 62, 64, and 66 that showed excellent activity were used in additional experimental examples.

화합물compound β-어레스틴 EC50 (nM)β-Arrestin EC 50 (nM) 내재화 EC50 (nM)Internalized EC 50 (nM) 화합물compound β-어레스틴 EC50 (nM)β-Arrestin EC 50 (nM) 내재화 EC50 (nM)Internalized EC 50 (nM) 1One 11.111.1 173.1173.1 3737 7.887.88 13.513.5 22 2.122.12 2.202.20 3838 0.580.58 0.140.14 33 23.623.6 116.5116.5 3939 39.239.2 159.6159.6 44 70.170.1 141.35141.35 4040 10.610.6 23.123.1 55 3.643.64 0.870.87 4141 0.900.90 9.529.52 66 0.370.37 0.0650.065 4242 0.810.81 0.370.37 77 1.171.17 4.334.33 4343 ＞1,000＞1,000 ＞1,000＞1,000 88 29.929.9 33.133.1 4444 ＞1,000＞1,000 ＞1,000＞1,000 99 1.821.82 1.591.59 4545 ＞1,000＞1,000 ＞1,000＞1,000 1010 0.450.45 0.360.36 4646 ＞1,000＞1,000 ＞1,000＞1,000 1111 1.491.49 12.612.6 4747 ＞1,000＞1,000 ＞1,000＞1,000 1212 1.411.41 1.481.48 4848 ＞1,000＞1,000 ＞1,000＞1,000 1313 0.220.22 0.0490.049 4949 ＞1,000＞1,000 ＞1,000＞1,000 1414 1.131.13 4.914.91 5050 567±16.4567±16.4 414±5.80414±5.80 1515 0.540.54 0.270.27 5151 ＞1,000＞1,000 ＞1,000＞1,000 1616 48.5348.53 139.5139.5 5252 ＞1,000＞1,000 ＞1,000＞1,000 1717 25.8525.85 81.381.3 5353 ＞1,000＞1,000 ＞1,000＞1,000 1818 3.243.24 9.269.26 5454 ＞1,000＞1,000 ＞±1,000＞±1,000 1919 1.141.14 0.970.97 5555 542±20.1542±20.1 973±24.3973±24.3 2020 3.053.05 118.7118.7 5656 25.9±0.2025.9±0.20 30.5±1.2330.5±1.23 2121 503503 378.6378.6 5757 ＞1,000＞1,000 286±4.78286±4.78 2222 8.598.59 97.3597.35 5858 34.6±0.2734.6±0.27 112±8.69112±8.69 2323 ＞1,000＞1,000 ＞1,000＞1,000 5959 95.7±3.9695.7±3.96 346±6.92346±6.92 2424 ＞1,000＞1,000 ＞1,000＞1,000 6060 18.1±0.1418.1±0.14 34.6±0.3134.6±0.31 2525 252.5252.5 346.7346.7 6161 100±0.50100±0.50 122±4.80122±4.80 2626 ＞1,000＞1,000 ＞1,000＞1,000 6262 20.4±0.6720.4±0.67 16.8±0.4616.8±0.46 2727 ＞1,000＞1,000 ＞1,000＞1,000 6363 23.1±0.6923.1±0.69 45.3±3.2445.3±3.24 2828 ＞1,000＞1,000 ＞1,000＞1,000 6464 7.03±0.097.03±0.09 11.8±0.2811.8±0.28 2929 635.1635.1 378.6378.6 6565 86.6±1.0586.6±1.05 38.5±0.8138.5±0.81 3030 8.508.50 205.4205.4 6666 5.57±0.095.57±0.09 5.09±0.085.09±0.08 3131 2.592.59 4.214.21 6767 392±5.42392±5.42 594±14.9594±14.9 3232 580.4580.4 518.6518.6 6868 346±6.08346±6.08 237±6.13237±6.13 3333 1.791.79 11.911.9 6969 74.4±1.9374.4±1.93 146±5.38146±5.38 3434 1.081.08 0.580.58 7070 11.1±0.1311.1±0.13 14.3±0.4414.3±0.44 3535 21.0521.05 11.511.5 7171 111±2.74111±2.74 80.6±3.0480.6±3.04 3636 2.032.03 2.622.62

실험예 2: 혈중 림프구 수 감소 검증Experimental Example 2: Verification of reduction in blood lymphocyte count

상기 실험예 1로부터 선택한 4종 화합물, 화합물 13, 62, 64 및 66의 투여에 의한 설치류 생체 내 혈중 림프구 수 감소에 대한 효과를 확인하기 위하여, 화합물 투여 전과 후에 혈액을 채취하여 자동 혈액 계수기를 이용하여 측정한 시간별 혈중 림프구 수 감소 정도를 도 1에 나타내었다.In order to confirm the effect on reducing the number of blood lymphocytes in rodents in vivo by administration of the four compounds selected from Experimental Example 1, compounds 13, 62, 64, and 66, blood was collected before and after compound administration and an automatic blood counter was used. The degree of decrease in the number of blood lymphocytes measured over time is shown in Figure 1.

구체적으로, 5주령의 수컷 랫드(rat, wister, 160-180 g)를 온도와 습도가 조절되는 사육실에서 적응시킨 후, 선택된 4종 화합물을 5% DMSO, 10% Kolliphor HS15 수용액에 용해시켜 10 mg/kg 용량으로 경구투여하였다. 4% 이소플루란(isoflurane)으로 흡입마취 중 꼬리 정맥으로부터 실린지로 혈액을 채취하여 EDTA 코팅 튜브에 옮겨담았다. 자동 혈액 계수기를 이용하여 채취한 혈액으로부터 림프구 수를 측정하였다. 양성대조군으로는 공지의 S1P1 수용체 조절제인 핀골리모드(Fingolimod)를 투여한 랫드를 사용하였다.Specifically, 5-week-old male rats (rat, wister, 160-180 g) were acclimatized in a breeding room with controlled temperature and humidity, and then the four selected compounds were dissolved in 5% DMSO and 10% Kolliphor HS15 aqueous solution and administered at 10 mg. It was administered orally at a dose of /kg. During inhalation anesthesia with 4% isoflurane, blood was collected from the tail vein using a syringe and transferred to an EDTA-coated tube. The number of lymphocytes was measured from the collected blood using an automatic blood counter. As a positive control group, rats administered Fingolimod, a known S1P 1 receptor modulator, were used.

도 1에 나타난 바와 같이, 화합물 투여 전 랫드의 림프구 수를 기준으로 화합물 투여 후 시간 경과에 따른 림프구 수를 백분율(%)로 나타내었다. 양성대조군인 핀골리모드 투여군에서와 같이, 약물 투여 후 5시간 이내에 실시예의 화합물을 투여한 군에서 50% 이하로 림프구 수의 감소를 유도하는 것을 확인하였다. 이는 정상 랫드에 본 발명의 화합물을 경구 투여시 혈중 림프구 수 감소를 유도함을 나타내는 것이다.As shown in Figure 1, the number of lymphocytes over time after administration of the compound was expressed as a percentage (%) based on the number of lymphocytes in the rat before administration of the compound. As in the positive control group administered with fingolimod, it was confirmed that the group administered the compound of the example within 5 hours after drug administration induced a decrease in the number of lymphocytes to less than 50%. This indicates that oral administration of the compound of the present invention to normal rats induces a decrease in the number of lymphocytes in the blood.

실험예 3: 다발성 경화증 동물 모델에서 증상 완화 효과 검증Experimental Example 3: Verification of symptom relief effect in multiple sclerosis animal model

상기 실험예 1로부터 선택한 4종 화합물, 화합물 13, 62, 64 및 66의 투여에 의한 다발성 경화증 동물 모델에서의 증상 완화에 대한 효과를 확인하기 위하여, MOG35-55 펩타이드 유도 다발성 경화증 모델에 상기 4종 화합물을 경구 투여하고, 경직 및 마비의 임상 증상 변화를 특정하여 도 2에 나타내었다.In order to confirm the effect on alleviating symptoms in a multiple sclerosis animal model by administration of the four compounds selected from Experimental Example 1, compounds 13, 62, 64, and 66, the above 4 was administered to the MOG 35-55 peptide-induced multiple sclerosis model. The compound was administered orally, and changes in clinical symptoms of stiffness and paralysis were identified and shown in Figure 2.

다발성 경화증 연구에 가장 많이 사용되고 있는 미엘린 당단백질 펩타이드(Myelin oligodendrocyte glycoprotein; MOG) 유도 자가면역성 뇌척수염(experimental autoimmune encephalomyelitis; EAE) 설치류 모델을 제작하였다.A myelin oligodendrocyte glycoprotein (MOG)-induced autoimmune encephalomyelitis (EAE) rodent model, which is most commonly used in multiple sclerosis research, was created.

구체적으로, 10주령의 C57BL6/J 수컷 마우스를 온도와 습도가 조절되는 사육실에서 적응시킨 후, MOG35-55 펩타이드 및 완전 프로인트 항원보강제(complete Freund's adjuvant, CFA)를 충분히 섞은 혼합물을 피하 주사하였다. 추가적으로, PBS에 용해시킨 백일해균 독소(pertussis toxin)를 0일차(Day 0)와 1일차(Day 1)에 복강 내 주사하였다. 상기 MOG 유도 EAE의 다발성 경화증 동물 모델 제작의 타임라인과 약물 투여 개요를 도 2A와 2G의 그래프 상단에 나타내었다.Specifically, 10-week-old C57BL6/J male mice were acclimatized in a breeding room with controlled temperature and humidity, and then subcutaneously injected with a sufficient mixture of MOG 35-55 peptide and complete Freund's adjuvant (CFA). . Additionally, pertussis toxin dissolved in PBS was injected intraperitoneally on Day 0 and Day 1. The timeline of the production of the multiple sclerosis animal model of MOG-induced EAE and the outline of drug administration are shown at the top of the graphs in Figures 2A and 2G.

본 발명의 화합물을 5% DMSO, 10% Kolliphor HS15 수용액에 용해시켜 0.3, 3, 또는 10 mg/kg 용량으로 매일 경구투여하였다. 음성대조군은 동일량의 비히클(vehicle)을 매일 경구투여하여 준비하였고, 양성대조군은 핀골리모드를 상기 본 발명의 화합물과 동일한 조성으로 준비하여 3 mg/kg 용량으로 매일 경구투여하여 준비하였다. 상기와 같이 준비한 음성대조군, 양성대조군 및 실험군의 동물모델에 대해 다음의 척도를 적용하여 증상을 평가하고 점수화하였다:The compound of the present invention was dissolved in 5% DMSO and 10% Kolliphor HS15 aqueous solution and orally administered daily at a dose of 0.3, 3, or 10 mg/kg. The negative control group was prepared by orally administering the same amount of vehicle every day, and the positive control group was prepared by orally administering fingolimod with the same composition as the compound of the present invention at a dose of 3 mg/kg daily. Symptoms were evaluated and scored by applying the following scale to the animal models of the negative control group, positive control group, and experimental group prepared as above:

0: 이상 없음,0: No abnormality,

0.5: 꼬리의 긴장 상실,0.5: loss of tail tension;

1.0: 꼬리의 반사성 상실,1.0: Loss of tail reflexivity;

2.0: 꼬리의 반사성 상실, 및 다리 하나의 지각 이상,2.0: Loss of reflexes in the tail and paresthesia in one leg,

3.0: 다리 하나의 지각 이상 및 마비,3.0: Paraesthesia and paralysis of one leg;

3.5: 양 뒷다리 마비,3.5: Paralysis of both hind limbs;

4.0: 앞다리 및 뒷다리 마비,4.0: Paralysis of fore and hind limbs;

5.0: 빈사상태 혹은 사망.5.0: Moribund or dead.

전술한 증상 척도로 약물의 효능을 평가한 결과, 도 2A 및 2G에 나타난 바와 같이, 약물을 처리하지 않은 음성대조군의 경우, 다발성 경화증의 증상이 시간 경과에 따라 심각해지는 반면, 본 발명의 화합물을 경구 투여한 경우, 일별 증상이 완화 또는 개선되었으며, 시험 기간에 걸쳐 축적된 유증상 정도 합계(도 2B) 및 증상의 최대 발전 정도(도 2C)의 증상 심각도가 농도 의존적으로 완화되는 것으로 나타났다. 또한, 도 2D 및 2E에 각각 나타난 바와 같이, 날짜별 체중 변화 및 최종 체중 변화율은 본 발명의 화합물 투여시 질병의 심각도를 낮추어 전반적인 염증 반응 및 마비에 의한 음식 섭취 제한을 저하시켜 체중의 감소를 현저히 저하시켰다. 나아가, 도 2F 및 2H에 나타난 바와 같이, 본 발명의 화합물 투여시 증상의 발현을 지연시키거나 억제함을 확인하였다.As a result of evaluating the efficacy of the drug using the above-mentioned symptom scale, as shown in Figures 2A and 2G, in the case of the negative control group that was not treated with the drug, the symptoms of multiple sclerosis became more severe over time, whereas the compound of the present invention When administered orally, daily symptoms were alleviated or improved, and the symptom severity of the total symptom severity accumulated over the test period (Figure 2B) and maximum symptom development (Figure 2C) appeared to be alleviated in a concentration-dependent manner. In addition, as shown in Figures 2D and 2E, respectively, the daily weight change and final weight change rate reduce the severity of the disease upon administration of the compound of the present invention, thereby lowering the overall inflammatory response and food intake restriction due to paralysis, resulting in a significant decrease in body weight. Degraded. Furthermore, as shown in Figures 2F and 2H, it was confirmed that administration of the compound of the present invention delayed or suppressed the onset of symptoms.

종합적으로, 본 발명의 화합물은 MOG 펩타이드에 의해 유도된 EAE 동물모델에서 질병의 신경학적 임상 증상 척도를 개선함을 확인하였는 바, 이는 본 발명의 화합물이 신경계 자가면역질환, 특히 다발성 경화증의 예방 또는 치료에 유용하게 사용될 수 있음을 나타내는 것이다.Overall, it was confirmed that the compound of the present invention improves the neurological and clinical symptom scale of the disease in the EAE animal model induced by MOG peptide, which means that the compound of the present invention is effective in preventing or preventing neurological autoimmune diseases, especially multiple sclerosis. This indicates that it can be useful for treatment.

이상의 설명으로부터, 본 발명이 속하는 기술분야의 당업자는 본 발명이 그 기술적 사상이나 필수적 특징을 변경하지 않고서 다른 구체적인 형태로 실시될 수 있다는 것을 이해할 수 있을 것이다. 이와 관련하여, 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적인 것이 아닌 것으로 이해해야만 한다. 본 발명의 범위는 상기 상세한 설명보다는 후술하는 특허 청구범위의 의미 및 범위 그리고 그 등가 개념으로부터 도출되는 모든 변경 또는 변형된 형태가 본 발명의 범위에 포함되는 것으로 해석되어야 한다.From the above description, those skilled in the art to which the present invention pertains will understand that the present invention can be implemented in other specific forms without changing its technical idea or essential features. In this regard, the embodiments described above should be understood in all respects as illustrative and not restrictive. The scope of the present invention should be construed as including the meaning and scope of the patent claims described below rather than the detailed description above, and all changes or modified forms derived from the equivalent concept thereof are included in the scope of the present invention.

Claims (18)

하기 화학식 1로 표시되는 화합물, 또는 이의 약학적으로 허용 가능한 염:
[화학식 1]
Figure 112023131639798-pat00080

상기 화학식 1에서,
Ring 1은 셀레나졸레닐(selenazolenyl) 또는 이소사졸레닐(isoxazolenyl),
Ring 2는 C6-10 아릴, 또는 5 내지 10원 헤테로아릴,
R1은 수소, 시아노, 할로(겐), 히드록시, C1-6 알킬, C1-6 알콕시, 및 C1-6 할로알킬로 구성된 군으로부터 선택되는 서로 동일 또는 상이한 하나 이상의 치환기,
R2 및 R3은 각각 독립적으로 수소, C1-6 알콕시카보닐-C1-6 알킬, 또는 소디움 카르복시-C1-6 알킬이거나,
R2 및 R3은 서로 연결되어 이들이 결합된 질소를 포함하여 비치환 또는 카르복시, 메톡시카보닐, 에톡시카보닐, tert-부톡시카보닐 및 소디움 카르복시로 구성된 군으로부터 선택되는 하나 이상으로 치환된 3원 내지 10원 헤테로사이클릴을 형성함.
A compound represented by the following formula (1), or a pharmaceutically acceptable salt thereof:
[Formula 1]
Figure 112023131639798-pat00080

In Formula 1,
Ring 1 is selenazolenyl or isoxazolenyl,
Ring 2 is C 6-10 aryl, or 5 to 10 membered heteroaryl,
R 1 is one or more substituents that are the same or different from each other selected from the group consisting of hydrogen, cyano, halo(gen), hydroxy, C 1-6 alkyl, C 1-6 alkoxy, and C 1-6 haloalkyl,
R 2 and R 3 are each independently hydrogen, C 1-6 alkoxycarbonyl-C 1-6 alkyl, or sodium carboxy-C 1-6 alkyl,
R 2 and R 3 are connected to each other and, including the nitrogen to which they are bonded, are unsubstituted or substituted with one or more selected from the group consisting of carboxy, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl and sodium carboxy. Forms a 3- to 10-membered heterocyclyl.
 제1항에 있어서,
하기 화학식 2 내지 4 중 어느 하나의 화학식으로 표시되는 것인, 화합물, 또는 이의 약학적으로 허용 가능한 염:
[화학식 2]
Figure 112021066570416-pat00081

[화학식 3]
Figure 112021066570416-pat00082

[화학식 4]
Figure 112021066570416-pat00083
.
According to paragraph 1,
A compound represented by any one of the following formulas 2 to 4, or a pharmaceutically acceptable salt thereof:
[Formula 2]
Figure 112021066570416-pat00081

[Formula 3]
Figure 112021066570416-pat00082

[Formula 4]
Figure 112021066570416-pat00083
.
 제1항에 있어서,
Ring 2는 페닐, 또는 피리디닐인 것인, 화합물, 또는 이의 약학적으로 허용 가능한 염.
According to paragraph 1,
Ring 2 is phenyl, or pyridinyl, a compound, or a pharmaceutically acceptable salt thereof.
 제1항에 있어서,
R1은 부재, 시아노, 브로모, 클로로, 히드록시, 에틸, 프로필, tert-부틸, 메톡시, 에톡시, 이소프로폭시, 클로로메틸, 또는 트리플루오로메틸인 것인, 화합물, 또는 이의 약학적으로 허용 가능한 염.
According to paragraph 1,
R 1 is absent, cyano, bromo, chloro, hydroxy, ethyl, propyl, tert-butyl, methoxy, ethoxy, isopropoxy, chloromethyl, or trifluoromethyl, or a compound thereof. Pharmaceutically acceptable salt.
 제1항에 있어서,
R2는 수소이고, R3은 에톡시카보닐메틸, 메톡시카보닐에틸, 소디움 카르복시메틸 또는 소디움 카르복시에틸인 것인, 화합물, 또는 이의 약학적으로 허용 가능한 염.
According to paragraph 1,
R 2 is hydrogen, and R 3 is ethoxycarbonylmethyl, methoxycarbonylethyl, sodium carboxymethyl, or sodium carboxyethyl, or a pharmaceutically acceptable salt thereof.
 제1항에 있어서,
R2 및 R3은 서로 연결되어 이들이 결합된 질소를 포함하여 비치환 또는 카르복시, 메톡시카보닐, 에톡시카보닐, tert-부톡시카보닐 및 소디움 카르복시로 구성된 군으로부터 선택되는 하나 이상으로 치환된 아제티디닐(azetidinyl), 피롤리디닐(pyrrolidinyl), 또는 피페리디닐(piperidinyl)을 형성하는 것인, 화합물, 또는 이의 약학적으로 허용 가능한 염.
According to paragraph 1,
R 2 and R 3 are connected to each other and, including the nitrogen to which they are bonded, are unsubstituted or substituted with one or more selected from the group consisting of carboxy, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, and sodium carboxy. A compound that forms azetidinyl, pyrrolidinyl, or piperidinyl, or a pharmaceutically acceptable salt thereof.
 제1항에 있어서,
상기 화합물은
1. 메틸 1-(4-(2-(4-tert-부틸페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트
2. 소디움 1-(4-(2-(4-tert-부틸페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트
3. 에틸 1-(4-(2-(4-tert-부틸페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트
4. tert-부틸 1-(4-(2-(4-tert-부틸페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트
5. 메틸 1-(4-(2-(3-이소시아노-4-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트
6. 소디움 1-(4-(2-(3-이소시아노-4-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트
7. 에틸 1-(4-(2-(3-시아노-4-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트
8. tert-부틸 1-(4-(2-(3-시아노-4-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트
9. 메틸 1-(4-(2-(4-이소프로폭시-3-(트리플루오로메틸)페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트
10. 1-(4-(2-(4-이소프로폭시-3-(트리플루오로메틸)페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실산
11. 에틸 1-(4-(2-(4-이소프로폭시-3-(트리플루오로메틸)페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트
12. 메틸 1-(4-(2-(3-클로로-4-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트
13. 소디움 1-(4-(2-(3-클로로-4-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트
14. 메틸 1-(4-(2-(3-클로로-4-에톡시페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트
15. 소디움 1-(4-(2-(3-클로로-4-에톡시페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트
16. 메틸 1-(4-(2-(4-메톡시페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트
17. 1-(4-(2-(4-메톡시페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실산
18. 메틸 1-(4-(2-(4-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트
19. 1-(4-(2-(4-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실산
20. 에틸 1-(4-(2-(4-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트
21. 메틸 1-(4-(2-(3-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트
22. 1-(4-(2-(3-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실산
23. 메틸 1-(4-(2-(2-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트
24. 1-(4-(2-(2-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실산
25. 에틸 1-(4-(2-(2-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트
26. 메틸 1-(4-(2-(피리딘-2-일)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트
27. 소디움 1-(4-(2-(피리딘-2-일)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트
28. 메틸 1-(4-(2-(피리딘-3-일)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트
29. 소디움 1-(4-(2-(피리딘-3-일)-1,3-셀레나졸-5-일)벤질)아제티딘-3-카르복실레이트
30. 메틸 1-(4-(2-(4-tert-부틸페닐)-1,3-셀레나졸-5-일)벤질)피롤리딘-3-카르복실레이트
31. 소디움 1-(4-(2-(4-tert-부틸페닐)-1,3-셀레나졸-5-일)벤질)피롤리딘-3-카르복실레이트
32. 메틸 1-(4-(2-(4-tert-부틸페닐)-1,3-셀레나졸-5-일)벤질)피페리딘-4-카르복실레이트
33. 메틸 1-(4-(2-(3-클로로-4-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질)피롤리딘-3-카르복실레이트
34. 소디움 1-(4-(2-(3-클로로-4-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질)피롤리딘-3-카르복실레이트
35. 에틸 2-(4-(2-(3-클로로-4-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질아미노)아세테이트
36. 소디움 2-(4-(2-(3-클로로-4-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질아미노)아세테이트
37. 메틸 3-(4-(2-(3-클로로-4-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질아미노)프로파노에이트
38. 소디움 3-(4-(2-(3-클로로-4-이소프로폭시페닐)-1,3-셀레나졸-5-일)벤질아미노)프로파노에이트
39. 메틸 1-(4-(5-(4-tert-부틸페닐)-1,3-셀레나졸-2-일)벤질)아제티딘-3-카르복실레이트
40. 소디움 1-(4-(5-(4-tert-부틸페닐)-1,3-셀레나졸-2-일)벤질)아제티딘-3-카르복실레이트
41. 메틸 1-(4-(5-(3-클로로-4-이소프로폭시페닐)-1,3-셀레나졸-2-일)벤질)아제티딘-3-카르복실레이트
42. 소디움 1-(4-(5-(3-클로로-4-이소프로폭시페닐)-1,3-셀레나졸-2-일)벤질)아제티딘-3-카르복실레이트
43. 메틸 1-(4-(5-페닐-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트
44. 1-(4-(5-페닐-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실산
45. 메틸 1-(4-(5-(2-브로모페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트
46. 1-(4-(5-(2-브로모페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실산
47. 메틸 1-(4-(5-(3-브로모페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트
48. 1-(4-(5-(3-브로모페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실산
49. 메틸 1-(4-(5-(4-브로모페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트
50. 1-(4-(5-(4-브로모페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실산
51. 1-(4-(5-(4-히드록시페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실산
52. 메틸 1-(4-(5-(4-(클로로메틸)페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트
53. 소디움 1-(4-(5-(4-(클로로메틸)페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트
54. 메틸 1-(4-(5-(4-에틸페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트
55. 소디움 1-(4-(5-(4-에틸페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트
56. 소디움 1-(4-(5-(4-프로필페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트
57. 메틸 1-(4-(5-(4-tert-부틸페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트
58. 소디움 1-(4-(5-(4-tert-부틸페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트
59. 메틸 1-(4-(5-(3-시아노-4-이소프로폭시페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트
60. 1-(4-(5-(3-시아노-4-이소프로폭시페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실산
61. 메틸 1-(4-(5-(3-클로로-4-에톡시페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트
62. 소디움 1-(4-(5-(3-클로로-4-에톡시페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트
63. 메틸 1-(4-(5-(3-클로로-4-이소프로폭시페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트
64. 소디움 1-(4-(5-(3-클로로-4-이소프로폭시페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트
65. 메틸 1-(4-(5-(4-이소프로폭시-3-(트리플루오로메틸)페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트
66. 소디움 1-(4-(5-(4-이소프로폭시-3-(트리플루오로메틸)페닐)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트
67. 메틸 1-(4-(5-(피리딘-2-일)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트
68. 소디움 1-(4-(5-(피리딘-2-일)-4,5-디하이드로이속사졸-3-일)벤질)아제티딘-3-카르복실레이트
69. 메틸 1-(4-(5-(3-클로로-4-이소프로폭시페닐)-4,5-디하이드로이속사졸-3-일)벤질)피롤리딘-3-카르복실레이트
70. 소디움 1-(4-(5-(3-클로로-4-이소프로폭시페닐)-4,5-디하이드로이속사졸-3-일)벤질)피롤리딘-3-카르복실레이트, 또는
71. 소디움 1-(4-(5-(3-클로로-4-이소프로폭시페닐)-4,5-디하이드로이속사졸-3-일)벤질)피페리딘-4-카르복실레이트인 것인, 화합물 또는 이의 약학적으로 허용 가능한 염.
According to paragraph 1,
The compound is
1. Methyl 1-(4-(2-(4-tert-butylphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate
2. Sodium 1-(4-(2-(4-tert-butylphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate
3. Ethyl 1-(4-(2-(4-tert-butylphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate
4. tert-Butyl 1-(4-(2-(4-tert-butylphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate
5. Methyl 1-(4-(2-(3-isocyano-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate
6. Sodium 1-(4-(2-(3-isocyano-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate
7. Ethyl 1-(4-(2-(3-cyano-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate
8. tert-Butyl 1-(4-(2-(3-cyano-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate
9. Methyl 1-(4-(2-(4-isopropoxy-3-(trifluoromethyl)phenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate
10. 1-(4-(2-(4-isopropoxy-3-(trifluoromethyl)phenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylic acid
11. Ethyl 1-(4-(2-(4-isopropoxy-3-(trifluoromethyl)phenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate
12. Methyl 1-(4-(2-(3-chloro-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate
13. Sodium 1-(4-(2-(3-chloro-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate
14. Methyl 1-(4-(2-(3-chloro-4-ethoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate
15. Sodium 1-(4-(2-(3-chloro-4-ethoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate
16. Methyl 1-(4-(2-(4-methoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate
17. 1-(4-(2-(4-methoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylic acid
18. Methyl 1-(4-(2-(4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate
19. 1-(4-(2-(4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylic acid
20. Ethyl 1-(4-(2-(4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate
21. Methyl 1-(4-(2-(3-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate
22. 1-(4-(2-(3-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylic acid
23. Methyl 1-(4-(2-(2-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate
24. 1-(4-(2-(2-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylic acid
25. Ethyl 1-(4-(2-(2-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate
26. Methyl 1-(4-(2-(pyridin-2-yl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate
27. Sodium 1-(4-(2-(pyridin-2-yl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate
28. Methyl 1-(4-(2-(pyridin-3-yl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate
29. Sodium 1-(4-(2-(pyridin-3-yl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate
30. Methyl 1-(4-(2-(4-tert-butylphenyl)-1,3-selenazol-5-yl)benzyl)pyrrolidine-3-carboxylate
31. Sodium 1-(4-(2-(4-tert-butylphenyl)-1,3-selenazol-5-yl)benzyl)pyrrolidine-3-carboxylate
32. Methyl 1-(4-(2-(4-tert-butylphenyl)-1,3-selenazol-5-yl)benzyl)piperidine-4-carboxylate
33. Methyl 1-(4-(2-(3-chloro-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)pyrrolidine-3-carboxylate
34. Sodium 1-(4-(2-(3-chloro-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)pyrrolidine-3-carboxylate
35. Ethyl 2-(4-(2-(3-chloro-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzylamino)acetate
36. Sodium 2-(4-(2-(3-chloro-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzylamino)acetate
37. Methyl 3-(4-(2-(3-chloro-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzylamino)propanoate
38. Sodium 3-(4-(2-(3-chloro-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzylamino)propanoate
39. Methyl 1-(4-(5-(4-tert-butylphenyl)-1,3-selenazol-2-yl)benzyl)azetidine-3-carboxylate
40. Sodium 1-(4-(5-(4-tert-butylphenyl)-1,3-selenazol-2-yl)benzyl)azetidine-3-carboxylate
41. Methyl 1-(4-(5-(3-chloro-4-isopropoxyphenyl)-1,3-selenazol-2-yl)benzyl)azetidine-3-carboxylate
42. Sodium 1-(4-(5-(3-chloro-4-isopropoxyphenyl)-1,3-selenazol-2-yl)benzyl)azetidine-3-carboxylate
43. Methyl 1-(4-(5-phenyl-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate
44. 1-(4-(5-phenyl-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylic acid
45. Methyl 1-(4-(5-(2-bromophenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate
46. 1-(4-(5-(2-bromophenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylic acid
47. Methyl 1-(4-(5-(3-bromophenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate
48. 1-(4-(5-(3-bromophenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylic acid
49. Methyl 1-(4-(5-(4-bromophenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate
50. 1-(4-(5-(4-bromophenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylic acid
51. 1-(4-(5-(4-hydroxyphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylic acid
52. Methyl 1-(4-(5-(4-(chloromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate
53. Sodium 1-(4-(5-(4-(chloromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate
54. Methyl 1-(4-(5-(4-ethylphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate
55. Sodium 1-(4-(5-(4-ethylphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate
56. Sodium 1-(4-(5-(4-propylphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate
57. Methyl 1-(4-(5-(4-tert-butylphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate
58. Sodium 1-(4-(5-(4-tert-butylphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate
59. Methyl 1-(4-(5-(3-cyano-4-isopropoxyphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate
60. 1-(4-(5-(3-cyano-4-isopropoxyphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylic acid
61. Methyl 1-(4-(5-(3-chloro-4-ethoxyphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate
62. Sodium 1-(4-(5-(3-chloro-4-ethoxyphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate
63. Methyl 1-(4-(5-(3-chloro-4-isopropoxyphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate
64. Sodium 1-(4-(5-(3-chloro-4-isopropoxyphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate
65. Methyl 1-(4-(5-(4-isopropoxy-3-(trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-car voxylate
66. Sodium 1-(4-(5-(4-isopropoxy-3-(trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-car voxylate
67. Methyl 1-(4-(5-(pyridin-2-yl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate
68. Sodium 1-(4-(5-(pyridin-2-yl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate
69. Methyl 1-(4-(5-(3-chloro-4-isopropoxyphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)pyrrolidine-3-carboxylate
70. Sodium 1-(4-(5-(3-chloro-4-isopropoxyphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)pyrrolidine-3-carboxylate, or
71. Sodium 1-(4-(5-(3-chloro-4-isopropoxyphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)piperidine-4-carboxylate Phosphorus, a compound, or a pharmaceutically acceptable salt thereof.
 하기 화학식 5로 표시되는 화합물의 알데하이드기를 아민화하는 단계를 포함하는, 제1항 내지 제7항 중 어느 한 항의 화합물, 또는 이의 약학적으로 허용 가능한 염의 제조방법:
[화학식 5]
Figure 112021066570416-pat00084

상기 화학식 1에서,
Ring 1은 셀레나졸레닐(selenazolenyl) 또는 이소사졸레닐(isoxazolenyl),
Ring 2는 C6-10 아릴, 또는 5 내지 10원 헤테로아릴,
R1은 수소, 시아노, 할로(겐), 히드록시, C1-6 알킬, C1-6 알콕시, 및 C1-6 할로알킬로 구성된 군으로부터 선택되는 서로 동일 또는 상이한 하나 이상의 치환기임.
A method for producing the compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, comprising the step of amination of the aldehyde group of the compound represented by the following formula (5):
[Formula 5]
Figure 112021066570416-pat00084

In Formula 1,
Ring 1 is selenazolenyl or isoxazolenyl,
Ring 2 is C 6-10 aryl, or 5 to 10 membered heteroaryl,
R 1 is one or more substituents that are the same or different from each other selected from the group consisting of hydrogen, cyano, halo(gen), hydroxy, C 1-6 alkyl, C 1-6 alkoxy, and C 1-6 haloalkyl.
 제8항에 있어서,
상기 화학식 5의 화합물은
R1-Ring 2-니트릴 또는 4-(히드록시메틸)벤조니트릴을 셀레늄 및 일산화탄소와 반응시켜 R1-Ring 2-치환된 셀레노아미드(selenoamide) 또는 4-히드록시벤조셀레노아미드를 제조하는 제a단계;
이전 단계의 생성물을 2-브로모-1,1-디에톡시에탄 및 p-톨루엔술폰산과 반응시켜 5번 탄소에 Ring 2가 치환된 또는 2번 탄소에 페닐이 치환된 1,3-셀레나졸 고리를 형성하는 제b단계;
이전 단계의 생성물의 1,3-셀레나졸 고리의 치환되지 않은 2번 탄소 또는 5번 탄소를 할로겐화하는 제c단계; 및
이전 단계의 생성물을 4-포르밀페닐보론산 또는 R1-Ring 2-보론산과 반응시켜 상기 할로겐화된 2번 탄소 또는 5번 탄소에 추가적인 치환기를 도입하는 제d단계를 통해 준비된 것인, 제조방법.
According to clause 8,
The compound of Formula 5 is
R 1 -Ring 2-nitrile or 4-(hydroxymethyl)benzonitrile is reacted with selenium and carbon monoxide to produce R 1 -Ring 2-substituted selenoamide or 4-hydroxybenzoselenoamide. Step a;
The product from the previous step was reacted with 2-bromo-1,1-diethoxyethane and p-toluenesulfonic acid to produce a 1,3-selenazole ring with Ring 2 substituted at carbon 5 or phenyl substituted at carbon 2. Step b of forming;
Step c of halogenating the unsubstituted carbon 2 or carbon 5 of the 1,3-selenazole ring of the product of the previous step; and
A production method prepared through the d step of reacting the product of the previous step with 4-formylphenylboronic acid or R 1 -Ring 2-boronic acid to introduce an additional substituent to the halogenated carbon 2 or carbon 5. .
 제8항에 있어서,
상기 화학식 5의 화합물은
N-히드록시-4-(히드록시메틸)벤즈이미도일 클로라이드를 트리에틸아민과 반응시켜 염산을 제거하는 제a'단계;
이전 단계의 생성물을 에테닐 치환된 R1-Ring 2와 반응시켜 (4-(5-(R1-Ring 2)-4,5-디하이드로이속사졸-3-일)페닐)메탄올을 제조하는 제b'단계; 및
이전 단계의 생성물의 페닐 고리 상의 히드록시기를 산화시키는 제c'단계를 통해 준비된 것인, 제조방법.
According to clause 8,
The compound of Formula 5 is
Step a' of removing hydrochloric acid by reacting N-hydroxy-4-(hydroxymethyl)benzimidoyl chloride with triethylamine;
Reacting the product of the previous step with ethenyl substituted R 1 -Ring 2 to produce (4-(5-(R 1 -Ring 2)-4,5-dihydroisoxazol-3-yl)phenyl)methanol. Step b'; and
A production method prepared through the c'th step of oxidizing the hydroxy group on the phenyl ring of the product of the previous step.
 제1항 내지 제7항 중 어느 한 항의 화합물, 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 다발성 경화증(multiple sclerosis; MS)의 예방 또는 치료용 약학적 조성물.
A pharmaceutical composition for preventing or treating multiple sclerosis (MS), comprising the compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, as an active ingredient.
 제11항에 있어서,
상기 화합물은 이의 나트륨염의 형태로 포함되는 것인, 약학적 조성물.
According to clause 11,
A pharmaceutical composition wherein the compound is contained in the form of its sodium salt.
 제11항에 있어서,
상기 화합물은 스핑고신-1-포스페이트 수용체(sphingosine-1-phosphate receptor; S1P1) 조절제로 작용하는 것인, 약학적 조성물.
According to clause 11,
A pharmaceutical composition, wherein the compound acts as a sphingosine-1-phosphate receptor (S1P1) modulator.
 제11항에 있어서,
혈중 림프구(lymphocyte) 수를 감소시키는 것인, 약학적 조성물.
According to clause 11,
A pharmaceutical composition that reduces the number of lymphocytes in the blood.
 제11항에 있어서,
경직, 또는 마비의 증상을 완화시키는 것인, 약학적 조성물.
According to clause 11,
A pharmaceutical composition for alleviating symptoms of spasticity or paralysis.
 제11항에 있어서,
다발성 경화증 증상의 발현을 지연시키는 것인, 약학적 조성물.
According to clause 11,
A pharmaceutical composition for delaying the onset of multiple sclerosis symptoms.
 제1항 내지 제7항 중 어느 한 항의 화합물, 또는 이의 식품학적으로 허용 가능한 염을 유효성분으로 포함하는 다발성 경화증의 예방 또는 개선용 식품 조성물.
A food composition for preventing or improving multiple sclerosis comprising the compound of any one of claims 1 to 7, or a foodologically acceptable salt thereof, as an active ingredient.
 제1항 내지 제7항 중 어느 한 항의 화합물, 또는 이의 사료학적으로 허용 가능한 염을 유효성분으로 포함하는 다발성 경화증의 예방 또는 개선용 사료 조성물.
A feed composition for preventing or improving multiple sclerosis comprising the compound of any one of claims 1 to 7, or a feedologically acceptable salt thereof, as an active ingredient.
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