CN110545814A - 趋化因子cxcr4受体调节剂及其相关用途 - Google Patents
趋化因子cxcr4受体调节剂及其相关用途 Download PDFInfo
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Abstract
本公开内容涉及趋化因子CXCR4受体调节剂及其相关用途。该受体调节剂可以被配制以形成包含所公开的化合物或其药学上可接受的盐或前药的药物组合物。该组合物可以被用于控制CXCR4相关的状况,通常是预防或治疗病毒感染、异常细胞增殖、视网膜退化(retinal degeneration)、炎性疾病,或作为免疫刺激剂或免疫抑制剂,或用于控制癌症并且可以与另一种活性成分诸如抗病毒剂或化学治疗剂一起施用。
Description
相关申请的交叉引用
本申请要求于2017年2月21日提交的美国临时申请号62/461,682、于2017年2月21日提交的美国临时申请号62/461,690、于2017年2月21日提交的美国临时申请号62/461,695、以及于2017年2月21日提交的美国临时申请号62/461,698的权益。出于所有目的,这些申请的每一个的全部内容通过引用特此并入。
领域
本公开内容涉及趋化因子CXCR4受体调节剂及其相关的用途。在某些实施方案中,本公开内容涉及包含本文公开的化合物或其药学上可接受的盐或前药的药物组合物。在某些实施方案中,本文公开的组合物被用于控制CXCR4相关的状况,通常是预防或治疗病毒感染诸如HIV或用于控制癌症。
背景
截至2007年底,全世界估计有3300万人携带HIV/AIDS,并且美国疾病控制和预防中心(Centers for Disease Control and Prevention)(CDC)估计有1,200,000美国居民携带HIV感染(UNAIDS/WHO AIDS epidemic update,December 2008;The Henry J.KaiserFamily Foundation HIV/AIDS Policy Fact Sheet,July 2007)。尽管近年来新感染已经减少,但2007年期间在全球发生了估计260万例新HIV感染,并且在美国每年发生约40,000例HIV新感染。
HIV进入靶细胞内涉及一系列分子事件。病毒进入细胞内的三个主要步骤是:(i)病毒附着至受试细胞;(ii)病毒与协同受体相互作用;和(iii)病毒和受试细胞膜融合。考虑到病毒感染涉及的分子事件的复杂性,所有三个这些步骤已经被考虑用于药物设计。T淋巴细胞表面蛋白CD4是参与与病毒糖蛋白gp120的相互作用的主要受体,但细胞协同受体也是病毒成功进入细胞内所需要的。迄今为止,已经鉴定出至少两种类型的这样的协同受体,其两种是趋化因子受体,CCR5和CXCR4。因此,这些趋化因子受体是HIV进入的关口(gateway),是病毒趋性(tropism)和敏感性的决定因素。
靶向病毒进入的化合物具有优于靶向HIV-1逆转录酶或蛋白酶的那些化合物的两个优点:进入抑制剂不依赖于有效的细胞摄取或细胞内活化过程以发挥其生物作用,以及它们极不可能显示与蛋白酶抑制剂或逆转录酶抑制剂的任何交叉耐受性。通过第一种融合抑制剂恩夫韦地(enfuvirtide)已经将病毒进入验证为临床上有效的靶向干预途径。正在开发的其他类别的进入抑制剂靶向病毒gp120与CD4的初始结合以及gp120与用作HIV进入的协同受体的细胞表面趋化因子受体(CCR5或CXCR4)的相互作用。(Westby等人,Journalof Virology,2006,80(10),4909-4920)。
因为CXCR4是T-嗜性HIV感染的主要协同受体,靶向CXCR4的化合物已经被开发,主要用于HIV的治疗。例如,美国专利号6,429,308公开了一种用于作为抗HIV剂使用的针对CXCR4的反义寡核苷酸以抑制CXCR4蛋白的表达。PCT申请公布号WO 2001/56591描述了病毒巨噬细胞炎性蛋白II的肽片段,其被描述为选择性地阻止介导HIV-I进入的CXCR4信号转导和协同受体功能。趋化因子CXCR4受体的另外的分子拮抗剂被公开在PCT申请公布号WO2009/121063和WO 2006/020415以及美国专利号8,969,381中。
研究已经显示,CXCR4相互作用还调控转移性细胞的迁移。缺氧,即氧分压的降低,是发生于大多数实体肿瘤中的微环境变化,并且是肿瘤血管生成和治疗耐受性的主要诱导因素。缺氧增加CXCR4水平(Staller等人,2003,Nature 425:307-311)。对来自具有升高的转移活性的骨转移模型的细胞的亚群的微阵列分析显示,转移表型中增加的基因之一是CXCR4。此外,分离的细胞中CXCR4的过表达显著地增加了转移活性(Kang等人,2003,CancerCell 3:537-549)。在从多个乳腺癌患者收集的样品中,Muller等人(2001,Nature 410:50-56)发现,相对于正常乳腺或上皮细胞,在原发性肿瘤中CXCR4表达水平更高。这些结果表明,癌细胞表面上的CXCR4的表达可能将癌细胞引导到表达高水平的SDF-1的部位。与该假设一致,SDF-1在乳腺癌转移的最常见目的地(包括淋巴结、肺、肝脏和骨髓)中高表达。此外,当与全部转移到淋巴结和肺的对照同种型相比时,CXCR4抗体治疗已经显示对向局部淋巴结(regional lymph node)的转移的抑制(Muller等人,2001,Nature 410:50-56)。
除调控癌细胞的迁移之外,CXCR4-SDF-1相互作用可以调控转移所必需的血管形成。阻断CXCR4/SDF-1相互作用或CXCR4/SDF-1信号传导通路的主要G蛋白(Gαi)抑制了VEGF-依赖性新血管形成(neovascularization)。这些结果指示,SDF-1/CXCR4控制为内皮细胞形态发生和血管生成的调控物的VEGF信号传导系统。许多研究已经显示,VEGF和MMP积极地促进癌症进展和转移。
因此,存在鉴定用于在治疗或预防病毒感染诸如HIV中的治疗应用和用于治疗或预防癌症的CXCR4拮抗剂的需要。
概述
本公开内容涉及趋化因子CXCR4受体调节剂及其在治疗应用和诊断应用中的用途。
根据本发明的第一实施方案,提供了式(I)的化合物或其盐,
其中RA1是任选地取代的杂环基,其中取代基选自一个或更多个并且相同或不同的RX1;RA2是氢或烷基;RB选自包含烷基、任选地取代的氨基烷基和任选地取代的杂环基的组;其中取代基选自一个或更多个并且相同或不同的RX1;RC是氢、任选地取代的烷基或任选地取代的杂环基;并且RX1选自包含烷基、环烷基(cyloalkyl)、卤素、甲氧基和三氟甲基的组。
该实施方案的其他特征允许RA1选自以下:
RB选自包含以下的组:甲基、RC为以下:H、CH2RY2、CH=CHCH2RY2、OCH2CH2RY2、NHRY2、N(RY2)2、 RY2选自包含以下的组:H、OH、F、CH3、CH2CH3、CH2OCH3、CH2F、CF3、NH2、 其中取代基RY2在合适的情况下可以单独地并且独立地单取代或二取代到RX2上;并且RX1选自包含以下的组:甲基、乙基、乙烯、丙基、环丙基、氟、氯、甲氧基和三氟甲基。
在该实施方案的又其他特征中,RA1选自包含以下的组:
在一个示例性实施方案中,式(I)的化合物选自包含以下的组:
根据本发明的第二实施方案,提供了式(II)的化合物或其盐,
其中RD是H或烷基,RE是甲基、异丙基或氨基取代的碳环基;RF是任选地取代的杂环基;其中RF的取代基选自一个或更多个并且相同的或不同的RX2;并且RX2是任选地取代的芳基、任选地取代的杂环基或任选地取代的氨基,并且其中RX2的取代基选自一个或更多个并且相同的或不同的RY2;并且RY2选自包含以下的组:甲基、乙基、异丙基、环丙基、氧杂环丁烷、氨基、二甲氨基、甲基哌嗪、吡啶、吡啶基甲基、嘧啶和三氟甲基苯;条件是,当RD是H并且RE是CH3时,那么RF不是:
该实施方案的其他特征允许RE选自包含以下的组:
*CH3、
RF选自包含以下的组:
RX2选自包含以下的组:
CH2RY2、CH=CHCH2RY2、OCH2CH2RY2、NHRY2、N(RY2)2、 RY2选自包含以下的组的:H、OH、F、CH3、CH2CH3、CH2OCH3、CH2F、 其中取代基RY2在合适的情况下可以单独地并且独立地单取代或二取代到RX2上;并且
其中RZ是H或CH3,并且W是CH或N。
该实施方案的又其他特征允许RF选自包含以下的组:
在本发明的示例性实施方案中,式(II)的化合物可以选自包含以下的组:
根据本发明的第三实施方案,提供了式(III)的化合物或其盐,
其中RG是可以是E或Z的任选地取代的烯烃、任选地取代的碳环基、任选地取代的芳基、任选地取代的杂环基或任选地取代的季碳;X是C或N,并且当X是C时,RH是氢或杂环基,或当X是N时,RH不存在。
其他特征允许RG选自包含以下的组:
其中Y是H、烷基或卤素;RI选自包含H、NH2、卤素和CH2NHRJ的组,并且在碳环的情况中,芳基和杂环RI可以包括一个或更多个并且对于每个环相同的或不同的取代基;并且RJ选自包含以下的组:
H、
或RG为将附接的NMe连接至四氢喹啉的烷基;
且RH为以下:H、CH2RY2、CH=CHCH2RY2、OCH2CH2RY2、NHRY2、N(RY2)2、 RY2选自包含以下的组:H、OH、F、CH3、CH2CH3、CH2OCH3、CH2F、CF3、NH2、 其中取代基RY2在合适的情况下当X是C时可以单独地并且独立地单取代或二取代到RX2上,或当X是N时RY2不存在。
该实施方案的又其他特征提供了选自包含以下的组的RG:
和将NCH3连接至四氢喹啉的CH2CH2基团。
在一个示例性实施方案中,式(III)的化合物选自包含以下的组:
根据本发明的第四实施方案,提供了式(IV)的化合物或其盐,
其中环A是具有或不具有稠合苯环体系的杂芳环体系,RK是C1至C6烷基,并且Z是CH、NH、N或S。
该实施方案的其他特征允许A选自包含以下的组:
在一个示例性实施方案中,式(IV)的化合物选自包含以下的组:
在某些实施方案中,本公开内容涉及包含呈基本上纯的形式的本文公开的化合物的分离的组合物。
在某些实施方案中,本公开内容涉及包含如本文描述的化合物,包括其盐和前药以及药学上可接受的赋形剂、稀释剂或载体的药物组合物。
在某些实施方案中,药物组合物包含以大于60%、70%、80%、90%、95%、98%非对映体过量或对映体过量的化合物。
在某些实施方案中,本公开内容涉及本文公开的化合物在产生用于治疗CXCR4相关的状况的药物或作为免疫刺激剂或免疫抑制剂的用途,所述状况诸如病毒感染、异常细胞增殖、视网膜退化(retinal degeneration)、炎性疾病。
在某些实施方案中,本公开内容涉及包含如本文描述的化合物和另一种活性成分诸如抗病毒剂或化学治疗剂的药物组合物。
在某些实施方案中,本公开内容涉及与CCR5拮抗剂诸如马拉维若(maraviroc)(selzentry)或vicriviroc组合施用本文公开的CXCR4拮抗剂。
在某些实施方案中,本公开内容涉及治疗或预防病毒感染的方法,所述方法包括向有相应需要的受试者施用包含任选地与另一种活性成分组合的如本文描述的化合物的药物组合物。在其他实施方案中,受试者处于病毒感染的风险、展现病毒感染的症状或被诊断为具有病毒感染。
在某些实施方案中,本公开内容涉及如本文描述的化合物在产生用于治疗病毒感染的药物中的用途。在典型的实施方案中,病毒感染是HIV感染。
在某些实施方案中,本公开内容涉及治疗或预防癌症的方法,所述方法包括向有相应需要的受试者施用包含任选地与另一种活性成分组合的如本文描述的化合物的药物组合物。在其他实施方案中,受试者处于癌症的风险、展现癌症的症状或被诊断为具有癌症。
详细描述
术语
当描述在本公开内容中使用的化合物时,除非上下文另有说明,否则使用的术语应根据以下定义来解释。
对于R取代基,符号*表示形成附接至马库什结构的点的碳。例如,在式:中,其中RB是建议的物质是
如本文使用的,“烷基”意指非环状、直链或支链的、不饱和或饱和的烃,诸如包含从1个至10个碳原子的那些烃,通常是1个至4个以其他方式命名的C1-4烷基。代表性的饱和直链烷基包括甲基、乙基、正丙基、正丁基、正戊基、正己基、正庚基(n-septyl)、正辛基、正壬基等;而饱和支链烷基包括异丙基、仲丁基、异丁基、叔丁基、异戊基等。不饱和烷基包含在相邻的碳原子之间的至少一个双键或三键(分别地被称为“烯基”或“炔基”)。代表性直链烯基和支链烯基包括乙烯基、丙烯基、1-丁烯基、2-丁烯基、异丁烯基、1-戊烯基、2-戊烯基、3-甲基-1-丁烯基、2-甲基-2-丁烯基、2,3-二甲基-2-丁烯基等;而代表性直链炔基和支链炔基包括乙炔基、丙炔基、1-丁炔基、2-丁炔基、1-戊炔基、2-戊炔基、3-甲基-1-丁炔基等。
非芳族单环烷基或多环烷基在本文中被称为“碳环”或“碳环基”基团。代表性饱和碳环包括环丙基、环丁基、环戊基、环己基等;而不饱和碳环包括环戊烯基和环己烯基等。
“杂碳环”或“杂碳环基”基团是包含1个至4个独立地选自氮、氧和硫的杂原子的碳环,其可以是饱和的或不饱和的(但不是芳族的)、单环的或多环的,并且其中氮杂原子和硫杂原子可以任选地被氧化,并且氮杂原子可以任选地被季铵化。杂碳环包括吗啉基、吡咯烷酮基、吡咯烷基、哌啶基、乙内酰脲基、戊内酰胺基、环氧乙烷基、氧杂环丁烷基、四氢呋喃基、四氢吡喃基、四氢吡啶基、四氢嘧啶基(tetrahydroprimidinyl)、四氢噻吩基、四氢硫代吡喃基等。
术语“芳基”是指芳族同环的(即,烃)包含单环、二环或三环的基团,优选地具有6元至12元,诸如苯基、萘基和联苯基。苯基是优选的芳基基团。术语“取代的芳基”是指用优选地选自以下的一个或更多个基团取代的芳基基团:烷基、取代的烷基、烯基(任选地取代的)、芳基(任选地取代的)、杂环(任选地取代的)、卤素、羟基、烷氧基(任选地取代的)、芳氧基(任选地取代的)、烷酰基(任选地取代的)、芳酰基(任选地取代的)、烷基酯(任选地取代的)、芳基酯(任选地取代的)、氰基、硝基、氨基、取代的氨基、酰胺基、内酰胺、脲、氨基甲酸酯、磺酰基等,其中任选地一对或更多对取代基与其键合的原子一起形成3元至7元环。
如本文使用的,“杂芳基”或“杂芳族”是指具有1个至4个选自氮、氧和硫的杂原子并且包含至少1个碳原子的芳族杂碳环,包括单环体系和多环体系二者。多环体系可以但不是必须包含一个或更多个非芳族环,只要所述环之一是芳族环。代表性杂芳基是呋喃基、苯并呋喃基、噻吩基、苯并噻吩基、吡咯基、吲哚基、异吲哚基、氮杂吲哚基、吡啶基、喹啉基、异喹啉基、噁唑基、异噁唑基、苯并噁唑基、吡唑基、咪唑基、苯并咪唑基、噻唑基、苯并噻唑基、异噻唑基、哒嗪基、嘧啶基、吡嗪基、三嗪基、噌啉基、酞嗪基和喹唑啉基。预期术语“杂芳基”的使用包括N-烷基化衍生物,诸如1-甲基咪唑-5-基取代基。
如本文使用的,“杂环”或“杂环基”是指具有1个至4个选自氮、氧和硫的杂原子并且包含至少1个碳原子的单环体系和多环体系。单环体系和多环体系可以是芳族的、非芳族的或芳环和非芳环的混合物。杂环包括杂碳环、杂芳基等。
“烷硫基”是指通过硫桥附接的如上文定义的烷基基团。烷硫基的一个实例是甲硫基,(即,--S--CH3)。
“烷氧基”是指通过氧桥附接的如上文定义的烷基基团。烷氧基的实例包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基、和仲戊氧基。优选的烷氧基基团是甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基。“烷基氨基”是指通过氨基桥附接的如上文定义的烷基基团。烷基氨基的一个实例是甲基氨基,(即,--NH--CH3)。
“氨基烷基”是指通过烷基桥附接的如上文定义的氨基基团(即,NH2-烷基-)。
“烷酰基”是指通过羰基桥附接的如上文定义的烷基(即,--(C=O)烷基)。
“烷基磺酰基”是指通过磺酰基桥附接的如上文定义的烷基(即,--S(=O)2烷基)诸如甲磺酰基等,并且“芳基横酰基”是指通过磺酰基桥附接的芳基(即,--S(=O)2芳基)。
“烷基氨横酰基”是指通过氨磺酰基桥附接的如上文定义的烷基(即,--NHS(=O)2烷基),并且“芳基氨横酰基”是指通过氨磺酰基桥附接的烷基(即,--NHS(=O)2芳基)。
“烷基亚磺酰基”是指通过亚磺酰基桥附接的如上文定义的烷基(即--S(=O)烷基)。
术语“卤素(halogen)”和“卤素(halo)”是指氟、氯、溴和碘。
术语“取代的”是指其中至少一个氢原子被取代基替代的分子。当被取代时,一个或更多个基团是“取代基”。分子可以被多重取代。在氧代取代基(″=O”)的情况中,两个氢原子被替代。本文中的示例性取代基可以包括卤素、羟基、烷基、烷氧基、硝基、氰基、氧代、碳环基、碳环烷基、杂碳环基、杂碳环烷基、芳基、芳基烷基、杂芳基、杂芳基烷基、--NRaRb、--NRaC(=O)Rb、--NR.aC(=O)NRaNRb、--NRaC(=)ORb、--NRaSO2Rb、--C(=O)Ra、--C(=O)ORa、--C(=O)NRaRb、--OC(=O)NRaRb、--ORa、--SRa、--SORa、--S(=O)2Ra、--OS(=O)2Ra和--S(=O)2ORa。在本文中,Ra和Rb可以是相同的或不同的,并且独立地为氢、卤素羟基、烷基、烷氧基、烷基、氨基、烷基氨基、二烷基氨基、碳环基、碳环烷基、杂碳环基、杂碳环烷基、芳基、芳基烷基、杂芳基、杂芳基烷基。
如本文使用的,术语“任选地取代的”意指取代是任选的并且因此对于指定的原子可能是未取代的。
如本文使用的,“盐”是指所公开的化合物的衍生物,其中母体化合物被修饰而制备其酸盐或碱盐。盐的实例包括但不限于碱性残基诸如胺、烷基胺或二烷基胺的无机酸盐或有机酸盐;酸性残基诸如羧酸的碱金属盐或有机盐;等。在优选的实施方案中,盐是常规无毒性的药学上可接受的盐,包括形成的母体化合物、和无毒性的无机酸或有机酸的季铵盐。优选的盐包括衍生自诸如以下无机酸的那些盐:盐酸、氢溴酸、硫酸、氨基磺酸、磷酸、硝酸等;以及从诸如以下有机酸制备的盐:乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、双羟萘酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、对氨基苯磺酸、2-乙酰氧基苯甲酸、富马酸、甲苯磺酸、甲磺酸、乙烷二磺酸、草酸、羟乙基磺酸等。
“受试者”是指任何动物,优选地人类患者、牲畜或家养宠物。
术语“前药”是指在体内转化成生物活性形式的剂。前药通常是有用的,因为在一些情况中,它们可能比母体化合物更容易施用。它们可以,例如,是通过口服施用而生物可利用的,而母体化合物则不是。前药还可能具有超过母体药物的改善的在药物组合物中的溶解度。前药可以通过多种机制包括酶促过程和代谢水解转化成母体药物。
如本文使用的,术语“预防(prevent)”和“预防(preventing)”包括复发、扩散或发作的预防。意图本公开内容不限于完全预防。在一些实施方案中,发作被延迟,或疾病的严重程度被降低。
如本文使用的,术语“治疗(treat)”和“治疗(treating)”不限于其中受试者(例如患者)被治愈并且疾病被根除的情况。而是,本公开内容的实施方案还预期了仅仅降低症状和/或延迟疾病进展的治疗。
“癌症”是指具有以细胞的增殖为特征的恶性赘生物的多种细胞疾病的任何一种。不预期患病的细胞必须真正地侵入周围组织并且转移至新的身体部位。癌症可以涉及身体的任何组织,并且在每个身体区域中具有许多不同的形式。在某些实施方案的上下文中,是否“癌症被降低”可以通过本领域技术人员已知的许多诊断方式来鉴定,包括但不限于观察肿瘤块的大小或数目的降低或是否观察到癌细胞的凋亡的增加,例如,是否观察到与不具有化合物的对照相比对于样品化合物的癌细胞的凋亡增加多于5%。还可以通过相关的生物标志物或基因表达谱诸如用于前列腺癌的PSA、用于乳腺癌的HER2等的变化来鉴定。
使用的方法
在某些实施方案中,本文描述的化合物可用于治疗病毒感染,其中病毒利用CXCR4来感染细胞。
在一个实施方案中,本公开内容涉及一种治疗或预防HIV感染或降低与AIDS相关的症状的方法,该方法包括向受试者施用本文公开的化合物。在某些实施方案中,可以在用另一种化合物治疗感染前向受试者提供该化合物。在一个单独的实施方案中,向已被治疗HIV感染的患者提供该化合物以降低复发的可能性,或降低与AIDS相关症状相关的死亡率。在另一个实施方案中,向处于患有HIV感染的高风险的受试者施用该化合物。
可以通过在药学上可接受的载体或稀释剂的存在下施用有效量的活性化合物或其药学上可接受的前药或盐来治疗受试者,包括患有HIV感染或处于HIV感染的风险的人类。
施用可以预防性地用于预防HIV感染或减少与AIDS相关的症状。活性物质可以以液体或固体形式通过任何适当的途径来施用,例如,口服、肠胃外、静脉内、皮内、皮下或局部。然而,该化合物特别适合于口服递送。
在一个单独的实施方案中,提供了一种用于通过向需要治疗的受试者施用本公开内容的化合物或其药学上可接受的盐、溶剂化物、前药或酯来治疗或预防HIV感染或降低与AIDS相关的症状的方法。本公开内容的化合物或其药学上可接受的盐、溶剂化物、前药或酯可以向有相应需要的受试者施用以降低AIDS相关的紊乱(disorder)的严重程度。在本公开内容的一个实施方案中,受试者是人类。
在一个单独的实施方案中,提供了一种用于治疗、预防与病毒感染相关的肝脏疾病或降低与病毒感染相关的肝脏疾病的严重程度的方法,该方法包括施用本文描述的至少一种化合物。
慢性丙型肝炎病毒(HCV)和乙型肝炎病毒(HBV)感染伴随着炎症和纤维化,最终导致肝硬化。测试肝脏浸润的淋巴细胞(LIL)上的CXCR4的表达和功能的一项研究揭示了CXCL12/CXCR4途径在慢性HCV和HBV感染期间将免疫细胞募集和保留在肝脏中的重要作用(Wald等人,(2004)European Journal of Immunology.34(4):1164-1174)。已经从感染HCV的患者获得的肝脏样品中检测到高水平的CXCR4和TGFβ。(Mitra等人,(1999)Int.J.Oncol.14:917-925)。在体外,已表明TGFβ上调T细胞上CXCR4的表达并且增加其迁移。CD69/TGFβ/CXCR4途径可能参与了新近活化的淋巴细胞在肝脏中的保留(Wald等人,European Journal of Immunology,2004;34(4):1164-1174)。
在另一个实施方案中,本公开内容涉及一种通过使细胞与本公开内容的化合物或其药学上可接受的盐、溶剂化物、前药或酯接触来治疗与其他感染相关的症状的方法,所述其他感染与趋化因子受体活化相关,例如,与黄病毒或瘟病毒感染并且特别是HCV或HBV相关的肝脏疾病。细胞可以是在受试动物体内的,特别是在人体内的。
化合物通常可以被用于治疗异常细胞增殖的紊乱,其实例包括但不限于下文列出的癌症和增殖性紊乱的类型。异常细胞增殖,特别是过度增殖,可因许多种因素而发生,所述因素包括遗传突变、感染、暴露于毒素、自身免疫紊乱以及良性肿瘤诱导或恶性肿瘤诱导。
存在与细胞过度增殖相关的许多皮肤紊乱。例如,银屑病是人类皮肤的一种良性疾病,通常地以增厚的鳞片覆盖的斑块(plaque)为特征。该疾病由未知原因的表皮细胞的增殖增加导致。在正常皮肤中,细胞从基底层移动到上部颗粒层所需要的时间为约五周。在银屑病中,部分地由于增殖细胞的数目的增加和正在分裂的细胞的比例的增加,这一时间仅为6天至9天(G.Grove,Int.J.Dermatol.18:111,1979)。慢性湿疹也与表皮的明显过度增殖相关。由皮肤细胞的过度增殖导致的其他疾病包括特应性皮炎、扁平苔藓、疣、寻常天疱疮、光化性角化病、基底细胞癌和鳞状细胞癌。
其他过度增殖性细胞紊乱包括血管增殖紊乱、纤维化紊乱、自身免疫紊乱、移植物抗宿主排斥、肿瘤和癌症。
血管增殖性紊乱包括血管生成(angiogenic)紊乱和血管形成(vasculogenic)紊乱。在斑块在血管组织中的发展的进程中,平滑肌细胞的增殖导致例如,再狭窄、视网膜病和动脉粥样硬化。动脉粥样硬化的晚期病变是由对动脉壁的内皮和平滑肌的损伤的过度炎性-增殖性响应导致的(Ross,R.Nature,1993,362:801-809)。细胞迁移和细胞增殖都在动脉粥样硬化病变的形成中起作用。
纤维化紊乱通常是由于细胞外基质的异常形成。纤维化紊乱的实例包括肝硬化和系膜增殖性细胞紊乱。肝硬化以导致肝瘢痕(hepatic scar)形成的细胞外基质成分的增加为特征。肝硬化可以导致诸如肝脏的硬化的疾病。导致肝瘢痕的增加的细胞外基质还可以由病毒感染诸如肝炎导致。脂肪细胞似乎在肝硬化中起主要作用。
系膜紊乱是由系膜细胞的异常增殖带来的。系膜过度增殖性细胞紊乱包括多种人类肾脏疾病,诸如肾小球肾炎、糖尿病肾病、恶性肾硬化、血栓性微血管病综合征、移植排斥和肾小球病。
具有增殖性组分的另一种疾病是类风湿性关节炎。类风湿性关节炎通常被认为是一种自身免疫疾病,其被认为与自身反应性T细胞的活跃相关(参见,例如,Harris,E.D.,Jr.(1990)The New England Journal of Medicine,322:1277-1289),并且由针对胶原蛋白和IgE产生的自身抗体导致。
可能包括异常细胞增殖性组分的其他紊乱包括白塞综合征(Behcet′ssyndrome)、急性呼吸窘迫综合征(ARDS)、缺血性心脏病、透析后综合征、白血病、获得性免疫缺陷综合征、血管炎、脂质组织细胞增生症、脓毒性休克和一般炎症。
可以是被治疗的原发性肿瘤的癌症或增殖性紊乱的实例包括但不限于位于以下的赘生物:结肠、腹部、骨、乳房、消化系统、肝脏、胰腺、腹膜、内分泌腺(肾上腺、甲状旁腺、垂体、睾丸、卵巢、胸腺、甲状腺)、眼、头颈部、神经(中枢和外周)、淋巴系统、骨盆、皮肤、软组织、脾脏、胸腔和泌尿生殖道。
在某些实施方案中,受试者被诊断为具有急性儿童淋巴母细胞白血病;急性淋巴母细胞白血病、急性淋巴细胞白血病、急性髓细胞白血病、肾上腺皮质癌、成人(原发性)肝细胞癌、成人(原发性)肝癌、成人急性淋巴细胞白血病、成人急性髓细胞白血病、成人霍奇金病(adult Hodgkin′s disease)、成人霍奇金淋巴瘤、成人淋巴细胞白血病、成人非霍奇金淋巴瘤、成人原发性肝癌、成人软组织肉瘤、AIDS相关的淋巴瘤、AIDS相关的恶性肿瘤、肛门癌、星形细胞瘤、胆管癌、膀胱癌、骨癌、脑干胶质瘤、脑肿瘤、乳腺癌、肾盂和输尿管癌、中枢神经系统(原发性)淋巴瘤、中枢神经系统淋巴瘤、小脑星形细胞瘤、脑星形细胞瘤、宫颈癌、儿童(原发性)肝细胞癌、儿童(原发性)肝癌、儿童急性淋巴母细胞白血病、儿童急性髓细胞白血病、儿童脑干胶质瘤、儿童小脑星形细胞瘤、儿童脑星形细胞瘤、儿童颅外生殖细胞瘤、儿童霍奇金病、儿童霍奇金淋巴瘤、儿童下丘脑和视觉通路胶质瘤、儿童淋巴母细胞白血病、儿童髓母细胞瘤、儿童非霍奇金淋巴瘤、儿童松果体和幕上原始神经外胚层肿瘤、儿童原发性肝癌、儿童横纹肌肉瘤、儿童软组织肉瘤、儿童视觉通路和下丘脑胶质瘤、慢性淋巴细胞白血病、慢性髓细胞性白血病、结肠癌、皮肤T细胞淋巴瘤、内分泌胰岛细胞癌、子宫内膜癌、室管膜瘤、上皮癌、食道癌、尤因肉瘤(Ewing’s sarcoma)和相关的肿瘤、外分泌胰腺癌、颅外生殖细胞肿瘤、性腺外生殖细胞肿瘤、肝外胆管癌、眼癌、女性乳腺癌、戈谢病(Gaucher′s disease)、胆囊癌、胃癌、胃肠类癌肿瘤、胃肠肿瘤、生殖细胞肿瘤、妊娠滋养层肿瘤、毛细胞白血病、头颈癌、肝细胞癌、霍奇金病、霍奇金淋巴瘤、高丙种球蛋白血症、下咽癌、肠癌、眼内黑素瘤、胰岛细胞癌、胰岛细胞胰腺癌、卡波西肉瘤、肾癌、喉癌、唇和口腔癌、肝癌、肺癌、淋巴增殖性紊乱、巨球蛋白血症、男性乳腺癌、恶性间皮瘤、恶性胸腺瘤、髓母细胞瘤、黑素瘤、间皮瘤、转移性隐匿性原发性鳞状颈癌、转移性原发性鳞状颈癌、转移性鳞状颈癌、多发性骨髓瘤、多发性骨髓瘤/浆细胞肿瘤、髓异常增生综合征(myelodysplasiasyndrome)、髓细胞性白血病、髓细胞白血病、髓增殖性紊乱(myeloproliferativedisorders)、鼻腔和鼻旁窦癌、鼻咽癌、神经母细胞瘤、妊娠期非霍奇金淋巴瘤、非黑素瘤皮肤癌、非小细胞肺癌、隐匿性原发性转移性鳞状颈癌、口咽癌、骨/恶性纤维肉瘤、骨肉瘤/恶性纤维组织细胞瘤、骨肉瘤/恶性骨纤维组织细胞瘤、卵巢上皮癌、卵巢生殖细胞肿瘤、卵巢低度恶性潜能肿瘤(ovarian low malignant potential tumor)、胰腺癌、副蛋白血症、紫癜、甲状旁腺癌、阴茎癌、嗜铬细胞瘤、垂体肿瘤、浆细胞肿瘤/多发性骨髓瘤、原发性中枢神经系统淋巴瘤、原发性肝癌、前列腺癌、直肠癌、肾细胞癌、肾盂和输尿管癌、视网膜母细胞瘤、横纹肌肉瘤、唾液腺癌、结节病肉瘤(sarcoidosis sarcomas)、塞扎里综合征(sezarysyndrome)、皮肤癌、小细胞肺癌、小肠癌、软组织肉瘤、鳞状颈癌、胃癌、幕上原始神经外胚层和松果体肿瘤、T细胞淋巴瘤、睾丸癌、胸腺瘤、甲状腺癌、肾盂和输尿管的移行细胞癌、移行肾盂和输尿管癌、滋养层肿瘤、输尿管和肾盂细胞癌、输尿管癌、子宫癌、子宫肉瘤、阴道癌、视觉通路和下丘脑胶质瘤、外阴癌、华氏巨球蛋白血症(Waldenstrom′smacroglobulinemia)、威氏肿瘤(Wilm′s tumor)、以及位于上文列出的器官系统中的任何其他过度增殖性疾病。
在某些实施方案中,本文公开的化合物可以被用于治疗或预防过度增殖性紊乱,包括但不限于,血管滤泡纵隔淋巴结增生、具有嗜酸性粒细胞增多症的血管淋巴增生、非典型黑素细胞增生、基底细胞增生、良性巨大淋巴结增生、牙骨质增生、先天性肾上腺增生、先天性皮脂腺增生、囊性增生、乳腺的囊性增生、义齿增生、导管增生、子宫内膜增生、纤维肌增生、局灶性上皮增生、牙龈增生、炎性纤维增生、炎性乳头状增生、血管内乳头状内皮增生、前列腺的结节性增生、结节性再生性增生、假上皮瘤样增生、老年皮脂腺增生和疣状增生;白血病(包括急性白血病(例如,急性淋巴细胞白血病、急性髓细胞白血病(包括髓母细胞白血病、幼粒细胞白血病、髓单核细胞白血病、单核细胞白血病和红白血病))和慢性白血病(例如,慢性髓细胞(粒细胞)白血病和慢性淋巴细胞白血病))、真性红细胞增多症、淋巴瘤(例如,霍奇金病和非霍奇金病)、多发性骨髓瘤、华氏巨球蛋白血症、重链疾病、和实体肿瘤,包括但不限于肉瘤和癌诸如纤维肉瘤、黏液肉瘤、脂肪肉瘤(fiposarcoma)、软骨肉瘤、成骨性肉瘤、脊髓瘤、血管肉瘤、内皮肉瘤、淋巴管肉瘤、淋巴管内皮肉瘤、滑膜瘤、间皮瘤、尤因肿瘤、平滑肌肉瘤、横纹肌肉瘤、结肠癌、胰腺癌、乳腺癌、卵巢癌、前列腺癌、鳞状细胞癌、基底细胞癌、腺癌、汗腺癌、皮脂腺癌、乳头状癌、乳头状腺癌、囊腺癌、髓样癌、支气管癌、肾细胞癌、肝癌、胆管癌、绒毛膜癌、精原细胞瘤、胚胎癌、威氏肿瘤、宫颈癌、睾丸肿瘤、肺癌、小细胞肺癌、膀胱癌、上皮癌、胶质瘤、星形细胞瘤、髓母细胞瘤、颅咽管瘤、室管膜瘤、松果体瘤、成血管细胞瘤(emangioblastoma)、听神经瘤、少突胶质细胞瘤(oligodendrogliomia)、脑脊膜瘤(menangioma)、黑素瘤、神经母细胞瘤和视网膜母细胞瘤。
在一个单独的实施方案中,本公开内容涉及一种通过向有相应需要的受试者施用本文描述的至少一种化合物来治疗、预防年龄相关性黄斑退化(age-related maculardegeneration)(ARMD)和涉及黄斑视网膜色素上皮(RPE)细胞的其他致病状态或降低年龄相关性黄斑退化(ARMD)和涉及黄斑视网膜色素上皮(RPE)细胞的其他致病状态的严重程度的方法。
CXCR4在涉及视网膜的眼病诸如年龄相关性黄斑退化(ARMD)中起作用。视网膜色素上皮在感光细胞外节段(outer segments)的生理更新中具有主要作用,提供用于对感光细胞层必需的营养物的转运和储存系统。视网膜色素上皮(RPE)细胞主要地表达CXCR4受体。(Crane,等人(2000)J.Immunol.165:4372-4278)。来自血液-视网膜屏障的人类视网膜色素上皮细胞上的CXCR4受体表达导致趋化因子响应于基质细胞衍生的因子Ia而分泌和迁移。(J.Immunol.200;165:4372-4278)。CXCR4 mRNA表达的水平在用IL-1β或TNFα刺激后增加(Dwinell,等人(1999)Gastroenterology.117:359-367)。RPE细胞还响应于SDF-1α而迁移,指示SDF-1α/CXCR4相互作用可能调节在血液-视网膜屏障的RPE部位处的慢性炎症和视网膜下新血管形成的作用。(Crane U,Wallace C A,McKillop-Smith S,Forrester JV.CXCR4 receptor expression on human retinal pigment epithelial cells fromthe blood-retina barrier leads to chemokine secretion and migration inresponse to stromal cell-derived factor Ia.J.Immunol.200;165:4372-4278)。
年龄相关性黄斑退化以黄斑RPE细胞的原发性损伤和继发性损伤二者为特征。ARMD的早期以黄斑玻璃疣(drusen)和RPE的不规律增殖和萎缩为特征。ARMD的晚期表现出区域性RPE萎缩、RPE脱离和破裂、脉络膜新血管形成和纤维血管盘状瘢痕形成(disciformscarring)。通常的第一症状包括导致阅读障碍和面部识别困难的视物变形症和/或一般中央视力丧失(general central vision loss)。ARMD的晚期导致中央盲点,如果发生在双侧,其是极其导致失能的(extremely disabling)(Bressler和Bressler(1995)Ophthalmology.1995;102:1206-1211)。
在一个单独的实施方案中,一种用于治疗、预防炎性疾病状态、新血管形成和伤口愈合或降低炎性疾病状态、新血管形成和伤口愈合的严重程度的方法,该方法包括向有相应需要的受试者施用本文描述的至少一种化合物。血管内皮细胞表达多种趋化因子受体,而CXCR4是特别突出的(Gupta;等人(1998)J Biol Chem.273:4282;Volin,等人(1998)Biochem Biophys Res Commnun.242:46)。
利用CXCR4特异性引物的基于RT-PCR的策略证明,趋化因子受体CXCR4的mRNA不仅在原代培养物和转化的II型肺泡上皮细胞(肺细胞)中表达,而且在许多衍生自多种其他组织的上皮细胞系中表达。(Murdoch,等人(1998)Immunology.98(1):36-41)。与内皮细胞不同,CXCR4是唯一表达于上皮细胞上的趋化因子受体。该受体可能在上皮病理学中具有功能作用。在上皮细胞上表达的CXCR4可以通过对上皮细胞的直接作用来促进吞噬细胞到炎症部位的募集。CXCR4还可能在免疫应答内具有其他功能作用,或参与伤口愈合或新血管形成。CXCR4还可能参与与上皮相关的若干种急性或慢性炎性疾病状态的病理生理学。
某些炎性趋化因子可以在免疫应答期间被诱导,以促进免疫系统的细胞到达感染的部位。炎性趋化因子主要地作为针对白细胞的化学吸引物起作用,将单核细胞、中性粒细胞和其他效应细胞从血液募集到感染或组织损伤的部位。某些炎性趋化因子活化细胞以启动免疫应答或促进伤口愈合。对趋化因子的应答包括增加或减少膜蛋白的表达、增殖和效应物分子的分泌。
在一个特定实施方案中,本公开内容的化合物可以向处于炎性状况的风险或患有炎性状况的宿主施用。在一个实施方案中,化合物被施用以便治疗或预防炎性紊乱。在某些实施方案中,炎性紊乱或状况由趋化因子介导。
通常,炎性紊乱包括但不限于呼吸紊乱(包括哮喘、COPD、慢性支气管炎和囊性纤维化);心血管相关的紊乱(包括动脉粥样硬化、血管成形术后再狭窄、冠状动脉疾病和心绞痛);关节的炎性疾病(包括类风湿性关节炎和骨关节炎);皮肤紊乱(包括皮炎、湿疹性皮炎和银屑病);移植后晚期和慢性实体器官排斥;多发性硬化症;自身免疫状况(包括系统性红斑狼疮、皮肌炎、多发性肌炎、干燥综合征(Sjogren′s syndrome)、风湿性多肌痛、颞动脉炎、白塞病、吉兰-巴雷(Guillain Barre)综合征、韦氏肉芽肿病(Wegener’sgranulomatosus)、结节性多动脉炎);炎性神经病(包括炎性多神经病);血管炎(包括Churg-Strauss综合征、Takayasu动脉炎);脂肪组织的炎性紊乱;和增殖性紊乱(包括卡波西肉瘤和平滑肌细胞的其他增殖性紊乱)。
在一个实施方案中,提供了化合物、组合物和治疗呼吸紊乱的方法,该方法包括向有相应需要的受试者施用如本文描述的化合物。可以被预防或治疗的呼吸紊乱包括可影响呼吸道的任何部分的呼吸系统的疾病或紊乱。呼吸紊乱包括但不限于感冒病毒感染、支气管炎、肺炎、结核病、肺组织的刺激、花粉热和其他呼吸过敏、哮喘、支气管炎、单纯和脓黏液性慢性支气管炎、不明慢性支气管炎(unspecified chronic bronchitis)(包括慢性支气管炎NOS、慢性气管炎和慢性气管支气管炎)、肺气肿、其他慢性阻塞性肺疾病、哮喘、哮喘持续状态和支气管扩张。其他呼吸紊乱包括过敏性鼻炎和非过敏性鼻炎以及气道通路和肺的非恶性增殖性和/或炎性疾病。气道通路或肺的非恶性增殖性和/或炎性疾病意指以下的一种或更多种:(1)肺泡炎,诸如外源性过敏性肺泡炎和诸如由例如细胞毒性剂和/或烷化剂导致的药物毒性;(2)血管炎,诸如韦氏肉芽肿病、过敏性肉芽肿病、肺血管瘤和特发性肺纤维化、慢性嗜酸性粒细胞肺炎、嗜酸性粒细胞肉芽肿和结节病。
在一个实施方案中,向患有与炎症相关的心血管紊乱的患者施用本公开内容的化合物。心血管炎性紊乱包括动脉粥样硬化、血管成形术后再狭窄、冠状动脉疾病、心绞痛和其他心血管疾病。
在某些实施方案中,紊乱是非心血管炎性紊乱,诸如类风湿性关节炎和骨关节炎、皮炎、银屑病、囊性纤维化、移植后晚期和慢性实体器官排斥、湿疹性皮炎、卡波西肉瘤或多发性硬化症。在又另一个实施方案中,可以选择本文公开的化合物以治疗由单核白细胞介导的抗炎性状况。
此外,本公开内容涉及治疗动物受试者,特别是兽医学受试者和人类受试者的方法,以增强或升高祖细胞和/或干细胞的数目。祖细胞和/或干细胞可以被收获并且用于细胞移植。在一个实施方案中,骨髓祖细胞和/或干细胞被动员用于心肌修复。此外,本公开内容涉及治疗动物受试者,特别是兽医学患者和人类患者的方法,其白细胞(WBQ 8计数是不足的,或其将受益于使用本文公开的化合物而升高WBC水平。此外,本公开内容涉及使用所公开的化合物在需要再生的受试者中实现心脏组织的此类再生的方法。
本公开内容的化合物可以被用于治疗与免疫抑制相关的疾病,诸如经历以下的个体:化学疗法、放射疗法、增强的伤口愈合和烧伤治疗、用于自身免疫疾病的疗法或其他药物疗法(例如,皮质类固醇疗法)或被用于治疗自身免疫疾病和移植(graft)/移植(transplantation)排斥的导致免疫抑制的常规药物的组合;由于受体功能的先天性缺陷或其他原因导致的免疫抑制;和感染性疾病,诸如寄生虫疾病,包括但不限于蠕虫感染,诸如线虫(因此,整个公开内容靶向宽范围的状况,对于所述状况,受试者中的祖细胞和/或干细胞的升高将是有益的或其中收获祖细胞和/或干细胞用于随后的干细胞移植将是有益的)。此外,本公开内容的方法靶向宽范围的状况,所述状况以白细胞计数不足为特征或其将受益于所述WBC计数的升高。
组合疗法
在某些实施方案中,本公开内容涉及包含本文公开的CXCR4调节剂与另一种活性成分的药物组合物。
在某些实施方案中,本公开内容涉及将本文公开的趋化因子CXCR4受体调节剂与CCR5和CXCR4的天然配体组合施用。趋化因子受体CCR5的天然配体(RANTES、MIP-1α和MIP-1β)和CXCR4的天然配体(SDF-1)可以在病毒进入的水平作为人类免疫缺陷病毒1型(HIV-1)感染的有效抑制剂起作用。与抗体介导的抑制不同,趋化因子介导的抑制是广泛地有效的。不同的HIV-1株可以利用一种或更多种相同的协同受体以便病毒进入,并且因此可以被一种或更多种相同的趋化因子阻断。对V3特异性抗体的中和高度耐受的HIV-1株对趋化因子的抑制敏感。因此,趋化因子调节剂的使用构成了预防HIV-1感染的治疗途径。(Alkhatib等人,Science.1996,272:1955-1988和Challita-Eid等人,AIDS Research and HumanRetroviruses,1998,14(18):1617-1624)。
在一些实施方案中,本公开内容涉及通过与另一种第二抗病毒剂组合施用CXCR4调节剂来治疗病毒感染。在特定实施方案中,本文描述的化合物与通过不依赖CXCR4的机制抑制HIV进入到细胞中的至少一种化合物组合或交替施用,并且在特定实施方案中,与抑制CCR5、gp120、gp41或CD4结合或活性的化合物组合或交替施用。在一些实施方案中,这样的化合物是马拉维若(Maraviroc)(Celsentri)或恩夫韦地(Fuzeon)的至少一种。在其他实施方案中,这样的化合物选自TNX-355、PRO 250、BMS-488043、茶黄素、Vicriviroc、Gruffithsin、DCM205、ESN196、TBR220、TMB355、尼非韦罗(Nifeviroc)、BMS663068、CYT107、西夫韦肽(Sifuvirtide)、AMD070、PF232798、SP01A。
在其他实施方案中,对受试者共施用阿巴卡韦(abacavir)、阿昔洛韦(acyclovir)、阿昔洛韦、阿德福韦(adefovir)、金刚烷胺(amantadine)、安普那韦(amprenavir)、安普利更(ampligen)、阿比朵(arbidol)、阿扎那韦(atazanavir)、立普妥(atripla)、博赛泼维(boceprevir)、西多福韦(cidofovir)、可比韦(combivir)、地瑞那韦(darunavir)、地拉韦啶(delavirdine)、地达诺新(didanosine)、二十二烷醇(docosanol)、依度尿苷(edoxudine)、依法韦仑(efavirenz)、恩曲他滨(emtricitabine)、恩夫韦地、恩替卡韦(entecavir)、泛昔洛韦(famciclovir)、福米韦生(fomivirsen)、福沙那韦(fosamprenavir)、膦甲酸(foscamet)、膦乙酸(fosfonet)、更昔洛韦(ganciclovir)、依巴他滨(ibacitabine)、imunovir、碘苷(idoxuridine)、咪喹莫特(imiquimod)、茚地那韦(indinavir)、肌苷、III型干扰素、II型干扰素、I型干扰素、拉米夫定(lamivudine)、洛匹那韦(lopinavir)、洛韦胺(loviride)、马拉维若、吗啉胍(moroxydine)、美替沙腙(methisazone)、奈非那韦(nelfinavir)、奈韦拉平(nevirapine)、nexavir、奥司他韦(oseltamivir)(Tamiflu)、聚乙二醇化干扰素α-2a、喷昔洛韦(penciclovir)、帕拉米韦(peramivir)、普来可那利(pleconaril)、鬼臼毒素、拉替拉韦(raltegravir)、利巴韦林(ribavirin)、金刚乙胺(rimantadine)、利托那韦(ritonavir)、pyramidine、沙奎那韦(saquinavir)、司他夫定(stavudine)、替诺福韦(tenofovir)、替诺福韦二吡呋酯(tenofovir disoproxil)、替拉那韦(tipranavir)、曲氟尿苷(trifluridine)、三协维(trizivir)、曲金刚胺(tromantadine)、特鲁瓦达(truvada)、伐昔洛韦(valaciclovir)(Valtrex)、缬更昔洛韦(valganciclovir)、vicriviroc、阿糖腺苷(vidarabine)、韦拉密仃(viramidine)、扎西他滨(zalcitabine)、扎那米韦(zanamivir)(Relenza)、和/或齐多夫定(zidovudine)。
HIV通常用抗病毒剂例如两种核苷类似物逆转录抑制剂和一种非核苷类似物逆转录抑制剂或蛋白酶抑制剂的组合来治疗。三种药物组合通常被称为三联混合物(triplecocktail)。在某些实施方案中,本公开内容涉及通过施用本文公开的趋化因子CXCR4受体调节剂与两种核苷类似物逆转录抑制剂和/或一种非核苷类似物逆转录抑制剂或蛋白酶抑制剂组合来治疗被诊断为具有HIV的受试者。
在某些实施方案中,本公开内容涉及通过施用本文公开的趋化因子CXCR4受体调节剂、恩曲他滨、替诺福韦和依法韦仑来治疗受试者。在某些实施方案中,本公开内容涉及通过施用本文公开的趋化因子CXCR4受体调节剂、恩曲他滨、替诺福韦和拉替拉韦来治疗受试者。在某些实施方案中,本公开内容涉及通过施用本文公开的趋化因子CXCR4受体调节剂、恩曲他滨、替诺福韦、利托那韦和地瑞那韦来治疗受试者。在某些实施方案中,本公开内容涉及通过施用本文公开的趋化因子CXCR4受体调节剂、恩曲他滨、替诺福韦、利托那韦和阿扎那韦来治疗受试者。
在某些实施方案中,本公开内容涉及将本文公开的CXCR4拮抗剂与CCR5拮抗剂诸如马拉维若(selzentry)或vicriviroc组合施用。
香蕉凝集素(BanLec或BanLec-1)是成熟香蕉的果肉中的主要蛋白质之一,并且具有对甘露糖和包含甘露糖的寡糖的结合特异性。BanLec与HIV-1包膜蛋白gp120结合。在某些实施方案中,本公开内容涉及通过施用与香蕉凝集素组合的本文公开的趋化因子CXCR4受体调节剂来治疗病毒感染,诸如HIV。
癌症治疗可以作为单独的疗法被施加或可以包括常规的手术或放射疗法或化学疗法。这样的化学疗法可以包括以下类别的抗肿瘤剂的一种或更多种:
(i)抗增殖性药物/抗肿瘤药物及其组合,如在医学肿瘤学中使用的,诸如烷化剂(例如顺铂、卡铂、环磷酰胺、氮芥、美法仑(melphalan)、苯丁酸氮芥(chlorambucil)、白消安(busulfan)和亚硝基脲类);抗代谢物(例如抗叶酸剂诸如氟嘧啶类,如5-氟尿嘧啶和吉西他滨(gemcitabine)、替加氟(tegafur)、雷替曲塞(raltitrexed)、氨甲蝶呤(methotrexate)、阿糖胞苷和羟基脲);抗肿瘤抗生素类(例如蒽环霉素,如阿霉素、博来霉素、多柔比星(doxorubicin)、道诺霉素、表柔比星(epirubicin)、伊达比星(idarubicin)、丝裂霉素-C、更生霉素(dactinomycin)和光神霉素(mithramycin));抗有丝分裂剂(例如长春花生物碱类,如长春花新碱(vincristine)、长春花碱(vinblastine)、长春地辛(vindesine)和长春瑞滨(vinorelbine)和紫衫烷类(taxoids)如紫杉醇和泰素替尔(taxotere));和拓扑异构酶抑制剂(例如表鬼臼毒素类如依托泊苷(etoposide)和替尼泊苷(teniposide)、安吖啶(amsacrine)、拓扑替康(topotecan)和喜树碱);和蛋白酶抑制剂(例如硼替佐米(bortezomib)[Velcade.RTM.]);和剂,阿那格雷(anegrilide)[Agrylin.RTM.];和剂,α-干扰素;
(ii)细胞抑制剂诸如抗雌激素(例如他莫昔芬(tamoxifen)、托瑞米芬(toremifene)、雷洛昔芬(raloxifene)、屈洛昔芬(droloxifene)和iodoxyfene)、雌激素受体下调物(例如氟维司群(fulvestrant))、抗雄激素类(例如比卡鲁胺(bicalutamide)、氟他胺(flutamide)、尼鲁米特(nilutamide)和乙酸环丙孕酮(cyproterone acetate))、LHRH拮抗剂或LHRH激动剂(例如戈舍瑞林(goserelin)、亮丙瑞林(leuprorelin)和布赛米灵(buserelin))、孕激素(例如醋酸甲地孕酮(megestrol acetate))、芳香酶抑制剂(例如如阿那曲唑(anastrozole)、来曲唑(letrozole)、伏氯唑和依西美坦(exemestane))以及5α-还原酶的抑制剂诸如非那雄胺(finasteride);
(iii)抑制癌细胞侵入的剂(例如金属蛋白酶抑制剂如马立马司他(marimastat)和尿激酶纤溶酶原活化物受体功能的抑制剂);
(iv)生长因子功能的抑制剂,例如这样的抑制剂包括生长因子抗体、生长因子受体抗体(例如抗Her2抗体曲妥珠单抗(trastuzumab)和抗表皮生长因子受体(EGFR)抗体西妥昔单抗(cetuximab))、法尼基转移酶抑制剂、酪氨酸激酶抑制剂和丝氨酸/苏氨酸激酶抑制剂,例如表皮生长因子家族的抑制剂(例如EGFR家族酪氨酸激酶抑制剂,诸如:N-(3-氯-4-氟苯基)-7-甲氧基-6-(3-吗啉基丙氧基)喹唑啉-4-胺(吉非替尼(gefitinib))、N-(3-乙炔基苯基)-6,7-二(2-甲氧基乙氧基)喹唑啉-4-胺(埃罗替尼(erlotinib))和6-丙烯酰胺基-N-(3-氯-4-氟苯基)-7-(3-吗啉基丙氧基)喹唑啉-4-胺(CI 1033),例如血小板衍生的生长因子家族的抑制剂和例如肝细胞生长因子家族的抑制剂,例如磷脂酰肌醇3-激酶(PIK3)的抑制剂,和例如丝裂原活化的蛋白激酶激酶(MEK1/2)的抑制剂,和例如蛋白激酶B(PKB/Akt)的抑制剂,例如Src酪氨酸激酶家族和/或Abelson(AbI)酪氨酸激酶家族的抑制剂诸如达沙替尼(dasatinib)(BMS-354825)和甲磺酸伊马替尼(imatinib mesylate)(Gleevec.TM.);以及修饰STAT信号转导的任何剂;
(v)抗血管生成剂,诸如抑制血管内皮生长因子的作用的那些抗血管生成剂(例如抗血管内皮细胞生长因子抗体贝伐单抗(bevacizumab)[Avastin.TM.])和通过其他机制起作用的化合物(例如利诺胺(linomide)、整联蛋白ocvβ3功能的抑制剂和血管抑素);
(vi)血管损伤剂,诸如康普瑞汀(Combretastatin)A4;
(vii)反义疗法,例如针对上文列出的靶的那些反义疗法,诸如抗-ras反义物;和
(viii)免疫疗法方法,包括例如增加患者肿瘤细胞的免疫原性的离体和体内方法,诸如用细胞因子诸如白细胞介素2、白细胞介素4或粒细胞-巨噬细胞集落刺激因子转染,减少T细胞无反应性的方法,使用被转染的免疫细胞诸如细胞因子转染的树突细胞的方法,使用细胞因子转染的肿瘤细胞系的方法和使用抗独特型(anti-idiotypic)抗体的方法,和使用免疫调节性药物沙利度胺(thalidomide)和来那度胺(lenalidomide)[Revlimid.RTM.]的方法。
制剂
本文公开的药物组合物可以呈药学上可接受的盐的形式,如下文一般性地描述的。合适的药学上可接受的有机酸和/或无机酸的一些优选的但非限制性实例是盐酸、氢溴酸、硫酸、硝酸、乙酸和柠檬酸,以及本身是已知的其他药学上可接受的酸(关于其,参考了下文提到的参考文献)。
当本公开内容的化合物包含酸性基团以及碱性基团时,本公开内容的化合物也可以形成内盐,并且这样的化合物在本公开内容的范围内。当化合物包含供氢杂原子(例如NH)时,盐被预期包括通过将所述氢原子转移到分子内的碱性基团或原子而形成的异构体。
化合物的药学上可接受的盐包括其酸加成盐和碱盐。合适的酸加成盐由形成无毒性盐的酸形成。实例包括乙酸盐、己二酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、硼酸盐、樟脑磺酸盐(camsylate)、柠檬酸盐、环己基氨基磺酸盐、乙二磺酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐、葡萄糖酸盐、葡萄糖醛酸盐、六氟磷酸盐、海苯酸盐(hibenzate)、盐酸盐/氯化物、氢溴酸盐/溴化物、氢碘酸盐/碘化物、羟乙基磺酸盐、乳酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、甲基磺酸盐、萘酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、乳清酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、焦谷氨酸盐、蔗糖盐、硬脂酸盐、琥珀酸盐、鞣酸盐、酒石酸盐、甲苯磺酸盐、三氟乙酸盐和羟萘甲酸盐(xinofoate)。合适的碱盐由形成无毒性盐的碱形成。实例包括铝盐、精氨酸盐、苄星青霉素盐、钙盐、胆碱盐、二乙胺盐、二乙醇胺(diolamine)盐、甘氨酸盐、赖氨酸盐、镁盐、甲基葡胺盐、乙醇胺盐、钾盐、钠盐、氨丁三醇盐和锌盐。还可以形成酸和碱的半盐,例如半硫酸盐和半钙盐。对于关于合适的盐的综述,参见Stahl和Wermuth的Handbook ofPharmaceutical Salts:Properties,Selection,and Use(Wiley-VCH,2002),通过参考并入本文。
本文所述的化合物可以以前药的形式被施用。前药可以包括共价地键合的载体,当向哺乳动物受试者施用时,其释放活性母体药物。前药可以通过修饰存在于化合物中的官能团来制备,制备方式使得修饰物(modification)在常规操作中或在体内被裂解成母体化合物。前药包括,例如,其中羟基基团与任何基团键合的化合物,当向哺乳动物受试者施用时,其裂解以形成游离羟基基团。前药的实例包括但不限于活性化合物中的醇官能团的乙酸酯衍生物、甲酸酯衍生物和苯甲酸酯衍生物。将化合物构建为前药的方法可以在Testa和Mayer的书籍Hydrolysis in Drug and Prodrug Metabolism,Wiley(2006)中找到。典型的前药通过水解酶对前药的转化,酰胺、内酰胺、肽、羧酸酯、环氧化物的水解或无机酸的酯的裂解来形成活性代谢物。用于在本公开内容中使用的药物组合物通常包含有效量的化合物和合适的药学上可接受的载体。制剂可以以本身是已知的方式被制备,其通常涉及将根据本公开内容的至少一种化合物与一种或更多种药学上可接受的载体混合,并且如果期望,当必要时在无菌条件下与其他药学活性化合物组合。再次参考美国专利号6,372,778、美国专利号6,369,086、美国专利号6,369,087和美国专利号6,372,733和上文提及的其他参考文献,以及标准手册,诸如Remington′s Pharmaceutical Sciences的最新版。
通常地,对于药物用途,化合物可以被配制成药物制剂,该药物制剂包含至少一种化合物和至少一种药学上可接受的载体、稀释剂或赋形剂和/或佐剂,以及任选地一种或更多种其他药学上活性的化合物。
本公开内容的药物制剂优选地呈单位剂型,并且可以被合适地包装,例如在盒、泡状物(blister)、小瓶、瓶、小袋(sachet)、安瓿中或在任何其他合适的单剂量或多剂量储器(holder)或容器中(其可以被适当地标记);任选地具有包含产品信息和/或使用说明的一个或更多个小册子。通常地,这样的单位剂量将包含在1mg和1000mg之间、并且通常在5mg和500mg之间的本公开内容的至少一种化合物,例如每单位剂量约10mg、25mg、50mg、100mg、200mg、300mg或400mg。
化合物可以通过多种途径被施用,包括口服、眼、直肠、透皮、皮下、静脉内、肌肉内或鼻内途径,主要取决于使用的具体制剂。化合物将通常以“有效量”被施用,“有效量”意指在合适的施用后足以在其被施用的受试者中实现期望的治疗效果或预防效果的化合物的任何量。通常地,取决于待被预防或治疗的状况和施用的途径,这样的有效量将通常是每天每千克患者体重0.01mg和1000mg之间,更通常是每天每千克患者体重0.1mg和500mg之间,诸如1mg和250mg之间,例如约5mg、10mg、20mg、50mg、100mg、150mg、200mg或250mg,其可以作为单个每日剂量被施用,分为一个或更多个每日剂量被施用。取决于诸如患者的年龄、性别和全身状况和待被治疗的疾病/症状的特性和严重程度的因素,待被施用的一种或更多种量、施用的途径和其他治疗方案可以由治疗的临床医师来确定。再次参考美国专利号6,372,778;美国专利号6,369,086;美国专利号6,369,087;和美国专利号6,372,733和上文提及的其他参考文献,以及标准手册,诸如Remington′s Pharmaceutical Sciences的最新版。
取决于引入的方式,本文描述的化合物可以以多种方式被配制。包含一种或更多种化合物的制剂可以被制备成多种药物形式,诸如颗粒、片剂、胶囊、栓剂、粉末、控释制剂、悬浮液、乳液、乳膏、凝胶、软膏、油膏、洗剂或气雾剂等。优选地,这些制剂以适合用于简单、并且优选地口服施用精确剂量的固体剂型被使用。用于口服施用的固体剂型包括但不限于片剂、软明胶或硬明胶或非明胶胶囊和囊片。然而,液体剂型,诸如溶液、糖浆、悬浮液、奶昔(shakes)等也可以被利用。在另一个实施方案中,制剂被局部施用。合适的局部制剂包括但不限于洗剂、软膏、乳膏和凝胶。在优选的实施方案中,局部制剂是凝胶。在另一个实施方案中,制剂被鼻内施用。
包含本文描述的一种或更多种化合物的制剂可以使用包含被认为安全并且有效的材料的药学上可接受的载体来制备,并且可以向个体施用而不导致不期望的生物副作用或不期望的相互作用。载体是除一种或更多种活性成分之外存在于药物制剂中的所有组分。如本文通常使用的,“载体”包括但不限于稀释剂、粘合剂、润滑剂、崩解剂、填料、pH调节剂、防腐剂、抗氧化剂、增溶剂和包衣组合物。
载体还包括包衣组合物的所有组分,其可以包括增塑剂、色素、着色剂、稳定剂和助流剂。延迟释放药剂(dosage formulation)、延长释放药剂和/或脉冲释放药剂可以如在标准参考文献中描述的制备,诸如″Pharmaceutical dosage form tablets″,eds.Liberman等人(New York,Marcel Dekker,Inc.,1989)、″Remington--The scienceand practice of pharmacy″,第20版,Lippincott Williams&Wilkins,Baltimore,Md.,2000,和″Pharmaceutical dosage forms and drug delivery systems″,第6版,Ansel等人,(Media,Pa.:Williams and Wilkins,1995)。这些参考文献提供了关于用于制备片剂和胶囊以及片剂、胶囊和颗粒的延迟释放剂型的载体、材料、设备和方法的信息。
合适的包衣材料的实例包括但不限于,纤维素聚合物,诸如纤维素乙酸邻苯二甲酸酯、羟丙基纤维素、羟丙基甲基纤维素、羟丙基甲基纤维素邻苯二甲酸酯、和羟丙基甲基纤维素乙酸琥珀酸酯;聚乙烯乙酸邻苯二甲酸酯、丙烯酸聚合物和共聚物,以及以商品名EUDRAGIT.RTM.(Roth Pharma,Westerstadt,Germany)商购可得的甲基丙烯酸树脂、玉米醇溶蛋白、虫胶和多糖。
另外地,包衣材料可以包含常规载体,诸如增塑剂、色素、着色剂、助流剂、稳定剂、成孔剂和表面活性剂。
存在于包含药物的片剂、珠、颗粒(granules)或微粒(particles)中的任选的药学上可接受的赋形剂包括但不限于稀释剂、粘合剂、润滑剂、崩解剂、着色剂、稳定剂和表面活性剂。稀释剂,也被称为“填料”,通常是增加固体剂型的体积所必要的,使得实用尺寸被提供用于片剂的压缩或珠和颗粒的形成。合适的稀释剂包括但不限于二水磷酸二钙、硫酸钙、乳糖、蔗糖、甘露醇、山梨醇、纤维素、微晶纤维素、高岭土、氯化钠、干淀粉、水解淀粉、预糊化淀粉、二氧化硅、氧化钛、硅酸镁铝和糖粉。
粘合剂被使用以赋予固体药剂粘性(cohesive qualities),并且因此确保片剂或珠或颗粒在形成剂型后保持完整。合适的粘合剂材料包括但不限于淀粉、预糊化淀粉、明胶、糖(包括蔗糖、葡萄糖、右旋糖、乳糖和山梨醇)、聚乙二醇、蜡、天然胶和合成胶诸如阿拉伯胶、黄芪胶、藻酸钠、纤维素,包括羟丙基甲基纤维素、羟丙基纤维素、乙基纤维素和硅酸镁铝(veegum)以及合成聚合物诸如丙烯酸和甲基丙烯酸共聚物、甲基丙烯酸共聚物、甲基丙烯酸甲酯共聚物、甲基丙烯酸氨基烷基酯共聚物、聚丙烯酸/聚甲基丙烯酸和聚乙烯吡咯烷酮。
润滑剂被使用以促进片剂制备。合适的润滑剂的实例包括但不限于硬脂酸镁、硬脂酸钙、硬脂酸、山嵛酸甘油酯、聚乙二醇、滑石和矿物油。
崩解剂被使用以促进剂型在施用后崩解或“分解”,并且通常包括但不限于淀粉、羟乙酸淀粉钠、羧甲基淀粉钠、羧甲基纤维素钠、羟丙基纤维素、预糊化淀粉、粘土、纤维素、藻酸盐、胶或交联的聚合物,诸如交联的PVP(来自GAF Chemical Corp的PolyplasdoneXL)。
使用稳定剂以抑制或延缓药物分解反应,其包括,举例而言,氧化反应。
表面活性剂可以是阴离子表面活性剂、阳离子表面活性剂、两性表面活性剂或非离子表面活性剂。合适的阴离子表面活性剂包括但不限于包含羧酸根、磺酸根和硫酸根离子的那些阴离子表面活性剂。阴离子表面活性剂的实例包括长链烷基磺酸和烷基芳基磺酸的钠盐、钾盐、铵盐,诸如十二烷基苯磺酸钠;二烷基磺基琥珀酸钠,诸如十二烷基苯磺酸钠;二烷基磺基琥珀酸钠,诸如二-(2-乙基硫氧基)磺基琥珀酸钠;和烷基硫酸盐诸如月桂基硫酸钠。阳离子表面活性剂包括但不限于季铵化合物,诸如苯扎氯铵(benzalkoniumchloride)、苄索氯铵(benzethonium chloride)、西曲溴铵(cetrimonium bromide)、硬脂基二甲基苄基氯化铵、聚氧乙烯和椰子胺。非离子表面活性剂的实例包括乙二醇单硬脂酸酯、丙二醇肉豆蔻酸酯、单硬脂酸甘油酯、硬脂酸甘油酯、聚甘油-4-油酸酯、脱水山梨醇酰化物、蔗糖酰化物、PEG-150月桂酸酯、PEG-400单月桂酸酯、聚氧乙烯单月桂酸酯、聚山梨酸酯、聚氧乙烯辛基苯基醚、PEG-1000十六烷基醚、聚氧乙烯十三烷基醚、聚丙二醇丁基醚、泊洛沙姆(Poloxamer).RTM.401、硬脂酰单异丙醇酰胺和聚氧乙烯氢化牛脂酰胺。两性表面活性剂的实例包括N-十二烷基-β-丙氨酸钠、N-月桂基-β-亚氨基二丙酸钠、肉豆蔻酸两性乙酸酯(myristoamphoacetate)、月桂基甜菜碱和月桂基磺基甜菜碱。
如果期望,片剂、珠、颗粒(granules)或微粒(particles)还可以包含少量的无毒性辅助物质诸如润湿剂或乳化剂、染料、pH缓冲剂或防腐剂。
一种或更多种化合物对载体和/或其他物质的浓度可以从约0.5wt.%(重量百分比)至约100wt.%(重量百分比)变化。对于口服使用,药物制剂将通常包含以重量计约5%至约100%的活性物质。对于其他用途,药物制剂将通常具有从约0.5wt.%至约50wt.%的活性物质。
本文描述的组合物可以被配制成用于修改的释放(modified release)或控释。控释剂型的实例包括延长释放剂型、延迟释放剂型、脉冲释放剂型及其组合。
延长释放制剂通常被制备成扩散或渗透系统,例如,如在″Remington--Thescience and practice of pharmacy″(第20版,Lippincott Williams&Wilkins,Baltimore,Md.,2000)中描述的。扩散系统通常由两种类型的装置组成,即贮库(reservior)和基质,并且是本领域中熟知并被描述的。基质装置通常通过用缓慢地溶解的聚合物载体将药物压缩成片剂形式来制备。在制备基质装置中使用的三种主要类型的材料是不可溶塑料、亲水性聚合物和脂肪化合物。塑料基质包括但不限于丙烯酸甲酯-甲基丙烯酸甲酯、聚氯乙烯和聚乙烯。亲水性聚合物包括但不限于纤维素聚合物诸如甲基和乙基纤维素、羟烷基纤维素诸如羟丙基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠和卡波姆(Carbopol).RTM.934、聚氧乙烯及其混合物。脂肪化合物包括但不限于多种蜡诸如巴西棕榈蜡和三硬脂酸甘油酯,以及蜡型物质包括氢化蓖麻油或氢化植物油,或其混合物。
在某些优选的实施方案中,塑料材料是药学上可接受的丙烯酸聚合物,包括但不限于丙烯酸和甲基丙烯酸共聚物、甲基丙烯酸甲酯、甲基丙烯酸甲酯共聚物、甲基丙烯酸乙氧基乙酯、甲基丙烯酸氰乙酯、甲基丙烯酸氨基烷基酯共聚物、聚(丙烯酸)、聚(甲基丙烯酸)、甲基丙烯酸烷基胺共聚物、聚(甲基丙烯酸甲酯)、聚(甲基丙烯酸)(酸酐)、聚甲基丙烯酸酯、聚丙烯酰胺、聚(甲基丙烯酸酸酐)和甲基丙烯酸缩水甘油酯共聚物。
在某些优选的实施方案中,丙烯酸聚合物包括一种或更多种甲基丙烯酸铵共聚物。甲基丙烯酸铵共聚物是本领域中熟知的,并且在NF XVII中被描述为具有低含量的季铵基团的丙烯酸酯和甲基丙烯酸酯的完全聚合的共聚物。
在一个优选的实施方案中,丙烯酸聚合物是丙烯酸树脂漆,诸如以商品名从Rohm Pharma商购可得的丙烯酸树脂漆。在其他优选的实施方案中,丙烯酸聚合物包括分别以商品名RL30D和RS30D从Rohm Pharma商购可得的两种丙烯酸树脂漆的混合物。RL30D和RS30D是具有低含量的季铵基团的丙烯酸酯和甲基丙烯酸酯的共聚物,铵基团与其余的中性(甲基)丙烯酸酯的摩尔比在RL30D中为1∶20而在RS30D中为1∶40。平均分子量是约150,000。S-100和L-100也是优选的。代码名称RL(高渗透性)和RS(低渗透性)是指这些剂的渗透性特性。RL/RS混合物不可溶于水中和消化液中。然而,形成为包括其的多颗粒系统在水性溶液和消化液中是可膨胀和可渗透的。
如上文描述的聚合物,诸如RL/RS,可以以任何期望的比率混合在一起,以最终获得具有期望的溶解谱的持续释放制剂。期望的持续释放多颗粒系统可以例如从100%RL、50%RL和50%RS、以及10%RL和90%RS获得。本领域技术人员将认识到,还可以使用其他丙烯酸聚合物,诸如,例如,L。
可选地,延长释放制剂可以使用渗透系统或通过将半可渗透包衣施加到剂型中来制备。在后一种情况中,期望的药物释放谱可以通过以合适的比例将低可渗透包衣材料和高可渗透包衣材料组合来实现。
上文描述的具有不同的药物释放机制的装置可以被组合成包含单个或多个单位的最终剂型。多个单位的实例包括但不限于包含片剂、珠或颗粒的多层片剂和胶囊。立即释放部分可以通过使用包衣或压缩方法将立即释放层施加于延长释放核(core)之上或施加在多单位系统(诸如包含延长释放珠和立即释放珠的胶囊)中而被添加到延长释放系统。
包含亲水性聚合物的延长释放片剂通过本领域中通常已知的技术诸如直接压缩(direct compression)、湿法制粒(wet granulation)或干法制粒(dry granulation)来制备。它们的制剂通常包含聚合物、稀释剂、粘合剂和润滑剂以及活性药物成分。通常的稀释剂包括惰性粉末状物质,诸如淀粉、粉末状纤维素,特别是结晶纤维素和微晶纤维素、糖诸如果糖、甘露醇和蔗糖、谷物粉和相似的可食用粉末。典型的稀释剂包括例如多种类型的淀粉、乳糖、甘露醇、高岭土、磷酸钙或硫酸钙、无机盐诸如氯化钠、和糖粉。粉末状纤维素衍生物也是有用的。典型的片剂粘合剂包括诸如淀粉、明胶和糖诸如乳糖、果糖和葡萄糖的物质。天然胶和合成胶,包括阿拉伯胶、藻酸盐、甲基纤维素和聚乙烯吡咯烷酮也可以被使用。聚乙二醇、亲水性聚合物、乙基纤维素和蜡也可以用作粘合剂。在片剂制剂中润滑剂是必要的,以防止片剂和冲头粘在模具中。润滑剂选自光滑固体诸如滑石、硬脂酸镁和硬脂酸钙、硬脂酸和氢化植物油。
包含蜡材料的延长释放片剂通常使用本领域中已知的方法诸如直接共混方法(direct blend method)、凝结方法(congealing method)和水性分散方法(aqueousdispersion method)来制备。在凝结方法中,药物与蜡材料混合,并被喷雾凝结或凝结,并被筛选和处理。
延迟释放制剂通过用聚合物薄膜对固体剂型加包衣而产生,该聚合物膜不可溶于胃的酸性环境中,而可溶于小肠的中性环境中。
延迟释放剂量单位可以例如通过用选择的包衣材料对药物或包含药物的组合物加包衣来制备。包含药物的组合物可以是例如用于掺入到胶囊中的片剂、用于作为“带包衣的核”剂型中的内核使用的片剂、或用于掺入到片剂或胶囊中的多于一个包含药物的珠、粒子(particle)或颗粒(granule)。优选的包衣材料包括生物可溶蚀的、逐渐可水解的、逐渐水可溶的和/或酶促可降解的聚合物,并且可以是常规的“肠溶”聚合物。如本领域技术人员将理解的,肠溶聚合物在下部胃肠道的更高pH环境中变得可溶,或当剂型穿过胃肠道而缓慢地溶蚀,而酶促可降解的聚合物被存在于下部胃肠道中,特别是结肠中的细菌酶降解。用于实现延迟释放的合适的包衣材料包括但不限于纤维素聚合物,诸如羟丙基纤维素、羟乙基纤维素、羟甲基纤维素、羟丙基甲基纤维素、羟丙基甲基纤维素乙酸琥珀酸酯、羟丙基甲基纤维素邻苯二甲酸酯、甲基纤维素、乙基纤维素、纤维素乙酸酯、纤维素乙酸邻苯二甲酸酯、纤维素乙酸偏苯三酸酯和羧甲基纤维素钠;丙烯酸聚合物和共聚物,优选地从丙烯酸、甲基丙烯酸、丙烯酸甲酯、丙烯酸乙酯、甲基丙烯酸甲酯和/或甲基丙烯酸乙酯形成,以及以商品名(Rohm Pharma;Westerstadt,Germany)商购可得的其他甲基丙烯酸树脂,包括L30D-55和L100-55(在pH 5.5以及pH 5.5以上可溶)、L-100(在pH 6.0以及pH 6.0以上可溶)、S(由于较高程度的酯化,在pH 7.0以及pH7.0以上可溶),以及NE、RL和RS(具有不同程度的渗透性和膨胀性的水不可溶聚合物);乙烯基聚合物和共聚物,诸如聚乙烯吡咯烷酮、乙酸乙烯酯、邻苯二甲酸乙酸乙烯酯、乙酸乙烯巴豆酸共聚物和乙烯-乙酸乙烯酯共聚物;酶促可降解的聚合物诸如偶氮聚合物、果胶、壳聚糖、直链淀粉和瓜尔胶;玉米醇溶蛋白和虫胶。还可以使用不同的包衣材料的组合。还可以施加使用不同的聚合物的多层包衣。
本领域技术人员可以通过评价对于用不同量的多种包衣材料制备的片剂、珠和颗粒的单个释放谱容易地确定用于特定包衣材料的优选的包衣重量。正是材料、方法和应用的形式的组合产生了人们只能从临床研究确定的期望的释放特征。
包衣组合物可以包括常规添加剂,诸如增塑剂、色素、着色剂、稳定剂、助流剂等。增塑剂通常存在以降低包衣的易碎性,并且将通常占相对于聚合物干重的约10wt.%至50wt.%。典型的增塑剂的实例包括聚乙二醇、丙二醇、三醋精、邻苯二甲酸二甲酯、邻苯二甲酸二乙酯、邻苯二甲酸二丁酯、癸二酸二丁酯、柠檬酸三乙酯、柠檬酸三丁酯、乙酰柠檬酸三乙酯、蓖麻油和乙酰化单甘油酯。稳定剂优选地被用于稳定分散体中的微粒。典型的稳定剂是非离子乳化剂诸如脱水山梨醇酯、聚山梨醇酯和聚乙烯吡咯烷酮。助流剂被推荐以降低在膜形成和干燥期间的粘性作用,并且将通常占包衣溶液中聚合物重量的约25wt.%至100wt.%。一种有效的助流剂是滑石。还可以使用其他助流剂诸如硬脂酸镁和单硬脂酸甘油酯。还可以使用色素诸如二氧化钛。还可以将小量的消泡剂,诸如硅酮(例如,二甲基硅油)添加到包衣组合物。
制剂可以提供一种或更多种化合物的脉冲递送。“脉冲”意指以间隔开的时间间隔释放多于一个药物剂量。通常地,在摄入剂型后,起始剂量的释放基本上是立即的,即第一次药物释放“脉冲”发生于摄入的约一个小时内。在该起始脉冲之后是第一时间间隔(滞后时间),在这期间很少或没有药物从剂型释放,在其之后第二剂量然后被释放。相似地,可以设计在第二药物释放脉冲和第三药物释放脉冲之间的第二几乎无药物释放的时间间隔。几乎无药物释放的时间间隔的持续时间将取决于剂型设计例如每日两次给药谱、每日三次给药谱等而变化。对于提供每日两次剂量谱的剂型,几乎无药物释放的时间间隔在第一剂量和第二剂量之间具有约3小时至14小时的持续时间。对于提供每日三次谱的剂型,几乎无药物释放的时间间隔在三次剂量的每一次之间具有约2小时至8小时的持续时间。
在一个实施方案中,脉冲释放谱用封闭的剂型并且优选地容纳至少两个包含药物的“剂量单位”的密封的胶囊来实现,其中胶囊内的每个剂量单位提供不同的药物释放谱。一种或更多种延迟释放剂量单位的控制通过剂量单位上的控释聚合物包衣或通过将活性剂掺入控释聚合物基质中来实现。每个剂量单位可以包括压缩的或模制的片剂,其中胶囊内的每个片剂提供不同的药物释放谱。对于模拟每天两次给药谱的剂型,第一片剂在摄入剂型之后基本上立即释放药物,而第二片剂在摄入剂型之后的约3小时至不到14小时释放药物。对于模拟每日三次给药谱的剂型,第一片剂在摄入剂型之后基本上立即地释放药物,第二片剂在摄入剂型之后的约3小时至不到10小时释放药物,而第三片剂在摄入剂型之后至少5小时至约18小时释放药物。剂型可能包括多于三个片剂。虽然剂型将通常不包括多于第三个片剂,但可以利用容纳多于三个片剂的剂型。
可选地,胶囊中的每个剂量单位可以包含多于一个包含药物的珠、颗粒或粒子。如本领域中已知的,包含药物的“珠”是指用药物和一种或更多种赋形剂或聚合物制成的珠。包含药物的珠可以通过将药物施加到惰性支持物(例如用药物包衣的惰性糖珠),或通过产生包含药物和一种或更多种赋形剂二者的“核”来产生。如也是已知的,包含药物的“颗粒”和“粒子”包含药物粒子,其可以包括或可以不包括一种或更多种另外的赋形剂或聚合物。与包含药物的珠不同,颗粒和粒子不包含惰性支持物。颗粒通常包含药物粒子并且需要进一步处理。通常地,粒子比颗粒小,并且不被进一步处理。虽然珠、颗粒和粒子可以被配制成提供立即释放,但珠和颗粒通常被用于提供延迟释放。
在一个实施方案中,化合物被配制用于局部施用。合适的局部剂型包括洗剂、乳膏、软膏和凝胶。“凝胶”是在液体媒介物中包含活性剂即Nox抑制剂的分散体的半固体系统,其通过溶解或悬浮于液体媒介物中的增稠剂或聚合材料的作用而变成半固体。液体可以包括亲脂性组分、水性组分或二者。一些乳液可以是凝胶或以其他方式包含凝胶组分。然而,一些凝胶不是乳液,因为它们不包含不混溶组分的均质共混物。用于制备洗剂、乳膏、软膏和凝胶的方法是本领域中熟知的。
本文描述的化合物可以与其他活性化合物一起被辅助施用。这些化合物包括但不限于镇痛剂、抗炎药、解热药、抗抑郁剂、抗癫痫剂、抗组胺剂、抗偏头痛药、抗毒蕈碱剂、抗焦虑剂、镇静剂、催眠剂、抗精神病剂、支气管扩张剂、抗哮喘药、心血管药、皮质类固醇、多巴胺能剂、电解质、胃肠药、肌肉松弛剂、营养剂、维生素、副交感神经剂、刺激剂、厌食剂和抗嗜睡药。如本文使用的,“辅助施用”意指化合物可以与一种或更多种其他活性剂以相同的剂型或以单独的剂型被施用。
一种或更多种另外的活性剂可以被配制为用于立即释放、控制释放或其组合。
现在将参考以下非限制性实施例来更详细地描述本公开内容。应注意的是,在实施例部分中使用的特定测定被设计成提供对活性的指示。存在许多其他测定可用于确定给定化合物的活性,并且因此任何一种特定测定中的结果都不是决定性的。
实验
一般程序:除非另有指示,否则所有反应均在烘箱(150℃)或火焰干燥的玻璃器皿中,使用蒸馏的和脱气的溶剂,在干燥氩气的正压下,用标准Schlenk技术进行。已经烘箱干燥的(150℃)并且在氩气气氛下或在干燥器中冷却的不锈钢注射器或套管被用于转移对空气和水分敏感的液体。所得物(yield)是指色谱学上(LC-MS(ESI-API,254nm)在H2O中的MeOH(0.1%HCO2H),C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z)和光谱学上(1H NMR)同质的物质,除非另有说明。反应通过薄层色谱(TLC)来监测,薄层色谱(TLC)在硅胶(0.25mm)60 F254的预包被的玻璃板上使用指定的溶剂系统来实施。可视化用紫外光(UV254nm)或通过在包含硅胶和碘的密封的瓶中摇动板来完成。可选地,用以下溶液之一处理板(这是通过用钳或镊子夹住TLC板的边缘并且将板浸入到包含期望的染色溶液的广口瓶中完成的),并且用热风枪(450℃)小心地加热约1-2min(注:通过在加热之前将TLC放置在纸巾上来去除过量的染色剂):乙醇中10%磷钼酸,1%高锰酸钾/7%碳酸钾/0.5%氢氧化钠水性溶液,和/或具有10%硫酸的乙醇中的茴香醛。快速柱色谱使用来自Silicycle的SilicaP60硅胶(40-63μm)或Teledyne Isco Combiflash进行。所有的处理和纯化程序用空气中的试剂级溶剂实施。
一般程序A:
在室温搅拌叔丁基(4-氨基丁基)氨基甲酸酯(1.05-1.1当量)、DCE(0.5M)和取代的醛(1.0当量),随后分三部分添加STAB-H(1.5-1.8当量)。将反应在RT搅拌过夜(12-18h),然后用DCM稀释并且用1.0M NaOH洗涤。将有机物分离,用Na2SO4干燥,过滤并且浓缩,然后通过硅胶色谱(combiflash,DCM∶混合物B{80∶20∶3,DCM∶MeOH∶NH4OH},0%B持续5分钟,10%B持续8分钟,50%B持续8分钟)纯化。除非另有说明,所有纯化使用该标准混合物进行。为了提供A1-A22
遵循一般程序A,将叔丁基(4-氨基丁基)氨基甲酸酯(1.933g,10.27mmol)、DCE(体积:20ml)和吡啶甲醛(0.888ml,9.34mmol),随后是STAB-H(2.97g,14.00mmol)组合并且搅拌过夜。经combiflash纯化产生作为黄色油状物的叔丁基(4-((吡啶-2-基甲基)氨基)丁基)氨基甲酸酯A1(1.8g,6.44mmol,收率为69%)。1H NMR(400MHz,CDCl3):δ=8.55(dd,J=5.0,1.2Hz,1H),7.63(dt,J=7.6,1.8Hz,1H),7.29(d,J=7.8Hz,1H),7.15(dd,J=7.5,5.0Hz,1H),4.76(s,1H),3.90(s,2H),3.12(q,J=4.1Hz,2H),2.67(t,J=6.6Hz,2H),1.60-1.50(m,4H),1.43(s,9H);LC/MS H2O中75-95%MeOH,经过3分钟,rt=0.527,在254nM,MS(+)280.2。
遵循一般程序A,将叔丁基(4-氨基丁基)氨基甲酸酯(2.1g,11.15mmol)、DCE(体积:40mL)和3-甲基吡啶甲醛(0.98g,8.1mmol),随后是STAB-H(3.25g,15.3mmol)组合并且搅拌过夜。经combiflash纯化产生作为黄色油状物的叔丁基(4-((3-甲基吡啶-2-基甲基)氨基)丁基)氨基甲酸酯A2(1.98g,6.72mmol,收率为83%)。1H NMR(400MHz,CDCl3):δ=8.38(d,J=4.7Hz,1H),7.42(dq,J=7.6,0.8Hz,1H),7.07(dd,J=7.6,4.8Hz,1H),4.76(s,1H),3.87(s,2H),3.13(q,J=7.2Hz,2H),2.72(t,J=6.4Hz,2H),1.61-1.56(m,4H),1.43(s,9H);LC/MS H2O中75-95%MeOH,经过3分钟,rt=0.488,在254nM,MS(+)292.2。
遵循一般程序A,将叔丁基(4-氨基丁基)氨基甲酸酯(1.318g,7.00mmol)、DCE(体积:15.91ml)、喹啉-2-甲醛(1.0g,6.36mmol)和STAB-H(2.023g,9.54mmol)搅拌过夜。经combiflash纯化产生叔丁基(4-((喹啉-2-基甲基)氨基)丁基)氨基甲酸酯A3(1.1g,3.34mmol,收率为53%)。1H NMR(400MHz,CDCl3):δ=8.12(d,J=8.5Hz,1H),8.05(d,J=8.5Hz,1H),7.80(d,J=8.4Hz,1H),7.70(dt,J=8.4,1.2Hz,1H),7.52(dt,J=8.4,1.2Hz,1H),7.45(d,J=8.5Hz,1H),4.76(s,1H),4.12(s,2H),3.14(q,J=6.6Hz,2H),2.77(t,J=6.4Hz,2H),1.63-1.57(m,4H),1.42(s,9H);LC/MS H2O中75-95%MeOH,经过3分钟,rt=0.509,在254nM,MS(+)330.2。
遵循一般程序A,将叔丁基(4-氨基丁基)氨基甲酸酯(1.658ml,8.67mmol)、DCE(体积:16.51ml)、6-甲基吡啶甲醛(1g,8.26mmol)和STAB-H(2.62g,12.38mmol)搅拌过夜。经combiflash纯化产生叔丁基(4-(((6-甲基吡啶-2-基)甲基)氨基)丁基)氨基甲酸酯A4(0.7g,2.386mmol,收率为29%)。1H NMR(400MHz,CDCl3):δ=7.51(t,J=7.6Hz,1H),7.09(d,J=7.6Hz,1H),7.00(d,J=7.6Hz,1H),4.77(s,1H),3.84(s,2H),3.12(q,J=6.4Hz,2H),2.66(t,J=6.3Hz,2H),1.59-1.47(m,4H),1.43(s,9H);LC/MS H2O中75-95%MeOH,经过3分钟,rt=0.503,在254nM,MS(+)294.2。
遵循一般程序A,将叔丁基(4-氨基丁基)氨基甲酸酯(1.658ml,8.67mmol)、DCE(体积:16.51ml)、5-甲基吡啶甲醛(1g,8.26mmol)和STAB-H(2.62g,12.38mmol)搅拌过夜。经combiflash纯化产生叔丁基(4-(((5-甲基吡啶-2-基)甲基)氨基)丁基)氨基甲酸酯A5(0.82g,2.79mmol,收率为34%)。1H NMR(400MHz,CDCl3):δ=8.37(dd,J=2.4,1.0Hz 1H),7.44(dd,J=7.9,2.3Hz,1H),7.18(d,J=7.8Hz,1H),4.77(s,1H),3.84(s,2H),3.12(q,J=6.0Hz,2H),2.64(t,J=6.0Hz,2H),1.58-1.53(m,4H),1.43(s,9H);LC/MS H2O中75-95%MeOH,经过3分钟,rt=0.501,在254nM,MS(+)294.2。
遵循一般程序A,将叔丁基(4-氨基丁基)氨基甲酸酯(1.597ml,8.35mmol)、DCE(体积:15.90ml)、4-甲基吡啶甲醛(0.963g,7.95mmol)和STAB-H(2.53g,11.92mmol)搅拌过夜。经combiflash纯化产生叔丁基(4-(((4-甲基吡啶-2-基)甲基)氨基)丁基)氨基甲酸酯A6(1.87g,6.37mmol,收率为80%)。1H NMR(400MHz,CDCl3):δ=8.36(d,J=4.8Hz,1H),7.09(d,J=4.1Hz,1H),6.96(d,J=6.0Hz,1H),4.73(s,1H),3.82(s,2H),3.09(br s,2H),2.63(t,J=5.6Hz,2H),2.32(s,3H),1.53-1.50(m,4H),1.43(s,9H);LC/MS H2O中75-95%MeOH,经过3分钟,rt=0.505,在254nM,MS(+)294.2。
遵循一般程序A,将叔丁基(4-氨基丁基)氨基甲酸酯(0.320ml,1.670mmol)、DCE(体积:3.18ml)、异喹啉-3-甲醛(0.25g,1.591mmol)和STAB-H(0.506g,2.386mmol)搅拌过夜。经combiflash纯化产生叔丁基(4-((异喹啉-3-基甲基)氨基)丁基)氨基甲酸酯A7(0.41g,1.245mmol,收率为78%)。1H NMR(400MHz,CDCl3):δ=9.22(s,1H),7.95(d,J=8.2Hz,1H),7.79(d,J=8.2Hz,1H),7.68(dt,J=6.8,1.3Hz,1H),7.63(s,1H),7.57(dt,J=8.2,1.2Hz,1H),4.75(s,1H),4.04(s,2H),3.13(q,J=6.0Hz,2H),2.70(t,J=6.0Hz,2H),1.60-1.51(m,4H),1.43(s,9H);LC/MS H2O中75-95%MeOH,经过3分钟,rt=0.508,在254nM,MS(+)330.2。
遵循一般程序A,将叔丁基(4-氨基丁基)氨基甲酸酯(1.655g,8.79mmol)、DCE(体积:15.99ml)、5-氟吡啶甲醛(1g,7.99mmol)和STAB-H(2.54g,11.99mmol)搅拌过夜。经combiflash纯化产生叔丁基(4-(((5-氟吡啶-2-基)甲基)氨基)丁基)氨基甲酸酯A8(1.64g,5.52mmol,收率为69%)。1H NMR(400MHz,CDCl3):δ=8.40(d,J=2.7Hz,1H),7.35(dd,J=8.5,2.8Hz,1H),7.32(dd,J=8.6,4.7Hz,1H),4.73(s,1H),3.89(s,2H),3.12(q,J=6.0Hz,2H),2.67(t,J=6.6Hz,2H),1.58-1.54(m,4H),1.43(s,9H);LC/MS H2O中75-95%MeOH,经过3分钟,rt=0.498,在254nM,MS(+)298.2。
遵循一般程序A,将叔丁基(4-氨基丁基)氨基甲酸酯(1.655g,8.79mmol)、DCE(体积:15.99ml)、3-氟吡啶甲醛(1g,7.99mmol)和STAB-H(2.54g,11.99mmol)搅拌过夜。经combiflash纯化产生叔丁基(4-(((3-氟吡啶-2-基)甲基)氨基)丁基)氨基甲酸酯A9(1.44g,4.84mmol,收率为61%)。1H NMR(400MHz,CDCl3):δ=8.38(dt,J=4.7,1.5Hz,1H),7.35(ddd,J=9.6,8.3,1.4Hz,1H),7.20(ddd,J=8.3,4.7,4.2Hz,1H),4.72(s,1H),3.98(s,2H),3.12(q,J=4.4Hz,2H),2.68(t,J=6.8Hz,2H),1.61-1.54(m,4H),1.43(s,9H);LC/MS H2O中75-95%MeOH,经过3分钟,rt=0.484,在254nM,MS(+)298.2。
遵循一般程序A,将叔丁基(4-氨基丁基)氨基甲酸酯(0.591g,3.14mmol)、DCE(体积:5.71ml)、5-(三氟甲基)吡啶甲醛(0.5g,2.86mmol)和STAB-H(0.908g,4.28mmol)搅拌过夜。经combiflash纯化产生叔丁基(4-(((5-(三氟甲基)吡啶-2-基)甲基)氨基)丁基)氨基甲酸酯A10(.716g,2.061mmol,收率为72%)。1H NMR(400MHz,CDCl3):δ=8.81(s,1H),7.88(dd,J=8.3,2.4Hz,1H),7.46(d,J=8.1Hz,1H),4.71(s,1H),3.97(s,2H),3.13(q,J=6.2Hz,2H),2.66(t,J=6.5Hz,2H),1.59-1.53(m,4H),1.43(s,9H);LC/MS H2O中75-95%MeOH,经过3分钟,rt=0.497,在254nM,MS(+)348.2。
遵循一般程序A,将叔丁基(4-氨基丁基)氨基甲酸酯(0.755g,4.01mmol)、DCE(体积:7.29ml)、5-甲氧基吡啶甲醛(0.5g,3.65mmol)和STAB-H(1.159g,5.47mmol)搅拌过夜。经combiflash纯化产生叔丁基(4-(((5-甲氧基吡啶-2-基)甲基)氨基)丁基)氨基甲酸酯A11(.91g,2.94mmol,收率为81%)。1H NMR(400MHz,CDCl3):δ=8.24(d,J=2.8Hz,1H),7.21(d,J=8.4Hz,1H),7.15(dd,J=8.4,2.8Hz,1H),4.77(s,1H),3.84(s,3H),3.82(s,2H),3.11(q,J=6.4Hz,2H),2.664(t,J=7.8Hz,2H),1.58-1.47(m,4H),1.43(s,9H);LC/MS H2O中75-95%MeOH,经过3分钟,rt=0.487,在254nM,MS(+)310.2。
遵循一般程序A,将叔丁基(4-氨基丁基)氨基甲酸酯(0.755g,4.01mmol)、DCE(体积:7.29ml)、3-甲氧基吡啶甲醛(0.5g,3.65mmol)和STAB-H(1.159g,5.47mmol)搅拌过夜。经combiflash纯化产生叔丁基(4-(((3-甲氧基吡啶-2-基)甲基)氨基)丁基)氨基甲酸酯A12(0.77g,2.489mmol,收率为68%)。1H NMR(400MHz,CDCl3):δ=8.13(d,J=4.5,1.6Hz,1H),7.15(dd,J=8.4,4.2Hz,1H),7.11(dd,J=8.4,1.6Hz,1H),4.76(s,1H),3.93(s,2H),3.84(s,3H),3.12(q,J=6.8Hz,2H),2.66(t,J=7.4Hz,2H),1.57-1.51(m,4H),1.43(s,9H);LC/MS H2O中75-95%MeOH,经过3分钟,rt=0.498,在254nM,MS(+)310.2。
遵循一般程序A,将叔丁基(4-氨基丁基)氨基甲酸酯(1.075g,5.71mmol)、3-(三氟甲基)吡啶甲醛(0.5g,2.86mmol)、DCE(体积:5.71ml)和STAB-H(0.908g,4.28mmol)搅拌过夜。经combiflash纯化产生叔丁基(4-(((3-(三氟甲基)吡啶-2-基)甲基)氨基)丁基)氨基甲酸酯A13(0.660g,1.900mmol,收率为67%)。1H NMR(400MHz,CDCl3):δ=8.73(d,J=5.0Hz,1H),7.92(d,J=8.0Hz,1H),7.30(dd,J=8.5,5.0Hz,1H),4.73(s,1H),4.05(s,2H),3.12(q,J=6.1Hz,2H),2.65(t,J=7.4Hz,2H),1.59-1.51(m,4H),1.43(s,9H);LC/MS H2O中75-95%MeOH,经过3分钟,rt=0.503,在254nM,MS(+)348.2。
遵循一般程序A,将叔丁基(4-氨基丁基)氨基甲酸酯(0.998g,5.30mmol)、DCE(体积:8.84ml)、噻唑-4-甲醛(0.4g,3.54mmol)和STAB-H(1.349g,6.36mmol)搅拌过夜。经combiflash的纯化产生叔丁基(4-((噻唑-4-基甲基)氨基)丁基)氨基甲酸酯A14(.653g,2.288mmol,收率为65%)。1H NMR(400MHz,CDCl3):δ=8.77(d,J=1.6Hz,1H),7.16(d,J=1.6Hz,1H),4.75(s,1H),3.95(s,2H),3.12(q,J=5.0Hz,2H),2.65(t,J=5.9Hz,2H),1.58-1.50(m,4H),1.43(s,9H);LC/MS H2O中75-95%MeOH,经过3分钟,rt=0.491,在254nM,MS(+)286.0。
遵循一般程序A,将叔丁基(4-氨基丁基)氨基甲酸酯(0.666g,3.54mmol)、DCE(体积:5.90ml)、2-甲基噻唑-4-甲醛(0.3g,2.359mmol)和STAB-H(0.750g,3.54mmol)搅拌过夜。经combiflash纯化产生叔丁基(4-(((2-甲基噻唑-4-基)甲基)氨基)丁基)氨基甲酸酯A15(0.21g,0.701mmol,收率为30%)。1H NMR(400MHz,CDCl3):δ=6.89(s,1H),4.81(s,1H),3.80(s,2H),3.07(q,J=6.4Hz,2H),2.64(s,3H),2.60(t,J=7.0Hz,2H),1.50-1.47(m,4H),1.38(s,9H)。
遵循一般程序A,将叔丁基(4-氨基丁基)氨基甲酸酯(0.659g,3.50mmol)、DCE(体积:7.95ml)、异喹啉-1-甲醛(0.5g,3.18mmol)和三乙酰氧基硼氢化钠(sodiumtriacetixyborohydride)(1.011g,4.77mmol)搅拌过夜。经combiflash纯化产生叔丁基(4-((异喹啉-1-基甲基)氨基)丁基)氨基甲酸酯A16(.779g,2.365mmol,收率为74%)。1H NMR(400MHz,CDCl3):δ=8.45(d,J=5.7Hz,1H),8.17(dq,J=8.4,0.9Hz,1H),7.82(d,J=8.0Hz,1H),7.68(ddd,J=8.1,6.8,1.3Hz,1H),7.60(ddd,J=8.3,6.8,1.4Hz,1H),7.55(d,J=5.8Hz,1H),4.74(s,1H),4.41(s,2H),3.14(q,J=6.4Hz,2H),2.80(t,J=6.8Hz,2H),1.67-1.52(m,4H),1.43(s,9H);LC/MS H2O中75-95%MeOH,经过3分钟,rt=0.518,在254nM,MS(+)330.2。
遵循一般程序A,将叔丁基(4-氨基丁基)氨基甲酸酯(0.915g,4.86mmol)、DCE(体积:8.84ml)、噻唑-2-甲醛(0.5g,4.42mmol)和STAB-H(1.405g,6.63mmol)搅拌过夜。经combiflash纯化产生叔丁基(4-((噻唑-2-基甲基)氨基)丁基)氨基甲酸酯A17(1.01g,3.54mmol,收率为80%)。1H NMR(400MHz,CDCl3):δ=7.71(d,J=3.3Hz,1H),7.26(d,J=4.8Hz,1H),4.64(s,1H),4.12(s,2H),3.12(q,J=5.1Hz,2H),2.71(t,J=6.6Hz,2H),1.57-1.53(m,4H),1.43(s,9H);LC/MS H2O中75-95%MeOH,经过3分钟,rt=0.485,在254nM,MS(+)286.2。
遵循一般程序A,将叔丁基(4-氨基丁基)氨基甲酸酯(1.596g,8.48mmol)、DCE(体积:17.66ml)、5-氯吡啶甲醛(1g,7.06mmol)和STAB-H(2.70g,12.72mmol)搅拌过夜。经combiflash的纯化产生叔丁基(4-(((5-氯吡啶-2-基)甲基)氨基)丁基)氨基甲酸酯A18(1.24g,3.95mmol,收率为56%)。1H NMR(400MHz,CDCl3):δ=8.50(dd,J=2.5,0.7Hz,1H),7.61(dd,J=8.3,2.5Hz,1H),7.27(d,J=8.8Hz,1H),4.72(s,1H),3.87(s,2H),3.12(q,J=6.4Hz,2H),2.65(t,J=6.7Hz,2H),1.56-1.53(m,4H),1.43(s,9H);LC/MS H2O中75-95%MeOH,经过3分钟,rt=0.483,在254nM,MS(+)314.0。
遵循一般程序A,将叔丁基(4-氨基丁基)氨基甲酸酯(1.596g,8.48mmol)、DCE(体积:14.13ml)、4-氯吡啶甲醛(1g,7.06mmol)和STAB-H(2.70g,12.72mmol)搅拌过夜。经combiflash纯化产生叔丁基(4-(((4-氯吡啶-2-基)甲基)氨基)丁基)氨基甲酸酯A19(1.45g,4.62mmol,收率为65%)。1H NMR(400MHz,CDCl3):δ=8.44(d,J=5.4Hz,1H),7.35(d,J=2.0Hz,1H),7.17(dd,J=5.2,2.0Hz,1H),4.71(s,1H),3.88(s,2H),3.12(q,J=5.0Hz,2H),2.65(t,J=6.8Hz,2H),1.56-1.53(m,4H),1.43(s,9H);LC/MS H2O中75-95%MeOH,经过3分钟,rt=0.480,在254nM,MS(+)314.0。
遵循一般程序A,将叔丁基(4-氨基丁基)氨基甲酸酯(0.798g,4.24mmol)、DCE(体积:8.83ml)、3-氯吡啶甲醛(0.5g,3.53mmol)和STAB-H(1.348g,6.36mmol)搅拌过夜。经combiflash纯化产生叔丁基(4-(((3-氯吡啶-2-基)甲基)氨基)丁基)氨基甲酸酯A20(0.81g,2.58mmol,收率为73%)。1H NMR(400MHz,CDCl3):δ=8.46(dd,J=4.6,1.5Hz,1H),7.64(dd,J=8.0,1.5Hz,1H),7.14(dd,J=8.0,4.6Hz,1H),4.74(s,1H),4.02(s,2H),3.12(q,J=6.0Hz,2H),2.69(t,J=6.7Hz,2H),1.60-1.53(m,4H),1.43(s,9H);LC/MS H2O中75-95%MeOH,经过3分钟,rt=0.488,在254nM,MS(+)314.0。
遵循一般程序A,将叔丁基(4-氨基丁基)氨基甲酸酯(0.352g,1.869mmol)、DCE(体积:5.66ml)、3-环丙基吡啶甲醛(0.25g,1.699mmol)和STAB-H(0.648g,3.06mmol)搅拌过夜。经combiflash纯化产生叔丁基(4-(((3-环丙基吡啶-2-基)甲基)氨基)丁基)氨基甲酸酯A21(.405g,1.268mmol,收率为75%)。1H NMR(400MHz,CDCl3):δ=8.36(dd,J=5.5,0.6Hz,1H),7.33(d,J=7.6Hz,1H),7.14(dd,J=7.9,5.0Hz,1H),4.79(s,1H),4.25(s,2H),3.15(q,J=6.2Hz,2H),2.90(t,J=7.2Hz,2H),1.89-1.82(m,1H),1.79-1.53(m,4H),1.43(s,9H),1.03-0.98(m,2H),0.67-0.63(m,2H);LC/MS H2O中75-95%MeOH,经过3分钟,rt=0.498,在254nM,MS(+)320.2。
遵循一般程序A,将叔丁基(4-氨基丁基)氨基甲酸酯(0.296g,1.570mmol)、DCE(体积:3.57ml)、3-乙烯基吡啶甲醛(.190g,1.427mmol)和STAB-H(0.544g,2.57mmol)搅拌过夜。经combiflash纯化产生叔丁基(4-(((3-乙烯基吡啶-2-基)甲基)氨基)丁基)氨基甲酸酯A22(0.31g,1.015mmol,收率为71%)。1H NMR(400MHz,CDCl3):δ=8.45(dd,J=4.8,1.8Hz,1H),7.76(dd,J=7.8,1.8Hz,1H),7.19(dd,J=7.8,4.8Hz,1H),6.91(dd,J=17.4,11.0Hz,1H),5.69(d,J=17.4Hz,1H),5.44(d,J=11.0Hz,1H),4.74(s,1H),4.02(s,2H),3.13(q,J=6.4Hz,2H),2.76(t,J=6.7Hz,2H),1.67-1.52(m,4H),1.43(s,9H);LC/MS H2O中75-95%MeOH,经过3分钟,rt=0.497,在254nM,MS(+)306.2。
一般程序B:方案1:两步骤程序
向20mL小瓶添加氨基吡啶(A1-A22,1.0当量)、DCE(0.4M)、(R)-叔丁基3-甲酰基-3,4-二氢异喹啉-2(1H)-羧酸酯(THIQ,1.1当量)和STAB-H(1.5当量)。允许将反应搅拌过夜(12-24h),然后用DCM稀释并且用1.0M NaOH淬灭。有机层用MgSO4干燥,过滤,浓缩并且通过硅胶色谱(combiflash,DCM∶混合物B{80∶20∶3,DCM∶MeOH∶NH4OH},0%B持续5分钟,10%B持续8分钟,50%B持续8分钟)纯化。除非另有说明,所有纯化使用该标准混合物进行。将纯化的氨基甲酸酯保护的物质溶解在DCM(0.1M)和TFA(DCM∶TFA比为5∶1)中。允许将反应搅拌过夜(12-24h)。反应物用DCM稀释并且用1.0M NaOH淬灭。有机物用MgSO4干燥,过滤,浓缩并且经combiflash纯化以提供最终化合物EMU013-EMU015、EMU025-EMU028、EMU047-EMU048、EMU079-EMU081、EMU103-EMU104、EMU110-EMU112、EMU128-EMU129、EMU131、和EMU189-EMU190。
EMU015:遵循一般程序B,将A1(.515g,1.843mmol)、DCE(体积:4.61ml)、THIQ(0.530g,2.028mmol)和STAB-H(0.586g,2.77mmol)搅拌过夜。经combiflash纯化提供了作为黄色半固体的(R)-叔丁基3-(((4-((叔丁氧基羰基)氨基)丁基)(吡啶-2-基甲基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯(氨基甲酸酯10.7g,1.334mmol,收率为72.4%)。将氨基甲酸酯1(.46g,0.877mmol)、DCM(体积:8.77ml)和TFA(1.351ml,17.53mmol)搅拌过夜。经combiflash纯化产生了作为黄褐色油状物的(R)-N1-(吡啶-2-基甲基)-N1-((1,2,3,4-四氢异喹啉-3-基)甲基)丁烷-1,4-二胺(.241g,0.743mmol,收率为85%)。(经过两个步骤79%)。1H NMR(400MHz,CDCl3):δ=8.51(dd,J=4.8,1.0Hz,1H),7.66(dt,J=7.7,1.8Hz,1H),7.45(d,J=7.8Hz,1H),7.15(t,J=5.0Hz,1H),7.09-7.05(m,3H),7.00-6.98(m,1H),4.01(d,J=15.2Hz,1H),3.93(d,J=15.0Hz,1H),3.47(d,J=14.6Hz,1H),3.71(d,J=14.4Hz,1H),2.90-2.86(m,1H),2.68-2.60(m,6H),2.58-2.52(m,1H),2.46(dd,J=16.5,11.5Hz,1H),1.59-1.52(m,2H),1.49-1.36(m,2H);13C NMR(100MHz,CDCl3):δ=160.2,149.1,136.4,135.6,134.5,129.1,126.4,126.0,125.6,122.8,122.0,61.6,60.7,55.5,51.8,48.6,42.1,33.9,31.6,24.7;HRMS(ESI)[M+H]+,对于C20H28N4计算为325.23867,实测为325.23840;LC/MS H2O中75-95%MeOH,经过3分钟,rt=0.816,在254nM,MS(+)325.2,MS(+)/2 163.2;纯度(>95%)H2O中10-95%MeOH,经过10分钟,rt=6.356,在254nM,MS(+)325.2,MS(+)/2 163.2。
EMU013:遵循一般程序B,将A2(.206g,0.702mmol)、DCE(体积:10ml)、THIQ(0.202g,0.772mmol)和STAB-H(0.223g,1.053mmol)搅拌过夜。通过combiflash的纯化提供了(R)-叔丁基3-(((4-((叔丁氧基羰基)氨基)丁基)(3-甲基吡啶-2-基)甲基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯(氨基甲酸酯2,0.289g,0.536mmol,收率为76%)。将氨基甲酸酯2(0.16g,0.297mmol)、DCM(体积:3ml)和TFA(1.0ml)搅拌过夜。经combiflash纯化产生了(R)-N1-(3-甲基吡啶-2-基)甲基)-N1-((1,2,3,4-四氢异喹啉-3-基)甲基)丁烷-1,4-二胺(.042g,0.124mmol,收率为41.8%),经过2个步骤59%。1H NMR(400MHz,CDCl3):δ=8.34(dd,J=4.8,1.2Hz,1H),7.42(dd,J=7.6,0.8Hz,1H),7.10-7.06(m,3H),7.03(dd,J=9.0,5.4Hz,1H),6.97(dd,J=5.4,3.2Hz,1H),3.97(d,J=15.0Hz,1H),3.89(d,J=15.0Hz,1H),3.87(d,J=12.4Hz,1H),3.67(d,J=12.6Hz,1H),2.89-2.87(m,1H),2.63-2.55(m,6H),2.50(dd,J=8.4,5.6Hz,1H),2.43(s,3H),1.55-1.46(m,2H),1.41-1.30(m,2H);13C NMR(100MHz,CDCl3):δ=157.2,146.3,138.1,135.5,134.5,132.8,129.2,126.4,126.0,125.6,122.5,60.8,60.7,55.4,51.8,48.6,42.0,33.9,31.6,24.2,18.4;LC/MS H2O中50-95%MeOH,经过3分钟,rt=0.797,在254nM,MS(+)339.2,MS(+)/2 170.2
EMU014:遵循一般程序B,将A3(.390g,1.184mmol)、DCE(体积:2.96ml)、THIQ(0.340g,1.302mmol)和STAB-H(0.376g,1.776mmol)搅拌过夜。经combiflash纯化提供了(R)-叔丁基3-(((4-((叔丁氧基羰基)氨基)丁基)(喹啉-2-基甲基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯(氨基甲酸酯3,0.59g,1.027mmol,收率为87%)。将氨基甲酸酯3(0.34g,0.592mmol)、DCM(体积:6.0ml)和TFA(1.0ml)搅拌过夜。经combiflash纯化产生了作为黄褐色油状物的(R)-N1-(喹啉-2-基甲基)-N1-((1,2,3,4-四氢异喹啉-3-基)甲基)丁烷-1,4-二胺(.187g,0.499mmol,收率为84%)。经过两个步骤86%。1H NMR(400MHz,CDCl3):δ=8.14(d,J=8.3Hz,1H),8.03(d,J=8.6Hz,1H),7.80(d,J=8.0Hz,1H),7.69(dt,J=8.3,1.2Hz,1H),7.63(d,J=8.5Hz,1H),7.51(dt,J=7.9,0.8Hz,1H),7.09-7.03(m,3H),6.99-6.97(m,1H),4.03(d,J=14.2Hz,2H),3.94(d,J=15.1Hz,1H),3.88(d,J=14.6Hz,1H),2.99-2.93(m,1H),2.71-2.63(m,6H),2.61-2.53(m,1H),2.47(dd,J=15.0,10.4Hz,1H),1.62-1.54(m,2H),1.51-1.36(m,2H);13C NMR(100MHz,CDCl3):δ=160.9,147.6,136.4,135.6,134.5,129.5,129.2,129.0,127.6,127.4,126.4,125.6,120.8,62.5,60.9,55.6,51.8,48.6,42.1,33.9,31.6,24.7;HRMS(ESI)[M+H]+,对于C24H30N4计算为375.25432,实测为375.25391;LC/MS H2O中75-95%MeOH,经过3分钟,rt=0.689,在254nM,MS(+)375.2,MS(+)/2 188.2
EMU025:遵循一般程序B,将A4(0.486g,1.656mmol)、DCE(体积:4ml)、THIQ(0.476g,1.822mmol)和STAB-H(0.527g,2.485mmol)搅拌过夜。经combiflash纯化提供了(R)-叔丁基3-(((4-((叔丁氧基羰基)氨基)丁基)((6-甲基吡啶-2-基)甲基)氨基)甲基)-3,4-二氢异喹啉-2(lH)-羧酸酯(氨基甲酸酯4,0.780g,1.448mmol,收率为87%)。将氨基甲酸酯4(.379g,0.704mmol)、DCM(体积:6.0ml)和TFA(1.0ml)搅拌过夜。经combiflash纯化产生了作为黄色油状物的(R)-N1-(6-甲基吡啶-2-基)甲基)-N1-((1,2,3,4-四氢异喹啉-3-基)甲基)丁烷-1,4-二胺(.124g,0.366mmol,收率为52%)。经过2个步骤70%。1H NMR(400MHz,CDCl3):δ=7.55(t,J=7.0Hz,1H),7.28(d,J=8.7Hz,1H),7.10-7.03(m,3H),7.01-6.99(m,2H),4.03(d,J=15.1Hz,1H),3.94(d,J=15.3Hz,1H),3.82(d,J=14.7Hz,1H),3.67(d,J=14.7Hz,1H),2.93-2.87(m,1H),2.69-2.57(m,7H),2.52(s,3H),2.50-2.48(m,1H),1.59-1.51(m,2H),1.49-1.37(m,2H);13C NMR(100MHz,CDCl3):δ=159.5,157.4,136.5,135.4,129.0,126.2,125.8,125.4,121.2,119.3,61.5,60.5,55.4,51.6,48.4,41.9,33.7,31.3,24.5,24.3;HRMS(ESI)[M+H]+,对于C21H30N4计算为339.25432,实测为339.25410;LC/MS H2O中55%MeOH,经过3分钟,rt=0.822,在254nM,MS(+)339.2,MS(+)/2170.2
EMU026:遵循一般程序B,将A5(0.519g,1.767mmol)、DCE(体积:4.5ml)、THIQ(0.508g,1.944mmol)和STAB-H(0.562g,2.65mmol)搅拌过夜。经combiflash纯化提供了(R)-叔丁基3-(((4-((叔丁氧基羰基)氨基)丁基)((5-甲基吡啶-2-基)甲基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯(氨基甲酸酯5,0.762g,1.414mmol,收率为80%)。外消旋氨基甲酸酯5使用外消旋THIQ合成并且通过手性HPLC,(254nm)己烷中5%iPrOH,等度,30分钟,1.0mL/min,AD-H(Daicel,ChiralPak,150mm,4.6mm,5um),t1=13.820,t2=14.888,er=52∶48分析。氨基甲酸酯5通过手性HPLC,(254nm)己烷中5%iPrOH,等度,30分钟,1.0mL/min,AD-H(Daicel,ChiralPak,150mm,4.6mm,5um),t1=13.892,t2=14.977,er=98.5∶1.5分析。将氨基甲酸酯5(0.305g,0.566mmol)、DCM(体积:5.0ml)和TFA(1.0ml)搅拌过夜。经combiflash纯化产生了作为黄色油状物的(R)-N1-((5-甲基吡啶-2-基)甲基)-N1-((1,2,3,4-四氢异喹啉-3-基)甲基)丁烷-1,4-二胺(0.091g,0.269mmol,收率为48%),经过2个步骤64%。1H NMR(400MHz,CDCl3):δ=8.30(s,1H),7.43(d,J=7.8Hz,1H),7.28(d,J=7.8Hz,1H),7.04-6.99(m,3H),6.95-6.94(m,1H),3.99(d,J=15.0Hz,1H),3.88(d,J=15.0Hz,1H),3.78(d,J=14.3Hz,1H),3.63(d,J=14.3Hz,1H),2.89-2.82(m,1H),2.63-2.53(m,6H),2.49-2.39(m,2H),2.25(s,3H),1.85(bs,3NH),1.54-1.47(m,2H),1.37-1.32(m,2H);13C NMR(100MHz,CDCl3):δ=156.9,149.3,137.1,135.4,131.3,129.1,126.3,125.9,125.5,122.4,61.1,60.4,55.3,51.6,48.4,41.8,33.7,31.2,24.6,18.1;HRMS(ESI)[M+H]+,对于C21H30N4计算为339.25432,实测为339.25411;LC/MS H2O中55%MeOH,经过3分钟,rt=0.810,在254nM,MS(+)339.2,MS(+)/2 170.2。
EMU027:遵循一般程序B,将A6(0.519g,1.767mmol)、DCE(体积:4.5ml)、THIQ(0.508g,1.944mmol)和STAB-H(0.562g,2.65mmol)搅拌过夜。经combiflash纯化提供了(R)-叔丁基3-(((4-((叔丁氧基羰基)氨基)丁基)((4-甲基吡啶-2-基)甲基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯(氨基甲酸酯6,0.72g,1.336mmol,收率为76%)。将氨基甲酸酯6(0.293g,0.544mmol)、DCM(体积:4.5ml)和TFA(1.0ml)搅拌过夜。经combiflash纯化产生了作为黄色油状物的(R)-N1-(4-甲基吡啶-2-基)甲基)-N1-((1,2,3,4-四氢异喹啉-3-基)甲基)丁烷-1,4-二胺(.064g,0.189mmol,收率为35%)。经过2个步骤56%。1H NMR(400MHz,CDCl3):δ=8.33(d,J=5.2Hz,1H),7.20(s,1H),7.06-7.01(m,3H),6.97-6.92(m,2H),3.98(d,J=15.1Hz,1H),3.89(d,J=15.5Hz,1H),3.77(d,J=14.2Hz,1H),3.65(d,J=14.2Hz,1H),2.88-2.81(m,1H),2.65-2.61(m,3H),2.57-2.56(m,3H),2.52-2.40(m,2H),2.32(s,3H),1.56-1.49(m,2H),1.47-1.33(m,2H);13C NMR(100MHz,CDCl3):δ=159.8,148.8,147.5,135.6,134.5,129.1,126.4,126.0,125.6,123.7,123.1,61.5,60.7,55.6,51.8,48.4,42.0,33.8,31.4,24.7,21.2;HRMS(ESI)[M+H]+,对于C20H28N4计算为339.25432,实测为339.25415;LC/MS H2O中65%MeOH,经过3分钟,rt=1.069,在254nM,MS(+)339.2,MS(+)/2 170.2
EMU028:遵循一般程序B,将A7(.38g,1.153mmol)、DCE(体积:3ml)、THIQ(0.322g,1.269mmol)和STAB-H(0.367g,1.730mmol)搅拌过夜。经combiflash的纯化提供了(R)-叔丁基3-(((4-((叔丁氧基羰基)氨基)丁基)(异喹啉-3-基甲基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯(氨基甲酸酯7,0.429g,0.746mmol,收率为65%)。将氨基甲酸酯7(0.2g,0.348mmol)、DCM(体积:3ml)和TFA(0.6ml)搅拌过夜。经combiflash纯化产生了作为黄色油状物的(R)-N1-(异喹啉-3-基甲基)-N1-((1,2,3,4-四氢异喹啉-3-基)甲基)丁烷-1,4-二胺(.071g,0.19mmol,收率为55%)。经过2个步骤60%。1H NMR(400MHz,CDCl3):δ=9.18(s,1H),7.90(d,J=7.8Hz,1H),7.77(d,J=7.8Hz,1H),7.69(s,1H),7.63(ddd,J=8.1,6.9,1.2Hz,1H),7.51(ddd,J=8.0,6.9,1.0Hz,1H),7.08-6.93(m,4H),4.03(d,J=15.4Hz,1H),3.98(d,J=14.8Hz,1H),3.90(d,J=15.4Hz,1H),3.84(d,J=14.7Hz,1H),2.96-2.89(m,1H),2.67-2.62(m,6H),2.59-2.53(m,1H),2.46(dd,J=16.0,10.8Hz,1H),1.63-1.55(m,2H),1.48-1.35(m,2H);13C NMR(100MHz,CDCl3):δ=153.2,152.2,136.4,135.7,134.5,130.4,129.1,127.7,127.6,126.8,126.5,126.4,125.9,125.6,118.7,61.2,60.5,55.6,51.9,48.6,42.1,33.9,31.7,24.7;HRMS(ESI)[M+H]+,对于C24H30N4计算375.25432,实测为375.25406;LC/MS H2O中75-95%MeOH,经过3分钟,rt=0.689,在254nM,MS(+)375.2,MS(+)/2 188.2
EMU047:遵循一般程序B,将A8(0.379g,1.276mmol)、DCE(体积:3.19ml)、THIQ(0.35g,1.339mmol)和STAB-H(0.406g,1.913mmol)搅拌过夜。经combiflash纯化提供了(R)-叔丁基3-(((4-((叔丁氧基羰基)氨基)丁基)((5-氟吡啶-2-基)甲基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯(氨基甲酸酯8,0.621g,1.144mmol,收率为90%)。将氨基甲酸酯8(0.275g,0.507mmol)、DCM(体积:2.5ml,比率:3)和TFA(体积:0.833ml,比率:1)搅拌过夜。经combiflash纯化产生了(R)-N1-(5-氟吡啶-2-基)甲基)-N1-((1,2,3,4-四氢异喹啉-3-基)甲基)丁烷-1,4-二胺(.141g,0.412mmol,收率为81%)。经过2个步骤86%。1H NMR(400MHz,CDCl3):δ=8.33(d,J=2.2Hz,1H),7.42(dd,J=8.5,4.5Hz,1H),7.34(dd,J=8.3,2.6Hz,1H),7.07-6.96(m,4H),3.99(d,J=15.1Hz,1H),3.92(d,J=15.1Hz,1H),3.79(d,J=14.4Hz,1H),3.66(d,J=14.4Hz,1H),2.87-2.85(m,1H),2.65-2.41(m,10H),1.55-1.32(m,4H);13C NMR(100MHz,CDCl3):δ=158.5(d,C-F J=252.8Hz),156.0(d,C-F J=4.0Hz),137.0(dd,C-F J=23.2,2.3Hz),135.4,134.3,129.1,126.3,125.9,125.6,123.6(d,C-F J=3.9Hz),123.3(d,C-F J=18.3Hz),60.6,60.4,55.2,51.6,48.5,42.0,33.8,31.4,24.5;19F NMR(375.8MHz,CDCl3):δ=-129.7(dd,J=7.7,4.6Hz);LC/MS H2O中50-95%MeOH,经过3分钟,rt=0.778,在254nM,MS(+)343.2,MS(+)/2 172.2
EMU048:遵循一般程序B,将A9(.270g,0.908mmol)、DCE(体积:2.270ml)、THIQ(0.249g,0.953mmol)和STAB-H(0.289g,1.362mmol)搅拌过夜。经combiflash纯化提供了(R)-叔丁基3-(((4-((叔丁氧基羰基)氨基)丁基)((3-氟吡啶-2-基)甲基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯(氨基甲酸酯9,0.621g,1.144mmol,收率为90%)。将氨基甲酸酯9(0.210g,0.387mmol)、DCM(体积:2.5ml,比率:3)和TFA(体积:0.833ml,比率:1)搅拌过夜。经combiflash纯化产生了(R)-N1-(3-氟吡啶-2-基)甲基)-N1-((1,2,3,4-四氢异喹啉-3-基)甲基)丁烷-1,4-二胺(.121g,0.353mmol,收率为91%)。经过2个步骤91%。1H NMR(400MHz,CDCl3):δ=8.39(d,J=4.8Hz,1H),7.38(ddd,J=9.7,8.3,1.3Hz,1H),7.23(dd,J=8.5,4.3Hz,1H),7.11-7.00(m,4H),4.04(d,J=15.2Hz,1H),3.99(d,J=15.2Hz,1H),3.98(dd,J=13.2,2.0Hz,1H),3.73(dd,J=13.4,1.6Hz,1H),3.03-2.96(m,1H),2.69-2.45(m,10H),1.60-1.34(m,4H);13C NMR(100MHz,CDCl3):δ=158.6(d,C-F J=258.2Hz),147.5(d,C-F J=14.4Hz),144.7(dd,C-F J=5.2,2.0Hz),135.6,134.5,129.1,126.4,125.9,125.5,123.7(d,C-F J=3.9Hz),123.0(d,C-F J=19.5Hz),60.1,54.9,54.8,51.6,48.5,41.9,33.7,31.3,24.4;19F NMR(375.8MHz,CDCl3):δ=-124.4(d,J=8.3Hz);LC/MS H2O中50-95%MeOH,经过3分钟,rt=0.778,在254nM,MS(+)343.2,MS(+)/2 172.2
EMU081:遵循一般程序B,将A10(0.350g,1.008mmol)、DCE(体积:2.52ml)、THIQ(0.290g,1.108mmol)和STAB-H(0.320g,1.511mmol)搅拌过夜。经combiflash纯化提供了(R)-叔丁基3-(((4-((叔丁氧基羰基)氨基)丁基)((5-(三氟甲基)吡啶-2-基)甲基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯(氨基甲酸酯10,0.525g,0.886mmol,收率为88%)。将氨基甲酸酯10(.269g,0.454mmol)、DCM(体积:2.5ml,比率:3)和TFA(体积:0.833ml,比率:1)搅拌过夜。经combiflash纯化产生了(R)-N1-((1,2,3,4-四氢异喹啉-3-基)甲基)-N1-((5-(三氟甲基)吡啶-2-基)甲基)丁烷-1,4-二胺(.140g,0.357mmol,收率为79%)。经过2个步骤84%。1H NMR(400MHz,CDCl3):δ=8.77(d,J=2.0Hz,1H),7.89(dd,J=8.2,2.2Hz,1H),7.60(d,J=8.0Hz,1H),7.09-6.97(m,4H),4.02(d,J=15.5Hz,1H),3.94(d,J=15.5Hz,1H),3.91(d,J=14.9Hz,1H),3.76(d,J=15.1Hz,1H),2.98-2.91(m,1H),2.69-2.63(m,1H)2.66(t,J=7.0Hz,2H),2.61-2.56(m,3H),2.53(dd,J=10.2,3.1Hz,1H),2.48(dd,J=16.8,10.8Hz,1H),2.21(bs,3NH),1.56-1.48(m,2H),1.46-1.35(m,2H);13C NMR(100MHz,CDCl3):δ=164.3(q,C-F,J=1.4Hz),145.9(q,C-F,J=4.1Hz),135.2,134.1,133.6(q,C-F,J=3.6Hz),129.0,126.3,126.0,125.6,125.0(q,C-F,J=33.2Hz),123.5(q,C-F,J=272.2Hz),122.3,61.0,60.4,55.2,51.6,48.3,41.8,33.6,31.0,24.5;19F NMR(375.8MHz,CDCl3):δ=-62.25;HRMS(ESI)[M+H]+,对于C21H27N4F3计算为393.22606,实测为393.22585;LC/MS H2O中85%MeOH,经过3分钟,rt=0.692,在254nM,MS(+)393.2,MS(+)/2197.2
EMU080:遵循一般程序B,将A11(0.290g,0.937mmol)、DCE(体积:2.5ml)、THIQ(0.269g,1.031mmol)和STAB-H(0.298g,1.406mmol)搅拌过夜。经combiflash纯化提供了(R)-叔丁基3-(((4-((叔丁氧基羰基)氨基)丁基)((5-甲氧基吡啶-2-基)甲基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯(氨基甲酸酯11,0.448g,0.808mmol,收率为86%)。将氨基甲酸酯11(.206g,0.371mmol)、DCM(体积:3ml,比率:3)和TFA(体积:1ml,比率:1)搅拌过夜。经combiflash纯化产生了(R)-N1-((5-甲氧基吡啶-2-基)甲基)-N1-((1,2,3,4-四氢异喹啉-3-基)甲基)丁烷-1,4-二胺(.088g,0.248mmol,收率为67%),经过2个步骤77%。1HNMR(400MHz,CDCl3):δ=8.18(d,J=2.8Hz,1H),7.30(d,J=8.7Hz,1H),7.16(dd,J=8.7,3.0Hz,1H),7.07-6.96(m,4H),3.99(d,J=15.4Hz,1H),3.91(d,J=15.0Hz,1H),3.81(s,3H),3.77(d,J=14.1Hz,1H),3.60(d,J=14.1Hz,1H),2.90-2.83(m,1H),2.65-2.59(m,1H),2.64(t,J=6.9Hz,2H),2.57-2.52(m,3H),2.49-2.41(m,2H),2.31(bs,3NH),1.55-1.47(m,2H),1.45-1.33(m,2H);13C NMR(100MHz,CDCl3):δ=154.6,151.8,136.1,135.5,134.4,129.1,126.4,126.0,125.6,123.3,121.4,60.7,60.3,55.6,55.2,51.7,48.5,41.9,33.8,31.3,24.6;HRMS(ESI)[M+H]+,对于C21H30ON4计算为355.24924,实测为355.24899;LC/MS H2O中75%MeOH,经过3分钟,rt=0.730,在254nM,MS(+)355.2,MS(+)/2 178.2
EMU079:遵循一般程序B,将A12(0.330g,1.067mmol)、DCE(体积:2.67ml)、THIQ(0.307g,1.173mmol)和STAB-H(0.339g,1.600mmol)搅拌过夜。经combiflash纯化提供了(R)-叔丁基3-(((4-((叔丁氧基羰基)氨基)丁基)((3-甲氧基吡啶-2-基)甲基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯(氨基甲酸酯12,0.446g,0.804mmol,收率为75%)。将氨基甲酸酯12(.192g,0.346mmol)、DCM(体积:3ml,比率:3)和TFA(体积:1.000ml,比率:1)搅拌过夜。经combiflash纯化产生了(R)-N1-((3-甲氧基吡啶-2-基)甲基)-N1-((1,2,3,4-四氢异喹啉-3-基)甲基)丁烷-1,4-二胺(.061g,0.172mmol,收率为50%)。经过2个步骤63%。1H NMR(400MHz,CDCl3):δ=8.11(dd,J=4.1,1.7Hz,1H),7.25-7.11(m,2H),7.07-7.01(m,3H),6.99-6.97(m,1H),4.01(d,J=15.0Hz,1H),3.95(d,J=15.2Hz,1H),3.93(d,J=13.0Hz,1H),3.82(s,3H),3.61(d,J=13.0Hz,1H),2.99-2.92(m,1H),2.66-2.56(m,6H),2.50-2.42(m,2H),2.37(bs,3NH),1.50-1.43(m,2H),1.42-1.25(m,2H);13C NMR(100MHz,CDCl3):δ=154.4,148.8,140.3,135.6,134.6,129.1,126.4,125.9,125.5,123.0,117.3,60.3,55.4,55.3,55.0,51.7,48.5,41.8,33.7,31.2,24.3;LC/MS H2O中75%MeOH,经过3分钟,rt=0.708,在254nM,MS(+)355.2,MS(+)/2 178.2
EMU103:遵循一般程序B,将A13(0.318g,0.915mmol)、DCE(体积:2.266ml)、THIQ(0.237g,0.906mmol)和STAB-H(0.288g,1.360mmol)搅拌过夜。经combiflash纯化提供了(R)-叔丁基3-(((4-((叔丁氧基羰基)氨基)丁基)((3-(三氟甲基)吡啶-2-基)甲基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯(氨基甲酸酯13,0.44g,0.742mmol,收率为82%)。将氨基甲酸酯13(.44g,0.742mmol)、DCM(体积:4ml,比率:4)和TFA(体积:1.000ml,比率:1)搅拌过夜。经combiflash纯化产生了(R)-N1-((1,2,3,4-四氢异喹啉-3-基)甲基)-N1-((3-(三氟甲基)吡啶-2-基)甲基)丁烷-1,4-二胺(0.189g,0.482mmol,收率为65%)。经过2个步骤74%。1H NMR(400MHz,CDCl3):δ=8.73(d,J=4.3Hz,1H),7.89(d,J=7.0Hz,1H),7.26(dd,J=8.0,4.8Hz,1H),7.07-6.94(m,4H),4.03(d,J=13.9Hz,1H),3.96(d,J=15.0Hz,1H),3.86(d,J=15.0Hz,1H),3.85(d,J=13.9Hz,1H),2.77-2.71(m,1H),2.68-2.51(m,5H),2.60(t,J=7.0Hz,2H),2.42(dd,J=15.6,10.9Hz,1H),2.06(bs,3NH),1.54-1.45(m,2H),1.4-1.28(m,2H);13C NMR(100MHz,CDCl3):δ=158.0,151.7,135.6,134.4,134.4(q,C-F,J=5.7Hz),129.0,126.4,125.8,125.4,125.1(q,C-F,J=32.0Hz),123.9(q,C-F,J=274.4Hz),121.7,60.6,58.4,55.7,51.6,48.4,41.9,33.6,31.4,24.1;19F NMR(375.8MHz,CDCl3):δ=-59.86;HRMS(ESI)[M+H]+,对于C21H28N4F3计算为393.22606,实测为393.22577;LC/MS H2O中55%MeOH,经过3分钟,rt=0.883,在254nM,MS(+)393.2,MS(+)/2 197.2
EMU104:遵循一般程序B,将A14(0.4g,1.402mmol)、THIQ(0.374g,1.430mmol)、DCE(体积:3.50ml)和STAB-H(0.446g,2.102mmol)搅拌过夜。经combiflash纯化提供了(R)-叔丁基3-(((4-((叔丁氧基羰基)氨基)丁基)(噻唑-4-基甲基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯(氨基甲酸酯14,0.576g,1.085mmol,收率为77%)。将氨基甲酸酯14(0.576g,1.085mmol)、DCM(体积:4.5ml,比率:5)和TFA(体积:1.000ml,比率:1)搅拌过夜。经combiflash纯化产生了(R)-N1-((1,2,3,4-四氢异喹啉-3-基)甲基)-N1-(噻唑-4-基甲基)丁烷-1,4-二胺(.211g,0.638mmol,收率为59%)。经过2个步骤68%。1H NMR(500MHz,CDCl3):δ=8.74(d,J=2.0Hz,1H),7.16(d,J=1.8Hz,1H),7.07-6.97(m,4H),4.01(d,J=15.1Hz,1H),3.96(d,J=15.1Hz,1H),3.89(d,J=14.9Hz,1H),3.81(d,J=14.6Hz,1H),2.95-2.89(m,1H),2.65(t,J=6.9Hz,2H),2.63-2.56(m,5H),2.50-2.44(m,2H),2.02(bs,3NH),1.57-1.53(m,2H),1.49-1.37(m,2H);13C NMR(125MHz,CDCl3):δ=155.8,152.6,135.6,134.4,129.1,126.4,125.9,125.6,115.3,,60.1,55.0,54.5,51.7,48.6,42.0,33.9,31.4,24.8;HRMS(ESI)[M+H]+,对于C18H27N4S计算为331.19509,实测为331.19501;LC/MS H2O中65%MeOH,经过3分钟,rt=0.747,在254nM,MS(+)331.2,MS(+)/2 166.2
EMU110:遵循一般程序B,将A15(0.095g,0.317mmol)、THIQ(0.087g,0.333mmol)、DCE(体积:0.8ml)和STAB-H(0.101g,0.476mmol)搅拌过夜。经combiflash纯化提供了黄色油状物,将其溶解在DCM(体积:4.5ml,比率:5)和TFA(体积:1.000ml,比率:1)中并且搅拌过夜。经combiflash纯化产生了(R)-N1-((2-甲基噻唑-4-基)甲基)-N1-((1,2,3,4-四氢异喹啉-3-基)甲基)丁烷-1,4-二胺(.071g,0.206mmol)。经过2个步骤,收率为65.0%。1H NMR(500MHz,CDCl3):δ=7.09-6.99(m,4H),6.94(s,1H),4.03(d,J=15.2Hz,1H),3.98(d,J=15.2Hz,1H),3.80(d,J=14.7Hz,1H),3.71(d,J=14.7Hz,1H),2.95-2.89(m,1H),2.70-2.67(m,2H),2.68(s,3H),2.64-2.60(m,2H),2.58-2.57(m,2H),2.53-2.45(m,2H),2.03(bs,3NH),1.59-1.51(m,2H),1.49-1.41(m,2H);13C NMR(125MHz,CDCl3):δ=165.7,154.6,135.5,134.4,129.1,126.3,125.9,125.6,114.7,60.0,55.2,54.9,51.7,48.5,42.0,33.8,31.4,24.7,19.2;HRMS(ESI)[M+H]+,对于C19H29N4S计算为345.21074,实测为345.21076;LC/MS H2O中10-95%MeOH,经过10分钟,rt=7.781,在254nM,MS(+)345.2,MS(+)/2 173.2
EMU112:遵循一般程序B,将A16(0.358g,1.087mmol)、THIQ(0.284g,1.087mmol)、DCE(体积:2.72ml)和STAB-H(0.345g,1.630mmol)搅拌过夜。经combiflash纯化提供了(R)-叔丁基3-(((4-((叔丁氧基羰基)氨基)丁基)(异喹啉-1-基甲基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯(氨基甲酸酯16,0.494g,0.859mmol,收率为79%)。将氨基甲酸酯16(0.264g,0.459mmol)、DCM(体积:5ml,比率:5)和TFA(体积:1.000ml,比率:1)搅拌过夜。经combiflash纯化产生了作为黄色油状物的(R)-N1-(异喹啉-1-基甲基)-N1-((1,2,3,4-四氢异喹啉-3-基)甲基)丁烷-1,4-二胺(.13g,0.347mmol,收率为76%)。经过2个步骤收率为78%。1H NMR(400MHz,CDCl3):δ=8.43(d,J=8.4Hz,1H),8.39(d,J=5.7Hz,1H),7.78(d,J=8.1Hz,1H),7.67(dt,J=6.8,1.0Hz,1H),7.60(dt,J=6.8,1.0Hz,1H),7.54(d,J=5.7Hz,1H),7.04-7.02(m,2H),6.97-6.95(m,2H),6.92-6.90(m,1H),4.30(d,J=12.5Hz,1H),4.18(d,J=12.5Hz,1H),3.82(d,J=15.0Hz,1H),3.61(d,J=15.0Hz,1H),2.71-2.60(m,1H),2.58(t,J=6.9Hz,3H),2.34(dd,J=16.0,9.3Hz,1H),1.80(bs,3NH),1.59-1.49(m,2H),1.41-1.27(m,2H);13C NMR(100MHz,CDCl3):δ=158.8,141.5,136.4,135.4,134.3,130.0,129.1,127.6,127.3,126.8,126.3,125.9,125.5,120.7,61.3,60.8,55.9,51.8,48.3,41.9,33.8,31.5,24.1;HRMS(ESI)[M+H]+,对于C24H31N4计算为375.25432,实测为375.25423;LC/MS H2O中10-95%MeOH,经过10分钟,rt=7.624,在254nM,MS(+)375.2,MS(+)/2 188.2
EMU111:遵循一般程序B,将A17(0.176g,0.617mmol)、THIQ(0.161g,0.617mmol)、DCE(体积:3.08ml)和STAB-H(0.196g,0.925mmol)搅拌过夜。经combiflash纯化提供了黄色油状物,将其溶解在DCM(体积:5ml,比率:5)和TFA(体积:1.000ml,比率:1)中并且搅拌过夜。经combiflash纯化产生了作为淡黄色油状物B17的(R)-N1-((1,2,3,4-四氢异喹啉-3-基)甲基)-N1-(噻唑-2-基甲基)丁烷-1,4-二胺(0.130g,0.393mmol),经过2个步骤收率为64%。1H NMR(400MHz,CDCl3):δ=7.65(d,J=3.3Hz,1H),7.24(d,J=3.3Hz,1H),7.09-7.02(m,3H),7.00-6.99(m,1H),4.04(d,J=15.2Hz,1H),3.99(d,J=15.7Hz,1H),3.98(d,J=15.2Hz,1H),3.94(d,J=15.7Hz,1H),2.98-2.90(m,1H),2.69-2.58(m,6H),2.57-2.46(m,2H),1.73(bs,3NH),1.59-1.50(m,2H),1.49-1.35(m,2H);13C NMR(100MHz,CDCl3):δ=171.7,142.4,135.4,134.2,129.1,126.3,125.9,125.6,119.2,60.5,56.7,55.4,51.8,48.5,42.0,33.7,31.4,24.8;HRMS(ESI)[M+H]+,对于C18H27N4S计算为331.19509,实测为331.19607;LC/MS H2O中75%MeOH,经过3分钟,rt=0.757,在254nM,MS(+)331.2,MS(+)/2166.2
EMU129:遵循一般程序B,将A18(0.5g,1.593mmol)、DCE(体积:3.79ml)、THIQ(0.397g,1.517mmol)和STAB-H(0.579g,2.73mmol)搅拌过夜。经combiflash纯化提供了(R)-叔丁基3-(((4-((叔丁氧基羰基)氨基)丁基)((5-氯吡啶-2-基)甲基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯(氨基甲酸酯18,0.666g,1.191mmol,收率为78%)。将氨基甲酸酯18(0.335g,0.599mmol)、DCM(体积:5ml,比率:5)和TFA(体积:1.000ml,比率:1)搅拌过夜。经combiflash纯化产生了作为黄色油状物的(R)-N1-((5-氯吡啶-2-基)甲基)-N1-((1,2,3,4-四氢异喹啉-3-基)甲基)丁烷-1,4-二胺(0.154g,0.429mmol,收率为72%)。经过2个步骤收率为76%。1H NMR(500MHz,CDCl3):δ=8.42(d,J=1.8Hz,1H),7.59(dd,J=8.2,1.8Hz,1H),7.37(d,J=8.2Hz,1H),7.05-7.00(m,3H),6.96-6.95(m,1H),3.98(d,J=15.0Hz,1H),3.92(d,J=15.0Hz,1H),3.78(d,J=14.6Hz,1H),3.64(d,J=14.6Hz,1H),2.91-2.85(m,1H),2.62(t,J=6.6Hz,3H),2.58-2.51(m,3H),2.49-2.41(m,2H),1.68(s,3H),1.54-1.47(m,2H),1.42-1.33(m,2H);13C NMR(125MHz,CDCl3):δ=158.3,147.8,136.2,135.4,134.3,130.2,129.1,126.3,125.9,125.6,123.5,60.7,60.4,51.6,48.5,42.0,33.8,31.5,24.5;HRMS(ESI)[M+H]+,对于C20H28N4Cl计算为359.19970,实测为359.19966;LC/MS H2O中10-95%MeOH,经过10分钟,rt=7.900,在254nM,MS(+)359.4,MS(+)/2 180.3
EMU128:遵循一般程序B,将A19(0.430g,1.370mmol)、DCE(体积:3.26ml)、THIQ(0.341g,1.305mmol)和STAB-H(0.498g,2.349mmol)搅拌过夜。经combiflash纯化提供了(R)-叔丁基3-(((4-((叔丁氧基羰基)氨基)丁基)((4-氯吡啶-2-基)甲基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯(氨基甲酸酯19,0.616g,1.102mmol,收率为84%)。将氨基甲酸酯19(0.319g,0.571mmol)、DCM(体积:5ml,比率:5)和TFA(体积:1.000ml,比率:1)搅拌过夜。经combiflash纯化产生了作为黄色油状物的(R)-N1-((4-氯吡啶-2-基)甲基)-N1-((1,2,3,4-四氢异喹啉-3-基)甲基)丁烷-1,4-二胺(0.162g,0.451mmol,收率为79%)。经过2个步骤收率为83%。1H NMR(500MHz,CDCl3):δ=8.37(d,J=5.4Hz,1H),7.44(d,J=1.8Hz,1H),7.13(dd,J=5.4,1.8Hz,1H),7.09-7.03(m,3H),6.99-6.97(m,1H),4.02(d,J=15.3Hz,1H),3.93(d,J=15.3Hz,1H),3.81(d,J=15.3Hz,1H),3.70(d,J=15.3Hz,1H),2.89-2.83(m,1H),2.66-2.65(m,3H),2.64-2.54(m,3H),2.52-2.43(m,2H),1.72(s,3H),1.54-1.50(m,2H),1.45-1.34(m,2H);13C NMR(125MHz,CDCl3):δ=162.1,149.9,144.5,135.5,134.3,129.1,126.3,125.9,125.6,122.9,122.4,61.1,60.7,55.5,51.7,48.4,42.0,33.8,31.5,24.5;HRMS(ESI)[M+H]+,对于C20H28N4Cl计算为359.19970,实测为359.19973;LC/MS H2O中10-95%MeOH,经过10分钟,rt=7.804,在254nM,MS(+)359.4,MS(+)/2 180.3
EMU131:遵循一般程序B,将A20(0.491g,1.565mmol)、DCE(体积:3.73ml)、THIQ(0.389g,1.490mmol)和STAB-H(0.568g,2.68mmol)搅拌过夜。经combiflash纯化提供了(R)-叔丁基3-(((4-((叔丁氧基羰基)氨基)丁基)((3-氯吡啶-2-基)甲基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯(氨基甲酸酯20,0.592g,1.058mmol,收率为71%)。将氨基甲酸酯20(0.331g,0.592mmol)、DCM(体积:5ml,比率:5)和TFA(体积:1.000ml,比率:1)搅拌过夜。经combiflash纯化产生了作为黄色油状物的(R)-N1-(3-氯吡啶-2-基)甲基)-N1-((1,2,3,4-四氢异喹啉-3-基)甲基)丁烷-1,4-二胺(0.157g,0.437mmol,收率为74%)。经过2个步骤收率为73%。1H NMR(500MHz,CDCl3):δ=8.46(dd,J=4.5,1.4Hz,1H),7.67(dd,J=8.0,1.4Hz,1H),7.16(dd,J=8.0,4.5Hz,1H),7.09-7.04(m,3H),7.01-6.99(m,1H),4.03(d,J=13.0Hz,1H),4.00(d,J=14.9Hz,1H),3.94(d,J=14.9Hz,1H),3.74(d,J=13.0Hz,1H),2.95-2.89(m,1H),2.70-2.60(m,6H),2.58-2.50(m,1H),2.46(dd,J=15.9,10.9Hz,1H),1.62(s,3H),1.55-1.46(m,2H),1.44-1.30(m,2H);13C NMR(125MHz,CDCl3):δ=156.2,146.9,137.4,135.6,134.4,132.1,129.1,126.4,125.9,125.5,123.4,60.4,58.6,55.1,51.5,48.5,41.9,33.7,31.4,24.7;HRMS(ESI)[M+H]+,对于C20H28N4Cl计算为359.19970,实测为359.19972;LC/MS H2O中75%MeOH,经过3分钟,rt=0.783,在254nM,MS(+)359.2,MS(+)/2 180.2
EMU189:遵循一般程序B,将A21(0.2g,0.626mmol)、DCE(体积:1.491ml)、STAB-H(0.227g,1.073mmol)和THIQ(0.156g,0.596mmol)搅拌过夜。经combiflash纯化提供了黄色油状物,将其溶解在DCM(体积:5ml,比率:5)和TFA(体积:1.000ml,比率:1)中并且搅拌过夜。经combiflash纯化产生了(R)-N1-((3-环丙基吡啶-2-基)甲基)-N1-((1,2,3,4-四氢异喹啉-3-基)甲基)丁烷-1,4-二胺。(0.157g,0.431mmol,经过两个步骤收率为72%)。1H NMR(500MHz,CDCl3):δ=8.29(dd,J=4.6,1.1Hz,1H),7.14(d,J=7.2Hz,1H),7.08-7.04(m,3H),7.00-6.98(m,1H),6.94-6.92(m,1H),4.02(d,J=12.6Hz,1H),3.93(d,J=15.1Hz,1H),3.82(d,J=12.3Hz,1H),3.77(d,J=14.8Hz,1H),2.74-2.69(m,1H),2.63-2.49(m,7H),2.58(t,J=7.0Hz,2H),2.37(dd,J=15.9,10.9Hz,1H),2.30-2.25(m,1H)1.82(br s,3NH),1.51-1.44(m,2H),1.39-1.28(m,2H),0.9(dd,J=8.6,1.6Hz,1H),0.69-0.62(m,1H);13C NMR(125MHz,CDCl3):δ=157.9,145.6,138.2,135.4,134.4,132.1,129.1,126.3,125.9,125.5,122.5,60.6,60.6,55.6,51.8,48.5,41.9,33.8,31.5,24.2,11.4,8.4,8.1;HRMS(ESI)[M+H]+,对于C23H33N4计算为365.26997,实测为365.26970;LC/MS H2O中10-95%MeOH,经过10分钟,rt=2.723,在254nM,MS(+)365.2,MS(+)/2 183.2
EMU190:遵循一般程序B,将A22(0.2g,0.655mmol)、DCE(体积:1.559ml)、STAB-H(0.238g,1.123mmol)和THIQ(0.163g,0.624mmol)搅拌过夜。经combiflash纯化提供了黄色油状物,将其溶解在DCM(体积:5ml,比率:5)和TFA(体积:1.000ml,比率:1)中并且搅拌过夜。经combiflash纯化产生了(R)-N1-((1,2,3,4-四氢异喹啉-3-基)甲基)-N1-((3-乙烯基吡啶-2-基)甲基)丁烷-1,4-二胺。(0.134g,0.382mmol,经过两个步骤收率为61%)。1H NMR(500MHz,CDCl3):δ=8.40(dd,J=4.5,1.0Hz,1H),7.80(d,J=7.0Hz,1H),7.18(dd,J=7.6,5.0Hz,1H),7.15(dd,J=17.6,11.1Hz,1H),7.07-7.04(m,2H),7.02-7.00(m,1H),6.97-6.96(m,1H),5.71(d,J=17.4Hz,1H),5.40(d,J=10.8Hz,1H),3.96(d,J=15.2Hz,1H),3.95(d,J=12.6Hz,1H),3.87(d,J=15.2Hz,1H),3.74(d,J=12.6Hz,1H),2.75-2.70(m,1H),2.62-2.47(m,6H),2.39(dd,J=15.9,10.7Hz,1H),1.86(br s,3NH),1.53-1.46(m,2H),1.41-1.27(m,2H);13C NMR(125MHz,CDCl3):δ=156.1,147.9,135.5,134.5,133.4,133.4,133.1,129.1,126.4,126.0,125.6,122.9,116.4,60.8,60.4,55.4,51.8,48.5,42.0,33.8,31.6,24.1;HRMS(ESI)[M+H]+,对于C22H31N4计算为351.25423,实测为351.25390;LC/MS H2O中75%MeOH,经过3分钟,rt=0.450,在254nM,MS(+)351.2,MS(+)/2176.2
一般程序C:
在0℃向MeOH(0.1M)中的3,5-二甲基吡啶腈(1当量)的搅拌的溶液添加BOC-酸酐(2当量)和六水合氯化镍(II)(0.1当量)。在30分钟内向搅拌的混合物以小份添加NaBH4(7-10当量),以防止放热喷溅,并且允许将反应物搅拌3h。如果反应不完全,则添加另外的NaBH4,并且允许搅拌过夜。添加N1-(2-氨基乙基)乙烷-1,2-二胺(2当量)以完成反应。将混合物浓缩成油状物,溶解在EtOAc中,用饱和碳酸氢钠、卤水洗涤,并且用MgSO4干燥,过滤并且浓缩以得到固体。将固体溶解在DCM(0.7M)中,并且添加TFA(DCM∶TFA的比率,5∶1),并且将反应搅拌过夜。反应用2M NaOH淬灭,用DCM萃取,用MgSO4干燥,过滤并且浓缩以提供吡啶胺。
遵循一般程序C,3,5-二甲基吡啶腈(3.67g,27.8mmol)、MeOH(体积:214ml)、BOC-酸酐(12.89ml,55.5mmol)、六水合氯化镍(II)(0.660g,2.78mmol)、NaBH4(7.35g,194mmol)。将另外的2g NaBH4添加并且允许将反应物搅拌过夜。添加N1-(2-氨基乙基)乙烷-1,2-二胺(6.00ml,55.5mmol)以完成反应。处理并且浓缩以得到白色固体(2.05g)。将固体(1g,4.23mmol)、DCM(体积:5ml,比率:5)和TFA(体积:1ml,比率:1.000)搅拌过夜,然后处理并且浓缩以提供(3,5-二甲基吡啶-2-基)甲胺(0.45g,3.30mmol,收率为78%),经过2个步骤55%。1H NMR(400MHz,CDCl3):δ=8.33(s,1H),7.44(s,1H),3.89(s,2H),2.49(s,3H),2.36(s,3H);
遵循一般程序C,5-氟-3-甲基吡啶腈(0.672g,4.94mmol)、MeOH(体积:38.0ml)、二碳酸二叔丁酯(2.155g,9.87mmol)、六水合氯化镍(II)(0.117g,0.494mmol),然后是硼氢化钠(1.868g,49.4mmol)。将N1-(2-氨基乙基)乙烷-1,2-二胺(1.067ml,9.87mmol)添加到淡棕色反应物并且搅拌30分钟(棕色变成粉色)。然后将反应物浓缩成油状物,用EtOAc稀释,用NaHCO3洗涤,用MgSO4干燥,过滤并且浓缩成黄色油状物,其在高真空(high vac)固化(0.9g,3.75mmol,收率为76%)。允许固体(0.755g,3.14mmol)、DCM(体积:5ml,比率:5)和TFA(体积:1ml,比率:1.000)搅拌过夜。处理并且浓缩成黄色油状物,其通过硅胶色谱(己烷中30%EtOAc)纯化以得到(5-氟-3-甲基吡啶-2-基)甲胺(0.18g,1.284mmol,收率为41%)。经过2个步骤59%。1H NMR(400MHz,CDCl3):δ=8.26(d,J=2.7Hz,1H),7.18(dd,J=9.0,2.7Hz,1H),3.92(s,2H),2.30(s,3H)。
遵循一般程序C,3-氟-5-甲基吡啶腈(2.04g,14.99mmol)、MeOH(体积:100mL)、二碳酸二叔丁酯(6.54g,30.0mmol)、NiCl2 6H2O(0.355g,1.499mmol)、NaBH4(5.67g,150mmol)。将N1-(2-氨基乙基)乙烷-1,2-二胺(3.24mL,30.0mmol)添加到淡绿色反应物并且搅拌30分钟变为粉色。然后将反应物浓缩成油状物并且经combiflash(己烷中10%-30%EA梯度)纯化以提供固体(1.22g,5.08mmol,收率为33.9%)。将固体(0.5g,2.081mmol)、DCM(体积:8.67ml,比率:5)和TFA(体积:1.734ml,比率:1.000)搅拌过夜,处理并且浓缩以提供(3-氟-5-甲基吡啶-2-基)甲胺(.220g,1.570mmol,收率为75%)。经过2个步骤收率为55%。1HNMR(500MHz,CDCl3):δ=8.22(s,1H),7.17(d,J=8.3Hz,1H),4.01(s,2H),2.36(s,3H)
用于EMU078、EMU102、EMU109的程序
EMU078:向20mL小瓶添加(3,5-二甲基吡啶-2-基)甲胺(0.250g,1.836mmol)、THIQ(0.504g,1.927mmol)、DCE(体积:4.59ml)和Na(OAc)3BH(0.584g,2.75mmol)。将混合物剧烈地搅拌2h,然后用2M NaOH淬灭,用DCM萃取,用MgSO4干燥,过滤并且浓缩成油状物,其经combiflash(DCM 5min,10%B(80∶20∶3,DCM∶MeOH∶NH4OH)7min,50%B 10min)纯化以提供黄色半固体(0.4g,1.048mmol,收率为57%)。向20mL小瓶添加黄色半固体(0.165g,0.432mmol)、DCE(2.0mL)、丁醛(0.249g,0.865mmol)和STAB-H(0.137g,0.649mmol)。允许将反应搅拌过夜,然后用2M NaOH淬灭,用DCM萃取,用MgSO4干燥,过滤并且浓缩以得到黄色油状物。将油状物溶解在DCM(4mL)中,并且逐滴添加TFA(0.5mL),并且允许将混合物搅拌过夜。反应用2M NaOH淬灭,用DCM萃取,用MgSO4干燥,过滤并且浓缩成黄色油状物。粗物质经combiflash(DCM 5min,10%B-(80∶20∶3,DCM∶MeOH∶NH4OH)7min,50%B 10min)纯化得到(R)-N1-((3,5-二甲基吡啶-2-基)甲基)-N1-((1,2,3,4-四氢异喹啉-3-基)甲基)丁烷-1,4-二胺(64mg,0.182mmol,收率为41%),经过3个步骤收率为46%。1H NMR(400MHz,CDCl3):δ=8.15(d,J=1.6Hz,1H),7.24(d,J=1.6Hz,1H),7.07-6.95(m,4H),3.97(d,J=14.9Hz,1H),3.89(d,J=15.1Hz,1H),3.84(d,J=12.5Hz,1H),3.59(d,J=12.5Hz,1H),2.86-2.79(m,1H),2.61(t,J=7.0Hz,1H),2.60-2.53(m,3H),2.45(dd,J=8.3,5.3Hz,1H),2.42(dd,J=11.6,6.1Hz,1H),2.37(s,3H),2.24(s,3H),2.05(bs,3NH),1.54-1.43(m,2H),1.42-1.28(m,2H);13C NMR(100MHz,CDCl3):δ=154.0,146.4,138.8,135.4,132.0,131.8,129.0,126.3,125.9,125.5,60.3,60.2,55.2,51.7,48.4,41.9,33.7,31.4,24.1,18.2,17.9;HRMS(ESI)[M+H]+,对于C21H30N4计算为353.26997,实测为353.26968;LC/MS H2O中75%MeOH,经过3分钟,rt=0.779,在254nM,MS(+)353.2,MS(+)/2 177.2
EMU102:向20mL小瓶添加(5-氟-3-甲基吡啶-2-基)甲胺(0.186g,1.327mmol)、DCE(体积:5ml,比率:5.00)和甲醇(体积:1ml,比率:1.000)、丁醛(0.400g,1.393mmol)和STAB-H(0.506g,2.389mmol)。将反应搅拌过夜,并且用2M NaOH淬灭,用DCM萃取,用MgSO4干燥,过滤并且浓缩以提供仲胺(0.45g,1.094mmol,收率为82%)。向20mL小瓶添加THIQ(0.254g,0.972mmol)、DCE(体积:2.4ml)、仲胺(0.4g,0.972mmol)和STAB-H(0.371g,1.750mmol)。将反应搅拌过夜,用DCM稀释,用1M NaOH洗涤,用MgSO4干燥,过滤并且浓缩成黄色油状物。残余物经combiflash(DCM 2分钟,10%B(80∶20∶3,DCM∶MeOH∶NH4OH)5分钟和50%B 9分钟)纯化。将级分(frations)浓缩以提供boc保护的中间体,将其用4mL DCM溶解,随后添加1mLTFA并且然后搅拌过夜。混合物用DCM稀释并且用2M NaOH洗涤,用MgSO4干燥,过滤并且浓缩成黄色油状物。经combiflash(DCM 2分钟,10%B(80∶20∶3,DCM∶MeOH∶NH4OH)5分钟和50%B9分钟)纯化。将级分浓缩以提供(R)-N1-((5-氟-3-甲基吡啶-2-基)甲基)-N1-((1,2,3,4-四氢异喹啉-3-基)甲基)丁烷-1,4-二胺(0.201g,0.564mmol,收率为58%)。经过3个步骤收率为66%。1H NMR(400MHz,CDCl3):δ=8.17(d,J=2.8Hz,1H),7.15(dd,J=9.0,2.7Hz,1H),7.07-6.94(m,4H),3.95(d,J=15.2Hz,1H),3.88(d,J=15.2Hz,1H),3.82(d,J=12.7Hz,1H),3.61(d,J=12.6Hz,1H),2.84-2.77(m,1H),2.59(t,J=6.8Hz,2H),2.56-2.50(m,3H),2.46(dd,J=8.3,5.3Hz,1H),2.41(s,3H),2.38(dd,J=16.3,10.9Hz,1H)1.82(bs,2NH),1.52-1.43(m,2H),1.39-1.27(m,2H);13C NMR(100MHz,CDCl3):δ=158.6(d,C-F,J=259.8Hz),153.1(d,C-F,J=3.9Hz),135.2,134.5(d,C-F,J=3.9Hz),134.2,133.8(d,C-F,J=22.4Hz),129.0,126.2,125.8,125.4,124.6(d,C-F,J=17.7Hz),60.2,59.7(d,C-F,J=0.8Hz),55.0,51.5,48.3,41.8,33.6,31.4,23.9,18.3(d,C-F,J=0.9Hz);19F NMR(375.8MHz,CDCl3):δ=-130.19(d,J=9.1Hz);HRMS(ESI)[M+H]+,对于C21H30ON4计算为357.24490,实测为357.244769;LC/MS H2O中75%MeOH,经过3分钟,rt=0.808,在254nM,MS(+)357.2,MS(+)/2 179.2
EMU109:向20mL小瓶添加(3-氟-5-甲基吡啶-2-基)甲胺(0.09g,0.642mmol)、丁醛(0.194g,0.674mmol)、DCE(体积:2.5ml)和STAB-H(0.245g,1.156mmol)。允许将反应搅拌过夜。反应物用DCM稀释,用2M NaOH洗涤,用MgSO4干燥,过滤并且浓缩以得到作为澄清油状物的仲胺,其不经纯化即使用。向20mL小瓶添加THIQ(0.088g,0.336mmol)、仲胺(0.145g,0.352mmol)、DCE(体积:0.8ml)和STAB-H(0.107g,0.503mmol)。将反应搅拌过夜,然后用DCM稀释,用2M NaOH洗涤,用Na2SO4干燥,过滤并且浓缩成黄色油状物。将油状物溶解在2mL DCM中并且添加0.5mL TFA,并且将反应搅拌过夜。反应用DCM稀释并且通过添加1M NaOH淬灭。水层用DCM(3×10mL)萃取并且合并的有机物用Na2SO4干燥,过滤并且浓缩成黄色油状物。经combiflash(DCM 2分钟,10%B(80∶20∶3,DCM∶MeOH∶NH4OH)5分钟和50%B 9分钟)纯化以提供作为黄色胶状物的(R)-N1-((3-氟-5-甲基吡啶-2-基)甲基)-N1-((1,2,3,4-四氢异喹啉-3-基)甲基)丁烷-1,4-二胺(0.037g,0.104mmol,收率为31%)。经过3个步骤收率为55%。1H NMR(400MHz,CDCl3):δ=8.17(s,1H),7.17(d,J=10.3Hz,1H),7.08-6.98(m,4H),3.99(重叠d,J=15.0Hz,2H),3.91(dd,J=13.3,2.0Hz,1H),3.64(dd,J=13.2,1.8Hz,1H),3.00-2.93(m,1H),2.66-2.54(m,3H),2.61(t,J=7.0Hz,2H),2.52-2.42(m,2H),2.32(s,3H),2.09(bs,3NH),1.57-1.45(m,2H),1.44-1.31(m,2H);13C NMR(100MHz,CDCl3):δ=159.1(d,C-F,J=323.5Hz),145.5(d,C-F,J=5.0Hz),144.6(d,C-F,J=17.4Hz),136.0,134.8,134.7(d,C-F,J=5.0Hz),129.4,126.7,126.2,125.8,123.7(d,C-F,J=23.8Hz),59.9,54.9,54.5(d,C-F J=3.8Hz),51.5,48.4,41.8,33.5,31.1,24.3,17.6(d,C-F J=1.3Hz);19F NMR(375.8MHz,CDCl3):δ=-126.33(d,J=9.6Hz);HRMS(ESI)[M+H]+,对于C21H29FN4计算为357.24490,实测为357.24496;LC/MS H2O中75%MeOH,经过3分钟,rt=0.779,在254nM,MS(+)357.2,MS(+)/2 179.2
一般程序D:(S)-甲基氨基吡啶
遵循从Boggs,S.;Elitzin,V.I.;Gudmundsson,K.;Martin,M.T.;Sharp,M.J.Organic Process Research&Development 2009,13,781改编的程序。
在rt,向250mL RBF添加(S)-1-(4-甲氧基苯基)乙胺(5.65ml,38.1mmol,1.0当量)、1-(吡啶-2-基)乙酮(4.49ml,40mmol,1.05当量)、DCE(体积:38.1ml,1.0M)和STAB-H(16.15g,76mmol,2.0当量)并且将反应搅拌24h。反应通过添加1N NaOH直到实现pH为8来淬灭。将相分离,并且有机层用1N NaOH处理,直到观察到pH为11。DCM层用MgSO4干燥,过滤并且浓缩成油状残余物。将残余物通过combiflash纯化以分离非对映体(通过粗NMR,80g柱,己烷中10%-30%EtOAc,经过40min为~4∶1)。将级分浓缩成澄清油状物,其在静置后固化。(S)-1-(4-甲氧基苯基)-N-((S)-1-(吡啶-2-基)乙基)乙胺(3.86g,15.06mmol,收率为40%)。1H NMR(400MHz,CDCl3):δ=8.60(d,J=5.2Hz,1H),7.61(dt,J=7.6,1.8Hz,1H),7.21-7.12(m,1H),7.13(d,J=9.2Hz,2H),7.06(d,J=7.2Hz 1H),3.80(s,3H),3.57(q,J=7.4Hz,1H),3.39(q,J=6.9Hz,1H),1.29(d,J=6.8Hz,3H),1.26(d,J=7.3Hz,3H);LC/MSH2O中75%MeOH,经过3分钟,rt=0.480,在254nM,MS(+)257.2
从Astatech商购购得:边搅拌边向50mL RBF添加(S)-1-(4-甲氧基苯基)-N-((S)-1-(吡啶-2-基)乙基)乙胺(2g,7.80mmol)和TFA(12.02ml,156mmol)。将固体缓慢地溶解,并且溶液变成砖红色,并且允许将反应搅拌过夜。将反应物用水稀释并且用醚萃取。醚层用水洗涤并且然后留存。用2M NaOH使水层成为碱性,pH为14,然后用DCM萃取。DCM层用MgSO4干燥,过滤并且浓缩成黄色油状物(S)-1-(吡啶-2-基)乙胺(0.938g,7.68mmol,收率为98%),其不经进一步纯化即使用。1H NMR(400MHz,CDCl3):δ=8.55(d,J=4.5Hz,1H),7.64(dt,J=7.7,1.8Hz,1H),7.29(d,J=8.2Hz,1H),7.14(ddd,J=7.6,4.9,1.2Hz 1H),4.16(q,J=6.7Hz,1H),1.43(d,J=6.7Hz,3H);LC/MS H2O中75%MeOH,经过3分钟,rt=0.484,在254nM,MS(+)123.2
在rt,向250mL RBF添加(S)-1-(4-甲氧基苯基)乙胺(6.24ml,42.3mmol)、1-(5-甲基吡啶-2-基)乙酮(6.0g,44.4mmol)、DCM(体积:106ml)和STAB-H(17.92g,85mmol),并且将反应搅拌24h。反应通过添加1N NaOH直到实现pH为8来淬灭。将相分离,并且有机层用1NNaOH处理,直到观察到pH为11。DCM层用MgSO4干燥,过滤并且浓缩成油状残余物。将残余物通过combiflash纯化以分离非对映体(通过粗NMR,80g柱,己烷中10%-30%EtOAc,经过40min)。将级分浓缩成澄清油状物,使用己烷将其结晶为(S)-1-(4-甲氧基苯基)-N-((S)-1-(5-甲基吡啶-2-基)乙基)乙胺(5.1g,18.86mmol,收率为45%)。1H NMR(400MHz,CDCl3):δ=8.40(d,J=2.1Hz,1H),7.39(ddd,J=7.8,2.4,0.8Hz,1H),7.15(d,J=8.5Hz,2H),6.93(d,J=8.1Hz,1H),6.83(d,J=8.5Hz,2H),3.78(s,3H),3.53(q,J=6.8Hz,1H),3.37(q,J=6.6Hz,1H),1.26(d,J=6.4Hz,3H),1.24(d,J=6.5Hz,3H);LC/MS H2O中75%MeOH,经过3分钟,rt=0.480,在254nM,MS(+)271.2。
边搅拌边向50mL RBF添加(S)-1-(4-甲氧基苯基)-N-((S)-1-(5-甲基吡啶-2-基)乙基)乙胺(2g,7.40mmol)和TFA(11.40ml,148mmol)。将固体缓慢地溶解,并且溶液变成砖红色,并且允许将反应搅拌过夜。反应物用水稀释并且用醚萃取。醚层用水洗涤并且然后留存。用2M NaOH使水层成为碱性,pH为14,然后用DCM萃取。DCM层用MgSO4干燥,过滤并且浓缩成黄色油状物(S)-1-(5-甲基吡啶-2-基)乙胺(0.76g,5.58mmol,收率为75%),其不经进一步纯化即使用。1H NMR(400MHz,CDCl3):δ=8.35(d,J=2.2Hz,1H),7.43(ddd,J=8.0,2.2,0.8Hz,1H),7.17(d,J=7.8Hz,1H),4.10(q,J=6.6Hz,1H),1.39(d,J=6.6Hz,3H);
在rt,向250mL RBF添加(S)-1-(4-甲氧基苯基)乙胺(6.39g,42.3mmol)、1-(3-甲基吡啶-2-基)乙酮(6g,44.4mmol)、DCM(体积:106ml)和STAB-H(17.92g,85mmol),并且将反应搅拌24h。反应通过添加1N NaOH直到实现pH为8来淬灭。将相分离,并且有机层用1N NaOH处理,直到观察到pH为11。DCM层用MgSO4干燥,过滤并且浓缩成油状残余物。将残余物通过combiflash纯化以分离非对映体(通过粗NMR,80g柱,10%-30%梯度,经过40min为~4∶1)。1HNMR(400MHz,CDCl3):δ=8.45(d,J=4.8Hz,1H),7.34(d,J=7.6Hz,1H),7.13(d,J=8.5Hz,2H),7.04(dd,J=7.8,4.6Hz,1H),6.82(d,J=9.2Hz,2H),3.79(s,3H),3.74(q,J=6.0Hz,1H),3.27(q,J=5.9Hz,1H),1.24(d,J=6.3Hz,3H),1.20(d,J=6.3Hz,3H);LC/MS H2O中75%MeOH,经过3分钟,rt=0.480,在254nM,MS(+)271.2
边搅拌边向50mL RBF添加(S)-1-(4-甲氧基苯基)-N-((S)-1-(3-甲基吡啶-2-基)乙基)乙胺(2.26g,8.36mmol)和TFA(12.88ml,167mmol)。将固体缓慢地溶解,并且溶液变成砖红色,并且允许将反应搅拌过夜。反应用水稀释并且用醚萃取。醚层用水洗涤并且然后留存。用2M NaOH使水层成为碱性,pH为14,然后用DCM萃取。DCM层用MgSO4干燥,过滤并且浓缩成黄色油状物(S)-1-(3-甲基吡啶-2-基)乙胺(0.56g,4.11mmol,收率为49%),其不经进一步纯化即使用。1H NMR(400MHz,CDCl3):δ=8.39(d,J=4.0Hz,1H),7.38(d,J=7.8Hz,1H),7.03(dd,J=7.6,4.7Hz,1H),4.27(q,J=6.2Hz,1H),1.33(d,J=6.6Hz,3H);
用于EMU065、EMU066、EMU067和EMU108的程序
EMU065(S)-1-(吡啶-2-基)乙胺(0.45g,3.68mmol)、DCE(18ml)、THIQ(1.011g,3.87mmol)和STAB-H(1.405g,6.63mmol)。将反应搅拌24h,然后用2M NaOH淬灭,用DCM萃取,用MgSO4干燥,过滤并且浓缩成半固体。将粗物质溶解在DCM和TFA中然后搅拌过夜。反应用DCM稀释并且用1M NaOH使之成为碱性。将层分离并且用DCM(2×10mL)萃取水层。有机物用Na2SO4干燥,过滤并且浓缩成棕色油状物,其通过combiflash(DCM 2分钟,10%B(B=80∶20∶3 DCM∶MeOH∶NH4OH)7分钟,50%B 8分钟)纯化以得到(S)-1-(吡啶-2-基)-N,N-二(((R)-1,2,3,4-四氢异喹啉-3-基)甲基)乙胺(0.095g,0.230mmol,收率为53%)。1H NMR(400MHz,CDCl3):δ=8.57(d,J=4.5Hz,1H),7.65(t,J=7.5Hz,1H),7.29(d,J=7.8Hz,1H),7.17(dd,J=7.4,4.8Hz,1H),7.15-6.99(m,8H),4.16(q,J=6.9Hz,1H),4.08(d,J=15.3Hz,1H),4.02(d,J=15.3Hz,1H),3.00-2.93(m,2H),2.73-2.62(m,8H),2.45(dd,J=16.3,10.6Hz,2H),1.54(d,J=6.9Hz,3H);13C NMR(125MHz,CDCl3):δ=161.5,148.9,136.0,135.4,134.3,129.1,126.3,126.0,125.6,122.6,122.1,61.4,57.3,48.4,33.6,16.5;HRMS(ESI)[M+H]+,对于C27H33N4计算为413.26997,实测为413.26952;LC/MS H2O中75-95%MeOH,经过3分钟,rt=0.951,在254nM,MS(+)413.2,MS(+)/2 207.2
EMU108:向20mL小瓶添加(S)-1-(吡啶-2-基)乙胺(0.3g,2.456mmol)、DCE(体积:5.85ml)、丁醛(0.672g,2.339mmol)和STAB-H(0.744g,3.51mmol),并且允许将反应搅拌过夜。将反应搅拌16h,然后用2M NaOH淬灭,用DCM萃取,用MgSO4干燥,过滤并且浓缩成半固体。将粗物质通过combiflash(DCM 2分钟,10%B(B=80∶20∶3 DCM∶MeOH∶NH4OH)7分钟,50%B 8分钟)纯化以提供仲胺(0.733g,1.863mmol,收率为80%)。向20mL小瓶添加THIQ(0.203g,0.777mmol)、DCE(体积:1.943ml)、仲胺(0.312g,0.793mmol)和STAB-H(0.247g,1.166mmol)。将反应搅拌过夜持续14h。反应用DCM稀释,用2M NaOH洗涤,用MgSO4干燥,过滤并且浓缩成黄色油状物。将油状物溶解在10mL DCM中,并且允许用TFA(1mL)搅拌12h。反应物用DCM稀释并且用1M NaOH使之成为碱性。将层分离并且用DCM(2×10mL)萃取水层。将有机物用Na2SO4干燥,过滤并且浓缩成棕色油状物,其通过combiflash(DCM 2分钟,10%B(B=80∶20∶3 DCM∶MeOH∶NH4OH)7分钟,50%B 8分钟)纯化以提供作为黄色油状物的N1-((S)-1-(吡啶-2-基)乙基)-N1-(((R)-1,2,3,4-四氢异喹啉-3-基)甲基)丁烷-1,4-二胺(0.097g,0.287mmol,经过3个步骤产率为37%)。1H NMR(500MHz,CDCl3):δ=8.51(dd,J=4.8,0.8Hz,1H),7.61(dt,J=7.6,1.8Hz,1H),7.31(d,J=7.8Hz,1H),7.11(ddd,J=7.4,5.0,0.8Hz,1H),7.08-6.96(m,4H),4.03(d,J=14.6Hz,1H),4.03(q,J=6.9Hz,1H),3.96(d,J=14.9Hz,1H),2.85-2.80(m,1H),2.62(t,J=6.9Hz,2H),2.59-2.53(m,2H),2.52(dd,J=13.1,4.2Hz,1H),2.45(dd,J=13.8,7.1Hz,1H),2.39(dd,J=15.4,10.5Hz,1H),1.80(bs,2NH),1.49-1.41(m,2H),1.43(d,J=6.9Hz,3H),1.41-1.32(m,2H);13C NMR(125MHz,CDCl3):δ=162.5,148.7,136.0,135.6,134.6,129.1,126.4,125.9,125.5,122.6,121.9,60.1,56.6,52.2,51.3,48.7,42.1,33.9,31.5,25.7,16.2;HRMS(ESI)[M+H]+,对于C21H31N4计算为339.25432,实测为339.25409;LC/MS H2O中75%MeOH,经过3分钟,rt=0.763,在254nM,MS(+)339.2,MS(+)/2 170.2
EMU066:向50mL RBF添加(S)-1-(5-甲基吡啶-2-基)乙胺(0.45g,3.30mmol)、DCE(体积:16.52ml)、THIQ(0.907g,3.47mmol)和STAB-H(1.260g,5.95mmol)。将反应搅拌16h,然后用2M NaOH淬灭,用DCM萃取,用MgSO4干燥,过滤并且浓缩成半固体。粗物质通过combiflash(DCM 5min,10%B(80∶20∶3,DCM∶MeOH∶NH4OH)7min,50%B 10min)纯化以得到(R)-叔丁基3-((((S)-1-(5-甲基吡啶-2-基)乙基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯(1.01g,2.65mmol,收率为80%),将其直接地带到下一个步骤。向20mL小瓶添加(R)-叔丁基3-((((S)-1-(5-甲基吡啶-2-基)乙基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯(0.5g,1.311mmol)、DCE(体积:4.37ml)和丁基胺醛,随后是STAB-H(0.500g,2.359mmol),并且将反应搅拌过夜。反应通过添加2M NaOH淬灭,并且用DCM萃取。有机相用MgSO4干燥、过滤并且浓缩成黄色油状物。将粗油状物溶解在3mL DCM中并且添加TFA(1ml)并且允许将混合物搅拌过夜。反应用2M NaOH淬灭,用DCM萃取,用MgSO4干燥,过滤并且浓缩成黄色油状物。将油状物通过combiflash(DCM 5min,10%B(80∶20∶3,DCM∶MeOH∶NH4OH)7min,50%B10min)纯化以提供N1-((S)-1-(5-甲基吡啶-2-基)乙基)-N1-(((R)-1,2,3,4-四氢异喹啉-3-基)甲基)丁烷-1,4-二胺(.167g,0.474mmol,经过3个步骤收率为36%)。1H NMR(400MHz,CDCl3):δ=8.36(s,1H),7.44(d,J=8.6Hz,1H),7.22(d,J=8.4Hz,1H),7.10-7.08(m,2H),7.05-7.00(m,2H),4.06(d,J=15.4Hz,1H),4.01(q,J=7.0Hz,1H),4.00(d,J=14.8Hz,1H),2.89-2.83(m,1H),2.67-2.38(m,9H),2.30(s,3H),1.52-1.35(m,6H),1.43(d,J=6.8Hz,3H);13C NMR(100MHz,CDCl3):δ=159.5,149.4,136.5,135.6,134.6,131.1,129.0,126.3,125.8,125.4,122.0,60.7,56.5,52.1,51.2,48.7,42.1,33.89,31.51,25.6,18.0,16.5;HRMS(ESI)[M+H]+,对于C22H33N4计算为353.26997,实测为353.26950;LC/MS H2O中75-95%MeOH,经过3分钟,rt=0.781,在254nM,MS(+)353.2,MS(+)/2 177.2
EMU067:向50mL RBF添加(S)-1-(3-甲基吡啶-2-基)乙胺(0.45g,3.30mmol)、DCE(体积:16.52ml)、THIQ(0.907g,3.47mmol)和STAB-H(1.260g,5.95mmol)。将反应搅拌16h,然后用2M NaOH淬灭,用DCM萃取,用MgSO4干燥,过滤并且浓缩成半固体。将粗物质通过combiflash(DCM 5min,10%B(80∶20∶3,DCM∶MeOH∶NH4OH)7min,50%B 10min)纯化以提供(R)-叔丁基3-((((S)-1-(3-甲基吡啶-2-基)乙基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯(0.85g,2.228mmol,收率为67%)。向20mL小瓶添加(R)-叔丁基3-((((S)-1-(3-甲基吡啶-2-基)乙基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯(0.5g,1.311mmol)、DCE(体积:4.37ml)和醛(0.753g),随后是STAB-H(0.500g,2.359mmol),并且将反应搅拌过夜。反应通过添加2M NaOH淬灭,并且用DCM萃取。有机相用MgSO4干燥、过滤并且浓缩成黄色油状物。将粗油状物溶解在3mL DCM中并且添加TFA(1mL),然后允许将混合物搅拌过夜。反应用2MNaOH淬灭,用DCM萃取,用MgSO4干燥,过滤并且浓缩成黄色油状物。将油状物通过combiflash(DCM 5min,10%B(80∶20∶3,DCM∶MeOH∶NH4OH)7min,50%B 10min)纯化以提供N1-((S)-1-(3-甲基吡啶-2-基)乙基)-N1-(((R)-1,2,3,4-四氢异喹啉-3-基)甲基)丁烷-1,4-二胺(0.281g,0.797mmol,收率为61%)。1H NMR(400MHz,CDCl3):δ=8.37(d,J=4.7Hz,1H),7.42(d,J=7.6Hz,1H),7.08-7.04(m,3H),6.99-6.96(m,2H),4.27(q,J=6.6Hz,1H),3.99(d,J=15.2Hz,1H),3.87(d,J=15.2Hz,1H),2.81(dd,J=11.4,2.8Hz,1H),2.71-2.65(m,1H),2.60-2.49(m,8H),2.46(s,3H),2.22(dd,J=16.6,10.4Hz,1H),1.43(d,J=6.6Hz,3H),1.32-1.24(m,4H);13C NMR(100MHz,CDCl3):δ=160.3,145.8,137.7,135.5,134.6,132.3,129.1,126.2,125.8,125.4,121.9,58.4,57.8,52.7,52.0,48.6,42.0,33.8,31.6,26.8,18.7,11.8;HRMS(ESI)[M+H]+,对于C22H33N4计算为353.26997,实测为353.26955;LC/MS H2O中85%MeOH,经过3分钟,rt=0.689,在254nM,MS(+)353.2,MS(+)/2 177.2
用于EMU107、EMU127和EMU130的程序
向25mL rbf添加叔丁基(3,5-二甲基吡啶-2-基)甲基)氨基甲酸酯(0.4g,1.693mmol)和DMF(体积:8.46ml)。向澄清溶液一次性添加氢化钠(0.102g,2.54mmol),并且溶液随着少量气体逸出而变成红色。允许将红色溶液搅拌15分钟,随后逐滴添加碘甲烷(0.158ml,2.54mmol)。溶液在添加期间变成黄色。允许将混合物搅拌另外的20分钟,然后通过TLC判断为完全。将反应混合物倾倒入50mL的水中,并且用EtOAc(50mL)萃取。有机层用另外的75mL水洗涤,然后用MgSO4干燥,过滤并且浓缩成黄色油状物。将油状物通过combiflash(己烷中10-25%EA梯度)纯化以得到叔丁基((3,5-二甲基吡啶-2-基)甲基)(甲基)氨基甲酸酯(0.256g,1.023mmol,收率为60%)。向20mL小瓶添加叔丁基(3,5-二甲基吡啶-2-基)甲基)(甲基)氨基甲酸酯(0.250g,0.999mmol)、DCM(体积:4.54ml,比率:10)和TFA(体积:0.454ml,比率:1)。将反应搅拌过夜,然后用DCM稀释,用2M NaOH淬灭,用MgSO4干燥,过滤并且浓缩成澄清油状物。不经进一步纯化即使用澄清油状物1-(3,5-二甲基吡啶-2-基)-N-甲基甲胺(.13g,0.865mmol,收率为87%),经过两个步骤收率为74%。1H NMR(400MHz,CDCl3):δ=8.19(s,1H),7.37(s,1H),4.21(s,2H),2.84(s,3H),2.31(s,3H),2.24(s,3H);
向100mL RBF添加3-甲基吡啶甲醛(1g,8.26mmol)和DCE(体积:40.0ml,比率:8)。向搅拌的溶液一次性添加盐酸甲胺(1.672g,24.77mmol)。将MeOH(体积:5ml,比率:1.000)添加,随后是一次性添加STAB-H(3.15g,14.86mmol),并且允许将反应搅拌过夜。反应用DCM稀释,并且用1M NaOH洗涤,用Na2SO4干燥,过滤并且浓缩以提供N-甲基-1-(3-甲基吡啶-2-基)甲胺(0.890g,6.53mmol,收率为79%),其通过1H NMR而足够纯。1H NMR(400MHz,CDCl3):δ=8.37(d,J=4.4Hz,1H),7.40(d,J=7.6Hz,1H),7.05(dd,J=7.6,4.8Hz,1H),3.82(s,2H),2.50(s,3H),2.29(s,3H);LC/MS H2O中75-95%MeOH,经过3分钟,rt=0.491,在254nM,MS(+)137.2
向100mL RBF添加5-甲基吡啶甲醛(1g,8.26mmol)和DCE(体积:40.0ml,比率:8)。向搅拌的溶液一次性添加盐酸甲胺(1.672g,24.77mmol)。添加MeOH(体积:5ml,比率:1.000),随后是一次性添加STAB-H(3.15g,14.86mmol),并且允许将反应搅拌过夜。反应用DCM稀释,并且用1M NaOH洗涤,用Na2SO4干燥,过滤并且浓缩以提供N-甲基-1-(5-甲基吡啶-2-基)甲胺(0.92g,6.76mmol,收率为82%),其通过1H NMR而足够地纯。1H NMR(400MHz,CDCl3):δ=8.37(s,1H),7.44(d,J=8.4Hz,1H),7.17(d,J=7.9Hz,1H),3.82(s,2H),2.46(s,3H),2.30(s,3H);LC/MS H2O中75-95%MeOH,经过3分钟,rt=0.488,在254nM,MS(+)137.2
2-(叔丁基)3-甲基(R)-5-溴-3,4-二氢异喹啉-2,3(1H)-二羧酸酯:根据PCTInt.Appl.(2014),WO 2014193781 A1 20141204制备
步骤1)向50mL Schlenk管添加所有固体,并且将容器放置在真空下。将二噁烷(体积:6.10ml)脱气持续1h,然后添加到20mL小瓶中的(R)-2-叔丁基3-甲基5-溴-3,4-二氢异喹啉-2,3(1H)-二羧酸酯(0.904g,2.440mmol)中并且溶解。将溶液添加到固体的搅拌混合物中,然后用三个循环的蒸发和氩气吹扫(argon purge)使溶液脱气。然后将溶液在油浴(预加热至120℃)中加热伴随指形冷凝管(cold finger)附接至schlenk管。反应从红色变成淡绿色,并且通过TLC(10%EA/hex)监测。允许将反应搅拌过夜(22h)。反应为红棕色,并且冷却至RT,用DCM稀释,过滤通过硅藻土并且浓缩成橙色油状物,其通过硅胶色谱(0-30%EA/hex)纯化(R)-2-叔丁基3-甲基5-(4-(叔丁氧基羰基)哌嗪-1-基)-3,4-二氢异喹啉-2,3(1H)-二羧酸酯(酯10.705g,1.482mmol,收率为61%)。步骤2)向50mL schlenk管添加酯1(0.5g,1.051mmol)和甲苯(体积:5.26ml)。将溶液冷却至-78℃,然后逐滴添加二异丁基氢化铝(2.63ml,3.15mmol)。允许将反应在-78℃搅拌,直到SM被消耗。反应用甲醇稀释,并且倾倒入罗谢尔盐的饱和溶液并且搅拌30分钟。水相用EtOAc(3×25mL)萃取,用Na2SO4干燥,过滤并且浓缩成白色固体(R)-叔丁基5-(4-(叔丁氧基羰基)哌嗪-1-基)-3-甲酰基-3,4-二氢异喹啉-2(1H)-羧酸酯(CHO 1,0.44g,0.988mmol,收率为94%),其不经进一步操作即使用。
EMU107:向20mL小瓶添加CHO 1(0.270g,0.605mmol)、1-(3,5-二甲基吡啶-2-基)-N-甲基甲胺(0.1g,0.666mmol)、DCE(体积:3.03ml)和STAB-H(0.192g,0.908mmol),然后允许将混合物搅拌过夜。反应用DCM稀释,用1M NaOH洗涤,用Na2SO4干燥,过滤并且浓缩以提供黄色油状物。将粗物质通过combiflash(DCM 2分钟,10%B(80∶20∶3,DCM∶MeOH∶NH4OH)5分钟和50%B 9分钟)纯化。将级分浓缩以提供黄色油状物,将其溶解在5mL DCM和0.5mL TFA中。溶液变成蓝色,然后变成绿色。允许将反应搅拌过夜。反应用DCM稀释,用1M NaOH洗涤,用Na2SO4干燥,过滤并且浓缩以提供黄色油状物。将粗物质通过combiflash(DCM 2分钟,10%B(80∶20∶3,DCM∶MeOH∶NH4OH)5分钟和50%B 9分钟)纯化。将级分浓缩以提供作为橙色半固体的(R)-1-(3,5-二甲基吡啶-2-基)-N-甲基-N-((5-(哌嗪-1-基)-1,2,3,4-四氢异喹啉-3-基)甲基)甲胺(0.110g,0.290mmol,经过两个步骤收率为48%)。1H NMR(500MHz,CDCl3):δ=8.19(s,1H),7.09(t,J=7.7Hz,1H),6.87(d,J=7.8Hz,1H),6.75(d,J=7.5Hz,1H),4.04(s,2H),3.73(d,J=12.4Hz,1H),3.60(d,J=12.4Hz,1H),3.03-2.88(m,9H),2.69-2.65(m,2H),2.58(dd,J=12.3,9.6Hz,1H),2.51(dd,J=12.3,3.4Hz,1H),2.41(s,3H),2.27(3,3H),2.26(s,3H),2.16(dd,J=16.8,11.0Hz,1H);13C NMR(100MHz,CDCl3):δ=153.7,151.7,146.4,138.9,136.3,132.2,131.8,129.8,126.0,121.6,116.8,63.4,63.1,53.1,51.2,48.6,46.5,42.9,30.1,18.3,17.9;HRMS(ESI)[M+H]+,对于C23H34N5计算为380.28087,实测为380.28068;LC/MS H2O中10-95%MeOH,经过10分钟,rt=5.701,在254nM,MS(+)380.3,MS(+)/2 190.7
EMU127:向20mL小瓶添加N-甲基-1-(3-甲基吡啶-2-基)甲胺(0.110g,0.808mmol)、DCE(体积:1.68ml)、STAB-H(.257g,1.212mmol)和CHO 1(0.3g,0.673mmol),然后允许将混合物搅拌过夜。反应用DCM稀释,用1M NaOH洗涤,用Na2SO4干燥,过滤并且浓缩以提供黄色油状物。将粗物质通过combiflash(DCM 2分钟,10%B(80∶20∶3,DCM∶MeOH∶NH4OH)5分钟和50%B 9分钟)纯化。将级分浓缩以提供黄色油状物,将其溶解在5mL DCM和0.5mLTFA中。溶液变成蓝色,然后变成绿色。允许将反应搅拌过夜。反应用DCM稀释,用1M NaOH洗涤,用Na2SO4干燥,过滤并且浓缩以得到黄色油状物。将粗物质通过combiflash(DCM 2分钟,10%B(80∶20∶3,DCM∶MeOH∶NH4OH)5分钟和50%B 9分钟)纯化。将级分浓缩以提供作为橙色半固体的(R)-N-甲基-1-(3-甲基吡啶-2-基)-N-((5-(哌嗪-1-基)-1,2,3,4-四氢异喹啉-3-基)甲基)甲胺(0.145g,0.397mmol,经过两个步骤收率为59%)。1H NMR(500MHz,CDCl3):δ=8.35(d,J=4.7Hz,1H),7.43(d,J=7.5Hz,1H),7.09-7.06(m,2H),6.84(d,J=7.5Hz,1H),6.73(d,J=7.5Hz,1H),4.03(d,J=15.0Hz,1H),4.00(d,J=15.0Hz,1H),3.73(d,J=12.5Hz,1H),3.62(d,J=12.5Hz,1H),3.02-2.88(m,8H),2.66(t,J=7.2Hz,3H),2.61(dd,J=12.0,9.5Hz,1H),2.52(dd,J=12.2,3.5Hz,1H),2.44(s,3H),2.28(s,3H),2.18(dd,J=17.0,11.0Hz,1H);13C NMR(125MHz,CDCl3):δ=156.8,151.8,146.2,138.1,136.4,133.0,129.8,126.1,122.5,121.6,116.8,63.7,63.6,53.2,51.3,48.7,46.6,43.0,30.3,18.5;HRMS(ESI)[M+H]+,对于C22H32N5计算为366.26522,实测为366.26504;LC/MS H2O中10-95%MeOH,经过10分钟,rt=6.687,在254nM,MS(+)364.4,MS(+)/2 182.8;LC/MS H2O中75%MeOH,经过3分钟,rt=0.800,在254nM,MS(+)366.6,MS(+)/2 183.8
EMU130:向20mL小瓶添加N-甲基-1-(5-甲基吡啶-2-基)甲胺(0.110g,0.808mmol)、DCE(体积:1.683ml)、STAB-H(0.257g,1.212mmol)和CHO1(.3g,0.673mmol),然后允许将混合物搅拌过夜。反应用DCM稀释,用1M NaOH洗涤,用Na2SO4干燥,过滤并且浓缩以提供黄色油状物。将粗物质通过combiflash(DCM 2分钟,10%B(80∶20∶3,DCM∶MeOH∶NH4OH)5分钟和50%B 9分钟)纯化。将级分浓缩以提供黄色油状物,将其溶解在5mL DCM和0.5mLTFA中。溶液变成蓝色,然后变成绿色。允许将反应搅拌过夜。反应用DCM稀释,用1M NaOH洗涤,用Na2SO4干燥,过滤并且浓缩以得到黄色油状物。将粗物质通过combiflash(DCM 2分钟,10%B(80∶20∶3,DCM∶MeOH∶NH4OH)5分钟和50%B 9分钟)纯化。将级分浓缩以提供作为橙色半固体的(R)-N-甲基-1-(5-甲基吡啶-2-基)-N-((5-(哌嗪-1-基)-1,2,3,4-四氢异喹啉-3-基)甲基)甲胺(0.166g,0.454mmol,收率为67%)。1H NMR(500MHz,CDCl3):δ=8.32(d,J=0.5Hz,1H),7.42(dd,J=7.9,1.6Hz,1H),7.29(d,J=7.9Hz,1H),7.05(t,J=7.6Hz,1H),6.82(d,J=7.6Hz,1H),6.72(d,J=7.6Hz,1H),4.04(d,J=15.3Hz,1H),4.01(d,J=15.3Hz,1H),3.71(d,J=13.9Hz,1H),3.57(d,J=13.9Hz,1H),2.99-2.85(m,8H),2.65(brs,2H),2.56(dd,J=12.6,10.0Hz,1H),2.47(dd,J=12.6,3.4Hz,1H),2.34(brs,3H),2.28(s,3H),2.25(s,3H),2.14(dd,J=16.8,11.3Hz,1H);13C NMR(125MHz,CDCl3):δ=156.3,151.7,149.4,137.1,136.5,131.4,129.8,126.0,122.6,121.6,116.8,64.4,63.2,53.2,51.3,48.7,46.5,43.2,30.2,18.1;HRMS(ESI)[M+H]+,对于C22H32N5计算为366.26522,实测为366.26501;LC/MS H2O中75%MeOH,经过3分钟,rt=0.810,在254nM,MS(+)366.6,MS(+)/2 183.9
用于N-丙基哌嗪侧链的程序
向50mL RBF添加叔丁基4-(3-氨基丙基)哌嗪-1-羧酸酯(1.105g,4.54mmol)、DCE(体积:10.32ml)、3-甲基吡啶甲醛(.5g,4.13mmol)和STAB-H(1.575g,7.43mmol)。将反应搅拌过夜,然后用DCM稀释,并且用2M NaOH淬灭。有机层用Na2SO4干燥,过滤并且浓缩成黄色油状物,其通过硅胶色谱(DCM 2分钟,10%B(80∶20∶3,DCM∶MeOH∶NH4OH)5分钟和50%B 9分钟)纯化以提供叔丁基4-(3-(((5-甲基吡啶-2-基)甲基)氨基)丙基)哌嗪-1-羧酸酯(0.75g,2.152mmol,收率为52%)。1H NMR(400MHz,CDCl3):δ=8.36(d,J=2.0Hz,1H),7.44(dd,J=7.9,2.2Hz,1H),7.18(d,J=7.9Hz,1H),3.87(s,2H),3.42(t,J=5.1Hz,4H),2.73(t,J=6.8Hz,2H),2.42(t,J=7.1Hz,2H),2.38(t,J=5.0Hz,4H),2.31(s,3H),1.75(pent,J=6.9Hz,2H),1.45(s,9H);
向50mL RBF添加叔丁基4-(3-氨基丙基)哌嗪-1-羧酸酯(1.105g,4.54mmol)、DCE(体积:10.32ml)、3-甲基吡啶甲醛(.5g,4.13mmol)和STAB-H(1.575g,7.43mmol)。将反应搅拌过夜,然后用DCM稀释,并且用2M NaOH淬灭。有机层用Na2SO4干燥,过滤并且浓缩成黄色油状物,其通过硅胶色谱(DCM 2分钟,10%B(80∶20∶3,DCM∶MeOH∶NH4OH)5分钟和50%B 9分钟)纯化以提供叔丁基4-(3-(((3-甲基吡啶-2-基)甲基)氨基)丙基)哌嗪-1-羧酸酯(0.88g,2.53mmol,收率为61%)。1H NMR(400MHz,CDCl3):δ=8.37(d,J=5.0Hz,1H),7.42(d,J=7.3Hz,1H),7.07(dd,J=7.6,4.8Hz,1H),3.88(s,2H),3.43(t,J=5.2Hz,4H),2.79(t,J=6.8Hz,2H),2.45(t,J=7.2Hz,2H),2.39(t,J=5.2Hz,4H),2.30(s,3H),1.78(pent,J=7.0Hz,2H),1.45(s,9H);
EMU148:向20mL小瓶添加叔丁基4-(3-(((5-甲基吡啶-2-基)甲基)氨基)丙基)哌嗪-1-羧酸酯(0.2g,0.574mmol)、STAB-H(0.219g,1.033mmol)和THIQ(0.165g,0.631mmol)(R)-,然后允许将混合物搅拌过夜。反应用DCM稀释,用1M NaOH洗涤,用Na2SO4干燥,过滤并且浓缩以提供黄色油状物。将粗物质通过combiflash(DCM 2分钟,10%B(80∶20∶3,DCM∶MeOH∶NH4OH)5分钟和50%B 9分钟)纯化。将级分浓缩以提供黄色油状物,将其溶解在2.5mLDCM和0.5mL TFA中。允许将反应搅拌过夜。反应用DCM稀释,用1M NaOH洗涤,用Na2SO4干燥,过滤并且浓缩以提供黄色油状物。将粗物质通过combiflash(DCM 2分钟,10%B(80∶20∶3,DCM∶MeOH∶NH4OH)5分钟和50%B 9分钟)纯化。将级分浓缩以提供(R)-N-((5-甲基吡啶-2-基)甲基)-3-(哌嗪-1-基)-N-((1,2,3,4-四氢异喹啉-3-基)甲基)丙烷-1-胺(0.101g,0.257mmol,收率为45%)。1H NMR(500MHz,CDCl3):δ=8.30(s,1H),7.42(d,J=8.4Hz,1H),7.28(d,J=8.4Hz,1H),7.06-7.00(m,3H),6.97-6.95(m,1H),3.98(d,J=15.3Hz,1H),3.92(d,J=15.1Hz,1H),3.78(d,J=14.3Hz,1H),3.64(d,J=14.3Hz,1H),2.90-2.86(m,1H),2.82(t,J=4.8Hz,3H),2.65-2.29(m,16H),2.27(s,3H),1.76-1.63(m,2H);13C NMR(125MHz,CDCl3):δ=156.9,149.3,137.1,135.5,134.4,131.3,129.1,126.3,125.9,125.5,122.4,61.1,60.4,57.0,54.6,53.4,51.7,48.5,46.0,33.8,24.2,18.1;HRMS(ESI)[M+H]+,对于C24H36N5计算为394.29652,实测为394.29578;LC/MS H2O中10-95%MeOH,经过10分钟,rt=6.430,在254nM,MS(+)394.3,MS(+)/2 197.8
EMU149:向20mL小瓶添加叔丁基4-(3-(((3-甲基吡啶-2-基)甲基)氨基)丙基)哌嗪-1-羧酸酯(0.2g,0.574mmol)、DCE(1.5mL)、STAB-H(0.219g,1.033mmol)和THIQ(0.165g,0.631mmol),然后允许将混合物搅拌过夜。反应用DCM稀释,用1M NaOH洗涤,用Na2SO4干燥,过滤并且浓缩以提供黄色油状物。将粗物质通过combiflash(DCM 2分钟,10%B(80∶20∶3,DCM∶MeOH∶NH4OH)5分钟和50%B 9分钟)纯化。将级分浓缩以提供黄色油状物,将其溶解在2.5mL DCM和0.5mL TFA中。允许将反应搅拌过夜。反应用DCM稀释,用1M NaOH洗涤,用Na2SO4干燥,过滤并且浓缩以提供黄色油状物。将粗物质通过combiflash(DCM 2分钟,10%B(80∶20∶3,DCM∶MeOH∶NH4OH)5分钟和50%B 9分钟)纯化。将级分浓缩以提供(R)-N-((3-甲基吡啶-2-基)甲基)-3-(哌嗪-1-基)-N-((1,2,3,4-四氢异喹啉-3-基)甲基)丙烷-1-胺(0.134g,0.340mmol,收率为59%)。1H NMR(500MHz,CDCl3):δ=8.31(d,J=3.6Hz,1H),7.40(d,J=7.3Hz,1H),7.10-6.94(m,5H),3.94(d,J=15.6Hz,1H),3.86(d,J=15.6Hz,1H),3.85(d,J=12.8Hz,1H),3.65(d,J=12.8Hz,1H),2.84-2.79(m,1H),2.80(t,J=4.6Hz,3H),2.63-2.46(m,8H),2.40(s,3H),2.34-2.19(m,3H),1.68-1.62(m,2H);13C NMR(125MHz,CDCl3):δ=157.0,146.2,138.1,135.3,134.4,132.8,129.1,126.3,126.0,125.5,122.5,60.6,60.5,57.0,54.5,53.5,51.7,48.4,45.9,33.7,23.9,18.4;HRMS(ESI)[M+H]+,对于C24H36N5计算为394.29652,实测为394.29593;LC/MS H2O中10-95%MeOH,经过10分钟,rt=6.080,在254nM,MS(+)394.3,MS(+)/2 197.8
EMU164:向20mL小瓶添加叔丁基4-(3-(((3-甲基吡啶-2-基)甲基)氨基)丙基)哌嗪-1-羧酸酯(0.2g,0.574mmol)、DCE(体积:1.435ml)、STAB-H(0.219g,1.033mmol)和CHO 1(0.281g,0.631mmol),然后允许将混合物搅拌过夜。反应用DCM稀释,用1M NaOH洗涤,用Na2SO4干燥,过滤并且浓缩以提供黄色油状物。将粗物质通过combiflash(DCM 2分钟,10%B(80∶20∶3,DCM∶MeOH∶NH4OH)5分钟和50%B 9分钟)纯化。将级分浓缩以提供黄色油状物,将其溶解在2.5mL DCM和0.5mL TFA中。允许将反应搅拌过夜。反应用DCM稀释,用1M NaOH洗涤,用Na2SO4干燥,过滤并且浓缩以提供黄色油状物。将粗物质通过combiflash(DCM 2分钟,10%B(80∶20∶3,DCM∶MeOH∶NH4OH)5分钟,50%B 9分钟,100%B 10分钟)纯化。将级分浓缩以提供(R)-N-((3-甲基吡啶-2-基)甲基)-3-(哌嗪-1-基)-N-((5-(哌嗪-1-基)-1,2,3,4-四氢异喹啉-3-基)甲基)丙烷-1-胺(0.134g,0.281mmol,收率为49%)。1H NMR(500MHz,CDCl3):δ=8.32(dd,J=4.8,1.1Hz,1H),7.40(d,J=7.0Hz,1H),7.05(t,J=7.7Hz,1H),7.04(dd,J=7.0,4.8Hz,1H),6.82(d,J=7.7Hz,1H),6.71(d,J=7.7Hz,1H),4.02(d,J=15.3Hz,1H),3.93(d,J=15.3Hz,1H),3.86(d,J=12.8Hz,1H),3.65(d,J=12.8Hz,1H),2.99-2.83(m,6H),2.79(t,J=4.8Hz,4H),2.67-2.56(m,3H),2.51-2.44(m,2H),2.39(s,3H),2.24-2.17(m,4H),2.13(dd,J=15.8,10.4Hz,1H),1.70-1.59(m,2H);13C NMR(125MHz,CDCl3):δ=157.1,151.8,146.2,138.1,136.1,132.7,129.7,126.1,122.5,121.6,116.9,60.6,60.6,57.1,54.5,53.4,53.2,51.7,48.4,46.6,46.0,30.0,23.9,18.5;HRMS(ESI)[M+H]+,对于C28H44N7计算为478.36527,实测为478.36487;LC/MS H2O中75%MeOH,经过3分钟,rt=0.481,在254nM,MS(+)478.4,MS(+)/2 239.8
EMU165:向20mL小瓶添加叔丁基(4-(((5-甲基吡啶-2-基)甲基)氨基)丁基)氨基甲酸酯(0.15g,0.511mmol)、DCE(体积:1.162ml)、CHO 1(0.207g,0.465mmol)和STAB-H(0.177g,0.837mmol),然后允许将混合物搅拌过夜。反应用DCM稀释,用1M NaOH洗涤,用Na2SO4干燥,过滤并且浓缩以得到黄色油状物。将粗物质通过combiflash(DCM 2分钟,10%B(80∶20∶3,DCM∶MeOH∶NH4OH)5分钟和50%B 9分钟)纯化。将级分浓缩以提供黄色油状物(R)-叔丁基3-(((4-((叔丁氧基羰基)氨基)丁基)((5-甲基吡啶-2-基)甲基)氨基)甲基)-5-(4-(叔丁氧基羰基)哌嗪-1-基)-3,4-二氢异喹啉-2(1H)-羧酸酯(.238g,0.329mmol,收率为71%)。向20mL小瓶添加(R)-叔丁基3-(((4-((叔丁氧基羰基)氨基)丁基)((5-甲基吡啶-2-基)甲基)氨基)甲基)-5-(4-(叔丁氧基羰基)哌嗪-1-基)-3,4-二氢异喹啉-2(1H)-羧酸酯(.238g,0.329mmol)、DCM(体积:1.372ml,比率:5)和TFA(体积:0.274ml,比率:1.000),然后允许将混合物搅拌过夜。反应用DCM稀释,用1M NaOH洗涤,用Na2SO4干燥,过滤并且浓缩以提供黄色油状物。将粗物质通过combiflash(DCM 2分钟,10%B(80∶20∶3,DCM∶MeOH∶NH4OH)5分钟和50%B 9分钟)纯化。将级分浓缩以提供作为黄色半固体的(R)-N1-((5-甲基吡啶-2-基)甲基)-N1-((5-(哌嗪-1-基)-1,2,3,4-四氢异喹啉-3-基)甲基)丁烷-1,4-二胺(0.072g,0.170mmol,收率为52%)。1H NMR(500MHz,CD3OD):δ=8.58(s,1H),8.15(d,J=7.8Hz,1H),7.74(d,J=7.8Hz,1H),7.12(t,J=7.8Hz,1H),6.96(d,J=7.8Hz,1H),6.86(d,J=7.8Hz,1H),4.34(d,J=16.6Hz,1H),4.27(d,J=16.6Hz,1H),4.18(d,J=16.6Hz,1H),3.84(d,J=15.8Hz,1H),3.62-3.58(m,1H),3.21-3.10(m,5H),3.02-2.99(m,2H),2.93-2.83(m,4H),2.71(t,J=7.0Hz,1H),2.56(dd,J=17.5,11.4Hz,1H),2.45(t,J=7.0Hz,1H),2.35(s,3H),1.51-1.37(m,4H);13C NMR(125MHz,CD3OD):δ=152.4,151.3,147.9,143.0,138.5,130.7,129.1,128.2,127.5,124.1,120.6,57.4,56.5,55.2,53.0,50.1,45.9,45.2,40.3,26.6,26.1,23.6,18.0;HRMS(ESI)[M+H]+,对于C25H39N6计算为423.32307,实测为423.32311;LC/MS H2O中75%MeOH,经过3分钟,rt=0.449,在254nM,MS(+)423.2,MS(+)/2 212.2;LC/MS H2O中10-95%MeOH,经过10分钟,rt=0.702,在254nM,MS(+)423.2,MS(+)/2 212.2
EMU166:向20mL小瓶添加叔丁基(4-(((3-甲基吡啶-2-基)甲基)氨基)丁基)氨基甲酸酯(0.15g,0.511mmol)、DCE(体积:1.162ml)、(R)-叔丁基5-(4-(叔丁氧基羰基)哌嗪-1-基)-3-甲酰基-3,4-二氢异喹啉。然后允许将混合物搅拌过夜。反应用DCM稀释,用1MNaOH洗涤,用Na2SO4干燥,过滤并且浓缩以提供黄色油状物。将粗物质通过combiflash(DCM2分钟,10%B(80∶20∶3,DCM∶MeOH∶NH4OH)5分钟和50%B 9分钟)纯化。将级分浓缩以提供黄色油状物(R)-叔丁基3-(((4-((叔丁氧基羰基)氨基)丁基)((3-甲基吡啶-2-基)甲基)氨基)甲基)-5-(4-(叔丁氧基羰基)哌嗪-1-基)-3,4-二氢异喹啉-2(1H)-羧酸酯(0.208g,0.288mmol,收率为62%),将其溶解在DCM(体积:1.199ml,比率:5)和TFA(体积:0.240ml,比率:1.000)中,然后允许将混合物搅拌过夜。反应用DCM稀释,用1M NaOH洗涤,用Na2SO4干燥,过滤并且浓缩以提供黄色油状物。将粗物质通过combiflash(DCM 2分钟,10%B(80∶20∶3,DCM∶MeOH∶NH4OH)5分钟和50%B 9分钟)纯化。将级分浓缩以提供作为黄色油状物的(R)-N1-((3-甲基吡啶-2-基)甲基)-N1-((5-(哌嗪-1-基)-1,2,3,4-四氢异喹啉-3-基)甲基)丁烷-1,4-二胺(0.077g,0.182mmol,收率为63%)。1H NMR(500MHz,CDCl3):δ=8.36(d,J=4.3Hz,1H),7.43(d,J=8.0Hz,1H),7.10-7.06(m,1H),7.07(t,J=8.0Hz,1H),6.85(d,J=8.0Hz,1H),6.73(d,J=8.0Hz,1H),4.04(d,J=15.5Hz,1H),3.90(d,J=15.5Hz,1H),3.87(d,J=13.0Hz,1H),3.64(d,J=13.6Hz,1H),3.01-2.92(m,11H),2.66-2.62(m,5H),2.60-2.54(m,1H),2.50-2.43(m,1H),2.39(s,3H),2.18(dd,J=16.1,10.5Hz,1H),1.55-1.47(m,2H),1.45-1.37(m,2H);13C NMR(125MHz,CDCl3):δ=157.0,151.8,146.3,138.3,136.0,132.6,129.6,126.3,122.6,121.7,117.0,60.8,60.2,55.4,53.2,51.7,48.2,46.6,41.4,30.6,29.9,24.4,18.5;HRMS(ESI)[M+H]+,对于C25H39N6计算为423.32307,实测为423.32311;LC/MS H2O中75%MeOH,经过3分钟,rt=0.450,在254nM,MS(+)423.2,MS(+)/2212.2
EMU023和EMU024的合成:方案1:
1-((苄氧基)羰基)-4-(叔丁氧基羰基)哌嗪-2-羧酸(化合物6)
将1,4-二噁烷(100ml)、水(50ml)和三甲胺(TEA)(10.78ml,77mmol)中的4-(叔丁氧基羰基)哌嗪-2-羧酸(7.12g,30.9mmol)的溶液冷却至0℃,并且缓慢地添加氯甲酸苄酯(5.5ml,37.1mmol)。将反应在0℃搅拌30分钟,然后让其升温至室温,并且搅拌另外的2小时。反应用1N HCl稀释并且然后用DCM萃取3次。合并的有机层经Na2SO4干燥;过滤掉并且蒸发。将粗产物照原样用于下一个步骤。
1-苄基-4-(叔丁基)-2-(羟甲基)哌嗪-1,4-二羧酸酯(化合物7)
将155ml无水THF中的化合物6(11.27g,30.9mmol)的溶液冷却至0℃,并且将硼烷-甲基硫化物络合物(27.8ml,55.7mmol)逐滴添加到反应混合物。在完成添加后,让反应混合物升温并且在室温搅拌过夜。在用冰浴冷却后,用卤水淬灭它;搅拌10分钟,然后用DCM萃取3次。合并的有机层经MgSO4干燥,过滤掉并且蒸发。将粗产物照原样用于下一个步骤。
1-苄基-4-(叔丁基)-2-甲酰基哌嗪-1,4-二羧酸酯(化合物8)
将80ml无水DCM和TEA(14.11ml,101mmol)中的化合物7(8.87g,25.3mmol)的溶液冷却至0℃。将80ml DMSO中的三氧化硫-吡啶络合物(12.33g,76mmol)添加到溶液并且继续搅拌2小时。反应用饱和NaHCO3淬灭并且用醚稀释。水相用醚洗涤3次。合并的有机层用NaHPO4溶液、1N HCl和卤水洗涤,然后经MgSO4干燥;过滤掉并且蒸发。将粗产物照原样用于下一个步骤。
1-苄基-4-(叔丁基)2-((((S)-5,6,7,8-四氢喹啉-8-基)氨基)甲基)哌嗪-1,4-二羧酸酯(化合物9)
将((S)-5,6,7,8-四氢喹啉-8-胺(4.39g,29.6mmol))和(1-苄基4-叔丁基2-甲酰基哌嗪-1,4-二羧酸酯(8.26g,23.71mmol))在室温溶解在30ml 1,2-二氯乙烷中并且搅拌10-15分钟。然后添加三乙酰氧基硼氢化钠(7.54g,35.6mmol)并且继续搅拌1小时。反应用饱和NaHCO3溶液淬灭。有机相用水和卤水洗涤;经Na2SO4干燥;过滤掉并且浓缩。用使用DCM∶MeOH∶NH4OH(9∶1∶0.1)的柱色谱纯化以提供100%收率。1H NMR(400Hz,CDCl3):δ1.400(s,4.5H),1.468(s,4.5H)1.625-2.021(m,4H),2.519(宽s,1H),2.684-3.017(m,7H),3.719-4.321(m,5H),5.152(m,2H),7.042(m,1H),7.336(m,6H),8.336(s,1H);MS:m/z 481.0(M+H)
1-苄基-4-(叔丁基)2-((甲基((S)-5,6,7,8-四氢喹啉-8-基)氨基)甲基)哌嗪-1,4-二羧酸酯(化合物10)
向100ml 1,2-DCE中的化合物9(11.39g,23.70mmol)的溶液添加多聚甲醛(3.75g,118mmol)和乙酸(1.05ml,18.25mmol)并且在室温搅拌1小时。在用三乙酰氧基硼氢化钠(12.56g,59.2mmol)处理后,将反应混合物搅拌另外的2小时,随后是添加3.75g多聚甲醛、1.05ml乙酸和6.0g三乙酰氧基硼氢化钠。这被允许在室温搅拌过夜并且用饱和NaHCO3溶液淬灭。水相用DCM萃取。合并的有机相用水和卤水洗涤,经Na2SO4干燥,并且过滤掉并且蒸发。用使用DCM∶MeOH∶NH4OH(9∶1∶0.1)的柱色谱纯化它以得到黄色油状物(收率为59%)。1H NMR(400Hz,CDCl3):δ1.39(s,4.5H),1.46(s,4.5H)1.60-2.10(m,4H),2.29(s,3H),2.67-3.02(m,7H),3.70-4.32(m,5H),5.12-5.15(m,2H),7.02-7.05(m,1H),7.31-7.36(m,6H),8.34(s,1H)
苄基(R)-2-((甲基((S)-5,6,7,8-四氢喹啉-8-基)氨基)甲基)哌嗪-1-羧酸酯和苄基(S)-2-((甲基((S)-5,6,7,8-四氢喹啉-8-基)氨基)甲基)哌嗪-1-羧酸酯(化合物11和12)
将化合物10(6.46g,13.06mmol)用TFA(20.12ml,261mmol)处理,并且将反应在室温搅拌过夜。用1N NaOH溶液使它碱化至pH>10-12。水相用DCM萃取2次。合并的有机层经无水Na2SO4干燥;过滤掉并且蒸发。非对映体用柱色谱分离,从DCM开始,然后用DCM∶MeOH∶NH4OH(9∶1∶0.1)增加极性。(化合物11:收率为31%)。1H NMR(400Hz,CDCl3):δ1.65-1.79(m,2H),1.80-2.10(m,2H),2.29(s,3H),2.30-2.51(m,1H),2.60-2.83(m,7H),3.83-3.85(m,1H),3.73-4.07(m,3H),5.12(q,J=12.4Hz,2H),7.04-7.08(m,1H),7.26-7.38(m,6H),8.47(d,J=4.4Hz,1H);化合物12(收率为22%):1H NMR(400Hz,CDCl3):δ1.65-1.80(m,2H),1.82-2.10(m,2H),2.29(s,3H),2.30-2.51(m,1H),2.60-3.22(m,8H),3.73-4.01(m,3H),5.11(d,J=3.6Hz,2H),7.04-7.08(m,1H),7.28-7.36(m,6H),8.43(d,J=3.6Hz,1H)
苄基(R)-2-((甲基((S)-5,67,8-四氢喹啉-8-基)氨基)甲基)-4-(吡啶-2-基甲基)哌嗪-1-羧酸酯(化合物13)
将10ml DCM中的化合物11的溶液用2-吡啶甲醛(0.097ml,1.022mmol)和三乙酰氧基硼氢化钠(0.335g,1.532mmol)处理。在室温搅拌6小时后,用饱和NaHCO3溶液淬灭它。水相用DCM萃取;合并的有机层用水萃取,并且经无水MgSO4干燥,并且过滤掉并且蒸发。将产物用使用DCM∶MeOH∶NH4OH(9∶1∶0.1)的柱色谱纯化,具有88%的收率。1H NMR(400MHz,氯仿-d)δ8.49(d,J=4.0Hz,1H),8.39(d,J=4.9Hz,1H),7.56(td,J=7.7,1.8Hz,1H),7.37-7.26(m,6H),7.17-7.10(m,1H),7.08(d,J=7.8Hz,1H),6.87(dd,J=7.6,4.7Hz,1H),5.19-5.07(m,2H),4.20-4.04(m,1H),3.88-3.73(m,2H),3.57(d,J=14.3Hz,1H),3.46(d,J=14.3Hz,1H),3.10(t,J=11.0Hz,2H),2.80(ddd,J=15.2,9.3,5.0Hz,2H),2.65(dt,J=17.0,4.9Hz,1H),2.53(s,2H),2.20(dd,J=11.2,4.0Hz,1H),2.03-1.83(m,5H),1.75(s,2H),1.60(s,1H)。
苄基(S)-2-((甲基((S)-5,6,7,8-四氢喹啉-8-基)氨基)甲基)-4-(吡啶-2-基甲基)哌嗪-1-羧酸酯(化合物14)
向10ml DCM中的化合物12的溶液添加2-吡啶甲醛(0.098ml,1.022mmol)和三乙酰氧基硼氢化钠(0.325g,1.532mmol),并且在室温搅拌过夜。反应用饱和NaHCO3溶液淬灭。水相用DCM萃取;合并的有机层用水萃取,并且经无水MgSO4干燥,并且过滤掉并且蒸发。将产物用具有DCM∶MeOH∶NH4OH(9∶1∶0.1)的柱色谱纯化,具有58%的收率。1H NMR(400MHz,氯仿-d)δ8.48(d,J=4.0Hz,1H),8.39(d,J=4.0Hz,1H),7.57(td,J=7.7,1.9Hz,1H),7.40-7.27(m,7H),7.07(dd,J=7.4,5.0Hz,1H),7.00(dd,J=7.5,4.8Hz,1H),5.09(s,2H),4.26-4.04(m,1H),3.98-3.69(m,2H),3.58(q,J=13.8Hz,2H),3.13-2.94(m,3H),2.70(d,J=31.6Hz,4H),2.34-2.22(m,3H),2.21-2.03(m,1H),1.87(d,J=18.5Hz,2H),1.74(s,3H)。
EMU023:(立体异构体1):向15ml DCM中的化合物13(0.338g,0.696mmol)的溶液添加甲磺酸(0.904ml,13.92mmol)并且在室温搅拌过夜。将反应冷却至0℃,并且用饱和NaHCO3溶液使反应碱化,直到pH>8-9。有机相用水洗涤;经MgSO4干燥;过滤掉并且蒸发。用使用DCM∶MeOH∶NH4OH(9∶1∶0.1)的柱色谱纯化它以得到黄色油状物(收率为37%)。1H NMR(400MHz,氯仿-d)δ1.78-1.58(m,2H),2.04-1.90(m,3H),2.41-2.30(m,4H),2.21-2.12(m,1H),1.89-1.58(m,4H),2.96-2.60(m,9H),2.42(s,3H),2.17(td,J=11.0,3.3Hz,1H),2.04-1.91(m,2H),1.90-1.79(m,1H),2.44-2.41(m,4H),8.53(ddd,J=4.9,1.9,0.9Hz,1H),8.41(dd,J=4.7,1.7Hz,1H),7.62(td,J=7.6,1.8Hz,1H),7.36(dt,J=7.9,1.1Hz,1H),7.32(ddt,J=7.7,1.8,0.8Hz,1H),7.13(ddd,J=7.5,4.9,1.2Hz,1H),7.04-6.99(m,1H),3.91(dd,J=9.2,5.7Hz,1H),3.70-3.54(m,2H),2.97-2.58(m,9H);MS:m/z 352.2(M+H);HRMS对于C21H30N5(M+H)计算为:352.24230,实测为:352.24919;EMU023(立体异构体2):在室温向15ml DCM中的14(0.282g,0.581mmol)的溶液添加甲磺酸(0.754ml,11.61mmol)并且搅拌过夜。将反应冷却至0℃,并且用饱和NaHCO3溶液碱化,直到pH为约8。有机相用水洗涤;经MgSO4干燥;过滤掉并且蒸发。用使用DCM∶MeOH∶NH4OH(9∶1∶0.1)的柱色谱纯化它以得到黄色油状物(收率为39%)。1H NMR(400MHz,氯仿-d)δ8.57-8.54(m,1H),8.47-8.42(m,1H),7.63(td,J=7.7,1.9Hz,1H),7.36(d,J=7.8Hz,1H),7.35-7.30(m,1H),7.15(ddd,J=7.5,4.9,1.2Hz,1H),7.03(dd,J=7.7,4.7Hz,1H),3.87(dd,J=9.4,6.0Hz,1H),3.64(s,2H),2.94-2.85(m,4H),2.83-2.58(m,5H),2.57-2.42(m,2H),2.32(s,3H),2.22(dt,J=10.8,6.8Hz,1H),2.11-2.02(m,1H),1.98(dd,J=13.0,7.5Hz,1H),1.91-1.74(m,2H);MS:m/z 352.2(M+H);HRMS对于C21H30N5(M+H)计算为:351.24230,实测为:352.24910
方案2:至S,R-非对映体和S,S-非对映体的外消旋途径
通过方案2合成EMU034和EMU035
2-叔丁基3-甲基5-(4-(叔丁氧基羰基)哌嗪-1-基)-3,4-二氢异喹啉-2,3(1H)-二羧酸酯
将外消旋2-叔丁基3-甲基5-溴-3,4-二氢异喹啉-2,3(1H)-二羧酸酯(1.03g,2.78mmol)、叔丁基哌嗪-1-羧酸酯(0.622g,3.34mmol)、Pd2(dba)3(0.127g,0.139mmol)、rac-BINAP(0.260g,0.417mmol)和碳酸铯(1.269g,3.89mmol)装入配备有Teflon包被的磁性搅拌棒的烘箱干燥的Biotage 10-20mL微波小瓶。将小瓶用Teflon衬覆(Teflon-lined)的隔膜密封并且用氩气吹扫5分钟。添加脱气的甲苯(13.91mL)并且用氩气将容器脱气持续另外的5分钟。将所得的混合物在油浴中在120℃加热48小时。在如通过TLC分析判断反应完全后,允许混合物冷却至室温,过滤通过硅藻土垫,并且浓缩成粗物质,其通过CombiFlash系统(40克硅柱,5分钟己烷,然后30分钟0-30%乙酸乙酯)纯化以提供作为淡黄色凝胶状物的产物(1.4011g,2.95mmol,定量收率)。1H NMR(400MHz,氯仿-d)δ7.13(td,J=7.8,4.2Hz,1H),6.98-6.65(m,2H),5.03(dd,J=6.1,3.5Hz,0.5H),4.80-4.55(m,1.5H),4.42(dd,J=34.5,16.1Hz,1H),3.75-3.39(m,7H),3.15(ddd,J=52.9,15.5,5.9Hz,1H),2.98-2.60(m,5H),1.62-1.27(m,18H)。HRMS对于[C25H37N3O6+H]+计算为:476.27606,实测为:476.27542。
叔丁基5-(4-(叔丁氧基羰基)哌嗪-1-基)-3-甲酰基-3,4-二氢异喹啉-2(1H)-羧酸酯:
将外消旋2-叔丁基3-甲基5-(4-(叔丁氧基羰基)哌嗪-1-基)-3,4-二氢异喹啉-2,3(1H)-二羧酸酯(0.50g,1.051mmol)和无水甲苯(13.14mL)装入包含Teflon包被的搅拌棒的100mL圆底烧瓶。在-78℃逐滴添加在甲苯(5.26ml,5.26mmol)中的二异丁基氢化铝1M溶液。在-78℃2h后,在氩气气氛下用甲醇小心地淬灭反应,然后允许升温至0℃。添加罗谢尔盐的饱和溶液并且在室温搅拌1-2小时。将双相混合物转移到分液漏斗。将水层分离并且用乙酸乙酯萃取(2次)。合并的有机相经无水硫酸钠干燥,并且在减压下浓缩以得到粗醛,其不经纯化即被用于下一个步骤。1H NMR(400MHz,氯仿-d)δ9.54-9.21(m,1H),7.12(td,J=7.6,5.1Hz,1H),6.95-6.69(m,2H),4.91-4.17(m,3H),3.90-3.09(m,5H),3.09-2.50(m,5H),1.64-1.26(m,18H)。
(R)-叔丁基5-(4-(叔丁氧基羰基)哌嗪-1-基)-3-((甲基((S)-5,6,7,8-四氢喹啉-8-基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯和(S)-叔丁基5-(4-(叔丁氧基羰基)哌嗪-1-基)-3-((甲基((S)-5,6,7,8-四氢喹啉-8-基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯
将(S)-N-甲基-5,6,7,8-四氢喹啉-8-胺(0.114g,0.705mmol)、三乙酰氧基硼氢化钠(0.179g,0.846mmol)和1,2-二氯乙烷(1.349mL)装入配备有Teflon包被的磁性搅拌棒的20mL闪烁小瓶。在搅拌持续5分钟后,逐滴添加1,2-二氯乙烷(1mL)中的外消旋叔丁基5-(4-(叔丁氧基羰基)哌嗪-1-基)-3-甲酰基-3,4-二氢异喹啉-2(1H)-羧酸酯(0.2093g,0.470mmol)的溶液。将所得的混合物在室温搅拌持续48小时。通过TLC和LCMS分析判断反应完全后,通过添加1M NaOH淬灭混合物。将双相混合物转移到分液漏斗。将水层分离并且用DCM萃取(3次)。合并的有机萃取物经无水硫酸钠干燥,并且在减压下浓缩成粗非对映体混合物,其通过CombiFlash系统(24g金硅柱,5分钟DCM,然后30分钟0-10%MeOH/DCM)分离和纯化以得到两种非对映体。立体异构体1:黄色泡沫状物(0.147g,0.249mmol,收率为53%)。1HNMR(400MHz,氯仿-d)δ8.23(d,J=4.7Hz,1H),7.29(d,J=7.8Hz,1H),7.05(t,J=7.7Hz,1H),6.96(dd,J=7.7,4.6Hz,1H),6.79(d,J=7.9Hz,1H),6.66(dd,J=14.9,7.5Hz,1H),4.66-4.37(m,2H),3.85(d,J=17.0Hz,1H),3.68-3.35(m,5H),3.21(d,J=16.0Hz,1H),2.92(dt,J=10.4,4.5Hz,2H),2.83-2.53(m,7H),2.24(s,3H),1.99-1.90(m,1H),1.84(q,J=6.2Hz,2H),1.47(d,J=2.7Hz,19H)。ESI-MS对于[C34H49N5O4+H]+计算为:592.38628,实测为:592.38611。立体异构体2:黄色泡沫状物(0.086g,0.146mmol,收率为31%)。1H NMR(400MHz,氯仿-d)δ8.44-8.29(m,1H),7.26-7.17(m,1H),7.09(q,J=6.3,4.8Hz,1H),7.01-6.90(m,1H),6.77(dd,J=20.4,7.7Hz,2H),4.51(dd,J=67.8,12.3Hz,2H),4.24(d,J=16.8Hz,1H),3.71-3.19(m,6H),2.93(t,J=9.0Hz,2H),2.68-2.53(m,5H),2.46(dd,J=12.8,5.4Hz,1H),2.33(s,3H),1.86(d,J=8.5Hz,2H),1.56(d,J=52.6Hz,21H)。ESI-MS对于[C34H49N5O4+H]+计算为:592.38628,实测为:592.38507。
用于全面脱保护(global deprotection)的一般程序:
将Boc保护的基底(substrate)(1当量)和DCM(0.13M)装入配备有Teflon包被的磁性搅拌棒的20mL闪烁小瓶。逐滴添加三氟乙酸(36当量),并且将所得的混合物在室温搅拌过夜。在如通过LCMS分析判断反应完全后,混合物用DCM稀释,在冰浴中冷却,并且通过添加3M NaOH直到pH>12淬灭。将双相混合物转移到分液漏斗。将水层分离并且用DCM萃取(3次)。合并的有机萃取物经无水硫酸钠干燥,并且在减压下浓缩成粗物质,其通过使用溶剂A(DCM)至溶剂B(8∶2∶0.6DCM/MeOH/NH3溶液,MeoH中为7N)的梯度作为硅胶柱上的洗脱剂的CombiFlash系统纯化以得到最终产物。
EMU034(立体异构体1):根据用于全面脱保护的一般程序制备。通过CombiFlash(12g柱,5分钟A,然后30分钟0-100%B)纯化粗物质以得到作为淡黄色泡沫状物的产物(67.5mg,定量收率)。1H NMR(400MHz,氯仿-d)δ8.43(d,J=4.7Hz,1H),7.36(d,J=7.6Hz,1H),7.17-7.01(m,2H),6.88(d,J=7.8Hz,1H),6.77(d,J=7.5Hz,1H),4.66(s,2H),4.22-4.11(m,1H),4.08-3.95(m,2H),3.05-2.87(m,8H),2.86-2.56(m,6H),2.44(s,4H),2.11-1.87(m,3H),1.80-1.64(m,1H)。HRMS对于[C24H33N5+H]+计算为:392.28142,实测为:392.28082。EMU034(立体异构体2):根据用于全面脱保护的一般程序制备。通过ConbiFlash(12g柱,5分钟A,然后30分钟0-100%B)纯化粗物质以得到作为淡黄色泡沫状物的产物(32.7mg,收率为83%)。1H NMR(400MHz,氯仿-d)δ8.44(dd,J=4.7,2.0Hz,1H),7.35(dd,J=7.7,1.7Hz,1H),7.15-7.02(m,2H),6.94-6.85(m,1H),6.85-6.75(m,1H),6.58(s,1H),4.23(t,J=6.4Hz,2H),3.86(dd,J=9.9,5.5Hz,1H),3.37-3.17(m,1H),3.07-2.86(m,5H),2.69(ddd,J=41.9,20.3,10.7Hz,7H),2.49(s,3H),2.24-2.09(m,1H),2.09-1.92(m,1H),1.87-1.59(m,2H),1.23(s,2H)。
HRMS对于[C24H33N5+H]+计算为:392.28142,实测为:392.28090。
根据方案2获得以下这些化合物:
EMU044(立体异构体1):淡黄色泡沫状物。1H NMR(400MHz,甲醇-d4)δ8.45(dd,J=4.9,1.6Hz,1H),7.61(dd,J=7.8,1.6Hz,1H),7.28(dd,J=7.7,4.8Hz,1H),7.13(t,J=7.9Hz,1H),6.72(d,J=8.2Hz,1H),6.59(d,J=7.7Hz,1H),4.98(s,3H),4.37(d,J=3.2Hz,1H),4.12-4.08(m,1H),3.73(dtd,J=10.9,5.6,2.3Hz,2H),3.44(dt,J=13.1,4.0Hz,2H),3.18-3.03(m,4H),2.98-2.54(m,5H),2.25-2.17(m,2H),2.12(s,5H),1.96-1.70(m,4H)。HRMS对于[C25H35N5+H]+计算为:406.29707,实测为:406.29646。EMU044(立体异构体2):灰白色泡沫状物。1H NMR(400MHz,氯仿-d)δ8.41(d,J=4.7Hz,1H),7.23(d,J=7.7Hz,1H),7.01-6.81(m,2H),6.33(dd,J=7.9,4.5Hz,2H),3.97(d,J=15.0Hz,1H),3.93-3.83(m,2H),3.43-3.20(m,4H),2.94(dtd,J=23.6,10.5,9.3,5.4Hz,3H),2.74-2.55(m,5H),2.39(s,3H),2.19-1.73(m,8H),1.61(dp,J=11.4,4.2,3.1Hz,1H),1.30-1.16(m,2H)。HRMS对于[C25H35N5+H]+计算为:406.29707,实测为:406.29599。
EMU058(立体异构体1):1H NMR(400MHz,氯仿-d)δ8.44(dd,J=4.9,1.7Hz,1H),7.38-7.31(m,1H),7.12-7.03(m,2H),6.86(dd,J=7.9,1.2Hz,1H),6.75(dd,J=7.8,1.2Hz,1H),4.13(d,J=15.5Hz,1H),4.04-3.92(m,2H),3.47-3.22(m,4H),3.13-2.93(m,2H),2.90-2.81(m,4H),2.68(dt,J=17.0,5.2Hz,2H),2.43(s,3H),2.30(dd,J=17.6,10.9Hz,1H),2.03-1.81(m,4H),1.71(dddd,J=18.6,13.3,6.7,3.4Hz,1H),1.61-1.44(m,2H);HRMS对于C25H36N5(M+H)计算为:406.28925,实测为:406.29826
EMU096(立体异构体1):白色泡沫状物。1H NMR(400MHz,氯仿-d)δ8.38(dd,J=4.7,1.7Hz,1H),7.29-7.19(m,1H),7.02-6.90(m,2H),6.75(d,J=7.9Hz,1H),6.66(d,J=7.6Hz,1H),3.97(d,J=15.2Hz,1H),3.88-3.76(m,2H),2.98-2.55(m,11H),2.41(d,J=26.6Hz,5H),2.19-2.02(m,2H),1.91(td,J=15.0,12.9,7.9Hz,3H),1.66-1.57(m,1H),0.97(dd,J=22.7,6.3Hz,6H)。HRMS对于[C26H37N5+H]+计算为:420.31272,实测为:420.31131。EMU096(立体异构体2):白色泡沫状物。1H NMR(400MHz,氯仿-d)δ8.41(dd,J=4.7,1.7Hz,1H),7.27-7.18(m,1H),7.00-6.92(m,2H),6.73(d,J=7.9Hz,1H),6.66(d,J=7.6Hz,1H),4.03(q,J=15.3Hz,2H),3.86(dd,J=9.7,6.0Hz,1H),2.98-2.65(m,8H),2.59(d,J=13.0Hz,2H),2.37(d,J=21.4Hz,5H),2.07(dt,J=13.9,7.7Hz,2H),1.95-1.85(m,2H),1.74(td,J=9.8,5.0Hz,1H),1.60(tdd,J=12.1,7.4,4.2Hz,1H),0.96(dd,J=28.0,6.3Hz,6H)。HRMS对于[C26H37N5+H]+计算为:420.31272,实测为:420.31202。
方案3:手性途径:侧链修饰
通过方案3合成EMU162
叔丁基5-(4-(叔丁氧基羰基)哌嗪-1-基)-3-((((S)-5,6,7,8-四氢喹啉-8-基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯
遵循在从(R)-2-叔丁基3-甲基5-溴-3,4-二氢异喹啉-2,3(1H)-二羧酸酯开始的EMU034的合成中描述的相似的途径,其使用由Beadle等人(PCT Int.Appl.,2014193781,04Dec 2014)的文献方法以克规模制备。黄色凝胶状物。1H NMR(400MHz,氯仿-d)δ8.36-8.29(m,1H),7.35(d,J=7.5Hz,1H),7.16(t,J=7.8Hz,1H),7.09-7.01(m,1H),6.93-6.79(m,2H),4.67(d,J=16.8Hz,2H),4.32(d,J=16.5Hz,1H),3.86-3.22(m,6H),2.95(s,2H),2.85-2.61(m,6H),2.59-2.24(m,2H),1.95(s,2H),1.65(d,J=8.7Hz,2H),1.49(d,J=8.8Hz,18H)。HRMS对于[C33H47N5O4+H]+计算为:578.37063,实测为:578.36923。
(R)-叔丁基5-(4-(叔丁氧基羰基)哌嗪-1-基)-3-((乙基((S)-5,6,7,8-四氢喹啉-8-基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯
将叔丁基5-(4-(叔丁氧基羰基)哌嗪-1-基)-3-((((S)-5,6,7,8-四氢喹啉-8-基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯(0.15g,0.260mmol)、三乙酰氧基硼氢化钠(0.099g,0.467mmol)和1,2-二氯乙烷(2.60mL)装入配备有Teflon包被的磁性搅拌棒的20mL闪烁小瓶。在搅拌持续5分钟后,添加乙醛(0.073mL,1.298mmol)。将所得的混合物在室温搅拌48小时。通过TLC和LCMS分析判断反应完全后,混合物通过添加1M NaOH淬灭。将双相混合物转移到分液漏斗。将水层分离并且用DCM萃取(3次)。合并的有机萃取物经无水硫酸钠干燥,并且在减压下浓缩成粗物质,其通过CombiFlash系统(24g金硅柱,5分钟DCM,然后30分钟0-10%MeOH/DCM)纯化以得到作为黄色泡沫状物的产物(0.0874g,0.144mmol,收率为55.6%)。1H NMR(400MHz,氯仿-d)δ8.29(d,J=5.5Hz,1H),7.28(d,J=7.6Hz,1H),7.09(t,J=7.8Hz,1H),6.97(dd,J=7.7,4.6Hz,1H),6.82(d,J=7.9Hz,1H),6.79-6.67(m,1H),4.61(d,J=17.5Hz,2H),4.06(d,J=16.9Hz,1H),3.79-3.30(m,6H),2.98(s,2H),2.76-2.57(m,7H),2.38(dd,J=13.8,7.0Hz,1H),2.05(s,1H),1.94(s,1H),1.75(dd,J=17.2,6.8Hz,1H),1.48(s,20H),0.92(t,J=7.0Hz,3H)。HRMS对于[C35H51N5O4+H]+计算为:606.40193,实测为:606.40175。
根据用于全面脱保护的一般程序制备。通过CombiFlash(12g柱,5分钟A,然后30分钟0-60%B)纯化粗物质以得到作为淡黄色泡沫状物的产物(47.9mg,收率为82%)。1H NMR(400MHz,氯仿-d)δ8.43(dd,J=4.7,1.7Hz,1H),7.30(dd,J=7.7,1.7Hz,1H),7.12-6.97(m,2H),6.84(d,J=7.8Hz,1H),6.74(d,J=7.6Hz,1H),4.14-4.03(m,2H),3.88(d,J=15.2Hz,1H),3.09-2.61(m,17H),2.46(dd,J=13.2,10.4Hz,1H),2.17(dd,J=16.5,10.8Hz,1H),2.06-1.85(m,3H),1.76-1.64(m,1H),1.09(t,J=7.1Hz,3H)。HRMS对于[C25H35N5+H]+计算为:406.29707,实测为:406.29618。
根据方案3获得以下这些化合物:
EMU163:白色泡沫状物。1H NMR(400MHz,氯仿-d)δ8.41(dd,J=4.7,1.7Hz,1H),7.25(dd,J=9.5,1.9Hz,1H),7.08-6.95(m,2H),6.82(d,J=7.7Hz,1H),6.68(d,J=7.6Hz,1H),4.12-3.97(m,2H),3.43(d,J=15.3Hz,1H),3.24-3.07(m,2H),3.07-2.49(m,13H),2.26(d,J=10.9Hz,2H),2.05-1.94(m,3H),1.74(dt,J=11.2,5.6Hz,1H),1.11(dd,J=27.8,6.6Hz,6H)。HRMS对于[C26H37N5+H]+计算为:420.31272,实测为:420.31198。
方案4:后期Buchwald-Hartwig偶联
通过方案4合成EMU183
(R)-叔丁基5-溴-3-((甲基((S)-5,6,7,8-四氢喹啉-8-基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯
遵循在从(R)-2-叔丁基3-甲基5-溴-3,4-二氢异喹啉-2,3(1H)-二羧酸酯开始的EMU034的合成中描述的相似的途径,其使用Beadle等人(PCT Int.Appl.,2014193781,04Dec 2014)的文献方法以克规模制备。无色凝胶状物。1H NMR(400MHz,氯仿-d)δ8.30(s,1H),7.35(d,J=7.8Hz,1H),7.28(s,1H),6.94(t,J=7.4Hz,2H),6.87(s,1H),4.83-4.30(m,2H),3.96-3.60(m,2H),3.14(d,J=17.0Hz,1H),2.84-2.70(m,2H),2.70-2.48(m,2H),2.36(s,4H),2.09-1.72(m,3H),1.62(s,1H),1.47(s,9H)。HRMS对于[C25H32BrN3O2+H]+计算为:486.17561,实测为:486.17731。
(R)-叔丁基3-((甲基((S)-5,67,8-四氢喹啉-8-基)氨基)甲基)-5-(4-(氧杂环丁烷-3-基)哌嗪-1-基)-3,4-二氢异喹啉-2(1H)-羧酸酯
将(R)-叔丁基5-溴-3-((甲基((S)-5,6,7,8-四氢喹啉-8-基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯(0.254g,0.522mmol)、Pd2(dba)3(0.024g,0.026mmol)、rac-BINAP(0.049g,0.078mmol)和碳酸铯(0.238g,0.731mmol)装入配备有Teflon包被的磁性搅拌棒的烘箱干燥的Biotage 5-10mL微波小瓶。将小瓶用Teflon衬覆的隔膜密封并且用氩气吹扫持续5分钟。添加脱气的甲苯(2.61ml,0.522mmol)并且用氩气将容器脱气持续另外的5分钟。通过注射器一次性添加1-(氧杂环丁烷-3-基)哌嗪(0.089g,0.627mmol)。将所得的混合物在油浴中在120℃加热24小时。在如通过TLC和LCMS分析判断反应完全后,允许混合物冷却至室温,过滤通过硅藻土垫,并且浓缩成粗物质,其通过CombiFlash系统(24克硅金柱,5分钟DCM,然后30分钟0-10%MeOH)纯化以得到作为淡黄色泡沫状物的产物(0.1975g,0.361mmol,收率为69.1%)。1H NMR(400MHz,氯仿-d)δ8.14(d,J=5.1Hz,1H),7.20(d,J=7.7Hz,1H),6.97(t,J=7.8Hz,1H),6.87(t,J=6.2Hz,1H),6.76(d,J=7.9Hz,1H),6.56(dd,J=15.7,7.6Hz,1H),4.60-4.44(m,5H),3.77(d,J=16.8Hz,1H),3.47(p,J=6.2Hz,2H),3.11-2.95(m,3H),2.73-2.13(m,16H),1.82(dq,J=39.9,6.1Hz,3H),1.39(s,9H)。HRMS对于[C32H45N5O3+H]+计算为:548.36007,实测为:548.35931。
EMU183:根据用于全面脱保护的一般程序制备。通过CombiFlash(12g柱,5分钟A,然后30分钟0-50%B)纯化粗物质以得到作为白色泡沫状物的产物(146.2mg,收率为91%)。1HNMR(400MHz,氯仿-d)δ8.46(dd,J=4.7,1.7Hz,1H),7.40-7.32(m,1H),7.15-7.04(m,2H),6.90(dd,J=7.8,1.2Hz,1H),6.78(dd,J=7.6,1.1Hz,1H),4.70-4.64(m,4H),4.11(d,J=15.5Hz,1H),3.97(q,J=8.1Hz,2H),3.58(q,J=6.5Hz,1H),3.05(dt,J=10.5,4.3Hz,2H),2.86-2.40(m,16H),2.24(s,1H),2.08-1.91(m,3H),1.78-1.67(m,1H)。HRMS对于[C27H37N5O+H]+计算为:448.30764,实测为:448.30681。
根据方案4获得以下这些化合物:
EMU116:白色泡沫状物。1H NMR(400MHz,氯仿-d)δ8.42(dd,J=4.8,1.7Hz,1H),7.36-7.28(m,1H),7.10-6.99(m,2H),6.86(dd,J=7.9,1.2Hz,1H),6.73(dd,J=7.6,1.1Hz,1H),4.07(d,J=15.4Hz,1H),3.98-3.87(m,2H),3.00(dt,J=10.2,4.6Hz,2H),2.85-2.45(m,15H),2.37-2.14(m,5H),2.06-1.87(m,3H),1.68(dddd,J=15.5,10.3,7.2,4.8Hz,1H)。HRMS对于[C25H35N5+H]+计算为:406.29707,实测为:406.29649。
EMU172:(S)-N-甲基-N-(((R)-5-吗啉基-1,2,3,4-四氢异喹啉-3-基)甲基)-5,6,7,8-四氢喹啉-8-胺。1H NMR(400MHz,CDCl3):1.71(m,1H),1.98(m,3H),2.22(m,1H),2.47(s,3H),2.59(m,1H),2.69(m,3H),2.83(m,3H),2.98(m,2H),3.79(m,4H),3.97(m,2H),4.09(d,1H,J=16Hz),6.77(d,1H,J=8Hz),6.86(d,1H,J=8Hz),7.05(dd,1H,J=5Hz,J=8Hz),7.1(t,1H,J=8Hz),7.34(d,1H,J=7Hz),8.44(dd,1H,J=1Hz,J=4Hz);MS(m/z):393.2(M+H)+
EMU173:(S)-N-甲基-N-(((R)-5-((2-吗啉基乙基)氨基)-1,2,3,4-四氢异喹啉-3-基)甲基)-5,6,7,8-四氢喹啉-8-胺。1H NMR(400MHz,CDCl3):1.74(m,1H),1.91(m,2H),2.07(m,1H),2.37(s,3H),2.45(m,4H),2.65(m,4H),2.82(m,2H),3.15(m,4H),3.69(t,4H,J=5Hz),4.07(m,2H),4.15(m,2H),6.44(dd,2H,J=2Hz,J=8Hz),7.05(t,1H,J=8Hz),7.08(t,1H,J=3Hz),7.36(d,1H,J=8Hz),8.4(d,1H,J=4Hz);MS(m/z):436.2(M+H)+。
EMU229:淡橙色泡沫状物。1H NMR(400MHz,氯仿-d)δ8.45(dd,J=4.7,1.7Hz,1H),7.37-7.29(m,1H),7.10-6.93(m,3H),6.47(dd,J=6.3,2.6Hz,1H),4.24(s,1H),4.06-3.86(m,3H),3.06-2.33(m,17H),2.30(s,3H),2.10-1.84(m,4H),1.68(dddt,J=16.1,11.2,8.0,3.0Hz,1H)。HRMS对于[C25H36N6+H]+计算为:421.30797,实测为:421.30811。
EMU198:淡黄色泡沫状物。1H NMR(400MHz,氯仿-d)δ8.38(dd,J=4.7,1.7Hz,1H),7.33-7.20(m,1H),7.06-6.91(m,2H),6.76(d,J=7.9Hz,1H),6.66(d,J=7.6Hz,1H),3.99(d,J=15.4Hz,1H),3.91-3.79(m,2H),2.88-2.54(m,8H),2.44(s,4H),2.33-2.09(m,7H),2.01-1.83(m,3H),1.65(t,J=6.4Hz,1H),1.02(dd,J=25.3,6.2Hz,6H)。HRMS对于[C27H39N5+H]+计算为:434.32837,实测为:434.32964。
EMU136:黄色泡沫状物。1H NMR(400MHz,氯仿-d)δ8.38(dd,J=4.8,1.7Hz,1H),7.25-7.20(m,1H),7.03-6.90(m,2H),6.75(d,J=7.8Hz,1H),6.67(d,J=7.6Hz,1H),3.96(d,J=15.3Hz,1H),3.89-3.76(m,2H),3.00-2.30(m,17H),2.12(dd,J=16.5,10.4Hz,1H),1.99-1.83(m,3H),1.65-1.56(m,1H),1.12(d,J=25.6Hz,6H)。HRMS对于[C26H37N5+H]+计算为:420.31272,实测为:420.31334。
EMU135:黄色泡沫状物。1H NMR(400MHz,氯仿-d)δ8.31(dd,J=4.7,1.8Hz,1H),7.20(dd,J=7.7,1.7Hz,1H),6.95-6.83(m,2H),6.41(dd,J=14.1,7.8Hz,2H),3.96-3.79(m,4H),3.69(dd,J=9.0,2.5Hz,1H),3.57(s,1H),3.35-3.30(m,1H),2.92(dd,J=10.2,2.1Hz,1H),2.71-2.51(m,7H),2.43-2.30(m,5H),2.11(dd,J=15.8,10.2Hz,1H),1.96-1.78(m,4H),1.58(ddd,J=9.7,5.2,2.8Hz,2H)。HRMS对于[C25H33N5+H]+计算为:404.28142,实测为:404.28069。
EMU200:淡黄色泡沫状物。1H NMR(400MHz,氯仿-d)δ8.37(s,1H),7.38(d,J=7.7Hz,1H),7.16-7.02(m,2H),6.99(d,J=8.0Hz,1H),6.73(d,J=7.6Hz,1H),6.22(s,2H),4.34(dd,J=16.0,4.7Hz,1H),4.21-3.96(m,4H),3.79-3.70(m,1H),3.50-3.38(m,1H),3.27-2.54(m,9H),2.27(d,J=2.9Hz,3H),2.11-1.80(m,5H),1.73(d,J=8.9Hz,1H)。HRMS对于[C25H33N5+H]+计算为:404.28142,实测为:404.28088。
EMU160:白色泡沫状物。1H NMR(400MHz,氯仿-d)δ8.35(dd,J=4.8,1.7Hz,1H),7.21(dd,J=7.7,1.7Hz,1H),7.00-6.88(m,2H),6.78(d,J=7.9Hz,1H),6.63(d,J=7.6Hz,1H),3.96(d,J=15.5Hz,1H),3.87-3.78(m,2H),2.95(dddd,J=26.7,13.1,6.7,2.2Hz,4H),2.77-2.59(m,5H),2.58-2.49(m,2H),2.46-2.33(m,4H),2.29(td,J=10.9,3.1Hz,1H),2.07(ddp,J=15.1,10.4,5.6,5.1Hz,3H),1.96-1.54(m,8H),1.36(dq,J=15.6,5.0Hz,1H)。HRMS对于[C27H37N5+H]+计算为:432.31272,实测为:432.31401。
EMU161:白色泡沫状物。1H NMR(400MHz,氯仿-d)δ8.38(dd,J=4.8,1.7Hz,1H),7.24(dd,J=7.7,1.7Hz,1H),7.04-6.91(m,2H),6.83(d,J=7.8Hz,1H),6.67(d,J=7.6Hz,1H),3.97(d,J=15.4Hz,1H),3.91-3.76(m,2H),3.09-2.96(m,4H),2.75(tdd,J=26.2,11.2,4.4Hz,5H),2.57(dd,J=16.6,4.8Hz,1H),2.52-2.37(m,4H),2.31-2.09(m,5H),2.01-1.55(m,8H),1.31(tt,J=10.9,4.6Hz,1H)。HRMS对于[C27H37N5+H]+计算为:432.31272,实测为:432.31206。
EMU199:白色泡沫状物。1H NMR(400MHz,氯仿-d)δ8.45(dd,J=4.8,1.7Hz,1H),7.39-7.32(m,1H),7.12-7.05(m,2H),6.90(dd,J=7.9,1.2Hz,1H),6.77(dd,J=7.6,1.1Hz,1H),4.13(d,J=15.5Hz,1H),4.02-3.95(m,2H),3.05(dd,J=11.7,5.0Hz,2H),2.89-2.45(m,18H),2.40-2.23(m,1H),2.08-1.92(m,3H),1.78-1.67(m,1H),1.12(t,J=7.2Hz,3H)。HRMS对于[C26H37N5+H]+计算为:420.31272,实测为:420.31300。
EMU196:白色泡沫状物。1H NMR(400MHz,氯仿-d)δ8.46(dd,J=4.8,1.7Hz,1H),7.36(ddd,J=7.6,1.8,0.9Hz,1H),7.12-7.04(m,2H),6.87(dd,J=7.9,1.1Hz,1H),6.76(dd,J=7.6,1.1Hz,1H),4.13(d,J=15.4Hz,1H),3.99(q,J=8.6Hz,2H),3.01-2.62(m,15H),2.48(s,3H),2.35-2.26(m,1H),2.09-1.91(m,3H),1.75-1.63(m,2H),0.49-0.42(m,4H)。HRMS对于[C27H37N5+H]+计算为:432.31272,实测为:432.31173。
EMU197:淡黄色泡沫状物。1H NMR(400MHz,氯仿-d)δ8.39(dd,J=4.7,1.7Hz,1H),7.29-7.23(m,1H),7.04-6.95(m,2H),6.81(d,J=7.9Hz,1H),6.68(d,J=7.6Hz,1H),4.00(d,J=15.4Hz,1H),3.92-3.82(m,2H),3.01-2.44(m,19H),2.12(dd,J=16.3,10.5Hz,1H),1.99-1.83(m,3H),1.65(s,1H),1.02(d,J=6.7Hz,6H)。HRMS对于[C27H39N5+H]+计算为:434.32837,实测为:434.32803。
EMU202:白色泡沫状物。1H NMR(400MHz,氯仿-d)δ8.50(d,J=4.9Hz,1H),8.40(d,J=4.6Hz,1H),7.58(td,J=7.6,1.8Hz,1H),7.37(d,J=7.8Hz,1H),7.25(s,1H),7.08(dd,J=7.4,5.1Hz,1H),7.03-6.96(m,2H),6.80(d,J=7.9Hz,1H),6.68(d,J=7.6Hz,1H),4.00(d,J=15.4Hz,1H),3.91-3.82(m,2H),3.69-3.64(m,2H),2.99(dt,J=10.0,4.1Hz,2H),2.80-2.41(m,16H),2.10(dd,J=16.5,10.2Hz,1H),2.01-1.84(m,3H),1.67-1.58(m,1H)。HRMS对于[C30H38N6+H]+计算为:483.32362,实测为:483.32315。
EMU201:白色泡沫状物。1H NMR(400MHz,氯仿-d)δ8.43(dd,J=4.7,1.8Hz,1H),8.17(dd,J=5.0,1.9Hz,1H),7.44(ddd,J=8.9,7.1,2.0Hz,1H),7.29(dd,J=7.8,1.7Hz,1H),7.11-6.96(m,2H),6.84(d,J=7.9Hz,1H),6.75(d,J=7.6Hz,1H),6.64(d,J=8.6Hz,1H),6.59(dd,J=7.1,5.0Hz,1H),4.04(d,J=15.4Hz,1H),3.99-3.84(m,2H),3.60(d,J=33.1Hz,4H),3.07(dt,J=10.4,4.5Hz,2H),2.90-2.44(m,11H),2.19(dd,J=16.4,10.4Hz,1H),2.07-1.86(m,3H),1.72-1.60(m,1H)。HRMS对于[C29H36N6+H]+计算为:469.30797,实测为:469.30711。
EMU203:淡黄色泡沫状物。1H NMR(400MHz,氯仿-d)δ8.43(d,J=4.6Hz,1H),8.28(t,J=4.6Hz,2H),7.29(d,J=7.7Hz,1H),7.07-6.97(m,2H),6.81(d,J=7.9Hz,1H),6.74(d,J=7.6Hz,1H),6.44(t,J=4.8Hz,1H),4.20-3.69(m,7H),2.99(dq,J=12.2,7.2,5.9Hz,2H),2.89(dd,J=16.3,3.0Hz,1H),2.81-2.59(m,6H),2.57-2.40(m,4H),2.19(dd,J=16.2,10.2Hz,1H),2.06-1.88(m,3H),1.67(h,J=9.4Hz,1H)。HRMS对于[C28H35N7+H]+计算为:470.30322,实测为:470.30297。
EMU226:淡黄色泡沫状物。1H NMR(399MHz,氯仿-d)δ8.46(dd,J=4.8,1.7Hz,1H),7.39-7.29(m,2H),7.16-7.01(m,5H),6.90(d,J=7.8Hz,1H),6.80(d,J=7.6Hz,1H),4.08(d,J=15.4Hz,1H),4.01-3.90(m,2H),3.33(dt,J=31.4,10.7Hz,5H),3.15(ddd,J=10.3,6.2,3.7Hz,2H),2.91-2.74(m,6H),2.66(dt,J=16.6,4.6Hz,1H),2.52(s,4H),2.21(dd,J=16.3,10.4Hz,1H),1.99(dddd,J=29.6,22.0,11.3,3.3Hz,3H),1.75-1.62(m,1H)。HRMS对于[C31H36F3N5+H]+计算为:536.30011,实测为:536.29919。
EMU062:灰白色泡沫状物。1H NMR(399MHz,甲醇-d4)δ8.41(d,J=5.0Hz,1H),7.57(d,J=7.9Hz,1H),7.29-7.14(m,2H),7.02(d,J=8.0Hz,1H),6.97-6.85(m,1H),4.31(t,J=8.4Hz,2H),4.02(dd,J=10.2,5.5Hz,1H),3.50-3.41(m,2H),3.29-2.57(m,17H),2.15-2.00(m,5H),1.91(q,J=11.7,11.1Hz,1H),1.71(d,J=13.7Hz,1H)。HRMS对于[C26H35N5+H]+计算为:418.29707,实测为:418.29653。
EMU240:黄色泡沫状物。1H NMR(400MHz,氯仿-d)δ8.44(dd,J=4.8,1.7Hz,1H),7.38-7.32(m,1H),7.10-7.03(m,2H),6.93(dd,J=7.9,1.2Hz,1H),6.76(dd,J=7.6,1.1Hz,1H),4.13(d,J=15.4Hz,1H),4.03-3.93(m,2H),2.88-2.65(m,9H),2.59(s,3H),2.45(s,3H),2.24(s,3H),2.08-1.53(m,12H)。HRMS对于[C27H39N5+H]+计算为:434.32837,实测为:434.32803。
EMU228:白色泡沫状物。1H NMR(400MHz,氯仿-d)δ8.44(dd,J=4.8,1.7Hz,1H),7.39-7.33(m,1H),7.12-7.06(m,2H),6.86(dd,J=8.0,1.1Hz,1H),6.75(dd,J=7.6,1.1Hz,1H),4.17(d,J=15.5Hz,1H),4.00(d,J=15.8Hz,2H),3.16-3.05(m,2H),2.90-2.65(m,7H),2.44(s,3H),2.33(s,6H),2.29-2.14(m,2H),2.09-1.83(m,6H),1.79-1.54(m,4H)。HRMS对于[C27H39N5+H]+计算为:434.32837,实测为:434.32751。
EMU227:白色泡沫状物。1H NMR(400MHz,氯仿-d)δ8.44(dd,J=4.8,1.7Hz,1H),7.36(dd,J=7.7,1.7Hz,1H),7.10-7.04(m,2H),6.83(dd,J=8.1,1.1Hz,1H),6.71(dd,J=7.6,1.1Hz,1H),4.16(d,J=15.5Hz,1H),4.04-3.98(m,2H),3.28(dd,J=9.2,6.5Hz,1H),3.11(dd,J=9.2,2.5Hz,1H),2.89-2.63(m,13H),2.44(s,3H),2.34(d,J=8.1Hz,5H),2.26(dd,J=8.8,4.9Hz,1H),2.08-1.91(m,3H),1.79-1.65(m,1H)。HRMS对于[C27H37N5+H]+计算为:432.31272,实测为:432.31279。
EMU235:白色泡沫状物。1H NMR(400MHz,氯仿-d)δ8.42(ddd,J=9.6,4.8,1.7Hz,1H),7.37(ddd,J=7.7,1.8,0.9Hz,1H),7.10-7.03(m,2H),6.79(t,J=7.6Hz,1H),6.69(ddd,J=7.6,4.2,1.1Hz,1H),4.22(dd,J=29.2,15.7Hz,1H),4.13-3.97(m,2H),3.31(dq,J=7.4,2.5Hz,1H),3.07-2.63(m,13H),2.39(dd,J=9.4,3.8Hz,6H),2.13-1.86(m,5H),1.85-1.61(m,3H)。HRMS对于[C27H37N5+H]+计算为:432.31272,实测为:432.31329。
EMU236:白色泡沫状物。1H NMR(400MHz,氯仿-d)δ8.40(dd,J=4.8,1.6Hz,1H),7.38(dd,J=7.7,1.7Hz,1H),7.10-7.05(m,2H),6.81-6.77(m,1H),6.72-6.66(m,1H),4.29(d,J=15.6Hz,1H),4.13-4.00(m,2H),3.34-3.30(m,1H),3.08-3.02(m,3H),2.96-2.67(m,10H),2.40(d,J=3.5Hz,3H),2.36(s,3H),2.11-1.92(m,5H),1.86-1.65(m,3H)。HRMS对于[C27H37N5+H]+计算为:432.31272,实测为:432.31243。
EMU237:淡黄色泡沫状物。1H NMR(400MHz,氯仿-d)δ8.43(dd,J=4.7,1.7Hz,1H),7.37-7.33(m,1H),7.08-7.03(m,2H),6.74(d,J=8.0Hz,1H),6.67-6.62(m,1H),4.21(d,J=15.5Hz,1H),4.07-3.98(m,2H),3.50-3.44(m,1H),3.30(d,J=8.5Hz,1H),3.08-3.04(m,1H),2.99-2.94(m,1H),2.85-2.60(m,8H),2.43(s,3H),2.27(s,6H),2.14-1.69(m,7H)。HRMS对于[C26H37N5+H]+计算为:420.31272,实测为:420.31315。
EMU238:淡黄色泡沫状物。1H NMR(400MHz,氯仿-d)δ8.45(dd,J=4.7,1.7Hz,1H),7.38-7.33(m,1H),7.10-7.02(m,2H),6.81(dd,J=8.0,1.1Hz,1H),6.67(dd,J=7.6,1.1Hz,1H),4.12(d,J=15.5Hz,1H),4.04-3.94(m,2H),3.38-3.27(m,2H),3.01-2.75(m,7H),2.71-2.62(m,2H),2.44(s,3H),2.25(s,7H),2.12-1.79(m,6H),1.76-1.65(m,1H)。HRMS对于[C26H37N5+H]+计算为:420.31272,实测为:420.31278。
方案5.EMU234的合成
苄基4-((R)-3-((甲基((S)-5,6,7,8-四氢喹啉-8-基)氨基)甲基)-1,2,3,4-四氢异喹啉-5-基)哌嗪-1-羧酸酯:通过(R)-叔丁基5-(4-((苄氧基)羰基)哌嗪-1-基)-3-((甲基((S)-5,6,7,8-四氢喹啉-8-基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯的Boc脱保护来制备,其根据方案4合成。粗物质不经纯化即被用于下一个步骤。
苄基4-((R)-2-甲基-3-((甲基((S)-5,6,7,8-四氢喹啉-8-基)氨基)甲基)-1,2,3,4-四氢异喹啉-5-基)哌嗪-1-羧酸酯:将苄基4-((R)-3-((甲基((S)-5,6,7,8-四氢喹啉-8-基)氨基)甲基)-1,2,3,4-四氢异喹啉-5-基)哌嗪-1-羧酸酯(0.336g,0.639mmol)、三乙酰氧基硼氢化钠(0.406g,1.918mmol)、二氯甲烷(6.39ml)装入配备有Teflon包被的磁性搅拌棒的20mL闪烁小瓶。在搅拌持续5分钟后,一次性添加多聚甲醛(0.058g,1.918mmol)。将所得的混合物在室温搅拌持续48小时。如由TLC和LCMS分析判断反应完全后,混合物通过添加饱和NaHCO3淬灭。将双相混合物转移到分液漏斗。将水层分离并且用DCM萃取(3次)。合并的有机萃取物经无水硫酸钠干燥,并且在减压下浓缩成粗物质,其用CombiFlash系统(24g硅柱,5分钟DCM,然后30分钟0-30%8∶2∶0.6 DCM/MeOH/NH3溶液,MeOH中为7N)纯化以得到作为黄色凝胶状物的产物(0.4101g,0.760mmol,定量收率)。1H NMR(400MHz,氯仿-d)δ8.46-8.37(m,1H),7.41-7.30(m,6H),7.10(t,J=7.7Hz,1H),7.02(dd,J=7.7,4.7Hz,1H),6.84(d,J=7.9Hz,1H),6.77(d,J=7.6Hz,1H),5.17(s,2H),3.84-3.61(m,7H),2.88(t,J=25.2Hz,8H),2.67(dd,J=16.7,5.3Hz,2H),2.48(d,J=23.7Hz,4H),2.30(s,3H),1.95(s,3H),1.65(dt,J=9.2,4.8Hz,1H)。HRMS对于[C33H41N5O2+H]+计算为:540.33385,实测为:540.33370。
EMU234:将苄基4-((R)-2-甲基-3-((甲基((S)-5,6,7,8-四氢喹啉-8-基)氨基)甲基)-1,2,3,4-四氢异喹啉-5-基)哌嗪-1-羧酸酯(0.4101g,0.760mmol)和三氟乙酸(3.80ml)装入配备有Teflon包被的磁性搅拌棒的20mL闪烁小瓶。在0℃逐滴添加三氟甲磺酸(0.202ml,2.280mmol),并且将所得混合物在室温搅拌持续1小时。在如通过LCMS分析判断反应完全后,混合物用DCM稀释,在冰浴中冷却,并且通过添加3M NaOH直到pH>12小心地淬灭。将双相混合物转移到分液漏斗。将水层分离并且用DCM萃取(3次)。合并的有机萃取物经无水硫酸钠干燥,并且在减压下浓缩成粗物质,其用CombiFlash系统(12g硅柱,5分钟DCM,然后30分钟0-80%8∶2∶0.6 DCM/MeOH/NH3溶液,MeOH中为7N)纯化以得到作为淡黄色泡沫状物的最终产物(193.1mg,收率为63%)。1H NMR(400MHz,氯仿-d)δ8.44(td,J=4.5,1.6Hz,1H),7.38-7.30(m,1H),7.12(t,J=7.7Hz,1H),7.05(ddd,J=7.4,4.8,2.6Hz,1H),6.95-6.86(m,1H),6.81-6.72(m,1H),4.23(s,1H),3.90-3.77(m,3H),3.13(t,J=4.8Hz,3H),3.02-2.78(m,8H),2.74-2.44(m,7H),2.29(s,3H),2.07-1.86(m,3H),1.73-1.61(m,1H)。HRMS对于[C25H35N5+H]+计算为:406.29707,实测为:406.29641。
1-苄基4-(叔丁基)2-((甲基((S)-5,6,7,8-四氢喹啉-8-基)氨基)甲基)哌嗪-1,4-二羧酸酯:1-苄基4-(叔丁基)2-((((S)-5,6,7,8-四氢喹啉-8-基)氨基)甲基)哌嗪-1,4-二羧酸酯(非对映体的混合物)根据zhao,H.等人;Bioorg.Med.CHem.Lett.;2015;25;4950-4955制备。向DCE(114mL)中的1-苄基4-(叔丁基)2-((((S)-5,6,7,8-四氢喹啉-8-基)氨基)甲基)哌嗪-1,4-二羧酸酯的非对映体的混合物(5.50g,11.4mmol,1.00当量)的溶液添加多聚甲醛(2.06g,68.6mmol,6.00当量),并且将所得混合物在室温搅拌持续30分钟。然后添加三乙酰氧基硼氢化钠(7.27g,34.3mmol,3.00当量),并且将所得反应混合物在室温搅拌持续29hr。在该时间后,反应用饱和水性碳酸氢钠淬灭,并且所得水层用DCM萃取。合并的有机层用水洗涤一次,用卤水洗涤一次,经无水硫酸钠干燥,过滤并且在减压下蒸发。将粗物质通过柱色谱纯化以产生期望的非对映体的混合物(3.65g,7.38mmol,收率为65%)。
苄基2-((甲基((S)-5,6,7,8-四氢喹啉-8-基)氨基)甲基)哌嗪-1-羧酸酯:将DCM(20.0mL)中的1-苄基4-(叔丁基)2-((甲基((S)-5,6,7,8-四氢喹啉-8-基)氨基)甲基)哌嗪-1,4-二羧酸酯的非对映体的混合物(0.650g,1.31mmol,1.00当量)的溶液添加到具有搅拌棒的烧瓶,并且将所得溶液在室温在Ar下搅拌。添加TFA(2.00mL,26.0mmol,19.8当量),并且将所得反应混合物在室温在Ar下搅拌持续24hr。在该时间后,反应用1M水性氢氧化钠淬灭和碱化,并且所得水层用DCM萃取两次。合并的有机层用水洗涤一次,用卤水洗涤一次,经无水硫酸钠干燥,过滤并且在减压下蒸发。非对映体的粗混合物通过柱色谱纯化,用DCM,随后是DCM中25%90∶10∶1 DCM/MeOH/NH4OH,随后是DCM中50%90∶10∶1 DCM/MeOH/NH4OH,随后是90∶10∶1 DCM/MeOH/NH4OH洗脱以产生单个非对映体(0.140g,0.355mmol,收率为27%)。
EMU070:(8S)-N-甲基-N-((4-(2-(4-甲基哌嗪-1-基)苄基)哌嗪-2-基)甲基)-5,6,7,8-四氢喹啉-8-胺:将DCM(4.82mL)中的苄基2-((甲基((S)-5,6,7,8-四氢喹啉-8-基)氨基)甲基)哌嗪-1-羧酸酯(0.285g,0.722mmol,1.00当量)和2-(4-甲基哌嗪-1-基)苯甲醛(0.221g,1.08mmol,1.50当量)的溶液在室温搅拌持续6hr。在该时间后,添加三乙酰氧基硼氢化钠(0.258g,1.16mmol,1.60当量),并且将所得反应混合物在室温搅拌持续24hr。在该时间后,反应用1N水性碳酸钾淬灭。所得水层用DCM(3×40mL)萃取,并且合并的有机层用1N水性碳酸钾(2×100mL)洗涤,用卤水洗涤一次,经无水硫酸钠干燥,过滤并且在减压下蒸发。将粗物质通过柱色谱纯化,用DCM,随后是99∶1 DCM/MeOH,随后是50∶1 DCM/MeOH,随后是25∶1 DCM/MeOH,随后是9∶1 DCM/MeOH,随后是44∶5∶1 DCM/MeOH/NH4OH洗脱以产生期望的产物(0.255g,0.438mmol,收率为61%)。1H NMR(600MHz,CDCl3)δ8.30(d,J=3.6Hz,1H),7.23-7.29(m,6H),7.12-7.15(m,1H),7.09(d,J=6.0Hz,1H),7.00(d,J=6.0Hz,1H),6.93(t,J=7.2Hz,1H),6.86(dd,J=4.5Hz,J=7.5Hz,1H),5.08(q,J=12.6Hz,2H),4.12(m,1H),3.75(m,2H),3.43(d,J=13.2Hz,1H),3.27(d,J=12.6Hz,1H),2.91-2.97(m,7H),2.69-2.72(m,2H),2.43-2.59(m,7H),2.35-2.37(m,1H),2.32(s,3H),2.09-2.19(m,3H),1.85-1.88(m,1H),1.69(m,2H),1.51(m,1H)。HRMS(ESI)m/z=583.37575(M+H);理论上对于C35H46O2N6+H=583.37550。向MeOH(11.0mL)中的苄基2-((甲基((S)-5,6,7,8-四氢喹啉-8-基)氨基)甲基)哌嗪-1-羧酸酯(0.255g,0.438mmol,1.00当量)的溶液添加碳载钯(0.250g,0.235mmol,0.54当量),并且将所得混合物在Ar下剧烈地搅拌。在弱真空随后是Ar冲洗(flush)的两个循环后,再次使用弱真空将烧瓶抽空,随后用氢气最终冲洗。将所得反应混合物在室温在氢气下剧烈地搅拌持续25hr。在该时间后,反应混合物过滤通过硅藻土的短柱(plug of celite),其随后用MeOH洗涤,并且所得母液在减压下蒸发。将粗物质通过柱色谱纯化,用9∶1 DCM/MeOH洗脱,随后是38∶10∶1 DCM/MeOH/NH4OH以产生作为黄色泡沫状物的期望的产物(0.132g,0.294mmol,收率为67%)。1H NMR(600MHz,CDCl3)δ8.32(d,J=4.2Hz,1H),7.43(d,J=7.8Hz,1H),7.36(d,J=7.8Hz,1H),7.21(m,1H),7.03-7.12(m,3H),4.70(s,2H),4.19(m,1H),3.67(d,J=12.6Hz,1H),3.57(d,J=12.6Hz,1H),3.49(dd,J=11.7Hz,J=14.1Hz,1H),3.36(m,1H),3.27(m,1H),2.92-3.06(m,6H),2.86-2.92(m,2H),2.58-2.82(m,7H),2.47(s,3H),2.13-2.17(m,3H),2.04-2.06(m,1H),1.96-1.98(m,1H),1.80-1.87(m,1H),1.73-1.77(m,1H)。HRMS(APCI)m/z=449.33818(M+H);理论上对于C27H40N6+H=449.33872。
EMU090:通过使用方案4中描述的条件用多聚甲醛(5当量)使EMU034甲基化来制备。黄色凝胶状物。1H NMR(400MHz,氯仿-d)δ8.40(dd,J=4.8,1.7Hz,1H),7.30-7.23(m,1H),7.07-6.95(m,2H),6.84(dd,J=8.0,1.2Hz,1H),6.71-6.65(m,1H),3.78-3.63(m,3H),2.88-2.75(m,7H),2.65-2.45(m,7H),2.39(s,3H),2.33(s,3H),2.27(s,3H),2.04-1.80(m,4H),1.61(tdd,J=10.9,5.6,3.2Hz,1H)。HRMS对于[C26H37N5+H]+计算为:420.31272,实测为:420.31212。
EMU239:通过使用方案5中描述的条件用多聚甲醛(3当量)使EMU161甲基化来制备。橙色凝胶状物。1H NMR(400MHz,氯仿-d)δ8.42(dd,J=4.8,1.7Hz,1H),7.31(ddd,J=7.8,1.9,1.0Hz,1H),7.07(t,J=7.7Hz,1H),7.00(dd,J=7.7,4.7Hz,1H),6.90(dd,J=7.9,1.2Hz,1H),6.72(dd,J=7.6,1.1Hz,1H),3.82-3.70(m,3H),3.15-2.98(m,4H),2.96-2.75(m,5H),2.75-2.37(m,8H),2.34-2.13(m,5H),2.05-1.58(m,7H),1.52-1.39(m,1H)。HRMS对于[C28H39N5+H]+计算为:446.32837,实测为:446.32747。
EMU241:通过使用方案5中描述的条件用多聚甲醛(3当量)使EMU160甲基化来制备。橙色凝胶状物。1H NMR(400MHz,氯仿-d)δ8.42(dd,J=4.7,1.7Hz,1H),7.32(dd,J=7.7,1.7Hz,1H),7.07(t,J=7.7Hz,1H),7.01(dd,J=7.6,4.7Hz,1H),6.90(dd,J=7.9,1.2Hz,1H),6.72(dd,J=7.6,1.2Hz,1H),3.84-3.69(m,3H),3.17-2.73(m,9H),2.73-2.33(m,8H),2.33-2.15(m,5H),2.04-1.60(m,7H),1.45(tt,J=11.2,5.3Hz,1H)。HRMS对于[C28H39N5+H]+计算为:446.32837,实测为:446.32761。
EMU230:向20mL小瓶添加(S)-3-甲基-5,6,7,8-四氢喹啉-8-胺(0.2g,1.233mmol)、DCE(体积:2.80ml)、(R)-叔丁基5-(4-(叔丁氧基羰基)哌嗪-1-基)-3-甲酰基-3,4-二氢异喹啉-2(1H)-羧酸酯(0.499g,1.121mmol)和STAB-H(0.428g,2.017mmol),然后允许将反应搅拌过夜。反应用DCM稀释,用1M NaOH洗涤,用Na2SO4干燥,过滤并且浓缩以得到黄色油状物。将粗物质通过combiflash(DCM 2分钟,10%B(80∶20∶3,DCM∶MeOH∶NH4OH)5分钟和50%B 9分钟)纯化以得到(R)-叔丁基5-(4-(叔丁氧基羰基)哌嗪-1-基)-3-((((S)-3-甲基-5,6,7,8-四氢喹啉-8-基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯(.268g,0.453mmol,产率为40%)。向20mL小瓶添加仲胺(0.268g,0.453mmol)、DCE(体积:3.0ml)、多聚甲醛(0.041g,1.359mmol)和STAB-H(0.173g,0.815mmol),然后将反应搅拌过夜。反应用DCM稀释,用1M NaOH洗涤,用Na2SO4干燥,过滤并且浓缩以得到黄色油状物。将粗物质通过combiflash(DCM 2分钟,10%B(80∶20∶3,DCM∶MeOH∶NH4OH)5分钟和50%B 9分钟)纯化以得到灰白色固体(.257g,0.424mmol,产率为94%)。向20mL小瓶添加(R)-叔丁基5-(4-(叔丁氧基羰基)哌嗪-1-基)-3-((甲基((S)-3-甲基-5,6,7,8-四氢喹啉-8-基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯(0.18g,0.297mmol)、DCM(体积:3ml,比率:5)和TFA(体积:0.600ml,比率:1.000),然后允许将混合物搅拌过夜。反应用DCM稀释,用1M NaOH洗涤,用Na2SO4干燥,过滤并且浓缩以得到黄色油状物。将粗物质通过combiflash(DCM 2分钟,10%B(80∶20∶3,DCM∶MeOH∶NH4OH)5分钟和50%B 9分钟)纯化。将级分浓缩以得到作为黄色油状物的(S)-N,3-二甲基-N-(((R)-5-(哌嗪-1-基)-1,2,3,4-四氢异喹啉-3-基)甲基)-5,6,7,8-四氢喹啉-8-胺(0.091g,0.224mmol,收率为76%)。1H NMR(500MHz,CDCl3):δ=8.28(d,J=1.4Hz,1H),7.14(d,J=1.0Hz,1H),7.07(t,J=7.8Hz,1H),6.85(d,J=7.6Hz,1H),6.74(d,J=7.6Hz,1H),4.04(d,J=15.2Hz,1H),3.91(d,J=15.2Hz,1H),3.91-3.88(m,1H),3.01-2.91(m,6H),2.85-2.60(m,6H),2.55-2.47(m,1H),2.51(s,3H),2.26(s,3H),2.14(dd,J=16.1,10.6Hz,1H),2.05-1.91(m,2H),1.72-1.63(m,1H);13C NMR(125MHz,CDCl3):δ=155.1,151.9,147.4,137.2,136.8,133.2,130.8,130.1,126.0,121.8,116.8,64.3,59.9,53.3,51.7,48.8,46.7,41.6,30.3,29.2,26.3,21.3,18.1;HRMS(ESI)[M+H]+,对于C25H36N5计算为406.29652,实测为406.29611;LC/MS H2O中75%MeOH,经过3分钟,rt=0.460,在254nM,MS(+)406.2,MS(+)/2 203.6
用仲胺和大体积羰基还原胺化
一般方案
EMU073(立体.异构体1)和EMU073(立体异构体2)的合成
将1.00g的叔丁基(4-氧代环己基)氨基甲酸酯(4.69mmol,1当量)、0.834g的(S)-5,6,7,8-四氢喹啉-8-胺(5.63mmol,1.2当量)、403μL的乙酸(7.03mmol,1.5当量)和23.4mL的DCE装入配备有橡胶隔膜和搅拌棒的100mL rb烧瓶。然后添加1.49g的STAB(7.03mmol,1.5当量),并且将悬浮液在rt搅拌持续20h。反应混合物通过添加饱和Na2CO3溶液淬灭,用CH2Cl2(3×)萃取,并且经Na2SO4干燥。将粗产物在硅胶柱上纯化,使用EA中0-10%MeOH作为洗脱剂,得到作为具有少量副产物的混合物的626mg(39%)的立体异构体26和785mg的立体异构体25。将异构体25从EA重结晶,得到538mg(33%)的纯异构体25。对于异构体26:1H NMR(400MHz,CDCl3,ppm)δ:8.40-8.37(m,1H),7.37-7.34(m,1H),7.05(ddd,J=7.7,4.7,0.7Hz,1H),4.68(br s,1H),3.88(t,J=6.4Hz,1H),3.69(br s,1H),2.87-2.70(m,2H),2.13(dt,J=13.2,6.2Hz,1H),2.02-1.94(m,1H),1.90-1.48(m,11H),1.44(s,9H)。
LC-MS(ESI-API,254nm)H2O中95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=346.2(M+H),t=0.462min;对于异构体25:1H NMR(400MHz,CDCl3,ppm)δ:8.38(dd,J=4.7,1.7Hz,1H),7.35(dd,J=7.7,1.7Hz,1H),7.04(dd,J=7.7,4.7Hz,1H),4.39(br s,1H),3.91(t,J=6.5Hz,1H),3.45(brs,1H),2.86-2.75(m,1H),2.73(dt,J=17.1,5.1Hz,1H),2.63(tt,J=10.9,3.7Hz,1H),2.25-1.92(m,4H),1.79-1.65(m,2H),1.44(s,9H),1.35-1.08(m,6H).LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=346.2(M+H),t=0.479min;
将0.314g的胺26(0.912mmol,1当量)、0.262g的叔丁基(R)-3-甲酰基-3,4-二氢异喹啉-2(1H)-羧酸酯(1.00mmol,1.1当量)和9.1mL的CH2Cl2装入配备有搅拌棒和橡胶隔膜的50mL Schlenk管。然后添加401μL的异丙氧钛(1.37mmol,1.5当量)。在rt搅拌持续1h后,添加0.386g的STAB(1.82mmol,2当量),并且将反应混合物在rt搅拌持续5h。反应混合物通过添加饱和NaHCO3溶液淬灭,用CH2Cl2(3×)萃取,用卤水洗涤,并且经Na2SO4干燥。将粗产物在硅胶柱上纯化,使用己烷中0至50%EA作为洗脱剂,得到作为微黄色油状物的0.492g(92%)的产物27。1H NMR(400MHz,CDCl3,ppm)δ:8.40(s,1H),7.24(d,J=7.2Hz,1H),7.15-6.94(m,5H),4.94(br s,0.5H),4.73-4.61(m,1H),4.56(br s,1H),4.35(br s,0.5H),4.23(AB的B,JAB=17.0Hz,1H),3.96(dd,J=6.4,8.7Hz,1H),3.70(br s,1H),3.17-2.37(m,7H),2.06(brs,1H),1.95-1.86(m,1H),1.84-1.23(m,10H),1.48(s,9H),1.43(s,9H).LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=591.3(M+H),t=1.549min;遵循用于化合物27的合成的程序,从胺25和叔丁基(R)-3-甲酰基-3,4-二氢异喹啉-2(1H)-羧酸酯合成化合物28。将粗产物在硅胶柱上纯化,使用CH2Cl2中0至100%EA,得到作为微黄色粉末的0.523g(94%)的产物28。1H NMR(400MHz,CDCl3,ppm)δ:8.39(s,1H),7.25(d,J=7.7Hz,1H),7.14-6.95(m,5H),4.69(d,J=16.7Hz,1H),4.53(br s,0.5H),4.36(s,0.5H),4.23(br s,1H),4.19(d,J=17.2Hz,1H),4.06-3.91(m,1H),3.26-2.30(m,7H),2.10-1.23(m,8H),1.48(s,9H),1.41(s,9H),1.05-0.82(m,2H).LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=591.2(M+H),t=0.663min,纯度为93%;
EMU073(立体异构体1):将溶解在3.2mL的CH2Cl2中的187mg的胺28(0.317mmol,1当量)装入配备有搅拌棒的20mL小瓶。然后添加733μL的TFA(9.51mmol,30当量)。在rt搅拌持续12h后,反应混合物通过添加饱和Na2CO3和2N NaOH溶液淬灭,用CH2Cl2(3×)萃取,用卤水洗涤并且经Na2SO4干燥。将粗物质在硅胶柱上纯化,使用CH2Cl2中0-60%的溶剂2(溶剂2=70%CH2Cl2、30%MeOH、3%NH4OH)作为洗脱剂,得到作为微黄色粉末的61mg(49%)的产物EMU073(立体异构体1)。1H NMR(600MHz,CDCl3,ppm)δ:8.44(d,J=4.6Hz,1H),7.26(d,J=7.0Hz,1H),7.07-6.99(m,4H),6.95-6.92(m,1H),4.08(t,J=7.6Hz,1H),3.89(AB的A,JAB=15.2Hz,1H),3.37(AB的B,JAB=15.1Hz,1H),3.13(dd,J=13.5,3.1Hz,1H),2.77(ddd,J=15.6,10.6,4.7Hz,1H),2.72-2.63(m,2H),2.59(tt,J=11.0,3.9Hz,1H),2.54(dd,J=15.9,3.5Hz,1H),2.46-2.34(m,2H),2.24(br s,1H),2.09-1.70(m,8H),1.50(qd,J=12.8,3.5Hz,1H),1.42(qd,J=12.8,3.4Hz,1H),1.15(qd,J=12.7,3.4Hz,1H),1.06(qd,J=12.9,3.5Hz,1H)。13C NMR(400MHz,CDCl3,ppm)δ:159.18,146.82,136.34,135.77,134.56,133.27,128.87,126.34,125.62,125.25,121.22,62.59,60.56,53.08,52.27,50.35,48.43,36.51,36.41,33.77,31.04,29.99,29.44,29.13,21.87。HRMS(ESI+)对于C25H35N4([M+H]+)计算为:391.2856。实测为:391.2857,误差0.1ppm.LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=391.2(M+H),196.2(M/2+H),t=0.887min;EMU073(立体异构体2):将溶解在2.9mL的CH2Cl2中的170mg的胺27(0.288mmol,1当量)装入配备有搅拌棒的20mL小瓶。然后添加666μL的TFA(8.65mmol,30当量)。在rt搅拌持续12h后,反应混合物通过添加饱和Na2CO3和2N NaOH溶液淬灭,用CH2Cl2(3×)萃取,并且经Na2SO4干燥。将粗物质在硅胶柱上纯化,使用CH2Cl2中0-60%的溶剂2(溶剂2=70%CH2Cl2、30%MeOH、3%NH4OH)作为洗脱剂,得到作为微黄色粉末的93mg(83%)的产物EMU073(立体异构体2)。1H NMR(600MHz,CDCl3,ppm)δ:8.45(d,J=4.7Hz,1H),7.26(d,J=7.0Hz,1H),7.09-6.99(m,4H),6.94(d,J=6.5Hz,1H),4.15(t,J=7.8Hz,1H),3.89(d,J=15.0Hz,1H),3.38(d,J=15.0Hz,1H),3.14(dd,J=13.5,3.0Hz,1H),3.08(t,J=3.5Hz,1H),2.82-2.71(m,2H),2.66(dt,J=16.4,4.2Hz,1H),2.54(dd,J=15.6,3.1Hz,2H),2.43(dt,J=45.3,13.3Hz,1H),2.26(br s,1H),2.09-1.96(m,2H),1.85-1.47(m,9H)。13C NMR(400MHz,CDCl3,ppm)δ:159.31,146.80,136.28,135.75,134.56,133.29,128.85,126.32,125.60,125.22,121.14,62.70,60.13,53.39,52.39,48.45,45.26,33.79,32.96,32.87,29.46,29.03,26.43,25.54,21.99。HRMS(ESI+)对于C25H35N4([M+H]+)计算为:391.2856。实测为:391.2935,误差7.9ppm.LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=391.2(M+H),196.2(M/2+H),t=0.739min;
与参考文献(Organic Syntheses,Coll.Vol.8,p.528(1993);Vol.68,p.77(1990))相似,111从(R)-2-氨基-3-(2-溴苯基)丙酸合成,收率为78%。将3.76g的噁唑烷酮111(14.7mmol,1当量)、0.485g的多聚甲醛(16.2mmol,1.1当量)、14.3mL的乙酸和4.8mL的硫酸(酸必须预先混合)装入配备有搅拌棒的50mL rb烧瓶。在rt搅拌持续12h后,将反应混合物逐份倾倒入饱和Na2CO3溶液中,用CH2Cl2(3×)萃取,并且经Na2SO4干燥。将粗产物在硅胶柱上纯化,使用CH2Cl2中0至10%EA作为洗脱剂。允许将产物从CH2Cl2溶液结晶出来,得到作为白色针状物的3.04g(77%)的产物112。1H NMR(400MHz,CDCl3,ppm)δ:7.51-7.47(m,1H),7.14-7.11(m,2H),4.84(AB的A,JAB=17.1Hz,1H),4.62(dd,J=8.7,7.9Hz,1H),4.36(AB的B,JAB=17.1,1H),4.22(dd,J=8.7,4.8Hz,1H),3.96(ddt,J=10.8,7.8,4.6Hz,1H),3.25(ABX的A,JAB=16.4Hz,JAX=4.2Hz,1H),2.67(ABX的B,JAB=16.4Hz,JBX=11.1Hz,1H)。
将500mg的溴化物112(1.87mmol,1当量)、480mg的叔丁基((1r,4r)-4-氨基环己基)氨基甲酸酯(2.24mmol,1.2当量)、186mg的BINAP(0.298mmol,0.16当量)、1.22g的Cs2CO3(3.73mmol,2当量)和85.0mg的Pd2(dba)3(0.093mmol,0.05当量)装入配备有搅拌棒的10-20mLμW管,并且通过由Ar冲洗持续1h而将系统放置在Ar气氛下。然后添加12.4mL的二噁烷(通过由Ar鼓泡而脱气持续1h)。在μW反应器(正常功率)中在140℃搅拌持续3h后,添加EA并且悬浮液过滤通过硅藻土短柱。将粗产物在硅胶柱上纯化,使用己烷中0-100%EA作为洗脱剂,得到227mg(30%)的作为白色固体的产物113和193mg(26%)的作为白色固体的de-Boc产物。1H NMR(400MHz,CDCl3,ppm)δ:7.12(t,J=7.9Hz,1H),6.54(d,J=3.8Hz,1H),6.52(d,J=4.3Hz,1H),4.77(AB的A,JAB=16.7Hz,1H),4.61(t,J=8.1Hz,1H),4.42(d,J=7.7Hz,1H),4.33(AB的B,JAB=16.9Hz,1H),4.19(dd,J=8.7,5.0Hz,1H),3.97(ddd,J=12.6,9.8,4.8Hz,1H),3.49(br s,1H),3.25(br s,2H),2.68(ABX的A,JAB=14.9Hz,JAX=4.6Hz,1H),2.41(ABX的B,JAB=15.0Hz,JBX=10.6Hz,1H),2.21-2.03(m,4H),1.45(s,9H),1.31-1.20(m,4H)。
将0.330g的噁唑烷酮113(0.822mmol,1当量)、3.0mL的3M NaOH溶液(9.00mmol,11当量)和7.0mL的EtOH装入配备有搅拌棒的10-20mLμW管。在μW反应器(正常功率)中在110℃搅拌持续1.5h后,将反应混合物转移到50mL rb烧瓶,冷却至0℃,并且将溶解于6.6mL的二噁烷和3.3mL的水中的0.538g的Boc2O(2.47mmol,3当量)装入。在rt搅拌持续48h后,反应混合物通过添加饱和NH4Cl溶液和稀释的HCl中和,用CH2Cl2(3×)萃取,并且经Na2SO4干燥。将粗产物在硅胶柱(40g)上纯化,使用己烷中0-100%EA作为洗脱剂以得到作为白色固体的0.208g(53%)的产物114。1H NMR(400MHz,CDCl3,ppm)δ:7.07(t,J=7.8Hz,1H),6.49(d,J=8.4Hz,2H),4.71(br s,1H),4.63-4.55(m,1H),4.46-4.36(m,1H),4.31-4.18(m,1H),3.66-3.17(m,3H),2.63(ABX的A,JAB=15.9Hz,JAX=6.5Hz,1H),2.45(ABX的B,JAB=15.9Hz,JBX=2.6Hz,1H),2.20-2.12(m,2H),2.11-2.03(m,2H),1.60(br s,3H),1.48(s,9H),1.45(s,9H),1.31-1.17(m,2H)。
将0.208g的醇114(0.437mmol,1当量)、0.323mL的TEA(2.32mmol,5.3当量)和1.33mL的CH2Cl2装入配备有磁性搅拌棒和隔膜的50mL Schlenk管。在将反应混合物冷却至0℃后,逐滴添加溶解在1.33mL的DMSO中的0.278g的SO3*Py(1.75mmol,4当量),并且允许反应混合物在5h中升温至rt。反应混合物通过添加饱和NaHCO3溶液淬灭,用CH2Cl2(3×)萃取,并且经Na2SO4干燥。将粗产物在硅胶柱上纯化,使用CH2Cl2中0至10%EA作为洗脱剂,得到作为微黄色油状物的150mg(72%)的产物115。
将0.150g的醛115(0.317mmol,1当量)、0.067g的胺V(0.412mmol,1.3当量)和3.2mL的DCE装入配备有搅拌棒的20mL小瓶。然后添加0.101g的STAB(0.475mmol,1.5当量),并且将悬浮液在rt搅拌持续3h。反应混合物通过添加饱和NaHCO3溶液淬灭,用CH2Cl2(3×)萃取,并且经Na2SO4干燥。将粗产物在硅胶柱上纯化,使用己烷中0至100%EA作为洗脱剂,得到作为微黄色油状物的131mg(67%)的产物116。1H NMR(400MHz,CDCl3,ppm)δ:8.33(br s,1H),7.24(d,J=7.7Hz,1H),6.98-6.89(m,2H),6.38(d,J=8.1Hz,1H),6.31(br s,1H),4.78-4.43(m,2H),3.86(d,J=17.0Hz,1H),3.79(dd,J=8.8,4.9Hz,1H),3.49(br s,2H),3.27-3.15(m,1H),2.75(AB的A,JAB=15.8Hz,1H),2.76-2.68(m,1H),2.60(dt,J=16.8,5.0Hz,1H),2.55-2.45(m,2H),2.39(s,3H),2.23-2.16(m,1H),2.14-2.03(m,3H),1.99-1.88(m,2H),1.80-1.69(m,1H),1.67-1.55(m,1H),1.46(s,9H),1.44(s,9H),1.33-1.17(m,4H).LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),6min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=620.3(M+H),t=0.730min;
EMU089:将溶解在2.1mL的CH2Cl2中的131mg的胺116(0.211mmol,1当量)装入配备有搅拌棒的20mL小瓶。然后添加488μL的TFA(6.34mmol,30当量)。在rt搅拌持续20h后,反应混合物通过添加1N KOH溶液淬灭,用CH2Cl2(3×)萃取并且经Na2SO4干燥。将粗物质在硅胶柱上纯化,使用CH2Cl2中0-60%的溶剂2(溶剂2=70%CH2Cl2、30%MeOH、3%NH4OH)作为洗脱剂,得到作为微黄色粉末的77mg(87%)的产物EMU089。1H NMR(600MHz,CDCl3,ppm)δ:8.47(d,J=4.7Hz,1H),7.34(d,J=7.7Hz,1H),7.06(dd,J=7.7,4.7Hz,1H),7.00(t,J=7.8Hz,1H),6.45(d,J=8.1Hz,1H),6.39(d,J=7.6Hz,1H),4.00(dd,J=8.9,6.4Hz,1H),3.94(AB的A,JAB=15.3Hz,1H),3.89(AB的B,JAB=15.3Hz,1H),3.33-3.22(m,2H),2.91(br s,1H),2.82-2.64(m,4H),2.54(s,3H),2.35(dd,J=15.5,4.2Hz,1H),2.17-1.64(m,9H),1.30-1.14(m,4H)。13C NMR(400MHz,CDCl3,ppm)δ:157.70,146.80,144.74,136.52,136.25,133.88,126.03,121.43,118.60,114.61,107.61,64.13,59.67,51.57,51.18,50.21,48.95,41.37,35.35,35.31,32.18,32.11,29.19,28.82,24.84,21.24。HRMS(ESI+)对于C26H38N5([M+H]+)计算为:420.3122。实测为:420.3123,误差0.2ppm.LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=420.2(M+H),210.6(M/2+H),t=0.495min;
吡啶TIQ-15
如在参考文献(Organic Process Research&Development 2002,6,938-942,Bioorganic&Medicinal Chemistry 2003,11,433-450)中,74从吡啶-2,3-二羧酸合成,收率为55%。
将26.9g的酯74(101mol,1当量)、42.2mL的TEA(303mmol,3当量)、1.23g的DMAP(10.1mmol,0.1当量)和253mL的THF装入配备有磁性搅拌棒和橡胶隔膜的1L rb烧瓶。然后添加27.6g的Boc2O(126mmol,1.25当量),并且将悬浮液搅拌持续3h。悬浮液不变成溶液,并且添加另一份的21mL的TEA(151mmol,1.5当量)随后是300mL的乙腈和100mL的MeOH。在rt搅拌澄清溶液持续12h后,将反应混合物浓缩并且添加EA。铵盐通过过滤分离,并且将有机物在真空下浓缩。将粗物质在硅胶柱上纯化,使用己烷中0-65%EA作为洗脱剂,得到2.24g(8%)的作为黄色油状物的76和8.12g(28%)的作为黄色油状物的75,其在冷冻器中结晶成白色固体。对于76(构象异构体的4:1混合物):1H NMR(400MHz,CDCl3,ppm)δ:8.47-8.41(m,1.25H),7.46(d,J=7.7Hz,1.25H),7.11(dd,J=7.7,4.8Hz,1.25H),5.27(dd,J=5.9,2.1Hz,1H),5.02(br s,0.25H),4.89(AB的A,JAB=18.1Hz,0.25H),4.87(AB的A,JAB=17.9Hz,1H),4.56(AB的B,JAB=18.2Hz,1H),4.51(AB的B,JAB=18.2Hz,0.25H),3.63(s,3.75H),3.29(ABX的A,JAB=16.5Hz,JAX=2.2Hz,1H),3.24(ABX的A,JAB=16.5Hz,JAX=2.2Hz,0.25H),3.17(ABX的B,JAB=16.2Hz,JBX=6.3Hz,1H),1.52(s,9H),1.48(s,2.25H).LC-MS(ESI-API,254nm)H2O中95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(AgilentZorbax XDB-18,50mm×4.6mm,3.5μm),m/z=315.0(M+Na),293.0(M+H),t=0.562min;对于75(构象异构体的1∶1混合物):1H NMR(400MHz,CDCl3,ppm)δ:8.42(d,J=4.9Hz,1H),7.44(d,J=7.9Hz,0.5H),7.41(d,J=7.7Hz,0.5H),7.14(dd,J=7.8,4.9Hz,1H),5.32(d,J=6.9Hz,0.5H),5.01(dd,J=6.5,3.7Hz,0.5H),4.80(AB的A,JAB=17.4Hz,0.5H),4.76(AB的B,JAB=17.4Hz,0.5H),4.57(AB的B,JAB=17.0Hz,0.5H),4.50(d,J=16.7Hz,1H),3.65(s,1.5H),3.63(s,1.5H),3.47(AB的A,JAB=16.8Hz,0.5H),3.40(ABX的A,JAB=17.1Hz,JAX=3.9Hz,0.5H),3.32(ABX的B,JAB=17.5Hz,JBX=6.6Hz,1H),1.53(s,4.5H),1.47(s,4.5H).LC-MS(ESI-API,254nm)H2O中95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(AgilentZorbax XDB-18,50mm×4.6mm,3.5μm),m/z=315.0(M+Na),293.1(M+H),t=0.560min;
将1.00g的酯75(3.42mmol,1当量)和17.1mL的甲苯装入配备有搅拌棒和橡胶隔膜的100mL rb烧瓶。在将反应混合物冷却至78℃后,逐滴添加5.70mL的1.2M DIBAL-H溶液(6.84mL,2当量),并且将溶液在78℃搅拌持续2h。然后反应混合物通过添加2.5mL的MeOH随后是罗谢尔盐的饱和溶液淬灭。在rt搅拌持续30min后,产物用EA(3×)萃取,并且经Na2SO4干燥。粗产物77(994mg)不经纯化即被用于下一个步骤中。
将608mg的(S)-5,6,7,8-四氢喹啉-8-胺(4.10mmol,1.2当量)、897mg的醛77(3.42mmol,1当量)、942mg的STAB(4.45mmol,1.3当量)和11.4mL的DCE加入配备有搅拌棒的20mL小瓶。在rt搅拌持续1.5h后,反应混合物通过添加饱和Na2CO3溶液淬灭,并且产物用CH2Cl2(3×)萃取,用饱和Na2CO3溶液、卤水洗涤,并且经Na2SO4干燥。将粗产物在硅胶柱上纯化,使用EA、随后是CH2Cl2中20%MeOH作为洗脱剂,得到0.905(67%)g的产物78。1H NMR(400MHz,CDCl3,ppm)δ:8.44-8.40(m,1H),8.35(d,J=4.5Hz,1H),7.39(d,J=7.4Hz,1H),7.34(d,J=7.7Hz,1H),7.147.09(m,1H),7.05(t,J=4.2Hz,0.5H),7.03(t,J=4.2Hz,0.5H),5.02-4.58(m,2H),4.24(AB的B,JAB=18.3Hz,1H),3.76(br s,0.5H),3.69(br s,0.5H),3.23(ABX的A,JAB=16.6Hz,JAX=6.2Hz,0.5H),3.19(ABX的A,JAB=16.6Hz,JAX=6.2Hz,0.5H),3.07(AB的B,JAB=16.9Hz,0.5H),2.94(AB的B,JAB=16.8Hz,0.5H),2.85-2.63(m,4H),2.04-1.91(m,1H),1.72-1.63(m,1H),1.52-1.28(m,2H),1.49(s,4.5H),1.42(s,4.5H).LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=417.2(M+Na),395.2(M+H),t=0.511min,纯度为86%;
将0.086g的多聚甲醛(2.85mmol,2当量)、0.563g的胺78(1.43mmol,1当量)、82μL的乙酸(1.43mmol,1当量)和14.3mL的DCE装入配备有搅拌棒的20mL小瓶。然后添加0.605g的STAB(2.85mmol,2当量)。在搅拌持续2天后,反应混合物通过添加饱和NaHCO3溶液淬灭,用CH2Cl2(3×)萃取,并且经Na2SO4干燥。将粗产物在硅胶柱上纯化,使用EA中0至10%MeOH作为洗脱剂,得到208mg(36%)的URf-97(立体异构体1)、66mg(11%)的异构体的混合物和189mg(32%)的LRf-97(立体异构体2)。在使用EA中10%MeOH的TLC上,立体异构体2比立体异构体1洗脱更快。对于立体异构体1:1H NMR(400MHz,CDCl3,ppm)δ:8.30(d,J=4.1Hz,1H),8.24(s,lH),7.31-7.15(m,2H),7.00(dd,J=7.8,4.8Hz,1H),6.89(s,1H),4.85-4.66(m,1.5H),4.55(br s,0.5H),4.29-4.12(m,1H),3.70(dd,J=8.8,5.1Hz,1H),3.06(ABX的A,JAB=16.7,JAX=6.3Hz,1H),2.97-2.87(m,1H),2.72-2.44(m,4H),2.40-2.25(m,1H),2.29(s,3H),1.96-1.82(m,2H),1.80-1.67(m,1H),1.63-1.52(m,1H),1.44(s,9H).LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),6min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=431.2(M+Na),409.2(M+H),205.2(M/2+H),t=0.499min;对于立体异构体2:1H NMR(400MHz,CDCl3,ppm)δ:8.31(s,1H),8.22(s,1H),7.24(d,J=7.6Hz,1H),7.14(d,J=7.7Hz,1H),6.97(dd,J=7.7,4.8Hz,1H),6.92(br s,1H),4.79-4.48(m,2H),3.81-3.43(m,2H),3.03(s,2H),2.78-2.66(m,1H),2.62-2.53(m,2H),2.33(s,3H),1.96-1.86(m,1H),1.86-1.76(m,2H),1.63-1.51(m,1H),1.44(s,9H).LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),6min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=431.2(M+Na),409.2(M+H),205.2(M/2+H),t=0.481min;
EMU174(立体异构体1):将溶解在4.7mL的CH2Cl2中的192mg的胺URf-97(0.470mmol,1当量)装入配备有搅拌棒的20mL小瓶。然后添加1.09mL的TFA(14.1mmol,30当量)。在rt搅拌持续12h后,反应混合物通过添加2N NaOH溶液淬灭,用CH2Cl2(3×)萃取并且经Na2SO4干燥。将粗物质在硅胶柱上纯化,使用CH2Cl2中0至45%的溶剂2(溶剂2=30%MeOH、70%CH2Cl2和3%NH4OH)作为洗脱剂,得到131mg(90%)的产物EMU174(立体异构体1)。1H NMR(600MHz,CDCl3,ppm)δ:8.52(d,J=4.4Hz,1H),8.34(d,J=4.7Hz,1H),7.34(d,J=1.0Hz,1H),7.31(d,J=7.7Hz,1H),7.06(dd,J=7.7,4.7Hz,1H),7.01(dd,J=7.7,4.7Hz,1H),4.10(AB的A,JAB=15.2Hz,1H),4.00(AB的B,JAB=14.9Hz,1H),3.98(dd,J=9.7,6.0Hz,1H),3.06(t,J=10.8Hz,1H),2.81(ddd,J=16.3,10.9,5.2Hz,1H),2.75(dd,J=16.7,3.7Hz,1H),2.70(dt,J=16.6,4.6Hz,1H),2.59(dd,J=12.9,2.0Hz,1H),2.53(s,3H),2.53(dd,J=16.3,11.9Hz,1H),2.40(dd,J=12.7,10.1Hz,1H),2.23-2.17(m,1H),2.06-2.00(m,1H),1.84(tdd,J=12.5,9.4,3.0Hz,1H),1.70-1.67(m,1H).13C NMR(400MHz,CDCl3,ppm)δ:156.72,155.14,147.22,146.92,136.53,133.99,133.86,131.16,121.73,120.51,64.52,58.51,51.85,47.73,40.24,36.97,29.12,22.61,21.18。HRMS(ESI+)对于C19H25N4([M+H]+)计算为:309.2074。实测为:309.2071,误差-1.0ppm.LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=309.2(M+H),155.2(M/2+H),t=0.465min;EMU174(立体异构体2):将溶解在3.1mL的CH2Cl2中的127mg的胺LRf-97(0.311mmol,1当量)装入配备有搅拌棒的20mL小瓶。然后添加0.718mL的TFA(9.33mmol,30当量)。在rt搅拌持续12h后,反应混合物通过添加2NNaOH溶液淬灭,用CH2Cl2(3×)萃取并且经Na2SO4干燥。将粗物质在硅胶柱上纯化,使用CH2Cl2中0至45%的溶剂2(溶剂2=30%MeOH、70%CH2Cl2和3%NH4OH)作为洗脱剂,得到80mg(83%)的产物EMU174(立体异构体2)。1H NMR(600MHz,CDCl3,ppm)δ:8.47(d,J=4.1Hz,1H),8.35(d,J=4.8Hz,1H),7.35(dd,J=7.6,0.9Hz,1H),7.31(d,J=7.2Hz,1H),7.06(dd,J=7.7,4.7Hz,1H),7.02(dd,J=7.7,4.8Hz,1H),4.00(AB的A,JAB=15.2Hz,1H),3.96(dd,J=9.3,6.0Hz,1H),3.89(AB的B,JAB=15.2Hz,1H),2.92(tt,J=10.5,3.5Hz,1H),2.83-2.76(m,3H),2.68(dt,J=16.2,4.5Hz,1H),2.57(dd,J=16.9,10.9Hz,1H),2.51(dd,J=12.9,10.1Hz,1H),2.52(s,3H),2.10-2.04(m,1H),2.05-1.98(m,1H),1.97-1.90(m,1H),1.74-1.67(m,1H).13C NMR(400MHz,CDCl3,ppm)δ:157.76,155.06,147.13,146.75,136.46,133.86,133.64,130.94,121.38,120.63,64.36,59.44,51.72,47.48,41.14,37.00,29.10,25.80,21.22.HRMS(ESI+)对于C19H25N4([M+H]+)计算为:309.2074。实测为:309.2074,误差0.0ppm.LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=309.2(M+H),155.2(M/2+H),t=0.475min;
如下文描述的,确定选择的化合物的立体化学分配(stereochemicalassignment),并且使用被保护的前体形成多种立体异构体(例如,EMU142、EMU174、EMU192、EMU193、EMU194、EMU209、EMU212,见下文和上文)。
具有不同侧链的类似物的合成。合成从具有已知的立体化学的胺S,S-S27开始,并且产物S29-33的1H NMR与先前合成的不同的侧链类似物的1H NMR进行比较。
将824μL的对茴香醛(6.78mmol,1.1当量)、2.43g的胺4a-b(6.16mmol,1当量)、70.5μL的乙酸(1.23mmol,0.2当量)和41.1mL的DCE装入配备有搅拌棒的20mL小瓶。然后添加1.70g的NaBH(OAc)3(8.01mmol,1.3当量)。在rt搅拌持续4h后,反应尚未完全,并且添加353μL的乙酸(6.15mmol,1当量)和0.392g的NaBH(OAc)3(2.33mmol,0.3当量)。在rt搅拌持续12h后,反应混合物通过添加饱和NaHCO3溶液淬灭,用CH2Cl2(3×)萃取,并且经Na2SO4干燥。将粗产物在硅胶柱上纯化,使用己烷中0至100%EA作为洗脱剂,得到1.00g(32%)的S,S-S27、350mg(11%)的异构体的混合物和600mg(19%)的R,S-S27。在使用EA中10%MeOH的TLC上,R,S-异构体比S,S-异构体洗脱更快。对于S,S-异构体:1H NMR(400MHz,CDCl3,ppm)δ:8.41-8.35(m,2H),7.38-7.24(m,3H),7.21(d,J=7.6Hz,1H),7.05(dd,J=5.0,6.4Hz,1H),6.96(dd,J=7.7,4.8Hz,1H),6.80(d,J=7.5Hz,2H),4.72(AB的A,JAB=17.7Hz,1H),4.71(br s,0.5H),4.53(br s,0.5H),4.26(br s,1H),4.12(AB的A,JAB=17.5Hz,1H),3.97-3.89(m,1H),3.83-3.74(m,1H),3.79(s,3H),3.30(br s,1H),3.04(ABX的B,JAB=16.6Hz,JBX=6.1Hz,1H),2.77(d,J=13.1Hz,1H),2.56-2.39(m,2H),2.31-2.13(m,1H),2.02-1.93(m,1H),1.83-1.67(m,2H),1.56-1.37(m,1H),1.45(s,9H).LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=515.0(M+H),258.0(M/2+H),t=0.744min;对于R,S-异构体:1H NMR(400MHz,CDCl3,ppn)δ:8.39(s,1H),8.35(dd,J=4.8,1.6Hz,1H),7.25(d,J=7.7Hz,1H),7.23-7.13(m,2H),7.10-6.95(m,2H),6.97(dd,J=7.7,4.7Hz,1H),6.75(d,J=8.5Hz,2H),4.93(br s,0.5H),4.77(d,J=17.6Hz,0.5H),4.65(br s,0.5H),4.47(d,J=17.7Hz,0.5H),4.14(br s,0.5H),3.96(br s,0.5H),3.78(s,3H),3.86-3.26(m,3H),3.21-2.93(m,2H),2.72-2.42(m,3H),2.27(br s,0.5H),2.15(br s,0.5H),1.99-1.88(m,1H),1.81-1.38(m,3H),1.53(s,4.5H),1.44(s,4.5H).LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=515.0(M+H),258.0(M/2+H),t=0.738min;
将378mg的R,S-S27(0.735mmol,1当量)和3.40mL的CF3COOH(44.1mmol,60当量)装入配备有搅拌棒的5mL微波小瓶,并且将小瓶密封。在40℃搅拌持续4h后,反应混合物通过添加2M NaOH溶液淬灭,用CH2Cl2(3×)萃取并且经Na2SO4干燥。将有机物在真空(旋转蒸发器)中浓缩,并且将粗产物在硅胶柱上纯化,使用CH2Cl2中0至60%溶剂2(溶剂2=CH2Cl2中30%MeOH+3%NH4OH)作为洗.脱剂,得到216mg(100%)的作为黄色油状物的产物4a。1H NMR(400MHz,CDCl3,ppm)δ:8.24(dd,J=4.7,1.7Hz,1H),8.21(dd,J=4.8,1.7Hz,1H),7.20(dd,J=7.7,1.7Hz,1H),7.14(dd,J=7.7,1.7Hz,1H),6.89(dd,J=7.9,4.7Hz,1H),6.87(dd,J=7.5,4.9Hz,1H),3.87(s,2H),3.66(dd,J=7.6,5.2Hz,1H),2.96(ddt,J=10.8,8.2,3.9Hz,1H),2.84(dd,J=4.0,1.7Hz,1H),2.80(dd,J=6.8,3.9Hz,1H),2.64(AB的A,JAB=8.8Hz,1H),2.61(AB的B,JAB=8.9Hz,1H),2.69-2.47(m,2H),2.39(br s,2H),2.03-1.95(m,1H),1.91-1.78(m,1H),1.70-1.52(m,2H).13C NMR(400MHz,CDCl3,ppm)δ:157.09,154.74,146.97,146.46,136.41,133.25,131.95,131.02,121.38,120.56,57.89,54.03,52.38,46.92,36.43,28.74,28.43,19.21.LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=295.0(M+H),t=0.508min;
将200mg的胺4a(0.679mmol,1当量)、237μL的Et3N(1.70mmol,2.5当量)、8.30mg的DMAP(0.0679mmol,0.1当量)和6.7mL的CH2Cl2装入配备有搅拌棒的20mL小瓶。然后添加399mg的4-溴苯磺酰氯(1.56mmol,2.3当量),并且将反应混合物在rt搅拌持续12h。反应混合物通过添加饱和NaHCO3溶液淬灭,用CH2Cl2(2×)萃取,并且经Na2SO4干燥。将有机物浓缩,并且将粗产物在硅胶柱上纯化,使用己烷中0-100%EA作为洗脱剂,得到380mg(76%)的作为白色固体的产物S28。将产物从乙酸乙酯和CH2Cl2的混合物(5∶1)重结晶,得到被提交用于x-射线晶体学的无色针状物。1H NMR(400MHz,CDCl3,ppm)δ:8.39(dd,J=4.9,1.6Hz,1H),7.93(dd,J=4.7,1.6Hz,1H),7.58-7.44(m,8H),7.31(dd,J=7.7,1.6Hz,1H),7.26(dd,J=7.7,1.6Hz,1H),7.05(dd,J=7.7,4.8Hz,1H),6.96(dd,J=7.7,4.6Hz,1H),4.83(dd,J=11.2,6.4Hz,1H),4.70-4.60(m,1H),4.60(AB的A,JAB=17.0Hz,1H),4.28(AB的B,JAB=16.9Hz,1H),3.39-3.27(m,2H),3.16(ABX的A,JAB=17.2Hz,JAX=2.7Hz,1H),2.91(ABX的B,JAB=17.3Hz,JBX=6.7Hz,1H),2.89-2.77(m,1H),2.67(AB的B,JAB=16.7Hz,1H),2.52-2.43(m,1H),2.29(q,J=12.2Hz,1H),2.10-2.01(m,1H),1.78-1.65(m,1H).13C NMR(400MHz,CDCl3,ppm)δ:153.22,152.41,148.71,146.80,139.15,138.35,136.70,134.24,133.38,132.34,131.50,129.37,128.49,127.78,126.95,126.34,122.10,121.49,61.43,51.74,50.14,42.88,32.45,30.89,28.79,22.58.LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=732.4(M+H),365.8(M/2+H),t=2.265min;
为了证明所有2,6-萘啶的立体化学,合成了具有不同侧链的所有通常中间体,并且获得了1H NMR谱,并且与先前记录的数据进行比较。
将109mg的20w%的碳载Pd(OH)2(0.155mmol,0.1当量)和392mg的甲酸铵(6.22mmol,4当量)装入配备有搅拌棒的20mL微波小瓶,并且将小瓶密封并且放置在Ar下。然后添加溶解在16mL的无水乙醇中的800mg的氨基甲酸酯S,S-S27(1.55mmol,1当量)(通过鼓泡Ar而脱气持续30min)。在45℃搅拌持续12h后,反应没有完全,并且添加109mg的20w%的碳载Pd(OH)2(0.155mmol,0.1当量)和250mg的甲酸铵(3.96mmol,2.6当量),并且继续搅拌持续多于18小时。然后将反应混合物过滤通过硅藻土短柱,并且用乙醇洗涤硅藻土短柱。将有机物在真空(旋转蒸发器)中浓缩,并且将粗产物在硅胶柱上纯化,使用CH2Cl2中0至30%溶剂2(溶剂2=CH2Cl2中30%MeOH+3%NH4OH)作为洗脱剂,得到314mg(51%)的作为白色泡沫状物的产物4b。1H NMR(600MHz,CDCl3,ppm)δ:8.39(dd,J=4.9,1.6Hz,1H),8.33(d,J=4.7Hz,1H),7.37(d,J=7.8Hz,1H),7.31(d,J=7.7Hz,1H),7.09(dd,J=7.7,4.8Hz,1H),7.01(dd,J=7.7,4.7Hz,1H),4.97-4.62(m,2H),4.23(br s,2H),3.75(s,1H),3.21(ABX的A,JAB=16.9Hz,JAX=6.4Hz,1H),2.92(ABX的B,JAB=16.9,JBX=1.6Hz,1H),2.80-2.63(m,4H),2.04-1.90(m,2H),1.66(br s,2H),1.40(s,9H).LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent ZorbaX XDB-18,50mm×4.6mm,3.5μm),m/z=395.0(M+H),t=0.527min。
化合物S29从30mg的胺4b合成,并且根据用于S8的合成的程序纯化,得到20mg(44%)的产物。化合物S29和S,S-异构体-S8的1H NMR是相同的。LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=596.0(M+H),298.6(M/2+H),t=0.644min;
化合物S30从30mg的胺4b合成,并且根据用于S9的合成的程序纯化,得到25mg(55%)的产物。化合物S30和S,S-异构体-S9的1H NMR是相同的。LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=594.0(M+H),297.5(M/2+H),t=0.740min;
化合物S31从30mg的胺4b合成,并且根据用于S10的合成的程序纯化,得到35mg(78%)的产物。化合物S30和S,S-异构体-S10的1H NMR是相同的。LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=593.8(M+H),297.5(M/2+H),t=0.654min;
化合物S32从30mg的胺4b合成,并且根据用于S11的合成的程序纯化,得到39mg(81%)的产物。化合物S32和S,S-异构体-S11的1H NMR是相同的。LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=643.8(M+H),322.5(M/2+H),t=0.720min;
化合物S33从30mg的胺4b合成,并且根据用于S7的合成的程序纯化,得到25mg(81%)的产物。化合物S33和S,S-异构体-S7的1H NMR是相同的。LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=409.0(M+H),t=0.578min;
硫代吗啉类似物的合成
将化合物1(0.268g,0.551mmol)、Pd2(dba)3(0.025g,0.028mmol)、BINAP(0.051g,0.083mmol)和碳酸铯(0.251g,0.771mmol)装入烘箱干燥的Biotage 5-10ml微波小瓶。将小瓶用teflon隔膜密封并且用氩气吹扫持续几分钟。然后通过注射器添加2.75ml脱气的甲苯和硫代吗啉(0.066ml,0.661mmol),并且脱气持续另外的5分钟。在加热至120℃持续24小时后,反应混合物经硅藻土过滤掉,并且用EtOAc洗涤硅藻土。蒸发合并的滤液,并且用柱色谱纯化,使用0-100%DCM∶MeOH∶NH3(9∶1∶0.2)。1H NMR(400MHz,氯仿-d)δ8.26(s,1H),7.36-7.30(m,1H),7.08(t,J=7.7Hz,1H),7.03-6.95(m,1H),6.84(dd,J=7.9,1.2Hz,1H),6.69(d,J=11.1Hz,1H),4.57(d,J=16.7Hz,1H),4.43(s,1H),3.83(d,J=17.1Hz,1H),3.57(s,1H),3.26-3.11(m,4H),3.03(s,2H),2.92-2.71(m,4H),2.65(m,4H),2.26(s,3H),2.04-1.92(m,1H),1.88(m,2H),1.60(m,1H),1.49(s,9H)。
将化合物3(0.170g,0.334mmol)溶解在DCM中并且添加TFA(0.515ml,6.68mmol),并且在室温搅拌过夜。反应混合物用冰浴冷却,并且用1M NaOH溶液碱化至pH>12,并且用DCM萃取3次。合并的有机层经无水硫酸钠干燥并且浓缩。将产物用柱色谱纯化,使用0-100%DCM∶MeOH∶NH3(9∶1∶0.2)。1H NMR(500MHz,氯仿-d)δ8.37(dd,J=4.7,1.8Hz,1H),7.43(dd,J=7.5,1.9Hz,1H),7.18-7.10(m,2H),6.92(dd,J=7.8,1.2Hz,1H),6.77(d,J=7.7Hz,1H),4.69(s,2H),4.44(d,J=16.1Hz,1H),4.27(d,J=16.1Hz,1H),4.17(dd,J=10.6,6.0Hz,1H),3.44-3.34(m,2H),3.05-2.97(m,3H),2.79-2.69(m,8H),2.15(s,3H),2.10-2.02(m,1H),2.02-1.94(m,1H),1.91-1.79(m,1H),1.76-1.65(m,1H),1.22(s,1H);13CNMR(126MHz,CDCl3)δ156.54,152.35,146.00,138.28,134.74,129.54,127.45,122.35,121.92,121.71,119.09,74.69,64.55,57.98,54.41,52.47,43.53,35.34,28.98,28.43,25.20,21.22。
将0.030g的多聚甲醛(1.00mmol,3当量)、0.131g的(S)-N-甲基-N-(((R)-5-吗啉基-1,2,3,4-四氢异喹啉-3-基)甲基)-5,6,7,8-四氢喹啉-8-胺(0.334mmol,1当量)和3.3mL的DCE装入配备有搅拌棒的20mL小瓶。然后添加0.212g的NaBH(OAc)3(1.00mmol,3当量)。在搅拌持续2天后,反应混合物通过添加饱和NaHCO3溶液淬灭,用CH2Cl2(3×)萃取,并且经Na2SO4干燥。将粗产物在硅胶柱(12g)上纯化,使用CH2Cl2中0至50%的溶剂2(CH2Cl2中30%MeOH和3%的NH4OH),得到123mg(91%)的作为黄色稠油状物的产物1。1H NMR(400MHz,CDCl3)δ8.41(d,J=4.9Hz,1H),7.30(d,J=7.8Hz,1H),7.08(t,J=7.7Hz,1H),7.00(dd,J=7.7,4.7Hz,1H),6.85(d,J=7.9Hz,1H),6.73(d,J=7.5Hz,1H),3.84(t,J=4.5Hz,4H),3.80-3.74(m,1H),3.75(AB的A,JAB=17.5Hz,1H),3.68(AB的B,JAB=15.8Hz,1H),2.98-2.75(m,8H),2.70-2.58(m,2H),2.48(dd,J=12.2,7.5Hz,1H),2.41(s,3H),2.28(s,3H),2.08-1.95(m,1H),1.95-1.87(m,2H),1.68-1.57(m,1H)。(7%的其他构象异构体被注意到为8.46(d,J=4.9Hz,0.07H);13C NMR(100MHz,CDCl3)δ157.64,151.02,146.49,136.37,135.43,133.68,129.10,125.89,121.57,121.39,116.49,67.30,64.86,57.02,56.35,55.94,52.12,40.72,39.49,28.60,27.33,25.76,20.09;HRMS(ESI+)对于C25H35N4O([M+H]+)计算为:407.2805。实测为:407.2806,误差0.1ppm;LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=407.2(M+H),204.2(M/2+H),t=0.502min。
将250mg的叔丁基(R)-5-溴-3-((甲基((S)-5,6,7,8-四氢喹啉-8-基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯(0.514mmol,1当量),90.0mg的硫代吗啉1,1-二氧化物(0.668mmol,1.3当量)、48.0mg的BINAP(0.077mmol,0.15当量)、0.251g的Cs2CO3(0.771mmol,1.5定量)和24.0mg的Pd2(dba)3(0.026mmol,0.05当量)装入配备有搅拌棒的5mLμW管,并且通过由Ar冲洗持续1h而将系统放置在Ar气氛下。然后添加2.57mL的二噁烷(通过由Ar鼓泡而脱气持续1h)。在μW反应器(正常功率)中在140℃搅拌持续3h后,添加EA并且将悬浮液过滤通过硅藻土短柱。将粗产物在硅胶柱上纯化,使用己烷中0-100%EA作为洗脱剂,得到252mg(91%)的产物15。1H NMR(400MHz,CDCl3)δ8.28(s,1H),7.35(d,J=7.6Hz,1H),7.11(t,J=7.8Hz,1H),7.07-6.99(m,1H),6.91(d,J=7.6Hz,1H),6.80-6.72(m,1H),4.70(br s,0.5H),4.58(d,J=17.1Hz,1H),4.50(br s,0.5H),3.89-3.77(m,1H),3.65(s,1H),3.50-3.34(m,4H),3.31-3.15(m,5H),2.87-2.61(m,4H),2.47-2.20(m,1H),2.23(s,3H),2.02-1.80(m,3H),1.66-1.56(m,1H),1.50(s,9H);LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=541.2(M+H),t=0.514min。
将溶解在3.6mL的CH2Cl2中的192mg的胺15(0.355mmol,1当量)装入配备有搅拌棒的20mL小瓶。然后添加821μL的TFA(10.7mmol,30当量)。在rt搅拌持续20h后,反应混合物通过添加1N KOH溶液淬灭,用CH2Cl2(3×)萃取,并且经Na2SO4干燥。将粗物质在硅胶柱上纯化,使用CH2Cl2中0至25%溶剂2(溶剂2=70%CH2Cl2、30%MeOH、3%NH4OH)作为洗脱剂,得到132mg(84%)的作为黄色稠油状物的产物3。1H NMR(400MHz,CDCl3)δ8.42(dd,J=4.7,1.7Hz,1H),7.32(d,J=7.6Hz,1H),7.05(t,J=8.8Hz,1H),7.03(dd,J=8.7,3.7Hz,1H),6.86(dd,J=7.9,1.1Hz,1H),6.80(dd,J=7.6,1.1Hz,1H),4.01(AB的A,JAB=15.5Hz,1H),3.96-3.89(m,1H),3.89(AB的B,JAB=15.7Hz,1H),3.41-3.04(m,10H),2.82-2.70(m,3H),2.68-2.60(m,1H),2.50(dd,J=13.0,9.8Hz,1H),2.44(s,3H),2.13(dd,J=17.0,11.1Hz,1H),2.06-1.85(m,3H),1.72-1.60(m,1H);13C NMR(100MHz,CDCl3)δ157.54,149.77,146.64,137.04,136.57,133.72,129.65,126.07,123.07,121.43,117.84,64.18,59.66,52.39,51.27,50.32,48.31,40.56,29.72,29.05,25.26,21.15;HRMS(ESI+)对于C24H33N4O2S([M+H]+)计算为:441.2319。实测为:441.2317,误差0.15ppm;LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=441.2(M+H),221.2(M/2+H),t=0.495min。
将250mg的叔丁基(R)-5-溴-3-((甲基((S)-5,6,7,8-四氢喹啉-8-基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯(0.514mmol,1当量),90.0mg的4,4-二氟哌啶(4,4-difluoropioeridine)(0.668mmol,1.3当量)、48.0mg的BINAP(0.077mmol,0.15当量)、0.251g的Cs2CO3(0.771mmol,1.5定量)、和24.0mg的Pd2(dba)3(0.026mmol,0.05当量)装入配备有搅拌棒的5mLμW管,并且通过由Ar冲洗持续1h将系统放置在Ar气氛下。然后添加2.57mL的二噁烷(通过由Ar鼓泡而脱气持续1h)。在μW反应器(正常功率)中在140℃搅拌持续3h后,添加EA并且将悬浮液过滤通过硅藻土短柱。将粗产物在硅胶柱上纯化,使用己烷中0-100%EA作为洗脱剂,得到252mg(91%)的产物16。1H NMR(400MHz,CDCl3)δ8.25(s,1H),7.33(d,J=7.7Hz,1H),7.08(t,J=7.8Hz,1H),7.00(t,J=6.3Hz,1H),6.86(dd,J=8.0,1.1Hz,1H),6.74-6.63(m,1H),4.66(br s,0.5H),4.58(AB的A,JAB=17.1Hz,1H),4.44(brs,0.5H),3.85(AB的B,JAB=17.0Hz,1H),3.63-3.54(m,1H),3.24-3.13(m,1H),3.08(ddd,J=11.8,7.4,4.1Hz,2H),2.93-2.77(m,3H),2.72-2.59(m,3H),2.43(br s,0.5H),2.32(dd,J=13.1,8.2Hz,0.5H),2.27(s,3H),2.24-1.93(m,5H),1.90-1.83(m,2H),1.64-1.53(m,1H),1.50(s,9H);LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=527.2(M+H),t=0.616min。
将溶解在2.8mL的CH2Cl2中的148mg的胺16(0.281mmol,1当量)装入配备有搅拌棒的20mL小瓶。然后添加650μL的TFA(8.43mmol,30当量)。在rt搅拌持续20h后,反应混合物通过添加1N KOH溶液淬灭,用CH2Cl2(3×)萃取,并且经Na2SO4干燥。将粗物质在硅胶柱上纯化,使用CH2Cl2中0至25%溶剂2(溶剂2=70%CH2Cl2、30%MeOH、3%NH4OH)作为洗脱剂,得到92.0mg(77%)的作为橙色稠油状物的产物2。1H NMR(400MHz,CDCl3)δ8.46(dd,J=4.7,1.7Hz,1H),7.34(d,J=7.6Hz,1H),7.10-7.03(m,2H),6.86(dd,J=7.9,1.1Hz,1H),6.78(dd,J=7.7,1.1Hz,1H),4.05(AB的A,JAB=15.5Hz,1H),3.98-3.92(m,1H),3.92(AB的B,JAB=15.6Hz,1H),3.12-2.99(m,4H),2.87-2.74(m,5H),2.71-2.63(m,1H),2.51(dd,J=12.3,9.7Hz,1H),2.49(s,3H),2.19-1.89(m,8H),1.77-1.63(m,1H).13C NMR(100MHz,CDCl3)δ157.86,150.68,146.76,136.85,136.62,133.78,129.89,125.95,122.15,121.87(t,J=241.6Hz),121.48,117.05,64.42,59.93,51.43,48.89(t,J=5.5Hz),48.60,41.00,34.76(t,J=22.6Hz),29.92,29.18,25.72,21.25.19F NMR(376MHz,CDCl3)δ-98.69(br s).HRMS(ESI+)对于C25H33N4F4([M+H]+)计算为:427.2668。实测为:427.2667,误差0.13ppm.LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=427.2(M+H),214.2(M/2+H),t=0.548min。
将250mg的叔丁基(R)-5-溴-3-((甲基((S)-5,6,7,8-四氢喹啉-8-基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯(0.514mmol,1当量),66.0mg的4-甲基哌啶(0.668mmol,1.3当量)、48.0mg的BINAP(0.077mmol,0.15当量)、0.251g的Cs2CO3(0.771mmol,1.5定量)、和24.0mg的Pd2(dba)3(0.026mmol,0.05当量)装入配备有搅拌棒的5mLμW管,并且通过由Ar冲洗持续1h将系统放置在Ar气氛下。然后添加2.57mL的二噁烷(通过由Ar鼓泡而脱气持续1h)。在μW反应器(正常功率)中在140℃搅拌持续3h后,添加EA并且将悬浮液过滤通过硅藻土短柱。将粗产物在硅胶柱上纯化,使用己烷中0-30%EA作为洗脱剂,得到143mg(55%)的产物17。1H NMR(400MHz,CDCl3)δ8.27(s,1H),7.32(d,J=8.4Hz,1H),7.06(t,J=7.8Hz,1H),6.99(dd,J=7.7,4.6Hz,1H),6.83(d,J=8.2Hz,1H),6.66(d,J=7.6Hz,0.6H),6.61(d,J=7.6Hz,0.4H),4.64-4.59(m,0.4H),4.55(AB的A,JAB=16.9Hz,1H),4.43-4.34(m,0.6H),3.90(AB的B,JAB=16.3Hz,1H),3.60-3.53(m,1H),3.24-3.16(m,1H),3.08(d,J=10.8Hz,1H),3.01(d,J=11.4Hz,1H),2.86-2.75(m,2H),2.69-2.57(m,3H),2.50-2.29(m,2H),2.27(s,3H),2.02-1.81(m,3H),1.76(d,J=12.6Hz,1H),1.69-1.29(m,5H),1.49(s,9H),0.99(d,J=6.0Hz,3H).LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=505.2(M+H),253.2(M/2+H),t=0.726min。
将溶解在2.8mL的CH2Cl2中的143mg的胺17(0.283mmol,1当量)装入配备有搅拌棒的20mL小瓶。然后添加655μL的TFA(8.50mmol,30当量)。在rt搅拌持续20h后,反应混合物通过添加1N KOH溶液淬灭,用CH2Cl2(3×)萃取,并且经Na2SO4干燥。将粗物质在硅胶柱上纯化,使用CH2Cl2中0至20%溶剂2(溶剂2=70%CH2Cl2、30%MeOH、3%NH4OH)作为洗脱剂,得到102.0mg(89%)的作为黄色稠油状物的产物6。1H NMR(400MHz,CDCl3)δ8.46(dd,J=4.8,1.7Hz,1H),7.32(dd,J=7.7,1.0Hz,1H),7.08-7.02(m,2H),6.83(dd,J=7.9,1.1Hz,1H),6.71(dd,J=7.6,1.1Hz,1H),4.05(AB的A,JAB=15.4Hz,1H),3.98-3.91(m,1H),3.90(AB的B,JAB=15.4Hz,1H),3.29(br s,1H),3.09-3.01(m,1H),3.00-2.91(m,1H),2.85-2.61(m,6H),2.52(s,3H),2.50(dd,J=12.7,9.9Hz,1H),2.31(td,J=11.8,2.4Hz,1H),2.15(dd,J=16.3,10.4Hz,1H),2.09-1.90(m,3H),1.75-1.57(m,3H),1.52-1.24(m,3H),0.96(d,J=6.3Hz,3H).13C NMR(100MHz,CDCl3)δ158.01,152.35,146.71,136.52,136.33,133.67,129.82,125.73,121.39,121.05,116.51,64.39,59.83,53.07,51.93,51.52,48.60,41.40,35.02,34.83,30.74,30.01,29.15,25.97,21.97,21.23.HRMS(ESI+)对于C26H37N4([M+H]+)计算为:405.3013。实测为:405.3013,误差0.00ppm.LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=405.2(M+H),203.2(M/2+H),t=0.654min。
将250mg的叔丁基(R)-5-溴-3-((甲基((S)-5,6,7,8-四氢喹啉-8-基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯(0.514mmol,1当量),94.0mg的(2-氟吡啶-4-基)硼酸(0.668mmol,1.3当量)、54.0mg的PPh3(0.206mmol,0.4当量)、1.0mL的2M K2CO3水溶液(2.06mmol,4当量)(通过由Ar鼓泡脱气持续30min)、24.0mg的Pd2(dba)3(0.026mmol,0.05当量)和5.1mL的二噁烷(通过由Ar鼓泡脱气持续1h)装入配备有搅拌棒和冷指回流冷凝器的50mL Schlenk管。在100℃搅拌持续12h后,反应混合物通过添加水淬灭,用CH2Cl2(3×)萃取并且经Na2SO4干燥。将有机物浓缩,并且将粗产物在硅胶柱上纯化,使用己烷中0-100%EA作为洗脱剂,得到121mg(47%)的产物18。1H NMR(400MHz,CDCl3)δ8.26(d,J=5.1Hz,1H),8.18(dd,J=4.8,1.7Hz,1H),7.30(d,J=7.6Hz,1H),7.23(t,J=7.6Hz,1H),7.19(dt,J=5.2,1.7Hz,1H),7.12-7.04(m,1H),7.11(d,J=7.7Hz,1H),6.98(dd,J=7.6,4.6Hz,1H),6.92(s,1H),4.64(AB的A,JAB=17.0Hz,1H),4.52(br s,0.5H),4.33(br s,0.5H),4.05(AB的B,JAB=16.9Hz,1H),3.47(br s,1H),2.92(d,J=4.0Hz,2H),2.76(dd,J=12.8,5.5Hz,1H),2.70(dd,J=9.1,6.6Hz,1H),2.60(dt,J=16.8,5.3Hz,1H),2.42-2.27(m,1H),2.17(s,3H),1.94-1.83(m,1H),1.75-1.46(m,3H),1.50(s,9H).LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=503.2(M+H),t=0.530min;
将溶解在2.0mL的CH2Cl2中的101mg的胺18(0.201mmol,1当量)装入配备有搅拌棒的20mL小瓶。然后添加464μL的TFA(6.03mmol,30当量)。在rt搅拌持续20h后,反应混合物通过添加1N KOH溶液淬灭,用CH2Cl2(3×)萃取,并且经Na2SO4干燥。将粗物质在硅胶柱上纯化,使用CH2Cl2中0至25%溶剂2(溶剂2=70%CH2Cl2、30%MeOH、3%NH4OH)作为洗脱剂,得到81.0mg(100%)的作为黄色稠油状物的产物4。1H NMR(400MHz,CDCl3)δ8.39(dd,J=4.8,1.7Hz,1H),8.20(d,J=5.1Hz,1H),7.31(d,J=7.7Hz,1H),7.18(t,J=7.6Hz,1H),7.10-7.06(m,2H),7.03(dd,J=7.7,4.7Hz,1H),6.98(d,J=7.3Hz,1H),6.81(s,1H),4.11(AB的A,JAB=15.4Hz,1H),3.98(AB的B,JAB=15.4Hz,1H),3.91(dd,J=9.2,5.8Hz,1H),2.99(brs,1H),2.80-2.70(m,2H),2.68-2.58(m,2H),2.45(s,3H),2.39(dd,J=12.9,9.6Hz,1H),2.35-2.26(m,2H),2.06-1.81(m,3H),1.73-1.58(m,1H).13C NMR(100MHz,CDCl3)δ163.64(d,J=238.9Hz),157.66,155.11(d,J=7.8Hz),147.18(d,J=15.3Hz),146.79,138.21(d,J=3.1Hz),136.60,136.48,133.77,131.66,127.14,126.67,125.71,122.09(d,J=4.0Hz),121.49,109.75(d,J=37.1Hz),64.40,59.53,51.59,48.83,41.07,32.78,29.16,25.52,21.25.19F NMR(376MHz,CDCl3)δ-69.21.HRMS(ESI+)对于C25H28N4F([M+H]+)计算为:403.2293。实测为:403.2294,误差0.14ppm.LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=403.2(M+H),203.2(M/2+H),t=0.517min。
将350mg的叔丁基(R)-5-溴-3-((甲基((S)-5,6,7,8-四氢喹啉-8-基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯(0.720mmol,1当量)、219mg的苄基哌啶-4-基氨基甲酸酯(0.935mmol,1.3当量)、67.0mg的BINAP(0.108mmol,0.15当量)、0.352g的Cs2CO3(1.08mmol,1.5定量)、和33.0mg的Pd2(dba)3(0.036mmol,0.05当量)装入配备有搅拌棒的5mLμW管,并且通过由Ar冲洗持续1h将系统放置在Ar气氛下。然后添加3.60mL的二噁烷(通过由Ar鼓泡而脱气持续1h)。在μW反应器(正常功率)中在140℃搅拌持续3h后,添加EA并且将悬浮液过滤通过硅藻土短柱。将粗产物在硅胶柱上纯化,使用己烷中0-100%EA作为洗脱剂,得到180mg(39%)的产物19。LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=640.2(M+H),320.6(M/2+H),t=0.717min;(纯度为90%,存在10%的脱卤素的起始物质:m/z=408.2(M+H),t=0.545min)。
将配备有搅拌棒和隔膜的20mL小瓶放置在氩气气氛下,并且将180mg的胺19(0.281mmol,1当量)、30mg的Pd/C(10w%)(0.028mmol,0.1当量)和1.4mL的脱气MeOH(将Ar鼓泡持续30min)装入。然后分若干份添加32mg的NaBH4(0.844mmol,3当量)。注意到氢气的快速鼓泡。将系统关闭,并且附接空的气球。在rt搅拌持续3h后,反应混合物通过添加饱和NH4Cl水溶液,随后是饱和Na2CO3溶液淬灭,用CH2Cl2(3×)萃取,并且经Na2SO4干燥。将粗物质在硅胶柱上纯化,使用EA、随后是具有3%的NH4OH的CH2Cl2中30%MeOH作为洗脱剂,得到80.0mg(56%)的产物13。1H NMR(400MHz,CDCl3)δ8.26(dd,J=5.0,1.6Hz,1H),7.32(d,J=7.6Hz,1H),7.06(t,J=7.8Hz,1H),6.99(dd,J=7.6,4.7Hz,1H),6.83(dd,J=8.0,1.1Hz,1H),6.70-6.59(m,1H),4.63(br s,0.5H),4.57(AB的A,JAB=16.9Hz,1H),4.46-4.36(m,0.5H),3.87(AB的B,JAB=17.0Hz,1H),3.60-3.52(m,1H),3.24-3.00(m,3H),2.92-2.76(m,3H),2.71-2.57(m,3H),2.49-2.28(m,2H),2.26(s,3H),2.04-1.52(m,10H),1.49(s,9H).LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(AgilentZorbax XDB-18,50mm×4.6mm,3.5μm),m/z=528.2(M+Na),506.2(M+H),253.6(M/2+H),t=0.489min。
将80.0mg的胺13(0.158mmol,1当量)、33.0μL的TEA(0.237mmol,1.5当量)和1.6mL的CH2Cl2装入配备有搅拌棒的20mL小瓶。然后在0℃逐滴添加溶解在0.8mL的CH2Cl2中的37.0mg的4-氟苯磺酰氯(0.190mmol,1.2当量)。在rt搅拌持续12h后,反应混合物通过添加饱和NaHCO3溶液淬灭,用CH2Cl2(2×)萃取,并且经Na2SO4干燥。将有机物浓缩,并且将粗产物在硅胶柱上纯化,使用己烷中0-100%EA作为洗脱剂,得到84.0mg(80%)的产物20。1H NMR(400MHz,CDCl3)δ8.23(d,J=4.8Hz,1H),7.95-7.90(m,2H),7.32(d,J=8.2Hz,1H),7.24-7.19(m,2H),7.05(t,J=7.8Hz,1H),7.02-6.96(m,1H),6.77(d,J=7.9Hz,lH),6.70-6.59(m,1H),4.63(br s,0.5H),4.55(AB的A,JAB=17.0Hz,1H),4.46-4.35(m,1.5H),3.88-3.77(m,1H),3.56(br s,1H),3.31(br s,1H),3.14-2.91(m,3H),2.87-2.76(m,2H),2.69-2.57(m,4H),2.46-2.25(m,1H),2.27(s,3H),2.01-1.51(m,8H),1.48(s,9H).LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=664.2(M+H),332.6(M/2+H),t=0.707min。
将溶解在1.2mL的CH2Cl2中的80.0mg的胺20(0.121mmol,1当量)装入配备有搅拌棒的20mL小瓶。然后添加279μL的TFA(3.62mmol,30当量)。在rt搅拌持续20h后,反应混合物通过添加1N KOH溶液淬灭,用CH2Cl2(3×)萃取,并且经Na2SO4干燥。将粗物质在硅胶柱上纯化,使用CH2Cl2中0至30%溶剂2(溶剂2=70%CH2Cl2、30%MeOH、3%NH4OH)作为洗脱剂,得到58.0mg(85%)的作为白色固体的产物5。1H NMR(400MHz,CDCl3)δ8.46(d,J=4.2Hz,1H),7.95-7.89(m,2H),7.35(dd,J=7.8,1.7Hz,1H),7.23-7.17(m,2H),7.06(dd,J=7.4,4.3Hz,1H),7.05(t,J=7.7Hz,1H),6.78(d,J=7.8Hz,1H),6.75(d,J=7.5Hz,1H),4.45(brs,1H),4.03(AB的A,JAB=15.3Hz,1H),3.97-3.89(m,1H),3.89(AB的B,JAB=16.7Hz,1H),3.29(br s,1H),2.98(d,J=12.7Hz,1H),2.93-2.64(m,7H),2.55(s,3H),2.50-2.34(m,2H),2.12-1.46(m,10H).13C NMR(100MHz,CDCl3)δ164.75(d,J=254.3Hz),157.94,151.30,146.75,137.54(d,J=3.4Hz),136.60(2个信号),133.76,129.93,129.46(d,J=9.2Hz),125.88,121.88,121.46,116.77,116.17(d,J=22.5Hz),64.41,59.75,51.62,51.10,50.88,50.62,48.61,41.19,33.74,33.40,29.83,29.14,25.99,21.20.19F NMR(376MHz,CDCl3)δ-106.33.HRMS(ESI+)对于C31H39N5O2FS([M+H]+)计算为:564.2803。实测为:564.2804,误差0.07ppm.LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=564.2(M+H),282.6(M/2+H),t=0.544min;
一般还原方案:将羧酸(1.00当量)添加到具有搅拌棒的火焰干燥的烧瓶。用THF(0.10M)稀释,并且将所得溶液在室温在Ar下剧烈地搅拌。通过注射泵以6.0mL/hr的速率逐滴添加硼烷一二甲基硫化物络合物(3.50当量),并且允许将所得反应混合物在室温在Ar下搅拌过夜。在早晨,反应在室温逐滴用MeOH淬灭,确保随后的气体排出不变得太剧烈。添加1M水性氢氧化钠,并且所得水层用EtOAc萃取3次。合并的有机层用1M水性氢氧化钠洗涤一次,用卤水洗涤一次,经无水硫酸钠干燥,过滤并且在减压下蒸发。
一般还原胺化方案A:将Dess-Martin高碘烷(1.25当量)添加到具有搅拌棒的烧瓶。用DCM(0.25M)稀释,并且将所得浆液在室温剧烈地搅拌。以逐滴方式添加DCM(0.20M)中的乙醇(1.00当量)的溶液,并且将所得反应混合物在室温在Ar下剧烈地搅拌。在2.5hr后,TLC指示起始物质的完全转化。将反应混合物倾倒入饱和水性NaHCO3和饱和水性Na2S2O3的1∶1混合物(每mmol醇55mL)中。所得有机层经无水硫酸钠干燥,过滤并且在减压下蒸发。将DCM(0.12M)中的胺(1.00当量)的溶液添加到具有搅拌棒的烧瓶。添加DCM(0.53M)中的醛(1.05当量)的溶液,并且将所得混合物在室温在Ar下搅拌持续5min。在该时间后,添加乙酸(1.00当量),并且将所得混合物在室温在Ar下搅拌持续15min。在该时间后,添加三乙酰氧基硼氢化钠(3.00当量),并且将所得反应混合物在室温在Ar下搅拌过夜。在早晨,混合物用DCM稀释反应,并且用1M水性氢氧化钠洗涤一次。所得水层用DCM萃取3次。合并的有机层经无水硫酸钠干燥,过滤并且在减压下蒸发。将粗物质吸收(take up)在DCM(每mmol胺40mL)中,过滤,并且在减压下蒸发。
一般还原胺化方案B:将DCM(0.30M)中的胺(1.00当量)的溶液添加到具有搅拌棒的烧瓶。添加DCM(0.30M)中的醛(1.00当量)的溶液,并且将所得混合物在室温在Ar下搅拌持续10min。以逐滴的方式添加异丙氧钛(1.50当量),并且将所得混合物在室温在Ar下搅拌持续2hr。在该时间后,添加硼氢化钠(3.00当量)和MeOH(0.90M),并且将所得反应混合物在室温在Ar下搅拌。在2hr后,TLC指示起始物质的几乎完全转化。反应用1M水性氢氧化钠淬灭。将有机层分离,并且将来自水层的MeOH在减压下蒸发。所得水层用DCM萃取两次,并且合并的有机层经无水硫酸钠干燥,过滤,并且在减压下蒸发。
一般还原胺化方案C:将DCM(0.12M)中的胺(1.00当量)的溶液添加到具有搅拌棒的烧瓶。添加DCM中的酮(1.00当量)的溶液(0.54M),并且将所得反应混合物在室温在Ar下搅拌持续5min。添加乙酸(0.031mL,0.538mmol,1.00当量),并且将所得混合物在室温在Ar下搅拌持续2.5hr。添加三乙酰氧基硼氢化钠(0.342g,1.61mmol,3.00当量),并且所得反应混合物在室温在Ar下搅拌过夜。一旦LC-MS指示起始物质的消失,反应混合物用DCM稀释,并且用1M水性氢氧化钠洗涤一次。所得水层用DCM萃取3次。合并的有机层经无水硫酸钠干燥,过滤并且在减压下蒸发。
一般脱保护方案:将Boc保护的胺(1.00当量)添加到具有搅拌棒的烧瓶。用DCM(0.10M)稀释,并且将所得溶液在Ar下和室温搅拌持续5min。添加2,2,2-三氟乙酸(32.0当量),并且允许将所得反应混合物在室温在Ar下搅拌过夜。一旦TLC指示起始物质的完全转化,反应混合物用1M水性氢氧化钠淬灭,直到pH达到13-14。所得水层用DCM萃取3次,并且合并的有机层经无水硫酸钠干燥,过滤,并且在减压下蒸发。
叔丁基(4-(羟甲基)苄基)氨基甲酸酯:根据一般还原方案实施合成。通过柱色谱(CombiFlash,24g柱,30mL/min)纯化,用以下梯度洗脱以产生白色固体(462mg,1.95mmol,收率为49%):0-5min,DCM中5%MeOH;5-10min,DCM中5-10%MeOH;10-20min,DCM中10%MeOH;20-25min,DCM中10-50%MeOH.1H NMR(500MHz,CDCl3)δ7.33(d,C=8.0Hz,2H),7.26-7.28(m,2H),4.87(br s,1H),4.68(s,2H),4.31(d,J=5.5Hz,2H),1.87(br s,1H),1.46(s,9H).HRMS(NSI)m/z=238.14408(M+H);理论上对于C13H19O3N+H=238.14377.LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),5min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=260.2(M+Na),164.2(M-tBuO),t=1.862min。
叔丁基(3-(羟甲基)苄基)氨基甲酸酯:根据一般还原方案实施合成。通过柱色谱(CombiFlash,24g柱,30mL/min)纯化,用以下梯度洗脱以产生微黄色油状物(700mg,2.95mmol,收率为74%):0-5min,DCM中0%MeOH;5-10min,DCM中0-5%MeOH;10-15min,DCM中5%MeOH;15-20min,DCM中5-10%MeOH;20-30min,DCM中10%MeOH;30-35min,DCM中10-50%MeOH。1H NMR(500MHz,CDCl3)δ7.32(app t,J=7.5Hz,1H),7.28(m,1H),7.25-7.27(m,1H),7.21(d,J=7.5Hz,1H),4.92(br s,1H),4.67(s,2H),4.31(d,J=6.0Hz,2H),2.11(brs,1H),1.46(s,9H).HRMS(NSI)m/z=238.14399(M+H);理论上对于C13H19O3N+H=238.14377.LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),5min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=260.2(M+Na),196.2(M-tBuO+MeOH),164.2(M-tBuO),138.2(M+H-Boc),t=1.362min。
叔丁基(R)-3-(((4-(((叔丁氧基羰基)氨基)甲基)苄基)((S)-5,6,7,8-四氢喹啉-8-基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯:根据一般还原胺化3案A实施合成。通过柱色谱(CombiFlash,24g柱,30mL/min)纯化,用40∶1 DCM/MeOH洗脱以产生白色泡沫状物(275mg,0.449mmol,收率为51%)。1H NMR(500MHz,CDCl3)δ8.44(d,J=12.5Hz,1H),7.24-7.32(m,3H),7.16(br s,2H),7.06(m,2H),6.83-7.00(m,3H),4.65-4.80(m,2H),4.44-4.51(m,1H),4.29(s,2H),3.86-4.09(m,2H),3.55-3.71(m,2H),2.85-3.05(m,2H),2.51-2.69(m,4H),2.10-2.22(m,1H),1.95(br s,1H),1.66-1.82(m,2H),1.45-1.53(m,18H).HRMS(NSI)m/z=613.37490(M+H);理论上对于C37H48O4N4+H=613.37483.LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),5min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=613.3(M+H),t=4.666min;H2O中50-95%MeOH(0.1%HCO2H),8min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=613.2(M+H),t=6.799min。
叔丁基(R)-3-(((3-(((叔丁氧基羰基)氨基)甲基)苄基)((S)-5,6,7,8-四氢喹啉-8-基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯:根据一般还原胺化方案A实施合成。通过柱色谱(CombiFlash,24g柱,30mL/min)纯化,用以下梯度洗脱以产生白色泡沫状物(298mg,0.486mmol,收率为55%):0-3min,DCM中0%MeOH;3-15min,DCM中0-5%MeOH;15-20min,DCM中5%MeOH;20-25min,DCM中5-25%MeOH。1H NMR(600MHz,CDCl3)δ8.45(d,J=9.0Hz,1H),7.25-7.29(m,2H),7.17-7.24(m,2H),7.14(d,J=6.0Hz,1H),7.04-7.09(m,2H),6.84-7.01(m,3H),5.34(br s,0.5H),4.96(br s,0.5H),4.62(d,J=16.8Hz,1H),4.49(d,J=16.8Hz,1H),4.24-4.35(m,2H),3.99-4.03(m,1H),3.55-3.78(m,3H),2.88-3.00(m,3H),2.60-2.71(m,3H),2.21(br s,1H),1.97(br s,1H),1.79-1.83(m,2H),1.64-1.71(m,1H),1.47-1.52(m,18H).HRMS(NSI)m/z=613.37482(M+H);理论上对于C37H48O4N4+H=613.37483.LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),8min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=613.3(M+H),t=5.047min;H2O中50-95%MeOH(0.1%HCO2H),8min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=613.2(M+H),t=4.848min。
EMU093:(S)-N-(4-(氨基甲基)苄基)-N-(((R)-1,2,3,4-四氢异喹啉-3-基)甲基)-5,6,7,8-四氢喹啉-8-胺:根据一般脱保护方案实施合成。通过柱色谱(CombiFlash,12g柱,25mL/min)纯化,用以下梯度洗脱以产生澄清油状物(82mg,0.199mmol,收率为49%):0-3min,DCM中0%100∶10∶1 DCM/MeOH/NH4OH;3-15min,DCM中0-100%100∶10∶1DCM/MeOH/NH4OH;15-25min,100%100∶10∶1 DCM/MeOH/NH4OH。1H NMR(500MHz,CDCl3)δ8.51(dd,J=1.5Hz,J=4.5Hz,1H),7.43(d,J=8.0Hz,2H),7.34(dt,J=0.9Hz,J=7.8Hz,1H),7.26(d,J=8.0Hz,2H),7.03-7.07(m,3H),6.96-7.02(m,2H),4.37(d,J=14.0Hz,1H),4.11(dd,J=6.5Hz,J=10.0Hz,1H),3.97(d,J=15.0Hz,1H),3.90(d,J=14.5Hz,1H),3.84(s,2H),3.68(d,J=15.0Hz,1H),2.91(dd,J=2.8Hz,J=13.3Hz,1H),2.74-2.80(m,1H),2.64-2.70(m,2H),2.55(dd,J=3.5Hz,J=16.0Hz,1H),2.36-2.46(m,3H),2.11-2.16(m,1H),1.91-2.00(m,3H),1.62-1.88(m,2H).13C NMR(125MHz,CDCl3)δ158.9,146.9,141.8,140.5,136.5,135.7,134.7,134.2,129.1,128.6(2C),127.1(2C),126.5,125.9,125.5,121.5,62.1,59.2,58.0,52.1,48.6,46.4,33.8,29.6,29.5,22.2.HRMS(NSI)m/z=413.26930(M+H);理论上对于C27H32N4+H=413.26997.LC-MS(ESI-API,254nm)H2O中50-95%MeOH(0.1%HCO2H),8min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=413.3(M+H),207.2(M/2+H),t=0.844min;H2O中10-95%MeOH(0.1%HCO2H),10min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=413.3(M+H),207.2(M/2+H),t=6.354min。
EMU094:(S)-N-(3-(氨基甲基)苄基)-N-(((R)-1,2,3,4-四氢异喹啉-3-基)甲基)-5,6,7,8-四氢喹啉-8-胺:根据一般脱保护3案实施合成。通过柱色谱(CombiFlash,12g柱,25mL/min)纯化,用以下梯度洗脱以产生白色泡沫状物(121mg,0.293mmol,收率为65%):0-3min,DCM中0%100∶10∶1 DCM/MeOH/NH4OH;3-15min,DCM中0-100%100∶10∶1DCM/MeOH/NH4OH;15-25min,100%100∶10∶1 DCM/MeOH/NH4OH。1H NMR(500MHz,CDCl3)δ8.47-8.49(m,1H),7.23-7.39(m,4H),7.14(d,J=7.5Hz,1H),7.01-7.05(m,3H),6.93-6.98(m,2H),4.34-4.43(m,1H),4.08(dd,J=6.5Hz,J=10.5Hz,1H),3.94(d,J=15.0Hz,1H),3.86(d,J=14.5Hz,1H),3.84(s,2H),3.62-3.68(m,1H),2.89(m,1H),2.71-2.77(m,1H),2.60-2.65(m,2H),2.53(dd,J=3.5Hz,J=16.0Hz,1H),2.32-2.44(m,2H),2.09-2.15(m,2H),1.89-1.97(m,3H),1.59-1.68(m,2H).13C NMR(125MHz,CDCl3)δ158.9,146.9,143.3,142.4,136.5,135.8,134.7,134.2,129.1,128.5,127.2,126.9,126.5,125.9,125.5,125.5,121.5,62.3,59.5,58.2,52.1,48.7,46.7,33.9,29.5,29.5,22.2.HRMS(NSI)m/z=413.26977(M+H);理论上对于C27H32N4+H=413.26997.LC-MS(ESI-API,254nm)H2O中50-95%MeOH(0.1%HCO2H),8min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=413.2(M+H),207.2(M/2+H),t=0.885min;H2O中10-95%MeOH(0.1%HCO2H),10min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=413.2(M+H),207.2(M/2+H),t=6.694min。
叔丁基(R)-3-(((4-((1,3-二氧异吲哚啉-2-基)甲基)苄基)((S)-5,6,7,8-四氢喹啉-8-基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯:将(4-(氨基甲基)苯基)甲醇(5.00g,36.4mmol,1.00当量)添加到具有搅拌棒的500mL烧瓶。用THF(121mL)稀释,添加三乙胺(5.08mL,36.4mmol,1.00当量)和乙基1,3-二氧异吲哚啉-2-羧酸酯(7.99g,36.4mmol,1.00当量),并且将所得反应混合物在室温在Ar下剧烈地搅拌过夜。在17hr后,TLC指示起始物质完全转化为一个主要斑点(major spot)。将溶剂在减压下蒸发以产生黄色糊状物,其不经进一步纯化即继续进行。将Dess-Martin高碘烷(17.0g,40.1mmol,1.10当量)添加到具有搅拌棒的500mL烧瓶。用DCM(121mL)稀释白色固体,并且将所得浆液在室温剧烈地搅拌。通过加料漏斗以逐滴方式添加DCM(121mL)中的2-(4-(羟甲基)苄基)异吲哚啉-1,3-二酮(9.74g,36.4mmol,1.00当量)的溶液,并且将所得反应混合物在室温在Ar下剧烈地搅拌。在3hr后,TLC指示起始物质的完全消耗。将反应混合物倾倒入750mL的饱和水性碳酸氢钠和饱和水性硫代硫酸钠的1∶1混合物中。所得有机层用150mL的饱和水性碳酸氢钠和饱和水性硫代硫酸钠的1∶1混合物洗涤一次,用卤水洗涤一次,经无水硫酸钠干燥,过滤,并且在减压下蒸发以产生橙色油状物。一半的粗物质不经进一步提纯即被立即继续进行。1H NMR(400MHz,CDCl3)δ9.99(s,1H),7.84-7.89(m,4H),7.71-7.76(m,2H),7.58(d,J=8.0Hz,2H),4.93(s,2H)。将三乙酰氧基硼氢化钠(11.1g,52.1mmol,3.00当量)添加到具有搅拌棒的500mL烧瓶。用DCM(87.0mL)稀释,并且将所得浆液在室温在Ar下剧烈地搅拌。添加DCM(43.4mL)中的(R)-叔丁基3-((((S)-5,6,7,8-四氢喹啉-8-基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯(6.84g,17.4mmol,1.00当量)的溶液,随后是DCM(43.4mL)中的4-((1,3-二氧异吲哚啉-2-基)甲基)苯甲醛(4.84g,18.3mmol,1.05当量)的溶液,并且将所得反应混合物在室温在Ar下剧烈地搅拌过夜。在15hr后,TLC指示起始物质的完全消耗。反应混合物用DCM稀释,并且用1M水性氢氧化钠洗涤三次。所得水层用DCM萃取两次。合并的有机层用卤水洗涤一次,经无水硫酸钠干燥,过滤,并且在减压下蒸发以产生黄色泡沫状物(11.0g)。将粗物质通过柱色谱(CombiFlash,120g柱,75mL/min)纯化,用以下梯度洗脱以产生白色泡沫状物(7.30g,11.4mmol,收率为65%):0-3min:DCM中0%MeOH;3-8min:DCM中0-1%MeOH;8-13min:DCM中1%MeOH;13-23min:DCM中1-2%MeOH;23-30min:DCM中2%MeOH;30-40min:DCM中2-20%MeOH。1H NMR(600MHz,CDCl3)δ8.40(d,J=14.4Hz,1H),7.85-7.87(m,2H),7.72(dd,J=3.0Hz,J=5.4Hz,2H),7.29-7.30(m,3H),7.19-7.26(m,2H),7.03(app t,J=6.6Hz,1.5H),6.93-6.97(m,3H),6.74(d,J=6.6Hz,0.5H),4.83-4.88(m,2H),4.61-4.76(m,1H),4.36-4.39(m,1H),4.01-4.10(m,1H),3.85-3.88(m,1H),3.60(app t,J=16.2Hz,1H),3.50(d,J=14.4Hz,0.5H),3.36(d,J=17.4Hz,0.5H),2.89-3.09(m,2H),2.80(d,J=16.2Hz,0.5H),2.62-2.66(m,3H),2.48(dd,J=9.6Hz,J=12.0Hz,0.5H),2.25-2.27(m,0.5H),2.08(m,0.5H),1.93-1.95(m,1H),1.75(dd,J=11.7Hz,J=23.1Hz,1H),1.59-1.69(m,1H),1.48(s,4.5H),1.42(s,4.5H).HRMS(NSI)m/z=643.32782(M+H);理论上对于C40H42N4O4+H=643.32788.LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),5min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=643.2(M+H),t=1.137min;H2O中50-95%MeOH(0.1%HCO2H),8min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=643.2(M+H),t=3.216min。
叔丁基(R)-3-((((E)-4-(1,3-二氧异吲哚啉-2-基)丁-2-烯-1-基)((S)-5,6,78-四氢喹啉-8-基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯:将(R)-叔丁基3-((((S)-5,6,7,8-四氢喹啉-8-基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯(4.96g,12.6mmol,1.00当量)添加到配备有搅拌棒和回流冷凝器的250mL烧瓶。用乙腈(126mL)稀释,并且将所得溶液在室温在Ar下剧烈地搅拌。添加(E)-2-(4-溴丁-2-烯-1-基)异吲哚啉-1,3-二酮(4.24g,15.1mmol,1.20当量)、碘化钾(0.209g,1.26mmol,0.100当量)和二异丙基乙胺(4.39mL,25.2mmol,2.00当量),升温至50℃,并且将所得反应混合物在Ar下搅拌过夜。在19hr后,TLC指示起始物质完全转化为一个主要斑点。反应混合物用卤水洗涤一次,并且所得水层用DCM萃取3次。合并的有机层用卤水洗涤一次,经无水硫酸钠干燥,过滤,并且在减压下蒸发以产生棕色油状物。通过柱色谱(CombiFlash,120g柱,75mL/min)纯化,用以下梯度洗脱以产生黄色泡沫状物(3.78g,6.38mmol,收率为51%):0-3min:DCM中0%100∶10∶1DCM/MeOH/NH4OH;3-18min:DCM中0-100%100∶10∶1 DCM/MeOH/NH4OH;18-30min:DCM中100%100∶10∶1 DCM/MeOH/NH4OH。1H NMR(600MHz,CDCl3)δ8.34(br s,1H),7.83-7.88(m,2H),7.71-7.78(m,2H),7.19(d,J=7.2Hz,1H),7.07-7.08(m,2H),6.98-7.03(m,2H),6.92(dd,J=4.8Hz,J=7.8Hz,1H),5.75-5.76(m,1H),5.57(dt,J=6.0Hz,J=15.6Hz,1H),4.61-4.67(m,1.5H),4.40(br s,0.5H),4.18(d,J=6.0Hz,2H),4.06-4.10(m,1H),3.91(m,1H),3.33-3.40(m,1H),3.14-3.15(m,1H),2.89-3.00(m,2H),2.60-2.67(m,2H),2.44-2.57(m,2H),1.91-1.98(m,2H),1.57-1.71(m,2H),1.47(s,9H).LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),5min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=593.2(M+H),t=0.709min;H2O中50-95%MeOH(0.1%HCO2H),8min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=593.2(M+H),t=2.762min。
叔丁基(R)-3-(((4-(氨基甲基)苄基)((S)-5,6,7,8-四氢喹啉-8-基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯:将(R)-叔丁基3-(((4-((1,3-二氧异吲哚啉-2-基)甲基)苄基)((S)-5,6,7,8-四氢喹啉-8-基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯(0.769g,1.20mmol,1.00当量)添加到具有搅拌棒的50mL烧瓶。用MeOH(12.0mL)稀释,添加小体积的DCM以迫使(coerce)所有起始物质变为溶液,并且将所得溶液在室温在Ar下剧烈地搅拌。通过注射泵以4mL/hr的速率以逐滴方式添加水(以wt.计24%)中的肼(1.29ml,9.57mmol,8.00当量)的溶液,并且将所得反应混合物在室温在Ar下剧烈地搅拌过夜。在17hr后,TLC指示起始物质几乎完全转化为一个主要产物斑点。将反应混合物在DCM和1M水性氢氧化钠之间分隔。所得水层用DCM萃取3次,并且合并的有机层经无水硫酸钠干燥,过滤,并且在减压下蒸发以产生黄色泡沫状物(617mg)。粗物质通过柱色谱(CombiFlash,24g柱,30mL/min)纯化,用以下梯度洗脱以产生白色泡沫状物(474mg,0.925mmol,收率为77%):0-3min:DCM中0%100∶10∶1 DCM/MeOH/NH4OH;3-18min:DCM中0-100%100∶10∶1DCM/MeOH/NH4OH;18-30min:100%100∶10∶1 DCM/MeOH/NH4OH。1H NMR(500MHz,CDCl3)δ8.43(d,J=10.0Hz,1H),7.29-7.34(m,2H),7.25(d,J=7.5Hz,1H),7.19-7.20(m,2H),7.04-7.09(m,2H),6.82-7.00(m,3H),4.65-4.78(m,1H),4.45-4.52(m,1H),3.89-4.10(m,2H),3.85(s,2H),3.57-3.81(m,2H),2.86-3.05(m,2H),2.52-2.75(m,3H),2.10-2.24(m,1H),1.94-1.95(m,1H),1.79(app p,J=11.0Hz,1H),1.42-1.66(m,12H).HRMS(NSI)m/z=513.32201(M+H);理论上对于C32H40N4O2+H=513.32240.LC-MS(ESI-API,254nm)H2O中50-95%MeOH(0.1%HCO2H),6min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=513.2(M+H),457.2(M-tBu+H),413.2(M-Boc+H),257.1(M/2+H),t=0.854min;H2O中25-95%MeOH(0.1%HCO2H),8min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=513.2(M+H),457.2(M-tBu+H),413.2(M-Boc+H),257.1(M/2+H),t=4.136min。
叔丁基(R)-3-((((E)-4-氨基丁-2-烯-1-基)((S)-5,6,7,8-四氢喹啉-8-基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯:将(R)-叔丁基3-((((E)-4-(1,3-二氧异吲哚啉-2-基)丁-2-烯-1-基)((S)-5,6,7,8-四氢喹啉-8-基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯(3.76g,6.34mmol,1.00当量)添加到具有搅拌棒的500mL烧瓶。起始物质用MeOH(63.4mL)稀释,并且将所得溶液在室温在Ar下剧烈地搅拌。通过注射泵以6mL/hr的速率以逐滴方式添加水(以wt.计24%)中的肼(6.78mL,50.7mmol,8.00当量)的溶液,并且将所得反应混合物在室温在Ar下剧烈地搅拌过夜。在23hr后,将反应混合物在DCM和1M水性氢氧化钠之间分隔。所得水层用DCM萃取3次,并且合并的有机层经无水硫酸钠干燥,过滤,并且在减压下蒸发以产生白色泡沫状物(2.64g)。粗物质通过柱色谱(CombiFlash,80g柱,50mL/min)纯化,用以下梯度洗脱以产生白色泡沫状物(2.23g,4.81mmol,收率为76%):0-3min:DCM中0%100∶10∶1 DCM/MeOH/NH4OH;3-18min:DCM中0-100%100∶10∶1 DCM/MeOH/NH4OH;18-40min:DCM中100%100∶10∶1 DCM/MeOH/NH4OH。1H NMR(500MHz,CDCl3)δ8.39(d,J=17.5Hz,1H),7.25(d,J=6.5Hz,1H),7.06-7.11(m,2H),6.98-7.03(m,3H),5.55-5.64(m,2H),4.68(dd,J=17.8Hz,J=26.8Hz,1.5H),4.47(br s,0.5H),4.10(app t,J=15.3Hz,1H),3.98(dd,J=6.0Hz,J=8.5Hz,1H),3.27-3.35(m,1H),3.18(d,J=4.5Hz,2H),3.09(dd,J=4.5Hz,J=14.0Hz,1H),2.92-3.03(m,2H),2.63-2.72(m,2H),2.51-2.59(m,2H),1.92-2.02(m,2H),1.74(dd,J=10.5Hz,J=21.0Hz,1H),1.58-1.66(m,1H),1.50(s,9H),1.26-1.42(m,2H).HRMS(NSI)m/z=463.30612(M+H);理论上对于C28H38N4O2+H=463.30675.LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),5min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=463.2(M+H),t=0.558min;H2O中50-95%MeOH(0.1%HCO2H),8min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=463.2(M+H),363.2(M-Boc+H),232.2(M/2+H),t=0.719min。
叔丁基(R)-3-(((4-((((四氢-2H-吡喃-4-基)甲基)氨基)甲基)苄基)((S)-5,6,7,8-四氢喹啉-8-基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯:根据一般还原胺化方案B实施合成。通过柱色谱(CombiFlash,24g柱,30mL/min)纯化,用以下梯度洗脱以产生澄清油状物(110mg,0.180mmol,收率为37%):0-3min:DCM中0%100∶10∶1 DCM/MeOH/NH4OH;3-18min:DCM中0-100%100∶10∶1 DCM/MeOH/NH4OH;18-30min:100%100∶10∶1 DCM/MeOH/NH4OH。1H NMR(500MHz,CDCl3)δ8.43(d,J=10.0Hz,1H),7.29-7.32(m,2H),7.24(d,J=7.0Hz,1H),7.19(br s,2H),7.04-7.07(m,2H),6.81-7.00(m,3H),4.65-4.78(m,1H),4.45-4.50(m,1H),3.89-4.09(m,4H),3.57-3.81(m,4H),3.40(dt,J=1.8Hz,J=11.8Hz,2H),2.85-3.03(m,3H),2.57-2.75(m,3H),2.54(d,J=7.0Hz,2H),2.10-2.24(m,1H),1.93-1.95(m,1H),1.71-1.78(m,2H),1.66-1.67(m,3H),1.46-1.58(m,10H),1.26-1.36(m,2H).HRMS(NSI)m/z=611.39646(M+H);理论上对于C38H50N4O3+H=611.39557.LC-MS(ESI-API,254nm)H2O中50-95%MeOH(0.1%HCO2H),6min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=611.2(M+H),306.2(M/2+H),t=1.126min;H2O中25-95%MeOH(0.1%HCO2H),8min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=611.2(M+H),306.2(M/2+H),t=4.534min。
叔丁基(R)-3-(((4-(((4,4-二甲基环己基)氨基)甲基)苄基)((S)-5,67,8-四氢喹啉-8-基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯:根据一般还原胺化方案C实施合成。通过柱色谱(CombiFlash,24g柱,30mL/min)纯化,用以下梯度洗脱以产生白色泡沫状物(166mg,0.267mmol,收率为59%):0-3min:DCM中0%100∶10∶1 DCM/MeOH/NH4OH;3-18min:DCM中0-100%100∶10∶1 DCM/MeOH/NH4OH;18-30min:100%100∶10∶1 DCM/MeOH/NH4OH。1HNMR(500MHz,CDCl3)δ8.43(d,J=9.0Hz,1H),7.23-7.31(m,3H),7.19(br s,2H),7.05-7.07(m,2H),6.82-7.00(m,3H),4.65-4.79(m,1H),4.44-4.51(m,1H),4.00-4.11(m,1H),3.89-3.92(m,1H),3.79(s,2H),3.56-3.75(m,2H),3.02-3.05(m,1H),2.71-2.99(m,2H),2.52-2.74(m,3H),2.46(m,1H),2.10-2.24(m,1H),1.94-1.95(m,1H),1.63-1.77(m,5H),1.46-1.58(m,9H),1.32-1.43(m,4H),1.18-1.24(m,2H),0.92(s,3H),0.91(s,3H).HRMS(NSI)m/z=623.43140(M+H);理论上对于C40H54N4O2+H=623.43195.LC-MS(ESI-API,254nm)H2O中50-95%MeOH(0.1%HCO2H),8min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=623.3(M+H),312.2(M/2+H),t=2.592min;H2O中25-95%MeOH(0.1%HCO2H),8min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=623.2(M+H),312.2(M/2+H),t=5.806min。
叔丁基(R)-3-(((4-(((4,4-二氟环己基)氨基)甲基)苄基)((S)-5,67,8-四氢喹啉-8-基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯:根据一般还原胺化3案C实施合成。通过柱色谱(CombiFlash,24g柱,30mL/min)纯化,用以下梯度洗脱以产生澄清油状物(238mg,0.377mmol,收率为84%):0-3min:DCM中0%100∶10∶1 DCM/MeOH/NH4OH;3-18min:DCM中0-100%100∶10∶1 DCM/MeOH/NH4OH;18-30min:100%100∶10∶1 DCM/MeOH/NH4OH。1HNMR(500MHz,CDCl3)δ8.43(d,J=9.5Hz,1H),7.30-7.32(m,2H),7.24(d,J=7.5Hz,1H),7.19(m,2H),7.04-7.07(m,2H),6.82-7.00(m,3H),4.65-4.77(m,1H),4.45-4.52(m,1H),3.90-4.08(m,2H),3.59-3.82(m,4H),2.87-3.03(m,2H),2.53-2.75(m,4H),2.10-2.24(m,3H),1.90-1.94(m,3H),1.71-1.87(m,4H),1.64-1.66(m,1H),1.46-1.60(m,12H).HRMS(NSI)m/z=631.38184(M+H);理论上C38H48F2N4O2+H=631.38181.LC-MS(ESI-API,254nm)H2O中50-95%MeOH(0.1%HCO2H),8min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=631.2(M+H),316.2(M/2+H),t=1.620min;H2O中25-95%MeOH(0.1%HCO2H),8min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=631.2(M+H),316.2(M/2+H),t=4.864min。
叔丁基(R)-3-(((4-(((四氢-2H-吡喃-4-基)氨基)甲基)苄基)((S)-5,6,78-四氢喹啉-8-基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯:根据一般还原胺化方案C实施合成。通过柱色谱(CombiFlash,24g柱,30mL/min)纯化,用以下梯度洗脱以产生白色泡沫状物(220mg,0.369mmol,收率为76%):0-3min:DCM中0%100∶10∶1 DCM/MeOH/NH4OH;3-18min:DCM中0-100%100∶10∶1 DCM/MeOH/NH4OH;18-30min:100%100∶10∶1 DCM/MeOH/NH4OH。1HNMR(500MHz,CDCl3)δ8.43(d,J=9.0Hz,1H),7.29-7.32(m,2H),7.24(d,J=7.5Hz,1H),7.20(br s,2H),7.04-7.07(m,2H),6.83-7.00(m,3H),4.66-4.77(m,1H),4.45-4.52(m,1H),3.90-4.08(m,4H),3.59-3.85(m,4H),3.41(dt,J=2.0Hz,J=11.8Hz,2H),2.86-3.03(m,3H),2.53-2.78(m,4H),2.11-2.22(m,1H),1.93(m,1H),1.87(dd,J=1.5Hz,J=12.5Hz,2H),1.78(app p,J=10.3Hz,1H),1.64-1.65(m,1H),1.43-1.58(m,12H).HRMS(NSI)m/z=597.38109(M+H);理论上对于C37H48N4O3+H=597.37992.LC-MS(ESI-API,254nm)H2O中50-95%MeOH(0.1%HCO2H),6min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=597.2(M+H),299.2(M/2+H),t=0.906min;H2O中25-95%MeOH(0.1%HCO2H),8min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=597.2(M+H),299.2(M/2+H),t=4.219min。
叔丁基(R)-3-(((4-(((吡啶-4-基甲基)氨基)甲基)苄基)((S)-5,6,7,8-四氢喹啉-8-基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯:根据一般还原胺化方案B实施合成。通过柱色谱(CombiFlash,24g柱,30mL/min)纯化,用以下梯度洗脱以产生白色泡沫状物(192mg,0.318mmol,收率为65%):0-3min:DCM中0%100∶10∶1 DCM/MeOH/NH4OH;3-18min:DCM中0-100%100∶10∶1DCM/MeOH/NH4OH;18-30min:100%100∶10∶1 DCM/MeOH/NH4OH。1HNMR(500MHz,CDCl3)δ8.56-8.57(m,2H),8.44(d,J=10.0Hz,1H),7.31-7.32(m,4H),7.22-7.26(m,3H),7.04-7.05(m,2H),6.78-7.00(m,3H),4.65-4.78(m,1H),4.46-4.52(m,1H),3.87-4.09(m,2H),3.83(s,2H),3.56-3.79(4H),2.72-3.03(m,3H),2.53-2.70(m,3H),2.12-2.25(m,1H),1.94(m,1H),1.65-1.81(m,3H),1.53(s,4.5H),1.46(s,4.5H).HRMS(NSI)m/z=604.36456(M+H);理论上对于C38H45N5O2+H=604.36460.LC-MS(ESI-API,254nm)H2O的75-95%MeOH(0.1%HCO2H),5min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=604.2(M+H),302.8(M/2+H),t=0.553min;H2O中25-95%MeOH(0.1%HCO2H),8min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=604.2(M+H),302.6(M/2+H),t=4.253min。
叔丁基(R)-3-(((4-(((吡啶-3-基甲基)氨基)甲基)苄基)((S)-5,6,7,8-四氢喹啉-8-基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯:根据一般还原胺化方案B实施合成。通过柱色谱(CombiFlash,24g柱,30mL/min)纯化,用以下梯度洗脱以产生白色泡沫状物(179mg,0.296mmol,收率为61%):0-3min:DCM中0%100∶10∶1 DCM/MeOH/NH4OH;3-18min:DCM中0-100%100∶10∶1 DCM/MeOH/NH4OH;18-30min:100%100∶10∶1 DCM/MeOH/NH4OH。1HNMR(500MHz,CDCl3)δ8.59(br s,1H),8.52(dd,J=1.5Hz,J=4.5Hz,1H),8.43(d,J=9.5Hz,1H),7.72(dt,J=1.8Hz,J=7.8Hz,1H),7.30-7.32(m,2H),7.27(dd,J=5.0Hz,J=7.5Hz,1H),7.22-7.25(m,3H),7.04-7.05(m,2H),6.78-7.00(m,3H),4.65-4.78(m,1H),4.45-4.52(m,1H),3.86-4.09(m,2H),3.82(s,2H),3.58-3.80(m,4H),2.71-3.04(m,3H),2.53-2.70(m,3H),2.11-2.24(m,1H),1.95(m,1H),1.65-1.80(m,3H),1.53(s,4.5H),1.46(s,4.5H).HRMS(NSI)m/z=604.36444(M+H);理论上对于C38H45N5O2+H=604.36460.LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),5min,1.00mL/min,C18(Agilent ZorbaxXDB-18,50mm×4.6mm,3.5μm),m/z=604.2(M+H),302.6(M/2+H),t=0.592min;H2O中25-95%MeOH(0.1%HCO2H),8min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=604.2(M+H),302.6(M/2+H),t=4.309min。
叔丁基(R)-3-(((4-(((吡啶2-基甲基)氨基)甲基)苄基)((S)-5,6,7,8-四氢喹啉-8-基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯:根据一般还原胺化方案B实施合成。通过柱色谱(CombiFlash,24g柱,30mL/min)纯化,用以下梯度洗脱以产生黄色泡沫状物(181mg,0.300mmol,收率为62%):0-3min:DCM中0%100∶10∶1 DCM/MeOH/NH4OH;3-18min:DCM中0-100%100∶10∶1 DCM/MeOH/NH4OH;18-30min:100%100∶10∶1 DCM/MeOH/NH4OH。1HNMR(500MHz,CDCl3)δ8.58(d,J=5.0Hz,1H),8.43(d,J=10.0Hz,1H),7.65(dt,J=1.8Hz,J=7.9Hz,1H),7.34(d,J=8.0Hz,1H),7.29-7.31(m,2H),7.25(m,3H),7.17(dd,J=4.5Hz,J=7.5Hz,1H),7.04-7.06(m,2H),6.79-7.00(m,3H),4.65-4.79(m,1H),4.44-4.50(m,1H),3.99-4.11(m,1H),3.95(s,2H),3.89-3.92(m,1H),3.84(app d,J=4.0Hz,2H),3.56-3.71(m,2H),3.02-3.09(m,1H),2.91-2.99(m,1H),2.72-2.87(m,1H),2.52-2.69(m,3H),2.11-2.26(m,2H),1.94-1.95(m,1H),1.77-1.80(m,1H),1.58-1.69(m,1H),1.53(s,4.5H),1.46(s,4.5H).HRMS(NSI)m/z=604.36452(M+H);理论上对于C38H45N5O2+H=604.36460.LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),5min,1.00mL/min,C18(Agilent ZorbaxXDB-18,50mm×4.6mm,3.5μm),m/z=604.2(M+H),302.6(M/2+H),t=0.535min;H2O中25-95%MeOH(0.1%HCO2H),8min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=604.2(M+H),302.7(M/2+H),t=4.604min。
EMU216:(S)-N-(4-((((四氢-2H-吡喃-4-基)甲基)氨基)甲基)苄基)-N-(((R)-1,2,3,4-四氢异喹啉-3-基)甲基)-5,6,7,8-四氢喹啉-8-胺:根据一般脱保护方案实施合成。通过柱色谱(CombiFlash,12g柱,25mL/min)纯化,用以下梯度洗脱以产生澄清油状物(81.0mg,0.159mmol,收率为88%):0-3min:DCM中0%100∶10∶1 DCM/MeOH/NH4OH;3-18min:DCM中0-100%100∶10∶1 DCM/MeOH/NH4OH;18-30min:100%100∶10∶1 DCM/MeOH/NH4OH。1HNMR(500MHz,CDCl3)δ8.51(d,J=4.0Hz,1H),7.42(d,J=7.5Hz,2H),7.33(d,J=7.5Hz,1H),7.25(d,J=8.0Hz,2H),7.04-7.08(m,3H),6.95-7.01(m,2H),4.38(d,J=14.0Hz,1H),4.11(dd,J=6.5Hz,J=9.5Hz,1H),3.90-3.98(m,4H),3.76(s,2H),3.67(d,J=15.0Hz,1H),3.38(dt,J=1.3Hz,J=11.8Hz,2H),2.90(dd,J=2.8Hz,J=13.3Hz,1H),2.73-2.80(m,1H),2.63-2.68(m,2H),2.55(dd,J=3.5Hz,J=16.0Hz,1H),2.51(d,J=7.0Hz,2H),2.35-2.48(m,2H),2.12-2.16(m,1H),1.91-1.99(m,3H),1.66-1.76(m,2H),1.62-1.65(m,2H),1.25-1.33(m,3H).13C NMR(125MHz,CDCl3)δ159.0,146.9,140.8,139.0,136.6,135.7,134.7,134.2,129.2,128.5(2C),128.1(2C),126.5,126.0,125.5,121.5,68.0(2C),62.4,59.4,58.1,55.7,54.0,52.1,48.7,35.6,33.9,31.5(2C),29.7,29.6,22.2.HRMS(NSI)m/z=511.34459(M+H);理论上对于C33H424O+H=511.34314.LC-MS(ESI-API,254nm)H2O中25-95%MeOH(0.1%HCO2H),8min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=511.2(M+H),256.2(M/2+H),t=0.722min;H2O中10-95%MeOH(0.1%HCO2H),10min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=511.2(M+H),256.2(M/2+H),t=3.070min。
EMU181:(S)-N-(4-(((4,4-二甲基环己基)氨基)甲基)苄基)-N-(((R)-1,2,3,4-四氢异喹啉-3-基)甲基)-5,6,7,8-四氢喹啉-8-胺:根据一般脱保护3案实施合成。通过柱色谱(CombiFlash,12g柱,25mL/min)纯化,用以下梯度洗脱以产生白色泡沫状物(99.0mg,0.189mmol,收率为71%):0-3min:DCM中0%100∶10∶1 DCM/MeOH/NH4OH;3-18min:DCM中0-100%100∶10∶1 DCM/MeOH/NH4OH;18-30min:100%100∶10∶1 DCM/MeOH/NH4OH。1H NMR(500MHz,CDCl3)δ8.51(dd,J=1.5Hz,J=5.0Hz,1H),7.41(d,J=8.0Hz,2H),7.33(dt,J=0.8Hz,J=7.8Hz,1H),7.26(d,J=8.0Hz,2H),7.04-7.08(m,3H),6.95-7.02(m,2H),4.40(d,J=14.0Hz,1H),4.10(dd,J=6.5Hz,J=10.0Hz,1H),3.94(dd,J=14.3Hz,J=26.3Hz,2H),3.79(s,2H),3.69(d,J=15.0Hz,1H),2.89(dd,J=2.8Hz,J=13.3Hz,1H),2.63-2.79(m,4H),2.55(dd,J=3.5Hz,J=16.0Hz,1H),2.35-2.47(m,3H),2.10-2.15(m,1H),1.90-1.99(m,2H),1.70-1.75(m,2H),1.61-1.69(m,1H),1.37-1.40(m,2H),1.27-1.34(m,3H),1.19(dt,J=3.5Hz,J=12.8Hz,2H),0.91(s,3H),0.90(s,3H).13C NMR(125MHz,CDCl3)δ159.0,146.9,140.6,139.4,136.5,135.8,134.8,134.2129.2,128.5(2C),128.1(2C),126.5,125.9,125.5,121.5,62.2,59.4,58.0,56.5,52.1,51.1,48.7,37.9,33.9,32.3,30.3,29.8,29.5,29.4,25.0,22.2.HRMS(NSI)m/z=523.37923(M+H);理论上对于C35H46N4+H=523.37952.LC-MS(ESI-API,254nm)H2O中25-95%MeOH(0.1%HCO2H),8min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=523.2(M+H),262.2(M/2+H),t=3.052min;H2O中10-95%MeOH(0.1%HCO2H),10min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=523.2(M+H),262.2(M/2+H),t=4.873min。
EMU182:(S)-N-(4-(((4,4-二氟环己基)氨基)甲基)苄基)-N-(((R)-1,2,3,4-四氢异喹啉-3-基)甲基)-5,6,7,8-四氢喹啉-8-胺:根据一般脱保护方案实施合成。通过柱色谱(CombiFlash,12g柱,25mL/min)纯化,用以下梯度洗脱以产生白色泡沫状物(147mg,0.277mmol,收率为73%):0-3min:DCM中0%100∶10∶1 DCM/MeOH/NH4OH;3-18min:DCM中0-100%100∶10∶1 DCM/MeOH/NH4OH;18-30min:100%100∶10∶1 DCM/MeOH/NH4OH。1H NMR(500MHz,CDCl3)δ8.51(dd,J=1.5Hz,J=5.0Hz,1H),7.43(d,J=8.0Hz,2H),7.33(dt,J=0.8Hz,J=7.5Hz,1H),7.26(d,J=8.0Hz,2H),7.04-7.08(m,3H),6.95-7.02(m,2H),4.39(d,J=14.5Hz,1H),4.10(dd,J=6.8Hz,J=10.3Hz,1H),3.94(dd,J=14.8Hz,J=24.8Hz,2H),3.78(s,2H),3.68(d,J=15.0Hz,1H),2.90(dd,J=3.0Hz,J=13.0Hz,1H),2.74-2.80(m,2H),2.63-2.70(m,3H),2.55(dd,J=3.5Hz,J=16.0Hz,1H),2.35-2.45(m,2H),2.07-2.16(m,3H),1.88-1.99(m,4H),1.65-1.80(m,4H),1.50-1.58(m,2H).13C NMR(125MHz,CDCl3)δ158.9,146.9,140.9,138.9,136.5,135.7,134.7,134.2,129.1,128.6(2C),128.0(2C),126.5,125.9,125.5,123.5(t,J=239.4Hz),121.5,62.3,59.4,58.0,53.2,52.1,51.2,48.7,33.9,31.5(t,J=23.8Hz,2C),29.6,29.5,28.8(t,J=4.4Hz,2C),22.2.19F NMR(376MHz,CDCl3,TFA标准)δ-95.7(app d,J=236.9Hz),-98.6(app d,J=229.4Hz).HRMS(NSI)m/z=531.32872(M+H);理论上对于C33H40F2N4+H=531.32938.LC-MS(ESI-API,254nm)H2O中25-95%MeOH(0.1%HCO2H),8min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=531.2(M+H),266.2(M/2+H),t=1.124min;H2O中10-95%MeOH(0.1%HCO2H),10min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=531.2(M+H),266.2(M/2+H),t=3.512min。
EMU217:(S)-N-(4-(((四氢-2H-吡喃-4-基)氨基)甲基)苄基)-N-(((R)-1,2,3,4-四氢异喹啉-3-基)甲基)-5,6,7,8-四氢喹啉-8-胺:根据一般脱保护方案实施合成。通过柱色谱(CombiFlash,12g柱,25mL/min)纯化,用以下梯度洗脱以产生白色泡沫状物(159mg,0.320mmol,收率为87%)。0-3min:DCM中0%100∶10∶1 DCM/MeOH/NH4OH;3-18min:DCM中0-100%100∶10∶1 DCM/MeOH/NH4OH;18-30min:100%100∶10∶1 DCM/MeOH/NH4OH。1H NMR(500MHz,CDCl3)δ8.51(d,J=3.5Hz,1H),7.43(d,J=8.0Hz,2H),7.33(dd,J=0.5Hz,J=7.5Hz,1H),7.26(d,J=7.0Hz,2H),7.04-7.07(m,3H),6.95-7.01(m,2H),4.39(d,J=14.0Hz,1H),4.10(dd,J=6.5Hz,J=10.0Hz,1H),3.90-3.98(m,4H),3.81(s,2H),3.68(d,J=15.0Hz,1H),3.70(dt,J=2.0Hz,J=11.8Hz,2H),2.90(dd,J=2.5Hz,J=8.3Hz,1H),2.64-2.80(m,5H),2.55(dd,J=3.5Hz,J=16.0Hz,1H),2.35-2.45(m,2H),2.11-2.15(m,1H),1.91-1.99(m,2H),1.83-1.86(m,2H),1.62-1.70(m,1H),1.26-1.49(m,3H).13C NMR(125MHz,CDCl3)δ158.9,146.9,140.7,138.9,136.5,135.7,134.7,134.1,129.1,128.5(2C),128.0(2C),126.4,125.9,125.5,121.4,66.8(2C),62.2,59.3,58.0,53.2,52.1,50.3,48.7,33.9,33.8,33.8,29.6,29.5,22.2.HRMS(NSI)m/z=497.32792(M+H);理论上对于C32H40N4O+H=497.32749 LC-MS(ESI-API,254nm)H2O中25-95%MeOH(0.1%HCO2H),8min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=497.2(M+H),249.2(M/2+H),t=0.631min;H2O中10-95%MeOH(0.1%HCO2H),10min,1.00mL/min,C18(AgilentZorbax XDB-18,50mm×4.6mm,3.5μm),m/z=497.2(M+H),249.2(M/2+H),t=2.688min。
EMU218:(S)-N-(4-(((吡啶-4-基甲基)氨基)甲基)苄基)-N-(((R)-1,2,3,4-四氢异喹啉-3-基)甲基)-5,6,7,8-四氢喹啉-8-胺:根据一般脱保护3案实施合成。通过柱色谱(CombiFlash,12g柱,25mL/min)纯化,用100∶10∶1 DCM/MeOH/NH4OH洗脱以产生白色泡沫状物(132mg,0.262mmol,收率为82%)。1H NMR(500MHz,CDCl3)δ8.54-8.55(m,2H),8.52(d,J=4.5Hz,1H),8.45(d,J=8.0Hz,2H),7.34(d,J=7.5Hz,1H),7.27-7.29(m,4H),6.99-7.08(m,3H),6.93-7.00(m,2H),4.38(d,J=14.0Hz,1H),4.11(dd,J=6.8Hz,J=9.8Hz,1H),3.94(app t,J=15.8Hz,2H),3.80(s,2H),3.79(s,2H),3.66(d,J=15.0Hz,1H),2.90(dd,J=2.3Hz,J=13.3Hz,1H),2.74-2.80(m,1H),2.62-2.68(m,2H),2.55(dd,J=3.0Hz,J=16.0Hz,1H),2.43(dd,J=11.0Hz,J=12.5Hz,1H),2.37(dd,J=11.3Hz,J=15.8Hz,1H),2.13-2.17(m,1H),1.92-1.99(m,3H),1.64-1.71(m,2H).13C NMR(125MHz,CDCl3)δ158.9,149.9(2C),149.5,146.9,141.1,138.3,136.5,135.7,134.7,134.2,129.1,128.6(2C),128.1(2C),126.5,125.9,125.5,123.1(2C),121.5,62.4,59.4,58.1,53.1,52.1,51.8,48.7,33.9,29.5,29.5,22.2.HRMS(NSI)m/z=504.31252(M+H);理论上对于C33H37N5+H=504.31217.LC-MS(ESI-API,254nm)H2O中25-95%MeOH(0.1%HCO2H),8min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=504.2(M+H),252.6(M/2+H),t=0.636min;H2O中10-95%MeOH(0.1%HCO2H),10min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=504.2(M+H),252.7(M/2+H),t=2.506min。
EMU219:(S)-N-(4-(((吡啶-3-基甲基)氨基)甲基)苄基)-N-(((R)-1,2,3,4-四氢异喹啉-3-基)甲基)-5,6,7,8-四氢喹啉-8-胺:根据一般脱保护3案实施合成。通过柱色谱(CombiFlash,12g柱,25mL/min)纯化,用100∶10∶1 DCM/MeOH/NH4OH洗脱以产生白色泡沫状物(137mg,0.272mmol,收率为92%)。1H NMR(500MHz,CDCl3)δ8.57(m,1H),8.50-8.52(m,2H),7.67-7.70(m,1H),7.44(d,J=7.5Hz,2H),7.33(d,J=7.5Hz,1H),7.24-7.29(m,3H),7.02-7.08(m,3H),6.92-7.01(m,2H),4.39(d,J=14.0Hz,1H),4.10(dd,J=6.8Hz,J=10.3Hz,1H),3.94(dd,J=14.8Hz,J=18.8Hz,2H),3.80(s,2H),3.79(s,2H),3.67(d,J=15.0Hz,1H),2.90(dd,J=2.5Hz,J=13.0Hz,1H),2.74-2.80(m,2H),2.63-2.67(m,2H),2.55(dd,J=3.0Hz,J=16.0Hz,1H),2.43(dd,J=10.5Hz,J=13.0Hz,1H),2.37(dd,J=11.0Hz,J=16.0Hz,1H),2.12-2.16(m,1H),1.91-1.99(m,3H),1.62-1.71(m,1H).13C NMR(125MHz,CDCl3)δ158.9,149.8,148.5,146.9,141.0,138.4,136.5,135.9,135.8,134.7,134.2,129.1,128.6(2C),128.1(2C),126.5,125.9,125.5,123.5,121.5,62.3,59.4,58.1,53.1,52.1,50.4,48.7,33.9,29.6,29.5,22.2.HRMS(NSI)m/z=504.31292(M+H);理论上对于C33H37N5+H=504.31217.LC-MS(ESI-API,254nm)H2O中25-95%MeOH(0.1%HCO2H),8min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=504.2(M+H),252.6(M/2+H),t=0.663min;H2O中10-95%MeOH(0.1%HCO2H),10min,1.00mL/min,C18(AgilentZorbax XDB-18,50mm×4.6mm,3.5μm),m/z=504.2(M+H),252.6(M/2+H),t=2.495min。
EMU220:(S)-N-(4-(((吡啶-2-基甲基)氨基)甲基)苄基)-N-(((R)-1,2,3,4-四氢异喹啉-3-基)甲基)-5,6,7,8-四氢喹啉-8-胺:根据一般脱保护方案实施合成。通过柱色谱(CombiFlash,12g柱,25mL/min)纯化,用100∶10∶1 DCM/MeOH/NH4OH洗脱以产生白色泡沫状物(106mg,0.210mmol,收率为70%)。1H NMR(500MHz,CDCl3)δ8.56-8.57(m,1H),8.51(d,J=4.5Hz,1H),7.63(dt,J=1.8Hz,J=7.8Hz,1H),7.43(d,J=8.0Hz,2H),7.29-7.34(m,4H),7.15-7.17(m,1H),7.02-7.07(m,3H),6.94-7.01(m,2H),4.42(d,J=14.0Hz,1H),4.10(dd,J=6.5Hz,J=10.0Hz,1H),3.94(dd,J=15.0Hz,J=17.5Hz,2H),3.92(s,2H),3.84(s,2H),3.68(d,J=14.5Hz,1H),2.73-2.91(m,3H),2.63-2.71(m,2H),2.55(dd,J=3.5Hz,J=16.0Hz,1H),2.35-2.44(m,2H),2.11-2.15(m,2H),1.91-1.98(m,2H),1.62-1.71(m,1H).13CNMR(125MHz,CDCl3)δ159.9,159.0,149.4,146.9,140.8,138.6,136.5,135.8,134.8,134.2,129.1,128.5(2C),128.3(2C),126.5,125.9,125.5,122.4,122.0,121.4,62.2,59.4,58.0,54.6,53.4,52.1,48.7,33.9,29.7,29.5,22.2.HRMS(NSI)m/z=504.31269(M+H);理论上对于C33H37N5+H=504.31217.LC-MS(ESI-API,254nm)H2O中25-95%MeOH(0.1%HCO2H),8min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=504.2(M+H),252.6(M/2+H),t=0.852min;H2O中10-95%MeOH(0.1%HCO2H),10min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=504.2(M+H),252.6(M/2+H),t=3.286min。
叔丁基(R)-3-((((E)-4-(((四氢-2H-吡喃-4-基)甲基)氨基)丁-2-烯-1-基)((S)-5,6,7,8-四氢喹啉-8-基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯:根据一般还原胺化方案B实施合成。通过柱色谱(CombiFlash,24g柱,30mL/min)纯化,用以下梯度洗脱以产生澄清油状物(120mg,0.214mmol,收率为40%):0-3min:DCM中0%100∶10∶1 DCM/MeOH/NH4OH;3-18min:DCM中0-100%100∶10∶1 DCM/MeOH/NH4OH;18-30min:100%100∶10∶1DCM/MeOH/NH4OH。1H NMR(500MHz,CDCl3)δ8.39(d,J=14.0Hz,1H),7.24(d,J=7.0Hz,1H),7.05-7.10(m,2H),6.97(m,3H),5.58-5.70(m,2H),4.45-4.69(m,2H),4.04-4.09(m,1H),3.95-3.97(m,3H),3.35-3.41(m,3H),3.09-3.19(m,3H),2.91-3.00(m,2H),2.65-2.71(m,1H),2.49-2.61(m,3H)2.46(d,J=6.5Hz,2H),1.91-1.98(m,2H),1.53-1.77(m,6H),1.49(s,9H),1.28(ddd,J=4.5Hz,J=12.3Hz,J=24.0Hz,2H).HRMS(NSI)m/z=561.37977(M+H);理论上对于C34H48N4O3+H=561.37992.LC-MS(ESI-API,254nm)H2O中50-95%MeOH(0.1%HCO2H),8min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=561.2(M+H),281.2(M/2+H),t=0.793min;H2O中25-95%MeOH(0.1%HCO2H),8min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=561.2(M+H),281.2(M/2+H),t=3.987min。
叔丁基(R)-3-((((E)-4-((4,4-二甲基环己基)氨基)丁-2-烯-1-基)((S)-5,6,7,8-四氢喹啉-8-基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯:根据一般还原胺化方案C实施合成。通过柱色谱(CombiFlash,24g柱,30mL/min)纯化,用以下梯度洗脱以产生澄清油状物(173mg,0.302mmol,收率为63%):0-3min:DCM中0%100∶10∶1 DCM/MeOH/NH4OH;3-18min:DCM中0-100%100∶10∶1 DCM/MeOH/NH4OH;18-30min:100%100∶10∶1 DCM/MeOH/NH4OH。1H NMR(500MHz,CDCl3)δ4.39(d,J=14.5Hz,1H),7.24(d,J=7.5Hz,1H),7.05-7.10(m,2H),6.97(m,3H),5.58-5.67(m,2H),4.44-4.69(m,2H),4.07(app t,J=16.5Hz,1H),3.97(app t,J=7.0Hz,1H),3.34-3.41(m,1H),3.18(d,J=5.0Hz,2H),3.11(dd,J=5.5Hz,J=14.0Hz,1H),2.91-3.00(m,2H),2.65-2.72(m,1H),2.48-2.62(m,3H),2.35-2.39(m,1H),1.92-1.98(m,2H),1.58-1.77(m,5H),1.50(s,9H),1.36-1.39(m,2H),1.15-1.29(m,4H),0.89(s,3H),0.89(s,3H).HRMS(NSI)m/z=573.41600(M+H);理论上对于C36H52N4O2+H=573.41630.LC-MS(ESI-API,254nm)H2O中25-95%MeOH(0.1%HCO2H),8min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=573.2(M+H),287.2(M/2+H),t=2.102min;H2O中25-95%MeOH(0.1%HCO2H),8min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=574.2(M+H),287.2(M/2+H),t=5.200min。
叔丁基(R)-3-((((E)-4-((4,4-二氟环己基)氨基)丁-2-烯-1-基)((S)-5,67,8-四氢喹啉-8-基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯:根据一般还原胺化3案C实施合成。通过柱色谱(CombiFlash,24g柱,30mL/min)纯化,用以下梯度洗脱以产生澄清油状物(143mg,0.246mmol,收率为51%):0-3min:DCM中0%100∶10∶1 DCM/MeOH/NH4OH;3-18min:DCM中0-100%100∶10∶1 DCM/MeOH/NH4OH;18-30min:100%100∶10∶1 DCM/MeOH/NH4OH。1HNMR(500MHz,CDCl3)δ8.39(d,J=13.5Hz,1H),7.25(d,J=7.0Hz,1H),7.06-7.10(m,2H),6.98(m,3H),5.58-5.70(m,2H),4.46-4.70(m,2H),4.07(app t,J=15.5Hz,1H),3.96(brs,1H),3.36-3.37(m,1H),3.17(d,J=5.5Hz,2H),3.12(dd,J=5.8Hz,J=14.3Hz,1H),2.91-3.00(m,2H),2.51-2.71(m,5H),2.06-2.13(m,2H),1.86-1.99(m,4H),1.67-1.80(m,4H),1.57-1.64(m,1H),1.42-1.53(m,11H).HRMS(NSI)m/z=581.36530(M+H);理论上对于C34H46F2N4O2+H=581.36616.LC-MS(ESI-API,254nm)H2O中50-95%MeOH(0.1%HCO2H),8min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=581.2(M+H),291.2(M/2+H),t=1.106min;H2O中25-95%MeOH(0.1%HCO2H),8min,1.00mL/min,C18(AgilentZorbax XDB-18,50mm×4.6mm,3.5μm),m/z=581.2(M+H),291.1(M/2+H),t=4.471min。
叔丁基(R)-3-((((E)-4-((四氢-2H-吡喃-4-基)氨基)丁-2-烯-1-基)((S)-5,6,7,8-四氢喹啉-8-基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯:根据一般还原胺化3案C实施合成。通过柱色谱(CombiFlash,24g柱,30mL/min)纯4,用以下梯度洗脱以产生澄清油状物(160mg,0.160mmol,收率为61%):0-3min:DCM中0%100∶10∶1 DCM/MeOH/NH4OH;3-18min:DCM中0-100%100∶10∶1 DCM/MeOH/NH4OH;18-30min:100%100∶10∶1 DCM/MeOH/NH4OH。1H NMR(500MHz,CDCl3)δ8.38(d,J=13.5Hz,1H),7.24(d,J=5.5Hz,1H),7.05-7.09(m,2H),6.97(m,3H),5.59-5.70(m,2H),4.45-4.69(m,2H),4.07(app t,J=14.5Hz,1H),3.95-3.97(m,3H),3.34-3.39(m,3H),3.20(d,J=4.5Hz,2H),3.11(dd,J=5.3Hz,J=14.3Hz,1H),2.91-3.00(m,2H),2.50-2.68(m,5H),1.91-1.98(m,2H),1.70-1.82(m,4H),1.57-1.64(m,1H),1.45-1.54(m,9H),1.36-1.41(m,2H).HRMS(NSI)m/z=547.36397(M+H);理论上对于C33H46N4O3+H=547.36427.LC-MS(ESI-API,254nm)H2O中50-95%MeOH(0.1%HCO2H),8min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=547.2(M+H),274.2(M/2+H),t=0.859min;H2O中25-95%MeOH(0.1%HCO2H),8min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=547.2(M+H),274.2(M/2+H),t=4.085min。
叔丁基(R)-3-((((E)-4-((吡啶-4-基甲基)氨基)丁-2-烯-1-基)((S)-5,67,8-四氢喹啉-8-基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯:根据一般还原胺化方案B实施合成。通过柱色谱(CombiFlash,24g柱,30mL/min)纯化,用以下梯度洗脱以产生黄色泡沫状物(175mg,0.316mmol,收率为59%):0-3min:DCM中0%100∶10∶1 DCM/MeOH/NH4OH;3-18min:DCM中0-100%100∶10∶1 DCM/MeOH/NH4OH;18-30min:100%100∶10∶1 DCM/MeOH/NH4OH。1H NMR(500MHz,CDCl3)δ8.54(dd,J=1.5Hz,J=4.5Hz,2H),8.38(d,J=14.5Hz,1H),7.25(m,3H),7.04-7.06(m,2H),6.97(m,3H),5.61-5.71(m,2H),4.47-4.70(m,2H),4.09(app t,J=15.8Hz,1H),3.96-3.97(m,1H),3.76(s,2H),3.31-3.37(m,1H),3.10-3.17(m,3H),2.91-3.01(m,2H),2.53-2.68(m,4H),1.91-2.00(m,2H),1.71-1.77(m,2H),1.53-1.65(m,1H),1.48(s,9H).HRMS(NSI)m/z=554.34869(M+H);理论上对于C34H43N5O2+H=554.34895.LC-MS(ESI-API,254nm)H2O中50-95%MeOH(0.1%HCO2H),8min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=554.2(M+H),277.6(M/2+H),t=0.861min;H2O中25-95%MeOH(0.1%HCO2H),8min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=554.2(M+H),277.6(M/2+H),t=3.979min。
叔丁基(R)-3-((((E)-4-((吡啶-3-基甲基)氨基)丁-2-烯-1-基)((S)-5,67,8-四氢喹啉-8-基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯:根据一般还原胺化方案B实施合成。通过柱色谱(CombiFlash,24g柱,30mL/min)纯化,用以下梯度洗脱以产生黄色泡沫状物(188mg,0.340mmol,收率为63%):0-3min:DCM中0%100∶10∶1 DCM/MeOH/NH4OH;3-18min:DCM中0-100%100∶10∶1 DCM/MeOH/NH4OH;18-30min:100%100∶10∶1 DCM/MeOH/NH4OH。1H NMR(500MHz,CDCl3)δ8.54(d,J=1.5Hz,1H),8.51(dd,J=1.8Hz,J=4.8Hz,1H),8.39(d,J=15.5Hz,1H),7.67(m,1H),7.24-7.26(m,2H),7.03-7.06(m,2H),6.97(m,3H),5.60-5.70(m,2H),4.46-4.70(m,2H),4.09(app t,J=16.0Hz,1H),3.97(dd,J=6.0Hz,J=8.0Hz,1H),3.75(s,2H),3.31-3.38(m,1H),3.18(d,J=5.5Hz,2H),3.11(dd,J=5.8Hz,J=14.3Hz,1H),2.92-3.01(m,2H),2.52-2.72(m,4H),1.92-2.00(m,2H),1.74(dd,J=10.0Hz,J=21.0Hz,1H),1.58-1.66(m,2H),1.48(s,9H).HRMS(NSI)m/z=554.34895(M+H);理论上对于C34H43N5O2+H=554.34895.LC-MS(ESI-API,254nm)H2O中50-95%MeOH(0.1%HCO2H),8min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=554.2(M+H),277.6(M/2+H),t=0.932min;H2O中25-95%MeOH(0.1%HCO2H),8min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=554.2(M+H),277.6(M/2+H),t=4.144min。
叔丁基(R)-3-((((E)-4-((吡啶-2-基甲基)氨基)丁-2-烯-1-基)((S)-5,67,8-四氢喹啉-8-基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯:根据一般还原胺化方案B实施合成。通过柱色谱(CombiFlash,24g柱,30mL/min)纯化,用以下梯度洗脱以产生黄色泡沫状物(161mg,0.291mmol,收率为54%):0-3min:DCM中0%100∶10∶1 DCM/MeOH/NH4OH;3-18min:DCM中0-100%100∶10∶1 DCM/MeOH/NH4OH;18-30min:100%100∶10∶1 DCM/MeOH/NH4OH。1H NMR(500MHz,CDCl3)δ8.56(dd,J=0.8Hz,J=4.8Hz,1H),8.38(d,J=12.5Hz,1H),7.64(dt,J=1.8Hz,J=7.6Hz,1H),7.24-7.29(m,2H),7.16(dd,J=5.3Hz,J=6.8Hz,1H),7.04-7.07(m,2H),6.97(m,3H),5.61-5.71(m,2H),4.45-4.69(m,2H),4.07(app t,J=16.5Hz,1H),3.98(m,1H),3.86(s,2H),3.32-3.40(m,1H),3.18-3.25(m,2H),3.11(dd,J=5.5Hz,J=14.5Hz,1H),2.91-3.02(m,2H),2.51-2.72(m,4H),1.92-2.00(m,3H),1.74(dd,J=10.0Hz,J=21.0Hz,1H),1.57-1.65(m 1H),1.49(s,9H).HRMS(NSI)m/z=554.34870(M+H);理论上对于C34H43N5O2+H=554.34895.LC-MS(ESI-API,254nm)H2O中50-95%MeOH(0.1%HCO2H),8min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=554.2(M+H),277.6(M/2+H),t=1.029min;H2O中25-95%MeOH(0.1%HCO2H),8min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=554.2(M+H),277.6(M/2+H),t=4.339min。
EMU180:(E)-N1-((四氢-2H-吡喃-4-基)甲基)-N4-(((R)-1,2,3,4-四氢异喹啉-3-基)甲基)-N4-((S)-5,6,7,8-甲氢喹啉-8-基)丁-2-烯-1,4-二胺:根据一般脱保护方案实施合成。通过柱色谱(CombiFlash,12g柱,25mL/min)纯化,用以下梯度洗脱以产生澄清油状物(74.0mg,0.161mmol,收率为75%):0-3min:DCM中0%100∶10∶1 DCM/MeOH/NH4OH;3-18min:DCM中0-100%100∶10∶1 DCM/MeOH/NH4OH;18-30min:100%100∶10∶1 DCM/MeOH/NH4OH。1H NMR(500MHz,CDCl3)δ8.46(dd,J=1.3Hz,J=4.8Hz,1H),7.32(m,1H),7.07-7.09(m,2H),7.02-7.06(m,2H),6.97-7.01(m,1H),5.69-5.78(m,2H),4.10(dd,J=6.3Hz,J=9.8Hz,1H),4.01(d,J=10.5Hz,1H),3.94(dt,J=2.0Hz,J=11.5Hz,2H),3.82(d,J=15.0Hz,1H),3.63(dd,J=5.3Hz,J=14.3Hz,1H),3.32-3.38(m,3H),3.22(d,J=4.5Hz,2H),2.87(dd,J=3.5Hz,J=13.0Hz,1H),2.71-2.80(m,2H),2.65-2.68(m,1H),2.60(dd,J=3.5Hz,J=16.0Hz,1H),2.47(d,J=7.0Hz,2H),2.37-2.44(m,3H),2.05-2.09(m,1H),1.94-2.01(m,1H),1.87-1.93(m,1H),1.63-1.74(m,2H),1.58-1.61(m,2H),1.22-1.30(m,3H).13C NMR(125MHz,CDCl3)δ158.7,146.9,136.6,135.7,134.8,134.0,131.9,130.3,129.2,126.5,126.0,125.6,121.5,68.0(2C),61.3,57.2,56.6,55.7,52.1,51.7,48.7,35.5,33.9,31.4(2C),29.5,28.1,22.0.HRMS(NSI)m/z=461.32697(M+H);理论上对于C29H40N4O+H=461.32749.LC-MS(ESI-API,254nm)H2O中25-95%MeOH(0.1%HCO2H),8min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=461.2(M+H),231.2(M/2+H),t=0.535min;H2O中10-95%MeOH(0.1%HCO2H),10min,1.00mL/min,C18(AgilentZorbax XDB-18,50mm×4.6mm,3.5μm),m/z=461.2(M+H),231.2(M/2+H),t=1.198min。
EMU153:(E)-N1-(4,4-二甲基环己基)-N4-(((R)-1,2,3,4-四氢异喹啉-3-基)甲基)-N4-((S)-5,6,7,8-四氢喹啉-8-基)丁-2-烯-1,4-二胺:根据一般脱保护方案实施合成。通过柱色谱(CombiFlash,12g柱,25mL/min)纯化,用以下梯度洗脱以产生澄清油状物(27.0mg,0.057mmol,收率为19%):0-3min:DCM中0%100∶10∶1 DCM/MeOH/NH4OH;3-18min:DCM中0-100%100∶10∶1 DCM/MeOH/NH4OH;18-30min:100%100∶10∶1 DCM/MeOH/NH4OH。1HNMR(500MHz,CDCl3)δ8.45(dd,J=1.0Hz,J=4.5Hz,1H),7.31(d,J=7.0Hz,1H),7.06-7.09(m,2H),6.98-7.05(m,3H),5.69-5.77(m,2H),4.10(dd,J=6.3Hz,J=9.8Hz,1H),4.00(d,J=15.0Hz,1H),3.81(d,J=15.0Hz,1H),3.59-3.63(m,1H),3.28-3.32(m,1H),3.21-3.25(m,2H),2.88(dd,J=3.0Hz,J=13.0Hz,1H),2.70-2.79(m,2H),2.64-2.67(m,1H),2.59(dd,J=3.5Hz,J=16.0Hz,1H),2.36-2.44(m,5H),2.04-2.09(m,1H),1.94-2.01(m,1H),1.87-1.92(m,1H),1.66-1.74(m,3H),1.33-1.38(m,2H),1.21-1.29(m,3H),1.12-1.19(m,1H),0.88(s,3H),0.87(s,3H).13C NMR(125MHz,CDCl3)δ158.8,147.0,136.7,135.8,134.8,134.1,131.6,130.8,129.2,126.6,126.0,125.6,121.6,61.2,57.2,56.6,53.6,52.2,48.8,48.7,38.0,38.0,33.9,32.4,30.3,29.6,29.4(2C),28.1,24.8,22.1.HRMS(NSI)m/z=473.36329(M+H);理论上对于C31H44N4+H=473.36387.LC-MS(ESI-API,254nm)H2O中25-95%MeOH(0.1%HCO2H),8min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=473.2(M+H),237.2(M/2+H),t=2.547min;H2O中10-95%MeOH(0.1%HCO2H),10min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=473.2(M+H),237.2(M/2+H),t=4.437min。
EMU154:(E)-N1-(4,4-二氟环己基)-N4-(((R)-1,2,3,4-四氢异喹啉-3-基)甲基)-N4-((S)-5,6,7,8-四氢喹啉-8-基)丁-2-烯-1,4-二胺:根据一般脱保护方案实施合成。通过柱色谱(CombiFlash,12g柱,25mL/min)纯化,用以下梯度洗脱以产生澄清油状物(116mg,0.241mmol,收率为98%):0-3min:DCM中0%100∶10∶1 DCM/MeOH/NH4OH;3-18min:DCM中0-100%100∶10∶1 DCM/MeOH/NH4OH;18-30min:100%100∶10∶1 DCM/MeOH/NH4OH。1HNMR(500MHz,CDCl3)δ8.46(dd,J=1.0Hz,J=4.5Hz,1H),7.32(dd,J=0.5Hz,J=7.5Hz,1H),7.06-7.10(m,2H),2.99(m,3H),5.68-5.78(m,2H),4.10(dd,J=6.3Hz,J=9.8Hz,1H),4.01(d,J=15.0Hz,1H),3.82(d,J=15.0Hz,1H),3.62(dd,J=6.0Hz,J=14.0Hz,1H),3.33(dd,J=5.3Hz,J=14.3Hz,1H),3.24(d,J=5.5Hz,2H),2.87(dd,J=3.5Hz,J=13.0Hz,1H),2.71-2.80(m,2H),2.70(m,1H),2.58-2.65(m,2H),2.38-2.44(m,2H),1.92-2.13(m,5H),1.86-1.91(m,3H),1.65-1.79(m,3H),1.42-1.49(m,2H).13C NMR(125MHz,CDCl3)δ158.6,146.9,136.6,135.6,134.7,134.0,131.9,130.3,129.2,126.5,126.0,125.6,123.4(t,J=239.4Hz),121.5,61.2,57.2,56.5,53.5,52.1,48.9,48.6,33.9,31.8(t,J=24.4Hz,2C),29.5,28.9(t,J=2.5Hz),28.9(t,J=3.8Hz),27.9,22.0.19F NMR(400MHz,CDCl3,TFA标准)δ-96.8(app d,J=248.0Hz),-101.1(app d,J=220.0Hz).HRMS(NSI)m/z=481.31303(M+H);理论上对于C29H38F2N4+H=481.31373.LC-MS(ESI-API,254nm)H2O中25-95%MeOH(0.1%HCO2H),8min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=481.2(M+H),241.2(M/2+H),t=0.591min;H2O中10-95%MeOH(0.1%HCO2H),10min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=481.2(M+H),241.2(M/2+H),t=2.382min。
EMU155:(E)-N1-(四氢-2H-吡喃-4-基)-N4-(((R)-1,2,3,4-四氢异喹啉-3-基)甲基)-N4-((S)-5,6,7,8-四氢喹啉-8-基)丁-2-烯-1,4-二胺:根据一般脱保护方案实施合成。通过柱色谱(CombiFlash,12g柱,25mL/min)纯化,用以下梯度洗脱以产生澄清油状物(126mg,0.282mmol,收率为96%):0-3min:DCM中0%100∶10∶1 DCM/MeOH/NH4OH;3-18min:DCM中0-100%100∶10∶1 DCM/MeOH/NH4OH;18-30min:100%100∶10∶1 DCM/MeOH/NH4OH。1HNMR(500MHz,CDCl3)δ8.46(dd,J=1.3Hz,J=4.8Hz,1H),7.32(dd,J=0.8Hz,J=7.8Hz,1H),7.06-7.10(m,2H),6.98-7.05(m,3H),5.69-5.79(m,2H),4.10(dd,J=6.3Hz,J=9.8Hz,1H),4.01(d,J=15.0Hz,1H),3.92-3.97(m,2H),3.81(d,J=15.0Hz,1H),3.63(dd,J=5.3Hz,J=14.3Hz,1H),3.31-3.38(m,3H),3.27(d,J=5.0Hz,2H),2.88(dd,J=3.5Hz,J=13.0Hz,1H),2.58-2.80(m,6H),2.38-2.44(m,2H),2.04-2.09(m,1H),1.94-2.01(m,1H),1.87-1.93(m,1H),1.79-1.82(m,2H),1.65-1.74(m,1H),1.34-1.42(m,2H).13C NMR(125MHz,CDCl3)δ158.6,146.8,136.5,135.6,134.6,133.9,131.7,130.3,129.1,126.4,125.9,125.5,121.4,66.9,66.8,61.0,57.1,56.4,53.3,52.0,48.6,48.0,33.8,33.7(2C),29.4,27.9,21.9.HRMS(NSI)m/z=447.31120(M+H);理论上对于C28H38N4O+H=447.31184.LC-MS(ESI-API,254nm)H2O中25-95%MeOH(0.1%HCO2H),8min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=447.2(M+H),224.2(M/2+H),t=0.523min;H2O中10-95%MeOH(0.1%HCO2H),10min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=447.2(M+H),224.2(M/2+H),t=1.126min。
EMU221:(E)-N1-(吡啶-4-基甲基)-N4-(((R)-1,2,3,4-四氢异喹啉-3-基)甲基)-N4-((S)-5,6,7,8-四氢喹啉-8-基)丁-2-烯-1,4-二胺:根据一般脱保护方案实施合成。通过柱色谱(CombiFlash,12g柱,25mL/min)纯化,用100∶10∶1 DCM/MeOH/NH4OH洗脱以产生黄色油状物(137mg,0.302mmol,收率为96%)。1H NMR(500MHz,CDCl3)δ8.50-8.51(m,2H),8.45(dd,J=1.5Hz,J=4.5Hz,1H),7.31(d,J=7.5Hz,1H),7.22-7.23(m,2H),7.07-7.10(m,2H),7.01-7.06(m,2H),6.98-6.99(m,1H),5.70-5.80(m,2H),4.10(dd,J=6.5Hz,J=9.5Hz,1H),4.00(d,J=15.5Hz,1H),3.82(d,J=15.0Hz,1H),3.78(s,2H),3.64(dd,J=5.8Hz,J=14.3Hz,1H),3.34(dd,J=5.0Hz,J=14.0Hz,1H),3.25(d,J=5.5Hz,2H),2.87(dd,J=3.5Hz,J=13.0Hz,1H),2.58-2.80(m,5H),2.37-2.43(m,2H),2.04-2.09(m,1H),1.87-2.00(m,2H),1.65-1.73(m,1H),1.40(br s,1H).13C NMR(125MHz,CDCl3)δ158.6,149.8(2C),149.4,146.9,136.6,135.7,134.7,134.0,132.4,129.7,129.1,126.4,125.9,125.5,123.0(2C),121.5,61.2,57.2,56.5,52.1,51.9,50.9,48.7,33.9,29.5,28.1,21.9.HRMS(NSI)m/z=454.29778(M+H);理论上对于C29H35N5+H=454.29652.LC-MS(ESI-API,254nm)H2O中25-95%MeOH(0.1%HCO2H),8min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=454.2(M+H),227.6(M/2+H),t=0.528min;H2O中10-95%MeOH(0.1%HCO2H),10min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=454.2(M+H),227.8(M/2+H),t=0.834min。
EMU222:(E)-N1-(吡啶-3-基甲基)-N4-(((R)-1,2,3,4-四氢异喹啉-3-基)甲基)-N4-((S)-5,6,7,8-四氢喹啉-8-基)丁-2-烯-1,4-二胺:根据一般脱保护方案实施合成。通过柱色谱(CombiFlash,12g柱,25mL/min)纯化,用100∶10∶1 DCM/MeOH/NH4OH洗脱以产生黄色油状物(138mg,0.304mmol,收率为90%)。1H NMR(500MHz,CDCl3)δ8.53(d,J=2.0Hz,1H),8.49(dd,J=1.8Hz,J=4.8Hz,1H),8.46(d,J=5.0Hz,1H),7.64-7.66(m,1H),7.31(d,J=8.0Hz,1H),7.22(dd,J=4.8Hz,J=7.8Hz,1H),7.06-7.09(m,2H),7.01-7.05(m,2H),6.98-6.99(m,1H),5.70-5.80(m,2H),4.10(dd,J=6.3Hz,J=9.8Hz,1H),4.00(d,J=15.0Hz,1H),3.82(d,J=15.0Hz,1H),3.78(s,2H),3.63-3.68(m,1H),3.34(dd,J=4.8Hz,J=13.8Hz,1H),3.25(d,J=5.0Hz,2H),2.87(dd,J=3.5Hz,J=13.5Hz,1H),2.58-2.79(m,5H),2.37-2.43(m,2H),2.05-2.09(m,1H),1.87-2.00(m,2H),1.65-1.73(m,1H)1.34(br s,1H).13C NMR(125MHz,CDCl3)δ158.6,149.7,148.5,146.8,136.5,135.9,135.7,135.6,134.7,134.0,132.3,129.8,129.1,126.4,125.9,125.5,123.4,121.5,61.1,57.2,56.4,52.0,50.8,50.6,48.6,33.8,29.4,28.1,21.9.HRMS(NSI)m/z=454.29690(M+H);理论上对于C29H35N5+H=454.29652.LC-MS(ESI-API,254nm)H2O中25-95%MeOH(0.1%HCO2H),8min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=454.2(M+H),227.6(M/2+H),t=0.534min;H2O中10-95%MeOH(0.1%HCO2H),10min,1.00mL/min,C18(AgilentZorbax XDB-18,50mm×4.6mm,3.5μm),m/z=454.2(M+H),227.6(M/2+H),t=1.015min。
EMU223:(E)-N1-(吡啶-2-基甲基)-N4-(((R)-1,2,3,4-四氢异喹啉-3-基)甲基)-N4-((S)-5,6,7,8-四氢喹啉-8-基)丁-2-烯-1,4-二胺:根据一般脱保护方案实施合成。通过柱色谱(CombiFlash,12g柱,25mL/min)纯化,用100∶10∶1 DCM/MeOH/NH4OH洗脱以产生黄色油状物(130mg,0.287mmol,收率为99%)。1H NMR(500MHz,CDCl3)δ8.53-8.54(m,1H),8.45-8.46(m,1H),7.58-7.62(m,1H),7.31(d,J=8.0Hz,1H),7.25-7.27(m,1H),7.13-7.15(m,1H),7.05-7.09(m,2H),7.01-7.05(m,2H),6.98-6.99(m,1H),5.73-5.81(m,2H),4.10(dd,J=6.5Hz,J=9.5Hz,1H),4.00(d,J=15.5Hz,1H),3.88(s,2H),3.83(d,J=15.0Hz,1H),3.68(dd,J=2.8Hz,J=15.8Hz,1H),3.33-3.36(m,1H),3.28-3.29(m,2H),2.86(dd,J=3.0Hz,J=13.0Hz,1H),2.58-2.79(m,5H),2.37-2.43(m,2H),2.05-2.09(m,1H),1.87-1.99(m,2H),1.65-1.73(m,1H).13C NMR(125MHz,CDCl3)δ159.7,158.6,149.3,146.8,136.5,136.4,135.7,134.7,133.9,132.0,130.1,129.1,126.4,125.9,125.4,122.4,121.9,121.4,61.1,57.2,56.4,54.6,52.0,51.0,48.6,33.8,29.4,28.1,21.9.HRMS(NSI)m/z=454.29750(M+H);理论上对于C29H35N5+H=454.29652.LC-MS(ESI-API,254nm)H2O中25-95%MeOH(0.1%HCO2H),8min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=454.2(M+H),227.6(M/2+H),t=0.551min;H2O中10-95%MeOH(0.1%HCO2H),10min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=454.2(M+H),227.8(M/2+H),t=2.148min。
外消旋途径:EMU100(立体异构体1)和EMU100(立体异构体2)的合成
2-叔丁基3-甲基5-(4-(叔丁氧基羰基)哌嗪-1-基)-3,4-二氢异喹啉-2,3(1H)-二羧酸酯
将外消旋2-叔丁基3-甲基5-溴-3,4-二氢异喹啉-2,3(1H)-二羧酸酯(1.03g,2.78mmol)、叔丁基哌嗪-1-羧酸酯(0.622g,3.34mmol)、Pd2(dba)3(0.127g,0.139mmol)、rac-BINAP(0.260g,0.417mmol)和碳酸铯(1.269g,3.89mmol)装入配备有Teflon包被的磁性搅拌棒的烘箱干燥的Biotage 10-20mL微波小瓶。将小瓶用Teflon衬覆的隔膜密封并且用氩气吹扫持续5分钟。添加脱气的甲苯(13.91mL)并且用氩气将容器脱气持续另外的5分钟。将所得混合物在油浴中在120℃加热持续48小时。在如通过TLC分析判断反应完全后,允许将混合物冷却至室温,过滤通过硅藻土垫,并且浓缩成粗物质,其通过CombiFlash系统(40克硅柱,5分钟己烷,然后30分钟0-30%乙酸乙酯)纯化以得到作为淡黄色凝胶状物的产物(1.4011g,2.95mmol,定量收率)。1H NMR(400MHz,氯仿-d)δ7.13(td,J=7.8,4.2Hz,1H),6.98-6.65(m,2H),5.03(dd,J=6.1,3.5Hz,0.5H),4.80-4.55(m,1.5H),4.42(dd,J=34.5,16.1Hz,1H),3.75-3.39(m,7H),3.15(ddd,J=52.9,15.5,5.9Hz,1H),2.98-2.60(m,5H),1.62-1.27(m,18H).HRMS对于[C25H37N3O6+H]+计算为:476.27606,实测为:476.27542。
叔丁基5-(4-(叔丁氧基羰基)哌嗪-1-基)-3-甲酰基-3,4-二氢异喹啉-2(1H)-羧酸酯:
将外消旋2-叔丁基3-甲基5-(4-(叔丁氧基羰基)哌嗪-1-基)-3,4-二氢异喹啉-2,3(1H)-二羧酸酯(0.50g,1.051mmol)和无水甲苯(13.14mL)装入包含Teflon包被的搅拌棒的100mL圆底烧瓶中。在-78℃逐滴添加甲苯中的二异丁基氢化铝1M溶液(5.26ml,5.26mmol)。在-78℃2h后,在氩气气氛下用甲醇小心地淬灭反应,然后允许升温至0℃。添加罗谢尔盐的饱和溶液并且在室温搅拌持续1-2小时。将双相混合物转移到分液漏斗。将水层分离并且用乙酸乙酯萃取(2次)。将合并的有机相经无水硫酸钠干燥,并且在减压下浓缩以得到粗醛,其不经纯化即被用于下一个步骤。1H NMR(400MHz,氯仿-d)δ9.54-9.21(m,1H),7.12(td,J=7.6,5.1Hz,1H),6.95-6.69(m,2H),4.91-4.17(m,3H),3.90-3.09(m,5H),3.09-2.50(m,5H),1.64-1.26(m,18H)。
叔丁基5-(4-(叔丁氧基羰基)哌嗪1-基)-3-((((S)-5,6,7,8-四氢喹啉-8-基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯
将(S)-5,6,7,8-四氢喹啉-8-胺(0.105g,0.705mmol)、三乙酰氧基硼氢化钠(0.179g,0.846mmol)和1,2-二氯乙烷(1.349mL)装入配备有Teflon包被的磁性搅拌棒的20mL闪烁小瓶。在搅拌持续5分钟后,逐滴添加1,2-二氯乙烷(1mL)中的外消旋叔丁基5-(4-(叔丁氧基羰基)哌嗪-1-基)-3-甲酰基-3,4-二氢异喹啉-2(1H)-羧酸酯(0.2093g,0.470mmol)的溶液。将所得混合物在室温搅拌持续48小时。在如由TLC和LCMS分析判断反应完全后,通过添加饱和NaHCO3淬灭混合物。将双相混合物转移到分液漏斗。将水层分离并且用DCM萃取(3次)。合并的有机萃取物经无水硫酸钠干燥,并且在减压下浓缩成粗物质,其通过CombiFlash系统(24g金硅柱,5分钟DCM,然后30分钟0-10%MeOH/DCM)纯化以得到作为淡黄色凝胶状物的两种非对映体的不可分离的混合物(0.1847g,0.320mmol,收率为68%)。1HNMR(400MHz,氯仿-d)δ8.29(d,J=4.5Hz,1H),7.29(t,J=6.6Hz,1H),7.11(t,J=7.8Hz,1H),6.99(dd,J=7.9,4.6Hz,1H),6.84(dt,J=10.7,5.3Hz,2H),4.72-4.19(m,3H),3.75-3.09(m,5H),3.04-2.25(m,1OH),2.10-1.77(m,2H),1.60(t,J=9.8Hz,2H),1.53-1.25(m,18H).HRMS对于[C33H47N5O4+H]+计算为:578.37063,实测为:578.37036。
(R)-叔丁基5-(4-(叔丁氧基羰基)哌嗪-1-基)-3-(((环己基甲基)((S)-5,6,7,8-四氢喹啉-8-基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯和(S)-叔丁基5-(1-(叔丁氧基羰基)哌啶-4-基)-3-(((环己基甲基)((S)-5,6,78-四氢喹啉-8-基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯
将叔丁基5-(4-(叔丁氧基羰基)哌嗪-1-基)-3-((((S)-5,6,7,8-四氢喹啉-8-基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯(非对映体的1∶1混合物)(0.4899g,0.848mmol)、三乙酰氧基硼氢化钠(0.323g,1.526mmol)和1,2-二氯乙烷(4.24mL)装入配备有Teflon包被的磁性搅拌棒的20mL闪烁小瓶。在搅拌持续5分钟后,逐滴添加环己烷甲醛(0.308ml,2.54mmol)。将所得混合物在室温搅拌持续48-72小时。在如由TLC和LCMS分析判断反应完全后,混合物通过添加1M NaOH淬灭。将双相混合物转移到分液漏斗。将水层分离并且用DCM萃取(3次)。合并的有机萃取物经无水硫酸钠干燥,并且在减压下浓缩成粗非对映体混合物,其通过CombiFlash系统(24g金硅柱,5分钟DCM,然后30分钟0-10%MeOH/DCM)分离和纯化以得到作为淡黄色凝胶状物的立体异构体1(0.2345g,0.348mmol,收率为41%)和立体异构体2(0.0956g,0.142mmol,收率为17%),将其推至脱保护步骤。
用于全面脱保护的一般程序:将Boc保护的基底(1当量)和DCM(0.13M)装入配备有Teflon包被的磁性搅拌棒的20mL闪烁小瓶。逐滴添加三氟乙酸(36当量),并且将所得混合物在室温搅拌过夜。在如通过LCMS分析判断反应完全后,混合物用DCM稀释,在冰浴中冷却,并且通过添加3M NaOH直到pH>12淬灭。将双相混合物转移到分液漏斗。将水层分离并且用DCM萃取(3次)。合并的有机萃取物经无水硫酸钠干燥,并且在减压下浓缩成粗物质,其通过使用溶剂A(DCM)至溶剂B(8∶2∶0.6 DCM/MeOH/NH3溶液,MeoH中为7N)的梯度作为硅胶柱上的洗脱剂通过CombiFlash系统纯化以得到最终产物。
EMU100(立体异构体1):白色泡沫状物。1H NMR(400MHz,氯仿-d)δ8.42(dd,J=4.7,1.7Hz,1H),7.30(dd,J=7.7,1.7Hz,1H),7.13-6.96(m,2H),6.84(dt,J=8.0,1.9Hz,1H),6.80-6.68(m,1H),4.12(d,J=15.1Hz,1H),4.08-3.96(m,2H),3.11(dd,J=12.8,5.3Hz,1H),3.00-2.59(m,14H),2.39-2.28(m,2H),2.10(dd,J=16.0,11.1Hz,2H),1.99-1.58(m,9H),1.45-1.37(m,1H),1.25-1.09(m,3H),0.86-0.74(m,2H).HRMS对于[C30H43N5+H]+计算为:474.35967,实测为:474.35953。EMU100(立体异构体2):白色泡沫状物。1H NMR(400MHz,氯仿-d)δ8.46(dd,J=4.8,1.7Hz,1H),7.30(dd,J=7.7,1.7Hz,1H),7.10-7.00(m,2H),6.84(d,J=7.8Hz,1H),6.76(d,J=7.6Hz,1H),4.13(d,J=6.9Hz,2H),3.97(dd,J=9.8,5.9Hz,1H),3.04-2.83(m,9H),2.81-2.58(m,7H),2.44(dd,J=13.1,6.4Hz,1H),2.29(ddd,J=27.1,12.0,5.9Hz,2H),2.13(ddt,J=13.0,5.3,2.2Hz,1H),2.01-1.90(m,2H),1.78-1.57(m,6H),1.38(dtd,J=14.4,7.1,3.3Hz,1H),1.20-1.06(m,3H),0.74(ddd,J=25.4,12.7,3.1Hz,2H).HRMS对于[C30H43N5+H]+计算为:474.35967,实测为:474.35881。
以下这些化合物根据上文方案获得,但从对映体纯的(R)-2-叔丁基3-甲基5-溴-3,4-二氢异喹啉-2,3(1H)-二羧酸酯开始,其使用由Beadle等人(PCT Int.Appl.,2014193781,04 Dec 2014)的文献方法以克规模制备:
EMU119:白色泡沫状物。1H NMR(400MHz,氯仿-d)δ8.48(dd,J=4.7,1.7Hz,1H),7.36(dd,J=7.7,1.7Hz,1H),7.19-7.02(m,2H),6.91(dd,J=7.9,4.1Hz,1H),6.81(dd,J=7.7,4.1Hz,1H),4.28(dd,J=10.3,6.2Hz,1H),4.18(d,J=15.2Hz,1H),3.97(d,J=15.2Hz,1H),3.58-2.56(m,18H),2.32-2.11(m,2H),2.07-1.91(m,2H),1.84-1.71(m,1H),1.04-0.93(m,1H),0.53(dqt,J=26.1,8.8,4.3Hz,2H),0.28-0.01(m,2H).HRMS对于[C27H37N5+H]+计算为:432.31272,实测为:432.31179。
EMU120:白色泡沫状物。1H NMR(400MHz,氯仿-d)δ8.43(dd,J=4.8,1.7Hz,1H),7.38-7.31(m,1H),7.14-7.04(m,2H),6.88(dd,J=7.9,1.1Hz,1H),6.79(dd,J=7.6,1.1Hz,1H),4.23-3.96(m,3H),3.12-2.85(m,9H),2.84-2.60(m,6H),2.37(dd,J=13.5,8.5Hz,1H),2.16-1.79(m,9H),1.52(s,5H),1.16(t,J=12.1Hz,2H).HRMS对于[C30H41F2N5+H]+计算为:510.34083,实测为:510.34065。
TIQ-15类似物:用仲胺的还原胺化
一般方案
EMU030和EMU031的合成
根据参考文献J.Am.Chem.Soc.2009,131,4513-4520,化合物1从(Z)-丁-2-烯-1,4-二醇合成,收率为32%。将939mg的醇1(4.34mmol,1当量)、766mg的邻苯二甲酰亚胺(5.21mmol.1.2当量)、1.31g的三苯基膦(4.99mmol,1.15当量)和22mL的THF装入配备有搅拌棒和隔膜的100mL rb烧瓶。然后在rt添加1.02mL的DIAD(5.25mmol,1.21当量)。黄色立即消失,并且获得澄清溶液。在rt搅拌持续2.5h后,反应混合物通过添加水淬灭,用CH2Cl2(2×)萃取,用水和卤水洗涤,并且经Na2SO4干燥。将粗产物在硅胶柱上纯化,使用己烷中10%EA作为洗脱剂,得到1.28g(85%)的作为白色固体的产物2。1H NMR(400MHz,CDCl3,ppm)δ:7.84(dd,J=5.5,3.1Hz,2H),7.70(dd,J=5.5,3.0Hz,2H),3.97-3.85(m,2H),3.64-3.54(m,2H),1.50-1.35(m,1H),1.26-1.09(m,1H),0.87(s,9H),0.70(td,J=8.4,5.0Hz,1H),0.36(q,J=5.5Hz,1H),0.04(s,2H),0.03(s,2H);13C NMR(300MHz,CDCl3,ppm)δ:167.89,133.39,132.04,122.75,62.72,37.58,25.66,18.34,18.05,18.00,14.75,8.51,-5.47,-5.59;LC-MS(ESI-API,254nm)H2O中95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(AgilentZorbax XDB-18,50mm×4.6mm,3.5μm),m/z=368.0(M+Na),346.0(M+H),t=1.081min。
将1.23g的TBS醚2(3.66mmol,1当量)、3.7mL 2M HCl(7.40mmol,2当量)和3.7mL的THF装入配备有搅拌棒和隔膜的25mL rb烧瓶。在rt搅拌持续1.5h后,反应混合物通过添加饱和NaHCO3溶液淬灭,用CH2Cl2(2×)萃取,并且经Na2SO4干燥。将粗产物在硅胶柱上纯化,使用己烷中30-100%EA,得到0.826g(97%)的作为白色固体的产物3。1H NMR(400MHz,CDCl3,ppm)δ:7.86(dd,J=5.4,3.1Hz,2H),7.73(dd,J=5.4,3.1Hz,2H),4.03-3.94(m,2H),3.59-3.50(m,2H),2.89(dd,J=8.3,4.4Hz,1H),1.34-1.19(m,2H),0.80(td,J=8.7,5.1Hz,1H),0.18(q,J=5.6Hz,1H);LC-MS(ESI-API,254nm)H2O中95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=254.0(M+Na),t=0.546min。
将415mg的醇3(1.80mmol,1当量)、1.33mL的TEA(9.51mmol,5.3当量)和5.4mL的CH2Cl2装入配备有磁性搅拌棒和隔膜的50mL的Schlenk烧瓶。在将反应混合物冷却至0℃后,逐滴添加溶解在5.4mL的DMSO中的1.14g的SO3*Py(7.18mmol,4当量),并且将反应混合物在rt搅拌持续2h。然后反应混合物通过添加水淬灭,用乙醚(3×)萃取,用水、卤水洗涤,并且经Na2SO4干燥。将粗产物在硅胶柱上纯化,使用己烷中30%EA作为洗脱剂,得到0.323g(79%)的作为白色固体的产物4。1H NMR(400MHz,CDCl3,ppm)δ:9.57(d,J=4.8Hz,1H),7.82-7.75(m,2H),7.71-7.65(m,2H),3.96(dd,J=14.4,6.8Hz,1H),3.72(dd,J=14.4,7.7Hz,1H),2.03-1.94(m,2H),1.82(sext,J=7.6Hz,1H),1.40(dt,J=7.0,5.3Hz,1H),1.23(td,J=8.1,5.0Hz,1H);13C NMR(400MHz,CDCl3,ppm)δ:199.98,167.83,133.91,131.83,123.16,36.24,27.03,22.26,12.82。
将554mg的胺I(1.41mmol,1当量)、323mg的醛4(1.41mmol,1当量)、105μL的乙酸(1.83mmol,1.3当量)、373mg的STAB(1.76mmol,1.25当量)和14.1mL的DCE装入配备有隔膜和搅拌棒的50mL Schlenk管。在rt搅拌持续12h后,反应混合物通过添加1N K2CO3溶液淬灭,用乙醚(3×)萃取,用1N K2CO3溶液、卤水洗涤,并且经Na2SO4干燥。将粗产物在硅胶柱上纯化,使用己烷中0-70%EA作为洗脱剂,得到291mg(34%)的作为澄清油状物的URf-5异构体、174mg(20%)的两种异构体的混合物和340mg(40%)的LRf-5异构体。对于URf-5异构体: 1HNMR(400MHz,CDCl3,ppm)δ:8.38(br s,1H),7.80(dd,J=5.5,3.0Hz,2H),7.67(dd,J=5.4,3.1Hz,2H),7.28-7.22(m,1H),7.13-7.05(m,3H),7.05-6.99(m,1H),6.97(br s,1H),4.79(br s,0.5H),4.72(s,0.5H),4.68(s,0.5H),4.56(s,0.5H),4.30(d,J=17.2Hz,0.5H),4.19(d,J=16.5Hz,0.5H),4.10-3.76(m,2H),3.41(dd,J=13.8,10.0Hz,1H),3.22-2.40(m,7H),2.15-2.02(m,1H),1.99-1.88(m,1H),1.86-1.73(m,1H),1.71-1.56(m,1H),1.48(s,9H),1.51-1.31(m,1H),1.25-1.12(m,1H),1.05(h,J=7.4Hz,1H),0.61(td,J=8.3,4.7Hz,1H),0.18(q,J=5.4Hz,1H);LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),6min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=607.2(M+H),t=0.624min,纯度为97%。对于LRf-5异构体: 1H NMR(400MHz,CDCl3,ppm)δ:8.41-8.28(m,1H),7.84-7.73(m,2H),7.72-7.62(m,2H),7.23(d,J=6.7Hz,1H),7.11-6.86(m,5H),4.75-4.43(m,2H),4.25-4.09(m,2H),3.86-3.68(m,1H),3.37-3.26(m,1H),3.19-3.03(m,1H),3.02-2.48(m,6H),2.14-1.30(m,5H),1.48(s,9H),1.28-1.18(m,1H),0.96(dt,J=14.2,7.0Hz,1H),0.54(td,J=8.3,4.7Hz,1H),0.13(q,J=5.4Hz,1H);LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),6min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=607.2(M+H),t=0.640min;
将溶解在1.7mL的MeOH中的202mg的胺URf-5(0.333mmol,1当量)装入配备有搅拌棒的20mL小瓶。然后添加水中的352μL的24%肼溶液(2.66mmol,8当量)。在rt搅拌持续12h后,反应混合物通过添加饱和Na2CO3溶液淬灭,用CH2Cl2(4×)萃取,并且经Na2SO4干燥。粗产物URf-6不经纯化即被用于下一个步骤。使用相同的程序以合成LRf-6异构体。
将溶解在3.34mL的CH2Cl2中的159mg的胺URf-6(0.334mmol,1当量)装入配备有搅拌棒的20mL小瓶。然后添加771μL的TFA(10.0mmol,30当量)。在rt搅拌持续5h后,反应混合物通过添加饱和Na2CO3溶液和2N KOH溶液淬灭,用CH2Cl2(3×)萃取,用卤水洗涤并且经Na2SO4干燥。将粗物质(94mg)在硅胶柱上纯化,使用具有1%NH4OH的CH2Cl2中0-20%MeOH作为洗脱剂,得到87mg(69%)的作为微黄色固体的产物EMU030。使用相同的程序以从LRf-6开始合成98mg(70%)的作为微黄色固体的EMU031。
对于EMU030(立体异构体1):1H NMR(600MHz,CDCl3,ppm)δ:8.58(s,1H),7.35(d,J=7.7Hz,1H),7.14-6.99(m,5H),4.17-4.05(m,1H),4.10(AB的A,JAB=16.2Hz,1H),3.81(AB的B,JAB=16.2Hz,1H),3.35(br s,1H),3.28(dd,J=13.2,4.6Hz,1H),2.88(d,J=12.8Hz,1H),2.81-2.61(m,3H),2.56(dd,J=11.4,13.0Hz,2H),2.51-2.40(m,2H),2.33(br s,1H),2.15-2.09(m,1H),2.07-1.95(m,2H),1.79-1.69(m,1H),0.98(br s,1H),0.77(q,J=9.0,7.8Hz,1H),0.07(d,J=5.1Hz,1H);13C NMR(400MHz,CDCl3,ppm)δ:157.90,146.57,136.69,135.39,134.06,133.16.128.90,126.04,125.74,125.49,121.50,62.12,57.28,53.11,51.45,47.58,40.68,33.43,29.25,25.68,21.97,16.87,15.14,10.67;HRMS(ESI+)对于C25H33N4([M+H]+)计算为:377.2700。实测为:377.2695,误差-0.5ppm;LC-MS(ESI-API,254nm)H2O中55%MeOH(0.1%HCO2H),6min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=377.2(M+H),189.2(M/2+H),t=0.754min。对于EMU030(立体异构体)2:1H NMR(600MHz,CDCl3,ppm)δ:8.44(d,J=4.6Hz,1H),7.31(d,J=7.7Hz,1H),7.09-6.97(m,5H),4.27(dd,J=10.0,6.4Hz,1H),4.00(AB的A,JAB=15.2Hz,1H),3.81(AB的B,JAB=15.2Hz,1H),2.92(ABX的A,JAB=13.2Hz,JAX=6.3Hz,1H),2.89-2.70(m,5H),2.67(AB的B,JAB=16.5Hz,1H),2.61(dd,J=16.1,3.8Hz,1H),2.57(dd,J=13.1,8.4Hz,1H),2.41-2.35(m,2H),2.13-2.07(m,1H),2.02-1.89(m,2H),1.76-1.66(m,1H),1.16-1.02(m,2H),0.73(td,J=8.4,4.6Hz,1H),0.03(q,J=5.2Hz,1H);13C NMR(400MHz,CDCl3,ppm)δ:158.30,146.71,136.32,135.61,134.51,133.74.128.96,126.20,125.68,125.28,121.25,60.76,57.49,53.89,52.33,48.47,41.99,33.78,29.35,26.35,21.92,19.70,15.54,9.36.HRMS(ESI+)对于C25H33N4([M+H]+)计算为:377.2700。实测为:377.2699,误差-0.1ppm;LC-MS(ESI-API,254nm)H2O中55%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(AgilentZorbax XDB-18,50mm×4.6mm,3.5μm),m/z=377.2(M+H),189.2(M/2+H),t=0.783min。
EMU074的合成
将2.5g的4-氨基环己烷羧酸(17.5mmol,1当量)、17.5mL的二噁烷和36.7mL的1MNaOH溶液(36.7mmol,2.1当量)装入配备有磁性搅拌棒的100mL rb烧瓶。将溶液冷却至0℃,并且逐滴添加溶解在17.5mL的二噁烷中的4.38g的Boc2O(20.1mmol,1.15当量)。在rt搅拌持续5h后,乳液的pH达到7。反应混合物通过添加稀释的HCl酸化至pH为5,用CH2Cl2(3×)萃取,并且经Na2SO4干燥。将有机物浓缩,并且获得4.03g(95%)的作为白色固体的粗产物17,其不经纯化即被用于下一个步骤中。1H NMR(400MHz,CDCl3,ppm)δ:4.41(br s,1H),3.42(brs,1H),2.25(tt,J=11.8,3.3Hz,1H),2.11-2.00(m,4H),1.60-1.41(m,2H),1.44(s,9H),1.12(q,J=12.7Hz,2H)。
将4.25g的酸17(17.5mmol,1当量)和58mL的THF装入配备有搅拌棒、适配器、隔膜和加料漏斗的100mL rb烧瓶。然后将反应混合物冷却至0℃,并且逐滴添加5.14mL的硼烷(54.1mmol,3.1当量)。在rt搅拌持续18h后,反应混合物通过在0℃添加5mL的MeOH、随后添加1N NaOH溶液淬灭。产物用EA(3×)萃取,用卤水洗涤并且经Na2SO4干燥。将粗产物通过从CH2Cl2结晶纯化,得到1.64g的作为白色固体的产物18。将滤液浓缩,用乙醚研磨,得到1.01g的更多产物18(总共2.65g,66%)。1H NMR(400MHz,CDCl3,ppm)δ:4.39(br s,1H),3.45(t,J=6.0Hz,2H),3.39(br s,1H),2.04(d,J=10.0Hz,2H),1.82(d,J=10.8Hz,2H),1.44(s,9H),1.33(t,J=5.6Hz,1H),1.15-0.98(m,4H)。
化合物19遵循用于化合物4的合成的程序从醇18合成。将粗产物在硅胶柱上纯化,使用己烷中0-30%EA作为洗脱剂,得到734mg(74%)的作为淡黄色油状物的产物19,其结晶成白色固体。1H NMR(400MHz,CDCl3,ppm)δ:9.61(d,J=1.5Hz,1H),4.42(br s,1H),3.40(brs,1H),2.21-1.97(m,4H),1.43(s,10H),1.39(ABX的A,JAB=13.1Hz,JAX=3.7Hz,1H),1.34(ABX的B,JAB=13.1Hz,JBX=3.4Hz,1H),1.18(ABX的A,JAB=12.8Hz,JAX=3.6Hz,1H),1.11(ABX的B,JAB=12.7Hz,JBX=3.6Hz,1H)。
化合物20遵循用于化合物5的合成的程序从胺I和醛19合成。将粗产物在硅胶柱上纯化,使用己烷中0至30%EA作为洗脱剂,得到263mg(84%)的作为微黄色油状物的产物20。1HNMR(400MHz,CDCl3,ppm)δ:8.41-8.29(m,1H),7.23(dd,J=7.7,1.7Hz,1H),7.17-6.90(m,5H),4.76-4.64(m,1.5H),4.45-4.32(m,1.5H),4.29-4.17(m,1H),3.97(br s,0.5H),3.79(br s,0.5H),3.29(br s,1H),3.18(d,J=15.8Hz,1H),3.13-2.88(m,2H),2.74-2.50(m,4H),2.33-2.21(m,1H),2.17-1.78(m,5H),1.73-1.42(m,3H),1.49(s,9H),1.42(s,9H),1.10-0.94(m,1H),0.96(qd,J=12.5,3.6Hz,1H),0.76(q,J=13.0Hz,1H),0.71-0.59(m,1H);LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),6min,1.00mL/min,C18(Agilent ZorbaxXDB-18,50mm×4.6mm,3.5μm),m/z=605.2(M+H),t=0.761min。
EMU074:化合物EMU074遵循用于化合物EMU030的合成的程序从胺20合成。将粗物质在硅胶柱上纯化,使用CH2Cl2中0-60%的溶剂2(溶剂2=70%CH2Cl2、30%MeOH、3%NH4OH)作为洗脱剂,得到作为微黄色油状物的107mg(94%)的产物EMU074。1H NMR(600MHz,CDCl3,ppm)δ:8.42(dd,J=4.8,1.6Hz,1H),7.32(d,J=8.5Hz,1H),7.10-7.06(m,2H),7.06-6.99(m,3H),4.07(AB的A,JAB=14.8Hz,1H),4.03(dd,J=10.5,6.4Hz,1H),3.97(AB的B,JAB=14.9Hz,1H),3.16(dd,J=13.8,5.6Hz,1H),2.90(d,J=13.1Hz,1H),2.82-2.71(m,2H),2.65(AB的B,JAB=16.6Hz,1H),2.62-2.53(m,2H),2.44-2.38(m,1H),2.37(dd,J=13.6,8.1Hz,1H),2.24(dd,J=13.4,10.2Hz,1H),2.14-2.07(m,1H),2.01-1.94(m,2H),1.90-1.83(m,4H),1.74-1.65(m,1H),1.42-1.34(m,1H),1.12-1.03(m,2H),0.92-0.84(m,2H);13CNMR(400MHz,CDCl3,ppm)δ:158.91,146.51,136.22,135.61,134.69,133.79,128.99,126.37,125.74,125.33,121.17,61.97,61.73,58.13,52.34,51.07,48.78,37.26,36.72,36.61,33.71,30.46,30.31,29.37,22.12;HRMS(ESI+)对于C26H37N4([M+H]+)计算为:405.3013。实测为:405.3062,误差5.0ppm;LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=405.2(M+H),203.2(M/2+H),t=0.767min。
EMU121的合成
化合物21遵循用于化合物4的合成的程序从叔丁基(((1r,4r)-4-(羟甲基)环己基)甲基)氨基甲酸酯合成。将粗产物在硅胶柱上纯化,使用己烷中0-50%EA作为洗脱剂,得到390mg(79%)的作为白色固体的产物21。1H NMR(400MHz,CDCl3,ppm)δ:9.62(d,J=1.5Hz,1H),4.59(br s,1H),3.00(t,J=6.5Hz,2H),2.18(ttd,J=12.2,3.6,1.6Hz,1H),2.05-1.98(m,2H),1.91-1.84(m,2H),1.44(s,9H),1.29(ABX的A,JAB=12.7Hz,JAX=3.1Hz,1H),1.23(ABX的B,JAB=13.2Hz,JBX=3.5Hz,1H),1.02(ABX的A,JAB=13.1Hz,JAX=3.5Hz,1H),0.96(ABX的B,JAB=13.0Hz,JBX=3.6Hz,1H)。
化合物20遵循用于化合物5的合成的程序从叔丁基(R)-3-((((S)-5,6,7,8-四氢喹啉-8-基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯和醛21合成。将粗产物在硅胶柱上纯化,使用己烷中0至50%EA作为洗脱剂,得到作为微澄清玻璃状物的342mg(76%)的产物22。1H NMR(400MHz,CDCl3,ppm)δ:8.38(br s,0.5H),8.34(br s,0.5H),7.25(d,J=8.0Hz,1H),7.16-7.04(m,4H),7.02-6.93(m,1H),4.72(br s,0.5H),4.73(AB的A,JAB=14.8Hz,0.5H),4.68(AB的A,JAB=14.8Hz,0.5H),4.55(br s,1H),4.35(br s,0.5H),4.25(AB的B,JAB=15.3Hz,0.5H),4.21(AB的B,JAB=15.3Hz,0.5H),3.98(br s,0.5H),3.77(br s,0.5H),3.19(AB的A,JAB=15.9Hz,0.5H),3.13-2.88(m,4.5H),2.75-2.50(m,3H),2.28(dd,J=13.2,6.1Hz,1H),2.16-1.79(m,4H),1.78-1.40(m,5H),1.50(s,9H),1.44(s,9H),1.36-1.23(m,1H),1.05(br s,1H),0.90-0.52(m,4H).LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),6min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=619.3(M+H),t=0.744min。
EMU121:化合物EMU121遵循用于化合物EMU030的合成的程序从胺22合成。将粗物质在硅胶柱上纯化,使用CH2Cl2中0-60%的溶剂2(溶剂2=70%CH2Cl2、30%MeOH、3%NH4OH)作为洗脱剂,得到110mg(定量)的作为微黄色油状物的产物EMU121。1H NMR(600MHz,CDCl3,ppm)δ:8.42(d,J=4.1Hz,1H),7.32(d,J=7.6Hz,1H),7.10-7.01(m,5H),4.15-3.95(m,3H),3.12(br s,1H),2.93(d,J=13.2Hz,1H),2.82(br s,1H),2.75(ddd,J=16.5,11.5,5.0Hz,1H),2.65(AB的B,JAB=16.5Hz,1H),2.58(d,J=15.4Hz,1H),2.52(dd,J=6.4Hz,4H),2.47-2.22(m,1H),2.14-1.65(m,8H),1.39(s,1H),1.28-1.18(m,1H),0.97-0.78(m,4H).13C NMR(400MHz,CDCl3,ppm)δ:158.93,146.45,136.26,135.41,134.63,133.80,128.98,126.36,125.77,125.34,121.17,62.03,61.74,58.09,52.38,48.70,48.64,41.54,38.04,33.56,31.19,31.10,30.46,30.38,29.34,22.08.HRMS(ESI+)对于C27H39N4([M+H]+)计算为:419.3169。实测为:419.3168,误差-0.1ppm。LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=419.2(M+H),210.2(M/2+H),t=0.499min。
用仲胺和大体积羰基还原胺化
一般方案
EMU075的合成
将配备有橡胶隔膜和磁性搅拌棒的250mL rb烧瓶放置在Ar气氛下,并且装入19.7mL的2M三甲基铝溶液(39.4mmol,3当量),并且将溶液冷却至0℃。然后逐滴添加6.84mL的1-辛烷硫醇(39.4mmol,3当量)。在rt搅拌持续20min后,逐滴添加溶解在30.6mL的CH2Cl2中的1.50g的3,3-二甲基二氢呋喃-2(3H)-酮(13.1mmol,1当量),并且将反应混合物在rt搅拌持续12h。然后反应混合物通过添加77mL的乙醚和116mL的1NHCl溶液淬灭。产物用乙醚(3×)萃取,用1N HCl和饱和NaHCO3溶液洗涤并且经Na2SO4干燥。将粗产物在硅胶柱上纯化,使用己烷中5-25%EA作为洗脱剂,得到作为澄清液体的2.26g(66%)的产物13。
化合物29遵循用于化合物2的合成的程序从醇13合成。将粗产物在硅胶柱上纯化,使用己烷中10%至20%EA作为洗脱剂,得到作为澄清油状物的594mg(93%)的产物29。1HNMR(400MHz,CDCl3,ppm)δ:7.79(dd,J=5.4,3.1Hz,2H),7.67(dd,J=5.5,3.0Hz,2H),3.68-3.63(m,2H),2.70(t,J=7.4Hz,2H),1.97-1.92(m,2H),1.45(p,J=7.5Hz,1H),1.28(s,6H),1.34-1.18(m,10H),0.83(t,J=6.8Hz,3H).13C NMR(400MHz,CDCl3,ppm)δ:205.38,167.88,133.73,132.09,123.03,48.45,38.57,34.07,31.69,29.32,29.05,28.97,28.84,28.59,25.20,22.54,14.00.LC-MS(ESI-API,254nm)H2O中95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent ZorbaxXDB-18,50mm×4.6mm,3.5μm),m/z=412.0(M+Na),t=1.407min;
将594mg的硫酯29(1.53mmol,1当量)、27.0mg的PdCl2(0.152mmol,0.1当量)、43μL的TEA(0.305mmol,0.2当量)和3.1mL的CH2Cl2装入配备有搅拌棒的20mL小瓶。然后逐滴添加731μL的三乙基硅烷(4.57mmol,3当量),并且溶液变成黑色悬浮液。在rt搅拌持续20min后,反应混合物通过添加10%柠檬酸溶液淬灭,过滤通过硅藻土短柱,用CH2Cl2(2×)萃取,并且经Na2SO4干燥。将粗产物在硅胶柱上纯化,使用己烷中10-30%EA作为洗脱剂,得到321mg(86%)的作为澄清油状物的产物30。1H NMR(400MHz,CDCl3,ppm)δ:9.47(s,1H),7.84(dd,J=5.4,3.1Hz,2H),7.71(dd,J=5.5,3.0Hz,2H),3.70-3.61(m,2H),1.93-1.84(m,2H),1.16(s,6H).LC-MS(ESI-API,254nm)H2O中95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=246.0(M+H),t=0.580min;
化合物31遵循用于化合物25的合成的程序从醛30和(S)-5,6,7,8-四氢喹啉-8-胺合成。将粗产物在硅胶柱上纯化,使用EA作为洗脱剂,得到492mg(100%)的产物31,其在冷冻器中结晶成白色固体。1H NMR(400MHz,CDCl3,ppm)δ:8.38(d,J=4.7Hz,1H),7.82(dd,J=5.5,3.0Hz,2H),7.68(dd,J=5.5,3.0Hz,2H),7.35(d,J=7.7Hz,1H),7.05(dd,J=7.6,4.7Hz,2H),3.75-3.69(m,3H),2.81(dt,J=13.6,6.6Hz,1H),2.72(dt,J=16.8,5.6Hz,1H),2.61(AB的A,JAB=11.3Hz,1H),2.55(AB的B,JAB=11.4Hz,1H),2.14-1.98(m,2H),1.84-1.62(m,4H),1.04(s,3H),1.03(s,3H).LC-MS(ESI-API,254nm)H2O中95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=378.2(M/2+H),t=0.469min。
化合物32遵循用于化合物27的合成的程序从叔丁基(R)-3-甲酰基-3,4-二氢异喹啉-2(1H)-羧酸酯和胺31合成。将粗产物在硅胶柱上纯化,使用己烷中0至40%EA作为洗脱剂,得到作为微黄色粉末的0.207g(56%)的产物32。1H NMR(400MHz,CDCl3,ppm)δ:8.38(brs,0.7H),8.33(br s,0.3H),7.82(dd,J=5.5,3.0Hz,2H),7.70(dd,J=5.5,3.1Hz,2H),7.21-7.10(m,1H),7.08-6.92(m,4H),6.88(dd,J=7.7,4.6Hz,1H),4.71(br s,0.3H),4.71(AB的A,JAB=16.8Hz,0.7H),4.67(AB的A,JAB=16.8Hz,0.3H),4.44(br s,0.7H),4.27(AB的B,JAB=17.4Hz,0.3H),4.15(AB的B,JAB=17.2Hz,0.7H),4.05(br s,0.3H),3.94(br s,0.7H),3.69-3.54(m,2H),3.30(AB的A,JAB=16.1Hz,0.7H),3.15(AB的A,JAB=16.2Hz,0.3H),3.02-2.82(m,2H),2.68-2.08(m,7H),1.95-1.87(m,1H),1.80-1.31(m,3H),1.49(s,6.3H),1.46(s,2.7H),0.98(s,2.1H),0.91(s,2.1H),0.87(s,0.9H),0.84(s,0.9H).LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),6min,1.00mL/min,C18(Agilent ZorbaxXDB-18,50mm×4.6mm,3.5μm),m/z=623.2(M+H),t=0.946min,纯度为97%。
化合物33遵循用于化合物6的合成的程序从胺32合成。将粗产物用于下一个步骤中。
EMU075:化合物EMU075遵循用于化合物EMU030的合成的程序从胺33合成。将粗物质在硅胶柱上纯化,使用CH2Cl2中0至60%的溶剂2(溶剂2=70%CH2Cl2、30%MeOH、3%NH4OH)作为洗脱剂,得到作为微黄色粉末的69mg(85%)的产物EMU075。1H NMR(600MHz,CDCl3,ppm)δ:8.44(d,J=4.7Hz,1H),7.30(d,J=7.7Hz,1H),7.08-7.02(m,3H),7.01-6.98(m,2H),4.02(dd,J=11.0,6.2Hz,1H),4.00(AB的A,JAB=14.5Hz,1H),3.79(AB的B,JAB=14.9Hz,1H),3.54(d,J=14.5Hz,1H),2.84(d,J=13.5Hz,1H),2.78-2.71(m,2H),2.66-2.58(m,1H),2.48(dd,J=15.8,3.4Hz,1H),2.44(d,J=14.5Hz,1H),2.34(dd,J=16.0,11.2Hz,1H),2.2-2.19(m,1H),2.12(t,J=12.0Hz,1H),2.00-1.88(m,2H),1.73-1.64(m,1H),1.53(dt,J=13.1,8.2Hz,1H),1.44(dt,J=13.1,8.2Hz,1H),0.97(s,3H),0.95(s,3H).13C NMR(400MHz,CDCl3,ppm)δ:158.94,146.43,136.33,135.52,134.56,133.57,128.93,126.44,125.74,125.34,121.28,68.89,64.31,59.58,52.14,48.40,44.73,37.81,35.39,33.63,29.94,29.50,25.79,25.30,22.48.HRMS(ESI+)C25H37N4([M+H]+)计算为:393.3013。实测为:393.3092,误差7.9ppm。LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=393.2(M+H),197.2(M/2+H),t=0.855min;
具有烯烃侧链的类似物的合成
一般方案
EMU124的合成
将5.24g的LAH(138mmol,4.2当量)和33mL的乙醚装入配备有搅拌棒和橡胶隔膜的250mL rb烧瓶。在将悬浮液冷却至0℃后,逐滴添加溶解在33mL的乙醚中的5.00g的4,5,6,7-四氢异苯并呋喃-1,3-二酮(32.9mol,1当量),并且将悬浮液在rt搅拌持续3h。反应混合物通过小心地添加5mL的水和10mL的2N NaOH随后是25mL的水淬灭。然后添加乙醚和硅藻土,并且将悬浮液过滤通过硅藻土短柱并且经Na2SO4干燥。将有机物浓缩,并且获得2.89g(62%)的产物34。1H NMR(400MHz,CDCl3,ppm)δ:δ4.12(s,4H),2.32-2.22(m,2H),2.17-2.11(m,4H),1.65-1.58(m,4H)。
将2.89g的二醇34(20.3mmol,1当量)、1.52g的咪唑(22.4mmol,1.1当量)、3.22g的TBSCl(21.3mmol,1.05当量)和20.3mL的CH2Cl2装入配备有磁性搅拌棒和橡胶隔膜的250mLrb烧瓶。在rt搅拌持续12h后,反应混合物通过添加NH4Cl溶液淬灭,用CH2Cl2(3×)萃取并且经Na2SO4干燥。将粗产物在硅胶柱上纯化,使用己烷中0至20%EA作为洗脱剂,得到1.71g(33%)的产物35。1H NMR(400MHz,CDCl3,ppm)δ:δ4.15(s,2H),4.05(s,2H),2.16-2.03(m,5H),1.62-1.57(m,4H),0.90(s,9H),0.08(s,6H)。
化合物36遵循用于化合物2的合成的程序从醇35合成。将粗产物在硅胶柱上纯化,使用己烷中0至10%的EA作为洗脱剂,得到2.17g(88%)的产物36。1H NMR(400MHz,CDCl3,ppm)δ:7.85-783(m,2H),7.72-7.68(m,2H),4.42(s,2H),4.36(s,2H),2.11(br s,2H),1.96(br s,2H),1.60-1.50(m,4H),0.92(s,9H),0.11(s,6H)。
化合物37遵循用于化合物3的合成的程序从TBS醚36合成。粗产物通过将产物溶解在最少量的CH2Cl2中并且通过添加乙醚使产物沉淀来纯化。将醚倒出,并且用乙醚研磨产物。将产品在高真空下干燥,得到1.28g(84%)的作为白色固体的产物37。1H NMR(400MHz,CDCl3,ppm)δ:7.84(dd,J=5.5,3.0Hz,2H),7.73(dd,J=5.4,3.1Hz,2H),4.42(s,2H),4.24(d,J=6.4Hz,2H),3.28(t,J=6.5Hz,1H),2.20(br s,2H),1.93(br s,2H),1.62-1.52(m,4H).LC-MS(ESI-API,254nm)H2O中95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(AgilentZorbax XDB-18,50mm×4.6mm,3.5μm),m/z=294.0(M+Na),t=0.615min,纯度为86%;
将0.350g的醇37(1.29mmol,1当量)、0.389g的三苯基膦(1.48mmol,1.15当量)和6.5mL的CH2Cl2装入配备有搅拌棒和橡胶隔膜的100mL rb烧瓶。然后逐份添加0.492g的CBr4(1.48mmol,1.15当量),并且将混合物在rt搅拌持续2h。反应混合物通过添加水淬灭,用CH2Cl2(2×)萃取并且经Na2SO4干燥。将粗产物在硅胶柱上纯化,使用CH2Cl2作为洗脱剂,得到414mg(96%)的作为白色固体的产物38。1H NMR(400MHz,CDCl3,ppm)δ:7.87-7.81(m,2H),7.74-7.70(m,2H),4.36(s,2H),4.30(s,2H),2.22-2.17(m,2H),2.07-2.01(m,2H),1.64-1.52(m,4H)。
将0.386g的溴化物38(1.16mmol,1.2当量)和0.016g的KI(0.096mmol,0.1当量)装入配备有冷指冷凝器和搅拌棒的50mL Schlenk管。然后添加溶解在3.2mL的乙腈中的0.379g的叔丁基(R)-3-((((S)-5,6,7,8-四氢喹啉-8-基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯(0.962mmol,1当量)和0.252mL的DIPEA(1.44mmol,1.5当量)。在60℃搅拌持续24h后,反应混合物通过添加水淬灭,用乙醚(3×)萃取并且经Na2SO4干燥。将粗产物在硅胶柱上纯化,使用己烷中0至30%EA作为洗脱剂,得到408mg(66%)的产物39。1H NMR(400MHz,CDCl3,ppm)δ:8.38(s,1H),7.79-7.73(m,2H),7.70-7.63(m,2H),7.28-7.23(m,1H),7.19-7.02(m,4H),6.96(dd,J=7.6,4.7Hz,1H),4.82(br s,0.5H),4.86-4.69(m,1H),4.59(brs,0.5H),4.36(d,J=14.8Hz,1H),4.28-4.03(m,3H),3.63-3.51(m,1H),3.20-2.83(m,4H),2.77-2.47(m,3H),2.30-1.64(m,8H),1.50(s,9H),1.54-1.38(4H).LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),6min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=647.2(M+H),t=1.119min;
化合物40遵循用于化合物6的合成的程序从胺39合成。将有机物浓缩,并且将粗产物用于下一个步骤。
EMU124:化合物EMU124遵循用于EMU030的合成的程序从胺40合成。将粗物质在硅胶柱上纯化,使用CH2Cl2中0至60%的溶剂2(溶剂2=30%MeOH、70%CH2Cl2和3%NH4OH)作为洗脱剂,得到59mg(43%)的产物EMU124。1H NMR(600MHz,CDCl3,ppm)δ:8.53(d,J=4.8Hz,1H),7.35(d,J=7.5Hz,1H),7.11-6.98(m,5H),4.05(AB的A,JAB=15.8Hz,1H),4.02(dd,J=10.1,6.5Hz,1H),3.81(AB的B,JAB=15.9Hz,1H),3.64(d,J=12.8Hz,1H),3.33(d,J=12.8Hz,1H),3.10(d,J=13.0Hz,1H),2.87-2.73(m,2H),2.70-2.63(m,1H),2.59(d,J=16.2Hz,1H),2.41-2.26(m,3H),2.18-2.04(d,J=11.2Hz,3H),2.02-1.89(m,3H),1.69(q,J=11.5,10.9Hz,1H),1.62-1.47(m,6H).13C NMR(400MHz,CDCl3,ppm)δ:157.82,146.58,136.83,135.45,134.23,134.16,134.13,133.00,129.10,126.14,125.88,125.54,121.63,59.14,56.96,56.06,51.53,47.90,42.23,33.63,30.68,29.37,29.23,25.72,22.77,22.75,22.00。HRMS(ESI+)对于C27H37N4([M+H]+)计算为:417.3013。实测为:417.3010,误差0.3ppm。LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(AgilentZorbax XDB-18,50mm×4.6mm,3.5μm),m/z=417.2(M+H),209.2(M/2+H),t=0.856min;
EMU125、EMU126、EMU140和EMU141的合成
如在参考文献(Nucleosides,Nucleotides,and NucleicAcids 2008,27,213-223)中,将20.9mL的乙基2-(二乙氧基磷酰基)-2-氟乙酸酯(103mmol,1当量)和313mL的THF装入配备有搅拌棒、加料漏斗和橡胶隔膜的1L 3颈烧瓶。在将反应混合物冷却至-78℃后,逐滴添加己烷(103mmol,1当量)中的41.3mL的2.5M nBuLi溶液,并且允许将反应混合物在30min期间升温至0℃。将溶液冷却至-78℃,并且通过加料漏斗逐滴添加溶解在38mL的THF中的19.9mL的1-((叔丁基二甲基硅烷基)氧基)丙-2-酮(103mmol,1当量)。在-78℃搅拌持续1h和在0℃搅拌持续1h后,允许将反应混合物升温至rt并且继续搅拌持续多于12h。然后反应混合物通过添加饱和NH4Cl溶液淬灭,用己烷(1×)和乙醚(2×)萃取,用卤水洗涤并且经Na2SO4干燥。将粗产物在硅胶柱上纯化,使用己烷中0至5%EA作为洗脱剂以得到作为Z/E(2∶1)异构体的混合物的25.9g(91%)的产物41。1HNMR(400MHz,CDCl3,ppm)δ:4.67(d,J=2.7Hz,0.8H),4.36(d,J=3.7Hz,2H),4.28(q,J=7.1Hz,2H),4.27(q,J=7.1Hz,0.8H),2.12(d,J=3.2Hz,2H),1.92(d,J=4.4Hz,0.8H),1.34(t,J=7.1Hz,3H),1.34(t,J=7.1Hz,1.2H),0.90(s,12.6H),0.08(s,6H),0.07(s,2.4H)。
将13.6g的酯41(49.2mmol,1当量)和246ml的CH2Cl2装入配备有搅拌棒和橡胶隔膜的1L rb烧瓶。在冷却至-78℃后,添加甲苯中的90mL的1.2M DIBAL-H溶液(108mmol,2.2当量),并且将反应混合物在0℃搅拌持续2h。然后反应混合物通过添加40mL的MeOH淬灭,并且在rt继续搅拌持续12h。将悬浮液过滤通过硅藻土短柱并且浓缩。将粗产物在硅胶柱上纯化,使用己烷中0至30%EA作为洗脱剂,得到作为黄色油状物的10.1g(88%)的产物42。1HNMR(400MHz,CDCl3,ppm)δ:4.27(d,J=22.4Hz,1H),4.26(d,J=3.2Hz,2H),4.25(d,J=22.1Hz,2H),4.15(d,J=2.4Hz,1H),1.72(d,J=2.9Hz,4.5H),1.69(br s,1.5H),0.90(s,4.9H),0.90(s,9H),0.08(s,3H),0.07(s,6H)。
化合物43遵循用于化合物2的合成的程序从醇42合成。将粗产物在硅胶柱上纯化,使用己烷中0至10%的EA作为洗脱剂,得到7.45g(89%)的产物43。1H NMR(400MHz,CDCl3,ppm)δ:7.86-7.82(m,3H),7.73-7.69(m,3H),4.52(d,J=20.9Hz,1H),4.46(d,J=20.3Hz,2H),4.35(d,J=2.0Hz,1H),4.22(d,J=3.2Hz,2H),1.88(d,J=2.9Hz,3H),1.70(d,J=3.5Hz,1.5H),0.91(s,4.5H),0.87(s,9H),0.11(s,3H),0.02(s,6H)。
化合物44遵循用于化合物3的合成的程序从TBS醚43合成。将粗产物通过结晶纯化,得到2.46g(48%,7∶1Z/E)、1.04g(20%,1∶3Z/E)、0.916g(18%,1.8∶1Z/E)的作为白色固体的产物44。
化合物45遵循用于化合物38的合成的程序从醇44合成。将有机物通过硅胶短柱过滤并且浓缩以得到801mg(85%)的作为白色固体的产物45。
化合物46和47遵循用于化合物39的合成的程序从叔丁基(R)-3-((((S)-5,6,7,8-四氢喹啉-8-基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯和溴化物45合成。将粗产物在硅胶柱上纯化,使用CH2Cl2中0至20%EA,得到330mg(31%)的46、158mg(15%)的异构体的混合物和339mg(32%)的47。对于46异构体: 1H NMR(400MHz,CDCl3,ppm)δ:8.40(br s,1H),7.79(br s,2H),7.70(br s,2H),7.27(br s,1H),7.17-6.94(m,5H),4.81-4.65(m,2H),4.58-4.36(m,1H),4.29-4.14(m,2H),4.15-3.99(m,1H),3.62(d,J=13.4Hz,1H),3.24-2.78(m,3H),2.77-2.46(m,4H),2.25-2.09(m,1H),1.95(br s,1H),1.87-1.63(m,2H),1.74(s,3H),1.50(s,9H).LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),6min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=625.2(M+H),t=1.272min;对于47异构体: 1H NMR(400MHz,CDCl3,ppm)δ:8.41(br s,1H),7.84-7.79(dd,J=5.4,3.0Hz,2H),7.70(dd,J=5.5,3.0Hz,2H),7.22(br s,1H),7.12-6.90(m,5H),4.74-4.62(m,1H),4.53-4.07(m,3H),3.98(br s,1H),3.28-2.89(m,4H),2.84-2.46(m,4H),2.21-2.05(m,1H),1.90(s,3H),1.94-1.56(m,4H),1.48(s,9H).LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),6min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=625.2(M+H),t=0.849min,纯度为95%;
化合物48遵循用于化合物6的合成的程序从胺46合成。该粗物质不经纯化即被用于下一个步骤中。
化合物49遵循用于化合物6的合成的程序从胺47合成。该粗物质不经纯化即被用于下一个步骤中。
EMU125:化合物EMU125遵循用于化合物EMU030的合成的程序从胺48合成。将粗物质在硅胶柱上纯化,使用CH2Cl2中0至60%的溶剂2(溶剂2=30%MeOH、70%CH2Cl2和3%NH4OH)作为洗脱剂,得到118mg(100%)的产物EMU125。1H NMR(400MHz,CDCl3,ppm)δ:8.42(d,J=4.1Hz,1H),7.32(d,J=7.9Hz,1H),7.12-7.06(m,2H),7.05-7.01(m,3H),4.16(brs,1H),4.11(AB的A,JAB=14.9Hz,1H),4.06-4.01(m,1H),4.00(AB的B,JAB=15.1Hz,1H),3.60(ABX的A,JAX=24.5Hz,JAB=14.9Hz,1H),3.52(ABX的B,JBX=21.8Hz,JAB=14.9Hz,1H),3.16(dd,J=13.0,4.0Hz,1H),2.93-2.88(m,1H),2.79-2.70(m,1H),2.70-2.61(m,2H),2.57(dd,J=16.0,3.6Hz,1H),2.51-2.32(m,2H),2.09-2.03(m,1H),1.99-1.85(m,2H),1.76(d,J=3.2Hz,3H),1.73-1.63(m,1H).13C NMR(400MHz,CDCl3,ppm)δ:158.92,158.04(d,J=247.6Hz),146.52,136.24,135.12,134.27,134.03,128.91,126.30,125.82,125.40,121.16,111.24(d,J=14.6Hz),57.90,56.04,54.39(d,J=8.9Hz),51.47,48.52,39.34(d,J=30.1Hz),33.51,29.86,29.26,22.21,12.76(d,J=8.3Hz).19F NMR(400MHz,CDCl3,ppm)δ:-114.36(t,J=23.4Hz).HRMS(ESI+)对于C24H32FN4([M+H]+)计算为:395.2606。实测为:395.2603,误差-0.3ppm。LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=395.2(M+H),198.2(M/2+H),t=0.773min;
EMU126:化合物EMU126遵循用于化合物EMU030的合成的程序从胺49合成。将粗物质在硅胶柱上纯化,使用CH2Cl2中0至60%的溶剂2(溶剂2=30%MeOH、70%CH2Cl2和3%NH4OH)作为洗脱剂,得到129mg(100%)的产物EMU126。1H NMR(400MHz,CDCl3,ppm)δ:8.45(d,J=4.7Hz,1H),7.31(d,J=7.7Hz,1H),7.13-6.98(m,5H),4.10-4.00(m,2H),3.86(d,J=15.1Hz,1H),3.81-4.75(m,1H),3.40(d,J=21.7Hz,2H),3.19(d,J=13.3Hz,1H),2.99(d,J=13.3Hz,1H),2.76(ddd,J=16.3,10.9,4.9Hz,2H),2.66(AB的B,JAB=16.4Hz,1H),2.61(d,J=15.1Hz,1H),2.45(br s,2H),2.12-2.06(m,1H),2.00-1.89(m,2H),1.76(s,3H),1.78-1.67(m,1H).13CNMR(400MHz,CDCl3,ppm)δ:158.43,156.06(d,J=245.6Hz),146.62,136.20,135.08,134.38,133.64,128.92,126.24,125.78,125.32,121.18,111.53(d,J=12.7Hz),60.90,57.16,52.08,52.00(d,J=14.2Hz),48.28,39.56(d,J=30.8Hz),33.41,29.29,28.07,21.92,14.03(d,J=4.8Hz).19F NMR(400MHz,CDCl3,ppm)δ:-120.90(t,J=21.7Hz).HRMS(ESI+)对于C24H32FN4([M+H]+)计算为:395.2606。实测为:395.2649,误差4.3ppm。LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=395.2(M+H),198.2(M/2+H),t=0.797min;
化合物50遵循用于化合物38的合成的程序从醇42合成。产物不经纯化即被用于下一步骤。
化合物51遵循用于化合物39的合成的步骤从叔丁基(R)-3-((((S)-5,6,7,8-四氢喹啉-8-基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯和溴化物50合成。将粗产物在硅胶柱上纯化,使用己烷中0至30%EA作为洗脱剂,得到408mg的产物51。
化合物52和53遵循用于化合物39的合成的程序从胺I和溴化物51合成。将粗产物在硅胶柱上纯化,使用CH2Cl2中0至60%EA,得到0.440g(16%)的52和1.04g(37%)的53。对 于52: 1H NMR(400MHz,CDCl3,ppm)δ:8.44(br s,1H),7.19(d,J=8.0Hz,1H),7.06-6.84(m,5H),4.64-4.43(m,2.5H),4.36(br s,0.5H),4.17(d,J=16.6Hz,1H),4.13-3.98(m,1H),3.75(brs,1H),3.20-2.90(m,2H),2.86(dd,J=15.8,5.6Hz,1H),2.55-2.47(m,2H),2.37-1.97(m,4H),1.83(s,3H),1.89-1.31(m,2H),1.50(s,9H).LC-MS(ESI-API,254nm)H2O中95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=496.2(M+H),t=1.031min;对于53: 1H NMR(400MHz,CDCl3,ppm)δ:8.34(d,J=4.5Hz,1H),7.29(d,J=7.7Hz,1H),7.16-6.95(m,5H),4.61(AB的A,JAB=17.0Hz,1H),4.55(d,J=11.7Hz,1H),4.52-4.45(m,1H),4.26(AB的B,JAB=17.1Hz,1H),3.87-3.78(m,1H),3.69(dd,J=10.6,6.1Hz,1H),3.44-3.28(m,2H),3.18(AB的A,JAB=15.9Hz,1H),3.03-2.58(m,5H),2.26-2.18(m,1H),2.02-1.95(m,1H),1.82(q,J=11.3Hz,1H),1.73-1.58(m,1H),1.70(s,3H),1.48(s,9H).LC-MS(ESI-API,254nm)H2O中95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=496.2(M+H),t=0.725min;
化合物54遵循用于化合物2的合成的程序从醇52合成。将粗产物在硅胶柱上纯化,使用己烷中0至40%的EA作为洗脱剂,得到0.640g(128%)的产物54。1H NMR(400MHz,CDCl3,ppm)δ:8.36(br s,1H),7.79(dd,J=5.4,3.1Hz,2H),7.69(dd,J=5.5,3.1Hz,2H),7.30(d,J=7.3Hz,1H),7.11(s,3H),7.05-6.98(m,1H),6.98(dd,J=7.8,4.8Hz,1H),4.81-4.66(m,1.5H),4.54(br s,0.5H),4.30-4.02(m,4H),3.51-3.28(m,1H),3.16-2.91(m,3H),2.83-2.62(m,4H),2.25-1.66(m,4H),1.54(d,J=3.3Hz,3H),1.50(s,9H).LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),6min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=625.2(M+H),t=0.989min;
化合物55遵循用于化合物2的合成的程序从醇53合成。将粗产物在硅胶柱上纯化,使用己烷中0至40%的EA作为洗脱剂,得到0.958g(78%)的产物55。1H NMR(400MHz,CDCl3,ppm)δ:8.31(br s,1H),7.83(dd,J=5.4,3.0Hz,2H),7.74-7.67(m,2H),7.27(d,J=7.2Hz,1H),7.16-7.06(m,3H),7.03(br s,1H),6.98-6.93(m,1H),4.74-4.62(m,1.5H),4.43(brs,0.5H),4.39(AB的A,JAB=17.6Hz,1H),4.33(AB的B,JAB=15.6Hz,1H),4.14(AB的B,JAB=17.1Hz,1H),3.95(br s,1H),3.28-2.88(m,3H),2.77-2.56(m,5H),2.15-1.63(m,4H),1.46(s,9H),1.39(d,J=2.8Hz,3H).LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),6min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=625.2(M+H),t=0.987min,纯度为96%;
化合物56遵循用于化合物6的合成的程序从胺54合成。该粗物质不经纯化即被用于下一个步骤中。
化合物57遵循用于化合物6的合成的程序从胺55合成。该粗物质不经纯化即被用于下一个步骤中。
EMU140:化合物EMU140遵循用于化合物EMU030的合成的程序从胺56合成。将粗物质在硅胶柱上纯化,使用CH2Cl2中0至60%的溶剂2(溶剂2=30%MeOH、70%CH2Cl2和3%NH4OH)作为洗脱剂,得到109mg(56%)的产物EMU140。1H NMR(600MHz,CDCl3,ppm)δ:8.43(d,J=4.7Hz,1H),7.33(d,J=7.7Hz,1H),7.10-7.00(m,5H),4.27(dd,J=30.3,14.6Hz,1H),4.09(dd,J=10.7,6.5Hz,1H),4.05(AB的A,JAB=15.0Hz,1H),3.94(AB的B,JAB=15.1Hz,1H),3.46(t,J=14.9Hz,1H),3.34(AB的A,JAB=13.5Hz,1H),3.30(AB的B,JAB=13.5Hz,1H),2.87(t,J=10.9Hz,1H),2.82(dd,J=13.3,2.9Hz,1H),2.78-2.71(m,1H),2.65(AB的B,JAB=16.6Hz,1H),2.57(dd,J=15.8,3.6Hz,1H),2.41(dd,J=16.0,10.9Hz,1H),2.35(dd,J=12.5,11.0Hz,1H),2.15-2.08(m,1H),2.00-1.94(m,1H),1.93-1.86(m,1H),1.76(d,J=3.1Hz,3H),1.74-1.65(m,1H).13C NMR(400MHz,CDCl3,ppm)δ:158.60,154.19(d,J=248.9Hz),146.57,136.40,135.56,134.37,133.96,128.92,126.36,125.73,125.37,121.33,116.73(d,J=12.9Hz),60.01,56.49,51.54,51.46(d,J=26.6Hz),48.57,42.81(d,J=7.6Hz),33.62,29.22,22.08,12.37(d,J=8.3Hz)。19F NMR(400MHz,CDCl3,ppm)δ:-112.40(br s).HRMS(ESI+)对于C24H32FN4([M+H]+)计算为:395.2606。实测为:395.2618,误差1.2ppm。LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=395.2(M+H),198.2(M/2+H),t=0.815min;
EMU141:化合物EMU141遵循用于化合物EMU030的合成的程序从胺57合成。将粗物质在硅胶柱上纯化,使用CH2Cl2中0至60%的溶剂2(溶剂2=30%MeOH、70%CH2Cl2和3%NH4OH)作为洗脱剂,得到186mg(90%)的产物EMU141。1H NMR(600MHz,CDCl3,ppm)δ:8.43(d,J=4.7Hz,1H),7.33(d,J=7.7Hz,1H),7.11-6.99(m,5H),4.24(dd,J=29.9,14.8Hz,1H),4.09(dd,J=10.8,6.5Hz,1H),4.07(AB的A,JAB=15.1Hz,1H),3.98(AB的B,JAB=15.0Hz,1H),3.43(t,J=15.5Hz,1H),3.36(ABX的A,JAB=13.3Hz,JAX=2.5Hz,1H),3.32(ABX的B,JAB=13.3Hz,JBX=2.6Hz,1H),2.94-2.87(m,2H),2.75(ddd,J=16.7,11.6,5.0Hz,1H),2.65(AB的B,JAB=16.6Hz,1H),2.57(dd,J=16.0,3.4Hz,1H),2.48-2.31(m,2H),2.13-2.07(m,1H),2.00-1.86(m,2H),1.73(d,J=2.6Hz,3H),1.79-1.65(m,1H).13C NMR(400MHz,CDCl3,ppm)δ:158.60,153.23(d,J=245.9Hz),146.43,136.26,135.47,134.37,133.78,128.83,126.29,125.63,125.24,121.20,116.11(d,J=15.2Hz),60.56,56.62,51.71,51.43(d,J=26.5Hz),48.58,40.65(d,J=9.9Hz),33.48,30.08,29.08,21.93,13.88(d,J=5.3Hz).19FNMR(400MHz,CDCl3,ppm)δ:-116.37(dd,J=30.3,16.2Hz).HRMS(ESI+)对于C24H32FN4([M+H]+)计算为:395.2606。实测为:395.2602,误差-0.3ppm。LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=395.2(M+H),198.2(M/2+H),t=0.818min;
EMU177和EMU208的合成
将5.00mL的3-甲基呋喃-2(5H)-酮(57.6mmol,1当量)和48.0ml的甲苯装入配备有搅拌棒和橡胶隔膜的250mL rb烧瓶。在冷却至0℃后,添加在甲苯(127mmol,2.2当量)中的106mL的1.2M DIBAL-H溶液,并且将反应混合物在0℃搅拌持续2h。然后反应通过添加32mL的MeOH随后是51mL的甲苯和11mL的水淬灭。将反应混合物搅拌持续30min并且添加硅藻土。在搅拌持续30min后,将悬浮液过滤通过硅藻土短柱并且用EA洗涤硅藻土短柱。将有机物浓缩,并且获得5.71g(97%)的产物58。1HNMR(400MHz,CDCl3,ppm)δ:5.60(t,J=7.1Hz,1H),4.16(d,J=7.9Hz,2H),4.15(s,2H),2.46(br s,1H),2.26(br s,1H),1.83(s,3H)。
化合物59遵循用于化合物35的合成的程序从二醇58合成。将粗产物在硅胶柱上纯化,使用己烷中0-30%EA作为洗脱剂,得到3.42g(27%)的作为区域异构体(regioisomer)的混合物的产物59。1H NMR(400MHz,CDCl3,ppm)δ:5.54(t,J=7.0Hz,0.3H),5.51(t,J=7.0Hz,0.7H),4.21(d,J=6.4Hz,0.7H),4.18(s,0.3H),4.15(t,J=6.7Hz,0.3H),4.11(d,J=6.1Hz,0.7H),2.14(t,J=6.1Hz,1H),1.81(s,2.1H),1.77(s,0.9H),0.90(s,9H),0.08(s,6H)。
化合物60遵循用于化合物2的合成的程序从醇59合成。将粗产物在硅胶柱上纯化,使用己烷中0至10%EA作为洗脱剂。将有机物浓缩,并且将产物用于下一个步骤。
化合物61和62遵循用于化合物3的合成的程序从TBS醚60合成。将粗产物在硅胶柱上纯化,使用己烷中0至60%EA作为洗脱剂,得到0.297g(8%)的62、1.36g(37%)的异构体的混合物和1.91g(52%)的61。对于第一异构体62:1H NMR(300MHz,CDCl3,ppm)δ:7.85-7.81(m,2H),7.74-7.69(m,2H),5.32(t,J=8.0Hz,1H),4.38(dd,J=8.0,0.9Hz,2H),4.28(s,2H),2.83(br s,1H),1.83-1.81(m,3H).LC-MS(ESI-API,254nm)H2O中95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=254.0(M+Na),232.0(M+H),t=0.548min;对于第二异构体61:_1H NMR(400MHz,CDCl3,ppm)δ:7.85(dd,J=5.5,3.0Hz,2H),7.74(dd,J=5.4,3.1Hz,2H),5.76(t,J=7.6Hz,1H),4.40(d,J=0.8Hz,2H),4.31(d,J=7.5Hz,2H),2.82(br s,1H),1.72-1.70(m,3H).LC-MS(ESI-API,254nm)H2O中95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=254.0(M+Na),t=0.548min。
化合物63遵循用于化合物38的合成的程序从醇61合成。将粗产物在硅胶柱上纯化,使用CH2Cl2作为洗脱剂,得到883mg(68%)的作为白色固体的产物63。1H NMR(600MHz,CDCl3,ppm)δ:7.86(dd,J=5.5,3.0Hz,2H),7.73(dd,J=5.5,3.0Hz,2H),5.73(t,J=8.6Hz,1H),4.36(s,2H),4.27(dt,J=8.6,0.8Hz,2H),1.78(d,J=0.8Hz,3H)。
化合物64遵循用于化合物39的合成的程序从叔丁基(R)-3-((((S)-5,6,7,8-四氢喹啉-8-基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯和溴化物63合成。将粗产物在硅胶柱上纯化,使用己烷中0至40%EA作为洗脱剂,得到374mg(60%)的产物64。1H NMR(400MHz,CDCl3,ppm)δ:8.40(br s,1H),7.83-7.77(m,2H),7.72-7.67(m,2H),7.26(d,J=6.6Hz,1H),7.07-6.92(m,5H),5.47(t,J=6.6Hz,1H),4.74-4.59(m,1.5H),4.51(brs,0.5H),4.26(AB的A,JAB=14.7Hz,1H),4.20(AB的B,JAB=14.8Hz,1H),4.14-4.00(m,2H),3.62-3.53(m,1H),3.47-3.30(m,1H),3.06-2.91(m,2H),2.79-2.44(m,4H),2.14-1.91(m,1H),1.82(q,J=11.1Hz,1H),1.74-1.61(m,2H),1.58(s,3H),1.50(s,9H).LC-MS(ESI-API,254nm)H2O中95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=607.2(M+H),t=0.480min;
化合物65遵循用于化合物6的合成的程序从胺64合成。将有机物浓缩,并且将粗产物用于下一个步骤。
EMU177:化合物EMU177遵循用于化合物EMU030的合成的程序从胺65合成。将粗物质在硅胶柱上纯化,使用CH2Cl2中0至45%的溶剂2(溶剂2=30%MeOH、70%CH2Cl2和3%NH4OH)作为洗脱剂,得到74mg(74%)的产物EMU177。1H NMR(600MHz,CDCl3,ppm)δ:8.45(d,J=4.7Hz,1H),7.31(d,J=7.6Hz,1H),7.09-6.98(m,5H),5.43(t,J=7.0Hz,1H),4.10(dd,J=10.2,6.5Hz,1H),4.02(AB的A,JAB=15.1Hz,1H),3.84(AB的B,JAB=15.0Hz,1H),3.81(dd,J=13.8,8.0Hz,1H),3.39(AB的A,JAB=13.1Hz,1H),3.29(dd,J=13.9,5.9Hz,1H),3.24(AB的B,JAB=13.2Hz,1H),2.82-2.72(m,3H),2.65(AB的B,JAB=16.5Hz,1H),2.58(ABX的A,JAB=16.1Hz,JAX=3.7Hz,1H),2.44-2.34(m,2H),2.08-2.03(m,1H),2.00-1.94(m,1H),1.94-1.85(m,1H),1.81(s,3H),1.74-1.63(m,1H).13C NMR(400MHz,CDCl3,ppm)δ:158.75,146.66,139.09,136.33,135.57,134.52,133.92,128.97,126.29,125.76,125.53,125.36,121.22,59.92,57.02,51.66,51.20,48.50,42.44,33.81,29.37,28.27,22.08,21.99.HRMS(ESI+)对于C24H33N4([M+H]+)计算为:377.2700。实测为:377.2696,误差-0.4ppm。LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=377.2(M+H),189.2(M/2+H),t=0.465min;
化合物66遵循用于化合物38的合成的程序从醇62合成。将粗产物在硅胶柱上纯化,使用CH2Cl2作为洗脱剂,得到785mg(139%)的作为白色固体的产物66。1H NMR(400MHz,CDCl3,ppm)δ:7.84(dd,J=5.5,3.0Hz,2H),7.71(dd,J=5.4,3.1Hz,2H),5.51(tq,J=7.5,1.5Hz,1H),4.31(dd,J=7.6,1.0Hz,2H),4.19(s,2H),1.87-1.86(m,3H)。
化合物67遵循用于化合物39的合成的程序从叔丁基(R)-3-((((S)-5,6,7,8-四氢喹啉-8-基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯和溴化物66合成。将粗产物在硅胶柱上纯化,使用己烷中0至30%EA作为洗脱剂,得到312mg(76%)的产物67。1H NMR(400MHz,CDCl3,ppm)δ:8.44(br s,1H),7.78(br s,2H),7.68(br s,2H),7.25(d,J=6.5Hz,1H),7.08-6.92(m,5H),5.28(br s,1H),4.80-4.63(m,1.5H),4.49(br s,0.5H),4.32-3.98(m,4H),3.57(AB的A,JAB=13.4Hz,0.5H),3.44(AB的A,JAB=13.6Hz,0.5H),3.22(AB的B,JAB=13.3Hz,0.5H),3.11-2.84(m,2.5H),2.74-2.47(m,4H),2.18(br s,1H),2.00-1.61(m,3H),1.81(s,3H),1.49(s,9H).LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),6min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=607.2(M+H),t=0.972min,纯度为96%;
化合物68遵循用于化合物6的合成的程序从胺67合成。将有机物浓缩,并且将粗产物用于下一个步骤。
EMU208:化合物EMU208遵循用于化合物EMU030的合成的程序从胺68合成。将粗物质在硅胶柱上纯化,使用CH2Cl2中0至45%的溶剂2(溶剂2=30%MeOH、70%CH2Cl2和3%NH4OH)作为洗脱剂,得到84mg(66%)的产物EMU208。1H NMR(600MHz,CDCl3,ppm)δ:8.45(d,J=4.8Hz,1H),7.32(d,J=7.8Hz,1H),7.10-7.06(m,2H),7.05-6.99(m,3H),5.55(t,J=7.3Hz,1H),4.11(d,J=12.9Hz,1H),4.06(AB的A,JAB=15.1Hz,1H),4.00(dd,J=10.5,6.6Hz,1H),3.91(AB的B,JAB=15.1Hz,1H),3.51(ABX的A,JAB=13.7Hz,JAX=7.6Hz,1H),3.38(ABX的B,JAB=13.7Hz,JBX=6.9Hz,1H),3.10(d,J=12.9Hz,1H),2.85(tt,J=10.8,3.5Hz,1H),2.79-2.72(m,1H),2.72(ABX的B,JAB=13.1Hz,JBX=3.2Hz,1H),2.65(AB的B,JAB=16.7Hz,1H),2.57(ABX的A,JAB=16.2Hz,JAX=3.6Hz,1H),2.40(ABX的B,JAB=16.4Hz,JBX=11.3Hz,1H),2.33(dd,J=13.3,10.3Hz,1H),2.11-2.05(m,1H),1.99-1.86(m,5H),1.85(s,3H),1.73-1.64(m,1H).13C NMR(400MHz,CDCl3,ppm)δ:158.66,146.51,136.72,136.35,135.45,134.39,133.97,128.97,128.82,128.79,126.26,125.76,125.37,121.24,58.57,56.59,54.34,51.50,48.49,38.54,33.68,29.32,28.53,23.05,22.10.HRMS(ESI+)对于C24H33N4([M+H]+)计算为:377.2700。实测为:377.2695,误差0.5ppm。LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=377.2(M+H),189.2(M/2+H),t=0.454min;
EMU143和EMU211的合成
将3.00g的(Z)-4-氯丁-2-烯-1-胺的HCl盐(21.1mol,1当量)、7.36mL的TEA(52.8mmol,2.5当量)、0.129g的DMAP(1.06mmol,0.05当量)和70mL的THF装入配备有磁性搅拌棒和橡胶隔膜的250mL rb烧瓶。然后添加4.86g的乙基1,3-二氧异吲哚啉-2-羧酸酯(22.2mmol,1.05当量)。在rt搅拌持续48h后,反应混合物通过添加水淬灭,用乙醚(2×)萃取,经Na2SO4干燥。将粗物质在硅胶柱上纯化,使用CH2Cl2作为洗脱剂,得到3.11g(63%)的作为白色固体的产物69。1H NMR(400MHz,CDCl3,ppm)δ:7.84(dd,J=5.5,3.0Hz,2H),7.72(dd,J=5.4,3.1Hz,2H),5.84(dtt,J=10.3,7.7,1.2Hz,1H),5.70(dtt,J=10.6,7.4,1.0Hz,1H),4.35(dd,J=7.4,1.3Hz,2H),4.32(dd,J=7.8,1.0Hz,2H)。
化合物70遵循用于化合物39的合成的程序从叔丁基(R)-3-((((S)-5,6,7,8-四氢喹啉-8-基)氨基)甲基)-3,4-二氢异喹啉-2(1H)-羧酸酯和氯化物69合成。将粗产物在硅胶柱上纯化,使用CH2Cl2中0至30%EA作为洗脱剂,得到881mg(82%)的产物70。1H NMR(400MHz,CDCl3,ppm)δ:8.37(s,1H),7.77-7.71(m,2H),7.69-7.55(m,2H),7.22(d,J=7.7Hz,1H),7.02-6.84(m,5H),5.68(dt,J=12.7,6.8Hz,1H),5.41(dt,J=11.2,6.9Hz,1H),4.75-4.41(m,2H),4.25(ABX的A,JAB=15.1,JAX=6.8Hz,1H),4.17(ABX的B,JAB=15.1,JBX=6.8Hz,1H),4.10-3.94(m,2H),3.63-3.53(m,1H),3.44-3.33(m,1H),3.06-2.84(m,2H),2.74-2.41(m,4H),2.03(br s,1H),1.92(br s,1H),1.84-1.72(m,1H),1.68-1.57(m,1H),1.47(s,9H).LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),6min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=593.2(M+H),t=0.705min,纯度为96%;
化合物71遵循用于化合物6的合成的程序从胺70合成。将粗产物在硅胶柱上纯化,使用CH2Cl2中0至30%的Solv 2(Solv2=30%MeOH、70%CH2Cl2、3%NH4OH),得到573mg(87%)的产物71。1H NMR(400MHz,CDCl3,ppm)δ:8.36(br s,1H),7.23(d,J=7.7Hz,1H),7.11-6.92(m,5H),5.58-5.45(m,2H),4.72-4.56(m,1.5H),4.45(br s,0.5H),4.16-4.04(m,1H),3.94(dd,J=8.4,5.8Hz,1H),3.51-3.40(m,1H),3.34-3.01(m,3H),2.93(d,J=3.1Hz,2H),2.73-2.42(m,4H),2.04-1.85(m,2H),1.79-1.31(m,4H),1.47(s,9H).LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent ZorbaxXDB-18,50mm×4.6mm,3.5μm),m/z=463.2(M+H),t=0.540min;
将0.085g的4,4-二氟环己酮(0.635mmol,1.3当量)、0.226g的胺71(0.489mmol,1当量)、34μL的乙酸(0.586mmol,1.2当量)和2.0mL的DCE装入配备有搅拌棒的20mL小瓶。然后以3份(30min的时间间隔)添加0.155g的STAB(0.733mmol,1.5当量),并且将悬浮液在rt搅拌持续12h。反应混合物通过添加饱和NaHCO3溶液淬灭,用CH2Cl2(3×)萃取,并且经Na2SO4干燥。将粗产物在硅胶柱上纯化,使用己烷中0至100%EA作为洗脱剂,得到229mg(81%)的产物72。1H NMR(400MHz,CDCl3,ppm)δ:8.36(br s,1H),7.28-7.23(m,1H),7.14-6.95(m,5H),5.67-5.58(m,1H),5.57-5.48(m,1H),4.76-4.57(m,1.5H),4.47(br s,0.5H),4.17-4.07(m,1H),3.99-3.92(m,1H),3.62-3.48(m,1H),3.32-3.05(m,3H),3.01-2.87(m,2H),2.74-2.45(m,5H),2.13-1.56(m,8H),1.49(s,9H),1.54-1.32(s,5H).LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=581.2(M+H),291.2(M/2+H),t=0.560min;
EMU143:化合物EMU143遵循用于化合物EMU030的合成的程序从胺72合成。将粗物质在硅胶柱上纯化,使用CH2Cl2中0至60%的溶剂2(溶剂2=30%MeOH、70%CH2Cl2和3%NH4OH)作为洗脱剂,得到89mg(108%)的产物EMU143。1H NMR(600MHz,CDCl3,ppm)δ:8.43(d,J=4.5Hz,1H),7.32(d,J=7.6Hz,1H),7.10-6.99(m,5H),5.74-5.69(m,1H),5.62(dt,J=11.7,6.8Hz,1H),4.09(dd,J=10.2,6.4Hz,1H),4.03(AB的A,JAB=15.0Hz,1H),3.95(dd,J=14.3,8.2Hz,1H),3.89(AB的B,JAB=15.0Hz,1H),3.40(ABX的A,JAB=13.4Hz,JAX=7.3Hz,1H),3.32-3.25(m,2H),2.84-2.72(m,3H),2.65(AB的B,JAB=16.5Hz,1H),2.65-2.59(m,1H),2.58(dd,J=16.1,3.4Hz,1H),2.43-2.33(m,2H),2.10-1.80(m,7H),1.75-1.61(m,3H),1.48-1.37(m,2H)。13C NMR(400MHz,CDCl3,ppm)δ:158.75,146.56,136.36,135.54,134.47,133.93,131.42,130.37,128.93,126.31,125.75,125.36,123.25(t,J=240.0Hz),60.04,56.89,53.33,51.55,51.05,48.61,43.76,33.78,31.51(t,J=24.3Hz),31.46(t,J=24.3Hz),29.28,29.08,28.81-28.54(m),21.96.19F NMR(400MHz,CDCl3,ppm)δ:-96.23(d,J=234.4Hz),-100.29(d,J=233.7Hz).HRMS(ESI+)对于C29H39F2N4([M+H]+)计算为:481.3137。实测为:481.3146,误差0.9ppm。LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=481.2(M+H),241.2(M/2+H),t=0.818min;
将0.181g的胺71(0.390mmol,1当量)、136μL的DIPEA(0.781mmol,2当量)和3.9mL的THF装入配备有搅拌棒和橡胶隔膜的50mL Schlenk管。然后逐滴添加81μL的85w%TMSNCO(0.508mmol,1.3当量)。在rt搅拌持续12h后,反应混合物通过添加饱和Na2CO3溶液淬灭,用CH2Cl2(3×)萃取,并且经Na2SO4干燥。将粗产物在硅胶柱上纯化,使用EA中0至20%MeOH作为洗脱剂,得到170mg(86%)的产物73。1H NMR(400MHz,CDCl3,ppm)δ:8.30(d,J=4.6Hz,1H),7.22(d,J=8.1Hz,1H),7.14-6.90(m,5H),5.75(s,2H),4.75-4.49(m,3H),4.17(AB的B,JAB=16.2Hz,1H),4.10-3.88(m,2H),3.76(br s,2H),3.49(br s,1H),3.24(AB的A,JAB=15.7Hz,1H),3.05-2.82(m,3H),2.76-2.41(m,3H),2.22(br s,1H),2.04(br s,1H),1.89(br s,1H),1.79-1.63(m,1H),1.49(s,9H).LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),6min,1.00mL/min,C18(AgilentZorbax XDB-18,50mm×4.6mm,3.5μm),m/z=506.2(M+H),t=0.533min;
EMU211:化合物EMU211遵循用于化合物EMU030的合成的程序从胺73合成。将粗物质在硅胶柱上纯化,使用CH2Cl2中0至45%的溶剂2(溶剂2=30%MeOH、70%CH2Cl2和3%NH4OH)作为洗脱剂,得到128mg(102%)的产物EMU211。1H NMR(600MHz,CDCl3,ppm)δ:8.43(d,J=4.5Hz,2H),7.36(d,J=7.3Hz,1H),7.11-7.05(m,3H),7.03-7.01(m,1H),6.98-6.96(m,1H),5.91-5.85(m,1H),5.77(dt,J=10.6,7.1Hz,1H),4.70(s,2H),4.19(dd,J=9.4,7.0Hz,1H),4.02-3.92(m,1H),3.95(AB的A,JAB=15.4Hz,1H),3.87-3.80(m,1H),3.74(AB的B,JAB=15.4Hz,1H),3.68(dd,J=12.9,7.9Hz,1H),3.23(dd,J=13.0,6.2Hz,1H),2.78(ddd,J=16.3,11.2,4.9Hz,1H),2.74-2.61(m,4H),2.45(dd,J=13.1,8.8Hz,1H),2.32(dd,J=16.4,10.8Hz,1H),2.13-1.87(m,5H),1.69(q,J=12.3Hz,1H).13C NMR(400MHz,CDCl3,ppm)δ:159.34,158.04,146.48,136.77,135.29,134.36,134.24,130.71,130.18,128.95,126.10,125.78,125.38,121.62,59.97,57.05,51.60,50.31,48.22,37.25,33.70,29.36,25.71,21.72.HRMS(ESI+)对于C24H32N5O([M+H]+)计算为:406.2601。实测为:406.2597,误差-0.4ppm。LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=406.2(M+H),203.6(M/2+H),t=0.490min;
吡啶TIQ-15
如在参考文献(Organic Process Research&Development 2002,6,938-942,Bioorganic&Medicinal Chemistry 2003,11,433-450)中,74从吡啶-2,3-二羧酸合成,收率为55%。
将26.9g的酯74(101mol,1当量)、42.2mL的TEA(303mmol,3当量)、1.23g的DMAP(10.1mmol,0.1当量)和253mL的THF装入配备有磁性搅拌棒和橡胶隔膜的1L rb烧瓶。然后添加27.6g的Boc2O(126mmol,1.25当量),并且将悬浮液搅拌持续3h。悬浮液不变成溶液,并且添加另一份的21mL的TEA(151mmol,1.5当量)、随后是300mL的乙腈和100mL的MeOH。在rt搅拌澄清溶液持续12h后,将反应混合物浓缩并且添加EA。将铵盐通过过滤分离,并且将有机物在真空下浓缩。将粗物质在硅胶柱上纯化,使用己烷中0-65%EA作为洗脱剂,得到2.24g(8%)的作为黄色油状物的76和8.12g(28%)的作为黄色油状物的75,其在冷冻器中结晶成白色固体。对于76(构象异构体的4∶1混合物):1H NMR(400MHz,CDCl3,ppm)δ:8.47-8.41(m,1.25H),7.46(d,J=7.7Hz,1.25H),7.11(dd,J=7.7,4.8Hz,1.25H),5.27(dd,J=5.9,2.1Hz,1H),5.02(br s,0.25H),4.89(AB的A,JAB=18.1Hz,0.25H),4.87(AB的A,JAB=17.9Hz,1H),4.56(AB的B,JAB=18.2Hz,1H),4.51(AB的B,JAB=18.2Hz,0.25H),3.63(s,3.75H),3.29(ABX的A,JAB=16.5Hz,JAX=2.2Hz,1H),3.24(ABX的A,JAB=16.5Hz,JAX=2.2Hz,0.25H),3.17(ABX的B,JAB=16.2Hz,JBX=6.3Hz,1H),1.52(s,9H),1.48(s,2.25H).LC-MS(ESI-API,254nm)H2O中95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(AgilentZorbax XDB-18,50mm×4.6mm,3.5μm),m/z=315.0(M+Na),293.0(M+H),t=0.562min;对于75(构象异构体的1∶1混合物):_1H NMR(400MHz,CDCl3,ppm)δ:8.42(d,J=4.9Hz,1H),7.44(d,J=7.9Hz,0.5H),7.41(d,J=7.7Hz,0.5H),7.14(dd,J=7.8,4.9Hz,1H),5.32(d,J=6.9Hz,0.5H),5.01(dd,J=6.5,3.7Hz,0.5H),4.80(AB的A,JAB=17.4Hz,0.5H),4.76(AB的B,JAB=17.4Hz,0.5H),4.57(AB的B,JAB=17.0Hz,0.5H),4.50(d,J=16.7Hz,1H),3.65(s,1.5H),3.63(s,1.5H),3.47(AB的A,JAB=16.8Hz,0.5H),3.40(ABX的A,JAB=17.1Hz,JAX=3.9Hz,0.5H),3.32(ABX的B,JAB=17.5Hz,JBX=6.6Hz,1H),1.53(s,4.5H),1.47(s,4.5H).LC-MS(ESI-API,254nm)H2O中95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(AgilentZorbax XDB-18,50mm×4.6mm,3.5μm),m/z=315.0(M+Na),293.1(M+H),t=0.560min;
将1.00g的酯75(3.42mmol,1当量)和17.1mL的甲苯装入配备有搅拌棒和橡胶隔膜的100mL rb烧瓶。在将反应混合物冷却至78℃后,逐滴添加5.70mL的1.2M DIBAL-H溶液(6.84mL,2当量),并且将溶液在78℃搅拌持续2h。然后反应混合物通过添加2.5mL的MeOH随后是罗谢尔盐的饱和溶液淬灭。在rt搅拌持续30min后,产物用EA(3×)萃取,并且经Na2SO4干燥。粗产物77(994mg)不经纯化即被用于下一个步骤中。
将608mg的(S)-5,6,7,8-四氢喹啉-8-胺(4.10mmol,1.2当量)、897mg的醛77(3.42mmol,1当量)、942mg的STAB(4.45mmol,1.3当量)和11.4mL的DCE装入配备有搅拌棒的20mL小瓶。在rt搅拌持续1.5h后,反应混合物通过添加饱和Na2CO3溶液淬灭,并且产物用CH2Cl2(3×)萃取,用饱和Na2CO3溶液、卤水洗涤,并且经Na2SO4干燥。将粗产物在硅胶柱上纯化,使用EA、随后是CH2Cl2中20%MeOH作为洗脱剂,得到0.905(67%)g的产物78。1H NMR(400MHz,CDCl3,ppm)δ:8.44-8.40(m,1H),8.35(d,J=4.5Hz,1H),7.39(d,J=7.4Hz,1H),7.34(d,J=7.7Hz,1H),7.147.09(m,1H),7.05(t,J=4.2Hz,0.5H),7.03(t,J=4.2Hz,0.5H),5.02-4.58(m,2H),4.24(AB的B,JAB=18.3Hz,1H),3.76(br s,0.5H),3.69(br s,0.5H),3.23(ABX的A,JAB=16.6Hz,JAX=6.2Hz,0.5H),3.19(ABX的A,JAB=16.6Hz,JAX=6.2Hz,0.5H),3.07(AB的B,JAB=16.9Hz,0.5H),2.94(AB的B,JAB=16.8Hz,0.5H),2.85-2.63(m,4H),2.04-1.91(m,1H),1.72-1.63(m,1H),1.52-1.28(m,2H),1.49(s,4.5H),1.42(s,4.5H).LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=417.2(M+Na),395.2(M+H),t=0.511min,纯度为86%;
化合物98遵循用于化合物79的合成的程序从胺78和4-((1,3-二氧异吲哚啉-2-基)甲基)苯甲醛合成。将粗产物在硅胶柱上纯化,使用EA中0至10%MeOH作为洗脱剂,得到516mg(36%)的URf-98(立体异构体1)、337mg(23%)的异构体的混合物和304mg(21%)的LRf-98(立体异构体2)。在使用EA中10%MeOH的TLC上,立体异构体2比立体异构体1洗脱更快。对于立体异构体1:LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),6min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=644.2(M+H),322.6(M/2+H),t=0.556min;
化合物99(立体异构体1)遵循用于化合物6的合成的程序从胺URf-98(立体异构体1)合成。将有机物浓缩,并且将粗产物用于下一个步骤。化合物99(立体异构体2)遵循用于化合物6的合成的程序从胺LRf-98(立体异构体2)合成。将有机物浓缩,并且将粗产物用于下一个步骤。
EMU193:化合物EMU193(立体异构体1)遵循用于化合物EMU030的合成的程序从胺99(立体异构体1)合成。将粗物质在硅胶柱上纯化,使用CH2Cl2中0至45%的溶剂2(溶剂2=30%MeOH、70%CH2Cl2和3%NH4OH)作为洗脱剂,得到71mg(42%)的产物EMU193。1H NMR(600MHz,CDCl3,ppm)δ:8.53(dd,J=4.6,1.6Hz,1H),8.32(dd,J=4.9,1.6Hz,1H),7.45(d,J=7.7Hz,2H),7.32(d,J=7.5Hz,1H),7.26(d,J=7.3Hz,1H),7.23(d,J=7.8Hz,2H),7.05(dd,J=7.6,4.7Hz,1H),6.99(dd,J=7.7,4.7Hz,1H),4.05(dd,J=10.2,6.0Hz,1H),3.94(AB的A,JAB=15.1Hz,1H),3.82(s,2H),3.78(AB的A,JAB=14.8Hz,1H),3.75(AB的B,JAB=14.8Hz,1H),3.73(AB的B,JAB=15.0Hz,1H),3.04(dd,J=12.7,2.9Hz,1H),2.84-2.65(m,5H),2.52(dd,J=16.9,11.0Hz,1H),2.30-2.24(m,1H),2.05-1.98(m,1H),1.95-1.85(m,1H),1.73-1.64(m,1H).13C NMR(400MHz,CDCl3,ppm)δ:157.95,155.33,147.08,147.00,141.68,139.87,136.23,134.00,133.88,131.22,128.16,126.81,121.47,120.53,62.05,59.27,56.03,52.51,47.60,46.15,37.10,29.26,26.24,21.65.HRMS(ESI+)对于C26H32N5([M+H]+)计算为:414.2652。实测为:414.2647,误差-0.5ppm。LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(AgilentZorbax XDB-18,50mm×4.6mm,3.5μm),m/z=414.2(M+H),207.6(M/2+H),t=0.460min;化合物EMU193(立体异构体2)遵循用于化合物EMU030的合成的程序从胺99(立体异构体2)合成。将粗物质在硅胶柱上纯化,使用CH2Cl2中0至45%的溶剂2(溶剂2=30%MeOH、70%CH2Cl2和3%NH4OH)作为洗脱剂,得到115mg(77%)的产物EMU194。1H NMR(600MHz,CDCl3,ppm)δ:8.51(d,J=4.8Hz,1H),8.33(d,J=4.4Hz,1H),7.43(d,J=8.0Hz,2H),7.33(d,J=7.5Hz,1H),7.26(d,J=7.5Hz,1H),7.25(d,J=7.8Hz,2H),7.06(dd,J=7.6,4.7Hz,1H),6.99(dd,J=7.7,4.7Hz,1H),4.37(d,J=14.3Hz,1H),4.10(dd,J=10.3,6.5Hz,1H),3.94(d,J=15.0Hz,1H),3.90(d,J=14.3Hz,1H),3.84(s,2H),3.62(d,J=14.9Hz,1H),2.98(dd,J=13.2,2.7Hz,1H),2.81-2.62(m,4H),2.53-2.43(m,2H),2.17-2.11(m,1H),2.00-1.91(m,2H),1.72-1.61(m,1H).13C NMR(400MHz,CDCl3,ppm)δ:158.51,155.03,146.99,146.60,141.57,140.16,136.15,133.80,133.70,130.85,128.27,126.73,121.16,120.45,61.89,58.94,57.55,52.02,47.45,46.04,36.92,29.35,29.15,21.88.HRMS(ESI+)对于C26H32N5([M+H]+)计算为:414.2652。实测为:414.2647,误差-0.6ppm。LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=414.2(M+H),207.6(M/2+H),t=0.460min;
一般方案
将0.717g的(Z)-2-(4-氯丁-2-烯-1-基)异吲哚啉-1,3-二酮(3.04mmol,1.2当量)和0.042g的KI(0.253mmol,0.1当量)装入配备有冷指冷凝器和搅拌棒的50mL Schlenk管。然后添加溶解在8.5mL的乙腈中的1.00g的胺78(2.53mmol,1当量)和0.662mL的DIPEA(3.80mmol,1.5当量)。在50℃搅拌持续12h后,反应混合物通过添加水淬灭,用乙醚(3×)萃取并且经Na2SO4干燥。将粗产物在硅胶柱上纯化,使用EA中0至10%MeOH作为洗脱剂,得到495mg(33%)的URf-103(立体异构体1)和491mg(33%)的LRf-103(立体异构体2)。在使用EA中10%MeOH的TLC上,立体异构体2比立体异构体1洗脱更快。对于立体异构体1:1H NMR(400MHz,CDCl3,ppm)δ:8.37(d,J=4.9Hz,1H),8.35(d,J=4.7Hz,1H),7.81(dd,J=5.4,3.1Hz,2H),7.70(dd,J=5.5,3.0Hz,2H),7.25(d,J=4.4Hz,1H),7.21(br s,1H),6.97(dd,J=7.7,4.7Hz,1H),6.96(br s,1H),5.67(br s,1H),5.35(br s,1H),4.83-4.66(m,1.5H),4.56(br s,0.5H),4.28-4.00(m,4H),3.86-3.64(m,1H),3.32-3.17(m,2H),3.04(ABX的B,JAB=16.7,JBX=6.1Hz,1H),2.91(ABX的A,JAB=13.3,JAX=5.7Hz,1H),2.67-2.29(m,3H),2.01-1.60(m,4H),1.47(s,9H).LC-MS(ESI-API,254nm)H2O中95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=594.2(M+H),297.8(M/2+H),t=0.813min;对于立体异构体2:1HNMR(400MHz,CDCl3,ppm)δ:8.39-8.32(m,2H),7.81(dd,J=5.5,3.1Hz,2H),7.70(dd,J=5.5,3.1Hz,2H),7.30(d,J=7.7Hz,1H),7.20(brs,1H),7.03-6.94(m,2H),5.67(br s,1H),5.44-5.35(m,1H),4.93-4.63(m,2H),4.25(ABX的A,JAB=15.1,JAX=7.3Hz,1H),4.17(ABX的B,JAB=14.8,JBX=6.4Hz,1H),4.12-3.91(d,J=21.9Hz,2H),3.63-3.53(m,1H),3.40-3.03(s,3H),2.87-2.55(m,4H),2.15-1.60(m,4H),1.50(s,9H)。LC-MS(ESI-API,254nm)H2O中95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=594.2(M+H),297.7(M/2+H),t=0.678min。
化合物EMU104(立体异构体1)遵循用于化合物6的合成的程序从胺LRf-103(立体异构体2)合成。将粗物质在硅胶柱上纯化,使用CH2Cl2中0至60%的溶剂2(溶剂2=30%MeOH、70%CH2Cl2和3%NH4OH)作为洗脱剂,得到311mg(96%)的产物104。1H NMR(400MHz,CDCl3,ppm)δ:8.41-8.33(m,2H),7.32-7.26(m,2H),7.08(dd,J=7.8,4.9Hz,1H),6.99(brs,1H),5.51(br s,2H),4.87-4.61(m,2H),4.17-3.93(m,2H),3.45(br s,1H),3.30-2.99(m,5H),2.83-2.48(m,4H),2.10-1.59(m,6H),1.50(s,9H).LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=463.2(M+H),t=0.546min;化合物104(立体异构体2)遵循用于化合物6的合成的程序从胺URf-103合成。将有机物浓缩,并且将粗产物用于下一个步骤。
EMU142:化合物EMU142(立体异构体1)遵循用于化合物EMU030的合成的程序从胺104(立体异构体1)合成。将粗物质在硅胶柱上纯化,使用CH2C12中0至60%的溶剂2(溶剂2=30%MeOH、70%CH2Cl2和3%NH4OH)作为洗脱剂,得到94mg(77%)的产物EMU142(立体异构体1)。1H NMR(600MHz,CDCl3,ppm)δ:8.44(d,J=4.5Hz,1H),8.34(d,J=4.6Hz,1H),7.32(d,J=7.6Hz,1H),7.30(d,J=7.7Hz,1H),7.04(dd,J=7.7,4.7Hz,1H),7.01(dd,J=7.7,4.7Hz,1H),5.63(t,J=4.6Hz,2H),4.10(dd,J=10.2,6.4Hz,1H),4.00(AB的A,JAB=15.0Hz,1H),3.87(dd,J=14.5,6.0Hz,1H),3.83(AB的B,JAB=15.0Hz,1H),3.42(dd,J=14.2,5.1Hz,1H),3.30(dd,J=14.4,9.4Hz,1H),3.30(AB的B,JAB=14.7Hz,1H),2.90(dd,J=13.2,3.0Hz,1H),2.82(tt,J=10.6,3.4Hz,1H),2.79-2.72(m,2H),2.65(AB的B,JAB=16.5Hz,1H),2.51(dd,J=16.9,11.0Hz,1H),2.40(dd,J=13.2,10.3Hz,1H),2.10-2.03(m,1H),2.00-1.94(m,1H),1.95-1.85(m,1H),1.74-1.65(m,1H).13C NMR(400MHz,CDCl3,ppm)δ:158.43,154.95,147.07,146.56,136.27,133.90,133.70,132.09,130.84,129.65,121.19,120.58,60.19,56.70,51.73,50.86,47.52,38.78,36.93,29.17,28.76,21.83.HRMS(ESI+)对于C22H30N5([M+H]+)计算为:364.2496。实测为:364.2491,误差-0.5ppm。LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=364.2(M+H),182.7(M/2+H),t=0.821min;化合物EMU142(立体异构体2)遵循用于化合物EMU030的合成的程序从胺104(立体异构体2)合成。将粗物质在硅胶柱上纯化,使用CH2Cl2中0至60%的溶剂2(溶剂2=30%MeOH、70%CH2Cl2和3%NH4OH)作为洗脱剂,得到143mg(95%)的产物EMU142(立体异构体2)。1HNMR(600MHz,CDCl3,ppm)δ:8.50(d,J=4.7Hz,1H),8.34(d,J=4.7Hz,1H),7.34(d,J=7.7Hz,1H),7.31(d,J=7.7Hz,1H),7.05(dd,J=7.7,4.7Hz,1H),7.01(dd,J=7.7,4.9Hz,1H),5.75-5.64(m,2H),4.09(dd,J=9.8,6.1Hz,1H),4.05(AB的A,JAB=15.4Hz,1H),4.02(AB的B,JAB=15.4Hz,1H),3.40(ABX的A,JAB=14.1Hz,JAX=6.7Hz,1H),3.40-3.32(m,2H),3.32(ABX的B,JAB=14.5Hz,JBX=6.8Hz,1H),3.05(t,J=10.3Hz,1H),2.83-2.65(m,4H),2.51(dd,J=16.7,11.0Hz,1H),2.46(dd,J=13.0,10.0Hz,1H),2.15-2.10(m,1H),2.04-1.98(m,1H),1.89-1.79(m,1H),1.74-1.64(m,1H).13C NMR(400MHz,CDCl3,ppm)δ:157.22,154.94,147.01,146.90,136.45,134.15,133.82,132.66,131.11,129.52,121.59,120.55,60.52,56.98,52.17,48.24,47.48,38.28,36.88,29.09,23.60,21.30.HRMS(ESI+)对于C22H30N5([M+H]+)计算为:364.2496。实测为:364.2494,误差-0.2ppm。LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=364.2(M+H),182.6(M/2+H),t=0.466min;
化合物106遵循用于化合物103的合成的程序从胺78和(E)-2-(4-溴丁-2-烯-1-基)异吲哚啉-1,3-二酮合成。将粗产物在硅胶柱上纯化,使用EA中0至10%MeOH作为洗脱剂,得到435mg(34%)的URf-106(立体异构体1)和466mg(28%)的LRf-106(立体异构体2)。在使用EA中10%MeOH的TLC上,立体异构体2比立体异构体1洗脱更快。对于立体异构体1:1HNMR(400MHz,CDCl3,ppm)δ:8.39(d,J=5.0Hz,1H),8.27(d,J=4.2Hz,1H),7.82(dd,J=5.5,3.0Hz,1H),7.70(dd,J=5.5,3.1Hz,1H),7.31(d,J=7.7Hz,1H),7.19(d,J=7.6Hz,1H),7.06(dd,J=7.7,4.8Hz,1H),6.90(dd,J=7.1;5.3Hz 1H),5.80-5.67(m,1H),5.54(brs,1H),4.80-4.62(m,1.5H),4.47(br s,0.5H),4.26-4.07(m,4H),3.95(t,J=7.3Hz,1H),3.57-3.40(m,1H),3.27-3.10(m,2H),3.02(ABX的B,JAB=16.7,JBX=6.0Hz,1H),2.79-2.70(m,1H),2.55(s,2H),2.43-2.20(m,1H),1.98-1.80(m,2H),1.67-1.51(m,2H),1.45(s,9H).LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(AgilentZorbax XDB-18,50mm×4.6mm,3.5μm),m/z=594.2(M+H),297.6(M/2+H),t=0.525min;对于立体异构体2:1H NMR(400MHz,CDCl3,ppm)δ:8.37(dd,J=4.8,1.7Hz,1H),8.28(d,J=4.7Hz,1H),7.83(dd,J=5.4,3.1Hz,2H),7.71(dd,J=5.5,3.1Hz,2H),7.32(dd,J=7.8,1.6Hz,1H),7.23(d,J=7.5Hz,1H),7.03(dd,J=7.7,4.8Hz,1H),6.93(dd,J=7.7,4.7Hz,1H),5.69(br s,1H),5.59-5.46(m,1H),4.90-4.59(m,2H),4.20-3.86(m,4H),3.31-2.91(m,4H),2.77-2.46(m,4H),2.00-1.76(m,2H),1.64(s,2H),1.47(s,9H).LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(AgilentZorbax XDB-18,50mm×4.6mm,3.5μm),m/z=594.2(M+H),297.6(M/2+H),t=0.575min;
化合物107(立体异构体1)遵循用于化合物6的合成的程序从胺LRf-106(立体异构体2)合成。将有机物浓缩,并且将粗产物用于下一个步骤。
EMU192:化合物EMU192(立体异构体1)遵循用于化合物EMU030的合成的程序从胺107(立体异构体1)合成。将粗物质在硅胶柱上纯化,使用CH2Cl2中0至60%的溶剂2(溶剂2=30%MeOH、70%CH2Cl2和3%NH4OH)作为洗脱剂,得到82mg(67%)的产物EMU192。1H NMR(600MHz,CDCl3,ppm)δ:8.44(d,J=4.5Hz,1H),8.35(d,J=4.8Hz,1H),7.33(d,J=7.8Hz,1H),7.30(d,J=7.8Hz,1H),7.05(dd,J=7.7,4.7Hz,1H),7.02(dd,J=7.7,4.7Hz,1H),5.77-5.66(m,2H),4.09(dd,J=10.1,6.2Hz,1H),4.04(AB的A,JAB=15.2Hz,1H),3.82(AB的B,JAB=15.0Hz,1H),3.59(dd,J=14.3,6.3Hz,1H),3.32-3.27(m,1H),3.29(d,J=4.3Hz,2H),3.01(dd,J=13.5,3.0Hz,1H),2.86-2.73(m,3H),2.70-2.64(m,1H),2.57(dd,J=16.9,11.0Hz,1H),2.50(dd,J=13.4,10.2Hz,1H),2.11-2.05(m,1H),2.01-1.95(m,1H),1.95-1.85(m,1H),1.75-1.66(m,1H).13C NMR(400MHz,CDCl3,ppm)δ:158.17,154.81,147.14,146.51,136.44,133.88,133.75,131.32,130.66,130.38,121.33,120.66,61.33,56.99,55.86,52.13,47.24,42.85,36.75,29.16,27.70,21.66.HRMS(ESI+)对于C22H30N5([M+H]+)计算为:364.2496。实测为:364.2491,误差-0.5ppm。LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=364.2(M+H),182.6(M/2+H),t=0.463min;
将0.138g的胺104(立体异构体1)(0.298mmol,1当量)、104μL的DIPEA(0.595mmol,2当量)和3.0mL的THF装入配备有搅拌棒和橡胶隔膜的50mL Schlenk管。然后逐滴添加62μL的85w%TMSNCO(0.387mmol,1.3当量)。在rt搅拌持续12h后,反应混合物通过添加饱和Na2CO3溶液淬灭,用CH2Cl2(3×)萃取,并且经Na2SO4干燥。将粗产物在硅胶柱上纯化,使用EA中0至20%MeOH作为洗脱剂,得到109mg(72%)的产物109。
EMU209:化合物EMU209(立体异构体1)遵循用于化合物EMU030的合成的程序从胺109(立体异构体1)合成。将粗物质在硅胶柱上纯化,使用CH2Cl2中0至45%的溶剂2(溶剂2=30%MeOH、70%CH2Cl2和3%NH4OH)作为洗脱剂,得到86mg(98%)的产物EMU209(立体异构体1)。1H NMR(600MHz,CDCl3,ppm)δ:8.44(d,J=4.4Hz,1H),8.34(d,J=4.5Hz,1H),7.37(d,J=7.8Hz,1H),7.28(d,J=7.6Hz,1H),7.10(dd,J=7.7,4.7Hz,1H),7.02(dd,J=7.7,4.7Hz,1H),6.73(br s,1H),5.88-5.83(m,1H),5.79-5.73(m,1H),4.69(s,2H),4.18(dd,J=9.8,6.7Hz,1H),3.95(AB的A,JAB=15.3Hz,1H),3.87-3.81(m,1H),3.74-3.66(m,1H),3.70(AB的B,JAB=14.7Hz,1H),3.27(dd,J=13.1,6.0Hz,1H),2.83-2.65(m,6H),2.47(AB的A,JAB=9.8Hz,1H),2.45(AB的B,JAB=9.7Hz,1H),2.16-1.87(m,3H),1.74-1.65(m,1H).13CNMR(400MHz,CDCl3,ppm)δ:159.26,158.05,154.78,147.16,146.55,136.86,134.33,133.96,130.78,130.68,130.27,121.69,120.77,60.15,56.76,51.93,50.54,47.37,37.38,36.98,29.36,26.09,21.78.HRMS(ESI+)对于C23H31N6O([M+H]+)计算为:407.2554。实测为:407.2550,误差-1.0ppm。LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=429.2(M+Na),407.2(M+H),204.2(M/2+H),t=0.489min;
化合物110(立体异构体1)遵循用于化合物109(立体异构体1)的合成的程序从胺107(立体异构体1)合成。将粗产物在硅胶柱上纯化,使用EA中0至20%MeOH作为洗脱剂,得到128mg(83%)的产物110。
EMU212:化合物EMU212(立体异构体1)遵循用于化合物EMU030的合成的程序从胺110(立体异构体1)合成。将粗物质在硅胶柱上纯化,使用CH2Cl2中0至45%的溶剂2(溶剂2=30%MeOH、70%CH2Cl2和3%NH4OH)作为洗脱剂,得到89mg(95%)的产物EMU212(立体异构体1)。1H NMR(600MHz,CDCl3,ppm)δ:8.44(d,J=4.2Hz,1H),8.35(d,J=4.9Hz,1H),7.33(d,J=7.6Hz,1H),7.31(d,J=7.6Hz,1H),7.06(dd,J=7.7,4.7Hz,1H),7.03(dd,J=7.7,4.7Hz,1H),5.75(dt,J=13.3,6.3Hz,1H),5.66(dt,J=15.4,5.5Hz,1H),5.20(s,1H),4.46(s,2H),4.07(dd,J=9.9,6.3Hz,1H),3.98(AB的A,JAB=15.1Hz,1H),3.80-3.71(m,3H),3.45(dd,J=14.2,7.4Hz,1H),3.25(dd,J=14.3,5.2Hz,1H),3.09(dd,J=13.5,3.2Hz,1H),2.77(dd,J=16.6,4.2Hz,2H),2.81-2.65(m,3H),2.54(dd,J=16.3,10.4Hz,1H),2.50(dd,J=13.3,9.9Hz,1H),2.11-1.86(m,3H),1.75-1.66(m,1H).13C NMR(400MHz,CDCl3,ppm)δ:159.34,158.07,154.90,147.04,146.59,136.47,134.03,133.79,130.86,130.82,128.77,121.38,120.72,61.18,56.85,55.86,52.08,47.30,41.55,36.79,29.18,27.49,21.62.HRMS(ESI+)对于C23H31N6O([M+H]+)计算为:407.2554。实测为:407.2549,误差-1.1ppm。LC-MS(ESI-API,254nm)H2O中75-95%MeOH(0.1%HCO2H),3min,1.00mL/min,C18(Agilent Zorbax XDB-18,50mm×4.6mm,3.5μm),m/z=407.2(M+H),204.2(M/2+H),t=0.605min;
根据以下一般方案制备化合物EMU232:
向10mL的二氯甲胺中的310mg(1.65mmol)的(10bS)-1,2,3,4,4a,5,6,10b-八氢-1,10-菲咯啉(根据Catalano,J.G.等人Bioorg.Med.Chem.Lett.2010,20,2186-2190制备)和365mg(1.02mmol)的叔丁基-(R)-3-甲酰基-5-(4-甲基哌嗪-1-基)-3,4-二氢异喹啉-2(1H)-羧酸酯添加667mg的三乙酰氧基硼氢化钠。将反应搅拌持续24小时,并且在柱色谱后处理以产生388mg的白色泡沫状物(收率为73%)。然后该物质经历使用三氟乙酸的全面脱保护程序以产生209mg的作为淡黄色泡沫状物的标题化合物(收率为79%)。
EMU232:(4aR,10bS)-1-(((R)-5-(4-甲基哌嗪-1-基)-1,2,3,4-四氢异喹啉-3-基)甲基)-1,2,3,4,4a25,6,10b-八氢-1,10-菲咯啉。1H NMR(400MHz,CDCl3):
1.69(m,6H),2.119m,1H),2.24(m,3H),2.34(s,3H),2.51(m,4H),2.73(m,6H),2.97(m,6H),3.61(m,1H),4.04(m,2H),6.69(d,1H,J=8Hz),6.85(d,1H,J=7Hz),7.08(m,2H),7.39(d,1H,J=8Hz),8.36(d,1H,J=5Hz);MS(m/z):432.2(M+H)+
方案1:
叔丁基(S)-4-(3-((5,6,7,8-四氢喹啉-8-基)氨基)丙基)哌嗪-1-羧酸酯(化合物15)
将(S)-5,6,7,8-四氢喹啉-8-胺(0.941g,6.35mmol)、叔丁基4-(3-溴丙基)哌嗪-1-羧酸酯(1.5g,4.88mmol)和DIPEA(2.132ml,12.21mmol)溶解在20ml乙腈中并且搅拌持续过夜。反应混合物用EtOAc稀释;用饱和NaHCO3溶液、水和卤水萃取;经无水MgSO4干燥,过滤掉并且蒸发。用柱色谱纯化它,使用DCM∶MeOH∶NH4OH(9∶1∶0.1)。1H NMR(400MHz,氯仿-d)δ8.35(dd,J=4.8,1.5Hz,1H),7.41-7.32(m,1H),7.05(dd,J=7.7,4.7Hz,1H),3.77(d,J=8.2Hz,1H),3.49-3.39(m,4H),2.77(m,4H),2.38(d,J=5.0Hz,4H),2.32-2.23(m,2H),2.23-2.05(m,1H),2.05-1.87(m,2H),1.83-1.67(m,4H),1.43(s,9H)。
叔丁基(S)-4-(3-((异喹啉-3-基甲基)-(5,6,7,8-四氢喹啉-8-基)氨基)丙基)哌嗪-1-羧酸酯(化合物16a)
向10ml DCE中的叔丁基(S)-4-(3-((5,6,7,8-四氢喹啉-8-基)氨基)丙基)哌嗪-1-羧酸酯(0.300g,0.801mmol)(化合物15)的溶液添加异喹啉-3-甲醛(0.126g,0.801mmol)和三乙酰氧基硼氢化钠(0.340g,1.602mmol),并且在室温搅拌持续过夜。反应用饱和NaHCO3溶液淬灭。水相用DCM萃取;合并的有机层用水萃取,并且经无水MgSO4干燥,并且过滤掉并且蒸发。它被照原样用于下一个步骤。
用于化合物16b-d的一般程序:
将叔丁基(S)-4-(3-((5,6,7,8-四氢喹啉-8-基)氨基)丙基)哌嗪-1-羧酸酯(0.500g,1.3mmol)(化合物15)、2.0mmol的R-Cl(对应的氯化物)、DIPEA(0.93ml,5.34mmol)和KI(0.022g,0.13mmol)悬浮在20ml的乙腈中,并且加热至65℃持续过夜。反应混合物用EtOAc稀释;用饱和NaHCO3溶液、水和卤水萃取;经无水MgSO4干燥,过滤掉并且蒸发。它被照原样用于下一个步骤。
用于EMU168、EMU185、EMU186和EMU187的用于Boc脱保护的一般程序
将Boc保护的化合物16a-d(0.5mmol)溶解在5ml DCM中,并且将0.8ml TFA添加到反应溶液。将它在室温搅拌1-24小时。反应混合物用1NNaOH溶液碱化至pH>10-12,并且水相用DCM萃取3次。合并的有机层经无水MgSO4干燥。过滤掉并且蒸发。将产物用柱色谱纯化,使用DCM/MeOH/NH4OH梯度。
(S)-N-(异喹啉-3-基甲基)-N-(3-哌嗪-1-基)丙基)-5,6,7,8-四氢喹啉-8-胺(EMU168):1H NMR(500MHz,氯仿-d)δ9.20-9.18(m,1H),8.50(dd,J=4.7,1.7Hz,1H),8.01(s,1H),7.95(dq,J=8.3,1.0Hz,1H),7.84(dt,J=8.3,1.0Hz,1H),7.68(ddd,J=8.2,6.9,1.2Hz,1H),7.56(ddd,J=8.1,6.9,1.1Hz,1H),7.37(dd,J=7.6,1.8Hz,1H),7.07(dd,J=7.7,4.7Hz,1H),4.23-4.13(m,2H),4.02(d,J=15.1Hz,1H),3.08-3.03(m,4H),2.86-2.79(m,3H),2.77-2.70(m,1H),2.70-2.59(m,6H),2.49(t,J=7.0Hz,2H),2.26-2.20(m,1H),2.08-1.99(m,1H),1.93(m,1H),1.68(m,4H);MS:m/z 416.2(M+H);HRMS对于C26H34N5(M+H)计算为:416.27360,实测为:416.28096
(S)-N-((1H-苯并[d]咪唑-2基)甲基)-N-(3-(哌嗪-1基)丙基)-5,6,7,8-四氢喹啉-8-胺(EMU185):1H NMR(500MHz,氯仿-d)δ8.57(dd,J=4.8,1.7Hz,1H),7.58(dt,J=7.1,3.6Hz,2H),7.47-7.44(m,1H),7.21(dd,J=6.0,3.2Hz,2H),7.19-7.13(m,1H),4.16-3.99(m,4H),2.94(q,J=5.8Hz,3H),2.89-2.80(m,1H),2.77-2.70(m,2H),2.59(m,1H),2.49-2.43(m,4H),2.31-2.19(m,2H),2.10-2.01(m,1H),1.96-1.84(m,1H),1.70(m,1H),1.60-1.51(m,2H),1.30-1.23(m,1H).MS:m/z 405.2(M+H);HRMS对于C24H33N6(M+H)计算为:405.26885,实测为:405.27644
(S)-N-((1H-苯并[d]噻唑-2基)甲基)-N-(3-(哌嗪-1基)丙基)-5,6,7,8-四氢喹啉-8-胺(EMU186):1H NMR(500MHz,氯仿-d)δ8.46(dd,J=4.7,1.8Hz,1H),7.91(dt,J=8.1,0.9Hz,1H),7.89-7.84(m,1H),7.43(dd,J=8.3,7.2Hz,1H),7.38-7.31(m,2H),7.06(dd,J=7.7,4.6Hz,1H),4.52(d,J=16.8Hz,1H),4.15(td,J=9.3,8.7,6.6Hz,1H),4.04(d,J=16.7Hz,1H),3.00(m,5H),2.81-2.68(m,3H),2.55(m,4H),2.48(t,J=7.4Hz,2H),2.24(m,1H),2.07-1.96(m,1H),1.86(m,1H),1.76-1.69(m,3H);MS:m/z 423.2(M+H);HRMS对于C24H32N5S(M+H)计算为:422.23002,实测为:422.23720
(S)-N-(3-(哌嗪-1基)丙基)-N-(嘧啶-2基甲基)-5,6,7,8-四氢喹啉-8-胺(EMU187):1H NMR(500MHz,氯仿-d)δ8.77-8.72(m,4H),7.27-7.22(m,1H),7.21(t,J=4.9Hz,1H),4.27-3.90(m,5H),3.55-3.27(m,1H),3.17(m,3H),2.94(m,1H),2.86-2.60(m,6H),2.41(m,1H),2.09(m,2H),1.95-1.55(m,2H),1.26(m,1H),0.88(m,1H);MS:m/z 367.3(M+H);HRMS对于C21H31N6(M+H)计算为:367.25319,实测为:367.23720
CXCR4-CEM钙通量测定
测试了本发明的示例性化合物在CCRF-CEM细胞(内源地表达CXCR4的人类细胞系)中诱导或抑制钙通量的能力。CXCR4的活化刺激G蛋白信号传导,其在CCRF-CEM细胞中导致一系列导致细胞内钙储备的释放或钙通量的下游事件。钙离子浓度可以使用许多种比色钙指示物容易地测量,并且因此,钙通量测定是通常使用的用于测量G蛋白偶联受体(GPCR)活性的方法。因为CXCR4拮抗剂作为抗癌剂的治疗潜力可能依赖于它们抑制CXCR4介导的G蛋白信号传导的能力,所以该测定被用作抑制剂效力的首过(first-pass)量度。实验程序和结果提供在下文。接下来举例说明的生物测定已经用本发明的化合物和/或其盐实施。
程序:使表达内源的CXCR4受体的人类T淋巴母细胞(CCRF-CEM)在悬浮液培养物中生长,并且以每孔40,000个细胞铺板透明底384孔微量板(Greiner bio-one Cat#789146)的补充有20mM HEPES(Gibco Cat#15630-080)和0.1%无脂肪酸的BSA(Sigma Cat#A9205)的测定缓冲液[Hank’s缓冲盐水溶液(Gibco Cat#14025-092)中。细胞在37℃用等体积的钙指示物染料(AAT Bioquest Inc,Cat#34601)装载30分钟。然后在测定前将细胞平衡至室温,持续30分钟。将溶解并且连续地稀释在DMSO中的测试化合物转移到384孔板(MatrixCat#4307)。用相同的测定缓冲液将连续稀释的化合物稀释至0.5%DMSO的工作浓度。通过FDSS6000(Hamamatsu)将它们以范围从25,000nM至0.423nM的最终浓度添加到细胞。通过FDSS以“激动剂模式”监测化合物诱导钙通量的活性持续90sec。对于“拮抗剂模式”评估,将细胞随后在室温孵育25分钟。然后添加最终浓度为4nM的SDF-1α(R&D System Cat#350-NS/CF)以刺激细胞。通过FDSS6000监测SDF-1α诱导的对钙通量的抑制,持续90秒。
将对于测试化合物在一定范围的浓度内的活化数据描绘为测试化合物的活化百分比(100%=由饱和浓度即160nM的SDF-1α,触发的最大响应)。在对背景校正后,确定EC50值。将EC50定义为测试化合物产生50%的最大响应的浓度,并且使用4参数逻辑方程定量以拟合数据。将对于测试化合物在一定范围的浓度内的抑制数据描绘为如测试化合物与内部对照化合物相比较的抑制百分比。将IC50定义为测试化合物抑制最大响应的50%的浓度,并且使用4参数逻辑方程定量以拟合数据。
在钙通量测定中,没有一种测试的化合物展示了激动剂活性。所有化合物展示EC50值>30μM,指示它们不是由CCRF-CEM细胞内源性表达的GPCR(包括CXCR4)的激动剂。相反,化合物展示了在抑制SDF-1α诱导的钙通量方面的一定范围的效力,指示它们抑制CXCR4介导的G蛋白信号传导。
Claims (25)
1.一种式(I)的化合物或其盐,
其中RA1是任选地取代的杂环基,其中取代基选自一个或更多个并且相同或不同的RX1;RA2是氢或烷基;RB选自包含烷基、任选地取代的氨基烷基和任选地取代的杂环基的组;其中RA2上的取代基选自一个或更多个并且相同或不同的RX1;RC是氢、任选地取代的烷基或任选地取代的杂环基;并且RX1选自包含烷基、环烷基、卤素、甲氧基和三氟甲基的组。
2.如权利要求1所述的化合物,其中RA1选自:
RB选自包含以下的组:甲基、RC选自包含以下的组:H、CH2RY2、CH=CHCH2RY2、OCH2CH2RY2、NHRY2、N(RY2)2、 RY2选自包含以下的组:H、OH、F、CH3、CH2CH3、CH2OCH3、CH2F、CF3、NH2、 其中所述取代基RY2在合适的情况下单独地并且独立地单取代或二取代到RX2上;并且RX1选自包含甲基、乙基、乙烯、丙基、环丙基、氟、氯、甲氧基和三氟甲基的组。
3.如权利要求1所述的化合物,其中RA1选自包含以下的组:
4.如权利要求1所述的化合物,所述化合物选自包含以下的组:
5.一种式(II)的化合物或其盐,
其中RD是H或烷基,RE是甲基、异丙基或氨基取代的碳环基;RF是任选地取代的杂环基;其中RF的取代基选自一个或更多个并且相同的或不同的RX2;并且RX2是任选地取代的芳基、任选地取代的杂环基或任选地取代的氨基,并且其中RX2的取代基选自一个或更多个并且相同的或不同的RY2;并且RY2选自包含以下的组:甲基、乙基、异丙基、环丙基、氧杂环丁烷、氨基、二甲氨基、甲基哌嗪、吡啶、吡啶基甲基、嘧啶和三氟甲基苯;条件是,当RD是H并且RE是CH3时,那么RF不是:
6.如权利要求5所述的化合物,其中RE选自包含以下的组:
*CH3、RF选自包含以下的组:
RX2选自包含以下的组:
CH2RY2、CH=CHCH2RY2、OCH2CH2RY2、NHRY2、N(RY2)2、
RY2选自包含以下的组:H、OH、F、CH3、CH2CH3、CH2OCH3、CH2F、CF3、NH2、 其中取代基RY2在合适的情况下可以单独地并且独立地单取代或二取代到RX2上;并且RZ是H或CH3并且W是CH或N。
7.如权利要求5所述的化合物,其中RF选自包含以下的组:
8.如权利要求5所述的化合物,所述化合物选自包含以下的组:
9.一种式(III)的化合物或其盐,
其中RG是可以是E或Z的任选地取代的烯烃、任选地取代的碳环基、任选地取代的芳基、任选地取代的杂环基或任选地取代的季碳;X是C或N,并且当X是C时,RH是氢或杂环基,或当X是N时,RH不存在。
10.如权利要求9所述的化合物,其中RG选自包含以下的组:
其中Y是H、烷基或卤素;RI选自包含H、NH2、卤素和CH2NHRJ的组,并且在碳环的情况中,芳基和杂环RI任选地包括对于每个环的一个或更多个并且相同的或不同的取代基;并且RJ选自包含以下的组:
H、或RG是将附接的NMe连接至四氢喹啉的烷基;并且RH是H、 CH2RY2、CH=CHCH2RY2、OCH2CH2RY2、NHRY2、N(RY2)2、 RY2选自包含以下的组:H、OH、F、CH3、CH2CH3、CH2OCH3、CH2F、CF3、NH2、
其中取代基RY2在合适的情况下当X是C时可以单独地并且独立地单取代或二取代到RX2上,或当X是N时RY2不存在。
11.如权利要求9所述的化合物,其中RG选自包含以下的组:
和将NCH3连接至四氢喹啉的CH2CH2基团。
12.如权利要求9所述的化合物,所述化合物选自包含以下的组:
13.一种式(IV)的化合物或其盐,
其中环A是具有或不具有稠合苯环体系的杂芳环体系,RK是C1至C6烷基,并且Z是CH、NH、N或S。
14.如权利要求13所述的化合物,其中环A选自包含以下的组:
15.如权利要求13所述的化合物,所述化合物选自包含以下的组:
16.一种药物组合物,所述药物组合物包含如权利要求1、5、9或13中任一项所述的化合物,包括其盐和前药,以及药学上可接受的赋形剂、稀释剂或载体。
17.如权利要求16所述的药物组合物,所述药物组合物包含以大于60%、70%、80%、90%、95%、98%非对映体过量或对映体过量的所述化合物。
18.如权利要求1、5、9或13中任一项所述的化合物在制备用于治疗CXCR4相关的状况的药物或作为免疫刺激剂或免疫抑制剂的用途,所述CXCR4相关的状况包括病毒感染、异常细胞增殖、视网膜退化、炎性疾病。
19.如权利要求18所述的用途,其中所述病毒感染是HIV感染。
20.一种药物组合物,所述药物组合物包含如权利要求1、5、9或13中任一项所述的化合物以及选自抗病毒剂或化学治疗剂的另一种活性成分。
21.一种CXCR4拮抗剂,所述CXCR4拮抗剂包含与CCR5拮抗剂组合的如权利要求1、5、9或13中任一项所述的化合物。
22.一种治疗或预防病毒感染的方法,所述方法包括向有相应需要的受试者施用包含任选地与另一种活性成分组合的如权利要求1、5、9或13中任一项所述的化合物的药物组合物。
23.如权利要求22所述的方法,其中所述受试者处于病毒感染的风险、展现病毒感染的症状或被诊断为具有病毒感染。
24.一种治疗或预防癌症的方法,所述方法包括向有相应需要的受试者施用包含任选地与另一种活性成分组合的如权利要求1、5、9或13中任一项所述的化合物的药物组合物。
25.如权利要求24所述的方法,其中所述受试者处于癌症的风险、展现癌症的症状或被诊断为具有癌症。
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CN108602829A (zh) | 2015-12-15 | 2018-09-28 | 百时美施贵宝公司 | Cxcr4受体拮抗剂 |
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