KR20120096842A

KR20120096842A - 5-(substituted alkylaminomethyl)isoxazole derivatives as t-type calcium channel antagonists

Info

Publication number: KR20120096842A
Application number: KR1020110016203A
Authority: KR
Inventors: 추현아; 배애님; 조용서; 이효선; 이지은; 조경희; 임혜원; 서선희; 송치만; 정혜진; 남길수; 금교창; 김동진; 최경일; 최기현; 이재균; 강용구; 박웅서; 이주현; 신선미
Original assignee: 한국과학기술연구원
Priority date: 2011-02-23
Filing date: 2011-02-23
Publication date: 2012-08-31
Also published as: WO2012115446A2; KR101389374B1; WO2012115446A3

Abstract

PURPOSE: A 5-(substituted alkylaminomethyl)isoxazole based compound as T-type calcium channel blocker is provided to have excellent activity as an antagonist of T- type calcium ion channel. CONSTITUTION: A 5-(substituted alkylaminomethyl)isoxazole based compound as T-type calcium channel blocker is represented by chemical formula 1. The encephalopathy therapy and for prevention agent selected from epilepsy, depression, Parkinson's disease, dementia, sleep disorder, an agent for cancer treatment and prevention, an agent for heart disease treatment and prevention selected from hypertensive, cardiac arrhythmia, angina, myocardial infarction, congestive heart failure, pharmaceutical composition for alleviating pain selected from neuropathic pain and chronic and acute pain includes a compound represented by chemical formula 1.

Description

Ｔ-형 칼슘 채널 길항제로서의 5-(치환된알킬아미노메틸)아이속사졸계 화합물 {5-(Substituted alkylaminomethyl)isoxazole derivatives as T-type calcium channel antagonists} 5- (Substituted alkylaminomethyl) isoxazole derivatives as T-type calcium channel antagonists} as T-type calcium channel antagonists

본 발명은 T-형 칼슘 채널에 대하여 약학적 활성을 보이는 5-(치환된알킬아미노메틸)아이속사졸계 화합물 및 약제학적으로 허용 가능한 이의 염, 이들 화합물의 제조방법, 그리고 이들 화합물이 유효성분으로 함유된 약제조성물에 관한 것이다.
The present invention relates to a 5- (substituted alkylaminomethyl) isoxazole-based compound and a pharmaceutically acceptable salt thereof, a method for preparing these compounds, and a pharmaceutically active compound for the T-type calcium channel. It relates to a pharmaceutical composition contained.

칼슘채널은 신경세포의 자극에 의해 칼슘의 농도를 높여줌으로써 세포내 다양한 신호전달에 중요한 역할을 하게 된다. 이러한 칼슘채널은 고전압 활성화 칼슘채널(high-voltage activated calcium channel)과 저전압 활성화 칼슘채널 (low-voltage activated calcium channel)로 나뉘게 되는데, 대표적인 저전압 활성화 칼슘채널이 T-형 칼슘채널이다.Calcium channels play an important role in intracellular signal transduction by increasing the concentration of calcium by stimulation of nerve cells. The calcium channel is divided into a high-voltage activated calcium channel and a low-voltage activated calcium channel. A typical low-voltage activated calcium channel is a T-type calcium channel.

T-형 칼슘채널은 중추 근육, 부신의 내분비선, 동방결절, 심장 등에 존재하며, T-형 칼슘채널의 길항제는 간질, 고혈압, 협심증 등의 뇌질환과 심장질환 치료에 효과가 있다고 이미 잘 알려져 있다. [ 1) Hosravani, Houman et al., "Effects of Cav3.2 channel mutations linked to idiopathic generalized epilepsy", Annals of Neurology, 2005, 57(5) , 745-749; 2) Vitko, Iuliia et al., "Functional characterization and neuronal modeling of the effects of childhood absence epilepsy variants of CACNA1H, a T-type calcium channel", Journal of Neuroscience, 2005, 25(19) , 4844-4855; 3) Clozel, Cardiovas Drugs Ther., 1990, 4 , 731-736; 4) Hefti, Arzneimittelforschung, 1990, 40 , 417-421; 5) Moosmang, Sven et al., "Antihypertensive Effects of the Putative T-Type Calcium Channel Antagonist Mibefradil Are Mediated by the L-Type Calcium Channel Cav1. 2", Circulation Research, 2006, 98(1) , 105-110] T-type calcium channels are present in the central muscles, adrenal glands, isotopes, and the heart, and the antagonists of T-type calcium channels are well known for the treatment of brain diseases such as epilepsy, hypertension and angina. . [1) Hosravani, Houman et al., "Effects of Cav3.2 channel mutations linked to idiopathic generalized epilepsy", Annals of Neurology , 2005 , 57 (5) , 745-749; 2) Vitko, Iuliia et al., "Functional characterization and neuronal modeling of the effects of childhood absence epilepsy variants of CACNA1H, a T-type calcium channel", Journal of Neuroscience , 2005 , 25 (19) , 4844-4855; 3) Clozel, Cardiovas Drugs Ther ., 1990 , 4 , 731-736; 4) Hefti, Arzneimittel forschung, 1990 , 40 , 417-421; 5) Moosmang, Sven et al., "Antihypertensive Effects of the Putative T-Type Calcium Channel Antagonist Mibefradil Are Mediated by the L-Type Calcium Channel Cav1.2", Circulation Research , 2006 , 98 (1) , 105-110].

또한, 최근에는 T-형 칼슘채널의 길항제가 만성 통증치료에 효과가 있다고 발표되었다. [Flatters, Sarah J. L., "T-type calcium channels: A potential target for the treatment of chronic pain", Drugs of the Future, 2005, 40 , 573-580] α1G 넉아웃(knock-out) 마우스에 척수신경결찰 (spinal nerve ligation)을 일으켜 신경성 통증을 유발한 결과, T-형 칼슘채널의 길항제가 신경성 통증을 경감하는 효과가 있다고 발표된 바도 있다. [Molecules & Cells, 2008, 25 , 242-246]. 그리고, T-형 칼슘채널의 길항제로서 미베프라딜 (Mibefradil)과 에소숙시마이드 (Ethosuximide)가 척수신경결찰 (spinal nerve ligation) 동물모델에서 기계적 열적 유발 반응의 저해 정도가 약물 투여량에 따른다고 보고됨으로써 T-형 칼슘채널의 길항제가 신경성 통증치료에 효과가 있다는 것을 보였다. [Dogrul, Ahmet et al., "Reversal of experimental neuropathic pain by T-type calcium channel blockers", Pain, 2003, 105 , 159-168] Recently, antagonists of T-type calcium channels have been reported to be effective in treating chronic pain. [Flatters, Sarah JL, "T-type calcium channels: A potential target for the treatment of chronic pain", Drugs of the Future , 2005 , 40 , 573-580] Spinal nerve ligation in α1G knock-out mice It has been reported that antagonists of T-type calcium channels have the effect of alleviating neurological pain as a result of spontaneous nerve ligation. Molecules & Cells , 2008 , 25 , 242-246. In addition, we report that the degree of inhibition of the mechanical thermal induced response of mibefradil and ethosuximide as an antagonist of T-type calcium channel in spinal nerve ligation animal model depends on the dose of drug. It has been shown that antagonists of T-type calcium channels are effective in treating neurological pain. Dogrul, Ahmet et al., "Reversal of experimental neuropathic pain by T-type calcium channel blockers", Pain , 2003 , 105 , 159-168]

또한, 칼슘은 세포내 신호전달물질로서 중요한 역할을 하고 다양한 세포작용을 조절하는데, 세포작용 중에서 칼슘은 세포성장에 관여하는 것으로 알려져 있어 T-형 칼슘채널의 길항제가 항암 효과를 낼 것이라는 예측이 가능하다. [Nat. Rev. Mol. Cell Biol. 2003, 4 , 517-529]In addition, calcium plays an important role as an intracellular signaling substance and regulates various cellular actions. Calcium is known to be involved in cell growth during cell action, so it can be predicted that an antagonist of T-type calcium channel will have anticancer effect Do. Nat. Rev. Mol. Cell Biol. 2003 , 4 , 517-529]

T-형 칼슘채널의 길항제로서 시판되었던 미베프라딜 (Mibefradil, Ro 40-5967, WO 98/49149)은 고혈압과 협심증 치료제로서 사용되었으나, 미베프라딜은사이토크롬(cytochrome) P-450 3A4와 2D6에 의해 다른 약물들과 대사되어 약물 동력학적 결합을 함으로써 여러 부작용을 일으켜 약물로 사용이 부적합한 것으로 밝혀짐에 따라 판매가 금지되었다. 이로써 T-형 칼슘채널의 길항제의 시급한 개발이 요구되어지고 있다. Mibefradil (Mibefradil, Ro 40-5967, WO 98/49149), which was marketed as an antagonist of T-type calcium channels, was used as a treatment for hypertension and angina, but mibepradil was used for cytochrome P-450 3A4 and 2D6. The drug was banned as it was metabolized with other drugs and pharmacokineticly combined, causing several side effects, making it inappropriate for use as a drug. There is an urgent need for the development of antagonists of T-type calcium channels.

현재까지 T-형 칼슘채널의 길항제를 개발하려는 많은 노력은 있었으나, 선택적인 T-형 칼슘채널의 길항제는 극히 드물다. T-형 칼슘채널에 작용하는 물질로서 대한민국특허등록 제784,195호, 제754,325호 및 제749743호 등에는 퀴나졸린을 기본 골격구조로 갖는 화합물이 개시되어 있고, 대한민국특허등록 제743,255호에는 1,3-다이옥소아이소인돌을 기본 골격구조로 갖는 화합물이 개시되어 있다. While many efforts have been made to develop antagonists of T-type calcium channels, selective antagonists of T-type calcium channels are extremely rare. As substances that act on T-type calcium channels, Korean Patent Registration Nos. 784,195, 754,325 and 749743 disclose compounds having quinazoline as a basic skeleton structure, and Korean Patent Registration No. 743,255 discloses 1,3 A compound having a dioxoisoindole as a basic skeleton structure is disclosed.

그러나 여전히 T-형 칼슘채널에 선택적이고 약물동력학 프로파일이 좋고, ADME(흡수, 분배, 대사, 배출)이 좋으면서도 간질 (epilepsy); 암; 고혈압 (hypertensive), 심부정맥, 협심증, 심근 경색증, 울혈성 심부전증과 같은 심장 질환; 신경성 통증 (neuropathic pain), 만성 및 급성 통증 (chronic and acute pain)과 같은 통증 질환의 치료에 유효한 T-형 칼슘채널의 길항제가 요구되고 있다.However, it is still selective for T-type calcium channels and has a good pharmacokinetic profile, epilepsy with good ADME (absorption, distribution, metabolism, excretion); cancer; Heart diseases such as hypertensive, deep vein, angina pectoris, myocardial infarction, congestive heart failure; There is a need for antagonists of T-type calcium channels that are effective in the treatment of pain diseases such as neuropathic pain, chronic and acute pain.

또한, 대한민국특허등록 제616,099호에는 아이속사졸 고리의 3번 위치에 페닐 또는 나프탈렌과 같은 방향족기가 치환된 피페라지닐알킬아이속사졸 화합물이 개시되어 있다. 그러나, 본 발명의 화합물은 아이속사졸 고리의 3번 위치에 지방족 알킬기가 치환된 신규 화합물 관련한 발명으로, 방향족기가 치환된 피페라지닐알킬아이속사졸 화합물에 비교하여 신경성 통증 동물모델 실험에서 통증완화를 개선시킨 진보된 효과를 얻고 있다.
In addition, Korean Patent No. 616,099 discloses a piperazinylalkyl isoxazole compound in which an aromatic group such as phenyl or naphthalene is substituted at the 3 position of the isoxazole ring. However, the compound of the present invention relates to a novel compound in which an aliphatic alkyl group is substituted at the 3 position of the isoxazole ring, and compared to the piperazinylalkyl isoxazole compound substituted with an aromatic group, pain relief in a neurological pain animal model experiment. To get an improved effect.

본 발명은 아이속사졸의 5각형 고리의 3번 위치에 지방족 알킬기가 치환되어 있는 신규 구조의 5-(치환된알킬아미노메틸)아이속사졸계 화합물 또는 약제학적으로 허용 가능한 이의 염을 제공하는데 그 목적이 있다.The present invention provides a 5- (substituted alkylaminomethyl) isoxazole compound or a pharmaceutically acceptable salt thereof having a novel structure in which an aliphatic alkyl group is substituted at position 3 of the pentagonal ring of isoxazole. There is this.

또한, 본 발명은 상기한 5-(치환된알킬아미노메틸)아이속사졸계 화합물 또는 약제학적으로 허용 가능한 이의 염이 유효성분으로 포함되어 있는 T-형 칼슘채널 길항작용을 갖는 약제조성물을 제공하는데 또 다른 목적이 있다.In addition, the present invention provides a pharmaceutical composition having a T-type calcium channel antagonism, wherein the 5- (substituted alkylaminomethyl) isoxazole-based compound or a pharmaceutically acceptable salt thereof is included as an active ingredient. There is another purpose.

또한, 본 발명은 상기한 5-(치환된알킬아미노메틸)아이속사졸계 화합물 및 약제학적으로 허용 가능한 이의 염이 유효성분으로 포함되어 있는 간질 (epilepsy), 우울증, 파킨스씨병 (Parkinson's disease), 치매 (dementia), 수면장애 (sleep disorder)로부터 선택된 뇌질환 치료 및 예방제용; 암 치료 및 예방제용; 고혈압 (hypertensive), 심부정맥, 협심증, 심근 경색증, 울혈성 심부전증으로부터 선택된 심장질환 치료 및 예방제용; 또는 신경성 통증 (neuropathic pain), 만성 및 급성 통증 (chronic and acute pain)으로부터 선택된 통증 완화제용으로 유용한 약학적 조성물을 제공하는데 또 다른 목적이 있다.
In addition, the present invention is epilepsy, depression, Parkinson's disease (Parkinson's disease), wherein the 5- (substituted alkylaminomethyl) isoxazole-based compound and a pharmaceutically acceptable salt thereof as an active ingredient, For treating and preventing brain diseases selected from dementia, sleep disorders; For treating and preventing cancer; For the treatment and prevention of heart diseases selected from hypertensive, heart arrhythmia, angina pectoris, myocardial infarction, congestive heart failure; Another object is to provide a pharmaceutical composition useful for pain relievers selected from neuropathic pain, chronic and acute pain.

상기의 목적을 실현하기 위하여, 본 발명은 T-형 칼슘채널 길항제로서 그리고 통증 완화제로서 탁월한 약효를 나타내는 하기 화학식 1로 표시되는 5-(치환된알킬아미노메틸)아이속사졸계 화합물 및 약제학적으로 허용 가능한 이의 염을 그 특징으로 한다.In order to achieve the above object, the present invention provides a 5- (substituted alkylaminomethyl) isoxazole-based compound represented by the following Chemical Formula 1, which shows excellent efficacy as a T-type calcium channel antagonist and as a pain mitigator, and a pharmaceutically acceptable compound. Possible salts thereof are characterized by that.

상기 화학식 1에서,In Formula 1,

에서

가 단일결합일 때 X는 N 또는 CH를 나타내고,

가 이중결합일 때 X는 C를 나타내고,

in

X represents N or CH when is a single bond,

X is C when is a double bond,

Y는 N 또는 CH를 나타내고,Y represents N or CH,

R¹은 페닐 및 할로페닐 중에서 선택된 1 내지 2개의 치환기로 치환 또는 비치환된 C₁-C₆알킬기; 또는 할로, 시아노, C₁-C₆알킬, C₁-C₆알콕시, C₁-C₆할로알킬, 및 C₁-C₆할로알콕시 중에서 선택된 1 내지 4개의 치환기로 치환 또는 비치환된 페닐기를 나타내고, R ¹ is a C ₁ -C ₆ alkyl group unsubstituted or substituted with 1 to 2 substituents selected from phenyl and halophenyl; Or a phenyl group unsubstituted or substituted with 1 to 4 substituents selected from halo, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, and C ₁ -C ₆ haloalkoxy Indicates,

R²및 R³은 서로 같거나 다른 것으로서, 수소원자; 또는 C₁-C₆알킬기를 나타내고, R ² and R ³ are the same as or different from each other, and are a hydrogen atom; Or a C ₁ -C ₆ alkyl group,

R⁴는 수소원자; 또는

를 나타내고, R ⁴ is a hydrogen atom; or

Lt; / RTI >

R⁵는 C₁-C₆알킬기; -C(O)NR⁶R⁷; -C(O)OR⁸를 나타내고, R ⁵ is a C ₁ -C ₆ alkyl group; -C (O) NR ⁶ R ⁷ ; -C (O) OR ⁸ ,

R⁶및 R⁷은 서로 같거나 다른 것으로서, 수소원자; 또는 C₁-C₆알킬기를 나타내고,R ⁶ and R ⁷ are the same as or different from each other, a hydrogen atom; Or a C ₁ -C ₆ alkyl group,

R⁸은 수소원자; 알칼리금속원자; 또는 C₁-C₆알킬기를 나타내고,R ⁸ is a hydrogen atom; Alkali metal atoms; Or a C ₁ -C ₆ alkyl group,

n은 0 내지 5의 정수를 나타낸다.
n represents the integer of 0-5.

도 1은 본원의 화합물번호 6 화합물과 가바펜틴(gabapentin) 및 KST005468 각각에 대하여 기계적인 이질통(mechanical allodynia) 치료효과를 비교한 결과로서, 50% 회피역치(50% withdrawal threshold)를 나타낸 그래프이다.
도 2는 본원의 화합물번호 6 화합물과 가바펜틴(gabapentin) 및 KST005468 각각에 대하여 냉각 이질통(cold allodynia) 치료효과를 비교한 결과로서, 회피잠복기(withdrawal latency, sec)를 나타낸 그래프이다.
도 3은 본원의 화합물번호 6 화합물과 가바펜틴(gabapentin) 및 KST005468 각각에 대하여 열 통각과민(heat hyperalgesia) 치료효과를 비교한 결과로서, 회피잠복기(withdrawal latency, sec)를 나타낸 그래프이다.
FIG. 1 is a graph showing a 50% withdrawal threshold as a result of comparing a mechanical allodynia treatment effect with respect to the compound No. 6 of the present application, gabapentin, and KST005468.
Figure 2 is a graph showing the withdrawal latency (sec) as a result of comparing the cold allodynia treatment effect for the compound No. 6 compound of the present application, gabapentin and KST005468.
FIG. 3 is a graph showing the withdrawal latency (sec) as a result of comparing heat hyperalgesia treatment effects with respect to the compound No. 6 of the present application, gabapentin, and KST005468, respectively.

본 발명에 따른 상기 화학식 1로 표시되는 5-(치환된알킬아미노메틸)아이속사졸계 화합물은 당해 기술 분야에서 통상적인 방법에 의해 약제학적으로 허용 가능한 염을 형성할 수 있다. 예를 들면, 염산, 브롬산, 술폰산, 아미도황산, 인산, 질산과 같은 무독성의 무기산, 또는 아세트산, 프로피온산, 숙신산, 글리콜산, 스테아르산, 젖산, 타르타르산, 시트르산, 파라톨루엔설폰산, 메탄설폰산과 같은 무독성의 유기산과 함께 약제학적으로 허용 가능한 이들의 산이 부가된 염을 형성할 수도 있다.The 5- (substituted alkylaminomethyl) isoxazole-based compound represented by Formula 1 according to the present invention may form a pharmaceutically acceptable salt by a conventional method in the art. Non-toxic inorganic acids such as hydrochloric acid, bromic acid, sulfonic acid, amido sulfuric acid, phosphoric acid, nitric acid, or acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, tartaric acid, citric acid, paratoluenesulfonic acid, methanesulfone In addition to nontoxic organic acids such as acids, pharmaceutically acceptable salts of these acids may be added.

본 발명에 따른 상기 화학식 1로 표시되는 5-(치환된알킬아미노메틸)아이속사졸계 화합물을 정의하기 위해 사용된 치환기를 좀 더 자세히 설명하면 다음과 같다. The substituents used to define the 5- (substituted alkylaminomethyl) isoxazole compound represented by Chemical Formula 1 according to the present invention will be described in more detail as follows.

"알킬기"는 1 내지 6개의 탄소원자를 가진 직쇄상, 분쇄상 및 고리상의 탄소사슬을 모두 포함하며, 선호하는 알킬기는 메틸, 에틸기, 노말프로필기, 아이소프로필기, 노말부틸기, 아이소부틸기, tert-부틸기, 시클로펜틸기, 시클로헥실기 등이 있다. "할로알킬기"는 플루오로, 클로로, 브로모, 아이오도와 같은 할로겐원자가 1 내지 13개 포함되고, 1 내지 6개의 탄소원자를 가진 직쇄상, 분쇄상 및 고리상의 탄소사슬을 모두 포함하며, 선호하는 할로알킬기는 플루오로메틸, 트리플루오로메틸, 1,2-디클로로에틸기, 1,1-디클로로에틸기, 펜타플루오로에틸기 등이 있다. "알콕시기"는 산소에 연결된 탄소의 알킬기를 의미하는 것으로, 이때 알킬은 상기에서 정의한 바와 같다. "할로알콕시기"는 플루오로, 클로로, 브로모, 아이오도와 같은 할로겐원자가 1 내지 13개 포함된 알콕시기를 의미하는 것으로, 이때 알콕시는 상기에서 정의한 바와 같으며, 선호하는 할로알콕시기는 플루오로메톡시기, 트리플루오로메톡시기, 1,2-디클로로에톡시기, 1,1-디클로로에톡시기, 펜타플루오로에톡시기 등이 있다."Alkyl group" includes all linear, pulverized and cyclic carbon chains having 1 to 6 carbon atoms, and preferred alkyl groups are methyl, ethyl, normal propyl, isopropyl, normal butyl, isobutyl, tert -butyl group, cyclopentyl group, cyclohexyl group, and the like. A "haloalkyl group" includes one to thirteen halogen atoms such as fluoro, chloro, bromo and iodo, and includes all linear, pulverized and cyclic carbon chains having one to six carbon atoms, and the preferred halo. The alkyl group includes a fluoromethyl, trifluoromethyl, 1,2-dichloroethyl group, 1,1-dichloroethyl group, pentafluoroethyl group and the like. "Alkoxy group" means an alkyl group of carbon linked to oxygen, wherein alkyl is as defined above. "Haloalkoxy group" means an alkoxy group containing 1 to 13 halogen atoms such as fluoro, chloro, bromo, and iodo, wherein alkoxy is as defined above, and the preferred haloalkoxy group is a fluoromethoxy group. , Trifluoromethoxy group, 1,2-dichloroethoxy group, 1,1-dichloroethoxy group, pentafluoroethoxy group and the like.

상기 화학식 1로 표시되는 5-(치환된알킬아미노메틸)아이속사졸계 화합물에 있어서, 바람직하기로는 상기 R¹은 디페닐메틸기, 디(p-클로로페닐)메틸기, 디(p-플루오로페닐)메틸기, 페닐기, m-시아노페닐기, m-플루오로페닐기, p-플루오로페닐기, m-클로로페닐기, p-클로로페닐기, 3,4-디클로로페닐기, 3,5-디클로로페닐기, m-메틸페닐기, p-메틸페닐기, 3,4-디메틸페닐기, 2,4-디메틸페닐기, m-메톡시페닐기, p-메톡시페닐기, 3,4-디메톡시페닐기, m-트리플루오로메틸페닐기, p-트리플루오로메틸페닐기, 또는 p-트리플루오로메톡시페닐기를 나타내고, 상기 R²는 수소원자를 나타내고, 상기 R³은 수소원자를 나타내고, 상기 R⁴는 수소원자, 아이속사졸-5-일메틸기, 3-메틸아이속사졸-5-일메틸기, 또는 3-아이소프로필아이속사졸-5-일메틸기를 나타내고, 상기 R⁵는 메틸기, 에틸기, 노말프로필기, 이소프로필기, 노말부틸기, 이소부틸기, tert-부틸기, 아마이드기, 메틸카복실레이트기, 또는 소듐카복실레이트기를 나타내는 화합물의 경우이다.In the 5- (substituted alkylaminomethyl) isoxazole compound represented by Chemical Formula 1, preferably, R ¹ is a diphenylmethyl group, a di ( p -chlorophenyl) methyl group, and a di ( p -fluorophenyl) Methyl group, phenyl group, m -cyanophenyl group, m -fluorophenyl group, p -fluorophenyl group, m -chlorophenyl group, p -chlorophenyl group, 3,4-dichlorophenyl group, 3,5-dichlorophenyl group, m -methylphenyl group , p -methylphenyl group, 3,4-dimethylphenyl group, 2,4-dimethylphenyl group, m -methoxyphenyl group, p -methoxyphenyl group, 3,4-dimethoxyphenyl group, m -trifluoromethylphenyl group, p- Trifluoromethylphenyl group or p -trifluoromethoxyphenyl group, R ² represents a hydrogen atom, R ³ represents a hydrogen atom, R ⁴ represents a hydrogen atom, isoxazol-5-ylmethyl group , 3-methylisoxazol-5-ylmethyl group, or 3-isopropylisoxazol-5-ylmethyl group, R ⁵ is methyl, ethyl, n-propyl, isopropyl, n-butyl group, isobutyl group, tert - in the case of a compound represents a butyl group, an amide group, a methyl carboxylate group, or sodium carboxylate.

특히 바람직한 상기 화학식 1로 표시되는 5-(치환된알킬아미노메틸)아이속사졸계 화합물을 예시하면 하기와 같다.Particularly preferred 5- (substituted alkylaminomethyl) isoxazole-based compound represented by Formula 1 is as follows.

화합물 1 : [2-[4-(3-클로로페닐)-피페라진-1-일]-에틸]-(3-메틸아이속사졸-5-일메틸)아민 Compound 1: [2- [4- (3-chlorophenyl) -piperazin-1-yl] -ethyl]-(3-methylisoxazol-5-ylmethyl) amine

화합물 2 : [2-[4-(3-클로로페닐)-피페라진-1-일]-에틸]-(3-에틸아이속사졸-5-일메틸)아민 Compound 2: [2- [4- (3-chlorophenyl) -piperazin-1-yl] -ethyl]-(3-ethylisoxazol-5-ylmethyl) amine

화합물 3 : [2-[4-(3-클로로페닐)-피페라진-1-일]-에틸]-(3-아이소프로필아이속사졸-5-일메틸)아민Compound 3: [2- [4- (3-chlorophenyl) -piperazin-1-yl] -ethyl]-(3-isopropylisoxazol-5-ylmethyl) amine

화합물 4 : [2-[4-(4-클로로페닐)-피페라진-1-일]-에틸]-(3-메틸아이속사졸-5-일메틸)아민 Compound 4: [2- [4- (4-chlorophenyl) -piperazin-1-yl] -ethyl]-(3-methylisoxazol-5-ylmethyl) amine

화합물 5 : [2-[4-(4-클로로페닐)-피페라진-1-일]-에틸]-(3-에틸아이속사졸-5-일메틸)아민 Compound 5: [2- [4- (4-chlorophenyl) -piperazin-1-yl] -ethyl]-(3-ethylisoxazol-5-ylmethyl) amine

화합물 6 : [2-[4-(4-클로로페닐)-피페라진-1-일]-에틸]-(3-아이소프로필아이속사졸-5-일메틸)아민Compound 6: [2- [4- (4-chlorophenyl) -piperazin-1-yl] -ethyl]-(3-isopropylisoxazol-5-ylmethyl) amine

화합물 7 : [2-(4-벤즈하이드릴-피페라진-1-일)에틸]-(3-메틸아이속사졸-5-일메틸)아민 Compound 7: [2- (4-benzhydryl-piperazin-1-yl) ethyl]-(3-methylisoxazol-5-ylmethyl) amine

화합물 8 : [2-(4-벤즈하이드릴-피페라진-1-일)에틸]-(3-에틸아이속사졸-5-일메틸)아민 Compound 8: [2- (4-benzhydryl-piperazin-1-yl) ethyl]-(3-ethylisoxazol-5-ylmethyl) amine

화합물 9 : [2-(4-벤즈하이드릴-피페라진-1-일)에틸]-(3-아이소프로필아이속사졸-5-일메틸)아민Compound 9: [2- (4-benzhydryl-piperazin-1-yl) ethyl]-(3-isopropylisoxazol-5-ylmethyl) amine

화합물 10 : (3-메틸아이속사졸-5-일메틸)-[2-(4-페닐피페라진-1-일)에틸]아민 Compound 10: (3-methylisoxazol-5-ylmethyl)-[2- (4-phenylpiperazin-1-yl) ethyl] amine

화합물 11 : (3-에틸아이속사졸-5-일메틸)-[2-(4-페닐피페라진-1-일)에틸]아민 Compound 11: (3-ethylisoxazol-5-ylmethyl)-[2- (4-phenylpiperazin-1-yl) ethyl] amine

화합물 12 : (3-아이소프로필아이속사졸-5-일메틸)-[2-(4-페닐피페라진-1-일)에틸]아민 Compound 12: (3-isopropylisoxazol-5-ylmethyl)-[2- (4-phenylpiperazin-1-yl) ethyl] amine

화합물 13 : N-((3-아이소프로필아이속사졸-5-일)메틸)-N-메틸-2-(4-(3-(트리플루오로메틸)페닐)피페라진-1-일)에탄아민Compound 13: N -((3-isopropylisoxazol-5-yl) methyl) -N -methyl-2- (4- (3- (trifluoromethyl) phenyl) piperazin-1-yl) ethane Amine

화합물 14 : 2-(4-(2,4-디메틸페닐)피페라진-1-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)에탄아민Compound 14: 2- (4- (2,4-dimethylphenyl) piperazin-1-yl) -N -((3-isopropylisoxazol-5-yl) methyl) ethanamine

화합물 15 : 2-(4-(2,4-디메틸페닐)피페라진-1-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)-N-메틸에탄아민Compound 15: 2- (4- (2,4-dimethylphenyl) piperazin-1-yl) -N -((3-isopropylisoxazol-5-yl) methyl) -N -methylethanamine

화합물 16 : 2-(4-(4-클로로페닐)피페라진-1-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)-N-메틸에탄아민Compound 16: 2- (4- (4-chlorophenyl) piperazin-1-yl) -N -((3-isopropylisoxazol-5-yl) methyl) -N -methylethanamine

화합물 17 : N-((3-tert-부틸아이속사졸-5-일)메틸)-2-(4-(4-클로로페닐)피페라진-1-일)에탄아민Compound 17: N -((3- tert - butylisoxazol -5-yl) methyl) -2- (4- (4-chlorophenyl) piperazin-1-yl) ethanamine

화합물 18 : N-((3-tert-부틸아이속사졸-5-일)메틸)-2-(4-(4-클로로페닐)피페라진-1-일)-N-메틸에탄아민Compound 18: N -((3- tert - butylisoxazol -5-yl) methyl) -2- (4- (4-chlorophenyl) piperazin-1-yl) -N -methylethanamine

화합물 19 : N-((3-tert-부틸아이속사졸-5-일)메틸)-2-(4-(3-(트리플루오로메틸)페닐)피페라진-1-일)에탄아민Compound 19: N -((3- tert - butylisoxazol -5-yl) methyl) -2- (4- (3- (trifluoromethyl) phenyl) piperazin-1-yl) ethanamine

화합물 20 : N-((3-tert-부틸아이속사졸-5-일)메틸)-N-메틸-2-(4-(3-(트리플루오로메틸)페닐)피페라진-1-일)에탄아민Compound 20: N -((3- tert - butylisoxazol -5-yl) methyl) -N -methyl-2- (4- (3- (trifluoromethyl) phenyl) piperazin-1-yl) Ethanamine

화합물 21 : N-((3-tert-부틸아이속사졸-5-일)메틸)-2-(4-(2,4-디메틸페닐)피페라진-1-일)에탄아민Compound 21: N -((3- tert - butylisoxazol -5-yl) methyl) -2- (4- (2,4-dimethylphenyl) piperazin-1-yl) ethanamine

화합물 22 : 2-(4-(4-클로로페닐)피페라진-1-일)-N-((3-아이소부틸아이속사졸-5-일)메틸)에탄아민Compound 22: 2- (4- (4-chlorophenyl) piperazin-1-yl) -N -((3-isobutylisoxazol-5-yl) methyl) ethanamine

화합물 23 : 2-(4-(4-클로로페닐)피페라진-1-일)-N-((3-아이소부틸아이속사졸-5-일)메틸)-N-메틸에탄아민Compound 23: 2- (4- (4-chlorophenyl) piperazin-1-yl) -N -((3-isobutylisoxazol-5-yl) methyl) -N -methylethanamine

화합물 24 : N-((3-아이소부틸아이속사졸-5-일)메틸)-2-(4-(3-(트리플루오로메틸)페닐)피페라진-1-일) 에탄아민Compound 24: N -((3-isobutylisoxazol-5-yl) methyl) -2- (4- (3- (trifluoromethyl) phenyl) piperazin-1-yl) ethanamine

화합물 25 : N-((3-아이소부틸아이속사졸-5-일)메틸)-N-메틸-2-(4-(3-(트리플루오로메틸)페닐)피페라진-1-일)에탄아민Compound 25: N -((3-isobutylisoxazol-5-yl) methyl) -N -methyl-2- (4- (3- (trifluoromethyl) phenyl) piperazin-1-yl) ethane Amine

화합물 26 : N-(2-(4-(4-클로로페닐)피페라진-1-일)에틸)-N-((3-아이소프로필아이속사졸-5-일)메틸)프로판-2-아민Compound 26: N- (2- (4- (4-chlorophenyl) piperazin-1-yl) ethyl) -N -((3-isopropylisoxazol-5-yl) methyl) propan-2-amine

화합물 27 : N-(2-(4-(2,4-디메틸페닐)피페라진-1-일)에틸)-N-((3-아이소프로필아이속사졸-5-일)메틸)프로판-2-아민Compound 27: N- (2- (4- (2,4-dimethylphenyl) piperazin-1-yl) ethyl) -N -((3-isopropylisoxazol-5-yl) methyl) propane-2 -Amine

화합물 28 : 2-(4-(3,4-디메틸페닐)피페라진-1-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)에탄아민Compound 28: 2- (4- (3,4-dimethylphenyl) piperazin-1-yl) - N - ((3- isopropyl-isoxazol-5-yl) methyl) ethanamine

화합물 29 : 2-(4-(3,4-디메틸페닐)피페라진-1-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)-N-메틸에탄아민Compound 29: 2- (4- (3,4-dimethylphenyl) piperazin-1-yl) -N -((3-isopropylisoxazol-5-yl) methyl) -N -methylethanamine

화합물 30 : N-(2-(4-(3,4-디메틸페닐)피페라진-1-일)에틸)-N-((3-아이소프로필아이속사졸-5-일)메틸)프로판-2-아민Compound 30: N- (2- (4- (3,4-dimethylphenyl) piperazin-1-yl) ethyl) -N -((3-isopropylisoxazol-5-yl) methyl) propane-2 -Amine

화합물 31 : N-((3-아이소프로필아이속사졸-5-일)메틸)-N-(2-(4-(3-(트리플루오로메틸)페닐)피페라진-1-일)에틸)프로판-2-아민Compound 31: N - ((3-isopropyl-isoxazol-5-yl) methyl) - N - (ethyl-2- (4- (3- (trifluoromethyl) phenyl) piperazin-1-yl)) Propane-2-amine

화합물 32 : N-((3-tert-부틸아이속사졸-5-일)메틸)-2-(4-(3,4-디메틸페닐)피페라진-1-일)에탄아민Compound 32: N -((3- tert - butylisoxazol -5-yl) methyl) -2- (4- (3,4-dimethylphenyl) piperazin-1-yl) ethanamine

화합물 33 : N-((3-tert-부틸아이속사졸-5-일)메틸)-2-(4-(3,4-디메틸페닐)피페라진-1-일)-N-메틸에탄아민Compound 33: N -((3- tert - butylisoxazol -5-yl) methyl) -2- (4- (3,4-dimethylphenyl) piperazin-1-yl) -N -methylethanamine

화합물 34 : N-((3-tert-부틸아이속사졸-5-일)메틸)-2-(4-(2,4-디메틸페닐)피페라진-1-일)-N-메틸에탄아민Compound 34: N -((3- tert - butylisoxazol -5-yl) methyl) -2- (4- (2,4-dimethylphenyl) piperazin-1-yl) -N -methylethanamine

화합물 35 : N-((3-tert-부틸아이속사졸-5-일)메틸)-N-(2-(4-(3-(트리플루오로메틸)페닐)피페라진-1-일)에틸)프로판-2-아민Compound 35: N - ((3-tert - butyl-isoxazol-5-yl) methyl) - N - (2- (methyl) phenyl-4- (3- (trifluoromethyl) piperazin-1-yl) ethyl Propan-2-amine

화합물 36 : 2-(4-(2,4-디메틸페닐)피페라진-1-일)-N-((3-아이소부틸아이속사졸-5-일)메틸)에탄아민Compound 36: 2- (4- (2,4-dimethylphenyl) piperazin-1-yl) -N -((3-isobutylisoxazol-5-yl) methyl) ethanamine

화합물 37 : 2-(4-(3,4-디메틸페닐)피페라진-1-일)-N-((3-아이소부틸아이속사졸-5-일)메틸)에탄아민Compound 37: 2- (4- (3,4-dimethylphenyl) piperazin-1-yl) -N -((3-isobutylisoxazol-5-yl) methyl) ethanamine

화합물 38 : N-((3-아이소프로필아이속사졸-5-일)메틸)-2-(4-(3-트리플루오로메틸페닐)피페라진-1-일)에탄아민Compound 38: N -((3-isopropylisoxazol-5-yl) methyl) -2- (4- (3-trifluoromethylphenyl) piperazin-1-yl) ethanamine

화합물 39 : N-((3-아이소프로필아이속사졸-5-일)메틸)-2-(4-(4-메톡시페닐)피페라진-1-일)에탄아민Compound 39: N -((3-isopropylisoxazol-5-yl) methyl) -2- (4- (4-methoxyphenyl) piperazin-1-yl) ethanamine

화합물 40 : N-((3-아이소프로필아이속사졸-5-일)메틸)-2-(4-(4-메톡시페닐)피페라진-1-일)-N-메틸에탄아민Compound 40: N -((3-isopropylisoxazol-5-yl) methyl) -2- (4- (4-methoxyphenyl) piperazin-1-yl) -N -methylethanamine

화합물 41 : N-((3-아이소프로필아이속사졸-5-일)메틸)-2-(4-p-톨릴피페라진-1-일)에탄아민Compound 41: N -((3-isopropylisoxazol-5-yl) methyl) -2- (4-p-tolylpiperazin-1-yl) ethanamine

화합물 42 : 2-(4-(2,4-디메틸페닐)피페라진-1-일)-N-((3-아이소부틸아이속사졸-5-일)메틸)-N-메틸에Compound 42: 2- (4- (2,4-dimethylphenyl) piperazin-1-yl) -N -((3-isobutylisoxazol-5-yl) methyl) -N -methyl

화합물 43 : 2-(4-(3,4-디메틸페닐)피페라진-1-일)-N-((3-아이소부틸아이속사졸-5-일)메틸)-N-메틸에탄아민Compound 43: 2- (4- (3,4-dimethylphenyl) piperazin-1-yl) -N -((3-isobutylisoxazol-5-yl) methyl) -N -methylethanamine

화합물 44 : 2-(4-(3-클로로페닐)피페라진-1-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)-N-메틸에탄아민Compound 44: 2- (4- (3-chlorophenyl) piperazin-1-yl) -N -((3-isopropylisoxazol-5-yl) methyl) -N -methylethanamine

화합물 45 : N-((3-아이소프로필아이속사졸-5-일)메틸)-2-(4-(4-(트리플루오로메틸)페닐)피페라진-1-일)에탄아민Compound 45: N -((3-isopropylisoxazol-5-yl) methyl) -2- (4- (4- (trifluoromethyl) phenyl) piperazin-1-yl) ethanamine

화합물 46 : N-((3-아이소프로필아이속사졸-5-일)메틸)-N-메틸-2-(4-(4-(트리플루오로메틸)페닐)피페라진-1-일)에탄아민Compound 46: N -((3-isopropylisoxazol-5-yl) methyl) -N -methyl-2- (4- (4- (trifluoromethyl) phenyl) piperazin-1-yl) ethane Amine

화합물 47 : N-((3-아이소프로필아이속사졸-5-일)메틸)-2-(4-(3-메톡시페닐)피페라진-1-일)에탄아민Compound 47: N -((3-isopropylisoxazol-5-yl) methyl) -2- (4- (3-methoxyphenyl) piperazin-1-yl) ethanamine

화합물 48 : N-((3-아이소프로필아이속사졸-5-일)메틸)-2-(4-m-톨릴피페라진-1-일)에탄아민Compound 48: N -((3-isopropylisoxazol-5-yl) methyl) -2- (4- m -tolylpiperazin-1-yl) ethanamine

화합물 49 : N-((3-아이소프로필아이속사졸-5-일)메틸)-N-메틸-2-(4-p-톨릴피페라진-1-일)에탄아민Compound 49: N -((3-isopropylisoxazol-5-yl) methyl) -N -methyl-2- (4-p-tolylpiperazin-1-yl) ethanamine

화합물 50 : 2-(4-(4-플루오로페닐)피페라진-1-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)에탄아민Compound 50: 2- (4- (4-fluorophenyl) piperazin-1-yl) -N -((3-isopropylisoxazol-5-yl) methyl) ethanamine

화합물 51 : 2-(4-(4-플루오로페닐)피페라진-1-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)-N-메틸에탄아민Compound 51: 2- (4- (4-fluorophenyl) piperazin-1-yl) -N -((3-isopropylisoxazol-5-yl) methyl) -N -methylethanamine

화합물 52 : 2-(4-(3,4-디클로로페닐)피페라진-1-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)에탄아민Compound 52: 2- (4- (3,4-dichlorophenyl) piperazin-1-yl) -N -((3-isopropylisoxazol-5-yl) methyl) ethanamine

화합물 53 : 2-(4-(3,4-디클로로페닐)피페라진-1-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)-N-메틸에탄아민Compound 53: 2- (4- (3,4-dichlorophenyl) piperazin-1-yl) -N -((3-isopropylisoxazol-5-yl) methyl) -N -methylethanamine

화합물 54 : N-((3-아이소프로필아이속사졸-5-일)메틸)-2-(4-(3-메톡시페닐)피페라진-1-일)-N-메틸에탄아민Compound 54: N -((3-isopropylisoxazol-5-yl) methyl) -2- (4- (3-methoxyphenyl) piperazin-1-yl) -N -methylethanamine

화합물 55 : N-((3-아이소프로필아이속사졸-5-일)메틸)-N-메틸-2-(4-m-톨릴피페라진-1-일)에탄아민Compound 55: N - ((3- isopropyl-isoxazol-5-yl) methyl) - N - methyl -2- (4- m - tolyl-l-yl) ethanamine

화합물 56 : 3-(4-(3-클로로페닐)피페라진-1-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)프로판-1-아민Compound 56: 3- (4- (3-chlorophenyl) piperazin-1-yl) -N -((3-isopropylisoxazol-5-yl) methyl) propan-1-amine

화합물 57 : 3-(4-(3-클로로페닐)피페라진-1-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)-N-메틸프로판-1-아민Compound 57: 3- (4- (3-chlorophenyl) piperazin-1-yl) -N -((3-isopropylisoxazol-5-yl) methyl) -N -methylpropan-1-amine

화합물 58 : 3-(4-(3,4-디메틸페닐)피페라진-1-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)프로판-1-아민Compound 58: 3- (4- (3,4-dimethylphenyl) piperazin-1-yl) -N -((3-isopropylisoxazol-5-yl) methyl) propan-1-amine

화합물 59 : 3-(4-(3,4-디메틸페닐)피페라진-1-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)-N-메틸프로판-1-아민Compound 59: 3- (4- (3,4-dimethylphenyl) piperazin-1-yl) -N -((3-isopropylisoxazol-5-yl) methyl) -N -methylpropane-1- Amine

화합물 60 : N-((3-아이소프로필아이속사졸-5-일)메틸)-3-(4-p-톨릴피페라진-1-일)프로판-1-아민Compound 60: N -((3-isopropylisoxazol-5-yl) methyl) -3- (4-p-tolylpiperazin-1-yl) propan-1-amine

화합물 61 : N-((3-아이소프로필아이속사졸-5-일)메틸)-N-메틸-3-(4-p-톨릴피페라진-1-일)프로판-1-아민Compound 61: N -((3-isopropylisoxazol-5-yl) methyl) -N -methyl-3- (4-p-tolylpiperazin-1-yl) propan-1-amine

3-(4-(4-플루오로페닐)피페라진-1-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)프로판-1-아민3- (4- (4-fluorophenyl) piperazin-1-yl) -N -((3-isopropylisoxazol-5-yl) methyl) propan-1-amine

화합물 63 : 3-(4-(4-플루오로페닐)피페라진-1-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)-N-메틸프로판-1-아민Compound 63: 3- (4- (4-fluorophenyl) piperazin-1-yl) -N -((3-isopropylisoxazol-5-yl) methyl) -N -methylpropan-1-amine

화합물 64 : N-((3-아이소프로필아이속사졸-5-일)메틸)-3-(4-(4-메톡시페닐)피페라진-1-일)프로판-1-아민Compound 64: N -((3-isopropylisoxazol-5-yl) methyl) -3- (4- (4-methoxyphenyl) piperazin-1-yl) propan-1-amine

화합물 65 : N-((3-아이소프로필아이속사졸-5-일)메틸)-3-(4-(4-메톡시페닐)피페라진-1-일)-N-메틸프로판-1-아민Compound 65: N -((3-isopropylisoxazol-5-yl) methyl) -3- (4- (4-methoxyphenyl) piperazin-1-yl) -N -methylpropan-1-amine

화합물 66 : 2-(4-(3,4-디메톡시페닐)피페라진-1-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)에탄아민Compound 66: 2- (4- (3,4-dimethoxyphenyl) piperazin-1-yl) -N -((3-isopropylisoxazol-5-yl) methyl) ethanamine

화합물 67 : 3-(4-(4-클로로페닐)피페라진-1-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)프로판-1-아민Compound 67: 3- (4- (4-chlorophenyl) piperazin-1-yl) -N -((3-isopropylisoxazol-5-yl) methyl) propan-1-amine

화합물 68 : 3-(4-(4-클로로페닐)피페라진-1-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)-N-메틸프로판-1-아민Compound 68: 3- (4- (4-chlorophenyl) piperazin-1-yl) -N -((3-isopropylisoxazol-5-yl) methyl) -N -methylpropan-1-amine

화합물 69 : N-((3-아이소프로필아이속사졸-5-일)메틸)-3-(4-(3-메톡시페닐)피페라진-1-일)프로판-1-아민Compound 69: N -((3-isopropylisoxazol-5-yl) methyl) -3- (4- (3-methoxyphenyl) piperazin-1-yl) propan-1-amine

화합물 70 : N-((3-아이소프로필아이속사졸-5-일)메틸)-3-(4-(3-메톡시페닐)피페라진-1-일)-N-메틸프로판-1-아민Compound 70: N -((3-isopropylisoxazol-5-yl) methyl) -3- (4- (3-methoxyphenyl) piperazin-1-yl) -N -methylpropan-1-amine

화합물 71 : N-((3-아이소프로필아이속사졸-5-일)메틸)-3-(4-m-톨릴피페라진-1-일)프로판-1-아민Compound 71: N -((3-isopropylisoxazol-5-yl) methyl) -3- (4- m -tolylpiperazin-1-yl) propan-1-amine

화합물 72 : N-((3-아이소프로필아이속사졸-5-일)메틸)-N-메틸-3-(4-m-톨릴피페라진-1-일)프로판-1-아민Compound 72: N -((3-isopropylisoxazol-5-yl) methyl) -N -methyl-3- (4- m -tolylpiperazin-1-yl) propan-1-amine

화합물 73 : 3-(4-(3,4-디클로로페닐)피페라진-1-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)프로판-1-아민Compound 73: 3- (4- (3,4-dichlorophenyl) piperazin-1-yl) -N -((3-isopropylisoxazol-5-yl) methyl) propan-1-amine

화합물 74 : 3-(4-(3,4-디클로로페닐)피페라진-1-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)-N-메틸프로판-1-아민Compound 74: 3- (4- (3,4-dichlorophenyl) piperazin-1-yl) -N -((3-isopropylisoxazol-5-yl) methyl) -N -methylpropane-1- Amine

화합물 75 : 3-(4-(3,4-디메톡시페닐)피페라진-1-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)프로판-1-아민Compound 75: 3- (4- (3,4-dimethoxyphenyl) piperazin-1-yl) -N -((3-isopropylisoxazol-5-yl) methyl) propan-1-amine

화합물 76 : 2-(4-(4-클로로페닐)-2-메틸피페라진-1-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)에탄아민Compound 76: 2- (4- (4-chlorophenyl) -2-methylpiperazin-1-yl) - N - ((3- isopropyl-isoxazol-5-yl) methyl) ethanamine

화합물 77 : 2-(4-(3,4-디클로로페닐)-2-메틸피페라진-1-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)에탄아민Compound 77: 2- (4- (3,4-dichlorophenyl) -2-methylpiperazin-1-yl) -N -((3-isopropylisoxazol-5-yl) methyl) ethanamine

화합물 78 : N-((3-아이소프로필아이속사졸-5-일)메틸)-2-(4-(4-(트리플루오로메톡시)페닐)피페라진-1-일)에탄아민Compound 78: N -((3-isopropylisoxazol-5-yl) methyl) -2- (4- (4- (trifluoromethoxy) phenyl) piperazin-1-yl) ethanamine

화합물 79 : 2-(4-(3,5-디클로로페닐)피페라진-1-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)에탄아민Compound 79: 2- (4- (3,5-dichlorophenyl) piperazin-1-yl) -N -((3-isopropylisoxazol-5-yl) methyl) ethanamine

화합물 80 : 2-(1-(4-플루오로페닐)피페리딘-4-일)-N-((3-이소프로필아이속사졸-5-일)메틸)에탄아민Compound 80: 2- (1- (4-fluorophenyl) piperidin-4-yl) -N -((3-isopropylisoxazol-5-yl) methyl) ethanamine

화합물 81 : 2-(1-(4-클로로페닐)피페리딘-4-일)-N-((3-이소프로필아이속사졸-5-일)메틸)에탄아민Compound 81: 2- (1- (4-chlorophenyl) piperidin-4-yl) -N -((3-isopropylisoxazol-5-yl) methyl) ethanamine

화합물 82 : N-((3-tert-부틸아이속사졸-5-일)메틸)-2-(1-(4-클로로페닐)피페리딘-4-일)에탄아민Compound 82: N -((3- tert - butylisoxazol -5-yl) methyl) -2- (1- (4-chlorophenyl) piperidin-4-yl) ethanamine

화합물 83 : N-((3-tert-부틸아이속사졸-5-일)메틸)-2-(1-(4-플루오로페닐)피페리딘-4-일)에탄아민Compound 83: N -((3- tert - butylisoxazol -5-yl) methyl) -2- (1- (4-fluorophenyl) piperidin-4-yl) ethanamine

화합물 84 : N-((3-이소프로필아이속사졸-5-일)메틸)-2-(1-(4-(트리플루오로메틸)페닐)피페리딘-4-일)에탄아민Compound 84: N -((3-isopropylisoxazol-5-yl) methyl) -2- (1- (4- (trifluoromethyl) phenyl) piperidin-4-yl) ethanamine

화합물 85 : N-((3-이소프로필아이속사졸-5-일)메틸)-2-(1-p-톨릴피페리딘-4-일)에탄아민 Compound 85: N -((3-isopropylisoxazol-5-yl) methyl) -2- (1-p-tolylpiperidin-4-yl) ethanamine

화합물 86 : 2-(1-(3,4-디클로로페닐)피페리딘-4-일)-N-((3-이소프로필아이속사졸-5-일)메틸)에탄아민 Compound 86: 2- (1- (3,4-dichlorophenyl) piperidin-4-yl) -N -((3-isopropylisoxazol-5-yl) methyl) ethanamine

화합물 87 : N-((3-이소프로필아이속사졸-5-일)메틸)-2-(1-(4-메톡시페닐)피페리딘-4-일)에탄아민Compound 87: N -((3-isopropylisoxazol-5-yl) methyl) -2- (1- (4-methoxyphenyl) piperidin-4-yl) ethanamine

화합물 88 : 2-(1-(3-클로로페닐)피페리딘-4-일)-N-((3-이소프로필아이속사졸-5-일)메틸)에탄아민Compound 88: 2- (1- (3-chlorophenyl) piperidin-4-yl) -N -((3-isopropylisoxazol-5-yl) methyl) ethanamine

화합물 89 : 2-(1-(3-플루오로페닐)피페리딘-4-일)-N-((3-이소프로필아이속사졸-5-일)메틸)에탄아민Compound 89: 2- (1- (3-fluorophenyl) piperidin-4-yl) -N -((3-isopropylisoxazol-5-yl) methyl) ethanamine

화합물 90 : N-((3-이소프로필아이속사졸-5-일)메틸)-2-(1-m-톨릴피페리딘-4-일)에탄아민Compound 90: N -((3-isopropylisoxazol-5-yl) methyl) -2- (1- m -tolylpiperidin-4-yl) ethanamine

화합물 91 : N-((3-이소프로필아이속사졸-5-일)메틸)-2-(1-(3-(트리플루오로메틸)페닐)피페리딘-4-일)에탄아민Compound 91: N -((3-isopropylisoxazol-5-yl) methyl) -2- (1- (3- (trifluoromethyl) phenyl) piperidin-4-yl) ethanamine

화합물 92 : 2-(1-(2-((3-아이소프로필아이속사졸-5-일)메틸아미노)에틸)-1,2,3,6-테트라하이드로피리딘-4-일)벤조나이트릴Compound 92: 2- (1- (2-((3-isopropylisoxazol-5-yl) methylamino) ethyl) -1,2,3,6-tetrahydropyridin-4-yl) benzonitrile

화합물 93 : N-((3-아이소프로필아이속사졸-5-일)메틸)-2-(4-페닐-1,2,3,6-테트라하이드로피리딘-4-일)에탄아민Compound 93: N -((3-isopropylisoxazol-5-yl) methyl) -2- (4-phenyl-1,2,3,6-tetrahydropyridin-4-yl) ethanamine

화합물 94 : 2-(4-(4-클로로페닐)-1,2,3,6-테트라하이드로피리딘-4-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)에탄아민Compound 94: 2- (4- (4-chlorophenyl) -1,2,3,6-tetrahydropyridin-4-yl) -N -((3-isopropylisoxazol-5-yl) methyl) Ethanamine

화합물 95 : 3-(1-(2-((3-아이소프로필아이속사졸-5-일)메틸아미노)에틸)-1,2,3,6-테트라하이드로피리딘-4-일)벤조나이트릴 Compound 95: 3- (1- (2-((3-isopropylisoxazol-5-yl) methylamino) ethyl) -1,2,3,6-tetrahydropyridin-4-yl) benzonitrile

화합물 96 : N-((3-아이소프로필아이속사졸-5-일)메틸)-2-(4-(4-메톡시페닐)-1,2,3,6-테트라하이드로피리딘-4-일)에탄아민Compound 96: N -((3-isopropylisoxazol-5-yl) methyl) -2- (4- (4-methoxyphenyl) -1,2,3,6-tetrahydropyridin-4-yl Ethanamine

화합물 97 : N,N-비스((3-아이소프로필아이속사졸-5-일)메틸)-2-(4-o-톨릴-1,2,3,6-테트라하이드로피리딘-4-일)에탄아민Compound 97: N , N -bis ((3-isopropylisoxazol-5-yl) methyl) -2- (4- o -tolyl-1,2,3,6-tetrahydropyridin-4-yl) Ethanamine

화합물 98 : 2-(4-(3,4-다이클로로페닐)-1,2,3,6-테트라하이드로피리딘-4-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)에탄아민Compound 98: 2- (4- (3,4-dichlorophenyl) -1,2,3,6-tetrahydropyridin-4-yl) -N -((3-isopropylisoxazol-5-yl ) Methyl) ethanamine

화합물 99 : 2-(4-(3,4-다이클로로페닐)-1,2,3,6-테트라하이드로피리딘-4-일)-N,N-비스((3-아이소프로필아이속사졸-5-일)메틸)에탄아민Compound 99: 2- (4- (3,4-dichlorophenyl) -1,2,3,6-tetrahydropyridin-4-yl) -N , N -bis ((3-isopropylisoxazole- 5-yl) methyl) ethanamine

화합물 100 : 2-(4-(3,4-다이클로로페닐)피페리딘-1-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)에탄아민Compound 100: 2- (4- (3,4-dichlorophenyl) piperidin-1-yl) -N -((3-isopropylisoxazol-5-yl) methyl) ethanamine

화합물 101 : N-((3-아이소프로필아이속사졸-5-일)메틸)-2-(4-페닐피페리딘-1-일)에탄아민Compound 101: N -((3-isopropylisoxazol-5-yl) methyl) -2- (4-phenylpiperidin-1-yl) ethanamine

화합물 102 : 메틸 5-((2-(4-페닐피페라진-1-일)에틸아미노)메틸)아이속사졸-3-카복실레이트Compound 102: Methyl 5-((2- (4-phenylpiperazin-1-yl) ethylamino) methyl) isoxazole-3-carboxylate

화합물 103 : 에틸 5-((2-(4-페닐피페라진-1-일)에틸아미노)메틸)아이속사졸-3-카복실레이트Compound 103: ethyl 5-((2- (4-phenylpiperazin-1-yl) ethylamino) methyl) isoxazole-3-carboxylate

화합물 104 : 에틸 5-((2-(4-페닐피페라진-1-일)에틸아미노)메틸)아이속사졸-3-카복실레이트 염산염Compound 104: Ethyl 5-((2- (4-phenylpiperazin-1-yl) ethylamino) methyl) isoxazole-3-carboxylate hydrochloride

화합물 105 : 소듐 5-((2-(4-페닐피페라진-1-일)에틸아미노)메틸)아이속사졸-3-카복실레이트Compound 105: Sodium 5-((2- (4-phenylpiperazin-1-yl) ethylamino) methyl) isoxazole-3-carboxylate

화합물 106 : 에틸 5-((2-(4-(비스(4-플루오로페닐)메틸)피페라진-1-일)에틸아미노)메틸)아이속사졸-3-카복실레이트Compound 106: Ethyl 5-((2- (4- (bis (4-fluorophenyl) methyl) piperazin-1-yl) ethylamino) methyl) isoxazole-3-carboxylate

화합물 107 : 소듐 5-((2-(4-(비스(4-플루오로페닐)메틸)피페라진-1-일)에틸아미노)메틸)아이속사졸-3-카복실레이트Compound 107: sodium 5-((2- (4- (bis (4-fluorophenyl) methyl) piperazin-1-yl) ethylamino) methyl) isoxazole-3-carboxylate

화합물 108 : 에틸 5-((2-(4-벤즈하이드릴피페라진-1-일)에틸아미노)메틸)아이속사졸-3-카복실레이트Compound 108: Ethyl 5-((2- (4-benzhydrylpiperazin-1-yl) ethylamino) methyl) isoxazole-3-carboxylate

화합물 109 : 소듐 5-((2-(4-벤즈하이드릴피페라진-1-일)에틸아미노)메틸)아이속사졸-3-카복실레이트Compound 109: sodium 5-((2- (4-benzhydrylpiperazin-1-yl) ethylamino) methyl) isoxazole-3-carboxylate

화합물 110 : 2-(4-벤즈하이드릴피페라진-1-일)-N-((3-메틸아이속사졸-5-일)메틸)에탄아민Compound 110: 2- (4-benzhydrylpiperazin-1-yl) -N -((3-methylisoxazol-5-yl) methyl) ethanamine

화합물 111 : 2-(4-(비스(4-플루오로페닐)메틸)피페라진-1-일)-N-((3-메틸아이속사졸-5-일)메틸)에탄아민Compound 111: 2- (4- (bis (4-fluorophenyl) methyl) piperazin-1-yl) -N -((3-methylisoxazol-5-yl) methyl) ethanamine

화합물 112 : 2-(4-(비스(4-클로로페닐)메틸)피페라진-1-일)-N-((3-메틸아이속사졸-5-일)메틸)에탄아민Compound 112: 2- (4- (bis (4-chlorophenyl) methyl) piperazin-1-yl) -N -((3-methylisoxazol-5-yl) methyl) ethanamine

화합물 113 : 에틸 5-((2-(4-(비스(4-클로로페닐)메틸)피페라진-1-일)에틸아미노)메틸)아이속사졸-3-카복실레이트 Compound 113: ethyl 5-((2- (4- (bis (4-chlorophenyl) methyl) piperazin-1-yl) ethylamino) methyl) isoxazole-3-carboxylate

화합물 114 : 5-((2-(4-(비스(4-플루오로페닐)메틸)피페라진-1-일)에틸아미노)메틸)아이속사졸-3-카복사마이드Compound 114: 5-((2- (4- (bis (4-fluorophenyl) methyl) piperazin-1-yl) ethylamino) methyl) isoxazole-3-carboxamide

화합물 115 : 5-((2-(4-(비스(4-플루오로페닐)메틸)피페라진-1-일)에틸아미노)메틸)-N-메틸아이속사졸-3-카복사마이드Compound 115: 5-((2- (4- (bis (4-fluorophenyl) methyl) piperazin-1-yl) ethylamino) methyl) -N -methylisoxazole-3-carboxamide

화합물 116 : 5-((2-(4-(비스(4-플루오로페닐)메틸)피페라진-1-일)에틸아미노)메틸)-N,N-디메틸아이속사졸-3-카복사마이드
Compound 116: 5-((2- (4- (bis (4-fluorophenyl) methyl) piperazin-1-yl) ethylamino) methyl) -N, N -dimethylisoxazole-3-carboxamide

한편, 본 발명은 상기 화학식 1로 표시되는 5-(치환된알킬아미노메틸)아이속사졸계 화합물의 제조방법을 포함하는 바, 본 발명에 따른 제조방법은 하기 반응식 1로 표시할 수 있다.On the other hand, the present invention includes a method for preparing a 5- (substituted alkylaminomethyl) isoxazole compound represented by the formula (1), the production method according to the invention can be represented by the following scheme 1.

[반응식 1] [Reaction Scheme 1]

상기 반응식 1에서, R¹,R², R³, R⁴, R⁵, n, X, 및 Y는 각각 상기 화학식 1에서 정의한 바와 같다. In Scheme 1, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , n, X, and Y are as defined in Formula 1, respectively.

상기 반응식 1에서 따르면, 상기 화학식 2 또는 화학식 5로 표시되는 아민화합물과 상기 화학식 3 또는 화학식 4로 표시되는 알데하이드 화합물을 환원성 아민화 반응하여, R⁴=수소 또는

인 상기 화학식 1로 표시되는 화합물을 제조할 수 있다. 또한 R⁴=수소인 상기 화학식 1로 표시되는 화합물을 알킬화 반응시켜 R⁴=

인 상기 화학식 1로 표시되는 화합물을 제조할 수 있다.According to Scheme 1, the amine compound represented by Formula 2 or Formula 5 and the aldehyde compound represented by Formula 3 or Formula 4 are subjected to reductive amination reaction, whereby R ⁴ = hydrogen or

Phosphorus can be prepared a compound represented by the formula (1). In addition, by alkylating the compound represented by Formula 1 wherein R ⁴ = hydrogen, R ⁴ =

Phosphorus can be prepared a compound represented by the formula (1).

상기 반응식 1에 따른 제조방법에서 수행하게 되는 환원성 아민화 반응은 분자체(molecular sieve, 4Å, 4?8 mesh)를 사용할 수 있으며, 출발물질의 반응성이 떨어지는 경우에는 반응 중에 첨가제로 빙초산 1 내지 3 당량을 첨가할 수도 있다. 또한, 아민과 알데하이드간의 축합 반응에 의해서 생성된 이민을 환원시키기 위하여 환원제를 사용할 수 있다. 이때 환원제로는 NaBH(OAc)₃, NaBH₃CN, NaBH₄ 등을 사용할 수 있으며, 환원제의 사용량은 반응성에 따라 다소 차이가 있는데 2 내지 10 당량 정도이며, 바람직하기로는 2 내지 3 당량 범위로 사용한다. 본 발명의 환원성 아민화 반응에서 사용 가능한 반응용매로는 통상의 유기용매를 사용할 수 있으며, 구체적으로는 테트라하이드로퓨란, 1,2-디클로로에탄, 아세토니트릴, 메틸렌클로라이드, 메탄올 등이며, 본 발명의 실시예에서는 메탄올을 주로 사용하였다. 반응온도는 실온 주변의 온도를 유지하더라도 원활하게 진행될 수 있으며, 구체적으로는 10 내지 40℃ 온도범위, 바람직하기로는 20 내지 30℃ 온도범위를 유지하는 것이다. 반응 시간은 3 내지 24 시간 정도이며, 바람직하게 6 내지 12 시간이 적당하다. 반응의 진행정도는 박층 크로마토그래피(TLC)를 사용하여 추적한다. 반응이 완결된 후, 포화 NaHCO₃수용액을 가하고 적당한 유기용매로 반응물을 추출하며, 추출용매로는 에테르, 메틸렌클로라이드, 에틸 아세테이트를 사용할 수 있으며, 가장 적합한 추출용매는 메틸렌클로라이드이다. Reducing amination reaction to be carried out in the production method according to Scheme 1 may use a molecular sieve (molecular sieve, 4 Å, 4 ~ 8 mesh), when the reactivity of the starting material is less than 1 to 3 glacial acetic acid as an additive during the reaction Equivalent weight may be added. In addition, a reducing agent may be used to reduce the imine produced by the condensation reaction between the amine and the aldehyde. In this case, as the reducing agent, NaBH (OAc) ₃ , NaBH ₃ CN, NaBH _4, etc. may be used. The amount of the reducing agent may vary depending on the reactivity, but may be 2 to 10 equivalents, preferably 2 to 3 equivalents. do. As a reaction solvent usable in the reductive amination reaction of the present invention, a conventional organic solvent may be used, and specifically, tetrahydrofuran, 1,2-dichloroethane, acetonitrile, methylene chloride, methanol, and the like may be used. In the examples, methanol was mainly used. The reaction temperature can proceed smoothly even if the temperature around the room temperature is maintained, specifically, the temperature range of 10 to 40 ° C, preferably 20 to 30 ° C. The reaction time is about 3 to 24 hours, preferably 6 to 12 hours. The progress of the reaction is tracked using thin layer chromatography (TLC). After completion of the reaction, saturated NaHCO ₃ aqueous solution is added and the reaction mixture is extracted with a suitable organic solvent. The extraction solvent may be ether, methylene chloride, ethyl acetate, and the most suitable extraction solvent is methylene chloride.

또한 R⁴=

인 상기 화학식 1로 표시되는 화합물은, R⁴=H인 상기 화학식 1로 표시되는 화합물을 적절한 알데하이드 화합물 또는 케톤 화합물과 알킬화 반응시켜 제조할 수 있다. 상기 알킬화 반응은 환원화 알킬반응을 통해 이루어진다. 이때 환원제로는 NaBH(OAc)₃, NaBH₃CN, NaBH₄ 등을 사용할 수 있으며, 환원제의 사용량은 반응성에 따라 다소 차이가 있는데 2 내지 10 당량 정도이며, 바람직하기로는 2 내지 3 당량 범위로 사용한다. 본 발명의 환원성 아민화 반응에서 사용 가능한 반응용매로는 통상의 유기용매를 사용할 수 있으며, 구체적으로는 테트라하이드로퓨란, 1,2-디클로로에탄, 아세토니트릴, 메틸렌클로라이드, 메탄올 등이며, 본 발명의 실시예에서는 메탄올을 주로 사용하였다. 반응온도는 실온 주변의 온도를 유지하더라도 원활하게 진행될 수 있으며, 구체적으로는 10 내지 40℃ 온도범위, 바람직하기로는 20 내지 30℃ 온도범위를 유지하는 것이다. 반응 시간은 3 내지 24 시간 정도이며, 바람직하게 6 내지 12 시간이 적당하다. 반응의 진행정도는 박층 크로마토그래피(TLC)를 사용하여 추적한다. 반응이 완결된 후, 포화 NaHCO₃수용액을 가하고 적당한 유기용매로 반응물을 추출하며, 추출용매로는 에테르, 메틸렌클로라이드, 에틸 아세테이트를 사용할 수 있으며, 가장 적합한 추출용매는 메틸렌클로라이드이다. R ⁴ =

The compound represented by Chemical Formula 1 may be prepared by alkylating the compound represented by Chemical Formula 1, wherein R ⁴ = H, with an appropriate aldehyde compound or ketone compound. The alkylation reaction is carried out through a reduced alkylation reaction. In this case, as the reducing agent, NaBH (OAc) ₃ , NaBH ₃ CN, NaBH _4, etc. may be used. The amount of the reducing agent may vary depending on the reactivity, but may be 2 to 10 equivalents, preferably 2 to 3 equivalents. do. As a reaction solvent usable in the reductive amination reaction of the present invention, a conventional organic solvent may be used, and specifically, tetrahydrofuran, 1,2-dichloroethane, acetonitrile, methylene chloride, methanol, and the like may be used. In the examples, methanol was mainly used. The reaction temperature can proceed smoothly even if the temperature around the room temperature is maintained, specifically, the temperature range of 10 to 40 ° C, preferably 20 to 30 ° C. The reaction time is about 3 to 24 hours, preferably 6 to 12 hours. The progress of the reaction is tracked using thin layer chromatography (TLC). After completion of the reaction, saturated NaHCO ₃ aqueous solution is added and the reaction mixture is extracted with a suitable organic solvent. The extraction solvent may be ether, methylene chloride, ethyl acetate, and the most suitable extraction solvent is methylene chloride.

또한, 상기 화학식 1로 표시되는 화합물의 약제학적으로 허용 가능한 염의 제조방법은 공지된 문헌에 따른 통상적인 합성방법에 의하여 쉽게 제조될 수 있으며, 별다른 정제과정 없이도 순수하게 분리해 낼 수 있다. 다음에서는 염산염의 제조과정을 중심으로 상기 화학식 1로 표시되는 화합물의 약제학적으로 허용 가능한 염의 제조방법을 설명하고자 한다. 즉, 상기한 추출용매를 건조하고 증발시킨 다음, 잔여물을 에테르 소량에 녹이고, 여기에 염화수소의 에테르 용액을 약 1 내지 10 당량 정도 가하면 원하는 목표화합물의 염산염이 고체 형태로 생성된다. 염화수소 용액을 제조하는데 사용 할 수 있는 유기용매는 클로로포름, 메틸렌클로라이드, 에테르, 메탄올, 에틸 아세테이트 또는 이들의 혼합용매를 사용할 수 있는데, 바람직하게는 에테르가 유용하다. 이때, 고체 형태로 얻어진 생성물은 원심 분리기나 간단한 솜을 사용한 용매 제거 장치를 사용하여 분리할 수 있다. 고체를 2 내지 3회에 걸쳐 디에틸 에테르로 씻어 준 다음 잘 건조시키면 높은 순도의 염산염이 얻어지게 된다.In addition, a method for preparing a pharmaceutically acceptable salt of the compound represented by Chemical Formula 1 may be easily prepared by a conventional synthetic method according to known literature, and may be purely separated without any further purification. Next, a method for preparing a pharmaceutically acceptable salt of a compound represented by Chemical Formula 1 will be described based on the preparation of hydrochloride. That is, the extractant is dried and evaporated, and then the residue is dissolved in a small amount of ether, and about 1 to 10 equivalents of an ether solution of hydrogen chloride is added to form a hydrochloride of a desired target compound in solid form. The organic solvent that can be used to prepare the hydrogen chloride solution may be used chloroform, methylene chloride, ether, methanol, ethyl acetate or a mixed solvent thereof, preferably ether is useful. At this time, the product obtained in the solid form can be separated using a centrifuge or a solvent removal device using a simple cotton. The solids are washed 2-3 times with diethyl ether and then well dried to obtain high purity hydrochloride.

한편, 상기 반응식 1에 따른 제조방법에서 원료물질로 사용하는 상기 화학식 3으로 표시되는 알데하이드 화합물과 상기 화학식 5로 표시되는 아민 화합물은, 하기 반응식 2 에 나타낸 제조방법을 수행하여 합성할 수 있다.On the other hand, the aldehyde compound represented by the formula (3) and the amine compound represented by the formula (5) used as a raw material in the production method according to the reaction formula 1 can be synthesized by performing the production method shown in the reaction scheme 2.

[반응식 2]Scheme 2

상기 반응식 2에서, R⁵는 각각 화학식 1에서 정의한 바와 같다. In Scheme 2, R ⁵ is as defined in formula (1), respectively.

하기 반응식 2의 제조방법을 좀 더 구체적으로 설명하면 다음과 같다.Hereinafter, the preparation method of Scheme 2 will be described in more detail.

먼저 상기 화학식 6로 표시되는 알킬알데하이드과 하이드록실아민을 사용해서 상기 화학식 7로 표시되는 옥심화합물을 제조한다. 즉, 상기 화학식 6로 표시되는 알킬알데하이드를 에탄올과 물이 섞인 용매에 녹인 용액에 하이드록실아민 염산염과 Na₂CO₃와 같은 염기를 넣은 후 50 내지 100 ℃ 온도로 가열하는 조건에서 반응시킨다. 반응이 종료되면, 반응혼합물에 물을 첨가하여 희석시킨 후 에틸 아세테이트와 같은 유기용매로 추출하여 상기 화학식 7로 표시되는 옥심화합물을 얻는다.First, an oxime compound represented by Chemical Formula 7 is prepared using alkylaldehyde and hydroxylamine represented by Chemical Formula 6. That is, a base such as hydroxylamine hydrochloride and Na ₂ CO ₃ is added to a solution in which the alkyl aldehyde represented by Chemical Formula 6 is dissolved in a solvent mixed with ethanol and water, and then reacted under a condition of heating to a temperature of 50 to 100 ° C. When the reaction is completed, the reaction mixture is diluted with water and extracted with an organic solvent such as ethyl acetate to obtain an oxime compound represented by Chemical Formula 7.

그런 다음, 상기 화학식 7로 표시되는 옥심화합물을 프로파질알콜과 반응시켜 상기 화학식 8로 표시되는 아이속사졸알콜 제조한다. 즉, 상기 화학식 7로 표시되는 옥심화합물을 테트라하이드로퓨란과 같은 유기용매에 녹이고 온도를 -10 ℃ 내지 0 ℃ 근처로 낮추어 N-클로로숙신이미드를 천천히 가하여 1시간 정도 교반 반응시킨다. 그리고, 반응혼합물에 프로파질알콜과 트리에틸아민과 같은 유기염기를 가한 뒤 12시간정도 상온에서 교반 반응시킨다. 반응이 종료되면, 반응용액은 물과 포화 NaHCO₃ 수용액으로 묽힌 뒤 메틸렌클로라이드와 같은 유기용매로 추출하고 실리카젤 컬럼크로마토그래피로 정제하여 상기 화학식 8로 표시되는 아이속사졸을 얻는다.Then, an isoxazole alcohol represented by Chemical Formula 8 is prepared by reacting an oxime compound represented by Chemical Formula 7 with propazyl alcohol. That is, the oxime compound represented by the formula (7) is dissolved in an organic solvent such as tetrahydrofuran, the temperature is lowered to around -10 ° C to 0 ° C, and N -chlorosuccinimide is slowly added, followed by stirring for about 1 hour. Then, after adding an organic base such as propazyl alcohol and triethylamine to the reaction mixture, the reaction mixture is stirred at room temperature for about 12 hours. When the reaction is completed, the reaction solution is diluted with water and saturated NaHCO ₃ aqueous solution, extracted with an organic solvent such as methylene chloride and purified by silica gel column chromatography to obtain isoxazole represented by the formula (8).

그런 다음, 상기 화학식 8로 표시되는 아이속사졸알콜을 산화반응시켜 상기 화학식 3으로 표시되는 알데하이드 화합물을 제조한다. 상기 산화반응은 PCC를 이용한 산화반응 또는 스원 산화반응에 의해 수행할 수 있다. PCC 산화 반응은 0 ℃ 내지 50 ℃의 온도범위에서 수행한다.Then, an oxidized compound represented by Chemical Formula 3 is prepared by oxidizing the isoxazole alcohol represented by Chemical Formula 8. The oxidation reaction may be carried out by an oxidation reaction using a PCC or a one-way oxidation reaction. PCC oxidation reaction is carried out at a temperature range of 0 ℃ to 50 ℃.

또한, 상기 화학식 8로 표시되는 아이속사졸알콜을 아자이드로 전환시킨 후에 환원반응시켜 상기 화학식 5로 표시되는 아민화합물을 제조한다. 즉, 상기 화학식 8로 표시되는 아이속사졸알콜을 싸이오닐 클로라이드를 이용하여 알콜 그룹을 클로라이드로 치환하고, NaN₃와 같은 아자이드 무기물과 반응시켜 상기 화학식 9로 표시되는 아자이드 화합물을 제조한다. 그리고, 상기 화학식 9로 표시되는 아자이드 화합물은 트리페닐포스핀(Ph₃P)과 물을 이용하여 환원시켜 화학식 5로 표시되는 아민화합물을 얻는다. 환원반응은 상온 내지 90 ℃의 온도범위에서 수행한다.In addition, after converting the isoxazole alcohol represented by the formula (8) to azide and reduction reaction to prepare an amine compound represented by the formula (5). That is, the azide compound represented by the formula (9) is prepared by substituting the isoxazole alcohol represented by the formula (8) with a thionyl chloride to replace an alcohol group with a chloride, and reacting with an azide mineral such as NaN ₃ . The azide compound represented by Chemical Formula 9 is reduced using triphenylphosphine (Ph ₃ P) and water to obtain an amine compound represented by Chemical Formula 5. The reduction reaction is carried out in a temperature range of room temperature to 90 ℃.

또한, 상기 반응식 1에 따른 제조방법에서 원료물질로 사용하는 상기 화학식 2로 표시되는 아민 화합물과 상기 화학식 4로 표시되는 알데하이드 화합물은, 하기 반응식 3에 나타낸 제조방법을 수행하여 합성할 수 있다.In addition, the amine compound represented by Chemical Formula 2 and the aldehyde compound represented by Chemical Formula 4, which are used as raw materials in the production method according to Scheme 1, may be synthesized by performing the production method shown in Scheme 3 below.

[반응식 3]Scheme 3

상기 반응식 3에서, R¹, R², R³, n, 및 X는 각각 화학식 1에서 정의한 바와 같다.In Reaction Scheme 3, R ¹ , R ² , R ³ , n, and X are as defined in Formula 1, respectively.

상기 반응식 3에 의하면, 상기 화학식 10으로 표시되는 아릴화합물과 상기 화학식 11로 표시되는 피페라진을 축합시켜 상기 화학식 12로 표시되는 아릴 피페라진을 합성하였고, 브로모에틸 또는 브로모프로필 프탈라지논과 친핵성치환반응을 통해 상기 화학식 13으로 표시되는 화합물(

가 N- 임)을 생성하고, 하이드라진 등과 같은 탈프탈라지논 반응을 통해 상기 화학식 2로 표시되는 화합물을 얻을 수 있다. 또한 상기 화학식 14로 표시되는 피페라지닐에탄올을 이용하여 트리부틸실릴기(TBS) 등과 같은 실릴보호기를 도입하여 상기 화학식 15로 표시되는 화합물을 얻고, 아릴 보로닉 산을 이용하여 축합반응을 통해 상기 화학식 16으로 표시되는 화합물을 생성하고, 탈보호기 반응을 통해 상기 화학식 17로 표시되는 화합물을 얻은 후, 프탈이미드와 미쯔노부 반응을 통해 상기 화학식 13으로 표시되는 화합물 (

가 N- 임)을 얻은 후, 하이드라진 등과 같은 탈프탈라지논 반응을 통해 상기 화학식 2로 표시되는 화합물을 얻을 수 있다. 또한 상기 화학식 18로 표시되는 화합물을 아릴할라이드와 n-부틸리튬으로 형성된 아릴리튬을 이용하여 상기 화학식 19로 표시되는 화합물을 형성하고, 메실클로라이드와 유기염기를 이용하여 이중결합을 도입하여 상기 화학식 20으로 표시되는 화합물을 얻을 수 있다. 또한 상기 화학식 18로 표시되는 화합물을 트리부틸틴을 이용하여 상기 화학식 22로 표시되는 화합물을 얻고, 스틸리 축합반응을 통해 상기 화학식 20으로 표시되는 화합물을 얻을 수 있다. 또한 상기 화학식 18로 표시되는 화합물과 LDA, 1,1,1-트리플루오르-N-페틸-N-(트리플루오르메틸설포닐)메탄설폰아마이드를 이용하여 상기 화학식 23으로 표시되는 트리플레이트를 얻고, 상기 화학식 23으로 표시되는 화합물과 비스(피나콜라토)디보론, 팔라듐 촉매를 이용해서 상기 화학식 24로 표시되는 화합물을 형성한 후, 스즈끼 축합반응을 이용해서 상기 화학식 20으로 표시되는 화합물을 얻을 수 있다. 상기 화학식 20으로 표시되는 화합물은 수소화 반응을 통해 이중결합을 단일 결합으로 만들어서 상기 화합물 21로 표시되는 화합물을 얻을 수 있다. 상기 화학식 20 또는 21로 표시되는 화합물은 산 조건 하에서 탈보호 반응을 하여 상기 화학식 25로 표시되는 화합물을 얻고, 2-브로모에틸 또는 3-브로모프로필프탈이미드를 이용해서 상기 화학식 13으로 표시되는 화합물을 얻은 후, 하이드라진 등과 같은 탈프탈라지논 반응을 통해 상기 화학식 2로 표시되는 화합물을 얻을 수 있다.According to Scheme 3, the aryl compound represented by Chemical Formula 10 and the piperazine represented by Chemical Formula 11 were condensed to synthesize an aryl piperazine represented by Chemical Formula 12, and bromoethyl or bromopropyl phthalazinone. Compound represented by Formula 13 through the nucleophilic substitution reaction (

Is N-), and a compound represented by Chemical Formula 2 may be obtained through a dephthalazinone reaction such as hydrazine. In addition, by introducing a silyl protecting group such as tributylsilyl group (TBS) using the piperazinyl ethanol represented by the formula (14) to obtain a compound represented by the formula (15), through the condensation reaction using an aryl boronic acid After the compound represented by Chemical Formula 16 is produced and the compound represented by Chemical Formula 17 is obtained through a deprotection group reaction, the compound represented by Chemical Formula 13 through phthalimide and Mitsunobu reaction (

Is N-), and a compound represented by Chemical Formula 2 may be obtained through a dephthalazinone reaction such as hydrazine. In addition, the compound represented by the formula (18) using the aryl halide and aryl lithium formed of n-butyllithium to form a compound represented by the formula (19), and introduced a double bond using mesyl chloride and organic base to the formula (20) The compound represented by can be obtained. In addition, the compound represented by the formula (18) using tributyltin to obtain the compound represented by the formula (22), through the stiley condensation reaction can be obtained the compound represented by the formula (20). In addition, using the compound represented by the formula (18) and LDA, 1,1,1-trifluoro- N -pentyl- N- (trifluoromethylsulfonyl) methanesulfonamide to obtain a triflate represented by the formula (23), After the compound represented by the formula (23), the bis (pinacolato) diborone, and the palladium catalyst to form the compound represented by the formula (24), the compound represented by the formula (20) can be obtained using the Suzuki condensation reaction have. Compound represented by Formula 20 may be a compound represented by the compound 21 by making a double bond to a single bond through a hydrogenation reaction. The compound represented by Formula 20 or 21 is subjected to deprotection under acidic conditions to obtain a compound represented by Formula 25, and represented by Formula 13 using 2-bromoethyl or 3-bromopropylphthalimide After obtaining the compound, a compound represented by Chemical Formula 2 may be obtained through a dephthalazinone reaction such as hydrazine.

이상에서 설명한 바와 같은 제조방법을 통해 제조된 중간체 화합물 또는 목적 화합물은 통상의 정제방법을 수행하여 정제될 수 있다.The intermediate compound or the target compound prepared through the preparation method as described above may be purified by performing a conventional purification method.

한편, 본 발명은 상기 화학식 1로 표시되는 5-(치환된알킬아미노메틸)아이속사졸계 화합물 또는 이의 약제학적 허용 가능한 염을 질환의 예방 및 치료를 목적으로 유효성분으로 포함하는 약제조성물을 포함한다. On the other hand, the present invention comprises a pharmaceutical composition comprising a 5- (substituted alkylaminomethyl) isoxazole-based compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient for the purpose of preventing and treating diseases. .

본 발명의 약제조성물은 상기 화학식 1로 표시되는 5-(치환된알킬아미노메틸)아이속사졸계 화합물 또는 이의 약제학적 허용 가능한 염과 함께 기타 통상적인 담체, 보조제 또는 희석제 등을 포함시켜 통상의 제제화 방법으로 제형화하여 경구투여 또는 비경구투여에 적합한 형태로 제조될 수 있다. 경구투여의 경우에는 정제, 캡슐제, 용액, 시럽제, 현탁제 등의 형태로 제조될 수 있고, 비경구투여의 경우에는 복강, 피하, 근육, 경피에 대한 주사제의 형태로 제조될 수 있다.The pharmaceutical composition of the present invention can be prepared by incorporating 5- (substituted alkylaminomethyl) isoxazole-based compound represented by the above formula (1) or its pharmaceutically acceptable salt with other conventional carrier, adjuvant or diluent, And may be formulated into a form suitable for oral administration or parenteral administration. In the case of oral administration, it may be prepared in the form of tablets, capsules, solutions, syrups, suspensions, etc., and in the case of parenteral administration, it may be prepared in the form of injections for intraperitoneal, subcutaneous, muscle, and transdermal.

본 발명의 약제조성물의 T-형 칼슘채널 길항제로서 1일 유효투여량은 성인을 기준으로 0.01 내지 1000 mg/day이나, 투여용량은 환자의 나이, 몸무게, 성별, 투여형태, 건강상태 및 질환 정도에 따라 달라질 수 있으며, 의사 또는 약사의 판단에 따라 일정 시간간격으로 1일 1회 내지 수회로 분할 투여할 수도 있다. T-type calcium channel antagonist of the pharmaceutical composition of the present invention effective daily dose is 0.01 to 1000 mg / day based on the adult, but the dosage is the age, weight, sex, dosage form, health status and disease degree of the patient Depending on the judgment of the doctor or pharmacist may be divided doses once a day to several times a day.

따라서, 본 발명은 상기 화학식 1로 표시되는 5-(치환된알킬아미노메틸)아이속사졸계 화합물 또는 약제학적으로 허용 가능한 이들의 염 또는 이를 함유하는 약제학적 조성물을 질환의 예방 및 치료를 목적으로 사용하는 의약적 용도를 제공한다.Accordingly, the present invention uses the 5- (substituted alkylaminomethyl) isoxazole-based compound represented by the formula (1) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same for the purpose of preventing and treating diseases. It provides a medicinal use.

즉, 본 발명은 T-형 칼슘채널에 대한 활성을 가지므로, 뇌 질환, 암, 심장 질환의 예방 및 치료를 목적으로 또는 통증 완화를 목적으로 사용되는 의약적 용도를 포함한다.That is, the present invention has an activity against the T-type calcium channel, and thus includes a medicinal use used for the purpose of preventing and treating brain disease, cancer, and heart disease or for pain relief.

상기한 바와 같은 본 발명은 다음의 실시예 및 실험예를 통하여 보다 상세히 설명하겠는 바, 본 발명이 이들 실시예 및 실험예에 의해 한정되는 것은 아니다.
The present invention as described above will be described in more detail through the following Examples and Experimental Examples, but the present invention is not limited to these Examples and Experimental Examples.

[실시예]
[Example]

실시예 1. (3-아이소프로필아이속사졸-5-일)메탄올Example 1. (3-isopropylisoxazol-5-yl) methanol

에탄올과 물을 1:1로 섞은 용매 60 mL에 아이소부탄알 (5.0 g, 22 mmol)을 넣은 후, 하이드록실아민 염산염 (6.3 g, 90.1 mmol)과 Na₂CO₃ (9.5 g, 90.1 mmol)를 넣고 교반하였다. 반응혼합물을 90℃에서 24시간동안 환류시켰다. 반응혼합물의 온도를 상온으로 낮춘 후, 물 30 mL로 희석시키고 에틸 아세테이트로 추출하고, 유기용액을 MgSO₄로 건조시킨 후 여과 및 감압하에서 농축시켜 옥심화합물을 얻었다.Isobutanal (5.0 g, 22 mmol) was added to 60 mL of a 1: 1 mixture of ethanol and water, followed by hydroxylamine hydrochloride (6.3 g, 90.1 mmol) and Na ₂ CO ₃ (9.5 g, 90.1 mmol). Was added and stirred. The reaction mixture was refluxed at 90 ° C. for 24 hours. The reaction mixture was cooled to room temperature, diluted with 30 mL of water, extracted with ethyl acetate, the organic solution was dried over MgSO ₄ , filtered and concentrated under reduced pressure to obtain an oxime compound.

얻어진 옥심화합물을 THF 40 mL에 녹인 후 온도를 0℃로 낮추고 N-클로로숙신이미드 (10.1 g, 76 mmol)를 천천히 첨가하고 1시간동안 교반하였다. 프로파질알콜 (5.6 mL, 94.7 mmol)과 트리에틸아민 (10.6 g, 75.8 mmol)을 첨가하고, 상온에서 12시간동안 교반하였다. 반응이 종결된 후, 물과 포화 NaHCO₃ 수용액 각각 15 mL를 반응용액에 첨가하고 메틸렌클로라이드로 추출하였다. 유기용액을 MgSO₄로 건조시킨 후 여과 및 감압하에서 농축하고, 농축물을 실리카겔 컬럼크로마토그래피법으로 정제하여 표제화합물 (4.0 g, 28.3 mmol, 50%)을 얻었다.After dissolving the obtained oxime compound in 40 mL of THF, the temperature was lowered to 0 ° C., and N -chlorosuccinimide (10.1 g, 76 mmol) was added slowly and stirred for 1 hour. Propargyl alcohol (5.6 mL, 94.7 mmol) and triethylamine (10.6 g, 75.8 mmol) were added and stirred at room temperature for 12 hours. After the reaction was completed, 15 mL each of water and saturated aqueous NaHCO ₃ solution was added to the reaction solution and extracted with methylene chloride. The organic solution was dried over MgSO ₄ , filtered and concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography to obtain the title compound (4.0 g, 28.3 mmol, 50%).

¹H NMR (300 MHz, CDCl₃) δ 6.11 (s, 1H), 4.68 (s, 2H), 3.90 (s, 1H), 3.05-2.95 (m, 1H), 1.24 (d, J = 7.0 Hz, 6H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 6.11 (s, 1H), 4.68 (s, 2H), 3.90 (s, 1H), 3.05-2.95 (m, 1H), 1.24 (d, J = 7.0 Hz, 6H)

실시예 2. 3-아이소프로필아이속사졸-5-카발데하이드Example 2. 3-isopropylisoxazole-5-carbaldehyde

메틸렌클로라이드 180 mL에 PCC (7.91 g, 36.7 mmol)과 실리카겔 (7.91 g)을 넣은 후, (3-아이소프로필아이속사졸-5-일)메탄올 (2.59 g, 18.4 mmol)을 상온에서 첨가하였다. 반응용액을 5시간동안 상온에서 교반시킨 후 실리카겔을 이용하여 여과하였고, 얻어진 유기용액을 감압하에서 농축시켜 표제화합물 (2.25 g, 16.2 mmol, 99%)을 얻었다. PCC (7.91 g, 36.7 mmol) and silica gel (7.91 g) were added to 180 mL of methylene chloride, and (3-isopropylisoxazol-5-yl) methanol (2.59 g, 18.4 mmol) was added at room temperature. The reaction solution was stirred at room temperature for 5 hours, filtered using silica gel, and the obtained organic solution was concentrated under reduced pressure to obtain the title compound (2.25 g, 16.2 mmol, 99%).

¹H NMR (300 MHz, CDCl₃) δ 9.95 (s, 1H), 6.88 (s, 1H), 3.21-3.12 (m, 1H), 1.34 (d, J = 7.0 Hz, 6H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 9.95 (s, 1H), 6.88 (s, 1H), 3.21-3.12 (m, 1H), 1.34 (d, J = 7.0 Hz, 6H)

실시예 3. [2-[4-(3-클로로페닐)-피페라진-1-일]-에틸]-(3-메틸아이속사졸-5-일메틸)아민 (화합물번호 1)Example 3. [2- [4- (3-Chlorophenyl) -piperazin-1-yl] -ethyl]-(3-methylisoxazol-5-ylmethyl) amine (Compound No. 1)

3-메틸아이속사졸-5-카발데하이드 (300 mg, 2.7 mmol)과 3-클로로페닐피페라지닐에틸아민 (777 mg, 3.24 mmol)과 4Å 분자체를 메틸렌클로라이드 20 mL에 섞어 2시간동안 교반한 후에 NaBH(OAc)₃ (1.72 g, 8.10 mmol)를 첨가하여 5시간 상온에서 교반하였다. 포화 NaHCO₃ 수용액을 첨가하여 메틸렌클로라이드로 추출하고 유기용액은 MgSO₄로 건조시킨 후 여과 및 농축한 뒤 실리카겔 컬럼크로마토그래피법으로 정제하여 표제화합물 (300 mg, 0.90 mmol, 33%)을 얻었다.
3-methylisoxazole-5-carbaldehyde (300 mg, 2.7 mmol), 3-chlorophenylpiperazinylethylamine (777 mg, 3.24 mmol), and 4 'molecular sieves were mixed in 20 mL of methylene chloride for 2 hours. After stirring, NaBH (OAc) ₃ (1.72 g, 8.10 mmol) was added thereto, followed by stirring at room temperature for 5 hours. Aqueous solution of saturated NaHCO ₃ was added, followed by extraction with methylene chloride. The organic solution was dried over MgSO ₄ , filtered and concentrated, and purified by silica gel column chromatography to obtain the title compound (300 mg, 0.90 mmol, 33%).

실시예 4. [2-[4-(3-클로로페닐)-피페라진-1-일]-에틸]-(3-아이소프로필아이속사졸-5-일메틸)아민 (화합물번호 3)Example 4. [2- [4- (3-Chlorophenyl) -piperazin-1-yl] -ethyl]-(3-isopropylisoxazol-5-ylmethyl) amine (Compound No. 3)

3-아이소프로필아이속사졸-5-카발데하이드 (1.6 g, 11.5 mmol)를 메탄올 (40 mL)에 녹인 후, 상온에서 3-클로로페닐피페라지닐에틸아민 (3.2 g, 12.7 mmol)과 아세트산 (0.5 mL)을 첨가하고 2시간동안 교반하였다. 반응혼합물에 NaBH(OAc)₃ (7.3 g, 34.5 mmol)를 첨가하고 8시간동안 교반한 후 용매를 감압하에 농축시켰다. 농축물에 물과 포화 NaHCO₃수용액 각각 10 mL씩 첨가하여 희석시킨 후 메틸렌클로라이드로 추출하고, 유기용액은 MgSO₄로 건조시킨 후 여과 및 감압하에 농축시킨 뒤 실리카겔 컬럼크로마토그래피법 (MC:MeOH = 10 : 1)로 정제하여 표제화합물 (3.2 g, 8.5 mmol, 74%)을 얻었다.
3-Isopropylisoxazole-5-carbaldehyde (1.6 g, 11.5 mmol) was dissolved in methanol (40 mL), followed by 3-chlorophenylpiperazinylethylamine (3.2 g, 12.7 mmol) and acetic acid at room temperature. (0.5 mL) was added and stirred for 2 hours. NaBH (OAc) ₃ (7.3 g, 34.5 mmol) was added to the reaction mixture, stirred for 8 hours, and the solvent was concentrated under reduced pressure. 10 mL each of water and saturated aqueous NaHCO ₃ solution was added to the concentrate, diluted with methylene chloride, and the organic solution was dried over MgSO ₄ , filtered and concentrated under reduced pressure, followed by silica gel column chromatography (MC: MeOH =). 10: 1) to give the title compound (3.2 g, 8.5 mmol, 74%).

실시예 5. 4-(2-(tert-부틸디메틸실릴록시)에틸)피페리딘Example 5. 4- (2- ( tert -butyldimethylsilyloxy) ethyl) piperidine

2-(피페리딘-4-일)에탄올(2.3 g, 17.8 mmol)을 메틸렌클로라이드에 녹인 후 tert-부틸디메틸실릴 클로라이드 (TBSCl; 3.2 g, 21.3 mmol)와 이미다졸 (2.4 g, 35.6 mmol)을 넣고 상온에서 2시간동안 반응시켰다. TLC로 반응완결을 확인한 후에, NH₄Cl를 넣어 반응을 종료시켰다. 메틸렌클로라이드로 추출한 후 실리카겔 컬럼크로마토그래피법 (MC:MeOH:TEA=85:10:5)으로 정제 하였다. 정제하여 얻은 화합물을 0.5N NaOH 수용액으로 처리하고 용매 (MC:MeOH=10:1)로 추출하여 화합물 (4.2 g, 12.4 mmol, 98%)을 얻었다.2- (piperidin-4-yl) ethanol (2.3 g, 17.8 mmol) was dissolved in methylene chloride, followed by tert -butyldimethylsilyl chloride (TBSCl; 3.2 g, 21.3 mmol) and imidazole (2.4 g, 35.6 mmol). Was added and reacted at room temperature for 2 hours. After completion of the reaction by TLC, NH ₄ Cl was added to terminate the reaction. The mixture was extracted with methylene chloride and purified by silica gel column chromatography (MC: MeOH: TEA = 85: 10: 5). The obtained compound was treated with 0.5N NaOH aqueous solution and extracted with a solvent (MC: MeOH = 10: 1) to give a compound (4.2 g, 12.4 mmol, 98%).

¹H NMR (CDCl₃, 300 MHz) δ 0.03 (s, 6H), 0.87 (s, 9H), 1.07-1.12 (q, J = 4.97 Hz, 2H), 1.43-1.47 (t, J = 6.33 Hz, 2H), 1.47-1.62 (m, 1H), 1.62-1.66 (bd, J = 12.6 Hz, 2H), 1.85 (db, 1H), 2.52-2.61 (tb, J = 13.28, 2.42 Hz, 2H), 3.01-3.05 (d, J = 9.25 Hz, 2H), 3.61-3.65 (t, J = 6.43 Hz, 2H)
¹ H NMR (CDCl ₃ , 300 MHz) δ 0.03 (s, 6H), 0.87 (s, 9H), 1.07-1.12 (q, J = 4.97 Hz, 2H), 1.43-1.47 (t, J = 6.33 Hz, 2H), 1.47-1.62 (m, 1H), 1.62-1.66 (bd, J = 12.6 Hz, 2H), 1.85 (db, 1H), 2.52-2.61 (tb, J = 13.28, 2.42 Hz, 2H), 3.01 -3.05 (d, J = 9.25 Hz, 2H), 3.61-3.65 (t, J = 6.43 Hz, 2H)

실시예 6. 4-(2-(tert-부틸디메틸실릴록시)에틸)-1-(4-플루오로페닐)피페리딘Example 6. 4- (2- ( tert -butyldimethylsilyloxy) ethyl) -1- (4-fluorophenyl) piperidine

건조된 상태의 둥근 바닥 플라스크에 4Å 분자체와 4-플루오로페닐보로닉 산 (0.49 g, 3.53 mmol), Cu(OAc)₂(0.03 g, 0.17 mmol)를 메틸렌클로라이드에 순서대로 녹인 후 0℃에서 5분동안 반응시켰다. 메틸렌클로라이드에 4-(2-(tert-부틸디메틸실릴록시)에틸)피페리딘 (0.43 g, 1.76 mmol)을 녹인 용액을 반응혼합물에 적가하고, 수분제거된 공기 기류하에서 24?36시간동안 반응시켰다. TLC로 반응진행을 확인하고, 반응이 종결되면 감압 여과 하여 4Å 분자체와 Cu(OAc)₂를 제거하였다. 여액을 감압 증발시킨 후 실리카겔 컬럼크로마토그래피법으로 정제하여 표제화합물 (0.34 g, 1.02 mmol, 58%)을 얻었다.In a dried round bottom flask, 4 Å molecular sieve, 4-fluorophenylboronic acid (0.49 g, 3.53 mmol), and Cu (OAc) ₂ (0.03 g, 0.17 mmol) were dissolved in methylene chloride in that order, and then 0. The reaction was carried out at 5 캜 for 5 minutes. A solution of 4- (2- ( tert -butyldimethylsilyloxy) ethyl) piperidine (0.43 g, 1.76 mmol) dissolved in methylene chloride was added dropwise to the reaction mixture, and the reaction was carried out for 24 to 36 hours under a water-free air stream. I was. The reaction progress was confirmed by TLC. When the reaction was completed, the mixture was filtered under reduced pressure to remove 4 Å molecular sieve and Cu (OAc) ₂ . The filtrate was evaporated under reduced pressure and purified by silica gel column chromatography to obtain the title compound (0.34 g, 1.02 mmol, 58%).

¹H NMR (CDCl₃, 300 MHz) δ 0.07 (s, 6H), 0.92 (s, 9H), 1.41-1.42 (m, 2H), 1.52-1.55 (m, 3H), 1.81 (bd, J = 6.48 Hz, 1H), 2.61-2.70 (td, J = 7.18, 2.48 Hz, 2H), 3.54 (d, J = 12.25 Hz, 2H), 3.70 (t, J = 3.20 Hz, 2H), 6.87-6.98 (m, 4H)
¹ H NMR (CDCl ₃ , 300 MHz) δ 0.07 (s, 6H), 0.92 (s, 9H), 1.41-1.42 (m, 2H), 1.52-1.55 (m, 3H), 1.81 (bd, J = 6.48 Hz, 1H), 2.61-2.70 (td, J = 7.18, 2.48 Hz, 2H), 3.54 (d, J = 12.25 Hz, 2H), 3.70 (t, J = 3.20 Hz, 2H), 6.87-6.98 (m , 4H)

실시예 7. 2-(1-(4-플루오로페닐)피페리딘-4-일)에탄올Example 7. 2- (1- (4-fluorophenyl) piperidin-4-yl) ethanol

THF에 4-(2-(tert-부틸디메틸실릴록시)에틸)-1-(4-플루오로페닐)피페리딘 (1.1 g, 3.26 mmol)을 녹이고, 0℃로 낮추었다. TBAF(2.83 mL, 9.77 mmol)을 넣은 후 20분동안 반응시킨 후 상온으로 온도를 올려 다시 3시간동안 반응시킨 다음, NHCl₃를 반응혼합물에 넣어 반응을 종결하였다. H₂O와 메틸렌클로라이드를 이용하여 추출하고, 유기용액은 MgSO₄로 건조시킨 후 감압 여과하고 실리카겔 컬럼크로마토그래피법 (에틸 아세테이트:헥산=1:1)으로 정제하여 표제화합물 (0.7 g, 3.45 mmol, 99%)을 얻었다. Dissolve 4- (2- ( tert -butyldimethylsilyloxy) ethyl) -1- (4-fluorophenyl) piperidine (1.1 g, 3.26 mmol) in THF and lower to 0 ° C. After adding TBAF (2.83 mL, 9.77 mmol) for 20 minutes, the reaction mixture was heated to room temperature, and reacted for another 3 hours. NHCl ₃ was added to the reaction mixture to terminate the reaction. Extract with H ₂ O and methylene chloride. The organic solution was dried over MgSO ₄ , filtered under reduced pressure and purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to give the title compound (0.7 g, 3.45 mmol). , 99%).

¹H NMR (CDCl₃, 300 MHz) δ 1.27-1.29 (m, 1H), 1.40-1.48 (m, 2H), 1.50-1.60 (m, 4H), 1.82 (bd, J = 12.50 Hz, 2H), 2.65 (td, J = 11.98 Hz, J = 2.19 Hz, 2H), 3.54 (bd, J = 12.25 Hz, 2H), 3.76 (bs, 2H), 6.87-6.99 (m, 4H)
¹ H NMR (CDCl ₃ , 300 MHz) δ 1.27-1.29 (m, 1H), 1.40-1.48 (m, 2H), 1.50-1.60 (m, 4H), 1.82 (bd, J = 12.50 Hz, 2H), 2.65 (td, J = 11.98 Hz, J = 2.19 Hz, 2H), 3.54 (bd, J = 12.25 Hz, 2H), 3.76 (bs, 2H), 6.87-6.99 (m, 4H)

실시예 8. 2-(2-(1-(4-플루오로페닐)피페리딘-4-일)에틸)이소인돌린-1,3-디온Example 8. 2- (2- (1- (4-fluorophenyl) piperidin-4-yl) ethyl) isoindoline-1,3-dione

둥근 바닥 플라스크에서 프탈아마이드(0.12 g, 0.85 mmol) 와 트라이페닐포스핀(0.22 g, 0.85 mmol)을 THF에 녹인 후, 2-(1-(4-플루오로페닐)피페리딘-4-일)에탄올 (0.12 g, 0.57 mmol)을 THF에 녹인 용액을 상온에서 적가하였다. 다이아이소프로필아조디카복실레이트 (DIAD; 0.17 mL, 0.85 mmol)를 천천히 적가하고 4시간동안 반응시킨 다음, TLC로 반응의 완결을 확인하였다. 메틸렌클로라이드를 이용하여 추출한 후 MgSO₄로 건조 및 감압 여과하고 실리카겔 컬럼크로마토그래피법 (에틸 아세테이트:헥산=1:4)으로 정제하여 표제화합물 (0.17g, 0.49 mmol, 78%)을 얻었다. Phthalide (0.12 g, 0.85 mmol) and triphenylphosphine (0.22 g, 0.85 mmol) were dissolved in THF in a round bottom flask, followed by 2- (1- (4-fluorophenyl) piperidin-4-yl A solution of ethanol (0.12 g, 0.57 mmol) in THF was added dropwise at room temperature. Diisopropylazodicarboxylate (DIAD; 0.17 mL, 0.85 mmol) was slowly added dropwise and reacted for 4 hours, and then TLC confirmed the completion of the reaction. The mixture was extracted with methylene chloride, dried over MgSO ₄ , filtered under reduced pressure, and purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4) to obtain the title compound (0.17 g, 0.49 mmol, 78%).

¹H NMR (CDCl₃, 300 MHz) δ 1.43-1.47 (m, 4H), 1.68 (bt, J = 6.23 Hz, 2H), 1.92 (bd, J = 9.07 Hz, 2H), 2.64 (bt, J = 10.62 Hz, 2H), 3.55 (bd, J = 12.04 Hz, 2H), 3.77(t, J = 7.18 Hz, 2H), 6.88-6.98(m, 4H), 7.72-7.75(m, 4H), 7.85(m, 2H)
¹ H NMR (CDCl ₃ , 300 MHz) δ 1.43-1.47 (m, 4H), 1.68 (bt, J = 6.23 Hz, 2H), 1.92 (bd, J = 9.07 Hz, 2H), 2.64 (bt, J = 10.62 Hz, 2H), 3.55 (bd, J = 12.04 Hz, 2H), 3.77 (t, J = 7.18 Hz, 2H), 6.88-6.98 (m, 4H), 7.72-7.75 (m, 4H), 7.85 ( m, 2H)

실시예 9. 2-(1-(4-플루오로페닐)피페리딘-4-일)에탄아민Example 9. 2- (1- (4-fluorophenyl) piperidin-4-yl) ethanamine

2-(2-(1-(4-플루오로페닐)피페리딘-4-일)에틸)이소인돌-1,3-디온 (0.17 g, 0.49 mmol)을 에탄올에 넣고 온도를 80℃로 올려 녹인 후, 모노하이드라진 (0.07 mL, 1.47 mmol)을 넣고 8시간동안 반응시켰다. TLC(전개용매: EA)로 반응완결을 확인 후 상온으로 온도를 내린 후 생성된 고체를 감압 여과하고 여액을 실리카겔 컬럼크로마토그래피법 (EA:MeOH:암모니아수=10:1:0.1)으로 정제하여 표제화합물 (0.09 g, 0.43 mmol, 89%)을 얻었다. 2- (2- (1- (4-fluorophenyl) piperidin-4-yl) ethyl) isoindole-1,3-dione (0.17 g, 0.49 mmol) was added to ethanol and the temperature was raised to 80 ° C. After dissolving, monohydrazine (0.07 mL, 1.47 mmol) was added thereto and reacted for 8 hours. After confirming the completion of the reaction by TLC (developing solvent: EA), the mixture was cooled to room temperature, and the resulting solid was filtered under reduced pressure, and the filtrate was purified by silica gel column chromatography (EA: MeOH: ammonia water = 10: 1: 0.1). Compound (0.09 g, 0.43 mmol, 89%) was obtained.

¹H NMR (CDCl₃, 300 MHz) δ 1.37-1.49 (m, 7H), 1.81 (bd, J = 10.56 Hz, 2H), 2.65 (t, J = 11.62 Hz, 2H), 2.78 (t, J = 6.99 Hz, 2H), 3.54 (bd, J = 12.39 Hz, 2H), 6.87-6.98 (m, 4H)
¹ H NMR (CDCl ₃ , 300 MHz) δ 1.37-1.49 (m, 7H), 1.81 (bd, J = 10.56 Hz, 2H), 2.65 (t, J = 11.62 Hz, 2H), 2.78 (t, J = 6.99 Hz, 2H), 3.54 (bd, J = 12.39 Hz, 2H), 6.87-6.98 (m, 4H)

실시예 10. 2-(1-(4-플루오로페닐)피페리딘-4-일)-N-((3-이소프로필아이속사졸-5-일)메틸)에탄아민 Example 10. 2- (1- (4-fluorophenyl) piperidin-4-yl) -N -((3-isopropylisoxazol-5-yl) methyl) ethanamine

2-(1-(4-플루오로페닐)피페리딘-4-일)에탄아민 (50 mg, 0.22 mmol)과 알데하이드(34 mg, 0.24 mmol)를 메틸렌클로라이드에 녹인 후 3시간동안 반응시켰다. NaBH(OAc)₃(143 mg, 0.67 mmol)을 넣고 3시간동안 반응시켰다. TLC로 반응완결을 확인 후 물과 메틸렌클로라이드를 이용하여 추축하고, 유기용액은 MgSO₄로 건조시키고 감압 여과한 후 실리카겔 컬럼크로마토그래피법으로 정제하여 표제화합물 (38 mg, 0.11 mmol, 49%)을 얻었다. 2- (1- (4-fluorophenyl) piperidin-4-yl) ethanamine (50 mg, 0.22 mmol) and aldehyde (34 mg, 0.24 mmol) were dissolved in methylene chloride and reacted for 3 hours. NaBH (OAc) ₃ (143 mg, 0.67 mmol) was added and reacted for 3 hours. After completion of the reaction by TLC, the mixture was extracted with water and methylene chloride. The organic solution was dried over MgSO ₄ , filtered under reduced pressure and purified by silica gel column chromatography to obtain the title compound (38 mg, 0.11 mmol, 49%). Got it.

¹H NMR (CDCl₃, 300 MHz) δ 1.29 (d, J = 6.95 Hz, 6H), 1.38-1.53 (m, 7H), 1.79 (bd, J = 11.28 Hz, 2H), 2.64 (t, J = 12.07 Hz, 2H), 2.72 (t, J = 7.23 Hz, 2H), 3.04-3.08 (m, 1H), 3.53 (bd, J = 12.33 Hz, 2H), 3.90 (s, 2H), 6.03 (s, 1H), 6.86-6.98 (m, 4H)
¹ H NMR (CDCl ₃ , 300 MHz) δ 1.29 (d, J = 6.95 Hz, 6H), 1.38-1.53 (m, 7H), 1.79 (bd, J = 11.28 Hz, 2H), 2.64 (t, J = 12.07 Hz, 2H), 2.72 (t, J = 7.23 Hz, 2H), 3.04-3.08 (m, 1H), 3.53 (bd, J = 12.33 Hz, 2H), 3.90 (s, 2H), 6.03 (s, 1H), 6.86-6.98 (m, 4H)

실시예 11. 2-(1-(3-클로로페닐)피페리딘-4-일)아세탈데하이드Example 11. 2- (1- (3-chlorophenyl) piperidin-4-yl) acetalaldehyde

상기 실시예 7에서와 같은 방법으로 얻어진 알콜과 2-(1-(3-클로로페닐)피페리딘-4-일)에탄올 (48 mg, 0.17 mmol)을 메틸렌클로라이드에 녹이고, PCC (95mg, 0.44 mmol)를 가하였다. SO₂ 역시 PCC와 같은 양을 가하였다. 반응혼합물을 상온에서 4?8시간동안 반응시킨 후 셀라이트로 여과하였다. 여액은 포화 NaHCO₃ 수용액으로 씻어주고, 수용액은 다시 메틸렌클로라이드로 추출(10 mL×3회)하였다. 유기용액을 합하여 MgSO₄로 건조시키고 감압 여과한 후 실리카겔 컬럼크로마토그래피법으로 정제하여 표제화합물 (19 mg, 0.07 mmol, 40%)을 얻었다.
The alcohol obtained in the same manner as in Example 7 and 2- (1- (3-chlorophenyl) piperidin-4-yl) ethanol (48 mg, 0.17 mmol) were dissolved in methylene chloride, and PCC (95 mg, 0.44 mmol) was added. SO ₂ also added the same amount as PCC. The reaction mixture was reacted at room temperature for 4-8 hours and filtered through celite. The filtrate was washed with saturated NaHCO ₃ aqueous solution, and the aqueous solution was extracted again with methylene chloride (10 mL × 3 times). The combined organic solution was dried over MgSO ₄ , filtered under reduced pressure and purified by silica gel column chromatography to obtain the title compound (19 mg, 0.07 mmol, 40%).

실시예 12. 5-(클로로메틸)-3-이소프로필아이속사졸Example 12. 5- (Chloromethyl) -3-isopropylisoxazole

메틸렌클로라이드에 (3-이소프로필아이속사졸-5-일)메탄올 (0.84 g, 5.95 mmol)을 녹인 용액에, 트리에틸아민 (2.48 mL, 17.85 mmol)을 가하였다. 상온에서 반응용액을 교반해 주면서, 메틸렌클로라이드에 티오닐클로라이드 (1.29 mL, 17.85 mmol)를 녹인 용액을 반응용액에 천천히 적가하였다. 반응이 완결된 후 1M NaHCO₃ 수용액 (20 mL)을 천천히 반응용액에 적가하고 층분리시켜 유기용액층을 수득하였다. 수용액층은 메틸렌클로라이드 (15 mL×3)로 추출하여 유기용액층을 수득하였다. 수득된 유기용액층을 합하여 MgSO₄로 건조시키고 감압 여과한 후, 실리카겔 컬럼크로마토그래피법 (에틸 아세테이트:헥산=1:4)으로 정제하여 표제화합물 (0.73 g, 4.6 mmol, 77%)을 얻었다. Triethylamine (2.48 mL, 17.85 mmol) was added to a solution of (3-isopropylisoxazol-5-yl) methanol (0.84 g, 5.95 mmol) in methylene chloride. While stirring the reaction solution at room temperature, a solution of thionyl chloride (1.29 mL, 17.85 mmol) in methylene chloride was slowly added dropwise to the reaction solution. After the reaction was completed, 1M NaHCO ₃ aqueous solution (20 mL) was slowly added dropwise to the reaction solution, and the layers were separated to obtain an organic solution layer. The aqueous layer was extracted with methylene chloride (15 mL × 3) to obtain an organic solution layer. The combined organic solution layers were dried over MgSO ₄ , filtered under reduced pressure, and then purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4) to obtain the title compound (0.73 g, 4.6 mmol, 77%).

¹H NMR (CDCl₃, 400 MHz) δ 6.19 (s, 1H), 4.58 (s, 2H), 3.11-3.00 (m, 1H, J = 6.96 Hz), 1.33 (d, 6H, J = 16.06 Hz)
¹ H NMR (CDCl ₃ , 400 MHz) δ 6.19 (s, 1H), 4.58 (s, 2H), 3.11-3.00 (m, 1H, J = 6.96 Hz), 1.33 (d, 6H, J = 16.06 Hz)

실시예 13. 5-(아지도메틸)-3-이소프로필아이속사졸Example 13. 5- (azidomethyl) -3-isopropylisoxazole

N,N-다이메틸폼아마이드에 5-(클로로메틸)-3-이소프로필아이속사졸 (0.73 g, 4.6 mmol)을 녹인 용액에, NaI (0.34 g, 2.3 mmol)과 NaN₃ (1.49 g, 23.02 mmol)을 넣어 주었다. 반응용액을 교반하면서 60℃로 가열하여 12시간동안 반응시켰다. 반응이 완결된 후, 반응용기에 증류수 10 mL를 넣어주고, 에틸 아세테이트 (20 mL×5)로 추출하였다. 유기용액 층을 합하여 MgSO₄로 건조시키고 감압 여과한 후 농축하고 실리카겔 컬럼크로마토그래피법 (에틸 아세테이트:헥산=1:8)으로 정제하여 표제화합물 (0.24 g, 1.43 mmol, 31%)을 얻었다. In a solution of 5- (chloromethyl) -3-isopropylisoxazole (0.73 g, 4.6 mmol) in N, N -dimethylformamide, NaI (0.34 g, 2.3 mmol) and NaN ₃ (1.49 g, 23.02 mmol) was added. The reaction solution was heated to 60 ° C. while stirring to react for 12 hours. After the reaction was completed, 10 mL of distilled water was added to the reaction vessel and extracted with ethyl acetate (20 mL × 5). The combined organic solution layers were dried over MgSO ₄ , filtered under reduced pressure, concentrated, and purified by silica gel column chromatography (ethyl acetate: hexane = 1: 8) to obtain the title compound (0.24 g, 1.43 mmol, 31%).

¹H NMR (CDCl₃, 400 MHz) δ 6.15 (s, 1H), 4.41 (s, 2H), 3.12-3.03 (m, 1H, J = 6.95 Hz), 1.34 (d, 6H, J = 15.66 Hz)
¹ H NMR (CDCl ₃ , 400 MHz) δ 6.15 (s, 1H), 4.41 (s, 2H), 3.12-3.03 (m, 1H, J = 6.95 Hz), 1.34 (d, 6H, J = 15.66 Hz)

실시예 14. (3-이소프로필아이속사졸-5-일) 메탄아민Example 14 (3-isopropylisoxazol-5-yl) Methanamine

THF와 H₂O의 혼합용액 (THF:H₂O=10:1)에 5-(아지도메틸)-3-아이소프로필아이속사졸 (0.24 g, 1.43 mmol)을 녹인 후 트리페닐포스핀 (Ph₃P; 0.37 g, 1.43 mmol)을 넣고 70℃에서 4시간동안 반응시켰다. 반응이 완결되면 상온으로 식힌 후 반응용기에 증류수를 넣어주고, 에틸 아세테이트 (20 mL×3)로 추출하였다. 유기용액 층을 합하여 MgSO₄로 건조시키고 감압 여과한 후 농축하고 실리카겔 컬럼크로마토그래피법으로 정제하여 표제화합물 (0.14 g, 0.97 mmol, 68%)을 얻었다. Dissolve 5- (azidomethyl) -3-isopropylisoxazole (0.24 g, 1.43 mmol) in a mixed solution of THF and H ₂ O (THF: H ₂ O = 10: 1), and then add triphenylphosphine ( Ph ₃ P; 0.37 g, 1.43 mmol) was added and reacted at 70 ° C. for 4 hours. When the reaction was completed, cooled to room temperature, distilled water was added to the reaction vessel, extracted with ethyl acetate (20 mL × 3). The combined organic solution layers were dried over MgSO ₄ , filtered under reduced pressure, concentrated, and purified by silica gel column chromatography to obtain the title compound (0.14 g, 0.97 mmol, 68%).

¹H NMR (CDCl₃, 300 MHz) δ 6.00 (s, 1H), 3.93 (s, 2H), 3.09-3.00 (m, 1H, J = 6.95 Hz), 1.49 (b, 2H), 1.29 (d, 6H, J = 6.95 Hz)
¹ H NMR (CDCl ₃ , 300 MHz) δ 6.00 (s, 1H), 3.93 (s, 2H), 3.09-3.00 (m, 1H, J = 6.95 Hz), 1.49 (b, 2H), 1.29 (d, 6H, J = 6.95 Hz)

실시예 15. 2-(1-(3-클로로페닐)피페리딘-4-일)-N-((3-이소프로필아이속사졸-5-일)메틸)에탄아민Example 15. 2- (1- (3-Chlorophenyl) piperidin-4-yl) -N -((3-isopropylisoxazol-5-yl) methyl) ethanamine

메틸렌클로라이드에 2-(1-(3-클로로페닐)피페리딘-4-일)아세탈데하이드 (22 mg, 0.09 mmol)를 녹인 용액에, (3-이소프로필아이속사졸-5-일)메탄아민 (19 mg, 0.1 mmol)을 적가하고 질소기류 하에서 30분동안 교반 반응시켰다. NaBH(OAc)₃ (59 mg, 0.28 mmol)을 반응용액에 넣어준 후 상온에서 3시간동안 교반하여 주었다. 반응이 완결되면 물을 가하여 반응을 종결시키고, 포화 NaHCO₃ 수용액 10 mL를 가하고, 메틸렌클로라이드로 유기물질을 추출하였다. 유기용액 층을 합하여 MgSO₄로 건조시키고 감압 여과한 후 농축하고 실리카겔 컬럼크로마토그래피법으로 정제하여 표제화합물 (15 mg, 0.04 mmol, 45%)을 얻었다.To a solution of 2- (1- (3-chlorophenyl) piperidin-4-yl) acetalaldehyde (22 mg, 0.09 mmol) in methylene chloride, (3-isopropylisoxazol-5-yl) Methanamine (19 mg, 0.1 mmol) was added dropwise and stirred under nitrogen stream for 30 minutes. NaBH (OAc) ₃ (59 mg, 0.28 mmol) was added to the reaction solution and stirred at room temperature for 3 hours. Upon completion of the reaction, water was added to terminate the reaction, 10 mL of saturated NaHCO ₃ aqueous solution was added, and the organic material was extracted with methylene chloride. The combined organic solution layers were dried over MgSO ₄ , filtered under reduced pressure, concentrated, and purified by silica gel column chromatography to obtain the title compound (15 mg, 0.04 mmol, 45%).

¹H NMR (CDCl₃, 400 MHz) δ 7.15-6.75 (m, 4H), 6.10 (s, 1H), 4.05 (s, 2H), 3.89 (m, 2H), 3.07-3.03 (m, 1H), 2.73-2.67 (m, 4H), 1.78 (m, 2H), 1.51-1.29 (m, 6H), 1.27 (d, 6H, J = 3.00 Hz)
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.15-6.75 (m, 4H), 6.10 (s, 1H), 4.05 (s, 2H), 3.89 (m, 2H), 3.07-3.03 (m, 1H), 2.73-2.67 (m, 4H), 1.78 (m, 2H), 1.51-1.29 (m, 6H), 1.27 (d, 6H, J = 3.00 Hz)

실시예 16. tert-부틸 4-(2-사이아노페닐)-5,6-다이하이드로피리딘-1(2H)-카르복실레이트의 합성Example 16 Synthesis of tert -Butyl 4- (2-cyanophenyl) -5,6-dihydropyridine-1 ( 2H ) -carboxylate

아르곤 대기 하에서 2-브로모벤조나이트릴 (914 mg, 5.02 mmol)을 무수 테트라하이드로퓨란 (46 mL)에 용해시킨 후, -78 ℃로 냉각하고 헥산에 녹아있는 노말부틸리튬 용액 (2.0 mL, 2.5 M)을 천천히 적가하고 30분동안 반응시켰다. 테트라하이드로퓨란 (4.3 mL)에 녹아 있는 1-tert-부톡시카르보닐-4-피페리돈 (1.0 g, 5.02 mmol) 용액을 -78 ℃에서 천천히 적가하고 1시간동안 반응시켰다. 상온으로 승온하여 다시 1시간동안 교반시킨 후, 메탄설포닐 클로라이드 (1.6 mL, 20.08 mmol)와 트리에틸아민 (5.6 mL, 40.15 mmol)을 -78 ℃에서 적가하고, 상온에서 15시간동안 교반하였다. TLC로 반응 종결을 확인한 다음 에틸 아세테이트로 추출하고, 유기용액 층은 물과 포화 염화나트륨 수용액으로 다시 세척한 후 황산나트륨으로 건조시키고 여과한 후 감압 증류하였다. 잔사는 실리카겔 컬럼크로마토그래피법 (헥산/에틸 아세테이트 = 20:1)으로 정제하여 표제화합물 (658 mg, 45%)을 얻었다.2-bromobenzonitrile (914 mg, 5.02 mmol) was dissolved in anhydrous tetrahydrofuran (46 mL) under argon atmosphere, then cooled to -78 ° C and a solution of normal butyllithium (2.0 mL, 2.5) M) was slowly added dropwise and reacted for 30 minutes. A solution of 1- tert -butoxycarbonyl-4-piperidone (1.0 g, 5.02 mmol) dissolved in tetrahydrofuran (4.3 mL) was slowly added dropwise at -78 ° C and reacted for 1 hour. After warming to room temperature and stirring for another hour, methanesulfonyl chloride (1.6 mL, 20.08 mmol) and triethylamine (5.6 mL, 40.15 mmol) were added dropwise at -78 ° C, and stirred at room temperature for 15 hours. After completion of the reaction by TLC, the mixture was extracted with ethyl acetate, and the organic solution layer was washed again with water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and distilled under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 20: 1) to obtain the title compound (658 mg, 45%).

¹H NMR (300 MHz, CDCl₃) δ 7.51 (d, J = 7.8 Hz, 1H), 7.43 (dt, J = 10.6 Hz, 3.9 Hz, 1H), 7.22 (t, J = 7.8 Hz, 2H), 5.83 (bs, 1H), 3.96 (d, J = 2.9 Hz, 2H), 3.52 (t, J = 5.6 Hz, 2H), 2.39 (bs, 2H), 1.37 (s, 9H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.51 (d, J = 7.8 Hz, 1H), 7.43 (dt, J = 10.6 Hz, 3.9 Hz, 1H), 7.22 (t, J = 7.8 Hz, 2H), 5.83 (bs, 1H), 3.96 (d, J = 2.9 Hz, 2H), 3.52 (t, J = 5.6 Hz, 2H), 2.39 (bs, 2H), 1.37 (s, 9H)

실시예 17. tert-부틸 4-(트리부틸스탠닐)-5,6-다이하이드로피리딘-1(2H)-카르복실레이트의 합성Example 17 Synthesis of tert -Butyl 4- (tributylstannyl) -5,6-dihydropyridine-1 ( 2H ) -carboxylate

아르곤 대기 하에 디아이소프로필아민 (4.2 mL, 30.11 mmol)을 무수 테트라하이드로퓨란 (90 mL)에 용해시킨 후 0 ℃로 냉각하고 헥산에 녹아 있는 부틸리튬 용액 (15.1 mL, 2.5 M)을 천천히 적가하였다. 30분 후에 트리부틸틴하이드라이드 (7.5 mL, 25.09 mmol)를 0 ℃에서 천천히 적가한 후, 30분 후에 테트라하이드로퓨란 (10 mL)에 녹아 있는 1-tert-부톡시카르보닐-4-피페리돈 (5.0 g, 25.09 mmol)을 -78 ℃에서 천천히 적가하였다. 2시간 후에 메탄설포닐클로라이드 (7.8 mL, 100.38 mmol)와 트리에틸아민 (28.0 mL, 200.75 mmol)을 -78 ℃에서 적가한 후, 상온에서 15시간동안 교반하였다. 반응 종결을 TLC로 확인 한 다음 헥산과 아세토나이트릴로 추출하였다. 유기용액 층을 합하여 MgSO₄로 건조시키고 감압 여과한 후 농축하고 실리카겔 컬럼크로마토그래피법[헥산/에틸 아세테이트 = 50:1]으로 정제하여 표제화합물 (5.4 g, 45%)을 얻었다.Diisopropylamine (4.2 mL, 30.11 mmol) was dissolved in anhydrous tetrahydrofuran (90 mL) under argon atmosphere, then cooled to 0 ° C. and butyllithium solution (15.1 mL, 2.5 M) dissolved in hexane was slowly added dropwise. . After 30 minutes tributyltinhydride (7.5 mL, 25.09 mmol) was slowly added dropwise at 0 ° C., and after 30 minutes 1- tert -butoxycarbonyl-4-piperidone dissolved in tetrahydrofuran (10 mL) (5.0 g, 25.09 mmol) was added slowly dropwise at -78 ° C. After 2 hours, methanesulfonylchloride (7.8 mL, 100.38 mmol) and triethylamine (28.0 mL, 200.75 mmol) were added dropwise at -78 ° C, followed by stirring at room temperature for 15 hours. The reaction was terminated by TLC and then extracted with hexane and acetonitrile. The combined organic solution layers were dried over MgSO ₄ , filtered under reduced pressure, concentrated, and purified by silica gel column chromatography [hexane / ethyl acetate = 50: 1] to obtain the title compound (5.4 g, 45%).

¹H NMR (300 MHz, CDCl₃) δ 5.73 (bs, 1H), 3.90 (d, J = 2.6 Hz, 2H), 3.45 (t, J = 5.5 Hz, 2H), 2.26 (bs, 2H), 1.51-1.43 (m, 6H), 1.46 (s, 9H), 1.36-1.27 (m, 6H), 0.89 (t, J = 7.2 Hz, 15H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 5.73 (bs, 1H), 3.90 (d, J = 2.6 Hz, 2H), 3.45 (t, J = 5.5 Hz, 2H), 2.26 (bs, 2H), 1.51 -1.43 (m, 6H), 1.46 (s, 9H), 1.36-1.27 (m, 6H), 0.89 (t, J = 7.2 Hz, 15H)

실시예 18. tert-부틸 4-(4-클로로페닐)-5,6-다이하이드로피리딘-1(2H)-카르복실레이트의 합성Example 18 Synthesis of tert -Butyl 4- (4-chlorophenyl) -5,6-dihydropyridine-1 ( 2H ) -carboxylate

아르곤 대기 하에 tert-부틸 4-(트리부틸스탠닐)-5,6-다이하이드로피리딘-1(2H)-카르복실레이트 (5.4 g, 11.36 mmol), 1-브로모-4-클로로벤젠 (2.6 g, 13.64 mmol)과 Pd(PPh₃)₄ (1.3 g, 1.14 mmol)를 무수 톨루엔 81 mL에 용해시킨 후 120 ℃에서 하룻밤동안 환류 교반하였다. 감압 증류한 후 얻어진 혼합물을 실리카겔 컬럼크로마토그래피법 (헥산/에틸 아세테이트 = 15:1)으로 정제하여 표제화합물 (3.5 g, 100%)을 얻었다. Tert -butyl 4- (tributylstannyl) -5,6-dihydropyridine-1 ( 2H ) -carboxylate (5.4 g, 11.36 mmol), 1-bromo-4-chlorobenzene under argon atmosphere ( 2.6 g, 13.64 mmol) and Pd (PPh ₃ ) ₄ (1.3 g, 1.14 mmol) were dissolved in 81 mL of anhydrous toluene, followed by stirring under reflux at 120 ° C. overnight. After distillation under reduced pressure, the obtained mixture was purified by silica gel column chromatography (hexane / ethyl acetate = 15: 1) to obtain the title compound (3.5 g, 100%).

¹H NMR (400 MHz, CDCl₃) δ 7.34-7.27 (m, 4H), 6.01 (bs, 1H), 4.06 (bs, 2H), 3.63 (bs, 2H), 2.47 (bs, 2H), 1.48 (s, 9H)
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.34-7.27 (m, 4H), 6.01 (bs, 1H), 4.06 (bs, 2H), 3.63 (bs, 2H), 2.47 (bs, 2H), 1.48 ( s, 9H)

실시예 19. tert-부틸 4-(트리플루오르메틸설포닐옥시)-5,6-다이하이드로피리딘-1(2H)-카르복실레이트의 합성Example 19 Synthesis of tert -Butyl 4- (trifluoromethylsulfonyloxy) -5,6-dihydropyridine-1 ( 2H ) -carboxylate

아르곤 대기 하에 디아이소프로필아민 (1.7 mL, 12.05 mmol)을 무수 테트라하이드로퓨란 (60 mL)에 용해시킨 후 -78 ℃로 냉각하고 헥산에 녹아 있는 부틸리튬 용액 (4.8 mL, 2.5 M)을 천천히 적가하였다. 15분 후에 테트라하이드로퓨란 (25 mL)에 녹아 있는 1-tert-부톡시카르보닐-4-피페리돈 (2.0 g, 10.04 mmol)을 -78 ℃에서 천천히 적가한 후, 20분 후에 테트라하이드로퓨란 (12 mL)에 녹아 있는 1,1,1-트리플루오르-N-페틸-N-(트리플루오르메틸설포닐)메탄설폰아마이드 (3.9 g, 11.04 mmol)를 천천히 적가한 후 0 ℃에서 3시간동안 교반시켰다. 반응 종결을 TLC로 확인한 후 감압 증류하고, 잔사를 실리카겔 컬럼크로마토그래피법 (헥산/에틸 아세테이트 = 20:1)으로 정제하여 표제화합물 (3.9 g, 100%)을 얻었다.Diisopropylamine (1.7 mL, 12.05 mmol) was dissolved in anhydrous tetrahydrofuran (60 mL) under argon atmosphere, cooled to -78 ° C and slowly added dropwise a butyllithium solution (4.8 mL, 2.5 M) dissolved in hexane. It was. After 15 minutes, 1- tert -butoxycarbonyl-4-piperidone (2.0 g, 10.04 mmol) dissolved in tetrahydrofuran (25 mL) was slowly added dropwise at -78 ° C, and after 20 minutes, tetrahydrofuran ( 12 mL), slowly added dropwise 1,1,1-trifluoro- N -petyl- N- (trifluoromethylsulfonyl) methanesulfonamide (3.9 g, 11.04 mmol) and stirred at 0 ° C. for 3 hours. I was. After completion of the reaction by TLC, the residue was distilled under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 20: 1) to obtain the title compound (3.9 g, 100%).

¹H NMR (300 MHz, CDCl₃) δ 5.77 (bs, 1H), 4.05 (d, J = 2.9 Hz, 2H), 3.64 (t, J = 5.7 Hz, 2H), 2.47-2.44 (m, 2H), 1.48 (s, 9H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 5.77 (bs, 1H), 4.05 (d, J = 2.9 Hz, 2H), 3.64 (t, J = 5.7 Hz, 2H), 2.47-2.44 (m, 2H) , 1.48 (s, 9H)

실시예 20. tert-부틸 4-(4,4,5,5-테트라메틸-1,3,2-디옥사보로란-2-일)-5,6-다이하이드로피리딘-1(2H)-카르복실레이트의 합성Example 20. tert -Butyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -5,6-dihydropyridine-1 (2 H Synthesis of) -carboxylate

아르곤 대기 하에 tert-부틸 4-(트리플루오르메틸설포닐옥시)-5,6-다이하이드로피리딘-1(2H)-카르복실레이트 (3.9 g, 11.74 mmol), 비스(피나콜라토)디보론 (3.3 g, 13.03 mmol), 초산칼륨 (3.5 g, 35.5 mmol), dppf (325 mg, 0.59 mmol), PdCl₂(dppf)₂ (479 mg, 0.59 mmol)을 무수 1,4-다이옥산 (59 mL)에 용해시킨 후 80 ℃로 하룻밤도안 교반하였다. 반응 종결을 TLC로 확인 한 후 에틸 아세테이트로 추출하고, 유기용액 층을 물과 포화 염화나트륨 수용액으로 다시 세척한 후 황산나트륨으로 건조시키고 여과한 후 감압 증류하였다. 잔사를 실리카겔 컬럼크로마토그래피법 (헥산/에틸 아세테이트 = 9:1)으로 정제하여 표제화합물 (2.7 g, 74%)을 얻었다. Tert -butyl 4- (trifluoromethylsulfonyloxy) -5,6-dihydropyridine-1 ( 2H ) -carboxylate (3.9 g, 11.74 mmol), bis (pinacolato) diborone under argon atmosphere (3.3 g, 13.03 mmol), potassium acetate (3.5 g, 35.5 mmol), dppf (325 mg, 0.59 mmol), PdCl ₂ (dppf) ₂ (479 mg, 0.59 mmol) was dried over anhydrous 1,4-dioxane (59 mL After dissolving in), it was stirred at 80 ° C. overnight. After completion of the reaction by TLC, the mixture was extracted with ethyl acetate, and the organic solution layer was washed again with water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and distilled under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 9: 1) to obtain the title compound (2.7 g, 74%).

¹H NMR (300 MHz, CDCl₃) δ 6.37 (bs, 1H), 3.86 (bs, 2H), 3.34 (t, J = 5.2 Hz), 2.13 (bs, 2H), 1.37 (s, 9H), 1.17 (s, 10H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 6.37 (bs, 1H), 3.86 (bs, 2H), 3.34 (t, J = 5.2 Hz), 2.13 (bs, 2H), 1.37 (s, 9H), 1.17 (s, 10H)

실시예 21. tert-부틸 4-(3,4-다이클로로페닐)-5,6-다이하이드로피리딘-1(2H)-카르복실레이트의 합성 Example 21 Synthesis of tert -Butyl 4- (3,4-dichlorophenyl) -5,6-dihydropyridine-1 ( 2H ) -carboxylate

아르곤 대기 하에 tert-부틸 4-(4,4,5,5-테트라메틸-1,3,2-디옥사보로란-2-일)-5,6-다이하이드로피리딘-1(2H)-카르복실레이트 (2.7 g, 8.67 mmol), 4-브로모-1,2-다이클로로벤젠 (2.2 g, 9.53 mmol), 제삼인산칼륨 (2.8 g, 13.00 mmol)과 Pd(PPh₃)₄ (361 mg, 0.31 mmol)을 무수 1,4-다이옥산 (7 mL)에 용해시킨 후, 물 (1.8 mL)을 넣고 85 ℃ 온도에서 하룻밤동안 교반하였다. 반응 종결을 TLC로 확인한 후 감압 증류하였다. 잔사를 실리카겔 컬럼크로마토그래피법 (헥산/에틸 아세테이트 = 6:1)으로 정제하여 표제화합물 (2.1 g, 72%)을 얻었다. Tert -butyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -5,6-dihydropyridine-1 ( 2H ) under argon atmosphere -Carboxylate (2.7 g, 8.67 mmol), 4-bromo-1,2-dichlorobenzene (2.2 g, 9.53 mmol), potassium triphosphate (2.8 g, 13.00 mmol) and Pd (PPh ₃ ) ₄ ( 361 mg, 0.31 mmol) was dissolved in anhydrous 1,4-dioxane (7 mL), water (1.8 mL) was added thereto, and the mixture was stirred at 85 ° C. overnight. After completion of the reaction by TLC, distillation was carried out under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 6: 1) to obtain the title compound (2.1 g, 72%).

¹H NMR (300 MHz, CDCl₃) δ 7.45 (d, J = 1.9 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.49 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 6.06 (bs, 1H), 4.08 (d, J = 2.4 Hz, 1H), 3.64 (t, J = 5.6 Hz, 2H), 2.48 (bs, 2H), 1.50 (s, 9H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.45 (d, J = 1.9 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.49 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 6.06 (bs, 1H), 4.08 (d, J = 2.4 Hz, 1H), 3.64 (t, J = 5.6 Hz, 2H), 2.48 (bs, 2H), 1.50 (s, 9H)

실시예 22. tert-부틸 4-(3,4-다이클로로페닐)피페리딘-1-카르복실레이트의 합성Example 22 Synthesis of tert -Butyl 4- (3,4-dichlorophenyl) piperidine-1-carboxylate

tert-부틸 4-(3,4-다이클로로페닐)-5,6-다이하이드로피리딘-1(2H)-카르복실레이트 (2.3 g, 6.91 mmol)를 무수 메탄올 (58 mL)에 용해시키고, Pd/C (147 mg, 1.38 mmol)을 넣은 후 수소 대기 하에 상온에서 하룻밤동안 교반하였다. 셀라이트로 필터하고 감압한 후 반응을 종결을 NMR로 확인하였다. 반응 혼합물을 실리카겔 혼합물을 실리카겔로 여과 정제하여 표제화합물 (2.03 g, 89%)을 얻었다. tert -butyl 4- (3,4-dichlorophenyl) -5,6-dihydropyridine-1 ( 2H ) -carboxylate (2.3 g, 6.91 mmol) is dissolved in anhydrous methanol (58 mL), Pd / C (147 mg, 1.38 mmol) was added thereto, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. After filtering with celite and depressurizing, the reaction was terminated by NMR. The reaction mixture was purified by silica gel mixture with silica gel to give the title compound (2.03 g, 89%).

¹H NMR (300 MHz, CDCl₃) δ 7.23 (d, J = 8.3 Hz, 1H), 7.17 (d, J = 1.8 Hz, 3H), 6.92 (dd, J = 8.3 Hz, 1.8 Hz, 1H), 4.15 (d, J = 11.0 Hz, 2H), 2.71 (t, J = 12.4 Hz, 2H), 2.54 (d, J = 12.1 Hz, 1H), 1.65 (d, J = 12.3 Hz, 2H), 1.54-1.44 (m, 2H), 1.39 (s, 9H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.23 (d, J = 8.3 Hz, 1H), 7.17 (d, J = 1.8 Hz, 3H), 6.92 (dd, J = 8.3 Hz, 1.8 Hz, 1H), 4.15 (d, J = 11.0 Hz, 2H), 2.71 (t, J = 12.4 Hz, 2H), 2.54 (d, J = 12.1 Hz, 1H), 1.65 (d, J = 12.3 Hz, 2H), 1.54- 1.44 (m, 2H), 1.39 (s, 9H)

실시예 23. 4-(3,4-다이클로로페닐)피페리딘의 합성Example 23. Synthesis of 4- (3,4-dichlorophenyl) piperidine

아르곤 대기 하에 tert-부틸 4-(3,4-다이클로로페닐)피페리딘-1-카르복실레이트 (2.03 g, 6.15 mmol)을 무수 다이클로로메탄 (31 mL)에 용해시킨 후 0 ℃로 냉각하고 트리플루오르아세트산 (16.0 mL, 209.0 mmol)을 적가한 후 상온에서 5시간동안 교반하였다. 반응 종결을 TLC로 확인 한 다음 1 N 수산화나트륨 수용액으로 세척한 다음, 다이클로로메탄으로 추출하고 유기용액 층을 물과 포화 염화나트륨 수용액으로 다시 세척한 후 황산나트륨으로 건조시키고 여과한 후 감압 증류하여 표제화합물 (1.3 g, 91%)을 얻었다. Tert -butyl 4- (3,4-dichlorophenyl) piperidine-1-carboxylate (2.03 g, 6.15 mmol) was dissolved in anhydrous dichloromethane (31 mL) under argon atmosphere and then cooled to 0 ° C. Trifluoroacetic acid (16.0 mL, 209.0 mmol) was added dropwise and stirred at room temperature for 5 hours. After completion of the reaction by TLC, the mixture was washed with 1N aqueous sodium hydroxide solution, extracted with dichloromethane, the organic layer was washed again with water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and distilled under reduced pressure. (1.3 g, 91%) was obtained.

¹H NMR (300 MHz, CDCl₃) δ 7.23 (d, J = 8.3 Hz, 1H), 7.17 (d, J = 1.8 Hz, 1H), 6.92 (dd, J = 8.3 Hz, 1.8 Hz, 1H), 3.03 (d, J = 13.8 Hz, 2H), 2.60 (t, J = 12.1 Hz, 2H), 2.48 (t, J = 13.8 1H), 1.63 (d, J = 12.7 1H), 1.51-1.43 (m, 2H+1H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.23 (d, J = 8.3 Hz, 1H), 7.17 (d, J = 1.8 Hz, 1H), 6.92 (dd, J = 8.3 Hz, 1.8 Hz, 1H), 3.03 (d, J = 13.8 Hz, 2H), 2.60 (t, J = 12.1 Hz, 2H), 2.48 (t, J = 13.8 1H), 1.63 (d, J = 12.7 1H), 1.51-1.43 (m, 2H + 1H)

실시예 24. 2-(2-(4-(3,4-다이클로로페닐)피페리딘-1-일)에틸)아이소인돌린-1,3-다이온의 합성Example 24. Synthesis of 2- (2- (4- (3,4-dichlorophenyl) piperidin-1-yl) ethyl) isoindolin-1,3-dione

아르곤 대기 하에 4-(3,4-다이클로로페닐)피페리딘 (1.3 g, 5.65 mmol)을 무수 N,N-다이메틸폼아마이드 (17 mL)에 용해시킨 후 N-(2-브로모에틸)프탈이마이드 (1.4 g, 5.65 mmol), 탄산나트륨 (599 mg, 5.65 mmol)과 소듐아이오다이드 (169 mg, 1.13 mmol)를 적가한 후 90 ℃에서 하룻밤동안 교반하였다. 반응 종결을 TLC로 확인한 후 포화 NaHCO₃ 수용액으로 세척한 다음 헥산과 에틸 아세테이트 혼합용매(헥산:에틸 아세테이트=2:1)로 추출하였다. 유기용액 층을 물과 포화 염화나트륨 수용액으로 다시 세척한 후 황산나트륨으로 건조시키고 여과한 후 감압 증류하였다. 잔사를 실리카겔 컬럼크로마토그래피법 (헥산/에틸 아세테이트 = 5:1)으로 정제하여 표제화합물 (1.0 g, 45%)을 백색 고체로 얻었다.4- (3,4-dichlorophenyl) piperidine (1.3 g, 5.65 mmol) was dissolved in anhydrous N, N -dimethylformamide (17 mL) under argon atmosphere and then N- (2-bromoethyl Phthalimide (1.4 g, 5.65 mmol), sodium carbonate (599 mg, 5.65 mmol) and sodium iodide (169 mg, 1.13 mmol) were added dropwise and stirred overnight at 90 ° C. After completion of the reaction by TLC, the resultant was washed with saturated NaHCO ₃ aqueous solution and extracted with hexane and ethyl acetate mixed solvent (hexane: ethyl acetate = 2: 1). The organic solution layer was washed again with water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and distilled under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 5: 1) to give the title compound (1.0 g, 45%) as a white solid.

¹H NMR (300 MHz, CDCl₃) δ 7.87-7.81 (m, 2H), 7.73-7.68 (m, 2H), 7.43 (d, J = 2.1 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.19 (dd, J = 8.4 Hz, 2.1 Hz, 1H), 6.07 (bs, 1H), 3.75 (t, J = 8.6 Hz, 2H), 3.00 (d, J = 13.1 Hz, 2H), 2.56 (t, J = 8.6 Hz, 2H), 2.41-2.30 (m, 1H), 2.03 (dt, J = 14.3 Hz, 5.6 Hz, 2H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.87-7.81 (m, 2H), 7.73-7.68 (m, 2H), 7.43 (d, J = 2.1 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.19 (dd, J = 8.4 Hz, 2.1 Hz, 1H), 6.07 (bs, 1H), 3.75 (t, J = 8.6 Hz, 2H), 3.00 (d, J = 13.1 Hz, 2H), 2.56 (t, J = 8.6 Hz, 2H), 2.41-2.30 (m, 1H), 2.03 (dt, J = 14.3 Hz, 5.6 Hz, 2H)

실시예 25. 2-(4-(3,4-다이클로로페닐)피페리딘-1-일)에탄아민의 합성Example 25 Synthesis of 2- (4- (3,4-Dichlorophenyl) piperidin-1-yl) ethanamine

아르곤 대기 하에 2-(2-(4-(3,4-다이클로로페닐)피페리딘-1-일)에틸)아이소인돌린-1,3-다이온 (1.0 g, 2.48 mmol)을 무수 에탄올 (9 mL)에 용해시킨 후, 하이드라진 하이드레이트 용액 (0.47 mL, 7.44 mmol)을 적가한 후 70 ℃에서 2시간동안 교반하였다. 반응종결을 TLC로 확인한 후 다이클로로메탄으로 추출하고, 유기용액 층을 물과 포화 염화나트륨 수용액으로 다시 세척한 후 황산나트륨으로 건조시키고 여과한 후 감압 증류하여 표제화합물 (542 mg, 80%)을 얻었다.Under argon atmosphere, 2- (2- (4- (3,4-dichlorophenyl) piperidin-1-yl) ethyl) isoindolin-1,3-dione (1.0 g, 2.48 mmol) was dissolved in anhydrous ethanol. After dissolving in (9 mL), hydrazine hydrate solution (0.47 mL, 7.44 mmol) was added dropwise and stirred at 70 ° C. for 2 hours. After completion of the reaction by TLC, the mixture was extracted with dichloromethane, and the organic solution layer was washed again with water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and distilled under reduced pressure to obtain the title compound (542 mg, 80%).

¹H NMR (300 MHz, CDCl₃) δ 7.38 (d, J = 1.5 Hz, 1H), 7.29 (d, J = 8.5 Hz, 1H), 7.14 (dd, J = 8.4 Ha, 1.5 Hz, 1H), 2.83 (d, J = 13.1 Hz, 2H), 2.49 (t, J = 7.7 Hz, 2H), 2.23-2.2.00 (m, 1H+2H), 1.99 (dt, J = 17.5 Hz, 7.3 Hz, 2H), 1.76-1.54 (m, 2H+2H), 1.33 (bs, 2H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.38 (d, J = 1.5 Hz, 1H), 7.29 (d, J = 8.5 Hz, 1H), 7.14 (dd, J = 8.4 Ha, 1.5 Hz, 1H), 2.83 (d, J = 13.1 Hz, 2H), 2.49 (t, J = 7.7 Hz, 2H), 2.23-2.2.00 (m, 1H + 2H), 1.99 (dt, J = 17.5 Hz, 7.3 Hz, 2H ), 1.76-1.54 (m, 2H + 2H), 1.33 (bs, 2H)

실시예 26. 2-(4-(3,4-다이클로로페닐)피페리딘-1-일)에탄아민의 합성Example 26. Synthesis of 2- (4- (3,4-dichlorophenyl) piperidin-1-yl) ethanamine

아르곤 대기 하에 2-(2-(4-(3,4-다이클로로페닐)피페리딘-1-일)에틸)아이소인돌린-1,3-다이온 (1.0 g, 2.48 mmol)을 무수 에탄올 (9 mL)에 용해시킨 후 하이드라진 하이드레이트 용액 (0.47 mL, 7.44 mmol)을 적가하고 70 ℃에서 2시간동안 교반하였다. 반응 종결을 TLC로 확인한 후 다이클로로메탄으로 추출하고, 유기용액 층을 물과 포화 염화나트륨 수용액으로 다시 세척한 후 황산나트륨으로 건조시키고 여과한 후 감압 증류하여 표제화합물 (542 mg, 80%)을 얻었다.Under argon atmosphere, 2- (2- (4- (3,4-dichlorophenyl) piperidin-1-yl) ethyl) isoindolin-1,3-dione (1.0 g, 2.48 mmol) was dissolved in anhydrous ethanol. After dissolving in (9 mL), hydrazine hydrate solution (0.47 mL, 7.44 mmol) was added dropwise and stirred at 70 ° C. for 2 hours. After completion of the reaction by TLC, the mixture was extracted with dichloromethane, the organic solution layer was washed again with water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and distilled under reduced pressure to obtain the title compound (542 mg, 80%).

실시예 27. 2-(4-(3,4-다이클로로페닐)피페리딘-1-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)에탄아민과 2-(4-(3,4-다이클로로페닐)-5,6-다이하이드로피리딘-1(2H)-일)-N,N-비스((3-아이소프로필아이속사졸-5-일)메틸)에탄아민의 합성Example 27. 2- (4- (3,4-Dichlorophenyl) piperidin-1-yl) -N -((3-isopropylisoxazol-5-yl) methyl) ethanamine and 2- (4- (3,4-Dichlorophenyl) -5,6-dihydropyridin-1 ( 2H ) -yl) -N, N -bis ((3-isopropylisoxazol-5-yl) methyl Synthesis of Ethanamine

아르곤 대기 하에 2-(4-(3,4-다이클로로페닐)-5,6-다이하이드로피리딘-1(2H)-일)에탄아민 (549 mg, 2.02 mmol)을 무수 다이클로로메탄 (41 mL)에 용해시킨 후, 다이클로로메탄 (8 mL)에 녹아 있는 3-아이소프로필아이속사졸-5-카르발데하이드 (281 mg, 2.02 mmol)를 적가한 후, 4 Å 분자체 분말 (1.29 g)을 첨가하였다. 2시간 후에 소듐 트리아세톡시보로하이드라이드 (643 mg, 3.03 mmol)을 적가한 후 상온에서 2시간동안 교반하였다. 반응 종결을 TLC로 확인한 후 1 N 수산화나트륨 수용액으로 세척한 다음, 다이클로로메탄으로 추출하였다. 유기용액 층을 물과 포화 염화나트륨 수용액으로 다시 세척한 후 황산나트륨으로 건조시키고 여과한 후 감압 증류하였다. 잔사를 실리카겔 컬럼크로마토그래피법 (CH₂Cl₂/MeOH = 50:1)으로 정제하여 표제화합물을 각각 분리하여 얻었다.Under argon atmosphere, 2- (4- (3,4-dichlorophenyl) -5,6-dihydropyridin-1 ( 2H ) -yl) ethanamine (549 mg, 2.02 mmol) was dissolved in anhydrous dichloromethane (41 mL), then 3- dropwise 3-isopropylisoxazole-5-carbaldehyde (281 mg, 2.02 mmol) dissolved in dichloromethane (8 mL) was added dropwise, followed by 4 Å molecular sieve powder (1.29 g ) Was added. After 2 hours, sodium triacetoxyborohydride (643 mg, 3.03 mmol) was added dropwise and stirred at room temperature for 2 hours. The reaction was terminated by TLC, washed with 1N aqueous sodium hydroxide solution, and then extracted with dichloromethane. The organic solution layer was washed again with water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and distilled under reduced pressure. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ / MeOH = 50: 1) to obtain the title compound.

2-(4-(3,4-다이클로로페닐)피페리딘-1-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)에탄아민 : 수율 72%, ¹H NMR (300 MHz, CDCl₃) δ 7.31 (d, J = 1.6 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.07 (dd, J = 8.5 Hz, 1.6 Hz, 1H), 5.94 (bs, 1H), 3.78 (s, 2H), 3.02 (bs, 2H), 2.96-2.87 (m, 1H), 2.68 (t, J = 5.7 Hz, 2H), 2.57-2.48 (m, 4H), 2.35 (bs, 2H), 2.26 (bs, 1H), 1.15 (d, J = 6.9 Hz, 6H)2- (4- (3,4-dichlorophenyl) piperidin-1-yl) - N - ((3- isopropyl-isoxazol-5-yl) methyl) ethanamine: yield 72%, ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.31 (d, J = 1.6 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.07 (dd, J = 8.5 Hz, 1.6 Hz, 1H), 5.94 ( bs, 1H), 3.78 (s, 2H), 3.02 (bs, 2H), 2.96-2.87 (m, 1H), 2.68 (t, J = 5.7 Hz, 2H), 2.57-2.48 (m, 4H), 2.35 (bs, 2H), 2.26 (bs, 1H), 1.15 (d, J = 6.9 Hz, 6H)

2-(4-(3,4-다이클로로페닐)-5,6-다이하이드로피리딘-1(2H)-일)-N,N-비스((3-아이소프로필아이속사졸-5-일)메틸)에탄아민 : 수율 3%, ¹H NMR (300 MHz, CDCl₃) δ 7.44 (d, J = 2.1 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.20 (dd, J = 8.4 Hz, 2.1 Hz, 1H), 6.09 (s, 2H), 6.08 (bs, 1H), 3.87 (s, 4H), 3.18 (q, J = 3.0 Hz, 2H), 3.10-3.01 (m, 2H), 2.81-2.65 (m, 7H), 2.50 (bs, 2H), 1.29 (d, J = 6.9 Hz, 12H)
2- (4- (3,4-Dichlorophenyl) -5,6-dihydropyridin-1 ( 2H ) -yl) -N, N -bis ((3-isopropylisoxazol-5-yl ) Methyl) ethanamine: yield 3%, ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.44 (d, J = 2.1 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.20 (dd, J = 8.4 Hz, 2.1 Hz, 1H), 6.09 (s, 2H), 6.08 (bs, 1H), 3.87 (s, 4H), 3.18 (q, J = 3.0 Hz, 2H), 3.10-3.01 (m, 2H ), 2.81-2.65 (m, 7H), 2.50 (bs, 2H), 1.29 (d, J = 6.9 Hz, 12H)

실시예 28. N,N-비스((3-아이소프로필아이속사졸-5-일)메틸)-2-(4-o-톨릴-5,6-다이하이드로피리딘-1(2H)-일)에탄아민의 합성Example 28. N, N -bis ((3-isopropylisoxazol-5-yl) methyl) -2- (4- o -tolyl-5,6-dihydropyridin-1 ( 2H ) -yl Synthesis of Ethanamine

아르곤 대기 하에 2-(4-o-톨릴-5,6-다이하이드로피리딘-1(2H)-일)에탄아민 (23 mg, 0.11 mmol)을 무수 다이클로로메탄 (3 mL)에 용해시킨 후, 다이클로로메탄 (2 mL)에 녹아 있는 3-아이소프로필아이속사졸-5-카르발데하이드 (0.02 mg, 0.11 mmol)을 적가한 후, 4 Å 분자체 분말 (54 mg)를 첨가하였다. 2시간 후에 소듐 트리아세톡시보로하이드라이드 (0.03 g, 0.16 mmol)를 적가한 후 상온에서 2시간동안 교반하였다. 반응 종결을 TLC로 확인 한 후 1 N 수산화나트륨 수용액으로 세척한 다음, 다이클로로메탄으로 추출하였다. 유기용액 층을 물과 포화 염화나트륨 수용액으로 다시 세척한 후 황산나트륨으로 건조시키고 여과한 후 감압 증류하였다. 잔사를 실리카겔 컬럼크로마토그래피법 (CH₂Cl₂/MeOH = 50:1)으로 정제하여 표제화합물 (4.5 mg, 9%)을 얻었다.Dissolve 2- (4- o -tolyl-5,6-dihydropyridin-1 ( 2H ) -yl) ethanamine (23 mg, 0.11 mmol) in anhydrous dichloromethane (3 mL) under an argon atmosphere. , 3-isopropylisoxazole-5-carbaldehyde (0.02 mg, 0.11 mmol) dissolved in dichloromethane (2 mL) was added dropwise, followed by 4 Å molecular sieve powder (54 mg). After 2 hours, sodium triacetoxyborohydride (0.03 g, 0.16 mmol) was added dropwise and stirred at room temperature for 2 hours. The reaction was terminated by TLC, washed with 1N aqueous sodium hydroxide solution, and then extracted with dichloromethane. The organic solution layer was washed again with water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and distilled under reduced pressure. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ / MeOH = 50: 1) to obtain the title compound (4.5 mg, 9%).

¹H NMR (300 MHz, CDCl₃) δ 7.18-7.10 (m, 4H), 6.11 (s, 2H), 5.53 (bs, 1H), 3.89 (s, 4H), 3.16 (d, J = 2.9 Hz, 2H), 3.11-3.00 (m, 2H), 2.82 (t, J = 6.6 Hz, 2H), 2.74-2.67 (m, 4H), 2.39 (bs, 2H), 2.30 (s, 3H), 1.30 (d, J = 7.0 Hz, 12H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.18-7.10 (m, 4H), 6.11 (s, 2H), 5.53 (bs, 1H), 3.89 (s, 4H), 3.16 (d, J = 2.9 Hz, 2H), 3.11-3.00 (m, 2H), 2.82 (t, J = 6.6 Hz, 2H), 2.74-2.67 (m, 4H), 2.39 (bs, 2H), 2.30 (s, 3H), 1.30 (d , J = 7.0 Hz, 12H)

상기 실시예들에서 예시된 방법을 근거로 하여, 상기 화학식 1로 표시되는 화합물을 합성하였다. 제조된 상기 화학식 1로 표시되는 화합물의 분광학적 데이터는 하기에 나타내었다.
Based on the method illustrated in the above examples, the compound represented by Formula 1 was synthesized. Spectroscopic data of the compound represented by Formula 1 is shown below.

33% 수율: ¹H NMR (400 MHz, CDCl₃) δ ppm 2.24 (s, 3H) 2.45-2.56 (m, 6H) 2.71 (t, J = 5.81 Hz, 2H) 3.14 (br t, J = 5.05 Hz, 5H) 3.86 (s, 2H) 5.96 (s, 1H) 6.74 (t, J = 6.69 Hz, 2H) 6.82 (t, J = 2.15 Hz, 1H) 7.11 (t, J = 8.08 Hz, 2H)
33% yield: ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 2.24 (s, 3H) 2.45-2.56 (m, 6H) 2.71 (t, J = 5.81 Hz, 2H) 3.14 (br t, J = 5.05 Hz , 5H) 3.86 (s, 2H) 5.96 (s, 1H) 6.74 (t, J = 6.69 Hz, 2H) 6.82 (t, J = 2.15 Hz, 1H) 7.11 (t, J = 8.08 Hz, 2H)

33% 수율: ¹H NMR (400 MHz, CDCl₃) δ ppm 1.25 (t, J = 7.58 Hz, 3H) 2.05 (br s, 1H) 2.49-2.59 (m, 6H) 2.67 (q, J = 7.75 Hz, 2H) 2.75 (t, J = 5.94 Hz, 2H) 3.17 (br t, J = 5.31 Hz, 4H) 3.90 (s, 2H) 6.01 (s, 1H) 6.77 (td, J = 8.27, 2.15 Hz, 2H), 6.85 (t, J = 2.15 Hz, 1H), 7.14 (t, J = 8.21 Hz, 1H)
33% yield: ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.25 (t, J = 7.58 Hz, 3H) 2.05 (br s, 1H) 2.49-2.59 (m, 6H) 2.67 (q, J = 7.75 Hz , 2H) 2.75 (t, J = 5.94 Hz, 2H) 3.17 (br t, J = 5.31 Hz, 4H) 3.90 (s, 2H) 6.01 (s, 1H) 6.77 (td, J = 8.27, 2.15 Hz, 2H ), 6.85 (t, J = 2.15 Hz, 1H), 7.14 (t, J = 8.21 Hz, 1H)

74% 수율: ¹H NMR (400 MHz, CDCl₃) δ ppm 1.15 (d, J = 7.07 Hz, 6H) 2.41(br d, J = 5.81 Hz, 6H) 2.63(t, J = 5.81 Hz, 2H) 2.87-2.94(m, 1H) 3.03(br t, J = 5.05 Hz, 4H) 3.77(s, 2H) 5.92(s, 1H) 6.64(t, J = 7.83 Hz, 2H) 6.73(d, J = 1.77 Hz, 1H) 7.01(t, J = 8.08 Hz, 1H)
74% yield: ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.15 (d, J = 7.07 Hz, 6H) 2.41 (br d, J = 5.81 Hz, 6H) 2.63 (t, J = 5.81 Hz, 2H) 2.87-2.94 (m, 1H) 3.03 (br t, J = 5.05 Hz, 4H) 3.77 (s, 2H) 5.92 (s, 1H) 6.64 (t, J = 7.83 Hz, 2H) 6.73 (d, J = 1.77 Hz, 1H) 7.01 (t, J = 8.08 Hz, 1H)

44% 수율: ¹H NMR (400 MHz, CDCl₃) δ ppm 2.28 (s, 3H), 2.59-2.67 (m, 6H), 2.79 (t, J = 5.94 Hz, 2H), 3.17 (br t, J = 4.80 Hz, 4H), 3.92 (s, 2H), 6.02 (s, 1H), 6.83 (d, J = 8.84 Hz, 2H), 7.20 (d, J = 9.09 Hz, 2H)
44% yield: ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 2.28 (s, 3H), 2.59-2.67 (m, 6H), 2.79 (t, J = 5.94 Hz, 2H), 3.17 (br t, J = 4.80 Hz, 4H), 3.92 (s, 2H), 6.02 (s, 1H), 6.83 (d, J = 8.84 Hz, 2H), 7.20 (d, J = 9.09 Hz, 2H)

29% 수율: ¹H NMR (400 MHz, CDCl₃) δ ppm 1.25 (t, J = 7.71 Hz, 3H), 2.28 (s, 1H), 2.56 (br t, J = 6.32 Hz, 4H), 2.50-2.60 (m, 2H), 2.67 (q, J = 7.75 Hz, 2H), 2.75 (t, J = 5.94 Hz, 2H), 3.14 (br t, J = 5.05 Hz, 4H), 3.90 (s, 2H), 6.02 (s, 1H), 6.77-6.85 (m, 2H), 7.14-7.21 (m, 2H)
29% yield: ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.25 (t, J = 7.71 Hz, 3H), 2.28 (s, 1H), 2.56 (br t, J = 6.32 Hz, 4H), 2.50- 2.60 (m, 2H), 2.67 (q, J = 7.75 Hz, 2H), 2.75 (t, J = 5.94 Hz, 2H), 3.14 (br t, J = 5.05 Hz, 4H), 3.90 (s, 2H) , 6.02 (s, 1H), 6.77-6.85 (m, 2H), 7.14-7.21 (m, 2H)

27% 수율: ¹H NMR (400 MHz, CDCl₃) δ ppm 1.22 (d, J = 7.07 Hz, 6H), 2.00 (br s, 1H), 2.44-2.58 (m, 6H), 2.71 (t, J = 5.94 Hz, 2H), 2.95-3.02 (m, 1H), 3.08 (br t, J = 5.05 Hz, 4H), 3.85 (s, 2H), 5.99 (s, 1H), 6.77 (d, J = 9.09 Hz, 2H), 7.13 (d, J = 9.09 Hz, 6H)
27% yield: ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.22 (d, J = 7.07 Hz, 6H), 2.00 (br s, 1H), 2.44-2.58 (m, 6H), 2.71 (t, J = 5.94 Hz, 2H), 2.95-3.02 (m, 1H), 3.08 (br t, J = 5.05 Hz, 4H), 3.85 (s, 2H), 5.99 (s, 1H), 6.77 (d, J = 9.09 Hz, 2H), 7.13 (d, J = 9.09 Hz, 6H)

36% 수율: ¹H NMR (400 MHz, CDCl₃) δ ppm 2.22 (s, 3H), 2.43-2.48 (m, 10H), 2.67 (t, J = 5.94 Hz, 2H), 3.83 (s, 2H), 4.21 (s, 1H), 5.94 (s, 1H), 7.14 (t, J = 7.58 Hz, 2H), 7.24 (t, J = 7.58 Hz, 4H), 7.40 (d, J = 7.58 Hz, 4H)
36% yield: ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 2.22 (s, 3H), 2.43-2.48 (m, 10H), 2.67 (t, J = 5.94 Hz, 2H), 3.83 (s, 2H) , 4.21 (s, 1H), 5.94 (s, 1H), 7.14 (t, J = 7.58 Hz, 2H), 7.24 (t, J = 7.58 Hz, 4H), 7.40 (d, J = 7.58 Hz, 4H)

39% 수율: ¹H NMR (400 MHz, CDCl₃) δ ppm 1.25 (q, J = 7.41 Hz, 3H), 2.47(br s, 6H), 2.51 (t, J = 6.06 Hz, 4H), 2.65 (q, J = 7.58 Hz, 2H), 2.71 (t, J = 6.06 Hz, 2H), 3.08 (br s, 1H), 3.87 (s, 2H), 4.22 (s, 1H), 6.00 (s, 1H), 7.15 (t, J = 6.1 Hz, 2H), 7.26 (t, J = 7.45 Hz, 4H), 7.40 (d, J = 7.07 Hz, 4H)
39% yield: ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.25 (q, J = 7.41 Hz, 3H), 2.47 (br s, 6H), 2.51 (t, J = 6.06 Hz, 4H), 2.65 ( q, J = 7.58 Hz, 2H), 2.71 (t, J = 6.06 Hz, 2H), 3.08 (br s, 1H), 3.87 (s, 2H), 4.22 (s, 1H), 6.00 (s, 1H) , 7.15 (t, J = 6.1 Hz, 2H), 7.26 (t, J = 7.45 Hz, 4H), 7.40 (d, J = 7.07 Hz, 4H)

52% 수율: ¹H NMR (400 MHz, CDCl₃) δ ppm 1.22 (d, J = 6.82 Hz, 6H), 2.03 (br s, 1H), 2.42 (br s, 6H), 2.46 (t, J = 6.06 Hz, 4H), 2.67 (t, J = 5.81 Hz, 2H), 2.95-3.02 (m, 1H), 3.81 (s, 2H), 4.20 (s, 1H), 5.98 (s, 1H), 7.08-7.17 (m, 2H), 7.23 (t, J = 7.58 Hz, 4H), 7.39 (d, J = 8.08 Hz, 4H)
52% ^{yield: 1 H NMR (400 MHz,} CDCl 3) δ ppm 1.22 (d, J = 6.82 Hz, 6H), 2.03 (br s, 1H), 2.42 (br s, 6H), 2.46 (t, J = 6.06 Hz, 4H), 2.67 ( t, J = 5.81 Hz, 2H), 2.95-3.02 (m, 1H), 3.81 (s, 2H), 4.20 (s, 1H), 5.98 (s, 1H), 7.08- J = 8.08 Hz, 4H), 7.17 (m, 2H), 7.23 (t, J = 7.58 Hz,

59% 수율: ¹H NMR (400 MHz, CDCl₃) δ ppm 2.21 (s, 3H), 2.43-2.57 (m, 7H), 2.69 (t, J = 5.94 Hz, 2H), 2.91 (s, 1H), 3.12 (t, J = 5.05 Hz, 4H), 3.83 (s, 2H), 5.93 (s, 1H), 6.78 (t, J = 7.20 Hz, 1H), 6.85 (d, J = 7.83 Hz, 2H), 7.19 (t, J = 7.33 Hz, 2H)
59% yield: ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 2.21 (s, 3H), 2.43-2.57 (m, 7H), 2.69 (t, J = 5.94 Hz, 2H), 2.91 (s, 1H) , 3.12 (t, J = 5.05 Hz, 4H), 3.83 (s, 2H), 5.93 (s, 1H), 6.78 (t, J = 7.20 Hz, 1H), 6.85 (d, J = 7.83 Hz, 2H) , 7.19 (t, J = 7.33 Hz, 2H)

25% 수율: ¹H NMR (400 MHz, CDCl₃) δ ppm 1.26 (t, J = 7.58 Hz, 3H), 2.11 (br s, 1H), 2.51-2.61 (m, 6H), 2.67 (q, J = 7.58 Hz, 2H), 2.76 (t, J = 5.94 Hz, 2H), 3.18 (br t, J = 5.31 Hz, 4H), 3.91 (s, 2H), 6.02 (s, 1H), 6.84 (t, J = 7.20 Hz, 1H), 6.92 (d, J = 7.83 Hz, 2H), 7.20-7.30 (m, 2H)
25% yield: ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.26 (t, J = 7.58 Hz, 3H), 2.11 (br s, 1H), 2.51-2.61 (m, 6H), 2.67 (q, J = 7.58 Hz, 2H), 2.76 (t, J = 5.94 Hz, 2H), 3.18 (br t, J = 5.31 Hz, 4H), 3.91 (s, 2H), 6.02 (s, 1H), 6.84 (t, J = 7.20 Hz, 1H), 6.92 (d, J = 7.83 Hz, 2H), 7.20-7.30 (m, 2H)

41% 수율: ¹H NMR (400 MHz, CDCl₃) δ ppm 1.28 (d, J = 6.82 Hz, 6H), 2.0 (br s, 1H), 2.56-2.66 (m, 6H), 2.79 (t, J = 5.94 Hz, 2H), 3.01-3.08 (m, 1H), 3.21 (br t, J = 5.05 Hz, 4H), 3.92 (s, 2H), 6.04 (s, 1H), 6.86 (t, J = 7.27 Hz, 1H), 6.93 (d, J = 7.83 Hz, 2H), 7.22-7.31 (m, 2H)
41% yield: ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.28 (d, J = 6.82 Hz, 6H), 2.0 (br s, 1H), 2.56-2.66 (m, 6H), 2.79 (t, J = 5.94 Hz, 2H), 3.01-3.08 (m, 1H), 3.21 (br t, J = 5.05 Hz, 4H), 3.92 (s, 2H), 6.04 (s, 1H), 6.86 (t, J = 7.27 Hz, 1H), 6.93 (d, J = 7.83 Hz, 2H), 7.22-7.31 (m, 2H)

67% 수율: ¹H NMR (300 MHz, CDCl₃) δ 7.32-7.38 (m, 1H), 7.04-7.11 (m, 3H), 6.06 (s, 1H), 3.75 (s, 2H), 3.24-3.27 (m, 4H), 3.02-3.11 (m, 1H), 2.56-2.66 (m, 8H), 2.37 (s, 3H), 1.29 (d, J = 6.9 Hz, 6H)
67% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.32-7.38 (m, 1H), 7.04-7.11 (m, 3H), 6.06 (s, 1H), 3.75 (s, 2H), 3.24-3.27 (m, 4H), 3.02-3.11 (m, 1H), 2.56-2.66 (m, 8H), 2.37 (s, 3H), 1.29 (d, J = 6.9 Hz, 6H)

50% 수율: ¹H NMR (300 MHz, CDCl₃) δ 7.01-6.92 (m, 3H), 6.06 (s, 1H), 3.93 (s, 2H), 3.08-3.01 (m, 1H), 2.61-2.55 (m, 8H), 2.28 (d, J =3.3 Hz, 6H), 2.06 (s, 1H), 1.31 (d, J = 21.8 Hz, 6H)
50% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.01-6.92 (m, 3H), 6.06 (s, 1H), 3.93 (s, 2H), 3.08-3.01 (m, 1H), 2.61-2.55 (m, 8H), 2.28 (d, J = 3.3 Hz, 6H), 2.06 (s, 1H), 1.31 (d, J = 21.8 Hz, 6H)

93% 수율: ¹H NMR (300 MHz, CDCl₃) δ 6.92-7.01 (m, 3H), 6.06 (s, 1H), 3.75 (s, 2H), 3.02-3.09 (m, 1H), 2.91-2.94 (m, 4H), 2.57-2.66 (m, 8H), 2.36 (s, 3H), 2.28 (s, 6H), 1.29 (d, J = 7.0 Hz, 6H)
93% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ 6.92-7.01 (m, 3H), 6.06 (s, 1H), 3.75 (s, 2H), 3.02-3.09 (m, 1H), 2.91-2.94 (m, 4H), 2.57-2.66 (m, 8H), 2.36 (s, 3H), 2.28 (s, 6H), 1.29 (d, J = 7.0 Hz, 6H)

67% 수율: ¹H NMR (300 MHz, CDCl₃) δ 7.19-7.23 (m, 2H), 6.82-6.86 (m, 2H), 6.05 (s, 1H), 3.74 (s, 2H), 3.15-3.19 (m, 4H), 3.01-3.08 (m, 1H), 2.56-2.64 (m, 8), 2.36 (s, 3H), 1.29 (d, J = 6.9 Hz, 6H)
67% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.19-7.23 (m, 2H), 6.82-6.86 (m, 2H), 6.05 (s, 1H), 3.74 (s, 2H), 3.15-3.19 (m, 4H), 3.01-3.08 (m, 1H), 2.56-2.64 (m, 8), 2.36 (s, 3H), 1.29 (d, J = 6.9 Hz, 6H)

33% 수율: ¹H NMR (300 MHz, CDCl₃) δ 7.20 (dd, J = 5.0, 2.1 Hz, 2H), 6.84 (dd, J = 5.1, 2.0 Hz, 2H), 6.07 (s, 1H), 3.91 (s, 2H), 3.14-3.18 (m, 4H), 2.77-2.81 (m, 2H), 2.55-2.60 (m, 6H), 1.33 (s, 9H)33% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.20 (dd, J = 5.0, 2.1 Hz, 2H), 6.84 (dd, J = 5.1, 2.0 Hz, 2H), 6.07 (s, 1H), 3.91 (s, 2H), 3.14-3.18 (m, 4H), 2.77-2.81 (m, 2H), 2.55-2.60 (m, 6H), 1.33 (s, 9H)

97% 수율 : ¹H NMR (300 MHz, CDCl₃) δ 7.21 (d, J = 6.8 Hz, 2H), 6.84 (d, J = 6.9 Hz, 2H), 6.08 (s, 1H), 3.74 (s, 2H), 3.15-3.19 (m, 4H), 2.56-2.64 (m, 8H), 2.36 (s, 3H), 1.34 (s, 9H)
97% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.21 (d, J = 6.8 Hz, 2H), 6.84 (d, J = 6.9 Hz, 2H), 6.08 (s, 1H), 3.74 (s, 2H), 3.15-3.19 (m, 4H), 2.56-2.64 (m, 8H), 2.36 (s, 3H), 1.34 (s, 9H)

37% 수율: ¹H NMR (300 MHz, CDCl₃) δ 7.33-7.38 (m, 1H), 7.05-7.12 (m, 3H), 6.08 (s, 1H), 3.93 (s, 2H), 3.23-3.27 (m, 4H), 2.78-2.82 (m, 2H), 2.57-2.63 (m, 6H), 1.34 (s, 9H)
37% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.33-7.38 (m, 1H), 7.05-7.12 (m, 3H), 6.08 (s, 1H), 3.93 (s, 2H), 3.23-3.27 (m, 4H), 2.78-2.82 (m, 2H), 2.57-2.63 (m, 6H), 1.34 (s, 9H)

97% 수율 : ¹H NMR (300 MHz, CDCl₃) δ 7.28-7.35 (m, 1H), 7.05-7.11 (m, 3H), 6.09 (s, 1H), 3.75 (s, 2H), 3.24-3.27 (m, 4H), 2.59-2.66 (m, 8H), 2.37 (s, 3H), 1.34 (s, 9H)
97% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.28-7.35 (m, 1H), 7.05-7.11 (m, 3H), 6.09 (s, 1H), 3.75 (s, 2H), 3.24-3.27 (m, 4H), 2.59-2.66 (m, 8H), 2.37 (s, 3H), 1.34 (s, 9H)

35% 수율: ¹H NMR (300 MHz, CDCl₃) δ 6.92-7.00 (m, 3H), 6.10 (s, 1H), 3.93 (s, 2H), 2.90-2.93 (m, 4H), 2.80-2.84 (m, 2H), 2.60-2.63 (m, 6H), 2.28 (d, J = 3.5 Hz, 6H), 1.33 (s, 9H)
35% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ 6.92-7.00 (m, 3H), 6.10 (s, 1H), 3.93 (s, 2H), 2.90-2.93 (m, 4H), 2.80-2.84 (m, 2H), 2.60-2.63 (m, 6H), 2.28 (d, J = 3.5 Hz, 6H), 1.33 (s, 9H)

33% 수율: ¹H NMR (300 MHz, CDCl₃) δ 7.19 (d, J = 8.6 Hz, 2H), 6.82 (d, J = 8.9 Hz, 2H), 6.01 (s, 1H), 3.92 (s, 2H), 3.13-3.17 (m, 4H), 2.76-2.79 (m, 2H), 2.51-2.60 (m, 8H), 1.94-2.04 (m, 1H), 0.96 (d, J = 6.6 Hz, 6H)
33% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.19 (d, J = 8.6 Hz, 2H), 6.82 (d, J = 8.9 Hz, 2H), 6.01 (s, 1H), 3.92 (s, 2H), 3.13-3.17 (m, 4H), 2.76-2.79 (m, 2H), 2.51-2.60 (m, 8H), 1.94-2.04 (m, 1H), 0.96 (d, J = 6.6 Hz, 6H)

99% 수율: ¹H NMR (300 MHz, CDCl₃) δ 7.17-7.21 (m, 2H), 6.80-6.86 (m, 2H), 6.01 (s, 1H), 3.75 (s, 2H), 3.15-3.18 (m, 4H), 2.58-2.64 (m, 8H), 2.53-2.55 (d, J = 8.9 Hz, 2H), 2.35 (s, 3H), 1.92-2.01 (m, 1H), 0.96 (d, J = 6.7 Hz, 6H)
99% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.17-7.21 (m, 2H), 6.80-6.86 (m, 2H), 6.01 (s, 1H), 3.75 (s, 2H), 3.15-3.18 (m, 4H), 2.58-2.64 (m, 8H), 2.53-2.55 (d, J = 8.9 Hz, 2H), 2.35 (s, 3H), 1.92-2.01 (m, 1H), 0.96 (d, J = 6.7 Hz, 6H)

54% 수율: ¹H NMR (300 MHz, CDCl₃) δ 7.35 (t, J = 7.9 Hz, 1H), 7.04-7.11 (m, 3H), 6.01 (s, 1H), 3.93 (s, 2H), 3.22-3.25 (m, 4H), 2.76-2.80 (m, 2H), 2.52-2.61 (m, 8H), 1.92-2.01 (m, 1H), 0.97 (d, J = 6.7 Hz, 6H)
54% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.35 (t, J = 7.9 Hz, 1H), 7.04-7.11 (m, 3H), 6.01 (s, 1H), 3.93 (s, 2H), 3.22-3.25 (m, 4H), 2.76-2.80 (m, 2H), 2.52-2.61 (m, 8H), 1.92-2.01 (m, 1H), 0.97 (d, J = 6.7 Hz, 6H)

91% 수율: ¹H NMR (300 MHz, CDCl₃) δ 7.37-7.32 (m, 1H) 7.10-7.04 (m. 3H) 6.02 (s, 1H) 3.76 (s, 2H) 3.27-3.23 (m, 4H) 2.66-2.60 (m, 8H) 2.54 (d, J =7.1 Hz, 2H) 2.36 (s, 3H) 1.85 (s, 1H) 0.97 (d, J = 6.6 Hz, 6H)
91% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.37-7.32 (m, 1H) 7.10-7.04 (m. 3H) 6.02 (s, 1H) 3.76 (s, 2H) 3.27-3.23 (m, 4H ) 2.66-2.60 (m, 8H) 2.54 (d, J = 7.1 Hz, 2H) 2.36 (s, 3H) 1.85 (s, 1H) 0.97 (d, J = 6.6 Hz, 6H)

78% 수율 : ¹H NMR (300 MHz, CDCl₃) δ 7.20 (d, J = 6.9 Hz, 2H), 6.83 (d, J = 6.9 Hz, 2H), 6.04 (s, 1H), 3.74 (s, 2H), 3.13-3.17 (m, 4H), 2.98-3.05 (m, 2H), 2.67-2.72 (m, 2H), 2.59-2.63 (m, 4H), 2.45-2.50 (m, 2H), 1.29 (d, J = 7.0 Hz, 6H), 1.05 (d, J = 6.6 Hz, 6H)
78% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.20 (d, J = 6.9 Hz, 2H), 6.83 (d, J = 6.9 Hz, 2H), 6.04 (s, 1H), 3.74 (s, 2H), 3.13-3.17 (m, 4H), 2.98-3.05 (m, 2H), 2.67-2.72 (m, 2H), 2.59-2.63 (m, 4H), 2.45-2.50 (m, 2H), 1.29 ( d, J = 7.0 Hz, 6H), 1.05 (d, J = 6.6 Hz, 6H)

86% 수율: ¹H NMR (300 MHz, CDCl₃) δ 6.92-7.01 (m, 3H), 6.06 (s, 1H), 3.75 (s, 2H), 2.99-3.06 (m, 2H), 2.89-2.92 (m, 4H), 2.68-2.73 (m, 2H), 2.55-2.65 (m, 4H), 2.47-2.52 (m, 2H), 2.28 (s, 3H), 2.27 (s, 3H), 1.29 (d, J = 6.9 Hz, 6H), 1.06 (d, J = 6.6 Hz, 6H)
86% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ 6.92-7.01 (m, 3H), 6.06 (s, 1H), 3.75 (s, 2H), 2.99-3.06 (m, 2H), 2.89-2.92 (m, 4H), 2.68-2.73 (m, 2H), 2.55-2.65 (m, 4H), 2.47-2.52 (m, 2H), 2.28 (s, 3H), 2.27 (s, 3H), 1.29 (d , J = 6.9 Hz, 6H), 1.06 (d, J = 6.6 Hz, 6H)

34% 수율: ¹H NMR (300 MHz, CDCl₃) δ 7.03 (d, J = 7.9 Hz, 1H), 6.75 (s, 1H), 6.69 (dd, J = 8.1, 2.2 Hz, 1H), 6.05 (s, 1H), 3.92 (s, 2H), 3.13-3.16 (m, 4H), 3.04-3.11 (m, 1H), 2.77-2.81 (m, 2H), 2.55-2.61 (m, 6H), 2.24 (s, 3H), 2.19 (s, 3H), 1.29 (d, J = 7.0 Hz, 6H)
34% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.03 (d, J = 7.9 Hz, 1H), 6.75 (s, 1H), 6.69 (dd, J = 8.1, 2.2 Hz, 1H), 6.05 ( s, 1H), 3.92 (s, 2H), 3.13-3.16 (m, 4H), 3.04-3.11 (m, 1H), 2.77-2.81 (m, 2H), 2.55-2.61 (m, 6H), 2.24 ( s, 3H), 2.19 (s, 3H), 1.29 (d, J = 7.0 Hz, 6H)

88% 수율 : ¹H NMR (300 MHz, CDCl₃) δ 7.03 (d, J = 8.2 Hz, 1H), 6.75 (s, 1H), 6.69 (dd, J = 8.2, 2.5 Hz, 1H), 6.06 (s, 1H), 3.74 (s, 2H), 3.14-3.18 (m, 4H), 3.04-3.11 (m, 1H), 2.57-2.66 (m, 8H), 2.36 (s, 3H), 2.24 (s, 3H), 2.19 (s, 3H), 1.29 (d, J = 7.0 Hz, 6H)
88% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.03 (d, J = 8.2 Hz, 1H), 6.75 (s, 1H), 6.69 (dd, J = 8.2, 2.5 Hz, 1H), 6.06 ( s, 1H), 3.74 (s, 2H), 3.14-3.18 (m, 4H), 3.04-3.11 (m, 1H), 2.57-2.66 (m, 8H), 2.36 (s, 3H), 2.24 (s, 3H), 2.19 (s, 3H), 1.29 (d, J = 7.0 Hz, 6H)

97% 수율 : ¹H NMR (300 MHz, CDCl₃) δ 7.03 (d, J = 8.2 Hz, 1H), 6.75 (s, 1H), 6.68 (dd, J = 8.2, 2.5 Hz, 1H), 6.05 (s, 1H), 3.74 (s, 2H), 3.12-3.16 (m, 4H), 2.99-3.05 (m, 2H), 2.67-2.72 (m, 2H), 2.60-2.63 (m, 4H), 2.48-2.51 (m, 2H), 2.24 (s, 3H), 2.19 (s, 3H), 1.05 (d, J = 6.6 Hz, 6H)
97% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.03 (d, J = 8.2 Hz, 1H), 6.75 (s, 1H), 6.68 (dd, J = 8.2, 2.5 Hz, 1H), 6.05 ( s, 1H), 3.74 (s, 2H), 3.12-3.16 (m, 4H), 2.99-3.05 (m, 2H), 2.67-2.72 (m, 2H), 2.60-2.63 (m, 4H), 2.48- 2.51 (m, 2H), 2.24 (s, 3H), 2.19 (s, 3H), 1.05 (d, J = 6.6 Hz, 6H)

81% 수율: ¹H NMR (300 MHz, CDCl₃) δ 7.32-7.37 (m, 1H), 7.04-7.10 (m, 3H), 6.05 (s, 1H), 3.75 (s, 2H), 3.21-3.25 (m, 4H), 2.99-3.05 (m, 2H), 2.70-2.73 (m, 2H), 2.61-2.68 (m, 4H), 2.49-2.51 (m, 2H), 1.29 (d, J = 7.0 Hz, 6H), 1.05 (d, J = 6.6 Hz, 6H)
81% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.32-7.37 (m, 1H), 7.04-7.10 (m, 3H), 6.05 (s, 1H), 3.75 (s, 2H), 3.21-3.25 (m, 4H), 2.99-3.05 (m, 2H), 2.70-2.73 (m, 2H), 2.61-2.68 (m, 4H), 2.49-2.51 (m, 2H), 1.29 (d, J = 7.0 Hz , 6H), 1.05 (d, J = 6.6 Hz, 6H)

30% 수율: ¹H NMR (300 MHz, CDCl₃) δ 7.03 (d, J = 8.2 Hz, 1H), 6.75 (s, 1H), 6.69 (dd, J = 8.2, 2.5 Hz, 1H), 6.08 (s, 1H), 3.92 (s, 2H), 3.13-3.16 (m, 4H), 2.77-2.81 (m, 2H), 2.55-2.61 (m, 6H), 2.24 (s, 3H), 2.19 (s, 3H)
30% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.03 (d, J = 8.2 Hz, 1H), 6.75 (s, 1H), 6.69 (dd, J = 8.2, 2.5 Hz, 1H), 6.08 ( s, 1H), 3.92 (s, 2H), 3.13-3.16 (m, 4H), 2.77-2.81 (m, 2H), 2.55-2.61 (m, 6H), 2.24 (s, 3H), 2.19 (s, 3H)

81% 수율: ¹H NMR (300 MHz, CDCl₃) δ 7.03 (d, J = 8.2 Hz, 1H), 6.76 (d, J = 2.3 Hz, 1H), 6.69 (dd, J = 8.2, 2.6 Hz, 1H), 6.09 (s, 1H), 3.74 (s, 2H), 3.14-3.18 (m, 4H), 2.56-2.66 (m, 8H), 2.36 (s, 3H), 2.24 (s, 3H), 2.19 (s, 3H), 1.34 (s, 9H)
81% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.03 (d, J = 8.2 Hz, 1H), 6.76 (d, J = 2.3 Hz, 1H), 6.69 (dd, J = 8.2, 2.6 Hz, 1H), 6.09 (s, 1H), 3.74 (s, 2H), 3.14-3.18 (m, 4H), 2.56-2.66 (m, 8H), 2.36 (s, 3H), 2.24 (s, 3H), 2.19 (s, 3H), 1.34 (s, 9H)

84% 수율: ¹H NMR (300 MHz, CDCl₃) δ 6.92-7.01 (m, 3H), 6.09 (s, 1H), 3.75 (s, 2H), 2.92 (t, J = 4.7 Hz, 4H), 2.58-2.66 (m, 8H), 2.37 (s, 3H), 2.28 (s, 6H), 1.34 (s, 9H)
84% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ 6.92-7.01 (m, 3H), 6.09 (s, 1H), 3.75 (s, 2H), 2.92 (t, J = 4.7 Hz, 4H), 2.58-2.66 (m, 8H), 2.37 (s, 3H), 2.28 (s, 6H), 1.34 (s, 9H)

76 % 수율 : ¹H NMR (300 MHz, CDCl₃) δ 7.32-7.37 (m, 1H), 7.04-7.10 (m, 3H), 6.07 (s, 1H), 3.75 (s, 2H), 3.21-3.25 (m, 4H), 2.97-2.99 (m, 1H), 2.68-2.73 (m, 2H), 2.61-2.64 (m, 4H), 2.46-2.51 (m, 2H), 1.33 (s, 9H), 1.06 (d, J = 6.6 Hz, 6H)
76% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.32-7.37 (m, 1H), 7.04-7.10 (m, 3H), 6.07 (s, 1H), 3.75 (s, 2H), 3.21-3.25 (m, 4H), 2.97-2.99 (m, 1H), 2.68-2.73 (m, 2H), 2.61-2.64 (m, 4H), 2.46-2.51 (m, 2H), 1.33 (s, 9H), 1.06 (d, J = 6.6 Hz, 6H)

20% 수율: ¹H NMR (300 MHz, CDCl₃) δ 6.92-7.01 (m, 3H), 6.02 (s, 1H), 3.94 (s, 2H), 2.89-2.92 (m, 4H), 2.76-2.80 (m, 2H), 2.52-2.60 (m, 8H), 2.28 (s, 3H), 2.27 (s, 3H), 0.97 (d, J = 6.6 Hz, 6H)
20% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ 6.92-7.01 (m, 3H), 6.02 (s, 1H), 3.94 (s, 2H), 2.89-2.92 (m, 4H), 2.76-2.80 (m, 2H), 2.52-2.60 (m, 8H), 2.28 (s, 3H), 2.27 (s, 3H), 0.97 (d, J = 6.6 Hz, 6H)

37% 수율: ¹H NMR (300 MHz, CDCl₃) δ 7.03 (d, J = 8.2 Hz, 1H), 6.75 (s, 1H), 6.69 (dd, J = 8.2, 2.5 Hz, 1H), 3.93 (s, 1H), 3.13-3.16 (m, 4H), 2.76-2.80 (m, 2H), 2.52-2.60 (m, 8H), 2.24 (s, 3H), 2.19 (s, 3H), 1.92-1.97 (m, 1H), 0.97 (d, J = 6.7 Hz, 6H)
37% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.03 (d, J = 8.2 Hz, 1H), 6.75 (s, 1H), 6.69 (dd, J = 8.2, 2.5 Hz, 1H), 3.93 ( s, 1H), 3.13-3.16 (m, 4H), 2.76-2.80 (m, 2H), 2.52-2.60 (m, 8H), 2.24 (s, 3H), 2.19 (s, 3H), 1.92-1.97 ( m, 1H), 0.97 (d, J = 6.7 Hz, 6H)

48% 수율: ¹H NMR (300 MHz, CDCl₃) δ 7.35 (t, J = 7.9 Hz, 1H), 7.11-7.05 (m, 3H), 6.04 (s, 1H), 3.93 (s, 2H), 3.24 (t, J = 4.9 Hz, 4H), 3.11-3.02 (m, 1H), 2.79 (t, J = 5.8 Hz, 2H), 2.62-2.56 (m, 6H), 1.85 (s, 1H), 1.27 (d, J = 9.9 Hz, 6H)
48% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.35 (t, J = 7.9 Hz, 1H), 7.11-7.05 (m, 3H), 6.04 (s, 1H), 3.93 (s, 2H), 3.24 (t, J = 4.9 Hz, 4H), 3.11-3.02 (m, 1H), 2.79 (t, J = 5.8 Hz, 2H), 2.62-2.56 (m, 6H), 1.85 (s, 1H), 1.27 (d, J = 9.9 Hz, 6H)

49% 수율: ¹H NMR (300 MHz, CDCl₃) δ 6.82-6.92 (m, 4H), 6.04 (s, 1H), 3.91 (s, 2H), 3.77 (s, 3H), 3.03-3.11 (m, 5H), 2.79 (t, J = 5.8 Hz, 2H), 2.55-2.62 (m, 6H), 1.28 (d, J = 6.9 Hz, 6H)
49% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ 6.82-6.92 (m, 4H), 6.04 (s, 1H), 3.91 (s, 2H), 3.77 (s, 3H), 3.03-3.11 (m , 5H), 2.79 (t, J = 5.8 Hz, 2H), 2.55-2.62 (m, 6H), 1.28 (d, J = 6.9 Hz, 6H)

86% 수율: ¹H NMR (300 MHz, CDCl₃) δ 6.83-6.92 (m, 4H), 6.05 (s, 1H), 3.77 (s, 3H), 3.74 (s, 2H), 3.04-3.12 (m, 5H), 2.55-2.66 (m, 8H), 2.36 (s, 3H), 1.30 (d, J = 7.0 Hz, 6H)
86% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ 6.83-6.92 (m, 4H), 6.05 (s, 1H), 3.77 (s, 3H), 3.74 (s, 2H), 3.04-3.12 (m , 5H), 2.55-2.66 (m, 8H), 2.36 (s, 3H), 1.30 (d, J = 7.0 Hz, 6H)

26% 수율; ¹H NMR (400 MHz, CDCl₃) δ 7.07 (d, J = 8.2 Hz, 2H), 6.84 (d, J = 13.9 Hz, 2H), 6.04 (s, 1H), 3.91 (s, 2H), 3.14 (t, J = 4.9 Hz, 4H),3.05 (septet, J = 6.9 Hz, 1H), 2.78 (t, J = 5.8 Hz, 2H), 2.60-2.27 (m, 6H), 2.55 (s, 3H), 1.95 (s, 1H),1.28 (d, J = 6.9 Hz, 6H)
26% yield; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.07 (d, J = 8.2 Hz, 2H), 6.84 (d, J = 13.9 Hz, 2H), 6.04 (s, 1H), 3.91 (s, 2H), 3.14 (t , J = 4.9 Hz, 4H), 3.05 (septet, J = 6.9 Hz, 1H), 2.78 (t, J = 5.8 Hz, 2H), 2.60-2.27 (m, 6H), 2.55 (s, 3H), 1.95 (s, 1H), 1.28 (d, J = 6.9 Hz, 6H)

화합물 42 : 2-(4-(2,4-디메틸페닐)피페라진-1-일)-N-((3-아이소부틸아이속사졸-5-일)메틸)-N-메틸에탄아민Compound 42: 2- (4- (2,4-dimethylphenyl) piperazin-1-yl) -N -((3-isobutylisoxazol-5-yl) methyl) -N -methylethanamine

83% 수율: ¹H NMR (300 MHz, CDCl₃) δ 6.92-7.01 (m, 3H), 6.03 (s, 1H), 3.76 (s, 2H), 2.90-2.93 (m, 4H), 2.58-2.63 (m, 7H), 2.55 (d, J = 7.2 Hz, 2H), 2.36 (s, 3H), 2.28 (s, 6H), 1.93-2.02 (m, 1H), 0.97 (d, J = 6.6 Hz, 6H)
83% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ 6.92-7.01 (m, 3H), 6.03 (s, 1H), 3.76 (s, 2H), 2.90-2.93 (m, 4H), 2.58-2.63 (m, 7H), 2.55 (d, J = 7.2 Hz, 2H), 2.36 (s, 3H), 2.28 (s, 6H), 1.93-2.02 (m, 1H), 0.97 (d, J = 6.6 Hz, 6H)

87% 수율: ¹H NMR (400 MHz, CDCl₃) δ 7.02 (d, J = 8.2 Hz, 1H), 6.75 (s, 1H), 6.68 (dd, J = 8.2, 2.5 Hz, 1H), 6.02 (s, 1H), 3.75 (s, 2H), 3.15-3.17 (m, 4H), 2.53-2.65 (m, 10H), 2.34 (s, 3H), 2.23 (s, 3H), 2.18 (s, 3H), 1.93-198 (m, 1H), 0.96 (d, J = 6.6 Hz, 6H)
87% yield: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.02 (d, J = 8.2 Hz, 1H), 6.75 (s, 1H), 6.68 (dd, J = 8.2, 2.5 Hz, 1H), 6.02 ( s, 1H), 3.75 (s, 2H), 3.15-3.17 (m, 4H), 2.53-2.65 (m, 10H), 2.34 (s, 3H), 2.23 (s, 3H), 2.18 (s, 3H) , 1.93-198 (m, 1H), 0.96 (d, J = 6.6 Hz, 6H)

94% 수율; ¹H NMR (400 MHz, CDCl₃) δ 7.15 (t, J = 8.0 Hz, 1H), 6.86 (s, 1H), 6.78 (t, J = 10.8 Hz, 2H), 6.04 (s, 1H), 3.73 (s, 2H), 3.19 (t, J = 5.1 Hz, 4H), 3.05 (septet, J = 6.9 Hz, 1H), 2.04-2.63 (m, 6H), 2.34 (s, 3H),1.27 (t, J = 7.0 Hz, 6H)
94% yield; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.15 (t, J = 8.0 Hz, 1H), 6.86 (s, 1H), 6.78 (t, J = 10.8 Hz, 2H), 6.04 (s, 1H), 3.73 (s , 2H), 3.19 (t, J = 5.1 Hz, 4H), 3.05 (septet, J = 6.9 Hz, 1H), 2.04-2.63 (m, 6H), 2.34 (s, 3H), 1.27 (t, J = 7.0 Hz, 6H)

38% 수율: ¹H NMR (400 MHz, CDCl₃) δ 7.47 (d, J = 8.6 Hz, 2H), 6.91 (d, J = 8.7 Hz, 2H), 6.04 (s, 1H), 3.92 (s, 2H), 3.27-3.29 (m, 4H), 3.02-3.09 (m, 1H), 2.76-2.79 (m, 2H), 2.25-2.60 (m, 6H), 1.28 (d, J = 7.0 Hz, 6H)
38% yield: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.47 (d, J = 8.6 Hz, 2H), 6.91 (d, J = 8.7 Hz, 2H), 6.04 (s, 1H), 3.92 (s, 2H), 3.27-3.29 (m, 4H), 3.02-3.09 (m, 1H), 2.76-2.79 (m, 2H), 2.25-2.60 (m, 6H), 1.28 (d, J = 7.0 Hz, 6H)

91% 수율: ¹H NMR (400 MHz, CDCl₃) δ 7.47 (d, J = 8.8 Hz, 2H), 6.91 (d, J = 8.7 Hz, 2H), 6.05 (s, 1H), 3.74 (s, 2H), 3.28-3.31 (m, 4H), 3.02-3.09 (m, 1H), 2.55-2.65 (m, 8H), 2.36 (s, 3H), 1.29 (d, J = 7.0 Hz, 6H)
91% yield: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.47 (d, J = 8.8 Hz, 2H), 6.91 (d, J = 8.7 Hz, 2H), 6.05 (s, 1H), 3.74 (s, 2H), 3.28-3.31 (m, 4H), 3.02-3.09 (m, 1H), 2.55-2.65 (m, 8H), 2.36 (s, 3H), 1.29 (d, J = 7.0 Hz, 6H)

26% 수율; ¹H NMR (400 MHz, CDCl₃) δ 7.17 (t, J = 8.2 Hz, 1H),6.53 (d, J = 8.2 Hz, 1H), 6.46 (s, 1H), 6.42 (d, J = 6.2 Hz, 1H), 6.04 (s, 1H), 3.92 (s, 2H), 3.79 (s, 3H),3.19 (t, J = 5.1 Hz, 4H), 3.05 (septet, J = 6.9Hz, 1H), 2.79 (t, J = 6.1 Hz, 2H), 2.56-2.61 (m, 6H), 1.27 (d, J = 7.0 Hz, 6H)
26% yield; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.17 (t, J = 8.2 Hz, 1H), 6.53 (d, J = 8.2 Hz, 1H), 6.46 (s, 1H), 6.42 (d, J = 6.2 Hz, 1H ), 6.04 (s, 1H), 3.92 (s, 2H), 3.79 (s, 3H), 3.19 (t, J = 5.1 Hz, 4H), 3.05 (septet, J = 6.9 Hz, 1H), 2.79 (t , J = 6.1 Hz, 2H), 2.56-2.61 (m, 6H), 1.27 (d, J = 7.0 Hz, 6H)

67% 수율; ¹H NMR (400 MHz, CDCl₃) δ 7.15 (t, J = 7.9 Hz, 1H),6.75 (s, 1H), 6.74 (d, J = 8.1 Hz, 1H), 6.7 (d, J = 7.6 Hz, 1H), 6.04 (s, 1H), 3.91 (s, 2H), 3.18 (t, J = 4.9 Hz, 4H), 3.06 (septet, J = 7.0 Hz, 1H), 2.78 (t, J = 6.2 Hz, 2H), 2.32-2.60 (m, 6H), 2.32 (s, 3H), 1.81 (s, 1H),1.28 (d, J = 7.0 Hz, 6H)
67% yield; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.15 (t, J = 7.9 Hz, 1H), 6.75 (s, 1H), 6.74 (d, J = 8.1 Hz, 1H), 6.7 (d, J = 7.6 Hz, 1H ), 6.04 (s, 1H), 3.91 (s, 2H), 3.18 (t, J = 4.9 Hz, 4H), 3.06 (septet, J = 7.0 Hz, 1H), 2.78 (t, J = 6.2 Hz, 2H ), 2.32-2.60 (m, 6H), 2.32 (s, 3H), 1.81 (s, 1H), 1.28 (d, J = 7.0 Hz, 6H)

97% 수율; ¹H NMR (300 MHz, CDCl₃) δ 7.08 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.4 Hz, 2H), 6.05 (s, 1H), 3.74 (s, 1H), 3.16 (t, J = 4.6 Hz, 4H), 3.06 (septet, J = 6.9 Hz, 1H), 2.56-2.66 (m, 6H), 2.36 (s, 3H), 2.28 (s, 3H), 1.29 (d, J = 7.0 Hz, 6H)
97% yield; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.08 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.4 Hz, 2H), 6.05 (s, 1H), 3.74 (s, 1H), 3.16 (t , J = 4.6 Hz, 4H), 3.06 (septet, J = 6.9 Hz, 1H), 2.56-2.66 (m, 6H), 2.36 (s, 3H), 2.28 (s, 3H), 1.29 (d, J = 7.0 Hz, 6H)

53% 수율: ¹H NMR (400 MHz, CDCl₃) δ 6.93-6.97 (m, 2H), 6.85-6.88 (m, 2H), 6.03 (s, 1H), 3.91 (s, 2H), 3.01-3.91 (m, 5H), 2.76-2.79 (m, 2H), 2.55-2.60 (m, 6H), 1.27 (d, J = 6.9 Hz, 6H)
53% yield: ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.93-6.97 (m, 2H), 6.85-6.88 (m, 2H), 6.03 (s, 1H), 3.91 (s, 2H), 3.01-3.91 (m, 5H), 2.76-2.79 (m, 2H), 2.55-2.60 (m, 6H), 1.27 (d, J = 6.9 Hz, 6H)

82% 수율: ¹H NMR (300 MHz, CDCl₃) δ 6.94-6.99 (m, 2H), 6.85-6.90 (m, 2H), 6.05 (s, 1H), 3.75 (s, 2H), 3.01-3.15 (m, 5H), 2.57-2.67 (m, 8H), 2.36 (s, 3H), 1.29 (d, J = 6.9 Hz, 6H)
82% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ 6.94-6.99 (m, 2H), 6.85-6.90 (m, 2H), 6.05 (s, 1H), 3.75 (s, 2H), 3.01-3.15 (m, 5H), 2.57-2.67 (m, 8H), 2.36 (s, 3H), 1.29 (d, J = 6.9 Hz, 6H)

58% 수율: ¹H NMR (300 MHz, CDCl₃) δ 7.26 (d, J = 8.8 Hz, 1H), 6.94 (d, J = 2.8 Hz, 1H), 6.73 (dd, J = 8.9, 2.9 Hz, 1H), 6.04 (s, 1H), 3.91 (s, 2H), 3.14-3.18 (m, 4H), 3.02-3.07 (m, 1H), 2.75-2.79 (m, 2H), 2.54-2.58 (m, 6H), 1.28 (d, J = 7.0 Hz, 6H)
58% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.26 (d, J = 8.8 Hz, 1H), 6.94 (d, J = 2.8 Hz, 1H), 6.73 (dd, J = 8.9, 2.9 Hz, 1H), 6.04 (s, 1H), 3.91 (s, 2H), 3.14-3.18 (m, 4H), 3.02-3.07 (m, 1H), 2.75-2.79 (m, 2H), 2.54-2.58 (m, 6H), 1.28 (d, J = 7.0 Hz, 6H)

89% 수율: ¹H NMR (300 MHz, CDCl₃) δ 7.26 (d, J = 8.7 Hz, 1H), 6.94 (d, J = 2.8 Hz, 1H), 6.73 (dd, J = 8.9, 2.8 Hz, 1H), 6.04 (s, 1H), 3.74 (s, 2H), 3.16-3.19 (m, 4H), 3.01-3.10 (m, 1H), 2.58-2.61 (m, 8H), 2.35 (s, 3H), 1.29 (d, J = 6.9 Hz, 6H)
89% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.26 (d, J = 8.7 Hz, 1H), 6.94 (d, J = 2.8 Hz, 1H), 6.73 (dd, J = 8.9, 2.8 Hz, 1H), 6.04 (s, 1H), 3.74 (s, 2H), 3.16-3.19 (m, 4H), 3.01-3.10 (m, 1H), 2.58-2.61 (m, 8H), 2.35 (s, 3H) , 1.29 (d, J = 6.9 Hz, 6H)

47% 수율; ¹H NMR (300 MHz, CDCl₃) δ 7.18 (t, J = 8.2 Hz, 1H), 6.55 (d, J = 6.0 Hz, 1H), 6.47 (s, 1H), 6.42 (d, J = 6.3 Hz, 1H), 6.05 (s, 1H), 3.80 (s, 3H), 3.74 (s, 2H), 3.21 (t, J = 5.1 Hz, 4H), 3.06 (septet, J = 6.9 Hz, 1H),2.56-2.65 (m, 8H), 2.36 (s, 3H), 1.29 (d, J = 7.0 Hz, 6H)
47% yield; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.18 (t, J = 8.2 Hz, 1H), 6.55 (d, J = 6.0 Hz, 1H), 6.47 (s, 1H), 6.42 (d, J = 6.3 Hz, 1H ), 6.05 (s, 1H), 3.80 (s, 3H), 3.74 (s, 2H), 3.21 (t, J = 5.1 Hz, 4H), 3.06 (septet, J = 6.9 Hz, 1H), 2.56-2.65 (m, 8H), 2.36 (s, 3H), 1.29 (d, J = 7.0 Hz, 6H)

82% 수율; ¹H NMR (400 MHz, CDCl₃) δ 7.15 (t, J = 7.7 Hz, 1H) 6.75 (s, 1H) 6.73 (d, J = 7.9 Hz, 1H) 6.68 (d, J = 7.3 Hz, 1H) 6.05 (s, 1H) 3.74 (s, 2H) 3.20 (t, J = 4.9 Hz, 4H) 3.05 (septet, J = 6.9 Hz, 1H) 2.63 (t, J = 5.5 Hz, 6H) 2.57 (t, J = 9.8Hz, 2H) 2.36 (s, 3H) 2.32 (s, 3H) 1.29 (d, J = 6.9 Hz, 6H)
82% yield; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.15 (t, J = 7.7 Hz, 1H) 6.75 (s, 1H) 6.73 (d, J = 7.9 Hz, 1H) 6.68 (d, J = 7.3 Hz, 1H) 6.05 ( s, 1H) 3.74 (s, 2H) 3.20 (t, J = 4.9 Hz, 4H) 3.05 (septet, J = 6.9 Hz, 1H) 2.63 (t, J = 5.5 Hz, 6H) 2.57 (t, J = 9.8 Hz, 2H) 2.36 (s, 3H) 2.32 (s, 3H) 1.29 (d, J = 6.9 Hz, 6H)

74% 수율: ¹H NMR (300 MHz, CDCl₃) δ 7.15 (t, J = 8.1 Hz, 1H), 6.86-6.87 (m, 1H), 6.76-6.81 (m, 2H), 6.02 (s, 1H), 3.88 (s, 2H), 3.17-3.21 (m, 4H), 3.02-3.06 (m, 1H), 2.74 (t, J = 6.8 Hz, 2H), 2.57-2.60 (m, 4H), 2.47 (t, J = 7.1 Hz, 2H), 1.72-1.76 (m, 2H), 1.27 (d, J = 7.0 Hz, 6H)
74% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.15 (t, J = 8.1 Hz, 1H), 6.86-6.87 (m, 1H), 6.76-6.81 (m, 2H), 6.02 (s, 1H ), 3.88 (s, 2H), 3.17-3.21 (m, 4H), 3.02-3.06 (m, 1H), 2.74 (t, J = 6.8 Hz, 2H), 2.57-2.60 (m, 4H), 2.47 ( t, J = 7.1 Hz, 2H), 1.72-1.76 (m, 2H), 1.27 (d, J = 7.0 Hz, 6H)

99% 수율: ¹H NMR (300 MHz, CDCl₃) δ 7.16 (t, J = 8.1 Hz, 1H), 6.88 (s, 1H), 6.78-6.82 (m, 2H), 6.03 (s, 1H), 3.68 (s, 2H), 3.19-3.22 (m, 4H), 3.01-3.08 (m, 1H), 2.58-2.61 (m, 4H), 2.31 (s, 3H), 1.70-1.77 (m, 2H), 1.29 (d, J = 6.9 Hz, 6H)
99% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.16 (t, J = 8.1 Hz, 1H), 6.88 (s, 1H), 6.78-6.82 (m, 2H), 6.03 (s, 1H), 3.68 (s, 2H), 3.19-3.22 (m, 4H), 3.01-3.08 (m, 1H), 2.58-2.61 (m, 4H), 2.31 (s, 3H), 1.70-1.77 (m, 2H), 1.29 (d, J = 6.9 Hz, 6H)

68% 수율: ¹H NMR (300 MHz, CDCl₃) δ 7.02 (d, J = 8.2 Hz, 1H), 6.76 (d, J = 2.3 Hz, 1H), 6.69 (dd, J = 8.2, 2.4 Hz, 1H), 6.03 (s, 1H), 3.88 (s, 2H), 3.13-3.17 (m, 4H), 3.02-3.07 (m, 1H), 2.74 (t, J = 6.8 Hz, 2H), 2.60-2.63 (m, 4H), 2.48 (t, J = 7.1 Hz, 2H), 2.24 (s, 3H), 2.19 (s, 3H), 1.73-1.78 (m, 2H), 1.28 (d, J = 7.0 Hz, 6H)
68% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.02 (d, J = 8.2 Hz, 1H), 6.76 (d, J = 2.3 Hz, 1H), 6.69 (dd, J = 8.2, 2.4 Hz, 1H), 6.03 (s, 1H), 3.88 (s, 2H), 3.13-3.17 (m, 4H), 3.02-3.07 (m, 1H), 2.74 (t, J = 6.8 Hz, 2H), 2.60-2.63 (m, 4H), 2.48 (t, J = 7.1 Hz, 2H), 2.24 (s, 3H), 2.19 (s, 3H), 1.73-1.78 (m, 2H), 1.28 (d, J = 7.0 Hz, 6H)

73% 수율: ¹H NMR (300 MHz, CDCl₃) δ 7.03 (d, J = 8.2 Hz, 1H), 6.76 (s, 1H), 6.70 (dd, J = 8.1, 2.4 Hz, 1H), 6.04 (s, 1H), 3.68 (s, 2H), 3.15-3.18 (m, 4H), 3.04-3.08 (m, 1H), 2.60-2.63 (m, 4H), 2.42-2.50 (m, 4H), 2.31 (s, 3H), 2.24 (s, 3H), 2.19 (s, 3H), 1.73-1.81 (m, 2H), 1.29 (d, J = 6.9 Hz, 6H)
73% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.03 (d, J = 8.2 Hz, 1H), 6.76 (s, 1H), 6.70 (dd, J = 8.1, 2.4 Hz, 1H), 6.04 ( s, 1H), 3.68 (s, 2H), 3.15-3.18 (m, 4H), 3.04-3.08 (m, 1H), 2.60-2.63 (m, 4H), 2.42-2.50 (m, 4H), 2.31 ( s, 3H), 2.24 (s, 3H), 2.19 (s, 3H), 1.73-1.81 (m, 2H), 1.29 (d, J = 6.9 Hz, 6H)

49% 수율: ¹H NMR (300 MHz, CDCl₃) δ 7.07 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.5 Hz, 2H), 6.03 (s, 1H), 3.88 (s, 2H), 3.13-3.17 (m, 4H), 3.02-3.07 (m, 1H), 2.74 (t, J = 6.7 Hz, 2H), 2.59-2.63 (m, 4H), 2.48 (t, J = 7.1 Hz, 2H), 2.27 (s, 3H), 1.72-1.77 (m, 2H), 1.27 (d, J = 6.9 Hz, 6H)
49% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.07 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.5 Hz, 2H), 6.03 (s, 1H), 3.88 (s, 2H), 3.13-3.17 (m, 4H), 3.02-3.07 (m, 1H), 2.74 (t, J = 6.7 Hz, 2H), 2.59-2.63 (m, 4H), 2.48 (t, J = 7.1 Hz , 2H), 2.27 (s, 3H), 1.72-1.77 (m, 2H), 1.27 (d, J = 6.9 Hz, 6H)

60% 수율: ¹H NMR (400 MHz, CDCl₃) δ 7.08 (d, J = 9.3 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 6.03 (s, 1H), 3.68 (s, 2H), 3.14-3.18 (m, 4H), 3.03-3.10 (m, 1H), 2.60-2.63 (m, 4H), 2.30 (s, 3H), 2.27 (s, 3H), 1.73-1.80 (m, 2H), 1.29 (d, J = 7.0 Hz, 6H)
60% yield: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.08 (d, J = 9.3 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 6.03 (s, 1H), 3.68 (s, 2H), 3.14-3.18 (m, 4H), 3.03-3.10 (m, 1H), 2.60-2.63 (m, 4H), 2.30 (s, 3H), 2.27 (s, 3H), 1.73-1.80 (m, 2H), 1.29 (d, J = 7.0 Hz, 6H)

화합물 62 : 3-(4-(4-플루오로페닐)피페라진-1-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)프로판-1-아민Compound 62: 3- (4- (4-fluorophenyl) piperazin-1-yl) -N -((3-isopropylisoxazol-5-yl) methyl) propan-1-amine

70% 수율: ¹H NMR (300 MHz, CDCl₃) δ 6.92-6.98 (m, 2H), 6.84-6.88 (m, 2H), 6.02 (s, 1H), 3.87 (s, 2H), 3.01-3.12 (m, 5H), 2.73 (t, J = 6.7 Hz, 2H), 2.58-2.61 (4H), 2.47 (t, J = 7.1 Hz, 2H), 1.71-1.78 (m, 2H), 1.26 (d, J = 7.0 Hz, 6H)
70% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ 6.92-6.98 (m, 2H), 6.84-6.88 (m, 2H), 6.02 (s, 1H), 3.87 (s, 2H), 3.01-3.12 (m, 5H), 2.73 (t, J = 6.7 Hz, 2H), 2.58-2.61 (4H), 2.47 (t, J = 7.1 Hz, 2H), 1.71-1.78 (m, 2H), 1.26 (d, J = 7.0 Hz, 6H)

82% 수율: ¹H NMR (400 MHz, CDCl₃) δ 6.85-6.99 (m, 4H), 6.03 (s, 1H), 3.67 (s, 2H), 3.00-3.15 (m, 5H), 2.60-2.63 (m, 4H), 2.42-2.49 (m, 4H), 2.30 (s, 3H), 1.72-1.80 (m, 2H), 1.28 (d, J = 7.0 Hz, 6H)
82% yield: ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.85-6.99 (m, 4H), 6.03 (s, 1H), 3.67 (s, 2H), 3.00-3.15 (m, 5H), 2.60-2.63 (m, 4H), 2.42-2.49 (m, 4H), 2.30 (s, 3H), 1.72-1.80 (m, 2H), 1.28 (d, J = 7.0 Hz, 6H)

31% 수율; ¹H NMR (400 MHz, CDCl₃) δ 6.90 (d, J = 5.2 Hz, 2H), 6.83 (d, J = 5.7 Hz, 2H), 6.02 (s, 1H), 3.88 (s, 2H), 3.77 (s, 3H), 3.09 (t, J = 4.7 Hz, 4H), 3.04 (septet, J = 6.9 Hz, 1H), 2.73 (t, J = 6.8 Hz, 2H), 2.61 (t, J = 4.9 Hz, 4H), 2.48 (t, J = 7.2 Hz, 2H), 1.74 (t, J = 7.0 Hz, 2H), 1.27 (d, J = 7.0 Hz, 6H)
31% yield; ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.90 (d, J = 5.2 Hz, 2H), 6.83 (d, J = 5.7 Hz, 2H), 6.02 (s, 1H), 3.88 (s, 2H), 3.77 (s , 3H), 3.09 (t, J = 4.7 Hz, 4H), 3.04 (septet, J = 6.9 Hz, 1H), 2.73 (t, J = 6.8 Hz, 2H), 2.61 (t, J = 4.9 Hz, 4H ), 2.48 (t, J = 7.2 Hz, 2H), 1.74 (t, J = 7.0 Hz, 2H), 1.27 (d, J = 7.0 Hz, 6H)

49% 수율; ¹H NMR (400 MHz, CDCl₃) δ 6.90 (d, J = 6.9 Hz, 2H), 6.84 (d, J = 6.7 Hz, 2H), 6.03 (s, 1H), 3.77 (s, 3H), 3.68 (s, 2H), 3.10 (t, J = 5.1 Hz, 4H), 3.05 (septet, J = 6.9 Hz, 1H), 2.62 (t, J = 4.8 Hz, 4H), 2.42-2.48 (m, 4H), 2.30 (s, 3H), 1.75 (quintet, J = 7.7 Hz, 2H), 1.29 (d, J = 5.2 Hz, 6H)
49% yield; ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.90 (d, J = 6.9 Hz, 2H), 6.84 (d, J = 6.7 Hz, 2H), 6.03 (s, 1H), 3.77 (s, 3H), 3.68 (s , 2H), 3.10 (t, J = 5.1 Hz, 4H), 3.05 (septet, J = 6.9 Hz, 1H), 2.62 (t, J = 4.8 Hz, 4H), 2.42-2.48 (m, 4H), 2.30 (s, 3H), 1.75 (quintet, J = 7.7 Hz, 2H), 1.29 (d, J = 5.2 Hz, 6H)

70% 수율: ¹H NMR (400 MHz, CDCl₃) δ 6.78 (d, J = 8.7 Hz, 1H), 6.57 (s, 1H), 6.44 (dd, J = 8.6, 2.5 Hz, 1H), 6.03 (s, 1H), 3.91 (s, 2H), 3.86 (s, 3H), 3.83 (s, 3H), 3.01-3.11 (m, 5H), 2.76-2.79 (m, 2H), 2.55-2.61 (m, 6H), 1.27 (d, J = 7.0 Hz, 6H)
70% yield: ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.78 (d, J = 8.7 Hz, 1H), 6.57 (s, 1H), 6.44 (dd, J = 8.6, 2.5 Hz, 1H), 6.03 ( s, 1H), 3.91 (s, 2H), 3.86 (s, 3H), 3.83 (s, 3H), 3.01-3.11 (m, 5H), 2.76-2.79 (m, 2H), 2.55-2.61 (m, 6H), 1.27 (d, J = 7.0 Hz, 6H)

62% 수율: ¹H NMR (400 MHz, CDCl₃) δ 7.16-7.20 (m, 2H), 6.80-6.83 (m, 2H), 6.01 (s, 1H), 3.86 (s, 2H), 3.12-3.15 (m, 4H), 2.99-3.04 (m, 1H), 2.72 (t, J = 6.8 Hz, 2H), 2.56-2.59 (m, 4H), 2.45 (t, J = 7.1 Hz, 2H), 1.70-1.76 (m, 2H), 1.25 (d, J = 7.0 Hz, 6H)62% yield: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.16-7.20 (m, 2H), 6.80-6.83 (m, 2H), 6.01 (s, 1H), 3.86 (s, 2H), 3.12-3.15 (m, 4H), 2.99-3.04 (m, 1H), 2.72 (t, J = 6.8 Hz, 2H), 2.56-2.59 (m, 4H), 2.45 (t, J = 7.1 Hz, 2H), 1.70- 1.76 (m, 2H), 1.25 (d, J = 7.0 Hz, 6H)

68% 수율: ¹H NMR (300 MHz, CDCl₃) δ 7.17-7.21 (m, 2H), 6.82-6.86 (m, 2H), 6.03 (s, 1H), 3.67 (s, 2H), 3.15-3.18 (m, 4H), 3.03-3.10 (m, 1H), 2.58-2.62 (m, 4H), 2.41-2.49 (m, 4H), 2.30 (s, 3H), 1.72-1.79 (m, 2H), 1.28 (d, J = 7.0 Hz, 6H)
68% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.17-7.21 (m, 2H), 6.82-6.86 (m, 2H), 6.03 (s, 1H), 3.67 (s, 2H), 3.15-3.18 (m, 4H), 3.03-3.10 (m, 1H), 2.58-2.62 (m, 4H), 2.41-2.49 (m, 4H), 2.30 (s, 3H), 1.72-1.79 (m, 2H), 1.28 (d, J = 7.0 Hz, 6H)

36% 수율; ¹H NMR (400 MHz, CDCl₃) δ 7.17 (t, J = 8.2 Hz, 1H), 6.54 (d, J = 6.1 Hz, 1H), 6.46 (s, 1H), 6.41 (d, J = 6.2 Hz, 1H), 6.02 (s, 1H), 3.88 (s, 2H), 3.87 (s, 3H), 3.19 (t, J = 5.1 Hz, 4H), 3.04 (septet, J = 7.0 Hz, 1H), 2.73 (t, J = 6.8 Hz, 2H), 2.59 (t, J = 5.0 Hz, 4H), 2.47 (t, J = 7.3 Hz, 2H), 1.74 (d, J = 7.0 Hz, 2H), 1.27 (d, J = 7.0 Hz, 6H)
36% yield; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.17 (t, J = 8.2 Hz, 1H), 6.54 (d, J = 6.1 Hz, 1H), 6.46 (s, 1H), 6.41 (d, J = 6.2 Hz, 1H ), 6.02 (s, 1H), 3.88 (s, 2H), 3.87 (s, 3H), 3.19 (t, J = 5.1 Hz, 4H), 3.04 (septet, J = 7.0 Hz, 1H), 2.73 (t , J = 6.8 Hz, 2H), 2.59 (t, J = 5.0 Hz, 4H), 2.47 (t, J = 7.3 Hz, 2H), 1.74 (d, J = 7.0 Hz, 2H), 1.27 (d, J = 7.0 Hz, 6H)

77% 수율; ¹H NMR (400 MHz, CDCl₃) δ 7.17 (t, J = 8.2 Hz, 1H), 6.55 (d, J = 6.0 Hz, 1H), 6.47 (s, 1H), 6.42 (d, J = 5.8 Hz, 1H), 6.03 (s, 1H), 3.79 (s, 3H), 3.68 (s, 2H), 3.20 (t, J = 5.1 Hz, 4H),3.04 (septet, J = 6.9 Hz, 1H), 2.60 (t, J = 4.9 Hz, 4H), 2.41-2.48 (m, 4H), 2.30 (s, 3H), 1.74 (quintet, J = 7.6 Hz, 2H), 1.28 (d, J = 7.0 Hz, 6H)
77% yield; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.17 (t, J = 8.2 Hz, 1H), 6.55 (d, J = 6.0 Hz, 1H), 6.47 (s, 1H), 6.42 (d, J = 5.8 Hz, 1H ), 6.03 (s, 1H), 3.79 (s, 3H), 3.68 (s, 2H), 3.20 (t, J = 5.1 Hz, 4H), 3.04 (septet, J = 6.9 Hz, 1H), 2.60 (t , J = 4.9 Hz, 4H), 2.41-2.48 (m, 4H), 2.30 (s, 3H), 1.74 (quintet, J = 7.6 Hz, 2H), 1.28 (d, J = 7.0 Hz, 6H)

69% 수율: ¹H NMR (400 MHz, CDCl₃) δ 7.14 (t, J = 7.7 Hz, 1H), 6.72-6.74 (m, 2H), 6.68 (d, J = 7.3 Hz, 1H), 6.02 (s, 1H), 3.87 (s, 2H), 3.17-3.19 (m, 4H), 3.00-3.05 (m, 1H), 2.73 (t, J = 6.7 Hz, 2H), 2.58-2.61 (m, 4H), 2.47 (t, J = 7.1 Hz, 2H), 1.72-1.76 (m, 2H), 1.27 (d, J = 6.9 Hz, 6H)
69% yield: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.14 (t, J = 7.7 Hz, 1H), 6.72-6.74 (m, 2H), 6.68 (d, J = 7.3 Hz, 1H), 6.02 ( s, 1H), 3.87 (s, 2H), 3.17-3.19 (m, 4H), 3.00-3.05 (m, 1H), 2.73 (t, J = 6.7 Hz, 2H), 2.58-2.61 (m, 4H) , 2.47 (t, J = 7.1 Hz, 2H), 1.72-1.76 (m, 2H), 1.27 (d, J = 6.9 Hz, 6H)

53% 수율: ¹H NMR (400 MHz, CDCl₃) δ 7.15 (t, J = 7.7 Hz, 1H), 6.73-6.75 (m, 2H), 6.68 (d, J = 7.3 Hz, 1H), 6.03 (s, 1H), 3.67 9s, 2H), 3.18-3.21 (m, 4H), 3.03-3.07 (m, 1H), 2.59-2.62 (m, 4H), 2.41-2.48 (m, 4H), 2.31 (s, 3H), 2.30 (s, 3H), 1.73-1.77 (m, 2H), 1.28 (d, J = 7.0 Hz, 6H)53% yield: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.15 (t, J = 7.7 Hz, 1H), 6.73-6.75 (m, 2H), 6.68 (d, J = 7.3 Hz, 1H), 6.03 ( s, 1H), 3.67 9s, 2H), 3.18-3.21 (m, 4H), 3.03-3.07 (m, 1H), 2.59-2.62 (m, 4H), 2.41-2.48 (m, 4H), 2.31 (s , 3H), 2.30 (s, 3H), 1.73-1.77 (m, 2H), 1.28 (d, J = 7.0 Hz, 6H)

18% 수율; ¹H NMR (400 MHz, CDCl₃) δ 7.27 (d, J = 8.9 Hz, 1H), 6.95 (s, 1H), 6.74 (d, J = 6.0 Hz, 1H), 6.10 (s, 1H), 3.93 (s, 2H), 3.18 (t, J = 5.1 Hz, 4H), 3.04 (septet, J = 6.9 Hz, 1H), 2.80 (t, J = 6.5 Hz, 2H), 2.64 (t, J = 5.0 Hz, 4H), 2.53 (t, J = 6.9 Hz, 2H), 2.18 (s, 2H), 2.05 (s, 3H), 1.78 (quintet, J = 6.7 Hz, 2H), 1.27 (d, J = 4.4 Hz, 6H)
18% yield; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.27 (d, J = 8.9 Hz, 1H), 6.95 (s, 1H), 6.74 (d, J = 6.0 Hz, 1H), 6.10 (s, 1H), 3.93 (s , 2H), 3.18 (t, J = 5.1 Hz, 4H), 3.04 (septet, J = 6.9 Hz, 1H), 2.80 (t, J = 6.5 Hz, 2H), 2.64 (t, J = 5.0 Hz, 4H ), 2.53 (t, J = 6.9 Hz, 2H), 2.18 (s, 2H), 2.05 (s, 3H), 1.78 (quintet, J = 6.7 Hz, 2H), 1.27 (d, J = 4.4 Hz, 6H )

63% 수율; ¹H NMR (400 MHz, CDCl₃) δ 7.26 (d, J = 9.6 Hz, 1H), 6.95 (s, 1H), 6.74 (d, J = 6.1 Hz, 1H), 6.02 (s, 1H), 3.67 (s, 2H), 3.17 (t, J = 5.1 Hz, 4H), 3.05 (septet, J = 7.0 Hz, 1H), 2.58 (t, J = 4.9 Hz, 4H), 2.40-2.48 (m, 4H), 2.30 (s, 3H), 1.75 (quintet, J = 7.2 Hz, 2H), 1.28 (d, J = 7.0 Hz, 6H)
63% yield; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.26 (d, J = 9.6 Hz, 1H), 6.95 (s, 1H), 6.74 (d, J = 6.1 Hz, 1H), 6.02 (s, 1H), 3.67 (s , 2H), 3.17 (t, J = 5.1 Hz, 4H), 3.05 (septet, J = 7.0 Hz, 1H), 2.58 (t, J = 4.9 Hz, 4H), 2.40-2.48 (m, 4H), 2.30 (s, 3H), 1.75 (quintet, J = 7.2 Hz, 2H), 1.28 (d, J = 7.0 Hz, 6H)

51% 수율: ¹H NMR (400 MHz, CDCl₃) δ 6.79 (d, J = 8.7 Hz, 1H), 658 (d, J = 2.6 Hz, 1H), 6.46 (dd, J = 8.7, 2.7 Hz, 1H), 6.03 (s, 1H), 3.88 (s, 2H), 3.87 (s, 3H), 3.84 (s, 3H), 3.03-3.12 (m, 5H), 2.74 (t, J = 6.8 Hz, 2H), 2.61-2.63 (m, 4H), 2.49 (t, J = 7.0 Hz, 2H), 1.72-1.78 (m, 2H), 1.27 (d, J = 7.0 Hz, 6H)
51% yield: ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.79 (d, J = 8.7 Hz, 1H), 658 (d, J = 2.6 Hz, 1H), 6.46 (dd, J = 8.7, 2.7 Hz, 1H), 6.03 (s, 1H), 3.88 (s, 2H), 3.87 (s, 3H), 3.84 (s, 3H), 3.03-3.12 (m, 5H), 2.74 (t, J = 6.8 Hz, 2H ), 2.61-2.63 (m, 4H), 2.49 (t, J = 7.0 Hz, 2H), 1.72-1.78 (m, 2H), 1.27 (d, J = 7.0 Hz, 6H)

49% 수율: ¹H NMR (400 MHz, CDCl₃) δ 7.19 (d, J = 8.8 Hz, 2H), 6.82 (d, J = 8.8 Hz, 2H), 6.03 (s, 1H), 3.90 (s, 2H), 3.30-3.35 (m, 2H), 2.90-3.06 (m, 4H), 2.71-2.72 (m, 2H), 2.61-2.64 (m, 2H), 2.31-2.37 (m, 2H), 1.88 (s, 1H), 1.28 (d, J = 7.0 Hz, 6H), 1.12 (d, J = 5.9 Hz, 3H)
49% yield: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.19 (d, J = 8.8 Hz, 2H), 6.82 (d, J = 8.8 Hz, 2H), 6.03 (s, 1H), 3.90 (s, 2H), 3.30-3.35 (m, 2H), 2.90-3.06 (m, 4H), 2.71-2.72 (m, 2H), 2.61-2.64 (m, 2H), 2.31-2.37 (m, 2H), 1.88 ( s, 1H), 1.28 (d, J = 7.0 Hz, 6H), 1.12 (d, J = 5.9 Hz, 3H)

29% 수율: ¹H NMR (400 MHz, CDCl₃) δ 7.23-7.25 (m, 1H), 6.90 (s, 1H), 6.70 (dd, J = 8.9, 2.9 Hz, 1H), 6.02 (s, 1H), 3.89 (d, J = 3.5 Hz, 2H), 3.28-3.32 (m, 2H), 2.88-3.05 (m, 4H), 2.47-2.82 (m, 4H), 2.29-2.34 (m, 2H), 1.88 (s, 1H), 1.42 (d, J = 7.0 Hz, 6H), 1.10 (d, J = 6.2 Hz, 3H)
29% yield: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.23-7.25 (m, 1H), 6.90 (s, 1H), 6.70 (dd, J = 8.9, 2.9 Hz, 1H), 6.02 (s, 1H ), 3.89 (d, J = 3.5 Hz, 2H), 3.28-3.32 (m, 2H), 2.88-3.05 (m, 4H), 2.47-2.82 (m, 4H), 2.29-2.34 (m, 2H), 1.88 (s, 1H), 1.42 (d, J = 7.0 Hz, 6H), 1.10 (d, J = 6.2 Hz, 3H)

50% 수율: ¹H NMR (300 MHz, CDCl₃) δ 7.13-7.16 (m, 2H), 6.88-6.93 (m, 2H), 6.07 (s, 1H), 3.94 (s, 2H), 3.05-3.23 (m, 5H), 2.78-2.83 (m, 2H), 2.58-2.64 (m, 6H), 1.32 (d, J = 6.9 Hz, 6H)
50% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.13-7.16 (m, 2H), 6.88-6.93 (m, 2H), 6.07 (s, 1H), 3.94 (s, 2H), 3.05-3.23 (m, 5H), 2.78-2.83 (m, 2H), 2.58-2.64 (m, 6H), 1.32 (d, J = 6.9 Hz, 6H)

30% 수율: ¹H NMR (300 MHz, CDCl₃) δ 6.80 (s, 1H), 6.74 (s, 2H), 6.05 (s, 1H), 3.93 (s, 3H), 3.19-3.22 (m, 4H), 3.04-3.09 (m, 1H), 2.76-2.80 (m, 2H), 2.55-2.58 (m, 6H), 1.82 (s, 1H), 1.29 (d, J = 7.0 Hz, 6H)
30% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ 6.80 (s, 1H), 6.74 (s, 2H), 6.05 (s, 1H), 3.93 (s, 3H), 3.19-3.22 (m, 4H ), 3.04-3.09 (m, 1H), 2.76-2.80 (m, 2H), 2.55-2.58 (m, 6H), 1.82 (s, 1H), 1.29 (d, J = 7.0 Hz, 6H)

49% 수율: ¹H NMR (CDCl₃, 300 MHz) δ 1.29 (d, J = 6.95 Hz, 6H), 1.38-1.53 (m, 7H), 1.79 (bd, J = 11.28 Hz, 2H), 2.64 (t, J = 12.07 Hz, 2H), 2.72 (t, J = 7.23 Hz, 2H), 3.04-3.08 (m, 1H), 3.53 (bd, J = 12.33 Hz, 2H), 3.90 (s, 2H), 6.03 (s, 1H), 6.86-6.98 (m, 4H)
49% yield: ¹ H NMR (CDCl ₃ , 300 MHz) δ 1.29 (d, J = 6.95 Hz, 6H), 1.38-1.53 (m, 7H), 1.79 (bd, J = 11.28 Hz, 2H), 2.64 ( t, J = 12.07 Hz, 2H), 2.72 (t, J = 7.23 Hz, 2H), 3.04-3.08 (m, 1H), 3.53 (bd, J = 12.33 Hz, 2H), 3.90 (s, 2H), 6.03 (s, 1 H), 6.86-6.98 (m, 4 H)

67% 수율: ¹H NMR (CDCl₃, 300 MHz) δ 0.97 (d, J = 6.60 Hz, 6H), 1.51 (m, 8H), 1.78 (bd, J = 11.57 Hz, 2H), 2.64-2.74 (m, 4H), 3.06 (m, 1H), 3.61 (d, J = 12.62 Hz, 2H), 3.89 (s, 2H), 6.03 (s, 1H), 6.85 (dd, J = 4.71 Hz, J = 2.16 Hz, 2H), 7.19 (dd, J = 4.73 Hz, J = 2.13 Hz, 2H)
67% yield: ¹ H NMR (CDCl ₃ , 300 MHz) δ 0.97 (d, J = 6.60 Hz, 6H), 1.51 (m, 8H), 1.78 (bd, J = 11.57 Hz, 2H), 2.64-2.74 ( m, 4H), 3.06 (m, 1H), 3.61 (d, J = 12.62 Hz, 2H), 3.89 (s, 2H), 6.03 (s, 1H), 6.85 (dd, J = 4.71 Hz, J = 2.16 Hz, 2H), 7.19 (dd, J = 4.73 Hz, J = 2.13 Hz, 2H)

54% 수율: ¹H NMR (CDCl₃, 300 MHz) δ 0.96 (d, J = 4.98 Hz, 9H), 1.23-1.40 (m, 3H), 1.49 (t, J = 3.24 Hz, 3H), 1.76 (bd, J = 9.24 Hz, 2H), 1.92-1.97 (m, 3H), 2.53 (q, J = 2.85 Hz, 3H), 2.65-2.72 (m, 4H), 3.59 (bd, J = 9.24 Hz, 2H), 3.90 (s, 2H), 5.99 (s, 1H), 6.84 (dt, J = 6.75 Hz, J = 2.49 Hz, 2H), 7.18 (dt, J = 6.75 Hz, J = 2.46 Hz, 2H)
54% yield: ¹ H NMR (CDCl ₃ , 300 MHz) δ 0.96 (d, J = 4.98 Hz, 9H), 1.23-1.40 (m, 3H), 1.49 (t, J = 3.24 Hz, 3H), 1.76 ( bd, J = 9.24 Hz, 2H), 1.92-1.97 (m, 3H), 2.53 (q, J = 2.85 Hz, 3H), 2.65-2.72 (m, 4H), 3.59 (bd, J = 9.24 Hz, 2H ), 3.90 (s, 2H), 5.99 (s, 1H), 6.84 (dt, J = 6.75 Hz, J = 2.49 Hz, 2H), 7.18 (dt, J = 6.75 Hz, J = 2.46 Hz, 2H)

45% 수율: ¹H NMR (CDCl₃, 300 MHz) δ 1.33 (s, 9H), 1.36-1.53 (m, 7H), 1.79 (bd, J = 11.62 Hz, 2H), 2.64 (t, J = 11.72 Hz, 2H), 2.72 (t, J = 7.01 Hz, 2H), 3.53 (bd, J = 12.44 Hz, 2H), 3.89 (s, 2H), 6.06 (s, 1H), 6.86-6.98 (m, 4H)
45% yield: ¹ H NMR (CDCl ₃ , 300 MHz) δ 1.33 (s, 9H), 1.36-1.53 (m, 7H), 1.79 (bd, J = 11.62 Hz, 2H), 2.64 (t, J = 11.72 Hz, 2H), 2.72 (t, J = 7.01 Hz, 2H), 3.53 (bd, J = 12.44 Hz, 2H), 3.89 (s, 2H), 6.06 (s, 1H), 6.86-6.98 (m, 4H )

27% 수율: ¹H NMR (CDCl₃, 300 MHz) δ 1.28 (d, J = 6.95 Hz, 6H), 1.46-1.53 (m, 3H), 1.78 (bd, J = 12.56 Hz, 2H), 1.97 (bs, 2H), 2.69-2.82 (m, 4H), 3.03-3.08 (m, 1H), 3.78 (bd, J = 12.62 Hz, 2H), 3.89 (s, 2H), 6.04 (s, 1H), 6.91 (d, J = 8.69 Hz, 2H), 7.45 (d, J = 8.72 Hz, 2H)
27% yield: ¹ H NMR (CDCl ₃ , 300 MHz) δ 1.28 (d, J = 6.95 Hz, 6H), 1.46-1.53 (m, 3H), 1.78 (bd, J = 12.56 Hz, 2H), 1.97 ( bs, 2H), 2.69-2.82 (m, 4H), 3.03-3.08 (m, 1H), 3.78 (bd, J = 12.62 Hz, 2H), 3.89 (s, 2H), 6.04 (s, 1H), 6.91 (d, J = 8.69 Hz, 2H), 7.45 (d, J = 8.72 Hz, 2H)

화합물 85 : N-((3-이소프로필아이속사졸-5-일)메틸)-2-(1-p-톨릴피페리딘-4-일)에탄아민 Compound 85: N -((3-isopropylisoxazol-5-yl) methyl) -2- (1- p -tolylpiperidin-4-yl) ethanamine

47% 수율: ¹H NMR (CDCl₃, 300 MHz) δ 1.28 (d, J = 5.21 Hz, 6H), 1.34-1.46 (m, 3H), 1.51 (s, 4H), 1.77 (bd, J = 8.68 Hz, 2H), 2.26 (s, 3H), 2.63 (td, J = 8.85 Hz, J = 1.65 Hz, 2H), 2.71 (t, J = 5.16 Hz, 2H), 3.0-3.09 (m, 1H), 3.59 (bd, J = 9.29 Hz, 2H), 3.89 (s, 2H), 6.03 (s, 1H), 6.86 (d, J = 6.41 Hz, 2H), 7.06 (d, J = 6.26 Hz, 2H)
47% yield: ¹ H NMR (CDCl ₃ , 300 MHz) δ 1.28 (d, J = 5.21 Hz, 6H), 1.34-1.46 (m, 3H), 1.51 (s, 4H), 1.77 (bd, J = 8.68 Hz, 2H), 2.26 (s, 3H), 2.63 (td, J = 8.85 Hz, J = 1.65 Hz, 2H), 2.71 (t, J = 5.16 Hz, 2H), 3.0-3.09 (m, 1H), 3.59 (bd, J = 9.29 Hz, 2H), 3.89 (s, 2H), 6.03 (s, 1H), 6.86 (d, J = 6.41 Hz, 2H), 7.06 (d, J = 6.26 Hz, 2H)

94% 수율: ¹H NMR (CDCl₃, 300 MHz) δ 1.27 (d, J = 6.95 Hz, 6H), 1.32-1.36 (m, 2H), 1.46-1.52 (m, 3H), 1.76 (bd, J = 12.33 Hz, 2H), 2.68 (td, J = 12.00 Hz, J = 2.58 Hz, 4H), 3.02-3.06 (m, 1H), 3.59 (bd, J = 12.48 Hz, 2H), 3.88 (s, 2H), 6.02 (s, 1H), 6.72 (dd, J = 8.95 Hz, J = 2.87 Hz, 1H), 6.94 (d, J = 2.86 Hz, 2H), 7.23 (d, J = 8.93 Hz, 2H)
94% yield: ¹ H NMR (CDCl ₃ , 300 MHz) δ 1.27 (d, J = 6.95 Hz, 6H), 1.32-1.36 (m, 2H), 1.46-1.52 (m, 3H), 1.76 (bd, J = 12.33 Hz, 2H), 2.68 (td, J = 12.00 Hz, J = 2.58 Hz, 4H), 3.02-3.06 (m, 1H), 3.59 (bd, J = 12.48 Hz, 2H), 3.88 (s, 2H ), 6.02 (s, 1H), 6.72 (dd, J = 8.95 Hz, J = 2.87 Hz, 1H), 6.94 (d, J = 2.86 Hz, 2H), 7.23 (d, J = 8.93 Hz, 2H)

22% 수율: ¹H NMR (CDCl₃, 300 MHz) δ 1.29 (d, J = 6.94 Hz, 6H), 1.43-1.54 (m, 3H), 1.78 (bd, J = 9.58 Hz, 2H), 2.62 (bt, J = 11.14 Hz, 2H), 2.74 (t, J = 7.06 Hz, 2H), 2.88 (bs, 4H), 3.01-3.11 (m, 1H), 3.49 (bd, J = 11.78 Hz, 2H), 3.77 (s, 3H), 6.06 (s, 1H), 6.83 (d, J = 9.04 Hz, 2H), 6.93 (d, J = 9.08 Hz, 2H)
22% yield: ¹ H NMR (CDCl ₃ , 300 MHz) δ 1.29 (d, J = 6.94 Hz, 6H), 1.43-1.54 (m, 3H), 1.78 (bd, J = 9.58 Hz, 2H), 2.62 ( bt, J = 11.14 Hz, 2H), 2.74 (t, J = 7.06 Hz, 2H), 2.88 (bs, 4H), 3.01-3.11 (m, 1H), 3.49 (bd, J = 11.78 Hz, 2H), 3.77 (s, 3H), 6.06 (s, 1H), 6.83 (d, J = 9.04 Hz, 2H), 6.93 (d, J = 9.08 Hz, 2H)

45% 수율: ¹H NMR (CDCl₃, 400 MHz) δ 7.15-6.75 (m, 4H), 6.10 (s, 1H), 4.05 (s, 2H), 3.89 (m, 2H), 3.07-3.03 (m, 1H), 2.73-2.67 (m, 4H), 1.78 (m, 2H), 1.51-1.29 (m, 6H), 1.27 (d, 6H, J = 3.00 Hz)
45% yield: ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.15-6.75 (m, 4H), 6.10 (s, 1H), 4.05 (s, 2H), 3.89 (m, 2H), 3.07-3.03 (m , 1H), 2.73-2.67 (m, 4H), 1.78 (m, 2H), 1.51-1.29 (m, 6H), 1.27 (d, 6H, J = 3.00 Hz)

23% 수율: ¹H NMR (CDCl₃, 400 MHz) δ 7.17-6.48 (m, 4H), 6.02 (s, 1H),3.89 (s, 2H), 3.67 (m, 2H), 3.07-3.03 (m, 1H), 2.74-2.69 (m, 4H), 1.78 (m, 2H), 1.51-1.33 (m, 6H), 1.28 (d, 6H, J = 3.89 Hz)
23% yield: ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.17-6.48 (m, 4H), 6.02 (s, 1H), 3.89 (s, 2H), 3.67 (m, 2H), 3.07-3.03 (m , 1H), 2.74-2.69 (m, 4H), 1.78 (m, 2H), 1.51-1.33 (m, 6H), 1.28 (d, 6H, J = 3.89 Hz)

11% 수율: ¹H NMR (CDCl₃, 400 MHz) δ 7.15 (t, 1H, J = 7.82 Hz), 6.76 (m, 2H), 6.66 (dd, 1H, J = 7.89 Hz), 6.03 (s, 1H), 3.89 (s, 2H), 3.66 (m, 2H), 3.07 (m, 1H), 2.73 (m, 4H), 2.31 (s, 3H), 1.78 (m, 2H), 1.51 (m, 5H), 1.28 (d, 6H, J = 2.86 Hz)
11% yield: ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.15 (t, 1H, J = 7.82 Hz), 6.76 (m, 2H), 6.66 (dd, 1H, J = 7.89 Hz), 6.03 (s, 1H), 3.89 (s, 2H), 3.66 (m, 2H), 3.07 (m, 1H), 2.73 (m, 4H), 2.31 (s, 3H), 1.78 (m, 2H), 1.51 (m, 5H ), 1.28 (d, 6H, J = 2.86 Hz)

37% 수율: ¹H NMR (CDCl₃, 400 MHz) δ 7.34-7.02 (m, 4H), 6.02 (s, 1H), 3.89 (s, 2H), 3.71 (m, 2H), 3.07 (m, 1H), 2.77-2.70 (m, 4H), 1.81 (m, 2H), 1.52-1.32 (m, 6H), 1.28 (d, 6H, J = 3.24 Hz)
37% yield: ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.34-7.02 (m, 4H), 6.02 (s, 1H), 3.89 (s, 2H), 3.71 (m, 2H), 3.07 (m, 1H ), 2.77-2.70 (m, 4H), 1.81 (m, 2H), 1.52-1.32 (m, 6H), 1.28 (d, 6H, J = 3.24 Hz)

57% 수율 : ¹H NMR (300 MHz, CDCl₃) δ 7.64 (td, J = 4.1 Hz, 2.5 Hz, 1H), 7.53 (dt, J = 10.5 Hz, 3.9 Hz, 1H), 7.35-7.27 (m, 2H), 6.06 (s, 1H), 5.99 (bs, 1H), 3.92 (s, 2H), 3.19 (q, J = 2.7 Hz, 2H), 3.09-3.0 (m, 1H), 2.81 (t, J = 5.9 Hz, 2H), 2.73 (t, J = 5.5 Hz, 2H), 2.65 (t, J = 5.9 Hz, 2H), 2.55 (bs, 2H), 1.27 (d, J = 7.0 Hz, 6H)
57% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.64 (td, J = 4.1 Hz, 2.5 Hz, 1H), 7.53 (dt, J = 10.5 Hz, 3.9 Hz, 1H), 7.35-7.27 (m , 2H), 6.06 (s, 1H), 5.99 (bs, 1H), 3.92 (s, 2H), 3.19 (q, J = 2.7 Hz, 2H), 3.09-3.0 (m, 1H), 2.81 (t, J = 5.9 Hz, 2H), 2.73 (t, J = 5.5 Hz, 2H), 2.65 (t, J = 5.9 Hz, 2H), 2.55 (bs, 2H), 1.27 (d, J = 7.0 Hz, 6H)

39% 수율 : ¹H NMR (300 MHz, CDCl₃) δ 7.24 (d, J = 6.9 Hz, 2H), 7.15 (t, J = 7.2 Hz, 2H), 7.07 (t, J = 6.7 Hz, 1H), 5.90 (bs, 2H), 3.73 (s, 2H), 2.99 (bs, 2H), 2.93-2.84 (m, 1H), 2.64 (t, J = 5.4 Hz, 2H), 2.60 (bs, 1H), 2.53 (t, J = 5.2 Hz, 2H), 2.46 (t, J = 5.6 Hz, 2H), 2.40 (bs, 2H), 1.13 (d, J = 6.9 Hz, 6H)
39% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.24 (d, J = 6.9 Hz, 2H), 7.15 (t, J = 7.2 Hz, 2H), 7.07 (t, J = 6.7 Hz, 1H) , 5.90 (bs, 2H), 3.73 (s, 2H), 2.99 (bs, 2H), 2.93-2.84 (m, 1H), 2.64 (t, J = 5.4 Hz, 2H), 2.60 (bs, 1H), 2.53 (t, J = 5.2 Hz, 2H), 2.46 (t, J = 5.6 Hz, 2H), 2.40 (bs, 2H), 1.13 (d, J = 6.9 Hz, 6H)

25% 수율 : ¹H NMR (300 MHz, CDCl₃) δ 7.32-7.25 (m, 4H), 6.04 (bs, 2H), 3.91 (s, 2H), 3.14 (d, J = 3.1 Hz, 2H), 3.09-3.00 (m, 1H), 2.81 (t, J = 6.0 Hz, 2H), 2.69 (t, J = 5.6 Hz, 2H), 2.63 (t, J = 6.0 Hz, 2H), 2.52 (bs, 2H), 2.04 (bs, 1H), 1.27 (d, J = 7.0 Hz, 6H)
25% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.32-7.25 (m, 4H), 6.04 (bs, 2H), 3.91 (s, 2H), 3.14 (d, J = 3.1 Hz, 2H), 3.09-3.00 (m, 1H), 2.81 (t, J = 6.0 Hz, 2H), 2.69 (t, J = 5.6 Hz, 2H), 2.63 (t, J = 6.0 Hz, 2H), 2.52 (bs, 2H ), 2.04 (bs, 1H), 1.27 (d, J = 7.0 Hz, 6H)

53% 수율 : ¹H NMR (300 MHz, CDCl₃) δ 7.63 (s, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.50 (d, J =7.7 Hz, 1H), 7.40 (t, J = 7.7 Hz, 1H), 6.12 (bs, 1H), 6.03 (s, 1H), 3.90 (s, 2H), 3.16 (q, J = 2.8 Hz, 2H), 3.08-2.99 (m, 1H), 2.81 (t, J = 5.9 Hz, 2H), 2.70 (t, J = 5.6 Hz, 2H), 2.63 (t, J = 5.9 Hz, 2H), 2.52 (bs, 2H), 1.97 (bs, 1H)
53% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.63 (s, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.50 (d, J = 7.7 Hz, 1H), 7.40 (t, J = 7.7 Hz, 1H), 6.12 (bs, 1H), 6.03 (s, 1H), 3.90 (s, 2H), 3.16 (q, J = 2.8 Hz, 2H), 3.08-2.99 (m, 1H), 2.81 (t, J = 5.9 Hz, 2H), 2.70 (t, J = 5.6 Hz, 2H), 2.63 (t, J = 5.9 Hz, 2H), 2.52 (bs, 2H), 1.97 (bs, 1H)

35% 수율 : ¹H NMR (300 MHz, CDCl₃) δ 7.31 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.9 Hz, 2H), 6.03 (s, 1H), 5.95 (bs, 1H), 3.90 (s, 2H), 3.78 (s, 3H), 3.12 (d, J = 3.1 Hz, 2H), 3.08-2.99 (m, 1H), 2.80 (t, J = 6.0 Hz, 2H), 2.68 (t, J = 5.6 Hz, 2H), 2.61 (t, J = 6.0 Hz, 2H), 2.52 (bs, 2H), 2.00 (bs, 1H), 1.26 (d, J = 7.0 Hz, 6H)
35% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.31 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.9 Hz, 2H), 6.03 (s, 1H), 5.95 (bs, 1H), 3.90 (s, 2H), 3.78 (s, 3H), 3.12 (d, J = 3.1 Hz, 2H), 3.08-2.99 (m, 1H), 2.80 (t, J = 6.0 Hz, 2H), 2.68 (t, J = 5.6 Hz, 2H), 2.61 (t, J = 6.0 Hz, 2H), 2.52 (bs, 2H), 2.00 (bs, 1H), 1.26 (d, J = 7.0 Hz, 6H)

화합물 97 : N,N-비스((3-아이소프로필아이속사졸-5-일)메틸)-2-(4-o-톨릴-1,2,3,6-테트라하이드로피리딘-4-일)에탄아민Compound 97: N, N -bis ((3-isopropylisoxazol-5-yl) methyl) -2- (4- o -tolyl-1,2,3,6-tetrahydropyridin-4-yl) Ethanamine

9% 수율 : ¹H NMR (300 MHz, CDCl₃) δ 7.18-7.10 (m, 4H), 6.11 (s, 2H), 5.53 (bs, 1H), 3.89 (s, 4H), 3.16 (d, J = 2.9 Hz, 2H), 3.11-3.00 (m, 2H), 2.82 (t, J = 6.6 Hz, 2H), 2.74-2.67 (m, 4H), 2.39 (bs, 2H), 2.30 (s, 3H), 1.30 (d, J = 7.0 Hz, 12H)
9% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.18-7.10 (m, 4H), 6.11 (s, 2H), 5.53 (bs, 1H), 3.89 (s, 4H), 3.16 (d, J = 2.9 Hz, 2H), 3.11-3.00 (m, 2H), 2.82 (t, J = 6.6 Hz, 2H), 2.74-2.67 (m, 4H), 2.39 (bs, 2H), 2.30 (s, 3H) , 1.30 (d, J = 7.0 Hz, 12H)

72% 수율 : ¹H NMR (300 MHz, CDCl₃) δ 7.31 (d, J = 1.6 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.07 (dd, J = 8.5 Hz, 1.6 Hz, 1H), 5.94 (bs, 1H), 3.78 (s, 2H), 3.02 (bs, 2H), 2.96-2.87 (m, 1H), 2.68 (t, J = 5.7 Hz, 2H), 2.57-2.48 (m, 4H), 2.35 (bs, 2H), 2.26 (bs, 1H), 1.15 (d, J = 6.9 Hz, 6H)
72% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.31 (d, J = 1.6 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.07 (dd, J = 8.5 Hz, 1.6 Hz , 1H), 5.94 (bs, 1H), 3.78 (s, 2H), 3.02 (bs, 2H), 2.96-2.87 (m, 1H), 2.68 (t, J = 5.7 Hz, 2H), 2.57-2.48 ( m, 4H), 2.35 (bs, 2H), 2.26 (bs, 1H), 1.15 (d, J = 6.9 Hz, 6H)

화합물 99 : 2-(4-(3,4-다이클로로페닐)-1,2,3,6-테트라하이드로피리딘-4-일)-N,N-비스((3-아이소프로필아이속사졸-5-일)메틸)에탄아민Compound 99: 2- (4- (3,4-dichlorophenyl) -1,2,3,6-tetrahydropyridin-4-yl) -N, N -bis ((3-isopropylisoxazole- 5-yl) methyl) ethanamine

3% 수율 : ¹H NMR (300 MHz, CDCl₃) δ 7.44 (d, J = 2.1 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.20 (dd, J = 8.4 Hz, 2.1 Hz, 1H), 6.09 (s, 2H), 6.08 (bs, 1H), 3.87 (s, 4H), 3.18 (q, J = 3.0 Hz, 2H), 3.10-3.01 (m, 2H), 2.81-2.65 (m, 7H), 2.50 (bs, 2H), 1.29 (d, J = 6.9 Hz, 12H)
3% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.44 (d, J = 2.1 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.20 (dd, J = 8.4 Hz, 2.1 Hz , 1H), 6.09 (s, 2H), 6.08 (bs, 1H), 3.87 (s, 4H), 3.18 (q, J = 3.0 Hz, 2H), 3.10-3.01 (m, 2H), 2.81-2.65 ( m, 7H), 2.50 (bs, 2H), 1.29 (d, J = 6.9 Hz, 12H)

화합물 100 : 2-(4-(3,4-다이클로로페닐)피페리딘-1-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)에탄아민의 합성Compound 100: Synthesis of 2- (4- (3,4-Dichlorophenyl) piperidin-1-yl) -N -((3-isopropylisoxazol-5-yl) methyl) ethanamine

77% 수율 : ¹H NMR (300 MHz, CDCl₃) δ 7.31 (d, J = 1.6 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.07 (dd, J = 8.5 Hz, 1.6 Hz, 1H), 6.06 (bs, 1H), 3.92 (s, 2H), 3.10-2.98 (m, 2H+1H)), 2.68 (t, J = 5.7 Hz, 2H), 2.46-2.35 (m, 2H+1H), 1.97 (dt, J = 17.6 Hz, 7.3 Hz, 2H+1H), 1.77-1.71 (m, 4H), 1.15 (d, J = 5.8 Hz, 6H)
77% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.31 (d, J = 1.6 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.07 (dd, J = 8.5 Hz, 1.6 Hz , 1H), 6.06 (bs, 1H), 3.92 (s, 2H), 3.10-2.98 (m, 2H + 1H)), 2.68 (t, J = 5.7 Hz, 2H), 2.46-2.35 (m, 2H + 1H), 1.97 (dt, J = 17.6 Hz, 7.3 Hz, 2H + 1H), 1.77-1.71 (m, 4H), 1.15 (d, J = 5.8 Hz, 6H)

37% 수율 : ¹H NMR (300 MHz, CDCl₃) δ 7.29-7.24 (m, 2H), 7.21-7.13 (m, 3H), 6.02 (s, 1H), 3.87 (s, 2H), 3.06-2.94 (m, 2H+1H), 2.74 (t, J = 5.8 Hz, 2H), 2.52-2.41 (m, 2H+1H), 2.03 (dt, J = 15.8 Hz, 5.5 Hz, 2H+1H), 1.78-1.72 (m, 4H), 1.25 (d, J = 7.0 Hz, 6H)
37% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.29-7.24 (m, 2H), 7.21-7.13 (m, 3H), 6.02 (s, 1H), 3.87 (s, 2H), 3.06-2.94 (m, 2H + 1H), 2.74 (t, J = 5.8 Hz, 2H), 2.52-2.41 (m, 2H + 1H), 2.03 (dt, J = 15.8 Hz, 5.5 Hz, 2H + 1H), 1.78- 1.72 (m, 4H), 1.25 (d, J = 7.0 Hz, 6H)

53.5% 수율 : ¹H NMR (CDCl₃, 400 MHz) δ 7.29 (t, 2H), 6.95 (d, 2H, J = 1.20 Hz), 6.89 (t, 1H), 6.62 (s, 1H), 4.03 (s, 2H), 3.98 (s, 3H), 3.21 (m, 4H), 2.78 (t, 2H), 2.63-2.57 (m, 6H), 2.00 (bs, 1H).
53.5% yield: ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.29 (t, 2H), 6.95 (d, 2H, J = 1.20 Hz), 6.89 (t, 1H), 6.62 (s, 1H), 4.03 ( s, 2H), 3.98 (s, 3H), 3.21 (m, 4H), 2.78 (t, 2H), 2.63-2.57 (m, 6H), 2.00 (bs, 1H).

53.5% 수율 : ¹H NMR (CDCl₃, 400 MHz) δ 7.27 (t, 2H), 6.92 (d, 2H, J = 10.66 Hz), 6.84 (t, 1H), 6.61 (s, 1H), 4.46 (q, 2H), 4.03 (s, 2H), 3.21 (m, 4H), 2.75 (t, 2H), 2.61-2.55 (m, 6H), 1.90 (bs, 1H), 1.42 (t, 3H).
53.5% yield: ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.27 (t, 2H), 6.92 (d, 2H, J = 10.66 Hz), 6.84 (t, 1H), 6.61 (s, 1H), 4.46 ( q, 2H), 4.03 (s, 2H), 3.21 (m, 4H), 2.75 (t, 2H), 2.61-2.55 (m, 6H), 1.90 (bs, 1H), 1.42 (t, 3H).

에틸 5-((2-(4-페닐피페라진-1-일)에틸아미노)메틸)옥사졸-3-카복실레이트 (화합물 103) (40 mg 10 mmol), 1M-HCl Et₂O 용액 10 mL에 용해 후 결정화 방법으로 목적화합물 42 mg (95%)을 얻었다.10 mL of ethyl 5-((2- (4-phenylpiperazin-1-yl) ethylamino) methyl) oxazole-3-carboxylate (Compound 103) (40 mg 10 mmol), 1M-HCl Et ₂ O solution 42 mg (95%) of the title compound was obtained by crystallization after dissolution in.

95% 수율 : ¹H NMR (CDCl₃, 400 MHz) δ 7.26 (t, 2H), 6.90 (d, 2H, J = 10.24 Hz), 6.84 (t, 1H), 6.61 (s, 1H), 4.47 (q, 2H), 4.03 (s, 2H), 3.23 (m, 4H), 2.75 (t, 2H), 2.61-2.55 (m, 6H), 1.42 (t, 3H).
95% yield: ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.26 (t, 2H), 6.90 (d, 2H, J = 10.24 Hz), 6.84 (t, 1H), 6.61 (s, 1H), 4.47 ( q, 2H), 4.03 (s, 2H), 3.23 (m, 4H), 2.75 (t, 2H), 2.61-2.55 (m, 6H), 1.42 (t, 3H).

에틸 5-((2-(4-페닐피페라진-1-일)에틸아미노)메틸)아이속사졸-3-카복실레이트 (화합물 103) (40 mg 10 mmol)를 NaOH를 사용하여 일반적인 방법으로 Na 염 화합물 목적 화합물을 35 mg (90%) 얻었다.Ethyl 5-((2- (4-phenylpiperazin-1-yl) ethylamino) methyl) isoxazole-3-carboxylate (Compound 103) (40 mg 10 mmol) was dissolved in the usual manner using NaOH. Salt Compound 35 mg (90%) of the title compound were obtained.

90% 수율 : ¹H NMR (CDCl₃, 400 MHz) δ 7.27 (t, 2H), 6.92 (d, 2H, J = 10.66 Hz), 6.84 (t, 1H), 6.61 (s, 1H), 4.03 (s, 2H), 3.21 (m, 4H), 2.75 (t, 2H), 2.61-2.55 (m, 6H)
90% yield: ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.27 (t, 2H), 6.92 (d, 2H, J = 10.66 Hz), 6.84 (t, 1H), 6.61 (s, 1H), 4.03 ( s, 2H), 3.21 (m, 4H), 2.75 (t, 2H), 2.61-2.55 (m, 6H)

56.0% 수율 : ¹H NMR (CDCl₃, 400 MHz) δ 7.37 (t, 4H), 7.00 (t, 4H), 6.59 (s, 1H), 4.43 (q, 2H), 4.21 (s, 1H), 3.96 (s, 2H), 2.70 (t, 2H), 2.52-2.31 (m, 10H), 1.42 (t, 3H).
56.0% yield: ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.37 (t, 4H), 7.00 (t, 4H), 6.59 (s, 1H), 4.43 (q, 2H), 4.21 (s, 1H), 3.96 (s, 2H), 2.70 (t, 2H), 2.52-2.31 (m, 10H), 1.42 (t, 3H).

90% 수율 : ¹H NMR (CDCl₃, 400 MHz) δ 7.35 (t, 4H), 6.97 (t, 4H), 6.57 (s, 1H), 4.21 (s, 1H), 3.96 (s, 2H), 2.70 (t, 2H), 2.52-2.31 (m, 10H).
90% ^{_{yield: 1 H NMR (CDCl 3,}} 400 MHz) δ 7.35 (t, 4H), 6.97 (t, 4H), 6.57 (s, 1H), 4.21 (s, 1H), 3.96 (s, 2H), 2.70 (t, 2H), 2.52 - 2.31 (m, 10H).

55.8% 수율 : ¹H NMR (CDCl₃, 400 MHz) δ 7.42 (t, 4H), 7.29 (t, 4H), 7.17 (t, 2H), 6.57 (s, 1H), 4.46 (q, 2H), 4.22 (s, 1H), 3.97 (s, 2H), 2.73 (t, 2H), 2.53-2.46 (m, 10H), 1.40 (t, 3H).
55.8% yield: ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.42 (t, 4H), 7.29 (t, 4H), 7.17 (t, 2H), 6.57 (s, 1H), 4.46 (q, 2H), 4.22 (s, 1H), 3.97 (s, 2H), 2.73 (t, 2H), 2.53-2.46 (m, 10H), 1.40 (t, 3H).

90% 수율 : ¹H NMR (CDCl₃, 400 MHz) δ 7.44 (t, 4H), 7.26 (t, 4H), 7.16 (t, 2H), 6.57 (s, 1H), 4.22 (s, 1H), 3.96 (s, 2H), 2.73 (t, 2H), 2.53-2.46 (m, 10H).
90% yield: ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.44 (t, 4H), 7.26 (t, 4H), 7.16 (t, 2H), 6.57 (s, 1H), 4.22 (s, 1H), 3.96 (s, 2 H), 2.73 (t, 2 H), 2.53-2.46 (m, 10 H).

52.1% 수율 : ¹H NMR (CDCl₃, 400 MHz) δ 7.42 (t, 4H), 7.29 (t, 4H), 7.20 (t, 2H), 5.97 (s, 1H), 4.23 (s, 1H), 2.70 (t, 2H), 2.53-2.46 (m, 10H), 2.27 (s, 3H).
52.1% yield: ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.42 (t, 4H), 7.29 (t, 4H), 7.20 (t, 2H), 5.97 (s, 1H), 4.23 (s, 1H), 2.70 (t, 2H), 2.53-2.46 (m, 10H), 2.27 (s, 3H).

56.1% 수율 : ¹H NMR (CDCl₃, 400 MHz) δ 7.35 (t, 4H), 6.98 (t, 4H), 5.96 (s, 1H), 4.20 (s, 1H), 3.86 (s, 2H), 2.69 (t, 2H), 2.51-2.43 (m, 10H), 2.26 (s, 3H).
56.1% yield: ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.35 (t, 4H), 6.98 (t, 4H), 5.96 (s, 1H), 4.20 (s, 1H), 3.86 (s, 2H), 2.69 (t, 2H), 2.51-2.43 (m, 10H), 2.26 (s, 3H).

55.6% 수율 : ¹H NMR (CDCl₃, 400 MHz) δ 7.32-7.22 (q, 8H), 5.97 (s, 1H), 4.18 (s, 1H), 3.87 (s, 2H), 2.71 (t, 2H), 2.53-2.39 (m, 10H), 2.26 (s, 3H).
55.6% yield: ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.32-7.22 (q, 8H), 5.97 (s, 1H), 4.18 (s, 1H), 3.87 (s, 2H), 2.71 (t, 2H ), 2.53-2.39 (m, 10 H), 2.26 (s, 3 H).

57.8% 수율 : ¹H NMR (CDCl₃, 400 MHz) δ 7.31-7.25 (q, 8H), 5.96 (s, 1H), 4.34 (q, 2H), 4.18 (s, 1H), 3.97 (s, 2H), 2.69 (t, 2H), 2.50-2.43 (m, 10H), 1.40 (t, 3H).
57.8% yield: ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.31-7.25 (q, 8H), 5.96 (s, 1H), 4.34 (q, 2H), 4.18 (s, 1H), 3.97 (s, 2H ), 2.69 (t, 2H), 2.50-2.43 (m, 10H), 1.40 (t, 3H).

에틸 5-((2-(4-(비스(4-플루오로페닐)메틸)피페라진-1-일)에틸아미노)메틸)아이속사졸-3-카복실레이트 (화합물 106) (50 mg, 1.03 mmol), NH₄OH 0. 2 mL, 메탄올 1.1 mL를 상온에서 2시간 교반 후 용매 제거, 관크로마토그래피 정제로부터 목적화합물 42.8 mg (85%)을 얻었다.Ethyl 5-((2- (4- (bis (4-fluorophenyl) methyl) piperazin-1-yl) ethylamino) methyl) isoxazole-3-carboxylate (Compound 106) (50 mg, 1.03 mmol), NH ₄ OH 0.2 mL, and methanol 1.1 mL were stirred at room temperature for 2 hours, and then solvent was removed to obtain 42.8 mg (85%) of the title compound.

85% 수율 : ¹H NMR (CDCl₃, 400 MHz) δ 7.36 (t, 4H), 6.97 (t, 4H), 6.70 (bs, 1H), 6.61 (s, 1H), 5.61 (bs, 1H), 4.21 (s, 1H), 3.97 (s, 2H), 2.70 (t, 2H), 2.52-2.33 (m, 10H).
85% yield: ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.36 (t, 4H), 6.97 (t, 4H), 6.70 (bs, 1H), 6.61 (s, 1H), 5.61 (bs, 1H), 4.21 (s, 1 H), 3.97 (s, 2 H), 2.70 (t, 2 H), 2.52-2.33 (m, 10 H).

에틸 5-((2-(4-(비스(4-플루오로페닐)메틸)피페라진-1-일)에틸아미노)메틸)아이속사졸-3-카복실레이트 (화합물 106) (50 mg, 1.03 mmol), 메탄올 5 mL, 2M-메틸아민 1.5 mL 넣고 상온에서 3시간동안 교반 하였다. 용매 제거 후 관크로마토그래피 정제로부터 화합물 64 46.5 mg (95%)을 얻었다.Ethyl 5-((2- (4- (bis (4-fluorophenyl) methyl) piperazin-1-yl) ethylamino) methyl) isoxazole-3-carboxylate (Compound 106) (50 mg, 1.03 mmol), 5 mL of methanol, 1.5 mL of 2M-methylamine, and stirred at room temperature for 3 hours. 46.5 mg (95%) of Compound 64 was obtained from tube chromatography after solvent removal.

95% 수율 : ¹H NMR (CDCl₃, 400 MHz) δ 7.36 (t, 4H), 6.97 (t, 4H), 6.78 (bs, 1H), 6.59 (s, 1H), 4.21 (s, 1H), 3.96 (s, 2H), 3.00 (d, 3H, J = 6.67 Hz), 2.70 (t, 2H), 2.52-2.31 (m, 10H).
95% yield: ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.36 (t, 4H), 6.97 (t, 4H), 6.78 (bs, 1H), 6.59 (s, 1H), 4.21 (s, 1H), 3.96 (s, 2H), 3.00 (d, 3H, J = 6.67 Hz), 2.70 (t, 2H), 2.52-2.31 (m, 10H).

화합물 116 : 5-((2-(4-(비스(4-플루오로페닐)메틸)피페라진-1-일)에틸아미노)메틸)-N,N-디메틸아이속사졸-3-카복사마이드Compound 116: 5-((2- (4- (bis (4-fluorophenyl) methyl) piperazin-1-yl) ethylamino) methyl) -N, N -dimethylisoxazole-3-carboxamide

에틸 5-((2-(4-(비스(4-플루오로페닐)메틸)피페라진-1-일)에틸아미노)메틸)아이속사졸-3-카복실레이트 (화합물 106) (50 mg, 1.03 mmol), 메탄올 5 mL, 2M-디메틸아민 1.5 mL 넣고 상온에서 3시간동안 교반 하였다. 용매 제거 후 관크로마토그래피 정제로부터 화합물 65 49.0 mg (95%)을 얻었다.Ethyl 5-((2- (4- (bis (4-fluorophenyl) methyl) piperazin-1-yl) ethylamino) methyl) isoxazole-3-carboxylate (Compound 106) (50 mg, 1.03 mmol), 5 mL of methanol and 1.5 mL of 2M-dimethylamine were added and stirred at room temperature for 3 hours. 49.0 mg (95%) of compound 65 was obtained from tube chromatography after solvent removal.

95% 수율 : ¹H NMR (CDCl₃, 400 MHz) δ 7.36 (t, 4H), 6.97 (t, 4H), 6.49 (s, 1H), 4.21 (s, 1H), 3.96 (s, 2H), 3.25 (s, 3H), 3.12 (s, 3H), 2.72 (t, 2H), 2.52-2.44 (m, 10H).
95% yield: ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.36 (t, 4H), 6.97 (t, 4H), 6.49 (s, 1H), 4.21 (s, 1H), 3.96 (s, 2H), 3.25 (s, 3H), 3.12 (s, 3H), 2.72 (t, 2H), 2.52-2.44 (m, 10H).

[제제예] [Example]

한편, 본 발명에 따른 상기 화학식 1로 표시되는 신규 화합물은 목적에 따라 여러 형태로 제제화가 가능하다. 다음은 본 발명에 따른 상기 화학식 1로 표시되는 화합물을 활성성분으로 함유시킨 몇몇 제제화 방법을 예시한 것으로 본 발명이 이에 한정되는 것은 아니다.
On the other hand, the novel compound represented by Formula 1 according to the present invention can be formulated in various forms according to the purpose. The following is a description of some formulations containing the compound of Formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.

제제 1 : 정제(직접 가압)Formulation 1: tablet (direct pressure)

활성성분 5.0 ㎎을 체로 친 후, 락토스 14.1 ㎎, 크로스포비돈 USNF 0.8 ㎎ 및 마그네슘 스테아레이트 0.1 ㎎을 혼합하고 가압하여 정제로 만들었다.
After 5.0 mg of the active ingredient was sieved, 14.1 mg of lactose, 0.8 mg of crospovidone USNF and 0.1 mg of magnesium stearate were mixed and pressurized to make tablets.

제제 2 : 정제(습식 조립)Formulation 2: Tablet (Wet Granulation)

활성성분 5.0 ㎎을 체로 친 후, 락토스 16.0 ㎎과 녹말 4.0 ㎎을 섞었다. 폴리솔베이트 80 0.3 ㎎을 순수한 물에 녹인 후 이 용액의 적당량을 첨가한 다음, 미립화하였다. 건조 후에 미립을 체질한 후 콜로이달 실리콘 디옥사이드 2.7 ㎎ 및 마그네슘 스테아레이트 2.0 ㎎과 섞었다. 미립을 가압하여 정제로 만들었다.
After 5.0 mg of the active ingredient was sieved, 16.0 mg of lactose and 4.0 mg of starch were mixed. 0.3 mg of Polysorbate 80 was dissolved in pure water, and an appropriate amount of this solution was added, followed by atomization. After drying, the granules were sieved and mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The granules were pressed into tablets.

제제 3 : 분말과 캡슐제Formulation 3: Powders and Capsules

활성성분 5.0 ㎎을 체로 친 후에, 락토스 14.8 ㎎, 폴리비닐 피롤리돈 10.0 ㎎, 마그네슘 스테아레이트 0.2 ㎎와 함께 섞었다. 혼합물을 적당한 장치를 사용하여 단단한 No. 5 젤라틴 캡슐에 채웠다.
5.0 mg of the active ingredient was sieved, followed by mixing with 14.8 mg of lactose, 10.0 mg of polyvinyl pyrrolidone, and 0.2 mg of magnesium stearate. The mixture was filtered through a hard No. Filled in 5 gelatin capsules.

제제 4 : 주사제Formulation 4: Injection

활성성분으로서 100 mg을 함유시키고, 그 밖에도 만니톨 180 mg, Na₂HPO₄?12H₂O 26 mg 및 증류수 2974 mg를 함유시켜 주사제를 제조하였다.
Injectables were prepared by containing 100 mg as the active ingredient, as well as 180 mg of mannitol, 26 mg of Na ₂ HPO ₄ -12H ₂ O and 2974 mg of distilled water.

[실험예][Experimental Example]

한편, 본 발명에 따른 상기 화학식 1로 표시되는 신규 화합물에 대해서는 하기 실험예에 나타낸 바와 같은 방법으로 T-형 칼슘채널에 대한 길항작용에 대해 테스트를 하였다. 실험결과로서 FDSS6000를 이용하여 T-형 칼슘채널에 대한 %억제율을 구하였고, 우수한 활성을 보이는 몇몇 화합물을 중심으로 자동 패치클램프를 이용하여 IC₅₀를 구하였다.
On the other hand, for the novel compound represented by the formula (1) according to the present invention was tested for the antagonism of the T-type calcium channel by the method as shown in the following experimental example. As a result of the experiment, FDSS6000 was used to determine the% inhibition of T-type calcium channel, and IC ₅₀ was obtained by using automatic patch clamp, focusing on several compounds showing excellent activity.

실험예 1: FDSS6000을 이용한 T-형 칼슘채널 활성검색 방법Experimental Example 1: T-type calcium channel activity detection method using FDSS6000

활성 검색 12 시간 내지 24 시간 전에 폴리-L-라이신 (0.05 ㎎/㎖)으로 처리된 96-웰 플레이트에 96-웰 세포 분배기 (Titertek 제품)를 이용하여 α1G T-형 칼슘채널과 Kir2.1이 안정적으로 발현되어 있는 HEK293 세포주 (α1G 세포주: KCTC 10519BP, 한국생명공학연구원 유전자은행)의 세포를 한 웰당 4 × 10⁴밀도로 분주해 주었다. 실험 당일 96-웰 플레이트에 부착된 세포들은 96-웰 플레이트 자동 세척 기기 (Bio Tek)를 이용하여 HEPES 완충용액 (단위 mM: 150 NaCl, 5 KCl, 1 MgCl₂, 2 CaCl₂, 10 HEPES, 10 글루코스, pH 7.4)으로 3회 세척한 후 5 μM 플루오-3/AM과 0.001% 플루로닉(Pluronic) F-127을 포함하는 HEPES 완충용액의 실온 조건에서 1 시간 반응시켜 형광 염료로 표지한 후 HEPES 완충용액으로 다시 2 회 세척하였다. 그 후 FDSS6000 기기 측정 10분 전에 10 mM CaCl₂을 포함하는 HEPES 완충용액으로 1회 씻고 최종 부피를 81 μL로 조정하였다. 세포가 준비된 96-웰 플레이트와는 별도로 T-형 칼슘 채널을 활성화시킬 KCl (최종농도 75 mM)과 차단제 약물을 포함할 2개의 96-웰 약물 플레이트를 준비하였다. 대부분의 세포기반 HTS 기기의 경우 약물 주입에 필요한 액체 애플리케이션 시스템은 있지만 액체 흡입 시스템은 없기 때문에 검색하고자 하는 차단제 약물 및 KCl을 5 배의 고농도로 10 mM CaCl₂HEPES 완충용액에 27 μL씩 준비하여 세포 플레이트의 최종 부피인 135 μL에서 1/5 로 희석하여 측정하였다. 구체적인 FDSS6000 측정조건으로는 20초의 기준 수치 기록 후 75초간의 약물 전처리 후 KCl 투여에 의해 변화되는 세포내 칼슘농도 변화를 측정한 것으로, 시험물질을 처리하지 않은 대조군에서의 340/380 비율값의 면적을 100%로 잡고, 시험물질의 억제 효과에 대한 백분율(%) 억제효과를 구하였고, 항상 10 μM의 미베프라딜을 대조약물로 사용하였다.12-24 hours before activity detection, 96-well plates treated with poly-L-lysine (0.05 mg / mL) were used to generate α1G T-type calcium channel and Kir2.1 using a 96-well cell distributor (Titertek). Cells of the stably expressed HEK293 cell line (α1G cell line: KCTC 10519BP, Korea Biotechnology Research Institute Gene Bank) were dispensed at a density of 4 × 10 ⁴ per well. On the day of the experiment, the cells attached to the 96-well plate were subjected to HEPES buffer (unit mM: 150 NaCl, 5 KCl, 1 MgCl ₂ , 2 CaCl ₂ , 10 HEPES, 10) using a 96-well plate self-cleaning device (Bio Tek). After washing three times with glucose, pH 7.4) and reacting for 1 hour at room temperature in HEPES buffer solution containing 5 μM fluor-3 / AM and 0.001% Pluronic F-127, and labeled with fluorescent dye Washed again with HEPES buffer twice. It was then washed once with HEPES buffer containing 10 mM CaCl ₂ and adjusted to a final volume of 81 μL 10 minutes before measuring the FDSS6000 instrument. Apart from the 96-well plates in which the cells were prepared, two 96-well drug plates were prepared to contain KCl (final concentration 75 mM) and blocker drug to activate T-type calcium channels. Most of the liquid application systems for drug injection, if the cell-based HTS machine, but a liquid suction system, by preparing a blocker drugs and KCl to search by 27 μL in 10 mM CaCl ₂ HEPES buffer solution at a high concentration of 10 times because the cells Measured by diluting to 1/5 in 135 μL, the final volume of the plate. Specific FDSS6000 measurement conditions were a change in intracellular calcium concentration, which was changed by KCl administration after drug pretreatment for 75 seconds after recording the reference value of 20 seconds. The area of the 340/380 ratio value in the control group not treated with the test substance Was 100%, and the inhibitory effect of the test substance on the percentage (%) was obtained. Mibefradil of 10 μM was always used as the reference drug.

자세한 칼슘 영상화 기술로는 FDSS6000에 장착된 크세논 램프 4개의 광원을 비추어 컴퓨터 제어 필터 휠 (computer-controlled filter wheel)에 의해 여기 파장 (340 nm 및 380 nm)을 선택적으로 세포에 노출시켰다. 매 1.23초 간격으로 데이터를 얻었으며 515 nm 고대역 통과 여파기(long-pass filter)를 통과하여 들어온 방출 형광 (emitter fluorescence light)은 기기안에 내장된 냉각 CCD 카메라를 지나 디지털 형광 분석기에 의해 96-웰 상에서의 웰 각각에 대해 평균 340/380의 비율값으로 얻었다. 모든 영상 데이터와 분석은 하마마쯔 포노닉스 (Hamamatsu Photonics)에서 제공된 FDSS6000 전용 프로그램을 이용하였다.As a detailed calcium imaging technique, the excitation wavelengths (340 nm and 380 nm) were selectively exposed to cells by a computer-controlled filter wheel in view of four light sources of xenon lamps mounted on the FDSS6000. Data were obtained every 1.23 seconds, and the emitter fluorescence light entering through a 515 nm long-pass filter was passed through a cooling CCD camera built into the instrument and then 96-well by a digital fluorescence analyzer. Average values of 340/380 were obtained for each well in the phase. All image data and analysis was done using the FDSS6000 dedicated program provided by Hamamatsu Photonics.

본 발명에 따른 신규 화합물의 T-형 칼슘채널에 대한 칼슘이동의 %억제율 결과는 하기 표 1에 나타내었다. The% inhibition rate of calcium migration of T-type calcium channels of the novel compounds according to the present invention is shown in Table 1 below.

실험화합물Experimental compound FDSS
%억제율, (10 μM)FDSS
% Inhibition rate, (10 μM) 실험화합물Experimental compound FDSS
%억제율, (10 μM)FDSS
% Inhibition rate, (10 μM) 화합물 1Compound 1 23.9823.98 화합물 41Compound 41 35.70 35.70 화합물 2Compound 2 32.4532.45 화합물 42Compound 42 63.65 63.65 화합물 3Compound 3 34.8734.87 화합물 43Compound 43 62.60 62.60 화합물 4Compound 4 22.0322.03 화합물 44Compound 44 63.24 63.24 화합물 5Compound 5 26.8426.84 화합물 45Compound 45 65.87 65.87 화합물 6Compound 6 40.5240.52 화합물 46Compound 46 73.87 73.87 화합물 7Compound 7 31.6231.62 화합물 47Compound 47 30.52 30.52 화합물 8Compound 8 46.5746.57 화합물 48Compound 48 38.62 38.62 화합물 9Compound 9 60.6660.66 화합물 49Compound 49 45.93 45.93 화합물 10Compound 10 14.6814.68 화합물 50Compound 50 43.94 43.94 화합물 11Compound 11 12.7212.72 화합물 51Compound 51 47.47 47.47 화합물 12Compound 12 21.9521.95 화합물 52Compound 52 68.36 68.36 화합물 13Compound 13 8.07 8.07 화합물 53Compound 53 68.56 68.56 화합물 14Compound 14 10.35 10.35 화합물 54Compound 54 35.10 35.10 화합물 15Compound 15 3.42 3.42 화합물 55Compound 55 45.32 45.32 화합물 16Compound 16 19.15 19.15 화합물 56Compound 56 43.68 43.68 화합물 17Compound 17 16.67 16.67 화합물 57Compound 57 54.44 54.44 화합물 18Compound 18 13.98 13.98 화합물 58Compound 58 41.09 41.09 화합물 19Compound 19 51.72 51.72 화합물 59Compound 59 49.10 49.10 화합물 20Compound 20 69.72 69.72 화합물 60Compound 60 37.20 37.20 화합물 21Compound 21 51.86 51.86 화합물 61Compound 61 39.21 39.21 화합물 22Compound 22 54.90 54.90 화합물 62Compound 62 34.87 34.87 화합물 23Compound 23 60.02 60.02 화합물 63Compound 63 56.17 56.17 화합물 24Compound 24 60.72 60.72 화합물 64Compound 64 22.59 22.59 화합물 25Compound 25 86.99 86.99 화합물 65Compound 65 25.84 25.84 화합물 26Compound 26 51.31 51.31 화합물 66Compound 66 9.13 9.13 화합물 27Compound 27 50.79 50.79 화합물 67Compound 67 25.91 25.91 화합물 28Compound 28 35.29 35.29 화합물 68Compound 68 32.58 32.58 화합물 29Compound 29 35.50 35.50 화합물 69Compound 69 18.57 18.57 화합물 30Compound 30 59.99 59.99 화합물 70Compound 70 34.44 34.44 화합물 31Compound 31 69.98 69.98 화합물 71Compound 71 25.76 25.76 화합물 32Compound 32 51.14 51.14 화합물 72Compound 72 43.82 43.82 화합물 33Compound 33 57.47 57.47 화합물 73Compound 73 47.22 47.22 화합물 34Compound 34 46.64 46.64 화합물 74Compound 74 69.88 69.88 화합물 35Compound 35 66.27 66.27 화합물 75Compound 75 20.17 20.17 화합물 36Compound 36 66.33 66.33 화합물 76Compound 76 48.50 48.50 화합물 37Compound 37 57.40 57.40 화합물 77Compound 77 48.85 48.85 화합물 38Compound 38 52.40 52.40 화합물 78Compound 78 50.38 50.38 화합물 39Compound 39 11.22 11.22 화합물 79Compound 79 53.92 53.92 화합물 40Compound 40 12.64 12.64 미베프라딜Mibepradil 79.2979.29

실험예 2: 자동 패치 클램프를 이용한 T-형 칼슘채널에 대한 이온 전류 저해도 측정 Experimental Example 2 Measurement of Ion Current Inhibition on T-type Calcium Channel Using Automatic Patch Clamp

1. 세포 배양과 준비1. Cell Culture and Preparation

α1G T-형 칼슘채널과 Kir2.1이 안정적으로 발현되어 있는 HEK293 세포주 (α1G 세포주: KCTC 10519BP)를 한국생명공학연구원 유전자은행으로부터 제공 받아 사용하였다. 95% 산소와 5% 이산화탄소가 공급되는 37℃의 세포 배양기에서, T-형 칼슘 채널 발현 세포는 10% 소태아혈청(FBS)이 포함된 DMEM 배지(Dulbecco's modified Eagle's medium)에서, hERG 채널의 경우는 10% FBS가 포함된 MEM 배지에서 배양하였다. hERG 채널을 발현시키기 위해 사용하기 20시간 전 1 μg/mL 독시사이클린(doxycycline)을 배지에 처리하여 Tet-expression system을 활성화 하였다. 실험에 쓰이는 세포는 3일에 1번씩 계대하였으며, 배양 접시에 50% 내지 80% 정도로 찼을 때 사용하였다. 실험 전에 트립신-EDTA (0.25 ×)를 사용하여 세포를 접시에서 분리한 후 피펫을 이용하여 단일 세포로 만든 다음, 원심 분리기(1100 rpm, 3분)를 이용하여 트립신을 제거하고 세포 외부 용액을 첨가하여 실온에서 패치라이너(Patchliner)로 자동 부유시킨 것을 이용하였다.HEK293 cell line (α1G cell line: KCTC 10519BP) stably expressing α1G T-type calcium channel and Kir2.1 was used from the Korea Institute of Biotechnology and Gene Bank. In a cell incubator at 37 ° C., supplied with 95% oxygen and 5% carbon dioxide, T-type calcium channel expressing cells were found in DMEMbe's modified Eagle's medium containing 10% fetal bovine serum (FBS), for hERG channels. Was incubated in MEM medium containing 10% FBS. Tet-expression system was activated by treating the medium with 1 μg / mL doxycycline 20 hours before use to express hERG channels. The cells used for the experiments were passaged once every 3 days and used when the culture dish was filled with 50% to 80%. Prior to the experiment, cells were removed from the dish using trypsin-EDTA (0.25 ×), then made into single cells using a pipette, followed by centrifuge (1100 rpm, 3 minutes) to remove trypsin and addition of extracellular solution. Was used to automatically stir at room temperature with a patchliner.

2. 실험 용액 2. Experimental solution

T-형 칼슘 채널의 활성 측정을 위한 용액 조성으로는 세포 외부 용액으로 140 mM NaCl, 2 mM CaCl₂, 4 mM KCl, 1 mM MgCl₂, 5 mM D-글루코스, 10 mM HEPES(pH 7.4)를 사용하였고 세포 내부 용액으로는 50 mM KCl, 10 mM NaCl, 60 mM KF, 2 mM MgCl₂, 10 mM HEPES, 20 mM EGTA (pH 7.2)를 사용하였다. 전세포 상태를 잘 유지하기 위해 seal 강화 용액을 첨가하였고, T-형 칼슘 채널 발현 세포의 경우에는 10 mM Ba²⁺이 들어간 세포 외부 용액을 첨가한 후 기록하였다. 각 실험화합물은 100% 디메틸술폭사이드 (DMSO)에 녹여 100 mM 스톡 용액으로 만들어, T-형 칼슘 채널 활성 측정을 위해서는 Ba²⁺이 첨가된 세포 외부 용액에 10 nM 내지 100 μM로 희석하여 IC₅₀를 측정하였다. 그 결과는 하기 표 2에 나타내었다.The solution composition for the activity measurement of T-type calcium channel was 140 mM NaCl, 2 mM CaCl ₂ , 4 mM KCl, 1 mM MgCl ₂ , 5 mM D-glucose, 10 mM HEPES (pH 7.4) as an extracellular solution. 50 mM KCl, 10 mM NaCl, 60 mM KF, 2 mM MgCl ₂ , 10 mM HEPES, 20 mM EGTA (pH 7.2) were used as the intracellular solution. In order to maintain the whole cell state, a seal strengthening solution was added, and in case of T-type calcium channel expressing cells, an extracellular solution containing 10 mM Ba ²⁺ was added and recorded. Each test compound was dissolved in 100% dimethyl sulfoxide (DMSO) to form a 100 mM stock solution. For the determination of T-type calcium channel activity, diluted ₅₀ to 100 μM in an extracellular solution containing Ba ²⁺ was added to the IC ₅₀ Was measured. The results are shown in Table 2 below.

실험화합물Experimental compound a1G IC₅₀(μM)a1G IC ₅₀ (μM) 화합물 6Compound 6 0.880.88 KST005468KST005468 1.431.43 미베프라딜Mibepradil 1.431.43

상기 표 2의 결과에 의하면, T-형 칼슘 채널 차단제로 알려진 미베프라딜과 아이속사졸 고리의 3번 위치에 방향족기가 치환된 화합물(KST005468)이 α1G IC₅₀값이 1.43 μM이나, 본 발명에 본 발명에 따른 화합물은 α1G IC₅₀값이 0.88으로 개선되었음을 확인할 수 있었다.
According to the results of Table 2, the compound (KST005468) substituted with an aromatic group at the 3 position of mibepradyl and isoxazole ring, known as T-type calcium channel blocker, has an α1G IC ₅₀ value of 1.43 μM. Compound according to the present invention was confirmed that the α1G IC ₅₀ value was improved to 0.88.

실험예 3 : 신경성 통증 동물 모델 실험 (Na Model)Experimental Example 3: Neurological Pain Animal Model Experiment (Na Model)

1. 실험 동물 준비1. Preparation of experimental animals

몸무게 150?200 g의 수컷 랫트 SD(Rat Sprague Dawley)를 4% 엔풀루란(enflurane)과 95% 산소의 혼합가스로 마취를 유도하였다. 수술 전 과정에 걸쳐 2?3% 엔풀루란(enflurane)과 95% 산소 혼합가스로 마취를 유지시켰다. 쥐의 꼬리에 분포하는 상하위 미간(superior inferior caudal trunk)의 제1,2 천수신경 사이를 1?2 mm 잘라내어 신경병증성 통증을 유발하여, 신경성 통증 동물 모델(Na Model)을 만들었다.
150-200 g of male rat SD (Rat Sprague Dawley) were induced anesthesia with a gas mixture of 4% enflurane and 95% oxygen. Anesthesia was maintained with 2-3% enflurane and 95% oxygen mixture throughout the entire procedure. A neurological pain animal model (Na Model) was created by cutting 1 to 2 mm between the first and second shallow nerves of the superior inferior caudal trunk distributed in the tail of the rat to induce neuropathic pain.

2. 약물실험2. Drug experiment

모든 행동검사는 약제투여 여부를 모르는 연구자에 의해 맹검법(blind study)으로 시행하였다.All behavioral tests were conducted in blind studies by researchers who did not know whether or not drugs were administered.

(가) 기계적 이질통(mechanical allodynia)(A) Mechanical allodynia

쥐를 둥근 아크릴 통(5.5×15, 6.5×18 cm, 몸 크기에 따라 맞게 사용)에 넣고 꼬리만 밖으로 빼낸 후, 판 위에 올려놓았다. 기계적 이질통에 대한 측정은 여러 가지 폰 프레이 헤어(von-Frey hair; 0.4, 0.6, 1.0, 2.0, 4.0, 6.0, 8.0, 15.0 g)를 이용하여 업다운(Up-Down) 방식(Chaplan et al, 1994)으로 꼬리를 자극하여 50% 회피반응을 보이는 폰 프레이 헤어(von-Frey hair의 그램(g)을 산정하는 방식으로 시행하였다. 신경 손상 전과 비교하여 통계적으로 유의하게 회피반응 역치가 감소한 것을 기계적 이질통이 발생한 것으로 판정하였다.The rats were placed in round acrylic barrels (5.5 × 15, 6.5 × 18 cm, used according to body size), with only the tails pulled out and placed on a plate. Measurements of mechanical allodynia were carried out using up-down methods (Chaplan et al, 1994) using various von-Frey hairs (0.4, 0.6, 1.0, 2.0, 4.0, 6.0, 8.0, 15.0 g). Grams of von-Frey hair, which stimulated the tail with 50% avoidance response, were measured. Was determined to have occurred.

(나) 냉 이질통(cold allodynia)(B) cold allodynia

쥐를 둥근 아크릴 통에 넣고 꼬리만 밖으로 꺼내 늘어뜨린 후 4℃ 물 속에 넣어 꼬리가 회피반응을 보일 때까지의 시간을 측정하여 기록하였다. 실험결과는 5분간의 간격을 두고 5회 실시한 평균값으로 하였다. 15초까지 회피하지 않을 때는 꼬리의 민감화를 막기 위해 물 속에서 꼬리를 빼내고 15초를 결과로 하였다. 수술 전보다 유의성 있게 빨리 회피하는 경우는 냉 이질통의 결과로 추정하였다.The rats were placed in a round acrylic container, and only the tails were taken out and hanged. Then, the rats were placed in water at 4 ° C. and the time until the tails showed an avoidance reaction was recorded. The experimental result was made into the average value performed 5 times with the interval of 5 minutes. When not avoided by 15 seconds, the tail was subtracted from the water to prevent tail sensitization, resulting in 15 seconds. Significantly faster avoidance was presumed to be a result of cold allodynia.

(다) 온 이질통(warm allodynia)(C) warm allodynia

실험은 냉 이질통과 같은 방법으로 시행하되 물의 온도를 40℃로 하였다. 수술 전보다 유의하게 빨리 회피하는 경우를 온 이질통의 결과로 추정하였다.The experiment was carried out in the same way as cold allodynia but the water temperature was 40 ℃. The case of avoiding significantly earlier than preoperatively was presumed to be the result of allodynia.

이상의 행동검사결과에서 신경에 손상을 주기 전과 비교하여 신경손상 후에 유의한 회피반응을 보이면 통증이 유발된 것으로 추정하였다.
In the above behavioral test results, it was estimated that the pain was induced when a significant avoidance response occurred after the nerve injury compared with before the nerve injury.

상기 실험예 3에 의한 신경성 통증 동물모델 실험결과는 도 1, 도 2 및 도 3으로 각각 첨부하였다. 도면에 나타낸 실험결과에 의하면, 본 발명에 따른 화합물은 통증완화제로서 상용화되어 있는 가바펜틴(Gabapentin) 약물에 비교하여 동등 내지는 우수한 활성을 나타내고 있다. 또한, 본 발명에 따른 화합물은 공지화합물로서 아이속사졸 고리의 3번 위치에 방향족기가 치환된 화합물(KST005468)에 비교하여서는 우수한 통증완화 효과를 보이고 있고, 특히 약물 투여 후 1시간 경과하였을 때의 치료효과가 매우 우수하였다.
The neurological pain animal model experiment results according to Experimental Example 3 were attached to FIGS. 1, 2, and 3, respectively. According to the experimental results shown in the drawings, the compound according to the present invention shows an equivalent to superior activity compared to the Gabapentin drug commercially available as a pain relief agent. In addition, the compound according to the present invention shows an excellent pain relief effect compared to the compound (KST005468) substituted with an aromatic group at position 3 of the isoxazole ring as a known compound, especially treatment after 1 hour after drug administration The effect was very good.

이상에서 설명한 바와 같이, 본 발명에 따른 상기 화학식 1로 표시되는 5-(치환된알킬아미노메틸)아이속사졸계 화합물 또는 약제학적으로 허용 가능한 이의 염은 T-형 칼슘이온 채널의 길항제로서 우수한 활성을 나타낸다.As described above, the 5- (substituted alkylaminomethyl) isoxazole compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof has excellent activity as an antagonist of T-type calcium ion channel. Indicates.

따라서, 본 발명의 화합물은 T-형 칼슘이온 채널의 길항제로서 유효하므로 간질 (epilepsy), 우울증, 파킨스씨병 (Parkinson's disease), 치매 (dementia), 수면장애 (sleep disorder)로부터 선택된 뇌질환 치료 및 예방제용; 암 치료 및 예방제용; 고혈압 (hypertensive), 심부정맥, 협심증, 심근 경색증, 울혈성 심부전증으로부터 선택된 심장질환 치료 및 예방제용; 또는 신경성 통증 (neuropathic pain), 만성 및 급성 통증 (chronic and acute pain)으로부터 선택된 통증 완화제용; 으로 유용한 약학적 조성물로서 유용하다.Thus, the compounds of the present invention are effective as antagonists of T-type calcium ion channels, thus treating brain diseases selected from epilepsy, depression, Parkinson's disease, dementia, sleep disorders, and For prevention; For treating and preventing cancer; For treating and preventing cardiac diseases selected from hypertensive, deep vein, angina pectoris, myocardial infarction, congestive heart failure; Or for pain relievers selected from neuropathic pain, chronic and acute pain; &Lt; / RTI >

Claims

하기 화학식 1로 표시되는 5-(치환된알킬아미노메틸)아이속사졸계 화합물 및 약제학적으로 허용 가능한 이의 염으로부터 선택된 것을 특징으로 하는 화합물 :
[화학식 1]

상기 화학식 1에서,

에서

가 단일결합일 때 X는 N 또는 CH를 나타내고,

가 이중결합일 때 X는 C를 나타내고,
Y는 N 또는 CH를 나타내고,
R¹은 페닐 및 할로페닐 중에서 선택된 1 내지 2개의 치환기로 치환 또는 비치환된 C₁-C₆알킬기; 또는 할로, 시아노, C₁-C₆알킬, C₁-C₆알콕시, C₁-C₆할로알킬, 및 C₁-C₆할로알콕시 중에서 선택된 1 내지 4개의 치환기로 치환 또는 비치환된 페닐기를 나타내고,
R²및 R³은 서로 같거나 다른 것으로서, 수소원자; 또는 C₁-C₆알킬기를 나타내고,
R⁴는 수소원자; 또는

를 나타내고,
R⁵는 C₁-C₆알킬기; -C(O)NR⁶R⁷; -C(O)OR⁸를 나타내고,
R⁶및 R⁷은 서로 같거나 다른 것으로서, 수소원자; 또는 C₁-C₆알킬기를 나타내고,
R⁸은 수소원자; 알칼리금속원자; 또는 C₁-C₆알킬기를 나타내고,
n은 0 내지 5의 정수를 나타낸다.
A compound characterized in that it is selected from 5- (substituted alkylaminomethyl) isoxazole-based compound represented by Formula 1 and a pharmaceutically acceptable salt thereof:
[Formula 1]

In Chemical Formula 1,

in

X represents N or CH when is a single bond,

X is C when is a double bond,
Y represents N or CH,
R ¹ is a C ₁ -C ₆ alkyl group unsubstituted or substituted with 1 to 2 substituents selected from phenyl and halophenyl; Or a phenyl group unsubstituted or substituted with 1 to 4 substituents selected from halo, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, and C ₁ -C ₆ haloalkoxy Indicates,
R ² and R ³ are the same as or different from each other, and are a hydrogen atom; Or a C ₁ -C ₆ alkyl group,
R ⁴ is a hydrogen atom; or

Lt; / RTI >
R ⁵ is a C ₁ -C ₆ alkyl group; -C (O) NR ⁶ R ⁷ ; -C (O) OR ⁸ ,
R ⁶ and R ⁷ are the same as or different from each other, a hydrogen atom; Or a C ₁ -C ₆ alkyl group,
R ⁸ is a hydrogen atom; Alkali metal atoms; Or a C ₁ -C ₆ alkyl group,
n represents the integer of 0-5.

청구항 1에 있어서,
상기 R¹은 디페닐메틸기, 디(p-클로로페닐)메틸기, 디(p-플루오로페닐)메틸기, 페닐기, m-시아노페닐기, m-플루오로페닐기, p-플루오로페닐기, m-클로로페닐기, p-클로로페닐기, 3,4-디클로로페닐기, 3,5-디클로로페닐기, m-메틸페닐기, p-메틸페닐기, 3,4-디메틸페닐기, 2,4-디메틸페닐기, m-메톡시페닐기, p-메톡시페닐기, 3,4-디메톡시페닐기, m-트리플루오로메틸페닐기, p-트리플루오로메틸페닐기, 또는 p-트리플루오로메톡시페닐기를 나타내고,
상기 R²는 수소원자를 나타내고,
상기 R³은 수소원자를 나타내고,
상기 R⁴는 수소원자, 아이속사졸-5-일메틸기, 3-메틸아이속사졸-5-일메틸기,또는 3-아이소프로필아이속사졸-5-일메틸기를 나타내고,
상기 R⁵는 메틸기, 에틸기, 노말프로필기, 이소프로필기, 노말부틸기, 이소부틸기, tert-부틸기, 아마이드기, 메틸카복실레이트기, 또는 소듐카복실레이트기를 나타내는 것을 특징으로 하는 화합물.
The method according to claim 1,
R ¹ is diphenylmethyl group, di ( p -chlorophenyl) methyl group, di ( p -fluorophenyl) methyl group, phenyl group, m -cyanophenyl group, m -fluorophenyl group, p -fluorophenyl group, m -chloro Phenyl group, p -chlorophenyl group, 3,4-dichlorophenyl group, 3,5-dichlorophenyl group, m -methylphenyl group, p -methylphenyl group, 3,4-dimethylphenyl group, 2,4-dimethylphenyl group, m -methoxyphenyl group , p -methoxyphenyl group, 3,4-dimethoxyphenyl group, m -trifluoromethylphenyl group, p -trifluoromethylphenyl group, or p -trifluoromethoxyphenyl group,
R ² represents a hydrogen atom,
R ³ represents a hydrogen atom,
R ⁴ represents a hydrogen atom, isoxazol-5-ylmethyl group, 3-methylisoxazol-5-ylmethyl group, or 3-isopropylisoxazol-5-ylmethyl group,
R ⁵ represents a methyl group, ethyl group, normal propyl group, isopropyl group, normal butyl group, isobutyl group, tert -butyl group, amide group, methyl carboxylate group, or sodium carboxylate group.

청구항 1에 있어서,
[2-[4-(3-클로로페닐)-피페라진-1-일]-에틸]-(3-메틸아이속사졸-5-일메틸)아민;
[2-[4-(3-클로로페닐)-피페라진-1-일]-에틸]-(3-에틸아이속사졸-5-일메틸)아민;
[2-[4-(3-클로로페닐)-피페라진-1-일]-에틸]-(3-아이소프로필아이속사졸-5-일메틸)아민;
[2-[4-(4-클로로페닐)-피페라진-1-일]-에틸]-(3-메틸아이속사졸-5-일메틸)아민;
[2-[4-(4-클로로페닐)-피페라진-1-일]-에틸]-(3-에틸아이속사졸-5-일메틸)아민;
[2-[4-(4-클로로페닐)-피페라진-1-일]-에틸]-(3-아이소프로필아이속사졸-5-일메틸)아민;
[2-(4-벤즈하이드릴-피페라진-1-일)에틸]-(3-메틸아이속사졸-5-일메틸)아민;
[2-(4-벤즈하이드릴-피페라진-1-일)에틸]-(3-에틸아이속사졸-5-일메틸)아민;
[2-(4-벤즈하이드릴-피페라진-1-일)에틸]-(3-아이소프로필아이속사졸-5-일메틸)아민;
(3-메틸아이속사졸-5-일메틸)-[2-(4-페닐피페라진-1-일)에틸]아민;
(3-에틸아이속사졸-5-일메틸)-[2-(4-페닐피페라진-1-일)에틸]아민;
(3-아이소프로필아이속사졸-5-일메틸)-[2-(4-페닐피페라진-1-일)에틸]아민;
N-((3-아이소프로필아이속사졸-5-일)메틸)-N-메틸-2-(4-(3-(트리플루오로메틸)페닐)피페라진-1-일)에탄아민;
2-(4-(2,4-디메틸페닐)피페라진-1-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)에탄아민;
2-(4-(2,4-디메틸페닐)피페라진-1-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)-N-메틸에탄아민;
2-(4-(4-클로로페닐)피페라진-1-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)-N-메틸에탄아민;
N-((3-tert-부틸아이속사졸-5-일)메틸)-2-(4-(4-클로로페닐)피페라진-1-일)에탄아민;
N-((3-tert-부틸아이속사졸-5-일)메틸)-2-(4-(4-클로로페닐)피페라진-1-일)-N-메틸에탄아민;
N-((3-tert-부틸아이속사졸-5-일)메틸)-2-(4-(3-(트리플루오로메틸)페닐)피페라진-1-일)에탄아민;
N-((3-tert-부틸아이속사졸-5-일)메틸)-N-메틸-2-(4-(3-(트리플루오로메틸)페닐)피페라진-1-일)에탄아민;
N-((3-tert-부틸아이속사졸-5-일)메틸)-2-(4-(2,4-디메틸페닐)피페라진-1-일)에탄아민;
2-(4-(4-클로로페닐)피페라진-1-일)-N-((3-아이소부틸아이속사졸-5-일)메틸)에탄아민;
2-(4-(4-클로로페닐)피페라진-1-일)-N-((3-아이소부틸아이속사졸-5-일)메틸)-N-메틸에탄아민;
N-((3-아이소부틸아이속사졸-5-일)메틸)-2-(4-(3-(트리플루오로메틸)페닐)피페라진-1-일) 에탄아민;
N-((3-아이소부틸아이속사졸-5-일)메틸)-N-메틸-2-(4-(3-(트리플루오로메틸)페닐)피페라진-1-일)에탄아민;
N-(2-(4-(4-클로로페닐)피페라진-1-일)에틸)-N-((3-아이소프로필아이속사졸-5-일)메틸)프로판-2-아민;
N-(2-(4-(2,4-디메틸페닐)피페라진-1-일)에틸)-N-((3-아이소프로필아이속사졸-5-일)메틸)프로판-2-아민;
2-(4-(3,4-디메틸페닐)피페라진-1-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)에탄아민;
2-(4-(3,4-디메틸페닐)피페라진-1-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)-N-메틸에탄아민;
N-(2-(4-(3,4-디메틸페닐)피페라진-1-일)에틸)-N-((3-아이소프로필아이속사졸-5-일)메틸)프로판-2-아민;
N-((3-아이소프로필아이속사졸-5-일)메틸)-N-(2-(4-(3-(트리플루오로메틸)페닐)피페라진-1-일)에틸)프로판-2-아민;
N-((3-tert-부틸아이속사졸-5-일)메틸)-2-(4-(3,4-디메틸페닐)피페라진-1-일)에탄아민;
N-((3-tert-부틸아이속사졸-5-일)메틸)-2-(4-(3,4-디메틸페닐)피페라진-1-일)-N-메틸에탄아민;
N-((3-tert-부틸아이속사졸-5-일)메틸)-2-(4-(2,4-디메틸페닐)피페라진-1-일)-N-메틸에탄아민;
N-((3-tert-부틸아이속사졸-5-일)메틸)-N-(2-(4-(3-(트리플루오로메틸)페닐)피페라진-1-일)에틸)프로판-2-아민;
2-(4-(2,4-디메틸페닐)피페라진-1-일)-N-((3-아이소부틸아이속사졸-5-일)메틸)에탄아민;
2-(4-(3,4-디메틸페닐)피페라진-1-일)-N-((3-아이소부틸아이속사졸-5-일)메틸)에탄아민;
N-((3-아이소프로필아이속사졸-5-일)메틸)-2-(4-(3-트리플루오로메틸페닐)피페라진-1-일)에탄아민;
N-((3-아이소프로필아이속사졸-5-일)메틸)-2-(4-(4-메톡시페닐)피페라진-1-일)에탄아민;
N-((3-아이소프로필아이속사졸-5-일)메틸)-2-(4-(4-메톡시페닐)피페라진-1-일)-N-메틸에탄아민;
N-((3-아이소프로필아이속사졸-5-일)메틸)-2-(4-p-톨릴피페라진-1-일)에탄아민;
2-(4-(2,4-디메틸페닐)피페라진-1-일)-N-((3-아이소부틸아이속사졸-5-일)메틸)-N-메틸에탄아민;
2-(4-(3,4-디메틸페닐)피페라진-1-일)-N-((3-아이소부틸아이속사졸-5-일)메틸)-N-메틸에탄아민;
2-(4-(3-클로로페닐)피페라진-1-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)-N-메틸에탄아민;
N-((3-아이소프로필아이속사졸-5-일)메틸)-2-(4-(4-(트리플루오로메틸)페닐)피페라진-1-일)에탄아민;
N-((3-아이소프로필아이속사졸-5-일)메틸)-N-메틸-2-(4-(4-(트리플루오로메틸)페닐)피페라진-1-일)에탄아민;
N-((3-아이소프로필아이속사졸-5-일)메틸)-2-(4-(3-메톡시페닐)피페라진-1-일)에탄아민;
N-((3-아이소프로필아이속사졸-5-일)메틸)-2-(4-m-톨릴피페라진-1-일)에탄아민;
N-((3-아이소프로필아이속사졸-5-일)메틸)-N-메틸-2-(4-p-톨릴피페라진-1-일)에탄아민;
2-(4-(4-플루오로페닐)피페라진-1-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)에탄아민;
2-(4-(4-플루오로페닐)피페라진-1-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)-N-메틸에탄아민;
2-(4-(3,4-디클로로페닐)피페라진-1-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)에탄아민;
2-(4-(3,4-디클로로페닐)피페라진-1-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)-N-메틸에탄아민;
N-((3-아이소프로필아이속사졸-5-일)메틸)-2-(4-(3-메톡시페닐)피페라진-1-일)-N-메틸에탄아민;
N-((3-아이소프로필아이속사졸-5-일)메틸)-N-메틸-2-(4-m-톨릴피페라진-1-일)에탄아민;
3-(4-(3-클로로페닐)피페라진-1-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)프로판-1-아민;
3-(4-(3-클로로페닐)피페라진-1-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)-N-메틸프로판-1-아민;
3-(4-(3,4-디메틸페닐)피페라진-1-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)프로판-1-아민;
3-(4-(3,4-디메틸페닐)피페라진-1-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)-N-메틸프로판-1-아민;
N-((3-아이소프로필아이속사졸-5-일)메틸)-3-(4-p-톨릴피페라진-1-일)프로판-1-아민;
N-((3-아이소프로필아이속사졸-5-일)메틸)-N-메틸-3-(4-p-톨릴피페라진-1-일)프로판-1-아민;
3-(4-(4-플루오로페닐)피페라진-1-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)프로판-1-아민;
3-(4-(4-플루오로페닐)피페라진-1-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)-N-메틸프로판-1-아민;
N-((3-아이소프로필아이속사졸-5-일)메틸)-3-(4-(4-메톡시페닐)피페라진-1-일)프로판-1-아민;
N-((3-아이소프로필아이속사졸-5-일)메틸)-3-(4-(4-메톡시페닐)피페라진-1-일)-N-메틸프로판-1-아민;
2-(4-(3,4-디메톡시페닐)피페라진-1-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)에탄아민;
3-(4-(4-클로로페닐)피페라진-1-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)프로판-1-아민;
3-(4-(4-클로로페닐)피페라진-1-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)-N-메틸프로판-1-아민;
N-((3-아이소프로필아이속사졸-5-일)메틸)-3-(4-(3-메톡시페닐)피페라진-1-일)프로판-1-아민;
N-((3-아이소프로필아이속사졸-5-일)메틸)-3-(4-(3-메톡시페닐)피페라진-1-일)-N-메틸프로판-1-아민;
N-((3-아이소프로필아이속사졸-5-일)메틸)-3-(4-m-톨릴피페라진-1-일)프로판-1-아민;
N-((3-아이소프로필아이속사졸-5-일)메틸)-N-메틸-3-(4-m-톨릴피페라진-1-일)프로판-1-아민;
3-(4-(3,4-디클로로페닐)피페라진-1-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)프로판-1-아민;
3-(4-(3,4-디클로로페닐)피페라진-1-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)-N-메틸프로판-1-아민;
3-(4-(3,4-디메톡시페닐)피페라진-1-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)프로판-1-아민;
2-(4-(4-클로로페닐)-2-메틸피페라진-1-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)에탄아민;
2-(4-(3,4-디클로로페닐)-2-메틸피페라진-1-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)에탄아민;
N-((3-아이소프로필아이속사졸-5-일)메틸)-2-(4-(4-(트리플루오로메톡시)페닐)피페라진-1-일)에탄아민;
2-(4-(3,5-디클로로페닐)피페라진-1-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)에탄아민;
2-(1-(4-플루오로페닐)피페리딘-4-일)-N-((3-이소프로필아이속사졸-5-일)메틸)에탄아민;
2-(1-(4-클로로페닐)피페리딘-4-일)-N-((3-이소프로필아이속사졸-5-일)메틸)에탄아민;
N-((3-tert-부틸아이속사졸-5-일)메틸)-2-(1-(4-클로로페닐)피페리딘-4-일)에탄아민;
N-((3-tert-부틸아이속사졸-5-일)메틸)-2-(1-(4-플루오로페닐)피페리딘-4-일)에탄아민;
N-((3-이소프로필아이속사졸-5-일)메틸)-2-(1-(4-(트리플루오로메틸)페닐)피페리딘-4-일)에탄아민;
N-((3-이소프로필아이속사졸-5-일)메틸)-2-(1-p-톨릴피페리딘-4-일)에탄아민;
2-(1-(3,4-디클로로페닐)피페리딘-4-일)-N-((3-이소프로필아이속사졸-5-일)메틸)에탄아민;
N-((3-이소프로필아이속사졸-5-일)메틸)-2-(1-(4-메톡시페닐)피페리딘-4-일)에탄아민;
2-(1-(3-클로로페닐)피페리딘-4-일)-N-((3-이소프로필아이속사졸-5-일)메틸)에탄아민;
2-(1-(3-플루오로페닐)피페리딘-4-일)-N-((3-이소프로필아이속사졸-5-일)메틸)에탄아민;
N-((3-이소프로필아이속사졸-5-일)메틸)-2-(1-m-톨릴피페리딘-4-일)에탄아민;
N-((3-이소프로필아이속사졸-5-일)메틸)-2-(1-(3-(트리플루오로메틸)페닐)피페리딘-4-일)에탄아민;
2-(1-(2-((3-아이소프로필아이속사졸-5-일)메틸아미노)에틸)-1,2,3,6-테트라하이드로피리딘-4-일)벤조나이트릴;
N-((3-아이소프로필아이속사졸-5-일)메틸)-2-(4-페닐-1,2,3,6-테트라하이드로피리딘-4-일)에탄아민;
2-(4-(4-클로로페닐)-1,2,3,6-테트라하이드로피리딘-4-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)에탄아민;
3-(1-(2-((3-아이소프로필아이속사졸-5-일)메틸아미노)에틸)-1,2,3,6-테트라하이드로피리딘-4-일)벤조나이트릴;
N-((3-아이소프로필아이속사졸-5-일)메틸)-2-(4-(4-메톡시페닐)-1,2,3,6-테트라하이드로피리딘-4-일)에탄아민;
N,N-비스((3-아이소프로필아이속사졸-5-일)메틸)-2-(4-o-톨릴-1,2,3,6-테트라하이드로피리딘-4-일)에탄아민;
2-(4-(3,4-다이클로로페닐)-1,2,3,6-테트라하이드로피리딘-4-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)에탄아민;
2-(4-(3,4-다이클로로페닐)-1,2,3,6-테트라하이드로피리딘-4-일)-N,N-비스((3-아이소프로필아이속사졸-5-일)메틸)에탄아민;
2-(4-(3,4-다이클로로페닐)피페리딘-1-일)-N-((3-아이소프로필아이속사졸-5-일)메틸)에탄아민;
N-((3-아이소프로필아이속사졸-5-일)메틸)-2-(4-페닐피페리딘-1-일)에탄아민;
메틸 5-((2-(4-페닐피페라진-1-일)에틸아미노)메틸)아이속사졸-3-카복실레이트;
에틸 5-((2-(4-페닐피페라진-1-일)에틸아미노)메틸)아이속사졸-3-카복실레이트;
에틸 5-((2-(4-페닐피페라진-1-일)에틸아미노)메틸)아이속사졸-3-카복실레이트 염산염;
소듐 5-((2-(4-페닐피페라진-1-일)에틸아미노)메틸)아이속사졸-3-카복실레이트;
에틸 5-((2-(4-(비스(4-플루오로페닐)메틸)피페라진-1-일)에틸아미노)메틸)아이속사졸-3-카복실레이트;
소듐 5-((2-(4-(비스(4-플루오로페닐)메틸)피페라진-1-일)에틸아미노)메틸)아이속사졸-3-카복실레이트;
에틸 5-((2-(4-벤즈하이드릴피페라진-1-일)에틸아미노)메틸)아이속사졸-3-카복실레이트;
소듐 5-((2-(4-벤즈하이드릴피페라진-1-일)에틸아미노)메틸)아이속사졸-3-카복실레이트;
2-(4-벤즈하이드릴피페라진-1-일)-N-((3-메틸아이속사졸-5-일)메틸)에탄아민;
2-(4-(비스(4-플루오로페닐)메틸)피페라진-1-일)-N-((3-메틸아이속사졸-5-일)메틸)에탄아민;
2-(4-(비스(4-클로로페닐)메틸)피페라진-1-일)-N-((3-메틸아이속사졸-5-일)메틸)에탄아민;
에틸 5-((2-(4-(비스(4-클로로페닐)메틸)피페라진-1-일)에틸아미노)메틸)아이속사졸-3-카복실레이트;
5-((2-(4-(비스(4-플루오로페닐)메틸)피페라진-1-일)에틸아미노)메틸)아이속사졸-3-카복사마이드;
5-((2-(4-(비스(4-플루오로페닐)메틸)피페라진-1-일)에틸아미노)메틸)-N-메틸아이속사졸-3-카복사마이드;
5-((2-(4-(비스(4-플루오로페닐)메틸)피페라진-1-일)에틸아미노)메틸)-N,N-디메틸아이속사졸-3-카복사마이드; 및
이들의 약제학적으로 허용 가능한 염으로부터 선택된 것임을 특징으로 하는 화합물.
The method according to claim 1,
[2- [4- (3-chlorophenyl) -piperazin-1-yl] -ethyl]-(3-methylisoxazol-5-ylmethyl) amine;
[2- [4- (3-chlorophenyl) -piperazin-1-yl] -ethyl]-(3-ethylisoxazol-5-ylmethyl) amine;
[2- [4- (3-chlorophenyl) -piperazin-1-yl] -ethyl]-(3-isopropylisoxazol-5-ylmethyl) amine;
[2- [4- (4-chlorophenyl) -piperazin-1-yl] -ethyl]-(3-methylisoxazol-5-ylmethyl) amine;
[2- [4- (4-chlorophenyl) -piperazin-1-yl] -ethyl]-(3-ethylisoxazol-5-ylmethyl) amine;
[2- [4- (4-chlorophenyl) -piperazin-1-yl] -ethyl]-(3-isopropylisoxazol-5-ylmethyl) amine;
[2- (4-benzhydryl-piperazin-1-yl) ethyl]-(3-methylisoxazol-5-ylmethyl) amine;
[2- (4-benzhydryl-piperazin-1-yl) ethyl]-(3-ethylisoxazol-5-ylmethyl) amine;
[2- (4-benzhydryl-piperazin-1-yl) ethyl]-(3-isopropylisoxazol-5-ylmethyl) amine;
(3-methylisoxazol-5-ylmethyl)-[2- (4-phenylpiperazin-1-yl) ethyl] amine;
(3-ethylisoxazol-5-ylmethyl)-[2- (4-phenylpiperazin-1-yl) ethyl] amine;
(3-isopropylisoxazol-5-ylmethyl)-[2- (4-phenylpiperazin-1-yl) ethyl] amine;
N -((3-isopropylisoxazol-5-yl) methyl) -N -methyl-2- (4- (3- (trifluoromethyl) phenyl) piperazin-1-yl) ethanamine;
2- (4- (2,4-dimethylphenyl) piperazin-1-yl) -N -((3-isopropylisoxazol-5-yl) methyl) ethanamine;
2- (4- (2,4-dimethylphenyl) piperazin-1-yl) -N -((3-isopropylisoxazol-5-yl) methyl) -N -methylethanamine;
2- (4- (4-chlorophenyl) piperazin-1-yl) -N -((3-isopropylisoxazol-5-yl) methyl) -N -methylethanamine;
N -((3- tert - butylisoxazol -5-yl) methyl) -2- (4- (4-chlorophenyl) piperazin-1-yl) ethanamine;
N -((3- tert - butylisoxazol -5-yl) methyl) -2- (4- (4-chlorophenyl) piperazin-1-yl) -N -methylethanamine;
N -((3- tert - butylisoxazol -5-yl) methyl) -2- (4- (3- (trifluoromethyl) phenyl) piperazin-1-yl) ethanamine;
N -((3- tert - butylisoxazol -5-yl) methyl) -N -methyl-2- (4- (3- (trifluoromethyl) phenyl) piperazin-1-yl) ethanamine;
N -((3- tert - butylisoxazol -5-yl) methyl) -2- (4- (2,4-dimethylphenyl) piperazin-1-yl) ethanamine;
2- (4- (4-chlorophenyl) piperazin-1-yl) -N -((3-isobutylisoxazol-5-yl) methyl) ethanamine;
2- (4- (4-chlorophenyl) piperazin-1-yl) -N -((3-isobutylisoxazol-5-yl) methyl) -N -methylethanamine;
N -((3-isobutylisoxazol-5-yl) methyl) -2- (4- (3- (trifluoromethyl) phenyl) piperazin-1-yl) ethanamine;
N -((3-isobutylisoxazol-5-yl) methyl) -N -methyl-2- (4- (3- (trifluoromethyl) phenyl) piperazin-1-yl) ethanamine;
N- (2- (4- (4-chlorophenyl) piperazin-1-yl) ethyl) -N -((3-isopropylisoxazol-5-yl) methyl) propan-2-amine;
N - (2- (4- (2,4- dimethylphenyl) piperazin-1-yl) ethyl) - N - ((3- isopropyl-isoxazol-5-yl) methyl) propan-2-amine;
2- (4- (3,4-dimethylphenyl) piperazin-1-yl) -N -((3-isopropylisoxazol-5-yl) methyl) ethanamine;
2- (4- (3,4-dimethylphenyl) piperazin-1-yl) -N -((3-isopropylisoxazol-5-yl) methyl) -N -methylethanamine;
N- (2- (4- (3,4-dimethylphenyl) piperazin-1-yl) ethyl) -N -((3-isopropylisoxazol-5-yl) methyl) propan-2-amine;
N - ((3- isopropyl-isoxazol-5-yl) methyl) - N - (2- (4- (3- ( trifluoromethyl) phenyl) piperazin-1-yl) ethyl) propane -2 Amines;
N -((3- tert - butylisoxazol -5-yl) methyl) -2- (4- (3,4-dimethylphenyl) piperazin-1-yl) ethanamine;
N -((3- tert - butylisoxazol -5-yl) methyl) -2- (4- (3,4-dimethylphenyl) piperazin-1-yl) -N -methylethanamine;
N -((3- tert - butylisoxazol -5-yl) methyl) -2- (4- (2,4-dimethylphenyl) piperazin-1-yl) -N -methylethanamine;
N - ((3-tert-butyl-isoxazol-5-yl) methyl) - N - (ethyl-2- (4- (3- (trifluoromethyl) phenyl) piperazin-1-yl)) propane- 2-amine;
2- (4- (2,4-dimethylphenyl) piperazin-1-yl) -N -((3-isobutylisoxazol-5-yl) methyl) ethanamine;
2- (4- (3,4-dimethylphenyl) piperazin-1-yl) -N -((3-isobutylisoxazol-5-yl) methyl) ethanamine;
N -((3-isopropylisoxazol-5-yl) methyl) -2- (4- (3-trifluoromethylphenyl) piperazin-1-yl) ethanamine;
N -((3-isopropylisoxazol-5-yl) methyl) -2- (4- (4-methoxyphenyl) piperazin-1-yl) ethanamine;
N -((3-isopropylisoxazol-5-yl) methyl) -2- (4- (4-methoxyphenyl) piperazin-1-yl) -N -methylethanamine;
N -((3-isopropylisoxazol-5-yl) methyl) -2- (4- p -tolylpiperazin-1-yl) ethanamine;
2- (4- (2,4-dimethylphenyl) piperazin-1-yl) -N -((3-isobutylisoxazol-5-yl) methyl) -N -methylethanamine;
2- (4- (3,4-dimethylphenyl) piperazin-1-yl) -N -((3-isobutylisoxazol-5-yl) methyl) -N -methylethanamine;
2- (4- (3-chlorophenyl) piperazin-1-yl) -N -((3-isopropylisoxazol-5-yl) methyl) -N -methylethanamine;
N -((3-isopropylisoxazol-5-yl) methyl) -2- (4- (4- (trifluoromethyl) phenyl) piperazin-1-yl) ethanamine;
N -((3-isopropylisoxazol-5-yl) methyl) -N -methyl-2- (4- (4- (trifluoromethyl) phenyl) piperazin-1-yl) ethanamine;
N -((3-isopropylisoxazol-5-yl) methyl) -2- (4- (3-methoxyphenyl) piperazin-1-yl) ethanamine;
N -((3-isopropylisoxazol-5-yl) methyl) -2- (4- m -tolylpiperazin-1-yl) ethanamine;
N -((3-isopropylisoxazol-5-yl) methyl) -N -methyl-2- (4- p -tolylpiperazin-1-yl) ethanamine;
2- (4- (4-fluorophenyl) piperazin-1-yl) -N -((3-isopropylisoxazol-5-yl) methyl) ethanamine;
2- (4- (4-fluorophenyl) piperazin-1-yl) -N -((3-isopropylisoxazol-5-yl) methyl) -N -methylethanamine;
2- (4- (3,4-dichlorophenyl) piperazin-1-yl) -N -((3-isopropylisoxazol-5-yl) methyl) ethanamine;
2- (4- (3,4-dichlorophenyl) piperazin-1-yl) -N -((3-isopropylisoxazol-5-yl) methyl) -N -methylethanamine;
N -((3-isopropylisoxazol-5-yl) methyl) -2- (4- (3-methoxyphenyl) piperazin-1-yl) -N -methylethanamine;
N -((3-isopropylisoxazol-5-yl) methyl) -N -methyl-2- (4- m -tolylpiperazin-1-yl) ethanamine;
3- (4- (3-chlorophenyl) piperazin-1-yl) -N -((3-isopropylisoxazol-5-yl) methyl) propan-1-amine;
3- (4- (3-chlorophenyl) piperazin-1-yl) -N -((3-isopropylisoxazol-5-yl) methyl) -N -methylpropan-1-amine;
3- (4- (3,4-dimethylphenyl) piperazin-1-yl) -N -((3-isopropylisoxazol-5-yl) methyl) propan-1-amine;
3- (4- (3,4-dimethylphenyl) piperazin-1-yl) -N -((3-isopropylisoxazol-5-yl) methyl) -N -methylpropan-1-amine;
N -((3-isopropylisoxazol-5-yl) methyl) -3- (4- p -tolylpiperazin-1-yl) propan-1-amine;
N -((3-isopropylisoxazol-5-yl) methyl) -N -methyl-3- (4- p -tolylpiperazin-1-yl) propan-1-amine;
3- (4- (4-fluorophenyl) piperazin-1-yl) -N -((3-isopropylisoxazol-5-yl) methyl) propan-1-amine;
3- (4- (4-fluorophenyl) piperazin-1-yl) -N -((3-isopropylisoxazol-5-yl) methyl) -N -methylpropan-1-amine;
N -((3-isopropylisoxazol-5-yl) methyl) -3- (4- (4-methoxyphenyl) piperazin-1-yl) propan-1-amine;
N -((3-isopropylisoxazol-5-yl) methyl) -3- (4- (4-methoxyphenyl) piperazin-1-yl) -N -methylpropan-1-amine;
2- (4- (3,4-dimethoxyphenyl) piperazin-1-yl) -N -((3-isopropylisoxazol-5-yl) methyl) ethanamine;
3- (4- (4-chlorophenyl) piperazin-1-yl) -N -((3-isopropylisoxazol-5-yl) methyl) propan-1-amine;
3- (4- (4-chlorophenyl) piperazin-1-yl) -N -((3-isopropylisoxazol-5-yl) methyl) -N -methylpropan-1-amine;
N -((3-isopropylisoxazol-5-yl) methyl) -3- (4- (3-methoxyphenyl) piperazin-1-yl) propan-1-amine;
N -((3-isopropylisoxazol-5-yl) methyl) -3- (4- (3-methoxyphenyl) piperazin-1-yl) -N -methylpropan-1-amine;
N -((3-isopropylisoxazol-5-yl) methyl) -3- (4- m -tolylpiperazin-1-yl) propan-1-amine;
N -((3-isopropylisoxazol-5-yl) methyl) -N -methyl-3- (4- m -tolylpiperazin-1-yl) propan-1-amine;
3- (4- (3,4-dichlorophenyl) piperazin-1-yl) -N -((3-isopropylisoxazol-5-yl) methyl) propan-1-amine;
3- (4- (3,4-dichlorophenyl) piperazin-1-yl) -N -((3-isopropylisoxazol-5-yl) methyl) -N -methylpropan-1-amine;
3- (4- (3,4-dimethoxyphenyl) piperazin-1-yl) -N -((3-isopropylisoxazol-5-yl) methyl) propan-1-amine;
2- (4- (4-chlorophenyl) -2-methylpiperazin-1-yl) -N -((3-isopropylisoxazol-5-yl) methyl) ethanamine;
2- (4- (3,4-dichlorophenyl) -2-methylpiperazin-1-yl) -N -((3-isopropylisoxazol-5-yl) methyl) ethanamine;
N -((3-isopropylisoxazol-5-yl) methyl) -2- (4- (4- (trifluoromethoxy) phenyl) piperazin-1-yl) ethanamine;
2- (4- (3,5-dichlorophenyl) piperazin-1-yl) -N -((3-isopropylisoxazol-5-yl) methyl) ethanamine;
2- (1- (4-fluorophenyl) piperidin-4-yl) -N -((3-isopropylisoxazol-5-yl) methyl) ethanamine;
2- (1- (4-chlorophenyl) piperidin-4-yl) -N -((3-isopropylisoxazol-5-yl) methyl) ethanamine;
N -((3- tert - butylisoxazol -5-yl) methyl) -2- (1- (4-chlorophenyl) piperidin-4-yl) ethanamine;
N -((3- tert - butylisoxazol -5-yl) methyl) -2- (1- (4-fluorophenyl) piperidin-4-yl) ethanamine;
N -((3-isopropylisoxazol-5-yl) methyl) -2- (1- (4- (trifluoromethyl) phenyl) piperidin-4-yl) ethanamine;
N -((3-isopropylisoxazol-5-yl) methyl) -2- (1- p -tolylpiperidin-4-yl) ethanamine;
2- (1- (3,4-dichlorophenyl) piperidin-4-yl) -N -((3-isopropylisoxazol-5-yl) methyl) ethanamine;
N -((3-isopropylisoxazol-5-yl) methyl) -2- (1- (4-methoxyphenyl) piperidin-4-yl) ethanamine;
2- (1- (3-chlorophenyl) piperidin-4-yl) -N -((3-isopropylisoxazol-5-yl) methyl) ethanamine;
2- (1- (3-fluorophenyl) piperidin-4-yl) -N -((3-isopropylisoxazol-5-yl) methyl) ethanamine;
N -((3-isopropylisoxazol-5-yl) methyl) -2- (1- m -tolylpiperidin-4-yl) ethanamine;
N -((3-isopropylisoxazol-5-yl) methyl) -2- (1- (3- (trifluoromethyl) phenyl) piperidin-4-yl) ethanamine;
2- (1- (2-((3-isopropylisoxazol-5-yl) methylamino) ethyl) -1,2,3,6-tetrahydropyridin-4-yl) benzonitrile;
N -((3-isopropylisoxazol-5-yl) methyl) -2- (4-phenyl-1,2,3,6-tetrahydropyridin-4-yl) ethanamine;
2- (4- (4-chlorophenyl) -1,2,3,6-tetrahydropyridin-4-yl) -N -((3-isopropylisoxazol-5-yl) methyl) ethanamine;
3- (1- (2-((3-isopropylisoxazol-5-yl) methylamino) ethyl) -1,2,3,6-tetrahydropyridin-4-yl) benzonitrile;
N -((3-isopropylisoxazol-5-yl) methyl) -2- (4- (4-methoxyphenyl) -1,2,3,6-tetrahydropyridin-4-yl) ethanamine ;
N, N -bis ((3-isopropylisoxazol-5-yl) methyl) -2- (4- o -tolyl-1,2,3,6-tetrahydropyridin-4-yl) ethanamine;
2- (4- (3,4-Dichlorophenyl) -1,2,3,6-tetrahydropyridin-4-yl) -N -((3-isopropylisoxazol-5-yl) methyl) Ethanamine;
2- (4- (3,4-Dichlorophenyl) -1,2,3,6-tetrahydropyridin-4-yl) -N, N -bis ((3-isopropylisoxazol-5-yl ) Methyl) ethanamine;
2- (4- (3,4-dichlorophenyl) piperidin-1-yl) -N -((3-isopropylisoxazol-5-yl) methyl) ethanamine;
N -((3-isopropylisoxazol-5-yl) methyl) -2- (4-phenylpiperidin-1-yl) ethanamine;
Methyl 5-((2- (4-phenylpiperazin-1-yl) ethylamino) methyl) isoxazole-3-carboxylate;
Ethyl 5 - ((2- (4-phenylpiperazin-1-yl) ethylamino) methyl) isoxazole-3-carboxylate;
Ethyl 5-((2- (4-phenylpiperazin-1-yl) ethylamino) methyl) isoxazole-3-carboxylate hydrochloride;
Sodium 5-((2- (4-phenylpiperazin-1-yl) ethylamino) methyl) isoxazole-3-carboxylate;
Ethyl 5-((2- (4- (bis (4-fluorophenyl) methyl) piperazin-1-yl) ethylamino) methyl) isoxazole-3-carboxylate;
Sodium 5-((2- (4- (bis (4-fluorophenyl) methyl) piperazin-1-yl) ethylamino) methyl) isoxazole-3-carboxylate;
Ethyl 5-((2- (4-benzhydrylpiperazin-1-yl) ethylamino) methyl) isoxazole-3-carboxylate;
Sodium 5-((2- (4-benzhydrylpiperazin-1-yl) ethylamino) methyl) isoxazole-3-carboxylate;
2- (4-benzhydrylpiperazin-1-yl) -N -((3-methylisoxazol-5-yl) methyl) ethanamine;
2- (4- (bis (4-fluorophenyl) methyl) piperazin-1-yl) -N -((3-methylisoxazol-5-yl) methyl) ethanamine;
2- (4- (bis (4-chlorophenyl) methyl) piperazin-1-yl) -N -((3-methylisoxazol-5-yl) methyl) ethanamine;
Ethyl 5-((2- (4- (bis (4-chlorophenyl) methyl) piperazin-1-yl) ethylamino) methyl) isoxazole-3-carboxylate;
5-((2- (4- (bis (4-fluorophenyl) methyl) piperazin-1-yl) ethylamino) methyl) isoxazole-3-carboxamide;
5-((2- (4- (bis (4-fluorophenyl) methyl) piperazin-1-yl) ethylamino) methyl) -N -methylisoxazole-3-carboxamide;
5-((2- (4- (bis (4-fluorophenyl) methyl) piperazin-1-yl) ethylamino) methyl) -N, N -dimethylisoxazole-3-carboxamide; And
And a pharmaceutically acceptable salt thereof.

상기 청구항 1 내지 3 항 중에서 선택된 어느 한 항의 화합물을 유효성분으로 하는 것을 특징으로 하는 간질 (epilepsy), 우울증, 파킨스씨병 (Parkinson's disease), 치매 (dementia), 수면장애 (sleep disorder)로부터 선택된 뇌질환 치료 및 예방제용; 암 치료 및 예방제용; 고혈압 (hypertensive), 심부정맥, 협심증, 심근 경색증, 울혈성 심부전증으로부터 선택된 심장질환 치료 및 예방제용; 또는 신경성 통증 (neuropathic pain), 만성 및 급성 통증 (chronic and acute pain)으로부터 선택된 통증 완화제용; 으로 유용한 약학적 조성물.
Brain selected from epilepsy, depression, Parkinson's disease, dementia, sleep disorder, characterized in that the compound of any one of the claims 1 to 3 as an active ingredient For treating and preventing diseases; For treating and preventing cancer; For the treatment and prevention of heart diseases selected from hypertensive, heart arrhythmia, angina pectoris, myocardial infarction, congestive heart failure; Or for pain relievers selected from neuropathic pain, chronic and acute pain; Useful pharmaceutical compositions.

하기 화학식 2로 표시되는 아민 화합물과 하기 화학식 3으로 표시되는 알데하이드 화합물을 환원성 아민화 반응시켜, R⁵=수소인 하기 화학식 1a로 표시되는 화합물을 제조하는 과정; 및

(상기에서, R¹,R², R³, R⁵, n, X, 및 Y은 각각 상기 청구항 1에서 정의한 바와 같다)
R⁵=수소인 하기 화학식 1a로 표시되는 화합물을 알킬화 반응시켜, 하기 화학식 1c로 표시되는 화합물을 제조하는 과정;

(상기에서, R¹,R², R³, R⁴, R⁵, n, X, 및 Y는 각각 상기 청구항 1에서 정의한 바와 같다)
을 포함하는 5-(치환된알킬아미노메틸)아이속사졸계 화합물의 제조방법.
Reducing amination reaction of the amine compound represented by the formula (2) and the aldehyde compound represented by the formula (3) to produce a compound represented by the formula (1a) wherein R ⁵ = hydrogen; And

(In the above, R ¹ , R ² , R ³ , R ⁵ , n, X, and Y are each as defined in claim 1 above)
Preparing a compound represented by the following Chemical Formula 1c by alkylating the compound represented by the following Chemical Formula 1a, wherein R ⁵ = hydrogen;

(In the above, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , n, X, and Y are each as defined in claim 1 above)
Method for preparing 5- (substituted alkylaminomethyl) isoxazole compound comprising a.

하기 화학식 4로 표시되는 알데하이드 화합물과 하기 화학식 5로 표시되는 아민 화합물을 환원성 아민화 반응시켜, R⁵=수소인 하기 화학식 1a로 표시되는 화합물을 제조하는 과정; 및

(상기에서, R¹,R², R³, R⁵, n, X, 및 Y는 각각 상기 청구항 1에서 정의한 바와 같다)
R⁵=수소인 하기 화학식 1a로 표시되는 화합물을 알킬화 반응시켜, R⁵=알킬인 하기 화학식 1c로 표시되는 화합물을 제조하는 과정;

(상기에서, R¹,R², R³, R⁴, R⁵, n, X, 및 Y는 각각 상기 청구항 1에서 정의한 바와 같다)
을 포함하는 5-(치환된알킬아미노메틸)아이속사졸계 화합물의 제조방법.
Preparing a compound represented by the following Formula 1a wherein R ⁵ = hydrogen by reacting a aldehyde compound represented by the following Formula 4 with an amine compound represented by the following Formula 5; And

(In the above, R ¹ , R ² , R ³ , R ⁵ , n, X, and Y are each as defined in claim 1 above)
Preparing a compound represented by the following Chemical Formula 1c wherein R ⁵ = hydrogen is alkylated to produce a compound represented by the following Chemical Formula 1c wherein R ⁵ = alkyl;

제 5 항 또는 제 6 항에 있어서,
상기 환원성 아민화 반응은 NaBH(OAc)₃, NaBH₃CN, 및 NaBH₄중에서 선택된 환원제의 존재하에서 수행하는 것을 특징으로 하는 제조방법.The method according to claim 5 or 6,
The reductive amination reaction is carried out in the presence of a reducing agent selected from NaBH (OAc) ₃ , NaBH ₃ CN, and NaBH ₄ .