KR102034538B1 - Jak inhibitor compounds, and method of preparing the same - Google Patents
Jak inhibitor compounds, and method of preparing the sameDownload PDFInfo
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Abstract
Translated fromKorean
Description
Translated fromKorean본 발명은 JAK 저해제 화합물, 및 이의 제조방법에 관한 것이다.The present invention relates to JAK inhibitor compounds, and methods for their preparation.
단백질 키나제(PK)는 특히 세포 성장, 생존 및 분화, 기관 형성 및 발생, 신혈관형성, 조직 보수 및 재생을 비롯한 다양하고 중요한 생물학적 과정을 조절하는 일단의 효소이다. 단백질 키나제는 단백질(또는 기질)의 포스포릴화에 촉매 작용을 함으로써 그 생물학적 기능을 발휘하고, 이로써 다양한 생물학적 맥락에서 기질의 세포활성을 조정한다. 정상의 조직/기관에서의 기능 이외에도, 많은 단백질 키나제는 암을 비롯한 인체 질병의 숙주에서 보다 특수한 역할도 한다. 단백질 키나제의 하위집단(종양 단백질 키나제로도 언급함)은, 조절되지 않을 경우에, 종양 형성 및 성장을 유발하고, 또한 종양의 지속 및 진행에도 기여한다. 따라서, 종양 단백질 키나제는 암 조정 및 약물 개발에 대한 가장 크고 가장 관심이 가는 단백질 표적의 군 중의 대표적인 하나이다.Protein kinases (PKs) are a group of enzymes that regulate a variety of important biological processes, particularly cell growth, survival and differentiation, organ formation and development, neovascularization, tissue repair and regeneration. Protein kinases exert their biological functions by catalyzing the phosphorylation of proteins (or substrates), thereby modulating the cellular activity of the substrates in various biological contexts. In addition to functioning in normal tissues / organs, many protein kinases also play a more specific role in hosts of human disease, including cancer. Subpopulations of protein kinases (also referred to as tumor protein kinases), when unregulated, cause tumor formation and growth, and also contribute to tumor persistence and progression. Thus, tumor protein kinases are one of the largest and most interesting groups of protein targets for cancer modulation and drug development.
야누스 키나제(Janus Kinase, JAK) 부류는 면역 반응에 관여하는 세포의 증식 및 작용의 시토킨 의존적 조절에 있어서 중요한 역할을 한다. 현재, 다음과 같은 4종의 포유류 JAK 부류 구성원이 알려져 있다: JAK1(야누스 키나제-1), JAK-2(야누스 키나제-2), JAK3(야누스 키나제-3) 및 TYK2(단백질-티로신 키나제 2). JAK 단백질의 크기는 120 kDa 내지 140 kDa 범위이며, 7개의 보존된 JAK 상동성(JH) 도메인을 포함하며, 이중 하나는 기능성 촉매 키나제 도메인이고, 다른 하나는 잠재적으로 조절 기능을 하고/하거나 STAT에 대한 도킹(docking) 부위로서 기능할 수 있는 슈도키나제 도메인이다.Janus Kinase (JAK) family plays an important role in cytokine dependent regulation of the proliferation and action of cells involved in immune responses. Currently, four mammalian JAK family members are known: JAK1 (Janus kinase-1), JAK-2 (Janus kinase-2), JAK3 (Janus kinase-3) and TYK2 (protein-tyrosine kinase 2) . JAK proteins range in size from 120 kDa to 140 kDa and contain seven conserved JAK homology (JH) domains, one of which is a functional catalytic kinase domain and the other potentially regulatory and / or STAT. It is a pseudokinase domain that can function as a docking site for.
JAK 키나제의 수준에서 신호 형질도입을 차단하는 것은, 예컨대 염증성 질환, 자가면역 질환, 골수증식성 질환, 및 인체의 암에 대한 치료법의 개발에 대한 가능성을 갖고, 건선 및 피부 감작과 같은 피부 면역 질환에 걸린 환자에서 치료학적으로 유리한 효과를 가질 것이다.Blocking signal transduction at the level of JAK kinase has the potential for the development of treatments for, for example, inflammatory diseases, autoimmune diseases, myeloproliferative diseases, and human cancers, and skin immune diseases such as psoriasis and skin sensitization It will have a therapeutically beneficial effect in patients with the disease.
따라서, 야누스 키나제 또는 관련 키나제에 대한 억제제들을 광범위하게 찾고 있으며, 몇가지 특허 공보들은 유효한 부류의 화합물들을 보고하고 있다. 예를 들면, 피롤로피리딘 및 피롤로피리미딘이 일부의 JAK 억제제로서 작용할 수 있음이 미국출원공개공보 US2007/0135461 A1 등에 개시되어 있다(특허문헌 1). 이로써, 특허문헌 1에 개시된 내용 전부는 본 명세서 상의 종래기술로 모두 인용·합체된다.Thus, there are extensive searches for inhibitors of Janus kinase or related kinases, and several patent publications report a valid class of compounds. For example, it is disclosed in US Patent Application Publication US2007 / 0135461 A1 and the like that pyrrolopyridine and pyrrolopyrimidine can act as some JAK inhibitors (Patent Document 1). As a result, all of the contents disclosed in Patent Document 1 are cited and incorporated in the prior art described herein.
야누스 키나제 억제 활성을 갖는 신규화합물 제공하는 것을 본 발명의 목적으로 한다.It is an object of the present invention to provide a novel compound having Janus kinase inhibitory activity.
본 발명은 상기한 종래기술의 문제점을 해결하기 위해 안출된 것으로서,The present invention has been made to solve the above problems of the prior art,
하기 화학식 I의 화합물 또는 그의 약제학적으로 허용되는 염을 제공한다.There is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof.
[화학식 I][Formula I]
상기 식에서,Where
R1은 수소기, C1-C3 알킬기, 또는 C3-C8 시클로알킬기이고;R1 is a hydrogen group, a C1 -C3 alkyl group, or a C3 -C8 cycloalkyl group;
R2는 수소기, 또는 C1-C3 알킬기이고;R2 is a hydrogen group or a C1 -C3 alkyl group;
R3는 수소기,
R4, 및 R5는, 각각 독립적으로, 수소기, C1-C3 알킬기, C1-C3 알콕시기, 할로겐기, 히드록시기, 또는 시아노기이며; n은 0, 또는 1의 정수이다.R4 and R5 are each independently a hydrogen group, a C1 -C3 alkyl group, a C1 -C3 alkoxy group, a halogen group, a hydroxy group, or a cyano group; n is 0 or an integer of 1;
단, R4, 및 R5가 동시에 수소기인 경우, R1은 수소기가 아니다.However, when R <4> and R <5> are hydrogen groups at the same time, R <1> is not a hydrogen group.
본 발명에 있어서, R1은 메틸기인 것인 화합물 또는 그의 약제학적으로 허용되는 염을 제공한다.In the present invention, R1 is a methyl group or a pharmaceutically acceptable salt thereof.
본 발명에 있어서, R2는 수소기, 또는 메틸기인 것인 화합물 또는 약제학적으로 허용되는 염을 제공한다.In the present invention, R2 provides a compound or a pharmaceutically acceptable salt which is a hydrogen group or a methyl group.
본 발명에 있어서, R4, R5는, 각각 독립적으로, 수소기, 메틸기, 메톡시기, 할로겐기, 히드록시기, 또는 시아노기인 것인 화합물 또는 그의 약제학적으로 허용되는 염을 제공한다.In the present invention, each of R4 and R5 independently represents a hydrogen group, a methyl group, a methoxy group, a halogen group, a hydroxy group, or a cyano group, or a pharmaceutically acceptable salt thereof.
또한, 본 발명의 어느 한 한 항의 화합물 또는 그의 약제학적으로 허용되는 염을 포함하는 자가면역 질병, 염증성 질병, 또는 암을 치료 또는 예방에 사용하기 위한 의약 조성물을 제공한다.Also provided is a pharmaceutical composition for use in the treatment or prevention of an autoimmune disease, inflammatory disease, or cancer comprising the compound of any one of the present invention or a pharmaceutically acceptable salt thereof.
본 발명은, JAK 키나제의 수준에서 신호 형질도입을 조절하여, 예컨대 염증성 질환, 자가면역 질환, 골수증식성 질환, 및 인체의 암 등에 대한 치료 효과를 나타낼 수 있다.The present invention can modulate signal transduction at the level of JAK kinase, such as to exhibit therapeutic effects against inflammatory diseases, autoimmune diseases, myeloproliferative diseases, cancer of the human body, and the like.
이하, 본 발명에 대해서 상세히 설명한다.EMBODIMENT OF THE INVENTION Hereinafter, this invention is demonstrated in detail.
본 발명의 일측면은 하기 화학식 I의 화합물 또는 그의 약제학적으로 허용되는 염에 관한 것이다.One aspect of the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof.
[화학식 I][Formula I]
상기 식에서,Where
R1은 수소기, C1-C3 알킬기, 또는 C3-C8 시클로알킬기이고;R1 is a hydrogen group, a C1 -C3 alkyl group, or a C3 -C8 cycloalkyl group;
R2는 수소기, 또는 C1-C3 알킬기이고;R2 is a hydrogen group or a C1 -C3 alkyl group;
R3는 수소기,
R4, 및 R5는, 각각 독립적으로, 수소기, C1-C3 알킬기, C1-C3 알콕시기, 할로겐기, 히드록시기, 또는 시아노기이며; n은 0, 또는 1의 정수이다.R4 and R5 are each independently a hydrogen group, a C1 -C3 alkyl group, a C1 -C3 alkoxy group, a halogen group, a hydroxy group, or a cyano group; n is 0 or an integer of 1;
단, R4, 및 R5가 동시에 수소기인 경우, R1은 수소기가 아니다.However, when R <4> and R <5> are hydrogen groups at the same time, R <1> is not a hydrogen group.
상기 본 발명의 화합물은 하나 이상의 비대칭 중심을 가질 수 있다. 달리 나타내지 않는 한, 본 발명의 화합물의 모든 키랄 (거울상이성질체 및 부분입체이성질체) 및 라세미 형태는 본 발명에 포함된다. 또한 올레핀, C=N 이중결합 등의 다수의 기하이성질체가 화합물 중에 존재할 수 있고, 그 모든 안정한 이성질체가 본 발명에서 고려된다. 본 발명의 화합물의 시스 및 트랜스 기하 이성질체가 기재되어 있고, 이들은 이성질체의 혼합물로서 또는 분리된 이성질체 형태로서 단리될 수 있다. 본 발명의 화합물은 광학 활성 형태 또는 라세미 형태로 단리될 수 있다. 광학적으로 활성인 형태를 제조하는 방법 (예를 들어, 라세미 형태의 분할에 의해 또는 광학적으로 활성인 출발 물질로부터의 합성에 의해)은 당업계에 널리 공지되어 있다. 특정 입체화학 또는 이성질체 형태가 구체적으로 표시되지 않는다면, 구조의 모든 키랄 (거울상이성질체 및 부분입체이성질체) 및 라세미 형태, 및 모든 기하이성질체 형태가 의도된다.The compounds of the present invention may have one or more asymmetric centers. Unless otherwise indicated, all chiral (enantiomers and diastereomers) and racemic forms of the compounds of the invention are included in the invention. In addition, many geometric isomers such as olefins, C═N double bonds, etc. may be present in the compound, and all of the stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the invention are described and they can be isolated as a mixture of isomers or as isolated isomeric forms. The compounds of the present invention can be isolated in optically active or racemic forms. Methods of preparing optically active forms (eg, by cleavage of racemic forms or by synthesis from optically active starting materials) are well known in the art. Unless specific stereochemical or isomeric forms are specifically indicated, all chiral (enantiomer and diastereomeric) and racemic forms of the structure, and all geometric isomeric forms, are intended.
상기 화학식 I로 표시되는 화합물들은 야누스 키나제(JAK)의 활성을 조절할 수 있다. 여기서, 용어 "조절한다"의 의미는 1종 이상의 JAK 부류의 키나제의 활성을 증가 또는 감소시킬 수 있는 능력을 언급한 것이다. 따라서, 본 발명의 화합물은, JAK와 본 발명의 화합물 또는 조성물 1종 이상을 접촉시킴으로써 JAK를 조절하는 방법에 사용될 수 있다. 특히, 일부의 실시양태에서, 본 발명의 화합물은 1종 이상의 JAK의 억제제로서 작용할 수 있다.The compounds represented by Formula I may modulate the activity of Janus kinase (JAK). Here, the term "modulate" refers to the ability to increase or decrease the activity of one or more JAK classes of kinases. Thus, the compounds of the present invention can be used in a method of controlling JAK by contacting JAK with one or more compounds or compositions of the present invention. In particular, in some embodiments, the compounds of the present invention may act as inhibitors of one or more JAKs.
본 발명의 화합물이 결합 및/또는 조절하는 JAK는 JAK 부류중 임의의 구성원을 포함한다. 일부의 실시양태에서, JAK는 JAK1, JAK2, JAK3 또는 TYK2이다. 일부의 실시양태에서, JAK는 JAK1 또는 JAK2이다. 일부의 실시양태에서, JAK는 JAK2이다. 일부의 실시양태에서, JAK는 JAK3이다.JAKs to which the compounds of the invention bind and / or regulate include any member of the JAK family. In some embodiments, JAK is JAK1, JAK2, JAK3 or TYK2. In some embodiments, JAK is JAK1 or JAK2. In some embodiments, JAK is JAK2. In some embodiments, JAK is JAK3.
본 발명의 다른 측면은 상기 화학식 I로 표시되는 화합물 또는 그의 약제학적으로 허용되는 염을 포함하는 자가면역 질병, 염증성 질병, 또는 암을 치료 또는 예방에 사용하기 위한 의약 조성물에 관한 것이다.Another aspect of the present invention relates to a pharmaceutical composition for use in the treatment or prophylaxis of an autoimmune disease, inflammatory disease, or cancer comprising the compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
JAK 관련 질병으로서는, JAK의 형질발현 또는 활성, 예를 들면 과형질발현 및/또는 비정상적인 활성도와 직접 또는 간접적으로 연관된 질병, 질환 또는 증상을 들 수 있다. 또한, JAK 관련 질병으로는, JAK 활성을 조절함으로써 예방, 경감 또는 치유될 수 있는 질병, 질환 또는 증상을 들 수 있다.JAK-related diseases include diseases, diseases or symptoms that are directly or indirectly associated with the expression or activity of JAK, such as overexpression and / or abnormal activity. In addition, JAK-related diseases include diseases, diseases or symptoms that can be prevented, alleviated or cured by modulating JAK activity.
JAK 관련 질병의 예로서는, 면역계 관련 질병, 예를 들면 기관 이식 거부반응(예: 이식거절반응 및 이식편대숙주반응), 다발성 경화증, 류마티스 관절염, 연소성 관절염, 건선성 관절염, I형 당뇨병, 루푸스, 건선, 염증성 장 질환, 궤양성 대장염, 크론병(Crohn's disease), 중증근 무력증, 면역글로불린 신증, 자가면역 갑상선 질환, 천식, 음식 알레르기, 아토피 피부염, 건선, 자가면역 수포성 피부 질환, 예컨대 심상성천포창(PV) 또는 수포성 유천포창(BP) 등을 들 수 있다.Examples of JAK related diseases include immune system related diseases, such as organ transplant rejection (eg, graft rejection and graft versus host reaction), multiple sclerosis, rheumatoid arthritis, juvenile arthritis, psoriatic arthritis, type I diabetes, lupus, psoriasis , Inflammatory bowel disease, ulcerative colitis, Crohn's disease, myasthenia gravis, immunoglobulin nephropathy, autoimmune thyroid disease, asthma, food allergy, atopic dermatitis, psoriasis, autoimmune bullous skin diseases such as vulgaris (PV) or a blistering bleb (BP) etc. are mentioned.
JAK 관련 질병의 다른 예로서는, 염증 및 염증성 질병을 들 수 있다. 염증성 질병의 예로서는, 눈의 염증성 질병(예: 홍채염, 포도막염, 공막염, 결막염 또는 관련 질병), 호흡관의 염증성 질병(예: 코 및 부비동을 포함한 상부 호흡관, 예컨대 비염 또는 부비동염, 또는 기관지, 만성 폐색성 폐 질환 등을 비롯한 하부 호흡관의 질병), 염증성 근병증, 예컨대 심근염 및 기타 염증성 질병을 들 수 있다. 다른 염증성 질환으로는, 예컨대 전신성 염증성 반응 증후군(SIRS) 및 패혈증 쇼크를 들 수 있고, 이들을 치료하는 데에도 사용될 수도 있다.Other examples of JAK related diseases include inflammatory and inflammatory diseases. Examples of inflammatory diseases include inflammatory diseases of the eye (e.g. iris, uveitis, scleritis, conjunctivitis or related diseases), inflammatory diseases of the respiratory tract (e.g., upper respiratory tract including nasal and sinus, such as rhinitis or sinusitis, or bronchial, chronic Diseases of the lower respiratory tract, including obstructive pulmonary disease), and inflammatory myopathy such as myocarditis and other inflammatory diseases. Other inflammatory diseases include, for example, systemic inflammatory response syndrome (SIRS) and sepsis shock, and may also be used to treat them.
JAK 관련 질병의 또 다른 예로서는, 고형 종양을 특징으로 하는 암(예: 전립선암, 신장암, 간암, 췌장암, 위암, 유방암, 폐암, 두경부암, 갑상선암, 교아종, 카포시 육종, 캐슬만(Castleman)병, 흑색종), 혈액암(예: 림프종, 백혈병, 예컨대 급성 림프성 백혈병, 급성 골수성 백혈병(AML) 또는 다발성 골수종), 및 피부암, 예컨대 피부 T세포 림프종(CTCL) 및 피부 B세포 림프종을 들 수 있다. 피부 T세포 림프종의 예로서는 세저리(Sezary) 증후군 및 균상식육종을 들 수 있다.Other examples of JAK-related diseases include cancers characterized by solid tumors, such as prostate cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, Kaposi's sarcoma, and Castleman. Diseases, melanoma), hematological cancers (eg, lymphomas, leukemias such as acute lymphocytic leukemia, acute myeloid leukemia (AML) or multiple myeloma), and skin cancers such as cutaneous T-cell lymphoma (CTCL) and cutaneous B-cell lymphoma. Can be. Examples of cutaneous T-cell lymphomas include Sezary syndrome and myxosarcoma.
이외에도, 허혈 재관류 손상 또는 졸중 또는 심장 정지와 같은 염증성 허혈 사례와 관련된 질병 또는 증상을 치료하는 데에도 사용될 수 있고, 협착증, 경피성 피부염 또는 섬유증을 치료하는 데에도 사용될 수 있다.In addition, it can be used to treat diseases or symptoms associated with inflammatory ischemic events such as ischemia reperfusion injury or stroke or cardiac arrest, and can also be used to treat stenosis, percutaneous dermatitis or fibrosis.
또한, 본 발명의 JAK 억제제는 저산소증 또는 성상교세포증, 예컨대 당뇨병성 망막증, 암 또는 신경퇴화와 관련된 증상을 치료하는 데에도 사용될 수 있다. 이에 관해서는 문헌 [Dudley, A.C. et al. Biochem. J. 2005, 390(Pt 2):427-36] 및 [Sriram, K. et al. J. Biol. Chem. 2004, 279(19): 19936-47. Epub 2004 Mar 2]을 참조할 수 있다. 본 발명의 JAK 억제제는 알츠하이머병을 치료하는 데에도 사용될 수 있다.In addition, the JAK inhibitors of the present invention can also be used to treat hypoxia or astrocytosis, such as diabetic retinopathy, cancer or symptoms associated with neurodegeneration. See, for example, Dudley, A.C. et al. Biochem. J. 2005, 390 (Pt 2): 427-36 and Sriram, K. et al. J. Biol. Chem. 2004, 279 (19): 19936-47. Epub 2004 Mar 2]. The JAK inhibitors of the invention can also be used to treat Alzheimer's disease.
나아가, 본 발명의 JAK 억제제는 통풍 및 예를 들면 양성 전립선 비대증 또는 전립선 비대증에 기인한 전립선 크기 증가를 치료하는 데에도 사용될 수 있다.Furthermore, the JAK inhibitors of the present invention can also be used to treat gout and an increase in prostate size due to, for example, benign or enlarged prostate.
본 발명의 의약 조성물은 정제, 캡슐 (이들 각각은 지속 방출형 또는 시간 방출형 제제를 포함함), 환제, 분말, 과립, 엘릭시르, 팅크제, 현탁액, 시럽 및 에멀젼과 같은 경구 투여 형태로 투여될 수 있다. 이들은 또한 정맥 내 (볼루스 또는 주입), 복강내, 피하 또는 근육내 형태로 투여될 수 있고, 모든 사용되는 투여 형태는 제약 업계의 통상의 기술자에게 널리 공지되어 있다. 이들은 단독으로 투여될 수 있지만, 일반적으로 선택된 투여 경로 및 표준 제약 실무를 기초로 하여 선택되는 제약 담체와 함께 투여될 것이다.The pharmaceutical compositions of the present invention may be administered in oral dosage forms such as tablets, capsules (each of which include sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. Can be. They can also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous or intramuscular forms and all used dosage forms are well known to those skilled in the pharmaceutical arts. They may be administered alone, but will generally be administered with a pharmaceutical carrier selected based on the chosen route of administration and standard pharmaceutical practice.
또한, 본 발명의 의약 조성물은 적합한 비내 비히클의 국소 사용을 통해 비내 형태로, 또는 경피 피부 패치를 사용하여 경피 경로를 통해 투여될 수 있다. 경피 전달 시스템의 형태로 투여되는 경우에, 투여량의 투여는 물론 투여 요법 전반에 걸쳐 간헐적이기보다는 연속적일 것이다.In addition, the pharmaceutical compositions of the present invention may be administered in intranasal form via topical use of a suitable intranasal vehicle, or via the transdermal route using transdermal skin patches. When administered in the form of a transdermal delivery system, administration of the dose will of course be continuous rather than intermittent throughout the dosing regimen.
상기의 화힉식 I으로 표현되는 화합물들의 각종 실시형태에서, 당해 화합물은 표 1 및 2의 화합물들을 구체적으로 예시할 수 있다. JAK1, JAK2, JAK3의 수치는 각 화합물의 IC50 농도를 시험하여 나타낸 것이다.In various embodiments of the compounds represented by Formula I above, the compounds may specifically illustrate the compounds of Tables 1 and 2. JAK1, JAK2, JAK3 values are shown by testing the IC50 concentration of each compound.
상기 표 1, 및 2의 예시된 화합물을 포함하는 화학식 I로 표시되는 본 발명의 화합물들은, 후술할 일반적인 합성 절차에서 구체적으로 기재된 방법을 포함하여 제조될 수 있다. 해당 분야 통상의 기술자로서는, 이러한 일반적 합성 절차 설명을 통해서, 구체적인 예시 화합물들이나 실시예 화합물들에 대한 합성방법에 대해서도 미루어 보아 이해할 수 있으므로, 각각의 화합물에 대한 개별적인 제조방법 설명은 생략하기로 한다.The compounds of the present invention represented by the formula (I), including the exemplified compounds of Tables 1 and 2 above, may be prepared including the methods specifically described in the general synthetic procedures described below. As a person skilled in the art can understand the synthesis method for specific exemplary compounds or example compounds through the description of the general synthetic procedure, the description of the individual preparation method for each compound will be omitted.
스킴Scheme 1. 1- 1.1-benzylpiperidinbenzylpiperidin-4-amine 또는 그의 유도체 화합물 합성의 일반적 절차General Procedure of Synthesis of 4-amine or Derivative Compounds thereof
[일반적 반응식 Ⅰ]General Reaction Scheme I
시약 및 조건: (a)t-butyl piperidin-4-yl carbamate, K2CO3, DMF, 실온; (b) 10% HCl in MeOH, 실온Reagents and Conditions: (a)t- butyl piperidin-4-yl carbamate, K2 CO3 , DMF, room temperature; (b) 10% HCl in MeOH, room temperature
일반적 절차 AGeneral Procedure A
용액(용매 DMF(5ml),t-butyl piperidin-4-yl carbamate (0.50 g, 2.5 mmol))에 K2CO3 (0.83 g, 5.99 mmol) 및 aryl halide(ex.bromide) (2.75 mmol)를 실온에서 적가하였다. 상기 반응 혼합물은 실온에서 약 8시간 동안 혼합되어졌다. 반응 이후, 결과물을 Et2O (40 ml)에 붓고, H2O (40 ml), 브라인 (40 ml), 건조 MgSO4으로 세척하였다. 조화합물들은 실리카겔 속성 크로마토그래피 (30% Ethyl acetate in n-Hexane elution) 로 정제하였다(0.61 g, 수율 78%).To a solution (solvent DMF (5 ml),t -butyl piperidin-4-yl carbamate (0.50 g, 2.5 mmol)) was added K2 CO3 (0.83 g, 5.99 mmol) and aryl halide (ex.bromide) (2.75 mmol). Dropwise at room temperature. The reaction mixture was mixed at room temperature for about 8 hours. After reaction, the resultant was poured into Et2 O (40 ml) and washed with H2 O (40 ml), brine (40 ml), dry MgSO4 . The crude compounds were purified by silica gel chromatography (30% Ethyl acetate in n-Hexane elution) (0.61 g, yield 78%).
일반적 절차 BGeneral procedure B
tert-butyl (1-aryl piperidin-4-yl)carbamate (2 mmol)를 10% HCl 메탄올 용액에 넣고 약 18시간 동안 실온에서 혼합하였다. 반응 후, 혼합물은 감압 농축되었다. 수득물(수율~100%)은 추가적인 정제없이 사용되었다.tert-butyl (1-aryl piperidin-4-yl) carbamate (2 mmol) was added to 10% HCl methanol solution and mixed at room temperature for about 18 hours. After the reaction, the mixture was concentrated under reduced pressure. Yield (yield-100%) was used without further purification.
terttert--ButylButyl (1-(3- (1- (3-cyanobenzylcyanobenzyl))piperidinpiperidin-4--4-ylyl))carbamatecarbamate
일반적 절차 A에 따라 합성하였다(수율: 78%);1H NMR (400 MHz, CD3OD) δ 7.73 (br. s, 1 H), 7.68-7.63 (m, 1 H), 7.53 (t,J=7.6 Hz, 1 H), 3.58 (s, 2 H), 3.40-3.32 (m, 1 H), 2.87-2.80 (m, 2 H), 2.19-2.10 (m, 2 H), 1.89-1.91 (m, 2 H), 1.55-1.46 (m, 2 H), 1.45 (s, 9 H). MS (ESI,m/z) calculated for C18H25N3O2 [M+H]+ 315.19, found 316.10.Synthesized according to General Procedure A (yield: 78%);1 H NMR (400 MHz, CD3 OD) δ 7.73 (br. S, 1 H), 7.68-7.63 (m, 1 H), 7.53 (t,J = 7.6 Hz, 1 H), 3.58 (s, 2 H), 3.40-3.32 (m, 1H), 2.87-2.80 (m, 2H), 2.19-2.10 (m, 2H), 1.89-1.91 (m, 2H), 1.55-1.46 (m, 2 H), 1.45 (s, 9 H). MS (ESI,m / z ) calculated for C18 H25 N3 02 [M + H]+ 315.19, found 316.10.
terttert--ButylButyl (1-(3- (1- (3-methoxymethoxy))piperidinpiperidin-4--4-ylyl))carbamatecarbamate
일반적 절차 A에 따라 합성하였다(수율: 74%);1H NMR (400 MHz, CD3OD) δ 7.24 (t,J=7.6 Hz, 1 H), 6.94-6.88 (m, 2 H), 6.84 (dd,J=2.4, 8.4 Hz, 1 H), 3.80 (S, 3 H), 3.50 (s, 2 H), 3.39-3.32 (m, 1 H), 2.90-2.83 (m, 2 H), 2.16-2.07 (m, 2 H), 1.88-1.81 (m, 2 H), 1.55-1.46 (m, 2 H), 1.45 (s, 9 H). MS (ESI,m/z) calculated for C18H28N2O3 [M+H]+ 320.21, found 321.25.Synthesized according to General Procedure A (yield: 74%);1 H NMR (400 MHz, CD3 OD) δ 7.24 (t,J = 7.6 Hz, 1 H), 6.94-6.88 (m, 2H), 6.84 (dd,J = 2.4, 8.4 Hz, 1 H), 3.80 (S, 3H), 3.50 (s, 2H), 3.39-3.32 (m, 1H), 2.90-2.83 (m, 2H), 2.16-2.07 (m, 2H), 1.88-1.81 ( m, 2H), 1.55-1.46 (m, 2H), 1.45 (s, 9H). MS (ESI,m / z ) calculated for C18 H28 N2 03 [M + H]+ 320.21, found 321.25.
terttert--ButylButyl (1-( (One-(pyridinepyridine-4--4-ylmethylylmethyl))piperidinpiperidin-4--4-ylyl))carbamatecarbamate
일반적 절차 A에 따라 합성하였다(수율: 54%);1H NMR (400 MHz, CD3OD) δ 8.49 (d,J=6.0 Hz, 2 H), 7.44 (d,J=6.0 Hz, 2 H), 3.58 (s, 2 H), 3.41-3.31 (m, 1 H), 2.87-2.81 (m, 2 H), 2.20-2.12 (m, 2 H), 1.89-1.83 (m, 2 H), 1.57-1.49 (m, 2 H), 1.45 (s, 9 H). MS (ESI,m/z) calculated for C16H25N3O2 [M+H]+ 291.19, found 292.30.Synthesized according to General Procedure A (Yield 54%);1 H NMR (400 MHz, CD3 OD) δ 8.49 (d,J = 6.0 Hz, 2H), 7.44 (d,J = 6.0 Hz, 2H), 3.58 (s, 2H), 3.41-3.31 ( m, 1H), 2.87-2.81 (m, 2H), 2.20-2.12 (m, 2H), 1.89-1.83 (m, 2H), 1.57-1.49 (m, 2H), 1.45 (s, 9 H). MS (ESI,m / z ) calculated for C16 H25 N3 02 [M + H]+ 291.19, found 292.30.
terttert--ButylButyl (1-(3,4- (1- (3,4-dimethoxybenzyldimethoxybenzyl))piperidinpiperidin-4--4-ylyl))carbamatecarbamate
일반적 절차 A에 따라 합성하였다(수율: 55%);1H NMR (400 MHz, CDCl3) δ 6.87 (br. s, 1 H), 6.84-6.77 (m, 2 H), 3.89 (s, 3 H), 3.87 (s, 3 H), 3.53-3.42 (m, 1 H), 3.42 (s, 2 H), 2.83-2.74 (m, 2 H), 2.11-2.00 (m, 2 H), 1.94-1.86 (m, 2 H), 1.45-1.34 (m, 2 H), 1.44 (s, 9 H). MS (ESI,m/z) calculated for C19H30N2O4 [M+H]+ 350.22, found 351.30.Synthesized according to General Procedure A (yield: 55%);1 H NMR (400 MHz, CDCl3 ) δ 6.87 (br. S, 1 H), 6.84-6.77 (m, 2 H), 3.89 (s, 3 H), 3.87 (s, 3 H), 3.53-3.42 (m, 1H), 3.42 (s, 2H), 2.83-2.74 (m, 2H), 2.11-2.00 (m, 2H), 1.94-1.86 (m, 2H), 1.45-1.34 (m , 2H), 1.44 (s, 9H). MS (ESI,m / z ) calculated for C19 H30 N2 04 [M + H]+ 350.22, found 351.30.
terttert--ButylButyl (1-(2- (1- (2-methoxybenzylmethoxybenzyl))piperidinpiperidin-4--4-ylyl))carbamatecarbamate
일반적 절차 A에 따라 합성하였다(수율: 93%);1H NMR (400 MHz, CD3OD) δ 7.31-7.25 (m, 2 H), 6.98 (d,J=8.2 Hz, 1 H), 6.93 (t,J=7.5 Hz, 1 H), 3.84 (s, 3 H), 3.59 (s, 2 H), 3.33-3.27 (m, 1 H), 2.95-2.88 (m, 2 H), 2.23-2.13 (m, 2 H), 1.87-.179 (m, 2 H), 1.55-1.45 (m, 2 H), 1.44 (s, 9 H). MS (ESI,m/z) calculated for C18H28N2O3 [M+H]+ 320.21, found 321.10.Synthesized according to General Procedure A (yield: 93%);1 H NMR (400 MHz, CD3 OD) δ 7.31-7.25 (m, 2H), 6.98 (d,J = 8.2 Hz, 1H), 6.93 (t,J = 7.5 Hz, 1H), 3.84 ( s, 3H), 3.59 (s, 2H), 3.33-3.27 (m, 1H), 2.95-2.88 (m, 2H), 2.23-2.13 (m, 2H), 1.87-.179 (m , 2H), 1.55-1.45 (m, 2H), 1.44 (s, 9H). MS (ESI,m / z ) calculated for C18 H28 N2 03 [M + H]+ 320.21, found 321.10.
terttert--ButylButyl (1-(4- (1- (4-methoxybenzylmethoxybenzyl))piperidinpiperidin-4--4-ylyl))carbamatecarbamate
일반적 절차 A에 따라 합성하였다(수율: 81%);1H NMR (400 MHz, CD3OD) δ 7.24 (d,J=8.6 Hz, 2 H), 6.89 (d,J=8.6 Hz, 2 H), 3.80 (s, 3 H), 3.47 (s, 2 H), 3.38-3.28 (m, 1 H), 2.90-2.82 (m, 2 H), 2.14-2.05 (m, 2 H), 1.88-1.80 (m, 2 H), 1.53-1.44 (m, 2 H), 1.44 (s, 9 H). MS (ESI,m/z) calculated for C18H28N2O3 [M+H]+ 320.21, found 321.30.Synthesized according to General Procedure A (yield: 81%);1 H NMR (400 MHz, CD3 OD) δ 7.24 (d,J = 8.6 Hz, 2H), 6.89 (d,J = 8.6 Hz, 2H), 3.80 (s, 3H), 3.47 (s, 2H), 3.38-3.28 (m, 1H), 2.90-2.82 (m, 2H), 2.14-2.05 (m, 2H), 1.88-1.80 (m, 2H), 1.53-1.44 (m, 2 H), 1.44 (s, 9 H). MS (ESI,m / z ) calculated for C18 H28 N2 03 [M + H]+ 320.21, found 321.30.
terttert--ButylButyl (1-(3- (1- (3-hydroxybenzylhydroxybenzyl))piperidinpiperidin-4--4-ylyl))carbamatecarbamate
일반적 절차 A에 따라 합성하였다(수율: 87%);1H NMR (400 MHz, CD3OD) δ 7.15 (t,J=8.4 Hz, 1 H), 6.82-6.77 (m, 2 H), 6.73-6.69 (m, 1 H), 3.48 (s, 2 H), 3.40-3.33 (m, 1 H), 2.93-2.85 (m, 2 H), 2.19-2.09 (m, 2 H), 1.89-1.81 (m, 2 H), 1.55-1.45 (m, 2 H), 1.44 (s, 9 H). MS (ESI,m/z) calculated for C17H26N2O3 [M+H]+ 306.19, found 307.20.Synthesized according to General Procedure A (yield: 87%);1 H NMR (400 MHz, CD3 OD) δ 7.15 (t,J = 8.4 Hz, 1 H), 6.82-6.77 (m, 2H), 6.73-6.69 (m, 1H), 3.48 (s, 2 H), 3.40-3.33 (m, 1H), 2.93-2.85 (m, 2H), 2.19-2.09 (m, 2H), 1.89-1.81 (m, 2H), 1.55-1.45 (m, 2 H), 1.44 (s, 9 H). MS (ESI,m / z ) calculated for C17 H26 N2 03 [M + H]+ 306.19, found 307.20.
terttert--ButylButyl (1-(3- (1- (3-bromobenzylbromobenzyl))piperidinpiperidin-4--4-ylyl))carbamatecarbamate
일반적 절차 A에 따라 합성하였다(수율: 81%);1H NMR (400 MHz, CDCl3) δ 7.47 (br. s, 1 H), 7.37 (d,J=8.0 Hz, 1 H), 7.22 (d,J=8.0 Hz, 1 H), 7.16 (t,J=7.6 Hz, 1 H), 3.53-3.40 (m, 1 H), 3.43 (s, 2 H), 2.82-2.72 (m, 2 H), 2.12-2.02 (m, 2 H), 1.94-1.86 (m, 2 H), 1.48-1.38 (m, 2 H), 1.44 (s, 9 H). MS (ESI,m/z) calculated for C17H25BrN2O2 [M+H]+ 368.11, found 371.25.Synthesized according to General Procedure A (yield: 81%);1 H NMR (400 MHz, CDCl3 ) δ 7.47 (br. S, 1 H), 7.37 (d,J = 8.0 Hz, 1 H), 7.22 (d,J = 8.0 Hz, 1 H), 7.16 (t ,J = 7.6 Hz, 1H), 3.53-3.40 (m, 1H), 3.43 (s, 2H), 2.82-2.72 (m, 2H), 2.12-2.02 (m, 2H), 1.94- 1.86 (m, 2H), 1.48-1.38 (m, 2H), 1.44 (s, 9H). MS (ESI,m / z ) calculated for C17 H25 BrN2 O2 [M + H]+ 368.11, found 371.25.
terttert--ButylButyl (1-(3- (1- (3-methylbenzylmethylbenzyl))piperidinpiperidin-4--4-ylyl))carbamatecarbamate
일반적 절차 A에 따라 합성하였다(수율: 57%);1H NMR (400 MHz, CD3OD) δ 7.21 (t,J=7.6 Hz, 1 H), 7.16 (br. s, 1 H), 7.13-7.08 (m, 2 H), 3.49 (s, 2 H), 3.39-3.31 (m, 1 H), 2.90-2.82 (m, 2 H), 2.35 (s, 3 H), 2.16-2.06 (m, 2 H), 1.88-1.80 (m, 2 H), 1.55-1.45 (m, 2 H), 1.45 (s, 9 H). MS (ESI,m/z) calculated for C18H28N2O2 [M+H]+ 304.22, found 305.00.Synthesized according to General Procedure A (Yield: 57%);1 H NMR (400 MHz, CD3 OD) δ 7.21 (t,J = 7.6 Hz, 1 H), 7.16 (br. S, 1 H), 7.13-7.08 (m, 2H), 3.49 (s, 2 H), 3.39-3.31 (m, 1H), 2.90-2.82 (m, 2H), 2.35 (s, 3H), 2.16-2.06 (m, 2H), 1.88-1.80 (m, 2H) , 1.55-1.45 (m, 2H), 1.45 (s, 9H). MS (ESI,m / z ) calculated for C18 H28 N2 02 [M + H]+ 304.22, found 305.00.
3-((4-3-((4-aminopiperidinaminopiperidin-1--One-ylyl))methylmethyl))benzonitrilebenzonitrilehydrochloridehydrochloride
일반적 절차 B에 따라 합성하였다;1H NMR (400 MHz, CD3OD) δ 8.07 (br. s, 1 H), 7.98 (d,J=7.8 Hz, 1 H), 7.90 (d,J=7.8 Hz, 1 H), 7.71 (t,J=7.8 Hz, 1 H), 4.47 (s, 2 H), 3.67-3.58 (m, 2 H), 3.58-3.48 (m, 1 H), 3.32-3.22 (m, 2 H), 2.35-2.26 (m, 2 H), 2.17-2.03 (m, 2 H). MS (ESI,m/z) calculated for C13H17N3 [M+H]+ 215.14, found 216.10.Synthesized according to General Procedure B;1 H NMR (400 MHz, CD3 OD) δ 8.07 (br. S, 1 H), 7.98 (d,J = 7.8 Hz, 1 H), 7.90 (d,J = 7.8 Hz, 1 H), 7.71 ( t,J = 7.8 Hz, 1 H), 4.47 (s, 2 H), 3.67-3.58 (m, 2 H), 3.58-3.48 (m, 1 H), 3.32-3.22 (m, 2 H), 2.35 -2.26 (m, 2H), 2.17-2.03 (m, 2H). MS (ESI,m / z ) calculated for C13 H17 N3 [M + H]+ 215.14, found 216.10.
1-(3-1- (3-MethoxybenzylMethoxybenzyl))piperidinpiperidin-4--4-amineaminehydrochloridehydrochloride
일반적 절차 B에 따라 합성하였다;1H NMR (400 MHz, CD3OD) δ 7.42 (t,J=7.9 Hz, 1 H), 7.23 (br. s, 1 H), 7.14 (d,J=7.4 Hz, 1 H), 7.06 (d,J=8.2 Hz, 1 H), 4. 34 (s, 2 H), 3.86 (s, 3 H), 3.63-3.55 (m, 2 H), 3.57-3.44 (m, 1 H), 3.28-3.17 (m, 2 H), 2.31-2.23 (m, 2 H), 2.15-2.01 (m, 2 H). MS (ESI,m/z) calculated for C13H20N2O [M+H]+ 220.16, found 221.15.Synthesized according to General Procedure B;1 H NMR (400 MHz, CD3 OD) δ 7.42 (t,J = 7.9 Hz, 1 H), 7.23 (br. S, 1 H), 7.14 (d,J = 7.4 Hz, 1 H), 7.06 ( d,J = 8.2 Hz, 1H), 4. 34 (s, 2H), 3.86 (s, 3H), 3.63-3.55 (m, 2H), 3.57-3.44 (m, 1H), 3.28 -3.17 (m, 2H), 2.31-2.23 (m, 2H), 2.15-2.01 (m, 2H). MS (ESI,m / z ) calculated for C13 H20 N2 0 [M + H]+ 220.16, found 221.15.
1-(One-(PyridinPyridin-4--4-ylmethylylmethyl))piperidinpiperidin-4--4-amineaminehydrochloridehydrochloride
일반적 절차 B에 따라 합성하였다;1H NMR (400 MHz, DMSO-d6) δ 8.86 (d,J = 6.3 Hz, 2 H), 8.32 (br. s, 2 H), 7.82 (d,J = 6.4 Hz, 2 H), 4.45 (s, 2 H), 3.45 (d,J = 12.3 Hz, 2 H), 3.37-3.25 (m, 1 H), 3.20-3.00 (m, 2 H), 2.17-1.99 (m, 2 H), 1.94-1.68 (m, 2 H). MS (ESI,m/z) calculated for C11H17N3 [M+H]+ 191.14, found 192.10.Synthesized according to General Procedure B;1 H NMR (400 MHz, DMSO-d6 ) δ 8.86 (d,J = 6.3 Hz, 2 H), 8.32 (br. S, 2 H), 7.82 (d,J = 6.4 Hz, 2H), 4.45 (s, 2H), 3.45 (d,J = 12.3 Hz, 2H), 3.37-3.25 (m, 1H), 3.20-3.00 (m, 2H), 2.17-1.99 (m, 2H), 1.94-1.68 (m, 2H). MS (ESI,m / z ) calculated for C11 H17 N3 [M + H]+ 191.14, found 192.10.
1-(3,4-1- (3,4-diMethoxybenzyldiMethoxybenzyl))piperidinpiperidin-4--4-amineaminehydrochloridehydrochloride
일반적 절차 B에 따라 합성하였다;1H NMR (400 MHz, DMSO-d6) δ 8.51 (br. s, 3 H), 7.41 (d,J=1.6 Hz, 1 H), 7.06 (dd,J=1.5, 8.2 Hz, 1 H), 6.99 (d,J=8.3 Hz, 1 H), 4.17 (d,J=4.7 Hz, 2 H), 3.80 (s, 3 H), 3.77 (s, 3 H), 3.38-3.30 (m, 2 H), 3.31-3.14 (m, 1 H), 3.06-2.94 (m, 2 H), 2.18-2.09 (m, 2 H), 2.09-1.96 (m, 2 H). MS (ESI,m/z) calculated for C14H22N2O2 [M+H]+ 250.17, found 251.15.Synthesized according to General Procedure B;1 H NMR (400 MHz, DMSO-d6 ) δ 8.51 (br. S, 3 H), 7.41 (d,J = 1.6 Hz, 1 H), 7.06 (dd,J = 1.5, 8.2 Hz, 1 H) , 6.99 (d,J = 8.3 Hz, 1H), 4.17 (d,J = 4.7 Hz, 2H), 3.80 (s, 3H), 3.77 (s, 3H), 3.38-3.30 (m, 2 H), 3.31-3.14 (m, 1H), 3.06-2.94 (m, 2H), 2.18-2.09 (m, 2H), 2.09-1.96 (m, 2H). MS (ESI,m / z ) calculated for C14 H22 N2 02 [M + H]+ 250.17, found 251.15.
1-(2-1- (2-MethoxybenzylMethoxybenzyl))piperidinpiperidin-4--4-amineaminehydrochloridehydrochloride
일반적 절차 B에 따라 합성하였다;1H NMR (400 MHz, DMSO-d6) δ 8.61 (br. s, 3 H), 7.64 (d,J=7.5 Hz, 1 H), 7.45 (t,J=7.5 Hz, 1 H), 7.12 (d,J=8.2 Hz, 1 H), 7.02 (t,J=7.4 Hz, 1 H), 4.19 (d,J=4.6 Hz, 2 H), 3.85 (s, 3 H), 3.43-3.34 (m, 2 H), 3.33-3.19 (m, 1 H), 3.10-2.98 (m, 2 H), 2.17-2.09 (m, 2 H), 2.08-1.95 (m, 2 H). MS (ESI,m/z) calculated for C13H20N2O [M+H]+ 220.16, found 221.25.Synthesized according to General Procedure B;1 H NMR (400 MHz, DMSO-d6 ) δ 8.61 (br. S, 3 H), 7.64 (d,J = 7.5 Hz, 1 H), 7.45 (t,J = 7.5 Hz, 1 H), 7.12 (d,J = 8.2 Hz, 1H), 7.02 (t,J = 7.4 Hz, 1H), 4.19 (d,J = 4.6 Hz, 2H), 3.85 (s, 3H), 3.43-3.34 ( m, 2H), 3.33-3.19 (m, 1H), 3.10-2.98 (m, 2H), 2.17-2.09 (m, 2H), 2.08-1.95 (m, 2H). MS (ESI,m / z ) calculated for C13 H20 N2 0 [M + H]+ 220.16, found 221.25.
1-(4-1- (4-MethoxybenzylMethoxybenzyl))piperidinpiperidin-4--4-amineaminehydrochloridehydrochloride
일반적 절차 B에 따라 합성하였다;1H NMR (400 MHz, DMSO-d6) δ 8.50 (br. s, 3 H), 7.53 (d,J=8.6 Hz, 2 H), 6.99 (d,J=8.7 Hz, 2 H), 4.17 (d,J=4.8 Hz, 2 H), 3.78 (s, 3 H), 3.39-3.31 (m, 2 H), 3.28-3.13 (m, 1 H), 3.03-2.92 (m, 2 H), 2.16-2.07 (m, 2 H), 2.04-1.92 (m, 2 H). MS (ESI,m/z) calculated for C13H20N2O [M+H]+ 220.16, found 221.25.Synthesized according to General Procedure B;1 H NMR (400 MHz, DMSO-d6 ) δ 8.50 (br. S, 3 H), 7.53 (d,J = 8.6 Hz, 2 H), 6.99 (d,J = 8.7 Hz, 2 H), 4.17 (d,J = 4.8 Hz, 2H), 3.78 (s, 3H), 3.39-3.31 (m, 2H), 3.28-3.13 (m, 1H), 3.03-2.92 (m, 2H), 2.16-2.07 (m, 2H), 2.04-1.92 (m, 2H). MS (ESI,m / z ) calculated for C13 H20 N2 0 [M + H]+ 220.16, found 221.25.
3-((4-3-((4-AminopiperidinAminopiperidin-1--One-ylyl))methylmethyl))phenolphenolhydrochloridehydrochloride
일반적 절차 B에 따라 합성하였다;1H NMR (400 MHz, DMSO-d6) δ 8.34 (br. s, 3 H), 7.24 (t,J=7.8 Hz, 1 H), 6.99 (d,J=7.7 Hz, 1 H), 6.96 (br. s, 1 H), 6.86 (d,J=8.0 Hz, 1 H), 4.14 (d,J=4.8 Hz, 2 H), 3.40-3.30 (m, 2 H), 3.27-3.17 (m, 1 H), 3.03-2.91 (m, 2 H), 2.14-2.04 (m, 2 H), 2.01-1.89 (m, 2 H). MS (ESI,m/z) calculated for C12H18N2O [M+H]+ 206.14, found 207.25.Synthesized according to General Procedure B;1 H NMR (400 MHz, DMSO-d6 ) δ 8.34 (br. S, 3 H), 7.24 (t,J = 7.8 Hz, 1 H), 6.99 (d,J = 7.7 Hz, 1 H), 6.96 (br. s, 1 H), 6.86 (d,J = 8.0 Hz, 1 H), 4.14 (d,J = 4.8 Hz, 2 H), 3.40-3.30 (m, 2H), 3.27-3.17 (m , 1H), 3.03-2.91 (m, 2H), 2.14-2.04 (m, 2H), 2.01-1.89 (m, 2H). MS (ESI,m / z ) calculated for C12 H18 N2 O [M + H]+ 206.14, found 207.25.
1-(3-1- (3-BromobenzylBromobenzyl))piperidinpiperidin-4--4-amineaminehydrochloridehydrochloride
일반적 절차 B에 따라 합성하였다;1H NMR (400 MHz, DMSO-d6) δ 8.50 (br. s, 3 H), 7.92 (br. s, 1 H), 7.68-7.62 (m, 2 H), 7.42 (t,J=7.8 Hz, 1 H), 4.27 (d,J=4.6 Hz, 2 H), 3.43-3.32 (m, 2 H), 3.29-3.18 (m, 1 H), 3.08-2.97 (m, 2 H), 2.18-2.08 (m, 2 H), 2.06-1.95 (m, 2 H). MS (ESI,m/z) calculated for C12H17BrN2 [M+H]+ 268.06, found 271.10.Synthesized according to General Procedure B;1 H NMR (400 MHz, DMSO-d6 ) δ 8.50 (br. S, 3 H), 7.92 (br. S, 1 H), 7.68-7.62 (m, 2H), 7.42 (t,J = 7.8 Hz, 1H), 4.27 (d,J = 4.6 Hz, 2H), 3.43-3.32 (m, 2H), 3.29-3.18 (m, 1H), 3.08-2.97 (m, 2H), 2.18 -2.08 (m, 2H), 2.06-1.95 (m, 2H). MS (ESI,m / z ) calculated for C12 H17 BrN2 [M + H]+ 268.06, found 271.10.
1-(3-1- (3-MethylbenzylMethylbenzyl))piperidinpiperidin-4--4-amineaminehydrochloridehydrochloride
일반적 절차 B에 따라 합성하였다;1H NMR (400 MHz, DMSO-d6) δ 8.44 (br. s, 3 H), 7.43-7.38 (m, 2 H), 7.34 (t,J=7.4 Hz, 1 H), 7.27 (d,J=7.5 Hz, 1 H), 4.19 (d,J=4.8 Hz, 2 H), 3.39-3.31 (m, 2 H), 3.28-3.16 (m, 1 H), 3.05-2.94 (m, 2 H), 2.33 (s, 3 H), 2.15-2.06 (m, 2 H), 2.04-1.93 (m, 2 H). MS (ESI,m/z) calculated for C13H20N2 [M+H]+ 204.16, found 205.25.Synthesized according to General Procedure B;1 H NMR (400 MHz, DMSO-d6 ) δ 8.44 (br. S, 3 H), 7.43-7.38 (m, 2 H), 7.34 (t,J = 7.4 Hz, 1 H), 7.27 (d,J = 7.5 Hz, 1 H), 4.19 (d,J = 4.8 Hz, 2 H), 3.39-3.31 (m, 2 H), 3.28-3.16 (m, 1 H), 3.05-2.94 (m, 2 H ), 2.33 (s, 3H), 2.15-2.06 (m, 2H), 2.04-1.93 (m, 2H). MS (ESI,m / z ) calculated for C13 H20 N2 [M + H]+ 204.16, found 205.25.
스킴Scheme 2. 화합물의 합성 2. Synthesis of Compound
[일반적인 반응식 Ⅱ]General Reaction Scheme II
시약 및 조건: (a) Amines, CDI, DMF, 실온; (b) Amines, TEA, NMP, microwave, 180℃Reagents and Conditions: (a) Amines, CDI, DMF, room temperature; (b) Amines, TEA, NMP, microwave, 180 ℃
일반적 절차 CGeneral procedure C
DMF (10 ml) 중의 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (1.00 g, 5.09 mmol) 용액에 CDI (1.07 g, 6.61 mmol)를 실온에서 적가한 후, 반응 혼합물을 실온에서 약 1시간 정도 교반하였다. 상기 혼합물에 다양한 아민 30 mmol(용매 THF) 2.0M을 천천히 적가한 후, 약 1시간 동안 실온에서 교반하였다. 수득 혼합물을 에틸 아세테이트에 부었고, 백색 고체물이 침전물로 얻어졌다.To a solution of 4-chloro-1H -pyrrolo [2,3-b ] pyridine-5-carboxylic acid (1.00 g, 5.09 mmol) in DMF (10 ml) was added dropwise CDI (1.07 g, 6.61 mmol) at room temperature. The reaction mixture was stirred at room temperature for about 1 hour. 30 mmol (solvent THF) 2.0 M of various amines were slowly added dropwise to the mixture, followed by stirring at room temperature for about 1 hour. The resulting mixture was poured into ethyl acetate and a white solid was obtained as a precipitate.
일반적 절차 DGeneral procedure D
NMP (2 ml) 중의 1-(benzyl)piperidin-4-amine hydrogen chloride salt (0.36 g, 1.43 mmol) 용액에 TEA (0.40 ml, 2.86 mmol) 및 4-chloro-N-alkyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (0.286 mmol)를 적가한 후, 마이크로웨이브 조사 하 약 180℃에서 약 3시간 동안 교반하였다. 결과물은 실온으로 냉각되었고, 에틸 아세테이트로 증류된 이후, H2O, 브라인, 건조MgSO4으로 세척되었다. 조화합물들은 실리카겔 속성 크로마토그래피(20% Methaol in dichloromethane elution)로 정제되어 표제의 생성물을 얻었다.In a solution of 1- (benzyl) piperidin-4-amine hydrogen chloride salt (0.36 g, 1.43 mmol) in NMP (2 ml), TEA (0.40 ml, 2.86 mmol) and 4-chloro-N- alkyl-1H -pyrrolo [ 2,3-b ] pyridine-5-carboxamide (0.286 mmol) was added dropwise, followed by stirring at about 180 ° C. under microwave irradiation. The result was cooled to rt, distilled with ethyl acetate and then washed with H2 O, brine, dry MgSO4 . The crude compounds were purified by silica gel flash chromatography (20% Methaol in dichloromethane elution) to give the title product.
4-Chloro-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide4-Chloro-N-methyl-1H-pyrrolo [2,3-b] pyridine-5-carboxamide
일반적 절차 C에 따라 합성하였다(수율 76%);1H NMR (400 MHz, DMSO-d6) δ 12.19 (br. s, 1 H), 8.45-8.38 (m, 1 H), 7.66 (d,J=3.5 Hz, 1 H), 6.57 (d,J=3.5 Hz, 1 H), 2.80 (d,J=4.6 Hz, 3 H).13C NMR (100 MHz, DMSO-d6) δ 166.24, 148.98, 142.77, 132.01, 128.82, 124.87, 118.97, 99.31, 26.66. MS (ESI,m/z) calculated for C9H8ClN3O [M+H]+ 209.04, found 210.00.Synthesized according to General Procedure C (yield 76%);1 H NMR (400 MHz, DMSO-d6 ) δ 12.19 (br. S, 1 H), 8.45-8.38 (m, 1 H), 7.66 (d,J = 3.5 Hz, 1 H), 6.57 (d,J = 3.5 Hz, 1 H), 2.80 (d,J = 4.6 Hz, 3 H).13 C NMR (100 MHz, DMSO-d6 ) δ 166.24, 148.98, 142.77, 132.01, 128.82, 124.87, 118.97, 99.31, 26.66. MS (ESI,m / z ) calculated for C9 H8 ClN3 O [M + H]+ 209.04, found 210.00.
4-Chloro-N-cyclopropyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide4-Chloro-N-cyclopropyl-1H-pyrrolo [2,3-b] pyridine-5-carboxamide
일반적 절차 C에 따라 합성하였다(수율 62%);1H NMR (400 MHz, DMSO-d6) δ 12.18 (s, 1 H), 8.53 (d,J=4.4 Hz, 1 H), 8.21 (s, 1 H), 7.65 (d,J=3.5 Hz, 1 H), 6.56 (d,J=3.5 Hz, 1 H), 2.91-2.80 (m, 1 H), 0.76-0.66 (m, 2 H), 0.60-0.51 (m, 2 H).13C NMR (100 MHz, DMSO-d6) δ 167.01, 148.94, 142.63, 132.06, 128.81, 124.79, 118.93, 99.29, 23.39, 6.25. MS (ESI,m/z) calculated for C11H10ClN3O [M+H]+ 235.05, found 235.95.Synthesized according to General Procedure C (yield 62%);1 H NMR (400 MHz, DMSO-d6 ) δ 12.18 (s, 1 H), 8.53 (d,J = 4.4 Hz, 1 H), 8.21 (s, 1 H), 7.65 (d,J = 3.5 Hz , 1H), 6.56 (d,J = 3.5 Hz, 1H), 2.91-2.80 (m, 1H), 0.76-0.66 (m, 2H), 0.60-0.51 (m, 2H).13 C NMR (100 MHz, DMSO- d 6) δ 167.01, 148.94, 142.63, 132.06, 128.81, 124.79, 118.93, 99.29, 23.39, 6.25. MS (ESI,m / z ) calculated for C11 H10 ClN3 O [M + H]+ 235.05, found 235.95.
4-Chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxamide4-Chloro-1H-pyrrolo [2,3-b] pyridine-5-carboxamide
일반적 절차 C에 따라 합성하였다(수율 71%);1H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 1 H), 7.49 (d,J=3.4 Hz, 1 H), 6.47 (d,J=3.4 Hz, 1 H).13C NMR (100 MHz, DMSO-d6) δ 168.76, 148.24, 145.29, 132.33, 128.10, 127.23, 119.13, 99.24. MS (ESI,m/z) calculated for C8H6ClN3O [M+H]+ 195.02, found 196.90.Synthesized according to General Procedure C (yield 71%);1 H NMR (400 MHz, DMSO-d6 ) δ 8.44 (s, 1 H), 7.49 (d,J = 3.4 Hz, 1 H), 6.47 (d,J = 3.4 Hz, 1 H).13 C NMR (100 MHz, DMSO- d 6) δ 168.76, 148.24, 145.29, 132.33, 128.10, 127.23, 119.13, 99.24. MS (ESI,m / z ) calculated for C8 H6 ClN3 O [M + H]+ 195.02, found 196.90.
4-Chloro-N-cyclopentyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide4-Chloro-N-cyclopentyl-1H-pyrrolo [2,3-b] pyridine-5-carboxamide
일반적 절차 C에 따라 합성하였다(수율 32%);1H NMR (400 MHz, DMSO-d6) δ 8.44 (d,J=7.2 Hz, 1 H), 8.20 (s, 1 H), 7.65 (d,J=3.4 Hz, 1 H), 6.56 (d,J=3.4 Hz, 1 H), 4.27-4.17 (m, 1 H), 1.96-1.82 (m, 2 H), 1.78-1.61 (m, 3 H), 1.59-1.42 (m, 5 H).13C NMR (100 MHz, DMSO-d6) δ 165.27, 148.90, 142.64, 131.96, 128.74, 125.29, 118.89, 99.19, 51.43, 32.64, 24.03. MS (ESI,m/z) calculated for C13H14ClN3O [M+H]+ 263.08, found 263.95.Synthesized according to General Procedure C (yield 32%);1 H NMR (400 MHz, DMSO-d6 ) δ 8.44 (d,J = 7.2 Hz, 1 H), 8.20 (s, 1 H), 7.65 (d,J = 3.4 Hz, 1 H), 6.56 (d ,J = 3.4 Hz, 1 H), 4.27-4.17 (m, 1 H), 1.96-1.82 (m, 2H), 1.78-1.61 (m, 3H), 1.59-1.42 (m, 5H).13 C NMR (100 MHz, DMSO- d 6) δ 165.27, 148.90, 142.64, 131.96, 128.74, 125.29, 118.89, 99.19, 51.43, 32.64, 24.03. MS (ESI,m / z ) calculated for C13 H14 ClN3 O [M + H]+ 263.08, found 263.95.
실시예Example 1 One
4-((1-(3-Cyanobenzyl)piperidin-4-yl)amino)-4-((1- (3-Cyanobenzyl) piperidin-4-yl) amino)-NN-methyl-1-methyl-1HH-pyrrolo[2,3-b]pyridine-5-carboxamide-pyrrolo [2,3-b] pyridine-5-carboxamide
일반적 절차 D에 따라 합성하였다(수율 17%);1H NMR (400 MHz, CD3OD) δ 8.38 (s, 1 H), 7.99 (br. s, 1 H), 7.93-7.89 (m, 8.1 Hz, 2 H), 7.73 (t, J=8.0 Hz, 1 H), 7.38 (d,J=4.0 Hz, 1 H), 6.96 (d,J=4.0 Hz, 1 H), 4.62-4.52 (m, 1 H), 4.50 (s, 2 H), 3.67-3.50 (m, 2 H), 3.50-3.38 (m, 2 H), 2.93 (s, 3 H), 2.52-2.40 (m, 2 H), 2.18-1.90 (m, 2 H).13C NMR (100 MHz, CD3OD) δ 168.08, 152.04, 138.93, 135.68, 135.68, 134.79, 134.68, 133.53, 130.63, 123.83, 117.49, 113.22, 106.50, 104.86, 103.67, 58.85, 48.44, 29.26, 25.37. MS (ESI,m/z) calculated for C22H24N6O [M+H]+ 388.20, found 389.10.Synthesized according to General Procedure D (yield 17%);1 H NMR (400 MHz, CD3 OD) δ 8.38 (s, 1 H), 7.99 (br. S, 1 H), 7.93-7.89 (m, 8.1 Hz, 2 H), 7.73 (t,J = 8.0 Hz, 1H), 7.38 (d,J = 4.0 Hz, 1H), 6.96 (d,J = 4.0 Hz, 1H), 4.62-4.52 (m, 1H), 4.50 (s, 2H), 3.67-3.50 (m, 2H), 3.50-3.38 (m, 2H), 2.93 (s, 3H), 2.52-2.40 (m, 2H), 2.18-1.90 (m, 2H).13 C NMR (100 MHz, CD3 OD) δ 168.08, 152.04, 138.93, 135.68, 135.68, 134.79, 134.68, 133.53, 130.63, 123.83, 117.49, 113.22, 106.50, 104.86, 103.67, 58.85, 48.44, 29.26, 25.37. MS (ESI,m / z ) calculated for C22 H24 N6 O [M + H]+ 388.20, found 389.10.
실시예Example 2 2
4-((1-(3-Methoxybenzyl)piperidin-4-yl)amino)-4-((1- (3-Methoxybenzyl) piperidin-4-yl) amino)-NN-methyl-1-methyl-1HH-pyrrolo[2,3-b]pyridine-5-carboxamide-pyrrolo [2,3-b] pyridine-5-carboxamide
일반적 절차 D에 따라 합성하였다(수율 27%);1H NMR (400 MHz, DMSO-d6) δ 9.44 (d,J=7.9 Hz, 1 H), 8.28 (s, 1 H), 8.22 (d,J=4.4 Hz, 1 H), 7.23 (t,J=8.0 Hz, 1 H), 7.15-7.12 (m, 1 H), 6.92-6.87 (m, 2 H), 6.81 (d,J=7.1 Hz, 1 H), 6.48 (br. s, 1 H), 4.02-3.92 (m., 1 H), 3.75 (s, 3 H), 3.47 (s, 2 H), 2.78-2.66 (m, 2 H), 2.74 (d,J=4.3 Hz, 3 H), 2.30-2.22 (m, 2 H), 2.05-1.97 (m, 2 H), 1.58-1.47 (m, 2 H).13C NMR (100 MHz, CD3OD) δ 167.96, 160.40, 152.11, 138.61, 134.49, 130.17, 130.14, 130.09, 123.85, 122.87, 121.45, 116.21, 115.47, 104.88, 103.74, 60.26, 54.46, 50.67, 29.58, 25.36. MS (ESI,m/z) calculated for C22H27N5O2 [M+H]+ 393.22, found 394.10.Synthesized according to General Procedure D (yield 27%);1 H NMR (400 MHz, DMSO-d6 ) δ 9.44 (d,J = 7.9 Hz, 1 H), 8.28 (s, 1 H), 8.22 (d,J = 4.4 Hz, 1 H), 7.23 (t ,J = 8.0 Hz, 1 H), 7.15-7.12 (m, 1 H), 6.92-6.87 (m, 2H), 6.81 (d,J = 7.1 Hz, 1 H), 6.48 (br.s, 1 H), 4.02-3.92 (m., 1H), 3.75 (s, 3H), 3.47 (s, 2H), 2.78-2.66 (m, 2H), 2.74 (d,J = 4.3 Hz, 3 H), 2.30-2.22 (m, 2H), 2.05-1.97 (m, 2H), 1.58-1.47 (m, 2H).13 C NMR (100 MHz, CD3 OD) δ 167.96, 160.40, 152.11, 138.61, 134.49, 130.17, 130.14, 130.09, 123.85, 122.87, 121.45, 116.21, 115.47, 104.88, 103.74, 60.26, 54.46, 50.67, 29.58, 29.58 25.36. MS (ESI,m / z ) calculated for C22 H27 N5 02 [M + H]+ 393.22, found 394.10.
실시예Example 3 3
NN-Methyl-4-((1-(pyridin-4-ylmethyl)piperidin-4-yl)amino)-1-Methyl-4-((1- (pyridin-4-ylmethyl) piperidin-4-yl) amino) -1HH-pyrrolo[2,3--pyrrolo [2,3-bb]pyridine-5-carboxamidepyridine-5-carboxamide
일반적 절차 D에 따라 합성하였다(수율 20%);1H NMR (400 MHz, DMSO-d6) δ 9.45 (d,J=7.8 Hz, 1 H), 8.51 (d,J=5.6 Hz, 2 H), 8.29 (s, 1 H), 8.23 (d,J=4.3 Hz, 1 H), 7.35 (d,J=5.5 Hz, 2 H), 7.14 (br. s, 1 H), 6.49 (br. s, 1 H), 4.04-3.95 (m, 1 H), 3.54 (s, 2 H), 2.78-2.67 (m, 2 H), 2.74 (d,J=4.2 Hz, 2 H), 2.35-2.26 (m, 2 H), 2.06-1.98 (m, 2 H), 1.60-1.49 (m, 2 H).13C NMR (100 MHz, DMSO-d6) δ 170.61, 150.71, 150.00, 149.31, 148.21, 144.98, 124.15, 122.29, 104.97, 103.09, 102.18, 61.16, 51.51, 49.29, 33.19, 26.54. MS (ESI,m/z) calculated for C20H24N6O [M+H]+ 364.20, found 365.20.Synthesized according to General Procedure D (yield 20%);1 H NMR (400 MHz, DMSO-d6 ) δ 9.45 (d,J = 7.8 Hz, 1 H), 8.51 (d,J = 5.6 Hz, 2 H), 8.29 (s, 1 H), 8.23 (d ,J = 4.3 Hz, 1 H), 7.35 (d,J = 5.5 Hz, 2 H), 7.14 (br. S, 1 H), 6.49 (br. S, 1 H), 4.04-3.95 (m, 1 H), 3.54 (s, 2H), 2.78-2.67 (m, 2H), 2.74 (d,J = 4.2 Hz, 2H), 2.35-2.26 (m, 2H), 2.06-1.98 (m, 2H), 1.60-1.49 (m, 2H).13 C NMR (100 MHz, DMSO-d6 ) δ 170.61, 150.71, 150.00, 149.31, 148.21, 144.98, 124.15, 122.29, 104.97, 103.09, 102.18, 61.16, 51.51, 49.29, 33.19, 26.54. MS (ESI,m / z ) calculated for C20 H24 N6 O [M + H]+ 364.20, found 365.20.
실시예Example 4 4
4-((1-(3,4-Dimethoxybenzyl)piperidin-4-yl)amino)-4-((1- (3,4-Dimethoxybenzyl) piperidin-4-yl) amino)-NN-methyl-1-methyl-1HH-pyrrolo[2,3-b]pyridine-5-carboxamide-pyrrolo [2,3-b] pyridine-5-carboxamide
일반적 절차 D에 따라 합성하였다(수율 36%);1H NMR (400 MHz, CD3OD) δ 8.36 (br. s, 1 H), 7.40-7.35 (m, 1 H), 7.19-7.05 (m, 4 H), 6.99-6.92 (m, 1 H), 4.58-4.47 (m, 1 H), 4.33 (br. s, 2 H), 3.90 (s, 3 H), 3.87 (s, 3 H), 3.69-3.61 (m, 2 H), 3.38-3.27 (m, 2 H), 2.91 (s, 3 H), 2.53-2.44 (m, 2 H), 2.02-1.87 (m, 2 H).13C NMR (100 MHz, CD3OD) δ 167.90, 150.68, 149.54, 138.54, 134.44, 124.08, 123.85, 121.05, 117.91, 115.01, 113.88, 111.50, 106.41, 104.90, 103.74, 60.22, 55.07, 55.02, 50.39, 29.61, 25.35. MS (ESI,m/z) calculated for C23H29N5O3 [M+H]+ 423.23, found 424.20.Synthesized according to General Procedure D (yield 36%);1 H NMR (400 MHz, CD3 OD) δ 8.36 (br. S, 1 H), 7.40-7.35 (m, 1 H), 7.19-7.05 (m, 4 H), 6.99-6.92 (m, 1 H ), 4.58-4.47 (m, 1H), 4.33 (br. S, 2H), 3.90 (s, 3H), 3.87 (s, 3H), 3.69-3.61 (m, 2H), 3.38- 3.27 (m, 2H), 2.91 (s, 3H), 2.53-2.44 (m, 2H), 2.02-1.87 (m, 2H).13 C NMR (100 MHz, CD3 OD) δ 167.90, 150.68, 149.54, 138.54, 134.44, 124.08, 123.85, 121.05, 117.91, 115.01, 113.88, 111.50, 106.41, 104.90, 103.74, 60.22, 55.07, 55.02, 50.39, 50 29.61, 25.35. MS (ESI,m / z ) calculated for C23 H29 N5 O3 [M + H]+ 423.23, found 424.20.
실시예Example 5 5
4-((1-(2-Methoxybenzyl)piperidin-4-yl)amino)-4-((1- (2-Methoxybenzyl) piperidin-4-yl) amino)-NN-methyl-1-methyl-1HH-pyrrolo[2,3-b]pyridine-5-carboxamide-pyrrolo [2,3-b] pyridine-5-carboxamide
일반적 절차 D에 따라 합성하였다(수율 20%);1H NMR (400 MHz, CD3OD) δ 8.21 (s, 1 H), 7.38-7.28 (m, 2 H), 7.13 (d,J=3.4 Hz, 1 H), 7.04-6.93 (m, 2 H), 6.61 (d,J=3.6 Hz, 1 H), 4.20-4.08 (m, 1 H), 3.87 (s, 3 H), 3.75 (s, 2 H), 3.05-2.94 (m, 2 H), 2.89 (s, 3 H), 2.62-2.50 (m, 2 H), 2.22-2.12 (m, 2 H), 1.80-1.69 (m, 2 H).13C NMR (100 MHz, CD3OD) δ 171.29, 158.20, 149.39, 149.35, 143.63, 131.39, 129.02, 123.65, 121.60, 119.96, 110.36, 105.24, 103.49, 101.85, 55.63, 54.44, 50.95, 31.78, 31.35, 25.23. MS (ESI,m/z) calculated for C22H27N5O2 [M+H]+ 393.22, found 394.00.Synthesized according to General Procedure D (yield 20%);1 H NMR (400 MHz, CD3 OD) δ 8.21 (s, 1 H), 7.38-7.28 (m, 2H), 7.13 (d,J = 3.4 Hz, 1H), 7.04-6.93 (m, 2 H), 6.61 (d,J = 3.6 Hz, 1 H), 4.20-4.08 (m, 1 H), 3.87 (s, 3 H), 3.75 (s, 2 H), 3.05-2.94 (m, 2 H ), 2.89 (s, 3H), 2.62-2.50 (m, 2H), 2.22-2.12 (m , 2H), 1.80-1.69 (m, 2H).13 C NMR (100 MHz, CD3 OD) δ 171.29, 158.20, 149.39, 149.35, 143.63, 131.39, 129.02, 123.65, 121.60, 119.96, 110.36, 105.24, 103.49, 101.85, 55.63, 54.44, 50.95, 31.78, 31.35, 31.35 25.23. MS (ESI,m / z ) calculated for C22 H27 N5 02 [M + H]+ 393.22, found 394.00.
실시예Example 6 6
4-((1-(4-Methoxybenzyl)piperidin-4-yl)amino)-4-((1- (4-Methoxybenzyl) piperidin-4-yl) amino)-NN-methyl-1-methyl-1HH-pyrrolo[2,3-b]pyridine-5-carboxamide-pyrrolo [2,3-b] pyridine-5-carboxamide
일반적 절차 D에 따라 합성하였다(수율 21%);1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1 H), 7.27-7.23 (m, 3 H), 7.03 (d,J=3.5 Hz, 1 H), 6.87(d,J=8.6 Hz, 2 H), 6.53 (d,J=3.5 Hz, 1 H), 4.05-3.95 (m, 1 H), 3.81 (s, 3 H), 3.50 (s, 2 H), 2.98 (s, 3 H), 2.89-2.77 (m, 2 H), 2.32-2.22 (m, 2 H), 2.15-2.08 (m, 2 H), 1.83-1.68 (m, 2 H).13C NMR (100 MHz, CDCl3) δ 170.66, 158.71, 149.89, 149.76, 143.37, 130.33, 120.96, 113.59, 105.12, 103.51, 102.75, 62.44, 55.27, 51.63, 32.83, 32.10, 26.65, 26.51. MS (ESI,m/z) calculated for C22H27N5O2 [M+H]+ 393.22, found 394.05.Synthesized according to General Procedure D (yield 21%);1 H NMR (400 MHz, CDCl3 ) δ 8.23 (s, 1 H), 7.27-7.23 (m, 3H), 7.03 (d,J = 3.5 Hz, 1 H), 6.87 (d,J = 8.6 Hz , 2 H), 6.53 (d,J = 3.5 Hz, 1 H), 4.05-3.95 (m, 1 H), 3.81 (s, 3 H), 3.50 (s, 2 H), 2.98 (s, 3 H ), 2.89-2.77 (m, 2H), 2.32-2.22 (m, 2H), 2.15-2.08 (m, 2H), 1.83-1.68 (m, 2H).13 C NMR (100 MHz, CDCl3 ) δ 170.66, 158.71, 149.89, 149.76, 143.37, 130.33, 120.96, 113.59, 105.12, 103.51, 102.75, 62.44, 55.27, 51.63, 32.83, 32.10, 26.65, 26.51. MS (ESI,m / z ) calculated for C22 H27 N5 02 [M + H]+ 393.22, found 394.05.
실시예Example 7 7
NN-Methyl-4-((1-phenylpiperidin-4-yl)amino)-1-Methyl-4-((1-phenylpiperidin-4-yl) amino) -1HH-pyrrolo[2,3--pyrrolo [2,3-bb]pyridine-5-carboxamidepyridine-5-carboxamide
일반적 절차 D에 따라 합성하였다(수율 30%);1H NMR (400 MHz, CD3OD) δ 8.28 (s, 1 H), 7.26 (t,J=8.7 Hz, 2 H), 7.15 (d,J=3.7 Hz, 1 H), 7.05 (d,J=7.9 Hz, 2 H), 6.86 (t,J=7.3 Hz, 1 H), 6.69 (d,J=3.7 Hz, 1 H), 4.30-4.21 (m, 1 H), 3.67-3.58 (m, 2 H), 3.37 (s, 2 H), 3.13-3.05 (m, 2 H), 2.89 (s, 3 H), 2.32-2.24 (m, 2 H), 1.88-1.77 (m, 2 H).13C NMR (100 MHz, CD3OD) δ 171.33, 151.51, 149.46, 149.38, 143.64, 128.65, 121.56, 119.74, 116.82, 105.30, 103.51, 102.01, 60.14, 49.48, 32.44, 25.24. MS (ESI,m/z) calculated for C20H23N5O [M+H]+ 349.19, found 350.05.Synthesized according to General Procedure D (yield 30%);1 H NMR (400 MHz, CD3 OD) δ 8.28 (s, 1 H), 7.26 (t,J = 8.7 Hz, 2 H), 7.15 (d,J = 3.7 Hz, 1 H), 7.05 (d,J = 7.9 Hz, 2H), 6.86 (t,J = 7.3 Hz, 1H), 6.69 (d,J = 3.7 Hz, 1H), 4.30-4.21 (m, 1H), 3.67-3.58 (m , 2H), 3.37 (s, 2H), 3.13-3.05 (m, 2H), 2.89 (s, 3H), 2.32-2.24 (m, 2H), 1.88-1.77 (m, 2H) .13 C NMR (100 MHz, CD3 OD) δ 171.33, 151.51, 149.46, 149.38, 143.64, 128.65, 121.56, 119.74, 116.82, 105.30, 103.51, 102.01, 60.14, 49.48, 32.44, 25.24. MS (ESI,m / z ) calculated for C20 H23 N5 O [M + H]+ 349.19, found 350.05.
실시예Example 8 8
4-((1-(3-Hydroxybenzyl)piperidin-4-yl)amino)-4-((1- (3-Hydroxybenzyl) piperidin-4-yl) amino)-NN-methyl-1-methyl-1HH-pyrrolo[2,3-b]pyridine-5-carboxamide-pyrrolo [2,3-b] pyridine-5-carboxamide
일반적 절차 D에 따라 합성하였다(수율 22%);1H NMR (400 MHz, CD3OD) δ 8.24 (br. s, 1 H), 7.23 (br. s, 1 H), 7.21 (d,J=7.8 Hz, 1 H), 6.90-6.78 (m, 4 H), 4.48-4.30 (m, 1 H), 4.21 (br. s, 2 H), 3.58-3.43 (m, 2 H), 2.80 (s, 3 H), 2.40-2.35 (m, 2 H), 1.90-1.73 (m, 2 H), 1.29-1.15 (m, 2 H).13C NMR (100 MHz, CD3OD) δ 167.99, 158.13, 152.07, 138.70, 134.56, 130.12, 130.07, 123.84, 121.61, 117.60, 116.72, 116.69, 104.86, 103.72, 65.50, 50.64, 41.49, 29.58, 25.37. MS (ESI,m/z) calculated for C21H25N5O2 [M+H]+ 379.20, found 379.80.Synthesized according to General Procedure D (yield 22%);1 H NMR (400 MHz, CD3 OD) δ 8.24 (br. S, 1 H), 7.23 (br. S, 1 H), 7.21 (d,J = 7.8 Hz, 1 H), 6.90-6.78 (m , 4 H), 4.48-4.30 (m, 1 H), 4.21 (br. S, 2 H), 3.58-3.43 (m, 2 H), 2.80 (s, 3 H), 2.40-2.35 (m, 2 H), 1.90-1.73 (m, 2H), 1.29-1.15 (m, 2H).13 C NMR (100 MHz, CD3 OD) δ 167.99, 158.13, 152.07, 138.70, 134.56, 130.12, 130.07, 123.84, 121.61, 117.60, 116.72, 116.69, 104.86, 103.72, 65.50, 50.64, 41.49, 29.58, 25.37 MS (ESI,m / z ) calculated for C21 H25 N5 02 [M + H]+ 379.20, found 379.80.
실시예Example 9 9
4-((1-(3-Bromobenzyl)piperidin-4-yl)amino)-4-((1- (3-Bromobenzyl) piperidin-4-yl) amino)-NN-methyl-1-methyl-1HH-pyrrolo[2,3-b]pyridine-5-carboxamide-pyrrolo [2,3-b] pyridine-5-carboxamide
일반적 절차 D에 따라 합성하였다(수율 36%);1H NMR (400 MHz, CDCl3) δ 8.13 (s, 1 H), 7.51 (br. s, 1 H), 7.40 (d,J=7.8 Hz, 1 H), 7.28 (d,J=7.6 Hz, 1 H), 7.21 (t,J=7.6 Hz, 1 H), 7.04 (d,J=3.7 Hz, 1 H), 6.52 (d,J=3.6 Hz, 1 H), 4.09-3.99 (m, 1 H), 3.53 (s, 2 H), 2.95 (s, 3 H), 2.88-2.78 (m, 2 H), 2.37-2.27 (m, 2 H), 2.17-2.08 (m, 2 H), 1.82-1.71 (m, 2 H).13C NMR (100 MHz, CD3OD) δ 170.78, 149.75, 149.24, 143.47, 140.42, 132.08, 130.24, 129.84, 127.77, 122.38, 121.13, 77.28, 62.38, 51.53, 32.51, 26.38. MS (ESI,m/z) calculated for C21H24BrN5O [M+H]+ 441.12, found 443.50.Synthesized according to General Procedure D (yield 36%);1 H NMR (400 MHz, CDCl3 ) δ 8.13 (s, 1 H), 7.51 (br. S, 1 H), 7.40 (d,J = 7.8 Hz, 1 H), 7.28 (d,J = 7.6 Hz , 1 H), 7.21 (t,J = 7.6 Hz, 1 H), 7.04 (d,J = 3.7 Hz, 1 H), 6.52 (d,J = 3.6 Hz, 1 H), 4.09-3.99 (m, 1 H), 3.53 (s, 2 H), 2.95 (s, 3 H), 2.88-2.78 (m, 2 H), 2.37-2.27 (m, 2 H), 2.17-2.08 (m, 2 H), 1.82-1.71 (m, 2H).13 C NMR (100 MHz, CD3 OD) δ 170.78, 149.75, 149.24, 143.47, 140.42, 132.08, 130.24, 129.84, 127.77, 122.38, 121.13, 77.28, 62.38, 51.53, 32.51, 26.38. MS (ESI,m / z ) calculated for C21 H24 BrN5 O [M + H]+ 441.12, found 443.50.
실시예Example 10 10
N-Methyl-4-((1-(3-methylbenzyl)piperidin-4-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxamideN-Methyl-4-((1- (3-methylbenzyl) piperidin-4-yl) amino) -1H-pyrrolo [2,3-b] pyridine-5-carboxamide
일반적 절차 D에 따라 합성하였다(수율 21%);1H NMR (400 MHz, CDCl3) δ 8.14 (s, 1 H), 7.23 (t,J=7.5 Hz, 1 H), 7.19-7.13 (m, 2 H), 7.10 (d,J=7.4 Hz, 1 H), 7.04 (d,J=3.6 Hz, 1 H), 6.52 (d,J=3.6 Hz, 1 H), 4.10-4.00 (m, 1 H), 3.57 (s, 2 H), 2.94 (s, 3 H), 2.92-2.82 (m, 2 H), 2.43-2.32 (m, 2 H), 2.36 (s, 3 H), 2.20-2.10 (m, 2 H), 1.83-1.72 (m, 2 H).13C NMR (100 MHz, CD3OD) δ 170.75, 149.77, 148.93, 143.23, 137.92, 136.87, 130.26, 128.16, 128.10, 126.58, 121.23, 105.23, 103.56, 102.64, 77.29, 35.94, 51.34, 32.19, 26.35, 21.28. MS (ESI,m/z) calculated for C22H27N5O [M+H]+ 377.22, found 378.60.Synthesized according to General Procedure D (yield 21%);1 H NMR (400 MHz, CDCl3 ) δ 8.14 (s, 1 H), 7.23 (t,J = 7.5 Hz, 1 H), 7.19-7.13 (m, 2H), 7.10 (d,J = 7.4 Hz , 1 H), 7.04 (d,J = 3.6 Hz, 1 H), 6.52 (d,J = 3.6 Hz, 1 H), 4.10-4.00 (m, 1 H), 3.57 (s, 2 H), 2.94 (s, 3H), 2.92-2.82 (m, 2H), 2.43-2.32 (m, 2H), 2.36 (s, 3H), 2.20-2.10 (m, 2H), 1.83-1.72 (m , 2 H).13 C NMR (100 MHz, CD3 OD) δ 170.75, 149.77, 148.93, 143.23, 137.92, 136.87, 130.26, 128.16, 128.10, 126.58, 121.23, 105.23, 103.56, 102.64, 77.29, 35.94, 51.34, 32.19, 26.35 21.28. MS (ESI,m / z ) calculated for C22 H27 N5 O [M + H]+ 377.22, found 378.60.
실시예Example 11 11
4-((1-(3-Cyanobenzyl)piperidin-4-yl)amino)-4-((1- (3-Cyanobenzyl) piperidin-4-yl) amino)-NN-cyclopropyl-1-cyclopropyl-1HH-pyrrolo[2,3-b]pyridine-5-carboxamide-pyrrolo [2,3-b] pyridine-5-carboxamide
일반적 절차 D에 따라 합성하였다(수율 16%);1H NMR (400 MHz, CD3OD) δ 8.37 (s, 1 H), 8.01 (s, 1 H), 7.95-7.89 (m, 2 H), 7.39 (d,J=4.0 Hz, 1 H), 6.98 (d,J=4.0 Hz, 1 H), 4.63-4.53 (m, 1 H), 4.51 (s, 2 H), 3.71-3.55 (m, 2 H), 3.51-3.39 (m, 2 H), 2.93-2.81 (m, 1 H), 2.54-2.38 (m, 2 H), 2.10-1.97 (m, 2 H), 0.89-0.82 (m, 2 H), 0.71-0.64 (m, 2 H). MS (ESI,m/z) calculated for C24H26N6O [M+H]+ 414.22, found 415.15.Synthesized according to General Procedure D (yield 16%);1 H NMR (400 MHz, CD3 OD) δ 8.37 (s, 1 H), 8.01 (s, 1 H), 7.95-7.89 (m, 2H), 7.39 (d,J = 4.0 Hz, 1 H) , 6.98 (d,J = 4.0 Hz, 1 H), 4.63-4.53 (m, 1 H), 4.51 (s, 2 H), 3.71-3.55 (m, 2 H), 3.51-3.39 (m, 2 H ), 2.93-2.81 (m, 1H), 2.54-2.38 (m, 2H), 2.10-1.97 (m, 2H), 0.89-0.82 (m, 2H), 0.71-0.64 (m, 2H) ). MS (ESI,m / z ) calculated for C24 H26 N6 O [M + H]+ 414.22, found 415.15.
실시예Example 12 12
N-N-cyclopropylcyclopropyl-4-((1-(3--4-((1- (3-methoxybenzylmethoxybenzyl))piperidinpiperidin-4--4-ylyl)amino)-1H-pyrrolo[2,3-b]pyridine -5-carboxamide) amino) -1H-pyrrolo [2,3-b] pyridine -5-carboxamide
일반적 절차 D에 따라 합성하였다(수율 20%);1H NMR (400 MHz, CD3OD) δ 8.23 (br. s, 1 H), 7.37-7.29 (m, 1 H), 7.05-6.93 (m, 3 H), 6.82 (br. s, 1 H), 4.48-4.31 (m, 1 H), 4.25 (br. s, 2 H), 3.60-3.48 (m, 2 H), 3.30-3.20 (m, 2 H), 2.84-2.70 (m, 1 H), 2.43-2.31 (m, 2 H), 1.90-1.73 (m, 2 H), 0.80-0.69 (m, 2 H), 0.60-0.49 (m, 2 H). MS (ESI,m/z) calculated for C24H29N5O2 [M+H]+ 419.23, found 420.15.Synthesized according to General Procedure D (yield 20%);1 H NMR (400 MHz, CD3 OD) δ 8.23 (br. S, 1 H), 7.37-7.29 (m, 1 H), 7.05-6.93 (m, 3 H), 6.82 (br. S, 1 H ), 4.48-4.31 (m, 1 H), 4.25 (br. S, 2 H), 3.60-3.48 (m, 2 H), 3.30-3.20 (m, 2 H), 2.84-2.70 (m, 1 H ), 2.43-2.31 (m, 2H), 1.90-1.73 (m, 2H), 0.80-0.69 (m, 2H), 0.60-0.49 (m, 2H). MS (ESI,m / z ) calculated for C24 H29 N5 02 [M + H]+ 419.23, found 420.15.
실시예Example 13 13
4-((1-(3-Methoxybenzyl)piperidin-4-yl)amino)-14-((1- (3-Methoxybenzyl) piperidin-4-yl) amino) -1HH-pyrrolo[2,3--pyrrolo [2,3-bb]pyridine-5-carboxamidepyridine-5-carboxamide
일반적 절차 D에 따라 합성하였다(수율 14%);1H NMR (400 MHz, CD3OD) δ 8.49 (br. s, 1 H), 7.50-7.42 (m, 1 H), 7.37 (br. s, 1 H), 7.18-7.09 (m, 3 H), 6.95 (br. s, 1 H), 4.59-4.43 (m, 1 H), 4.37 (br. s, 2 H), 3.70-3.59 (m, 2 H), 3.42-3.32 (m, 2 H), 2.57-2.49 (m, 2 H), 1.99-1.84 (m, 2 H); MS (ESI,m/z) calculated for C21H25N5O2 [M+H]+ 379.20, found 380.15.Synthesized according to General Procedure D (yield 14%);1 H NMR (400 MHz, CD3 OD) δ 8.49 (br. S, 1 H), 7.50-7.42 (m, 1 H), 7.37 (br. S, 1 H), 7.18-7.09 (m, 3 H ), 6.95 (br. S, 1 H), 4.59-4.43 (m, 1 H), 4.37 (br. S, 2 H), 3.70-3.59 (m, 2 H), 3.42-3.32 (m, 2 H ), 2.57-2.49 (m, 2H), 1.99-1.84 (m, 2H); MS (ESI,m / z ) calculated for C21 H25 N5 02 [M + H]+ 379.20, found 380.15.
실시예Example 14 14
N-N-cyclopentylcyclopentyl-4-((1-(3--4-((1- (3-methoxybenzylmethoxybenzyl))piperidinpiperidin-4--4-ylyl)amino)-1H-pyrrolo[2,3-b]pyridine -5-carboxamide) amino) -1H-pyrrolo [2,3-b] pyridine -5-carboxamide
일반적 절차 D에 따라 합성하였다(수율 11%);1H NMR (400 MHz, CD3OD) δ 8.40 (br. s, 1 H), 7.49-7.40 (m, 1 H), 7.38 (d, J=4.0 Hz, 1 H), 7.18-7.09 (m, 3 H), 6.95 (br. s, 1 H), 4.58-4.45 (m, 1 H), 4.37 (s, 2 H), 4.34-4.26 (m, 1 H), 3.70-3.60 (m, 2 H), 3.40-3.30 (m, 2 H), 2.57-2.41 (m, 2 H), 2.11-2.00 (m, 4 H), 2.00-1.88 (m, 2 H), 1.74-1.56 (m, 4 H).MS (ESI,m/z) calculated for C26H33N5O2 [M+H]+ 447.26, found 448.20.Synthesized according to General Procedure D (yield 11%);1 H NMR (400 MHz, CD3 OD) δ 8.40 (br. S, 1 H), 7.49-7.40 (m, 1 H), 7.38 (d,J = 4.0 Hz, 1 H), 7.18-7.09 (m , 3 H), 6.95 (br. S, 1 H), 4.58-4.45 (m, 1 H), 4.37 (s, 2 H), 4.34-4.26 (m, 1 H), 3.70-3.60 (m, 2 H), 3.40-3.30 (m, 2H), 2.57-2.41 (m, 2H), 2.11-2.00 (m, 4H), 2.00-1.88 (m, 2H), 1.74-1.56 (m, 4 H). MS (ESI,m / z ) calculated for C26 H33 N5 02 [M + H]+ 447.26, found 448.20.
실시예Example 15 15
4-((1-(3-Cyanobenzyl)piperidin-4-yl)amino)-4-((1- (3-Cyanobenzyl) piperidin-4-yl) amino)-NN-cyclopentyl-1-cyclopentyl-1HH-pyrrolo[2,3--pyrrolo [2,3-bb]pyridine-5-carboxamidepyridine-5-carboxamide
일반적 절차 D에 따라 합성하였다(수율 22%);1H NMR (400 MHz, CD3OD) δ 8.41 (s, 1 H), 7.98 (s, 1 H), 7.96-7.88 (m, 2 H), 7.78-7.70 (m, 1 H), 7.39 (d, J=4.0 Hz, 1 H), 6.96 (d, J=4.0 Hz, 1 H), 4.61-4.53 (m, 1 H), 4.32 (s, 2 H), 4.40-4.29 (m, 1 H), 3.72-3.54 (m, 2 H), 3.54-3.38 (m, 2 H), 2.55-2.40 (m, 2 H), 2.12-2.00 (m, 4 H), 1.88-1.75 (m, 2 H), 1.75-1.57 (m, 4 H).MS (ESI,m/z) calculated for C26H30N6O [M+H]+ 442.25, found 443.15.Synthesized according to General Procedure D (yield 22%);1 H NMR (400 MHz, CD3 OD) δ 8.41 (s, 1 H), 7.98 (s, 1 H), 7.96-7.88 (m, 2 H), 7.78-7.70 (m, 1 H), 7.39 ( d,J = 4.0 Hz, 1H), 6.96 (d,J = 4.0 Hz, 1H), 4.61-4.53 (m, 1H), 4.32 (s, 2H), 4.40-4.29 (m, 1H ), 3.72-3.54 (m, 2H), 3.54-3.38 (m, 2H), 2.55-2.40 (m, 2H), 2.12-2.00 (m, 4H), 1.88-1.75 (m, 2H) ), 1.75-1.57 (m, 4H). MS (ESI,m / z ) calculated for C26 H30 N6 O [M + H]+ 442.25, found 443.15.
실시예Example 16 16
4-((1-Benzylpiperidin-4-yl)amino)-4-((1-Benzylpiperidin-4-yl) amino)-NN-methyl-1-methyl-1HH-pyrrolo[2,3--pyrrolo [2,3-bb]pyridine-5-carboxamidepyridine-5-carboxamide
일반적 절차 D에 따라 합성하였다(수율 6%);1H NMR (400 MHz, CDCl3) δ 9.21 (d,J=7.8 Hz, 1 H), 8.19 (s, 1 H), 7.38-7.23 (m, 5 H), 7.04 (d,J=3.7 Hz, 1 H), 6.56 (d,J=3.7 Hz, 1 H), 6.04 (s, 1 H), 4.07-3.96 (m, 1 H), 3.56 (s, 2 H), 2.99 (d,J=4.8 Hz, 3 H), 2.91-2.80 (m, 2 H), 2.35-2.22 (m, 2 H), 2.17-2.08 (m, 2 H), 1.82-1.73 (m, 2 H); MS (ESI,m/z) calculated for C21H25N5O [M+H]+ 363.21, found 363.90.Synthesized according to General Procedure D (yield 6%);1 H NMR (400 MHz, CDCl3 ) δ 9.21 (d,J = 7.8 Hz, 1 H), 8.19 (s, 1 H), 7.38-7.23 (m, 5H), 7.04 (d,J = 3.7 Hz , 1 H), 6.56 (d,J = 3.7 Hz, 1 H), 6.04 (s, 1 H), 4.07-3.96 (m, 1 H), 3.56 (s, 2 H), 2.99 (d,J = 4.8 Hz, 3H), 2.91-2.80 (m, 2H), 2.35-2.22 (m, 2H), 2.17-2.08 (m, 2H), 1.82-1.73 (m, 2H); MS (ESI,m / z ) calculated for C21 H25 N5 O [M + H]+ 363.21, found 363.90.
실시예Example 17 17
4-((1-Benzylpiperidin-4-yl)(methyl)amino)-4-((1-Benzylpiperidin-4-yl) (methyl) amino)-NN-methyl-1-methyl-1HH-pyrrolo[2,3--pyrrolo [2,3-bb]pyridine-5-carboxamidepyridine-5-carboxamide
일반적 절차 D에 따라 합성하였다(수율 12%);1H NMR (400 MHz, CDCl3) δ 10.50 (s, 1 H), 9.36 (d, J=4.6 Hz, 1 H), 9.05 (s, 1 H), 7.38-7.21 (m, 5 H), 6.61 (d, J=3.3 Hz, 1 H), 3.48 (s, 2 H), 3.32-3.27 (m, 1 H), 3.10-2.95 (m, 8 H), 2.90-2.82 (m, 2 H), 2.00-1.91 (m, 2 H), 1.78-1.70 (m, 2 H). MS (ESI,m/z) calculated for C22H27N5O [M+H]+ 377.22, found 378.00.Synthesized according to General Procedure D (yield 12%);1 H NMR (400 MHz, CDCl3 ) δ 10.50 (s, 1 H), 9.36 (d,J = 4.6 Hz, 1 H), 9.05 (s, 1 H), 7.38-7.21 (m, 5 H), 6.61 (d,J = 3.3 Hz, 1 H), 3.48 (s, 2 H), 3.32-3.27 (m, 1 H), 3.10-2.95 (m, 8 H), 2.90-2.82 (m, 2 H) , 2.00-1.91 (m, 2H), 1.78-1.70 (m, 2H). MS (ESI,m / z ) calculated for C22 H27 N5 O [M + H]+ 377.22, found 378.00.
실시예Example 18 18
4-((1-4-((1-BenzylpiperidinBenzylpiperidin-4--4-ylyl)amino)-1) amino) -1HH--pyrrolo[2,3-pyrrolo [2,3-bb]pyridine] pyridine-5-carboxylic acid-5-carboxylic acid
일반적 절차 D에 따라 합성하였다(수율 12%);1H NMR (400 MHz, CD3OD) δ 7.96 (s, 1 H), 7.67-7.44 (m, 5 H), 7.35-7.23 (m, 1 H), 6.90 (d,J=3.6 Hz, 1 H), 6.74 (s, 1 H), 4.39 (s, 2 H), 4.19-4.02 (m, 1 H), 3.73-3.56 (m, 2 H), 3.29-3.15 (m, 2 H), 2.41-2.23 (m, 2 H), 2.10-1.91 (m, 2 H). MS (ESI,m/z) calculated for C20H22N4O2 [M+H]+ 350.17, found 348.15.Synthesized according to General Procedure D (yield 12%);1 H NMR (400 MHz, CD3 OD) δ 7.96 (s, 1 H), 7.67-7.44 (m, 5 H), 7.35-7.23 (m, 1 H), 6.90 (d,J = 3.6 Hz, 1 H), 6.74 (s, 1H), 4.39 (s, 2H), 4.19-4.02 (m, 1H), 3.73-3.56 (m, 2H), 3.29-3.15 (m, 2H), 2.41 -2.23 (m, 2H), 2.10-1.91 (m, 2H). MS (ESI,m / z ) calculated for C20 H22 N4 O2 [M + H]+ 350.17, found 348.15.
실시예Example 19 19
4-((1-Benzylpiperidin-4-yl)amino)-4-((1-Benzylpiperidin-4-yl) amino)-NN-cyclopropyl-1-cyclopropyl-1HH-pyrrolo[2,3--pyrrolo [2,3-bb]pyridine-5-carboxamidepyridine-5-carboxamide
일반적 절차 D에 따라 합성하였다(수율 11%);1H NMR (400 MHz, CDCl3) δ 9.34 (br. s, 1 H), 9.28 (d,J=7.8 Hz, 1 H), 8.12 (s, 1 H), 7.38-7.30 (m, 4 H), 7.30-7.27 (m, 1 H), 7.03 (d,J=3.6 Hz, 1 H), 6.55 (d,J=3.7 Hz, 1 H), 6.18 (s, 1 H), 4.08-3.91 (m, 1 H), 3.56 (s, 2 H), 2.94-2.77 (m, 2 H), 2.34-2.20 (m, 2 H), 2.16-2.06 (m, 2 H), 2.08-1.97 (m, 1 H), 1.81-1.71 (m, 2 H), 0.92-0.85 (m, 2 H), 0.67-0.59 (m, 2 H). MS (ESI,m/z) calculated for C23H27N5O [M+H]+ 389.22, found 389.75.Synthesized according to General Procedure D (yield 11%);1 H NMR (400 MHz, CDCl3 ) δ 9.34 (br.s, 1 H), 9.28 (d,J = 7.8 Hz, 1 H), 8.12 (s, 1 H), 7.38-7.30 (m, 4 H ), 7.30-7.27 (m, 1H), 7.03 (d,J = 3.6 Hz, 1H), 6.55 (d,J = 3.7 Hz, 1H), 6.18 (s, 1H), 4.08-3.91 ( m, 1H), 3.56 (s, 2H), 2.94-2.77 (m, 2H), 2.34-2.20 (m, 2H), 2.16-2.06 (m, 2H), 2.08-1.97 (m, 1H), 1.81-1.71 (m, 2H), 0.92-0.85 (m, 2H), 0.67-0.59 (m, 2H). MS (ESI,m / z ) calculated for C23 H27 N5 O [M + H]+ 389.22, found 389.75.
실시예Example 20 20
4-((1-Benzylpiperidin-4-yl)amino)-4-((1-Benzylpiperidin-4-yl) amino)-NN-cyclopentyl-1-cyclopentyl-1HH-pyrrolo[2,3--pyrrolo [2,3-bb]pyridine-5-carboxamidepyridine-5-carboxamide
일반적 절차 D에 따라 합성하였다(수율 23%);1H NMR (400 MHz, CD3OD) δ 8.39 (s, 1 H), 7.61-7.52 (m, 5 H), 7.40 (d, J=4.0 Hz, 1 H), 6.97 (d, J=4.0 Hz, 1 H), 4.57-4.48 (m, 1 H), 4.34 (s, 2 H), 4.34-4.26 (m, 1 H), 3.72-3.62 (m, 2 H), 3.50-3.40 (m, 2 H), 2.56-2.44 (m, 2 H), 2.11-2.02 (m, 2 H), 1.99-1.89 (m, 2 H), 1.88-1.76 (m, 2 H), 1.76-1.54 (m, 4 H). MS (ESI,m/z) calculated for C25H29N5O2 [M+H]+ 417.25, found 418.15.Synthesized according to General Procedure D (yield 23%);1 H NMR (400 MHz, CD3 OD) δ 8.39 (s, 1 H), 7.61-7.52 (m, 5H), 7.40 (d,J = 4.0 Hz, 1H), 6.97 (d,J = 4.0 Hz, 1H), 4.57-4.48 (m, 1H), 4.34 (s, 2H), 4.34-4.26 (m, 1H), 3.72-3.62 (m, 2H), 3.50-3.40 (m, 2H), 2.56-2.44 (m, 2H), 2.11-2.02 (m, 2H), 1.99-1.89 (m, 2H), 1.88-1.76 (m, 2H), 1.76-1.54 (m, 4 H). MS (ESI,m / z ) calculated for C25 H29 N5 02 [M + H]+ 417.25, found 418.15.
Claims (8)
Translated fromKorean[화학식 I]
상기 식에서,
R1은 메틸기이고;
R2는 수소기이고;
R3는
R4, 및 R5는, 각각 독립적으로, 수소기, C1-C3 알킬기, C1-C3 알콕시기, 할로겐기, 히드록시기, 또는 시아노기이며; n은 1의 정수이다.
단, R4, 및 R5 중 적어도 하나 이상은 수소기이다.A compound of formula (I) or a pharmaceutically acceptable salt thereof.
[Formula I]
Where
R1 is a methyl group;
R2 is a hydrogen group;
R3 is
R4 and R5 are each independently a hydrogen group, a C1 -C3 alkyl group, a C1 -C3 alkoxy group, a halogen group, a hydroxy group, or a cyano group; n is an integer of 1.
Provided that at least one of R4 and R5 is a hydrogen group.
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| KR102551758B1 (en)* | 2020-11-30 | 2023-07-05 | 주식회사한국파마 | Novel jak specific inhibitor compounds, and method for the preparation thereof |
| AR127972A1 (en)* | 2021-12-17 | 2024-03-13 | Pi Industries Ltd | NOVEL FUSED SUBSTITUTED BICYCLIC CARBOXAMIDE PYRIDINE COMPOUNDS TO COMBAT PHYTOPATHOGENIC FUNGI |
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| PT2455382T (en) | 2005-12-13 | 2017-01-31 | Incyte Holdings Corp | PYRIDOLES [2,3-B] PYRIDINES AND PYRROLE [2,3-B] PYRIMIDINES SUBSTITUTED BY HETEROARYLO AS JANUS KINASES INHIBITORS |
| WO2008084861A1 (en)* | 2007-01-12 | 2008-07-17 | Astellas Pharma Inc. | Condensed pyridine compound |
| EP3112370A1 (en)* | 2011-08-12 | 2017-01-04 | Nissan Chemical Industries, Ltd. | Tricyclic heterocyclic compounds and jak inhibitors |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2007529486A (en) | 2004-03-16 | 2007-10-25 | グラクソ グループ リミテッド | Pyrazolo [3,4-b] pyridine compounds and their use as PDE4 inhibitors |
| WO2008135232A1 (en) | 2007-05-02 | 2008-11-13 | Riccardo Cortese | Use and compositions of purine derivatives for the treatment of proliferative disorders |
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| BIOORGANIC & MEDICINAL CHEMISTRY 23 (2015) 4871-4883* |
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| KR20190062081A (en) | 2019-06-05 |
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