KR20200022710A - Novel pyrrolidine or piperidine derivatives having activity for T-type calcium channel - Google Patents

Novel pyrrolidine or piperidine derivatives having activity for T-type calcium channel Download PDF

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KR20200022710A
KR20200022710A KR1020180098677A KR20180098677A KR20200022710A KR 20200022710 A KR20200022710 A KR 20200022710A KR 1020180098677 A KR1020180098677 A KR 1020180098677A KR 20180098677 A KR20180098677 A KR 20180098677A KR 20200022710 A KR20200022710 A KR 20200022710A
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compound
methyl
pyrrolidin
phenyl
carboxamide
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배애님
임상민
서선희
손우승
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한국과학기술연구원
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Abstract

The present invention relates to a pyrrolidine or piperidine compound having activity for a T-type calcium channel. More specifically, a pyrrolidine or piperidine compound represented by chemical formula 1 according to the present invention has an excellent antagonism on the T-type calcium channel, thereby being able to be usefully used as an agent for preventing or treating brain diseases such as epilepsy, high blood pressure, etc., heart diseases such as angina pectoris etc., pain diseases such as chronic pain, neurogenic pain, etc., or diseases related to cancer.

Description

Ｔ-형 칼슘 채널에 활성을 가지는 피롤리딘 또는 피페리딘 화합물 {Novel pyrrolidine or piperidine derivatives having activity for T-type calcium channel}Novel pyrrolidine or piperidine derivatives having activity for T-type calcium channel

본 발명은 T-형 칼슘 채널에 대하여 약학적 활성을 보이는 피롤리딘 또는 피페리딘 화합물 및 이의 약학적으로 허용 가능한 염, 이들 화합물의 제조방법, 그리고 이들 화합물이 유효성분으로 함유된 약제조성물에 관한 것이다. The present invention relates to a pyrrolidine or piperidine compound and a pharmaceutically acceptable salt thereof, a method for preparing these compounds, and a pharmaceutical composition containing these compounds as an active ingredient, which exhibit pharmacological activity against T-type calcium channels. It is about.

칼슘채널은 세포막의 활동전압에 의해 세포내에 칼슘의 농도를 높여줌으로써 다양한 신호전달에 중요한 역할을 하게 된다. 칼슘채널은 크게 강한 탈분극에 반응하는 고전압 활성화 칼슘채널(high-voltage activated calcium channel)과 약한 탈분극에 반응하는 저전압 활성화 칼슘채널 (low-voltage activated calcium channel)로 나뉜다. 그 중에 T-형 칼슘채널은 저전압 활성화 칼슘채널이다.Calcium channel plays an important role in various signal transmission by increasing the concentration of calcium in the cell by the action voltage of the cell membrane. The calcium channel is divided into a high-voltage activated calcium channel that responds to strong depolarization and a low-voltage activated calcium channel that reacts to weak depolarization. Among them, the T-type calcium channel is a low voltage activated calcium channel.

T-형 칼슘채널은 뇌, 중추 신경계, 심장, 평활근, 내분비기관 등에 존재하며, Cav3.1 (α1G), Cav3.2 (α1H), Cav3.3 (α1I)의 세 종류의 동형단백질을 가지고 있다. 그 중, 척수신경결찰 (spinal nerve ligation)을 일으켜 신경성 통증을 유발했을 때, Cav3.1(a1G) 넉아웃(knock-out)된 마우스는 정상쥐보다 기계적 자극에 대한 한계점이 더 컸고 신경성 통증이 경감된다고 발표되었다. 그리고, Cav3.2 (α1H)이 과발현된 신경성 통증 쥐 모델에 Cav3.2 안티센스 올리고뉴클레오타이드를 주입했을 때는 신경성 통증이 감소된 것으로 발표되었다. 또한, 척수신경결찰 (spinal nerve ligation)을 유발시킨 동물모델에 T-형 칼슘채널의 길항제인 미베프라딜 (mibefradil)과 에소숙시마이드(ethosuximide) 약물을 투여함에 따라 기계적 열적 유발 반응의 저해효과를 나타내었고, 이런 것들을 봤을 때 T-형 칼슘채널의 길항제가 신경성 통증치료에 효과를 보였다. T- type calcium channels are present in the brain, central nervous system, heart, smooth muscle, such as endocrine organs, three types of protein in the same type Cav3.1 (α 1G), Cav3.2 ( α 1H), Cav3.3 (α 1I) Have Among them, Cav3.1 (a1G) knocked-out mice had a greater limit on mechanical stimulation and neurological pain than normal mice when they caused spinal nerve ligation to cause neurological pain. It was announced to be alleviated. In addition, the neurological pain was reported to be reduced when Ca v 3.2 antisense oligonucleotides were injected into a rat model of neurological pain overexpressing Cav3.2 (α 1H ). In addition, the administration of mibefradil and ethosuximide, which are antagonists of T-type calcium channels, in animal models that induce spinal nerve ligation resulted in the inhibition of mechanical thermal induced responses. These results showed that antagonists of T-type calcium channel were effective in the treatment of neurological pain.

또한, 고혈압과 협심증 치료제로 시판되었던 미베프라딜(Mibefradil)이 T-형 칼슘채널의 길항제로서 신경성 통증치료 효과가 있었으나, 미베프라딜은 astemizole과 같은 항히스타민제들과의 상호작용으로 판매가 금지되었다. 이에 따라, 새로운 구조를 가진 T-형 칼슘채널의 길항제의 시급한 개발의 필요성이 커지고 있다.In addition, mibefradil, a commercially available drug for treating hypertension and angina, was effective in treating neurological pain as an antagonist of T-type calcium channels, but mibepradil was banned due to its interaction with antihistamines such as astemizole. Accordingly, there is an increasing need for urgent development of antagonists of T-type calcium channels with new structures.

앞서 본바와 같이, 여러 논문들을 통해 T-형 칼슘채널의 길항제가 간질 등의 뇌질환 치료제, 협심증 등의 심장질환 치료제, 신경성 통증 등의 통증질환 치료제로서 유효함을 보여주었다. 또한, 다른 약과의 상호작용이 없으며 T-형 칼슘채널에 선택적이고 좋은 약물동력학 프로파일과 ADME (흡수, 분배, 대사, 배출)를 가지면서 심장질환, 간질, 신경성 통증등과 관련 질병 등에 효능있는 새로운 T-형 칼슘채널의 길항제 개발이 요구된다.As previously seen, several papers have shown that antagonists of T-type calcium channel are effective as a treatment for brain diseases such as epilepsy, for treating heart diseases such as angina pectoris, and for treating pain diseases such as neuropathic pain. In addition, it has no interaction with other drugs, and is selective for T-type calcium channels and has a good pharmacokinetic profile and ADME (absorption, distribution, metabolism, excretion) and is effective in cardiac disease, epilepsy, neuropathic pain and related diseases. There is a need for the development of antagonists of T-type calcium channels.

본 발명은 상기의 문제점을 해결하기 위한 것으로, 하기와 같은 발명의 목적을 갖고 있다.The present invention has been made to solve the above problems and has the object of the following invention.

즉, 본 발명은 신규한 구조의 피롤리딘 또는 피페리딘 화합물 및/또는 이의 약학적으로 허용 가능한 염을 제공하는데 그 목적이 있다.That is, an object of the present invention is to provide a pyrrolidine or piperidine compound having a novel structure and / or a pharmaceutically acceptable salt thereof.

또한, 본 발명은 상기한 피롤리딘 또는 피페리딘 화합물을 제조하는 방법을 제공하는데 다른 목적이 있다.It is another object of the present invention to provide a method for preparing the pyrrolidine or piperidine compound described above.

또한, 본 발명은 상기한 피롤리딘 또는 피페리딘 화합물 및/또는 이의 약학적으로 허용 가능한 염이 유효성분으로 포함되어 있는 T-형 칼슘채널 길항작용을 갖는 약제학적 조성물을 제공하는데 또 다른 목적이 있다.In another aspect, the present invention provides a pharmaceutical composition having a T-type calcium channel antagonism containing the pyrrolidine or piperidine compound and / or a pharmaceutically acceptable salt thereof as an active ingredient. There is this.

또한, 본 발명은 상기한 피롤리딘 또는 피페리딘 화합물 및/또는 이의 약학적으로 허용 가능한 염이 유효성분으로 포함되어 있는 간질, 고혈압 등의 뇌질환, 협심증 등의 심장질환, 만성 통증, 신경성 통증 등의 통증질환, 및 암 중에서 선택된 T-형 칼슘채널과 관련된 질환의 예방 및/또는 치료용 약제를 제공하는데 또 다른 목적이 있다.In addition, the present invention is a brain disease such as epilepsy, hypertension, heart disease such as angina pectoris, chronic pain, neuropathy containing the pyrrolidine or piperidine compound and / or pharmaceutically acceptable salts thereof as an active ingredient Another object is to provide a medicament for the prevention and / or treatment of pain diseases such as pain and diseases associated with T-type calcium channels selected from cancer.

상기의 목적을 실현하기 위한 본 발명은 하기 화학식 1로 표시되는 피롤리딘 또는 피페리딘 또는 이것의 약학적으로 허용 가능한 염인 것을 특징으로 하는 화합물이다:The present invention for achieving the above object is a compound characterized in that the pyrrolidine or piperidine represented by the formula (1) or a pharmaceutically acceptable salt thereof:

[화학식 1][Formula 1]

Figure pat00001
Figure pat00001

상기 화학식 1에서,In Chemical Formula 1,

R1은 수소원자, C1-C6 알킬기, C1-C6 아세틸기, 아릴기, 또는 헤테로아릴기를 나타내고, 상기 아릴기는 할로겐, C1 알킬, 및 C1 할로알킬 중에서 선택된 1개 내지 2개의 치환기로 치환될 수 있으며; R 1 represents a hydrogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 acetyl group, an aryl group, or a heteroaryl group, wherein the aryl group is 1 to 2 selected from halogen, C 1 alkyl, and C 1 haloalkyl May be substituted with 4 substituents;

R2는 수소원자, 질소원자와 산소원자 중에서 선택된 1개∼2개 포함된 5각형 또는 6각형의 헤테로아릴기, 아릴기, 페닐 다이하이드로피리딘을 나타내고, 상기 헤테로아릴기, 아릴기, 페닐 다이하이드로피리딘은 페닐, 할로겐, C1-C4 알킬, C1 할로알킬, 할로알콕시, 니트로 및 에스터 중에서 선택된 1개 내지 2개의 치환기로 치환될 수 있으며;R 2 represents a pentagonal or hexagonal heteroaryl group, an aryl group, or a phenyl dihydropyridine containing 1 to 2 selected from a hydrogen atom, a nitrogen atom and an oxygen atom, and the heteroaryl group, aryl group, and phenyl di Hydropyridine may be substituted with 1 to 2 substituents selected from phenyl, halogen, C 1 -C 4 alkyl, C 1 haloalkyl, haloalkoxy, nitro and ester;

R3은 수소원자, 또는 하이드록시메틸을 나타내고;R 3 represents a hydrogen atom or hydroxymethyl;

n은 1 또는 2의 정수를 나타내고;n represents an integer of 1 or 2;

* 로 표시된 탄소원자는 비대칭 중심이고 (R) 배열과 (S) 배열의 이성질체로 되어 있음.Carbon atoms marked with * are asymmetric centers and consist of isomers of (R) and (S) configurations.

본 발명에 따른 화학식 1로 표시되는 피롤리딘 또는 피페리딘 화합물은, T-형 칼슘채널에 대하여 우수한 길항작용을 가지고 있다.The pyrrolidine or piperidine compound represented by the general formula (1) according to the present invention has excellent antagonism with respect to the T-type calcium channel.

본 발명에 따른 화합물은 T-형 칼슘채널에 대한 우수한 억제효능, 길항작용, 및 칼슘이동 억제 효능을 가지고 있어서, 간질, 고혈압 등의 뇌질환, 협심증 등의 심장질환, 만성 통증, 신경성 통증 등의 통증질환, 또는 암과 관련 질병의 예방 또는 치료제로서 유용하게 사용될 수 있다.The compound according to the present invention has excellent inhibitory effect, antagonism, and calcium migration inhibitory effect on T-type calcium channel, such as brain diseases such as epilepsy and hypertension, heart diseases such as angina pectoris, chronic pain, and neuropathic pain. It can be usefully used as a prophylactic or therapeutic agent for pain diseases or cancer and related diseases.

도 1은 본원의 일 실시예에 따른 신규 화합물(화합물번호 30)의 기계적, 냉적 통증 동물모델에 대한 통증 억제 결과를 나타낸 그래프이다.
도 2는 본원의 일 실시예에 따른 신규 화합물(화합물번호 40)의 기계적, 냉적 통증 동물모델에 대한 통증 억제 결과를 나타낸 그래프이다.1 is a graph showing the results of pain inhibition for the mechanical and cold pain animal model of the novel compound (Compound No. 30) according to an embodiment of the present application.
Figure 2 is a graph showing the pain inhibition results for the mechanical, cold pain animal model of the novel compound (Compound No. 40) according to an embodiment of the present application.

본 발명은 다양한 변환을 가할 수 있고 여러 가지 실시 예를 가질 수 있는 바, 특정 실시 예들을 도면에 예시하고 상세한 설명에서 상세하게 설명하고자 한다. 그러나, 이는 본 발명을 특정한 실시 형태에 대해 한정하려는 것이 아니며, 본 발명의 사상 및 기술 범위에 포함되는 모든 변환, 균등물 내지 대체물을 포함하는 것으로 이해되어야 한다. 본 발명을 설명함에 있어서 관련된 공지 기술에 대한 구체적인 설명이 본 발명의 요지를 흐릴 수 있다고 판단되는 경우 그 상세한 설명을 생략한다.As the inventive concept allows for various changes and numerous embodiments, particular embodiments will be illustrated in the drawings and described in detail in the written description. However, this is not intended to limit the present invention to specific embodiments, it should be understood to include all transformations, equivalents, and substitutes included in the spirit and scope of the present invention. In the following description of the present invention, if it is determined that the detailed description of the related known technology may obscure the gist of the present invention, the detailed description thereof will be omitted.

본 출원에서 사용한 용어는 단지 특정한 실시예를 설명하기 위해 사용된 것으로, 본 발명을 한정하려는 의도가 아니다. 단수의 표현은 문맥상 명백하게 다르게 뜻하지 않는 한, 복수의 표현을 포함한다. 본 출원에서, "포함하다" 또는 "가지다" 등의 용어는 명세서상에 기재된 특징, 숫자, 단계, 동작, 구성요소, 부품 또는 이들을 조합한 것이 존재함을 지정하려는 것이지, 하나 또는 그 이상의 다른 특징들이나 숫자, 단계, 동작, 구성요소, 부품 또는 이들을 조합한 것들의 존재 또는 부가 가능성을 미리 배제하지 않는 것으로 이해되어야 한다.The terminology used herein is for the purpose of describing particular example embodiments only and is not intended to be limiting of the present invention. Singular expressions include plural expressions unless the context clearly indicates otherwise. In this application, the terms "comprise" or "have" are intended to indicate that there is a feature, number, step, operation, component, part, or combination thereof described in the specification, and one or more other features. It is to be understood that the present invention does not exclude the possibility of the presence or the addition of numbers, steps, operations, components, components, or a combination thereof.

제1, 제2 등의 용어는 다양한 구성요소들을 설명하는데 사용될 수 있지만, 상기 구성요소들은 상기 용어들에 의해 한정되어서는 안 된다. 상기 용어들은 하나의 구성요소를 다른 구성요소로부터 구별하는 목적으로만 사용된다. Terms such as first and second may be used to describe various components, but the components should not be limited by the terms. The terms are used only for the purpose of distinguishing one component from another.

아래에서는 첨부한 도면을 참조하여 본원이 속하는 기술 분야에서 통상의 지식을 가진 자가 용이하게 실시할 수 있도록 본원의 실시예를 상세히 설명한다. 그러나 본원은 여러 가지 상이한 형태로 구현될 수 있으며 여기에서 설명하는 실시예에 한정되지 않는다. 그리고 도면에서 본원을 명확하게 설명하기 위해서 설명과 관계없는 부분은 생략하였으며, 명세서 전체를 통하여 유사한 부분에 대해서는 유사한 도면 부호를 붙였다.DETAILED DESCRIPTION Hereinafter, exemplary embodiments of the present disclosure will be described in detail with reference to the accompanying drawings so that those skilled in the art may easily implement the present disclosure. As those skilled in the art would realize, the described embodiments may be modified in various different ways, all without departing from the spirit or scope of the present invention. In the drawings, parts irrelevant to the description are omitted for simplicity of explanation, and like reference numerals designate like parts throughout the specification.

본원 명세서 전체에서, 어떤 부분이 어떤 구성 요소를 “포함”한다고 할 때, 이는 특별히 반대되는 기재가 없는 한 다른 구성 요소를 제외하는 것이 아니라 다른 구성 요소를 더 포함할 수 있는 것을 의미한다. 본원 명세서 전체에서 사용되는 정도의 용어 “약”, “실질적으로” 등은 언급된 의미에 고유한 제조 및 물질 허용오차가 제시될 때 그 수치에서 또는 그 수치에 근접한 의미로 사용되고, 본원의 이해를 돕기 위해 정확하거나 절대적인 수치가 언급된 개시 내용을 비양심적인 침해자가 부당하게 이용하는 것을 방지하기 위해 사용된다. 본원 명세서 전체에서 사용되는 정도의 용어 “~(하는) 단계” 또는 “~의 단계”는 “~ 를 위한 단계”를 의미하지 않는다.Throughout this specification, when a part is said to "include" a certain component, it means that it can further include other components, without excluding the other components unless specifically stated otherwise. As used throughout this specification, the terms “about”, “substantially”, and the like, are used at, or in close proximity to, numerical values when manufacturing and material tolerances inherent in the meanings indicated are provided, and an understanding of the present application may occur. Accurate or absolute figures are used to assist in the prevention of unfair use by unscrupulous infringers. As used throughout this specification, the term “step of” or “step of” does not mean “step for”.

본원 명세서 전체에서, 마쿠시 형식의 표현에 포함된 “이들의 조합(들)”의 용어는 마쿠시 형식의 표현에 기재된 구성 요소들로 이루어진 군에서 선택되는 하나 이상의 혼합 또는 조합을 의미하는 것으로서, 상기 구성 요소들로 이루어진 군에서 선택되는 하나 이상을 포함하는 것을 의미한다.Throughout this specification, the term “combination (s) thereof” included in the expression of a makushi form refers to one or more mixtures or combinations selected from the group consisting of the components described in the expression of makushi form, It means to include one or more selected from the group consisting of the above components.

본원 명세서 전체에서, “A 및/또는 B”의 기재는 “A 또는 B, 또는 A 및 B”를 의미한다.Throughout this specification, the description of “A and / or B” means “A or B, or A and B”.

다른 식으로 정의되지 않는 한, 본 명세서에서 사용된 모든 기술적 및 과학적 용어들은 본 발명이 속하는 기술 분야에서 숙련된 전문가에 의해서 통상적으로 이해되는 것과 동일한 의미를 갖는다. 일반적으로, 본 명세서에서 사용된 명명법은 본 기술 분야에서 잘 알려져 있고 통상적으로 사용되는 것이다.Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In general, the nomenclature used herein is well known and commonly used in the art.

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

본 발명은 T-형 칼슘채널 길항제로서 유효한 하기 화학식 1로 표시되는 피롤리딘 또는 피페리딘 화합물, 이 화합물의 제조방법, 이 화합물을 포함하는 약제조성물에 대한 것이다.The present invention relates to a pyrrolidine or piperidine compound represented by the following formula (1), which is effective as a T-type calcium channel antagonist, a method for preparing the compound, and a pharmaceutical composition comprising the compound.

본 발명의 일 실시형태는, 하기 화학식 1로 표시되는 피롤리딘 또는 피페리딘 또는 이것의 약학적으로 허용 가능한 염인 것을 특징으로 하는 화합물이다:One embodiment of the present invention is a compound characterized in that the pyrrolidine or piperidine represented by the formula (1) or a pharmaceutically acceptable salt thereof:

[화학식 1][Formula 1]

Figure pat00002
Figure pat00002

상기 화학식 1에서,In Chemical Formula 1,

R1은 수소원자, C1-C6 알킬기, C1-C6 아세틸기, 비치환되거나 치환된 아릴기, 또는 비치환되거나 치환된 헤테로아릴기를 나타내고, 상기 아릴기는 할로겐, C1 알킬, 및 C1 할로알킬 중에서 선택된 1개 내지 2개의 치환기로 치환될 수 있으며; R 1 represents a hydrogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 acetyl group, an unsubstituted or substituted aryl group, or an unsubstituted or substituted heteroaryl group, wherein the aryl group is halogen, C 1 alkyl, and May be substituted with 1 to 2 substituents selected from C 1 haloalkyl;

R2는 수소원자, 질소원자와 산소원자 중에서 선택된 1개∼2개 포함된 5각형 또는 6각형의 비치환되거나 치환된 헤테로아릴기, 비치환되거나 치환된 아릴기, 비치환되거나 치환된 페닐 다이하이드로피리딘을 나타내고, 상기 헤테로아릴기, 아릴기, 페닐 다이하이드로피리딘은 페닐, 할로겐, C1-C4 알킬, C1 할로알킬, 할로알콕시, 니트로 및 에스터 중에서 선택된 1개 내지 2개의 치환기로 치환될 수 있으며;R 2 is a pentagonal or hexagonal unsubstituted or substituted heteroaryl group containing 1 to 2 selected from a hydrogen atom, a nitrogen atom and an oxygen atom, an unsubstituted or substituted aryl group, an unsubstituted or substituted phenyl di Hydropyridine, wherein the heteroaryl group, aryl group, phenyl dihydropyridine is substituted with one or two substituents selected from phenyl, halogen, C 1 -C 4 alkyl, C 1 haloalkyl, haloalkoxy, nitro and ester Can be;

R3은 수소원자, 또는 하이드록시메틸을 나타내고;R 3 represents a hydrogen atom or hydroxymethyl;

n은 1 또는 2의 정수를 나타내고;n represents an integer of 1 or 2;

* 로 표시된 탄소원자는 비대칭 중심이고 (R) 배열과 (S) 배열의 이성질체로 되어 있음.Carbon atoms marked with * are asymmetric centers and consist of isomers of (R) and (S) configurations.

일 구현예로서, 상기 화합물은 상기 화학식 1로 표시되는 피롤리딘 화합물이고, 상기 화학식 1의, R1은 수소원자, C1-C6 알킬기, C1-C6 아세틸기, 치환된 아릴기, 또는 헤테로아릴기를 나타내고, 상기 치환된 아릴기는 할로겐, C1 알킬, 및 C1 할로알킬 중에서 선택된 1개 내지 2개의 치환기로 치환된 것이며; R2는 수소원자, 질소원자와 산소원자 중에서 선택된 1개∼2개 포함된 5각형 또는 6각형의 치환된 헤테로아릴기, 치환된 아릴기, 치환된 페닐 다이하이드로피리딘을 나타내고, 상기 헤테로아릴기, 아릴기, 페닐 다이하이드로피리딘은 페닐, 할로겐, C1-C4 알킬, C1 할로알킬, 할로알콕시, 니트로 및 에스터 중에서 선택된 1개 내지 2개의 치환기로 치환된 것이며; n은 1의 정수를 나타내는 것을 특징으로 할 수 있다. In one embodiment, the compound is a pyrrolidine compound represented by Formula 1, wherein in Formula 1, R 1 is a hydrogen atom, C 1 -C 6 alkyl group, C 1 -C 6 acetyl group, substituted aryl group Or a heteroaryl group, wherein the substituted aryl group is substituted with 1 to 2 substituents selected from halogen, C 1 alkyl, and C 1 haloalkyl; R 2 represents a pentagonal or hexagonal substituted heteroaryl group containing 1 to 2 selected from a hydrogen atom, a nitrogen atom and an oxygen atom, a substituted aryl group, a substituted phenyl dihydropyridine, and the heteroaryl group , Aryl group, phenyl dihydropyridine is substituted with 1 to 2 substituents selected from phenyl, halogen, C 1 -C 4 alkyl, C 1 haloalkyl, haloalkoxy, nitro and ester; n may represent an integer of 1.

다른 구현예로서, 상기 화합물은 상기 화학식 1로 표시되는 피페리딘 화합물이고, 상기 화학식 1의, R1은 수소원자, C1-C6 알킬기, C1-C6 아세틸기, 치환된 아릴기, 또는 헤테로아릴기를 나타내고, 상기 치환된 아릴기는 할로겐, C1 알킬, 및 C1 할로알킬 중에서 선택된 1개 내지 2개의 치환기로 치환된 것이며; R2는 수소원자, 질소원자와 산소원자 중에서 선택된 1개∼2개 포함된 5각형 또는 6각형의 치환된 헤테로아릴기, 치환된 아릴기, 치환된 페닐 다이하이드로피리딘을 나타내고, 상기 헤테로아릴기, 아릴기, 페닐 다이하이드로피리딘은 페닐, 할로겐, C1-C4 알킬, C1 할로알킬, 할로알콕시, 니트로 및 에스터 중에서 선택된 1개 내지 2개의 치환기로 치환된 것이며; n은 2의 정수를 나타내는 것을 특징으로 하는 것이 가능하다. In another embodiment, the compound is a piperidine compound represented by Formula 1, and in Formula 1, R 1 is a hydrogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 acetyl group, a substituted aryl group Or a heteroaryl group, wherein the substituted aryl group is substituted with 1 to 2 substituents selected from halogen, C 1 alkyl, and C 1 haloalkyl; R 2 represents a pentagonal or hexagonal substituted heteroaryl group containing 1 to 2 selected from a hydrogen atom, a nitrogen atom and an oxygen atom, a substituted aryl group, a substituted phenyl dihydropyridine, and the heteroaryl group , Aryl group, phenyl dihydropyridine is substituted with 1 to 2 substituents selected from phenyl, halogen, C 1 -C 4 alkyl, C 1 haloalkyl, haloalkoxy, nitro and ester; n can represent the integer of 2. It can be characterized by the above-mentioned.

즉, 본 발명에 따라 화학식 1로 표시되는 화합물은, 화학식 1에서 n이 1인 경우 5각형 피롤리딘 화합물일 수 있고, 화학식 1에서 n이 2인 경우 6각형 피페리딘 화합물인 것도 가능하다. That is, according to the present invention, the compound represented by Formula 1 may be a pentagonal pyrrolidine compound when n is 1 in Formula 1, or may be a hexagonal piperidine compound when n is 2 in Formula 1 .

또한, 본 발명에 따른 상기 화학식 1로 표시되는 화합물은 당해 기술 분야에서 통상적인 방법에 의해 약학적으로 허용 가능한 염을 형성할 수 있다. 예를 들면, 염산, 브롬산, 술폰산, 아미도황산, 인산, 질산과 같은 무독성의 무기산, 또는 아세트산, 프로피온산, 숙신산, 글리콜산, 스테아르산, 젖산, 타르타르산, 시트르산, 파라톨루엔설폰산, 메탄설폰산과 같은 무독성의 유기산과 함께 결합하여 약학적으로 허용 가능한 산부가 염을 형성할 수도 있다.In addition, the compound represented by Chemical Formula 1 according to the present invention may form a pharmaceutically acceptable salt by a conventional method in the art. Non-toxic inorganic acids such as hydrochloric acid, bromic acid, sulfonic acid, amido sulfuric acid, phosphoric acid, nitric acid or acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, tartaric acid, citric acid, paratoluenesulfonic acid, methanesulfone It may also be combined with non-toxic organic acids such as acids to form pharmaceutically acceptable acid addition salts.

본 발명에 따른 화합물을 정의하는데 사용된 용어들은 하기와 같은 의미를 갖는다.The terms used to define the compounds according to the invention have the following meanings.

용어 "약학적으로 허용 가능한"이라 함은 화합물의 생물학적 활성과 물성을 손상시키지 않는 성질을 의미한다.The term "pharmaceutically acceptable" means a property that does not impair the biological activity and physical properties of the compound.

용어 "약학적 조성물"은 본 발명의 화합물과 함께 필요에 따라 약학적으로 허용 가능한 담체, 희석제, 부형제, 또는 이들의 조합을 포함할 수 있다.The term "pharmaceutical composition" may include a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof as needed with the compound of the present invention.

용어 "치료"라 함은 발병 증상을 보이는 객체에 사용될 때 질병의 진행을 중단 또는 지연시키는 것을 의미한다.The term "treatment" means stopping or delaying the progression of the disease when used in a subject with symptoms of onset.

용어 "담체(carrier)"라 함은 세포 또는 조직 내로 화합물의 부가를 용이하게 하는 물질을 의미한다.The term "carrier" refers to a substance that facilitates the addition of a compound into a cell or tissue.

용어 "희석제(diluent)"라 함은 대상 화합물의 생물학적 활성 형태를 안정화시킬 뿐만 아니라, 화합물을 용해시키는 물에서 희석되는 물질로 정의된다.The term "diluent" is defined as a substance that not only stabilizes the biologically active form of a compound of interest, but also is diluted in water to dissolve the compound.

기타 본 명세서에서 사용된 용어와 약어들은 달리 정의되지 않는 한 본 발명이 속하는 기술 분야의 통상의 기술자에게 통상적으로 이해되는 의미로서 해석될 수 있다.Other terms and abbreviations used herein may be interpreted as meanings that are commonly understood by those skilled in the art to which the present invention belongs unless otherwise defined.

본 발명에 따른 상기 화학식 1로 표시되는 화합물에 있어서, 치환기를 좀 더 자세히 설명하면 다음과 같다.In the compound represented by Chemical Formula 1 according to the present invention, the substituents will be described in more detail as follows.

용어 "할로겐"의 구체적인 예로는 플루오르(F), 클로린(Cl), 브롬(Br) 및 요오드(I)를 들 수 있고, 특히 플루오르(F) 및 클로린(Cl)일 수 있다.Specific examples of the term "halogen" include fluorine (F), chlorine (Cl), bromine (Br) and iodine (I), and in particular fluorine (F) and chlorine (Cl).

용어 "아릴(aryl)"은 공유 파이 전자계를 가지는 적어도 하나의 환을 포함하며, 예를 들어 모노사이클릭 또는 융합환 폴리사이클릭(즉, 탄소 원자들의 인접한 쌍들을 나눠가지는 링들)그룹을 포함한다. 즉, 본 명세서에서 아릴은 달리 정의하지 않는 한 페닐, 나프틸 등과 바이아릴을 포함할 수 있다. 본 발명의 일 실시예에서 아릴은 탄소수 6 내지 10의 방향족 고리를 지칭한다.The term "aryl" includes at least one ring having a shared pi electron system and includes, for example, a monocyclic or fused polycyclic (ie rings that divide adjacent pairs of carbon atoms) groups. . That is, in the present specification, aryl may include aryl, phenyl, naphthyl and the like, unless otherwise defined. In one embodiment of the present invention aryl refers to an aromatic ring having 6 to 10 carbon atoms.

용어 치환된 아릴기의 "아릴기"는 방향족 고리기를 의미하는 것으로, 아릴기는 6개의 원자를 가진 하나의 고리나 인접 탄소 원자에 이중 결합으로 공명 안정화된 상태를 말하며, 아릴기로는 페닐기가 포함될 수 있다. 상기한 아릴기는 할로겐, C1 알킬 및 C1 할로알킬, C1 할로알콕시 등 중에서 선택된 치환체가 하나 이상 치환될 수도 있다. 본 명세서에서 "아릴"과 "아릴기"는 같은 의미로 사용될 수도 있다.The term "aryl group" of a substituted aryl group refers to an aromatic ring group, wherein the aryl group refers to a ring having six atoms resonancely stabilized by a double bond to an adjacent carbon atom, and the aryl group may include a phenyl group. have. Wherein the aryl group may be substituted with one or more substituent selected from halogen, C 1 alkyl and C 1 haloalkyl, C 1 haloalkoxy. As used herein, "aryl" and "aryl group" may be used interchangeably.

용어 "헤테로아릴기"는 포화 또는 불포화이거나 단일고리 또는 결합고리(fused ring)에 관계없이 안정한 5 내지 6개의 원자로 구성된 헤테로고리를 나타내며, N, O로 구성된 1 내지 2개의 헤테로원자 및 탄소원자로 구성되며, 이러한 헤테로아릴기의 예를 들면, 피리디닐, 피라졸릴, 아이소옥사졸릴 등이 포함될 수 있다. 상기한 헤테로아릴기는 할로, C1-C4 알킬, 페닐 등 중에서 선택된 치환체가 하나 이상 치환될 수도 있다. 상기한 페닐 다이하이드로피리딘는 나이트로, 에스터. C1 알킬 등 중에서 선택된 치환체가 하나 이상 치환될 수도 있다.The term "heteroaryl group" refers to a heterocycle consisting of 5 to 6 atoms which is saturated or unsaturated or stable regardless of monocyclic or fused ring and consists of 1 to 2 heteroatoms and carbon atoms consisting of N and O. Examples of such heteroaryl groups may include pyridinyl, pyrazolyl, isoxazolyl and the like. The heteroaryl group may be substituted with one or more substituents selected from halo, C 1 -C 4 alkyl, phenyl and the like. Said phenyl dihydropyridine is nitro, ester. One or more substituents selected from C 1 alkyl and the like may be substituted.

용어 "알킬기"는 1~6개의 탄소원자를 가진 직쇄상, 분쇄상의 탄소사슬을 모두 포함하며, 선호하는 알킬기는 메틸, 프로필, 3,3-다이메틸부틸 등이 있다. The term "alkyl group" includes both straight and pulverized carbon chains having 1 to 6 carbon atoms, with preferred alkyl groups being methyl, propyl, 3,3-dimethylbutyl and the like.

용어 "아세틸기"는 6개의 탄소원자를 가진 직쇄상, 분쇄상의 탄소사슬을 모두 포함하며, 선호하는 아세틸기는 3,3-다이메틸부테인노일 등이 있다. The term "acetyl group" includes both straight and pulverized carbon chains having six carbon atoms, and preferred acetyl groups include 3,3-dimethylbutenyl.

본 발명에 따른 화합물로서, 상기 화학식 1로 표시되는 화합물을 예시하면 다음과 같다. 즉, 본 발명에 따른 화학식 1의 화합물은 하기 화합물 1 내지 화합물 61로 이루어진 군에서 선택된 것을 특징으로 하는 화합물일 수 있다.As a compound according to the present invention, examples of the compound represented by Formula 1 are as follows. That is, the compound of Formula 1 according to the present invention may be a compound characterized in that selected from the group consisting of Compound 1 to Compound 61.

(R)-N-((1-(3,3-다이메틸부틸)피롤리딘-3-일)메틸)-3-아이소프로필아이소사졸-5-카르복사미드 (화합물 1);( R ) -N -((1- (3,3-dimethylbutyl) pyrrolidin-3-yl) methyl) -3-isopropylisoazole-5-carboxamide (Compound 1);

(R)-3,5-다이클로로-N-((1-(3,3-다이메틸부틸)피롤리딘-3-일)메틸)벤즈아미드 (화합물 2);( R ) -3,5-dichloro- N -((1- (3,3-dimethylbutyl) pyrrolidin-3-yl) methyl) benzamide (Compound 2);

(R)-N-((1-(3,3-다이메틸부틸)피롤리딘-3-일)메틸)-1-메틸-3-프로필-1H-피라졸-5-카르복사미드 (화합물 3);( R ) -N -((1- (3,3-dimethylbutyl) pyrrolidin-3-yl) methyl) -1-methyl-3-propyl-1 H -pyrazole-5-carboxamide ( Compound 3);

(R)-N-((1-(3,3-다이메틸부틸)피롤리딘-3-일)메틸)-5-아이소부틸-1-페닐-1H -피라졸-3-카르복사미드 (화합물 4);( R ) -N -((1- (3,3-dimethylbutyl) pyrrolidin-3-yl) methyl) -5-isobutyl-1-phenyl-1 H -pyrazole-3-carboxamide (Compound 4);

(R)-3-아이소프로필-N-((1-(피리딘-3-일메틸)피롤리딘-3-일)메틸)아이소옥사졸-5-카르복사미드 (화합물 5);( R ) -3-isopropyl- N -((1- (pyridin-3-ylmethyl) pyrrolidin-3-yl) methyl) isoxazole-5-carboxamide (Compound 5);

(R)-3,5-다이클로로-N-((1-(피리딘-3-일메틸)피롤리딘-3-일)메틸)벤즈아미드 (화합물 6);( R ) -3,5-dichloro- N -((1- (pyridin-3-ylmethyl) pyrrolidin-3-yl) methyl) benzamide (Compound 6);

(R)-1-메틸-3-프로필-N-((1-(피리딘-3-일메틸)피롤리딘-3-일)메틸)-1H-피라졸-5-카르복사미드 (화합물 7);( R ) -1-Methyl-3-propyl- N -((1- (pyridin-3-ylmethyl) pyrrolidin-3-yl) methyl) -1 H -pyrazole-5-carboxamide (compound 7);

(R)-5-아이소부틸-1-페닐-N-((1-(피리딘-3-일메틸)피롤리딘-3-일)메틸)-1H-피라졸-3-카르복사미드 (화합물 8);( R ) -5-isobutyl-1-phenyl- N -((1- (pyridin-3-ylmethyl) pyrrolidin-3-yl) methyl) -1 H -pyrazole-3-carboxamide ( Compound 8);

(R)-3-아이소프로필-N-((1-(4-(트리플루오로메틸)페네틸)피롤리딘-3-일)메틸)아이소옥사졸-5-카르복사미드 (화합물 9);( R ) -3-isopropyl- N -((1- (4- (trifluoromethyl) phenethyl) pyrrolidin-3-yl) methyl) isoxazole-5-carboxamide (Compound 9) ;

(R)-3,5-다이클로로-N-((1-(4-(트리플루오로메틸)페네틸)피롤리딘-3-일)메틸)벤즈아미드 (화합물 10);( R ) -3,5-dichloro- N -((1- (4- (trifluoromethyl) phenethyl) pyrrolidin-3-yl) methyl) benzamide (Compound 10);

(R)-1-메틸-3-프로필-N-((1-(4-(트리플루오로메틸)페네틸)피롤리딘-3-일)메틸)-1H-피라졸-5-카르복사미드 (화합물 11);( R ) -1-methyl-3-propyl- N -((1- (4- (trifluoromethyl) phenethyl) pyrrolidin-3-yl) methyl) -1 H -pyrazole-5-car Radiamide (compound 11);

(R)-5-아이소부틸-1-페닐-N-((1-(4-(트리플루오로메틸)페네틸)피롤리딘-3-일)메틸)-1H-피라졸-3-카르복사미드 (화합물 12);( R ) -5-isobutyl-1-phenyl- N -((1- (4- (trifluoromethyl) phenethyl) pyrrolidin-3-yl) methyl) -1 H -pyrazole-3- Carboxamide (compound 12);

(R)-3,5-다이클로로-N-((1-(3,3-다이메틸부테노일)피롤리딘-3-일)메틸)벤즈아미드 (화합물 13);( R ) -3,5-dichloro- N -((1- (3,3-dimethylbutenoyl) pyrrolidin-3-yl) methyl) benzamide (Compound 13);

(R)-3,5-다이클로로-N-((1-(2-(4-(트리플루오로메틸)페닐)아세틸)피롤리딘-3-일)메틸)벤즈아마이드 (화합물 14);( R ) -3,5-dichloro- N -((1- (2- (4- (trifluoromethyl) phenyl) acetyl) pyrrolidin-3-yl) methyl) benzamide (Compound 14);

(R)-N-((1-(3,3-다이메틸부테노일)피롤리딘-3-일)메틸)-3-아이소프로필아이소옥사졸-5-카르복사미드 (화합물 15);( R ) -N -((1- (3,3-dimethylbutenoyl) pyrrolidin-3-yl) methyl) -3-isopropylisoxazole-5-carboxamide (Compound 15);

(R)-3-아이소프로필-N-((1-(2-(4-(트리플루오로메틸)페닐)아세틸)피롤리딘-3-일)메틸)아이소옥사졸-5-카르복사미드(화합물 16);( R ) -3-isopropyl- N -((1- (2- (4- (trifluoromethyl) phenyl) acetyl) pyrrolidin-3-yl) methyl) isoxazole-5-carboxamide (Compound 16);

(S)-N-((1-(3,3-다이메틸부테노일)피롤리딘-3-일)메틸)-3-아이소프로필아이소옥사졸-5-카르복사미드 (화합물 17);( S ) -N -((1- (3,3-dimethylbutenoyl) pyrrolidin-3-yl) methyl) -3-isopropylisoxazole-5-carboxamide (Compound 17);

(R)-N-((1-(3,3-다이메틸부테노일)피롤리딘-3-일)메틸)-1-메틸-3-프로필-1H-피라졸-5-카르복사미드 (화합물 18);( R ) -N -((1- (3,3-dimethylbutenoyl) pyrrolidin-3-yl) methyl) -1-methyl-3-propyl-1 H -pyrazole-5-carboxamide (Compound 18);

(R)-1-메틸-3-프로필-N-((1-(2-(4-(트리플루오로메틸)페닐)아세틸)피롤리딘-3-일)메틸)-1H-피라졸-5-카르복사미드(화합물 19);( R ) -1-methyl-3-propyl- N -((1- (2- (4- (trifluoromethyl) phenyl) acetyl) pyrrolidin-3-yl) methyl) -1 H -pyrazole -5-carboxamide (compound 19);

(S)-N-((1-(3,3-다이메틸부테노일)피롤리딘-3-일)메틸)-1-메틸-3-프로필-1H -피라졸-5-카르복사미드 (화합물 20);( S ) -N -((1- (3,3-dimethylbutenoyl) pyrrolidin-3-yl) methyl) -1-methyl-3-propyl-1 H -pyrazole-5-carboxamide (Compound 20);

(S)-1-메틸-3-프로필-N-((1-(2-(4-(트리플루오로메틸)페닐)아세틸)피롤리딘-3-일)메틸)-1H-피라졸-5-카르복사미드 (화합물 21);( S ) -1-methyl-3-propyl- N -((1- (2- (4- (trifluoromethyl) phenyl) acetyl) pyrrolidin-3-yl) methyl) -1 H -pyrazole -5-carboxamide (compound 21);

(S)-N-((1-(3,3-다이메틸부테노일)피롤리딘-3-일)메틸)-5-아이소부틸-1-페닐-1H-피라졸-3-카르복사미드 (화합물 22);( S ) -N -((1- (3,3-dimethylbutenoyl) pyrrolidin-3-yl) methyl) -5-isobutyl-1-phenyl-1 H -pyrazole-3-carbox Mead (compound 22);

(S)-5-아이소부틸-1-페닐-N-((1-(2-(4-(트리플루오로메틸)페닐)아세틸)피롤리딘-3-일)메틸)-1H-피라졸-3-카르복사미드 (화합물 23);( S ) -5-isobutyl-1-phenyl- N -((1- (2- (4- (trifluoromethyl) phenyl) acetyl) pyrrolidin-3-yl) methyl) -1 H -pyra Sol-3-carboxamide (compound 23);

(S)-3-아이소프로필-N-((1-(2-(4-(트리플루오로메틸)페닐)아세틸)피롤리딘-3-일)메틸)아이소옥사졸-5-카르복사미드 (화합물 24);( S ) -3-isopropyl- N -((1- (2- (4- (trifluoromethyl) phenyl) acetyl) pyrrolidin-3-yl) methyl) isoxazole-5-carboxamide (Compound 24);

(S)-3,5-다이클로로-N-((1-(3,3-다이메틸부테노일)피롤리딘-3-일)메틸)벤즈아미드 (화합물 25);( S ) -3,5-dichloro- N -((1- (3,3-dimethylbutenoyl) pyrrolidin-3-yl) methyl) benzamide (Compound 25);

(S)-3,5-다이클로로-N-((1-(2-(4-(트리플루오로메틸)페닐)아세틸)피롤리딘-3-일)메틸)벤즈아미드 (화합물 26);( S ) -3,5-dichloro- N -((1- (2- (4- (trifluoromethyl) phenyl) acetyl) pyrrolidin-3-yl) methyl) benzamide (Compound 26);

(R)-N-((1-(3,3-다이메틸부테노일)피롤리딘-3-일)메틸)-5-아이소부틸-1-페닐-1H-피라졸-3-카복스아미드 (화합물 27);( R ) -N -((1- (3,3-dimethylbutenoyl) pyrrolidin-3-yl) methyl) -5-isobutyl-1-phenyl-1 H -pyrazole-3-carbox Amides (compound 27);

(R)-5-아이소부틸-1-페닐-N-((1-(2-(4-(트리플루오로메틸)페닐)아세틸)피롤리딘-3-일)메틸)-1H-피라졸-3-카르복사미드 (화합물 28);( R ) -5-isobutyl-1-phenyl- N -((1- (2- (4- (trifluoromethyl) phenyl) acetyl) pyrrolidin-3-yl) methyl) -1 H -pyra Sol-3-carboxamide (compound 28);

(R)-5-아이소부틸-1-페닐-N-((1-(2-(3-(트리플루오로메틸)페닐)아세틸)피롤리딘-3-일)메틸)-1H-피라졸-3-카르복사미드 (화합물 29);( R ) -5-isobutyl-1-phenyl- N -((1- (2- (3- (trifluoromethyl) phenyl) acetyl) pyrrolidin-3-yl) methyl) -1 H -pyra Sol-3-carboxamide (compound 29);

(R)-5-아이소부틸-N-((1-(4-메틸-3-(트리플루오로메틸)페네틸)피롤리딘-3-일)메틸)-1-페닐-1H-피라졸-3-카르복사미드 (화합물 30);( R ) -5-isobutyl- N -((1- (4-methyl-3- (trifluoromethyl) phenethyl) pyrrolidin-3-yl) methyl) -1-phenyl-1 H -pyra Sol-3-carboxamide (compound 30);

(R)-5-아이소부틸-N-((1-(2-메틸-5-(트리플루오로메틸)페네틸)피롤리딘-3-일)메틸)-1-페닐-1H-피라졸-3-카르복사미드 (화합물 31);( R ) -5-isobutyl- N -((1- (2-methyl-5- (trifluoromethyl) phenethyl) pyrrolidin-3-yl) methyl) -1-phenyl-1 H -pyra Sol-3-carboxamide (compound 31);

(R)-N-((1-(2,4-비스(트리플루오로메틸)페네틸)피롤리딘-3-일)메틸)-5-아이소부틸-1-페닐-1H-피라졸-3-카르복사미드 (화합물 32);( R ) -N -((1- (2,4-bis (trifluoromethyl) phenethyl) pyrrolidin-3-yl) methyl) -5-isobutyl-1-phenyl-1 H -pyrazole -3-carboxamide (compound 32);

(R)-5-아이소부틸-N-((1-(5-메틸-2-(트리플루오로메틸)페네틸)피롤리딘-3-일)메틸)-1-페닐-1H-피라졸-3-카르복사미드 (화합물 33);( R ) -5-isobutyl- N -((1- (5-methyl-2- (trifluoromethyl) phenethyl) pyrrolidin-3-yl) methyl) -1-phenyl-1 H -pyra Sol-3-carboxamide (compound 33);

(R)-5-아이소부틸-1-페닐-N-((1-(3-(트라이플루오로메틸)페네틸)피롤리딘-3-일)메틸)-1H-피라졸-3-카르복사미드 (화합물 34);( R ) -5-isobutyl-1-phenyl- N -((1- (3- (trifluoromethyl) phenethyl) pyrrolidin-3-yl) methyl) -1H-pyrazole-3-car Radiamide (compound 34);

메틸 2,6-다이메틸-4-(3-나이트로페닐)-5-((((R)-1-(4-(트리플루오로메틸)페네틸)피롤리딘-3-일)메틸)카르바모일l)-1,4-다이하이드로피리딘-3-카르복시산염(화합물 35);Methyl 2,6-dimethyl-4- (3-nitrophenyl) -5-(((( R ) -1- (4- (trifluoromethyl) phenethyl) pyrrolidin-3-yl) methyl ) Carbamoyl l) -1,4-dihydropyridine-3-carboxylate (Compound 35);

(R)-N-((1-(3,4-다이클로로페네틸)피롤리딘-3-일)메틸)-3-아이소프로필아이소옥사졸-5-카르복사미드 (화합물 36); (R) -N -((1- (3,4-dichlorophenethyl) pyrrolidin-3-yl) methyl) -3-isopropylisoxazole-5-carboxamide (Compound 36);

메틸 5-((((R)-1-(3,4-다이클로로페네틸)피롤리딘-3-일)메틸)카르바모일)-2, 6-다이메틸-4-(3-나이트로페닐)-1,4-다이하이드로피리딘-3-카르복시산염 (화합물 37);Methyl 5-((( (R) -1- (3,4-dichlorophenethyl) pyrrolidin-3-yl) methyl) carbamoyl) -2,6-dimethyl-4- (3-knight Rophenyl) -1,4-dihydropyridine-3-carboxylate (compound 37);

메틸 2,6-다이메틸-5-((((R)-1-(4-메틸-3-(트리플루오로메틸)페네틸)피롤리딘-3-일)메틸)카르바모일)-4-(3-나이트로페닐)-1,4-다이하이드로피리딘-3-카르복시산염 (화합물 38);Methyl 2,6-dimethyl-5-((( (R) -1- (4-methyl-3- (trifluoromethyl) phenethyl) pyrrolidin-3-yl) methyl) carbamoyl)- 4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylate (Compound 38);

메틸 5-((((R)-1-(4-클로로-3-플루오로페네틸)피롤리딘-3-일)메틸)카르바모일)-2,6-다이메틸-4-(3-나이트로페닐)-1,4-다이하이드로피리딘-3-카르복시산염 (화합물 39);Methyl 5-(((( (R) -1- (4-chloro-3-fluorophenethyl) pyrrolidin-3-yl) methyl) carbamoyl) -2,6-dimethyl-4- (3 Nitrophenyl) -1,4-dihydropyridine-3-carboxylate (compound 39);

(R)-3-아이소프로필-N-((1-(4-메틸-3-(트리플루오로메틸)페네틸)피롤리딘-3-일)메틸)아이소옥사졸-5-카르복사미드 (화합물 40);( R ) -3-isopropyl- N -((1- (4-methyl-3- (trifluoromethyl) phenethyl) pyrrolidin-3-yl) methyl) isoxazole-5-carboxamide (Compound 40);

(R)-N-((1-(4-클로로-3-플루오로페네틸)피롤리딘-3-일)메틸)-3-아이소프로필아이소옥사졸-5-카르복사미드 (화합물 41);( R ) -N -((1- (4-chloro-3-fluorophenethyl) pyrrolidin-3-yl) methyl) -3-isopropylisoxazole-5-carboxamide (Compound 41) ;

메틸 5-((((R)-1-(3-플루오로-4-(트리플루오로메톡시)페네틸)피롤리딘-3-일)메틸)카르바모일)-2,6-다이메틸-4-(3-나이트로페닐)-1,4-다이하이드로피리딘-3-카르복시산염 (화합물 42);Methyl 5-((((( R ) -1- (3-fluoro-4- (trifluoromethoxy) phenethyl) pyrrolidin-3-yl) methyl) carbamoyl) -2,6-dimethyl -4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylate (Compound 42);

(R)-N-((1-(3-플루오로-4-(트리플루오로메톡시)페네틸)피롤리딘-3-일)메틸)-5-아이소부틸-1-페닐-1H-피라졸-3-카르복사미드(화합물 43);( R ) -N -((1- (3-fluoro-4- (trifluoromethoxy) phenethyl) pyrrolidin-3-yl) methyl) -5-isobutyl-1-phenyl-1 H- Pyrazole-3-carboxamide (compound 43);

(R)-5-아이소부틸-1-페닐-N-((1-(2-(트라이플루오로메틸)페네틸) 피롤리딘-3-일)메틸)-1H-피라졸-3-카르복사미드 (화합물 44);( R ) -5-isobutyl-1-phenyl- N -((1- (2- (trifluoromethyl) phenethyl) pyrrolidin-3-yl) methyl) -1 H -pyrazole-3- Carboxamide (compound 44);

(R)-N-((1-(3-플루오로-4-(트리플루오로메톡시)페네틸)피롤리딘-3-일)메틸)-3-아이소프로필아이소옥사졸-5-카르복사미드 (화합물 45);( R ) -N -((1- (3-fluoro-4- (trifluoromethoxy) phenethyl) pyrrolidin-3-yl) methyl) -3-isopropylisoxazole-5-carbox Mead (Compound 45);

(R)-N-((1-(3,4-다이클로로페네틸)피롤리딘-3-일)메틸)-5-아이부틸-1-페닐-1H-피라졸-3-카르복사미드 (화합물 46);( R ) -N -((1- (3,4-dichlorophenethyl) pyrrolidin-3-yl) methyl) -5-ibutyl-1-phenyl-1 H -pyrazole-3-carbox Mead (compound 46);

(R)-N-((1-(4-클로로-3-플루오로페네틸)피롤리딘-3-일)메틸)-5-아이소부틸-1-페닐-1H-피라졸-3-카르복사미드 (화합물 47);(R)-N-((1- (4-chloro-3-fluorophenethyl) pyrrolidin-3-yl) methyl) -5-isobutyl-1-phenyl-1H-Pyrazole-3-carboxamide (Compound 47);

(R)-N-((1-(2,3-다이플루오로페네틸)피롤리딘-3-일)메틸)-5-아이소부틸-1-페닐-1H-피라졸-3-카르복사미드 (화합물 48);( R ) -N -((1- (2,3-difluorophenethyl) pyrrolidin-3-yl) methyl) -5-isobutyl-1-phenyl-1 H -pyrazole-3-car Radiamide (compound 48);

(R)-N-((1-(3,4-다이플루오로페네틸)피롤리딘-3-일)메틸)-5-아이소부틸-1-페닐-1H-피라졸-3-카르복사미드 (화합물 49);( R ) -N -((1- (3,4-difluorophenethyl) pyrrolidin-3-yl) methyl) -5-isobutyl-1-phenyl-1 H -pyrazole-3-car Radiamide (Compound 49);

(R)-5-아이소부틸-1-페닐-N-((1-(4-(트리플루오로메톡시)-3-(트리플루오로메틸)페네틸)피롤리딘-3-일)메틸)-1H-피라졸-3-카르복사미드 (화합물 50);( R ) -5-isobutyl-1-phenyl- N -((1- (4- (trifluoromethoxy) -3- (trifluoromethyl) phenethyl) pyrrolidin-3-yl) methyl) -1 H -pyrazole-3-carboxamide (Compound 50);

(R)-N-((1-(3,5-다이플루오로페네틸)피롤리딘-3-일)메틸)-5-아이소부틸-1-페닐-1H-피라졸-3-카르복사미드 (화합물 51);( R ) -N -((1- (3,5-difluorophenethyl) pyrrolidin-3-yl) methyl) -5-isobutyl-1-phenyl-1 H -pyrazole-3-car Radiamide (Compound 51);

(R)-N-((1-(3-클로로-5-플루오로페네틸)피롤리딘-3-일)메틸)-5-아이소부틸-1-페닐-1H-피라졸-3-카르복사미드 (화합물 52);( R ) -N -((1- (3-chloro-5-fluorophenethyl) pyrrolidin-3-yl) methyl) -5-isobutyl-1-phenyl-1 H -pyrazole-3- Carboxamide (Compound 52);

(R)-N-((1-(3-플루오로페네틸)피롤리딘-3-일)메틸)-5-아이소부틸-1-페닐-1H-피라졸-3-카르복사미드 (화합물 53);( R ) -N -((1- (3-fluorophenethyl) pyrrolidin-3-yl) methyl) -5-isobutyl-1-phenyl-1 H -pyrazole-3-carboxamide (Compound 53);

(R)-N-((1-(3-클로로-5-플루오로페네틸)피롤리딘-3-일)메틸)-5-메틸-1-페닐-1H-피라졸-3-카르복사미드 (화합물 54);( R ) -N -((1- (3-chloro-5-fluorophenethyl) pyrrolidin-3-yl) methyl) -5-methyl-1-phenyl-1 H -pyrazole-3-car Radiamide (compound 54);

N-((4-(하이드록시메틸)-1-(4-메틸-3-(트리플루오로메틸)페네틸)피페리딘-4-일)메틸)-5-아이소부틸-1-페닐-1H-피라졸-3-카르복사미드 (화합물 55); N -((4- (hydroxymethyl) -1- (4-methyl-3- (trifluoromethyl) phenethyl) piperidin-4-yl) methyl) -5-isobutyl-1-phenyl- 1 H -pyrazole-3-carboxamide (Compound 55);

N-((3-(하이드록시메틸)-1-(4-메틸-3-(트리플루오로메틸)페네틸)피롤리딘-3-일)메틸)-5-아이소부틸-1-페닐-1H-피라졸-3-카르복사미드 (화합물 56); N -((3- (hydroxymethyl) -1- (4-methyl-3- (trifluoromethyl) phenethyl) pyrrolidin-3-yl) methyl) -5-isobutyl-1-phenyl- 1 H -pyrazole-3-carboxamide (Compound 56);

(S)-5-아이소부틸-1-페닐-N-(피롤리딘-3-일메틸)-1H-피라졸-3-카르복사미드 (화합물 57);( S ) -5-isobutyl-1-phenyl- N- (pyrrolidin-3-ylmethyl) -1 H -pyrazole-3-carboxamide (Compound 57);

(S)-3-아이소프로필-N-(피롤리딘-3-일메틸)아이소옥사졸-5-카르복사미드(화합물 58);( S ) -3-isopropyl- N- (pyrrolidin-3-ylmethyl) isoxazole-5-carboxamide (Compound 58);

메틸 2,6-다이메틸-4-(3-나이트로페닐)-5-(((S)-피롤리딘-3-일메틸)카르바모일)-1,4-다이하이드로피리딘-3-카르복시산염 (화합물 59);Methyl 2,6-dimethyl-4- (3-nitrophenyl) -5-((( S ) -pyrrolidin-3-ylmethyl) carbamoyl) -1,4-dihydropyridine-3- Carboxylates (compound 59);

(R)-N-((1-(3-클로로-5-플루오로페네틸)피롤리딘-3-일)메틸)-3-아이소프로필아이소옥사졸-5-카르복사미드 (화합물 60); ( R ) -N -((1- (3-chloro-5-fluorophenethyl) pyrrolidin-3-yl) methyl) -3-isopropylisoxazole-5-carboxamide (Compound 60) ;

(R)-N-((1-(2-(3-클로로-5-플루오로페닐)아세틸)피롤리딘-3-일)메틸)-5-아이소부틸-1-페닐-1H-피라졸-3-카르복사미드 (화합물 61).( R ) -N -((1- (2- (3-chloro-5-fluorophenyl) acetyl) pyrrolidin-3-yl) methyl) -5-isobutyl-1-phenyl-1 H -pyra Sol-3-carboxamide (compound 61).

상기한 본 발명에 따른 각 화합물의 구조식은 하기 표 1에 나타난 바와 같다. Structural formula of each compound according to the present invention is as shown in Table 1 below.

화합물 번호Compound number 구조식constitutional formula 1One

Figure pat00003
Figure pat00003
22
Figure pat00004
Figure pat00004
 33
Figure pat00005
Figure pat00005
 44
Figure pat00006
Figure pat00006
 55
Figure pat00007
Figure pat00007
 66
Figure pat00008
Figure pat00008
 77
Figure pat00009
Figure pat00009
 88
Figure pat00010
Figure pat00010
 99
Figure pat00011
Figure pat00011
 1010
Figure pat00012
Figure pat00012
 1111
Figure pat00013
Figure pat00013
 1212
Figure pat00014
Figure pat00014
 1313
Figure pat00015
Figure pat00015
 1414
Figure pat00016
Figure pat00016
 1515
Figure pat00017
Figure pat00017
 1616
Figure pat00018
Figure pat00018
 1717
Figure pat00019
Figure pat00019
 1818
Figure pat00020
Figure pat00020
 1919
Figure pat00021
Figure pat00021
 2020
Figure pat00022
Figure pat00022
 2121
Figure pat00023
Figure pat00023
 2222
Figure pat00024
Figure pat00024
 2323
Figure pat00025
Figure pat00025
 2424
Figure pat00026
Figure pat00026
 2525
Figure pat00027
Figure pat00027
 2626
Figure pat00028
Figure pat00028
 2727
Figure pat00029
Figure pat00029
 2828
Figure pat00030
Figure pat00030
 2929
Figure pat00031
Figure pat00031
 3030
Figure pat00032
Figure pat00032
 3131
Figure pat00033
Figure pat00033
 3232
Figure pat00034
Figure pat00034
 3333
Figure pat00035
Figure pat00035
 3434
Figure pat00036
Figure pat00036
 3535
Figure pat00037
Figure pat00037
 3636
Figure pat00038
Figure pat00038
 3737
Figure pat00039
Figure pat00039
 3838
Figure pat00040
Figure pat00040
 3939
Figure pat00041
Figure pat00041
 4040
Figure pat00042
Figure pat00042
 4141
Figure pat00043
Figure pat00043
 4242
Figure pat00044
Figure pat00044
 4343
Figure pat00045
Figure pat00045
 4444
Figure pat00046
Figure pat00046
 4545
Figure pat00047
Figure pat00047
 4646
Figure pat00048
Figure pat00048
 4747
Figure pat00049
Figure pat00049
 4848
Figure pat00050
Figure pat00050
 4949
Figure pat00051
Figure pat00051
 5050
Figure pat00052
Figure pat00052
 5151
Figure pat00053
Figure pat00053
 5252
Figure pat00054
Figure pat00054
 5353
Figure pat00055
Figure pat00055
 5454
Figure pat00056
Figure pat00056
 5555
Figure pat00057
Figure pat00057
 5656
Figure pat00058
Figure pat00058
 5757
Figure pat00059
Figure pat00059
 5858
Figure pat00060
Figure pat00060
 5959
Figure pat00061
Figure pat00061
 6060
Figure pat00062
Figure pat00062
 6161
Figure pat00063
Figure pat00063

본 발명자들은 상기한 화합물 1 내지 61번 화합물이 T-형 칼슘채널에 대하여 우수한 길항작용을 가지고 있다는 것을 확인한 후, 본 발명을 완성하였다. The present inventors completed the present invention after confirming that the compounds 1 to 61 described above have an excellent antagonistic action on the T-type calcium channel.

후술하는 실시예 및 실험예에 나타난 바와 같이, 본 발명자들은 상기한 1 내지 61번 화합물 각각을 실제로 제조하였고, 그것들의 T-형 칼슘채널에 대한 효과를 테스한 결과, 본 발명에 따른 화합물은 전체적으로 T-형 칼슘채널에 대한 억제효과가 우수하였다. As shown in Examples and Experimental Examples described below, the inventors of the present invention actually prepared each of the compounds 1 to 61 described above, and tested their effect on their T-type calcium channels. The inhibitory effect on T-type calcium channel was excellent.

구체적으로는, FDSS6000를 이용하여 T-형 칼슘채널에 대한 % 억제율을 테스한 결과, 본 발명에 따른 화합물은 전체적으로 T-형 칼슘채널에 대한 칼슘이동 억제효과가 우수하였고, 그 중에서도 화합물 4, 9~14, 16, 19, 21~34, 36, 39~44, 46~56 은 α1형과 α1H형의 T-형 칼슘채널에 대하여 공통적으로 고르게 효과가 더욱 우수하였다(실험예 1 참조). 이에 따르면, 본 발명에 따른 화합물은 화합물 4, 9, 10, 11, 12, 13, 14, 16, 19, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 36, 39, 40, 41, 42, 43, 44, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55 및 56 으로 이루어진 군에서 선택된 것이 가능하다. Specifically, as a result of testing the% inhibition rate for the T-type calcium channel using FDSS6000, the compound according to the present invention was excellent in inhibiting the calcium movement on the T-type calcium channel as a whole, among others, compounds 4, 9 ˜14, 16, 19, 21-34, 36, 39-44, 46-56 were more evenly effective in common to T-type calcium channels of α1 and α1H types (see Experimental Example 1). According to this, the compounds according to the invention are compounds 4, 9, 10, 11, 12, 13, 14, 16, 19, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, It is possible to select from the group consisting of 32, 33, 34, 36, 39, 40, 41, 42, 43, 44, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55 and 56.

또한, T-형 칼슘채널이 발현되어 있는 HEK 293 Cell을 이용하여 IC50 약효를 테스트한 결과, 본 발명에 따른 화합물은 대체로 T-형 칼슘채널에 대한 억제 효과가 우수하였고, 그 중에서도, 화합물 30, 48, 49, 50, 51, 52, 53, 54, 55, 56 의 효과가 우수하였으며, 특히 화합물 50, 53은 α1G형과 α1H형의 T-형 칼슘채널에 대하여 공통적으로 고르게 효과가 더욱 우수하였다(실험예 2 참조). 이에 따르면, 본 발명에 따른 화합물은 화합물 30, 48, 49, 50, 51, 52, 53, 54, 55 및 56 으로 이루어진 군에서 선택된 것일 수 있다. In addition, IC 50 efficacy test using HEK 293 Cell expressing T-type calcium channel, the compound according to the present invention was generally excellent in inhibitory effect on T-type calcium channel, among them, Compound 30 , 48, 49, 50, 51, 52, 53, 54, 55, 56. The compounds 50 and 53 have a particularly good effect on T-type calcium channels of α1G and α1H types. (See Experimental Example 2). According to this, the compound according to the present invention may be selected from the group consisting of compounds 30, 48, 49, 50, 51, 52, 53, 54, 55 and 56.

한편, 본 발명은 상기 화학식 1로 표시되는 피롤리딘 또는 피페리딘 화합물을 특정 질환의 예방 및/또는 치료 목적에 부합하도록 유효성분으로 포함하는 약학 조성물일 수 있다. On the other hand, the present invention may be a pharmaceutical composition comprising a pyrrolidine or piperidine compound represented by the formula (1) as an active ingredient to meet the purpose of preventing and / or treating certain diseases.

본 발명에 따른 화합물은 T-형 칼슘채널에 길항작용을 갖고 있으므로, 간질, 고혈압 등의 뇌질환, 협심증 등의 심장질환, 만성 통증, 신경성 통증 등의 통증질환, 또는 암과 관련 질병의 예방 또는 치료제로서 유용하게 사용될 수 있다.Since the compound according to the present invention has an antagonistic action on the T-type calcium channel, prevention of epilepsy, brain diseases such as hypertension, heart diseases such as angina pectoris, pain diseases such as chronic pain and neurological pain, or cancer-related diseases or It can be usefully used as a therapeutic agent.

일 구현예로서, 본 발명은 상기한 화합물을 포함하는, T-형 칼슘채널 관련 질환의 예방용 또는 치료용 약학 조성물일 수 있다. 여기서, 상기 T-형 칼슘채널 관련 질환은 간질, 고혈압, 협심증, 만성 통증, 신경성 통증, 및 암으로 이루어진 군에서 선택된 하나 이상인 것이 가능하다. 그리고, 상기 조성물은 T-형 칼슘채널에 대한 억제효능, 길항작용, 및 칼슘이동 억제 효능 중 하나 이상을 갖는 것일 수 있다. In one embodiment, the present invention may be a pharmaceutical composition for preventing or treating T-type calcium channel-related diseases, including the compound described above. Here, the T-type calcium channel-related disease may be at least one selected from the group consisting of epilepsy, hypertension, angina pectoris, chronic pain, neurological pain, and cancer. In addition, the composition may have one or more of an inhibitory effect, an antagonism, and a calcium migration inhibitory effect on the T-type calcium channel.

또한, 본 발명은 담체, 보조제 또는 희석제를 더 포함하는 것을 특징으로 하는 약학 조성물일 수 있다. 본 발명의 약학 조성물은 상기 화학식 1로 표시되는 피롤리딘 또는 피페리딘 화합물 또는 이의 약제학적 허용 가능한 염과 함께 기타 통상적인 담체, 보조제 또는 희석제 등을 포함시켜서, 통상의 제제화 방법으로 제형화하여 경구투여 또는 비경구투여에 적합한 형태로 제조될 수 있다. 경구투여의 경우에는 정제, 캡슐제, 용액, 시럽제, 현탁제 등의 형태로 제조될 수 있고, 비경구투여의 경우에는 복강, 피하, 근육, 경피에 대한 주사제의 형태로 제조될 수 있다.In addition, the present invention may be a pharmaceutical composition characterized in that it further comprises a carrier, adjuvant or diluent. The pharmaceutical composition of the present invention includes other conventional carriers, adjuvants or diluents together with a pyrrolidine or piperidine compound represented by the formula (1) or a pharmaceutically acceptable salt thereof, and is formulated by a conventional formulation method. It may be prepared in a form suitable for oral or parenteral administration. In the case of oral administration, it may be prepared in the form of tablets, capsules, solutions, syrups, suspensions, etc., and in the case of parenteral administration, it may be prepared in the form of injections for intraperitoneal, subcutaneous, muscle, and transdermal.

본 발명의 일 실시예에 의하면, 버퍼 용액에 용해되어 있는 염을 희석제로 사용하고, 통상 사용되는 버퍼 용액은 인간 용액의 염 형태를 모방하고 있는 포스페이트 버퍼 식염수일 수 있다. 버퍼 염은 낮은 농도에서 용액의 pH를 제어할 수 있기 때문에, 버퍼 희석제가 화합물의 생물학적 활성을 변형시키지 않는다.According to one embodiment of the present invention, a salt dissolved in a buffer solution is used as a diluent, and a commonly used buffer solution may be phosphate buffer saline that mimics the salt form of a human solution. Because buffer salts can control the pH of the solution at low concentrations, the buffer diluent does not modify the biological activity of the compound.

본 발명의 약학 조성물을 T-형 칼슘채널 길항제로 투여함에 있어, 1일 유효투여량은 성인을 기준으로 0.01 내지 1,000 mg/day이나, 투여용량은 환자의 나이, 몸무게, 성별, 투여형태, 건강상태 및 질환 정도에 따라 달라질 수 있으며, 의사 또는 약사의 판단에 따라 일정 시간간격으로 1일 1회 내지 수회로 분할 투여할 수도 있다. In administering the pharmaceutical composition of the present invention as a T-type calcium channel antagonist, the effective daily dose is 0.01 to 1,000 mg / day based on an adult, but the dosage is based on the age, weight, sex, dosage form, health of the patient. Depending on the condition and the degree of disease, depending on the doctor or pharmacist's judgment may be administered once a day or divided into several times at regular intervals.

나아가, 본 발명은 상기 화학식 1로 표시되는 피롤리딘 또는 피페리딘 화합물 또는 이를 함유하는 조성물을 포함하는 특정 질환의 개선 및/또는 예방을 목적으로 사용하는 식품 용도를 제공할 수 있다. 즉, 본 발명은 상기한 화합물을 포함하는, T-형 칼슘채널 관련 질환의 개선 또는 예방용 건강기능식품일 수 있다.Furthermore, the present invention can provide a food use for the purpose of improving and / or preventing certain diseases including the pyrrolidine or the piperidine compound represented by Formula 1 or a composition containing the same. That is, the present invention may be a health functional food for improving or preventing T-type calcium channel-related diseases, including the compound described above.

한편, 본 발명은 상기 화학식 1로 표시되는 피롤리딘 또는 피페리딘 화합물의 제조방법을 포함한다. 본 발명에 따른 대표적인 제조방법은 상기 화학식 1에서 결합자에 따라 하기 반응식 1 내지 3에 나타낸 바와 같은 3가지 제조방법으로 대별될 수 있다. On the other hand, the present invention includes a method for producing a pyrrolidine or piperidine compound represented by the formula (1). Exemplary preparation methods according to the present invention can be roughly divided into three preparation methods as shown in Schemes 1 to 3 according to the binder in Chemical Formula 1.

첫 번째 제조방법은, 하기 반응식 1에 나타낸 바와 같은 제조방법이다. 하기 반응식 1은 본 발명에 따른 화학식 1에서 R3가 수소원자인 피롤리딘 화합물(I-9)을 제조하는 예이다. 하기 반응식 1의 I-4 화합물은 I-9 화합물를 제조하기 위한 중간체이다. The first manufacturing method is a manufacturing method as shown in Scheme 1 below. Scheme 1 below is an example of preparing a pyrrolidine compound (I-9) in which R 3 is a hydrogen atom in Chemical Formula 1 according to the present invention. The I-4 compound of Scheme 1 below is an intermediate for preparing the I-9 compound.

[반응식 1]Scheme 1

Figure pat00064
Figure pat00064

상기 반응식 1의 R1, R2는 각각 상기 화학식 1에서 정의한 바와 같다. 또한, Ra, Rb, Rc, Rd는 수소원자, 질소원자와 산소원자가 1∼2개 포함된 5각형의 헤테로아릴기, 치환된 아릴기, 치환된 페닐 다이하이드로피리딘을 나타낼 수 있다.R 1 and R 2 in Scheme 1 are the same as defined in Chemical Formula 1. In addition, R a , R b , R c , and R d may represent a pentagonal heteroaryl group containing 1 to 2 hydrogen atoms, nitrogen atoms, and oxygen atoms, substituted aryl groups, and substituted phenyl dihydropyridine. .

상기 반응식 1에 따른 결합반응에 의하면, 털트-부틸 (R)-3-하이드록시피롤리딘-1-카르복시산염 화합물(I-1) 또는 털트-부틸 (S)-3-하이드록시피롤리딘-1-카르복시산염 화합물(I-1)을 염화메테인술포닐(MsCl)과 트리에틸아민(TEA) 존재 하에서 반응하여, 털트-부틸 (R)-3-((메틸설포닐)옥시)피롤리딘-1-카르복시산염 화합물(I-2) 또는 털트-부틸 (S)-3-((메틸설포닐)옥시)피롤리딘-1-카르복시산염 화합물(I-2)을 각각 제조한다. 상기 제조된털트-부틸 (R)-3-((메틸설포닐)옥시)피롤리딘-1-카르복시산염 화합물(I-2) 또는 털트-부틸 (S)-3-((메틸설포닐)옥시)피롤리딘-1-카르복시산염 화합물(I-2)을 사이안화나트륨(NaCN) 존재 하에서 반응하여, 털트-부틸 (R)-3-사이아노피롤리딘-1-카르복시산염(I-3) 또는 털트-부틸 (S)-3-사이아노피롤리딘-1-카르복시산염(I-3)을 제조한다. 이어서 상기 제조된 털트-부틸 (R)-3-사이아노피롤리딘-1-카르복시산염(I-3) 또는 털트-부틸 (S)-3-사이아노피롤리딘-1-카르복시산염(I-3)을 수소화알루미늄리튬(LAH)과 알루미늄 클로라이드(AlCl3) 존재 하에서 반응하여 털트-부틸 (S)-3-(아미노메틸)피롤리딘-1-카르복시산염(I-4) 또는 털트-부틸 (R)-3-(아미노메틸)피롤리딘-1-카르복시산염(I-4)를 각각 제조할 수 있다.According to the coupling reaction according to Scheme 1, the butyl t-butyl ( R ) -3-hydroxypyrrolidine-1-carboxylate compound (I-1) or the butyl t-butyl ( S ) -3-hydroxypyrrolidine Reaction of the 1-carboxylate compound (I-1) in the presence of methanesulfonyl chloride (MsCl) and triethylamine (TEA) to give butyl- ( R ) -3-((methylsulfonyl) oxy) pyrroli A dine-1-carboxylate compound (I-2) or a tert-butyl ( S ) -3-((methylsulfonyl) oxy) pyrrolidine-1-carboxylate compound (I-2) is prepared, respectively. Tert-Butyl ( R ) -3-((methylsulfonyl) oxy) pyrrolidine-1-carboxylate compound (I-2) or Tult-Butyl ( S ) -3-((methylsulfonyl)) Oxy) pyrrolidine-1-carboxylate compound (I-2) is reacted in the presence of sodium cyanide (NaCN) to give butyl t-butyl ( R ) -3-cyanopyrrolidine-1-carboxylate (I- 3) or tuft-butyl ( S ) -3-cyanopyrrolidine-1-carboxylate (I-3). Subsequently, the prepared butyl t-butyl ( R ) -3-cyanopyrrolidine-1-carboxylate (I-3) or tet-butyl ( S ) -3-cyanopyrrolidine-1-carboxylate (I -3) is reacted in the presence of lithium aluminum hydride (LAH) with aluminum chloride (AlCl 3 ) to give the butyl t-butyl ( S ) -3- (aminomethyl) pyrrolidine-1-carboxylate (I-4) or Butyl ( R ) -3- (aminomethyl) pyrrolidine-1-carboxylate (I-4) can be prepared respectively.

이어서, 상기 털트-부틸 (R)-3-(아미노메틸)피롤리딘-1-카복르복시산염(I-4) 또는 털트-부틸 (S)-3-(아미노메틸)피롤리딘-1-카르복시산염(I-4)을 카복실산 화합물(I-5), 1,1'-카보닐다이이미다졸(CDI) 존재 하에서 결합반응시켜, 털트-부틸 (R)-피롤리딘 카르복사미드(I-6) 또는 털트-부틸 (S)-피롤리딘 카카르복사미드(I-6)를 제조한다. 상기 제조된 털트-부틸 (R)-피롤리딘 카르복사미드(I-6) 또는 털트-부틸 (S)-피롤리딘 카르복사미드(I-6)를 트리플루오로아세트산(TFA) 존재하에서 반응시켜, (R)-피롤리딘 카르복사미드(I-7) 또는 (S)-피롤리딘 카르복사미드(I-7) 화합물을 제조한다. 이어서 상기 제조된 (R)-피롤리딘 카르복사미드(I-7) 또는 (S)-피롤리딘 카르복사미드(I-7) 화합물을 알데하이드(Ra-CHO)와 소듐 트리아세톡시보로하이드라이드(NaBH(OAc)3)의 존재 하에서, 카복실산(Rb-COOH)과 1,1'-카보닐다이이미다졸(CDI) 존재 하에서, 메틸벤젠술폰산염(I-8; Rc-OTs)과 포타슘 카보네이트(K2CO3) 존재 하에서, 아실 클로라이드(Rd-CClO)와 트리에틸아민(TEA) 존재 하에서 각각 결합반응시켜, 피롤리딘 화합물(I-9)을 직접 제조할 수 있다. Subsequently, the said butyl t-butyl ( R ) -3- (aminomethyl) pyrrolidine-l-carboxylate (I-4) or the butyl t-butyl ( S ) -3- (aminomethyl) pyrrolidine-1 -Carboxylate (I-4) is bound and reacted in the presence of a carboxylic acid compound (I-5) and 1,1'-carbonyldiimidazole (CDI) to form a tert-butyl ( R ) -pyrrolidine carboxamide (I). -6) or turt-butyl ( S ) -pyrrolidine carcaramide (I-6). The prepared butyl t-butyl ( R ) -pyrrolidine carboxamide (I-6) or butyl t-butyl ( S ) -pyrrolidine carboxamide (I-6) in the presence of trifluoroacetic acid (TFA) Reaction produces a ( R ) -pyrrolidine carboxamide (I-7) or ( S ) -pyrrolidine carboxamide (I-7) compound. Subsequently, the prepared ( R ) -pyrrolidine carboxamide (I-7) or ( S ) -pyrrolidine carboxamide (I-7) compound was added with aldehyde (R a -CHO) and sodium triacetoxyboro Methylbenzenesulfonate (I-8; R c -OTs) in the presence of hydride (NaBH (OAc) 3 ), in the presence of carboxylic acid (R b -COOH) and 1,1'-carbonyldiimidazole (CDI) And potassium carbonate (K 2 CO 3 ) in the presence of acyl chloride (R d -CC10) and triethylamine (TEA) in the presence of the respective coupling reaction, pyrrolidin compound (I-9) can be prepared directly.

이와 관련하여, 상기 반응식 1에서 I-5 화합물의 일례를 제조하는 과정은, 하기 반응식 1-1에 의해 이루어질 수 있다. 상기 반응식 1-1의 결과물인 I-5a 화합물은 상기 반응식 1의 I-5 화합물인 카르복시산의 구체적인 합성 반응식을 나타낸 것이며, 이것을 이용한 화합물은 화학식 1에서 R2가 질소원자 및 산소원자 각각 1개가 포함된 5각형의 헤테로아릴기인 경우이다.In this regard, the process for preparing an example of the compound I-5 in Scheme 1 may be made by the following Scheme 1-1. The resulting compounds I-5a of Scheme 1-1 will showing a specific synthetic reaction scheme for the carboxylic acid I-5 a compound of Scheme 1, using the same compound is R 2 that comprises each have one nitrogen atom and an oxygen atom in the formula (1) This is the case of a pentagram heteroaryl group.

[반응식 1-1]Scheme 1-1

Figure pat00065
Figure pat00065

상기 반응식 1-1에 따른 반응에 의하면, 알데하이드 화합물(I-5-1)을 하이드록실아민 염화수소염(HONH2-HCl)과 탄산나트륨(Na2CO3)의 존재 하에서 반응시켜, (E)-아이소부티르알데하이드 옥심 화합물(I-5-2)을 제조한다. (E)-아이소부티르알데하이드 옥심 화합물(I-5-2)을 프로파르길 알코올(Propargyl alcohol; 2-Propyn-1-ol; C3H4O), N-클로로숙신이마이드(NCS)와 트리에틸아민(TEA) 존재하에서 반응시켜, 아이소옥사졸 알코올 화합물(I-5-3)을 제조할 수 있다. 상기 제조된 아이소옥사졸 알코올 화합물(I-5-3)을 피리딘늄 클로로크로메이트(PCC) 존재하에서 반응시켜, 아이소옥사졸 알데하이드 화합물(I-5-4)을 제조한다. 상기 제조된 아이소옥사졸 알데하이드 화합물(I-5-4)을 존스 시약(Jones Reagent) 존재하에서 반응시켜, 아이소옥사졸 카복실산(I-5a)을 제조한다. 또한, 상기 아이소옥사졸 알코올 화합물(I-5-3)을 존스 시약(Jones Reagent) 존재하에서 반응시켜, 아이소옥사졸 카복실산(I-5a)을 제조할 수 있다.According to the reaction according to Scheme 1-1, the aldehyde compound (I-5-1) was reacted in the presence of hydroxylamine hydrogen chloride (HONH 2 -HCl) and sodium carbonate (Na 2 CO 3 ), and (E)- Isobutyraldehyde oxime compound (I-5-2) is prepared. (E) -isobutyraldehyde oxime compound (I-5-2) to propargyl alcohol; 2-Propyn-1-ol; C 3 H 4 O), N -chlorosuccinimide (NCS) And react in the presence of triethylamine (TEA) to produce isoxazole alcohol compound (I-5-3). The isooxazole alcohol compound (I-5-3) prepared above is reacted in the presence of pyridinium chlorochromate (PCC) to prepare an isoxazole aldehyde compound (I-5-4). The isoxazole aldehyde compound (I-5-4) prepared above is reacted in the presence of Jones Reagent to prepare isoxazole carboxylic acid (I-5a). In addition, the isoxazole alcohol compound (I-5-3) may be reacted in the presence of Jones Reagent to prepare isoxazole carboxylic acid (I-5a).

또한, 상기 반응식 1에서 I-5 화합물의 다른 일례를 제조하는 과정은, 하기 반응식 1-2에 의해 이루어질 수 있다. 상기 반응식 1-2의 결과물인 I-5b 화합물은 상기 반응식 1의 I-5 화합물인 카르복시산의 구체적인 합성 반응식을 나타낸 것이며, 이것을 이용한 화합물은 화학식 1에서 R2가 질소원자가 2개 포함된 5각형의 헤테로아릴기인 경우이다.In addition, the process of preparing another example of the compound I-5 in Scheme 1 may be made by the following scheme 1-2. The resulting I-5b compound of Scheme 1-2 shows a specific synthetic scheme of the carboxylic acid, which is the I-5 compound of Scheme 1, and the compound using the compound of Formula 1 is a pentagon containing two nitrogen atoms of R 2 in Formula 1 In the case of a heteroaryl group.

[반응식 1-2]Scheme 1-2

Figure pat00066
Figure pat00066

상기 반응식 1-2에 따른 반응에 의하면, 메틸펜테인논 화합물(I-5-5)을 나트륨 에톡시드(Na, EtOH)와 옥살산다이에틸((EtOCO)2)의 존재 하에서 반응시켜, 에틸-6-메틸-2,4-다이옥소헵타노에이트 화합물(I-5-6)을 제조한다. 상기 제조된 에틸-6-메틸-2,4-다이옥소헵타노에이트 화합물(I-5-6)을 페닐하이드라진(Ph-NHNH2) 존재하에서 반응시켜, 페닐 피라졸 카르복시산염 화합물(I-5-7)을 제조할 수 있다. 상기 제조된 페닐 피라졸 카르복시산염 화합물(I-5-7)을 1N 수산화 나트륨 수용액(1N-NaOH) 존재하에서 반응시켜, 페닐 피라졸 카복실산 화합물(I-5b)을 제조할 수 있다.According to the reaction according to Scheme 1-2, the methylpentanenon compound (I-5-5) was reacted in the presence of sodium ethoxide (Na, EtOH) with diethyl oxalate ((EtOCO) 2 ), and ethyl- Prepare 6-Methyl-2,4-dioxoheptanoate compound (I-5-6). The ethyl-6-methyl-2,4-dioxoheptanoate compound (I-5-6) prepared above was reacted in the presence of phenylhydrazine (Ph-NHNH 2 ) to form a phenyl pyrazole carboxylate compound (I-5). -7) can be prepared. Phenyl pyrazole carboxylic acid compound (I-5b) may be prepared by reacting the phenyl pyrazole carboxylate compound (I-5-7) prepared above in the presence of 1N aqueous sodium hydroxide solution (1N-NaOH).

또한, 상기 반응식 1에서 I-5 화합물의 또 다른 일례를 제조하는 과정은, 하기 반응식 1-3에 의해 이루어질 수 있다. 상기 반응식 1-3의 결과물인 I-5c 화합물은 상기 반응식 1의 I-5 화합물인 카르복시산의 구체적인 합성 반응식을 나타낸 것이며, 이것을 이용한 화합물은 화학식 1에서 R2가 질소원자가 2개 포함된 5각형의 헤테로아릴기인 경우이다.In addition, the process of preparing another example of the compound I-5 in Scheme 1 may be made by the following scheme 1-3. The resulting I-5c compound of Scheme 1-3 shows a specific synthetic scheme of the carboxylic acid, which is the I-5 compound of Scheme 1, and the compound using the compound of Formula 1 is a pentagon containing two nitrogen atoms of R 2 in Formula 1 In the case of a heteroaryl group.

[반응식 1-3]Scheme 1-3

Figure pat00067
Figure pat00067

상기 반응식 1-3에 따른 반응에 의하면, 피라졸 카르복시산염 화합물(I-5-8)을 1N 수산화 나트륨 수용액(1N-NaOH) 존재하에서 반응시켜, 메틸 피라졸 카복실산 화합물(I-5c)을 제조할 수 있다.According to the reaction according to Scheme 1-3, the pyrazole carboxylate compound (I-5-8) was reacted in the presence of 1N sodium hydroxide solution (1N-NaOH) to prepare methyl pyrazole carboxylic acid compound (I-5c). can do.

이와 함께, 상기 반응식 1에서 I-8 화합물의 일례를 제조하는 과정은, 하기 반응식 1-4에 의해 이루어질 수 있다. 상기 반응식 1-4의 결과물인 I-8a 화합물은 상기 반응식 1의 I-8 화합물인 Rc-OTs의 구체적인 합성 반응식을 나타낸 것이다.In addition, a process of preparing an example of the compound I-8 in Scheme 1 may be performed by the following Scheme 1-4. Compound I-8a, the result of Scheme 1-4, illustrates a specific synthetic scheme of R c -OTs, which is the compound I-8 of Scheme 1.

[반응식 1-4]Scheme 1-4

Figure pat00068
Figure pat00068

상기 반응식 I-4에 따른 반응에 의하면, 카르복시산 화합물(I-8-1)을 테트라히드로푸란(THF)에 녹여져 있는 1.0M 수소화 알루미늄리튬(LAH) 존재 하에서 반응시켜, 알코올 화합물(I-8-2)을 제조한다. 상기 제조된 알코올 화합물(I-8-2)을 p-톨루엔술포닐클로라이드(TsCl)과 트리에틸아민(TEA) 존재 하에서 반응시켜, 토실레이트 화합물(I-8a)을 제조할 수 있다. According to the reaction according to Scheme I-4, the carboxylic acid compound (I-8-1) is reacted in the presence of 1.0 M lithium aluminum hydride (LAH) dissolved in tetrahydrofuran (THF) to give an alcohol compound (I-8). -2) is prepared. The tosylate compound (I-8a) may be prepared by reacting the prepared alcohol compound (I-8-2) in the presence of p-toluenesulfonyl chloride (TsCl) and triethylamine (TEA).

두 번째 제조방법은, 하기 반응식 2에 나타낸 바와 같은 제조방법이다. 하기 반응식 2는 본 발명에 따른 화합물 56을 제조하는 과정의 일례이다. The second manufacturing method is a manufacturing method as shown in Scheme 2 below. Scheme 2 below is an example of a process for preparing Compound 56 according to the present invention.

[반응식 2]Scheme 2

Figure pat00069
Figure pat00069

상기 반응식 2에 따른 반응에 의하면, 털트-부틸 3-사이아노-3-(하이드록시메틸)피롤리딘-1-카르복시산염 화합물(II-1)을 리튬 알루미늄 하이드라이드(LAH)와 알루미늄 클로라이드(AlCl3) 존재하에서 반응시켜, 털트-부틸 3-(아미노메틸)-3-(하이드록시메틸)피롤리딘-1-카르복시산염 화합물(II-2)을 제조한다. 상기 제조된 털트-부틸 3-(아미노메틸)-3-(하이드록시메틸)피롤리딘-1-카르복시산염 화합물(II-2)을 5-아이소부틸-1-페닐-1H-피라졸-3-카복실산와 1,1'-카보닐다이이미다졸(CDI) 존재하에서 반응시켜, 털트-부틸 3-(하이드록시메틸)-3-((5-아이소부틸-1-페닐-1H-피라졸-3-카르복스아미도)메틸)피롤리딘-1-카르복시산염 화합물(II-3)을 제조한다. t상기 제조된 털트-부틸 3-(하이드록시메틸)-3-((5-아이소부틸-1-페닐-1H-피라졸-3-카르복스아미도)메틸)피롤리딘-1-카르복시산염 화합물(II-3)을 트리플루오로아세트산(TFA) 존재하에서 반응시켜, N-((3-(하이드록시메틸)피롤리딘-3-일)메틸)-5-아이소부틸-1-페닐-1H-피라졸-3-카르복사미드 화합물(II-4)을 제조한다. 이어서 상기 제조된 N-((3-(하이드록시메틸)피롤리딘-3-일)메틸)-5-아이소부틸-1-페닐-1H-피라졸-3-카르복사미드 화합물(II-4)을 4-메틸-3-(트리플루오로메틸)페네틸 4-메틸벤젠술폰산염과 탄산칼륨(K2CO3) 존재하에서 반응시켜, N-((3-(하이드록시메틸)-1-(4-메틸-3-(트리플루오로메틸)페네틸)피롤리딘-3-일)메틸)-5-아이소부틸-1-페닐-1H-피라졸-3-카르복사미드 화합물(II-5)을 제조할 수 있다.According to the reaction according to Scheme 2, the tuft-butyl 3-cyano-3- (hydroxymethyl) pyrrolidine-1-carboxylate compound (II-1) was converted to lithium aluminum hydride (LAH) and aluminum chloride ( The reaction is carried out in the presence of AlCl 3 ) to prepare the tult-butyl 3- (aminomethyl) -3- (hydroxymethyl) pyrrolidine-1-carboxylate compound (II-2). The above-prepared lutet-butyl 3- (aminomethyl) -3- (hydroxymethyl) pyrrolidine-1-carboxylate compound (II-2) 5-isobutyl-1-phenyl- 1H -pyrazole- Reaction with 3-carboxylic acid in the presence of 1,1'-carbonyldiimidazole (CDI) to give the butyl t-butyl 3- (hydroxymethyl) -3-((5-isobutyl-1-phenyl-1 H -pyrazole- 3-Carboxamido) methyl) pyrrolidine-1-carboxylate Compound (II-3) is prepared. t-butyl 3- (hydroxymethyl) -3-((5-isobutyl-1-phenyl- 1H -pyrazole-3-carboxamido) methyl) pyrrolidine-1-carboxylic acid The salt compound (II-3) is reacted in the presence of trifluoroacetic acid (TFA) to give N -((3- (hydroxymethyl) pyrrolidin-3-yl) methyl) -5-isobutyl-1-phenyl -1 H - pyrazole-3-carboxamide to produce the compound (II-4). Subsequently prepared N -((3- (hydroxymethyl) pyrrolidin-3-yl) methyl) -5-isobutyl-1-phenyl-1 H -pyrazole-3-carboxamide compound (II- 4) is reacted with 4-methyl-3- (trifluoromethyl) phenethyl 4-methylbenzenesulfonate in the presence of potassium carbonate (K 2 CO 3 ) to give N -((3- (hydroxymethyl) -1 -(4-methyl-3- (trifluoromethyl) phenethyl) pyrrolidin-3-yl) methyl) -5-isobutyl-1-phenyl-1 H -pyrazole-3-carboxamide compound ( II-5) can be prepared.

세 번째 제조방법은, 하기 반응식 3에 나타낸 바와 같은 제조방법이다. 하기 반응식 3은 본 발명에 따른 화합물 55를 제조하는 과정의 일례이다. The third manufacturing method is a manufacturing method as shown in Scheme 3 below. Scheme 3 below is an example of a process for preparing Compound 55 according to the present invention.

[반응식 3]Scheme 3

Figure pat00070
Figure pat00070

상기 반응식 3에 따른 반응에 의하면, 털트-부틸 4-(아미노메틸)-4-(하이드록시메틸)피페리딘-1-카르복시산염 화합물(III-1)을 5-아이소부틸-1-페닐-1H-피라졸-3-카복실산와 1,1'-카보닐다이이미다졸(CDI) 존재하에서 반응시켜, 털트-부틸 4-(하이드록시메틸)-4-((5-아이소부틸-1-페닐-1H-피라졸-3-카복스아미도)메틸)피페리딘-1-카르복시산염 화합물(III-2)을 제조한다. 상기 제조된 털트-부틸 4-(하이드록시메틸)-4-((5-아이소부틸-1-페닐-1H-피라졸-3-카복스아미도)메틸)피페리딘-1-카르복시산염 화합물(III-2)을 트리플루오로아세트산(TFA) 존재하에서 반응시켜, N-((4-(하이드록시메틸)피페리딘-4-일)메틸)-5-아이소부틸-1-페닐-1H-피라졸-3-카르복사미드 화합물(III-3)을 제조한다. 이어서 상기 제조된 N-((3-(하이드록시메틸)피롤리딘-3-일)메틸)-5-아이소부틸-1-페닐-1H-피라졸-3-카르복사미드 화합물(III-3)을 4-메틸-3-(트리플루오로메틸)페네틸 4-메틸벤젠술폰산염과 탄산칼륨(K2CO3) 존재하에서 반응시켜, 결과적으로 N-((4-(하이드록시메틸)-1-(4-메틸-3-(트라이플우로로메틸)페네틸)피페리딘-4-일)메틸)-5-아이소부틸-1-페닐-1-피라졸-3-카르복사미드 화합물(III-4)을 제조할 수 있다.According to the reaction according to Scheme 3, the tert-butyl 4- (aminomethyl) -4- (hydroxymethyl) piperidine-1-carboxylate compound (III-1) was substituted with 5-isobutyl-1-phenyl-. Reaction with 1 H -pyrazole-3-carboxylic acid in the presence of 1,1'-carbonyldiimidazole (CDI) to give the solution of tuft-butyl 4- (hydroxymethyl) -4-((5-isobutyl-1-phenyl- 1 H -pyrazole-3-carboxamido) methyl) piperidine-1-carboxylate compound (III-2) is prepared. The above prepared tuft-butyl 4- (hydroxymethyl) -4-((5-isobutyl-1-phenyl-1 H -pyrazole-3-carboxamido) methyl) piperidine-1-carboxylate Compound (III-2) is reacted in the presence of trifluoroacetic acid (TFA) to give N -((4- (hydroxymethyl) piperidin-4-yl) methyl) -5-isobutyl-1-phenyl- 1 H -pyrazole-3-carboxamide compound (III-3) is prepared. Subsequently prepared N -((3- (hydroxymethyl) pyrrolidin-3-yl) methyl) -5-isobutyl-1-phenyl-1 H -pyrazole-3-carboxamide compound (III- 3) is reacted with 4-methyl-3- (trifluoromethyl) phenethyl 4-methylbenzenesulfonate in the presence of potassium carbonate (K 2 CO 3 ), resulting in N -((4- (hydroxymethyl) -1- (4-methyl-3- (trifluorouromethyl) phenethyl) piperidin-4-yl) methyl) -5-isobutyl-1-phenyl-1-pyrazole-3-carboxamide Compound (III-4) can be prepared.

상기 반응식 1 내지 3에 따른 제조과정에서 사용된 시작물질 및 반응물질은 공지 문헌에 의해 쉽게 제조하여 사용하거나, 또는 판매 제품을 직접 구입하여 사용할 수 있다. 또한, 당업자라면 유기합성 분야에서 널리 알려진 일반적인 방법에 의해 반응물질이나 목적 화합물에 다양한 치환기를 용이하게 도입할 수 있다.The starting materials and reactants used in the manufacturing process according to Schemes 1 to 3 may be easily prepared and used by known literature, or may be directly purchased and used for sale. In addition, those skilled in the art can easily introduce various substituents into the reactant or the target compound by a general method well known in the field of organic synthesis.

즉, 본 명세서에 기재되거나 선행 기술에 개시된 여러 합성법들을 임의로 조합하여 화학식 1의 화합물을 제조할 수 있고, 이는 본 발명의 범위에 속하는 것으로 이해되고, 화학식 1 화합물의 제조 방법이 상기 설명된 것으로 제한되는 것은 아니다That is, the compounds of formula 1 may be prepared by arbitrarily combining various synthesis methods described herein or disclosed in the prior art, which is understood to be within the scope of the present invention, and the method for preparing the compound of formula 1 is limited to that described above It doesn't become

이상에서 설명한 바와 같은 본 발명은 하기 제조예, 실시예, 제제예, 및 실험예에 의거하여 더욱 상세히 설명하겠는 바, 하기의 제조예, 실시예, 제제예, 및 실험예는 본 발명을 예시하는 것 일뿐 본 발명의 범위가 이들에 의해 한정되는 것은 아니다.The present invention as described above will be described in more detail based on the following Preparation Examples, Examples, Formulation Examples, and Experimental Examples, the following Preparation Examples, Examples, Formulation Examples, and Experimental Examples illustrate the present invention. It is only one thing and the scope of the present invention is not limited by these.

[[ 제조예Production Example 및  And 실시예Example ]]

본 발명에 따라 상기 화학식 1로 표시되는 화합물 1 내지 61의 구체적인 제조과정을 아래 실시예 1 내지 61을 참조로 하여 설명한다.According to the present invention will be described in detail with reference to Examples 1 to 61 of the specific manufacturing process of the compound 1 to 61 represented by the formula (1).

이에 앞서서, 상기 실시예 1 내지 61에서 사용되는 시작물질 또는 중간물질은 미리 준비될 수 있고, 이것은 아래 제조예 1 내지 64에서 예를 들어서 설명하였다.Prior to this, the starting material or the intermediate material used in Examples 1 to 61 may be prepared in advance, which has been described by way of example in Preparation Examples 1 to 64 below.

제조예Production Example

제조예Production Example 1 :  One : (E)-(E)- 아이소부티르알데하이드Isobutyraldehyde 옥심(Oxime 1-I-21-I-2 )의)of 제조 Produce

Figure pat00071
Figure pat00071

질소 하에서 아이소부티르알데하이드 (1-I-1; 6.33 mL, 69.3 mmol)을 EtOH:H2O=1:1 용액 100ml에 용해시킨 후 Na2CO3 (9.55 g, 90.1 mmol)와 하이드록시아민 하이드로클로라이드 (HONH2-HCL; 6.26 g, 90.1 mmol)을 첨가하였다. 반응 혼합물을 상온에서 10시간 교반하였다. 반응이 완결되면 증류수와 에테르를 이용하여 추출하고, 유기층을 무수 황산마그네슘으로 건조시킨 후 여과하였다. 여과액을 감압 농축을 통하여 상기 표제화합물(1-I-2) 5.89 g (수율 98%)을 얻었다.Isobutyraldehyde ( 1-I-1 ; 6.33 mL, 69.3 mmol) was dissolved in 100 ml of EtOH: H 2 O = 1: 1 solution under nitrogen, followed by Na 2 CO 3 (9.55 g, 90.1 mmol) and hydroxyamine. Hydrochloride (HONH 2 -HCL; 6.26 g, 90.1 mmol) was added. The reaction mixture was stirred at room temperature for 10 hours. After the reaction was completed, the mixture was extracted with distilled water and ether, and the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain 5.89 g (yield 98%) of the title compound ( 1-I-2 ).

1H NMR (300 MHz, CDCl3) δ 7.92 (br, s, 1H), 7.39 (d, J = 5.7 Hz, 1H), 2.51-2.46 (m, 1H), 1.14 (d, J = 6.9 Hz, 6H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.92 (br, s, 1H), 7.39 (d, J = 5.7 Hz, 1H), 2.51-2.46 (m, 1H), 1.14 (d, J = 6.9 Hz, 6H).

제조예Production Example 2 :  2 : (3-(3- 아이소프로필아이소옥사졸Isopropylisoxazole -5-일)메탄올(-5-yl) methanol ( 1-I-31-I-3 )의 제조Manufacturing

Figure pat00072
Figure pat00072

(E)-아이소부티르알데하이드 옥심 (1-I-2; 14.8 g, 170.1 mmol)와 N-클로로숙신이미드(NCS; 27.2 g, 204 mmol)을 테트라하이드로퓨란 (THF; 120 mL)에 용해시킨 후 0℃에서 1.5시간 교반하였다. 프로파르길 알코올 (Propargyl alcohol; 2-Propyn-1-ol; C3H4O; 15.1 mL, 255.1 mmol)와 TEA (28.7 mL, 204.1 mmol)를 적가한 후 12시간 더 교반하였다. 반응이 완결되면 증류수와 에틸아세테이트을 이용하여 추출하여 유기층을 무수 황산마그네슘으로 건조시킨 후 여과하였다. 여과액을 감압 농축시켜, 농축액을 관 크로마토그래피를 통하여 상기 표제화합물(1-I-3) 17.7 g (수율 74%)을 얻었다.(E) -Isobutyraldehyde oxime ( 1-I-2 ; 14.8 g, 170.1 mmol) and N -chlorosuccinimide (NCS; 27.2 g, 204 mmol) were dissolved in tetrahydrofuran (THF; 120 mL) After stirring, the mixture was stirred at 0 ° C. for 1.5 hours. Propargyl alcohol (Propargyl alcohol; 2-Propyn-1-ol; C 3 H 4 O; 15.1 mL, 255.1 mmol) and TEA (28.7 mL, 204.1 mmol) were added dropwise, followed by further stirring for 12 hours. After the reaction was completed, the mixture was extracted with distilled water and ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography to give 17.7 g (yield 74%) of the title compound ( 1-I-3 ).

1H NMR (300 MHz, CDCl3) δ 6.13 (s, 1H), 4.71 (s, 2H), 3.72 (br, s, 1H), 3.06-2.99 (m, 1H), 1.26 (d, J = 7.0 Hz, 6H). 1 H NMR (300 MHz, CDCl 3 ) δ 6.13 (s, 1H), 4.71 (s, 2H), 3.72 (br, s, 1H), 3.06-2.99 (m, 1H), 1.26 (d, J = 7.0 Hz, 6H).

제조예Production Example 3 : 3: 33 -- 아이소프로필아이소옥사졸Isopropylisoxazole -5--5- 카르발데히드(Carbaldehyde ( 1-I-41-I-4 )의)of 제조 Produce

Figure pat00073
Figure pat00073

피리디늄 클로로크로메이트 (PCC; 14.0 g, 64.8 mmol)와 실리카겔 (14.0 g)을 무수 다이클로로메테인 (50 mL)에 가한다. 반응 혼합물에 (3-아이소프로필아이소옥사졸-5-일)메탄올 (1-I-3; 4.6 g, 32.4 mmol)을 무수 다이클로로메테인에 용해시켜 천천히 적가한 후 5시간 교반하였다. 반응이 완결되면 필터하여 실리카겔을 여과하였다. 여과액을 감압 농축시켜, 농축액을 관 크로마토그래피를 통하여 상기 표제화합물(1-I-4) 3.5 g (수율 77%)을 얻었다.Pyridinium chlorochromate (PCC; 14.0 g, 64.8 mmol) and silica gel (14.0 g) are added to anhydrous dichloromethane (50 mL). To the reaction mixture, (3-isopropylisoxazol-5-yl) methanol ( 1-I-3 ; 4.6 g, 32.4 mmol) was dissolved in anhydrous dichloromethane, slowly added dropwise and stirred for 5 hours. After the reaction was completed, the silica gel was filtered by filtration. The filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography to obtain 3.5 g (yield 77%) of the title compound ( 1-I-4 ).

1H NMR (300 MHz, CDCl3) δ 9.98 (s, 1H), 6.91 (s, 1H), 3.21-3.17 (m, 1H), 1.36 (d, J = 8.4 Hz, 6H). 1 H NMR (300 MHz, CDCl 3 ) δ 9.98 (s, 1H), 6.91 (s, 1H), 3.21-3.17 (m, 1H), 1.36 (d, J = 8.4 Hz, 6H).

제조예Production Example 4 : 4 : 33 -- 아이소프로필아이소옥사졸Isopropylisoxazole -5--5- 카복실산(Carboxylic acid ( 1-I-51-I-5 )의)of 제조 Produce

Figure pat00074
Figure pat00074

3-아이소프로필아이소옥사졸-5-카르발데히드 (1-I-4; 500 mg, 3.6 mmol)을 아세톤에 녹이고 반응혼합물을 0℃로 낮추었다. 반응물에 존스 시약 (Jones Reagent; 7.2 mL)를 가한 후에 30분 동안 교반하였다. 반응 완결하면 pH 8이 될 때까지 포화 탄산 수소 나트륨 수용액과 에틸 아세테이트을 이용해서 추출하고, 유기층을 무수 황산마그네슘으로 건조시킨 후 여과하였다. 여과액을 감압 농축시켜, 상기 표제화합물(1-I-5) 550 mg (수율 98%)을 얻었다.3-Isopropylisoxazole-5-carbaldehyde ( 1-I-4 ; 500 mg, 3.6 mmol) was dissolved in acetone and the reaction mixture was lowered to 0 ° C. Jones Reagent (7.2 mL) was added to the reaction and stirred for 30 minutes. Upon completion of the reaction, the mixture was extracted with saturated aqueous sodium hydrogen carbonate solution and ethyl acetate until pH 8, and the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 550 mg (yield 98%) of the title compound ( 1-I-5 ).

1H NMR (300 MHz, CDCl3) δ 6.99 (s, 1H), 3.23-3.18 (m, 1H), 1.37 (d, J = 7.2 Hz, 6H). 1 H NMR (300 MHz, CDCl 3 ) δ 6.99 (s, 1H), 3.23-3.18 (m, 1H), 1.37 (d, J = 7.2 Hz, 6H).

제조예Production Example 5 : 5: 33 -- 아이소프로필아이소옥사졸Isopropylisoxazole -5--5- 카복실산(Carboxylic acid ( 1-I-51-I-5 )의)of 제조 Produce

Figure pat00075
Figure pat00075

(3-아이소프로필아이소옥사졸-5-일)메탄올 (1-I-3; 13.8 g, 97.8 mmol)과 존스 시약 (Jones Reagent; 195.6 mL, 391.2 mmol)을 이용하여 상기 표제화합물(1-I-5) 13.5 g (수율 89%)을 얻었다.(3-Isopropylisoxazol-5-yl) methanol ( 1-I-3 ; 13.8 g, 97.8 mmol) and Jones Reagent (195.6 mL, 391.2 mmol) were used for the title compound ( 1-I). -5 ) 13.5 g (yield 89%) were obtained.

1H NMR (300 MHz, CDCl3) δ 6.99 (s, 1H), 3.23-3.18 (m, 1H), 1.37 (d, J = 7.2 Hz, 6H). 1 H NMR (300 MHz, CDCl 3 ) δ 6.99 (s, 1H), 3.23-3.18 (m, 1H), 1.37 (d, J = 7.2 Hz, 6H).

제조예Production Example 6 :  6: 에틸 6-Ethyl 6- 메틸methyl -2,4--2,4- 다이옥소헵타노에이트(Dioxoheptanoate ( 1-II-21-II-2 )의)of 제조 Produce

Figure pat00076
Figure pat00076

소듐 금속(Na; 444 mg, 19.3 mmol)을 에탄올(EtOH; 10 mL)에 0℃에서 금속이 다 녹을 때까지 용해시킨다. 반응물에 4-메틸-2-펜테이논 (1-II-1; 2.5 mL, 19.3 mmol)을 가한 후 상온에서 30분 교반하였다. 반응물에 옥살산다이에틸 ((EtOCO)2; 2.6 mL, 19.3 mmol)를 첨가하고 45분 동안 80℃에서 교반하였다. 반응이 완결되면 상온으로 식히고 물과 다이클로로메테인를 이용하여 추출하고, 유기층을 무수 황산마그네슘으로 건조시킨 후 여과하였다. 여과액을 감압 농축시켜, 상기 표제화합물(1-II-2) 3.6 g (수율 93%)을 얻었다.Sodium metal (Na; 444 mg, 19.3 mmol) is dissolved in ethanol (EtOH; 10 mL) at 0 ° C. until the metal is dissolved. 4-methyl-2 - pentenone ( 1-II-1 ; 2.5 mL, 19.3 mmol) was added to the reaction, followed by stirring at room temperature for 30 minutes. Diethyl oxalate ((EtOCO) 2 ; 2.6 mL, 19.3 mmol) was added to the reaction and stirred at 80 ° C. for 45 minutes. After the reaction was completed, the mixture was cooled to room temperature, extracted with water and dichloromethane, and the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 3.6 g (yield 93%) of the title compound ( 1-II-2 ).

1H NMR (300 MHz, CDCl3)δ 14.65 (brs, 1H), 6.38 (s, 1H), 4.38 (q, J = 7.2 Hz, 2H), 2.48 (d, J = 6.6 Hz, 2H), 2.39-2.12 (m, 1H), 1.41 (t, J = 7.2 Hz, 3H), 1.00 (d, J = 6.6 Hz, 6H). 1 H NMR (300 MHz, CDCl 3 ) δ 14.65 (brs, 1H), 6.38 (s, 1H), 4.38 (q, J = 7.2 Hz, 2H), 2.48 (d, J = 6.6 Hz, 2H), 2.39 -2.12 (m, 1H), 1.41 (t, J = 7.2 Hz, 3H), 1.00 (d, J = 6.6 Hz, 6H).

제조예Production Example 7 :  7: 에틸 5-Ethyl 5- 아이소부틸Isobutyl -1-페닐-1-1-phenyl-1 HH -- 피라졸Pyrazole -3--3- 카르복시산염(Carboxylates ( 1-II-31-II-3 )의)of 제조 Produce

Figure pat00077
Figure pat00077

에틸 6-메틸-2,4-다이옥소헵타노에이트 (1-II-2; 2.0 g, 10 mmol)를 에탄올에 용해시키고 페닐하이드라진 (Pheynylhydrazine; 0.74 mL, 11 mmol)을 천천히 가한 후 3시간동안 교반하였다. 반응이 완결되면 에탄올을 감압농축하여 제거한 후 증류수와 다이클로로메테인를 이용하여 추출하고 유기층을 무수 황산마그네슘으로 건조시킨 후 여과하였다. 여과액을 감압 농축시켜, 상기 표제화합물(1-II-3) 1.94 g (수율 71%)을 얻었다.Ethyl 6-methyl-2,4-dioxoheptanoate ( 1-II-2 ; 2.0 g, 10 mmol) was dissolved in ethanol and slowly added phenylhydrazine (Pheynylhydrazine; 0.74 mL, 11 mmol) for 3 hours. Stirred After the reaction was completed, ethanol was concentrated under reduced pressure, and then extracted with distilled water and dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 1.94 g (yield 71%) of the title compound ( 1-II-3 ).

1H NMR (300 MHz, CDCl3) δ 7.55-7.43 (m, 5H), 6.79 (s, 1H), 4.45 (q, J = 7.2 Hz, 2H), 2.54 (d, J = 7.2 Hz, 2H), 1.93-1.80 (m, 1H), 1.44 (t, J = 7.2 Hz, 3H), 0.90 (d, J = 6.6 Hz, 6H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.55-7.43 (m, 5H), 6.79 (s, 1H), 4.45 (q, J = 7.2 Hz, 2H), 2.54 (d, J = 7.2 Hz, 2H) , 1.93-1.80 (m, 1H), 1.44 (t, J = 7.2 Hz, 3H), 0.90 (d, J = 6.6 Hz, 6H).

제조예Production Example 8 : 8 : 55 -- 아이소부틸Isobutyl -1-페닐-1-1-phenyl-1 HH -- 피라졸Pyrazole -3--3- 카복실산(Carboxylic acid ( 1-II-41-II-4 )의)of 제조 Produce

Figure pat00078
Figure pat00078

에틸 5-아이소부틸-1-페닐-1H-피라졸-3-카르복시산염 (1-II-3; 1.0 g, 5.1 mmol)을 에탄올에 용해시키고 1N 수산화나트륨 수용액 (1N-NaOH; 15.3 mL, 15.3 mmol)을 가하고 상온에서 2시간 교반하였다. 반응이 완결되면 에탄올을 감압 농축하여 제거한다. 소량의 증류수로 반응 혼합물을 녹인 후 1N HCl 수용액을 이용하여 고체화한다. 고체를 감압여과하여 에틸 아세테이트를 이용해서 추출하고 유기층을 무수 황산마그네슘으로 건조시킨 후 여과하였다. 상기 표제화합물(1-II-4) 829 mg (수율 97%)을 얻었다.Ethyl 5-isobutyl-1-phenyl-1 H -pyrazole -3- carboxylate ( 1-II-3 ; 1.0 g, 5.1 mmol) was dissolved in ethanol and aqueous 1N sodium hydroxide solution (1N-NaOH; 15.3 mL, 15.3 mmol) was added and stirred at room temperature for 2 hours. When the reaction is complete, ethanol is removed by concentration under reduced pressure. The reaction mixture is dissolved in a small amount of distilled water, and then solidified using a 1N HCl aqueous solution. The solid was filtered under reduced pressure, extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and filtered. 829 mg (97%) of the title compound ( 1-II-4 ) were obtained.

1H NMR (300 MHz, CDCl3) δ 7.42-7.30 (m, 5H), 6.81 (s, 1H), 2.52 (d, J = 7.2 Hz, 2H), 1.92-1.79 (m, 1H), 0.89 (d, J = 6.6 Hz, 6H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.42-7.30 (m, 5H), 6.81 (s, 1H), 2.52 (d, J = 7.2 Hz, 2H), 1.92-1.79 (m, 1H), 0.89 ( d, J = 6.6 Hz, 6H).

제조예Production Example 9 : 9: 1One -- 메틸methyl -3-프로필-1-3-propyl-1 HH -- 피라졸Pyrazole -5--5- 카복실산(Carboxylic acid ( 1-III-21-III-2 )의)of 제조 Produce

Figure pat00079
Figure pat00079

에틸 1-메틸-3-프로필-1H-피라졸-5-카르복시산염 (1-III- 1;1.0 g, 5.1 mmol)과 1N 수산화 나트륨 수용액 (15.3 mL, 15.3 mmol)을 이용하여 상기 표제화합물(1-III-2) 829 mg (수율 97%)을 얻었다.The title compound using ethyl 1-methyl-3-propyl-1 H -pyrazole-5-carboxylate ( 1-III- 1; 1.0 g, 5.1 mmol) and 1N aqueous sodium hydroxide solution (15.3 mL, 15.3 mmol) (1-III-2) to give the 829 mg (97% yield).

1H NMR (300 MHz, CDCl3) δ 6.79 (s, 1H), 4.20 (s, 3H), 2.66 (t, J = 7.8 Hz, 2H), 1.72 (m, 2H), 1.02 (t, J = 7.5 Hz, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 6.79 (s, 1H), 4.20 (s, 3H), 2.66 (t, J = 7.8 Hz, 2H), 1.72 (m, 2H), 1.02 (t, J = 7.5 Hz, 3H).

제조예Production Example 10 : 10: 22 -(4--(4- 메틸methyl -3-(-3- ( 트리플루오로메틸Trifluoromethyl )페닐)에탄올((Phenyl) ethanol ( 2-I-22-I-2 )의 제조Manufacturing

Figure pat00080
Figure pat00080

테트라하이드로퓨란(THF)에 녹여져있는 1.0M 리튬 알루미늄 하이드라이드 (LAH; 3.4 mL, 3.4 mmol)을 테트라하이드로퓨란에 녹인 2-(4-메틸-3-(트리플루오로메틸)페닐)아세트산(2-I-1; 500 mg, 2.3 mmol) 혼합물에 0℃에서 천천히 가한 후 2시간동안 상온에서 교반하였다. 반응이 완결된 후에 온도를 0℃로 낮춘 후 메탄올를 천천히 가한 다음 감압 농축하여 용매를 제거하였다. 증류수을 이용하여 염을 녹여 1N HCl 수용액으로 pH 2~3으로 낮춘 후 에틸 아세테이트를 이용하여 추출하였다. 무수 황산 마그네슘으로 건조시킨 후 필터 하였고, 유기층을 감압 농축하여 목적화합물(2-I-2) 448 mg (수율 96%)을 얻었다.2- (4-methyl-3- (trifluoromethyl) phenyl) acetic acid (1.0 M lithium aluminum hydride (LAH; 3.4 mL, 3.4 mmol) dissolved in tetrahydrofuran (THF) dissolved in tetrahydrofuran) 2-I-1 ; 500 mg, 2.3 mmol) was slowly added to the mixture at 0 ° C. and stirred at room temperature for 2 hours. After the reaction was completed, the temperature was lowered to 0 ° C., and methanol was slowly added thereto, followed by concentration under reduced pressure to remove the solvent. The salt was dissolved using distilled water, lowered to pH 2-3 with 1N HCl aqueous solution, and extracted with ethyl acetate. After drying over anhydrous magnesium sulfate and filtering, the organic layer was concentrated under reduced pressure to give 448 mg (96% yield) of the title compound ( 2-I-2 ).

1H NMR (300MHz, CDCl3) δ 7.50 (s, 1H), 7.34-7.23 (m, 2H), 3.01 (t, J = 6.3 Hz, 2H), 2.91 (t, J = 6.6 Hz, 2H), 2.49 (s, 3H), 1.49 (brs, 1H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.50 (s, 1H), 7.34-7.23 (m, 2H), 3.01 (t, J = 6.3 Hz, 2H), 2.91 (t, J = 6.6 Hz, 2H), 2.49 (s, 3 H), 1.49 (brs, 1 H).

제조예Production Example 11 : 11: 22 -(2--(2- 메틸methyl -5-(-5- ( 트리플루오로메틸Trifluoromethyl )페닐)에탄올((Phenyl) ethanol ( 2-II-22-II-2 )의 제조Manufacturing

Figure pat00081
Figure pat00081

2-(2-메틸-5-(트리플루오로메틸)페닐)아세트산 (2-II-1; 200 mg, 0.9 mmol)과 1.0M 리튬 알루미늄 하이드라이드 (1.4 mL, 1.4 mmol)을 이용하여 상기 표제화합물(2-II-2) 174 mg (수율 93%)을 얻었다.The title using 2- (2-methyl-5- (trifluoromethyl) phenyl) acetic acid ( 2-II-1 ; 200 mg, 0.9 mmol) and 1.0 M lithium aluminum hydride (1.4 mL, 1.4 mmol) 174 mg (yield 93%) of compound ( 2-II-2 ) were obtained.

1H NMR (400 MHz, CDCl3) δ 7.45 (s, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.29 (d, J = 6.8 Hz, 1H), 3.90 (t, J = 6.8 Hz, 2H), 2.96 (t, J = 6.8 Hz, 2H), 2.41 (s, 3H), 1.45 (brs, 1H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.45 (s, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.29 (d, J = 6.8 Hz, 1H), 3.90 (t, J = 6.8 Hz , 2H), 2.96 (t, J = 6.8 Hz, 2H), 2.41 (s, 3H), 1.45 (brs, 1H).

제조예Production Example 12 : 12: 22 -(2,4--(2,4- 비스(트리플루오로메틸)페닐Bis (trifluoromethyl) phenyl )에탄올()ethanol( 2-III-22-III-2 )의 제조Manufacturing

Figure pat00082
Figure pat00082

2-(2,4-비스(트리플루오로메틸)페닐)아세트산 (2-III-1; 250 mg, 0.9 mmol)과 1.0M 리튬 알루미늄 하이드라이드 (LAH, 1.4 mL, 1.4 mmol)을 이용하여 상기 표제화합물(2-III-2) 93 mg (수율 39%)을 얻었다.Using 2- (2,4-bis (trifluoromethyl) phenyl) acetic acid ( 2-III-1 ; 250 mg, 0.9 mmol) and 1.0 M lithium aluminum hydride (LAH, 1.4 mL, 1.4 mmol) 93 mg (39% yield) of the title compound ( 2-III-2 ) were obtained.

1H NMR (400 MHz, CDCl3) δ 7.92 (s, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 3.91 (t, J = 6.8 Hz, 2H), 3.13 (t, J = 6.8 Hz, 2H), 1.96 (brs, 1H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.92 (s, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 3.91 (t, J = 6.8 Hz , 2H), 3.13 (t, J = 6.8 Hz, 2H), 1.96 (brs, 1H).

제조예Production Example 13 :13: 2 2 -(5--(5- 메틸methyl -2-(-2-( 트리플루오로메틸Trifluoromethyl )페닐)에탄올((Phenyl) ethanol ( 2-IV-22-IV-2 )의 제조Manufacturing

Figure pat00083
Figure pat00083

2-(5-메틸-2-(트리플루오로메틸)페닐)아세트산(2-IV-1; 450 mg, 2.1 mmol)과 1.0M 리튬 알루미늄 하이드라이드 (3.1 mL, 3.1 mmol)을 이용하여 상기 표제화합물(2-IV-2) 277 mg (수율 66%)을 얻었다.Titled above using 2- (5-methyl-2- (trifluoromethyl) phenyl) acetic acid ( 2-IV-1 ; 450 mg, 2.1 mmol) and 1.0 M lithium aluminum hydride (3.1 mL, 3.1 mmol) 277 mg (66% yield) of compound ( 2-IV-2 ) were obtained.

1H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 8.0 Hz, 1H), 7.23 (s, 1H), 7.15 (d, J = 8.0 Hz, 1H), 3.90 (t, J = 6.8 Hz, 2H), 3.06 (t, J = 6.8 Hz, 2H), 2.41 (s, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.55 (d, J = 8.0 Hz, 1H), 7.23 (s, 1H), 7.15 (d, J = 8.0 Hz, 1H), 3.90 (t, J = 6.8 Hz , 2H), 3.06 (t, J = 6.8 Hz, 2H), 2.41 (s, 3H).

제조예Production Example 14 :14: 2 2 -(3,4--(3,4- 다이클로로페닐Dichlorophenyl )에탄올()ethanol( 2-V-22-V-2 )의 제조Manufacturing

Figure pat00084
Figure pat00084

2-(3,4-다이클로로페닐)아세트산 (2-V-1; 250 mg, 1.2 mmol)과 1.0M 리튬 알루미늄 하이드라이드 (LAH; 1.8 mL, 1.8 mmol)을 이용하여 상기 표제화합물(2-V-2) 207 mg (수율 89%)을 얻었다.2- (3,4-dichloro phenyl) acetic acid (2-V-1; 250 mg, 1.2 mmol) and a 1.0M lithium aluminum hydride; the title compound was obtained using (LAH 1.8 mL, 1.8 mmol) (2- V-2 ) 207 mg (yield 89%) were obtained.

1H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 8.0 Hz, 1H), 7.37 (s, 1H), 7.10 (dd, J = 8.0, 2.0 Hz, 1H), 3.89 (t, J = 6.4 Hz, 2H), 2.85 (t, J = 6.4 Hz, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.40 (d, J = 8.0 Hz, 1H), 7.37 (s, 1H), 7.10 (dd, J = 8.0, 2.0 Hz, 1H), 3.89 (t, J = 6.4 Hz, 2H), 2.85 (t, J = 6.4 Hz, 2H).

제조예Production Example 15 :15: 2 2 -(4--(4- 클로로Chloro -3--3- 플루오로페닐Fluorophenyl )에탄올()ethanol( 2-VI-22-VI-2 )의 제조Manufacturing

Figure pat00085
Figure pat00085

2-(4-클로로-3-플루오로페닐)아세트산 (2-VI-1; 500 mg, 2.7 mmol)과 1.0M 리튬 알루미늄 하이드라이드 (4.0 mL, 4.0 mmol)을 이용하여 상기 표제화합물(2-VI-2) 427 mg (수율 92%)을 얻었다.2- (4-chloro-3-fluorophenyl) acetic acid (2-VI-1; 500 mg, 2.7 mmol) and a 1.0M lithium aluminum hydride (4.0 mL, 4.0 mmol) was converted to the title compound using (2 VI-2 ) 427 mg (92% yield) were obtained.

1H NMR (400 MHz, CDCl3) δ 7.35 (t, J = 8.0 Hz, 1H), 7.07 (dd, J = 10.0, 2.0 Hz, 1H), 6.99 (dd, J = 8.0, 1.2 Hz, 1H), 3.89 (t, J = 6.4 Hz, 2H), 2.87 (t, J = 6.4 Hz, 2H), 1.49 (brs, 1H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.35 (t, J = 8.0 Hz, 1H), 7.07 (dd, J = 10.0, 2.0 Hz, 1H), 6.99 (dd, J = 8.0, 1.2 Hz, 1H) , 3.89 (t, J = 6.4 Hz, 2H), 2.87 (t, J = 6.4 Hz, 2H), 1.49 (brs, 1H).

제조예Production Example 16 :16: 2 2 -- (3-플루오로-4-(트리플루오로메톡시)페닐)에탈올((3-fluoro-4- (trifluoromethoxy) phenyl) ethanol ( 2-VII-22-VII-2 )의)of 제조 Produce

Figure pat00086
Figure pat00086

2-(3-플루오로-4-(트리플루오로메톡시)페닐)아세트산 (2-VII-1; 350 mg, 1.5 mmol)과 1.0M 리튬 알루미늄 하이드라이드 (LAH; 2.2 mL, 2.2 mmol)을 이용하여 상기 표제화합물(2-VII-2) 320 mg (수율 97%)을 얻었다.2- (3-fluoro-4- (trifluoromethoxy) phenyl) acetic acid ( 2-VII-1 ; 350 mg, 1.5 mmol) and 1.0 M lithium aluminum hydride (LAH; 2.2 mL, 2.2 mmol) To give 320 mg (97%) of the title compound ( 2-VII-2 ).

1H NMR (400 MHz, CDCl3) δ 7.29-7.24 (m, 1H), 7.13 (dd, J = 10.8, 1.6 Hz, 1H), 7.05 (dd, J = 8.4, 1.2 Hz, 1H), 3.90 (t, J = 6.4 Hz, 2H), 2.89 (t, J = 6.4 Hz, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.29-7.24 (m, 1H), 7.13 (dd, J = 10.8, 1.6 Hz, 1H), 7.05 (dd, J = 8.4, 1.2 Hz, 1H), 3.90 ( t, J = 6.4 Hz, 2H), 2.89 (t, J = 6.4 Hz, 2H).

제조예Production Example 17 :17: 2 2 -(4-(-(4-( 트리플루오로메톡시Trifluoromethoxy )-3-() -3- ( 트리플루오로메틸Trifluoromethyl )페닐)에탄올((Phenyl) ethanol ( 2-VIII-22-VIII-2 )의 제조Manufacturing

Figure pat00087
Figure pat00087

2-(4-(트리플루오로메톡시)-3-(트리플루오로메틸)페닐)아세트산 (2-VIII-1; 200 mg, 0.7 mmol)과 1.0M 리튬 알루미늄 하이드라이드 (LAH; 1.0 mL, 1.04 mmol)을 이용하여 상기 표제화합물(2-VIII-2) 175 mg (수율 93%)을 얻었다.2- (4- (trifluoromethoxy) -3- (trifluoromethyl) phenyl) acetic acid ( 2-VIII-1 ; 200 mg, 0.7 mmol) with 1.0 M lithium aluminum hydride (LAH; 1.0 mL, 1.04 mmol) was used to obtain 175 mg (yield 93%) of the title compound ( 2-VIII-2 ).

1H NMR (400 MHz, CDCl3) δ 7.60 (s, 1H), 7.50 (dd, J = 8.4, 1.6 Hz, 1H), 7.38 (d, J = 8.4, Hz, 1H), 3.93 (t, J = 6.4 Hz, 2H), 2.95 (t, J = 6.4 Hz, 2H), 1.48 (brs, 1H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.60 (s, 1H), 7.50 (dd, J = 8.4, 1.6 Hz, 1H), 7.38 (d, J = 8.4, Hz, 1H), 3.93 (t, J = 6.4 Hz, 2H), 2.95 (t, J = 6.4 Hz, 2H), 1.48 (brs, 1H).

제조예Production Example 18 :18: 2 2 -(3,5--(3,5- 다이플루오로페닐Difluorophenyl )에탄올()ethanol( 2-IX-22-IX-2 )의 제조Manufacturing

Figure pat00088
Figure pat00088

2-(3,5-다이플루오로페닐)아세트산 (2-IX-2; 300 mg, 1.7 mmol)과 1.0M 리튬 알루미늄 하이드라이드 (LAH; 2.6 mL, 2.6 mmol)을 이용하여 상기 표제화합물(2-IX-2) 252 mg (수율 92%)을 얻었다.2- (3,5-difluorophenyl) acetic acid (2-IX-2; 300 mg, 1.7 mmol) and a 1.0M lithium aluminum hydride (LAH; 2.6 mL, 2.6 mmol ) was converted to the title compound using (2 -IX-2 ) 252 mg (92% yield) were obtained.

1H NMR (400 MHz, CDCl3) δ 6.79 (dd, J = 8.0, 2.0 Hz, 2H), 6.73-6.68 (m, 1H), 3.90 (t, J = 6.4 Hz, 2H), 2.88 (t, J = 6.4 Hz, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 6.79 (dd, J = 8.0, 2.0 Hz, 2H), 6.73-6.68 (m, 1H), 3.90 (t, J = 6.4 Hz, 2H), 2.88 (t, J = 6.4 Hz, 2H).

제조예Production Example 19 :19: 2 2 -(3--(3- 클로로Chloro -5--5- 플루오로페닐Fluorophenyl )에탄올()ethanol( 2-X-22-X-2 )의 제조Manufacturing

Figure pat00089
Figure pat00089

2-(3-클로로-5-플루오로페닐)아세트산 (2-X-1; 300 mg, 1.6 mmol)과 1.0M 리튬 알루미늄 하이드라이드 (2.4 mL, 2.mmol)을 이용하여 상기 표제화합물(2-X-2) 264 mg (수율 95%)을 얻었다.2- (3-chloro-5-fluorophenyl) acetic acid (2-X-1; 300 mg, 1.6 mmol) and a 1.0M lithium aluminum hydride (2.4 mL, 2.mmol) the title compound was obtained using (2 -X-2 ) 264 mg (95% yield) were obtained.

1H NMR (400 MHz, CDCl3) δ 7.06 (d, J = 1.2 Hz, 1H), 6.99 (dt, J = 8.4, 2.0 Hz, 1H), 6.90-6.87 (m, 1H), 3.88 (t, J = 6.0 Hz, 2H), 2.86 (t, J = 6.4 Hz, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.06 (d, J = 1.2 Hz, 1H), 6.99 (dt, J = 8.4, 2.0 Hz, 1H), 6.90-6.87 (m, 1H), 3.88 (t, J = 6.0 Hz, 2H), 2.86 (t, J = 6.4 Hz, 2H).

실시예Example 20 : 20: 22 -(3--(3- 플루오로페닐Fluorophenyl )에탄올()ethanol( 2-XI-22-XI-2 )의 제조Manufacturing

Figure pat00090
Figure pat00090

2-(3-플루오로페닐)아세트산 (2-XI-2; 500 mg, 3.2 mmol)과 1.0M 리튬 알루미늄 하이드라이드 (LAH; 4.9 mL, 4.9 mmol)을 이용하여 상기 표제화합물(2-XI-2) 425 mg (수율 94%)을 얻었다.Using the 2- (3-fluorophenyl) acetic acid ( 2-XI-2 ; 500 mg, 3.2 mmol) and 1.0 M lithium aluminum hydride (LAH; 4.9 mL, 4.9 mmol), the title compound ( 2-XI- 2 ) 425 mg (94% yield) were obtained.

1H NMR (400 MHz, CDCl3) δ 7.31-7.29 (m, 1H), 7.04 (d, J = 7.6 Hz, 1H), 6.99-6.96 (m, 1H), 3.90 (t, J = 6.4 Hz, 2H), 2.90 (t, J = 6.4 Hz, 2H), 1.48 (brs, 1H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.31-7.29 (m, 1H), 7.04 (d, J = 7.6 Hz, 1H), 6.99-6.96 (m, 1H), 3.90 (t, J = 6.4 Hz, 2H), 2.90 (t, J = 6.4 Hz, 2H), 1.48 (brs, 1H).

제조예Production Example 21 :21: 4 4 -- 메틸methyl -3-(-3- ( 트리플루오로메틸Trifluoromethyl )) 페네틸Phenethyl 4- 4- 메틸벤젠술폰산염(Methylbenzenesulfonate ( 2-I-32-I-3 )의)of 제조 Produce

Figure pat00091
Figure pat00091

트리에틸아민 (TEA; 1.5 mL, 11.0 mmol)을 무수 다이클로로메테인에 녹여져 있는 2-(4-메틸-3-(트리플루오로메틸)페닐)에탄올 (2-I-2; 448 mg, 2.2 mmol) 혼합물에 천천히 가한 후 상온에서 1시간동안 교반하였다. 온도를 0℃로 낮춘 후 무수 다이클로로메테인에 녹인 p-톨루엔설포닐 클로라이드 (TsCl; 1.0 g, 5.5 mmol)을 혼합물에 천천히 가한 후 상온에서 5시간동안 교반하였다. 반응 완결 후에 증류수와 다이클로로메테인으로 추출한 후 무수 황산 마그네슘으로 수분을 건조하여 건조시킨 후 여과하였다. 여과액을 감압 농축시켜, 농축액을 관 크로마토그래피를 통하여 상기 표제화합물(2-I-3) 503 mg (수율 64%)을 얻었다. Triethylamine (TEA; 1.5 mL, 11.0 mmol) dissolved in anhydrous dichloromethane 2- (4-methyl-3- (trifluoromethyl) phenyl) ethanol ( 2-I-2 ; 448 mg, 2.2 mmol) was slowly added to the mixture, followed by stirring at room temperature for 1 hour. After the temperature was lowered to 0 ° C., p -toluenesulfonyl chloride (TsCl; 1.0 g, 5.5 mmol) dissolved in anhydrous dichloromethane was slowly added to the mixture, followed by stirring at room temperature for 5 hours. After completion of the reaction, the mixture was extracted with distilled water and dichloromethane, dried with anhydrous magnesium sulfate, dried, and filtered. The filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography to obtain 503 mg (yield 64%) of the title compound ( 2-I-3 ).

1H NMR (400 MHz, CDCl3) δ 7.69 (dd, J = 16.8, 8.0 Hz, 2H), 7.30-7.27 (m, 3H), 7.21-7.16 (m, 2H), 4.23 (t, J = 6.4 Hz, 2H), 2.96 (t, J = 6.8 Hz, 2H), 2.45-2.43 (m, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.69 (dd, J = 16.8, 8.0 Hz, 2H), 7.30-7.27 (m, 3H), 7.21-7.16 (m, 2H), 4.23 (t, J = 6.4 Hz, 2H), 2.96 (t, J = 6.8 Hz, 2H), 2.45-2.43 (m, 6H).

제조예Production Example 22 :22: 4 4 -(-( 트리플루오로메틸Trifluoromethyl )) 페네틸Phenethyl -4--4- 메틸벤젠술폰산염(Methylbenzenesulfonate ( 2-XII-22-XII-2 )의)of 제조 Produce

Figure pat00092
Figure pat00092

2-(4-(트리플루오로메틸)페닐)에탄올 (2-XII-1; 1.0 mL, 6.6 mmol)과 TEA (5.6 mL, 39.5 mmol)와 p-톨루엔설포닐 클로라이드 (TsCl; 3.8 g, 19.8 mmol)을 이용하여 상기 표제화합물(2-XII-2) 2.0 g (수율 86%)을 얻었다.2- (4- (trifluoromethyl) phenyl) ethanol ( 2-XII-1 ; 1.0 mL, 6.6 mmol) with TEA (5.6 mL, 39.5 mmol) and p -toluenesulfonyl chloride (TsCl; 3.8 g, 19.8 mmol) was used to obtain 2.0 g (yield 86%) of the title compound ( 2-XII-2 ).

1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.0 Hz, 2H), 7.29-7.23 (m, 4H), 4.27 (t, J = 6.4 Hz, 2H), 3.03 (t, J = 6.4 Hz, 2H), 2.45 (s, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.66 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.0 Hz, 2H), 7.29-7.23 (m, 4H), 4.27 (t, J = 6.4 Hz, 2H), 3.03 (t, J = 6.4 Hz, 2H), 2.45 (s, 3H).

제조예Production Example 23 :23: 3 3 -(-( 트리플루오로메틸Trifluoromethyl )) 페네틸Phenethyl -4--4- 메틸벤젠술폰산염(Methylbenzenesulfonate ( 2-XIII-22-XIII-2 )의)of 제조 Produce

Figure pat00093
Figure pat00093

3-(트리플루오로메틸)페닐)에탄올 (2-XIII-1; 462 mg, 2.4 mmol)과 TEA (0.7 mL, 4.9 mmol)와 p-톨루엔설포닐 클로라이드 (TsCl; 1.6 g, 8.5 mmol)을 이용하여 상기 표제화합물(2-XIII-2) 487 mg (수율 58%)을 얻었다.3- (trifluoromethyl) phenyl) ethanol ( 2-XIII-1 ; 462 mg, 2.4 mmol), TEA (0.7 mL, 4.9 mmol) and p -toluenesulfonyl chloride (TsCl; 1.6 g, 8.5 mmol) 487 mg (yield 58%) of the title compound ( 2-XIII-2 ) were obtained.

1H NMR (300 MHz, CDCl3) δ 7.65 (d, J = 4.2 Hz, 2H), 7.47-7.38 (m, 2H), 7.33-7.31 (m, 2H), 7.27-7.26 (m, 2H), 4.24 (t, J = 3.3 Hz, 2H), 3.01 (t, J = 3.3 Hz, 2H), 2.42 (s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.65 (d, J = 4.2 Hz, 2H), 7.47-7.38 (m, 2H), 7.33-7.31 (m, 2H), 7.27-7.26 (m, 2H), 4.24 (t, J = 3.3 Hz, 2H), 3.01 (t, J = 3.3 Hz, 2H), 2.42 (s, 3H).

제조예Production Example 24 :24: 2 2 -(-( 트리플루오로메틸Trifluoromethyl )) 페네틸Phenethyl -4--4- 메틸벤젠술폰산염(Methylbenzenesulfonate ( 2-XIV-22-XIV-2 )의)of 제조 Produce

Figure pat00094
Figure pat00094

2-(트리플루오로메틸)페닐)에탄올 (2- XIV -2; 410 mg, 2.2 mmol)과 TEA (0.6 mL, 4.3 mmol)와 p-톨루엔설포닐 클로라이드 (TsCl; 1.4 g, 7.5 mmol)을 이용하여 상기 표제화합물(2- XIV -2) 89 mg (수율 12%)을 얻었다.2- (trifluoromethyl) phenyl) ethanol ( 2- XIV- 2 ; 410 mg, 2.2 mmol), TEA (0.6 mL, 4.3 mmol) and p -toluenesulfonyl chloride (TsCl; 1.4 g, 7.5 mmol) To give 89 mg (yield 12%) of the title compound ( 2- XIV- 2 ).

1H NMR (300 MHz, CDCl3) δ 7.70 (d, J = 4.0 Hz, 2H), 7.59 (m, 1H), 7.46-7.45 (m, 1H), 7.35-7.32 (m, 2H), 7.30-7.26 (m, 2H), 4.22 (t, J = 3.3 Hz, 2H), 3.14 (t, J = 3.3 Hz, 2H), 2.43 (s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.70 (d, J = 4.0 Hz, 2H), 7.59 (m, 1H), 7.46-7.45 (m, 1H), 7.35-7.32 (m, 2H), 7.30- 7.26 (m, 2H), 4.22 (t, J = 3.3 Hz, 2H), 3.14 (t, J = 3.3 Hz, 2H), 2.43 (s, 3H).

제조예Production Example 25 :25: 2 2 -- 메틸methyl -5-(-5- ( 트리플루오로메틸Trifluoromethyl )) 페네틸Phenethyl 4- 4- 메틸벤젠술폰산염(Methylbenzenesulfonate ( 2-II-32-II-3 )의)of 제조 Produce

Figure pat00095
Figure pat00095

2-(2-메틸-5-(트리플루오로메틸)페닐)에탄올 (2-II-2; 174 mg, 0.9 mmol)과 TEA (0.6 mL, 4.3 mmol)와 p-톨루엔설포닐 클로라이드 (TsCl; 324 mg, 1.7 mmol)을 이용하여 상기 표제화합물(2-II-3) 261 mg (수율 85%)을 얻었다.2- (2-methyl-5- (trifluoromethyl) phenyl) ethanol ( 2-II-2 ; 174 mg, 0.9 mmol) with TEA (0.6 mL, 4.3 mmol) and p -toluenesulfonyl chloride (TsCl; 324 mg, 1.7 mmol) gave 261 mg (yield 85%) of the title compound ( 2-II-3 ).

1H NMR (400 MHz, CDCl3) δ 7.69 (dd, J = 14.4, 8.0 Hz, 2H), 7.39 (d, J = 8.0 Hz, 1H), 7.31-7.22 (m, 4H), 4.23 (t, J = 6.8 Hz, 2H), 3.03 (t, J = 7.2 Hz, 2H), 2.44 (s, 3H), 2.33 (s, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.69 (dd, J = 14.4, 8.0 Hz, 2H), 7.39 (d, J = 8.0 Hz, 1H), 7.31-7.22 (m, 4H), 4.23 (t, J = 6.8 Hz, 2H), 3.03 (t, J = 7.2 Hz, 2H), 2.44 (s, 3H), 2.33 (s, 3H).

제조예Production Example 26 :26: 2 2 ,4-,4- 비스(트리플루오로메틸)페네틸Bis (trifluoromethyl) phenethyl 4- 4- 메틸벤젠술폰산염(Methylbenzenesulfonate ( 2-III-32-III-3 )의)of 제조 Produce

Figure pat00096
Figure pat00096

2-(2,4-비스(트리플루오로메틸)페닐)에탄올 (2-III-2; 114 mg, 0.4 mmol)과 TEA (0.4 mL, 2.6 mmol)와 p-톨루엔설포닐 클로라이드 (TsCl; 252 mg, 1.3 mmol)을 이용하여 상기 표제화합물(2-III-3) 120 mg (수율 66%)을 얻었다.2- (2,4-bis (trifluoromethyl) phenyl) ethanol ( 2-III-2 ; 114 mg, 0.4 mmol) with TEA (0.4 mL, 2.6 mmol) and p -toluenesulfonyl chloride (TsCl; 252 mg, 1.3 mmol) was used to obtain 120 mg (yield 66%) of the title compound ( 2-III-3 ).

1H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.69 (dd, J = 6.4, 1.6 Hz, 2H), 7.51 (d, J = 8.0 Hz, 1H), 7.31-7.29 (m, 2H), 4.28 (t, J = 6.4 Hz, 2H), 3.23 (t, J = 6.4 Hz, 2H), 2.45 (s, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.86 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.69 (dd, J = 6.4, 1.6 Hz, 2H), 7.51 (d, J = 8.0 Hz, 1H), 7.31-7.29 (m, 2H), 4.28 (t, J = 6.4 Hz, 2H), 3.23 (t, J = 6.4 Hz, 2H), 2.45 (s, 3H).

제조예Production Example 27 :27: 5 5 -- 메틸methyl -2-(-2-( 트리플루오로메틸Trifluoromethyl )) 페네틸Phenethyl 4- 4- 메틸벤젠술폰산염(Methylbenzenesulfonate ( 2-IV-32-IV-3 )의)of 제조 Produce

Figure pat00097
Figure pat00097

2-(5-메틸-2-(트리플루오로메틸)페닐)에탄올 (2-IV-2; 277 mg, 1.4 mmol)과 TEA (1.1 mL, 8.2 mmol)와 p-톨루엔설포닐 클로라이드 (TsCl; 776 mg, 4.1 mmol)을 이용하여 상기 표제화합물(2-IV-3) 364 mg (수율 75%)을 얻었다.2- (5-methyl-2- (trifluoromethyl) phenyl) ethanol ( 2-IV-2 ; 277 mg, 1.4 mmol) with TEA (1.1 mL, 8.2 mmol) and p -toluenesulfonyl chloride (TsCl; 776 mg, 4.1 mmol) gave 364 mg (yield 75%) of the title compound ( 2-IV-3 ).

1H NMR (400 MHz, CDCl3) δ 7.75-7.72 (m, 2H), 7.49 (d, J = 8.0 Hz, 1H), 7.33-7.31 (m, 2H), 7.15-7.12 (m, 2H), 4.24 (t, J = 7.2 Hz, 2H), 3.12 (t, J = 7.2 Hz, 2H), 2.46 (s, 3H), 2.38 (s, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.75-7.72 (m, 2H), 7.49 (d, J = 8.0 Hz, 1H), 7.33-7.31 (m, 2H), 7.15-7.12 (m, 2H), 4.24 (t, J = 7.2 Hz, 2H), 3.12 (t, J = 7.2 Hz, 2H), 2.46 (s, 3H), 2.38 (s, 3H).

제조예Production Example 28 :28: 3 3 ,4-,4- 다이클로로페네틸Dichlorophenethyl 4- 4- 메틸벤젠술폰산염(Methylbenzenesulfonate ( 2-V-32-V-3 )의)of 제조 Produce

Figure pat00098
Figure pat00098

2-(3,4-다이클로로페닐)에탄올 (2-V-2; 202 mg, 1.1 mmol)과 TEA (0.9 mL, 6.4 mmol)와 p-톨루엔설포닐 클로라이드 (TsCl; 604 mg, 3.2 mmol)을 이용하여 상기 표제화합물(2-V-3) 320 mg (수율 87%)을 얻었다.2- (3,4-dichlorophenyl) ethanol ( 2-V-2 ; 202 mg, 1.1 mmol) with TEA (0.9 mL, 6.4 mmol) and p -toluenesulfonyl chloride (TsCl; 604 mg, 3.2 mmol) The title compound ( 2-V-3 ) was obtained 320 mg (yield 87%).

1H NMR (400 MHz, CDCl3) δ 7.65 (dd, J = 6.4, 1.6 Hz, 2H), 7.32-7.28 (m, 3H), 7.14 (d, J = 2.0 Hz, 1H), 6.96 (dd, J = 8.0, 2.0 Hz, 1H), 4.23 (t, J = 6.4 Hz, 2H), 2.91 (t, J = 6.4 Hz, 2H), 2.47 (s, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.65 (dd, J = 6.4, 1.6 Hz, 2H), 7.32-7.28 (m, 3H), 7.14 (d, J = 2.0 Hz, 1H), 6.96 (dd, J = 8.0, 2.0 Hz, 1H), 4.23 (t, J = 6.4 Hz, 2H), 2.91 (t, J = 6.4 Hz, 2H), 2.47 (s, 3H).

제조예Production Example 29 : 29: 44 -- 클로로Chloro -3--3- 플루오로페네틸Fluorophenethyl 4- 4- 메틸벤젠술폰산염(Methylbenzenesulfonate ( 2-VI-32-VI-3 )의)of 제조 Produce

Figure pat00099
Figure pat00099

2-(4-클로로-3-플루오로페닐)에탄올 (2-VI-2; 415 mg, 2.4 mmol)과 TEA (2.0 mL, 14.3 mmol)와 p-톨루엔설포닐 클로라이드 (TsCl; 1.4 g, 7.1 mmol)을 이용하여 상기 표제화합물(2-VI-3) 653 mg (수율 83%)을 얻었다.2- (4-chloro-3-fluorophenyl) ethanol ( 2-VI-2 ; 415 mg, 2.4 mmol) with TEA (2.0 mL, 14.3 mmol) and p -toluenesulfonyl chloride (TsCl; 1.4 g, 7.1 mmol) was used to obtain 653 mg (yield 83%) of the title compound ( 2-VI-3 ).

1H NMR (400 MHz, CDCl3) δ 7.67 (dd, J = 6.8, 1.6 Hz, 2H), 7.31-7.24 (m, 3H), 6.86-6.83 (m, 2H), 4.23 (t, J = 6.4 Hz, 2H), 2.93 (t, J = 6.4 Hz, 2H), 2.47 (s, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.67 (dd, J = 6.8, 1.6 Hz, 2H), 7.31-7.24 (m, 3H), 6.86-6.83 (m, 2H), 4.23 (t, J = 6.4 Hz, 2H), 2.93 (t, J = 6.4 Hz, 2H), 2.47 (s, 3H).

제조예Production Example 30 :30: 3 3 -- 플루오로Fluoro -4-(-4-( 트리플루오로메톡시Trifluoromethoxy )) 페네틸Phenethyl 4- 4- 메틸벤젠술폰산염(Methylbenzenesulfonate ( 2-VII-32-VII-3 )의)of 제조 Produce

Figure pat00100
Figure pat00100

2-(3-플루오로-4-(트리플루오로메톡시)페닐)에탄올 (2-VII-2; 299 mg, 1.3 mmol)과 TEA (0.9 mL, 6.7 mmol)와 p-톨루엔설포닐 클로라이드 (635 mg, 3.3 mmol)을 이용하여 상기 표제화합물(2-VII-3) 344 mg (수율 68%)을 얻었다.2- (3-fluoro-4- (trifluoromethoxy) phenyl) ethanol ( 2-VII-2 ; 299 mg, 1.3 mmol) with TEA (0.9 mL, 6.7 mmol) and p -toluenesulfonyl chloride (635 mg, 3.3 mmol) was used to give 344 mg (yield 68%) of the title compound ( 2-VII-3 ).

1H NMR (400 MHz, CDCl3) δ 7.65 (dd, J = 6.4, 1.6 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 7.18-7.13 (m, 1H), 6.93-6.90 (m, 2H), 4.22 (t, J = 6.4 Hz, 2H), 2.93 (t, J = 6.4 Hz, 2H), 2.41 (s, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.65 (dd, J = 6.4, 1.6 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 7.18-7.13 (m, 1H), 6.93-6.90 ( m, 2H), 4.22 (t, J = 6.4 Hz, 2H), 2.93 (t, J = 6.4 Hz, 2H), 2.41 (s, 3H).

제조예Production Example 31 :31: 2 2 ,3-, 3- 다이플루오로페네틸Difluorophenethyl 4- 4- 메틸벤젠술폰산염(Methylbenzenesulfonate ( 2-XV-22-XV-2 )의)of 제조 Produce

Figure pat00101
Figure pat00101

2-(2,3-다이플루오로페닐)에탄올 (2- XV -1; 250 mg, 1.6 mmol)과 TEA (1.1 mL, 7.9 mmol)와 p-톨루엔설포닐 클로라이드 (TsCl; 753 mg, 4.0 mmol)을 이용하여 상기 표제화합물(2- XV -2) 423 mg (수율 86%)을 얻었다.2- (2,3-difluorophenyl) ethanol ( 2- XV- 1 ; 250 mg, 1.6 mmol) with TEA (1.1 mL, 7.9 mmol) and p-toluenesulfonyl chloride (TsCl; 753 mg, 4.0 mmol ) To give 423 mg (yield 86%) of the title compound ( 2- XV- 2 ).

1H NMR (400 MHz, CDCl3) δ 7.70 (dt, J = 8.0, 2.0 Hz, 2H), 7.32-7.29 (m, 2H), 7.07-6.94 (m, 3H), 4.26 (t, J = 6.8 Hz, 2H), 3.04 (t, J = 6.8 Hz, 2H), 2.46 (s, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.70 (dt, J = 8.0, 2.0 Hz, 2H), 7.32-7.29 (m, 2H), 7.07-6.94 (m, 3H), 4.26 (t, J = 6.8 Hz, 2H), 3.04 (t, J = 6.8 Hz, 2H), 2.46 (s, 3H).

제조예Production Example 32 :32: 3 3 ,4-,4- 다이플루오르페네틸Difluorophenethyl 4- 4- 메틸벤젠술폰산염(Methylbenzenesulfonate ( 2-XVI-22-XVI-2 )의)of 제조 Produce

Figure pat00102
Figure pat00102

2-(3,4-다이플루오로페닐)에탄올 (2- XVI -1; 250 mg, 1.6 mmol)과 TEA (1.1 mL, 7.9 mmol)와 p-톨루엔설포닐 클로라이드 (TsCl; 753 mg, 4.0 mmol)을 이용하여 상기 표제화합물(2- XVI -2) 429 mg (수율 87%)을 얻었다.2- (3,4-difluorophenyl) ethanol ( 2- XVI- 1 ; 250 mg, 1.6 mmol) with TEA (1.1 mL, 7.9 mmol) and p -toluenesulfonyl chloride (TsCl; 753 mg, 4.0 mmol ), 429 mg (yield 87%) of the title compound ( 2- XVI- 2 ) were obtained.

1H NMR (400 MHz, CDCl3) δ 7.70-7.68 (m, 2H), 7.32-7.29 (m, 2H), 7.08-7.01 (m, 1H), 6.91-6.83 (m, 2H), 4.22 (t, J = 6.4 Hz, 2H), 2.93 (t, J = 6.8 Hz, 2H), 2.47 (s, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.70-7.68 (m, 2H), 7.32-7.29 (m, 2H), 7.08-7.01 (m, 1H), 6.91-6.83 (m, 2H), 4.22 (t , J = 6.4 Hz, 2H), 2.93 (t, J = 6.8 Hz, 2H), 2.47 (s, 3H).

제조예Production Example 33 :33: 4 4 -(-( 트리플루오로메톡시Trifluoromethoxy )-3-() -3- ( 트리플루오로메틸Trifluoromethyl )) 페네틸Phenethyl 4- 4- 메틸벤젠술폰산염(Methylbenzenesulfonate ( 2-VIII-32-VIII-3 )의)of 제조 Produce

Figure pat00103
Figure pat00103

2-(4-(트리플루오로메톡시)-3-(트리플루오로메틸)페닐)에탄올 (2-VIII-2; 302 mg, 1.1 mmol)과 TEA (0.8 mL, 5.5 mmol)와 p-톨루엔설포닐 클로라이드 (524 mg, 2.8 mmol)을 이용하여 상기 표제화합물(2-VIII-3) 311 mg (수율 66%)을 얻었다.2- (4- (trifluoromethoxy) -3- (trifluoromethyl) phenyl) ethanol ( 2-VIII-2 ; 302 mg, 1.1 mmol) with TEA (0.8 mL, 5.5 mmol) and p -toluenesul 311 mg (66% yield) of the title compound ( 2-VIII-3 ) were obtained using polyvinyl chloride (524 mg, 2.8 mmol).

1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.0 Hz, 2H), 7.41-7.38 (m, 2H), 7.32-7.29 (m, 3H), 4.28 (t, J = 6.4 Hz, 2H), 3.04 (t, J = 6.4 Hz, 2H), 2.45 (s, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.68 (d, J = 8.0 Hz, 2H), 7.41-7.38 (m, 2H), 7.32-7.29 (m, 3H), 4.28 (t, J = 6.4 Hz, 2H), 3.04 (t, J = 6.4 Hz, 2H), 2.45 (s, 3H).

제조예Production Example 34 :34: 3 3 ,5-, 5- 다이플루오로페네틸Difluorophenethyl 4- 4- 메틸벤젠술폰산염(Methylbenzenesulfonate ( 2-IX-32-IX-3 )의)of 제조 Produce

Figure pat00104
Figure pat00104

2-(3,5-다이플루오로페닐)에탄올 (2-IX-2; 242 mg, 1.5 mmol)과 TEA (1.1 mL, 7.7 mmol)와 p-톨루엔설포닐 클로라이드 (TsCl; 730 mg, 3.8 mmol)을 이용하여 상기 표제화합물(2-IX-3) 359 mg (수율 75%)을 얻었다.2- (3,5-difluorophenyl) ethanol ( 2-IX-2 ; 242 mg, 1.5 mmol) with TEA (1.1 mL, 7.7 mmol) and p -toluenesulfonyl chloride (TsCl; 730 mg, 3.8 mmol ), 359 mg (yield 75%) of the title compound ( 2-IX-3 ) were obtained.

1H NMR (400 MHz, CDCl3) δ 7.72-7.70 (m, 2H), 7.33-7.29 (m, 2H), 6.68-6.62 (m, 3H), 4.24 (t, J = 6.4 Hz, 2H), 2.95 (t, J = 6.4 Hz, 2H), 2.47 (s, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.72-7.70 (m, 2H), 7.33-7.29 (m, 2H), 6.68-6.62 (m, 3H), 4.24 (t, J = 6.4 Hz, 2H), 2.95 (t, J = 6.4 Hz, 2H), 2.47 (s, 3H).

제조예Production Example 35 :35: 3 3 -- 클로로Chloro -5--5- 플루오로페네틸Fluorophenethyl 4- 4- 메틸벤젠술폰산염(Methylbenzenesulfonate ( 2-X-32-X-3 )의)of 제조 Produce

Figure pat00105
Figure pat00105

2-(3-클로로-5-플루오로페닐)에탄올 (2-X-2; 257 mg, 1.5 mmol)과 TEA (1.0 mL, 7.4 mmol)와 p-톨루엔설포닐 클로라이드 (TsCl; 702 mg, 3.7 mmol)을 이용하여 상기 표제화합물(2-X-3) 356 mg (수율 74%)을 얻었다.2- (3-chloro-5-fluorophenyl) ethanol ( 2-X-2 ; 257 mg, 1.5 mmol) with TEA (1.0 mL, 7.4 mmol) and p -toluenesulfonyl chloride (TsCl; 702 mg, 3.7 mmol) was used to obtain 356 mg (yield 74%) of the title compound ( 2-X-3 ).

1H NMR (400 MHz, CDCl3) δ 7.70 (dd, J = 6.8, 1.6 Hz, 2H), 7.33-7.29 (m, 2H), 6.96 (dt, J = 8.4, 2.0 Hz, 1H), 6.88 (s, 1H), 6.72 (dt, J = 8.8, 2.0 Hz, 1H), 4.24 (t, J = 6.4 Hz, 2H), 2.93 (t, J = 6.8 Hz, 2H), 2.47 (s, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.70 (dd, J = 6.8, 1.6 Hz, 2H), 7.33-7.29 (m, 2H), 6.96 (dt, J = 8.4, 2.0 Hz, 1H), 6.88 ( s, 1H), 6.72 (dt, J = 8.8, 2.0 Hz, 1H), 4.24 (t, J = 6.4 Hz, 2H), 2.93 (t, J = 6.8 Hz, 2H), 2.47 (s, 3H).

제조예Production Example 36 :36: 3 3 -- 플루오로페네틸Fluorophenethyl 4- 4- 메틸벤젠술폰산염(Methylbenzenesulfonate ( 2-XI-32-XI-3 )의)of 제조 Produce

Figure pat00106
Figure pat00106

2-(3-플루오로페닐)에탄올 (2-XI-3; 411 mg, 2.9 mmol) 과 TEA (2.0 mL, 14.7 mmol)와 p-톨루엔설포닐 클로라이드 (TsCl; 1.4 g, 7.3 mmol) 을 이용하여 상기 표제화합(2-XI-3)물 714 mg (수율 83%)을 얻었다.2- (3-fluorophenyl) ethanol ( 2-XI-3 ; 411 mg, 2.9 mmol) with TEA (2.0 mL, 14.7 mmol) and p -toluenesulfonyl chloride (TsCl; 1.4 g, 7.3 mmol) The title compound ( 2-XI-3 ) afforded 714 mg (yield 83%).

1H NMR (400 MHz, CDCl3) δ 7.71 (dd, J = 6.8, 1.6 Hz, 2H), 7.32-7.29 (m, 2H), 7.25-7.23 (m, 1H), 6.94-6.91 (m, 2H), 6.80 (d, J = 10.0 Hz, 1H), 4.24 (t, J = 6.8 Hz, 2H), 2.97 (t, J = 6.8 Hz, 2H), 2.46 (s, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.71 (dd, J = 6.8, 1.6 Hz, 2H), 7.32-7.29 (m, 2H), 7.25-7.23 (m, 1H), 6.94-6.91 (m, 2H ), 6.80 (d, J = 10.0 Hz, 1H), 4.24 (t, J = 6.8 Hz, 2H), 2.97 (t, J = 6.8 Hz, 2H), 2.46 (s, 3H).

제조예Production Example 37 :  37: 털트Ult -부틸 (-Butyl ( RR )-3-(() -3-(( 메틸설포닐Methylsulfonyl )) 옥시Oxy )) 피롤리딘Pyrrolidine -1--One- 카르복시산염(Carboxylates ( 3-I-23-I-2 )의)of 제조  Produce

Figure pat00107
Figure pat00107

(R)-(-)-N-Boc-3-피롤리디놀 (3-I-1; 3.0 g, 16.0 mmol)을 무수 다이클로로메테인에 녹인 후 메실 클로라이드 (MsCl; 1.5 mL, 19.2 mmol)과 트리에틸 아민 (TEA; 2.9 ml, 20.8 mmol)을 0℃에서 천천히 첨가하여 반응하였다. 온도를 상온으로 올린 후 7시간 반응하였다. 반응 완결 후에 NaCl 포화 수용액과 다이클로로메테인으로 3회 추출한 후 무수 황산 마그네슘으로 수분을 건조하여 건조시킨 후 여과하였다. 여과액을 감압 농축시켜, 농축액을 관 크로마토그래피를 통하여 상기 표제화합물(3-I-2) 4.3 g (수율 100%)을 얻었다. ( R )-(-)- N- Boc-3-pyrrolidinol ( 3-I-1 ; 3.0 g, 16.0 mmol) was dissolved in anhydrous dichloromethane followed by mesyl chloride (MsCl; 1.5 mL, 19.2 mmol) And triethyl amine (TEA; 2.9 ml, 20.8 mmol) were added slowly at 0 ° C. to react. After raising the temperature to room temperature, the reaction was performed for 7 hours. After completion of the reaction, the mixture was extracted three times with a saturated aqueous NaCl solution and dichloromethane, dried with anhydrous magnesium sulfate, dried, and filtered. The filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography to obtain 4.3 g (yield 100%) of the title compound ( 3-I-2 ).

1H NMR (300MHz, CDCl3) δ 5.24-5.20 (m, 1H), 3.63-3.41 (m, 4H), 3.01 (s, 3H), 2.22-2.10 (m, 2H), 1.42 (s, 9H). 1 H NMR (300MHz, CDCl 3 ) δ 5.24-5.20 (m, 1H), 3.63-3.41 (m, 4H), 3.01 (s, 3H), 2.22-2.10 (m, 2H), 1.42 (s, 9H) .

제조예Production Example 38 : 38: 털트Ult -부틸 (-Butyl ( SS )-3-) -3- 시아노피롤리딘Cyanopyrrolidine -1--One- 카르복시산염(Carboxylates ( 3-I-33-I-3 )의)of 제조 Produce

Figure pat00108
Figure pat00108

털트-부틸 (R)-3-((메틸설포닐)옥시)피롤리딘-1-카르복시산염(3-I-2; 4.3 g, 16.0 mmol)을 다이메틸폼아미드에 녹인 후 사이안화나트륨 (NaCN; 3.1 g, 64.0 mmol)을 가한다. 80℃에서 12시간 교반하였다. 반응 완결 후에 증류수와 다이클로로메테인으로 3회 추출하고 유기층을 무수 황산 마그네슘으로 건조시켜 관 크로마토그래피(Hex:EA=3:1)를 통하여 상기 표제화합물(3-I-3) 2.6 g (수율 84%)을 얻었다.After dissolving turt-butyl ( R ) -3-((methylsulfonyl) oxy) pyrrolidine-1-carboxylate ( 3-I-2 ; 4.3 g, 16.0 mmol) in dimethylformamide, sodium cyanide ( NaCN; 3.1 g, 64.0 mmol) is added. It stirred at 80 degreeC for 12 hours. After completion of the reaction, the mixture was extracted three times with distilled water and dichloromethane, and the organic layer was dried over anhydrous magnesium sulfate, and then purified by column chromatography (Hex: EA = 3: 1) to obtain the title compound ( 3-I-3 ) 2.6 g (yield). 84%).

1H NMR (300MHz, CDCl3) δ 3.67-3.44 (m, 4H) 3.12-3.05 (m, 1H) 2.31-2.22 (m, 2H) 1.48 (s, 9H). 1 H NMR (300 MHz, CDCl 3 ) δ 3.67-3.44 (m, 4H) 3.12-3.05 (m, 1H) 2.31-2.22 (m, 2H) 1.48 (s, 9H).

제조예Production Example 39 :  39: 털트Ult -부틸 (-Butyl ( RR )-3-() -3- ( 아미노메틸Aminomethyl )) 피롤리딘Pyrrolidine -1--One- 카르복시산염(Carboxylates ( 3-I-43-I-4 )의)of 제조 Produce

Figure pat00109
Figure pat00109

리튬 알루미늄 하이드라이드 (LAH; 425 mg, 11.2mmol)을 테트라하이드로퓨란(THF)에 녹인 후 알루미늄 클로라이드 (AlCl3; 1.3 g, 9.4 mmol)을 테트라하이드로퓨란(THF)에 녹인 혼합물을 상온에서 천천히 가한 후 20분간 격렬히 교반하였다. 온도를 0℃로 낮춘 후 (S)-털트-부틸-3-사이아노피롤리딘-1-카르복시산염 (3-I-3; 2.0 g, 11.5 mmol)을 테트라하이드로퓨란(THF)에 녹여 천천히 적가한 후 상온에서 1시간 교반하였다. 반응이 완결된 후에 메탄올 10mL를 천천히 가한 다음 감압 농축하여 용매를 제거하였다. 증류수(1 mL)을 이용하여 염을 녹여 1N HCl 수용액으로 pH 2~3으로 낮춘 후 에틸 아세테이트를 이용하여 3회 추출하였다. 물 층에 10N 수산화 나트륨 수용액을 이용하여 pH 8로 조절한 후 다이클로로메테인를 이용하여 3회 추출하였다. 무수 황산 나트륨으로 건조시킨 후 필터 하였고, 유기층을 감압 농축하여 목적화합물(3-I-4) 1.3 g (수율 61%)을 얻었다.Lithium aluminum hydride (LAH; 425 mg, 11.2 mmol) was dissolved in tetrahydrofuran (THF), and a mixture of aluminum chloride (AlCl 3 ; 1.3 g, 9.4 mmol) in tetrahydrofuran (THF) was slowly added at room temperature. After vigorously stirring for 20 minutes. After the temperature was lowered to 0 ° C., ( S ) -talt-butyl-3-cyanopyrrolidine-1-carboxylate ( 3-I-3 ; 2.0 g, 11.5 mmol) was slowly dissolved in tetrahydrofuran (THF). After dropping, the mixture was stirred at room temperature for 1 hour. After the reaction was completed, 10 mL of methanol was slowly added thereto, followed by concentration under reduced pressure to remove the solvent. The salt was dissolved using distilled water (1 mL), lowered to pH 2-3 with 1N HCl aqueous solution, and extracted three times with ethyl acetate. The aqueous layer was adjusted to pH 8 with 10N aqueous sodium hydroxide solution and extracted three times with dichloromethane. After drying over anhydrous sodium sulfate and filtering, the organic layer was concentrated under reduced pressure to give 1.3 g (yield 61%) of the target compound ( 3-I-4 ).

1H NMR (300MHz, CDCl3) δ 3.55-3.30 (m, 3H), 3.02-3.00 (m, 1H), 2.73 (t, J = 6.2 Hz, 2H), 2.24 (brs, 1H), 2.01-1.98 (m, 1H), 1.60-1.57 (m, 1H), 1.26 (s, 9H). 1 H NMR (300 MHz, CDCl 3 ) δ 3.55-3.30 (m, 3H), 3.02-3.00 (m, 1H), 2.73 (t, J = 6.2 Hz, 2H), 2.24 (brs, 1H), 2.01-1.98 (m, 1 H), 1.60-1.57 (m, 1 H), 1.26 (s, 9 H).

제조예Production Example 40 :  40: 털트Ult -부틸 (-Butyl ( SS )-3-(() -3-(( 메틸설포닐Methylsulfonyl )) 옥시Oxy )) 피롤리딘Pyrrolidine -1--One- 카르복시산염(Carboxylates ( 3-II-23-II-2 )의)of 제조  Produce

Figure pat00110
Figure pat00110

제조예 37과 같은 방법으로 (S)-(-)-N-Boc-3-피롤리디놀 (3-II-1; 3.0 g, 16.0 mmol)과 메실 클로라이드 (MsCl; 1.5 mL, 19.2 mmol)과 트리에틸 아민 (TEA; 2.9 mL, 20.8 mmol)을 이용하여 상기 표제화합물(3-II-2) 4.3 g (수율 100%)을 얻었다.( S )-(-)- N- Boc-3-pyrrolidinol ( 3-II-1 ; 3.0 g, 16.0 mmol) and mesyl chloride (MsCl; 1.5 mL, 19.2 mmol) were prepared in the same manner as in Preparation Example 37. Triethyl amine (TEA; 2.9 mL, 20.8 mmol) gave 4.3 g (yield 100%) of the title compound ( 3-II-2 ).

1H NMR (300 MHz, CDCl3) δ 5.28-5.25 (m, 1H), 3.68-3.50 (m, 4H), 3.15 (s, 3H), 2.29-2.16 (m, 2H), 1.47 (s, 9H). 1 H NMR (300 MHz, CDCl 3 ) δ 5.28-5.25 (m, 1H), 3.68-3.50 (m, 4H), 3.15 (s, 3H), 2.29-2.16 (m, 2H), 1.47 (s, 9H ).

제조예Production Example 41 : 41: 털트Ult -부틸 (-Butyl ( RR )-3-) -3- 시아노피롤리딘Cyanopyrrolidine -1--One- 카르복시산염(Carboxylates ( 3-II-33-II-3 )의)of 제조 Produce

Figure pat00111
Figure pat00111

털트-부틸 (S)-3-((메틸설포닐)옥시)피롤리딘-1-카르복시산염(3-II-2; 4.3 g, 16.0 mmol)과 사이안화나트륨 (NaCN; 3.1 g, 63.9 mmol)을 이용하여 상기 표제화합물(3-II-3) 2.3 g (수율 72%)을 얻었다.Tert-butyl ( S ) -3-((methylsulfonyl) oxy) pyrrolidine-1-carboxylate ( 3-II-2 ; 4.3 g, 16.0 mmol) with sodium cyanide (NaCN; 3.1 g, 63.9 mmol ), 2.3 g (72% yield) of the title compound ( 3-II-3 ) were obtained.

1H NMR (300 MHz, CDCl3) δ 3.69-3.46 (m, 4H), 3.14-3.09 (m, 1H), 2.29-2.23 (m, 2H), 1.48 (s, 9H). 1 H NMR (300 MHz, CDCl 3 ) δ 3.69-3.46 (m, 4H), 3.14-3.09 (m, 1H), 2.29-2.23 (m, 2H), 1.48 (s, 9H).

제조예Production Example 42 : 42: 털트Ult -부틸 (-Butyl ( SS )-3-() -3- ( 아미노메틸Aminomethyl )) 피롤리딘Pyrrolidine -1--One- 카르복시산염(Carboxylates ( 3-II-43-II-4 )의)of 제조 Produce

Figure pat00112
Figure pat00112

제조예 39와 같은 방법으로 털트-부틸 (R)-털트-부틸-3-사이아노피롤리딘-1-카르복시산염 (3-II-3; 2.3 g, 11.5 mmol)과 리튬 알루미늄 하이드라이드 (LAH; 482 mg, 12.7 mmol)과 알루미늄 클로라이드 (AlCl3; 1.4 g, 10.6 mmol)을 이용하여 상기 표제화합물(3-II-4) 1.3 g (수율 56%)을 얻었다.In the same manner as in Preparation Example 39, butt-butyl ( R ) -talt-butyl-3-cyanopyrrolidine-1-carboxylate ( 3-II-3 ; 2.3 g, 11.5 mmol), 1.3 g (yield) of the title compound ( 3-II-4 ) using lithium aluminum hydride (LAH; 482 mg, 12.7 mmol) and aluminum chloride (AlCl 3 ; 1.4 g, 10.6 mmol) 56%).

1H NMR (300MHz, CDCl3) δ 3.51-3.30 (m, 3H), 3.01-2.99 (m, 1H), 2.72 (t, J = 6.1 Hz, 2H), 2.22 (brs, 1H), 2.01-1.99 (m, 1H), 1.67-1.52 (m, 1H), 1.46 (s, 9H), 1.40-1.25 (m, 2H). 1 H NMR (300 MHz, CDCl 3 ) δ 3.51-3.30 (m, 3H), 3.01-2.99 (m, 1H), 2.72 (t, J = 6.1 Hz, 2H), 2.22 (brs, 1H), 2.01-1.99 (m, 1H), 1.67-1.52 (m, 1H), 1.46 (s, 9H), 1.40-1.25 (m, 2H).

제조예Production Example 43 : 43: ( ( RR )-)- 털트Ult -부틸 3-((3--Butyl 3-((3- 아이소프로필아이소옥사졸Isopropylisoxazole -5--5- 카르복사이미도Carboxamido )메틸)피롤리딘-1-카르복시산염((Methyl) pyrrolidine-1-carboxylate ( 4-I-14-I-1 )의 제조Manufacturing

Figure pat00113
Figure pat00113

1,1'-카보닐다이이미다졸 (CDI; 365 mg, 2.3 mmol)을 무수 테트라하이드로퓨란(THF)에 녹인 후에 3-아이소프로필아이소옥사졸-5-카복실산 (1-I-5; 268 mg, 1.7 mmol)을 무수 테트라하이드로퓨란에 녹인 혼합물에 천천히 가한 후 상온에서 2시간 교반하였다. 무수 테트라하이드로퓨란에 녹인 (R)-털트-부틸 3-(아미노메틸)피롤리딘-1-카르복시산염 (3-I-4; 450 mg, 2.3 mmol)을 혼합물에 천천히 가한 후 상온에서 3시간 교반하였다. 반응이 완결된 후에 감압 농축하여 용매를 제거하고 증류수와 에틸 아세테이트를 이용해서 추출하였다. 무수 황산 나트륨으로 건조시킨 후 필터 하였고 관 크로마토그래피를 통하여 상기 표제화합물(4-I-1) 508 mg (수율 87%)을 얻었다.Dissolve 1,1'-carbonyldiimidazole (CDI; 365 mg, 2.3 mmol) in anhydrous tetrahydrofuran (THF) and then 3-isopropylisoxazole-5-carboxylic acid ( 1-I-5 ; 268 mg, 1.7 mmol) was slowly added to the mixture dissolved in anhydrous tetrahydrofuran and stirred at room temperature for 2 hours. ( R ) -talt-butyl 3- (aminomethyl) pyrrolidine-1-carboxylate ( 3-I-4 ; 450 mg, 2.3 mmol) dissolved in anhydrous tetrahydrofuran was slowly added to the mixture, followed by 3 hours at room temperature. Stirred After the reaction was completed, the mixture was concentrated under reduced pressure to remove the solvent, and extracted with distilled water and ethyl acetate. After drying over anhydrous sodium sulfate and filtering, 508 mg (yield 87%) of the title compound ( 4-I-1 ) were obtained by column chromatography.

1H NMR (400MHz, CDCl3) δ 6.82 (s, 1H), 6.70 (brs, 1H), 3.58-3.34 (m, 5H), 3.17-3.08 (m, 2H), 2.54-2.51 (m, 1H), 2.08-2.01 (m, 1H), 1.68 (brs, 1H), 1.48 (s, 9H), 1.33 (d, J = 7.2 Hz, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 6.82 (s, 1H), 6.70 (brs, 1H), 3.58-3.34 (m, 5H), 3.17-3.08 (m, 2H), 2.54-2.51 (m, 1H) , 2.08-2.01 (m, 1H), 1.68 (brs, 1H), 1.48 (s, 9H), 1.33 (d, J = 7.2 Hz, 6H).

제조예Production Example 44 : 44: ( ( SS )-)- 털트Ult -부틸 3-((3--Butyl 3-((3- 아이소프로필아이소옥사졸Isopropylisoxazole -5--5- 카르복사이미도Carboxamido )메틸)피롤리딘-1-카르복시산염((Methyl) pyrrolidine-1-carboxylate ( 4-II-14-II-1 )의 제조Manufacturing

Figure pat00114
Figure pat00114

제조예 43과 같은 방법으로 3-아이소프로필아이소옥사졸-5-카복실산 (1-I-5; 150 mg, 1.5 mmol)과 1,1'-카보닐다이이미다졸 (CDI; 230 mg, 1.7 mmol)과 털트-부틸 (S)-털트-부틸 3-(아미노메틸)피롤리딘-1-카르복시산염 (3-II-4; 150 mg, 0.8 mmol)을 이용하여 상기 표제화합물(4-II-1) 214 mg (수율 84%)을 얻었다.3-Isopropylisoxazole-5-carboxylic acid ( 1-I-5 ; 150 mg, 1.5 mmol) and 1,1'-carbonyldiimidazole (CDI; 230 mg, 1.7 mmol) in the same manner as in Preparation Example 43 And the title compound ( 4-II-1 ) by using a tert-butyl ( S ) -talt-butyl 3- (aminomethyl) pyrrolidine-1-carboxylate ( 3-II-4 ; 150 mg, 0.8 mmol). ) 214 mg (yield 84%).

1H NMR (300MHz, CDCl3) δ 6.84 (s, 1H), 6.68 (brs, 1H), 3.55-3.37 (m, 5H), 3.20-3.11 (m, 1H), 2.58-2.53 (m, 1H), 2.10-2.02 (m, 1H), 1.71-1.69 (m, 1H), 1.50 (s, 9H), 1.40 (d, J = 6.9 Hz, 6H). 1 H NMR (300 MHz, CDCl 3 ) δ 6.84 (s, 1H), 6.68 (brs, 1H), 3.55-3.37 (m, 5H), 3.20-3.11 (m, 1H), 2.58-2.53 (m, 1H) , 2.10-2.02 (m, 1H), 1.71-1.69 (m, 1H), 1.50 (s, 9H), 1.40 (d, J = 6.9 Hz, 6H).

제조예Production Example 45 : 45: ( ( RR )-)- 털트Ult -부틸 3-((5--Butyl 3-((5- 아이소부틸Isobutyl -1-페닐-1-1-phenyl-1 HH -- 피라졸Pyrazole -3--3- 카르복사미도Carboxamido )메틸)피롤리딘-1-카르복시산염((Methyl) pyrrolidine-1-carboxylate ( 4-III-14-III-1 )의 제조Manufacturing

Figure pat00115
Figure pat00115

제조예 43과 같은 방법으로 5-아이소부틸-1-페닐-1H-피라졸-3-카복실산 (1-II-4; 2.0 g, 8.2 mmol)과 1,1'-카보닐다이이미다졸 (CDI; 1.5 g, 8.9 mmol)과 털트-부틸 (R)-털트-부틸 3-(아미노메틸)피롤리딘-1-카르복시산염 (3-I-4; 1.5 g, 7.4 mmol)을 이용하여 상기 표제화합물(4-III-1) 3.1 g (수율 96%)을 얻었다.5-Isobutyl-1-phenyl-1 H -pyrazole-3-carboxylic acid ( 1-II-4 ; 2.0 g, 8.2 mmol) and 1,1'-carbonyldiimidazole (CDI) in the same manner as in Preparation Example 43 1.5 g, 8.9 mmol) and the above-mentioned headings using the tet-butyl ( R ) -tet-butyl 3- (aminomethyl) pyrrolidine-1-carboxylate ( 3-I-4 ; 1.5 g, 7.4 mmol) 3.1 g (yield 96%) of compound ( 4-III-1 ) was obtained.

1H NMR (400MHz, CDCl3) δ 7.56-7.41 (m, 5H), 7.08 (t, J = 6.0 Hz, 1H), 6.77 (s, 1H), 3.56-3.32 (m, 5H), 3.14-3.06 (m, 1H), 2.53 (d, J = 7.2 Hz, 3H), 2.07-2.00 (m, 1H), 1.91-1.84 (m, 1H), 1.71-1.68 (m, 1H), 1.47 (s, 9H), 0.89 (d, J = 6.6 Hz, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.56-7.41 (m, 5H), 7.08 (t, J = 6.0 Hz, 1H), 6.77 (s, 1H), 3.56-3.32 (m, 5H), 3.14-3.06 (m, 1H), 2.53 (d, J = 7.2 Hz, 3H), 2.07-2.00 (m, 1H), 1.91-1.84 (m, 1H), 1.71-1.68 (m, 1H), 1.47 (s, 9H ), 0.89 (d, J = 6.6 Hz, 6H).

제조예Production Example 46 : 46: ( ( SS )-)- 털트Ult -부틸 3-((5--Butyl 3-((5- 아이소부틸Isobutyl -1-페닐-1-1-phenyl-1 HH -- 피라졸Pyrazole -3--3- 카르복사미도Carboxamido )메틸)피롤리딘-1-카르복시산염((Methyl) pyrrolidine-1-carboxylate ( 4-IV-14-IV-1 )의 제조Manufacturing

Figure pat00116
Figure pat00116

제조예 43과 같은 방법으로 5-아이소부틸-1-페닐-1H-피라졸-3-카복실산 (1-II-4; 350 mg, 1.3 mmol)과 1,1'-카보닐다이이미다졸 (CDI; 223 mg, 1.4 mmol)과 털트-부틸 (S)-털트-부틸 3-(아미노메틸)피롤리딘-1-카르복시산염 (3-II-4; 250 mg, 1.3 mmol)을 이용하여 상기 표제화합물(4-IV-1) 158 mg (수율 90%)을 얻었다.5-Isobutyl-1-phenyl-1 H -pyrazole-3-carboxylic acid (1-II-4; 350 mg, 1.3 mmol) and 1,1'-carbonyldiimidazole (CDI) in the same manner as in Preparation Example 43 223 mg, 1.4 mmol) and the above heading using tuft-butyl ( S ) -talt-butyl 3- (aminomethyl) pyrrolidine-1-carboxylate ( 3-II-4 ; 250 mg, 1.3 mmol) 158 mg (yield 90%) of compound ( 4-IV-1 ) were obtained.

1H NMR (300MHz, CDCl3) δ 7.54-7.45 (m, 3H), 7.42-7.39 (m, 2H), 7.05 (t, J = 5.9Hz, 1H), 6.76 (brs, 1H), 3.58-3.28 (m, 5H), 3.14-3.01 (m, 1H), 2.52-2.49 (m, 3H), 2.06-1.96 (m, 1H), 1.89-1.80 (m, 1H), 1.68-1.66 (m, 1H), 1.45 (s, 9H), 0.87 (d, J = 6.6Hz, 6H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.54-7.45 (m, 3H), 7.42-7.39 (m, 2H), 7.05 (t, J = 5.9 Hz, 1H), 6.76 (brs, 1H), 3.58-3.28 (m, 5H), 3.14-3.01 (m, 1H), 2.52-2.49 (m, 3H), 2.06-1.96 (m, 1H), 1.89-1.80 (m, 1H), 1.68-1.66 (m, 1H) , 1.45 (s, 9H), 0.87 (d, J = 6.6 Hz, 6H).

제조예Production Example 47 : 47: ( ( RR )-)- 털트Ult -부틸-3-((1--Butyl-3-((1- 메틸methyl -3-프로필-1-3-propyl-1 HH -- 피라졸Pyrazole -5--5- 카르복사미도Carboxamido )메틸)피롤리딘-1-카르복시산염((Methyl) pyrrolidine-1-carboxylate ( 4-V-14-V-1 )의 제조Manufacturing

Figure pat00117
Figure pat00117

제조예 43과 같은 방법으로 1-메틸-3-프로필-1H-피라졸-5-카복실산 (1-III-2; 168 mg, 1.0 mmol)과 1,1'-카보닐다이이미다졸 (CDI; 178 mg, 1.1 mmol)과 털트-부틸 (R)-털트-부틸 3-(아미노메틸)피롤리딘-1-카르복시산염 (3-I-4; 200 mg, 1.0 mmol)을 이용하여 상기 표제화합물(4-V-1) 326 mg (수율 93%)을 얻었다.1-Methyl-3-propyl-1 H -pyrazole-5-carboxylic acid ( 1-III-2 ; 168 mg, 1.0 mmol) and 1,1'-carbonyldiimidazole (CDI; 178 mg, 1.1 mmol) and the above-mentioned title compound using tetlt-butyl ( R ) -tetlt-butyl 3- (aminomethyl) pyrrolidine-1-carboxylate (3-I-4; 200 mg, 1.0 mmol) (4-V-1) 326 mg (yield: 93%).

1H NMR (300MHz, CDCl3) δ 6.30 (s, 1H), 6.10 (brs, 1H), 4.12 (s, 3H), 3.68-3.17 (m, 6H), 2.61 (t, J = 7.2 Hz, 2H), 2.55-2.50 (m, 1H), 2.11-2.01 (m, 1H), 1.75-1.63 (m, 3H), 1.50 (s, 9H), 1.00 (t, J = 7.2 Hz, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 6.30 (s, 1H), 6.10 (brs, 1H), 4.12 (s, 3H), 3.68-3.17 (m, 6H), 2.61 (t, J = 7.2 Hz, 2H ), 2.55-2.50 (m, 1H), 2.11-2.01 (m, 1H), 1.75-1.63 (m, 3H), 1.50 (s, 9H), 1.00 (t, J = 7.2 Hz, 3H).

제조예Production Example 48 :  48: (S)-(S)- 털트Ult -부틸-3-((1--Butyl-3-((1- 메틸methyl -3-프로필-1H--3-propyl-1H- 피라졸Pyrazole -5--5- 카르복사미도Carboxamido )메틸)피롤리딘-1-카르복시산염((Methyl) pyrrolidine-1-carboxylate ( 4-VI-14-VI-1 )의 제조Manufacturing

Figure pat00118
Figure pat00118

제조예 43과 같은 방법으로 1-메틸-3-프로필-1H-피라졸-5-카복실산 (1-III-2; 168 mg, 1.00 mmol)과 1,1'-카보닐다이이미다졸 (CDI; 178 mg, 1.1 mmol)과 털트-부틸 (S)-털트-부틸 3-(아미노메틸)피롤리딘-1-카르복시산염 (3-II-4; 200 mg, 1.0 mmol)을 이용하여 상기 표제화합물(4-VI-1) 335 mg (수율 96%)을 얻었다.1-Methyl-3-propyl-1 H -pyrazole-5-carboxylic acid ( 1-III-2 ; 168 mg, 1.00 mmol) and 1,1'-carbonyldiimidazole (CDI; 178 mg, 1.1 mmol) and tert-butyl ( S ) -talt-butyl 3- (aminomethyl) pyrrolidine-1-carboxylate ( 3-II-4 ; 200 mg, 1.0 mmol) 335 mg (yield 96%) of ( 4-VI-1 ) were obtained.

1H NMR (300MHz, CDCl3) δ 6.31 (s, 1H), 6.10 (brs, 1H), 4.13 (s, 3H), 3.55-3.17 (m, 6H) 2.65-2.53 (m, 3H), 2.12-2.02 (m, 1H), 1.76-1.66 (m, 1H), 1.50 (s, 9H), 1.00 (t, J = 6.0Hz, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 6.31 (s, 1H), 6.10 (brs, 1H), 4.13 (s, 3H), 3.55-3.17 (m, 6H) 2.65-2.53 (m, 3H), 2.12- 2.02 (m, 1H), 1.76-1.66 (m, 1H), 1.50 (s, 9H), 1.00 (t, J = 6.0 Hz, 3H).

제조예Production Example 49 : 49: ( ( RR )-)- 털트Ult -부틸-3-((3,5--Butyl-3-((3,5- 다이클로로벤즈아미도Dichlorobenzamido )) 메틸methyl )) 피롤리딘Pyrrolidine -1-카르복시산염(-1-carboxylate ( 4-VII-14-VII-1 )의 제조Manufacturing

Figure pat00119
Figure pat00119

제조예 43과 같은 방법으로 3,5-다이클로로벤조산 (1-IV-1; 1.19g, 6.24 mmol)과 1,1'-카보닐다이이미다졸 (CDI' 1.1 g, 6.7 mmol)과 털트-부틸 (R)-털트-부틸 3-(아미노메틸)피롤리딘-1-카르복시산염 (3-I-4; 1.3 g, 6.2 mmol)을 이용하여 상기 표제화합물(4-VII-1) 2.0 g (수율 85%)을 얻었다.In the same manner as in Preparation 43, 3,5-dichlorobenzoic acid ( 1-IV-1 ; 1.19 g, 6.24 mmol), 1,1'-carbonyldiimidazole (CDI '1.1 g, 6.7 mmol) and tultyl-butyl 2.0 g of the title compound ( 4-VII-1 ) using ( R ) -talt-butyl 3- (aminomethyl) pyrrolidine-1-carboxylate ( 3-I-4 ; 1.3 g, 6.2 mmol) Yield 85%).

1H NMR (300MHz, CDCl3) δ 7.64 (s, 2H), 7.49 (s, 1H), 6.74 (s, 0.5H), 6.39 (s, 0.5H), 3.61-3.06 (m, 6H), 2.58-2.49 (m, 1H), 2.09-1.99 (m, 1H), 1.74-1.64 (m, 1H), 1.50 (s, 9H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.64 (s, 2H), 7.49 (s, 1H), 6.74 (s, 0.5H), 6.39 (s, 0.5H), 3.61-3.06 (m, 6H), 2.58 -2.49 (m, 1H), 2.09-1.99 (m, 1H), 1.74-1.64 (m, 1H), 1.50 (s, 9H).

제조예Production Example 50 : 50: (S)- (S)- 털트Ult -부틸-3-((3,5--Butyl-3-((3,5- 다이클로로벤즈아미도Dichlorobenzamido )) 메틸methyl )) 피롤리딘Pyrrolidine -1-카르복시산염(-1-carboxylate ( 4-VIII-14-VIII-1 )의 제조Manufacturing

Figure pat00120
Figure pat00120

제조예 43과 같은 방법으로 3,5-다이클로로벤조산 (1-IV-1; 287 mg, 1.5 mmol)과 1,1'-카보닐다이이미다졸 (CDI; 268 mg, 1.7 mmol)과 털트-부틸 (S)-털트-부틸 3-(아미노메틸)피롤리딘-1-카르복시산염 (3-II-4; 300 mg, 1.5 mmol)을 이용하여 상기 표제화합물(4-VIII-1) 497 mg (수율 83%)을 얻었다.In the same manner as in Preparation 43, 3,5-dichlorobenzoic acid ( 1-IV-1 ; 287 mg, 1.5 mmol), 1,1'-carbonyldiimidazole (CDI; 268 mg, 1.7 mmol) and tult-butyl 497 mg of the title compound ( 4-VIII-1 ) using ( S ) -talt-butyl 3- (aminomethyl) pyrrolidine-1-carboxylate ( 3-II-4 ; 300 mg, 1.5 mmol) Yield 83%).

1H NMR (300MHz, CDCl3) δ 7.67 (s, 2H), 7.53 (s, 1H), 6.45 (s, 0.5H), 6.29 (s, 0.5H), 3.61-3.12 (m, 6H), 2.61-2.51 (m, 1H), 2.13-2.03 (m, 1H), 1.71-1.66 (m, 1H), 1.50 (s, 9H). 1 H NMR (300MHz, CDCl 3 ) δ 7.67 (s, 2H), 7.53 (s, 1H), 6.45 (s, 0.5H), 6.29 (s, 0.5H), 3.61-3.12 (m, 6H), 2.61 -2.51 (m, 1H), 2.13-2.03 (m, 1H), 1.71-1.66 (m, 1H), 1.50 (s, 9H).

제조예Production Example 51 :  51: (( RR )-)- 털트Ult -부틸 3-((5--Butyl 3-((5- 메틸methyl -1-페닐-1-1-phenyl-1 HH -- 피라졸Pyrazole -3--3- 카르복사미도Carboxamido )) 메Me 틸)-피롤리딘-1-카르복시산염(Tyl) -pyrrolidine-1-carboxylate ( 4-IX-14-IX-1 )의 제조Manufacturing

Figure pat00121
Figure pat00121

제조예 43과 같은 방법으로 5-메틸-1-페닐-1H-피라졸-3-카복실산 (1-V-1; 1.5 g, 7.4 mmol)과 1,1'-카보닐다이이미다졸 (CDI; 1.4 g, 8.9 mmol)과 털트-부틸 (R)-털트-부틸 3-(아미노메틸)피롤리딘-1-카르복시산염 (3-I-4; 1.8 g, 8.9 mmol)을 이용하여 상기 표제화합물(4-IX-1) 2.5 g (수율 88%)을 얻었다.5-Methyl-1-phenyl-1 H -pyrazole-3-carboxylic acid ( 1-V-1 ; 1.5 g, 7.4 mmol) and 1,1'-carbonyldiimidazole (CDI; 1.4 g, 8.9 mmol) and tert-butyl ( R ) -talt-butyl 3- (aminomethyl) pyrrolidine-1-carboxylate ( 3-I-4 ; 1.8 g, 8.9 mmol) 2.5 g (88% yield) of ( 4-IX-1 ) were obtained.

1H NMR (300MHz, CDCl3) δ 7.56-7.46 (m, 5H), 7.06 (brs, 1H), 6.76 (s, 1H), 3.57-3.33 (m, 5H), 3.16-3.03 (m, 1H), 2.54-2.49 (m, 1H), 2.36 (s, 3H), 2.06-1.99 (m, 1H), 1.74-1.68 (m, 1H), 1.47 (s, 9H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.56-7.46 (m, 5H), 7.06 (brs, 1H), 6.76 (s, 1H), 3.57-3.33 (m, 5H), 3.16-3.03 (m, 1H) , 2.54-2.49 (m, 1H), 2.36 (s, 3H), 2.06-1.99 (m, 1H), 1.74-1.68 (m, 1H), 1.47 (s, 9H).

제조예Production Example 52 : 52: 메틸methyl 5-(((( 5-(((( RR )-1-(털트-부톡시카보닐)피롤리딘-3-일)메틸)카르바모일)-2,6-다이메틸-4-(3-나이트로페닐)-1,4-다이하이드로피리딘-3-카르복시산염() -1- (talt-butoxycarbonyl) pyrrolidin-3-yl) methyl) carbamoyl) -2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydro Pyridine-3-carboxylate ( 4-X-14-X-1 )의 제조Manufacturing

Figure pat00122
Figure pat00122

1-에틸-3-(3-다이메틸아미노프로필)카보다이이미드 하이드클로라이드 (518 mg, 2.70 mmol)와 하이드록시벤조트리아졸 (365 mg, 2.7 mmol)를 무수 다이클로로메테인(THF)에 녹인 후에 5-(메톡시카보닐)-2,6-다이메틸-4-(3-나이크로페닐)-1,4-다이하이드로피리딘-3-카복실산 (1-VI-1; 500 mg, 1.5 mmol)을 무수 다이클로로메테인을 녹인 혼합물에 가한다. 그리고 N-메틸-모르폴린 (N-Methylmorpholine; C5H11NO; 0.3 mL, 2.7 mmol)을 혼합물에 가 한 후 상온에서 1시간 교반하였다. 무수 다이클로로메테인에 녹인 (R)-털트-부틸 3-(아미노메틸)피롤리딘-1-카르복시산염 (3-I-4; 391 mg, 2.0 mmol)을 혼합물에 가한 후 상온에서 2시간 교반하였다. 반응이 완결된 후에 증류수와 다이클로로메테인을 이용해서 추출하였다. 무수 황산 나트륨으로 건조시킨 후 필터 하였고 관 크로마토그래피를 통하여 상기 표제화합물(4-X-1) 577 mg (수율 75%)을 얻었다.Dissolve 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (518 mg, 2.70 mmol) and hydroxybenzotriazole (365 mg, 2.7 mmol) in anhydrous dichloromethane (THF) 5- (methoxycarbonyl) -2,6-dimethyl-4- (3-microphenyl) -1,4-dihydropyridine-3-carboxylic acid ( 1-VI-1 ; 500 mg, 1.5 mmol ) Is added to a mixture of anhydrous dichloromethane. And N-morpholine-methyl was stirred for 1 hour at (N-Methylmorpholine; 0.3 mL, 2.7 mmol; 5 C H 11 NO) and then the mixture is room temperature. ( R ) -talt-butyl 3- (aminomethyl) pyrrolidine-1-carboxylate ( 3-I-4 ; 391 mg, 2.0 mmol) dissolved in anhydrous dichloromethane was added to the mixture, followed by 2 hours at room temperature. Stirred After the reaction was completed, the mixture was extracted with distilled water and dichloromethane. After drying over anhydrous sodium sulfate, the mixture was filtered, and 577 mg (yield 75%) of the title compound ( 4-X-1 ) was obtained by column chromatography.

1H NMR (400MHz, CDCl3) δ 8.14 (s, 1H), 8.07 (dd, J = 8.4, 1.2 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.46 (td, J = 8.0, 1.6 Hz, 1H), 5.65 (s, 1H), 5.44 (s, 1H), 4.93 (s, 1H), 3.68 (s, 3H), 3.39-3.25 (m, 6H), 2.92-2.84 (m, 1H), 2.36 (s, 3H), 2.28 (s, 4H), 1.83-1.81 (m, 1H), 1.47 (s, 9H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.14 (s, 1H), 8.07 (dd, J = 8.4, 1.2 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.46 (td, J = 8.0 , 1.6 Hz, 1H), 5.65 (s, 1H), 5.44 (s, 1H), 4.93 (s, 1H), 3.68 (s, 3H), 3.39-3.25 (m, 6H), 2.92-2.84 (m, 1H), 2.36 (s, 3H), 2.28 (s, 4H), 1.83-1.81 (m, 1H), 1.47 (s, 9H).

제조예Production Example 53 : 53: ( ( RR )-3-) -3- 아이소프로필Isopropyl -- NN -(-( 피롤리딘Pyrrolidine -3--3- 일메틸Methyl )) 아이소옥사졸Isoxazole -5--5- 카르Carr 복사미드(Copy Mid ( 4-II-24-II-2 )의 제조Manufacturing

Figure pat00123
Figure pat00123

(S)-털트-부틸 3-((3-아이소프로필아이소옥사졸-5-카르복사미도)메틸)피롤리딘-1-카르복시산염 (4-II-1; 262 mg, 0.8 mmol)과 트리플루오로아세트산 (TFA; 2.5 mL)을 이용하여 상기 표제화합물(4-II-2; 175 mg (수율 95%)을 얻었다.( S ) -Talt-butyl 3-((3-isopropylisoxazole-5-carboxamido) methyl) pyrrolidine-1-carboxylate ( 4-II-1 ; 262 mg, 0.8 mmol) and tri Fluoroacetic acid (TFA; 2.5 mL) was used to afford the title compound ( 4-II-2 ; 175 mg (95% yield)).

1H NMR (300MHz, CDCl3) δ 7.40 (brs, 1H), 6.80 (s, 1H), 3.48-3.44 (m, 2H), 3.10-2.93 (m, 5H), 2.61-2.57 (m, 1H), 2.11-2.05 (m, 1H), 1.69-1.62 (m, 1H), 1.29 (d, J = 6.9Hz, 6H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.40 (brs, 1H), 6.80 (s, 1H), 3.48-3.44 (m, 2H), 3.10-2.93 (m, 5H), 2.61-2.57 (m, 1H) , 2.11-2.05 (m, 1 H), 1.69-1.62 (m, 1 H), 1.29 (d, J = 6.9 Hz, 6 H).

제조예Production Example 54 : 54: ( ( RR )-5-) -5- 아이소부틸Isobutyl -1-페닐--1-phenyl- NN -(-( 피롤리딘Pyrrolidine -3--3- 일메틸Methyl )-1)-One HH -- 피라졸Pyrazole -3-카르복사이드(3-carboxide ( 4-IV-24-IV-2 )의 제조Manufacturing

Figure pat00124
Figure pat00124

(S)-털트-부틸 3-((5-아이소부틸-1-페닐-1H-피라졸-3-카르복사미도)메틸)피롤리딘-1-카르복시산염 (4-IV-1; 318 mg, 0.8 mmol)과 트리플루오로아세트산 (TFA; 2.2 mL)을 이용하여 상기 표제화합물(4-IV-2) 178 mg (수율 73%)을 얻었다.( S ) -Talt-butyl 3-((5-isobutyl-1-phenyl-1 H -pyrazole-3-carboxamido) methyl) pyrrolidine-1-carboxylate ( 4-IV-1 ; 318 mg, 0.8 mmol) and trifluoroacetic acid (TFA; 2.2 mL) were used to obtain 178 mg (yield 73%) of the title compound ( 4-IV-2 ).

1H NMR (300MHz, CDCl3) δ 9.95 (brs, 0.5H), 9.40 (brs, 0.5H), 7.66-7.38 (m, 5H), 6.74 (s, 1H), 3.55-3.14 (m, 6H), 2.72-2.57 (m, 1H), 2.50 (d, J = 7.5Hz, 2H), 2.25-2.14 (m, 1H), 1.85-1.81 (m, 2H), 0.86 (d, J = 6.6Hz, 6H). 1 H NMR (300 MHz, CDCl 3 ) δ 9.95 (brs, 0.5H), 9.40 (brs, 0.5H), 7.66-7.38 (m, 5H), 6.74 (s, 1H), 3.55-3.14 (m, 6H) , 2.72-2.57 (m, 1H), 2.50 (d, J = 7.5 Hz, 2H), 2.25-2.14 (m, 1H), 1.85-1.81 (m, 2H), 0.86 (d, J = 6.6 Hz, 6H ).

제조예Production Example 55 : 55: ( ( SS )-1-)-One- 메틸methyl -3-프로필--3-propyl- NN -(-( 피롤리딘Pyrrolidine -3--3- 일메틸Methyl )-1)-One HH -- 피라졸Pyrazole - 5--5- 카르Carr 복사미드(Copy Mid ( 4-V-24-V-2 )의 제조Manufacturing

Figure pat00125
Figure pat00125

(R)-털트-부틸-3-((1-메틸-3-프로필-1H-피라졸-5-카르복사미도)메틸)피롤리딘-1-카르복시산염 (4-V-1; 326mg, 0.9 mmol)과 트리플루오로아세트산 (TFA; 3.3 mL)을 이용하여 상기 표제화합물(4-V-2) 232 mg (수율 100%)을 얻었다.( R ) -Tlt-butyl-3-((1-methyl-3-propyl-1 H -pyrazole-5-carboxamido) methyl) pyrrolidine-1-carboxylate ( 4-V-1 ; 326 mg , 0.9 mmol) and trifluoroacetic acid (TFA; 3.3 mL) were used to obtain 232 mg (yield 100%) of the title compound ( 4-V-2 ).

1H NMR (300MHz, CDCl3) δ 7.12 (brs, 1H), 6.44 (s, 1H), 4.10 (s, 3H), 3.59-3.28 (m, 6H), 2.89-2.78 (m, 1H), 2.57 (t, J = 7.7Hz, 2H), 2.22-2.11 (m, 1H), 1.94-1.83 (m, 1H), 1.69-1.61 (m, 2H), 0.96 (t, J = 7.4Hz, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.12 (brs, 1H), 6.44 (s, 1H), 4.10 (s, 3H), 3.59-3.28 (m, 6H), 2.89-2.78 (m, 1H), 2.57 (t, J = 7.7 Hz, 2H), 2.22-2.11 (m, 1H), 1.94-1.83 (m, 1H), 1.69-1.61 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H).

제조예Production Example 56 : 56: ( ( RR )-1-)-One- 메틸methyl -3-프로필--3-propyl- NN -(-( 피롤리딘Pyrrolidine -3--3- 일메틸Methyl )-1)-One HH -- 피라졸Pyrazole - 5--5- 카르Carr 복사미드(Copy Mid ( 4-VI-24-VI-2 )의 제조Manufacturing

Figure pat00126
Figure pat00126

(S)-털트-부틸-3-((1-메틸-3-프로필-1H-피라졸-5-카르복사미도)메틸)피롤리딘-1-카르복시산염 (4-VI-1; 318 mg 0.91 mmol)과 트리플루오로아세트산 (TFA; 3.2 mL)을 이용하여 상기 표제화합물(4-VI-2) 153 mg (수율 67%)을 얻었다.( S ) -Talt-butyl-3-((1-methyl-3-propyl-1 H -pyrazole-5-carboxamido) methyl) pyrrolidine-1-carboxylate ( 4-VI-1 ; 318 mg 0.91 mmol) and trifluoroacetic acid (TFA; 3.2 mL) were used to obtain 153 mg (yield 67%) of the title compound ( 4-VI-2 ).

1H NMR (300MHz, CDCl3) δ 7.03 (brs, 1H), 6.40 (s, 1H), 4.14 (s, 3H), 3.90 (brs, 1H), 3.48-3.00 (m, 5H), 2.64-2.57 (m, 3H), 2.13-2.07 (m, 1H), 1.72-1.62 (m, 3H), 1.01 (t, J = 7.5Hz, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.03 (brs, 1H), 6.40 (s, 1H), 4.14 (s, 3H), 3.90 (brs, 1H), 3.48-3.00 (m, 5H), 2.64-2.57 (m, 3H), 2.13-2.07 (m, 1H), 1.72-1.62 (m, 3H), 1.01 (t, J = 7.5 Hz, 3H).

제조예Production Example 57 : 57: ( ( SS )-3,5-) -3,5- 다이클로로Dichloro -- NN -(-( 피롤리딘Pyrrolidine -3--3- 일메틸Methyl )벤즈아미드(Benzamide 4-VII-24-VII-2 )의 제조Manufacturing

Figure pat00127
Figure pat00127

(R)-털트-부틸-3-((3,5-다이클로로벤즈아미드)메틸)피롤리딘-1-카르복시산염 (4-VII-1; 2.0 g, 5.3 mmol)과 트리플루오로아세트산 (TFA; 15 mL)을 이용하여 상기 표제화합물(4-VII-2) 1.2 g (수율 82%)을 얻었다.( R ) -talt-butyl-3-((3,5-dichlorobenzamide) methyl) pyrrolidine-1-carboxylate ( 4-VII-1 ; 2.0 g, 5.3 mmol) and trifluoroacetic acid ( TFA; 15 mL) gave 1.2 g (yield 82%) of the title compound ( 4-VII-2 ).

1H NMR (300MHz, CDCl3) δ 7.70 (s, 2H), 7.50-7.45 (m, 2H), 3.67-3.58 (m, 1H), 3.42-3.21(m, 5H), 2.81-2.74 (m, 1H), 2.25-2.11 (m, 1H), 1.89-1.75 (m, 1H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.70 (s, 2H), 7.50-7.45 (m, 2H), 3.67-3.58 (m, 1H), 3.42-3.21 (m, 5H), 2.81-2.74 (m, 1H), 2.25-2.11 (m, 1H), 1.89-1.75 (m, 1H).

제조예Production Example 58 : 58: ( ( RR )-3,5-) -3,5- 다이클로로Dichloro -- NN -(-( 피롤리딘Pyrrolidine -3--3- 일메틸Methyl )벤즈아미드(Benzamide 4-VIII-24-VIII-2 )의 제조Manufacturing

Figure pat00128
Figure pat00128

(S)-털트-부틸-3-((3,5-다이클로로벤즈아미드)메틸)피롤리딘-1-카르복시산염 (4-VIII-1; 497 mg, 1.3 mmol)과 트리플루오로아세트산 (3 mL)을 이용하여 상기 표제화합물(4-VIII-2) 233 mg (수율 64%)을 얻었다.( S ) -talt-butyl-3-((3,5-dichlorobenzamide) methyl) pyrrolidine-1-carboxylate ( 4-VIII-1 ; 497 mg, 1.3 mmol) and trifluoroacetic acid ( 3 mL) was used to obtain 233 mg (yield 64%) of the title compound ( 4-VIII-2 ).

1H NMR (300MHz, CDCl3) δ 9.59 (brs, 1H), 7.70 (s, 2H), 7.67 (brs, 1H), 7.50 (s, 1H), 3.69-3.61 (m, 1H), 3.47-3.32 (m, 5H), 2.90-2.82 (m, 1H), 2.30-2.21 (m, 1H), 1.93 (m, 1H). 1 H NMR (300MHz, CDCl 3 ) δ 9.59 (brs, 1H), 7.70 (s, 2H), 7.67 (brs, 1H), 7.50 (s, 1H), 3.69-3.61 (m, 1H), 3.47-3.32 (m, 5H), 2.90-2.82 (m, 1H), 2.30-2.21 (m, 1H), 1.93 (m, 1H).

제조예Production Example 59 : 59: ( ( SS )-5-) -5- 메틸methyl -1-페닐--1-phenyl- NN -(-( 피롤리딘Pyrrolidine -3--3- 일메틸Methyl )-1)-One HH -- 피라졸Pyrazole -3--3- 카르복Carboxy 사미드(Samide ( 4-IX-24-IX-2 )의 제조Manufacturing

Figure pat00129
Figure pat00129

(R)-털트-부틸 3-((5-메틸-1-페닐-1H-피라졸-3-카르복사미도)메틸)-피롤리딘-1-카르복시산염 (4-IX-1; 2.5 g, 6.5 mmol)과 트리플루오로아세트산 (TFA; 3.5 mL)을 이용하여 상기 표제화합물(4-IX-2) 2.0 g (수율 99%)을 얻었다.( R ) -Tlt-butyl 3-((5-methyl-1-phenyl-1 H -pyrazole-3-carboxamido) methyl) -pyrrolidine-1-carboxylate ( 4-IX-1 ; 2.5 g, 6.5 mmol) and trifluoroacetic acid (TFA; 3.5 mL) were used to obtain 2.0 g (yield 99%) of the title compound ( 4-IX-2 ).

1H NMR (400MHz, MeOD) δ 7.59-7.52 (m, 5H), 6.72 (s, 1H), 3.49 (d, J = 1.2 Hz, 2H), 3.48-3.34 (m, 2H), 3.27-3.24 (m, 1H), 3.04 (dd, J = 12.0, 8.0 Hz, 1H), 2.72-2.65 (m, 1H), 2.37 (s, 3H), 2.22-2.14 (m, 1H), 1.85-1.79 (m, 1H). 1 H NMR (400 MHz, MeOD) δ 7.59-7.52 (m, 5H), 6.72 (s, 1H), 3.49 (d, J = 1.2 Hz, 2H), 3.48-3.34 (m, 2H), 3.27-3.24 ( m, 1H), 3.04 (dd, J = 12.0, 8.0 Hz, 1H), 2.72-2.65 (m, 1H), 2.37 (s, 3H), 2.22-2.14 (m, 1H), 1.85-1.79 (m, 1H).

제조예Production Example 60 : 60: 털트Ult -부틸 3-(-Butyl 3- ( 아미노메틸Aminomethyl )-3-() -3- ( 하이드록시메틸Hydroxymethyl )) 피롤리딘Pyrrolidine -1--One- 카르Carr 복시산염(Carboxylate ( 3-III-23-III-2 )의 제조Manufacturing

Figure pat00130
Figure pat00130

털트-부틸 3-사이아노-3-(하이드록시메틸)피롤리딘-1-카르복시산염 (3-III-1; 255 mg, 1.1 mmol)과 알루미늄 클로라이드(AlCl3; 139 mg, 1.0 mmol)과 테트라하이드로퓨란(THF)에 녹여져 있는 1.0M 리튬 알루미늄 하이드라이드 (LAH; 2.8 mL, 2.8 mmol)을 이용하여 상기 표제화합물(3-III-2) 195 mg (수율 75%)을 얻었다.Lutet-butyl 3-cyano-3- (hydroxymethyl) pyrrolidine-1-carboxylate ( 3-III-1 ; 255 mg, 1.1 mmol) and aluminum chloride (AlCl 3 ; 139 mg, 1.0 mmol) 195 mg (yield 75%) of the title compound ( 3-III-2 ) were obtained using 1.0 M lithium aluminum hydride (LAH; 2.8 mL, 2.8 mmol) dissolved in tetrahydrofuran (THF).

1H NMR (400MHz, MeOD) δ 3.57-3.54 (m, 1H), 3.43 (d, J = 11.6 Hz, 3H), 3.28 (d, J = 8.8 Hz, 1H), 3.17-3.14 (m, 1H), 2.77-2.71 (m, 1H), 2.36 (d, J = 4.8 Hz, 1H), 1.82-1.75 (m, 2H), 1.48 (s, 10H). 1 H NMR (400 MHz, MeOD) δ 3.57-3.54 (m, 1H), 3.43 (d, J = 11.6 Hz, 3H), 3.28 (d, J = 8.8 Hz, 1H), 3.17-3.14 (m, 1H) , 2.77-2.71 (m, 1 H), 2.36 (d, J = 4.8 Hz, 1 H), 1.82-1.75 (m, 2H), 1.48 (s, 10 H).

제조예Production Example 61 : 61: 털트Ult -부틸 3-(-Butyl 3- ( 하이드록시메틸Hydroxymethyl )-3-((5-) -3-((5- 아이소부틸Isobutyl -1-페닐-1-1-phenyl-1 HH -- 피blood 라졸-3-카르복사미도)메틸)피롤리딘-1-카르복시산염(Razole-3-carboxamido) methyl) pyrrolidine-1-carboxylate ( 4-XI-14-XI-1 )의 제조Manufacturing

Figure pat00131
Figure pat00131

5-아이소부틸-1-페닐-1H-피라졸-3-카복실산 (1-II-4; 202 mg, 0.8 mmol)과 1,1'-카보닐다이이미다졸 (160 mg, 1.0 mmol)과 털트-부틸 3-(아미노메틸)-3-(하이드록시메틸)피롤리딘-1-카르복시산염 (3-III-2; 210 mg, 0.9 mmol)을 이용하여 상기 표제화합물(4-XI-1) 169 mg (수율 45%)을 얻었다.5-Isobutyl-1-phenyl-1H-pyrazole-3-carboxylic acid ( 1-II-4 ; 202 mg, 0.8 mmol) with 1,1'-carbonyldiimidazole (160 mg, 1.0 mmol) and tult- The title compound ( 4-XI-1 ) 169 using butyl 3- (aminomethyl) -3- (hydroxymethyl) pyrrolidine-1-carboxylate ( 3-III-2 ; 210 mg, 0.9 mmol). mg (yield 45%) were obtained.

1H NMR (400MHz, CDCl3) δ 7.48-7.46 (m, 4H), 7.35 (d, J = 6.8 Hz, 2H), 6.72 (s, 1H), 4.61-4.52 (m, 1H), 3.54-3.08 (m, 8H), 2.47 (d, J = 7.2 Hz, 2H), 1.81-1.66 (m, 3H), 1.40 (s, 9H), 0.83 (d, J = 6.8 Hz, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.48-7.46 (m, 4H), 7.35 (d, J = 6.8 Hz, 2H), 6.72 (s, 1H), 4.61-4.52 (m, 1H), 3.54-3.08 (m, 8H), 2.47 (d, J = 7.2 Hz, 2H), 1.81-1.66 (m, 3H), 1.40 (s, 9H), 0.83 (d, J = 6.8 Hz, 6H).

제조예Production Example 62 : 62: 털트Ult -부틸 4-(-Butyl 4- ( 하이드록시메틸Hydroxymethyl )-4-((5-) -4-((5- 아이소부틸Isobutyl -1-페닐-1-1-phenyl-1 HH -- 피blood 라졸-3-카르복사미도)메틸)피페리딘-1-카르복시산염(Razole-3-carboxamido) methyl) piperidine-1-carboxylate ( 4-XII-14-XII-1 )의 제조Manufacturing

Figure pat00132
Figure pat00132

5-아이소부틸-1-페닐-1H-피라졸-3-카복실산 (1-II-4; 180 mg, 0.7 mmol)과 1,1'-카보닐다이이미다졸 (CDI; 144 mg, 0.9 mmol)과 털트-부틸 4-(아미노메틸)-4-(하이드록시메틸)피페리딘-1-카르복시산염 (3-IV-1; 180 mg, 0.7 mmol)을 이용하여 상기 표제화합물(4-XII-1) 164 mg (수율 47%)을 얻었다.5-isobutyl-1-phenyl-1H-pyrazole-3-carboxylic acid ( 1-II-4 ; 180 mg, 0.7 mmol) and 1,1'-carbonyldiimidazole (CDI; 144 mg, 0.9 mmol) The title compound ( 4-XII-1 ) was obtained using butyl t-butyl 4- (aminomethyl) -4- (hydroxymethyl) piperidine-1-carboxylate ( 3-IV-1 ; 180 mg, 0.7 mmol). ) 164 mg (yield 47%).

1H NMR (400MHz, CDCl3) δ 7.53-7.50 (m, 3H), 7.42-7.39 (m, 2H), 7.29-7.26 (m, 1H), 6.76 (s, 1H), 4.38 (brs, 1H), 3.53-3.28 (m, 8H), 2.51 (d, J = 7.2 Hz, 2H), 1.86-1.83 (m, 1H), 1.54-1.46 (m, 2H), 1.43 (s, 9H), 1.42-1.37 (m, 2H), 0.88 (d, J = 6.8 Hz, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.53-7.50 (m, 3H), 7.42-7.39 (m, 2H), 7.29-7.26 (m, 1H), 6.76 (s, 1H), 4.38 (brs, 1H) , 3.53-3.28 (m, 8H), 2.51 (d, J = 7.2 Hz, 2H), 1.86-1.83 (m, 1H), 1.54-1.46 (m, 2H), 1.43 (s, 9H), 1.42-1.37 (m, 2H), 0.88 (d, J = 6.8 Hz, 6H).

제조예Production Example 63 : 63: NN -((3-(-((3- ( 하이드록시메틸Hydroxymethyl )) 피롤리딘Pyrrolidine -3-일)-3 days) 메틸methyl )-5-) -5- 아이소부틸Isobutyl -1-페닐-1-1-phenyl-1 HH -피라졸-3-카르복사미드(-Pyrazole-3-carboxamide ( 4-XI-24-XI-2 )의 제조Manufacturing

Figure pat00133
Figure pat00133

털트-부틸 3-(하이드록시메틸)-3-((5-아이소부틸-1-페닐-1H-피라졸-3-카르복사미도)메틸)피롤리딘-1-카르복시산염 (4-XI-1; 141 mg, 0.3 mmol) 과 트리플루오로아세트산 (TFA; 0.8 mL)을 이용하여 상기 표제화합물(4-XI-2) 103 mg (수율 93%)을 얻었다.Tert-butyl 3- (hydroxymethyl) -3-((5-isobutyl-1-phenyl-1 H -pyrazole-3-carboxamido) methyl) pyrrolidine-1-carboxylate ( 4-XI -1 ; 141 mg, 0.3 mmol) and trifluoroacetic acid (TFA; 0.8 mL) gave 103 mg (yield 93%) of the title compound ( 4-XI-2 ).

1H NMR (400MHz, CDCl3) δ 7.55-7.40 (m, 5H), 6.77 (s, 1H), 3.75 (brs, 2H), 3.52-3.40 (m, 4H), 3.13 (brs, 1H), 2.91-2.85 (m, 1H), 2.52 (d, J = 6.8 Hz, 2H), 1.88-1.81 (m, 1H), 1.69-1.63 (m, 2H), 0.89 (d, J = 6.0 Hz, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.55-7.40 (m, 5H), 6.77 (s, 1H), 3.75 (brs, 2H), 3.52-3.40 (m, 4H), 3.13 (brs, 1H), 2.91 -2.85 (m, 1H), 2.52 (d, J = 6.8 Hz, 2H), 1.88-1.81 (m, 1H), 1.69-1.63 (m, 2H), 0.89 (d, J = 6.0 Hz, 6H).

제조예Production Example 64 : 64: NN -((4-(-((4-( 하이드록시메틸Hydroxymethyl )피페리딘-4-일)Piperidin-4-yl) 메틸methyl )-5-) -5- 아이소부틸Isobutyl -1-페닐-1-1-phenyl-1 HH -피라졸-3-카르복사미드(-Pyrazole-3-carboxamide ( 4-XII-24-XII-2 )의 제조Manufacturing

Figure pat00134
Figure pat00134

털트-부틸 4-(하이드록시메틸)-4-((5-아이소부틸-1-페닐-1H-피라졸-3-카르복사미도)메틸)피페리딘-1-카르복시산염 (4-XII-1; 164 mg, 0.4 mmol) 과 트리플루오로아세트산 (TFA; 1 mL)을 이용하여 상기 표제화합물(4-XII-2) 129 mg (수율 99%)을 얻었다.Tert-butyl 4- (hydroxymethyl) -4-((5-isobutyl-1-phenyl-1 H -pyrazole-3-carboxamido) methyl) piperidine-1-carboxylate ( 4-XII -1 ; 164 mg, 0.4 mmol) and trifluoroacetic acid (TFA; 1 mL) were used to obtain 129 mg (yield 99%) of the title compound ( 4-XII-2 ).

1H NMR (400MHz, MeOD) δ 8.39 (t, J = 6.4 Hz, 1H), 7.60-7.47 (m, 5H), 6.76 (s, 1H), 3.53 (d, J = 6.4 Hz, 2H), 3.48 (s, 2H), 3.34-3.22 (m, 4H), 2.59 (d, J = 7.2 Hz, 2H), 1.86-1.78 (m, 1H), 1.75-1.72 (m, 4H), 0.86 (d, J = 6.8 Hz, 6H). 1 H NMR (400 MHz, MeOD) δ 8.39 (t, J = 6.4 Hz, 1H), 7.60-7.47 (m, 5H), 6.76 (s, 1H), 3.53 (d, J = 6.4 Hz, 2H), 3.48 (s, 2H), 3.34-3.22 (m, 4H), 2.59 (d, J = 7.2 Hz, 2H), 1.86-1.78 (m, 1H), 1.75-1.72 (m, 4H), 0.86 (d, J = 6.8 Hz, 6H).

실시예Example

상기 제조예를 따라서 제조한 시작물질 및 중간물질을 이용하여, 아래 실시예 1 내지 61에 나타난 바와 같이 본 발명에 따른 화합물 1 내지 61을 제조하였다. Using starting materials and intermediates prepared according to the above preparation, compounds 1 to 61 according to the present invention were prepared as shown in Examples 1 to 61 below.

아래 실시예 1 내지 61에서 제조한 본 발명에 따른 화합물 1 내지 61은 하기 표 2에 정리하여 나타내었다.Compounds 1 to 61 according to the present invention prepared in Examples 1 to 61 below are summarized in Table 2 below.

실시예Example 화합물번호Compound number 실시예Example 화합물번호Compound number 1One 5858 3131 2828 22 5757 3232 2929 33 5959 3333 3030 44 1One 3434 3131 55 22 3535 3232 66 33 3636 3333 77 44 3737 3434 88 55 3838 3535 99 66 3939 3636 1010 77 4040 3737 1111 88 4141 3838 1212 99 4242 3939 1313 1010 4343 4040 1414 1111 4444 4141 1515 1212 4545 4242 1616 1313 4646 4343 1717 1414 4747 4444 1818 1515 4848 4545 1919 1616 4949 4646 2020 1717 5050 4747 2121 1818 5151 4848 2222 1919 5252 4949 2323 2020 5353 5050 2424 2121 5454 5151 2525 2222 5555 5252 2626 2323 5656 5353 2727 2424 5757 5454 2828 2525 5858 5555 2929 2626 5959 5656 3030 2727 6060 6060 6161 6161

실시예Example 1 : One : ( ( SS )-3-) -3- 아이소프로필Isopropyl -- NN -(-( 피롤리딘Pyrrolidine -3--3- 일메틸Methyl )) 아이소옥사졸Isoxazole -5--5- 카르Carr 복사미드의(Of copying ( 화합물 번호 58Compound number 58 ) 제조) Produce

Figure pat00135
Figure pat00135

(R)-털트-부틸 3-((3-아이소프로필아이소옥사졸-5-카르복사미도)메틸)피롤리딘-1-카르복시산염 (4-I-1; 508 mg, 1.5 mmol)을 무수 다이클로로메테인을 녹인 혼합물에 트리플루오로아세트산 (TFA; 1.6 mL)을 가한 후에 상온에서 2시간 교반하였다. 반응이 완결된 후에 감압 농축하여 용매를 제거하고 포화 탄산수소나트륨 수용액을 이용하여 중화시킨다. 그리고 증류수와 에틸 아세테이트를 이용해서 추출하고 무수 황산 나트륨으로 건조시킨 후 필터 하여 상기 표제화합물(화합물 번호 58) 355 mg (수율 99%)을 얻었다.( R ) -Talt-butyl 3-((3-isopropylisoxazole-5-carboxamido) methyl) pyrrolidine-1-carboxylate ( 4-I-1 ; 508 mg, 1.5 mmol) Trifluoroacetic acid (TFA; 1.6 mL) was added to the mixture of dichloromethane, followed by stirring at room temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent and neutralized with saturated aqueous sodium hydrogen carbonate solution. Then, the mixture was extracted with distilled water and ethyl acetate, dried over anhydrous sodium sulfate, and filtered to obtain 355 mg (yield 99%) of the title compound ( Compound No. 58 ).

1H NMR (400MHz, DMSO) δ 9.10 (t, J = 5.6 Hz, 1H), 7.07 (s, 1H), 3.34-3.15 (m, 4H), 3.10-3.02 (m, 2H), 2.84 (dd, J = 11.6, 7.6 Hz, 1H), 2.49-2.45 (m, 1H), 1.97-1.93 (m, 1H), 1.65-1.56 (m, 1H), 1.24 (d, J = 6.8 Hz, 6H); 1 H NMR (400 MHz, DMSO) δ 9.10 (t, J = 5.6 Hz, 1H), 7.07 (s, 1H), 3.34-3.15 (m, 4H), 3.10-3.02 (m, 2H), 2.84 (dd, J = 11.6, 7.6 Hz, 1H), 2.49-2.45 (m, 1H), 1.97-1.93 (m, 1H), 1.65-1.56 (m, 1H), 1.24 (d, J = 6.8 Hz, 6H);

13C NMR (100 MHz, MeOD) δ 170.18, 162.71, 157.53, 104.60, 44.79, 40.41, 38.26, 27.74, 26.41, 20.50. 13 C NMR (100 MHz, MeOD) δ 170.18, 162.71, 157.53, 104.60, 44.79, 40.41, 38.26, 27.74, 26.41, 20.50.

실시예Example 2 : 2 : ( ( SS )-5-) -5- 아이소부틸Isobutyl -1-페닐--1-phenyl- NN -(-( 피롤리딘Pyrrolidine -3--3- 일메틸Methyl )-1)-One HH -- 피라졸Pyrazole -3--3- 카Ka 르복사이드(Lebokside ( 화합물 번호 57Compound number 57 )의 제조Manufacturing

Figure pat00136
Figure pat00136

(R)-털트-부틸 3-((5-아이소부틸-1-페닐-1H-피라졸-3-카르복사미도)메틸)피롤리딘-1-카르복시산염 (4-III-1; 2.9 g, 6.9 mmol)과 트리플루오로아세트산 (TFA; 10 mL)을 이용하여 상기 표제화합물(화합물 번호 57) 2.2 g (수율 99%)을 얻었다.( R ) -Tlt-butyl 3-((5-isobutyl-1-phenyl-1 H -pyrazole-3-carboxamido) methyl) pyrrolidine-1-carboxylate ( 4-III-1 ; 2.9 g, 6.9 mmol) and trifluoroacetic acid (TFA; 10 mL) were used to obtain 2.2 g (yield 99%) of the title compound ( Compound No. 57 ).

1H NMR (400MHz, CDCl3) δ 7.54-7.40 (m, 5H), 6.75 (s, 1H), 3.45 (d, J = 7.2 Hz, 2H), 3.30-3.24 (m, 2H), 3.17-3.14 (m, 1H), 3.00 (dd, J = 11.6, 6.4 Hz, 1H), 2.63-2.56 (m, 1H), 2.51 (d, J = 7.2 Hz, 2H), 2.10-2.05 (m, 1H), 1.88-1.81 (m, 1H), 1.73-1.68 (m, 1H), 0.87 (d, J = 6.8 Hz, 6H); 1 H NMR (400 MHz, CDCl 3 ) δ 7.54-7.40 (m, 5H), 6.75 (s, 1H), 3.45 (d, J = 7.2 Hz, 2H), 3.30-3.24 (m, 2H), 3.17-3.14 (m, 1H), 3.00 (dd, J = 11.6, 6.4 Hz, 1H), 2.63-2.56 (m, 1H), 2.51 (d, J = 7.2 Hz, 2H), 2.10-2.05 (m, 1H), 1.88-1.81 (m, 1 H), 1.73-1.68 (m, 1 H), 0.87 (d, J = 6.8 Hz, 6H);

13C NMR (100 MHz, CDCl3) δ 162.89, 146.04, 145.22, 139.16, 129.27, 128.84, 125.84, 106.26, 48.29, 44.70, 40.67, 38.65, 34.93, 28.19, 22.20. 13 C NMR (100 MHz, CDCl 3 ) δ 162.89, 146.04, 145.22, 139.16, 129.27, 128.84, 125.84, 106.26, 48.29, 44.70, 40.67, 38.65, 34.93, 28.19, 22.20.

실시예Example 3 : 3: 메틸methyl 2,6- 2,6- 다이메틸Dimethyl -4-(3--4- (3- 나이트로페닐Nitrophenyl )-5-((() -5-((( SS )-)- 피롤리딘Pyrrolidine -3--3- 일메Ilme 틸)카르바모일)-1,4-다이하이드로피리딘-3-카르복시산염(Thi) carbamoyl) -1,4-dihydropyridine-3-carboxylate ( 화합물 번호 59Compound number 59 )의 제조Manufacturing

Figure pat00137
Figure pat00137

메틸 5-((((R)-1-(털트-부톡시카보닐)피롤리딘-3-일)메틸)카르바모일)-2,6-다이메틸-4-(3-나이트로페닐)-1,4-다이하이드로피리딘-3-카르복시산염 (4-X-1; 350 mg, 0.7 mmol)과 트리플루오로아세트산 (1.5 mL)을 이용하여 상기 표제화합물(화합물 번호 59) 279 mg (수율 99%)을 얻었다.Methyl 5-((((( R ) -1- (talt-butoxycarbonyl) pyrrolidin-3-yl) methyl) carbamoyl) -2,6-dimethyl-4- (3-nitrophenyl 279 mg of the title compound ( Compound No. 59 ) using 1,4-dihydropyridine-3-carboxylate ( 4-X-1 ; 350 mg, 0.7 mmol) and trifluoroacetic acid (1.5 mL). Yield 99%).

1H NMR (400MHz, DMSO) δ 8.58 (s, 1H), 8.02-7.96 (m, 2H), 7.82 (brs, 1H), 7.60-7.52 (m, 2H), 3.50 (s, 3H), 3.10-2.98 (m, 6H), 2.70-2.63 (m, 1H), 2.27 (s, 3H), 2.04 (s, 3H), 1.83-1.72 (m, 1H), 1.46-1.37 (m, 1H); 1 H NMR (400 MHz, DMSO) δ 8.58 (s, 1H), 8.02-7.96 (m, 2H), 7.82 (brs, 1H), 7.60-7.52 (m, 2H), 3.50 (s, 3H), 3.10- 2.98 (m, 6H), 2.70-2.63 (m, 1H), 2.27 (s, 3H), 2.04 (s, 3H), 1.83-1.72 (m, 1H), 1.46-1.37 (m, 1H);

13C NMR (100 MHz, MeOD) δ 144.92, 144.87, 135.04, 134.70, 134.65, 132.69, 132.65, 132.26, 131.92, 129.53, 127.42, 125.82, 125.76, 70.51, 34.15, 33.99, 20.24, 17.70, 17.68, 17.66. 13 C NMR (100 MHz, MeOD) δ 144.92, 144.87, 135.04, 134.70, 134.65, 132.69, 132.65, 132.26, 131.92, 129.53, 127.42, 125.82, 125.76, 70.51, 34.15, 33.99, 20.24, 17.70, 17.68, 17.68, 17.68,

실시예Example 4 : 4 : ( ( RR )-)- NN -((1-(3,3--((1- (3,3- 다이메틸부틸Dimethylbutyl )) 피롤리딘Pyrrolidine -3-일)-3 days) 메틸methyl )-3-) -3- 아이소프로Isopro 필아이소옥사졸-5-카르복사미드(Philisoxazole-5-carboxamide ( 화합물번호 1Compound number 1 )의 제조Manufacturing

Figure pat00138
Figure pat00138

(S)-3-아이소프로필-N-(피롤리딘-3-일메틸)아이소옥사졸-5-카르복사미드 (화합물번호 58; 100 mg, 0.4 mmol)과 3,3-다이메틸부틸알데하이드 (2- XVII -1; 53 μL, 0.4 mmol)을 무수 다이클로로메테인 용매에 녹인 후 몰레큘러 시브를 가루형태로 가하고 2시간동안 교반하였다. 반응 혼합물에 소듐 트리아세톡시보로하이드라이드 (NaBH(OAc)3; 267 mg, 1.3 mmol)을 가한 후 10시간 교반하였다. 반응이 종료되면 포화 탄산수소나트륨을 이용하여 중화시킨 후 다이클로로메테인를 이용하여 추출하였다. 유기층을 무수 황산 마그네슘을 이용하여 건조한 후 감압 농축하였고 관 크로마토그래피로 분리하여 상기표제 화합물(화합물번호 1) 11 mg (수율 8%)을 얻었다.( S ) -3-isopropyl- N- (pyrrolidin-3-ylmethyl) isoxazole-5-carboxamide ( Compound No. 58 ; 100 mg, 0.4 mmol) with 3,3-dimethylbutylaldehyde ( 2- XVII- 1 ; 53 μL, 0.4 mmol) was dissolved in anhydrous dichloromethane solvent, and then molecular sieves were added in powder form and stirred for 2 hours. Sodium triacetoxyborohydride (NaBH (OAc) 3 ; 267 mg, 1.3 mmol) was added to the reaction mixture, which was then stirred for 10 hours. After the reaction was completed, the mixture was neutralized with saturated sodium bicarbonate and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 11 mg (yield 8%) of the title compound ( Compound No. 1 ).

1H NMR (300MHz, CDCl3) δ 7.76 (brs, 1H) 6.78(s, 1H) 3.47-3.45(m, 2H) 3.12-3.09(m, 1H) 2.91-2.76(m, 1H) 2.67-2.48(m, 7H) 2.21-2.01(m, 2H) 1.56- 1.48(m, 4H) 1.31(d, J = 6.9 Hz, 6H) 0.92(s, 9H); 1 H NMR (300 MHz, CDCl 3 ) δ 7.76 (brs, 1H) 6.78 (s, 1H) 3.47-3.45 (m, 2H) 3.12-3.09 (m, 1H) 2.91-2.76 (m, 1H) 2.67-2.48 ( m, 7H) 2.21-2.01 (m, 2H) 1.56- 1.48 (m, 4H) 1.31 (d, J = 6.9 Hz, 6H) 0.92 (s, 9H);

13C NMR (300MHz, CDCl3) δ 170.24, 163.25, 156.71, 104.92, 58.15, 53.68, 52.02, 44.42, 41.86, 35.94, 29.76, 29.45, 27.96, 26.54, 21.66. 13 C NMR (300 MHz, CDCl 3 ) δ 170.24, 163.25, 156.71, 104.92, 58.15, 53.68, 52.02, 44.42, 41.86, 35.94, 29.76, 29.45, 27.96, 26.54, 21.66.

실시예Example 5 : 5: ( ( RR )-3,5-) -3,5- 다이클로로Dichloro -- NN -((1-(3,3--((1- (3,3- 다이메틸부틸Dimethylbutyl )) 피롤리딘Pyrrolidine -3-일)-3 days) 메Me 틸)벤즈아미드(Teal) benzamide ( 화합물번호 2Compound number 2 )의 제조Manufacturing

Figure pat00139
Figure pat00139

(S)-3,5-다이클로로-N-(피롤리딘-3-일메틸)벤즈이미드 (4-VII-2; 104 mg, 0.4 mmol)과 3,3-다이메틸부틸알데하이드 (2- XVII -1; 48 μL, 0.4mmol)과 소듐 트리아세톡시보로하이드라이드 (NaBH(OAc)3; 242 mg, 1.1 mmol)을 이용하여 상기 표제화합물(화합물번호 2) 10 mg (수율 8%)을 얻었다.( S ) -3,5-Dichloro- N- (pyrrolidin-3-ylmethyl) benzimid ( 4-VII-2 ; 104 mg, 0.4 mmol) and 3,3-dimethylbutylaldehyde ( 2- 10 mg (yield 8%) of the title compound ( Compound No. 2 ) was prepared using XVII- 1 ; 48 μL, 0.4 mmol) and sodium triacetoxyborohydride (NaBH (OAc) 3 ; 242 mg, 1.1 mmol). Got it.

1H NMR (300 MHz, CDCl3) δ 8.45(brs, 1H), 7.71(d, J = 1.9 Hz, 2H), 7.48(t, J = 1.9 Hz, 1H), 3.48-3.40 (m, 2H), 3.17-3.08 (m, 1H), 2.91 (d, J = 9.4Hz, 1H), 2.60-2.43 (m, 4H), 2.22-2.06 (m, 2H), 1.72-1.56 (m, 1H), 1.57-1.50 (m, 2H), 0.94 (s, 9H); 1 H NMR (300 MHz, CDCl 3 ) δ 8.45 (brs, 1H), 7.71 (d, J = 1.9 Hz, 2H), 7.48 (t, J = 1.9 Hz, 1H), 3.48-3.40 (m, 2H) , 3.17-3.08 (m, 1H), 2.91 (d, J = 9.4 Hz, 1H), 2.60-2.43 (m, 4H), 2.22-2.06 (m, 2H), 1.72-1.56 (m, 1H), 1.57 -1.50 (m, 2H), 0.94 (s, 9H);

13C NMR (75 MHz, CDCl3) δ 165.03, 137.56, 135.29, 131.02, 125.66, 59.38, 53.97, 52.10, 46.38, 42.77, 34.56, 29.82, 29.71, 29.49, 27.84. 13 C NMR (75 MHz, CDCl 3 ) δ 165.03, 137.56, 135.29, 131.02, 125.66, 59.38, 53.97, 52.10, 46.38, 42.77, 34.56, 29.82, 29.71, 29.49, 27.84.

실시예Example 6 : 6: ( ( RR )-)- NN -((1-(3,3--((1- (3,3- 다이메틸부틸Dimethylbutyl )) 피롤리딘Pyrrolidine -3-일)-3 days) 메틸methyl )-1-)-One- 메틸methyl -3-프로필-1-3-propyl-1 HH -피라졸-5-카르복사미드(-Pyrazole-5-carboxamide ( 화합물번호 3Compound number 3 )의 제조Manufacturing

Figure pat00140
Figure pat00140

(S)-1-메틸-3-프로필-N-(피롤리딘-3-일메틸)-1H-피라졸-5-카르복사미드 (4-V-2; 100 mg 0.4 mmol)과 3,3-다이메틸부틸알데하이드 (2- XVII -1; 50 μL, 0.4 mmol)과 소듐 트리아세톡시보로하이드라이드 (NaBH(OAc)3; 254 mg, 1.2 mmol)을 이용하여 상기 표제화합물(화합물번호 3) 16 mg (수율 12%)을 얻었다.( S ) -1-Methyl-3-propyl- N- (pyrrolidin-3-ylmethyl) -1 H -pyrazole-5-carboxamide ( 4-V-2 ; 100 mg 0.4 mmol) and 3 The title compound ( Compound No. ) was prepared using, 3-dimethylbutylaldehyde ( 2- XVII- 1 ; 50 μL, 0.4 mmol) and sodium triacetoxyborohydride (NaBH (OAc) 3 ; 254 mg, 1.2 mmol). 3 ) 16 mg (yield 12%) were obtained.

1H NMR (300 MHz, CDCl3) δ 7.77(brs, 1H), 6.28(s, 1H), 4.14(s, 3H), 3.44-3.25 (m, 2H), 3.06-2.99 (m, 1H), 2.75(d, J = 7.5 Hz, 1H), 2.61-2.36 (m, 6H), 2.28-2.03 (m, 2H), 1.71-1.61 (m, 3H), 1.51-1.45 (m, 2H), 0.98(t, J = 7.3 Hz, 3H), 0.93 (s, 9H); 1 H NMR (300 MHz, CDCl 3 ) δ 7.77 (brs, 1H), 6.28 (s, 1H), 4.14 (s, 3H), 3.44-3.25 (m, 2H), 3.06-2.99 (m, 1H), 2.75 (d, J = 7.5 Hz, 1H), 2.61-2.36 (m, 6H), 2.28-2.03 (m, 2H), 1.71-1.61 (m, 3H), 1.51-1.45 (m, 2H), 0.98 ( t, J = 7.3 Hz, 3H), 0.93 (s, 9H);

13C NMR (75 MHz, CDCl3) δ 160.33, 151.55, 135.37, 104.53, 61.09, 46.78, 41.74, 38.85, 33.60, 31.91, 29.99, 29.68, 22.89, 22.67, 14.82, 14.09, 13.82. 13 C NMR (75 MHz, CDCl 3 ) δ 160.33, 151.55, 135.37, 104.53, 61.09, 46.78, 41.74, 38.85, 33.60, 31.91, 29.99, 29.68, 22.89, 22.67, 14.82, 14.09, 13.82.

실시예Example 7 :  7: (( RR )-)- NN -((1-(3,3--((1- (3,3- 다이메틸부틸Dimethylbutyl )) 피롤리딘Pyrrolidine -3-일)-3 days) 메틸methyl )-5-) -5- 아이소부틸Isobutyl -1-페닐-1-1-phenyl-1 HH -피라졸-3-카르복사미드( -Pyrazole-3-carboxamide ( 화합물번호 4Compound number 4 )의 제조Manufacturing

Figure pat00141
Figure pat00141

(S)-5-아이소부틸-1-페닐-N-(피롤리딘-3-일메틸)-1H-피라졸-3-카르복사이드 (화합물번호 57; 114 mg, 0.4 mmol)과 3,3-다이메틸부틸알데하이드 (2- XVII -1; 44 μL, 0.4 mmol)과 소듐 트리아세톡시보로하이드라이드 (NaBH(OAc)3; 223 mg, 1.1 mmol)을 이용하여 상기 표제화합물(화합물번호 4) 14 mg (수율 10%)을 얻었다.( S ) -5-isobutyl-1-phenyl- N- (pyrrolidin-3-ylmethyl) -1 H -pyrazole-3-carboxide ( Compound No. 57 ; 114 mg, 0.4 mmol) and 3 The title compound ( Compound No. ) was prepared using, 3-dimethylbutylaldehyde ( 2- XVII- 1 ; 44 μL, 0.4 mmol) and sodium triacetoxyborohydride (NaBH (OAc) 3 ; 223 mg, 1.1 mmol). 4 ) 14 mg (yield 10%) were obtained.

1H NMR (300 MHz, CDCl3) δ 7.52-7.47(m, 3H), 7.43-7.40(m,2H), 6.75 (s, 1H), 3.50-3.44 (m, 2H), 3.05 (m, 1H), 2.80 (brs, 2H), 2.63-2.60 (m, 4H), 2.51(d, J = 7.2 Hz, 2H), 2.17-2.01 (m, 1H), 1.87-1.82 (m, 1H), 1.72-1.58 (m, 1H), 1.54-1.48 (m, 2H), 0.89 (s, 9H), 0.86(d, J = 6.8 Hz, 6H); 1 H NMR (300 MHz, CDCl 3 ) δ 7.52-7.47 (m, 3H), 7.43-7.40 (m, 2H), 6.75 (s, 1H), 3.50-3.44 (m, 2H), 3.05 (m, 1H ), 2.80 (brs, 2H), 2.63-2.60 (m, 4H), 2.51 (d, J = 7.2 Hz, 2H), 2.17-2.01 (m, 1H), 1.87-1.82 (m, 1H), 1.72- 1.58 (m, 1 H), 1.54-1.48 (m, 2H), 0.89 (s, 9H), 0.86 (d, J = 6.8 Hz, 6H);

13C NMR (75 MHz, CDCl3) δ 162.91, 146.15, 145.29, 139.27, 129.32, 128.83, 125.90, 106.51, 57.09, 53.21, 52.54, 41.66, 39.25, 37.78, 35.09, 29.76, 29.18, 28.32, 27.58, 22.32. 13 C NMR (75 MHz, CDCl 3 ) δ 162.91, 146.15, 145.29, 139.27, 129.32, 128.83, 125.90, 106.51, 57.09, 53.21, 52.54, 41.66, 39.25, 37.78, 35.09, 29.76, 29.18, 28.32, 27.58, 22.32 .

실시예Example 8 : 8 : ( ( RR )-3-) -3- 아이소프로필Isopropyl -- NN -((1-(피리딘-3--((1- (pyridine-3- 일메틸Methyl )) 피롤리딘Pyrrolidine -3-일)-3 days) 메Me 틸)아이소옥사졸-5-카르복사미드(Tyl) isoxazole-5-carboxamide ( 화합물번호 5Compound number 5 )의 제조Manufacturing

Figure pat00142
Figure pat00142

(S)-3-아이소프로필-N-(피롤리딘-3-일메틸)아이소옥사졸-5-카르복사미드 (화합물번호 58; 135 mg, 0.6 mmol)과 니코틴알데히드 (2- XVIII -1; 53 μL, 0.6 mmol)과 소듐 트리아세톡시보로하이드라이드 (NaBH(OAc)3; 362 mg, 1.7 mmol)을 이용하여 상기 표제화합물(화합물번호 5) 38 mg (수율 20%)을 얻었다.( S ) -3-isopropyl- N- (pyrrolidin-3-ylmethyl) isoxazole-5-carboxamide ( Compound No. 58 ; 135 mg, 0.6 mmol) with nicotinaldehyde ( 2- XVIII- 1 53 μL, 0.6 mmol) and sodium triacetoxyborohydride (NaBH (OAc) 3 ; 362 mg, 1.7 mmol) gave 38 mg (yield 20%) of the title compound ( Compound No. 5 ).

1H NMR (300 MHz, CDCl3) δ 8.57(s, 1H), 8.53(dd, J = 4.8, 1.6 Hz, 1H), 7.86(d, J = 7.7 Hz, 1H), 7.70(brs, 1H), 7.31(dd, J = 5.0, 2.8 Hz, 1H), 6.79 (s, 1H), 3.64 (s, 2H), 3.53-3.28 (m, 3H), 3.17-3.12 (m, 1H), 2.94-2.83 (m, 1H), 2.63 (d, J = 6.2Hz, 1H), 2.55-2.52 (m, 2H), 2.39-2.28 (m, 1H), 2.14-2.01 (m, 1H), 1.31 (d, J = 7.0Hz, 6H); 1 H NMR (300 MHz, CDCl 3 ) δ 8.57 (s, 1H), 8.53 (dd, J = 4.8, 1.6 Hz, 1H), 7.86 (d, J = 7.7 Hz, 1H), 7.70 (brs, 1H) , 7.31 (dd, J = 5.0, 2.8 Hz, 1H), 6.79 (s, 1H), 3.64 (s, 2H), 3.53-3.28 (m, 3H), 3.17-3.12 (m, 1H), 2.94-2.83 (m, 1H), 2.63 (d, J = 6.2 Hz, 1H), 2.55-2.52 (m, 2H), 2.39-2.28 (m, 1H), 2.14-2.01 (m, 1H), 1.31 (d, J = 7.0 Hz, 6H);

13C NMR (75 MHz, CDCl3) δ 170.36, 163.81, 156.70, 149.89, 148.77, 136.69, 134.76, 123.62, 105.04, 58.49, 57.44, 53.87, 45.11, 35.47, 27.93, 26.57, 21.66. 13 C NMR (75 MHz, CDCl 3 ) δ 170.36, 163.81, 156.70, 149.89, 148.77, 136.69, 134.76, 123.62, 105.04, 58.49, 57.44, 53.87, 45.11, 35.47, 27.93, 26.57, 21.66.

실시예Example 9 : 9: ( ( RR )-3,5-) -3,5- 다이클로로Dichloro -- NN -((1-(피리딘-3--((1- (pyridine-3- 일메틸Methyl )) 피롤리딘Pyrrolidine -3-일)-3 days) 메Me 틸)벤즈아미드(Teal) benzamide ( 화합물번호 6Compound number 6 )의 제조Manufacturing

Figure pat00143
Figure pat00143

(S)-3,5-다이클로로-N-(피롤리딘-3-일메틸)벤즈아미드 (4-VII-2; 100 mg, 0.4 mmol)과 니코틴알데히드 (2- XVIII -1; 34 μL, 0.4 mmol)과 소듐 트리아세톡시보로하이드라이드 (NaBH(OAc)3; 233 mg, 1.1 mmol)을 이용하여 상기 표제화합물(화합물번호 6) 15 mg (수율 11%)을 얻었다.( S ) -3,5-Dichloro- N- (pyrrolidin-3-ylmethyl) benzamide ( 4-VII-2 ; 100 mg, 0.4 mmol) and nicotinaldehyde ( 2- XVIII- 1 ; 34 μL , 0.4 mmol) and sodium triacetoxyborohydride (NaBH (OAc) 3 ; 233 mg, 1.1 mmol) gave 15 mg (yield 11%) of the title compound ( Compound No. 6 ).

1H NMR (300MHz, CDCl3) δ 8.54-8.52 (m, 2H), 7.67-7.64 (m, 3H), 7.51(t, J = 1.9 Hz, 1H), 7.35 (brs, 1H), 7.28-7.24 (m, 1H), 3.65 (s, 2H), 3.49-3.39 (m, 2H), 3.01-2.91 (m, 1H), 2.71 (d, J = 7.6 Hz, 1H), 2.54- 2.34 (m, 2H), 2.34(q, J = 8.7 Hz, 1H), 2.22-2.09 (m, 1H), 1.72-1.59 (m, 1H); 1 H NMR (300 MHz, CDCl 3 ) δ 8.54-8.52 (m, 2H), 7.67-7.64 (m, 3H), 7.51 (t, J = 1.9 Hz, 1H), 7.35 (brs, 1H), 7.28-7.24 (m, 1H), 3.65 (s, 2H), 3.49-3.39 (m, 2H), 3.01-2.91 (m, 1H), 2.71 (d, J = 7.6 Hz, 1H), 2.54- 2.34 (m, 2H ), 2.34 (q, J = 8.7 Hz, 1H), 2.22-2.09 (m, 1H), 1.72-1.59 (m, 1H);

13C NMR (75 MHz, CDCl3) δ 165.27, 150.05, 148.88, 137.74, 136.42, 135.43, 133.80, 131.20, 125.56, 123.56, 58.66, 57.65, 54.16, 45.78, 35.37, 27.87. 13 C NMR (75 MHz, CDCl 3 ) δ 165.27, 150.05, 148.88, 137.74, 136.42, 135.43, 133.80, 131.20, 125.56, 123.56, 58.66, 57.65, 54.16, 45.78, 35.37, 27.87.

실시예Example 10 : 10: ( ( RR )-1-)-One- 메틸methyl -3-프로필--3-propyl- NN -((1-(피리딘-3--((1- (pyridine-3- 일메틸Methyl )) 피롤리딘Pyrrolidine -3-일)-3 days) 메Me 틸)-1Teal) -1 HH -피라졸-5-카르복사미드(-Pyrazole-5-carboxamide ( 화합물번호 7Compound number 7 )의 제조Manufacturing

Figure pat00144
Figure pat00144

(S)-1-메틸-3-프로필-N-(피롤리딘-3-일메틸)-1H-피라졸-5-카르복사미드 (4-V-2; 158 mg, 0.6 mmol)과 니코틴알데히드 (2- XVIII -1; 59 μL, 0.6 mmol)과 소듐 트리아세톡시보로하이드라이드 (NaBH(OAc)3; 401 mg, 1.9 mmol)을 이용하여 상기 표제화합물(화합물번호 7) 45 mg (수율 21%)을 얻었다.( S ) -1-Methyl-3-propyl- N- (pyrrolidin-3-ylmethyl) -1 H -pyrazole-5-carboxamide ( 4-V-2 ; 158 mg, 0.6 mmol) 45 mg of the title compound ( Compound No. 7 ) using nicotinaldehyde ( 2- XVIII- 1 ; 59 μL, 0.6 mmol) and sodium triacetoxyborohydride (NaBH (OAc) 3 ; 401 mg, 1.9 mmol). Yield 21%).

1H NMR (300 MHz, CDCl3) δ 8.55-8.52 (m, 2H), 7.64 (d, J = 7.8 Hz, 1H), 7.28-7.22 (m, 1H), 6.97 (brs, 1H), 6.20 (s, 1H), 4.11 (s, 3H), 3.63 (s, 2H), 3.50-3.28 (m, 2H), 2.94-2.89 (m, 1H), 2.63-2.53 (m, 5H), 2.37(q, J = 8.1 Hz, 1H), 2.17-2.03 (m, 1H), 1.70-1.60 (m, 5H), 0.98 (t, J = 7.3 Hz, 3H); 1 H NMR (300 MHz, CDCl 3 ) δ 8.55-8.52 (m, 2H), 7.64 (d, J = 7.8 Hz, 1H), 7.28-7.22 (m, 1H), 6.97 (brs, 1H), 6.20 ( s, 1H), 4.11 (s, 3H), 3.63 (s, 2H), 3.50-3.28 (m, 2H), 2.94-2.89 (m, 1H), 2.63-2.53 (m, 5H), 2.37 (q, J = 8.1 Hz, 1H), 2.17-2.03 (m, 1H), 1.70-1.60 (m, 5H), 0.98 (t, J = 7.3 Hz, 3H);

13C NMR (75 MHz, CDCl3) δ 160.60, 151.43, 150.14, 148.79, 136.32, 135.94, 134.09, 123.36, 104.38, 58.69, 57.60, 54.02, 44.85, 38.77, 35.80, 30.06, 27.94, 23.01, 13.86. 13 C NMR (75 MHz, CDCl 3 ) δ 160.60, 151.43, 150.14, 148.79, 136.32, 135.94, 134.09, 123.36, 104.38, 58.69, 57.60, 54.02, 44.85, 38.77, 35.80, 30.06, 27.94, 23.01, 13.86.

실시예Example 11 : 11: ( ( RR )-5-) -5- 아이소부틸Isobutyl -1-페닐--1-phenyl- NN -((1-(피리딘-3--((1- (pyridine-3- 일메틸Methyl )) 피롤리딘Pyrrolidine -3-일)메틸)-1-3-yl) methyl) -1 HH -피라졸-3-카르복사미드(-Pyrazole-3-carboxamide ( 화합물번호 8Compound number 8 )의 제조Manufacturing

Figure pat00145
Figure pat00145

(S)-5-아이소부틸-1-페닐-N-(피롤리딘-3-일메틸)-1H-피라졸-3-카르복사이드 (화합물번호 57; 100 mg, 0.3 mmol)과 니코틴알데히드 (2- XVIII -1; 29 μL, 0.3 mmol)과 소듐 트리아세톡시보로하이드라이드 (NaBH(OAc)3; 195 mg, 0.9 mmol)을 이용하여 상기 표제화합물(화합물번호 8) 38 mg (수율 29%)을 얻었다.( S ) -5-Isobutyl-1-phenyl- N- (pyrrolidin-3-ylmethyl) -1 H -pyrazole-3-carboxyside ( Compound No. 57 ; 100 mg, 0.3 mmol) and nicotine 38 mg (Yield) of the title compound ( Compound No. 8 ) using aldehyde ( 2- XVIII- 1 ; 29 μL, 0.3 mmol) and sodium triacetoxyborohydride (NaBH (OAc) 3 ; 195 mg, 0.9 mmol) 29%).

1H NMR (300MHz, CDCl3) δ 8.54(s, 1H), 8.49-8.47(m, 1H), 7.76(d, J = 8.1 Hz, 1H), 7.58-7.55 (m, 5H), 7.50 (brs, 1H), 7.08-7.04 (m, 1H), 6.80 (s, 1H), 3.69-3.58 (m, 2H), 3.51-3.45 (m, 2H), 2.72-2.65 (m, 2H), 2.54-2.43(m, 5H), 2.10-2.04 (m, 1H), 1.93-1.84 (m, 1H), 1.66-1.62 (m, 1H), 0.91(d, J = 6.6 Hz, 6H); 1 H NMR (300 MHz, CDCl 3 ) δ 8.54 (s, 1H), 8.49-8.47 (m, 1H), 7.76 (d, J = 8.1 Hz, 1H), 7.58-7.55 (m, 5H), 7.50 (brs , 1H), 7.08-7.04 (m, 1H), 6.80 (s, 1H), 3.69-3.58 (m, 2H), 3.51-3.45 (m, 2H), 2.72-2.65 (m, 2H), 2.54-2.43 (m, 5H), 2.10-2.04 (m, 1H), 1.93-1.84 (m, 1H), 1.66-1.62 (m, 1H), 0.91 (d, J = 6.6 Hz, 6H);

13C NMR (75MHz, CDCl3) δ 163.34, 150.63, 149.22, 147.62, 145.85, 140.25, 137.29, 135.32, 130.05, 129.47, 126.80, 124.09, 107.33, 59.20, 58.31, 54.60, 44.77, 37.63, 35.87, 29.03, 23.11. 13 C NMR (75 MHz, CDCl 3 ) δ 163.34, 150.63, 149.22, 147.62, 145.85, 140.25, 137.29, 135.32, 130.05, 129.47, 126.80, 124.09, 107.33, 59.20, 58.31, 54.60, 44.77, 37.63, 35.87, 23.11.

실시예Example 12 : 12: ( ( RR )-5-) -5- 아이소부틸Isobutyl -1-페닐--1-phenyl- NN -((1-(피리딘-3--((1- (pyridine-3- 일메틸Methyl )) 피롤리딘Pyrrolidine -3-일)메틸)-1-3-yl) methyl) -1 HH -피라졸-3-카르복사미드(-Pyrazole-3-carboxamide ( 화합물번호 9Compound number 9 )의 제조Manufacturing

Figure pat00146
Figure pat00146

(S)-3-아이소프로필-N-(피롤리딘-3-일메틸)아이소옥사졸-5-카르복사미드(화합물번호 58; 80 mg, 0.3 mmol), 4-(트리플루오로메틸)페네틸 4-메틸벤젠술폰산염 (2-XII-2; 65 mg, 0.2 mmol) 그리고 포타슘 카보네이트 (K2CO3; 141 mg, 1.0 mmol)을 아세토나이트릴(4 mL)에 가한 후 6시간동안 교반하며 환류 시켰다. 반응이 종료되면 반응혼합물을 상온으로 식히고 증류수와 다이클로로메테인를 이용하여 추출하였다. 유기층을 무수 황산 마그네슘로 건조시킨 후 감압 증류하였고, 관 크로마토그래피로 분리하여 상기 표제화합물(화합물번호 9) 34 mg (수율 24%)을 얻었다.( S ) -3-isopropyl- N- (pyrrolidin-3-ylmethyl) isoxazole-5-carboxamide ( Compound No. 58 ; 80 mg, 0.3 mmol), 4- (trifluoromethyl) Phenyl 4-methylbenzenesulfonate ( 2-XII-2 ; 65 mg, 0.2 mmol) and potassium carbonate (K 2 CO 3 ; 141 mg, 1.0 mmol) were added to acetonitrile (4 mL) for 6 hours. It was stirred to reflux. After the reaction was completed, the reaction mixture was cooled to room temperature and extracted with distilled water and dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, distilled under reduced pressure, and separated by column chromatography to obtain 34 mg (yield 24%) of the title compound ( Compound No. 9 ).

1H NMR (300MHz, CDCl3) δ 7.81(brs, 1H) 7.54(d, J = 7.9 Hz, 2H) 7.36(d, J = 7.9 Hz, 2H) 6.79(s, 1H) 3.49-3.41(m, 2H) 3.15-3.10(m, 1H) 2.97-2.82(m, 3H) 2.78-2.68(m, 3H) 2.61-2.56(m, 2H) 2.42-2.39(m, 1H) 2.11-2.08(m, 1H) 1.32(d, J = 7.0 Hz, 6H); 1 H NMR (300 MHz, CDCl 3 ) δ 7.81 (brs, 1 H) 7.54 (d, J = 7.9 Hz, 2H) 7.36 (d, J = 7.9 Hz, 2H) 6.79 (s, 1H) 3.49-3.41 (m, 2H) 3.15-3.10 (m, 1H) 2.97-2.82 (m, 3H) 2.78-2.68 (m, 3H) 2.61-2.56 (m, 2H) 2.42-2.39 (m, 1H) 2.11-2.08 (m, 1H) 1.32 (d, J = 7.0 Hz, 6H);

13C NMR (300MHz, CDCl3) δ 170.60, 163.60, 156.93, 144.66, 129.20, 129.11, 128.55, 126.15, 125.63, 125.59, 125.53, 125.49, 122.34, 105.29, 58.73, 57.29, 54.09, 45.27, 35.97, 35.63, 28.21, 26.83, 21.90. 13 C NMR (300MHz, CDCl 3 ) δ 170.60, 163.60, 156.93, 144.66, 129.20, 129.11, 128.55, 126.15, 125.63, 125.59, 125.53, 125.49, 122.34, 105.29, 58.73, 57.29, 54.09, 45.27, 35.97, 35.97, 35.97 28.21, 26.83, 21.90.

실시예Example 13 : 13: ( ( RR )-3-) -3- 아이소프로필Isopropyl -- NN -((1-(4-(-((1- (4- ( 트리플루오로메틸Trifluoromethyl )) 페네틸Phenethyl )) 피롤리Pyrroly 딘-3-일)메틸)아이소옥사졸-5-카르복사미드(Din-3-yl) methyl) isoxazole-5-carboxamide ( 화합물번호 10Compound number 10 )의 제조Manufacturing

Figure pat00147
Figure pat00147

(S)-3,5-다이클로로-N-(피롤리딘-3-일메틸)벤즈아미드 (4-VII-2; 71 mg, 0.3 mmol)과 4-(트리플루오로메틸)페네틸 4-메틸벤젠술폰산염 (2-XII-2; 50 mg, 0.2 mmol)과 포타슘 카보네이트 (K2CO3; 24 mg, 0.2 mmol)을 이용하여 상기 표제화합물(화합물번호 10) 13 mg (수율 11%)을 얻었다.( S ) -3,5-Dichloro- N- (pyrrolidin-3-ylmethyl) benzamide ( 4-VII-2 ; 71 mg, 0.3 mmol) and 4- (trifluoromethyl) phenethyl 4 13 mg (yield 11%) of the title compound ( Compound No. 10 ) using methylbenzenesulfonate ( 2-XII-2 ; 50 mg, 0.2 mmol) and potassium carbonate (K 2 CO 3 ; 24 mg, 0.2 mmol). )

1H NMR (400 MHz, CDCl3) δ 7.82 (brs, 1H), 7.54 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 6.80 (s, 1H), 3.55-3.38 (m, 2H), 3.17-3.10 (m, 1H), 2.98-2.93 (m, 3H), 2.81-2.68 (m, 3H), 2.61-2.53 (m, 2H), 2.41 (dd, J = 16.4, 8.8 Hz, 1H), 2.13-2.06 (m, 1H), 1.64-1.60 (m, 1H), 1.33 (d, J = 7.2 Hz, 6H); 1 H NMR (400 MHz, CDCl 3 ) δ 7.82 (brs, 1H), 7.54 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 6.80 (s, 1H), 3.55 -3.38 (m, 2H), 3.17-3.10 (m, 1H), 2.98-2.93 (m, 3H), 2.81-2.68 (m, 3H), 2.61-2.53 (m, 2H), 2.41 (dd, J = 16.4, 8.8 Hz, 1H), 2.13-2.06 (m, 1H), 1.64-1.60 (m, 1H), 1.33 (d, J = 7.2 Hz, 6H);

13C NMR (100 MHz, CDCl3) δ 170.31, 163.34, 156.66, 144.40, 128.92, 128.42 (q, J C -F = 32.0 Hz), 125.28(q, J C -F = 3.8 Hz), 124.30(q, J C -F = 270.1 Hz, CF3), 105.01, 58.47, 57.00, 53.81, 45.00, 35.72, 35.36, 27.95, 26.55, 21.62. 13 C NMR (100 MHz, CDCl 3 ) δ 170.31, 163.34, 156.66, 144.40, 128.92, 128.42 (q, J C -F = 32.0 Hz), 125.28 (q, J C -F = 3.8 Hz), 124.30 (q , J C -F = 270.1 Hz, CF 3 ), 105.01, 58.47, 57.00, 53.81, 45.00, 35.72, 35.36, 27.95, 26.55, 21.62.

실시예Example 14 : 14: ( ( RR )-1-)-One- 메틸methyl -3-프로필--3-propyl- NN -((1-(4-(-((1- (4- ( 트리플루오로메틸Trifluoromethyl )) 페네틸Phenethyl )) 피롤Pyrrole 리딘-3-일)메틸)-1Ridin-3-yl) methyl) -1 HH -피라졸-5-카르복사미드(-Pyrazole-5-carboxamide ( 화합물번호 11Compound number 11 )의 제조Manufacturing

Figure pat00148
Figure pat00148

(S)-1-메틸-3-프로필-N-(피롤리딘-3-일메틸)-1H-피라졸- 5-카르복사미드 (4-V-2; 84 mg, 0.3 mmol)과 4-(트리플루오로메틸)페네틸-4-메틸벤젠술폰산염 (2-XII-2; 65 mg, 0.2 mmol)과 포타슘 카보네이트 (K2CO3; 140 mg, 1.0 mmol)을 이용하여 상기 표제화합물(화합물번호 11) 18 mg (수율 13%)을 얻었다.( S ) -1-Methyl-3-propyl- N- (pyrrolidin-3-ylmethyl) -1 H -pyrazole-5-carboxamide ( 4-V-2 ; 84 mg, 0.3 mmol) The title using 4- (trifluoromethyl) phenethyl-4-methylbenzenesulfonate ( 2-XII-2 ; 65 mg, 0.2 mmol) and potassium carbonate (K 2 CO 3 ; 140 mg, 1.0 mmol) 18 mg (yield 13%) of compound ( Compound No. 11 ) were obtained.

1H NMR (300 MHz, CDCl3) δ 7.55 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 6.26 (s, 1H), 4.13 (s, 3H), 3.43-3.38 (m, 2H), 3.11-3.01 (m, 1H), 2.93-2.90 (m, 2H), 2.80-2.75 (m, 3H), 2.61-2.56 (m, 4H), 2.53-2.42(m, 1H), 2.17-2.06 (m, 1H), 1.70-1.62 (m, 3H), 0.94 (t, J = 7.4 Hz, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.55 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 6.26 (s, 1H), 4.13 (s, 3H), 3.43 -3.38 (m, 2H), 3.11-3.01 (m, 1H), 2.93-2.90 (m, 2H), 2.80-2.75 (m, 3H), 2.61-2.56 (m, 4H), 2.53-2.42 (m, 1H), 2.17-2.06 (m, 1H), 1.70-1.62 (m, 3H), 0.94 (t, J = 7.4 Hz, 3H).

실시예Example 15 : 15: ( ( RR )-5-) -5- 아이소부틸Isobutyl -1-페닐--1-phenyl- NN -((1-(4-(-((1- (4- ( 트리플루오로메틸Trifluoromethyl )) 페네틸Phenethyl )피롤리딘-3-일)메틸)-1) Pyrrolidin-3-yl) methyl) -1 HH -피라졸-3-카르복사미드(-Pyrazole-3-carboxamide ( 화합물번호 12Compound number 12 )의 제조Manufacturing

Figure pat00149
Figure pat00149

(S)-5-아이소부틸-1-페닐-N-(피롤리딘-3-일메틸)-1H-피라졸-3-카르복사이드 (화합물번호 57; 380 mg, 1.2 mmol)과 4-(트리플루오로메틸)페네틸4-메틸벤젠술폰산염 (2-XII-2; 223 mg, 0.7 mmol)과 포타슘 카보네이트 (K2CO3; 270 mg, 2.0 mmol)을 이용하여 상기 표제화합물(화합물번호 12) 234 mg (수율 72%)을 얻었다. ( S ) -5-isobutyl-1-phenyl- N- (pyrrolidin-3-ylmethyl) -1 H -pyrazole-3-carboxide ( Compound No. 57 ; 380 mg, 1.2 mmol) and 4 -(Trifluoromethyl) phenethyl4-methylbenzenesulfonate ( 2-XII-2 ; 223 mg, 0.7 mmol) and potassium carbonate (K 2 CO 3 ; 270 mg, 2.0 mmol) to give the title compound ( Compound number 12 ) 234 mg (72% yield) were obtained.

1H NMR (300 MHz, CDCl3) δ 7.52-7.40 (m, 8H), 7.27-7.24 (m, 2H), 6.78 (s, 1H), 3.48-3.43 (m, 2H), 2.88-2.83 (m, 2H), 2.76-2.65 (m, 4H), 2.56-2.47 (m, 5H), 2.14-1.97 (m, 1H), 1.88-1.83 (m, 1H), 1.64-1.53 (m, 1H), 0.88 (d, J = 6.6 Hz, 6H); 1 H NMR (300 MHz, CDCl 3 ) δ 7.52-7.40 (m, 8H), 7.27-7.24 (m, 2H), 6.78 (s, 1H), 3.48-3.43 (m, 2H), 2.88-2.83 (m , 2H), 2.76-2.65 (m, 4H), 2.56-2.47 (m, 5H), 2.14-1.97 (m, 1H), 1.88-1.83 (m, 1H), 1.64-1.53 (m, 1H), 0.88 (d, J = 6.6 Hz, 6H);

13C NMR (75 MHz, CDCl3) δ 162.98, 146.09, 145.37, 141.22, 139.26, 129.60, 129.34, 129.11, 128.88, 125.90, 125.77, 125.67, 122.27, 106.48, 57.15, 56.65, 53.53, 41.65, 37.93, 35.08, 32.60, 28.32, 27.61, 22.32. 13 C NMR (75 MHz, CDCl 3 ) δ 162.98, 146.09, 145.37, 141.22, 139.26, 129.60, 129.34, 129.11, 128.88, 125.90, 125.77, 125.67, 122.27, 106.48, 57.15, 56.65, 53.53, 41.65, 37.93, 37.08 , 32.60, 28.32, 27.61, 22.32.

실시예Example 16 : 16: ( ( RR )-3,5-) -3,5- 다이클로로Dichloro -- NN -((1-(3,3--((1- (3,3- 다이메틸부테노일Dimethylbutenoyl )) 피롤리딘Pyrrolidine -3-일)메틸)벤즈아미드(-3-yl) methyl) benzamide ( 화합물번호 13Compound number 13 )의 제조Manufacturing

Figure pat00150
Figure pat00150

(S)-3,5-다이클로로-N-(피롤리딘-3-일메틸)벤즈아미드 (4-VII-2; 100 mg, 0.4 mmol)을 테트라하이드로퓨란(THF)에 녹인 혼합물에 트리에틸아민(TEA; 0.2 mL, 1.1 mmol)를 가한 후 10분 동안 교반하였다. 반응 혼합물에 3,3-다이메틸부테노일 클로라이드 (2- XIX -1; 66 μL, 0.5 mmol)을 천천히 가한 후 3시간 교반하였다. 반응 완결 후에 테트라하이드로퓨란을 감압하여 제거한 후 증류수를 넣고 에틸 아세테이트로 추출하였다. 유기층을 무수 황산 마그네슘 로 건조시켜 여과한 후 관 크로마토그래피로 분리하여 상기 표제화합물(화합물번호 13) 46 mg (수율 34%) 을 얻었다.( S ) -3,5-Dichloro- N- (pyrrolidin-3-ylmethyl) benzamide ( 4-VII-2 ; 100 mg, 0.4 mmol) in a mixture of tetrahydrofuran (THF) Ethylamine (TEA; 0.2 mL, 1.1 mmol) was added and stirred for 10 minutes. 3,3-dimethylbutenoyl chloride ( 2- XIX- 1 ; 66 μL, 0.5 mmol) was slowly added to the reaction mixture, followed by stirring for 3 hours. After completion of the reaction, the tetrahydrofuran was removed under reduced pressure, distilled water was added and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and separated by column chromatography to obtain 46 mg (yield 34%) of the title compound ( Compound No. 13 ).

1H NMR (300 MHz, CDCl3) δ 7.74 (d, J = 1.8 Hz, 1H), 7.70(d, J = 2.1 Hz, 1H), 7.54-7.49(m, 1H), 7.42(brs, 1H), 3.77-3.22 (m, 6H), 2.22 (s, 2H), 2.18-2.08 (m, 1H), 1.84-1.69 (m, 1H), 1.06 (s, 9H); 1 H NMR (300 MHz, CDCl 3 ) δ 7.74 (d, J = 1.8 Hz, 1H), 7.70 (d, J = 2.1 Hz, 1H), 7.54-7.49 (m, 1H), 7.42 (brs, 1H) , 3.77-3.22 (m, 6H), 2.22 (s, 2H), 2.18-2.08 (m, 1H), 1.84-1.69 (m, 1H), 1.06 (s, 9H);

13C NMR (75 MHz, CDCl3) δ 171.18, 170.98, 165.33, 165.28, 137.35, 137.22, 135.43, 135.18, 131.39, 131.13, 126.01, 125.80, 50.97, 49.40, 46.96, 46.91, 46.68, 44.83, 42.35, 39.57, 37.56, 31.49, 29.92, 29.77, 28.07. 13 C NMR (75 MHz, CDCl 3 ) δ 171.18, 170.98, 165.33, 165.28, 137.35, 137.22, 135.43, 135.18, 131.39, 131.13, 126.01, 125.80, 50.97, 49.40, 46.96, 46.91, 46.68, 44.83, 42.35, 42.35 , 37.56, 31.49, 29.92, 29.77, 28.07.

실시예Example 17 : 17: ( ( RR )-3,5-) -3,5- 다이클로로Dichloro -- NN -- (( (1-(2-(4-((1- (2- (4- ( 트리플루오로메틸Trifluoromethyl )페닐)아세틸)피롤리딘-3-일)메틸)벤즈아마이드() Phenyl) acetyl) pyrrolidin-3-yl) methyl) benzamide ( 화합물번호 14Compound number 14 )의 제조Manufacturing

Figure pat00151
Figure pat00151

2-(4-(트리플루오로메틸)페닐)아세트산 (2- XX -1; 75 mg, 0.4 mmol)를 테트라하이드로퓨란에 녹인 혼합물에 1,1'-카보닐 다이이미다졸(CDI; 65 mg, 0.4 mmol)를 가한 후 2시간 동안 교반하였다. (S)-3,5-다이클로로-N-(피롤리딘-3-일메틸)벤즈아미드 (4-VII-2; 100 mg, 0.4 mmol)를 테트라하이드로퓨란에 용해시킨 후 반응 혼합물에 천천히 적가 하였다. 반응이 종료되면 감압 여과하여 테트라하이드로퓨란를 제거하고 증류수와 에틸 아세테이트로 추출하였다. 유기층을 무수 황산 마그네슘로 건조시킨 후 여과한 후 유기층을 감압 여과한 후 관 크로마토그래피로 분리하여 상기 표제화합물(화합물번호 14) 59 mg (수율 33%)을 얻었다.1,1'-carbonyl diimidazole (CDI; 65 mg) in a mixture of 2- (4- (trifluoromethyl) phenyl) acetic acid ( 2- XX -1 ; 75 mg, 0.4 mmol) in tetrahydrofuran , 0.4 mmol) was added and stirred for 2 hours. ( S ) -3,5-Dichloro- N- (pyrrolidin-3-ylmethyl) benzamide ( 4-VII-2 ; 100 mg, 0.4 mmol) was dissolved in tetrahydrofuran and slowly added to the reaction mixture. It was added dropwise. After the reaction was completed, the mixture was filtered under reduced pressure to remove tetrahydrofuran and extracted with distilled water and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the organic layer was filtered under reduced pressure and separated by column chromatography to obtain 59 mg (yield 33%) of the title compound ( Compound No. 14 ).

1H NMR (300 MHz, CDCl3) δ 7.63-7.48 (m, 5H), 7.37 (t, J = 7.2 Hz, 1H), 6.62(brs, 0.5H), 6.27 (brs, 0.5H), 3.76-3.60 (m, 4H), 3.53-3.39 (m, 2H), 3.34-3.20 (m, 2H), 2.63-2.51(m, 1H), 2.16-2.04 (m, 1H), 1.82-1.65 (m, 1H); 1 H NMR (300 MHz, CDCl 3 ) δ 7.63-7.48 (m, 5H), 7.37 (t, J = 7.2 Hz, 1H), 6.62 (brs, 0.5H), 6.27 (brs, 0.5H), 3.76- 3.60 (m, 4H), 3.53-3.39 (m, 2H), 3.34-3.20 (m, 2H), 2.63-2.51 (m, 1H), 2.16-2.04 (m, 1H), 1.82-1.65 (m, 1H );

13C NMR (75 MHz, CDCl3) δ 169.00, 168.85, 165.30, 165.17, 138.72, 138.53, 137.17, 137.04, 135.47, 135.20, 131.47, 131.17, 129.46, 125.90, 125.71, 125.49, 125.44, 122.69, 50.28, 49.94, 46.44, 45.29, 42.22, 42.09, 41.60, 41.36, 39.63, 37.66, 29.67, 27.94. 13 C NMR (75 MHz, CDCl 3 ) δ 169.00, 168.85, 165.30, 165.17, 138.72, 138.53, 137.17, 137.04, 135.47, 135.20, 131.47, 131.17, 129.46, 125.90, 125.71, 125.49, 125.44, 122.69, 50. , 46.44, 45.29, 42.22, 42.09, 41.60, 41.36, 39.63, 37.66, 29.67, 27.94.

실시예Example 18 : 18: ( ( RR )-)- NN -((1-(3,3--((1- (3,3- 다이메틸부테노일Dimethylbutenoyl )) 피롤리딘Pyrrolidine -3-일)-3 days) 메틸methyl )-3-) -3- 아이Child 소프로필아이소옥사졸-5-카르복사미드(Sopropylisoxazole-5-carboxamide ( 화합물번호 15Compound no.15 )의 제조Manufacturing

Figure pat00152
Figure pat00152

(S)-3-아이소프로필-N-(피롤리딘-3-일메틸)아이소옥사졸-5-카르복사미드 (화합물번호 58; 81 mg, 0.3 mmol)과 트리에틸아민(TEA; 0.1 mL, 1.0 mmol)과 3,3-다이메틸부테노일 클로라이드 (2- XIX -1; 45 μL, 0.4 mmol)을 이용하여 상기 표제화합물(화합물번호 15) 41 mg (수율 40%)을 얻었다.( S ) -3-isopropyl- N- (pyrrolidin-3-ylmethyl) isoxazole-5-carboxamide ( Compound No. 58 ; 81 mg, 0.3 mmol) with triethylamine (TEA; 0.1 mL , 1.0 mmol) and 3,3-dimethylbutenoyl chloride ( 2- XIX- 1 ; 45 μL, 0.4 mmol) gave 41 mg (yield 40%) of the title compound ( Compound No. 15 ).

1H NMR (300 MHz, CDCl3) δ 6.85 (d, J = 7.2 Hz, 1H), 6.80 (brs, 1H), 3.74-3.42 (m, 5H), 3.32-3.13 (m, 2H), 2.22-2.07 (m, 3H), 1.85-1.67 (m, 1H), 1.34 (d, J = 6.0 Hz, 6H), 1.10 (s, 9H); 1 H NMR (300 MHz, CDCl 3 ) δ 6.85 (d, J = 7.2 Hz, 1H), 6.80 (brs, 1H), 3.74-3.42 (m, 5H), 3.32-3.13 (m, 2H), 2.22- 2.07 (m, 3H), 1.85-1.67 (m, 1H), 1.34 (d, J = 6.0 Hz, 6H), 1.10 (s, 9H);

13C NMR (75 MHz, CDCl3) δ 171.13, 171.02, 170.68, 170.54, 163.00, 162.91, 156.69, 156.65, 105.75, 105.61, 51.03, 49.11, 46.99, 46.85, 46.82, 44.98, 41.80, 41.77, 39.90, 37.78, 31.59, 31.57, 30.10, 29.94, 29.87, 28.29, 26.76, 26.73, 21.81. 13 C NMR (75 MHz, CDCl 3 ) δ 171.13, 171.02, 170.68, 170.54, 163.00, 162.91, 156.69, 156.65, 105.75, 105.61, 51.03, 49.11, 46.99, 46.85, 46.82, 44.98, 41.80, 41.77, 39.90, 37.90, 37.90 , 31.59, 31.57, 30.10, 29.94, 29.87, 28.29, 26.76, 26.73, 21.81.

실시예Example 19 : 19: ( ( RR )-3-) -3- 아이소프로필Isopropyl -- NN -((1-(2-(4-(-((1- (2- (4- ( 트리플루오로메틸Trifluoromethyl )페닐)아세틸 )피롤리딘-3-일)메틸)아이소옥사졸-5-카르복사미드() Phenyl) acetyl) pyrrolidin-3-yl) methyl) isoxazole-5-carboxamide ( 화합물번호 16Compound number 16 )의 제조Manufacturing

Figure pat00153
Figure pat00153

(S)-3-아이소프로필-N-(피롤리딘-3-일메틸)아이소옥사졸-5-카르복사미드 (화합물번호 58; 77 mg, 0.3 mmol)과 2-(4-(트리플루오로메틸)페닐)아세트산 (2- XX -1; 66 mg, 0.3 mmol)과 1,1'-카보닐 다이이미다졸(CDI; 57 mg, 0.4 mmol)을 이용하여 상기 표제화합물(화합물번호 16) 32 mg (수율 24%)을 얻었다.( S ) -3-isopropyl- N- (pyrrolidin-3-ylmethyl) isoxazole-5-carboxamide ( Compound No. 58 ; 77 mg, 0.3 mmol) and 2- (4- (trifluoro) Romethyl) phenyl) acetic acid ( 2- XX- 1 ; 66 mg, 0.3 mmol) and 1,1'-carbonyl diimidazole (CDI; 57 mg, 0.4 mmol) to provide the title compound ( Compound No. 16 ). 32 mg (24% yield) were obtained.

1H NMR (300 MHz, CDCl3) δ 7.58 (d, J = 8.1 Hz, 2H), 7.39 (d, J = 8.1Hz, 2H), 6.81 (d, J = 4.5 Hz, 1H), 6.69 (s, 1H), 3.76-3.07 (m, 9H), 2.62-2.49 (m, 1H), 2.15-2.04 (m, 1H), 1.83-1.65 (m, 1H), 1.31(d, J = 6.9 Hz, 6H); 1 H NMR (300 MHz, CDCl 3 ) δ 7.58 (d, J = 8.1 Hz, 2H), 7.39 (d, J = 8.1 Hz, 2H), 6.81 (d, J = 4.5 Hz, 1H), 6.69 (s , 1H), 3.76-3.07 (m, 9H), 2.62-2.49 (m, 1H), 2.15-2.04 (m, 1H), 1.83-1.65 (m, 1H), 1.31 (d, J = 6.9 Hz, 6H );

13C NMR (75 MHz, CDCl3) δ 170.55, 170.42, 168.84, 168.78, 162.79, 162.65, 156.52, 138.80, 129.59, 129.55, 129.39, 129.36, 128.96, 128.93, 125.98, 125.56, 125.51, 125.46, 125.41, 122.38, 105.65, 105.53, 50.22, 49.44, 46.20, 45.28, 41.60, 41.48, 41.43, 41.35, 39.70, 37.59, 29.62, 27.95, 26.56, 21.64. 13 C NMR (75 MHz, CDCl 3 ) δ 170.55, 170.42, 168.84, 168.78, 162.79, 162.65, 156.52, 138.80, 129.59, 129.55, 129.39, 129.36, 128.96, 128.93, 125.98, 125.56, 125.51, 125.46, 125.4638 , 105.65, 105.53, 50.22, 49.44, 46.20, 45.28, 41.60, 41.48, 41.43, 41.35, 39.70, 37.59, 29.62, 27.95, 26.56, 21.64.

실시예Example 20 : 20: ( ( SS )-)- NN -((1-(3,3--((1- (3,3- 다이메틸부테노일Dimethylbutenoyl )) 피롤리딘Pyrrolidine -3-일)-3 days) 메틸methyl )-3-) -3- 아이Child 소프로필아이소옥사졸-5-카르복사미드(Sopropylisoxazole-5-carboxamide ( 화합물번호 17Compound number 17 )의 제조Manufacturing

Figure pat00154
Figure pat00154

(R)-3-아이소프로필-N-(피롤리딘-3-일메틸)아이소옥사졸-5-카르복사미드 (4-II-2; 92 mg, 0.4 mmol)과 트리에틸아민(TEA; 0.2 mL, 1.2 mmol)과 3,3-다이메틸부테노일 클로라이드 (2- XIX -1; 71 μL, 0.5 mmol)을 이용하여 상기 표제화합물(화합물번호 17) 55 mg (수율 42%)을 얻었다.( R ) -3-isopropyl- N- (pyrrolidin-3-ylmethyl) isoxazole-5-carboxamide ( 4-II-2 ; 92 mg, 0.4 mmol) and triethylamine (TEA; 0.2 mL, 1.2 mmol) and 3,3-dimethylbutenoyl chloride ( 2- XIX- 1 ; 71 μL, 0.5 mmol) gave 55 mg (yield 42%) of the title compound ( Compound No. 17 ).

수율 42%; 1H NMR (300 MHz, CDCl3) δ 6.85-6.80 (m, 2H), 3.74-3.09 (m, 7H), 2.62-2.48 (m, 1H), 2.21 (s, 2H), 2.18-2.05 (m, 1H), 1.81-1.72 (m, 1H), 1.30 (d, J = 6.9 Hz, 6H), 0.88 (s, 9H);Yield 42%; 1 H NMR (300 MHz, CDCl 3 ) δ 6.85-6.80 (m, 2H), 3.74-3.09 (m, 7H), 2.62-2.48 (m, 1H), 2.21 (s, 2H), 2.18-2.05 (m , 1H), 1.81-1.72 (m, 1H), 1.30 (d, J = 6.9 Hz, 6H), 0.88 (s, 9H);

13C NMR (75 MHz, CDCl3) δ 170.97, 170.90, 170.48, 170.33, 162.88, 162.79, 156.55, 156.50, 105.56, 105.41, 50.86, 48.99, 46.80, 46.73, 46.62, 44.81, 41.59, 39.66, 37.60, 31.44, 31.40, 29.92, 29.74, 29.70, 28.09, 26.65, 26.54, 21.65. 13 C NMR (75 MHz, CDCl 3 ) δ 170.97, 170.90, 170.48, 170.33, 162.88, 162.79, 156.55, 156.50, 105.56, 105.41, 50.86, 48.99, 46.80, 46.73, 46.62, 44.81, 41.59, 39.66, 37.60, 31.44 , 31.40, 29.92, 29.74, 29.70, 28.09, 26.65, 26.54, 21.65.

실시예Example 21 : 21: ( ( RR )-)- NN -((1-(3,3--((1- (3,3- 다이메틸부테노일Dimethylbutenoyl )) 피롤리딘Pyrrolidine -3-일)-3 days) 메틸methyl )-1-)-One- 메틸methyl -3-프로필-1-3-propyl-1 HH -피라졸-5-카르복사미드(-Pyrazole-5-carboxamide ( 화합물번호 18Compound number 18 )의 제조Manufacturing

Figure pat00155
Figure pat00155

(S)-1-메틸-3-프로필-N-(피롤리딘-3-일메틸)-1H-피라졸- 5-카르복사미드 (4-V-2; 100 mg, 0.4 mmol)과 트리에틸아민(TEA; 0.2 mL, 1.2 mmol)과 3,3-다이메틸부테노일 클로라이드 (2- XIX -1; 72 μL, 0.5 mmol)을 이용하여 상기 표제화합물(화합물번호 18) 61 mg (수율 44%)을 얻었다.( S ) -1-Methyl-3-propyl- N- (pyrrolidin-3-ylmethyl) -1 H -pyrazole-5-carboxamide ( 4-V-2 ; 100 mg, 0.4 mmol) 61 mg (Yield) of the title compound ( Compound No. 18 ) using triethylamine (TEA; 0.2 mL, 1.2 mmol) and 3,3-dimethylbutenoyl chloride ( 2- XIX- 1 ; 72 μL, 0.5 mmol) 44%).

1H NMR (300 MHz, CDCl3) δ 6.32(s, 1H), 6.22(brs, 0.5H), 6.14(brs, 0.5H), 4.15(s, 3H), 3.71-3.24 (m, 6H), 2.64-2.58 (m, 3H), 2.25-2.06 (m, 3H), 1.86-1.75 (m, 1H), 1.73-1.65 (m, 2H), 1.10 (s, 9H), 1.00 (t, J = 7.2 Hz, 3H); 1 H NMR (300 MHz, CDCl 3 ) δ 6.32 (s, 1H), 6.22 (brs, 0.5H), 6.14 (brs, 0.5H), 4.15 (s, 3H), 3.71-3.24 (m, 6H), 2.64-2.58 (m, 3H), 2.25-2.06 (m, 3H), 1.86-1.75 (m, 1H), 1.73-1.65 (m, 2H), 1.10 (s, 9H), 1.00 (t, J = 7.2 Hz, 3H);

13C NMR (75 MHz, CDCl3) δ 171.00, 170.87, 160.54, 151.44, 151.35, 135.55, 135.43, 105.03, 104.86, 50.91, 49.16, 46.86, 46.81, 46.66, 44.82, 41.66, 41.51, 39.73, 38.84, 37.69, 33.05, 31.44, 31.42, 31.22, 30.00, 29.77, 28.05, 27.39, 22.03, 17.59. 13 C NMR (75 MHz, CDCl 3 ) δ 171.00, 170.87, 160.54, 151.44, 151.35, 135.55, 135.43, 105.03, 104.86, 50.91, 49.16, 46.86, 46.81, 46.66, 44.82, 41.66, 41.51, 39.73, 38.84, 37.69 , 33.05, 31.44, 31.42, 31.22, 30.00, 29.77, 28.05, 27.39, 22.03, 17.59.

실시예Example 22 : 22: ( ( RR )-1-)-One- 메틸methyl -3-프로필--3-propyl- NN -((1-(2-(4-(-((1- (2- (4- ( 트리플루오로메틸Trifluoromethyl )페닐)아세틸)피롤리딘-3-일)메틸)-1) Phenyl) acetyl) pyrrolidin-3-yl) methyl) -1 HH -피라졸-5-카르복사미드(-Pyrazole-5-carboxamide ( 화합물번호 19Compound number 19 )의 제조Manufacturing

Figure pat00156
Figure pat00156

(S)-1-메틸-3-프로필-N-(피롤리딘-3-일메틸)-1H-피라졸-5-카르복사미드 (4-V-2; 100 mg, 0.4 mmol)과 2-(4-(트리플루오로메틸)페닐)아세트산 (2- XX -1; 82 mg, 0.4 mmol)과 1,1'-카보닐 다이이미다졸(CDI; 72 mg, 0.4 mmol)을 이용하여 상기 표제화합물(화합물번호 19) 61 mg (수율 35%)을 얻었다.( S ) -1-methyl-3-propyl- N- (pyrrolidin-3-ylmethyl) -1 H -pyrazole-5-carboxamide ( 4-V-2 ; 100 mg, 0.4 mmol) 2- (4- (trifluoromethyl) phenyl) acetic acid ( 2- XX- 1 ; 82 mg, 0.4 mmol) and 1,1'-carbonyl diimidazole (CDI; 72 mg, 0.4 mmol) 61 mg (yield 35%) of the title compound ( Compound No. 19 ) were obtained.

1H NMR (300 MHz, CDCl3) δ 7.56 (d, J = 8.1 Hz, 2H), 7.37 (d, J = 8.1 Hz, 2H), 6.31-6.16 (m, 2H), 4.11(s, 3H), 3.67-3.19 (s, 8H), 2.60-2.45 (m, 3H), 2.17-2.00 (m, 1H), 1.84-1.58 (m, 3H), 0.99-0.90 (m, 3H); 1 H NMR (300 MHz, CDCl 3 ) δ 7.56 (d, J = 8.1 Hz, 2H), 7.37 (d, J = 8.1 Hz, 2H), 6.31-6.16 (m, 2H), 4.11 (s, 3H) , 3.67-3.19 (s, 8H), 2.60-2.45 (m, 3H), 2.17-2.00 (m, 1H), 1.84-1.58 (m, 3H), 0.99-0.90 (m, 3H);

13C NMR (75 MHz, CDCl3) δ 169.00, 168.90, 160.50, 160.47, 151.52, 151.41, 138.73, 138.62, 135.41, 135.28, 129.76, 129.53, 129.46, 129.05, 128.99, 125.92, 125.58, 125.54, 125.49, 125.45, 125.37, 125.32, 122.32, 104.93, 104.78, 50.29, 49.62, 46.29, 45.33, 41.58, 41.44, 41.32, 39.79, 38.85, 37.73, 29.95, 29.60, 27.93, 22.91, 22.89, 13.83. 13 C NMR (75 MHz, CDCl 3 ) δ 169.00, 168.90, 160.50, 160.47, 151.52, 151.41, 138.73, 138.62, 135.41, 135.28, 129.76, 129.53, 129.46, 129.05, 128.99, 125.92, 125.58, 125.54, 125.54, 125. , 125.37, 125.32, 122.32, 104.93, 104.78, 50.29, 49.62, 46.29, 45.33, 41.58, 41.44, 41.32, 39.79, 38.85, 37.73, 29.95, 29.60, 27.93, 22.91, 22.89, 13.83.

실시예Example 23 : 23: ( ( SS )-)- NN -((1-(3,3--((1- (3,3- 다이메틸부테노일Dimethylbutenoyl )) 피롤리딘Pyrrolidine -3-일)-3 days) 메틸methyl )-1-)-One- 메틸methyl -3-프로필-1-3-propyl-1 HH -피라졸-5-카르복사미드( -Pyrazole-5-carboxamide ( 화합물번호 20Compound number 20 )의 제조Manufacturing

Figure pat00157
Figure pat00157

(R)-1-메틸-3-프로필-N-(피롤리딘-3-일메틸)-1H-피라졸- 5-카르복사미드 (4-VI-2; 77 mg, 0.3 mmol)과 트리에틸아민(TEA; 0.1 mL, 0.9 mmol)과 3,3-다이메틸부테노일 클로라이드 (2- XIX -1; 56 μL, 0.4 mmol)을 이용하여 상기 표제화합물(화합물번호 20) 20 mg (수율 19%)을 얻었다.( R ) -1-methyl-3-propyl- N- (pyrrolidin-3-ylmethyl) -1 H -pyrazole-5-carboxamide ( 4-VI-2 ; 77 mg, 0.3 mmol) 20 mg (Yield) of the title compound ( Compound No. 20 ) using triethylamine (TEA; 0.1 mL, 0.9 mmol) and 3,3-dimethylbutenoyl chloride ( 2- XIX- 1 ; 56 μL, 0.4 mmol) 19%).

1H NMR (300 MHz, CDCl3) δ 6.28 (s, 1H), 6.18 (brs, 0.5H), 6.10 (brs, 0.5H), 4.10 (s, 3H), 3.72-3.17 (m, 6H), 2.57 (t, J = 9 Hz, 2H), 2.51-2.47 (m, 1H), 2.18 (s, 2H), 2.15-2.04 (m, 1H), 1.83-1.69 (m, 3H), 1.06 (s, 9H), 0.97 (t, J = 6.0 Hz, 3H); 1 H NMR (300 MHz, CDCl 3 ) δ 6.28 (s, 1H), 6.18 (brs, 0.5H), 6.10 (brs, 0.5H), 4.10 (s, 3H), 3.72-3.17 (m, 6H), 2.57 (t, J = 9 Hz, 2H), 2.51-2.47 (m, 1H), 2.18 (s, 2H), 2.15-2.04 (m, 1H), 1.83-1.69 (m, 3H), 1.06 (s, 9H), 0.97 (t, J = 6.0 Hz, 3H);

13C NMR (75 MHz, CDCl3) δ 171.06, 170.86, 162.32, 160.44, 151.51, 135.39, 135.30, 104.79, 104.66, 50.88, 49.03, 46.85, 46.75, 46.66, 44.84, 41.68, 41.57, 39.82, 38.92, 37.69, 31.46, 30.01, 29.94, 29.79, 28.13, 22.92, 13.88. 13 C NMR (75 MHz, CDCl 3 ) δ 171.06, 170.86, 162.32, 160.44, 151.51, 135.39, 135.30, 104.79, 104.66, 50.88, 49.03, 46.85, 46.75, 46.66, 44.84, 41.68, 41.57, 39.82, 38.92, 37.69 , 31.46, 30.01, 29.94, 29.79, 28.13, 22.92, 13.88.

실시예Example 24 : 24: ( ( SS )-1-)-One- 메틸methyl -3-프로필--3-propyl- NN -((1-(2-(4-(-((1- (2- (4- ( 트리플루오로메틸Trifluoromethyl )페닐)아세틸)피롤리딘-3-일)메틸)-1) Phenyl) acetyl) pyrrolidin-3-yl) methyl) -1 HH -피라졸-5-카르복사미드(-Pyrazole-5-carboxamide ( 화합물번호 21Compound number 21 )의 제조Manufacturing

Figure pat00158
Figure pat00158

(R)-1-메틸-3-프로필-N-(피롤리딘-3-일메틸)-1H-피라졸- 5-카르복사미드 (4-VI-2; 70 mg, 0.3 mmol)과 2-(4-(트리플루오로메틸)페닐)아세트산 (2- XX -1; 57 mg, 0.3 mmol)과 1,1'-카보닐 다이이미다졸(CDI; 50 mg, 0.3 mmol)을 이용하여 상기 표제화합물(화합물번호 21) 38 mg (수율 31%)을 얻었다.( R ) -1-methyl-3-propyl- N- (pyrrolidin-3-ylmethyl) -1 H -pyrazole-5-carboxamide ( 4-VI-2 ; 70 mg, 0.3 mmol) 2- (4- (trifluoromethyl) phenyl) acetic acid ( 2- XX- 1 ; 57 mg, 0.3 mmol) and 1,1'-carbonyl diimidazole (CDI; 50 mg, 0.3 mmol) 38 mg (31%) of the title compound ( Compound No. 21 ) was obtained.

1H NMR (300 MHz, CDCl3) δ 7.58 (d, J = 8.1 Hz, 2H), 7.39 (d, J = 7.8 Hz, 2H), 6.18 (d, J = 6.0 Hz, 1H), 6.28 (brs, 0.5H) 6.12(brs, 0.5H) 4.10 (s, 3H) 3.74-3.22 (m, 8H) 2.60-2.48 (m, 3H) 2.14-2.05 (m, 1H) 1.82-1.60 (m, 3H) 0.99-0.91 (m, 3H); 1 H NMR (300 MHz, CDCl 3 ) δ 7.58 (d, J = 8.1 Hz, 2H), 7.39 (d, J = 7.8 Hz, 2H), 6.18 (d, J = 6.0 Hz, 1H), 6.28 (brs , 0.5H) 6.12 (brs, 0.5H) 4.10 (s, 3H) 3.74-3.22 (m, 8H) 2.60-2.48 (m, 3H) 2.14-2.05 (m, 1H) 1.82-1.60 (m, 3H) 0.99 -0.91 (m, 3 H);

13C NMR (75 MHz, CDCl3) δ 169.06, 168.91, 160.66, 160.62, 151.79, 151.72, 138.98, 138.87, 135.48, 135.37, 129.71, 129.67, 129.58, 129.36, 125.75, 125.72, 125.70, 125.25, 123.44, 104.91, 104.81, 104.80, 50.45, 49.66, 46.39, 45.50, 41.86, 41.71, 41.68, 41.60, 40.10, 39.12, 39.09, 37.96, 30.20, 29.91, 29.85, 28.22, 23.13, 23.10, 14.04. 13 C NMR (75 MHz, CDCl 3 ) δ 169.06, 168.91, 160.66, 160.62, 151.79, 151.72, 138.98, 138.87, 135.48, 135.37, 129.71, 129.67, 129.58, 129.36, 125.75, 125.72, 125.70, 125.25, 123. , 104.81, 104.80, 50.45, 49.66, 46.39, 45.50, 41.86, 41.71, 41.68, 41.60, 40.10, 39.12, 39.09, 37.96, 30.20, 29.91, 29.85, 28.22, 23.13, 23.10, 14.04.

실시예Example 25 : 25: ( ( SS )-)- NN -((1-(3,3--((1- (3,3- 다이메틸부테노일Dimethylbutenoyl )) 피롤리딘Pyrrolidine -3-일)-3 days) 메틸methyl )-5-) -5- 아이Child 소부틸-1-페닐-1Sobutyl-1-phenyl-1 HH -피라졸-3-카르복사미드(-Pyrazole-3-carboxamide ( 화합물번호 22Compound number 22 )의 제조Manufacturing

Figure pat00159
Figure pat00159

(R)-5-아이소부틸-1-페닐-N-(피롤리딘-3-일메틸)-1H-피라졸-3-카르복사이드 (4-IV-2; 100 mg, 0.3 mmol)과 트리에틸아민(TEA; 0.13 mL, 0.9 mmol)과 3,3-다이메틸부테노일 클로라이드 (2- XIX -1; 56 μL, 0.4 mmol)을 이용하여 상기 표제화합물(화합물번호 22) 61 mg (수율 46%)을 얻었다.( R ) -5-isobutyl-1-phenyl- N- (pyrrolidin-3-ylmethyl) -1 H -pyrazole-3-carboxyside ( 4-IV-2 ; 100 mg, 0.3 mmol) And 61 mg of the title compound ( Compound No. 22 ) using triethylamine (TEA; 0.13 mL, 0.9 mmol) and 3,3-dimethylbutenoyl chloride ( 2- XIX- 1 ; 56 μL, 0.4 mmol). Yield 46%).

1H NMR (300 MHz, CDCl3) δ 7.55-7.38 (m, 5H), 7.08(brs, 1H), 6.75(d, J = 6.3 Hz, 1H), 3.72-3.17 (m, 6H), 2.52-2.46 (m, 3H), 2.16 (s, 2H), 2.10-2.02 (m, 1H), 1.88-1.65 (m, 2H), 1.05 (s, 9H), 0.87 (d, J = 6.6 Hz, 6H); 1 H NMR (300 MHz, CDCl 3 ) δ 7.55-7.38 (m, 5H), 7.08 (brs, 1 H), 6.75 (d, J = 6.3 Hz, 1H), 3.72-3.17 (m, 6H), 2.52- 2.46 (m, 3H), 2.16 (s, 2H), 2.10-2.02 (m, 1H), 1.88-1.65 (m, 2H), 1.05 (s, 9H), 0.87 (d, J = 6.6 Hz, 6H) ;

13C NMR (75 MHz, CDCl3) δ 171.06, 170.99, 162.69, 162.67, 146.64, 145.51, 145.38, 139.52, 129.52, 129.46, 129.06, 128.96, 126.13, 106.75, 106.70, 51.16, 49.19, 46.93, 46.90, 46.80, 45.07, 41.44, 41.35, 40.23, 38.02, 35.26, 31.57, 31.54, 30.11, 30.10, 29.93, 28.49, 28.35, 22.49. 13 C NMR (75 MHz, CDCl 3 ) δ 171.06, 170.99, 162.69, 162.67, 146.64, 145.51, 145.38, 139.52, 129.52, 129.46, 129.06, 128.96, 126.13, 106.75, 106.70, 51.16, 49.19, 46.93, 46.93, 46. , 45.07, 41.44, 41.35, 40.23, 38.02, 35.26, 31.57, 31.54, 30.11, 30.10, 29.93, 28.49, 28.35, 22.49.

실시예Example 26 : 26: ( ( SS )-5-) -5- 아이소부틸Isobutyl -1-페닐--1-phenyl- NN -((1-(2-(4-(-((1- (2- (4- ( 트리플루오로메틸Trifluoromethyl )페닐)아세틸)피롤리딘-3-일)메틸)-1) Phenyl) acetyl) pyrrolidin-3-yl) methyl) -1 HH -피라졸-3-카르복사미드의(Of pyrazole-3-carboxamide ( 화합물번호 23Compound number 23 ) 제조) Produce

Figure pat00160
Figure pat00160

(R)-5-아이소부틸-1-페닐-N-(피롤리딘-3-일메틸)-1H-피라졸-3-카르복사이드 (4-IV-2; 100 mg, 0.3 mmol)과 2-(4-(트리플루오로메틸)페닐)아세트산 (2- XX -1; 63 mg, 0.3 mmol)과 1,1'-카보닐 다이이미다졸(CDI; 55 mg, 0.3 mmol)을 이용하여 상기 표제화합물(화합물번호 23) 85 mg (수율 54%)을 얻었다.( R ) -5-isobutyl-1-phenyl- N- (pyrrolidin-3-ylmethyl) -1 H -pyrazole-3-carboxyside ( 4-IV-2 ; 100 mg, 0.3 mmol) With 2- (4- (trifluoromethyl) phenyl) acetic acid ( 2- XX- 1 ; 63 mg, 0.3 mmol) and 1,1'-carbonyl diimidazole (CDI; 55 mg, 0.3 mmol) To give 85 mg (yield 54%) of the title compound ( Compound No. 23 ).

1H NMR (300 MHz, CDCl3) δ 7.58-7.47 (m, 5H), 7.41-7.37 (m, 4H), 7.10 (brs, 1H), 6.75 (d, J = 5.7 Hz, 1H), 3.74-3.24 (m, 8H), 2.63-2.46 (m, 3H), 2.16-1.99 (m, 1H), 1.88-1.62 (m, 2H), 0.87 (d, J = 6.6 Hz, 6H); 1 H NMR (300 MHz, CDCl 3 ) δ 7.58-7.47 (m, 5H), 7.41-7.37 (m, 4H), 7.10 (brs, 1H), 6.75 (d, J = 5.7 Hz, 1H), 3.74- 3.24 (m, 8H), 2.63-2.46 (m, 3H), 2.16-1.99 (m, 1H), 1.88-1.62 (m, 2H), 0.87 (d, J = 6.6 Hz, 6H);

13C NMR (75 MHz, CDCl3) δ 169.00, 168.90, 160.50, 160.47, 151.52, 151.41, 138.73, 138.62, 135.41, 135.28, 129.76, 129.53, 129.46, 129.05, 128.99, 125.92, 125.58, 125.54, 125.49, 125.45, 125.37, 125.32, 122.32, 104.93, 104.78, 50.29, 49.62, 46.29, 45.33, 41.58, 41.44, 41.32, 39.79, 38.85, 37.73, 29.95, 29.60, 27.93, 22.91, 22.89, 13.83. 13 C NMR (75 MHz, CDCl 3 ) δ 169.00, 168.90, 160.50, 160.47, 151.52, 151.41, 138.73, 138.62, 135.41, 135.28, 129.76, 129.53, 129.46, 129.05, 128.99, 125.92, 125.58, 125.54, 125.54, 125. , 125.37, 125.32, 122.32, 104.93, 104.78, 50.29, 49.62, 46.29, 45.33, 41.58, 41.44, 41.32, 39.79, 38.85, 37.73, 29.95, 29.60, 27.93, 22.91, 22.89, 13.83.

실시예 27 : ( S )-3- 아이소프로필 - N -((1-(2-(4-( 트리플루오로메틸 )페닐)아세틸)피롤리딘-3-일)메틸)아이소옥사졸-5-카르복사미드( 화합물번호 24 )의 제조 Example 27: ( S ) -3 -isopropyl - N -((1- (2- (4- ( trifluoromethyl ) phenyl) acetyl) pyrrolidin-3-yl) methyl) isoxazole-5 Preparation of Carboxamides ( Compound No. 24 )

Figure pat00161
Figure pat00161

(R)-3-아이소프로필-N-(피롤리딘-3-일메틸)아이소옥사졸-5-카르복사미드 (4-II-2; 100 mg, 0.4 mmol)과 2-(4-(트리플루오로메틸)페닐)아세트산 (2- XX -1; 86 mg, 0.4 mmol)과 1,1'-카보닐 다이이미다졸(CDI; 75 mg, 0.5 mmol)을 이용하여 상기 표제화합물(화합물번호 24) 59 mg (수율 33%)을 얻었다.( R ) -3-isopropyl- N- (pyrrolidin-3-ylmethyl) isoxazole-5-carboxamide ( 4-II-2 ; 100 mg, 0.4 mmol) and 2- (4- ( Trifluoromethyl) phenyl) acetic acid ( 2- XX- 1 ; 86 mg, 0.4 mmol) and 1,1'-carbonyl diimidazole (CDI; 75 mg, 0.5 mmol) gave the title compound ( Compound No. 24 ) 59 mg (yield 33%) were obtained.

1H NMR (300 MHz, CDCl3) δ 7.57 (d, J = 8.1Hz, 2H), 7.39 (d, J = 8.1Hz, 2H), 6.80 (d, J = 5.1Hz, 1H), 6.73 (brs, 1H), 3.76-3.37(m, 7H), 3.30-3.24 (m, 1H), 3.16-3.06 (m, 1H), 2.62-2.49 (m, 1H), 2.14-2.05 (m, 1H), 1.83-1.64 (m, 1H), 1.24 (d, J = 6.9Hz, 6H); 1 H NMR (300 MHz, CDCl 3 ) δ 7.57 (d, J = 8.1 Hz, 2H), 7.39 (d, J = 8.1 Hz, 2H), 6.80 (d, J = 5.1 Hz, 1H), 6.73 (brs , 1H), 3.76-3.37 (m, 7H), 3.30-3.24 (m, 1H), 3.16-3.06 (m, 1H), 2.62-2.49 (m, 1H), 2.14-2.05 (m, 1H), 1.83 -1.64 (m, 1 H), 1.24 (d, J = 6.9 Hz, 6 H);

13C NMR (75 MHz, CDCl3) δ 170.54, 170.42, 168.88, 168.81, 162.77, 162.65, 156.53, 138.78, 129.58, 129.53, 125.52, 125.47, 105.65, 105.53, 50.23, 49.42, 46.19, 45.28, 41.60, 41.47, 41.42, 41.36, 39.70, 37.60, 29.61, 27.95, 26.57, 21.62. 13 C NMR (75 MHz, CDCl 3 ) δ 170.54, 170.42, 168.88, 168.81, 162.77, 162.65, 156.53, 138.78, 129.58, 129.53, 125.52, 125.47, 105.65, 105.53, 50.23, 49.42, 46.19, 45.28, 41.60, 41.60 , 41.42, 41.36, 39.70, 37.60, 29.61, 27.95, 26.57, 21.62.

실시예Example 28 : 28: ( ( SS )-3,5-) -3,5- 다이클로로Dichloro -- NN -((1-(3,3--((1- (3,3- 다이메틸부테노일Dimethylbutenoyl )) 피롤리딘Pyrrolidine -3-일)메틸)벤즈아미드(-3-yl) methyl) benzamide ( 화합물번호 25Compound number 25 )의 제조Manufacturing

Figure pat00162
Figure pat00162

(R)-3,5-다이클로로-N-(피롤리딘-3-일메틸)벤즈아미드 (4-VIII-2; 100 mg, 0.4 mmol)과 트리에틸아민(TEA; 0.2 mL, 1.1 mmol)과 3,3-다이메틸부테노일 클로라이드 (2- XIX -1; 66 μL, 0.5 mmol)을 이용하여 상기 표제화합물(화합물번호 25) 81 mg (수율 59%)을 얻었다.( R ) -3,5-Dichloro- N- (pyrrolidin-3-ylmethyl) benzamide ( 4-VIII-2 ; 100 mg, 0.4 mmol) and triethylamine (TEA; 0.2 mL, 1.1 mmol ) And 3,3-dimethylbutenoyl chloride ( 2- XIX- 1 ; 66 μL, 0.5 mmol) gave 81 mg (yield 59%) of the title compound ( Compound No. 25 ).

1H NMR (300 MHz, CDCl3) δ 7.71-7.66 (m, 2H), 7.50-7.42 (m, 1H), 6.76 (brs, 1H), 3.72-3.19 (m, 6H), 2.65-2.49 (m, 1H), 2.18-2.01 (m, 3H), 1.83-1.73 (m, 1H), 1.02(s, 9H); 1 H NMR (300 MHz, CDCl 3 ) δ 7.71-7.66 (m, 2H), 7.50-7.42 (m, 1H), 6.76 (brs, 1H), 3.72-3.19 (m, 6H), 2.65-2.49 (m , 1H), 2.18-2.01 (m, 3H), 1.83-1.73 (m, 1H), 1.02 (s, 9H);

13C NMR (75 MHz, CDCl3) δ 171.28, 171.23, 171.13, 165.45, 137.43, 137.33, 135.48, 135.40, 135.27, 131.45, 131.37, 131.23, 126.11, 125.94, 51.05, 49.53, 49.22, 46.88, 46.77, 45.04, 44.91, 42.51, 42.40, 39.58, 37.65, 30.04, 30.01, 28.90, 28.12; 13 C NMR (75 MHz, CDCl 3 ) δ 171.28, 171.23, 171.13, 165.45, 137.43, 137.33, 135.48, 135.40, 135.27, 131.45, 131.37, 131.23, 126.11, 125.94, 51.05, 49.53, 49.22, 46.88, 46.88. , 44.91, 42.51, 42.40, 39.58, 37.65, 30.04, 30.01, 28.90, 28.12;

실시예Example 29 : 29: ( ( SS )-3,5-) -3,5- 다이클로로Dichloro -- NN -((1-(2-(4-(-((1- (2- (4- ( 트리플루오로메틸Trifluoromethyl )페닐)아세틸)피롤리딘-3-일)메틸)벤즈아미드() Phenyl) acetyl) pyrrolidin-3-yl) methyl) benzamide ( 화합물번호 26Compound number 26 )의 제조Manufacturing

Figure pat00163
Figure pat00163

(R)-3,5-다이클로로-N-(피롤리딘-3-일메틸)벤즈아미드 (4-VIII-2; 100 mg, 0.4 mmol)과 2-(4-(트리플루오로메틸)페닐)아세트산 (2- XX -1; 84 mg, 0.4 mmol)과 1,1'-카보닐 다이이미다졸(CDI; 72 mg, 0.4 mmol)을 이용하여 상기 표제화합물(화합물번호 26) 78 mg (수율 46%)을 얻었다.( R ) -3,5-Dichloro- N- (pyrrolidin-3-ylmethyl) benzamide ( 4-VIII-2 ; 100 mg, 0.4 mmol) and 2- (4- (trifluoromethyl) 78 mg (of the title compound ( Compound No. 26 )) using phenyl) acetic acid ( 2- XX- 1 ; 84 mg, 0.4 mmol) and 1,1'-carbonyl diimidazole (CDI; 72 mg, 0.4 mmol) Yield 46%).

1H NMR (300 MHz, CDCl3) δ 7.64-7.62 (m, 2H), 7.57-7.46 (m, 3H), 7.39-7.32 (m, 2H), 6.99 (brs, 0.5H), 6.52 (brs, 0.5H), 3.74-3.59 (m, 5H), 3.52-3.40 (m, 2H), 3.34-3.21 (m, 1H), 2.63-2.49 (m, 1H), 2.14-2.05 (m, 1H), 1.83-1.68 (m, 1H); 1 H NMR (300 MHz, CDCl 3 ) δ 7.64-7.62 (m, 2H), 7.57-7.46 (m, 3H), 7.39-7.32 (m, 2H), 6.99 (brs, 0.5H), 6.52 (brs, 0.5H), 3.74-3.59 (m, 5H), 3.52-3.40 (m, 2H), 3.34-3.21 (m, 1H), 2.63-2.49 (m, 1H), 2.14-2.05 (m, 1H), 1.83 -1.68 (m, 1 H);

13C NMR (75 MHz, CDCl3) δ 167.97, 167.84, 164.28, 164.23, 164.20, 137.71, 137.53, 136.17, 136.06, 134.47, 134.23, 130.45, 130.20, 130.19, 128.71, 128.61, 128.53, 128.43, 128.40, 128.34, 128.12, 125.75, 124.86, 124.69, 124.46, 124.43, 124.40, 124.38, 124.01, 123.94, 122.21, 122.14, 49.27, 48.85, 48.81, 45.41, 44.26, 41.19, 41.16, 41.09, 40.58, 40.36, 38.61, 38.59, 36.63, 28.64, 26.91. 13 C NMR (75 MHz, CDCl 3 ) δ 167.97, 167.84, 164.28, 164.23, 164.20, 137.71, 137.53, 136.17, 136.06, 134.47, 134.23, 130.45, 130.20, 130.19, 128.71, 128.61, 128.53, 128.43, 128.43, 128.43, 128.43. , 128.12, 125.75, 124.86, 124.69, 124.46, 124.43, 124.40, 124.38, 124.01, 123.94, 122.21, 122.14, 49.27, 48.85, 48.81, 45.41, 44.26, 41.19, 41.16, 41.09, 40.58, 40.36, 38.36, 38.36. , 28.64, 26.91.

실시예Example 30 : 30: ( ( RR )-)- NN -((1-(3,3--((1- (3,3- 다이메틸부테노일Dimethylbutenoyl )) 피롤리딘Pyrrolidine -3-일)-3 days) 메틸methyl )-5-) -5- 아이Child 소부틸-1-페닐-1Sobutyl-1-phenyl-1 HH -피라졸-3-카복스아미드(-Pyrazole-3-carboxamide ( 화합물번호 27Compound number 27 )의 제조Manufacturing

Figure pat00164
Figure pat00164

(S)-5-아이소부틸-1-페닐-N-(피롤리딘-3-일메틸)-1H-피라졸-3-카르복사이드 (화합물번호 57; 100 mg, 0.3 mmol)과 트리에틸아민(TEA; 0.13 mL, 0.9 mmol)과 3,3-다이메틸부테노일 클로라이드 (2- XIX -1; 47 μL, 0.3 mmol)을 이용하여 상기 표제화합물(화합물번호 27) 105 mg (수율 80%)을 얻었다.( S ) -5-isobutyl-1-phenyl- N- (pyrrolidin-3-ylmethyl) -1 H -pyrazole-3-carboxide ( Compound No. 57 ; 100 mg, 0.3 mmol) and tri 105 mg of the title compound ( Compound No. 27 ) using ethylamine (TEA; 0.13 mL, 0.9 mmol) and 3,3-dimethylbutenoyl chloride ( 2- XIX- 1 ; 47 μL, 0.3 mmol) (yield 80) %) Was obtained.

1H NMR (300 MHz, CDCl3) δ 7.56-7.39 (m, 5H), 7.09(brs, 1H), 6.75 (d, J = 6.0Hz, 1H), 3.72-3.18 (m, 6H), 2.60-2.47 (m, 3H), 2.12 (s, 2H), 2.10-2.03 (m, 1H), 1.88-1.65 (m, 2H), 1.07 (s, 9H), 0.87 (d, J = 6.3 Hz, 6H); 1 H NMR (300 MHz, CDCl 3 ) δ 7.56-7.39 (m, 5H), 7.09 (brs, 1 H), 6.75 (d, J = 6.0 Hz, 1H), 3.72-3.18 (m, 6H), 2.60- 2.47 (m, 3H), 2.12 (s, 2H), 2.10-2.03 (m, 1H), 1.88-1.65 (m, 2H), 1.07 (s, 9H), 0.87 (d, J = 6.3 Hz, 6H) ;

13C NMR (75 MHz, CDCl3) δ 173.80, 162.49, 146.43, 145.37, 145.30, 145.22, 139.33, 139.30, 129.37, 129.31, 129.09, 125.98, 106.57, 106.51, 50.99, 50.77, 49.01, 46.76, 46.63, 41.70, 41.25, 41.20, 37.84, 35.08, 31.49, 31.42, 29.93, 29.80, 29.76, 28.24, 28.18, 22.32. 13 C NMR (75 MHz, CDCl 3 ) δ 173.80, 162.49, 146.43, 145.37, 145.30, 145.22, 139.33, 139.30, 129.37, 129.31, 129.09, 125.98, 106.57, 106.51, 50.99, 50.77, 49.01, 46.76, 46. , 41.25, 41.20, 37.84, 35.08, 31.49, 31.42, 29.93, 29.80, 29.76, 28.24, 28.18, 22.32.

실시예Example 31 : 31: ( ( RR )-5-) -5- 아이소부틸Isobutyl -1-페닐--1-phenyl- NN -((1-(2-(4-(-((1- (2- (4- ( 트리플루오로메틸Trifluoromethyl )페닐)아세틸)피롤리딘-3-일)메틸)-1) Phenyl) acetyl) pyrrolidin-3-yl) methyl) -1 HH -피라졸-3-카르복사미드(-Pyrazole-3-carboxamide ( 화합물번호 28Compound number 28 )의 제조Manufacturing

Figure pat00165
Figure pat00165

(S)-5-아이소부틸-1-페닐-N-(피롤리딘-3-일메틸)-1H-피라졸-3-카르복사이드 (화합물번호 57; 100 mg, 0.3 mmol)과 2-(4-(트리플루오로메틸)페닐)아세트산 (2-XX-1; 63 mg, 0.3 mmol)과 1,1'-카보닐 다이이미다졸(CDI; 55 mg, 0.3 mmol)을 이용하여 상기 표제화합물(화합물번호 28) 85 mg (수율 54%)을 얻었다.( S ) -5-isobutyl-1-phenyl- N- (pyrrolidin-3-ylmethyl) -1 H -pyrazole-3-carboxide ( Compound No. 57 ; 100 mg, 0.3 mmol) and 2 -(4- (trifluoromethyl) phenyl) acetic acid ( 2-XX-1 ; 63 mg, 0.3 mmol) and 1,1'-carbonyl diimidazole (CDI; 55 mg, 0.3 mmol) 85 mg (yield 54%) of the title compound ( Compound No. 28 ) were obtained.

1H NMR (300 MHz, CDCl3) δ 7.64-7.47 (m, 5H), 7.41-7.37 (m, 4H), 7.12(brs, 1H), 6.75 (d, J = 5.7 Hz, 1H), 3.80-3.24 (m, 8H), 2.61-2.49 (m, 3H), 2.16-2.04 (m, 1H), 1.88-1.65 (m, 2H), 0.87 (d, J = 6.6 Hz, 6H); 1 H NMR (300 MHz, CDCl 3 ) δ 7.64-7.47 (m, 5H), 7.41-7.37 (m, 4H), 7.12 (brs, 1 H), 6.75 (d, J = 5.7 Hz, 1H), 3.80- 3.24 (m, 8H), 2.61-2.49 (m, 3H), 2.16-2.04 (m, 1H), 1.88-1.65 (m, 2H), 0.87 (d, J = 6.6 Hz, 6H);

13C NMR (75 MHz, CDCl3) δ 168.95, 168.92, 162.77, 162.73, 146.58, 146.55, 145.64, 145.50, 139.51, 139.10, 139.05, 129.96, 129.78, 129.68, 129.56, 129.51, 129.41, 129.25, 129.19, 129.14, 129.04, 126.18, 125.71, 125.68, 125.66, 125.63, 125.61, 125.32, 106.75, 50.61, 49.66, 46.41, 45.61, 41.76, 41.71, 41.23, 41.18, 40.33, 38.08, 35.28, 29.90, 29.81, 28.51, 28.24, 22.50. 13 C NMR (75 MHz, CDCl 3 ) δ 168.95, 168.92, 162.77, 162.73, 146.58, 146.55, 145.64, 145.50, 139.51, 139.10, 139.05, 129.96, 129.78, 129.68, 129.56, 129.51, 129.41, 129.41, 129.41, 129.41 , 129.04, 126.18, 125.71, 125.68, 125.66, 125.63, 125.61, 125.32, 106.75, 50.61, 49.66, 46.41, 45.61, 41.76, 41.71, 41.23, 41.18, 40.33, 38.08, 35.28, 29.90, 29.81, 28.51, 28.24, 28.24 .

실시예Example 32 : 32: ( ( RR )-5-) -5- 아이소부틸Isobutyl -1-페닐--1-phenyl- NN -((1-(2-(3-(-((1- (2- (3- ( 트리플루오로메틸Trifluoromethyl )페닐)아세틸)피롤리딘-3-일)메틸)-1) Phenyl) acetyl) pyrrolidin-3-yl) methyl) -1 HH -피라졸-3-카르복사미드(-Pyrazole-3-carboxamide ( 화합물번호 29Compound number 29 )의 제조Manufacturing

Figure pat00166
Figure pat00166

(S)-5-아이소부틸-1-페닐-N-(피롤리딘-3-일메틸)-1H-피라졸-3-카르복사이드 (화합물번호 57; 160 mg, 0.5 mmol)과 2-(3-(트리플루오로메틸)페닐)아세트산 (2-XXI-1; 100 mg, 0.5 mmol)과 1,1'-카보닐 다이이미다졸(CDI; 95 mg, 0.6 mmol)을 이용하여 상기 표제화합물(화합물번호 29) 184 mg (수율 89%)을 얻었다.( S ) -5-isobutyl-1-phenyl- N- (pyrrolidin-3-ylmethyl) -1 H -pyrazole-3-carboxide ( Compound No. 57 ; 160 mg, 0.5 mmol) and 2 -(3- (trifluoromethyl) phenyl) acetic acid ( 2-XXI-1 ; 100 mg, 0.5 mmol) and 1,1'-carbonyl diimidazole (CDI; 95 mg, 0.6 mmol) 184 mg (yield 89%) of the title compound ( Compound No. 29 ) were obtained.

1H NMR (300MHz, CDCl3) δ 7.53-7.38 (m, 8H), 7.07 (brs, 1H), 6.75 (d, J = 5.4 Hz, 1H), 3.73-3.25 (m, 8H), 2.60-2.50 (m, 3H), 2.12-2.05 (m, 1H), 1.85-1.81 (m, 1.5H), 1.71-1.67 (m, 0.5H), 0.88-0.86 (m, 6H); 1 H NMR (300MHz, CDCl 3 ) δ 7.53-7.38 (m, 8H), 7.07 (brs, 1H), 6.75 (d, J = 5.4 Hz, 1H), 3.73-3.25 (m, 8H), 2.60-2.50 (m, 3H), 2.12-2.05 (m, 1H), 1.85-1.81 (m, 1.5H), 1.71-1.67 (m, 0.5H), 0.88-0.86 (m, 6H);

13C NMR (75 MHz, CDCl3) δ 168.90, 168.87, 162.76, 162.71, 146.64, 146.60, 145.60, 145.47, 139.57, 139.56, 136.02, 135.96, 132.91, 132.79, 129.55, 129.49, 129.17, 129.11, 129.10, 129.01, 126.27, 126.24, 126.22, 126.19, 126.18, 123.92, 123.90, 123.87, 123.85, 106.76, 106.72, 50.59, 49.66, 46.40, 45.57, 41.61, 41.57, 41.29, 41.25, 40.35, 38.11, 35.29, 29.86, 28.52, 28.26, 22.50. 13 C NMR (75 MHz, CDCl 3 ) δ 168.90, 168.87, 162.76, 162.71, 146.64, 146.60, 145.60, 145.47, 139.57, 139.56, 136.02, 135.96, 132.91, 132.79, 129.55, 129.129, 129.17, 129.17. , 126.27, 126.24, 126.22, 126.19, 126.18, 123.92, 123.90, 123.87, 123.85, 106.76, 106.72, 50.59, 49.66, 46.40, 45.57, 41.61, 41.57, 41.29, 41.25, 40.35, 38.11, 35.28. , 22.50.

실시예Example 33 : 33: ( ( RR )-5-) -5- 아이소부틸Isobutyl -- NN -((1-(4--((1- (4- 메틸methyl -3-(-3- ( 트리플루오로메틸Trifluoromethyl )) 페네틸Phenethyl )피롤리딘-3-일)메틸)-1-페닐-1) Pyrrolidin-3-yl) methyl) -1-phenyl-1 HH -피라졸-3-카르복사미드(-Pyrazole-3-carboxamide ( 화합물번호 30Compound number 30 )의 제조Manufacturing

Figure pat00167
Figure pat00167

(S)-5-아이소부틸-1-페닐-N-(피롤리딘-3-일메틸)-1H-피라졸-3-카르복사이드 (화합물번호 57; 392 mg, 1.2 mmol)과 4-메틸-3-(트리플루오로메틸)페네틸 4-메틸벤젠술폰산염 (2-I-3; 359 mg, 1.0 mmol)과 포타슘 카보네이트 (K2CO3; 691 mg, 5.0 mmol)을 이용하여 상기 표제화합물(화합물번호 30) 457 mg (수율 89%)을 얻었다. ( S ) -5-isobutyl-1-phenyl- N- (pyrrolidin-3-ylmethyl) -1 H -pyrazole-3-carboxide ( Compound No. 57 ; 392 mg, 1.2 mmol) and 4 -Methyl-3- (trifluoromethyl) phenethyl 4-methylbenzenesulfonate ( 2-I-3 ; 359 mg, 1.0 mmol) and potassium carbonate (K 2 CO 3 ; 691 mg, 5.0 mmol) 457 mg (yield 89%) of the title compound ( Compound No. 30 ) were obtained.

1H NMR (400 MHz, CDCl3) δ 7.49-7.37 (m, 7H), 7.17-7.15 (m, 2H), 6.76 (s, 1H), 3.48-3.39 (m, 2H), 2.80-2.61 (m, 6H), 2.55-2.46 (m, 5H), 2.42 (d, J = 1.6 Hz, 3H), 2.05-2.00 (m, 1H), 1.87-1.80 (m, 1H), 1.61-1.56 (m, 1H), 0.86 (d, J = 6.4 Hz, 6H); 1 H NMR (400 MHz, CDCl 3 ) δ 7.49-7.37 (m, 7H), 7.17-7.15 (m, 2H), 6.76 (s, 1H), 3.48-3.39 (m, 2H), 2.80-2.61 (m , 6H), 2.55-2.46 (m, 5H), 2.42 (d, J = 1.6 Hz, 3H), 2.05-2.00 (m, 1H), 1.87-1.80 (m, 1H), 1.61-1.56 (m, 1H ), 0.86 (d, J = 6.4 Hz, 6H);

13C NMR (100 MHz, CDCl3) δ 162.50, 146.84, 144.97, 139.42, 138.00, 134.04, 131.84, 131.77, 129.28, 129.18, 128.63 (q, J C -F = 29.3 Hz), 128.61, 125.87, 125.83, 125.77, 125.72, 124.59 (q, J C -F = 272.0 Hz, CF3), 106.47, 58.33, 57.59, 53.76, 43.85, 37.03, 35.06, 34.81, 28.31, 22.26, 18.81. 13 C NMR (100 MHz, CDCl 3 ) δ 162.50, 146.84, 144.97, 139.42, 138.00, 134.04, 131.84, 131.77, 129.28, 129.18, 128.63 (q, J C -F = 29.3 Hz), 128.61, 125.87, 125.83, 125.77, 125.72, 124.59 (q, J C -F = 272.0 Hz, CF 3 ), 106.47, 58.33, 57.59, 53.76, 43.85, 37.03, 35.06, 34.81, 28.31, 22.26, 18.81.

실시예Example 34 : 34: ( ( RR )-5-) -5- 아이소부틸Isobutyl -- NN -((1-(2--((1- (2- 메틸methyl -5-(-5- ( 트리플루오로메틸Trifluoromethyl )) 페네틸Phenethyl )피롤리딘-3-일)메틸)-1-페닐-1) Pyrrolidin-3-yl) methyl) -1-phenyl-1 HH -피라졸-3-카르복사미드(-Pyrazole-3-carboxamide ( 화합물번호 Compound number 3131 )의)of 제조 Produce

Figure pat00168
Figure pat00168

(S)-5-아이소부틸-1-페닐-N-(피롤리딘-3-일메틸)-1H-피라졸-3-카르복사이드 (화합물번호 57; 271 mg, 0.8 mmol)과 2-메틸-5-(트리플루오로메틸)페네틸 4-메틸벤젠술폰산염 (2-II-3; 229 mg, 0.6 mmol)과 포타슘 카보네이트 (K2CO3; 442 mg, 3.2 mmol)을 이용하여 상기 표제화합물(화합물번호 31) 227 mg (수율 69%)을 얻었다. ( S ) -5-isobutyl-1-phenyl- N- (pyrrolidin-3-ylmethyl) -1 H -pyrazole-3-carboxide ( Compound No. 57 ; 271 mg, 0.8 mmol) and 2 -Methyl-5- (trifluoromethyl) phenethyl 4-methylbenzenesulfonate ( 2-II-3 ; 229 mg, 0.6 mmol) and potassium carbonate (K 2 CO 3 ; 442 mg, 3.2 mmol) 227 mg (69% yield) of the title compound ( Compound No. 31 ) were obtained.

1H NMR (400 MHz, CDCl3) δ 7.49-7.38 (m, 6H), 7.33 (s, 2H), 7.20 (t, J = 4.4 Hz, 1H), 6.76 (s, 1H), 3.51-3.40 (m, 2H), 2.88-2.76 (m, 4H), 2.67-2.61 (m, 3H), 2.58-2.55 (m, 2H), 2.50 (d, J = 7.2 Hz, 2H), 2.32 (s, 3H), 2.11-2.02 (m, 1H), 1.88-1.78 (m, 1H), 1.67-1.58 (m, 1H), 0.86 (d, J = 6.4 Hz, 6H); 1 H NMR (400 MHz, CDCl 3 ) δ 7.49-7.38 (m, 6H), 7.33 (s, 2H), 7.20 (t, J = 4.4 Hz, 1H), 6.76 (s, 1H), 3.51-3.40 ( m, 2H), 2.88-2.76 (m, 4H), 2.67-2.61 (m, 3H), 2.58-2.55 (m, 2H), 2.50 (d, J = 7.2 Hz, 2H), 2.32 (s, 3H) , 2.11-2.02 (m, 1H), 1.88-1.78 (m, 1H), 1.67-1.58 (m, 1H), 0.86 (d, J = 6.4 Hz, 6H);

13C NMR (100 MHz, CDCl3) δ 162.57, 146.76, 145.05, 140.30, 139.39, 138.92, 130.46, 129.20, 128.66, 128.25 (q, J C -F = 31.6 Hz), 125.87, 125.75, 125.68, 125.64, 124.35(q, J C -F = 271.8 Hz, CF3), 122.96, 122.92, 106.49, 58.22, 56.17, 53.76, 43.64, 37.14, 35.06, 32.44, 28.27, 22.27, 19.30. 13 C NMR (100 MHz, CDCl 3 ) δ 162.57, 146.76, 145.05, 140.30, 139.39, 138.92, 130.46, 129.20, 128.66, 128.25 (q, J C -F = 31.6 Hz), 125.87, 125.75, 125.68, 125.64, 124.35 (q, J C -F = 271.8 Hz, CF 3 ), 122.96, 122.92, 106.49, 58.22, 56.17, 53.76, 43.64, 37.14, 35.06, 32.44, 28.27, 22.27, 19.30.

실시예Example 35 : 35: ( ( RR )-)- NN -((1-(2,4--((1- (2,4- 비스(트리플루오로메틸)페네틸Bis (trifluoromethyl) phenethyl )) 피롤리딘Pyrrolidine -3-일)메틸)-5-아이소부틸-1-페닐-1-3-yl) methyl) -5-isobutyl-1-phenyl-1 HH -피라졸-3-카르복사미드(-Pyrazole-3-carboxamide ( 화합물번호 32Compound number 32 )의 제조Manufacturing

Figure pat00169
Figure pat00169

(S)-5-아이소부틸-1-페닐-N-(피롤리딘-3-일메틸)-1H-피라졸-3-카르복사이드 (화합물번호 57; 85 mg, 0.3 mmol)과 2,4-비스(트리플루오로메틸)페네틸 4-메틸벤젠술폰산염 (2-III-3; 89 mg, 0.2 mmol)과 포타슘 카보네이트 (K2CO3; 152 mg, 1.1 mmol)을 이용하여 상기 표제화합물(화합물번호 32) 50 mg (수율 40%)을 얻었다.( S ) -5-isobutyl-1-phenyl-N- (pyrrolidin-3-ylmethyl) -1H-pyrazole-3-carboxyside ( Compound No. 57 ; 85 mg, 0.3 mmol) and 2, The title using 4-bis (trifluoromethyl) phenethyl 4-methylbenzenesulfonate ( 2-III-3 ; 89 mg, 0.2 mmol) and potassium carbonate (K 2 CO 3 ; 152 mg, 1.1 mmol) 50 mg (40% yield) of compound ( Compound No. 32 ) were obtained.

1H NMR (400 MHz, CDCl3) δ 7.87 (s, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.51-7.40 (m, 7H), 6.78 (s, 1H), 3.52-3.40 (m, 2H), 3.04 (t, J = 7.6 Hz, 2H), 2.79-2.67 (m, 4H), 2.60-2.49 (m, 5H), 2.10-2.01 (m, 1H), 1.89-1.82 (m, 1H), 1.65-1.57 (m, 1H), 0.88 (d, J = 6.4 Hz, 6H); 1 H NMR (400 MHz, CDCl 3 ) δ 7.87 (s, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.51-7.40 (m, 7H), 6.78 (s, 1H), 3.52-3.40 ( m, 2H), 3.04 (t, J = 7.6 Hz, 2H), 2.79-2.67 (m, 4H), 2.60-2.49 (m, 5H), 2.10-2.01 (m, 1H), 1.89-1.82 (m, 1H), 1.65-1.57 (m, 1H), 0.88 (d, J = 6.4 Hz, 6H);

13C NMR (100 MHz, CDCl3) δ 162.52, 146.83, 145.09, 143.42, 139.43, 132.30, 129.37 (q, J C -F = 30.0 Hz), 129.22, 128.73 (q, J C -F = 33.3 Hz), 128.65, 128.38, 125.94, 123.72 (q, J C -F = 272.4 Hz, CF3), 123.50 (q, J C -F = 270.4 Hz, CF3), 123.10, 123.06, 123.00, 106.52, 58.20, 57.03, 53.63, 43.85, 37.14, 35.08, 32.00, 28.36, 22.29. 13 C NMR (100 MHz, CDCl 3 ) δ 162.52, 146.83, 145.09, 143.42, 139.43, 132.30, 129.37 (q, J C -F = 30.0 Hz), 129.22, 128.73 (q, J C -F = 33.3 Hz) , 128.65, 128.38, 125.94, 123.72 (q, J C -F = 272.4 Hz, CF 3 ), 123.50 (q, J C -F = 270.4 Hz, CF 3 ), 123.10, 123.06, 123.00, 106.52, 58.20, 57.03 , 53.63, 43.85, 37.14, 35.08, 32.00, 28.36, 22.29.

실시예Example 36 : 36: ( ( RR )-5-) -5- 아이소부틸Isobutyl -- NN -((1-(5--((1- (5- 메틸methyl -2-(-2-( 트리플루오로메틸Trifluoromethyl )) 페네틸Phenethyl )피롤리딘-3-일)메틸)-1-페닐-1) Pyrrolidin-3-yl) methyl) -1-phenyl-1 HH -피라졸-3-카르복사미드(-Pyrazole-3-carboxamide ( 화합물번호 33Compound number 33 )의 제조Manufacturing

Figure pat00170
Figure pat00170

(S)-5-아이소부틸-1-페닐-N-(피롤리딘-3-일메틸)-1H-피라졸-3-카르복사이드 (화합물번호 57; 281 mg, 0.9 mmol)과 5-메틸-2-(트리플루오로메틸)페네틸 4-메틸벤젠술폰산염 (2-IV-3; 257 mg, 0.7 mmol)과 포타슘 카보네이트 (498 mg, 3.6 mmol)을 이용하여 상기 표제화합물(화합물번호 33) 251 mg (수율 68%)을 얻었다.( S ) -5-Isobutyl-1-phenyl-N- (pyrrolidin-3-ylmethyl) -1H-pyrazole-3-carboxyside ( Compound No. 57 ; 281 mg, 0.9 mmol) and 5- Methyl-2- (trifluoromethyl) phenethyl 4-methylbenzenesulfonate ( 2-IV-3 ; 257 mg, 0.7 mmol) and potassium carbonate (498 mg, 3.6 mmol) gave the title compound ( Compound No. 33 ) 251 mg (yield 68%) were obtained.

1H NMR (400 MHz, CDCl3) δ 7.48-7.38 (m, 7H), 7.07-7.04 (m, 2H), 6.76 (s, 1H), 3.46-3.42 (m, 2H), 2.94-2.90 (m, 2H), 2.74-2.70 (m, 2H), 2.65-2.46 (m, 7H), 2.33 (s, 3H), 2.07-1.98 (m, 2H), 1.88-1.78 (m, 1H), 1.62-1.54 (m, 1H), 0.85 (d, J = 6.8 Hz, 6H); 1 H NMR (400 MHz, CDCl 3 ) δ 7.48-7.38 (m, 7H), 7.07-7.04 (m, 2H), 6.76 (s, 1H), 3.46-3.42 (m, 2H), 2.94-2.90 (m , 2H), 2.74-2.70 (m, 2H), 2.65-2.46 (m, 7H), 2.33 (s, 3H), 2.07-1.98 (m, 2H), 1.88-1.78 (m, 1H), 1.62-1.54 (m, 1 H), 0.85 (d, J = 6.8 Hz, 6H);

13C NMR (100 MHz, CDCl3) δ 162.50, 146.83, 144.97, 141.90, 139.42, 138.60, 132.24, 129.18, 128.58, 126.77, 125.87, 125.81 (q, J C -F = 29.5 Hz), 125.80, 125.75, 124.77 (q, J C -F = 271.7 Hz, CF3), 106.49, 58.23, 57.75, 53.62, 43.80, 37.12, 35.07, 31.99, 28.26, 22.28, 21.16. 13 C NMR (100 MHz, CDCl 3 ) δ 162.50, 146.83, 144.97, 141.90, 139.42, 138.60, 132.24, 129.18, 128.58, 126.77, 125.87, 125.81 (q, J C -F = 29.5 Hz), 125.80, 125.75, 124.77 (q, J C -F = 271.7 Hz, CF 3 ), 106.49, 58.23, 57.75, 53.62, 43.80, 37.12, 35.07, 31.99, 28.26, 22.28, 21.16.

실시예Example 37 : 37: (R)-5- (R) -5- 아이소부틸Isobutyl -1-페닐-N-((1-(3-(-1-phenyl-N-((1- (3- ( 트라이플루오로메틸Trifluoromethyl )) 페네Penne 틸) 피롤리딘-3-일)메틸)-1H-피라졸-3-카르복사미드(Tyl) pyrrolidin-3-yl) methyl) -1H-pyrazole-3-carboxamide ( 화합물번호 34Compound number 34 )의 제조Manufacturing

Figure pat00171
Figure pat00171

(S)-5-아이소부틸-1-페닐-N-(피롤리딘-3-일메틸)-1H-피라졸-3-카르복사이드 (화합물번호 57; 100 mg, 0.3 mmol)과 3-(트리플루오로메틸)페네틸 4-메틸벤젠술폰산염 (2-XIII-3; 105 mg, 0.3 mmol)과 포타슘 카보네이트 (K2CO3; 127 mg, 0.9 mmol)을 이용하여 상기 표제화합물 54 mg(화합물번호 34) (수율 35%)을 얻었다.( S ) -5-isobutyl-1-phenyl-N- (pyrrolidin-3-ylmethyl) -1H-pyrazole-3-carboxide ( compound No. 57 ; 100 mg, 0.3 mmol) and 3- 54 mg of the title compound using (trifluoromethyl) phenethyl 4-methylbenzenesulfonate ( 2-XIII-3 ; 105 mg, 0.3 mmol) and potassium carbonate (K 2 CO 3 ; 127 mg, 0.9 mmol) ( Compound No. 34 ) (Yield 35%) was obtained.

1H NMR (300MHz, CDCl3) δ 7.51-7.30 (m, 9H), 6.79 (s, 1H), 3.47-3.38 (m, 2H), 2.87-2.2.82 (m, 2H), 2.78-2.65 (m, 4H), 2.58-2.49 (m, 5H), 2.08 (s, 1H), 1.9-1.78 (m, 1H), 1.64-1.53 (m, 1H), 0.89 (d, J = 6.6 Hz, 6H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.51-7.30 (m, 9H), 6.79 (s, 1H), 3.47-3.38 (m, 2H), 2.87-2.2.82 (m, 2H), 2.78-2.65 ( m, 4H), 2.58-2.49 (m, 5H), 2.08 (s, 1H), 1.9-1.78 (m, 1H), 1.64-1.53 (m, 1H), 0.89 (d, J = 6.6 Hz, 6H) .

실시예Example 38 :  38: 메틸methyl 2,6-다이메틸-4-(3-나이트로페닐)-5-(((( 2,6-dimethyl-4- (3-nitrophenyl) -5-(((( RR )-1-(4-(트리플루오로메틸)페네틸)피롤리딘-3-일)메틸)카르바모일l)-1,4-다이하이드로피리딘-3-카르복시산염() -1- (4- (trifluoromethyl) phenethyl) pyrrolidin-3-yl) methyl) carbamoyll) -1,4-dihydropyridine-3-carboxylate ( 화합물번호 35Compound number 35 )의 제조Manufacturing

Figure pat00172
Figure pat00172

(메틸 2,6-다이메틸-4-(3-나이트로페닐)-5-(((S)-피롤리딘-3-일메틸)카르바모일)-1,4-다이하이드로피리딘-3-카르복시산염 (화합물번호 59; 50 mg, 0.1 mmol)과 4-(트리플루오로메틸)페네틸 4-메틸벤젠술폰산염 (2-XII-2; 48 mg, 0.1 mmol)과 포타슘 카보네이트 (K2CO3; 83 mg, 0.6 mmol)을 이용하여 상기 표제화합물(화합물번호 35) 36 mg (수율 51%)을 얻었다.(Methyl 2,6-dimethyl-4- (3-nitrophenyl) -5-((( S ) -pyrrolidin-3-ylmethyl) carbamoyl) -1,4-dihydropyridine-3 -Carboxylates ( Compound No. 59 ; 50 mg, 0.1 mmol) and 4- (trifluoromethyl) phenethyl 4-methylbenzenesulfonate ( 2-XII-2 ; 48 mg, 0.1 mmol) and potassium carbonate (K 2 CO 3 ; 83 mg, 0.6 mmol) gave 36 mg (yield 51%) of the title compound ( Compound No. 35 ).

1H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 2.0 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.55 (dd, J = 8.4, 2.8 Hz, 2H), 7.43 (t, J = 8.0 Hz, 1H), 7.34 (t, J = 9.2 Hz, 2H), 6.52 (brs, 0.5H), 6.20 (brs, 0.5H), 5.94 (d, J = 8.4 Hz, 1H), 4.99 (s, 1H), 3.64 (d, J = 3.2 Hz, 3H), 3.303.17 (m, 2H), 2.932.40 (m, 9H), 2.34 (d, J = 4.0 Hz, 3H), 2.27 (s, 1.5H), 2.20 (s, 1.5H), 1.951.90 (m, 1H), 1.421.29 (m, 1H); 1 H NMR (400 MHz, CDCl 3 ) δ 8.15 (d, J = 2.0 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.55 (dd , J = 8.4, 2.8 Hz, 2H), 7.43 (t, J = 8.0 Hz, 1H), 7.34 (t, J = 9.2 Hz, 2H), 6.52 (brs, 0.5H), 6.20 (brs, 0.5H) , 5.94 (d, J = 8.4 Hz, 1H), 4.99 (s, 1H), 3.64 (d, J = 3.2 Hz, 3H), 3.303.17 (m, 2H), 2.932.40 (m, 9H), 2.34 (d, J = 4.0 Hz, 3H), 2.27 (s, 1.5H), 2.20 (s, 1.5H), 1.951.90 (m, 1H), 1.421.29 (m, 1H);

13C NMR (100 MHz, CDCl3) δ 168.36, 167.72, 167.68, 148.99, 148.73, 148.53, 148.44, 146.09, 146.04, 144.39, 144.04, 138.18, 137.16, 133.89, 133.83, 129.20, 128.90, 128.86 (q, J C -F = 31.0 Hz), 125.35 (q, J C -F = 3.3 Hz), 124.29 (q, J C -F = 269.4 Hz, CF3), 122.42, 122.39, 121.66, 107.72, 107.00, 100.75, 100.71, 58.36, 58.11, 57.24, 57.14, 54.15, 53.74, 51.06, 51.03, 44.77, 44.25, 41.28, 41.06, 36.22, 35.66, 34.84, 34.72, 29.69, 27.74, 20.02, 19.94, 18.36, 18.21. 13 C NMR (100 MHz, CDCl 3 ) δ 168.36, 167.72, 167.68, 148.99, 148.73, 148.53, 148.44, 146.09, 146.04, 144.39, 144.04, 138.18, 137.16, 133.89, 133.83, 129.20, 128.90, J. C -F = 31.0 Hz), 125.35 (q, J C -F = 3.3 Hz), 124.29 (q, J C -F = 269.4 Hz, CF 3 ), 122.42, 122.39, 121.66, 107.72, 107.00, 100.75, 100.71 , 58.36, 58.11, 57.24, 57.14, 54.15, 53.74, 51.06, 51.03, 44.77, 44.25, 41.28, 41.06, 36.22, 35.66, 34.84, 34.72, 29.69, 27.74, 20.02, 19.94, 18.36, 18.21.

실시예Example 39 : 39: (R)(R) -- NN -((1-(3,4--((1- (3,4- 다이클로로페네틸Dichlorophenethyl )) 피롤리딘Pyrrolidine -3-일)-3 days) 메틸methyl )-3-) -3- 아이Child 소프로필아이소옥사졸-5-카르복사미드(Sopropylisoxazole-5-carboxamide ( 화합물번호 36Compound number 36 )의 제조Manufacturing

Figure pat00173
Figure pat00173

(S)-3-아이소프로필-N-(피롤리딘-3-일메틸)아이소옥사졸-5-카르복사미드 (화합물번호 58; 52 mg, 0.2 mmol)과 3,4-다이클로로페네틸 4-메틸벤젠술폰산염 (2-V-3; 50 mg, 0.1 mmol)과 포타슘 카보네이트 (K2CO3; 97 mg, 0.7 mmol)을 이용하여 상기 표제화합물(화합물번호 36) 14 mg (수율 25%)을 얻었다.( S ) -3-isopropyl-N- (pyrrolidin-3-ylmethyl) isoxazole-5-carboxamide ( Compound No. 58 ; 52 mg, 0.2 mmol) with 3,4-dichlorophenethyl 14 mg (Yield 25) of the title compound ( Compound No. 36 ) using 4-methylbenzenesulfonate ( 2-V-3 ; 50 mg, 0.1 mmol) and potassium carbonate (K 2 CO 3 ; 97 mg, 0.7 mmol). %) Was obtained.

1H NMR (400 MHz, CDCl3) δ 7.81 (brs, 1H), 7.377.34 (m, 2H), 7.09 (dd, J = 8.4, 2.0 Hz, 1H), 6.81 (s, 1H), 3.563.41 (m, 2H), 3.173.10 (m, 1H), 3.01 (brs, 1H), 2.922.54 (m, 8H), 2.172.04 (m, 1H), 1.711.65 (m, 1H), 1.33 (d, J = 7.2 Hz, 6H); 1 H NMR (400 MHz, CDCl 3 ) δ 7.81 (brs, 1H), 7.377.34 (m, 2H), 7.09 (dd, J = 8.4, 2.0 Hz, 1H), 6.81 (s, 1H), 3.563. 41 (m, 2H), 3.173.10 (m, 1H), 3.01 (brs, 1H), 2.922.54 (m, 8H), 2.172.04 (m, 1H), 1.711.65 (m, 1H), 1.33 (d, J = 7.2 Hz, 6H);

13C NMR (100 MHz, CDCl3) δ 170.29, 163.20, 156.71, 139.90, 132.31, 130.55, 130.37, 130.24, 128.11, 105.08, 58.21, 56.86, 53.71, 44.46, 35.95, 34.11, 27.86, 26.56, 21.63. 13 C NMR (100 MHz, CDCl 3 ) δ 170.29, 163.20, 156.71, 139.90, 132.31, 130.55, 130.37, 130.24, 128.11, 105.08, 58.21, 56.86, 53.71, 44.46, 35.95, 34.11, 27.86, 26.56, 21.63.

실시예Example 40 :  40: 메틸methyl 5-((( 5-((( (R)(R) -1-(3,4-다이클로로페네틸)피롤리딘-3-일)메틸)카르바모일)-2,6-다이메틸-4-(3-나이트로페닐)-1,4-다이하이드로피리딘-3-카르복시산염(-1- (3,4-Dichlorophenethyl) pyrrolidin-3-yl) methyl) carbamoyl) -2,6-dimethyl-4- (3-nitrophenyl) -1,4-di Hydropyridine-3-carboxylate ( 화합물번호 37Compound number 37 )의 제조Manufacturing

Figure pat00174
Figure pat00174

메틸 2,6-다이메틸-4-(3-나이트로페닐)-5-(((S)-피롤리딘-3-일메틸)카르바모일)-1,4-다이하이드로피리딘-3-카르복시산염 (화합물번호 59; 50 mg, 0.1 mmol)과 3,4-다이클로로페네틸 4-메틸벤젠술폰산염 (2-V-3; 48 mg, 0.1 mmol)과 포타슘 카보네이트 (K2CO3; 83 mg, 0.6 mmol)을 이용하여 상기 표제화합물(화합물번호 37) 33 mg (수율 41%)을 얻었다.Methyl 2,6-dimethyl-4- (3-nitrophenyl) -5-((( S ) -pyrrolidin-3-ylmethyl) carbamoyl) -1,4-dihydropyridine-3- Carboxylate ( Compound No. 59 ; 50 mg, 0.1 mmol), 3,4-dichlorophenethyl 4-methylbenzenesulfonate ( 2-V-3 ; 48 mg, 0.1 mmol) and potassium carbonate (K 2 CO 3 ; 83 mg, 0.6 mmol) was used to obtain 33 mg (yield 41%) of the title compound ( Compound No. 37 ).

1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 1.6 Hz, 1H), 8.05-8.02 (m, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.42 (td, J = 8.0, 3.2 Hz, 1H), 7.37-7.31 (m, 2H), 7.06 (td, J = 8.8, 2.0 Hz, 1H), 6.62 (brs, 0.5H), 6.18 (brs, 0.5H), 5.90 (d, J = 9.6 Hz, 1H), 4.96 (d, J = 14.8 Hz, 1H), 3.65 (d, J = 7.6 Hz, 3H), 3.28-3.18 (m, 2H), 2.86-2.55 (m, 6H), 2.48-2.29 (m, 8H), 2.18 (s, 1H), 1.97-1.84 (m, 1H), 1.39-1.27 (m, 1H); 1 H NMR (400 MHz, CDCl 3 ) δ 8.14 (d, J = 1.6 Hz, 1H), 8.05-8.02 (m, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.42 (td, J = 8.0, 3.2 Hz, 1H), 7.37-7.31 (m, 2H), 7.06 (td, J = 8.8, 2.0 Hz, 1H), 6.62 (brs, 0.5H), 6.18 (brs, 0.5H), 5.90 (d , J = 9.6 Hz, 1H), 4.96 (d, J = 14.8 Hz, 1H), 3.65 (d, J = 7.6 Hz, 3H), 3.28-3.18 (m, 2H), 2.86-2.55 (m, 6H) , 2.48-2.29 (m, 8H), 2.18 (s, 1H), 1.97-1.84 (m, 1H), 1.39-1.27 (m, 1H);

13C NMR (100 MHz, CDCl3) δ 168.34, 167.75, 167.70, 149.00, 148.69, 148.54, 148.42, 146.07, 145.92, 140.52, 140.47, 138.40, 136.99, 133.90, 133.82, 132.22, 130.60, 130.52, 130.29, 130.26, 130.00, 129.18, 128.07, 128.04, 122.42, 122.37, 121.66, 107.80, 106.84, 100.81, 100.69, 58.62, 58.32, 57.21, 57.11, 54.34, 53.84, 51.09, 51.04, 45.17, 44.57, 41.31, 41.03, 36.06, 35.38, 34.34, 34.26, 27.75, 27.72, 20.14, 20.01, 18.40, 18.17. 13 C NMR (100 MHz, CDCl 3 ) δ 168.34, 167.75, 167.70, 149.00, 148.69, 148.54, 148.42, 146.07, 145.92, 140.52, 140.47, 138.40, 136.99, 133.90, 133.82, 132.22, 130.60, 130. , 130.00, 129.18, 128.07, 128.04, 122.42, 122.37, 121.66, 107.80, 106.84, 100.81, 100.69, 58.62, 58.32, 57.21, 57.11, 54.34, 53.84, 51.09, 51.04, 45.17, 44.57, 41.31, 41.03, 36.0338 , 34.34, 34.26, 27.75, 27.72, 20.14, 20.01, 18.40, 18.17.

실시예Example 41 :41: 메틸  methyl 2,6-다이메틸-5-((( 2,6-dimethyl-5-((( (R)(R) -1-(4-메틸-3-(트리플루오로메틸)페네틸)피롤리딘-3-일)메틸)카르바모일)-4-(3-나이트로페닐)-1,4-다이하이드로피리딘-3-카르복시산염(-1- (4-methyl-3- (trifluoromethyl) phenethyl) pyrrolidin-3-yl) methyl) carbamoyl) -4- (3-nitrophenyl) -1,4-dihydro Pyridine-3-carboxylate ( 화합물번호 38Compound number 38 )의 제조Manufacturing

Figure pat00175
Figure pat00175

메틸 2,6-다이메틸-4-(3-나이트로페닐)-5-(((S)-피롤리딘-3-일메틸)카르바모일)-1,4-다이하이드로피리딘-3-카르복시산염 (화합물번호 59; 181 mg, 0.44 mmol)과 4-메틸-3-(트리플루오로메틸)페네틸 4-메틸벤젠술폰산염 (2-I-3; 208 mg, 0.58 mmol)과 포타슘 카보네이트 (K2CO3; 304 mg, 2.20 mmol)을 이용하여 상기 표제화합물(화합물번호 38) 116 mg (수율 44%)을 얻었다.Methyl 2,6-dimethyl-4- (3-nitrophenyl) -5-(((S) -pyrrolidin-3-ylmethyl) carbamoyl) -1,4-dihydropyridine-3- Carboxylate ( Compound No. 59 ; 181 mg, 0.44 mmol) with 4-methyl-3- (trifluoromethyl) phenethyl 4-methylbenzenesulfonate ( 2-I-3 ; 208 mg, 0.58 mmol) and potassium carbonate 116 mg (yield 44%) of the title compound ( Compound No. 38 ) were obtained using (K 2 CO 3 ; 304 mg, 2.20 mmol).

1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 1.6 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.66 (d, J = 6.4 Hz, 1H), 7.47-7.37 (m, 2H), 7.27-7.13 (m, 2H), 6.67 (brs, 0.5H) 6.42 (d, J = 8.0 Hz, 1H), 6.33 (brs, 0.5H), 4.99 (d, J = 8.0 Hz, 1H), 3.62 (d, J = 2.4 Hz, 3H), 3.31-3.15 (m, 2H), 2.84-2.74 (m, 2H), 2.72-2.55 (m, 3H), 2.53-2.28 (m, 12H), 2.20 (s, 1H), 2.06-1.87 (m, 2H), 0.90-0.72 (m, 3H); 1 H NMR (400 MHz, CDCl 3 ) δ 8.14 (d, J = 1.6 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.66 (d, J = 6.4 Hz, 1H), 7.47-7.37 (m, 2H), 7.27-7.13 (m, 2H), 6.67 (brs, 0.5H) 6.42 (d, J = 8.0 Hz, 1H), 6.33 (brs, 0.5H), 4.99 (d, J = 8.0 Hz , 1H), 3.62 (d, J = 2.4 Hz, 3H), 3.31-3.15 (m, 2H), 2.84-2.74 (m, 2H), 2.72-2.55 (m, 3H), 2.53-2.28 (m, 12H ), 2.20 (s, 1 H), 2.06-1.87 (m, 2 H), 0.90-0.72 (m, 3H);

13C NMR (100 MHz, CDCl3) δ 168.50, 167.83, 167.78, 149.09, 148.84, 148.49, 148.40, 146.48, 146.30, 138.59, 137.90, 137.85, 137.29, 134.20, 133.85, 132.02 (q, J C -F = 23.0 Hz), 131.97, 131.74, 131.14, 130.72, 129.16, 128.71 (q, J C -F = 29.3 Hz), 125.86 (q, J C -F = 5.8 Hz), 124.61 (q, J C -F = 271.9 Hz, CF3), 122.39, 122.37, 121.61, 107.64, 106.73, 100.56, 100.40, 58.57, 58.33, 57.58, 57.54, 54.27, 53.84, 51.01, 50.98, 45.20, 44.72, 41.28, 41.01, 36.05, 35.45, 34.83, 29.68, 27.83, 19.85, 19.78, 18.87, 18.25, 18.04. 13 C NMR (100 MHz, CDCl 3) δ 168.50, 167.83, 167.78, 149.09, 148.84, 148.49, 148.40, 146.48, 146.30, 138.59, 137.90, 137.85, 137.29, 134.20, 133.85, 132.02 (q, J C -F = 23.0 Hz), 131.97, 131.74, 131.14, 130.72, 129.16, 128.71 (q, J C -F = 29.3 Hz), 125.86 (q, J C -F = 5.8 Hz), 124.61 (q, J C -F = 271.9 Hz, CF 3 ), 122.39, 122.37, 121.61, 107.64, 106.73, 100.56, 100.40, 58.57, 58.33, 57.58, 57.54, 54.27, 53.84, 51.01, 50.98, 45.20, 44.72, 41.28, 41.01, 36.05, 35.45, 34.83, 34.83, 29.68, 27.83, 19.85, 19.78, 18.87, 18.25, 18.04.

실시예Example 42 : 42: 메틸methyl 5-((( 5-((( (R)(R) -1-(4-클로로-3-플루오로페네틸)피롤리딘-3-일)메틸)카르바모일)-2,6-다이메틸-4-(3-나이트로페닐)-1,4-다이하이드로피리딘-3-카르복시산염(-1- (4-chloro-3-fluorophenethyl) pyrrolidin-3-yl) methyl) carbamoyl) -2,6-dimethyl-4- (3-nitrophenyl) -1,4 Dihydropyridine-3-carboxylate ( 화합물번호 39Compound number 39 )의 제조Manufacturing

Figure pat00176
Figure pat00176

메틸 2,6-다이메틸-4-(3-나이트로페닐)-5-(((S)-피롤리딘-3-일메틸)카르바모일)-1,4-다이하이드로피리딘-3-카르복시산염 (화합물번호 59; 58 mg, 0.1 mmol)과 4-클로로-3-플루오로페네틸 4-메틸벤젠술폰산염 (2-VI-3; 39 mg, 0.1 mmol)과 포타슘 카보네이트 (K2CO3; 83 mg, 0.6 mmol)을 이용하여 상기 표제화합물(화합물번호 39) 32 mg (수율 46%)을 얻었다.Methyl 2,6-dimethyl-4- (3-nitrophenyl) -5-(((S) -pyrrolidin-3-ylmethyl) carbamoyl) -1,4-dihydropyridine-3- Carboxylate ( Compound No. 59 ; 58 mg, 0.1 mmol), 4-Chloro-3-fluorophenethyl 4-methylbenzenesulfonate ( 2-VI-3 ; 39 mg, 0.1 mmol) and potassium carbonate (K 2 CO 3 ; 83 mg, 0.6 mmol) gave 32 mg (yield 46%) of the title compound ( Compound No. 39 ).

1H NMR (400 MHz, CDCl3) δ 8.13 (s, 1H), 8.05-8.02 (m, 1H), 7.66 (dd, J = 7.6, 1.6 Hz, 1H), 7.42 (td, J = 7.6, 2.8 Hz, 1H), 7.29 (td, J = 7.6, 5.2 Hz, 1H), 7.04 (qd, J = 10.0, 2.0 Hz, 1H), 6.94 (td, J = 8.0, 1.2 Hz, 1H), 6.61 (brs, 0.5H), 6.17 (brs, 0.5H), 5.94 (d, J = 8.4 Hz, 1H), 4.96 (d, J = 14.8 Hz, 1H), 3.65 (d, J = 6.8 Hz, 3H), 3.31-3.16 (m, 2H,) 2.86-2.73 (m, 2H), 2.69-2.54 (m, 3H), 2.48-2.28 (m, 8H), 2.17 (s, 1H), 1.93-1.86 (m, 1H), 1.39-1.31 (m, 1H); 1 H NMR (400 MHz, CDCl 3 ) δ 8.13 (s, 1H), 8.05-8.02 (m, 1H), 7.66 (dd, J = 7.6, 1.6 Hz, 1H), 7.42 (td, J = 7.6, 2.8 Hz, 1H), 7.29 (td, J = 7.6, 5.2 Hz, 1H), 7.04 (qd, J = 10.0, 2.0 Hz, 1H), 6.94 (td, J = 8.0, 1.2 Hz, 1H), 6.61 (brs , 0.5H), 6.17 (brs, 0.5H), 5.94 (d, J = 8.4 Hz, 1H), 4.96 (d, J = 14.8 Hz, 1H), 3.65 (d, J = 6.8 Hz, 3H), 3.31 -3.16 (m, 2H,) 2.86-2.73 (m, 2H), 2.69-2.54 (m, 3H), 2.48-2.28 (m, 8H), 2.17 (s, 1H), 1.93-1.86 (m, 1H) , 1.39-1.31 (m, 1 H);

13C NMR (100 MHz, CDCl3) δ 168.37, 167.75, 167.70, 157.93 (d, J C -F = 246.6 Hz), 149.02, 148.69, 148.52, 148.40, 146.12, 145.99, 141.23, 138.34, 136.95, 133.86, (d, J C -F = 7.6 Hz), 130.33 (d, J C -F = 4.7 Hz), 129.18, 125.04 (d, J C -F = 3.0 Hz), 122.41, 122.36, 121.65, 118.35 (d, J C -F = 17.5 Hz), 116.75 (d, J C -F = 20.5 Hz), 116.69 (d, J C -F = 20.5 Hz), 107.81, 106.86, 100.72, 100.64, 58.64, 58.31, 57.18, 57.06, 54.34, 53.84, 51.06, 51.03, 45.17, 44.57, 41.31, 41.06, 36.04, 35.38, 34.55, 34.46, 27.74, 27.71, 20.11, 19.98, 18.33, 18.14. 13 C NMR (100 MHz, CDCl 3 ) δ 168.37, 167.75, 167.70, 157.93 (d, J C -F = 246.6 Hz), 149.02, 148.69, 148.52, 148.40, 146.12, 145.99, 141.23, 138.34, 136.95, 133.86, (d, J C -F = 7.6 Hz), 130.33 (d, J C -F = 4.7 Hz), 129.18, 125.04 (d, J C -F = 3.0 Hz), 122.41, 122.36, 121.65, 118.35 (d, J C -F = 17.5 Hz), 116.75 (d, J C -F = 20.5 Hz), 116.69 (d, J C -F = 20.5 Hz), 107.81, 106.86, 100.72, 100.64, 58.64, 58.31, 57.18, 57.06 , 54.34, 53.84, 51.06, 51.03, 45.17, 44.57, 41.31, 41.06, 36.04, 35.38, 34.55, 34.46, 27.74, 27.71, 20.11, 19.98, 18.33, 18.14.

실시예Example 43 :  43: (( RR )-3-) -3- 아이소프로필Isopropyl -- NN -((1-(4--((1- (4- 메틸methyl -3-(-3- ( 트리플루오로메틸Trifluoromethyl )) 페네Penne 틸)피롤리딘-3-일)메틸)아이소옥사졸-5-카르복사미드(Tyl) pyrrolidin-3-yl) methyl) isoxazole-5-carboxamide ( 화합물번호 40Compound number 40 )의 제조Manufacturing

Figure pat00177
Figure pat00177

(S)-3-아이소프로필-N-(피롤리딘-3-일메틸)아이소옥사졸-5-카르복사미드 (화합물번호 58; 737 mg, 3.1 mmol)과 4-메틸-3-(트리플루오로메틸)페네틸 4-메틸벤젠술폰산염 (2-I-3; 248 mg, 0.7 mmol)과 포타슘 카보네이트 (K2CO3; 574 mg, 4.2 mmol)을 이용하여 상기 표제화합물(화합물번호 40) 163 mg (수율 56%)을 얻었다.( S ) -3-isopropyl- N- (pyrrolidin-3-ylmethyl) isoxazole-5-carboxamide ( Compound No. 58 ; 737 mg, 3.1 mmol) and 4-methyl-3- (tri Fluoromethyl) phenethyl 4-methylbenzenesulfonate ( 2-I-3 ; 248 mg, 0.7 mmol) and potassium carbonate (K 2 CO 3 ; 574 mg, 4.2 mmol) gave the title compound ( Compound No. 40). ) 163 mg (yield 56%).

1H NMR (400 MHz, CDCl3) δ 7.82 (brs, 1H), 7.47 (s, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 6.80 (s, 1H), 3.55-3.40 (m, 2H), 3.17-3.10 (m, 1H), 2.99-2.89 (m, 3H), 2.76-2.55 (m, 5H), 2.45 (s, 3H), 2.41 (d, J = 7.6 Hz, 1H), 2.13-2.06 (m, 1H), 1.65-1.58 (m, 1H), 1.33 (d, J = 6.8 Hz, 6H); 1 H NMR (400 MHz, CDCl 3 ) δ 7.82 (brs, 1H), 7.47 (s, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 6.80 (s, 1H), 3.55-3.40 (m, 2H), 3.17-3.10 (m, 1H), 2.99-2.89 (m, 3H), 2.76-2.55 (m, 5H), 2.45 (s, 3H), 2.41 (d, J = 7.6 Hz, 1H), 2.13-2.06 (m, 1H), 1.65-1.58 (m, 1H), 1.33 (d, J = 6.8 Hz, 6H);

13C NMR (100 MHz, CDCl3) δ 170.29, 163.35, 156.66, 137.89, 134.21, 131.97, 131.79, 128.92, 128.63, 125.88 (q, J C -F = 5.3 Hz), 104.98, 58.45, 57.29, 53.75, 44.94, 35.75, 34.88, 27.99, 26.56, 21.64, 18.87. 13 C NMR (100 MHz, CDCl 3 ) δ 170.29, 163.35, 156.66, 137.89, 134.21, 131.97, 131.79, 128.92, 128.63, 125.88 (q, J C -F = 5.3 Hz), 104.98, 58.45, 57.29, 53.75, 44.94, 35.75, 34.88, 27.99, 26.56, 21.64, 18.87.

실시예Example 44 : 44: ( ( RR )-)- NN -((1-(4--((1- (4- 클로로Chloro -3--3- 플루오로페네틸Fluorophenethyl )) 피롤리딘Pyrrolidine -3-일)-3 days) 메틸methyl )-3-아이소프로필아이소옥사졸-5-카르복사미드() -3-isopropylisoxazole-5-carboxamide ( 화합물번호 41Compound number 41 )의 제조Manufacturing

Figure pat00178
Figure pat00178

(S)-3-아이소프로필-N-(피롤리딘-3-일메틸)아이소옥사졸-5-카르복사미드 (화합물번호 58; 57 mg, 0.2 mmol)과 4-클로로-3-플루오로페네틸 4-메틸벤젠술폰산염 (2-VI-3; 39 mg, 0.1 mmol)과 포타슘 카보네이트 (K2CO3; 83 mg, 0.6 mmol)을 이용하여 상기 표제화합물(화합물번호 41) 9 mg (수율 19%)을 얻었다.( S ) -3-isopropyl- N- (pyrrolidin-3-ylmethyl) isoxazole-5-carboxamide ( Compound No. 58 ; 57 mg, 0.2 mmol) with 4-chloro-3-fluoro 9 mg of the title compound ( Compound No. 41 ) using phenethyl 4-methylbenzenesulfonate ( 2-VI-3 ; 39 mg, 0.1 mmol) and potassium carbonate (K 2 CO 3 ; 83 mg, 0.6 mmol) Yield 19%).

1H NMR (400 MHz, CDCl3) δ 7.81 (brs, 1H), 7.29 (t, J = 7.6 Hz, 1H), 7.04 (dd, J = 10.0, 2.0 Hz, 1H), 6.97 (dd, J = 8.4, 1.6 Hz, 1H), 6.80 (s, 1H), 3.53-3.38 (m, 2H), 3.17-3.10 (m, 1H), 2.94 (td, J = 8.8, 4.0 Hz, 1H), 2.88-2.85 (m, 2H), 2.77-2.69 (m, 3H), 2.61-2.54 (m, 2H), 2.41 (q, J = 8.0 Hz, 1H), 2.13-2.06 (m, 1H), 1.65-1.59 (m, 1H), 1.33 (d, J = 7.2 Hz, 6H); 1 H NMR (400 MHz, CDCl 3 ) δ 7.81 (brs, 1H), 7.29 (t, J = 7.6 Hz, 1H), 7.04 (dd, J = 10.0, 2.0 Hz, 1H), 6.97 (dd, J = 8.4, 1.6 Hz, 1H), 6.80 (s, 1H), 3.53-3.38 (m, 2H), 3.17-3.10 (m, 1H), 2.94 (td, J = 8.8, 4.0 Hz, 1H), 2.88-2.85 (m, 2H), 2.77-2.69 (m, 3H), 2.61-2.54 (m, 2H), 2.41 (q, J = 8.0 Hz, 1H), 2.13-2.06 (m, 1H), 1.65-1.59 (m , 1H), 1.33 (d, J = 7.2 Hz, 6H);

13C NMR (100 MHz, CDCl3) δ 170.31, 163.30, 157.95 (d, J C -F = 246.8 Hz), 156.66, 141.14 (d, J C -F = 8.0Hz), 130.34, 125.06 (d, J C -F = 3.5 Hz), 118.41 (d, J C-F = 17.2 Hz), 116.73 (d, J C -F = 20.5 Hz), 105.01, 58.41, 56.89, 53.78, 44.90, 35.75, 34.76, 30.91, 27.94, 26.57, 21.63. 13 C NMR (100 MHz, CDCl 3 ) δ 170.31, 163.30, 157.95 (d, J C -F = 246.8 Hz), 156.66, 141.14 (d, J C -F = 8.0 Hz), 130.34, 125.06 (d, J C -F = 3.5 Hz), 118.41 (d, J CF = 17.2 Hz), 116.73 (d, J C -F = 20.5 Hz), 105.01, 58.41, 56.89, 53.78, 44.90, 35.75, 34.76, 30.91, 27.94, 26.57, 21.63.

실시예Example 45 :  45: 메틸methyl 5-(((( 5-(((( RR )-1-(3-플루오로-4-(트리플루오로메톡시)페네틸)피롤리딘-3-일)메틸)카르바모일)-2,6-다이메틸-4-(3-나이트로페닐)-1,4-다이하이드로피리딘-3-카르복시산염() -1- (3-fluoro-4- (trifluoromethoxy) phenethyl) pyrrolidin-3-yl) methyl) carbamoyl) -2,6-dimethyl-4- (3-nitro Phenyl) -1,4-dihydropyridine-3-carboxylate ( 화합물번호 42Compound number 42 )의 제조Manufacturing

Figure pat00179
Figure pat00179

메틸 2,6-다이메틸-4-(3-나이트로페닐)-5-(((S)-피롤리딘-3-일메틸)카르바모일)-1,4-다이하이드로피리딘-3-카르복시산염 (화합물번호 59; 41 mg, 0.1 mmol)과 3-플루오로-4-(트리플루오로메톡시)페네틸 4-메틸벤젠술폰산염 (2-VII-3; 45 mg, 0.1 mmol)과 포타슘 카보네이트 (K2CO3; 69 mg, 0.5 mmol)을 이용하여 상기 표제화합물(화합물번호 42) 30 mg (수율 48%)을 얻었다.Methyl 2,6-dimethyl-4- (3-nitrophenyl) -5-(((S) -pyrrolidin-3-ylmethyl) carbamoyl) -1,4-dihydropyridine-3- Carboxylate ( Compound No. 59 ; 41 mg, 0.1 mmol) and 3-Fluoro-4- (trifluoromethoxy) phenethyl 4-methylbenzenesulfonate ( 2-VII-3 ; 45 mg, 0.1 mmol) and potassium 30 mg (yield 48%) of the title compound ( Compound No. 42 ) were obtained using carbonate (K 2 CO 3 ; 69 mg, 0.5 mmol).

1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 2.0 Hz, 1H), 8.05-8.02 (m, 1H), 7.68-7.66 (m, 1H), 7.45-7.41 (m, 1H), 7.25-7.20 (m, 1H), 7.11 (qd, J = 11.2, 2.0 Hz, 1H), 7.01 (t, J = 8.0 Hz, 1H), 6.55 (brs, 0.5H), 6.20 (brs, 0.5H), 5.91 (d, J = 5.6 Hz, 1H), 4.97 (d, J = 4.8 Hz, 1H), 3.65 (d, J = 3.6 Hz, 3H), 3.31-3.16 (m, 2H), 2.89-2.51 (m, 7H), 2.49-2.39 (m, 2H), 2.34 (d, J = 4.8 Hz, 3H), 2.30 (s, 1.5H), 2.22 (s, 1.5H), 1.96-1.89 (m, 1H), 1.41-1.32 (m, 1H); 1 H NMR (400 MHz, CDCl 3 ) δ 8.14 (d, J = 2.0 Hz, 1H), 8.05-8.02 (m, 1H), 7.68-7.66 (m, 1H), 7.45-7.41 (m, 1H), 7.25-7.20 (m, 1H), 7.11 (qd, J = 11.2, 2.0 Hz, 1H), 7.01 (t, J = 8.0 Hz, 1H), 6.55 (brs, 0.5H), 6.20 (brs, 0.5H) , 5.91 (d, J = 5.6 Hz, 1H), 4.97 (d, J = 4.8 Hz, 1H), 3.65 (d, J = 3.6 Hz, 3H), 3.31-3.16 (m, 2H), 2.89-2.51 ( m, 7H), 2.49-2.39 (m, 2H), 2.34 (d, J = 4.8 Hz, 3H), 2.30 (s, 1.5H), 2.22 (s, 1.5H), 1.96-1.89 (m, 1H) , 1.41-1.32 (m, 1 H);

13C NMR (100 MHz, CDCl3) δ 168.32, 167.75, 167.68, 154.32 (d, J C -F = 250.8 Hz), 148.96, 148.68, 148.52, 148.43, 146.02, 145.91, 141.07, 140.93, 138.38, 137.32, 133.87 (d, J C -F = 7.2 Hz), 129.56 (q, J C -F = 30.5 Hz), 129.20, 124.61 (d, J C -F = 3.5 Hz), 123.60, 123.55, 122.40 (d, J C -F = 3.0 Hz), 121.66, 120.48 (q, J C -F = 256.7 Hz, CF3), 117.35( d, J C -F = 18.1 Hz), 117.29 (d, JC -F = 18.2 Hz), 107.61, 106.85, 100.82, 100.77, 58.24, 58.02, 57.07, 54.15, 53.70, 51.06, 51.03, 44.74, 44.16, 41.28, 41.05, 36.27, 35.64, 34.32, 34.16, 29.68, 27.73, 20.06, 19.96, 18.39, 18.25. 13 C NMR (100 MHz, CDCl 3 ) δ 168.32, 167.75, 167.68, 154.32 (d, J C -F = 250.8 Hz), 148.96, 148.68, 148.52, 148.43, 146.02, 145.91, 141.07, 140.93, 138.38, 137.32, 133.87 (d, J C -F = 7.2 Hz), 129.56 (q, J C -F = 30.5 Hz), 129.20, 124.61 (d, J C -F = 3.5 Hz), 123.60, 123.55, 122.40 (d, J C -F = 3.0 Hz), 121.66, 120.48 (q, J C -F = 256.7 Hz, CF 3 ), 117.35 (d, J C -F = 18.1 Hz), 117.29 (d, J C -F = 18.2 Hz ), 107.61, 106.85, 100.82, 100.77, 58.24, 58.02, 57.07, 54.15, 53.70, 51.06, 51.03, 44.74, 44.16, 41.28, 41.05, 36.27, 35.64, 34.32, 34.16, 29.68, 27.73, 20.06, 19.96, 18.39, 18.39 18.25.

실시예Example 46 : 46: ( ( RR )-)- NN -((1-(3--((1- (3- 플루오로Fluoro -4-(-4-( 트리플루오로메톡시Trifluoromethoxy )) 페네틸Phenethyl )) 피롤리딘Pyrrolidine -3-일)메틸)-5-아이소부틸-1-페닐-1-3-yl) methyl) -5-isobutyl-1-phenyl-1 HH -피라졸-3-카르복사미드(-Pyrazole-3-carboxamide ( 화합물번호 Compound number 4343 )의)of 제조 Produce

Figure pat00180
Figure pat00180

(S)-5-아이소부틸-1-페닐-N-(피롤리딘-3-일메틸)-1H-피라졸-3-카르복사이드 (화합물번호 57; 148 mg, 0.4 mmol)과 3-플루오로-4-(트리플루오로메톡시)페네틸 4-메틸벤젠술폰산염 (2-VII-3; 143 mg, 0.4 mmol)과 포타슘 카보네이트 (K2CO3; 263 mg, 1.9 mmol)을 이용하여 상기 표제화합물(화합물번호 43) 126 mg (수율 62%)을 얻었다.( S ) -5-isobutyl-1-phenyl- N- (pyrrolidin-3-ylmethyl) -1 H -pyrazole-3-carboxide ( Compound No. 57 ; 148 mg, 0.4 mmol) and 3 Using -fluoro-4- (trifluoromethoxy) phenethyl 4-methylbenzenesulfonate ( 2-VII-3 ; 143 mg, 0.4 mmol) and potassium carbonate (K 2 CO 3 ; 263 mg, 1.9 mmol) To give 126 mg (yield 62%) of the title compound ( Compound No. 43 ).

1H NMR (400 MHz, CDCl3) δ 7.52-7.40 (m, 6H), 7.17 (td, J = 8.0, 0.8 Hz, 1H), 6.97 (dd, J = 11.2, 2.0 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 6.77 (s, 1H), 3.49-3.41 (m, 2H), 2.82-2.65 (m, 6H), 2.60-2.49 (m, 5H), 2.08-2.02 (m, 1H), 1.88-1.82 (m, 1H), 1.63-1.58 (m, 1H), 0.88 (d, J = 6.4 Hz, 6H); 1 H NMR (400 MHz, CDCl 3 ) δ 7.52-7.40 (m, 6H), 7.17 (td, J = 8.0, 0.8 Hz, 1H), 6.97 (dd, J = 11.2, 2.0 Hz, 1H), 6.92 ( d, J = 8.4 Hz, 1H), 6.77 (s, 1H), 3.49-3.41 (m, 2H), 2.82-2.65 (m, 6H), 2.60-2.49 (m, 5H), 2.08-2.02 (m, 1H), 1.88-1.82 (m, 1H), 1.63-1.58 (m, 1H), 0.88 (d, J = 6.4 Hz, 6H);

13C NMR (100 MHz, CDCl3) δ 162.54 154.23 (d, J C -F = 250.4 Hz), 146.80, 145.07, 141.37 (d, J C -F = 6.4 Hz), 139.44, 134.58 (d, J C -F = 1.9 Hz), 134.46 (d, J C-F = 2.1 Hz), 129.22, 128.67, 125.92, 125.83, 124.66, 124.60, 124.53 (d, J C -F = 6.9 Hz), 123.41, 123.32, 120.48 (q, J C -F = 256.6 Hz, CF3), 117.25 (d, J C -F = 18.1 Hz), 115.41 (d, J C -F = 20.1 Hz), 112.89 (d, J C -F = 19.4 Hz), 106.49, 58.14, 57.38, 57.08, 53.69, 43.74, 43.63, 37.10, 35.08, 34.91, 34.62, 28.28, 22.28. 13 C NMR (100 MHz, CDCl 3 ) δ 162.54 154.23 (d, J C -F = 250.4 Hz), 146.80, 145.07, 141.37 (d, J C -F = 6.4 Hz), 139.44, 134.58 (d, J C -F = 1.9 Hz), 134.46 (d, J CF = 2.1 Hz), 129.22, 128.67, 125.92, 125.83, 124.66, 124.60, 124.53 (d, J C -F = 6.9 Hz), 123.41, 123.32, 120.48 (q , J C -F = 256.6 Hz, CF 3 ), 117.25 (d, J C -F = 18.1 Hz), 115.41 (d, J C -F = 20.1 Hz), 112.89 (d, J C -F = 19.4 Hz ), 106.49, 58.14, 57.38, 57.08, 53.69, 43.74, 43.63, 37.10, 35.08, 34.91, 34.62, 28.28, 22.28.

실시예Example 47 : 47: ( ( RR )-5-) -5- 아이소부틸Isobutyl -1-페닐--1-phenyl- NN -((1-(3-(-((1- (3- ( 트라이플루오로메틸Trifluoromethyl )) 페네Penne 틸) 피롤리딘-3-일)메틸)-1Thi) pyrrolidin-3-yl) methyl) -1 HH -피라졸-3-카르복사미드(-Pyrazole-3-carboxamide ( 화합물번호 44Compound number 44 )의 제조Manufacturing

Figure pat00181
Figure pat00181

(S)-5-아이소부틸-1-페닐-N-(피롤리딘-3-일메틸)-1H-피라졸-3-카르복사이드 (화합물번호 57; 82 mg, 0.3 mmol)과 2-(트리플루오로메틸)페네틸 4-메틸벤젠술폰산염 (2- XIV -2; 86 mg, 0.3 mmol)과 포타슘 카보네이트 (K2CO3; 105 mg, 0.8 mmol)을 이용하여 상기 표제화합물(화합물번호 44) 33 mg (수율 27%)을 얻었다.( S ) -5-isobutyl-1-phenyl-N- (pyrrolidin-3-ylmethyl) -1H-pyrazole-3-carboxide ( compound No. 57 ; 82 mg, 0.3 mmol) and 2- (Trifluoromethyl) phenethyl 4-methylbenzenesulfonate ( 2- XIV- 2 ; 86 mg, 0.3 mmol) and potassium carbonate (K 2 CO 3 ; 105 mg, 0.8 mmol) were used to give the title compound ( compound Number 44 ) to 33 mg (yield 27%).

1H NMR (300MHz, CDCl3) δ 7.58-7.24 (m, 9H), 6.75 (s, 1H), 3.46-3.43 (m, 2H), 2.97-2.94 (m, 2H), 2.78-2.46 (m, 9H), 2.18-1.99 (m, 1H), 1.88-1.78 (m, 1H), 1.63-1.55 (m, 1H), 0.87 (d, J = 6.6 Hz, 6H); 1 H NMR (300 MHz, CDCl 3 ) δ 7.58-7.24 (m, 9H), 6.75 (s, 1H), 3.46-3.43 (m, 2H), 2.97-2.94 (m, 2H), 2.78-2.46 (m, 9H), 2.18-1.99 (m, 1H), 1.88-1.78 (m, 1H), 1.63-1.55 (m, 1H), 0.87 (d, J = 6.6 Hz, 6H);

13C NMR (75MHz, CDCl3) δ 162.54, 146.82, 145.08, 139.43, 138.89, 131.72, 131.59, 129.27, 128.80, 128.69, 128.41, 126.37, 126.13, 125.97, 125.89, 125.82, 125.74, 122.74, 106.53, 58.24, 57.74, 53.68, 43.85, 37.14, 35.12, 32.10, 28.41, 28.33, 22.35. 13 C NMR (75 MHz, CDCl 3 ) δ 162.54, 146.82, 145.08, 139.43, 138.89, 131.72, 131.59, 129.27, 128.80, 128.69, 128.41, 126.37, 126.13, 125.97, 125.89, 125.82, 125.74, 122.74, 106.53. 57.74, 53.68, 43.85, 37.14, 35.12, 32.10, 28.41, 28.33, 22.35.

실시예Example 48 : 48: ( ( RR )-)- NN -((1-(3--((1- (3- 플루오로Fluoro -4-(-4-( 트리플루오로메톡시Trifluoromethoxy )) 페네틸Phenethyl )) 피롤리딘Pyrrolidine -3-일)메틸)-3-아이소프로필아이소옥사졸-5-카르복사미드(-3-yl) methyl) -3-isopropylisoxazole-5-carboxamide ( 화합물번호 45Compound number 45 )의 제조Manufacturing

Figure pat00182
Figure pat00182

(S)-3-아이소프로필-N-(피롤리딘-3-일메틸)아이소옥사졸-5-카르복사미드 (화합물번호 58; 125 mg, 0.5 mmol)과 3-플루오로-4-(트리플루오로메톡시)페네틸 4-메틸벤젠술폰산염 (2-VII-3; 50 mg, 0.1 mmol)과 포타슘 카보네이트 (K2CO3; 108 mg, 0.8 mmol)을 이용하여 상기 표제화합물(화합물번호 45) 31 mg (수율 53%)을 얻었다.( S ) -3-isopropyl- N- (pyrrolidin-3-ylmethyl) isoxazole-5-carboxamide ( Compound No. 58 ; 125 mg, 0.5 mmol) and 3-fluoro-4- ( Trifluoromethoxy) phenethyl 4-methylbenzenesulfonate ( 2-VII-3 ; 50 mg, 0.1 mmol) and potassium carbonate (K 2 CO 3 ; 108 mg, 0.8 mmol) were used to give the title compound ( Compound No. 45 ) was obtained 31 mg (yield 53%).

1H NMR (400 MHz, CDCl3) δ 7.80 (brs, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.09 (dd, J = 10.8, 1.2 Hz, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.80 (s, 1H), 3.54-3.40 (m, 2H), 3.16-3.09 (m, 1H), 3.01-2.96 (m, 1H), 2.92-2.88 (m, 2H), 2.83-2.73 (m, 3H), 2.68-2.64 (m, 1H), 2.58-2.46 (m, 2H), 2.16-2.06 (m, 1H), 1.69-1.60 (m, 1H), 1.32 (d, J = 6.8 Hz, 6H); 1 H NMR (400 MHz, CDCl 3 ) δ 7.80 (brs, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.09 (dd, J = 10.8, 1.2 Hz, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.80 (s, 1H), 3.54-3.40 (m, 2H), 3.16-3.09 (m, 1H), 3.01-2.96 (m, 1H), 2.92-2.88 (m, 2H), 2.83 -2.73 (m, 3H), 2.68-2.64 (m, 1H), 2.58-2.46 (m, 2H), 2.16-2.06 (m, 1H), 1.69-1.60 (m, 1H), 1.32 (d, J = 6.8 Hz, 6H);

13C NMR (100 MHz, CDCl3) δ 170.33, 163.22, 156.71, 154.32 (d, J C -F = 250.7 Hz), 140.96 (d, J C -F = 6.3 Hz), 134.67 (d, J C -F = 12.4 Hz), 124.64 (d, J C -F = 3.4 Hz), 123.59, 120.46 (q, J C -F = 256.9 Hz, CF3), 117.31 (d, J C -F = 18.2 Hz), 105.06, 58.24, 56.83, 53.73, 44.63, 35.85, 34.54, 27.90, 26.55, 21.63. 13 C NMR (100 MHz, CDCl 3) δ 170.33, 163.22, 156.71, 154.32 (d, J C -F = 250.7 Hz), 140.96 (d, J C -F = 6.3 Hz), 134.67 (d, J C - F = 12.4 Hz), 124.64 (d, J C -F = 3.4 Hz), 123.59, 120.46 (q, J C -F = 256.9 Hz, CF 3 ), 117.31 (d, J C -F = 18.2 Hz), 105.06, 58.24, 56.83, 53.73, 44.63, 35.85, 34.54, 27.90, 26.55, 21.63.

실시예Example 49 : 49: ( ( RR )-)- NN -((1-(3,4--((1- (3,4- 다이클로로페네틸Dichlorophenethyl )) 피롤리딘Pyrrolidine -3-일)-3 days) 메틸methyl )-5-) -5- 아이Child 부틸-1-페닐-1Butyl-1-phenyl-1 HH -피라졸-3-카르복사미드(-Pyrazole-3-carboxamide ( 화합물번호 46Compound number 46 )의 제조Manufacturing

Figure pat00183
Figure pat00183

(S)-5-아이소부틸-1-페닐-N-(피롤리딘-3-일메틸)-1H-피라졸-3-카르복사이드 (화합물번호 57; 244 mg, 0.8 mmol)과 3,4-다이클로로페네틸 4-메틸벤젠술폰산염 (2-V-3; 215 mg, 0.6 mmol)과 포타슘 카보네이트 (K2CO3; 428 mg, 3.1 mmol)을 이용하여 상기 표제화합물(화합물번호 46) 240 mg (수율 77%)을 얻었다.( S ) -5-isobutyl-1-phenyl- N- (pyrrolidin-3-ylmethyl) -1 H -pyrazole-3-carboxide ( Compound No. 57 ; 244 mg, 0.8 mmol) and 3 , 4-Dichlorophenethyl 4-methylbenzenesulfonate ( 2-V-3 ; 215 mg, 0.6 mmol) and potassium carbonate (K 2 CO 3 ; 428 mg, 3.1 mmol) to provide the title compound ( Compound No. 46 ) 240 mg (yield 77%) were obtained.

1H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 5.2 Hz, 1H), 7.47-7.36 (m, 5H), 7.25 (d, J = 8.0 Hz, 1H), 7.17 (d, J = 2.0 Hz, 1H), 6.92 (dd, J = 8.0, 1.6 Hz, 1H), 6.73 (s, 1H), 3.44-3.35 (m, 2H), 2.71-2.55 (m, 6H), 2.49-2.42 (m, 5H), 2.02-1.94 (m, 1H), 1.84-1.77 (m, 1H), 1.58-1.50 (m, 1H), 0.83 (d, J = 6.8 Hz, 6H); 1 H NMR (400 MHz, CDCl 3 ) δ 7.50 (d, J = 5.2 Hz, 1H), 7.47-7.36 (m, 5H), 7.25 (d, J = 8.0 Hz, 1H), 7.17 (d, J = 2.0 Hz, 1H), 6.92 (dd, J = 8.0, 1.6 Hz, 1H), 6.73 (s, 1H), 3.44-3.35 (m, 2H), 2.71-2.55 (m, 6H), 2.49-2.42 (m , 5H), 2.02-1.94 (m, 1H), 1.84-1.77 (m, 1H), 1.58-1.50 (m, 1H), 0.83 (d, J = 6.8 Hz, 6H);

13C NMR (100 MHz, CDCl3) δ 162.48, 146.84, 144.94, 140.73, 139.41, 131.99, 130.47, 130.09, 129.76, 129.19, 128.62, 128.09, 125.85, 106.47, 58.31, 57.20, 53.75, 43.92, 36.95, 35.05, 34.58, 28.29, 28.25, 22.28. 13 C NMR (100 MHz, CDCl 3 ) δ 162.48, 146.84, 144.94, 140.73, 139.41, 131.99, 130.47, 130.09, 129.76, 129.19, 128.62, 128.09, 125.85, 106.47, 58.31, 57.20, 53.75, 43.92, 36.95 , 34.58, 28.29, 28.25, 22.28.

실시예Example 50 : 50: ( ( RR )-)- NN -((1-(4--((1- (4- 클로로Chloro -3--3- 플루오로페네틸Fluorophenethyl )) 피롤리딘Pyrrolidine -3-일)-3 days) 메틸methyl )-5-아이소부틸-1-페닐-1) -5-isobutyl-1-phenyl-1 HH -피라졸-3-카르복사미드(-Pyrazole-3-carboxamide ( 화합물번호 47Compound number 47 )의 제조Manufacturing

Figure pat00184
Figure pat00184

(S)-5-아이소부틸-1-페닐-N-(피롤리딘-3-일메틸)-1H-피라졸-3-카르복사이드 (화합물번호 57; 298 mg, 0.9 mmol)과 4-클로로-3-플루오로페네틸 4-메틸벤젠술폰산염 (2-VI-3; 250 mg, 0.8 mmol)과 포타슘 카보네이트 (K2CO3; 525 mg, 3.8 mmol)을 이용하여 상기 표제화합물(화합물번호 47) 283 mg (수율 77%)을 얻었다.( S ) -5-isobutyl-1-phenyl- N- (pyrrolidin-3-ylmethyl) -1 H -pyrazole-3-carboxide ( Compound No. 57 ; 298 mg, 0.9 mmol) and 4 -Chloro-3-fluorophenethyl 4-methylbenzenesulfonate ( 2-VI-3 ; 250 mg, 0.8 mmol) and potassium carbonate (K 2 CO 3 ; 525 mg, 3.8 mmol) were used for the title compound ( Compound number 47 ) 283 mg (yield 77%) was obtained.

1H NMR (400 MHz, CDCl3) δ 7.49 (t, J = 5.2 Hz, 1H), 7.45-7.34 (m, 5H), 7.17 (t, J = 7.6 Hz, 1H), 6.85 (dd, J = 10.0, 1.6 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H), 6.72 (s, 1H), 3.42-3.33 (m, 2H), 2.71-2.55 (m, 6H), 2.47-2.41 (m, 5H), 2.00-1.92 (m, 1H), 1.82-1.75 (m, 1H), 1.56-1.48 (m, 1H), 0.81 (d, J = 6.4 Hz, 6H); 1 H NMR (400 MHz, CDCl 3 ) δ 7.49 (t, J = 5.2 Hz, 1H), 7.45-7.34 (m, 5H), 7.17 (t, J = 7.6 Hz, 1H), 6.85 (dd, J = 10.0, 1.6 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H), 6.72 (s, 1H), 3.42-3.33 (m, 2H), 2.71-2.55 (m, 6H), 2.47-2.41 (m , 5H), 2.00-1.92 (m, 1H), 1.82-1.75 (m, 1H), 1.56-1.48 (m, 1H), 0.81 (d, J = 6.4 Hz, 6H);

13C NMR (100 MHz, CDCl3) δ 162.47, 157.76 (d, J C -F = 246.7 Hz), 146.83, 144.93, 141.50, 141.44, 139.41, 130.12, 129.17, 128.60, 125.83, 125.04 (d, J C -F = 3.3 Hz), 118.08 (d, J C -F = 17.5 Hz), 116.63 (d, J C -F = 20.4 Hz) 106.46, 58.27, 57.14, 53.74, 43.89, 36.96, 35.03, 34.77, 28.28, 28.23, 22.25. 13 C NMR (100 MHz, CDCl 3 ) δ 162.47, 157.76 (d, J C -F = 246.7 Hz), 146.83, 144.93, 141.50, 141.44, 139.41, 130.12, 129.17, 128.60, 125.83, 125.04 (d, J C -F = 3.3 Hz), 118.08 (d, J C -F = 17.5 Hz), 116.63 (d, J C -F = 20.4 Hz) 106.46, 58.27, 57.14, 53.74, 43.89, 36.96, 35.03, 34.77, 28.28, 28.23, 22.25.

실시예Example 51 :  51: (( RR )-)- NN -((1-(2,3--((1- (2,3- 다이플루오로페네틸Difluorophenethyl )) 피롤리딘Pyrrolidine -3-일)-3 days) 메틸methyl )-5-) -5- 아Ah 이소부틸-1-페닐-1Isobutyl-1-phenyl-1 HH -피라졸-3-카르복사미드(-Pyrazole-3-carboxamide ( 화합물번호 48Compound number 48 )의 제조Manufacturing

Figure pat00185
Figure pat00185

(S)-5-아이소부틸-1-페닐-N-(피롤리딘-3-일메틸)-1H-피라졸-3-카르복사이드 (화합물번호 57; 255 mg, 0.8 mmol)과 2,3-다이플루오로페네틸 4-메틸벤젠술폰산염 (2-XV-2; 202 mg, 0.7 mmol)과 포타슘 카보네이트 (K2CO3; 447 mg, 3.2 mmol)을 이용하여 상기 표제화합물(화합물번호 48) 230 mg (수율 76%)을 얻었다.( S ) -5-isobutyl-1-phenyl- N- (pyrrolidin-3-ylmethyl) -1 H -pyrazole-3-carboxide ( Compound No. 57 ; 255 mg, 0.8 mmol) and 2 , 3-Difluorophenethyl 4-methylbenzenesulfonate ( 2-XV-2 ; 202 mg, 0.7 mmol) and potassium carbonate (K 2 CO 3 ; 447 mg, 3.2 mmol) were used to provide the title compound ( compound 48 ) 230 mg (yield 76%) were obtained.

1H NMR (400 MHz, CDCl3) δ 7.45-7.35 (m, 6H), 6.93-6.84 (m, 3H), 6.72 (s, 1H), 3.43-3.35 (m, 2H), 2.82-2.78 (m, 2H), 2.70-2.58 (m, 4H), 2.52-2.43 (m, 5H), 2.00-1.94 (m, 1H), 1.83-1.76 (m, 1H), 1.55-1.51 (m, 1H), 0.82 (d, J = 6.8 Hz, 6H); 1 H NMR (400 MHz, CDCl 3 ) δ 7.45-7.35 (m, 6H), 6.93-6.84 (m, 3H), 6.72 (s, 1H), 3.43-3.35 (m, 2H), 2.82-2.78 (m , 2H), 2.70-2.58 (m, 4H), 2.52-2.43 (m, 5H), 2.00-1.94 (m, 1H), 1.83-1.76 (m, 1H), 1.55-1.51 (m, 1H), 0.82 (d, J = 6.8 Hz, 6H);

13C NMR (100 MHz, CDCl3) δ 162.45, 150.53 (d, J C -F = 245.7 Hz), 150.40 (d, J C -F = 245.6 Hz), 148.98 (d, J C -F = 244.5 Hz), 148.86 (d, J C -F = 244.6 Hz), 146.82, 139.40, 129.77, 129.64, 129.15, 128.56, 125.83, 125.44 (d, J C -F = 3.6 Hz), 125.40 (d, J C -F = 3.5 Hz), 123.70 (d, J C -F = 6.8 Hz), 123.66 (d, J C -F = 6.9 Hz), 114.84 (d, J C -F = 16.9 Hz), 106.45, 58.20, 55.94, 53.68, 43.85, 37.04, 35.03, 28.50, 28.30, 28.23, 22.24. 13 C NMR (100 MHz, CDCl 3 ) δ 162.45, 150.53 (d, J C -F = 245.7 Hz), 150.40 (d, J C -F = 245.6 Hz), 148.98 (d, J C -F = 244.5 Hz ), 148.86 (d, J C -F = 244.6 Hz), 146.82, 139.40, 129.77, 129.64, 129.15, 128.56, 125.83, 125.44 (d, J C -F = 3.6 Hz), 125.40 (d, J C -F = 3.5 Hz), 123.70 (d, J C -F = 6.8 Hz), 123.66 (d, J C -F = 6.9 Hz), 114.84 (d, J C -F = 16.9 Hz), 106.45, 58.20, 55.94, 53.68, 43.85, 37.04, 35.03, 28.50, 28.30, 28.23, 22.24.

실시예Example 52 : 52: ( ( RR )-)- NN -((1-(3,4--((1- (3,4- 다이플루오로페네틸Difluorophenethyl )) 피롤리딘Pyrrolidine -3-일)-3 days) 메틸methyl )-5-) -5- 아Ah 이소부틸-1-페닐-1Isobutyl-1-phenyl-1 HH -피라졸-3-카르복사미드(-Pyrazole-3-carboxamide ( 화합물번호 49Compound number 49 )의 제조Manufacturing

Figure pat00186
Figure pat00186

(S)-5-아이소부틸-1-페닐-N-(피롤리딘-3-일메틸)-1H-피라졸-3-카르복사이드 (화합물번호 57; 271 mg, 0.8 mmol)과 3,4-다이플루오로페네틸 4-메틸벤젠술폰산염 (2-XVI-2; 216 mg, 0.7 mmol)과 포타슘 카보네이트 (K2CO3; 477 mg, 3.5 mmol)을 이용하여 상기 표제화합물(화합물번호 49) 240 mg (수율 75%)을 얻었다.( S ) -5-isobutyl-1-phenyl- N- (pyrrolidin-3-ylmethyl) -1 H -pyrazole-3-carboxide ( Compound No. 57 ; 271 mg, 0.8 mmol) and 3 , 4-Difluorophenethyl 4-methylbenzenesulfonate ( 2-XVI-2 ; 216 mg, 0.7 mmol) and potassium carbonate (K 2 CO 3 ; 477 mg, 3.5 mmol) to provide the title compound ( compound Number 49 ) to 240 mg (yield 75%).

1H NMR (400 MHz, CDCl3) δ 7.47-7.37 (m, 6H), 7.01-6.94 (m, 1H), 6.92-6.86 (m, 1H), 6.81-6.79 (m, 1H), 6.74 (s, 1H), 3.43-3.38 (m, 2H), 2.73-2.58 (m, 6H), 2.51-2.43 (m, 5H), 2.04-1.95 (m, 1H), 1.85-1.78 (m, 1H), 1.59-1.51 (m, 1H), 0.84 (d, J = 6.4 Hz, 6H); 1 H NMR (400 MHz, CDCl 3 ) δ 7.47-7.37 (m, 6H), 7.01-6.94 (m, 1H), 6.92-6.86 (m, 1H), 6.81-6.79 (m, 1H), 6.74 (s , 1H), 3.43-3.38 (m, 2H), 2.73-2.58 (m, 6H), 2.51-2.43 (m, 5H), 2.04-1.95 (m, 1H), 1.85-1.78 (m, 1H), 1.59 -1.51 (m, 1 H), 0.84 (d, J = 6.4 Hz, 6H);

13C NMR (100 MHz, CDCl3) δ 162.49, 150.05 (d, J C -F = 245.6 Hz), 149.92 (d, J C -F = 245.7 Hz), 148.79 (d, J C -F = 244.1 Hz), 148.66 (d, J C -F = 244.1 Hz), 146.84, 144.98, 139.42, 137.41 (d, J C -F = 4.2 Hz), 137.35 (d, J C -F = 4.0 Hz), 129.19, 128.62, 125.87, 124.39 (d, J C -F = 3.5 Hz), 124.33 (d, J C -F = 3.5 Hz), 117.23 (d, J C -F = 16.7 Hz), 116.80 (d, J C -F = 16.8 Hz), 106.47, 58.28, 57.43, 53.76, 43.88, 36.99, 35.04, 34.64, 28.29, 28.25, 22.26. 13 C NMR (100 MHz, CDCl 3 ) δ 162.49, 150.05 (d, J C -F = 245.6 Hz), 149.92 (d, J C -F = 245.7 Hz), 148.79 (d, J C -F = 244.1 Hz ), 148.66 (d, J C -F = 244.1 Hz), 146.84, 144.98, 139.42, 137.41 (d, J C -F = 4.2 Hz), 137.35 (d, J C -F = 4.0 Hz), 129.19, 128.62 , 125.87, 124.39 (d, J C -F = 3.5 Hz), 124.33 (d, J C -F = 3.5 Hz), 117.23 (d, J C -F = 16.7 Hz), 116.80 (d, J C -F = 16.8 Hz), 106.47, 58.28, 57.43, 53.76, 43.88, 36.99, 35.04, 34.64, 28.29, 28.25, 22.26.

실시예Example 53 : 53: ( ( RR )-5-) -5- 아이소부틸Isobutyl -1-페닐--1-phenyl- NN -((1-(4-(-((1- (4- ( 트리플루오로메톡시Trifluoromethoxy )-3-() -3- ( 트리플루오로메틸Trifluoromethyl )페네틸)피롤리딘-3-일)메틸)-1) Phenethyl) pyrrolidin-3-yl) methyl) -1 HH -피라졸-3-카르복사미드(-Pyrazole-3-carboxamide ( 화합물번호 50Compound number 50 )의 제조Manufacturing

Figure pat00187
Figure pat00187

(S)-5-아이소부틸-1-페닐-N-(피롤리딘-3-일메틸)-1H-피라졸-3-카르복사이드 (화합물번호 57; 183 mg, 0.6 mmol)과 4-(트리플루오로메톡시)-3-(트리플루오로메틸)페네틸 4-메틸벤젠술폰산염 (2-VIII-3; 200 mg, 0.5 mmol)과 포타슘 카보네이트 (K2CO3; 325 mg, 2.4 mmol)을 이용하여 상기 표제화합물(화합물번호 50) 185 mg (수율 68%)을 얻었다.( S ) -5-isobutyl-1-phenyl-N- (pyrrolidin-3-ylmethyl) -1H-pyrazole-3-carboxide ( Compound No. 57 ; 183 mg, 0.6 mmol) and 4- (Trifluoromethoxy) -3- (trifluoromethyl) phenethyl 4-methylbenzenesulfonate ( 2-VIII-3 ; 200 mg, 0.5 mmol) and potassium carbonate (K 2 CO 3 ; 325 mg, 2.4 mmol 185 mg (yield 68%) of the title compound ( Compound No. 50 ) were obtained.

1H NMR (400 MHz, CDCl3) δ 7.51 (t, J = 5.2 Hz, 1H), 7.47-7.37 (m, 6H), 7.33 (dd, J = 8.4, 1.6 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 6.76 (s, 1H), 3.49-3.36 (m, 2H), 2.82 (t, J = 7.6 Hz, 2H), 2.76-2.61 (m, 4H), 2.52-2.46 (m, 5H), 2.05-1.97 (m, 1H), 1.85-1.79 (m, 1H), 1.62-1.56 (m, 1H), 0.85 (d, J = 6.8 Hz, 6H); 1 H NMR (400 MHz, CDCl 3 ) δ 7.51 (t, J = 5.2 Hz, 1H), 7.47-7.37 (m, 6H), 7.33 (dd, J = 8.4, 1.6 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 6.76 (s, 1H), 3.49-3.36 (m, 2H), 2.82 (t, J = 7.6 Hz, 2H), 2.76-2.61 (m, 4H), 2.52-2.46 (m , 5H), 2.05-1.97 (m, 1H), 1.85-1.79 (m, 1H), 1.62-1.56 (m, 1H), 0.85 (d, J = 6.8 Hz, 6H);

13C NMR (100 MHz, CDCl3) δ 162.53, 146.83, 145.03, 144.71, 139.46, 139.41, 133.46, 129.18, 128.63, 127.47 (q, J C -F = 4.7 Hz), 125.87, 122.71 (q, J C-F = 31.5 Hz), 122.49 (q, J C -F = 271.3 Hz, OCF3), 120.89, 120.88, 120.26 (q, J C -F = 257.5 Hz, CF3), 106.47, 58.28, 57.10, 53.71, 43.91, 36.99, 35.03, 34.62, 28.29, 28.26, 22.23. 13 C NMR (100 MHz, CDCl 3 ) δ 162.53, 146.83, 145.03, 144.71, 139.46, 139.41, 133.46, 129.18, 128.63, 127.47 (q, J C -F = 4.7 Hz), 125.87, 122.71 (q, J CF = 31.5 Hz), 122.49 (q, J C -F = 271.3 Hz, OCF 3 ), 120.89, 120.88, 120.26 (q, J C -F = 257.5 Hz, CF 3 ), 106.47, 58.28, 57.10, 53.71, 43.91 , 36.99, 35.03, 34.62, 28.29, 28.26, 22.23.

실시예Example 54 : 54: ( ( RR )-)- NN -((1-(3,5--((1- (3,5- 다이플루오로페네틸Difluorophenethyl )) 피롤리딘Pyrrolidine -3-일)-3 days) 메틸methyl )-5-) -5- 아Ah 이소부틸-1-페닐-1Isobutyl-1-phenyl-1 HH -피라졸-3-카르복사미드(-Pyrazole-3-carboxamide ( 화합물번호 51Compound number 51 )의 제조Manufacturing

Figure pat00188
Figure pat00188

(S)-5-아이소부틸-1-페닐-N-(피롤리딘-3-일메틸)-1H-피라졸-3-카르복사이드 (화합물번호 57; 226 mg, 0.7 mmol)과 3,5-다이플루오로페네틸 4-메틸벤젠술폰산염 (2-IX-3; 180 mg, 0.6 mmol)과 포타슘 카보네이트 (K2CO3; 401 mg, 2.9 mmol)을 이용하여 상기 표제화합물(화합물번호 51) 189 mg (수율 70%)을 얻었다.( S ) -5-isobutyl-1-phenyl-N- (pyrrolidin-3-ylmethyl) -1H-pyrazole-3-carboxyside ( Compound No. 57 ; 226 mg, 0.7 mmol) and 3, 5-Tifluorophenethyl 4-methylbenzenesulfonate ( 2-IX-3 ; 180 mg, 0.6 mmol) and potassium carbonate (K 2 CO 3 ; 401 mg, 2.9 mmol) were used for the title compound ( Compound No. 51 ) 189 mg (70% yield) were obtained.

1H NMR (400 MHz, CDCl3) δ 7.51-7.39 (m, 6H), 6.76 (s, 1H), 6.66-6.59 (m, 3H), 3.48-3.39 (m, 2H), 2.78-2.62 (m, 6H), 2.55-2.46 (m, 5H), 2.06-1.99 (m, 1H), 1.87-1.81 (m, 1H), 1.61-1.56 (m, 1H), 0.86 (d, J = 6.4 Hz, 6H); 1 H NMR (400 MHz, CDCl 3 ) δ 7.51-7.39 (m, 6H), 6.76 (s, 1H), 6.66-6.59 (m, 3H), 3.48-3.39 (m, 2H), 2.78-2.62 (m , 6H), 2.55-2.46 (m, 5H), 2.06-1.99 (m, 1H), 1.87-1.81 (m, 1H), 1.61-1.56 (m, 1H), 0.86 (d, J = 6.4 Hz, 6H );

13C NMR (100 MHz, CDCl3) δ 164.17, 162.94 (d, J C -F = 245.9 Hz), 162.81 (d, J C -F = 246.2 Hz), 146.83, 145.03, 144.29 (d, J C -F = 18.0Hz), 144.29, 139.43, 129.23, 128.68, 125.91, 111.42 (d, J C -F = 6.4 Hz), 111.24 (d, J C -F = 6.2 Hz), 106.49, 101.51 (d, J C -F = 25.3 Hz), 101.25 (d, J C -F = 25.1 Hz), 58.30, 56.98, 53.75, 43.88, 37.00, 35.20, 35.07, 28.32, 28.28, 22.30. 13 C NMR (100 MHz, CDCl 3) δ 164.17, 162.94 (d, J C -F = 245.9 Hz), 162.81 (d, J C -F = 246.2 Hz), 146.83, 145.03, 144.29 (d, J C - F = 18.0 Hz), 144.29, 139.43, 129.23, 128.68, 125.91, 111.42 (d, J C -F = 6.4 Hz), 111.24 (d, J C -F = 6.2 Hz), 106.49, 101.51 (d, J C -F = 25.3 Hz), 101.25 (d, J C -F = 25.1 Hz), 58.30, 56.98, 53.75, 43.88, 37.00, 35.20, 35.07, 28.32, 28.28, 22.30.

실시예Example 55 : 55: ( ( RR )-)- NN -((1-(3--((1- (3- 클로로Chloro -5--5- 플루오로페네틸Fluorophenethyl )) 피롤리딘Pyrrolidine -3-일)-3 days) 메틸methyl )-5-아이소부틸-1-페닐-1) -5-isobutyl-1-phenyl-1 HH -피라졸-3-카르복사미드(-Pyrazole-3-carboxamide ( 화합물번호 52Compound number 52 )의 제조Manufacturing

Figure pat00189
Figure pat00189

(S)-5-아이소부틸-1-페닐-N-(피롤리딘-3-일메틸)-1H-피라졸-3-카르복사이드 (화합물번호 57; 215 mg, 0.7 mmol)과 3-클로로-5-플루오로페네틸 4-메틸벤젠술폰산염 (2-X-3; 180 mg, 0.6 mmol)과 포타슘 카보네이트 (K2CO3; 380 mg, 2.8 mmol)을 이용하여 상기 표제화합물(화합물번호 52) 188 mg (수율 71%)을 얻었다.( S ) -5-isobutyl-1-phenyl-N- (pyrrolidin-3-ylmethyl) -1H-pyrazole-3-carboxide ( compound No. 57 ; 215 mg, 0.7 mmol) and 3- Chloro-5-fluorophenethyl 4-methylbenzenesulfonate ( 2-X-3 ; 180 mg, 0.6 mmol) and potassium carbonate (K 2 CO 3 ; 380 mg, 2.8 mmol) were used to obtain the title compound ( compound 52 ) 188 mg (71% yield) were obtained.

1H NMR (400 MHz, CDCl3) δ 7.49-7.39 (m, 6H), 6.89 (dd, J = 7.6, 1.6 Hz, 2H), 6.76 (s, 1H), 6.73 (d, J = 9.2 Hz, 1H), 3.49-3.37 (m, 2H), 2.76-2.60 (m, 6H), 2.51-2.47 (m, 5H), 2.07-1.99 (m, 1H), 1.87-1.80 (m, 1H), 1.62-1.56 (m, 1H), 0.86 (d, J = 6.8 Hz, 6H); 1 H NMR (400 MHz, CDCl 3 ) δ 7.49-7.39 (m, 6H), 6.89 (dd, J = 7.6, 1.6 Hz, 2H), 6.76 (s, 1H), 6.73 (d, J = 9.2 Hz, 1H), 3.49-3.37 (m, 2H), 2.76-2.60 (m, 6H), 2.51-2.47 (m, 5H), 2.07-1.99 (m, 1H), 1.87-1.80 (m, 1H), 1.62- 1.56 (m, 1 H), 0.86 (d, J = 6.8 Hz, 6H);

13C NMR (100 MHz, CDCl3) δ 162.56 (d, J C -F = 247.2 Hz), 162.51, 146.88, 144.99, 144.21 (d, J C -F = 8.2 Hz), 139.45, 134.53 (d, J C -F = 10.8 Hz), 129.21, 128.66, 125.90, 124.62 (d, J C -F = 2.8 Hz), 113.99 (d, J C -F = 21.2 Hz), 113.76 (d, J C -F = 25.3 Hz), 106.48, 58.38, 57.00, 53.76, 43.96, 36.96, 35.08, 28.34, 28.28, 22.29. 13 C NMR (100 MHz, CDCl 3 ) δ 162.56 (d, J C -F = 247.2 Hz), 162.51, 146.88, 144.99, 144.21 (d, J C -F = 8.2 Hz), 139.45, 134.53 (d, J C -F = 10.8 Hz), 129.21, 128.66, 125.90, 124.62 (d, J C -F = 2.8 Hz), 113.99 (d, J C -F = 21.2 Hz), 113.76 (d, J C -F = 25.3 Hz), 106.48, 58.38, 57.00, 53.76, 43.96, 36.96, 35.08, 28.34, 28.28, 22.29.

실시예Example 56 : 56: ( ( RR )-)- NN -((1-(3--((1- (3- 플루오로페네틸Fluorophenethyl )) 피롤리딘Pyrrolidine -3-일)-3 days) 메틸methyl )-5-) -5- 아이소부Isobu 틸-1-페닐-1Thil-1-phenyl-1 HH -피라졸-3-카르복사미드(-Pyrazole-3-carboxamide ( 화합물번호 53Compound number 53 )의 제조Manufacturing

Figure pat00190
Figure pat00190

(S)-5-아이소부틸-1-페닐-N-(피롤리딘-3-일메틸)-1H-피라졸-3-카르복사이드 (화합물번호 57; 266 mg, 0.8 mmol)과 3-플루오로페네틸 4-메틸벤젠술폰산염 (2-XI-3; 200 mg, 0.7 mmol)과 포타슘 카보네이트 (K2CO3; 470 mg, 3.4 mmol)을 이용하여 상기 표제화합물(화합물번호 53) 214 mg (수율 70%)을 얻었다.( S ) -5-isobutyl-1-phenyl-N- (pyrrolidin-3-ylmethyl) -1H-pyrazole-3-carboxide ( compound No. 57 ; 266 mg, 0.8 mmol) and 3- The title compound ( Compound No. 53 ) using fluorophenethyl 4-methylbenzenesulfonate ( 2-XI-3 ; 200 mg, 0.7 mmol) and potassium carbonate (K 2 CO 3 ; 470 mg, 3.4 mmol) 214 mg (yield 70%) were obtained.

1H NMR (400 MHz, CDCl3) δ 7.49-7.38 (m, 6H), 7.20-7.15 (m, 1H), 6.90-6.80 (m, 3H), 6.76 (s, 1H), 3.46-3.38 (m, 2H), 2.79-2.61 (m, 6H), 2.54-2.44 (m, 5H), 2.04-1.98 (m, 1H), 1.86-1.79 (m, 1H), 1.61-1.54 (m, 1H), 0.85 (d, J = 6.4 Hz, 6H); 1 H NMR (400 MHz, CDCl 3 ) δ 7.49-7.38 (m, 6H), 7.20-7.15 (m, 1H), 6.90-6.80 (m, 3H), 6.76 (s, 1H), 3.46-3.38 (m , 2H), 2.79-2.61 (m, 6H), 2.54-2.44 (m, 5H), 2.04-1.98 (m, 1H), 1.86-1.79 (m, 1H), 1.61-1.54 (m, 1H), 0.85 (d, J = 6.4 Hz, 6H);

13C NMR (100 MHz, CDCl3) δ 162.78 (d, J C -F = 243.7 Hz), 162.50, 146.86, 144.97, 142.97 (d, J C -F = 7.2 Hz), 139.43, 129.63 (d, J C -F = 8.2 Hz), 129.21, 128.63, 125.88, 124.23 (d, J C -F = 2.7 Hz), 115.39 (d, J C -F = 20.8 Hz), 112.76 (d, J C -F = 20.9 Hz), 106.50, 58.34, 57.49, 53.82, 43.92, 37.01, 35.28, 35.07, 28.34, 28.26, 22.29. 13 C NMR (100 MHz, CDCl 3 ) δ 162.78 (d, J C -F = 243.7 Hz), 162.50, 146.86, 144.97, 142.97 (d, J C -F = 7.2 Hz), 139.43, 129.63 (d, J C -F = 8.2 Hz), 129.21, 128.63, 125.88, 124.23 (d, J C -F = 2.7 Hz), 115.39 (d, J C -F = 20.8 Hz), 112.76 (d, J C -F = 20.9 Hz), 106.50, 58.34, 57.49, 53.82, 43.92, 37.01, 35.28, 35.07, 28.34, 28.26, 22.29.

실시예Example 57 : 57: ( ( RR )-)- NN -((1-(3--((1- (3- 클로로Chloro -5--5- 플루오로페네틸Fluorophenethyl )) 피롤리딘Pyrrolidine -3-일)-3 days) 메틸methyl )-5-메틸-1-페닐-1) -5-methyl-1-phenyl-1 HH -피라졸-3-카르복사미드(-Pyrazole-3-carboxamide ( 화합물번호 54Compound number 54 )의 제조Manufacturing

Figure pat00191
Figure pat00191

(S)-5-메틸-1-페닐-N-(피롤리딘-3-일메틸)-1H-피라졸-3-카르복사미드 (4-IX-2; 726 mg, 2.6 mmol)과 3-클로로-5-플루오로페네틸 4-메틸벤젠술폰산염 (2-XI-3; 168 mg, 0.5 mmol)과 포타슘 카보네이트 (K2CO3; 423 mg, 3.1 mmol)을 이용하여 상기 표제화합물(화합물번호 54) 157 mg (수율 70%)을 얻었다.( S ) -5-methyl-1-phenyl- N- (pyrrolidin-3-ylmethyl) -1 H -pyrazole-3-carboxamide ( 4-IX-2 ; 726 mg, 2.6 mmol) The title compound was prepared using 3-chloro-5-fluorophenethyl 4-methylbenzenesulfonate ( 2-XI-3 ; 168 mg, 0.5 mmol) and potassium carbonate (K 2 CO 3 ; 423 mg, 3.1 mmol). ( Compound No. 54 ) 157 mg (yield 70%) were obtained.

1H NMR (400 MHz, CDCl3) δ 7.49-7.41 (m, 6H), 6.89 (d, J = 12.4 Hz, 2H), 6.73 (s, 2H), 6.73 (d, J = 9.2 Hz, 1H), 3.49-3.38 (m, 2H), 2.77-2.63 (m, 6H), 2.56-2.49 (m, 3H), 2.32 (s, 3H), 2.03 (brs, 1H), 1.59 (brs, 1H); 1 H NMR (400 MHz, CDCl 3 ) δ 7.49-7.41 (m, 6H), 6.89 (d, J = 12.4 Hz, 2H), 6.73 (s, 2H), 6.73 (d, J = 9.2 Hz, 1H) , 3.49-3.38 (m, 2H), 2.77-2.63 (m, 6H), 2.56-2.49 (m, 3H), 2.32 (s, 3H), 2.03 (brs, 1H), 1.59 (brs, 1H);

13C NMR (100 MHz, CDCl3) δ 162.56 (d, J C -F = 247.3 Hz), 162.45, 146.85, 144.03 (d, J C -F = 8.2 Hz), 140.77, 139.27, 134.56 (d, J C -F = 10.8 Hz), 129.22, 128.43, 125.12, 124.62 (d, J C -F = 2.9 Hz), 114.01 (d, J C -F = 20.7 Hz), 113.81 (d, J C -F = 24.4 Hz), 107.29, 58.27, 56.97, 53.77, 43.81, 36.98, 34.96, 28.27, 12.39. 13 C NMR (100 MHz, CDCl 3 ) δ 162.56 (d, J C -F = 247.3 Hz), 162.45, 146.85, 144.03 (d, J C -F = 8.2 Hz), 140.77, 139.27, 134.56 (d, J C -F = 10.8 Hz), 129.22, 128.43, 125.12, 124.62 (d, J C -F = 2.9 Hz), 114.01 (d, J C -F = 20.7 Hz), 113.81 (d, J C -F = 24.4 Hz), 107.29, 58.27, 56.97, 53.77, 43.81, 36.98, 34.96, 28.27, 12.39.

실시예Example 58 : 58: NN -((4-(하이드록시메틸)-1-(4-메틸-3-(트리플루오로메틸)페네틸)피페리딘-4-일)메틸)-5-아이소부틸-1-페닐-1-((4- (hydroxymethyl) -1- (4-methyl-3- (trifluoromethyl) phenethyl) piperidin-4-yl) methyl) -5-isobutyl-1-phenyl-1 HH -피라졸-3-카르복사미드(-Pyrazole-3-carboxamide ( 화합물번호 55Compound number 55 )의 제조Manufacturing

Figure pat00192
Figure pat00192

N-((4-(하이드록시메틸)피페리딘-4-일)메틸)-5-아이소부틸-1-페닐-1H-피라졸-3-카르복사미드 (4-XII-2; 233 mg, 0.6 mmol)과 4-메틸-3-(트리플루오로메틸)페네틸 4-메틸벤젠술폰산염 (2-I-3; 271 mg, 0.8 mmol)과 포타슘 카보네이트 (K2CO3; 429 mg, 3.1 mmol)을 이용하여 상기 표제화합물(화합물번호 55) 218 mg (수율 62%)을 얻었다. N -((4- (hydroxymethyl) piperidin-4-yl) methyl) -5-isobutyl-1-phenyl-1 H -pyrazole-3-carboxamide ( 4-XII-2 ; 233 mg, 0.6 mmol) and 4-methyl-3- (trifluoromethyl) phenethyl 4-methylbenzenesulfonate ( 2-I-3 ; 271 mg, 0.8 mmol) and potassium carbonate (K 2 CO 3 ; 429 mg , 3.1 mmol) was used to obtain 218 mg (yield 62%) of the title compound ( Compound No. 55 ).

1H NMR (400 MHz, CDCl3) δ 7.52-7.36 (m, 7H), 7.23 (d, J = 7.6 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 6.76 (s, 1H), 3.38 (s, 2H), 3.35 (d, J = 6.8 Hz, 2H), 2.81-2.77 (m, 2H), 2.58-2.42 (m, 11H), 1.86-1.78 (m, 1H), 1.64-1.48 (m, 4H), 0.86 (d, J = 6.8 Hz, 6H); 1 H NMR (400 MHz, CDCl 3 ) δ 7.52-7.36 (m, 7H), 7.23 (d, J = 7.6 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 6.76 (s, 1H) , 3.38 (s, 2H), 3.35 (d, J = 6.8 Hz, 2H), 2.81-2.77 (m, 2H), 2.58-2.42 (m, 11H), 1.86-1.78 (m, 1H), 1.64-1.48 (m, 4H), 0.86 (d, J = 6.8 Hz, 6H);

13C NMR (100 MHz, CDCl3) δ 164.00, 145.94, 145.38, 139.22, 138.10, 134.10, 134.08, 131.92, 131.83, 129.31, 128.90, 128.70 (q, J C -F = 29.4 Hz), 125.98, 125.87 (q, J C -F = 5.3 Hz), 124.59 (q, J C -F = 272.0 Hz, CF3), 106.69, 64.84, 60.45, 49.27, 43.90, 37.63, 35.02, 33.05, 30.51, 28.26, 22.27, 18.84, 18.82. 13 C NMR (100 MHz, CDCl 3 ) δ 164.00, 145.94, 145.38, 139.22, 138.10, 134.10, 134.08, 131.92, 131.83, 129.31, 128.90, 128.70 (q, J C -F = 29.4 Hz), 125.98, 125.87 ( q, J C -F = 5.3 Hz), 124.59 (q, J C -F = 272.0 Hz, CF 3 ), 106.69, 64.84, 60.45, 49.27, 43.90, 37.63, 35.02, 33.05, 30.51, 28.26, 22.27, 18.84 , 18.82.

실시예Example 59 : 59: NN -((3-(하이드록시메틸)-1-(4-메틸-3-(트리플루오로메틸)페네틸)피롤리딘-3-일)메틸)-5-아이소부틸-1-페닐-1-((3- (hydroxymethyl) -1- (4-methyl-3- (trifluoromethyl) phenethyl) pyrrolidin-3-yl) methyl) -5-isobutyl-1-phenyl-1 HH -피라졸-3-카르복사미드(-Pyrazole-3-carboxamide ( 화합물번호 56Compound number 56 )의 제조Manufacturing

Figure pat00193
Figure pat00193

N-((3-(하이드록시메틸)피롤리딘-3-일)메틸)-5-아이소부틸-1-페닐-1H-피라졸-3-카르복사미드 (4-XI-2; 67 mg, 0.2 mmol)과 4-메틸-3-(트리플루오로메틸)페네틸 4-메틸벤젠술폰산염 (2-I-3; 81 mg, 0.2 mmol)과 포타슘 카보네이트 (K2CO3; 131 mg, 1.0 mmol)을 이용하여 상기 표제화합물(화합물번호 56) 64 mg (수율 62%)을 얻었다. N -((3- (hydroxymethyl) pyrrolidin-3-yl) methyl) -5-isobutyl-1-phenyl-1 H -pyrazole-3-carboxamide ( 4-XI-2 ; 67 mg, 0.2 mmol) and 4-methyl-3- (trifluoromethyl) phenethyl 4-methylbenzenesulfonate ( 2-I-3 ; 81 mg, 0.2 mmol) and potassium carbonate (K 2 CO 3 ; 131 mg , 1.0 mmol) gave 64 mg (yield 62%) of the title compound ( Compound No. 56 ).

1H NMR (400 MHz, CDCl3) δ 7.54-7.40 (m, 7H), 7.23-7.17 (m, 2H), 6.77 (s, 1H), 3.55-3.50 (m, 1H), 3.46-3.41 (m, 3H), 2.81-2.77 (m, 2H), 2.72-2.57 (m, 4H), 2.52 (d, J = 7.2 Hz, 2H), 2.49 (s, 2H), 2.44 (s, 3H), 1.88-1.82 (m, 1H), 1.73-1.60 (m, 2H), 0.88 (d, J = 6.8 Hz, 6H); 1 H NMR (400 MHz, CDCl 3 ) δ 7.54-7.40 (m, 7H), 7.23-7.17 (m, 2H), 6.77 (s, 1H), 3.55-3.50 (m, 1H), 3.46-3.41 (m , 3H), 2.81-2.77 (m, 2H), 2.72-2.57 (m, 4H), 2.52 (d, J = 7.2 Hz, 2H), 2.49 (s, 2H), 2.44 (s, 3H), 1.88- 1.82 (m, 1 H), 1.73-1.60 (m, 2 H), 0.88 (d, J = 6.8 Hz, 6H);

13C NMR(100MHz, CDCl3) δ 163.96, 145.97, 145.37, 139.28, 138.18, 138.06, 134.10, 134.09, 131.86, 131.77, 131.06, 130.77, 129.30, 128.87, 128.69 (q, J C -F = 29.4 Hz), 125.85 (q, J C -F = 5.6 Hz), 124.61(q, J C -F = 272.0 Hz, CF3), 106.69, 66.48, 61.24, 57.67, 57.53, 53.61, 48.19, 44.38, 35.06, 34.76, 31.78, 28.28, 22.28, 18.85. 13 C NMR (100 MHz, CDCl 3 ) δ 163.96, 145.97, 145.37, 139.28, 138.18, 138.06, 134.10, 134.09, 131.86, 131.77, 131.06, 130.77, 129.30, 128.87, 128.69 (q, J C -F = 29.4 Hz) , 125.85 (q, J C -F = 5.6 Hz), 124.61 (q, J C -F = 272.0 Hz, CF 3 ), 106.69, 66.48, 61.24, 57.67, 57.53, 53.61, 48.19, 44.38, 35.06, 34.76, 31.78, 28.28, 22.28, 18.85.

실시예Example 60 : 60: ( ( RR )-)- NN -((1-(3--((1- (3- 클로로Chloro -5--5- 플루오로페네틸Fluorophenethyl )) 피롤리딘Pyrrolidine -3-일)-3 days) 메틸methyl )-3-아이소프로필아이소옥사졸-5-카르복사미드() -3-isopropylisoxazole-5-carboxamide ( 화합물번호 60Compound number 60 )의 제조Manufacturing

Figure pat00194
Figure pat00194

(S)-3-아이소프로필-N-(피롤리딘-3-일메틸)아이소옥사졸-5-카르복사미드 (화합물번호 58; 866 mg, 3.7 mmol)과 3-클로로-5-트리플루오로페네틸 4-메틸벤젠술폰산염 (2-X-3; 300 mg, 0.9 mmol)과 포타슘 카보네이트 (K2CO3; 629 mg, 4.6 mmol)을 이용하여 상기 표제화합물(화합물번호 60) 125 mg (수율 35%)을 얻었다.( S ) -3-isopropyl- N- (pyrrolidin-3-ylmethyl) isoxazole-5-carboxamide ( Compound No. 58 ; 866 mg, 3.7 mmol) and 3-chloro-5-trifluoro 125 mg of the title compound ( Compound No. 60 ) using lofenethyl 4-methylbenzenesulfonate ( 2-X-3 ; 300 mg, 0.9 mmol) and potassium carbonate (K 2 CO 3 ; 629 mg, 4.6 mmol) (Yield 35%) was obtained.

1H NMR (400 MHz, CDCl3) δ 7.80 (brs, 1H), 7.04 (s, 1H), 6.93 (dt, J = 8.4, 2.0 Hz, 1H), 6.87 (d, J = 9.2 Hz, 1H), 6.80 (s, 1H), 3.54-3.39 (m, 2H), 3.17-3.10 (m, 1H), 2.96-2.84 (m, 3H), 2.74-2.65 (m, 3H), 2.61-2.53 (m, 2H), 2.41 (dd, J = 16.4, 8.8 Hz, 1H), 2.15-2.09 (m, 1H), 1.66-1.59 (m, 1H), 1.33 (d, J = 6.8 Hz, 6H); 1 H NMR (400 MHz, CDCl 3 ) δ 7.80 (brs, 1H), 7.04 (s, 1H), 6.93 (dt, J = 8.4, 2.0 Hz, 1H), 6.87 (d, J = 9.2 Hz, 1H) , 6.80 (s, 1H), 3.54-3.39 (m, 2H), 3.17-3.10 (m, 1H), 2.96-2.84 (m, 3H), 2.74-2.65 (m, 3H), 2.61-2.53 (m, 2H), 2.41 (dd, J = 16.4, 8.8 Hz, 1H), 2.15-2.09 (m, 1H), 1.66-1.59 (m, 1H), 1.33 (d, J = 6.8 Hz, 6H);

13C NMR (100 MHz, CDCl3) δ 170.30, 163.35, 162.67 (d, J C -F = 247.4 Hz), 156.65, 144.05 (d, J C -F = 8.2 Hz), 134.69 (d, J C -F = 10.9 Hz), 124.69 (d, J C -F = 3.0 Hz), 114.06 (d, J C -F = 20.9 Hz), 113.93 (d, J C -F = 24.7 Hz), 104.99, 58.48, 56.74, 53.73, 44.99, 35.75, 35.16 (d, J C -F = 1.3 Hz), 28.03, 26.57, 21.63. 13 C NMR (100 MHz, CDCl 3) δ 170.30, 163.35, 162.67 (d, J C -F = 247.4 Hz), 156.65, 144.05 (d, J C -F = 8.2 Hz), 134.69 (d, J C - F = 10.9 Hz), 124.69 (d, J C -F = 3.0 Hz), 114.06 (d, J C -F = 20.9 Hz), 113.93 (d, J C -F = 24.7 Hz), 104.99, 58.48, 56.74 , 53.73, 44.99, 35.75, 35.16 (d, J C -F = 1.3 Hz), 28.03, 26.57, 21.63.

실시예Example 61 : 61: ( ( RR )-)- NN -((1-(2-(3--((1- (2- (3- 클로로Chloro -5--5- 플루오로페닐Fluorophenyl )아세틸)Acetyl) 피롤리딘Pyrrolidine -3-일)메틸)-5-아이소부틸-1-페닐-1-3-yl) methyl) -5-isobutyl-1-phenyl-1 HH -피라졸-3-카르복사미드(-Pyrazole-3-carboxamide ( 화합물번호 61Compound number 61 )의 제조Manufacturing

Figure pat00195
Figure pat00195

(S)-5-아이소부틸-1-페닐-N-(피롤리딘-3-일메틸)-1H-피라졸-3-카르복사이드 (화합물번호 57; 154 mg, 0.5 mmol)과 2-(3-클로로-5-플루오로페닐)아세트산 (2-XXII-1; 89 mg, 0.5 mmol)과 1,1'-카보닐 다이이미다졸(CDI; 88 mg, 0.5 mmol)을 이용하여 상기 표제화합물(화합물번호 61) 154 mg (수율 66%)을 얻었다.( S ) -5-isobutyl-1-phenyl- N- (pyrrolidin-3-ylmethyl) -1 H -pyrazole-3-carboxide ( Compound No. 57 ; 154 mg, 0.5 mmol) and 2 -(3-chloro-5-fluorophenyl) acetic acid ( 2-XXII-1 ; 89 mg, 0.5 mmol) and 1,1'-carbonyl diimidazole (CDI; 88 mg, 0.5 mmol) 154 mg (yield 66%) of the title compound ( Compound No. 61 ) were obtained.

1H NMR (400 MHz, CDCl3) δ 7.50-7.41 (m, 3H), 7.38-7.35 (m, 2H), 7.19 (dt, J = 19.6, 6.4 Hz, 1H), 7.02 (s, 1H), 6.94-6.86 (m, 2H), 6.72 (d, J = 8.8 Hz, 1H), 3.68-3.18 (m, 8H), 2.55-2.44 (m, 3H), 2.08-1.95 (m, 1H), 1.84-1.75 (m, 1.5H), 1.66-1.60 (m, 0.5H), 0.84 (dd, J = 6.8, 2.8 Hz, 6H); 1 H NMR (400 MHz, CDCl 3 ) δ 7.50-7.41 (m, 3H), 7.38-7.35 (m, 2H), 7.19 (dt, J = 19.6, 6.4 Hz, 1H), 7.02 (s, 1H), 6.94-6.86 (m, 2H), 6.72 (d, J = 8.8 Hz, 1H), 3.68-3.18 (m, 8H), 2.55-2.44 (m, 3H), 2.08-1.95 (m, 1H), 1.84- 1.75 (m, 1.5H), 1.66-1.60 (m, 0.5H), 0.84 (dd, J = 6.8, 2.8 Hz, 6H);

13C NMR (100 MHz, CDCl3) δ 168.10, 168.08, 162.56 (d, J C -F = 247.8 Hz), 162.53 (d, J C -F = 247.7 Hz), 162.53, 162.45, 146.40, 146.38, 145.26, 145.15, 139.29, 138.52 (d, J C -F = 8.3 Hz), 138.44 (d, J C -F = 8.2 Hz), 134.82 (d, J C -F = 10.8 Hz), 134.75 (d, J C -F = 10.7 Hz), 129.28, 129.24, 128.82, 128.74, 125.89, 125.87, 125.33 (d, J C -F = 3.0 Hz), 125.25 (d, J C -F = 2.9 Hz), 114.86 (d, J C -F = 22.0 Hz), 114.77 (d, J C -F = 21.4 Hz), 114.59 (d, J C -F = 19.0 Hz), 114.55 (d, J C -F = 21.7 Hz), 106.50, 106.46, 50.30, 49.42, 46.15, 45.33, 40.96 (d, J C -F = 3.0 Hz), 40.93 (d, J C-F = 3.0 Hz), 40.07, 37.82, 35.02, 29.55, 28.25, 27.96, 22.26. 13 C NMR (100 MHz, CDCl 3 ) δ 168.10, 168.08, 162.56 (d, J C -F = 247.8 Hz), 162.53 (d, J C -F = 247.7 Hz), 162.53, 162.45, 146.40, 146.38, 145.26 , 145.15, 139.29, 138.52 (d, J C -F = 8.3 Hz), 138.44 (d, J C -F = 8.2 Hz), 134.82 (d, J C -F = 10.8 Hz), 134.75 (d, J C -F = 10.7 Hz), 129.28, 129.24, 128.82, 128.74, 125.89, 125.87, 125.33 (d, J C -F = 3.0 Hz), 125.25 (d, J C -F = 2.9 Hz), 114.86 (d, J C -F = 22.0 Hz), 114.77 (d, J C -F = 21.4 Hz), 114.59 (d, J C -F = 19.0 Hz), 114.55 (d, J C -F = 21.7 Hz), 106.50, 106.46 , 50.30, 49.42, 46.15, 45.33, 40.96 (d, J C -F = 3.0 Hz), 40.93 (d, J CF = 3.0 Hz), 40.07, 37.82, 35.02, 29.55, 28.25, 27.96, 22.26.

[제제예][Example]

한편, 본 발명에 따라 상기 화학식 1로 표시되는 신규 화합물은 목적에 따라 여러 형태로 제제화가 가능하다. 다음은 본 발명에 따른 하기 화학식 1로 표시되는 화합물을 활성성분으로 함유시킨 몇몇 제제화 방법을 예시한 것으로 본 발명이 이에 한정되는 것은 아니다.Meanwhile, according to the present invention, the novel compound represented by Chemical Formula 1 may be formulated in various forms according to the purpose. The following illustrates some formulation methods in which the compound represented by Formula 1 according to the present invention is contained as an active ingredient, but the present invention is not limited thereto.

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

활성성분 5.0 ㎎을 체로 친 후, 락토스 14.1 ㎎, 크로스포비돈 USNF 0.8 ㎎ 및 마그네슘 스테아레이트 0.1 ㎎을 혼합하고 가압하여 정제로 만들었다.After sifting 5.0 mg of the active ingredient, 14.1 mg of lactose, 0.8 mg of crospovidone USNF and 0.1 mg of magnesium stearate were mixed and pressed to form a tablet.

* 제제 2 : 정제(습식 조립)Formulation 2: tablet (wet granulation)

활성성분 5.0 ㎎을 체로 친 후, 락토스 16.0 ㎎과 녹말 4.0 ㎎을 섞었다. 폴리솔베이트 80 0.3 ㎎을 순수한 물에 녹인 후 이 용액의 적당량을 첨가한 다음, 미립화하였다. 건조 후에 미립을 체질한 후 콜로이달 실리콘 다이옥사이드 2.7 ㎎ 및 마그네슘 스테아레이트 2.0 ㎎과 섞었다. 미립을 가압하여 정제로 만들었다.After 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 and 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 to tablets.

* 제제 3 : 분말과 캡슐제Formulation 3: Powders and Capsules

활성성분 5.0 ㎎을 체로 친 후에, 락토스 14.8 ㎎, 폴리비닐 피롤리돈 10.0 ㎎, 마그네슘 스테아레이트 0.2 ㎎와 함께 섞었다. 혼합물을 적당한 장치를 사용하여 단단한 No. 5 젤라틴 캡슐에 채웠다. After sieving 5.0 mg of the 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.

* 제제 4 : 주사제Formulation 4: Injection

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

[실험예]Experimental Example

한편, 본 발명에 따라 상기 화학식 1로 표시되는 신규 화합물에 대하여, 하기 실험예에 나타낸 바와 같은 방법으로 T-형 칼슘채널에 대한 길항작용을 테스트를 하였다. On the other hand, with respect to the novel compound represented by the formula (1) according to the present invention, the antagonism of the T-type calcium channel was tested by the method as shown in the following experimental example.

상기한 실시에에 따라 합성된 화합물을 다음 실험예의 방법으로 FDSS6000를 이용하여 T-형 칼슘채널에 대한 % 억제율을 구하였다.Compounds synthesized according to the above-described examples were obtained using the FDSS6000 as a method of the following experimental example to determine the percent inhibition of the T-type calcium channel.

실험예Experimental Example 1 :  One : FDSS6000을FDSS6000 이용한 T-형 칼슘채널 활성 테스트 T-type calcium channel activity test using

활성 테스트 12 내지 24 시간 전에 폴리-L-라이신 (0.05 ㎎/㎖)으로 처리된 96-웰 플레이트에 96-웰 세포 분배기 (Titertek 제품)를 이용하여 α1G형과 α1H형 각각의 T-형 칼슘채널과 Kir2.1이 안정적으로 발현되어 있는 HEK293 세포주(α1G 세포주: KCTC 10519BP, 한국생명공학연구원 유전자은행)를 한 웰당 4 x 104 밀도로 분주해 주었다. T-type calcium channels of α1G and α1H types, respectively, using 96-well cell distributors (Titertek) in 96-well plates treated with poly-L-lysine (0.05 mg / ml) 12 to 24 hours prior to the activity test. HEK293 cell line stably expressing Kir2.1 (α1G cell line: KCTC 10519BP, Korea Research Institute of Bioscience and Biotechnology) was dispensed at 4 x 10 4 density per well.

실험 당일 96-웰 플레이트에 부착된 세포들은 96-웰 플레이트 자동세척 기기 (Bio Tek)를 이용하여 HEPES 완충용액 (단위 mM: 150 NaCl, 5 KCl, 1 MgCl2, 2 CaCl2, 10 HEPES, 10 글루코스, pH 7.4)으로 3 회 세척한 후 5 μM 플루오-3/AM과 0.001% 플루로닉(Pluronic) F-127을 포함하는 HEPES 완충용액의 실온 조건에서 1 시간 반응시켜 형광 염료로 표지한 후 HEPES 완충용액으로 다시 2 회 세척하였다. 그 후, FDSS6000 기기 측정 10분 전에 10 mM CaCl2을 포함하는 HEPES 완충용액으로 1회 씻고 최종 부피를 81 μL로 조정하였다. 세포가 준비된 96-웰 플레이트와는 별도로 T-형 칼슘 채널을 활성화시킬 KCl (최종농도 75 mM)과 차단제 약물을 포함하는 2개의 96-웰 약물 플레이트를 준비하였다. 대부분의 세포기반 HTS 기기의 경우 약물 주입에 필요한 액체 애플리케이션 시스템은 있지만 액체 흡입 시스템은 없기 때문에 검색하고자 하는 차단제 약물 및 KCl을 5 배의 고농도로 10 mM CaCl2 HEPES 완충용액에 27 μL씩 준비하여 세포 플레이트의 최종 부피인 135 μL에서 1/5로 희석하여 측정하였다. On the day of the experiment, the cells attached to the 96-well plate were subjected to HEPES buffer solution (unit mM: 150 NaCl, 5 KCl, 1 MgCl 2 , 2 CaCl 2 , 10 HEPES, 10) using a 96-well plate auto washing machine (Bio Tek). After washing three times with glucose, pH 7.4) and reacting for 1 hour at room temperature in HEPES buffer solution containing 5 μM Fluoro-3 / AM and 0.001% Pluronic F-127, it was labeled with fluorescent dye. Washed again with HEPES buffer twice. Thereafter, 10 minutes before measuring the FDSS6000 instrument, it was washed once with HEPES buffer containing 10 mM CaCl 2 and the final volume was adjusted to 81 μL. Apart from the 96-well plates in which cells were prepared, two 96-well drug plates were prepared containing KCl (final concentration 75 mM) and blocker drug to activate T-type calcium channels. Since most cell-based HTS instruments have a liquid application system for drug injection but no liquid inhalation system, 27 μL of the blocking agent drug and KCl to be searched in 10 mM CaCl 2 HEPES buffer at 5 times higher concentration are prepared. Measured by diluting to 1/5 in 135 μL, the final volume of the plate.

구체적인 FDSS6000 측정조건으로는 20초의 기준 수치 기록 후 75초간의 약물 전처리 후 KCl 투여에 의해 변화되는 세포내 칼슘농도 변화를 측정하였다. 시험물질을 처리하지 않은 대조군에서의 340/380 비율값의 면적을 100%로 잡고, 시험물질의 억제 효과에 대한 퍼센티지 (%) 억제효과를 구하였고 항상 10 μM의 미베프라딜을 대조약물로 사용하였다.As specific FDSS6000 measurement conditions, intracellular calcium concentrations changed by KCl administration after 75 seconds of pretreatment for 20 seconds were measured. The area of 340/380 ratio in the control group was not 100%, the percentage (%) inhibitory effect on the inhibitory effect was obtained, and 10 μM of mibepradil was always used as a control drug. It was.

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

본 발명에 따른 화합물의 T-형 칼슘채널에 대한 칼슘이동 %억제율 결과는 하기 표 3에 나타내었다. T-형 칼슘채널에 대한 칼슘이동 %억제율 값이 높을수록 약학적 활성이 좋음을 나타낸다. The results of% inhibition rate of calcium movement on T-type calcium channel of the compound according to the present invention are shown in Table 3 below. The higher the% inhibition rate of calcium movement on the T-type calcium channel, the better the pharmaceutical activity.

시험 화합물Test compound FDSS % InhibitionFDSS% Inhibition 시험 화합물Test compound FDSS % InhibitionFDSS% Inhibition α1G 10 μMα1G 10 μM α1H 10 μMα1H 10 μM α1G 10 μMα1G 10 μM α1H 10 μMα1H 10 μM 화합물번호 1Compound number 1 23.27 23.27 21.09 21.09 화합물번호 31Compound number 31 74.8474.84 71.6771.67 화합물번호 2Compound number 2 48.59 48.59 44.46 44.46 화합물번호 32Compound number 32 75.5675.56 69.0869.08 화합물번호 3Compound number 3 26.45 26.45 22.18 22.18 화합물번호 33Compound number 33 81.5181.51 79.1879.18 화합물번호 4Compound number 4 47.27 47.27 53.10 53.10 화합물번호 34Compound number 34 76.6576.65 85.3485.34 화합물번호 5Compound number 5 2.40 2.40 11.61 11.61 화합물번호 35Compound number 35 43.5043.50 34.1434.14 화합물번호 6Compound number 6 30.55 30.55 29.41 29.41 화합물번호 36Compound number 36 71.7371.73 69.6569.65 화합물번호 7Compound number 7 8.46 8.46 13.98 13.98 화합물번호 37Compound number 37 32.5532.55 31.3231.32 화합물번호 8Compound number 8 35.39 35.39 35.00 35.00 화합물번호 38Compound number 38 26.4326.43 33.6833.68 화합물번호 9Compound number 9 70.9070.90 70.6170.61 화합물번호 39Compound number 39 78.3178.31 65.2065.20 화합물번호 10Compound number 10 56.70 56.70 68.88 68.88 화합물번호 40Compound number 40 46.7646.76 51.8651.86 화합물번호 11Compound number 11 56.18 56.18 65.68 65.68 화합물번호 41Compound number 41 59.9059.90 50.0650.06 화합물번호 12Compound number 12 65.50 65.50 66.06 66.06 화합물번호 42Compound number 42 80.3580.35 69.6669.66 화합물번호 13Compound number 13 66.3166.31 66.3566.35 화합물번호 43Compound number 43 67.3067.30 69.4169.41 화합물번호 14Compound number 14 78.4478.44 73.8473.84 화합물번호 44Compound number 44 71.1471.14 81.6481.64 화합물번호 15Compound no.15 23.1023.10 17.8317.83 화합물번호 45Compound number 45 36.4136.41 59.7259.72 화합물번호 16Compound number 16 57.7857.78 53.2153.21 화합물번호 46Compound number 46 71.1671.16 69.2969.29 화합물번호 17Compound number 17 26.6526.65 26.5926.59 화합물번호 47Compound number 47 68.8868.88 68.8368.83 화합물번호 18Compound number 18 25.8025.80 18.7718.77 화합물번호 48Compound number 48 87.4287.42 65.1865.18 화합물번호 19Compound number 19 69.9769.97 62.7662.76 화합물번호 49Compound number 49 89.5189.51 71.6371.63 화합물번호 20Compound number 20 31.4931.49 27.2227.22 화합물번호 50Compound number 50 93.2293.22 72.1172.11 화합물번호 21Compound number 21 66.4466.44 66.0866.08 화합물번호 51Compound number 51 88.7588.75 68.5968.59 화합물번호 22Compound number 22 88.3888.38 76.1876.18 화합물번호 52Compound number 52 92.7292.72 77.0177.01 화합물번호 23Compound number 23 89.0089.00 74.8174.81 화합물번호 53Compound number 53 86.9586.95 56.2356.23 화합물번호 24Compound number 24 71.5671.56 71.0171.01 화합물번호 54Compound number 54 77.9977.99 64.0564.05 화합물번호 25Compound number 25 74.6874.68 64.9964.99 화합물번호 55Compound number 55 68.8268.82 62.0162.01 화합물번호 26Compound number 26 74.5974.59 74.5274.52 화합물번호 56Compound number 56 85.0985.09 76.5776.57 화합물번호 27Compound number 27 83.4583.45 72.1772.17 화합물번호 57Compound number 57 18.6018.60 10.7210.72 화합물번호 28Compound number 28 78.5578.55 60.8860.88 화합물번호 58Compound number 58 11.4211.42 8.368.36 화합물번호 29Compound number 29 67.1267.12 68.7568.75 화합물번호 59Compound number 59 5.495.49 21.8021.80 화합물번호 30Compound number 30 81.4281.42 74.5374.53

상기 표 3에 나타난 바와 같이, 본 발명에 따른 화합물은 전체적으로 T-형 칼슘채널에 대한 칼슘이동 억제효과가 우수하였다. As shown in Table 3, the compound according to the present invention was excellent in inhibiting calcium migration to the T-type calcium channel as a whole.

그 중에서도, 화합물 4, 9~14, 16, 19, 21~34, 36, 39~44, 46~56 은 α1형과 α1H형의 T-형 칼슘채널에 대하여 공통적으로 고르게 효과가 더욱 우수하였다.Among them, Compounds 4, 9-14, 16, 19, 21-34, 36, 39-44, 46-56 were more evenly effective in common to T-type calcium channels of α1 and α1H types.

실험예 2 : T-형 칼슘채널에 대한 억제활성 확인 실험Experimental Example 2: Experiment to confirm the inhibitory activity on T-type calcium channel

본 발명에 따른 화합물에 대한 T-형 칼슘채널에 대한 억제활성을 확인하기 위하여, α1G형과 α1H형의 T-형 칼슘채널이 발현되어 있는 HEK 293 Cell을 이용하여 IC50 약효를 테스트하였다. In order to confirm the inhibitory activity against T-type calcium channels of the compounds according to the present invention, IC 50 medicinal effects were tested using HEK 293 Cells expressing α-G and α-H type T-type calcium channels.

실험대상은 상기 실험예 1에서 효과가 더욱 우수했던 화합물 중 12개(화합물 30, 40, 46~ 56)를 선별하여, 진행하였다. The test subject proceeded by selecting 12 (compounds 30, 40, 46-56) among the compounds which were more excellent in Experimental Example 1.

그 결과는 하기 표 4에 나타난 바와 같다. 하기 표 4에는 본 발명에 따른 일부 화합물들의 T-형 칼슘채널에 대한 억제 효과를 IC50(μM)으로 나타내었다. The results are as shown in Table 4 below. Table 4 below shows the inhibitory effect of some compounds according to the invention on T-type calcium channels as IC 50 (μM).

시험화합물Test compound T-type ICT-type IC 5050 (μM)(μM) α1Gα1G α1Hα1H 화합물번호 30Compound number 30 3.36±0.253.36 ± 0.25 6.24±0.656.24 ± 0.65 화합물번호 40Compound number 40 5.13±0.355.13 ± 0.35 7.61±0.987.61 ± 0.98 화합물번호 46Compound number 46 5.95±0.645.95 ± 0.64 8.14±0.758.14 ± 0.75 화합물번호 47Compound number 47 6.11±0.126.11 ± 0.12 8.11±0.708.11 ± 0.70 화합물번호 48Compound number 48 3.42±0.203.42 ± 0.20 6.96±0.936.96 ± 0.93 화합물번호 49Compound number 49 3.20±0.343.20 ± 0.34 6.45±0.526.45 ± 0.52 화합물번호 50Compound number 50 2.14±0.082.14 ± 0.08 2.88±0.232.88 ± 0.23 화합물번호 51Compound number 51 3.28±0.313.28 ± 0.31 5.99±0.715.99 ± 0.71 화합물번호 52Compound number 52 2.75±0.202.75 ± 0.20 5.07±0.235.07 ± 0.23 화합물번호 53Compound number 53 2.83±0.422.83 ± 0.42 3.59±0.363.59 ± 0.36 화합물번호 54Compound number 54 3.27±0.193.27 ± 0.19 6.70±0.536.70 ± 0.53 화합물번호 56Compound number 56 3.08±0.403.08 ± 0.40 6.26±0.496.26 ± 0.49

상기 표 4에서, IC50 값이 낮을수록 α1G형 및 α1H의 T-형 칼슘채널에 대한 억제효과 및 그에 따른 약효가 좋은 것을 의미한다.In Table 4, the lower the IC 50 value means that the α 1G type and α 1H inhibitory effect on the T-type calcium channel and the drug efficacy accordingly.

이에 따르면, 본 발명에 따른 화합물은 대체로 T-형 칼슘채널에 대한 억제 효과가 우수하였다.According to this, the compounds according to the present invention were generally excellent in the inhibitory effect on the T-type calcium channel.

그 중에서도, 화합물 30, 48, 49, 50, 51, 52, 53, 54, 55, 56 의 효과가 우수하였고, 특히 화합물 50, 53은 α1G형과 α1H형의 T-형 칼슘채널에 대하여 공통적으로 고르게 효과가 더욱 우수하였다.Among them, the effects of Compounds 30, 48, 49, 50, 51, 52, 53, 54, 55, 56 were excellent, and in particular, Compounds 50 and 53 had common effects on T-type calcium channels of α1G and α1H types. Evenly the effect was better.

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

본 발명에 따른 화합물을 이용하여, 신경성 통증 동물 모델에 대한 실험을 진행하였다. 상기한 화합물 중에서도 생체 내 대사 안정성이 우수한 화합물 30번과 40번의 화합물을 이용하여 실험하였다. Using the compounds according to the invention, experiments were conducted on neurological pain animal models. Among the compounds described above, experiments were carried out using compounds No. 30 and No. 40 with excellent metabolic stability in vivo.

1. 실험 동물 준비1. Preparation of experimental animals

몸무게 300∼320 g의 수컷 랫트 SD(Rat Sprague Dawley)를 2% 아이소플루란(isoflurane)과 95% 산소의 혼합 가스로 마취를 유도하였다. 수술 전 과정에 걸쳐 1.5% 아이소플루란(isoflurane)과 95% 산소 혼합가스로 마취를 유지시켰다. 쥐의 좌측 L6 척추골의 횡돌기를 제거한 뒤, L5 척수 신경의 왼쪽에서 L4~L5 척수 신경 연결을 분리하고 L5 척수 신경을 6-0 실크 실로 단단히 고정하여 신경병증성 통증을 유발해, 신경성 통증 동물 모델(SNL Model)을 만들었다. 300-320 g of male rat SD (Rat Sprague Dawley) were induced anesthesia with a gas mixture of 2% isoflurane and 95% oxygen. Anesthesia was maintained with 1.5% isoflurane and 95% oxygen mixture throughout the entire procedure. Neuropathic pain animal model, after removing the left L6 vertebra of the left vertebra, causing the neuropathic pain by separating the L4 to L5 spinal nerve connections from the left side of the L5 spinal nerve and firmly fixing the L5 spinal nerve with 6-0 silk thread. (SNL Model) was created.

2. 약물실험2. Drug experiment

모든 행동 검사는 약제 투여 여부를 모르는 연구자에 의해 맹검법(blind study)으로 시행하였다. All behavioral tests were conducted in blind study by a researcher who did not know whether or not medication was administered.

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

쥐를 둥근 아크릴 통(5.5×15, 6.5×18 cm, 몸 크기에 따라 맞게 사용)에 넣고 꼬리만 밖으로 빼낸 후, 판 위에 올려놓았다. 기계적 이질통에 대한 측정은 여러 가지 폰 프레이 헤어 (von-Fry hair: 0.4, 0.6, 1.0, 2.0, 4.0, 6.0, 8.0, 15.0 g)를 이용하여 업다운 (Up-Down) 방식으로 꼬리를 자극하여 50% 회피반응을 보이는 폰 프레이 헤어 (von-Frey hair)의 그램(g)을 산정하는 방식으로 시행하였다. The rats were placed in round acrylic barrels (5.5 × 15, 6.5 × 18 cm, used according to body size), with only the tails pulled out and placed on a plate. Measurements for mechanical allodynia were performed by stimulating the tail in an up-down manner using various von-Fry hairs (0.4, 0.6, 1.0, 2.0, 4.0, 6.0, 8.0, 15.0 g). The grams (g) of von-Frey hair with% avoidance were calculated.

신경 손상 전과 비교하여 통계적으로 유의하게 회피반응 역치가 감소한 것을 기계적 이질통이 발생한 것으로 판정하였다. It was determined that mechanical allodynia occurred as a statistically significant decrease in the avoidance response threshold compared to before nerve injury.

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

쥐를 둥근 아크릴 통에 넣고 꼬리만 밖으로 꺼내 늘어뜨린 후 4℃ 물 속에 넣어 꼬리가 회피반응을 보일 때까지의 시간을 측정하여 기록하였다. 실험결과는 5분간의 간격을 두고 5회 실시한 평균값으로 하였다. 15초까지 회피하지 않을 때는 꼬리의 민감화를 막기 위해 물 속에 꼬리를 빼내고 15초를 결과로 하였다. 수술 전보다 유의성 있게 빨리 회피하는 경우는 냉 이질통의 결과로 추정하였다. 이상의 행동 검사결과에서 신경에 손상을 주기 전과 비교하여 신경손상 후에 유의한 회피반응을 보이면 통증이 유발 된 것으로 추정하였다.The rats were placed in a round acrylic container, and the tails were taken out and hanged. Then, the rats were placed in water at 4 ° C., and the time until the tail showed an avoidance reaction was recorded. The experimental result was made into the average value performed 5 times with the interval of 5 minutes. When not avoided by 15 seconds, the tail was subtracted into the water to prevent tail sensitization, resulting in 15 seconds. Significantly faster avoidance was presumed to be a result of cold allodynia. In the above behavioral test results, it was estimated that the pain was induced when a significant avoidance reaction occurred after the nerve injury compared with before the nerve injury.

이러한 신경성 통증 동물 모델의 실험결과는 도 1 및 도 2에 나타난 바와 같다. 도 1은 본원의 일 실시예에 따른 신규 화합물(화합물번호 30)의 기계적, 냉적 통증 동물모델에 대한 통증 억제 결과를 나타낸 그래프이고, 도 2는 본원의 일 실시예에 따른 신규 화합물(화합물번호 40)의 기계적, 냉적 통증 동물모델에 대한 통증 억제 결과를 나타낸 그래프이다.Experimental results of these neurological pain animal models are shown in FIGS. 1 and 2. 1 is a graph showing the pain inhibition results for the mechanical and cold pain animal model of the novel compound (Compound No. 30) according to an embodiment of the present application, Figure 2 is a novel compound (Compound No. 40 according to an embodiment of the present application) ) Is a graph showing the results of pain inhibition for mechanical and cold pain animal models.

실험결과에 의하면, 본 발명에 따른 화합물은 통증완화제로서 상용화되어 있는 가바펜틴 (Gabapentin) 약물에 비교하여 동등 내지는 우수한 활성을 나타내고 있다. According to the experimental results, the compound according to the present invention shows the equivalent or superior activity compared to the gabapentin drug which is commercialized as a pain relief agent.

구체적으로, 도 1에 나타난 바와 같이, 본 발명의 화합물 30은 투여 후 1시간째부터 현저한 기계적, 냉적 통증억제를 보였다. 기계적 통증 억제는 3시간까지 지속되다 서서히 사라졌고 냉적 통증 억제는 5시간까지 지속되었다. 즉, 화합물 30의 경우, 투여 후 3시간 이후에는 가바펜틴보다 기계적 통증 억제가 우수하였고, 냉적 통증 억제는 가바펜틴과 비슷한 활성을 나타내었다. Specifically, as shown in Figure 1, Compound 30 of the present invention showed a significant mechanical and cold pain suppression from 1 hour after administration. Mechanical pain suppression lasted up to 3 hours and gradually disappeared, while cold pain suppression lasted up to 5 hours. That is, Compound 30 showed better mechanical pain inhibition than gabapentin after 3 hours after administration, and cold pain inhibition showed similar activity to gabapentin.

또한, 도 2에 나타난 바와 같이, 본 발명의 화합물 40은 투여 후 3시간째부터 기계적 통증 억제 효과가 보였다. 냉적 이질통은 1시간부터 5시간째까지 억제효과를 보였다. 즉, 화합물 40의 경우, 가바펜틴보다 기계적 통증 억제는 낮은 활성을 나타내고 있지만, 냉적 통증 억제는 가바펜틴과 같이 투여 후 비슷한 활성을 5시간 내내 효과를 지속하고 있음을 알 수 있었다.In addition, as shown in Figure 2, Compound 40 of the present invention showed a mechanical pain inhibitory effect from 3 hours after administration. Cold allodynia had an inhibitory effect from 1 hour to 5 hours. That is, in the case of compound 40, mechanical pain inhibition was lower than that of gabapentin, but cold pain inhibition was similar to that of gabapentin and maintained similar effects for 5 hours after administration.

이에 따르면, 본 발명에 따른 화합물 30은 우수한 기계적 통증 억제를 가지면서 냉적 통증 억제는 비교군(가바펜틴)만큼의 효과를 가지고 있고, 본 발명에 따른 화합물 40은 냉적 통증 억제에 지속적인 효과를 나타냄을 알 수 있었다.According to this, the compound 30 according to the present invention has excellent mechanical pain suppression while the cold pain suppression has the same effect as the comparative group (gabapentin), and the compound 40 according to the present invention is shown to have a continuous effect on cold pain suppression Could.

상기에서는 본 발명을 특정의 바람직한 실시예에 관련하여 도시하고 설명하였지만, 이하의 특허청구범위에 의해 마련되는 본 발명의 기술적 특징이나 분야를 이탈하지 않는 한도 내에서 본 발명이 다양하게 개조 및 변화될 수 있다는 것은 당업계에서 통상의 지식을 가진 자에게 명백한 것이다.While the invention has been shown and described with respect to certain preferred embodiments thereof, it will be understood that the invention may be modified and modified in various ways without departing from the spirit or scope of the invention provided by the following claims. It will be apparent to one of ordinary skill in the art that it can.

Claims (11)

하기 화학식 1로 표시되는 피롤리딘 또는 피페리딘 또는 이것의 약학적으로 허용 가능한 염인 것을 특징으로 하는 화합물:
[화학식 1]
Figure pat00196

상기 화학식 1에서,
R1은 수소원자, C1-C6 알킬기, C1-C6 아세틸기, 아릴기, 또는 헤테로아릴기를 나타내고, 상기 아릴기는 할로겐, C1 알킬, 및 C1 할로알킬 중에서 선택된 1개 내지 2개의 치환기로 치환될 수 있으며;
R2는 수소원자, 질소원자와 산소원자 중에서 선택된 1개∼2개 포함된 5각형 또는 6각형의 헤테로아릴기, 아릴기, 페닐 다이하이드로피리딘을 나타내고, 상기 헤테로아릴기, 아릴기, 페닐 다이하이드로피리딘은 페닐, 할로겐, C1-C4 알킬, C1 할로알킬, 할로알콕시, 니트로 및 에스터 중에서 선택된 1개 내지 2개의 치환기로 치환될 수 있으며;
R3은 수소원자, 또는 하이드록시메틸을 나타내고;
n은 1 또는 2의 정수를 나타내고;
* 로 표시된 탄소원자는 비대칭 중심이고 (R) 배열과 (S) 배열의 이성질체로 되어 있음.
A compound characterized in that the pyrrolidine or piperidine represented by the formula (1) or a pharmaceutically acceptable salt thereof
[Formula 1]
Figure pat00196

In Chemical Formula 1,
R 1 represents a hydrogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 acetyl group, an aryl group, or a heteroaryl group, wherein the aryl group is 1 to 2 selected from halogen, C 1 alkyl, and C 1 haloalkyl May be substituted with 4 substituents;
R 2 represents a pentagonal or hexagonal heteroaryl group, an aryl group, or a phenyl dihydropyridine containing 1 to 2 selected from a hydrogen atom, a nitrogen atom and an oxygen atom, and the heteroaryl group, aryl group, and phenyl di Hydropyridine may be substituted with 1 to 2 substituents selected from phenyl, halogen, C 1 -C 4 alkyl, C 1 haloalkyl, haloalkoxy, nitro and ester;
R 3 represents a hydrogen atom or hydroxymethyl;
n represents an integer of 1 or 2;
Carbon atoms marked with * are asymmetric centers and consist of isomers of (R) and (S) configurations.
제 1 항에 있어서,
상기 화합물은 상기 화학식 1로 표시되는 피롤리딘 화합물이고,
상기 화학식 1의,
R1은 수소원자, C1-C6 알킬기, C1-C6 아세틸기, 치환된 아릴기, 또는 헤테로아릴기를 나타내고, 상기 치환된 아릴기는 할로겐, C1 알킬, 및 C1 할로알킬 중에서 선택된 1개 내지 2개의 치환기로 치환된 것이며;
R2는 수소원자, 질소원자와 산소원자 중에서 선택된 1개∼2개 포함된 5각형 또는 6각형의 헤테로아릴기, 치환된 아릴기, 치환된 페닐 다이하이드로피리딘을 나타내고, 상기 헤테로아릴기, 아릴기, 페닐 다이하이드로피리딘은 페닐, 할로겐, C1-C4 알킬, C1 할로알킬, 할로알콕시, 니트로 및 에스터 중에서 선택된 1개 내지 2개의 치환기로 치환된 것이며;
n은 1의 정수를 나타내는 것을 특징으로 하는 화합물.
The method of claim 1,
The compound is a pyrrolidine compound represented by Formula 1,
Of Chemical Formula 1,
R 1 represents a hydrogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 acetyl group, a substituted aryl group, or a heteroaryl group, wherein the substituted aryl group is selected from halogen, C 1 alkyl, and C 1 haloalkyl Substituted with 1 to 2 substituents;
R 2 represents a pentagonal or hexagonal heteroaryl group containing 1 to 2 selected from a hydrogen atom, a nitrogen atom and an oxygen atom, a substituted aryl group, a substituted phenyl dihydropyridine, and the heteroaryl group and aryl The group, phenyl dihydropyridine, is substituted with 1 to 2 substituents selected from phenyl, halogen, C 1 -C 4 alkyl, C 1 haloalkyl, haloalkoxy, nitro and ester;
n represents an integer of 1;
제 1 항에 있어서,
상기 화합물은 상기 화학식 1로 표시되는 피페리딘 화합물이고,
상기 화학식 1의,
R1은 수소원자, C1-C6 알킬기, C1-C6 아세틸기, 치환된 아릴기, 또는 헤테로아릴기를 나타내고, 상기 치환된 아릴기는 할로겐, C1 알킬, 및 C1 할로알킬 중에서 선택된 1개 내지 2개의 치환기로 치환된 것이며;
R2는 수소원자, 질소원자와 산소원자 중에서 선택된 1개∼2개 포함된 5각형 또는 6각형의 헤테로아릴기, 치환된 아릴기, 치환된 페닐 다이하이드로피리딘을 나타내고, 상기 헤테로아릴기, 아릴기, 페닐 다이하이드로피리딘은 페닐, 할로겐, C1-C4 알킬, C1 할로알킬, 할로알콕시, 니트로 및 에스터 중에서 선택된 1개 내지 2개의 치환기로 치환된 것이며;
n은 2의 정수를 나타내는 것을 특징으로 하는 화합물.
The method of claim 1,
The compound is a piperidine compound represented by Formula 1,
Of Chemical Formula 1,
R 1 represents a hydrogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 acetyl group, a substituted aryl group, or a heteroaryl group, wherein the substituted aryl group is selected from halogen, C 1 alkyl, and C 1 haloalkyl Substituted with 1 to 2 substituents;
R 2 represents a pentagonal or hexagonal heteroaryl group containing 1 to 2 selected from a hydrogen atom, a nitrogen atom and an oxygen atom, a substituted aryl group, a substituted phenyl dihydropyridine, and the heteroaryl group and aryl The group, phenyl dihydropyridine, is substituted with 1 to 2 substituents selected from phenyl, halogen, C 1 -C 4 alkyl, C 1 haloalkyl, haloalkoxy, nitro and ester;
n represents an integer of 2;
제 1 항에 있어서,
상기 화합물은 하기 화합물 1 내지 화합물 61로 이루어진 군에서 선택된 것임을 특징으로 하는 화합물:
(R)-N-((1-(3,3-다이메틸부틸)피롤리딘-3-일)메틸)-3-아이소프로필아이소사졸-5-카르복사미드 (화합물 1);
(R)-3,5-다이클로로-N-((1-(3,3-다이메틸부틸)피롤리딘-3-일)메틸)벤즈아미드 (화합물 2);
(R)-N-((1-(3,3-다이메틸부틸)피롤리딘-3-일)메틸)-1-메틸-3-프로필-1H-피라졸-5-카르복사미드 (화합물 3);
(R)-N-((1-(3,3-다이메틸부틸)피롤리딘-3-일)메틸)-5-아이소부틸-1-페닐-1H -피라졸-3-카르복사미드 (화합물 4);
(R)-3-아이소프로필-N-((1-(피리딘-3-일메틸)피롤리딘-3-일)메틸)아이소옥사졸-5-카르복사미드 (화합물 5);
(R)-3,5-다이클로로-N-((1-(피리딘-3-일메틸)피롤리딘-3-일)메틸)벤즈아미드 (화합물 6);
(R)-1-메틸-3-프로필-N-((1-(피리딘-3-일메틸)피롤리딘-3-일)메틸)-1H-피라졸-5-카르복사미드 (화합물 7);
(R)-5-아이소부틸-1-페닐-N-((1-(피리딘-3-일메틸)피롤리딘-3-일)메틸)-1H-피라졸-3-카르복사미드 (화합물 8);
(R)-3-아이소프로필-N-((1-(4-(트리플루오로메틸)페네틸)피롤리딘-3-일)메틸)아이소옥사졸-5-카르복사미드 (화합물 9);
(R)-3,5-다이클로로-N-((1-(4-(트리플루오로메틸)페네틸)피롤리딘-3-일)메틸)벤즈아미드 (화합물 10);
(R)-1-메틸-3-프로필-N-((1-(4-(트리플루오로메틸)페네틸)피롤리딘-3-일)메틸)-1H-피라졸-5-카르복사미드 (화합물 11);
(R)-5-아이소부틸-1-페닐-N-((1-(4-(트리플루오로메틸)페네틸)피롤리딘-3-일)메틸)-1H-피라졸-3-카르복사미드 (화합물 12);
(R)-3,5-다이클로로-N-((1-(3,3-다이메틸부테노일)피롤리딘-3-일)메틸)벤즈아미드 (화합물 13);
(R)-3,5-다이클로로-N-((1-(2-(4-(트리플루오로메틸)페닐)아세틸)피롤리딘-3-일)메틸)벤즈아마이드 (화합물 14);
(R)-N-((1-(3,3-다이메틸부테노일)피롤리딘-3-일)메틸)-3-아이소프로필아이소옥사졸-5-카르복사미드 (화합물 15);
(R)-3-아이소프로필-N-((1-(2-(4-(트리플루오로메틸)페닐)아세틸)피롤리딘-3-일)메틸)아이소옥사졸-5-카르복사미드(화합물 16);
(S)-N-((1-(3,3-다이메틸부테노일)피롤리딘-3-일)메틸)-3-아이소프로필아이소옥사졸-5-카르복사미드 (화합물 17);
(R)-N-((1-(3,3-다이메틸부테노일)피롤리딘-3-일)메틸)-1-메틸-3-프로필-1H-피라졸-5-카르복사미드 (화합물 18);
(R)-1-메틸-3-프로필-N-((1-(2-(4-(트리플루오로메틸)페닐)아세틸)피롤리딘-3-일)메틸)-1H-피라졸-5-카르복사미드(화합물 19);
(S)-N-((1-(3,3-다이메틸부테노일)피롤리딘-3-일)메틸)-1-메틸-3-프로필-1H -피라졸-5-카르복사미드 (화합물 20);
(S)-1-메틸-3-프로필-N-((1-(2-(4-(트리플루오로메틸)페닐)아세틸)피롤리딘-3-일)메틸)-1H-피라졸-5-카르복사미드 (화합물 21);
(S)-N-((1-(3,3-다이메틸부테노일)피롤리딘-3-일)메틸)-5-아이소부틸-1-페닐-1H-피라졸-3-카르복사미드 (화합물 22);
(S)-5-아이소부틸-1-페닐-N-((1-(2-(4-(트리플루오로메틸)페닐)아세틸)피롤리딘-3-일)메틸)-1H-피라졸-3-카르복사미드 (화합물 23);
(S)-3-아이소프로필-N-((1-(2-(4-(트리플루오로메틸)페닐)아세틸)피롤리딘-3-일)메틸)아이소옥사졸-5-카르복사미드 (화합물 24);
(S)-3,5-다이클로로-N-((1-(3,3-다이메틸부테노일)피롤리딘-3-일)메틸)벤즈아미드 (화합물 25);
(S)-3,5-다이클로로-N-((1-(2-(4-(트리플루오로메틸)페닐)아세틸)피롤리딘-3-일)메틸)벤즈아미드 (화합물 26);
(R)-N-((1-(3,3-다이메틸부테노일)피롤리딘-3-일)메틸)-5-아이소부틸-1-페닐-1H-피라졸-3-카복스아미드 (화합물 27);
(R)-5-아이소부틸-1-페닐-N-((1-(2-(4-(트리플루오로메틸)페닐)아세틸)피롤리딘-3-일)메틸)-1H-피라졸-3-카르복사미드 (화합물 28);
(R)-5-아이소부틸-1-페닐-N-((1-(2-(3-(트리플루오로메틸)페닐)아세틸)피롤리딘-3-일)메틸)-1H-피라졸-3-카르복사미드 (화합물 29);
(R)-5-아이소부틸-N-((1-(4-메틸-3-(트리플루오로메틸)페네틸)피롤리딘-3-일)메틸)-1-페닐-1H-피라졸-3-카르복사미드 (화합물 30);
(R)-5-아이소부틸-N-((1-(2-메틸-5-(트리플루오로메틸)페네틸)피롤리딘-3-일)메틸)-1-페닐-1H-피라졸-3-카르복사미드 (화합물 31);
(R)-N-((1-(2,4-비스(트리플루오로메틸)페네틸)피롤리딘-3-일)메틸)-5-아이소부틸-1-페닐-1H-피라졸-3-카르복사미드 (화합물 32);
(R)-5-아이소부틸-N-((1-(5-메틸-2-(트리플루오로메틸)페네틸)피롤리딘-3-일)메틸)-1-페닐-1H-피라졸-3-카르복사미드 (화합물 33);
(R)-5-아이소부틸-1-페닐-N-((1-(3-(트라이플루오로메틸)페네틸)피롤리딘-3-일)메틸)-1H-피라졸-3-카르복사미드 (화합물 34);
메틸 2,6-다이메틸-4-(3-나이트로페닐)-5-((((R)-1-(4-(트리플루오로메틸)페네틸)피롤리딘-3-일)메틸)카르바모일l)-1,4-다이하이드로피리딘-3-카르복시산염(화합물 35);
(R)-N-((1-(3,4-다이클로로페네틸)피롤리딘-3-일)메틸)-3-아이소프로필아이소옥사졸-5-카르복사미드 (화합물 36);
메틸 5-((((R)-1-(3,4-다이클로로페네틸)피롤리딘-3-일)메틸)카르바모일)-2, 6-다이메틸-4-(3-나이트로페닐)-1,4-다이하이드로피리딘-3-카르복시산염 (화합물 37);
메틸 2,6-다이메틸-5-((((R)-1-(4-메틸-3-(트리플루오로메틸)페네틸)피롤리딘-3-일)메틸)카르바모일)-4-(3-나이트로페닐)-1,4-다이하이드로피리딘-3-카르복시산염 (화합물 38);
메틸 5-((((R)-1-(4-클로로-3-플루오로페네틸)피롤리딘-3-일)메틸)카르바모일)-2,6-다이메틸-4-(3-나이트로페닐)-1,4-다이하이드로피리딘-3-카르복시산염 (화합물 39);
(R)-3-아이소프로필-N-((1-(4-메틸-3-(트리플루오로메틸)페네틸)피롤리딘-3-일)메틸)아이소옥사졸-5-카르복사미드 (화합물 40);
(R)-N-((1-(4-클로로-3-플루오로페네틸)피롤리딘-3-일)메틸)-3-아이소프로필아이소옥사졸-5-카르복사미드 (화합물 41);
메틸 5-((((R)-1-(3-플루오로-4-(트리플루오로메톡시)페네틸)피롤리딘-3-일)메틸)카르바모일)-2,6-다이메틸-4-(3-나이트로페닐)-1,4-다이하이드로피리딘-3-카르복시산염 (화합물 42);
(R)-N-((1-(3-플루오로-4-(트리플루오로메톡시)페네틸)피롤리딘-3-일)메틸)-5-아이소부틸-1-페닐-1H-피라졸-3-카르복사미드(화합물 43);
(R)-5-아이소부틸-1-페닐-N-((1-(2-(트라이플루오로메틸)페네틸) 피롤리딘-3-일)메틸)-1H-피라졸-3-카르복사미드 (화합물 44);
(R)-N-((1-(3-플루오로-4-(트리플루오로메톡시)페네틸)피롤리딘-3-일)메틸)-3-아이소프로필아이소옥사졸-5-카르복사미드 (화합물 45);
(R)-N-((1-(3,4-다이클로로페네틸)피롤리딘-3-일)메틸)-5-아이부틸-1-페닐-1H-피라졸-3-카르복사미드 (화합물 46);
(R)-N-((1-(4-클로로-3-플루오로페네틸)피롤리딘-3-일)메틸)-5-아이소부틸-1-페닐-1H-피라졸-3-카르복사미드 (화합물 47);
(R)-N-((1-(2,3-다이플루오로페네틸)피롤리딘-3-일)메틸)-5-아이소부틸-1-페닐-1H-피라졸-3-카르복사미드 (화합물 48);
(R)-N-((1-(3,4-다이플루오로페네틸)피롤리딘-3-일)메틸)-5-아이소부틸-1-페닐-1H-피라졸-3-카르복사미드 (화합물 49);
(R)-5-아이소부틸-1-페닐-N-((1-(4-(트리플루오로메톡시)-3-(트리플루오로메틸)페네틸)피롤리딘-3-일)메틸)-1H-피라졸-3-카르복사미드 (화합물 50);
(R)-N-((1-(3,5-다이플루오로페네틸)피롤리딘-3-일)메틸)-5-아이소부틸-1-페닐-1H-피라졸-3-카르복사미드 (화합물 51);
(R)-N-((1-(3-클로로-5-플루오로페네틸)피롤리딘-3-일)메틸)-5-아이소부틸-1-페닐-1H-피라졸-3-카르복사미드 (화합물 52);
(R)-N-((1-(3-플루오로페네틸)피롤리딘-3-일)메틸)-5-아이소부틸-1-페닐-1H-피라졸-3-카르복사미드 (화합물 53);
(R)-N-((1-(3-클로로-5-플루오로페네틸)피롤리딘-3-일)메틸)-5-메틸-1-페닐-1H-피라졸-3-카르복사미드 (화합물 54);
N-((4-(하이드록시메틸)-1-(4-메틸-3-(트리플루오로메틸)페네틸)피페리딘-4-일)메틸)-5-아이소부틸-1-페닐-1H-피라졸-3-카르복사미드 (화합물 55);
N-((3-(하이드록시메틸)-1-(4-메틸-3-(트리플루오로메틸)페네틸)피롤리딘-3-일)메틸)-5-아이소부틸-1-페닐-1H-피라졸-3-카르복사미드 (화합물 56);
(S)-5-아이소부틸-1-페닐-N-(피롤리딘-3-일메틸)-1H-피라졸-3-카르복사미드 (화합물 57);
(S)-3-아이소프로필-N-(피롤리딘-3-일메틸)아이소옥사졸-5-카르복사미드(화합물 58);
메틸 2,6-다이메틸-4-(3-나이트로페닐)-5-(((S)-피롤리딘-3-일메틸)카르바모일)-1,4-다이하이드로피리딘-3-카르복시산염 (화합물 59);
(R)-N-((1-(3-클로로-5-플루오로페네틸)피롤리딘-3-일)메틸)-3-아이소프로필아이소옥사졸-5-카르복사미드 (화합물 60);
(R)-N-((1-(2-(3-클로로-5-플루오로페닐)아세틸)피롤리딘-3-일)메틸)-5-아이소부틸-1-페닐-1H-피라졸-3-카르복사미드 (화합물 61).
The method of claim 1,
The compound is characterized in that the compound selected from the group consisting of Compound 1 to Compound 61:
( R ) -N -((1- (3,3-dimethylbutyl) pyrrolidin-3-yl) methyl) -3-isopropylisoazole-5-carboxamide (Compound 1);
( R ) -3,5-dichloro- N -((1- (3,3-dimethylbutyl) pyrrolidin-3-yl) methyl) benzamide (Compound 2);
( R ) -N -((1- (3,3-dimethylbutyl) pyrrolidin-3-yl) methyl) -1-methyl-3-propyl-1 H -pyrazole-5-carboxamide ( Compound 3);
( R ) -N -((1- (3,3-dimethylbutyl) pyrrolidin-3-yl) methyl) -5-isobutyl-1-phenyl-1 H -pyrazole-3-carboxamide (Compound 4);
( R ) -3-isopropyl- N -((1- (pyridin-3-ylmethyl) pyrrolidin-3-yl) methyl) isoxazole-5-carboxamide (Compound 5);
( R ) -3,5-dichloro- N -((1- (pyridin-3-ylmethyl) pyrrolidin-3-yl) methyl) benzamide (Compound 6);
( R ) -1-Methyl-3-propyl- N -((1- (pyridin-3-ylmethyl) pyrrolidin-3-yl) methyl) -1 H -pyrazole-5-carboxamide (compound 7);
( R ) -5-isobutyl-1-phenyl- N -((1- (pyridin-3-ylmethyl) pyrrolidin-3-yl) methyl) -1 H -pyrazole-3-carboxamide ( Compound 8);
( R ) -3-isopropyl- N -((1- (4- (trifluoromethyl) phenethyl) pyrrolidin-3-yl) methyl) isoxazole-5-carboxamide (Compound 9) ;
( R ) -3,5-dichloro- N -((1- (4- (trifluoromethyl) phenethyl) pyrrolidin-3-yl) methyl) benzamide (Compound 10);
( R ) -1-methyl-3-propyl- N -((1- (4- (trifluoromethyl) phenethyl) pyrrolidin-3-yl) methyl) -1 H -pyrazole-5-car Radiamide (compound 11);
( R ) -5-isobutyl-1-phenyl- N -((1- (4- (trifluoromethyl) phenethyl) pyrrolidin-3-yl) methyl) -1 H -pyrazole-3- Carboxamide (compound 12);
( R ) -3,5-dichloro- N -((1- (3,3-dimethylbutenoyl) pyrrolidin-3-yl) methyl) benzamide (Compound 13);
( R ) -3,5-dichloro- N -((1- (2- (4- (trifluoromethyl) phenyl) acetyl) pyrrolidin-3-yl) methyl) benzamide (Compound 14);
( R ) -N -((1- (3,3-dimethylbutenoyl) pyrrolidin-3-yl) methyl) -3-isopropylisoxazole-5-carboxamide (Compound 15);
( R ) -3-isopropyl- N -((1- (2- (4- (trifluoromethyl) phenyl) acetyl) pyrrolidin-3-yl) methyl) isoxazole-5-carboxamide (Compound 16);
( S ) -N -((1- (3,3-dimethylbutenoyl) pyrrolidin-3-yl) methyl) -3-isopropylisoxazole-5-carboxamide (Compound 17);
( R ) -N -((1- (3,3-dimethylbutenoyl) pyrrolidin-3-yl) methyl) -1-methyl-3-propyl-1 H -pyrazole-5-carboxamide (Compound 18);
( R ) -1-methyl-3-propyl- N -((1- (2- (4- (trifluoromethyl) phenyl) acetyl) pyrrolidin-3-yl) methyl) -1 H -pyrazole -5-carboxamide (compound 19);
( S ) -N -((1- (3,3-dimethylbutenoyl) pyrrolidin-3-yl) methyl) -1-methyl-3-propyl-1 H -pyrazole-5-carboxamide (Compound 20);
( S ) -1-methyl-3-propyl- N -((1- (2- (4- (trifluoromethyl) phenyl) acetyl) pyrrolidin-3-yl) methyl) -1 H -pyrazole -5-carboxamide (compound 21);
( S ) -N -((1- (3,3-dimethylbutenoyl) pyrrolidin-3-yl) methyl) -5-isobutyl-1-phenyl-1 H -pyrazole-3-carbox Mead (compound 22);
( S ) -5-isobutyl-1-phenyl- N -((1- (2- (4- (trifluoromethyl) phenyl) acetyl) pyrrolidin-3-yl) methyl) -1 H -pyra Sol-3-carboxamide (compound 23);
( S ) -3-isopropyl- N -((1- (2- (4- (trifluoromethyl) phenyl) acetyl) pyrrolidin-3-yl) methyl) isoxazole-5-carboxamide (Compound 24);
( S ) -3,5-dichloro- N -((1- (3,3-dimethylbutenoyl) pyrrolidin-3-yl) methyl) benzamide (Compound 25);
( S ) -3,5-dichloro- N -((1- (2- (4- (trifluoromethyl) phenyl) acetyl) pyrrolidin-3-yl) methyl) benzamide (Compound 26);
( R ) -N -((1- (3,3-dimethylbutenoyl) pyrrolidin-3-yl) methyl) -5-isobutyl-1-phenyl-1 H -pyrazole-3-carbox Amides (compound 27);
( R ) -5-isobutyl-1-phenyl- N -((1- (2- (4- (trifluoromethyl) phenyl) acetyl) pyrrolidin-3-yl) methyl) -1 H -pyra Sol-3-carboxamide (compound 28);
( R ) -5-isobutyl-1-phenyl- N -((1- (2- (3- (trifluoromethyl) phenyl) acetyl) pyrrolidin-3-yl) methyl) -1 H -pyra Sol-3-carboxamide (compound 29);
( R ) -5-isobutyl- N -((1- (4-methyl-3- (trifluoromethyl) phenethyl) pyrrolidin-3-yl) methyl) -1-phenyl-1 H -pyra Sol-3-carboxamide (compound 30);
( R ) -5-isobutyl- N -((1- (2-methyl-5- (trifluoromethyl) phenethyl) pyrrolidin-3-yl) methyl) -1-phenyl-1 H -pyra Sol-3-carboxamide (compound 31);
( R ) -N -((1- (2,4-bis (trifluoromethyl) phenethyl) pyrrolidin-3-yl) methyl) -5-isobutyl-1-phenyl-1 H -pyrazole -3-carboxamide (compound 32);
( R ) -5-isobutyl- N -((1- (5-methyl-2- (trifluoromethyl) phenethyl) pyrrolidin-3-yl) methyl) -1-phenyl-1 H -pyra Sol-3-carboxamide (compound 33);
( R ) -5-isobutyl-1-phenyl- N -((1- (3- (trifluoromethyl) phenethyl) pyrrolidin-3-yl) methyl) -1H-pyrazole-3-car Radiamide (compound 34);
Methyl 2,6-dimethyl-4- (3-nitrophenyl) -5-(((( R ) -1- (4- (trifluoromethyl) phenethyl) pyrrolidin-3-yl) methyl ) Carbamoyl l) -1,4-dihydropyridine-3-carboxylate (Compound 35);
(R) -N -((1- (3,4-dichlorophenethyl) pyrrolidin-3-yl) methyl) -3-isopropylisoxazole-5-carboxamide (Compound 36);
Methyl 5-((( (R) -1- (3,4-dichlorophenethyl) pyrrolidin-3-yl) methyl) carbamoyl) -2,6-dimethyl-4- (3-knight Rophenyl) -1,4-dihydropyridine-3-carboxylate (compound 37);
Methyl 2,6-dimethyl-5-((( (R) -1- (4-methyl-3- (trifluoromethyl) phenethyl) pyrrolidin-3-yl) methyl) carbamoyl)- 4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylate (Compound 38);
Methyl 5-(((( (R) -1- (4-chloro-3-fluorophenethyl) pyrrolidin-3-yl) methyl) carbamoyl) -2,6-dimethyl-4- (3 Nitrophenyl) -1,4-dihydropyridine-3-carboxylate (compound 39);
( R ) -3-isopropyl- N -((1- (4-methyl-3- (trifluoromethyl) phenethyl) pyrrolidin-3-yl) methyl) isoxazole-5-carboxamide (Compound 40);
( R ) -N -((1- (4-chloro-3-fluorophenethyl) pyrrolidin-3-yl) methyl) -3-isopropylisoxazole-5-carboxamide (Compound 41) ;
Methyl 5-((((( R ) -1- (3-fluoro-4- (trifluoromethoxy) phenethyl) pyrrolidin-3-yl) methyl) carbamoyl) -2,6-dimethyl -4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylate (Compound 42);
( R ) -N -((1- (3-fluoro-4- (trifluoromethoxy) phenethyl) pyrrolidin-3-yl) methyl) -5-isobutyl-1-phenyl-1 H- Pyrazole-3-carboxamide (compound 43);
( R ) -5-isobutyl-1-phenyl- N -((1- (2- (trifluoromethyl) phenethyl) pyrrolidin-3-yl) methyl) -1 H -pyrazole-3- Carboxamide (compound 44);
( R ) -N -((1- (3-fluoro-4- (trifluoromethoxy) phenethyl) pyrrolidin-3-yl) methyl) -3-isopropylisoxazole-5-carbox Mead (Compound 45);
( R ) -N -((1- (3,4-dichlorophenethyl) pyrrolidin-3-yl) methyl) -5-ibutyl-1-phenyl-1 H -pyrazole-3-carbox Mead (compound 46);
( R ) -N -((1- (4-chloro-3-fluorophenethyl) pyrrolidin-3-yl) methyl) -5-isobutyl-1-phenyl-1 H -pyrazole-3- Carboxamide (Compound 47);
( R ) -N -((1- (2,3-difluorophenethyl) pyrrolidin-3-yl) methyl) -5-isobutyl-1-phenyl-1 H -pyrazole-3-car Radiamide (compound 48);
( R ) -N -((1- (3,4-difluorophenethyl) pyrrolidin-3-yl) methyl) -5-isobutyl-1-phenyl-1 H -pyrazole-3-car Radiamide (Compound 49);
( R ) -5-isobutyl-1-phenyl- N -((1- (4- (trifluoromethoxy) -3- (trifluoromethyl) phenethyl) pyrrolidin-3-yl) methyl) -1 H -pyrazole-3-carboxamide (Compound 50);
( R ) -N -((1- (3,5-difluorophenethyl) pyrrolidin-3-yl) methyl) -5-isobutyl-1-phenyl-1 H -pyrazole-3-car Radiamide (Compound 51);
( R ) -N -((1- (3-chloro-5-fluorophenethyl) pyrrolidin-3-yl) methyl) -5-isobutyl-1-phenyl-1 H -pyrazole-3- Carboxamide (Compound 52);
( R ) -N -((1- (3-fluorophenethyl) pyrrolidin-3-yl) methyl) -5-isobutyl-1-phenyl-1 H -pyrazole-3-carboxamide (Compound 53);
( R ) -N -((1- (3-chloro-5-fluorophenethyl) pyrrolidin-3-yl) methyl) -5-methyl-1-phenyl-1 H -pyrazole-3-car Radiamide (compound 54);
N -((4- (hydroxymethyl) -1- (4-methyl-3- (trifluoromethyl) phenethyl) piperidin-4-yl) methyl) -5-isobutyl-1-phenyl- 1 H -pyrazole-3-carboxamide (Compound 55);
N -((3- (hydroxymethyl) -1- (4-methyl-3- (trifluoromethyl) phenethyl) pyrrolidin-3-yl) methyl) -5-isobutyl-1-phenyl- 1 H -pyrazole-3-carboxamide (Compound 56);
( S ) -5-isobutyl-1-phenyl- N- (pyrrolidin-3-ylmethyl) -1 H -pyrazole-3-carboxamide (Compound 57);
( S ) -3-isopropyl- N- (pyrrolidin-3-ylmethyl) isoxazole-5-carboxamide (Compound 58);
Methyl 2,6-dimethyl-4- (3-nitrophenyl) -5-((( S ) -pyrrolidin-3-ylmethyl) carbamoyl) -1,4-dihydropyridine-3- Carboxylates (compound 59);
( R ) -N -((1- (3-chloro-5-fluorophenethyl) pyrrolidin-3-yl) methyl) -3-isopropylisoxazole-5-carboxamide (Compound 60) ;
( R ) -N -((1- (2- (3-chloro-5-fluorophenyl) acetyl) pyrrolidin-3-yl) methyl) -5-isobutyl-1-phenyl-1 H -pyra Sol-3-carboxamide (compound 61).
제 1 항에 있어서,
상기 화합물은 화합물 4, 9, 10, 11, 12, 13, 14, 16, 19, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 36, 39, 40, 41, 42, 43, 44, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55 및 56 으로 이루어진 군에서 선택된 것임을 특징으로 하는 화합물.
The method of claim 1,
The compound is compound 4, 9, 10, 11, 12, 13, 14, 16, 19, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 36, 39, 40, 41, 42, 43, 44, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55 and 56.
제 1 항에 있어서,
상기 화합물은 화합물 30, 48, 49, 50, 51, 52, 53, 54, 55 및 56 으로 이루어진 군에서 선택된 것임을 특징으로 하는 화합물.
The method of claim 1,
The compound is selected from the group consisting of compounds 30, 48, 49, 50, 51, 52, 53, 54, 55 and 56.
제 1 항 내지 제 6 항 중 어느 한 항에 따른 화합물을 포함하는, T-형 칼슘채널 관련 질환의 예방용 또는 치료용 약학 조성물.
A pharmaceutical composition for preventing or treating a T-type calcium channel related disease, comprising the compound according to any one of claims 1 to 6.
제 7 항에 있어서,
상기 T-형 칼슘채널 관련 질환은 간질, 고혈압, 협심증, 만성 통증, 신경성 통증, 및 암으로 이루어진 군에서 선택된 하나 이상인 것을 특징으로 하는 약학 조성물.
The method of claim 7, wherein
The T-type calcium channel-related diseases are epilepsy, high blood pressure, angina pectoris, chronic pain, neurological pain, and cancer, wherein the pharmaceutical composition, characterized in that at least one selected from the group consisting of.
제 7 항에 있어서,
T-형 칼슘채널에 대한 억제효능, 길항작용, 및 칼슘이동 억제 효능 중 하나 이상을 갖는 것을 특징으로 하는 약학 조성물.
The method of claim 7, wherein
Pharmaceutical composition, characterized in that it has at least one of inhibitory effect, antagonism, and calcium migration inhibitory effect on T-type calcium channel.
제 7 항에 있어서,
담체, 보조제 또는 희석제를 더 포함하는 것을 특징으로 하는 약학 조성물.
The method of claim 7, wherein
A pharmaceutical composition further comprising a carrier, adjuvant or diluent.
제 1 항 내지 제 6 항 중 어느 한 항에 따른 화합물을 포함하는, T-형 칼슘채널 관련 질환의 예방용 또는 개선용 식품 조성물.
A food composition for preventing or ameliorating a T-type calcium channel related disease, comprising the compound according to any one of claims 1 to 6.
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004105750A1 (en) * 2003-05-30 2004-12-09 Neuromed Technologies, Inc. 3-aminomethyl-pyrrolidines as n-type calcium channel blockers

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004105750A1 (en) * 2003-05-30 2004-12-09 Neuromed Technologies, Inc. 3-aminomethyl-pyrrolidines as n-type calcium channel blockers

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