KR100967589B1 - 1-3-alkoxyquinoxaline-2-yl-3-[1-arylmethylpiperidin-4-yl] urea derivatives and pharmaceutically acceptable salt thereof, process for preparation and use thereof - Google Patents

1-3-alkoxyquinoxaline-2-yl-3-[1-arylmethylpiperidin-4-yl] urea derivatives and pharmaceutically acceptable salt thereof, process for preparation and use thereof Download PDF

Info

Publication number
KR100967589B1
KR100967589B1 KR1020080016256A KR20080016256A KR100967589B1 KR 100967589 B1 KR100967589 B1 KR 100967589B1 KR 1020080016256 A KR1020080016256 A KR 1020080016256A KR 20080016256 A KR20080016256 A KR 20080016256A KR 100967589 B1 KR100967589 B1 KR 100967589B1
Authority
KR
South Korea
Prior art keywords
mmol
urea
piperidin
alkoxyquinoxalin
reaction
Prior art date
Application number
KR1020080016256A
Other languages
Korean (ko)
Other versions
KR20090090791A (en
Inventor
공영대
전문국
이태호
황순희
이병호
오광석
유성은
Original Assignee
한국화학연구원
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 한국화학연구원 filed Critical 한국화학연구원
Priority to KR1020080016256A priority Critical patent/KR100967589B1/en
Publication of KR20090090791A publication Critical patent/KR20090090791A/en
Application granted granted Critical
Publication of KR100967589B1 publication Critical patent/KR100967589B1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • 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
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

본 발명은 우수한 멜라닌-집중형 호르몬 수용체(melanin-concentrating hormone 1 receptor, 이하 "MCH1R"이라 한다) 억제 활성을 가지는 하기 화학식 1로 표시되는 1-(3-알콕시퀴녹살린-2-일)-3-[1-(아릴메틸)피페리딘-4-일] 우레아 유도체 및 약제학적으로 허용 가능한 그의 염, 그 제조방법 및 그를 유효성분으로 함유하는 비만치료제에 관한 것이다. The present invention provides 1- (3-alkoxyquinoxalin-2-yl) -3 represented by the following Chemical Formula 1 having excellent melanin-concentrating hormone 1 receptor (hereinafter referred to as "MCH1R") inhibitory activity. -[1- (arylmethyl) piperidin-4-yl] urea derivatives, pharmaceutically acceptable salts thereof, preparation methods thereof, and anti-obesity agents containing the same as active ingredients.

Figure 112008013294843-pat00001
Figure 112008013294843-pat00001

(상기에서, R1, R2, R3, R4, R5, R6, R7, R8, R9 및 R10은 명세서에서 정의한 바와 같다)(In the above, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are as defined in the specification)

퀴녹살린, 피페리딘, 우레아, MCH1R, 비만치료제 Quinoxaline, Piperidine, Urea, MCH1R, Anti-obesity

Description

1-(3-알콕시퀴녹살린-2-일)-3-[1-(아릴메틸)피페리딘-4-일] 우레아 유도체 및 약제학적으로 허용 가능한 그의 염, 그 제조방법 및 그의 용도{1-(3-ALKOXYQUINOXALINE-2-YL)-3-[1-(ARYLMETHYL)PIPERIDIN-4-YL] UREA DERIVATIVES AND PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, PROCESS FOR PREPARATION AND USE THEREOF}1- (3-alkoxyquinoxalin-2-yl) -3- [1- (arylmethyl) piperidin-4-yl] urea derivatives and pharmaceutically acceptable salts thereof, preparation methods thereof and uses thereof {1 -(3-ALKOXYQUINOXALINE-2-YL) -3- [1- (ARYLMETHYL) PIPERIDIN-4-YL] UREA DERIVATIVES AND PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, PROCESS FOR PREPARATION AND USE THEREOF}

본 발명은 MCH1R 억제 활성을 가지는 1-(3-알콕시퀴녹살린-2-일)-3-[1-(아릴메틸)피페리딘-4-일] 우레아 유도체 및 약제학적으로 허용 가능한 그의 염, 그 제조방법 및 그를 유효성분으로 함유하는 비만치료제에 관한 것이다. The present invention provides a 1- (3-alkoxyquinoxalin-2-yl) -3- [1- (arylmethyl) piperidin-4-yl] urea derivative having MCH1R inhibitory activity and a pharmaceutically acceptable salt thereof, The manufacturing method and the obesity treatment containing it as an active ingredient.

비만은 지방조직이 체내에 과다하게 축적되어 있는 상태를 의미하며, 당뇨병, 심장병, 고혈압, 뇌졸중 등 합병증을 일으키는 원인으로 지목되면서, 비만치료제에 대한 관심과 연구가 집중되고 있다. Obesity refers to a condition in which adipose tissue is excessively accumulated in the body, and as a cause of complications such as diabetes, heart disease, high blood pressure, and stroke, attention and research on obesity treatments have been focused.

비만을 치료하기 위한 대표적인 방법으로는 식이요법, 운동요법, 행동교정 및 수술 등과 같은 비약물요법이 있고, 상기 비약물요법을 제외한 약물치료법으로 크게 분류된다.Representative methods for treating obesity include non-drug therapies such as diet, exercise therapy, behavioral correction and surgery, and are classified into drug treatments except for the non-drug therapy.

또한, 약물치료법으로 접근할 수 있는 비만 치료방법은 약물의 작용기전에 따라, 식욕억제제, 음식물 흡수억제제, 에너지대사촉진제 등으로 구분하는 비만치료제가 등장하고 있다.In addition, the obesity treatment method that can be approached by drug treatment has emerged as an obesity treatment agent divided into appetite suppressant, food absorption inhibitor, energy metabolic accelerator and the like depending on the mechanism of action of the drug.

미국식품의약국(FDA)이 판매를 인가한 대표적인 비만치료제로서, 국내에서도 비만치료제 전문의약품으로 인정받고 있는 약물로는, 시부트라민(sibutramine)과 올리스태트(orlistat)가 있다. As a representative obesity treatment drug approved by the US Food and Drug Administration (FDA), drugs that are recognized in Korea as specialty medicines for obesity treatment include sibutramine (sibutramine) and orlistat.

시부트라민은 세로토닌의 재흡수를 억제하여 소량의 식사만으로도 포만감을 증가시키는 식욕억제 작용을 나타내며, 올리스태트는 지방을 분해하는 췌장의 리파아제(pancreatic lipase) 효소작용을 억제하여 지방흡수를 방해한다.Sibutramine inhibits the reuptake of serotonin, and the appetite suppression effect increases satiety even with a small amount of meal.Olistat inhibits the absorption of pancreatic lipase enzymes that break down fat, thereby preventing fat absorption.

그러나, 현재까지 알려진 비만에 대한 약물치료는 식이요법, 운동요법, 행동교정, 및 수술 등과 같은 비약물요법의 보조적인 수단으로 사용되고 있을 뿐, 근본적인 치료를 제시하지는 못하고 있다. However, currently known drug treatment for obesity is being used as an auxiliary means of non-drug therapy, such as diet, exercise therapy, behavioral correction, and surgery, and does not suggest a fundamental treatment.

대부분의 비만치료제로서 사용되는 약물들이 초기에는 두드러진 효과를 나타내지만 시간이 지나면서 차츰 감소하고 6 내지 8개월 후에는 효과가 아예 없어지는 문제점이 있으며, 일단 약물 투여를 중단하게 되면, 체중 증가 현상이 재현된다. Most drugs used to treat obesity have a noticeable effect in the beginning, but gradually decrease over time and disappear after 6 to 8 months. Is reproduced.

또한, 과거 사용된 비만치료 약물의 가장 큰 문제점은 체중감량 및 체중유지에 어느 정도 효과가 있기는 했으나, 복용 중에 나타난 부작용으로 인해 시판이 중단된 경우가 대부분이다. 이러한 부작용에 대한 문제는 현재 비만치료제로 인정받고 있는 시부트라민과 올리스태트의 경우에도 여전하다.In addition, the biggest problem of obesity treatment drugs used in the past, although there was some effect on weight loss and weight maintenance, most of the market was stopped due to side effects during taking. Problems with these side effects are still present with sibutramine and olistat, which are currently recognized as obesity drugs.

따라서, 최근에는 효능성과 안전성이 동시에 보장되는 새로운 비만치료제의 개발을 위하여, 체중조절에 관련된 새로운 호르몬 및 펩타이드를 규명하고, 이들의 작용기 전을 이용한 비만치료제 개발에 노력이 집중되고 있다. Therefore, in recent years, in order to develop a novel obesity treatment agent that guarantees both efficacy and safety at the same time, efforts have been focused on identifying new hormones and peptides related to weight control and developing obesity treatments using their mechanism of action.

이러한 맥락에서 MCH1R가 식욕억제에 효과적이라는 최근 보고에 따라, 안전한 비만치료제 개발을 위한 표적으로 많은 주목을 받고 있다. 그 일례로서, MCH1R의 활성을 억제하는 효과적인 유기저분자의 발굴 및 비만치료제 개발이 보고된 바 있다[Expert Opinion on Drug Discovery 2007, 2(10), 1301-1327; BioDrugs 2007, 21(5), 311-321; Life Sciences 2007, 81(6), 423-440; Annual Reports in Medicinal Chemistry 2005, 40, 119-133; Journal of Medicinal Chemistry 2006, 49(14), 4017-4022; J. Expert Opinion on Therapeutic Targets 2006, 10(2), 211-229.].According to recent reports that MCH1R is effective in suppressing appetite in this context, much attention has been paid to the development of a safe obesity treatment. As an example, the discovery of an effective organic small molecule inhibiting the activity of MCH1R and the development of obesity treatments have been reported [ Expert Opinion on Drug Discovery 2007 , 2 (10) , 1301-1327; BioDrugs 2007 , 21 (5) , 311-321; Life Sciences 2007 , 81 (6) , 423-440; Annual Reports in Medicinal Chemistry 2005 , 40 , 119-133; Journal of Medicinal Chemistry 2006 , 49 (14) , 4017-4022; J. Expert Opinion on Therapeutic Targets 2006 , 10 (2) , 211-229.].

이에, 본 발명자들은 효능성과 안전성이 보장되는 비만치료제를 개발하고자 노력한 결과, MCH1R 억제 활성을 가지는 신규한 1-(3-알콕시퀴녹살린-2-일)-3-[1-(아릴메틸)피페리딘-4-일] 우레아 유도체 및 약제학적으로 허용 가능한 그의 염을 제조하고, 그를 유효성분으로 함유하는 비만치료제를 제공함으로써, 본 발명을 완성하였다.Accordingly, the present inventors have tried to develop an obesity therapeutic agent that guarantees efficacy and safety, and as a result, the novel 1- (3-alkoxyquinoxalin-2-yl) -3- [1- (arylmethyl) pi with MCH1R inhibitory activity Ferridin-4-yl] The present invention was completed by preparing a urea derivative and a pharmaceutically acceptable salt thereof and providing an anti-obesity agent containing the same as an active ingredient.

본 발명의 목적은 MCH1R 억제 활성을 가지는 1-(3-알콕시퀴녹살린-2-일)-3-[1-(아릴메틸)피페리딘-4-일] 우레아 유도체 및 약제학적으로 허용 가능한 그의 염을 제공하는 것이다.It is an object of the present invention to provide a 1- (3-alkoxyquinoxalin-2-yl) -3- [1- (arylmethyl) piperidin-4-yl] urea derivative having MCH1R inhibitory activity and a pharmaceutically acceptable thereof. To provide a salt.

본 발명은 다른 목적은 상기 1-(3-알콕시퀴녹살린-2-일)-3-[1-(아릴메틸)피페리딘- 4-일] 우레아 유도체의 제조방법을 제공하는 것이다.Another object of the present invention is to provide a method for preparing the 1- (3-alkoxyquinoxalin-2-yl) -3- [1- (arylmethyl) piperidin-4-yl] urea derivative.

본 발명의 또 다른 목적은 상기 1-(3-알콕시퀴녹살린-2-일)-3-[1-(아릴메틸)피페리딘-4-일] 우레아 유도체의 비만치료제로서의 용도를 제공하는 것이다.Still another object of the present invention is to provide a use of the 1- (3-alkoxyquinoxalin-2-yl) -3- [1- (arylmethyl) piperidin-4-yl] urea derivative as a therapeutic agent for obesity. .

상기 목적을 달성하기 위하여, 본 발명은 우수한 MCH1R 억제 활성을 가지는 신규한 화합물로서, 하기 화학식 1로 표시되는 1-(3-알콕시퀴녹살린-2-일)-3-[1-(아릴메틸)피페리딘-4-일] 우레아 유도체 및 약제학적으로 허용 가능한 그의 염을 제공한다. In order to achieve the above object, the present invention is a novel compound having excellent MCH1R inhibitory activity, 1- (3-alkoxyquinoxalin-2-yl) -3- [1- (arylmethyl) Piperidin-4-yl] urea derivatives and pharmaceutically acceptable salts thereof.

화학식 1Formula 1

Figure 112008013294843-pat00002
Figure 112008013294843-pat00002

(상기에서, R1, R2, R3, R4, R5, R6, R7, R8, R9 및 R10는 이하에서 정의한 바와 같다)(In the above, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are as defined below.)

본 발명의 1-(3-알콕시퀴녹살린-2-일)-3-[1-(아릴메틸)피페리딘-4-일] 우레아 유도체 및 약제학적으로 허용 가능한 그의 염은 용매화물 또는 수화물 형태로 존재하며, 그로부터 분리된 거울상 이성질체 또는 부분 입체 이성질체를 포함한다.The 1- (3-alkoxyquinoxalin-2-yl) -3- [1- (arylmethyl) piperidin-4-yl] urea derivatives of the invention and pharmaceutically acceptable salts thereof are in the form of solvates or hydrates. And enantiomers or diastereomers separated therefrom.

또한, 본 발명은 상기 화학식 1로 표시되는 1-(3-알콕시퀴녹살린-2-일)-3-[1-(아릴메틸)피페리딘-4-일] 우레아 유도체의 제조방법을 제공한다.The present invention also provides a method for preparing a 1- (3-alkoxyquinoxalin-2-yl) -3- [1- (arylmethyl) piperidin-4-yl] urea derivative represented by Formula 1 above. .

본 발명의 바람직한 제1의 제조방법은 에틸 또는 페닐 N-(2-알콕시퀴녹살린-3-일) 카바메이트 화합물과 1 위치에 보호기를 가진 4-아미노피페리딘 화합물을 축합반응하여, 1-(3-알콕시퀴녹살린-2-일)-3-(1-보호-피페리딘-4-일) 우레아 화합물을 제조(제1단계)하고, 상기 제조된 화합물을 탈보호기화 반응하여, 1-(3-알콕시퀴녹살린-2-일)-3-피페리딘-4-일 우레아 화합물을 제조(제2단계)한 후, 아릴 알데히드 화합물의 환원 알킬화 반응을 통하여, 목적화합물인 화학식 1로 표시되는 1-(3-알콕시퀴녹살린-2-일)-3-[1-(아릴메틸)피페리딘-4-일] 우레아 화합물을 제조(제3단계)하는 것으로 이루어진다.According to a first preferred method of the present invention, a condensation reaction of ethyl or phenyl N- (2-alkoxyquinoxalin-3-yl) carbamate compound with 4-aminopiperidine compound having a protecting group at position 1 is carried out. (3-alkoxyquinoxalin-2-yl) -3- (1-protected-piperidin-4-yl) urea compound was prepared (first step), and the prepared compound was subjected to deprotection reaction to give 1 -(3-Alkoxyquinoxalin-2-yl) -3-piperidin-4-yl urea compound was prepared (second step), and then reduced alkylation reaction of the aryl aldehyde compound was carried out to the target compound (1). 1- (3-alkoxyquinoxalin-2-yl) -3- [1- (arylmethyl) piperidin-4-yl] urea compound represented by the present invention is prepared (third step).

또한, 본 발명의 바람직한 제2의 제조방법은 에틸 또는 페닐 N-(2-알콕시퀴녹살린-3-일)카바메이트 화합물과 1-아릴메틸-4-아미노피페리딘 화합물을 축합반응하여, 목적화합물인 화학식 1로 표시되는 1-(3-알콕시퀴녹살린-2-일)-3-[1-(아릴메틸)피페리딘-4-일] 우레아 화합물을 제조하는 것이다. Moreover, the 2nd preferable manufacturing method of this invention is condensation reaction of ethyl or phenyl N- (2-alkoxyquinoxalin-3-yl) carbamate compound, and the 1-arylmethyl-4-aminopiperidine compound, To prepare a 1- (3-alkoxyquinoxalin-2-yl) -3- [1- (arylmethyl) piperidin-4-yl] urea compound represented by the formula (1).

나아가, 본 발명은 상기 화학식 1로 표시되는 1-(3-알콕시퀴녹살린-2-일)-3-[1-(아릴메틸)피페리딘-4-일] 우레아 유도체에 대한, 우수한 MCH1R 억제 활성을 확인함으로써, 상기 1-(3-알콕시퀴녹살린-2-일)-3-[1-(아릴메틸)피페리딘-4-일] 우레아 유도체 및 약제학적으로 허용 가능한 그의 염을 유효성분으로 함유하는 비만치료제를 제공한다. 특히, 상기 비만치료제가 MCH 활성으로 유발되는 비만관련 질환에 유용한 것을 특징으로 한다.Furthermore, the present invention provides excellent MCH1R inhibition against 1- (3-alkoxyquinoxalin-2-yl) -3- [1- (arylmethyl) piperidin-4-yl] urea derivative represented by Formula 1 By confirming the activity, the 1- (3-alkoxyquinoxalin-2-yl) -3- [1- (arylmethyl) piperidin-4-yl] urea derivative and pharmaceutically acceptable salts thereof are active ingredients. Provides a therapeutic agent for obesity. In particular, the anti-obesity agent is characterized in that it is useful for obesity-related diseases caused by MCH activity.

본 발명은 1-(3-알콕시퀴녹살린-2-일)-3-[1-(아릴메틸)피페리딘-4-일] 우레아 유도체 및 약제학적으로 허용 가능한 그의 염을 제공하고, 상기 유도체가 세포 수준 및 동물실험을 통하여 우수한 MCH1R 억제 활성을 확인함으로써, 신규 비만치료약물의 개발로서 유용하다.The present invention provides a 1- (3-alkoxyquinoxalin-2-yl) -3- [1- (arylmethyl) piperidin-4-yl] urea derivative and a pharmaceutically acceptable salt thereof, wherein the derivative It is useful as a novel obesity treatment drug by confirming the excellent MCH1R inhibitory activity through cell level and animal experiments.

이하, 본 발명을 상세히 설명하고자 한다.Hereinafter, the present invention will be described in detail.

본 발명은 하기 화학식 1로 표시되는 1-(3-알콕시퀴녹살린-2-일)-3-[1-(아릴메틸)피페리딘-4-일] 우레아 유도체 및 약제학적으로 허용 가능한 그의 염을 제공한다. The present invention provides a 1- (3-alkoxyquinoxalin-2-yl) -3- [1- (arylmethyl) piperidin-4-yl] urea derivative represented by the following formula (1) and a pharmaceutically acceptable salt thereof To provide.

화학식 1Formula 1

Figure 112008013294843-pat00003
Figure 112008013294843-pat00003

(상기에서, R1, R2, R3 및 R4는 수소원자, 할로겐원자, C1-C3의 알킬기 또는 C1-C3의 알콕시기를 나타내고; R5는 C1-C3의 알킬기 또는 C1-C3의 할로알킬기를 나타내고; R6 R7, R8, R9 및 R10는 수소원자, 할로겐원자, 하이드록시기, 니트로기, 시아노기, 아세톡시기, C1-C3의 알킬기, C1-C3의 알콕시기 또는 메탄디옥소기를 나타낸다.)(Wherein, R 1, R 2, R 3 and R 4 represents a hydrogen atom, a halogen atom, a C 1 -C 3 alkyl or C 1 -C 3 alkoxy; R 5 represents an alkyl group of C 1 -C 3 Or a C 1 -C 3 haloalkyl group; R 6 R 7 , R 8 , R 9 and R 10 are hydrogen atom, halogen atom, hydroxy group, nitro group, cyano group, acetoxy group, C 1 -C 3 alkyl group, C 1 -C 3 alkoxy group or methane Dioxo group is represented.)

본 발명에 따른 상기 화학식 1로 표시되는 우레아 유도체는 용매화물(예를 들면 수화물)의 형태로 존재할 수 있다.The urea derivative represented by Chemical Formula 1 according to the present invention may exist in the form of a solvate (for example, a hydrate).

또한, 본 발명에 따른 상기 화학식 1로 표시되는 우레아 유도체는 하나 또는 그 이 상의 비대칭 중심을 가질 수 있고, 이러한 화합물의 경우 거울상 이성질체 또는 부분 입체 이성질체가 존재할 수 있다. 따라서, 본 발명은 상기 거울상 이성질체 또는 이들 부분 이성질체 혼합물을 포함한다.In addition, the urea derivative represented by Formula 1 according to the present invention may have one or more asymmetric centers, and in the case of such compounds, enantiomers or diastereomers may be present. Accordingly, the present invention includes the enantiomers or mixtures of these partial isomers.

본 발명에서의 '할로겐 원자'라 함은 불소, 염소, 브롬, 요오드원자를 의미한다.In the present invention, the term "halogen atom" means a fluorine, chlorine, bromine or iodine atom.

본 발명에서의 'C1-C3의 알킬기'라 함은 메틸, 에틸, n-프로필, i-프로필, 싸이클로프로필을 포함하는 1개에서 3개까지의 탄소원자를 가지는 지방족 포화 탄화수소기를 의미한다.In the present invention, the "C 1 -C 3 alkyl group" means an aliphatic saturated hydrocarbon group having 1 to 3 carbon atoms including methyl, ethyl, n -propyl, i -propyl, and cyclopropyl.

본 발명에서의 'C1-C3의 알콕시기'라 함은 메톡시, 에톡시, n-프로폭시, i-프로폭시 등을 포함하는, C1-C5의 알킬기에서 선택된 치환체에 의해 수소원자가 치환된 하이드록시기를 의미한다.In the present invention, 'C 1 -C 3 alkoxy group' means hydrogen by a substituent selected from C 1 -C 5 alkyl groups including methoxy, ethoxy, n -propoxy, i -propoxy and the like. It means the hydroxyl group by which the atom was substituted.

본 발명에서의'C1-C3의 할로알킬기'라 함은 트라이플루오르메틸기와 같이 한 개 이상의 할로겐 원자에 의해 수소원자가 치환된 C1-C3의 알킬기를 의미한다.In the present invention, the "C 1 -C 3 haloalkyl group" means a C 1 -C 3 alkyl group in which a hydrogen atom is substituted by one or more halogen atoms, such as a trifluoromethyl group.

본 발명은 하기 반응식 1과 같이 수행되는, 화학식 1로 표시되는 1-(3-알콕시퀴녹살린-2-일)-3-[1-(아릴메틸)피페리딘-4-일] 우레아 유도체의 제조방법을 제공한다.The present invention provides a urea derivative of 1- (3-alkoxyquinoxalin-2-yl) -3- [1- (arylmethyl) piperidin-4-yl] urea represented by Formula 1, which is carried out as in Scheme 1 below. It provides a manufacturing method.

Figure 112008013294843-pat00004
Figure 112008013294843-pat00004

(상기에서, R1, R2, R3, R4, R5, R6, R7, R8, R9 및 R10는 상기에서 정의한 바와 같다)(Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are as defined above)

본 발명의 1-(3-알콕시퀴녹살린-2-일)-3-[1-(아릴메틸)피페리딘-4-일] 우레아 유도체를 제조하기 위한 제1의 제조방법은 The first production method for preparing the 1- (3-alkoxyquinoxalin-2-yl) -3- [1- (arylmethyl) piperidin-4-yl] urea derivative of the present invention

상기 화학식 2로 표시되는 에틸 또는 페닐 N-(2-알콕시퀴녹살린-3-일)카바메이트 화합물과 상기 화학식 3으로 표시된 1 위치에 보호기를 가진 4-아미노피페리딘 화합물을 축합 반응하여, 상기 화학식 4로 표시된 1-(3-알콕시퀴녹살린-2-일)-3-(1-보호-피페리딘-4-일) 우레아 화합물을 제조하는 제1단계,Condensation reaction of ethyl or phenyl N- (2-alkoxyquinoxalin-3-yl) carbamate compound represented by Formula 2 with a 4-aminopiperidine compound having a protecting group at a position represented by Formula 3 above, A first step of preparing a 1- (3-alkoxyquinoxalin-2-yl) -3- (1-protected-piperidin-4-yl) urea compound represented by Formula 4,

상기 제조된 화학식 4로 표시되는 화합물을 탈보호기화 반응하여, 상기 화학식 5로 표시되는 1-(3-알콕시퀴녹살린-2-일)-3-피페리딘-4-일 우레아 화합물을 제조하는 제2단계 및Deprotection reaction of the compound represented by Formula 4 to prepare a 1- (3-alkoxyquinoxalin-2-yl) -3-piperidin-4-yl urea compound represented by Formula 5 Second step and

상기 화학식 5로 표시되는 화합물과 상기 화학식 6으로 표시된 아릴 알데히드 화합 물의 환원 알킬화 반응을 통하여, 상기 화학식 1로 표시되는 1-(3-알콕시퀴녹살린-2-일)-3-[1-(아릴메틸)피페리딘-4-일] 우레아 화합물을 얻는 제3단계로 이루어진 다.1- (3-alkoxyquinoxalin-2-yl) -3- [1- (aryl represented by Chemical Formula 1 through reduction alkylation of the compound represented by Chemical Formula 5 and the aryl aldehyde compound represented by Chemical Formula 6 Methyl) piperidin-4-yl] urea compound.

상기 제1의 제조방법을 단계별로 상세히 설명하면, 본 제조방법의 제1단계에서 출발물질로 사용되는 상기 화학식 2로 표시되는 에틸 또는 페닐 N-(2-알콕시퀴녹살린-3-일)카바메이트 (X = 에톡시 또는 페녹시) 화합물은 본 출원인에 의해 공지된 기술로부터 제조된다[국제특허번호 제2006054830호]. In detail step by step in the first manufacturing method, ethyl or phenyl N- (2-alkoxyquinoxalin-3-yl) carbamate represented by the formula (2) used as a starting material in the first step of the production method (X = ethoxy or phenoxy) compounds are prepared from techniques known by the applicant (International Patent No. 2006054830).

나아가, 제1단계는 상기 화학식 2로 표시되는 화합물과 상기 화학식 3으로 표시된 1 위치에 보호기를 가진 4-아미노피페리딘 화합물의 축합반응을 통하여, 상기 화학식 4로 표시된 1-(3-알콕시퀴녹살린-2-일)-3-(1-보호-피페리딘-4-일) 우레아 화합물을 제조한다.Further, the first step is a 1- (3-alkoxyquinol represented by the formula (4) through the condensation reaction of the compound represented by the formula (2) and the 4-aminopiperidine compound having a protecting group in the 1 position represented by the formula (3) Prepare a salin-2-yl) -3- (1-protected-piperidin-4-yl) urea compound.

이때, 제조된 상기 화학식 4로 표시되는 화합물의 제조과정에서, 1 위치에 보호기를 가진 4-아미노피페리딘 화합물에 대한 보호기로서 t-부톡시카르보닐(이하 'Boc'이라 함)를 포함하는 통상적인 아미노기 보호기를 이용할 수 있다. At this time, in the process of preparing the compound represented by the formula (4), containing t -butoxycarbonyl (hereinafter referred to as 'Boc') as a protecting group for the 4-aminopiperidine compound having a protecting group at position 1 Conventional amino group protecting groups can be used.

또한, 상기 화학식 2로 표시되는 화합물에 대해서, 상기 화학식 3으로 표시되는 화합물을 1.0 내지 1.5 몰 당량을 사용하는 것이 좋으며, 더욱 바람직하게는 1.0 몰 당량을 사용한다. In addition, the compound represented by the formula (2), it is preferable to use 1.0 to 1.5 molar equivalents, more preferably 1.0 molar equivalents of the compound represented by the formula (3).

이때, 반응 시, 트리에틸아민, 디이소프로필에틸아민 (이하 'DIEA'라 함), 피리딘, 4-디메틸아미노피리딘, 2,6-루티딘, 1,8-디아자바이싸이클로[5.4.0]-운데쓰-7-엔(이하, 'DBU'라 함) 등의 통상의 유기염기를 사용하거나 유기염기를 사용하지 않고 반응을 수행할 수 있으며, 테트라하이드로퓨란 (이하 'THF'라 함), 메탄올, 에탄올, 디클로로메탄, 아세토니트릴, 디메틸포름아마이드 (이하 'DMF'라 함) 등의 통상의 유기용매 또는 통상의 유기용매의 혼합물을 사용하여 수행한다. 반응온도는 실온 내지 용매의 비점 범위가 좋으며, 더욱 바람직하게는 용매의 비점을 유지하는 것이 좋다. 반응시간은 1 내지 24시간이며, 바람직하게는 1 내지 8시간 동안 수행한다.At this time, in the reaction, triethylamine, diisopropylethylamine (hereinafter referred to as 'DIEA'), pyridine, 4-dimethylaminopyridine, 2,6-lutidine, 1,8-diazabicyclo [5.4.0] -Reaction can be carried out using a conventional organic base such as Undeth-7-en (hereinafter referred to as 'DBU') or without using an organic base, and tetrahydrofuran (hereinafter referred to as 'THF'), It is carried out using a conventional organic solvent or a mixture of conventional organic solvents such as methanol, ethanol, dichloromethane, acetonitrile and dimethylformamide (hereinafter referred to as 'DMF'). The reaction temperature has a good boiling point range from room temperature to a solvent, and more preferably maintains the boiling point of the solvent. The reaction time is 1 to 24 hours, preferably 1 to 8 hours.

본 발명의 제2단계는 상기 제조된 화학식 4로 표시되는 1-(3-알콕시퀴녹살린-2-일)-3-(1-보호-피페리딘-4-일) 우레아 화합물의 탈보호기화 반응을 통하여 상기 화학식 5로 표시되는 1-(3-알콕시퀴녹살린-2-일)-3-피페리딘-4-일 우레아 화합물을 제조하는 것이다.The second step of the present invention is the deprotection of the 1- (3-alkoxyquinoxalin-2-yl) -3- (1-protected-piperidin-4-yl) urea compound represented by Chemical Formula 4 prepared above. Through the reaction to prepare a 1- (3-alkoxyquinoxalin-2-yl) -3-piperidin-4-yl urea compound represented by the formula (5).

제2단계에서 사용되는 용매는 통상의 유기산, 예를 들면 트리플루오르아세트산(이하 'TFA'라 함) 등을 사용하여 통상적인 유기용매, 예를 들면 디클로로메탄(이하 'DCM'이라 함) 등 내에서 수행한다. 이때, 반응온도는 0℃ 내지 실온 범위, 바람직하게는 실온을 유지하는 것이 좋다. 반응시간은 1 내지 24시간, 바람직하게는 1 내지 5시간 동안 반응시킨다. The solvent used in the second step is a conventional organic solvent, for example, dichloromethane (hereinafter referred to as 'DCM') using a conventional organic acid, for example trifluoroacetic acid (hereinafter referred to as 'TFA') and the like Perform on At this time, the reaction temperature is preferably in the range of 0 ℃ to room temperature, preferably room temperature. The reaction time is 1 to 24 hours, preferably 1 to 5 hours.

본 발명의 제3단계는 상기 제조된 화학식 5로 표시되는 1-(3-알콕시퀴녹살린-2-일)-3-피페리딘-4-일 우레아 화합물과 상기 화학식 6으로 표시된 아릴 알데히드 화합물의 환원알킬화 반응을 통하여, 상기 화학식 1로 표시되는 1-(3-알콕시퀴녹살린-2-일)-3-[1-(아릴메틸)피페리딘-4-일] 우레아 화합물을 얻는 것이다.The third step of the present invention is the 1- (3-alkoxyquinoxalin-2-yl) -3-piperidin-4-yl urea compound represented by Formula 5 prepared above and the aryl aldehyde compound represented by Formula 6 Through a reduction alkylation reaction, a 1- (3-alkoxyquinoxalin-2-yl) -3- [1- (arylmethyl) piperidin-4-yl] urea compound represented by Chemical Formula 1 is obtained.

상기 제조단계는 소듐 트리아세톡시보로하이드라이드 (이하 'NaBH(OAc)3'라 함) 등의 환원제의 존재 하에서, 통상의 유기용매, 예를 들면 디클로로에탄(이하 'DCE'라 함), 디클로로메탄, 아세토니트릴, 디메틸포름아마이드 등을 사용하여 수행한다. 상기 화학식 5로 표시되는 화합물에 대하여, 환원제는 1.0 내지 3.0 몰 당량을 사용하는 것이 좋으며, 더욱 바람직하게는 1.0 내지 2.0 몰당량을 사용하는 것이다. 또한, 상기 화학식 6으로 표시되는 화합물에 대해서는 1.0 내지 1.5 몰 당량을 사용하는 것이 좋으며, 더욱 바람직하게는 1.0 내지 1.1 몰 당량을 사용하는 것이다.The preparation step is carried out in the presence of a reducing agent such as sodium triacetoxyborohydride (hereinafter referred to as 'NaBH (OAc) 3 '), a conventional organic solvent, for example dichloroethane (hereinafter referred to as 'DCE'), dichloro Methane, acetonitrile, dimethylformamide and the like. For the compound represented by Formula 5, it is preferable to use 1.0 to 3.0 molar equivalents, more preferably 1.0 to 2.0 molar equivalents. In addition, it is preferable to use 1.0 to 1.5 molar equivalents, and more preferably 1.0 to 1.1 molar equivalents, for the compound represented by the formula (6).

이때, 반응온도는 0℃ 내지 용매의 비점 범위가 좋으며, 더욱 바람직하게는 실온을 유지하는 것이 좋다. 반응시간은 1 내지 24시간, 바람직하게는 1 내지 8시간 동안 반응시킨다. At this time, the reaction temperature is good in the boiling point range of 0 ℃ to the solvent, more preferably it is good to maintain the room temperature. The reaction time is 1 to 24 hours, preferably 1 to 8 hours.

또한, 본 발명은 화학식 1로 표시되는 1-(3-알콕시퀴녹살린-2-일)-3-[1-(아릴메틸)피페리딘-4-일] 우레아 유도체의 제조하기 위하여, 하기 반응식 1과 같이 수행되는 바람직한 제2의 제조방법을 제공한다.In addition, the present invention is to prepare a 1- (3-alkoxyquinoxalin-2-yl) -3- [1- (arylmethyl) piperidin-4-yl] urea derivative represented by the formula (1), It provides a second preferred manufacturing method performed as described above.

Figure 112008013294843-pat00005
Figure 112008013294843-pat00005

(상기에서, R1, R2, R3, R4, R5, R6, R7, R8, R9 및 R10는 상기에서 정의한 바와 같다)(Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are as defined above)

본 발명의 제2의 제조방법은 출발물질로서, 본 출원인에 의해 공지된 기술[국제특허번호 제2006054830호]로부터 제조된 상기 화학식 2로 표시되는 에틸 또는 페닐 N-(2-알콕시퀴녹살린-3-일)카바메이트 (X = 에톡시 또는 페녹시) 화합물과 상기 화학식 7로 표시된 1-아릴메틸-4-아미노피페리딘 화합물의 축합반응을 통해서 제조할 수 있다.The second production method of the present invention is ethyl or phenyl N- (2-alkoxyquinoxaline-3 represented by Chemical Formula 2 prepared from a technology known by the applicant [International Patent No. 2006054830] as a starting material. -Yl) carbamate (X = ethoxy or phenoxy) compound and the 1-arylmethyl-4-aminopiperidine compound represented by the formula (7) can be prepared through the condensation reaction.

이때, 상기 화학식 2로 표시되는 화합물에 대하여, 상기 화학식 7로 표시되는 화합물을 1.0 내지 1.5 몰 당량을 사용하는 것이 좋으며, 더욱 바람직하게는 1.0 몰당량을 사용한다. 또한, 반응 시, 트리에틸아민, 디이소프로필에틸아민, 피리딘, 4-디메틸아미노피리딘, 2,6-루티딘, 1,8-디아자바이싸이클로[5.4.0]-운데쓰-7-엔 등의 통상의 유기염기를 사용하거나 유기염기를 사용하지 않고 반응을 수행할 수 있으며, 테트라하이드로퓨란, 메탄올, 에탄올, 디클로로메탄, 아세토니트릴, 디메틸포름아마이드 등의 통상의 유기용매 또는 통상의 유기용매의 혼합물을 사용하여 수행한다. 바람직한 반응온도는 실온 내지 용매의 비점 범위에서 수행하는 것이다. 또한, 반응시간은 1 내지 24시간이며, 바람직하게는 1 내지 8시간 동안 반응시킨다.At this time, it is preferable to use 1.0 to 1.5 molar equivalents of the compound represented by the general formula (7) with respect to the compound represented by the general formula (2), more preferably 1.0 molar equivalent. In the reaction, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 2,6-lutidine, 1,8-diazabicyclo [5.4.0] -undeth-7-ene, and the like The reaction may be carried out using a conventional organic base or without using an organic base, and may be a conventional organic solvent such as tetrahydrofuran, methanol, ethanol, dichloromethane, acetonitrile, dimethylformamide, or a conventional organic solvent. It is carried out using a mixture. Preferred reaction temperatures are those carried out at room temperature to the boiling point of the solvent. In addition, the reaction time is 1 to 24 hours, preferably 1 to 8 hours.

상기 화학식 2로 표시되는 화합물과 상기 화학식 7로 표시되는 화합물로부터, 상기 화학식 1로 표시되는 화합물의 제조과정에서 통상의 유기염기 대신 트리메틸알루미늄 (이하 'Me3Al'이라 함) 등과 같은 루이스산을 사용할 수 있다. From the compound represented by Formula 2 and the compound represented by Formula 7, Lewis acid, such as trimethylaluminum (hereinafter referred to as 'Me 3 Al'), in place of a conventional organic base in the process of preparing the compound represented by Formula 1 Can be used.

이때, 상기 화학식 2로 표시되는 화합물에 대하여 화학식 7로 표시되는 화합물을 1.0 내지 1.5 몰 당량을 사용하는 것이 좋으며, 더욱 바람직하게는 1.0 몰 당량을 사용하는 것이다. 용매로는 톨루엔, 테트라하이드로퓨란, 아세토니트릴, 디메틸포름아마이드, 디클로로메탄 등의 통상의 유기용매 또는 통상의 유기용매의 혼합물을 사용하여 수행한다. 또한, 바람직한 반응온도는 실온 내지 용매의 비점 범위가 좋으며, 반응시간은 1 내지 24시간, 더욱 바람직하게는 1 내지 8시간 동안 반응시키는 것이다.In this case, it is preferable to use 1.0 to 1.5 molar equivalents of the compound represented by the general formula (7) with respect to the compound represented by the general formula (2), and more preferably 1.0 molar equivalent. The solvent is carried out using a common organic solvent or a mixture of conventional organic solvents such as toluene, tetrahydrofuran, acetonitrile, dimethylformamide, dichloromethane and the like. In addition, the reaction temperature is preferably in the boiling point range of room temperature to the solvent, the reaction time is 1 to 24 hours, more preferably 1 to 8 hours to react.

본 발명의 제1의 제조방법 및 제2의 제조방법에 따른, 상기 화학식 1로 표시되는 화합물들의 생성여부를 확인하기 위하여, 최종 반응 후 다중 컬럼크로마토그래피 장비(Quad3+; 미국 Biotage사 제품)로 분리 정제하였으며, NMR 및 Mass 스펙트럼으로 구조를 분석하였다.In order to confirm the production of the compound represented by Formula 1 according to the first manufacturing method and the second manufacturing method of the present invention, after the final reaction is separated by a multi-column chromatography equipment (Quad3 +; Biotage, USA) Purified and analyzed by NMR and Mass spectra.

나아가, 본 발명은 상기 화학식 1로 표시되는 1-(3-알콕시퀴녹살린-2-일)-3-[1-(아릴메틸)피페리딘-4-일] 우레아 유도체 및 약제학적으로 허용 가능한 그의 염을 유효성분으로 함유하는 비만치료제로서의 용도를 제공한다. Furthermore, the present invention provides 1- (3-alkoxyquinoxalin-2-yl) -3- [1- (arylmethyl) piperidin-4-yl] urea derivative represented by Formula 1 and pharmaceutically acceptable It provides a use as a therapeutic agent for obesity containing a salt thereof as an active ingredient.

특히, 본 발명에 따른 상기 화학식 1로 표시되는 1-(3-알콕시퀴녹살린-2-일)-3-[1-(아릴메틸)피페리딘-4-일] 우레아 유도체는 우수한 MCH1R 억제 활성을 가지므로, MCH 활성으로 유발되는 비만관련 질환 치료에 유용하게 사용될 수 있다. In particular, the 1- (3-alkoxyquinoxalin-2-yl) -3- [1- (arylmethyl) piperidin-4-yl] urea derivative represented by Formula 1 according to the present invention has excellent MCH1R inhibitory activity. Therefore, it can be useful for the treatment of obesity-related diseases caused by MCH activity.

따라서, 상기 1-(3-알콕시퀴녹살린-2-일)-3-[1-(아릴메틸)피페리딘-4-일] 우레아 유도체 및 약제학적으로 허용 가능한 그 염을 유효성분으로 함유하여, 지방조직이 체내에 과다하게 축적되어 있는 상태인 비만의 치료제로 유효한 약제조성물을 제공할 수 있다. Therefore, it contains the 1- (3-alkoxyquinoxalin-2-yl) -3- [1- (arylmethyl) piperidin-4-yl] urea derivative and a pharmaceutically acceptable salt thereof as an active ingredient In addition, an effective pharmaceutical composition can be provided as a therapeutic agent for obesity in which adipose tissue is excessively accumulated in the body.

본 발명에서의 약제학적으로 허용 가능한 염은 당해 기술 분야에서 통상적인 방법에 의해 제조될 수 있는 것으로, 예를 들면 염산, 브롬산, 황산, 황산수소나트륨, 인산, 질산, 탄산 등과 같은 무기산과의 염, 개미산, 초산, 프로피온산, 옥살산, 석신산, 벤조산, 시트르산, 말레인산, 말론산, 타르타르산, 글루콘산, 락트산, 게스티스산, 푸마르산, 락토비온산, 살리실릭산, 또는 아세틸살리실릭산(아스피린)과 같은 유기산과의 염, 글리신, 알라닌, 바닐린, 이소루신, 세린, 시스테인, 시스틴, 아스파라진산, 글루타민, 리진, 아르기닌, 타이로신, 프롤린 등과 같은 아미노산과의 염, 메탄설폰산, 에탄설폰산, 벤젠설폰산, 톨루엔설폰산 등과 같은 설폰산과의 염, 나트륨, 칼륨 등의 알칼리금속과의 반응에 의한 금속염, 또는 암모늄 이온과의 염 등을 포함한다. Pharmaceutically acceptable salts in the present invention may be prepared by conventional methods in the art, for example, with inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid, sodium hydrogen sulfate, phosphoric acid, nitric acid, carbonic acid, and the like. Salts, formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, benzoic acid, citric acid, maleic acid, malonic acid, tartaric acid, gluconic acid, lactic acid, gestyic acid, fumaric acid, lactobionic acid, salicylic acid, or acetylsalicylic acid (aspirin Salts with organic acids such as), salts with amino acids such as glycine, alanine, vanillin, isoleucine, serine, cysteine, cystine, aspartic acid, glutamine, lysine, arginine, tyrosine, proline, methanesulfonic acid, ethanesulfonic acid And salts with sulfonic acids such as benzenesulfonic acid and toluenesulfonic acid, metal salts by reaction with alkali metals such as sodium and potassium, salts with ammonium ions and the like.

또한, 본 발명의 약제 조성물은 상기 화학식 1로 표시되는 화합물 또는 약제학적으로 허용 가능한 이들의 염에 통상의 무독성 약제학적으로 허용 가능한 담체, 보강제 및 부형제 등을 첨가하여 약제학적 분야에서 통상적인 제제 예를 들면 정제, 캅셀제, 트로키제, 액제, 현탁제 등의 경구 투여용 제제 또는 비경구 투여용 제제로 제조하여, 비만의 치료에 사용될 수 있다. In addition, the pharmaceutical composition of the present invention is a conventional formulation in the pharmaceutical field by adding a conventional non-toxic pharmaceutically acceptable carrier, adjuvant and excipient to the compound represented by the formula (1) or pharmaceutically acceptable salts thereof For example, it may be prepared by oral administration or preparations for parenteral administration such as tablets, capsules, troches, solutions, suspensions, and the like, and may be used for the treatment of obesity.

본 발명의 약제 조성물에 사용될 수 있는 부형제로는 감미제, 결합제, 용해제, 용해보조제, 습윤제, 유화제, 등장화제, 흡착제, 붕해제, 산화방지제, 방부제, 활탁 제, 충진제, 방향제 등이 포함될 수 있다. 예를 들면 락토스, 덱스트로스, 슈크로스, 만니톨, 솔비톨, 셀룰로오스, 글라이신, 실리카, 탈크, 스테아린산, 스테린, 마그네슘 스테아린산염, 마그네슘 알루미늄 규산염, 녹말, 젤라틴, 트라가칸트 고무, 알지닌산, 소듐 알진산염, 메틸셀룰로오스, 소듐 카르복실메틸셀룰로오스, 아가, 물, 에탄올, 폴리에틸렌글리콜, 폴리비닐피롤리돈, 염화나트륨, 염화칼슘, 오렌지 엣센스, 딸기 엣센스, 바닐라 향 등을 들 수 있다. Excipients that may be used in the pharmaceutical compositions of the present invention may include sweeteners, binders, solubilizers, solubilizers, wetting agents, emulsifiers, isotonic agents, adsorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, fragrances and the like. For example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, sterin, magnesium stearate, magnesium aluminum silicate, starch, gelatin, tragacanth rubber, alginate, sodium Alginate, methyl cellulose, sodium carboxymethyl cellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor and the like.

또한, 본 발명에 따른 화학식 1로 표시되는 화합물의 인체에 대한 투여용량은 환자의 나이, 몸무게, 성별, 투여형태, 건강상태 및 질병정도에 따라 달라질 수 있으며, 몸무게가 70 kg인 성인환자를 기준으로 할 때 일반적으로 1일 0.01 mg 내지 5,000 mg이며, 의사 또는 약사의 판단에 따라 일정 시간간격으로 1일 1회 내지 수회로 분할 투여할 수도 있다. In addition, the dosage of the compound represented by Formula 1 according to the present invention to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, based on an adult patient with a weight of 70 kg In general, 0.01 mg to 5,000 mg per day, and may be dividedly administered once to several times a day at regular intervals according to the judgment of a doctor or pharmacist.

이하, 본 발명을 실시예에 의하여 상세히 설명한다.Hereinafter, the present invention will be described in detail with reference to examples.

하기 실시예는 본 발명을 예시하는 것일 뿐, 본 발명의 범위가 하기 실시예에 한정되는 것은 아니다. The following examples are merely illustrative of the present invention, but the scope of the present invention is not limited to the following examples.

<실시예 1> &Lt; Example 1 >

1-(1-피페로닐피페리딘-4-일)-3-(3-메톡시퀴녹살린-2-일) 우레아의 제조Preparation of 1- (1-piperonylpiperidin-4-yl) -3- (3-methoxyquinoxalin-2-yl) urea

페닐 (3-메톡시퀴녹살린-2-일)카르바메이트 (50 mg, 0.17 mmol)와 4-아미노-1-피페로닐피페리딘 (59 mg, 0.25 mmol)을 실온에서 THF 1 ㎖와 DMF 0.25 ㎖의 혼합용매에 녹인 후 DIEA (24 mg, 0.19 mmol)를 더하고, 같은 온도에서 12 시간동안 교반하 였다. 반응 종료 후에 용매를 감압 증발시킨 뒤, 실리카겔 관 크로마토그래피(디클로로메탄:에탄올, 20:1 v/v)로 정제하여 상기 목적화합물 (55 mg, 75%)을 얻었다.Phenyl (3-methoxyquinoxalin-2-yl) carbamate (50 mg, 0.17 mmol) and 4-amino-1-piperonylpiperidine (59 mg, 0.25 mmol) were treated with 1 mL of THF and DMF at room temperature. After dissolving in 0.25 mL of mixed solvent, DIEA (24 mg, 0.19 mmol) was added thereto, and the resultant was stirred at the same temperature for 12 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and then purified by silica gel column chromatography (dichloromethane: ethanol, 20: 1 v / v) to obtain the target compound (55 mg, 75%).

<실시예 2> <Example 2>

1-(1-벤질피페리딘-4-일)-3-(3-메톡시퀴녹살린-2-일) 우레아 제조Preparation of 1- (1-benzylpiperidin-4-yl) -3- (3-methoxyquinoxalin-2-yl) urea

실시예 1과 동일한 방법으로 수행하되, 페닐 (3-메톡시퀴녹살린-2-일)카르바메이트 (30 mg, 0.10 mmol)와 4-아미노-1-벤질피페리딘 (29 mg, 0.15 mmol)을 실온에서 THF 1 ㎖ 에 녹인 후, DIEA (15 mg, 0.11 mmol)를 더하고, 같은 온도에서 16 시간동안 교반하였다. 반응 종료 후에 용매를 감압 증발시킨 뒤, 실리카겔 관 크로마토그래피 (디클로로메탄:에탄올, 20:1 v/v)로 정제하여, 상기 목적화합물 (26 mg, 66%)을 얻었다.Performed in the same manner as in Example 1, except for phenyl (3-methoxyquinoxalin-2-yl) carbamate (30 mg, 0.10 mmol) and 4-amino-1-benzylpiperidine (29 mg, 0.15 mmol ) Was dissolved in 1 mL of THF at room temperature, DIEA (15 mg, 0.11 mmol) was added, and the mixture was stirred at the same temperature for 16 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and then purified by silica gel column chromatography (dichloromethane: ethanol, 20: 1 v / v) to obtain the target compound (26 mg, 66%).

<실시예 3> <Example 3>

1-[1-(4-메톡시벤질)피페리딘-4-일]-3-(3-메톡시퀴녹살린-2-일) 우레아의 제조Preparation of 1- [1- (4-methoxybenzyl) piperidin-4-yl] -3- (3-methoxyquinoxalin-2-yl) urea

실시예 1과 동일한 방법으로 수행하되, 페닐 (3-메톡시퀴녹살린-2-일)카르바메이트 (25 mg, 0.085 mmol)와 4-아미노-1-(4-메톡시벤질)피페리딘 (28 mg, 0.13 mmol)을 실온에서 THF 1 ㎖에 녹인 후, DIEA (12 mg, 0.091 mmol)를 더하고 같은 온도에서 14 시간동안 교반하였다. 반응 종료 후에 용매를 감압 증발시킨 뒤, 실리카겔 관 크로마토그래피 (디클로로메탄:에탄올, 20:1 v/v)로 정제하여, 상기 목적화합물 (28 mg, 79%)을 얻었다.Performed in the same manner as in Example 1, except for phenyl (3-methoxyquinoxalin-2-yl) carbamate (25 mg, 0.085 mmol) and 4-amino-1- (4-methoxybenzyl) piperidine (28 mg, 0.13 mmol) was dissolved in 1 mL of THF at room temperature, and then DIEA (12 mg, 0.091 mmol) was added and stirred at the same temperature for 14 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and then purified by silica gel column chromatography (dichloromethane: ethanol, 20: 1 v / v) to obtain the target compound (28 mg, 79%).

<실시예 4> <Example 4>

1-[1-(3-메톡시벤질)피페리딘-4-일]-3-(3-메톡시퀴녹살린-2-일) 우레아 제조Preparation of 1- [1- (3-methoxybenzyl) piperidin-4-yl] -3- (3-methoxyquinoxalin-2-yl) urea

실시예 1과 동일한 방법으로 수행하되, 페닐 (3-메톡시퀴녹살린-2-일)카르바메이트 (25 mg, 0.085 mmol)와 4-아미노-1-(3-메톡시벤질)피페리딘 (28 mg, 0.13 mmol)을 실온에서 THF 1 ㎖에 녹인 후, DIEA (12 mg, 0.091 mmol)를 더하고 같은 온도에서 14 시간동안 교반하였다. 반응 종료 후에 용매를 감압 증발시킨 뒤, 실리카겔 관 크로마토그래피 (디클로로메탄:에탄올, 20:1 v/v)로 정제하여 상기 목적화합물 (28 mg, 78%)을 얻었다.Performed in the same manner as in Example 1, except for phenyl (3-methoxyquinoxalin-2-yl) carbamate (25 mg, 0.085 mmol) and 4-amino-1- (3-methoxybenzyl) piperidine (28 mg, 0.13 mmol) was dissolved in 1 mL of THF at room temperature, and then DIEA (12 mg, 0.091 mmol) was added and stirred at the same temperature for 14 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and then purified by silica gel column chromatography (dichloromethane: ethanol, 20: 1 v / v) to obtain the target compound (28 mg, 78%).

<< 실시예Example 5>  5>

1-[1-(2-메톡시벤질)피페리딘-4-일]-3-(3-메톡시퀴녹살린-2-일) 우레아 제조Preparation of 1- [1- (2-methoxybenzyl) piperidin-4-yl] -3- (3-methoxyquinoxalin-2-yl) urea

실시예 1과 동일한 방법으로 수행하되, 페닐 (3-메톡시퀴녹살린-2-일)카르바메이트 (50 mg, 0.17 mmol)와 4-아미노-1-(2-메톡시벤질)피페리딘 (60 mg, 0.27 mmol)을 실온에서 THF 1 ㎖에 녹인 후, DIEA (24 mg, 0.19 mmol)를 더하고 같은 온도에서 14 시간동안 교반하였다. 반응 종료 후에 용매를 감압 증발시킨 뒤, 실리카겔 관 크로마토그래피 (디클로로메탄:에탄올, 20:1 v/v)로 정제하여 상기 목적화합물 (59 mg, 83%)을 얻었다.Performed in the same manner as in Example 1, except for phenyl (3-methoxyquinoxalin-2-yl) carbamate (50 mg, 0.17 mmol) and 4-amino-1- (2-methoxybenzyl) piperidine (60 mg, 0.27 mmol) was dissolved in 1 mL of THF at room temperature, and then DIEA (24 mg, 0.19 mmol) was added and stirred at the same temperature for 14 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and then purified by silica gel column chromatography (dichloromethane: ethanol, 20: 1 v / v) to obtain the target compound (59 mg, 83%).

<실시예 6><Example 6>

1-(1-피페로닐피페리딘-4-일)-3-(7-플루오르-3-메톡시퀴녹살린-2-일) 우레아 제조Preparation of 1- (1-piperonylpiperidin-4-yl) -3- (7-fluoro-3-methoxyquinoxalin-2-yl) urea

실시예 1과 동일한 방법으로 수행하되, 페닐 (7-플루오르-3-메톡시퀴녹살린-2-일)카르바메이트 (30 mg, 0.096 mmol)와 4-아미노-1-피페로닐피페리딘 (34 mg, 0.14 mmol)을 실온에서 THF 1 ㎖와 DMF 1 ㎖의 혼합용매에 녹인 후, DIEA (13 mg, 0.11 mmol)를 더하고 같은 온도에서 14 시간동안 교반하였다. 반응 종료 후에 용매를 감압 증발시킨 뒤, 실리카겔 관 크로마토그래피 (디클로로메탄:에탄올, 30:1 v/v)로 정제하여 상기 목적화합물 (33 mg, 75%)을 얻었다.The same procedure as in Example 1 was conducted, except that phenyl (7-fluoro-3-methoxyquinoxalin-2-yl) carbamate (30 mg, 0.096 mmol) and 4-amino-1-piperonylpiperidine ( 34 mg, 0.14 mmol) was dissolved in a mixed solvent of 1 mL of THF and 1 mL of DMF at room temperature, and then DIEA (13 mg, 0.11 mmol) was added and stirred at the same temperature for 14 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and then purified by silica gel column chromatography (dichloromethane: ethanol, 30: 1 v / v) to obtain the target compound (33 mg, 75%).

<실시예 7><Example 7>

1-(1-벤질피페리딘-4-일)-3-(7-플루오르-3-메톡시퀴녹살린-2-일) 우레아 제조Preparation of 1- (1-benzylpiperidin-4-yl) -3- (7-fluoro-3-methoxyquinoxalin-2-yl) urea

실시예 1과 동일한 방법으로 수행하되, 페닐 (7-플루오르-3-메톡시퀴녹살린-2-일)카르바메이트 (30 mg, 0.096 mmol)와 4-아미노-1-벤질피페리딘 (27 mg, 0.14 mmol)을 실온에서 THF 1 ㎖에 녹인 후, DIEA (13 mg, 0.11 mmol)를 더하고 같은 온도에서 13 시간동안 교반하였다. 반응 종료 후에 용매를 감압 증발시킨 뒤, 실리카겔 관 크로마토그래피 (디클로로메탄:에탄올, 30:1 v/v)로 정제하여 상기 목적화합물 (28 mg, 71%)을 얻었다.Performed in the same manner as in Example 1, except for phenyl (7-fluoro-3-methoxyquinoxalin-2-yl) carbamate (30 mg, 0.096 mmol) and 4-amino-1-benzylpiperidine (27 mg, 0.14 mmol) was dissolved in 1 mL of THF at room temperature, and then DIEA (13 mg, 0.11 mmol) was added and stirred at the same temperature for 13 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and then purified by silica gel column chromatography (dichloromethane: ethanol, 30: 1 v / v) to obtain the target compound (28 mg, 71%).

<실시예 8> <Example 8>

1-(1-피페로닐피페리딘-4-일)-3-(6,7-디플루오르-3-메톡시퀴녹살린-2-일) 우레아 제조 Preparation of 1- (1-piperonylpiperidin-4-yl) -3- (6,7 - difluoro-3-methoxyquinoxalin-2-yl) urea

에틸 (6,7-디플루오르-3-메톡시퀴녹살린-2-일)카르바메이트 (40 mg, 0.14 mmol)와 4-아미노-1-피페로닐피페리딘 (50 mg, 0.21 mmol)을 실온에서 THF 1 ㎖에 녹인 후, DBU (43 mg, 0.28 mmol)를 더하고 45℃에서 23 시간동안 교반하였다. 반응 종료 후에 용매를 감압 증발시킨 뒤, 실리카겔 관 크로마토그래피 (디클로로메탄:메탄올, 98:2 v/v)로 정제하여, 상기 목적화합물 (48 mg, 72%)을 얻었다.Ethyl (6,7-difluoro-3-methoxyquinoxalin-2-yl) carbamate (40 mg, 0.14 mmol) and 4-amino-1-piperonylpiperidine (50 mg, 0.21 mmol) After dissolving in 1 mL of THF at room temperature, DBU (43 mg, 0.28 mmol) was added and stirred at 45 ° C. for 23 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and then purified by silica gel column chromatography (dichloromethane: methanol, 98: 2 v / v) to obtain the target compound (48 mg, 72%).

<실시예 9>Example 9

1-(1-벤질피페리딘-4-일)-3-(6,7-디플루오르-3-메톡시퀴녹살린-2-일) 우레아 제조Preparation of 1- (1-benzylpiperidin-4-yl) -3- (6,7-difluoro-3-methoxyquinoxalin-2-yl) urea

실시예 8과 동일한 방법으로 수행하되, 에틸 (6,7-디플루오르-3-메톡시퀴녹살린-2-일)카르바메이트 (40 mg, 0.14 mmol)와 4-아미노-1-벤질피페리딘 (40 mg, 0.21 mmol)을 실온에서 THF 1 ㎖에 녹인 후, DBU (42 mg, 0.22 mmol)를 더하고 45℃에서 14 시간동안 교반하였다. 반응 종료 후에 용매를 감압 증발시킨 뒤, 실리카겔 관 크로마토그래피 (디클로로메탄:메탄올, 98:2 v/v)로 정제하여, 상기 목적화합물 (54 mg, 90%)을 얻었다.Performed in the same manner as in Example 8, except for ethyl (6,7 - difluoro-3-methoxyquinoxalin-2-yl) carbamate (40 mg, 0.14 mmol) and 4-amino-1-benzylpiperi Dean (40 mg, 0.21 mmol) was dissolved in 1 mL of THF at room temperature, then DBU (42 mg, 0.22 mmol) was added and stirred at 45 ° C. for 14 hours. After which the solvent is evaporated under reduced pressure after the completion of the reaction, silica gel column chromatography (di dichloromethane: methanol, 98: 2 v / v) to yield the desired compound (54 mg, 90%).

<실시예 10><Example 10>

1-(1-피페로닐피페리딘-4-일)-3-(7-클로로-3-메톡시퀴녹살린-2-일) 우레아 제조Preparation of 1- (1-piperonylpiperidin-4-yl) -3- (7-chloro-3-methoxyquinoxalin-2-yl) urea

실시예 1과 동일한 방법으로 수행하되, 페닐 (7-클로로-3-메톡시퀴녹살린-2-일)카르바메이트 (40 mg, 0.12 mmol)와 4-아미노-1-피페로닐피페리딘 (43 mg, 0.18 mmol)을 실온에서 THF 1 ㎖와 DMF 1 ㎖의 혼합용매에 녹인 후, DIEA (17 mg, 0.13 mmol)를 더하고 같은 온도에서 15 시간동안 교반하였다. 반응 종료 후에 용매를 감압 증발시킨 뒤, 실리카겔 관 크로마토그래피 (디클로로메탄:에탄올, 30:1 v/v)로 정제하여, 상기 목적화합물 (50 mg, 88%)을 얻었다.In the same manner as in Example 1, except for phenyl (7-chloro-3-methoxyquinoxalin-2-yl) carbamate (40 mg, 0.12 mmol) and 4-amino-1-piperonylpiperidine ( 43 mg, 0.18 mmol) was dissolved in a mixed solvent of 1 mL of THF and 1 mL of DMF at room temperature, and then DIEA (17 mg, 0.13 mmol) was added and stirred at the same temperature for 15 hours. After which, after the completion of the reaction the solvent is evaporated under reduced pressure, the residue was subjected to silica gel column chromatography (di dichloromethane: ethanol, 30: 1 v / v) to yield the desired compound (50 mg, 88%).

<실시예 11><Example 11>

1-(1-벤질피페리딘-4-일)-3-(7-클로로-3-메톡시퀴녹살린-2-일) 우레아 제조Preparation of 1- (1-benzylpiperidin-4-yl) -3- (7-chloro-3-methoxyquinoxalin-2-yl) urea

실시예 1과 동일한 방법으로 수행하되, 페닐 (7-클로로-3-메톡시퀴녹살린-2-일)카르바메이트 (30 mg, 0.10 mmol)와 4-아미노-1-벤질피페리딘 (26 mg, 0.14 mmol)을 실온에서 THF 1 ㎖에 녹인 후, DIEA (13 mg, 0.11 mmol)를 더하고 같은 온도에서 2 시간동안 교반하였다. 반응 종료 후에 용매를 감압 증발시킨 뒤, 실리카겔 관 크로마토그래피 (디클로로메탄:에탄올, 30:1 v/v)로 정제하여, 상기 목적화합물 (31 mg, 79%)을 얻었다.Performed in the same manner as in Example 1, except for phenyl (7-chloro-3-methoxyquinoxalin-2-yl) carbamate (30 mg, 0.10 mmol) and 4-amino-1-benzylpiperidine (26 mg, 0.14 mmol) was dissolved in 1 mL of THF at room temperature, and then DIEA (13 mg, 0.11 mmol) was added and stirred at the same temperature for 2 hours. After which the solvent under reduced pressure after the completion of the reaction evaporated and was purified by silica gel column chromatography (di dichloromethane: ethanol, 30: 1 v / v) to yield the desired compound (31 mg, 79%).

<실시예 12><Example 12>

1-(1-피페로닐피페리딘-4-일)-3-(6,7-디클로로-3-메톡시퀴녹살린-2-일) 우레아 제조Preparation of 1- (1-piperonylpiperidin-4-yl) -3- (6,7-dichloro-3-methoxyquinoxalin-2-yl) urea

실시예 8과 동일한 방법으로 수행하되, 에틸 (6,7-디클로로-3-메톡시퀴녹살린-2-일)카르바메이트 (40 mg, 0.13 mmol)와 4-아미노-1-피페로닐피페리딘 (44 mg, 0.19 mmol)을 실온에서 THF 1 ㎖에 녹인 후, DBU (38 mg, 0.25 mmol)를 더하고 45℃에서 23 시간동안 교반하였다. 반응 종료 후에 용매를 감압 증발시킨 뒤, 실리카겔 관 크로마토그래피 (디클로로메탄:메탄올, 98:2 v/v)로 정제하여, 상기 목적화합물 (56 mg, 85%)을 얻었다.Performed in the same manner as in Example 8, except ethyl (6,7 - dichloro-3-methoxyquinoxalin-2-yl) carbamate (40 mg, 0.13 mmol) and 4-amino-1-piperonylpy Ferridine (44 mg, 0.19 mmol) was dissolved in 1 mL of THF at room temperature, then DBU (38 mg, 0.25 mmol) was added and stirred at 45 ° C. for 23 hours. After which the solvent is evaporated under reduced pressure after the completion of the reaction, silica gel column chromatography (di dichloromethane: methanol, 98: 2 v / v) to yield the desired compound (56 mg, 85%).

<실시예 13>Example 13

1-(1-벤질피페리딘-4-일)-3-(6,7-디클로로-3-메톡시퀴녹살린-2-일) 우레아 제조Preparation of 1- (1-benzylpiperidin-4-yl) -3- (6,7-dichloro-3-methoxyquinoxalin-2-yl) urea

실시예 8과 동일한 방법으로 수행하되, 에틸 (6,7-디클로로-3-메톡시퀴녹살린-2-일)카르바메이트 (40 mg, 0.13 mmol)와 4-아미노-1-벤질피페리딘 (36 mg, 0.19 mmol)을 실온에서 THF 1 ㎖에 녹인 후, DBU (38 mg, 0.25 mmol)를 더하고 45℃에서 14 시간동안 교반하였다. 반응 종료 후에 용매를 감압 증발시킨 뒤, 실리카겔 관 크로마토그래피 (디클로로메탄:메탄올, 98:2 v/v)로 정제하여, 상기 목적화합물 (52 mg, 87%)을 얻었다.Carried out in the same manner as in Example 8, except ethyl (6,7 - dichloro-3-methoxyquinoxalin-2-yl) carbamate (40 mg, 0.13 mmol) and 4-amino-1-benzylpiperi Dean (36 mg, 0.19 mmol) was dissolved in 1 mL of THF at room temperature, then DBU (38 mg, 0.25 mmol) was added and stirred at 45 ° C. for 14 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and then purified by silica gel column chromatography (dichloromethane: methanol, 98: 2 v / v) to obtain the target compound (52 mg, 87%).

<실시예 14><Example 14>

1-(1-피페로닐피페리딘-4-일)-3-(6,8-디클로로-3-메톡시퀴녹살린-2-일) 우레아 제조Preparation of 1- (1-piperonylpiperidin-4-yl) -3- (6,8-dichloro-3-methoxyquinoxalin-2-yl) urea

실시예 8과 동일한 방법으로 수행하되, 에틸 (6,8-디클로로-3-메톡시퀴녹살린-2-일)카르바메이트 (40 mg, 0.13 mmol)와 4-아미노-1-피페로닐피페리딘 (44 mg, 0.19 mmol)을 실온에서 THF 1 ㎖에 녹인 후, DBU (38 mg, 0.25 mmol)를 더하고 45℃에서 23 시간동안 교반하였다. 반응 종료 후에 용매를 감압 증발시킨 뒤, 실리카겔 관 크로마토그래피 (디클로로메탄:메탄올, 98:2 v/v)로 정제하여, 상기 목적화합물 (52 mg, 79%)을 얻었다.Performed in the same manner as Example 8, except for ethyl (6,8-dichloro-3-methoxyquinoxalin-2-yl) carbamate (40 mg, 0.13 mmol) and 4-amino-1-piperonylpiperi Dean (44 mg, 0.19 mmol) was dissolved in 1 mL of THF at room temperature, then DBU (38 mg, 0.25 mmol) was added and stirred at 45 ° C. for 23 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and then purified by silica gel column chromatography (dichloromethane: methanol, 98: 2 v / v) to obtain the target compound (52 mg, 79%).

<실시예 15><Example 15>

1-(1-벤질피페리딘-4-일)-3-(6,8-디클로로-3-메톡시퀴녹살린-2-일) 우레아 제조Preparation of 1- (1-benzylpiperidin-4-yl) -3- (6,8-dichloro-3-methoxyquinoxalin-2-yl) urea

실시예 8과 동일한 방법으로 수행하되, 에틸 (6,8-디클로로-3-메톡시퀴녹살린-2-일)카르바메이트 (40 mg, 0.13 mmol)와 4-아미노-1-벤질피페리딘 (36 mg, 0.19 mmol)을 실온에서 THF 1 ㎖에 녹인 후, DBU (38 mg, 0.25 mmol)를 더하고 45℃에서 13 시간동안 교반하였다. 반응 종료 후에 용매를 감압 증발시킨 뒤, 실리카겔 관 크로마토그래피 (디클로로메탄:메탄올, 98:2 v/v)로 정제하여, 상기 목적화합물 (53 mg, 88%)을 얻었다.Performed in the same manner as Example 8, except for ethyl (6,8-dichloro-3-methoxyquinoxalin-2-yl) carbamate (40 mg, 0.13 mmol) and 4-amino-1-benzylpiperidine (36 mg, 0.19 mmol) was dissolved in 1 mL of THF at room temperature, then DBU (38 mg, 0.25 mmol) was added and stirred at 45 ° C. for 13 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and then purified by silica gel column chromatography (dichloromethane: methanol, 98: 2 v / v) to obtain the target compound (53 mg, 88%).

<실시예 16><Example 16>

1-(1-피페로닐피페리딘-4-일)-3-(5,7-디클로로-3-메톡시퀴녹살린-2-일) 우레아 제조Preparation of 1- (1-piperonylpiperidin-4-yl) -3- (5,7-dichloro-3-methoxyquinoxalin-2-yl) urea

실시예 1과 동일한 방법으로 수행하되, 페닐 (5,7-디클로로-3-메톡시퀴녹살린-2-일)카르바메이트 (24 mg, 0.066 mmol)와 4-아미노-1-피페로닐피페리딘 (23 mg, 0.10 mmol)을 실온에서 THF 1 ㎖와 DMF 1 ㎖의 혼합용매에 녹인 후, DIEA (9 mg, 0.07 mmol)를 더하고 같은 온도에서 15 시간동안 교반하였다. 반응 종료 후에 용매를 감압 증발시킨 뒤, 실리카겔 관 크로마토그래피 (디클로로메탄:에탄올, 30:1 v/v)로 정제하여, 상기 목적화합물 (23 mg, 69%)을 얻었다.Performed in the same manner as in Example 1, except for phenyl (5,7-dichloro-3-methoxyquinoxalin-2-yl) carbamate (24 mg, 0.066 mmol) and 4-amino-1-piperonylpiperi Dean (23 mg, 0.10 mmol) was dissolved in a mixed solvent of 1 mL of THF and 1 mL of DMF at room temperature, and then DIEA (9 mg, 0.07 mmol) was added and stirred at the same temperature for 15 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and then purified by silica gel column chromatography (dichloromethane: ethanol, 30: 1 v / v) to obtain the target compound (23 mg, 69%).

<실시예 17><Example 17>

1-(1-피페로닐피페리딘-4-일)-3-(3-메톡시-7-메틸퀴녹살린-2-일) 우레아 제조Preparation of 1- (1-piperonylpiperidin-4-yl) -3- (3-methoxy-7-methylquinoxalin-2-yl) urea

실시예 1과 동일한 방법으로 수행하되, 페닐 (3-메톡시-7-메틸퀴녹살린-2-일)카르바메이트 (45 mg, 0.15 mmol)와 4-아미노-1-피페로닐피페리딘 (51 mg, 0.22 mmol)을 실온에서 THF 1 ㎖와 DMF 1 ㎖의 혼합용매에 녹인 후, DIEA (20 mg, 0.16 mmol)를 더하고 같은 온도에서 15 시간동안 교반하였다. 반응 종료 후에 용매를 감압 증발시킨 뒤, 실리카겔 관 크로마토그래피 (디클로로메탄:에탄올, 30:1 v/v)로 정제하여, 상기 목적화합물 (56 mg, 83%)을 얻었다.Performed in the same manner as in Example 1, except that phenyl (3-methoxy-7-methylquinoxalin-2-yl) carbamate (45 mg, 0.15 mmol) and 4-amino-1-piperonylpiperidine ( 51 mg, 0.22 mmol) was dissolved in a mixed solvent of 1 mL of THF and 1 mL of DMF at room temperature, and then DIEA (20 mg, 0.16 mmol) was added thereto and stirred at the same temperature for 15 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and then purified by silica gel column chromatography (dichloromethane: ethanol, 30: 1 v / v) to obtain the target compound (56 mg, 83%).

<실시예 18>&Lt; Example 18 >

1-(1-벤질피페리딘-4-일)-3-(3-메톡시-7-메틸퀴녹살린-2-일) 우레아 제조Preparation of 1- (1-benzylpiperidin-4-yl) -3- (3-methoxy-7-methylquinoxalin-2-yl) urea

실시예 1과 동일한 방법으로 수행하되, 페닐 (3-메톡시-7-메틸퀴녹살린-2-일)카르바메이트 (30 mg, 0.10 mmol)와 4-아미노-1-벤질피페리딘 (28 mg, 0.15 mmol)을 실온에서 THF 1 ㎖에 녹인 후, DIEA (14 mg, 0.11 mmol)를 더하고 같은 온도에서 15 시간동안 교반하였다. 반응 종료 후에 용매를 감압 증발시킨 뒤, 실리카겔 관 크 로마토그래피 (디클로로메탄:에탄올, 30:1 v/v)로 정제하여, 상기 목적화합물 (24 mg, 58%)을 얻었다.Performed in the same manner as in Example 1, except for phenyl (3-methoxy-7-methylquinoxalin-2-yl) carbamate (30 mg, 0.10 mmol) and 4-amino-1-benzylpiperidine (28 mg, 0.15 mmol) was dissolved in 1 mL of THF at room temperature, and then DIEA (14 mg, 0.11 mmol) was added and stirred at the same temperature for 15 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and then purified by silica gel column chromatography (dichloromethane: ethanol, 30: 1 v / v) to obtain the target compound (24 mg, 58%).

<실시예 19>&Lt; Example 19 >

1-(1-피페로닐피페리딘-4-일)-3-(3-메톡시-6-메틸퀴녹살린-2-일) 우레아 제조Preparation of 1- (1-piperonylpiperidin-4-yl) -3- (3-methoxy-6-methylquinoxalin-2-yl) urea

실시예 8과 동일한 방법으로 수행하되, 에틸 (3-메톡시-6-메틸퀴녹살린-2-일)카르바메이트 (40 mg, 0.15 mmol)와 4-아미노-1-피페로닐피페리딘 (54 mg, 0.23 mmol)을 실온에서 THF 1 ㎖에 녹인 후, DBU (47 mg, 0.31 mmol)를 더하고 45℃에서 23 시간동안 교반하였다. 반응 종료 후에 용매를 감압 증발시킨 뒤, 실리카겔 관 크로마토그래피 (디클로로메탄:메탄올, 98:2 v/v)로 정제하여, 상기 목적화합물 (61 mg, 90%)을 얻었다.In the same manner as in Example 8, except that ethyl (3-methoxy-6-methylquinoxalin-2-yl) carbamate (40 mg, 0.15 mmol) and 4-amino-1-piperonylpiperidine ( 54 mg, 0.23 mmol) was dissolved in 1 mL of THF at room temperature, then DBU (47 mg, 0.31 mmol) was added and stirred at 45 ° C. for 23 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and then purified by silica gel column chromatography (dichloromethane: methanol, 98: 2 v / v) to obtain the target compound (61 mg, 90%).

<실시예 20>Example 20

1-(1-벤질피페리딘-4-일)-3-(3-메톡시-6-메틸퀴녹살린-2-일) 우레아 제조Preparation of 1- (1-benzylpiperidin-4-yl) -3- (3-methoxy-6-methylquinoxalin-2-yl) urea

실시예 8과 동일한 방법으로 수행하되, 에틸 (3-메톡시-6-메틸퀴녹살린-2-일)카르바메이트 (40 mg, 0.15 mmol)와 4-아미노-1-벤질피페리딘 (44 mg, 0.23 mmol)을 실온에서 THF 1 ㎖에 녹인 후, DBU (47 mg, 0.31 mmol)를 더하고 45℃에서 13 시간동안 교반하였다. 반응 종료 후에 용매를 감압 증발시킨 뒤, 실리카겔 관 크로마토그래피 (디클로로메탄:메탄올, 98:2 v/v)로 정제하여, 상기 목적화합물 (43 mg, 71%)을 얻었다.Performed in the same manner as in Example 8, except that ethyl (3-methoxy-6-methylquinoxalin-2-yl) carbamate (40 mg, 0.15 mmol) and 4-amino-1-benzylpiperidine (44 mg, 0.23 mmol) was dissolved in 1 mL of THF at room temperature, then DBU (47 mg, 0.31 mmol) was added and stirred at 45 ° C. for 13 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and then purified by silica gel column chromatography (dichloromethane: methanol, 98: 2 v / v) to obtain the target compound (43 mg, 71%).

<실시예 21>Example 21

1-(1-피페로닐피페리딘-4-일)-3-(3-메톡시-6,7-디메틸퀴녹살린-2-일)우레아 제조Preparation of 1- (1-piperonylpiperidin-4-yl) -3- (3-methoxy-6,7-dimethylquinoxalin-2-yl) urea

실시예 1과 동일한 방법으로 수행하되, 페닐 (3-메톡시-6,7-디메틸퀴녹살린-2-일)카르바메이트 (30 mg, 0.093 mmol)와 4-아미노-1-피페로닐피페리딘 (33 mg, 0.14 mmol)을 실온에서 THF 1 ㎖와 DMF 1 ㎖의 혼합용매에 녹인 후, DIEA (13 mg, 0.10 mmol)를 더하고 같은 온도에서 15 시간동안 교반하였다. 반응 종료 후에 용매를 감압 증발시킨 뒤, 실리카겔 관 크로마토그래피 (디클로로메탄:에탄올, 30:1 v/v)로 정제하여, 상기 목적화합물 (19 mg, 44%)을 얻었다.Performed in the same manner as in Example 1, except for phenyl (3-methoxy-6,7-dimethylquinoxalin-2-yl) carbamate (30 mg, 0.093 mmol) and 4-amino-1-piperonylpiperi Dean (33 mg, 0.14 mmol) was dissolved in a mixed solvent of 1 mL of THF and 1 mL of DMF at room temperature, and then DIEA (13 mg, 0.10 mmol) was added and stirred at the same temperature for 15 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and then purified by silica gel column chromatography (dichloromethane: ethanol, 30: 1 v / v) to obtain the target compound (19 mg, 44%).

<실시예 22><Example 22>

1-(1-피페로닐피페리딘-4-일)-3-(3-메톡시-8-메틸퀴녹살린-2-일) 우레아 제조Preparation of 1- (1-piperonylpiperidin-4-yl) -3- (3-methoxy-8-methylquinoxalin-2-yl) urea

실시예 8과 동일한 방법으로 수행하되, 에틸 (3-메톡시-8-메틸퀴녹살린-2-일)카르바메이트 (40 mg, 0.15 mmol)와 4-아미노-1-피페로닐피페리딘 (54 mg, 0.23 mmol)을 실온에서 THF 1 ㎖에 녹인 후, DBU (47 mg, 0.31 mmol)를 더하고 45℃에서 23 시간동안 교반하였다. 반응 종료 후에 용매를 감압 증발시킨 뒤, 실리카겔 관 크로마토그래피 (디클로로메탄:메탄올, 98:2 v/v)로 정제하여, 상기 목적화합물 (50 mg, 74%)을 얻었다.In the same manner as in Example 8, except that ethyl (3-methoxy-8-methylquinoxalin-2-yl) carbamate (40 mg, 0.15 mmol) and 4-amino-1-piperonylpiperidine ( 54 mg, 0.23 mmol) was dissolved in 1 mL of THF at room temperature, then DBU (47 mg, 0.31 mmol) was added and stirred at 45 ° C. for 23 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and then purified by silica gel column chromatography (dichloromethane: methanol, 98: 2 v / v) to obtain the target compound (50 mg, 74%).

<실시예 23><Example 23>

1-(1-벤질피페리딘-4-일)-3-(3-메톡시-8-메틸퀴녹살린-2-일) 우레아 제조Preparation of 1- (1-benzylpiperidin-4-yl) -3- (3-methoxy-8-methylquinoxalin-2-yl) urea

실시예 8과 동일한 방법으로 수행하되, 에틸 (3-메톡시-8-메틸퀴녹살린-2-일)카르바메이트 (40 mg, 0.15 mmol)와 4-아미노-1-벤질피페리딘 (44 mg, 0.23 mmol)을 실온에서 THF 1 ㎖에 녹인 후, DBU (47 mg, 0.31 mmol)를 더하고 45℃에서 13 시간동안 교반하였다. 반응 종료 후에 용매를 감압 증발시킨 뒤, 실리카겔 관 크로마토 그래피 (디클로로메탄:메탄올, 98:2 v/v)로 정제하여, 상기 목적화합물 (57 mg, 94%)을 얻었다.Performed in the same manner as in Example 8, except ethyl (3-methoxy-8-methylquinoxalin-2-yl) carbamate (40 mg, 0.15 mmol) and 4-amino-1-benzylpiperidine (44 mg, 0.23 mmol) was dissolved in 1 mL of THF at room temperature, then DBU (47 mg, 0.31 mmol) was added and stirred at 45 ° C. for 13 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and then purified by silica gel column chromatography (dichloromethane: methanol, 98: 2 v / v) to obtain the target compound (57 mg, 94%).

<실시예 24><Example 24>

1-(1-피페로닐피페리딘-4-일)-3-(3,7-디메톡시퀴녹살린-2-일) 우레아 제조Preparation of 1- (1-piperonylpiperidin-4-yl) -3- (3,7-dimethoxyquinoxalin-2-yl) urea

실시예 1과 동일한 방법으로 수행하되, 페닐 (3,7-디메톡시퀴녹살린-2-일)카르바메이트 (30 mg, 0.092 mmol)와 4-아미노-1-피페로닐피페리딘 (32 mg, 0.14 mmol)을 실온에서 THF 1 ㎖와 DMF 1 ㎖의 혼합용매에 녹인 후, DIEA (13 mg, 0.10 mmol)를 더하고 같은 온도에서 15 시간동안 교반하였다. 반응 종료 후에 용매를 감압 증발시킨 뒤, 실리카겔 관 크로마토그래피 (디클로로메탄:에탄올, 30:1 v/v)로 정제하여, 상기 목적화합물 (25 mg, 58%)을 얻었다.Performed in the same manner as in Example 1, except for phenyl (3,7-dimethoxyquinoxalin-2-yl) carbamate (30 mg, 0.092 mmol) and 4-amino-1-piperonylpiperidine (32 mg , 0.14 mmol) was dissolved in a mixed solvent of 1 mL of THF and 1 mL of DMF at room temperature, and then DIEA (13 mg, 0.10 mmol) was added thereto and stirred at the same temperature for 15 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and then purified by silica gel column chromatography (dichloromethane: ethanol, 30: 1 v / v) to obtain the target compound (25 mg, 58%).

<실시예 25><Example 25>

1-(1-벤질피페리딘-4-일)-3-(3,7-디메톡시퀴녹살린-2-일) 우레아 제조Preparation of 1- (1-benzylpiperidin-4-yl) -3- (3,7-dimethoxyquinoxalin-2-yl) urea

실시예 1과 동일한 방법으로 수행하되, 페닐 (3,7-디메톡시퀴녹살린-2-일)카르바메이트 (30 mg, 0.092 mmol)와 4-아미노-1-벤질피페리딘 (27 mg, 0.14 mmol)을 실온에서 THF 1 ㎖에 녹인 후, DIEA (13 mg, 0.10 mmol)를 더하고 같은 온도에서 15 시간동안 교반하였다. 반응 종료 후에 용매를 감압 증발시킨 뒤, 실리카겔 관 크로마토그래피 (디클로로메탄:에탄올, 30:1 v/v)로 정제하여, 상기 목적화합물 (34 mg, 88%)을 얻었다.In the same manner as in Example 1, except that phenyl (3,7-dimethoxyquinoxalin-2-yl) carbamate (30 mg, 0.092 mmol) and 4-amino-1-benzylpiperidine (27 mg, 0.14 mmol) was dissolved in 1 mL of THF at room temperature, and then DIEA (13 mg, 0.10 mmol) was added and stirred at the same temperature for 15 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and then purified by silica gel column chromatography (dichloromethane: ethanol, 30: 1 v / v) to obtain the target compound (34 mg, 88%).

<실시예 26><Example 26>

1-(1-피페로닐피페리딘-4-일)-3-(3-에톡시-7-메톡시퀴녹살린-2-일) 우레아 제조Preparation of 1- (1-piperonylpiperidin-4-yl) -3- (3-ethoxy-7-methoxyquinoxalin-2-yl) urea

페닐 (3-에톡시-7-메톡시퀴녹살린-2-일)카르바메이트 (30 mg, 0.088 mmol)와 4-아미노-1-피페로닐피페리딘 (23 mg, 0.098 mmol)을 실온에서 THF 1.5 ㎖에 녹인 후, DBU (20 mg, 0.13 mmol)를 더하고 같은 온도에서 13 시간동안 교반하였다. 반응 종료 후에 용매를 감압 증발시킨 뒤, 실리카겔 관 크로마토그래피 (디클로로메탄:에탄올, 30:1 v/v)로 정제하여, 상기 목적화합물 (30 mg, 72%)을 얻었다.Phenyl (3-ethoxy-7-methoxyquinoxalin-2-yl) carbamate (30 mg, 0.088 mmol) and 4-amino-1-piperonylpiperidine (23 mg, 0.098 mmol) at room temperature After dissolving in 1.5 mL of THF, DBU (20 mg, 0.13 mmol) was added and stirred at the same temperature for 13 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and then purified by silica gel column chromatography (dichloromethane: ethanol, 30: 1 v / v) to obtain the target compound (30 mg, 72%).

<실시예 27>Example 27

1-(1-벤질피페리딘-4-일)-3-(3-에톡시-7-메톡시퀴녹살린-2-일) 우레아 제조Preparation of 1- (1-benzylpiperidin-4-yl) -3- (3-ethoxy-7-methoxyquinoxalin-2-yl) urea

실시예 26과 동일한 방법으로 수행하되, 페닐 (3-에톡시-7-메톡시퀴녹살린-2-일)카르바메이트 (30 mg, 0.088 mmol)와 4-아미노-1-벤질피페리딘 (19 mg, 0.10 mmol)을 실온에서 THF 1 ㎖에 녹인 후, DBU (20 mg, 0.13 mmol)를 더하고 같은 온도에서 13 시간동안 교반하였다. 반응 종료 후에 용매를 감압 증발시킨 뒤, 실리카겔 관 크로마토그래피 (디클로로메탄:에탄올, 30:1 v/v)로 정제하여, 상기 목적화합물 (34 mg, 90%)을 얻었다.In the same manner as in Example 26, except for phenyl (3-ethoxy-7-methoxyquinoxalin-2-yl) carbamate (30 mg, 0.088 mmol) and 4-amino-1-benzylpiperidine ( 19 mg, 0.10 mmol) was dissolved in 1 mL of THF at room temperature, then DBU (20 mg, 0.13 mmol) was added and stirred at the same temperature for 13 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and then purified by silica gel column chromatography (dichloromethane: ethanol, 30: 1 v / v) to obtain the target compound (34 mg, 90%).

<실시예 28><Example 28>

1-(1-피페로닐피페리딘-4-일)-3-(3-아이소프로폭시-7-메톡시퀴녹살린-2-일) 우레아 제조Preparation of 1- (1-piperonylpiperidin-4-yl) -3- (3-isopropoxy-7-methoxyquinoxalin-2-yl) urea

실시예 26과 동일한 방법으로 수행하되, 페닐 (3-아이소프로폭시-7-메톡시퀴녹살린-2-일)카르바메이트 (30 mg, 0.085 mmol)와 4-아미노-1-피페로닐피페리딘 (22 mg, 0.094 mmol)을 실온에서 THF 1 ㎖에 녹인 후, DBU (19 mg, 0.13 mmol)를 더하고 같은 온도에서 1 시간동안 교반하였다. 반응 종료 후에 용매를 감압 증발시킨 뒤, 실리카겔 관 크로마토그래피 (디클로로메탄:에탄올, 30:1 v/v)로 정제하여, 상기 목적화합물 (36 mg, 85%)을 얻었다.Performed in the same manner as in Example 26, except for phenyl (3-isopropoxy-7-methoxyquinoxalin-2-yl) carbamate (30 mg, 0.085 mmol) and 4-amino-1-piperonylpiperi Dean (22 mg, 0.094 mmol) was dissolved in 1 mL of THF at room temperature, then DBU (19 mg, 0.13 mmol) was added and stirred at the same temperature for 1 hour. After completion of the reaction, the solvent was evaporated under reduced pressure, and then purified by silica gel column chromatography (dichloromethane: ethanol, 30: 1 v / v) to obtain the target compound (36 mg, 85%).

<실시예 29><Example 29>

1-(1-벤질피페리딘-4-일)-3-(3-아이소프로폭시-7-메톡시퀴녹살린-2-일) 우레아 제조Preparation of 1- (1-benzylpiperidin-4-yl) -3- (3-isopropoxy-7-methoxyquinoxalin-2-yl) urea

실시예 26과 동일한 방법으로 수행하되, 페닐 (3-아이소프로폭시-7-메톡시퀴녹살린-2-일)카르바메이트 (30 mg, 0.085 mmol)와 4-아미노-1-벤질피페리딘 (18 mg, 0.095 mmol)을 실온에서 THF 1 ㎖에 녹인 후, DBU (19 mg, 0.13 mmol)를 더하고 같은 온도에서 1 시간동안 교반하였다. 반응 종료 후에 용매를 감압 증발시킨 뒤, 실리카겔 관 크로마토그래피 (디클로로메탄:에탄올, 30:1 v/v)로 정제하여, 상기 목적화합물 (30 mg, 78%)을 얻었다.Performed in the same manner as in Example 26, except for phenyl (3-isopropoxy-7-methoxyquinoxalin-2-yl) carbamate (30 mg, 0.085 mmol) and 4-amino-1-benzylpiperidine (18 mg, 0.095 mmol) was dissolved in 1 mL of THF at room temperature, then DBU (19 mg, 0.13 mmol) was added and stirred at the same temperature for 1 hour. After completion of the reaction, the solvent was evaporated under reduced pressure, and then purified by silica gel column chromatography (dichloromethane: ethanol, 30: 1 v / v) to obtain the target compound (30 mg, 78%).

<실시예 30><Example 30>

1-(1-피페로닐피페리딘-4-일)-3-[7-메톡시-3-(2,2,2-트리플루오르에톡시)퀴녹살린-2-일] 우레아 제조Preparation of 1- (1-piperonylpiperidin-4-yl) -3- [7-methoxy-3- (2,2,2-trifluoroethoxy) quinoxalin-2-yl] urea

실시예 26과 동일한 방법으로 수행하되, 페닐 [3-(2,2,2-트리플루오르에톡시)-7-메톡시퀴녹살린-2-일]카르바메이트 (30 mg, 0.076 mmol)와 4-아미노-1-피페로닐피페리딘 (20 mg, 0.085 mmol)을 실온에서 THF 1 ㎖에 녹인 후, DBU (17 mg, 0.11 mmol)를 더하고 같은 온도에서 3 시간동안 교반하였다. 반응 종료 후에 용매를 감압 증발시킨 뒤, 실리카겔 관 크로마토그래피 (디클로로메탄:에탄올, 30:1 v/v)로 정제하여, 상기 목적화합물 (35 mg, 86%)을 얻었다.In the same manner as in Example 26, except for phenyl [3- (2,2,2- trifluoroethoxy ) -7-methoxyquinoxalin-2-yl] carbamate (30 mg, 0.076 mmol) and 4 -Amino-1-piperonylpiperidine (20 mg, 0.085 mmol) was dissolved in 1 mL of THF at room temperature, then DBU (17 mg, 0.11 mmol) was added and stirred at the same temperature for 3 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and then purified by silica gel column chromatography (dichloromethane: ethanol, 30: 1 v / v) to obtain the target compound (35 mg, 86%).

<실시예 31><Example 31>

1-(1-벤질피페리딘-4-일)-3-[7-메톡시-3-(2,2,2-트리플루오르에톡시)퀴녹살린-2-일] 우레아 제조Preparation of 1- (1-benzylpiperidin-4-yl) -3- [7-methoxy-3- (2,2,2-trifluoroethoxy) quinoxalin-2-yl] urea

실시예 26과 동일한 방법으로 수행하되, 페닐 [3-(2,2,2-트리플루오르에톡시)-7-메톡시퀴녹살린-2-일]카르바메이트 (30 mg, 0.076 mmol)와 4-아미노-1-벤질피페리딘 (16 mg, 0.084 mmol)을 실온에서 THF 1 ㎖에 녹인 후, DBU (17 mg, 0.11 mmol)를 더하고 같은 온도에서 3 시간동안 교반하였다. 반응 종료 후에 용매를 감압 증발시킨 뒤, 실리카겔 관 크로마토그래피 (디클로로메탄:에탄올, 30:1 v/v)로 정제하여, 상기 목적화합물 (25 mg, 68%)을 얻었다.In the same manner as in Example 26, except for phenyl [3- (2,2,2-trifluoroethoxy) -7-methoxyquinoxalin-2-yl] carbamate (30 mg, 0.076 mmol) and 4 -Amino-1-benzylpiperidine (16 mg, 0.084 mmol) was dissolved in 1 mL of THF at room temperature, then DBU (17 mg, 0.11 mmol) was added and stirred at the same temperature for 3 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and then purified by silica gel column chromatography (dichloromethane: ethanol, 30: 1 v / v) to obtain the target compound (25 mg, 68%).

<실시예 32><Example 32>

1-[1-(4-메톡시벤질)피페리딘-4-일]-3-[7-메톡시-3-(2,2,2-트리플루오르에톡시)퀴녹살린-2-일] 우레아 제조1- [1- (4-methoxybenzyl) piperidin-4-yl] -3- [7-methoxy-3- (2,2,2-trifluoroethoxy) quinoxalin-2-yl] Urea manufacturing

실시예 26과 동일한 방법으로 수행하되, 페닐 [3-(2,2,2-트리플루오르에톡시)-7-메톡시퀴녹살린-2-일]카르바메이트 (30 mg, 0.076 mmol)와 4-아미노-1-(4-메톡시벤질)피페리딘 (18 mg, 0.082 mmol)을 실온에서 THF 1 ㎖에 녹인 후, DBU (17 mg, 0.11 mmol)를 더하고 같은 온도에서 3 시간동안 교반하였다. 반응 종료 후에 용매를 감압 증발시킨 뒤, 실리카겔 관 크로마토그래피 (디클로로메탄:에탄올, 30:1 v/v)로 정제하여, 상기 목적화합물 (35 mg, 88%)을 얻었다.In the same manner as in Example 26, except for phenyl [3- (2,2,2-trifluoroethoxy) -7-methoxyquinoxalin-2-yl] carbamate (30 mg, 0.076 mmol) and 4 -Amino-1- (4-methoxybenzyl) piperidine (18 mg, 0.082 mmol) was dissolved in 1 mL of THF at room temperature, then DBU (17 mg, 0.11 mmol) was added and stirred at the same temperature for 3 hours. . After completion of the reaction, the solvent was evaporated under reduced pressure, and then purified by silica gel column chromatography (dichloromethane: ethanol, 30: 1 v / v) to obtain the target compound (35 mg, 88%).

<실시예 33><Example 33>

1-[1-(2-메톡시벤질)피페리딘-4-일]-3-[7-메톡시-3-(2,2,2-트리플루오르에톡시)퀴 녹살린-2-일] 우레아 제조1- [1- (2-methoxybenzyl) piperidin-4-yl] -3- [7-methoxy-3- (2,2,2-trifluoroethoxy) quinoxalin-2-yl Urea manufacturing

실시예 26과 동일한 방법으로 수행하되, 페닐 [3-(2,2,2-트리플루오르에톡시)-7-메톡시퀴녹살린-2-일]카르바메이트 (30 mg, 0.076 mmol)와 4-아미노-1-(2-메톡시벤질)피페리딘 (18 mg, 0.082 mmol)을 실온에서 THF 1 ㎖에 녹인 후, DBU (17 mg, 0.11 mmol)를 더하고 같은 온도에서 3 시간동안 교반하였다. 반응 종료 후에 용매를 감압 증발시킨 뒤, 실리카겔 관 크로마토그래피 (디클로로메탄:에탄올, 30:1 v/v)로 정제하여, 상기 목적화합물 (28 mg, 71%)을 얻었다.In the same manner as in Example 26, except for phenyl [3- (2,2,2-trifluoroethoxy) -7-methoxyquinoxalin-2-yl] carbamate (30 mg, 0.076 mmol) and 4 -Amino-1- (2-methoxybenzyl) piperidine (18 mg, 0.082 mmol) was dissolved in 1 mL of THF at room temperature, then DBU (17 mg, 0.11 mmol) was added and stirred at the same temperature for 3 hours. . After completion of the reaction, the solvent was evaporated under reduced pressure, and then purified by silica gel column chromatography (dichloromethane: ethanol, 30: 1 v / v) to obtain the target compound (28 mg, 71%).

<실시예 34><Example 34>

1-[1-(4-아세톡시벤질)피페리딘-4-일]-3-(3,7-디메톡시퀴녹살린-2-일) 우레아 제조Preparation of 1- [1- (4-acetoxybenzyl) piperidin-4-yl] -3- (3,7-dimethoxyquinoxalin-2-yl) urea

(a) 단계: 1-[1-(4-t-부톡시카르보닐)피페리딘-4-일]-3-(3,7-디메톡시퀴녹살린-2-일) 우레아 제조(a) step: preparing 1- [1- (4- t -butoxycarbonyl) piperidin-4-yl] -3- (3,7-dimethoxyquinoxalin-2-yl) urea

페닐 (3,7-디메톡시퀴녹살린-2-일)카르바메이트 (1.50 g, 4.61 mmol)와 4-아미노-1-B℃-피페리딘 (1.10 g, 5.49 mmol)을 실온에서 THF 80 ㎖에 녹인 후, DIEA (715 mg, 5.53 mmol)를 더하고 같은 온도에서 5 시간동안 교반하였다. 반응 종료 후에 반응 혼합물에 물을 더하고 에틸 아세이트로 추출하였다. 에틸 아세이트 층을 마그네슘 설페이트를 이용하여 건조한 다음 용매를 감압 증발시킨 뒤, 잔류물을 n-헥산과 디클로로메탄 혼합용매에서 재결정하여, 상기 목적화합물 (1.70 g, 85%)을 얻었다.Phenyl (3,7-dimethoxyquinoxalin-2-yl) carbamate (1.50 g, 4.61 mmol) and 4-amino-1-B ° C-piperidine (1.10 g, 5.49 mmol) at room temperature THF 80 After dissolving in ㎖, DIEA (715 mg, 5.53 mmol) was added and stirred at the same temperature for 5 hours. After the reaction was completed, water was added to the reaction mixture, which was then extracted with ethyl acetate. The ethyl acetate layer was dried using magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was recrystallized from a mixed solvent of n -hexane and dichloromethane to obtain the target compound (1.70 g, 85%).

1H NMR (500 MHz, CDCl3) δ 1.49 (9H, s), 1.60 (2H, m), 2.08 (2H, m), 3.08 (2H, m), 3.93 (3H, s), 4.00-4.08 (3H, m), 4.10 (3H, s), 6.98 (1H, d, J = 2.7 Hz), 7.14 (1H, dd, J = 9.0 and 2.7 Hz), 7.63 (1H, d, J = 9.0 Hz), 7.67 (1H, br s), 9.58 (1H, br d, J = 7.4 Hz). MS (ESI) m/z 432 ([M+H]+). 1 H NMR (500 MHz, CDCl 3 ) δ 1.49 (9H, s), 1.60 (2H, m), 2.08 (2H, m), 3.08 (2H, m), 3.93 (3H, s), 4.00-4.08 ( 3H, m), 4.10 (3H, s), 6.98 (1H, d, J = 2.7 Hz), 7.14 (1H, dd, J = 9.0 and 2.7 Hz), 7.63 (1H, d, J = 9.0 Hz), 7.67 (1H, broad singlet), 9.58 (1H, broad doublet, J = 7.4 Hz). MS (ESI) m / z 432 ([M + H] + ).

(b) 단계: 1-(3,7-디메톡시퀴녹살린-2-일)-3-피페리딘-4-일 우레아 제조(b) Step: Preparation of 1- (3,7-dimethoxyquinoxalin-2-yl) -3-piperidin-4-yl urea

1-[1-(4-t-부톡시카르보닐)피페리딘-4-일]-3-(3,7-디메톡시퀴녹살린-2-일) 우레아 (1.70 g, 3.94 mmol)를 실온에서 50% TFA/DCM 용액 100 ㎖으로 처리하여 30 분동안 교반하였다. 반응 종료 후에 용매를 감압 증발하고 잔류물을 소듐 바이카르보네이트 포화 수용액으로 처리하여 중화시켰다. 중화된 혼합물을 에틸 아세테이트로 추출한 다음, 마그네슘 설페이트로 건조하고 용매를 감압 증발하였다. 잔류물을 실리카겔 관 크로마토그래피 (디클로로메탄:에탄올, 10:1 v/v)로 정제하여, 상기 목적화합물 (1.11 g, 85%)을 얻었다. 1- [1- (4-t-butoxycarbonyl) piperidin-4-yl] -3- (3,7-dimethoxyquinoxalin-2-yl) urea (1.70 g, 3.94 mmol) was cooled to room temperature. Treated with 100 mL of 50% TFA / DCM solution at and stirred for 30 minutes. After completion of the reaction, the solvent was evaporated under reduced pressure and the residue was neutralized by treatment with saturated aqueous sodium bicarbonate solution. The neutralized mixture was extracted with ethyl acetate, then dried over magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: ethanol, 10: 1 v / v) to afford the target compound (1.11 g, 85%).

1H NMR (500 MHz, CDCl3) δ 1.60 (2H, m), 2.11 (2H, m), 2.81 (2H, m), 3.17 (2H, m), 3.93 (3H, s), 3.998 (1H, m), 4.11 (3H, s), 7.02 (1H, d, J = 2.7 Hz), 7.15 (1H, dd, J = 9.0 and 2.7 Hz), 7.62 (1H, br s), 7.64 (1H, d, J = 9.0 Hz), 9.60 (1H, br d, J = 7.7 Hz). MS (ESI) m/z 332 ([M+H]+). 1 H NMR (500 MHz, CDCl 3 ) δ 1.60 (2H, m), 2.11 (2H, m), 2.81 (2H, m), 3.17 (2H, m), 3.93 (3H, s), 3.998 (1H, m), 4.11 (3H, s), 7.02 (1H, d, J = 2.7 Hz), 7.15 (1H, dd, J = 9.0 and 2.7 Hz), 7.62 (1H, br s), 7.64 (1H, d, J = 9.0 Hz), 9.60 (1H, broad doublet, J = 7.7 Hz). MS (ESI) m / z 332 ([M + H] + ).

(c) 단계: 1-[1-(4-아세톡시벤질)피페리딘-4-일]-3-(3,7-디메톡시퀴녹살린-2-일) 우레아(c) step: 1- [1- (4-acetoxybenzyl) piperidin-4-yl] -3- (3,7-dimethoxyquinoxalin-2-yl) urea

실온에서 1-(3,7-디메톡시퀴녹살린-2-일)-3-피페리딘-4-일 우레아 (20 mg, 0.060 mmol)와 4-아세톡시벤즈알데히드 (15 mg, 0.090 mmol)를 디클로로메탄 (3 ㎖)에 넣은 다음 NaBH(OAc)3 (19 mg, 0.090 mmol) 로 처리하고 같은 온도에서 24 시간 동안 교반하였다. 반응 종료 후에 소듐 바이카르보네이트 포화 수용액을 다하고 디클로로메탄으로 추출하였다. 유기층을 마그네슘 설페이트로 건조한 뒤 용매를 감압 증발하고 잔류물을 실리카겔 관 크로마토그래피(에틸 아세테이트)로 정제하여, 상기 목적화합물 (22 mg, 75%)을 얻었다.1- (3,7-dimethoxyquinoxalin-2-yl) -3-piperidin-4-yl urea (20 mg, 0.060 mmol) and 4-acetoxybenzaldehyde (15 mg, 0.090 mmol) at room temperature Dichloromethane (3 mL) was then treated with NaBH (OAc) 3 (19 mg, 0.090 mmol) and stirred at the same temperature for 24 hours. After completion of the reaction, saturated aqueous sodium bicarbonate solution was exhausted and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to obtain the target compound (22 mg, 75%).

<실시예 35><Example 35>

1-(3,7-디메톡시퀴녹살린-2-일)-3-[1-(4-메톡시벤질)피페리딘-4-일] 우레아 제조Preparation of 1- (3,7-dimethoxyquinoxalin-2-yl) -3- [1- (4-methoxybenzyl) piperidin-4-yl] urea

실시예 34(c)와 동일한 방법으로 수행하되, 실시예 34(a)-(b)를 통해 얻은 1-(3,7-디메톡시퀴녹살린-2-일)-3-피페리딘-4-일 우레아 (20 mg, 0.060 mmol)와 4-메톡시벤즈알데히드 (12 mg, 0.090 mmol)를 실온에서 디클로로메탄 3 ㎖에 넣은 다음 NaBH(OAc)3 (19 mg, 0.090 mmol)로 처리하고 같은 온도에서 24 시간 동안 교반하였다. 반응 종료 후에 소듐 바이카르보네이트 포화 수용액을 다하고 디클로로메탄으로 추출하였다. 유기층을 마그네슘 설페이트로 건조한 뒤 용매를 감압 증발하고 잔류물을 실리카겔 관 크로마토그래피 (디클로로메탄:에탄올, 20:1 v/v)로 정제하여, 상기 목적화합물 (24 mg, 87%)을 얻었다.1- (3,7-dimethoxyquinoxalin-2-yl) -3-piperidine-4 obtained in the same manner as Example 34 (c), but obtained via Examples 34 (a)-(b) -Yl urea (20 mg, 0.060 mmol) and 4-methoxybenzaldehyde (12 mg, 0.090 mmol) were added to 3 ml of dichloromethane at room temperature followed by treatment with NaBH (OAc) 3 (19 mg, 0.090 mmol) and the same temperature. Stirred for 24 h. After completion of the reaction, saturated aqueous sodium bicarbonate solution was exhausted and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: ethanol, 20: 1 v / v) to obtain the target compound (24 mg, 87%).

<실시예 36><Example 36>

1-(3,7-디메톡시퀴녹살린-2-일)-3-[1-(3-메톡시벤질)피페리딘-4-일] 우레아 제조Preparation of 1- (3,7-dimethoxyquinoxalin-2-yl) -3- [1- (3-methoxybenzyl) piperidin-4-yl] urea

실시예 34(c)와 동일한 방법으로 수행하되, 실시예 34(a)-(b)를 통해 얻은 1-(3,7- 디메톡시퀴녹살린-2-일)-3-피페리딘-4-일 우레아 (20 mg, 0.060 mmol)와 3-메톡시벤즈알데히드 (12 mg, 0.090 mmol) 를 실온에서 디클로로메탄 3 ㎖에 넣은 다음 NaBH(OAc)3 (19 mg, 0.090 mmol)로 처리하고 같은 온도에서 24 시간 동안 교반하였다. 반응 종료 후에 소듐 바이카르보네이트 포화 수용액을 다하고 디클로로메탄으로 추출하였다. 유기층을 마그네슘 설페이트로 건조한 뒤 용매를 감압 증발하고 잔류물을 실리카겔 관 크로마토그래피(에틸 아세테이트)로 정제하여, 상기 목적화합물(24 mg, 90%)을 얻었다.1- (3,7-dimethoxyquinoxalin-2-yl) -3-piperidine-4 obtained in the same manner as Example 34 (c), but obtained via Examples 34 (a)-(b) -Yl urea (20 mg, 0.060 mmol) and 3-methoxybenzaldehyde (12 mg, 0.090 mmol) were added to 3 ml of dichloromethane at room temperature followed by treatment with NaBH (OAc) 3 (19 mg, 0.090 mmol) and the same temperature. Stirred for 24 h. After completion of the reaction, saturated aqueous sodium bicarbonate solution was exhausted and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to obtain the target compound (24 mg, 90%).

<실시예 37><Example 37>

1-(3,7-디메톡시퀴녹살린-2-일)-3-[1-(2-메톡시벤질)피페리딘-4-일] 우레아 제조Preparation of 1- (3,7-dimethoxyquinoxalin-2-yl) -3- [1- (2-methoxybenzyl) piperidin-4-yl] urea

실시예 34(c)와 동일한 방법으로 수행하되, 실시예 34(a)-(b)를 통해 얻은 1-(3,7-디메톡시퀴녹살린-2-일)-3-피페리딘-4-일 우레아 (20 mg, 0.060 mmol)와 2-메톡시벤즈알데히드 (12 mg, 0.090 mmol)를 실온에서 디클로로메탄 3 ㎖에 넣은 다음 NaBH(OAc)3 (19 mg, 0.090 mmol)로 처리하고 같은 온도에서 24 시간 동안 교반하였다. 반응 종료 후에 소듐 바이카르보네이트 포화 수용액을 다하고 디클로로메탄으로 추출하였다. 유기층을 마그네슘 설페이트로 건조한 뒤 용매를 감압 증발하고 잔류물을 실리카겔 관 크로마토그래피 (디클로로메탄:에탄올, 20:1 v/v)로 정제하여, 상기 목적화합물 (20 mg, 74%)을 얻었다.1- (3,7-dimethoxyquinoxalin-2-yl) -3-piperidine-4 obtained in the same manner as Example 34 (c), but obtained via Examples 34 (a)-(b) -Yl urea (20 mg, 0.060 mmol) and 2-methoxybenzaldehyde (12 mg, 0.090 mmol) were added to 3 mL of dichloromethane at room temperature followed by treatment with NaBH (OAc) 3 (19 mg, 0.090 mmol) and the same temperature. Stirred for 24 h. After completion of the reaction, saturated aqueous sodium bicarbonate solution was exhausted and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: ethanol, 20: 1 v / v) to obtain the target compound (20 mg, 74%).

<실시예 38><Example 38>

1-[1-(4-1- [1- (4- tt -부틸벤질)피페리딘-4-일]-3-(3,7-디메톡시퀴녹살린-2-일) 우레아 제조Butylbenzyl) piperidin-4-yl] -3- (3,7-dimethoxyquinoxalin-2-yl) urea

실시예 34(c)와 동일한 방법으로 수행하되, 실시예 34(a)-(b)를 통해 얻은 1-(3,7-디메톡시퀴녹살린-2-일)-3-피페리딘-4-일 우레아 (20 mg, 0.060 mmol)와 4-t-부틸벤즈알데히드 (15 mg, 0.090 mmol)를 실온에서 디클로로메탄 3 ㎖에 넣은 다음 NaBH(OAc)3 (19 mg, 0.090 mmol)로 처리하고 같은 온도에서 24 시간 동안 교반하였다. 반응 종료 후에 소듐 바이카르보네이트 포화 수용액을 다하고 디클로로메탄으로 추출하였다. 유기층을 마그네슘 설페이트로 건조한 뒤 용매를 감압 증발하고 잔류물을 실리카겔 관 크로마토그래피(에틸 아세테이트)로 정제하여, 상기 목적화합물 (27 mg, 94%)을 얻었다.1- (3,7-dimethoxyquinoxalin-2-yl) -3-piperidine-4 obtained in the same manner as Example 34 (c), but obtained via Examples 34 (a)-(b) -Yl urea (20 mg, 0.060 mmol) and 4- t -butylbenzaldehyde (15 mg, 0.090 mmol) were added to 3 ml of dichloromethane at room temperature followed by treatment with NaBH (OAc) 3 (19 mg, 0.090 mmol) and Stir at temperature for 24 hours. After completion of the reaction, saturated aqueous sodium bicarbonate solution was exhausted and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to obtain the target compound (27 mg, 94%).

<실시예 39><Example 39>

1-[1-(3-클로로벤질)피페리딘-4-일]-3-(3,7-디메톡시퀴녹살린-2-일) 우레아 제조Preparation of 1- [1- (3-chlorobenzyl) piperidin-4-yl] -3- (3,7-dimethoxyquinoxalin-2-yl) urea

실시예 34(c)와 동일한 방법으로 수행하되, 실시예 34(a)-(b)를 통해 1-(3,7-디메톡시퀴녹살린-2-일)-3-피페리딘-4-일 우레아 (20 mg, 0.060 mmol)와 3-클로로벤즈알데히드 (13 mg, 0.090 mmol)를 실온에서 디클로로메탄 3 ㎖에 넣은 다음 NaBH(OAc)3 (19 mg, 0.090 mmol)로 처리하고 같은 온도에서 24 시간 동안 교반하였다. 반응 종료 후에 소듐 바이카르보네이트 포화 수용액을 다하고 디클로로메탄으로 추출하였다. 유기층을 마그네슘 설페이트로 건조한 뒤 용매를 감압 증발하고 잔류물을 실리카겔 관 크로마토그래피 (n-헥산:에틸 아세테이트, 1:3 v/v)로 정제하여, 상기 목적화합물 (25 mg, 91%)을 얻었다.The same procedure as in Example 34 (c), except for 1- (3,7-dimethoxyquinoxalin-2-yl) -3-piperidin-4- via Example 34 (a)-(b) Il urea (20 mg, 0.060 mmol) and 3-chlorobenzaldehyde (13 mg, 0.090 mmol) were added to 3 mL of dichloromethane at room temperature followed by treatment with NaBH (OAc) 3 (19 mg, 0.090 mmol) and 24 at the same temperature. Stir for hours. After completion of the reaction, saturated aqueous sodium bicarbonate solution was exhausted and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography ( n -hexane: ethyl acetate, 1: 3 v / v) to obtain the target compound (25 mg, 91%). .

<실시예 40><Example 40>

1-[1-(4-클로로벤질)피페리딘-4-일]-3-(3,7-디메톡시퀴녹살린-2-일) 우레아 제조Preparation of 1- [1- (4-chlorobenzyl) piperidin-4-yl] -3- (3,7-dimethoxyquinoxalin-2-yl) urea

실시예 34(c)와 동일한 방법으로 수행하되, 실시예 34(a)-(b)를 통해 1-(3,7-디메톡시퀴녹살린-2-일)-3-피페리딘-4-일 우레아 (20 mg, 0.060 mmol)와 4-클로로벤즈알데히드 (13 mg, 0.090 mmol)를 실온에서 디클로로메탄 3 ㎖에 넣은 다음 NaBH(OAc)3 (19 mg, 0.090 mmol)로 처리하고 같은 온도에서 24 시간 동안 교반하였다. 반응 종료 후에 소듐 바이카르보네이트 포화 수용액을 다하고 디클로로메탄으로 추출하였다. 유기층을 마그네슘 설페이트로 건조한 뒤 용매를 감압 증발하고 잔류물을 실리카겔 관 크로마토그래피 (n-헥산:에틸 아세테이트, 1:3 v/v)로 정제하여, 상기 목적화합물 (23 mg, 85%)을 얻었다.The same procedure as in Example 34 (c), except for 1- (3,7-dimethoxyquinoxalin-2-yl) -3-piperidin-4- via Example 34 (a)-(b) Il urea (20 mg, 0.060 mmol) and 4-chlorobenzaldehyde (13 mg, 0.090 mmol) were added to 3 mL of dichloromethane at room temperature followed by treatment with NaBH (OAc) 3 (19 mg, 0.090 mmol) and 24 at the same temperature. Stir for hours. After completion of the reaction, saturated aqueous sodium bicarbonate solution was exhausted and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography ( n -hexane: ethyl acetate, 1: 3 v / v) to obtain the target compound (23 mg, 85%). .

<실시예 41><Example 41>

1-[1-(2-시아노벤질)피페리딘-4-일]-3-(3,7-디메톡시퀴녹살린-2-일) 우레아 제조Preparation of 1- [1- (2-cyanobenzyl) piperidin-4-yl] -3- (3,7-dimethoxyquinoxalin-2-yl) urea

실시예 34(c)와 동일한 방법으로 수행하되, 실시예 34(a)-(b)를 통해 1-(3,7-디메톡시퀴녹살린-2-일)-3-피페리딘-4-일 우레아 (20 mg, 0.060 mmol)와 2-시아노벤즈알데히드 (12 mg, 0.090 mmol)를 실온에서 디클로로메탄 3 ㎖에 넣은 다음 NaBH(OAc)3 (19 mg, 0.090 mmol)로 처리하고 같은 온도에서 24 시간 동안 교반하였다. 반응 종료 후에 소듐 바이카르보네이트 포화 수용액을 다하고 디클로로메탄으로 추출하였다. 유기층을 마그네슘 설페이트로 건조한 뒤 용매를 감압 증발하고 잔류물을 실리카겔 관 크로마토그래피 (n-헥산:에틸 아세테이트, 1:3 v/v)로 정제하여, 상기 목적화합물 (25 mg, 94%)을 얻었다.The same procedure as in Example 34 (c), except for 1- (3,7-dimethoxyquinoxalin-2-yl) -3-piperidin-4- via Example 34 (a)-(b) Il urea (20 mg, 0.060 mmol) and 2-cyanobenzaldehyde (12 mg, 0.090 mmol) were added to 3 ml of dichloromethane at room temperature followed by treatment with NaBH (OAc) 3 (19 mg, 0.090 mmol) and at the same temperature. Stir for 24 hours. After completion of the reaction, saturated aqueous sodium bicarbonate solution was exhausted and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography ( n -hexane: ethyl acetate, 1: 3 v / v) to obtain the target compound (25 mg, 94%). .

<실시예 42><Example 42>

1-[1-(4-시아노벤질)피페리딘-4-일]-3-(3,7-디메톡시퀴녹살린-2-일) 우레아 제조Preparation of 1- [1- (4-cyanobenzyl) piperidin-4-yl] -3- (3,7-dimethoxyquinoxalin-2-yl) urea

실시예 34(c)와 동일한 방법으로 수행하되, 실시예 34(a)-(b)를 통해 1-(3,7-디메톡시퀴녹살린-2-일)-3-피페리딘-4-일 우레아 (20 mg, 0.060 mmol)와 4-시아노벤즈알데히드 (12 mg, 0.090 mmol)를 실온에서 디클로로메탄 3 ㎖에 넣은 다음 NaBH(OAc)3 (19 mg, 0.090 mmol)로 처리하고 같은 온도에서 24 시간 동안 교반하였다. 반응 종료 후에 소듐 바이카르보네이트 포화 수용액을 다하고 디클로로메탄으로 추출하였다. 유기층을 마그네슘 설페이트로 건조한 뒤 용매를 감압 증발하고 잔류물을 실리카겔 관 크로마토그래피 (n-헥산:에틸 아세테이트, 1:3 v/v)로 정제하여, 상기 목적화합물 (26 mg, 96%)을 얻었다.The same procedure as in Example 34 (c), except for 1- (3,7-dimethoxyquinoxalin-2-yl) -3-piperidin-4- via Example 34 (a)-(b) Il urea (20 mg, 0.060 mmol) and 4-cyanobenzaldehyde (12 mg, 0.090 mmol) were added to 3 mL of dichloromethane at room temperature followed by treatment with NaBH (OAc) 3 (19 mg, 0.090 mmol) and at the same temperature. Stir for 24 hours. After completion of the reaction, saturated aqueous sodium bicarbonate solution was exhausted and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography ( n -hexane: ethyl acetate, 1: 3 v / v) to obtain the target compound (26 mg, 96%). .

<실시예 43><Example 43>

1-[1-(2,6-디플루오르벤질)피페리딘-4-일]-3-(3,7-디메톡시퀴녹살린-2-일) 우레아 제조Preparation of 1- [1- (2,6-difluorobenzyl) piperidin-4-yl] -3- (3,7-dimethoxyquinoxalin-2-yl) urea

실시예 34(c)와 동일한 방법으로 수행하되, 실시예 34(a)-(b)를 통해 1-(3,7-디메톡시퀴녹살린-2-일)-3-피페리딘-4-일 우레아 (20 mg, 0.060 mmol)와 2,6-디플루오르벤즈알데히드 (13 mg, 0.090 mmol)를 실온에서 디클로로메탄 3 ㎖에 넣은 다음 NaBH(OAc)3 (19 mg, 0.090 mmol)로 처리하고 같은 온도에서 24 시간 동안 교반하였다. 반응 종료 후에 소듐 바이카보네이트 포화 수용액을 다하고 디클로로메탄으로 추출하였다. 유기층을 마그네슘 설페이트로 건조한 뒤 용매를 감압 증발하고 잔류 물을 실리카겔 관 크로마토그래피 (n-헥산:에틸 아세테이트, 1:3 v/v)로 정제하여, 상기 목적화합물 (24 mg, 87%)을 얻었다.The same procedure as in Example 34 (c), except for 1- (3,7-dimethoxyquinoxalin-2-yl) -3-piperidin-4- via Example 34 (a)-(b) Il urea (20 mg, 0.060 mmol) and 2,6-difluorobenzaldehyde (13 mg, 0.090 mmol) were added to 3 ml of dichloromethane at room temperature followed by treatment with NaBH (OAc) 3 (19 mg, 0.090 mmol) and Stir at temperature for 24 hours. After completion of the reaction, saturated aqueous sodium bicarbonate solution was exhausted and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography ( n -hexane: ethyl acetate, 1: 3 v / v) to obtain the target compound (24 mg, 87%). .

<실시예 44><Example 44>

1-[1-(2,4-디메톡시벤질)피페리딘-4-일]-3-(3,7-디메톡시퀴녹살린-2-일) 우레아 제조Preparation of 1- [1- (2,4-dimethoxybenzyl) piperidin-4-yl] -3- (3,7-dimethoxyquinoxalin-2-yl) urea

실시예 34(c)와 동일한 방법으로 수행하되, 실시예 34(a)-(b)를 통해 1-(3,7-디메톡시퀴녹살린-2-일)-3-피페리딘-4-일 우레아 (20 mg, 0.060 mmol)와 2,4-디메톡시벤즈알데히드 (15 mg, 0.090 mmol)를 실온에서 디클로로메탄 3 ㎖에 넣은 다음 NaBH(OAc)3 (19 mg, 0.090 mmol)로 처리하고 같은 온도에서 24 시간 동안 교반하였다. 반응 종료 후에 소듐 바이카보네이트 포화 수용액을 다하고 디클로로메탄으로 추출하였다. 유기층을 마그네슘 설페이트로 건조한 뒤 용매를 감압 증발하고 잔류물을 실리카겔 관 크로마토그래피 (디클로로메탄:에탄올, 15:1 v/v)로 정제하여, 상기 목적화합물 (23 mg, 79%)을 얻었다.The same procedure as in Example 34 (c), except for 1- (3,7-dimethoxyquinoxalin-2-yl) -3-piperidin-4- via Example 34 (a)-(b) Il urea (20 mg, 0.060 mmol) and 2,4-dimethoxybenzaldehyde (15 mg, 0.090 mmol) were added to 3 mL of dichloromethane at room temperature followed by treatment with NaBH (OAc) 3 (19 mg, 0.090 mmol) and Stir at temperature for 24 hours. After completion of the reaction, saturated aqueous sodium bicarbonate solution was exhausted and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: ethanol, 15: 1 v / v) to obtain the target compound (23 mg, 79%).

<실시예 45><Example 45>

1-[1-(3,5-디-1- [1- (3,5-di- tt -부틸-4-하이드록시벤질)피페리딘-4-일]-3-(3,7-디메톡시퀴녹살린-2-일) 우레아 제조Butyl-4-hydroxybenzyl) piperidin-4-yl] -3- (3,7-dimethoxyquinoxalin-2-yl) urea

실시예 34(c)와 동일한 방법으로 수행하되, 실시예 34(a)-(b)를 통해 1-(3,7-디메톡시퀴녹살린-2-일)-3-피페리딘-4-일 우레아 (20 mg, 0.060 mmol)와 3,5-디-t-부틸-4-하이드록시벤즈알데히드 (21 mg, 0.090 mmol)를 실온에서 디클로로메탄 3 ㎖에 넣은 다음 NaBH(OAc)3 (19 mg, 0.090 mmol)로 처리하고 같은 온도에서 24 시간 동안 교반하였다. 반응 종료 후에 소듐 바이카보네이트 포화 수용액을 다하고 디클로로메탄으로 추출하였다. 유기층을 마그네슘 설페이트로 건조한 뒤 용매를 감압 증발하고 잔류물을 실리카겔 관 크로마토그래피 (n-헥산:에틸 아세테이트, 1:3 v/v)로 정제하여, 상기 목적화합물 (31 mg, 94%)을 얻었다.The same procedure as in Example 34 (c), except for 1- (3,7-dimethoxyquinoxalin-2-yl) -3-piperidin-4- via Example 34 (a)-(b) Il urea (20 mg, 0.060 mmol) and 3,5-di- t -butyl-4-hydroxybenzaldehyde (21 mg, 0.090 mmol) were added to 3 mL of dichloromethane at room temperature followed by NaBH (OAc) 3 (19 mg). , 0.090 mmol) and stirred at the same temperature for 24 hours. After completion of the reaction, saturated aqueous sodium bicarbonate solution was exhausted and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography ( n -hexane: ethyl acetate, 1: 3 v / v) to obtain the target compound (31 mg, 94%). .

<실시예 46>Example 46

1-(3,7-디메톡시퀴녹살린-2-일)-3-[1-(2-플루오르벤질)피페리딘-4-일] 우레아 제조Preparation of 1- (3,7-dimethoxyquinoxalin-2-yl) -3- [1- (2-fluorobenzyl) piperidin-4-yl] urea

실시예 34(c)와 동일한 방법으로 수행하되, 실시예 34(a)-(b)를 통해 1-(3,7-디메톡시퀴녹살린-2-일)-3-피페리딘-4-일 우레아 (20 mg, 0.060 mmol)와 2-플루오르벤즈알데히드 (11 mg, 0.090 mmol)를 실온에서 디클로로메탄 3 ㎖에 넣은 다음 NaBH(OAc)3 (19 mg, 0.090 mmol)로 처리하고 같은 온도에서 24 시간 동안 교반하였다. 반응 종료 후에 소듐 바이카르보네이트 포화 수용액을 다하고 디클로로메탄으로 추출하였다. 유기층을 마그네슘 설페이트로 건조한 뒤 용매를 감압 증발하고 잔류물을 실리카겔 관 크로마토그래피 (n-헥산:에틸 아세테이트, 1:3 v/v)로 정제하여, 상기 목적화합물 (22 mg, 82%)을 얻었다.The same procedure as in Example 34 (c), except for 1- (3,7-dimethoxyquinoxalin-2-yl) -3-piperidin-4- via Example 34 (a)-(b) Il urea (20 mg, 0.060 mmol) and 2-fluorbenzaldehyde (11 mg, 0.090 mmol) were added to 3 mL of dichloromethane at room temperature followed by treatment with NaBH (OAc) 3 (19 mg, 0.090 mmol) and 24 at the same temperature. Stir for hours. After completion of the reaction, saturated aqueous sodium bicarbonate solution was exhausted and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography ( n -hexane: ethyl acetate, 1: 3 v / v) to obtain the target compound (22 mg, 82%). .

<실시예 47><Example 47>

1-(3,7-디메톡시퀴녹살린-2-일)-3-[1-(4-플루오르벤질)피페리딘-4-일] 우레아 제조Preparation of 1- (3,7-dimethoxyquinoxalin-2-yl) -3- [1- (4-fluorobenzyl) piperidin-4-yl] urea

실시예 34(c)와 동일한 방법으로 수행하되, 실시예 34(a)-(b)를 통해 1-(3,7-디메톡시퀴녹살린-2-일)-3-피페리딘-4-일 우레아 (20 mg, 0.060 mmol)와 4-플루오르벤 즈알데히드 (11 mg, 0.090 mmol)를 실온에서 디클로로메탄 3 ㎖에 넣은 다음 NaBH(OAc)3 (19 mg, 0.090 mmol)로 처리하고 같은 온도에서 24 시간 동안 교반하였다. 반응 종료 후에 소듐 바이카보네이트 포화 수용액을 다하고 디클로로메탄으로 추출하였다. 유기층을 마그네슘 설페이트로 건조한 뒤 용매를 감압 증발하고 잔류물을 실리카겔 관 크로마토그래피 (n-헥산:에틸 아세테이트, 1:3 v/v)로 정제하여, 상기 목적화합물 (24 mg, 91%)을 얻었다.The same procedure as in Example 34 (c), except for 1- (3,7-dimethoxyquinoxalin-2-yl) -3-piperidin-4- via Example 34 (a)-(b) Il urea (20 mg, 0.060 mmol) and 4-fluorbenzaldehyde (11 mg, 0.090 mmol) were added to 3 mL of dichloromethane at room temperature followed by treatment with NaBH (OAc) 3 (19 mg, 0.090 mmol) and the same temperature. Stirred for 24 h. After completion of the reaction, saturated aqueous sodium bicarbonate solution was exhausted and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography ( n -hexane: ethyl acetate, 1: 3 v / v) to obtain the target compound (24 mg, 91%). .

<실시예 48><Example 48>

1-(3,7-디메톡시퀴녹살린-2-일)-3-[1-(3-플루오르벤질)피페리딘-4-일] 우레아 제조Preparation of 1- (3,7-dimethoxyquinoxalin-2-yl) -3- [1- (3-fluorobenzyl) piperidin-4-yl] urea

실시예 34(c)와 동일한 방법으로 수행하되, 실시예 34(a)-(b)를 통해 1-(3,7-디메톡시퀴녹살린-2-일)-3-피페리딘-4-일 우레아 (20 mg, 0.060 mmol)와 3-플루오르벤즈알데히드 (11 mg, 0.090 mmol)를 실온에서 디클로로메탄 3 ㎖에 넣은 다음 NaBH(OAc)3 (19 mg, 0.090 mmol)로 처리하고 같은 온도에서 24 시간 동안 교반하였다. 반응 종료 후에 소듐 바이카르보네이트 포화 수용액을 다하고 디클로로메탄으로 추출하였다. 유기층을 마그네슘 설페이트로 건조한 뒤 용매를 감압 증발하고 잔류물을 실리카겔 관 크로마토그래피 (n-헥산:에틸 아세테이트, 1:3 v/v)로 정제하여, 상기 목적화합물 (26 mg, 97%)을 얻었다.The same procedure as in Example 34 (c), except for 1- (3,7-dimethoxyquinoxalin-2-yl) -3-piperidin-4- via Example 34 (a)-(b) Il urea (20 mg, 0.060 mmol) and 3-fluorbenzaldehyde (11 mg, 0.090 mmol) were added to 3 mL of dichloromethane at room temperature followed by treatment with NaBH (OAc) 3 (19 mg, 0.090 mmol) and 24 at the same temperature. Stir for hours. After completion of the reaction, saturated aqueous sodium bicarbonate solution was exhausted and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography ( n -hexane: ethyl acetate, 1: 3 v / v) to obtain the target compound (26 mg, 97%). .

<실시예 49><Example 49>

1-(3,7-디메톡시퀴녹살린-2-일)-3-[1-(3-하이드록시-4-메톡시벤질)피페리딘-4-일] 우레아 제조Preparation of 1- (3,7-dimethoxyquinoxalin-2-yl) -3- [1- (3-hydroxy-4-methoxybenzyl) piperidin-4-yl] urea

실시예 34(c)와 동일한 방법으로 수행하되, 실시예 34(a)-(b)를 통해 1-(3,7-디메톡시퀴녹살린-2-일)-3-피페리딘-4-일 우레아 (20 mg, 0.060 mmol)와 3-하이드록시-4-메톡시벤즈알데히드 (14 mg, 0.090 mmol)를 실온에서 디클로로메탄 3 ㎖에 넣은 다음 NaBH(OAc)3 (19 mg, 0.090 mmol)로 처리하고 같은 온도에서 24 시간 동안 교반하였다. 반응 종료 후에 소듐 바이카르보네이트 포화 수용액을 다하고 디클로로메탄으로 추출하였다. 유기층을 마그네슘 설페이트로 건조한 뒤 용매를 감압 증발하고 잔류물을 실리카겔 관 크로마토그래피 (디클로로메탄:에탄올, 15:1 v/v)로 정제하여, 상기 목적화합물 (25 mg, 89%)을 얻었다.The same procedure as in Example 34 (c), except for 1- (3,7-dimethoxyquinoxalin-2-yl) -3-piperidin-4- via Example 34 (a)-(b) Il urea (20 mg, 0.060 mmol) and 3-hydroxy-4-methoxybenzaldehyde (14 mg, 0.090 mmol) were added to 3 mL of dichloromethane at room temperature followed by NaBH (OAc) 3 (19 mg, 0.090 mmol). The treatment was stirred at the same temperature for 24 hours. After completion of the reaction, saturated aqueous sodium bicarbonate solution was exhausted and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: ethanol, 15: 1 v / v) to obtain the target compound (25 mg, 89%).

<실시예 50><Example 50>

1-(3,7-디메톡시퀴녹살린-2-일)-3-[1-(2-하이드록시-4-메톡시벤질)피페리딘-4-일] 우레아 제조Preparation of 1- (3,7-dimethoxyquinoxalin-2-yl) -3- [1- (2-hydroxy-4-methoxybenzyl) piperidin-4-yl] urea

실시예 34(c)와 동일한 방법으로 수행하되, 실시예 34(a)-(b)를 통해 1-(3,7-디메톡시퀴녹살린-2-일)-3-피페리딘-4-일 우레아 (20 mg, 0.060 mmol)와 2-하이드록시-4-메톡시벤즈알데히드 (14 mg, 0.090 mmol)를 실온에서 디클로로메탄 3 ㎖에 넣은 다음 NaBH(OAc)3 (19 mg, 0.090 mmol)로 처리하고 같은 온도에서 24 시간 동안 교반하였다. 반응 종료 후에 소듐 바이카르보네이트 포화 수용액을 다하고 디클로로메탄으로 추출하였다. 유기층을 마그네슘 설페이트로 건조한 뒤 용매를 감압 증발하고 잔류물을 실리카겔 관 크로마토그래피 (n-헥산:에틸 아세테이트, 1:3 v/v)로 정제하여, 상기 목적화합물 (24 mg, 85%)을 얻었다.The same procedure as in Example 34 (c), except for 1- (3,7-dimethoxyquinoxalin-2-yl) -3-piperidin-4- via Example 34 (a)-(b) Il urea (20 mg, 0.060 mmol) and 2-hydroxy-4-methoxybenzaldehyde (14 mg, 0.090 mmol) were added to 3 ml of dichloromethane at room temperature followed by NaBH (OAc) 3 (19 mg, 0.090 mmol). The treatment was stirred at the same temperature for 24 hours. After completion of the reaction, saturated aqueous sodium bicarbonate solution was exhausted and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography ( n -hexane: ethyl acetate, 1: 3 v / v) to obtain the target compound (24 mg, 85%). .

<실시예 51><Example 51>

1-(3,7-디메톡시퀴녹살린-2-일)-3-[1-(2-니트로벤질)피페리딘-4-일] 우레아 제조Preparation of 1- (3,7-dimethoxyquinoxalin-2-yl) -3- [1- (2-nitrobenzyl) piperidin-4-yl] urea

실시예 34(c)와 동일한 방법으로 수행하되, 실시예 34(a)-(b)를 통해 1-(3,7-디메톡시퀴녹살린-2-일)-3-피페리딘-4-일 우레아 (20 mg, 0.060 mmol)와 2-니트로벤즈알데히드 (14 mg, 0.090 mmol)를 실온에서 디클로로메탄 3 ㎖에 넣은 다음 NaBH(OAc)3 (19 mg, 0.090 mmol)로 처리하고 같은 온도에서 24 시간 동안 교반하였다. 반응 종료 후에 소듐 바이카르보네이트 포화 수용액을 다하고 디클로로메탄으로 추출하였다. 유기층을 마그네슘 설페이트로 건조한 뒤 용매를 감압 증발하고 잔류물을 실리카겔 관 크로마토그래피 (n-헥산:에틸 아세테이트, 1:3 v/v)로 정제하여, 상기 목적화합물 (26 mg, 93%)을 얻었다.The same procedure as in Example 34 (c), except for 1- (3,7-dimethoxyquinoxalin-2-yl) -3-piperidin-4- via Example 34 (a)-(b) Il urea (20 mg, 0.060 mmol) and 2-nitrobenzaldehyde (14 mg, 0.090 mmol) were added to 3 mL of dichloromethane at room temperature followed by treatment with NaBH (OAc) 3 (19 mg, 0.090 mmol) and 24 at the same temperature. Stir for hours. After completion of the reaction, saturated aqueous sodium bicarbonate solution was exhausted and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography ( n -hexane: ethyl acetate, 1: 3 v / v) to obtain the target compound (26 mg, 93%). .

<실시예 52><Example 52>

1-(3,7-디메톡시퀴녹살린-2-일)-3-[1-(4-니트로벤질)피페리딘-4-일] 우레아 제조Preparation of 1- (3,7-dimethoxyquinoxalin-2-yl) -3- [1- (4-nitrobenzyl) piperidin-4-yl] urea

실시예 34(c)와 동일한 방법으로 수행하되, 실시예 34(a)-(b)를 통해 1-(3,7-디메톡시퀴녹살린-2-일)-3-피페리딘-4-일 우레아 (20 mg, 0.060 mmol)와 4-니트로벤즈알데히드 (14 mg, 0.090 mmol)를 실온에서 디클로로메탄 3 ㎖에 넣은 다음 NaBH(OAc)3 (19 mg, 0.090 mmol)로 처리하고 같은 온도에서 24 시간 동안 교반하였다. 반응 종료 후에 소듐 바이카르보네이트 포화 수용액을 다하고 디클로로메탄으로 추출하였다. 유기층을 마그네슘 설페이트로 건조한 뒤 용매를 감압 증발하고 잔류물을 실리카겔 관 크로마토그래피 (n-헥산:에틸 아세테이트, 1:5 v/v)로 정제 하여, 상기 목적화합물 (25 mg, 89%)을 얻었다.The same procedure as in Example 34 (c), except for 1- (3,7-dimethoxyquinoxalin-2-yl) -3-piperidin-4- via Example 34 (a)-(b) Il urea (20 mg, 0.060 mmol) and 4-nitrobenzaldehyde (14 mg, 0.090 mmol) were added to 3 mL of dichloromethane at room temperature followed by treatment with NaBH (OAc) 3 (19 mg, 0.090 mmol) and 24 at the same temperature. Stir for hours. After completion of the reaction, saturated aqueous sodium bicarbonate solution was exhausted and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography ( n -hexane: ethyl acetate, 1: 5 v / v) to obtain the target compound (25 mg, 89%). .

<실시예 53><Example 53>

1-(3,7-디메톡시퀴녹살린-2-일)-3-[1-(3-니트로벤질)피페리딘-4-일] 우레아 제조Preparation of 1- (3,7-dimethoxyquinoxalin-2-yl) -3- [1- (3-nitrobenzyl) piperidin-4-yl] urea

실시예 34(c)와 동일한 방법으로 수행하되, 실시예 34(a)-(b)를 통해 1-(3,7-디메톡시퀴녹살린-2-일)-3-피페리딘-4-일 우레아 (20 mg, 0.060 mmol)와 3-니트로벤즈알데히드 (14 mg, 0.090 mmol)를 실온에서 디클로로메탄 3 ㎖에 넣은 다음 NaBH(OAc)3 (19 mg, 0.090 mmol)로 처리하고 같은 온도에서 24 시간 동안 교반하였다. 반응 종료 후에 소듐 바이카르보네이트 포화 수용액을 다하고 디클로로메탄으로 추출하였다. 유기층을 마그네슘 설페이트로 건조한 뒤 용매를 감압 증발하고 잔류물을 실리카겔 관 크로마토그래피 (n-헥산:에틸 아세테이트, 1:5 v/v)로 정제하여, 상기 목적화합물 (25 mg, 91%)을 얻었다.The same procedure as in Example 34 (c), except for 1- (3,7-dimethoxyquinoxalin-2-yl) -3-piperidin-4- via Example 34 (a)-(b) Il urea (20 mg, 0.060 mmol) and 3-nitrobenzaldehyde (14 mg, 0.090 mmol) were added to 3 ml of dichloromethane at room temperature followed by treatment with NaBH (OAc) 3 (19 mg, 0.090 mmol) and 24 at the same temperature. Stir for hours. After completion of the reaction, saturated aqueous sodium bicarbonate solution was exhausted and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography ( n -hexane: ethyl acetate, 1: 5 v / v) to obtain the target compound (25 mg, 91%). .

<실시예 54><Example 54>

1-(1-피페로닐피페리딘-4-일)-3-(3,6-디메톡시퀴녹살린-2-일) 우레아 제조Preparation of 1- (1-piperonylpiperidin-4-yl) -3- (3,6-dimethoxyquinoxalin-2-yl) urea

실시예 8과 동일한 방법으로 수행하되, 에틸 (3,6-디메톡시퀴녹살린-2-일)카르바메이트 (40 mg, 0.14 mmol)와 4-아미노-1-피페로닐피페리딘 (51 mg, 0.22 mmol)을 실온에서 THF 1 ㎖에 녹인 후, DBU (44 mg, 0.29 mmol)를 더하고 45℃에서 23 시간동안 교반하였다. 반응 종료 후에 용매를 감압 증발시킨 뒤, 실리카겔 관 크로마토그래피 (디클로로메탄:메탄올, 98:2 v/v)로 정제하여, 상기 목적화합물 (57 mg, 88%)을 얻었다.Performed in the same manner as in Example 8, except ethyl (3,6-dimethoxyquinoxalin-2-yl) carbamate (40 mg, 0.14 mmol) and 4-amino-1-piperonylpiperidine (51 mg , 0.22 mmol) was dissolved in 1 mL of THF at room temperature, then DBU (44 mg, 0.29 mmol) was added and stirred at 45 ° C. for 23 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and then purified by silica gel column chromatography (dichloromethane: methanol, 98: 2 v / v) to obtain the target compound (57 mg, 88%).

<실시예 55><Example 55>

1-(1-벤질피페리딘-4-일)-3-(3,6-디메톡시퀴녹살린-2-일) 우레아 제조Preparation of 1- (1-benzylpiperidin-4-yl) -3- (3,6-dimethoxyquinoxalin-2-yl) urea

실시예 8과 동일한 방법으로 수행하되, 에틸 (3,6-디메톡시퀴녹살린-2-일)카르바메이트 (40 mg, 0.14 mmol)와 4-아미노-1-벤질피페리딘 (51 mg, 0.27 mmol)을 실온에서 THF 1 ㎖에 녹인 후, DBU (44 mg, 0.29 mmol)를 더하고 45℃에서 13 시간동안 교반하였다. 반응 종료 후에 용매를 감압 증발시킨 뒤, 실리카겔 관 크로마토그래피 (디클로로메탄:메탄올, 98:2 v/v)로 정제하여, 상기 목적화합물 (54 mg, 91%)을 얻었다.In the same manner as in Example 8, except that ethyl (3,6-dimethoxyquinoxalin-2-yl) carbamate (40 mg, 0.14 mmol) and 4-amino-1-benzylpiperidine (51 mg, 0.27 mmol) was dissolved in 1 mL of THF at room temperature, then DBU (44 mg, 0.29 mmol) was added and stirred at 45 ° C. for 13 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and then purified by silica gel column chromatography (dichloromethane: methanol, 98: 2 v / v) to obtain the target compound (54 mg, 91%).

<실시예 56><Example 56>

1-(1-피페로닐피페리딘-4-일)-3-(3,6,7-트리메톡시퀴녹살린-2-일) 우레아 제조Preparation of 1- (1-piperonylpiperidin-4-yl) -3- (3,6,7-trimethoxyquinoxalin-2-yl) urea

화합물 4-아미노-1-피페로닐피페리딘 (61 mg, 0.26 mmol)과 트리메틸 알루미늄 (2.0 M 톨루엔 용액; 0.117 ㎖, 0.234 mmol)을 실온에서 톨루엔 1 ㎖에 더하고 10 분동안 교반한 다음, 에틸 (3,6,7-트리메톡시퀴녹살린-2-일)카르바메이트 (40 mg, 0.13 mmol)을 첨가한 후 80℃에서 4 시간 동안 교반하였다. 반응 종료 후에 용매를 감압 증발시킨 뒤, 실리카겔 관 크로마토그래피 (디클로로메탄:메탄올, 98:2 v/v)로 정제하여, 상기 목적화합물 (54 mg, 84%)을 얻었다.Compound 4-amino-1-piperonylpiperidine (61 mg, 0.26 mmol) and trimethyl aluminum (2.0 M toluene solution; 0.117 mL, 0.234 mmol) were added to 1 mL of toluene at room temperature and stirred for 10 minutes, then ethyl (3,6,7-trimethoxyquinoxalin-2-yl) carbamate (40 mg, 0.13 mmol) was added and stirred at 80 ° C. for 4 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and then purified by silica gel column chromatography (dichloromethane: methanol, 98: 2 v / v) to obtain the target compound (54 mg, 84%).

<실시예 57><Example 57>

1-(1-벤질피페리딘-4-일)-3-(3,6,7-트리메톡시퀴녹살린-2-일) 우레아 제조Preparation of 1- (1-benzylpiperidin-4-yl) -3- (3,6,7-trimethoxyquinoxalin-2-yl) urea

실시예 8과 동일한 방법으로 수행하되, 에틸 (3,6,7-트리메톡시퀴녹살린-2-일)카르바메이트 (40 mg, 0.13 mmol)와 4-아미노-1-벤질피페리딘 (37 mg, 0.19 mmol)을 실 온에서 THF 1 ㎖에 녹인 후, DBU (30 mg, 0.19 mmol)를 더하고 45℃에서 23 시간동안 교반하였다. 반응 종료 후에 용매를 감압 증발시킨 뒤, 실리카겔 관 크로마토그래피 (디클로로메탄:메탄올, 98:2 v/v)로 정제하여, 상기 목적화합물 (53 mg, 90%)을 얻었다.In the same manner as in Example 8, except that ethyl (3,6,7-trimethoxyquinoxalin-2-yl) carbamate (40 mg, 0.13 mmol) and 4-amino-1-benzylpiperidine ( 37 mg, 0.19 mmol) was dissolved in 1 mL of THF at room temperature, then DBU (30 mg, 0.19 mmol) was added and stirred at 45 ° C. for 23 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and then purified by silica gel column chromatography (dichloromethane: methanol, 98: 2 v / v) to obtain the target compound (53 mg, 90%).

<실시예 58><Example 58>

1-(1-피페로닐피페리딘-4-일)-3-(3,8-디메톡시퀴녹살린-2-일) 우레아 제조Preparation of 1- (1-piperonylpiperidin-4-yl) -3- (3,8-dimethoxyquinoxalin-2-yl) urea

실시예 8과 동일한 방법으로 수행하되, 에틸 (3,8-디메톡시퀴녹살린-2-일)카르바메이트 (40 mg, 0.14 mmol)와 4-아미노-1-피페로닐피페리딘 (51 mg, 0.22 mmol)을 실온에서 THF 1 ㎖에 녹인 후, DBU (44 mg, 0.29 mmol)를 더하고 45℃에서 23 시간동안 교반하였다. 반응 종료 후에 용매를 감압 증발시킨 뒤, 실리카겔 관 크로마토그래피 (디클로로메탄:메탄올, 98:2 v/v)로 정제하여, 상기 목적화합물 (58 mg, 89%)을 얻었다.Performed in the same manner as in Example 8, except ethyl (3,8-dimethoxyquinoxalin-2-yl) carbamate (40 mg, 0.14 mmol) and 4-amino-1-piperonylpiperidine (51 mg , 0.22 mmol) was dissolved in 1 mL of THF at room temperature, then DBU (44 mg, 0.29 mmol) was added and stirred at 45 ° C. for 23 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and then purified by silica gel column chromatography (dichloromethane: methanol, 98: 2 v / v) to obtain the target compound (58 mg, 89%).

<실시예 59><Example 59>

1-(1-벤질피페리딘-4-일)-3-(3,8-디메톡시퀴녹살린-2-일) 우레아 제조Preparation of 1- (1-benzylpiperidin-4-yl) -3- (3,8-dimethoxyquinoxalin-2-yl) urea

실시예 8과 동일한 방법으로 수행하되, 에틸 (3,8-디메톡시퀴녹살린-2-일)카르바메이트 (40 mg, 0.14 mmol)와 4-아미노-1-벤질피페리딘 (51 mg, 0.27 mmol)을 실온에서 THF 1 ㎖에 녹인 후, DBU (44 mg, 0.29 mmol)를 더하고 45℃에서 13 시간동안 교반하였다. 반응 종료 후에 용매를 감압 증발시킨 뒤, 실리카겔 관 크로마토그래피 (디클로로메탄:메탄올, 98:2 v/v)로 정제하여, 상기 목적화합물 (55 mg, 94%)을 얻었다.In the same manner as in Example 8, except that ethyl (3,8-dimethoxyquinoxalin-2-yl) carbamate (40 mg, 0.14 mmol) and 4-amino-1-benzylpiperidine (51 mg, 0.27 mmol) was dissolved in 1 mL of THF at room temperature, then DBU (44 mg, 0.29 mmol) was added and stirred at 45 ° C. for 13 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and then purified by silica gel column chromatography (dichloromethane: methanol, 98: 2 v / v) to obtain the target compound (55 mg, 94%).

<실시예 60><Example 60>

1-(1-피페로닐피페리딘-4-일)-3-(3,5-디메톡시퀴녹살린-2-일) 우레아 제조Preparation of 1- (1-piperonylpiperidin-4-yl) -3- (3,5-dimethoxyquinoxalin-2-yl) urea

실시예 8과 동일한 방법으로 수행하되, 에틸 (3,5-디메톡시퀴녹살린-2-일)카르바메이트 (40 mg, 0.14 mmol)와 4-아미노-1-피페로닐피페리딘 (51 mg, 0.22 mmol)을 실온에서 THF 1 ㎖에 녹인 후, DBU (44 mg, 0.29 mmol)를 더하고 45℃에서 23 시간동안 교반하였다. 반응 종료 후에 용매를 감압 증발시킨 뒤, 실리카겔 관 크로마토그래피 (디클로로메탄:메탄올, 98:2 v/v)로 정제하여, 상기 목적화합물 (57 mg, 87%)을 얻었다.Performed in the same manner as in Example 8, except ethyl (3,5-dimethoxyquinoxalin-2-yl) carbamate (40 mg, 0.14 mmol) and 4-amino-1-piperonylpiperidine (51 mg , 0.22 mmol) was dissolved in 1 mL of THF at room temperature, then DBU (44 mg, 0.29 mmol) was added and stirred at 45 ° C. for 23 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and then purified by silica gel column chromatography (dichloromethane: methanol, 98: 2 v / v) to obtain the target compound (57 mg, 87%).

<실시예 61><Example 61>

1-(1-벤질피페리딘-4-일)-3-(3,5-디메톡시퀴녹살린-2-일) 우레아 제조Preparation of 1- (1-benzylpiperidin-4-yl) -3- (3,5-dimethoxyquinoxalin-2-yl) urea

실시예 8과 동일한 방법으로 수행하되, 에틸 (3,5-디메톡시퀴녹살린-2-일)카르바메이트 (40 mg, 0.14 mmol)와 4-아미노-1-벤질피페리딘 (51 mg, 0.27 mmol)을 실온에서 THF 1 ㎖에 녹인 후, DBU (44 mg, 0.29 mmol)를 더하고 45℃에서 13 시간동안 교반하였다. 반응 종료 후에 용매를 감압 증발시킨 뒤, 실리카겔 관 크로마토그래피 (디클로로메탄:메탄올, 98:2 v/v)로 정제하여, 상기 목적화합물 (51 mg, 86%)을 얻었다.In the same manner as in Example 8, except that ethyl (3,5-dimethoxyquinoxalin-2-yl) carbamate (40 mg, 0.14 mmol) and 4-amino-1-benzylpiperidine (51 mg, 0.27 mmol) was dissolved in 1 mL of THF at room temperature, then DBU (44 mg, 0.29 mmol) was added and stirred at 45 ° C. for 13 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and then purified by silica gel column chromatography (dichloromethane: methanol, 98: 2 v / v) to obtain the target compound (51 mg, 86%).

상기 실시예 1 내지 61에서 제조된 화합물들의 구조를 확인하기 위하여, 최종 반응 후 다중 컬럼크로마토그래피 장비(Quad3+; 미국 Biotage사 제품)로 분리 정제하였 으며, 1H NMR(Bruker Avance 500 MHz) 및 Mass 스펙트럼으로 구조를 분석하여 하기 표 1에 기재하였다.In order to confirm the structure of the compounds prepared in Examples 1 to 61, after the final reaction was separated and purified by a multi-column chromatography equipment (Quad3 +; Biotage, USA), 1 H NMR (Bruker Avance 500 MHz) and Mass The structure is analyzed by spectra and shown in Table 1 below.

Figure 112008013294843-pat00006
Figure 112008013294843-pat00006

Figure 112008013294843-pat00007
Figure 112008013294843-pat00007

Figure 112008013294843-pat00008
Figure 112008013294843-pat00008

Figure 112008013294843-pat00009
Figure 112008013294843-pat00009

Figure 112008013294843-pat00010
Figure 112008013294843-pat00010

Figure 112008013294843-pat00011
Figure 112008013294843-pat00011

Figure 112008013294843-pat00012
Figure 112008013294843-pat00012

Figure 112008013294843-pat00013
Figure 112008013294843-pat00013

Figure 112008013294843-pat00014
Figure 112008013294843-pat00014

Figure 112008013294843-pat00015
Figure 112008013294843-pat00015

Figure 112008013294843-pat00016
Figure 112008013294843-pat00016

<< 실험예Experimental Example 1> 약리활성 확인 실험( 1> Pharmacological activity confirmation experiment ( MCH1MCH1 결합 억제 활성) Binding inhibitory activity)

완충용액은 세척용액(25 mM HEPES pH 7.4, 5 mM MgCl2, 1 mM CaCl2)과 실험용액(세척용액에 BSA를 0.5%가 되도록 첨가)의 두 종류를 준비하고, MCH R1(Melanin Concentration Hormone receptor subtype-1; Euroscreen, Gosselies, Belgium)과 1 μM의 유로퓸(Eu)으로 표지된 멜라닌 농축호르몬(Europium-labeled MCH(Eu-MCH), PerkinElmer, Turku, Finland) 및 1 mM의 멜라닌 농축호르몬(MCH, #070-47, Phoenix, Belmont CA, USA)을 4℃에서 준비하였다. 1μM의 Eu-MCH와 1 mM의 MCH를 각각 8 nM(최종 반응농도: 2 nM)과 2 μM(최종 반응농도: 0.5 μM)이 되도록 희석하였다. 모든 희석과 준비과정에서 사용되는 완충용액은 실험용액이며, 세척용액은 마지막에 플레이트를 씻어 줄 때만 사용하였다. The buffer solution is prepared by two kinds of washing solution (25 mM HEPES pH 7.4, 5 mM MgCl 2 , 1 mM CaCl 2 ) and experimental solution (adding 0.5% BSA to the washing solution), and MCH R1 (Melanin Concentration Hormone). receptor subtype-1; Euroscreen, Gosselies, Belgium) and 1 μM of europium (Eu) -labeled melanin enriched hormone (Europium-labeled MCH (Eu-MCH), PerkinElmer, Turku, Finland) and 1 mM melanin enriched hormone ( MCH, # 070-47, Phoenix, Belmont CA, USA) was prepared at 4 ° C. 1 μM Eu-MCH and 1 mM MCH were diluted to 8 nM (final reaction concentration: 2 nM) and 2 μM (final reaction concentration: 0.5 μM), respectively. The buffer solution used in all dilutions and preparations was the experimental solution, and the washing solution was used only to wash the plate at the end.

먼저, MCH R1(200 assays/vial)을 1 ㎖의 실험용액에 희석하여 균질화시킨 후, 여과지가 부착된 미소판(Multiwell 96 well filter plates PN5020, Pall Co. Ann Arbor MI, USA)에 8채널 파이펫(multi 8-channel, Eppendorf, Hamburg, Germany)을 이용하여 각 웰당 전체부피가 100 ㎕가 되게 반응물을 분주하였다. 이때, 비특이적결합(non specific binding) 대조군으로는 Eu-MCH 25㎕, 수용체 50㎕ 및 MCH 25㎕를 사용하였으며, 전체결합(total binding) 대조군으로는 10% DMSO 실험용액 25 ㎕, Eu-MCH 25㎕ 및 수용체 50㎕을 사용하였다. 실험군으로는 실시예에서 제조한 화합물 25㎕, Eu-MCH 25㎕ 및 수용체 50㎕를 사용하였다. 각 시험 화합물, Eu-MCH 및 MCH는 반응 시 전체부피의 25%로 차지하게 되므로 첨가직전에는 4배의 농도로 준비하였다. 이후, 15초간 약하게 흔들어 주고 상온에서 90분간 반응시켰다. 반응이 끝나면, 부분적으로 수정하여 자체 제작한 세척기(microplate washer, EMBLA, Molecular Devices)에 압력을 걸어 플레이트를 세척하였다. 세척 용액으로 웰당 300 ㎕씩 3회 여과시켜 반응하지 않고 남아 있는 Eu-MCH를 제거하였다. 바닥의 물기를 닦아내고 웰당 150㎕가 되게 해리용액(DELFIA Enhancement solution, PerkinElmer, Turku, Finland)을 첨가하여 주었다. 상온에서 그대로 2∼4시간 방치시킨 후 시차성 형광(Time-resolved fluorescence, TRF) 값을 다기능 형광측정기(multilabel counter, Victor2, PerkinElmer, Turku, Finland)를 이용하여 측정하였으며(방출파장: 615nm, 여기파장: 340nm), 하기 수학식에 따라 시차성 형광 억제율을 계산하고, 그 결과를 in vitro에서 MCH 수용체를 50% 저해한 시험물질의 농도인 IC50값으로 표시하였다.First, homogenize by diluting MCH R1 (200 assays / vial) in 1 ml of experimental solution, and then using an 8-channel pie on a filter paper-attached microplate (Multiwell 96 well filter plates PN5020, Pall Co. Ann Arbor MI, USA). The reaction was dispensed using a pet (multi 8-channel, Eppendorf, Hamburg, Germany) to 100 μl total volume per well. At this time, 25 μl of Eu-MCH, 50 μl of receptor and 25 μl of MCH were used as a non-specific binding control. 25 μl of 10% DMSO experimental solution and 25 μl of Eu-MCH 25 were used as the total binding control. Μl and 50 μl of receptor were used. As the experimental group, 25 µl of the compound prepared in Example, 25 µl of Eu-MCH and 50 µl of receptor were used. Each test compound, Eu-MCH and MCH, accounted for 25% of the total volume during the reaction, was prepared at a concentration of 4 times immediately before addition. Then, shake gently for 15 seconds and reacted at room temperature for 90 minutes. After the reaction, the plate was washed by applying pressure to a partially prepared washer (microplate washer, EMBLA, Molecular Devices). 300 μl / well of the wash solution was filtered three times to remove Eu-MCH that remained without reaction. Wipe off the water on the bottom of the dissolution solution (DELFIA Enhancement solution, PerkinElmer, Turku, Finland) was added to 150μl per well. After standing at room temperature for 2 to 4 hours, the time-resolved fluorescence (TRF) value was measured using a multi-function fluorometer (multilabel counter, Victor2, PerkinElmer, Turku, Finland) (emission wavelength: 615nm, excitation) Wavelength: 340 nm), and the differential fluorescence inhibition rate was calculated according to the following equation, and the result was expressed as IC 50 value, which is the concentration of test substance which inhibited MCH receptor by 50% in vitro .

Figure 112008013294843-pat00017
Figure 112008013294843-pat00017

상기 MCH1 결합 억제 활성 결과의 일부를 하기 표 2에 나타내었다. Some of the MCH1 binding inhibitory activity results are shown in Table 2 below.

Figure 112008013294843-pat00018
Figure 112008013294843-pat00018

본 발명의 실시예에서 제조된 1-(3-알콕시퀴녹살린-2-일)-3-[1-(아릴메틸)피페리딘-4-일] 우레아 유도체는 기존화합물들과는 차별화된 골격을 가지며, 세포 수준 및 동물실험을 통하여 10μM 이하 수준의 MCH1 결합 억제 활성을 확인함으로써, 지방조직이 체내에 과다하게 축적되어 있는 상태인 비만의 치료제로서 유효한 약제조성물로 활용될 수 있다.The 1- (3-alkoxyquinoxalin-2-yl) -3- [1- (arylmethyl) piperidin-4-yl] urea derivative prepared in the embodiment of the present invention has a skeleton that is different from existing compounds. By confirming MCH1 binding inhibitory activity at a level of 10 μM or less through cell level and animal experiments, it can be used as an effective pharmaceutical composition as a therapeutic agent for obesity in which adipose tissue is excessively accumulated in the body.

하기 제제예는 본 발명에 따른 1-(3-알콕시퀴녹살린-2-일)-3-[1-(아릴메틸)피페리딘-4-일] 우레아 유도체를 활성성분으로 함유시킨 제제예를 예시하는 것일 뿐, 이에 한정되는 것은 아니다.The following formulation example contains a formulation example containing 1- (3-alkoxyquinoxalin-2-yl) -3- [1- (arylmethyl) piperidin-4-yl] urea derivative according to the present invention as an active ingredient. It is only illustrative, but is not limited thereto.

<제제예 1> 정제(직접 가압 방식)의 제조Preparation Example 1 Preparation of Tablet (Direct Press Method)

활성성분으로서, 본 발명의 화학식 1로 표시되는 1-(3-알콕시퀴녹살린-2-일)-3-[1-(아릴메틸)피페리딘-4-일] 우레아 유도체 5.0 mg을 체로 친 후, 락토스 14.1 mg, 크로스포비돈 USNF 0.8 mg 및 마그네슘 스테아레이트 0.1 mg을 혼합하고 가압하여 정제로 만들었다. As an active ingredient, 5.0 mg of 1- (3-alkoxyquinoxalin-2-yl) -3- [1- (arylmethyl) piperidin-4-yl] urea derivative represented by Chemical Formula 1 of the present invention is sieved. Later, 14.1 mg lactose, 0.8 mg crospovidone USNF and 0.1 mg magnesium stearate were mixed and pressurized into tablets.

<제제예 2> 정제(습식 조립)의 제조Preparation Example 2 Preparation of Tablet (Wet Granulation)

활성성분 5.0 mg을 체로 친 후, 락토스 16.0 mg과 녹말 4.0 mg을 섞었다. 폴리솔베이트 80 0.3 mg을 순수한 물에 녹인 후, 이 용액의 적당량을 첨가한 다음, 미립화하였다. 건조 후에 미립을 체질한 후 콜로이달 실리콘 디옥사이드 2.7 mg 및 마그네슘 스테아레이트 2.0 mg과 섞었다. 미립을 가압하여 정제로 만들었다. After sifting 5.0 mg of the active ingredient, 16.0 mg of lactose and 4.0 mg of starch were mixed. 0.3 mg of polysorbate 80 was dissolved in pure water, then an appropriate amount of this solution was added and then atomized. 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.

<제제예 3> 분말 및 캡슐제의 제조Preparation Example 3 Preparation of Powder and Capsule

활성성분 5.0 mg을 체로 친 후에, 락토스 14.8 mg, 폴리비닐 피롤리돈 10.0 mg, 마그네슘 스테아레이트 0.2 mg와 함께 섞었다. 혼합물을 적당한 장치를 사용하여 단단한 No. 5 젤라틴 캡슐에 채웠다. After sifting 5.0 mg of active ingredient, it was mixed with 14.8 mg of lactose, 10.0 mg of polyvinyl pyrrolidone, and 0.2 mg of magnesium stearate. No. solid the mixture using a suitable device. Filled in 5 gelatin capsules.

<제제예 4><Example 4> 주사제의 제조Preparation of Injectables

활성성분 100 mg을 함유시키고, 그 밖에도 만니톨 180 mg, Na2HPO4·12H2O 26 mg 및 증류수 2974 mg를 함유시켜 주사제를 제조하였다. Injectables were prepared by containing 100 mg of the active ingredient, followed by 180 mg of mannitol, 26 mg of Na2HPO4.12H2O and 2974 mg of distilled water.

상기에서 살펴본 바와 같이, 본 발명은 MCH1R 억제 활성 효과를 가지는 신규한 화합물로서, 1-(3-알콕시퀴녹살린-2-일)-3-[1-(아릴메틸)피페리딘-4-일] 우레아 유도체 및 약제학적으로 허용 가능한 그의 염을 제공하였고, 그의 제조방법을 제공하였으며, 상기 1-(3-알콕시퀴녹살린-2-일)-3-[1-(아릴메틸)피페리딘-4-일] 우레아 유도체에 대한 MCH1R 억제 활성 측정결과, 세포 수준 및 동물실험을 통하여 10μM 이 하 수준까지 억제되는 활성을 확인함으로써, 신규 비만치료제를 제공하였다.As described above, the present invention is a novel compound having an MCH1R inhibitory activity effect, 1- (3-alkoxyquinoxalin-2-yl) -3- [1- (arylmethyl) piperidin-4-yl Urea derivatives and pharmaceutically acceptable salts thereof, and methods for their preparation are provided, wherein the 1- (3-alkoxyquinoxalin-2-yl) -3- [1- (arylmethyl) piperidine- 4-day] measurement of MCH1R inhibitory activity against urea derivatives, 10μM through cell level and animal experiment By identifying the activity inhibited to this level, new obesity treatments were provided.

이상에서 본 발명은 기재된 실시예에 대해서만 상세히 기술되었지만, 본 발명의 기술사상 범위 내에서 다양한 변형 및 수정이 가능함은 당업자에게 있어서 명백한 것이며, 이러한 변형 및 수정이 첨부된 특허청구범위에 속함은 당연한 것이다.Although the present invention has been described in detail only with respect to the embodiments described, it will be apparent to those skilled in the art that various modifications and variations are possible within the technical spirit of the present invention, and such modifications and variations belong to the appended claims. .

Claims (8)

하기 화학식 1로 표시되는 1-(3-알콕시퀴녹살린-2-일)-3-[1-(아릴메틸)피페리딘-4-일] 우레아 유도체 또는 약제학적으로 허용 가능한 그의 염. 1- (3-alkoxyquinoxalin-2-yl) -3- [1- (arylmethyl) piperidin-4-yl] urea derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof. 화학식 1Formula 1
Figure 112010008436006-pat00019
Figure 112010008436006-pat00019
 (상기에서, R1, R2, R3 및 R4는 수소원자, 할로겐원자, C1-C3의 알킬기 또는 C1-C3의 알콕시기를 나타내고; R5는 C1-C3의 알킬기 또는 C1-C3의 할로알킬기를 나타내고; R6 R7, R8, R9 및 R10는 수소원자, 할로겐원자, 하이드록시기, 니트로기, 시아노기, 아세톡시기, C1-C3의 알킬기, C1-C3의 알콕시기 또는 메탄디옥소기를 나타낸다.)(Wherein, R 1, R 2, R 3 and R 4 represents a hydrogen atom, a halogen atom, a C 1 -C 3 alkyl or C 1 -C 3 alkoxy; R 5 represents an alkyl group of C 1 -C 3 Or a C 1 -C 3 haloalkyl group, R 6 R 7 , R 8 , R 9 and R 10 represent a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an acetoxy group, C 1 -C 3 represents an alkyl group, a C 1 -C 3 alkoxy group, or a methanedioxo group.) 제1항에 있어서, 상기 1-(3-알콕시퀴녹살린-2-일)-3-[1-(아릴메틸)피페리딘-4-일] 우레아 유도체 또는 약제학적으로 허용 가능한 그의 염이 멜라닌-집중형 호르몬 수용체(MCH1R) 억제 활성을 가지는 것을 특징으로 하는 상기 유도체 또는 약제학적으로 허용 가능한 그의 염.The method according to claim 1, wherein the 1- (3-alkoxyquinoxalin-2-yl) -3- [1- (arylmethyl) piperidin-4-yl] urea derivative or pharmaceutically acceptable salt thereof is melanin -Said derivative or pharmaceutically acceptable salt thereof characterized by having a concentrated hormone receptor (MCH1R) inhibitory activity. 제1항에 있어서, 상기 1-(3-알콕시퀴녹살린-2-일)-3-[1-(아릴메틸)피페리딘-4-일] 우레아 유도체 또는 약제학적으로 허용 가능한 그의 염이 용매화물 또는 수화물 형태로 존재하는 것을 특징으로 하는 상기 유도체 또는 약제학적으로 허용 가능한 그의 염.The method of claim 1, wherein the 1- (3-alkoxyquinoxalin-2-yl) -3- [1- (arylmethyl) piperidin-4-yl] urea derivative or pharmaceutically acceptable salt thereof is a solvent The derivative or pharmaceutically acceptable salt thereof, which is present in the form of a cargo or a hydrate. 제1항에 있어서, 상기 1-(3-알콕시퀴녹살린-2-일)-3-[1-(아릴메틸)피페리딘-4-일] 우레아 유도체 또는 약제학적으로 허용 가능한 그의 염이 그로부터 분리된 거울상 이성질체 또는 부분 입체 이성질체를 포함하는 것을 특징으로 하는 상기 유도체 또는 약제학적으로 허용 가능한 그의 염.The method of claim 1, wherein the 1- (3-alkoxyquinoxalin-2-yl) -3- [1- (arylmethyl) piperidin-4-yl] urea derivative or pharmaceutically acceptable salt thereof is derived from The derivative or pharmaceutically acceptable salt thereof, characterized in that it comprises separated enantiomers or diastereomers. 하기 화학식 2로 표시되는 에틸 또는 페닐 N-(2-알콕시퀴녹살린-3-일)카바메이트 화합물과 하기 화학식 3으로 표시된 1 위치에 보호기를 가진 4-아미노피페리딘 화합물을 축합반응하여, 하기 화학식 4로 표시된 1-(3-알콕시퀴녹살린-2-일)-3-(1-보호-피페리딘-4-일) 우레아 화합물을 제조하는 제1단계,Condensation reaction of ethyl or phenyl N- (2-alkoxyquinoxalin-3-yl) carbamate compound represented by the following Chemical Formula 2 with a 4-aminopiperidine compound having a protecting group at the 1 position represented by the following Chemical Formula 3, A first step of preparing a 1- (3-alkoxyquinoxalin-2-yl) -3- (1-protected-piperidin-4-yl) urea compound represented by Formula 4, 하기 제조된 화학식 4로 표시되는 화합물을 탈보호기화 반응하여, 하기 화학식 5로 표시되는 1-(3-알콕시퀴녹살린-2-일)-3-피페리딘-4-일 우레아 화합물을 제조하는 제2단계, 및A deprotection reaction is carried out on the compound represented by Chemical Formula 4 to prepare 1- (3-alkoxyquinoxalin-2-yl) -3-piperidin-4-yl urea compound represented by Chemical Formula 5 below. Second stage, and 하기 화학식 5로 표시되는 화합물과 하기 화학식 6으로 표시된 아릴 알데히드 화합물의 환원 알킬화 반응을 통하여, 하기 화학식 1로 표시되는 1-(3-알콕시퀴녹살린- 2-일)-3-[1-(아릴메틸)피페리딘-4-일] 우레아 화합물을 얻는 제3단계로 이루어진 것을 특징으로 하는 화학식 1로 표시되는 유도체의 제조방법.1- (3-alkoxyquinoxalin-2-yl) -3- [1- (aryl represented by the following Chemical Formula 1 through a reduction alkylation reaction of the compound represented by the following Chemical Formula 5 and the aryl aldehyde compound represented by the following Chemical Formula 6 Methyl) piperidin-4-yl] A process for preparing a derivative represented by the formula (1), comprising the third step of obtaining a urea compound. 반응식 1Scheme 1
Figure 112008013294843-pat00020
Figure 112008013294843-pat00020
 (상기에서, R1, R2, R3, R4, R5, R6, R7, R8, R9 및 R10는 청구항 제1항에서 정의한 바와 같다.)(In the above, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are as defined in claim 1.) 하기 화학식 2로 표시되는 에틸 또는 페닐 N-(2-알콕시퀴녹살린-3-일)카바메이트 화합물과 하기 화학식 7로 표시된 1-아릴메틸-4-아미노피페리딘 화합물을 축합반응하여, 하기 화학식 1로 표시되는 1-(3-알콕시퀴녹살린-2-일)-3-[1-(아릴메틸)피페리딘-4-일] 우레아 화합물을 얻는 것을 특징으로 하는 화학식 1로 표시되는 유도체의 제조방법.Condensation reaction of ethyl or phenyl N- (2-alkoxyquinoxalin-3-yl) carbamate compound represented by Formula 2 with the 1-arylmethyl-4-aminopiperidine compound represented by Formula 7 below, 1- (3-alkoxyquinoxalin-2-yl) -3- [1- (arylmethyl) piperidin-4-yl] urea compound represented by 1 is obtained. Manufacturing method. 반응식 2Scheme 2
Figure 112008013294843-pat00021
Figure 112008013294843-pat00021
 (상기에서, R1, R2, R3, R4, R5, R6, R7, R8, R9 및 R10는 청구항 제1항에서 정의한 바와 같다.)(In the above, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are as defined in claim 1.) 제1항의 화학식 1로 표시되는 1-(3-알콕시퀴녹살린-2-일)-3-[1-(아릴메틸)피페리딘-4-일] 우레아 유도체 또는 약제학적으로 허용 가능한 그의 염을 유효성분으로 함유하는 것을 특징으로 하는 비만치료제. A 1- (3-alkoxyquinoxalin-2-yl) -3- [1- (arylmethyl) piperidin-4-yl] urea derivative represented by Formula 1 of claim 1 or a pharmaceutically acceptable salt thereof An anti-obesity agent comprising as an active ingredient. 제7항에 있어서, 상기 비만치료제가 MCH 활성으로 유발되는 비만관련 질환에 유용한 것을 특징으로 하는 상기 비만치료제.The obesity treatment agent according to claim 7, wherein the obesity treatment agent is useful for obesity-related diseases caused by MCH activity.
KR1020080016256A 2008-02-22 2008-02-22 1-3-alkoxyquinoxaline-2-yl-3-[1-arylmethylpiperidin-4-yl] urea derivatives and pharmaceutically acceptable salt thereof, process for preparation and use thereof KR100967589B1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
KR1020080016256A KR100967589B1 (en) 2008-02-22 2008-02-22 1-3-alkoxyquinoxaline-2-yl-3-[1-arylmethylpiperidin-4-yl] urea derivatives and pharmaceutically acceptable salt thereof, process for preparation and use thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
KR1020080016256A KR100967589B1 (en) 2008-02-22 2008-02-22 1-3-alkoxyquinoxaline-2-yl-3-[1-arylmethylpiperidin-4-yl] urea derivatives and pharmaceutically acceptable salt thereof, process for preparation and use thereof

Publications (2)

Publication Number Publication Date
KR20090090791A KR20090090791A (en) 2009-08-26
KR100967589B1 true KR100967589B1 (en) 2010-07-05

Family

ID=41208530

Family Applications (1)

Application Number Title Priority Date Filing Date
KR1020080016256A KR100967589B1 (en) 2008-02-22 2008-02-22 1-3-alkoxyquinoxaline-2-yl-3-[1-arylmethylpiperidin-4-yl] urea derivatives and pharmaceutically acceptable salt thereof, process for preparation and use thereof

Country Status (1)

Country Link
KR (1) KR100967589B1 (en)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101140133B1 (en) * 2010-02-17 2012-05-02 한국화학연구원 1-6,7-difluoro-3-methoxyquinoxalin-2-yl-3-[1-heteroarylmethylpiperidin-4-yl] urea derivatives and pharmaceutically acceptable salt thereof, process for preparation and use thereof
CN107935944B (en) * 2017-10-31 2021-12-21 广西师范大学 Diaryl urea quinoxaline derivative with anti-tumor activity and synthetic method thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Expert Opinion on Drug Discovery 2007, 2(10), 1301-1327

Also Published As

Publication number Publication date
KR20090090791A (en) 2009-08-26

Similar Documents

Publication Publication Date Title
CN102134230B (en) Depeptidyl peptidase inhibitors
EP3381896B1 (en) Biphenyl compound or salt thereof
ES2443127T3 (en) New tricyclic derivatives or pharmaceutically acceptable salts thereof, their manufacturing process and pharmaceutical compositions containing them
ES2548131T3 (en) Pharmaceutically acceptable salts of 2- {4 - [(3S) -piperidin-3-yl] phenyl} -2H-indazol-7-carboxamide
RU2765152C2 (en) New biphenyl compound or its salt
DE60025243T2 (en) PYRIMIDIN-5-CARBOXIMIDE COMPOUNDS, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE
US20060247439A1 (en) Mchir antagonists
ES2728199T3 (en) Amide substituted indazoles as poly (ADP-ribose) polymerase (PARP) inhibitors
EP2205593B1 (en) Quinazolinedione derivatives, preparation thereof and therapeutic uses thereof
EA007966B1 (en) Pyridinoylpiperidines as 5-htagonists
US20070004765A1 (en) New compounds
TW201420565A (en) Pyrrole sulfonamide derivatives, preparation method and medical use thereof
WO2007055418A1 (en) Aza-substituted spiro derivative
TW201524952A (en) Covalent inhibitors of KRAS G12C
TW201307284A (en) FAAH inhibitors
US9765056B2 (en) Indole and pyrrole compounds, a process for their preparation and pharmaceutical compositions containing them
KR102569031B1 (en) Pyrrolopyrimidine derivatives as nr2b nmda receptor antagonists
EP3191466B1 (en) Azetidinyloxyphenylpyrrolidine compounds
JP2009541463A (en) Piperidine or pyrrolidine urea derivatives, their preparation and their therapeutic use
CN114430743A (en) Thyroid hormone receptor beta agonist compounds
JP2014514246A (en) Protease activated receptor 2 (PAR2) antagonist
EA011274B1 (en) Substituted 20carbonylamino-6-piperidinaminopyridines and substituted 1-carbonylamino-3-piperidinaminobenzenes as 5-ht1f agonists
KR100967589B1 (en) 1-3-alkoxyquinoxaline-2-yl-3-[1-arylmethylpiperidin-4-yl] urea derivatives and pharmaceutically acceptable salt thereof, process for preparation and use thereof
EP1122253B1 (en) Quinazolinone derivatives
EP4053108A1 (en) Compound containing benzene ring and application thereof

Legal Events

Date Code Title Description
A201 Request for examination
E902 Notification of reason for refusal
E701 Decision to grant or registration of patent right
GRNT Written decision to grant
FPAY Annual fee payment

Payment date: 20130329

Year of fee payment: 4

LAPS Lapse due to unpaid annual fee