KR20200096455A - Novel pyridine derivatives having inhibition activity against SHIP2 and pharmaceutical compositions with the components - Google Patents
Novel pyridine derivatives having inhibition activity against SHIP2 and pharmaceutical compositions with the components Download PDFInfo
- Publication number
- KR20200096455A KR20200096455A KR1020200096804A KR20200096804A KR20200096455A KR 20200096455 A KR20200096455 A KR 20200096455A KR 1020200096804 A KR1020200096804 A KR 1020200096804A KR 20200096804 A KR20200096804 A KR 20200096804A KR 20200096455 A KR20200096455 A KR 20200096455A
- Authority
- KR
- South Korea
- Prior art keywords
- compound
- oxy
- pyridin
- ethoxy
- dichlorobenzyl
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Psychiatry (AREA)
- Hospice & Palliative Care (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
본 발명은 신규한 피리딘 유도체에 대한 것으로, 더욱 상세하게는 지질 인산화효소인 SHIP2(SH2-containing-inositol-5-phosphatases)를 억제함으로써 알츠하이머병과 같은 퇴행성 뇌질환을 치료할 수 있는 신규한 피리딘 유도체 및/또는 이의 약학적으로 허용 가능한 염, 이들 화합물의 제조방법, 그리고 이들 화합물이 유효성분으로 함유된 약학 조성물에 관한 것이다.The present invention relates to a novel pyridine derivative, and more particularly, a novel pyridine derivative capable of treating degenerative brain diseases such as Alzheimer's disease by inhibiting SHIP2 (SH2-containing-inositol-5-phosphatases), a lipid kinase, and/ Or a pharmaceutically acceptable salt thereof, a method for preparing these compounds, and to a pharmaceutical composition containing these compounds as active ingredients.
알츠하이머성 치매는 점진적으로 기억력이 상실되는 퇴행성 뇌질환으로, 고령화 사회가 진행됨에 따라 치매 환자 수가 급증하면서 그 치료제 개발에 대한 중요성은 더욱 강조되고 있다. 치매 환자들의 뇌에서는 아밀로이드 베타에 의한 노인성 플라그 (senile plaque)와 타우단백질의 과인산화(hyperphosphorylation)에 의한 신경섬유 다발(neurofibrillary tangle)이 특징적으로 관찰된다. 아밀로이드 베타는 뉴런 표면의 다양한 수용체와 결합한다고 알려져 있으며, 특히 최근 연구에 따르면 FcrRllb 수용체(Fc region receptor II-b)와 결합하여 타우 단백질의 과인산화를 유발시킴과 동시에 알츠하이머성 치매과 같은 퇴행성 뇌질환으로 발전될 수 있다고 보고되고 있다.Alzheimer's dementia is a degenerative brain disease in which memory is gradually lost. As the aging society progresses, the number of patients with dementia rapidly increases, and the importance of the development of the treatment is more emphasized. In the brains of dementia patients, senile plaques caused by amyloid beta and neurofibrillary tangles caused by hyperphosphorylation of tau protein are characteristically observed. Amyloid beta is known to bind to various receptors on the surface of neurons.In particular, according to recent studies, it binds to the FcrRllb receptor (Fc region receptor II-b), inducing hyperphosphorylation of tau protein, and at the same time leading to degenerative brain diseases such as Alzheimer's dementia. It is reported that it can be improved.
한편, SHIP2는 세포 내 다양한 신호전달을 조절하는 포스파티딜이노시톨 (phospha- tidylinositol: PI)을 기질로 하는 지질 포스파타제(lipid phosphatase)이다. 특히 포스파티딜이노시톨(3,4,5)-트리포스페이트(PI(3,4,5)P3 : Phosphatidylinositol-3,4,5-trisphosphate(PtdIns-3,4,5-P3))를 PI(3,4)P2로 전환시킴으로서, 세포의 성장, 증식, 생존 등을 조절하는 역할을 한다. 그래서, 화합물을 이용한 SHIP2 단백질의 조절은 암, 염증성 질환, 당뇨 및 치매 등을 포함한 다양한 질병의 치료방법이 될 수 있다. On the other hand, SHIP2 is a lipid phosphatase based on phosphatidylinositol (PI), which regulates various signaling in cells. In particular, phosphatidylinositol (3,4,5)-triphosphate (PI(3,4,5)P3: Phosphatidylinositol-3,4,5-trisphosphate (PtdIns-3,4,5-P3)) was converted into PI(3, 4) By converting to P2, it plays a role in regulating cell growth, proliferation, and survival. Therefore, the control of SHIP2 protein using a compound can be a treatment method for various diseases including cancer, inflammatory diseases, diabetes and dementia.
특히, 아밀로이드 베타가 FcrRllb 수용체와 결합하게 되면, 세포 내에 존재하는 SHIP2 포스파타제가 활성화되고, GSK3beta(Glycogen synthase kinase-3 beta)의 활성화로 인한 타우 단백질의 과인산화가 기억상실 및 학습능력 저하를 일으킨다는 것에 착안했을 때, SHIP2 억제제를 활용한 효과적인 치매치료제 개발이 요구된다.In particular, when amyloid beta binds to the FcrRllb receptor, SHIP2 phosphatase present in cells is activated, and hyperphosphorylation of tau protein due to the activation of GSK3beta (Glycogen synthase kinase-3 beta) causes memory loss and learning ability decline. When conceived, there is a need to develop effective dementia treatments using SHIP2 inhibitors.
본 발명의 목적은 SHIP2 단백질을 억제함으로써 알츠하이머성 치매와 같은 퇴행성 뇌질환을 치료할 수 있는 피리딘 유도체, 또는 이의 약학적으로 허용 가능한 염 및/또는 그 제조방법을 제공하는데 있다. An object of the present invention is to provide a pyridine derivative capable of treating degenerative brain diseases such as Alzheimer's dementia by inhibiting SHIP2 protein, or a pharmaceutically acceptable salt thereof, and/or a method for preparing the same.
또한. 본 발명은 피리딘 유도체, 또는 이의 약학적으로 허용 가능한 염이 유효성분으로 포함되어 있는 SHIP2 활성 관련 질환의 치료 또는 예방용 약학 조성물을 제공하는데 또 다른 목적이 있다.Also. Another object of the present invention is to provide a pharmaceutical composition for the treatment or prevention of diseases related to SHIP2 activity, which contains a pyridine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
상기 목적을 달성하기 위하여, 본 발명은 하기 화학식 I로 표시되는 피리딘 유도체 및 약학적으로 허용 가능한 이의 염으로 이루어진 군으로부터 선택된 화합물이다:In order to achieve the above object, the present invention is a compound selected from the group consisting of a pyridine derivative represented by the following formula (I) and a pharmaceutically acceptable salt thereof:
[화학식 I][Formula I]
상기 화학식 I에서,In Formula I,
X. Y. 및 Z는 각각 독립적으로 탄소(C) 또는 질소(N)이고, 상기 X. Y. 및 Z 중 하나는 질소(N)이며,X. Y. and Z are each independently carbon (C) or nitrogen (N), and one of X. Y. and Z is nitrogen (N),
W는 수소(H) 또는 아민(NH2)이고,W is hydrogen (H) or amine (NH 2 ),
R1은 치환되지 않은 것이거나 또는 할로겐, 메톡시, 시아노, 트리플루오로메틸, 니트로 및 벤조일기로 이루어진 군에서 선택된 1개 내지 3개의 치환기이고,R 1 is unsubstituted or 1 to 3 substituents selected from the group consisting of halogen, methoxy, cyano, trifluoromethyl, nitro and benzoyl groups,
R2는 수소, 메틸(CH3) 또는 각각 다른 비대칭 중심을 가지는 (S), (R)-메틸(methyl)이고,R 2 is hydrogen, methyl (CH 3 ) or (S), (R)-methyl (methyl) each having a different asymmetric center,
R3은 비치환되거나 치환된 아릴 또는 헤테로아릴이고, 상기 치환된 아릴 또는 헤테로아릴은 메틸, 할로겐, 아민, 하이드록시, 시아노, 피페라진일, 피페리딘일, 피라닐, 알데하이드, 니트로, 메틸피페라진일, 메틸피롤리딘일, 메틸몰폴린일, 몰폴린일, 알데히드, 피롤리딘일메탄온, 메탄아민, 메틸아민, 다이메틸아민, 트리플루오로메틸, 아세틸피페리딘일, 페닐메탄아민 및 메탄올로 이루어진 군에서 선택된 1개 이상의 치환기로 치환된 것이다.R 3 is unsubstituted or substituted aryl or heteroaryl, and the substituted aryl or heteroaryl is methyl, halogen, amine, hydroxy, cyano, piperazinyl, piperidinyl, pyranyl, aldehyde, nitro, methyl Piperazinyl, methylpyrrolidinyl, methylmorpholinyl, morpholinyl, aldehyde, pyrrolidinylmethanone, methanamine, methylamine, dimethylamine, trifluoromethyl, acetylpiperidinyl, phenylmethanamine and It is substituted with one or more substituents selected from the group consisting of methanol.
본 발명에 따른 화학식 I의 화합물 및/또는 이의 약학적으로 허용 가능한 염은 SHIP2에 대하여 우수한 억제 활성을 나타내므로, SHIP2 단백질과 관련된 질환, 예컨대 알츠하이머성 치매, 기능 또는 거동으로부터 야기되는 퇴행성 뇌질환 등을 치료 또는 예방하는데 사용할 수 있다.Since the compound of formula I and/or a pharmaceutically acceptable salt thereof according to the present invention exhibits excellent inhibitory activity against SHIP2, diseases related to SHIP2 protein, such as Alzheimer's dementia, degenerative brain disease resulting from function or behavior, etc. It can be used to treat or prevent.
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.The present invention can be applied to a variety of transformations and may have various embodiments, and specific embodiments will be illustrated in the drawings and described in detail in the detailed description. However, this is not intended to limit the present invention to a specific embodiment, it is to be understood to include all conversions, equivalents, and substitutes included in the spirit and scope of the present invention. In describing the present invention, when it is determined that a detailed description of a related known technology may obscure the subject matter of the present invention, a 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 terms used in the present application are only used to describe specific embodiments, and are not intended to limit the present invention. Singular expressions include plural expressions unless the context clearly indicates otherwise. In the present application, terms such as "comprise" or "have" are intended to designate the presence of features, numbers, steps, actions, components, parts, or combinations thereof described in the specification, but one or more other features. It is to be understood that the presence or addition of elements or numbers, steps, actions, components, parts, or combinations thereof does not preclude in advance.
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 elements, but the elements should not be limited by the terms. These terms are only used for the purpose of distinguishing one component from another component.
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.Hereinafter, embodiments of the present application will be described in detail with reference to the accompanying drawings so that those of ordinary skill in the art may easily implement the present application. However, the present application may be implemented in various different forms, and is not limited to the embodiments described herein. In the drawings, parts irrelevant to the description are omitted in order to clearly describe the present application, and similar reference numerals are attached to similar parts throughout the specification.
본원 명세서 전체에서, 어떤 부분이 다른 부분과 “연결”되어 있다고 할 때, 이는 “직접적으로 연결”되어 있는 경우뿐 아니라, 그 중간에 다른 소자를 사이에 두고 “전기적으로 연결”되어 있는 경우도 포함한다. Throughout this specification, when a part is “connected” to another part, this includes not only “directly connected” but also “electrically connected” with another element in between. do.
본원 명세서 전체에서, 어떤 부재가 다른 부재 “상에” 위치하고 있다고 할 때, 이는 어떤 부재가 다른 부재에 접해 있는 경우뿐 아니라 두 부재 사이에 또 다른 부재가 존재하는 경우도 포함한다.Throughout this specification, when one member is positioned “on” another member, this includes not only the case where one member abuts another member, but also the case where another member exists between the two members.
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 the present specification, when a part “includes” a certain component, it means that the component may further include other components, not to exclude other components, unless specifically stated to the contrary. The terms “about”, “substantially”, etc., as used throughout this specification are used in or at a value close to that value when manufacturing and material tolerances specific to the stated meaning are given, and are understood herein. To help, accurate or absolute figures are used to prevent unconscionable abusers from unduly using the disclosed disclosure. As used throughout the specification of the present application, the term "step (to)" 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 the present specification, the term “combination(s) thereof” included in the expression of the Makushi format refers to one or more mixtures or combinations selected from the group consisting of components described in the expression of the Makushi format, It means to include at least one 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 otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by an expert skilled in the art to which the present invention belongs. In general, the nomenclature used in this specification 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 하기 화학식 I로 표시되는 피리딘 유도체 및 약학적으로 허용 가능한 이의 염으로 이루어진 군으로부터 선택된 화합물이다:The present invention is a compound selected from the group consisting of a pyridine derivative represented by the following formula (I) and a pharmaceutically acceptable salt thereof:
[화학식 I][Formula I]
상기 화학식 I에서,In Formula I,
X. Y. 및 Z는 각각 독립적으로 탄소(C) 또는 질소(N)이고, 상기 X. Y. 및 Z 중 하나는 질소(N)이며,X. Y. and Z are each independently carbon (C) or nitrogen (N), and one of X. Y. and Z is nitrogen (N),
W는 수소(H) 또는 아민(NH2)이고,W is hydrogen (H) or amine (NH 2 ),
R1은 치환되지 않은 것이거나 또는 할로겐, 메톡시, 시아노, 트리플루오로메틸, 니트로 및 벤조일기로 이루어진 군에서 선택된 1개 내지 3개의 치환기이고,R 1 is unsubstituted or 1 to 3 substituents selected from the group consisting of halogen, methoxy, cyano, trifluoromethyl, nitro and benzoyl groups,
R2는 수소, 메틸(CH3) 또는 각각 다른 비대칭 중심을 가지는 (S), (R)-메틸(methyl)이고,R 2 is hydrogen, methyl (CH 3 ) or (S), (R)-methyl (methyl) each having a different asymmetric center,
R3은 비치환되거나 치환된 아릴 또는 헤테로아릴이고, 상기 치환된 아릴 또는 헤테로아릴은 메틸, 할로겐, 아민, 하이드록시, 시아노, 피페라진일, 피페리딘일, 피라닐, 알데하이드, 니트로, 메틸피페라진일, 메틸피롤리딘일, 메틸몰폴린일, 몰폴린일, 알데히드, 피롤리딘일메탄온, 메탄아민, 메틸아민, 다이메틸아민, 트리플루오로메틸, 아세틸피페리딘일, 페닐메탄아민 및 메탄올로 이루어진 군에서 선택된 1개 이상의 치환기로 치환된 것일 수 있다.R 3 is unsubstituted or substituted aryl or heteroaryl, and the substituted aryl or heteroaryl is methyl, halogen, amine, hydroxy, cyano, piperazinyl, piperidinyl, pyranyl, aldehyde, nitro, methyl Piperazinyl, methylpyrrolidinyl, methylmorpholinyl, morpholinyl, aldehyde, pyrrolidinylmethanone, methanamine, methylamine, dimethylamine, trifluoromethyl, acetylpiperidinyl, phenylmethanamine and It may be substituted with one or more substituents selected from the group consisting of methanol.
본 발명의 일 구현예로서, 상기 화학식 I에서, 상기 X는 질소(N)이고, 상기 R1은 할로겐으로 이루어진 2개 내지 3개의 치환기이고, 상기 R2는 수소 또는 각각 다른 비대칭 중심을 가지는 (S), (R)-메틸(methyl)이고, 상기 R3은 비치환되거나 치환된 아릴, 피리딘, 피리미딘, 피라졸, 티오펜, 인돌린온, 스티릴기, 또는 피롤로피리딘이고, 상기 치환된 아릴, 피리딘, 피리미딘, 피라졸, 티오펜, 인돌린온, 스티릴기, 또는 피롤로피리딘은 할로겐, 아민, 하이드록시, 시아노, 피페라진일, 피페리딘일, 피라닐, 알데하이드, 니트로, 알데히드, 메틸아민, 다이메틸아민, 및 아세틸피페리딘일로 이루어진 군에서 선택된 1개 내지 3개의 치환기로 치환된 것이 가능하다. As an embodiment of the present invention, in Formula I, X is nitrogen (N), R 1 is 2 to 3 substituents consisting of halogen, and R 2 is hydrogen or each having a different asymmetric center ( S), (R)-methyl (methyl), wherein R 3 is unsubstituted or substituted aryl, pyridine, pyrimidine, pyrazole, thiophene, indolinone, styryl group, or pyrrolopyridine, and the substituted Aryl, pyridine, pyrimidine, pyrazole, thiophene, indolinone, styryl group, or pyrrolopyridine is halogen, amine, hydroxy, cyano, piperazinyl, piperidinyl, pyranyl, aldehyde, nitro, aldehyde , Methylamine, dimethylamine, and it is possible to be substituted with 1 to 3 substituents selected from the group consisting of acetylpiperidinyl.
바람직하게는, 상기 화학식 I에서, 상기 X는 질소(N)이고, 상기 W는 수소(H)이고, 상기 R1은 할로겐으로 이루어진 2개 내지 3개의 치환기이고, 상기 R2는 수소 또는 비대칭 중심을 가지는 (R)-메틸(methyl)이고, 상기 R3은 비치환되거나 치환된 피리딘, 피리미딘, 피라졸, 또는 티오펜이고, 상기 치환된 피리딘, 피리미딘, 피라졸, 또는 티오펜은 할로겐, 아민, 하이드록시, 시아노, 피페라진일, 피페리딘일, 및 아세틸피페리딘일로 이루어진 군에서 선택된 1개 내지 3개의 치환기로 치환된 것이 효과적이다. Preferably, in the formula (I), X is nitrogen (N), W is hydrogen (H), R 1 is 2 to 3 substituents composed of halogen, and R 2 is hydrogen or an asymmetric center Having (R)-methyl (methyl), wherein R 3 is unsubstituted or substituted pyridine, pyrimidine, pyrazole, or thiophene, and the substituted pyridine, pyrimidine, pyrazole, or thiophene is halogen , Amine, hydroxy, cyano, piperazinyl, piperidinyl, and substituted with 1 to 3 substituents selected from the group consisting of acetylpiperidinyl is effective.
더욱 바람직하게는, 상기 화학식 I에서, 상기 X는 질소(N)이고, 상기 W는 수소(H)이고, 상기 R1은 할로겐으로 이루어진 2개 내지 3개의 치환기이고, 상기 R2는 수소 또는 비대칭 중심을 가지는 (R)-메틸(methyl)이고, 상기 R3은 비치환되거나 치환된 피리미딘, 또는 티오펜이고, 상기 치환된 피리미딘, 또는 티오펜은 할로겐, 아민, 및 시아노로 이루어진 군에서 선택된 1개 내지 3개의 치환기로 치환된 것이 더욱 효과적이다. More preferably, in Formula I, X is nitrogen (N), W is hydrogen (H), R 1 is 2 to 3 substituents consisting of halogen, and R 2 is hydrogen or asymmetric (R)-methyl (methyl) having a center, R 3 is an unsubstituted or substituted pyrimidine, or thiophene, and the substituted pyrimidine, or thiophene is from the group consisting of halogen, amine, and cyano It is more effective to be substituted with 1 to 3 substituents selected.
본 발명에 따른 화합물을 정의하는데 사용된 용어들은 하기와 같은 의미를 갖는다.The terms used to define the compounds according to the present invention have the following meanings.
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 "시아노"는 -CN으로 나타낼 수 있고, 탄소와 질소가 1원자씩 결합한 원자단으로 삼중결합을 가지며, 다른 원자나 작용기가 탄소 원자에 결합하여 사이안화수소, 금속 사이안화물 또는 나이트릴일 수 있다.The term "cyano" may be represented by -CN, has a triple bond as an atomic group in which carbon and nitrogen are bonded one atom at a time, and other atoms or functional groups are bonded to the carbon atom to be hydrogen cyanide, metal cyanide or nitrile have.
용어 "니트로"는 -NO2로 나타내는 작용기를 의미한다.The term "nitro" means a functional group represented by -NO 2 .
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 covalent pi electron system, for example a monocyclic or fused ring polycyclic (ie, rings dividing adjacent pairs of carbon atoms) groups. . That is, in the present specification, aryl may include phenyl, naphthyl, and biaryl unless otherwise defined. In one embodiment of the present invention, aryl refers to an aromatic ring having 6 to 10 carbon atoms.
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 a disease when used in a subject showing onset symptoms.
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 a combination thereof, as necessary, together with the compound of the present invention.
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 a compound.
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 is diluted in water to dissolve the compound as well as stabilize the biologically active form of the compound of interest.
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 in this specification may be interpreted as meanings commonly understood by one of ordinary skill in the art to which the present invention belongs, unless otherwise defined.
본 발명에 따른 상기 화학식 I로 표시되는 피리딘 유도체에 있어서, 치환기를 좀 더 자세히 설명하면 다음과 같다.In the pyridine derivative represented by Formula I according to the present invention, the substituents will be described in more detail as follows.
'아릴기'는 방향족 고리기를 의미하는 것으로, 아릴은 최소한 6개의 원자를 가진 하나의 고리, 또는 최소한 10개의 원자를 가진 두 개의 고리나 인접 탄소 원자에 이중 결합으로 공명 안정화된 상태를 말하며, 아릴기로는 페닐기 등이 포함될 수 있다. '헤테로아릴기'는 포화 또는 불포화이거나 단일고리 또는 결합고리(fused ring)에 관계없이 안정한 5 내지 6개의 원자로 구성된 헤테로고리를 나타내며, N, S로 구성된 1 내지 3개의 헤테로원자 및 탄소원자로 구성되며, 이러한 헤테로아릴기의 예를 들면, 피리디닐, 피리미디닐, 피라졸릴, 티오펜닐 등이 포함될 수 있다. 상기한 헤테로아릴기는 치환되지 않거나 또는 메틸, 할로겐, 아미노, 하이드록시, 시아노, 피페라진일, 피페리딘일, 피라닐, 피롤리딘일, 알데하이드, 니트로, 메탄아민, 메탄올, 아세틸, 알데히드, 몰폴린일 등에서 선택된 치환체가 하나 이상 치환된 것일 수도 있다.'Aryl group' refers to an aromatic ring group, and aryl refers to a state in which one ring having at least 6 atoms, two rings having at least 10 atoms, or a state in which the resonance is stabilized by a double bond to an adjacent carbon atom. The group may include a phenyl group and the like. 'Heteroaryl group' represents a heterocycle consisting of 5 to 6 atoms, which is saturated or unsaturated or stable regardless of a single ring or a fused ring, and consists of 1 to 3 heteroatoms and carbon atoms consisting of N and S. , Examples of such a heteroaryl group may include pyridinyl, pyrimidinyl, pyrazolyl, thiophenyl, and the like. The aforementioned heteroaryl group is unsubstituted or methyl, halogen, amino, hydroxy, cyano, piperazinyl, piperidinyl, pyranyl, pyrrolidinyl, aldehyde, nitro, methanamine, methanol, acetyl, aldehyde, mole One or more substituents selected from folinyl may be substituted.
본 발명에 따른 상기 화학식 I로 표시되는 피리딘 유도체들은 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, 메틸설폰산, 트리플루오로아세트산과 같은 무독성의 유기산과 함께 결합하여 약학적으로 허용 가능한 산부가 염을 형성할 수도 있다.The pyridine derivatives represented by Formula I according to the present invention may form a pharmaceutically acceptable salt by a method conventional in the art. For example, non-toxic inorganic acids such as hydrochloric acid, bromic acid, sulfonic acid, amidosulfuric acid, phosphoric acid, nitric acid, or acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, tartaric acid, citric acid, paratoluenesulfonic acid, methylsulfonic acid , It may be combined with a non-toxic organic acid such as trifluoroacetic acid to form a pharmaceutically acceptable acid addition salt.
본 발명에 따른 화합물로서, 상기 화학식 I로 표시되는 5각형의 헤테로방향족 화합물을 예시하면 다음과 같다. 즉, 본 발명에 따른 화학식 I의 화합물은 하기 화합물 1 내지 화합물 163으로 이루어진 군에서 선택된 것을 특징으로 하는 화합물일 수 있다.As the compound according to the present invention, a pentagonal heteroaromatic compound represented by Formula I is illustrated as follows. That is, the compound of formula I according to the present invention may be a compound selected from the group consisting of the following compounds 1 to 163.
(화합물 1) tert-부틸 4-(4-(5-(벤질옥시)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트;(Compound 1) tert-butyl 4-(4-(5-(benzyloxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;
(화합물 2) 3-(벤질옥시)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘;(Compound 2) 3-(benzyloxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridine;
(화합물 3) tert-부틸 4-(4-(5-((2-시아노벤질)옥시)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트;(Compound 3) tert-butyl 4-(4-(5-((2-cyanobenzyl)oxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate ;
(화합물 4) 2-(((5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)옥시)메틸)벤조니트릴;(Compound 4) 2-(((5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)oxy)methyl)benzonitrile;
(화합물 5) tert-부틸 4-(4-(5-((2-(트리플루오로메틸)벤질)옥시)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트;(Compound 5) tert-butyl 4-(4-(5-((2-(trifluoromethyl)benzyl)oxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1 -Carboxylate;
(화합물 6) 3-(1-(피페리딘-4-일)-1H-피라졸-4-일)-5-((2-(트리플루오로메틸)벤질)옥시)피리딘;(Compound 6) 3-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-5-((2-(trifluoromethyl)benzyl)oxy)pyridine;
(화합물 7) tert-부틸 4-(4-(5-((2-클로로-4-플루오로벤질)옥시)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트;(Compound 7) tert-Butyl 4-(4-(5-((2-chloro-4-fluorobenzyl)oxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1 -Carboxylate;
(화합물 8) 3-((2-클로로-4-플루오로벤질)옥시)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘;(Compound 8) 3-((2-chloro-4-fluorobenzyl)oxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridine;
(화합물 9) tert-부틸 4-(4-(5-((2,6-디플루오로벤질)옥시)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트;(Compound 9) tert-Butyl 4-(4-(5-((2,6-difluorobenzyl)oxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1- Carboxylate;
(화합물 10) 3-((2,6-디플루오로벤질)옥시)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘;(Compound 10) 3-((2,6-difluorobenzyl)oxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridine;
(화합물 11) tert-부틸 4-(4-(5-((4-클로로벤질)옥시)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트;(Compound 11) tert-butyl 4-(4-(5-((4-chlorobenzyl)oxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;
(화합물 12) 3-((4-클로로벤질)옥시)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘;(Compound 12) 3-((4-chlorobenzyl)oxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridine;
(화합물 13) tert-부틸 4-(4-(5-((4-시아노벤질)옥시)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트;(Compound 13) tert-Butyl 4-(4-(5-((4-cyanobenzyl)oxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate ;
(화합물 14) 3-(벤질옥시)-5-(1-(1-벤질피페리딘-4-일)-1H-피라졸-4-일)피리딘;(Compound 14) 3-(Benzyloxy)-5-(1-(1-benzylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridine;
(화합물 15) tert-부틸 4-(4-(5-((2,4-디클로로벤질)옥시)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트;(Compound 15) tert-butyl 4-(4-(5-((2,4-dichlorobenzyl)oxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxyl Rate;
(화합물 16) 3-((2,4-디클로로벤질)옥시)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘;(Compound 16) 3-((2,4-dichlorobenzyl)oxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridine;
(화합물 17) tert-부틸 (R)-4-(4-(5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트;(Compound 17) tert-butyl (R)-4-(4-(5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazole- 1-yl)piperidine-1-carboxylate;
(화합물 18) (R)-3-(1-(2,6-디클로로-3-플루오로페닐)에톡시)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘;(Compound 18) (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazole- 4-yl)pyridine;
(화합물 19) tert-부틸 (S)-4-(4-(5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트;(Compound 19) tert-butyl (S)-4-(4-(5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazole- 1-yl)piperidine-1-carboxylate;
(화합물 20) (S)-3-(1-(2,6-디클로로-3-플루오로페닐)에톡시)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘;(Compound 20) (S)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazole- 4-yl)pyridine;
(화합물 21) (R)-5-(1-(2,6-디플루오로페닐)에톡시)-6'-니트로-3,3'-비피리딘;(Compound 21) (R)-5-(1-(2,6-difluorophenyl)ethoxy)-6'-nitro-3,3'-bipyridine;
(화합물 22) 6'-니트로-5-((2-(트리플루오로메틸)벤질)옥시)-3,3'-비피리딘;(Compound 22) 6'-nitro-5-((2-(trifluoromethyl)benzyl)oxy)-3,3'-bipyridine;
(화합물 23) 2-(((6'-니트로-[3,3'-비피리딘]-5-일)옥시)메틸)벤조니트릴;(Compound 23) 2-(((6'-Nitro-[3,3'-bipyridin]-5-yl)oxy)methyl)benzonitrile;
(화합물 24) 5-((4-메톡시벤질)옥시)-6'-니트로-3,3'-비피리딘;(Compound 24) 5-((4-methoxybenzyl)oxy)-6'-nitro-3,3'-bipyridine;
(화합물 25) 5-((4-클로로벤질)옥시)-6'-니트로-3,3'-비피리딘;(Compound 25) 5-((4-chlorobenzyl)oxy)-6'-nitro-3,3'-bipyridine;
(화합물 26) 6'-니트로-5-((4-니트로벤질)옥시)-3,3'-비피리딘;(Compound 26) 6'-Nitro-5-((4-nitrobenzyl)oxy)-3,3'-bipyridine;
(화합물 27) 5-(5-((2-클로로-4-플루오로벤질)옥시)피리딘-3-일)피리미딘-2-아민;(Compound 27) 5-(5-((2-chloro-4-fluorobenzyl)oxy)pyridin-3-yl)pyrimidin-2-amine;
(화합물 28) 5'-((2,6-디플루오로벤질)옥시)-[3,3'-비피리딘]-6-아민;(Compound 28) 5'-((2,6-difluorobenzyl)oxy)-[3,3'-bipyridin]-6-amine;
(화합물 29) 5'-((2-(트리플루오로메틸)벤질)옥시)-[3,3'-비피리딘]-6-아민;(Compound 29) 5'-((2-(trifluoromethyl)benzyl)oxy)-[3,3'-bipyridin]-6-amine;
(화합물 30) 2-(((6'-아미노-[3,3'-비피리딘]-5-일)옥시)메틸)벤조니트릴;(Compound 30) 2-(((6'-amino-[3,3'-bipyridin]-5-yl)oxy)methyl)benzonitrile;
(화합물 31) 5'-((4-메톡시벤질)옥시)-[3,3'-비피리딘]-6-아민;(Compound 31) 5'-((4-methoxybenzyl)oxy)-[3,3'-bipyridin]-6-amine;
(화합물 32) 5'-((4-클로로벤질)옥시)-[3,3'-비피리딘]-6-아민;(Compound 32) 5'-((4-chlorobenzyl)oxy)-[3,3'-bipyridin]-6-amine;
(화합물 33) 5'-((4-니트로벤질)옥시)-[3,3'-비피리딘]-6-아민;(Compound 33) 5'-((4-nitrobenzyl)oxy)-[3,3'-bipyridin]-6-amine;
(화합물 34) 4-(((6'-아미노-[3,3'-비피리딘]-5-일)옥시)메틸)페닐 벤조에이트;(Compound 34) 4-(((6'-amino-[3,3'-bipyridin]-5-yl)oxy)methyl)phenyl benzoate;
(화합물 35) (R)-1-(4-(4-(5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-일)에탄-1-온;(Compound 35) (R)-1-(4-(4-(5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazole- 1-yl)piperidin-1-yl)ethan-1-one;
(화합물 36) (R)-3-(1-(2,6-디클로로-3-플루오로페닐)에톡시)-5-(1-(1-메틸피페리딘-4-일)-1H-피라졸-4-일)피리딘;(Compound 36) (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(1-methylpiperidin-4-yl)-1H- Pyrazol-4-yl)pyridine;
(화합물 37) (R)-3-(1-(2,6-디클로로-3-플루오로페닐)에톡시)-5-(1-(테트라하이드로-2H-파이란-4-일)-1H-피라졸-4-일)피리딘;(Compound 37) (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H- Pyrazol-4-yl)pyridine;
(화합물 38) (R)-3-(1-(2,6-디클로로-3-플루오로페닐)에톡시)-5-(1-메틸-1H-피라졸-4-일)피리딘;(Compound 38) (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-methyl-1H-pyrazol-4-yl)pyridine;
(화합물 39) (R)-3-(1-(2,6-디클로로-3-플루오로페닐)에톡시)-5-(1H-피라졸-4-일)피리딘;(Compound 39) (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1H-pyrazol-4-yl)pyridine;
(화합물 40) (R)-4-(5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-3-일)아닐린;(Compound 40) (R)-4-(5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)aniline;
(화합물 41) tert-부틸 (R)-4-(5-(5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-3-일)피리미딘-2-일)피페라진-1-카르복실레이트;(Compound 41) tert-butyl (R)-4-(5-(5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)pyrimidin-2-yl ) Piperazine-1-carboxylate;
(화합물 42) (R)-5-(5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-3-일)-2-(피페라진-1-일)피리미딘;(Compound 42) (R)-5-(5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-2-(piperazin-1-yl)pyri Mydin;
(화합물 43) (R)-5-(5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-3-일)피리미딘-2-아민;(Compound 43) (R)-5-(5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)pyrimidin-2-amine;
(화합물 44) (R)-4-(5-(5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-3-일)피리미딘-2-일)몰폴린;(Compound 44) (R)-4-(5-(5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)pyrimidin-2-yl)morpholine ;
(화합물 45) (R)-5-(5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-3-일)-N-메틸피리미딘-2-아민;(Compound 45) (R)-5-(5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-N-methylpyrimidin-2-amine;
(화합물 46) (R)-5-(5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-3-일)-N,N-디메틸피리미딘-2-아민;(Compound 46) (R)-5-(5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-N,N-dimethylpyrimidin-2-amine ;
(화합물 47) (R)-5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)-6'-니트로-3,3'-비피리딘;(Compound 47) (R)-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-6'-nitro-3,3'-bipyridine;
(화합물 48) (R)-5'-(1-(2,6-디클로로-3-플루오로페닐)에톡시)-[3,3'-비피리딘]-6-아민;(Compound 48) (R)-5'-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-[3,3'-bipyridin]-6-amine;
(화합물 49) (R)-5-(5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-3-일)티오펜-2-카르보니트릴;(Compound 49) (R)-5-(5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)thiophene-2-carbonitrile;
(화합물 50) (S)-1-(4-(4-(5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-일)에탄-1-온;(Compound 50) (S)-1-(4-(4-(5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazole- 1-yl)piperidin-1-yl)ethan-1-one;
(화합물 51) (S)-3-(1-(2,6-디클로로-3-플루오로페닐)에톡시)-5-(1-(1-메틸피페리딘-4-일)-1H-피라졸-4-일)피리딘;(Compound 51) (S)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(1-methylpiperidin-4-yl)-1H- Pyrazol-4-yl)pyridine;
(화합물 52) (S)-5-(5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-3-일)티오펜-2-카르보니트릴;(Compound 52) (S)-5-(5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)thiophene-2-carbonitrile;
(화합물 53) (S)-5'-(1-(2,6-디클로로-3-플루오로페닐)에톡시)-[3,3'-비피리딘]-6-아민;(Compound 53) (S)-5'-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-[3,3'-bipyridin]-6-amine;
(화합물 54) tert-부틸 (S)-4-(5'-(1-(2,6-디클로로-3-플루오로페닐)에톡시)-[3,3'-비피리딘]-6-일)피페라진-1-카르복실레이트;(Compound 54) tert-butyl (S)-4-(5'-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-[3,3'-bipyridin]-6-yl ) Piperazine-1-carboxylate;
(화합물 55) (S)-5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)-6'-(피페라진-1-일)-3,3'-비피리딘;(Compound 55) (S)-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-6'-(piperazin-1-yl)-3,3'-bipyridine;
(화합물 56) (S)-5-(5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-3-일)피리미딘-2-아민;(Compound 56) (S)-5-(5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)pyrimidin-2-amine;
(화합물 57) (S)-5-(5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-3-일)-N-메틸피리미딘-2-아민;(Compound 57) (S)-5-(5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-N-methylpyrimidin-2-amine;
(화합물 58) (S)-5-(5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-3-일)-N,N-디메틸피리미딘-2-아민;(Compound 58) (S)-5-(5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-N,N-dimethylpyrimidin-2-amine ;
(화합물 59) tert-부틸 (S)-4-(5-(5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-3-일)피리미딘-2-일)피페라진-1-카르복실레이트;(Compound 59) tert-butyl (S)-4-(5-(5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)pyrimidin-2-yl ) Piperazine-1-carboxylate;
(화합물 60) (S)-5-(5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-3-일)-2-(피페라진-1-일)피리미딘;(Compound 60) (S)-5-(5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-2-(piperazin-1-yl)pyri Mydin;
(화합물 61) 1-(4-(4-(5-((2,4-디클로로벤질)옥시)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-일)에탄-1-온;(Compound 61) 1-(4-(4-(5-((2,4-dichlorobenzyl)oxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl) Ethan-1-one;
(화합물 62) 3-((2,4-디클로로벤질)옥시)-5-(1-(1-메틸피페리딘-4-일)-1H-피라졸-4-일)피리딘;(Compound 62) 3-((2,4-dichlorobenzyl)oxy)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridine;
(화합물 63) 3-((2,4-디클로로벤질)옥시)-5-(1-(테트라하이드로-2H-파이란-2-일)-1H-피라졸-4-일)피리딘;(Compound 63) 3-((2,4-dichlorobenzyl)oxy)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyridine;
(화합물 64) 3-((2,4-디클로로벤질)옥시)-5-(1-(테트라하이드로-2H-파이란-2-일)-1H-피라졸-5-일)피리딘;(Compound 64) 3-((2,4-dichlorobenzyl)oxy)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridine;
(화합물 65) 5-(5-((2,4-디클로로벤질)옥시)피리딘-3-일)피리미딘-2-아민;(Compound 65) 5-(5-((2,4-dichlorobenzyl)oxy)pyridin-3-yl)pyrimidin-2-amine;
(화합물 66) 5-(5-((2,4-디클로로벤질)옥시)피리딘-3-일)-N-메틸피리미딘-2-아민;(Compound 66) 5-(5-((2,4-dichlorobenzyl)oxy)pyridin-3-yl)-N-methylpyrimidin-2-amine;
(화합물 67) 5-(5-((2,4-디클로로벤질)옥시)피리딘-3-일)-N,N-디메틸피리미딘-2-아민;(Compound 67) 5-(5-((2,4-dichlorobenzyl)oxy)pyridin-3-yl)-N,N-dimethylpyrimidin-2-amine;
(화합물 68) tert-부틸 4-(5-(5-((2,4-디클로로벤질)옥시)피리딘-3-일)피리미딘-2-일)피페라진-1-카르복실레이트;(Compound 68) tert-butyl 4-(5-(5-((2,4-dichlorobenzyl)oxy)pyridin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate;
(화합물 69) 5-(5-((2,4-디클로로벤질)옥시)피리딘-3-일)-2-(피페라진-1-일)피리미딘;(Compound 69) 5-(5-((2,4-dichlorobenzyl)oxy)pyridin-3-yl)-2-(piperazin-1-yl)pyrimidine;
(화합물 70) 5-((2,4-디클로로벤질)옥시)-3,3'-비피리딘;(Compound 70) 5-((2,4-dichlorobenzyl)oxy)-3,3'-bipyridine;
(화합물 71) 5-((2,4-디클로로벤질)옥시)-6'-니트로-3,3'-비피리딘;(Compound 71) 5-((2,4-dichlorobenzyl)oxy)-6'-nitro-3,3'-bipyridine;
(화합물 72) 5'-((2,4-디클로로벤질)옥시)-[3,3'-비피리딘]-6-아민;(Compound 72) 5'-((2,4-dichlorobenzyl)oxy)-[3,3'-bipyridin]-6-amine;
(화합물 73) 5'-((2,4-디클로로벤질)옥시)-[3,3'-비피리딘]-6-카르보니트릴;(Compound 73) 5'-((2,4-dichlorobenzyl)oxy)-[3,3'-bipyridin]-6-carbonitrile;
(화합물 74) 5-((2,4-디클로로벤질)옥시)-6'-플루오로-3,3'-비피리딘;(Compound 74) 5-((2,4-dichlorobenzyl)oxy)-6'-fluoro-3,3'-bipyridine;
(화합물 75) 5-((2,4-디클로로벤질)옥시)-6'-메틸-3,3'-비피리딘;(Compound 75) 5-((2,4-dichlorobenzyl)oxy)-6'-methyl-3,3'-bipyridine;
(화합물 76) 5'-((2,4-디클로로벤질)옥시)-5-니트로-[3,3'-비피리딘]-6-아민;(Compound 76) 5'-((2,4-dichlorobenzyl)oxy)-5-nitro-[3,3'-bipyridin]-6-amine;
(화합물 77) 5'-((2,4-디클로로벤질)옥시)-5-(트리플루오로메틸)-[3,3'-비피리딘]-6-아민;(Compound 77) 5'-((2,4-dichlorobenzyl)oxy)-5-(trifluoromethyl)-[3,3'-bipyridin]-6-amine;
(화합물 78) tert-부틸 4-(5'-((2,4-디클로로벤질)옥시)-[3,3'-비피리딘]-6-일)피페라진-1-카르복실레이트;(Compound 78) tert-butyl 4-(5'-((2,4-dichlorobenzyl)oxy)-[3,3'-bipyridin]-6-yl)piperazine-1-carboxylate;
(화합물 79) 5-((2,4-디클로로벤질)옥시)-6'-(피페라진-1-일)-3,3'-비피리딘;(Compound 79) 5-((2,4-dichlorobenzyl)oxy)-6'-(piperazin-1-yl)-3,3'-bipyridine;
(화합물 80) 5'-((2,4-디클로로벤질)옥시)-[3,3'-비피리딘]-6-올;(Compound 80) 5'-((2,4-dichlorobenzyl)oxy)-[3,3'-bipyridin]-6-ol;
(화합물 81) 5-(5-((2,4-디클로로벤질)옥시)피리딘-3-일)-1H-피롤로[2,3-b]피리딘;(Compound 81) 5-(5-((2,4-dichlorobenzyl)oxy)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine;
(화합물 82) 5'-((2,4-디클로로벤질)옥시)-N-메틸-[3,3'-비피리딘]-6-아민;(Compound 82) 5'-((2,4-dichlorobenzyl)oxy)-N-methyl-[3,3'-bipyridin]-6-amine;
(화합물 83) 5-(5-((2,4-디클로로벤질)옥시)피리딘-3-일)티오펜-2-카르보니트릴;(Compound 83) 5-(5-((2,4-dichlorobenzyl)oxy)pyridin-3-yl)thiophene-2-carbonitrile;
(화합물 84) (5-(5-((2,4-디클로로벤질)옥시)피리딘-3-일)티오펜-2-일)메탄아민;(Compound 84) (5-(5-((2,4-dichlorobenzyl)oxy)pyridin-3-yl)thiophen-2-yl)methanamine;
(화합물 85) 4-(5-((2,4-디클로로벤질)옥시)피리딘-3-일)벤즈아미드;(Compound 85) 4-(5-((2,4-dichlorobenzyl)oxy)pyridin-3-yl)benzamide;
(화합물 86) 6-(5-((2,4-디클로로벤질)옥시)피리딘-3-일)인돌린-2-온;(Compound 86) 6-(5-((2,4-dichlorobenzyl)oxy)pyridin-3-yl)indolin-2-one;
(화합물 87) (4-(5-((2,4-디클로로벤질)옥시)피리딘-3-일)페닐)(피롤리딘-1-일)메탄온;(Compound 87) (4-(5-((2,4-dichlorobenzyl)oxy)pyridin-3-yl)phenyl)(pyrrolidin-1-yl)methanone;
(화합물 88) (3-(5-((2,4-디클로로벤질)옥시)피리딘-3-일)페닐)(피롤리딘-1-일)메탄온;(Compound 88) (3-(5-((2,4-dichlorobenzyl)oxy)pyridin-3-yl)phenyl)(pyrrolidin-1-yl)methanone;
(화합물 89) tert-부틸 5-((2,4-디클로로벤질)옥시)-3',6'-디하이드로-[3,4'-비피리딘]-1'(2'H)-카르복실레이트;(Compound 89) tert-butyl 5-((2,4-dichlorobenzyl)oxy)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxyl Rate;
(화합물 90) 5-((2,4-디클로로벤질)옥시)-1',2',3',6'-테트라하이드로-3,4'-b비피리딘;(Compound 90) 5-((2,4-dichlorobenzyl)oxy)-1',2',3',6'-tetrahydro-3,4'-b bipyridine;
(화합물 91) (E)-3-(3,5-비s(트리플루오로메틸)스티릴)-5-((2,4-디클로로벤질)옥시)피리딘;(Compound 91) (E)-3-(3,5-bis(trifluoromethyl)styryl)-5-((2,4-dichlorobenzyl)oxy)pyridine;
(화합물 92) 5-(5-((2,4-디클로로벤질)옥시)피리딘-3-일)티오펜-2-카르바알데히드;(Compound 92) 5-(5-((2,4-dichlorobenzyl)oxy)pyridin-3-yl)thiophene-2-carbaaldehyde;
(화합물 93) tert-부틸 4-((5-(5-((2,4-디클로로벤질)옥시)피리딘-3-일)티오펜-2-일)메틸)피페라진-1-카르복실레이트;(Compound 93) tert-butyl 4-((5-(5-((2,4-dichlorobenzyl)oxy)pyridin-3-yl)thiophen-2-yl)methyl)piperazine-1-carboxylate ;
(화합물 94) 1-((5-(5-((2,4-디클로로벤질)옥시)피리딘-3-일)티오펜-2-일)메틸)피페라진;(Compound 94) 1-((5-(5-((2,4-dichlorobenzyl)oxy)pyridin-3-yl)thiophen-2-yl)methyl)piperazine;
(화합물 95) 4-((5-(5-((2,4-디클로로벤질)옥시)피리딘-3-일)티오펜-2-일)메틸)몰폴린;(Compound 95) 4-((5-(5-((2,4-dichlorobenzyl)oxy)pyridin-3-yl)thiophen-2-yl)methyl)morpholine;
(화합물 96) 3-((2,4-디클로로벤질)옥시)-5-(5-(피롤리딘-1-일메틸)티오펜-2-일)피리딘;(Compound 96) 3-((2,4-dichlorobenzyl)oxy)-5-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)pyridine;
(화합물 97) 3-((2,4-디클로로벤질)옥시)-5-(5-(피페리딘-1-일메틸)티오펜-2-일)피리딘;(Compound 97) 3-((2,4-dichlorobenzyl)oxy)-5-(5-(piperidin-1-ylmethyl)thiophen-2-yl)pyridine;
(화합물 98) (E)-1-(5-(5-((2,4-디클로로벤질)옥시)피리딘-3-일)티오펜-2-일)-N-페닐메탄이민;(Compound 98) (E)-1-(5-(5-((2,4-dichlorobenzyl)oxy)pyridin-3-yl)thiophen-2-yl)-N-phenylmethanimine;
(화합물 99) 3-((2,4-디클로로벤질)옥시)-5-(티오펜-2-일)피리딘;(Compound 99) 3-((2,4-dichlorobenzyl)oxy)-5-(thiophen-2-yl)pyridine;
(화합물 100) 3-((2,4-디클로로벤질)옥시)-5-(티오펜-3-일)피리딘;(Compound 100) 3-((2,4-dichlorobenzyl)oxy)-5-(thiophen-3-yl)pyridine;
(화합물 101) 3-([2,2'-비티오펜]-5-일)-5-((2,4-디클로로벤질)옥시)피리딘;(Compound 101) 3-([2,2'-bithiophene]-5-yl)-5-((2,4-dichlorobenzyl)oxy)pyridine;
(화합물 102) (5-(5-((2,4-디클로로벤질)옥시)피리딘-3-일)티오펜-2-일)메탄올;(Compound 102) (5-(5-((2,4-dichlorobenzyl)oxy)pyridin-3-yl)thiophen-2-yl)methanol;
(화합물 103) 5-(5-(1-(2,4-디클로로페닐)에톡시)피리딘-3-일)피리미딘-2-아민;(Compound 103) 5-(5-(1-(2,4-dichlorophenyl)ethoxy)pyridin-3-yl)pyrimidin-2-amine;
(화합물 104) 5'-(1-(2,4-디클로로페닐)에톡시)-N-메틸-[3,3'-비피리딘]-6-아민;(Compound 104) 5'-(1-(2,4-dichlorophenyl)ethoxy)-N-methyl-[3,3'-bipyridin]-6-amine;
(화합물 105) 5-(5-(1-(2,4-디클로로페닐)에톡시)피리딘-3-일)티오펜-2-카르보니트릴;(Compound 105) 5-(5-(1-(2,4-dichlorophenyl)ethoxy)pyridin-3-yl)thiophene-2-carbonitrile;
(화합물 106) 5'-(1-(2,4-디클로로페닐)에톡시)-[3,3'-비피리딘]-6-아민;(Compound 106) 5'-(1-(2,4-dichlorophenyl)ethoxy)-[3,3'-bipyridin]-6-amine;
(화합물 107) 5-(4-((2,4-디클로로벤질)옥시)피리딘-2-일)피리미딘-2-아민;(Compound 107) 5-(4-((2,4-dichlorobenzyl)oxy)pyridin-2-yl)pyrimidin-2-amine;
(화합물 108) 4-((2,4-디클로로벤질)옥시)-6'-니트로-2,3'-비피리딘;(Compound 108) 4-((2,4-dichlorobenzyl)oxy)-6'-nitro-2,3'-bipyridine;
(화합물 109) 4-((2,4-디클로로벤질)옥시)-[2,3'-비피리딘]-6'-아민;(Compound 109) 4-((2,4-dichlorobenzyl)oxy)-[2,3'-bipyridin]-6'-amine;
(화합물 110) 5-(4-((2,4-디클로로벤질)옥시)피리딘-2-일)티오펜-2-카르보니트릴;(Compound 110) 5-(4-((2,4-dichlorobenzyl)oxy)pyridin-2-yl)thiophene-2-carbonitrile;
(화합물 111) tert-부틸 4-(4-(6-((2,4-디클로로벤질)옥시)피리딘-2-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트;(Compound 111) tert-butyl 4-(4-(6-((2,4-dichlorobenzyl)oxy)pyridin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxyl Rate;
(화합물 112) 2-((2,4-디클로로벤질)옥시)-6-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘;(Compound 112) 2-((2,4-dichlorobenzyl)oxy)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridine;
(화합물 113) 5-(6-((2,4-디클로로벤질)옥시)피리딘-2-일)피리미딘-2-아민;(Compound 113) 5-(6-((2,4-dichlorobenzyl)oxy)pyridin-2-yl)pyrimidin-2-amine;
(화합물 114) 6-((2,4-디클로로벤질)옥시)-[2,3'-비피리딘]-6'-아민;(Compound 114) 6-((2,4-dichlorobenzyl)oxy)-[2,3'-bipyridin]-6'-amine;
(화합물 115) tert-부틸 4-(6-((2,4-디클로로벤질)옥시)-[2,3'-비피리딘]-6'-일)피페라진-1-카르복실레이트;(Compound 115) tert-butyl 4-(6-((2,4-dichlorobenzyl)oxy)-[2,3'-bipyridin]-6'-yl)piperazine-1-carboxylate;
(화합물 116) 6-((2,4-디클로로벤질)옥시)-6'-(피페라진-1-일)-2,3'-비피리딘;(Compound 116) 6-((2,4-dichlorobenzyl)oxy)-6'-(piperazin-1-yl)-2,3'-bipyridine;
(화합물 117) 5-(6-((2,4-디클로로벤질)옥시)피리딘-2-일)티오펜-2-카르보니트릴;(Compound 117) 5-(6-((2,4-dichlorobenzyl)oxy)pyridin-2-yl)thiophene-2-carbonitrile;
(화합물 118) (R)-3-(1-(2,6-디클로로-3-플루오로페닐)에톡시)-5-페닐피리딘-2-아민;(Compound 118) (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-phenylpyridin-2-amine;
(화합물 119) (R)-3-(1-(2,6-디클로로-3-플루오로페닐)에톡시)-5-(2-몰폴리노피리미딘-5-일)피리딘-2-아민;(Compound 119) (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(2-morpholinopyrimidin-5-yl)pyridin-2-amine ;
(화합물 120) (R)-5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)-6'-니트로-[3,3'-비피리딘]-6-아민;(Compound 120) (R)-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-6'-nitro-[3,3'-bipyridin]-6-amine;
(화합물 121) 디-tert-부틸 (R)-(6'-아미노-5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)-[3,3'-비피리딘]-6-일)디카르바메이트;(Compound 121) Di-tert-butyl (R)-(6'-amino-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-[3,3'-bipyridine] -6-yl)dicarbamate;
(화합물 122) (R)-5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)-[3,3'-비피리딘]-6,6'-디아민;(Compound 122) (R)-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-[3,3'-bipyridin]-6,6'-diamine;
(화합물 123) 디-tert-부틸 (R)-(5-(2-아미노피리미딘-5-일)-3-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-2-일)디카르바메이트;(Compound 123) Di-tert-butyl (R)-(5-(2-aminopyrimidin-5-yl)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridine -2-yl)dicarbamate;
(화합물 124) (R)-5-(6-아미노-5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-3-일)피리미딘-2-아민;(Compound 124) (R)-5-(6-amino-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)pyrimidin-2-amine;
(화합물 125) (R)-5-(6-아미노-5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-3-일)티오펜-2-카르보니트릴;(Compound 125) (R)-5-(6-amino-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)thiophene-2-carbonitrile;
(화합물 126) (R)-5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)-6'-(피페라진-1-일)-[3,3'-비피리딘]-6-아민;(Compound 126) (R)-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-6'-(piperazin-1-yl)-[3,3'-bipyridine ]-6-amine;
(화합물 127) tert-부틸 (R)-4-(5-(6-아미노-5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-3-일)피리미딘-2-일)피페라진-1-카르복실레이트;(Compound 127) tert-butyl (R)-4-(5-(6-amino-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)pyrimidine -2-yl)piperazine-1-carboxylate;
(화합물 128) 디-tert-부틸 (R)-4-(5-(6-((tert-부톡시카르보닐)아미노)-5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-3-일)피리미딘-2-일)피페라진-1-카르복실레이트;(Compound 128) Di-tert-butyl (R)-4-(5-(6-((tert-butoxycarbonyl)amino)-5-(1-(2,6-dichloro-3-fluorophenyl) )Ethoxy)pyridin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate;
(화합물 129) (R)-3-(1-(2,6-디클로로-3-플루오로페닐)에톡시)-5-(2-(피페라진-1-일)피리미딘-5-일)피리딘-2-아민;(Compound 129) (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(2-(piperazin-1-yl)pyrimidin-5-yl) Pyridin-2-amine;
(화합물 130) 디-tert-부틸 (S)-(6'-아미노-5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)-[3,3'-비피리딘]-6-일)디카르바메이트;(Compound 130) Di-tert-butyl (S)-(6'-amino-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-[3,3'-bipyridine] -6-yl)dicarbamate;
(화합물 131) (S)-5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)-[3,3'-비피리딘]-6,6'-디아민;(Compound 131) (S)-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-[3,3'-bipyridin]-6,6'-diamine;
(화합물 132) 디-tert-부틸 (S)-(5-(2-아미노피리미딘-5-일)-3-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-2-일)카르바메이트;(Compound 132) Di-tert-butyl (S)-(5-(2-aminopyrimidin-5-yl)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridine -2-yl)carbamate;
(화합물 133) (S)-5-(6-아미노-5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-3-일)피리미딘-2-아민;(Compound 133) (S)-5-(6-amino-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)pyrimidin-2-amine;
(화합물 134) (S)-5-(6-아미노-5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-3-일)티오펜-2-카르보니트릴;(Compound 134) (S)-5-(6-amino-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)thiophene-2-carbonitrile;
(화합물 135) 디-tert-부틸 (S)-4-(4-(6-((tert-부톡시카르보닐)아미노)-5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트;(Compound 135) Di-tert-butyl (S)-4-(4-(6-((tert-butoxycarbonyl)amino)-5-(1-(2,6-dichloro-3-fluorophenyl) )Ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;
(화합물 136) (S)-5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)-6'-(피페라진-1-일)-[3,3'-비피리딘]-6-아민;(Compound 136) (S)-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-6'-(piperazin-1-yl)-[3,3'-bipyridine ]-6-amine;
(화합물 137) (S)-5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)-6'-(피페라진-1-일)-[3,3'-비피리딘]-6-아민;(Compound 137) (S)-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-6'-(piperazin-1-yl)-[3,3'-bipyridine ]-6-amine;
(화합물 138) 디-tert-부틸 (S)-4-(6'-((tert-부톡시카르보닐)아미노)-5'-(1-(2,6-디클로로-3-플루오로페닐)에톡시)-[3,3'-비피리딘]-6-일)피페라진-1-카르복실레이트;(Compound 138) Di-tert-butyl (S)-4-(6'-((tert-butoxycarbonyl)amino)-5'-(1-(2,6-dichloro-3-fluorophenyl) Ethoxy)-[3,3'-bipyridin]-6-yl)piperazine-1-carboxylate;
(화합물 139) 디-tert-부틸 (S)-(5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)-6'-(피페라진-1-일)-[3,3'-비피리딘]-6-일)디카르바메이트;(Compound 139) Di-tert-butyl (S)-(5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-6'-(piperazin-1-yl)-[3 ,3'-bipyridin]-6-yl)dicarbamate;
(화합물 140) (S)-5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)-6'-(피페라진-1-일)-[3,3'-비피리딘]-6-아민;(Compound 140) (S)-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-6'-(piperazin-1-yl)-[3,3'-bipyridine ]-6-amine;
(화합물 141) 디-tert-부틸 (S)-4-(5-(6-((tert-부톡시카르보닐)아미노)-5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-3-일)피리미딘-2-일)피페라진-1-카르복실레이트;(Compound 141) Di-tert-butyl (S)-4-(5-(6-((tert-butoxycarbonyl)amino)-5-(1-(2,6-dichloro-3-fluorophenyl) )Ethoxy)pyridin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate;
(화합물 142) (S)-3-(1-(2,6-디클로로-3-플루오로페닐)에톡시)-5-(2-(피페라진-1-일)피리미딘-5-일)피리딘-2-아민;(Compound 142) (S)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(2-(piperazin-1-yl)pyrimidin-5-yl) Pyridin-2-amine;
(화합물 143) 디-tert-부틸 (6'-아미노-5-((2,4-디클로로벤질)옥시)-[3,3'-비피리딘]-6-일)디카르바메이트;(Compound 143) Di-tert-butyl (6'-amino-5-((2,4-dichlorobenzyl)oxy)-[3,3'-bipyridin]-6-yl)dicarbamate;
(화합물 144) 5-((2,4-디클로로벤질)옥시)-[3,3'-비피리딘]-6,6'-디아민;(Compound 144) 5-((2,4-dichlorobenzyl)oxy)-[3,3'-bipyridin]-6,6'-diamine;
(화합물 145) 디-tert-부틸 (5-(2-아미노피리미딘-5-일)-3-((2,4-디클로로벤질)옥시)피리딘-2-일)디카르바메이트;(Compound 145) Di-tert-butyl (5-(2-aminopyrimidin-5-yl)-3-((2,4-dichlorobenzyl)oxy)pyridin-2-yl)dicarbamate;
(화합물 146) 5-(6-아미노-5-((2,4-디클로로벤질)옥시)피리딘-3-일)피리미딘-2-아민;(Compound 146) 5-(6-amino-5-((2,4-dichlorobenzyl)oxy)pyridin-3-yl)pyrimidin-2-amine;
(화합물 147) 디-tert-부틸 (5-(5-시아노티오펜-2-일)-3-((2,4-디클로로벤질)옥시)피리딘-2-일)디카르바메이트;(Compound 147) Di-tert-butyl (5-(5-cyanothiophen-2-yl)-3-((2,4-dichlorobenzyl)oxy)pyridin-2-yl)dicarbamate;
(화합물 148) 5-(6-아미노-5-((2,4-디클로로벤질)옥시)피리딘-3-일)티오펜-2-카르보니트릴;(Compound 148) 5-(6-amino-5-((2,4-dichlorobenzyl)oxy)pyridin-3-yl)thiophene-2-carbonitrile;
(화합물 149) 디-tert-부틸 4-(4-(6-((tert-부톡시카르보닐)아미노)-5-((2,4-디클로로벤질)옥시)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트;(Compound 149) Di-tert-butyl 4-(4-(6-((tert-butoxycarbonyl)amino)-5-((2,4-dichlorobenzyl)oxy)pyridin-3-yl)-1H -Pyrazol-1-yl)piperidine-1-carboxylate;
(화합물 150) 3-((2,4-디클로로벤질)옥시)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;(Compound 150) 3-((2,4-dichlorobenzyl)oxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
(화합물 151) 5-((2,4-디클로로벤질)옥시)-6'-(피페라진-1-일)-[3,3'-비피리딘]-6-아민;(Compound 151) 5-((2,4-dichlorobenzyl)oxy)-6'-(piperazin-1-yl)-[3,3'-bipyridin]-6-amine;
(화합물 152) 디-tert-부틸 4-(5-(6-((tert-부톡시카르보닐)아미노)-5-((2,4-디클로로벤질)옥시)피리딘-3-일)피리미딘-2-일)피페라진-1-카르복실레이트;(Compound 152) Di-tert-butyl 4-(5-(6-((tert-butoxycarbonyl)amino)-5-((2,4-dichlorobenzyl)oxy)pyridin-3-yl)pyrimidine -2-yl)piperazine-1-carboxylate;
(화합물 153) 3-((2,4-디클로로벤질)옥시)-5-(2-(피페라진-1-일)피리미딘-5-일)피리딘-2-아민;(Compound 153) 3-((2,4-dichlorobenzyl)oxy)-5-(2-(piperazin-1-yl)pyrimidin-5-yl)pyridin-2-amine;
(화합물 154) 디-tert-부틸 (6'-아미노-5-(1-(2,4-디클로로페닐)에톡시)-[3,3'-비피리딘]-6-일)디카르바메이트;(Compound 154) Di-tert-butyl (6'-amino-5-(1-(2,4-dichlorophenyl)ethoxy)-[3,3'-bipyridin]-6-yl)dicarbamate;
(화합물 155) 5-(1-(2,4-디클로로페닐)에톡시)-[3,3'-비피리딘]-6,6'-디아민;(Compound 155) 5-(1-(2,4-dichlorophenyl)ethoxy)-[3,3'-bipyridin]-6,6'-diamine;
(화합물 156) 디-tert-부틸 (5-(2-아미노피리미딘-5-일)-3-(1-(2,4-디클로로페닐)에톡시)피리딘-2-일)카르바메이트;(Compound 156) Di-tert-butyl (5-(2-aminopyrimidin-5-yl)-3-(1-(2,4-dichlorophenyl)ethoxy)pyridin-2-yl)carbamate;
(화합물 157) 5-(6-아미노-5-(1-(2,4-디클로로페닐)에톡시)피리딘-3-일)피리미딘-2-아민;(Compound 157) 5-(6-amino-5-(1-(2,4-dichlorophenyl)ethoxy)pyridin-3-yl)pyrimidin-2-amine;
(화합물 158) 디-tert-부틸 (5-(5-시아노티오펜-2-일)-3-(1-(2,4-디클로로페닐)에톡시)피리딘-2-일)디카르바메이트;(Compound 158) Di-tert-butyl (5-(5-cyanothiophen-2-yl)-3-(1-(2,4-dichlorophenyl)ethoxy)pyridin-2-yl)dicarbamate;
(화합물 159) 5-(6-아미노-5-(1-(2,4-디클로로페닐)에톡시)피리딘-3-일)티오펜-2-카르보니트릴;(Compound 159) 5-(6-amino-5-(1-(2,4-dichlorophenyl)ethoxy)pyridin-3-yl)thiophene-2-carbonitrile;
(화합물 160) 디-tert-부틸 4-(4-(6-((tert-부톡시카르보닐)아미노)-5-(1-(2,4-디클로로페닐)에톡시)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트;(Compound 160) Di-tert-butyl 4-(4-(6-((tert-butoxycarbonyl)amino)-5-(1-(2,4-dichlorophenyl)ethoxy)pyridin-3-yl )-1H-pyrazol-1-yl)piperidine-1-carboxylate;
(화합물 161) 3-(1-(2,4-디클로로페닐)에톡시)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;(Compound 161) 3-(1-(2,4-dichlorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine ;
(화합물 162) 디-tert-부틸 4-(5-(6-((tert-부톡시카르보닐)아미노)-5-(1-(2,4-디클로로페닐)에톡시)피리딘-3-일)피리미딘-2-일)피페라진-1-카르복실레이트;(Compound 162) Di-tert-butyl 4-(5-(6-((tert-butoxycarbonyl)amino)-5-(1-(2,4-dichlorophenyl)ethoxy)pyridin-3-yl )Pyrimidin-2-yl)piperazine-1-carboxylate;
(화합물 163) 3-(1-(2,4-디클로로페닐)에톡시)-5-(2-(피페라진-1-일)피리미딘-5-일)피리딘-2-아민;(Compound 163) 3-(1-(2,4-dichlorophenyl)ethoxy)-5-(2-(piperazin-1-yl)pyrimidin-5-yl)pyridin-2-amine;
한편, 본 발명은 상기 화학식 I로 표시되는 피리딘 유도체의 제조방법을 포함한다. 본 발명에 따른 대표적인 제조방법은 상기 화학식 I에서 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 preparing a pyridine derivative represented by Formula I. Representative manufacturing methods according to the present invention can be roughly divided into three manufacturing methods as shown in Schemes 1 to 3 below, depending on the linker in Formula I.
첫 번째 제조방법은, 하기 반응식 I에 나타낸 바와 같이 R3 = 피라졸일피페리딘일인 피리딘 유도체을 제조하는 하나의 방법이다.The first preparation method is one method of preparing a pyridine derivative with R 3 =pyrazolylpiperidinyl as shown in Scheme I below.
본 발명의 일 구현예로서, 본 발명은 아래 반응식 I에 따라, 화학식 I-1로 표시되는 브로모하이드록시피리딘 화합물을 팔라듐 촉매(II)와 탄산나트륨 수용액의 존재 하에 화학식 I-2으로 표시되는 보론화합물을 반응시켜서, 화학식 I-3으로 표시되는 화합물을 제조하고, 상기 제조한 화학식 I-3으로 표시되는 화합물을 DIAD와 PPH3 의 존재하에 화학식 I-4로 표시되는 화합물과 반응시킨 후, 트리플로로아세트산을 이용한 Boc 보호 그룹 제거반응을 이용해서, 화학식 I-5로 표시되는 피리딘 유도체를 제조하는, 피리딘 유도체의 제조방법이다: As an embodiment of the present invention, the present invention provides a bromohydroxypyridine compound represented by Formula I-1 according to Scheme I below in the presence of a palladium catalyst (II) and an aqueous sodium carbonate solution, in the presence of a boron represented by Formula I-2. By reacting the compound, a compound represented by Formula I-3 was prepared, and the prepared compound represented by Formula I-3 was added to DIAD and PPH 3 This is a method for preparing a pyridine derivative in which a pyridine derivative represented by the formula I-5 is prepared by reacting with a compound represented by the formula I-4 in the presence of, and then removing the Boc protecting group using trifluoroacetic acid. :
[반응식 I][Scheme I]
상기 반응식 I의 화학식에서, R1은 치환되지 않은 것이거나 또는 할로겐, 메톡시, 시아노, 및 트리플루오로메틸로 이루어진 군에서 선택된 1개 내지 2개의 치환기이고, R2 및 R2 ' 는 각각 수소이다.In the formula of Scheme I, R 1 is unsubstituted or 1 to 2 substituents selected from the group consisting of halogen, methoxy, cyano, and trifluoromethyl, and R 2 and R 2 ′ are each It is hydrogen.
상기 반응식 I에서, R1 및 R2는 각각 상기 화학식 I에서 정의한 바와 같을 수도 있다.In Reaction Scheme I, R 1 and R 2 may each be as defined in Formula I.
더욱 구체적인 예를 들어서, 상기 반응식 I에 따른 결합반응에 의하면, 상기 화학식 I-1로 표시되는 브로모하이드록시피리딘 화합물에 상기 화학식 I-2로 표시되는 보론화합물 (예컨대 보론산 또는 보론산피나콜에스터), 팔라듐 촉매(II), 탄산나트륨 수용액을 염기로 사용하는 스즈키(Suzuki) 타입의 반응을 이용하며, 1,4-다이옥산을 용매로 하여 80℃로 가열하고 교반하여 브롬 자리에 R3를 치환시킨다. 그런 다음, 상기 화학식 I-3으로 표시되는 화합물과 화학식 I-4(벤질알코올 혹은 벤질클로라이드)를 약염기를 사용한 친핵성 치환반응 및 DIAD, PPH3를 이용한 미츠노부(mitsnobu) 타입의 반응을 이용하여 결합시킨 후, 트리플로로아세트산을 이용한 Boc 보호 그룹 제거반응을 이용하여 화학식 I-5로 표시되는 피리딘 유도체를 제조할 수 있다. For a more specific example, according to the coupling reaction according to Scheme I, a boron compound represented by Formula I-2 (eg, boronic acid or pinacol boronic acid) to the bromohydroxypyridine compound represented by Formula I-1 Ester), a palladium catalyst (II), and a Suzuki type reaction using an aqueous sodium carbonate solution as a base, heating to 80°C using 1,4-dioxane as a solvent and stirring to replace R 3 in the bromine site Let it. Then, using a nucleophilic substitution reaction using a weak base of the compound represented by Formula I-3 and Formula I-4 (benzyl alcohol or benzyl chloride) and a mitsnobu type reaction using DIAD and PPH 3 After bonding, a pyridine derivative represented by Formula I-5 can be prepared by using a Boc protecting group removal reaction using trifluoroacetic acid.
상기 결합에서 사용되는 염기로는 탄산세슘, 탄산포타슘, 등과 같은 염기를 사용할 수 있다. 반응 온도는 -20℃ 내지 60℃ 온도 범위를 유지하도록 하며, 반응 용매로는 결합반응에 영향을 미치지 않는 비활성 유기 용매로서 톨루엔, DMF, 아세토나이트릴 등이 사용될 수 있다.The base used in the bonding may be a base such as cesium carbonate, potassium carbonate, or the like. The reaction temperature is maintained in a temperature range of -20°C to 60°C, and toluene, DMF, acetonitrile, etc. may be used as an inert organic solvent that does not affect the bonding reaction as the reaction solvent.
상기 반응식 I에 따른 제조방법에서 사용된 반응물질로서 상기 화학식, I-1, I-2, I-3, I-4로 표시되는 화합물은 통상의 유기합성법을 이용하여 제조하여 사용할 수도 있고, 또는 시중에서 판매되고 있는 제품으로 구입하여 사용할 수도 있다.As a reactant used in the preparation method according to Scheme I, the compounds represented by Chemical Formulas I-1, I-2, I-3, and I-4 may be prepared and used using a conventional organic synthesis method, or It can also be purchased and used as a commercially available product.
두 번째 제조방법은, 하기 반응식 II에 나타낸 바와 같이 R3가 다양한 헤테로아릴기로 치환된 화합물의 대표적인 제조방법이다.The second preparation method is a typical preparation method of a compound in which R 3 is substituted with various heteroaryl groups as shown in Scheme II below.
본 발명의 일 구현예로서, 본 발명은 아래 반응식 II에 따라, 화학식 Ⅱ-1로 표시되는 브로모하이드록시피리딘 화합물을 DIAD와 PPH3 의 존재하에 화학식 Ⅱ-2로 표시되는 화합물과 반응시켜서, 화학식 Ⅱ-3으로 표시되는 화합물을 제조하고, 상기 제조한 화학식 Ⅱ-3으로 표시되는 화합물을 팔라듐 촉매(II)와 탄산나트륨 수용액의 존재 하에 화학식 Ⅱ-4로 표시되는 보론화합물과 반응시켜서, 화학식 Ⅱ-5로 표시되는 피리딘 유도체를 제조하는, 피리딘 유도체의 제조방법이다: As an embodiment of the present invention, according to the following Scheme II, the bromohydroxypyridine compound represented by Formula II-1 is prepared by DIAD and PPH 3 In the presence of the compound represented by the formula II-2 by reacting with the compound represented by the formula II-3, the prepared compound represented by the formula II-3 in the presence of a palladium catalyst (II) and sodium carbonate aqueous solution This is a method for preparing a pyridine derivative by reacting with a boron compound represented by Formula II-4 to prepare a pyridine derivative represented by Formula II-5:
[반응식 II][Scheme II]
상기 반응식 II의 화학식에서, X. Y. 및 Z는 각각 독립적으로 탄소(C) 또는 질소(N)이고, 상기 X. Y. 및 Z 중 하나는 질소(N)이며, R1은 할로겐으로 이루어진 1개 내지 3개의 치환기이고, R2 및 R2 ' 는 각각 수소, 메틸(CH3) 또는 각각 다른 비대칭 중심을 가지는 (S), (R)-메틸(methyl)이고, R3은 비치환되거나 치환된 아릴 또는 헤테로아릴이고, 상기 치환된 아릴 또는 헤테로아릴은 메틸, 할로겐, 아민, 하이드록시, 시아노, 피페라진일, 피페리딘일, 피라닐, 알데하이드, 니트로, 메틸피페라진일, 메틸피롤리딘일, 메틸몰폴린일, 몰폴린일, 알데히드, 피롤리딘일메탄온, 메탄아민, 메틸아민, 다이메틸아민, 트리플루오로메틸, 아세틸피페리딘일, 페닐메탄아민 및 메탄올로 이루어진 군에서 선택된 1개 이상의 치환기로 치환된 것일 수 있다.In the formula of Scheme II, XY and Z are each independently carbon (C) or nitrogen (N), one of XY and Z is nitrogen (N), and R 1 is 1 to 3 substituents consisting of halogen And R 2 and R 2 ′ are each hydrogen, methyl (CH 3 ) or (S), (R)-methyl (methyl) each having a different asymmetric center, and R 3 is an unsubstituted or substituted aryl or heteroaryl And, the substituted aryl or heteroaryl is methyl, halogen, amine, hydroxy, cyano, piperazinyl, piperidinyl, pyranyl, aldehyde, nitro, methylpiperazinyl, methylpyrrolidinyl, methylmorpholine Substituted with one or more substituents selected from the group consisting of mono, morpholinyl, aldehyde, pyrrolidinylmethanone, methanamine, methylamine, dimethylamine, trifluoromethyl, acetylpiperidinyl, phenylmethanamine and methanol It may have been.
상기 반응식 II에서 X. Y. Z. R1. R2 및 R3는 각각 상기 화학식 I에서 정의한 바와 같을 수 있다.In Scheme II, XYZ R 1 . R 2 and R 3 may each be as defined in Formula I.
더욱 구체적인 예를 들어서, 상기 반응식 II에 따른 결합반응에 의하면, 상기 화학식 Ⅱ-1로 표시되는 브로모하이드록시피리딘 화합물에 상기 화학식 Ⅱ-2로 표시되는 화합물(벤질알코올 혹은 벤질클로라이드)을 약염기를 사용한 친핵성 치환반응 및 DIAD, PPH3를 이용한 미츠노부(mitsnobu) 타입의 반응을 이용하여 화학식 Ⅱ-3로 표시되는 브로모벤질옥시피리딘 화합물을 제조할 수 있다. For a more specific example, according to the coupling reaction according to Scheme II, a weak base of a compound represented by Formula II-2 (benzyl alcohol or benzyl chloride) to the bromohydroxypyridine compound represented by Formula II-1. A bromobenzyloxypyridine compound represented by Formula II-3 can be prepared by using the nucleophilic substitution reaction used and a mitsnobu type reaction using DIAD and PPH 3 .
그런 다음, 화학식 Ⅱ-3과 화학식 Ⅱ-4로 표시되는 보론화합물(예컨대 보론산 또는 보론산피나콜에스터), 팔라듐 촉매(II), 탄산나트륨 수용액을 염기로 사용하는 스즈키(Suzuki) 타입의 반응을 이용하여 화학식 Ⅱ-5로 표시되는 피리딘 유도체를 직접 제조할 수 있다.Then, a Suzuki type reaction using a boron compound represented by Formula II-3 and Formula II-4 (eg boronic acid or boronic acid pinacol ester), a palladium catalyst (II), and an aqueous sodium carbonate solution as a base. The pyridine derivative represented by the formula II-5 can be prepared directly.
상기 반응식 2에 따른 제조방법에서 사용된 반응물질로서 상기 화학식 Ⅱ-1, Ⅱ-2, Ⅱ-3, Ⅱ-4로 표시되는 화합물은 통상의 유기합성법을 이용하여 제조하여 사용할 수도 있고, 또는 시중에서 판매되고 있는 제품으로 구입하여 사용할 수도 있다.As a reactant used in the preparation method according to Scheme 2, the compounds represented by Formulas Ⅱ-1, Ⅱ-2, Ⅱ-3, and Ⅱ-4 may be prepared and used using conventional organic synthesis methods, or commercially available. It can also be purchased and used as a product sold in.
세 번째 제조방법은, 하기 반응식 III에 나타낸 바와 같이 R3가 다양한 헤테로아릴기로 치환된 화합물의 대표적인 제조방법이다.The third preparation method is a typical preparation method of a compound in which R 3 is substituted with various heteroaryl groups as shown in Scheme III below.
본 발명의 일 구현예로서, 본 발명은 아래 반응식 III에 따라, 화학식 Ⅲ-1로 표시되는 2-니트로피리딘-3 올을 DIAD와 PPH3 의 존재하에 화학식 Ⅲ-2로 표시되는 화합물과 반응시켜서, 화학식 Ⅲ-3으로 표시되는 화합물을 제조하고, 상기 제조한 화학식 Ⅲ-3으로 표시되는 화합물을 철과 아세트산의 존재하에 환원반응시켜서, 화학식 Ⅲ-4로 표시되는 화합물을 제조하며, 상기 제조한 화학식 Ⅲ-4로 표시되는 화합물을 N-브로모숙신이미드의 존재하에서 반응시켜서, 화학식 Ⅲ-5로 표시되는 화합물을 제조하고, 상기 제조한 화학식 Ⅲ-5로 표시되는 화합물을 디-tert-부틸-디카보네이트와 디-메틸아미노피리딘의 존재하에서 반응시켜서, Boc 보호기가 붙은 화학식 Ⅲ-6으로 표시되는 화합물을 제조하며, 상기 제조한 화학식 Ⅲ-6으로 표시되는 화합물을 팔라듐 촉매(II)와 탄산나트륨 수용액의 존재 하에 화학식 Ⅲ-7로 표시되는 보론화합물과 반응시켜서, 화학식 Ⅲ-8로 표시되는 화합물을 제조하고, 상기 제조한 화학식 Ⅲ-8로 표시되는 화합물을 염산 혹은 트리플루오로아세트산 존재하에서 반응시켜, Boc 보호그룹이 제거된 화학식 Ⅲ-9로 표시되는 피리딘 유도체를 제조하는, 피리딘 유도체의 제조방법이다:As an embodiment of the present invention, according to Scheme III below, the present invention uses 2-nitropyridin-3ol represented by Chemical Formula III-1 with DIAD and PPH 3. By reacting with a compound represented by Formula III-2 in the presence of a compound represented by Formula III-3, a reduction reaction of the compound represented by Formula III-3 was carried out in the presence of iron and acetic acid, To prepare a compound represented by III-4, and reacting the compound represented by Formula III-4 in the presence of N-bromosuccinimide to prepare a compound represented by Formula III-5, and the preparation A compound represented by Formula III-5 was reacted in the presence of di-tert-butyl-dicarbonate and di-methylaminopyridine to prepare a compound represented by Formula III-6 with a Boc protecting group, and the prepared formula By reacting the compound represented by Ⅲ-6 with the boron compound represented by Formula III-7 in the presence of a palladium catalyst (II) and an aqueous sodium carbonate solution, a compound represented by Formula III-8 was prepared, and the prepared Formula III- This is a method for preparing a pyridine derivative in which the compound represented by 8 is reacted in the presence of hydrochloric acid or trifluoroacetic acid to prepare a pyridine derivative represented by Formula III-9 from which the Boc protecting group has been removed:
[반응식 III][Scheme III]
상기 반응식 III의 화학식에서, R1은 할로겐으로 이루어진 1개 내지 3개의 치환기이고, R2 및 R2 ' 는 각각 수소, 메틸(CH3) 또는 각각 다른 비대칭 중심을 가지는 (S), (R)-메틸(methyl)이고, R3은 비치환되거나 치환된 아릴, 피리딘, 피리미딘, 피라졸, 또는 티오펜이고, 상기 치환된 아릴, 피리딘, 피리미딘, 피라졸, 또는 티오펜은 아민, 시아노, 피페라진일, 피페리딘일, 및 몰폴린일로 이루어진 군에서 선택된 1개 이상의 치환기로 치환된 것이다.In the formula of Scheme III, R 1 is 1 to 3 substituents consisting of halogen, and R 2 and R 2 ′ are each hydrogen, methyl (CH 3 ), or (S), (R) each having a different asymmetric center -Methyl (methyl), R 3 is unsubstituted or substituted aryl, pyridine, pyrimidine, pyrazole, or thiophene, and the substituted aryl, pyridine, pyrimidine, pyrazole, or thiophene is an amine, cyanide It is substituted with one or more substituents selected from the group consisting of no, piperazinyl, piperidinyl, and morpholinyl.
상기 반응식 III에서 R1. R2 및 R3는 각각 상기 화학식 I에서 정의한 바와 같을 수 있다.R 1 in Scheme III above. R 2 and R 3 may each be as defined in Formula I.
더욱 구체적인 예를 들어서, 상기 반응식 III에 따른 결합반응에 의하면, 상기 화학식 Ⅲ-1로 표시되는 2-니트로피리딘-3 올과 상기 화학식 Ⅲ-2를 탄산세슘을 염기로 사용한 친핵성 치환반응 및 DIAD, PPh3를 이용한 미츠노부(mitsunobu)타입의 반응을 이용하여 결합시킨다. 그런 다음 상기 화학식 Ⅲ-3으로 표시되는 화합물을 철과 아세트산 존재 하에 환원반응시켜 상기 화학식 Ⅲ-4로 표시되는 화합물을 제조한다. 상기 화학식 Ⅲ-4로 표시되는 화합물을 N-브로모숙신이미드의 존재 하에서 반응시켜 상기 화학식 Ⅲ-5로 표시되는 화합물을 제조할 수 있다. 그런 다음, 상기 화학식 Ⅲ-5로 표시되는 화합물과 디-tert-부틸-디카보네이트와 디-메틸아미노피리딘의 존재 하에서 반응하여 Boc 보호기가 붙은 상기 화학식 Ⅲ-6으로 표시되는 화합물을 제조할 수 있다. 상기 화학식 Ⅲ-6으로 표시되는 화합물과 상기 화학식 Ⅲ-7로 표시되는 보론 화합물 (예컨대 보론산 또는 보론산피나콜에스터)을 팔라듐 촉매(II), 탄산나트륨 혹은 탄산 세슘 수용액을 염기로 사용하는 스즈키(Suzuki) 타입의 반응을 이용하여, 상기 화학식 Ⅲ-8로 표시되는 화합물을 제조할 수 있다. 마지막으로 화학식 Ⅲ-8로 표시되는 화합물을 염산 혹은 트리플루오로아세트산 존재 하에서 반응시켜, Boc 보호그룹이 제거된 상기 화학식 Ⅲ-9로 표시되는 3-(벤질옥시)-5-페닐피리딘-2-아민 유도체를 제조할 수 있다.For a more specific example, according to the coupling reaction according to Scheme III, a nucleophilic substitution reaction and DIAD using 2-nitropyridin-3ol represented by Formula III-1 and cesium carbonate as a base of Formula III-2. , PPh 3 was combined using a mitsunobu type reaction. Then, a reduction reaction of the compound represented by Formula III-3 in the presence of iron and acetic acid to prepare the compound represented by Formula III-4. The compound represented by Formula III-5 may be prepared by reacting the compound represented by Formula III-4 in the presence of N-bromosuccinimide. Then, the compound represented by Formula III-5 may be reacted with the compound represented by Formula III-5 in the presence of di-tert-butyl-dicarbonate and di-methylaminopyridine to prepare a compound represented by Formula III-6 with a Boc protecting group attached thereto. . Suzuki using a palladium catalyst (II) and an aqueous sodium carbonate or cesium carbonate solution as a base using a compound represented by Formula III-6 and a boron compound represented by Formula III-7 (e.g., boronic acid or pinacol ester boronic acid) as a base Suzuki) type reaction can be used to prepare the compound represented by Formula III-8. Finally, the compound represented by Formula III-8 was reacted in the presence of hydrochloric acid or trifluoroacetic acid to remove the Boc protecting group, and 3-(benzyloxy)-5-phenylpyridine-2- represented by Formula III-9. Amine derivatives can be prepared.
상기 반응식 3에 따른 제조방법에서 사용된 반응물질로서 상기 화학식 Ⅲ-1, Ⅲ-2, Ⅲ-3, Ⅲ-4, Ⅲ-5, Ⅲ-6, Ⅲ-7, Ⅲ-8로 표시되는 화합물은 통상의 유기합성법을 이용하여 제조하여 사용할 수도 있고, 또는 시중에서 판매되고 있는 제품으로 구입하여 사용할 수도 있다.Compounds represented by Chemical Formulas Ⅲ-1, Ⅲ-2, Ⅲ-3, Ⅲ-4, Ⅲ-5, Ⅲ-6, Ⅲ-7, and Ⅲ-8 as reactants used in the manufacturing method according to Scheme 3 Silver may be prepared and used using a conventional organic synthesis method, or may be purchased and used as a commercially available product.
본 발명이 속한 기술 분야에서 통상의 지식을 가진 자라면 화학식 I의 구조를 바탕으로 다양한 방법에 의해 화학식 I의 화합물을 제조할 수 있으며, 이러한 방법들은 모두 본 발명의 범주에 포함되는 것으로 해석되어야 한다.Those of ordinary skill in the art to which the present invention pertains can prepare the compound of Formula I by various methods based on the structure of Formula I, and all of these methods should be interpreted as being included in the scope of the present invention. .
즉, 본 명세서에 기재되거나 선행 기술에 개시된 여러 합성법들을 임의로 조합하여 화학식 I의 화합물을 제조할 수 있고, 이는 본 발명의 범위에 속하는 것으로 이해되고, 화학식 I 화합물의 제조 방법이 상기 설명된 것으로 제한되는 것은 아니다.That is, it is possible to prepare a compound of formula (I) by arbitrarily combining several synthetic methods described herein or disclosed in the prior art, which is understood to be within the scope of the present invention, and the method of preparing the compound of formula (I) is limited to those described above. It does not become.
한편, 본 발명은 상기 화학식 I로 표시되는 피리딘 유도체 또는 그것의 염을 특정 질환의 예방 및/또는 치료 목적에 부합하도록 유효성분으로 포함하는 약학 조성물일 수 있다. Meanwhile, the present invention may be a pharmaceutical composition comprising a pyridine derivative represented by Formula I or a salt thereof as an active ingredient to meet the purpose of preventing and/or treating a specific disease.
본 발명에 따른 상기 화학식 I의 피리딘 유도체 및/또는 이의 약학적으로 허용 가능한 염의 SHIP2 억제 활성은, AS1938909 라는 공지된 SHIP2 억제제의 활성을 함께 측정하여 비교 기준으로 삼았다. 또한 PIP3에 대해서 경쟁적인 저해작용을 확인하고자, PIP3 100 μM을 처리하여, 배지에서 반응 완충액과 본 발명에 따른 화합물을 함께 처리하여 물질의 효소활성 정도인 IC50 값을 구하였다. IC50 값은 효소의 활성을 50% 저해할 수 있는 화합물의 농도로서 그 값이 작을수록 더욱 효과가 크다. 아래의 실험예에서 확인할 수 있는 바와 같이, 본 발명에 따른 화합물은 공지된 SHIP2 억제제인 AS1938909와 동등한 수준의 SHIP2 활성을 가지고 있었다(본 발명의 실험예 참조). The SHIP2 inhibitory activity of the pyridine derivative of Formula I and/or a pharmaceutically acceptable salt thereof according to the present invention was measured as a standard for comparison by measuring the activity of a known SHIP2 inhibitor called AS1938909. In addition, to determine the competitive inhibition with respect to PIP 3, PIP 3 by treatment with 100 μM, were treated with the compounds according to the present invention and reaction buffer in a medium was determined IC 50 value of approximately enzymatic activity of the substance. The IC 50 value is the concentration of a compound capable of 50% inhibition of enzyme activity. The smaller the value, the greater the effect. As can be seen in the experimental examples below, the compounds according to the present invention had the same level of SHIP2 activity as AS1938909, a known SHIP2 inhibitor (see Experimental Examples of the present invention).
그래서, 본 발명의 화합물은 SHIP2에 대한 효과적인 억제 활성을 가지고 있으므로, 알츠하이머성 치매, 기능 또는 거동으로부터 야기되는 퇴행성 뇌질환; 암; 고혈압 (hypertensive); 당뇨 관련 질병의 예방 또는 치료제로서 유용하게 사용될 수 있다.So, since the compound of the present invention has an effective inhibitory activity against SHIP2, Alzheimer's dementia, degenerative brain disease resulting from function or behavior; cancer; Hypertensive; It can be usefully used as a preventive or therapeutic agent for diabetes-related diseases.
이에 따라, 본 발명의 다른 일 구현예는 상기한 본 발명에 따른 화합물을 포함하는, SHIP2 활성 관련 질환의 치료 또는 예방용 약학 조성물이다.Accordingly, another embodiment of the present invention is a pharmaceutical composition for the treatment or prevention of diseases related to SHIP2 activity, comprising the compound according to the present invention.
여기서, 상기 SHIP2 활성 관련 질환은 알츠하이머성 치매, 퇴행성 뇌질환, 암, 고혈압(hypertensive) 및 당뇨로 이루어진 군에서 선택된 하나 이상인 것이 가능하다. 그 중에서도, 상기 SHIP2 활성 관련 질환은 알츠하이머성 치매인 것이 바람직하다.Here, the SHIP2 activity-related disease may be at least one selected from the group consisting of Alzheimer's dementia, degenerative brain disease, cancer, hypertensive, and diabetes. Among them, the SHIP2 activity-related disease is preferably Alzheimer's dementia.
또한, 본 발명은 담체, 보조제 또는 희석제를 더 포함하는 것을 특징으로 하는 약학 조성물일 수 있다. 본 발명의 약학 조성물은 상기 화학식 I로 표시되는 피리딘 유도체 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 comprises a pyridine derivative represented by the above formula (I) or a pharmaceutically acceptable salt thereof, and other conventional carriers, adjuvants or diluents, and is formulated by a conventional formulation method for oral administration or parenteral administration. It can be prepared in a form suitable for. In the case of oral administration, it may be prepared in the form of tablets, capsules, solutions, syrups, suspensions, and the like, 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 an embodiment of the present invention, a salt dissolved in a buffer solution is used as a diluent, and the buffer solution commonly used may be a phosphate buffered saline solution that mimics the salt form of a human solution. Since the buffer salt 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 SHIP2 억제제로 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 SHIP2 inhibitor, the effective daily dose is 0.01 to 1,000 mg/day based on an adult, but the dose is the patient's age, weight, sex, dosage form, health condition and degree of disease. According to the judgment of the doctor or pharmacist, the administration may be divided once a day or several times a day at predetermined time intervals.
나아가, 본 발명은 상기 화학식 I로 표시되는 피리딘 유도체 또는 이를 함유하는 약제학적 조성물을 포함하는 특정 질환의 예방 및 치료를 목적으로 사용하는 식품 용도를 제공할 수 있다. 즉, 본 발명은 상기한 화합물을 포함하는, SHIP2 활성 관련 질환의 치료 또는 예방용 건강기능식품일 수 있다.Furthermore, the present invention can provide a food use for the purpose of preventing and treating specific diseases, including the pyridine derivative represented by the above formula (I) or a pharmaceutical composition containing the same. That is, the present invention may be a health functional food for the treatment or prevention of diseases related to SHIP2 activity, including the above compound.
이상에서 설명한 바와 같은 본 발명은 하기 실시예, 제제예, 및 실험예에 의거하여 더욱 상세히 설명하겠는 바, 하기의 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 examples, formulation examples, and experimental examples, and the following examples, formulation examples, and experimental examples are merely illustrative of the present invention and the scope of the present invention. Is not limited by these.
[[ 실시예Example ]]
본 발명에 따른 상기 화학식 I로 표시되는 화합물의 대표적 합성예를, 아래 실시예(화합물 2, 44, 52, 71, 107, 113, 129, 133, 144, 155의 제조)로서 예시하였는바, 본 발명의 화합물은 이들 실시예에서 예시된 제조방법에 의해 용이하게 합성할 수 있다.A representative synthesis example of the compound represented by Formula I according to the present invention was illustrated as the following examples (Preparation of Compounds 2, 44, 52, 71, 107, 113, 129, 133, 144, 155). The compounds of the invention can be easily synthesized by the preparation methods exemplified in these Examples.
실시예Example 1 : 화합물 2의 제조 1: Preparation of compound 2
실시예Example 1- One- 1 :tert1: tert -부틸 4-(4-(5--Butyl 4-(4-(5- 히드록시피리딘Hydroxypyridine -3-일)-1H--3-yl)-1H- 피라졸Pyrazole -1-일)피페리딘-1-카르복실레이트 (화합물 2-I--1-yl) piperidine-1-carboxylate (compound 2-I- 3)의3) of 제조 Produce
질소 하에서 5-브로모피리딘-3-올(150 mg, 0.87 mmol)과 tert-부틸 4-(4-(4,4,5,5-테트라메틸-1,3,2-디옥사보로란-2-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트(359.56 mg, 0.95 mmol)을 1,4-디옥산 용액 20 ml에 용해 시킨 후 Pd(PPh3)4 (49.69 mg, 0.043 mM)와 1.0 노르말 탄산칼륨 수용액 (359.47 mg, 2.60 mmol)을 첨가하였다. 반응 혼합물을 90℃에서 2 시간 교반하였다. 반응이 완결되면 증류수와 아세트산에틸을 이용하여 추출하고, 유기층을 무수황산마그네슘으로 건조시킨 후 여과하였다. 여과액을 감압 농축시켜, 농축액을 관 크로마토그래피를 통하여 표제화합물 86.42 mg (수율 29%)을 얻었다.5-bromopyridin-3-ol (150 mg, 0.87 mmol) and tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) under nitrogen -2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (359.56 mg, 0.95 mmol) was dissolved in 20 ml of 1,4-dioxane solution and then Pd(PPh 3 ) 4 (49.69 mg, 0.043 mM) and 1.0 normal potassium carbonate aqueous solution (359.47 mg, 2.60 mmol) were added. The reaction mixture was stirred at 90° C. for 2 hours. When the reaction was completed, extraction was performed 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 subjected to column chromatography to give 86.42 mg (yield 29%) of the title compound.
1H-NMR (400 MHz, CDCl3): δ 9.76 (br s, 1H), 8.29 (d, 1H, J = 2.0 Hz), 8.17 (d, 1H, J = 2.4 Hz), 7.80 (s, 1H), 7.71 (s, 1H), 7.35 (t, 1H, J = 2.0 Hz), 4.27-4.35 (m, 3H), 2.91 (br s, 2H), 2.17 (d, 2H, J = 10.0 Hz), 1.95 (qd, 2H, J = 12.8 Hz, 4.8 Hz), 1.49 (s, 9H). 1 H-NMR (400 MHz, CDCl 3 ): δ 9.76 (br s, 1H), 8.29 (d, 1H, J = 2.0 Hz), 8.17 (d, 1H, J = 2.4 Hz), 7.80 (s, 1H ), 7.71 (s, 1H), 7.35 (t, 1H, J = 2.0 Hz), 4.27-4.35 (m, 3H), 2.91 (br s, 2H), 2.17 (d, 2H, J = 10.0 Hz), 1.95 (qd, 2H, J = 12.8 Hz, 4.8 Hz), 1.49 (s, 9H).
실시예Example 1- One- 2 : 32: 3 -(-( 벤질옥시Benzyloxy )-5-(1-(피페리딘-4-일)-1H-)-5-(1-(piperidin-4-yl)-1H- 피라졸Pyrazole -4-일)피리딘 (화합물 -4-yl)pyridine (compound 2)의2) of 제조 Produce
질소 하에서 tert-부틸 4-(4-(5-히드록시피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트 (60 mg, 0.17 mmol)과 벤질클로라이드 (0.021 ml, 0.19 mmol)을 아세토니트릴 용액 15 ml에 용해 시킨 후 탄산세슘 (62.23 mg, 0.19 mM)을 첨가하였다. 반응 혼합물을 90℃에서 1시간 교반하였다. 반응이 완결되면 증류수와 아세트산에틸을 이용하여 추출하고, 유기층을 무수황산마그네슘으로 건조시킨 후 여과하였다. 여과액을 감압 농축시켜, 농축액을 관 크로마토그래피를 통하여 중간체를 얻었다. 그런 다음, 질소 하에서 tert-부틸 4-(4-(5-(벤질옥시)피리딘-3-일)-1H-피라졸-1-일)피피리딘-1-카르복실레이트 (20.00 mg, 0.046 mmol)를 1,4-디옥산 용액 10 ml에 용해시킨 후 4.0 노르말 염산 1,4-디옥산 용액 (0.11 ml, 0.46 mmol)을 첨가하였다. 반응 혼합물을 40℃에서 1 시간 교반하였다. 반응이 완결되면 감압 농축을 통하여 상기 표제화합물 13.00 mg (수율 76%)을 얻었다.Tert-butyl 4-(4-(5-hydroxypyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (60 mg, 0.17 mmol) and benzyl chloride under nitrogen (0.021 ml, 0.19 mmol) was dissolved in 15 ml of acetonitrile solution, and then cesium carbonate (62.23 mg, 0.19 mM) was added. The reaction mixture was stirred at 90° C. for 1 hour. When the reaction was completed, extraction was performed 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 subjected to column chromatography to obtain an intermediate. Then, under nitrogen, tert-butyl 4-(4-(5-(benzyloxy)pyridin-3-yl)-1H-pyrazol-1-yl)pipyridin-1-carboxylate (20.00 mg, 0.046 mmol ) Was dissolved in 10 ml of a 1,4-dioxane solution, and then a 1,4-dioxane solution of 4.0 normal hydrochloric acid (0.11 ml, 0.46 mmol) was added. The reaction mixture was stirred at 40° C. for 1 hour. When the reaction was completed, 13.00 mg (yield 76%) of the title compound was obtained through concentration under reduced pressure.
1H-NMR (400 MHz, DMSO-d 6): δ 9.23 (br, s, 1H), 9.09 (br, s, 1H), 8.76 (s, 1H), 8.62 (s, 1H), 8.46 (s, 1H), 8.24-8.27 (m, 2H), 7.51-7.53 (m, 2H), 7.37-7.46 (m, 3H), 5.34 (s, 2H), 4.54 (dd, 1H, J = 10.4 Hz, 6.0 Hz), 3.39 (t, 2H, J = 6.0 Hz), 2.19-2.50 (m, 4H); 1 H-NMR (400 MHz, DMSO- d 6 ): δ 9.23 (br, s, 1H), 9.09 (br, s, 1H), 8.76 (s, 1H), 8.62 (s, 1H), 8.46 (s , 1H), 8.24-8.27 (m, 2H), 7.51-7.53 (m, 2H), 7.37-7.46 (m, 3H), 5.34 (s, 2H), 4.54 (dd, 1H, J = 10.4 Hz, 6.0 Hz), 3.39 (t, 2H, J = 6.0 Hz), 2.19-2.50 (m, 4H);
실시예Example 2 : 화합물 44의 제조 2: Preparation of compound 44
실시예Example 2-1 : (R)-3- 2-1: (R)-3- 브로모Bromo -5-(1-(2,6--5-(1-(2,6- 디클로로Dichloro -3--3- 플루오로페닐Fluorophenyl )) 에톡시Ethoxy )피리딘 (화합물 44-Ⅱ-) Pyridine (compound 44-Ⅱ- 3)의3) of 제조 Produce
질소 하에서 (S)-1-(2,6-디클로로-3-플루오로페닐)에탄올 (500 mg, 2.39 mmol)과 5-브로모-3-히드록시피리딘(437.00 mg, 2.51 mmol)을 THF 용액 20 ml에 용해 시킨 후 DIAD (0.66 ml, 3.35 mmol)와 PPh3 (878.40 mg, 3.35 mmol)을 첨가하였다. 반응 혼합물을 0℃에서 4 시간 교반하였다. 반응이 완결되면 증류수와 아세트산에틸을 이용하여 추출하고, 유기층을 무수황산마그네슘으로 건조시킨 후 여과하였다. 여과액을 감압 농축시켜, 농축액을 관 크로마토그래피를 통하여 표제화합물 619.30 mg (수율 71%)을 얻었다.(S)-1-(2,6-dichloro-3-fluorophenyl)ethanol (500 mg, 2.39 mmol) and 5-bromo-3-hydroxypyridine (437.00 mg, 2.51 mmol) in a THF solution under nitrogen After dissolving in 20 ml, DIAD (0.66 ml, 3.35 mmol) and PPh3 (878.40 mg, 3.35 mmol) were added. The reaction mixture was stirred at 0° C. for 4 hours. When the reaction was completed, extraction was performed 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 subjected to column chromatography to give 619.30 mg (yield 71%) of the title compound.
1H-NMR (400 MHz, MeOD): δ 8.22 (d, 1H, J = 2.0 Hz), 8.16 (d, 1H, J = 2.8 Hz), 7.50-7.45 (m, 2H), 7.28 (t, 1H, J = 4.4 Hz), 6.19 (q, 1H, J = 6.4 Hz), 1.84 (d, 3H, J = 6.4 Hz). 1 H-NMR (400 MHz, MeOD): δ 8.22 (d, 1H, J = 2.0 Hz), 8.16 (d, 1H, J = 2.8 Hz), 7.50-7.45 (m, 2H), 7.28 (t, 1H , J = 4.4 Hz), 6.19 (q, 1H, J = 6.4 Hz), 1.84 (d, 3H, J = 6.4 Hz).
실시예Example 2-2 : (R)-5-(5-(1-(2,6- 2-2: (R)-5-(5-(1-(2,6- 디클로로Dichloro -3--3- 플루오로페닐Fluorophenyl )) 에톡시Ethoxy )피리딘-3-일)피리미딘-2-아민 (화합물 )Pyridin-3-yl)pyrimidin-2-amine (compound 44)의44) of 제조 Produce
질소 하에서 (R)-3-브로모-5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘 (67.00 mg, 0.18 mmol) 과 5-(4,4,5,5-테트라메틸-1,3,2-디옥사보로란-2-일)피리미딘-2-아민 (36.90 mg, 0.17 mM)을 1,4-디옥산 (15 ml)에 용해시킨 후 PdCl2(PPh3) (7.02 mg, 0.01 mM)와 1.0 노르말 탄산나트륨 수용액 (76.31 mg, 0.72 mM)을 첨가하였다. 반응 혼합물을 90 ℃에서 1시간 교반하였다. 반응이 완결되면 증류수와 아세트산 에틸을 이용하여 추출하고, 유기층을 무수황산마그네슘으로 건조시킨 후 여과하였다. 여과액을 감압 농축시켜, 농축액을 관 크로마토그래피를 통하여 표제화합물 24.02 mg (수율 38%)을 얻었다. Under nitrogen (R)-3-bromo-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridine (67.00 mg, 0.18 mmol) and 5-(4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (36.90 mg, 0.17 mM) was dissolved in 1,4-dioxane (15 ml) and then PdCl 2 (PPh 3 ) (7.02 mg, 0.01 mM) and 1.0 normal sodium carbonate aqueous solution (76.31 mg, 0.72 mM) were added. The reaction mixture was stirred at 90° C. for 1 hour. When the reaction was completed, extraction was performed using 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 subjected to column chromatography to obtain 24.02 mg (yield 38%) of the title compound.
1H-NMR (400 MHz, MeOD): δ 8.87 (s, 2H), 8.78 (s, 1H), 8.45 (dd, 1H, J = 7.2 Hz, 2.4 Hz), 7.52 (dd, 1H, J = 9.2 Hz, 4.8 Hz), 7.35 (t, 1H, J = 8.4 Hz), 6.47 (q, 1H, J = 6.8 Hz), 1.94 (d, 3H, J = 6.8 Hz). 1 H-NMR (400 MHz, MeOD): δ 8.87 (s, 2H), 8.78 (s, 1H), 8.45 (dd, 1H, J = 7.2 Hz, 2.4 Hz), 7.52 (dd, 1H, J = 9.2 Hz, 4.8 Hz), 7.35 (t, 1H, J = 8.4 Hz), 6.47 (q, 1H, J = 6.8 Hz), 1.94 (d, 3H, J = 6.8 Hz).
실시예Example 3 : 화합물 52의 제조 3: Preparation of compound 52
실시예Example 3- 3- 1 :(One :( S)-3-S)-3- 브로모Bromo -5-(1-(2,6--5-(1-(2,6- 디클로로Dichloro -3--3- 플루오로페닐Fluorophenyl )) 에톡시Ethoxy )피리딘(화합물 52-Ⅱ-) Pyridine (Compound 52-II- 3)의3) of 제조 Produce
질소 하에서 (R)-1-(2,6-디클로로-3-플루오로페닐)에탄올 (1.00 g, 4.78 mmol)과 5-브로모-3-히드록시피리딘(0.87 g, 5.02 mmol)을 THF 용액 30 ml에 용해 시킨 후 DIAD (1.32 ml, 7.70 mmol)와 PPh3 (1.76 g, 7.70 mmol)을 첨가하였다. 반응 혼합물을 0℃에서 4 시간 교반하였다. 반응이 완결되면 증류수와 아세트산에틸을 이용하여 추출하고, 유기층을 무수황산마그네슘으로 건조시킨 후 여과하였다. 여과액을 감압 농축시켜, 농축액을 관 크로마토그래피를 통하여 표제화합물 619.20 mg (수율 71%)을 얻었다.(R)-1-(2,6-dichloro-3-fluorophenyl)ethanol (1.00 g, 4.78 mmol) and 5-bromo-3-hydroxypyridine (0.87 g, 5.02 mmol) in a THF solution under nitrogen After dissolving in 30 ml, DIAD (1.32 ml, 7.70 mmol) and PPh 3 (1.76 g, 7.70 mmol) were added. The reaction mixture was stirred at 0° C. for 4 hours. When the reaction was completed, extraction was performed 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 subjected to column chromatography to give 619.20 mg (yield 71%) of the title compound.
1H-NMR (400 MHz, DMSO-d 6): δ 8.28 (d, 1H, J = 1.6 Hz), 8.19 (d, 1H, J = 2.4 Hz), 7.56-7.59 (m, 1H), 7.45-7.51 (m, 2H), 6.19 (q, 1H, J = 6.8 Hz), 1.75 (d, 3H, J = 6.4 Hz). 1 H-NMR (400 MHz, DMSO- d 6 ): δ 8.28 (d, 1H, J = 1.6 Hz), 8.19 (d, 1H, J = 2.4 Hz), 7.56-7.59 (m, 1H), 7.45- 7.51 (m, 2H), 6.19 (q, 1H, J = 6.8 Hz), 1.75 (d, 3H, J = 6.4 Hz).
실시예Example 3-2 : (S)-5-(5-(1-(2,6- 3-2: (S)-5-(5-(1-(2,6- 디클로로Dichloro -3--3- 플루오로페닐Fluorophenyl )) 에톡시Ethoxy )피리딘-3-일)티오펜-2-카르보니트릴(화합물 )Pyridin-3-yl)thiophene-2-carbonitrile (compound 52)의52) of 제조 Produce
질소 하에서 (S)-3-브로모-5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘 (100.00 mg, 0.27 mmol) 과 5-(4,4,5,5-테트라메틸-1,3,2-디옥사보로란-2-일)티오펜-2-카르보니트릴 (64.41 mg, 0.27 mM)을 1,4-디옥산 (15 ml)에 용해시킨 후 PdCl2(PPh3) (7.02 mg, 0.01 mM)와 1.0 노르말 탄산나트륨 수용액 (114.47 mg, 1.08 mM)을 첨가하였다. 반응 혼합물을 90℃에서 1시간 교반하였다. 반응이 완결되면 증류수와 아세트산 에틸을 이용하여 추출하고, 유기층을 무수황산마그네슘으로 건조시킨 후 여과하였다. 여과액을 감압 농축시켜, 농축액을 관 크로마토그래피를 통하여 표제화합물 51.50 mg (수율 47%)을 얻었다.Under nitrogen (S)-3-bromo-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridine (100.00 mg, 0.27 mmol) and 5-(4,4,5, After dissolving 5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carbonitrile (64.41 mg, 0.27 mM) in 1,4-dioxane (15 ml) PdCl 2 (PPh 3 ) (7.02 mg, 0.01 mM) and 1.0 normal sodium carbonate aqueous solution (114.47 mg, 1.08 mM) were added. The reaction mixture was stirred at 90° C. for 1 hour. When the reaction was completed, extraction was performed using 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 subjected to column chromatography to give 51.50 mg (yield 47%) of the title compound.
1H-NMR (400 MHz, MeOD): δ 8.48 (s, 1H), 8.23 (d, 1H, J = 2.4 Hz), 7.79 (d, 1H, J = 4.0 Hz), 7.53 (d, 2H, J = 4.0 Hz), 7.46-7.50 (m, 1H), 7.26 (t, 1H, J = 8.4 Hz), 6.28 (q, 1H, J = 6.8 Hz), 1.88 (d, 3H, J = 6.8 Hz). 1 H-NMR (400 MHz, MeOD): δ 8.48 (s, 1H), 8.23 (d, 1H, J = 2.4 Hz), 7.79 (d, 1H, J = 4.0 Hz), 7.53 (d, 2H, J = 4.0 Hz), 7.46-7.50 (m, 1H), 7.26 (t, 1H, J = 8.4 Hz), 6.28 (q, 1H, J = 6.8 Hz), 1.88 (d, 3H, J = 6.8 Hz).
실시예Example 4 : 화합물 71의 제조 4: Preparation of compound 71
실시예Example 4- 4- 1 : 31: 3 -- 브로모Bromo -5-((2,4--5-((2,4- 디클로로벤질Dichlorobenzyl )) 옥시Oxy )피리딘 (화합물 71-Ⅱ-)Pyridine (Compound 71-Ⅱ- 3)의3) of 제조 Produce
질소 하에서 2,4-디클로로-벤질클로라이드 (281.20 mg, 1.44 mmol)과 5-브로모-3-히드록시피리딘 (250.00 mg, 1.44 mmol)을 DMF 용액 20 ml에 용해 시킨 후 탄산세슘 (515.80 mg, 1.58 mmol)을 첨가하였다. 반응 혼합물을 70℃에서 2 시간 교반하였다. 반응이 완결되면 증류수와 아세트산에틸을 이용하여 추출하고, 유기층을 무수황산마그네슘으로 건조시킨 후 여과하였다. 여과액을 감압 농축시켜, 농축액을 관 크로마토그래피를 통하여 표제화합물 335.40 mg (수율 70%)을 얻었다.After dissolving 2,4-dichloro-benzyl chloride (281.20 mg, 1.44 mmol) and 5-bromo-3-hydroxypyridine (250.00 mg, 1.44 mmol) in 20 ml of DMF solution under nitrogen, cesium carbonate (515.80 mg, 1.58 mmol) was added. The reaction mixture was stirred at 70° C. for 2 hours. When the reaction was completed, extraction was performed 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 subjected to column chromatography to give 335.40 mg (yield 70%) of the title compound.
1H-NMR (400 MHz, MeOD): δ 8.33 (d, 1H, J = 2.4 Hz), 8.30 (d, 1H, J = 2.0 Hz), 7.77 (dd, 1H, J = 2.4 Hz, 2.0 Hz), 7.57-7.61 (m, 2H), 7.41 (dd, 1H, J = 8.4 Hz, 2.4 Hz), 5.27 (s, 2H). 1 H-NMR (400 MHz, MeOD): δ 8.33 (d, 1H, J = 2.4 Hz), 8.30 (d, 1H, J = 2.0 Hz), 7.77 (dd, 1H, J = 2.4 Hz, 2.0 Hz) , 7.57-7.61 (m, 2H), 7.41 (dd, 1H, J = 8.4 Hz, 2.4 Hz), 5.27 (s, 2H).
실시예Example 4- 4- 2 : 52: 5 -((2,4--((2,4- 디클로로벤질Dichlorobenzyl )) 옥시Oxy )-6'-니트로-3,3'-)-6'-nitro-3,3'- 비피리딘(화합물 71)의Of bipyridine (compound 71) 제조 Produce
질소 하에서 3-브로모-5-((2,4-디클로로벤질)옥시)피리딘 (150.00 mg, 0.45 mmol)과 2-니트로-5-(4,4,5,5-테트라메틸-1,3,2-디옥사보로란-2-일)피리딘 (102.27 mg, 0.41 mM)을 1,4-디옥산 (15 ml)에 용해시킨 후 PdCl2(PPh3)(21.06 mg, 0.03 mM)와 1.0 노르말 탄산나트륨 수용액을 첨가하였다. 반응 혼합물을 90℃에서 1 시간 교반하였다. 반응이 완결되면 증류수와 아세트산에틸을 이용하여 추출하고, 유기층을 무수황산마그네슘으로 건조시킨 후 여과하였다. 여과액을 감압 농축시켜, 농축액을 관 크로마토그래피를 통하여 표제화합물 72.00 mg (수율 48%)을 얻었다.3-bromo-5-((2,4-dichlorobenzyl)oxy)pyridine (150.00 mg, 0.45 mmol) and 2-nitro-5-(4,4,5,5-tetramethyl-1,3 under nitrogen ,2-dioxaborolan-2-yl)pyridine (102.27 mg, 0.41 mM) was dissolved in 1,4-dioxane (15 ml), followed by PdCl 2 (PPh 3 ) (21.06 mg, 0.03 mM) and A 1.0 normal sodium carbonate aqueous solution was added. The reaction mixture was stirred at 90° C. for 1 hour. When the reaction was completed, extraction was performed 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 subjected to column chromatography to give 72.00 mg (yield 48%) of the title compound.
1H-NMR(400MHz,CDCl3):δ 8.87 (d, 1H, J = 2.0 Hz), 8.55-8.58 (m, 1H), 8.42 (d, 1H, J = 8.4 Hz), 8.24 (dd, 1H, J = 8.4 Hz, 2.0 Hz), 7.50-7.55 (m, 3H), 7.35 (dd, 1H, J = 8.4 Hz, 2.0 Hz), 5.31 (s, 2H). 1 H-NMR (400MHz, CDCl 3 ): δ 8.87 (d, 1H, J = 2.0 Hz), 8.55-8.58 (m, 1H), 8.42 (d, 1H, J = 8.4 Hz), 8.24 (dd, 1H , J = 8.4 Hz, 2.0 Hz), 7.50-7.55 (m, 3H), 7.35 (dd, 1H, J = 8.4 Hz, 2.0 Hz), 5.31 (s, 2H).
실시예Example 5 : 화합물 107의 제조 5: Preparation of compound 107
실시예Example 5- 5- 1 : 21: 2 -- 브로모Bromo -4-((2,4--4-((2,4- 디클로로벤질Dichlorobenzyl )) 옥시Oxy )피리딘 (화합물 107-Ⅱ-3)의 제조) Preparation of pyridine (Compound 107-II-3)
질소 하에서 2,4-디클로로-벤질클로라이드 (224.60 mg, 1.15 mmol)과 2-브로모피리딘-4-올 (200.00 mg, 1.15 mmol)을 DMF 용액 30 ml에 용해 시킨 후 탄산세슘 (411.80 mg, 1.26 mmol)을 첨가하였다. 반응 혼합물을 70℃에서 5 시간 교반하였다. 반응이 완결되면 증류수와 아세트산에틸을 이용하여 추출하고, 유기층을 무수황산마그네슘으로 건조시킨 후 여과하였다. 여과액을 감압 농축시켜, 농축액을 관 크로마토그래피를 통하여 표제화합물 230.00 mg (수율 60%)을 얻었다.After dissolving 2,4-dichloro-benzyl chloride (224.60 mg, 1.15 mmol) and 2-bromopyridin-4-ol (200.00 mg, 1.15 mmol) in 30 ml of DMF solution under nitrogen, cesium carbonate (411.80 mg, 1.26 mmol) mmol) was added. The reaction mixture was stirred at 70° C. for 5 hours. When the reaction was completed, extraction was performed 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 subjected to column chromatography to give 230.00 mg (yield 60%) of the title compound.
1H-NMR (400 MHz, DMSO-d 6):δ 8.22 (d, 1H, J = 1.6 Hz), 7.72 (s, 1H), 7.64 (d, 1H, J = 8.4 Hz), 7.39 (s, 1H), 7.13 (d, 1H, J = 8.0 Hz), 5.27 (s, 2H). 1 H-NMR (400 MHz, DMSO- d 6 ): δ 8.22 (d, 1H, J = 1.6 Hz), 7.72 (s, 1H), 7.64 (d, 1H, J = 8.4 Hz), 7.39 (s, 1H), 7.13 (d, 1H, J = 8.0 Hz), 5.27 (s, 2H).
실시예Example 5- 5- 2 : 52: 5 -(4-((2,4--(4-((2,4- 디클로로벤질Dichlorobenzyl )) 옥시Oxy )피리딘-2-일)피리미딘-2-)Pyridin-2-yl)pyrimidin-2- 아민Amine (화합물 (compound 107)의107) of 제조 Produce
질소 하에서 2-브로모-4-((2,4-디클로로벤질)옥시)피리딘 (50.00 mg, 0.15 mmol) 과 5-(4,4,5,5-테트라메틸-1,3,2-디옥사보로란-2-일)피리미딘-2-아민 (31.59 mg, 0.14 mM)을 1,4-디옥산 (15 ml)에 용해시킨 후 PdCl2(PPh3)(4.91mg,0.007mM)와 1.0 노르말 탄산나트륨 수용액 (59.35 mg, 0.56 mM)을 첨가하였다. 반응 혼합물을 90℃에서 1 시간 교반하였다. 반응이 완결되면 증류수와 아세트산에틸을 이용하여 추출하고, 유기층을 무수황산마그네슘으로 건조시킨 후 여과하였다. 여과액을 감압 농축시켜, 농축액을 관 크로마토그래피를 통하여 표제화합물 23.00 mg (수율 44%)을 얻었다.2-bromo-4-((2,4-dichlorobenzyl)oxy)pyridine (50.00 mg, 0.15 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-di Oxaborolan-2-yl)pyrimidin-2-amine (31.59 mg, 0.14 mM) was dissolved in 1,4-dioxane (15 ml) and then PdCl 2 (PPh 3 ) (4.91 mg, 0.007 mM) And 1.0 normal sodium carbonate aqueous solution (59.35 mg, 0.56 mM) were added. The reaction mixture was stirred at 90° C. for 1 hour. When the reaction was completed, extraction was performed 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 subjected to column chromatography to give 23.00 mg (yield 44%) of the title compound.
1H-NMR (400 MHz, DMSO-d 6):δ 8.96 (s, 2H), 8.44 (d, 1H, J = 6.4 Hz), 7.74 (s, 1H), 7.69 (d, 1H, J = 8.4 Hz), 7.58 (s, 1H), 7.53 (d, 1H, J = 8.4 Hz), 6.99 (br s, 3H), 5.33 (s, 2H). 1 H-NMR (400 MHz, DMSO- d 6 ): δ 8.96 (s, 2H), 8.44 (d, 1H, J = 6.4 Hz), 7.74 (s, 1H), 7.69 (d, 1H, J = 8.4 Hz), 7.58 (s, 1H), 7.53 (d, 1H, J = 8.4 Hz), 6.99 (br s, 3H), 5.33 (s, 2H).
실시예Example 6 : 화합물 113의 제조 6: Preparation of compound 113
실시예Example 6- 6- 1 : 21: 2 -- 브로모Bromo -6-((2,4--6-((2,4- 디클로로벤질Dichlorobenzyl )) 옥시Oxy )피리딘 (화합물 113-Ⅱ-3)의 제조) Preparation of pyridine (Compound 113-II-3)
질소 하에서 2,4-디클로로-벤질클로라이드 (1.24 g, 1.15 mmol)과 6-브로모피리딘-4-올 (1.00 g, 5.75 mmol)을 DMF 용액 30 ml에 용해 시킨 후 탄산세슘 (2.25 g, 6.90 mmol)을 첨가하였다. 반응 혼합물을 90℃에서 2 시간 교반하였다. 반응이 완결되면 증류수와 아세트산에틸을 이용하여 추출하고, 유기층을 무수황산마그네슘으로 건조시킨 후 여과하였다. 여과액을 감압 농축시켜, 농축액을 관 크로마토그래피를 통하여 표제화합물 1.91 g (수율 99%)을 얻었다.After dissolving 2,4-dichloro-benzyl chloride (1.24 g, 1.15 mmol) and 6-bromopyridin-4-ol (1.00 g, 5.75 mmol) in 30 ml of DMF solution under nitrogen, cesium carbonate (2.25 g, 6.90) mmol) was added. The reaction mixture was stirred at 90° C. for 2 hours. When the reaction was completed, extraction was performed 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 subjected to column chromatography to obtain 1.91 g (yield 99%) of the title compound.
1H-NMR (400 MHz, CDCl3):δ 7.39-7.46 (m, 3H). 7.24 (dd, 1H, J = 8.4 Hz, 2.0 Hz), 7.08 (d, 1H, J = 8.4 Hz), 6.74 (d, 1H, J = 8.0 Hz). 5.40 (s, 2H). 1 H-NMR (400 MHz, CDCl 3 ): δ 7.39-7.46 (m, 3H). 7.24 (dd, 1H, J = 8.4 Hz, 2.0 Hz), 7.08 (d, 1H, J = 8.4 Hz), 6.74 (d, 1H, J = 8.0 Hz). 5.40 (s, 2H).
실시예Example 6- 6- 2 : 52: 5 -(6-((2,4--(6-((2,4- 디클로로벤질Dichlorobenzyl )) 옥시Oxy )피리딘-2-일)피리미딘-2-)Pyridin-2-yl)pyrimidin-2- 아민Amine (화합물 (compound 113)의113) of 제조 Produce
질소 하에서 2-브로모-6-((2,4-디클로로벤질)옥시)피리딘 (150.00 mg, 0.45 mmol)과 5-(4,4,5,5-테트라메틸-1,3,2-디옥사보로란-2-일)피리미딘-2-아민 (309.50 mg, 0.64 mM)을 디메톡시에탄 (15 ml)에 용해시킨 후 Pd(dppf)Cl2CH2Cl2(16.33 mg,0.02 mM)와 1.0 노르말 탄산세슘 수용액 (586.48 mg, 1.80 mM)을 첨가하였다. 반응 혼합물을 90℃에서 2 시간 교반하였다. 반응이 완결되면 증류수와 아세트산에틸을 이용하여 추출하고, 유기층을 무수황산마그네슘으로 건조시킨 후 여과하였다. 여과액을 감압 농축시켜, 농축액을 관 크로마토그래피를 통하여 표제화합물 62.00 mg (수율 39%)을 얻었다.2-bromo-6-((2,4-dichlorobenzyl)oxy)pyridine (150.00 mg, 0.45 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-di Oxaborolan-2-yl)pyrimidin-2-amine (309.50 mg, 0.64 mM) was dissolved in dimethoxyethane (15 ml), followed by Pd(dppf)Cl 2 CH 2 Cl 2 (16.33 mg, 0.02 mM) ) And 1.0 normal cesium carbonate aqueous solution (586.48 mg, 1.80 mM) were added. The reaction mixture was stirred at 90° C. for 2 hours. When the reaction was completed, extraction was performed 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 subjected to column chromatography to give 62.00 mg (yield 39%) of the title compound.
1H-NMR (400 MHz, DMSO-d 6):δ 8.89 (s, 2H), 7.78 (t, 1H, J = 8.0 Hz), 7.70 (d, 1H, J = 2.0 Hz), 7.60 (d, 1H, J = 8.4 Hz), 7.50 (d, 1H, J = 7.6 Hz), 7.46 (dd, 1H, J = 8.4 Hz, 2.4 Hz), 7.00 (br s, 2H), 6.81 (d, 1H J = 8.4 Hz), 5.52 (s, 2H). 1 H-NMR (400 MHz, DMSO- d 6 ): δ 8.89 (s, 2H), 7.78 (t, 1H, J = 8.0 Hz), 7.70 (d, 1H, J = 2.0 Hz), 7.60 (d, 1H, J = 8.4 Hz), 7.50 (d, 1H, J = 7.6 Hz), 7.46 (dd, 1H, J = 8.4 Hz, 2.4 Hz), 7.00 (br s, 2H), 6.81 (d, 1H J = 8.4 Hz), 5.52 (s, 2H).
실시예Example 7 : 화합물 129의 제조 7: Preparation of compound 129
실시예Example 7-1 : (R)-3-(1-(2,6- 7-1: (R)-3-(1-(2,6- 디클로로Dichloro -3--3- 플루오로페닐Fluorophenyl )) 에톡시Ethoxy )-2-)-2- 니트로피리딘Nitropyridine (화합물 129-Ⅲ- (Compound 129-Ⅲ- 3)의3) of 제조 Produce
질소 하에서 (S)-1-(2,6-디클로로-3-플루오로페닐)에탄올 (1.00g, 4.78 mmol)과 2-니트로피리딘-3-올 (0.70 g, 5.02 mmol)을 THF 용액 20 ml에 용해 시킨 후 DIAD (1.34 ml, 6.82 mmol)와 PPh3 (1.79 g, 6.84 mmol)을 첨가하였다. 반응 혼합물을 0℃에서 4 시간 교반하였다. 반응이 완결되면 증류수와 아세트산에틸을 이용하여 추출하고, 유기층을 무수황산마그네슘으로 건조시킨 후 여과하였다. 여과액을 감압 농축시켜, 농축액을 관 크로마토그래피를 통하여 표제화합물 1.29 g (수율 81%)을 얻었다. (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol (1.00g, 4.78 mmol) and 2-nitropyridin-3-ol (0.70 g, 5.02 mmol) in 20 ml of THF solution under nitrogen After dissolving in DIAD (1.34 ml, 6.82 mmol) and PPh3 (1.79 g, 6.84 mmol) were added. The reaction mixture was stirred at 0° C. for 4 hours. When the reaction was completed, extraction was performed 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 subjected to column chromatography to obtain 1.29 g (yield 81%) of the title compound.
1H-NMR (400 MHz, DMSO-d 6) : δ 8.10 (d, 1H, J = 4.4 Hz), 7.70 (dd, 1H, J = 8.4 Hz, 4.8 Hz), 7.59 (dd, 1H, J = 8.4 Hz, 4. 8Hz), 7.48-7.52 (m, 2H), 6.30 (q, 1H, J = 6.8 Hz), 1.76 (d, 3H, J = 6.8 Hz). 1 H-NMR (400 MHz, DMSO- d 6 ): δ 8.10 (d, 1H, J = 4.4 Hz), 7.70 (dd, 1H, J = 8.4 Hz, 4.8 Hz), 7.59 (dd, 1H, J = 8.4 Hz, 4.8 Hz), 7.48-7.52 (m, 2H), 6.30 (q, 1H, J = 6.8 Hz), 1.76 (d, 3H, J = 6.8 Hz).
실시예Example 7-2 : (R)-3-(1-(2,6- 7-2: (R)-3-(1-(2,6- 디클로로Dichloro -3--3- 플루오로페닐Fluorophenyl )) 에톡시Ethoxy )피리딘-2-) Pyridine-2- 아민Amine (화합물 129-Ⅲ- (Compound 129-Ⅲ- 4)의4) of 제조 Produce
질소 하에서 (R)-3-(1-(2,6-디클로로-3-플루오로페닐)에톡시)-2-니트로피리딘 (0.98 g, 2.96 mmol)를 에탄올:아세트산 = 8:3 용액 55 ml에 용해시킨 후 철 (1.65 g, 29.60 mmol)을 첨가하였다. 반응 혼합물은 반응 혼합물을 90℃에서 1 시간 교반하였다. 반응이 완결되면 증류수와 아세트산에틸을 이용하여 추출하고, 유기층을 무수황산마그네슘으로 건조시킨 후 여과하였다. 여과액을 감압 농축시켜, 농축액을 관 크로마토그래피를 통하여 표제화합물 0.80 g (수율 90%)을 얻었다.55 ml of (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-2-nitropyridine (0.98 g, 2.96 mmol) in ethanol:acetic acid = 8:3 solution under nitrogen After dissolving in iron (1.65 g, 29.60 mmol) was added. The reaction mixture was stirred at 90°C for 1 hour. When the reaction was completed, extraction was performed 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 subjected to column chromatography to obtain 0.80 g (yield 90%) of the title compound.
1H-NMR (400 MHz, CDCl3) :δ 7.58 (d, 1H, J = 4.8 Hz), 7.27 (dd, 1H, J = 8.4 Hz, 4.4 Hz), 7.03 (t, 1H, J = 8.4 Hz), 6.69 (d, 1H, J = 7.6 Hz), 6.46 (t, 1H, J = 7.2 Hz), 6.00 (q, 1H, J = 6.8 Hz), 4.99 (s, 2H), 1.81 (d, 3H, J = 6.8 Hz). 1 H-NMR (400 MHz, CDCl 3 ): δ 7.58 (d, 1H, J = 4.8 Hz), 7.27 (dd, 1H, J = 8.4 Hz, 4.4 Hz), 7.03 (t, 1H, J = 8.4 Hz ), 6.69 (d, 1H, J = 7.6 Hz), 6.46 (t, 1H, J = 7.2 Hz), 6.00 (q, 1H, J = 6.8 Hz), 4.99 (s, 2H), 1.81 (d, 3H , J = 6.8 Hz).
실시예Example 7- 7- 3 :(3 :( R)-5-R)-5- 브로모Bromo -3-(1-(2,6--3-(1-(2,6- 디클로로Dichloro -3--3- 플루오로페닐Fluorophenyl )) 에톡시Ethoxy )피리딘-2-아민 (화합물 129-Ⅲ-)Pyridine-2-amine (Compound 129-III- 5)의5) of 제조 Produce
질소 하에서 (R)-3-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-2-아민 (0.50 g, 1.66 mmol)와 N-브로모숙신이미드 (0.32 g, 1.83 mmol)을 아세토니트릴 20 ml 용액에 용해 시킨 후 0℃에서 10 분간 교반하였다. 반응이 완결되면 증류수와 아세트산에틸을 이용하여 추출하고, 유기층을 무수황산마그네슘으로 건조시킨 후 여과하였다. 여과액을 감압 농축시켜, 농축액을 관 크로마토그래피를 통하여 표제화합물 0.51 g (수율 81%)을 얻었다.(R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine (0.50 g, 1.66 mmol) and N-bromosuccinimide (0.32 g) under nitrogen , 1.83 mmol) was dissolved in a 20 ml solution of acetonitrile and then stirred at 0° C. for 10 minutes. When the reaction was completed, extraction was performed 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 subjected to column chromatography to obtain 0.51 g (yield 81%) of the title compound.
1H-NMR (400 MHz, CDCl3):δ 7.69 (d, 1H, J = 2.0 Hz) 7.34 (dd, 1H, J = 8.8 Hz, 4.8 Hz), 7.29 (s, 1H), 7.11 (t, 1H, J = 8.8 Hz), 6.86 (d, 1H, J = 1.6 Hz), 6.02 (q, 1H, J = 6.8 Hz), 1.85 (d, 3H, J = 6.8 Hz). 1 H-NMR (400 MHz, CDCl 3 ): δ 7.69 (d, 1H, J = 2.0 Hz) 7.34 (dd, 1H, J = 8.8 Hz, 4.8 Hz), 7.29 (s, 1H), 7.11 (t, 1H, J = 8.8 Hz), 6.86 (d, 1H, J = 1.6 Hz), 6.02 (q, 1H, J = 6.8 Hz), 1.85 (d, 3H, J = 6.8 Hz).
실시예Example 7- 7- 4 :디4:D -- terttert -부틸 (R)--Butyl (R)- (5-브로모-3-(1-(5-bromo-3-(1- (2,6-(2,6- 디클로로Dichloro -3--3- 플루오로페닐Fluorophenyl )에톡시)피리딘-2-일)디카르바메이트(화합물 129-Ⅲ-)Ethoxy)pyridin-2-yl)dicarbamate (Compound 129-III- 6)의6) of 제조 Produce
질소 하에서 (R)-5-브로모-3-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-2-아민 (0.80 g, 2.11 mmol), 디-tert-부틸-디카보네이트(1.32 g, 6.07 mmol)와 디-메틸아미노피리딘(0.05 g, 0.40 mmol)을 DMF(25 ml)용액에 용해 시킨 후 실온에서 18 시간 교반하였다. 반응이 완결되면 증류수와 아세트산에틸을 이용하여 추출하고, 유기층을 무수황산마그네슘으로 건조시킨 후 여과하였다. 여과액을 감압 농축시켜, 농축액을 관 크로마토그래피를 통하여 표제화합물 1.22 g (수율 99%)을 얻었다.(R)-5-bromo-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine (0.80 g, 2.11 mmol), di-tert-butyl under nitrogen -Dicarbonate (1.32 g, 6.07 mmol) and di-methylaminopyridine (0.05 g, 0.40 mmol) were dissolved in DMF (25 ml) solution and stirred at room temperature for 18 hours. When the reaction was completed, extraction was performed 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 subjected to column chromatography to obtain 1.22 g (yield 99%) of the title compound.
1H-NMR (400 MHz, CDCl3):δ 8.11 (d, 1H, J = 2.0 Hz), 7.30 (dd, 1H, J = 8.8 Hz, 4.0 Hz), 7.24 (d, 1H, J = 2.0 Hz), 7.09 (t, 1H, J = 8.8 Hz), 5.98 (q, 1H, J = 6.8 Hz), 1.79 (d, 3H J = 6.8 Hz), 1.41 (m, 18H, J = 26.0 Hz). 1 H-NMR (400 MHz, CDCl 3 ): δ 8.11 (d, 1H, J = 2.0 Hz), 7.30 (dd, 1H, J = 8.8 Hz, 4.0 Hz), 7.24 (d, 1H, J = 2.0 Hz ), 7.09 (t, 1H, J = 8.8 Hz), 5.98 (q, 1H, J = 6.8 Hz), 1.79 (d, 3H J = 6.8 Hz), 1.41 (m, 18H, J = 26.0 Hz).
실시예Example 7-5 : 디-tert-부틸 (R)-4-(5-(6-((tert-부톡시카르보닐)아미노)-5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-3-일)피리미딘-2-일)피페라진-1-카르복실레이트 (화합물 129-Ⅲ-8)의 제조 7-5: Di-tert-butyl (R)-4-(5-(6-((tert-butoxycarbonyl)amino)-5-(1-(2,6-dichloro-3-fluorophenyl )Ethoxy)pyridin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate (Compound 129-III-8) Preparation
질소 하에서 디-tert-부틸 (R)-(5-브로모-3-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-2-일)카르바메이트 (150.00 mg, 0.26 mmol) 과 tert-부틸 4-(5-(4,4,5,5-테트라메틸-1,3,2-디옥사보로란-2-일)피리미딘-2-일)피페라진-1-카르복실레이트 (121.38 mg, 0.31 mM)을 1,4-디옥산 (15 ml)에 용해시킨 후 PdCl2(PPh3)2 (7.01 mg, 0.01 mM)와 1.0 노르말 탄산나트륨 수용액을 첨가하였다. 반응 혼합물을 90℃에서 1 시간 교반하였다. 반응이 완결되면 증류수와 아세트산에틸을 이용하여 추출하고, 유기층을 무수황산마그네슘으로 건조시킨 후 여과하였다. 여과액을 감압 농축시켜, 농축액을 관 크로마토그래피를 통하여 표제화합물 45.00 mg (수율 23%)을 얻었다.Di-tert-butyl (R)-(5-bromo-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-yl)carbamate (150.00 mg under nitrogen , 0.26 mmol) and tert-butyl 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)piperazine -1-carboxylate (121.38 mg, 0.31 mM) was dissolved in 1,4-dioxane (15 ml) and then PdCl 2 (PPh 3 ) 2 (7.01 mg, 0.01 mM) and 1.0 normal sodium carbonate aqueous solution were added. The reaction mixture was stirred at 90° C. for 1 hour. When the reaction was completed, extraction was performed 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 subjected to column chromatography to give 45.00 mg (yield 23%) of the title compound.
1H-NMR (400 MHz, DMSO-d 6) : δ 8.79 (s, 2H), 8.36 (d, 1H, J = 2.0 Hz), 7.77 (d, 1H, J = 1.6 Hz), 7.57 (dd, 1H, J = 8.8 Hz, 4.8 Hz), 7.47 (t, 1H, J = 8.8 Hz), 6.35 (q, 1H, J = 6.8 Hz), 3.81 (t, 4H, J = 5.6 Hz), 3.45 (m 4H), 1.78 (d, 18H, J = 6.4 Hz), 1.45-1.27 (m, 27H). 1 H-NMR (400 MHz, DMSO- d 6 ): δ 8.79 (s, 2H), 8.36 (d, 1H, J = 2.0 Hz), 7.77 (d, 1H, J = 1.6 Hz), 7.57 (dd, 1H, J = 8.8 Hz, 4.8 Hz), 7.47 (t, 1H, J = 8.8 Hz), 6.35 (q, 1H, J = 6.8 Hz), 3.81 (t, 4H, J = 5.6 Hz), 3.45 (m 4H), 1.78 (d, 18H, J = 6.4 Hz), 1.45-1.27 (m, 27H).
실시예Example 7- 7- 6 :(6:( R)-3-(1-(2,6-R)-3-(1-(2,6- 디클로로Dichloro -3--3- 플루오로페닐Fluorophenyl )) 에톡시Ethoxy )-5-(2-(피페라진-1-일)피리미딘-5-일)피리딘-2-아민 (화합물 )-5-(2-(piperazin-1-yl)pyrimidin-5-yl)pyridin-2-amine (compound 129)의129) of 제조 Produce
질소 하에서 디-tert-부틸 (R)-4-(5-(6-((tert-부톡시카르보닐)아미노)-5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-3-일)피리미딘-2-일)피페라진-1-카르복실레이트 (30.00 mg, 0.04 mmol)을 1,4-디옥산 용액 10 ml에 용해시킨 후 4.0 노르말 염산 1,4-디옥산 용액 (0.01 ml, 0.39 mmol)을 첨가하였다. 반응 혼합물을 40℃에서 1 시간 교반하였다. 반응이 완결되면 감압 농축을 통하여 상기 표제화합물 12.00 mg (수율 63%)을 얻었다.Under nitrogen to di-tert-butyl (R)-4-(5-(6-((tert-butoxycarbonyl)amino)-5-(1-(2,6-dichloro-3-fluorophenyl) Toxic) pyridin-3-yl) pyrimidin-2-yl) piperazine-1-carboxylate (30.00 mg, 0.04 mmol) was dissolved in 10 ml of 1,4-dioxane solution and then 4.0 normal hydrochloric acid 1,4 -Dioxane solution (0.01 ml, 0.39 mmol) was added. The reaction mixture was stirred at 40° C. for 1 hour. When the reaction was completed, 12.00 mg (yield 63%) of the title compound was obtained through concentration under reduced pressure.
1H-NMR (400 MHz, MeOD) : δ 8.49 (s, 2H), 7.69 (d, 1H, J = 1.2 Hz), 7.52 (dd, 1H, J = 8.8 Hz, 4.8 Hz), 7.32 (t, 1H, J = 8.4 Hz), 7.16 (d, 1H, J = 1.2 Hz), 6.40 (q, 1H, J= 6.8 Hz), 4.15 (t, 4H, J = 5.2 Hz), 3.33-3.32 (m, 4H), 1.98 (d, 3H, J = 6.8 Hz). 1 H-NMR (400 MHz, MeOD): δ 8.49 (s, 2H), 7.69 (d, 1H, J = 1.2 Hz), 7.52 (dd, 1H, J = 8.8 Hz, 4.8 Hz), 7.32 (t, 1H, J = 8.4 Hz), 7.16 (d, 1H, J = 1.2 Hz), 6.40 (q, 1H, J = 6.8 Hz), 4.15 (t, 4H, J = 5.2 Hz), 3.33-3.32 (m, 4H), 1.98 (d, 3H, J = 6.8 Hz).
실시예Example 8 : 화합물 133의 제조 8: Preparation of compound 133
실시예Example 8-1 : (S)-3-(1-(2,6- 8-1: (S)-3-(1-(2,6- 디클로로Dichloro -3--3- 플루오로페닐Fluorophenyl )) 에톡시Ethoxy )-2-)-2- 니트로피리딘Nitropyridine (화합물 133-Ⅲ- (Compound 133-Ⅲ- 3)의3) of 제조 Produce
질소 하에서 (R)-1-(2,6-디클로로-3-플루오로페닐)에탄올 (1.21 g, 5.81 mmol)과 2-니트로피리딘-3-올 (0.74 g, 5.28 mmol)을 THF 용액 15 ml에 용해 시킨 후 DIAD (1.57 ml, 7.55 mmol)와 PPh3(1.98g,7.55mmol)을 첨가하였다. 반응 혼합물을 0℃에서 4 시간 교반하였다. 반응이 완결되면 증류수와 아세트산에틸을 이용하여 추출하고, 유기층을 무수황산마그네슘으로 건조시킨 후 여과하였다. 여과액을 감압 농축시켜, 농축액을 관 크로마토그래피를 통하여 표제화합물 1.67 g (수율 95%)을 얻었다.(R)-1-(2,6-dichloro-3-fluorophenyl)ethanol (1.21 g, 5.81 mmol) and 2-nitropyridin-3-ol (0.74 g, 5.28 mmol) in 15 ml of THF solution under nitrogen After dissolving in DIAD (1.57 ml, 7.55 mmol) and PPh 3 (1.98g, 7.55mmol) were added. The reaction mixture was stirred at 0° C. for 4 hours. When the reaction was completed, extraction was performed 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 subjected to column chromatography to obtain 1.67 g (yield 95%) of the title compound.
1H-NMR (400 MHz, CDCl3):δ 8.03 (dd, 1H, J = 4.4Hz, 0.8 Hz), 7.38 (dd, 1H, J = 8.4 Hz, 4.8 Hz), 7.31 (dd, 1H, J = 8.8 Hz, 4.8 Hz), 7.22 (dd, 1H, J = 8.4 Hz, 0.8 Hz), 7.09 (t, 1H, J = 8.4 Hz), 6.11 (q, 1H, J = 6.4 Hz), 1.85 (d, 3H, J = 6.4 Hz). 1 H-NMR (400 MHz, CDCl 3 ): δ 8.03 (dd, 1H, J = 4.4 Hz, 0.8 Hz), 7.38 (dd, 1H, J = 8.4 Hz, 4.8 Hz), 7.31 (dd, 1H, J = 8.8 Hz, 4.8 Hz), 7.22 (dd, 1H, J = 8.4 Hz, 0.8 Hz), 7.09 (t, 1H, J = 8.4 Hz), 6.11 (q, 1H, J = 6.4 Hz), 1.85 (d , 3H, J = 6.4 Hz).
실시예Example 8- 8- 2 :(2 :( S)-3-(1-(2,6-S)-3-(1-(2,6- 디클로로Dichloro -3--3- 플루오로페닐Fluorophenyl )) 에톡시Ethoxy )피리딘-2-) Pyridine-2- 아민(화합물 133-Ⅲ-4)의Of amine (Compound 133-III-4) 제조 Produce
질소 하에서 (S)-3-(1-(2,6-디클로로-3-플루오로페닐)에톡시)-2-니트로피리딘 (1.00 g, 3.02 mmol)를 에탄올:아세트산 = 8:3 용액 55 ml에 용해시킨 후 철 (1.69 g, 30.20 mmol)을 첨가하였다. 반응 혼합물은 반응 혼합물을 90℃에서 1 시간 교반하였다. 반응이 완결되면 증류수와 아세트산에틸을 이용하여 추출하고, 유기층을 무수황산마그네슘으로 건조시킨 후 여과하였다. 여과액을 감압 농축시켜, 농축액을 관 크로마토그래피를 통하여 표제화합물 0.55 g (수율 61%)을 얻었다.55 ml of (S)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-2-nitropyridine (1.00 g, 3.02 mmol) in ethanol:acetic acid = 8:3 solution under nitrogen Iron (1.69 g, 30.20 mmol) was added after dissolving in. The reaction mixture was stirred at 90°C for 1 hour. When the reaction was completed, extraction was performed 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 subjected to column chromatography to obtain 0.55 g (61% yield) of the title compound.
1H-NMR (400 MHz, CDCl3):δ 7.64 (dd, 1H, J = 5.2 Hz, 1.2 Hz), 7.30 (dd, 1H, J = 4.0 Hz, 0.8 Hz), 7.06 (t, 1H, J = 8.4 Hz), 6.72 (d, 1H, J = 7.6 Hz), 6.49 (dd, 1H, J = 8.0 Hz, 5.2 Hz), 6.04 (q, 1H, J = 6.8 Hz), 4.852 (br s, 2H), 1.84 (d, 3H, J = 6.8 Hz). 1 H-NMR (400 MHz, CDCl 3 ): δ 7.64 (dd, 1H, J = 5.2 Hz, 1.2 Hz), 7.30 (dd, 1H, J = 4.0 Hz, 0.8 Hz), 7.06 (t, 1H, J = 8.4 Hz), 6.72 (d, 1H, J = 7.6 Hz), 6.49 (dd, 1H, J = 8.0 Hz, 5.2 Hz), 6.04 (q, 1H, J = 6.8 Hz), 4.852 (br s, 2H ), 1.84 (d, 3H, J = 6.8 Hz).
실시예Example 8- 8- 3 :(3 :( S)-5-S)-5- 브로모Bromo -3-(1-(2,6--3-(1-(2,6- 디클로로Dichloro -3--3- 플루오로페닐Fluorophenyl )) 에톡시Ethoxy )피리딘-2-아민 (화합물 133-Ⅲ-)Pyridine-2-amine (Compound 133-III- 5)의5) of 제조 Produce
질소 하에서 (S)-3-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-2-아민 (1.34 g, 4.44 mmol)와 N-브로모숙신이미드 (0.87 g, 4.89 mmol)을 아세토니트릴 20 ml 용액에 용해시킨 후 0℃에서 10 분간 교반하였다. 반응이 완결되면 증류수와 아세트산에틸을 이용하여 추출하고, 유기층을 무수황산마그네슘으로 건조시킨 후 여과하였다. 여과액을 감압 농축시켜, 농축액을 관 크로마토그래피를 통하여 표제화합물 1.25 g (수율 74%)을 얻었다. (S)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine (1.34 g, 4.44 mmol) and N-bromosuccinimide (0.87 g) under nitrogen , 4.89 mmol) was dissolved in a 20 ml solution of acetonitrile and then stirred at 0° C. for 10 minutes. When the reaction was completed, extraction was performed 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 subjected to column chromatography to obtain 1.25 g (74% yield) of the title compound.
1H-NMR (400 MHz, CDCl3):δ 7.66 (d, 1H, J = 1.6 Hz), 7.31 (dd, 1H, J = 8.8 Hz, 4,8 Hz), 7.07 (t, 1H, J = 8.0 Hz), 6.83 (d, 1H, J = 1.6 Hz), 5.98 (q, 1H, J = 6.8 Hz), 4.98 (br s, 2H), 1.82 (d, 3H, J = 6.8 Hz). 1 H-NMR (400 MHz, CDCl 3 ): δ 7.66 (d, 1H, J = 1.6 Hz), 7.31 (dd, 1H, J = 8.8 Hz, 4,8 Hz), 7.07 (t, 1H, J = 8.0 Hz), 6.83 (d, 1H, J = 1.6 Hz), 5.98 (q, 1H, J = 6.8 Hz), 4.98 (br s, 2H), 1.82 (d, 3H, J = 6.8 Hz).
실시예Example 8- 8- 4 :디4:D -- terttert -부틸 (S)--Butyl (S)- (5-브로모-3-(1-(5-bromo-3-(1- (2,6-(2,6- 디클로로Dichloro -3--3- 플루오로페닐Fluorophenyl )에톡시)피리딘-2-일)디카르바메이트(화합물 133-Ⅲ-)Ethoxy)pyridin-2-yl)dicarbamate (Compound 133-III- 6)의6) of 제조 Produce
질소 하에서 (S)-5-브로모-3-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-2-아민(1.20 g, 3.16 mmol), 디-tert-부틸-디카보네이트 (2.41 g, 11.05 mmol) 와 디-메틸아미노피리딘(0.08 g, 0.65 mmol)을 DMF (25 ml)용액에 용해 시킨 후 실온에서 18 시간 교반하였다. 반응이 완결되면 증류수와 아세트산에틸을 이용하여 추출하고, 유기층을 무수황산마그네슘으로 건조시킨 후 여과하였다. 여과액을 감압 농축시켜, 농축액을 관 크로마토그래피를 통하여 표제화합물 1.83 g (수율 99%)을 얻었다. (S)-5-bromo-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine (1.20 g, 3.16 mmol), di-tert-butyl under nitrogen -Dicarbonate (2.41 g, 11.05 mmol) and di-methylaminopyridine (0.08 g, 0.65 mmol) were dissolved in DMF (25 ml) solution and stirred at room temperature for 18 hours. When the reaction was completed, extraction was performed 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 subjected to column chromatography to obtain 1.83 g (yield 99%) of the title compound.
1H-NMR (400 MHz, CDCl3):δ 8.12 (d, 1H, J = 1.6 Hz), 7.30 (dd, 1H, J = 9.2 Hz, 4.8 Hz), 7.25 (d, 1H, J = 1.6 Hz), 7.10 (t, 1H, J = 8.0 Hz), 6.00 (q, 1H, J = 6.8 Hz), 1.80 (d, 3H, J = 6.4 Hz), 1.42 (br d, 18H, J = 30.4 Hz). 1 H-NMR (400 MHz, CDCl 3 ): δ 8.12 (d, 1H, J = 1.6 Hz), 7.30 (dd, 1H, J = 9.2 Hz, 4.8 Hz), 7.25 (d, 1H, J = 1.6 Hz ), 7.10 (t, 1H, J = 8.0 Hz), 6.00 (q, 1H, J = 6.8 Hz), 1.80 (d, 3H, J = 6.4 Hz), 1.42 (br d, 18H, J = 30.4 Hz) .
실시예Example 8- 8- 5:디5:D -- terttert -부틸 (S)-(5-(2--Butyl (S)-(5-(2- 아미노피리미딘Aminopyrimidine -5-일)-3-(1-(2,6--5-yl)-3-(1-(2,6- 디클로로Dichloro -3-플루오로페닐)에톡시)피리딘-2-일)디카르바메이트 (화합물 133-Ⅲ--3-Fluorophenyl)ethoxy)pyridin-2-yl)dicarbamate (Compound 133-III- 8)의8) of 제조 Produce
질소 하에서 디-tert-부틸 (S)-(5-브로모-3-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-2-일)디카르바메이트 (180.00 mg, 0.26 mmol) 과 5-(4,4,5,5-테트라메틸-1,3,2-디옥사보로란-2-일)피리미딘-2-아민 (75.38 mg, 0.34 mM)을 디메톡시에탄 (15 ml)에 용해시킨 후 Pd(dppf)Cl2CH2Cl2 (12.25 mg,0.02 mM)와 1.0 노르말 탄산세슘 수용액 (404.02 mg, 1.24 mM)을 첨가하였다. 반응 혼합물을 90℃에서 1 시간 30 분 교반하였다. 반응이 완결되면 증류수와 아세트산에틸을 이용하여 추출하고, 유기층을 무수황산마그네슘으로 건조시킨 후 여과하였다. 여과액을 감압 농축시켜, 농축액을 관 크로마토그래피를 통하여 표제화합물 48.00 mg (수율 26%)을 얻었다.Under nitrogen di-tert-butyl (S)-(5-bromo-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-yl)dicarbamate (180.00 mg , 0.26 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (75.38 mg, 0.34 mM) After dissolving in oxyethane (15 ml), Pd(dppf)Cl 2 CH 2 Cl 2 (12.25 mg, 0.02 mM) and 1.0 normal cesium carbonate aqueous solution (404.02 mg, 1.24 mM) were added. The reaction mixture was stirred at 90° C. for 1 hour and 30 minutes. When the reaction was completed, extraction was performed 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 subjected to column chromatography to give 48.00 mg (yield 26%) of the title compound.
1H-NMR (400 MHz, DMSO-d 6):δ 8.62 (s, 2H), 8.31 (d, 1H, J = 2.0 Hz), 7.73 (d, 1H, J = 2.0 Hz), 7.56 (dd, 1H, J = 8.8 Hz, 5.2 Hz), 7.46 (t, 1H, J = 8.8 Hz), 6.97 (br s, 2H), 6.34 (q, 1H, J = 6.8 Hz), 1.77 (d, 3H, J = 6.4 Hz), 1.41-1.24 (m, 18H); 1 H-NMR (400 MHz, DMSO- d 6 ): δ 8.62 (s, 2H), 8.31 (d, 1H, J = 2.0 Hz), 7.73 (d, 1H, J = 2.0 Hz), 7.56 (dd, 1H, J = 8.8 Hz, 5.2 Hz), 7.46 (t, 1H, J = 8.8 Hz), 6.97 (br s, 2H), 6.34 (q, 1H, J = 6.8 Hz), 1.77 (d, 3H, J =6.4 Hz), 1.41-1.24 (m, 18H);
실시예Example 8- 8- 6 :(6:( S)-5-(6-아미노-5-(1-(2,6-S)-5-(6-amino-5-(1-(2,6- 디클로로Dichloro -3--3- 플루오로페닐Fluorophenyl )) 에톡시Ethoxy )피리딘-3-일)피리미딘-2-아민 (화합물 )Pyridin-3-yl)pyrimidin-2-amine (compound 133)의Of 133) 제조 Produce
질소 하에서 디-tert-부틸 (S)-(5-(2-아미노피리미딘-5-일)-3-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-2-일)디카르바메이트 (25.00 mg, 0.04 mmol)을 디클로로메탄 용액 8 ml에 용해시킨 후 트리플루오로아세트산 (61.22 μl, 0.80 mmol)을 첨가하였다. 반응 혼합물을 30℃에서 1 시간 교반하였다. 반응이 완결되면 감압 농축을 통하여 상기 표제화합물 14.00 mg (수율 70%)을 얻었다. Di-tert-butyl (S)-(5-(2-aminopyrimidin-5-yl)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2 under nitrogen -Yl)dicarbamate (25.00 mg, 0.04 mmol) was dissolved in 8 ml of dichloromethane solution, and then trifluoroacetic acid (61.22 μl, 0.80 mmol) was added. The reaction mixture was stirred at 30° C. for 1 hour. When the reaction was completed, 14.00 mg (70% yield) of the title compound was obtained through concentration under reduced pressure.
1H-NMR (400 MHz, MeOD):δ 8.34 (s, 2H), 7.66 (s, 1H), 7.53 (dd, 1H, J = 8.8 Hz, 4.8 Hz), 7.32 (t, 1H, J = 8.4 Hz), 7.13 (s, 1H), 6.39 (q, 1H, J = 6.8 Hz), 1.97 (d, 3H, J = 6.8 Hz); 1 H-NMR (400 MHz, MeOD): δ 8.34 (s, 2H), 7.66 (s, 1H), 7.53 (dd, 1H, J = 8.8 Hz, 4.8 Hz), 7.32 (t, 1H, J = 8.4 Hz), 7.13 (s, 1H), 6.39 (q, 1H, J = 6.8 Hz), 1.97 (d, 3H, J = 6.8 Hz);
실시예Example 9 : 화합물 144의 제조 9: Preparation of compound 144
실시예Example 9- 9- 1 : 31: 3 -((2,4--((2,4- 디클로로벤질Dichlorobenzyl )) 옥시Oxy )-2-)-2- 니트로피리딘Nitropyridine (화합물 144-Ⅲ-3)의 제조 Preparation of (Compound 144-III-3)
질소 하에서 2,4-디클로로-벤질클로라이드 (0.75 g, 5.37 mmol)과 2-니트로피리딘-3-올 (1.00 g, 5.11 mmol)을 아세토니트릴 용액 30 ml에 용해 시킨 후 탄산세슘 (2.01 g, 5.63 mmol)을 첨가하였다. 반응 혼합물을 90℃에서 2 시간 교반하였다. 반응이 완결되면 증류수와 아세트산에틸을 이용하여 추출하고, 유기층을 무수황산마그네슘으로 건조시킨 후 여과하였다. 여과액을 감압 농축시켜, 농축액을 관 크로마토그래피를 통하여 표제화합물 1.34 g (수율 88%)을 얻었다.After dissolving 2,4-dichloro-benzyl chloride (0.75 g, 5.37 mmol) and 2-nitropyridin-3-ol (1.00 g, 5.11 mmol) in 30 ml of acetonitrile solution under nitrogen, cesium carbonate (2.01 g, 5.63 mmol) was added. The reaction mixture was stirred at 90° C. for 2 hours. When the reaction was completed, extraction was performed 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 subjected to column chromatography to obtain 1.34 g (88% yield) of the title compound.
1H-NMR (400 MHz, DMSO-d 6):δ 8.16 (d, 1H, J = 4.0 Hz), 8.12 (d, 1H, J = 8.4 Hz), 7.81 (dd, 1H, J = 8.4 Hz, 4.4 Hz), 7.72 (d, 1H, J = 2.0 Hz), 7.60 (d, 1H, J = 8.4 Hz), 7.53 (dd, 1H, J = 8.4 Hz, 1.6 Hz), 5.41 (s, 2H). 1 H-NMR (400 MHz, DMSO- d 6 ): δ 8.16 (d, 1H, J = 4.0 Hz), 8.12 (d, 1H, J = 8.4 Hz), 7.81 (dd, 1H, J = 8.4 Hz, 4.4 Hz), 7.72 (d, 1H, J = 2.0 Hz), 7.60 (d, 1H, J = 8.4 Hz), 7.53 (dd, 1H, J = 8.4 Hz, 1.6 Hz), 5.41 (s, 2H).
실시예Example 9- 9- 2 : 32: 3 -((2,4--((2,4- 디클로로벤질Dichlorobenzyl )) 옥시Oxy )피리딘-2-) Pyridine-2- 아민Amine (화합물 144-Ⅲ- (Compound 144-Ⅲ- 4)의4) of 제조 Produce
질소 하에서 3-((2,4-디클로로벤질)옥시)-2-니트로피리딘 (1.00 g, 3.34 mmol)를 에탄올:아세트산 = 3:1 용액 40 ml에 용해시킨 후 철 (1.86 g, 33.43 mmol)을 첨가하였다. 반응 혼합물은 반응 혼합물을 90℃에서 1 시간 교반하였다. 반응이 완결되면 증류수와 아세트산에틸을 이용하여 추출하고, 유기층을 무수황산마그네슘으로 건조시킨 후 여과하였다. 여과액을 감압 농축시켜, 농축액을 관 크로마토그래피를 통하여 표제화합물 0.67 g (수율 74%)을 얻었다.Under nitrogen, 3-((2,4-dichlorobenzyl)oxy)-2-nitropyridine (1.00 g, 3.34 mmol) was dissolved in 40 ml of ethanol:acetic acid = 3:1 solution, followed by iron (1.86 g, 33.43 mmol). Was added. The reaction mixture was stirred at 90°C for 1 hour. When the reaction was completed, extraction was performed 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 subjected to column chromatography to obtain 0.67 g (yield 74%) of the title compound.
1H-NMR (400 MHz, DMSO-d 6):δ 7.73 (d, 1H, J = 8.4Hz), 7.68 (d, 1H, J = 2.0 Hz), 7.54 (d, 1H, 4.8Hz), 7.47 (dd, 1H, J = 8.4 Hz, 2.0 Hz), 7.10 (d, 1H, J = 7.6 Hz), 5.70 (s, 2H), 5.13 (s, 2H). 1 H-NMR (400 MHz, DMSO- d 6 ): δ 7.73 (d, 1H, J = 8.4Hz), 7.68 (d, 1H, J = 2.0 Hz), 7.54 (d, 1H, 4.8Hz), 7.47 (dd, 1H, J = 8.4 Hz, 2.0 Hz), 7.10 (d, 1H, J = 7.6 Hz), 5.70 (s, 2H), 5.13 (s, 2H).
실시예Example 9- 9- 3 : 53: 5 -- 브로모Bromo -3-((2,4--3-((2,4- 디클로로벤질Dichlorobenzyl )) 옥시Oxy )피리딘-2-) Pyridine-2- 아민Amine (화합물 144-Ⅲ-5)의 제조 Preparation of (Compound 144-III-5)
질소 하에서 3-((2,4-디클로로벤질)옥시)피리딘-2-아민 (0.46 g, 1.70 mmol) 와 N-브로모숙신이미드 (0.33 g, 1.88 mmol)을 아세토니트릴 20 ml 용액에 용해시킨 후 0℃에서 10 분간 교반하였다. 반응이 완결되면 증류수와 아세트산에틸을 이용하여 추출하고, 유기층을 무수황산마그네슘으로 건조시킨 후 여과하였다. 여과액을 감압 농축시켜, 농축액을 관 크로마토그래피를 통하여 표제화합물 0.42 g (수율 70%)을 얻었다.3-((2,4-dichlorobenzyl)oxy)pyridin-2-amine (0.46 g, 1.70 mmol) and N-bromosuccinimide (0.33 g, 1.88 mmol) are dissolved in a solution of 20 ml of acetonitrile under nitrogen. Then, the mixture was stirred at 0°C for 10 minutes. When the reaction was completed, extraction was performed 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 subjected to column chromatography to obtain 0.42 g (70% yield) of the title compound.
1H-NMR (400 MHz, DMSO-d 6):δ 7.75 (d, 1H, J = 8.4 Hz), 7.69 (d, 1H, J = 1.6 Hz), 7.62 (d, 1H, J = 1.6 Hz), 7.48 (dd, 1H, J = 8.4 Hz, 2.0 Hz), 7.34 (d, 1H, J = 1.6 Hz), 5.99 (s, 2H), 5.17 (s, 2H). 1 H-NMR (400 MHz, DMSO- d 6 ): δ 7.75 (d, 1H, J = 8.4 Hz), 7.69 (d, 1H, J = 1.6 Hz), 7.62 (d, 1H, J = 1.6 Hz) , 7.48 (dd, 1H, J = 8.4 Hz, 2.0 Hz), 7.34 (d, 1H, J = 1.6 Hz), 5.99 (s, 2H), 5.17 (s, 2H).
실시예Example 9- 9- 4 :디4:D -- terttert -부틸 (5--Butyl (5- 브로모Bromo -3-((2,4--3-((2,4- 디클로로벤질Dichlorobenzyl )) 옥시Oxy )피리딘-2-일)디카르바메이트 (화합물 144-Ⅲ-)Pyridin-2-yl)dicarbamate (Compound 144-III- 6)의6) of 제조 Produce
질소 하에서 5-브로모-3-((2,4-디클로로벤질)옥시)피리딘-2-아민 (0.50 g, 1.43 mmol), 디-tert-부틸-디카보네이트 (0.94 g, 4.31 mmol) 와 디-메틸아미노피리딘(0.03 g, 0.27 mmol)을 DMF (25 ml)용액에 용해 시킨 후 실온에서 24 시간 교반하였다. 반응이 완결되면 증류수와 아세트산에틸을 이용하여 추출하고, 유기층을 무수황산마그네슘으로 건조시킨 후 여과하였다. 여과액을 감압 농축시켜, 농축액을 관 크로마토그래피를 통하여 표제화합물 0.54 g (수율 69%)을 얻었다.5-bromo-3-((2,4-dichlorobenzyl)oxy)pyridin-2-amine (0.50 g, 1.43 mmol), di-tert-butyl-dicarbonate (0.94 g, 4.31 mmol) and di -Methylaminopyridine (0.03 g, 0.27 mmol) was dissolved in DMF (25 ml) solution and stirred at room temperature for 24 hours. When the reaction was completed, extraction was performed 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 subjected to column chromatography to obtain 0.54 g (yield 69%) of the title compound.
1H-NMR (400 MHz, DMSO-d 6):δ 8.23 (d, 1H, J = 2.0 Hz), 8.08 (d, 1H, J = 2.0 Hz), 7.73 (d, 1H, J = 1.6 Hz), 7.50-7.56 (m, 2H), 5.31 (s, 2H), 1.36 (s, 18). 1 H-NMR (400 MHz, DMSO- d 6 ): δ 8.23 (d, 1H, J = 2.0 Hz), 8.08 (d, 1H, J = 2.0 Hz), 7.73 (d, 1H, J = 1.6 Hz) , 7.50-7.56 (m, 2H), 5.31 (s, 2H), 1.36 (s, 18).
실시예Example 9-5 : 디-tert-부틸 (6'-아미노-5-((2,4-디클로로벤질)옥시)-[3,3'-비피리딘]-6-yl)디카르바메이트 (화합물 144-Ⅲ- 9-5: Di-tert-butyl (6'-amino-5-((2,4-dichlorobenzyl)oxy)-[3,3'-bipyridin]-6-yl)dicarbamate (Compound 144- Ⅲ- 8)의8) of 제조 Produce
질소 하에서 디-tert-부틸 (5-브로모-3-((2,4-디클로로벤질)옥시)피리딘-2-일) 디카르바메이트 (150.00 mg, 0.27 mmol) 과 5-(4,4,5,5-테트라메틸-1,3,2-디옥사보로란-2-일)피리딘-2-아민 (66.24 mg, 0.30 mM)을 1,4-디옥산 (10 ml)에 용해시킨 후 PdCl2(PPh3)2 (18.95 mg,0.03 mmol)와 1.0 노르말 탄산나트륨 수용액 (116.17 mg, 1.10 mmol)을 첨가하였다. 반응 혼합물을 90℃에서 1 시간 교반하였다. 반응이 완결되면 증류수와 아세트산에틸을 이용하여 추출하고, 유기층을 무수황산마그네슘으로 건조시킨 후 여과하였다. 여과액을 감압 농축시켜, 농축액을 관 크로마토그래피를 통하여 표제화합물 70.00 mg (수율 46%)을 얻었다.Under nitrogen di-tert-butyl (5-bromo-3-((2,4-dichlorobenzyl)oxy)pyridin-2-yl) dicarbamate (150.00 mg, 0.27 mmol) and 5-(4,4, After dissolving 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (66.24 mg, 0.30 mM) in 1,4-dioxane (10 ml) PdCl 2 (PPh 3 ) 2 (18.95 mg, 0.03 mmol) and 1.0 normal sodium carbonate aqueous solution (116.17 mg, 1.10 mmol) were added. The reaction mixture was stirred at 90° C. for 1 hour. When the reaction was completed, extraction was performed 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 subjected to column chromatography to give 70.00 mg (yield 46%) of the title compound.
1H-NMR (400 MHz, DMSO-d 6):δ 8.40 (s, 1H), 8.29 (s, 1H), 7.86-7.84 (m, 2H), 7.71 (d, 1H, J = 1.6 Hz), 7.56 (d, 1H, J = 8.4 Hz), 7.50 (dd, 1H, J = 8.4 Hz, 2.0 Hz), 6.56 (d, 1H, J = 8.4 H), 6.25 (br s, 2H), 5.34 (s, 2H), 1.32 (s, 18H). 1 H-NMR (400 MHz, DMSO- d 6 ): δ 8.40 (s, 1H), 8.29 (s, 1H), 7.86-7.84 (m, 2H), 7.71 (d, 1H, J = 1.6 Hz), 7.56 (d, 1H, J = 8.4 Hz), 7.50 (dd, 1H, J = 8.4 Hz, 2.0 Hz), 6.56 (d, 1H, J = 8.4 H), 6.25 (br s, 2H), 5.34 (s , 2H), 1.32 (s, 18H).
실시예Example 9- 9- 6 : 56: 5 -((2,4--((2,4- 디클로로벤질Dichlorobenzyl )) 옥시Oxy )-[3,3'-)-[3,3'- 비피리딘Bipyridine ]-6,6'-]-6,6'- 디아민Diamine (화합물 (compound 144)의Of 144) 제조 Produce
질소 하에서 디-tert-부틸 (6'-아미노-5-((2,4-디클로로벤질)옥시)-[3,3'-비피리딘]-6-yl)디카르바메이트 (50.00 mg, 0.09 mmol)을 1,4-디옥산 용액 10 ml에 용해시킨 후 4.0 노르말 염산 1,4-디옥산 용액 (0.22 ml, 0.89 mmol)을 첨가하였다. 반응 혼합물을 40℃에서 1 시간 교반하였다. 반응이 완결되면 감압 농축을 통하여 상기 표제화합물 28.00 mg (수율 88%)을 얻었다.Di-tert-butyl (6'-amino-5-((2,4-dichlorobenzyl)oxy)-[3,3'-bipyridin]-6-yl)dicarbamate under nitrogen (50.00 mg, 0.09 mmol ) Was dissolved in 10 ml of 1,4-dioxane solution, and then a 1,4-dioxane solution of 4.0 normal hydrochloric acid (0.22 ml, 0.89 mmol) was added. The reaction mixture was stirred at 40° C. for 1 hour. When the reaction was completed, 28.00 mg (yield 88%) of the title compound was obtained through concentration under reduced pressure.
1H-NMR (400 MHz, DMSO-d 6):δ8.43 (d, 1H, J = 1.6 Hz), 8.31 (dd, 1H, J = 9.2 Hz, 2.0 Hz), 8.21-7.98 (m, 5H), 7.94 (s,1H), 7.83 (d, 1H, J = 8.4 Hz), 7.75 (d, 1H, J= 2.0 Hz), 7.53 (dd, 1H, J = 8.4 Hz, 2.0 Hz), 7.11 (d, 1H, J = 9.6 Hz), 5.41 (s, 2H). 1 H-NMR (400 MHz, DMSO- d 6 ): δ8.43 (d, 1H, J = 1.6 Hz), 8.31 (dd, 1H, J = 9.2 Hz, 2.0 Hz), 8.21-7.98 (m, 5H) ), 7.94 (s,1H), 7.83 (d, 1H, J = 8.4 Hz), 7.75 (d, 1H, J = 2.0 Hz), 7.53 (dd, 1H, J = 8.4 Hz, 2.0 Hz), 7.11 ( d, 1H, J = 9.6 Hz), 5.41 (s, 2H).
실시예Example 10 : 화합물 155의 제조 10: Preparation of compound 155
실시예Example 10- 10- 1 : 31: 3 -(1-(2,4--(1-(2,4- 디클로로페닐Dichlorophenyl )) 에톡시Ethoxy )-2-)-2- 니트로피리딘Nitropyridine (화합물 155-Ⅲ-3)의 제조 Preparation of (Compound 155-III-3)
질소 하에서 1-(2,4-디클로로페닐)에탄-1-올 (272.63 mg, 1.43 mmol)과 2-니트로피리딘-3-올 (200.00 mg, 1.43 mmol)을 THF 용액 10 ml에 용해 시킨 후 DIAD (0.40 ml, 2.04 mmol)와 PPh3 (535.33 mg,2.04 mmol)을 첨가하였다. 반응 혼합물을 0℃에서 4 시간 교반하였다. 반응이 완결되면 증류수와 아세트산에틸을 이용하여 추출하고, 유기층을 무수황산마그네슘으로 건조시킨 후 여과하였다. 여과액을 감압 농축시켜, 농축액을 관 크로마토그래피를 통하여 표제화합물 229.61 mg (수율 51%)을 얻었다.Under nitrogen, 1-(2,4-dichlorophenyl)ethan-1-ol (272.63 mg, 1.43 mmol) and 2-nitropyridin-3-ol (200.00 mg, 1.43 mmol) were dissolved in 10 ml of THF solution and then DIAD (0.40 ml, 2.04 mmol) and PPh 3 (535.33 mg, 2.04 mmol) was added. The reaction mixture was stirred at 0° C. for 4 hours. When the reaction was completed, extraction was performed 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 subjected to column chromatography to give 229.61 mg (yield 51%) of the title compound.
1H-NMR (400 MHz, CDCl3):δ8.03 (d, 1H, J = 4.4 Hz), 7.47 (d, 1H, J = 8.8 Hz), 7.39-7.43 (m, 2H), 7.22-7.28 (m, 2H), 5.82 (q, 1H, J = 6.0 Hz), 1.67 (d, 3H, J = 6.0 Hz). 1 H-NMR (400 MHz, CDCl 3 ): δ8.03 (d, 1H, J = 4.4 Hz), 7.47 (d, 1H, J = 8.8 Hz), 7.39-7.43 (m, 2H), 7.22-7.28 (m, 2H), 5.82 (q, 1H, J = 6.0 Hz), 1.67 (d, 3H, J = 6.0 Hz).
실시예Example 10- 10- 2 : 32: 3 -(1-(2,4--(1-(2,4- 디클로로페닐Dichlorophenyl )) 에톡시Ethoxy )피리딘-2-) Pyridine-2- 아민Amine (화합물 155-Ⅲ-4)의 제조 Preparation of (Compound 155-III-4)
질소 하에서 3-(1-(2,4-디클로로페닐)에톡시)-2-니트로피리딘 (200.00 mg, 0.64 mmol)를 에탄올:아세트산 = 5:2 용액 28 ml에 용해시킨 후 철 (356.32 mg, 6.38 mmol)을 첨가하였다. 반응 혼합물은 반응 혼합물을 90℃에서 1 시간 교반하였다. 반응이 완결되면 증류수와 아세트산에틸을 이용하여 추출하고, 유기층을 무수황산마그네슘으로 건조시킨 후 여과하였다. 여과액을 감압 농축시켜, 농축액을 관 크로마토그래피를 통하여 표제화합물 177.47 mg (수율 98%)을 얻었다.Under nitrogen, 3-(1-(2,4-dichlorophenyl)ethoxy)-2-nitropyridine (200.00 mg, 0.64 mmol) was dissolved in 28 ml of ethanol:acetic acid = 5:2 solution and then iron (356.32 mg, 6.38 mmol) was added. The reaction mixture was stirred at 90°C for 1 hour. When the reaction was completed, extraction was performed 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 subjected to column chromatography to give 177.47 mg (yield 98%) of the title compound.
1H-NMR (400 MHz, CDCl3):δ 7.61 (d, 1H, J = 4.8 Hz), 7.39 (d, 1H, J = 1.6 Hz), 7.30 (d, 1H, J = 8.4 Hz), 7.19 (dd, 1H, J = 8.4 Hz, 1.2 Hz), 6.56 (d, 1H, J = 7.6 Hz), 6.44 (dd, J = 8.0 Hz, 5.2 Hz), 5.61 (q, 1H, J = 6.4 Hz), 4.89 (br s, 2H), 1.63 (d, 3H, J = 6.0 Hz). 1 H-NMR (400 MHz, CDCl 3 ): δ 7.61 (d, 1H, J = 4.8 Hz), 7.39 (d, 1H, J = 1.6 Hz), 7.30 (d, 1H, J = 8.4 Hz), 7.19 (dd, 1H, J = 8.4 Hz, 1.2 Hz), 6.56 (d, 1H, J = 7.6 Hz), 6.44 (dd, J = 8.0 Hz, 5.2 Hz), 5.61 (q, 1H, J = 6.4 Hz) , 4.89 (br s, 2H), 1.63 (d, 3H, J = 6.0 Hz).
실시예Example 10- 10- 3 : 53: 5 -- 브로모Bromo -3-(1-(2,4--3-(1-(2,4- 디클로로페닐Dichlorophenyl )) 에톡시Ethoxy )피리딘-2-) Pyridine-2- 아민Amine (화합물 155-Ⅲ- (Compound 155-Ⅲ- 5)의5) of 제조 Produce
질소 하에서 3-(1-(2,4-디클로로페닐)에톡시)피리딘-2-아민 (150.00 mg, 0.53 mmol) 와 N-브로모숙신이미드 (98.96 g, 0.56 mmol)을 아세토니트릴 20 ml 용액에 용해시킨 후 0℃에서 10 분간 교반하였다. 반응이 완결되면 증류수와 아세트산에틸을 이용하여 추출하고, 유기층을 무수황산마그네슘으로 건조시킨 후 여과하였다. 여과액을 감압 농축시켜, 농축액을 관 크로마토그래피를 통하여 표제화합물 181.87 mg (수율 95%)을 얻었다.Under nitrogen, 3-(1-(2,4-dichlorophenyl)ethoxy)pyridin-2-amine (150.00 mg, 0.53 mmol) and N-bromosuccinimide (98.96 g, 0.56 mmol) were added to 20 ml of acetonitrile. After dissolving in the solution, the mixture was stirred at 0°C for 10 minutes. When the reaction was completed, extraction was performed 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 subjected to column chromatography to give 181.87 mg (yield 95%) of the title compound.
1H-NMR (400 MHz, CDCl3):δ 7.66 (d, 1H, J = 1.6 Hz), 7.40 (d, 1H, J = 2.0 Hz), 7.31 (d, 1H, J = 8.4 Hz), 7.20 (dd, 1H, J = 8.4 Hz, 2.0 Hz), 6.69 (d, 1H, J = 1.6 Hz), 5.59 (q, 1H, J = 6.4 Hz), 5.06 (br s, 2H), 1.62 (d, 3H, J = 6.4 Hz). 1 H-NMR (400 MHz, CDCl 3 ): δ 7.66 (d, 1H, J = 1.6 Hz), 7.40 (d, 1H, J = 2.0 Hz), 7.31 (d, 1H, J = 8.4 Hz), 7.20 (dd, 1H, J = 8.4 Hz, 2.0 Hz), 6.69 (d, 1H, J = 1.6 Hz), 5.59 (q, 1H, J = 6.4 Hz), 5.06 (br s, 2H), 1.62 (d, 3H, J = 6.4 Hz).
실시예Example 10-4 : 디-tert-부틸 (5-브로모-3-(1-(2,4-디클로로페닐)에톡시)피리딘-2-일)디카르바메이트 (화합물 155-Ⅲ- 10-4: Di-tert-butyl (5-bromo-3-(1-(2,4-dichlorophenyl)ethoxy)pyridin-2-yl)dicarbamate (Compound 155-III- 6)의6) of 제조 Produce
질소 하에서 5-브로모-3-(1-(2,4-디클로로페닐)에톡시)피리딘-2-아민 (1.03 g, 2.85 mmol), 디-tert-부틸-디카보네이트 (1.79 g, 8.22 mmol)와 디-메틸아미노피리딘(0.07 g, 0.54 mmol)을 DMF (25 ml)용액에 용해 시킨 후 실온에서 24 시간 교반하였다. 반응이 완결되면 증류수와 아세트산에틸을 이용하여 추출하고, 유기층을 무수황산마그네슘으로 건조시킨 후 여과하였다. 여과액을 감압 농축시켜, 농축액을 관 크로마토그래피를 통하여 표제화합물 1.60 g (수율 99%)을 얻었다. 5-Bromo-3-(1-(2,4-dichlorophenyl)ethoxy)pyridin-2-amine (1.03 g, 2.85 mmol), di-tert-butyl-dicarbonate (1.79 g, 8.22 mmol) under nitrogen ) And di-methylaminopyridine (0.07 g, 0.54 mmol) were dissolved in DMF (25 ml) solution and stirred at room temperature for 24 hours. When the reaction was completed, extraction was performed 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 subjected to column chromatography to obtain 1.60 g (yield 99%) of the title compound.
1H-NMR (400 MHz, CDCl3):δ 8.10 (d, 1H, J = 1.2 Hz), 7.37-7.42 (m, 2H), 7.23 (dd, 1H, J = 8.0 Hz, 1.2 Hz), 7.06 (d, 1H, J = 0.8 Hz), 5.65 (q, 1H, J = 6.4 Hz), 1.62 (d, 3H, J = 6.0 Hz), 1.45 (s, 18H). 1 H-NMR (400 MHz, CDCl 3 ): δ 8.10 (d, 1H, J = 1.2 Hz), 7.37-7.42 (m, 2H), 7.23 (dd, 1H, J = 8.0 Hz, 1.2 Hz), 7.06 (d, 1H, J = 0.8 Hz), 5.65 (q, 1H, J = 6.4 Hz), 1.62 (d, 3H, J = 6.0 Hz), 1.45 (s, 18H).
실시예Example 10-5: 디-tert-부틸 (6'-아미노-5-(1-(2,4-디클로로페닐)에톡시)-[3,3'-비리딘]-6-일)디카르바메이트 (화합물 155-Ⅲ- 10-5: di-tert-butyl (6'-amino-5-(1-(2,4-dichlorophenyl)ethoxy)-[3,3'-viridine]-6-yl)dicarbamate ( Compound 155-III- 8)의8) of 제조 Produce
질소 하에서 디-tert-부틸 (5-브로모-3-(1-(2,4-디클로로페닐)에톡시)피리딘-2-일)디카르바메이트 (180.00 mg, 0.32 mmol) 와 5-(4,4,5,5-테트라메틸-1,3,2-디옥사보로란-2-일)피리딘-2-아민 (77.47 mg, 0.35 mM)을 디메톡시에탄 (10 ml)에 용해시킨 후 Pd(dppf)Cl2CH2Cl2 (13.07 mg,0.02 mmol)와 1.0 노르말 탄산세슘 수용액 (417.05 mg, 1.28 mmol)을 첨가하였다. 반응 혼합물을 90℃에서 1 시간 교반하였다. 반응이 완결되면 증류수와 아세트산에틸을 이용하여 추출하고, 유기층을 무수황산마그네슘으로 건조시킨 후 여과하였다. 여과액을 감압 농축시켜, 농축액을 관 크로마토그래피를 통하여 표제화합물 69.00 mg (수율 38%)을 얻었다. Di-tert-butyl (5-bromo-3-(1-(2,4-dichlorophenyl)ethoxy)pyridin-2-yl)dicarbamate (180.00 mg, 0.32 mmol) and 5-(4) under nitrogen After dissolving,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (77.47 mg, 0.35 mM) in dimethoxyethane (10 ml) Pd(dppf)Cl 2 CH 2 Cl 2 (13.07 mg, 0.02 mmol) and 1.0 normal cesium carbonate aqueous solution (417.05 mg, 1.28 mmol) were added. The reaction mixture was stirred at 90° C. for 1 hour. When the reaction was completed, extraction was performed 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 subjected to column chromatography to give 69.00 mg (yield 38%) of the title compound.
1H-NMR (400 MHz, CDCl3):δ 8.18 (d, 1H, J = 1.2 Hz), 8.14 (d, 1H, J = 2.0 Hz), 7.53 (dd, 1H, J = 8.4 Hz, 2.4 Hz), 7.44-7.40 (m, 2H), 7.21 (dd, 1H, J = 8.4 Hz, 1.6 Hz), 7.00 (d, 1H, J = 1.2 Hz), 6.56 (d, 1H, J = 8.4 Hz), 5.75 (q, 1H, J = 6.4 Hz), 4.58 (br s, 2H), 1.63 (d, 3H, J = 6.4 Hz), 1.48 (s, 18H); 1 H-NMR (400 MHz, CDCl 3 ): δ 8.18 (d, 1H, J = 1.2 Hz), 8.14 (d, 1H, J = 2.0 Hz), 7.53 (dd, 1H, J = 8.4 Hz, 2.4 Hz ), 7.44-7.40 (m, 2H), 7.21 (dd, 1H, J = 8.4 Hz, 1.6 Hz), 7.00 (d, 1H, J = 1.2 Hz), 6.56 (d, 1H, J = 8.4 Hz), 5.75 (q, 1H, J = 6.4 Hz), 4.58 (br s, 2H), 1.63 (d, 3H, J = 6.4 Hz), 1.48 (s, 18H);
실시예Example 10- 10- 6 : 56: 5 -(1-(2,4--(1-(2,4- 디클로로페닐Dichlorophenyl )) 에톡시Ethoxy )-[3,3'-)-[3,3'- 비피리딘Bipyridine ]-6,6'-]-6,6'- 디아민Diamine (화합물 (compound 155)의155) of 제조 Produce
질소 하에서 디-tert-부틸 (6'-아미노-5-(1-(2,4-디클로로페닐)에톡시)-[3,3'-비리딘]-6-일)디카르바메이트 (20.00 mg, 0.03 mmol)을 디클로로메탄 10 ml 과 메탄올 2 ml에 용해 시킨 후 트리플루오로아세트산 (30.60 μl, 0.68 mmol)을 첨가하였다. 반응 혼합물을 40℃에서 1 시간 교반하였다. 반응이 완결되면 감압 농축을 통하여 상기 표제화합물 15.00 mg (수율 90%)을 얻었다.Di-tert-butyl (6'-amino-5-(1-(2,4-dichlorophenyl)ethoxy)-[3,3'-viridine]-6-yl)dicarbamate under nitrogen (20.00 mg , 0.03 mmol) was dissolved in 10 ml of dichloromethane and 2 ml of methanol, and then trifluoroacetic acid (30.60 μl, 0.68 mmol) was added. The reaction mixture was stirred at 40° C. for 1 hour. When the reaction was completed, 15.00 mg (yield 90%) of the title compound was obtained through concentration under reduced pressure.
1H-NMR (400 MHz, MeOD) : δ 8.03 (dd, 1H, J = 9.6 Hz, 1.6 Hz), 7.97 (s, 1H), 7.72 (s, 1H), 7.59 (d, 1H, J = 8.8 Hz), 7.55 (d, 1H, J = 1.6 Hz), 7.40 (d, 1H, J = 8.4 Hz), 7.26 (br s, 1H), 7.08 (d, 1H, J = 9.2 Hz), 6.09 (q, 1H, J = 6.4 Hz), 1.78 (d, 3H, J = 6.4 Hz). 1 H-NMR (400 MHz, MeOD): δ 8.03 (dd, 1H, J = 9.6 Hz, 1.6 Hz), 7.97 (s, 1H), 7.72 (s, 1H), 7.59 (d, 1H, J = 8.8 Hz), 7.55 (d, 1H, J = 1.6 Hz), 7.40 (d, 1H, J = 8.4 Hz), 7.26 (br s, 1H), 7.08 (d, 1H, J = 9.2 Hz), 6.09 (q , 1H, J = 6.4 Hz), 1.78 (d, 3H, J = 6.4 Hz).
상기 본 발명에 따른 일 실시예 화합물의 반응식, 실시예, 및 반응화합물(중간체)을 정리하면 하기 표 1과 같다. Table 1 below summarizes the reaction formula, examples, and reaction compounds (intermediates) of the compound of an example according to the present invention.
1-21-1
1-2
2-I-3, 2-I-4 2-I-1, 2-I-2, 2-I-3,
2-I-3, 2-I-4
2-22-1
2-2
44-Ⅱ-444-Ⅱ-1, 44-Ⅱ-2, 44-Ⅱ-3,
44-Ⅱ-4
3-23-1
3-2
52-Ⅱ-452-Ⅱ-1, 52-Ⅱ-2, 52-Ⅱ-3,
52-Ⅱ-4
4-24-1
4-2
71-Ⅱ-471-Ⅱ-1, 71-Ⅱ-2, 71-Ⅱ-3,
71-Ⅱ-4
5-25-1
5-2
6-26-1
6-2
7-2
7-3
7-4
7-5
7-67-1
7-2
7-3
7-4
7-5
7-6
8-2
8-3
8-4
8-5
8-68-1
8-2
8-3
8-4
8-5
8-6
9-2
9-3
9-4
9-5
9-69-1
9-2
9-3
9-4
9-5
9-6
10-2
10-3
10-4
10-5
10-610-1
10-2
10-3
10-4
10-5
10-6
상기와 같은 실시예에 나타난 방법에 따라, 본 발명의 화합물 1 내지 화합물 163을 제조하였다. According to the method shown in Examples as above, Compounds 1 to 163 of the present invention were prepared.
구체적으로, 본 발명의 화합물 1 내지 14 는, 반응식 I에 따라, 상기 실시예 1(1-1, 1-2)에 나타난 것과 동일한 방법으로, 출발물질이나 중간물질 또는 반응조건을 다르게 해서, 제조하였다.Specifically, compounds 1 to 14 of the present invention are prepared in the same manner as those shown in Example 1 (1-1, 1-2) according to Scheme I, by different starting materials, intermediates, or reaction conditions. I did.
또한, 본 발명의 화합물 15 내지 117은, 반응식 II에 따라, 상기 실시예 2(2-1, 2-2), 3(3-1, 3-2), 4(4-1, 4-2), 5(5-1, 5-2), 6(6-1, 6-2)에 나타난 것과 동일한 방법으로, 출발물질이나 중간물질 또는 반응조건을 다르게 해서, 제조하였다.In addition, compounds 15 to 117 of the present invention are, according to Scheme II, in Examples 2 (2-1, 2-2), 3 (3-1, 3-2), 4 (4-1, 4-2 ), 5(5-1, 5-2), 6(6-1, 6-2), prepared by different starting materials, intermediates, or reaction conditions.
또한, 본 발명의 화합물 118 내지 163은, 반응식 III에 따라, 상기 실시예 실시예 7(7-1 ~ 7-6), 8(8-1 ~ 8-6), 9(9-1 ~ 9-6), 10(10-1 ~ 10-6)에 나타난 것과 동일한 방법으로, 출발물질이나 중간물질 또는 반응조건을 다르게 해서, 제조하였다.In addition, compounds 118 to 163 of the present invention are, according to Scheme III, in Examples 7 (7-1 to 7-6), 8 (8-1 to 8-6), 9 (9-1 to 9) In the same manner as shown in -6) and 10 (10-1 to 10-6), it was prepared by different starting materials, intermediates, or reaction conditions.
본 발명에서 상기 실시예의 방법에 의해 합성된 본 발명의 화합물 1 내지 화합물 163의 구조확인 데이터는 아래 [표 2]에 나타내었다.In the present invention, the structure confirmation data of the compounds 1 to 163 of the present invention synthesized by the method of the above example are shown in [Table 2] below.
[[ 제제예]Formulation example]
한편, 본 발명에 따른 상기 화학식 I로 표시되는 신규 화합물은 목적에 따라 여러 형태로 제제화가 가능하다. 다음은 본 발명에 따른 상기 화학식 I로 표시되는 화합물을 활성성분으로 함유시킨 몇몇 제제화 방법을 예시한 것으로 본 발명이 이에 한정되는 것은 아니다.Meanwhile, the novel compound represented by Formula I according to the present invention can be formulated in various forms depending on the purpose. The following exemplifies some formulation methods in which the compound represented by Formula I according to the present invention is contained as an active ingredient, and 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 sieving 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 into tablets.
제제 2 : 정제(습식 조립)Formulation 2: tablet (wet granulation)
활성성분 5.0 ㎎을 체로 친 후, 락토스 16.0 ㎎과 녹말 4.0 ㎎을 섞었다. 폴리솔베이트 80 0.3 ㎎을 순수한 물에 녹인 후 이 용액의 적당량을 첨가한 다음, 미립화하였다. 건조 후에 미립을 체질한 후 콜로이달 실리콘 다이옥사이드 2.7 ㎎ 및 마그네슘 스테아레이트 2.0 ㎎과 섞었다. 미립을 가압하여 정제로 만들었다.After sieving 5.0 mg of the active ingredient, 16.0 mg of lactose and 4.0 mg of starch were mixed. After dissolving 0.3 mg of polysorbate 80 in pure water, an appropriate amount of this solution was added, followed by atomization. After drying, the fine particles were sieved and mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The fine particles were pressed into tablets.
제제 3 : 분말과 Formulation 3: powder and 캡슐제Capsule
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. Mixture using a suitable device to solid No. Filled in 5 gelatin capsules.
제제 4 : 주사제Formulation 4: injection
활성성분으로서 100 mg을 함유시키고, 그 밖에도 만니톨 180 mg, Na2HPO412H2O 26 mg 및 증류수 2,974 mg를 함유시켜 주사제를 제조하였다.An injection was prepared by containing 100 mg as an active ingredient, in addition to 180 mg of mannitol, 26 mg of Na 2 HPO 4 12H 2 O and 2,974 mg of distilled water.
[[ 실험예Experimental example ] : ]: 말라카이트Malachite 그린 Green 포스페이트Phosphate 어세이를The assay 이용한 Used SHIP2SHIP2 억제 활성 측정 Inhibitory activity measurement
본 발명에 따른 화학식 I로 표시되는 구체적인 화합물에 대한 SHIP2 억제 활성에 대한 측정은 아래와 같이 실시하였다.Measurement of the SHIP2 inhibitory activity for the specific compound represented by Formula I according to the present invention was carried out as follows.
활성 검색 12 내지 24 시간 전에 폴리-L-라이신 (0.05 ㎎/㎖)으로 처리된 384-웰 플레이트(Corning 3640)에 SHIP2 단백질과 PIP3 및 상기와 같이 제조된 본 발명의 화합물 1 내지 163의 화합물들을 각각 총 15 μL 용량이 되도록 분주해 주었다. dH2O에 1 mM 농도로 녹아 있는 PIP3 (Echelon P-3908, Salt lake city, UT, USA)를 이용하여 실험 시 100 M 농도로 사용하고 SHIP2 단백질은 완충용액(6 mM MgCl2, 10 mM HEPES, 0.25 mM EDTA, 0.1% CHAPS, 250 mM sucrose, dH2O, pH ± 7.25)으로 희석시켜 30 nM 농도로 실험에 사용하였다. 실험 당일, SHIP2 단백질과 화학식 I로 표시되는 화합물들을 27℃에서 20 분 동안 처리한 후, PIP3를 넣어주고 50 분 동안 반응을 진행시켰다. 그 후, 40μL 의 말라카이트 그린 용액 (Echelon K-1501)을 동일 온도에서 넣어주고 20 분 동안 반응을 진행시켰다. 결과 분석을 위해 620 nM의 흡광도를 측정할 수 있는 spectra max M2 (molecular Devices)를 사용하였고, IC50 값은 GraphPad Prism 5.0 을 이용하여 측정하였다.SHIP2 protein and PIP 3 in a 384-well plate (Corning 3640) treated with poly-L-lysine (0.05 mg/ml) 12 to 24 hours before the activity screening, and the compounds of the compounds 1 to 163 of the present invention prepared as described above Each of them was dispensed to a total volume of 15 μL. PIP 3 (Echelon P-3908, Salt lake city, UT, USA) dissolved in dH 2 O at a concentration of 1 mM was used at a concentration of 100 M, and SHIP2 protein was a buffer solution (6 mM MgCl2, 10 mM HEPES). , 0.25 mM EDTA, 0.1% CHAPS, 250 mM sucrose, dH2O, pH ± 7.25) and diluted with 30 nM concentration was used in the experiment. On the day of the experiment, the SHIP2 protein and the compounds represented by Formula I were treated at 27° C. for 20 minutes, and then PIP 3 was added and the reaction was allowed to proceed for 50 minutes. Thereafter, 40 μL of malachite green solution (Echelon K-1501) was added at the same temperature and the reaction was allowed to proceed for 20 minutes. For the analysis of the results, spectra max M2 (molecular Devices), which can measure absorbance of 620 nM, was used, and the IC 50 value was measured using GraphPad Prism 5.0.
본 발명에 따른 SHIP2 억제제의 생물학적, 생화학적 저해효과의 척도를 측정하기 위하여 30μM 농도의 화합물이 처리되었을 때의 SHIP2 억제 활성을 Inhibitory activity (%)로 나타내었다. 그 중 50% 이상의 억제활성을 가지는 화합물에 대해 농도에 따른 활성 측정을 하였고, 측정된 결과는 아래 표 3에 IC50 값으로 나타내었다. IC50 값은 효소 혹은 세포의 활성이 50%로 억제될 때 사용한 화합물의 몰농도이다.In order to measure the measure of the biological and biochemical inhibitory effect of the SHIP2 inhibitor according to the present invention, the SHIP2 inhibitory activity when 30 μM concentration of the compound was treated was expressed as Inhibitory activity (%). Among them, a compound having an inhibitory activity of 50% or more was measured for activity according to the concentration, and the measured results are shown as IC 50 values in Table 3 below. The IC 50 value is the molar concentration of the compound used when the enzyme or cell activity is inhibited by 50%.
((
μMμM
))
((
μMμM
))
((
μMμM
))
1938909AS
1938909
상기 실험예 및 표 3에서 보는 바와 같이, 본 발명에 따라 상기 화학식 I로 표시되는 피리딘 유도체는 수 μM 수준의 준수한 SHIP2 억제 활성을 보여 주었으며, 그 중 몇몇 화합물들은 공지된 SHIP2 억제제인 AS1938909와 동등한 수준으로 SHIP2 활성을 억제할 수 있음을 확인할 수 있다. 이는 본 발명에 따른 화학식 I로 표시되는 피리딘 유도체들이 효과적으로 SHIP2 활성을 억제할 수 있음을 나타낸다. As shown in the above Experimental Examples and Table 3, the pyridine derivative represented by Formula I according to the present invention showed a satisfactory SHIP2 inhibitory activity of several μM, and some of the compounds were equivalent to the known SHIP2 inhibitor AS1938909. It can be seen that SHIP2 activity can be inhibited. This indicates that the pyridine derivatives represented by Formula I according to the present invention can effectively inhibit SHIP2 activity.
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.In the above, the present invention has been shown and described in relation to certain preferred embodiments, but the present invention may be variously modified and changed within the scope of not departing from the technical features or field of the present invention provided by the following claims. It is obvious to one of ordinary skill in the art that it can be.
Claims (13)
[화학식 I]
상기 화학식 I에서,
X. Y. 및 Z는 각각 독립적으로 탄소(C) 또는 질소(N)이고, 상기 X. Y. 및 Z 중 하나는 질소(N)이며,
W는 수소(H) 또는 아민(NH2)이고,
R1은 치환되지 않은 것이거나 또는 할로겐, 메톡시, 시아노, 트리플루오로메틸, 니트로 및 벤조일기로 이루어진 군에서 선택된 1개 내지 3개의 치환기이고,
R2는 수소, 메틸(CH3) 또는 각각 다른 비대칭 중심을 가지는 (S), (R)-메틸(methyl)이고,
R3은 비치환되거나 치환된 아릴 또는 헤테로아릴이고, 상기 치환된 아릴 또는 헤테로아릴은 메틸, 할로겐, 아민, 하이드록시, 시아노, 피페라진일, 피페리딘일, 피라닐, 알데하이드, 니트로, 메틸피페라진일, 메틸피롤리딘일, 메틸몰폴린일, 몰폴린일, 알데히드, 피롤리딘일메탄온, 메탄아민, 메틸아민, 다이메틸아민, 트리플루오로메틸, 아세틸피페리딘일, 페닐메탄아민 및 메탄올로 이루어진 군에서 선택된 1개 이상의 치환기로 치환된 것임.
A compound selected from the group consisting of a pyridine derivative represented by the following formula (I) and a pharmaceutically acceptable salt thereof:
[Formula I]
In Formula I,
XY and Z are each independently carbon (C) or nitrogen (N), and one of XY and Z is nitrogen (N),
W is hydrogen (H) or amine (NH 2 ),
R 1 is unsubstituted or 1 to 3 substituents selected from the group consisting of halogen, methoxy, cyano, trifluoromethyl, nitro and benzoyl groups,
R 2 is hydrogen, methyl (CH 3 ) or (S), (R)-methyl (methyl) each having a different asymmetric center,
R 3 is unsubstituted or substituted aryl or heteroaryl, and the substituted aryl or heteroaryl is methyl, halogen, amine, hydroxy, cyano, piperazinyl, piperidinyl, pyranyl, aldehyde, nitro, methyl Piperazinyl, methylpyrrolidinyl, methylmorpholinyl, morpholinyl, aldehyde, pyrrolidinylmethanone, methanamine, methylamine, dimethylamine, trifluoromethyl, acetylpiperidinyl, phenylmethanamine and It is substituted with one or more substituents selected from the group consisting of methanol.
상기 X는 질소(N)이고,
상기 R1은 할로겐으로 이루어진 2개 내지 3개의 치환기이고,
상기 R2는 수소 또는 각각 다른 비대칭 중심을 가지는 (S), (R)-메틸(methyl)이고,
상기 R3은 비치환되거나 치환된 아릴, 피리딘, 피리미딘, 피라졸, 티오펜, 인돌린온, 스티릴기, 또는 피롤로피리딘이고, 상기 치환된 아릴, 피리딘, 피리미딘, 피라졸, 티오펜, 인돌린온, 스티릴기, 또는 피롤로피리딘은 할로겐, 아민, 하이드록시, 시아노, 피페라진일, 피페리딘일, 피라닐, 알데하이드, 니트로, 알데히드, 메틸아민, 다이메틸아민, 및 아세틸피페리딘일로 이루어진 군에서 선택된 1개 내지 3개의 치환기로 치환된 것임을 특징으로 하는 화합물.
The method of claim 1,
X is nitrogen (N),
R 1 is 2 to 3 substituents consisting of halogen,
R 2 is hydrogen or (S), (R)-methyl (methyl) each having a different asymmetric center,
R 3 is unsubstituted or substituted aryl, pyridine, pyrimidine, pyrazole, thiophene, indolinone, styryl group, or pyrrolopyridine, and the substituted aryl, pyridine, pyrimidine, pyrazole, thiophene, Indolinone, styryl group, or pyrrolopyridine is halogen, amine, hydroxy, cyano, piperazinyl, piperidinyl, pyranyl, aldehyde, nitro, aldehyde, methylamine, dimethylamine, and acetylpiperidine. A compound, characterized in that it is substituted with 1 to 3 substituents selected from the group consisting of one.
상기 X는 질소(N)이고,
상기 W는 수소(H)이고,
상기 R1은 할로겐으로 이루어진 2개 내지 3개의 치환기이고,
상기 R2는 수소 또는 비대칭 중심을 가지는 (R)-메틸(methyl)이고,
상기 R3은 비치환되거나 치환된 피리딘, 피리미딘, 피라졸, 또는 티오펜이고, 상기 치환된 피리딘, 피리미딘, 피라졸, 또는 티오펜은 할로겐, 아민, 하이드록시, 시아노, 피페라진일, 피페리딘일, 및 아세틸피페리딘일로 이루어진 군에서 선택된 1개 내지 3개의 치환기로 치환된 것임을 특징으로 하는 화합물.
The method of claim 1,
X is nitrogen (N),
W is hydrogen (H),
R 1 is 2 to 3 substituents consisting of halogen,
R 2 is hydrogen or (R)-methyl (methyl) having an asymmetric center,
R 3 is unsubstituted or substituted pyridine, pyrimidine, pyrazole, or thiophene, and the substituted pyridine, pyrimidine, pyrazole, or thiophene is halogen, amine, hydroxy, cyano, piperazinyl , Piperidinyl, and acetylpiperidinyl, characterized in that the compound is substituted with 1 to 3 substituents selected from the group consisting of.
상기 X는 질소(N)이고,
상기 W는 수소(H)이고,
상기 R1은 할로겐으로 이루어진 2개 내지 3개의 치환기이고,
상기 R2는 수소 또는 비대칭 중심을 가지는 (R)-메틸(methyl)이고,
상기 R3은 비치환되거나 치환된 피리미딘, 또는 티오펜이고, 상기 치환된 피리미딘, 또는 티오펜은 할로겐, 아민, 및 시아노로 이루어진 군에서 선택된 1개 내지 3개의 치환기로 치환된 것임을 특징으로 하는 화합물.
The method of claim 1,
X is nitrogen (N),
W is hydrogen (H),
R 1 is 2 to 3 substituents consisting of halogen,
R 2 is hydrogen or (R)-methyl (methyl) having an asymmetric center,
Wherein R 3 is unsubstituted or substituted pyrimidine or thiophene, and the substituted pyrimidine or thiophene is substituted with 1 to 3 substituents selected from the group consisting of halogen, amine, and cyano Compound.
상기 화학식 I은 하기 화합물 1 내지 화합물 163으로 이루어진 군에서 선택된 것을 특징으로 하는 화합물:
(화합물 1) tert-부틸 4-(4-(5-(벤질옥시)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트;
(화합물 2) 3-(벤질옥시)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘;
(화합물 3) tert-부틸 4-(4-(5-((2-시아노벤질)옥시)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트;
(화합물 4) 2-(((5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)옥시)메틸)벤조니트릴;
(화합물 5) tert-부틸 4-(4-(5-((2-(트리플루오로메틸)벤질)옥시)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트;
(화합물 6) 3-(1-(피페리딘-4-일)-1H-피라졸-4-일)-5-((2-(트리플루오로메틸)벤질)옥시)피리딘;
(화합물 7) tert-부틸 4-(4-(5-((2-클로로-4-플루오로벤질)옥시)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트;
(화합물 8) 3-((2-클로로-4-플루오로벤질)옥시)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘;
(화합물 9) tert-부틸 4-(4-(5-((2,6-디플루오로벤질)옥시)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트;
(화합물 10) 3-((2,6-디플루오로벤질)옥시)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘;
(화합물 11) tert-부틸 4-(4-(5-((4-클로로벤질)옥시)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트;
(화합물 12) 3-((4-클로로벤질)옥시)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘;
(화합물 13) tert-부틸 4-(4-(5-((4-시아노벤질)옥시)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트;
(화합물 14) 3-(벤질옥시)-5-(1-(1-벤질피페리딘-4-일)-1H-피라졸-4-일)피리딘;
(화합물 15) tert-부틸 4-(4-(5-((2,4-디클로로벤질)옥시)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트;
(화합물 16) 3-((2,4-디클로로벤질)옥시)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘;
(화합물 17) tert-부틸 (R)-4-(4-(5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트;
(화합물 18) (R)-3-(1-(2,6-디클로로-3-플루오로페닐)에톡시)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘;
(화합물 19) tert-부틸 (S)-4-(4-(5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트;
(화합물 20) (S)-3-(1-(2,6-디클로로-3-플루오로페닐)에톡시)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘;
(화합물 21) (R)-5-(1-(2,6-디플루오로페닐)에톡시)-6'-니트로-3,3'-비피리딘;
(화합물 22) 6'-니트로-5-((2-(트리플루오로메틸)벤질)옥시)-3,3'-비피리딘;
(화합물 23) 2-(((6'-니트로-[3,3'-비피리딘]-5-일)옥시)메틸)벤조니트릴;
(화합물 24) 5-((4-메톡시벤질)옥시)-6'-니트로-3,3'-비피리딘;
(화합물 25) 5-((4-클로로벤질)옥시)-6'-니트로-3,3'-비피리딘;
(화합물 26) 6'-니트로-5-((4-니트로벤질)옥시)-3,3'-비피리딘;
(화합물 27) 5-(5-((2-클로로-4-플루오로벤질)옥시)피리딘-3-일)피리미딘-2-아민;
(화합물 28) 5'-((2,6-디플루오로벤질)옥시)-[3,3'-비피리딘]-6-아민;
(화합물 29) 5'-((2-(트리플루오로메틸)벤질)옥시)-[3,3'-비피리딘]-6-아민;
(화합물 30) 2-(((6'-아미노-[3,3'-비피리딘]-5-일)옥시)메틸)벤조니트릴;
(화합물 31) 5'-((4-메톡시벤질)옥시)-[3,3'-비피리딘]-6-아민;
(화합물 32) 5'-((4-클로로벤질)옥시)-[3,3'-비피리딘]-6-아민;
(화합물 33) 5'-((4-니트로벤질)옥시)-[3,3'-비피리딘]-6-아민;
(화합물 34) 4-(((6'-아미노-[3,3'-비피리딘]-5-일)옥시)메틸)페닐 벤조에이트;
(화합물 35) (R)-1-(4-(4-(5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-일)에탄-1-온;
(화합물 36) (R)-3-(1-(2,6-디클로로-3-플루오로페닐)에톡시)-5-(1-(1-메틸피페리딘-4-일)-1H-피라졸-4-일)피리딘;
(화합물 37) (R)-3-(1-(2,6-디클로로-3-플루오로페닐)에톡시)-5-(1-(테트라하이드로-2H-파이란-4-일)-1H-피라졸-4-일)피리딘;
(화합물 38) (R)-3-(1-(2,6-디클로로-3-플루오로페닐)에톡시)-5-(1-메틸-1H-피라졸-4-일)피리딘;
(화합물 39) (R)-3-(1-(2,6-디클로로-3-플루오로페닐)에톡시)-5-(1H-피라졸-4-일)피리딘;
(화합물 40) (R)-4-(5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-3-일)아닐린;
(화합물 41) tert-부틸 (R)-4-(5-(5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-3-일)피리미딘-2-일)피페라진-1-카르복실레이트;
(화합물 42) (R)-5-(5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-3-일)-2-(피페라진-1-일)피리미딘;
(화합물 43) (R)-5-(5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-3-일)피리미딘-2-아민;
(화합물 44) (R)-4-(5-(5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-3-일)피리미딘-2-일)몰폴린;
(화합물 45) (R)-5-(5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-3-일)-N-메틸피리미딘-2-아민;
(화합물 46) (R)-5-(5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-3-일)-N,N-디메틸피리미딘-2-아민;
(화합물 47) (R)-5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)-6'-니트로-3,3'-비피리딘;
(화합물 48) (R)-5'-(1-(2,6-디클로로-3-플루오로페닐)에톡시)-[3,3'-비피리딘]-6-아민;
(화합물 49) (R)-5-(5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-3-일)티오펜-2-카르보니트릴;
(화합물 50) (S)-1-(4-(4-(5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-일)에탄-1-온;
(화합물 51) (S)-3-(1-(2,6-디클로로-3-플루오로페닐)에톡시)-5-(1-(1-메틸피페리딘-4-일)-1H-피라졸-4-일)피리딘;
(화합물 52) (S)-5-(5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-3-일)티오펜-2-카르보니트릴;
(화합물 53) (S)-5'-(1-(2,6-디클로로-3-플루오로페닐)에톡시)-[3,3'-비피리딘]-6-아민;
(화합물 54) tert-부틸 (S)-4-(5'-(1-(2,6-디클로로-3-플루오로페닐)에톡시)-[3,3'-비피리딘]-6-일)피페라진-1-카르복실레이트;
(화합물 55) (S)-5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)-6'-(피페라진-1-일)-3,3'-비피리딘;
(화합물 56) (S)-5-(5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-3-일)피리미딘-2-아민;
(화합물 57) (S)-5-(5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-3-일)-N-메틸피리미딘-2-아민;
(화합물 58) (S)-5-(5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-3-일)-N,N-디메틸피리미딘-2-아민;
(화합물 59) tert-부틸 (S)-4-(5-(5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-3-일)피리미딘-2-일)피페라진-1-카르복실레이트;
(화합물 60) (S)-5-(5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-3-일)-2-(피페라진-1-일)피리미딘;
(화합물 61) 1-(4-(4-(5-((2,4-디클로로벤질)옥시)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-일)에탄-1-온;
(화합물 62) 3-((2,4-디클로로벤질)옥시)-5-(1-(1-메틸피페리딘-4-일)-1H-피라졸-4-일)피리딘;
(화합물 63) 3-((2,4-디클로로벤질)옥시)-5-(1-(테트라하이드로-2H-파이란-2-일)-1H-피라졸-4-일)피리딘;
(화합물 64) 3-((2,4-디클로로벤질)옥시)-5-(1-(테트라하이드로-2H-파이란-2-일)-1H-피라졸-5-일)피리딘;
(화합물 65) 5-(5-((2,4-디클로로벤질)옥시)피리딘-3-일)피리미딘-2-아민;
(화합물 66) 5-(5-((2,4-디클로로벤질)옥시)피리딘-3-일)-N-메틸피리미딘-2-아민;
(화합물 67) 5-(5-((2,4-디클로로벤질)옥시)피리딘-3-일)-N,N-디메틸피리미딘-2-아민;
(화합물 68) tert-부틸 4-(5-(5-((2,4-디클로로벤질)옥시)피리딘-3-일)피리미딘-2-일)피페라진-1-카르복실레이트;
(화합물 69) 5-(5-((2,4-디클로로벤질)옥시)피리딘-3-일)-2-(피페라진-1-일)피리미딘;
(화합물 70) 5-((2,4-디클로로벤질)옥시)-3,3'-비피리딘;
(화합물 71) 5-((2,4-디클로로벤질)옥시)-6'-니트로-3,3'-비피리딘;
(화합물 72) 5'-((2,4-디클로로벤질)옥시)-[3,3'-비피리딘]-6-아민;
(화합물 73) 5'-((2,4-디클로로벤질)옥시)-[3,3'-비피리딘]-6-카르보니트릴;
(화합물 74) 5-((2,4-디클로로벤질)옥시)-6'-플루오로-3,3'-비피리딘;
(화합물 75) 5-((2,4-디클로로벤질)옥시)-6'-메틸-3,3'-비피리딘;
(화합물 76) 5'-((2,4-디클로로벤질)옥시)-5-니트로-[3,3'-비피리딘]-6-아민;
(화합물 77) 5'-((2,4-디클로로벤질)옥시)-5-(트리플루오로메틸)-[3,3'-비피리딘]-6-아민;
(화합물 78) tert-부틸 4-(5'-((2,4-디클로로벤질)옥시)-[3,3'-비피리딘]-6-일)피페라진-1-카르복실레이트;
(화합물 79) 5-((2,4-디클로로벤질)옥시)-6'-(피페라진-1-일)-3,3'-비피리딘;
(화합물 80) 5'-((2,4-디클로로벤질)옥시)-[3,3'-비피리딘]-6-올;
(화합물 81) 5-(5-((2,4-디클로로벤질)옥시)피리딘-3-일)-1H-피롤로[2,3-b]피리딘;
(화합물 82) 5'-((2,4-디클로로벤질)옥시)-N-메틸-[3,3'-비피리딘]-6-아민;
(화합물 83) 5-(5-((2,4-디클로로벤질)옥시)피리딘-3-일)티오펜-2-카르보니트릴;
(화합물 84) (5-(5-((2,4-디클로로벤질)옥시)피리딘-3-일)티오펜-2-일)메탄아민;
(화합물 85) 4-(5-((2,4-디클로로벤질)옥시)피리딘-3-일)벤즈아미드;
(화합물 86) 6-(5-((2,4-디클로로벤질)옥시)피리딘-3-일)인돌린-2-온;
(화합물 87) (4-(5-((2,4-디클로로벤질)옥시)피리딘-3-일)페닐)(피롤리딘-1-일)메탄온;
(화합물 88) (3-(5-((2,4-디클로로벤질)옥시)피리딘-3-일)페닐)(피롤리딘-1-일)메탄온;
(화합물 89) tert-부틸 5-((2,4-디클로로벤질)옥시)-3',6'-디하이드로-[3,4'-비피리딘]-1'(2'H)-카르복실레이트;
(화합물 90) 5-((2,4-디클로로벤질)옥시)-1',2',3',6'-테트라하이드로-3,4'-b비피리딘;
(화합물 91) (E)-3-(3,5-비s(트리플루오로메틸)스티릴)-5-((2,4-디클로로벤질)옥시)피리딘;
(화합물 92) 5-(5-((2,4-디클로로벤질)옥시)피리딘-3-일)티오펜-2-카르바알데히드;
(화합물 93) tert-부틸 4-((5-(5-((2,4-디클로로벤질)옥시)피리딘-3-일)티오펜-2-일)메틸)피페라진-1-카르복실레이트;
(화합물 94) 1-((5-(5-((2,4-디클로로벤질)옥시)피리딘-3-일)티오펜-2-일)메틸)피페라진;
(화합물 95) 4-((5-(5-((2,4-디클로로벤질)옥시)피리딘-3-일)티오펜-2-일)메틸)몰폴린;
(화합물 96) 3-((2,4-디클로로벤질)옥시)-5-(5-(피롤리딘-1-일메틸)티오펜-2-일)피리딘;
(화합물 97) 3-((2,4-디클로로벤질)옥시)-5-(5-(피페리딘-1-일메틸)티오펜-2-일)피리딘;
(화합물 98) (E)-1-(5-(5-((2,4-디클로로벤질)옥시)피리딘-3-일)티오펜-2-일)-N-페닐메탄이민;
(화합물 99) 3-((2,4-디클로로벤질)옥시)-5-(티오펜-2-일)피리딘;
(화합물 100) 3-((2,4-디클로로벤질)옥시)-5-(티오펜-3-일)피리딘;
(화합물 101) 3-([2,2'-비티오펜]-5-일)-5-((2,4-디클로로벤질)옥시)피리딘;
(화합물 102) (5-(5-((2,4-디클로로벤질)옥시)피리딘-3-일)티오펜-2-일)메탄올;
(화합물 103) 5-(5-(1-(2,4-디클로로페닐)에톡시)피리딘-3-일)피리미딘-2-아민;
(화합물 104) 5'-(1-(2,4-디클로로페닐)에톡시)-N-메틸-[3,3'-비피리딘]-6-아민;
(화합물 105) 5-(5-(1-(2,4-디클로로페닐)에톡시)피리딘-3-일)티오펜-2-카르보니트릴;
(화합물 106) 5'-(1-(2,4-디클로로페닐)에톡시)-[3,3'-비피리딘]-6-아민;
(화합물 107) 5-(4-((2,4-디클로로벤질)옥시)피리딘-2-일)피리미딘-2-아민;
(화합물 108) 4-((2,4-디클로로벤질)옥시)-6'-니트로-2,3'-비피리딘;
(화합물 109) 4-((2,4-디클로로벤질)옥시)-[2,3'-비피리딘]-6'-아민;
(화합물 110) 5-(4-((2,4-디클로로벤질)옥시)피리딘-2-일)티오펜-2-카르보니트릴;
(화합물 111) tert-부틸 4-(4-(6-((2,4-디클로로벤질)옥시)피리딘-2-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트;
(화합물 112) 2-((2,4-디클로로벤질)옥시)-6-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘;
(화합물 113) 5-(6-((2,4-디클로로벤질)옥시)피리딘-2-일)피리미딘-2-아민;
(화합물 114) 6-((2,4-디클로로벤질)옥시)-[2,3'-비피리딘]-6'-아민;
(화합물 115) tert-부틸 4-(6-((2,4-디클로로벤질)옥시)-[2,3'-비피리딘]-6'-일)피페라진-1-카르복실레이트;
(화합물 116) 6-((2,4-디클로로벤질)옥시)-6'-(피페라진-1-일)-2,3'-비피리딘;
(화합물 117) 5-(6-((2,4-디클로로벤질)옥시)피리딘-2-일)티오펜-2-카르보니트릴;
(화합물 118) (R)-3-(1-(2,6-디클로로-3-플루오로페닐)에톡시)-5-페닐피리딘-2-아민;
(화합물 119) (R)-3-(1-(2,6-디클로로-3-플루오로페닐)에톡시)-5-(2-몰폴리노피리미딘-5-일)피리딘-2-아민;
(화합물 120) (R)-5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)-6'-니트로-[3,3'-비피리딘]-6-아민;
(화합물 121) 디-tert-부틸 (R)-(6'-아미노-5-(1-(2,6-디클로로-3-플루오로페닐)에톡시) -[3,3'-비피리딘]-6-일)디카르바메이트;
(화합물 122) (R)-5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)-[3,3'-비피리딘]-6,6'-디아민;
(화합물 123) 디-tert-부틸 (R)-(5-(2-아미노피리미딘-5-일)-3-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-2-일)디카르바메이트;
(화합물 124) (R)-5-(6-아미노-5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-3-일)피리미딘-2-아민;
(화합물 125) (R)-5-(6-아미노-5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-3-일)티오펜-2-카르보니트릴;
(화합물 126) (R)-5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)-6'-(피페라진-1-일)-[3,3'-비피리딘]-6-아민;
(화합물 127) tert-부틸 (R)-4-(5-(6-아미노-5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-3-일)피리미딘-2-일)피페라진-1-카르복실레이트;
(화합물 128) 디-tert-부틸 (R)-4-(5-(6-((tert-부톡시카르보닐)아미노)-5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-3-일)피리미딘-2-일)피페라진-1-카르복실레이트;
(화합물 129) (R)-3-(1-(2,6-디클로로-3-플루오로페닐)에톡시)-5-(2-(피페라진-1-일)피리미딘-5-일)피리딘-2-아민;
(화합물 130) 디-tert-부틸 (S)-(6'-아미노-5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)-[3,3'-비피리딘]-6-일)디카르바메이트;
(화합물 131) (S)-5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)-[3,3'-비피리딘]-6,6'-디아민;
(화합물 132) 디-tert-부틸 (S)-(5-(2-아미노피리미딘-5-일)-3-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-2-일)카르바메이트;
(화합물 133) (S)-5-(6-아미노-5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-3-일)피리미딘-2-아민;
(화합물 134) (S)-5-(6-아미노-5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-3-일)티오펜-2-카르보니트릴;
(화합물 135) 디-tert-부틸 (S)-4-(4-(6-((tert-부톡시카르보닐)아미노)-5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트;
(화합물 136) (S)-5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)-6'-(피페라진-1-일)-[3,3'-비피리딘]-6-아민;
(화합물 137) (S)-5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)-6'-(피페라진-1-일)-[3,3'-비피리딘]-6-아민;
(화합물 138) 디-tert-부틸 (S)-4-(6'-((tert-부톡시카르보닐)아미노)-5'-(1-(2,6-디클로로-3-플루오로페닐)에톡시)-[3,3'-비피리딘]-6-일)피페라진-1-카르복실레이트;
(화합물 139) 디-tert-부틸 (S)-(5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)-6'-(피페라진-1-일)-[3,3'-비피리딘]-6-일)디카르바메이트;
(화합물 140) (S)-5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)-6'-(피페라진-1-일)-[3,3'-비피리딘]-6-아민;
(화합물 141) 디-tert-부틸 (S)-4-(5-(6-((tert-부톡시카르보닐)아미노)-5-(1-(2,6-디클로로-3-플루오로페닐)에톡시)피리딘-3-일)피리미딘-2-일)피페라진-1-카르복실레이트;
(화합물 142) (S)-3-(1-(2,6-디클로로-3-플루오로페닐)에톡시)-5-(2-(피페라진-1-일)피리미딘-5-일)피리딘-2-아민;
(화합물 143) 디-tert-부틸 (6'-아미노-5-((2,4-디클로로벤질)옥시)-[3,3'-비피리딘]-6-일)디카르바메이트;
(화합물 144) 5-((2,4-디클로로벤질)옥시)-[3,3'-비피리딘]-6,6'-디아민;
(화합물 145) 디-tert-부틸 (5-(2-아미노피리미딘-5-일)-3-((2,4-디클로로벤질)옥시)피리딘-2-일)디카르바메이트;
(화합물 146) 5-(6-아미노-5-((2,4-디클로로벤질)옥시)피리딘-3-일)피리미딘-2-아민;
(화합물 147) 디-tert-부틸 (5-(5-시아노티오펜-2-일)-3-((2,4-디클로로벤질)옥시)피리딘-2-일)디카르바메이트;
(화합물 148) 5-(6-아미노-5-((2,4-디클로로벤질)옥시)피리딘-3-일)티오펜-2-카르보니트릴;
(화합물 149) 디-tert-부틸 4-(4-(6-((tert-부톡시카르보닐)아미노)-5-((2,4-디클로로벤질)옥시)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트;
(화합물 150) 3-((2,4-디클로로벤질)옥시)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;
(화합물 151) 5-((2,4-디클로로벤질)옥시)-6'-(피페라진-1-일)-[3,3'-비피리딘]-6-아민;
(화합물 152) 디-tert-부틸 4-(5-(6-((tert-부톡시카르보닐)아미노)-5-((2,4-디클로로벤질)옥시)피리딘-3-일)피리미딘-2-일)피페라진-1-카르복실레이트;
(화합물 153) 3-((2,4-디클로로벤질)옥시)-5-(2-(피페라진-1-일)피리미딘-5-일)피리딘-2-아민;
(화합물 154) 디-tert-부틸 (6'-아미노-5-(1-(2,4-디클로로페닐)에톡시)-[3,3'-비피리딘]-6-일)디카르바메이트;
(화합물 155) 5-(1-(2,4-디클로로페닐)에톡시)-[3,3'-비피리딘]-6,6'-디아민;
(화합물 156) 디-tert-부틸 (5-(2-아미노피리미딘-5-일)-3-(1-(2,4-디클로로페닐)에톡시)피리딘-2-일)카르바메이트;
(화합물 157) 5-(6-아미노-5-(1-(2,4-디클로로페닐)에톡시)피리딘-3-일)피리미딘-2-아민;
(화합물 158) 디-tert-부틸 (5-(5-시아노티오펜-2-일)-3-(1-(2,4-디클로로페닐)에톡시)피리딘-2-일)디카르바메이트;
(화합물 159) 5-(6-아미노-5-(1-(2,4-디클로로페닐)에톡시)피리딘-3-일)티오펜-2-카르보니트릴;
(화합물 160) 디-tert-부틸 4-(4-(6-((tert-부톡시카르보닐)아미노)-5-(1-(2,4-디클로로페닐)에톡시)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트;
(화합물 161) 3-(1-(2,4-디클로로페닐)에톡시)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;
(화합물 162) 디-tert-부틸 4-(5-(6-((tert-부톡시카르보닐)아미노)-5-(1-(2,4-디클로로페닐)에톡시)피리딘-3-일)피리미딘-2-일)피페라진-1-카르복실레이트;
(화합물 163) 3-(1-(2,4-디클로로페닐)에톡시)-5-(2-(피페라진-1-일)피리미딘-5-일)피리딘-2-아민.
The method of claim 1,
The formula I is a compound, characterized in that selected from the group consisting of the following compounds 1 to 163:
(Compound 1) tert-butyl 4-(4-(5-(benzyloxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;
(Compound 2) 3-(benzyloxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridine;
(Compound 3) tert-butyl 4-(4-(5-((2-cyanobenzyl)oxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate ;
(Compound 4) 2-(((5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)oxy)methyl)benzonitrile;
(Compound 5) tert-butyl 4-(4-(5-((2-(trifluoromethyl)benzyl)oxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1 -Carboxylate;
(Compound 6) 3-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-5-((2-(trifluoromethyl)benzyl)oxy)pyridine;
(Compound 7) tert-Butyl 4-(4-(5-((2-chloro-4-fluorobenzyl)oxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1 -Carboxylate;
(Compound 8) 3-((2-chloro-4-fluorobenzyl)oxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridine;
(Compound 9) tert-Butyl 4-(4-(5-((2,6-difluorobenzyl)oxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1- Carboxylate;
(Compound 10) 3-((2,6-difluorobenzyl)oxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridine;
(Compound 11) tert-butyl 4-(4-(5-((4-chlorobenzyl)oxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;
(Compound 12) 3-((4-chlorobenzyl)oxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridine;
(Compound 13) tert-Butyl 4-(4-(5-((4-cyanobenzyl)oxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate ;
(Compound 14) 3-(Benzyloxy)-5-(1-(1-benzylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridine;
(Compound 15) tert-butyl 4-(4-(5-((2,4-dichlorobenzyl)oxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxyl Rate;
(Compound 16) 3-((2,4-dichlorobenzyl)oxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridine;
(Compound 17) tert-butyl (R)-4-(4-(5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazole- 1-yl)piperidine-1-carboxylate;
(Compound 18) (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazole- 4-yl)pyridine;
(Compound 19) tert-butyl (S)-4-(4-(5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazole- 1-yl)piperidine-1-carboxylate;
(Compound 20) (S)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazole- 4-yl)pyridine;
(Compound 21) (R)-5-(1-(2,6-difluorophenyl)ethoxy)-6'-nitro-3,3'-bipyridine;
(Compound 22) 6'-nitro-5-((2-(trifluoromethyl)benzyl)oxy)-3,3'-bipyridine;
(Compound 23) 2-(((6'-Nitro-[3,3'-bipyridin]-5-yl)oxy)methyl)benzonitrile;
(Compound 24) 5-((4-methoxybenzyl)oxy)-6'-nitro-3,3'-bipyridine;
(Compound 25) 5-((4-chlorobenzyl)oxy)-6'-nitro-3,3'-bipyridine;
(Compound 26) 6'-Nitro-5-((4-nitrobenzyl)oxy)-3,3'-bipyridine;
(Compound 27) 5-(5-((2-chloro-4-fluorobenzyl)oxy)pyridin-3-yl)pyrimidin-2-amine;
(Compound 28) 5'-((2,6-difluorobenzyl)oxy)-[3,3'-bipyridin]-6-amine;
(Compound 29) 5'-((2-(trifluoromethyl)benzyl)oxy)-[3,3'-bipyridin]-6-amine;
(Compound 30) 2-(((6'-amino-[3,3'-bipyridin]-5-yl)oxy)methyl)benzonitrile;
(Compound 31) 5'-((4-methoxybenzyl)oxy)-[3,3'-bipyridin]-6-amine;
(Compound 32) 5'-((4-chlorobenzyl)oxy)-[3,3'-bipyridin]-6-amine;
(Compound 33) 5'-((4-nitrobenzyl)oxy)-[3,3'-bipyridin]-6-amine;
(Compound 34) 4-(((6'-amino-[3,3'-bipyridin]-5-yl)oxy)methyl)phenyl benzoate;
(Compound 35) (R)-1-(4-(4-(5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazole- 1-yl)piperidin-1-yl)ethan-1-one;
(Compound 36) (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(1-methylpiperidin-4-yl)-1H- Pyrazol-4-yl)pyridine;
(Compound 37) (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H- Pyrazol-4-yl)pyridine;
(Compound 38) (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-methyl-1H-pyrazol-4-yl)pyridine;
(Compound 39) (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1H-pyrazol-4-yl)pyridine;
(Compound 40) (R)-4-(5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)aniline;
(Compound 41) tert-butyl (R)-4-(5-(5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)pyrimidin-2-yl ) Piperazine-1-carboxylate;
(Compound 42) (R)-5-(5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-2-(piperazin-1-yl)pyri Mydin;
(Compound 43) (R)-5-(5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)pyrimidin-2-amine;
(Compound 44) (R)-4-(5-(5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)pyrimidin-2-yl)morpholine ;
(Compound 45) (R)-5-(5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-N-methylpyrimidin-2-amine;
(Compound 46) (R)-5-(5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-N,N-dimethylpyrimidin-2-amine ;
(Compound 47) (R)-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-6'-nitro-3,3'-bipyridine;
(Compound 48) (R)-5'-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-[3,3'-bipyridin]-6-amine;
(Compound 49) (R)-5-(5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)thiophene-2-carbonitrile;
(Compound 50) (S)-1-(4-(4-(5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazole- 1-yl)piperidin-1-yl)ethan-1-one;
(Compound 51) (S)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(1-methylpiperidin-4-yl)-1H- Pyrazol-4-yl)pyridine;
(Compound 52) (S)-5-(5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)thiophene-2-carbonitrile;
(Compound 53) (S)-5'-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-[3,3'-bipyridin]-6-amine;
(Compound 54) tert-butyl (S)-4-(5'-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-[3,3'-bipyridin]-6-yl ) Piperazine-1-carboxylate;
(Compound 55) (S)-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-6'-(piperazin-1-yl)-3,3'-bipyridine;
(Compound 56) (S)-5-(5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)pyrimidin-2-amine;
(Compound 57) (S)-5-(5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-N-methylpyrimidin-2-amine;
(Compound 58) (S)-5-(5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-N,N-dimethylpyrimidin-2-amine ;
(Compound 59) tert-butyl (S)-4-(5-(5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)pyrimidin-2-yl ) Piperazine-1-carboxylate;
(Compound 60) (S)-5-(5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-2-(piperazin-1-yl)pyri Mydin;
(Compound 61) 1-(4-(4-(5-((2,4-dichlorobenzyl)oxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl) Ethan-1-one;
(Compound 62) 3-((2,4-dichlorobenzyl)oxy)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridine;
(Compound 63) 3-((2,4-dichlorobenzyl)oxy)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyridine;
(Compound 64) 3-((2,4-dichlorobenzyl)oxy)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridine;
(Compound 65) 5-(5-((2,4-dichlorobenzyl)oxy)pyridin-3-yl)pyrimidin-2-amine;
(Compound 66) 5-(5-((2,4-dichlorobenzyl)oxy)pyridin-3-yl)-N-methylpyrimidin-2-amine;
(Compound 67) 5-(5-((2,4-dichlorobenzyl)oxy)pyridin-3-yl)-N,N-dimethylpyrimidin-2-amine;
(Compound 68) tert-butyl 4-(5-(5-((2,4-dichlorobenzyl)oxy)pyridin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate;
(Compound 69) 5-(5-((2,4-dichlorobenzyl)oxy)pyridin-3-yl)-2-(piperazin-1-yl)pyrimidine;
(Compound 70) 5-((2,4-dichlorobenzyl)oxy)-3,3'-bipyridine;
(Compound 71) 5-((2,4-dichlorobenzyl)oxy)-6'-nitro-3,3'-bipyridine;
(Compound 72) 5'-((2,4-dichlorobenzyl)oxy)-[3,3'-bipyridin]-6-amine;
(Compound 73) 5'-((2,4-dichlorobenzyl)oxy)-[3,3'-bipyridin]-6-carbonitrile;
(Compound 74) 5-((2,4-dichlorobenzyl)oxy)-6'-fluoro-3,3'-bipyridine;
(Compound 75) 5-((2,4-dichlorobenzyl)oxy)-6'-methyl-3,3'-bipyridine;
(Compound 76) 5'-((2,4-dichlorobenzyl)oxy)-5-nitro-[3,3'-bipyridin]-6-amine;
(Compound 77) 5'-((2,4-dichlorobenzyl)oxy)-5-(trifluoromethyl)-[3,3'-bipyridin]-6-amine;
(Compound 78) tert-butyl 4-(5'-((2,4-dichlorobenzyl)oxy)-[3,3'-bipyridin]-6-yl)piperazine-1-carboxylate;
(Compound 79) 5-((2,4-dichlorobenzyl)oxy)-6'-(piperazin-1-yl)-3,3'-bipyridine;
(Compound 80) 5'-((2,4-dichlorobenzyl)oxy)-[3,3'-bipyridin]-6-ol;
(Compound 81) 5-(5-((2,4-dichlorobenzyl)oxy)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine;
(Compound 82) 5'-((2,4-dichlorobenzyl)oxy)-N-methyl-[3,3'-bipyridin]-6-amine;
(Compound 83) 5-(5-((2,4-dichlorobenzyl)oxy)pyridin-3-yl)thiophene-2-carbonitrile;
(Compound 84) (5-(5-((2,4-dichlorobenzyl)oxy)pyridin-3-yl)thiophen-2-yl)methanamine;
(Compound 85) 4-(5-((2,4-dichlorobenzyl)oxy)pyridin-3-yl)benzamide;
(Compound 86) 6-(5-((2,4-dichlorobenzyl)oxy)pyridin-3-yl)indolin-2-one;
(Compound 87) (4-(5-((2,4-dichlorobenzyl)oxy)pyridin-3-yl)phenyl)(pyrrolidin-1-yl)methanone;
(Compound 88) (3-(5-((2,4-dichlorobenzyl)oxy)pyridin-3-yl)phenyl)(pyrrolidin-1-yl)methanone;
(Compound 89) tert-butyl 5-((2,4-dichlorobenzyl)oxy)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxyl Rate;
(Compound 90) 5-((2,4-dichlorobenzyl)oxy)-1',2',3',6'-tetrahydro-3,4'-b bipyridine;
(Compound 91) (E)-3-(3,5-bis(trifluoromethyl)styryl)-5-((2,4-dichlorobenzyl)oxy)pyridine;
(Compound 92) 5-(5-((2,4-dichlorobenzyl)oxy)pyridin-3-yl)thiophene-2-carbaaldehyde;
(Compound 93) tert-butyl 4-((5-(5-((2,4-dichlorobenzyl)oxy)pyridin-3-yl)thiophen-2-yl)methyl)piperazine-1-carboxylate ;
(Compound 94) 1-((5-(5-((2,4-dichlorobenzyl)oxy)pyridin-3-yl)thiophen-2-yl)methyl)piperazine;
(Compound 95) 4-((5-(5-((2,4-dichlorobenzyl)oxy)pyridin-3-yl)thiophen-2-yl)methyl)morpholine;
(Compound 96) 3-((2,4-dichlorobenzyl)oxy)-5-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)pyridine;
(Compound 97) 3-((2,4-dichlorobenzyl)oxy)-5-(5-(piperidin-1-ylmethyl)thiophen-2-yl)pyridine;
(Compound 98) (E)-1-(5-(5-((2,4-dichlorobenzyl)oxy)pyridin-3-yl)thiophen-2-yl)-N-phenylmethanimine;
(Compound 99) 3-((2,4-dichlorobenzyl)oxy)-5-(thiophen-2-yl)pyridine;
(Compound 100) 3-((2,4-dichlorobenzyl)oxy)-5-(thiophen-3-yl)pyridine;
(Compound 101) 3-([2,2'-bithiophene]-5-yl)-5-((2,4-dichlorobenzyl)oxy)pyridine;
(Compound 102) (5-(5-((2,4-dichlorobenzyl)oxy)pyridin-3-yl)thiophen-2-yl)methanol;
(Compound 103) 5-(5-(1-(2,4-dichlorophenyl)ethoxy)pyridin-3-yl)pyrimidin-2-amine;
(Compound 104) 5'-(1-(2,4-dichlorophenyl)ethoxy)-N-methyl-[3,3'-bipyridin]-6-amine;
(Compound 105) 5-(5-(1-(2,4-dichlorophenyl)ethoxy)pyridin-3-yl)thiophene-2-carbonitrile;
(Compound 106) 5'-(1-(2,4-dichlorophenyl)ethoxy)-[3,3'-bipyridin]-6-amine;
(Compound 107) 5-(4-((2,4-dichlorobenzyl)oxy)pyridin-2-yl)pyrimidin-2-amine;
(Compound 108) 4-((2,4-dichlorobenzyl)oxy)-6'-nitro-2,3'-bipyridine;
(Compound 109) 4-((2,4-dichlorobenzyl)oxy)-[2,3'-bipyridin]-6'-amine;
(Compound 110) 5-(4-((2,4-dichlorobenzyl)oxy)pyridin-2-yl)thiophene-2-carbonitrile;
(Compound 111) tert-butyl 4-(4-(6-((2,4-dichlorobenzyl)oxy)pyridin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxyl Rate;
(Compound 112) 2-((2,4-dichlorobenzyl)oxy)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridine;
(Compound 113) 5-(6-((2,4-dichlorobenzyl)oxy)pyridin-2-yl)pyrimidin-2-amine;
(Compound 114) 6-((2,4-dichlorobenzyl)oxy)-[2,3'-bipyridin]-6'-amine;
(Compound 115) tert-butyl 4-(6-((2,4-dichlorobenzyl)oxy)-[2,3'-bipyridin]-6'-yl)piperazine-1-carboxylate;
(Compound 116) 6-((2,4-dichlorobenzyl)oxy)-6'-(piperazin-1-yl)-2,3'-bipyridine;
(Compound 117) 5-(6-((2,4-dichlorobenzyl)oxy)pyridin-2-yl)thiophene-2-carbonitrile;
(Compound 118) (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-phenylpyridin-2-amine;
(Compound 119) (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(2-morpholinopyrimidin-5-yl)pyridin-2-amine ;
(Compound 120) (R)-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-6'-nitro-[3,3'-bipyridin]-6-amine;
(Compound 121) Di-tert-butyl (R)-(6'-amino-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-[3,3'-bipyridine] -6-yl)dicarbamate;
(Compound 122) (R)-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-[3,3'-bipyridin]-6,6'-diamine;
(Compound 123) Di-tert-butyl (R)-(5-(2-aminopyrimidin-5-yl)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridine -2-yl)dicarbamate;
(Compound 124) (R)-5-(6-amino-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)pyrimidin-2-amine;
(Compound 125) (R)-5-(6-amino-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)thiophene-2-carbonitrile;
(Compound 126) (R)-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-6'-(piperazin-1-yl)-[3,3'-bipyridine ]-6-amine;
(Compound 127) tert-butyl (R)-4-(5-(6-amino-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)pyrimidine -2-yl)piperazine-1-carboxylate;
(Compound 128) Di-tert-butyl (R)-4-(5-(6-((tert-butoxycarbonyl)amino)-5-(1-(2,6-dichloro-3-fluorophenyl) )Ethoxy)pyridin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate;
(Compound 129) (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(2-(piperazin-1-yl)pyrimidin-5-yl) Pyridin-2-amine;
(Compound 130) Di-tert-butyl (S)-(6'-amino-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-[3,3'-bipyridine] -6-yl)dicarbamate;
(Compound 131) (S)-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-[3,3'-bipyridin]-6,6'-diamine;
(Compound 132) Di-tert-butyl (S)-(5-(2-aminopyrimidin-5-yl)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridine -2-yl)carbamate;
(Compound 133) (S)-5-(6-amino-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)pyrimidin-2-amine;
(Compound 134) (S)-5-(6-amino-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)thiophene-2-carbonitrile;
(Compound 135) Di-tert-butyl (S)-4-(4-(6-((tert-butoxycarbonyl)amino)-5-(1-(2,6-dichloro-3-fluorophenyl) )Ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;
(Compound 136) (S)-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-6'-(piperazin-1-yl)-[3,3'-bipyridine ]-6-amine;
(Compound 137) (S)-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-6'-(piperazin-1-yl)-[3,3'-bipyridine ]-6-amine;
(Compound 138) Di-tert-butyl (S)-4-(6'-((tert-butoxycarbonyl)amino)-5'-(1-(2,6-dichloro-3-fluorophenyl) Ethoxy)-[3,3'-bipyridin]-6-yl)piperazine-1-carboxylate;
(Compound 139) Di-tert-butyl (S)-(5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-6'-(piperazin-1-yl)-[3 ,3'-bipyridin]-6-yl)dicarbamate;
(Compound 140) (S)-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-6'-(piperazin-1-yl)-[3,3'-bipyridine ]-6-amine;
(Compound 141) Di-tert-butyl (S)-4-(5-(6-((tert-butoxycarbonyl)amino)-5-(1-(2,6-dichloro-3-fluorophenyl) )Ethoxy)pyridin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate;
(Compound 142) (S)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(2-(piperazin-1-yl)pyrimidin-5-yl) Pyridin-2-amine;
(Compound 143) Di-tert-butyl (6'-amino-5-((2,4-dichlorobenzyl)oxy)-[3,3'-bipyridin]-6-yl)dicarbamate;
(Compound 144) 5-((2,4-dichlorobenzyl)oxy)-[3,3'-bipyridin]-6,6'-diamine;
(Compound 145) Di-tert-butyl (5-(2-aminopyrimidin-5-yl)-3-((2,4-dichlorobenzyl)oxy)pyridin-2-yl)dicarbamate;
(Compound 146) 5-(6-amino-5-((2,4-dichlorobenzyl)oxy)pyridin-3-yl)pyrimidin-2-amine;
(Compound 147) Di-tert-butyl (5-(5-cyanothiophen-2-yl)-3-((2,4-dichlorobenzyl)oxy)pyridin-2-yl)dicarbamate;
(Compound 148) 5-(6-amino-5-((2,4-dichlorobenzyl)oxy)pyridin-3-yl)thiophene-2-carbonitrile;
(Compound 149) Di-tert-butyl 4-(4-(6-((tert-butoxycarbonyl)amino)-5-((2,4-dichlorobenzyl)oxy)pyridin-3-yl)-1H -Pyrazol-1-yl)piperidine-1-carboxylate;
(Compound 150) 3-((2,4-dichlorobenzyl)oxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
(Compound 151) 5-((2,4-dichlorobenzyl)oxy)-6'-(piperazin-1-yl)-[3,3'-bipyridin]-6-amine;
(Compound 152) Di-tert-butyl 4-(5-(6-((tert-butoxycarbonyl)amino)-5-((2,4-dichlorobenzyl)oxy)pyridin-3-yl)pyrimidine -2-yl)piperazine-1-carboxylate;
(Compound 153) 3-((2,4-dichlorobenzyl)oxy)-5-(2-(piperazin-1-yl)pyrimidin-5-yl)pyridin-2-amine;
(Compound 154) Di-tert-butyl (6'-amino-5-(1-(2,4-dichlorophenyl)ethoxy)-[3,3'-bipyridin]-6-yl)dicarbamate;
(Compound 155) 5-(1-(2,4-dichlorophenyl)ethoxy)-[3,3'-bipyridin]-6,6'-diamine;
(Compound 156) Di-tert-butyl (5-(2-aminopyrimidin-5-yl)-3-(1-(2,4-dichlorophenyl)ethoxy)pyridin-2-yl)carbamate;
(Compound 157) 5-(6-amino-5-(1-(2,4-dichlorophenyl)ethoxy)pyridin-3-yl)pyrimidin-2-amine;
(Compound 158) Di-tert-butyl (5-(5-cyanothiophen-2-yl)-3-(1-(2,4-dichlorophenyl)ethoxy)pyridin-2-yl)dicarbamate;
(Compound 159) 5-(6-amino-5-(1-(2,4-dichlorophenyl)ethoxy)pyridin-3-yl)thiophene-2-carbonitrile;
(Compound 160) Di-tert-butyl 4-(4-(6-((tert-butoxycarbonyl)amino)-5-(1-(2,4-dichlorophenyl)ethoxy)pyridin-3-yl )-1H-pyrazol-1-yl)piperidine-1-carboxylate;
(Compound 161) 3-(1-(2,4-dichlorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine ;
(Compound 162) Di-tert-butyl 4-(5-(6-((tert-butoxycarbonyl)amino)-5-(1-(2,4-dichlorophenyl)ethoxy)pyridin-3-yl )Pyrimidin-2-yl)piperazine-1-carboxylate;
(Compound 163) 3-(1-(2,4-dichlorophenyl)ethoxy)-5-(2-(piperazin-1-yl)pyrimidin-5-yl)pyridin-2-amine.
A pharmaceutical composition for the treatment or prevention of diseases related to SHIP2 activity, comprising the compound of any one of claims 1 to 5.
상기 SHIP2 활성 관련 질환은 알츠하이머성 치매, 퇴행성 뇌질환, 암, 고혈압(hypertensive) 및 당뇨로 이루어진 군에서 선택된 하나 이상인 것을 특징으로 하는 약학 조성물.
The method of claim 6,
The SHIP2 activity-related disease is at least one selected from the group consisting of Alzheimer's dementia, degenerative brain disease, cancer, hypertensive and diabetes.
상기 SHIP2 활성 관련 질환은 알츠하이머성 치매인 것을 특징으로 하는 약학 조성물.
The method of claim 6,
The SHIP2 activity-related disease is a pharmaceutical composition, characterized in that Alzheimer's dementia.
담체, 보조제 또는 희석제를 더 포함하는 것을 특징으로 하는 약학 조성물.
The method of claim 6,
A pharmaceutical composition, characterized in that it further comprises a carrier, adjuvant or diluent.
A health functional food for the treatment or prevention of diseases related to SHIP2 activity, comprising the compound of any one of claims 1 to 5.
화학식 I-1로 표시되는 브로모하이드록시피리딘 화합물을 팔라듐 촉매(II)와 탄산나트륨 수용액의 존재 하에 화학식 I-2으로 표시되는 보론화합물을 반응시켜서, 화학식 I-3으로 표시되는 화합물을 제조하고,
상기 제조한 화학식 I-3으로 표시되는 화합물을 DIAD와 PPH3 의 존재하에 화학식 I-4로 표시되는 화합물과 반응시킨 후, 트리플로로아세트산을 이용한 boc 보호 그룹 제거반응을 이용해서, 화학식 I-5로 표시되는 피리딘 유도체를 제조하는, 피리딘 유도체의 제조방법:
[반응식 I]
상기 반응식 I의 화학식에서, R1은 치환되지 않은 것이거나 또는 할로겐, 메톡시, 시아노, 및 트리플루오로메틸로 이루어진 군에서 선택된 1개 내지 2개의 치환기이고, R2 및 R2 ' 는 각각 수소이다.
According to Scheme I below,
A bromohydroxypyridine compound represented by Formula I-1 was reacted with a boron compound represented by Formula I-2 in the presence of a palladium catalyst (II) and an aqueous sodium carbonate solution to prepare a compound represented by Formula I-3,
DIAD and PPH 3 the compound represented by the above prepared formula I- 3 After reacting with a compound represented by the formula (I-4) in the presence of, by using a boc protecting group removal reaction using trifluoroacetic acid, a method for preparing a pyridine derivative represented by the formula (I-5):
[Scheme I]
In the formula of Scheme I, R 1 is unsubstituted or 1 to 2 substituents selected from the group consisting of halogen, methoxy, cyano, and trifluoromethyl, and R 2 and R 2 ′ are each It is hydrogen.
화학식 Ⅱ-1로 표시되는 브로모하이드록시피리딘 화합물을 DIAD와 PPH3 의 존재하에 화학식 Ⅱ-2로 표시되는 화합물과 반응시켜서, 화학식 Ⅱ-3으로 표시되는 화합물을 제조하고,
상기 제조한 화학식 Ⅱ-3으로 표시되는 화합물을 팔라듐 촉매(II)와 탄산나트륨 수용액의 존재 하에 화학식 Ⅱ-4로 표시되는 보론화합물과 반응시켜서, 화학식 Ⅱ-5로 표시되는 피리딘 유도체를 제조하는, 피리딘 유도체의 제조방법:
[반응식 II]
상기 반응식 II의 화학식에서,
X. Y. 및 Z는 각각 독립적으로 탄소(C) 또는 질소(N)이고, 상기 X. Y. 및 Z 중 하나는 질소(N)이며,
R1은 할로겐으로 이루어진 1개 내지 3개의 치환기이고,
R2 및 R2 ' 는 각각 수소, 메틸(CH3) 또는 각각 다른 비대칭 중심을 가지는 (S), (R)-메틸(methyl)이고,
R3은 비치환되거나 치환된 아릴 또는 헤테로아릴이고, 상기 치환된 아릴 또는 헤테로아릴은 메틸, 할로겐, 아민, 하이드록시, 시아노, 피페라진일, 피페리딘일, 피라닐, 알데하이드, 니트로, 메틸피페라진일, 메틸피롤리딘일, 메틸몰폴린일, 몰폴린일, 알데히드, 피롤리딘일메탄온, 메탄아민, 메틸아민, 다이메틸아민, 트리플루오로메틸, 아세틸피페리딘일, 페닐메탄아민 및 메탄올로 이루어진 군에서 선택된 1개 이상의 치환기로 치환된 것임.
According to Scheme II below,
DIAD and PPH 3 bromohydroxypyridine compound represented by the formula II-1 By reacting with a compound represented by Formula II-2 in the presence of, to prepare a compound represented by Formula II-3,
Pyridine for preparing a pyridine derivative represented by Formula II-5 by reacting the prepared compound represented by Formula II-3 with a boron compound represented by Formula II-4 in the presence of a palladium catalyst (II) and an aqueous sodium carbonate solution. Method for preparing derivatives:
[Scheme II]
In the formula of Scheme II,
XY and Z are each independently carbon (C) or nitrogen (N), and one of XY and Z is nitrogen (N),
R 1 is 1 to 3 substituents consisting of halogen,
R 2 and R 2 ′ are each hydrogen, methyl (CH 3 ) or (S), (R)-methyl (methyl) each having a different asymmetric center,
R 3 is unsubstituted or substituted aryl or heteroaryl, and the substituted aryl or heteroaryl is methyl, halogen, amine, hydroxy, cyano, piperazinyl, piperidinyl, pyranyl, aldehyde, nitro, methyl Piperazinyl, methylpyrrolidinyl, methylmorpholinyl, morpholinyl, aldehyde, pyrrolidinylmethanone, methanamine, methylamine, dimethylamine, trifluoromethyl, acetylpiperidinyl, phenylmethanamine and It is substituted with one or more substituents selected from the group consisting of methanol.
화학식 Ⅲ-1로 표시되는 2-니트로피리딘-3 올을 DIAD와 PPH3 의 존재하에 화학식 Ⅲ-2로 표시되는 화합물과 반응시켜서, 화학식 Ⅲ-3으로 표시되는 화합물을 제조하고,
상기 제조한 화학식 Ⅲ-3으로 표시되는 화합물을 철과 아세트산의 존재하에 환원반응시켜서, 화학식 Ⅲ-4로 표시되는 화합물을 제조하며,
상기 제조한 화학식 Ⅲ-4로 표시되는 화합물을 N-브로모숙신이미드의 존재하에서 반응시켜서, 화학식 Ⅲ-5로 표시되는 화합물을 제조하고,
상기 제조한 화학식 Ⅲ-5로 표시되는 화합물을 디-tert-부틸-디카보네이트와 디-메틸아미노피리딘의 존재하에서 반응시켜서, Boc 보호기가 붙은 화학식 Ⅲ-6으로 표시되는 화합물을 제조하며,
상기 제조한 화학식 Ⅲ-6으로 표시되는 화합물을 팔라듐 촉매(II)와 탄산나트륨 수용액의 존재 하에 화학식 Ⅲ-7로 표시되는 보론화합물과 반응시켜서, 화학식 Ⅲ-8로 표시되는 화합물을 제조하고,
상기 제조한 화학식 Ⅲ-8로 표시되는 화합물을 염산 혹은 트리플루오로아세트산 존재하에서 반응시켜, Boc 보호그룹이 제거된 화학식 Ⅲ-9로 표시되는 피리딘 유도체를 제조하는, 피리딘 유도체의 제조방법:
[반응식 III]
상기 반응식 III의 화학식에서,
R1은 할로겐으로 이루어진 1개 내지 3개의 치환기이고,
R2 및 R2 ' 는 각각 수소, 메틸(CH3) 또는 각각 다른 비대칭 중심을 가지는 (S), (R)-메틸(methyl)이고,
R3은 비치환되거나 치환된 아릴, 피리딘, 피리미딘, 피라졸, 또는 티오펜이고, 상기 치환된 아릴, 피리딘, 피리미딘, 피라졸, 또는 티오펜은 아민, 시아노, 피페라진일, 피페리딘일, 및 몰폴린일로 이루어진 군에서 선택된 1개 이상의 치환기로 치환된 것임.
According to Scheme III below,
DIAD and PPH 3 2-nitropyridin-3ol represented by Formula III-1 By reacting with the compound represented by Formula III-2 in the presence of, to prepare a compound represented by Formula III-3,
Reduction reaction of the compound represented by Formula III-3 prepared above in the presence of iron and acetic acid to prepare a compound represented by Formula III-4,
By reacting the prepared compound represented by Formula III-4 in the presence of N-bromosuccinimide, to prepare a compound represented by Formula III-5,
By reacting the prepared compound represented by Formula III-5 in the presence of di-tert-butyl-dicarbonate and di-methylaminopyridine to prepare a compound represented by Formula III-6 with a Boc protecting group,
By reacting the prepared compound represented by Formula III-6 with a boron compound represented by Formula III-7 in the presence of a palladium catalyst (II) and an aqueous sodium carbonate solution, a compound represented by Formula III-8 was prepared,
A method for preparing a pyridine derivative, wherein the compound represented by Formula III-8 is reacted in the presence of hydrochloric acid or trifluoroacetic acid to prepare a pyridine derivative represented by Formula III-9 from which the Boc protecting group has been removed:
[Scheme III]
In the formula of Scheme III,
R 1 is 1 to 3 substituents consisting of halogen,
R 2 and R 2 ′ are each hydrogen, methyl (CH 3 ) or (S), (R)-methyl (methyl) each having a different asymmetric center,
R 3 is unsubstituted or substituted aryl, pyridine, pyrimidine, pyrazole, or thiophene, and the substituted aryl, pyridine, pyrimidine, pyrazole, or thiophene is an amine, cyano, piperazinyl, pi It is substituted with one or more substituents selected from the group consisting of peridinyl and morpholinyl.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020200096804A KR20200096455A (en) | 2020-08-03 | 2020-08-03 | Novel pyridine derivatives having inhibition activity against SHIP2 and pharmaceutical compositions with the components |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020200096804A KR20200096455A (en) | 2020-08-03 | 2020-08-03 | Novel pyridine derivatives having inhibition activity against SHIP2 and pharmaceutical compositions with the components |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020180092447A Division KR102220428B1 (en) | 2018-08-08 | 2018-08-08 | Novel pyridine derivatives having inhibition activity against SHIP2 and pharmaceutical compositions with the components |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| KR20200096455A true KR20200096455A (en) | 2020-08-12 |
Family
ID=72039216
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020200096804A KR20200096455A (en) | 2020-08-03 | 2020-08-03 | Novel pyridine derivatives having inhibition activity against SHIP2 and pharmaceutical compositions with the components |
Country Status (1)
| Country | Link |
|---|---|
| KR (1) | KR20200096455A (en) |
-
2020
- 2020-08-03 KR KR1020200096804A patent/KR20200096455A/en active Application Filing
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US11623921B2 (en) | Indole carboxamide compounds | |
| US10858335B2 (en) | 2,3-Disubstituted pyridine compounds as TGF-β inhibitors and methods of use | |
| RU2615130C2 (en) | Heterocyclic compounds useful as pdk1 inhibitors | |
| EP3080108B1 (en) | Tropomyosin-related kinase (trk) inhibitors | |
| EA019723B1 (en) | cMET INHIBITORS | |
| JP2018533552A (en) | Novel pyrrolo [2,3-D] pyrimidine derivatives as dual DYRK1 / CLK1 inhibitors | |
| TW201225957A (en) | Glycine transporter inhibitor | |
| KR20200015515A (en) | Trisubstituted pyrimidine compounds and compositions for treating cancer, retinal disorders and cardiomyopathy | |
| JP2022515309A (en) | Substituted aryl compounds, their production methods and uses | |
| JP2022545364A (en) | Bicyclic Heteroaryl Compounds Useful as IRAK4 Inhibitors | |
| CA3214900A1 (en) | Carboxamide pyrolopyrazine and pyridine compounds useful as inhibitors of myt1 and use thereof in the treatment of cancer | |
| TW202220987A (en) | Substituted heterocyclic compounds and therapeutic uses thereof | |
| KR102220428B1 (en) | Novel pyridine derivatives having inhibition activity against SHIP2 and pharmaceutical compositions with the components | |
| EP1559716B1 (en) | Pyrazolonaphthyridine derivative | |
| KR20200096455A (en) | Novel pyridine derivatives having inhibition activity against SHIP2 and pharmaceutical compositions with the components | |
| CN111164084A (en) | Triazolotriazine derivatives useful as A2A receptor antagonists | |
| CN117396473A (en) | Imidazopyridinyl inhibitors of plasma kallikrein | |
| KR102655210B1 (en) | Adenosine A2A receptor antagonists and uses thereof | |
| JP2024512753A (en) | Novel dialkoxynaphtho[2,3-c]furan-1(3H)-one derivatives and pharmaceutical compositions containing the same for the prevention or treatment of respiratory diseases or SARS-CoV-2 infections | |
| TW202417429A (en) | Novel heterobicyclic compound for inhibiting yap-tead interaction and pharmaceutical composition comprising same |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A107 | Divisional application of patent |