KR101152657B1

KR101152657B1 - New diphenylpropanoyl compounds having activity for T-type calcium channel

Info

Publication number: KR101152657B1
Application number: KR1020100038514A
Authority: KR
Inventors: 조용서; 민선준; 이재균; 최연희; 배애님; 추현아; 임혜원; 최기현; 서선희; 송치만
Original assignee: 한국과학기술연구원
Priority date: 2010-04-26
Filing date: 2010-04-26
Publication date: 2012-06-05
Also published as: KR20110119045A

Abstract

본 발명은 T-형 칼슘 채널에 대한 활성을 갖는 다이페닐프로판노일 화합물, 상기 화합물의 제조방법, 그리고 상기 화합물을 유효성분으로 포함하는 약학조성물에 관한 것이다. 본 발명의 다이페닐프로판노일 화합물 또는 약학적으로 허용 가능한 이의 염은 T-형 칼슘 채널에 대한 길항작용을 가지므로 간질, 고혈압 등의 뇌질환 치료제, 협심증 등의 심장질환 치료제, 만성 통증, 신경성 통증 등의 통증질환 치료제, 또는 항암제로 유용하다.The present invention relates to a diphenylpropanenoyl compound having activity against a T-type calcium channel, a method for preparing the compound, and a pharmaceutical composition comprising the compound as an active ingredient. Since the diphenylpropanenoyl compound or pharmaceutically acceptable salt thereof of the present invention has an antagonistic action against T-type calcium channel, the agent for treating brain diseases such as epilepsy and hypertension, the treatment of heart diseases such as angina pectoris, chronic pain and neurological pain It is useful as a therapeutic agent for pain diseases such as or an anticancer agent.

Description

New diphenylpropanoyl compounds having activity for T-type calcium channel

본 발명은 T-형 칼슘 채널에 대한 활성을 갖는 다이페닐프로판노일 화합물, 상기 화합물의 제조방법, 그리고 상기 화합물을 유효성분으로 포함하는 약학조성물에 관한 것이다. 본 발명의 다이페닐프로판노일 화합물 또는 약학적으로 허용 가능한 이의 염은 T-형 칼슘 채널에 대한 길항작용을 가지므로 간질, 고혈압 등의 뇌질환 치료제, 협심증 등의 심장질환 치료제, 만성 통증, 신경성 통증 등의 통증질환 치료제, 또는 항암제로 유용하다.
The present invention relates to a diphenylpropanenoyl compound having activity against a T-type calcium channel, a method for preparing the compound, and a pharmaceutical composition comprising the compound as an active ingredient. Since the diphenylpropanenoyl compound or pharmaceutically acceptable salt thereof of the present invention has an antagonistic action against T-type calcium channel, the agent for treating brain diseases such as epilepsy and hypertension, the treatment of heart diseases such as angina pectoris, chronic pain and neurological pain It is useful as a therapeutic agent for pain diseases such as or an anticancer agent.

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 나뉜다. 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 representative 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 등의 뇌질환과 협심증 등의 심장질환 치료에 효과가 있다고 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, pp.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 antagonists of T-type calcium channels are known to be effective in treating brain diseases such as epilepsy and hypertension and heart diseases such as 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 , pp. 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 발표 [Drugs of the Future (2005), 40, 573-580] 되었고, a1G 넉아웃(knock-out) 마우스에 척수신경결찰 (spinal nerve ligation)을 일으켜 신경성 통증을 유발한 결과, 신경성 통증이 경감된다고 발표되었다. [Molecules & Cells, 2008, 25 , 242-246] 또한 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. [Pain, 2003, 105 , 159-168] Recently, antagonists of T-type calcium channels have been shown to be effective in treating chronic pain [ Drugs of the Future (2005), 40 , 573-580], and spinal nerve ligation in a1G knock-out mice. It has been reported that nerve pain can be relieved as a result of causing spinal nerve ligation. [ Molecules & Cells , 2008, 25 , 242-246] In addition, mibefradil and ethosuximide as antagonists of T-type calcium channels induce mechanical and thermal in animal models of spinal nerve ligation. The degree of inhibition was reported to be dependent on the drug dose, indicating that antagonists of T-type calcium channels are effective in treating neurological pain. [ Pain , 2003, 105 , 159-168]

다른 보고에 의하면, 칼슘이 세포성장에 관여하는 것으로 알려져 있어 T-형 칼슘채널의 길항제가 항암 효과를 낼 것이라는 예측이 가능하다. [Nat. Rev. Mol. Cell Biol. 2003, 4, 517-529]Other reports suggest that calcium is known to be involved in cell growth, suggesting that antagonists of T-type calcium channels may have anticancer effects. Nat. Rev. Mol. Cell Biol. 2003 , 4 , 517-529]

T-형 칼슘채널의 길항제로서 대표적으로 시판되었던 미베프라딜 (Mibefradil)이 고혈압과 협심증 치료제로 사용되었으나, 미베프라딜은 다양한 다른 약과 상호작용으로 판매가 금지되었다. 이로써 T-형 칼슘채널의 길항제의 시급한 개발이 요구되어지고 있다. 현재까지도 T-형 칼슘채널의 길항제를 개발하려는 노력은 많이 있었으나, 선택적인 T-형 칼슘채널의 길항제는 많이 알려져 있지 않고 있다.Mibefradil, a commercially available antagonist of T-type calcium channels, was used to treat hypertension and angina, but mibepradil was banned due to its interaction with various other drugs. There is an urgent need for the development of antagonists of T-type calcium channels. To date, there have been many efforts to develop antagonists of T-type calcium channels, but the antagonists of selective T-type calcium channels are not well known.

이상에서 살펴본 바와 같이, T-형 칼슘채널의 길항제는 여러 약리실험 결과를 통해 간질, 고혈압 등의 뇌질환 치료제, 협심증 등의 심장질환 치료제, 만성 통증, 신경성 통증 등의 통증질환 치료제, 항암제로서 유효함이 이미 여러 논문을 통해 밝혀져 있다. 또한, T-형 칼슘채널에 선택적이고 약물동력학 프로파일이 좋고, ADME (흡수, 분배, 대사, 배출)이 좋으면서 심장질환, 암, 간질, 신경성 통증등과 관련 질병 등에 효과적인 새로운 T-형 칼슘채널의 길항제 개발이 요구된다.
As described above, the antagonist of T-type calcium channel is effective as an anti-cancer agent for treating brain diseases such as epilepsy and hypertension, for treating heart diseases such as angina pectoris, for treating chronic pain, neuropathic pain, etc. Ham has already been revealed in several papers. It is also a new T-type calcium channel that is selective for T-type calcium channels, has a good pharmacokinetic profile, good ADME (absorption, distribution, metabolism, and excretion) and is effective in heart disease, cancer, epilepsy, neurological pain and related diseases. Antagonist development is required.

본 발명은 신규 구조의 다이페닐프로판노일 화합물 제공을 목적으로 한다.An object of the present invention is to provide a diphenylpropanenoyl compound having a novel structure.

본 발명은 신규 다이페닐프로판노일 화합물 또는 약학적으로 허용 가능한 염이 유효성분으로 포함되어 T-형 칼슘채널에 대하여 선택적 길항작용을 갖는 약학 조성물 제공을 다른 목적으로 한다.It is another object of the present invention to provide a pharmaceutical composition having a novel diphenylpropanenoyl compound or a pharmaceutically acceptable salt as an active ingredient and having a selective antagonism with respect to the T-type calcium channel.

본 발명은 신규 다이페닐프로판노일 화합물 또는 약학적으로 허용 가능한 염이 유효성분으로 포함되어 있는 간질, 고혈압 등의 뇌질환 치료제, 협심증 등의 심장질환 치료제, 만성 통증, 신경성 통증 등의 통증질환 치료제, 또는 항암제 제공을 또 다른 목적으로 한다.
The present invention is a novel diphenyl propane noyl compound or a pharmaceutically acceptable salt as an active ingredient, epilepsy, a treatment for brain diseases such as hypertension, cardiac diseases, such as angina pectoris, chronic pain, neurological pain, pain diseases treatment agents, Another object is to provide an anticancer agent.

상기의 목적을 실현하기 위하여, 본 발명은 T-형 칼슘채널에 대한 선택적 길항활성을 나타내는 하기 화학식 1로 표시되는 다이페닐프로판노일 화합물, 이 화합물의 제조방법, 이 화합물을 포함하는 약제조성물을 그 특징으로 한다.In order to achieve the above object, the present invention provides a diphenyl propanenoyl compound represented by the following formula (1) showing a selective antagonistic activity for T-type calcium channel, a method for preparing the compound, a pharmaceutical composition comprising the compound It features.

[화학식 1] [Formula 1]

상기 화학식 1에서,In Chemical Formula 1,

X는 N; 또는 CH를 나타내고,X is N; Or CH,

R¹은 C₁～C₆ 알킬, C₁～C₆ 하이드록시알킬, 하이드록시카보닐, C₁～C₆ 알콕시카보닐, 및 모폴리노카보닐 중에서 선택된 1 내지 3개의 치환기가 치환 또는 비치환된 옥사졸기 또는 벤조옥사졸기; 또는 할로겐원자가 1 내지 3개 치환 또는 비치환된 벤즈아미도기를 나타내고,R ¹ is substituted or unsubstituted with 1 to 3 substituents selected from C ₁ to C ₆ alkyl, C ₁ to C ₆ hydroxyalkyl, hydroxycarbonyl, C ₁ to C ₆ alkoxycarbonyl, and morpholinocarbonyl Substituted oxazole group or benzoxazole group; Or a benzamido group having 1 to 3 substituted or unsubstituted halogen atoms,

R²및 R³은 서로 같거나 다른 것으로서 수소원자, 할로겐원자, C₁～C₆ 알킬기, C₁～C₆ 알콕시기, 또는 C₁～C₆ 할로알킬기를 나타낸다.
R ² and R ³ are the same or different from each other as a hydrogen atom, a halogen atom, C ₁ ~ C ₆ alkyl group, C ₁ ~ C ₆ alkoxy group, or C ₁ ~ C ₆ haloalkyl group.

본 발명의 다이페닐프로판노일 화합물 또는 약학적으로 허용 가능한 이의 염은 T-형 칼슘 채널에 대하여 길항작용을 가지므로 간질, 고혈압 등의 뇌질환 치료제, 협심증 등의 심장질환 치료제, 만성 통증, 신경성 통증 등의 통증질환 치료제, 또는 항암제로 유용하다.
Since the diphenylpropanenoyl compound or a pharmaceutically acceptable salt thereof of the present invention has an antagonistic action against T-type calcium channel, the agent for treating brain diseases such as epilepsy and hypertension, the treatment for heart diseases such as angina pectoris, chronic pain and neurological pain It is useful as a therapeutic agent for pain diseases such as or an anticancer agent.

상기 화학식 1로 표시되는 다이페닐프로판노일 화합물의 약학적으로 허용 가능한 염은, 예를 들어, 금속염, 유기 염기와의 염, 무기산과의 염, 유기산과의 염, 염기성, 또는 산성 아미노산과의 염 등이 포함될 수 있다. 적합한 금속염은, 예를 들어, 나트륨염, 칼륨염 등과 같은 알칼리 금속염; 칼슘염, 마그네슘염, 바륨염 등과 같은 알칼리 토금속염; 알루미늄염 등이 포함될 수 있다. 유기 염기와의 염은, 예를 들어, 트리메틸아민, 트리에틸아민, 피리딘, 피콜린, 2,6-루티딘, 에탄올아민, 다이에탄올아민, 트리에탄올아민, 시클로헥실아민, 다이시클로헥실아민, N,N-다이벤질에틸렌다이아민 등과의 염이 포함될 수 있다. 무기산과의 염은, 예를 들어, 염산, 브롬화수소산, 질산, 황산, 인산 등과의 염이 포함될 수 있다. 유기산과의 염은, 예를 들어, 포름산, 아세트산, 트리플루오로아세트산, 프탈산, 푸마르산, 옥살산, 타르타르산, 말레인산, 시트르산, 숙신산, 메탄술폰산, 벤젠술폰산, p-톨루엔술폰산 등과의 염이 포함될 수 있다. 염기성 아미노산과의 염은, 예를 들어, 알기닌, 라이신, 오르니틴 등과의 염이 포함될 수 있다. 산성 아미노산과의 염은, 예를 들어, 아스파르트산, 글루탐산 등과의 염이 포함될 수 있다.Pharmaceutically acceptable salts of the diphenylpropanenoyl compound represented by Formula 1 include, for example, metal salts, salts with organic bases, salts with inorganic acids, salts with organic acids, basic or acidic amino acids. Etc. may be included. Suitable metal salts include, for example, alkali metal salts such as sodium salts, potassium salts and the like; Alkaline earth metal salts such as calcium salts, magnesium salts, barium salts and the like; Aluminum salts and the like. Salts with organic bases are, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N Salts with , N -dibenzylethylenediamine and the like. Salts with inorganic acids may include, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Salts with organic acids may include, for example, salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p -toluenesulfonic acid, and the like. . Salts with basic amino acids may include, for example, salts with arginine, lysine, ornithine and the like. Salts with acidic amino acids may include, for example, salts with aspartic acid, glutamic acid and the like.

본 발명에 따른 상기 화학식 1로 표시되는 다이페닐프로판노일 화합물의 정의에 사용된 치환기에 대해 좀 더 자세히 설명하면 다음과 같다.Hereinafter, the substituents used in the definition of the diphenylpropanenoyl compound represented by Chemical Formula 1 according to the present invention will be described in more detail.

'할로' 또는 '할로겐'은 서로 교환 가능하게 사용되는 용어로서, 원소인 플루오로, 클로로, 브로모, 아이오도를 의미한다. '알킬기'는 1 내지 6개의 탄소원자를 가진 직쇄상, 분쇄상 및 고리상의 탄소사슬을 모두 포함하며, 선호하는 알킬기는 메틸기, 에틸기, n-프로필기, 아이소프로필기, n-부틸기, 아이소부틸기, tert-부틸기, 네오펜틸기, 시클로펜틸기, 3,3-다이메틸부틸기, 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-다이클로로에틸기, 1,1-다이클로로에틸기, 펜타플루오로에틸기 등이 있다. '알콕시기'는 산소에 연결된 탄소의 알킬기를 의미하는 것으로, 이때 알킬은 상기에서 정의한 바와 같다.'Halo' or 'halogen' is used interchangeably with each other, and means the elements fluoro, chloro, bromo, iodo. 'Alkyl group' includes all linear, pulverized and cyclic carbon chains having 1 to 6 carbon atoms, with preferred alkyl groups being methyl, ethyl, n -propyl, isopropyl, n -butyl and isobutyl Groups , tert -butyl groups, neopentyl groups, cyclopentyl groups, 3,3-dimethylbutyl groups, cyclohexyl groups and the like. 'Haloalkyl group' includes 1 to 13 halogen atoms such as fluoro, chloro, bromo and iodo, and includes all linear, pulverized and cyclic carbon chains having 1 to 6 carbon atoms, and 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 connected to oxygen, wherein alkyl is as defined above.

상기 화학식 1로 표시되는 다이페닐프로판노일 화합물에 있어서, 바람직하기로는 상기 X는 N; 또는 CH를 나타내고, 상기 R¹은 옥사졸-2-일기, 벤조[d]옥사졸-2-일기, 4-(하이드록시카보닐)옥사졸-2-일기, 4-(메톡시카보닐)옥사졸-2-일기, 4-(모폴린-4-카보닐)옥사졸-2-일기, 6-메틸벤조[d]옥사졸-2-일기, 벤즈아미도기, 3,5-다이클로로벤즈아미도기를 나타내고, 상기 R²및 R³은 서로 같거나 다른 것으로서 수소원자, 플루오로, 클로로, 브로모, 메틸기, 메톡시기, 또는 트리플루오로메틸기를 나타내는 화합물이다.In the diphenyl propanenoyl compound represented by Formula 1, preferably X is N; Or CH, wherein R ¹ is an oxazol-2-yl group, a benzo [ d ] oxazol-2-yl group, a 4- (hydroxycarbonyl) oxazol-2-yl group, 4- (methoxycarbonyl) Oxazol-2-yl group, 4- (morpholin-4-carbonyl) oxazol-2-yl group, 6-methylbenzo [ d ] oxazol-2-yl group, benzamido group, 3,5-dichlorobenz Amido groups, wherein R ² and R ³ are the same as or different from each other and represent a hydrogen atom, fluoro, chloro, bromo, methyl group, methoxy group, or trifluoromethyl group.

특히 바람직한 상기 화학식 1로 표시되는 다이페닐프로판노일 화합물을 구체적으로 예시하면 다음과 같다:Particularly preferred examples of the diphenylpropanenoyl compound represented by Formula 1 are as follows:

메틸 2-((4-(3-(4-플루오로페닐)-3-페닐프로판노일)피페라진-1-일)메틸)옥사졸-4-카복실레이트 ;Methyl 2-((4- (3- (4-fluorophenyl) -3-phenylpropanenoyl) piperazin-1-yl) methyl) oxazole-4-carboxylate;

메틸 2-((4-(3-(4-브로모페닐)-3-페닐프로판노일)피페라진-1-일)메틸)옥사졸-4-카복실레이트 ;Methyl 2-((4- (3- (4-bromophenyl) -3-phenylpropanenoyl) piperazin-1-yl) methyl) oxazole-4-carboxylate;

메틸 2-((4-(3-페닐-3-(4-(트리플루오로메틸)페닐)프로판노일)피페라진-1-일)메틸)옥사졸-4-카복실레이트 ;Methyl 2-((4- (3-phenyl-3- (4- (trifluoromethyl) phenyl) propanenoyl) piperazin-1-yl) methyl) oxazole-4-carboxylate;

메틸 2-((4-(3-(4-클로로페닐)-3-페닐프로판노일)피페라진-1-일)메틸)옥사졸-4-카복실레이트 ;Methyl 2-((4- (3- (4-chlorophenyl) -3-phenylpropanenoyl) piperazin-1-yl) methyl) oxazole-4-carboxylate;

메틸 2-((4-(3-(4-메톡시페닐)-3-페닐프로판노일)피페라진-1-일)메틸)옥사졸-4-카복실레이트 ;Methyl 2-((4- (3- (4-methoxyphenyl) -3-phenylpropanenoyl) piperazin-1-yl) methyl) oxazole-4-carboxylate;

메틸 2-((4-(3,3-비스(4-플루오로페닐)프로판노일)피페라진-1-일)메틸)옥사졸-4-카복실레이트 ;Methyl 2-((4- (3,3-bis (4-fluorophenyl) propanenoyl) piperazin-1-yl) methyl) oxazole-4-carboxylate;

메틸 2-((4-(3-(4-브로모페닐)-3-(4-플루오로페닐)프로판노일)피페라진-1-일)메틸)옥사졸-4-카복실레이트 ;Methyl 2-((4- (3- (4-bromophenyl) -3- (4-fluorophenyl) propanenoyl) piperazin-1-yl) methyl) oxazole-4-carboxylate;

메틸 2-((4-(3-(4-플루오로페닐)-3-(4-(트리플루오로메틸)페닐)프로판노일)피페라진-1-일)메틸)옥사졸-4-카복실레이트 ;Methyl 2-((4- (3- (4-fluorophenyl) -3- (4- (trifluoromethyl) phenyl) propanenoyl) piperazin-1-yl) methyl) oxazole-4-carboxylate ;

메틸 2-((4-(3-(4-클로로페닐)-3-(4-플루오로페닐)프로판노일)피페라진-1-일)메틸)옥사졸-4-카복실레이트 ;Methyl 2-((4- (3- (4-chlorophenyl) -3- (4-fluorophenyl) propanenoyl) piperazin-1-yl) methyl) oxazole-4-carboxylate;

메틸 2-((4-(3-(4-플루오로페닐)-3-(4-메톡시페닐)플루오로페닐)프로판노일)피페라진-1-일)메틸)옥사졸-4-카복실레이트 ;Methyl 2-((4- (3- (4-fluorophenyl) -3- (4-methoxyphenyl) fluorophenyl) propanenoyl) piperazin-1-yl) methyl) oxazole-4-carboxylate ;

메틸 2-((4-(3-(3-플루오로페닐)-3-(4-플루오로페닐)프로판노일)피페라진-1-일)메틸)옥사졸-4-카복실레이트 ;Methyl 2-((4- (3- (3-fluorophenyl) -3- (4-fluorophenyl) propanenoyl) piperazin-1-yl) methyl) oxazole-4-carboxylate;

메틸 2-((4-(3-(4-브로모페닐)-3-(3-플루오로페닐)프로판노일)피페라진-1-일)메틸)옥사졸-4-카복실레이트 ;Methyl 2-((4- (3- (4-bromophenyl) -3- (3-fluorophenyl) propanenoyl) piperazin-1-yl) methyl) oxazole-4-carboxylate;

메틸 2-((4-(3-(3-플루오로페닐)-3-(4-(트리플루오로메틸)페닐)프로판노일)피페라진-1-일)메틸)옥사졸-4-카복실레이트 ;Methyl 2-((4- (3- (3-fluorophenyl) -3- (4- (trifluoromethyl) phenyl) propanenoyl) piperazin-1-yl) methyl) oxazole-4-carboxylate ;

메틸 2-((4-(3-(4-클로로페닐)-3-(3-플루오로페닐)프로판노일)피페라진-1-일)메틸)옥사졸-4-카복실레이트 ;Methyl 2-((4- (3- (4-chlorophenyl) -3- (3-fluorophenyl) propanenoyl) piperazin-1-yl) methyl) oxazole-4-carboxylate;

메틸 2-((4-(3-(3-플루오로페닐)-3-(4-메톡시페닐)프로판노일)피페라진-1-일)메틸)옥사졸-4-카복실레이트 ;Methyl 2-((4- (3- (3-fluorophenyl) -3- (4-methoxyphenyl) propanenoyl) piperazin-1-yl) methyl) oxazole-4-carboxylate;

3-(4-플루오로페닐)-1-(4-((6-메틸벤조[d]옥사졸-2-일)메틸)피페라진-1-일)-3-페닐프로판-1-온 ;3- (4-fluorophenyl) -1- (4-((6-methylbenzo [ d ] oxazol-2-yl) methyl) piperazin-1-yl) -3-phenylpropan-1-one;

3-(4-브로모페닐)-1-(4-((6-메틸벤조[d]옥사졸-2-일)메틸)피페라진-1-일)-3-페닐프로판-1-온 ;3- (4-bromophenyl) -1- (4-((6-methylbenzo [ d ] oxazol-2-yl) methyl) piperazin-1-yl) -3-phenylpropan-1-one;

1-(4-((6-메틸벤조[d]옥사졸-2-일)메틸)피페라진-1-일)-3-페닐-3-(4-(트리플루오로메틸)페닐)프로판-1-온 ;1- (4-((6-methylbenzo [ d ] oxazol-2-yl) methyl) piperazin-1-yl) -3-phenyl-3- (4- (trifluoromethyl) phenyl) propane- 1-on;

3-(4-클로로페닐)-1-(4-((6-메틸벤조[d]옥사졸-2-일)메틸)피페라진-1-일)-3-페닐프로판-1-온 ;3- (4-chlorophenyl) -1- (4-((6-methylbenzo [ d ] oxazol-2-yl) methyl) piperazin-1-yl) -3-phenylpropan-1-one;

3-(4-플루오로페닐)-3-(4-메톡시페닐)-1-(4-((6-메틸벤조[d]옥사졸-2-일)메틸)피페라진-1-일)프로판-1-온 ;3- (4-fluorophenyl) -3- (4-methoxyphenyl) -1- (4-((6-methylbenzo [ d ] oxazol-2-yl) methyl) piperazin-1-yl) Propane-1-one;

메틸 2-((4-(3-(3-플루오로페닐)-3-(4-플로로페닐)프로판노일)-피페라진-1-일)메틸)옥사졸-4-카르복실레이트 ;Methyl 2-((4- (3- (3-fluorophenyl) -3- (4-fluorophenyl) propanenoyl) -piperazin-1-yl) methyl) oxazole-4-carboxylate;

3-(4-브로모페닐)-3-(4-플루오로페닐)-1-(4-((6-메틸벤조[d]옥사졸-2-일)메틸)피페라진-1-일)프로판-1-온 ;3- (4-bromophenyl) -3- (4-fluorophenyl) -1- (4-((6-methylbenzo [ d ] oxazol-2-yl) methyl) piperazin-1-yl) Propane-1-one;

3-(4-플루오로페닐)-1-(4-((6-메틸벤조[d]옥사졸-2-일)메틸)피페라진-1-일)-3-(4-(트리플루오로메틸)페닐)프로판-1-온 ; 3- (4-fluorophenyl) -1- (4-((6-methylbenzo [ d ] oxazol-2-yl) methyl) piperazin-1-yl) -3- (4- (trifluoro Methyl) phenyl) propan-1-one;

3-(4-클로로페닐)-3-(4-플루오로페닐)-1-(4-((6-메틸벤조[d]옥사졸-2-일)메틸)피페라진-1-일)프로판-1-온 ;3- (4-chlorophenyl) -3- (4-fluorophenyl) -1- (4-((6-methylbenzo [ d ] oxazol-2-yl) methyl) piperazin-1-yl) propane -1-one;

3-(3-플루오로페닐)-3-(4-플루오로페닐)-1-(4-((6-메틸벤조[d]옥사졸-2-일)메틸)피페라진-1-일)프로판-1-온 ;3- (3-fluorophenyl) -3- (4-fluorophenyl) -1- (4-((6-methylbenzo [ d ] oxazol-2-yl) methyl) piperazin-1-yl) Propane-1-one;

3-(4-브로모페닐)-3-(3-플루오로페닐)-1-(4-((6-메틸벤조[d]옥사졸-2-일)메틸)피페라진-1-일)프로판-1-온 ; 3- (4-bromophenyl) -3- (3-fluorophenyl) -1- (4-((6-methylbenzo [ d ] oxazol-2-yl) methyl) piperazin-1-yl) Propane-1-one;

3-(3-플루오로페닐)-1-(4-((6-메틸벤조[d]옥사졸-2-일)메틸)피페라진-1-일)-3-(4-(트리플루오로메틸)페닐)프로판-1-온 ;3- (3-fluorophenyl) -1- (4-((6-methylbenzo [ d ] oxazol-2-yl) methyl) piperazin-1-yl) -3- (4- (trifluoro Methyl) phenyl) propan-1-one;

3-(4-클로로페닐)-3-(3-플루오로페닐)-1-(4-((6-메틸벤조[d]옥사졸-2-일)메틸)피페라진-1-일)프로판-1-온 ;3- (4-chlorophenyl) -3- (3-fluorophenyl) -1- (4-((6-methylbenzo [ d ] oxazol-2-yl) methyl) piperazin-1-yl) propane -1-one;

3-(3-플루오로페닐)-3-(4-메톡시페닐)-1-(4-((6-메틸벤조[d]옥사졸-2-일)메틸)피페라진-1-일)프로판-1-온 ; 3- (3-fluorophenyl) -3- (4-methoxyphenyl) -1- (4-((6-methylbenzo [ d ] oxazol-2-yl) methyl) piperazin-1-yl) Propane-1-one;

2-((4-(3-(4-플루오로페닐)-3-페닐프로판노일)피페라진-1-일)메틸)옥사졸-4-카르복실산 ;2-((4- (3- (4-fluorophenyl) -3-phenylpropanenoyl) piperazin-1-yl) methyl) oxazole-4-carboxylic acid;

2-((4-(3-(4-브로모페닐)-3-페닐프로판노일)피페라진-1-일)메틸)옥사졸-4-카르복실산 ;2-((4- (3- (4-bromophenyl) -3-phenylpropanenoyl) piperazin-1-yl) methyl) oxazole-4-carboxylic acid;

2-((4-(3-페닐-3-(4-(트리플루오로메틸)페닐)프로판노일)피페라진-1-일)메틸)옥사졸-4-카르복실산 ;2-((4- (3-phenyl-3- (4- (trifluoromethyl) phenyl) propanenoyl) piperazin-1-yl) methyl) oxazole-4-carboxylic acid;

2-((4-(3-(4-클로로페닐)-3-페닐프로판노일)피페라진-1-일)메틸)옥사졸-4-카르복실산 ;2-((4- (3- (4-chlorophenyl) -3-phenylpropanenoyl) piperazin-1-yl) methyl) oxazole-4-carboxylic acid;

2-((4-(3-(4-메톡시페닐)-3-페닐프로판노일)피페라진-1-일)메틸)옥사졸-4-카르복실산 ;2-((4- (3- (4-methoxyphenyl) -3-phenylpropanenoyl) piperazin-1-yl) methyl) oxazole-4-carboxylic acid;

2-((4-(3,3-비스(4-플루오로페닐)프로판노일)피페라진-1-일)메틸)옥사졸-4-카르복실산 ;2-((4- (3,3-bis (4-fluorophenyl) propanenoyl) piperazin-1-yl) methyl) oxazole-4-carboxylic acid;

2-((4-(3-(4-브로모페닐)-3-(4-플루오로페닐)프로판노일)피페라진-1-일)메틸)옥사졸-4-카르복실산 ;2-((4- (3- (4-bromophenyl) -3- (4-fluorophenyl) propanenoyl) piperazin-1-yl) methyl) oxazole-4-carboxylic acid;

2-((4-(3-(4-플루오로페닐)-3-(4-(트리플루오로메틸)페닐)프로판노일)피페라진-1-일)메틸)옥사졸-4-카르복실산 ;2-((4- (3- (4-fluorophenyl) -3- (4- (trifluoromethyl) phenyl) propanenoyl) piperazin-1-yl) methyl) oxazole-4-carboxylic acid ;

2-((4-(3-(4-클로로페닐)-3-(4-플루오로페닐)프로판노일)피페라진-1-일)메틸)옥사졸-4-카르복실산 ;2-((4- (3- (4-chlorophenyl) -3- (4-fluorophenyl) propanenoyl) piperazin-1-yl) methyl) oxazole-4-carboxylic acid;

2-((4-(3-(4-플루오로페닐)-3-(4-메톡시페닐)프로판노일)피페라진-1-일)메틸)옥사졸-4-카르복실산 ;2-((4- (3- (4-fluorophenyl) -3- (4-methoxyphenyl) propanenoyl) piperazin-1-yl) methyl) oxazole-4-carboxylic acid;

3-(3-플루오로페닐)-3-(4-플루오로페닐)-1-(4-((4-(하이드록시메틸)옥사졸-2-일)메틸)피페라진-1-일)프로판-1-온 ;3- (3-fluorophenyl) -3- (4-fluorophenyl) -1- (4-((4- (hydroxymethyl) oxazol-2-yl) methyl) piperazin-1-yl) Propane-1-one;

3-(4-브로모페닐)-3-(3-플루오로페닐)-1-(4-((4-(하이드록시메틸)옥사졸-2-일)메틸)피페라진-1-일)프로판-1-온 ;3- (4-bromophenyl) -3- (3-fluorophenyl) -1- (4-((4- (hydroxymethyl) oxazol-2-yl) methyl) piperazin-1-yl) Propane-1-one;

3-(3-플루오로페닐)-1-(4-((4-(하이드록시메틸)옥사졸-2-일)메틸)피페라진-1-일)-3-(4-(트리플루오로메틸)페닐)프로판-1-온 ;3- (3-fluorophenyl) -1- (4-((4- (hydroxymethyl) oxazol-2-yl) methyl) piperazin-1-yl) -3- (4- (trifluoro Methyl) phenyl) propan-1-one;

3-(4-클로로페닐)-3-(3-플루오로페닐)-1-(4-((4-(하이드록시메틸)옥사졸-2-일)메틸)피페라진-1-일)프로판-1-온 ;3- (4-chlorophenyl) -3- (3-fluorophenyl) -1- (4-((4- (hydroxymethyl) oxazol-2-yl) methyl) piperazin-1-yl) propane -1-one;

3-(3-플루오로페닐)-1-(4-((4-(하이드록시메틸)옥사졸-2-일)메틸)피페라진-1-일)-3-(4-메톡시페닐)프로판-1-온 ;3- (3-fluorophenyl) -1- (4-((4- (hydroxymethyl) oxazol-2-yl) methyl) piperazin-1-yl) -3- (4-methoxyphenyl) Propane-1-one;

3-(3-플루오로페닐)-3-(4-플루오로페닐)-1-(4-((4-(모폴린-4-카보닐)옥사졸-2-일)메틸)피페라진-1-일)프로판-1-온 ;3- (3-fluorophenyl) -3- (4-fluorophenyl) -1- (4-((4- (morpholin-4-carbonyl) oxazol-2-yl) methyl) piperazine- 1-yl) propan-1-one;

3-(4-브로모페닐)-3-(3-플루오로페닐)-1-(4-((4-(모폴린-4-카보닐)옥사졸-2-일)메틸)피페라진-1-일)프로판-1-온 ; 3- (4-bromophenyl) -3- (3-fluorophenyl) -1- (4-((4- (morpholin-4-carbonyl) oxazol-2-yl) methyl) piperazine- 1-yl) propan-1-one;

3-(3-플루오로페닐)-1-(4-((4-(모폴린-4-카보닐)옥사졸-2-일)메틸)피페라진-1-일)-3-(4-(트리플루오로메틸)페닐)프로판-1-온 ; 3- (3-fluorophenyl) -1- (4-((4- (morpholin-4-carbonyl) oxazol-2-yl) methyl) piperazin-1-yl) -3- (4- (Trifluoromethyl) phenyl) propan-1-one;

3-(4-클로로페닐)-3-(3-플루오로페닐)-1-(4-((4-(모폴린-4-카보닐)옥사졸-2-일)메틸)피페라진-1-일)프로판-1-온 ; 3- (4-chlorophenyl) -3- (3-fluorophenyl) -1- (4-((4- (morpholin-4-carbonyl) oxazol-2-yl) methyl) piperazin-1 -Yl) propan-1-one;

3-(3-플루오로페닐)-3-(4-메톡시페닐)-1-(4-((4-((모폴린-4-카보닐)옥사졸-2-일)메틸)피페라진-1-일)프로판-1-온 ; 3- (3-fluorophenyl) -3- (4-methoxyphenyl) -1- (4-((4-((morpholin-4-carbonyl) oxazol-2-yl) methyl) piperazine -1-yl) propan-1-one;

N-((1-(3-(4-브로모페닐)-3-페닐프로판노일)피페리딘-4-일)메틸)-3,5-다이클로로벤즈아마이드 ; N -((1- (3- (4-bromophenyl) -3-phenylpropanenoyl) piperidin-4-yl) methyl) -3,5-dichlorobenzamide;

3,5-다이클로로-N-((1-(3-페닐-3-(4-(트리플루오로메틸)페닐)프로판노일)피페리딘-4-일)메틸)벤즈아마이드 ;3,5-dichloro- N -((1- (3-phenyl-3- (4- (trifluoromethyl) phenyl) propannoyl) piperidin-4-yl) methyl) benzamide;

N-((1-(3-(4-브로모페닐)-3-(4-플루오로페닐)프로판노일)피페리딘-4-일)메틸)-3,5-다이클로로벤즈아마이드 ; N -((1- (3- (4-bromophenyl) -3- (4-fluorophenyl) propanenoyl) piperidin-4-yl) methyl) -3,5-dichlorobenzamide;

3,5-다이클로로-N-((1-(3-(4-플루오로페닐)-3-(4-트리플루오로메틸)페닐)프로판노일)피페리딘-4-일)메틸)벤즈아마이드 ;3,5-Dichloro- N -((1- (3- (4-fluorophenyl) -3- (4-trifluoromethyl) phenyl) propanenoyl) piperidin-4-yl) methyl) benz Amide;

N-((1-(3-(4-브로모페닐)-3-(3-플루오로페닐)프로판노일)피페리딘-4-일)메틸)-3,5-다이클로로벤즈아마이드 ; N -((1- (3- (4-bromophenyl) -3- (3-fluorophenyl) propanenoyl) piperidin-4-yl) methyl) -3,5-dichlorobenzamide;

3,5-다이클로로-N-((1-(3-(3-플루오로페닐)-3-(4-(트리플루오로메틸)페닐)프로판노일)피페리딘-4-일)메틸)벤즈아마이드.
3,5-Dichloro- N -((1- (3- (3-fluorophenyl) -3- (4- (trifluoromethyl) phenyl) propanenoyl) piperidin-4-yl) methyl) Benzamide.

한편, 본 발명은 상기 화학식 1로 표시되는 다이페닐프로판노일 화합물의 제조방법을 포함한다. 본 발명에 따른 제조방법은 하기 반응식 1 또는 반응식 2의 두 가지 방법으로 대별될 수 있다. On the other hand, the present invention includes a method for producing a diphenyl propane noyl compound represented by the formula (1). The preparation method according to the present invention can be roughly divided into two methods, the following scheme 1 or scheme 2.

본 발명에 따른 첫 번째 제조방법은 하기 반응식 1에 나타낸 바와 같이, The first manufacturing method according to the present invention, as shown in Scheme 1 below,

하기 화학식 2로 표시되는 화합물과 하기 화학식 3으로 표시되는 화합물을 결합반응시켜, 하기 화학식 1로 표시되는 다이페닐프로판노일 화합물을 제조하는 과정을 포함하여 이루어진다.It comprises the step of preparing a diphenyl propane noyl compound represented by the formula (1) by combining the compound represented by the formula (2) and the compound represented by the formula (3).

[반응식 1]Scheme 1

상기 반응식 1에서, R¹, R², 및 R³은 각각 상기에서 정의한 바와 같다.In Scheme 1, R ¹ , R ² , and R ³ are each as defined above.

상기 반응식 1에 따른 결합반응은 적당한 유기용매하에서 가열하여줌으로써 수행할 수 있다. 상기 결합반응에서 사용되는 용매는 당 분야에서 통상적으로 사용되어온 유기용매로서 반응에 영향을 주지 않는 비활성 유기용매를 사용할 수 있다. 상기 유기용매를 구체적으로 예시하면 다이에틸에테르, 메탄올, 에탄올, 프로판올과 같은 탄소수 1 내지 6의 저급 알콜류, 테트라하이드로퓨란 등과 같은 에테르류, 또는 클로로포름, 다이클로로메탄 등과 같은 할로겐화탄화수소류, 아세토니트릴 등과 같은 니트릴류, N,N-다이메틸포름아마이드 (DMF) 등의 아마이드류 등을 사용할 수 있다. 바람직하게는 아세토니트릴을 사용하는 것이다. 반응온도는 30℃ 내지 사용된 용매의 환류온도 범위에서 수행할 수 있으며, 보다 구체적으로는 30℃ 내지 120℃의 온도 범위, 보다 구체적으로는 50℃ 내지 100℃ 내에서 수행할 수 있다. The coupling reaction according to Scheme 1 may be performed by heating under a suitable organic solvent. The solvent used in the coupling reaction may be an inert organic solvent which does not affect the reaction as an organic solvent commonly used in the art. Specific examples of the organic solvent include diethyl ether, lower alcohols having 1 to 6 carbon atoms such as methanol, ethanol and propanol, ethers such as tetrahydrofuran, halogenated hydrocarbons such as chloroform and dichloromethane, acetonitrile and the like. Amides such as nitriles and N, N -dimethylformamide (DMF) can be used. Preferably, acetonitrile is used. The reaction temperature may be carried out in the reflux temperature range of 30 ℃ to the solvent used, more specifically may be carried out in a temperature range of 30 ℃ to 120 ℃, more specifically 50 ℃ to 100 ℃.

본 발명에 따른 두 번째 제조방법은 하기 반응식 2에 나타낸 바와 같이, As the second production method according to the present invention is shown in Scheme 2,

ⅰ) 하기 화학식 2로 표시되는 화합물과 하기 화학식 3으로 표시되는 화합물을 결합반응시켜, 하기 화학식 5로 표시되는 화합물을 제조하는 과정 ; 및 Iii) preparing a compound represented by the following Chemical Formula 5 by combining and reacting the compound represented by the following Chemical Formula 2 with the compound represented by the following Chemical Formula 3; And

ⅱ) 하기 화학식 5로 표시되는 화합물과 하기 화학식 6으로 표시되는 화합물과 알킬화 반응시켜, 하기 화학식 1로 표시되는 다이페닐프로판노일 화합물을 제조하는 과정; 을 포함하여 이루어진다.Ii) alkylating the compound represented by the following Chemical Formula 5 with the compound represented by the following Chemical Formula 6 to prepare a diphenylpropanenoyl compound represented by the following Chemical Formula 1; It is made, including.

[반응식 2]Scheme 2

상기 반응식 2에서, R¹, R², 및 R³은 각각 상기에서 정의한 바와 같고, Y는 수소원자 또는 tert-부톡시카보닐(t-Boc) 등의 아민 보호기를 나타낸다.In Reaction Scheme 2, R ¹ , R ² , and R ³ are each as defined above, and Y represents a hydrogen atom or an amine protecting group such as tert -butoxycarbonyl (t-Boc).

상기 반응식 2에 따른 ⅰ)결합반응은, 상기 반응식 1에서 제안한 바와 같이 적당한 유기용매하에서 가열하여줌으로써 수행할 수 있다. 이때, 사용되는 유기용매 및 가열반응 온도는 상기 반응식 1에서 예시한 바와 같다.(Iii) The coupling reaction according to Scheme 2 can be carried out by heating under a suitable organic solvent as suggested in Scheme 1 above. At this time, the organic solvent and the heating reaction temperature used are as illustrated in Scheme 1.

또한, 상기 화학식 4로 표시되는 화합물이 t-Boc 등의 보호기가 도입된 화합물을 사용한 경우는 탈보호 반응을 추가로 실시하여 상기 화학식 5로 표시되는 화합물을 얻을 수 있다. 탈보호 반응은 문헌(Protective Groups in Organic Synthesis, T.W. Green and R.G.M. Wuts, 3rd Ed. Wiely)에서 잘 알려진 기법에 의해 수행할 수 있다. 구체적으로 탈보호 반응은 무기산(예를 들면, 염산, 브롬산, 황산) 또는 유기산(예를 들면, 초산, 아세트산, 트리플루오로아세트산, 메탄술포닐산)의 존재 하에서 다이클로로메탄, 클로로포름, 에틸아세테이트, 벤젠, 톨루엔, 테트라하이드로퓨란, 다이옥산과 같은 용매 중에서 0℃ 내지 100℃에서 임의로 수행할 수 있다. In addition, when the compound represented by the formula (4) using a compound introduced with a protecting group such as t-Boc can be further subjected to a deprotection reaction to obtain a compound represented by the formula (5). Deprotection reactions can be carried out by techniques well known in Protective Groups in Organic Synthesis , TW Green and RGM Wuts, 3rd Ed. Wiely. Specifically, the deprotection reaction is carried out in the presence of an inorganic acid (e.g. hydrochloric acid, bromic acid, sulfuric acid) or an organic acid (e.g. acetic acid, acetic acid, trifluoroacetic acid, methanesulfonyl acid), dichloromethane, chloroform, ethyl acetate It may optionally be carried out at 0 ℃ to 100 ℃ in a solvent such as benzene, toluene, tetrahydrofuran, dioxane.

상기 반응식 2에 따른 ⅱ)과정은 알킬화 반응으로, 적당한 결합제와 유기 용매를 사용하는 조건에서 수행할 수 있다. 결합제로는 알칼리금속 또는 알칼리토금속의 탄산염, 황산염, 수산화물 등의 무기염기, 또는 모노(C₁-C₅알킬)아민, 다이(C₁-C₅알킬)아민, 트리(C₁-C₅알킬)아민 등의 유기염기 등을 사용할 수 있으며, 특히 바람직하게는 에틸 다이아이소프로필아민 (EDIPA)를 사용하는 것이다. 반응온도는 -30℃ 내지 사용된 용매의 환류온도 범위에서 수행할 수 있으며, 보다 구체적으로는 상온 내지 120℃의 온도 범위, 보다 구체적으로는 30℃ 내지 80℃ 내에서 수행할 수 있다. 상기 알킬화 반응에서 사용되는 용매는 당 분야에서 통상적으로 사용되어온 유기용매로서 반응에 영향을 주지 않는 비활성 유기용매를 사용할 수 있다. 본 발명에서 사용될 수 있는 유기용매를 구체적으로 예시하면 다이에틸에테르, 메탄올, 에탄올, 프로판올과 같은 탄소수 1 내지 6의 저급 알콜류, 테트라하이드로퓨란 등과 같은 에테르류, 또는 클로로포름, 다이클로로메탄 등과 같은 할로겐화탄화수소류, 아세토니트릴 등과 같은 니트릴류, N,N-다이메틸포름아마이드 (DMF) 등의 아마이드류 등을 사용할 수 있다. 바람직하게는 다이클로로메탄, N,N-다이메틸포름아마이드 (DMF)를 사용하는 것이다.The process ii) according to Scheme 2 is an alkylation reaction, which may be performed under conditions using an appropriate binder and an organic solvent. Examples of the binder include inorganic bases such as carbonates, sulfates, and hydroxides of alkali metals or alkaline earth metals, or mono (C ₁ -C ₅ alkyl) amines, di (C ₁ -C ₅ alkyl) amines, and tri (C ₁ -C ₅ alkyls). Organic bases, such as an amine, etc. can be used, Especially preferably, ethyl diisopropylamine (EDIPA) is used. The reaction temperature may be carried out in the range of -30 ℃ to the reflux temperature of the solvent used, more specifically in the temperature range of room temperature to 120 ℃, more specifically may be carried out within 30 ℃ to 80 ℃. The solvent used in the alkylation reaction may be an inert organic solvent that does not affect the reaction as an organic solvent that has been commonly used in the art. Specific examples of the organic solvent that can be used in the present invention include diethyl ether, lower alcohols having 1 to 6 carbon atoms such as methanol, ethanol and propanol, ethers such as tetrahydrofuran, or halogenated hydrocarbons such as chloroform and dichloromethane. Nitriles such as acetonitrile, amides such as N, N -dimethylformamide (DMF), and the like. Preferably, dichloromethane, N, N -dimethylformamide (DMF) is used.

또한, 상기 반응식 1 또는 반응식 2에 따른 제조방법에서 원료물질로 사용되는 상기 화학식 2로 표시되는 5-벤즈히드릴-1,3-다이옥산-4,6-다이온 화합물은, 하기 반응식 3에 따른 제조방법을 수행하여 제조할 수 있다.In addition, the 5-benzhydryl-1,3-dioxane-4,6-dione compound represented by Formula 2 used as a raw material in the production method according to Scheme 1 or Scheme 2, according to Scheme 3 It can be prepared by performing the manufacturing method.

[반응식 3] Scheme 3

상기 반응식 3에서, R², 및 R³은 각각 상기에서 정의한 바와 같다.In Scheme 3, R ² , and R ³ are as defined above, respectively.

상기 반응식 3에 따른 제조방법에 의하면, 먼저 상기 화학식 7로 표시되는 알데하이드 화합물과 1,3-다이옥산-4,6-다이온 화합물을 피롤리디늄 아세테이트 존재하에서 반응시켜 상기 화학식 9로 표시되는 5-벤질리덴-1,3-다이옥산-4,6-다이온 화합물을 제조한다. 상기 반응은 30℃ 내지 90℃의 가열 조건에서 수행할 수 있으며, 바람직하기로는 환류 조건에서 반응시키는 것이다.According to the preparation method according to Scheme 3, first, the aldehyde compound represented by Chemical Formula 7 and the 1,3-dioxane-4,6-dione compound are reacted in the presence of pyrrolidinium acetate to give 5- Benzylidene-1,3-dioxane-4,6-dione compound is prepared. The reaction may be carried out under heating conditions of 30 ° C. to 90 ° C., preferably under reflux conditions.

그런 다음, 상기 화학식 9로 표시되는 5-벤질리덴-1,3-다이옥산-4,6-다이온 화합물을 상기 화학식 10으로 표시되는 그리냐드 시약 및 요오드화구리(CuI)과 반응시켜, 상기 화학식 2로 표시되는 5-벤즈히드릴-1,3-다이옥산-4,6-다이온 화합물을 제조한다. 상기 그리냐드 시약과의 반응은 -20℃ 내지 30℃의 온도, 바람직하기로는 -10℃ 내지 10℃의 온도 조건에서 반응시키는 것이다.Then, the 5-benzylidene-1,3-dioxane-4,6-dione compound represented by Chemical Formula 9 is reacted with the Grignard reagent and copper iodide (CuI) represented by Chemical Formula 10, thereby To prepare a 5-benzhydryl-1,3-dioxane-4,6-dione compound represented by. The reaction with the Grignard reagent is a reaction at a temperature of -20 ° C to 30 ° C, preferably at a temperature of -10 ° C to 10 ° C.

한편, 본 발명은 상기 화학식 1로 표시되는 다이페닐프로판노일 화합물 또는 약학적 허용 가능한 이의 염을 유효성분으로 포함하는 약제조성물을 포함한다.On the other hand, the present invention includes a pharmaceutical composition comprising a diphenyl propane noyl compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

본 발명의 약제조성물은 상기 화학식 1로 표시되는 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 is suitable for oral or parenteral administration by formulating in a conventional formulation method including other conventional carriers, adjuvants or diluents together with the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof. It may be prepared in the form. 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 질환정도에 따라 달라질 수 있으며, 의사 또는 약사의 판단에 따라 일정 시간간격으로 1일 1회 내지 수회로 분할 투여할 수도 있다. The effective daily dose of T-type calcium channel antagonist of the pharmaceutical composition of the present invention is 0.01 to 1000 mg / day based on an adult, but the dosage is the age, weight, sex, dosage form, health condition and disease level 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 화합물 또는 약학적으로 허용 가능한 이의 염 또는 이를 함유하는 약제학적 조성물을 질환의 치료 및 예방을 목적으로 사용하는 의약적 용도를 제공한다.Accordingly, the present invention provides a pharmaceutical use of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same for the purpose of treating and preventing a disease.

즉, 본 발명은 T-형 칼슘채널에 대한 활성을 가지므로, T-형 칼슘채널 길항작용에 의해 치료 가능한 질환 예를 들면 간질, 고혈압 등의 뇌질환, 협심증 등의 심장질환, 만성 통증, 신경성 통증 등의 통증질환, 또는 암질환의 치료목적으로 사용되는 의약적 용도를 포함한다.That is, the present invention has an activity against T-type calcium channels, and thus diseases treatable by T-type calcium channel antagonism, such as brain diseases such as epilepsy and hypertension, heart diseases such as angina pectoris, chronic pain, and neuropathy It includes medicinal uses used for the treatment of pain diseases such as pain or cancer diseases.

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

대표합성예 1. 5-(4-플루오로벤질리덴)-2,2-다이메틸-1,3-다이옥산-4,6-다이온 (화학식 9)의 합성Representative Synthesis Example 1. Synthesis of 5- (4-fluorobenzylidene) -2,2-dimethyl-1,3-dioxane-4,6-dione (Formula 9)

벤젠 200 mL에 4-플루오로벤즈알데하이드 (5.0 g, 40.3 mmol)와 2,2-다이메틸-1,3-다이옥산-4,6-다이온 (6.39 g, 44.3 mmol)를 녹였다. 별도의 용기에서 아세트산에 피롤리딘을 가하여 피롤리디늄 아세테이트 (4.03 mmol)를 제조하여, 상기 반응용액에 천천히 가한 뒤, 65 ℃에서 24시간동안 환류 교반하여, 31%의 수율로 상기 목적화합물을 얻었다.4-fluorobenzaldehyde (5.0 g, 40.3 mmol) and 2,2-dimethyl-1,3-dioxane-4,6-dione (6.39 g, 44.3 mmol) were dissolved in 200 mL of benzene. Pyrrolidine was added to acetic acid in a separate vessel to prepare pyrrolidinium acetate (4.03 mmol), which was slowly added to the reaction solution and stirred at reflux for 24 hours at 65 ° C. to obtain the target compound in a yield of 31%. Got it.

¹H NMR (CDCl₃, 300 MHz) δ 8.39 (s, 1H), 8.19-8.15 (m, 2H), 7.21-7.14 (m, 2H), 1.80 (s, 6H).
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.39 (s, 1H), 8.19-8.15 (m, 2H), 7.21-7.14 (m, 2H), 1.80 (s, 6H).

대표합성예 2. 5-((4-플루오로페닐)(페닐)메틸)-2,2-다이메틸-1,3-다이옥산-4,6-다이온 (화학식 2)의 합성Representative Synthesis Example 2. Synthesis of 5-((4-fluorophenyl) (phenyl) methyl) -2,2-dimethyl-1,3-dioxane-4,6-dione (Formula 2)

정제된 테트라하이드로퓨란 5 mL에 5-(4-플루오로벤질리덴)-2,2-다이메틸-1,3-다이옥산-4,6-다이온 (500 mg, 2.00 mmol)과 요오드화구리 (CuI; 38 mg, 0.2o mmol)를 녹이고, 0 ℃에서 페닐마그네슘 브로마이드(1.0 M, 4.0 mL, 4.00 mmol)의 그리냐드 시약을 천천히 가한 뒤, 상온에서 2시간동안 교반하여, 77%의 수율로 목적화합물을 얻었다. 5- (4-fluorobenzylidene) -2,2-dimethyl-1,3-dioxane-4,6-dione (500 mg, 2.00 mmol) and copper iodide (CuI) in 5 mL of purified tetrahydrofuran Dissolve 38 mg, 0.2o mmol) and slowly add a Grignard reagent of phenylmagnesium bromide (1.0 M, 4.0 mL, 4.00 mmol) at 0 ° C., and then stir for 2 hours at room temperature, yielding a desired yield of 77%. The compound was obtained.

¹H NMR (CDCl₃, 400 MHz) δ 7.35-7.25 (m, 7H), 7.02-6.97 (m, 2H), 5.39 (d, J = 2.3 Hz, 1H), 4.28 (d, J = 2.6 Hz, 1H), 1.75 (s, 3H), 1.57 (s, 3H).
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.35-7.25 (m, 7H), 7.02-6.97 (m, 2H), 5.39 (d, J = 2.3 Hz, 1H), 4.28 (d, J = 2.6 Hz, 1H), 1.75 (s, 3H), 1.57 (s, 3H).

대표합성예 3. tert-부틸 4-(3-(4-플루오로페닐)-3-페닐프로판노일)피페라진-1-카복실레이트 (화학식 5)의 합성Representative Synthesis Example 3. Synthesis of tert -Butyl 4- (3- (4-fluorophenyl) -3-phenylpropanenoyl) piperazine-1-carboxylate (Formula 5)

아세토니트릴 15 mL에 5-((4-플루오로페닐)(페닐)메틸)-2,2-다이메틸-1,3-다이옥산-4,6-다이온 (504 mg, 1.54 mmol)과 tert-부틸 피페라진-1-카복실레이트 (286 mg, 1.54 mmol)를 넣고 75 ℃에서 15시간동안 환류 교반하여, 35%의 수율로 목적화합물을 얻었다. In 15 mL of acetonitrile 5-((4-fluorophenyl) (phenyl) methyl) -2,2-dimethyl-1,3-dioxane-4,6-dione (504 mg, 1.54 mmol) and tert- Butyl piperazine-1-carboxylate (286 mg, 1.54 mmol) was added thereto, and the mixture was stirred under reflux at 75 ° C. for 15 hours to obtain the target compound in a yield of 35%.

¹H NMR (CDCl₃, 300 MHz) δ 7.32-7.18 (m, 7H), 6.97 (t, J = 8.6 Hz, 2H), 4.65 (t, J = 7.5 Hz, 1H), 3.54-3.14 (m, 8H), 3.03 (d, J = 7.5 Hz, 2H), 1.45 (s, 9H).
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.32-7.18 (m, 7H), 6.97 (t, J = 8.6 Hz, 2H), 4.65 (t, J = 7.5 Hz, 1H), 3.54-3.14 (m, 8H), 3.03 (d, J = 7.5 Hz, 2H), 1.45 (s, 9H).

대표합성예 4. 메틸 2-((4-(3-(4-플루오로페닐)-3-페닐프로판노일)피페라진-1-일)메틸)옥사졸-4-카복실레이트 (화학식 1)의 합성Representative Synthesis Example 4 of methyl 2-((4- (3- (4-fluorophenyl) -3-phenylpropanenoyl) piperazin-1-yl) methyl) oxazole-4-carboxylate synthesis

다이클로로메탄 4 mL에 tert-부틸 4-(3-(4-플루오로페닐)-3-페닐프로판노일)피페라진-1-카복실레이트 (165 mg, 0.40 mmol)를 녹이고, 트리플루오로아세트산 (TFA; 0.82 mL, 11.0 mmol)을 천천히 가한 다음, 상온에서 2시간동안 교반하여 탈보호 반응을 수행한 후, 반응용액을 감압 농축시켰다.Dissolve tert -butyl 4- (3- (4-fluorophenyl) -3-phenylpropanenoyl) piperazine-1-carboxylate (165 mg, 0.40 mmol) in 4 mL of dichloromethane, trifluoroacetic acid ( TFA; 0.82 mL, 11.0 mmol) was added slowly, followed by stirring at room temperature for 2 hours to effect deprotection, and the reaction solution was concentrated under reduced pressure.

N,N-다이메틸포름아마이드 2 mL에 상기 농축된 반응물을 녹인 다음, 메틸 2-(클로로메틸옥사졸)-4-카복실레이트 (70. mg, 0.4 mmol)와 에틸 다이아이소프로필아민 (EDIPA; 0.35 mL, 2.00 mmol)을 넣고 75 ℃에서 15시간 동안 환류 교반하여, 목적화합물을 얻었다.
The concentrated reaction was dissolved in 2 mL of N, N -dimethylformamide , and then methyl 2- (chloromethyloxazole) -4-carboxylate (70. mg, 0.4 mmol) and ethyl diisopropylamine (EDIPA; 0.35 mL, 2.00 mmol) was added thereto, and the mixture was stirred at 75 ° C. for 15 hours to obtain a target compound.

대표합성예 5. tert-부틸 4-((3,5-다이클로로벤즈아미도)메틸)피페리딘-1-카복실레이트 (화학식 3)의 합성Representative Synthesis Example 5 Synthesis of tert -Butyl 4-((3,5-dichlorobenzamido) methyl) piperidine-1-carboxylate (Formula 3)

테트라하이드로퓨란 14 mL에 tert-부틸 4-(아미노메틸)피페리딘-1-카복실레이트 (0.61 mL, 2.88 mmol)과 3,5-다이클로로벤조일 클로라이드 (880 mg, 4.20 mmol), 및 트리에틸아민 (Et₃N; 1.17 mL, 8.40 mmol)을 넣고 상온에서 5시간 동안 교반하여 목적화합물 (98%)을 얻었다. Tert -butyl 4- (aminomethyl) piperidine-1-carboxylate (0.61 mL, 2.88 mmol) and 3,5-dichlorobenzoyl chloride (880 mg, 4.20 mmol), and triethyl in 14 mL of tetrahydrofuran An amine (Et ₃ N; 1.17 mL, 8.40 mmol) was added thereto, and the resultant was stirred at room temperature for 5 hours to obtain the target compound (98%).

¹H NMR (CDCl₃, 300 MHz) δ 7.63 (m, 2H), 7.45 (m, 1H), 6.68 (bs, 1H), 4.13-4.03 (m, 2H), 3.31 (m, 2H), 2.67 (m, 2H), 1.76 (m, 1H), 1.71-1.68 (m, 2H), 1.43 (s, 9H), 1.15 (m, 2H).
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.63 (m, 2H), 7.45 (m, 1H), 6.68 (bs, 1H), 4.13-4.03 (m, 2H), 3.31 (m, 2H), 2.67 ( m, 2H), 1.76 (m, 1H), 1.71-1.68 (m, 2H), 1.43 (s, 9H), 1.15 (m, 2H).

대표합성예 6. 3,5-다이클로로-N-(피페리딘-4-일메틸)벤자아마이드 (화학식 3)의 합성Representative Synthesis Example 6 Synthesis of 3,5-Dichloro- N- (piperidin-4-ylmethyl) benzaamide (Formula 3)

다이클로로메탄 9.4 mL에 tert-부틸 4-((3,5-다이클로로벤즈아미도)메틸)피페리딘-1-카복실레이트 (1.1 g, 2.84 mmol)를 녹이고, 여기에 트리플루오로아세트산 (2.27 mL, 30.5 mmol)을 천천히 가하고 상온에서 2시간동안 교반하여, 목적화합물(99%)을 얻었다.Dissolve tert -butyl 4-((3,5-dichlorobenzamido) methyl) piperidine-1-carboxylate (1.1 g, 2.84 mmol) in 9.4 mL dichloromethane and add trifluoroacetic acid ( 2.27 mL, 30.5 mmol) was added slowly and stirred at room temperature for 2 hours to obtain the target compound (99%).

¹H NMR (CDCl₃, 300 MHz) δ 7.62 (d, J = 1.9 Hz, 2H), 7.48 (t, J = 1.9 Hz, 1H), 6.14 (bs, 1H), 3.34 (t, J = 6.2 Hz, 2H), 3.13-3.09 (m, 2H), 2.64-2.56 (m, 2H), 1.75-1.68 (m, 3H), 1.26-1.16 (m, 2H).
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.62 (d, J = 1.9 Hz, 2H), 7.48 (t, J = 1.9 Hz, 1H), 6.14 (bs, 1H), 3.34 (t, J = 6.2 Hz , 2H), 3.13-3.09 (m, 2H), 2.64-2.56 (m, 2H), 1.75-1.68 (m, 3H), 1.26-1.16 (m, 2H).

대표합성예 7. N-((1-(3-(4-브로모페닐)-3-페닐프로판노일)피페리딘-4-일)메틸)-3,5-다이클로로벤즈아마이드 (화학식 1)의 합성Representative Synthesis Example 7 N -((1- (3- (4-bromophenyl) -3-phenylpropanenoyl) piperidin-4-yl) methyl) -3,5-dichlorobenzamide (Formula 1) ) Synthesis

아세토니트릴 1.1 mL에, 3,5-다이클로로-N-(피페리딘-4-일메틸)벤즈아마이드 (65.3 mg, 0.227 mmol)와 5-((4-브로모페닐)(페닐)메틸-2,2-다이메틸-1,3-다이옥산-4,6-다이온 (88.5 mg, 0.227 mmol)을 넣고, 100℃에서 19시간 동안 교반하여, 47%의 수율로 목적화합물을 얻었다.To 1.1 mL of acetonitrile, 3,5-dichloro- N- (piperidin-4-ylmethyl) benzamide (65.3 mg, 0.227 mmol) and 5-((4-bromophenyl) (phenyl) methyl- 2,2-dimethyl-1,3-dioxane-4,6-dione (88.5 mg, 0.227 mmol) was added thereto and stirred at 100 ° C. for 19 hours to obtain a target compound in a yield of 47%.

¹H NMR (CDCl₃, 300 MHz) δ 7.64 (d, J = 1.8 Hz, 2H), 7.44 (t, J = 1.8 Hz, 1H), 7.36-7.32 (m, 2H), 7.27-7.21 (m, 2H), 7.18-7.12 (m, 3H), 7.07-7.03 (m, 2H), 6.94 (bs, 1H), 4.54-4.50 (m, 2H), 3.83-3.79 (m, 1H), 3.35-3.26 (m, 1H), 3.12-2.82 (m, 4H), 2.45-2.37 (m, 1H), 1.81-1.77 (m, 1H), 1.64-1.61 (m, 2H), 0.96-0.74 (m, 2H).
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.64 (d, J = 1.8 Hz, 2H), 7.44 (t, J = 1.8 Hz, 1H), 7.36-7.32 (m, 2H), 7.27-7.21 (m, 2H), 7.18-7.12 (m, 3H), 7.07-7.03 (m, 2H), 6.94 (bs, 1H), 4.54-4.50 (m, 2H), 3.83-3.79 (m, 1H), 3.35-3.26 ( m, 1H), 3.12-2.82 (m, 4H), 2.45-2.37 (m, 1H), 1.81-1.77 (m, 1H), 1.64-1.61 (m, 2H), 0.96-0.74 (m, 2H).

하기의 실시예는 상기한 대표합성예를 이용하여 합성된 상기 화학식 1로 표시되는 화합물에 대한 일례이다.
The following examples are examples of the compound represented by Formula 1 synthesized using the above-described representative synthesis example.

실시예 1. 메틸 2-((4-(3-(4-플루오로페닐)-3-페닐프로판노일)피페라진-1-일)메틸)옥사졸-4-카복실레이트 (화합물번호 1) Example 1.Methyl 2-((4- (3- (4-fluorophenyl) -3-phenylpropanenoyl) piperazin-1-yl) methyl) oxazole-4-carboxylate (Compound No. 1)

상기 대표합성예 4와 같은 방법으로 수행하여 64%의 수율로 목적화합물을 얻었다. The target compound was obtained in the same manner as in the Synthesis Example 4, with a yield of 64%.

¹H NMR (CDCl₃, 400 MHz) δ 8.24 (s, 1H), 7.30-7.17 (m, 7H), 6.95 (t, J = 8.7 Hz, 2H), 4.64 (t, J = 7.5 Hz, 1H), 3.92 (s, 3H), 3.72 (s, 2H), 3.64-3.53 (m, 2H), 3.38 (t, J = 4.9 Hz, 2H), 3.01 (d, J = 7.5 Hz, 2H), 2.45-2.25 (m, 4H).
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.24 (s, 1H), 7.30-7.17 (m, 7H), 6.95 (t, J = 8.7 Hz, 2H), 4.64 (t, J = 7.5 Hz, 1H) , 3.92 (s, 3H), 3.72 (s, 2H), 3.64-3.53 (m, 2H), 3.38 (t, J = 4.9 Hz, 2H), 3.01 (d, J = 7.5 Hz, 2H), 2.45- 2.25 (m, 4 H).

실시예 2. 메틸 2-((4-(3-(4-브로모페닐)-3-페닐프로판노일)피페라진-1-일)메틸)옥사졸-4-카복실레이트 (화합물번호 2) Example 2. Methyl 2-((4- (3- (4-bromophenyl) -3-phenylpropanenoyl) piperazin-1-yl) methyl) oxazole-4-carboxylate (Compound No. 2)

상기 대표합성예 4와 같은 방법으로 수행하여 65%의 수율로 목적화합물을 얻었다. The target compound was obtained in the same manner as in the Synthesis Example 4, with a yield of 65%.

¹H NMR (CDCl₃, 300 MHz) δ 8.23 (s, 1H), 7.40-7.09 (m, 9H), 4.61 (t, J = 7.4 Hz, 1H), 3.93 (s, 3H), 3.71 (s, 2H), 3.64-3.51 (m, 2H), 3.38 (t, J = 4.9 Hz, 2H), 3.00 (d, J = 7.5 Hz, 2H), 2.42-2.26 (m, 4H).
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.23 (s, 1H), 7.40-7.09 (m, 9H), 4.61 (t, J = 7.4 Hz, 1H), 3.93 (s, 3H), 3.71 (s, 2H), 3.64-3.51 (m, 2H), 3.38 (t, J = 4.9 Hz, 2H), 3.00 (d, J = 7.5 Hz, 2H), 2.42-2.26 (m, 4H).

실시예 3. 메틸 2-((4-(3-페닐-3-(4-(트리플루오로메틸)페닐)프로판노일)피페라진-1-일)메틸)옥사졸-4-카복실레이트 (화합물번호 3) Example 3. Methyl 2-((4- (3-phenyl-3- (4- (trifluoromethyl) phenyl) propanenoyl) piperazin-1-yl) methyl) oxazole-4-carboxylate (compound Number 3)

상기 대표합성예 4와 같은 방법으로 수행하여 69%의 수율로 목적화합물을 얻었다. The target compound was obtained in the yield of 69% by the same method as in Synthesis Example 4.

¹H NMR (CDCl₃, 400 MHz) δ 8.22 (s, 1H), 7.52 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 8.2 Hz, 2H), 7.29-7.25 (m, 2H), 7.20-7.18 (m, 2H), 4.71 (t, J = 7.4 Hz, 1H), 3.91 (s, 3H), 3.70 (s, 2H), 3.62-3.51 (m, 2H), 3.40 (t, J = 5.0 Hz, 2H), 3.04 (d, J = 7.5 Hz, 2H), 2.42-2.28 (m, 4H).
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.22 (s, 1H), 7.52 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 8.2 Hz, 2H), 7.29-7.25 (m, 2H) , 7.20-7.18 (m, 2H), 4.71 (t, J = 7.4 Hz, 1H), 3.91 (s, 3H), 3.70 (s, 2H), 3.62-3.51 (m, 2H), 3.40 (t, J = 5.0 Hz, 2H), 3.04 (d, J = 7.5 Hz, 2H), 2.42-2.28 (m, 4H).

실시예 4. 메틸 2-((4-(3-(4-클로로페닐)-3-페닐프로판노일)피페라진-1-일)메틸)옥사졸-4-카복실레이트 (화합물번호 4) Example 4.Methyl 2-((4- (3- (4-chlorophenyl) -3-phenylpropanenoyl) piperazin-1-yl) methyl) oxazole-4-carboxylate (Compound No. 4)

상기 대표합성예 4와 같은 방법으로 수행하여 70%의 수율로 목적화합물을 얻었다. The target compound was obtained in the same manner as in the Synthesis Example 4, with a yield of 70%.

¹H NMR (CDCl₃, 300 MHz) δ 8.23 (s, 1H), 7.29-7.14 (m, 9H), 4.62 (t, J = 7.5 Hz, 1H), 3.92 (s, 3H), 3.71 (s, 2H), 3.60-3.54 (m, 2H), 3.38 (t, J = 4.9 Hz, 2H), 3.00 (d, J = 7.5 Hz, 2H), 2.42-2.27 (m, 4H).
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.23 (s, 1H), 7.29-7.14 (m, 9H), 4.62 (t, J = 7.5 Hz, 1H), 3.92 (s, 3H), 3.71 (s, 2H), 3.60-3.54 (m, 2H), 3.38 (t, J = 4.9 Hz, 2H), 3.00 (d, J = 7.5 Hz, 2H), 2.42-2.27 (m, 4H).

실시예 5. 메틸 2-((4-(3-(4-메톡시페닐)-3-페닐프로판노일)피페라진-1-일)메틸)옥사졸-4-카복실레이트 (화합물번호 5) Example 5. Methyl 2-((4- (3- (4-methoxyphenyl) -3-phenylpropanenoyl) piperazin-1-yl) methyl) oxazole-4-carboxylate (Compound No. 5)

상기 대표합성예 4와 같은 방법으로 수행하여 81%의 수율로 목적화합물을 얻었다. The target compound was obtained in the same manner as in the Synthesis Example 4, with a yield of 81%.

¹H NMR (CDCl₃, 300 MHz) δ 8.23 (s, 1H), 7.28-7.12 (m, 7H), 6.80 (dd, J ₁ = 6.9 Hz, J ₂ = 1.9 Hz, 2H), 4.58 (t, J = 7.5 Hz, 1H), 3.92 (s, 3H), 3.76 (s, 3H), 3.69 (s, 2H), 3.65-3.50 (m, 2H), 3.35 (t, J = 4.8 Hz, 2H), 3.00 (d, J = 7.5 Hz, 2H), 2.41-2.20 (m, 4H).
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.23 (s, 1H), 7.28-7.12 (m, 7H), 6.80 (dd, J ₁ = 6.9 Hz, J ₂ = 1.9 Hz, 2H), 4.58 (t, J = 7.5 Hz, 1H), 3.92 (s, 3H), 3.76 (s, 3H), 3.69 (s, 2H), 3.65-3.50 (m, 2H), 3.35 (t, J = 4.8 Hz, 2H), 3.00 (d, J = 7.5 Hz, 2H), 2.41-2.20 (m, 4H).

실시예 6. 메틸 2-((4-(3,3-비스(4-플루오로페닐)프로판노일)피페라진-1-일)메틸)옥사졸-4-카복실레이트 (화합물번호 6) Example 6.Methyl 2-((4- (3,3-bis (4-fluorophenyl) propanenoyl) piperazin-1-yl) methyl) oxazole-4-carboxylate (Compound No. 6)

상기 대표합성예 4와 같은 방법으로 수행하여 91%의 수율로 목적화합물을 얻었다. The target compound was obtained in the same manner as in Synthesis Example 4, with a yield of 91%.

¹H NMR (CDCl₃, 300 MHz) δ 7.59 (d, J = 8.1 Hz, 1H), 7.34-7.15 (m, 9H), 6.95 (t, J = 8.7 Hz, 2H), 4.64 (t, J = 7.5 Hz, 1H), 3.81 (s, 2H), 3.66-3.58 (m, 2H), 3.43-3.40 (m, 2H), 3.02 (d, J = 7.4 Hz, 2H), 2.53-2.06 (m, 7H).
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.59 (d, J = 8.1 Hz, 1H), 7.34-7.15 (m, 9H), 6.95 (t, J = 8.7 Hz, 2H), 4.64 (t, J = 7.5 Hz, 1H), 3.81 (s, 2H), 3.66-3.58 (m, 2H), 3.43-3.40 (m, 2H), 3.02 (d, J = 7.4 Hz, 2H), 2.53-2.06 (m, 7H ).

실시예 7. 메틸 2-((4-(3-(4-브로모페닐)-3-(4-플루오로페닐)프로판노일)피페라진-1-일)메틸)옥사졸-4-카복실레이트 (화합물번호 7) Example 7. Methyl 2-((4- (3- (4-bromophenyl) -3- (4-fluorophenyl) propanenoyl) piperazin-1-yl) methyl) oxazole-4-carboxylate (Compound No. 7)

상기 대표합성예 4와 같은 방법으로 수행하여 90%의 수율로 목적화합물을 얻었다. The target compound was obtained in the same manner as in Synthesis Example 4, by a yield of 90%.

¹H NMR (CDCl₃, 400 MHz) δ 7.58 (d, J = 8.1 Hz, 1H), 7.38-7.09 (m, 11H), 4.61 (t, J = 7.5 Hz, 1H), 3.79 (s, 2H), 3.64-3.58 (m, 2H), 3.42-3.39 (m, 2H), 3.00 (d, J = 7.5 Hz, 2H), 2.51-2.31 (m, 7H).
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.58 (d, J = 8.1 Hz, 1H), 7.38-7.09 (m, 11H), 4.61 (t, J = 7.5 Hz, 1H), 3.79 (s, 2H) , 3.64-3.58 (m, 2H), 3.42-3.39 (m, 2H), 3.00 (d, J = 7.5 Hz, 2H), 2.51-2.31 (m, 7H).

실시예 8. 메틸 2-((4-(3-(4-플루오로페닐)-3-(4-(트리플루오로메틸)페닐)프로판노일)피페라진-1-일)메틸)옥사졸-4-카복실레이트 (화합물번호 8) Example 8. Methyl 2-((4- (3- (4-fluorophenyl) -3- (4- (trifluoromethyl) phenyl) propanenoyl) piperazin-1-yl) methyl) oxazole- 4-carboxylate (Compound No. 8)

상기 대표합성예 4와 같은 방법으로 수행하여 72%의 수율로 목적화합물을 얻었다. The target compound was obtained in the same manner as in the Synthesis Example 4, with a yield of 72%.

¹H NMR (CDCl₃, 400 MHz) δ 7.59-7.51 (m, 3H), 7.36-7.17 (m, 9H), 4.72 (t, J = 7.4 Hz, 1H), 3.80 (s, 2H), 3.66-3.59 (m, 2H), 3.46-3.43 (m, 2H), 3.05 (d, J = 7.4 Hz, 2H), 2.49-2.35 (m, 7H).
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.59-7.51 (m, 3H), 7.36-7.17 (m, 9H), 4.72 (t, J = 7.4 Hz, 1H), 3.80 (s, 2H), 3.66- 3.59 (m, 2H), 3.46-3.43 (m, 2H), 3.05 (d, J = 7.4 Hz, 2H), 2.49-2.35 (m, 7H).

실시예 9. 메틸 2-((4-(3-(4-클로로페닐)-3-(4-플루오로페닐)프로판노일)피페라진-1-일)메틸)옥사졸-4-카복실레이트 (화합물번호 9) Example 9.Methyl 2-((4- (3- (4-chlorophenyl) -3- (4-fluorophenyl) propanenoyl) piperazin-1-yl) methyl) oxazole-4-carboxylate ( Compound number 9)

상기 대표합성예 4와 같은 방법으로 수행하여 84%의 수율로 목적화합물을 얻었다. The target compound was obtained in the same manner as in Synthesis Example 4, with a yield of 84%.

¹H NMR (CDCl₃, 300 MHz) δ 7.58 (d, J = 8.1 Hz, 1H), 7.33-7.12 (m, 11H), 4.62 (t, J = 7.5 Hz, 1H), 3.80 (s, 2H), 3.66-3.57 (m, 2H), 3.42-3.39 (m, 2H), 3.00 (d, J = 7.5 Hz, 2H), 2.52-2.32 (m, 7H).
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.58 (d, J = 8.1 Hz, 1H), 7.33-7.12 (m, 11H), 4.62 (t, J = 7.5 Hz, 1H), 3.80 (s, 2H) , 3.66-3.57 (m, 2H), 3.42-3.39 (m, 2H), 3.00 (d, J = 7.5 Hz, 2H), 2.52-2.32 (m, 7H).

실시예 10. 메틸 2-((4-(3-(4-플루오로페닐)-3-(4-메톡시페닐)플루오로페닐)프로판노일)피페라진-1-일)메틸)옥사졸-4-카복실레이트 (화합물번호 10) Example 10. Methyl 2-((4- (3- (4-fluorophenyl) -3- (4-methoxyphenyl) fluorophenyl) propanenoyl) piperazin-1-yl) methyl) oxazole- 4-carboxylate (Compound No. 10)

상기 대표합성예 4와 같은 방법으로 수행하여 89%의 수율로 목적화합물을 얻었다. The target compound was obtained in the same manner as in Synthesis Example 4, by a yield of 89%.

¹H NMR (CDCl₃, 300 MHz) δ 7.58 (d, J = 8.1 Hz, 1H), 7.33-7.10 (m, 9H), 6.80 (d, J = 8.6 Hz, 2H), 4.59 (t, J = 7.5 Hz, 1H), 3.78 (s, 2H), 3.76 (s, 3H), 3.66-3.57 (m, 2H), 3.41-3.37 (m, 2H), 3.00 (d, J = 7.5 Hz, 2H), 2.51-2.28 (m, 7H).
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.58 (d, J = 8.1 Hz, 1H), 7.33-7.10 (m, 9H), 6.80 (d, J = 8.6 Hz, 2H), 4.59 (t, J = 7.5 Hz, 1H), 3.78 (s, 2H), 3.76 (s, 3H), 3.66-3.57 (m, 2H), 3.41-3.37 (m, 2H), 3.00 (d, J = 7.5 Hz, 2H), 2.51-2.28 (m, 7 H).

실시예 11. 메틸 2-((4-(3-(3-플루오로페닐)-3-(4-플루오로페닐)프로판노일)피페라진-1-일)메틸)옥사졸-4-카복실레이트 (화합물번호 11) Example 11.Methyl 2-((4- (3- (3-fluorophenyl) -3- (4-fluorophenyl) propanenoyl) piperazin-1-yl) methyl) oxazole-4-carboxylate (Compound No. 11)

상기 대표합성예 4와 같은 방법으로 수행하여 74%의 수율로 목적화합물을 얻었다. The target compound was obtained in the same manner as in the Synthesis Example 4, with a yield of 74%.

¹H NMR (CDCl₃, 300 MHz) δ 8.24 (s, 1H), 7.18-7.12 (m, 4H), 6.99-6.90 (m, 4H), 4.62 (t, J = 7.5 Hz, 1H), 3.91 (s, 3H), 3.73 (s, 2H), 3.59-3.57 (m, 2H), 3.41-3.38 (m, 2H), 2.98 (d, J = 7.5 Hz, 2H), 2.44-2.33 (m, 4H).
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.24 (s, 1H), 7.18-7.12 (m, 4H), 6.99-6.90 (m, 4H), 4.62 (t, J = 7.5 Hz, 1H), 3.91 ( s, 3H), 3.73 (s, 2H), 3.59-3.57 (m, 2H), 3.41-3.38 (m, 2H), 2.98 (d, J = 7.5 Hz, 2H), 2.44-2.33 (m, 4H) .

실시예 12. 메틸 2-((4-(3-(4-브로모페닐)-3-(3-플루오로페닐)프로판노일)피페라진-1-일)메틸)옥사졸-4-카복실레이트 (화합물번호 12) Example 12. Methyl 2-((4- (3- (4-bromophenyl) -3- (3-fluorophenyl) propanenoyl) piperazin-1-yl) methyl) oxazole-4-carboxylate (Compound No. 12)

상기 대표합성예 4와 같은 방법으로 수행하여 71%의 수율로 목적화합물을 얻었다. The title compound was obtained in the same manner as in the Synthesis Example 4, with a yield of 71%.

¹H NMR (CDCl₃, 300 MHz) δ 8.21 (s, 1H), 7.37-7.34 (m, 2H), 7.14-7.03 (m, 4H), 6.95-6.89 (m, 2H), 4.57 (t, J = 7.4 Hz, 1H), 3.89 (s, 3H), 3.70 (s, 2H), 3.56-3.53 (m, 2H), 3.38-3.35 (m, 2H), 2.94 (d, J = 7.5 Hz, 2H), 2.42-2.31 (m, 4H).
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.21 (s, 1H), 7.37-7.34 (m, 2H), 7.14-7.03 (m, 4H), 6.95-6.89 (m, 2H), 4.57 (t, J = 7.4 Hz, 1H), 3.89 (s, 3H), 3.70 (s, 2H), 3.56-3.53 (m, 2H), 3.38-3.35 (m, 2H), 2.94 (d, J = 7.5 Hz, 2H) , 2.42-2.31 (m, 4H).

실시예 13. 메틸 2-((4-(3-(3-플루오로페닐)-3-(4-(트리플루오로메틸)페닐)프로판노일)피페라진-1-일)메틸)옥사졸-4-카복실레이트 (화합물번호 13) Example 13. Methyl 2-((4- (3- (3-fluorophenyl) -3- (4- (trifluoromethyl) phenyl) propanenoyl) piperazin-1-yl) methyl) oxazole- 4-carboxylate (Compound No. 13)

상기 대표합성예 4와 같은 방법으로 수행하여 86%의 수율로 목적화합물을 얻었다. The target compound was obtained in the yield of 86% by the same method as in Synthesis Example 4.

¹H NMR (CDCl₃, 300 MHz) δ 8.22 (s, 1H), 7.53 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 8.2 Hz, 2H), 7.18-7.13 (m, 2H), 7.00-6.94 (m, 2H), 4.71 (t, J = 7.5 Hz, 1H), 3.92 (s, 3H), 3.73 (s, 2H), 3.59-3.56 (m, 2H), 3.43-3.40 (m, 2H), 3.01 (d, J = 7.4 Hz, 2H), 2.45-2.36 (m, 4H).
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.22 (s, 1H), 7.53 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 8.2 Hz, 2H), 7.18-7.13 (m, 2H) , 7.00-6.94 (m, 2H), 4.71 (t, J = 7.5 Hz, 1H), 3.92 (s, 3H), 3.73 (s, 2H), 3.59-3.56 (m, 2H), 3.43-3.40 (m , 2H), 3.01 (d, J = 7.4 Hz, 2H), 2.45-2.36 (m, 4H).

실시예 14. 메틸 2-((4-(3-(4-클로로페닐)-3-(3-플루오로페닐)프로판노일)피페라진-1-일)메틸)옥사졸-4-카복실레이트 (화합물번호 14) Example 14. Methyl 2-((4- (3- (4-chlorophenyl) -3- (3-fluorophenyl) propanenoyl) piperazin-1-yl) methyl) oxazole-4-carboxylate ( Compound number 14)

¹H NMR (CDCl₃, 300 MHz) δ 8.24 (s, 1H), 7.25-7.12 (m, 6H), 6.98-6.92 (m, 2H), 4.62 (t, J = 7.4 Hz, 1H), 3.91 (s, 3H), 3.73 (s, 2H), 3.58 (bs, 2H), 3.41-3.38 (m, 2H), 2.98 (d, J = 7.5 Hz, 2H), 2.45-2.36 (m, 4H).
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.24 (s, 1H), 7.25-7.12 (m, 6H), 6.98-6.92 (m, 2H), 4.62 (t, J = 7.4 Hz, 1H), 3.91 ( s, 3H), 3.73 (s, 2H), 3.58 (bs, 2H), 3.41-3.38 (m, 2H), 2.98 (d, J = 7.5 Hz, 2H), 2.45-2.36 (m, 4H).

실시예 15. 메틸 2-((4-(3-(3-플루오로페닐)-3-(4-메톡시페닐)프로판노일)피페라진-1-일)메틸)옥사졸-4-카복실레이트 (화합물번호 15) Example 15. Methyl 2-((4- (3- (3-fluorophenyl) -3- (4-methoxyphenyl) propanenoyl) piperazin-1-yl) methyl) oxazole-4-carboxylate (Compound No. 15)

¹H NMR (CDCl₃, 300 MHz) δ 8.24 (s, 1H), 7.30-7.09 (m, 4H), 6.96-6.79 (m, 4H), 4.57 (t, J = 7.5 Hz, 1H), 3.91 (s, 3H), 3.75 (s, 3H), 3.71 (s, 2H), 3.57 (bs, 2H), 3.39-3.36 (m, 2H), 2.93 (d, J = 7.5 Hz, 2H), 2.43-2.32 (m, 4H).
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.24 (s, 1H), 7.30-7.09 (m, 4H), 6.96-6.79 (m, 4H), 4.57 (t, J = 7.5 Hz, 1H), 3.91 ( s, 3H), 3.75 (s, 3H), 3.71 (s, 2H), 3.57 (bs, 2H), 3.39-3.36 (m, 2H), 2.93 (d, J = 7.5 Hz, 2H), 2.43-2.32 (m, 4 H).

실시예 16. 3-(4-플루오로페닐)-1-(4-((6-메틸벤조[d]옥사졸-2-일)메틸)피페라진-1-일)-3-페닐프로판-1-온 (화합물번호 16) Example 16. 3- (4-Fluorophenyl) -1- (4-((6-methylbenzo [ d ] oxazol-2-yl) methyl) piperazin-1-yl) -3-phenylpropane- 1-one (Compound No. 16)

¹H NMR (CDCl₃, 400 MHz) δ 7.57 (d, J = 8.1 Hz, 1H), 7.32 (s, 1H), 7.16-7.12 (m, 5H), 6.97-6.91 (m, 4H), 4.62 (t, J = 7.5 Hz, 1H), 3.81 (s, 2H), 3.62-3.60 (m, 2H), 3.43-3.41 (m, 2H), 2.97 (d, J = 7.5 Hz, 2H), 2.52-2.41 (m, 7H).
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.57 (d, J = 8.1 Hz, 1H), 7.32 (s, 1H), 7.16-7.12 (m, 5H), 6.97-6.91 (m, 4H), 4.62 ( t, J = 7.5 Hz, 1H), 3.81 (s, 2H), 3.62-3.60 (m, 2H), 3.43-3.41 (m, 2H), 2.97 (d, J = 7.5 Hz, 2H), 2.52-2.41 (m, 7 H).

실시예 17. 3-(4-브로모페닐)-1-(4-((6-메틸벤조[d]옥사졸-2-일)메틸)피페라진-1-일)-3-페닐프로판-1-온 (화합물번호 17) Example 17. 3- (4-Bromophenyl) -1- (4-((6-methylbenzo [ d ] oxazol-2-yl) methyl) piperazin-1-yl) -3-phenylpropane- 1-one (Compound No. 17)

상기 대표합성예 4와 같은 방법으로 수행하여 61%의 수율로 목적화합물을 얻었다. The target compound was obtained in the yield of 61% by the same method as in Synthesis Example 4.

¹H NMR (CDCl₃, 300 MHz) δ 7.57 (d, J = 8.1 Hz, 1H), 7.39-7.32 (m, 3H), 7.16-7.05 (m, 5H), 6.97-6.90 (m, 2H), 4.60 (t, J = 7.4 Hz, 1H), 3.80 (s, 2H), 3.63-3.59 (m, 2H), 3.44-3.41 (m, 2H), 2.96 (d, J = 7.4 Hz, 2H), 2.52-2.41 (m, 7H).
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.57 (d, J = 8.1 Hz, 1H), 7.39-7.32 (m, 3H), 7.16-7.05 (m, 5H), 6.97-6.90 (m, 2H), 4.60 (t, J = 7.4 Hz, 1H), 3.80 (s, 2H), 3.63-3.59 (m, 2H), 3.44-3.41 (m, 2H), 2.96 (d, J = 7.4 Hz, 2H), 2.52 -2.41 (m, 7 H).

실시예 18. 1-(4-((6-메틸벤조[d]옥사졸-2-일)메틸)피페라진-1-일)-3-페닐-3-(4-(트리플루오로메틸)페닐)프로판-1-온 (화합물번호 18) Example 18. 1- (4-((6-methylbenzo [ d ] oxazol-2-yl) methyl) piperazin-1-yl) -3-phenyl-3- (4- (trifluoromethyl) Phenyl) propan-1-one (Compound No. 18)

상기 대표합성예 4와 같은 방법으로 수행하여 87%의 수율로 목적화합물을 얻었다. The target compound was obtained in the same manner as in the Synthesis Example 4, with a yield of 87%.

¹H NMR (CDCl₃, 400 MHz) δ 7.58-7.51 (m, 3H), 7.32-7.30 (m, 3H), 7.17-7.13 (m, 3H), 6.98-6.93 (m, 2H), 4.71 (t, J = 7.4 Hz, 1H), 3.80 (s, 2H), 3.63-3.61 (m, 2H), 3.47-3.44 (m, 2H), 3.01 (d, J = 7.4 Hz, 2H), 2.53-2.04 (m, 7H).
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.58-7.51 (m, 3H), 7.32-7.30 (m, 3H), 7.17-7.13 (m, 3H), 6.98-6.93 (m, 2H), 4.71 (t , J = 7.4 Hz, 1H), 3.80 (s, 2H), 3.63-3.61 (m, 2H), 3.47-3.44 (m, 2H), 3.01 (d, J = 7.4 Hz, 2H), 2.53-2.04 ( m, 7H).

실시예 19. 3-(4-클로로페닐)-1-(4-((6-메틸벤조[d]옥사졸-2-일)메틸)피페라진-1-일)-3-페닐프로판-1-온 (화합물번호 19) Example 19. 3- (4-Chlorophenyl) -1- (4-((6-methylbenzo [ d ] oxazol-2-yl) methyl) piperazin-1-yl) -3-phenylpropane-1 -On (Compound No. 19)

상기 대표합성예 4와 같은 방법으로 수행하여 77%의 수율로 목적화합물을 얻었다. The target compound was obtained in the same manner as in the Synthesis Example 4, with a yield of 77%.

¹H NMR (CDCl₃, 400 MHz) δ 7.57 (d, J = 8.1 Hz, 1H), 7.32-7.11 (m, 8H), 6.94 (t, J = 8.6 Hz, 2H), 4.61 (t, J = 7.5 Hz, 1H), 3.81 (s, 2H), 3.62-3.60 (m, 2H), 3.44-3.41 (m, 2H), 2.97 (d, J = 7.5 Hz, 2H), 2.52-2.42 (m, 7H).
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.57 (d, J = 8.1 Hz, 1H), 7.32-7.11 (m, 8H), 6.94 (t, J = 8.6 Hz, 2H), 4.61 (t, J = 7.5 Hz, 1H), 3.81 (s, 2H), 3.62-3.60 (m, 2H), 3.44-3.41 (m, 2H), 2.97 (d, J = 7.5 Hz, 2H), 2.52-2.42 (m, 7H ).

실시예 20. 3-(4-메톡시페닐)-1-(4-((6-메틸벤조[d]옥사졸-2-일)메틸)-피페라진-1-일)-3-페닐프로판-1-온 (화합물번호 20)Example 20. 3- (4-methoxyphenyl) -1- (4-((6-methylbenzo [ d ] oxazol-2-yl) methyl) -piperazin-1-yl) -3-phenylpropane -1-one (Compound No. 20)

상기 대표합성예 4와 같은 방법으로 수행하여 89 % 수율로 목적화합물을 얻었다. The target compound was obtained in the same manner as in Synthesis Example 4, by 89% yield.

¹H NMR (CDCl₃, 300 MHz) δ 7.58 (d, J = 8.1 Hz, 1H), 7.33-7.10 (m, 9H), 6.80 (d, J = 8.6 Hz, 2H), 4.50 (t, J = 7.5 Hz, 1H), 3.78 (s, 2H), 3.76 (s, 3H), 3.66-3.57 (m, 2H), 3.41-3.37 (m, 2H), 3.00 (d, J = 7.5 Hz, 2H), 2.51-2.28 (m, 7H).
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.58 (d, J = 8.1 Hz, 1H), 7.33-7.10 (m, 9H), 6.80 (d, J = 8.6 Hz, 2H), 4.50 (t, J = 7.5 Hz, 1H), 3.78 (s, 2H), 3.76 (s, 3H), 3.66-3.57 (m, 2H), 3.41-3.37 (m, 2H), 3.00 (d, J = 7.5 Hz, 2H), 2.51-2.28 (m, 7 H).

실시예 21. 3,3-비스(4-플로로페닐)-1-(4-(6-메틸벤조[d]옥사졸-2-일)메틸)피페라진-1-일)프로판-1-온 (화합물번호 21)Example 21. 3,3-bis (4-fluorophenyl) -1- (4- (6-methylbenzo [ d ] oxazol-2-yl) methyl) piperazin-1-yl) propane-1- On (Compound No. 21)

상기 대표합성예 4와 같은 방법으로 수행하여 71 %의 수율로 목적화합물을 얻었다. The target compound was obtained in the yield of 71% by the same method as in Synthesis Example 4.

¹H NMR (CDCl₃, 300 MHz) δ 7.57 (d, J = 8.1 Hz, 1H), 7.32 (s, 1H), 7.16-7.12 (m, 5H), 6.97-6.91 (m, 4H), 4.62 (t, J = 7.5 Hz, 1H), 3.81 (s, 2H), 3.62-3.60 (m, 2H), 3.43-3.41 (m, 2H), 2.97 (d, J = 7.5 Hz, 2H), 2.52-2.41 (m, 7H).
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.57 (d, J = 8.1 Hz, 1H), 7.32 (s, 1H), 7.16-7.12 (m, 5H), 6.97-6.91 (m, 4H), 4.62 ( t, J = 7.5 Hz, 1H), 3.81 (s, 2H), 3.62-3.60 (m, 2H), 3.43-3.41 (m, 2H), 2.97 (d, J = 7.5 Hz, 2H), 2.52-2.41 (m, 7 H).

실시예 22. 3-(4-브로모페닐)-3-(4-플루오로페닐)-1-(4-((6-메틸벤조[d]옥사졸-2-일)메틸)피페라진-1-일)프로판-1-온 (화합물번호 22) Example 22. 3- (4-Bromophenyl) -3- (4-fluorophenyl) -1- (4-((6-methylbenzo [ d ] oxazol-2-yl) methyl) piperazine- 1-yl) propan-1-one (Compound No. 22)

상기 대표합성예 4와 같은 방법으로 수행하여 62%의 수율로 목적화합물을 얻었다. The title compound was obtained in the same manner as in the Synthesis Example 4, with a yield of 62%.

¹H NMR (CDCl₃, 300 MHz) δ 8.21 (s, 1H), 7.40-7.35 (m, 2H), 7.24-7.17 (m, 1H), 7.06 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 7.8 Hz, 1H), 6.88-6.83 (m, 2H), 4.60 (t, J = 7.4 Hz, 1H), 3.89 (s, 3H), 3.71 (s, 2H), 3.65-3.49 (m, 2H), 3.40-3.37 (m, 2H), 2.95 (d, J = 7.5 Hz, 2H), 2.43-2.33 (m, 4H).
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.21 (s, 1H), 7.40-7.35 (m, 2H), 7.24-7.17 (m, 1H), 7.06 (d, J = 8.4 Hz, 2H), 6.95 ( d, J = 7.8 Hz, 1H), 6.88-6.83 (m, 2H), 4.60 (t, J = 7.4 Hz, 1H), 3.89 (s, 3H), 3.71 (s, 2H), 3.65-3.49 (m , 2H), 3.40-3.37 (m, 2H), 2.95 (d, J = 7.5 Hz, 2H), 2.43-2.33 (m, 4H).

실시예 23. 3-(4-플루오로페닐)-1-(4-((6-메틸벤조[d]옥사졸-2-일)메틸)피페라진-1-일)-3-(4-(트리플루오로메틸)페닐)프로판-1-온 (화합물번호 23) Example 23. 3- (4-fluorophenyl) -1- (4-((6-methylbenzo [ d ] oxazol-2-yl) methyl) piperazin-1-yl) -3- (4- (Trifluoromethyl) phenyl) propan-1-one (Compound No. 23)

상기 대표합성예 4와 같은 방법으로 수행하여 78%의 수율로 목적화합물을 얻었다. The target compound was obtained in the same manner as in the Synthesis Example 4, with a yield of 78%.

¹H NMR (CDCl₃, 300 MHz) δ 8.23 (s, 1H), 7.53 (d, J = 8.2 Hz, 2H), 7.33 (d, J = 8.2 Hz, 2H), 7.27-7.20 (m, 1H), 6.98 (d, J = 7.8 Hz, 1H), 6.91-6.86 (m, 2H), 4.73 (t, J = 7.4 Hz, 1H), 3.91 (s, 3H), 3.72 (s, 2H), 3.60-3.56 (m, 2H), 3.44-3.41 (m, 2H), 3.02 (d, J = 7.4 Hz, 2H), 2.45-2.37 (m, 4H).
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.23 (s, 1H), 7.53 (d, J = 8.2 Hz, 2H), 7.33 (d, J = 8.2 Hz, 2H), 7.27-7.20 (m, 1H) , 6.98 (d, J = 7.8 Hz, 1H), 6.91-6.86 (m, 2H), 4.73 (t, J = 7.4 Hz, 1H), 3.91 (s, 3H), 3.72 (s, 2H), 3.60- 3.56 (m, 2H), 3.44-3.41 (m, 2H), 3.02 (d, J = 7.4 Hz, 2H), 2.45-2.37 (m, 4H).

실시예 24. 3-(4-클로로페닐)-3-(4-플루오로페닐)-1-(4-((6-메틸벤조[d]옥사졸-2-일)메틸)피페라진-1-일)프로판-1-온 (화합물번호 24) Example 24. 3- (4-Chlorophenyl) -3- (4-fluorophenyl) -1- (4-((6-methylbenzo [ d ] oxazol-2-yl) methyl) piperazin-1 -Yl) propan-1-one (Compound No. 24)

¹H NMR (CDCl₃, 300 MHz) δ 8.24 (s, 1H), 7.27-7.13 (m, 5H), 6.98 (d, J = 7.8 Hz, 1H), 6.91-6.87 (m, 2H), 4.64 (t, J = 7.4 Hz, 1H), 3.92 (s, 3H), 3.74 (s, 2H), 3.61-3.56 (m, 2H), 3.43-3.40 (m, 2H), 2.99 (d, J = 7.4 Hz, 2H), 2.46-2.36 (m, 4H).
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.24 (s, 1H), 7.27-7.13 (m, 5H), 6.98 (d, J = 7.8 Hz, 1H), 6.91-6.87 (m, 2H), 4.64 ( t, J = 7.4 Hz, 1H), 3.92 (s, 3H), 3.74 (s, 2H), 3.61-3.56 (m, 2H), 3.43-3.40 (m, 2H), 2.99 (d, J = 7.4 Hz , 2H), 2.46-2.36 (m, 4H).

실시예 25. 3-(4-플루오로페닐)-3-(4-메톡시페닐)-1-(4-((6-메틸벤조[d]옥사졸-2-일)메틸)피페라진-1-일)프로판-1-온 (화합물번호 25) Example 25. 3- (4-Fluorophenyl) -3- (4-methoxyphenyl) -1- (4-((6-methylbenzo [ d ] oxazol-2-yl) methyl) piperazine- 1-yl) propan-1-one (Compound No. 25)

상기 대표합성예 4와 같은 방법으로 수행하여 55% 수율로 목적화합물을 얻었다. The target compound was obtained in the same manner as in Synthesis Example 4, by 55% yield.

¹H NMR (CDCl₃, 300 MHz) δ 7.57 (d, J = 8.1 Hz, 1H), 7.32 (s, 1H), 7.18-7.08 (m, 5H), 6.96-6.90 (m, 2H), 6.81-6.79 (m, 2H), 4.57 (t, J = 7.5 Hz, 1H), 3.79 (s, 2H), 3.76 (s, 3H), 3.63-3.59 (m, 2H), 3.42-3.39 (m, 2H), 2.97 (d, J = 7.5 Hz, 2H), 2.51-2.38 (m, 7H).
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.57 (d, J = 8.1 Hz, 1H), 7.32 (s, 1H), 7.18-7.08 (m, 5H), 6.96-6.90 (m, 2H), 6.81- 6.79 (m, 2H), 4.57 (t, J = 7.5 Hz, 1H), 3.79 (s, 2H), 3.76 (s, 3H), 3.63-3.59 (m, 2H), 3.42-3.39 (m, 2H) , 2.97 (d, J = 7.5 Hz, 2H), 2.51-2.38 (m, 7H).

실시예 26. 3-(3-플루오로페닐)-3-(4-플루오로페닐)-1-(4-((6-메틸벤조[d]옥사졸-2-일)메틸)피페라진-1-일)프로판-1-온 (화합물번호 26) Example 26. 3- (3-fluorophenyl) -3- (4-fluorophenyl) -1- (4-((6-methylbenzo [ d ] oxazol-2-yl) methyl) piperazine- 1-yl) propan-1-one (Compound No. 26)

상기 대표합성예 4와 같은 방법으로 수행하여 73%의 수율로 목적화합물을 얻었다. The target compound was obtained in the yield of 73% by the same method as in Synthesis Example 4.

¹H NMR (CDCl₃, 400 MHz) δ 7.57 (d, J = 8.1 Hz, 1H), 7.32 (s. 1H), 7.21-7.13 (m, 4H), 6.98-6.81 (m, 5H), 4.63 (t, J = 7.5 Hz, 1H), 3.81 (s, 2H), 3.66-3.57 (m, 2H), 3.44-3.42 (m, 2H), 2.97 (m, 2H), 2.52-2.38 (m, 7H).
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.57 (d, J = 8.1 Hz, 1H), 7.32 (s. 1H), 7.21-7.13 (m, 4H), 6.98-6.81 (m, 5H), 4.63 ( t, J = 7.5 Hz, 1H), 3.81 (s, 2H), 3.66-3.57 (m, 2H), 3.44-3.42 (m, 2H), 2.97 (m, 2H), 2.52-2.38 (m, 7H) .

실시예 27. 3-(4-브로모페닐)-3-(3-플루오로페닐)-1-(4-((6-메틸벤조[d]옥사졸-2-일)메틸)피페라진-1-일)프로판-1-온 (화합물번호 27) Example 27. 3- (4-Bromophenyl) -3- (3-fluorophenyl) -1- (4-((6-methylbenzo [ d ] oxazol-2-yl) methyl) piperazine- 1-yl) propan-1-one (Compound No. 27)

¹H NMR (CDCl₃, 400 MHz) δ 7.57 (d, J = 8.1 Hz, 1H), 7.40-7.37 (m, 2H), 7.33 (s. 1H), 7.21-7.14 (m, 2H), 7.09-7.06 (m, 2H), 6.96 (d, J = 7.8 Hz, 1H), 6.88-6.84 (m, 2H), 4.62 (t, J = 7.4 Hz, 1H), 3.82 (s, 2H), 3.65-3.60 (m, 2H), 3.45-3.43 (m, 2H), 2.97 (d, J = 7.4 Hz, 2H), 2.53-2.41 (m, 7H).
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.57 (d, J = 8.1 Hz, 1H), 7.40-7.37 (m, 2H), 7.33 (s. 1H), 7.21-7.14 (m, 2H), 7.09- 7.06 (m, 2H), 6.96 (d, J = 7.8 Hz, 1H), 6.88-6.84 (m, 2H), 4.62 (t, J = 7.4 Hz, 1H), 3.82 (s, 2H), 3.65-3.60 (m, 2H), 3.45-3.43 (m, 2H), 2.97 (d, J = 7.4 Hz, 2H), 2.53-2.41 (m, 7H).

실시예 28. 3-(3-플루오로페닐)-1-(4-((6-메틸벤조[d]옥사졸-2-일)메틸)피페라진-1-일)-3-(4-(트리플루오로메틸)페닐)프로판-1-온 (화합물번호 28) Example 28. 3- (3-fluorophenyl) -1- (4-((6-methylbenzo [ d ] oxazol-2-yl) methyl) piperazin-1-yl) -3- (4- (Trifluoromethyl) phenyl) propan-1-one (compound number 28)

¹H NMR (CDCl₃, 400 MHz) δ 7.58-7.52 (m, 3H), 7.33-7.31 (m, 3H), 7.25-7.14 (m, 2H), 6.99-6.83 (m, 3H), 4.73 (t, J = 7.4 Hz, 1H), 3.82 (s, 2H), 3.67-3.57 (m, 2H), 3.48-3.46 (m, 2H), 3.02 (d, J = 7.4 Hz, 2H), 2.54-2.45 (m, 7H).
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.58-7.52 (m, 3H), 7.33-7.31 (m, 3H), 7.25-7.14 (m, 2H), 6.99-6.83 (m, 3H), 4.73 (t , J = 7.4 Hz, 1H), 3.82 (s, 2H), 3.67-3.57 (m, 2H), 3.48-3.46 (m, 2H), 3.02 (d, J = 7.4 Hz, 2H), 2.54-2.45 ( m, 7H).

실시예 29. 3-(4-클로로페닐)-3-(3-플루오로페닐)-1-(4-((6-메틸벤조[d]옥사졸-2-일)메틸)피페라진-1-일)프로판-1-온 (화합물번호 29) Example 29. 3- (4-Chlorophenyl) -3- (3-fluorophenyl) -1- (4-((6-methylbenzo [ d ] oxazol-2-yl) methyl) piperazin-1 -Yl) propan-1-one (Compound No. 29)

상기 대표합성예 4와 같은 방법으로 수행하여 68%의 수율로 목적화합물을 얻었다. The target compound was obtained in the yield of 68% by the same method as in Synthesis Example 4.

¹H NMR (CDCl₃, 300 MHz) δ 7.57 (d, J = 8.1 Hz, 1H), 7.33 (s. 1H), 7.28-7.11 (m, 6H), 6.98-6.80 (m, 3H), 4.63 (t, J = 7.4 Hz, 1H), 3.81 (s, 2H), 3.69-3.55 (m, 2H), 3.45-3.42 (m, 2H), 2.98 (d, J = 7.4 Hz, 2H), 2.53-2.38 (m, 7H).
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.57 (d, J = 8.1 Hz, 1H), 7.33 (s. 1H), 7.28-7.11 (m, 6H), 6.98-6.80 (m, 3H), 4.63 ( t, J = 7.4 Hz, 1H), 3.81 (s, 2H), 3.69-3.55 (m, 2H), 3.45-3.42 (m, 2H), 2.98 (d, J = 7.4 Hz, 2H), 2.53-2.38 (m, 7 H).

실시예 30. 3-(3-플루오로페닐)-3-(4-메톡시페닐)-1-(4-((6-메틸벤조[d]옥사졸-2-일)메틸)피페라진-1-일)프로판-1-온 (화합물번호 30) Example 30. 3- (3-fluorophenyl) -3- (4-methoxyphenyl) -1- (4-((6-methylbenzo [ d ] oxazol-2-yl) methyl) piperazine- 1-yl) propan-1-one (Compound No. 30)

상기 대표합성예 4와 같은 방법으로 수행하여 32%의 수율로 목적화합물을 얻었다. The target compound was obtained in the same manner as in the Synthesis Example 4, with a yield of 32%.

¹H NMR (CDCl₃, 400 MHz) δ 7.58 (d, J = 8.1 Hz, 1H), 7.33-6.80 (m, 10H), 4.59 (t, J = 7.4 Hz, 1H), 3.84 (s, 2H), 3.76 (s, 3H), 3.69-3.45 (m, 4H), 3.01-2.95 (m, 2H), 2.54-2.43 (m, 7H).
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.58 (d, J = 8.1 Hz, 1H), 7.33-6.80 (m, 10H), 4.59 (t, J = 7.4 Hz, 1H), 3.84 (s, 2H) , 3.76 (s, 3H), 3.69-3.45 (m, 4H), 3.01-2.95 (m, 2H), 2.54-2.43 (m, 7H).

실시예 31. 2-((4-(3-(4-플루오로페닐)-3-페닐프로판노일)피페라진-1-일)메틸)옥사졸-4-카르복실산 (화합물번호 31) Example 31. 2-((4- (3- (4-fluorophenyl) -3-phenylpropanenoyl) piperazin-1-yl) methyl) oxazole-4-carboxylic acid (Compound No. 31)

메탄올 0.5 mL, 물 0.5 mL 및 테트라하이드로퓨란 1 mL의 혼합용매에, 메틸 2-((4-(3-(4-플루오로페닐)-3-페닐프로판노일)피페라진-1-일)메틸)옥사졸-4-카르복실레이트 (화합물번호 1; 0.089 mmol)과 1N NaOH (0.18 mL, 0.178 mmol)를 넣고 상온에서 교반하여 14 mg (37%)의 목적화합물을 얻었다.To a mixed solvent of 0.5 mL methanol, 0.5 mL water and 1 mL tetrahydrofuran, methyl 2-((4- (3- (4-fluorophenyl) -3-phenylpropanenoyl) piperazin-1-yl) methyl ) Oxazole-4-carboxylate (Compound No. 1; 0.089 mmol) and 1N NaOH (0.18 mL, 0.178 mmol) were added thereto, and stirred at room temperature to obtain 14 mg (37%) of the title compound.

¹H NMR (MeOH-d ₄ , 400 MHz) δ 8.54 (bs, 1H), 7.29-7.15 (m, 7H), 6.99 (t, J = 8.7 Hz, 2H), 4.52 (t, J = 7.5 Hz, 1H), 3.96 (s, 2H), 3.61-3.55 (m, 4H), 3.18-3.07 (m, 2H), 2.65-2.45 (m, 4H).
¹ H NMR (MeOH- d ₄ , 400 MHz) δ 8.54 (bs, 1H), 7.29-7.15 (m, 7H), 6.99 (t, J = 8.7 Hz, 2H), 4.52 (t, J = 7.5 Hz, 1H), 3.96 (s, 2H), 3.61-3.55 (m, 4H), 3.18-3.07 (m, 2H), 2.65-2.45 (m, 4H).

실시예 32. 2-((4-(3-(4-브로모페닐)-3-페닐프로판노일)피페라진-1-일)메틸)옥사졸-4-카르복실산 (화합물번호 32) Example 32. 2-((4- (3- (4-bromophenyl) -3-phenylpropanenoyl) piperazin-1-yl) methyl) oxazole-4-carboxylic acid (Compound No. 32)

상기 대표합성예 4와 같은 방법으로 수행하여 19%의 수율로 목적화합물을 얻었다.The target compound was obtained in the yield of 19% by the same method as in Synthesis Example 4.

¹H NMR (CDCl₃, 300 MHz) δ 8.28 (bs, 1H), 7.40-7.09 (m, 9H), 4.61 (bs, 1H), 3.63-3.41 (m, 6H), 3.01 (d, J = 7.4 Hz, 2H), 2.30-1.90 (m, 4H).
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.28 (bs, 1H), 7.40-7.09 (m, 9H), 4.61 (bs, 1H), 3.63-3.41 (m, 6H), 3.01 (d, J = 7.4 Hz, 2H), 2.30-1.90 (m, 4H).

실시예 33. 2-((4-(3-페닐-3-(4-(트리플루오로메틸)페닐)프로판노일)피페라진-1-일)메틸)옥사졸-4-카르복실산 (화합물번호 33) Example 33. 2-((4- (3-phenyl-3- (4- (trifluoromethyl) phenyl) propanenoyl) piperazin-1-yl) methyl) oxazole-4-carboxylic acid (compound Number 33)

상기 대표합성예 4와 같은 방법으로 수행하여 47%의 수율로 목적화합물을 얻었다.The target compound was obtained in the same manner as in Synthesis Example 4, with a yield of 47%.

¹H NMR (CDCl₃, 400 MHz) δ 7.84 (bs, 1H), 7.48 (d, J = 8.0 Hz, 2H), 7.31-7.14 (m, 7H), 4.64 (bs, 1H), 3.64-3.28 (m, 6H), 2.97 (bs, 2H), 2.20-1.98 (m, 4H).
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.84 (bs, 1H), 7.48 (d, J = 8.0 Hz, 2H), 7.31-7.14 (m, 7H), 4.64 (bs, 1H), 3.64-3.28 ( m, 6H), 2.97 (bs, 2H), 2.20-1.98 (m, 4H).

실시예 34. 2-((4-(3-(4-클로로페닐)-3-페닐프로판노일)피페라진-1-일)메틸)옥사졸-4-카르복실산 (화합물번호 34) Example 34. 2-((4- (3- (4-chlorophenyl) -3-phenylpropanenoyl) piperazin-1-yl) methyl) oxazole-4-carboxylic acid (Compound No. 34)

상기 대표합성예 4와 같은 방법으로 수행하여 53%의 수율로 목적화합물을 얻었다.The target compound was obtained in the same manner as in the Synthesis Example 4, with a yield of 53%.

¹H NMR (CDCl₃, 300 MHz) δ 8.00 (bs, 1H), 7.22-7.12 (m, 9H), 4.58 (bs, 1H), 3.66-2.96 (m, 8H), 2.30-2.27 (m, 4H).
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.00 (bs, 1H), 7.22-7.12 (m, 9H), 4.58 (bs, 1H), 3.66-2.96 (m, 8H), 2.30-2.27 (m, 4H ).

실시예 35. 2-((4-(3-(4-메톡시페닐)-3-페닐프로판노일)피페라진-1-일)메틸)옥사졸-4-카르복실산 (화합물번호 35) Example 35. 2-((4- (3- (4-methoxyphenyl) -3-phenylpropanenoyl) piperazin-1-yl) methyl) oxazole-4-carboxylic acid (Compound No. 35)

상기 대표합성예 4와 같은 방법으로 수행하여 15%의 수율로 목적화합물을 얻었다.The target compound was obtained in the yield of 15% by the same method as in Synthesis Example 4.

¹H NMR (MeOH-d ₄ , 400 MHz) δ 8.15 (bs, 1H), 7.27-7.15 (m, 7H), 6.83 (d, J = 8.7 Hz, 2H), 4.44 (t, J = 7.6 Hz, 1H), 3.75 (s, 3H), 3.65-3.35 (m, 6H), 3.10-3.07 (m, 2H), 2.38-2.16 (m, 4H).
¹ H NMR (MeOH- d ₄ , 400 MHz) δ 8.15 (bs, 1H), 7.27-7.15 (m, 7H), 6.83 (d, J = 8.7 Hz, 2H), 4.44 (t, J = 7.6 Hz, 1H), 3.75 (s, 3H), 3.65-3.35 (m, 6H), 3.10-3.07 (m, 2H), 2.38-2.16 (m, 4H).

실시예 36. 2-((4-(3,3-비스(4-플루오로페닐)프로판노일)피페라진-1-일)메틸)옥사졸-4-카르복실산 (화합물번호 36) Example 36. 2-((4- (3,3-bis (4-fluorophenyl) propanenoyl) piperazin-1-yl) methyl) oxazole-4-carboxylic acid (Compound No. 36)

상기 대표합성예 4와 같은 방법으로 수행하여 5%의 수율로 목적화합물을 얻었다.The target compound was obtained in the same manner as in the Synthesis Example 4, with a yield of 5%.

¹H NMR (MeOH-d ₄ , 400 MHz) δ 8.47 (s, 1H), 7.28-7.24 (m, 4H), 7.01-6.96 (m, 4H), 4.52 (t, J = 7.7 Hz, 1H), 3.82 (s, 2H), 3.55-3.53 (m, 4H), 3.11 (d, J = 7.7 Hz, 2H), 2.50-2.41 (m, 4H).
¹ H NMR (MeOH- d ₄ , 400 MHz) δ 8.47 (s, 1H), 7.28-7.24 (m, 4H), 7.01-6.96 (m, 4H), 4.52 (t, J = 7.7 Hz, 1H), 3.82 (s, 2H), 3.55-3.53 (m, 4H), 3.11 (d, J = 7.7 Hz, 2H), 2.50-2.41 (m, 4H).

실시예 37. 2-((4-(3-(4-브로모페닐)-3-(4-플루오로페닐)프로판노일)피페라진-1-일)메틸)옥사졸-4-카르복실산 (화합물번호 37) Example 37. 2-((4- (3- (4-bromophenyl) -3- (4-fluorophenyl) propanenoyl) piperazin-1-yl) methyl) oxazole-4-carboxylic acid (Compound No. 37)

상기 대표합성예 4와 같은 방법으로 수행하여 91%의 수율로 목적화합물을 얻었다.The target compound was obtained in the same manner as in Synthesis Example 4, with a yield of 91%.

¹H NMR (MeOH-d ₄ , 400 MHz) δ 8.47 (s, 1H), 7.41-7.39 (m, 2H), 7.27-7.17 (m, 4H), 7.01-6.96 (m, 2H), 4.50 (t, J = 7.7 Hz, 1H), 3.85 (s, 2H), 3.56-3.53 (m, 4H), 3.11 (d, J = 7.7 Hz, 2H), 2.52-2.46 (m, 4H).
¹ H NMR (MeOH- d ₄ , 400 MHz) δ 8.47 (s, 1H), 7.41-7.39 (m, 2H), 7.27-7.17 (m, 4H), 7.01-6.96 (m, 2H), 4.50 (t , J = 7.7 Hz, 1H), 3.85 (s, 2H), 3.56-3.53 (m, 4H), 3.11 (d, J = 7.7 Hz, 2H), 2.52-2.46 (m, 4H).

실시예 38. 2-((4-(3-(4-플루오로페닐)-3-(4-(트리플루오로메틸)페닐)프로판노일)피페라진-1-일)메틸)옥사졸-4-카르복실산 (화합물번호 38) Example 38. 2-((4- (3- (4-fluorophenyl) -3- (4- (trifluoromethyl) phenyl) propanenoyl) piperazin-1-yl) methyl) oxazole-4 -Carboxylic acid (compound number 38)

상기 대표합성예 4와 같은 방법으로 수행하여 64%의 수율로 목적화합물을 얻었다.The target compound was obtained in the same manner as in the Synthesis Example 4, with a yield of 64%.

¹H NMR (MeOH-d ₄ , 300 MHz) δ 8.47 (s, 1H), 7.59-7.45 (m, 4H), 7.31-7.27 (m, 2H), 7.04-6.98 (m, 2H), 4.63 (t, J = 7.7 Hz, 1H), 3.74 (s, 2H), 3.54-3.52 (m, 4H), 3.17 (d, J = 7.7 Hz, 2H), 2.43-2.37 (m, 4H).
¹ H NMR (MeOH- d ₄ , 300 MHz) δ 8.47 (s, 1H), 7.59-7.45 (m, 4H), 7.31-7.27 (m, 2H), 7.04-6.98 (m, 2H), 4.63 (t , J = 7.7 Hz, 1H), 3.74 (s, 2H), 3.54-3.52 (m, 4H), 3.17 (d, J = 7.7 Hz, 2H), 2.43-2.37 (m, 4H).

실시예 39. 2-((4-(3-(4-클로로페닐)-3-(4-플루오로페닐)프로판노일)피페라진-1-일)메틸)옥사졸-4-카르복실산 (화합물번호 39) Example 39. 2-((4- (3- (4-chlorophenyl) -3- (4-fluorophenyl) propanenoyl) piperazin-1-yl) methyl) oxazole-4-carboxylic acid ( Compound number 39)

상기 대표합성예 4와 같은 방법으로 수행하여 69%의 수율로 목적화합물을 얻었다.The target compound was obtained in the yield of 69% by the same method as in Synthesis Example 4.

¹H NMR (MeOH-d ₄ , 400 MHz) δ 8.48 (s, 1H), 7.28-7.22 (m, 6H), 7.01-6.97 (m, 2H), 4.51 (t, J = 7.7 Hz, 1H), 3.77 (s, 2H), 3.56-3.47 (m, 4H), 3.11 (d, J = 7.7 Hz, 2H), 2.47-2.38 (m, 4H).
¹ H NMR (MeOH- d ₄ , 400 MHz) δ 8.48 (s, 1H), 7.28-7.22 (m, 6H), 7.01-6.97 (m, 2H), 4.51 (t, J = 7.7 Hz, 1H), 3.77 (s, 2H), 3.56-3.47 (m, 4H), 3.11 (d, J = 7.7 Hz, 2H), 2.47-2.38 (m, 4H).

실시예 40. 2-((4-(3-(4-플루오로페닐)-3-(4-메톡시페닐)프로판노일)피페라진-1-일)메틸)옥사졸-4-카르복실산 (화합물번호 40) Example 40. 2-((4- (3- (4-fluorophenyl) -3- (4-methoxyphenyl) propanenoyl) piperazin-1-yl) methyl) oxazole-4-carboxylic acid (Compound No. 40)

상기 대표합성예 4와 같은 방법으로 수행하여 68%의 수율로 목적화합물을 얻었다.The target compound was obtained in the yield of 68% by the same method as in Synthesis Example 4.

¹H NMR (MeOH-d ₄ , 400 MHz) δ 8.47 (s, 1H), 7.26-7.22 (m, 2H), 7.14 (d, J = 8.7 Hz, 2H), 6.97 (t, J = 8.8 Hz, 2H), 6.82-6.80 (m, 2H), 4.44 (t, J = 7.7 Hz, 1H), 3.75 (s, 2H), 3.74 (s, 3H), 3.53-3.46 (m, 4H), 3.06 (d, J = 7.7 Hz, 2H), 2.44-2.25 (m, 4H).
¹ H NMR (MeOH- d ₄ , 400 MHz) δ 8.47 (s, 1H), 7.26-7.22 (m, 2H), 7.14 (d, J = 8.7 Hz, 2H), 6.97 (t, J = 8.8 Hz, 2H), 6.82-6.80 (m, 2H), 4.44 (t, J = 7.7 Hz, 1H), 3.75 (s, 2H), 3.74 (s, 3H), 3.53-3.46 (m, 4H), 3.06 (d , J = 7.7 Hz, 2H), 2.44-2.25 (m, 4H).

실시예 41. 3-(3-플루오로페닐)-3-(4-플루오로페닐)-1-(4-((4-(하이드록시메틸)옥사졸-2-일)메틸)피페라진-1-일)프로판-1-온 (화합물번호 41) Example 41. 3- (3-fluorophenyl) -3- (4-fluorophenyl) -1- (4-((4- (hydroxymethyl) oxazol-2-yl) methyl) piperazine- 1-yl) propan-1-one (Compound No. 41)

정제된 테트라하이드로퓨란 3 mL에, 메틸 2-(4-(3-(3-플루오로페닐)-3-(4-플로로페닐)프로판노일)-피페라진-1-일)메틸)옥사졸-4-카르복실레이트 (화합물번호 11; 0.134 mmol)을 녹이고 0 ℃에서 LiBH₄(0.536 mmol)를 천천히 가한 뒤, 상온에서 5시간동안 교반하였다. 반응 완료 후 산으로 처리하여 39%의 수율로 목적화합물을 얻었다. To 3 mL of purified tetrahydrofuran, methyl 2- (4- (3- (3-fluorophenyl) -3- (4-fluorophenyl) propanenoyl) -piperazin-1-yl) methyl) oxazole 4-carboxylate (Compound No. 11; 0.134 mmol) was dissolved, LiBH ₄ (0.536 mmol) was slowly added at 0 ° C., and the resultant was stirred at room temperature for 5 hours. After completion of the reaction was treated with acid to obtain the target compound in 39% yield.

¹H NMR (CDCl₃, 300 MHz) δ 7.57 (s, 1H), 7.27-7.13 (m, 3H), 6.99-6.85 (m, 5H), 4.66-4.59 (m, 3H), 3.65 (s, 2H), 3.60-3.57 (m, 2H), 3.42-3.39 (m, 2H), 2.98 (d, J = 7.5 Hz, 2H), 2.44-2.32 (m, 4H).
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.57 (s, 1H), 7.27-7.13 (m, 3H), 6.99-6.85 (m, 5H), 4.66-4.59 (m, 3H), 3.65 (s, 2H ), 3.60-3.57 (m, 2H), 3.42-3.39 (m, 2H), 2.98 (d, J = 7.5 Hz, 2H), 2.44-2.32 (m, 4H).

실시예 42. 3-(4-브로모페닐)-3-(3-플루오로페닐)-1-(4-((4-(하이드록시메틸)옥사졸-2-일)메틸)피페라진-1-일)프로판-1-온 (화합물번호 42) Example 42. 3- (4-Bromophenyl) -3- (3-fluorophenyl) -1- (4-((4- (hydroxymethyl) oxazol-2-yl) methyl) piperazine- 1-yl) propan-1-one (Compound No. 42)

상기 대표합성예 4와 같은 방법으로 수행하여 29%의 수율로 목적화합물을 얻었다.The target compound was obtained in the same manner as in the Synthesis Example 4, with a yield of 29%.

¹H NMR (CDCl₃, 300 MHz) δ 7.57 (s, 1H), 7.40 (d, J = 8.4 Hz, 2H), 7.27-7.20 (m, 2H), 7.08 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 7.8 Hz, 1H), 6.92-6.86 (m, 2H), 4.65-4.60 (m, 3H), 3.65 (s, 2H), 3.61-3.58 (m, 2H), 3.43-3.40 (m, 2H), 2.98 (d, J = 7.5 Hz, 2H), 2.45-2.34 (m, 4H).
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.57 (s, 1H), 7.40 (d, J = 8.4 Hz, 2H), 7.27-7.20 (m, 2H), 7.08 (d, J = 8.4 Hz, 2H) , 6.97 (d, J = 7.8 Hz, 1H), 6.92-6.86 (m, 2H), 4.65-4.60 (m, 3H), 3.65 (s, 2H), 3.61-3.58 (m, 2H), 3.43-3.40 (m, 2H), 2.98 (d, J = 7.5 Hz, 2H), 2.45-2.34 (m, 4H).

실시예 43. 3-(3-플루오로페닐)-1-(4-((4-(하이드록시메틸)옥사졸-2-일)메틸)피페라진-1-일)-3-(4-(트리플루오로메틸)페닐)프로판-1-온 (화합물번호 43) Example 43. 3- (3-fluorophenyl) -1- (4-((4- (hydroxymethyl) oxazol-2-yl) methyl) piperazin-1-yl) -3- (4- (Trifluoromethyl) phenyl) propan-1-one (Compound No. 43)

상기 대표합성예 4와 같은 방법으로 수행하여 31%의 수율로 목적화합물을 얻었다.The target compound was obtained in the same manner as in the Synthesis Example 4, with a yield of 31%.

¹H NMR (CDCl₃, 300 MHz) δ 7.57-7.53 (m, 3H), 7.34-7.21 (m, 3H), 6.98 (d, J = 7.8 Hz, 1H), 6.93-6.87 (m, 2H), 4.73 (t, J = 7.4 Hz, 1H), 4.59 (s, 2H), 3.65 (s, 2H), 3.61-3.58 (m, 2H), 3.46-3.42 (m, 2H), 3.02 (d, J = 7.4 Hz, 2H), 2.45-2.35 (m, 4H).
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.57-7.53 (m, 3H), 7.34-7.21 (m, 3H), 6.98 (d, J = 7.8 Hz, 1H), 6.93-6.87 (m, 2H), 4.73 (t, J = 7.4 Hz, 1H), 4.59 (s, 2H), 3.65 (s, 2H), 3.61-3.58 (m, 2H), 3.46-3.42 (m, 2H), 3.02 (d, J = 7.4 Hz, 2H), 2.45-2.35 (m, 4H).

실시예 44. 3-(4-클로로페닐)-3-(3-플루오로페닐)-1-(4-((4-(하이드록시메틸)옥사졸-2-일)메틸)피페라진-1-일)프로판-1-온 (화합물번호 44) Example 44. 3- (4-Chlorophenyl) -3- (3-fluorophenyl) -1- (4-((4- (hydroxymethyl) oxazol-2-yl) methyl) piperazin-1 -Yl) propan-1-one (Compound No. 44)

상기 대표합성예 4와 같은 방법으로 수행하여 44%의 수율로 목적화합물을 얻었다.The target compound was obtained in the same manner as in the Synthesis Example 4, with a yield of 44%.

¹H NMR (CDCl₃, 300 MHz) δ 7.57 (s, 1H), 7.27-7.12 (m, 5H), 6.97 (d, J = 7.8 Hz, 1H), 6.89-6.85 (m, 2H), 4.65-4.58 (m, 3H), 3.66 (s, 2H), 3.60-3.56 (m, 2H), 3.44-3.40 (m, 2H), 2.97 (d, J = 7.5 Hz, 2H), 2.45-2.34 (m, 4H).
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.57 (s, 1H), 7.27-7.12 (m, 5H), 6.97 (d, J = 7.8 Hz, 1H), 6.89-6.85 (m, 2H), 4.65- 4.58 (m, 3H), 3.66 (s, 2H), 3.60-3.56 (m, 2H), 3.44-3.40 (m, 2H), 2.97 (d, J = 7.5 Hz, 2H), 2.45-2.34 (m, 4H).

실시예 45. 3-(3-플루오로페닐)-1-(4-((4-(하이드록시메틸)옥사졸-2-일)메틸)피페라진-1-일)-3-(4-메톡시페닐)프로판-1-온 (화합물번호 45) Example 45. 3- (3-fluorophenyl) -1- (4-((4- (hydroxymethyl) oxazol-2-yl) methyl) piperazin-1-yl) -3- (4- Methoxyphenyl) propan-1-one (Compound No. 45)

상기 대표합성예 4와 같은 방법으로 수행하여 20%의 수율로 목적화합물을 얻었다.The target compound was obtained in the same manner as in Synthesis Example 4, with a yield of 20%.

¹H NMR (CDCl₃, 300 MHz) δ 7.58 (s, 1H), 7.26-7.09 (m, 3H), 6.99 (d, J = 7.7 Hz, 1H), 6.91-6.80 (m, 4H), 4.61-4.56 (m, 3H), 3.76 (s, 3H), 3.66 (s, 2H), 3.62-3.58 (m, 2H), 3.42-3.38 (m, 2H), 2.97 (d, J = 7.5 Hz, 2H), 2.46-2.32 (m, 4H).
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.58 (s, 1H), 7.26-7.09 (m, 3H), 6.99 (d, J = 7.7 Hz, 1H), 6.91-6.80 (m, 4H), 4.61- 4.56 (m, 3H), 3.76 (s, 3H), 3.66 (s, 2H), 3.62-3.58 (m, 2H), 3.42-3.38 (m, 2H), 2.97 (d, J = 7.5 Hz, 2H) , 2.46-2.32 (m, 4 H).

실시예 46. 3-(3-플루오로페닐)-3-(4-플루오로페닐)-1-(4-((4-(모폴린-4-카보닐)옥사졸-2-일)메틸)피페라진-1-일)프로판-1-온 (화합물번호 46)Example 46. 3- (3-fluorophenyl) -3- (4-fluorophenyl) -1- (4-((4- (morpholin-4-carbonyl) oxazol-2-yl) methyl Piperazin-1-yl) propan-1-one (Compound No. 46)

메탄올: 물: 테트라하이드로퓨란 (1:1:2)의 혼합용매 2 mL에 메틸 2-((4-(3-(3-플루오로페닐)-3-(4-플루오로페닐)프로판노일)피페라진-1-일)메틸)옥사졸-4-카복실레이트 (화합물번호 11; 0.042 mmol)을 녹인 후, 1N-NaOH를 서서히 가한 후 2시간 교반하였다. 1N HCl로 pH 3 내지 5로 맞춘 후 에틸 아세테이트로 추출하여 감압 증류 후 농축하여 카르복실산 화합물을 얻었다. 카르복실산 화합물 (0.036 mmol)을 2 mL 다이클로로메탄에 녹이고 1-하이드록시벤조트리아졸 (HOBT; 0.144 mmol)를 넣고 5분간 교반 후, 1-에틸-3-(3'-다이메틸아미노프로필)카보다이이미드 (EDCI; 0.144 mmol)를 넣고 2시간 교반하고 모폴린 (0.144 mmol)를 가한 후 3시간 교반하여 58%의 수율로 목적화합물을 얻었다.Methanol: Water: Methyl 2-((4- (3- (3-fluorophenyl) -3- (4-fluorophenyl) propanenoyl) in 2 mL of a mixed solvent of tetrahydrofuran (1: 1: 2) Piperazin-1-yl) methyl) oxazole-4-carboxylate (Compound No. 11; 0.042 mmol) was dissolved, and then slowly added 1N-NaOH, followed by stirring for 2 hours. The mixture was adjusted to pH 3 to 5 with 1N HCl, extracted with ethyl acetate, distilled under reduced pressure, and concentrated to obtain a carboxylic acid compound. The carboxylic acid compound (0.036 mmol) was dissolved in 2 mL dichloromethane, 1-hydroxybenzotriazole (HOBT; 0.144 mmol) was added thereto, stirred for 5 minutes, and then 1-ethyl-3- (3'-dimethylaminopropyl). ) Carbodiimide (EDCI; 0.144 mmol) was added thereto, stirred for 2 hours, morpholine (0.144 mmol) was added thereto, and stirred for 3 hours to obtain a target compound in a yield of 58%.

¹H NMR (CDCl₃, 300 MHz) δ 8.16 (s, 1H), 7.27-7.13 (m, 3H), 6.99-6.85 (m, 5H), 4.64 (t, J = 7.4 Hz, 1H), 4.15-4.08 (m, 2H), 3.74-3.56 (m, 10H), 3.41-3.38 (m, 2H), 2.98 (d, J = 7.4 Hz, 2H), 2.44-2.30 (m, 4H).
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.16 (s, 1H), 7.27-7.13 (m, 3H), 6.99-6.85 (m, 5H), 4.64 (t, J = 7.4 Hz, 1H), 4.15- 4.08 (m, 2H), 3.74-3.56 (m, 10H), 3.41-3.38 (m, 2H), 2.98 (d, J = 7.4 Hz, 2H), 2.44-2.30 (m, 4H).

실시예 47. 3-(4-브로모페닐)-3-(3-플루오로페닐)-1-(4-((4-(모폴린-4-카보닐)옥사졸-2-일)메틸)피페라진-1-일)프로판-1-온 (화합물번호 47)Example 47. 3- (4-Bromophenyl) -3- (3-fluorophenyl) -1- (4-((4- (morpholin-4-carbonyl) oxazol-2-yl) methyl Piperazin-1-yl) propan-1-one (Compound No. 47)

상기 대표합성예 4와 같은 방법으로 수행하여 57%의 수율로 목적화합물을 얻었다.The target compound was obtained in the yield of 57% by the same method as in Synthesis Example 4.

¹H NMR (CDCl₃, 300 MHz) δ 8.16 (s, 1H), 7.40 (d, J = 8.3 Hz, 2H), 7.25-7.20 (m, 1H), 7.08 (d, J = 8.3 Hz, 2H), 6.97 (d, J = 7.8 Hz, 1H), 6.91-6.86 (m, 2H), 4.62 (t, J = 7.4 Hz, 1H), 4.20-4.00 (m, 2H), 3.85-3.70 (m, 6H), 3.67 (s, 2H), 3.59-3.58 (m, 2H), 3.42-3.39 (m, 2H), 2.98 (d, J = 7.4 Hz, 2H), 2.45-2.31 (m, 4H).
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.16 (s, 1H), 7.40 (d, J = 8.3 Hz, 2H), 7.25-7.20 (m, 1H), 7.08 (d, J = 8.3 Hz, 2H) , 6.97 (d, J = 7.8 Hz, 1H), 6.91-6.86 (m, 2H), 4.62 (t, J = 7.4 Hz, 1H), 4.20-4.00 (m, 2H), 3.85-3.70 (m, 6H ), 3.67 (s, 2H), 3.59-3.58 (m, 2H), 3.42-3.39 (m, 2H), 2.98 (d, J = 7.4 Hz, 2H), 2.45-2.31 (m, 4H).

실시예 48. 3-(3-플루오로페닐)-1-(4-((4-(모폴린-4-카보닐)옥사졸-2-일)메틸)피페라진-1-일)-3-(4-(트리플루오로메틸)페닐)프로판-1-온 (화합물번호 48)Example 48. 3- (3-fluorophenyl) -1- (4-((4- (morpholin-4-carbonyl) oxazol-2-yl) methyl) piperazin-1-yl) -3 -(4- (trifluoromethyl) phenyl) propan-1-one (Compound No. 48)

상기 대표합성예 4와 같은 방법으로 수행하여 51%의 수율로 목적화합물을 얻었다.The target compound was obtained in the yield of 51% by the same method as in Synthesis Example 4.

¹H NMR (CDCl₃, 300 MHz) δ 8.16 (s, 1H), 7.55 (d, J = 8.1 Hz, 2H), 7.34-7.22 (m, 3H), 6.99 (d, J = 7.6 Hz, 1H), 6.93-6.87 (m, 2H), 4.74 (t, J = 7.4 Hz, 1H), 4.17-4.02 (m, 2H), 3.80-3.68 (m, 6H), 3.67 (s, 2H), 3.61-3.58 (m, 2H), 3.45-3.42 (m, 2H), 3.03 (d, J = 7.4 Hz, 2H), 2.45-2.28 (m, 4H).
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.16 (s, 1H), 7.55 (d, J = 8.1 Hz, 2H), 7.34-7.22 (m, 3H), 6.99 (d, J = 7.6 Hz, 1H) , 6.93-6.87 (m, 2H), 4.74 (t, J = 7.4 Hz, 1H), 4.17-4.02 (m, 2H), 3.80-3.68 (m, 6H), 3.67 (s, 2H), 3.61-3.58 (m, 2H), 3.45-3.42 (m, 2H), 3.03 (d, J = 7.4 Hz, 2H), 2.45-2.28 (m, 4H).

실시예 49. 3-(4-클로로페닐)-3-(3-플루오로페닐)-1-(4-((4-(모폴린-4-카보닐)옥사졸-2-일)메틸)피페라진-1-일)프로판-1-온 (화합물번호 49)Example 49. 3- (4-Chlorophenyl) -3- (3-fluorophenyl) -1- (4-((4- (morpholin-4-carbonyl) oxazol-2-yl) methyl) Piperazin-1-yl) propan-1-one (Compound No. 49)

상기 대표합성예 4와 같은 방법으로 수행하여 43%의 수율로 목적화합물을 얻었다.The target compound was obtained in the same manner as in Synthesis Example 4, with a yield of 43%.

¹H NMR (CDCl₃, 300 MHz) δ 8.16 (s, 1H), 7.26-7.12 (m, 5H), 6.97 (d, J = 7.7 Hz, 1H), 6.91-6.85 (m, 2H), 4.63 (t, J = 7.4 Hz, 1H), 4.20-3.96 (m, 2H), 3.80-3.70 (m, 6H), 3.67 (s, 2H), 3.61-3.56 (m, 2H), 3.42-3.39 (m, 2H), 2.98 (d, J = 7.4 Hz, 2H), 2.44-2.31 (m, 4H).
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.16 (s, 1H), 7.26-7.12 (m, 5H), 6.97 (d, J = 7.7 Hz, 1H), 6.91-6.85 (m, 2H), 4.63 ( t, J = 7.4 Hz, 1H), 4.20-3.96 (m, 2H), 3.80-3.70 (m, 6H), 3.67 (s, 2H), 3.61-3.56 (m, 2H), 3.42-3.39 (m, 2H), 2.98 (d, J = 7.4 Hz, 2H), 2.44-2.31 (m, 4H).

실시예 50. 3-(3-플루오로페닐)-3-(4-메톡시페닐)-1-(4-((4-((모폴린-4-카보닐)옥사졸-2-일)메틸)피페라진-1-일)프로판-1-온 (화합물번호 50)Example 50. 3- (3-fluorophenyl) -3- (4-methoxyphenyl) -1- (4-((4-((morpholin-4-carbonyl) oxazol-2-yl) Methyl) piperazin-1-yl) propan-1-one (Compound No. 50)

상기 대표합성예 4와 같은 방법으로 수행하여 58%의 수율로 목적화합물을 얻었다.The target compound was obtained in the yield of 58% by the same method as in Synthesis Example 4.

¹H NMR (CDCl₃, 300 MHz) δ 8.16 (s, 1H), 7.23-7.09 (m, 3H), 6.99 (d, J = 7.7 Hz, 1H), 6.91-6.80 (m, 4H), 4.59 (t, J = 7.4 Hz, 1H), 4.13-4.08 (m, 2H), 3.77 (s, 2H), 3.76-3.70 (m, 6H), 3.66 (s, 3H), 3.61-3.55 (m, 2H), 3.41-3.35 (m, 2H), 2.98 (d, J = 7.4 Hz, 2H), 2.44-2.29 (m, 4H).
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.16 (s, 1H), 7.23-7.09 (m, 3H), 6.99 (d, J = 7.7 Hz, 1H), 6.91-6.80 (m, 4H), 4.59 ( t, J = 7.4 Hz, 1H), 4.13-4.08 (m, 2H), 3.77 (s, 2H), 3.76-3.70 (m, 6H), 3.66 (s, 3H), 3.61-3.55 (m, 2H) , 3.41-3.35 (m, 2H), 2.98 (d, J = 7.4 Hz, 2H), 2.44-2.29 (m, 4H).

실시예 51. N-((1-(3-(4-브로모페닐)-3-페닐프로판노일)피페리딘-4-일)메틸)-3,5-다이클로로벤즈아마이드 (화합물번호 51) Example 51. N - ((1- (3- (4- bromophenyl) -3-phenylpropan-alkanoyl) piperidin-4-yl) methyl) -3,5-dichloro-benzamide (Compound No. 51 )

상기 대표합성예 7과 같은 방법으로 수행하여 47%의 수율로 목적화합물을 얻었다.The target compound was obtained in the yield of 47% by the same method as the representative synthesis example 7.

실시예 52. 3,5-다이클로로-N-((1-(3-페닐-3-(4-(트리플루오로메틸)페닐)프로판노일)피페리딘-4-일)메틸)벤즈아마이드 (화합물번호 52) Example 52. 3,5-Dichloro- N -((1- (3-phenyl-3- (4- (trifluoromethyl) phenyl) propanenoyl) piperidin-4-yl) methyl) benzamide (Compound No. 52)

상기 대표합성예 7과 같은 방법으로 수행하여 44%의 수율로 목적화합물을 얻었다.The target compound was obtained in the yield of 44% by the same method as in Synthesis Example 7.

¹H NMR (CDCl₃, 300 MHz) δ 7.63 (d, J = 1.8 Hz, 2H), 7.53-7.46 (m, 3H), 7.35-7.17 (m, 7H), 6.58 (bs, 1H), 4.71-4.54 (m, 2H), 3.90-3.75 (m, 1H), 3.36-3.27 (m, 1H), 3.17-2.86 (m, 4H), 2.48-2.40 (m, 1H), 1.81-1.72 (m, 1H), 1.69-1.64 (m, 2H), 1.01-0.78 (m, 2H).
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.63 (d, J = 1.8 Hz, 2H), 7.53-7.46 (m, 3H), 7.35-7.17 (m, 7H), 6.58 (bs, 1H), 4.71- 4.54 (m, 2H), 3.90-3.75 (m, 1H), 3.36-3.27 (m, 1H), 3.17-2.86 (m, 4H), 2.48-2.40 (m, 1H), 1.81-1.72 (m, 1H ), 1.69-1.64 (m, 2H), 1.01-0.78 (m, 2H).

실시예 53. N-((1-(3-(4-브로모페닐)-3-(4-플루오로페닐)프로판노일)피페리딘-4-일)메틸)-3,5-다이클로로벤즈아마이드 (화합물번호 53)Example 53. N -((1- (3- (4-Bromophenyl) -3- (4-fluorophenyl) propanenoyl) piperidin-4-yl) methyl) -3,5-dichloro Benzamide (Compound No. 53)

상기 대표합성예 7과 같은 방법으로 수행하여 33%의 수율로 목적화합물을 얻었다.The target compound was obtained in the yield of 33% by the same method as the representative synthesis example 7.

¹H NMR (CDCl₃, 300 MHz) δ 7.63 (d, J = 1.8 Hz, 2H), 7.48 (t, J = 1.8 Hz, 1H), 7.40-7.36 (m, 2H), 7.16-7.04 (m, 4H), 6.98-6.92 (m, 2H), 6.48 (bs, 1H), 4.61-4.54 (m, 2H), 3.85-3.81 (m, 1H), 3.38-3.31 (m, 1H), 3.20-2.87 (m, 4H), 2.50-2.41 (m, 1H), 1.83-1.72 (m, 1H), 1.70-1.66 (m, 2H), 1.01-0.81 (m, 2H). ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.63 (d, J = 1.8 Hz, 2H), 7.48 (t, J = 1.8 Hz, 1H), 7.40-7.36 (m, 2H), 7.16-7.04 (m, 4H), 6.98-6.92 (m, 2H), 6.48 (bs, 1H), 4.61-4.54 (m, 2H), 3.85-3.81 (m, 1H), 3.38-3.31 (m, 1H), 3.20-2.87 ( m, 4H), 2.50-2.41 (m, 1H), 1.83-1.72 (m, 1H), 1.70-1.66 (m, 2H), 1.01-0.81 (m, 2H).

실시예 54. 3,5-다이클로로-N-((1-(3-(4-플루오로페닐)-3-(4-트리플루오로메틸)페닐)프로판노일)피페리딘-4-일)메틸)벤즈아마이드 (화합물번호 54)Example 54. 3,5-Dichloro- N -((1- (3- (4-fluorophenyl) -3- (4-trifluoromethyl) phenyl) propannoyl) piperidin-4-yl Methyl) benzamide (Compound No. 54)

상기 대표합성예 7과 같은 방법으로 수행하여 31%의 수율로 목적화합물을 얻었다.The target compound was obtained in the same manner as in the Synthesis Example 7, with a yield of 31%.

¹H NMR (CDCl₃, 300 MHz) δ 7.62 (d, J = 1.8 Hz, 2H), 7.57-7.50 (m, 2H), 7.47 (t, J = 1.8 Hz, 1H), 7.32-7.30 (m, 2H), 7.17-7.13 (m, 2H), 6.99-6.93 (m, 2H), 6.59 (bs, 1H), 4.69 (t, J = 7.3 Hz, 1H), 4.57-4.53 (m, 1H), 3.90-3.78 (m, 1H), 3.37-3.11 (m, 2H), 3.03 (d, J = 7.3 Hz, 2H), 3.00-2.88 (m, 1H), 2.51-2.42 (m, 1H), 1.90-1.67 (m, 3H), 1.01-0.82 (m, 2H).
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.62 (d, J = 1.8 Hz, 2H), 7.57-7.50 (m, 2H), 7.47 (t, J = 1.8 Hz, 1H), 7.32-7.30 (m, 2H), 7.17-7.13 (m, 2H), 6.99-6.93 (m, 2H), 6.59 (bs, 1H), 4.69 (t, J = 7.3 Hz, 1H), 4.57-4.53 (m, 1H), 3.90 -3.78 (m, 1H), 3.37-3.11 (m, 2H), 3.03 (d, J = 7.3 Hz, 2H), 3.00-2.88 (m, 1H), 2.51-2.42 (m, 1H), 1.90-1.67 (m, 3 H), 1.01-0.82 (m, 2 H).

실시예 55. N-((1-(3-(4-브로모페닐)-3-(3-플루오로페닐)프로판노일)피페리딘-4-일)메틸)-3,5-다이클로로벤즈아마이드 (화합물번호 55)Example 55. N -((1- (3- (4-Bromophenyl) -3- (3-fluorophenyl) propanenoyl) piperidin-4-yl) methyl) -3,5-dichloro Benzamide (Compound No. 55)

상기 대표합성예 7과 같은 방법으로 수행하여 61%의 수율로 목적화합물을 얻었다.The target compound was obtained in the yield of 61% by the same method as the representative synthesis example 7.

¹H NMR (CDCl₃, 300 MHz) δ 7.63 (d, J = 1.8 Hz, 2H), 7.46 (t, J = 1.8 Hz, 1H), 7.40-7.36 (m, 2H), 7.23-7.18 (m, 1H), 7.10-7.04 (m, 2H), 6.98-6.84 (m, 3H), 6.68 (bs, 1H), 4.61-4.52 (m, 2H), 3.85-3.81 (m, 1H), 3.37-3.10 (m, 2H), 3.01-2.85 (m, 3H), 2.49-2.41 (m, 1H), 1.82-1.66 (m, 3H), 1.01-0.82 (m, 2H).
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.63 (d, J = 1.8 Hz, 2H), 7.46 (t, J = 1.8 Hz, 1H), 7.40-7.36 (m, 2H), 7.23-7.18 (m, 1H), 7.10-7.04 (m, 2H), 6.98-6.84 (m, 3H), 6.68 (bs, 1H), 4.61-4.52 (m, 2H), 3.85-3.81 (m, 1H), 3.37-3.10 ( m, 2H), 3.01-2.85 (m, 3H), 2.49-2.41 (m, 1H), 1.82-1.66 (m, 3H), 1.01-0.82 (m, 2H).

실시예 56. 3,5-다이클로로-N-((1-(3-(3-플루오로페닐)-3-(4-(트리플루오로메틸)페닐)프로판노일)피페리딘-4-일)메틸)벤즈아마이드 (화합물번호 56)Example 56. 3,5-Dichloro- N -((1- (3- (3-fluorophenyl) -3- (4- (trifluoromethyl) phenyl) propanenoyl) piperidine-4- I) methyl) benzamide (Compound No. 56)

상기 대표합성예 7과 같은 방법으로 수행하여 41%의 수율로 목적화합물을 얻었다.The target compound was obtained in the same manner as in the Synthesis Example 7, with a yield of 41%.

¹H NMR (CDCl₃, 300 MHz) δ 7.62 (d, J = 1.8 Hz, 2H), 7.54-7.50 (m, 2H), 7.45 (t, J = 1.8 Hz, 1H), 7.33-7.19 (m, 3H), 6.96 (d, J = 7.6 Hz, 1H), 6.90-6.85 (m, 2H), 6.73-6.66 (m, 1H), 4.72-4.52 (m, 2H), 3.87-3.84 (m, 1H), 3.35-2.92 (m, 5H), 2.51-2.43 (m, 1H), 1.84-1.67 (m, 3H), 1.00-0.86 (m, 2H).
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.62 (d, J = 1.8 Hz, 2H), 7.54-7.50 (m, 2H), 7.45 (t, J = 1.8 Hz, 1H), 7.33-7.19 (m, 3H), 6.96 (d, J = 7.6 Hz, 1H), 6.90-6.85 (m, 2H), 6.73-6.66 (m, 1H), 4.72-4.52 (m, 2H), 3.87-3.84 (m, 1H) , 3.35-2.92 (m, 5H), 2.51-2.43 (m, 1H), 1.84-1.67 (m, 3H), 1.00-0.86 (m, 2H).

[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 다이옥사이드 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 fine particles 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. 합성된 화합물을 다음 실험예의 방법으로 FDSS6000를 이용하여 T-형 칼슘채널에 대한 %억제율을 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. The synthesized compound was obtained by using the FDSS6000 as a method of the following experimental example to determine the percent inhibition of the T-type calcium channel.

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

활성 검색 12 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 x 10⁴밀도로 분주해 주었다. 실험 당일 96-웰 플레이트에 부착된 세포들은 96-웰 플레이트 자동세척 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 3 회 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 희석되어 측정되어진다. 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 퍼센티지 (%) 억제효과를 구하였고 항상 10 μM의 미베프라딜을 대조약물로 사용하였다.Stable α1G T-type calcium channel and Kir2.1 using 96-well cell distributor (Titertek) in 96-well plates treated with poly-L-lysine (0.05 mg / ml) 12-24 hours before activity detection The cells of HEK293 cell line (α1G cell line: KCTC 10519BP, Genetic Bank of Korea Research Institute of Bioscience and Biotechnology), which were expressed as, 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 auto washing machine (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 Fluoro-3 / AM and 0.001% Pluronic F-127, it was 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. Since most cell-based HTS instruments have a liquid application system for drug injection but no liquid inhalation system, 27 μL of blocking drug and KCl in 10 mM CaCl ₂ HEPES buffer at 5 times higher concentration are prepared. Diluted by 1/5 in 135 μL, the final volume of the plate, is measured. Specific FDSS6000 measurement conditions were to measure the change in intracellular calcium concentration changed by KCl administration after 75 seconds of drug pretreatment after recording 20 seconds of reference value. It was set at 100% and the percentage (%) inhibitory effect on the inhibitory effect of the test substance was obtained, and 10 μM of mibepradil was always used as a control 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.

시험화합물Test compound FDSS %억제율
(10 μM)FDSS% Inhibition Rate
(10 μM) 시험화합물Test compound FDSS %억제율
(10 μM)FDSS% Inhibition Rate
(10 μM) 화합물번호 1Compound number 1 27.6927.69 화합물번호 31Compound number 31 44.5444.54 화합물번호 2Compound number 2 42.8342.83 화합물번호 32Compound number 32 36.6036.60 화합물번호 3Compound number 3 60.4060.40 화합물번호 33Compound number 33 57.6557.65 화합물번호 4Compound number 4 35.0135.01 화합물번호 34Compound number 34 24.5324.53 화합물번호 5Compound number 5 22.8222.82 화합물번호 35Compound number 35 25.4725.47 화합물번호 6Compound number 6 42.6742.67 화합물번호 36Compound number 36 44.9344.93 화합물번호 8Compound number 8 22.3922.39 화합물번호 38Compound number 38 26.4226.42 화합물번호 9Compound number 9 25.9425.94 화합물번호 39Compound number 39 32.2432.24 화합물번호 10Compound number 10 63.5363.53 화합물번호 40Compound number 40 52.0252.02 화합물번호 11Compound number 11 33.5333.53 화합물번호 42Compound number 42 21.3221.32 화합물번호 12Compound number 12 42.1242.12 화합물번호 46Compound number 46 36.8736.87 화합물번호 13Compound number 13 51.7751.77 화합물번호 47Compound number 47 44.6444.64 화합물번호 14Compound number 14 45.0645.06 화합물번호 48Compound number 48 53.4153.41 화합물번호 15Compound number 15 24.5424.54 화합물번호 49Compound number 49 48.6348.63 화합물번호 16Compound number 16 30.9530.95 미베프라딜Mibepradil 79.2979.29 화합물번호 20Compound number 20 23.2623.26

본 발명의 화학식 1로 표시되는 신규 다이페닐프로판노일 화합물은 T-형 칼슘채널에 길항작용을 갖고 있으므로, 간질, 고혈압 등의 뇌질환, 협심증 등의 심장질환, 만성 통증, 신경성 통증 등의 통증질환, 또는 암과 관련 질병의 예방 또는 치료제로서 유용하게 사용될 수 있다. The novel diphenylpropanenoyl compound represented by Formula 1 of the present invention has an antagonistic action on T-type calcium channels, and thus, brain diseases such as epilepsy and hypertension, heart diseases such as angina pectoris, and pain diseases such as chronic pain and neurological pain. Or as a prophylactic or therapeutic agent for cancer and related diseases.

Claims

Compound which is a diphenyl propane noyl compound or a pharmaceutically acceptable salt thereof represented by the following formula (1):
[Formula 1]

In Chemical Formula 1,
X is N; Or CH,
R ¹ is substituted or unsubstituted with 1 to 3 substituents selected from C ₁ to C ₆ alkyl, C ₁ to C ₆ hydroxyalkyl, hydroxycarbonyl, C ₁ to C ₆ alkoxycarbonyl, and morpholinocarbonyl Ring benzoxazole group; Or a benzamido group having 1 to 3 substituted or unsubstituted halogen atoms,
R ² and R ³ are the same or different from each other as a hydrogen atom, a halogen atom, C ₁ ~ C ₆ alkyl group, C ₁ ~ C ₆ alkoxy group, or C ₁ ~ C ₆ haloalkyl group.

The method according to claim 1,
X is N; Or CH,
R ¹ represents a benzo [ d ] oxazol-2-yl group, a 6-methylbenzo [ d ] oxazol-2-yl group, a benzamido group, or a 3,5-dichlorobenzamido group,
R ² and R ³ are the same as or different from each other, and represent a hydrogen atom, fluoro, chloro, bromo, methyl group, methoxy group, or trifluoromethyl group.

The method according to claim 1,
3- (4-fluorophenyl) -1- (4-((6-methylbenzo [ d ] oxazol-2-yl) methyl) piperazin-1-yl) -3-phenylpropan-1-one;
3- (4-bromophenyl) -1- (4-((6-methylbenzo [ d ] oxazol-2-yl) methyl) piperazin-1-yl) -3-phenylpropan-1-one;
1- (4-((6-methylbenzo [ d ] oxazol-2-yl) methyl) piperazin-1-yl) -3-phenyl-3- (4- (trifluoromethyl) phenyl) propane- 1-on;
3- (4-chlorophenyl) -1- (4-((6-methylbenzo [ d ] oxazol-2-yl) methyl) piperazin-1-yl) -3-phenylpropan-1-one;
3- (4-fluorophenyl) -3- (4-methoxyphenyl) -1- (4-((6-methylbenzo [ d ] oxazol-2-yl) methyl) piperazin-1-yl) Propane-1-one;
3- (4-bromophenyl) -3- (4-fluorophenyl) -1- (4-((6-methylbenzo [ d ] oxazol-2-yl) methyl) piperazin-1-yl) Propane-1-one;
3- (4-fluorophenyl) -1- (4-((6-methylbenzo [ d ] oxazol-2-yl) methyl) piperazin-1-yl) -3- (4- (trifluoro Methyl) phenyl) propan-1-one;
3- (4-chlorophenyl) -3- (4-fluorophenyl) -1- (4-((6-methylbenzo [ d ] oxazol-2-yl) methyl) piperazin-1-yl) propane -1-one;
3- (4-fluorophenyl) -3- (4-methoxyphenyl) -1- (4-((6-methylbenzo [ d ] oxazol-2-yl) methyl) piperazin-1-yl) Propane-1-one;
3- (3-fluorophenyl) -3- (4-fluorophenyl) -1- (4-((6-methylbenzo [ d ] oxazol-2-yl) methyl) piperazin-1-yl) Propane-1-one;
3- (4-bromophenyl) -3- (3-fluorophenyl) -1- (4-((6-methylbenzo [ d ] oxazol-2-yl) methyl) piperazin-1-yl) Propane-1-one;
3- (3-fluorophenyl) -1- (4-((6-methylbenzo [ d ] oxazol-2-yl) methyl) piperazin-1-yl) -3- (4- (trifluoro Methyl) phenyl) propan-1-one;
3- (4-chlorophenyl) -3- (3-fluorophenyl) -1- (4-((6-methylbenzo [ d ] oxazol-2-yl) methyl) piperazin-1-yl) propane -1-one;
3- (3-fluorophenyl) -3- (4-methoxyphenyl) -1- (4-((6-methylbenzo [ d ] oxazol-2-yl) methyl) piperazin-1-yl) Propane-1-one;
N -((1- (3- (4-bromophenyl) -3-phenylpropanenoyl) piperidin-4-yl) methyl) -3,5-dichlorobenzamide;
3,5-dichloro- N -((1- (3-phenyl-3- (4- (trifluoromethyl) phenyl) propannoyl) piperidin-4-yl) methyl) benzamide;
N -((1- (3- (4-bromophenyl) -3- (4-fluorophenyl) propanenoyl) piperidin-4-yl) methyl) -3,5-dichlorobenzamide;
3,5-Dichloro- N -((1- (3- (4-fluorophenyl) -3- (4-trifluoromethyl) phenyl) propanenoyl) piperidin-4-yl) methyl) benz Amide;
N -((1- (3- (4-bromophenyl) -3- (3-fluorophenyl) propanenoyl) piperidin-4-yl) methyl) -3,5-dichlorobenzamide;
3,5-Dichloro- N -((1- (3- (3-fluorophenyl) -3- (4- (trifluoromethyl) phenyl) propanenoyl) piperidin-4-yl) methyl) Benzamide; And
Compound selected from pharmaceutically acceptable salts thereof.

A pharmaceutical for the treatment and prevention of diseases selected from epilepsy, hypertension, angina pectoris, chronic pain, neuropathic pain, and cancer, which contains a diphenylpropanenoyl compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient Composition:
[Formula 1]

In Chemical Formula 1,
X represents N; R ¹ is substituted or unsubstituted with 1 to 3 substituents selected from C ₁ to C ₆ alkyl, C ₁ to C ₆ hydroxyalkyl, hydroxycarbonyl, C ₁ to C ₆ alkoxycarbonyl, and morpholinocarbonyl Ring benzoxazole group; R ² and R ³ are the same or different from each other as a hydrogen atom, a halogen atom, C ₁ ~ C ₆ alkyl group, C ₁ ~ C ₆ alkoxy group, or C ₁ ~ C ₆ haloalkyl group.

A method of preparing a diphenylpropanenoyl compound, comprising: reacting a compound represented by Formula 2 with a compound represented by Formula 3 to produce a diphenylpropanenoyl compound represented by Formula 1 below:

In the above scheme, X, R ¹ , R ² , and R ³ are each as defined in claim 1 above.

Iii) combining the compound represented by the following formula (2) with the compound represented by the following formula (4) to prepare a compound represented by the following formula (5); And

(Wherein X, R ² , and R ³ are each as defined in claim 1, and Y represents a hydrogen atom or an amine protecting group)
Ii) alkylating the compound represented by the following Chemical Formula 5 with the compound represented by the following Chemical Formula 6 to prepare a diphenylpropanenoyl compound represented by the following Chemical Formula 1;

(Wherein X, R ¹ , R ² , and R ³ are each as defined in claim 1 above)
Method for producing a diphenyl propane noyl compound comprising a.