KR102502940B1 - Novel compounds as autotaxin inhibitors and use thereof - Google Patents
Novel compounds as autotaxin inhibitors and use thereof Download PDFInfo
- Publication number
- KR102502940B1 KR102502940B1 KR1020210169227A KR20210169227A KR102502940B1 KR 102502940 B1 KR102502940 B1 KR 102502940B1 KR 1020210169227 A KR1020210169227 A KR 1020210169227A KR 20210169227 A KR20210169227 A KR 20210169227A KR 102502940 B1 KR102502940 B1 KR 102502940B1
- Authority
- KR
- South Korea
- Prior art keywords
- carboxylate
- dichlorobenzyl
- piperidine
- amino
- methyl
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 64
- 102100021977 Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 Human genes 0.000 title abstract description 32
- 108050004000 Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 Proteins 0.000 title abstract description 31
- 239000003112 inhibitor Substances 0.000 title abstract description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 30
- 150000003839 salts Chemical class 0.000 claims abstract description 29
- 201000010099 disease Diseases 0.000 claims abstract description 23
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 17
- -1 3,5-dichlorobenzyl 4-((4-(2-aminothiazol-5-yl)phenyl)amino)piperidine-1-carboxylate Chemical compound 0.000 claims description 293
- 238000000034 method Methods 0.000 claims description 85
- 125000000217 alkyl group Chemical group 0.000 claims description 27
- 229910052736 halogen Inorganic materials 0.000 claims description 20
- DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 claims description 18
- 230000003287 optical effect Effects 0.000 claims description 17
- 150000002367 halogens Chemical class 0.000 claims description 16
- 229920006395 saturated elastomer Polymers 0.000 claims description 16
- 150000001412 amines Chemical class 0.000 claims description 13
- 125000005842 heteroatom Chemical group 0.000 claims description 12
- 125000000623 heterocyclic group Chemical group 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- 229910052717 sulfur Inorganic materials 0.000 claims description 11
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 206010016654 Fibrosis Diseases 0.000 claims description 9
- 230000004761 fibrosis Effects 0.000 claims description 9
- RFIOZSIHFNEKFF-UHFFFAOYSA-M piperazine-1-carboxylate Chemical compound [O-]C(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-M 0.000 claims description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
- 208000005069 pulmonary fibrosis Diseases 0.000 claims description 9
- 230000002792 vascular Effects 0.000 claims description 9
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 claims description 7
- 208000036971 interstitial lung disease 2 Diseases 0.000 claims description 7
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 230000002265 prevention Effects 0.000 claims description 6
- 125000001072 heteroaryl group Chemical group 0.000 claims description 5
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- 125000000524 functional group Chemical group 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 3
- 208000019425 cirrhosis of liver Diseases 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 2
- 125000006512 3,4-dichlorobenzyl group Chemical group [H]C1=C(Cl)C(Cl)=C([H])C(=C1[H])C([H])([H])* 0.000 claims description 2
- 125000006186 3,5-dimethyl benzyl group Chemical group [H]C1=C(C([H])=C(C([H])=C1C([H])([H])[H])C([H])([H])*)C([H])([H])[H] 0.000 claims description 2
- 208000032056 Radiation Fibrosis Syndrome Diseases 0.000 claims description 2
- 206010039710 Scleroderma Diseases 0.000 claims description 2
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- 125000005843 halogen group Chemical group 0.000 claims 4
- 125000006288 3,5-difluorobenzyl group Chemical group [H]C1=C(F)C([H])=C(C([H])=C1F)C([H])([H])* 0.000 claims 1
- 125000006163 5-membered heteroaryl group Chemical group 0.000 claims 1
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- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 abstract description 19
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- SEDZOYHHAIAQIW-UHFFFAOYSA-N trimethylsilyl azide Chemical compound C[Si](C)(C)N=[N+]=[N-] SEDZOYHHAIAQIW-UHFFFAOYSA-N 0.000 description 11
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- 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
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- 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
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- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
Description
본 발명은 오토탁신(ATX)의 억제제인 화합물에 관한 것이다. 보다 구체적으로 본 발명은 오토탁신 활성 억제 효과를 갖는 신규한 화합물 및 이러한 화합물을 활성 성분으로서 포함하는 약제학적 조성물 및 이의 용도에 관한 것이다.The present invention relates to compounds that are inhibitors of autotaxin (ATX). More specifically, the present invention relates to novel compounds having an autotaxin activity inhibitory effect, pharmaceutical compositions comprising such compounds as active ingredients, and uses thereof.
폐 섬유증(pulmonary fibrosis)은 폐조직이 굳어서 심각한 호흡장애를 불러일으키는 호흡기 질환이다. 폐가 굳는다 함은 섬유질 결합조직의 과다누적을 의미하며 이 과정을 섬유화라고 한다. 섬유화가 진행되면 폐벽이 두꺼워져 혈액에 공급되는 산소량이 줄어든다. 그 결과 환자는 지속적으로 끔찍한 숨가쁨을 느끼게 된다. Pulmonary fibrosis is a respiratory disease in which the lung tissue hardens, causing serious breathing difficulties. Hardening of the lungs means excessive accumulation of fibrous connective tissue, and this process is called fibrosis. As fibrosis progresses, the lung wall thickens, reducing the amount of oxygen supplied to the blood. As a result, the patient has a constant terrible feeling of shortness of breath.
섬유화의 명확한 이유를 진단할 수 있는 환자들도 있지만, 그 원인을 밝혀내지 못하는 경우도 있는데 이런 경우를 특발성 폐 섬유증이라고 한다. 폐 섬유증으로 인해 섬유화가 진행된 폐조직을 복구할 수 있는 방법은 없다. 다만, 약물 치료로 이를 늦출 수는 있기 때문에, 이러한 섬유화를 늦출 수 있는 약물에 대한 수요가 점점 증가하고 있다. Although there are patients who can diagnose a clear cause of fibrosis, there are cases where the cause cannot be identified, and this case is called idiopathic pulmonary fibrosis. Due to pulmonary fibrosis, there is no way to restore fibrotic lung tissue. However, because it can be slowed down by drug treatment, the demand for drugs that can slow down such fibrosis is gradually increasing.
오토탁신(ATX)은 복수 및 혈장에서의 리소포스파티드산(Lysophosphatidic acid, LPA)의 증가의 원인이 되는 효소로, 리소포스파티딜콜린(Lysophosphatidylcholine, LPC)을 생활성 신호화 분자인 리소포스파티드산(LPA)으로 전환하는데 중요한 분비 효소이다. 오토탁신은 엑토뉴클레오티드 피로포스파타제/포스포다이에스터라제 2 또는 리소포스포리파제 D로도 지칭된다.Autotaxin (ATX) is an enzyme that causes an increase in lysophosphatidic acid (LPA) in ascites and plasma. ) is an important secreted enzyme for conversion to Autotaxin is also referred to as ectonucleotide pyrophosphatase/phosphodiesterase 2 or lysophospholipase D.
이러한 오토탁신 및 리소포스파티드산이 폐섬유증 환자의 폐 조직에서 매우 높은 수준으로 발현된 것이 확인되었다. 따라서, 본 발명자들은 오토탁신을 저해하여 생체 내 리소포스파티드산의 수준을 감소시킨다면 이러한 섬유성 질환에 대한 치료적 용도를 제공할 수 있을 것이라는 관점하에 오토탁신을 선택적으로 저해할 수 있는 화합물을 개발하게 되었다.It was confirmed that these autotaxin and lysophosphatidic acid were expressed at very high levels in lung tissue of patients with pulmonary fibrosis. Therefore, the inventors of the present invention developed a compound capable of selectively inhibiting autotaxin with the view that if it inhibits autotaxin to reduce the level of lysophosphatidic acid in vivo, it can provide therapeutic uses for these fibrotic diseases. I did.
또한, ATX-LPA 신호화 축은 예를 들면, 신경계 작용, 혈관 발달, 심혈관 생리, 재생성, 면역계 작용, 만성 염증, 종양 전이 및 진행, 장기 섬유증 및 비만 및/또는 다른 대사성 질병, 예컨대 진성 당뇨병을 비롯한 다양한 범위의 생리학적 및 병리생리학적 작용에 수반된다. 따라서, ATX의 증가된 활성 및/또는 LPA의 증가된 수준, 변화된 LPA 수용체 발현 및 LPA에 대한 변화된 반응은 ATX/LPA 축과 관련된 다양한 상이한 병리생리학적 질환의 개시, 진행 및/또는 결과에 기여할 수 있다. In addition, the ATX-LPA signaling axis includes, for example, nervous system action, vascular development, cardiovascular physiology, regeneration, immune system action, chronic inflammation, tumor metastasis and progression, organ fibrosis and obesity and/or other metabolic diseases such as diabetes mellitus. It is involved in a wide range of physiological and pathophysiological actions. Thus, increased activity of ATX and/or increased levels of LPA, altered LPA receptor expression, and altered response to LPA may contribute to the initiation, progression and/or outcome of a variety of different pathophysiological diseases associated with the ATX/LPA axis. there is.
본 발명의 목적은 오토탁신 저해제로서의 신규 화합물, 이의 광학 이성질체 및 이의 약제학적으로 허용가능한 염을 제공하는 것이다.An object of the present invention is to provide novel compounds, optical isomers thereof and pharmaceutically acceptable salts thereof as autotaxin inhibitors.
본 발명의 다른 목적은 오토탁신 저해제로서의 신규 화합물, 이의 광학 이성질체 및 이의 약제학적으로 허용가능한 염을 유효성분으로 함유하는 오토탁신 활성과 관련된 질환의 예방 또는 치료용 약제학적 조성물을 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical composition for preventing or treating diseases related to autotaxin activity, containing a novel compound as an autotaxin inhibitor, an optical isomer thereof, and a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 또 다른 목적은 오토탁신(ATX) 저해제로서의 신규 화합물, 이의 광학 이성질체 및 이의 약제학적으로 허용가능한 염을 유효성분으로 함유하는 ATX의 활성 및/또는 리소포스파티드산(LPA)의 생물학적 활성에 관련된 장애 또는 질환의 치료 또는 예방, 특히 신장 질환, 간 질환, 염증성 질환, 신경계 질환, 호흡계 질환, 혈관 및 심혈관 질환, 섬유성 질병, 암, 안구 질환, 대사성 질환, 담즙울체성 형태 및 다른 형태의 만성 소양증 및 급성 및 만성 장기 이식 거부반응의 예방 또는 치료용 약제학적 조성물을 제공하는 것이다.Another object of the present invention is a novel compound as an autotaxin (ATX) inhibitor, an optical isomer thereof, and a pharmaceutically acceptable salt thereof containing as an active ingredient the activity of ATX and/or the biological activity of lysophosphatidic acid (LPA). treatment or prevention of disorders or diseases related to, in particular, kidney disease, liver disease, inflammatory disease, nervous system disease, respiratory system disease, vascular and cardiovascular disease, fibrotic disease, cancer, ocular disease, metabolic disease, cholestatic form and other forms To provide a pharmaceutical composition for preventing or treating chronic pruritus and acute and chronic organ transplant rejection.
상기 목적을 달성하기 위해, 본 발명은 하기 화학식 1로 표시되는 화합물, 이의 광학 이성질체 또는 이의 약제학적으로 허용 가능한 염을 제공한다:In order to achieve the above object, the present invention provides a compound represented by Formula 1 below, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
[화학식 1][Formula 1]
여기서, here,
Y는 또는 이고;Y is or ego;
R1 및 R2는 각각 독립적으로, 할로젠, C1-5 알킬, C1-5 알킬옥시, 및 하나 이상의 할로젠으로 치환된 C1-5 알킬로 이루어진 군으로부터 선택되며;R 1 and R 2 are each independently selected from the group consisting of halogen, C 1-5 alkyl, C 1-5 alkyloxy, and C 1-5 alkyl substituted with one or more halogens;
X는 O, -CH2-, NH 및 로 이루어진 군으로부터 선택되고;X is O, -CH 2 -, NH and It is selected from the group consisting of;
A는 N, O 및 S로 이루어진 군으로부터 선택되는 하나 이상의 헤테로 원자를 포함하는 5 내지 6원환의 2가 헤테로지환족 라디칼이며;A is a 5- to 6-membered divalent heteroalicyclic radical containing at least one heteroatom selected from the group consisting of N, O and S;
L1 및 L2는 각각 독립적으로 존재하지 않거나, , , , , , ,,, , , 및 로 이루어진 군으로부터 선택되고;L 1 and L 2 do not exist independently of each other; , , , , , , , , , , and It is selected from the group consisting of;
B는 존재하지 않거나, 6원환의 2가 방향족 라디칼 및 N, O 및 S로 이루어진 군으로부터 선택되는 둘 이상의 헤테로 원자를 포함하는 5 내지 6원환의 2가 헤테로방향족 라디칼로 이루어진 군으로부터 선택되며;B is absent or selected from the group consisting of a 6-membered ring divalent aromatic radical and a 5- to 6-membered ring divalent heteroaromatic radical containing two or more heteroatoms selected from the group consisting of N, O and S;
C는 N, O 및 S로 이루어진 군으로부터 선택되는 둘 이상의 헤테로 원자를 포함하는 5 내지 6원환의 포화 또는 불포화된 헤테로사이클릴이고;C is a 5- to 6-membered saturated or unsaturated heterocyclyl containing two or more heteroatoms selected from the group consisting of N, O and S;
상기 헤테로사이클릴은 하나 이상의 아민, 옥소, C1-5 알킬, C1-5 알킬옥시 및 하나 이상의 할로젠으로 치환된 C1-5 알킬로 이루어진 군으로부터 선택되는 치환기로 추가로 치환되거나 치환되지 않으며;The heterocyclyl is further substituted or unsubstituted with substituents selected from the group consisting of one or more amines, oxo, C 1-5 alkyl, C 1-5 alkyloxy and C 1-5 alkyl substituted with one or more halogens. no;
l, m 및 n은 각각 독립적으로 1 내지 3의 정수이다.l, m and n are each independently an integer of 1 to 3.
본 발명의 또 다른 양태에 따르면, 오토탁신 저해제로서의 신규 화합물, 이의 광학 이성질체 및 이의 약제학적으로 허용가능한 염을 유효성분으로 함유하는 ATX의 활성 및/또는 리소포스파티드산(LPA)의 생물학적 활성에 관련된 장애 또는 질환의 치료 또는 예방, 특히 신장 질환, 간 질환, 염증성 질환, 신경계 질환, 호흡계 질환, 혈관 및 심혈관 질환, 섬유성 질병, 암, 안구 질환, 대사성 질환, 담즙울체성 형태 및 다른 형태의 만성 소양증 및 급성 및 만성 장기 이식 거부반응의 예방 또는 치료용 약제학적 조성물을 제공한다.According to another aspect of the present invention, the novel compound as an autotaxin inhibitor, its optical isomer, and its pharmaceutically acceptable salt containing as an active ingredient the activity of ATX and / or the biological activity of lysophosphatidic acid (LPA) Treatment or prevention of related disorders or diseases, in particular renal disease, liver disease, inflammatory disease, nervous system disease, respiratory system disease, vascular and cardiovascular disease, fibrotic disease, cancer, ocular disease, metabolic disease, cholestatic form and other forms Provided is a pharmaceutical composition for preventing or treating chronic pruritus and acute and chronic organ transplant rejection.
본 발명의 오토탁신 저해제로서의 신규 화합물 및 이의 약제학적으로 허용가능한 염은 오토탁신에 대한 우수한 억제 활성을 제공하여 결과적으로 리소포스파티드산의 생성을 저해하므로 오토탁신의 활성화와 관련된 질환의 치료 또는 예방에 유용하게 사용할 수 있다.The novel compounds and pharmaceutically acceptable salts thereof as autotaxin inhibitors of the present invention provide excellent inhibitory activity against autotaxin and consequently inhibit the production of lysophosphatidic acid, thereby treating or preventing diseases related to autotaxin activation. can be useful for
구체적으로, 본 발명에 따른 화합물을 활성 성분으로 함유한 약제학적 조성물은 ATX의 활성 및/또는 리소포스파티드산(LPA)의 생물학적 활성에 관련된 장애 또는 질환의 치료 또는 예방, 특히 신장 질환, 간 질환, 염증성 질환, 신경계 질환, 호흡계 질환, 혈관 및 심혈관 질환, 섬유성 질병, 암, 안구 질환, 대사성 질환, 담즙울체성 형태 및 다른 형태의 만성 소양증 및 급성 및 만성 장기 이식 거부반응의 예방 또는 치료용으로 유용하게 사용할 수 있다.Specifically, the pharmaceutical composition containing the compound according to the present invention as an active ingredient is used for the treatment or prevention of disorders or diseases related to the activity of ATX and/or the biological activity of lysophosphatidic acid (LPA), particularly kidney disease and liver disease. , for the prevention or treatment of inflammatory diseases, diseases of the nervous system, diseases of the respiratory system, vascular and cardiovascular diseases, fibrotic diseases, cancer, ocular diseases, metabolic diseases, cholestatic and other forms of chronic pruritus and acute and chronic organ transplant rejection can be usefully used.
아래 열거된 정의는 본 발명을 기술하기 위해 사용된 다양한 용어들의 정의이다. 이들 정의는 달리 제한되지 않는 한, 개별적으로 또는 이들을 포함하는 용어의 일부분으로서 본 명세서 전체에 적용된다.The definitions listed below are definitions of various terms used to describe the present invention. These definitions apply throughout this specification, either individually or as part of a term comprising them, unless otherwise limited.
본 명세서에 사용되는 용어 '할로젠'은 다른 언급이 없으면, 플루오르, 염소, 브롬 또는 요오드 혹은 이들 모두 중 어느 하나를 의미한다.As used herein, the term 'halogen' means any one of fluorine, chlorine, bromine or iodine, or both, unless otherwise specified.
본 명세서에 사용되는 용어 '알킬'은 다른 언급이 없으면, CnH2n+1로 표시되는 포화된, 직쇄형 또는 분지형의 탄화수소 라디칼을 지칭하며, 구체적으로 각각 1 내지 6개 사이, 1 내지 8개 사이, 1 내지 10개 사이, 또는 1 내지 20개 사이의 탄소 원자를 포함하는 포화된, 직쇄형 또는 분지형의 탄화수소 라디칼을 지칭한다. 이들 라디칼의 예로는 메틸, 에틸, 프로필, 이소프로필, n-부틸, 터트-부틸, 네오펜틸, n-헥실, 헵틸, 옥틸 라디칼이 포함되지만, 이들로 제한되는 것은 아니다.As used herein, unless otherwise specified, the term 'alkyl' refers to a saturated, straight-chain or branched hydrocarbon radical represented by C n H 2n+1 , specifically between 1 to 6, 1 to 6, respectively. Refers to a saturated, straight-chain or branched hydrocarbon radical containing between 8, between 1 and 10, or between 1 and 20 carbon atoms. Examples of these radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl, and octyl radicals.
본 명세서에 사용되는 용어 '사이클로알킬'은 다른 언급이 없으면 모노사이클릭 또는 폴리사이클릭 포화 또는 부분적으로 불포화된 카보사이클릭 고리 화합물로부터 유래하는 1가 기를 나타낸다. 예를 들어, C3-C6 사이클로알킬의 예시에는, 이로 제한되지는 않지만, 사이클로프로필, 사이클로부틸, 사이클로펜틸 및 사이클로헥실이 포함되고; C3-C12-사이클로알킬의 예시에는, 이로 제한되지는 않지만, 사이클로프로필, 사이클로부틸, 사이클로펜틸, 사이클로헥실, 바이사이클로 [2.2.1] 헵틸, 및 바이사이클로 [2.2.2] 옥틸이 포함된다. As used herein, the term 'cycloalkyl', unless otherwise specified, denotes a monovalent group derived from a monocyclic or polycyclic saturated or partially unsaturated carbocyclic ring compound. For example, examples of C 3 -C 6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; Examples of C 3 -C 12 -cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.1] heptyl, and bicyclo [2.2.2] octyl. do.
본 명세서에 사용되는 용어 '아릴'은 다른 언급이 없으면, 융합 또는 비-융합된 하나 이상의 방향족 고리를 갖는, 모노- 또는 폴리-사이클릭 카르보사이클릭 고리 시스템을 지칭하고, 이로 제한되지는 않지만, 페닐, 나프틸, 테트라하이드로나프틸, 인덴일, 이덴일 등을 포함한다.As used herein, unless otherwise indicated, the term 'aryl' refers to, but is not limited to, a mono- or poly-cyclic carbocyclic ring system having one or more aromatic rings, fused or non-fused; phenyl, naphthyl, tetrahydronaphthyl, indenyl, idenyl, and the like.
본 명세서에 사용되는 용어 '헤테로지환족'은 다른 언급이 없으면 헤테로사이클로알킬기 및 헤테로사이클로알케닐기를 포함한다.As used herein, the term 'heteroalicyclic' includes a heterocycloalkyl group and a heterocycloalkenyl group unless otherwise specified.
본 명세서에 사용되는 용어 '헤테로사이클릴' 또는 '헤테로사이클로알킬'은 다른 언급이 없으면 N, O 및 S 중에서 선택된 1개 이상, 예를 들어 1개 내지 4개의 헤테로 원자를 함유하는 포화 또는 부분적으로 불포화된 3 내지 10원의 모노사이클릭 또는 폴리사이클릭 치환기를 의미한다. 모노사이클릭 헤테로사이클로알킬의 예로는 피페리딘일, 모폴린일, 티아모폴린일, 피롤리딘일, 이미다졸리딘일, 테트라하이드로퓨란일, 피페라진일 및 이와 유사한 그룹을 들 수 있으나 이들로 제한되는 것은 아니다.As used herein, the term 'heterocyclyl' or 'heterocycloalkyl', unless otherwise specified, is a saturated or partially saturated or partially containing at least one heteroatom selected from N, O and S, for example from 1 to 4 heteroatoms. It means an unsaturated 3- to 10-membered monocyclic or polycyclic substituent. Monocyclic heterocycloalkyls include, but are not limited to, piperidinyl, morpholinyl, thiamorpholinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, piperazinyl, and similar groups. it is not going to be
본 명세서에 사용되는 용어 '헤테로아릴'은 다른 언급이 없으면 O, N 및 S 중에서 선택된 1개 이상, 예를 들어 1개 내지 4개의 헤테로원자를 함유하는 5 내지 12원의 모노사이클릭 또는 바이사이클릭 이상의 방향족 그룹을 의미한다. 모노사이클릭 헤테로아릴의 예로는 티아졸일, 옥사졸일, 티오펜일, 퓨란일, 피롤일, 이미다졸일, 이소옥사졸일, 피라졸일, 트리아졸일, 티아디아졸일, 테트라졸일, 옥사디아졸일, 피리딘일, 피리다진일, 피리미딘일, 피라진일 및 이와 유사한 그룹을 들 수 있으나 이들로 제한되는 것은 아니다. 바이사이클릭 헤테로아릴의 예로는 인돌일, 벤조티오펜일, 벤조퓨란일, 벤즈이미다졸일, 벤즈옥사졸일, 벤즈이속사졸일, 벤즈티아졸일, 벤즈티아디아졸일, 벤즈트리아졸일, 퀴놀린일, 이소퀴놀린일, 퓨린일, 퓨로피리딘일 및 이와 유사한 그룹을 들 수 있으나, 이들로 제한되는 것은 아니다.As used herein, unless otherwise specified, the term 'heteroaryl' is a 5 to 12 membered monocyclic or bicyclic containing at least one selected from O, N and S, for example, 1 to 4 heteroatoms. Refers to an aromatic group above a click. Examples of monocyclic heteroaryls include thiazolyl, oxazolyl, thiophenyl, furanyl, pyrrolyl, imidazolyl, isoxazolyl, pyrazolyl, triazolyl, thiadiazolyl, tetrazolyl, oxadiazolyl, pyridine yl, pyridazinyl, pyrimidinyl, pyrazinyl, and similar groups, but are not limited thereto. Examples of bicyclic heteroaryls include indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzthiadiazolyl, benztriazolyl, quinolinyl, isoquinolinyl, purinyl, puropyridinyl and similar groups, but is not limited thereto.
이하, 본 발명을 보다 상세히 설명한다.Hereinafter, the present invention will be described in more detail.
본 발명은 하기 화학식 1로 표시되는 화합물, 이의 광학 이성질체 또는 이의 약제학적으로 허용 가능한 염을 제공한다:The present invention provides a compound represented by Formula 1 below, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
[화학식 1][Formula 1]
여기서,here,
Y는 또는 이고;Y is or ego;
R1 및 R2는 각각 독립적으로, 할로젠, C1-5 알킬, C3-6 사이클로알킬, C1-5 알킬옥시, C6-10 아릴 및 하나 이상의 할로젠으로 치환된 C1-5 알킬로 이루어진 군으로부터 선택되며; R 1 and R 2 are each independently halogen, C 1-5 alkyl, C 3-6 cycloalkyl, C 1-5 alkyloxy, C 6-10 aryl and C 1-5 substituted with one or more halogens. is selected from the group consisting of alkyl;
X는 O, -CH2-, NH 및 로 이루어진 군으로부터 선택되고;X is O, -CH 2 -, NH and It is selected from the group consisting of;
A는 N, O 및 S로 이루어진 군으로부터 선택되는 하나 이상의 헤테로 원자를 포함하는 5 내지 6원환의 2가 헤테로지환족 라디칼이며;A is a 5- to 6-membered divalent heteroalicyclic radical containing at least one heteroatom selected from the group consisting of N, O and S;
L1 및 L2는 각각 독립적으로 존재하지 않거나, , , , , , ,,, , , 및 로 이루어진 군으로부터 선택되고;L 1 and L 2 do not exist independently of each other; , , , , , , , , , , and It is selected from the group consisting of;
B는 존재하지 않거나, 6원환의 2가 방향족 라디칼 및 N, O 및 S로 이루어진 군으로부터 선택되는 둘 이상의 헤테로 원자를 포함하는 5 내지 6원환의 2가 헤테로방향족 라디칼로 이루어진 군으로부터 선택되며;B is absent or selected from the group consisting of a 6-membered ring divalent aromatic radical and a 5- to 6-membered ring divalent heteroaromatic radical containing two or more heteroatoms selected from the group consisting of N, O and S;
C는 N, O 및 S로 이루어진 군으로부터 선택되는 둘 이상의 헤테로 원자를 포함하는 5 내지 6원환의 포화 또는 불포화된 헤테로사이클릴 또는 5 내지 6원환의 헤테로아릴이고;C is a 5- to 6-membered saturated or unsaturated heterocyclyl containing at least two heteroatoms selected from the group consisting of N, O and S or a 5 to 6-membered heteroaryl;
상기 헤테로사이클릴 또는 헤테로아릴은 하나 이상의 아민, 옥소, C1-5 알킬, C1-5 알킬옥시 및 하나 이상의 할로젠으로 치환된 C1-5 알킬로 이루어진 군으로부터 선택되는 치환기로 추가로 치환되거나 치환되지 않으며;wherein said heterocyclyl or heteroaryl is further substituted with a substituent selected from the group consisting of one or more amines, oxo, C 1-5 alkyl, C 1-5 alkyloxy and C 1-5 alkyl substituted with one or more halogens; is not substituted or substituted;
l, m 및 n은 각각 독립적으로 1 내지 3의 정수이다.l, m and n are each independently an integer of 1 to 3.
본 발명의 구체적인 한 실시양태에서, 상기 화학식 1의 Y는 이고; R1 및 R2는 각각 독립적으로, H, 할로젠, C1-5 알킬, C1-5 알콕시 및 하나 이상의 할로젠으로 치환된 C1-5 알킬로 이루어진 군으로부터 선택될 수 있다.In one specific embodiment of the present invention, Y of Formula 1 is ego; R 1 and R 2 may each independently be selected from the group consisting of H, halogen, C 1-5 alkyl, C 1-5 alkoxy, and C 1-5 alkyl substituted with one or more halogens.
본 발명의 구체적인 한 실시양태에서, 상기 화학식 1의 Y는 이고; R1 및 R2는 각각 독립적으로, H, 할로젠, C1-5 알킬, C1-5 알콕시 및 하나 이상의 할로젠으로 치환된 C1-5 알킬로 이루어진 군으로부터 선택될 수 있다.In one specific embodiment of the present invention, Y of Formula 1 is ego; R 1 and R 2 may each independently be selected from the group consisting of H, halogen, C 1-5 alkyl, C 1-5 alkoxy, and C 1-5 alkyl substituted with one or more halogens.
본 발명의 구체적인 한 실시양태에서, 상기 화학식 1의 A는 또는 이다. In one specific embodiment of the present invention, A of Formula 1 is or am.
본 발명의 구체적인 한 실시양태에서, 상기 화학식 1의 B는 존재하지 않거나, , , 및 로 이루어진 군으로부터 선택된다.In one specific embodiment of the present invention, B in Formula 1 does not exist, , , and is selected from the group consisting of
본 발명의 구체적인 한 실시양태에서, 상기 화학식 1의 C는 N, O 및 S로 이루어진 군으로부터 선택되는 둘 이상의 헤테로 원자를 포함하는 5원환의 포화 또는 불포화된 헤테로사이클릴 또는 5 내지 6원환의 헤테로아릴이고, 상기 헤테로사이클릴 또는 헤테로아릴은 C1-5 알킬 또는 아민기로 추가로 치환되거나 치환되지 않을 수 있다.In a specific embodiment of the present invention, C in Formula 1 is a 5-membered saturated or unsaturated heterocyclyl containing two or more hetero atoms selected from the group consisting of N, O and S, or a 5- to 6-membered heterocyclyl. aryl, wherein the heterocyclyl or heteroaryl may be unsubstituted or further substituted with a C 1-5 alkyl or amine group.
본 발명의 구체적인 한 실시양태에서, 상기 화학식 1의 C는 , , , 및 로 이루어진 군으로부터 선택된 작용기(functional group)이고, 상기 작용기는 아미노 또는 C1-5 알킬로 추가로 치환되거나 치환되지 않을 수 있다.In one specific embodiment of the present invention, C of Formula 1 is , , , and A functional group selected from the group consisting of, and the functional group may be further substituted or unsubstituted with amino or C 1-5 alkyl.
본 발명의 구체적인 한 실시양태에서, 상기 화학식 1의 L1은 존재하지 않고, B는 또는 이며, L2는 및 로 이루어진 군으로부터 선택되고, l 및 m은 각각 독립적으로 1 또는 2일 수 있다.In one specific embodiment of the present invention, L 1 of Formula 1 is not present, and B is or , and L 2 is and It is selected from the group consisting of, and l and m may each independently be 1 or 2.
본 발명의 구체적인 한 실시양태에서, 상기 화학식 1의 Y는 이고; R1 및 R2는 각각 독립적으로 할로젠 및 C1-5 알킬로 이루어진 군으로부터 선택되고;In one specific embodiment of the present invention, Y of Formula 1 is ego; R 1 and R 2 are each independently selected from the group consisting of halogen and C 1-5 alkyl;
n은 1이며;n is 1;
X는 O이고;X is O;
A는 또는 이며;A is or is;
L1은 존재하지 않고, L 1 does not exist,
B는 이며,B is is,
L2는 및 로 이루어진 군으로부터 선택되고, L2 is and It is selected from the group consisting of
l 및 m은 각각 독립적으로 1 또는 2이다. l and m are each independently 1 or 2;
본 발명의 구체적인 한 실시양태에서, 상기 화학식 1의 화합물은 아래의 화합물로 이루어진 군으로부터 선택될 수 있으나, 이들로 제한되는 것은 아니다:In a specific embodiment of the present invention, the compound of Formula 1 may be selected from the group consisting of the following compounds, but is not limited thereto:
3,5-Dichlorobenzyl 4-((4-(2-aminothiazol-5-yl)phenyl)amino)piperidine-1-carboxylate
3,5-dichlorobenzyl 4-((4-(1 H -imidazol-5-yl)phenyl)amino)piperidine-1-carboxylate
3,5-디클로로벤질 4-(2-(4-(1H-이미다졸-5-일)피페리딘-1-일)에틸)피페라진-1-카복실레이트
3,5-dichlorobenzyl 4-(2-(4-(1 H -imidazol-5-yl)piperidin-1-yl)ethyl)piperazine-1-carboxylate
본 발명의 구체적인 한 실시양태에서, 오토탁신 저해제로서의 신규 화합물, 이의 광학 이성질체 및 이의 약제학적으로 허용가능한 염을 유효성분으로 함유하는 ATX의 활성 및/또는 리소포스파티드산(LPA)의 생물학적 활성에 관련된 장애 또는 질환의 치료 또는 예방, 특히 신장 질환, 간 질환, 염증성 질환, 신경계 질환, 호흡계 질환, 혈관 및 심혈관 질환, 섬유성 질병, 암, 안구 질환, 대사성 질환, 담즙울체성 형태 및 다른 형태의 만성 소양증 및 급성 및 만성 장기 이식 거부반응의 예방 또는 치료용 약제학적 조성물이 제공된다.In one specific embodiment of the present invention, the novel compound as an autotaxin inhibitor, its optical isomer and its pharmaceutically acceptable salt containing as an active ingredient the activity of ATX and / or the biological activity of lysophosphatidic acid (LPA) Treatment or prevention of related disorders or diseases, in particular renal disease, liver disease, inflammatory disease, nervous system disease, respiratory system disease, vascular and cardiovascular disease, fibrotic disease, cancer, ocular disease, metabolic disease, cholestatic form and other forms A pharmaceutical composition for preventing or treating chronic pruritus and acute and chronic organ transplant rejection is provided.
또한, 본 발명의 구체적인 한 실시양태에서, 오토탁신(ATX)의 활성을 억제하는 약제학적으로 유효한 양의 제1항에 따른 화합물을 포유류에 투여하는 것을 포함하는 오토탁신(ATX)의 활성 및/또는 리소포스파티드산(LPA)의 생물학적 활성에 관련된 장애 또는 질환을 치료하는 방법이 제공된다.In addition, in one specific embodiment of the present invention, the activity of autotaxin (ATX) and / or a disorder or disease related to the biological activity of lysophosphatidic acid (LPA).
신장 질환은 비제한적으로 급성 신부전, 및 단백뇨를 동반하거나 동반하지 않는 만성 신장병(말기 신장병 포함(ESRD))을 포함한다. 보다 상세히, 신장 질환은 감소된 크레아니틴 청소율 및 감소된 사구체 여과율, 미세알부민뇨, 알부민뇨 및 단백뇨, 유의한 세포과다를 갖거나 갖지 않는 망상 혈관간 기질의 팽창을 갖는 사구체 경화증(특히 당뇨병성 신장증 및 아밀로이드증), 사구체 모세관의 초점 혈전증(특히 혈전성 미세혈관증), 전반적인 섬유성 괴사, 허혈성 병변, 악성 신장 경화증(예컨대, 허혈성 수축, 감소된 신장 혈류량 및 신장 동맥질환), 모세혈관 내(내피 및 혈관사이) 및/또는 모세혈관 외 세포(반월체)의 부종 및 증식, 예컨대 사구체 신염 개체, 초점성 분절 사구체 경화증, IgA 신증, 혈관염/전신병 뿐만 아니라 급성 및 만성 신장 이식 거부반응을 포함하지만 이에 제한되는 것은 아니다.Renal disease includes, but is not limited to, acute renal failure, and chronic kidney disease with or without proteinuria (including end-stage renal disease (ESRD)). More specifically, renal disease is characterized by glomerulosclerosis (particularly diabetic nephropathy and diabetic nephropathy and amyloidosis), focal thrombosis of the glomerular capillaries (particularly thrombotic microangiopathy), global fibrotic necrosis, ischemic lesions, malignant renal sclerosis (e.g., ischemic contracture, reduced renal blood flow, and renal arterial disease), intracapillary (endothelial and edema and proliferation of intervascular) and/or extracapillary cells (hemis) including, but not limited to, glomerulonephritis entities, focal segmental glomerulosclerosis, IgA nephropathy, vasculitis/systemic diseases as well as acute and chronic kidney transplant rejection. it is not going to be
간 질환은 비제한적으로 간 경화증, 간 출혈, 담즙울체성 간 질환, 예컨대 소양증, 비알코올성 지방간염 및 급성 및 만성 간 이식 거부반응을 포함하지만 이에 제한되는 것은 아니다.Liver disease includes, but is not limited to, liver cirrhosis, hepatic hemorrhage, cholestatic liver disease such as pruritus, non-alcoholic steatohepatitis, and acute and chronic liver transplant rejection.
염증성 질환은 비제한적으로 관절염, 골관절염, 다발성 경화증, 전신 홍반성 낭창, 염증성 장 질병, 이상 배설 장애 등뿐만 아니라 염증성 기도 질병, 예컨대 특발성 폐 섬유증(IPF), 만성 폐쇄성 폐 질환(COPD) 또는 만성 기관지 천식을 포함하지만 이에 제한되는 것은 아니다.Inflammatory diseases include, but are not limited to, arthritis, osteoarthritis, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, abnormal excretory disorders, and the like, as well as inflammatory airway diseases such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) or chronic bronchial tuberculosis. including but not limited to asthma.
또한, 호흡계 질환은 비제한적으로 상이한 병인의 다른 미만성 간질성 폐 질환, 예컨대 의원성 약물-유도 섬유증, 직업적 및/또는 환경적 유도된 섬유증, 전신병 및 혈관염, 육아종성 질병(유육종증, 과민성 폐렴), 콜라겐 혈관 질병, 폐포 단백질증, 랑게르한스 세포 육아종증, 림프관평활근종증, 유전병(헤르만스키-푸드락(Hermansky-Pudlak) 증후군, 결정성 결화증, 신경섬유종증, 대사 축적병, 가족성 간질성 폐 질병), 방사선 유발 섬유증, 규폐증, 석면 유도된 폐 섬유증 또는 급성 호흡곤란 증후군(ARDS)을 포함하지만 이에 제한되는 것은 아니다.In addition, diseases of the respiratory system include, but are not limited to, other diffuse interstitial lung diseases of different etiologies, such as iatrogenic drug-induced fibrosis, occupationally and/or environmentally induced fibrosis, systemic diseases and vasculitis, granulomatous diseases (sarcomatosis, hypersensitivity pneumonitis), Collagen Vascular Disease, Alveolar Proteinosis, Langerhans Cell Granulomatosis, Lymphangioleiomyomatosis, Hereditary Diseases (Hermansky-Pudlak Syndrome, Crystalline Crystallosis, Neurofibromatosis, Metabolic Storage Disease, Familial Interstitial Lung Disease) , radiation-induced fibrosis, silicosis, asbestos-induced pulmonary fibrosis, or acute respiratory distress syndrome (ARDS).
신경계 질환은 비제한적으로 신경성 동통, 정신 분열증, 신경세포염증(예컨대, 성상교세포증), 말초 및/또는 자율신경 (당뇨병성) 신경장애 등을 포함하지만 이에 제한되는 것은 아니다.Nervous system disorders include, but are not limited to, neurogenic pain, schizophrenia, neuroinflammation (eg, astrocytosis), peripheral and/or autonomic (diabetic) neuropathy, and the like.
혈관 질환은 비제한적으로 아테롬성 동맥 경화증, 혈관 혈전 질환뿐만 아니라 혈전성 미세혈관증, 증식성 동맥병증(예컨대, 점액성 세포외 기질을 둘러싼 팽창된 근내막 세포 및 결절성 농밀화), 아테롬성 동맥 경화증, 감소된 혈관 탄성(예컨대, 강성, 감소된 심실 탄성 및 감소된 혈관 탄성), 내피 기능장애 등을 포함하지만 이에 제한되는 것은 아니다.Vascular diseases include, but are not limited to, atherosclerosis, vascular thrombotic diseases as well as thrombotic microangiopathy, proliferative arteriopathy (e.g., dilated endomyosclerosis and nodular densification surrounding mucous extracellular matrix), atherosclerosis, reduced vascular elasticity (eg, stiffness, reduced ventricular elasticity and reduced vascular elasticity), endothelial dysfunction, and the like.
심혈관 질환은 비제한적으로 급성 관동맥 증후군, 관동맥성 심장병, 심근 경색, 동맥 및 폐 고혈압, 심장 부정맥, 예컨대 심박 세동, 뇌졸중 및 다른 혈관 손상을 포함하지만 이에 제한되는 것은 아니다.Cardiovascular disease includes, but is not limited to, acute coronary syndrome, coronary heart disease, myocardial infarction, arterial and pulmonary hypertension, cardiac arrhythmias such as atrial fibrillation, stroke and other vascular damage.
섬유성 질병은 비제한적으로 심근 및 혈관 섬유증, 신장 섬유증, 간 섬유증, 폐 섬유증, 피부 섬유증, 경피증 및 포낭성 복막염을 포함하지만 이에 제한되는 것은 아니다. 구체적으로, 폐 섬유증은 특발성 폐 섬유증(IPF) 및 만성 폐쇄성 폐 질환(COPD)일 수 있다.Fibrotic diseases include, but are not limited to, myocardial and vascular fibrosis, renal fibrosis, liver fibrosis, pulmonary fibrosis, skin fibrosis, scleroderma, and cystic peritonitis. Specifically, pulmonary fibrosis can be idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD).
본 발명에 따른 화학식 1의 화합물은 무기산 또는 유기산이 부가된 약학적으로 허용가능한 염 형태로 제조될 수 있으며, 이때 바람직한 염으로는 염산, 브롬화수소산, 황산, 인산, 질산, 아세트산, 글리콜산, 락트산, 피루브산, 말론산, 석신산, 글루타르산, 푸마르산, 말산, 만델산, 타르타르산, 시트르산, 아스코르브산, 팔미트산, 말레산, 하이드록시말레산, 벤조산, 하이드록시벤조산, 페닐아세트산, 신남산, 살리실산, 메탄술폰산, 벤젠술폰산 또는 톨루엔술폰산 등으로부터 유도된 염을 들 수 있다.The compound of formula 1 according to the present invention can be prepared in the form of a pharmaceutically acceptable salt to which an inorganic acid or an organic acid is added, and preferred salts include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, and lactic acid. , pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid , salts derived from salicylic acid, methanesulfonic acid, benzenesulfonic acid or toluenesulfonic acid and the like.
구체적으로는 본 발명에 따른 약제학적으로 허용가능한 염은, 화학식 1의 화합물을 유기용매, 예를 들면 아세톤, 메탄올, 에탄올, 또는 아세토나이트릴 등에 녹이고 유기산 또는 무기산을 가하여 침전된 결정을 여과하여 제조한다. 또는 산이 부가된 반응 혼합물에서 용매나 과량의 산을 감압하여, 잔사를 건조시켜서 제조하거나, 또는 다른 유기용매를 가하여 석출된 염을 여과하여 제조할 수 있다.Specifically, the pharmaceutically acceptable salt according to the present invention is prepared by dissolving the compound of Formula 1 in an organic solvent, such as acetone, methanol, ethanol, or acetonitrile, and filtering the precipitated crystals by adding an organic or inorganic acid. do. Alternatively, it may be prepared by reducing the solvent or excess acid in the reaction mixture to which acid is added and drying the residue, or by filtering a precipitated salt by adding another organic solvent.
본 발명에 따른 화학식 1의 화합물 또는 이의 약학적으로 허용가능한 염은 수화물 또는 용매화물의 형태일 수 있으며, 그러한 화합물 역시 본 발명에 포함된다. The compound of Formula 1 or a pharmaceutically acceptable salt thereof according to the present invention may be in the form of a hydrate or solvate, and such compounds are also included in the present invention.
또한, 본 발명은 약제학적으로 허용 가능한 담체 및 약제학적으로 유효한 양의 상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체 또는 이의 약제학적으로 허용 가능한 염을 활성 성분으로 함유하는 약제학적 조성물을 제공한다.본 발명의 구체적인 일 실시 양태에서, 약제학적으로 유효한 양의 상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체 또는 이의 약제학적으로 허용 가능한 염을 활성 성분으로 함유하는 약제학적 조성물에 하나 이상의 약제학적으로 허용가능한 계면 활성제, 추가적인 담체, 희석제, 부형제, 평활화제(smoothing agent), 현탁제, 필름 형성 물질(film forming substance), 및 코팅 보조제(coating assistant) 등을 추가로 포함하는 약제학적 조성물이 제공된다.In addition, the present invention provides a pharmaceutical composition containing a pharmaceutically acceptable carrier and a pharmaceutically effective amount of the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. In a specific embodiment of the present invention, at least one pharmaceutically acceptable pharmaceutical composition containing a pharmaceutically effective amount of the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient A pharmaceutical composition is provided which further comprises possible surfactants, additional carriers, diluents, excipients, smoothing agents, suspending agents, film forming substances, coating assistants and the like.
본원에 사용된 용어 "약제학적으로 허용가능한 담체" 는 인산염 완충 염류 용액, 물, 유화액(예를 들어, 오일/물 또는 물/오일 유화액) 및 다양한 종류의 습윤제와 같은 임의의 표준 약제학적 담체를 말한다. 상기 조성물은 또한 안정화제 및 보존제를 포함할 수 있다. 담체, 안정화제 및 보조제의 예는 문헌[Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA, 1975]에 언급되어 있다.As used herein, the term “pharmaceutically acceptable carrier” refers to any standard pharmaceutical carrier such as phosphate buffered saline solutions, water, emulsions (eg, oil/water or water/oil emulsions) and wetting agents of various types. say The composition may also contain stabilizers and preservatives. Examples of carriers, stabilizers and adjuvants are described in Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA, 1975.
본 발명에 따른 약제학적 조성물이 경구제형의 형태로 제조되는 경우, 사용되는 담체의 예로는 셀룰로오스, 규산칼슘, 옥수수전분, 락토오스, 수크로스, 덱스트로스, 인산칼슘, 스테아르산, 스테아르산 마그네슘, 스테아르산 칼슘, 젤라틴, 탈크, 계면활성제, 현탁제, 유화제, 희석제 등을 들 수 있다. 본 발명에 따른 약제학적 조성물이 주사제의 형태로 제조되는 경우, 상기 담체로는 물, 식염수, 포도당 수용액, 유사 당 수용액, 알콜, 글리콜, 에테르(예: 폴리에틸렌글리콜 400), 오일, 지방산, 지방산에스테르, 글리세라이드, 계면활성제, 현탁제, 유화제 등을 사용할 수 있다.When the pharmaceutical composition according to the present invention is prepared in the form of an oral dosage form, examples of carriers used include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, and stearic acid. Calcium acid, gelatin, talc, surfactant, suspending agent, emulsifying agent, diluent, etc. are mentioned. When the pharmaceutical composition according to the present invention is prepared in the form of an injection, the carrier includes water, saline, glucose aqueous solution, analog sugar aqueous solution, alcohol, glycol, ether (eg polyethylene glycol 400), oil, fatty acid, fatty acid ester , glycerides, surfactants, suspending agents, emulsifying agents and the like can be used.
용어 "희석제(diluent)"는 목적 조성물을 용해시키고 화합물의 생물학적 활성 형태를 안정화시킬 물에 희석된 화합물을 의미한다. 완충용액에 용해된 염이 당해 분야에서 희석제로 이용된다. 통상적으로 사용되는 완충용액은 인산염 완충 염수(phosphate buffered saline)이고, 이는 인간 혈액의 염 조건을 모사하기 때문이다. 완충염(buffer salt)은 낮은 농도에서 용액의 pH를 조절할 수 있기 때문에, 완충된 희석제는 화합물의 생물학적 활성을 거의 변화시키지 않는다.The term "diluent" means a compound diluted in water that will dissolve the desired composition and stabilize the biologically active form of the compound. A salt dissolved in a buffer solution is used as a diluent in the art. A commonly used buffer solution is phosphate buffered saline because it simulates the salt conditions of human blood. Because buffer salts can adjust the pH of a solution at low concentrations, buffered diluents hardly change the biological activity of the compound.
본 명세서에서 사용된, "부형제(excipient)"는 조성물에 벌크(bulk), 농도(consistency), 안정성, 결합 능력(binding ability), 윤활, 붕해 능력 등을 포함하나, 이에 한정되지 않는 특성을 제공하기 위해 조성물에 첨가되는 비활성 물질을 의미한다. "희석제(dilunet)"는 부형제의 일종이다.As used herein, "excipient" provides properties to a composition, including but not limited to bulk, consistency, stability, binding ability, lubrication, disintegration ability, and the like. means an inactive substance added to the composition for A "dilunet" is a type of excipient.
또한, 보존제, 안정제, 염료, 감미제, 방향제(fragrance), 향미제(flavoring agent) 등이 본원 발명의 약제학적 조성물 중에 제공될 수 있다. 예를 들면, 소디움 벤조에이트, 아스코르브산 및 p-히드록시벤조산의 에스테르가 보존제로서 첨가될 수 있다. 또한, 항산화제 및 현탁제가 이용될 수 있다. 다양한 구체예에서, 알코올, 에스테르, 황산화 지방족 알코올(sulfated aliphatic alcohol) 등이 계면 활성제로 이용될 수 있고; 수크로오스, 글루코오스, 락토오스, 전분, 미정질 셀룰로오스, 결정화된 셀룰로오스, 만니톨, 연한 무수 실리케이트(light anhydrous silicate), 마그네슘 알루미네이트, 마그네슘 메타실리케이트 알루미네이트, 합성 알루미늄 실리케이트, 탄산칼슘, 탄산나트륨(sodium acid carbonate), 인산수소칼슘(calcium hydrogen phosphate), 칼슘 카르복시메틸 셀룰로오스 등이 부형제로 사용될 수 있으며; 마그네슘 스테아레이트, 활석, 경화유(hardened oil) 등이 평활화제로 사용될 수 있고; 코코넛 오일, 올리브 오일, 참기름(sesame oil), 땅콩유(peanut oil), 대두유(soya)가 현탁제 또는 윤활제로 사용될 수 있으며; 셀룰로오스 또는 당과 같은 탄수화물의 유도체로서, 셀룰로오스 아세테이트 프탈레이트, 또는 폴리비닐 유도체로서, 메틸아세테이트-메타크릴레이트 공중합체가 현탁제로 사용될 수 있고; 에스테르 프탈레이트 등과 같은 가소제가 현탁제로 이용될 수 있다.In addition, preservatives, stabilizers, dyes, sweeteners, fragrances, flavoring agents and the like may be provided in the pharmaceutical composition of the present invention. For example, sodium benzoate, ascorbic acid and esters of p-hydroxybenzoic acid may be added as preservatives. In addition, antioxidants and suspending agents may be used. In various embodiments, alcohols, esters, sulfated aliphatic alcohols, and the like may be used as surfactants; Sucrose, glucose, lactose, starch, microcrystalline cellulose, crystallized cellulose, mannitol, light anhydrous silicate, magnesium aluminate, magnesium metasilicate aluminate, synthetic aluminum silicate, calcium carbonate, sodium acid carbonate , calcium hydrogen phosphate, calcium carboxymethyl cellulose, etc. may be used as excipients; Magnesium stearate, talc, hardened oil and the like can be used as leveling agents; Coconut oil, olive oil, sesame oil, peanut oil, soya oil may be used as a suspending agent or lubricant; As a derivative of carbohydrates such as cellulose or sugar, cellulose acetate phthalate, or as a polyvinyl derivative, methyl acetate-methacrylate copolymer can be used as a suspending agent; Plasticizers such as ester phthalates and the like can be used as suspending agents.
본 명세서에 사용된 바와 같이, 본 발명에 따른 화합물의 "약제학적 유효량" 또는 "치료학적 유효량"은 대상에게서 증상 또는 장애를 감소시키기에 충분한 화합물의 양을 의미한다. 의학 분야에서 잘 이해되는 바와 같이, 본 발명에 따른 화합물의 약제학적 또는 치료학적 유효량은 임의의 의학적 치료에 적용가능한 합리적인 유익/유해 비율일 것이다.As used herein, a “pharmaceutically effective amount” or “therapeutically effective amount” of a compound according to the present invention refers to an amount of the compound sufficient to reduce a symptom or disorder in a subject. As is well understood in the medical arts, a pharmaceutically or therapeutically effective amount of a compound according to the present invention will be at a reasonable benefit/risk ratio applicable to any medical treatment.
본 발명에 따른 화학식 1의 화합물 또는 이의 약학적으로 허용가능한 염 등의 투여량은, 처리되는 대상, 질병 또는 상태의 심각도, 투여의 속도 및 처방 의사의 판단에 따라 다를 수 있으나, 통상 화학식 1의 화합물을 사람에게 활성성분으로서 체중 70 kg 기준시 하루 0.1 내지 2,000 ㎎, 바람직하게는 1 내지 1,000 ㎎의 양으로 1일 1 내지 4회 또는 온/오프(on/off) 스케줄로 경구 또는 비경구적 경로를 통해 투여될 수 있다. 일부 경우에 있어서, 상기 언급된 범위 보다 적은 투여량이 보다 적합할 수도 있고, 해로운 부작용을 일으키지 않으면서도 보다 많은 투여량이 사용될 수도 있으며, 보다 많은 투여량의 경우는 하루에 걸쳐 수회의 적은 투여량으로 분배된다.The dosage of the compound of Formula 1 or a pharmaceutically acceptable salt thereof according to the present invention may vary depending on the subject to be treated, the severity of the disease or condition, the speed of administration, and the judgment of the prescribing physician, but is usually Oral or parenteral route of the compound as an active ingredient for humans in an amount of 0.1 to 2,000 mg, preferably 1 to 1,000 mg per day based on body weight of 70 kg, 1 to 4 times a day or on an on / off schedule can be administered through In some cases, doses lower than the above-mentioned ranges may be more suitable, and larger doses may be used without adverse side effects, with larger doses divided into several smaller doses throughout the day. do.
본 발명에 따른 약제학적 조성물은 통상적인 방법에 따라 제제화할 수 있으며, 정제, 환제, 산제, 캅셀제, 시럽, 에멀젼, 마이크로에멀젼 등의 다양한 경구 투여 형태로, 또는 근육내, 정맥내 또는 피하투여와 같은 비경구 투여 형태로 제조될 수 있다.The pharmaceutical composition according to the present invention can be formulated according to a conventional method, and can be administered in various oral dosage forms such as tablets, pills, powders, capsules, syrups, emulsions, microemulsions, or intramuscular, intravenous or subcutaneous administration. The same parenteral dosage form can be prepared.
이하, 본 발명을 실시예에 의해 상세히 설명한다. 단, 하기 실시예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실시예에 의해 한정되는 것은 아니다.Hereinafter, the present invention will be described in detail by examples. However, the following examples are only to illustrate the present invention, and the content of the present invention is not limited by the following examples.
제법 1. 빌딩 블럭 A-E의 합성.Preparation 1. Synthesis of Building Blocks A-E.
시약 및 조건:(a) 티오우레아, EtOH, reflux, 2 h;(b)(Boc)2O, DMAP, THF, 90 ℃, 2 h;(c) H2, Pd/C 10%, MeOH, THF, 8 h;(d) 포름아미드, 150 ℃, 24 h;(e) NaH, CH3I, DMF, 6 h;(f) 아세트아미드, 180 ℃, 18 h;(g) HNO3(conc.), H2SO4(conc.), 0 ℃ to r.t. to 60 ℃, 4 h;(h) Br2, AcOH, 30 ℃, 18 h;(i) 트리포스젠, Et3N, THF, 12 h;(j) Me3SiN3, CuI, DMF, MeOH, 100 ℃, 12h. Reagents and conditions : (a) thiourea, EtOH, reflux, 2 h; (b) (Boc) 2 O, DMAP, THF, 90 °C, 2 h; (c) H 2 , Pd/C 10%, MeOH, THF, 8 h; (d) Formamide, 150 °C, 24 h; (e) NaH, CH 3 I, DMF, 6 h; (f) Acetamide, 180 °C, 18 h; (g) HNO 3 (conc .), H 2 SO 4 (conc.), 0 ℃ to rt to 60 ℃, 4 h; (h) Br 2 , AcOH, 30 ℃, 18 h; (i) Triphosgene, Et 3 N, THF, 12 h; (j) Me 3 SiN 3 , CuI, DMF, MeOH, 100° C., 12 h.
NONO 22 - 환원을 위한 일반적인 공정 A.- General process for reduction A.
둥근바닥플라스크에서 MeOH/THF(10 mL/10 mL) 중 나이트로-아릴 유도체(2.00 mmol) 혼합물에 팔라듐 온 카본(10% wt)(84 mg)을 실온에서 첨가하였다. 반응 혼합물을 수소 가스 대기 하에 실온에서 격렬히 교반하였다. 혼합물을 celite®를 통해 여과시키고 여과액을 농축하였다. 잔여물을 컬럼 크로마토그래피(에틸 아세테이트/헥산)에 의해 정제하여 아닐린을 얻었다.To a mixture of the nitro-aryl derivative (2.00 mmol) in MeOH/THF (10 mL/10 mL) in a round bottom flask was added palladium on carbon (10% wt) (84 mg) at room temperature. The reaction mixture was vigorously stirred at room temperature under a hydrogen gas atmosphere. The mixture was filtered through celite® and the filtrate was concentrated. The residue was purified by column chromatography (ethyl acetate/hexane) to give aniline.
이미다졸 고리 형성을 위한 일반적인 공정 B.General process for imidazole ring formation B.
2-브로모-아세토페논(5.00 mmol) 및 포름아미드(10 mL)의 혼합물을 150 ℃에서 24 h 동안 가열하였다. 냉각 후, 혼합물을 포화된 NaHCO3 용액에 부었다. 유기물을 에틸 아세테이트로 추출하고, 무수 Na2SO4로 건조시키고 농축시켰다. 생성물을 컬럼 크로마토그래피(CH2Cl2/MeOH)로 정제하여 목적한 이미다졸을 얻었다.A mixture of 2-bromo-acetophenone (5.00 mmol) and formamide (10 mL) was heated at 150 °C for 24 h. After cooling, the mixture was poured into saturated NaHCO 3 solution. The organics were extracted with ethyl acetate, dried over anhydrous Na 2 SO 4 and concentrated. The product was purified by column chromatography (CH 2 Cl 2 /MeOH) to obtain the desired imidazole.
5-(4-나이트로페닐)-1,3,4-티아다이아졸-2-아민(1a).5-(4-nitrophenyl)-1,3,4-thiadiazol-2-amine (1a).
에탄올(10 mL) 중 2-브로모-4' 나이트로아세토페논(2.44 g, 10.00 mmol) 및 티오우레아(0.91 g, 12.00 mmol)의 혼합물을 2시간 동안 환류시켰다. 냉각 후, 용매를 농축시키고 크루드 생성물을 컬럼 크로마토그래피(CH2Cl2/MeOH)로 정제하여 황색 고체로 1a(1.81 g, 81.8%)를 얻었다.A mixture of 2-bromo-4' nitroacetophenone (2.44 g, 10.00 mmol) and thiourea (0.91 g, 12.00 mmol) in ethanol (10 mL) was refluxed for 2 hours. After cooling, the solvent was concentrated and the crude product was purified by column chromatography (CH 2 Cl 2 /MeOH) to give 1a (1.81 g, 81.8%) as a yellow solid.
1H NMR(400 MHz, DMSO-d 6) δ 8.19(d, J = 8.9 Hz, 2H), 8.00(d, J = 9.0 Hz, 2H), 7.36(s, 1H), 7.19(s, 2H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.19 (d, J = 8.9 Hz, 2H), 8.00 (d, J = 9.0 Hz, 2H), 7.36 (s, 1H), 7.19 (s, 2H) .
tt -부틸(tert-부톡시카보닐)(5-(4-나이트로페닐)티아졸-2-일)카바메이트(2a).-Butyl(tert-butoxycarbonyl)(5-(4-nitrophenyl)thiazol-2-yl)carbamate (2a).
테트라하이드로푸란(20 mL) 중 1a(1.11 g, 5.00 mmol), 4-(디메틸아미노)피리딘(61.09 mg, 0.50 mmol)을 둥근바닥플라스크에 넣고 테트라하이드로푸란(10.91 g, 15.00 mmol) 중 디-tert-부틸 디카보네이트 30%를 상기 혼합물에 실온에서 첨가하였다. 반응 혼합물을 40 ℃에서 2 h 동안 가열한 후 2h 동안 환류시켰다. 용액을 농축시키고 잔여물을 컬럼 크로마토그래피(에틸아세테이트/헥산)로 정제하여 밝은 황색 고체(정량적)로서 2a를 얻었다.To a round bottom flask was placed 1a (1.11 g, 5.00 mmol), 4-(dimethylamino)pyridine (61.09 mg, 0.50 mmol) in tetrahydrofuran (20 mL) and di- tert-Butyl dicarbonate 30% was added to the mixture at room temperature. The reaction mixture was heated at 40 °C for 2 h and then refluxed for 2 h. The solution was concentrated and the residue was purified by column chromatography (ethyl acetate/hexane) to give 2a as a light yellow solid (quantitative).
1H NMR(400 MHz, CDCl3) δ 8.25(d, J = 9.0 Hz, 2H), 7.98(d, J = 9.0 Hz, 2H), 7.45(s, 1H), 1.59(s, 18H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.25 (d, J = 9.0 Hz, 2H), 7.98 (d, J = 9.0 Hz, 2H), 7.45 (s, 1H), 1.59 (s, 18H).
tt -부틸(tert-부톡시카보닐)(5-(3-나이트로페닐)티아졸-2-일)카바메이트(2b).-Butyl(tert-butoxycarbonyl)(5-(3-nitrophenyl)thiazol-2-yl)carbamate (2b).
1a에 대한 공정에 따라, 2-브로모-3' 나이트로아세토페논(2.44 g, 10.00 mmol)을 사용하여, 화합물(1b)를 황색 고체(1.81 g, 82.0%)로서 제조하였고 2a에 대한 하기 공정에 의해 1b(1.11 g, 5.00 mmol)를 사용하고 Boc-보호기를 도입하여 2b를 밝은 황색 고체(정량적)로 얻었다.Following the process for 1a , Compound (1b ) was prepared as a yellow solid (1.81 g, 82.0%) using 2-bromo-3' nitroacetophenone (2.44 g, 10.00 mmol) and obtained by the following procedure for 2a to obtain 1b ( 1.11 g). , 5.00 mmol) and introducing a Boc-protecting group to obtain 2b Obtained as a light yellow solid (quantitative).
1H NMR(400 MHz, CDCl3) δ 8.72(dd, J = 2.2, 1.7 Hz, 1H), 8.17 - 8.10(m, 2H), 7.58 - 7.52(m, 1H), 7.39(s, 1H), 1.60(s, 18H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.72 (dd, J = 2.2, 1.7 Hz, 1H), 8.17 - 8.10 (m, 2H), 7.58 - 7.52 (m, 1H), 7.39 (s, 1H), 1.60 (s, 18H).
tt -부틸(5-(4-아미노페닐)티아졸-2-일)(tert-부톡시카보닐)카바메이트(3a).-Butyl(5-(4-aminophenyl)thiazol-2-yl)(tert-butoxycarbonyl)carbamate (3a).
일반적인 공정 A에 따라, 2a(2.00 mmol)를 사용하여 3a를 흰색 고체(0.71 g, 90.4%)로 얻었다.Following General Procedure A, 2a (2.00 mmol) was used to obtain 3a as a white solid (0.71 g, 90.4%).
1H NMR(400 MHz, CDCl3) δ 7.64(d, J = 8.6 Hz, 2H), 7.06(s, 1H), 6.70(d, J = 8.6 Hz, 2H), 3.74(s, 2H), 1.54(s, 18H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.64 (d, J = 8.6 Hz, 2H), 7.06 (s, 1H), 6.70 (d, J = 8.6 Hz, 2H), 3.74 (s, 2H), 1.54 (s, 18H).
tt -부틸(5-(3-아미노페닐)티아졸-2-일)(tert-부톡시카보닐)카바메이트(3b).-Butyl(5-(3-aminophenyl)thiazol-2-yl)(tert-butoxycarbonyl)carbamate (3b).
일반적인 공정 A에 따라, 2b(0.84 g, 2.00 mmol)를 사용하여 3b를 흰색 고체(0.53 g, 67.2%)로 얻었다.Following General Procedure A, 2b ( 0.84 g, 2.00 mmol) was used to obtain 3b as a white solid (0.53 g, 67.2%).
1H NMR(400 MHz, CDCl3) δ 7.28 - 7.14(m, 4H), 6.69 - 6.61(m, 1H), 3.70(s, 2H), 1.54(s, 18H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.28 - 7.14 (m, 4H), 6.69 - 6.61 (m, 1H), 3.70 (s, 2H), 1.54 (s, 18H).
5-(4-나이트로페닐)-15-(4-nitrophenyl)-1 HH -이미다졸(4a).-imidazole (4a).
일반적인 공정 B에 따라, 2-브로모-4' 나이트로아세토페논(1.22 g, 5.00 mmol)을 사용하여 4a를 갈색 고체(0.50 g, 52.9%)로 얻었다.Following General Procedure B, 4a was obtained as a brown solid (0.50 g, 52.9%) using 2-bromo-4' nitroacetophenone (1.22 g, 5.00 mmol).
1H NMR(400 MHz, DMSO-d 6) δ 12.47(s, 1H), 8.23(d, J = 8.7 Hz, 2H), 8.04(d, J = 8.5 Hz, 2H), 7.95(s, 1H), 7.83(s, 1H). 1H NMR (400 MHz, DMSO- d6 ) δ 12.47 (s, 1H) , 8.23 (d, J = 8.7 Hz, 2H), 8.04 (d, J = 8.5 Hz, 2H), 7.95 (s, 1H) , 7.83(s, 1H).
5-(3-나이트로페닐)-15-(3-nitrophenyl)-1 HH -이미다졸(4b).-imidazole (4b).
일반적인 공정 B에 따라, 2-브로모-3' 나이트로아세토페논(1.22 g, 5.00 mmol)을 사용하여 4b를 갈색 고체(0.52 g, 55.1%)로 얻었다. 4b was prepared according to General Procedure B using 2-bromo-3' nitroacetophenone (1.22 g, 5.00 mmol). Obtained as a brown solid (0.52 g, 55.1%).
1H NMR(400 MHz, MeOD) δ 8.59(t, J = 2.0 Hz, 1H), 8.12 - 8.05(m, 2H), 7.79(d, J = 1.2 Hz, 1H), 7.65(s, 1H), 7.60(t, J = 8.0 Hz, 1H). 1H NMR (400 MHz, MeOD) δ 8.59 (t, J = 2.0 Hz, 1H), 8.12 - 8.05 (m, 2H), 7.79 (d, J = 1.2 Hz, 1H), 7.65 (s, 1H), 7.60 (t, J = 8.0 Hz, 1H).
1-메틸-5-(4-나이트로페닐)-11-methyl-5-(4-nitrophenyl)-1 HH -이미다졸(5a).-imidazole (5a).
교반되고 있는 DMF(4 mL) 중 4a(94.58 mg, 0.50 mmol)의 혼합물에 소듐 하이드라이드 60%(24 mg, 0.60 mmol)를 실온에서 첨가하였다. 반응 혼합물을 버블이 멈출때까지 연속적으로 실온에서 1h 동안 교반하였다. 메틸 아이오다이드(62.25 μL, 1.00 mmol)를 상기 혼합물에 첨가하고 반응 혼합물을 연속적으로 6h 동안 실온에서 교반하였다. 혼합물을 디에틸에터로 추출하고 물로 세척하였다. 유기층을 무수 소듐 설페이트로 탈수시키고 농축하였다. 생성물을 컬럼 크로마토그래피(에틸아세테이트/헥산)로 정제하여 5a를 밝은 황색 고체(59.23 mg, 58.3%)로 얻었다.To a stirred mixture of 4a ( 94.58 mg, 0.50 mmol) in DMF (4 mL) was added sodium hydride 60% (24 mg, 0.60 mmol) at room temperature. The reaction mixture was continuously stirred at room temperature for 1 h until bubbling ceased. Methyl iodide (62.25 μL, 1.00 mmol) was added to the mixture and the reaction mixture was continuously stirred at room temperature for 6 h. The mixture was extracted with diethyl ether and washed with water. The organic layer was dehydrated over anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (ethyl acetate/hexane) to obtain 5a. Obtained as a light yellow solid (59.23 mg, 58.3%).
1H NMR(400 MHz, CDCl-3) δ 8.21(d, J = 8.9 Hz, 2H), 7.88(d, J = 9.0 Hz, 2H), 7.52(s, 1H), 7.34(d, J = 1.3 Hz, 1H), 3.77(s, 3H). 1H NMR (400 MHz, CDCl- 3 ) δ 8.21 (d, J = 8.9 Hz, 2H), 7.88 (d, J = 9.0 Hz, 2H), 7.52 (s, 1H), 7.34 (d, J = 1.3 Hz, 1 H), 3.77 (s, 3 H).
1-메틸-5-(3-나이트로페닐)-1H-이미다졸(5b).1-methyl-5-(3-nitrophenyl)-1H-imidazole (5b).
5a에 대한 공정에 따라, 4b(94.58 mg, 0.50 mmol)를 사용하여 5b를 밝은 황색 고체(88.90 mg, 87.5%)로 얻었다. Following procedure for 5a , 5b was prepared using 4b (94.58 mg, 0.50 mmol) Obtained as a light yellow solid (88.90 mg, 87.5%).
1H NMR(400 MHz, CDCl3) δ 8.55(t, J = 2.0 Hz, 1H), 8.11(ddd, J = 7.8, 1.7, 1.0 Hz, 1H), 8.06(ddd, J = 8.2, 2.3, 1.0 Hz, 1H), 7.55 - 7.49(m, 2H), 7.31(d, J = 1.3 Hz, 1H), 3.77(s, 3H). 1H NMR (400 MHz, CDCl 3 ) δ 8.55 (t, J = 2.0 Hz, 1H), 8.11 (ddd, J = 7.8, 1.7, 1.0 Hz, 1H), 8.06 (ddd, J = 8.2, 2.3, 1.0 Hz, 1H), 7.55 - 7.49 (m, 2H), 7.31 (d, J = 1.3 Hz, 1H), 3.77 (s, 3H).
4-(1-메틸-14-(1-methyl-1 HH -이미다졸-5-일)아닐린(6a).-imidazol-5-yl)aniline (6a).
일반적인 공정 A에 따라, 5a(59.23 mg, 0.29 mmol)를 사용하여 6a를 흰색 고체(정량적)로 얻었다. 6a was prepared using 5a (59.23 mg, 0.29 mmol) according to General Procedure A. Obtained as a white solid (quantitative).
1H NMR(400 MHz, CDCl3) δ 7.56(d, J = 8.5 Hz, 2H), 7.41(s, 1H), 7.02(d, J = 1.4 Hz, 1H), 6.70(d, J = 8.5 Hz, 2H), 3.69(s, 3H), 3.65(s, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.56 (d, J = 8.5 Hz, 2H), 7.41 (s, 1H), 7.02 (d, J = 1.4 Hz, 1H), 6.70 (d, J = 8.5 Hz) , 2H), 3.69(s, 3H), 3.65(s, 2H).
3-(1-메틸-1 H -이미다졸-5-일)아닐린(6b): 3-(1-methyl-1 H -imidazol-5-yl)aniline (6b) :
일반적인 공정 A에 따라, 5b(88.90 mg, 0.44 mmol)를 사용하여 6b를 흰색 고체(정량적)로 얻었다.Following General Procedure A, 5b ( 88.90 mg, 0.44 mmol) was used to obtain 6b as a white solid (quantitatively).
1H NMR(400 MHz, CDCl3) δ 7.45 - 7.44(m, 1H), 7.19(ddd, J = 2.2, 1.5, 0.5 Hz, 1H), 7.17 - 7.09(m, 3H), 6.58(ddd, J = 7.6, 2.4, 1.3 Hz, 1H), 3.71(s, 3H), 3.67(s, 2H). 1H NMR (400 MHz, CDCl 3 ) δ 7.45 - 7.44 (m, 1H), 7.19 (ddd, J = 2.2, 1.5, 0.5 Hz, 1H), 7.17 - 7.09 (m, 3H), 6.58 (ddd, J = 7.6, 2.4, 1.3 Hz, 1H), 3.71(s, 3H), 3.67(s, 2H).
4-(14-(1 HH -이미다졸-5-일)아닐린(7a). -imidazol-5-yl)aniline (7a).
일반적인 공정 A에 따라, 4a(0.38 g, 2.00 mmol)를 사용하여 7a 를 흰색 고체(0.29 g, 91.1%)로 얻었다.Following General Procedure A, 4a (0.38 g, 2.00 mmol) was used to obtain 7a as a white solid (0.29 g, 91.1%).
1H NMR(400 MHz, MeOD) δ 7.64(d, J = 1.2 Hz, 1H), 7.44(d, J = 8.7 Hz, 2H), 7.19(d, J = 1.2 Hz, 1H), 6.75(d, J = 8.6 Hz, 2H). 1H NMR (400 MHz, MeOD) δ 7.64 (d, J = 1.2 Hz, 1H), 7.44 (d, J = 8.7 Hz, 2H), 7.19 (d, J = 1.2 Hz, 1H), 6.75 (d, J = 8.6 Hz, 2H).
3-(13-(1 HH -이미다졸-5-일)아닐린(7b).-imidazol-5-yl)aniline (7b).
일반적인 공정 A에 따라, 4b(0.38 g, 2.00 mmol)를 사용하여 7b 를 흰색 고체(0.29 g, 91.3%)로 얻었다.Following General Procedure A, 4b ( 0.38 g, 2.00 mmol) was used to obtain 7b as a white solid (0.29 g, 91.3%).
1H NMR(400 MHz, MeOD-d 4) δ 7.68(d, J = 1.1 Hz, 1H), 7.32(d, J = 1.1 Hz, 1H), 7.14 - 7.01(m, 3H), 6.62(ddd, J = 7.9, 2.3, 1.1 Hz, 1H). 1 H NMR (400 MHz, MeOD- d 4 ) δ 7.68 (d, J = 1.1 Hz, 1H), 7.32 (d, J = 1.1 Hz, 1H), 7.14 - 7.01 (m, 3H), 6.62 (ddd, J = 7.9, 2.3, 1.1 Hz, 1H).
2-메틸-5-(4-나이트로페닐)-12-methyl-5-(4-nitrophenyl)-1 HH -이미다졸(8a).-imidazole (8a).
2-브로모-4' 나이트로아세토페논(1.22 g, 5.00 mmol) 및 아세트아미드(10 mL)의 혼합물을 180 ℃에서 1일 동안 가열하였다. 냉각 후, 혼합물을 포화된 소듐하이드로젠카보네이트 용액에 붓고 에틸아세테이트로 추출하였다. 유기층을 무수 소듐 설페이트로 탈수시키고 농축하였다. 생성물을 컬럼 크로마토그래피(CH2Cl2/MeOH)로 정제하여 8a를 갈색 고체(0.73 g, 72.1%)로 얻었다.A mixture of 2-bromo-4' nitroacetophenone (1.22 g, 5.00 mmol) and acetamide (10 mL) was heated at 180 °C for 1 day. After cooling, the mixture was poured into a saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was dehydrated over anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (CH 2 Cl 2 /MeOH) to give 8a as a brown solid (0.73 g, 72.1%).
1H NMR(400 MHz, MeOD) δ 8.20(d, J = 9.0 Hz, 2H), 7.87(d, J = 9.0 Hz, 2H), 7.54(s, 1H), 2.43(s, 3H). 1 H NMR (400 MHz, MeOD) δ 8.20 (d, J = 9.0 Hz, 2H), 7.87 (d, J = 9.0 Hz, 2H), 7.54 (s, 1H), 2.43 (s, 3H).
2-메틸-5-(3-나이트로페닐)-12-methyl-5-(3-nitrophenyl)-1 HH -이미다졸(8b).-imidazole (8b).
8a에 대한 공정에 따라, 2-브로모-3' 나이트로아세토페논(1.22 g, 5.00 mmol)을 사용하여 8b를 밝은 황색 고체(0.30 g, 30.0%)로 얻었다.Following the process for 8a , 8b was obtained as a light yellow solid (0.30 g, 30.0%) using 2-bromo-3' nitroacetophenone (1.22 g, 5.00 mmol).
1H NMR(400 MHz, MeOD) δ 8.53(t, J = 2.0 Hz, 1H), 8.06 - 8.02(m, 2H), 7.57(t, J = 8.0 Hz, 1H), 7.48(s, 1H), 2.42(s, 3H). 1H NMR (400 MHz, MeOD) δ 8.53 (t, J = 2.0 Hz, 1H), 8.06 - 8.02 (m, 2H), 7.57 (t, J = 8.0 Hz, 1H), 7.48 (s, 1H), 2.42(s, 3H).
4-(2-메틸-14-(2-methyl-1 HH -이미다졸-5-일)아닐린(9a).-imidazol-5-yl)aniline (9a).
일반적인 공정 A에 따라, 8a(0.20 g, 1.00 mmol)를 사용하여 9a를 흰색 고체(0.14 g, 82.1%)로 얻었다.Following General Procedure A, 8a (0.20 g, 1.00 mmol) was used to obtain 9a as a white solid (0.14 g, 82.1%).
1H NMR(400 MHz, DMSO-d 6) δ 7.33(d, J = 8.5 Hz, 2H), 7.03(s, 1H), 6.53(d, J = 8.5 Hz, 2H), 5.00(br s, 2H), 2.27(s, 3H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.33 (d, J = 8.5 Hz, 2H), 7.03 (s, 1H), 6.53 (d, J = 8.5 Hz, 2H), 5.00 (br s, 2H) ), 2.27(s, 3H).
3-(2-메틸-13-(2-methyl-1 HH -이미다졸-5-일)아닐린(9b).-imidazol-5-yl)aniline (9b).
일반적인 공정 A에 따라, 8b(0.20 g, 1.00 mmol)를 사용하여 9b를 흰색 고체(0.16 g, 93.0%)로 얻었다.Following General Procedure A, 8b (0.20 g, 1.00 mmol) was used to obtain 9b as a white solid (0.16 g, 93.0%).
1H NMR(400 MHz, DMSO-d 6) δ 7.18(s, 1H), 6.99 - 6.90(m, 2H), 6.82(dt, J = 7.6, 1.2 Hz, 1H), 6.38(ddd, J = 7.9, 2.3, 1.1 Hz, 1H), 4.97(s, 2H), 2.28(s, 3H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.18 (s, 1H), 6.99 - 6.90 (m, 2H), 6.82 (dt, J = 7.6, 1.2 Hz, 1H), 6.38 (ddd, J = 7.9 , 2.3, 1.1 Hz, 1H), 4.97 (s, 2H), 2.28 (s, 3H).
4-메틸-5-페닐-14-methyl-5-phenyl-1 HH -이미다졸(10).-imidazole (10).
일반적인 공정 B에 따라, 2-브로모프로피오페논(2.13 g, 10.00 mmol)을 사용하여 10을 흰색 고체(1.34 g, 84.9%)로 얻었다.Following General Procedure B, using 2-bromopropiophenone (2.13 g, 10.00 mmol), 10 was obtained as a white solid (1.34 g, 84.9%).
1H NMR(400 MHz, CDCl3) δ 11.21(br s, 1H), 7.61 - 7.56(m, 2H), 7.50(s, 1H), 7.44 - 7.34(m, 2H), 7.28 - 7.21(m, 1H), 2.42(s, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 11.21 (br s, 1H), 7.61 - 7.56 (m, 2H), 7.50 (s, 1H), 7.44 - 7.34 (m, 2H), 7.28 - 7.21 (m, 1H), 2.42(s, 3H).
4-메틸-5-(4-나이트로페닐)-14-methyl-5-(4-nitrophenyl)-1 HH -이미다졸(11a).-imidazole (11a).
0 ℃ 에서 농축된 질산 및 황산(1:1, 10 mL)을 함유한 둥근바닥플라스크에서, 10(1.34 g, 8.49 mmol)를 상기 용액에 현탁시켰다. 반응 혼합물을 실온에서 2h 동안 교반한 후 60 ℃에서 4h 동안 가열하였다. 혼합물을 0 ℃로 냉각시키고 포화된 NaHCO3 용액으로 퀀칭하였다. 혼합물을 에틸아세테이트로 추출하고 브라인으로 세척하였다. 유기층을 무수 소듐 설페이트로 탈수시키고 농축하였다. 생성물을 컬럼 크로마토그래피(에틸아세테이트/헥산)로 정제하여 11a를 황색 고체(1.16 g, 67.0%)로 얻었다.0 ℃ In a round bottom flask containing concentrated nitric acid and sulfuric acid (1:1, 10 mL), 10 (1.34 g, 8.49 mmol) was suspended in the above solution. The reaction mixture was stirred at room temperature for 2 h and then heated at 60 °C for 4 h. The mixture was cooled to 0 °C and quenched with saturated NaHCO 3 solution. The mixture was extracted with ethyl acetate and washed with brine. The organic layer was dehydrated over anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (ethyl acetate/hexane) to give 11a as a yellow solid (1.16 g, 67.0%).
1H NMR(400 MHz, DMSO-d 6) δ 12.27(s, 1H), 8.24(d, J = 8.5 Hz, 2H), 7.93(d, J = 8.5 Hz, 2H), 7.68(s, 1H), 2.48(s, 3H). 1H NMR (400 MHz, DMSO- d6 ) δ 12.27 (s, 1H) , 8.24 (d, J = 8.5 Hz, 2H), 7.93 (d, J = 8.5 Hz, 2H), 7.68 (s, 1H) , 2.48(s, 3H).
4-(4-메틸-4-(4-methyl- 1H1H -이미다졸-5-일)아닐린(12a).-imidazol-5-yl)aniline (12a).
일반적인 공정 A에 따라, 11a(1.16 g, 5.71 mmol)를 사용하여 12a를 흰색 고체(정량적)로 얻었다. 12a was obtained as a white solid (quantitatively) using 11a (1.16 g, 5.71 mmol) according to General Procedure A.
1H NMR(400 MHz, MeOD) δ 7.73(s, 1H), 7.27(d, J = 8.5 Hz, 2H), 6.78(d, J = 8.5 Hz, 2H), 2.33(s, 3H). 1 H NMR (400 MHz, MeOD) δ 7.73 (s, 1H), 7.27 (d, J = 8.5 Hz, 2H), 6.78 (d, J = 8.5 Hz, 2H), 2.33 (s, 3H).
2-브로모-1-(3-나이트로페닐)프로판-1-온(13).2-Bromo-1-(3-nitrophenyl)propan-1-one (13).
아세트산(20 mL) 중 3'-나이트로프로피오페논(1.79 g, 10.00 mmol)의 혼합물에 브롬(0.28 mL, 11.00 mmol)을 방울로 적가하였다. 반응 혼합물을 30 ℃에서 밤새 교반하였다. 혼합물을 냉각한 포화된 소듐하이드로젠카보네이트로 퀀칭하고 CH2Cl2로 추출하였다. 유기층을 무수 소듐 설페이트로 탈수시키고 농축하였다. 생성물을 컬럼 크로마토그래피(헥산/에틸아세테이트)로 정제하여 13을 흰색 고체(2.35 g, 91.0%)로 얻었다.To a mixture of 3'-nitropropiophenone (1.79 g, 10.00 mmol) in acetic acid (20 mL) was added dropwise bromine (0.28 mL, 11.00 mmol). The reaction mixture was stirred overnight at 30 °C. The mixture was quenched with cold saturated sodium hydrogencarbonate and extracted with CH 2 Cl 2 . The organic layer was dehydrated over anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (hexane/ethyl acetate) to obtain 13 as a white solid (2.35 g, 91.0%).
1H NMR(400 MHz, CDCl3) δ 8.85(t, J = 1.9 Hz, 1H), 8.45(ddd, J = 8.2, 2.3, 1.1 Hz, 1H), 8.36(ddd, J = 7.8, 1.7, 1.1 Hz, 1H), 7.72(t, J = 7.9 Hz, 1H), 5.29(q, J = 6.6 Hz, 1H), 1.95(d, J = 6.6 Hz, 3H). 1H NMR (400 MHz, CDCl 3 ) δ 8.85 (t, J = 1.9 Hz, 1H), 8.45 (ddd, J = 8.2, 2.3, 1.1 Hz, 1H), 8.36 (ddd, J = 7.8, 1.7, 1.1 Hz, 1H), 7.72 (t, J = 7.9 Hz, 1H), 5.29 (q, J = 6.6 Hz, 1H), 1.95 (d, J = 6.6 Hz, 3H).
4-메틸-5-(3-나이트로페닐)-14-methyl-5-(3-nitrophenyl)-1 HH -이미다졸(11b).-imidazole (11b).
일반적인 공정 B에 따라, 13(1.29 g, 5.00 mmol)을 사용하여 11b를 밝은 황색 고체(0.80 g, 78.7%)로 얻었다.Following General Procedure B, 13 (1.29 g, 5.00 mmol) was used to obtain 11b as a light yellow solid (0.80 g, 78.7%).
1H NMR(400 MHz, MeOD) δ 8.45(t, J = 2.0 Hz, 1H), 8.10(ddd, J = 8.2, 2.4, 1.0 Hz, 1H), 7.98(ddd, J = 7.8, 1.7, 1.0 Hz, 1H), 7.67 - 7.61(m, 2H), 2.47(s, 3H). 1H NMR (400 MHz, MeOD) δ 8.45 (t, J = 2.0 Hz, 1H), 8.10 (ddd, J = 8.2, 2.4, 1.0 Hz, 1H), 7.98 (ddd, J = 7.8, 1.7, 1.0 Hz , 1H), 7.67 - 7.61 (m, 2H), 2.47 (s, 3H).
3-(4-메틸-1H-이미다졸-5-일)아닐린(12b).3-(4-methyl-1H-imidazol-5-yl)aniline (12b).
일반적인 공정 A에 따라, 11b(0.20 g, 1.00 mmol)를 사용하여 12b를 흰색 고체(0.15 g, 89.3%)로 얻었다.Following general procedure A, 11b (0.20 g, 1.00 mmol) was used to obtain 12b as a white solid (0.15 g, 89.3%).
1H NMR(400 MHz, DMSO-d 6) δ 11.70(br s, 1H), 7.51(s, 1H), 7.01(t, J = 7.8 Hz, 1H), 6.84(t, J = 1.9 Hz, 1H), 6.72(dt, J = 7.7, 1.3 Hz, 1H), 6.42(ddd, J = 7.9, 2.3, 1.0 Hz, 1H), 5.04(br s, 2H), 2.32(s, 3H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.70 (br s, 1H), 7.51 (s, 1H), 7.01 (t, J = 7.8 Hz, 1H), 6.84 (t, J = 1.9 Hz, 1H) ), 6.72 (dt, J = 7.7, 1.3 Hz, 1H), 6.42 (ddd, J = 7.9, 2.3, 1.0 Hz, 1H), 5.04 (br s, 2H), 2.32 (s, 3H).
5-(4-나이트로페닐)-1,3,4-옥사다이아졸-2(35-(4-nitrophenyl)-1,3,4-oxadiazole-2(3 HH )-론(13a).)-ron (13a).
테트라하이드로푸란(2 mL) 중 4-나이트로벤조하이드라자이드(0.90 g, 5.00 mmol) 및 트리에틸아민(1.02 g, 10.00 mmol)의 혼합물에 테트라하이드로푸란 중 트리포스젠(0.59 g, 2.00 mmol)의 용액을 0 ℃에서 방울로 적가하였다. 반응 혼합물을 실온에서 밤새 교반하였다. 용매를 증발시켜 건조시켰다. 생성물을 에틸아세테이트로 추출하고 브라인으로 세척하였다. 유기층을 무수 소듐 설페이트로 탈수시키고 농축하였다. 잔여물을 컬럼 크로마토그래피(에틸아세테이트/헥산)로 정제하여 13a를 황색 고체(0.93 g, 90.1%)로 얻었다.Triphosgene (0.59 g, 2.00 mmol) in tetrahydrofuran was added to a mixture of 4-nitrobenzohydrazide ( 0.90 g, 5.00 mmol) and triethylamine (1.02 g, 10.00 mmol) in tetrahydrofuran (2 mL). ) was added dropwise at 0 °C. The reaction mixture was stirred overnight at room temperature. The solvent was evaporated to dryness. The product was extracted with ethyl acetate and washed with brine. The organic layer was dehydrated over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (ethyl acetate/hexane) to give 13a as a yellow solid (0.93 g, 90.1%).
1H NMR(400 MHz, DMSO-d 6) δ 12.87(br s, 1H), 8.36(d, J = 9.0 Hz, 2H), 8.04(d, J = 9.0 Hz, 2H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 12.87 (br s, 1H), 8.36 (d, J = 9.0 Hz, 2H), 8.04 (d, J = 9.0 Hz, 2H).
5-(3-나이트로페닐)-1,3,4-옥사다이아졸-2(35-(3-nitrophenyl)-1,3,4-oxadiazole-2(3 HH )-론(13b).)-ron (13b).
13a 에 대한 공정에 따라, 3-나이트로벤조하이드라자이드(0.90 g, 5.00 mmol)를 사용하여 13b를 황색 고체(0.96 g, 92.6%)로 얻었다.Following the procedure for 13a , 3-nitrobenzohydrazide ( 0.90 g, 5.00 mmol) was used to obtain 13b as a yellow solid (0.96 g, 92.6%).
1H NMR(400 MHz, DMSO-d 6) δ 12.84(br s, 1H), 8.46 - 8.43(m, 1H), 8.40(ddd, J = 8.2, 2.4, 1.0 Hz, 1H), 8.21(ddd, J = 7.8, 1.7, 1.0 Hz, 1H), 7.89 - 7.82(m, 1H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 12.84 (br s, 1H), 8.46 - 8.43 (m, 1H), 8.40 (ddd, J = 8.2, 2.4, 1.0 Hz, 1H), 8.21 (ddd, J = 7.8, 1.7, 1.0 Hz, 1H), 7.89 - 7.82 (m, 1H).
5-(4-아미노페닐)-1,3,4-옥사다이아졸-2(35-(4-aminophenyl)-1,3,4-oxadiazole-2(3 HH )-론(14a).)-ron (14a).
일반적인 공정 A에 따라, 13a(0.83 g, 4.00 mmol)를 사용하여 14a를 흰색 고체(0.57 g, 80.3%)로 얻었다. 13a (0.83 g, 4.00 mmol) was used according to General Procedure A to obtain 14a as a white solid (0.57 g, 80.3%).
1H NMR(400 MHz, DMSO-d 6) δ 7.39(d, J = 8.6 Hz, 2H), 6.58(d, J = 8.7 Hz, 2H), 5.77(s, 2H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.39 (d, J = 8.6 Hz, 2H), 6.58 (d, J = 8.7 Hz, 2H), 5.77 (s, 2H).
5-(3-아미노페닐)-1,3,4-옥사다이아졸-2(35-(3-aminophenyl)-1,3,4-oxadiazole-2(3 HH )-론(14b).)-ron (14b).
일반적인 공정 A에 따라, 13b(0.83 g, 4.00 mmol)를 사용하여 14b를 흰색 고체(0.60 g, 80.3%)로 얻었다.Following General Procedure A, 13b (0.83 g, 4.00 mmol) was used to obtain 14b as a white solid (0.60 g, 80.3%).
1H NMR(400 MHz, DMSO-d 6) δ 7.10(t, J = 7.8 Hz, 1H), 6.95(t, J = 2.0 Hz, 1H), 6.86(dt, J = 7.6, 1.3 Hz, 1H), 6.67(ddd, J = 8.1, 2.3, 1.0 Hz, 1H), 5.39(s, 2H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.10 (t, J = 7.8 Hz, 1H), 6.95 (t, J = 2.0 Hz, 1H), 6.86 (dt, J = 7.6, 1.3 Hz, 1H) , 6.67 (ddd, J = 8.1, 2.3, 1.0 Hz, 1H), 5.39 (s, 2H).
3-(2-메틸옥사졸-5-릴)아닐린(15). 3-(2-methyloxazol-5-yl)aniline (15).
일반적인 공정 A에 따라, 2-메틸-5-(3-나이트로페닐)옥사졸(0.20 g, 1.00 mmol)을 사용하여 15를 흰색 고체(정량적)로 얻었다.According to General Procedure A, 15 was obtained as a white solid (quantitatively) using 2-methyl-5-(3-nitrophenyl)oxazole (0.20 g, 1.00 mmol).
1H NMR(400 MHz, CDCl3) δ 7.74(s, 1H), 7.15(t, J = 7.7 Hz, 1H), 7.08 - 7.03(m, 2H), 6.60(ddd, J = 7.8, 2.4, 1.1 Hz, 1H), 3.74(s, 2H), 2.48(s, 3H). 1H NMR (400 MHz, CDCl 3 ) δ 7.74 (s, 1H), 7.15 (t, J = 7.7 Hz, 1H), 7.08 - 7.03 (m, 2H), 6.60 (ddd, J = 7.8, 2.4, 1.1 Hz, 1H), 3.74 (s, 2H), 2.48 (s, 3H).
3-(13-(1 HH -1,2,3-트리아졸-5-일)아닐린(16).-1,2,3-triazol-5-yl)aniline (16).
3-에티닐아닐린(0.12 g, 1.00 mmol), 트리메틸실릴 아자이드(0.13 g, 1.10 mmol) 및 카파(I) 아이오다이드(9.52 mg, 0.05 mmol)을 DMF/MeOH(9/1, 2 mL)의 혼합물에 질소 가스하에 첨가하였다. 반응 혼합물을 100 ℃에서 12h 동안 질소 가스하에 가열하였다. 용매를 증발시켜 건조시키고, 에틸아세테이트로 추출하고 브라인으로 세척하였다. 유기층을 무수 소듐 설페이트로 탈수시키고 농축시켰다. 생성물을 컬럼 크로마토그래피(CH2Cl2/MeOH)로 정제하여 16을 흰색 고체(19.54 mg, 12.2%)로 얻었다.3-ethynylaniline (0.12 g, 1.00 mmol), trimethylsilyl azide (0.13 g, 1.10 mmol) and kappa(I) iodide (9.52 mg, 0.05 mmol) were added to DMF/MeOH (9/1, 2 mL). ) was added under nitrogen gas to the mixture. The reaction mixture was heated at 100 °C for 12 h under nitrogen gas. The solvent was evaporated to dryness, extracted with ethyl acetate and washed with brine. The organic layer was dehydrated with anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (CH 2 Cl 2 /MeOH) to give 16 as a white solid (19.54 mg, 12.2%).
1H NMR(400 MHz, CDCl3) δ 7.94(s, 1H), 7.23(t, J = 7.9 Hz, 1H), 7.21 - 7.17(m, 2H), 6.71(ddd, J = 7.7, 2.4, 1.3 Hz, 1H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.94 (s, 1H), 7.23 (t, J = 7.9 Hz, 1H), 7.21 - 7.17 (m, 2H), 6.71 (ddd, J = 7.7, 2.4, 1.3 Hz, 1H).
제법 2. 화합물 18a-n의 합성.Preparation 2. Synthesis of compounds 18a-n.
a 시약 및 조건:(a) i: CDI, DMF, 6 h, ii: 4-Piperidone, 15 h;(b) 3a-b, 6a-b, 7a-b, 9a-b, 12a-b, 14a-b, 15, 또는 16, NaBH(OAc)3, AcOH, CH2Cl2, 15 h;(c) 25% TFA, CH2Cl2, 3 h for Boc deprotection. a Reagents and conditions: (a) i: CDI, DMF, 6 h, ii: 4-Piperidone, 15 h; (b) 3a-b , 6a-b , 7a-b , 9a-b , 12a-b , 14a -b , 15 , or 16 , NaBH(OAc) 3 , AcOH, CH 2 Cl 2 , 15 h; (c) 25% TFA, CH 2 Cl 2 , 3 h for Boc deprotection.
카바메이트 형성을 위한 일반적인 공정 C.General process for carbamate formation C.
DMF(20 mL) 중 알코올(10.00 mmol)의 교반되는 용액에 1,1'-카보닐디이미다졸(1.94 g, 12.00 mmol)을 실온에서 첨가하고 6 h 동안 교반하였다. 아민(12 mmol)을 첨가한 후, 혼합물을 실온에서 밤새 교반하였다. 유기물을 디에틸에터로 추출하였고 물로 2회 세척하였다. 유기층을 무수 소듐 설페이트로 탈수시키고 농축하였다. 생성물을 컬럼 크로마토그래피(에틸아세테이트/헥산)로 정제하여 목적하는 카바메이트를 얻었다. To a stirred solution of alcohol (10.00 mmol) in DMF (20 mL) was added 1,1'-carbonyldiimidazole (1.94 g, 12.00 mmol) at room temperature and stirred for 6 h. After adding the amine (12 mmol), the mixture was stirred at room temperature overnight. The organics were extracted with diethyl ether and washed twice with water. The organic layer was dehydrated over anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (ethyl acetate/hexane) to obtain the desired carbamate.
환원성 아민화를 위한 일반적인 공정 D.General process for reductive amination D.
케톤(0.10 mmol), 아민(0.10 mmol), 및 아세트산(2 방울)을 함유하는 10 ml-바이알에 소듐 트리아세톡시보로하이드라이드(25.43 mg, 0.12 mmol)를 첨가하였다. 포화된 NaHCO3 용액으로 퀀칭하기 이전에 반응 혼합물을 실온에서 밤새 교반하였다. 유기물을 에틸아세테이트로 추출하고, 브라인으로 세척하고, 무수 Na2SO4로 건조시키고 농축하였다. 생성물을 컬럼 크로마토그래피(에틸아세테이트/헥산)로 정제하여 목적하는 치환된 아민을 얻었다. To a 10 ml-vial containing ketone (0.10 mmol), amine (0.10 mmol), and acetic acid (2 drops) was added sodium triacetoxyborohydride (25.43 mg, 0.12 mmol). The reaction mixture was stirred at room temperature overnight before quenching with saturated NaHCO 3 solution. The organics were extracted with ethyl acetate, washed with brine, dried over anhydrous Na 2 SO 4 and concentrated. The product was purified by column chromatography (ethyl acetate/hexane) to obtain the desired substituted amine.
3,5-디클로로벤질 4-옥소피페리딘-1-카복실레이트(17): 3,5-dichlorobenzyl 4-oxopiperidine-1-carboxylate (17) :
일반적인 공정 C에 따라, 3,5-디클로로벤질 알코올(1.77g, 10.00 mmol) 및 4-피페리돈 모노하이드레이트(3.07 g, 20 mmol)를 사용하여 17을 흰색 고체(2.76 g, 91.3%)로 얻었다.According to General Procedure C, using 3,5-dichlorobenzyl alcohol (1.77 g, 10.00 mmol) and 4-piperidone monohydrate (3.07 g, 20 mmol), 17 was obtained as a white solid (2.76 g, 91.3%). .
1H NMR(400 MHz, CDCl3) δ 7.33(t, J = 1.9 Hz, 1H), 7.26 - 7.23(m, 2H), 5.12(s, 2H), 3.81(t, J = 6.3 Hz, 4H), 2.49(t, J = 6.2 Hz, 4H). 1H NMR (400 MHz, CDCl 3 ) δ 7.33 (t, J = 1.9 Hz, 1H), 7.26 - 7.23 (m, 2H), 5.12 (s, 2H), 3.81 (t, J = 6.3 Hz, 4H) , 2.49 (t, J = 6.2 Hz, 4H).
3,5-디클로로벤질 4-((4-(2-아미노티아졸-5-일)페닐)아미노)피페리딘-1-카복실레이트(18a). 3,5-dichlorobenzyl 4-((4-(2-aminothiazol-5-yl)phenyl)amino)piperidine-1-carboxylate (18a).
일반적인 공정 D에 따라, 17(30.21 mg, 0.10 mmol) 및 3a(39.15 mg, 0.10 mmol)를 사용하여 3,5-디클로로벤질 4-((4-(2-(비스(tert-부톡시카보닐)아미노)티아졸-5-일)페닐)아미노)피페리딘-1-카복실레이트를 흰색 고체(35.78 mg, 52.8%)로 얻었다.3,5-Dichlorobenzyl 4-((4-(2-(bis(tert-butoxycarbonyl) using 17 (30.21 mg, 0.10 mmol) and 3a (39.15 mg, 0.10 mmol) according to General Procedure D Obtained )amino)thiazol-5-yl)phenyl)amino)piperidine-1-carboxylate as a white solid (35.78 mg, 52.8%).
1H NMR(400 MHz, CDCl3) δ 7.66(d, J = 8.6 Hz, 2H), 7.31(t, J = 1.9 Hz, 1H), 7.23(d, J = 1.8 Hz, 2H), 7.04(s, 1H), 6.61(d, J = 8.7 Hz, 2H), 5.07(s, 2H), 4.20 - 4.05(m, 2H), 3.66(s, 1H), 3.56 - 3.44(m, 1H), 3.13 - 2.96(m, 2H), 2.19 - 2.03(m, 2H), 1.54(s, 18H), 1.45 - 1.33(m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.66 (d, J = 8.6 Hz, 2H), 7.31 (t, J = 1.9 Hz, 1H), 7.23 (d, J = 1.8 Hz, 2H), 7.04 (s , 1H), 6.61 (d, J = 8.7 Hz, 2H), 5.07 (s, 2H), 4.20 - 4.05 (m, 2H), 3.66 (s, 1H), 3.56 - 3.44 (m, 1H), 3.13 - 2.96 (m, 2H), 2.19 - 2.03 (m, 2H), 1.54 (s, 18H), 1.45 - 1.33 (m, 2H).
이것을 CH2Cl2 중 25% TFA 용액에 용해시키고 실온에서 3 h 동안 교반하였다. 혼합물을 농축시키고 컬럼 크로마토그래피(에틸아세테이트/헥산)로 정제하여 표제 화합물 18a를 흰색 고체(15.91 mg, 63.1%)로 얻었다. It was dissolved in a 25% TFA solution in CH 2 Cl 2 and stirred at room temperature for 3 h. The mixture was concentrated and purified by column chromatography (ethyl acetate/hexane) to give the title compound 18a as a white solid (15.91 mg, 63.1%).
1H NMR(400 MHz, CDCl3) δ 7.59(d, J = 8.7 Hz, 2H), 7.32 - 7.29(m, 1H), 7.23 - 7.22(m, 2H), 6.60(d, J = 8.7 Hz, 2H), 6.49(s, 1H), 5.07(s, 2H), 5.04(s, 2H), 4.20 - 4.05(m, 2H), 3.61(d, J = 7.8 Hz, 1H), 3.55 - 3.44(m, 1H), 3.13 - 2.99(m, 2H), 2.13 - 2.07(m, 2H), 1.45 - 1.33(m, 2H). 13C NMR(100 MHz, CDCl3) δ 166.97, 154.72, 151.59, 146.27, 140.22, 135.11, 128.16, 127.32, 126.09, 124.82, 113.22, 99.73, 65.54, 49.85, 42.97, 32.33. HRMS(ESI) m/z(M+H)+ calcd for C22H23Cl2N4O2S = 477.09; found 477.0915. 1 H NMR (400 MHz, CDCl 3 ) δ 7.59 (d, J = 8.7 Hz, 2H), 7.32 - 7.29 (m, 1H), 7.23 - 7.22 (m, 2H), 6.60 (d, J = 8.7 Hz, 2H), 6.49(s, 1H), 5.07(s, 2H), 5.04(s, 2H), 4.20 - 4.05(m, 2H), 3.61(d, J = 7.8 Hz, 1H), 3.55 - 3.44(m) , 1H), 3.13 - 2.99 (m, 2H), 2.13 - 2.07 (m, 2H), 1.45 - 1.33 (m, 2H). 13 C NMR (100 MHz, CDCl 3 ) δ 166.97, 154.72, 151.59, 146.27, 140.22, 135.11, 128.16, 127.32, 126.09, 124.82, 113.22, 99.73, 65.295, 3.4.84, 49 HRMS(ESI) m/z(M+H) + calcd for C 22 H 23 Cl 2 N 4 O 2 S = 477.09; found 477.0915.
3,5-디클로로벤질 4-((3-(2-아미노티아졸-5-일)페닐)아미노)피페리딘-1-카복실레이트(18b). 3,5-dichlorobenzyl 4-((3-(2-aminothiazol-5-yl)phenyl)amino)piperidine-1-carboxylate (18b).
일반적인 공정 D에 따라, 17(30.21 mg, 0.10 mmol) 및 3b(39.15 mg, 0.10 mmol)를 사용하여 Boc-보호된 중간체 3,5-디클로로벤질 4-((3-(2-(비스(tert-부톡시카보닐)아미노)티아졸-5-일)페닐)아미노)피페리딘-1-카복실레이트를 흰색 고체(63.83 mg, 94.2%)로 얻었다;Boc - protected intermediate 3,5-dichlorobenzyl 4-( ( 3-(2-(bis(tert Obtained -butoxycarbonyl)amino)thiazol-5-yl)phenyl)amino)piperidine-1-carboxylate as a white solid (63.83 mg, 94.2%);
1H NMR(400 MHz, CDCl3 δ 7.31(t, J = 2.0 Hz, 1H), 7.25 - 7.22(m, 3H), 7.21 - 7.13(m, 3H), 6.59 - 6.54(m, 1H), 5.08(s, 2H), 4.18 - 4.07(m, 2H), 3.59(s, 1H), 3.57 - 3.50(m, 1H), 3.10 - 2.99(m, 2H), 2.13 - 2.06(m, 2H), 1.55(s, 18H), 1.43 - 1.33(m, 2H). 이것을 탈보호하여 18b를 흰색 고체(35.64 mg, 79.1%)로 얻었다. 1H NMR(400 MHz, CDCl3) δ 7.31 - 7.29(m, 1H), 7.24 - 7.21(m, 2H), 7.17(t, J = 8.0 Hz, 1H), 7.10 - 7.06(m, 2H), 6.68(s, 1H), 6.56 - 6.52(m, 1H), 5.09(s, 2H), 5.07(s, 2H), 4.18 - 4.03(m, 2H), 3.63 - 3.50(m, 2H), 3.04(s, 2H), 2.12 - 2.05(m, 2H), 1.43 - 1.31(m, 2H). 13C NMR(100 MHz, CDCl3) δ 167.02, 154.72, 151.60, 146.97, 140.25, 135.80, 135.11, 129.59, 128.14, 126.07, 115.49, 112.73, 111.40, 102.93, 65.52, 49.86, 42.98, 32.40. HRMS(ESI) m/z(M+H)+ calcd for C22H23Cl2N4O2S = 477.09; found 477.0914. 1 H NMR (400 MHz, CDCl 3 δ 7.31 (t, J = 2.0 Hz, 1H), 7.25 - 7.22 (m, 3H), 7.21 - 7.13 (m, 3H), 6.59 - 6.54 (m, 1H), 5.08 (s, 2H), 4.18 - 4.07 (m, 2H), 3.59 (s, 1H), 3.57 - 3.50 (m, 1H), 3.10 - 2.99 (m, 2H), 2.13 - 2.06 (m, 2H), 1.55 (s, 18H), 1.43 - 1.33 (m, 2H) This was deprotected to obtain 18b as a white solid (35.64 mg, 79.1%) 1 H NMR (400 MHz, CDCl 3 ) δ 7.31 - 7.29 (m, 1H), 7.24 - 7.21(m, 2H), 7.17(t, J = 8.0 Hz, 1H), 7.10 - 7.06(m, 2H), 6.68(s, 1H), 6.56 - 6.52(m, 1H), 5.09 (s, 2H), 5.07(s, 2H), 4.18 - 4.03(m, 2H), 3.63 - 3.50(m, 2H), 3.04(s, 2H), 2.12 - 2.05(m, 2H), 1.43 - 1.31 (m, 2h). 13 C NMR (100 MHz, CDCL 3 ) Δ 167.02, 154.72, 151.60, 146.97, 140.25, 135.80, 135.11, 129.59, 128.14, 126.07, 115.49, 112.73, 111.40, 102.93, 65.52, 49.98 HRMS(ESI) m/z(M+H) + calcd for C 22 H 23 Cl 2 N 4 O 2 S = 477.09;
3,5-디클로로벤질 4-((4-(1-메틸-13,5-dichlorobenzyl 4-((4-(1-methyl-1 HH -이미다졸-5-일)페닐)아미노)피페리딘-1-카복실레이트(18c).-imidazol-5-yl)phenyl)amino)piperidine-1-carboxylate (18c).
일반적인 공정 D에 따라, 17(30.21 mg, 0.10 mmol) 및 6a(17.32 mg, 0.10 mmol)를 사용하여 18c를 흰색 고체(31.74 mg, 69.1%)로 얻었다.Using 17 (30.21 mg, 0.10 mmol) and 6a (17.32 mg, 0.10 mmol) according to General Procedure D, 18c was obtained as a white solid (31.74 mg, 69.1%).
1H NMR(400 MHz, CDCl3) δ 7.58(d, J = 8.6 Hz, 2H), 7.41(d, J = 1.4 Hz, 1H), 7.30(t, J = 1.9 Hz, 1H), 7.23(d, J = 1.9 Hz, 2H), 7.01(d, J = 1.4 Hz, 1H), 6.62(d, J = 8.7 Hz, 2H), 5.07(s, 2H), 4.19 - 4.06(m, 2H), 3.69(s, 3H), 3.58 - 3.47(m, 2H), 3.12 - 2.94(m, 2H), 2.17 - 2.04(m, 2H), 1.45 - 1.32(m, 2H). 13C NMR(100 MHz, CDCl3) δ 154.72, 145.55, 142.79, 140.25, 137.63, 135.10, 128.14, 126.08, 126.05, 124.36, 114.19, 113.53, 65.51, 50.00, 43.00, 33.44, 32.31. HRMS(ESI) m/z(M+H)+ calcd for C23H25Cl2N4O2= 459.14; found 459.1350 1 H NMR (400 MHz, CDCl 3 ) δ 7.58 (d, J = 8.6 Hz, 2H), 7.41 (d, J = 1.4 Hz, 1H), 7.30 (t, J = 1.9 Hz, 1H), 7.23 (d , J = 1.9 Hz, 2H), 7.01 (d, J = 1.4 Hz, 1H), 6.62 (d, J = 8.7 Hz, 2H), 5.07 (s, 2H), 4.19 - 4.06 (m, 2H), 3.69 (s, 3H), 3.58 - 3.47 (m, 2H), 3.12 - 2.94 (m, 2H), 2.17 - 2.04 (m, 2H), 1.45 - 1.32 (m, 2H). 13 C NMR (100 MHz, CDCL 3 ) δ 154.72, 145.55, 142.79, 140.25, 137.63, 135.10, 128.14, 126.08, 126.05, 124.36, 114.19, 113.53, 65.51, 50.00, 43.00, 33.44, 32.31. HRMS(ESI) m/z(M+H) + calcd for C 23 H 25 Cl 2 N 4 O 2 = 459.14; found 459.1350
3,5-디클로로벤질 4-((3-(1-메틸-1H-이미다졸-5-일)페닐)아미노)피페리딘-1-카복실레이트(18d). 3,5-dichlorobenzyl 4-((3-(1-methyl-1H-imidazol-5-yl)phenyl)amino)piperidine-1-carboxylate (18d).
일반적인 공정 D에 따라, 17(30.21 mg, 0.10 mmol) 및 6b(17.32 mg, 0.10 mmol)를 사용하여 18d를 흰색 고체(40.42 mg, 88.0%)로 얻었다.According to General Procedure D, using 17 (30.21 mg, 0.10 mmol) and 6b (17.32 mg, 0.10 mmol), 18d was obtained as a white solid (40.42 mg, 88.0%).
1H NMR(400 MHz, CDCl3) δ 7.44(d, J = 1.4 Hz, 1H), 7.30(t, J = 1.9 Hz, 1H), 7.24 - 7.22(m, 2H), 7.18 - 7.12(m, 3H), 7.02(dt, J = 7.9, 1.1 Hz, 1H), 6.49(ddd, J = 7.8, 2.5, 1.0 Hz, 1H), 5.07(s, 2H), 4.22 - 3.99(m, 2H), 3.70(s, 3H), 3.61 - 3.50(m, 2H), 3.13 - 2.99(m, 2H), 2.16 - 2.06(m, 2H), 1.45 - 1.30(m, 2H). 13C NMR(100 MHz, CDCl3) δ 154.72, 147.06, 142.61, 140.28, 137.84, 135.34, 135.09, 129.52, 128.12, 126.07, 116.04, 114.44, 112.11, 109.75, 65.49, 49.82, 33.51, 32.43. HRMS(ESI) m/z(M+H)+ calcd for C23H25Cl2N4O2= 459.14; found 459.1351 1H NMR (400 MHz, CDCl 3 ) δ 7.44 (d, J = 1.4 Hz, 1H), 7.30 (t, J = 1.9 Hz, 1H), 7.24 - 7.22 (m, 2H), 7.18 - 7.12 (m, 3H), 7.02 (dt, J = 7.9, 1.1 Hz, 1H), 6.49 (ddd, J = 7.8, 2.5, 1.0 Hz, 1H), 5.07 (s, 2H), 4.22 - 3.99 (m, 2H), 3.70 (s, 3H), 3.61 - 3.50 (m, 2H), 3.13 - 2.99 (m, 2H), 2.16 - 2.06 (m, 2H), 1.45 - 1.30 (m, 2H). 13 C NMR (100 MHz, CDCL 3 ) δ 154.72, 147.06, 142.61, 140.28, 137.84, 135.34, 135.09, 129.52, 128.12, 126.07, 116.04, 114.44, 112.11, 109.75, 65.49, 49.82, 32.43. HRMS(ESI) m/z(M+H) + calcd for C 23 H 25 Cl 2 N 4 O 2 = 459.14; found 459.1351
3,5-디클로로벤질 4-((4-(13,5-Dichlorobenzyl 4-((4-(1 HH -이미다졸-5-일)페닐)아미노)피페리딘-1-카복실레이트(18e). -imidazol-5-yl)phenyl)amino)piperidine-1-carboxylate (18e).
일반적인 공정 D에 따라, 17(30.21 mg, 0.10 mmol) 및 7a(15.92 mg, 0.10 mmol)를 사용하여 18e를 흰색 고체(36.61 mg, 82.2%)로 얻었다.Using 17 (30.21 mg, 0.10 mmol) and 7a (15.92 mg, 0.10 mmol) according to General Procedure D, 18e was obtained as a white solid (36.61 mg, 82.2%).
1H NMR(400 MHz, CDCl3) δ 9.38(br s, 1H), 7.62(d, J = 1.1 Hz, 1H), 7.51(d, J = 8.6 Hz, 2H), 7.31 - 7.29(m, 1H), 7.23 - 7.21(m, 2H), 7.18(d, J = 1.1 Hz, 1H), 6.61(d, J = 8.6 Hz, 2H), 5.07(s, 2H), 4.17 - 4.07(m, 2H), 3.66(br s, 1H), 3.52 - 3.44(m, 1H), 3.09 - 2.97(m, 2H), 2.11 - 2.05(m, 2H), 1.42 - 1.32(m, 2H). 13C NMR(100 MHz, CDCl3) δ 154.91, 145.96, 140.37, 138.45, 135.28, 135.23, 128.33, 126.44, 126.24, 122.69, 114.64, 113.75, 65.72, 50.08, 43.15, 32.46. HRMS(ESI) m/z(M+H)+ calcd for C22H23Cl2N4O2 = 445.12; found 445.1194. 1H NMR (400 MHz, CDCl 3 ) δ 9.38 (br s, 1H), 7.62 (d, J = 1.1 Hz, 1H), 7.51 (d, J = 8.6 Hz, 2H), 7.31 - 7.29 (m, 1H) ), 7.23 - 7.21 (m, 2H), 7.18 (d, J = 1.1 Hz, 1H), 6.61 (d, J = 8.6 Hz, 2H), 5.07 (s, 2H), 4.17 - 4.07 (m, 2H) , 3.66 (br s, 1H), 3.52 - 3.44 (m, 1H), 3.09 - 2.97 (m, 2H), 2.11 - 2.05 (m, 2H), 1.42 - 1.32 (m, 2H). 13 C NMR (100 MHz, CDCl 3 ) δ 154.91, 145.96, 140.37, 138.45, 135.28, 135.23, 128.33, 126.44, 126.24, 122.69, 114.64, 113.75, 6, 43.72, 65.2.18, 5 HRMS(ESI) m/z(M+H) + calcd for C 22 H 23 Cl 2 N 4 O 2 = 445.12; found 445.1194.
3,5-디클로로벤질 4-((3-(13,5-Dichlorobenzyl 4-((3-(1 HH -이미다졸-5-일)페닐)아미노)피페리딘-1-카복실레이트(18f). -imidazol-5-yl)phenyl)amino)piperidine-1-carboxylate (18f).
일반적인 공정 D에 따라, 17(30.21 mg, 0.10 mmol), 7b(15.92 mg, 0.10 mmol)를 사용하여 18f를 흰색 고체(31.22 mg, 70.1%)를 얻었다.According to General Procedure D, 17 (30.21 mg, 0.10 mmol), 7b (15.92 mg, 0.10 mmol) was used to obtain 18f as a white solid (31.22 mg, 70.1%).
1H NMR(400 MHz, CDCl3) δ 7.68(d, J = 1.1 Hz, 1H), 7.32 - 7.29(m, 2H), 7.22(d, J = 1.9 Hz, 2H), 7.17(t, J = 7.8 Hz, 1H), 7.06(t, J = 2.0 Hz, 1H), 7.01(d, J = 7.7 Hz, 1H), 6.50(ddd, J = 8.1, 2.4, 1.0 Hz, 1H), 5.06(s, 2H), 4.18 - 3.94(m, 2H), 3.49(tt, J = 10.1, 3.9 Hz, 1H), 3.06 - 2.91(m, 2H), 2.09 - 2.00(m, 2H), 1.40 - 1.28(m, 2H). 13C NMR(100 MHz, CDCl3) δ 154.89, 147.33, 140.40, 138.95, 135.62, 135.28, 134.00, 129.98, 128.32, 126.22, 115.94, 114.62, 112.52, 109.93, 65.69, 49.92, 43.09, 32.44. HRMS(ESI) m/z(M+H)+ calcd for C22H23Cl2N4O2 = 445.12; found 445.1203. 1H NMR (400 MHz, CDCl 3 ) δ 7.68 (d, J = 1.1 Hz, 1H), 7.32 - 7.29 (m, 2H), 7.22 (d, J = 1.9 Hz, 2H), 7.17 (t, J = 7.8 Hz, 1H), 7.06 (t, J = 2.0 Hz, 1H), 7.01 (d, J = 7.7 Hz, 1H), 6.50 (ddd, J = 8.1, 2.4, 1.0 Hz, 1H), 5.06 (s, 2H), 4.18 - 3.94(m, 2H), 3.49(tt, J = 10.1, 3.9 Hz, 1H), 3.06 - 2.91(m, 2H), 2.09 - 2.00(m, 2H), 1.40 - 1.28(m, 2H). 13 C NMR (100 MHz, CDCL 3 ) δ 154.89, 147.33, 140.40, 138.95, 135.62, 135.28, 134.00, 129.98, 128.32, 126.22, 115.94, 114.62, 112.52, 109.93 HRMS(ESI) m/z(M+H) + calcd for C 22 H 23 Cl 2 N 4 O 2 = 445.12; found 445.1203.
3,5-디클로로벤질 4-((4-(2-메틸-13,5-dichlorobenzyl 4-((4-(2-methyl-1 HH -이미다졸-5-일)페닐)아미노)피페리딘-1-카복실레이트(18g).-imidazol-5-yl)phenyl)amino)piperidine-1-carboxylate (18 g).
일반적인 공정 D에 따라, 17(30.21 mg, 0.10 mmol) 및 9a(17.32 mg, 0.10 mmol)를 사용하여 18g를 흰색 고체(38.63 mg, 84.1%)로 얻었다.According to general process D, 17 (30.21 mg, 0.10 mmol) and 9a (17.32 mg, 0.10 mmol) to give 18g as a white solid (38.63 mg, 84.1%).
1H NMR(400 MHz, CDCl3) δ 7.48(d, J = 8.6 Hz, 2H), 7.30(t, J = 1.9 Hz, 1H), 7.24 - 7.21(m, 2H), 7.03(s, 1H), 6.60(d, J = 8.7 Hz, 2H), 5.07(s, 2H), 4.18 - 4.05(m, 2H), 3.50 - 3.42(m, 1H), 3.12 - 2.97(m, 2H), 2.42(s, 3H), 2.13 - 2.05(m, 2H), 1.42 - 1.31(m, 2H). 13C NMR(100 MHz, CDCl3) δ 154.72, 145.52, 144.37, 144.07, 140.20, 138.32, 135.10, 128.15, 126.06, 125.99, 122.90, 113.56, 65.53, 49.95, 42.97, 32.36, 14.24. HRMS(ESI) m/z(M+H)+ calcd for C23H25Cl2N4O2= 459.14; found 459.1351. 1 H NMR (400 MHz, CDCl 3 ) δ 7.48 (d, J = 8.6 Hz, 2H), 7.30 (t, J = 1.9 Hz, 1H), 7.24 - 7.21 (m, 2H), 7.03 (s, 1H) , 6.60 (d, J = 8.7 Hz, 2H), 5.07 (s, 2H), 4.18 - 4.05 (m, 2H), 3.50 - 3.42 (m, 1H), 3.12 - 2.97 (m, 2H), 2.42 (s , 3H), 2.13 - 2.05 (m, 2H), 1.42 - 1.31 (m, 2H). 13 C NMR (100 MHz, CDCL 3 ) δ 154.72, 145.52, 144.37, 144.07, 140.20, 138.32, 135.10, 128.15, 126.06, 125.99, 122.90, 113.56, 65.53, 49.95, 42.97, 32.36, 14.4. HRMS(ESI) m/z(M+H) + calcd for C 23 H 25 Cl 2 N 4 O 2 = 459.14; found 459.1351.
3,5-디클로로벤질 4-((3-(2-메틸-13,5-Dichlorobenzyl 4-((3-(2-methyl-1 HH -이미다졸-5-일)페닐)아미노)피페리딘-1-카복실레이트(18h).-imidazol-5-yl)phenyl)amino)piperidine-1-carboxylate (18h).
일반적인 공정 D에 따라, 17(30.21 mg, 0.10 mmol) 및 9b(17.32 mg, 0.10 mmol)를 사용하여 18h를 흰색 고체(40.38 mg, 87.9%)로 얻었다.According to general procedure D, using 17 (30.21 mg, 0.10 mmol) and 9b (17.32 mg, 0.10 mmol), 18h was obtained as a white solid (40.38 mg, 87.9%).
1H NMR(400 MHz, , CDCl3) δ 7.30(t, J = 1.9 Hz, 1H), 7.22(d, J = 1.9 Hz, 2H), 7.18 - 7.16(m, 1H), 7.13(t, J = 7.8 Hz, 1H), 7.02 - 6.99(m, 1H), 6.97(dt, J = 7.8, 1.2 Hz, 1H), 6.47(ddd, J = 8.1, 2.4, 1.0 Hz, 1H), 5.06(s, 2H), 4.14 - 3.96(m, 2H), 3.52 - 3.39(m, 1H), 3.05 - 2.86(m, 2H), 2.41(s, 3H), 2.07 - 1.99(m, 2H), 1.38 - 1.25(m, 2H). 13C NMR(100 MHz, CDCl3) δ 154.70, 147.10, 144.86, 140.23, 135.09, 134.11, 129.70, 128.13, 126.04, 114.23, 111.95, 109.63, 65.49, 49.76, 42.91, 32.37, 14.21. HRMS(ESI) m/z(M+H)+ calcd for C23H25Cl2N4O2= 459.14; found 459.1351 1H NMR (400 MHz, , CDCl 3 ) δ 7.30 (t, J = 1.9 Hz, 1H), 7.22 (d, J = 1.9 Hz, 2H), 7.18 - 7.16 (m, 1H), 7.13 (t, J = 7.8 Hz, 1H), 7.02 - 6.99 (m, 1H), 6.97 (dt, J = 7.8, 1.2 Hz, 1H), 6.47 (ddd, J = 8.1, 2.4, 1.0 Hz, 1H), 5.06 (s, 2H), 4.14 - 3.96(m, 2H), 3.52 - 3.39(m, 1H), 3.05 - 2.86(m, 2H), 2.41(s, 3H), 2.07 - 1.99(m, 2H), 1.38 - 1.25( m, 2H). 13 C NMR (100 MHz, CDCL 3 ) δ 154.70, 147.10, 144.86, 140.23, 135.09, 134.11, 129.70, 128.13, 126.04, 114.23, 111.95, 109.63, 65.49, 49.76, 42.91, 32.37, 14.21. HRMS(ESI) m/z(M+H) + calcd for C 23 H 25 Cl 2 N 4 O 2 = 459.14; found 459.1351
3,5-디클로로벤질 4-((4-(4-메틸-13,5-Dichlorobenzyl 4-((4-(4-methyl-1 HH -이미다졸-5-일)페닐)아미노)피페리딘-1-카복실레이트(18i).-imidazol-5-yl)phenyl)amino)piperidine-1-carboxylate (18i).
일반적인 공정 D에 따라, 17(30.21 mg, 0.10 mmol) 및 12a(17.32 mg, 0.10 mmol)를 사용하여 18i를 흰색 고체(23.11 mg, 50.3%)로 얻었다.According to General Procedure D, using 17 (30.21 mg, 0.10 mmol) and 12a (17.32 mg, 0.10 mmol), 18i was obtained as a white solid (23.11 mg, 50.3%).
1H NMR(400 MHz, CDCl3) δ 10.02(s, 1H), 7.47(s, 1H), 7.38(d, J = 8.6 Hz, 2H), 7.30(t, J = 1.9 Hz, 1H), 7.22(d, J = 2.0 Hz, 2H), 6.63(d, J = 8.7 Hz, 2H), 5.06(s, 2H), 4.18 - 4.04(m, 2H), 3.70 - 3.54(m, 1H), 3.52 - 3.43(m, 1H), 3.15 - 2.96(m, 2H), 2.38(s, 3H), 2.13 - 2.03(m, 2H), 1.45 - 1.31(m, 2H). 13C NMR(100 MHz, CDCl3) δ 154.72, 145.26, 140.18, 135.09, 133.01, 128.14, 127.96, 126.05, 113.40, 65.53, 49.90, 42.96, 32.31, 12.35. HRMS(ESI) m/z(M+H)+ calcd for C23H25Cl2N4O2= 459.14; found 459.1349 1 H NMR (400 MHz, CDCl 3 ) δ 10.02 (s, 1H), 7.47 (s, 1H), 7.38 (d, J = 8.6 Hz, 2H), 7.30 (t, J = 1.9 Hz, 1H), 7.22 (d, J = 2.0 Hz, 2H), 6.63 (d, J = 8.7 Hz, 2H), 5.06 (s, 2H), 4.18 - 4.04 (m, 2H), 3.70 - 3.54 (m, 1H), 3.52 - 3.43 (m, 1H), 3.15 - 2.96 (m, 2H), 2.38 (s, 3H), 2.13 - 2.03 (m, 2H), 1.45 - 1.31 (m, 2H). 13 C NMR (100 MHz, CDCl 3 ) δ 154.72, 145.26, 140.18, 135.09, 133.01, 128.14, 127.96, 126.05, 113.40, 65.53, 49.90, 42.96, 32.31, 12.35 HRMS(ESI) m/z(M+H) + calcd for C 23 H 25 Cl 2 N 4 O 2 = 459.14; found 459.1349
3,5-디클로로벤질 4-((3-(4-메틸-1H-이미다졸-5-일)페닐)아미노)피페리딘-1-카복실레이트(18j).3,5-dichlorobenzyl 4-((3-(4-methyl-1H-imidazol-5-yl)phenyl)amino)piperidine-1-carboxylate (18j).
일반적인 공정 D에 따라, 17(30.21 mg, 0.10 mmol) 및 12b(17.32 mg, 0.10 mmol)를 사용하여 18j를 흰색 고체(33.58 mg, 73.1%)로 얻었다.According to General Procedure D, using 17 (30.21 mg, 0.10 mmol) and 12b (17.32 mg, 0.10 mmol), 18j was obtained as a white solid (33.58 mg, 73.1%).
1H NMR(400 MHz, CDCl3) δ 9.14(s, 1H), 7.51(s, 1H), 7.29(t, J = 2.0 Hz, 1H), 7.21(d, J = 1.9 Hz, 2H), 7.17(t, J = 8.0 Hz, 1H), 6.91 - 6.85(m, 2H), 6.49(ddd, J = 8.1, 2.3, 1.0 Hz, 1H), 5.05(s, 2H), 4.14 - 3.97(m, 2H), 3.46 - 3.38(m, 1H), 3.01 - 2.84(m, 2H), 2.41(s, 3H), 2.06 - 1.98(m, 2H), 1.36 - 1.25(m, 2H). 13C NMR(100 MHz, CDCl3) δ 154.70, 146.96, 140.19, 135.08, 134.58, 133.36, 132.64, 129.54, 128.12, 126.61, 126.03, 116.11, 111.74, 111.53, 65.50, 49.77, 42.91, 32.18, 12.39. HRMS(ESI) m/z(M+H)+ calcd for C23H25Cl2N4O2= 459.14; found 459.1350 1 H NMR (400 MHz, CDCl 3 ) δ 9.14 (s, 1H), 7.51 (s, 1H), 7.29 (t, J = 2.0 Hz, 1H), 7.21 (d, J = 1.9 Hz, 2H), 7.17 (t, J = 8.0 Hz, 1H), 6.91 - 6.85 (m, 2H), 6.49 (ddd, J = 8.1, 2.3, 1.0 Hz, 1H), 5.05 (s, 2H), 4.14 - 3.97 (m, 2H) ), 3.46 - 3.38 (m, 1H), 3.01 - 2.84 (m, 2H), 2.41 (s, 3H), 2.06 - 1.98 (m, 2H), 1.36 - 1.25 (m, 2H). 13 C NMR (100 MHz, CDCL 3 ) δ 154.70, 146.96, 140.19, 135.08, 134.58, 133.36, 132.64, 129.54, 128.12, 126.61, 126.03, 116.11, 111.74 HRMS(ESI) m/z(M+H) + calcd for C 23 H 25 Cl 2 N 4 O 2 = 459.14; found 459.1350
3,5-디클로로벤질 4-((4-(5-옥소-4,5-디하이드로-1,3,4-옥사다이아졸-2-일)페닐)아미노)피페리딘-1-카복실레이트(18k).3,5-Dichlorobenzyl 4-((4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)amino)piperidine-1-carboxylate (18k).
일반적인 공정 D에 따라, 17(30.21 mg, 0.10 mmol) 및 14a(17.72 mg, 0.10 mmol)를 사용하여 18k를 흰색 고체(16.63 mg, 35.9%)로 얻었다.According to General Procedure D, using 17 (30.21 mg, 0.10 mmol) and 14a (17.72 mg, 0.10 mmol), 18k was obtained as a white solid (16.63 mg, 35.9%).
1H NMR(400 MHz, CDCl3) δ 9.04(s, 1H), 7.65(d, J = 8.8 Hz, 2H), 7.31(t, J = 2.0 Hz, 1H), 7.24(d, J = 1.9 Hz, 2H), 6.62(d, J = 8.8 Hz, 2H), 5.08(s, 2H), 4.22 - 4.09(m, 2H), 4.00(d, J = 7.8 Hz, 1H), 3.59 - 3.49(m, 1H), 3.15 - 2.99(m, 2H), 2.13 - 2.06(m, 2H), 1.49 - 1.37(m, 2H). 13C NMR(100 MHz, CDCl3) δ 155.91, 154.71, 149.33, 140.06, 135.12, 128.21, 127.60, 126.11, 112.64, 112.30, 65.64, 49.54, 42.86, 32.03. HRMS(ESI) m/z(M+H)+ calcd for C21H21Cl2N4O4= 463.09; found 463.0936 1H NMR (400 MHz, CDCl 3 ) δ 9.04 (s, 1H), 7.65 (d, J = 8.8 Hz, 2H), 7.31 (t, J = 2.0 Hz, 1H), 7.24 (d, J = 1.9 Hz , 2H), 6.62 (d, J = 8.8 Hz, 2H), 5.08 (s, 2H), 4.22 - 4.09 (m, 2H), 4.00 (d, J = 7.8 Hz, 1H), 3.59 - 3.49 (m, 1H), 3.15 - 2.99 (m, 2H), 2.13 - 2.06 (m, 2H), 1.49 - 1.37 (m, 2H). 13 C NMR (100 MHz, CDCl 3 ) δ 155.91, 154.71, 149.33, 140.06, 135.12, 128.21, 127.60, 126.11, 112.64, 112.30, 65.64, 49.54, 42.86, 32.06. HRMS (ESI) m/z(M+H) + calcd for C 21 H 21 Cl 2 N 4 O 4 = 463.09; found 463.0936
3,5-디클로로벤질 4-((3-(5-옥소-4,5-디하이드로-1,3,4-옥사다이아졸-2-일)페닐)아미노)피페리딘-1-카복실레이트(18l).3,5-Dichlorobenzyl 4-((3-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)amino)piperidine-1-carboxylate (18l).
일반적인 공정 D에 따라, 17(30.21 mg, 0.10 mmol) 및 14b(17.72 mg, 0.10 mmol)를 사용하여 18l를 흰색 고체(29.93 mg, 64.6%)로 얻었다.According to general procedure D, using 17 (30.21 mg, 0.10 mmol) and 14b (17.72 mg, 0.10 mmol), 18l was obtained as a white solid (29.93 mg, 64.6%).
1H NMR(400 MHz, CDCl3) δ 9.82(s, 1H), 7.30(t, J = 1.9 Hz, 1H), 7.27 - 7.25(m, 1H), 7.23(d, J = 2.2 Hz, 2H), 7.18(dt, J = 7.7, 1.3 Hz, 1H), 7.04(t, J = 2.0 Hz, 1H), 6.72(ddd, J = 8.1, 2.5, 1.1 Hz, 1H), 5.09(s, 2H), 4.23 - 4.05(m, 2H), 3.84 - 3.72(m, 1H), 3.59 - 3.47(m, 1H), 3.16 - 2.99(m, 2H), 2.16 - 2.04(m, 2H), 1.46 - 1.32(m, 2H). 13C NMR(100 MHz, CDCl3) δ 155.62, 155.02, 154.82, 147.00, 140.06, 135.12, 130.07, 128.20, 126.10, 124.75, 116.77, 114.99, 109.40, 65.69, 49.69, 42.93, 32.05. HRMS(ESI) m/z(M+H)+ calcd for C21H21Cl2N4O4= 463.09; found 463.0935 1 H NMR (400 MHz, CDCl 3 ) δ 9.82 (s, 1H), 7.30 (t, J = 1.9 Hz, 1H), 7.27 - 7.25 (m, 1H), 7.23 (d, J = 2.2 Hz, 2H) , 7.18 (dt, J = 7.7, 1.3 Hz, 1H), 7.04 (t, J = 2.0 Hz, 1H), 6.72 (ddd, J = 8.1, 2.5, 1.1 Hz, 1H), 5.09 (s, 2H), 4.23 - 4.05(m, 2H), 3.84 - 3.72(m, 1H), 3.59 - 3.47(m, 1H), 3.16 - 2.99(m, 2H), 2.16 - 2.04(m, 2H), 1.46 - 1.32(m , 2H). 13 C NMR (100 MHz, CDCL 3 ) Δ 155.62, 155.02, 154.82, 147.00, 140.06, 135.12, 130.07, 128.20, 126.10, 124.75, 116.77, 114.99, 109.40, 65.69, 49.69, 42.93, 32.05 HRMS (ESI) m/z(M+H) + calcd for C 21 H 21 Cl 2 N 4 O 4 = 463.09; found 463.0935
3,5-디클로로벤질 4-((3-(2-메틸옥사졸-5-일)페닐)아미노)피페리딘-1-카복실레이트(18m): 3,5-Dichlorobenzyl 4-((3-(2-methyloxazol-5-yl)phenyl)amino)piperidine-1-carboxylate (18m):
일반적인 공정 D에 따라, 17(30.21 mg, 0.10 mmol) 및 15(17.42 mg, 0.10 mmol)를 사용하여 18m을 흰색 고체(33.33 mg, 74.2%)로 얻었다.Using 17 (30.21 mg, 0.10 mmol) and 15 (17.42 mg, 0.10 mmol) according to General Procedure D, 18m was obtained as a white solid (33.33 mg, 74.2%).
1H NMR(400 MHz, CDCl3) δ 7.76(s, 1H), 7.30(t, J = 2.0 Hz, 1H), 7.23(d, J = 1.9 Hz, 2H), 7.18(t, J = 7.8 Hz, 1H), 7.03 - 6.97(m, 2H), 6.55(ddd, J = 8.1, 2.4, 1.0 Hz, 1H), 5.07(s, 2H), 4.18 - 4.04(m, 2H), 3.65 - 3.50(m, 2H), 3.13 - 2.99(m, 2H), 2.50(s, 3H), 2.14 - 2.05(m, 2H), 1.37(m, 2H). 13C NMR(100 MHz, CDCl3) δ 161.67, 154.71, 147.08, 140.83, 140.23, 135.10, 133.28, 132.25, 129.74, 128.15, 126.08, 114.84, 112.81, 110.45, 65.52, 49.77, 42.95, 32.41, 14.04. HRMS(ESI) m/z(M+H)+ calcd for C23H24Cl2N3O3= 460.12; found 460.1191 1H NMR (400 MHz, CDCl 3 ) δ 7.76 (s, 1H), 7.30 (t, J = 2.0 Hz, 1H), 7.23 (d, J = 1.9 Hz, 2H), 7.18 (t, J = 7.8 Hz , 1H), 7.03 - 6.97 (m, 2H), 6.55 (ddd, J = 8.1, 2.4, 1.0 Hz, 1H), 5.07 (s, 2H), 4.18 - 4.04 (m, 2H), 3.65 - 3.50 (m , 2H), 3.13 - 2.99 (m, 2H), 2.50 (s, 3H), 2.14 - 2.05 (m, 2H), 1.37 (m, 2H). 13 C NMR (100 MHz, CDCL 3 ) δ 161.67, 154.71, 147.08, 140.83, 140.23, 135.10, 133.28, 132.25, 129.74, 128.15, 126.08, 114.84, 112.81 HRMS(ESI) m/z(M+H) + calcd for C 23 H 24 Cl 2 N 3 O 3 = 460.12; found 460.1191
3,5-디클로로벤질 4-((3-(13,5-Dichlorobenzyl 4-((3-(1 HH -1,2,3-트리아졸-5-일)페닐)아미노)피페리딘-1-카복실레이트(18n).-1,2,3-triazol-5-yl)phenyl)amino)piperidine-1-carboxylate (18n).
일반적인 공정 D에 따라, 17(30.21 mg, 0.10 mmol) 및 16(16.02 mg, 0.10 mmol)을 사용하여 18n을 흰색 고체(9.06 mg, 50.3%)로 얻었다.According to General Procedure D, using 17 (30.21 mg, 0.10 mmol) and 16 (16.02 mg, 0.10 mmol), 18n was obtained as a white solid (9.06 mg, 50.3%).
1H NMR(400 MHz, CDCl3) δ 7.93(s, 1H), 7.30(t, J = 1.9 Hz, 1H), 7.26 - 7.21(m, 3H), 7.14 - 7.09(m, 2H), 6.62(ddd, J = 8.1, 2.4, 1.1 Hz, 1H), 5.08(s, 2H), 4.21 - 4.04(m, 2H), 3.60 - 3.52(m, 1H), 3.14 - 2.94(m, 2H), 2.18 - 2.03(m, 2H), 1.47 - 1.32(m, 2H). 13C NMR(100 MHz, CDCl3) δ 154.81, 147.19, 140.12, 135.11, 130.81, 130.02, 128.17, 126.08, 115.62, 113.77, 110.70, 65.62, 49.78, 42.96, 32.25. HRMS(ESI) m/z(M+H)+ calcd for C21H22Cl2N5O2= 446.12; found 446.1160. 1 H NMR (400 MHz, CDCl 3 ) δ 7.93 (s, 1H), 7.30 (t, J = 1.9 Hz, 1H), 7.26 - 7.21 (m, 3H), 7.14 - 7.09 (m, 2H), 6.62 ( ddd, J = 8.1, 2.4, 1.1 Hz, 1H), 5.08 (s, 2H), 4.21 - 4.04 (m, 2H), 3.60 - 3.52 (m, 1H), 3.14 - 2.94 (m, 2H), 2.18 - 2.03 (m, 2H), 1.47 - 1.32 (m, 2H). 13 C NMR (100 MHz, CDCl 3 ) δ 154.81, 147.19, 140.12, 135.11, 130.81, 130.02, 128.17, 126.08, 115.62, 113.77, 110.70, 65.62, 49.26, 42.96, 42.98 HRMS(ESI) m/z(M+H) + calcd for C 21 H 22 Cl 2 N 5 O 2 = 446.12; found 446.1160.
제법 3. 빌딩 블럭 F, G의 합성Preparation method 3. Synthesis of building blocks F and G
시약 및 조건:(a) Me3SiN3, CuI, DMF, MeOH, 100 ℃, 12 h;(b) 디옥산 중 4M HCl, 18 h;(c)(Boc)2O, Et3N, CH2-Cl2, 15 h;(d) N2H4.H2O, MeOH, reflux, 6 h;(e) CDI, DMF, 80 ℃, 15 h.Reagents and conditions: (a) Me 3 SiN 3 , CuI, DMF, MeOH, 100 °C, 12 h; (b) 4M HCl in dioxane, 18 h; (c) (Boc) 2 O, Et 3 N, CH 2- Cl 2 , 15 h; (d) N 2 H 4 .H 2 O, MeOH, reflux, 6 h; (e) CDI, DMF, 80 °C, 15 h.
tt -부틸 4-(1-Butyl 4-(1 HH -1,2,3-트리아졸-5-일)피페리딘-1-카복실레이트(19).-1,2,3-triazol-5-yl)piperidine-1-carboxylate (19).
t-부틸 4-에티닐피페리딘-1-카복실레이트(1.05 g, 5.00 mmol), 트라이메틸실릴 아자이드(5.5 mmol) 및 카파(I) 아이오다이드(0.25 mmol)를 아르곤하에서 DMF(9 mL) 및 MeOH(1 mL)의 용액에 첨가하였다. 반응 혼합물을 100 ℃에서 8h 동안 교반하였다. 용매를 증발시켜 건조시키고, 에틸아세테이트로 추출하고 브라인으로 세척하였다. 유기층을 무수 소듐 설페이트로 탈수시키고 농축하였다. 생성물을 컬럼 크로마토그래피(CH2Cl2/MeOH)로 정제하고 19를 흰색 고체(1.03 g, 81.3%)로 얻었다. t -Butyl 4-ethynylpiperidine-1-carboxylate (1.05 g, 5.00 mmol), trimethylsilyl azide (5.5 mmol) and kappa(I) iodide (0.25 mmol) were dissolved in DMF (9 mL) under argon. ) and MeOH (1 mL). The reaction mixture was stirred at 100 °C for 8 h. The solvent was evaporated to dryness, extracted with ethyl acetate and washed with brine. The organic layer was dehydrated over anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (CH 2 Cl 2 /MeOH) to give 19 as a white solid (1.03 g, 81.3%).
1H NMR(400 MHz, CDCl3) δ 12.73(br s, 1H), 7.52(s, 1H), 4.32 - 4.01(m, 2H), 3.00 - 2.86(m, 3H), 2.04 - 1.97(m, 2H), 1.73 - 1.60(m, 2H), 1.48(s, 9H). 1 H NMR (400 MHz, CDCl 3 ) δ 12.73 (br s, 1H), 7.52 (s, 1H), 4.32 - 4.01 (m, 2H), 3.00 - 2.86 (m, 3H), 2.04 - 1.97 (m, 2H), 1.73 - 1.60 (m, 2H), 1.48 (s, 9H).
4-(14-(1 HH -1,2,3-트리아졸-5-일)피페리딘 하이드로클로라이드(20).-1,2,3-triazol-5-yl)piperidine hydrochloride (20).
디옥산(10 mL) 중 19(1.01 g, 4.00 mmol)의 용액에 디옥산(2 mL) 중 4.0 M 하이드로젠 클로라이드 용액을 첨가하였다. 반응 혼합물을 실온에서 밤새 교반하였다. 용매를 증발시켜 건조시키고 20을 흰색 고체(정량적)로 얻었다.To a solution of 19 (1.01 g, 4.00 mmol) in dioxane (10 mL) was added a 4.0 M hydrogen chloride solution in dioxane (2 mL). The reaction mixture was stirred overnight at room temperature. The solvent was evaporated to dryness and 20 was obtained as a white solid (quantitative).
1H NMR(400 MHz, MeOD) δ 8.37(s, 1H), 3.56 - 3.47(m, 2H), 3.44 - 3.35(m, 1H), 3.27 - 3.18(m, 2H), 2.37 - 2.30(m, 2H), 2.12 - 1.98(m, 2H). 1 H NMR (400 MHz, MeOD) δ 8.37 (s, 1H), 3.56 - 3.47 (m, 2H), 3.44 - 3.35 (m, 1H), 3.27 - 3.18 (m, 2H), 2.37 - 2.30 (m, 2H), 2.12 - 1.98 (m, 2H).
1-One- tt -부틸 4-메틸 피페리딘-1,4-디카복실레이트(21).-Butyl 4-methylpiperidine-1,4-dicarboxylate (21).
CH2Cl2(20 mL) 중 메틸 피페리딘-4-카복실레이트(1.43 g, 10.00 mmol), 트리에틸아민(2.02 g, 20.00 mmol)을 함유한 둥근바닥플라스크에 0 ℃에서 테트라하이드로푸란 중 디-tert-부틸 디카보네이트 30% (10.91 g, 15.00 mmol)를 첨가하였다. 반응 혼합물을 실온에서 밤새 교반하였다. 용액을 농축시키고 잔여물을 컬럼 크로마토그래피(에틸아세테이트/헥산)로 정제하여 21을 흰색 고체(2.08 g, 85.5%)로 얻었다.To a round bottom flask containing methyl piperidine-4-carboxylate (1.43 g, 10.00 mmol), triethylamine (2.02 g, 20.00 mmol) in CH 2 Cl 2 (20 mL) in tetrahydrofuran at 0 °C. Di-tert-butyl dicarbonate 30% (10.91 g, 15.00 mmol) was added. The reaction mixture was stirred overnight at room temperature. The solution was concentrated and the residue was purified by column chromatography (ethyl acetate/hexane) to give 21 as a white solid (2.08 g, 85.5%).
1H NMR(400 MHz, CDCl3) δ 4.09 - 3.94(m, 2H), 3.69(s, 3H), 2.88 - 2.77(m, 2H), 2.50 - 2.41(m, 1H), 1.91 - 1.83(m, 2H), 1.69 - 1.57(m, 2H), 1.46(s, 9H). 1 H NMR (400 MHz, CDCl 3 ) δ 4.09 - 3.94 (m, 2H), 3.69 (s, 3H), 2.88 - 2.77 (m, 2H), 2.50 - 2.41 (m, 1H), 1.91 - 1.83 (m , 2H), 1.69 - 1.57 (m, 2H), 1.46 (s, 9H).
tt -부틸 4-(히드라진카보닐)피페리딘-1-카복실레이트(22).-Butyl 4-(hydrazinecarbonyl)piperidine-1-carboxylate (22).
MeOH(10 mL) 중 21(1.21 g, 5.00 mmol) 및 히드라진 모노하이드레이트(0.5 mL)의 혼합물을 1 h 동안 환류시켰다. 용매를 회전식 증발기로 제거하고 잔여물(크루드 22; 흰색 고체; 정량적)을 더 이상의 정제없이 다음 단계에 사용하였다.A mixture of 21 (1.21 g, 5.00 mmol) and hydrazine monohydrate (0.5 mL) in MeOH (10 mL) was refluxed for 1 h. The solvent was removed by rotary evaporator and the residue (crude 22; white solid; quantitative) was used in the next step without further purification.
1H NMR(400 MHz, CDCl3) δ 7.12(s, 1H), 4.25 - 4.07(m, 2H), 4.03 - 3.64(m, 2H), 2.82 - 2.66(m, 2H), 2.34 - 2.15(m, 1H), 1.86 - 1.75(m, 2H), 1.71 - 1.58(m, 2H), 1.46(s, 9H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.12 (s, 1H), 4.25 - 4.07 (m, 2H), 4.03 - 3.64 (m, 2H), 2.82 - 2.66 (m, 2H), 2.34 - 2.15 (m , 1H), 1.86 - 1.75 (m, 2H), 1.71 - 1.58 (m, 2H), 1.46 (s, 9H).
tt -부틸 4-(5-옥소-4,5-디하이드로-1,3,4-옥사다이아졸-2-일)피페리딘-1-카복실레이트(23).-Butyl 4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate (23).
DMF(25 mL) 중 22(1.22 g, 5.0 mmol)의 혼합물에 1,1'-카보닐디이미다졸(0.973 g, 6.0 mmol)을 첨가하였다. 반응 혼합물을 80 ℃에서 밤새 교반하였다. 용매를 증발시켜 건조시켰다. 생성물을 에틸아세테이트로 추출하고 물로 세척하였다. 유기층을 무수 소듐 설페이트로 탈수시키고 농축시켰다. 잔여물을 컬럼 크로마토그래피(에틸아세테이트/헥산)로 정제하여 23을 흰색 고체(0.97 g, 72.2%)로 얻었다.To a mixture of 22 (1.22 g, 5.0 mmol) in DMF (25 mL) was added 1,1'-carbonyldiimidazole (0.973 g, 6.0 mmol). The reaction mixture was stirred overnight at 80 °C. The solvent was evaporated to dryness. The product was extracted with ethyl acetate and washed with water. The organic layer was dehydrated with anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (ethyl acetate/hexane) to obtain 23 as a white solid (0.97 g, 72.2%).
1H NMR(400 MHz, CDCl3) δ 8.87(br s, 1H), 4.21 - 3.91(m, 2H), 2.99 - 2.85(m, 2H), 2.81 - 2.70(m, 1H), 2.00 - 1.93(m, 2H), 1.77 - 1.61(m, 2H), 1.47(s, 9H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.87 (br s, 1H), 4.21 - 3.91 (m, 2H), 2.99 - 2.85 (m, 2H), 2.81 - 2.70 (m, 1H), 2.00 - 1.93 ( m, 2H), 1.77 - 1.61 (m, 2H), 1.47 (s, 9H).
5-(피페리딘-4-일)-1,3,4-옥사다이아졸-2(35-(piperidin-4-yl)-1,3,4-oxadiazole-2(3 HH )-론 하이드로클로라이드(24). )-rone hydrochloride (24).
디옥산(10 mL) 중 23(0.97 g, 3.60 mmol)의 용액에 디옥산(2 mL) 중 4.0 M 하이드로젠 클로라이드 용액을 첨가하였다. 반응 혼합물을 실온에서 밤새 교반하였다. 용매를 증발시켜 건조시켜 24를 흰색 고체(정량적)로 얻었다.To a solution of 23 (0.97 g, 3.60 mmol) in dioxane (10 mL) was added a 4.0 M hydrogen chloride solution in dioxane (2 mL). The reaction mixture was stirred overnight at room temperature. The solvent was evaporated to dryness to give 24 as a white solid (quantitatively).
1H NMR(400 MHz, D2O ) δ 3.50 - 3.38(m, 2H), 3.19 - 3.04(m, 3H), 2.28 - 2.17(m, 2H), 1.98 - 1.83(m, 2H). 1 H NMR (400 MHz, D 2 O ) δ 3.50 - 3.38 (m, 2H), 3.19 - 3.04 (m, 3H), 2.28 - 2.17 (m, 2H), 1.98 - 1.83 (m, 2H).
제법 4. 화합물 27a-g의 합성Preparation 4. Synthesis of compounds 27a-g
f시약 및 조건:(a) i: CDI, DMF, 6 h, ii: 메틸 4-피페리딘카복실레이트, 15 h;(b); i: LiOH, THF, MeOH, H2O, 6 h, ii: 1M HCl;(c) i: HBTU, DIEA, DMF, ii: 3a-b, 7a-b, 4-(1H-이미다졸-5-일)피페리딘, 20, 또는 24,15 h;(d) TFA, CH2Cl2, 3 h. f Reagents and conditions: (a) i: CDI, DMF, 6 h, ii: methyl 4-piperidinecarboxylate, 15 h; (b); i: LiOH, THF, MeOH, H 2 O, 6 h, ii: 1M HCl; (c) i: HBTU, DIEA, DMF, ii: 3a-b , 7a-b , 4-( 1H -imidazole- 5-day) piperidine, 20 , or 24 , 15 h; (d) TFA, CH 2 Cl 2 , 3 h.
1-(3,5-디클로로벤질) 4-메틸 피페리딘-1,4-디카복실레이트(25). 1-(3,5-dichlorobenzyl) 4-methylpiperidine-1,4-dicarboxylate (25).
일반적인 공정 C에 따라, 3,5-디클로로벤질 알코올(1.77g, 10.00 mmol) 및 메틸 4-피페리딘카복실레이트(2.86 g, 20.00 mmol)을 사용하여 25를 무색 오일(2.55 g, 73.6%)로 얻었다.According to General Procedure C, using 3,5-dichlorobenzyl alcohol (1.77 g, 10.00 mmol) and methyl 4-piperidinecarboxylate (2.86 g, 20.00 mmol), 25 was prepared as a colorless oil (2.55 g, 73.6%) got it with
1H NMR(400 MHz, CDCl3) δ 7.32 - 7.29(m, 1H), 7.24 - 7.20(m, 2H), 5.06(d, J = 5.2 Hz, 2H), 4.17 - 3.99(m, 2H), 3.70(d, J = 0.8 Hz, 3H), 3.06 - 2.88(m, 2H), 2.55 - 2.45(m, 1H), 1.99 - 1.87(m, 2H), 1.73 - 1.61(m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.32 - 7.29 (m, 1H), 7.24 - 7.20 (m, 2H), 5.06 (d, J = 5.2 Hz, 2H), 4.17 - 3.99 (m, 2H), 3.70 (d, J = 0.8 Hz, 3H), 3.06 - 2.88 (m, 2H), 2.55 - 2.45 (m, 1H), 1.99 - 1.87 (m, 2H), 1.73 - 1.61 (m, 2H).
1-(((3,5-디클로로벤질)옥시)카보닐)피페리딘-4-카복실산(26). 1-(((3,5-dichlorobenzyl)oxy)carbonyl)piperidine-4-carboxylic acid (26).
물(10 mL) 중 리튬 하이드록사이드(0.600 g, 25 mmol)의 용액을 THF/MeOH(18ml / 2ml) 중 25(2.18 g, 5.00 mmol)의 혼합물의 용액에 첨가하였다. 반응 혼합물을 실온에서 6 h 동안 교반하였다. 다음에 용매를 증발시키고 물에 다시 용해시키고 1M HCl 용액으로 산성화시켰다. 혼합물을 에틸아세테이트로 추출하고 물로 세척하였다. 유기층을 무수 소듐 설페이트로 탈수시키고 농축하였다. 생성물을 컬럼 크로마토그래피(에틸아세테이트/헥산)로 정제하여 26을 흰색 고체(정량적)로 얻었다.A solution of lithium hydroxide (0.600 g, 25 mmol) in water (10 mL) was added to a solution of a mixture of 25 (2.18 g, 5.00 mmol) in THF/MeOH (18 ml / 2 ml). The reaction mixture was stirred at room temperature for 6 h. Then the solvent was evaporated, re-dissolved in water and acidified with 1M HCl solution. The mixture was extracted with ethyl acetate and washed with water. The organic layer was dehydrated over anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (ethyl acetate/hexane) to obtain 26 as a white solid (quantitatively).
1H NMR(400 MHz, CDCl3) δ 10.84(s, 1H), 7.30(t, J = 1.9 Hz, 1H), 7.22(d, J = 1.8 Hz, 2H), 5.07(d, J = 5.1 Hz, 2H), 4.16 - 4.02(m, 2H), 3.07 - 2.90(m, 2H), 2.62 - 2.45(m, 1H), 2.02 - 1.92(m, 2H), 1.77 - 1.61(m, 2H). 1H NMR (400 MHz, CDCl 3 ) δ 10.84 (s, 1H), 7.30 (t, J = 1.9 Hz, 1H), 7.22 (d, J = 1.8 Hz, 2H), 5.07 (d, J = 5.1 Hz , 2H), 4.16 - 4.02 (m, 2H), 3.07 - 2.90 (m, 2H), 2.62 - 2.45 (m, 1H), 2.02 - 1.92 (m, 2H), 1.77 - 1.61 (m, 2H).
아마이드 커플링을 위한 일반적인 공정 E. General process for amide coupling E.
2 ml DMF를 함유한 10-mL 바이알에 카복실산(0.10 mmol) 및 HBTU(45.51 mg, 0.12 mmol)를 첨가하고 10분간 교반하였다. 아민(0.10 mmol) 및 트리에틸아민(20.24 mg, 0.20 mmol)을 교반중인 혼합물에 첨가하였다. 반응 혼합물을 실온에서 밤새 교반하였다. 용매를 증발시켜 건조시키고 크루드 생성물을 컬럼 크로마토그래피(CH2Cl2/MeOH)로 분리시켜 목적하는 아마이드를 얻었다.Carboxylic acid (0.10 mmol) and HBTU (45.51 mg, 0.12 mmol) were added to a 10-mL vial containing 2 ml DMF and stirred for 10 minutes. Amine (0.10 mmol) and triethylamine (20.24 mg, 0.20 mmol) were added to the stirring mixture. The reaction mixture was stirred overnight at room temperature. The solvent was evaporated to dryness and the crude product was separated by column chromatography (CH 2 Cl 2 /MeOH) to obtain the desired amide.
3,5-디클로로벤질 4-((4-(2-아미노티아졸-5-일)페닐)카바모일)피페리딘-1-카복실레이트(27a).3,5-dichlorobenzyl 4-((4-(2-aminothiazol-5-yl)phenyl)carbamoyl)piperidine-1-carboxylate (27a).
일반적인 공정 E에 따라, 26(33.21 mg, 0.10 mmol) 및 3a(39.15 mg, 0.10 mmol)를 사용하여 Boc-보호된 생성물을 흰색 고체(61.74 mg, 87.5%)로 얻었다.According to general procedure E, using 26 (33.21 mg, 0.10 mmol) and 3a (39.15 mg, 0.10 mmol), the Boc-protected product was obtained as a white solid (61.74 mg, 87.5%).
1H NMR(400 MHz, CDCl3) δ 7.78(d, J = 8.6 Hz, 2H), 7.54(d, J = 8.5 Hz, 2H), 7.33(s, 1H), 7.32 - 7.30(m, 1H), 7.25 - 7.22(m, 2H), 7.20(s, 1H), 5.08(d, J = 18.5 Hz, 2H), 4.32 - 4.17(m, 2H), 3.00 - 2.85(m, 2H), 2.49 - 2.38(m, 1H), 1.99 - 1.91(m, 2H), 1.86 - 1.75(m, 2H), 1.56(s, 18H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.78 (d, J = 8.6 Hz, 2H), 7.54 (d, J = 8.5 Hz, 2H), 7.33 (s, 1H), 7.32 - 7.30 (m, 1H) , 7.25 - 7.22(m, 2H), 7.20(s, 1H), 5.08(d, J = 18.5 Hz, 2H), 4.32 - 4.17(m, 2H), 3.00 - 2.85(m, 2H), 2.49 - 2.38 (m, 1H), 1.99 - 1.91 (m, 2H), 1.86 - 1.75 (m, 2H), 1.56 (s, 18H).
이것을 CH2Cl2(20 mL) 중 25% TFA 용액에 용해시키고, 실온에서 3 h 동안 교반하였다. 혼합물을 농축시키고 컬럼 크로마토그래피(에틸아세테이트/헥산)로 정제하여 27a를 흰색 고체(35.08 mg, 79.3%)로 얻었다.This was dissolved in a solution of 25% TFA in CH 2 Cl 2 (20 mL) and stirred at room temperature for 3 h. The mixture was concentrated and purified by column chromatography (ethyl acetate/hexane) to give 27a as a white solid (35.08 mg, 79.3%).
1H NMR(400 MHz, DMSO-d 6) δ 9.96(s, 1H), 7.71(d, J = 8.7 Hz, 2H), 7.59(d, J = 8.8 Hz, 2H), 7.57 - 7.55(m, 1H), 7.45 - 7.40(m, 2H), 7.00(s, 2H), 6.87(s, 1H), 5.09(s, 2H), 4.12 - 4.02(m, 2H), 2.90(s, 2H), 2.58 - 2.51(m, 1H), 1.86 - 1.77(m, 2H), 1.54(qd, J = 12.5, 4.2 Hz, 2H). 13C NMR(100 MHz, DMSO) δ 173.28, 168.55, 154.54, 150.12, 141.84, 138.77, 134.55, 130.47, 127.90, 126.64, 126.35, 119.49, 100.64, 65.16, 43.57, 42.87, 28.51. HRMS(ESI) m/z(M+H)+ calcd for C23H23Cl2N4O3S= 505.09; found 505.0865. 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.96 (s, 1H), 7.71 (d, J = 8.7 Hz, 2H), 7.59 (d, J = 8.8 Hz, 2H), 7.57 - 7.55 (m, 1H), 7.45 - 7.40(m, 2H), 7.00(s, 2H), 6.87(s, 1H), 5.09(s, 2H), 4.12 - 4.02(m, 2H), 2.90(s, 2H), 2.58 - 2.51 (m, 1H), 1.86 - 1.77 (m, 2H), 1.54 (qd, J = 12.5, 4.2 Hz, 2H). 13 C NMR (100 MHz, DMSO) Δ 173.28, 168.55, 154.54, 150.12, 141.84, 138.77, 134.55, 130.47, 127.90, 126.64, 126.35, 119.49, 100.64, 65.16, 43.57, 42.87, 28.51. HRMS(ESI) m/z(M+H) + calcd for C 23 H 23 Cl 2 N 4 O 3 S = 505.09; found 505.0865.
3,5-디클로로벤질 4-((3-(2-아미노티아졸-5-일)페닐)카바모일)피페리딘-1-카복실레이트(27b). 3,5-dichlorobenzyl 4-((3-(2-aminothiazol-5-yl)phenyl)carbamoyl)piperidine-1-carboxylate (27b).
27a 에 대한 공정에 따라, 26(58.43 mg, 0.083 mmol) 및 3b(39.15 mg, 0.10 mmol)을 사용하여 boc-보호된 중간체(58.43 mg, 0.083 mmol)를 얻었다;Following the procedure for 27a , using 26 ( 58.43 mg, 0.083 mmol) and 3b (39.15 mg, 0.10 mmol) gave the boc-protected intermediate (58.43 mg, 0.083 mmol);
1H NMR(400 MHz, CDCl3) δ 7.96(s, 1H), 7.61(d, J = 7.7 Hz, 1H), 7.57 - 7.51(m, 1H), 7.39 - 7.32(m, 4H), 7.26 - 7.25(m, 2H), 5.10(d, J = 16.7 Hz, 2H), 4.34 - 4.19(m, 2H), 3.04 - 2.88(m, 2H), 2.49 - 2.40(m, 1H), 2.01 - 1.93(m, 2H), 1.89 - 1.78(m, 2H), 1.57(s, 18H) 그리고 흰색 고체(30.14 mg, 72.0%)로서 27b를 얻었다. 1H NMR(400 MHz, DMSO-d 6) δ 9.95(br s, 1H), 8.09(t, J = 1.9 Hz, 1H), 7.58 - 7.56(m, 1H), 7.49 - 7.44(m, 2H), 7.44 - 7.41(m, 2H), 7.26(t, J = 7.9 Hz, 1H), 7.03(s, 2H), 6.90(s, 1H), 5.10(s, 2H), 4.14 - 4.04(m, 2H), 3.02 - 2.78(m, 2H), 2.61 - 2.53(m, 1H), 1.87 - 1.79(m, 2H), 1.61 - 1.48(m, 2H). 13C NMR(100 MHz, DMSO-d 6) δ 172.83, 168.07, 154.05, 149.80, 141.35, 139.39, 135.33, 134.06, 128.64, 127.40, 126.14, 120.31, 118.09, 116.83, 101.51, 64.66, 43.08, 42.34, 28.11. HRMS(ESI) m/z(M+H)+ calcd for C23H23Cl2N4O3S= 505.09; found 505.0865. 1 H NMR (400 MHz, CDCl 3 ) δ 7.96 (s, 1H), 7.61 (d, J = 7.7 Hz, 1H), 7.57 - 7.51 (m, 1H), 7.39 - 7.32 (m, 4H), 7.26 - 7.25 (m, 2H), 5.10 (d, J = 16.7 Hz, 2H), 4.34 - 4.19 (m, 2H), 3.04 - 2.88 (m, 2H), 2.49 - 2.40 (m, 1H), 2.01 - 1.93 ( m, 2H), 1.89 - 1.78 (m, 2H), 1.57 (s, 18H) and 27b was obtained as a white solid (30.14 mg, 72.0%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.95 (br s, 1H), 8.09 (t, J = 1.9 Hz, 1H), 7.58 - 7.56 (m, 1H), 7.49 - 7.44 (m, 2H) , 7.44 - 7.41(m, 2H), 7.26(t, J = 7.9 Hz, 1H), 7.03(s, 2H), 6.90(s, 1H), 5.10(s, 2H), 4.14 - 4.04(m, 2H) ), 3.02 - 2.78 (m, 2H), 2.61 - 2.53 (m, 1H), 1.87 - 1.79 (m, 2H), 1.61 - 1.48 (m, 2H). 13 C NMR (100 MHz, DMSO- D 6 ) δ 172.83, 168.07, 154.05, 149.80, 141.35, 139.39, 135.33, 134.06, 128.64, 127.40, 126.14, 120.31, 118.09, 116.83, 101.51, 64.66, 43. . HRMS(ESI) m/z(M+H) + calcd for C 23 H 23 Cl 2 N 4 O 3 S = 505.09; found 505.0865.
3,5-디클로로벤질 4-((4-(13,5-Dichlorobenzyl 4-((4-(1 HH -이미다졸-5-일)페닐)카바모일)피페리딘-1-카복실레이트(27c). -imidazol-5-yl)phenyl)carbamoyl)piperidine-1-carboxylate (27c).
일반적인 공정 E에 따라, 26(33.21 mg, 0.10 mmol) 및 7a(15.92 mg, 0.10 mmol)를 사용하여 27c를 흰색 고체(24.33 mg, 51.4%)로 얻었다.According to General Procedure E, 26 (33.21 mg, 0.10 mmol) and 7a (15.92 mg, 0.10 mmol) were used to obtain 27c as a white solid (24.33 mg, 51.4%).
1H NMR(400 MHz, CD3OD) δ 7.70(d, J = 1.2 Hz, 1H), 7.65(d, J = 8.7 Hz, 2H), 7.57(d, J = 8.7 Hz, 2H), 7.39 - 7.38(m, 1H), 7.37(d, J = 1.2 Hz, 1H), 7.34 - 7.32(m, 2H), 5.10(s, 2H), 4.22(m, 2H), 3.00 - 2.86(m, 2H), 2.63 - 2.56(m, 1H), 1.88(m, 2H), 1.76 - 1.66(m, 2H). 13C NMR(100 MHz, CD3OD) δ 174.16, 154.96, 140.87, 137.20, 135.54, 134.79, 127.50, 125.88, 124.78, 120.04, 65.23, 43.20, 43.16, 28.19. HRMS(ESI) m/z(M+H)+ calcd for C23H23Cl2N4O3= 473.11; found 473.1147. 1H NMR (400 MHz, CD 3 OD) δ 7.70 (d, J = 1.2 Hz, 1H), 7.65 (d, J = 8.7 Hz, 2H), 7.57 (d, J = 8.7 Hz, 2H), 7.39 - 7.38(m, 1H), 7.37(d, J = 1.2 Hz, 1H), 7.34 - 7.32(m, 2H), 5.10(s, 2H), 4.22(m, 2H), 3.00 - 2.86(m, 2H) , 2.63 - 2.56 (m, 1H), 1.88 (m, 2H), 1.76 - 1.66 (m, 2H). 13 C NMR (100 MHz, CD 3 OD) δ 174.16, 154.96, 140.87, 137.20, 135.54, 134.79, 127.50, 125.88, 124.78, 120.04, 65.23, 43.20, 43.16, 28.19. HRMS (ESI) m/z(M+H) + calcd for C 23 H 23 Cl 2 N 4 O 3 = 473.11; found 473.1147.
3,5-디클로로벤질 4-((3-(13,5-Dichlorobenzyl 4-((3-(1 HH -이미다졸-5-일)페닐)카바모일)피페리딘-1-카복실레이트(27d). -imidazol-5-yl)phenyl)carbamoyl)piperidine-1-carboxylate (27d).
일반적인 공정 E에 따라, 26(33.21 mg, 0.10 mmol) 및 7b(15.92 mg, 0.10 mmol)를 사용하여 27d를 흰색 고체(35.41 mg, 74.8%)를 얻었다.Following General Procedure E, 26 (33.21 mg, 0.10 mmol) and 7b (15.92 mg, 0.10 mmol) were used to obtain 27d as a white solid (35.41 mg, 74.8%).
1H NMR(400 MHz, CD3OD) δ 7.85(t, J = 1.9 Hz, 1H), 7.76(d, J = 1.1 Hz, 1H), 7.48 - 7.43(m, 2H), 7.42(d, J = 1.2 Hz, 1H), 7.39(t, J = 1.9 Hz, 1H), 7.35 - 7.33(m, 2H), 7.31(t, J = 7.8 Hz, 1H), 5.11(s, 2H), 4.26 - 4.19(m, 2H), 3.04 - 2.88(m, 2H), 2.64 - 2.56(m, 1H), 1.93 - 1.86(m, 2H), 1.78 - 1.66(m, 2H). 13C NMR(100 MHz, CD3OD) δ 174.32, 155.00, 140.92, 138.83, 138.05, 135.73, 134.83, 133.55, 128.82, 127.54, 125.92, 120.40, 118.53, 116.34, 115.16, 65.27, 43.24, 43.22, 28.20. HRMS(ESI) m/z(M+H)+ calcd for C23H23Cl2N4O3= 473.11; found 473.1160. 1H NMR (400 MHz, CD 3 OD) δ 7.85 (t, J = 1.9 Hz, 1H), 7.76 (d, J = 1.1 Hz, 1H), 7.48 - 7.43 (m, 2H), 7.42 (d, J = 1.2 Hz, 1H), 7.39 (t, J = 1.9 Hz, 1H), 7.35 - 7.33 (m, 2H), 7.31 (t, J = 7.8 Hz, 1H), 5.11 (s, 2H), 4.26 - 4.19 (m, 2H), 3.04 - 2.88 (m, 2H), 2.64 - 2.56 (m, 1H), 1.93 - 1.86 (m, 2H), 1.78 - 1.66 (m, 2H). 13 C NMR (100 MHz, CD 3 OD) Δ 174.32, 155.00, 140.92, 138.83, 138.05, 135.73, 134.83, 133.55, 128.82, 127.54, 125.92, 120.40, 118.53, 116.34, 115.16, 65.27, 43.24 HRMS (ESI) m/z(M+H) + calcd for C 23 H 23 Cl 2 N 4 O 3 = 473.11; found 473.1160.
3,5-디클로로벤질 4-(4-(1H-이미다졸-5-일)피페리딘-1-카보닐)피페리딘-1-카복실레이트(27e).3,5-dichlorobenzyl 4-(4-(1H-imidazol-5-yl)piperidine-1-carbonyl)piperidine-1-carboxylate (27e).
일반적인 공정 E에 따라, 26(33.21 mg, 0.10 mmol) 및 4-(1H-이미다졸-4(5)-일)피페리딘(22.68 mg, 0.15 mmol)을 사용하여 27e를 흰색 고체(26.57 mg, 57.1%)로 얻었다. 27e was obtained as a white solid ( 26.57 mg, 57.1%).
1H NMR(400 MHz, CDCl3) δ 9.65(br s, 1H), 7.75(s, 1H), 7.29(t, J = 2.0 Hz, 1H), 7.22(d, J = 1.9 Hz, 2H), 6.81(s, 1H), 5.16 - 5.02(m, 2H), 4.67 - 4.59(m, 1H), 4.24 - 4.10(m, 2H), 4.04 - 3.92(m, 1H), 3.26 - 3.11(m, 1H), 2.98 - 2.81(m, 3H), 2.79 - 2.66(m, 2H), 2.16 - 1.99(m, 2H), 1.80 - 1.68(m, 4H), 1.65 - 1.51(m, 2H). 13C NMR(100 MHz, CDCl3) δ 172.75, 154.72, 141.19, 140.19, 135.07, 134.54, 128.12, 126.05, 113.91, 65.52, 45.55, 43.49, 42.02, 38.10, 34.53, 32.62, 31.31, 29.70, 28.42, 28.30. HRMS(ESI) m/z(M+H)+ calcd for C22H27Cl2N4O3= 465.15; found 465.1455. 1 H NMR (400 MHz, CDCl 3 ) δ 9.65 (br s, 1H), 7.75 (s, 1H), 7.29 (t, J = 2.0 Hz, 1H), 7.22 (d, J = 1.9 Hz, 2H), 6.81(s, 1H), 5.16 - 5.02(m, 2H), 4.67 - 4.59(m, 1H), 4.24 - 4.10(m, 2H), 4.04 - 3.92(m, 1H), 3.26 - 3.11(m, 1H) ), 2.98 - 2.81 (m, 3H), 2.79 - 2.66 (m, 2H), 2.16 - 1.99 (m, 2H), 1.80 - 1.68 (m, 4H), 1.65 - 1.51 (m, 2H). 13 C NMR (100 MHz, CDCL 3 ) δ 172.75, 154.72, 141.19, 140.19, 135.07, 134.54, 128.12, 126.05, 113.91, 65.52, 45.55, 43.49, 42.02, 38.10, 34.53, 32.62 . HRMS(ESI) m/z(M+H) + calcd for C 22 H 27 Cl 2 N 4 O 3 = 465.15; found 465.1455.
3,5-디클로로벤질 4-(4-(13,5-Dichlorobenzyl 4-(4-(1 HH -1,2,3-트리아졸-5-일)피페리딘-1-카보닐)피페리딘-1-카복실레이트(27f).-1,2,3-triazol-5-yl) piperidine-1-carbonyl) piperidine-1-carboxylate (27f).
일반적인 공정 E에 따라, 26(33.21 mg, 0.10 mmol) 및 20(22.64 mg, 0.12 mmol)을 사용하여 27f를 흰색 고체(32.55 mg, 69.8%)로 얻었다.According to General Procedure E, using 26 (33.21 mg, 0.10 mmol) and 20 (22.64 mg, 0.12 mmol), 27f was obtained as a white solid (32.55 mg, 69.8%).
1H NMR(400 MHz, CDCl3) δ 10.98(s, 1H), 7.49(s, 1H), 7.29(t, J = 1.9 Hz, 1H), 7.23(d, J = 1.9 Hz, 2H), 5.20 - 4.96(m, 2H), 4.71 - 4.60(m, 1H), 4.30 - 4.14(m, 2H), 4.05 - 3.92(m, 1H), 3.33 - 3.17(m, 1H), 3.12 - 3.02(m, 1H), 2.99 - 2.68(m, 4H), 2.20 - 2.01(m, 2H), 1.86 - 1.61(m, 6H). 13C NMR(100 MHz, CDCl3) δ 172.85, 154.78, 149.66, 140.11, 135.07, 128.78, 128.14, 126.10, 65.61, 45.48, 43.52, 41.98, 38.22, 33.17, 32.55, 31.39, 28.43, 28.25. HRMS(ESI) m/z(M+H)+ calcd for C21H26Cl2N5O3= 466.14; found 466.1412. 1 H NMR (400 MHz, CDCl 3 ) δ 10.98 (s, 1H), 7.49 (s, 1H), 7.29 (t, J = 1.9 Hz, 1H), 7.23 (d, J = 1.9 Hz, 2H), 5.20 - 4.96(m, 2H), 4.71 - 4.60(m, 1H), 4.30 - 4.14(m, 2H), 4.05 - 3.92(m, 1H), 3.33 - 3.17(m, 1H), 3.12 - 3.02(m, 1H), 2.99 - 2.68 (m, 4H), 2.20 - 2.01 (m, 2H), 1.86 - 1.61 (m, 6H). 13 C NMR (100 MHz, CDCL 3 ) δ 172.85, 154.78, 149.66, 140.11, 135.07, 128.78, 128.14, 126.10, 65.61, 45.48, 43.52, 41.98, 38.22, 33.17, 32.55, 31.39, 28.25. HRMS(ESI) m/z(M+H) + calcd for C 21 H 26 Cl 2 N 5 O 3 = 466.14; found 466.1412.
3,5-디클로로벤질 4-(4-(5-옥소-4,5-디하이드로-1,3,4-옥사다이아졸-2-일)피페리딘-1-카보닐)피페리딘-1-카복실레이트(27g).3,5-dichlorobenzyl 4-(4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidine-1-carbonyl)piperidine- 1-Carboxylate (27 g).
일반적인 공정 E에 따라, 26(33.21 mg, 0.10 mmol) 및 24(20.56 mg, 0.10 mmol)를 사용하여 27g를 흰색 고체(27.11 mg, 56.1%)로 얻었다.Following General Procedure E, using 26 (33.21 mg, 0.10 mmol) and 24 (20.56 mg, 0.10 mmol), 27 g was obtained as a white solid (27.11 mg, 56.1%).
1H NMR(400 MHz, CDCl3) δ 9.67(s, 1H), 7.30(t, J = 1.9 Hz, 1H), 7.23(d, J = 1.9 Hz, 2H), 5.17 - 5.00(m, 3H), 4.54 - 4.46(m, 1H), 4.29 - 4.13(m, 2H), 3.99 - 3.88(m, 1H), 3.29 - 3.20(m, 1H), 2.97 - 2.83(m, 4H), 2.75 - 2.67(m, 1H), 2.12 - 1.98(m, 2H), 1.80 - 1.68(m, 6H). 13C NMR(100 MHz, CDCl3) δ 172.79, 158.89, 154.91, 154.73, 140.10, 135.08, 128.15, 126.10, 65.62, 44.47, 43.45, 40.93, 38.15, 33.90, 28.77, 28.34, 28.21, 27.74. HRMS(ESI) m/z(M+Na)+ calcd for C21H24Cl2N4O5Na= 505.10; found 505.1017. 1H NMR (400 MHz, CDCl 3 ) δ 9.67 (s, 1H), 7.30 (t, J = 1.9 Hz, 1H), 7.23 (d, J = 1.9 Hz, 2H), 5.17 - 5.00 (m, 3H) ( m, 1H), 2.12 - 1.98 (m, 2H), 1.80 - 1.68 (m, 6H). 13 C NMR (100 MHz, CDCL 3 ) δ 172.79, 158.89, 154.91, 154.73, 140.10, 135.08, 128.15, 126.10, 65.62, 44.47, 43.45, 40.93, 38.15, 33.90, 28.77, 28.34, 28.21, 28.21 HRMS(ESI) m/z(M+Na) + calcd for C 21 H 24 Cl 2 N 4 O 5 Na = 505.10; found 505.1017.
제법 5. 화합물 27h-i의 합성.Preparation 5. Synthesis of compound 27h-i.
n시약 및 조건:(a) 메틸 4-아미노벤조에이트, EDC, DMAP, CH2Cl2, 18 h;(b) N2H4.H2O, 110 ℃, 1 day;(c) CDI, DMF, 90 ℃, 15 h;(d) 14b, EDC, DMAP, CH2Cl2, 18 h;(e) i: LiOH, THF, MeOH, H2O, 6 h, ii: 1M HCl. n Reagents and conditions: (a) methyl 4-aminobenzoate, EDC, DMAP, CH 2 Cl 2 , 18 h; (b) N 2 H 4 .H 2 O, 110 °C, 1 day; (c) CDI, DMF, 90° C., 15 h; (d) 14b , EDC, DMAP, CH 2 Cl 2 , 18 h; (e) i: LiOH, THF, MeOH, H 2 O, 6 h, ii: 1M HCl.
3,5-디클로로벤질 4-((4-(메톡시카보닐)페닐)카바모일)피페리딘-1-카복실레이트(28). 3,5-dichlorobenzyl 4-((4-(methoxycarbonyl)phenyl)carbamoyl)piperidine-1-carboxylate (28).
일반적인 공정 E에 따라, 26(33.22 mg, 0.10 mmol) 및 메틸 4-아미노벤조에이트(18.14 mg, 0.12 mmol)를 사용하여 28을 흰색 고체(37.23 mg, 80.0%)로 얻었다.Using 26 (33.22 mg, 0.10 mmol) and methyl 4-aminobenzoate (18.14 mg, 0.12 mmol) according to General Procedure E, 28 was obtained as a white solid (37.23 mg, 80.0%).
1H NMR(400 MHz, CDCl3) δ 7.99(d, J = 8.7 Hz, 2H), 7.84(s, 1H), 7.62(d, J = 8.8 Hz, 2H), 7.30(t, J = 1.9 Hz, 1H), 7.22(d, J = 2.0 Hz, 2H), 5.18 - 4.98(m, 2H), 4.37 - 4.15(m, 2H), 3.90(s, 3H), 3.03 - 2.78(m, 2H), 2.54 - 2.41(m, 1H), 1.97 - 1.89(m, 2H), 1.85 - 1.70(m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.99 (d, J = 8.7 Hz, 2H), 7.84 (s, 1H), 7.62 (d, J = 8.8 Hz, 2H), 7.30 (t, J = 1.9 Hz) , 1H), 7.22 (d, J = 2.0 Hz, 2H), 5.18 - 4.98 (m, 2H), 4.37 - 4.15 (m, 2H), 3.90 (s, 3H), 3.03 - 2.78 (m, 2H), 2.54 - 2.41 (m, 1H), 1.97 - 1.89 (m, 2H), 1.85 - 1.70 (m, 2H).
3,5-디클로로벤질 4-((4-(5-옥소-4,5-디하이드로-1,3,4-옥사다이아졸-2-일)페닐)카바모일)피페리딘-1-카복실레이트(27h).3,5-dichlorobenzyl 4-((4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)carbamoyl)piperidine-1-carboxyl Rate (27h).
28(38.25 mg, 0.086 mmol) 및 히드라진 모노하이드레이트(1 mL)의 혼합물을 24 h 동안 환류시키고 진공하에서 건조시켰다. 생성물 잔류물(44.33 mg, 0.1 mmol)을 DMF(2 mL)에 용해시키고 1,1'-카보닐디이미다졸(19.45 mg, 0.12 mmol)을 혼합하였다. 반응 혼합물을 80 ℃에서 밤새 가열하였다. 용매를 증발시켜 건조시켰다. 생성물을 에틸아세테이트로 추출하고 물로 세척하였다. 유기층을 무수 소듐 설페이트로 탈수시키고, 농축시키고, 컬럼 크로마토그래피(에틸아세테이트/헥산)로 정제하여 27h을 흰색 고체(17.92 mg, 45.6%)로 얻었다.A mixture of 28 (38.25 mg, 0.086 mmol) and hydrazine monohydrate (1 mL) was refluxed for 24 h and dried under vacuum. The product residue (44.33 mg, 0.1 mmol) was dissolved in DMF (2 mL) and 1,1'-carbonyldiimidazole (19.45 mg, 0.12 mmol) was mixed. The reaction mixture was heated at 80 °C overnight. The solvent was evaporated to dryness. The product was extracted with ethyl acetate and washed with water. The organic layer was dehydrated with anhydrous sodium sulfate, concentrated and purified by column chromatography (ethyl acetate/hexane) to give 27h as a white solid (17.92 mg, 45.6%).
1H NMR(400 MHz, DMSO-d 6) δ 7.57(t, J = 2.0 Hz, 1H), 7.54(d, J = 8.8 Hz, 2H), 7.43(d, J = 2.0 Hz, 2H), 6.66(d, J = 8.7 Hz, 2H), 6.08(s, 2H), 5.09(s, 2H), 4.09 - 4.01(m, 2H), 3.48 - 3.39(m, 1H), 3.07 - 2.90(m, 2H), 1.98 - 1.89(m, 2H), 1.60 - 1.46(m, 2H). 13C NMR(100 MHz, DMSO-d 6) δ 173.85, 155.03, 154.54, 154.20, 142.45, 141.83, 134.54, 127.90, 126.64, 126.57, 119.66, 118.82, 65.17, 43.51, 42.94, 28.51. HRMS(ESI) m/z(M+Na)+ calcd for C22H21Cl2N4O5Na= 513.07; found 513.0708. 1H NMR (400 MHz, DMSO- d6 ) δ 7.57 (t, J = 2.0 Hz, 1H), 7.54 (d, J = 8.8 Hz, 2H), 7.43 (d, J = 2.0 Hz , 2H), 6.66 (d, J = 8.7 Hz, 2H), 6.08 (s, 2H), 5.09 (s, 2H), 4.09 - 4.01 (m, 2H), 3.48 - 3.39 (m, 1H), 3.07 - 2.90 (m, 2H) ), 1.98 - 1.89 (m, 2H), 1.60 - 1.46 (m, 2H). 13 C NMR (100 MHz, DMSO- d6 ) δ 173.85, 155.03 , 154.54, 154.20, 142.45, 141.83, 134.54, 127.90, 126.64, 126.57, 119.66, 118.82, 4.2.81, 45.17, 4.2.81 HRMS(ESI) m/z(M+Na)+ calcd for C 22 H 21 Cl 2 N 4 O 5 Na = 513.07; found 513.0708.
1-(3,5-디클로로벤질) 4-(5-(3-(1-(((3,5-디클로로벤질)옥시)카보닐)피페리딘-4-카복사미도)페닐)-1,3,4-옥사다이아졸-2-일) 피페리딘-1,4-디카복실레이트(29).1-(3,5-dichlorobenzyl) 4-(5-(3-(1-(((3,5-dichlorobenzyl)oxy)carbonyl)piperidine-4-carboxamido)phenyl)-1 ,3,4-oxadiazol-2-yl) piperidine-1,4-dicarboxylate (29).
CH2Cl2(2 mL) 중 26(83.04 mg, 0.25 mmol), 14b(17.72 mg, 0.10 mmol) 및 DMAP(0.61 mg, 0.005 mmol)를 함유하는 혼합물에 EDCI(23.00 mg, 0.12 mmol)를 첨가하였다. 반응 혼합물을 실온에서 밤새 교반하였다. 혼합물을 CH2Cl2로 추출하고 물로 세척하였다. 유기층을 무수 소듐 설페이트로 탈수시키고 농축하였다. 크루드 생성물을 컬럼 크로마토그래피(에틸아세테이트/헥산)로 분리하여 29를 흰색 고체(45.19 mg, 56.1%)로 얻었다.To a mixture containing 26 (83.04 mg, 0.25 mmol), 14b (17.72 mg, 0.10 mmol) and DMAP (0.61 mg, 0.005 mmol) in CH 2 Cl 2 (2 mL) was added EDCI (23.00 mg, 0.12 mmol). did The reaction mixture was stirred overnight at room temperature. The mixture was extracted with CH 2 Cl 2 and washed with water. The organic layer was dehydrated over anhydrous sodium sulfate and concentrated. The crude product was separated by column chromatography (ethyl acetate/hexane) to obtain 29 as a white solid (45.19 mg, 56.1%).
1H NMR(400 MHz, CDCl3) δ 8.34 - 8.07(m, 1H), 8.01 - 7.79(m, 2H), 7.65 - 7.50(m, 1H), 7.48 - 7.36(m, 1H), 7.30 - 7.25(m, 2H), 7.23 - 7.17(m, 4H), 5.14 - 5.01(m, 4H), 4.31 - 4.15(m, 4H), 3.58 - 3.49(m, 1H), 3.13 - 2.84(m, 4H), 2.61 - 2.49(m, 1H), 2.05 - 1.92(m, 4H), 1.89 - 1.74(m, 4H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.34 - 8.07 (m, 1H), 8.01 - 7.79 (m, 2H), 7.65 - 7.50 (m, 1H), 7.48 - 7.36 (m, 1H), 7.30 - 7.25 (m, 2H), 7.23 - 7.17 (m, 4H), 5.14 - 5.01 (m, 4H), 4.31 - 4.15 (m, 4H), 3.58 - 3.49 (m, 1H), 3.13 - 2.84 (m, 4H) , 2.61 - 2.49 (m, 1H), 2.05 - 1.92 (m, 4H), 1.89 - 1.74 (m, 4H).
3,5-디클로로벤질 4-((3-(5-옥소-4,5-디하이드로-1,3,4-옥사다이아졸-2-일)페닐)카바모일)피페리딘-1-카복실레이트(27i). 3,5-dichlorobenzyl 4-((3-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)carbamoyl)piperidine-1-carboxyl Rate (27i).
물(2 mL) 중 리튬 하이드록사이드(0.12 g, 5 mmol)의 용액을 THF(18 mL) 및 MeOH(2 ml)의 혼합물에 29(45.19 mg, 0.056 mmol)의 용액에 첨가하였다. 반응 혼합물을 실온에서 6 h 동안 교반하였다. 다음에 용매를 증발시키고 물에 재용해시키고 1M HCl로 산성화시켰다. 혼합물을 에틸아세테이트로 추출하고 물로 세척하였다. 유기층을 무수 소듐 설페이트로 탈수시키고 농축시켰다. 생성물을 컬럼 크로마토그래피(에틸아세테이트/헥산)로 정제시키고 27i를 흰색 고체(11.36 mg, 41.2%)로 얻었다.A solution of lithium hydroxide (0.12 g, 5 mmol) in water (2 mL) was added to a solution of 29 (45.19 mg, 0.056 mmol) in a mixture of THF (18 mL) and MeOH (2 ml). The reaction mixture was stirred at room temperature for 6 h. The solvent was then evaporated, redissolved in water and acidified with 1M HCl. The mixture was extracted with ethyl acetate and washed with water. The organic layer was dehydrated with anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (ethyl acetate/hexane) to give 27i as a white solid (11.36 mg, 41.2%).
1H NMR(400 MHz, DMSO-d 6) δ 12.57(br s, 1H), 10.18(s, 1H), 8.18(q, J = 1.4 Hz, 1H), 7.75 - 7.67(m, 1H), 7.57(t, J = 2.0 Hz, 1H), 7.47 - 7.45(m, 2H), 7.43(d, J = 1.9 Hz, 2H), 5.10(s, 2H), 4.12 - 4.04(m, 2H), 3.04 - 2.84(m, 2H), 2.63 - 2.54(m, 1H), 1.87 - 1.79(m, 2H), 1.61 - 1.50(m, 2H). 13C NMR(100 MHz, DMSO) δ 173.75, 154.99, 154.54, 154.16, 141.83, 140.43, 134.55, 130.20, 127.89, 126.64, 124.85, 122.15, 120.26, 115.93, 65.17, 43.52, 42.91, 28.53. HRMS(ESI) m/z(M+H)+ calcd for C22H21Cl2N4O5= 491.09; found 491.0886. 1 H NMR (400 MHz, DMSO- d 6 ) δ 12.57 (br s, 1H), 10.18 (s, 1H), 8.18 (q, J = 1.4 Hz, 1H), 7.75 - 7.67 (m, 1H), 7.57 (t, J = 2.0 Hz, 1H), 7.47 - 7.45 (m, 2H), 7.43 (d, J = 1.9 Hz, 2H), 5.10 (s, 2H), 4.12 - 4.04 (m, 2H), 3.04 - 2.84 (m, 2H), 2.63 - 2.54 (m, 1H), 1.87 - 1.79 (m, 2H), 1.61 - 1.50 (m, 2H). 13 C NMR (100 MHz, DMSO) Δ 173.75, 154.99, 154.54, 154.16, 141.83, 140.43, 134.55, 130.20, 127.89, 126.64, 124.85, 122.15, 120.26, 115.93, 65.17, 43.52, 42.52, 42.52 HRMS(ESI) m/z(M+H) + calcd for C 22 H 21 Cl 2 N 4 O 5 = 491.09; found 491.0886.
제법 6. 빌딩 블럭 30a-c 및 32a-d의 합성.Preparation 6. Synthesis of building blocks 30a-c and 32a-d.
시약 및 조건:(a) 포름아미드, 150 ℃, 1 day;(b) 아세트아미드, 180 ℃, 18 h;(c) i: CDI, DMF, 6 h, ii: 아민, 15 h;(d) CBr4, PPh3, CH2Cl2, 0 ℃ to r.t., 6 h;(e) PCC, CH2Cl2, 15 h.Reagents and conditions: (a) formamide, 150 °C, 1 day; (b) acetamide, 180 °C, 18 h; (c) i: CDI, DMF, 6 h; ii: amine, 15 h; (d) CBr 4 , PPh 3 , CH 2 Cl 2 , 0 °C to rt, 6 h; (e) PCC, CH 2 Cl 2 , 15 h.
4-(14-(1 HH -이미다졸-5-일)페놀(30a). -imidazol-5-yl)phenol (30a).
일반적인 공정 B에 따라, 2-브로모-4' 하이드록시아세토페논(1.07 g, 5.00 mmol)을 사용하여 30a를 흰색 고체(0.65 g, 80.6%)로 얻었다.Following General Procedure B, using 2-bromo-4'hydroxyacetophenone (1.07 g, 5.00 mmol), 30a was obtained as a white solid (0.65 g, 80.6%).
1H NMR(400 MHz, DMSO-d 6) δ 12.09(br s, 1H), 9.33(s, 1H), 7.63(s, 1H), 7.54(d, J = 8.6 Hz, 2H), 7.33(s, 1H), 6.75(d, J = 8.6 Hz, 2H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 12.09 (br s, 1H), 9.33 (s, 1H), 7.63 (s, 1H), 7.54 (d, J = 8.6 Hz, 2H), 7.33 (s , 1H), 6.75 (d, J = 8.6 Hz, 2H).
3-(13-(1 HH -이미다졸-5-일)페놀(30b).-imidazol-5-yl)phenol (30b).
일반적인 공정 B에 따라, 2-브로모-3'-하이드록시아세토페논(1.07 g, 5.00 mmol)을 사용하여 30b를 흰색 고체(0.77 g, 96.7%)로 얻었다.Following General Procedure B, using 2-bromo-3'-hydroxyacetophenone (1.07 g, 5.00 mmol), 30b was obtained as a white solid (0.77 g, 96.7%).
1H NMR(400 MHz, DMSO-d 6) δ 12.18(br s, 1H), 9.35(s, 1H), 7.68(d, J = 1.1 Hz, 1H), 7.47(s, 1H), 7.21 - 7.15(m, 2H), 7.13(t, J = 7.6 Hz, 1H), 6.60(ddd, J = 7.5, 2.5, 1.5 Hz, 1H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 12.18 (br s, 1H), 9.35 (s, 1H), 7.68 (d, J = 1.1 Hz, 1H), 7.47 (s, 1H), 7.21 - 7.15 (m, 2H), 7.13 (t, J = 7.6 Hz, 1H), 6.60 (ddd, J = 7.5, 2.5, 1.5 Hz, 1H).
3-(2-메틸-13-(2-methyl-1 HH -이미다졸-5-일)페놀(30c).-imidazol-5-yl)phenol (30c).
2-브로모-3' 하이드록시아세토페논(1.07 g, 5.00 mmol) 및 아세트아미드(10 mL)의 혼합물을 180 ℃에서 18 h 동안 가열하였다. 냉각 후, 혼합물을 포화된 NaHCO3 용액에 붓고 에틸아세테이트로 추출하였다. 유기층을 무수 소듐 설페이트로 탈수시키고 농축하였다. 생성물을 컬럼 크로마토그래피(CH2Cl2/MeOH)로 정제하여 30c를 밝은 황색 고체(0.43 g, 49.4%)로 얻었다.A mixture of 2-bromo-3'hydroxyacetophenone (1.07 g, 5.00 mmol) and acetamide (10 mL) was heated at 180 °C for 18 h. After cooling, the mixture was poured into saturated NaHCO 3 solution and extracted with ethyl acetate. The organic layer was dehydrated over anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (CH 2 Cl 2 /MeOH) to give 30c as a light yellow solid (0.43 g, 49.4%).
1H NMR(400 MHz, DMSO-d 6) δ 9.35(s, 1H), 7.32(s, 1H), 7.16 - 7.08(m, 3H), 6.62 - 6.54(m, 1H), 2.31(s, 3H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.35 (s, 1H), 7.32 (s, 1H), 7.16 - 7.08 (m, 3H), 6.62 - 6.54 (m, 1H), 2.31 (s, 3H) ).
3,5-디클로로벤질 4-하이드록시피페리딘-1-카복실레이트(31a).3,5-dichlorobenzyl 4-hydroxypiperidine-1-carboxylate (31a).
일반적인 공정 C에 따라, 3,5-디클로로벤질 알코올(0.18g, 1.00 mmol) 및 4-하이드록시피페리딘(0.20 g, 2.00 mmol)을 사용하여 31a를 무색 오일(0.26 g, 85.4%)을 얻었다. 31a was prepared by General Procedure C using 3,5-dichlorobenzyl alcohol (0.18 g, 1.00 mmol) and 4-hydroxypiperidine (0.20 g, 2.00 mmol) as a colorless oil (0.26 g, 85.4%). got it
1H NMR(400 MHz, CDCl3) δ 7.30(t, J = 1.9 Hz, 1H), 7.23(d, J = 1.9 Hz, 2H), 5.06(s, 2H), 4.00 - 3.81(m, 3H), 3.27 - 3.11(m, 2H), 1.95 - 1.83(m, 2H), 1.57(d, J = 4.1 Hz, 1H), 1.55 - 1.46(m, 2H). 1H NMR (400 MHz, CDCl 3 ) δ 7.30 (t, J = 1.9 Hz, 1H), 7.23 (d, J = 1.9 Hz, 2H), 5.06 (s, 2H), 4.00 - 3.81 (m, 3H) , 3.27 - 3.11 (m, 2H), 1.95 - 1.83 (m, 2H), 1.57 (d, J = 4.1 Hz, 1H), 1.55 - 1.46 (m, 2H).
3,5-디클로로벤질 4-(하이드록시메틸)피페리딘-1-카복실레이트(31b).3,5-dichlorobenzyl 4-(hydroxymethyl)piperidine-1-carboxylate (31b).
일반적인 공정 C에 따라, 3,5-디클로로벤질 알코올(1.77g, 10.00 mmol) 및 4-피페리딘메탄올(2.30 g, 20.00 mmol)을 사용하여 31b를 무색 오일(2.92 g, 91.8%)로 얻었다. 31b was obtained as a colorless oil (2.92 g, 91.8%) by General Procedure C using 3,5-dichlorobenzyl alcohol (1.77 g, 10.00 mmol) and 4-piperidinemethanol (2.30 g, 20.00 mmol). .
1H NMR(400 MHz, CDCl3) δ 7.30(t, J = 1.9 Hz, 1H), 7.22(d, J = 1.9 Hz, 2H), 5.06(s, 2H), 4.28 - 4.13(m, 2H), 3.51(t, J = 5.6 Hz, 2H), 2.91 - 2.73(m, 2H), 1.81 - 1.74(m, 2H), 1.73 - 1.65(m, 1H), 1.47(t, J = 5.3 Hz, 1H), 1.25 - 1.13(m, 2H). 1H NMR (400 MHz, CDCl 3 ) δ 7.30 (t, J = 1.9 Hz, 1H), 7.22 (d, J = 1.9 Hz, 2H), 5.06 (s, 2H), 4.28 - 4.13 (m, 2H) , 3.51 (t, J = 5.6 Hz, 2H), 2.91 - 2.73 (m, 2H), 1.81 - 1.74 (m, 2H), 1.73 - 1.65 (m, 1H), 1.47 (t, J = 5.3 Hz, 1H) ), 1.25 - 1.13 (m, 2H).
3,5-디클로로벤질 4-(2-하이드록시에틸)피페리딘-1-카복실레이트(31c).3,5-dichlorobenzyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (31c).
일반적인 공정 C에 따라, 3,5-디클로로벤질 알코올(0.88 g, 5.00 mmol) 및 4-피페리딘에탄올(1.29 g, 10.00 mmol)을 사용하여 31c를 무색 오일(1.55 g, 93.3%)로 얻었다.According to the general process C, 31c was obtained as a colorless oil (1.55 g, 93.3%) using 3,5-dichlorobenzyl alcohol (0.88 g, 5.00 mmol) and 4-piperidineethanol (1.29 g, 10.00 mmol).
1H NMR(400 MHz, CDCl3) δ 7.30(t, J = 1.9 Hz, 1H), 7.22(d, J = 1.9 Hz, 2H), 5.06(s, 2H), 4.26 - 4.03(m, 2H), 3.76 - 3.67(m, 2H), 2.89 - 2.71(m, 2H), 1.76 - 1.70(m, 2H), 1.68 - 1.60(m, 1H), 1.53(q, J = 6.6 Hz, 2H), 1.34(t, J = 4.3 Hz, 1H), 1.22 - 1.11(m, 2H). 1H NMR (400 MHz, CDCl 3 ) δ 7.30 (t, J = 1.9 Hz, 1H), 7.22 (d, J = 1.9 Hz, 2H), 5.06 (s, 2H), 4.26 - 4.03 (m, 2H) , 3.76 - 3.67 (m, 2H), 2.89 - 2.71 (m, 2H), 1.76 - 1.70 (m, 2H), 1.68 - 1.60 (m, 1H), 1.53 (q, J = 6.6 Hz, 2H), 1.34 (t, J = 4.3 Hz, 1H), 1.22 - 1.11 (m, 2H).
3,5-디클로로벤질 4-브로모피페리딘-1-카복실레이트(32a). 3,5-dichlorobenzyl 4-bromopiperidine-1-carboxylate (32a).
CH2Cl2(2 mL) 중 31a(0.26 g, 0.85 mmol) 및 트리페닐포스핀(0.27 g, 1.02 mmol)의 혼합물에 0 ℃에서 CH2Cl2(2 mL) 중 테트라브로모메탄(0.34 g, 1.02 mmol)의 용액을 방울로 적가하였다. 반응 혼합물을 실온에서 밤새 교반하였다. 용매를 증발시키고 크루드 혼합물을 에틸아세테이트로 추출하고 물로 세척하였다. 유기층을 무수 소듐 설페이트로 탈수시키고 농축시켰다. 생성물을 컬럼 크로마토그래피(CH2Cl2/MeOH)로 정제하여 32a를 무색 오일(0.22 g, 70.4%)로 얻었다.To a mixture of 31a (0.26 g, 0.85 mmol) and triphenylphosphine (0.27 g, 1.02 mmol) in CH 2 Cl 2 (2 mL) at 0 °C, tetrabromomethane (0.34 g, 0.34 mmol) in CH 2 Cl 2 (2 mL) g, 1.02 mmol) was added dropwise. The reaction mixture was stirred overnight at room temperature. The solvent was evaporated and the crude mixture was extracted with ethyl acetate and washed with water. The organic layer was dehydrated with anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (CH 2 Cl 2 /MeOH) to give 32a as a colorless oil (0.22 g, 70.4%).
1H NMR(400 MHz, CDCl3) δ 7.30(t, J = 1.9 Hz, 1H), 7.22(d, J = 2.0 Hz, 2H), 5.07(s, 2H), 4.42 - 4.35(m, 1H), 3.77 - 3.68(m, 2H), 3.53 - 3.35(m, 2H), 2.18 - 2.07(m, 2H), 2.04 - 1.92(m, 2H). 1H NMR (400 MHz, CDCl 3 ) δ 7.30 (t, J = 1.9 Hz, 1H), 7.22 (d, J = 2.0 Hz, 2H), 5.07 (s, 2H), 4.42 - 4.35 (m, 1H) , 3.77 - 3.68 (m, 2H), 3.53 - 3.35 (m, 2H), 2.18 - 2.07 (m, 2H), 2.04 - 1.92 (m, 2H).
3,5-디클로로벤질 4-(브로모메틸)피페리딘-1-카복실레이트(32b). 3,5-dichlorobenzyl 4-(bromomethyl)piperidine-1-carboxylate (32b).
32a 에 대한 공정에 따라, 31b(0.32 g, 1.00 mmol), 트리페닐포스핀(0.31 g, 1.20 mmol), 테트라브로모메탄(0.40 g, 1.20 mmol)을 사용하여 32b를 무색 오일(정량적)로 얻었다.Following the procedure for 32a , using 31b (0.32 g, 1.00 mmol), triphenylphosphine (0.31 g, 1.20 mmol), tetrabromomethane (0.40 g, 1.20 mmol), 32b was prepared as a colorless oil (quantitatively). got it
1H NMR(400 MHz, CDCl3) δ 7.30(t, J = 2.0 Hz, 1H), 7.22(d, J = 1.8 Hz, 2H), 5.07(s, 2H), 4.39 - 4.09(m, 2H), 3.30(d, J = 6.1 Hz, 2H), 2.97 - 2.62(m, 2H), 1.92 - 1.77(m, 3H), 1.33 - 1.14(m, 2H). 1H NMR (400 MHz, CDCl 3 ) δ 7.30 (t, J = 2.0 Hz, 1H), 7.22 (d, J = 1.8 Hz, 2H), 5.07 (s, 2H), 4.39 - 4.09 (m, 2H) , 3.30 (d, J = 6.1 Hz, 2H), 2.97 - 2.62 (m, 2H), 1.92 - 1.77 (m, 3H), 1.33 - 1.14 (m, 2H).
3,5-디클로로벤질 4-(2-브로모에틸)피페리딘-1-카복실레이트(32c). 3,5-dichlorobenzyl 4-(2-bromoethyl)piperidine-1-carboxylate (32c).
32a 에 대한 공정에 따라, 31c(0.33 g, 1.00 mmol), 트리페닐포스핀(0.31 g, 1.20 mmol), 테트라브로모메탄 (0.40 g, 1.20 mmol)을 사용하여 32c를 무색 오일(0.25 g, 63.3%)로 얻었다.Following the procedure for 32a , 32c was prepared as a colorless oil (0.25 g, 63.3%).
1H NMR(400 MHz, CDCl3) δ 7.29(t, J = 1.9 Hz, 1H), 7.22(d, J = 1.9 Hz, 2H), 5.06(s, 2H), 4.24 - 4.06(m, 2H), 3.45(t, J = 6.8 Hz, 2H), 2.95 - 2.72(m, 2H), 1.82(q, J = 6.7 Hz, 2H), 1.76 - 1.68(m, 3H), 1.22 - 1.06(m, 2H). 1H NMR (400 MHz, CDCl 3 ) δ 7.29 (t, J = 1.9 Hz, 1H), 7.22 (d, J = 1.9 Hz, 2H), 5.06 (s, 2H), 4.24 - 4.06 (m, 2H) , 3.45 (t, J = 6.8 Hz, 2H), 2.95 - 2.72 (m, 2H), 1.82 (q, J = 6.7 Hz, 2H), 1.76 - 1.68 (m, 3H), 1.22 - 1.06 (m, 2H) ).
3,5-디클로로벤질 4-포밀피페리딘-1-카복실레이트(32d): 3,5-dichlorobenzyl 4-formylpiperidine-1-carboxylate (32d) :
CH2Cl2(10 mL) 중 31b(1.59 g, 5.00 mmol)의 용액에 피리디니움 클로로크로메이트(1.29 g, 6.00 mmol)를 분할로 첨가하였다. 반응 혼합물을 실온에서 밤새 교반하였다. 크루드 혼합물을 celite®를 통해 여과하였다. 유기층을 무수 소듐 설페이트로 탈수시키고 농축시켰다. 생성물을 컬럼 크로마토그래피(헥산/에틸아세테이트)로 정제하여 32d를 무색 오일(1.33 g, 84.0%)로 얻었다.To a solution of 31b (1.59 g, 5.00 mmol) in CH 2 Cl 2 (10 mL) was added pyridinium chlorochromate (1.29 g, 6.00 mmol) in portions. The reaction mixture was stirred overnight at room temperature. The crude mixture was filtered through celite®. The organic layer was dehydrated with anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (hexane/ethyl acetate) to give 32d as a colorless oil (1.33 g, 84.0%).
1H NMR(400 MHz, CDCl3) δ 9.63(s, 1H), 7.26(t, J = 1.9 Hz, 1H), 7.18(d, J = 1.9 Hz, 2H), 5.01(s, 2H), 4.04 - 3.94(m, 2H), 3.09 - 2.92(m, 2H), 2.47 - 2.35(m, 1H), 1.96 - 1.82(m, 2H), 1.63 - 1.50(m, 2H). 1H NMR (400 MHz, CDCl 3 ) δ 9.63 (s, 1H), 7.26 (t, J = 1.9 Hz, 1H), 7.18 (d, J = 1.9 Hz, 2H), 5.01 (s, 2H), 4.04 - 3.94 (m, 2H), 3.09 - 2.92 (m, 2H), 2.47 - 2.35 (m, 1H), 1.96 - 1.82 (m, 2H), 1.63 - 1.50 (m, 2H).
제법 7. 화합물 33a-p의 합성.Preparation 7. Synthesis of compounds 33a-p.
시약 및 조건:(a) 아민 또는 알코올, K2CO3, DMF, 80 ℃, overnight;(b) i: N2H4.H2O, MeOH, reflux, 24 h; ii: CDI, DMF, 80 ℃, 15 h.;(c) 3a-b, 7a-b, 또는 14a-b, NaBH(OAc)3, AcOH, CH2Cl2, 15 h;(d) TFA, CH2Cl2, 3 h. Reagents and conditions: (a) amine or alcohol, K 2 CO 3 , DMF, 80 °C, overnight; (b) i: N 2 H 4 .H 2 O, MeOH, reflux, 24 h; ii: CDI, DMF, 80 °C, 15 h; (c) 3a-b , 7a-b , or 14a-b , NaBH(OAc) 3 , AcOH, CH 2 Cl 2 , 15 h; (d) TFA; CH 2 Cl 2 , 3 h.
아민 또는 에터 형성을 위한 일반적인 공정 F. General process for amine or ether formation F.
DMF(1 mL) 중 알킬브로마이드(32b-c; 0.10 mmol), 아민 또는 알코올(0.15 mmol), 및 K2CO3(27.6 mg, 0.20 mmol)의 혼합물을 80 ℃에서 15 h 동안 교반하였다. 진공하에서 용매를 제거한 후, 유기물을 에틸아세테이트로 추출하고, 브라인으로 세척하고, 무수 Na2SO4로 탈수시키고 농축시켰다. 생성물을 컬럼 크로마토그래피(CH2Cl2/MeOH)로 정제하여 목적하는 아민 또는 에터를 얻었다.Alkyl bromide ( 32b-c ; in DMF (1 mL); 0.10 mmol), amine or alcohol (0.15 mmol), and K 2 CO 3 (27.6 mg, 0.20 mmol) were stirred at 80 °C for 15 h. After removing the solvent under vacuum, the organics were extracted with ethyl acetate, washed with brine, dried over anhydrous Na 2 SO 4 and concentrated. The product was purified by column chromatography (CH 2 Cl 2 /MeOH) to give the desired amine or ether.
3,5-디클로로벤질 4-((4-(13,5-Dichlorobenzyl 4-((4-(1 HH -이미다졸-5-일)피페리딘-1-일)메틸)피페리딘-1-카복실레이트(33a).-imidazol-5-yl)piperidin-1-yl)methyl)piperidine-1-carboxylate (33a).
일반적인 공정 C에 따라, 32b(38.11 mg, 0.10 mmol) 및 4-(1H-이미다졸-4(5)-일)피페리딘(22.68 mg, 0.15 mmol)을 사용하여 33a를 흰색 고체(32.50 mg, 72.0%)로 얻었다. 33a was prepared as a white solid ( 32.50 mg, 72.0%).
1H NMR(400 MHz, CDCl3) δ 10.31(br s, 1H), 7.63 - 7.52(m, 1H), 7.29(t, J = 2.0 Hz, 1H), 7.22(d, J = 2.0 Hz, 2H), 6.77(s, 1H), 5.06(s, 2H), 4.22 - 4.09(m, 2H), 2.94 - 2.87(m, 2H), 2.84 - 2.71(m, 2H), 2.60(tt, J = 11.8, 3.8 Hz, 1H), 2.18(d, J = 7.0 Hz, 2H), 2.07 - 1.93(m, 4H), 1.81 - 1.65(m, 5H), 1.17 - 1.04(m, 2H). 13C NMR(100 MHz, CDCl3) δ 154.81, 142.01, 140.43, 135.05, 134.40, 128.03, 125.95, 115.12, 65.33, 64.78, 54.41, 44.26, 34.69, 33.69, 32.18, 30.63. . HRMS(ESI) m/z(M+H)+ calcd for C22H29Cl2N4O2= 451.17; found 451.1669. 1H NMR (400 MHz, CDCl 3 ) δ 10.31 (br s, 1H), 7.63 - 7.52 (m, 1H), 7.29 (t, J = 2.0 Hz, 1H), 7.22 (d, J = 2.0 Hz, 2H) ), 6.77(s, 1H), 5.06(s, 2H), 4.22 - 4.09(m, 2H), 2.94 - 2.87(m, 2H), 2.84 - 2.71(m, 2H), 2.60(tt, J = 11.8 , 3.8 Hz, 1H), 2.18 (d, J = 7.0 Hz, 2H), 2.07 - 1.93 (m, 4H), 1.81 - 1.65 (m, 5H), 1.17 - 1.04 (m, 2H). 13 C NMR (100 MHz, CDCl 3 ) δ 154.81, 142.01, 140.43, 135.05, 134.40, 128.03, 125.95, 115.12, 65.33, 64.78, 54.41, 44.26, 34.69, 33.69, 33.69 . HRMS(ESI) m/z(M+H) + calcd for C 22 H 29 Cl 2 N 4 O 2 = 451.17; found 451.1669.
3,5-디클로로벤질 4-(2-(4-(13,5-Dichlorobenzyl 4-(2-(4-(1) HH -이미다졸-5-일)피페리딘-1-일)에틸)피페리딘-1-카복실레이트(33b).-imidazol-5-yl)piperidin-1-yl)ethyl)piperidine-1-carboxylate (33b).
일반적인 공정 C에 따라, 32c(39.51 mg, 0.10 mmol), 4-(1H-이미다졸-4(5)-일)피페리딘(22.68 mg, 0.15 mmol), 및 소듐 하이드로젠카보네이트(16.8 mg, 0.20 mmol)를 사용하여 33b를 흰색 고체(37.56 mg, 80.7%)로 얻었다.According to General Procedure C, 32c (39.51 mg, 0.10 mmol), 4-(1 H -imidazol-4(5)-yl)piperidine (22.68 mg, 0.15 mmol), and sodium hydrogencarbonate (16.8 mg , 0.20 mmol) was used to obtain 33b as a white solid (37.56 mg, 80.7%).
1H NMR(400 MHz, CDCl3) δ 10.09(br s, 1H), 7.55(d, J = 1.1 Hz, 1H), 7.29(t, J = 2.0 Hz, 1H), 7.22(d, J = 1.9 Hz, 2H), 6.76(s, 1H), 5.06(s, 2H), 4.22 - 4.04(m, 2H), 3.04 - 2.94(m, 2H), 2.91 - 2.69(m, 2H), 2.61(tt, J = 11.8, 3.7 Hz, 1H), 2.42 - 2.33(m, 2H), 2.08 - 1.98(m, 4H), 1.77 - 1.63(m, 4H), 1.55 - 1.43(m, 3H), 1.24 - 1.09(m, 2H). 13C NMR(100 MHz, CDCl3) δ 154.76, 140.43, 135.06, 134.31, 128.04, 125.98, 65.34, 56.44, 53.95, 44.32, 34.49, 33.67, 32.12. HRMS(ESI) m/z(M+H)+ calcd for C23H31Cl2N4O2= 465.18; found 465.1823. 1H NMR (400 MHz, CDCl 3 ) δ 10.09 (br s, 1H), 7.55 (d, J = 1.1 Hz, 1H), 7.29 (t, J = 2.0 Hz, 1H), 7.22 (d, J = 1.9 Hz, 2H), 6.76(s, 1H), 5.06(s, 2H), 4.22 - 4.04(m, 2H), 3.04 - 2.94(m, 2H), 2.91 - 2.69(m, 2H), 2.61(tt, J = 11.8, 3.7 Hz, 1H), 2.42 - 2.33 (m, 2H), 2.08 - 1.98 (m, 4H), 1.77 - 1.63 (m, 4H), 1.55 - 1.43 (m, 3H), 1.24 - 1.09 ( m, 2H). 13 C NMR (100 MHz, CDCl 3 ) δ 154.76, 140.43, 135.06, 134.31, 128.04, 125.98, 65.34, 56.44, 53.95, 44.32, 34.49, 33.67, 32.12. HRMS(ESI) m/z(M+H) + calcd for C 23 H 31 Cl 2 N 4 O 2 = 465.18; found 465.1823.
3,5-디클로로벤질 4-((4-(13,5-Dichlorobenzyl 4-((4-(1 HH -1,2,3-트리아졸-5-일)피페리딘-1-일)메틸)피페리딘-1-카복실레이트(33c). -1,2,3-triazol-5-yl)piperidin-1-yl)methyl)piperidine-1-carboxylate (33c).
일반적인 공정 C에 따라, 32b(38.11 mg, 0.10 mmol) 및 20(22.64 mg, 0.12 mmol)을 사용하여 33c를 흰색 고체(17.60 mg, 38.9%)로 얻었다.According to General Procedure C, using 32b (38.11 mg, 0.10 mmol) and 20 (22.64 mg, 0.12 mmol), 33c was obtained as a white solid (17.60 mg, 38.9%).
1H NMR(400 MHz, CDCl3) δ 11.73(br s, 1H), 7.51(s, 1H), 7.29(s, 1H), 7.22(d, J = 1.9 Hz, 2H), 5.07(s, 2H), 4.24 - 4.07(m, 2H), 3.01 - 2.91(m, 2H), 2.88 - 2.72(m, 3H), 2.23(d, J = 6.8 Hz, 2H), 2.14 - 2.05(m, 2H), 2.02 - 1.92(m, 2H), 1.87 - 1.70(m, 5H), 1.22 - 1.07(m, 2H). 13C NMR(100 MHz, CDCl3) δ 154.84, 150.80, 140.39, 135.05, 129.78, 128.05, 125.99, 65.39, 64.77, 54.16, 44.22, 33.66, 33.03, 31.88, 30.75. HRMS(ESI) m/z(M+H)+ calcd for C21H28Cl2N5O2= 452.16; found 452.1615. 1 H NMR (400 MHz, CDCl 3 ) δ 11.73 (br s, 1H), 7.51 (s, 1H), 7.29 (s, 1H), 7.22 (d, J = 1.9 Hz, 2H), 5.07 (s, 2H) ), 4.24 - 4.07 (m, 2H), 3.01 - 2.91 (m, 2H), 2.88 - 2.72 (m, 3H), 2.23 (d, J = 6.8 Hz, 2H), 2.14 - 2.05 (m, 2H), 2.02 - 1.92 (m, 2H), 1.87 - 1.70 (m, 5H), 1.22 - 1.07 (m, 2H). 13 C NMR (100 MHz, CDCl 3 ) δ 154.84, 150.80, 140.39, 135.05, 129.78, 128.05, 125.99, 65.39, 64.77, 54.16, 44.22, 33.66, 33.03, 30.87, 31.85. HRMS(ESI) m/z(M+H) + calcd for C 21 H 28 Cl 2 N 5 O 2 = 452.16; found 452.1615.
3,5-디클로로벤질 4-(2-(4-(13,5-Dichlorobenzyl 4-(2-(4-(1) HH -이미다졸-5-일)페녹시)에틸)피페리딘-1-카복실레이트(33d).-imidazol-5-yl)phenoxy)ethyl)piperidine-1-carboxylate (33d).
일반적인 공정 C에 따라, 32c(39.51 mg, 0.10 mmol) 및 30a(32.03 mg, 0.20 mmol)를 사용하여 33d를 흰색 고체(13.28 mg, 28.0%)로 얻었다.According to General Procedure C, using 32c (39.51 mg, 0.10 mmol) and 30a (32.03 mg, 0.20 mmol), 33d was obtained as a white solid (13.28 mg, 28.0%).
1H NMR(400 MHz, CDCl3) δ 8.98(s, 1H), 7.66(d, J = 1.1 Hz, 1H), 7.64(d, J = 8.8 Hz, 2H), 7.29(t, J = 1.9 Hz, 1H), 7.24(d, J = 1.1 Hz, 1H), 7.22(d, J = 1.9 Hz, 2H), 6.90(d, J = 8.7 Hz, 2H), 5.06(s, 2H), 4.23 - 4.11(m, 2H), 4.02(t, J = 5.8 Hz, 2H), 2.95 - 2.72(m, 2H), 1.83 - 1.68(m, 5H), 1.28 - 1.14(m, 2H). 13C NMR(100 MHz, CDCl3) δ 158.08, 154.77, 140.37, 138.65, 135.28, 135.06, 128.05, 126.20, 125.98, 125.88, 114.72, 114.18, 65.37, 65.29, 44.27, 35.68, 32.82, 31.78. HRMS(ESI) m/z(M+H)+ calcd for C24H26Cl2N3O3= 474.14; found 474.1348. 1 H NMR (400 MHz, CDCl 3 ) δ 8.98 (s, 1H), 7.66 (d, J = 1.1 Hz, 1H), 7.64 (d, J = 8.8 Hz, 2H), 7.29 (t, J = 1.9 Hz , 1H), 7.24 (d, J = 1.1 Hz, 1H), 7.22 (d, J = 1.9 Hz, 2H), 6.90 (d, J = 8.7 Hz, 2H), 5.06 (s, 2H), 4.23 - 4.11 (m, 2H), 4.02 (t, J = 5.8 Hz, 2H), 2.95 - 2.72 (m, 2H), 1.83 - 1.68 (m, 5H), 1.28 - 1.14 (m, 2H). 13 C NMR (100 MHz, CDCL 3 ) δ 158.08, 154.77, 140.37, 138.65, 135.28, 135.06, 128.05, 126.20, 125.98, 125.88, 114.72, 114.18, 65.37, 65.29, 44.27, 35.68, 32.82 HRMS(ESI) m/z(M+H) + calcd for C 24 H 26 Cl 2 N 3 O 3 = 474.14; found 474.1348.
3,5-디클로로벤질 4-((4-(13,5-Dichlorobenzyl 4-((4-(1 HH -이미다졸-5-일)페녹시)메틸)피페리딘-1-카복실레이트(33e).-imidazol-5-yl)phenoxy)methyl)piperidine-1-carboxylate (33e).
일반적인 공정 C에 따라, 32b(38.11 mg, 0.10 mmol) 및 30a(32.03 mg, 0.20 mmol)를 사용하여 33e를 흰색 고체(12.93 mg, 28.1%)로 얻었다.According to General Procedure C, using 32b (38.11 mg, 0.10 mmol) and 30a (32.03 mg, 0.20 mmol), 33e was obtained as a white solid (12.93 mg, 28.1%).
1H NMR(400 MHz, CDCl3) δ 10.38(s, 1H), 7.70 - 7.55(m, 3H), 7.32 - 7.27(m, 1H), 7.27 - 7.18(m, 3H), 6.89(d, J = 8.7 Hz, 2H), 5.11 - 5.02(m, 2H), 4.30 - 4.15(m, 2H), 3.82(d, J = 6.3 Hz, 2H), 2.96 - 2.77(m, 2H), 2.08 - 1.95(m, 1H), 1.91 - 1.83(m, 2H), 1.39 - 1.27(m, 2H). 13 C NMR(100 MHz, CDCl3) δ 158.12, 154.78, 140.32, 137.18, 135.27, 135.08, 128.09, 126.21, 126.02, 125.54, 114.74, 113.75, 77.35, 77.03, 76.72, 72.16, 65.43, 43.95, 36.07, 28.69. HRMS(ESI) m/z(M+H)+ calcd for C23H24Cl2N3O3= 460.12; found 460.1190. 1 H NMR (400 MHz, CDCl 3 ) δ 10.38 (s, 1H), 7.70 - 7.55 (m, 3H), 7.32 - 7.27 (m, 1H), 7.27 - 7.18 (m, 3H), 6.89 (d, J = 8.7 Hz, 2H), 5.11 - 5.02 (m, 2H), 4.30 - 4.15 (m, 2H), 3.82 (d, J = 6.3 Hz, 2H), 2.96 - 2.77 (m, 2H), 2.08 - 1.95 ( m, 1H), 1.91 - 1.83 (m, 2H), 1.39 - 1.27 (m, 2H). 13 C NMR (100 MHz, CDCL 3 ) Δ 158.12, 154.78, 140.32, 137.18, 135.27, 135.08, 128.09, 126.21, 126.02, 125.54, 114.74, 113.75, 77.35, 77.03 . HRMS(ESI) m/z(M+H) + calcd for C 23 H 24 Cl 2 N 3 O 3 = 460.12; found 460.1190.
3,5-디클로로벤질 4-(4-(13,5-Dichlorobenzyl 4-(4-(1 HH -이미다졸-5-일)페녹시)피페리딘-1-카복실레이트(33f).-imidazol-5-yl)phenoxy)piperidine-1-carboxylate (33f).
일반적인 공정 C에 따라, 32a(0.18 g, 0.50 mmol) 및 30a(0.16 g, 1.00 mmol)를 사용하여 33f를 흰색 고체(8.26 mg, 3.7%)로 얻었다.According to General Procedure C, using 32a ( 0.18 g, 0.50 mmol) and 30a ( 0.16 g, 1.00 mmol), 33f was obtained as a white solid (8.26 mg, 3.7%).
1H NMR(400 MHz, CDCl3) δ 7.68(d, J = 1.1 Hz, 1H), 7.66(d, J = 8.3 Hz, 2H), 7.31(t, J = 1.9 Hz, 1H), 7.25(d, J = 1.1 Hz, 1H), 7.24(d, J = 1.9 Hz, 2H), 6.94(d, J = 8.7 Hz, 2H), 5.08(s, 2H), 4.57 - 4.50(m, 1H), 3.80 - 3.69(m, 2H), 3.57 - 3.47(m, 2H), 1.98 - 1.90(m, 2H), 1.88 - 1.80(m, 2H). 13C NMR(100 MHz, CDCl3) δ 156.25, 154.78, 140.24, 135.16, 135.10, 128.14, 126.31, 126.07, 116.46, 71.62, 65.51, 40.76, 30.23. HRMS(ESI) m/z(M+Na)+ calcd for C22H21Cl2N3O3Na= 468.09; found 468.0860. 1H NMR (400 MHz, CDCl 3 ) δ 7.68 (d, J = 1.1 Hz, 1H), 7.66 (d, J = 8.3 Hz, 2H), 7.31 (t, J = 1.9 Hz, 1H), 7.25 (d , J = 1.1 Hz, 1H), 7.24 (d, J = 1.9 Hz, 2H), 6.94 (d, J = 8.7 Hz, 2H), 5.08 (s, 2H), 4.57 - 4.50 (m, 1H), 3.80 - 3.69 (m, 2H), 3.57 - 3.47 (m, 2H), 1.98 - 1.90 (m, 2H), 1.88 - 1.80 (m, 2H). 13 C NMR (100 MHz, CDCl 3 ) δ 156.25, 154.78, 140.24, 135.16, 135.10, 128.14, 126.31, 126.07, 116.46, 71.62, 65.51, 40.76, 30.23. HRMS(ESI) m/z(M+Na)+ calcd for C 22 H 21 Cl 2 N 3 O 3 Na = 468.09; found 468.0860.
3,5-디클로로벤질 4-((3-(13,5-Dichlorobenzyl 4-((3-(1 HH -이미다졸-5-일)페녹시)메틸)피페리딘-1-카복실레이트(33g).-imidazol-5-yl)phenoxy)methyl)piperidine-1-carboxylate (33 g).
일반적인 공정 C에 따라, 32b(38.11 mg, 0.10 mmol) 및 30b(32.03 mg, 0.20 mmol)를 사용하여 33g를 흰색 고체(9.71 mg, 21.1%)로 얻었다.Following General Procedure C, using 32b (38.11 mg, 0.10 mmol) and 30b (32.03 mg, 0.20 mmol), 33 g was obtained as a white solid (9.71 mg, 21.1%).
1H NMR(400 MHz, CDCl3) δ 10.18(s, 1H), 7.70(d, J = 1.1 Hz, 1H), 7.35(d, J = 1.1 Hz, 1H), 7.34 - 7.31(m, 1H), 7.30(t, J = 1.9 Hz, 1H), 7.29 - 7.26(m, 2H), 7.23(d, J = 1.9 Hz, 2H), 6.81 - 6.76(m, 1H), 5.07(d, J = 10.4 Hz, 2H), 4.31 - 4.12(m, 2H), 3.84(d, J = 6.3 Hz, 2H), 2.96 - 2.74(m, 2H), 2.06 - 1.92(m, 1H), 1.90 - 1.80(m, 2H), 1.37 - 1.23(m, 2H). 13C NMR(100 MHz, CDCl3) δ 159.38, 154.78, 140.32, 135.44, 135.07, 129.77, 128.08, 126.02, 117.39, 113.49, 110.63, 72.04, 65.42, 43.94, 36.07, 28.60. HRMS(ESI) m/z(M+H)+ calcd for C23H24Cl2N3O3= 460.12; found 460.1192. 1H NMR (400 MHz, CDCl 3 ) δ 10.18 (s, 1H), 7.70 (d, J = 1.1 Hz, 1H), 7.35 (d, J = 1.1 Hz, 1H), 7.34 - 7.31 (m, 1H) , 7.30 (t, J = 1.9 Hz, 1H), 7.29 - 7.26 (m, 2H), 7.23 (d, J = 1.9 Hz, 2H), 6.81 - 6.76 (m, 1H), 5.07 (d, J = 10.4 Hz, 2H), 4.31 - 4.12(m, 2H), 3.84(d, J = 6.3 Hz, 2H), 2.96 - 2.74(m, 2H), 2.06 - 1.92(m, 1H), 1.90 - 1.80(m, 2H), 1.37 - 1.23 (m, 2H). 13 C NMR (100 MHz, CDCl 3 ) δ 159.38, 154.78, 140.32, 135.44, 135.07, 129.77, 128.08, 126.02, 117.39, 113.49, 110.63, 72.04, 65.46, 0.26.42, 43.84 HRMS(ESI) m/z(M+H) + calcd for C 23 H 24 Cl 2 N 3 O 3 = 460.12; found 460.1192.
3,5-디클로로벤질 4-(3-(1H-이미다졸-5-일)페녹시)피페리딘-1-카복실레이트(33h).3,5-dichlorobenzyl 4-(3-(1H-imidazol-5-yl)phenoxy)piperidine-1-carboxylate (33h).
일반적인 공정 C에 따라, 32a(0.18 g, 0.50 mmol) 및 30b(0.16 g, 1.00 mmol)를 사용하여 33h를 흰색 고체(10.49 mg, 4.7%)로 얻었다.According to General Procedure C, using 32a ( 0.18 g, 0.50 mmol) and 30b ( 0.16 g, 1.00 mmol), 33h was obtained as a white solid (10.49 mg, 4.7%).
1H NMR(400 MHz, CDCl3) δ 9.56(br s, 1H), 7.70(d, J = 1.1 Hz, 1H), 7.52 - 7.31(m, 3H), 7.30(t, J = 1.9 Hz, 1H), 7.28(d, J = 7.6 Hz, 1H), 7.23(dt, J = 1.9, 0.7 Hz, 2H), 6.85 - 6.78(m, 1H), 5.08(s, 2H), 4.64 - 4.56(m, 1H), 3.78 - 3.67(m, 2H), 3.54 - 3.43(m, 2H), 2.00 - 1.88(m, 2H), 1.87 - 1.77(m, 2H). 13C NMR(100 MHz, CDCl3) δ 157.55, 154.78, 140.26, 135.37, 135.10, 129.86, 128.13, 126.25, 126.05, 117.88, 115.06, 112.60, 71.48, 65.49, 40.76, 30.30. HRMS(ESI) m/z(M+H)+ calcd for C22H22Cl2N3O3= 446.10; found 446.1037. 1H NMR (400 MHz, CDCl 3 ) δ 9.56 (br s, 1H), 7.70 (d, J = 1.1 Hz, 1H), 7.52 - 7.31 (m, 3H), 7.30 (t, J = 1.9 Hz, 1H) ), 7.28 (d, J = 7.6 Hz, 1H), 7.23 (dt, J = 1.9, 0.7 Hz, 2H), 6.85 - 6.78 (m, 1H), 5.08 (s, 2H), 4.64 - 4.56 (m, 1H), 3.78 - 3.67 (m, 2H), 3.54 - 3.43 (m, 2H), 2.00 - 1.88 (m, 2H), 1.87 - 1.77 (m, 2H). 13 C NMR (100 MHz, CDCl 3 ) δ 157.55, 154.78, 140.26, 135.37, 135.10, 129.86, 128.13, 126.25, 126.05, 117.88, 115.06, 112.60, 71.49, 0, 0.49, 65.48 HRMS(ESI) m/z(M+H) + calcd for C 22 H 22 Cl 2 N 3 O 3 = 446.10; found 446.1037.
3,5-디클로로벤질 4-((3-(2-메틸-13,5-Dichlorobenzyl 4-((3-(2-methyl-1 HH -이미다졸-5-일)페녹시)메틸)피페리딘-1-카복실레이트(33i).-imidazol-5-yl)phenoxy)methyl)piperidine-1-carboxylate (33i).
일반적인 공정 C에 따라, 32b(38.11 mg, 0.10 mmol) 및 30c(34.84 mg, 0.20 mmol)를 사용하여 33i를 흰색 고체(9.15 mg, 19.3%)로 얻었다.According to General Procedure C, using 32b (38.11 mg, 0.10 mmol) and 30c (34.84 mg, 0.20 mmol), 33i was obtained as a white solid (9.15 mg, 19.3%).
1H NMR(400 MHz, CDCl3) δ 7.30(t, J = 1.9 Hz, 1H), 7.27 - 7.24(m, 3H), 7.23(d, J = 1.8 Hz, 2H), 7.20(s, 1H), 6.80 - 6.71(m, 1H), 5.07(d, J = 10.4 Hz, 2H), 4.30 - 4.12(m, 2H), 3.84(d, J = 6.3 Hz, 2H), 2.98 - 2.75(m, 2H), 2.47(s, 3H), 2.06 - 1.92(m, 1H), 1.91 - 1.81(m, 2H), 1.38 - 1.26(m, 2H). 13C NMR(100 MHz, CDCl3) δ 159.36, 154.77, 144.88, 140.34, 135.07, 134.70, 129.68, 128.08, 126.03, 117.19, 113.15, 110.43, 72.04, 65.41, 43.95, 36.11, 28.63, 14.33. HRMS(ESI) m/z(M+H)+ calcd for C24H26Cl2N3O3= 474.14; found 474.1353. 1 H NMR (400 MHz, CDCl 3 ) δ 7.30 (t, J = 1.9 Hz, 1H), 7.27 - 7.24 (m, 3H), 7.23 (d, J = 1.8 Hz, 2H), 7.20 (s, 1H) , 6.80 - 6.71 (m, 1H), 5.07 (d, J = 10.4 Hz, 2H), 4.30 - 4.12 (m, 2H), 3.84 (d, J = 6.3 Hz, 2H), 2.98 - 2.75 (m, 2H) ), 2.47 (s, 3H), 2.06 - 1.92 (m, 1H), 1.91 - 1.81 (m, 2H), 1.38 - 1.26 (m, 2H). 13 C NMR (100 MHz, CDCL 3 ) δ 159.36, 154.77, 144.88, 140.34, 135.07, 134.70, 129.68, 128.08, 126.03, 117.19, 113.15, 110.43, 72.04, 65.41, 43.95, 36.11, 28.33. HRMS(ESI) m/z(M+H) + calcd for C 24 H 26 Cl 2 N 3 O 3 = 474.14; found 474.1353.
3,5-디클로로벤질 4-((4-(메톡시카보닐)피페리딘-1-일)메틸)피페리딘-1-카복실레이트(34).3,5-Dichlorobenzyl 4-((4-(methoxycarbonyl)piperidin-1-yl)methyl)piperidine-1-carboxylate (34).
DMF(10 mL) 중 32b(0.38 g, 1.00 mmol) 및 메틸 피페리딘-4-카복실레이트(0.29 g, 2.00 mmol)의 혼합물을 80 ℃에서 밤새 가열하였다. 유기물을 에틸아세테이트로 추출하고 물로 세척하였다. 유기층을 무수 소듐 설페이트로 탈수시키고 농축시켰다. 컬럼 크로마토그래피(에틸아세테이트/헥산)로 정제하여 34를 흰색 고체(0.36 g, 81.4%)로 얻었다.A mixture of 32b ( 0.38 g, 1.00 mmol) and methyl piperidine-4-carboxylate (0.29 g, 2.00 mmol) in DMF (10 mL) was heated at 80 °C overnight. The organic matter was extracted with ethyl acetate and washed with water. The organic layer was dehydrated with anhydrous sodium sulfate and concentrated. Purification by column chromatography (ethyl acetate/hexane) gave 34 as a white solid (0.36 g, 81.4%).
1H NMR(400 MHz, CDCl3) δ 7.29(t, J = 1.9 Hz, 1H), 7.22(d, J = 1.9 Hz, 2H), 5.06(s, 2H), 4.23 - 4.08(m, 2H), 3.67(s, 3H), 2.89 - 2.68(m, 4H), 2.33 - 2.23(m, 1H), 2.14(d, J = 7.1 Hz, 2H), 2.00 - 1.92(m, 2H), 1.90 - 1.83(m, 2H), 1.79 - 1.70(m, 4H), 1.69 - 1.60(m, 1H), 1.15 - 1.02(m, 2H). 1H NMR (400 MHz, CDCl 3 ) δ 7.29 (t, J = 1.9 Hz, 1H), 7.22 (d, J = 1.9 Hz, 2H), 5.06 (s, 2H), 4.23 - 4.08 (m, 2H) , 3.67(s, 3H), 2.89 - 2.68(m, 4H), 2.33 - 2.23(m, 1H), 2.14(d, J = 7.1 Hz, 2H), 2.00 - 1.92(m, 2H), 1.90 - 1.83 (m, 2H), 1.79 - 1.70 (m, 4H), 1.69 - 1.60 (m, 1H), 1.15 - 1.02 (m, 2H).
3,5-디클로로벤질 4-((4-(5-옥소-4,5-디하이드로-1,3,4-옥사다이아졸-2-일)피페리딘-1-일)메틸)피페리딘-1-카복실레이트(33j). 3,5-dichlorobenzyl 4-((4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidin-1-yl)methyl)piperi din-1-carboxylate (33j).
화합물 34(0.22 g, 0.50 mmol)를 MeOH 중 히드라진 모노하이드레이트(200 μL)와 함께 1h 동안 환류시켰다. 용매를 진공하에 제거하였다. 잔여물을 DMF(10 mL)에 용해시키고 1,1'-카보닐디이미다졸(97.25 mg, 0.60 mmol)과 혼합하였다. 12 h 동안 80 ℃에서 교반한 후, 용매를 증발시켜 건조시켰다. 유기물을 에틸아세테이트로 추출하고, 물로 세척하고, 무수 소듐 설페이트로 탈수시키고, 농축시켰다. 잔여물을 컬럼 크로마토그래피(에틸아세테이트/헥산)로 정제하여 33j를 흰색 고체(103.7 mg, 44.2%)로 얻었다.Compound 34 (0.22 g, 0.50 mmol) was refluxed with hydrazine monohydrate (200 μL) in MeOH for 1 h. Solvent was removed under vacuum. The residue was dissolved in DMF (10 mL) and mixed with 1,1'-carbonyldiimidazole (97.25 mg, 0.60 mmol). After stirring at 80 °C for 12 h, the solvent was evaporated to dryness. The organics were extracted with ethyl acetate, washed with water, dehydrated with anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (ethyl acetate/hexane) to give 33j as a white solid (103.7 mg, 44.2%).
1H NMR(400 MHz, CDCl3) δ 9.59(br s, 1H), 7.29(t, J = 1.9 Hz, 1H), 7.22(d, J = 1.9 Hz, 2H), 5.09 - 5.03(m, 2H), 4.24 - 4.06(m, 2H), 2.92 - 2.73(m, 4H), 2.62 - 2.52(m, 1H), 2.20(d, J = 7.0 Hz, 2H), 2.11 - 2.02(m, 2H), 1.99 - 1.91(m, 2H), 1.86 - 1.74(m, 4H), 1.73 - 1.62(m, 1H), 1.18 - 1.04(m, 2H). 13C NMR(100 MHz, CDCl3) δ 160.14, 155.50, 154.83, 140.34, 135.03, 128.04, 125.99, 65.41, 64.44, 53.07, 44.18, 34.01, 33.56, 30.71, 28.11. HRMS(ESI) m/z(M+H)+ calcd for C21H27Cl2N4O4= 469.14; found 469.1405. 1H NMR (400 MHz, CDCl 3 ) δ 9.59 (br s, 1H), 7.29 (t, J = 1.9 Hz, 1H), 7.22 (d, J = 1.9 Hz, 2H), 5.09 - 5.03 (m, 2H) ), 4.24 - 4.06(m, 2H), 2.92 - 2.73(m, 4H), 2.62 - 2.52(m, 1H), 2.20(d, J = 7.0 Hz, 2H), 2.11 - 2.02(m, 2H), 1.99 - 1.91 (m, 2H), 1.86 - 1.74 (m, 4H), 1.73 - 1.62 (m, 1H), 1.18 - 1.04 (m, 2H). 13 C NMR (100 MHz, CDCl 3 ) δ 160.14, 155.50, 154.83, 140.34, 135.03, 128.04, 125.99, 65.41, 64.44, 53.07, 44.18, 34.01, 33.56, 20.71, 38.71. HRMS(ESI) m/z(M+H) + calcd for C 21 H 27 Cl 2 N 4 O 4 = 469.14; found 469.1405.
3,5-디클로로벤질 4-(((4-(2-아미노티아졸-5-일)페닐)아미노)메틸)피페리딘-1-카복실레이트(33k).3,5-Dichlorobenzyl 4-(((4-(2-aminothiazol-5-yl)phenyl)amino)methyl)piperidine-1-carboxylate (33k).
일반적인 공정 C에 따라, 32d(31.62 mg, 0.10 mmol) 및 3a(39.15 mg, 0.10 mmol)를 사용하여 Boc-보호된 중간체를 흰색 고체(63.22 mg, 91.4%)로 얻었다;According to general procedure C, 32d (31.62 mg, 0.10 mmol) and 3a (39.15 mg, 0.10 mmol) were used to obtain the Boc-protected intermediate as a white solid (63.22 mg, 91.4%);
1H NMR(400 MHz, CDCl3) δ 7.65(d, J = 8.7 Hz, 2H), 7.30(t, J = 1.9 Hz, 1H), 7.22(d, J = 1.9 Hz, 2H), 7.03(s, 1H), 6.60(d, J = 8.7 Hz, 2H), 5.06(s, 2H), 4.28 - 4.11(m, 2H), 3.92 - 3.85(m, 1H), 3.07(d, J = 6.3 Hz, 2H), 2.90 - 2.72(m, 2H), 1.85 - 1.78(m, 3H), 1.54(s, 18H), 1.25 - 1.16(m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.65 (d, J = 8.7 Hz, 2H), 7.30 (t, J = 1.9 Hz, 1H), 7.22 (d, J = 1.9 Hz, 2H), 7.03 (s , 1H), 6.60 (d, J = 8.7 Hz, 2H), 5.06 (s, 2H), 4.28 - 4.11 (m, 2H), 3.92 - 3.85 (m, 1H), 3.07 (d, J = 6.3 Hz, 2H), 2.90 - 2.72(m, 2H), 1.85 - 1.78(m, 3H), 1.54(s, 18H), 1.25 - 1.16(m, 2H).
이것을 Boc 탈보호시켜 33k를 흰색 고체(27.31 mg, 60.8%)로 얻었다.This was subjected to Boc deprotection to obtain 33k as a white solid (27.31 mg, 60.8%).
1H NMR(400 MHz, CDCl3) δ 7.59(d, J = 8.6 Hz, 2H), 7.30(t, J = 1.9 Hz, 1H), 7.22(d, J = 1.9 Hz, 2H), 6.58(d, J = 8.6 Hz, 2H), 6.48(s, 1H), 5.15 - 4.97(m, 4H), 4.27 - 4.13(m, 2H), 3.94 - 3.75(m, 1H), 3.10 - 3.03(m, 2H), 2.88 - 2.72(m, 2H), 1.86 - 1.72(m, 3H), 1.28 - 1.16(m, 2H). 13C NMR(100 MHz, CDCl3) δ 167.03, 154.73, 151.63, 147.79, 140.36, 135.08, 128.09, 127.24, 126.05, 124.50, 112.60, 99.52, 65.42, 49.52, 44.07, 35.92, 30.04. HRMS(ESI) m/z(M+H)+ calcd for C23H25Cl2N4O2S= 491.11; found 491.1078. 1 H NMR (400 MHz, CDCl 3 ) δ 7.59 (d, J = 8.6 Hz, 2H), 7.30 (t, J = 1.9 Hz, 1H), 7.22 (d, J = 1.9 Hz, 2H), 6.58 (d , J = 8.6 Hz, 2H), 6.48(s, 1H), 5.15 - 4.97(m, 4H), 4.27 - 4.13(m, 2H), 3.94 - 3.75(m, 1H), 3.10 - 3.03(m, 2H) ), 2.88 - 2.72 (m, 2H), 1.86 - 1.72 (m, 3H), 1.28 - 1.16 (m, 2H). 13 C NMR (100 MHz, CDCL 3 ) δ 167.03, 154.73, 151.63, 147.79, 140.36, 135.08, 128.09, 127.24, 126.05, 124.50, 112.60, 99.52, 65.42, 49.52, 44.07, 35.92, 30.04. HRMS(ESI) m/z(M+H) + calcd for C 23 H 25 Cl 2 N 4 O 2 S = 491.11; found 491.1078.
3,5-디클로로벤질 4-(((3-(2-아미노티아졸-5-일)페닐)아미노)메틸)피페리딘-1-카복실레이트(33l). 3,5-dichlorobenzyl 4-(((3-(2-aminothiazol-5-yl)phenyl)amino)methyl)piperidine-1-carboxylate (33l).
일반적인 공정 D에 따라, 32d(31.62 mg, 0.10 mmol) 및 3b(39.15 mg, 0.10 mmol)를 사용하여 Boc-보호된 중간체를 흰색 고체(56.92 mg, 82.3%)로 얻었다;According to general procedure D, using 32d (31.62 mg, 0.10 mmol) and 3b ( 39.15 mg, 0.10 mmol), the Boc-protected intermediate was obtained as a white solid (56.92 mg, 82.3%);
1H NMR(400 MHz, CDCl3) δ 7.30(t, J = 1.9 Hz, 1H), 7.24 - 7.22(m, 3H), 7.21 - 7.13(m, 3H), 6.60 - 6.51(m, 1H), 5.07(s, 2H), 4.32 - 4.10(m, 2H), 3.87 - 3.77(m, 1H), 3.08(d, J = 6.3 Hz, 2H), 2.91 - 2.72(m, 2H), 1.89 - 1.74(m, 3H), 1.55(s, 18H), 1.28 - 1.16(m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.30 (t, J = 1.9 Hz, 1H), 7.24 - 7.22 (m, 3H), 7.21 - 7.13 (m, 3H), 6.60 - 6.51 (m, 1H), 5.07(s, 2H), 4.32 - 4.10(m, 2H), 3.87 - 3.77(m, 1H), 3.08(d, J = 6.3 Hz, 2H), 2.91 - 2.72(m, 2H), 1.89 - 1.74( m, 3H), 1.55 (s, 18H), 1.28 - 1.16 (m, 2H).
이것을 Boc 탈보호시켜 33l을 흰색 고체(30.21 mg, 74.7%)로 얻었다.This was Boc deprotected to give 33l as a white solid (30.21 mg, 74.7%).
1H NMR(400 MHz, CDCl3) δ 7.30(t, J = 1.9 Hz, 1H), 7.22(d, J = 1.9 Hz, 2H), 7.17(t, J = 8.1 Hz, 1H), 7.07(dt, J = 7.1, 1.5 Hz, 2H), 6.67(s, 1H), 6.56 - 6.49(m, 1H), 5.16(s, 2H), 5.06(s, 2H), 4.26 - 4.12(m, 2H), 3.93 - 3.74(m, 1H), 3.11 - 3.03(m, 2H), 2.90 - 2.68(m, 2H), 1.85 - 1.72(m, 3H), 1.26 - 1.11(m, 2H). 13C NMR(100 MHz, CDCl3) δ 167.15, 154.74, 151.66, 148.46, 140.38, 135.69, 135.07, 129.50, 128.08, 126.05, 115.18, 112.04, 110.72, 102.82, 65.41, 49.59, 44.07, 35.93, 30.15. HRMS(ESI) m/z(M+H)+ calcd for C23H25Cl2N4O2S= 491.11; found 491.1076. 1H NMR (400 MHz, CDCl 3 ) δ 7.30 (t, J = 1.9 Hz, 1H), 7.22 (d, J = 1.9 Hz, 2H), 7.17 (t, J = 8.1 Hz, 1H), 7.07 (dt , J = 7.1, 1.5 Hz, 2H), 6.67(s, 1H), 6.56 - 6.49(m, 1H), 5.16(s, 2H), 5.06(s, 2H), 4.26 - 4.12(m, 2H), 3.93 - 3.74 (m, 1H), 3.11 - 3.03 (m, 2H), 2.90 - 2.68 (m, 2H), 1.85 - 1.72 (m, 3H), 1.26 - 1.11 (m, 2H). 13 C NMR (100 MHz, CDCL 3 ) δ 167.15, 154.74, 151.66, 148.46, 140.38, 135.69, 135.07, 129.50, 128.08, 126.05, 115.18, 112.04, 110.72 HRMS(ESI) m/z(M+H) + calcd for C 23 H 25 Cl 2 N 4 O 2 S = 491.11; found 491.1076.
3,5-디클로로벤질 4-(((4-(13,5-Dichlorobenzyl 4-(((4-(1 HH -이미다졸-5-일)페닐)아미노)메틸)피페리딘-1-카복실레이트(33m).-imidazol-5-yl)phenyl)amino)methyl)piperidine-1-carboxylate (33m).
일반적인 공정 D에 따라, 32d(31.62 mg, 0.10 mmol) 및 7a(15.92 mg, 0.10 mmol)를 사용하여 33m을 흰색 고체(41.71 mg, 90.8%)로 얻었다.According to General Procedure D, using 32d (31.62 mg, 0.10 mmol) and 7a (15.92 mg, 0.10 mmol), 33m was obtained as a white solid (41.71 mg, 90.8%).
1H NMR(400 MHz, CDCl3) δ 9.86(s, 1H), 7.63(s, 1H), 7.52(d, J = 8.2 Hz, 2H), 7.30(t, J = 1.9 Hz, 1H), 7.22(d, J = 1.9 Hz, 2H), 7.18(s, 1H), 6.62(d, J = 8.7 Hz, 2H), 5.06(s, 2H), 4.27 - 4.13(m, 2H), 3.93 - 3.67(m, 1H), 3.06(d, J = 6.2 Hz, 2H), 2.89 - 2.72(m, 2H), 1.87 - 1.75(m, 3H), 1.27 - 1.15(m, 2H). 13C NMR(100 MHz, CDCl3) δ 154.74, 147.30, 140.32, 135.07, 134.91, 128.09, 126.16, 126.03, 112.90, 65.42, 49.60, 44.06, 35.91, 30.07. HRMS(ESI) m/z(M+H)+ calcd for C23H25Cl2N4O2= 459.14; found 459.1354. 1 H NMR (400 MHz, CDCl 3 ) δ 9.86 (s, 1H), 7.63 (s, 1H), 7.52 (d, J = 8.2 Hz, 2H), 7.30 (t, J = 1.9 Hz, 1H), 7.22 (d, J = 1.9 Hz, 2H), 7.18 (s, 1H), 6.62 (d, J = 8.7 Hz, 2H), 5.06 (s, 2H), 4.27 - 4.13 (m, 2H), 3.93 - 3.67 ( m, 1H), 3.06 (d, J = 6.2 Hz, 2H), 2.89 - 2.72 (m, 2H), 1.87 - 1.75 (m, 3H), 1.27 - 1.15 (m, 2H). 13 C NMR (100 MHz, CDCl 3 ) δ 154.74, 147.30, 140.32, 135.07, 134.91, 128.09, 126.16, 126.03, 112.90, 65.42, 49.60, 44.06, 35.91, 30.07. HRMS(ESI) m/z(M+H) + calcd for C 23 H 25 Cl 2 N 4 O 2 = 459.14; found 459.1354.
3,5-디클로로벤질 4-(((3-(13,5-Dichlorobenzyl 4-(((3-(1 HH -이미다졸-5-일)페닐)아미노)메틸)피페리딘-1-카복실레이트(33n).-imidazol-5-yl)phenyl)amino)methyl)piperidine-1-carboxylate (33n).
일반적인 공정 D에 따라, 32d(31.62 mg, 0.10 mmol) 및 7b(15.92 mg, 0.10 mmol)를 사용하여 33n을 흰색 고체(25.31 mg, 55.1%)로 얻었다.According to General Procedure D, using 32d (31.62 mg, 0.10 mmol) and 7b (15.92 mg, 0.10 mmol), 33n was obtained as a white solid (25.31 mg, 55.1%).
1H NMR(400 MHz, CDCl3) δ 7.67(s, 1H), 7.30 - 7.28(m, 2H), 7.21(d, J = 1.9 Hz, 2H), 7.15(t, J = 7.8 Hz, 1H), 7.04 - 6.96(m, 2H), 6.50 - 6.45(m, 1H), 5.05(s, 2H), 4.27 - 4.02(m, 2H), 3.07 - 2.92(m, 2H), 2.86 - 2.66(m, 2H), 1.83 - 1.64(m, 3H), 1.21 - 1.06(m, 2H). 13C NMR(100 MHz, CDCl3) δ 154.74, 148.64, 140.31, 138.43, 135.42, 135.06, 133.47, 129.69, 128.07, 126.00, 115.90, 114.10, 111.61, 109.16, 65.50, 65.41, 49.43, 44.02, 44.01, 35.83, 30.09. HRMS(ESI) m/z(M+H)+ calcd for C23H25Cl2N4O2= 459.14; found 459.1360. 1H NMR (400 MHz, CDCl 3 ) δ 7.67 (s, 1H), 7.30 - 7.28 (m, 2H), 7.21 (d, J = 1.9 Hz, 2H), 7.15 (t, J = 7.8 Hz, 1H) , 7.04 - 6.96(m, 2H), 6.50 - 6.45(m, 1H), 5.05(s, 2H), 4.27 - 4.02(m, 2H), 3.07 - 2.92(m, 2H), 2.86 - 2.66(m, 2H), 1.83 - 1.64 (m, 3H), 1.21 - 1.06 (m, 2H). 13 C NMR (100 MHz, CDCL 3 ) δ 154.74, 148.64, 140.31, 138.43, 135.42, 135.06, 133.47, 129.69, 128.07, 126.00, 115.90, 114.10, 111.61, 109.16, 65.50, 65.41, 49.43, 44. , 30.09. HRMS(ESI) m/z(M+H) + calcd for C 23 H 25 Cl 2 N 4 O 2 = 459.14; found 459.1360.
3,5-디클로로벤질 4-(((4-(5-옥소-4,5-디하이드로-1,3,4-옥사다이아졸-2-일)페닐)아미노)메틸)피페리딘-1-카복실레이트(33o).3,5-dichlorobenzyl 4-(((4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)amino)methyl)piperidin-1 -Carboxylate (33o).
일반적인 공정 D에 따라, 32d(31.62 mg, 0.10 mmol) 및 14a(17.72 mg, 0.10 mmol)를 사용하여 33o를 흰색 고체(15.80 mg, 33.1%)로 얻었다.According to General Procedure D, using 32d (31.62 mg, 0.10 mmol) and 14a (17.72 mg, 0.10 mmol), 33o was obtained as a white solid (15.80 mg, 33.1%).
1H NMR(400 MHz, DMSO-d 6) δ 12.14(s, 1H), 7.56(t, J = 2.0 Hz, 1H), 7.48(d, J = 8.8 Hz, 2H), 7.41(d, J = 1.9 Hz, 2H), 6.66(d, J = 8.9 Hz, 2H), 6.49(t, J = 5.8 Hz, 1H), 5.07(s, 2H), 4.08 - 3.98(m, 2H), 3.02 - 2.94(m, 2H), 2.90 - 2.70(m, 2H), 1.83 - 1.71(m, 3H), 1.18 - 1.03(m, 2H). 13C NMR(100 MHz, DMSO) δ 155.24, 155.19, 154.52, 151.99, 141.91, 134.54, 127.86, 127.13, 126.59, 112.08, 110.60, 65.05, 48.29, 44.00, 35.36, 30.01. HRMS(ESI) m/z(M+H)+ calcd for C22H23Cl2N4O4= 477.11; found 477.1094. 1 H NMR (400 MHz, DMSO- d 6 ) δ 12.14 (s, 1H), 7.56 (t, J = 2.0 Hz, 1H), 7.48 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 1.9 Hz, 2H), 6.66 (d, J = 8.9 Hz, 2H), 6.49 (t, J = 5.8 Hz, 1H), 5.07 (s, 2H), 4.08 - 3.98 (m, 2H), 3.02 - 2.94 ( m, 2H), 2.90 - 2.70 (m, 2H), 1.83 - 1.71 (m, 3H), 1.18 - 1.03 (m, 2H). 13 C NMR (100 MHz, DMSO) δ 155.24, 155.19, 154.52, 151.99, 141.91, 134.54, 127.86, 127.13, 126.59, 112.08, 110.60, 65.05, 48.29, 34.00, 44.00 HRMS (ESI) m/z(M+H) + calcd for C 22 H 23 Cl 2 N 4 O 4 = 477.11; found 477.1094.
3,5-디클로로벤질 4-(((3-(5-옥소-4,5-디하이드로-1,3,4-옥사다이아졸-2-일)페닐)아미노)메틸)피페리딘-1-카복실레이트(33p).3,5-dichlorobenzyl 4-(((3-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)amino)methyl)piperidin-1 -Carboxylate (33p).
일반적인 공정 D에 따라, 32d(31.62 mg, 0.10 mmol) 및 14b(17.72 mg, 0.10 mmol)를 사용하여 33p를 흰색 고체(34.13 mg, 71.5%)로 얻었다.According to General Procedure D, using 32d (31.62 mg, 0.10 mmol) and 14b (17.72 mg, 0.10 mmol), 33p was obtained as a white solid (34.13 mg, 71.5%).
1H NMR(400 MHz, CDCl3) δ 8.79(s, 1H), 7.29(t, J = 2.0 Hz, 1H), 7.27 - 7.21(m, 3H), 7.17(d, J = 7.7 Hz, 1H), 7.03(t, J = 2.0 Hz, 1H), 6.75 - 6.67(m, 1H), 5.08(d, J = 4.5 Hz, 2H), 4.31 - 4.14(m, 2H), 4.06 - 3.95(m, 1H), 3.12 - 3.02(m, 2H), 2.93 - 2.74(m, 2H), 1.88 - 1.73(m, 3H), 1.24(tt, J = 15.3, 7.8 Hz, 2H). 13C NMR(100 MHz, CDCl3) δ 155.66, 155.20, 154.88, 148.49, 140.19, 135.08, 129.92, 128.13, 126.06, 124.70, 116.11, 114.70, 108.92, 65.59, 49.31, 44.06, 35.81, 30.13. HRMS(ESI) m/z(M+H)+ calcd for C22H23Cl2N4O4= 477.11; found 477.1096. 1H NMR (400 MHz, CDCl 3 ) δ 8.79 (s, 1H), 7.29 (t, J = 2.0 Hz, 1H), 7.27 - 7.21 (m, 3H), 7.17 (d, J = 7.7 Hz, 1H) , 7.03 (t, J = 2.0 Hz, 1H), 6.75 - 6.67 (m, 1H), 5.08 (d, J = 4.5 Hz, 2H), 4.31 - 4.14 (m, 2H), 4.06 - 3.95 (m, 1H) ), 3.12 - 3.02 (m, 2H), 2.93 - 2.74 (m, 2H), 1.88 - 1.73 (m, 3H), 1.24 (tt, J = 15.3, 7.8 Hz, 2H). 13 C NMR (100 MHz, CDCL 3 ) Δ 155.66, 155.20, 154.88, 148.49, 140.19, 135.08, 129.92, 128.13, 126.06, 124.70, 116.11, 114.70, 108.92, 65.59, 49.31, 44.06, 35.81 HRMS (ESI) m/z(M+H) + calcd for C 22 H 23 Cl 2 N 4 O 4 = 477.11; found 477.1096.
제법 8. 화합물 38a-c의 합성.Preparation 8. Synthesis of compounds 38a-c.
시약 및 조건:(a) i: CDI, DMF, 6 h, ii: Boc-피페라진, 15 h;(b) TFA, CH2Cl2, 3 h;(c) 브로모에탄올, K2CO3, THF, reflux, 15 h;(d) CBr4, PPh3, CH2Cl2, 0 ℃ to r.t., 6 h;(e) 1,3-디브로모프로판, TEA, CH2Cl2, 15 h;(f) i: 클로로아세틸 클로라이드, TEA, CH2Cl2, 1 h; ii: 4-(1H-이미다졸-5-일)피페리딘, TEA, DMF, 75 ℃, 2 h;(g) 4-(1H-이미다졸-5-일)피페리딘, NaHCO3, DMF, 60 ℃, 12 h;(h) Boc-피페라진, CH2Cl2, 1 h. Reagents and conditions: (a) i: CDI, DMF, 6 h, ii: Boc-piperazine, 15 h; (b) TFA, CH 2 Cl 2 , 3 h; (c) bromoethanol, K 2 CO 3 , THF, reflux, 15 h; (d) CBr 4 , PPh 3 , CH 2 Cl 2 , 0 °C to rt, 6 h; (e) 1,3-dibromopropane, TEA, CH 2 Cl 2 , 15 h; (f) i: chloroacetyl chloride, TEA, CH 2 Cl 2 , 1 h; ii: 4-(1 H -imidazol-5-yl)piperidine, TEA, DMF, 75° C., 2 h; (g) 4-(1 H -imidazol-5-yl)piperidine, NaHCO 3 , DMF, 60° C., 12 h; (h) Boc-piperazine, CH 2 Cl 2 , 1 h.
1-One- tt -부틸 4-(3,5-디클로로벤질) 피페라진-1,4-디카복실레이트(34). -Butyl 4-(3,5-dichlorobenzyl)piperazine-1,4-dicarboxylate (34).
DMF(20 mL) 중 3,5-디클로로벤질 알코올(1.77g, 10.0 mmol)의 교반되는 혼합물에 실온에서 1,1'-카보닐디이미다졸(1.94 g, 12.0 mmol)을 첨가하고 실온에서 6 h 동안 교반하였다. t-부틸 피페라진-1-카복실레이트(3.72 g, 20.0 mmol)을 상기 혼합물에 첨가하고 추가로 실온에서 밤새 교반하였다. 상기 물질을 디에틸에터로 추출하고 물로 2회 세척하였다. 유기층을 무수 소듐 설페이트로 탈수시키고 농축시켰다. 생성물을 컬럼 크로마토그래피(에틸아세테이트/헥산)로 정제하여 34를 무색 오일(2.48 g, 63.7%)로 얻었다.To a stirred mixture of 3,5-dichlorobenzyl alcohol (1.77 g, 10.0 mmol) in DMF (20 mL) at room temperature was added 1,1'-carbonyldiimidazole (1.94 g, 12.0 mmol) and stirred at room temperature for 6 h. while stirring. t -Butylpiperazine-1-carboxylate (3.72 g, 20.0 mmol) was added to the mixture and further stirred at room temperature overnight. The material was extracted with diethyl ether and washed twice with water. The organic layer was dehydrated with anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (ethyl acetate/hexane) to give 34 as a colorless oil (2.48 g, 63.7%).
1H NMR(400 MHz, CDCl3) δ 7.31(t, J = 1.9 Hz, 1H), 7.23(dt, J = 2.0, 0.7 Hz, 2H), 5.08(s, 2H), 3.51 - 3.41(m, 8H), 1.47(s, 9H). 1H NMR (400 MHz, CDCl 3 ) δ 7.31 (t, J = 1.9 Hz, 1H), 7.23 (dt, J = 2.0, 0.7 Hz, 2H), 5.08 (s, 2H), 3.51 - 3.41 (m, 8H), 1.47(s, 9H).
3,5-디클로로벤질 피페라진-1-카복실레이트(35).3,5-dichlorobenzyl piperazine-1-carboxylate (35).
CH2Cl2(10 mL) 중 34(1.95 g, 5.00 mmol)의 용액에 트리플루오로아세트산(5 mL)을 첨가하였다. 반응 혼합물을 실온에서 3h 동안 교반하였다. 용매를 증발시켜 건조시켰다. 생성물을 1M K2CO3 용액으로 중성화시키고 에틸아세테이트로 추출하였다. 유기층을 무수 소듐 설페이트로 탈수시키고 농축시켰다. 생성물을 아미노 컬럼 크로마토그래피(헥산/에틸아세테이트)로 정제하여 35를 무색 오일(1.44 g, 93.2%)로 얻었다.To a solution of 34 ( 1.95 g, 5.00 mmol) in CH 2 Cl 2 (10 mL) was added trifluoroacetic acid (5 mL). The reaction mixture was stirred at room temperature for 3 h. The solvent was evaporated to dryness. The product was neutralized with 1M K 2 CO 3 solution and extracted with ethyl acetate. The organic layer was dehydrated with anhydrous sodium sulfate and concentrated. The product was purified by amino column chromatography (hexane/ethyl acetate) to give 35 as a colorless oil (1.44 g, 93.2%).
1H NMR(400 MHz, MeOD) δ 7.40(t, J = 1.9 Hz, 1H), 7.37(d, J = 1.9 Hz, 2H), 5.13(s, 2H), 3.82 - 3.69(m, 4H), 3.28 - 3.21(m, 4H). 1H NMR (400 MHz, MeOD) δ 7.40 (t, J = 1.9 Hz, 1H), 7.37 (d, J = 1.9 Hz, 2H), 5.13 (s, 2H), 3.82 - 3.69 (m, 4H), 3.28 - 3.21 (m, 4H).
3,5-디클로로벤질 4-(2-하이드록시에틸)피페라진-1-카복실레이트(36). 3,5-dichlorobenzyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (36).
THF(5 mL) 중 35(0.29 g, 1.00 mmol), 2-브로모에탄올(0.19 g, 1.50 mmol) 및 포타슘카보네이트(0.28 g, 2.00 mmol)의 혼합물을 밤새 환류시켰다. 용매를 증발시켜 건조시키고 혼합물을 디에틸에터로 추출하고 물로 세척하였다. 유기층을 무수 소듐 설페이트로 탈수시키고 농축시켰다. 생성물을 컬럼 크로마토그래피(CH2Cl2/MeOH)로 정제하여 36을 무색 오일(0.32 g, 96.1%)로 얻었다.A mixture of 35 ( 0.29 g, 1.00 mmol), 2-bromoethanol (0.19 g, 1.50 mmol) and potassium carbonate (0.28 g, 2.00 mmol) in THF (5 mL) was refluxed overnight. The solvent was evaporated to dryness and the mixture was extracted with diethyl ether and washed with water. The organic layer was dehydrated with anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (CH 2 Cl 2 /MeOH) to give 36 as a colorless oil (0.32 g, 96.1%).
1H NMR(400 MHz, CDCl3) δ 7.31(t, J = 1.9 Hz, 1H), 7.23(d, J = 1.9 Hz, 2H), 5.07(s, 2H), 3.64(t, 2H), 3.56 - 3.53(m, 4H), 2.58(t, J = 5.5 Hz, 2H), 2.54 - 2.48(m, 4H), 2.47 - 2.25(m, 1H). 1H NMR (400 MHz, CDCl 3 ) δ 7.31 (t, J = 1.9 Hz, 1H), 7.23 (d, J = 1.9 Hz, 2H), 5.07 (s, 2H), 3.64 (t, 2H), 3.56 - 3.53 (m, 4H), 2.58 (t, J = 5.5 Hz, 2H), 2.54 - 2.48 (m, 4H), 2.47 - 2.25 (m, 1H).
3,5-디클로로벤질 4-(2-브로모에틸)피페라진-1-카복실레이트(37a).3,5-dichlorobenzyl 4-(2-bromoethyl)piperazine-1-carboxylate (37a).
CH2Cl2(2 mL) 중 36(0.17 g, 0.50 mmol) 및 트리페닐포스핀(0.16 g, 0.60 mmol)의 혼합물에 0 ℃에서 CH2Cl2 중 CBr4(0.20 g, 0.60 mmol)의 용액을 방울로 적가하였다. 반응 혼합물을 실온에서 밤새 교반하였다. 용매를 증발시키고 크루드 혼합물을 에틸아세테이트로 추출하고 물로 세척하였다. 유기층을 무수 소듐 설페이트로 탈수시키고 농축시켰다. 생성물을 컬럼 크로마토그래피(CH2Cl2/MeOH)로 정제하여 37a를 무색 오일(70.70 mg, 35.7%)로 얻었다.To a mixture of 36 (0.17 g, 0.50 mmol) and triphenylphosphine (0.16 g, 0.60 mmol) in CH 2 Cl 2 (2 mL) was added CBr 4 (0.20 g, 0.60 mmol) in CH 2 Cl 2 at 0 °C. The solution was added dropwise. The reaction mixture was stirred overnight at room temperature. The solvent was evaporated and the crude mixture was extracted with ethyl acetate and washed with water. The organic layer was dehydrated with anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (CH 2 Cl 2 /MeOH) to give 37a as a colorless oil (70.70 mg, 35.7%).
1H NMR(400 MHz, CDCl3) δ 7.30(t, J = 1.9 Hz, 1H), 7.22(d, J = 1.9 Hz, 2H), 5.07(s, 2H), 3.57 - 3.49(m, 4H), 3.42(t, J = 7.2 Hz, 2H), 2.81(t, J = 7.2 Hz, 2H), 2.54 - 2.46(m, 4H). 1H NMR (400 MHz, CDCl 3 ) δ 7.30 (t, J = 1.9 Hz, 1H), 7.22 (d, J = 1.9 Hz, 2H), 5.07 (s, 2H), 3.57 - 3.49 (m, 4H) , 3.42 (t, J = 7.2 Hz, 2H), 2.81 (t, J = 7.2 Hz, 2H), 2.54 - 2.46 (m, 4H).
3,5-디클로로벤질 4-(3-브로모프로필)피페라진-1-카복실레이트(37b).3,5-dichlorobenzyl 4-(3-bromopropyl)piperazine-1-carboxylate (37b).
CH2Cl2(2 mL) 중 35(57.83 mg, 0.20 mmol) 및 TEA(40.48 mg, 0.40 mmol)의 혼합물에 0 ℃에서 1,3-디브로모프로판(40.38 mg, 0.40 mmol)을 첨가하였다. 반응 혼합물을 실온에서 밤새 교반하였다. 용매를 증발시키고 크루드 혼합물을 에틸아세테이트로 추출하고 물로 세척하였다. 유기층을 무수 소듐 설페이트로 탈수시키고 농축시켰다. 생성물을 컬럼 크로마토그래피(에틸아세테이트/헥산)로 정제하여 37b를 무색 오일(36.25 mg, 44.2%)로 얻었다;To a mixture of 35 (57.83 mg, 0.20 mmol) and TEA (40.48 mg, 0.40 mmol) in CH 2 Cl 2 (2 mL) at 0 °C was added 1,3-dibromopropane (40.38 mg, 0.40 mmol). . The reaction mixture was stirred overnight at room temperature. The solvent was evaporated and the crude mixture was extracted with ethyl acetate and washed with water. The organic layer was dehydrated with anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (ethyl acetate/hexanes) to give 37b as a colorless oil (36.25 mg, 44.2%);
1H NMR(400 MHz, CDCl3) δ 7.30(t, J = 2.0 Hz, 1H), 7.22(dd, J = 1.9, 0.8 Hz, 2H), 5.07(s, 2H), 3.54 - 3.50(m, 4H), 3.47(t, J = 6.6 Hz, 2H), 2.50(t, J = 6.9 Hz, 2H), 2.46 - 2.38(m, 4H), 2.02(p, J = 6.7 Hz, 2H). 1H NMR (400 MHz, CDCl 3 ) δ 7.30 (t, J = 2.0 Hz, 1H), 7.22 (dd, J = 1.9, 0.8 Hz, 2H), 5.07 (s, 2H), 3.54 - 3.50 (m, 4H), 3.47 (t, J = 6.6 Hz, 2H), 2.50 (t, J = 6.9 Hz, 2H), 2.46 - 2.38 (m, 4H), 2.02 (p, J = 6.7 Hz, 2H).
3,5-디클로로벤질 4-(2-(4-(1 H -이미다졸-5-일)피페리딘-1-일)아세틸)피페라진-1-카복실레이트(38a). 화합물 35(1 mmol) 및 TEA(1 mmol)를 CH2Cl2(10 mL)에 용해시켰다. 클로로아세틸 클로라이드(3 mmol)를 반응 혼합물에 첨가하였다. 얻어진 용액을 1 h 동안 교반하였다. 반응 완결 후, 용매를 진공하에서 제거하였다. 잔여물을 DMF에 용해시키고 DMF 중 TEA(2 mmol) 및 4-(1H-이미다졸-5-일)피페리딘(1.2 mmol)을 첨가하였다. 반응 혼합물을 75 ℃에서 2h 동안 교반하였다. 용매를 진공하에서 제거하였고 크루드 혼합물을 에틸아세테이트로 추출하고 브라인으로 세척하였다. 유기층을 무수 소듐 설페이트로 탈수시키고 농축시켰다. 생성물을 컬럼 크로마토그래피(CH2Cl2/MeOH)로 정제하여 38a(43.5%)를 얻었다; 3,5-dichlorobenzyl 4-(2-(4-(1 H -imidazol-5-yl)piperidin-1-yl)acetyl)piperazine-1-carboxylate (38a). Compound 35 (1 mmol) and TEA (1 mmol) were dissolved in CH 2 Cl 2 (10 mL). Chloroacetyl chloride (3 mmol) was added to the reaction mixture. The resulting solution was stirred for 1 h. After completion of the reaction, the solvent was removed under vacuum. The residue was dissolved in DMF and TEA (2 mmol) and 4-(1 H -imidazol-5-yl)piperidine (1.2 mmol) in DMF were added. The reaction mixture was stirred at 75 °C for 2 h. The solvent was removed under vacuum and the crude mixture was extracted with ethyl acetate and washed with brine. The organic layer was dehydrated with anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (CH 2 Cl 2 /MeOH) to give 38a ( 43.5%);
1H NMR(400 MHz, MeOD-d 4) δ 7.59(s, 1H), 7.37 - 7.31(m, 3H), 6.80(s, 1H), 3.65(t, J = 5.1 Hz, 2H), 3.61(t, J = 5.2 Hz, 2H), 3.56 - 3.52(m, 2H), 3.34(s, 2H), 3.07 - 2.97(m, 2H), 2.61(ddd, J = 11.8, 8.0, 4.1 Hz, 1H), 2.49(t, J = 5.1 Hz, 2H), 2.44(t, J = 5.1 Hz, 2H), 2.29(t, J = 11.6 Hz, 2H), 1.97(d, J = 12.8 Hz, 2H), 1.73(qd, J = 12.3, 3.7 Hz, 2H); MS(ESI, m/z) calcd for C22H28Cl2N5O3 [M+H]+ 480.15; found 480.10. 1H NMR (400 MHz, MeOD- d 4 ) δ 7.59 (s, 1H), 7.37 - 7.31 (m, 3H), 6.80 (s, 1H), 3.65 (t, J = 5.1 Hz, 2H), 3.61 ( t, J = 5.2 Hz, 2H), 3.56 - 3.52 (m, 2H), 3.34 (s, 2H), 3.07 - 2.97 (m, 2H), 2.61 (ddd, J = 11.8, 8.0, 4.1 Hz, 1H) , 2.49 (t, J = 5.1 Hz, 2H), 2.44 (t, J = 5.1 Hz, 2H), 2.29 (t, J = 11.6 Hz, 2H), 1.97 (d, J = 12.8 Hz, 2H), 1.73 (qd, J = 12.3, 3.7 Hz, 2H); MS (ESI, m/z) calcd for C 22 H 28 Cl 2 N 5 O 3 [M+H] + 480.15; found 480.10.
3,5-디클로로벤질 4-(2-(4-(13,5-Dichlorobenzyl 4-(2-(4-(1) HH -이미다졸-5-일)피페리딘-1-일)에틸)피페라진-1-카복실레이트(38b).-imidazol-5-yl)piperidin-1-yl)ethyl)piperazine-1-carboxylate (38b).
DMF(1 mL) 중 37a(39.61 mg, 0.10 mmol), 4-(1H-이미다졸-4(5)-일)피페리딘(22.68 mg, 0.15 mmol), 및 소듐 하이드로젠카보네이트(16.8 mg, 0.20 mmol)의 혼합물을 60 ℃에서 12 h 동안 교반하였다. 용매를 증발시켜 건조시키고 혼합물을 CH2Cl2에 용해시켰다. 크루드 혼합물을 아미노 컬럼 크로마토그래피(CH2Cl2/MeOH)로 정제하여 38b를 흰색 고체(26.77 mg, 57.4%)로 얻었다; 37a (39.61 mg, 0.10 mmol), 4-(1H-imidazol-4(5)-yl)piperidine (22.68 mg, 0.15 mmol), and sodium hydrogencarbonate (16.8 mg, 0.20 mmol) was stirred at 60 °C for 12 h. The solvent was evaporated to dryness and the mixture was dissolved in CH 2 Cl 2 . The crude mixture was purified by amino column chromatography (CH 2 Cl 2 /MeOH) to give 38b as a white solid (26.77 mg, 57.4%);
1H NMR(400 MHz, CDCl3) δ 9.76(br s, 1H), 7.56(d, J = 1.2 Hz, 1H), 7.30(t, J = 1.9 Hz, 1H), 7.22(d, J = 1.9 Hz, 2H), 6.75(d, J = 1.0 Hz, 1H), 5.06(s, 2H), 3.56 - 3.48(m, 4H), 3.03 - 2.97(m, 2H), 2.65 - 2.58(m, 1H), 2.57 - 2.51(m, 4H), 2.50 - 2.45(m, 4H), 2.16 - 2.08(m, 2H), 2.04 - 1.97(m, 2H), 1.75 - 1.63(m, 2H). 13C NMR(100 MHz, CDCl3) δ 160.87, 154.70, 140.14, 135.09, 134.36, 128.14, 126.05, 65.50, 56.21, 56.08, 54.30, 53.28, 43.88, 34.64, 32.05. HRMS(ESI) m/z(M+H)+ calcd for C22H30Cl2N5O2= 466.18; found 466.1773. 1H NMR (400 MHz, CDCl 3 ) δ 9.76 (br s, 1H), 7.56 (d, J = 1.2 Hz, 1H), 7.30 (t, J = 1.9 Hz, 1H), 7.22 (d, J = 1.9 Hz, 2H), 6.75 (d, J = 1.0 Hz, 1H), 5.06 (s, 2H), 3.56 - 3.48 (m, 4H), 3.03 - 2.97 (m, 2H), 2.65 - 2.58 (m, 1H) , 2.57 - 2.51 (m, 4H), 2.50 - 2.45 (m, 4H), 2.16 - 2.08 (m, 2H), 2.04 - 1.97 (m, 2H), 1.75 - 1.63 (m, 2H). 13 C NMR (100 MHz, CDCl 3 ) δ 160.87, 154.70, 140.14, 135.09, 134.36, 128.14, 126.05, 65.50, 56.21, 56.08, 54.30, 53.28, 43.88, 34.64, HRMS(ESI) m/z(M+H) + calcd for C 22 H 30 Cl 2 N 5 O 2 = 466.18; found 466.1773.
3,5-디클로로벤질 4-(3-(4-(13,5-Dichlorobenzyl 4-(3-(4-(1) HH -이미다졸-5-일)피페리딘-1-일)프로필)피페라진-1-카복실레이트(38c): -imidazol-5-yl)piperidin-1-yl)propyl)piperazine-1-carboxylate (38c):
DMF(1 mL) 중 37b(36.25 mg, 0.09 mmol), 4-(1H-이미다졸-4(5)-일)피페리딘(21.17 mg, 0.14 mmol) 및 소듐하이드로젠카보네이트(15.12 mg, 0.18 mmol)의 혼합물을 60 ℃에서 12 h 동안 교반하였다. 용매를 증발시켜 건조시키고 혼합물을 CH2Cl2.에 용해시켰다. 크루드 혼합물을 컬럼 크로마토그래피(CH2Cl2/MeOH)로 정제하여 38c를 흰색 고체(33.21 mg, 76.8%)로 얻었다. 37b (36.25 mg, 0.09 mmol), 4-(1 H -imidazol-4(5)-yl)piperidine (21.17 mg, 0.14 mmol) and sodium hydrogencarbonate (15.12 mg, 0.18 mmol) was stirred at 60 °C for 12 h. The solvent was evaporated to dryness and the mixture was dissolved in CH 2 Cl 2 . The crude mixture was purified by column chromatography (CH 2 Cl 2 /MeOH) to give 38c as a white solid (33.21 mg, 76.8%).
1H NMR(400 MHz, CDCl-3) δ 10.47(br s, 1H), 7.55(d, J = 1.1 Hz, 1H), 7.30(t, J = 1.9 Hz, 1H), 7.22(d, J = 1.9 Hz, 2H), 6.76(s, 1H), 5.06(s, 2H), 3.54 - 3.50(m, 4H), 3.01 - 2.96(m, 2H), 2.66 - 2.57(m, 1H), 2.45 - 2.37(m, 8H), 2.07 - 1.99(m, 4H), 1.75 - 1.66(m, 4H). 13C NMR(100 MHz, CDCl3) δ 154.70, 140.16, 135.09, 134.35, 128.13, 126.05, 65.48, 56.90, 56.71, 53.88, 52.87, 43.92, 34.69, 32.08, 24.43. HRMS(ESI) m/z(M+H)+ calcd for C23H32Cl2N5O2= 480.19; found 480.1941. 1H NMR (400 MHz, CDCl- 3 ) δ 10.47 (br s, 1H), 7.55 (d, J = 1.1 Hz, 1H), 7.30 (t, J = 1.9 Hz, 1H), 7.22 (d, J = 1.9 Hz, 2H), 6.76(s, 1H), 5.06(s, 2H), 3.54 - 3.50(m, 4H), 3.01 - 2.96(m, 2H), 2.66 - 2.57(m, 1H), 2.45 - 2.37 (m, 8H), 2.07 - 1.99 (m, 4H), 1.75 - 1.66 (m, 4H). 13 C NMR (100 MHz, CDCl 3 ) δ 154.70, 140.16, 135.09, 134.35, 128.13, 126.05, 65.48, 56.90, 56.71, 53.88, 52.87, 43.92, 34.69, 34.43, 24.08. HRMS(ESI) m/z(M+H)+ calcd for C 23 H 32 Cl 2 N 5 O 2 = 480.19; found 480.1941.
tt -부틸 4-((3-클로로펜에틸)카바모일)피페라진-1-카복실레이트(39). -Butyl 4-((3-chlorophenethyl)carbamoyl)piperazine-1-carboxylate (39).
CH2CL2(5 ml) 중 Boc-피페라진(0.5 mmol)의 용액에 1-클로로-3-(2-이소시아나토에틸)벤젠(0.5 mmol)을 첨가하고 실온에서 1 h 동안 교반하였다. 용매를 증발시켜 제거한 후, 잔여물을 컬럼 크로마토그래피로 정제하여 목적 화합물(정량적)을 얻었다;To a solution of Boc-piperazine (0.5 mmol) in CH 2 CL 2 (5 ml) was added 1-chloro-3-(2-isocyanatoethyl)benzene (0.5 mmol) and stirred at room temperature for 1 h. After evaporation of the solvent, the residue was purified by column chromatography to obtain the target compound (quantitatively);
1H NMR(400 MHz, CDCl3) δ 7.26 - 6.98(m, 4H), 4.65(t, J = 5.7 Hz, 1H), 3.47(td, J = 6.9, 5.7 Hz, 2H), 3.44 - 3.36(m, 4H), 3.30(dd, J = 6.9, 3.8 Hz, 4H), 2.81(t, J = 6.9 Hz, 2H), 1.47(s, 9H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.26 - 6.98 (m, 4H), 4.65 (t, J = 5.7 Hz, 1H), 3.47 (td, J = 6.9, 5.7 Hz, 2H), 3.44 - 3.36 ( m, 4H), 3.30 (dd, J = 6.9, 3.8 Hz, 4H), 2.81 (t, J = 6.9 Hz, 2H), 1.47 (s, 9H).
4-(2-(4-(1H-이미다졸-5-일)피페리딘-1-일)아세틸)-N-(3-클로로펜에틸)피페라진-1-카복사미드(38d). 4-(2-(4-(1H-imidazol-5-yl)piperidin-1-yl)acetyl)-N-(3-chlorophenethyl)piperazine-1-carboxamide (38d).
CH2Cl2(10 mL) 중 39(0.5 mmol)의 용액에 트리플루오로아세트산(5 mL)을 첨가하고 실온에서 3 h 동안 교반하였다. 용매를 증발시켜 건조시키고, 남은 유기 잔여물(0.5 mmol)을 CH2Cl2(10 mL)에 TEA(0.5 mmol)와 함께 용해시켰다. 클로로아세틸 클로라이드(3 mmol)를 반응 혼합물에 첨가한 후, 얻어진 용액을 1 h 동안 교반한 후 용매를 진공하에 제거하였다. 잔여물을 DMF(5 ml)에 용해시키고 TEA(1 mmol) 및 4-(1H-이미다졸-5-일)피페리딘(0.6 mmol)과 혼합하였다. 반응 혼합물을 75 ℃에서 2 h 동안 교반하였다. 용매를 진공하에 제거하고 크루드 혼합물을 에틸아세테이트로 추출하고 브라인으로 세척하였다. 유기층을 무수 소듐 설페이트로 탈수시키고 농축시켰다. 생성물을 컬럼 크로마토그래피(CH2Cl2/MeOH)로 정제하여 38d를 얻었다;To a solution of 39 (0.5 mmol) in CH 2 Cl 2 (10 mL) was added trifluoroacetic acid (5 mL) and stirred at room temperature for 3 h. The solvent was evaporated to dryness and the remaining organic residue (0.5 mmol) was dissolved in CH 2 Cl 2 (10 mL) with TEA (0.5 mmol). After adding chloroacetyl chloride (3 mmol) to the reaction mixture, the resulting solution was stirred for 1 h and then the solvent was removed under vacuum. The residue was dissolved in DMF (5 ml) and mixed with TEA (1 mmol) and 4-(1 H -imidazol-5-yl)piperidine (0.6 mmol). The reaction mixture was stirred at 75 °C for 2 h. The solvent was removed in vacuo and the crude mixture was extracted with ethyl acetate and washed with brine. The organic layer was dehydrated with anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (CH 2 Cl 2 /MeOH) to give 38d ;
1H NMR(400 MHz, MeOD) δ 7.65(d, J = 1.2 Hz, 1H), 7.30 - 7.20(m, 2H), 7.20(dd, J = 2.2, 1.3 Hz, 1H), 7.18 - 7.11(m, 1H), 6.84(s, 1H), 3.63 - 3.53(m, 4H), 3.48(s, 2H), 3.48 - 3.41(m, 2H), 3.38(td, J = 6.5, 2.1 Hz, 4H), 3.11(dt, J = 12.1, 3.7 Hz, 2H), 2.80(dd, J = 7.9, 6.6 Hz, 2H), 2.66(ddt, J = 11.7, 7.7, 3.8 Hz, 1H), 2.42(td, J = 11.8, 2.5 Hz, 2H), 2.07 - 1.95(m, 2H), 1.86 - 1.70(m, 2H); 13C NMR(100 MHz, MeOD) δ 169.5, 159.8, 143.3, 142.3, 135.9, 135.1, 130.9, 130.0, 128.4, 127.3, 115.9, 61.0, 54.8, 46.2, 45.0, 44.5, 43.1, 42.8, 36.9, 34.7, 32.3. MS(ESI) m/z(M+H)+ calcd for C23H32ClN6O2= 459.23; found 459.31. 1H NMR (400 MHz, MeOD) δ 7.65 (d, J = 1.2 Hz, 1H), 7.30 - 7.20 (m, 2H), 7.20 (dd, J = 2.2, 1.3 Hz, 1H), 7.18 - 7.11 (m , 1H), 6.84(s, 1H), 3.63 - 3.53(m, 4H), 3.48(s, 2H), 3.48 - 3.41(m, 2H), 3.38(td, J = 6.5, 2.1 Hz, 4H), 3.11 (dt, J = 12.1, 3.7 Hz, 2H), 2.80 (dd, J = 7.9, 6.6 Hz, 2H), 2.66 (ddt, J = 11.7, 7.7, 3.8 Hz, 1H), 2.42 (td, J = 11.8, 2.5 Hz, 2H), 2.07 - 1.95 (m, 2H), 1.86 - 1.70 (m, 2H); 13C NMR (100 MHz, MEOD) Δ 169.5, 159.8, 143.3, 142.3, 135.9, 135.1, 130.9, 130.0, 128.4, 127.3, 115.9, 61.0, 54.8, 46.2, 45.0, 44.5, 43.1, 42.8, 36.9, 34.9 . MS(ESI) m/z(M+H) + calcd for C 23 H 32 ClN 6 O 2 = 459.23; found 459.31.
제법 9. 빌딩 블럭 41a-d의 합성.Preparation 9. Synthesis of building blocks 41a-d.
(a) Me3SiN3, CuI, DMF, MeOH, 100 ℃, 8 h;(b) 디옥산 중 4M HCl, 1 h;(c)(아지도메틸)트라이메틸실란, CuI, DMF, MeOH, 60 ℃, 12 h;(d) TBAF, THF, H2O, 12 h;(e) NaN3, NH4Cl, DMF, 125 ℃, 8 h;(f) NaN3, NH4Cl, 디옥산, H2O, 75 ℃, 2 d;(g) i: PPh3, 디에틸 에터, 24 h; ii: H2O, THF, reflux, 1.5 h. (a) Me 3 SiN 3 , CuI, DMF, MeOH, 100° C., 8 h; (b) 4M HCl in dioxane, 1 h; (c) (azidomethyl)trimethylsilane, CuI, DMF, MeOH; 60 °C, 12 h; (d) TBAF, THF, H2O, 12 h; (e) NaN 3 , NH 4 Cl, DMF, 125 °C, 8 h; (f) NaN 3 , NH 4 Cl, dioxane, H 20 , 75 °C, 2 d; (g) i: PPh 3 , diethyl ether, 24 h; ii: H 2 O, THF, reflux, 1.5 h.
tt -부틸((1-butyl((1 HH -1,2,3-트리아졸-5-일)메틸)카바메이트-1,2,3-triazol-5-yl)methyl)carbamate (( 40a). 40a).
t-부틸 프로-2-핀-1-일카바메이트(5.00 mmol), 트라이메틸실릴 아자이드(5.5 mmol), 및 카파(I) 아이오다이드(0.25 mmol)를 아르곤 가스하에 DMF/MeOH(9/1, 10 mL)의 혼합물에 첨가하였다. 반응 혼합물을 100 ℃에서 8 h 동안 가열하였다. 용매를 증발시켜 건조시키고, 에틸아세테이트로 추출하고 브라인으로 세척하였다. 유기층을 무수 소듐 설페이트로 탈수시키고 농축하였다. 생성물을 컬럼 크로마토그래피(CH2Cl2/MeOH)로 정제하여 40a(42.5%)를 얻었다; t -Butyl pro-2-pin-1-ylcarbamate (5.00 mmol), trimethylsilyl azide (5.5 mmol), and kappa(I) iodide (0.25 mmol) were mixed in DMF/MeOH (9 mmol) under argon gas. /1, 10 mL) was added to the mixture. The reaction mixture was heated at 100 °C for 8 h. The solvent was evaporated to dryness, extracted with ethyl acetate and washed with brine. The organic layer was dehydrated over anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (CH 2 Cl 2 /MeOH) to give 40a (42.5%);
1H NMR(400 MHz, CDCl3) δ 12.97(s, 1H), 7.66(s, 1H), 4.44(d, J = 6.0 Hz, 2H), 1.46(s, 9H). 1 H NMR (400 MHz, CDCl 3 ) δ 12.97 (s, 1H), 7.66 (s, 1H), 4.44 (d, J = 6.0 Hz, 2H), 1.46 (s, 9H).
(1(One HH -1,2,3-트리아졸-5-일)메탄아민·HCl(41a). -1,2,3-triazol-5-yl)methanamine·HCl (41a).
디옥산(1 mL) 중 화합물 40a(1.7 mmol)에 4.0 M HCl을 첨가하고 실온에서 1 h 동안 교반하였다. 용매를 증발시켜 건조시켜 41a를 흰색 고체(정량적)로 얻었다.To compound 40a (1.7 mmol) in dioxane (1 mL) was added 4.0 M HCl and stirred at room temperature for 1 h. The solvent was evaporated to dryness to give 41a as a white solid (quantitatively).
1H NMR(400 MHz, D2O) δ 7.91(s, 1H), 4.25(s, 2H). 1 H NMR (400 MHz, D 2 O) δ 7.91 (s, 1H), 4.25 (s, 2H).
tt -부틸((1-((트라이메틸실릴)메틸)-1-Butyl((1-((trimethylsilyl)methyl)-1 HH -1,2,3-트리아졸-4-일)메틸)카바메이트(40b).-1,2,3-triazol-4-yl)methyl)carbamate (40b).
DMF 및 MeOH 중 t-부틸 프로-2-핀-1-일카바메이트(0.64 mmol)의 용액에 CuI(0.03 mmol) 및 (아지도메틸)트라이메틸실란(0.71 mmol)을 첨가하였다. 혼합물을 60 ℃에서 밤새 교반하였다. 반응이 완결된 후, 용매를 증발시켜 건조시켰다. 잔여물을 에틸아세테이트로 추출하고 셀라이트 패드를 통해 여과하였다. 이후, 여과액을 브라인으로 세척하였다. 유기층을 무수 마그네슘 설페이트로 탈수시키고, 농축하고, 컬럼 크로마토그래피(에틸아세테이트/헥산)로 정제하여 40b(32.1%)를 얻었다;To a solution of t -butyl prop-2-pin-1-ylcarbamate (0.64 mmol) in DMF and MeOH was added CuI (0.03 mmol) and (azidomethyl)trimethylsilane (0.71 mmol). The mixture was stirred at 60 °C overnight. After the reaction was completed, the solvent was evaporated to dryness. The residue was extracted with ethyl acetate and filtered through a pad of celite. Thereafter, the filtrate was washed with brine. The organic layer was dehydrated with anhydrous magnesium sulfate, concentrated, and purified by column chromatography (ethyl acetate/hexane) to give 40b (32.1%);
1H NMR(400 MHz, CDCl3) δ 7.39(s, 1H), 5.16(s, 1H), 4.37(d, J = 6.0 Hz, 2H), 3.89(s, 2H), 1.44(s, 9H), 0.13(s, 9H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.39 (s, 1H), 5.16 (s, 1H), 4.37 (d, J = 6.0 Hz, 2H), 3.89 (s, 2H), 1.44 (s, 9H) , 0.13(s, 9H).
(1-메틸-1 H -1,2,3-트리아졸-4-일)메탄아민 하이드로클로라이드 염(41b): (1-methyl- 1H -1,2,3-triazol-4-yl)methanamine hydrochloride salt (41b) :
THF(10 mL) 중 40b(2.2 mmol)의 용액에 TBAF 1M 용액(2.6 mmol) 및 H2O(4.4 mmol)을 첨가하고 12 hr 동안 실온에서 교반하였다. 용매를 증발시킨 후, 유기물을 디에틸에터로 추출하고, 브라인으로 세척하고, 무수 마그네슘 설페이트로 탈수시키고, 농축하였다. 이것을 CH2Cl2로 희석하고 디옥산(2mL) 중 4N HCl을 첨가하였다. 반응 혼합물을 실온에서 2h 동안 교반하였다. 용매를 증발시켜 건조시키고 41b를 얻었다. 생성물의 순도는 NMR 스펙트럼(yield: 16.4%) 상에서 약 80%였다;To a solution of 40b (2.2 mmol) in THF (10 mL) was added TBAF 1M solution (2.6 mmol) and H 2 O (4.4 mmol) and stirred for 12 hr at room temperature. After evaporation of the solvent, the organics were extracted with diethylether, washed with brine, dehydrated with anhydrous magnesium sulfate and concentrated. It was diluted with CH 2 Cl 2 and 4N HCl in dioxane (2 mL) was added. The reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated to dryness to give 41b . The purity of the product was about 80% on the NMR spectrum (yield: 16.4%);
1H NMR(400 MHz, D2O) δ 8.05(s, 1H), 4.33(s, 2H), 4.13(s, 3H). 1 H NMR (400 MHz, D 2 O) δ 8.05 (s, 1H), 4.33 (s, 2H), 4.13 (s, 3H).
tt -부틸((1-butyl((1 HH -테트라졸-5-일)메틸)카바메이트(40c). -tetrazol-5-yl)methyl)carbamate (40c).
t-부틸(시아노메틸)카바메이트(6.5 mmol), 암모늄 클로라이드(7.2 mmol) 및 소듐 아자이드(6.8 mmol)를 DMF(10 mL)에 용해시켰다. 반응 혼합물을 125 ℃에서 8 h 동안 교반하였다. 반응이 완결된 후, 10 % HCl 용액(15 mL)을 혼합물에 첨가하였다. 얻어진 침전물을 여과하고 진공하여 건조시켜 40c(43.8%)를 얻었다; t -Butyl(cyanomethyl)carbamate (6.5 mmol), ammonium chloride (7.2 mmol) and sodium azide (6.8 mmol) were dissolved in DMF (10 mL). The reaction mixture was stirred at 125 °C for 8 h. After the reaction was complete, 10% HCl solution (15 mL) was added to the mixture. The precipitate obtained was filtered and dried under vacuum to obtain 40c ( 43.8%);
1H NMR(400 MHz, DMSO-d 6) δ 7.55(t, J = 6.0 Hz, 1H), 4.41(d, J = 5.9 Hz, 2H), 1.39(s, 9H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.55 (t, J = 6.0 Hz, 1H), 4.41 (d, J = 5.9 Hz, 2H), 1.39 (s, 9H).
(1(One HH -테트라졸-5-일)메탄아민·HCl(41c):-tetrazol-5-yl)methanamine HCl (41c):
화합물 40c(2.27 mmol)를 디옥산 중 4M HCl(3 mL)에 용해시키고 실온에서 3 h 동안 교반하였다. 용매를 진공하에서 증발시켜 41c(정량적)를 얻었다;Compound 40c (2.27 mmol) was dissolved in 4M HCl in dioxane (3 mL) and stirred at room temperature for 3 h. The solvent was evaporated under vacuum to give 41c (quantitative);
1H NMR(400 MHz, DMSO-d 6) δ 9.15 - 8.63(m, 2H), 4.41(s, 2H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.15 - 8.63 (m, 2H), 4.41 (s, 2H).
5-(아지도메틸)-4-메틸-1 H -1,2,3-트리아졸(40d): 5-(azidomethyl)-4-methyl-1H - 1,2,3-triazole (40d) :
1-브로모부-2-틴(17 mmol), 소듐 아자이드(68 mmol) 및 암모늄 클로라이드(34 mmol)를 디옥산(24 mL) 및 H2O(6 mL)에 용해시켰다. 반응 혼합물을 75 ℃에서 2일간 교반하였다. 반응이 완결된 후, 용매를 증발시켜 건조시켰다. 생성물을 에틸아세테이트로 추출하고 브라인으로 세척하였다. 유기층을 무수 소듐 설페이트로 탈수시키고 농축하였다. 잔여물을 컬럼 크로마토그래피(EA/Hex)로 정제하여 40d(56%)를 얻었다;1-Bromobut-2-yne (17 mmol), sodium azide (68 mmol) and ammonium chloride (34 mmol) were dissolved in dioxane (24 mL) and H 2 O (6 mL). The reaction mixture was stirred at 75 °C for 2 days. After the reaction was completed, the solvent was evaporated to dryness. The product was extracted with ethyl acetate and washed with brine. The organic layer was dehydrated over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (EA/Hex) to give 40d (56%);
1H NMR(400 MHz, CDCl3) δ 13.36(s, 1H), 4.48(s, 2H), 2.41(s, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 13.36(s, 1H), 4.48(s, 2H), 2.41(s, 3H).
(4-메틸-1 H -1,2,3-트리아졸-5-일)메탄아민(41d): (4-methyl- 1H -1,2,3-triazol-5-yl)methanamine (41d) :
화합물 40d(2.1 mmol) 및 트리페닐포스핀(2.38 mmol)을 무수 디에틸에터(5 mL)에 용해시키고 24 h 동안 교반하였다. 용매를 진공하에서 제거하고 크루드 혼합물을 THF(10 mL)에 용해시켰다. 물(3 mL)을 반응 혼합물에 첨가하고 1.5 h 동안 환류시켰다. 반응이 완결된 후, 용매를 증발시켰다. 물을 첨가하고 디에틸에터로 세척하였다. 용매를 제거하여 41d를 흰색 고체(67.2%)로 얻었다;Compound 40d (2.1 mmol) and triphenylphosphine (2.38 mmol) were dissolved in dry diethyl ether (5 mL) and stirred for 24 h. The solvent was removed under vacuum and the crude mixture was dissolved in THF (10 mL). Water (3 mL) was added to the reaction mixture and refluxed for 1.5 h. After the reaction was complete, the solvent was evaporated. Water was added and washed with diethyl ether. Removal of the solvent gave 41d as a white solid (67.2%);
1H NMR(400 MHz, CDCl3) δ 4.70(s, 2H), 2.16(s, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 4.70 (s, 2H), 2.16 (s, 2H).
제법 10. 화합물 44a-n의 합성.Preparation 10. Synthesis of compounds 44a-n.
a 시약 및 조건:(a) 41a, BOP reagent, DIEA, DMF, 8 h;(b) 디옥산 중 4M HCl, 1 h;(c) CDI, TEA, DMF, 벤질 알코올, 5 h;(d) 3-(3,5-디클로로페닐)프로파노일 클로라이드, TEA, DMF, rt, 8 h;(e) i: 트리포스젠, TEA, CH2Cl2, 3 h; ii: 3,5-디클로로벤질아민, DMF, 5 h. a Reagents and conditions: (a) 41a , BOP reagent, DIEA, DMF, 8 h; (b) 4M HCl in dioxane, 1 h; (c) CDI, TEA, DMF, benzyl alcohol, 5 h; (d) 3-(3,5-dichlorophenyl)propanoyl chloride, TEA, DMF, rt, 8 h; (e) i: triphosgene, TEA, CH 2 Cl 2 , 3 h; ii: 3,5-dichlorobenzylamine, DMF, 5 h.
tt -부틸 4-(5-(((1-Butyl 4-(5-(((1 HH -1,2,3-트리아졸-5-일)메틸)아미노)-1,3,4-옥사다이아졸-2-일)피페리딘-1-카복실레이트(42).-1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate (42).
23(1 mmol), 41a(1.2 mmol), DIEA(3.5 mmol), 및 BOP 시약(1.2 mmol)을 DMF(5 mL)에 용해시키고 실온에서 8 h 동안 교반하였다. 반응이 완결된 후, 용매를 증발시켜 건조하였다. 생성물을 에틸아세테이트로 추출하고 브라인으로 세척하였다. 유기층을 무수 소듐 설페이트로 탈수시키고 농축하였다. 잔여물을 컬럼 크로마토그래피(CH2Cl2/MeOH)로 정제하여 41(57.8 %)을 얻었다; 23 (1 mmol), 41a (1.2 mmol), DIEA (3.5 mmol), and BOP reagent (1.2 mmol) were dissolved in DMF (5 mL) and stirred at room temperature for 8 h. After the reaction was completed, the solvent was evaporated and dried. The product was extracted with ethyl acetate and washed with brine. The organic layer was dehydrated over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (CH 2 Cl 2 /MeOH) to give 41 (57.8%);
1H NMR(400 MHz, DMSO-d 6) δ 14.78(s, 1H), 7.96(dt, J = 6.6, 4.4 Hz, 1H), 7.87 - 7.52(m, 1H), 4.43(d, J = 5.8 Hz, 2H), 3.98 - 3.79(m, 2H), 2.97(dtd, J = 15.0, 11.0, 5.6 Hz, 3H), 1.90(dt, J = 13.3, 3.6 Hz, 2H), 1.49(dtd, J = 13.2, 11.2, 4.2 Hz, 2H), 1.40(s, 9H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 14.78 (s, 1H), 7.96 (dt, J = 6.6, 4.4 Hz, 1H), 7.87 - 7.52 (m, 1H), 4.43 (d, J = 5.8 Hz, 2H), 3.98 - 3.79 (m, 2H), 2.97 (dtd, J = 15.0, 11.0, 5.6 Hz, 3H), 1.90 (dt, J = 13.3, 3.6 Hz, 2H), 1.49 (dtd, J = 13.2, 11.2, 4.2 Hz, 2H), 1.40(s, 9H).
NN -((1-((One HH -1,2,3-트리아졸-5-일)메틸)-5-(피페리딘-4-일)-1,3,4-옥사다이아졸-2-아민·HCl(43). -1,2,3-triazol-5-yl)methyl)-5-(piperidin-4-yl)-1,3,4-oxadiazol-2-amine HCl (43).
디옥산(1 mL) 중 42(1.7 mmol)의 용액에 디옥산 중 4 M HCl(3 mL)을 첨가하고 실온에서 1 hr 동안 교반하였다. 용매를 진공하에 제거하여 43을 흰색 고체(정량적)로 얻었다;To a solution of 42 (1.7 mmol) in dioxane (1 mL) was added 4 M HCl in dioxane (3 mL) and stirred at room temperature for 1 hr. The solvent was removed in vacuo to give 43 as a white solid (quantitative);
1H NMR(400 MHz, DMSO-d 6) δ 8.91(s, 1H), 8.73(s, 1H), 8.19(s, 1H), 7.78(s, 1H), 4.44(d, J = 5.1 Hz, 2H), 3.28(m, 2H), 3.14(m, 1H), 3.00(m, 2H), 2.14 - 2.01(m, 2H), 1.90 - 1.76(m, 2H). 1H NMR (400 MHz, DMSO- d 6 ) δ 8.91 (s, 1H), 8.73 (s, 1H), 8.19 (s, 1H), 7.78 (s, 1H), 4.44 (d, J = 5.1 Hz, 2H), 3.28 (m, 2H), 3.14 (m, 1H), 3.00 (m, 2H), 2.14 - 2.01 (m, 2H), 1.90 - 1.76 (m, 2H).
3,5-디클로로벤질 4-(5-(((13,5-Dichlorobenzyl 4-(5-(((1 HH -1,2,3-트리아졸-5-일)메틸)아미노)-1,3,4-옥사다이아졸-2-일)피페리딘-1-카복실레이트(44a). -1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate (44a).
일반적인 공정 C에 따라, 3,5-디클로로벤질아민을 사용하여 44a를 흰색 고체(53.1 %)를 얻었다;Following General Procedure C, 44a was obtained as a white solid (53.1%) using 3,5-dichlorobenzylamine;
1H NMR(400 MHz, CDCl3) δ 7.68(s, 1H), 7.29(t, J = 1.9 Hz, 1H), 7.21(d, J = 1.9 Hz, 2H), 7.02 - 6.66(m, 1H), 5.06(d, J = 13.9 Hz, 2H), 4.63(s, 2H), 4.15 - 4.05(m, 2H), 3.11 - 2.90(m, 3H), 2.06 - 1.96(m, 2H), 1.79 - 1.66(m, 2H). 13C NMR(100 MHz, CDCl3) δ 163.35, 162.46, 154.73, 142.59, 139.97, 135.09, 129.27, 128.19, 126.12, 65.68, 43.14, 38.12, 33.01, 28.65. HRMS(ESI, m/z) calculated for C18H20Cl2N7O3 [M+H]+ 452.0999, found 452.1004. 1H NMR (400 MHz, CDCl 3 ) δ 7.68 (s, 1H), 7.29 (t, J = 1.9 Hz, 1H), 7.21 (d, J = 1.9 Hz, 2H), 7.02 - 6.66 (m, 1H) , 5.06 (d, J = 13.9 Hz, 2H), 4.63 (s, 2H), 4.15 - 4.05 (m, 2H), 3.11 - 2.90 (m, 3H), 2.06 - 1.96 (m, 2H), 1.79 - 1.66 (m, 2H). 13 C NMR (100 MHz, CDCl 3 ) δ 163.35, 162.46, 154.73, 142.59, 139.97, 135.09, 129.27, 128.19, 126.12, 65.68, 43.14, 38.12, 33.01, 28.65. HRMS (ESI, m/z) calculated for C 18 H 20 Cl 2 N 7 O 3 [M+H] + 452.0999, found 452.1004.
3,5-디브로모벤질 4-(5-(((13,5-Dibromobenzyl 4-(5-(((1 HH -1,2,3-트리아졸-5-일)메틸)아미노)-1,3,4-옥사다이아졸-2-일)피페리딘-1-카복실레이트(44b). -1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate (44b).
일반적인 공정 C에 따라, 3,5-디브로모벤질아민을 사용하여 44b를 흰색 고체(37.3%)로 얻었다;Following General Procedure C, 44b was obtained as a white solid (37.3%) using 3,5-dibromobenzylamine;
1H NMR(400 MHz, CDCl3-d) δ 7.69(s, 1H), 7.60(t, J = 1.8 Hz, 1H), 7.42(d, J = 1.8 Hz, 2H), 6.54(s, 1H), 5.06(d, J = 11.1 Hz, 2H), 4.64(s, 2H), 4.10(d, J = 13.3 Hz, 2H), 3.18 - 2.86(m, 3H), 2.01(dd, J = 13.5, 3.9 Hz, 2H), 1.90 - 1.68(m, 2H); 13C NMR(100 MHz, CDCl3) δ 163.3, 162.5, 154.7, 142.7, 140.5, 133.7, 129.9, 129.5, 123.0, 65.5, 43.2, 38.3, 33.1, 28.7; HRMS(ESI, m/z) calculated for C18H20Br2N7O3 [M+H]+ 539.9899, found 539.9987. 1H NMR (400 MHz, CDCl 3 - d ) δ 7.69 (s, 1H), 7.60 (t, J = 1.8 Hz, 1H), 7.42 (d, J = 1.8 Hz, 2H), 6.54 (s, 1H) , 5.06 (d, J = 11.1 Hz, 2H), 4.64 (s, 2H), 4.10 (d, J = 13.3 Hz, 2H), 3.18 - 2.86 (m, 3H), 2.01 (dd, J = 13.5, 3.9 Hz, 2H), 1.90 - 1.68 (m, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 163.3, 162.5, 154.7, 142.7, 140.5, 133.7, 129.9, 129.5, 123.0, 65.5, 43.2, 38.3, 33.1, 28.7; HRMS (ESI, m/z) calculated for C 18 H 20 Br 2 N 7 O 3 [M+H] + 539.9899, found 539.9987.
3,5-비스(트리플루오로메틸)벤질 4-(5-(((13,5-bis(trifluoromethyl)benzyl 4-(5-(((1 HH -1,2,3-트리아졸-5-일)메틸)아미노)-1,3,4-옥사다이아졸-2-일)피페리딘-1-카복실레이트(44c). -1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate (44c).
일반적인 공정 C에 따라, 3,5-비스(트리플루오로메틸)벤질 아민을 사용하여 44c를 흰색 고체(36.5%)로 얻었다;Following General Procedure C, using 3,5-bis(trifluoromethyl)benzyl amine, 44c was obtained as a white solid (36.5%);
1H NMR(400 MHz, CDCl3-d ) δ 7.84(s, 1H), 7.80(d, J = 1.6 Hz, 2H), 7.72(s, 1H), 5.77(s, 1H), 5.32 - 5.18(m, 2H), 4.66(s, 2H), 4.13(d, J = 8.7 Hz, 2H), 3.23 - 2.93(m, 3H), 2.05(dd, J = 13.5, 3.8 Hz, 2H), 1.79(dtd, J = 14.8, 10.9, 4.2 Hz, 3H); 13C NMR(100 MHz, CDCl3-d) δ 163.25, 162.50, 154.56, 142.73, 139.32, 131.94(q, J = 33.6 Hz), 130.29-130.11(m), 127.95 - 127.74(m), 123.18(q, J = 272.8 Hz), 122.07(dt, J = 7.7, 3.8 Hz), 65.58, 43.20, 38.32, 33.03, 28.70; HRMS(ESI, m/z) calculated for C20H20F6N7O3 [M+H]+ 520.1526, found 520.1533. 1 H NMR (400 MHz, CDCl 3 - d ) δ 7.84 (s, 1H), 7.80 (d, J = 1.6 Hz, 2H), 7.72 (s, 1H), 5.77 (s, 1H), 5.32 - 5.18 ( m, 2H), 4.66(s, 2H), 4.13(d, J = 8.7 Hz, 2H), 3.23 - 2.93(m, 3H), 2.05(dd, J = 13.5, 3.8 Hz, 2H), 1.79(dtd) , J = 14.8, 10.9, 4.2 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 - d ) δ 163.25, 162.50, 154.56, 142.73, 139.32, 131.94 (q, J = 33.6 Hz), 130.29-130.11 (m), 127.95 - 127.74 (m), 123.18 , J = 272.8 Hz), 122.07 (dt, J = 7.7, 3.8 Hz), 65.58, 43.20, 38.32, 33.03, 28.70; HRMS (ESI, m/z) calculated for C 20 H 20 F 6 N 7 O 3 [M+H] + 520.1526, found 520.1533.
3,5-디메틸벤질 4-(5-(((13,5-dimethylbenzyl 4-(5-(((1 HH -1,2,3-트리아졸-5-일)메틸)아미노)-1,3,4-옥사다이아졸-2-일)피페리딘-1-카복실레이트(44d).-1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate (44d).
일반적인 공정 C에 따라, 3,5-디메틸벤질아민을 사용하여 44d를 흰색 고체(48.7%)로 얻었다;Following General Procedure C, 44d was obtained as a white solid (48.7%) using 3,5-dimethylbenzylamine;
1H NMR(400 MHz, CDCl3-d) δ 7.66(s, 1H), 6.94(d, J = 3.8 Hz, 3H), 5.13 - 4.97(m, 2H), 4.61(s, 2H), 4.11(d, J = 13.6 Hz, 2H), 3.04 - 2.83(m, 3H), 2.30(d, J = 0.7 Hz, 6H), 2.01 - 1.92(m, 2H), 1.71(dtd, J = 13.4, 11.0, 4.1 Hz, 2H); 13C NMR(100 MHz, CDCl3) δ 163.3, 162.6, 155.4, 142.7, 138.1, 136.3, 129.8, 129.2, 125.8, 67.5, 43.1, 38.1, 33.1, 28.7, 21.3; HRMS(ESI, m/z) calculated for C20H26N7O3 [M+H]+ 412.2092, found 412.2096. 1 H NMR (400 MHz, CDCl 3 - d ) δ 7.66 (s, 1H), 6.94 (d, J = 3.8 Hz, 3H), 5.13 - 4.97 (m, 2H), 4.61 (s, 2H), 4.11 ( d, J = 13.6 Hz, 2H), 3.04 - 2.83 (m, 3H), 2.30 (d, J = 0.7 Hz, 6H), 2.01 - 1.92 (m, 2H), 1.71 (dtd, J = 13.4, 11.0, 4.1 Hz, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 163.3, 162.6, 155.4, 142.7, 138.1, 136.3, 129.8, 129.2, 125.8, 67.5, 43.1, 38.1, 33.1, 28.7, 21.3; HRMS (ESI, m/z) calculated for C 20 H 26 N 7 O 3 [M+H] + 412.2092, found 412.2096.
3,5-디메톡시벤질 4-(5-(((13,5-Dimethoxybenzyl 4-(5-(((1 HH -1,2,3-트리아졸-5-일)메틸)아미노)-1,3,4-옥사다이아졸-2-일)피페리딘-1-카복실레이트(44e).-1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate (44e).
일반적인 공정 C에 따라, 3,5-디메톡시벤질아민을 사용하여 44e를 흰색 고체(55.8%)로 얻었다;Following General Procedure C, 44e was obtained as a white solid (55.8%) using 3,5-dimethoxybenzylamine;
1H NMR(400 MHz, CDCl3-d) δ 7.68(s, 1H), 6.64(d, J = 36.1 Hz, 1H), 6.49(d, J = 2.3 Hz, 2H), 6.40(t, J = 2.3 Hz, 1H), 5.06(s, 2H), 4.63(s, 2H), 4.12(d, J = 13.6 Hz, 2H), 3.78(s, 6H), 3.10 - 2.86(m, 4H), 1.99(dd, J = 13.6, 3.7 Hz, 2H), 1.73(dtd, J = 13.3, 11.0, 4.1 Hz, 2H); 13C NMR(100 MHz, CDCl3) δ 163.3, 162.6, 160.9, 155.2, 142.6, 138.9, 129.7, 105.7, 99.8, 67.2, 55.4, 43.1, 38.2, 33.1, 28.7; HRMS(ESI, m/z) calculated for C20H26N7O5 [M+H]+ 444.1990, found 444.1990. 1H NMR (400 MHz, CDCl 3 - d ) δ 7.68 (s, 1H), 6.64 (d, J = 36.1 Hz, 1H), 6.49 (d, J = 2.3 Hz, 2H), 6.40 (t, J = 2.3 Hz, 1H), 5.06(s, 2H), 4.63(s, 2H), 4.12(d, J = 13.6 Hz, 2H), 3.78(s, 6H), 3.10 - 2.86(m, 4H), 1.99( dd, J = 13.6, 3.7 Hz, 2H), 1.73 (dtd, J = 13.3, 11.0, 4.1 Hz, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 163.3, 162.6, 160.9, 155.2, 142.6, 138.9, 129.7, 105.7, 99.8, 67.2, 55.4, 43.1, 38.2, 33.1, 28.7; HRMS (ESI, m/z) calculated for C 20 H 26 N 7 O 5 [M+H] + 444.1990, found 444.1990.
3,5-디플루오로벤질 4-(5-(((13,5-difluorobenzyl 4-(5-(((1 HH -1,2,3-트리아졸-5-일)메틸)아미노)-1,3,4-옥사다이아졸-2-일)피페리딘-1-카복실레이트(44f).-1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate (44f).
일반적인 공정 C에 따라, 3,5-디플루오로벤질아민을 사용하여 44f를 흰색 고체(49.5%)로 얻었다;Following General Procedure C, 44f was obtained as a white solid (49.5%) using 3,5-difluorobenzylamine;
1H NMR(400 MHz, CDCl3-d) δ 13.90(s, 1H), 7.70(s, 1H), 6.90 - 6.80(m, 2H), 6.74(tt, J = 8.9, 2.4 Hz, 1H), 6.39(s, 1H), 5.10(d, J = 4.5 Hz, 2H), 4.66(s, 2H), 4.13(d, J = 12.4 Hz, 2H), 3.05(s, 2H), 2.97(tt, J = 10.7, 3.7 Hz, 1H), 2.10 - 1.95(m, 2H), 1.86 - 1.69(m, 2H); 13C NMR(100 MHz, CDCl3-d) δ 163.31, 163.05(dd, J = 249.0, 12.7 Hz), 162.53, 154.74, 142.64, 140.58(t, J = 9.1 Hz), 129.98, 112.38 - 108.44(m), 103.37(t, J = 25.3 Hz), 65.82(t, J = 2.2 Hz), 43.15, 38.24, 33.06, 28.71; HRMS(ESI, m/z) calculated for C18H20F2N7O3 [M+H]+ 420.1590, found 420.1593. 1 H NMR (400 MHz, CDCl 3 - d ) δ 13.90 (s, 1H), 7.70 (s, 1H), 6.90 - 6.80 (m, 2H), 6.74 (tt, J = 8.9, 2.4 Hz, 1H), 6.39(s, 1H), 5.10(d, J = 4.5 Hz, 2H), 4.66(s, 2H), 4.13(d, J = 12.4 Hz, 2H), 3.05(s, 2H), 2.97(tt, J = 10.7, 3.7 Hz, 1H), 2.10 - 1.95 (m, 2H), 1.86 - 1.69 (m, 2H); 13 C NMR (100 MHz, CDCl 3 - d ) δ 163.31, 163.05 (dd, J = 249.0, 12.7 Hz), 162.53, 154.74, 142.64, 140.58 (t, J = 9.1 Hz), 129.98, 112.38 - 108.44 (m ), 103.37 (t, J = 25.3 Hz), 65.82 (t, J = 2.2 Hz), 43.15, 38.24, 33.06, 28.71; HRMS (ESI, m/z) calculated for C 18 H 20 F 2 N 7 O 3 [M+H] + 420.1590, found 420.1593.
3-브로모-5-메틸벤질 4-(5-(((13-Bromo-5-methylbenzyl 4-(5-(((1 HH -1,2,3-트리아졸-5-일)메틸)아미노)-1,3,4-옥사다이아졸-2-일)피페리딘-1-카복실레이트(44g).-1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate (44 g).
일반적인 공정 C에 따라, 3-브로모-5-메틸벤질아민을 사용하여 44g를 흰색 고체(57.6%)로 얻었다;Following general procedure C, using 3-bromo-5-methylbenzylamine, 44 g was obtained as a white solid (57.6%);
1H NMR(400 MHz, CDCl3-d) δ 7.68(s, 1H), 7.31 - 7.25(m, 2H), 7.09 - 7.03(m, 1H), 6.59(s, 1H), 5.05(d, J = 6.4 Hz, 2H), 4.64(s, 2H), 4.11(d, J = 13.4 Hz, 2H), 3.13 - 2.85(m, 3H), 2.41 - 2.23(m, 3H), 2.00(dt, J = 13.7, 3.6 Hz, 2H), 1.74(dtd, J = 13.2, 11.0, 4.1 Hz, 2H); 13C NMR(100 MHz, CDCl3) δ 163.3, 162.6, 155.0, 142.6, 140.4, 138.6, 131.8, 129.7, 127.9, 127.3, 122.3, 66.4, 43.1, 38.2, 33.1, 21.1; HRMS(ESI, m/z) calculated for C19H23BrN7O3 [M+H]+ 476.1040, found 476.1041. 1 H NMR (400 MHz, CDCl 3 - d ) δ 7.68 (s, 1H), 7.31 - 7.25 (m, 2H), 7.09 - 7.03 (m, 1H), 6.59 (s, 1H), 5.05 (d, J = 6.4 Hz, 2H), 4.64(s, 2H), 4.11(d, J = 13.4 Hz, 2H), 3.13 - 2.85(m, 3H), 2.41 - 2.23(m, 3H), 2.00(dt, J = 13.7, 3.6 Hz, 2H), 1.74 (dtd, J = 13.2, 11.0, 4.1 Hz, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 163.3, 162.6, 155.0, 142.6, 140.4, 138.6, 131.8, 129.7, 127.9, 127.3, 122.3, 66.4, 43.1, 38.2, 33.1, 21.1; HRMS (ESI, m/z) calculated for C 19 H 23 BrN 7 O 3 [M+H] + 476.1040, found 476.1041.
3-브로모-5-클로로벤질 4-(5-(((13-Bromo-5-chlorobenzyl 4-(5-(((1 HH -1,2,3-트리아졸-5-일)메틸)아미노)-1,3,4-옥사다이아졸-2-일)피페리딘-1-카복실레이트(44h).-1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate (44h).
일반적인 공정 C에 따라, 3-브로모-5-클로로벤질아민을 사용하여 44h를 흰색 고체(48.2%)로 얻었다;Following general procedure C, using 3-bromo-5-chlorobenzylamine, 44h was obtained as a white solid (48.2%);
1H NMR(400 MHz, CDCl3-d) δ 7.69(s, 1H), 7.45(t, J = 1.9 Hz, 1H), 7.37(t, J = 1.6 Hz, 1H), 6.50(s, 1H), 5.06(d, J = 10.2 Hz, 2H), 4.65(s, 2H), 4.11(d, J = 13.4 Hz, 2H), 3.04(s, 2H), 2.96(ddt, J = 10.7, 6.9, 3.9 Hz, 1H), 2.02(dd, J = 13.6, 3.8 Hz, 2H), 1.83 - 1.69(m, 2H); 13C NMR(100 MHz, CDCl3) δ 163.3, 162.5, 154.7, 142.7, 140.3, 135.2, 131.0, 129.9, 129.0, 126.6, 122.8, 65.6, 43.2, 38.2, 33.0, 28.7; HRMS(ESI, m/z) calculated for C18H20BrClN7O3 [M+H]+ 496.0494, found 496.0495. 1 H NMR (400 MHz, CDCl 3 - d ) δ 7.69 (s, 1H), 7.45 (t, J = 1.9 Hz, 1H), 7.37 (t, J = 1.6 Hz, 1H), 6.50 (s, 1H) , 5.06 (d, J = 10.2 Hz, 2H), 4.65 (s, 2H), 4.11 (d, J = 13.4 Hz, 2H), 3.04 (s, 2H), 2.96 (ddt, J = 10.7, 6.9, 3.9 Hz, 1H), 2.02 (dd, J = 13.6, 3.8 Hz, 2H), 1.83 - 1.69 (m, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 163.3, 162.5, 154.7, 142.7, 140.3, 135.2, 131.0, 129.9, 129.0, 126.6, 122.8, 65.6, 43.2, 38.2, 33.0, 28.7; HRMS (ESI, m/z) calculated for C 18 H 20 BrClN 7 O 3 [M+H] + 496.0494, found 496.0495.
3-클로로-5-플루오로벤질 4-(5-(((13-chloro-5-fluorobenzyl 4-(5-(((1 HH -1,2,3-트리아졸-5-일)메틸)아미노)-1,3,4-옥사다이아졸-2-일)피페리딘-1-카복실레이트(44i).-1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate (44i).
일반적인 공정 C에 따라, 3-클로로-5-플루오로벤질아민을 사용하여 44i를 흰색 고체(49.8%)로 얻었다;Following general procedure C, using 3-chloro-5-fluorobenzylamine, 44i was obtained as a white solid (49.8%);
1H NMR(400 MHz, CDCl3-d) δ 7.69(s, 1H), 7.12(d, J = 1.8 Hz, 1H), 7.03(dt, J = 8.5, 2.2 Hz, 1H), 6.96(ddd, J = 8.9, 2.4, 1.4 Hz, 1H), 6.48(s, 1H), 5.09(d, J = 6.9 Hz, 2H), 4.65(s, 2H), 4.12(d, J = 13.4 Hz, 2H), 3.04(s, 3H), 2.96(ddt, J = 10.7, 7.7, 3.9 Hz, 1H), 2.10 - 1.97(m, 2H), 1.88 - 1.67(m, 2H); 13C NMR(100 MHz, CDCl3-d) δ 163.31, 162.69(d, J = 249.9 Hz), 162.53, 154.74, 142.71, 140.41(d, J = 8.3 Hz), 135.18(d, J = 10.6 Hz), 129.97, 123.52(d, J = 3.1 Hz), 115.81(d, J = 24.7 Hz), 113.04(d, J = 21.9 Hz), 65.73(d, J = 2.1 Hz), 43.16, 38.27, 33.07, 28.72; ; HRMS(ESI, m/z) calculated for C18H20ClFN7O3 [M+H]+ 436.1295, found 436.1299. 1 H NMR (400 MHz, CDCl 3 - d ) δ 7.69 (s, 1H), 7.12 (d, J = 1.8 Hz, 1H), 7.03 (dt, J = 8.5, 2.2 Hz, 1H), 6.96 (ddd, J = 8.9, 2.4, 1.4 Hz, 1H), 6.48 (s, 1H), 5.09 (d, J = 6.9 Hz, 2H), 4.65 (s, 2H), 4.12 (d, J = 13.4 Hz, 2H), 3.04 (s, 3H), 2.96 (ddt, J = 10.7, 7.7, 3.9 Hz, 1H), 2.10 - 1.97 (m, 2H), 1.88 - 1.67 (m, 2H); 13 C NMR (100 MHz, CDCl 3 - d ) δ 163.31, 162.69 (d, J = 249.9 Hz), 162.53, 154.74, 142.71, 140.41 (d, J = 8.3 Hz), 135.18 (d, J = 10.6 Hz) , 129.97, 123.52 (d, J = 3.1 Hz), 115.81 (d, J = 24.7 Hz), 113.04 (d, J = 21.9 Hz), 65.73 (d, J = 2.1 Hz), 43.16, 38.27, 33.07, 28.72 ; ; HRMS (ESI, m/z) calculated for C 18 H 20 ClFN 7 O 3 [M+H] + 436.1295, found 436.1299.
2,5-디클로로벤질 4-(5-(((12,5-Dichlorobenzyl 4-(5-(((1 HH -1,2,3-트리아졸-5-일)메틸)아미노)-1,3,4-옥사다이아졸-2-일)피페리딘-1-카복실레이트(44j).-1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate (44j).
일반적인 공정 C에 따라, 2,5-디클로로벤질아민을 사용하여 44j를 흰색 고체(58.1%)로 얻었다;Following General Procedure C, using 2,5-dichlorobenzylamine, 44j was obtained as a white solid (58.1%);
1H NMR(400 MHz, CDCl3-d) δ 7.69(s, 1H), 7.46 - 7.37(m, 2H), 7.19(dd, J = 8.2, 2.0 Hz, 1H), 6.47(s, 1H), 5.10 - 5.04(m, 2H), 4.64(s, 2H), 4.11(d, J = 13.4 Hz, 2H), 3.02(s, 1H), 2.95(tt, J = 10.7, 3.9 Hz, 2H), 2.01(dd, J = 13.6, 3.9 Hz, 2H), 1.75(dtd, J = 13.3, 10.9, 4.2 Hz, 2H); 13C NMR(100 MHz, CDCl3) δ 163.3, 162.5, 154.8, 142.6, 136.9, 132.6, 132.2, 130.6, 129.9, 127.2, 65.8, 43.1, 38.2, 33.1, 28.7; HRMS(ESI, m/z) calculated for C18H20Cl2N7O3 [M+H]+ 452.0999, found 436.129952.1001. 1 H NMR (400 MHz, CDCl 3 - d ) δ 7.69 (s, 1H), 7.46 - 7.37 (m, 2H), 7.19 (dd, J = 8.2, 2.0 Hz, 1H), 6.47 (s, 1H), 5.10 - 5.04(m, 2H), 4.64(s, 2H), 4.11(d, J = 13.4 Hz, 2H), 3.02(s, 1H), 2.95(tt, J = 10.7, 3.9 Hz, 2H), 2.01 (dd, J = 13.6, 3.9 Hz, 2H), 1.75 (dtd, J = 13.3, 10.9, 4.2 Hz, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 163.3, 162.5, 154.8, 142.6, 136.9, 132.6, 132.2, 130.6, 129.9, 127.2, 65.8, 43.1, 38.2, 33.1, 28.7; HRMS (ESI, m/z) calculated for C 18 H 20 Cl 2 N 7 O 3 [M+H] + 452.0999, found 436.129952.1001.
3,4-디클로로벤질 4-(5-(((13,4-dichlorobenzyl 4-(5-(((1 HH -1,2,3-트리아졸-5-일)메틸)아미노)-1,3,4-옥사다이아졸-2-일)피페리딘-1-카복실레이트(44k).-1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate (44k).
일반적인 공정 C에 따라, 3,4-디클로로벤질아민을 사용하여 44k를 흰색 고체(52.8%)로 얻었다;Following General Procedure C, 44k was obtained as a white solid (52.8%) using 3,4-dichlorobenzylamine;
1H NMR(400 MHz, CDCl3-d) δ 7.69(s, 1H), 7.36(d, J = 2.5 Hz, 1H), 7.30(d, J = 8.5 Hz, 1H), 7.22(dd, J = 8.5, 2.5 Hz, 1H), 6.69(s, 1H), 5.19(d, J = 3.8 Hz, 2H), 4.13(dt, J = 14.2, 4.1 Hz, 2H), 3.20 - 2.88(m, 3H), 2.12 - 1.96(m, 2H), 1.89 - 1.69(m, 2H); 13C NMR(100 MHz, CDCl3) δ 163.35, 162.51, 154.71, 136.02, 132.74, 131.54, 130.66, 129.33, 129.27, 129.25, 64.08, 43.18, 38.18, 33.06, 28.70; HRMS(ESI, m/z) calculated for C18H20Cl2N7O3 [M+H]+ 452.0999, found 452.1002. 1H NMR (400 MHz, CDCl 3 - d ) δ 7.69 (s, 1H), 7.36 (d, J = 2.5 Hz, 1H), 7.30 (d, J = 8.5 Hz, 1H), 7.22 (dd, J = 8.5, 2.5 Hz, 1H), 6.69 (s, 1H), 5.19 (d, J = 3.8 Hz, 2H), 4.13 (dt, J = 14.2, 4.1 Hz, 2H), 3.20 - 2.88 (m, 3H), 2.12 - 1.96 (m, 2H), 1.89 - 1.69 (m, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 163.35, 162.51, 154.71, 136.02, 132.74, 131.54, 130.66, 129.33, 129.27, 129.25, 64.08, 43.18, 38.18, 328.08, 33.18; HRMS (ESI, m/z) calculated for C 18 H 20 Cl 2 N 7 O 3 [M+H] + 452.0999, found 452.1002.
벤조[benzo[ dd ][1,3]디옥솔-5-일메틸 4-(5-(((1][1,3]dioxol-5-ylmethyl 4-(5-(((1 HH -1,2,3-트리아졸-5-일)메틸)아미노)-1,3,4-옥사다이아졸-2-일)피페리딘-1-카복실레이트(44l). -1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate (44l).
일반적인 공정 C에 따라, 벤조[d][1,3]디옥솔-5-일메탄아민을 사용하여 44l를 흰색 고체(48.6%)로 얻었다;Following general procedure C, using benzo[ d ][1,3]dioxol-5-ylmethanamine, 44l was obtained as a white solid (48.6%);
1H NMR(400 MHz, CDCl3-d) δ 7.68(s, 1H), 6.84(d, J = 1.6 Hz, 1H), 6.81(d, J = 1.6 Hz, 1H), 6.76(dd, J = 7.8, 0.5 Hz, 1H), 5.94(s, 2H), 5.02(s, 2H), 4.62(s, 2H), 4.18 - 4.00(m, 2H), 3.05 - 2.90(m, 2H), 2.94 - 2.85(m, 1H), 2.04 - 1.88(m, 2H), 1.78 - 1.61(m, 2H); 13C NMR(100 MHz, CDCl3) δ 163.3, 162.6, 155.3, 147.8, 147.5, 142.6, 130.3, 129.5, 121.9, 108.8, 108.2, 101.1, 67.3, 43.1, 38.2, 33.1, 28.7; ; HRMS(ESI, m/z) calculated for C19H22N7O5 [M+H]+ 428.1677, found 428.1681. 1H NMR (400 MHz, CDCl 3 - d ) δ 7.68 (s, 1H), 6.84 (d, J = 1.6 Hz, 1H), 6.81 (d, J = 1.6 Hz, 1H), 6.76 (dd, J = 7.8, 0.5 Hz, 1H), 5.94(s, 2H), 5.02(s, 2H), 4.62(s, 2H), 4.18 - 4.00(m, 2H), 3.05 - 2.90(m, 2H), 2.94 - 2.85 (m, 1H), 2.04 - 1.88 (m, 2H), 1.78 - 1.61 (m, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 163.3, 162.6, 155.3, 147.8, 147.5, 142.6, 130.3, 129.5, 121.9, 108.8, 108.2, 101.1, 67.3, 43.1, 38.1, 28.1, 33.1; ; HRMS (ESI, m/z) calculated for C 19 H 22 N 7 O 5 [M+H] + 428.1677, found 428.1681.
1-(4-(5-(((11-(4-(5-(((1 HH -1,2,3-트리아졸-5-일)메틸)아미노)-1,3,4-옥사다이아졸-2-일)피페리딘-1-일)-3-(3,5-디클로로페닐)프로판-1-온(44m). -1,2,3-triazol-5-yl) methyl) amino) -1,3,4-oxadiazol-2-yl) piperidin-1-yl) -3- (3,5-dichloro phenyl)propan-1-one (44 m).
옥살일 클로라이드(1 mL) 및 1 방울의 DMF를 얼음 배스에서 CH2Cl2(10 mL) 중 3,5-디클로로페닐 프로피온산(0.1 mmol)의 교반되는 용액에 첨가하였다. 실온에서 3h 동안 교반한 후, 용매를 진공하에서 제거하였다. 생성물인 크루드 3-(3,5-디클로로페닐)프로파노일 클로라이드를 DMF에 용해시키고 0 ℃에서 DMF 중 TEA(0.3 mmol) 및 43(0.1 mmol)의 혼합물에 첨가하였다. 반응 혼합물을 실온에서 8 h 동안 교반하였다. 반응이 완결된 후, 용매를 증발시켜 건조하였다. 생성물을 에틸아세테이트로 추출하고 브라인으로 세척하였다. 유기층을 무수 소듐 설페이트로 탈수시키고 농축하였다. 잔여물을 컬럼 크로마토그래피(CH2Cl2/MeOH)로 정제하여 44m(52.3%)을 얻었다;Oxalyl chloride (1 mL) and 1 drop of DMF were added to a stirred solution of 3,5-dichlorophenyl propionic acid (0.1 mmol) in CH 2 Cl 2 (10 mL) in an ice bath. After stirring at room temperature for 3 h, the solvent was removed under vacuum. The product, crude 3-(3,5-dichlorophenyl)propanoyl chloride, was dissolved in DMF and added to a mixture of TEA (0.3 mmol) and 43 (0.1 mmol) in DMF at 0 °C. The reaction mixture was stirred at room temperature for 8 h. After the reaction was completed, the solvent was evaporated and dried. The product was extracted with ethyl acetate and washed with brine. The organic layer was dehydrated over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (CH 2 Cl 2 /MeOH) to give 44m (52.3%);
1H NMR(400 MHz, MeOD-d 4) δ 7.78(s, 1H), 7.28 - 7.20(m, 3H), 4.55(s, 2H), 4.45 - 4.33(m, 1H), 3.98 - 3.89(m, 1H), 3.21(ddd, J = 14.2, 11.4, 2.9 Hz, 1H), 3.12 - 3.02(m, 1H), 2.96 - 2.85(m, 3H), 2.82 - 2.65(m, 2H), 2.07 - 1.96(m, 2H), 1.68 - 1.51(m, 2H); 13C NMR(100 MHz, MeOD-d 4) δ 172.4, 165.1, 163.9, 146.6, 136.0, 128.5, 127.3, 46.0, 42.1, 38.8, 34.8, 34.2, 31.9, 30.4, 29.9; HRMS(ESI, m/z) calculated for C19H22Cl2N7O2 [M+H]+ 450.1207, found 450.1208. 1 H NMR (400 MHz, MeOD- d 4 ) δ 7.78 (s, 1H), 7.28 - 7.20 (m, 3H), 4.55 (s, 2H), 4.45 - 4.33 (m, 1H), 3.98 - 3.89 (m , 1H), 3.21 (ddd, J = 14.2, 11.4, 2.9 Hz, 1H), 3.12 - 3.02 (m, 1H), 2.96 - 2.85 (m, 3H), 2.82 - 2.65 (m, 2H), 2.07 - 1.96 (m, 2H), 1.68 - 1.51 (m, 2H); 13 C NMR (100 MHz, MeOD- d 4 ) δ 172.4, 165.1, 163.9, 146.6, 136.0, 128.5, 127.3, 46.0, 42.1, 38.8, 34.8, 34.2, 31.9, 30.4, 29.9; HRMS (ESI, m/z) calculated for C 19 H 22 Cl 2 N 7 O 2 [M+H] + 450.1207, found 450.1208.
4-(5-(((14-(5-(((1 HH -1,2,3-트리아졸-5-일)메틸)아미노)-1,3,4-옥사다이아졸-2-일)--1,2,3-triazol-5-yl) methyl) amino) -1,3,4-oxadiazol-2-yl) - NN -(3,5-디클로로벤질)피페리딘-1-카복사미드(44n). -(3,5-dichlorobenzyl)piperidine-1-carboxamide (44n).
3,5-디클로로벤질 아민(0.1 mmol) 및 TEA(2.5 mmol)를 CH2Cl2(5 mL)에 용해시켰다. CH2Cl2 중 트리포스젠(0.1 mmol)을 반응 혼합물에 천천히 적가하고 3h 동안 교반하였다. 용매를 진공하에서 제거하고 크루드 혼합물을 DMF(3 mL)에 용해시켰다. 화합물 43(0.1 mmol)을 반응 혼합물에 첨가하고 실온에서 추가적으로 5 h 동안 교반하였다. 용매를 증발시킨 후, 유기물을 에틸아세테이트로 추출하고, 브라인으로 세척하고, 무수 소듐 설페이트로 탈수시키고, 농축하였다. 잔여물을 컬럼 크로마토그래피(CH2Cl2/MeOH)로 정제하여 44n(32.0%)을 얻었다;3,5-dichlorobenzyl amine (0.1 mmol) and TEA (2.5 mmol) were dissolved in CH 2 Cl 2 (5 mL). Triphosgene (0.1 mmol) in CH 2 Cl 2 was slowly added dropwise to the reaction mixture and stirred for 3h. The solvent was removed under vacuum and the crude mixture was dissolved in DMF (3 mL). Compound 43 (0.1 mmol) was added to the reaction mixture and stirred at room temperature for additional 5 h. After evaporation of the solvent, the organics were extracted with ethyl acetate, washed with brine, dehydrated with anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (CH 2 Cl 2 /MeOH) to give 44n ( 32.0%);
1H NMR(400 MHz, MeOD-d 4) δ 7.78(s, 1H), 7.28(t, J = 1.9 Hz, 1H), 7.24(d, J = 1.9 Hz, 2H), 4.55(s, 2H), 4.31(s, 2H), 4.07 - 3.98(m, 2H), 3.10 - 2.98(m, 3H), 2.07 - 1.98(m, 2H), 1.70(dtd, J = 13.4, 11.2, 4.0 Hz, 2H); 13C NMR(100 MHz, MeOD-d 4) δ 165.1, 164.2, 159.7, 146.0, 136.0, 127.8, 126.9, 44.5, 44.3, 38.8, 34.4, 30.0; HRMS(ESI, m/z) calculated for C18H21Cl2N8O2 [M+H]+ 451.1159, found 451.1162. 1H NMR (400 MHz, MeOD- d 4 ) δ 7.78 (s, 1H), 7.28 (t, J = 1.9 Hz, 1H), 7.24 (d, J = 1.9 Hz, 2H), 4.55 (s, 2H) , 4.31(s, 2H), 4.07 - 3.98(m, 2H), 3.10 - 2.98(m, 3H), 2.07 - 1.98(m, 2H), 1.70(dtd, J = 13.4, 11.2, 4.0 Hz, 2H) ; 13 C NMR (100 MHz, MeOD- d 4 ) δ 165.1, 164.2, 159.7, 146.0, 136.0, 127.8, 126.9, 44.5, 44.3, 38.8, 34.4, 30.0; HRMS (ESI, m/z) calculated for C 18 H 21 Cl 2 N 8 O 2 [M+H] + 451.1159, found 451.1162.
제법 11. 화합물 47a-c의 합성.Preparation 11. Synthesis of compounds 47a-c.
a 시약 및 조건:(a) i: Boc-NHNH2, EDC, DMAP, CH2Cl2, 15 h; ii: 디옥산 중 4M HCl, 3h;(b) 트리포스젠, TEA, THF, 3 h;(c) 41b-d, BOP reagent, DIEA, DMF, 8h. a Reagents and conditions: (a) i: Boc-NHNH 2 , EDC, DMAP, CH 2 Cl 2 , 15 h; ii: 4M HCl in dioxane, 3h; (b) Triphosgene, TEA, THF, 3h; (c) 41b-d , BOP reagent, DIEA, DMF, 8h.
3,5-디클로로벤질 4-(히드라진카보닐)피페리딘-1-카복실레이트(45). 3,5-dichlorobenzyl 4-(hydrazinecarbonyl)piperidine-1-carboxylate (45).
CH2Cl2(2 mL) 중 26(0.60 mmol), tert-부틸 히드라진카복실레이트(0.90 mmol), 및 4-(디메틸아미노)피리딘(0.03 mmol)의 혼합물에 N-(3-디메틸아미노프로필)-N'-에틸카보디이미드 하이드로클로라이드(0.90 mmol)를 첨가하고 실온에서 밤새 교반하였다. 유기물을 CH2Cl2로 추출하고, 물로 세척하고, 무수 소듐 설페이트로 탈수시키고, 진공하에서 건조시켰다. 컬럼 크로마토그래피(에틸아세테이트/헥산)하여 3,5-디클로로벤질 4-(2-(tert-부톡시카보닐)히드라진카보닐)피페리딘-1-카복실레이트를 흰색 고체(0.25 g, 92.3%)로 얻었다; N- ( 3 -dimethylaminopropyl) to a mixture of 26 (0.60 mmol), tert -butyl hydrazinecarboxylate (0.90 mmol), and 4-(dimethylamino)pyridine (0.03 mmol) in CH 2 Cl 2 (2 mL) - Added N' -ethylcarbodiimide hydrochloride (0.90 mmol) and stirred overnight at room temperature. The organics were extracted with CH 2 Cl 2 , washed with water, dehydrated over anhydrous sodium sulfate and dried under vacuum. Column chromatography (ethyl acetate/hexane) yielded 3,5-dichlorobenzyl 4-(2-(tert-butoxycarbonyl)hydrazinecarbonyl)piperidine-1-carboxylate as a white solid (0.25 g, 92.3%). ) was obtained;
1H NMR(400 MHz, CDCl3) δ 8.01(br s, 1H), 7.30(t, J = 1.9 Hz, 1H), 7.22(d, J = 1.9 Hz, 2H), 6.78(br s, 1H), 5.14 - 4.99(m, 2H), 4.25 - 4.08(m, 2H), 2.99 - 2.82(m, 2H), 2.46 - 2.34(m, 1H), 1.91 - 1.82(m, 2H), 1.79 - 1.67(m, 2H), 1.46(s, 9H). 1H NMR (400 MHz, CDCl 3 ) δ 8.01 (br s, 1H), 7.30 (t, J = 1.9 Hz, 1H), 7.22 (d, J = 1.9 Hz, 2H), 6.78 (br s, 1H) ( m, 2H), 1.46 (s, 9H).
이 디옥산(0.5 mL) 중 Boc-보호된 중간체(0.2 mmol)에 디옥산 중 4 M HCl(1.5 mL)를 첨가하였다. 실온에서 1 hr 동안 교반한 후, 용매를 증발시키고 잔여물을 진공하에서 건조시켜 크루드 45(정량적)를 얻었다;To this Boc-protected intermediate (0.2 mmol) in dioxane (0.5 mL) was added 4 M HCl in dioxane (1.5 mL). After stirring at room temperature for 1 hr, the solvent was evaporated and the residue was dried under vacuum to give crude 45 (quantitative);
1H NMR(400 MHz, CDCl3) δ 7.31(t, J = 1.9 Hz, 1H), 7.22(dd, J = 1.9, 0.6 Hz, 2H), 6.78(bs, 1H), 5.06(d, J = 13.5 Hz, 2H), 4.21(bs, 2H), 3.92(m, 2H), 2.87(m, 2H), 2.34 - 2.15(m, 1H), 1.87 - 1.78(m, 2H), 1.77 - 1.65(m, 2H). 1H NMR (400 MHz, CDCl 3 ) δ 7.31 (t, J = 1.9 Hz, 1H), 7.22 (dd, J = 1.9, 0.6 Hz, 2H), 6.78 (bs, 1H), 5.06 (d, J = 13.5 Hz, 2H), 4.21 (bs, 2H), 3.92 (m, 2H), 2.87 (m, 2H), 2.34 - 2.15 (m, 1H), 1.87 - 1.78 (m, 2H), 1.77 - 1.65 (m , 2H).
3,5-디클로로벤질 4-(5-옥소-4,5-디하이드로-1,3,4-옥사다이아졸-2-일)피페리딘-1-카복실레이트(46). 3,5-dichlorobenzyl 4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate (46).
TEA(8.96 mmol)와 함께 THF(20 mL)에 용해시킨 후, 혼합물을 0 ℃ 에서 THF(5 mL) 중 트리포스젠(1.69 mmol)의 용액을 첨가하고, 실온에서 추가적으로 3 h 동안 교반하였다. 반응이 완결된 후, 용매를 증발시켜 건조하였다. 생성물을 에틸아세테이트로 추출하고 브라인으로 세척하였다. 유기층을 무수 소듐 설페이트로 탈수시키고 농축하였다. 잔여물을 컬럼 크로마토그래피(에틸아세테이트/헥산)로 정제하고 18을 흰색 고체(69.23 mg, 93.0%)로 얻었다;After dissolving TEA (8.96 mmol) in THF (20 mL), the mixture was added at 0 °C to a solution of triphosgene (1.69 mmol) in THF (5 mL) and stirred at room temperature for an additional 3 h. After the reaction was completed, the solvent was evaporated and dried. The product was extracted with ethyl acetate and washed with brine. The organic layer was dehydrated over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (ethyl acetate/hexanes) to give 18 as a white solid (69.23 mg, 93.0%);
1H-NMR(400 MHz, CDCl3) δ 9.56(bs, 1H), 7.31(t, J = 1.9 Hz, 1H), 7.23(d, J = 1.9 Hz, 2H), 5.08(d, J = 6.4 Hz, 2H), 4.13(d, J = 16.1 Hz, 2H), 3.04(m, 2H), 2.87 - 2.73(m, 1H), 2.02(m, 2H), 1.82 - 1.63(m, 2H). 1 H-NMR (400 MHz, CDCl 3 ) δ 9.56 (bs, 1H), 7.31 (t, J = 1.9 Hz, 1H), 7.23 (d, J = 1.9 Hz, 2H), 5.08 (d, J = 6.4 Hz, 2H), 4.13 (d, J = 16.1 Hz, 2H), 3.04 (m, 2H), 2.87 - 2.73 (m, 1H), 2.02 (m, 2H), 1.82 - 1.63 (m, 2H).
일반적인 공정 G. General process G.
무수 DMF(2mL) 중 옥사다이아졸-2-온(0.1 mmol)의 용액에 DIEA(0.3 mmol), 아민(0.1 mmol), 및 BOP 시약(0.1 mmol)을 첨가하였다. 실온에서 8 h 동안 교반한 후, 용매를 증발시켜 건조하였다. 유기물을 에틸아세테이트로 추출하고, 브라인으로 세척하고, 무수 마그네슘 설페이트로 탈수시키고, 농축시켰다. 잔여물을 컬럼 크로마토그래피(MeOD/CH2Cl2)로 정제하여 목적 생성물을 얻었다.To a solution of oxadiazol-2-one (0.1 mmol) in anhydrous DMF (2 mL) was added DIEA (0.3 mmol), amine (0.1 mmol), and BOP reagent (0.1 mmol). After stirring at room temperature for 8 h, the solvent was evaporated to dryness. The organics were extracted with ethyl acetate, washed with brine, dehydrated with anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography (MeOD/CH 2 Cl 2 ) to give the desired product.
3,5-디클로로벤질 4-(5-(((13,5-Dichlorobenzyl 4-(5-(((1 HH -테트라졸-5-일)메틸)아미노)-1,3,4-옥사다이아졸-2-일)피페리딘-1-카복실레이트(47a). -tetrazol-5-yl)methyl)amino)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate (47a).
일반적인 공정 G에 따라, 46 및 41c를 사용하여 47a를 흰색 고체(35.1%)로 얻었다;According to General Procedure G, 46 and 41c were used to obtain 47a as a white solid (35.1%);
1H NMR(400 MHz, MeOD-d 4) δ 7.39(t, J = 1.9 Hz, 1H), 7.34(dd, J = 1.7, 0.9 Hz, 2H), 5.10(s, 2H), 4.71(s, 2H), 4.11(d, J = 13.5 Hz, 2H), 3.06(tt, J = 10.8, 3.8 Hz, 3H), 2.05(dd, J = 13.5, 3.7 Hz, 2H), 1.79 - 1.64(m, 2H); 13C NMR(100 MHz, DMSO-d 6) δ 163.2, 161.7, 156.6, 154.1, 141.4, 134.1, 127.5, 126.2, 64.8, 42.7, 37.6, 32.0, 29.1; HRMS(ESI, m/z) calculated for C18H19Cl2N8O3 [M+H]+ 453.0952, found 453.0952. 1 H NMR (400 MHz, MeOD- d 4 ) δ 7.39 (t, J = 1.9 Hz, 1H), 7.34 (dd, J = 1.7, 0.9 Hz, 2H), 5.10 (s, 2H), 4.71 (s, 2H), 4.11 (d, J = 13.5 Hz, 2H), 3.06 (tt, J = 10.8, 3.8 Hz, 3H), 2.05 (dd, J = 13.5, 3.7 Hz, 2H), 1.79 - 1.64 (m, 2H) ); 13 C NMR (100 MHz, DMSO- d6 ) δ 163.2, 161.7, 156.6, 154.1, 141.4, 134.1 , 127.5, 126.2, 64.8, 42.7, 37.6, 32.0, 29.1; HRMS (ESI, m/z) calculated for C 18 H 19 Cl 2 N 8 O 3 [M+H] + 453.0952, found 453.0952.
3,5-디클로로벤질 4-(5-(((1-메틸-1 H -1,2,3-트리아졸-4-일)메틸)아미노)-1,3,4-옥사다이아졸-2-일)피페리딘-1-카복실레이트(47b). 3,5-dichlorobenzyl 4-(5-(((1-methyl-1H - 1,2,3-triazol-4-yl)methyl)amino)-1,3,4-oxadiazole-2 -yl)piperidine-1-carboxylate (47b) .
일반적인 공정 G에 따라, 46 및 41b를 사용하여 47b를 흰색 고체(23.9%)로 얻었다;According to General Procedure G, 46 and 41b were used to obtain 47b as a white solid (23.9%);
1H NMR(400 MHz, CDCl3) δ 7.71(s, 1H), 7.30(t, J = 1.9 Hz, 1H), 7.22(d, J = 1.8 Hz, 2H), 6.23(d, J = 6.1 Hz, 1H), 5.16-4.96(m, 2H), 4.59(d, J = 5.2 Hz, 2H), 4.15-4.08(m, 2H), 4.07(s, 3H), 3.05(s, 2H), 3.00-2.88(m, 1H), 2.07-1.94(m, 2H), 1.85-1.68(m, 2H); 13C NMR(100 MHz, CDCl3) δ 163.13, 162.51, 154.64, 144.27, 140.11, 135.10, 128.17, 126.11, 123.76, 65.58, 43.14, 38.37, 36.72, 33.01, 28.73.;HRMS calculated for C19H22Cl2N7O3 [M+H]+ 466.1156, found 466.1162. 1H NMR (400 MHz, CDCl 3 ) δ 7.71 (s, 1H), 7.30 (t, J = 1.9 Hz, 1H), 7.22 (d, J = 1.8 Hz, 2H), 6.23 (d, J = 6.1 Hz , 1H), 5.16-4.96(m, 2H), 4.59(d, J = 5.2 Hz, 2H), 4.15-4.08(m, 2H), 4.07(s, 3H), 3.05(s, 2H), 3.00- 2.88 (m, 1H), 2.07-1.94 (m, 2H), 1.85-1.68 (m, 2H); 13 C NMR (100 MHz, CDCL 3 ) δ 163.13, 162.51, 154.64, 144.27, 140.11, 135.10, 128.17, 126.11, 123.76, 65.58 , 43.14, 38.37, 36.72, 33.01, 28.73 . 2 N 7 O 3 [M+H] + 466.1156, found 466.1162.
3,5-디클로로벤질 4-(5-(((4-메틸-13,5-dichlorobenzyl 4-(5-(((4-methyl-1 HH -1,2,3-트리아졸-5-일)메틸)아미노)-1,3,4-옥사다이아졸-2-일)피페리딘-1-카복실레이트(47c). -1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate (47c).
일반적인 공정 G에 따라, 46 및 41d를 사용하여47c를 흰색 고체(48.5%)로 얻었다; 46 and 41d were used according to General Procedure G to obtain 47c as a white solid (48.5%);
1H NMR(400 MHz, CDCl3) δ 7.29(t, J = 2.0 Hz, 1H), 7.22(d, J = 2.0 Hz, 2H), 6.63(s, 1H), 5.07(d, J = 9.7 Hz, 2H), 4.55(s, 2H), 4.11(d, J = 13.5 Hz, 2H), 3.15 - 2.86(m, 3H), 2.32(s, 3H), 2.02(dq, J = 12.0, 3.5 Hz, 2H), 1.85 - 1.68(m, 2H); 13C NMR(100 MHz, CDCl3) δ 163.4, 162.4, 154.7, 140.0, 135.1, 128.2, 126.1, 65.7, 43.2, 37.6, 33.0, 28.7, 9.1; HRMS(ESI, m/z) calculated for C19H22Cl2N7O3 [M+H]+ 466.1156, found 466.1155. 1H NMR (400 MHz, CDCl 3 ) δ 7.29 (t, J = 2.0 Hz, 1H), 7.22 (d, J = 2.0 Hz, 2H), 6.63 (s, 1H), 5.07 (d, J = 9.7 Hz , 2H), 4.55(s, 2H), 4.11(d, J = 13.5 Hz, 2H), 3.15 - 2.86(m, 3H), 2.32(s, 3H), 2.02(dq, J = 12.0, 3.5 Hz, 2H), 1.85 - 1.68 (m, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 163.4, 162.4, 154.7, 140.0, 135.1, 128.2, 126.1, 65.7, 43.2, 37.6, 33.0, 28.7, 9.1; HRMS (ESI, m/z) calculated for C 19 H 22 Cl 2 N 7 O 3 [M+H] + 466.1156, found 466.1155.
제법 12. 화합물 50a-c의 합성Preparation 12. Synthesis of compounds 50a-c
시약 및 조건:(a) 트리포스젠, Et3N, THF, 12 h;(b) i: TCDI, EtOH, 1 h; ii: N2H4.H2O, 18 h;(c) 4-펜틴나이트릴, TFA, 50 ℃, 24 h;(d) Me3SiN3, CuI, DMF, MeOH, 80 ℃, 24 h;(e) 48, BOP reagent, DIEA, DMF, 15 h;(f) 4-펜티노익산, EDC, DMAP, CH2Cl2, 15 h;(g) Burgess reagent, 디옥산, reflux, 5 h;Reagents and conditions: (a) Triphosgene, Et 3 N, THF, 12 h; (b) i: TCDI, EtOH, 1 h; ii: N 2 H 4 .H 2 O, 18 h; (c) 4-pentynnitrile, TFA, 50 °C, 24 h; (d) Me 3 SiN 3 , CuI, DMF, MeOH, 80 °C, 24 h (e) 48 , BOP reagent, DIEA, DMF, 15 h; (f) 4-pentinoic acid, EDC, DMAP, CH 2 Cl 2 , 15 h; (g) Burgess reagent, dioxane, reflux, 5 h ;
5-(부-3-틴-1-일)-1,3,4-옥사다이아졸-2(3 H )-론(48): 5-(but-3-yn-1-yl)-1,3,4-oxadiazole-2(3 H )-lone (48) :
13a에 대한 공정에 따라, 펜-4-틴 하이드라자이드(0.27 g, 1.82 mmol)를 사용하여 48을 무색 오일(53.79 mg, 21.4%)로 얻었다;Following the procedure for 13a , phen-4-tin hydrazide (0.27 g, 1.82 mmol) was used to obtain 48 as a colorless oil (53.79 mg, 21.4%);
1H NMR(400 MHz, CDCl3) δ 9.84(br s, 1H), 2.82(t, J = 7.2 Hz, 2H), 2.61(td, J = 7.0, 2.6 Hz, 3H), 2.06(d, J = 2.6 Hz, 1H). 1H NMR (400 MHz, CDCl 3 ) δ 9.84 (br s, 1H), 2.82 (t, J = 7.2 Hz, 2H), 2.61 (td, J = 7.0, 2.6 Hz, 3H), 2.06 (d, J = 2.6 Hz, 1H).
3,5-디클로로벤질 4-(5-(부-3-틴-1-일)-1,3,4-티아다이아졸-2-일)피페라진-1-카복실레이트(49a). 3,5-dichlorobenzyl 4-(5-(but-3-yn-1-yl)-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (49a).
실온에서 교반하고 있는 에탄올(5 mL) 중 35(0.29 g, 1.00 mmol)의 혼합물에 1,1'-티오카보닐디이미다졸(0.21 g, 1.20 mmol)을 첨가하였다. 실온에서 1 h 동안 교반한 후, 히드라진 모노하이드레이트(200 μL)를 혼합물에 첨가하였다. 반응 혼합물을 실온에서 밤새 교반하고 진공하에서 건조시켰다. 유기물을 에틸아세테이트로 추출하고, 브라인으로 세척하고, 무수 소듐 설페이트로 탈수시키고, 농축시켰다. 컬럼 크로마토그래피(에틸아세테이트/헥산)하여 3,5-디클로로벤질 4-(히드라진카보티오닐) 피페라진-1-카복실레이트를 흰색 고체(0.27 g, 74.6%)로 얻었다. 이것(0.55 mmol)을 4-펜틴나이트릴(43.50 mg, 0.55 mmol)과 함께 트리플루오로아세트산(3 mL)에 용해시킨 후, 50 ℃에서 밤새 가열하였다. 혼합물을 0 ℃로 냉각시키고 포화된 NaHCO3 용액으로 퀀칭한 후, 에틸아세테이트로 추출하였다. 유기층을 무수 Na2SO4로 탈수시켜 농축하고, 컬럼 크로마토그래피(CH2Cl2/MeOH)로 정제하여 49a를 흰색 고체(99.89 mg, 42.7%)로 얻었다;To a mixture of 35 (0.29 g, 1.00 mmol) in ethanol (5 mL) stirred at room temperature was added 1,1'-thiocarbonyldiimidazole (0.21 g, 1.20 mmol). After stirring at room temperature for 1 h, hydrazine monohydrate (200 μL) was added to the mixture. The reaction mixture was stirred at room temperature overnight and dried under vacuum. The organics were extracted with ethyl acetate, washed with brine, dehydrated with anhydrous sodium sulfate and concentrated. Column chromatography (ethyl acetate/hexane) gave 3,5-dichlorobenzyl 4-(hydrazinecarbothionyl)piperazine-1-carboxylate as a white solid (0.27 g, 74.6%). This (0.55 mmol) was dissolved in trifluoroacetic acid (3 mL) along with 4-pentynnitrile (43.50 mg, 0.55 mmol) and heated at 50 °C overnight. The mixture was cooled to 0 °C, quenched with saturated NaHCO 3 solution, and extracted with ethyl acetate. The organic layer was concentrated by dehydration with anhydrous Na 2 SO 4 and purified by column chromatography (CH 2 Cl 2 /MeOH) to give 49a as a white solid (99.89 mg, 42.7%);
1H NMR(400 MHz, CDCl3) δ 7.32(t, J = 1.9 Hz, 1H), 7.24(d, J = 1.9 Hz, 2H), 5.10(s, 2H), 3.71 - 3.62(m, 4H), 3.58 - 3.47(m, 4H), 3.15(t, J = 7.2 Hz, 2H), 2.63(td, J = 7.2, 2.7 Hz, 2H), 2.06(t, J = 2.6 Hz, 1H). 1H NMR (400 MHz, CDCl 3 ) δ 7.32 (t, J = 1.9 Hz, 1H), 7.24 (d, J = 1.9 Hz, 2H), 5.10 (s, 2H), 3.71 - 3.62 (m, 4H) , 3.58 - 3.47 (m, 4H), 3.15 (t, J = 7.2 Hz, 2H), 2.63 (td, J = 7.2, 2.7 Hz, 2H), 2.06 (t, J = 2.6 Hz, 1H).
3,5-디클로로벤질 4-(5-(부-3-틴-1-일)-1,3,4-옥사다이아졸-2-일)피페라진-1-카복실레이트(49b).3,5-dichlorobenzyl 4-(5-(but-3-yn-1-yl)-1,3,4-oxadiazol-2-yl)piperazine-1-carboxylate (49b).
일반적인 공정 G에 따라, 48(27.62 mg, 0.20 mmol) 및 35(69.40 mg, 0.24 mmol)를 사용하여 49b를 흰색 고체(38.88 mg, 47.5%)로 얻었다.Using 48 (27.62 mg, 0.20 mmol) and 35 (69.40 mg, 0.24 mmol) according to General Procedure G, 49b was obtained as a white solid (38.88 mg, 47.5%).
1H NMR(400 MHz, CDCl3) δ 7.32(t, J = 1.9 Hz, 1H), 7.24(d, J = 1.9 Hz, 2H), 5.10(s, 2H), 3.67 - 3.61(m, 4H), 3.55 - 3.48(m, 4H), 2.97(t, J = 7.5 Hz, 2H), 2.64(dt, J = 7.4, 2.7 Hz, 2H), 2.03(t, J = 2.7 Hz, 1H). 1H NMR (400 MHz, CDCl 3 ) δ 7.32 (t, J = 1.9 Hz, 1H), 7.24 (d, J = 1.9 Hz, 2H), 5.10 (s, 2H), 3.67 - 3.61 (m, 4H) , 3.55 - 3.48 (m, 4H), 2.97 (t, J = 7.5 Hz, 2H), 2.64 (dt, J = 7.4, 2.7 Hz, 2H), 2.03 (t, J = 2.7 Hz, 1H).
3,5-디클로로벤질 4-(5-(부-3-틴-1-일)-1,3,4-옥사다이아졸-2-일)피페리딘-1-카복실레이트(49c). 3,5-dichlorobenzyl 4-(5-(but-3-yn-1-yl)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate (49c).
CH2Cl2(2 mL) 중 45(86.55 mg, 0.25 mmol), 4-펜티노익산(29.43 mg, 0.30 mmol), 및 DMAP(0.03 mmol)의 혼합물에 EDCI(0.24 mmol)를 첨가하였다. 실온에서 12 h 동안 교반한 후, 유기물을 CH2Cl2로 추출하고 물로 세척하고 무수 소듐 설페이트로 탈수시키고 농축하였다. 컬럼 크로마토그래피(에틸아세테이트/헥산)로 정제하여 중간체인 3,5-디클로로벤질 4-(2-(펜-4-틴노일)히드라진카보닐)피페리딘-1-카복실레이트를 흰색 고체(63.94 mg, 0.15 mmol)로 얻었다. 이를 무수 디옥산(5 mL) 중 Burgess 시약(0.14 g, 0.60 mmol)과 혼합시키고 질소 가스하에 5 h 동안 환류시켰다. 반응 혼합물을 포화된 NaHCO3 용액으로 희석하였다. 유기물을 에틸아세테이트로 추출하고, 소듐 설페이트로 탈수시키고, 농축시켰다. 생성물을 컬럼 크로마토그래피(에틸아세테이트/헥산)로 정제하여 49c를 흰색 고체(32.15 mg, 52.7%)로 얻었다.To a mixture of 45 (86.55 mg, 0.25 mmol), 4-pentinoic acid (29.43 mg, 0.30 mmol), and DMAP (0.03 mmol) in CH 2 Cl 2 (2 mL) was added EDCI (0.24 mmol). After stirring at room temperature for 12 h, the organics were extracted with CH 2 Cl 2 , washed with water, dehydrated over anhydrous sodium sulfate and concentrated. Purification by column chromatography (ethyl acetate/hexane) yielded the intermediate 3,5-dichlorobenzyl 4-(2-(phen-4-tinnoyl)hydrazinecarbonyl)piperidine-1-carboxylate as a white solid (63.94 mg, 0.15 mmol). It was mixed with Burgess reagent (0.14 g, 0.60 mmol) in anhydrous dioxane (5 mL) and refluxed under nitrogen gas for 5 h. The reaction mixture was diluted with saturated NaHCO 3 solution. The organics were extracted with ethyl acetate, dehydrated with sodium sulfate and concentrated. The product was purified by column chromatography (ethyl acetate/hexane) to give 49c as a white solid (32.15 mg, 52.7%).
1H NMR(400 MHz, CDCl3) δ 7.31(t, J = 1.9 Hz, 1H), 7.23(d, J = 1.8 Hz, 2H), 5.15 - 5.01(m, 2H), 4.20 - 4.10(m, 2H), 3.19 - 3.01(m, 5H), 2.70(td, J = 7.4, 2.6 Hz, 2H), 2.13 - 2.04(m, 2H), 2.02(t, J = 2.6 Hz, 1H), 1.90 - 1.79(m, 2H). 1H NMR (400 MHz, CDCl 3 ) δ 7.31 (t, J = 1.9 Hz, 1H), 7.23 (d, J = 1.8 Hz, 2H), 5.15 - 5.01 (m, 2H), 4.20 - 4.10 (m, 2H), 3.19 - 3.01 (m, 5H), 2.70 (td, J = 7.4, 2.6 Hz, 2H), 2.13 - 2.04 (m, 2H), 2.02 (t, J = 2.6 Hz, 1H), 1.90 - 1.79 (m, 2H).
3,5-디클로로벤질 4-(5-(2-(13,5-Dichlorobenzyl 4-(5-(2-(1) HH -1,2,3-트리아졸-5-일)에틸)-1,3,4-티아다이아졸-2-일)피페라진-1-카복실레이트(50a). -1,2,3-triazol-5-yl)ethyl)-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (50a).
화합물 49a(97.82 mg, 0.23 mmol), 트라이메틸실릴 아자이드(0.25 mmol), 및 카파(I) 아이오다이드(0.025 mmol)를 아르곤 가스하에 DMF(0.9 mL) 및 MeOH(0.1 mL)의 용액에 첨가하였다. 반응 혼합물을 80 ℃에서 24 h 동안 교반하였다. 용매를 증발시켜 건조시키고, 에틸아세테이트로 추출하고 브라인으로 세척하였다. 유기층을 무수 소듐 설페이트로 탈수시키고 농축하였다. 생성물을 컬럼 크로마토그래피(CH2Cl2/MeOH)로 정제하여 50a를 흰색 고체(7.54 mg, 29.0%)로 얻었다.Compound 49a (97.82 mg, 0.23 mmol), trimethylsilyl azide (0.25 mmol), and kappa(I) iodide (0.025 mmol) were dissolved in a solution of DMF (0.9 mL) and MeOH (0.1 mL) under argon gas. added. The reaction mixture was stirred at 80 °C for 24 h. The solvent was evaporated to dryness, extracted with ethyl acetate and washed with brine. The organic layer was dehydrated over anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (CH 2 Cl 2 /MeOH) to give 50a as a white solid (7.54 mg, 29.0%).
1H NMR(400 MHz, CDCl3) δ 7.54(s, 1H), 7.32(t, J = 1.9 Hz, 1H), 7.24(d, J = 1.9 Hz, 2H), 5.10(s, 2H), 3.70 - 3.62(m, 4H), 3.56 - 3.46(m, 4H), 3.33(t, J = 6.9 Hz, 2H), 3.23(t, J = 7.0 Hz, 2H). 13C NMR(100 MHz, CDCl3) δ 172.08, 159.20, 154.60, 139.64, 135.19, 128.40, 126.28, 65.93, 49.28, 43.01, 29.62, 24.15. HRMS(ESI) m/z(M+H)+ calculated for C18H20Cl2N7O2S = 468.08; found 468.0779. 1H NMR (400 MHz, CDCl 3 ) δ 7.54 (s, 1H), 7.32 (t, J = 1.9 Hz, 1H), 7.24 (d, J = 1.9 Hz, 2H), 5.10 (s, 2H), 3.70 - 3.62 (m, 4H), 3.56 - 3.46 (m, 4H), 3.33 (t, J = 6.9 Hz, 2H), 3.23 (t, J = 7.0 Hz, 2H). 13 C NMR (100 MHz, CDCl 3 ) δ 172.08, 159.20, 154.60, 139.64, 135.19, 128.40, 126.28, 65.93, 49.28, 43.01, 29.62, 24.15. HRMS (ESI) m/z (M+H) + calculated for C 18 H 20 Cl 2 N 7 O 2 S = 468.08; found 468.0779.
3,5-디클로로벤질 4-(5-(2-(13,5-Dichlorobenzyl 4-(5-(2-(1) HH -1,2,3-트리아졸-5-일)에틸)-1,3,4-옥사다이아졸-2-일)피페라진-1-카복실레이트(50b). -1,2,3-triazol-5-yl)ethyl)-1,3,4-oxadiazol-2-yl)piperazine-1-carboxylate (50b).
50a에 대한 공정에 따라, 49b(40.93 mg, 0.10 mmol)를 사용하여 50b를 흰색 고체(13.12 mg, 29.0%)로 얻었다.Following the procedure for 50a , 49b ( 40.93 mg, 0.10 mmol) was used to obtain 50b as a white solid (13.12 mg, 29.0%).
1H NMR(400 MHz, CDCl3) δ 7.55(s, 1H), 7.32(t, J = 1.9 Hz, 1H), 7.24(d, J = 1.9 Hz, 2H), 5.10(s, 2H), 3.69 - 3.59(m, 4H), 3.54 - 3.44(m, 4H), 3.25 - 3.19(m, 2H), 3.18 - 3.09(m, 2H). 13C NMR(100 MHz, CDCl3) δ 164.12, 160.46, 154.64, 139.61, 135.19, 128.40, 126.30, 65.96, 45.86, 42.98, 25.21, 21.79. HRMS(ESI) m/z(M+H)+ calculated for C18H20Cl2N7O3 = 452.10; found 452.1003. 1H NMR (400 MHz, CDCl 3 ) δ 7.55 (s, 1H), 7.32 (t, J = 1.9 Hz, 1H), 7.24 (d, J = 1.9 Hz, 2H), 5.10 (s, 2H), 3.69 - 3.59 (m, 4H), 3.54 - 3.44 (m, 4H), 3.25 - 3.19 (m, 2H), 3.18 - 3.09 (m, 2H). 13 C NMR (100 MHz, CDCl 3 ) δ 164.12, 160.46, 154.64, 139.61, 135.19, 128.40, 126.30, 65.96, 45.86, 42.98, 25.21, 21.79. HRMS (ESI) m/z (M+H) + calculated for C 18 H 20 Cl 2 N 7 O 3 = 452.10; found 452.1003.
3,5-디클로로벤질 4-(5-(2-(1 H -1,2,3-트리아졸-5-일)에틸)-1,3,4-옥사다이아졸-2-일)피페리딘-1-카복실레이트(50c): 3,5-dichlorobenzyl 4-(5-(2-(1 H -1,2,3-triazol-5-yl)ethyl)-1,3,4-oxadiazol-2-yl)piperi Dean-1-carboxylate (50c) :
50a에 대한 공정에 따라, 49c(32.15 mg, 0.079 mmol)를 사용하여 50c를 흰색 고체(21.64 mg, 60.7%)로 얻었다.Following the procedure for 50a , 49c ( 32.15 mg, 0.079 mmol) was used to obtain 50c as a white solid (21.64 mg, 60.7%).
1H NMR(400 MHz, CDCl3) δ 12.16(s, 1H), 7.55(s, 1H), 7.31(t, J = 1.9 Hz, 1H), 7.23(d, J = 1.9 Hz, 2H), 5.08(d, J = 9.2 Hz, 2H), 4.21 - 4.07(m, 2H), 3.31 - 3.21(m, 4H), 3.15 - 3.01(m, 3H), 2.11 - 2.03(m, 2H), 1.89 - 1.77(m, 2H). 13C NMR(100 MHz, CDCl3) δ 168.41, 165.93, 154.69, 140.00, 135.13, 128.23, 126.16, 65.68, 43.15, 33.06, 28.78, 25.04, 21.88. HRMS(ESI) m/z(M+Na)+ calculated for C19H20Cl2N6-NaO3 = 473.09; found 473.0868. 1 H NMR (400 MHz, CDCl 3 ) δ 12.16 (s, 1H), 7.55 (s, 1H), 7.31 (t, J = 1.9 Hz, 1H), 7.23 (d, J = 1.9 Hz, 2H), 5.08 (d, J = 9.2 Hz, 2H), 4.21 - 4.07 (m, 2H), 3.31 - 3.21 (m, 4H), 3.15 - 3.01 (m, 3H), 2.11 - 2.03 (m, 2H), 1.89 - 1.77 (m, 2H). 13 C NMR (100 MHz, CDCl 3 ) δ 168.41, 165.93, 154.69, 140.00, 135.13, 128.23, 126.16, 65.68, 43.15, 33.06, 28.78, 25.04, 21.88. HRMS (ESI) m/z (M+Na) + calculated for C 19 H 20 Cl 2 N 6- NaO 3 = 473.09; found 473.0868.
제법 13. 화합물 53a-b의 합성.Preparation 13. Synthesis of compound 53a-b.
시약 및 조건:(a) 프로파길 브로마이드, K2CO3, DMF, 12 h;(b) 51, K2CO3, DMF, 12 h;(c) TFA, CH2Cl2, 2 h;(d) CuSO4, TMSN3, 소듐 아스코르베이트, THF, H2O, 80 ℃, 12 h;(e) 5-브로모-1,3,4-티아다이아졸-2-아민, K2CO3, DMF, 12 h;(f) CuI, TMSN3, sodium ascorbate, DMF, H2O, 80 ℃, 15 h;(g) 디옥산 중 4M HCl, 1 h;(h) 3,5-디클로로벤질 알코올, CDI, DMF, 18 h.Reagents and conditions: (a) propargyl bromide, K 2 CO 3 , DMF, 12 h; (b) 51 , K 2 CO 3 , DMF, 12 h; (c) TFA, CH 2 Cl 2 , 2 h; d) CuSO 4 , TMSN 3 , sodium ascorbate, THF, H 2 O, 80 °C, 12 h; (e) 5-bromo-1,3,4-thiadiazol-2-amine, K 2 CO 3 , DMF, 12 h; (f) CuI, TMSN 3 , sodium ascorbate, DMF, H 2 O, 80 °C, 15 h; (g) 4M HCl in dioxane, 1 h; (h) 3,5-dichloro Benzyl alcohol, CDI, DMF, 18 h.
tt -부틸(5-브로모티아졸-2-일)(프로-2-핀-1-일)카바메이트(51). -Butyl(5-bromotiazol-2-yl)(pro-2-pin-1-yl)carbamate (51).
DMF 중 NaH(60% in mineral oil)(2.1 mmol)의 용액에 t-부틸(5-브로모티아졸-2-일)카바메이트(2.1 mmol) 및 프로파길 브로마이드(2.1 mmol)를 첨가하였다. 실온에서 2h 동안 교반한 후, 용매를 증발시켜 건조하였다. 유기물을 에틸아세테이트로 추출하고, 브라인으로 세척하고, 무수 마그네슘 설페이트로 탈수시키고, 농축시켰다. 잔여물을 컬럼 크로마토그래피(에틸아세테이트/헥산)로 정제하여 49(수율: 95.8%)를 얻었다;To a solution of NaH (60% in mineral oil) (2.1 mmol) in DMF was added t-butyl(5-bromotiazol-2-yl)carbamate (2.1 mmol) and propargyl bromide (2.1 mmol). After stirring at room temperature for 2 h, the solvent was evaporated to dryness. The organics were extracted with ethyl acetate, washed with brine, dehydrated with anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography (ethyl acetate/hexane) to give 49 (yield: 95.8%);
1H NMR(400 MHz, CDCl3) δ 7.41-7.33(m, 1H), 4.81(t, J = 2.2 Hz, 2H), 2.23(t, J = 2.4 Hz, 1H), 1.60(s, 9H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.41-7.33 (m, 1H), 4.81 (t, J = 2.2 Hz, 2H), 2.23 (t, J = 2.4 Hz, 1H), 1.60 (s, 9H) .
3,5-디클로로벤질 4-(2-(프로-2-핀-1-일아미노)티아졸-5-일)피페라진-1-카복실레이트(52).3,5-dichlorobenzyl 4-(2-(pro-2-pin-1-ylamino)thiazol-5-yl)piperazine-1-carboxylate (52).
CH2Cl2 중 51(0.3 mmol)의 용액에 트리플루오로아세트산(1 mL)을 첨가하였다. 실온에서 2 h 동안 교반한 후, 혼합물을 진공하여 건조시켜 5-브로모-N-(프로-2-핀-1-일)티아졸-2-아민 트리플루오로아세테이트염을 얻었다. 이 염을 무수 DMF(2 mL)에 첨가한 후 실온에서 12 h 동안 K2CO3(1.0 mmol) 및 35(0.3 mmol)와 함께 교반하였다. 반응이 완결된 후, 용매를 증발시켜 건조하였다. 잔여물을 에틸아세테이트로 추출하고 브라인으로 세척하였다. 유기층을 무수 마그네슘 설페이트로 탈수시키고 농축시켰다. 잔여물을 컬럼 크로마토그래피(에틸아세테이트/헥산)로 정제하여 52(53.2%)를 얻었다;To a solution of 51 (0.3 mmol) in CH 2 Cl 2 was added trifluoroacetic acid (1 mL). After stirring at room temperature for 2 h, the mixture was dried in vacuo to obtain 5-bromo- N- (pro-2-pin-1-yl)thiazol-2-amine trifluoroacetate salt. This salt was added to anhydrous DMF (2 mL) and stirred with K 2 CO 3 (1.0 mmol) and 35 (0.3 mmol) at room temperature for 12 h. After the reaction was completed, the solvent was evaporated and dried. The residue was extracted with ethyl acetate and washed with brine. The organic layer was dehydrated with anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography (ethyl acetate/hexane) to give 52 (53.2%);
1H NMR(400 MHz, CDCl3) δ 7.31(t, J = 1.9 Hz, 1H), 7.23(d, J = 1.9 Hz, 2H), 6.61(s, 1H), 5.08(s, 2H), 4.07(d, J = 2.5 Hz, 2H), 3.68-3.54(m, 4H), 2.91(t, J = 5.1 Hz, 4H), 2.28(t, J = 2.5 Hz, 1H). 1H NMR (400 MHz, CDCl 3 ) δ 7.31 (t, J = 1.9 Hz, 1H), 7.23 (d, J = 1.9 Hz, 2H), 6.61 (s, 1H), 5.08 (s, 2H), 4.07 (d, J = 2.5 Hz, 2H), 3.68–3.54 (m, 4H), 2.91 (t, J = 5.1 Hz, 4H), 2.28 (t, J = 2.5 Hz, 1H).
3,5-디클로로벤질 4-(2-(((1 H -1,2,3-트리아졸-5-일)메틸)아미노)티아졸-5-일)피페라진-1-카복실레이트(53a). THF 및 H2O(2:1) 중 52(0.24 mmol)의 용액에 CuSO4·H2O(0.01 mmol), 소듐 아스코르베이트(0.02 mmol), 및 아지도트라이메틸실란(0.71 mmol)을 첨가하고 80 ℃에서 12 h 동안 격렬히 교반하였다. 반응이 완결된 후, 용매를 증발시켜 건조하였다. 잔여물을 에틸아세테이트로 추출하고 셀라이트 패드를 통해 여과하였다. 이후, 여과액을 브라인으로 세척하였다. 유기층을 무수 마그네슘 설페이트로 탈수시키고 농축하였다. 잔여물을 컬럼 크로마토그래피(에틸아세테이트/헥산)로 정제하여 53a(5.3%)를 얻었다; 3,5-dichlorobenzyl 4-(2-(((1H - 1,2,3-triazol-5-yl)methyl)amino)thiazol-5-yl)piperazine-1-carboxylate (53a ). CuSO 4 H 2 O (0.01 mmol), sodium ascorbate (0.02 mmol), and azidotrimethylsilane (0.71 mmol) were added to a solution of 52 (0.24 mmol) in THF and H 2 O (2:1). was added and vigorously stirred at 80 °C for 12 h. After the reaction was completed, the solvent was evaporated and dried. The residue was extracted with ethyl acetate and filtered through a pad of celite. Thereafter, the filtrate was washed with brine. The organic layer was dehydrated over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography (ethyl acetate/hexane) to give 53a (5.3%);
1H NMR(400 MHz, CDCl3) δ 12.76(s, 1H), 10.53(s, 1H), 7.97(s, 1H), 7.32(t, J = 1.9 Hz, 1H), 7.26-7.20(m, 2H), 6.39(s, 1H), 5.33(s, 2H), 5.09(s, 2H), 3.63(t, J = 4.9 Hz, 4H), 2.84(s, 4H); 13C NMR(100 MHz, CDCl3) δ 159.22, 154.73, 140.58, 139.74, 135.17, 131.16, 128.34, 126.32, 126.22, 103.80, 65.87, 52.50, 43.97, 38.01; HRMS calculated for C18H20Cl2N7O2S [M+H]+ 468.0771, found 468.0778. 1 H NMR (400 MHz, CDCl 3 ) δ 12.76 (s, 1H), 10.53 (s, 1H), 7.97 (s, 1H), 7.32 (t, J = 1.9 Hz, 1H), 7.26-7.20 (m, 2H), 6.39(s, 1H), 5.33(s, 2H), 5.09(s, 2H), 3.63(t, J = 4.9 Hz, 4H), 2.84(s, 4H); 13 C NMR (100 MHz, CDCl 3 ) δ 159.22, 154.73, 140.58, 139.74, 135.17, 131.16, 128.34, 126.32, 126.22, 103.80, 65.87, 52.50, 43.97, 38.01; HRMS calculated for C 18 H 20 Cl 2 N 7 O 2 S [M+H] + 468.0771, found 468.0778.
tt -부틸 4-(5-아미노-1,3,4-티아다이아졸-2-일)피페라진-1-카복실레이트(54). -Butyl 4-(5-amino-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (54).
N-Boc-피페라진(1.0 mmol) 및 5-브로모-1,3,4-티아다이아졸-2-아민(1.0 mmol)을 실온에서 K-2CO3(2 eq)와 함께 DMF에 혼합하였다. 12 h 동안 교반한 후, 용매를 진공하에 제거하였다. 잔여물을 실리카겔 컬럼 크로마토그래피(에틸아세테이트/헥산)로 정제하여 54(86%)를 얻었다; N -Boc-piperazine (1.0 mmol) and 5-bromo-1,3,4-thiadiazol-2-amine (1.0 mmol) were mixed in DMF with K- 2 CO 3 (2 eq) at room temperature. did After stirring for 12 h, the solvent was removed under vacuum. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give 54 (86%);
1H NMR(400 MHz, CDCl3) δ 4.78(s, 2H), 3.54(m, 4H), 3.35(m, 4H), 1.47(s, 9H). 13C NMR(100 MHz, CDCl3) δ 165.82, 160.25, 154.55, 80.35, 49.67, 42.83, 28.38. LRMS(ESI, m/z) calculated for C11H19N5O2S [M+H]+ 286.1259, found 186.10. 1 H NMR (400 MHz, CDCl 3 ) δ 4.78 (s, 2H), 3.54 (m, 4H), 3.35 (m, 4H), 1.47 (s, 9H). 13 C NMR (100 MHz, CDCl 3 ) δ 165.82, 160.25, 154.55, 80.35, 49.67, 42.83, 28.38. LRMS (ESI, m/z) calculated for C 11 H 19 N 5 O 2 S [M+H] + 286.1259, found 186.10.
tt -부틸 4-(5-(프로-2-핀-1-일아미노)-1,3,4-티아다이아졸-2-일)피페라진-1-카복실레이트(55). -Butyl 4-(5-(pro-2-pin-1-ylamino)-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (55).
화합물 54(1 mmol), 프로파길 브로마이드(1.2 mmol), 및 K2CO3(1.2 mmol)를 DMF에 혼합하였다. 50 ℃에서 18 h 동안 교반한 후, 혼합물을 진공하에 건조시켰다. 잔여물을 실리카겔 컬럼 크로마토그래피(EA/헥산)로 정제하여 55(32%)를 얻었다;Compound 54 (1 mmol), propargyl bromide (1.2 mmol), and K 2 CO 3 (1.2 mmol) were mixed in DMF. After stirring at 50 °C for 18 h, the mixture was dried under vacuum. The residue was purified by silica gel column chromatography (EA/Hexanes) to give 55 (32%);
1H NMR(400 MHz, CDCl3) δ 4.56(m, 1H), 4.10(m, 2H), 3.54(m, 5H), 3.36(m, 4H), 3.27 - 3.16(m, 2H), 2.33 - 2.27(m, 1H), 1.47(s, 9H). 13C NMR(100 MHz, CDCl3) δ 151.30, 150.01, 149.29, 80.54, 80.39, 71.99, 49.14, 48.00, 31.44, 28.38. MS(ESI, m/z) calculated for C14H21N5O2S [M+H]+ 324.1416, found 324.10. 1 H NMR (400 MHz, CDCl 3 ) δ 4.56 (m, 1H), 4.10 (m, 2H), 3.54 (m, 5H), 3.36 (m, 4H), 3.27 - 3.16 (m, 2H), 2.33 - 2.27(m, 1H), 1.47(s, 9H). 13 C NMR (100 MHz, CDCl 3 ) δ 151.30, 150.01, 149.29, 80.54, 80.39, 71.99, 49.14, 48.00, 31.44, 28.38. MS(ESI, m/z) calculated for C 14 H 21 N 5 O 2 S [M+H] + 324.1416, found 324.10.
t -부틸 4-(5-(((1 H -1,2,3-트리아졸-5-일)메틸)아미노)-1,3,4-티아다이아졸-2-일)피페라진-1-카복실레이트(56). 화합물 55(0.1 mmol)를 TMS 아자이드(0.2 mmol), 소듐 아스코르베이트(0.05 mmol) 및 CuI(30 mol%)와 함께 DMF(2 ml) 및 H2O(0.5 mL)에 용해시키고 80 oC에서 15 h 동안 교반하였다. 실온으로 냉각 후, 용매를 진공하에 제거하였다. 잔여물을 실리카겔 컬럼 크로마토그래피(EA/헥산)로 정제하여 56(26%)을 얻었다; t -Butyl 4-(5-(((1H - 1,2,3-triazol-5-yl)methyl)amino)-1,3,4-thiadiazol-2-yl)piperazine-1 -carboxylates (56). Compound 55 (0.1 mmol) was dissolved in DMF (2 ml) and H 2 O (0.5 mL) with TMS azide (0.2 mmol), sodium ascorbate (0.05 mmol) and CuI (30 mol%) and 80 °C C for 15 h. After cooling to room temperature, the solvent was removed under vacuum. The residue was purified by silica gel column chromatography (EA/Hexanes) to give 56 (26%);
1H NMR(400 MHz, CDCl3) δ 7.69(s, 1H), 4.61(s, 2H), 3.52(m, 5H), 3.33(m, 5H), 1.48(s, 1H), 1.47(s, 9H), 1.44(s, 1H), 1.30(s, 1H), 1.25(s, 1H). 13C NMR(100 MHz, CDCl3) δ 164.86, 162.20, 154.59, 142.18, 129.96, 80.48, 49.63, 42.81, 39.87, 28.39. LRMS(ESI, m/z) calculated for C14H22N8O2S [M+H]+ 367.1586, found 367.15. 1 H NMR (400 MHz, CDCl 3 ) δ 7.69 (s, 1H), 4.61 (s, 2H), 3.52 (m, 5H), 3.33 (m, 5H), 1.48 (s, 1H), 1.47 (s, 9H), 1.44(s, 1H), 1.30(s, 1H), 1.25(s, 1H). 13 C NMR (100 MHz, CDCl 3 ) δ 164.86, 162.20, 154.59, 142.18, 129.96, 80.48, 49.63, 42.81, 39.87, 28.39. LRMS (ESI, m/z) calculated for C 14 H 22 N 8 O 2 S [M+H] + 367.1586, found 367.15.
3,5-디클로로벤질 4-(5-(((13,5-Dichlorobenzyl 4-(5-(((1 HH -1,2,3-트리아졸-5-일)메틸)아미노)-1,3,4-티아다이아졸-2-일)피페라진-1-카복실레이트(53b). -1,2,3-triazol-5-yl)methyl)amino)-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (53b).
3,5-디클로로벤질 알코올(0.1 mmol)을 CDI(0.12 mmol)와 함께 실온에서 DMF(2 mL)에 용해시켰다. 5 h 동안 교반한 후, 53(0.1 mmol)을 상기 용액에 첨가하고 추가로 12 h 동안 교반하였다. 용매를 진공하에 제거하였다. 잔여물을 실리카겔 컬럼 크로마토그래피(EA/헥산)로 정제하여 53b(96 %)를 얻었다;3,5-Dichlorobenzyl alcohol (0.1 mmol) was dissolved in DMF (2 mL) along with CDI (0.12 mmol) at room temperature. After stirring for 5 h, 53 (0.1 mmol) was added to the solution and stirred for an additional 12 h. Solvent was removed under vacuum. The residue was purified by silica gel column chromatography (EA/Hexanes) to give 53b (96%);
1H NMR(400 MHz, CDCl3) δ 7.67(s, 1H), 7.31(m, 1H), 7.22(m, 2H), 5.08(s, 2H), 4.61(s, 2H), 3.61(m, 4H), 3.49(s, 1H), 3.37(m, 4H). 13C NMR(100 MHz, CDCl3) δ 164.61, 162.30, 154.63, 142.31, 139.69, 135.18, 130.07, 128.36, 126.25, 65.90, 43.03, 39.92, 29.70. HRMS(ESI, m/z) calculated for C17H18Cl2N8O2S [M+H]+ 469.0650, found 469.0727. 1 H NMR (400 MHz, CDCl 3 ) δ 7.67 (s, 1H), 7.31 (m, 1H), 7.22 (m, 2H), 5.08 (s, 2H), 4.61 (s, 2H), 3.61 (m, 4H), 3.49 (s, 1H), 3.37 (m, 4H). 13 C NMR (100 MHz, CDCl 3 ) δ 164.61, 162.30, 154.63, 142.31, 139.69, 135.18, 130.07, 128.36, 126.25, 65.90, 43.03, 39.92, 29.70. HRMS (ESI, m/z) calculated for C 17 H 18 Cl 2 N 8 O 2 S [M+H] + 469.0650, found 469.0727.
제법 14. 화합물 58의 합성.Preparation 14. Synthesis of Compound 58.
시약 및 조건:(a) 4-(프로-2-핀-1-일옥시)아닐린, AcOH, NaBH(OAc)-3, CH2Cl2, 18 h;(b) CuI, TMS 아자이드, DMF:H2O(9:1), 100 ℃, 5 h.Reagents and conditions: (a) 4-(pro-2-pin-1-yloxy)aniline, AcOH, NaBH(OAc)- 3 , CH 2 Cl 2 , 18 h; (b) CuI, TMS azide, DMF :H 2 O (9:1), 100 °C, 5 h.
3,5-디클로로벤질 4-((4-(프로-2-핀-1-일옥시)페닐)아미노)피페리딘-1-카복실레이트(57). 3,5-dichlorobenzyl 4-((4-(pro-2-pin-1-yloxy)phenyl)amino)piperidine-1-carboxylate (57).
화합물 17(1.0 mmol) 및 4-(2-프로핀-1-일옥시)벤젠아민(1.0 mmol)을 아세트산(1.0 eq) 및 소듐아세톡시보로하이드라이드(1.5 eq)와 함께 실온에서 CH2Cl2(10 mL)에 혼합하였다. 18 h 동안 교반한 후, 유기물을 CH2Cl2로 추출하고 브라인으로 세척하고, 무수 마그네슘 설페이트로 탈수시키고 농축하였다. 잔여물을 실리카겔 컬럼 크로마토그래피(CH2Cl2/MeOH)로 정제하여 57(98%)을 얻었다.Compound 17 (1.0 mmol) and 4-(2-propyn-1-yloxy)benzenamine (1.0 mmol) were dissolved in CH 2 with acetic acid (1.0 eq) and sodium acetoxyborohydride (1.5 eq) at room temperature. Cl 2 (10 mL). After stirring for 18 h, the organics were extracted with CH 2 Cl 2 , washed with brine, dehydrated over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (CH 2 Cl 2 /MeOH) to give 57 (98%).
1H NMR(400 MHz, CDCl3) δ 7.30(m, 1H), 7.23(m, 2H), 6.90 - 6.81(m, 2H), 6.62 - 6.53(m, 2H), 5.07(s, 2H), 4.61(m, 2H), 4.12(m, 3H), 3.38(m 1H), 3.27(s, 1H), 2.49(m, 1H), 2.04(s, 1H), 1.35(s, 1H), 1.34 - 1.22(m, 2H). 13C NMR(100 MHz, CDCl3) δ 154.83, 150.36, 141.70, 140.35, 135.21, 128.26, 126.19, 116.72, 114.88, 79.27, 75.28, 65.62, 60.53, 56.93, 50.92, 14.33; MS(ESI, m/z) calculated for C22H22Cl2N2O3 [M+H]+ 433.1080, found 433.05. 1 H NMR (400 MHz, CDCl 3 ) δ 7.30 (m, 1H), 7.23 (m, 2H), 6.90 - 6.81 (m, 2H), 6.62 - 6.53 (m, 2H), 5.07 (s, 2H), 4.61(m, 2H), 4.12(m, 3H), 3.38(m 1H), 3.27(s, 1H), 2.49(m, 1H), 2.04(s, 1H), 1.35(s, 1H), 1.34 1.22 (m, 2H). 13 C NMR (100 MHz, CDCl 3 ) δ 154.83, 150.36, 141.70, 140.35, 135.21, 128.26, 126.19, 116.72, 114.88, 79.27, 75.28, 65.62, 60.53, 551.93; MS(ESI, m/z) calculated for C 22 H 22 Cl 2 N 2 O 3 [M+H] + 433.1080, found 433.05.
3,5-디클로로벤질 4-((4-((1H-1,2,3-트리아졸-4-일)메톡시)페닐)아미노)피페리딘-1-카복실레이트 (58). 3,5-dichlorobenzyl 4-((4-((1H-1,2,3-triazol-4-yl)methoxy)phenyl)amino)piperidine-1-carboxylate (58).
DMF(4.5 mL) 및 H2O(0.5 mL) 중 57(0.5 mmol) 의 교반되는 용액에 실온에서 TMS 아자이드(0.75 mmol) 및 CuI(0.1 mmol)를 첨가하였다. 100 ℃ 에서 5 h 동안 교반한 후, 용매를 진공하에 제거하였다. 유기물을 CH2Cl2로 추출하고 브라인으로 세척하고, 무수 마그네슘 설페이트로 탈수시키고 진공하에 농축하였다. 잔여물을 실리카겔 컬럼 크로마토그래피(CH2Cl2/MeOH)로 정제하여 58(수율: 39%)을 얻었다;To a stirred solution of 57 (0.5 mmol) in DMF (4.5 mL) and H 2 O (0.5 mL) at room temperature was added TMS azide (0.75 mmol) and CuI (0.1 mmol). After stirring at 100 °C for 5 h, the solvent was removed in vacuo. The organics were extracted with CH 2 Cl 2 , washed with brine, dehydrated over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (CH 2 Cl 2 /MeOH) to give 58 (yield: 39%);
1H NMR(400 MHz, CDCl3) δ 7.75(s, 1H), 7.34 - 7.24(m, 1H), 7.22(m, 2H), 6.89 - 6.80(m, 2H), 6.62 - 6.53(m, 2H), 5.14(s, 2H), 5.10 - 5.05(m, 2H), 4.12(m, 1H), 3.38(m, 1H), 3.01(s, 2H), 2.05(m, 3H), 1.42(s, 1H), 1.40 - 1.22(m, 3H). 13C NMR(100 MHz, CDCl3) δ 154.95, 151.02, 143.93, 141.38, 140.23, 135.20, 131.44, 128.27, 126.18, 116.52, 115.25, 65.72, 62.54, 51.04, 43.14, 32.48. HRMS(ESI, m/z) calculated for C22H24Cl2N5O3 [M+H]+ 476.1251, found 476.1258. 1 H NMR (400 MHz, CDCl 3 ) δ 7.75 (s, 1H), 7.34 - 7.24 (m, 1H), 7.22 (m, 2H), 6.89 - 6.80 (m, 2H), 6.62 - 6.53 (m, 2H) ), 5.14(s, 2H), 5.10 - 5.05(m, 2H), 4.12(m, 1H), 3.38(m, 1H), 3.01(s, 2H), 2.05(m, 3H), 1.42(s, 1H), 1.40 - 1.22 (m, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 154.95, 151.02, 143.93, 141.38, 140.23, 135.20, 131.44, 128.27, 126.18, 116.52, 115.25, 65.72, 63.14, 84.04, 51.72 HRMS (ESI, m/z) calculated for C 22 H 24 Cl 2 N 5 O 3 [M+H] + 476.1251, found 476.1258.
제법 15. 화합물 61 및 64의 합성.Preparation 15. Synthesis of compounds 61 and 64.
시약 및 조건:(a) i: 프로파길 브로마이드, K2CO3, DMF, 1 h; ii: 디옥산 중 4M HCl;(b) NaBH(OAc)3, 아세트산, THF, 18 h;(c) CuI, TMS 아자이드, DMF:H2O(9:1), 100 ℃, 5 h;(d) i: 3-(피페리딘-4-일)페놀, 톨루엔, reflux, 1 h; ii: NaBH-4, EtOH.Reagents and conditions: (a) i: propargyl bromide, K 2 CO 3 , DMF, 1 h; ii: 4M HCl in dioxane; (b) NaBH(OAc) 3 , acetic acid, THF, 18 h; (c) CuI, TMS azide, DMF:H 2 O(9:1), 100° C., 5 h; (d) i: 3-(piperidin-4-yl)phenol, toluene, reflux, 1 h; ii: NaBH- 4 , EtOH.
4-(피페리딘-4-일)-N-(프로-2-핀-1-일)아닐린(59). 4-(piperidin-4-yl)-N-(pro-2-pin-1-yl)aniline (59).
4-(4-아미노페닐)피페리딘-1-카복실산 tert-부틸 에스터(1.0 mmol) 및 프로파길 브로마이드(1.2 mmol)를 K2CO3(3 eq)와 함께 DMF에 용해시켰다. 실온에서 1 h 동안 교반한 후, 용매를 진공하에 제거하였다. 유기물을 에틸아세테이트로 추출하고 브라인으로 세척하고, 무수 마그네슘 설페이트로 탈수시키고 진공하에 농축하였다. 주요 물질을 실리카겔 컬럼 크로마토그래피(에틸아세테이트/헥산)로 분리하고 진공하에 건조시켰다. 잔여물을 디옥산 중 4M HCl(5 mL)에 용해시키고 실온에서 1 h 동안 교반하였다. 용매를 진공하에 제거하여 59(45 %)를 얻었다;4-(4-aminophenyl)piperidine-1-carboxylic acid tert-butyl ester (1.0 mmol) and propargyl bromide (1.2 mmol) were dissolved in DMF with K 2 CO 3 (3 eq). After stirring at room temperature for 1 h, the solvent was removed under vacuum. The organics were extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The main material was isolated by silica gel column chromatography (ethyl acetate/hexane) and dried under vacuum. The residue was dissolved in 4M HCl in dioxane (5 mL) and stirred at room temperature for 1 h. The solvent was removed in vacuo to give 59 (45%);
1H NMR(400 MHz, CDCl3) δ 7.09 - 7.01(m, 2H), 6.69 - 6.61(m, 2H), 3.92(d, J = 2.4 Hz, 2H), 3.82(s, 1H), 2.78 m, 2H), 2.54(m, 1H), 2.21(m, 1H), 1.82 - 1.73(m, 2H), 1.65 - 1.52(m, 2H). 13C NMR(100 MHz, CDCl3) δ 145.40, 136.18, 127.63, 113.75, 79.47, 71.38, 41.93, 33.92, 28.63. LRMS(ESI, m/z) calculated for C14H18N2 [M+H]+ 215.1543, found 214.05 1 H NMR (400 MHz, CDCl 3 ) δ 7.09 - 7.01 (m, 2H), 6.69 - 6.61 (m, 2H), 3.92 (d, J = 2.4 Hz, 2H), 3.82 (s, 1H), 2.78 m , 2H), 2.54 (m, 1H), 2.21 (m, 1H), 1.82 - 1.73 (m, 2H), 1.65 - 1.52 (m, 2H). 13 C NMR (100 MHz, CDCl 3 ) δ 145.40, 136.18, 127.63, 113.75, 79.47, 71.38, 41.93, 33.92, 28.63. LRMS(ESI, m/z) calculated for C 14 H 18 N 2 [M+H] + 215.1543, found 214.05
3,5-디클로로벤질 4-(4-(프로-2-핀-1-일아미노)페닐)-[1,4'-바이피페리딘]-1'-카복실레이트(60).3,5-dichlorobenzyl 4-(4-(pro-2-pin-1-ylamino)phenyl)-[1,4′-bipiperidine]-1′-carboxylate (60).
화합물 17(1.0 mmol) 및 59(1.0 mmol)를 아세트산(1.0 eq) 및 소듐 트리아세톡시보로하이드라이드(1.5 mmol)와 함께 실온에서 THF(10 mL)에 용해시켰다. 18 h 동안 교반한 후, 용매를 진공하에 제거하였다. 유기물을 에틸아세테이트로 추출하고 브라인으로 세척하고, 무수 마그네슘 설페이트로 탈수시키고 진공하에 농축하였다. 잔여물을 실리카겔 컬럼 크로마토그래피(에틸아세테이트/헥산)로 정제하여 60(44%)을 얻었다.Compounds 17 (1.0 mmol) and 59 (1.0 mmol) were dissolved in THF (10 mL) at room temperature along with acetic acid (1.0 eq) and sodium triacetoxyborohydride (1.5 mmol). After stirring for 18 h, the solvent was removed under vacuum. The organics were extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give 60 (44%).
1H NMR(400 MHz, CDCl3) δ 7.30(m, 1H), 7.22(m, 2H), 7.11 - 7.03(m, 2H), 6.68 - 6.60(m, 2H), 5.09 - 5.03(m, 2H), 4.23(s, 2H), 3.91 m, 2H), 3.80(s, 1H), 3.01(m, 2H), 2.82(s, 2H), 2.44(m, 2H), 2.33 - 2.18(m, 3H), 1.85(m, 4H), 1.71(m, 2H), 1.50(m, 1H). 13C NMR(100 MHz, CDCl3) δ 154.76, 145.33, 140.41, 136.35, 135.21, 128.24, 127.68, 126.18, 113.74, 81.29, 71.36, 65.58, 62.14, 43.88, 41.97, 33.94, 33.67. LRMS(ESI, m/z) calculated for C27H31Cl2N3O2 [M+H]+ 500.1866, found 500.25. 1 H NMR (400 MHz, CDCl 3 ) δ 7.30 (m, 1H), 7.22 (m, 2H), 7.11 - 7.03 (m, 2H), 6.68 - 6.60 (m, 2H), 5.09 - 5.03 (m, 2H) ), 4.23(s, 2H), 3.91 m, 2H), 3.80(s, 1H), 3.01(m, 2H), 2.82(s, 2H), 2.44(m, 2H), 2.33 - 2.18(m, 3H) ), 1.85 (m, 4H), 1.71 (m, 2H), 1.50 (m, 1H). 13 C NMR (100 MHz, CDCL 3 ) δ 154.76, 145.33, 140.41, 136.35, 135.21, 128.24, 127.68, 126.18, 113.74, 81.29, 71.36, 65.58, 62.14, 43.88, 41.97, 33.94, 33.67. LRMS (ESI, m/z) calculated for C 27 H 31 Cl 2 N 3 O 2 [M+H] + 500.1866, found 500.25.
3,5-디클로로벤질 4-(4-(((1H-1,2,3-트리아졸-4-일)메틸)아미노)페닐)-[1,4'-바이피페리딘]-1'-카복실레이트(61). 3,5-dichlorobenzyl 4-(4-(((1H-1,2,3-triazol-4-yl)methyl)amino)phenyl)-[1,4′-bipiperidine]-1′ -carboxylates (61).
DMF(2.25 mL) 및 H2O(0.25 mL) 중 화합물 60(0.25 mmol)에 실온에서 TMS 아자이드(0.38 mmol) 및 CuI(0.05 mmol)를 첨가하였다. 100 ℃에서 5 h 동안 교반한 후, 용매를 진공하에 제거하였다. 유기물을 CH2Cl2로 추출하고 브라인으로 세척하고, 무수 마그네슘 설페이트로 탈수시키고 진공하에 농축하였다. 잔여물을 실리카겔 컬럼 크로마토그래피(CH2Cl2/MeOH)로 정제하여 61(13%)을 얻었다;To compound 60 (0.25 mmol) in DMF (2.25 mL) and H 2 O (0.25 mL) at room temperature was added TMS azide (0.38 mmol) and CuI (0.05 mmol). After stirring at 100 °C for 5 h, the solvent was removed under vacuum. The organics were extracted with CH 2 Cl 2 , washed with brine, dehydrated over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (CH 2 Cl 2 /MeOH) to give 61 (13%);
1H NMR(400 MHz, CDCl3) δ 8.12 - 7.47(m, 2H), 7.36 - 7.26(m, 1H), 7.22(m, 2H), 7.01(m, 2H), 6.62(t, J = 8.0 Hz, 2H), 5.11(s, 0H), 5.06 - 5.02(m, 2H), 4.43(s, 2H), 3.61(m, 4H), 3.08(m, 2H), 2.73 - 1.89(m, 4H), 1.82 - 0.66(m, 8H). 13C NMR(100 MHz, CDCl3) δ 154.81, 140.42, 135.21, 128.24, 127.73, 127.57, 126.18, 113.40, 65.59, 63.84, 62.25, 43.96, 42.09, 40.53, 33.98. HRMS(ESI, m/z) calculated for C27H32Cl2N6O2 [M+H]+ 543.2037, found 543.2038. 1 H NMR (400 MHz, CDCl 3 ) δ 8.12 - 7.47 (m, 2H), 7.36 - 7.26 (m, 1H), 7.22 (m, 2H), 7.01 (m, 2H), 6.62 (t, J = 8.0 Hz, 2H), 5.11 (s, 0H), 5.06 - 5.02 (m, 2H), 4.43 (s, 2H), 3.61 (m, 4H), 3.08 (m, 2H), 2.73 - 1.89 (m, 4H) , 1.82 - 0.66 (m, 8H). 13 C NMR (100 MHz, CDCl 3 ) δ 154.81, 140.42, 135.21, 128.24, 127.73, 127.57, 126.18, 113.40, 65.59, 63.84, 62.25, 43.96, 42.09, 43.53. HRMS (ESI, m/z) calculated for C 27 H 32 Cl 2 N 6 O 2 [M+H] + 543.2037, found 543.2038.
3,5-디클로로벤질 4-(3-하이드록시페닐)-[1,4'-바이피페리딘]-1'-카복실레이트(62). 3,5-dichlorobenzyl 4-(3-hydroxyphenyl)-[1,4′-bipiperidine]-1′-carboxylate (62).
3-(피페리딘-4-일)페놀(1.0 mmol) 및 17(1.0 mmol)을 톨루엔(20 ml)에 용해시키고 1 h 동안 환류시켰다. 용매를 진공하에 제거하고 잔여물을 실온에서 소듐 보로하이드라이드(1.2 mmol)와 함께 EtOH(5 mL)에 용해시키고 밤새 교반하였다. 용매를 진공하에 제거한 후, 유기물을 에틸아세테이트로 추출하고 브라인으로 세척하고, 무수 마그네슘 설페이트로 탈수시키고 진공하에 농축하였다. 잔여물을 실리카겔 컬럼 크로마토그래피(EA/헥산)로 정제하여 62(62%)를 얻었다.3-(piperidin-4-yl)phenol (1.0 mmol) and 17 (1.0 mmol) were dissolved in toluene (20 ml) and refluxed for 1 h. The solvent was removed in vacuo and the residue was dissolved in EtOH (5 mL) with sodium borohydride (1.2 mmol) at room temperature and stirred overnight. After removing the solvent in vacuo, the organics were extracted with ethyl acetate, washed with brine, dehydrated with anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (EA/Hexanes) to give 62 (62%).
1H NMR(400 MHz, CDCl3) δ 7.30(m, 1H), 7.22(m, 2H), 7.13(m, 1H), 6.71 m, 1H), 6.64(m, 1H), 6.59(m, 1H), 5.05(m, 2H), 4.23(s, 2H), 3.07 - 2.98(m, 2H), 2.79(s, 2H), 2.50(m, 1H), 2.37 m, 1H), 2.34 - 2.23(m, 2H), 1.88(m, 2H), 1.70(m, 4H), 1.53(m, 1H), 1.47(m, 1H). 13C NMR(100 MHz, CDCl3) δ 156.46, 154.78, 148.02, 140.33, 135.21, 129.69, 128.26, 126.19, 119.27, 113.74, 113.71, 65.65, 62.36, 43.90, 42.99, 33.35. LRMS(ESI, m/z) calculated for C24H28Cl2N2O3 [M+H]+ 463.1550, found 463.25. 1 H NMR (400 MHz, CDCl 3 ) δ 7.30 (m, 1H), 7.22 (m, 2H), 7.13 (m, 1H), 6.71 m, 1H), 6.64 (m, 1H), 6.59 (m, 1H) ), 5.05(m, 2H), 4.23(s, 2H), 3.07 - 2.98(m, 2H), 2.79(s, 2H), 2.50(m, 1H), 2.37 m, 1H), 2.34 - 2.23(m) , 2H), 1.88 (m, 2H), 1.70 (m, 4H), 1.53 (m, 1H), 1.47 (m, 1H). 13 C NMR (100 MHz, CDCl 3 ) δ 156.46, 154.78, 148.02, 140.33, 135.21, 129.69, 128.26, 126.19, 119.27, 113.74, 113.71, 65.65, 62.39, 5.4.39, 5.4.39, 43.39 LRMS(ESI, m/z) calculated for C 24 H 28 C l2 N 2 O 3 [M+H] + 463.1550, found 463.25.
3,5-디클로로벤질 4-(3-(프로-2-핀-1-일옥시)페닐)-[1,4'-바이피페리딘]-1'-카복실레이트(63). 3,5-dichlorobenzyl 4-(3-(pro-2-pin-1-yloxy)phenyl)-[1,4′-bipiperidine]-1′-carboxylate (63).
화합물 62(0.5 mmol), 프로파길 브로마이드(0.6 mmol), 및 K2CO3(0.6 mmol)를 DMF에 첨가하고 12 h 동안 교반하였다. 용매를 진공하에 제거한 후, 유기물을 에틸아세테이트로 추출하고 브라인으로 세척하고, 무수 마그네슘 설페이트로 탈수시키고 진공하에 농축하였다. 잔여물을 실리카겔 컬럼 크로마토그래피(에틸아세테이트/헥산)로 정제하여 63(58%)을 얻었다;Compound 62 (0.5 mmol), propargyl bromide (0.6 mmol), and K 2 CO 3 (0.6 mmol) were added to DMF and stirred for 12 h. After removing the solvent in vacuo, the organics were extracted with ethyl acetate, washed with brine, dehydrated with anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give 63 (58%);
1H NMR(400 MHz, CDCl3) δ 7.30(m, 1H), 7.26 - 7.18(m, 3H), 6.90 - 6.78(m, 3H), 5.06(m, 2H), 4.67(m, 2H), 4.23(s, 1H), 4.12(m, 1H), 3.02(m 2H), 2.82(m, 0H), 2.50 - 2.41(m, 2H), 2.30(m, 2H), 2.04(s, 1H), 1.91 - 1.67(m, 8H), 1.50(m, 2H); 13C NMR(100 MHz, CDCl3) δ 157.68, 154.66, 148.12, 140.34, 135.09, 129.37, 128.10, 126.05, 120.21, 113.69, 112.28, 78.71, 77.24, 75.44, 65.43, 62.10, 60.41, 55.71, 43.84, 43.04, 33.75; MS(ESI, m/z) calculated for C27H30Cl2N2O3 [M+H]+ 501.1706, found 501.30. 1 H NMR (400 MHz, CDCl 3 ) δ 7.30 (m, 1H), 7.26 - 7.18 (m, 3H), 6.90 - 6.78 (m, 3H), 5.06 (m, 2H), 4.67 (m, 2H), 4.23(s, 1H), 4.12(m, 1H), 3.02(m 2H), 2.82(m, 0H), 2.50 - 2.41(m, 2H), 2.30(m, 2H), 2.04(s, 1H), 1.91 - 1.67 (m, 8H), 1.50 (m, 2H); 13 C NMR (100 MHz, CDCL 3 ) δ 157.68, 154.66, 148.12, 140.34, 135.09, 129.37, 128.10, 126.05, 120.21, 113.69, 112.28, 78.71, 77.44, 75.44 , 33.75; MS(ESI, m/z) calculated for C 27 H 30 Cl 2 N 2 O 3 [M+H] + 501.1706, found 501.30.
3,5-디클로로벤질 4-(3-((1H-1,2,3-트리아졸-5-일)메톡시)페닐)-[1,4'-바이피페리딘]-1'-카복실레이트(64). 3,5-dichlorobenzyl 4-(3-((1H-1,2,3-triazol-5-yl)methoxy)phenyl)-[1,4'-bipiperidine]-1'-carboxyl Rate (64).
DMF(2.25 mL) 및 H2O(0.25 mL) 중 화합물 63(0.25 mmol)에 실온에서 TMS 아자이드(0.38 mmol) 및 CuI(0.05 mmol)를 첨가하였다. 100 ℃에서 5 h 동안 교반한 후, 용매를 진공하에 제거하였다. 유기물을 CH2Cl2로 추출하고 브라인으로 세척하고, 무수 마그네슘 설페이트로 탈수시키고 진공하에 농축하였다. 잔여물을 실리카겔 컬럼 크로마토그래피(CH2Cl2/MeOH)로 정제하여 64(32%)를 얻었다;To compound 63 (0.25 mmol) in DMF (2.25 mL) and H 2 O (0.25 mL) at room temperature was added TMS azide (0.38 mmol) and CuI (0.05 mmol). After stirring at 100 °C for 5 h, the solvent was removed under vacuum. The organics were extracted with CH 2 Cl 2 , washed with brine, dehydrated over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (CH 2 Cl 2 /MeOH) to give 64 (32%);
1H NMR(400 MHz, CDCl3) δ 7.77(s, 1H), 7.30(m, 2H), 7.21 - 7.08(m, 1H), 6.93(m, 1H), 6.82(m, 3H), 5.18(s, 2H), 5.07(s, 3H), 4.28(s, 3H), 3.13(m, 2H), 2.96(s, 1H), 2.89(m, 1H), 2.77 - 2.65(m, 1H), 2.60 - 2.49(m, 1H), 2.00(m, 5H), 1.59(m, 3H). 13C NMR(100 MHz, CDCl3) δ 158.73, 154.77, 147.73, 143.71, 140.30, 135.22, 132.08, 129.56, 128.27, 126.20, 120.49, 113.53, 112.26, 77.36, 65.68, 62.38, 61.67, 43.85, 42.85, 36.69, 33.02. HRMS(ESI, m/z) calculated for C27H31Cl2N5O3 [M+H]+ 544.1877, found 544.1881. 1 H NMR (400 MHz, CDCl 3 ) δ 7.77 (s, 1H), 7.30 (m, 2H), 7.21 - 7.08 (m, 1H), 6.93 (m, 1H), 6.82 (m, 3H), 5.18 ( s, 2H), 5.07(s, 3H), 4.28(s, 3H), 3.13(m, 2H), 2.96(s, 1H), 2.89(m, 1H), 2.77 - 2.65(m, 1H), 2.60 - 2.49(m, 1H), 2.00(m, 5H), 1.59(m, 3H). 13 C NMR (100 MHz, CDCL 3 ) Δ 158.73, 154.77, 147.73, 143.71, 140.30, 135.22, 132.08, 129.56, 128.27, 126.20, 120.49, 113.53, 112.26 , 33.02. HRMS (ESI, m/z) calculated for C 27 H 31 Cl 2 N 5 O 3 [M+H] + 544.1877, found 544.1881.
제법 16. 화합물 65의 합성.Preparation 16. Synthesis of compound 65.
시약 및 조건: i: 클로로아세틸 클로라이드, TEA, 1 drop of DMF, CH2Cl2, cool, 1h; ii: 1-(3,5-디클로로-벤질) 피페라진, TEA, DMF, 120 ℃, 3 h.Reagents and conditions: i: chloroacetyl chloride, TEA, 1 drop of DMF, CH 2 Cl 2 , cool, 1h; ii: 1-(3,5-dichloro-benzyl) piperazine, TEA, DMF, 120° C., 3 h.
1-(4-(11-(4-(1 HH -이미다졸-5-일)피페리딘-1-일)-2-(4-(3,5-디클로로벤질)피페라진-1-일)에탄-1-온(65). -imidazol-5-yl)piperidin-1-yl)-2-(4-(3,5-dichlorobenzyl)piperazin-1-yl)ethan-1-one (65).
4-(1H-이미다졸-5-일)피페리딘(1 mmol) 및 TEA(1 mmol)을 CH2Cl2(10 mL)에 용해시켰다. 클로로아세틸 클로라이드(3 mmol)를 반응 혼합물에 첨가하였다. 얻어진 용액을 1 h 동안 교반하였다. 반응 완결 후, 용매를 진공하에 제거하였다. 잔여물을 DMF에 용해시키고 DMF 중 TEA(2 mmol) 및 1-(3,5-디클로로-벤질) 피페라진(1.1 mmol)을 첨가하였다. 반응 혼합물을 75 ℃에서 2h 동안 교반하였다. 용매를 진공하에 제거하고 크루드 혼합물을 에틸아세테이트로 추출하고 브라인으로 세척하였다. 유기층을 무수 소듐 설페이트로 탈수시키고 농축시켰다. 생성물을 컬럼 크로마토그래피(CH2Cl2/MeOH)로 정제하여 목적 화합물을 흰색 고체(65%)로 얻었다;4-(1 H -imidazol-5-yl)piperidine (1 mmol) and TEA (1 mmol) were dissolved in CH 2 Cl 2 (10 mL). Chloroacetyl chloride (3 mmol) was added to the reaction mixture. The resulting solution was stirred for 1 h. After completion of the reaction, the solvent was removed under vacuum. The residue was dissolved in DMF and TEA (2 mmol) and 1-(3,5-dichloro-benzyl) piperazine (1.1 mmol) in DMF were added. The reaction mixture was stirred at 75 °C for 2 h. The solvent was removed in vacuo and the crude mixture was extracted with ethyl acetate and washed with brine. The organic layer was dehydrated with anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (CH 2 Cl 2 /MeOH) to obtain the desired compound as a white solid (65%);
1H NMR(400 MHz, MeOD-d 4) δ 7.59(s, 1H), 7.37 - 7.31(m, 3H), 6.80(s, 1H), 3.65(t, J = 5.1 Hz, 2H), 3.61(t, J = 5.2 Hz, 2H), 3.56 - 3.52(m, 2H), 3.34(s, 2H), 3.07 - 2.97(m, 2H), 2.61(ddd, J = 11.8, 8.0, 4.1 Hz, 1H), 2.49(t, J = 5.1 Hz, 2H), 2.44(t, J = 5.1 Hz, 2H), 2.29(t, J = 11.6 Hz, 2H), 1.97(d, J = 12.8 Hz, 2H), 1.73(qd, J = 12.3, 3.7 Hz, 2H); MS(ESI, m/z) calculated for C21H28Cl2N5O [M+H]+ 436.38, found 436.10. 1H NMR (400 MHz, MeOD- d 4 ) δ 7.59 (s, 1H), 7.37 - 7.31 (m, 3H), 6.80 (s, 1H), 3.65 (t, J = 5.1 Hz, 2H), 3.61 ( t, J = 5.2 Hz, 2H), 3.56 - 3.52 (m, 2H), 3.34 (s, 2H), 3.07 - 2.97 (m, 2H), 2.61 (ddd, J = 11.8, 8.0, 4.1 Hz, 1H) , 2.49 (t, J = 5.1 Hz, 2H), 2.44 (t, J = 5.1 Hz, 2H), 2.29 (t, J = 11.6 Hz, 2H), 1.97 (d, J = 12.8 Hz, 2H), 1.73 (qd, J = 12.3, 3.7 Hz, 2H); MS(ESI, m/z) calculated for C 21 H 28 Cl 2 N 5 O [M+H] + 436.38, found 436.10.
[실험예 1] 인간 오토탁신의 저해 활성 평가[Experimental Example 1] Evaluation of human autotaxin inhibitory activity
(1) 실험 방법(1) Experiment method
각 화합물 용액 (80 uM, 100% 디메틸설폭사이드)을 디메틸설폭사이드를 이용해 차례로 5배씩 희석하여 6개 농도를 만들었다. 각 농도의 화합물을 1x 시험 완충액 (50 mM Tris-Cl (pH 8.0), 5 mM KCl, 1 mM CaCl2, 1 mM MgCl2, 140 mM NaCl, 3차 증류수, 1 mg/mL BSA)으로 2배씩 희석하고, 96 well clear round bottom plate에 1 uL (1.25% 디메틸설폭사이드)를 분주하였다. 1x 시험 완충액을 9 uL 첨가하고, 240 nM의 인간 오토탁신 단백질 (완충액: 50 mM Tris-HCl, pH 8.0, with 150 mM sodium chloride and 20% glycerol) 20 uL를 첨가하였다. 초음파 처리된 360 uM 18:1 LysoPC (1x 시험 완충액으로 희석) 10 uL를 첨가하였다. 37 ℃ shaking incubator에서 2시간 동안 반응 시키고, 2차 반응 혼합물 (choline assay kit, KA1662) (1x 시험 완충액 65 uL: choline oxidase 1 uL: dye probe 1 uL)을 준비하였다. 반응을 진행한 plate에 2차 반응 혼합물 60 uL를 넣고 shaker에서 30분간 반응시켰다. SpectraMax iD3 microplate reader를 이용해, 570 nm 파장에서 흡광값을 측정하였다. (1 - 흡광값시험군/흡광값대조군) X 100의 계산식으로 저해 활성 백분율값 (% inhibition)을 계산하였다.Each compound solution (80 uM, 100% dimethyl sulfoxide) was serially diluted 5-fold with dimethyl sulfoxide to make 6 concentrations. Compounds at each concentration were diluted in duplicate with 1x test buffer (50 mM Tris-Cl (pH 8.0), 5 mM KCl, 1 mM CaCl 2 , 1 mM MgCl 2 , 140 mM NaCl, 3-distilled water, 1 mg/mL BSA). After dilution, 1 uL (1.25% dimethyl sulfoxide) was dispensed into a 96 well clear round bottom plate. 9 uL of 1x test buffer was added, and 20 uL of 240 nM human autotaxin protein (buffer: 50 mM Tris-HCl, pH 8.0, with 150 mM sodium chloride and 20% glycerol) was added. Add 10 uL of sonicated 360 uM 18:1 LysoPC (diluted in 1x test buffer). The reaction was performed in a 37° C. shaking incubator for 2 hours, and a secondary reaction mixture (choline assay kit, KA1662) (1x test buffer 65 uL: choline oxidase 1 uL: dye probe 1 uL) was prepared. 60 uL of the secondary reaction mixture was added to the reaction plate and reacted for 30 minutes on a shaker. Absorbance values were measured at a wavelength of 570 nm using a SpectraMax iD3 microplate reader. The percent inhibition (% inhibition) was calculated using the formula of (1 - absorbance value test group /absorbance value control group ) X 100.
(2) 결과(2) Results
실시예 화합물들에 대하여 500 nM 농도에서 측정된 오토탁신 저해 활성 백분율값 (% inhibition)을 하기 표2에 나타내었다.The percentage value (% inhibition) of autotaxin inhibitory activity measured at a concentration of 500 nM for the Example compounds is shown in Table 2 below.
Claims (18)
[화학식 1]
여기서,
Y는 또는 이고;
R1 및 R2는 각각 독립적으로, 할로젠, C1-5 알킬, C3-6 사이클로알킬, C1-5 알킬옥시, C6-10 아릴 및 하나 이상의 할로젠으로 치환된 C1-5 알킬로 이루어진 군으로부터 선택되며;
X는 O, -CH2-, NH 및 로 이루어진 군으로부터 선택되고;
A는 또는 이며;
L1 및 L2는 각각 독립적으로 존재하지 않거나, , , , , , , , , , 및 로 이루어진 군으로부터 선택되고;
B는 존재하지 않거나, , , 및 로 이루어진 군으로부터 선택되고;
C는 N, O 및 S로 이루어진 군으로부터 선택되는 둘 이상의 헤테로 원자를 포함하는 5 내지 6원환의 포화 또는 불포화된 헤테로사이클릴 또는 5 내지 6원환의 헤테로아릴이고;
상기 헤테로사이클릴 또는 헤테로아릴은 하나 이상의 아민, 옥소, C1-5 알킬, C1-5 알킬옥시 및 하나 이상의 할로젠으로 치환된 C1-5 알킬로 이루어진 군으로부터 선택되는 치환기로 추가로 치환되거나 치환되지 않으며;
l, m 및 n은 각각 독립적으로 1 내지 3의 정수이고,
단, B가 존재하지 않을 경우, L1은 이고, L2는 이다.A compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
[Formula 1]
here,
Y is or ego;
R 1 and R 2 are each independently halogen, C 1-5 alkyl, C 3-6 cycloalkyl, C 1-5 alkyloxy, C 6-10 aryl and C 1-5 substituted with one or more halogens. is selected from the group consisting of alkyl;
X is O, -CH 2 -, NH and It is selected from the group consisting of;
A is or is;
L 1 and L 2 do not exist independently of each other; , , , , , , , , , and It is selected from the group consisting of;
B does not exist, or , , and It is selected from the group consisting of;
C is a 5- to 6-membered saturated or unsaturated heterocyclyl containing at least two heteroatoms selected from the group consisting of N, O and S or a 5- to 6-membered heteroaryl;
wherein said heterocyclyl or heteroaryl is further substituted with a substituent selected from the group consisting of one or more amines, oxo, C 1-5 alkyl, C 1-5 alkyloxy and C 1-5 alkyl substituted with one or more halogens; is not substituted or substituted;
l, m and n are each independently an integer from 1 to 3;
However, if B does not exist, L 1 is and L 2 is am.
Y는 이고;
R1 및 R2는 각각 독립적으로, H, 할로젠, C1-5 알킬, C1-5 알콕시 및 하나 이상의 할로젠으로 치환된 C1-5 알킬로 이루어진 군으로부터 선택되는 화합물, 이의 광학 이성질체 또는 이의 약제학적으로 허용 가능한 염.According to claim 1,
Y is ego;
R 1 and R 2 are each independently a compound selected from the group consisting of H, halogen, C 1-5 alkyl, C 1-5 alkoxy and C 1-5 alkyl substituted with one or more halogens, optical isomers thereof or a pharmaceutically acceptable salt thereof.
Y는 이고;
R1 및 R2는 각각 독립적으로, H, 할로젠, C1-5 알킬, C1-5 알콕시 및 하나 이상의 할로젠으로 치환된 C1-5 알킬로 이루어진 군으로부터 선택되는 화합물, 이의 광학 이성질체 또는 이의 약제학적으로 허용 가능한 염.According to claim 4,
Y is ego;
R 1 and R 2 are each independently a compound selected from the group consisting of H, halogen, C 1-5 alkyl, C 1-5 alkoxy, and C 1-5 alkyl substituted with one or more halogens, optical isomers thereof or a pharmaceutically acceptable salt thereof.
C는 N, O 및 S로 이루어진 군으로부터 선택되는 둘 이상의 헤테로 원자를 포함하는 5원환의 포화 또는 불포화된 헤테로사이클릴 또는 5원환의 헤테로아릴이고,
상기 헤테로사이클릴 또는 헤테로아릴은 C1-5 알킬 또는 아민기로 추가로 치환되거나 치환되지 않는 화합물, 이의 광학 이성질체 또는 이의 약제학적으로 허용 가능한 염.According to claim 1,
C is a 5-membered saturated or unsaturated heterocyclyl or 5-membered heteroaryl containing at least two heteroatoms selected from the group consisting of N, O and S;
The heterocyclyl or heteroaryl may or may not be further substituted with a C 1-5 alkyl or amine group, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
C는 , , , 및 로 이루어진 군으로부터 선택된 작용기(functional group)이고,
상기 작용기는 아미노 또는 C1-5 알킬로 추가로 치환되거나 치환되지 않는 화합물, 이의 광학 이성질체 또는 이의 약제학적으로 허용 가능한 염.According to claim 6,
C is , , , and A functional group selected from the group consisting of
The functional group may or may not be further substituted with amino or C 1-5 alkyl, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
L1은 존재하지 않고,
B는 또는 이며,
L2는 및 로 이루어진 군으로부터 선택되고,
l 및 m은 각각 독립적으로 1 또는 2인 화합물, 이의 광학 이성질체 또는 이의 약제학적으로 허용 가능한 염.According to claim 1,
L 1 does not exist,
B is or is,
L2 is and It is selected from the group consisting of
1 and m are each independently 1 or 2, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
Y는 이고;
R1 및 R2는 각각 독립적으로 할로젠 및 C1-5 알킬로 이루어진 군으로부터 선택되고;
n은 1이며;
X는 O이고;
A는 또는 이며;
L1은 존재하지 않고,
B는 이며,
L2는 및 로 이루어진 군으로부터 선택되고,
l 및 m은 각각 독립적으로 1 또는 2인 화합물, 이의 광학 이성질체 또는 이의 약제학적으로 허용 가능한 염.According to claim 1,
Y is ego;
R 1 and R 2 are each independently selected from the group consisting of halogen and C 1-5 alkyl;
n is 1;
X is O;
A is or is;
L 1 does not exist,
B is is,
L2 is and It is selected from the group consisting of
1 and m are each independently 1 or 2, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
18a : 3,5-디클로로벤질 4-((4-(2-아미노티아졸-5-일)페닐)아미노)피페리딘-1-카복실레이트
18b : 3,5-디클로로벤질 4-((3-(2-아미노티아졸-5-일)페닐)아미노)피페리딘-1-카복실레이트
18c : 3,5-디클로로벤질 4-((4-(1-메틸-1H-이미다졸-5-일)페닐)아미노)피페리딘-1-카복실레이트
18d : 3,5-디클로로벤질 4-((3-(1-메틸-1H-이미다졸-5-일)페닐)아미노)피페리딘-1-카복실레이트
18e : 3,5-디클로로벤질 4-((4-(1H-이미다졸-5-일)페닐)아미노)피페리딘-1-카복실레이트
18f : 3,5-디클로로벤질 4-((3-(1H-이미다졸-5-일)페닐)아미노)피페리딘-1-카복실레이트
18g : 3,5-디클로로벤질 4-((4-(2-메틸-1H-이미다졸-5-일)페닐)아미노)피페리딘-1-카복실레이트
18h : 3,5-디클로로벤질 4-((3-(2-메틸-1H-이미다졸-5-일)페닐)아미노)피페리딘-1-카복실레이트
18i : 3,5-디클로로벤질 4-((4-(4-메틸-1H-이미다졸-5-일)페닐)아미노)피페리딘-1-카복실레이트
18j : 3,5-디클로로벤질 4-((3-(4-메틸-1H-이미다졸-5-일)페닐)아미노)피페리딘-1-카복실레이트
18k : 3,5-디클로로벤질 4-((4-(5-옥소-4,5-디하이드로-1,3,4-옥사다이아졸-2-일)페닐)아미노)피페리딘-1-카복실레이트
18l : 3,5-디클로로벤질 4-((3-(5-옥소-4,5-디하이드로-1,3,4-옥사다이아졸-2-일)페닐)아미노)피페리딘-1-카복실레이트
18m : 3,5-디클로로벤질 4-((3-(2-메틸옥사졸-5-일)페닐)아미노)피페리딘-1-카복실레이트
18n : 3,5-디클로로벤질 4-((3-(1H-1,2,3-트리아졸-5-일)페닐)아미노)피페리딘-1-카복실레이트
27a : 3,5-디클로로벤질 4-((4-(2-아미노티아졸-5-일)페닐)카바모일)피페리딘-1-카복실레이트
27b : 3,5-디클로로벤질 4-((3-(2-아미노티아졸-5-일)페닐)카바모일)피페리딘-1-카복실레이트
27c : 3,5-디클로로벤질 4-((4-(1H-이미다졸-5-일)페닐)카바모일)피페리딘-1-카복실레이트
27d : 3,5-디클로로벤질 4-((3-(1H-이미다졸-5-일)페닐)카바모일)피페리딘-1-카복실레이트
27e : 3,5-디클로로벤질 4-(4-(1H-이미다졸-5-일)피페리딘-1-카보닐)피페리딘-1-카복실레이트
27f : 3,5-디클로로벤질 4-(4-(1H-1,2,3-트리아졸-5-일)피페리딘-1-카보닐)피페리딘-1-카복실레이트
27g : 3,5-디클로로벤질 4-(4-(5-옥소-4,5-디하이드로-1,3,4-옥사다이아졸-2-일)피페리딘-1-카보닐)피페리딘-1-카복실레이트
27h : 3,5-디클로로벤질 4-((4-(5-옥소-4,5-디하이드로-1,3,4-옥사다이아졸-2-일)페닐)카바모일)피페리딘-1-카복실레이트
27i : 3,5-디클로로벤질 4-((3-(5-옥소-4,5-디하이드로-1,3,4-옥사다이아졸-2-일)페닐)카바모일)피페리딘-1-카복실레이트
33d : 3,5-디클로로벤질 4-(2-(4-(1H-이미다졸-5-일)페녹시)에틸)피페리딘-1-카복실레이트
33e : 3,5-디클로로벤질 4-((4-(1H-이미다졸-5-일)페녹시)메틸)피페리딘-1-카복실레이트
33f : 3,5-디클로로벤질 4-(4-(1H-이미다졸-5-일)페녹시)피페리딘-1-카복실레이트
33g : 3,5-디클로로벤질 4-((3-(1H-이미다졸-5-일)페녹시)메틸)피페리딘-1-카복실레이트
33h : 3,5-디클로로벤질 4-(3-(1H-이미다졸-5-일)페녹시)피페리딘-1-카복실레이트
33i : 3,5-디클로로벤질 4-((3-(2-메틸-1H-이미다졸-5-일)페녹시)메틸)피페리딘-1-카복실레이트
33k : 3,5-디클로로벤질 4-(((4-(2-아미노티아졸-5-일)페닐)아미노)메틸)피페리딘-1-카복실레이트
33l : 3,5-디클로로벤질 4-(((3-(2-아미노티아졸-5-일)페닐)아미노)메틸)피페리딘-1-카복실레이트
33m : 3,5-디클로로벤질 4-(((4-(1H-이미다졸-5-일)페닐)아미노)메틸)피페리딘-1-카복실레이트
33n : 3,5-디클로로벤질 4-(((3-(1H-이미다졸-5-일)페닐)아미노)메틸)피페리딘-1-카복실레이트
33o : 3,5-디클로로벤질 4-(((4-(5-옥소-4,5-디하이드로-1,3,4-옥사다이아졸-2-일)페닐)아미노)메틸)피페리딘-1-카복실레이트
33p : 3,5-디클로로벤질 4-(((3-(5-옥소-4,5-디하이드로-1,3,4-옥사다이아졸-2-일)페닐)아미노)메틸)피페리딘-1-카복실레이트
44a : 3,5-디클로로벤질 4-(5-(((1H-1,2,3-트리아졸-5-일)메틸)아미노)-1,3,4-옥사다이아졸-2-일)피페리딘-1-카복실레이트
44b : 3,5-디브로모벤질 4-(5-(((1H-1,2,3-트리아졸-5-일)메틸)아미노)-1,3,4-옥사다이아졸-2-일)피페리딘-1-카복실레이트
44c : 3,5-비스(트리플루오로메틸)벤질 4-(5-(((1H-1,2,3-트리아졸-5-일)메틸)아미노)-1,3,4-옥사다이아졸-2-일)피페리딘-1-카복실레이트
44d : 3,5-디메틸벤질 4-(5-(((1H-1,2,3-트리아졸-5-일)메틸)아미노)-1,3,4-옥사다이아졸-2-일)피페리딘-1-카복실레이트
44e : 3,5-디메톡시벤질 4-(5-(((1H-1,2,3-트리아졸-5-일)메틸)아미노)-1,3,4-옥사다이아졸-2-일)피페리딘-1-카복실레이트
44f : 3,5-디플루오로벤질 4-(5-(((1H-1,2,3-트리아졸-5-일)메틸)아미노)-1,3,4-옥사다이아졸-2-일)피페리딘-1-카복실레이트
44g : 3-브로모-5-메틸벤질 4-(5-(((1H-1,2,3-트리아졸-5-일)메틸)아미노)-1,3,4-옥사다이아졸-2-일)피페리딘-1-카복실레이트
44h : 3-브로모-5-클로로벤질 4-(5-(((1H-1,2,3-트리아졸-5-일)메틸)아미노)-1,3,4-옥사다이아졸-2-일)피페리딘-1-카복실레이트
44i : 3-클로로-5-플루오로벤질 4-(5-(((1H-1,2,3-트리아졸-5-일)메틸)아미노)-1,3,4-옥사다이아졸-2-일)피페리딘-1-카복실레이트
44j : 2,5-디클로로벤질 4-(5-(((1H-1,2,3-트리아졸-5-일)메틸)아미노)-1,3,4-옥사다이아졸-2-일)피페리딘-1-카복실레이트
44k : 3,4-디클로로벤질 4-(5-(((1H-1,2,3-트리아졸-5-일)메틸)아미노)-1,3,4-옥사다이아졸-2-일)피페리딘-1-카복실레이트
44l : 벤조[d][1,3]디옥솔-5-일메틸 4-(5-(((1H-1,2,3-트리아졸-5-일)메틸)아미노)-1,3,4-옥사다이아졸-2-일)피페리딘-1-카복실레이트
44m : 1-(4-(5-(((1H-1,2,3-트리아졸-5-일)메틸)아미노)-1,3,4-옥사다이아졸-2-일)피페리딘-1-일)-3-(3,5-디클로로페닐)프로판-1-온
44n : 4-(5-(((1H-1,2,3-트리아졸-5-일)메틸)아미노)-1,3,4-옥사다이아졸-2-일)-N-(3,5-디클로로벤질)피페리딘-1-카복사미드
47a : 3,5-디클로로벤질 4-(5-(((1H-테트라졸-5-일)메틸)아미노)-1,3,4-옥사다이아졸-2-일)피페리딘-1-카복실레이트
47b : 3,5-디클로로벤질 4-(5-(((1-메틸-1H-1,2,3-트리아졸-4-일)메틸)아미노)-1,3,4-옥사다이아졸-2-일)피페리딘-1-카복실레이트
47c : 3,5-디클로로벤질 4-(5-(((4-메틸-1H-1,2,3-트리아졸-5-일)메틸)아미노)-1,3,4-옥사다이아졸-2-일)피페리딘-1-카복실레이트
50a : 3,5-디클로로벤질 4-(5-(2-(1H-1,2,3-트리아졸-5-일)에틸)-1,3,4-티아다이아졸-2-일)피페라진-1-카복실레이트
50b : 3,5-디클로로벤질 4-(5-(2-(1H-1,2,3-트리아졸-5-일)에틸)-1,3,4-옥사다이아졸-2-일)피페라진-1-카복실레이트
50c : 3,5-디클로로벤질 4-(5-(2-(1H-1,2,3-트리아졸-5-일)에틸)-1,3,4-옥사다이아졸-2-일)피페리딘-1-카복실레이트
53a : 3,5-디클로로벤질 4-(2-(((1H-1,2,3-트리아졸-5-일)메틸)아미노)티아졸-5-일)피페라진-1-카복실레이트
53b : 3,5-디클로로벤질 4-(5-(((1H-1,2,3-트리아졸-5-일)메틸)아미노)-1,3,4-티아다이아졸-2-일)피페라진-1-카복실레이트
58 : 3,5-디클로로벤질 4-((4-((1H-1,2,3-트리아졸-4-일)메톡시)페닐)아미노)피페리딘-1-카복실레이트
61 : 3,5-디클로로벤질 4-(4-(((1H-1,2,3-트리아졸-4-일)메틸)아미노)페닐)-[1,4'-바이피페리딘]-1'-카복실레이트 및
64 : 3,5-디클로로벤질 4-(3-((1H-1,2,3-트리아졸-5-일)메톡시)페닐)-[1,4'-바이피페리딘]-1'-카복실레이트.The method of claim 1, wherein the compound represented by Formula 1 is any one compound selected from the group consisting of the following compounds, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
18a: 3,5-dichlorobenzyl 4-((4-(2-aminothiazol-5-yl)phenyl)amino)piperidine-1-carboxylate
18b: 3,5-dichlorobenzyl 4-((3-(2-aminothiazol-5-yl)phenyl)amino)piperidine-1-carboxylate
18c: 3,5-dichlorobenzyl 4-((4-(1-methyl-1H-imidazol-5-yl)phenyl)amino)piperidine-1-carboxylate
18d: 3,5-Dichlorobenzyl 4-((3-(1-methyl-1H-imidazol-5-yl)phenyl)amino)piperidine-1-carboxylate
18e: 3,5-dichlorobenzyl 4-((4-(1H-imidazol-5-yl)phenyl)amino)piperidine-1-carboxylate
18f: 3,5-dichlorobenzyl 4-((3-(1H-imidazol-5-yl)phenyl)amino)piperidine-1-carboxylate
18g: 3,5-dichlorobenzyl 4-((4-(2-methyl-1H-imidazol-5-yl)phenyl)amino)piperidine-1-carboxylate
18h: 3,5-dichlorobenzyl 4-((3-(2-methyl-1H-imidazol-5-yl)phenyl)amino)piperidine-1-carboxylate
18i: 3,5-dichlorobenzyl 4-((4-(4-methyl-1H-imidazol-5-yl)phenyl)amino)piperidine-1-carboxylate
18j: 3,5-dichlorobenzyl 4-((3-(4-methyl-1H-imidazol-5-yl)phenyl)amino)piperidine-1-carboxylate
18k: 3,5-dichlorobenzyl 4-((4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)amino)piperidin-1- carboxylate
18l: 3,5-dichlorobenzyl 4-((3-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)amino)piperidin-1- carboxylate
18m: 3,5-dichlorobenzyl 4-((3-(2-methyloxazol-5-yl)phenyl)amino)piperidine-1-carboxylate
18n: 3,5-dichlorobenzyl 4-((3-(1H-1,2,3-triazol-5-yl)phenyl)amino)piperidine-1-carboxylate
27a: 3,5-dichlorobenzyl 4-((4-(2-aminothiazol-5-yl)phenyl)carbamoyl)piperidine-1-carboxylate
27b: 3,5-dichlorobenzyl 4-((3-(2-aminothiazol-5-yl)phenyl)carbamoyl)piperidine-1-carboxylate
27c: 3,5-dichlorobenzyl 4-((4-(1H-imidazol-5-yl)phenyl)carbamoyl)piperidine-1-carboxylate
27d: 3,5-dichlorobenzyl 4-((3-(1H-imidazol-5-yl)phenyl)carbamoyl)piperidine-1-carboxylate
27e: 3,5-dichlorobenzyl 4-(4-(1H-imidazol-5-yl)piperidine-1-carbonyl)piperidine-1-carboxylate
27f: 3,5-dichlorobenzyl 4-(4-(1H-1,2,3-triazol-5-yl)piperidine-1-carbonyl)piperidine-1-carboxylate
27g: 3,5-dichlorobenzyl 4-(4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidine-1-carbonyl)piperi Dean-1-carboxylate
27h: 3,5-dichlorobenzyl 4-((4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)carbamoyl)piperidin-1 -Carboxylate
27i: 3,5-dichlorobenzyl 4-((3-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)carbamoyl)piperidine-1 -Carboxylate
33d: 3,5-dichlorobenzyl 4-(2-(4-(1H-imidazol-5-yl)phenoxy)ethyl)piperidine-1-carboxylate
33e: 3,5-dichlorobenzyl 4-((4-(1H-imidazol-5-yl)phenoxy)methyl)piperidine-1-carboxylate
33f: 3,5-dichlorobenzyl 4-(4-(1H-imidazol-5-yl)phenoxy)piperidine-1-carboxylate
33g: 3,5-dichlorobenzyl 4-((3-(1H-imidazol-5-yl)phenoxy)methyl)piperidine-1-carboxylate
33h: 3,5-dichlorobenzyl 4-(3-(1H-imidazol-5-yl)phenoxy)piperidine-1-carboxylate
33i: 3,5-dichlorobenzyl 4-((3-(2-methyl-1H-imidazol-5-yl)phenoxy)methyl)piperidine-1-carboxylate
33k: 3,5-dichlorobenzyl 4-(((4-(2-aminothiazol-5-yl)phenyl)amino)methyl)piperidine-1-carboxylate
33l: 3,5-dichlorobenzyl 4-(((3-(2-aminothiazol-5-yl)phenyl)amino)methyl)piperidine-1-carboxylate
33m: 3,5-Dichlorobenzyl 4-(((4-(1H-imidazol-5-yl)phenyl)amino)methyl)piperidine-1-carboxylate
33n: 3,5-dichlorobenzyl 4-(((3-(1H-imidazol-5-yl)phenyl)amino)methyl)piperidine-1-carboxylate
33o: 3,5-dichlorobenzyl 4-(((4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)amino)methyl)piperidine -1-carboxylate
33p: 3,5-dichlorobenzyl 4-(((3-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)amino)methyl)piperidine -1-carboxylate
44a: 3,5-dichlorobenzyl 4-(5-(((1H-1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazol-2-yl) Piperidine-1-carboxylate
44b: 3,5-dibromobenzyl 4-(5-(((1H-1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazole-2- 1) piperidine-1-carboxylate
44c: 3,5-bis(trifluoromethyl)benzyl 4-(5-(((1H-1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadia zol-2-yl)piperidine-1-carboxylate
44d: 3,5-dimethylbenzyl 4-(5-(((1H-1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazol-2-yl) Piperidine-1-carboxylate
44e: 3,5-dimethoxybenzyl 4-(5-(((1H-1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazol-2-yl )piperidine-1-carboxylate
44f: 3,5-difluorobenzyl 4-(5-(((1H-1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazole-2- 1) piperidine-1-carboxylate
44g: 3-bromo-5-methylbenzyl 4-(5-(((1H-1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazole-2 -yl)piperidine-1-carboxylate
44h: 3-Bromo-5-chlorobenzyl 4-(5-(((1H-1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazole-2 -yl)piperidine-1-carboxylate
44i: 3-chloro-5-fluorobenzyl 4-(5-(((1H-1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazole-2 -yl)piperidine-1-carboxylate
44j: 2,5-dichlorobenzyl 4-(5-(((1H-1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazol-2-yl) Piperidine-1-carboxylate
44k: 3,4-dichlorobenzyl 4-(5-(((1H-1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazol-2-yl) Piperidine-1-carboxylate
44l: Benzo[d][1,3]dioxol-5-ylmethyl 4-(5-(((1H-1,2,3-triazol-5-yl)methyl)amino)-1,3, 4-oxadiazol-2-yl)piperidine-1-carboxylate
44m: 1-(4-(5-(((1H-1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazol-2-yl)piperidine -1-yl)-3-(3,5-dichlorophenyl)propan-1-one
44n: 4-(5-(((1H-1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazol-2-yl)-N-(3, 5-dichlorobenzyl)piperidine-1-carboxamide
47a: 3,5-dichlorobenzyl 4-(5-(((1H-tetrazol-5-yl)methyl)amino)-1,3,4-oxadiazol-2-yl)piperidin-1- carboxylate
47b: 3,5-dichlorobenzyl 4-(5-(((1-methyl-1H-1,2,3-triazol-4-yl)methyl)amino)-1,3,4-oxadiazole- 2-yl)piperidine-1-carboxylate
47c: 3,5-dichlorobenzyl 4-(5-(((4-methyl-1H-1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazole- 2-yl)piperidine-1-carboxylate
50a: 3,5-dichlorobenzyl 4-(5-(2-(1H-1,2,3-triazol-5-yl)ethyl)-1,3,4-thiadiazol-2-yl)pipette Razine-1-carboxylate
50b: 3,5-dichlorobenzyl 4-(5-(2-(1H-1,2,3-triazol-5-yl)ethyl)-1,3,4-oxadiazol-2-yl)pipette Razine-1-carboxylate
50c: 3,5-dichlorobenzyl 4-(5-(2-(1H-1,2,3-triazol-5-yl)ethyl)-1,3,4-oxadiazol-2-yl)p Peridine-1-carboxylate
53a: 3,5-dichlorobenzyl 4-(2-(((1H-1,2,3-triazol-5-yl)methyl)amino)thiazol-5-yl)piperazine-1-carboxylate
53b: 3,5-dichlorobenzyl 4-(5-(((1H-1,2,3-triazol-5-yl)methyl)amino)-1,3,4-thiadiazol-2-yl) Piperazine-1-carboxylate
58: 3,5-dichlorobenzyl 4-((4-((1H-1,2,3-triazol-4-yl)methoxy)phenyl)amino)piperidine-1-carboxylate
61: 3,5-dichlorobenzyl 4-(4-(((1H-1,2,3-triazol-4-yl)methyl)amino)phenyl)-[1,4′-bipiperidine]- 1'-carboxylates and
64: 3,5-dichlorobenzyl 4-(3-((1H-1,2,3-triazol-5-yl)methoxy)phenyl)-[1,4'-bipiperidine]-1' -carboxylates.
14. The pharmaceutical composition according to claim 13, wherein the pulmonary fibrosis is radiation-induced fibrosis.
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European Journal of Medicinal Chemistry, 2018, 제148권, 페이지 397-409 * |
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