KR20120088398A - Novel five-membered heteroaromatic ring compounds having activity for T-type calcium channel - Google Patents
Novel five-membered heteroaromatic ring compounds having activity for T-type calcium channel Download PDFInfo
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- KR20120088398A KR20120088398A KR1020110009730A KR20110009730A KR20120088398A KR 20120088398 A KR20120088398 A KR 20120088398A KR 1020110009730 A KR1020110009730 A KR 1020110009730A KR 20110009730 A KR20110009730 A KR 20110009730A KR 20120088398 A KR20120088398 A KR 20120088398A
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- KR
- South Korea
- Prior art keywords
- compound
- piperazin
- methyl
- phenyl
- methylamino
- Prior art date
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D273/00—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
본 발명은 T-형 칼슘 채널에 대하여 약학적 활성을 보이는 5각형의 헤테로방향족 화합물 및 이의 약학적으로 허용 가능한 염, 이들 화합물의 제조방법, 그리고 이들 화합물이 유효성분으로 함유된 약제조성물에 관한 것이다.
The present invention relates to a pentagonal heteroaromatic compound and a pharmaceutically acceptable salt thereof, a preparation method of these compounds, and a pharmaceutical composition containing these compounds as an active ingredient. .
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 상기의 문제점을 해결하기 위한 것으로, 하기와 같은 발명의 목적을 갖고 있다.The present invention has been made to solve the above problems and has the object of the following invention.
즉, 본 발명은 신규 구조의 5각형의 헤테로방향족 화합물 및 이의 약학적으로 허용 가능한 염을 제공하는데 그 목적이 있다.That is, an object of the present invention is to provide a pentagonal heteroaromatic compound having a novel structure and a pharmaceutically acceptable salt thereof.
또한, 본 발명은 상기한 5각형의 헤테로방향족 화합물을 제조하는 방법을 제공하는데 다른 목적이 있다.It is another object of the present invention to provide a method for producing the pentagonal heteroaromatic compound described above.
또한, 본 발명은 상기한 5각형의 헤테로방향족 화합물 및 이의 약학적으로 허용 가능한 염이 유효성분으로 포함되어 있는 T-형 칼슘채널 길항작용을 갖는 약제조성물을 제공하는데 또 다른 목적이 있다.It is another object of the present invention to provide a pharmaceutical composition having a T-type calcium channel antagonism in which the pentagonal heteroaromatic compound and a pharmaceutically acceptable salt thereof are included as an active ingredient.
또한, 본 발명은 상기한 5각형의 헤테로방향족 화합물 및 이의 약학적으로 허용 가능한 염이 유효성분으로 포함되어 있는 간질, 고혈압 등의 뇌질환, 협심증 등의 심장질환, 만성 통증, 신경성 통증 등의 통증질환, 및 암 중에서 선택된 T-형 칼슘채널과 관련된 질환의 치료용 약제를 제공하는데 또 다른 목적이 있다.
In addition, the present invention is a pentagonal heteroaromatic compound and a pharmaceutically acceptable salt thereof as an active ingredient, epilepsy, brain diseases such as hypertension, heart diseases such as angina pectoris, chronic pain, neuropathic pain, etc. Another object is to provide a medicament for the treatment of diseases and diseases associated with T-type calcium channels selected from cancer.
상기의 목적을 실현하기 위하여, 본 발명은 T-형 칼슘채널 길항제로서 유효한 하기 화학식 1로 표시되는 5각형의 헤테로방향족 화합물, 이 화합물의 제조방법, 이 화합물을 포함하는 약제조성물을 그 특징으로 한다.In order to realize the above object, the present invention is characterized by a pentagonal heteroaromatic compound represented by the following formula (1) effective as a T-type calcium channel antagonist, a method for preparing the compound, and a pharmaceutical composition comprising the compound. .
[화학식 1][Formula 1]
상기 화학식 1에서,In Chemical Formula 1,
X, Y, 및 Z는 서로 같거나 다른 것으로서 질소원자(N)이거나, 또는 C-R2를 나타내고; E는 -(CH2)qC(O)-, -(CH2)nN(R3)(CH2)mC(O)-, -(CH2)nN(R3)(CH2)m-, 또는 -(CH2)nN(R3)C(O)(CH2)m- 를 나타내고; R1은 (C6-C15 아릴)2메틸기, C5-C15 헤테로아릴메틸기, C6-C15 아릴기, C6-C15 아릴카보닐기, 또는 C6-C15 아릴설포닐기를 나타내고, 이때 상기 아릴은 할로, C1-C6 알킬, 및 C1-C6 할로알킬 중에서 선택된 1 내지 3개의 치환기로 치환 또는 비치환될 수 있고; R2는 수소원자, C1-C6 알킬기, 또는 C6-C15 아릴기를 나타내고; R3은 수소원자, 또는 C1-C6 알킬기를 나타내고; ℓ은 1 또는 2의 정수를 나타내고; q는 1 내지 6의 정수를 나타내고; n, 및 m은 서로 같거나 다른 것으로서 0 내지 6의 정수를 나타낸다.
X, Y, and Z, which are the same as or different from each other, are nitrogen atoms (N) or represent CR 2 ; E is-(CH 2 ) q C (O)-,-(CH 2 ) n N (R 3 ) (CH 2 ) m C (O)-,-(CH 2 ) n N (R 3 ) (CH 2 ) m- , or-(CH 2 ) n N (R 3 ) C (O) (CH 2 ) m- ; R 1 represents a (C 6 -C 15 aryl) 2 methyl group, a C 5 -C 15 heteroarylmethyl group, a C 6 -C 15 aryl group, a C 6 -C 15 arylcarbonyl group, or a C 6 -C 15 arylsulfonyl group Wherein said aryl may be unsubstituted or substituted with 1 to 3 substituents selected from halo, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl; R 2 represents a hydrogen atom, a C 1 -C 6 alkyl group, or a C 6 -C 15 aryl group; R 3 represents a hydrogen atom or a C 1 -C 6 alkyl group; L represents an integer of 1 or 2; q represents an integer from 1 to 6; n and m are the same as or different from each other and represent an integer of 0 to 6;
본 발명에 따른 상기 화학식 1로 표시되는 5각형의 헤테로방향족 화합물은 당해 기술 분야에서 통상적인 방법에 의해 약학적으로 허용 가능한 염을 형성할 수 있다. 예를 들면, 염산, 브롬산, 술폰산, 아미도황산, 인산, 질산과 같은 무독성의 무기산, 또는 아세트산, 프로피온산, 숙신산, 글리콜산, 스테아르산, 젖산, 타르타르산, 시트르산, 파라톨루엔설폰산, 메탄설폰산과 같은 무독성의 유기산과 함께 결합하여 약학적으로 허용 가능한 산부가 염을 형성할 수도 있다.The pentagonal heteroaromatic compound represented by Chemical Formula 1 according to the present invention may form a pharmaceutically acceptable salt by a conventional method in the art. Non-toxic inorganic acids such as hydrochloric acid, bromic acid, sulfonic acid, amido sulfuric acid, phosphoric acid, nitric acid, or acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, tartaric acid, citric acid, paratoluenesulfonic acid, methanesulfone It may also be combined with non-toxic organic acids such as acids to form pharmaceutically acceptable acid addition salts.
본 발명에 따른 상기 화학식 1로 표시되는 5각형의 헤테로방향족 화합물에 있어서의 치환기를 좀 더 자세히 설명하면 다음과 같다. ‘알킬기’는 1 내지 6개의 탄소원자를 가진 직쇄상, 분쇄상 및 고리상의 탄소사슬을 모두 포함하며, 선호하는 알킬기는 메틸, 에틸기, 노말프로필기, 아이소프로필기, 노말부틸기, 아이소부틸기, tert-부틸기, 시클로펜틸기, 시클로헥실기 등이 있다. ‘할로알킬기’는 플루오로, 클로로, 브로모, 아이오도와 같은 할로겐원자가 1 내지 13개 포함되고, 1 내지 6개의 탄소원자를 가진 직쇄상, 분쇄상 및 고리상의 탄소사슬을 모두 포함하며, 선호하는 할로알킬기는 플루오로메틸, 트리플루오로메틸, 1,2-다이클로로에틸기, 1,1-다이클로로에틸기, 펜타플루오로에틸기 등이 있다. '아릴기'는 방향족 고리기를 의미하는 것으로, 아릴은 최소한 6개의 원자를 가진 하나의 고리, 또는 최소한 10개의 원자를 가진 두 개의 고리나 인접 탄소 원자에 이중 결합으로 공명 안정화된 상태를 말하며, 아릴기로는 페닐기, 나프틸기 등이 포함될 수 있다. 상기한 아릴기는 할로, C1-C6 알킬, C1-C6 할로알킬 등 중에서 선택된 치환체가 하나 이상 치환될 수도 있다. '헤테로아릴기'는 포화 또는 불포화이거나 단일고리 또는 결합고리(fused ring)에 관계없이 안정한 5 내지 15개의 원자로 구성된 헤테로고리를 나타내며, N, O, S로 구성된 1 내지 3개의 헤테로원자 및 탄소원자로 구성되며, 이러한 헤테로아릴기의 예를 들면, 피리디닐, 이미다지닐, 피리미디닐, 피리다지닐, 트리아지닐, 이미다졸릴, 트리아졸릴, 퀴놀리닐, 이소퀴놀리닐, 퀴나졸리닐, 퀴녹살리닐, 프탈라지닐, 옥사졸릴, 이소옥사졸릴, 티아졸릴, 이소티아졸릴, 티아디아졸릴, 벤조싸이아졸릴, 옥사디아졸릴, 피롤릴, 퓨라닐, 티오펜닐 등이 포함될 수 있다. 상기한 헤테로아릴기는 할로, C1-C6 알킬, C1-C6 할로알킬 등 중에서 선택된 치환체가 하나 이상 치환될 수도 있다. The substituent in the pentagonal heteroaromatic compound represented by Chemical Formula 1 according to the present invention will be described in more detail as follows. 'Alkyl group' includes all linear, pulverized and cyclic carbon chains having 1 to 6 carbon atoms, and preferred alkyl groups are methyl, ethyl, normal propyl, isopropyl, normal butyl, isobutyl, tert -butyl group, cyclopentyl group, cyclohexyl group, and the like. '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. 'Aryl group' means an aromatic ring group, and aryl refers to a ring having at least six atoms resonancely stabilized by a double bond to two rings or adjacent carbon atoms having at least 10 atoms, and aryl The group may include a phenyl group, naphthyl group and the like. The aryl group may be substituted with one or more substituents selected from halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl and the like. 'Heteroaryl group' refers to a heterocyclic ring composed of 5 to 15 atoms, which may be saturated or unsaturated or stable regardless of monocyclic or fused ring, and is composed of 1 to 3 heteroatoms and carbon atoms composed of N, O and S. Examples of such heteroaryl groups include pyridinyl, imidazinyl, pyrimidinyl, pyridazinyl, triazinyl, imidazolyl, triazolyl, quinolinyl, isoquinolinyl, quinazolinyl, Quinoxalinyl, phthalazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, benzothiazolyl, oxdiazolyl, pyrrolyl, furanyl, thiophenyl and the like. The heteroaryl group may be substituted with one or more substituents selected from halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl and the like.
상기 화학식 1로 표시되는 5각형의 헤테로방향족 화합물에 있어서, 바람직하기로는 상기 X, Y, 및 Z는 서로 같거나 다른 것으로서 질소원자(N)이거나, 또는 C-R2를 나타내고; 상기 E는 -(CH2)qC(O)-, -(CH2)nN(R3)(CH2)mC(O)-, -(CH2)nN(R3)(CH2)m-, 또는 -(CH2)nN(R3)C(O)(CH2)m- 를 나타내고; 상기 R1은 치환 또는 비치환된 벤즈하이드릴기, 벤조[d]싸이아졸-2-일메틸기, 치환 또는 비치환된 페닐기, 치환 또는 비치환된 벤조일기, 또는 치환 또는 비치환된 페닐설포닐기를 나타내고, 이때 치환된 벤즈하이드릴, 페닐, 벤조일, 또는 페닐설포닐기는 각각 할로, C1-C6 알킬, 및 트리플루오로메틸 중에서 선택된 1 내지 3개의 치환기로 치환된 페닐, 벤즈하이드릴, 벤조일, 또는 페닐설포닐기를 나타내고; 상기 R2는 수소원자, C1-C6 알킬기, 또는 페닐기를 나타내고; 상기 R3은 수소원자, 또는 C1-C6 알킬기를 나타내고; 상기 ℓ은 1 또는 2의 정수를 나타내고; 상기 q는 1 내지 6의 정수를 나타내고; 상기 n, 및 m은 서로 같거나 다른 것으로서 0 내지 6의 정수를 나타내는 화합물이 포함될 수 있다.In the pentagonal heteroaromatic compound represented by Chemical Formula 1, preferably X, Y, and Z are the same as or different from each other and represent a nitrogen atom (N), or represent CR 2 ; E is-(CH 2 ) q C (O)-,-(CH 2 ) n N (R 3 ) (CH 2 ) m C (O)-,-(CH 2 ) n N (R 3 ) (CH 2 ) m -or-(CH 2 ) n N (R 3 ) C (O) (CH 2 ) m- ; R 1 is a substituted or unsubstituted benzhydryl group, a benzo [ d ] thiazol-2-ylmethyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted benzoyl group, or a substituted or unsubstituted phenylsulfonyl Wherein the substituted benzhydryl, phenyl, benzoyl, or phenylsulfonyl group is phenyl, benzhydryl, substituted with 1 to 3 substituents each selected from halo, C 1 -C 6 alkyl, and trifluoromethyl, Benzoyl or phenylsulfonyl group; R 2 represents a hydrogen atom, a C 1 -C 6 alkyl group, or a phenyl group; R 3 represents a hydrogen atom or a C 1 -C 6 alkyl group; L represents an integer of 1 or 2; Q represents an integer of 1 to 6; The n and m may be the same or different from each other and may include a compound representing an integer of 0 to 6.
상기 화학식 1로 표시되는 5각형의 헤테로방향족 화합물에 있어서, 보다 바람직하기로는 상기 X, Y, 및 Z는 서로 같거나 다른 것으로서 N, CH, C-메틸기, C-프로필기, C-아이소프로필기, C-아이소부틸기, 또는 C-페닐기를 나타내고; 상기 E는 -(CH2)2C(O)-, -(CH2)3C(O)-, -N(CH3)CH2C(O)-, -CH2NHCH2CH2-, 또는 -CH2NHC(O)CH2- 를 나타내고; 상기 R1은 벤즈하이드릴기, (할로페닐)2CH-, 페닐기, 할로페닐기, 다이할로페닐기, 메틸페닐기, 다이메틸페닐기, 트리플루오로메틸페닐기, 벤조일기, 할로벤조일기, 트리플루오로메틸벤조일기, 또는 벤조[d]싸이아졸-2-일메틸기를 나타내고; ℓ은 1 또는 2의 정수를 나타내는 화합물이 포함될 수 있다.In the pentagonal heteroaromatic compound represented by Formula 1, more preferably, X, Y, and Z are the same as or different from each other, and are N, CH, C-methyl group, C-propyl group, and C-isopropyl group. , C-isobutyl group, or C-phenyl group; E is-(CH 2 ) 2 C (O)-,-(CH 2 ) 3 C (O)-, -N (CH 3 ) CH 2 C (O)-, -CH 2 NHCH 2 CH 2- , Or -CH 2 NHC (O) CH 2- ; R 1 is benzhydryl group, (halophenyl) 2 CH-, phenyl group, halophenyl group, dihalophenyl group, methylphenyl group, dimethylphenyl group, trifluoromethylphenyl group, benzoyl group, halobenzoyl group, trifluoro Methylbenzoyl group or benzo [ d ] thiazol-2-ylmethyl group; L may include a compound representing an integer of 1 or 2.
특히 바람직한 상기 화학식 1로 표시되는 5각형의 헤테로방향족 화합물을 예시하면 다음과 같다:Particularly preferred exemplified pentagonal heteroaromatic compounds represented by Formula 1 are as follows:
3-(3-페닐아이소옥사졸-5-일)-1-(4-페닐피페라진-1-일)프로판-1-온 (화합물번호 1);3- (3-phenylisoxazol-5-yl) -1- (4-phenylpiperazin-1-yl) propan-1-one (Compound No. 1);
3-(3-페닐-1,2,4-옥사다이아졸-5-일)-1-(4-페닐피페라진-1-일)프로판-1-온 (화합물번호 2);3- (3-phenyl-1,2,4-oxadiazol-5-yl) -1- (4-phenylpiperazin-1-yl) propan-1-one (Compound No. 2);
4-(3-페닐아이소옥사졸-5-일)-1-(4-페닐피페라진-1일)부탄-1-온 (화합물번호 3);4- (3-phenylisoxazol-5-yl) -1- (4-phenylpiperazin-1yl) butan-1-one (Compound No. 3);
4-(3-페닐-1,2,4-옥사다이아졸-5-일)-1-(4-페닐피페라진-1-일)부탄-1-온 (화합물번호 4);4- (3-phenyl-1,2,4-oxadiazol-5-yl) -1- (4-phenylpiperazin-1-yl) butan-1-one (Compound No. 4);
1-(4-(3-클로로페닐)피페라진-1-일)-4-(3-페닐-1,2,4-옥사다이아졸-5-일)부탄-1-온 (화합물번호 5);1- (4- (3-chlorophenyl) piperazin-1-yl) -4- (3-phenyl-1,2,4-oxadiazol-5-yl) butan-1-one (Compound No. 5) ;
1-(4-(3-클로로페닐)피페라진-1일)-4-(3-페닐아이소옥사졸-5-일)부탄-1-온 (화합물번호 6);1- (4- (3-chlorophenyl) piperazin-1yl) -4- (3-phenylisoxazol-5-yl) butan-1-one (Compound No. 6);
1-(4-(3-클로로페닐)피페라진-1-일)-3-(3-페닐아이소옥사졸-5-일)프로판-1-온 (화합물번호 7);1- (4- (3-chlorophenyl) piperazin-1-yl) -3- (3-phenylisoxazol-5-yl) propan-1-one (Compound No. 7);
1-(4-(4-클로로페닐)피페라진-1-일)-4-(3-페닐-1,2,4-옥사다이아졸-5-일)부탄-1-온 (화합물번호 8);1- (4- (4-chlorophenyl) piperazin-1-yl) -4- (3-phenyl-1,2,4-oxadiazol-5-yl) butan-1-one (Compound No. 8) ;
1-(4-(4-클로로페닐)피페라진-1-일)-3-(3-페닐-1,2,4-옥사다이아졸-5-일)프로판-1-온 (화합물번호 9);1- (4- (4-chlorophenyl) piperazin-1-yl) -3- (3-phenyl-1,2,4-oxadiazol-5-yl) propan-1-one (Compound No. 9) ;
1-(4-(4-클로로페닐)피페라진-1-일)-4-(3-페닐아이소옥사졸-5-일)부탄-1-온 (화합물번호 10);1- (4- (4-chlorophenyl) piperazin-1-yl) -4- (3-phenylisoxazol-5-yl) butan-1-one (Compound No. 10);
1-(4-(4-클로로페닐)피페라진-1-일)-3-(3-페닐아이소옥사졸-5-일)프로판-1-온 (화합물번호 11);1- (4- (4-chlorophenyl) piperazin-1-yl) -3- (3-phenylisoxazol-5-yl) propan-1-one (Compound No. 11);
1-(4-(2-클로로페닐)피페라진-1-일)-4-(3-페닐-1,2,4-옥사다이아졸-5-일)부탄-1-온 (화합물번호 12);1- (4- (2-chlorophenyl) piperazin-1-yl) -4- (3-phenyl-1,2,4-oxadiazol-5-yl) butan-1-one (Compound No. 12) ;
1-(4-(4-클로로페닐)피페라진-1-일)-3-(3-페닐-1,2,4-옥사다이아졸-5-일)프로판-1-온 (화합물번호 13);1- (4- (4-chlorophenyl) piperazin-1-yl) -3- (3-phenyl-1,2,4-oxadiazol-5-yl) propan-1-one (Compound No. 13) ;
1-(4-(2-클로로페닐)피페라진-1-일)-4-(3-페닐아이소옥사졸-5-일)부탄-1-온 (화합물번호 14);1- (4- (2-chlorophenyl) piperazin-1-yl) -4- (3-phenylisoxazol-5-yl) butan-1-one (Compound No. 14);
1-(4-벤즈하이드릴피페라진-1-일)-4-(3-페닐-1,2,4-옥사다이아졸-5-일)부탄-1-온 (화합물번호 15);1- (4-benzhydrylpiperazin-1-yl) -4- (3-phenyl-1,2,4-oxadiazol-5-yl) butan-1-one (Compound No. 15);
1-(4-벤즈하이드릴피페라진-1-일)-4-(3-페닐아이소옥사졸-5-일)부탄-1-온 (화합물번호 16);1- (4-benzhydrylpiperazin-1-yl) -4- (3-phenylisoxazol-5-yl) butan-1-one (Compound No. 16);
1-(4-벤즈하이드릴피페라진-1-일)-3-(3-페닐-1,2,4-옥사다이아졸-5-일)프로판-1-온 (화합물번호 17);1- (4-benzhydrylpiperazin-1-yl) -3- (3-phenyl-1,2,4-oxadiazol-5-yl) propan-1-one (Compound No. 17);
1-(4-(2-클로로페닐)피페라진-1-일)-3-(3-페닐아이소옥사졸-5-일)프로판-1-온 (화합물번호 18);1- (4- (2-chlorophenyl) piperazin-1-yl) -3- (3-phenylisoxazol-5-yl) propan-1-one (Compound No. 18);
1-(4-벤즈하이드릴피페라진-1-일)-3-(3-페닐아이소옥사졸-5-일)프로판-1-온 (화합물번호 19);1- (4-benzhydrylpiperazin-1-yl) -3- (3-phenylisoxazol-5-yl) propan-1-one (Compound No. 19);
2-((4-페닐-2-프로필옥사졸-5-일)메틸아미노)-1-(4-페닐피페라진-1-일)에탄논 (화합물번호 20);2-((4-phenyl-2-propyloxazol-5-yl) methylamino) -1- (4-phenylpiperazin-1-yl) ethanone (Compound No. 20);
1-(4-벤즈하이드릴피페라진-1-일)-2-((4-페닐-2-프로필옥사졸-5-일)메틸아미노)에탄논(화합물번호 21);1- (4-benzhydrylpiperazin-1-yl) -2-((4-phenyl-2-propyloxazol-5-yl) methylamino) ethanone (Compound No. 21);
1-(4-(비스(4-플루오로페닐)메틸)피페라진-1-일)-2-((4-페닐-2-프로필옥사졸-5-일)메틸아미노)에탄논 (화합물번호 22);1- (4- (bis (4-fluorophenyl) methyl) piperazin-1-yl) -2-((4-phenyl-2-propyloxazol-5-yl) methylamino) ethanone (Compound No. 22);
2-((4-페닐-5-프로필옥사졸-2-일)메틸아미노)-1-(4-페닐피페라진-1-일)에탄논 (화합물번호 23);2-((4-phenyl-5-propyloxazol-2-yl) methylamino) -1- (4-phenylpiperazin-1-yl) ethanone (Compound No. 23);
2-((5-메틸-4-페닐옥사졸-2-일)메틸아미노)-1-(4-페닐피페라진-1-일)에탄논 (화합물번호 24);2-((5-methyl-4-phenyloxazol-2-yl) methylamino) -1- (4-phenylpiperazin-1-yl) ethanone (Compound No. 24);
1-(4-벤즈하이드릴피페라진-1-일)-2-((4-페닐-5-프로필옥사졸-2-일)메틸아미노)에탄논 (화합물번호 25);1- (4-benzhydrylpiperazin-1-yl) -2-((4-phenyl-5-propyloxazol-2-yl) methylamino) ethanone (Compound No. 25);
1-(4-비스(4-플루오로페닐)메틸)피페라진-1-일)-2-((4-페닐-5-프로필옥사졸-2-일)메틸아미노)에탄논 (화합물번호 26);1- (4-bis (4-fluorophenyl) methyl) piperazin-1-yl) -2-((4-phenyl-5-propyloxazol-2-yl) methylamino) ethanone (Compound No. 26 );
2-((2-메틸-4-페닐옥사졸-5-일)메틸아미노)-1-(4-페닐피페라진-1-일)에탄논 (화합물번호 27);2-((2-methyl-4-phenyloxazol-5-yl) methylamino) -1- (4-phenylpiperazin-1-yl) ethanone (Compound No. 27);
1-(4-벤즈하이드릴피페라진-1-일)-2-((2-메틸-4-페닐옥사졸-5-일)메틸아미노)에탄논 (화합물번호 28);1- (4-benzhydrylpiperazin-1-yl) -2-((2-methyl-4-phenyloxazol-5-yl) methylamino) ethanone (Compound No. 28);
1-(4-비스(4-플루오로페닐)메틸)피페라진-1-일)-2-((2-메틸-4-페닐옥사졸-5-일)메틸아미노)에탄논 (화합물번호 29);1- (4-bis (4-fluorophenyl) methyl) piperazin-1-yl) -2-((2-methyl-4-phenyloxazol-5-yl) methylamino) ethanone (Compound No. 29 );
2-((4-페닐-2-프로필옥사졸-5-일)메틸아미노)-1-(4-(3-(트리플루오로메틸)페닐)피페라진-1-일)에탄논 (화합물번호 30);2-((4-phenyl-2-propyloxazol-5-yl) methylamino) -1- (4- (3- (trifluoromethyl) phenyl) piperazin-1-yl) ethanone (Compound No. 30);
1-(4-(2,4-다이메틸페닐)피페라진-1-일)-2-((4-페닐-5-프로필옥사졸-2-일)메틸아미노)에탄논 (화합물번호 31);1- (4- (2,4-dimethylphenyl) piperazin-1-yl) -2-((4-phenyl-5-propyloxazol-2-yl) methylamino) ethanone (Compound No. 31);
1-(4-(2,3-다이메틸페닐)피페라진-1-일)-2-((4-페닐-5-프로필옥사졸-2-일)메틸아미노)에탄논 (화합물번호 32);1- (4- (2,3-dimethylphenyl) piperazin-1-yl) -2-((4-phenyl-5-propyloxazol-2-yl) methylamino) ethanone (Compound No. 32);
1-(4-(3,4-다이메틸페닐)피페라진-1-일)-2-((4-페닐-5-프로필옥사졸-2-일)메틸아미노)에탄논 (화합물번호 33);1- (4- (3,4-dimethylphenyl) piperazin-1-yl) -2-((4-phenyl-5-propyloxazol-2-yl) methylamino) ethanone (Compound No. 33);
1-(4-(2,4-다이메틸페닐)피페라진-1-일)-2-((5-메틸-4-페닐옥사졸-2-일)메틸아미노)에탄논 (화합물번호 34);1- (4- (2,4-dimethylphenyl) piperazin-1-yl) -2-((5-methyl-4-phenyloxazol-2-yl) methylamino) ethanone (Compound No. 34);
2-((2-메틸-4-페닐옥사졸-5-일)메틸아미노)-1-(4-3-(트리플루오로메틸)페닐)피페라진-1-일)에탄논 (화합물번호 35);2-((2-methyl-4-phenyloxazol-5-yl) methylamino) -1- (4-3- (trifluoromethyl) phenyl) piperazin-1-yl) ethanone (Compound No. 35 );
1-(4-(2,4-다이메틸페닐)피페라진-1-일)-2-((2-메틸-4-페닐옥사졸-5-일)메틸아미노)에탄논 (화합물번호 36);1- (4- (2,4-dimethylphenyl) piperazin-1-yl) -2-((2-methyl-4-phenyloxazol-5-yl) methylamino) ethanone (Compound No. 36);
1-(4-(2,3-다이메틸페닐)피페라진-1-일)-2-((2-메틸-4-페닐옥사졸-5-일)메틸아미노)에탄논 (화합물번호 37);1- (4- (2,3-dimethylphenyl) piperazin-1-yl) -2-((2-methyl-4-phenyloxazol-5-yl) methylamino) ethanone (Compound No. 37);
1-(4-벤즈하이드릴피페라진-1-일)-2-((5-메틸-4-페닐옥사졸-2-일)메틸아미노)에탄논 (화합물번호 38);1- (4-benzhydrylpiperazin-1-yl) -2-((5-methyl-4-phenyloxazol-2-yl) methylamino) ethanone (Compound No. 38);
1-(4-(2,4-다이메틸페닐)피페라진-1-일)-2-((4-페닐-2-프로필옥사졸-5-일)메틸아미노)에탄논 (화합물번호 39);1- (4- (2,4-dimethylphenyl) piperazin-1-yl) -2-((4-phenyl-2-propyloxazol-5-yl) methylamino) ethanone (Compound No. 39);
1-(4-(2,3-다이메틸페닐)피페라진-1-일)-2-((4-페닐-2-프로필옥사졸-5-일)메틸아미노)에탄논 (화합물번호 40);1- (4- (2,3-dimethylphenyl) piperazin-1-yl) -2-((4-phenyl-2-propyloxazol-5-yl) methylamino) ethanone (Compound No. 40);
1-(4-(3,4-다이메틸페닐)피페라진-1-일)-2-((4-페닐-2-프로필옥사졸-5-일)메틸아미노)에탄논 (화합물번호 41);1- (4- (3,4-dimethylphenyl) piperazin-1-yl) -2-((4-phenyl-2-propyloxazol-5-yl) methylamino) ethanone (Compound No. 41);
2-((4-페닐-2-프로필옥사졸-5-일)메틸아미노)-1-(4-(3-(트리플루오로메틸)페닐)피페라진-1-일)에탄논 (화합물번호 42);2-((4-phenyl-2-propyloxazol-5-yl) methylamino) -1- (4- (3- (trifluoromethyl) phenyl) piperazin-1-yl) ethanone (Compound No. 42);
1-(4-(3,4-다이에틸페닐)피페라진-1-일)-2-((5-메틸-4-페닐옥사졸-2-일)메틸아미노)에탄논 (화합물번호 43);1- (4- (3,4-diethylphenyl) piperazin-1-yl) -2-((5-methyl-4-phenyloxazol-2-yl) methylamino) ethanone (Compound No. 43) ;
1-(4-(2,3-다이메틸페닐)피페라진-1-일)-2-((5-메틸-4-페닐옥사졸-2-일)메틸아미노)에탄논 (화합물번호 44);1- (4- (2,3-dimethylphenyl) piperazin-1-yl) -2-((5-methyl-4-phenyloxazol-2-yl) methylamino) ethanone (Compound No. 44);
1-(4-(3-클로로페닐)피페라진-1-일)-4-(3-페닐-1,2,4-옥사다이아졸-5-일)부탄-1-온 (화합물번호 45);1- (4- (3-chlorophenyl) piperazin-1-yl) -4- (3-phenyl-1,2,4-oxadiazol-5-yl) butan-1-one (Compound No. 45) ;
2-(4-(2,4-다이메틸페닐)피페라진-1-일)-N-((3-아이소프로필아이소옥사졸-5-일)메틸)에탄아민 (화합물번호 46);2- (4- (2,4-dimethylphenyl) piperazin-1-yl) -N -((3-isopropylisoxazol-5-yl) methyl) ethanamine (Compound No. 46);
2-(4-(2,3-다이메틸페닐)피페라진-1-일)-N-((3-아이소프로필아이소옥사졸-5-일)메틸)에탄아민 (화합물번호 47);2- (4- (2,3-dimethylphenyl) piperazin-1-yl) -N -((3-isopropylisoxazol-5-yl) methyl) ethanamine (Compound No. 47);
N-((3-아이소프로필아이소옥사졸-5-일)메틸)-2-(4-(3-(트리플루오로메틸)페닐)피페라진-1-일)에탄아민 (화합물번호 48); N -((3-isopropylisoxazol-5-yl) methyl) -2- (4- (3- (trifluoromethyl) phenyl) piperazin-1-yl) ethanamine (Compound No. 48);
1-(4-(3,4-다이메틸페닐)피페라진-1-일)-2-((2-메틸-4-페닐옥사졸-5-일)메틸아미노)에탄논 (화합물번호 49);1- (4- (3,4-dimethylphenyl) piperazin-1-yl) -2-((2-methyl-4-phenyloxazol-5-yl) methylamino) ethanone (Compound No. 49);
2-((2-메틸-4-페닐옥사졸-5-일)메틸아미노)-1-(4-(3-(트리플루오로메틸)페닐)피페라진-1-일)에탄논 (화합물번호 50);2-((2-methyl-4-phenyloxazol-5-yl) methylamino) -1- (4- (3- (trifluoromethyl) phenyl) piperazin-1-yl) ethanone (Compound No. 50);
2-(4-(2,3-다이메틸페닐)피페라진-1-일)-N-((3-메틸아이소옥사졸-5-일)메틸)에탄아민 (화합물번호 51);2- (4- (2,3-dimethylphenyl) piperazin-1-yl) -N -((3-methylisoxazol-5-yl) methyl) ethanamine (Compound No. 51);
2-(4-(3,4-다이메틸페닐)피페라진-1-일)-N-((3-메틸아이소옥사졸-5-일)메틸)에탄아민 (화합물번호 52);2- (4- (3,4-dimethylphenyl) piperazin-1-yl) -N -((3-methylisoxazol-5-yl) methyl) ethanamine (Compound No. 52);
N-((3-메틸아이소옥사졸-5-일)메틸)-2-(4-(3-(트리플루오로메틸)페닐)피페라진-1-일)에탄아민 (화합물번호 53); N -((3-methylisoxazol-5-yl) methyl) -2- (4- (3- (trifluoromethyl) phenyl) piperazin-1-yl) ethanamine (Compound No. 53);
N-((5-아이소부틸-4-페닐옥사졸-2-일)메틸)-2-(4-페닐피페라진-1-일)아세타마이드 (화합물번호 54); N -((5-isobutyl-4-phenyloxazol-2-yl) methyl) -2- (4-phenylpiperazin-1-yl) acetamide (Compound No. 54);
2-(4-벤즈하이드릴피페라진-1-일)-N-((5-아이소부틸-4-페닐옥사졸-2-일)메틸)아세타마이드 (화합물번호 55);2- (4-benzhydrylpiperazin-1-yl) -N -((5-isobutyl-4-phenyloxazol-2-yl) methyl) acetamide (Compound No. 55);
2-(4-(비스(4-플루오로페닐)메틸)피페라진-1-일)-N-((5-아이소부틸-4-페닐옥사졸-2-일)메틸)아세타마이드 (화합물번호 56);2- (4- (bis (4-fluorophenyl) methyl) piperazin-1-yl) -N -((5-isobutyl-4-phenyloxazol-2-yl) methyl) acetamide (compound Number 56);
2-(4-(비스(4-클로로페닐)메틸)피페라진-1-일)-N-((5-아이소부틸-4-페닐옥사졸-2-일)메틸)아세타마이드 (화합물번호 57);2- (4- (bis (4-chlorophenyl) methyl) piperazin-1-yl) -N -((5-isobutyl-4-phenyloxazol-2-yl) methyl) acetamide (Compound No. 57);
N-((5-아이소부틸-4-페닐옥사졸-2-일)메틸)-2-(4-(3-(트리플루오로메틸)페닐)피페라진-1-일)아세타마이드 (화합물번호 58); N -((5-isobutyl-4-phenyloxazol-2-yl) methyl) -2- (4- (3- (trifluoromethyl) phenyl) piperazin-1-yl) acetamide (compound Number 58);
2-(4-(2,3-다이메틸페닐)피페라진-1-일)-N-((5-아이소부틸-4-페닐옥사졸-2-일)메틸)아세타마이드 (화합물번호 59);2- (4- (2,3-dimethylphenyl) piperazin-1-yl) -N -((5-isobutyl-4-phenyloxazol-2-yl) methyl) acetamide (Compound No. 59) ;
2-(4-(3,4-다이메틸페닐)피페라진-1-일)-N-((5-아이소부틸-4-페닐옥사졸-2-일)메틸)아세타마이드 (화합물번호 60);2- (4- (3,4-dimethylphenyl) piperazin-1-yl) -N -((5-isobutyl-4-phenyloxazol-2-yl) methyl) acetamide (Compound No. 60) ;
2-(4-2,4-다이메틸페닐)피페라진-1-일)-N-((5-아이소부틸-4-페닐옥사졸-2-일)메틸)아세타마이드 (화합물번호 61);2- (4-2,4-dimethylphenyl) piperazin-1-yl) -N -((5-isobutyl-4-phenyloxazol-2-yl) methyl) acetamide (Compound No. 61);
N-((5-아이소부틸-4-페닐옥사졸-2-일)메틸)-2-((4-페닐설포닐)-1,4-다이아제판-1-일)아세타마이드 (화합물번호 62); N -((5-isobutyl-4-phenyloxazol-2-yl) methyl) -2-((4-phenylsulfonyl) -1,4-diazepan-1-yl) acetamide (Compound No. 62);
2-(4-(4-플루오로페닐설포닐)-1,4-다이아제판-1-일)-N-((5-아이소부틸-4-페닐옥사졸-2-일)메틸)아세타마이드 (화합물번호 63);2- (4- (4-fluorophenylsulfonyl) -1,4-diazepan-1-yl) -N -((5-isobutyl-4-phenyloxazol-2-yl) methyl) acetama Id (Compound No. 63);
2-(4-(벤조[d]싸이아졸-2-일메틸)피페라진-1-일)-N-((5-아이소부틸-4-페닐옥사졸-2-일)메틸)아세타마이드 (화합물번호 64);2- (4- (benzo [ d ] thiazol-2-ylmethyl) piperazin-1-yl) -N -((5-isobutyl-4-phenyloxazol-2-yl) methyl) acetamide (Compound No. 64);
N-((5-아이소부틸-4-페닐옥사졸-2-일)메틸)-2-(4-(3-(트리플루오로메틸)벤조일-1,4-다이아제판-1-일)아세타마이드 (화합물번호 65); N -((5-isobutyl-4-phenyloxazol-2-yl) methyl) -2- (4- (3- (trifluoromethyl) benzoyl-1,4-diazepan-1-yl) acet Tamid (Compound No. 65);
2-(4-(4-플루오로벤조일)-1,4-다이아제판-1-일)-N-((5-아이소부틸-4-페닐옥사졸-2-일)메틸)아세타마이드 (화합물번호 66);2- (4- (4-fluorobenzoyl) -1,4-diazepan-1-yl) -N -((5-isobutyl-4-phenyloxazol-2-yl) methyl) acetamide ( Compound no. 66);
N-((5-아이소부틸-4-페닐옥사졸-2-일)메틸)-2-(4-(3-(트리플루오로메틸)벤조일)피페라진-1-일)아세타마이드 (화합물번호 67); N -((5-isobutyl-4-phenyloxazol-2-yl) methyl) -2- (4- (3- (trifluoromethyl) benzoyl) piperazin-1-yl) acetamide (compound Number 67);
1-(4-(4--클로로페닐)피페라진-1-일)-2-((4-페닐-5-프로필옥사졸-2-일)메틸아미노)에탄논 (화합물번호 68);1- (4- (4--chlorophenyl) piperazin-1-yl) -2-((4-phenyl-5-propyloxazol-2-yl) methylamino) ethanone (Compound No. 68);
1-(4-(2,3-다이클로로페닐)피페라진-1-일)-2-((4-페닐-5-프로필옥사졸-2-일)메틸아미노)에탄논 (화합물번호 69);1- (4- (2,3-dichlorophenyl) piperazin-1-yl) -2-((4-phenyl-5-propyloxazol-2-yl) methylamino) ethanone (Compound No. 69) ;
1-(4-(3,4-다이클로로페닐)피페라진-1-일)-2-((4-페닐-5-프로필옥사졸-2-일)메틸아미노)에탄논 (화합물번호 70).1- (4- (3,4-Dichlorophenyl) piperazin-1-yl) -2-((4-phenyl-5-propyloxazol-2-yl) methylamino) ethanone (Compound No. 70) .
한편, 본 발명은 상기 화학식 1로 표시되는 5각형의 헤테로방향족 화합물의 제조방법을 포함한다. 본 발명에 따른 대표적인 제조방법은 상기 화학식 1에서 결합자 E에 따라 하기 반응식 1 내지 4에 나타낸 바와 같은 네 가지 제조방법으로 대별될 수 있다. On the other hand, the present invention includes a method for producing a pentagonal heteroaromatic compound represented by the formula (1). Exemplary preparation methods according to the present invention can be roughly divided into four preparation methods as shown in Schemes 1 to 4 according to the binder E in Chemical Formula 1.
첫 번째 제조방법은, 하기 반응식 1에 나타낸 바와 같이 E= -(CH2)nC(O)- 인 알칸논 화합물의 대표적인 제조방법이다.The first preparation method is a typical preparation method of an alkanone compound having E = − (CH 2 ) n C (O) — as shown in Scheme 1 below.
[반응식 1][Reaction Scheme 1]
상기 반응식 1에서, X, Y, Z, R1, ℓ, 및 n은 각각 상기 화학식 1에서 정의한 바와 같다.In Scheme 1, X, Y, Z, R 1 , L, and n are as defined in Formula 1, respectively.
상기 반응식 1에 따른 결합반응에 의하면, 상기 화학식 3a로 표시되는 카보클로라이드 화합물과 상기 화학식 2a로 표시되는 헤테로고리 아민화합물을 염기 존재하에서 반응시켜, 알칸논아민 결합그룹(E)을 갖는 상기 화학식 1a로 표시되는 헤테로방향족 화합물을 직접 제조할 수 있다. 상기 결합반응에서 사용되는 염기로는 트리에틸아민 등의 알킬아민류, 피리딘 등과 같은 유기염기를 사용할 수 있다. 반응온도는 -20℃ 내지 30℃ 온도 범위를 유지하도록 하며, 반응용매로는 결합반응에 영향을 미치지 않는 비활성 유기용매로서 클로로포름, 다이클로로메탄, 1,2-다이클로로에탄 등이 사용될 수 있다. According to the coupling reaction according to Scheme 1, the carbochloride compound represented by Chemical Formula 3a and the heterocyclic amine compound represented by Chemical Formula 2a are reacted in the presence of a base, and have Chemical Formula 1a having an alkanoneamine binding group (E). Heteroaromatic compounds represented by can be prepared directly. The base used in the coupling reaction may be an organic base such as alkylamines such as triethylamine, pyridine and the like. The reaction temperature is maintained at a temperature range of -20 ° C to 30 ° C, and as the reaction solvent, chloroform, dichloromethane, 1,2-dichloroethane, etc. may be used as an inert organic solvent that does not affect the coupling reaction.
두 번째 제조방법은, 하기 반응식 2에 나타낸 바와 같이 E= -(CH2)nNH(CH2)mC(O)- 인 아미노알칸논 화합물의 대표적인 제조방법이다.The second preparation method is a typical preparation method of an aminoalkanone compound having E = − (CH 2 ) n NH (CH 2 ) m C (O) — as shown in Scheme 2 below.
[반응식 2]Scheme 2
상기 반응식 2에서, X, Y, Z, R1, ℓ, 및 n은 각각 상기 화학식 1에서 정의한 바와 같다.In Scheme 2, X, Y, Z, R 1 , L, and n are as defined in Formula 1, respectively.
상기 반응식 2에 따른 결합반응에 의하면, 상기 화학식 3b로 표시되는 알데하이드 화합물과 상기 화학식 2b로 표시되는 아민화합물을 아세트산, 분자체, 및 소듐 트리아세톡시보로하이드라이드 (NaBH(OAc)3)의 존재하에서 결합반응시켜, 상기화학식 1b로 표시되는 아미노알칸논 결합그룹(E)을 갖는 헤테로방향족 화합물을 직접 제조할 수 있다. 상기 반응온도는 상온 주변의 온도로서 구체적으로는 10℃ 내지 30℃ 온도 범위에서 수행하면, 반응용매로는 비활성 유기용매로서 클로로포름, 다이클로로메탄, 1,2-다이클로로에탄 등이 사용될 수 있다. According to the coupling reaction according to Scheme 2, the aldehyde compound represented by Chemical Formula 3b and the amine compound represented by Chemical Formula 2b may contain acetic acid, molecular sieve, and sodium triacetoxyborohydride (NaBH (OAc) 3 ). By the coupling reaction under, a heteroaromatic compound having an aminoalkanone linking group (E) represented by Formula 1b may be directly prepared. When the reaction temperature is performed at a temperature range of about 10 ° C. to 30 ° C. as the ambient temperature, the reaction solvent may be chloroform, dichloromethane, 1,2-dichloroethane, or the like as an inert organic solvent.
세 번째 제조방법은, 하기 반응식 3에 나타낸 바와 같이 E= -(CH2)nNH(CH2)m- 인 알칸아민 화합물의 대표적인 제조방법이다.The third preparation method is a typical preparation method of an alkanamine compound having E = − (CH 2 ) n NH (CH 2 ) m − as shown in Scheme 3 below.
[반응식 3]Scheme 3
상기 반응식 3에서, X, Y, Z, R1, ℓ, m, 및 n은 각각 상기 화학식 1에서 정의한 바와 같다.In Scheme 3, X, Y, Z, R 1 , 1, m, and n are as defined in Formula 1, respectively.
상기 반응식 3에 따른 결합반응은, 상기 반응식 2에 따른 제조방법에 설명한 바와 같이 아세트산, 분자체, 소듐 트리아세톡시보로하이드라이드 (NaBH(OAc)3)의 존재하에서, 상기 화학식 3b로 표시되는 알데하이드 화합물과 상기 화학식 2c로 표시되는 아민화합물을 결합반응시켜, 상기 화학식 1c로 표시되는 아민 결합그룹(E)을 갖는 헤테로방향족 화합물을 직접 제조할 수 있다. 상기 반응온도는 상온 주변의 온도로서 구체적으로는 10℃ 내지 30℃ 온도 범위에서 수행하면, 반응용매로는 비활성 유기용매로서 클로로포름, 다이클로로메탄, 1,2-다이클로로에탄 등이 사용될 수 있다. The coupling reaction according to Scheme 3, as described in the preparation method according to Scheme 2, in the presence of acetic acid, molecular sieve, sodium triacetoxyborohydride (NaBH (OAc) 3 ), the aldehyde represented by the formula (3b) By combining the compound and the amine compound represented by Formula 2c, a heteroaromatic compound having an amine bond group (E) represented by Formula 1c may be directly prepared. When the reaction temperature is performed at a temperature range of about 10 ° C. to 30 ° C. as the ambient temperature, the reaction solvent may be chloroform, dichloromethane, 1,2-dichloroethane, or the like as an inert organic solvent.
네 번째 제조방법은, 하기 반응식 4에 나타낸 바와 같이 E= -(CH2)nNHC(O)(CH2)m- 인 아마이드 화합물의 대표적인 제조방법이다.The fourth production method is a typical production method of an amide compound having E = − (CH 2 ) n NHC (O) (CH 2 ) m − as shown in Scheme 4 below.
[반응식 4]Scheme 4
상기 반응식 4에서, X, Y, Z, R1, ℓ, m, 및 n은 각각 상기 화학식 1에서 정의한 바와 같다.In Scheme 4, X, Y, Z, R 1 , 1, m, and n are as defined in Formula 1, respectively.
상기 반응식 4에 따른 제조방법은 상기 화학식 3d로 표시되는 클로라이드 화합물과 상기 화학식 2d로 표시되는 헤테로고리 아민화합물을 알킬아민 염기의 존재하에서 결합반응시켜 상기 화학식 17d로 표시되는 화합물을 제조하는 과정; 및 상기 화학식 17d로 표시되는 화합물과 R1 치환기 함유 알데하이드 화합물 또는 클로라이드 화합물과 반응시켜 상기 화학식 1d로 표시되는 아마이드 결합그룹(E)을 갖는 헤테로방향족 화합물을 제조하는 과정을 포함하여 이루어진다.The preparation method according to Scheme 4 includes the steps of preparing a compound represented by Chemical Formula 17d by combining the chloride compound represented by Chemical Formula 3d with the heterocyclic amine compound represented by Chemical Formula 2d in the presence of an alkylamine base; And preparing a heteroaromatic compound having an amide linkage group (E) represented by Chemical Formula 1d by reacting the compound represented by Chemical Formula 17d with an R 1 substituent-containing aldehyde compound or a chloride compound.
상기 결합반응은 N,N-다이아이소프로필에틸아민 (EDIPA) 등의 알킬아민 염기 존재 하에서 수행한다. 반응온도는 상온 주변의 온도로서 구체적으로는 10℃ 내지 30℃ 온도 범위에서 수행하면, 반응용매로는 비활성 유기용매로서 클로로포름, 다이클로로메탄, 1,2-다이클로로에탄, 테트라하이드로퓨란 등이 사용될 수 있다. The coupling reaction is carried out in the presence of an alkylamine base such as N, N -diisopropylethylamine (EDIPA). When the reaction temperature is performed at room temperature, specifically, in a temperature range of 10 ° C. to 30 ° C., chloroform, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, etc. may be used as an inert organic solvent. Can be.
또한, R1 치환기 도입을 위해서는 R1기를 함유하는 알데하이드 화합물 또는 클로라이드 화합물을 반응물질로 사용할 수 있다. 알데하이드 화합물을 반응물질로 사용하는 경우는, 상기 반응식 2와 3에서 설명한 바와 같이 아세트산, 분자체, 소듐 트리아세톡시보로하이드라이드 (NaBH(OAc)3)가 존재하는 조건하에서 수행할 수 있다. 클로라이드 화합물을 반응물질로 사용하는 경우는, 트리에틸아민 등의 알킬아민류, 피리딘 등과 같은 유기염기를 사용할 수 있다. 반응용매로는 결합반응에 영향을 미치지 않는 비활성 유기용매로서 클로로포름, 다이클로로메탄, 1,2-다이클로로에탄, 테트라하이드로퓨란 등이 사용될 수 있다. In addition, to introduce an R 1 substituent, an aldehyde compound or a chloride compound containing an R 1 group may be used as a reactant. When using an aldehyde compound as a reactant, it can be carried out under the conditions in which acetic acid, molecular sieve, sodium triacetoxyborohydride (NaBH (OAc) 3 ) is present as described in Schemes 2 and 3. When using a chloride compound as a reaction material, alkylamines, such as triethylamine, and organic base, such as pyridine, can be used. As the reaction solvent, chloroform, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, etc. may be used as an inert organic solvent which does not affect the coupling reaction.
또한, 상기 반응식 1 내지 4에 따른 제조방법에서 사용된 반응물질은 공지 문헌에 의해 쉽게 제조하여 사용하거나, 또는 판매 제품을 직접 구입하여 사용할 수 있다. 또한, 당업자라면 유기합성 분야에서 널리 알려진 일반적인 방법에 의해 반응물질이나 목적 화합물에 다양한 치환기를 용이하게 도입할 수 있다.In addition, the reactants used in the production method according to Schemes 1 to 4 can be easily prepared and used according to the known literature, or can be used directly by purchasing a sale product. In addition, those skilled in the art can easily introduce various substituents into the reactant or the target compound by a general method well known in the field of organic synthesis.
한편, 본 발명은 상기 화학식 1로 표시되는 5각형의 헤테로방향족 화합물 또는 약학적으로 허용 가능한 이의 염을 유효성분으로 포함하는 약제조성물을 포함한다.On the other hand, the present invention includes a pharmaceutical composition comprising a pentagonal heteroaromatic 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 약학적으로 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 may be formulated in a conventional formulation method including other conventional carriers, adjuvants or diluents together with the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof, for oral or parenteral administration. It may be prepared in a suitable 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 약학적 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]
본 발명에 따른 상기 화학식 1로 표시되는 화합물의 대표적 합성예를 참고예 1 내지 4로서 예시하였는 바, 본 발명의 화합물은 이들 참고예에서 예시된 제조방법에 의해 용이하게 합성할 수 있다.
Representative synthesis examples of the compound represented by the formula (1) according to the present invention has been illustrated as Reference Examples 1 to 4, the compound of the present invention can be easily synthesized by the production method illustrated in these reference examples.
참고예 1. E= -(CH2)nC(O)- 인 알칸논 화합물의 대표합성예Reference Example 1. Representative Synthesis Example of an Alkanone Compound with E =-(CH 2 ) n C (O)-
i) 3-(3-페닐아이소옥사졸-5-일)프로판-1-올 (화학식 3)의 제조 i) Preparation of 3- (3-phenylisoxazol-5-yl) propan-1-ol (Formula 3)
질소 하에서 벤자알데하이드옥심 (NCS; 2 g, 16.5 mmol)을 무수 테트라하이드로퓨란 (30 mL)에 용해시킨 후 N-클로로숙신이미드 (2.6 g, 19.8 mmol)를 첨가하였다. 반응 혼합물을 상온에서 2시간 교반하면서 반응 진행과정을 TLC로 확인하였다. 펜타-4-인-1-올 (2.3 mL, 25 mmol)과 트리에틸아민 (2.8 mL, 19.8 mmol)을 적가한 후 1시간 더 교반하였다. 반응이 종결되면 물과 에틸 아세테이트를 이용하여 추출하고, 유기층을 무수 황산마그네슘으로 건조시킨 후 여과하였다. 여과액을 감압 농축시시고, 농축액을 관 크로마토그래피 (용출액: Hex/EA=1/1)를 통하여 상기 표제화합물 1.85 g (수율 55%)을 얻었다.Benzaaldehyde oxime (NCS; 2 g, 16.5 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL) under nitrogen and then N -chlorosuccinimide (2.6 g, 19.8 mmol) was added. While the reaction mixture was stirred at room temperature for 2 hours, the reaction progress was confirmed by TLC. Penta-4-yn-1-ol (2.3 mL, 25 mmol) and triethylamine (2.8 mL, 19.8 mmol) were added dropwise, followed by further stirring for 1 hour. After the reaction was completed, the mixture was extracted with water and ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography (eluent: Hex / EA = 1/1) to obtain 1.85 g (yield 55%) of the title compound.
1H NMR (300 MHz, DMSO-d 6, ppm) δ 7.87 (d, J = 5.4 Hz, 2H) 7.51 (t, J = 6.3 Hz, 3H) 6.84 (s, 1H) 3.48(m, 2H) 2.85 (t, J = 7.2 Hz, 2H) 1.45 (quint, J = 7.5 Hz, 2H) 1 H NMR (300 MHz, DMSO- d 6 , ppm) δ 7.87 (d, J = 5.4 Hz, 2H) 7.51 (t, J = 6.3 Hz, 3H) 6.84 (s, 1H) 3.48 (m, 2H) 2.85 (t, J = 7.2 Hz, 2H) 1.45 (quint, J = 7.5 Hz, 2H)
ⅱ) 3-(3-페닐아이소옥사졸-5-일)프로파노익 산 (화학식 4)의 제조Ii) Preparation of 3- (3-phenylisoxazol-5-yl) propanoic acid (Formula 4)
3-(3-페닐아이소옥사졸-5-일)프로판-1-올 (500 mg, 2.46 mmol)을 아세톤 (10 mL)에 용해시킨 후 0℃에서 교반하였다. 2M 존슨시약 (John’s reagent; 1.23 mL)를 적가한 후 0℃에서 2시간 더 교반하였고, 반응 진행과정을 TLC로 확인하였다. 반응이 종결되면 포화 NaHCO3 수용액을 넣고 추출하여 수층을 취하고, 수층에 1N HCl을 넣고 에틸 아세테이트로 다시 추출하였다. 유기층을 무수 황산마그네슘으로 건조시킨 후, 여과액을 감압 농축시켜 상기 표제화합물 230 mg (수율 43%)을 얻었다.3- (3-phenylisoxazol-5-yl) propan-1-ol (500 mg, 2.46 mmol) was dissolved in acetone (10 mL) and stirred at 0 ° C. 2M Johnson's reagent (1.23 mL) was added dropwise and stirred for 2 hours at 0 ° C. The reaction progress was confirmed by TLC. After the reaction was completed, the aqueous solution was added with saturated NaHCO 3 aqueous solution, and the aqueous layer was taken. Then, 1N HCl was added to the aqueous layer and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure to give 230 mg (yield 43%) of the title compound.
1H NMR (300 MHz, DMSO-d 6, ppm) δ 7.83 (d, J = 9.7 Hz, 2H) 7.52 (t, J = 3.7 Hz, 3H) 6.84 (s, 1H) 3.01 (t, J = 7.3 Hz, 2H) 2.70 (t, J = 7.3 Hz, 2H)
1 H NMR (300 MHz, DMSO- d 6 , ppm) δ 7.83 (d, J = 9.7 Hz, 2H) 7.52 (t, J = 3.7 Hz, 3H) 6.84 (s, 1H) 3.01 (t, J = 7.3 Hz, 2H) 2.70 (t, J = 7.3 Hz, 2H)
ⅲ) 3-(3-페닐아이소옥사졸-5-일)프로파노일클로라이드 (화학식 5)의 제조Iii) Preparation of 3- (3-phenylisoxazol-5-yl) propanoyl chloride (Formula 5)
3-(3-페닐아이소옥사졸-5-일)프로파노익 산 (50 mg, 0.2 mmol)을 무수 다이클로로메탄 (5 mL)에 용해시킨 후 N,N-다이메틸포름아마이드 (DMF; 0.2 mL)와 옥살릭 클로라이드 (35.5 μL, 0.4 mmol)를 천천히 적가하였다. 반응 혼합물을 상온에서 30분 교반시키고, 반응 진행과정을 TLC로 확인하였다. 반응이 종결되면 용매를 감압 증류하여 상기 표제화합물 60 mg (수율 100%)을 얻었다.
3- (3-phenylisoxazol-5-yl) propanoic acid (50 mg, 0.2 mmol) was dissolved in anhydrous dichloromethane (5 mL) followed by N, N -dimethylformamide (DMF; 0.2 mL) and oxalic chloride (35.5 μL, 0.4 mmol) were added slowly dropwise. The reaction mixture was stirred for 30 minutes at room temperature, and the reaction progress was confirmed by TLC. When the reaction was terminated, the solvent was distilled off under reduced pressure to obtain 60 mg (yield 100%) of the title compound.
ⅳ) 3-(3-페닐아이소옥사졸-5-일)-1-(4-페닐피페라진-1-일)프로판-1-온 (화학식 1a)의 제조Iii) Preparation of 3- (3-phenylisoxazol-5-yl) -1- (4-phenylpiperazin-1-yl) propan-1-one (Formula 1a)
1-메틸피페라진 (38.2 μL, 0.25 mmol)을 무수 다이클로로메탄에 녹이고 트리에틸아민 (53 μL, 0.38 mmol)을 첨가하였다. 반응혼합물을 0℃로 낮추고 3-(3-페닐아이소옥사졸-5-일)프로파노일클로라이드 (60 mg, 0.25 mmol)를 적가하였다. 상온에서 1시간동안 교반하면서 반응 진행과정을 TLC로 확인하였다. 포화 NaHCO3 수용액과 다이클로로메탄을 이용해서 추출하고, 유기층을 무수 황산마그네슘으로 건조시킨 후 여과하였다. 여과액을 감압 농축시켜, 농축액을 관 크로마토그래피 (용출액: EA/Hex=1/1)를 통하여 상기 표제화합물 80.4 mg (수율 87%)을 얻었다.1-Methylpiperazine (38.2 μL, 0.25 mmol) was dissolved in anhydrous dichloromethane and triethylamine (53 μL, 0.38 mmol) was added. The reaction mixture was lowered to 0 ° C. and 3- (3-phenylisoxazol-5-yl) propanoylchloride (60 mg, 0.25 mmol) was added dropwise. The reaction progress was confirmed by TLC while stirring at room temperature for 1 hour. The mixture was extracted with saturated aqueous NaHCO 3 solution and dichloromethane, and the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography (eluent: EA / Hex = 1/1) to obtain 80.4 mg (yield 87%) of the title compound.
1H NMR (300 MHz, CDCl3-d, ppm) δ 7.79 (m, 2H) 7.46 (t, J = 5 Hz, 3H) 7.30 (m, 2H) 6.94 (br s, 3H) 6.4 (s, 1H) 3.82 (s, 2H) 3.66 (s, 2H) 3.19 (m, 6H) 2.85 (t, J = 7.4 Hz, 2H)
1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.79 (m, 2H) 7.46 (t, J = 5 Hz, 3H) 7.30 (m, 2H) 6.94 (br s, 3H) 6.4 (s, 1H ) 3.82 (s, 2H) 3.66 (s, 2H) 3.19 (m, 6H) 2.85 (t, J = 7.4 Hz, 2H)
참고예 2. E= -(CH2)nNH(CH2)mC(O)- 인 아미노알칸논 화합물의 대표합성예Reference Example 2. Representative Synthesis Example of Amino Alkanone Compounds with E =-(CH 2 ) n NH (CH 2 ) m C (O)-
i) (5-메틸-4-페닐옥사졸-2-일)메탄올 (화학식 6)의 제조 i) Preparation of (5-methyl-4-phenyloxazol-2-yl) methanol (Formula 6)
프로피오페논 (2 g, 15 mmol)과 [하이드록시(2,4-다이나이트로벤젠설포닐옥시)아이오도]벤젠 (HDNIB; 10.5 g, 23 mmol)을 아세토나이트릴(50 mL)에 용해시킨 후 80℃에서 1시간 환류하였다. 글리코아마이드 (2.6 g, 34 mmol)를 첨가하고 2일 동안 교반하면서 반응 진행과정을 TLC로 확인하였다. 반응이 종결되면 상온으로 식히고 물과 에틸 아세테이트를 이용하여 추출하고, 유기층을 무수 황산마그네슘으로 건조시킨 후 여과하였다. 여과액을 감압 농축시켜, 농축액을 관 크로마토그래피 (용출액: Hex/EA=1/1)를 통하여 상기 표제화합물 1.3 g (수율 47%)을 얻었다.Propiophenone (2 g, 15 mmol) and [hydroxy (2,4-dinitrobenzenesulfonyloxy) iodo] benzene (HDNIB; 10.5 g, 23 mmol) are dissolved in acetonitrile (50 mL). After refluxing at 80 ° C. for 1 hour. Glycoamide (2.6 g, 34 mmol) was added and the reaction progress was checked by TLC with stirring for 2 days. After the reaction was completed, the mixture was cooled to room temperature, extracted with water and ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography (eluent: Hex / EA = 1/1) to obtain 1.3 g (yield 47%) of the title compound.
1H NMR (300 MHz, CDCl3-d, ppm) δ 7.67 (m, 2H) 7.46 (m, 3H) 4.81 (m, 2H) 2.52 (s, 3H)
1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.67 (m, 2H) 7.46 (m, 3H) 4.81 (m, 2H) 2.52 (s, 3H)
ⅱ) 5-메틸-4-페닐옥사졸-2-카바알데하이드 (화학식 7)의 제조Ii) Preparation of 5-methyl-4-phenyloxazole-2-carbaaldehyde (Formula 7)
옥살릭 클로라이드 (201 μL, 2.3 mmol)를 무수 다이클로로메탄(10 mL)에 용해시키고 -78℃로 온도를 낮추었다. 무수 다이클로로메탄(5 mL)에 다이메틸설폭사이드 (DMSO; 326 μL, 4.6 mmol)를 용해시켜 천천히 첨가하고, 10분간 교반하였다. (5-메틸-4-페닐옥사졸-2-일)메탄올 (353 mg, 1.9 mmol)을 무수 다이클로로메탄(5 mL)에 용해시킨 용액을, 상기 반응혼합물에 천천히 적가한 후 30분간 더 교반하였다. 트리에틸아민 (1.3 mL, 9.5 mmol)을 첨가하고 5분간 더 교반한 뒤 반응혼합물을 상온에서 1시간 교반하였다. 반응이 종결되면 물과 에틸 아세테이트를 이용하여 추출하고 유기층을 무수 황산마그네슘으로 건조시킨 후 여과하였다. 여과액을 감압 농축시켜, 농축액을 관 크로마토그래피 (용출액: Hex/EA=4/1)를 통하여 상기 표제화합물 212 mg (수율 61%)을 얻었다.Oxalic chloride (201 μL, 2.3 mmol) was dissolved in anhydrous dichloromethane (10 mL) and the temperature was lowered to -78 ° C. Dimethyl sulfoxide (DMSO; 326 μL, 4.6 mmol) was dissolved in anhydrous dichloromethane (5 mL) and added slowly and stirred for 10 minutes. A solution of (5-methyl-4-phenyloxazol-2-yl) methanol (353 mg, 1.9 mmol) in anhydrous dichloromethane (5 mL) was slowly added dropwise to the reaction mixture, followed by further stirring for 30 minutes. It was. Triethylamine (1.3 mL, 9.5 mmol) was added and further stirred for 5 minutes, and then the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was extracted with water and ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography (eluent: Hex / EA = 4/1) to give 212 mg (yield 61%) of the title compound.
1H NMR (300 MHz, CDCl3-d, ppm) δ 9.73 (s, 1H) 7.91 (m, 2H) 7.51 (m, 3H) 2.94 (s, 3H)
1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 9.73 (s, 1H) 7.91 (m, 2H) 7.51 (m, 3H) 2.94 (s, 3H)
ⅲ) 2-아미노-1-(4-페닐피페라진-1-일)에탄논 (화학식 8)의 제조Iii) Preparation of 2-amino-1- (4-phenylpiperazin-1-yl) ethanone (Formula 8)
1-에틸-3-(3-다이메틸아미노프로필)카보다이이미드 (EDCI, 165 mg, 0.86 mmol), 하이드록시벤조트리아졸 (HOBT, 116 mg, 0.86 mmol), 박글라이신 (100 mg, 0.57 mmol)을 무수 다이클로로메탄 (5 mL)에 용해시키고 N-메틸몰폴리딘 (NMM, 95 μL, 0.86 mmol)을 첨가하고 상온에서 2시간 교반하였다. 1-페닐피페라진 (104 μL, 0.68 mmol)을 첨가하고 다시 2시간 교반하면서 반응 진행과정을 TLC로 확인하였다. 반응이 종결되면 물과 에틸 아세테이트를 이용해서 추출하고 유기층을 무수 황산마그네슘으로 건조시킨 후 여과하였다. 여과액을 감압 농축시켜, 농축액을 관 크로마토그래피 (용출액: Hex/EA=1/1)를 통하여 테트라부틸 2-옥소-2-(4-페닐피페라진-1-일)에틸카바메이트 161 mg (수율 84%)을 얻었다.1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI, 165 mg, 0.86 mmol), hydroxybenzotriazole (HOBT, 116 mg, 0.86 mmol), bacglycine (100 mg, 0.57 mmol ) Was dissolved in anhydrous dichloromethane (5 mL) and N -methylmorpholidine (NMM, 95 μL, 0.86 mmol) was added and stirred at room temperature for 2 hours. 1-phenylpiperazine (104 μL, 0.68 mmol) was added and stirred for another 2 hours to confirm the reaction progress by TLC. After the reaction was completed, the mixture was extracted with water and ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography (eluent: Hex / EA = 1/1) to give 161 mg of tetrabutyl 2-oxo-2- (4-phenylpiperazin-1-yl) ethylcarbamate. Yield 84%).
1H NMR (300 MHz, CDCl3-d, ppm) δ 7.34 (m, 2H) 6.99 (m, 3H) 4.06 (m, 2H) 3.84 (m, 2H) 3.6 (m, 2H) 3.23 (m, 4H) 1.55 (s, 9H) 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.34 (m, 2H) 6.99 (m, 3H) 4.06 (m, 2H) 3.84 (m, 2H) 3.6 (m, 2H) 3.23 (m, 4H ) 1.55 (s, 9H)
테트라부틸 2-옥소-2-(4-페닐피페라진-1-일)에틸카바메이트 (100 mg, 0.31 mmol)를 무수 다이클로로메탄 (1 mL)에 용해시키고, 트리플루오로아세틱산 (TFA, 1 mL)을 무수 다이클로로메탄 (2 mL)에 용해시킨 후 천천히 적가하였다. 반응혼합물을 상온에서 2시간 교반하며 반응 진행과정을 TLC로 확인하였다. 반응이 종결되면 포화 NaHCO3 수용액과 다이클로로메탄을 이용해서 추출하고 유기층을 무수 황산마그네슘으로 건조시킨 후 여과하였다. 여과액을 감압 농축시켜 상기 표제화합물 40 mg (수율 53%)을 얻었다.Tetrabutyl 2-oxo-2- (4-phenylpiperazin-1-yl) ethylcarbamate (100 mg, 0.31 mmol) was dissolved in anhydrous dichloromethane (1 mL) and trifluoroacetic acid (TFA, 1 mL) was dissolved in anhydrous dichloromethane (2 mL) and then slowly added dropwise. The reaction mixture was stirred at room temperature for 2 hours, and the reaction progress was confirmed by TLC. After the reaction was completed, the mixture was extracted with saturated aqueous NaHCO 3 and dichloromethane, and the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain 40 mg of the title compound (yield 53%).
1H NMR (300 MHz, CDCl3-d, ppm) δ 7.36 (m, 2H) 6.98 (m, 3H) 3.86 (m, 2H) 3.60 (m, 4H) 3.23 (m, 4H) 1.72 (br s, 2H)
1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.36 (m, 2H) 6.98 (m, 3H) 3.86 (m, 2H) 3.60 (m, 4H) 3.23 (m, 4H) 1.72 (br s, 2H)
ⅳ) 2-((5-메틸-4-페닐옥사졸-2-일)메틸아미노)-1-(4-페닐피페라진-1-일)에탄논 (화학식 1b)의 제조Iii) Preparation of 2-((5-methyl-4-phenyloxazol-2-yl) methylamino) -1- (4-phenylpiperazin-1-yl) ethanone (Formula 1b)
5-메틸-4-페닐옥사졸-2-카바알데하이드 (50 mg, 0.27 mmol)을 무수 다이클로로메탄에 용해시키고 아세트산 (24 μL, 0.41 mmol), 분자체, 2-아미노-1-(4-페닐피페라진-1-일)에탄논 (90 mg, 0.41 mmol)을 첨가하여 질소 상태에서 30분간 상온에서 교반하였다. 소듐 트리아세톡시보로하이드라이드 (114.4 mg, 0.54 mmol)를 첨가하고 4시간동안 상온에서 교반하며 반응의 진행과정을 TLC로 확인하였다. 반응이 종결되면 2N-NaOH로 중화하고 규조토로 여과하였다. 여액을 감압 농축시키고 물과 다이클로로메탄을 이용하여 추출하였다. 유기층을 무수 황산마그네슘으로 건조시킨 후 여과하였다. 여과액을 감압 농축시켜, 농축액을 관 크로마토그래피 (용출액: EA)를 통하여 상기 표제화합물 88.5 mg (수율 85%)을 얻었다.5-methyl-4-phenyloxazole-2-carbaaldehyde (50 mg, 0.27 mmol) is dissolved in anhydrous dichloromethane and acetic acid (24 μL, 0.41 mmol), molecular sieve, 2-amino-1- (4- Phenylpiperazin-1-yl) ethanone (90 mg, 0.41 mmol) was added and stirred at room temperature for 30 minutes in a nitrogen state. Sodium triacetoxyborohydride (114.4 mg, 0.54 mmol) was added and stirred at room temperature for 4 hours to confirm the progress of the reaction by TLC. Upon completion of the reaction, neutralized with 2N- NaOH and filtered over diatomaceous earth. The filtrate was concentrated under reduced pressure and extracted with water and dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography (eluent: EA) to obtain 88.5 mg (yield 85%) of the title compound.
1H NMR (300 MHz, CDCl3-d, ppm) δ 7.70 (m, 2H) 7.38 (m, 2H) 7.21 (m, 3H) 6.92 (m, 3H) 4.59 (s, 2H) 3.74 (m, 2H) 3.43 (s, 2H) 3.41 (m, 2H) 3.11 (m, 4H) 2.5 (s, 3H) 2.33 (br s, 1H)
1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.70 (m, 2H) 7.38 (m, 2H) 7.21 (m, 3H) 6.92 (m, 3H) 4.59 (s, 2H) 3.74 (m, 2H ) 3.43 (s, 2H) 3.41 (m, 2H) 3.11 (m, 4H) 2.5 (s, 3H) 2.33 (br s, 1H)
참고예 3. E= -(CH2)nNH(CH2)m- 인 알칸아민 화합물의 대표합성예Reference Example 3. Representative Synthesis Example of an Alkanamine Compound E =-(CH 2 ) n NH (CH 2 ) m-
i) 3-(메틸아이소옥사졸-5-일)메탄올 (화학식 9)의 제조 i) Preparation of 3- (methylisoxazol-5-yl) methanol (Formula 9)
질소 하에서 프로피온알데하이드옥심 (2 g, 17.4 mmol)을 무수 다이클로로메탄 (20 mL)에 용해시킨 후 N-클로로숙신이미드 (2.8 g, 20.9 mmol)를 첨가하였다. 반응 혼합물을 상온에서 1시간 교반한 후 진행과 결과를 TLC로 확인하였다. 프로파질 알콜 (2.5 mL, 27 mmol)과 트리에틸아민 (3 mL, 20.9 mmol)을 적가한 후 1시간 더 교반하였다. 반응이 종결되면 포화 NaHCO3 수용액과 다이클로로메탄을 이용하여 추출하여 유기층을 무수 황산마그네슘으로 건조시킨 후 여과하였다. 여과액을 감압 농축시켜, 농축액을 관 크로마토그래피 (용출액: Hex/EA=2/1)를 통하여 상기 표제화합물 1.3 g (수율 44%)을 얻었다.Propionaldehyde oxime (2 g, 17.4 mmol) was dissolved in anhydrous dichloromethane (20 mL) under nitrogen and then N -chlorosuccinimide (2.8 g, 20.9 mmol) was added. After the reaction mixture was stirred at room temperature for 1 hour, progress and results were confirmed by TLC. Propargyl alcohol (2.5 mL, 27 mmol) and triethylamine (3 mL, 20.9 mmol) were added dropwise, followed by further stirring for 1 hour. After completion of the reaction, the mixture was extracted with saturated NaHCO 3 aqueous solution and dichloromethane, and the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography (eluent: Hex / EA = 2/1) to obtain 1.3 g (yield 44%) of the title compound.
1H NMR (300 MHz, CDCl3-d, ppm) δ 6.23 (s, 1 H) 4.54 (s, 2 H) 2.33 (s, 3 H)
1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 6.23 (s, 1 H) 4.54 (s, 2 H) 2.33 (s, 3 H)
ⅱ) 3-메틸아이소옥사졸-5-카바알데하이드 (화학식 10)의 제조Ii) Preparation of 3-methylisoxazole-5-carbaaldehyde (Formula 10)
옥살릭 클로라이드 (201 μL, 2.3 mmol)를 무수 다이클로로메탄 (5 mL)에 용해시킨 후 -78℃로 온도를 낮추었다. 무수 다이클로로메탄(5 mL)에 다이메틸설폭사이드 (DMSO; 326 μL)을 용해시켜 천천히 첨가하고, 10분간 교반하였다. 3-(메틸아이소옥사졸-5-일)메탄올 (353 mg, 1.9 mmol)을 무수 다이클로로메탄(5 mL)에 용해시키고 반응혼합물에 천천히 적가한 후 30분간 더 교반하였다. 트리에틸아민 (1.3 mL, 9.5 mmol)을 첨가하고 5분간 더 교반한 뒤 상온에서 1시간 더 교반하였다. 반응이 종결되면 물과 에틸 아세테이트를 이용하여 추출하여 유기층을 무수 황산마그네슘으로 건조시킨 후 여과하였다. 여과액을 감압 농축시켜, 농축액을 관 크로마토그래피 (용출액: Hex/EA=4/1)를 통하여 상기 표제화합물 212 mg (수율 61%)을 얻었다. Oxalic chloride (201 μL, 2.3 mmol) was dissolved in anhydrous dichloromethane (5 mL) and then cooled to -78 ° C. Dimethyl sulfoxide (DMSO; 326 μL) was dissolved in anhydrous dichloromethane (5 mL) and added slowly and stirred for 10 minutes. 3- (methylisoxazol-5-yl) methanol (353 mg, 1.9 mmol) was dissolved in anhydrous dichloromethane (5 mL) and slowly added dropwise to the reaction mixture, followed by further stirring for 30 minutes. Triethylamine (1.3 mL, 9.5 mmol) was added and stirred for another 5 minutes, followed by further stirring at room temperature for 1 hour. After the reaction was completed, the mixture was extracted with water and ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography (eluent: Hex / EA = 4/1) to give 212 mg (yield 61%) of the title compound.
1H NMR (300 MHz, CDCl3-d, ppm) δ 7.01 (s, 1H) 2.33 (s, 3 H)
1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.01 (s, 1H) 2.33 (s, 3 H)
ⅲ) 2-(4-(2,3-다이메틸페닐)피페라진-1-일)에탄아민 (화학식 11)의 제조Iii) Preparation of 2- (4- (2,3-dimethylphenyl) piperazin-1-yl) ethanamine (Formula 11)
1-(2,3-다이메틸페닐)피페라진 (2 g, 10.5 mmol)을 아세토나이트릴 (10 mL)에 용해시키고 2-(2-브로모에틸)아이소인돌린-1,3-다이온 (3.2 g, 12.6 mmol)과 탄산칼륨 (2.17 g, 16 mmol)을 첨가한 후 90℃에서 12시간 동안 환류하였다. 반응혼합물을 상온으로 식히고 물을 첨가하여 고체가 생성되면 여과하여 2-(2-(4-(2,3-다이메틸페닐)피페라진-1-일)에틸)아이소인돌-1,3-다이온 3.6 g (수율 93%)을 얻었다.1- (2,3-dimethylphenyl) piperazine (2 g, 10.5 mmol) was dissolved in acetonitrile (10 mL) and 2- (2-bromoethyl) isoindolin-1,3-dione ( 3.2 g, 12.6 mmol) and potassium carbonate (2.17 g, 16 mmol) were added and then refluxed at 90 ° C. for 12 hours. The reaction mixture is cooled to room temperature and water is added to form a solid. 3.6 g (93% yield) were obtained.
1H NMR (300 MHz, CDCl3-d, ppm) δ 7.91 (m, 2H) 7.87 (m, 2 H) 7.3 (t, J = 4.5 Hz, 1 H) 6.95 (t, J = 9 Hz, 2 H) 3.9 (br s, 2 H) 2.98 (br s, 4 H) 2.5 (br s, 4 H) 2.29 (s, 3H) 2.24 (s, 3H) 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.91 (m, 2H) 7.87 (m, 2H) 7.3 (t, J = 4.5 Hz, 1 H) 6.95 (t, J = 9 Hz, 2 H) 3.9 (br s, 2 H) 2.98 (br s, 4 H) 2.5 (br s, 4 H) 2.29 (s, 3H) 2.24 (s, 3H)
2-(2-(4-(2,3-다이메틸페닐)피페라진-1-일)에틸)아이소인돌-1,3-다이온 (2 g, 5.5 mmol)과 하이드라진 모노하이드레이트 (800 μL, 17 mmol)를 에탄올 (5 mL)에 용해시키고 2시간동안 환류하였다. 반응진행 과정을 TLC로 확인하였고, 반응이 종결되면 반응혼합물을 상온으로 식히고 생성된 고체를 여과하고 여액을 감압 증류하였다. 다시 생생되는 고체를 여과하고 여액을 감압증류하는 과정을 2번 반복하여 상기 표제화합물 1.2 g (수율 93%)을 얻었다.2- (2- (4- (2,3-dimethylphenyl) piperazin-1-yl) ethyl) isoindole-1,3-dione (2 g, 5.5 mmol) with hydrazine monohydrate (800 μL, 17 mmol) was dissolved in ethanol (5 mL) and refluxed for 2 hours. The reaction progress was confirmed by TLC. When the reaction was completed, the reaction mixture was cooled to room temperature, the resulting solid was filtered and the filtrate was distilled under reduced pressure. The resulting solid was filtered and the filtrate was distilled under reduced pressure twice to give 1.2 g (yield 93%) of the title compound.
1H NMR (300 MHz, CDCl3-d, ppm) δ 7.09 (t, J = 15.4 Hz, 1H) 6.92 (t, J = 13.2 Hz, 2H) 2.91 (m, 6H) 2.64 (br s, 4H) 2.55 (t, J = 12 Hz, 2H) 2.51 (s, 3H) 2.27 (s, 3H) 1.87 (br s, 2H)
1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.09 (t, J = 15.4 Hz, 1H) 6.92 (t, J = 13.2 Hz, 2H) 2.91 (m, 6H) 2.64 (br s, 4H) 2.55 (t, J = 12 Hz, 2H) 2.51 (s, 3H) 2.27 (s, 3H) 1.87 (br s, 2H)
ⅳ) 2-(4-(2,3-다이메틸페닐)피페라진-1-일)-N-((3-메틸아이소옥사졸-5-일)메틸)에탄아민 (화학식 1c)의 제조Iii) Preparation of 2- (4- (2,3-dimethylphenyl) piperazin-1-yl) -N -((3-methylisoxazol-5-yl) methyl) ethanamine (Formula 1c)
3-메틸아이소옥사졸-5-카바알데하이드 (50 mg, 0.45 mmol)을 무수 다이클로로메탄에 용해시키고 아세트산 (52 μL, 0.9 mmol), 분자체, 2-(4-(2,3-다이메틸페닐)피페라진-1-일)에탄아민 (157 mg, 0.68 mmol)을 첨가하여 질소 상태에서 30분간 상온에서 교반하였다. (NaBH(oAC)3 (144 mg, 0.68 mmol)을 첨가하고 4시간 동안 상온에서 교반하며 반응진행 과정을 TLC로 확인하였다. 반응이 종결되면 2M-NaOH로 중화하고 규조토로 여과하였다. 여액을 감압 농축시키고 물과 다이클로로메탄을 이용하여 추출하였다. 유기층을 무수 황산마그네슘으로 건조시킨 후 여과하였다. 여과액을 감압 농축시켜, 농축액을 관 크로마토그래피 (용출액: EA)를 통하여 상기 표제화합물 33 mg (수율 20%)을 얻었다.3-methylisoxazole-5-carbaaldehyde (50 mg, 0.45 mmol) was dissolved in anhydrous dichloromethane and acetic acid (52 μL, 0.9 mmol), molecular sieve, 2- (4- (2,3-dimethylphenyl ) Piperazin-1-yl) ethanamine (157 mg, 0.68 mmol) was added and stirred at room temperature for 30 minutes in nitrogen. (NaBH (oAC) 3 (144 mg, 0.68 mmol) was added and stirred at room temperature for 4 hours, and the reaction proceeded by TLC. Upon completion of the reaction, the reaction was neutralized with 2M-NaOH and filtered through diatomaceous earth. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography (eluent: EA). Yield 20%).
1H NMR (300 MHz, CDCl3-d, ppm) δ 7.09 (t, J = 7.7 Hz, 1 H) 6.92 (m, 2H) 6.02 (s, 1H) 3.93 (s, 2H) 2.91 (m, 4H) 2.78 (m, 2H) 2.59 (m, 6H) 2.28 (m, 6H) 2.22 (s, 3H)
1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.09 (t, J = 7.7 Hz, 1 H) 6.92 (m, 2H) 6.02 (s, 1H) 3.93 (s, 2H) 2.91 (m, 4H ) 2.78 (m, 2H) 2.59 (m, 6H) 2.28 (m, 6H) 2.22 (s, 3H)
참고예 4. E= -(CH2)nNHC(O)(CH2)m- 인 아마이드 화합물의 대표합성예Reference Example 4. Representative Synthesis Example of E =-(CH 2 ) n NHC (O) (CH 2 ) m -Phosphorus Amide Compound
i) (5-아이소부틸-4-페닐옥사졸-2-일)메탄올 (화학식 13)의 제조i) Preparation of (5-Isobutyl-4-phenyloxazol-2-yl) methanol
메틸발레로페논 (2 g, 11 mmol)과 HDNIB(8 g, 17 mmol)을 아세토나이트릴 (50 mL)에 용해시킨 후 80℃에서 1시간 동안 환류하였다. 글리코아마이드 (1.7 g, 23 mmol)를 첨가하고 2일 동안 교반하면서 반응진행 과정을 TLC로 확인하였다. 반응이 종결되면 상온으로 식히고 물과 에틸 아세테이트를 이용하여 추출하고, 유기층을 무수 황산마그네슘으로 건조시킨 후 여과하였다. 여과액을 감압 농축시켜, 농축액을 관 크로마토그래피 (용출액: Hex/EA=1/1)를 통하여 상기 표제화합물 405 mg (수율 15%)을 얻었다.Methylvalerophenone (2 g, 11 mmol) and HDNIB (8 g, 17 mmol) were dissolved in acetonitrile (50 mL) and then refluxed at 80 ° C. for 1 hour. Glycoamide (1.7 g, 23 mmol) was added and stirred for 2 days to confirm the reaction progress by TLC. After the reaction was completed, the mixture was cooled to room temperature, extracted with water and ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography (eluent: Hex / EA = 1/1) to obtain 405 mg (yield 15%) of the title compound.
1H NMR (300 MHz, CDCl3-d, ppm) δ 7.64 (d, J = 3.42 Hz, 2H) 7.42 (t, J = 6.83 Hz, 2H) 7.35 (t, J = 1.26 Hz, 1H) 4.74(s, 2H) 2.74 (d, J = 7.21 Hz, 2H) 2.08 (m, 1H), 0.97 (d, J = 6.64 Hz, 6H)
1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.64 (d, J = 3.42 Hz, 2H) 7.42 (t, J = 6.83 Hz, 2H) 7.35 (t, J = 1.26 Hz, 1H) 4.74 ( s, 2H) 2.74 (d, J = 7.21 Hz, 2H) 2.08 (m, 1H), 0.97 (d, J = 6.64 Hz, 6H)
ⅱ) 2-((5-아이소부틸-4-페닐옥사졸-2-일)메틸)아이소인돌린-1,3-다이온 (화학식 14)의 제조Ii) Preparation of 2-((5-isobutyl-4-phenyloxazol-2-yl) methyl) isoindolin-1,3-dione (Formula 14)
(5-아이소부틸-4-페닐옥사졸-2-일)메탄올 (100 mg, 0.43 mmol), 트리페닐포스핀 (170 mg, 0.65 mmol)와 프탈이미드 (96 mg, 0.65 mmol)를 무수 테트라하이드로퓨란에 용해시켰다. 다이아이소프로필아조다이카복실레이트 (DIAD, 123 μL, 0.65 mmol)를 천천히 적가하고, 상온에서 3시간 교반하였다. 반응혼합물을 감압 농축시켜 농축액을 관 크로마토그래피 (용출액: Hex/EA=5/1)를 통하여 상기 표제화합물 190 mg (수율 61%)을 얻었다.(5-isobutyl-4-phenyloxazol-2-yl) methanol (100 mg, 0.43 mmol), triphenylphosphine (170 mg, 0.65 mmol) and phthalimide (96 mg, 0.65 mmol) were dissolved in anhydrous tetra Dissolved in hydrofuran. Diisopropylazodicarboxylate (DIAD, 123 μL, 0.65 mmol) was slowly added dropwise and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to give 190 mg (yield 61%) of the title compound by column chromatography (eluent: Hex / EA = 5/1).
1H NMR (300 MHz, CDCl3-d, ppm) δ 7.59 (m, 6H) 7.38 (m, 3H) 4.89 (s, 2H) 2.79 (d, J = 7.21 Hz, 2H) 2.08 (m, 1H), 0.97 (d, J = 6.64 Hz, 6H)
1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.59 (m, 6H) 7.38 (m, 3H) 4.89 (s, 2H) 2.79 (d, J = 7.21 Hz, 2H) 2.08 (m, 1H) , 0.97 (d, J = 6.64 Hz, 6H)
ⅲ) (5-아이소부틸-4-페닐옥사졸-2-일)메탄아민 (화학식 15)의 제조Iii) Preparation of (5-isobutyl-4-phenyloxazol-2-yl) methanamine (Formula 15)
2-((5-아이소부틸-4-페닐옥사졸-2-일)메틸)아이소인돌린-1,3-다이온 (190 mg, 0.53 mmol)과 하이드라진 모노하이드레이트 (77 μL, 1.58 mmol)를 에탄올 (5 mL)에 용해시키고 2시간 동안 환류하였다. 반응진행 과정을 TLC로 확인하였고, 반응이 종결되면 반응혼합물을 상온으로 식히고 생성된 고체를 여과하고 여액을 감압 증류하였다. 다시 생성되는 고체를 여과하고 여액을 감압증류하는 과정을 2번 반복하여 상기 표제화합물 97 mg (수율 80%)을 얻었다.2-((5-isobutyl-4-phenyloxazol-2-yl) methyl) isoindolin-1,3-dione (190 mg, 0.53 mmol) and hydrazine monohydrate (77 μL, 1.58 mmol) It was dissolved in ethanol (5 mL) and refluxed for 2 hours. The reaction progress was confirmed by TLC. When the reaction was completed, the reaction mixture was cooled to room temperature, the resulting solid was filtered and the filtrate was distilled under reduced pressure. The resulting solid was filtered and the filtrate was distilled under reduced pressure twice to give 97 mg (yield 80%) of the title compound.
1H NMR (300 MHz, CDCl3-d, ppm) δ 7.8 (d, J = 6.7 Hz, 2H) 7.65 (m, 2H) 7.35 (m, 1H) 4.44 (s, 2H) 4.02 (s, 2H) 2.86 (m, 2H) 2.11 (m, 1 H) 1.89 (br s, 2 H) 0.97 (d, J = 6.64 Hz, 6H)
1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.8 (d, J = 6.7 Hz, 2H) 7.65 (m, 2H) 7.35 (m, 1H) 4.44 (s, 2H) 4.02 (s, 2H) 2.86 (m, 2H) 2.11 (m, 1H) 1.89 (br s, 2H) 0.97 (d, J = 6.64 Hz, 6H)
ⅳ) 2-클로로-N-((5-아이소부틸-4-페닐옥사졸-2-일)메틸)아세타아마이드 (화학식 16)의 제조Iii) Preparation of 2-chloro- N -((5-isobutyl-4-phenyloxazol-2-yl) methyl) acetamide (Formula 16)
(5-아이소부틸-4-페닐옥사졸-2-일)메탄아민 (500 mg, 2.2 mmol)을 무수 다이클로로메탄에 용해시키고 0℃에서 클로로아세틸클로라이드 (191 μL, 2.4 mmol)을 천천히 적가하였다. 반응혼합물을 상온에서 2시간 교반하면서 반응진행 과정을 TLC로 확인하였다. 반응이 종결되면 포화 NaHCO3 수용액과 다이클로로메탄을 이용하여 추출하고 유기층을 무수 황산마그네슘으로 건조시킨 후 여과하였다. 여과액을 감압 농축시켜, 농축액을 관 크로마토그래피 (용출액: Hex/EA=1/1)를 통하여 상기 표제화합물 450 mg (수율 68%)을 얻었다.(5-isobutyl-4-phenyloxazol-2-yl) methanamine (500 mg, 2.2 mmol) was dissolved in anhydrous dichloromethane and chloroacetylchloride (191 μL, 2.4 mmol) was slowly added dropwise at 0 ° C. . While stirring the reaction mixture at room temperature for 2 hours, the reaction progress was confirmed by TLC. After completion of the reaction, the mixture was extracted with saturated aqueous NaHCO 3 and dichloromethane, and the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography (eluent: Hex / EA = 1/1) to obtain 450 mg (yield 68%) of the title compound.
1H NMR (300 MHz, CDCl3-d, ppm) δ 7.79 (d, J = 13.5 Hz, 2H) 7.68 (m, 3H) 4.46 (s, 2H) 4.21 (s, 2H) 2.79 (d, J = 10.2 Hz, 2H) 2.31 (m, 1 H) 0.99 (s, 6H)
1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.79 (d, J = 13.5 Hz, 2H) 7.68 (m, 3H) 4.46 (s, 2H) 4.21 (s, 2H) 2.79 (d, J = 10.2 Hz, 2H) 2.31 (m, 1H) 0.99 (s, 6H)
v) N-((5-아이소부틸-4-페닐옥사졸-2-일)메틸)-2-(피페라진-1-일)아세타아마이드 (화학식 17)의 제조v) Preparation of N- ((5-isobutyl-4-phenyloxazol-2-yl) methyl) -2- (piperazin-1-yl) acetamide (Formula 17)
2-클로로-N-((5-아이소부틸-4-페닐옥사졸-2-일)메틸)아세타아마이드 (150 mg, 0.49 mmol)를 무수 다이클로로메탄에 용해시키고 피페라진 (129 mg, 1.5 mmol)과 N,N-다이아이소프로필에틸아민 (EDIPA; 171 μL, 0.98 mmol)을 적가하였다. 반응혼합물을 상온에서 12시간 교반하면서 반응진행과 결과를 TLC로 확인하였다. 반응이 종결되면 물과 다이클로로메탄을 이용하여 추출하고 유기층을 무수 황산마그네슘으로 건조시킨 후 여과하였다. 여과액을 감압 농축시켜, 농축액을 관 크로마토그래피 (용출액: CHCl3/MeOH/H2O/NH2OH=80/20/1/1)를 통하여 상기 표제화합물 112 mg (수율 64%)을 얻었다. 2-Chloro- N -((5-isobutyl-4-phenyloxazol-2-yl) methyl) acetamide (150 mg, 0.49 mmol) was dissolved in anhydrous dichloromethane and piperazine (129 mg, 1.5 mmol) and N, N -diisopropylethylamine (EDIPA; 171 μL, 0.98 mmol) were added dropwise. While stirring the reaction mixture at room temperature for 12 hours, the reaction progress and results were confirmed by TLC. After the reaction was completed, the mixture was extracted with water and dichloromethane, and the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography (eluent: CHCl 3 / MeOH / H 2 O / NH 2 OH = 80/20/1/1) to obtain 112 mg (yield 64%) of the title compound. .
1H NMR (300 MHz, CDCl3-d, ppm) δ 7.85 (s, 1H) 6.65 (d, J = 3.3 Hz, 2H) 7.41 (t, J = 15.2 Hz, 2H) 7.31 (m, 1H) 4.62 (d, J = 5.7 Hz, 2H) 3.08 (s, 2H) 2.94 (t, J = 10.2 Hz, 4H) 2.74 (d, J = 4.3 Hz, 2H) 2.57 (br s, 4H), 2.15 (s, 1H) 1.26 (s, 1H) 0.97 (d, J = 5.6 Hz, 6H)
1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.85 (s, 1H) 6.65 (d, J = 3.3 Hz, 2H) 7.41 (t, J = 15.2 Hz, 2H) 7.31 (m, 1H) 4.62 (d, J = 5.7 Hz, 2H) 3.08 (s, 2H) 2.94 (t, J = 10.2 Hz, 4H) 2.74 (d, J = 4.3 Hz, 2H) 2.57 (br s, 4H), 2.15 (s, 1H) 1.26 (s, 1H) 0.97 (d, J = 5.6 Hz, 6H)
vi) N-((5-아이소부틸-4-페닐옥사졸-2-일)메틸)-2-(4-(페닐설포닐)-1,4-다이아제판-1-일)아세타아마이드(화학식 1d)의 합성 vi) N- ((5-isobutyl-4-phenyloxazol-2-yl) methyl) -2- (4- (phenylsulfonyl) -1,4-diazepan-1-yl) acetamide ( Synthesis of Formula 1d)
N-((5-아이소부틸-4-페닐옥사졸-2-일)메틸)-2-(피페라진-1-일)아세타아마이드 (50 mg, 0.13 mmol)을 무수 테트라하이드로퓨란을 용매로 하여 트리에틸아민(54 μL, 0.39 mmol)와 벤젠설포닐클로라이드 (23 μL, 0.18 mmol)을 첨가하고 상온에서 2시간 동안 교반하였다. 반응 진행과정은 TLC로 확인하였고 반응이 종결되면 물과 다이클로로메탄을 사용하여 추출하였다. 유기층을 무수 황산마그네슘으로 건조시킨 후 여과하였다. 여과액을 감압 농축시켜, 농축액을 관 크로마토그래피 (용출액: EA)를 통하여 상기 표제화합물 57 mg (수율 82%)을 얻었다. N- ((5-isobutyl-4-phenyloxazol-2-yl) methyl) -2- (piperazin-1-yl) acetamide (50 mg, 0.13 mmol) with anhydrous tetrahydrofuran as a solvent Triethylamine (54 μL, 0.39 mmol) and benzenesulfonylchloride (23 μL, 0.18 mmol) were added and stirred at room temperature for 2 hours. The progress of the reaction was confirmed by TLC, and when the reaction was completed, the mixture was extracted with water and dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography (eluent: EA) to obtain 57 mg (yield 82%) of the title compound.
1H NMR (300 MHz, CDCl3-d, ppm) δ 7.75 (m, 3H) 7.57 (dd, J = 13.66 Hz, 3H) 7.43 (td, J = 18.17 Hz, 4H) 7.30 (t, J = 7.59 Hz, 1H) 4.59 (d, J = 2.84 Hz, 2H) 3.41 (m, 4H) 3.22 (s, 2H) 2.82 (m, 4H) 2.73 (d, J = 3.69 Hz, 2H) 2.07 (quint, J = 9.12 Hz, 1H) 1.91 (m, 2H) 0.96 (d, J = 3.33 Hz, 6H); 13C NMR (75 MHz, CDCl3-d, ppm) δ 170.53 158.39 147.99 139.20 135.14 132.49 132.17 129.10 128.56 127.39 126.90 126.76 61.37 57.19 55.24 48.42 47.17 36.41 34.77 28.37 28.14 22.46
1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.75 (m, 3H) 7.57 (dd, J = 13.66 Hz, 3H) 7.43 (td, J = 18.17 Hz, 4H) 7.30 (t, J = 7.59 Hz, 1H) 4.59 (d, J = 2.84 Hz, 2H) 3.41 (m, 4H) 3.22 (s, 2H) 2.82 (m, 4H) 2.73 (d, J = 3.69 Hz, 2H) 2.07 (quint, J = 9.12 Hz, 1 H) 1.91 (m, 2 H) 0.96 (d, J = 3.33 Hz, 6H); 13 C NMR (75 MHz, CDCl 3 - d , ppm) δ 170.53 158.39 147.99 139.20 135.14 132.49 132.17 129.10 128.56 127.39 126.90 126.76 61.37 57.19 55.24 48.42 47.17 36.41 34.77 28.37 28.14 22.46
상기 참고예 1 내지 4의 방법에 의해 합성된 화합물 및 이들 화합물의 구조확인데이터는 하기와 같다.
Compounds synthesized by the methods of Reference Examples 1 to 4 and structural confirmation data of these compounds are as follows.
실시예 1. 3-(3-페닐아이소옥사졸-5-일)-1-(4-페닐피페라진-1-일)프로판-1-온 (화합물번호 1)Example 1. 3- (3-phenylisoxazol-5-yl) -1- (4-phenylpiperazin-1-yl) propan-1-one (Compound No. 1)
수율 87%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 7.79 (m, 2H) 7.46 (t, J = 5 Hz, 3H) 7.30 (m, 2H) 6.94 (br s, 3H) 6.4 (s, 1H) 3.82 (s, 2H) 3.66 (s, 2H) 3.19 (m, 6H) 2.85 (t, J = 7.4 Hz, 2H)
Yield 87%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.79 (m, 2H) 7.46 (t, J = 5 Hz, 3H) 7.30 (m, 2H) 6.94 (br s, 3H) 6.4 (s, 1H ) 3.82 (s, 2H) 3.66 (s, 2H) 3.19 (m, 6H) 2.85 (t, J = 7.4 Hz, 2H)
실시예 2. 3-(3-페닐-1,2,4-옥사다이아졸-5-일)-1-(4-페닐피페라진-1-일)프로판-1-온 (화합물번호 2)Example 2. 3- (3-phenyl-1,2,4-oxadiazol-5-yl) -1- (4-phenylpiperazin-1-yl) propan-1-one (Compound No. 2)
수율 28%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 8.07 (m, 2H) 7.49 (m, 3H) 7.31 (t, J = 8.0 Hz, 2H) 6.95 (t, J = 8.1 Hz, 3H) 3.82 (s, 2H) 3.72 (s, 2H) 3.36 (t, J = 7.3 Hz, 2H) 3.25 (s, 2H) 3.21 (s, 2H) 3.01 (t, J = 7.3 Hz, 2H)
Yield 28%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 8.07 (m, 2H) 7.49 (m, 3H) 7.31 (t, J = 8.0 Hz, 2H) 6.95 (t, J = 8.1 Hz, 3H) 3.82 (s, 2H) 3.72 (s, 2H) 3.36 (t, J = 7.3 Hz, 2H) 3.25 (s, 2H) 3.21 (s, 2H) 3.01 (t, J = 7.3 Hz, 2H)
실시예 3. 4-(3-페닐아이소옥사졸-5-일)-1-(4-페닐피페라진-1일)부탄-1-온 (화합물번호 3)Example 3. 4- (3-phenylisoxazol-5-yl) -1- (4-phenylpiperazin-1yl) butan-1-one (Compound No. 3)
수율 87%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 7.8 (m, 2H) 7.47 (m, 3H) 7.31 (m, 3H) 6.93 (br s, 2H) 6.37 (s, 1H) 3.81 (s, 2H) 3.63 (s, 2H) 3.19 (s, 4H) 2.94 (t, J = 7.3 Hz, 2H) 2.48 (t, J = 7.3 Hz, 2H) 2.17 (quint, J = 11 Hz, 2H)
Yield 87%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.8 (m, 2H) 7.47 (m, 3H) 7.31 (m, 3H) 6.93 (br s, 2H) 6.37 (s, 1H) 3.81 (s, 2H) 3.63 (s, 2H) 3.19 (s, 4H) 2.94 (t, J = 7.3 Hz, 2H) 2.48 (t, J = 7.3 Hz, 2H) 2.17 (quint, J = 11 Hz, 2H)
실시예 4. 4-(3-페닐-1,2,4-옥사다이아졸-5-일)-1-(4-페닐피페라진-1-일)부탄-1-온 (화합물번호 4)Example 4. 4- (3-phenyl-1,2,4-oxadiazol-5-yl) -1- (4-phenylpiperazin-1-yl) butan-1-one (Compound No. 4)
수율 50%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 8.12 (m, 2H) 7.53 (m, 3H) 7.35 (m, 2H) 6.97 (d, J = 0.9 Hz, 3H) 3.85 (s, 2H) 3.69 (s, 2H) 3.22 (s, 4H) 3.13 (t, J = 7.05 Hz, 2H) 2.59 (t, J = 7.2 Hz, 2H) 2.33 (quint, J = 10.5 Hz, 2H)
Yield 50%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 8.12 (m, 2H) 7.53 (m, 3H) 7.35 (m, 2H) 6.97 (d, J = 0.9 Hz, 3H) 3.85 (s, 2H) 3.69 (s, 2H) 3.22 (s, 4H) 3.13 (t, J = 7.05 Hz, 2H) 2.59 (t, J = 7.2 Hz, 2H) 2.33 (quint, J = 10.5 Hz, 2H)
실시예 5. 1-(4-(3-클로로페닐)피페라진-1-일)-4-(3-페닐-1,2,4-옥사다이아졸-5-일)부탄-1-온 (화합물번호 5)Example 5. 1- (4- (3-chlorophenyl) piperazin-1-yl) -4- (3-phenyl-1,2,4-oxadiazol-5-yl) butan-1-one ( Compound number 5)
수율 42%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 7.79 (m, 2H) 7.46 (t, J = 5 Hz, 3H) 7.30 (m, 2H) 6.94 (br s, 3H) 6.4 (s, 1H) 3.82 (s, 2H) 3.66 (s, 2H) 3.19 (m, 6H) 2.85 (t, J = 7.4 Hz, 2H)
Yield 42%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.79 (m, 2H) 7.46 (t, J = 5 Hz, 3H) 7.30 (m, 2H) 6.94 (br s, 3H) 6.4 (s, 1H ) 3.82 (s, 2H) 3.66 (s, 2H) 3.19 (m, 6H) 2.85 (t, J = 7.4 Hz, 2H)
실시예 6. 1-(4-(3-클로로페닐)피페라진-1일)-4-(3-페닐아이소옥사졸-5-일)부탄-1-온 (화합물번호 6)Example 6. 1- (4- (3-chlorophenyl) piperazin-1yl) -4- (3-phenylisoxazol-5-yl) butan-1-one (Compound No. 6)
수율 32%; 1H NMR (300 MHz, DMSO-d 6, ppm) δ 7.99 (dd, J = 4.7 Hz, 2H) 7.57 (m, 3H) 7.21 (t, J = 8.1 Hz, 1H) 6.91 (t, J = 8.1 Hz, 2H) 6.80 (d, J = 7.7 Hz, 1H) 3.58 (s, 4H) 3.17 (s, 2H) 3.14 (s, 2H) 3.05 (t, J = 7.5 Hz, 2H) 2.03 (quint, J = 7.2 Hz, 2H)
Yield 32%; 1 H NMR (300 MHz, DMSO- d 6 , ppm) δ 7.99 (dd, J = 4.7 Hz, 2H) 7.57 (m, 3H) 7.21 (t, J = 8.1 Hz, 1H) 6.91 (t, J = 8.1 Hz, 2H) 6.80 (d, J = 7.7 Hz, 1H) 3.58 (s, 4H) 3.17 (s, 2H) 3.14 (s, 2H) 3.05 (t, J = 7.5 Hz, 2H) 2.03 (quint, J = 7.2 Hz, 2H)
실시예 7. 1-(4-(3-클로로페닐)피페라진-1-일)-3-(3-페닐아이소옥사졸-5-일)프로판-1-온 (화합물번호 7)Example 7. 1- (4- (3-chlorophenyl) piperazin-1-yl) -3- (3-phenylisoxazol-5-yl) propan-1-one (Compound No. 7)
수율 53%; 1H NMR (300 MHz, DMSO-d 6, ppm) δ 7.83 (m, 2H) 7.49 (m, 3H) 6.88 (m, 4H) 3.57 (s, 4H) 3.47 (t, J = 5.0 Hz, 1H) 3.41 (t, J = 4.8 Hz, 1H) 3.17 (m, 4H) 2.84 (t, J = 7.5 Hz, 2H) 1.93 (quint, J = 7.4 Hz, 2H)
Yield 53%; 1 H NMR (300 MHz, DMSO- d 6 , ppm) δ 7.83 (m, 2H) 7.49 (m, 3H) 6.88 (m, 4H) 3.57 (s, 4H) 3.47 (t, J = 5.0 Hz, 1H) 3.41 (t, J = 4.8 Hz, 1H) 3.17 (m, 4H) 2.84 (t, J = 7.5 Hz, 2H) 1.93 (quint, J = 7.4 Hz, 2H)
실시예 8. 1-(4-(4-클로로페닐)피페라진-1-일)-4-(3-페닐-1,2,4-옥사다이아졸-5-일)부탄-1-온 (화합물번호 8)Example 8. 1- (4- (4-Chlorophenyl) piperazin-1-yl) -4- (3-phenyl-1,2,4-oxadiazol-5-yl) butan-1-one ( Compound no.8)
수율 84%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 8.06(m, 2H) 7.48 (m, 3H) 7.23 (m, 3H) 6.9 (m, 2H) 6.8 (dd, J = 8.9 Hz, 1H) 3.81 (m, 2H) 3.72 (m, 2H) 3.36 (t, J = 7.2 Hz, 2H) 3.21 (m, 4H) 3.01 (t, J = 7.2 Hz, 2H)
Yield 84%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 8.06 (m, 2H) 7.48 (m, 3H) 7.23 (m, 3H) 6.9 (m, 2H) 6.8 (dd, J = 8.9 Hz, 1H) 3.81 (m, 2H) 3.72 (m, 2H) 3.36 (t, J = 7.2 Hz, 2H) 3.21 (m, 4H) 3.01 (t, J = 7.2 Hz, 2H)
실시예 9. 1-(4-(4-클로로페닐)피페라진-1-일)-3-(3-페닐-1,2,4-옥사다이아졸-5-일)프로판-1-온 (화합물번호 9)Example 9. 1- (4- (4-chlorophenyl) piperazin-1-yl) -3- (3-phenyl-1,2,4-oxadiazol-5-yl) propan-1-one ( Compound number 9)
수율 75%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 8.08 (m, 2H) 7.5 (m, 3H) 7.3 (m, 2H) 6.87 (d, J = 8.5 Hz, 2H) 3.81 (m, 2H) 3.65 (m, 2H) 3.11 (m, 6H) 2.54 (t, J = 7.0 Hz, 2H) 2.30 (quint, J = 9.0 Hz, 2H)
Yield 75%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 8.08 (m, 2H) 7.5 (m, 3H) 7.3 (m, 2H) 6.87 (d, J = 8.5 Hz, 2H) 3.81 (m, 2H) 3.65 (m, 2H) 3.11 (m, 6H) 2.54 (t, J = 7.0 Hz, 2H) 2.30 (quint, J = 9.0 Hz, 2H)
실시예 10. 1-(4-(4-클로로페닐)피페라진-1-일)-4-(3-페닐아이소옥사졸-5-일)부탄-1-온 (화합물번호 10)Example 10. 1- (4- (4-chlorophenyl) piperazin-1-yl) -4- (3-phenylisoxazol-5-yl) butan-1-one (Compound No. 10)
수율 65%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 8.07 (m, 2H) 7.47 (m, 3H) 7.25 (m, 2H) 6.85 (t, J = 9 Hz, 2H) 3.82 (m, 2H) 3.72 (m, 2H) 3.36 (t, J = 7.3 Hz, 2H) 3.2 (m, 2H) 3.14 (m, 2H) 3.0 (t, J = 7.3 Hz, 2H)
Yield 65%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 8.07 (m, 2H) 7.47 (m, 3H) 7.25 (m, 2H) 6.85 (t, J = 9 Hz, 2H) 3.82 (m, 2H) 3.72 (m, 2H) 3.36 (t, J = 7.3 Hz, 2H) 3.2 (m, 2H) 3.14 (m, 2H) 3.0 (t, J = 7.3 Hz, 2H)
실시예 11. 1-(4-(4-클로로페닐)피페라진-1-일)-3-(3-페닐아이소옥사졸-5-일)프로판-1-온 (화합물번호 11)Example 11. 1- (4- (4-chlorophenyl) piperazin-1-yl) -3- (3-phenylisoxazol-5-yl) propan-1-one (Compound No. 11)
수율 82%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 7.79(m, 2H) 7.46 (m, 3H) 7.25 (m, 2H) 7.0 (d, J = 8.8 Hz, 2H) 6.37 (s, 1H) 3.73 (m, 2H) 3.63 (m, 2H) 3.14 (s, 4H) 2.94 (t, J = 7.2 Hz, 2H) 2.48 (t, J = 7.2 Hz, 2H) 2.16 (quint, J = 14.4 Hz, 2H)
Yield 82%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.79 (m, 2H) 7.46 (m, 3H) 7.25 (m, 2H) 7.0 (d, J = 8.8 Hz, 2H) 6.37 (s, 1H) 3.73 (m, 2H) 3.63 (m, 2H) 3.14 (s, 4H) 2.94 (t, J = 7.2 Hz, 2H) 2.48 (t, J = 7.2 Hz, 2H) 2.16 (quint, J = 14.4 Hz, 2H )
실시예 12. 1-(4-(2-클로로페닐)피페라진-1-일)-4-(3-페닐-1,2,4-옥사다이아졸-5-일)부탄-1-온 (화합물번호 12)Example 12. 1- (4- (2-chlorophenyl) piperazin-1-yl) -4- (3-phenyl-1,2,4-oxadiazol-5-yl) butan-1-one ( Compound number 12)
수율 50%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 7.79(m, 2H) 7.45 (m, 3H) 7.23 (d, J = 4.8 Hz, 2H) 6.86 (d, J = 8.9 Hz, 2H) 6.40 (s, 1H) 3.80 (t, J = 5.0 Hz, 2H) 3.65 (t, J = 4.6 Hz 2H) 3.23 (t, J = 7.4 Hz, 2H) 3.13 (q, J = 7.1 Hz, 4H) 2.85 (t, J = 7.4 Hz, 2H)
Yield 50%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.79 (m, 2H) 7.45 (m, 3H) 7.23 (d, J = 4.8 Hz, 2H) 6.86 (d, J = 8.9 Hz, 2H) 6.40 (s, 1H) 3.80 (t, J = 5.0 Hz, 2H) 3.65 (t, J = 4.6 Hz 2H) 3.23 (t, J = 7.4 Hz, 2H) 3.13 (q, J = 7.1 Hz, 4H) 2.85 ( t, J = 7.4 Hz, 2H)
실시예 13. 1-(4-(4-클로로페닐)피페라진-1-일)-3-(3-페닐-1,2,4-옥사다이아졸-5-일)프로판-1-온 (화합물번호 13)Example 13. 1- (4- (4-Chlorophenyl) piperazin-1-yl) -3- (3-phenyl-1,2,4-oxadiazol-5-yl) propan-1-one ( Compound number 13)
수율 50%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 7.79(m, 2H) 7.45 (m, 3H) 7.23 (d, J = 4.8 Hz, 2H) 6.86 (d, J = 8.9 Hz, 2H) 6.40 (s, 1H) 3.80 (t, J = 5.0 Hz, 2H) 3.23 (t, J = 7.4 Hz, 2H) 3.13 (q, J = 7.1 Hz, 4H) 2.85 (t, J = 7.4 Hz, 2H)
Yield 50%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.79 (m, 2H) 7.45 (m, 3H) 7.23 (d, J = 4.8 Hz, 2H) 6.86 (d, J = 8.9 Hz, 2H) 6.40 (s, 1H) 3.80 (t, J = 5.0 Hz, 2H) 3.23 (t, J = 7.4 Hz, 2H) 3.13 (q, J = 7.1 Hz, 4H) 2.85 (t, J = 7.4 Hz, 2H)
실시예 14. 1-(4-(2-클로로페닐)피페라진-1-일)-4-(3-페닐아이소옥사졸-5-일)부탄-1-온 (화합물번호 14)Example 14 1- (4- (2-chlorophenyl) piperazin-1-yl) -4- (3-phenylisoxazol-5-yl) butan-1-one (Compound No. 14)
수율 55%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 7.80 (m, 2H) 7.41 (m, 3H) 7.22 (m, 5H) 7.01 (m, 2H) 7.01 (m, 2H) 6.37 (s, 1H) 3.82 (m, 3H) 3.65 (m, 3H) 3.03 (s, 4H) 2.94 (t, J = 7.3 Hz, 3H) 2.12 (m, 6H)
Yield 55%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.80 (m, 2H) 7.41 (m, 3H) 7.22 (m, 5H) 7.01 (m, 2H) 7.01 (m, 2H) 6.37 (s, 1H ) 3.82 (m, 3H) 3.65 (m, 3H) 3.03 (s, 4H) 2.94 (t, J = 7.3 Hz, 3H) 2.12 (m, 6H)
실시예 15. 1-(4-벤즈하이드릴피페라진-1-일)-4-(3-페닐-1,2,4-옥사다이아졸-5-일)부탄-1-온 (화합물번호 15)Example 15. 1- (4-Benzhydrylpiperazin-1-yl) -4- (3-phenyl-1,2,4-oxadiazol-5-yl) butan-1-one (Compound No. 15 )
수율 42%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 8.05 (m, 2H) 7.46 (m, 7H) 7.25 (m, 7H) 5.32 (s, 1H) 4.23 (s, 1H) 6.64 (m, 2H) 3.48 (m, 2H) 3.06 (t, J = 7.1 Hz, 2H) 2.47 (t, J = 7.2 Hz, 2H) 2.38 (m, 4H) 2.24 (quint, J = 7.1 Hz, 2H)
Yield 42%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 8.05 (m, 2H) 7.46 (m, 7H) 7.25 (m, 7H) 5.32 (s, 1H) 4.23 (s, 1H) 6.64 (m, 2H ) 3.48 (m, 2H) 3.06 (t, J = 7.1 Hz, 2H) 2.47 (t, J = 7.2 Hz, 2H) 2.38 (m, 4H) 2.24 (quint, J = 7.1 Hz, 2H)
실시예 16. 1-(4-벤즈하이드릴피페라진-1-일)-4-(3-페닐아이소옥사졸-5-일)부탄-1-온 (화합물번호 16)Example 16. 1- (4-Benzhydrylpiperazin-1-yl) -4- (3-phenylisoxazol-5-yl) butan-1-one (Compound No. 16)
수율 61%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 7.79 (m, 2H) 7.43 (m, 9H) 7.21 (m, 5H) 6.34 (s, 1H) 4.23 (s, 1H) 3.64 (m, 3H) 3.45 (m, 2H) 2.91 (t, J = 7.5 Hz, 2H) 2.38 (m, 7H) 2.08 (m, 2H)
Yield 61%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.79 (m, 2H) 7.43 (m, 9H) 7.21 (m, 5H) 6.34 (s, 1H) 4.23 (s, 1H) 3.64 (m, 3H ) 3.45 (m, 2H) 2.91 (t, J = 7.5 Hz, 2H) 2.38 (m, 7H) 2.08 (m, 2H)
실시예 17. 1-(4-벤즈하이드릴피페라진-1-일)-3-(3-페닐-1,2,4-옥사다이아졸-5-일)프로판-1-온 (화합물번호 17)Example 17. 1- (4-Benzhydrylpiperazin-1-yl) -3- (3-phenyl-1,2,4-oxadiazol-5-yl) propan-1-one (Compound No. 17 )
수율 75%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 8.07 (m, 2H) 7.50 (d, J = 5.0 Hz, 3H) 7.42 (d, J = 7.1 Hz, 4H) 7.31 (m, 10H) 7.21 (m, 2H) 4.25 (m, 1H) 3.65 (m, 2H) 3.54 (m, 2H) 3.31 (t, J = 14.7 Hz, 2H) 2.93 (m, 2H) 2.41 (m, 4H)
Yield 75%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 8.07 (m, 2H) 7.50 (d, J = 5.0 Hz, 3H) 7.42 (d, J = 7.1 Hz, 4H) 7.31 (m, 10H) 7.21 (m, 2H) 4.25 (m, 1H) 3.65 (m, 2H) 3.54 (m, 2H) 3.31 (t, J = 14.7 Hz, 2H) 2.93 (m, 2H) 2.41 (m, 4H)
실시예 18. 1-(4-(2-클로로페닐)피페라진-1-일)-3-(3-페닐아이소옥사졸-5-일)프로판-1-온 (화합물번호 18)Example 18. 1- (4- (2-chlorophenyl) piperazin-1-yl) -3- (3-phenylisoxazol-5-yl) propan-1-one (Compound No. 18)
수율 38%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 7.80 (m, 2H) 7.46 (m, 3H) 7.39 (m, 1H) 7.23 (m, 10H) 7.01 (m, 2H) 6.41 (s, 1H) 3.82 (m, 2H) 3.67 (m, 2H) 3.25 (t, J = 7.1 Hz, 2H) 3.01 (m, 5H) 2.84 (t, J = 7.0 Hz 2H)
Yield 38%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.80 (m, 2H) 7.46 (m, 3H) 7.39 (m, 1H) 7.23 (m, 10H) 7.01 (m, 2H) 6.41 (s, 1H ) 3.82 (m, 2H) 3.67 (m, 2H) 3.25 (t, J = 7.1 Hz, 2H) 3.01 (m, 5H) 2.84 (t, J = 7.0 Hz 2H)
실시예 19. 1-(4-벤즈하이드릴피페라진-1-일)-3-(3-페닐아이소옥사졸-5-일)프로판-1-온 (화합물번호 19)Example 19. 1- (4-Benzhydrylpiperazin-1-yl) -3- (3-phenylisoxazol-5-yl) propan-1-one (Compound No. 19)
수율 55%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 7.83 (m, 2H) 7.49 (m, 6H) 7.30 (m, 10H) 6.41 (s, 1H) 4.24 (s, 1H) 3.68 (m, 2H) 3.50 (m, 2H) 3.23 (t, J = 7.8 Hz, 2H) 2.80 (t, J = 7.5 Hz, 2H) 2.40 (m, 4H) 2.84 (t, J = 7.0 Hz, 2H)
Yield 55%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.83 (m, 2H) 7.49 (m, 6H) 7.30 (m, 10H) 6.41 (s, 1H) 4.24 (s, 1H) 3.68 (m, 2H ) 3.50 (m, 2H) 3.23 (t, J = 7.8 Hz, 2H) 2.80 (t, J = 7.5 Hz, 2H) 2.40 (m, 4H) 2.84 (t, J = 7.0 Hz, 2H)
실시예 20. 2-((4-페닐-2-프로필옥사졸-5-일)메틸아미노)-1-(4-페닐피페라진-1-일)에탄논 (화합물번호 20)Example 20. 2-((4-phenyl-2-propyloxazol-5-yl) methylamino) -1- (4-phenylpiperazin-1-yl) ethanone (Compound No. 20)
수율 90%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 7.69 (m, 2H) 7.47 (t, J = 5.4 Hz, 2H) 7.32 (m, 3H) 6.96 (m, 3H) 4.03 (s, 2H) 3.83 (m, 2H) 3.61 (m, 4H) 3.20 (s, 4H) 2.90 (t, J = 7.2 Hz, 2H) 1.85 (m, 2H) 1.05 (t, J = 6.0 Hz, 3H)
Yield 90%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.69 (m, 2H) 7.47 (t, J = 5.4 Hz, 2H) 7.32 (m, 3H) 6.96 (m, 3H) 4.03 (s, 2H) 3.83 (m, 2H) 3.61 (m, 4H) 3.20 (s, 4H) 2.90 (t , J = 7.2 Hz, 2H) 1.85 (m, 2H) 1.05 (t, J = 6.0 Hz, 3H)
실시예 21. 1-(4-벤즈하이드릴피페라진-1-일)-2-((4-페닐-2-프로필옥사졸-5-일)메틸아미노)에탄논 (화합물번호 21)Example 21. 1- (4-benzhydrylpiperazin-1-yl) -2-((4-phenyl-2-propyloxazol-5-yl) methylamino) ethanone (Compound No. 21)
수율 88%; 1H NMR (400 MHz, CDCl3-d, ppm) δ 7.63 (m, 2H) 7.41 (m, 7H) 7.29 (m, 8H) 7.23 (m, 3H) 4.18 (s, 1H) 3.94 (s, 2H) 3.61 (m, 2H) 3.49 (s, 2H) 3.38 (m, 2H) 2.83 (t, J = 15.1 Hz, 2H) 2.36 (m, 6H) 2.05 (s, 1H) 1.76 (m, 2H) 1.27 (m, 2H) 0.97 (m, 3H)
Yield 88%; 1 H NMR (400 MHz, CDCl 3 - d , ppm) δ 7.63 (m, 2H) 7.41 (m, 7H) 7.29 (m, 8H) 7.23 (m, 3H) 4.18 (s, 1H) 3.94 (s, 2H ) 3.61 (m, 2H) 3.49 (s, 2H) 3.38 (m, 2H) 2.83 (t, J = 15.1 Hz, 2H) 2.36 (m, 6H) 2.05 (s, 1H) 1.76 (m, 2H) 1.27 ( m, 2H) 0.97 (m, 3H)
실시예 22. 1-(4-(비스(4-플루오로페닐)메틸)피페라진-1-일)-2-((4-페닐-2-프로필옥사졸-5-일)메틸아미노)에탄논 (화합물번호 22)Example 22. 1- (4- (bis (4-fluorophenyl) methyl) piperazin-1-yl) -2-((4-phenyl-2-propyloxazol-5-yl) methylamino) ethane Rice fields (Compound No. 22)
수율 85%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 7.77 (m, 2H) 7.40 (m, 10H) 7.05 (t, J = 8.7 Hz, 5H) 4.21 (s, 1H) 3.99 (s, 2H) 3.64 (m, 2H) 3.54 (s, 2H) 3.42 (s, 2H) 2.88 (t, J = 15.3 Hz, 2H) 2.36 (s, 5H) 2.09 (m, 1H) 1.78 (quint, J = 14.7 Hz, 3H) 1.01 (t, J = 14.7 Hz, 4H).
Yield 85%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.77 (m, 2H) 7.40 (m, 10H) 7.05 (t, J = 8.7 Hz, 5H) 4.21 (s, 1H) 3.99 (s, 2H) 3.64 (m, 2H) 3.54 (s, 2H) 3.42 (s, 2H) 2.88 (t, J = 15.3 Hz, 2H) 2.36 (s, 5H) 2.09 (m, 1H) 1.78 (quint, J = 14.7 Hz, 3H) 1.01 (t, J = 14.7 Hz, 4H).
실시예 23. 2-((4-페닐-5-프로필옥사졸-2-일)메틸아미노)-1-(4-페닐피페라진-1-일)에탄논 (화합물번호 23)Example 23. 2-((4-phenyl-5-propyloxazol-2-yl) methylamino) -1- (4-phenylpiperazin-1-yl) ethanone (Compound No. 23)
수율 45%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 7.73 (d, J = 6.9 Hz, 2H) 7.46 (t, J = 7.2 Hz, 2H) 7.34 (m, 4H) 6.96 (m, 3H) 4.16 (m, 2H) 3.79 (m, 2H) 3.45 (m, 4H) 3.15 (m, 5H) 2.81 (t, J = 7.5 Hz, 2H) 2.09 (m, 1H) 1.86 (q, J = 7.5 Hz, 2H) 1.31 (m, 3H) 1.09 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3-d, ppm) δ 169.17 164.07 163.80 160.53 144.80 137.83 137.78 136.96 132.22 129.50 129.39 128.89 127.87 127.40 115.98 115.70 51.82 51.57 49.15 44.69 43.82 42.20 30.35 20.87 14.03
Yield 45%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.73 (d, J = 6.9 Hz, 2H) 7.46 (t, J = 7.2 Hz, 2H) 7.34 (m, 4H) 6.96 (m, 3H) 4.16 (m, 2H) 3.79 (m, 2H) 3.45 (m, 4H) 3.15 (m, 5H) 2.81 (t, J = 7.5 Hz, 2H) 2.09 (m, 1H) 1.86 (q, J = 7.5 Hz, 2H ) 1.31 (m, 3H) 1.09 (t, J = 7.2 Hz, 3H); 13 C NMR (75 MHz, CDCl 3 - d , ppm) δ 169.17 164.07 163.80 160.53 144.80 137.83 137.78 136.96 132.22 129.50 129.39 128.89 127.87 127.40 115.98 115.70 51.82 51.57 49.15 44.69 43.82 42.20 14.03 35
실시예 24. (2-((5-메틸-4-페닐옥사졸-2-일)메틸아미노)-1-(4-페닐피페라진-1-일)에탄논 (화합물번호 24)Example 24. (2-((5-methyl-4-phenyloxazol-2-yl) methylamino) -1- (4-phenylpiperazin-1-yl) ethanone (Compound No. 24)
수율 85%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 7.70 (m, 2H) 7.38 (m, 2H) 7.21 (m, 3H) 6.92 (m, 3H) 4.59 (s, 2H) 3.74 (m, 2H) 3.43 (s, 2H) 3.41 (m, 2H) 3.11 (m, 4H) 2.5 (s, 3H) 2.33 (br s, 1H)
Yield 85%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.70 (m, 2H) 7.38 (m, 2H) 7.21 (m, 3H) 6.92 (m, 3H) 4.59 (s, 2H) 3.74 (m, 2H ) 3.43 (s, 2H) 3.41 (m, 2H) 3.11 (m, 4H) 2.5 (s, 3H) 2.33 (br s, 1H)
실시예 25. 1-(4-벤즈하이드릴피페라진-1-일)-2-((4-페닐-5-프로필옥사졸-2-일)메틸아미노)에탄논 (화합물번호 25)Example 25. 1- (4-Benzhydrylpiperazin-1-yl) -2-((4-phenyl-5-propyloxazol-2-yl) methylamino) ethanone (Compound No. 25)
수율 75%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 7.73 (d, J = 1.5 Hz, 2H) 7.46 (m, 7H) 7.32 (m, 8H) 7.23 (m, 3H) 4.25 (s, 1H) 4.06 (s, 2H) 3.65 (m, 2H) 3.41 (s, 2H) 3.31 (m, 2H) 2.78 (t, J = 7.5 Hz, 2H) 2.46 (m, 2H) 2.33 (m, 2H) 1.86 (q, J = 7.2 Hz, 5H) 1.06 (t, J = 7.2 Hz, 4H)
Yield 75%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.73 (d, J = 1.5 Hz, 2H) 7.46 (m, 7H) 7.32 (m, 8H) 7.23 (m, 3H) 4.25 (s, 1H) 4.06 (s, 2H) 3.65 (m, 2H) 3.41 (s, 2H) 3.31 (m, 2H) 2.78 (t, J = 7.5 Hz, 2H) 2.46 (m, 2H) 2.33 (m, 2H) 1.86 (q , J = 7.2 Hz, 5H) 1.06 (t, J = 7.2 Hz, 4H)
실시예 26. 1-(4-비스(4-플루오로페닐)메틸)피페라진-1-일)-2-((4-페닐-5-프로필옥사졸-2-일)메틸아미노)에탄논 (화합물번호 26)Example 26. 1- (4-bis (4-fluorophenyl) methyl) piperazin-1-yl) -2-((4-phenyl-5-propyloxazol-2-yl) methylamino) ethanone (Compound No. 26)
수율 50%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 7.73 (d, J = 1.5 Hz, 2H) 7.46 (m, 7H) 7.32 (m, 8H) 7.23 (m, 3H) 4.25 (s, 1H) 4.06 (s, 2H) 3.65 (m, 2H) 3.41 (s, 2H) 3.31 (m, 2H) 2.78 (t, J = 7.5 Hz, 2H) 2.46 (m, 2H) 2.33 (m, 2H) 1.86 (q, J = 7.2 Hz, 5H) 1.06 (t, J = 7.2 Hz, 4H)
Yield 50%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.73 (d, J = 1.5 Hz, 2H) 7.46 (m, 7H) 7.32 (m, 8H) 7.23 (m, 3H) 4.25 (s, 1H) 4.06 (s, 2H) 3.65 (m, 2H) 3.41 (s, 2H) 3.31 (m, 2H) 2.78 (t, J = 7.5 Hz, 2H) 2.46 (m, 2H) 2.33 (m, 2H) 1.86 (q , J = 7.2 Hz, 5H) 1.06 (t, J = 7.2 Hz, 4H)
실시예 27. 2-((2-메틸-4-페닐옥사졸-5-일)메틸아미노)-1-(4-페닐피페라진-1-일)에탄논 (화합물번호 27)Example 27. 2-((2-methyl-4-phenyloxazol-5-yl) methylamino) -1- (4-phenylpiperazin-1-yl) ethanone (Compound No. 27)
수율 95%; 1H NMR (400 MHz, CDCl3-d, ppm) δ 7.64 (d, J = 7.7 Hz, 2H) 7.41 (t, J = 7.5 Hz, 2H) 7.27 (m, 4H) 6.89 (m, 3H) 3.97 (s, 2H) 3.77 (m, 2H) 3.57 (s, 2H) 3.52 (m, 2H) 3.13 (s, 5H) 2.52 (s, 3H); 13C NMR (75 MHz, CDCl3-d, ppm) δ 169.01 160.11 150.88 144.26 134.40 132.26 129.26 128.61 127.23 126.62 120.61 116.70 49.55 49.34 45.93 44.42 41.80 11.95
Yield 95%; 1 H NMR (400 MHz, CDCl 3 - d , ppm) δ 7.64 (d, J = 7.7 Hz, 2H) 7.41 (t, J = 7.5 Hz, 2H) 7.27 (m, 4H) 6.89 (m, 3H) 3.97 (s, 2H) 3.77 (m, 2H) 3.57 (s, 2H) 3.52 (m, 2H) 3.13 (s, 5H) 2.52 (s, 3H); 13 C NMR (75 MHz, CDCl 3 - d , ppm) δ 169.01 160.11 150.88 144.26 134.40 132.26 129.26 128.61 127.23 126.62 120.61 116.70 49.55 49.34 45.93 44.42 41.80 11.95
실시예 28. 1-(4-벤즈하이드릴피페라진-1-일)-2-((2-메틸-4-페닐옥사졸-5-일)메틸아미노)에탄논 (화합물번호 28)Example 28. 1- (4-Benzhydrylpiperazin-1-yl) -2-((2-methyl-4-phenyloxazol-5-yl) methylamino) ethanone (Compound No. 28)
수율 93%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 7.68 (m, 2H) 7.42 (m, 7H) 7.32 (m, 6H) 7.20 (m, 2H) 4.22 (s, 1H) 4.02 (s, 2H) 3.60 (m, 2H) 3.38 (s, 2H) 3.27 (m, 2H) 2.49 (s, 3H) 2.37 (m, 3H) 2.27 (m, 3H); 13C NMR (75 MHz, CDCl3-d, ppm) δ 168.86 160.11 144.20 142.07 134.38 132.33 128.61 128.55 127.84 127.17 126.64 102.99 51.78 51.48 49.17 45.94 44.64 42.08 29.69 11.89
Yield 93%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.68 (m, 2H) 7.42 (m, 7H) 7.32 (m, 6H) 7.20 (m, 2H) 4.22 (s, 1H) 4.02 (s, 2H ) 3.60 (m, 2H) 3.38 (s, 2H) 3.27 (m, 2H) 2.49 (s, 3H) 2.37 (m, 3H) 2.27 (m, 3H); 13 C NMR (75 MHz, CDCl 3 - d , ppm) δ 168.86 160.11 144.20 142.07 134.38 132.33 128.61 128.55 127.84 127.17 126.64 102.99 51.78 51.48 49.17 45.94 44.64 42.08 29.69 11.89
실시예 29. 1-(4-비스(4-플루오로페닐)메틸)피페라진-1-일)-2-((2-메틸-4-페닐옥사졸-5-일)메틸아미노)에탄논 (화합물번호 29)Example 29. 1- (4-bis (4-fluorophenyl) methyl) piperazin-1-yl) -2-((2-methyl-4-phenyloxazol-5-yl) methylamino) ethanone (Compound No. 29)
90%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 7.67 (d, J = 7.1 Hz, 2H) 7.33 (m, 7H) 6.98 (t, J = 1.7 Hz, 4H) 4.20 (s, 1H) 4.01 (s, 2H) 3.60 (m, 2H) 3.37 (s, 2H) 3.26 (m, 2H) 2.48 (s, 3H) 2.32 (m, 4H) 2.17 (m, 3H) 1.20 (m, 1H); 13C NMR (75 MHz, CDCl3-d, ppm) δ 168.92 163.56 160.38 160.30 144.74 137.53 137.49 136.89 131.82 129.24 129.14 128.65 127.66 127.07 115.73 115.44 51.57 51.32 48.87 44.45 43.53 41.96 25.35 13.97
90%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.67 (d, J = 7.1 Hz, 2H) 7.33 (m, 7H) 6.98 (t, J = 1.7 Hz, 4H) 4.20 (s, 1H) 4.01 (s, 2H) 3.60 (m, 2H) 3.37 (s, 2H) 3.26 (m, 2H) 2.48 (s, 3H) 2.32 (m, 4H) 2.17 (m, 3H) 1.20 (m, 1H); 13 C NMR (75 MHz, CDCl 3 - d , ppm) δ 168.92 163.56 160.38 160.30 144.74 137.53 137.49 136.89 131.82 129.24 129.14 128.65 127.66 127.07 115.73 115.44 51.57 51.32 48.87 44.45 43.53 41.96 25.35
실시예 30. 2-((4-페닐-2-프로필옥사졸-5-일)메틸아미노)-1-(4-(3-(트리플루오로메틸)페닐)피페라진-1-일)에탄논 (화합물번호 30)Example 30. 2-((4-phenyl-2-propyloxazol-5-yl) methylamino) -1- (4- (3- (trifluoromethyl) phenyl) piperazin-1-yl) ethane Rice fields (Compound No. 30)
수율 88%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 7.70 (d, J = 7.2 Hz, 2H) 7.38 (m, 3H) 7.29 (t, J = 7.7 Hz, 1H) 7.14 (d, J = 7.7 Hz, 1H) 7.04 (m, 2H) 4.07 (s, 2H) 3.77 (m, 2H) 3.45 (s, 2H) 3.41 (m, 2H) 3.12 (m, 4H) 2.77 (t, J = 7.7 Hz, 2H) 1.02 (t, J = 7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3-d, ppm) δ 169.09 163.92 150.95 144.37 136.88 131.92 129.72 128.66 127.70 127.14 119.38 116.78 112.80 48.92 48.85 44.10 43.49 41.55 30.12 20.62 13.76
Yield 88%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.70 (d, J = 7.2 Hz, 2H) 7.38 (m, 3H) 7.29 (t, J = 7.7 Hz, 1H) 7.14 (d, J = 7.7 Hz, 1H) 7.04 (m, 2H) 4.07 (s, 2H) 3.77 (m, 2H) 3.45 (s, 2H) 3.41 (m, 2H) 3.12 (m, 4H) 2.77 (t, J = 7.7 Hz, 2H ) 1.02 (t, J = 7.4 Hz, 3H); 13 C NMR (75 MHz, CDCl 3 - d , ppm) δ 169.09 163.92 150.95 144.37 136.88 131.92 129.72 128.66 127.70 127.14 119.38 116.78 112.80 48.92 48.85 44.10 43.49 41.55 30.12 20.62 13.76
실시예 31. 1-(4-(2,4-다이메틸페닐)피페라진-1-일)-2-((4-페닐-5-프로필옥사졸-2-일)메틸아미노)에탄논 (화합물번호 31)Example 31. 1- (4- (2,4-dimethylphenyl) piperazin-1-yl) -2-((4-phenyl-5-propyloxazol-2-yl) methylamino) ethanone (compound Number 31)
수율 44%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 7.65 (m, 2H) 7.43 (t, J=5.6Hz, 2H) 7.32 (d, J = 7.4 Hz, 1H) 7.02 (s, 1H) 6.98 (d, J = 8.1 Hz, 1H) 6.85 (d, J = 8.0 Hz, 1H) 4.00 (s, 2H) 3.76 (m, 2H) 3.59 (s, 2H) 3.53 (m, 2H) 2.86 (m, 6H) 2.27 (m, 7H) 1.77 (q, J = 7.5 Hz, 2H) 1.01 (t, J = 14.7 Hz, 3H); 13C NMR (75 MHz, CDCl3-d, ppm) δ 169.11 160.26 148.37 148.32 134.37 133.33 132.64 132.41 131.89 128.56 127.25 127.14 126.84 119.17 52.05 51.86 49.38 46.01 45.11 42.50 27.89 21.54 20.69 17.60 13.85
Yield 44%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.65 (m, 2H) 7.43 (t, J = 5.6 Hz, 2H) 7.32 (d, J = 7.4 Hz, 1H) 7.02 (s, 1H) 6.98 (d, J = 8.1 Hz, 1H) 6.85 (d, J = 8.0 Hz, 1H) 4.00 (s, 2H) 3.76 (m, 2H) 3.59 (s, 2H) 3.53 (m, 2H) 2.86 (m, 6H ) 2.27 (m, 7H) 1.77 (q, J = 7.5 Hz, 2H) 1.01 (t, J = 14.7 Hz, 3H); 13 C NMR (75 MHz, CDCl 3 - d , ppm) δ 169.11 160.26 148.37 148.32 134.37 133.33 132.64 132.41 131.89 128.56 127.25 127.14 126.84 119.17 52.05 51.86 49.38 46.01 45.11 42.50 27.89 21.54 20.85 69
실시예 32. 1-(4-(2,3-다이메틸페닐)피페라진-1-일)-2-((4-페닐-5-프로필옥사졸-2-일)메틸아미노)에탄논 (화합물번호 32)Example 32. 1- (4- (2,3-dimethylphenyl) piperazin-1-yl) -2-((4-phenyl-5-propyloxazol-2-yl) methylamino) ethanone (compound Number 32)
수율 38%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 7.65 (m, 2H) 7.43 (t, J = 1.2 Hz, 2H) 7.30 (m, 1H) 7.08 (t, J = 15.4 Hz, 1H) 6.94 (d, J = 7.3 Hz, 1H) 6.84 (d, J = 7.9 Hz, 1H) 4.00 (s, 2H) 3.78 (m, 1H) 3.60 (s, 2H) 3.55 (s, 2H) 2.86 (m, 6H) 2.45 (s, 1H) 2.29 (s, 3H) 2.24 (s, 3H) 1.78 (q, J = 7.56 Hz, 2H) 1.27 (s, 1H) 1.01 (t, J = 14.8 Hz, 3H); 13C NMR (75 MHz, CDCl3-d, ppm) δ 169.15 160.29 150.86 148.33 138.17 134.36 132.40 131.36 128.57 127.26 126.84 125.95 125.59 116.83 52.21 52.06 49.41 46.03 45.06 42.44 27.90 21.55 20.63 13.87
Yield 38%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.65 (m, 2H) 7.43 (t, J = 1.2 Hz, 2H) 7.30 (m, 1H) 7.08 (t, J = 15.4 Hz, 1H) 6.94 (d , J = 7.3 Hz, 1H) 6.84 (d, J = 7.9 Hz, 1H) 4.00 (s, 2H) 3.78 (m, 1H) 3.60 (s, 2H) 3.55 (s, 2H) 2.86 (m, 6H ) 2.45 (s, 1H) 2.29 (s, 3H) 2.24 (s, 3H) 1.78 (q, J = 7.56 Hz, 2H) 1.27 (s, 1H) 1.01 (t, J = 14.8 Hz, 3H); 13 C NMR (75 MHz, CDCl 3 - d , ppm) δ 169.15 160.29 150.86 148.33 138.17 134.36 132.40 131.36 128.57 127.26 126.84 125.95 125.59 116.83 52.21 52.06 49.41 46.03 45.06 42.44 27.90 21.55 20.63 13.87
실시예 33. 1-(4-(3,4-다이메틸페닐)피페라진-1-일)-2-((4-페닐-5-프로필옥사졸-2-일)메틸아미노)에탄논 (화합물번호 33)Example 33. 1- (4- (3,4-dimethylphenyl) piperazin-1-yl) -2-((4-phenyl-5-propyloxazol-2-yl) methylamino) ethanone (compound Number 33)
수율 56%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 7.65 (m, 2H) 7.42 (t, J = 7.3 Hz, 2H) 7.31 (m, 2H) 7.04 (d, J = 8.2 Hz, 1H) 6.71 (m, 2H) 3.99 (s, 2H) 3.78 (s, 2H) 3.57 (m, 4H) 3.10 (s, 4H) 2.85 (t, J = 15.1 Hz, 2H) 2.38 (m, 2H) 2.22 (d, J = 13.0 Hz, 7H) 1.74 (q, J = 7.4 Hz, 3H) 1.01 (t, J = 14.7 Hz, 4H); 13C NMR (75 MHz, CDCl3-d, ppm) δ 169.01 149.19 148.34 137.31 132.38 130.27 129.07 128.56 127.27 126.84 118.75 114.45 7 50.22 50.05 49.35 45.99 44.56 41.92 29.70 27.89 21.54 20.16 18.80 13.86
Yield 56%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.65 (m, 2H) 7.42 (t, J = 7.3 Hz, 2H) 7.31 (m, 2H) 7.04 (d, J = 8.2 Hz, 1H) 6.71 (m, 2H) 3.99 (s, 2H) 3.78 (s, 2H) 3.57 (m, 4H) 3.10 (s, 4H) 2.85 (t, J = 15.1 Hz, 2H) 2.38 (m, 2H) 2.22 (d, J = 13.0 Hz, 7H) 1.74 (q, J = 7.4 Hz, 3H) 1.01 (t, J = 14.7 Hz, 4H); 13 C NMR (75 MHz, CDCl 3 - d , ppm) δ 169.01 149.19 148.34 137.31 132.38 130.27 129.07 128.56 127.27 126.84 118.75 114.45 7 50.22 50.05 49.35 45.99 44.56 41.92 29.70 27.89 21.54 20.16 18.80
실시예 34. 1-(4-(2,4-다이메틸페닐)피페라진-1-일)-2-((5-메틸-4-페닐옥사졸-2-일)메틸아미노)에탄논 (화합물번호 34)Example 34. 1- (4- (2,4-dimethylphenyl) piperazin-1-yl) -2-((5-methyl-4-phenyloxazol-2-yl) methylamino) ethanone (compound Number 34)
수율 54%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 7.69 (d, J = 7.2 Hz, 2H) 7.42 (t, J = 15.1 Hz, 2H) 7.31 (m, 2H) 7.04 (d, J = 8.2 Hz, 1H) 6.70 (m, 2H) 4.06 (s, 2H) 3.76 (m, 2H) 3.42 (m, 4H) 3.08 (m, 2H) 3.01 (m, 2H) 2.51 (s, 3H) 2.25 (s, 3H) 2.20 (s, 4H) 2.02 (m, 3H) 1.27 (s, 3H); 13C NMR (75 MHz, CDCl3-d, ppm) δ 169.00 160.44 149.14 144.70 137.01 131.80 130.27 129.12 128.68 127.74 127.09 118.75 114.45 50.05 48.93 44.40 43.53 41.89 29.69 20.15 18.79 13.99
Yield 54%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.69 (d, J = 7.2 Hz, 2H) 7.42 (t, J = 15.1 Hz, 2H) 7.31 (m, 2H) 7.04 (d, J = 8.2 Hz, 1H) 6.70 (m, 2H) 4.06 (s, 2H) 3.76 (m, 2H) 3.42 (m, 4H) 3.08 (m, 2H) 3.01 (m, 2H) 2.51 (s, 3H) 2.25 (s, 3H) 2.20 (s, 4H) 2.02 (m, 3H) 1.27 (s, 3H); 13 C NMR (75 MHz, CDCl 3 - d , ppm) δ 169.00 160.44 149.14 144.70 137.01 131.80 130.27 129.12 128.68 127.74 127.09 118.75 114.45 50.05 48.93 44.40 43.53 41.89 29.69 20.15 18.79 13.99
실시예 35. 2-((2-메틸-4-페닐옥사졸-5-일)메틸아미노)-1-(4-3-(트리플루오로메틸)페닐)피페라진-1-일)에탄논 (화합물번호 35)Example 35. 2-((2-methyl-4-phenyloxazol-5-yl) methylamino) -1- (4-3- (trifluoromethyl) phenyl) piperazin-1-yl) ethanone (Compound No. 35)
수율 62%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 7.68 (m, 2H) 7.37 (m, 3H) 7.28 (m, 1H) 7.09 (m, 2H) 4.06 (s, 2H) 3.75 (m, 2H) 3.40 (m, 4H) 3.16 (m, 2H) 3.08 (m, 2H) 2.50 (s, 2H) 2.28 (m, 1H) 2.16 (m, 4H); 13C NMR (75 MHz, CDCl3-d, ppm) δ 169.08 160.47 150.93 144.61 137.03 131.77 131.35 129.71 128.68 127.75 127.06 125.98 122.37 119.38 116.79 116.74 112.77 112.72 48.82 44.08 43.43 41.54 30.88 13.97
Yield 62%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.68 (m, 2H) 7.37 (m, 3H) 7.28 (m, 1H) 7.09 (m, 2H) 4.06 (s, 2H) 3.75 (m, 2H ) 3.40 (m, 4H) 3.16 (m, 2H) 3.08 (m, 2H) 2.50 (s, 2H) 2.28 (m, 1H) 2.16 (m, 4H); 13 C NMR (75 MHz, CDCl 3 - d , ppm) δ 169.08 160.47 150.93 144.61 137.03 131.77 131.35 129.71 128.68 127.75 127.06 125.98 122.37 119.38 116.79 116.74 112.77 112.72 48.82 44.08 43.43 41.54 30.88
실시예 36. 1-(4-(2,4-다이메틸페닐)피페라진-1-일)-2-((2-메틸-4-페닐옥사졸-5-일)메틸아미노)에탄논 (화합물번호 36)Example 36. 1- (4- (2,4-dimethylphenyl) piperazin-1-yl) -2-((2-methyl-4-phenyloxazol-5-yl) methylamino) ethanone (compound Number 36)
수율 84%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 7.66 (m, 2H) 7.43 (t, J = 5.6 Hz, 2H) 7.32 (m, 1H) 6.99 (m, 2H) 6.86 (d, J = 8.0 Hz, 1H) 6.86 (d, J = 8.0 Hz, 1H) 3.99 (s, 2H) 3.76 (m, 2H) 3.59 (s, 2H) 3.53 (m, 2H) 2.85 (m, 4H) 2.55 (s, 3H) 2.29 (s, 6H); 13C NMR (75 MHz, CDCl3-d, ppm) δ 169.11 160.17 148.37 144.23 134.40 133.33 132.64 132.31 131.90 128.59 127.20 127.15 126.63 119.16 52.04 51.84 49.37 46.00 45.09 42.49 20.71 17.62 11.93
Yield 84%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.66 (m, 2H) 7.43 (t, J = 5.6 Hz, 2H) 7.32 (m, 1H) 6.99 (m, 2H) 6.86 (d, J = 8.0 Hz, 1H) 6.86 (d, J = 8.0 Hz, 1H) 3.99 (s, 2H) 3.76 (m, 2H) 3.59 (s, 2H) 3.53 (m, 2H) 2.85 (m, 4H) 2.55 (s, 3H) 2.29 (s, 6 H); 13 C NMR (75 MHz, CDCl 3 - d , ppm) δ 169.11 160.17 148.37 144.23 134.40 133.33 132.64 132.31 131.90 128.59 127.20 127.15 126.63 119.16 52.04 51.84 49.37 46.00 45.09 42.49 20.71 17.62 11.93
실시예 37. 1-(4-(2,3-다이메틸페닐)피페라진-1-일)-2-((2-메틸-4-페닐옥사졸-5-일)메틸아미노)에탄논 (화합물번호 37)Example 37. 1- (4- (2,3-dimethylphenyl) piperazin-1-yl) -2-((2-methyl-4-phenyloxazol-5-yl) methylamino) ethanone (compound Number 37)
수율 82%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 7.70 (m, 2H) 7.43 (t, J = 14.9 Hz, 2H) 7.30 (m, 2H) 7.08 (d, J = 7.4 Hz, 1H) 6.84 (d, J = 7.9 Hz, 1H) 4.07 (s, 2H) 3.46 (s, 2H) 3.41 (s, 2H) 2.80 (m, 4H) 2.52 (m, 3H) 2.26 (m, 7H) 1.86 (m, 3H); 13C NMR (75 MHz, CDCl3-d, ppm) δ 169.11 160.17 148.37 144.23 134.40 133.33 132.64 132.31 131.90 128.59 127.20 127.15 126.63 119.16 52.04 51.84 49.37 46.00 45.09 42.49 20.71 17.62 11.93
Yield 82%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.70 (m, 2H) 7.43 (t, J = 14.9 Hz, 2H) 7.30 (m, 2H) 7.08 (d, J = 7.4 Hz, 1H) 6.84 (d, J = 7.9 Hz, 1H) 4.07 (s, 2H) 3.46 (s, 2H) 3.41 (s, 2H) 2.80 (m, 4H) 2.52 (m, 3H) 2.26 (m, 7H) 1.86 (m, 3H); 13 C NMR (75 MHz, CDCl 3 - d , ppm) δ 169.11 160.17 148.37 144.23 134.40 133.33 132.64 132.31 131.90 128.59 127.20 127.15 126.63 119.16 52.04 51.84 49.37 46.00 45.09 42.49 20.71 17.62 11.93
실시예 38. 1-(4-벤즈하이드릴피페라진-1-일)-2-((5-메틸-4-페닐옥사졸-2-일)메틸아미노)에탄논 (화합물번호 38)Example 38. 1- (4-Benzhydrylpiperazin-1-yl) -2-((5-methyl-4-phenyloxazol-2-yl) methylamino) ethanone (Compound No. 38)
수율 75%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 7.73 (d, J = 1.5 Hz, 2H) 7.46 (m, 7H) 7.32 (m, 8H) 7.23 (m, 3H) 4.25 (s, 1H) 4.06 (s, 2H) 3.65 (m, 2H) 3.41 (s, 2H) 3.31 (m, 2H) 2.78 (t, J = 7.5 Hz, 2H) 2.46 (m, 2H) 2.33 (m, 2H) 1.86 (q, J = 7.2 Hz, 5H) 1.06 (t, J = 7.2 Hz, 4H)
Yield 75%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.73 (d, J = 1.5 Hz, 2H) 7.46 (m, 7H) 7.32 (m, 8H) 7.23 (m, 3H) 4.25 (s, 1H) 4.06 (s, 2H) 3.65 (m, 2H) 3.41 (s, 2H) 3.31 (m, 2H) 2.78 (t, J = 7.5 Hz, 2H) 2.46 (m, 2H) 2.33 (m, 2H) 1.86 (q , J = 7.2 Hz, 5H) 1.06 (t, J = 7.2 Hz, 4H)
실시예 39. 1-(4-(2,4-다이메틸페닐)피페라진-1-일)-2-((4-페닐-2-프로필옥사졸-5-일)메틸아미노)에탄논 (화합물번호 39)Example 39. 1- (4- (2,4-dimethylphenyl) piperazin-1-yl) -2-((4-phenyl-2-propyloxazol-5-yl) methylamino) ethanone (compound Number 39)
수율 89%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 7.71 (m, 2H) 7.41 (t, J = 13.3 Hz, 2H) 7.32 (m, 1H) 7.00 (m, 2H) 6.85 (d, J = 8.0 Hz, 1H) 4.07 (s, 2H) 3.74 (m, 2H) 3.46 (s, 2H) 3.39 (m, 2H) 2.81 (m, 6H) 2.29 (s, 6H) 2.22 (m, 2H) 1.04 (t, J = 14.8 Hz, 3H); 13C NMR (75 MHz, CDCl3-d, ppm) δ 169.15 163.86 148.33 144.54 136.81 133.36 132.63 131.98 131.91 128.66 127.66 127.18 127.14 119.15 51.95 51.83 49.01 44.97 43.60 42.46 30.14 20.69 17.60 13.78
Yield 89%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.71 (m, 2H) 7.41 (t, J = 13.3 Hz, 2H) 7.32 (m, 1H) 7.00 (m, 2H) 6.85 (d, J = 8.0 Hz, 1H) 4.07 (s, 2H) 3.74 (m, 2H) 3.46 (s, 2H) 3.39 (m, 2H) 2.81 (m, 6H) 2.29 (s, 6H) 2.22 (m, 2H) 1.04 (t , J = 14.8 Hz, 3H); 13 C NMR (75 MHz, CDCl 3 - d , ppm) δ 169.15 163.86 148.33 144.54 136.81 133.36 132.63 131.98 131.91 128.66 127.66 127.18 127.14 119.15 51.95 51.83 49.01 44.97 43.60 42.46 30.14 20.69
실시예 40. 1-(4-(2,3-다이메틸페닐)피페라진-1-일)-2-((4-페닐-2-프로필옥사졸-5-일)메틸아미노)에탄논 (화합물번호 40)Example 40. 1- (4- (2,3-dimethylphenyl) piperazin-1-yl) -2-((4-phenyl-2-propyloxazol-5-yl) methylamino) ethanone (compound Number 40)
수율 90%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 7.71 (m, 2H) 7.43 (m, 2H) 7.33 (m, 1H) 7.09 (t, J = 15.4 Hz, 1H) 6.50 (d, J = 7.3 Hz 1H) 6.84 (d, J = 7.9 Hz, 1H) 4.08 (s, 2H) 3.46 (s, 2H) 3.42 (m, 2H) 2.80 (m, 6H) 2.29 (s, 3H) 2.24 (s, 4H) 2.03 (m, 3H) 1.88 (q, J = 7.5 Hz, 3H) 1.04 (t, J = 14.8 Hz, 3H); 13C NMR (75 MHz, CDCl3-d, ppm) δ 169.17 163.89 150.81 144.52 138.21 136.82 131.96 131.35 128.67 127.67 127.18 125.94 125.62 116.8 52.10 52.04 48.98 44.92 43.58 42.41 30.15 20.65 13.86
Yield 90%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.71 (m, 2H) 7.43 (m, 2H) 7.33 (m, 1H) 7.09 (t, J = 15.4 Hz, 1H) 6.50 (d, J = 7.3 Hz 1H) 6.84 (d, J = 7.9 Hz, 1H) 4.08 (s, 2H) 3.46 (s, 2H) 3.42 (m, 2H) 2.80 (m, 6H) 2.29 (s, 3H) 2.24 (s, 4H ) 2.03 (m, 3H) 1.88 (q, J = 7.5 Hz, 3H) 1.04 (t, J = 14.8 Hz, 3H); 13 C NMR (75 MHz, CDCl 3 - d , ppm) δ 169.17 163.89 150.81 144.52 138.21 136.82 131.96 131.35 128.67 127.67 127.18 125.94 125.62 116.8 52.10 52.04 48.98 44.92 43.58 42.41 30.15 20.65 13.86
실시예 41. 1-(4-(3,4-다이메틸페닐)피페라진-1-일)-2-((4-페닐-2-프로필옥사졸-5-일)메틸아미노)에탄논 (화합물번호 41)Example 41. 1- (4- (3,4-dimethylphenyl) piperazin-1-yl) -2-((4-phenyl-2-propyloxazol-5-yl) methylamino) ethanone (compound Number 41)
수율 90%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 7.70 (m, 2H) 7.41 (t, J = 15.0 Hz, 2H) 7.30 (m, 2H) 6.70 (m, 3H) 4.10 (m, 2H) 3.76 (m, 2H) 3.40 (m, 4H) 3.05 (m, 5H) 2.79 (t, J = 15.1 Hz, 2H) 2.25 (s, 4H) 2.20 (s, 3H) 1.85 (q, J = 7.4 Hz, 2H) 1.02 (t, J = 7.4 Hz, 4H); 13C NMR (75 MHz, CDCl3-d, ppm) δ 168.88 163.94 149.13 144.29 137.34 136.93 131.89 130.27 129.14 128.67 127.72 127.16 118.76 114.45 50.07 48.90 44.41 43.52 41.89 30.13 20.64 20.17 18.81 13.79
Yield 90%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.70 (m, 2H) 7.41 (t, J = 15.0 Hz, 2H) 7.30 (m, 2H) 6.70 (m, 3H) 4.10 (m, 2H) 3.76 (m, 2H) 3.40 (m, 4H) 3.05 (m, 5H) 2.79 (t, J = 15.1 Hz, 2H) 2.25 (s, 4H) 2.20 (s, 3H) 1.85 (q, J = 7.4 Hz, 2H) 1.02 (t, J = 7.4 Hz, 4H); 13 C NMR (75 MHz, CDCl 3 - d , ppm) δ 168.88 163.94 149.13 144.29 137.34 136.93 131.89 130.27 129.14 128.67 127.72 127.16 118.76 114.45 50.07 48.90 44.41 43.52 41.89 30.13 20.64 20.17 18.
실시예 42. 2-((4-페닐-2-프로필옥사졸-5-일)메틸아미노)-1-(4-(3-(트리플루오로메틸)페닐)피페라진-1-일)에탄논 (화합물번호 42)Example 42. 2-((4-phenyl-2-propyloxazol-5-yl) methylamino) -1- (4- (3- (trifluoromethyl) phenyl) piperazin-1-yl) ethane Rice fields (Compound No. 42)
수율 59%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 7.63 (m, 2H) 7.38 (q, J = 7.9 Hz, 3H) 7.29 (m, 2H) 7.08 (m, 3H) 3.99 (s, 2H) 3.79 (m, 2H) 3.59 (m, 4H) 3.20 (m, 4H) 2.85 (t, J = 7.7 Hz, 2H) 2.25 (s, 2H) 1.77 (q, J = 7.5 Hz, 2H) 1.01 (t, J = 7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3-d, ppm) δ 169.12 160.16 150.98 148.36 134.37 132.34 131.81 131.39 129.71 128.56 127.29 126.80 119.34 116.79 112.80 49.36 48.97 48.86 45.95 44.26 41.59 27.88 21.53 13.84
Yield 59%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.63 (m, 2H) 7.38 (q, J = 7.9 Hz, 3H) 7.29 (m, 2H) 7.08 (m, 3H) 3.99 (s, 2H) 3.79 (m, 2H) 3.59 (m, 4H) 3.20 (m, 4H) 2.85 (t, J = 7.7 Hz, 2H) 2.25 (s, 2H) 1.77 (q , J = 7.5 Hz, 2H) 1.01 (t, J = 7.4 Hz, 3H); 13 C NMR (75 MHz, CDCl 3 - d , ppm) δ 169.12 160.16 150.98 148.36 134.37 132.34 131.81 131.39 129.71 128.56 127.29 126.80 119.34 116.79 112.80 49.36 48.97 48.86 45.95 44.26 41.59 27.88 21.53
실시예 43. 1-(4-(3,4-다이에틸페닐)피페라진-1-일)-2-((5-메틸-4-페닐옥사졸-2-일)메틸아미노)에탄논 (화합물번호 43)Example 43. 1- (4- (3,4-Diethylphenyl) piperazin-1-yl) -2-((5-methyl-4-phenyloxazol-2-yl) methylamino) ethanone ( Compound number 43)
수율 89%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 7.65 (m, 2H) 7.42 (t, J = 7.8 Hz, 2H) 7.31 (m, 2H) 7.04 (d, J = 8. 2Hz, 1H) 6.70 (m, 2H) 3.99 (s, 2H) 3.78 (m, 2H) 3.56 (m, 4H) 3.10 (m, 5H) 2.54 (s, 3H) 2.24 (s, 4H) 2.20 (s, 5H); 13C NMR (75 MHz, CDCl3-d, ppm) δ 169.19 160.67 149.35 144.92 137.52 137.22 132.02 130.47 129.31 128.89 127.95 127.28 118.95 114.66 50.25 49.11 44.61 43.72 42.09 20.38 19.03 14.23
Yield 89%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.65 (m, 2H) 7.42 (t, J = 7.8 Hz, 2H) 7.31 (m, 2H) 7.04 (d, J = 8. 2 Hz, 1H) 6.70 (m, 2H) 3.99 (s, 2H) 3.78 (m, 2H) 3.56 (m, 4H) 3.10 (m, 5H) 2.54 (s, 3H) 2.24 (s, 4H) 2.20 (s, 5H); 13 C NMR (75 MHz, CDCl 3 - d , ppm) δ 169.19 160.67 149.35 144.92 137.52 137.22 132.02 130.47 129.31 128.89 127.95 127.28 118.95 114.66 50.25 49.11 44.61 43.72 42.09 20.38 19.03 14.23
실시예 44. 1-(4-(2,3-다이메틸페닐)피페라진-1-일)-2-((5-메틸-4-페닐옥사졸-2-일)메틸아미노)에탄논 (화합물번호 44)Example 44. 1- (4- (2,3-dimethylphenyl) piperazin-1-yl) -2-((5-methyl-4-phenyloxazol-2-yl) methylamino) ethanone (compound Number 44)
수율 82%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 7.70 (m, 2H) 7.43 (t, J = 14.9 Hz, 2H) 7.30 (m, 2H) 7.08 (d, J = 7.4 Hz, 1H) 6.84 (d, J = 7.9 Hz, 1H) 4.07 (s, 2H) 3.46 (s, 2H) 3.41 (s, 2H) 2.80 (m, 4H) 2.52 (m, 3H) 2.26 (m, 7H) 1.86 (m, 3H); 13C NMR (75 MHz, CDCl3-d, ppm) δ 169.11 160.17 148.37 144.23 134.40 133.33 132.64 132.31 131.90 128.59 127.20 127.15 126.63 119.16 52.04 51.84 49.37 46.00 45.09 42.49 20.71 17.62 11.93
Yield 82%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.70 (m, 2H) 7.43 (t, J = 14.9 Hz, 2H) 7.30 (m, 2H) 7.08 (d, J = 7.4 Hz, 1H) 6.84 (d, J = 7.9 Hz, 1H) 4.07 (s, 2H) 3.46 (s, 2H) 3.41 (s, 2H) 2.80 (m, 4H) 2.52 (m, 3H) 2.26 (m, 7H) 1.86 (m, 3H); 13 C NMR (75 MHz, CDCl 3 - d , ppm) δ 169.11 160.17 148.37 144.23 134.40 133.33 132.64 132.31 131.90 128.59 127.20 127.15 126.63 119.16 52.04 51.84 49.37 46.00 45.09 42.49 20.71 17.62 11.93
실시예 45. 1-(4-(3-클로로페닐)피페라진-1-일)-4-(3-페닐-1,2,4-옥사다이아졸-5-일)부탄-1-온 (화합물번호 45)Example 45. 1- (4- (3-Chlorophenyl) piperazin-1-yl) -4- (3-phenyl-1,2,4-oxadiazol-5-yl) butan-1-one ( Compound number 45)
수율 50%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 7.79(m, 2H) 7.45 (m, 3H) 7.23 (d, J = 4.8 Hz, 2H) 6.86 (d, J = 8.9 Hz, 2H) 6.40 (s, 1H) 3.80 (t, J = 5.0 Hz, 2H) 3.65 (t, J = 4.6 Hz 2H) 3.23 (t, J = 7.4 Hz, 2H) 3.13 (q, J = 7.1 Hz, 4H) 2.85 (t, J = 7.4 Hz, 2H)
Yield 50%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.79 (m, 2H) 7.45 (m, 3H) 7.23 (d, J = 4.8 Hz, 2H) 6.86 (d, J = 8.9 Hz, 2H) 6.40 (s, 1H) 3.80 (t, J = 5.0 Hz, 2H) 3.65 (t, J = 4.6 Hz 2H) 3.23 (t, J = 7.4 Hz, 2H) 3.13 (q, J = 7.1 Hz, 4H) 2.85 ( t, J = 7.4 Hz, 2H)
실시예 46. 2-(4-(2,4-다이메틸페닐)피페라진-1-일)-N-((3-아이소프로필옥아이소옥사졸-5-일)메틸)에탄아민 (화합물번호 46)Example 46. 2- (4- (2,4-dimethylphenyl) piperazin-1-yl) -N -((3-isopropyloxisoxazol-5-yl) methyl) ethanamine (Compound No. 46 )
수율 85%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 6.97 (m, 3H) 6.07 (s, 1H) 3.93 (s, 2H) 3.17 (s, 2H) 3.06 (quint, J = 6.9 Hz, 1H) 2.90 (m, 4H) 2.80 (m, 2H) 2.60 (m, 6H) 2.70 (m, 6H) 1.30 (s, 3H) 1.27 (s, 4H); 13C NMR (75 MHz, CDCl3-d, ppm) δ 170.90 169.32 148.96 132.54 132.46 131.79 127.03 118.92 110.42 99.93 61.57 57.43 53.69 51.75 45.44 44.84 29.72 26.50 21.99 21.80 20.71 17.70
Yield 85%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 6.97 (m, 3H) 6.07 (s, 1H) 3.93 (s, 2H) 3.17 (s, 2H) 3.06 (quint, J = 6.9 Hz, 1H) 2.90 (m, 4H) 2.80 (m, 2H) 2.60 (m, 6H) 2.70 (m, 6H) 1.30 (s, 3H) 1.27 (s, 4H); 13 C NMR (75 MHz, CDCl 3 - d , ppm) δ 170.90 169.32 148.96 132.54 132.46 131.79 127.03 118.92 110.42 99.93 61.57 57.43 53.69 51.75 45.44 44.84 29.72 26.50 21.99 21.80 20.71 17.70
실시예 47. 2-(4-(2,3-다이메틸페닐)피페라진-1-일)-N-((3-아이소프로필아이소옥사졸-5-일)메틸)에탄아민 (화합물번호 47)Example 47. 2- (4- (2,3-dimethylphenyl) piperazin-1-yl) -N -((3-isopropylisoxazol-5-yl) methyl) ethanamine (Compound No. 47)
수율 89%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 7.09 (t, J = 7.7 Hz, 1H) 6.92 (t, J = 6.5 Hz, 2H) 6.06 (s, 1H) 3.93 (s, 2H) 3.05 (quint, J = 6.9 Hz, 1H) 2.91 (m, 4H) 2.80 (t, J = 5.8 Hz, 2H) 2.60 (m, 6H) 2.39 (s, 1H) 2.28 (s, 3H) 2.22 (s, 3H) 1.30 (s, 3H) 1.28 (s, 4H); 13C NMR (75 MHz, CDCl3-d, ppm) δ 171.21 169.33 151.53 137.95 131.23 125.84 124.94 116.62 99.77 57.72 53.76 52.11 45.75 45.11 29.73 26.50 21.81 20.65 13.97
Yield 89%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.09 (t, J = 7.7 Hz, 1H) 6.92 (t, J = 6.5 Hz, 2H) 6.06 (s, 1H) 3.93 (s, 2H) 3.05 (quint, J = 6.9 Hz, 1H) 2.91 (m, 4H) 2.80 (t, J = 5.8 Hz, 2H) 2.60 (m, 6H) 2.39 (s, 1H) 2.28 (s, 3H) 2.22 (s, 3H ) 1.30 (s, 3 H) 1.28 (s, 4 H); 13 C NMR (75 MHz, CDCl 3 - d , ppm) δ 171.21 169.33 151.53 137.95 131.23 125.84 124.94 116.62 99.77 57.72 53.76 52.11 45.75 45.11 29.73 26.50 21.81 20.65 13.97
실시예 48. N-((3-아이소프로필아이소옥사졸-5-일)메틸)-2-(4-(3-(트리플루오로메틸)페닐)피페라진-1-일)에탄아민 (화합물번호 48)Example 48. N - ((3- isopropyl-isoxazole-5-yl) methyl) -2- (4- (3- (trifluoromethyl) phenyl) piperazin-1-yl a) ethanamine (Compound Number 48)
수율 96%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 7.30 (m, 2H) 7.05 (m, 3H) 6.03 (m, 1H) 3.89 (s, 2H) 3.21 (m, 4H) 3.01 (quint, J = 6.9 Hz, 1H) 2.76 (t, J = 5.6 Hz, 2H) 2.56 (m, 6H) 2.17 (s, 1H) 1.28 (m, 4H) 1.25 (m, 3H); 13C NMR (75 MHz, CDCl3-d, ppm) δ 171.08 169.31 151.34 131.95 131.53 131.11 130.70 129.75 129.52 126.13 122.53 118.91 115.74 112.13 99.82 57.52 52.94 48.61 45.57 45.02 29.68 26.47 21.75
Yield 96%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.30 (m, 2H) 7.05 (m, 3H) 6.03 (m, 1H) 3.89 (s, 2H) 3.21 (m, 4H) 3.01 (quint, J = 6.9 Hz, 1H) 2.76 (t, J = 5.6 Hz, 2H) 2.56 (m, 6H) 2.17 (s, 1H) 1.28 (m, 4H) 1.25 (m, 3H); 13 C NMR (75 MHz, CDCl 3 - d , ppm) δ 171.08 169.31 151.34 131.95 131.53 131.11 130.70 129.75 129.52 126.13 122.53 118.91 115.74 112.13 99.82 57.52 52.94 48.61 45.57 45.02 29.68 26.47 21.75 21.75
실시예 49. 1-(4-(3,4-다이메틸페닐)피페라진-1-일)-2-((2-메틸-4-페닐옥사졸-5-일)메틸아미노)에탄논 (화합물번호 49)Example 49. 1- (4- (3,4-dimethylphenyl) piperazin-1-yl) -2-((2-methyl-4-phenyloxazol-5-yl) methylamino) ethanone (compound Number 49)
수율 89%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 7.65 (m, 2H) 7.42 (t, J = 7.8 Hz, 2H) 7.31 (m, 2H) 7.04 (d, J = 8. 2Hz, 1H) 6.70 (m, 2H) 3.99 (s, 2H) 3.78 (m, 2H) 3.56 (m, 4H) 3.10 (m, 5H) 2.54 (s, 3H) 2.24 (s, 4H) 2.20 (s, 5H); 13C NMR (75 MHz, CDCl3-d, ppm) δ 169.19 160.67 149.35 144.92 137.52 137.22 132.02 130.47 129.31 128.89 127.95 127.28 118.95 114.66 50.25 49.11 44.61 43.72 42.09 20.38 19.03 14.23
Yield 89%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.65 (m, 2H) 7.42 (t, J = 7.8 Hz, 2H) 7.31 (m, 2H) 7.04 (d, J = 8. 2 Hz, 1H) 6.70 (m, 2H) 3.99 (s, 2H) 3.78 (m, 2H) 3.56 (m, 4H) 3.10 (m, 5H) 2.54 (s, 3H) 2.24 (s, 4H) 2.20 (s, 5H); 13 C NMR (75 MHz, CDCl 3 - d , ppm) δ 169.19 160.67 149.35 144.92 137.52 137.22 132.02 130.47 129.31 128.89 127.95 127.28 118.95 114.66 50.25 49.11 44.61 43.72 42.09 20.38 19.03 14.23
실시예 50. 2-((2-메틸-4-페닐옥사졸-5-일)메틸아미노)-1-(4-(3-(트리플루오로메틸)페닐)피페라진-1-일)에탄논 (화합물번호 50)Example 50. 2-((2-methyl-4-phenyloxazol-5-yl) methylamino) -1- (4- (3- (trifluoromethyl) phenyl) piperazin-1-yl) ethane Rice fields (Compound No. 50)
수율 90%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 7.68 (m, 2H) 7.37 (m, 3H) 7.26 (m, 1H) 7.13 (d, J = 7.7 Hz, 1H) 7.05 (m, 2H) 4.08 (m, 2H) 3.75 (m, 2H) 3.43 (s, 2H) 3.40 (m, 2H) 3.15 (m, 2H) 3.06 (m, 2H) 2.72 (m, 1H) 2.50 (s, 3H) 1.25 (t, J = 7.1 Hz, 1H) 1.19 (d, J = 6.1 Hz, 2H); 13C NMR (75 MHz, CDCl3-d, ppm) δ 169.02 160.55 150.93 144.52 137.07 131.73 131.33 129.73 128.71 127.79 127.06 125.98 119.41 116.78 112.80 112.75 48.78 44.06 43.38 41.54 14.02
Yield 90%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.68 (m, 2H) 7.37 (m, 3H) 7.26 (m, 1H) 7.13 (d, J = 7.7 Hz, 1H) 7.05 (m, 2H) 4.08 (m, 2H) 3.75 (m, 2H) 3.43 (s, 2H) 3.40 (m, 2H) 3.15 (m, 2H) 3.06 (m, 2H) 2.72 (m, 1H) 2.50 (s, 3H) 1.25 ( t, J = 7.1 Hz, 1H) 1.19 (d, J = 6.1 Hz, 2H); 13 C NMR (75 MHz, CDCl 3 - d , ppm) δ 169.02 160.55 150.93 144.52 137.07 131.73 131.33 129.73 128.71 127.79 127.06 125.98 119.41 116.78 112.80 112.75 48.78 44.06 43.38 41.54 14.02
실시예 51. 2-(4-(2,3-다이메틸페닐)피페라진-1-일)-N-((3-메틸아이소옥사졸-5-일)메틸)에탄아민 (화합물번호 51)Example 51. 2- (4- (2,3-dimethylphenyl) piperazin-1-yl) -N -((3-methylisoxazol-5-yl) methyl) ethanamine (Compound No. 51)
수율 20%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 7.09 (t, J = 7.7 Hz, 1H) 6.92 (m, 2H) 6.02 (s, 1H) 3.93 (s, 2H) 2.91 (m, 4H) 2.78 (m, 2H) 2.59 (m, 6H) 2.28 (m, 6H) 2.22 (s, 3H)
Yield 20%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.09 (t, J = 7.7 Hz, 1H) 6.92 (m, 2H) 6.02 (s, 1H) 3.93 (s, 2H) 2.91 (m, 4H) 2.78 (m, 2H) 2.59 (m, 6H) 2.28 (m, 6H) 2.22 (s, 3H)
실시예 52. 2-(4-(3,4-다이메틸페닐)피페라진-1-일)-N-((3-메틸아이소옥사졸-5-일)메틸)에탄아민 (화합물번호 52)Example 52. 2- (4- (3,4-Dimethylphenyl) piperazin-1-yl) -N -((3-methylisoxazol-5-yl) methyl) ethanamine (Compound No. 52)
수율 88%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 7.03 (d, J = 8.2 Hz, 1H) 6.76 (m, 1H) 6.69 (m, 1H) 6.01 (s, 1H) 3.92 (s, 2H) 3.14 (m, 4H) 2.76 (m, 2H) 2.57 (m, 7H) 2.30 (s, 3H) 2.24 (s, 3H) 2.19 (s, 4H) 2.07 (m, 1H)
Yield 88%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.03 (d, J = 8.2 Hz, 1H) 6.76 (m, 1H) 6.69 (m, 1H) 6.01 (s, 1H) 3.92 (s, 2H) 3.14 (m, 4H) 2.76 (m, 2H) 2.57 (m, 7H) 2.30 (s, 3H) 2.24 (s, 3H) 2.19 (s, 4H) 2.07 (m, 1H)
실시예 53. N-((3-메틸아이소옥사졸-5-일)메틸)-2-(4-(3-(트리플루오로메틸)페닐)피페라진-1-일)에탄아민 (화합물번호 53)Example 53. N - ((3- methyl-isoxazole-5-yl) methyl) -2- (4- (3- (trifluoromethyl) phenyl) piperazin-1-yl) ethanamine (Compound 53)
수율 92%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 7.30 (m, 1H) 7.05 (m, 3H) 5.98 (s, 1H) 3.89 (s, 2H) 3.21 (m, 5H) 2.74 (m, 2H) 2.54 (m, 7H) 2.26 (s, 3H) 2.21 (s, 1H) 2.52 (m, 3H) 2.26 (m, 7H) 1.86 (m, 3H)
Yield 92%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.30 (m, 1H) 7.05 (m, 3H) 5.98 (s, 1H) 3.89 (s, 2H) 3.21 (m, 5H) 2.74 (m, 2H ) 2.54 (m, 7H) 2.26 (s, 3H) 2.21 (s, 1H) 2.52 (m, 3H) 2.26 (m, 7H) 1.86 (m, 3H)
실시예 54. N-((5-아이소부틸-4-페닐옥사졸-2-일)메틸)-2-(4-페닐피페라진-1-일)아세타마이드 (화합물번호 54)Example 54. N - ((5- isobutyl-4-phenyl-oxazol-2-yl) methyl) -2- (4-phenyl-piperazin-1-yl) acetic Tama Id (Compound No. 54)
수율 37%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 7.90(m, 1H) 7.65 (d, J = 4.00 Hz, 2H) 7.40 (t, J = 7.55 Hz, 2H) 7.30 (m, 3H) 6.92 (q, J = 12.25 Hz, 3H) 4.65(d, J = 2.81 Hz, 2H) 3.27(t, J = 5.00 Hz, 4H) 3.19 (s, 2H) 2.78 ( q, J = 9.77 Hz, 6H) 2.11 (quint, J = 12.56 Hz, 1H) 0.99 (d, J = 3.31 Hz, 6H); 13C NMR (75 MHz, CDCl3-d, ppm) δ 170.30 158.42 151.13 148.04 135.14 132.11 129.17 128.59 127.43 126.75 120.02 116.23 61.41 53.48 49.43 36.42 34.82 28.18.22.49
Yield 37%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.90 (m, 1H) 7.65 (d, J = 4.00 Hz, 2H) 7.40 (t, J = 7.55 Hz, 2H) 7.30 (m, 3H) 6.92 (q, J = 12.25 Hz, 3H) 4.65 (d, J = 2.81 Hz, 2H) 3.27 (t, J = 5.00 Hz, 4H) 3.19 (s, 2H) 2.78 (q, J = 9.77 Hz, 6H) 2.11 (quint, J = 12.56 Hz, 1 H) 0.99 (d, J = 3.31 Hz, 6 H); 13 C NMR (75 MHz, CDCl 3 - d , ppm) δ 170.30 158.42 151.13 148.04 135.14 132.11 129.17 128.59 127.43 126.75 120.02 116.23 61.41 53.48 49.43 36.42 34.82 28.18.22.49
실시예 55. 2-(4-벤즈하이드릴피페라진-1-일)-N-((5-아이소부틸-4-페닐옥사졸-2-일)메틸)아세타마이드 (화합물번호 55)Example 55. 2- (4-Benzhydrylpiperazin-1-yl) -N -((5-isobutyl-4-phenyloxazol-2-yl) methyl) acetamide (Compound No. 55)
수율 82%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 7.87(m, 1H) 7.64 (d, J = 4.14 Hz, 2H) 7.36 (m, 11H) 7.20 (t, J = 5.86 Hz, 2H) 4.62 (d, J = 2.85 Hz, 2H) 4.26 (s, 1H) 3.13 (s, 2H) 2.74 (d, J = 4.00 Hz, 2H) 2.66 (s, 4H) 2.50 (s. 4H) 2.09 (quint, J = 11.65 Hz, 1H) 0.95 (d, J = 4.66 Hz, 6H); 13C NMR (75 MHz, CDCl3-d, ppm) δ 170.55 158.47 147.96 142.60 135.12 132.18 128.56 127.90 127.37 127.04 126.74 77.55 77.12 76.70 76.32 61.37 53.75 52.11 36.30 34.84 28.14 22.47
Yield 82%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.87 (m, 1H) 7.64 (d, J = 4.14 Hz, 2H) 7.36 (m, 11H) 7.20 (t, J = 5.86 Hz, 2H) 4.62 (d, J = 2.85 Hz, 2H) 4.26 (s, 1H) 3.13 (s, 2H) 2.74 (d, J = 4.00 Hz, 2H) 2.66 (s, 4H) 2.50 (s. 4H) 2.09 (quint, J = 11.65 Hz, 1H) 0.95 (d, J = 4.66 Hz, 6H); 13 C NMR (75 MHz, CDCl 3 - d , ppm) δ 170.55 158.47 147.96 142.60 135.12 132.18 128.56 127.90 127.37 127.04 126.74 77.55 77.12 76.70 76.32 61.37 53.75 52.11 36.30 34.84 28.14 22.47
실시예 56. 2-(4-(비스(4-플루오로페닐)메틸)피페라진-1-일)-N-((5-아이소부틸-4-페닐옥사졸-2-일)메틸)아세타마이드 (화합물번호 56)Example 56. 2- (4- (bis (4-fluorophenyl) methyl) piperazin-1-yl) -N -((5-isobutyl-4-phenyloxazol-2-yl) methyl) acet Tamide (Compound No. 56)
수율 80%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 7.82(m, 1H) 7.61 (d, J = 4.73 Hz, 3H) 7.35 (m, 8H) 6.98 (t, J = 8.53 Hz, 4H) 4.60 (d, J = 2.86 Hz, 2H) 4.23 (s, 1H) 3.11 (s, 2H) 2.72 (d, J = 3.61 Hz, 2H) 2.64 (s, 4H) 2.45 (s, 4H) 2.06 (quint, J = 12.92 Hz, 1H) 0.94 (d, J = 3.33 Hz, 6H); 13C NMR (75 MHz, CDCl3-d, ppm) δ 170.43 163.48 160.22 158.46 147.99 138.07 135.08 132.16 129.27 128.52 127.38 126.72 115.61 115.33 74.53 61.30 53.65 51.91 36.27 34.80 28.13 22.44
Yield 80%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.82 (m, 1 H) 7.61 (d, J = 4.73 Hz, 3H) 7.35 (m, 8H) 6.98 (t, J = 8.53 Hz, 4H) 4.60 (d, J = 2.86 Hz, 2H) 4.23 (s, 1H) 3.11 (s, 2H) 2.72 (d, J = 3.61 Hz, 2H) 2.64 (s, 4H) 2.45 (s, 4H) 2.06 (quint, J = 12.92 Hz, 1H) 0.94 (d, J = 3.33 Hz, 6H); 13 C NMR (75 MHz, CDCl 3 - d , ppm) δ 170.43 163.48 160.22 158.46 147.99 138.07 135.08 132.16 129.27 128.52 127.38 126.72 115.61 115.33 74.53 61.30 53.65 51.91 36.27 34.80 28.13 22.44
실시예 57. 2-(4-(비스(4-클로로페닐)메틸)피페라진-1-일)-N-((5-아이소부틸-4-페닐옥사졸-2-일)메틸)아세타마이드 (화합물번호 57) Example 57. 2- (4- (bis (4-chlorophenyl) methyl) piperazin-1-yl) -N -((5-isobutyl-4-phenyloxazol-2-yl) methyl) acetama Id (Compound No. 57)
수율 92%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 7.81(m, 1H) 7.60 (d, J = 4.67 Hz, 2H) 7.32 (m, 12H) 4.60 (d, J = 2.85 Hz, 2H) 4.21 (s, 1H) 3.11 (s, 2H) 2.73 (d, J = 3.60 Hz, 2H) 2.64 (s, 4H) 2.45 (s, 4H) 2.06 (quint, J = 6.73 Hz, 1H) 0.95 (d, J = 3.32 Hz, 6H); 13C NMR (75 MHz, CDCl3-d, ppm) δ 170.37 158.46 147.99 140.56 135.09 132.96 132.16 129.08 128.86 128.52 127.39 126.72 77.48 77.06 76.63 74.72 61.29 53.59 51.90 36.28 34.81 29.71 28.13 22.44
Yield 92%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.81 (m, 1H) 7.60 (d, J = 4.67 Hz, 2H) 7.32 (m, 12H) 4.60 (d, J = 2.85 Hz, 2H) 4.21 (s, 1H) 3.11 (s, 2H) 2.73 (d, J = 3.60 Hz, 2H) 2.64 (s, 4H) 2.45 (s, 4H) 2.06 (quint, J = 6.73 Hz, 1H) 0.95 (d, J = 3.32 Hz, 6H); 13 C NMR (75 MHz, CDCl 3 - d , ppm) δ 170.37 158.46 147.99 140.56 135.09 132.96 132.16 129.08 128.86 128.52 127.39 126.72 77.48 77.06 76.63 74.72 61.29 53.59 51.90 36.28 34.81 29.71 28.13 22.44
실시예 58. N-((5-아이소부틸-4-페닐옥사졸-2-일)메틸)-2-(4-(3-(트리플루오로메틸)페닐)피페라진-1-일)아세타마이드 (화합물번호 58)Example 58. N -((5-isobutyl-4-phenyloxazol-2-yl) methyl) -2- (4- (3- (trifluoromethyl) phenyl) piperazin-1-yl) acet Tamide (Compound No. 58)
수율 92%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 7.89(m, 1H) 7.65(d, J = 7.75 Hz, 2H) 7.34 (m, 5H) 7.09 (m, 3H) 4.64 (d, J = 2.79 Hz, 2H) 3.31 (t, J = 4.98 Hz, 5H) 3.20 (s, 2H) 2.78 (m, 6H) 2.10 (quint, J = 6.06 Hz, 1H) 0.98 (d, J = 3.33 Hz, 6H); 13C NMR (75 MHz, CDCl3-d, ppm) δ 170.04 158.41 151.24 148.09 135.16 132.12 131.70 131.28 129.59 128.55 127.47 126.74 118.92 116.17 112.24 61.35 53.24 48.92 35.43 34.82 29.70 28.17 22.46
Yield 92%;OneH NMR (300 MHz, CDCl3-dppm) δ 7.89 (m, 1H) 7.65 (d,J= 7.75 Hz, 2H) 7.34 (m, 5H) 7.09 (m, 3H) 4.64 (d,J= 2.79 Hz, 2H) 3.31 (t,J= 4.98 Hz, 5H) 3.20 (s, 2H) 2.78 (m, 6H) 2.10 (quint,J= 6.06 Hz, 1H) 0.98 (d,J= 3.33 Hz, 6H); 13C NMR (75 MHz, CDCl3-d, ppm) δ 170.04 158.41 151.24 148.09 135.16 132.12 131.70 131.28 129.59 128.55 127.47 126.74 118.92 116.17 112.24 61.35 53.24 48.92 35.43 34.82 29.70 28.17 22.46
실시예 59. 2-(4-(2,3-다이메틸페닐)피페라진-1-일)-N-((5-아이소부틸-4-페닐옥사졸-2-일)메틸)아세타마이드 (화합물번호 59)Example 59. 2- (4- (2,3-dimethylphenyl) piperazin-1-yl) -N -((5-isobutyl-4-phenyloxazol-2-yl) methyl) acetamide ( Compound no.59)
수율 75%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 8.00(m, 1H) 7.68 (d, J = 4.20 Hz, 2H) 7.42 (t, J = 7.43 Hz, 2H) 7.31 (q, J = 10.65 Hz, 1H) 7.11 (t, J = 7.69 Hz, 1H) 6.94 (d, J = 3.84 Hz, 2H) 4.66 (d, J = 2.81 Hz, 2H) 3.21 (s, 2H) 2.98 (m, 4H) 2.78 (m, 6H) 2.27 (d, J = 7.61 Hz, 6H) 2.12 (quint, J = 6.79 Hz, 1H) 1.29 (s, 1H) 1.00 (d, J = 3.33 Hz, 6H); 13C NMR (75 MHz, CDCl3-d, ppm) δ 170.52 158.45 151.33 148.03 138.07 135.15 132.18 131.40 128.59 127.41 126.75 125.86 125.19 116.69 61.49 54.04 53.45 52.35 36.46 34.86 28.19 22.50 20.64 13.92
Yield 75%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 8.00 (m, 1H) 7.68 (d, J = 4.20 Hz, 2H) 7.42 (t, J = 7.43 Hz, 2H) 7.31 (q, J = 10.65 Hz, 1H) 7.11 (t, J = 7.69 Hz, 1H) 6.94 (d, J = 3.84 Hz, 2H) 4.66 (d, J = 2.81 Hz, 2H) 3.21 (s, 2H) 2.98 (m, 4H) 2.78 (m, 6H) 2.27 (d, J = 7.61 Hz, 6H) 2.12 (quint, J = 6.79 Hz, 1H) 1.29 (s, 1H) 1.00 (d, J = 3.33 Hz, 6H); 13 C NMR (75 MHz, CDCl 3 - d , ppm) δ 170.52 158.45 151.33 148.03 138.07 135.15 132.18 131.40 128.59 127.41 126.75 125.86 125.19 116.69 61.49 54.04 53.45 52.35 36.46 34.86 28.19 22.50 20.64 13.92
실시예 60. 2-(4-(3,4-다이메틸페닐)피페라진-1-일)-N-((5-아이소부틸-4-페닐옥사졸-2-일)메틸)아세타마이드 (화합물번호 60)Example 60. 2- (4- (3,4-Dimethylphenyl) piperazin-1-yl) -N -((5-isobutyl-4-phenyloxazol-2-yl) methyl) acetamide ( Compound no.60)
수율 66%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 7.91(m, 1H) 7.66 (d, J = 4.23 Hz, 2H) 7.41 (t, J = 7.65 Hz, 2H) 7.31 (m, 2H) 7.05 (d, J = 4.09 Hz, 1H) 6.73 (m, 2H) 4.65 (d, J = 2.82 Hz, 2H) 3.21 (m, 6H) 2.77 (m, 6H) 2.26 (d, J = 14.96 Hz, 6H) 2.11 (quint, J = 13.65 Hz, 1H) 1.04 (d, J = 18.42 Hz, 6H); 13C NMR (75 MHz, CDCl3-d, ppm) δ 170.32 158.43 149.44 148.01 137.16 135.16 132.16 130.21 128.58 128.35 127.41 126.76 118.23 113.96 61.45 53.57 50.01 36.41 34.84 29.74 28.18 22.50 20.22 18.81
Yield 66%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.91 (m, 1H) 7.66 (d, J = 4.23 Hz, 2H) 7.41 (t, J = 7.65 Hz, 2H) 7.31 (m, 2H) 7.05 (d, J = 4.09 Hz, 1H) 6.73 (m, 2H) 4.65 (d, J = 2.82 Hz, 2H) 3.21 (m, 6H) 2.77 (m, 6H) 2.26 (d, J = 14.96 Hz, 6H) 2.11 (quint , J = 13.65 Hz, 1 H) 1.04 (d, J = 18.42 Hz, 6H); 13 C NMR (75 MHz, CDCl 3 - d , ppm) δ 170.32 158.43 149.44 148.01 137.16 135.16 132.16 130.21 128.58 128.35 127.41 126.76 118.23 113.96 61.45 53.57 50.01 36.41 34.84 29.74 28.18 22.50 20.22 18.22
실시예 61. 2-(4-2,4-다이메틸페닐)피페라진-1-일)-N-((5-아이소부틸-4-페닐옥사졸-2-일)메틸)아세타마이드 (화합물번호 61)Example 61. 2- (4-2,4-dimethylphenyl) piperazin-1-yl) -N -((5-isobutyl-4-phenyloxazol-2-yl) methyl) acetamide (compound Number 61)
수율 92%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 7.98 (m, 1H) 7.68 (d, J = 4.27 Hz, 2H) 7.42 (t, J = 7.38 Hz, 2H) 7.31 (m, 1H) 6.98 (m, 3H) 4.66 (d, J = 2.81 Hz, 2H) 3.20 (s, 2H) 2.98 (t, J = 4.86 Hz, 4H) 2.77 (d, J = 3.58 Hz, 6H) 2.30 (d, J = 1.52 Hz, 6H) 2.12 (sextet, J = 7.23 Hz, 1H) 0.99 (d, J = 3.3 Hz, 6H); 13C NMR (75 MHz, CDCl3-d, ppm) δ 170.49 158.46 148.83 148.02 135.16 132.82 132.67 132.20 131.87 128.58 127.41 126.76 119.00 62.50 54.17 52.14 36.45 34.86 29.71 28.18 22.49 20.71 17.66
Yield 92%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.98 (m, 1H) 7.68 (d, J = 4.27 Hz, 2H) 7.42 (t, J = 7.38 Hz, 2H) 7.31 (m, 1H) 6.98 (m, 3H) 4.66 (d, J = 2.81 Hz, 2H) 3.20 (s, 2H) 2.98 (t, J = 4.86 Hz, 4H) 2.77 (d, J = 3.58 Hz, 6H) 2.30 (d, J = 1.52 Hz, 6H) 2.12 (sextet, J = 7.23 Hz, 1H) 0.99 (d, J = 3.3 Hz, 6H); 13 C NMR (75 MHz, CDCl 3 - d , ppm) δ 170.49 158.46 148.83 148.02 135.16 132.82 132.67 132.20 131.87 128.58 127.41 126.76 119.00 62.50 54.17 52.14 36.45 34.86 29.71 28.18 22.49 20.71 17.66
실시예 62. N-((5-아이소부틸-4-페닐옥사졸-2-일)메틸)-2-((4-페닐설포닐)-1,4-다이아제판-1-일)아세타마이드 (화합물번호 62)Example 62. N -((5-isobutyl-4-phenyloxazol-2-yl) methyl) -2-((4-phenylsulfonyl) -1,4-diazepan-1-yl) acetama Id (Compound No. 62)
수율 82%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 7.75 (m, 3H) 7.57 (dd, J = 13.66 Hz, 3H) 7.43 (td, J = 18.17 Hz, 4H) 7.30(t, J = 7.59 Hz, 1H) 4.59 (d, J = 2.84 Hz, 2H) 3.41 (m, 4H) 3.22 (s, 2H) 2.82 (m, 4H) 2.73 (d, J = 3.69 Hz, 2H) 2.07 (quint, J = 9.12 Hz, 1H) 1.91 (m, 2H) 0.96 (d, J = 3.33 Hz, 6H); 13C NMR (75 MHz, CDCl3-d, ppm) δ 170.53 158.39 147.99 139.20 135.14 132.49 132.17 129.10 128.56 127.39 126.90 126.76 61.37 57.19 55.24 48.42 47.17 36.41 34.77 28.37 28.14 22.46
Yield 82%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.75 (m, 3H) 7.57 (dd, J = 13.66 Hz, 3H) 7.43 (td, J = 18.17 Hz, 4H) 7.30 (t, J = 7.59 Hz, 1H) 4.59 (d, J = 2.84 Hz, 2H) 3.41 (m, 4H) 3.22 (s, 2H) 2.82 (m, 4H) 2.73 (d, J = 3.69 Hz, 2H) 2.07 (quint, J = 9.12 Hz, 1 H) 1.91 (m, 2 H) 0.96 (d, J = 3.33 Hz, 6H); 13 C NMR (75 MHz, CDCl 3 - d , ppm) δ 170.53 158.39 147.99 139.20 135.14 132.49 132.17 129.10 128.56 127.39 126.90 126.76 61.37 57.19 55.24 48.42 47.17 36.41 34.77 28.37 28.14 22.46
실시예 63. 2-(4-(4-플루오로페닐설포닐)-1,4-다이아제판-1-일)-N-((5-아이소부틸-4-페닐옥사졸-2-일)메틸)아세타마이드 (화합물번호 63)Example 63. 2- (4- (4-fluorophenylsulfonyl) -1,4-diazepan-1-yl) -N -((5-isobutyl-4-phenyloxazol-2-yl) Methyl) acetamide (Compound No. 63)
수율 90%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 7.76 (m, 3H) 7.60 (d, J = 4.22 Hz, 2H) 7.37 (t, J = 16.64 Hz, 2H) 4.59 (d, J = 2.82 Hz, 2H) 3.40 (m, 4H) 3.24 (s, 2H) 2.83 (m, 4H) 2.73 (d, J = 3.60 Hz, 2H) 2.08 (quint, J = 9.44 Hz, 1H) 1.93 (m, 2H) 0.96 (d, J = 3.32 Hz, 6H); 13C NMR (75 MHz, CDCl3-d, ppm) δ 170.48 166.62 163.25 158.41 148.04 135.35 135.13 132.18 129.62 129.50 128.57 127.43 126.76 116.46 116.16 61.44 57.15 55.31 48.45 47.16 36.41 34.77 28.41 28.15 22.45
Yield 90%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.76 (m, 3H) 7.60 (d, J = 4.22 Hz, 2H) 7.37 (t, J = 16.64 Hz, 2H) 4.59 (d, J = 2.82 Hz, 2H) 3.40 (m, 4H) 3.24 (s, 2H) 2.83 (m, 4H) 2.73 (d, J = 3.60 Hz, 2H) 2.08 (quint, J = 9.44 Hz, 1H) 1.93 (m, 2H) 0.96 (d, J = 3.32 Hz, 6H); 13 C NMR (75 MHz, CDCl 3 - d , ppm) δ 170.48 166.62 163.25 158.41 148.04 135.35 135.13 132.18 129.62 129.50 128.57 127.43 126.76 116.46 116.16 61.44 57.15 55.31 48.45 47.16 36.41 34.77 28.41 28.41 28.41
실시예 64. 2-(4-(벤조[d]싸이아졸-2-일메틸)피페라진-1-일)-N-((5-아이소부틸-4-페닐옥사졸-2-일)메틸)아세타마이드 (화합물번호 64)Example 64. 2- (4- (benzo [ d ] thiazol-2-ylmethyl) piperazin-1-yl) -N -((5-isobutyl-4-phenyloxazol-2-yl) methyl Acetamide (Compound No. 64)
수율 57%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 7.96 (m, 1H) 7.87 (d, J = 4.23 Hz, 2H) 7.64 (d, J = 4.18 Hz, 2H) 7.41 (m, 4H) 7.27 (m, 1H) 4.61 (d, J = 2.83 Hz, 2H) 3.98 (s, 2H) 3.14 (s, 2H) 2.72 (m, 10H) 2.08 (quint, J = 7.63 Hz, 1H) 0.96 (d, J = 3.32 Hz, 6H); 13C NMR (75 MHz, CDCl3-d, ppm) δ 171.78 170.32 158.38 153.27 147.99 135.40 135.13 132.13 128.58 127.42 126.73 125.87 124.94 122.82 121.74 61.33 60.16 53.49 53.43 36.37 34.81 29.71 28.16 22.49
Yield 57%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.96 (m, 1H) 7.87 (d, J = 4.23 Hz, 2H) 7.64 (d, J = 4.18 Hz, 2H) 7.41 (m, 4H) 7.27 (m, 1H) 4.61 (d, J = 2.83 Hz, 2H) 3.98 (s, 2H) 3.14 (s, 2H) 2.72 (m, 10H) 2.08 (quint, J = 7.63 Hz, 1H) 0.96 (d, J = 3.32 Hz, 6H); 13 C NMR (75 MHz, CDCl 3 - d , ppm) δ 171.78 170.32 158.38 153.27 147.99 135.40 135.13 132.13 128.58 127.42 126.73 125.87 124.94 122.82 121.74 61.33 60.16 53.49 53.43 36.37 34.81 29.71 28.16 22.16 22.16
실시예 65. N-((5-아이소부틸-4-페닐옥사졸-2-일)메틸)-2-(4-(3-(트리플루오로메틸)벤조일-1,4-다이아제판-1-일)아세타마이드 (화합물번호 65)Example 65. N -((5-isobutyl-4-phenyloxazol-2-yl) methyl) -2- (4- (3- (trifluoromethyl) benzoyl-1,4-diazepan-1 Acylamide (Compound No. 65)
수율 52%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 7.87 (m, 1H) 7.59 (m, 4H) 7.46 (m, 4H) 7.39 (t, J = 5.68 Hz, 4H) 7.29 (m, 1H) 4.60 (dd, J = 8.55 Hz, 2H) 3.84 (d, J = 1.96 Hz, 2H) 3.47 (m, 2H) 3.25 (d, J = 9.67 Hz, 2H) 2.97 (d, J = 2.18 Hz, 1H) 2.85 (m, 1H) 2.71 (m, 4H) 2.06 (m, 2H) 1.25 (m, 1H) 0.95 (m, 6H); 13C NMR (75 MHz, CDCl3-d, ppm) δ 170.34 158.41 158.29 148.11 140.12 135.18 132.13 131.61 131.29 128.60 127.51 127.04 126.80 126.72 125.64 125.05 61.64 61.36 57.51 56.48 55.57 55.05 49.87 48.75 46.14 45.29 36.46 34.75 29.01 28.16 26.87 22.46 14.19
Yield 52%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.87 (m, 1H) 7.59 (m, 4H) 7.46 (m, 4H) 7.39 (t, J = 5.68 Hz, 4H) 7.29 (m, 1H) 4.60 (dd, J = 8.55 Hz, 2H) 3.84 (d, J = 1.96 Hz, 2H) 3.47 (m, 2H) 3.25 (d, J = 9.67 Hz, 2H) 2.97 (d, J = 2.18 Hz, 1H) 2.85 (m, 1 H) 2.71 (m, 4 H) 2.06 (m, 2 H) 1.25 (m, 1 H) 0.95 (m, 6 H); 13 C NMR (75 MHz, CDCl 3 - d , ppm) δ 170.34 158.41 158.29 148.11 140.12 135.18 132.13 131.61 131.29 128.60 127.51 127.04 126.80 126.72 125.64 125.05 61.64 61.36 57.51 56.48 55.57 55.05 49.46 46.46 46 46 46
실시예 66. 2-(4-(4-플루오로벤조일)-1,4-다이아제판-1-일)-N-((5-아이소부틸-4-페닐옥사졸-2-일)메틸)아세타마이드 (화합물번호 66)Example 66. 2- (4- (4-fluorobenzoyl) -1,4-diazepan-1-yl) -N -((5-isobutyl-4-phenyloxazol-2-yl) methyl) Acetamide (Compound No. 66)
수율 60%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 8.07 (m, 0.2H) 7.92 (m, 0.5H) 7.80 (m, 0.4H) 7.62 (m, 2H) 7.34 (m, 5H) 7.08 (m, 2H) 4.61 (m, 2H) 3.81 (s, 2H) 3.51 (m, 2H) 3.26 (d, J = 8.34 Hz, 2H) 2.96 (s, 1H) 2.84 (m, 1H) 2.73 (m, 4H) 2.05 (m, 2H) 1.86 (s, 1H) 0.96 (m, 6H); 13C NMR (75 MHz, CDCl3-d, ppm) δ 170.82 170.46 158.42 148.07 135.16 132.51 132.10 128.93 128.58 127.46 126.79 115.70 115.41 61.53 61.31 57.50 56.53 55.64 55.02 48.94 46.19 45.39 36.43 34.75 28.93 28.14 26.91 22.45
Yield 60%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 8.07 (m, 0.2H) 7.92 (m, 0.5H) 7.80 (m, 0.4H) 7.62 (m, 2H) 7.34 (m, 5H) 7.08 ( m, 2H) 4.61 (m, 2H) 3.81 (s, 2H) 3.51 (m, 2H) 3.26 (d, J = 8.34 Hz, 2H) 2.96 (s, 1H) 2.84 (m, 1H) 2.73 (m, 4H ) 2.05 (m, 2H) 1.86 (s, 1H) 0.96 (m, 6H); 13 C NMR (75 MHz, CDCl 3 - d , ppm) δ 170.82 170.46 158.42 148.07 135.16 132.51 132.10 128.93 128.58 127.46 126.79 115.70 115.41 61.53 61.31 57.50 56.53 55.64 55.02 48.94 46.19 45.39 36.43 28.43 28.43
실시예 67. N-((5-아이소부틸-4-페닐옥사졸-2-일)메틸)-2-(4-(3-(트리플루오로메틸)벤조일)피페라진-1-일)아세타마이드 (화합물번호 67)Example 67. N - ((5- isobutyl-4-phenyl-oxazol-2-yl) methyl) -2- (4- (3- (trifluoromethyl) benzoyl) piperazin-1-yl) acetate Tamide (Compound No. 67)
수율 54%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 7.74 (m, 1H) 7.67 (d, J = 3.05 Hz, 2H) 7.53 (dd, J = 13.96 Hz, 4H) 7.32 (m, 3H) 4.59 (d, J = 5.86 Hz, 2H) 3.85 (s, 2H) 3.43 (s, 2H) 3.14 (m, 2H) 2.70 (d, J = 5.54 Hz, 4H) 2.57 (s, 2H) 2.05 (quint, J = 10.16 Hz, 1H) 0.93 (m, 6H); 13C NMR (75 MHz, CDCl3-d, ppm) δ 169.67 168.85 158.41 148.11 139.10 135.11 132.07 131.92 131.59 128.58 127.48 127.41 126.69 125.69 125.04 122.33 61.29 53.47 53.07 47.63 42.17 36.36 34.74 28.15 22.44
Yield 54%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.74 (m, 1H) 7.67 (d, J = 3.05 Hz, 2H) 7.53 (dd, J = 13.96 Hz, 4H) 7.32 (m, 3H) 4.59 (d, J = 5.86 Hz, 2H) 3.85 (s, 2H) 3.43 (s, 2H) 3.14 (m, 2H) 2.70 (d, J = 5.54 Hz, 4H) 2.57 (s, 2H) 2.05 (quint, J = 10.16 Hz, 1 H) 0.93 (m, 6 H); 13 C NMR (75 MHz, CDCl 3 - d , ppm) δ 169.67 168.85 158.41 148.11 139.10 135.11 132.07 131.92 131.59 128.58 127.48 127.41 126.69 125.69 125.04 122.33 61.29 53.47 53.07 47.63 42.17 36.36 34.74
실시예 68. 1-(4-(4--클로로페닐)피페라진-1-일)-2-((4-페닐-5-프로필옥사졸-2-일)메틸아미노)에탄논 (화합물번호 68)Example 68. 1- (4- (4--chlorophenyl) piperazin-1-yl) -2-((4-phenyl-5-propyloxazol-2-yl) methylamino) ethanone (Compound No. 68)
수율 45%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 7.64 (d, J = 7.77 Hz 2H) 7.41 (t, J = 7.36 Hz, 2H) 7.32 (d, J = 7.64 Hz, 1H) 7.24 (d, J = 8.71 Hz 2H) 6.83 (d, J = 8.81 Hz 2H) 3.99 (s, 2H) 3.78 (t, J = 4.69 Hz 2H) 3.60 (s, 2H) 3.57 (t, J = 4.94 Hz 2H) 3.12 (d, J = 4.94 Hz, 4H) 2.86 (t, J = 7.48 Hz 2H) 1.77 (sext, J = 7.43 Hz 2H) 1.01 (t, J = 7.43 Hz 3H); 13C NMR (75 MHz, CDCl3-d, ppm) δ 169.08 160.19 149.51 148.31 134.39 132.39 129.11 128.54 127.26 126.81 125.52 117.87 49.40 45.98 44.35 41.67 27.89 21.51 13.82
Yield 45%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.64 (d, J = 7.77 Hz 2H) 7.41 (t, J = 7.36 Hz, 2H) 7.32 (d, J = 7.64 Hz, 1H) 7.24 (d , J = 8.71 Hz 2H) 6.83 (d, J = 8.81 Hz 2H) 3.99 (s, 2H) 3.78 (t, J = 4.69 Hz 2H) 3.60 (s, 2H) 3.57 (t, J = 4.94 Hz 2H) 3.12 (d, J = 4.94 Hz, 4H) 2.86 (t, J = 7.48 Hz 2H) 1.77 (sext, J = 7.43 Hz 2H) 1.01 (t, J = 7.43 Hz 3H); 13 C NMR (75 MHz, CDCl 3 - d , ppm) δ 169.08 160.19 149.51 148.31 134.39 132.39 129.11 128.54 127.26 126.81 125.52 117.87 49.40 45.98 44.35 41.67 27.89 21.51 13.82
실시예 69. 1-(4-(2,3-다이클로로페닐)피페라진-1-일)-2-((4-페닐-5-프로필옥사졸-2-일)메틸아미노)에탄논 (화합물번호 69)Example 69. 1- (4- (2,3-Dichlorophenyl) piperazin-1-yl) -2-((4-phenyl-5-propyloxazol-2-yl) methylamino) ethanone ( Compound no.69)
수율 54%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 7.66 (d, J = 1.27 Hz 2H) 7.63 (t, J = 1.50 Hz, 2H) 7.28 (d, J = 1.46 Hz, 1H) 7.27 (s, 1H) 7.20 (m, 2H) 6.88 (d, J = 6.58 Hz 1H) 4.00 (s, 2H) 3.81 (s, 2H) 3.60 (s, 4H) 3.01 (s, 4H) 2.86 (t, J = 7.22 Hz, 2H) 2.52 (2, 1H) 1.77 (sext, 2H) 1.01 (t, J = 7.39 Hz, 3H); 13C NMR (75 MHz, CDCl3-d, ppm) δ 169.14 160.16 150.53 148.39 134.20 132.39 128.58 127.56 127.28 126.83 125.27 118.79 51.46 51.09 49.37 46.00 44.78 42.10 27.90 21.55 13.87
Yield 54%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.66 (d, J = 1.27 Hz 2H) 7.63 (t, J = 1.50 Hz, 2H) 7.28 (d, J = 1.46 Hz, 1H) 7.27 (s , 1H) 7.20 (m, 2H) 6.88 (d, J = 6.58 Hz 1H) 4.00 (s, 2H) 3.81 (s, 2H) 3.60 (s, 4H) 3.01 (s, 4H) 2.86 (t, J = 7.22 Hz, 2H) 2.52 (2, 1H) 1.77 (sext, 2H) 1.01 (t, J = 7.39 Hz, 3H); 13 C NMR (75 MHz, CDCl 3 - d , ppm) δ 169.14 160.16 150.53 148.39 134.20 132.39 128.58 127.56 127.28 126.83 125.27 118.79 51.46 51.09 49.37 46.00 44.78 42.10 27.90 21.55 13.87
실시예 70. 1-(4-(3,4-다이클로로페닐)피페라진-1-일)-2-((4-페닐-5-프로필옥사졸-2-일)메틸아미노)에탄논 (화합물번호 70).Example 70. 1- (4- (3,4-Dichlorophenyl) piperazin-1-yl) -2-((4-phenyl-5-propyloxazol-2-yl) methylamino) ethanone ( Compound number 70).
수율 45%; 1H NMR (300 MHz, CDCl3-d, ppm) δ 7.65 (d, 2.86 J = 1.04 Hz 1H) 7.62 (s, 1H) 7.40 (t, J = 7.23 Hz, 2H) 7.30 (t, J = 4.70 Hz 2H) 6.93 (d, J = 2.55 Hz, 1H) 6.72 (dd, J = 2.64 Hz 8.86 Hz 1H) 3.98 (s, 2H) 3.76 (s, 2H) 3.59 (s, 2H) 3.56 (s, 2H) 3.14 (s, 4H) 2.85 (t, J = 7.34 Hz 2H) 2.30 (s, 1H) 1.77 (sext, 2H) 1.01 (t, J = 7.34 Hz 3H); 13C NMR (75 MHz, CDCl3-d, ppm) δ 169.14 160.16 150.22 148.34 134.39 132.97 132.37 130.58 128.54 127.28 126.79 123.20 117.86 115.83 49.38 48.95 45.96 44.18 41.48 27.89 21.51 13.81
Yield 45%; 1 H NMR (300 MHz, CDCl 3 - d , ppm) δ 7.65 (d, 2.86 J = 1.04 Hz 1H) 7.62 (s, 1H) 7.40 (t, J = 7.23 Hz, 2H) 7.30 (t, J = 4.70 Hz 2H) 6.93 (d, J = 2.55 Hz, 1H) 6.72 (dd, J = 2.64 Hz 8.86 Hz 1H) 3.98 (s, 2H) 3.76 (s, 2H) 3.59 (s, 2H) 3.56 (s, 2H) 3.14 (s, 4H) 2.85 (t, J = 7.34 Hz 2H) 2.30 (s, 1H) 1.77 (sext, 2H) 1.01 (t, J = 7.34 Hz 3H); 13 C NMR (75 MHz, CDCl 3 - d , ppm) δ 169.14 160.16 150.22 148.34 134.39 132.97 132.37 130.58 128.54 127.28 126.79 123.20 117.86 115.83 49.38 48.95 45.96 44.18 41.48 27.89 21.51 13.81
[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, Na2HPO412H2O 26 mg 및 증류수 2974 mg를 함유시켜 주사제를 제조하였다.
Injectables were prepared by containing 100 mg as 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 1. FDSS6000을 이용한 T-형 칼슘채널 활성검색 방법Experimental Example 1. 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 104 밀도로 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 CaCl2 HEPES 완충용액에 27 μL씩 준비하여 세포 플레이트의 최종 부피인 135 μL에서 1/5로 희석하여 측정하였다. 구체적인 FDSS6000 측정조건으로는 20초의 기준 수치 기록 후 75초간의 약물 전처리 후 KCl 투여에 의해 변화되는 세포내 칼슘농도 변화를 측정한 것으로 시험물질을 처리하지 않은 대조군에서의 340/380 비율값의 면적을 100%로 잡고 시험물질의 억제 효과에 대한 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. Measured by diluting to 1/5 in 135 μL, the final volume of the plate. 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.
(at 10 μM)FDSS% Inhibition Rate
(at 10 μM)
(at 10 μM)FDSS% Inhibition Rate
(at 10 μM)
실험예 2. T-타입 칼슘채널에 대한 억제활성 확인 실험Experimental Example 2. Experiment for confirming inhibitory activity on T-type calcium channel
본 발명에 따른 신규 화합물에 대한 T-타입 칼슘채널에 대한 억제활성을 확인하기 위하여, α1G형 T-타입 칼슘채널이 발현되어 있는 HEK 293 Cell을 이용하여 IC50 약효를 검색하였다. 하기 표 2에는 몇몇 화합물들의 T-타입 칼슘채널에 대한 억제 효과를 IC50(μM)으로 나타내었다.In order to confirm the inhibitory activity of the T-type calcium channel for the novel compound according to the present invention, the IC 50 drug was searched using HEK 293 Cell expressing α1G type T-type calcium channel. Table 2 below shows the inhibitory effect of several compounds on T-type calcium channel in IC 50 (μM).
(at 100 μM)% Inhibition rate
(at 100 μM)
본 발명의 화학식 1로 표시되는 신규 5각형의 헤테로방향족 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.
Since the novel pentagonal heteroaromatic compound represented by the general formula (1) of the present invention has an antagonistic action on T-type calcium channel, it is a brain disease such as epilepsy and hypertension, heart disease such as angina pectoris, chronic pain, neuropathic pain, etc. It can be usefully used as a prophylactic or therapeutic agent for diseases or cancer and related diseases.
Claims (9)
[화학식 1]
상기 화학식 1에서,
X, Y, 및 Z는 서로 같거나 다른 것으로서 질소원자(N)이거나, 또는 C-R2를 나타내고;
E는 -(CH2)qC(O)-, -(CH2)nN(R3)(CH2)mC(O)-, -(CH2)nN(R3)(CH2)m-, 또는 -(CH2)nN(R3)C(O)(CH2)m- 를 나타내고;
R1은 (C6-C15 아릴)2메틸기, C5-C15 헤테로아릴메틸기, C6-C15 아릴기, C6-C15 아릴카보닐기, 또는 C6-C15 아릴설포닐기를 나타내고, 이때 상기 아릴은 할로, C1-C6 알킬, 및 C1-C6 할로알킬 중에서 선택된 1 내지 3개의 치환기로 치환 또는 비치환될 수 있고;
R2는 수소원자, C1-C6 알킬기, 또는 C6-C15 아릴기를 나타내고;
R3은 수소원자, 또는 C1-C6 알킬기를 나타내고;
ℓ은 1 또는 2의 정수를 나타내고;
q는 1 내지 6의 정수를 나타내고;
n, 및 m은 서로 같거나 다른 것으로서 0 내지 6의 정수를 나타낸다.
A compound characterized in that the pentagonal heteroaromatic compound represented by the formula (1) or a pharmaceutically acceptable salt thereof:
[Formula 1]
In Chemical Formula 1,
X, Y, and Z, which are the same as or different from each other, are nitrogen atoms (N) or represent CR 2 ;
E is-(CH 2 ) q C (O)-,-(CH 2 ) n N (R 3 ) (CH 2 ) m C (O)-,-(CH 2 ) n N (R 3 ) (CH 2 ) m- , or-(CH 2 ) n N (R 3 ) C (O) (CH 2 ) m- ;
R 1 represents a (C 6 -C 15 aryl) 2 methyl group, a C 5 -C 15 heteroarylmethyl group, a C 6 -C 15 aryl group, a C 6 -C 15 arylcarbonyl group, or a C 6 -C 15 arylsulfonyl group Wherein said aryl may be unsubstituted or substituted with 1 to 3 substituents selected from halo, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl;
R 2 represents a hydrogen atom, a C 1 -C 6 alkyl group, or a C 6 -C 15 aryl group;
R 3 represents a hydrogen atom or a C 1 -C 6 alkyl group;
L represents an integer of 1 or 2;
q represents an integer from 1 to 6;
n and m are the same as or different from each other and represent an integer of 0 to 6;
상기 X, Y, 및 Z는 서로 같거나 다른 것으로서 질소원자(N)이거나, 또는 C-R2를 나타내고;
상기 E는 -(CH2)qC(O)-, -(CH2)nN(R3)(CH2)mC(O)-, -(CH2)nN(R3)(CH2)m-, 또는 -(CH2)nN(R3)C(O)(CH2)m- 를 나타내고;
상기 R1은 치환 또는 비치환된 벤즈하이드릴기, 벤조[d]싸이아졸-2-일메틸기, 치환 또는 비치환된 페닐기, 치환 또는 비치환된 벤조일기, 또는 치환 또는 비치환된 페닐설포닐기를 나타내고, 이때 치환된 벤즈하이드릴, 페닐, 벤조일, 또는 페닐설포닐기는 각각 할로, C1-C6 알킬, 및 트리플루오로메틸 중에서 선택된 1 내지 3개의 치환기로 치환된 페닐, 벤즈하이드릴, 벤조일, 또는 페닐설포닐기를 나타내고;
상기 R2는 수소원자, C1-C6 알킬기, 또는 페닐기를 나타내고;
상기 R3은 수소원자, 또는 C1-C6 알킬기를 나타내고;
상기 ℓ은 1 또는 2의 정수를 나타내고;
상기 q는 1 내지 6의 정수를 나타내고;
상기 n, 및 m은 서로 같거나 다른 것으로서 0 내지 6의 정수를 나타내는 것을 특징으로 하는 화합물.
The method according to claim 1,
X, Y, and Z are the same as or different from each other and are a nitrogen atom (N) or represent CR 2 ;
E is-(CH 2 ) q C (O)-,-(CH 2 ) n N (R 3 ) (CH 2 ) m C (O)-,-(CH 2 ) n N (R 3 ) (CH 2 ) m -or-(CH 2 ) n N (R 3 ) C (O) (CH 2 ) m- ;
R 1 is a substituted or unsubstituted benzhydryl group, a benzo [ d ] thiazol-2-ylmethyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted benzoyl group, or a substituted or unsubstituted phenylsulfonyl Wherein the substituted benzhydryl, phenyl, benzoyl, or phenylsulfonyl group is phenyl, benzhydryl, substituted with 1 to 3 substituents each selected from halo, C 1 -C 6 alkyl, and trifluoromethyl, Benzoyl or phenylsulfonyl group;
R 2 represents a hydrogen atom, a C 1 -C 6 alkyl group, or a phenyl group;
R 3 represents a hydrogen atom or a C 1 -C 6 alkyl group;
L represents an integer of 1 or 2;
Q represents an integer of 1 to 6;
N and m are the same as or different from each other and represent an integer of 0 to 6;
상기 X, Y, 및 Z는 서로 같거나 다른 것으로서 N, CH, C-메틸기, C-프로필기, C-아이소프로필기, C-아이소부틸기, 또는 C-페닐기를 나타내고;
상기 E는 -(CH2)2C(O)-, -(CH2)3C(O)-, -N(CH3)CH2C(O)-, -CH2NHCH2CH2-, 또는 -CH2NHC(O)CH2- 를 나타내고;
상기 R1은 벤즈하이드릴기, (할로페닐)2CH-, 페닐기, 할로페닐기, 다이할로페닐기, 메틸페닐기, 다이메틸페닐기, 트리플루오로메틸페닐기, 벤조일기, 할로벤조일기, 트리플루오로메틸벤조일기, 또는 벤조[d]싸이아졸-2-일메틸기를 나타내는 것을 특징으로 하는 화합물.
The method according to claim 1,
X, Y, and Z are the same as or different from each other and represent N, CH, C-methyl group, C-propyl group, C-isopropyl group, C-isobutyl group, or C-phenyl group;
E is-(CH 2 ) 2 C (O)-,-(CH 2 ) 3 C (O)-, -N (CH 3 ) CH 2 C (O)-, -CH 2 NHCH 2 CH 2- , Or -CH 2 NHC (O) CH 2- ;
R 1 is benzhydryl group, (halophenyl) 2 CH-, phenyl group, halophenyl group, dihalophenyl group, methylphenyl group, dimethylphenyl group, trifluoromethylphenyl group, benzoyl group, halobenzoyl group, trifluoro A methyl benzoyl group or a benzo [ d ] thiazol-2-ylmethyl group.
3-(3-페닐아이소옥사졸-5-일)-1-(4-페닐피페라진-1-일)프로판-1-온 (화합물번호 1);
3-(3-페닐-1,2,4-옥사다이아졸-5-일)-1-(4-페닐피페라진-1-일)프로판-1-온 (화합물번호 2);
4-(3-페닐아이소옥사졸-5-일)-1-(4-페닐피페라진-1일)부탄-1-온 (화합물번호 3);
4-(3-페닐-1,2,4-옥사다이아졸-5-일)-1-(4-페닐피페라진-1-일)부탄-1-온 (화합물번호 4);
1-(4-(3-클로로페닐)피페라진-1-일)-4-(3-페닐-1,2,4-옥사다이아졸-5-일)부탄-1-온 (화합물번호 5);
1-(4-(3-클로로페닐)피페라진-1일)-4-(3-페닐아이소옥사졸-5-일)부탄-1-온 (화합물번호 6);
1-(4-(3-클로로페닐)피페라진-1-일)-3-(3-페닐아이소옥사졸-5-일)프로판-1-온 (화합물번호 7);
1-(4-(4-클로로페닐)피페라진-1-일)-4-(3-페닐-1,2,4-옥사다이아졸-5-일)부탄-1-온 (화합물번호 8);
1-(4-(4-클로로페닐)피페라진-1-일)-3-(3-페닐-1,2,4-옥사다이아졸-5-일)프로판-1-온 (화합물번호 9);
1-(4-(4-클로로페닐)피페라진-1-일)-4-(3-페닐아이소옥사졸-5-일)부탄-1-온 (화합물번호 10);
1-(4-(4-클로로페닐)피페라진-1-일)-3-(3-페닐아이소옥사졸-5-일)프로판-1-온 (화합물번호 11);
1-(4-(2-클로로페닐)피페라진-1-일)-4-(3-페닐-1,2,4-옥사다이아졸-5-일)부탄-1-온 (화합물번호 12);
1-(4-(4-클로로페닐)피페라진-1-일)-3-(3-페닐-1,2,4-옥사다이아졸-5-일)프로판-1-온 (화합물번호 13);
1-(4-(2-클로로페닐)피페라진-1-일)-4-(3-페닐아이소옥사졸-5-일)부탄-1-온 (화합물번호 14);
1-(4-벤즈하이드릴피페라진-1-일)-4-(3-페닐-1,2,4-옥사다이아졸-5-일)부탄-1-온 (화합물번호 15);
1-(4-벤즈하이드릴피페라진-1-일)-4-(3-페닐아이소옥사졸-5-일)부탄-1-온 (화합물번호 16);
1-(4-벤즈하이드릴피페라진-1-일)-3-(3-페닐-1,2,4-옥사다이아졸-5-일)프로판-1-온 (화합물번호 17);
1-(4-(2-클로로페닐)피페라진-1-일)-3-(3-페닐아이소옥사졸-5-일)프로판-1-온 (화합물번호 18);
1-(4-벤즈하이드릴피페라진-1-일)-3-(3-페닐아이소옥사졸-5-일)프로판-1-온 (화합물번호 19);
2-((4-페닐-2-프로필옥사졸-5-일)메틸아미노)-1-(4-페닐피페라진-1-일)에탄논 (화합물번호 20);
1-(4-벤즈하이드릴피페라진-1-일)-2-((4-페닐-2-프로필옥사졸-5-일)메틸아미노)에탄논(화합물번호 21);
1-(4-(비스(4-플루오로페닐)메틸)피페라진-1-일)-2-((4-페닐-2-프로필옥사졸-5-일)메틸아미노)에탄논 (화합물번호 22);
2-((4-페닐-5-프로필옥사졸-2-일)메틸아미노)-1-(4-페닐피페라진-1-일)에탄논 (화합물번호 23);
2-((5-메틸-4-페닐옥사졸-2-일)메틸아미노)-1-(4-페닐피페라진-1-일)에탄논 (화합물번호 24);
1-(4-벤즈하이드릴피페라진-1-일)-2-((4-페닐-5-프로필옥사졸-2-일)메틸아미노)에탄논 (화합물번호 25);
1-(4-비스(4-플루오로페닐)메틸)피페라진-1-일)-2-((4-페닐-5-프로필옥사졸-2-일)메틸아미노)에탄논 (화합물번호 26);
2-((2-메틸-4-페닐옥사졸-5-일)메틸아미노)-1-(4-페닐피페라진-1-일)에탄논 (화합물번호 27);
1-(4-벤즈하이드릴피페라진-1-일)-2-((2-메틸-4-페닐옥사졸-5-일)메틸아미노)에탄논 (화합물번호 28);
1-(4-비스(4-플루오로페닐)메틸)피페라진-1-일)-2-((2-메틸-4-페닐옥사졸-5-일)메틸아미노)에탄논 (화합물번호 29);
2-((4-페닐-2-프로필옥사졸-5-일)메틸아미노)-1-(4-(3-(트리플루오로메틸)페닐)피페라진-1-일)에탄논 (화합물번호 30);
1-(4-(2,4-다이메틸페닐)피페라진-1-일)-2-((4-페닐-5-프로필옥사졸-2-일)메틸아미노)에탄논 (화합물번호 31);
1-(4-(2,3-다이메틸페닐)피페라진-1-일)-2-((4-페닐-5-프로필옥사졸-2-일)메틸아미노)에탄논 (화합물번호 32);
1-(4-(3,4-다이메틸페닐)피페라진-1-일)-2-((4-페닐-5-프로필옥사졸-2-일)메틸아미노)에탄논 (화합물번호 33);
1-(4-(2,4-다이메틸페닐)피페라진-1-일)-2-((5-메틸-4-페닐옥사졸-2-일)메틸아미노)에탄논 (화합물번호 34);
2-((2-메틸-4-페닐옥사졸-5-일)메틸아미노)-1-(4-3-(트리플루오로메틸)페닐)피페라진-1-일)에탄논 (화합물번호 35);
1-(4-(2,4-다이메틸페닐)피페라진-1-일)-2-((2-메틸-4-페닐옥사졸-5-일)메틸아미노)에탄논 (화합물번호 36);
1-(4-(2,3-다이메틸페닐)피페라진-1-일)-2-((2-메틸-4-페닐옥사졸-5-일)메틸아미노)에탄논 (화합물번호 37);
1-(4-벤즈하이드릴피페라진-1-일)-2-((5-메틸-4-페닐옥사졸-2-일)메틸아미노)에탄논 (화합물번호 38);
1-(4-(2,4-다이메틸페닐)피페라진-1-일)-2-((4-페닐-2-프로필옥사졸-5-일)메틸아미노)에탄논 (화합물번호 39);
1-(4-(2,3-다이메틸페닐)피페라진-1-일)-2-((4-페닐-2-프로필옥사졸-5-일)메틸아미노)에탄논 (화합물번호 40);
1-(4-(3,4-다이메틸페닐)피페라진-1-일)-2-((4-페닐-2-프로필옥사졸-5-일)메틸아미노)에탄논 (화합물번호 41);
2-((4-페닐-2-프로필옥사졸-5-일)메틸아미노)-1-(4-(3-(트리플루오로메틸)페닐)피페라진-1-일)에탄논 (화합물번호 42);
1-(4-(3,4-다이에틸페닐)피페라진-1-일)-2-((5-메틸-4-페닐옥사졸-2-일)메틸아미노)에탄논 (화합물번호 43);
1-(4-(2,3-다이메틸페닐)피페라진-1-일)-2-((5-메틸-4-페닐옥사졸-2-일)메틸아미노)에탄논 (화합물번호 44);
1-(4-(3-클로로페닐)피페라진-1-일)-4-(3-페닐-1,2,4-옥사다이아졸-5-일)부탄-1-온 (화합물번호 45);
2-(4-(2,4-다이메틸페닐)피페라진-1-일)-N-((3-아이소프로필아이소옥사졸-5-일)메틸)에탄아민 (화합물번호 46);
2-(4-(2,3-다이메틸페닐)피페라진-1-일)-N-((3-아이소프로필아이소옥사졸-5-일)메틸)에탄아민 (화합물번호 47);
N-((3-아이소프로필아이소옥사졸-5-일)메틸)-2-(4-(3-(트리플루오로메틸)페닐)피페라진-1-일)에탄아민 (화합물번호 48);
1-(4-(3,4-다이메틸페닐)피페라진-1-일)-2-((2-메틸-4-페닐옥사졸-5-일)메틸아미노)에탄논 (화합물번호 49);
2-((2-메틸-4-페닐옥사졸-5-일)메틸아미노)-1-(4-(3-(트리플루오로메틸)페닐)피페라진-1-일)에탄논 (화합물번호 50);
2-(4-(2,3-다이메틸페닐)피페라진-1-일)-N-((3-메틸아이소옥사졸-5-일)메틸)에탄아민 (화합물번호 51);
2-(4-(3,4-다이메틸페닐)피페라진-1-일)-N-((3-메틸아이소옥사졸-5-일)메틸)에탄아민 (화합물번호 52);
N-((3-메틸아이소옥사졸-5-일)메틸)-2-(4-(3-(트리플루오로메틸)페닐)피페라진-1-일)에탄아민 (화합물번호 53);
N-((5-아이소부틸-4-페닐옥사졸-2-일)메틸)-2-(4-페닐피페라진-1-일)아세타마이드 (화합물번호 54);
2-(4-벤즈하이드릴피페라진-1-일)-N-((5-아이소부틸-4-페닐옥사졸-2-일)메틸)아세타마이드 (화합물번호 55);
2-(4-(비스(4-플루오로페닐)메틸)피페라진-1-일)-N-((5-아이소부틸-4-페닐옥사졸-2-일)메틸)아세타마이드 (화합물번호 56);
2-(4-(비스(4-클로로페닐)메틸)피페라진-1-일)-N-((5-아이소부틸-4-페닐옥사졸-2-일)메틸)아세타마이드 (화합물번호 57);
N-((5-아이소부틸-4-페닐옥사졸-2-일)메틸)-2-(4-(3-(트리플루오로메틸)페닐)피페라진-1-일)아세타마이드 (화합물번호 58);
2-(4-(2,3-다이메틸페닐)피페라진-1-일)-N-((5-아이소부틸-4-페닐옥사졸-2-일)메틸)아세타마이드 (화합물번호 59);
2-(4-(3,4-다이메틸페닐)피페라진-1-일)-N-((5-아이소부틸-4-페닐옥사졸-2-일)메틸)아세타마이드 (화합물번호 60);
2-(4-2,4-다이메틸페닐)피페라진-1-일)-N-((5-아이소부틸-4-페닐옥사졸-2-일)메틸)아세타마이드 (화합물번호 61);
N-((5-아이소부틸-4-페닐옥사졸-2-일)메틸)-2-((4-페닐설포닐)-1,4-다이아제판-1-일)아세타마이드 (화합물번호 62);
2-(4-(4-플루오로페닐설포닐)-1,4-다이아제판-1-일)-N-((5-아이소부틸-4-페닐옥사졸-2-일)메틸)아세타마이드 (화합물번호 63);
2-(4-(벤조[d]싸이아졸-2-일메틸)피페라진-1-일)-N-((5-아이소부틸-4-페닐옥사졸-2-일)메틸)아세타마이드 (화합물번호 64);
N-((5-아이소부틸-4-페닐옥사졸-2-일)메틸)-2-(4-(3-(트리플루오로메틸)벤조일-1,4-다이아제판-1-일)아세타마이드 (화합물번호 65);
2-(4-(4-플루오로벤조일)-1,4-다이아제판-1-일)-N-((5-아이소부틸-4-페닐옥사졸-2-일)메틸)아세타마이드 (화합물번호 66);
N-((5-아이소부틸-4-페닐옥사졸-2-일)메틸)-2-(4-(3-(트리플루오로메틸)벤조일)피페라진-1-일)아세타마이드 (화합물번호 67);
1-(4-(4--클로로페닐)피페라진-1-일)-2-((4-페닐-5-프로필옥사졸-2-일)메틸아미노)에탄논 (화합물번호 68);
1-(4-(2,3-다이클로로페닐)피페라진-1-일)-2-((4-페닐-5-프로필옥사졸-2-일)메틸아미노)에탄논 (화합물번호 69);
1-(4-(3,4-다이클로로페닐)피페라진-1-일)-2-((4-페닐-5-프로필옥사졸-2-일)메틸아미노)에탄논 (화합물번호 70) ; 및
약학적으로 허용 가능한 이들의 염으로부터 선택된 것임을 특징으로 하는 화합물.
The method according to claim 1,
3- (3-phenylisoxazol-5-yl) -1- (4-phenylpiperazin-1-yl) propan-1-one (Compound No. 1);
3- (3-phenyl-1,2,4-oxadiazol-5-yl) -1- (4-phenylpiperazin-1-yl) propan-1-one (Compound No. 2);
4- (3-phenylisoxazol-5-yl) -1- (4-phenylpiperazin-1yl) butan-1-one (Compound No. 3);
4- (3-phenyl-1,2,4-oxadiazol-5-yl) -1- (4-phenylpiperazin-1-yl) butan-1-one (Compound No. 4);
1- (4- (3-chlorophenyl) piperazin-1-yl) -4- (3-phenyl-1,2,4-oxadiazol-5-yl) butan-1-one (Compound No. 5) ;
1- (4- (3-chlorophenyl) piperazin-1yl) -4- (3-phenylisoxazol-5-yl) butan-1-one (Compound No. 6);
1- (4- (3-chlorophenyl) piperazin-1-yl) -3- (3-phenylisoxazol-5-yl) propan-1-one (Compound No. 7);
1- (4- (4-chlorophenyl) piperazin-1-yl) -4- (3-phenyl-1,2,4-oxadiazol-5-yl) butan-1-one (Compound No. 8) ;
1- (4- (4-chlorophenyl) piperazin-1-yl) -3- (3-phenyl-1,2,4-oxadiazol-5-yl) propan-1-one (Compound No. 9) ;
1- (4- (4-chlorophenyl) piperazin-1-yl) -4- (3-phenylisoxazol-5-yl) butan-1-one (Compound No. 10);
1- (4- (4-chlorophenyl) piperazin-1-yl) -3- (3-phenylisoxazol-5-yl) propan-1-one (Compound No. 11);
1- (4- (2-chlorophenyl) piperazin-1-yl) -4- (3-phenyl-1,2,4-oxadiazol-5-yl) butan-1-one (Compound No. 12) ;
1- (4- (4-chlorophenyl) piperazin-1-yl) -3- (3-phenyl-1,2,4-oxadiazol-5-yl) propan-1-one (Compound No. 13) ;
1- (4- (2-chlorophenyl) piperazin-1-yl) -4- (3-phenylisoxazol-5-yl) butan-1-one (Compound No. 14);
1- (4-benzhydrylpiperazin-1-yl) -4- (3-phenyl-1,2,4-oxadiazol-5-yl) butan-1-one (Compound No. 15);
1- (4-benzhydrylpiperazin-1-yl) -4- (3-phenylisoxazol-5-yl) butan-1-one (Compound No. 16);
1- (4-benzhydrylpiperazin-1-yl) -3- (3-phenyl-1,2,4-oxadiazol-5-yl) propan-1-one (Compound No. 17);
1- (4- (2-chlorophenyl) piperazin-1-yl) -3- (3-phenylisoxazol-5-yl) propan-1-one (Compound No. 18);
1- (4-benzhydrylpiperazin-1-yl) -3- (3-phenylisoxazol-5-yl) propan-1-one (Compound No. 19);
2-((4-phenyl-2-propyloxazol-5-yl) methylamino) -1- (4-phenylpiperazin-1-yl) ethanone (Compound No. 20);
1- (4-benzhydrylpiperazin-1-yl) -2-((4-phenyl-2-propyloxazol-5-yl) methylamino) ethanone (Compound No. 21);
1- (4- (bis (4-fluorophenyl) methyl) piperazin-1-yl) -2-((4-phenyl-2-propyloxazol-5-yl) methylamino) ethanone (Compound No. 22);
2-((4-phenyl-5-propyloxazol-2-yl) methylamino) -1- (4-phenylpiperazin-1-yl) ethanone (Compound No. 23);
2-((5-methyl-4-phenyloxazol-2-yl) methylamino) -1- (4-phenylpiperazin-1-yl) ethanone (Compound No. 24);
1- (4-benzhydrylpiperazin-1-yl) -2-((4-phenyl-5-propyloxazol-2-yl) methylamino) ethanone (Compound No. 25);
1- (4-bis (4-fluorophenyl) methyl) piperazin-1-yl) -2-((4-phenyl-5-propyloxazol-2-yl) methylamino) ethanone (Compound No. 26 );
2-((2-methyl-4-phenyloxazol-5-yl) methylamino) -1- (4-phenylpiperazin-1-yl) ethanone (Compound No. 27);
1- (4-benzhydrylpiperazin-1-yl) -2-((2-methyl-4-phenyloxazol-5-yl) methylamino) ethanone (Compound No. 28);
1- (4-bis (4-fluorophenyl) methyl) piperazin-1-yl) -2-((2-methyl-4-phenyloxazol-5-yl) methylamino) ethanone (Compound No. 29 );
2-((4-phenyl-2-propyloxazol-5-yl) methylamino) -1- (4- (3- (trifluoromethyl) phenyl) piperazin-1-yl) ethanone (Compound No. 30);
1- (4- (2,4-dimethylphenyl) piperazin-1-yl) -2-((4-phenyl-5-propyloxazol-2-yl) methylamino) ethanone (Compound No. 31);
1- (4- (2,3-dimethylphenyl) piperazin-1-yl) -2-((4-phenyl-5-propyloxazol-2-yl) methylamino) ethanone (Compound No. 32);
1- (4- (3,4-dimethylphenyl) piperazin-1-yl) -2-((4-phenyl-5-propyloxazol-2-yl) methylamino) ethanone (Compound No. 33);
1- (4- (2,4-dimethylphenyl) piperazin-1-yl) -2-((5-methyl-4-phenyloxazol-2-yl) methylamino) ethanone (Compound No. 34);
2-((2-methyl-4-phenyloxazol-5-yl) methylamino) -1- (4-3- (trifluoromethyl) phenyl) piperazin-1-yl) ethanone (Compound No. 35 );
1- (4- (2,4-dimethylphenyl) piperazin-1-yl) -2-((2-methyl-4-phenyloxazol-5-yl) methylamino) ethanone (Compound No. 36);
1- (4- (2,3-dimethylphenyl) piperazin-1-yl) -2-((2-methyl-4-phenyloxazol-5-yl) methylamino) ethanone (Compound No. 37);
1- (4-benzhydrylpiperazin-1-yl) -2-((5-methyl-4-phenyloxazol-2-yl) methylamino) ethanone (Compound No. 38);
1- (4- (2,4-dimethylphenyl) piperazin-1-yl) -2-((4-phenyl-2-propyloxazol-5-yl) methylamino) ethanone (Compound No. 39);
1- (4- (2,3-dimethylphenyl) piperazin-1-yl) -2-((4-phenyl-2-propyloxazol-5-yl) methylamino) ethanone (Compound No. 40);
1- (4- (3,4-dimethylphenyl) piperazin-1-yl) -2-((4-phenyl-2-propyloxazol-5-yl) methylamino) ethanone (Compound No. 41);
2-((4-phenyl-2-propyloxazol-5-yl) methylamino) -1- (4- (3- (trifluoromethyl) phenyl) piperazin-1-yl) ethanone (Compound No. 42);
1- (4- (3,4-diethylphenyl) piperazin-1-yl) -2-((5-methyl-4-phenyloxazol-2-yl) methylamino) ethanone (Compound No. 43) ;
1- (4- (2,3-dimethylphenyl) piperazin-1-yl) -2-((5-methyl-4-phenyloxazol-2-yl) methylamino) ethanone (Compound No. 44);
1- (4- (3-chlorophenyl) piperazin-1-yl) -4- (3-phenyl-1,2,4-oxadiazol-5-yl) butan-1-one (Compound No. 45) ;
2- (4- (2,4-dimethylphenyl) piperazin-1-yl) -N -((3-isopropylisoxazol-5-yl) methyl) ethanamine (Compound No. 46);
2- (4- (2,3-dimethylphenyl) piperazin-1-yl) -N -((3-isopropylisoxazol-5-yl) methyl) ethanamine (Compound No. 47);
N -((3-isopropylisoxazol-5-yl) methyl) -2- (4- (3- (trifluoromethyl) phenyl) piperazin-1-yl) ethanamine (Compound No. 48);
1- (4- (3,4-dimethylphenyl) piperazin-1-yl) -2-((2-methyl-4-phenyloxazol-5-yl) methylamino) ethanone (Compound No. 49);
2-((2-methyl-4-phenyloxazol-5-yl) methylamino) -1- (4- (3- (trifluoromethyl) phenyl) piperazin-1-yl) ethanone (Compound No. 50);
2- (4- (2,3-dimethylphenyl) piperazin-1-yl) -N -((3-methylisoxazol-5-yl) methyl) ethanamine (Compound No. 51);
2- (4- (3,4-dimethylphenyl) piperazin-1-yl) -N -((3-methylisoxazol-5-yl) methyl) ethanamine (Compound No. 52);
N -((3-methylisoxazol-5-yl) methyl) -2- (4- (3- (trifluoromethyl) phenyl) piperazin-1-yl) ethanamine (Compound No. 53);
N -((5-isobutyl-4-phenyloxazol-2-yl) methyl) -2- (4-phenylpiperazin-1-yl) acetamide (Compound No. 54);
2- (4-benzhydrylpiperazin-1-yl) -N -((5-isobutyl-4-phenyloxazol-2-yl) methyl) acetamide (Compound No. 55);
2- (4- (bis (4-fluorophenyl) methyl) piperazin-1-yl) -N -((5-isobutyl-4-phenyloxazol-2-yl) methyl) acetamide (compound Number 56);
2- (4- (bis (4-chlorophenyl) methyl) piperazin-1-yl) -N -((5-isobutyl-4-phenyloxazol-2-yl) methyl) acetamide (Compound No. 57);
N -((5-isobutyl-4-phenyloxazol-2-yl) methyl) -2- (4- (3- (trifluoromethyl) phenyl) piperazin-1-yl) acetamide (compound Number 58);
2- (4- (2,3-dimethylphenyl) piperazin-1-yl) -N -((5-isobutyl-4-phenyloxazol-2-yl) methyl) acetamide (Compound No. 59) ;
2- (4- (3,4-dimethylphenyl) piperazin-1-yl) -N -((5-isobutyl-4-phenyloxazol-2-yl) methyl) acetamide (Compound No. 60) ;
2- (4-2,4-dimethylphenyl) piperazin-1-yl) -N -((5-isobutyl-4-phenyloxazol-2-yl) methyl) acetamide (Compound No. 61);
N -((5-isobutyl-4-phenyloxazol-2-yl) methyl) -2-((4-phenylsulfonyl) -1,4-diazepan-1-yl) acetamide (Compound No. 62);
2- (4- (4-fluorophenylsulfonyl) -1,4-diazepan-1-yl) -N -((5-isobutyl-4-phenyloxazol-2-yl) methyl) acetama Id (Compound No. 63);
2- (4- (benzo [ d ] thiazol-2-ylmethyl) piperazin-1-yl) -N -((5-isobutyl-4-phenyloxazol-2-yl) methyl) acetamide (Compound No. 64);
N -((5-isobutyl-4-phenyloxazol-2-yl) methyl) -2- (4- (3- (trifluoromethyl) benzoyl-1,4-diazepan-1-yl) acet Tamid (Compound No. 65);
2- (4- (4-fluorobenzoyl) -1,4-diazepan-1-yl) -N -((5-isobutyl-4-phenyloxazol-2-yl) methyl) acetamide ( Compound no. 66);
N-((5-isobutyl-4-phenyloxazol-2-yl) methyl) -2- (4- (3- (trifluoromethyl) benzoyl) piperazin-1-yl) acetamide (compound Number 67);
1- (4- (4--chlorophenyl) piperazin-1-yl) -2-((4-phenyl-5-propyloxazol-2-yl) methylamino) ethanone (Compound No. 68);
1- (4- (2,3-dichlorophenyl) piperazin-1-yl) -2-((4-phenyl-5-propyloxazol-2-yl) methylamino) ethanone (Compound No. 69) ;
1- (4- (3,4-Dichlorophenyl) piperazin-1-yl) -2-((4-phenyl-5-propyloxazol-2-yl) methylamino) ethanone (Compound No. 70) ; And
Compound selected from pharmaceutically acceptable salts thereof.
The pharmaceutical composition for the treatment and prevention of diseases selected from epilepsy, hypertension, angina pectoris, chronic pain, neurological pain, and cancer, wherein the compound of any one selected from claims 1 to 4 is included as an active ingredient.
상기 반응식에서, X, Y, Z, R1, ℓ, 및 n은 각각 상기 청구항 1에서 정의한 바와 같다.
A carbochloride compound represented by the following Formula 3a and a heterocyclic amine compound represented by the following Formula 2a are combined and reacted in the presence of an alkylamine base to prepare a heteroaromatic compound having an alkanone linking group (E) represented by the following Formula 1a. Method for producing a heteroaromatic compound, characterized in that it comprises a process for:
In the above scheme, X, Y, Z, R 1 , 1, and n are as defined in claim 1, respectively.
상기 반응식에서, X, Y, Z, R1, ℓ, m, 및 n은 각각 상기 청구항 1에서 정의한 바와 같다.
The aldehyde compound represented by the following Chemical Formula 3b and the amine compound represented by the following Chemical Formula 2b are combined and reacted in the presence of acetic acid, molecular sieve, and sodium triacetoxyborohydride (NaBH (OAc) 3 ), and represented by the following Chemical Formula 1b. Method for producing a heteroaromatic compound comprising the step of preparing a heteroaromatic compound having an aminoalkanone linking group (E) to be:
In the scheme, X, Y, Z, R 1 , 1, m, and n are as defined in claim 1, respectively.
상기 반응식에서, X, Y, Z, R1, ℓ, m, 및 n은 각각 상기 청구항 1에서 정의한 바와 같다.
The aldehyde compound represented by the following Chemical Formula 3b and the amine compound represented by the following Chemical Formula 2c are combined and reacted in the presence of acetic acid, molecular sieve, and sodium triacetoxyborohydride (NaBH (OAc) 3 ), and represented by the following Chemical Formula 1c. Method for producing a heteroaromatic compound, characterized in that it comprises the step of preparing a heteroaromatic compound having an amine bond group (E):
In the scheme, X, Y, Z, R 1 , 1, m, and n are as defined in claim 1, respectively.
하기 화학식 17d로 표시되는 화합물과 R1 치환기 함유 알데하이드 화합물 또는 클로라이드 화합물과 반응시켜, 하기 화학식 1d로 표시되는 아마이드 결합그룹(E)을 갖는 헤테로방향족 화합물을 제조하는 과정;
을 포함하는 것을 특징으로 하는 헤테로방향족 화합물의 제조방법 :
상기 반응식에서, X, Y, Z, R1, ℓ, m, 및 n은 각각 상기 청구항 1에서 정의한 바와 같다.Preparing a compound represented by the following Chemical Formula 17d by combining the chloride compound represented by the following Chemical Formula 3d with the heterocyclic amine compound represented by the following Chemical Formula 2d in the presence of an alkylamine base; And
Reacting a compound represented by the following Formula 17d with an R 1 substituent-containing aldehyde compound or a chloride compound to prepare a heteroaromatic compound having an amide linking group (E) represented by the following Formula 1d;
Method for producing a heteroaromatic compound, comprising:
In the scheme, X, Y, Z, R 1 , 1, m, and n are as defined in claim 1, respectively.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104177348A (en) * | 2013-05-21 | 2014-12-03 | 苏州科捷生物医药有限公司 | Antineoplastic compound N-(2-(4-chlorophenyl)-5-oxazolyl)-2-(1,3-dioxo-2-isoindolinyl)acetamide synthesis method |
| CN108164476A (en) * | 2016-12-08 | 2018-06-15 | 沈阳化工研究院有限公司 | M-dicyanobenzene class compound, its application and the drug comprising the compound |
-
2011
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104177348A (en) * | 2013-05-21 | 2014-12-03 | 苏州科捷生物医药有限公司 | Antineoplastic compound N-(2-(4-chlorophenyl)-5-oxazolyl)-2-(1,3-dioxo-2-isoindolinyl)acetamide synthesis method |
| CN108164476A (en) * | 2016-12-08 | 2018-06-15 | 沈阳化工研究院有限公司 | M-dicyanobenzene class compound, its application and the drug comprising the compound |
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