CN117736134A - 通过e3泛素连接酶增强靶蛋白质及其他多肽降解的化合物和方法 - Google Patents
通过e3泛素连接酶增强靶蛋白质及其他多肽降解的化合物和方法 Download PDFInfo
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Classifications
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Abstract
本发明的发明名称为通过E3泛素连接酶增强靶蛋白质及其他多肽降解的化合物和方法。本发明涉及双功能化合物,其被发现可用作靶向泛素化的调节剂,特别是通过根据本发明所述的双功能化合物被降解和/或以其他方式被抑制的多种多肽及其他蛋白质的抑制剂。具体地,本发明涉及在一端包含结合泛素连接酶的VHL配体和在另一端包含结合靶蛋白质的部分的化合物,使得靶蛋白质被布置在邻近于泛素连接酶,从而引起该蛋白质降解(和抑制)。本发明呈现与根据本发明所述的化合物相关的与靶向多肽降解/抑制一致的宽范围的药理活性。
Description
本申请是分案申请,原申请的申请日是2013年1月11日,申请号为2013800138068(PCT/US2013/021136),发明名称为“通过E3泛素连接酶增强靶蛋白质及其他多肽降解的化合物和方法”。
发明领域
本发明涉及双功能化合物,其被发现作为靶向泛素化的调节剂的应用性,特别是作为多种被根据本发明所述的双功能化合物降解和/或以其他方式抑制的多肽及其他蛋白质的抑制剂。具体地,本发明涉及这样的化合物:其一端包含结合VHL E3泛素连接酶的VHL配体(定义为泛素配体结合部分或基团)并且另一端包含结合靶蛋白质的部分(定义为蛋白质/多肽靶向部分或/>基团),使得靶蛋白质/多肽被置于邻近泛素连接酶,以引起该蛋白质降解(和抑制)。本发明呈现与根据本发明所述的化合物有关的与靶向多肽降解/抑制一致的宽范围药理活性。
相关申请和准许支持
本申请要求2011年1月12日提交的相同标题的临时申请US61/585,769的优先权利益,其全部内容被引入本文作为参考。
本发明是以国家卫生研究院(the National Institutes of Health)的准许号AI084140在政府支持下完成的。政府享有本发明的某些权利。
发明背景
E3泛素连接酶(其中超过600种被人类所知)1为泛素化给予底物特异性,并且由于其对某些蛋白质底物的特异性,是比一般蛋白酶体抑制剂3,4更具吸引力的治疗靶。虽然E3连接酶的配体的发展已被证实困难——部分是由于其一定会中断蛋白质-蛋白质相互作用5的事实,但进来的发展已经提供结合(bind)这些连接酶的特异性配体。蛋白质-蛋白质相互作用众所周知由于其大接触表面和所含浅沟或平界面是难以用小分子靶向的。相反,大多数小分子药物结合在严密而明确的袋中的酶或受体6。自发现nutlins——第一种小分子E3连接酶抑制剂7——以来,已报告靶向凋亡蛋白质(IAPs)8,9、SCFMet30 10、和SCFCdc4 11的抑制剂的其他化合物;但是,该领域仍处于发展中。
一种具有令人振奋的治疗潜力的E3连接酶是冯希佩尔-林道(VHL)肿瘤抑制剂——E3连接酶复合物VCB的底物识别亚单位,其也由延伸蛋白B和C、Cul2和Rbx1组成12。VHL的主要底物是低氧诱导因子1α(HIF-1α),响应低氧水平上调基因如促血管生长因子VEGF和红细胞诱导细胞因子的促红细胞生成素的转录因子。虽然HIF-1α被组成型表达,但其胞内水平在常氧条件下保持很低——通过脯氨酰羟化酶结构域(PHD)蛋白使其羟基化和随后的VHL介导的泛素化(图1)。
采用合理的设计,我们已生成冯希佩尔-林道(VHL)的第一种小分子配体——E3连接酶VCB的底物识别亚单位,在癌症、慢性贫血和缺血中重要的靶标2。我们还已获得具有我们的最有效配体15的VHL的晶体结构,确定该化合物模拟转录因子HIF-1α——VHL的主要底物——的结合模式。
从较早的结合VHL的羟基化HIF肽的生物化学和结构研究中,已经清楚羟脯氨酸在介导这种蛋白质:蛋白质相互作用中发挥重要作用。基于该项工作,发明人研发了羟基化HIF肽:VHL荧光极化(FP)结合分析,借此他们分析了>120种具有侧接非肽部分的中心羟脯氨酸残基的化合物。深化该研究,发明人现已研究出与七种顶端化合物复合的VHL的共晶体结构。对这些配体结合结构的分析驱使下一代VHL配体的设计/合成,下一代VHL配体与蛋白质结合部分连接以产生根据本发明所述的双功能化合物。
本发明的主要理论依据是我们的普罗太克(PROTAC)(蛋白水解靶向嵌合体)技术需要小分子E3连接酶配体。该技术将靶向的蛋白质/多肽引至E3连接酶,以进行泛素化和随后的蛋白酶体降解。在几个思路证明实验中,本发明人证明了利用来自结合VHL的HIF的短肽序列的这种方法的应用性。为制成更‘像药物’的普罗太克,本发明人已用‘小分子’VHL配体替代HIF肽,从而提供将蛋白质募集至E3连接酶以进行泛素化和降解的方式,从而最终提供基于这种蛋白质降解的疗法。
发明目的
本发明的一个目的是提供具有将内源蛋白质募集至E3泛素连接酶以进行降解的功能的化合物。
本发明的另一目的是提供调节患者或对象内蛋白质降解并且可用于治疗通过降解蛋白质调节的疾病状态或状况的化合物。
本发明的另一目的是提供基于上述调节剂——特别是包括用于患者或对象的治疗处理的抑制剂——的药物组合物,该患者或对象优选包括人患者或对象。
本发明的又一目的是提供确定结合目标蛋白质的蛋白质结合部分的方法。
本发明的再一目的是提供鉴定生物学系统——特别是包括人系统——中结合根据本发明所述的化合物的蛋白质结合部分的内源蛋白质的方法。
本发明的再一目的是提供利用根据本发明所述的化合物鉴定降解生物学系统中的目标蛋白质的效果的方法。
本发明的再一方面是提供治疗患者的方法,其中靶向的蛋白质降解将产生目的治疗效果。
本发明的另一目的是提供可用于第一医疗应用的化合物和组合物。
本发明的再一方面是提供用于治疗患者的化合物和/或组合物,其中靶向的蛋白质降解将产生目的治疗效果。
本发明的这些和/或其他目目的中的任意一个或多个可通过对本发明下文描述的常规阅读而显而易见。
附图简述
图1显示(A)HIF-1α积累导致低氧响应涉及的基因如促红细胞生成素和VEGF的转录上调。(B)在常氧条件下,HIF-1α被羟基化,被VHL识别,被泛素化和被蛋白酶体降解,从而防止转录上调。
图2.WaterLOGSY NMR光谱显示3而非L-Hyp或NAc-Hyp-NMe与VHL结合。
图3显示图形表示显示15和VHL之间的关键相互作用。
图4显示结合VHL的15(最轻灰色碳)的共晶体结构,表示其结合模拟HIF-1α肽(轻灰色碳,pdb 1LM817)的结合。
图5显示V54BC apo(A)的晶体结构和在与15的复合物(B)中的晶体结构。Hyp结合位点残基(条状,黄色碳)和保守水分子(红色点)以及15(条状,青色碳)周围叠加的电子密度(2Fo-Fc)显示为蓝色,并且在1.2σ呈波状。蛋白质表面显示50%透明度,为绿色。
图6-12A和B显示在描述的VHL极化/移位分析中根据本发明所述的各个化合物的活性。根据本发明所述的化合物在各图顶部用编号标示。对照化合物显示在图12B中,并且充当最小极化(最大移位),以进行比较。显示的抑制百分比通过相对于最大和最小极化标准化而确定,和相对于log[VL]作图。每次重复(n=9)的IC50值利用Prism 5确定,然后平均化以确定平均IC50和平均值误差标准(SEM)。
图13(连同表2-亲和力表)显示根据本发明所述的多种示例性化合物。
图14显示根据本发明所述的、来自表2的多种优选化合物。
图15显示更多根据本发明所述的化合物和其活性。多数化合物在100μM浓度以下具有活性。
图16显示根据本发明所述的、来自图15的多种优选的化合物。
图17显示根据本发明所述的来自图15的八种特别优选的化合物。
图18显示根据本发明所述的六种优选的化合物,其包含连接至优选的泛素配体结合部分的雌激素结合蛋白靶向部分。
图19显示根据本发明所述的优选化合物种类。
发明概述
本发明基于如下发现:一旦泛素途径蛋白质和靶蛋白质通过结合泛素途径蛋白质和靶蛋白质的嵌合构建体被邻近安置,泛素途径蛋白质就使任何靶蛋白质泛素化。因此,本发明提供导致选定靶蛋白质泛素化的组合物。本发明还提供组合物库及其应用。
在一个实施方式中,本发明提供可用于调节蛋白质活性的组合物。组合物包括根据限定化学结构的泛素途径蛋白质结合部分(优选用于E3泛素连接酶,单独或与E2泛素结合酶的复合物,该E2泛素结合酶负责将泛素转移至靶向的蛋白质)和蛋白质靶向部分,其优选通过连接体连接在一起,其中泛素途径蛋白质结合部分识别泛素途径蛋白质,并且靶向部分识别靶蛋白质,并且其中泛素途径蛋白质结合部分偶联于靶向部分。
在另一实施方式中,本发明提供化合物库。该库包括一种以上化合物,其中每种组合物均具有式A-B,其中A是泛素途径蛋白质结合部分(优选地,E3泛素连接酶部分,如本文另外公开),并且B是分子库的蛋白质结合部件,其中A偶联(优选地,通过连接体部分)于B,并且其中泛素途径蛋白质结合部分识别泛素途径蛋白质,具体地,E3泛素连接酶。在具体实施方式中,该库包含E3泛素连接酶的VHL的特异性泛素化识别肽(泛素途径蛋白质结合部分,如本文另外公开)和随机靶蛋白质结合元件(例如,化学化合物库)。因此,靶蛋白质未被提前确定,并且该方法可用于确定在通过泛素连接酶降解后假定蛋白质结合元件的活性及其作为靶的药理值。
在又一实施方式中,本发明提供筛选本发明的库以识别包含靶向部分的化合物的方法,该靶向部分识别与细胞预定功能相关的靶蛋白质。方法包括用库实体群(pool ofentities)培育细胞;监测细胞预定功能;鉴定改变细胞预定功能的实体群;用来自被鉴定的实体群的组合物培育细胞;监测细胞预定功能;和鉴定改变细胞预定功能的组合物,其中被鉴定的组合物包含识别与预定功能相关的靶蛋白质的靶向部分。
在另一实施方式中,本发明提供筛选本发明的库以识别包含靶向部分的组合物的方法,该靶向部分识别与细胞预定功能相关的靶蛋白质。方法包括用来自库的各组合物培育细胞;监测细胞预定功能;鉴定改变细胞预定功能的组合物;其中被鉴定的组合物包含识别与预定功能相关的靶蛋白质的靶向部分。
在又一实施方式中,本发明提供鉴定与细胞预定功能相关的靶蛋白质的方法。方法包括用来自本发明的库的组合物培育细胞;监测细胞预定功能;鉴定改变细胞预定功能的组合物;鉴定结合被鉴定的组合物的靶蛋白质,其中靶蛋白质与细胞预定功能相关。
在又一实施方式中,本发明提供鉴定与细胞预定功能相关的靶蛋白质的方法。方法包括用来自本发明的库的实体群培育细胞;监测细胞预定功能;鉴定改变细胞预定功能的实体群;用来自被鉴定的实体群的组合物培育细胞;监测细胞预定功能;鉴定改变细胞预定功能的组合物;和鉴定结合被鉴定的组合物的靶蛋白质,其中靶蛋白质与细胞预定功能相关。
在又一实施方式中,本发明提供泛素化/降解细胞中的靶蛋白质的方法。方法包括给予双功能组合物,该双功能组合物包括泛素途径蛋白质结合部分和靶向部分,其优选通过连接体部分连接,如本文另外描述,其中泛素途径蛋白质结合部分偶联于靶向部分,并且其中泛素途径蛋白质结合部分识别泛素途径蛋白质(例如,泛素连接酶,优选E3泛素连接酶),并且靶向部分识别靶蛋白质,使得当靶蛋白质被置于邻近泛素连接酶时发生靶蛋白质降解,由此导致降解/抑制靶蛋白质的作用和控制蛋白质水平。本发明给予的蛋白质水平控制提供疾病状态或状况的治疗——经由靶蛋白质、通过降低患者细胞中该蛋白质的水平来调节。
在另一实施方式中,本发明涉及治疗需要通过蛋白质来调节疾病状态或状况的患者的方法,其中该蛋白质的降解会在该患者中产生治疗效果,方法包括给予有需要的患者有效量的根据本发明所述的化合物,任选地组合另一生物活性剂。疾病状态或状况可以是微生物剂或其他外源剂如病毒、细菌、真菌、原生动物或其他微生物引起的疾病,或可以是导致疾病状态和/或状况的蛋白质过表达所引起的疾病状态。
在一个实施方式中,本发明涉及根据下列结构的化合物:
其中L是连接体基团和
是泛素连接酶结合部分,其中所述连接体基团任选地进一步连接于/>基团。
在另一实施方式中,本发明涉及包括根据下列一般结构的基团的化合物:
其中是泛素连接酶结合部分,优选是配体——其结合泛素连接酶,优选E3泛素连接酶;
是化学部分(蛋白质靶向部分),其结合靶蛋白质或多肽,其通过泛素连接酶被泛素化并且化学地直接或通过连接体部分L连接于/>基团,或/>可选地是/>基团,其也是泛素连接酶结合部分,其可相同或不同于/>基团,并且直接或通过连接体部分连接于/>基团;和
L是连接体部分,其可存在或不存在,并且其使化学地(共价地)连接于
或其药学上可接受的盐、对映体、立体异构体、溶剂化物或多晶型物。
在本发明的某些方面中——其中是/>基团,化合物类似于二聚化合物,其中化合物两端均包括泛素连接酶结合部分,如本文另外描述。
在本发明的优选方面中,和存在时的/>各自独立地是根据下列化学结构的基团:
其中R1’是任选取代的C1-C6烷基、任选取代的-(CH2)nOH、任选取代的-(CH2)nSH、任选取代的(CH2)n-O-(C1-C6)烷基、包含环氧化物部分WCOCW的任选取代的(CH2)n-WCOCW-(C0-C6)烷基——其中各W独立地是H或C1-C3烷基、任选取代的-(CH2)nCOOH、任选取代的-(CH2)nC(O)-(C1-C6烷基)、任选取代的-(CH2)nNHC(O)-R1、任选取代的-(CH2)nC(O)-NR1R2、任选取代的-(CH2)nOC(O)-NR1R2、-(CH2O)nH、任选取代的-(CH2)nOC(O)-(C1-C6烷基)、任选取代的-(CH2)nC(O)-O-(C1-C6烷基)、任选取代的-(CH2O)nCOOH、任选取代的-(OCH2)nO-(C1-C6烷基)、任选取代的-(CH2O)nC(O)-(C1-C6烷基)、任选取代的-(OCH2)nNHC(O)-R1、任选取代的-(CH2O)nC(O)-NR1R2、-(CH2CH2O)nH、任选取代的-(CH2CH2O)nCOOH、任选取代的-(OCH2CH2)nO-(C1-C6烷基)、任选取代的-(CH2CH2O)nC(O)-(C1-C6烷基)、任选取代的-(OCH2CH2)nNHC(O)-R1、任选取代的-(CH2CH2O)nC(O)-NR1R2、任选取代的-SO2RS、任选被取代S(O)RS、NO2、CN或卤素(F、Cl、Br、I,优选F或Cl);
R1和R2各自独立地是H或可任选地用一个或两个羟基或上至三个卤素基团(优选氟)取代的C1-C6烷基;
RS是C1-C6烷基、任选取代的芳基、杂芳基或杂环基团或-(CH2)mNR1R2基团,X和X’各自独立地是C═O、C═S、-S(O)、S(O)2,(优选X和X’均为C═O);
R2’是任选取代的-(CH2)n-(C=O)u(NR1)v(SO2)w烷基、任选取代的-(CH2)n-(C=O)u(NR1)v(SO2)wNR1NR2N基团、任选取代的-(CH2)n-(C=O)u(NR1)v(SO2)w-芳基、任选取代的-(CH2)n-(C=O)u(NR1)v(SO2)w-杂芳基、
任选取代的-(CH2)n-(C=O)vNR1(SO2)w-杂环、
任选取代的-NR1-(CH2)n-C(O)u(NR1)v(SO2)w-烷基、
任选取代的-NR1-(CH2)n-C(O)u(NR1)v(SO2)w-NR1NR2N、
任选取代的-NR1-(CH2)n-C(O)u(NR1)v(SO2)w-NR1C(O)R1N、
任选取代的-NR1-(CH2)n-(C=O)u(NR1)v(SO2)w-芳基、
任选取代的-NR1-(CH2)n-(C=O)u(NR1)v(SO2)w-杂芳基或
任选取代的-NR1-(CH2)n-(C=O)vNR1(SO2)w-杂环、
任选取代的-XR2’-烷基;
任选取代的-XR2’-芳基;
任选取代的-XR2’-杂芳基;
任选取代的-XR2’-杂环基团;
R3’是任选取代的烷基、
任选取代的-(CH2)n-C(O)u(NR1)v(SO2)w-烷基、
任选取代的-(CH2)n-C(O)u(NR1)v(SO2)w-NR1NR2N、
任选取代的-(CH2)n-C(O)u(NR1)v(SO2)w-NR1C(O)R1N、
任选取代的-(CH2)n-C(O)u(NR1)v(SO2)w-C(O)NR1R2、
任选取代的-(CH2)n-C(O)u(NR1)v(SO2)w-芳基、
任选取代的-(CH2)n-C(O)u(NR1)v(SO2)w-杂芳基、
任选取代的-(CH2)n-C(O)u(NR1)v(SO2)w-杂环、
任选取代的-NR1-(CH2)n-C(O)u(NR1)v(SO2)w-烷基、
任选取代的-NR1-(CH2)n-C(O)u(NR1)v(SO2)w-NR1NR2N、
任选取代的-NR1-(CH2)n-C(O)u(NR1)v(SO2)w-NR1C(O)R1N、
任选取代的-NR1-(CH2)n-C(O)u(NR1)v(SO2)w-芳基、
任选取代的-NR1-(CH2)n-C(O)u(NR1)v(SO2)w-杂芳基、
任选取代的-NR1-(CH2)n-C(O)u(NR1)v(SO2)w-杂环、
任选取代的-O-(CH2)n-(C=O)u(NR1)v(SO2)w-烷基、
任选取代的-O-(CH2)n-(C=O)u(NR1)v(SO2)w-NR1NR2N、
任选取代的-O-(CH2)n-(C=O)u(NR1)v(SO2)w-NR1C(O)R1N、
任选取代的-O-(CH2)n-(C=O)u(NR1)v(SO2)w-芳基、
任选取代的-O-(CH2)n-(C=O)u(NR1)v(SO2)w-杂芳基或
任选取代的-O-(CH2)n-(C=O)u(NR1)v(SO2)w-杂环;
任选取代的-(CH2)n-(V)n’-(CH2)n-(V)n’-烷基、
任选取代的-(CH2)n-(V)n’-(CH2)n-(V)n’-芳基、
任选取代的-(CH2)n-(V)n’-(CH2)n-(V)n’-杂芳基、
任选取代的-(CH2)n-(V)n’-(CH2)n-(V)n’-杂环基团、
任选取代的-(CH2)n-N(R1’)(C=O)m’-(V)n’-烷基、
任选取代的-(CH2)n-N(R1’)(C=O)m’-(V)n’-芳基、
任选取代的-(CH2)n-N(R1’)(C=O)m’-(V)n’-杂芳基、
任选取代的-(CH2)n-N(R1’)(C=O)m’-(V)n’-杂环基团、
任选取代的-XR3’-烷基;
任选取代的-XR3’-芳基;
任选取代的-XR3’-杂芳基;
任选取代的-XR3’-杂环基团;
其中R1N和R2N各自独立地是H、任选地用一个或两个羟基和上至三个卤素基团取代的C1-C6烷基或任选取代的-(CH2)n-芳基、-(CH2)n-杂芳基或-(CH2)n-杂环基团;
V是O、S或NR1;
R1同上;
R1和R1’各自独立地是H或C1-C3烷基;
XR2’和XR3’各自独立地是任选取代的-CH2)n-、-CH2)n-CH(Xv)=CH(Xv)-(顺式或反式)、-CH2)n-CH≡CH-、-(CH2CH2O)n-或C3-C6环烷基,其中Xv是H、卤素或任选取代的C1-C3烷基;
各m独立地为0、1、2、3、4、5、6;
各m’独立地为0或1;
各n独立地为0、1、2、3、4、5、6;
各n’独立地为0或1;
各u独立地为0或1;
各v独立地为0或1;
各w独立地为0或1;和
其中当不是/>时,/>的R1’、R2’、R3’、X和X’中的任意一个或多个被修饰以通过连接体基团共价结合/>基团,或当/>是/>时,/>每一个的R1’、R2’、R3’、X和X’中的任意一个或多个被修饰以相互直接或通过连接体基团共价结合,或
其药学上可接受的盐、立体异构体、溶剂化物或多晶型物。
在本发明的可选方面中,和存在时的/>各自独立地是根据下列化学结构的基团:
其中R1’、R2’和R3’均同上,并且X是C=O、C=S、-S(O)基团或S(O)2基团,更优选C=O基团,并且
其中R1’、R2’和R3’中的任意一个或多个被修饰以结合连接体基团,当不是时,该连接体基团进一步共价结合/>基团,或当/>是/>时,/>和每一个的R1’、R2’、R3’中的任意一个或多个被修饰以相互直接或通过连接体基团共价结合,或
其药学上可接受的盐、对映体、非对映体、溶剂化物或多晶型物。
在本发明再进一步优选方面中,和存在时的/>各自独立地根据下列化学结构:
其中R1’、R2’和R3’中的任意一个或多个被修饰以结合连接体基团,当不是时,该连接体基团进一步共价结合/>基团,或当/>是/>时,/>和/>每一个的R1’、R2’、R3’中的任意一个或多个被修饰以相互直接或通过连接体基团共价结合,或
其药学上可接受的盐、对映体、非对映体、溶剂化物或多晶型物。
在本发明的进一步优选方面中,R1’优选是羟基或可被代谢成羟基或羧酸基团使得化合物是活性化合物的前药形式的基团。示例性优选R1’基团包括,例如,-(CH2)nOH、(CH2)n-O-(C1-C6)烷基、-(CH2)nCOOH、-(CH2O)nH、任选取代的-(CH2)nOC(O)-(C1-C6烷基)、或任选取代的-(CH2)nC(O)-O-(C1-C6烷基),其中n为0或1。在R1’是或包含羧酸基团、羟基或胺基团时,羟基、羧酸基团或胺(其均可任选地被取代)可被进一步化学修饰以提供与连接体基团的共价连接,该连接体基团结合基团(包括/>基团)。
在存在时,X和X’优选是C=O、C=S、-S(O)基团或S(O)2基团,更优选C=O基团。
R2’优选是任选取代的-NR1-T-芳基、任选取代的-NR1-T-杂芳基或任选取代的-NR1-T-杂环,其中R1是H或CH3,优选H,并且T是任选取代的-(CH2)n-基团,其中每一个亚甲基可任选地用一个或两个取代基取代,该取代基优选选自卤素、氨基酸侧链,如本文另外描述,或可任选取代的C1-C3烷基,优选一个或两个甲基;和n为0至6,通常0、1、2或3,优选0或1。可选地,T也可以是-(CH2O)n-基团、-(OCH2)n-基团、-(CH2CH2O)n-基团、-(OCH2CH2)n-基团,其均任选地被取代。
R2’的优选芳基包括任选取代的苯基或萘基,优选苯基,其中苯基任选地用下列取代:连接体基团,该连接体基团连接基团(包括/>基团)、卤素(优选F或Cl)、胺、单烷基-或二烷基胺(优选地,二甲基胺)、F、Cl、OH、COOH、C1-C6烷基,优选CH3、CF3、OMe、OCF3、NO2或CN基团(其均可在苯基环的邻-、间-和/或对-位,优选对位被取代)、任选取代的苯基(苯基本身优选用连接体基团取代,该连接体基团连接/>基团,包括/>基团)、和/或下列中的至少一种:F、Cl、OH、COOH、CH3、CF3、OMe、OCF3、NO2或CN基团(在苯基环的邻-、间-和/或对-位,优选对-位)、可任选取代的萘基、任选取代的杂芳基,优选任选取代的异/>唑——包括甲基取代的异/>唑、任选取代的/>唑——包括甲基取代的/>唑、任选取代的噻唑——包括甲基取代的噻唑、任选取代的异噻唑——包括甲基取代的异噻唑、任选取代的吡咯——包括甲基取代的吡咯、任选取代的咪唑——包括甲基咪唑、任选取代的苯并咪唑或甲氧基苄基咪唑、任选取代的氧代咪唑或甲基氧代咪唑、任选取代的二唑基团——包括甲基二唑基团、任选取代的三唑基团——包括甲基取代的三唑基团、任选取代的吡啶基团——包括卤素-(优选地,F)或甲基-取代的吡啶基团或氧杂吡啶(oxopyridine)基团(其中吡啶基团通过氧连接于苯基)、任选取代的呋喃、任选取代的苯并呋喃、任选取代的二氢苯并呋喃、任选取代的吲哚、吲嗪或氮杂吲嗪(2、3、或4-氮杂吲嗪)、任选取代的喹啉、任选取代的根据下列化学结构的基团:
其中Sc是CHRSS、NRURE、或O;
RHET是H、CN、NO2、卤素(优选Cl或F)、任选取代的C1-C6烷基(优选用下列取代:一个或两个羟基或上至三个卤素基团(例如,CF3)、任选取代的O(C1-C6烷基)(优选用一个或两个羟基或上至三个卤素基团取代)或任选取代的炔基团-C≡C-Ra,其中Ra是H或C1-C6烷基(优选C1-C3烷基);
RSS是H、CN、NO2、卤素(优选F或Cl)、任选取代的C1-C6烷基(优选用一个或两个羟基或上至三个卤素基团取代)、任选取代的O-(C1-C6烷基)(优选用一个或两个羟基或上至三个卤素基团取代)或任选取代的-C(O)(C1-C6烷基)(优选用一个或两个羟基或上至三个卤素基团取代);
RURE是H、C1-C6烷基(优选H或C1-C3烷基)或-C(O)(C1-C6烷基)——各基团均任选地用下列取代:一个或两个羟基或上至三个卤素(优选氟基团)、或任选取代的苯基、任选取代的杂芳基、或任选取代的杂环,优选例如哌啶、吗啉、吡咯烷、四氢呋喃);
RPRO是H、任选取代的C1-C6烷基或任选取代的芳基(苯基或萘基)、杂芳基或杂环基团——选自唑、异/>唑、噻唑、异噻唑、咪唑、二唑、氧代咪唑、吡咯、吡咯烷、呋喃、二氢呋喃、四氢呋喃、噻嗯、二氢噻嗯、四氢噻嗯、吡啶、哌啶、哌嗪、吗啉、喹啉、(每一个均优选用下列取代:C1-C3烷基,优选甲基或卤素基团,优选F或Cl)、苯并呋喃、吲哚、吲嗪、氮杂吲嗪;
RPRO1和RPRO2各自独立地是H、任选取代的C1-C3烷基或一起形成酮基团;和
各n独立地为0、1、2、3、4、5或6(优选0或1)、或
任选取代的杂环,优选四氢呋喃、四氢噻嗯、哌啶、哌嗪或吗啉(各基团在被取代时均优选用甲基或卤素(F、Br、Cl)取代、
各基团可任选地用连接体基团取代,该连接体基团连接基团(包括/>基团)。
在某些优选方面中,是
基团,
其中RPRO和n同上。
R2’的优选杂芳基包括任选取代的喹啉(其可连接药效团或在喹啉环内的任意碳原子上取代)、任选取代的吲哚、任选取代的吲嗪、任选取代的氮杂吲嗪、任选取代的苯并呋喃——包括任选取代的苯并呋喃、任选取代的异唑、任选取代的噻唑、任选取代的异噻唑、任选取代的噻吩、任选取代的吡啶(2-、3-、或4-吡啶)、任选取代的咪唑、任选取代的吡咯、任选取代的二唑、任选取代的三唑、四唑、任选取代的氧代咪唑,或根据下列化学结构的基团:
其中Sc是CHRSS、NRURE、或O;
RHET是H、CN、NO2、卤素(优选Cl或F)、任选取代的C1-C6烷基(优选用一个或两个羟基或上至三个卤素基团取代(例如,CF3)、任选取代的O(C1-C6烷基)(优选用一个或两个羟基或上至三个卤素基团取代)或任选取代的炔基团-C≡C-Ra,其中Ra是H或C1-C6烷基(优选C1-C3烷基);
RSS是H、CN、NO2、卤素(优选F或Cl)、任选取代的C1-C6烷基(优选用一个或两个羟基或上至三个卤素基团取代)、任选取代的O-(C1-C6烷基)(优选用一个或两个羟基或上至三个卤素基团取代)或任选取代的-C(O)(C1-C6烷基)(优选用一个或两个羟基或上至三个卤素基团取代);
RURE是H、C1-C6烷基(优选H或C1-C3烷基)或-C(O)(C1-C6烷基)——各基团均任选用下列取代:一个或两个羟基或上至三个卤素(优选氟基团)、或任选取代的杂环,例如哌啶、吗啉、吡咯烷、四氢呋喃、四氢噻吩、哌啶、哌嗪,其均任选被取代,和
YC是N或C-RYC,其中RYC是H、OH、CN、NO2、卤素(优选Cl或F)、任选取代的C1-C6烷基(优选用一个或两个羟基或上至三个卤素基团取代(例如,CF3)、任选取代的O(C1-C6烷基)(优选用一个或两个羟基或上至三个卤素基团取代)或任选取代的炔基团-C≡C-Ra,其中Ra是H或C1-C6烷基(优选C1-C3烷基),
各基团均可任选地用连接体基团取代,该连接体基团连接基团(包括/>基团);
R2’的优选杂环基团包括四氢呋喃、四氢噻嗯、四氢喹啉、哌啶、哌嗪、吡咯烷、吗啉、烷或噻烷,各基团均可任选被取代,或是根据下列化学结构的基团:
优选地,基团,
其中RPRO是H、任选取代的C1-C6烷基或任选取代的芳基、杂芳基或杂环基团;
RPRO1和RPRO2各自独立地是H、任选取代的C1-C3烷基或一起形成酮基团,和
各n独立地是0、1、2、3、4、5、或6(通常0或1),各基团均可任选地用连接体基团取代,该连接体基团连接基团(包括/>基团)。
用于本发明的优选R2’取代基还具体包括(不限于公开的具体化合物)在本文公开的被鉴定的化合物(包括在本说明书和附图中公开的具体化合物)中发现的R2’取代基。这些R2’取代基中的每一个均可与任意数量的R3’取代基联用,该R3’取代基也在本文中被公开。
R3’优选是任选取代的-T-芳基、任选取代的-T-杂芳基、任选取代的-T-杂环、任选取代的-NR1-T-芳基、任选取代的-NR1-T-杂芳基或任选取代的-NR1-T-杂环,其中R1是H或C1-C3烷基,优选H或CH3、T是任选取代的-(CH2)n-基团,其中每一个亚甲基可任选地用下列取代:一个或两个取代基,优选选自卤素、C1-C3烷基或氨基酸侧链,如本文另外描述,优选可任选取代的甲基;和n为0至6,通常0、1、2、或3,优选0或1。可选地,T也可以是-(CH2O)n-基团、-(OCH2)n-基团、-(CH2CH2O)n-基团、-(OCH2CH2)n-基团,各基团均任选被取代。
R3’的优选芳基包括任选取代的苯基或萘基,优选苯基,其中苯基或萘基任选地用下列取代:连接体基团——该连接体基团连接基团(包括/>基团)和/或卤素(优选F或Cl)、胺、单烷基-或二烷基胺(优选地,二甲基胺)、酰氨基(优选-(CH2)m-NR1C(O)R2基团,其中m、R1和R2同上)、卤素(通常F或Cl)、OH、CH3、CF3、OMe、OCF3、NO2、CN或S(O)2RS基团(RS是C1-C6烷基、任选取代的芳基、杂芳基或杂环基团或-(CH2)mNR1R2基团),每一个均可在苯基环的邻-、间-和/或对-位,优选在对位被取代)、或芳基(优选苯基)、杂芳基或杂环。优选所述取代基苯基是任选取代的苯基(即,取代基苯基本身优选用下列中的至少一个取代:F、Cl、OH、SH、COOH、CH3、CF3、OMe、OCF3、NO2、CN或连接体基团——该连接体基团连接/>基团(包括/>基团),其中取代发生在苯基环的邻-、间-和/或对-位,优选对位)、可任选取代的萘基——包括如上所述、任选取代的杂芳基(优选任选取代的异/>唑——包括甲基取代异唑、任选取代的/>唑——包括甲基取代/>唑、任选取代的噻唑——包括甲基取代噻唑、任选取代的吡咯——包括甲基取代吡咯、任选取代的咪唑——包括甲基咪唑、苄基咪唑或甲氧基苄基咪唑、氧代咪唑或甲基氧代咪唑、任选取代的二唑基团——包括甲基二唑基团、任选取代的三唑基团——包括甲基取代三唑基团、吡啶基团——包括卤素-(优选地,F)或甲基取代吡啶基团或氧杂吡啶基团(其中吡啶基团通过氧连接于苯基)或任选取代的杂环(四氢呋喃、四氢噻吩、吡咯烷、哌啶、吗啉、哌嗪、四氢喹啉、/>烷或噻烷。芳基、杂芳基或杂环基团中的每一个均可任选地用连接体基团取代,该连接体基团连接/>基团(包括/>基团)。
R3’的优选杂芳基包括任选取代的喹啉(其可连接于药效团或在喹啉环内的任意碳原子上被取代)、任选取代的吲哚(包括二氢吲哚)、任选取代的吲嗪、任选取代的氮杂吲嗪(2、3或4-氮杂吲嗪)、任选取代的苯并咪唑、苯并二唑、苯并氧杂呋喃(benzoxofuran)、任选取代的咪唑、任选取代的异唑、任选取代的/>唑(优选被甲基取代)、任选取代的二唑、任选取代的三唑、四唑、任选取代的苯并呋喃、任选取代的噻吩、任选取代的噻唑(优选被甲基和/或硫醇基取代)、任选取代的异噻唑、任选取代的三唑(优选被下列取代的1,2,3-三唑:甲基、三异丙基甲硅烷基、任选取代的-(CH2)m-O-C1-C6烷基或任选取代的-(CH2)m-C(O)-O-C1-C6烷基)、任选取代的吡啶(2-、3-、或4-吡啶)或根据下列化学结构的基团:
其中Sc是CHRSS、NRURE、或O;
RHET是H、CN、NO2、卤素(优选Cl或F)、任选取代的C1-C6烷基(优选用一个或两个羟基或上至三个卤素基团取代(例如,CF3)、任选取代的O(C1-C6烷基)(优选用一个或两个羟基或上至三个卤素基团取代)或任选取代的炔基团-C≡C-Ra,其中Ra是H或C1-C6烷基(优选C1-C3烷基);
RSS是H、CN、NO2、卤素(优选F或Cl)、任选取代的C1-C6烷基(优选用一个或两个羟基或上至三个卤素基团取代)、任选取代的O-(C1-C6烷基)(优选用一个或两个羟基或上至三个卤素基团取代)或任选取代的-C(O)(C1-C6烷基)(优选用一个或两个羟基或上至三个卤素基团取代);
RURE是H、C1-C6烷基(优选H或C1-C3烷基)或-C(O)(C1-C6烷基),各基团均任选被下列取代:一个或两个羟基或上至三个卤素,优选氟基团,或任选取代的杂环,例如哌啶、吗啉、吡咯烷、四氢呋喃、四氢噻吩、哌啶、哌嗪,每一个均任选被取代,和
YC是N或C-RYC,其中RYC是H、OH、CN、NO2、卤素(优选Cl或F)、任选取代的C1-C6烷基(优选用一个或两个羟基或上至三个卤素基团取代(例如,CF3)、任选取代的O(C1-C6烷基)(优选用一个或两个羟基或上至三个卤素基团取代)或任选取代的炔基团-C≡C-Ra,其中Ra是H或C1-C6烷基(优选C1-C3烷基)。各所述杂芳基可任选地用连接体基团取代,该连接体基团连接基团(包括/>基团)。
R3’的优选杂环基团包括四氢喹啉、哌啶、哌嗪、吡咯烷、吗啉、四氢呋喃、四氢噻吩、烷和噻烷——各基团均可任选被取代、或根据下列化学结构的基团:
优选地,基团,
其中RPRO是H、任选取代的C1-C6烷基或任选取代的芳基(苯基或萘基)、杂芳基或杂环基团——选自唑、异/>唑、噻唑、异噻唑、咪唑、二唑、氧代咪唑、吡咯、吡咯烷、呋喃、二氢呋喃、四氢呋喃、噻嗯、二氢噻嗯、四氢噻嗯、吡啶、哌啶、哌嗪、吗啉、喹啉、(每一个均优选被下列取代:C1-C3烷基,优选甲基,或卤素基团,优选F或Cl)、苯并呋喃、吲哚、吲嗪、氮杂吲嗪;
RPRO1和RPRO2各自独立地是H、任选取代的C1-C3烷基或一起形成酮基团,和
各n为0、1、2、3、4、5、或6(优选0或1),其中各所述杂环基团可任选地用连接体基团取代,该连接体基团连接基团(包括/>基团)。
用于本发明的优选R3’取代基还具体包括(不限于公开的具体化合物)在本文公开的被鉴定的化合物(包括在本说明书和附图中公开的具体化合物)中发现的R3’取代基。这些R3’取代基中的每一个均可与任意数量的R2’取代基联用,该R2’取代基也被本文公开。
在某些可选的优选实施方式中,R2’是任选取代的-NR1-XR2’-烷基、-NR1-XR2’-芳基;任选取代的-NR1-XR2’-HET、任选取代的-NR1-XR2’-芳基-HET或任选取代的-NR1-XR2’-HET-芳基,
其中R1是H或C1-C3烷基(优选H);
XR2’是任选取代的-CH2)n-、-CH2)n-CH(Xv)=CH(Xv)-(顺式或反式)、-CH2)n-CH≡CH-、-(CH2CH2O)n-或C3-C6环烷基;
其中Xv是H、卤素或任选被一个或两个羟基或上至三个卤素基团取代的C1-C3烷基;
烷基是任选取代的C1-C10烷基(优选C1-C6烷基)基团(在某些优选实施方式中,烷基用卤素基团封端,通常Cl或Br);
芳基是任选取代的苯基或萘基(优选地,苯基);和HET是任选取代的唑、异/>唑、噻唑、异噻唑、咪唑、二唑、氧代咪唑、吡咯、吡咯烷、呋喃、二氢呋喃、四氢呋喃、噻嗯、二氢噻嗯、四氢噻嗯、吡啶、哌啶、哌嗪、吗啉、苯并呋喃、吲哚、吲嗪、氮杂吲嗪、喹啉(在被取代时,每一个均优选被下列取代:C1-C3烷基,优选甲基或卤素基团,优选F或Cl)、或根据下列化学结构的基团:
其中Sc是CHRSS、NRURE、或O;
RHET是H、CN、NO2、卤素(优选Cl或F)、任选取代的C1-C6烷基(优选用一个或两个羟基或上至三个卤素基团取代(例如,CF3)、任选取代的O(C1-C6烷基)(优选用一个或两个羟基或上至三个卤素基团取代)或任选取代的炔基团-C≡C-Ra,其中Ra是H或C1-C6烷基(优选C1-C3烷基);
RSS是H、CN、NO2、卤素(优选F或Cl)、任选取代的C1-C6烷基(优选用一个或两个羟基或上至三个卤素基团取代)、任选取代的O-(C1-C6烷基)(优选用一个或两个羟基或上至三个卤素基团取代)或任选取代的-C(O)(C1-C6烷基)(优选用一个或两个羟基或上至三个卤素基团取代);
RURE是H、C1-C6烷基(优选H或C1-C3烷基)或-C(O)(C1-C6烷基),各基团均任选被下列取代:一个或两个羟基或上至三个卤素,优选氟基团,或任选取代的杂环,例如哌啶、吗啉、吡咯烷、四氢呋喃、四氢噻吩、哌啶、哌嗪,每一个均任选被取代,和
YC是N或C-RYC,其中RYC是H、OH、CN、NO2、卤素(优选Cl或F)、任选取代的C1-C6烷基(优选用一个或两个羟基或上至三个卤素基团取代(例如,CF3)、任选取代的O(C1-C6烷基)(优选用一个或两个羟基或上至三个卤素基团取代)或任选取代的炔基团-C≡C-Ra,其中Ra是H或C1-C6烷基(优选C1-C3烷基);
RPRO是H、任选取代的C1-C6烷基或任选取代的芳基(苯基或萘基)、杂芳基或杂环基团——选自唑、异/>唑、噻唑、异噻唑、咪唑、二唑、氧代咪唑、吡咯、吡咯烷、呋喃、二氢呋喃、四氢呋喃、噻嗯、二氢噻嗯、四氢噻嗯、吡啶、哌啶、哌嗪、吗啉、喹啉、(每一个均优选被下列取代:C1-C3烷基,优选甲基或卤素基团,优选F或Cl)、苯并呋喃、吲哚、吲嗪、氮杂吲嗪;
RPRO1和RPRO2各自独立地是H、任选取代的C1-C3烷基或一起形成酮基团,和
各n独立地是0、1、2、3、4、5、或6(优选0或1)。各所述基团可任选地用连接体基团取代,该连接体基团连接基团(包括/>基团)。
在本发明的某些可选的优选实施方式中,R3’是任选取代的-(CH2)n-(V)n’-(CH2)n-(V)n’-RS3’基团、任选取代的-(CH2)n-N(R1’)(C=O)m’-(V)n’-RS3’基团、任选取代的-XR3’-烷基、任选取代的-XR3’-芳基;任选取代的-XR3’-HET基团、任选取代的-XR3’-芳基-HET基团或任选取代的-XR3’-HET-芳基
其中RS3’是任选取代的烷基(C1-C10,优选C1-C6烷基)、任选取代的芳基或HET基团;
R1’是H或C1-C3烷基(优选H);
V是O、S或NR1’;
XR3’是-(CH2)n-、-(CH2CH2O)n-、-CH2)n-CH(Xv)=CH(Xv)-(顺式或反式)、-CH2)n-CH≡CH-、或C3-C6环烷基,全部任选被取代;
其中Xv是H、卤素或任选被一个或两个羟基或上至三个卤素基团取代的C1-C3烷基;
烷基是任选取代的C1-C10烷基(优选C1-C6烷基)基团(在某些优选实施方式中,烷基用卤素基团封端——通常Cl或Br);
芳基是任选取代的苯基或萘基(优选地,苯基);和
HET是任选取代的唑、异/>唑、噻唑、异噻唑、咪唑、二唑、氧代咪唑、吡咯、吡咯烷、呋喃、二氢呋喃、四氢呋喃、噻嗯、二氢噻嗯、四氢噻嗯、吡啶、哌啶、哌嗪、吗啉、苯并呋喃、吲哚、吲嗪、氮杂吲嗪、喹啉(在被取代时,每一个均优选被下列取代:C1-C3烷基,优选甲基或卤素基团,优选F或Cl)、或根据下列化学结构的基团:/>
其中Sc是CHRSS、NRURE、或O;
RHET是H、CN、NO2、卤素(优选Cl或F)、任选取代的C1-C6烷基(优选用一个或两个羟基或上至三个卤素基团取代(例如,CF3)、任选取代的O(C1-C6烷基)(优选用一个或两个羟基或上至三个卤素基团取代)或任选取代的炔基团-C≡C-Ra,其中Ra是H或C1-C6烷基(优选C1-C3烷基);
RSS是H、CN、NO2、卤素(优选F或Cl)、任选取代的C1-C6烷基(优选用一个或两个羟基或上至三个卤素基团取代)、任选取代的O-(C1-C6烷基)(优选用一个或两个羟基或上至三个卤素基团取代)或任选取代的-C(O)(C1-C6烷基)(优选用一个或两个羟基或上至三个卤素基团取代);
RURE是H、C1-C6烷基(优选H或C1-C3烷基)或-C(O)(C0-C6烷基),各基团均任选被下列取代:一个或两个羟基或上至三个卤素,优选氟基团,或任选取代的杂环,例如哌啶、吗啉、吡咯烷、四氢呋喃、四氢噻吩、哌啶、哌嗪,每一个均任选被取代,和
YC是N或C-RYC,其中RYC是H、OH、CN、NO2、卤素(优选Cl或F)、任选取代的C1-C6烷基(优选用一个或两个羟基或上至三个卤素基团取代(例如,CF3)、任选取代的O(C1-C6烷基)(优选用一个或两个羟基或上至三个卤素基团取代)或任选取代的炔基团-C≡C-Ra,其中Ra是H或C1-C6烷基(优选C1-C3烷基);
RPRO是H、任选取代的C1-C6烷基或任选取代的芳基(苯基或萘基)、杂芳基或杂环基团——选自唑、异/>唑、噻唑、异噻唑、咪唑、二唑、氧代咪唑、吡咯、吡咯烷、呋喃、二氢呋喃、四氢呋喃、噻嗯、二氢噻嗯、四氢噻嗯、吡啶、哌啶、哌嗪、吗啉、喹啉(每一个均优选被下列取代:C1-C3烷基,优选甲基或卤素基团,优选F或Cl)、苯并呋喃、吲哚、吲嗪、氮杂吲嗪;
RPRO1和RPRO2各自独立地是H、任选取代的C1-C3烷基或一起形成酮基团,和
各n独立地为0、1、2、3、4、5、或6(优选0或1);
各m’为0或1;和
各n’为0或1,
其中各所述化合物——优选在烷基、芳基或Het基团上——用连接体基团取代,该连接体基团连接基团(包括/>基团)。
在可选的实施方式中,R3’是-(CH2)n-芳基、-(CH2CH2O)n-芳基、-(CH2)n-HET或-(CH2CH2O)n-HET;
其中芳基是任选被一个或两个取代基取代的苯基,其中所述取代基(一个或多个)优选选自-(CH2)nOH、C1-C6烷基——本身进一步任选被CN、卤素(上至三个卤素基团)、OH、-(CH2)nO(C1-C6)烷基、胺、单-或二-(C1-C6烷基)胺取代,其中胺上的烷基任选被1或2个羟基或上至三个卤素(优选F、Cl)基团取代,或所述芳基被-(CH2)nOH、-(CH2)n-O-(C1-C6)烷基、-(CH2)n-O-(CH2)n-(C1-C6)烷基、-(CH2)n-C(O)(C0-C6)烷基、-(CH2)n-C(O)O(C0-C6)烷基、-(CH2)n-OC(O)(C0-C6)烷基,胺,单-或二-(C1-C6烷基)胺取代,其中胺上的烷基任选被下列取代:1或2个羟基或上至三个卤素(优选F、Cl)基团、CN、NO2、任选取代的-(CH2)n-(V)m’-CH2)n-(V)m’-(C1-C6)烷基、-(V)m’-(CH2CH2O)n-RPEG基团,其中V是O、S或NR1’、R1’是H或C1-C3烷基(优选H),和RPEG是H或任选取代的(包括任选被羧基取代)的C1-C6烷基,或所述芳基任选被下列取代:杂环,包括杂芳基,选自唑、异/>唑、噻唑、异噻唑、咪唑、二唑、氧代咪唑、吡咯、吡咯烷、呋喃、二氢呋喃、四氢呋喃、噻嗯、二氢噻嗯、四氢噻嗯、吡啶、哌啶、哌嗪、吗啉、喹啉、苯并呋喃、吲哚、吲嗪、氮杂吲嗪(在被取代时每一个均优选被下列取代:C1-C3烷基,优选甲基或卤素基团,优选F或Cl)、或根据下列化学结构的基团:
其中Sc是CHRSS、NRURE、或O;
RHET是H、CN、NO2、卤素(优选Cl或F)、任选取代的C1-C6烷基(优选用一个或两个羟基或上至三个卤素基团取代(例如,CF3)、任选取代的O(C1-C6烷基)(优选用一个或两个羟基或上至三个卤素基团取代)或任选取代的炔基团-C≡C-Ra,其中Ra是H或C1-C6烷基(优选C1-C3烷基);
RSS是H、CN、NO2、卤素(优选F或Cl)、任选取代的C1-C6烷基(优选用一个或两个羟基或上至三个卤素基团取代)、任选取代的O-(C1-C6烷基)(优选用一个或两个羟基或上至三个卤素基团取代)或任选取代的-C(O)(C1-C6烷基)(优选用一个或两个羟基或上至三个卤素基团取代);
RURE是H、C1-C6烷基(优选H或C1-C3烷基)或-C(O)(C0-C6烷基),各基团均任选被下列取代:一个或两个羟基或上至三个卤素,优选氟基团,或任选取代的杂环,例如哌啶、吗啉、吡咯烷、四氢呋喃、四氢噻吩、哌啶、哌嗪,每一个均任选被取代,和
YC是N或C-RYC,其中RYC是H、OH、CN、NO2、卤素(优选Cl或F)、任选取代的C1-C6烷基(优选用一个或两个羟基或上至三个卤素基团取代(例如,CF3)、任选取代的O(C1-C6烷基)(优选用一个或两个羟基或上至三个卤素基团取代)或任选取代的炔基团-C≡C-Ra,其中Ra是H或C1-C6烷基(优选C1-C3烷基);
RPRO是H、任选取代的C1-C6烷基或任选取代的芳基(苯基或萘基)、杂芳基或杂环基团,选自唑、异/>唑、噻唑、异噻唑、咪唑、二唑、氧代咪唑、吡咯、吡咯烷、呋喃、二氢呋喃、四氢呋喃、噻嗯、二氢噻嗯、四氢噻嗯、吡啶、哌啶、哌嗪、吗啉、喹啉(每一个均优选被下列取代:C1-C3烷基,优选甲基或卤素基团,优选F或Cl)、苯并呋喃、吲哚、吲嗪、氮杂吲嗪;
RPRO1和RPRO2各自独立地是H、任选取代的C1-C3烷基或一起形成酮基团;
HET优选是唑、异/>唑、噻唑、异噻唑、咪唑、二唑、氧代咪唑、吡咯、吡咯烷、呋喃、二氢呋喃、四氢呋喃、噻嗯、二氢噻嗯、四氢噻嗯、吡啶、哌啶、哌嗪、吗啉、喹啉(每一个均优选被下列取代:C1-C3烷基,优选甲基或卤素基团,优选F或Cl)、苯并呋喃、吲哚、吲嗪、氮杂吲嗪、或根据下列化学结构的基团:
其中Sc是CHRSS、NRURE、或O;
RHET是H、CN、NO2、卤素(优选Cl或F)、任选取代的C1-C6烷基(优选用一个或两个羟基或上至三个卤素基团取代(例如,CF3)、任选取代的O(C1-C6烷基)(优选用一个或两个羟基或上至三个卤素基团取代)或任选取代的炔基团-C≡C-Ra,其中Ra是H或C1-C6烷基(优选C1-C3烷基);
RSS是H、CN、NO2、卤素(优选F或Cl)、任选取代的C1-C6烷基(优选用一个或两个羟基或上至三个卤素基团取代)、任选取代的O-(C1-C6烷基)(优选用一个或两个羟基或上至三个卤素基团取代)或任选取代的-C(O)(C1-C6烷基)(优选用一个或两个羟基或上至三个卤素基团取代);
RURE是H、C1-C6烷基(优选H或C1-C3烷基)或-C(O)(C0-C6烷基),各基团均任选被下列取代:一个或两个羟基或上至三个卤素,优选氟基团,或任选取代的杂环,例如哌啶、吗啉、吡咯烷、四氢呋喃、四氢噻吩、哌啶、哌嗪,每一个均任选被取代,和
YC是N或C-RYC,其中RYC是H、OH、CN、NO2、卤素(优选Cl或F)、任选取代的C1-C6烷基(优选用一个或两个羟基或上至三个卤素基团取代(例如,CF3)、任选取代的O(C1-C6烷基)(优选用一个或两个羟基或上至三个卤素基团取代)或任选取代的炔基团-C≡C-Ra,其中Ra是H或C1-C6烷基(优选C1-C3烷基);
RPRO是H、任选取代的C1-C6烷基或任选取代的芳基、杂芳基或杂环基团;
RPRO1和RPRO2各自独立地是H、任选取代的C1-C3烷基或一起形成酮基团,各m’独立地为0或1,和
各n独立地为0、1、2、3、4、5、或6(优选0或1),
其中各所述化合物,优选在所述芳基或HET基团上,用连接体基团取代,该连接体基团连接基团(包括/>基团)。
在另外的实施方式中,优选化合物包括根据下列化学结构的那些:
其中R1’是OH或在患者或对象体内代谢成OH的基团;
R2’是-NH-CH2-芳基-HET(优选地,直接连接甲基取代的噻唑的苯基);
R3’是-CHRCR3’-NH-C(O)-R3P1基团或-CHRCR3’-R3P2基团;
其中RCR3’是C1-C4烷基,优选甲基,异丙基或叔丁基;
R3P1是C1-C3烷基(优选甲基)、任选取代的氧杂环丁烷基团(优选被甲基取代)、-(CH2)nOCH3基团——其中n为1或2(优选2)、或基团(乙基醚基团优选在苯基部分上间位取代)、吗啉基(在2-或3-位连接于羰基;
R3P2是基团,/>
其中芳基是苯基;
HET是任选取代的噻唑或异噻唑;和
RHET是H或卤素基团(优选H),
或其药学上可接受的盐、立体异构体、溶剂化物或多晶型物,其中各所述化合物用连接体基团取代,该连接体基团连接基团(包括/>基团)。
在可选的实施方式中,根据本发明所述的化合物包含的基团包括:
其中X是Cl、F、C1-C3烷基(优选甲基)或杂环(优选,任选取代的杂环,包括上述R3’的限定;
R1和R2各自独立地是H、C1-C3烷基(优选甲基)、或苯基,并且各所述化合物被连接体基团或连接基团的连接体基团取代,或
其药学上可接受的盐、对映体、非对映体、溶剂化物或多晶型物。
另外的根据本发明所述的化合物包含的优选基团包括:
其中n为0或1;
R是连接体或连接基团的连接体,
X是H、F、Cl、C1-C3烷基(优选甲基)或杂环(优选,任选取代的杂环,特别是包括水溶性杂环,如吗啉基,包括上述R3’的限定),或
其药学上可接受的盐、对映体、非对映体、溶剂化物或多晶型物。
另外的根据本发明所述的化合物包含的优选基团包括例如:/>
其中n为0或1;
R是连接体或连接基团的连接体,连接体或连接通过酰胺、酯、醚或氨基甲酸酯基团连接于/>基团的/>基团的连接体;
R1是C1-C3烷基(任选一个或两个羟基被取代)或-C(O)NR3R4,其中R3和R4各自独立地是H、C1-C3烷基(优选甲基)、苯基或杂环(包括杂环,如吗啉基、哌嗪或其他增加水溶性的基团),
X是H、F、Cl、C1-C3烷基(优选甲基)或杂环(优选,任选取代的杂环,包括水溶性杂环,包括上述R3’的限定),或其药学上可接受的盐、对映体、非对映体、溶剂化物或多晶型物。
根据本发明所述的化合物包含的再进一步优选基团包括例如:
其中n为0或1;
R1是连接体或连接基团的连接体,/>基团通过酰胺、酯、醚、氨基甲酸酯或杂环基团(优选,任选取代的杂环,包括上述R3’的限定)连接于/>基团;
R是H、F、Cl、C1-C3烷基(任选被一个或两个羟基取代,优选甲基)、-O-C(O)NR3R4或-C(O)NR3R4,其中R3和R4中的每一个独立地是H、C1-C3烷基(优选甲基)、苯基或杂环——包括水溶性杂环,或
其药学上可接受的盐、对映体、非对映体、溶剂化物或多晶型物。
根据本发明所述的化合物包含的还进一步优选的基团包括例如:
/>
其中n为0或1;
R是连接体或连接基团的连接体,/>基团通过酰胺、酯、醚、氨基甲酸酯或杂环基团连接于/>基团;和
各X独立地是H、F、Cl、C1-C3烷基(任选被一个或两个羟基取代,优选甲基)、杂环(优选,任选取代的杂环,包括水溶性杂环,和/或如上述R3’的限定)、-O-C(O)NR3R4或-C(O)NR3R4,其中R3和R4中的每一个独立地是H、C1-C3烷基(优选甲基)、或苯基,或
其药学上可接受的盐、对映体、非对映体、溶剂化物或多晶型物。
再另外的根据本发明所述的化合物包含的还进一步优选的基团包括例如:
其中n为0或1;
R是连接体或连接基团的连接体,/>基团通过酰胺、酯、醚、氨基甲酸酯或杂环基团连接于/>基团;
R1是任选被一个或两个羟基取代的C1-C3烷基、-O-C(O)NR3R4或-C(O)NR3R4,其中R3和R4中的每一个独立地是H、C1-C3烷基(优选甲基)、或苯基;和
X独立地是H、F、Cl、C1-C3烷基(任选被一个或两个羟基取代,优选甲基)或杂环(优选,任选取代的杂环,包括水溶性杂环,和/或如上述R3’的限定),或其药学上可接受的盐、对映体、非对映体、溶剂化物或多晶型物。
根据本发明所述的化合物包含的再另外的进一步优选的基团包括例如:
其中n为0或1;
R是连接体或连接基团的连接体,/>基团通过酰胺、酯、醚、氨基甲酸酯或杂环基团连接于/>基团;
R1是H、任选被一个或两个羟基取代的C1-C3烷基、-O-C(O)NR3R4或-C(O)NR3R4,其中R3和R4中的每一个独立地是H、C1-C3烷基(优选甲基)、或苯基;和
各X独立地是H、F、Cl、C1-C3烷基(任选被一个或两个羟基取代,优选甲基)或杂环(优选,任选取代的杂环,包括水溶性杂环和/或包括上述R3’的限定),或其药学上可接受的盐、对映体、非对映体、溶剂化物或多晶型物。
在另外的实施方式中,根据本发明所述的特别优选的化合物可根据图19所示化学结构中的任意一个或多个来鉴定:
其中R1PC、R2PC、R3PC、R4PC、R5PC、R6PC、R7PC、R8PC、R9PC、R10PC、R11PC、R12PC、R13PC和R14PC中的任意一个或多个是
基团,
其中L是连接体基团,和是蛋白质靶向部分,或
其药学上可接受的盐、立体异构体、溶剂化物或多晶型物。
在优选实施方式中,R1PC、R2PC、R3PC、R4PC、R5PC、R6PC、R7PC、R8PC、R9PC、R10PC、R11PC、R12PC、R13PC和R14PC中不超过两个是基团,并且R1PC、R2PC、R3PC、R4PC、R5PC、R6PC、R7PC、R8PC、R9PC、R10PC、R11PC、R12PC、R13PC和R14PC中的其他基团独立地是H或CH3基团,通常是H。
某些优选实施方式涉及根据下列化学结构的化合物:
其中R7PC和R10PC各自独立地是基团或H,或
其药学上可接受的盐、立体异构体、溶剂化物或多晶型物。优选地,R7PC或R10PC任一个是基团,R7PC或R10PC另一个是H。
在其他优选实施方式中,化合物具有下列化学结构:
其中R7PC是基团,或
其药学上可接受的盐、立体异构体、溶剂化物或多晶型物。
在再其他优选实施方式中,化合物具有化学结构:
其中R7PC、R11PC R12PC、R13PC和R14PC各自独立地是基团或H,或
其药学上可接受的盐、立体异构体、溶剂化物或多晶型物。优选地,R7PC、R11PC、R12PC、R13PC和R14PC其中之一是基团,并且其他基团是H,或
其药学上可接受的盐、立体异构体、溶剂化物或多晶型物。
在再其他优选实施方式中,化合物具有化学结构:
其中R4PC、R7PC、R11PC R12PC、R13PC和R14PC各自独立地是基团或H,或
其药学上可接受的盐、立体异构体、溶剂化物或多晶型物。优选地,R4PC、R7PC中任一个或R11PC、R12PC、R13PC和R14PC其中之一是基团,并且其他基团是H,或
其药学上可接受的盐、立体异构体、溶剂化物或多晶型物。
在再其他优选实施方式中,化合物具有化学结构:
其中R3PC、R7PC、R11PC、R12PC、R13PC和R14PC各自独立地是基团或H,或
其药学上可接受的盐、立体异构体、溶剂化物或多晶型物。优选地,R3PC、R7PC、R11PC、R12PC、R13PC和R14PC其中之一是基团,并且其他基团是H、或
其药学上可接受的盐、立体异构体、溶剂化物或多晶型物。
在再其他优选实施方式中,化合物具有化学结构:
其中R7PC和R10PC各自独立地是基团或H,或
其药学上可接受的盐、立体异构体、溶剂化物或多晶型物。优选地,R7PC和R10PC其中之一是基团,并且另一基团是H,或
其药学上可接受的盐、立体异构体、溶剂化物或多晶型物。
在再其他优选实施方式中,化合物具有化学结构:
其中R7PC和R10PC各自独立地是基团或H,并且R8PC是H或CH3,或
其药学上可接受的盐、立体异构体、溶剂化物或多晶型物。优选地,R7PC和R10PC其中之一是基团,另一基团是H,并且R8PC是H、或
其药学上可接受的盐、立体异构体、溶剂化物或多晶型物。
在再其他优选实施方式中,化合物具有化学结构:
其中R7PC和R10PC各自独立地是基团或H,并且R8PC是H或CH3,或
其药学上可接受的盐、立体异构体、溶剂化物或多晶型物。优选地,R7PC和R10PC其中之一是基团,另一基团是H,并且R8PC是H,或
其药学上可接受的盐、立体异构体、溶剂化物或多晶型物。
在再其他优选实施方式中,化合物具有化学结构:
其中R7PC和R10PC各自独立地是基团或H,并且R8PC是H或CH3,或
其药学上可接受的盐、立体异构体、溶剂化物或多晶型物。优选地,R7PC和R10PC其中之一是基团,另一基团是H,并且R8PC是H,或
其药学上可接受的盐、立体异构体、溶剂化物或多晶型物。
在再其他优选实施方式中,化合物具有化学结构:
其中R7PC和R10PC各自独立地是基团或H,或
其药学上可接受的盐、立体异构体、溶剂化物或多晶型物。优选地,R7PC和R10PC其中之一是基团,并且另一基团是H,或
其药学上可接受的盐、立体异构体、溶剂化物或多晶型物。
在再其他优选实施方式中,化合物具有化学结构:
其中R7PC和R9PC各自独立地是基团或H,或
其药学上可接受的盐、立体异构体、溶剂化物或多晶型物。优选地,R7PC和R9PC其中之一是基团和其他基团是H、或
其药学上可接受的盐、立体异构体、溶剂化物或多晶型物。
在再其他优选实施方式中,化合物具有化学结构:
其中R7PC和R14PC各自独立地是基团或H,和R12PC和R13PC中的每一个是H或CH3,或
其药学上可接受的盐、立体异构体、溶剂化物或多晶型物。优选地,R7PC和R14PC其中之一是基团,并且R7PC和R14PC基团中的另一个是H,和R12PC和R13PC中的每一个是H,
其药学上可接受的盐、立体异构体、溶剂化物或多晶型物。
在再其他优选实施方式中,化合物具有化学结构:
其中R7PC和R9PC各自独立地是基团或H,或
其药学上可接受的盐、立体异构体、溶剂化物或多晶型物。优选地,R7PC和R9PC其中之一是基团和其他基团是H、或
其药学上可接受的盐、立体异构体、溶剂化物或多晶型物。
在再其他优选实施方式中,化合物具有化学结构:
其中R7PC和R9PC各自独立地是基团或H,或
其药学上可接受的盐、立体异构体、溶剂化物或多晶型物。优选地,R7PC和R9PC其中之一是基团和其他基团是H、或
其药学上可接受的盐、立体异构体、溶剂化物或多晶型物。
在再其他优选实施方式中,化合物具有化学结构:
其中R7PC和R10PC各自独立地是基团或H和R9PC是H或CH3,或
其药学上可接受的盐、立体异构体、溶剂化物或多晶型物。优选地,R7PC和R10PC其中之一是基团,另一基团是H,并且R9PC是H,或
其药学上可接受的盐、立体异构体、溶剂化物或多晶型物。
在上述实施方式中,连接体基团可以是上文所述的任意连接体基团,下文优选如下大小范围的聚乙二醇基团:约1个至约12个乙二醇单元、1个和约10个乙二醇单元之间、约2个和约6个乙二醇单元之间、约2个和5个乙二醇单元之间、约2个和4个乙二醇单元之间。
在优选实施方式中,连接体基团L是下列基团:
其中Z是使连接至X的基团;和
X是使Z连接至基团(包括/>基团)的基团。
在优选方面,Z是不存在的(键)、-(CH2)i-O、-(CH2)i-S、-(CH2)i-N-R、基团,其中X1Y1形成酰胺基团、或尿烷基团、酯或硫酯基团、或
基团
各R是H、或C1-C3烷基、烷醇基团或杂环(包括水溶性杂环,优选地,吗啉基,哌啶或哌嗪基团,以促进连接体基团的水溶性);
各Y独立地是键、O、S或N-R;
并且各i独立地为0至100、1至75、1至60、1至55、1至50、1至45、1至40、2至35、3至30、1至15、1至10、1至8、1至6、1、2、3、4或5;
在优选方面,X是基团,
其中各D独立地是键(不存在),
/>
J为1至100、1至75、1至60、1至55、1至50、1至45、1至40、2至35、3至30、1至15、1至10、1至8、1至6、1、2、3、4或5;
K为1至100、1至75、1至60、1至55、1至50、1至45、1至40、2至35、3至30、1至15、1至10、1至8、1至6、1、2、3、4或5;优选k为1、2、3、4、或5;
m’为1至100、1至75、1至60、1至55、1至50、1至45、1至40、2至35、3至30、1至15、1至10、1至8、1至6、1、2、3、4或5;
n为1至100、1至75、1至60、1至55、1至50、1至45、1至40、2至35、3至30、1至15、1至10、1至8、1至6、1、2、3、4或5;
X1为O、S或N-R,优选O;
Y同上;和
在存在于连接体基团中时是连接Z与X的联接基团(其可以是键)。
在优选方面,是键(不存在)、杂环——包括水溶性杂环,如哌嗪基或其他基团、或
基团,
其中X2是O、S、NR4、S(O)、S(O)2、-S(O)2O、-OS(O)2、或OS(O)2O;
X3是O、S、CHR4、NR4;和
R4是H或任选被一个或两个羟基取代的C1-C3烷基,或其药学上可接受的盐、对映体或立体异构体。
在可选的优选方面,连接体基团是(聚)乙二醇,其具有1个和约100个之间的乙二醇单元、约1个和约50个之间的乙二醇单元、1个和约25个之间的乙二醇单元、约1个和10个之间的乙二醇单元、1个和约8个之间的乙二醇单元和1个和6个之间的乙二醇单元、2个和4个之间的乙二醇单元。
在可选的优选方面,是/>基团或酰胺基团。
虽然基团和/>基团(包括/>基团)可通过对于连接体化学适当和稳定的任何基团共价地连接于连接体基团,在本发明的优选方面,连接体独立地共价结合于基团和/>基团(包括/>基团)——优选通过酰胺、酯、硫酯、酮基团、氨基甲酸酯(尿烷)或醚,各基团均可插入/>基团和/>基团(包括/>基团)上的任何位置,以提供泛素连接酶上的/>基团和待降解靶蛋白质上的/>基团的最大结合。(注意,在其中/>基团是/>基团的某些方面,降解靶蛋白质可以是泛素连接酶本身)。在某些优选方面,连接体可连接于/>和/或/>基团上的任选取代的烷基、亚烷基、烯或炔基团、芳基或杂环基团。
在本发明的优选方面,基团是结合靶蛋白质的基团。/>基团的靶标具有多种类型,并且选自细胞表达的蛋白质,从而在细胞中找到至少部分序列,并且该至少部分序列可结合/>基团。术语“蛋白质”包括可结合根据本发明所述的/>基团的具有足够长度的寡肽和多肽序列。真核系统或微生物系统——包括病毒、细菌或真菌——中的任意蛋白质,如本文另外描述,是根据本发明所述的化合物介导的泛素化的靶。优选地,靶蛋白质是真核蛋白质。在某些方面,蛋白质结合部分是卤烷(优选被至少一个卤素基团取代的C1-C10烷基,该卤素基团优选是在烷基远端(即,远离连接体或/>基团)的卤素基团),其可共价结合患者或对象内或诊断分析中的脱卤素酶。
根据本发明所述的基团包括,例如,包括特异性结合蛋白质(结合靶蛋白质)的任意部分,并且包括小分子靶蛋白质部分的下列非限制性实例:Hsp90抑制剂、激酶抑制剂、MDM2抑制剂、靶向包含人BET布罗莫结构域(Bromodomain)的蛋白质的化合物、HDAC抑制剂、人赖氨酸甲基转移酶抑制剂、血管生成抑制剂、免疫抑制化合物、和靶向芳烃受体(AHR)的化合物等。下文描述的组合物示例这九种小分子靶蛋白质结合部分的其中一些成员。这种小分子靶蛋白质结合部分还包括这些组合物的药学上可接受的盐、对映体、溶剂化物和多晶型物,以及其他可靶向目标蛋白质的小分子。这些结合部分连接于泛素连接酶结合部分——优选通过连接体,从而使靶蛋白质(其结合蛋白质靶部分)邻近泛素连接酶,以进行泛素化和降解。
可结合蛋白质靶部分或基团并且作用于泛素连接酶或被泛素连接酶降解的任意蛋白质是根据本发明所述的靶蛋白质。总体上,靶蛋白质可包括,例如,结构蛋白质、受体、酶、细胞表面蛋白、细胞整体功能相关的蛋白质,包括涉及下列活性的蛋白质:催化活性、芳香酶活性、运动活性、解旋酶活性、代谢过程(合成代谢和分解代谢)、抗氧化剂活性、蛋白水解、生物合成、具有激酶活性的蛋白质、氧化还原酶活性、转移酶活性、水解酶活性、裂解酶活性、异构酶活性、连接酶活性、酶调节因子活性、信号转导活性、结构分子活性、结合活性(蛋白质、脂质糖)、受体活性、细胞运动性、膜融合、细胞通信、生物学过程调节、发育、细胞分化、刺激响应、行为蛋白质、细胞粘附蛋白质、细胞死亡涉及的蛋白质、转运涉及的蛋白质(包括蛋白质转运体活性、核转运、离子转运体活性、通道转运体活性、载体活性、通透酶活性、分泌活性、电子转运体活性、发病、分子伴侣调节因子活性、核酸结合活性、转录调节因子活性、胞外组织和生物发生活性、翻译调节因子活性。目标蛋白质可包括来自真核生物和原核生物的蛋白质,包括人——作为药物治疗靶,其他动物,包括家养动物、确定抗生素及其他抗微生物剂靶的微生物和植物、甚至病毒等。
在再其他实施方式中,基团是卤烷基,其中所述烷基通常大小范围为约1个或2个碳至约12个碳长度、通常约2个至10个碳长度、通常约3个碳至约8个碳长度、更通常约4个碳至约6个碳长度。卤烷基通常是直链烷基(虽然也可使用支链烷基),并且用至少一个卤素基团封端,优选单个卤素基团,通常单个氯基。用于本发明的卤烷基/>基团优选由化学结构-(CH2)v-卤素表示,其中v是如下任意整数:2至约12,通常约3至约8,更通常约4至约6。卤素可以是任意卤素,但优选是Cl或Br,更通常是Cl。
在再其他实施方式中,基团是
基团,其中w为0至3,优选1或2。该基团选择性地结合雌激素受体,并且可用于治疗通过雌激素受体调节的疾病,具体地癌症,如乳腺癌、子宫内膜癌、卵巢癌和子宫癌等。
本发明可用于治疗多种疾病状态和/或状况,包括其中蛋白质失调和患者从蛋白质降解受益的任意疾病状态和/或状况。
另一方面,本发明涉及药物组合物,其包括有效量的上述化合物,组合药学上可接受的载体、添加剂或赋形剂和任选地另外的生物活性剂。
在可选的方面,本发明涉及通过降解蛋白质或多肽(通过此调节疾病状态或状况)治疗疾病状态的方法,包括给予所述患者或对象有效量的至少一种上述化合物,任选地组合另外的生物活性剂。根据本发明所述的方法可用于通过给予有效量的至少一种本文所述化合物来治疗多种疾病状态或状况,包括癌症。
发明详述
下列术语用于描述本发明。例如,在本文未具体定义一个术语时,该术语被给予本领域技术人员公知的含义,使该术语在描述本发明时适用于其应用环境。
在提供值范围时,要理解,除非上下文明确另外指示,本发明包括在范围和上限和下限之间距离下限单位十分之一的每个中介值(如在基团包含多个碳原子的情况下,提供落入范围的每个碳原子数),以及所述范围内的任意其他所述或中介值。这些较小范围的上限和下限可独立地被包括在也被本发明包括的较小范围内,经过所述范围中任意被具体排除的极限。在所述范围包括极限其中一者或两者时,排除该被包括的极限中的一者或两者的范围,也被包括在本发明中。
术语“化合物”,如本文所用,除非另外指示,指代本文公开的任意具体化学化合物,并且包括其互变异构体、区域异构体、几何异构体、和在适当时立体异构体,包括光学异构体(对映体)及其他立体异构体(非对映体),以及其药学上可接受的盐和衍生物(包括前药形式)——在上下文中适当时。在其在上下文的应用中,术语化合物通常指代单一化合物,但还可包括其他化合物,如公开化合物的立体异构体、区域异构体和/或光学异构体(包括消旋混合物)以及具体对映体或对映体富集的混合物。在上下文中该术语还指代经修饰以有助于将化合物给予和递送至活性位点的化合物前药形式。注意,在描述当前化合物时,描述与其相关的多个取代基和变体等。本领域技术人员理解,本文描述的分子是下文一般性描述的稳定化合物。当显示键时,双键和单键均被表示在所示化合物的情况中。
术语“患者”或“对象”贯穿说明书用于描述被提供以根据本发明所述的组合物的治疗——包括预防性治疗的动物,优选人或家养动物。关于对针对具体动物如人患者的那些感染、病症或疾病状态的治疗,术语患者指代该具体动物,包括家养动物,如狗或猫,或农场动物,如马、牛、羊等。总体上,在本发明中,术语患者指代人患者,除非由该术语应用的上下文进行另外描述或暗示。
术语“有效”用于描述化合物、组合物或组分在用于其目的用途环境时产生目的效果的量。术语有效包括另外描述或用于本申请的所有其他有效量或有效浓度术语。
术语“VCB E3泛素连接酶”,“希佩尔-林道E3泛素连接酶”或“泛素连接酶”用于描述根据本发明所述的双功能(嵌合)化合物的泛素连接酶部分的目标酶(一种或多种)结合位点。VCB E3是组合E2泛素-结合酶导致泛素连接于靶蛋白质上的赖氨酸的蛋白质;E3泛素连接酶靶向特定蛋白质底物,以通过蛋白酶体降解。因此,单独或与E2泛素结合酶复合的E3泛素连接酶负责将泛素转移至靶向的蛋白质。总体上,泛素连接酶涉及多泛素化,使得第二泛素连接于第一泛素,第三泛素连接于第二泛素,等等。多泛素化标记了用于蛋白酶体降解的蛋白质。但是,一些泛素化事件限于单泛素化,其中仅通过泛素连接酶向底物分子添加单一泛素。单泛素化蛋白质不被靶向蛋白酶体以进行降解,但可反而改变其细胞位置或功能——例如,通过结合具有能够结合泛素的结构域的其他蛋白质。进一步复杂的问题,泛素上的不同赖氨酸可被E3靶向以成链。最常见的赖氨酸是泛素链上的Lys48。这是用于生成被蛋白酶体识别的多泛素的赖氨酸。
术语“蛋白质靶部分”或PTM用于描述这样的小分子,其结合靶蛋白质或其他目标蛋白质或多肽,并使该蛋白质或多肽位于/存在于泛素连接酶邻近,从而可发生泛素连接酶降解蛋白质或多肽。小分子靶蛋白质结合部分的非限制性实例包括Hsp90抑制剂、激酶抑制剂、MDM2抑制剂、靶向包含人BET布罗莫结构域的蛋白质的化合物、HDAC抑制剂、人赖氨酸甲基转移酶抑制剂、血管生成抑制剂、免疫抑制化合物、和靶向芳烃受体(AHR)的化合物,等等。下文描述的组合物示例这九种小分子靶蛋白质的其中一些成员。
根据本发明所述的蛋白质靶部分包括,例如,卤烷卤化酶抑制剂、Hsp90抑制剂、激酶抑制剂、MDM2抑制剂、靶向包含人BET布罗莫结构域的蛋白质的化合物、HDAC抑制剂、人赖氨酸甲基转移酶抑制剂、血管生成抑制剂、免疫抑制化合物、和靶向芳烃受体(AHR)的化合物。下文描述的组合物示例这些类型的小分子靶蛋白质结合部分的其中一些成员。这种小分子靶蛋白质结合部分还包括这些组合物的药学上可接受的盐、对映体、溶剂化物和多晶型物,以及可靶向目标蛋白质的其他小分子。下文引用的文献其全部内容被引入本文作为参考。
I.热激蛋白90(HSP90)抑制剂:
HSP90抑制剂,如本文所用,包括但不限于:
1.在Vallee等,"Tricyclic Series of Heat Shock Protein 90(HSP90)Inhibitors Part I:Discovery of Tricyclic Imidazo[4,5-C]Pyridines as PotentInhibitors of the HSP90 Molecular Chaperone(2011)J.Med.Chem.54:7206中鉴定的HSP90抑制剂,包括
YKB
N-[4-(3H-咪唑[4,5-C]吡啶-2-基)-9H-芴-9-基]-琥珀酰胺
其是衍生的,其中连接体基团L或基团通过末端酰胺基团连接;
2.HSP90抑制剂p54(经修饰):
p54
8-[(2,4-二甲基苯基)硫烷基]-3-戊-4-炔-1-基-3H-嘌呤-6-胺
其中连接体基团L或基团通过末端乙炔基团连接;
3.在Brough等,"4,5-Diarylisoxazole HSP90 Chaperone Inhibitors:Potential Therapeutic Agents for the Treatment of Cancer",J.MED.CHEM.vol:51,pag:196(2008)中鉴定的HSP90抑制剂(修饰型),包括化合物2GJ(5-[2,4-二羟基-5-(1-甲基乙基)苯基]-N-乙基-4-[4-(吗啉-4-基甲基)苯基]异唑-3-羧酰胺),具有结构:
,其是衍生的,其中连接体基团L或基团通过酰胺基团(在胺处或在胺上的烷基处)连接;
4.在Wright等,Structure-Activity Relationships in Purine-BasedInhibitor Binding to HSP90 Isoforms,Chem Biol.2004Jun;11(6):775-85中鉴定的HSP90抑制剂(经修饰),包括HSP90抑制剂PU3,其具有结构:
其中连接体基团L或通过丁基连接;和
5.HSP90抑制剂格尔德霉素((4E,6Z,8S,9S,10E,12S,13R,14S,16R)-13-羟基-8,14,19-三甲氧基-4,10,12,16-四甲基-3,20,22-三氧代-2-氮杂双环[16.3.1](衍生的)或其任意衍生物(例如,17-烷基氨基-17-去甲氧基格尔德霉素("17-AAG")或17-(2-二甲基氨基乙基)氨基-17-去甲氧基格尔德霉素("17-DMAG"))(衍生的,其中连接体基团L或基团通过酰胺基团连接)。
II.激酶和磷酸酶抑制剂:
激酶抑制剂,如本文所用,包括但不限于:
1.厄洛替尼(Erlotinib)衍生物酪氨酸激酶抑制剂
其中R是通过醚基团连接的连接体基团L或基团;
2.激酶抑制剂舒尼替尼(Sunitanib)(衍生的):
(衍生的,其中R是连接于吡咯部分的连接体基团L或基团);
l
3.激酶抑制剂索拉非尼(Sorafenib)(衍生的)
(衍生的,其中R是连接于苯基部分的连接体基团L或基团);
4.激酶抑制剂达沙替尼(Desatinib)(衍生的)
(衍生的,其中R是连接于嘧啶的连接体基团L或);
5.激酶抑制剂拉帕替尼(Lapatinib)(衍生的)
拉帕替尼
其是衍生的,其中连接体基团L或基团通过磺酰基甲基的末端甲基连接;
6.激酶抑制剂U09-CX-5279(衍生的)
CX-5279
3-(环丙基氨基)-5-{[3-(三氟甲基)苯基]氨基}嘧啶并[4,5-c]喹啉-8-羧酸
其是衍生的,其中连接体基团L或基团通过胺(苯胺)、羧酸或胺α连接于环丙基,或环丙基;
7.在Millan等,Design and Synthesis of Inhaled P38 Inhibitors for theTreatment of Chronic Obstructive Pulmonary Disease,J.MED.CHEM.vol:54,pag:7797(2011)中鉴定的激酶抑制剂,包括激酶抑制剂Y1W和Y1X(衍生的),其具有结构:
YIX
1-乙基-3-(2-{[3-(1-甲基乙基)[1,2,4]三唑并[4,3-a]吡啶-6-基]硫烷基}苄基)脲其是衍生的,其中连接体基团L或基团优选通过丙基连接;
YIW
1-(3-叔丁基-1-苯基-1H-吡唑-5-基)-3-(2-{[3-(1-甲基乙基)[1,2,4]三唑并[4,3-a]吡啶-6-基]硫烷基}苄基)脲,
其是衍生的,其中连接体基团L或基团优选通过丙基或丁基连接;
8.在Schenkel等,Discovery of Potent and Highly SelectiveThienopyridine Janus Kinase 2Inhibitors J.Med.Chem.,2011,54(24),pp 8440-8450中鉴定的激酶抑制剂,包括化合物6TP和0TP(衍生的),其具有结构:
6TP
4-氨基-2-[4-(叔丁基氨磺酰)苯基]-N-甲基噻吩并[3,2-c]吡啶-7-羧酰胺
噻吩并吡啶19
其是衍生的,其中连接体基团L或基团优选通过结合于酰胺部分的末端甲基连接;
0TP
4-氨基-N-甲基-2-[4-(吗啉-4-基)苯基]噻吩并[3,2-c]吡啶-7-羧酰胺
噻吩并吡啶8
其是其是衍生的,其中连接体基团L或基团优选通过结合于酰胺部分的末端甲基连接;
9.在Van Eis等,"2,6-Naphthyridines as potent and selective inhibitorsof the novel protein kinase C isozymes”,Biorg.Med.Chem.Lett.2011Dec 15;21(24):7367-72中鉴定的激酶抑制剂,包括激酶抑制剂07U,其具有结构:
07U
2-甲基-N~1~-[3-(吡啶-4-基)-2,6-萘啶-1-基]丙烷-1,2-二胺,
其是衍生的,其中连接体基团L或基团优选通过仲胺或末端氨基基团连接;
10.在Lountos等,"Structural Characterization of Inhibitor Complexeswith Checkpoint Kinase 2(Chk2),a Drug Target for Cancer Therapy",J.STRUCT.BIOL.vol:176,pag:292(2011)中鉴定的激酶抑制剂,包括激酶抑制剂YCF,其具有结构:
衍生的,其中连接体基团L或基团优选通过末端羟基中的任一个连接;
11.在Lountos等,"Structural Characterization of Inhibitor Complexeswith Checkpoint Kinase 2(Chk2),a Drug Target for Cancer Therapy",J.STRUCT.BIOL.vol:176,pag:292(2011)中鉴定的激酶抑制剂,包括激酶抑制剂XK9和NXP(衍生的),其具有结构:
XK9
N-{4-[(1E)-N-(N-羟基甲脒基)乙烷腙酰基]苯基}-7-硝基-1H-吲哚-2-羧酰胺
NXP
N-{4-[(1E)-N-甲脒基乙烷腙酰基]苯基}-1H-吲哚-3-羧酰胺
其是衍生的,其中连接体基团L或基团优选通过末端羟基(XK9)或腙基团(NXP)连接;
12.激酶抑制剂阿法替尼(Afatinib)(衍生的)(N-[4-[(3-氯-4-氟苯基)氨基]-7-[[(3S)-四氢-3-呋喃基]氧]-6-喹唑啉基]-4(二甲基氨基)-2-丁酰胺)(衍生的,其中连接体基团L或基团优选通过脂族胺基团连接);
13.激酶抑制剂福他替尼(Fostamatinib)(衍生的)([6-({5-氟-2-[(3,4,5-三甲氧基苯基)氨基]嘧啶-4-基}氨基)-2,2-二甲基-3-氧代-2,3-二氢-4H-吡啶并[3,2-b]-1,4-嗪-4-基]甲基磷酸二钠六水合物)(衍生的,其中连接体基团L或/>基团优选通过甲氧基连接);
14.激酶抑制剂吉非替尼(Gefitinib)(衍生的)(N-(3-氯-4-氟-苯基)-7-甲氧基-6-(3-吗啉-4-基丙氧基)喹唑啉-4-胺)(衍生的,其中连接体基团L或基团优选通过甲氧基或醚基团连接);
15.激酶抑制剂乐伐替尼(Lenvatinib)(衍生的)(4-[3-氯-4-(环丙基氨甲酰基氨基)苯氧基]-7-甲氧基-喹啉-6-羧酰胺)(衍生的,其中连接体基团L或基团优选通过环丙基连接);
16.激酶抑制剂凡德他尼(Vandetanib)(衍生的)(N-(4-溴-2-氟苯基)-6-甲氧基-7-[(1-甲基哌啶-4-基)甲氧基]喹唑啉-4-胺)(衍生的,其中连接体基团L或基团优选通过甲氧基或羟基连接);和
17.激酶抑制剂威罗菲尼(Vemurafenib)(衍生的)(丙烷-1-磺酸{3-[5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基]-2,4-二氟-苯基}-酰胺)
(衍生的,其中连接体基团L或基团优选通过磺酰基丙基连接);
18.激酶抑制剂格列卫(Gleevec)(衍生的):
(衍生的,其中R作为连接体基团L或基团优选通过酰胺基团或通过苯胺胺基团连接);
19.激酶抑制剂帕唑帕尼(Pazopanib)(衍生的)(VEGFR3抑制剂):
(衍生的,其中R是优选连接于苯基部分或通过苯胺胺基团连接的连接体基团L或基团);
20.激酶抑制剂AT-9283(衍生的)奥罗拉(Aurora)激酶抑制剂
(其中R是优选连接于苯基部分的连接体基团L或基团);
21.激酶抑制剂TAE684(衍生的)ALK抑制剂
(其中R是优选连接于苯基部分的连接体基团L或基团);
22.激酶抑制剂尼罗替尼(Nilotanib)(衍生的)Abl抑制剂:
(衍生的,其中R是优选连接于苯基部分或苯胺胺基团的连接体基团L或基团);
27.激酶抑制剂NVP-BSK805(衍生的)JAK2抑制剂
(衍生的,其中R是连接于苯基部分或二唑基团的连接体基团L或基团);
28.激酶抑制剂克里唑蒂尼(Crizotinid)衍生的Alk抑制剂
/>
(衍生的,其中R是连接于苯基部分或二唑基团的连接体基团L或基团);
29.激酶抑制剂JNJ FMS(衍生的)抑制剂
(衍生的,其中R是优选连接于苯基部分的连接体基团L或基团);
30.激酶抑制剂沃利替尼(Foretinib)(衍生的)Met抑制剂
(衍生的,其中R是连接于苯基部分或者喹啉部分上的羟基或醚基团的连接体基团L或基团);
31.变构蛋白酪氨酸磷酸酶抑制剂PTP1B(衍生的):
其是衍生的,其中连接体基团L或基团优选连接在R处,如所示。
32.酪氨酸磷酸酶的SHP-2结构域的抑制剂(衍生的):
其是衍生的,其中连接体基团L或基团优选连接在R处。
33.BRAF(BRAFV600E)/MEK的抑制剂(衍生的):
其是衍生的,其中连接体基团L或基团优选连接在R处。
34.酪氨酸激酶ABL抑制剂(衍生的)
(衍生的,其中“R”表示在哌嗪部分上连接体基团L或基团的连接位点)。
III.MDM2抑制剂:
MDM2抑制剂,如本文所用,包括但不限于:
1.在Vassilev等,In vivo activation of the p53 pathway by small-molecule antagonists of MDM2,SCIENCE vol:303,pag:844-848(2004),和SchneeklotH等,Targeted intracellular protein degradation induced by a small molecule:Enroute to chemical proteomics,Bioorg.Med.Chem.Lett.18(2008)5904-5908中鉴定的MDM2抑制剂,包括(或另外地)下文描述的化合物nutlin-3、nutlin-2、和nutlin-1(衍生的)、以及其全部衍生物和类似物:
(衍生的,其中连接体基团L或基团优选在甲氧基处或如羟基连接)
(衍生的,其中连接体基团L或基团优选连接在甲氧基或羟基处);
(衍生的,其中连接体基团L或基团通过甲氧基或如羟基连接);和
2.反式-4-碘-4'-硼烷基-查尔酮
(衍生的,其中连接体基团L或连接体基团L或基团通过羟基连接);
IV.靶向包含人BET布罗莫结构域的蛋白质的化合物:
靶向包含人BET布罗莫结构域的蛋白质的化合物包括但不限于,与下文描述的靶标相关化合物,其中“R”表示连接体基团L或基团连接的位点:
1.
蛋白质靶:Brd2、Brd3、Brd4
JQ1,Filippakopoulos et al.Selective inhibition of BETbromodomains.Nature(2010)
2.
I-BET,Nicodeme et al.Suppression of inflammation by a synthetichistone mimic.Nature(2010)Chung et al.Discovery and Characterization of SmallMolecule Inhibitors of the BET Family Bromodomains.Journal of medicinalchemistry(2011)
3.
4d,Hewings et al.3,5-Dimethylisoxazoles Act As Acetyl-lysine-mimeticBromodomain Ligands.J.Med.Chem.(2011)vol.54(19)pp.6761-70
4.
/>
I-BET151,Dawson et al.Inhibition of BET recruitment to chromatin asan effective treatment for MLL-fusion leukaemia.Nature(2011)
(其中在每种情况下,R表示连接体基团L或基团的连接位点)。
V.HDAC抑制剂:
HDAC抑制剂(衍生的)包括但不限于:
1.
Finnin,M.S.et al.Structures of a histone deacetylase homologue boundto the TSA and SAHA inhibitors.Nature 401,188-193(1999).
(衍生的,其中“R”表示连接体基团L或基团的连接位点);和
2.PCT WO0222577(“DEACETYLASE INHIBITORS”)的式(I)限定的化合物(衍生的,其中连接体基团L或基团通过羟基连接);
VI.人赖氨酸甲基转移酶抑制剂:
人赖氨酸甲基转移酶抑制剂包括但不限于:
1.
BIX-01294
Chang et al.Structural basis for G9a-like protein lysinemethyltransferase inhibition by BIX-01294.Nat Struct Mol Biol(2009)vol.16(3)pp.312-7
(衍生的,其中“R”表示连接体基团L或基团的连接位点);
2.
UNC0224
Liu F,Chen X,Allali-Hassani A,et al.Discovery of a 2,4-diamino-7-aminoalkoxyquinazoline as a potent and selective inhibitor of histone lysinemethyltransferase G9a.J Med Chem 2009;52(24):7950-3
(衍生的,其中“R”表示连接体基团L或基团的潜在连接位点);
3.阿扎胞苷(Azacitidine)(衍生的)(4-氨基-1-β-D-呋喃核糖基-1,3,5-三嗪-2(1H)-酮)(衍生的,其中连接体基团L或基团通过羟基或氨基连接);和
4.地西他滨(Decitabine)(衍生的)(4-氨基-1-(2-脱氧-b-D-赤藓-戊呋喃糖基)-1,3,5-三嗪-2(1H)-酮)(衍生的,其中连接体基团L或基团通过羟基中的任一个或在氨基处连接)。
VII.血管生成抑制剂:
血管生成抑制剂包括但不限于:
1.GA-1(衍生的)和其衍生物和类似物,具有结构(一种或多种)并结合于连接体,如Sakamoto等,Development of Protacs to target cancer-promoting proteins forubiquitination and degradation,Mol Cell Proteomics 2003Dec;2(12):1350-8所述;
2.雌二醇(衍生的),其可结合于连接体基团L或基团,如Rodriguez-Gonzalez等,Targeting steroid hormone receptors for ubiquitinationand degradation in breast and prostate cancer,Oncogene(2008)27,7201-7211一般性描述;
3.雌二醇、睾酮(衍生的)和相关衍生物,包括但不限于DHT和其衍生物和类似物,具有结构(一种或多种)并且结合于连接体基团L或基团,如Sakamoto等,Development of Protacs to target cancer-promoting proteins for ubiquitinationand degradation,Mol Cell Proteomics 2003Dec;2(12):1350-8一般性描述;和
4.卵假散囊菌素(Ovalicin)、烟曲霉素(fumagillin)(衍生的)、和其衍生物和类似物,具有结构(一种或多种)并结合于连接体基团L或基团,如Sakamoto等,Protacs:chimeric molecules that target proteins to the Skp1-Cullin-F boxcomplex for ubiquitination and degradation Proc Natl Acad Sci USA.2001Jul 17;98(15):8554-9和美国专利号7,208,157一般性描述。
VIII.免疫抑制化合物:
免疫抑制化合物,包括但不限于:
1.AP21998(衍生的),具有结构(一种或多种)并结合于连接体基团L或基团,如Schneekloth等,Chemical Genetic Control of ProteinLevels:Selective in Vivo Targeted Degradation,J.AM.CHEM.SOC.2004,126,3748-3754一般性描述;
2.糖皮质激素(Glucocorticoids)(例如,氢化可的松、强的松(prednisone)、泼尼松龙(prednisolone)、和甲基泼尼松龙)(衍生的,其中连接体基团L或基团例如结合至任意羟基)和二丙酸倍氯米松(beclometasone dipropionate)(衍生的,其中连接体基团或/>例如结合至丙酸酯);
3.氨甲喋呤(衍生的,其中连接体基团或基团可例如结合至任一末端羟基);
4.环孢素(Ciclosporin)(衍生的,其中连接体基团或基团可例如结合在任意丁基处);
5.他克莫司(Tacrolimus)(FK-506)和雷帕霉素(rapamycin)(衍生的,其中连接体基团L或基团可例如结合在其中一个甲氧基处);和
6.放线菌素(衍生的,其中连接体基团L或基团可例如结合在其中一个异丙基处)。
IX.靶向芳烃受体(AHR)的化合物:
靶向芳烃受体(AHR)的化合物包括但不限于:
1.芹菜素(Apigenin)(以结合连接体基团L或基团的方式衍生,如Lee等,Targeted Degradation of the Aryl Hydrocarbon Receptor by the PROTACApproach:A Useful Chemical Genetic Tool,ChemBioChem Volume 8,Issue17,第2058-2062页,2007年11月23日)一般性示例;和
2.SR1和LGC006(衍生的,使得连接体基团L或结合),如Boitano等,Aryl Hydrocarbon Receptor Antagonists Promote the Expansion of HumanHematopoietic Stem Cells,Science 10September 2010:Vol.329no.5997第1345-1348页所述。
X.靶向RAF受体(激酶)的化合物:
PLX4032
(衍生的,其中“R”表示连接体基团L或基团连接的位点)。
XI.靶向FKBP的化合物
(衍生的,其中“R”表示连接体基团L或基团连接的位点)。
XII.靶向雄激素受体(AR)的化合物
1.雄激素受体的RU59063配体(衍生的)
(衍生的,其中“R”表示连接体基团L或基团连接的位点)。
2.雄激素受体的SARM配体(衍生的)
(衍生的,其中“R”表示连接体基团L或基团连接的位点)。
3.雄激素受体配体DHT(衍生的)
/>
(衍生的,其中“R”表示连接体基团L或基团连接的位点)。
XIII.靶向雌激素受体(ER)的化合物ICI-182780
1.雌激素受体配体
(衍生的,其中“R”表示连接体基团L或基团连接的位点)。
XIV.靶向甲状腺激素受体(TR)的化合物
1.甲状腺激素受体配体(衍生的)
(衍生的,其中“R”表示连接体基团L或基团连接的位点,并且MOMO表示甲氧基甲氧基基团)。
XV.靶向HIV蛋白酶的化合物
1.HIV蛋白酶抑制剂(衍生的)
(衍生的,其中“R”表示连接体基团L或基团连接的位点)。参见,J.Med.Chem.2010,53,521-538。
2.HIV蛋白酶抑制剂
(衍生的,其中“R”表示连接体基团L或基团连接的潜在位点)。See,J.Med.Chem.2010,53,521-538。/>
XVI.靶向HIV整合酶的化合物
1.HIV整合酶抑制剂(衍生的)
(衍生的,其中“R”表示连接体基团L或基团连接的位点)。参见,J.Med.Chem.2010,53,6466。
2.HIV整合酶抑制剂(衍生的)
(衍生的,其中“R”表示连接体基团L或基团连接的位点)。参见,J.Med.Chem.2010,53,6466。
XVII.靶向HCV蛋白酶的化合物
1.HCV蛋白酶抑制剂(衍生的)
(衍生的,其中“R”表示连接体基团L或基团连接的位点)。
XVIII.靶向酰基-蛋白质硫酯酶-1和-2(APT1和APT2)的化合物
1.APT1和APT2抑制剂(衍生的)
(衍生的,其中“R”表示连接体基团L或基团连接的位点)。参见,Angew.Chem.Int.Ed.2011,50,9838-9842,其中
L是连接体基团,如本文另外描述,和所述基团如本文另外描述,从而使/>基团结合至/>基团,如本文另外描述。
术语“靶蛋白质”用于描述蛋白质或多肽,其是结合根据本发明所述的化合物和通过下文泛素连接酶降解的靶。这种小分子靶蛋白质结合部分还包括这些组合物的药学上可接受的盐、对映体、溶剂化物和多晶型物、以及可靶向目标蛋白质的其他小分子。这些结合部分通过连接体基团L连接于基团。
靶蛋白质——可结合蛋白质靶部分并通过泛素连接酶结合部分结合的连接酶进行降解,包括结构蛋白质、受体、酶、细胞表面蛋白质、细胞整体功能相关蛋白质——包括下列活性涉及的蛋白质:催化活性、芳香酶活性、运动活性、解旋酶活性、代谢过程(合成代谢和分解代谢)、抗氧化剂活性、蛋白水解、生物合成,如下蛋白质——具有激酶活性、氧化还原酶活性、转移酶活性、水解酶活性、裂解酶活性、异构酶活性、连接酶活性、酶调节因子活性、信号转导活性、结构分子活性、结合活性(蛋白质、脂质糖)、受体活性、细胞运动性、膜融合、细胞通信、生物学过程调节、发育、细胞分化、刺激响应、行为蛋白质、细胞粘附蛋白质、细胞死亡涉及的蛋白质、转运涉及的蛋白质(包括蛋白质转运体活性、核转运、离子转运体活性、通道转运体活性、载体活性、通透酶活性、分泌活性、电子转运体活性、发病、分子伴侣调节因子活性、核酸结合活性、转录调节因子活性、胞外组织和生物发生活性、翻译调节因子活性。目标蛋白质可包括真核生物和原核生物的蛋白质,真核生物和原核生物包括微生物、病毒、真菌和寄生虫,包括人、微生物、病毒、真菌和寄生虫等作为药物治疗靶标,其他动物,包括家养动物、微生物,用于确定抗生素及其他抗微生物剂的靶、和植物,甚至病毒等。
更具体地,用于人类治疗的多种药物靶标是可结合蛋白质靶部分并被掺入根据本发明所述的化合物中的蛋白质靶标。这些包括可用于恢复多种多基因疾病中的功能的蛋白质,包括,例如B7.1和B7、TINFRlm、TNFR2、NADPH氧化酶、BclIBax及凋亡途径中的其他配偶体、C5a受体、HMG-CoA还原酶、PDE V磷酸二酯酶类型、PDE IV磷酸二酯酶4型、PDE I、PDEII、PDEIII、角鲨烯环化酶抑制剂、CXCR1、CXCR2、一氧化氮(NO)合成酶、环氧酶1、环氧酶2、5HT受体、多巴胺受体、G蛋白、即,Gq、组胺受体、5-脂氧合酶、类胰蛋白酶丝氨酸蛋白酶、胸苷酸合成酶、嘌呤核苷磷酸化酶、GAPDH锥虫、糖原磷酸化酶、碳酸酐酶、趋化因子受体、JAWSTAT、RXR和类似的、HIV 1蛋白酶、HIV 1整合酶、流感、神经氨酸酶、乙肝逆转录酶、钠通道、多药物抗性(MDR)、蛋白质P-糖蛋白(和MRP)、酪氨酸激酶、CD23、CD124、酪氨酸激酶p56lck、CD4、CD5、IL-2受体、IL-1受体、TNF-αR、ICAM1、Cat+通道、VCAM、VLA-4整联蛋白、选择素、CD40/CD40L、神经激肽和受体、肌苷单磷酸脱氢酶、p38 MAP激酶、RaslRaflMEWERK途径、白介素-1转化酶、胱天蛋白酶、HCV、NS3蛋白酶、HCV NS3 RNA解旋酶、甘氨酰胺核糖核苷酸甲酰基转移酶、鼻病毒3C蛋白酶、单纯疱疹病毒-1(HSV-I)、蛋白酶、巨细胞病毒(CMV)蛋白酶、聚(ADP-核糖)聚合酶、细胞周期蛋白依赖性激酶、血管内皮生长因子、催产素受体、微粒体转移蛋白抑制剂、胆汁酸转运抑制剂、5α还原酶抑制剂、血管紧张素11、甘氨酸受体、去甲肾上腺素再摄取受体、内皮素受体、神经肽Y和受体、雌激素受体、雄激素受体、腺苷受体、腺苷激酶和AMP脱氨酶、嘌呤受体(P2Y1、P2Y2、P2Y4、P2Y6、P2X1-7)、法尼基转移酶、香叶基香叶基转移酶、NGF的TrkA a受体、β-淀粉状蛋白、酪氨酸激酶Flk-IIKDR、玻连蛋白受体、整联蛋白受体、Her-21 neu、端粒酶抑制、细胞浆磷脂酶A2和EGF受体酪氨酸激酶。另外的蛋白质靶标包括,例如,蜕皮激素20-单氧酶、GABA门控的氯离子通道的离子通道、乙酰胆碱酯酶、电压敏感性钠通道蛋白、钙释放通道和氯离子通道。再进一步的靶蛋白质包括乙酰基-CoA羧化酶、腺苷酸琥珀酸合成酶、原卟啉原氧化酶和烯醇丙酮酸莽草酸(enolpyruvylshikimate)-磷酸合成酶。
卤烷脱卤素酶是根据本发明所述的具体化合物的另一个靶标。根据本发明所述的化合物——其包含氯烷肽结合部分(C1-C12,通常约C2-C10烷基卤素基团)可用于抑制和/或降解用于融合蛋白质或相关诊断性蛋白质的卤烷脱卤素酶,如2011年12月6日提交并在2012年6月14日以WO 2012/078559公开的PCT/US2012/063401所述,其内容被引入本文作为参考。
这些不同蛋白质靶标可用于筛选,鉴定结合于该蛋白质的化合物部分,并且通过将该部分掺入根据本发明所述的化合物,改变蛋白质的活性水平,以获得治疗最终效果。
术语“疾病状态或状况”用于描述任意疾病状态或状况,其中存在蛋白质失调(即,患者体内的蛋白质表达量升高),并且其中患者体内一种或多种蛋白质的降解可为对其有需要的患者提供有益治疗或症状减轻。在某些实例中,可治愈疾病状态或状况。
可利用根据本发明所述的化合物治疗的疾病状态或状况包括,例如,哮喘、自身免疫性疾病如多发性硬化症、各种癌症、纤毛疾病(ciliopathies)、腭裂、糖尿病、心脏病、高血压、炎症性肠道疾病、精神发育迟缓、情绪障碍、肥胖、屈光不正、不孕不育、安格曼综合征、卡纳万病、腹腔疾病、夏-马-图三氏病、囊性纤维化、杜氏肌营养不良、血色素沉着、血友病、克兰费尔特综合征、神经纤维瘤病、苯丙酮酸尿症、多囊肾病、(PKD1)或4(PKD2)普拉德-威利综合症、镰状细胞病、泰萨二氏症、特纳氏综合症。
可通过根据本发明所述的化合物治疗的进一步的疾病状态或状况包括阿尔茨海默病、肌萎缩侧索硬化症(鲁盖瑞氏症)、神经性厌食症、焦虑障碍、动脉粥样硬化、注意力缺乏多动障碍、自闭症、双相性精神障碍、慢性疲劳综合征、慢性阻塞性肺病、克罗恩病、冠状动脉心脏病、痴呆、抑郁症、1型糖尿病、2型糖尿病、癫痫、吉-巴二氏综合征、过敏性大肠综合征、狼疮、代谢综合征、多发性硬化症、心肌梗塞、肥胖、强迫症、恐慌症、帕金森病、银屑病、类风湿性关节炎、结节病、精神分裂症、中风、血栓闭塞性脉管炎、特纳氏综合征、血管炎。
可通过根据本发明所述的化合物治疗的还另外的疾病状态或状况包括血浆铜蓝蛋白缺乏症(aceruloplasminemia)、软骨成长不全Ⅱ型(Achondrogenesis type II)、软骨发育不全、尖头(畸形)、戈谢病2型、急性间歇性卟啉病、卡纳万病、腺瘤性结肠息肉病(Adenomatous Polyposis Coli)、ALA脱水酶缺乏症、腺苷酸琥珀酸裂解酶缺乏症、肾上腺生殖器综合征、肾上腺脑白质营养不良、ALA-D卟啉症、ALA脱水酶缺乏症、尿黑酸尿、亚历山大病、尿黑酸尿褐黄病、α1-抗胰蛋白酶缺乏症、α-1蛋白酶抑制剂、气肿、肌萎缩侧索硬化症、阿尔斯特伦综合征、亚历山大病、牙釉质发育不全、ALA脱水酶缺乏症、安德森—费勃莱氏病、雄激素不敏感综合征、贫血、弥漫性躯体性血管角化瘤(Angiokeratoma CorporisDiffusum)、视网膜血管瘤病(冯希佩尔-林道病)、阿佩尔综合征、蜘蛛脚样指(趾)(马凡综合征)、斯蒂克勒综合征、先天性多关节挛缩(Arthrochalasis multiplex congenital)(埃-丹二氏综合征#arthrochalasia类型)、共济失调性毛细血管扩张症、瑞特综合征、原发性肺高血压、桑德霍夫病、神经纤维瘤病II型、比-斯二氏脓疱性皮肤综合征、地中海热、家族性、本杰明综合征、β-地中海贫血、双侧听觉神经纤维瘤病(神经纤维瘤病II型)、凝血因子V莱顿易栓症(factor V Leiden thrombophilia)、布-西二氏综合征(色素失调症)、布卢姆综合征、X连锁铁粒幼细胞性贫血(X-linked sideroblastic anemia)、邦-乌二氏综合征(特纳氏综合症)、布尔纳维病(结节性硬化症)、朊病毒疾病、Birt-Hogg-Dubé综合征、脆骨疾病(成骨不全症)、Broad Thumb-Hallux综合征(鲁-塔二氏综合征)、青铜色糖尿病/青铜色肝硬化(血色素沉着症)、延髓性肌萎缩(Bulbospinal muscular atrophy)(肯尼迪氏病)、伯-格二氏综合征(脂蛋白脂酶缺乏症)、CGD慢性肉芽肿性疾病、弯肢性发育不良、生物素酶缺乏症、心肌病(努南综合征)、猫叫综合征、CAVD(先天性无输精管(congenitalabsence of the vas deferens))、Caylor心面综合征(CBAVD)、CEP(先天性红细胞生成性卟啉症)、囊性纤维化、先天性甲状腺功能减退症、软骨营养障碍综合征(软骨发育不全)、otospondylomegaepiphyseal发育不良、莱施-奈恩综合征、半乳糖症、埃-丹二氏综合征、致死性发育不良、科-洛二氏综合征、科克因综合征、(家族性腺瘤性息肉病)、先天性红细胞生成性卟啉症、先天性心脏病、高铁血红蛋白血症/先天性高铁血红蛋白血症、软骨发育不全、X连锁铁粒幼细胞性贫血、结缔组织疾病、圆锥动脉异常面容综合征(Conotruncal anomalyface syndrome)、库利贫血(β-地中海贫血)、铜贮积病(威尔逊氏病)、铜转运病(门克斯病)、遗传性粪卟啉病(hereditary coproporphyria)、考登综合征、颅面关节变形(克鲁宗综合征)、克-雅二氏病(朊病毒疾病)、科克因综合征、考登综合征、库什曼-巴滕-斯坦纳特综合征(肌强直性营养不良)、比-斯二氏脓疱性皮肤综合征、原发性高草酸尿症、脊椎干骺端发育不良(斯特鲁德维克)、肌营养不良、杜兴和贝克型(DBMD)、亚瑟综合征、退行性神经疾病——包括德-格罗乌稀综合征和代-索二氏综合征、发育障碍、远端脊髓性肌萎缩V型、雄激素不敏感综合征、弥漫性球样体硬化(克拉伯病)、迪格奥尔格综合征、二氢睾酮受体缺乏症、雄激素不敏感综合征、唐氏综合征、侏儒症、红细胞生成性原卟啉症、红细胞系5-氨基乙酰丙酸酯合成酶缺乏症、红细胞生成性卟啉症、红细胞生成性原卟啉症、红细胞生成性尿卟啉症、弗里德希氏共济失调、家族性发作性多浆膜炎、迟发性皮肤卟啉病、家族性压力敏感神经病变、原发性肺高血压(PPH)、胰腺纤维囊性疾病、脆性X综合征、半乳糖血症、遗传性脑部疾病、巨细胞肝炎(新生儿血色素沉着症)、格-斯二氏综合征(弹性假黄瘤)、巩特尔病(先天性红细胞生成性卟啉症)、血色素沉着、哈格仑综合征、镰状细胞贫血、血友病、肝红细胞生成性卟啉症(HEP)、希佩尔-林道病(冯希佩尔-林道病)、亨廷顿病、赫-吉二氏早衰综合征(早衰症)、高雄激素血症、季肋发育不全、低色素性贫血、免疫系统紊乱——包括X-连锁重症联合免疫缺陷、因-阿二氏综合征、杰克逊-魏斯综合征、朱伯特综合征、莱施-奈恩综合征、杰克逊-魏斯综合征、肾病——包括高草酸尿症、克兰费尔特综合征、克尼斯特综合征、间隙性痴呆、朗格尔-萨尔帝诺软骨成长不全(achondrogenesis)、共济失调性毛细血管扩张症、兰什综合征、赖氨酰羟化酶缺乏症、麦查多-约瑟夫病、代谢紊乱、包括——克尼斯特综合征、马凡综合征、运动障碍、莫厄特-威尔逊综合征、囊性纤维化、穆恩克综合征、多发性神经纤维瘤病、南-因二氏综合征、南-斯二氏软骨发育不良、尼曼—匹克病、诺雅克综合征(法伊弗综合征)、奥-韦-朗三氏疾病、普-杰二氏、多囊肾病、多骨纤维发育不良(麦-奥二氏综合征)、普-杰二氏综合症、普-拉-韦三氏综合征、血色素沉着症、原发性高尿酸血症综合征(莱施-奈恩综合征)、原发性肺高血压、原发性老年退行性痴呆、朊病毒疾病、早衰症(赫吉早衰综合征)、进行性舞蹈病、进行性舞蹈病慢性遗传性(亨廷顿)(亨廷顿病)、进行性肌萎缩症、脊髓性肌萎缩、丙酸血症、原卟啉症、近端肌强直性营养不良、肺动脉高血压、PXE(弹性假黄瘤)、Rb(视网膜母细胞瘤)、雷克林霍曾病(神经纤维瘤病I型)、复发性多浆膜炎、视网膜疾病、视网膜母细胞瘤、瑞特综合征、RFALS 3型、雷克综合征、赖-戴二氏综合征、罗-雷二氏综合征、严重软骨发育不全,伴随发育迟缓和黑棘皮病(SADDAN)、李法美尼综合征、肉瘤、乳腺、白血病、和肾上腺(SBLA)综合征、结节状硬化(结节性硬化症)、SDAT、先天性SED(先天性脊椎骨骺发育不良)、SED Strudwick(脊椎干骺端发育不良、斯特鲁德维克型)、SEDc(先天性脊椎骨骺发育不良)、SEMD、斯特鲁德维克型(脊椎干骺端发育不良、斯特鲁德维克型)、Shprintzen综合征、皮肤色素沉着症、史-伦-奥三氏综合征、南非遗传性卟啉症(混合性卟啉病(variegate porphyria))、婴幼儿期发病上升的遗传性痉挛性瘫痪、言语和沟通障碍、鞘脂类代谢障碍、泰-萨二氏病、脊髓小脑性共济失调、斯蒂克勒综合征、中风、雄激素不敏感综合征、四氢生物蝶呤缺乏症、β-地中海贫血、甲状腺疾病、腊肠体样神经病(Tomaculous neuropathy)(遗传性神经病、产生压力麻痹)、特雷歇-柯林斯综合征、三体X综合征(三X综合征)、三体21(唐氏综合征)、三体X、VHL综合征(冯希佩尔-林道病)、视力损伤和失明(阿尔斯特伦综合征)、夫罗利克疾病、瓦登伯格综合征、Warburg Sjo Fledelius综合征、Weissenbacher-Zweymüller综合征、午-希二氏综合征、午非周期性疾病、Weissenbacher-Zweymüller综合征和着色性干皮病等。
术语“瘤形成”或“癌症”贯穿说明书用于指代这样的病理学过程,其导致形成和生长癌性或恶性瘤,即,通过细胞增殖、通常快于正常生长并且在引起新生长的刺激停止后继续生长的异常组织。恶性瘤显示部分或完全缺乏结构组织和与正常组织的功能协调,并且大多数侵入周围组织,转移至多个位点,和可能在被尝试去除后复发并导致患者死亡——除非得到充分治疗。如本文所用,术语瘤形成用于描述所有癌症疾病状态,并且包括或包含与恶性造血、腹水和实体肿瘤相关的病理学过程。可通过本发明化合物单独或组合至少一种另外的抗癌剂治疗的示例性癌症包括鳞状细胞癌、基底细胞癌、腺癌、肝细胞癌和肾细胞癌、膀胱、肠、乳腺、宫颈、结肠、食管、头、肾、肝、肺、颈、卵巢、胰腺、前列腺、和胃的癌症;白血病;良性和恶性淋巴瘤,具体地伯基特淋巴瘤和非霍奇金淋巴瘤;良性和恶性黑素瘤;骨髓增殖性疾病;肉瘤,包括尤文肉瘤、血管肉瘤、卡波西氏肉瘤、脂肉瘤、肌肉瘤、周围神经上皮瘤、滑膜肉瘤、神经胶质瘤、星形细胞瘤、少突神经胶质瘤、室管膜瘤、成胶质细胞瘤、成神经细胞瘤、神经节瘤、神经节神经胶质瘤、成神经管细胞瘤、松果体细胞瘤、脑膜瘤、脑膜肉瘤、神经纤维瘤、和神经鞘瘤;肠癌、乳腺癌、前列腺癌、宫颈癌、子宫癌、肺癌、卵巢癌、睾丸癌、甲状腺癌、星形细胞瘤、食管癌、胰腺癌、胃癌、肝癌、结肠癌、黑素瘤;癌肉瘤、霍奇金病、维尔姆斯瘤和畸胎瘤。可利用根据本发明所述的化合物治疗的另外的癌症包括,例如,T系急性淋巴细胞白血病(T-ALL)、T系淋巴母细胞淋巴瘤(T-LL)、周围T-细胞淋巴瘤、成体T-细胞白血病、前B ALL、前B淋巴瘤、大B-细胞淋巴瘤、伯基特淋巴瘤、B-细胞ALL、费城染色体阳性ALL和费城染色体阳性CML。
术语“生物活性剂”用于描述非根据本发明所述的化合物的试剂,其作为具有生物学活性的试剂与本发明化合物组合使用,从而协助产生本发明化合物应用的目标治疗、抑制和/或防止/预防。本文使用的优选生物活性剂包括具有与本发明化合物的应用或给予类似的药理活性的那些试剂,并且包括例如,抗癌剂、抗病毒剂——特别是包括抗HIV剂和抗HCV剂、抗微生物剂、抗真菌剂等。
术语“另外的抗癌剂”用于描述可与根据本发明所述的化合物组合以治疗癌症的抗癌剂。这些试剂包括,例如,依维莫司(everolimus)、曲贝替定(trabectedin)、阿布烷(abraxane)、TLK 286、AV-299、DN-101、帕唑帕尼、GSK690693、RTA 744、ON 0910.Na、AZD6244(ARRY-142886)、AMN-107、TKI-258、GSK461364、AZD 1152、因扎妥雷(enzastaurin)、凡德他尼、ARQ-197、MK-0457、MLN8054、PHA-739358、R-763、AT-9263、FLT-3抑制剂、VEGFR抑制剂、EGFR TK抑制剂、奥罗拉激酶抑制剂、PIK-1调节剂、Bcl-2抑制剂、HDAC抑制剂、c-MET抑制剂、PARP抑制剂、Cdk抑制剂、EGFR TK抑制剂、IGFR-TK抑制剂、抗HGF抗体、PI3激酶抑制剂、AKT抑制剂、JAK/STAT抑制剂、检查点-1或2抑制剂、焦点粘连激酶抑制剂、Map激酶激酶(mek)抑制剂、VEGF诱捕抗体、培美曲塞(pemetrexed)、厄洛替尼、达沙替尼(dasatanib)、尼洛替尼(nilotinib)、德卡坦尼(decatanib)、帕尼单抗(panitumumab)、氨柔比星(amrubicin)、奥戈伏单抗(oregovomab)、Lep-etu、洛拉曲克(nolatrexed)、azd2171、巴他布林(batabulin)、奥法木单抗(ofatumumab)、扎木单抗(zanolimumab)、艾特咔林(edotecarin)、粉防己碱(tetrandrine)、鲁比特康(rubitecan)、替米利芬(tesmilifene)、奥利默森(oblimersen)、塔西单抗(ticilimumab)、易普利姆玛(ipilimumab)、棉酚、Bio111、131-I-TM-601、ALT-110、BIO 140、CC 8490、西仑吉肽(cilengitide)、吉马替康(gimatecan)、IL13-PE38QQR、INO 1001、IPdR1 KRX-0402、硫蒽酮(lucanthone)、LY317615、纽落递(neuradiab)、维特斯朋(vitespan)、Rta 744、Sdx 102、他仑帕奈(talampanel)、阿曲生坦(atrasentan)、Xr 311、罗米地辛(romidepsin)、ADS-100380、舒尼替尼(sunitinib)、5-氟尿嘧啶、伏立诺他(vorinostat)、依托泊苷(etoposide)、吉西他滨(gemcitabine)、多柔比星(doxorubicin)、脂质体多柔比星、5'-脱氧-5-氟尿苷、长春新碱(vincristine)、替莫唑胺(temozolomide)、ZK-304709、塞里西利(seliciclib);PD0325901、AZD-6244、卡培他滨(Capecitabine)、L-谷氨酸、N-[4-[2-(2-氨基-4,7-二氢-4-氧代-1H-吡咯并[2,3-d]嘧啶-5-基)乙基]苯甲酰基]-、二钠盐、七水合物、喜树碱(camptothecin)、PEG标记的伊立替康(irinotecan)、他莫昔芬(tamoxifen)、柠檬酸托来米芬(toremifene citrate)、阿那曲唑(anastrazole)、依西美坦(exemestane)、来曲唑(letrozole)、DES(二乙基己烯雌酚)、雌二醇、雌激素、共轭雌激素、贝伐单抗(bevacizumab)、IMC-1C11、CHIR-258);3-[5-(甲基磺酰基哌啶甲基)-吲哚基-喹诺酮、瓦他拉尼(vatalanib)、AG-013736、AVE-0005、[D-Ser(Bu t)6,Azgly 10](焦-Glu-His-Trp-Ser-Tyr-D-Ser(Bu t)-Leu-Arg-Pro-Azgly-NH2乙酸酯的乙酸盐[C59H84N18Oi4-(C2H4O2)X,其中x=1至2.4]、乙酸戈舍瑞林(goserelin acetate)、乙酸亮丙瑞林(leuprolideacetate)、扑酸曲普瑞林、乙酸甲羟孕酮(medroxyprogesterone acetate)、己酸羟孕酮(hydroxyprogesterone caproate)、乙酸甲地孕酮(megestrol acetate)、雷洛昔芬(raloxifene)、比卡鲁胺(bicalutamide)、氟他胺(flutamide)、尼鲁米特(nilutamide)、乙酸甲地孕酮、CP-724714;TAK-165、HKI-272、厄洛替尼、拉帕替尼(lapatanib)、卡奈替尼(Canertinib)、ABX-EGF抗体、爱必妥(erbitux)、EKB-569、PKI-166、GW-572016、洛那法尼(Ionafarnib)、BMS-214662、替吡法尼(tipifarnib);氨磷汀(amifostine)、NVP-LAQ824、辛二酰苯胺异羟肟酸(suberoyl analide hydroxamic acid)、丙戊酸(valproic acid)、曲古抑菌素A(trichostatin A)、FK-228、SU11248、索拉非尼、KRN951、氨鲁米特(aminoglutethimide)、安沙可林(arnsacrine)、阿那格雷(anagrelide)、L-天冬酰胺酶、卡介苗(BCG)疫苗、阿霉素(adriamycin)、博来霉素(bleomycin)、布舍瑞林(buserelin)、白消安(busulfan)、卡铂(carboplatin)、卡莫司汀(carmustine)、苯丁酸氮芥(chlorambucil)、顺铂(cisplatin)、克拉屈滨(cladribine)、氯膦酸盐(clodronate)、环丙孕酮(cyproterone)、阿糖胞苷(cytarabine)、达卡巴嗪(dacarbazine)、更生霉素(dactinomycin)、道诺霉素(daunorubicin)、二乙基己烯雌酚、表柔比星(epirubicin)、氟达拉滨(fludarabine)、氟氢可的松(fludrocortisone)、氟甲睾酮(fluoxymesterone)、氟他胺、格列卫、吉西他滨、羟基脲、伊达比星(idarubicin)、异环磷酰胺(ifosfamide)、伊马替尼(imatinib)、亮丙瑞林(leuprolide)、左旋咪唑(levamisole)、洛莫司汀(lomustine)、氮芥(mechlorethamine)、马法兰(melphalan)、6-巯基嘌呤、美司钠(mesna)、氨甲喋呤、丝裂霉素(mitomycin)、米托坦(mitotane)、米托蒽醌(mitoxantrone)、尼鲁米特、奥曲肽(octreotide)、奥沙利铂(oxaliplatin)、帕米膦酸盐(pamidronate)、喷司他丁(pentostatin)、普卡霉素(plicamycin)、卟吩姆(porfimer)、丙卡巴肼(procarbazine)、雷替曲塞(raltitrexed)、利妥昔单抗(rituximab)、链脲菌素(streptozocin)、替尼泊苷(teniposide)、睾酮、沙利度胺(thalidomide)、硫鸟嘌呤(thioguanine)、噻替哌(thiotepa)、维甲酸(tretinoin)、长春地辛(vindesine)、13-顺式视黄酸、苯丙氨酸芥子气(phenylalanine mustard)、尿嘧啶氮芥(uracil mustard)、雌莫司汀(estramustine)、六甲蜜胺(altretamine)、氟尿苷(floxuridine)、5-脱氧尿苷、阿糖胞苷(cytosinearabinoside)、6-巯基嘌呤、脱氧柯福霉素(deoxycoformycin)、骨化三醇(calcitriol)、戊柔比星(valrubicin)、光辉霉素(mithramycin)、长春花碱(vinblastine)、长春瑞滨(vinorelbine)、托泊替康(topotecan)、雷佐生(razoxin)、马司他(marimastat)、COL-3、新伐司他(neovastat)、BMS-275291、角鲨胺(squalamine)、内皮抑素(endostatin)、SU5416、SU6668、EMD121974、白介素-12、IM862、血管抑素(angiostatin)、维塔辛(vitaxin)、屈洛昔芬(droloxifene)、idoxyfene、安体舒通(spironolactone)、非那雄胺(finasteride)、西米替丁(cimitidine)、曲妥珠单抗(trastuzumab)、地尼白介素(denileukin diftitox)、吉非替尼、硼替佐米(bortezimib)、紫杉醇(paclitaxel)、无聚氧乙烯蓖麻油的紫杉醇(cremophor-free paclitaxel)、多西他赛(docetaxel)、埃博霉素B(epithilone B)、BMS-247550、BMS-310705、屈洛昔芬、4-羟基他莫昔芬、哌喷昔芬(pipendoxifene)、ERA-923、阿佐昔芬(arzoxifene)、氟维司群(fulvestrant)、阿考比芬(acolbifene)、拉索昔芬(lasofoxifene)、艾多昔芬(idoxifene)、TSE-424、HMR-3339、ZK186619、托泊替康、PTK787/ZK 222584、VX-745、PD 184352、雷帕霉素、40-O-(2-羟基乙基)-雷帕霉素、替西罗莫司(temsirolimus)、AP-23573、RAD001、ABT-578、BC-210、LY294002、LY292223、LY292696、LY293684、LY293646、渥曼青霉素(wortmannin)、ZM336372、L-779,450、PEG-非格司亭(PEG-filgrastim)、达贝泊汀(darbepoetin)、促红细胞生成素、粒细胞集落刺激因子、唑来膦酸(zolendronate)、强的松、西妥昔单抗(cetuximab)、粒细胞巨噬细胞集落刺激因子、组氨瑞林(histrelin)、聚乙二醇干扰素α-2a、干扰素α-2a、聚乙二醇干扰素α-2b、干扰素α-2b、阿扎胞苷、PEG-L-天冬酰胺酶、来那度胺(lenalidomide)、吉妥珠单抗(gemtuzumab)、氢化可的松、白介素-11、右雷佐生(dexrazoxane)、阿仑单抗(alemtuzumab)、全反式维甲酸(全反式维甲酸)、酮康唑(ketoconazole)、白介素-2、甲地孕酮(megestrol)、免疫球蛋白、氮芥(nitrogen mustard)、甲基泼尼松龙、替伊莫单抗(ibritgumomab tiuxetan)、雄激素、地西他滨、六甲基蜜胺(hexamethylmelamine)、贝沙罗汀(bexarotene)、托西莫单抗(tositumomab)、三氧化二砷、可的松(cortisone)、editronate、米托坦、环孢素(cyclosporine)、脂质体道诺霉素、Edwina-天冬酰胺酶、锶89、卡索匹坦(casopitant)、奈妥吡坦(netupitant)、NK-1受体拮抗剂、帕洛诺司琼(palonosetron)、阿瑞匹坦(aprepitant)、苯海拉明(diphenhydramine)、羟嗪、胃复安(metoclopramide)、劳拉西泮(lorazepam)、阿普唑仑(alprazolam)、氟哌啶醇(haloperidol)、氟哌利多(droperidol)、屈大麻酚(dronabinol)、地塞米松(dexamethasone)、甲基泼尼松龙、普鲁氯嗪(prochlorperazine)、格拉司琼(granisetron)、昂丹司琼(ondansetron)、多拉司琼(dolasetron)、托烷司琼(tropisetron)、乙二醇化非格司亭(pegfilgrastim)、促红细胞生成素、依泊亭α(epoetin alfa)、达贝泊汀α及其混合物。
术语“抗HIV剂”或“另外的抗HIV剂”包括,例如,核苷类逆转录酶抑制剂(NRTI)、其他非核苷类逆转录酶抑制剂(即,非本发明中的代表的那些)、蛋白酶抑制剂、融合抑制剂等,其示例性化合物可包括,例如,3TC(拉米夫定(Lamivudine))、AZT(齐多夫定(Zidovudine))、(-)-FTC、ddI(地达诺新(Didanosine))、ddC(扎西他滨(zalcitabine))、阿巴卡韦(abacavir)(ABC)、替诺福韦(tenofovir)(PMPA)、D-D4FC(Reverset)、D4T(司他夫定(Stavudine))、拉西韦(Racivir)、L-FddC、L-FD4C、NVP(奈韦拉平(Nevirapine))、DLV(地拉夫定(Delavirdine))、EFV(依法韦仑(Efavirenz))、SQVM(甲磺酸沙奎那韦(Saquinavirmesylate))、RTV(利托那韦(Ritonavir))、IDV(茚地那韦(Indinavir))、SQV(沙奎那韦(Saquinavir))、NFV(奈非那韦(Nelfinavir))、APV(安普那韦(Amprenavir))、LPV(洛匹那韦(Lopinavir))、融合抑制剂如T20等、fuseon及其混合物,包括当前临床试验或研发中的抗HIV化合物。
可用于与根据本发明所述的化合物共同给予的其他抗HIV剂包括,例如,其他NNRTI’s(即,非根据本发明所述的NNRTI’s),可选自奈韦拉平(BI-R6-587)、地拉夫定(U-90152S/T)、依法韦仑(DMP-266)、UC-781(N-[4-氯-3-(3-甲基-2-丁烯氧基)苯基]-2甲基3-呋喃硫羰基酰胺(furancarbothiamide))、依曲韦林(etravirine)(TMC125)、曲韦定(Trovirdine)(Ly300046.HCl)、MKC-442(乙米韦林(emivirine)、Coactinon)、HI-236、HI-240、HI-280、HI-281、利匹韦林(rilpivirine)(TMC-278)、MSC-127、HBY 097、DMP266、黄芩苷(Baicalin)(TJN-151)ADAM-II(甲基3’,3’-二氯-4’,4”-二甲氧基-5’,5”-双(甲氧基羰基)-6,6-二苯基己烯酸酯)、甲基3-溴-5-(1-5-溴-4-甲氧基-3-(甲氧基羰基)苯基)庚-1-烯基)-2-甲氧基苯甲酸酯(烯基二芳基甲烷类似物、Adam类似物)、5Cl3PhS-2Indo1CONH2(5-氯-3-(苯基亚磺酰基)-2’-吲哚羧酰胺)、AAP-BHAP(U-104489或PNU-104489)、卡普韦林(Capravirine)(AG-1549、S-1153)、阿替韦啶(atevirdine)(U-87201E)、金精三羧酸(SD-095345)、1-[(6-氰基-2-吲哚基)羰基]-4-[3-(异丙基氨基)-2-吡啶基]哌嗪(哌嗪1吡啶4吲哚基衍生物)、1-[5-[[N-(甲基)甲基磺酰基氨基]-2-吲哚基羰基-4-[3-(异丙基氨基)-2-吡啶基]哌嗪(哌嗪1吡啶5吲哚基衍生物)、1-[3-(乙基氨基)-2-[吡啶基]-4-[(5-羟基-2-吲哚基)羰基]哌嗪、1-[(6-甲酰基-2-吲哚基)羰基]-4-[3-(异丙基氨基)-2-吡啶基]哌嗪、1-[[5-(甲基磺酰氧基)-2-吲哚基)羰基]-4-[3-(异丙基氨基)-2-吡啶基]哌嗪、U88204E、双(2-硝基苯基)砜(NSC 633001)、胡桐内酯A(Calanolide A)(NSC675451)、胡桐内酯B、6-苄基-5-甲基-2-(环己氧基)嘧啶-4-酮(DABO-546)、DPC 961、E-EBU、E-EBU-dm、E-EPSeU、E-EPU、膦甲酸(Foscarnet、Foscavir)、HEPT(1-[(2-羟基乙氧基)甲基]-6-(苯基硫代)胸腺嘧啶)、HEPT-M(1-[(2-羟基乙氧基)甲基]-6-(3-甲基苯基)硫代)胸腺嘧啶)、HEPT-S(1-[(2-羟基乙氧基)甲基]-6-(苯基硫代)-2-硫代胸腺嘧啶)、海棠果素P(InophyllumP)、L-737、126、米歇尔胺A(Michellamine A)(NSC650898)、米歇尔胺B(NSC649324)、米歇尔胺F、6-(3,5-二甲基苄基)-1-[(2-羟基乙氧基)甲基]-5-异丙基尿嘧啶、6-(3,5-二甲基苄基)-1-(乙氧基甲基)-5-异丙基尿嘧啶、NPPS、E-BPTU(NSC 648400)、奥替普拉(Oltipraz)(4-甲基-5-(吡嗪基)-3H-1,2-二硫杂环戊二烯(dithiole)-3-硫酮)、N-{2-(2-氯-6-氟苯乙基]-N’-(2-噻唑基)硫脲(PETT Cl、F衍生物)、N-{2-(2,6-二氟苯乙基]-N’-[2-(5-溴吡啶基)]硫脲{PETT衍生物)、N-{2-(2,6-二氟苯乙基]-N’-[2-(5-甲基吡啶基)]硫脲{PETT吡啶基衍生物)、N-[2-(3-氟呋喃基)乙基]-N’-[2-(5-氯吡啶基)]硫脲、N-[2-(2-氟-6-乙氧基苯乙基)]-N’-[2-(5-溴吡啶基)]硫脲、N-(2-苯乙基)-N'-(2-噻唑基)硫脲(LY-73497)、L-697,639、L-697,593、L-697,661、3-[2-(4,7-二氟苯并唑-2-基)乙基}-5-乙基-6-甲基(吡啶-2(1H)-硫酮(2-吡啶酮衍生物)、3-[[(2-甲氧基-5,6-二甲基-3-吡啶基)甲基]胺]-5-乙基-6-甲基(吡啶-2(1H)-硫酮(2-吡啶酮3吡啶3MeNH衍生物)、R82150、R82913、R87232、R88703、R89439(洛韦胺(Loviride))、R90385、S-2720、苏拉明钠(Suramin Sodium)、TBZ(噻唑苯并咪唑、NSC 625487)、噻唑异吲哚-5-酮、(+)(R)-9b-(3,5-二甲基苯基-2,3-二氢噻唑[2,3-a]异吲哚-5(9bH)-酮、韦拉平(Tivirapine)(R86183)、UC-38和UC-84,等等。
术语“药学上可接受的盐”贯穿说明书用于描述,在适当时,本文描述的化合物其中一种或多种的盐形式,其呈现增加化合物在患者胃肠道胃液中的溶解度,从而促进化合物的溶解和生物利用性。药学上可接受的盐包括在适当时衍生自药学上可接受的无机或有机碱和酸的那些。适当的盐包括衍生自碱金属如钾和钠、碱土金属如钙、镁和铵盐以及制药领域公知的多种其他酸和碱的那些。钠和钾盐特别优选作为根据本发明所述的磷酸盐(酯)的中和盐。
术语“药学上可接受的衍生物”贯穿说明书用于描述任何药学上可接受的前药形式(如酯、酰胺其他前药群),其在被给予患者后直接或间接提供本发明化合物或本发明化合物的活性代谢物。
术语“独立地”在本文中用于表示独立应用的变量在应用与应用之间独立地变化。
术语“烃基”意为这样的化合物:包含碳和氢,并且可以是完全饱和的、部分不饱和的或芳族的,包括芳基、烷基、烯基和炔基。
术语“烷基”在其上下文中意为直链、支链、或环状完全饱和的烃自由基或烷基,优选C1-C10、更优选C1-C6,可选地C1-C3烷基,其可任选被取代。烷基实例是甲基、乙基、正丁基、仲丁基、正己基、正庚基、正辛基、正壬基、正癸基、异丙基、2-甲基丙基、环丙基、环丙基甲基、环丁基、环戊基、环戊基乙基、环己基乙基和环己基等。在某些优选实施方式中,根据本发明所述的化合物可用于共价结合脱卤素酶。这些化合物通常包含侧链(通常通过聚乙二醇基团连接),该侧链终止于其远端具有卤素取代基(通常氯或溴)的烷基,导致包含该部分的化合物与蛋白质共价结合。术语“烯基”指代包含至少一个C=C键的直链、支链或环C2-C10(优选C2-C6)烃自由基。术语“炔基”指代包含至少一个C≡C键的直链、支链或环C2-C10(优选C2-C6)烃自由基。术语“亚烷基”在使用时指代-(CH2)n-基团(n是整数,通常为0-6),其可以任选地被取代。在被取代时,亚烷基优选在亚甲基的一个或多个上被C1-C6烷基(包括环丙基或叔丁基),更优选甲基取代,但也可被一个或多个卤素基团——优选1至3个卤素基团、或一个或两个羟基、O-(C1-C6烷基)基团或氨基酸侧链取代,如本文另外公开。在某些实施方式中,亚烷基可被尿烷或烷氧基基团(或其他基团)取代,该尿烷或烷氧基基团(或其他基团)进一步用聚乙二醇链(具有1至10,优选1至6,通常1至4个乙二醇单元)取代,该聚乙二醇链用烷基链取代(优选地,但不仅仅在聚乙二醇链远端上),该烷基链用单一卤素基团,优选氯基团取代。在再其他实施方式中,亚烷基(通常,亚甲基)可用氨基酸侧链基团取代,如天然或非天然氨基酸的侧链基团,例如,丙氨酸、β-丙氨酸、精氨酸、天冬酰胺、天冬氨酸、半胱氨酸、胱氨酸、谷氨酸、谷氨酰胺、甘氨酸、苯丙氨酸、组氨酸、异亮氨酸、赖氨酸、亮氨酸、甲硫氨酸、脯氨酸、丝氨酸、苏氨酸、缬氨酸、色氨酸或酪氨酸。
术语“未取代的”意为仅用氢原子取代。包括C0的碳原子范围意为碳不存在,由H替代。因此,C0-C6的碳原子范围包括1、2、3、4、5和6个碳原子,对于C0,H代替碳。术语“取代的”或“任选取代的”意为在上下文分子上任意位置的碳(或氮)位处独立地(即,在存在一个以上取代基时,每个取代基与另一取代基无关)一个或多个取代基(独立地上至5个取代基,优选上至3个取代基,通常1或2个取代基,在根据本发明所述的化合物的部分上,并且可包括本身可进一步被取代的取代基),并且包括作为取代基的羟基、硫醇基、羧基、氰基(C≡N)、硝基(NO2)、卤素(优选地、1、2或3个卤素,特别是在烷基上,特别是甲基,如三氟甲基)、烷基(优选地,C1-C10,更优选地,C1-C6)、芳基(特别是苯基和取代苯基,例如苄基或苯甲酰基)、烷氧基(优选地,C1-C6烷基或芳基,包括苯基和取代苯基)、硫醚(C1-C6烷基或芳基)、酰基(优选地,C1-C6酰基)、酯或硫酯(优选地,C1-C6烷基或芳基)——包括亚烷基酯(使得连接处于亚烷基上,而非在优选用C1-C6烷基或芳基取代的酯官能团处),优选地,C1-C6烷基或芳基、卤素(优选地,F或Cl),胺(包括五元或六元环亚烷基胺,进一步包括C1-C6烷基胺或C1-C6二烷基胺,该烷基可用一个或两个羟基取代)或任选取代的-N(C0-C6烷基)C(O)(O-C1-C6烷基)基团(其可任选地用聚乙二醇链取代,该聚乙二醇链进一步结合烷基,该烷基包含单一卤素,优选氯取代基)、肼、酰氨基——其优选用一个或两个C1-C6烷基取代(包括羧酰胺,其任选用一个或两个C1-C6烷基取代)、烷醇(优选地,C1-C6烷基或芳基)或烷酸(优选地,C1-C6烷基或芳基)。根据本发明所述的取代基可包括,例如-SiR1R2R3基团,其中R1和R2均如本文另外描述,并且R3是H或C1-C6烷基,优选这种情况下的R1、R2、R3是C1-C3烷基(包括异丙基或叔丁基)。上述基团均可直接连接于取代部分,或可选地,取代基可通过任选取代的-(CH2)m-或可选地任选取代的-(OCH2)m-、-(OCH2CH2)m-或-(CH2CH2O)m-基团——可用任意一个或多个上述取代基取代——连接于取代部分(优选在芳基或杂芳基部分的情况下)。亚烷基-(CH2)m-或-(CH2)n-基团或其他链如乙二醇链,如上文确定,可在链上的任何位置被取代。亚烷基上的优选取代基包括卤素或C1-C6(优选C1-C3)烷基——其可任选地用下列取代:一个或两个羟基、一个或两个醚基团(O-C1-C6基团)、上至三个卤素基团(优选F)、或如本文另外描述的氨基酸侧链、和任选取代的酰胺(优选如上述取代的羧酰胺)或尿烷基团(通常具有一个或两个C0-C6烷基取代基,该基团(一个或多个)可被进一步取代)。在某些实施方式中,亚烷基(通常单一亚甲基)用下列取代:一个或两个任选取代的C1-C6烷基,优选C1-C4烷基,最通常是甲基或O-甲基,或如本文另外描述的氨基酸侧链。在本发明中,分子的部分可任选用上至五个取代基,优选上至三个取代基取代。最通常地,在本发明中,取代部分用一个或两个取代基取代。
术语“取代(的)”(各取代基独立于任意其他取代基)还在其应用的上下文中意指C1-C6烷基、C1-C6烷氧基、卤素、酰氨基、羧酰胺基、砜,包括磺胺、酮、羧基、C1-C6酯(氧酯或羰基酯)、C1-C6酮、尿烷-O-C(O)-NR1R2或-N(R1)-C(O)-O-R1、硝基、氰基和胺(特别是包括C1-C6亚烷基-NR1R2、可任选用一个或两个羟基取代的单-或二-C1-C6烷基取代胺)。除非另外指示,在上下文中,这些基团均包含1至6个碳原子。在某些实施方式中,优选取代基包括例如,-NH-、-NHC(O)-、-O-、=O、-(CH2)m-(在此,m和n在上下文中为1、2、3、4、5或6)、-S-、-S(O)-、SO2-或-NH-C(O)-NH-、-(CH2)nOH、-(CH2)nSH、-(CH2)nCOOH、C1-C6烷基、-(CH2)nO-(C1-C6烷基)、-(CH2)nC(O)-(C1-C6烷基)、-(CH2)nOC(O)-(C1-C6烷基)、-(CH2)nC(O)O-(C1-C6烷基)、-(CH2)nNHC(O)-R1、-(CH2)nC(O)-NR1R2、-(OCH2)nOH、-(CH2O)nCOOH、C1-C6烷基、-(OCH2)nO-(C1-C6烷基)、-(CH2O)nC(O)-(C1-C6烷基)、-(OCH2)nNHC(O)-R1、-(CH2O)nC(O)-NR1R2、-S(O)2-RS、-S(O)-RS(RS是C1-C6烷基或-(CH2)m-NR1R2基团)、NO2、CN或卤素(F、Cl、Br,I,优选F或Cl),其取决于取代基应用的环境。R1和R2在上下文中均是H或C1-C6烷基(其可任选用一个或两个羟基或上至三个卤素基团,优选氟取代)。术语“取代(的)”在所述化合物和所用取代基的化学环境内还意指任选取代的芳基或杂芳基或任选取代的杂环基团,如本文另外描述。亚烷基也可被取代,如本文另外公开,优选用下列取代:任选取代的C1-C6烷基(优选甲基、乙基或羟基甲基或羟基乙基,因此提供手性中心)、如本文另外描述的氨基酸基团侧链、上述酰氨基、或尿烷基团O-C(O)-NR1R2基团,其中R1和R2如本文另外描述,虽然多种其他基团也可用作取代基。不同的任选取代的部分可用3个或更多个取代基取代,优选不多于3个取代基,并且优选1或2个取代基。注意,在化合物的分子具体位置处需要取代(主要由于化合价)但未显示取代的情况下,该取代基被解释或理解为H,除非取代上下文另外指示。
术语“芳基”或“芳族的”在上下文中指代具有单个环(例如,苯,苯基、苄基)或缩合环(例如,萘基、蒽基、菲基、等)的取代(如本文另外描述)或未取代的单价芳族基团,并且可在环(一个或多个)上任意可利用的稳定位置处或如在所示化学结构中另外指明结合于根据本发明所述的化合物。芳基的其他实例在上下文中可包括杂环芳族环系统,环(单环)中具有一个或多个氮、氧、或硫原子的“杂芳基”,如咪唑、呋喃基(furyl)、吡咯、呋喃基(furanyl)、噻嗯、噻唑、吡啶、嘧啶、吡嗪、三唑、唑或稠合环系统如吲哚、喹啉、吲嗪、氮杂吲嗪、苯并呋咱等等,其可如上所述是任选地取代的。可述及的杂芳基包括含氮杂芳基,如吡咯、吡啶、吡啶酮、哒嗪、嘧啶、吡嗪、吡唑、咪唑、三唑、三嗪、四唑、吲哚、异吲哚、吲嗪、氮杂吲嗪、嘌呤、吲唑、喹啉、二氢喹啉、四氢喹啉、异喹啉、二氢异喹啉、四氢异喹啉、喹嗪、酞嗪、萘啶、喹喔啉、喹唑啉、噌啉、蝶啶、咪唑并吡啶、咪唑并三嗪、吡嗪并哒嗪、吖啶、菲啶、咔唑、咔唑啉(carbazoline)、萘嵌间二氮杂苯、菲绕啉、phenacene、/>二唑、苯并咪唑、吡咯并吡啶、吡咯并嘧啶和吡啶并嘧啶;含硫芳族杂环,如噻吩和苯并噻吩;含氧芳族杂环,如呋喃、吡喃、环五吡喃、苯并呋喃和异苯并呋喃;和包括2个或更多个选自氮、硫和氧的杂原子的芳族杂环,如噻唑、噻二唑、异噻唑、苯并/>唑、苯并噻唑、苯并噻二唑、吩噻嗪、异/>唑、呋咱、吩/>嗪、吡唑并/>唑、咪唑并噻唑、噻吩并呋喃、呋喃并吡咯、吡啶并/>嗪、呋喃并吡啶、呋喃并嘧啶、噻吩并嘧啶和/>唑等,其全部均可以是任选地取代的。
术语“杂环”指代这样的环基团:包含至少一种杂原子,即,O、N或S,并且可以是芳族(杂芳基)或非芳族。因此,杂芳基部分被归类到杂环定义下——这取决于其应用的上下文。示例性杂芳基如上所述。用于本发明的示例性非芳族杂环基团包括,例如,吡咯烷基、吡咯啉基、哌啶基、哌嗪基、N-甲基哌嗪基、吡唑烷基、咪唑烷基、吗啉基、四氢吡喃基、吖丁啶基、氧杂环丁烷基、氧硫环戊烷基(oxathiolanyl)、吡啶酮、2-吡咯烷酮、亚乙基脲、1,3-二氧戊环、1,3-二烷、1,4-二/>烷、邻苯二甲酰亚胺和琥珀酰亚胺等,如本文所述。
术语“治疗”(“treat”、“treating”和“treatment”)等,如本文所用,指代为本发明化合物可给予的患者提供效益的任何行为,包括通过本发明化合物所结合的蛋白质调控的任意疾病状态或状况的治疗。可利用根据本发明所述的化合物治疗的疾病状态或状况,包括癌症,如上所述。
术语“共同给予”或“组合治疗”意为同时给予患者至少两种化合物或组合物,使得两种或更多种化合物中的每一种均可在给定时间点、在患者体内被测得有效量或浓度。虽然根据本发明所述的化合物可被同时共同给予患者,但该术语包括同时或在不同时间给予两种或更多种试剂,条件是所有共同给予的化合物或组合物可在给定时间、在对象内被测得有效浓度。在本发明的某些优选方面中,上述本发明化合物中的一种或多种与至少一种另外的生物活性剂——特别是包括抗癌剂——组合被共同给予。在本发明的特别优选方面中,化合物共同给予产生协同治疗,包括抗癌治疗。
药物组合物——包括有效量的至少一种根据本发明所述的双功能化合物和一种或多种本文另外描述的化合物(均处于有效量)与药学上有效量的载体、添加剂或赋形剂相组合的组合物,代表本发明的进一步方面。
本发明在适当时包括组合物,其包括本发明化合物的药学上可接受的盐,具体地,酸或碱加成盐。用于制备可用于本发明的上述碱性化合物的药学上可接受的酸加成盐的酸是形成非毒性酸加成盐的酸,该非毒性酸加成盐即包含药理学上可接受的阴离子的盐,该药理学上可接受的阴离子如氢氯离子、氢溴离子、氢碘离子、硝酸根、硫酸根、硫酸氢根、磷酸根、酸式磷酸根、乙酸根、乳酸根、柠檬酸根、酸式柠檬酸根、酒石酸根、酒石酸氢根、琥珀酸根、马来酸根、富马酸根、葡萄糖酸根、糖酸根、苯甲酸酯、甲磺酸根、乙磺酸根、苯磺酸根、对甲苯磺酸根和双羟萘酸根[即,1,1'-亚甲基-二-(2-羟基-3萘甲酸根)]等。
药学上可接受的碱加成盐也可用于生产根据本发明所述的化合物或衍生物的药学上可接受的盐形式。可用作反应剂来制备本质上是酸性的本发明化合物的药学上可接受的碱式盐的化学碱是与这种化合物形成非毒性碱式盐的那些碱。这种非毒性碱式盐包括但不限于,衍生自这种药理学上可接受的阳离子如碱金属阳离子(例如,钾和钠)和碱土金属阳离子(例如,钙、锌和镁)、铵的碱式盐、或水溶性胺加成盐如N-甲基葡萄糖胺-(葡甲胺)、和低级烷醇铵及药学上可接受的有机胺的其他碱式盐等。
本发明的化合物根据本发明可以单剂量或拆分剂量通过口服、胃肠外或局部途径给予。活性化合物的给予可在连续(静脉内滴注)至每日数次口服给予(例如,Q.I.D.)的范围内,并且可包括口服、局部、胃肠外、肌内、静脉内、皮下、透皮(其可包括渗透增强剂)、颊部、舌下和栓剂给予等给予途径。肠溶包衣口服片剂也可用于促进来自口服给予途径的化合物的生物利用度。最有效剂型将取决于所选具体试剂的药代动力学以及患者疾病的严重程度。还可应用作为用于鼻内、气管内或肺给予的喷雾、液雾、或气溶胶的根据本发明所述的化合物的给予。因此本发明还涉及药物组合物,其包括有效量的根据本发明所述的化合物,任选地组合药学上可接受的载体、添加剂或赋形剂。根据本发明所述的化合物可以立即释放、中途释放或持续或受控释放形式给予。持续或受控释放形式优选被口服给予,但也以栓剂和透皮或其他局部形式给予。脂质体形式的肌内注射也可用于控制或维持化合物在注射位点的释放。
本发明的组合物可利用一种或多种药学上可接受的载体以常规方式配制,并且也可以受控释放制剂给予。可用于这些药物组合物的药学上可接受的载体包括但不限于,离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白如人血清白蛋白、缓冲剂物质如磷酸盐、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的部分甘油酯混合物、水、盐或电解质如硫酸醇溶蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、胶体二氧化硅、三硅酸镁、聚乙烯吡咯烷酮、纤维素基物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯嵌段聚合物、聚乙二醇和羊毛脂。
本发明的组合物可口服、胃肠外、通过吸入喷雾、局部、直肠、鼻部、颊部、阴道或通过植入的储器给予。术语“胃肠外”,如本文所用,包括皮下、静脉内、肌内、关节内、滑膜内、胸骨内、鞘内、肝内、病损内和颅内注射或输注技术。优选地,组合物被口服、腹膜内或静脉内给予。
本发明组合物的无菌注射形式可以是含水或含油悬浮液。这些悬浮液可利用适当的分散剂或润湿剂和悬浮剂根据本领域已知的技术配制。无菌注射制剂也可以是在非毒性胃肠外可接受的稀释剂或溶剂中的无菌注射溶液或悬浮液,例如作为1,3-丁二醇溶液。可用的可接受的媒介和溶剂之中有水、林格溶液和等渗氯化钠溶液。此外,无菌固定油常用作溶剂或悬浮介质。因此,可利用任意温和的固定油,包括合成的单-或二-甘油酯。脂肪酸,如油酸及其甘油酯衍生物,可用于制备注射剂,因为其是天然药学上可接受的油,如橄榄油或蓖麻籽油,特别是其聚氧乙烯化形式。这些油溶液或悬浮液还可包含长链醇类稀释剂或分散剂,如Ph.Helv或类似的醇。
本发明的药物组合物可以任何口服可接受的剂型口服给予,包括但不限于,胶囊、片剂、含水悬浮液或溶液。在口服应用片剂的情况下,常用的载体包括乳糖和玉米淀粉。而且一般添加润滑剂,如硬脂酸镁。对于胶囊形式的口服给予,可用的稀释剂包括乳糖和干燥的玉米淀粉。当口服应用需要含水悬浮液时,将活性成分与乳化剂和悬浮剂组合。如需,还可添加某些甜味剂、调味剂或着色剂。
可选地,本发明的药物组合物可以直肠给予栓剂的形式给予。这些组合物可通过混合药剂与适当的非刺激性赋形剂而制备,该非刺激性赋形剂在室温下是固体但在直肠温度下是液体,因此会在直肠中融化以释放药物。这种物质包括可可脂、蜂蜡和聚乙二醇。
本发明的药物组合物也可被局部给予。适于这些区域或器官的每一种的局部制剂均容易制备。下肠道局部施用可以直肠栓剂制剂(参见上文)形式或以适当的灌肠制剂形式进行。也可应用局部可接受的透皮贴剂。
对于局部施用,药物组合物可配制在适当的油膏中,该油膏包含悬浮或溶解在一种或多种载体中的活性组分。本发明化合物的局部给予载体包括但不限于,矿物油、液体矿脂、白矿脂、丙二醇、聚氧乙烯、聚氧丙烯化合物、乳化蜡和水。在本发明的某些优选方面中,化合物可被涂覆在将要手术植入患者体内的支架上,从而抑制或降低支架在患者体内发生阻塞的可能性。
可选地,药物组合物可配制在适当的洗液或乳膏中,该洗液或乳膏包含悬浮或溶解在一种或多种药学上可接受的载体中的活性组分。适当的载体包括但不限于,矿物油、失水山梨醇单硬脂酸酯、聚山梨酯60、鲸蜡酯蜡、鲸蜡硬脂醇、2-辛基十二醇、苄醇和水。
对于眼部应用,药物组合物可配制成等渗的、pH调节的无菌盐水中的微粒化悬浮液,或优选地,配制成等渗的、pH调节的无菌盐水中的溶液——具有或不具有防腐剂如苯扎氯铵(benzylalkonium chloride)。可选地,对于眼部应用,药物组合物可配制在油膏如矿脂中。
本发明的药物组合物也可通过鼻用气溶胶或吸入给予。这种组合物根据药物配制领域公知的技术制备,并且可制备成盐水中的溶液——利用苄醇或其他适当的防腐剂、增加生物利用度的吸收促进剂、碳氟化合物、和/或其他常规增溶剂或分散剂。
本发明的药物组合物中可与载体物质组合生成单个剂型的化合物量根据宿主和所治疗的疾病、具体给予模式而不同。优选地,组合物应被配制以包含约0.05毫克至约750毫克或更多,更优选约1毫克至约600毫克,甚至更优选约10毫克至约500毫克的活性成分——单独或组合至少一种根据本发明所述的其他化合物。
还应理解,针对任何具体患者的具体剂量和治疗方案将取决于多种因素,包括所用具体化合物的活性、年龄、体重、一般健康状况、性别、饮食、给药时间、排泄速率、药物组合和治疗医师的判断以及所治疗的具体疾病或症状的严重程度。
需要利用根据本发明所述的化合物治疗的患者或对象可通过给予患者(对象)有效量的根据本发明所述的化合物来治疗,其包括其药学上可接受的盐、溶剂化物或多晶型物,任选地在药学上可接受的载体或稀释剂中,单独或组合本文另外确定的其他已知的红细胞生成刺激剂。
这些化合物可通过任意适当的途径给予,例如,口服、胃肠外、静脉内、皮内、皮下、或局部形式——包括透皮,以液体、乳膏、凝胶或固体形式,或通过气溶胶形式。
活性化合物被包含在药学上可接受的载体或稀释剂中的量足以向患者递送预期指征的治疗有效量,而不在所治疗患者体内引起严重的毒性效应。针对本文所述全部症状的活性化合物优选剂量在如下范围内:每日约10ng/kg至300mg/kg,优选0.1至100mg/kg,更一般地每日每千克受体/患者体重0.5至约25mg。典型的局部剂量在如下范围内:适当载体中0.01-5%wt/wt。
化合物以任何适当的单位剂型被方便地给予,包括但不限于每单位剂型包含小于1mg、1mg至3000mg,优选5至500mg活性成分的单位剂型。约25-250mg的口服剂量通常是方便的。
活性成分优选被给予,以实现约0.00001-30mM,优选约0.1-30μM的活性化合物峰值血浆浓度。这可例如通过如下实现:静脉内注射活性成分溶液或制剂——任选地在盐水或含水介质中,或以活性成分大丸剂给予。口服给予也适于生成活性剂的有效血浆浓度。
药物组合物中活性化合物的浓度将取决于药物的吸收、分布、失活和排泄速率以及本领域技术人员已知的其他因素。注意,剂量值还将根据所要缓解的症状的严重程度而不同。要进一步理解,对于任何具体对象,应根据对象需要和给予或监督组合物给予的人士的专业判断随时间调节具体的剂量方案,并且本文描述的浓度范围仅是示例性的,并不意为限制所请求保护的组合物的范围或实践。活性成分可被一次性给予,或可被分成多个较小剂量,从而在不同时间间隔下给予。
口服组合物一般包括惰性稀释剂或可食用载体。其可被封装在明胶胶囊中或压制成片剂。为口服治疗给予,活性化合物或其前药衍生物可掺有赋形剂,并以片剂、锭剂、或胶囊形式应用。药学上相容的粘合剂和/或佐剂物质可被包含作为组合物的部分。
片剂、丸剂、胶囊、锭剂及类似形式可包含任何下列成分或类似性质的化合物:粘合剂,如微晶纤维素、黄蓍胶或明胶;赋形剂,如淀粉或乳糖;分散剂,如海藻酸、羧甲淀粉钠、或玉米淀粉;润滑剂,如硬脂酸镁或Sterotes;助流剂,如胶体二氧化硅;甜味剂,如蔗糖或糖精;或调味剂,如薄荷、水杨酸甲酯、或香橙调味剂。当单位剂型是胶囊时,其除上述类型的物质外还可包含液体载体,如脂肪油。此外,单位剂型可包含修饰单位剂型的物理形式的多种其他物质,例如,糖、虫胶或肠溶剂包衣。
活性化合物或其药学上可接受的盐可作为酏剂、悬浮液、糖浆、糯米纸囊剂、口香糖或类似物的组分被给予。糖浆除活性化合物外还可包含蔗糖作为甜味剂和某些防腐剂、染料和着色剂和调味剂。
活性化合物或其药学上可接受的盐也可与如下混合:不削弱预期作用的其他活性物质,或补充预期作用的物质,如促红细胞生成素刺激剂,包括EPO和达依泊汀α(darbapoietin alfa)等。在本发明的某些优选方面,一种或多种根据本发明所述的化合物与下列共同给予:另一生物活性剂,如促红细胞生成素刺激剂,或伤口愈合剂,包括抗生素,如本文另外描述。
用于胃肠外、皮内、皮下、或局部施用的溶液或悬浮液可包括下列组分:无菌稀释剂,如注射用水、盐水溶液、固定油、聚乙二醇、甘油、丙二醇或其他合成溶剂;抗细菌剂,如苄醇或对羟基苯甲酸甲酯;抗氧化剂,如抗坏血酸或亚硫酸氢钠;螯合剂,如乙二胺四乙酸;缓冲剂,如乙酸盐、柠檬酸盐或磷酸盐;和张度调节剂,如氯化钠或葡萄糖。原制剂(parental preparation)可被封装在安瓿瓶、一次性注射器或由玻璃或塑料制成的多剂量小瓶中。
如果静脉内给予,优选载体是生理盐水或磷酸缓冲剂盐水(PBS)。
在一个实施方式中,用防止化合物从身体快速清除的载体制备活性化合物,如受控释放制剂,包括植入物和微胶囊化递送系统。可使用可生物降解的生物相容性聚合物,如乙烯乙酸乙烯酯、聚酸酐、聚乙醇酸、胶原蛋白、聚原酸酯、和聚乳酸。这种制剂的制备方法对于本领域技术人员而言是显而易见的。
脂质体悬浮液也可以是药学上可接受的载体。这些可根据本领域技术人员已知的方法制备,例如,如美国专利号4,522,811(其全部内容被引入本文作为参考)所述。例如,脂质体制剂可通过如下制备:在无机溶剂中溶解适当的脂质(一种或多种)(如硬脂酰磷脂酰乙醇胺、硬脂酰磷脂酰胆碱、花生酰磷脂酰胆碱(arachadoyl phosphatidyl choline)和胆固醇),然后蒸发该无机溶剂,在容器表面上留下干燥脂质的薄膜。然后将活性化合物的含水溶液引入容器。然后用手旋转容器,以使脂质物质离开容器各侧并分散脂质聚集体,从而形成脂质体悬浮液。
一般合成方法
在此描述ULM衍生物的一般合成方案。简而言之,根据一般溶液相合成方案(下文所示)和/或涉及根据本发明所述的化合物的相合成的一般方案I,合成根据本发明所述的化合物。首先,使羟基保护的羧基取代的(和保护的)吡咯烷化合物与含羧酸反应剂进行反应,该含羧酸反应剂在吡咯烷环的胺处引入羰基基团,形成酰胺基团。可选地,吡咯烷胺可被保护,并且羧酸部分可与右手区段上亲核基团缩合,在吡咯烷部分的右手部分上提供酰胺。将要分别缩合到吡咯烷部分的胺和羧酸基团上的左手和右手区段优选在缩合到吡咯烷基团上前制备,但可采取其他方法在吡咯烷基团上引入基团。组合生成ULM基团的各个组分可利用阻断基团制备,该阻断基团在ULM基团上的优选官能团处,其可被去除从而与连接体基团反应并共价连接连接体基团,该连接体基团被制备以容纳已结合蛋白质结合部分的PTM部分或PTM基团,或可进一步反应以与PTM基团形成共价键,该PTM基团也可包括ULM’基团,如本文另外描述。因此,含羧酸左手区段可被缩合到吡咯啉的胺基团上,从而与下述R1左手区段形成酰胺基团。在羧基上,任意数量的亲核(优选地,含胺)右手区段(预合成的)可被缩合到羧基上,以与下述R2右区段一起提供酰胺基团。将要缩合到吡咯烷的胺和/或羧基部分上的预合成基团的形成以简单的方式进行。实际上,任何化合物均可利用此方法容易地合成。还可应用固相合成方法和利用用于溶液相合成的类似方法,主要区别是羟基可在其他合成步骤进行时结合于固体支撑物。一般合成的方法可用于基本上全部本发明化合物,其中在直接应用时进行符合化学合成领域情况的简单修改,或由下列实例的具体教导进行改动。
方案1根据本发明所述的UML衍生物的溶液相合成
方案2根据本发明所述的化合物的固相合成
在此描述根据本发明所述的VHL配体的固相合成的可选一般方法(其详细内容在第二组实例中显示):
化合物生成的合成方法以筛选本发明的靶蛋白质结合元件(PTM)和泛素化配体部分(ULM)
组合化学中用于识别PTM部分和ULM部分的两个基本方法是固相和溶液相方法。利用这些方法,通过溶液相合成或通过生成共价结合固相颗粒的化合物,生成组合化合物。在鉴定其部分后,可利用适当的基团(亲电子和/或亲核)将其修饰,和将其缩合到连接体基团上,产生根据本发明所述的双功能化合物。
固相方法
固相方法依据Fruchtel等.1996,Angew.Chem.Int.Ed.Engl.35,17-42的教导;其全部内容被引入本文作为参考)。
固相合成更容易实施多步反应和推动反应至完成,因为可添加过量反应剂,然后在各反应步骤后容易洗去反应剂。支持固相合成的另一关键因素是其能够应用1982年创建的分离合成技术。分离合成产生大支撑物结合库——其中每种固相颗粒固定单一化合物,或可溶库——通过从固体支撑物切割化合物产生。例如,在分离合成方法中,如果有3个化合物添加步骤并且每个步骤使用10种化合物,即10个容器用于那些化合物,这将生成103种化合物。而如果考虑合成包括的全部反应步骤,利用三步化学通过固相方法制成的10,000种化合物可仅需要约22容器用于化学和约66个液体处理步骤——相对于10,000个容器和30,000个液体处理步骤。当组合固相合成与分离合成的这些优势时,实现了显著水平的协同。
溶液相方法
由于溶液相合成——大多数合成有机化学技术人员传统使用的技术——可用的有机反应范围较宽,很多人青睐溶液相化学用于库构建,并且溶液中的产物可较容易在标准药物靶分析中被确定和被表征。一次一种分子的溶液相合成的问题是最终纯化,其可能成本高昂且缓慢。层析法通常是首选的方法,因为其通常是有效的。此外,当试图制备数万种化合物以建立库或库`书`时,与溶液化学相关的问题被复合。
在化合物库的建立中,已设计出多种方法,使得大型化学剂库广泛使用,从而容易发现潜在药物候选者。在溶液中游离的化学库的建立一般是大多数制药业的目标。该目标基于多种药物靶的本质和相关分析。而且,化学库的构建和应用一般是容易的,但溶液中化合物的主平板(master plates)生成以形成化学库基础则不容易。因此,固相合成方法的总体优势在当前药物发现工作的环境下一般没有被充分认识。其主要原因是感兴趣之处不在于化合物与药物靶的结合,而是证明药物靶的活性被改变,这一般需要化合物在溶液中游离。与固相上的化合物库有关的进一步顾虑来源于连接体的潜在影响和对于结合于固相的化合物的空间位阻效应的顾虑。
因此,发现结合靶分子的化合物的方法是本领域已知的。而且,对最初发现的化合物的优化是本领域公知的,其中通过如下提高亲和力:通过更具选择性的组合化学方法创建相关化合物库。
本发明提供克服药物和小分子发现中的这些问题的机制。
泛素连接酶结合部分(ULM)的添加
在这点上,在本发明化合物发现途径中,本发明的化合物的靶蛋白质结合元件已被鉴定。然后,根据本申请的公开内容,使这些最佳结合分子进行进一步化学处理,从而添加泛素连接酶结合部分(ULM)。
发现靶蛋白质结合部分的可选方法是基于溶液相筛选。在该实例中,获得化合物(通过合成、天然产物可获得的,或来自公司如ArQule(www.arqule.com),Pharmacopeia(www.pharmacopiea),和Cerep(www.cerep.com),并将其添加至目标靶蛋白质,然后进行尺寸排阻,从而去除未结合化合物。然后使蛋白质结合部分经过GC/MS,以鉴定分子。以这种方式,溶液中化合物的溶液相筛选快速且简单。还有多种另外的方式来鉴定配体结合,包括,例如,在配体结合后检测蛋白质Tm的变化,等等。
靶蛋白质结合元件的筛选
最初,选择靶蛋白质,例如,具体生物学过程涉及的酶或蛋白质。本发明的靶蛋白质来自多个领域,其中小分子用于实现真核生物体的生物学系统的调节。这种领域的实例是抗病毒剂、抗微生物剂、抗寄生虫剂、或人患者体内的其他药物靶标——其可以是相当多样性的,等等。
然后将靶蛋白质从天然来源纯化以提供足够用于筛选的物质,或通过重组方法表达以提供足够用于筛选的物质。
然后将靶蛋白质直接用可检测物种如放射性的、电化学发光和化学发光或荧光标记进行标记,或用间接可检测物种如酶、或颗粒标记。可选地,标记具有靶蛋白质结合活性的抗体或等同形式。
下一步是提供用于筛选的化合物库。1,000至1,000,000的库是典型筛选尺寸。这些可来自一系列本领域公知的公司。这些化合物库用于筛选靶蛋白质结合。理想地,使化合物静止结合固相,或利用下文描述的筛选方法筛选直接结合固定化靶蛋白质的化合物。
还可以按照常规方法创建多种可能结合于固相的结合分子的化学库,从而导致区分可能的化合物。构建化学库的最佳方法是利用与固相结合的分离合成方法(如上所述)。利用一系列固相化学术创建库,从而产生构成库基础的不同汇集体。筛选库形式或汇集体形式的库。一般会从分离合成获得产物,和汇集固相,并将其用作筛选基础。
向用作合成固相的小珠的汇集体添加缓冲剂混合物、清洗剂、盐和阻断剂如血清白蛋白或其他蛋白质。该缓冲剂添加步骤用于阻断小珠或固相,使得不发生所选靶蛋白质的任意显著非特异性结合。在该阻断步骤后,将小珠洗涤,然后添加靶蛋白质——标记或不标记的。然后温育小珠或固相,以允许靶蛋白质结合元件结合于靶蛋白质上。在将靶分子温育至小珠或固相后,洗涤小珠,然后直接检测标记靶蛋白质的结合。以可选的方式,如果靶蛋白质标记有可间接检测的标记如酶,则将小珠置于底物反应溶液中,以检测酶标记的存在。在酶标记的情况下,这些检测方法的底物基于不可溶显色产物。在其中靶蛋白质未被标记并且抗体或等同形式可获得的情况下,使小珠进行另一结合反应,其中抗体或等同形式如对标记靶蛋白质所述被直接或间接标记。在此步骤还可以不使用标记抗体或等同形式,而添加进一步的步骤,其中使用标记抗体或等同形式。这些另外的步骤可利用本领域已知的相同标准方法检测,如关于直接标记的靶蛋白质所述。
在这些步骤后,鉴定一系列小珠,这些小珠选自小珠群,并且经过分析以确定在本实例中能够结合靶蛋白质的结合分子的结构。这通过利用GC/MS或通过前述库构建期间所用的分子标签实现。可选地,重新制成阳性汇集体,生成一系列亚汇集体,用于筛选和进一步重新合成和划分出多种不同汇集化合物,直到单个分析孔中存在单一化合物,允许确定活性化合物。
这种方法可重复进行,和/或适于鉴定实际上任何靶蛋白质的肽靶结合部分(PTM)。
从化学库筛选结合分子
筛选具体分子的步骤在本发明中容易进行,因为仅需要结合活性,而无需传统药物发现中所需的对靶蛋白质的特异性调节。
可购买用于筛选的化合物库。1,000至1,000,000的库是可被筛选的一般尺寸。这些可来自多个公司。这些化合物库用于筛选靶蛋白质的结合。理想地,购买静止结合于固相的化合物,或利用下文描述的筛选方法筛选直接结合固定化靶蛋白质的化合物。
还可以利用如前所述的分离合成方法生成固相上包含1,000至100,000种化合物的库。该库可利用一系列化学方法构建,生成合成期间所用的固相的汇集体,其形成构成库的项目(entries)的基础。此外,在用于构建不同项目的最终化学偶联步骤时,固相汇集体被存储在库中的亚汇集体中。这些所谓项目和亚汇集体形成筛选基础,因为其不仅包含化合物汇集体,而且包含用于合成的已知化学偶联步骤。
然后可利用两种方法筛选库。在两种情况下,将待筛选化学库的固相用分析缓冲剂和如下阻断剂进行温育:如例如,蛋白质(即,BSA、明胶),聚乙烯吡咯烷酮、聚蔗糖、肝素、清洗剂(即,SDS、Tween、NP40、Triton X-100)。此温育步骤阻断用于生成库的固相上的非特异性结合位点,并允许鉴定特异性结合事件。此初步温育是在不同结合分析如ELISA、southerns、westerns等中本领域公知的步骤。在此经阻断剂温育后,然后将目标蛋白质加入缓冲剂,该缓冲剂一般与阻断步骤期间的缓冲剂具有相同的组成,但也可用较低的另外的阻断剂或不用另外的阻断剂改性,清洗剂除外,清洗剂一般总是存在于结合反应期间。
在其中一个筛选方法中,然后使阻断步骤后的项目进行与纯化的靶蛋白质的结合。然后洗涤来自此温育的固相,并使其进行与标记反应剂的第二结合步骤,该标记反应剂结合在受体亚单位表达重组改造期间加入受体亚单位的标签序列。一般,该标签的抗体识别标签序列;常用的实例是myc、flag和his表位。在用标签特异性结合物质温育后,通过标记的存在检测标记的结合物质的存在,该标记一般是酶如碱性磷酸酶或过氧化酶。检测步骤一般利用不可溶显色底物,其容易通过肉眼或通过图像分析系统检测。
在可选的方法中,还可使用和利用ELISA平板阅读器、肉眼或其他分光光度法筛选可溶底物。库的各种项目以其最简形式被通过肉眼筛选,以寻找已由于对显色底物的酶促作用而显色的小珠。这些显色的小珠指示受体亚单位正结合于项目组中的化合物的其中一种,下个步骤是要确定是否这些所谓的阳性项目组包含特异性结合或是否结合只是与标签结合反应剂的结合或显色底物的一些非特异性激活。为将此实现,在不存在与受体亚单位的特异性结合步骤的情况下筛选阳性项目。如果这些阳性项目现变成阴性或就混合物中的阳性固相而言显示显著降低的信号,则这些被认为是筛选中的真阳性项目。这些真阳性项目然后进行重新合成。在此重新合成中,生成特异性结合分子的最初化学步骤是未知的,只有化合物合成中最后的化学偶联步骤是已知的,因为这构成构建项目组的最后化学步骤。在阳性部分(chapter)的重新合成期间,在最后的化学偶联之前的化学步骤如最初合成般进行,但固相不被汇集和分割以用于最终的化学偶联,而是保持独立的汇集体,然后经过对于该部分而言已知的化学偶联步骤。此重新合成导致固相化合物汇集体新系列形成,该固相化合物汇集体新系列的最后两个化学偶联步骤是已知的。该固相化合物汇集体新系列如最初筛选般被筛选,并且如前检测结合特异性来检测阳性汇集体,以确定阳性汇集体。阳性汇集体(一个或多个)现允许通过最后两个化合物生成步骤重新合成汇集体(一种或多种),其特异性结合受体亚单位。然后使阳性汇集体经历相同的如刚才描述的重新合成和筛选循环,但其中最后两个化学偶联步骤是已知的,汇集体在最后的已知步骤前保持独立。以这种方式,化学库中能够结合受体亚单位的特异性化合物的合成被解卷枳(deconvoluted),并且被鉴定。
在可选的方法中,从筛选中去除并收集阳性固相。然后使其进行切割反应——从固相去除特异性化学术,然后利用GC分析不同化学物质以分离各种化合物,然后进行MS以确定分子量。利用该信息加上所用的合成方法确定化合物身份。在确定这些不同候选者特异性结合分子后,将其重新合成并进行结合分析,以检测这些是否是生成阳性固相的特异性化合物。
泛素连接酶结合部分的筛选
此筛选工作,遵循本领域已知的方法和方案,能够鉴定结合泛素连接酶的根据本发明所述的化合物。在此已被鉴定的这些化合物构成本发明的化合物的开发基础。然后基于用于固相化学研发的连接体基团的应用,使这些化合物经历进一步的化学处理。向这种连接体基团添加不同的泛素连接酶结合部分和/或蛋白质结合部分——一般通过缩合反应或其他反应以使配体偶联于泛素连接酶结合部分或蛋白质结合部分。这些反应是本领域公知的。连接体基团衍生化是本领域公知的,并且可由下列组成:在连接体基团——可用于将适当修饰的ULM基团和/或PTM基团缩合到连接体上以生成共价键——的任一端或两端提供亲核基团(例如醇、胺、硫醇基或其他亲核基团)或亲电子基团(例如酯、羧酸、酰卤、卤素等)。此最终化学步骤生成本发明的化合物。然后使本发明的化合物经过分析,确定化学库中用哪种单独泛素连接酶结合部分元件筛选的哪种化合物能够在靶蛋白质的靶向泛素化和/或降解中最有效地发挥作用。可通过下文实例章节中另外描述的方法确定泛素连接酶结合部分。此外,可在哺乳动物组织培养系统中测试本发明的化合物,其中表达完整或作为改造区段的靶蛋白质。在这种哺乳动物组织培养系统中,通过利用可在哺乳动物组织培养测试系统构建期间被设计到靶蛋白质重组表达中的标签序列,确定化合物对靶蛋白质水平的影响。在用如上所述筛选和合成的可能化合物温育期间,利用标签序列确定靶蛋白质水平。标签序列分析可例如采用蛋白质印迹(western blot)的形式或通过ELISA进行。其他值得采用的标签是基于绿色荧光蛋白质的那些,其能够分析活细胞和/或生物体中的蛋白质水平。
然后测试系统中显示最佳活性的化合物构成药物研发下个阶段的基础。在此下个阶段中,这些选定的化合物经过已知的药物研发路径。通过评价一系列因素,包括生物利用度;毒理学、药理学和动物模型中的效力,药物研发路径确定化合物的潜力值,然后将化合物考虑用于人测试。
蛋白质水平控制
本发明还涉及用细胞控制蛋白质水平的方法。这是基于本发明化合物的应用,已知本发明化合物与特异性靶蛋白质相互作用,使得靶蛋白质体内降解将导致对生物学系统中蛋白质量的控制,优选关于具体治疗效益。
下列实施例用于协助描述本发明,但不应以任何方式被视为限制本发明。
实施例
第一组
发明人最初假设可利用羟脯氨酸(Hyp)作为起点合理地设计VHL/HIF-1α相互作用的小分子抑制剂,因为HIF-1α上的残基Hyp564产生与VHL14关键的相互作用,并且对于HIF-1α结合15非常重要。发明人利用重新(de-novo)设计软件BOMB,以指导似乎合理的羟脯氨酸类似物的选择16。合成1和2以测试有希望的设计——特征在于异唑部分被布置以与结合于HIF肽(549-582)14的VHL的结构中观察到的结晶水和沿Tyr98的侧链堆叠的苄基相互作用。利用荧光极化(FP)的荧光HIF-1α肽竞争17测量其结合VHL的能力。虽然以高浓度(表1A),两者均能替代荧光肽。虽然较小的3不能完全替代荧光肽,但通过利用WaterLOGSY和饱和转移差异(STD)NMR观察到与VHL的结合。由于未观察到与单独羟脯氨酸的结合,这表明发明人鉴定到了最小的药效团(参见图2)。
a通过三个独立试验确定平均IC50值,每个重复三次。
得到这些最初结果的鼓励,发明人试图通过修饰1的苄基胺部分同时保持甲基-异唑区段来增加我们的VHL配体的亲和力。为迅速生成类似物,研发了固相合成,其包括连接Fmoc-Hyp-OAllyl于Wang树脂。18Fmoc去保护,与3-甲基-5-异/>唑乙酸偶联,然后烯丙基酯去保护和与不同胺偶联,随后用三氟乙酸切割,导致VHL配体快速生成(方案1)。19,20然后利用HIF肽FP移位分析测试这些配体结合VHL的能力。
不同卤化苄基胺的掺入显示,对位取代产生最高亲和力,并且氯基和溴基的亲和力之间仅存在略微区别,虽然相应的氟基不太有效。还发现,吸电子基团如酯、硝基、腈、和酮的取代导致比供电子甲氧基和叔丁基取代基取代更有效的配体。分子动力学模拟表明,Arg107具有灵活性,并且可以在对位容纳较大基团。因此,我们在苄基胺部分的对位考虑较大杂环取代基,并合成15,发现其以4.1μMIC50值结合(下文表2)。
荧光极化分析
通过如文献(Buckley等.JACS,2012,134,4465-4468)所述的荧光极化竞争分析,确定VHL配体竞争VCB上的HIF1α结合位点的能力。
表2亲和力表——大多数化合物显示约200微摩尔或更低的范围内的活性
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合成方法
一般化学术
所有反应在烘箱干燥的或火焰干燥的配备橡胶隔垫的玻璃器皿中在氮气正压下进行,除非另外注明。将空气和湿度敏感的液体通过注射器或导管转移。从钠/二苯甲酮中蒸馏THF。从氢化钙中蒸馏二氯甲烷。利用预涂覆有硅胶(0.25mm)的玻璃板进行分析薄层层析法(TLC)。通过暴露于UV光(UV)或KMnO4可视化TLC板。利用硅胶60(230-400目,Merck)和所示溶剂进行快速柱层析法。
在Bruker Avance DPX-500或Bruker Avance DPX-400NMR光谱仪上记录1H和13C谱图。1H NMR谱图显示如下:化学位移、多重性(s=单重,d=双重,t=三重,q=四重,m=多重,br=宽)、积分、和偶合常数(J),以赫兹(Hz)表示。相对于CDCl3(7.26ppm)、d6-DMSO(2.50ppm)和d4-MeOD(3.31ppm),报告1H NMR化学位移。相对于CDCl3(77.16ppm)、d6-DMSO(39.52ppm)和d4-MeOD(49.00ppm)的中线,记录13C NMR。在大多数情况下,仅报告主要旋转异构体的峰。利用Perkin-Elmer API 150EX光谱仪获得质谱。纯化样品的MALDI-TOF分析利用氰基-4-羟基肉桂酸基质、在Voyager-DE-PRO 6268(Applied Bio系统)中进行。除非另外注明,HPLC利用如下进行:Dynamax SD200溶剂递送系统,连接于Dynamax UV-1吸光度检测器——具有YMC-Pack ODS-AM制备柱(250×20mm,5μm颗粒尺寸、12nm孔尺寸)。20%至100%MeCN的H2O中MeCN的线性梯度——具有恒定0.1% TFA,运行超过40分钟。
化学合成的一般方法
提供下列八种(8)一般化学合成方法(下文描述的方法A至F和固相合成A和B),用于合成上文表2亲和力表显示的多种根据本发明所述的化合物。各方法参考具体化合物显示,其合成细节在上文显示。所有编号化合物可利用下文描述的直接方法相对容易地合成。在某些实例中,提供某些优选实施方式的较多合成细节,从而显示信息,使得其可充当合成本文另外公开的多种其他化合物的模板。
A
作为实例,参见下文描述的表II的化合物VL133的合成。
B
参见具有羟基保护的表II的VL116的一般合成。
C
参见下文描述的表II的化合物VL156的一般合成。
D
参见下文描述的表II的化合物VL 217的一般合成。
E
参见下文描述的表II的VL 219的一般合成。
F
方法F包括方法C、D和E,并且是通过可购买的胺进行的一般方法。
在上述和前述一般合成方法后,通过类似方法合成下列化合物。
(2S,4R)-1-((9H-芴-9-基)甲基)2-烯丙基4-(叔丁氧基)吡咯烷-1,2-二羧酸酯
(Fmoc-Hyp(OtBu)-O烯丙基)
将Fmoc-Hyp(OtBu)OH(24.9g,60.8mmol,1eq)在室温下溶解于DMF(300mL)中。添加碳酸氢钠(12.8g,152mmol,2.5eq),然后烯丙基溴(25.3mL,300mmol,4.9eq)。将溶液装配空气冷凝器,并加热至50℃20小时。然后将其冷却至室温,用EtOAc稀释,用含水1M HCl、饱和碳酸氢钠、水和盐水洗涤。将有机层用硫酸钠干燥,过滤和浓缩。15通过柱层析(15至33%EtOAc/己烷)纯化提供Fmoc-Hyp(OtBu)O烯丙基(23.42g,52.1mmol,86%),淡黄色油。1HNMR(500MHz,CDCl3)δ7.76(t,J=6.3Hz,2H),7.63-7.54(m,2H),7.43-7.37(m,2H),7.31(t,J=7.0Hz,2H),5.99-5.79(m,1H),5.39-5.18(m,2H),4.66(d,J=5.6Hz,1H),4.63-4.13(m,6H),3.81(ddd,J=16.6,10.7,6.2Hz,1H),3.48-3.33(m,1H),2.31-2.18(m,1H),2.18-2.08(m,1H),1.21(d,J=11.6Hz,9H)。13C NMR(126MHz,CDCl3)(旋转异构体混合物)δ172.49,155.01,154.49,144.31,144.18,144.06,143.84,141.44,141.41,141.36,131.91,131.74,127.80,127.76,127.20,127.16,125.31,125.28,125.11,120.08,120.05,118.93,118.61,74.29,69.37,68.48,67.73,65.86,58.09,57.79,54.01,53.52,47.40,47.28,38.90,37.87,28.41,28.37。MS(ESI)450.5(M+H)。
(2S,4R)-1-((9H-芴-9-基)甲基)2-烯丙基4-羟基吡咯烷-1,2-二羧酸酯
(Fmoc-Hyp(OH)-O烯丙基)
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将Fmoc-Hyp(OtBu)-O烯丙基(23.42g,52.1mmol)在室温下溶解于DCM(306mL)中。添加TFA(54mL、15%vol/vol),并将溶液搅拌13小时。将溶液倒入水中,通过缓慢添加饱和含水碳酸氢钠中和,并用DCM萃取两次和用EtOAc萃取一次。将组合有机层用硫酸钠干燥,过滤和浓缩。通过柱层析(30至80% EtOAc/己烷)纯化提供Fmoc-Hyp(OH)-O烯丙基,为微黄油(16.7g,42.4mmol,81%)。1H和13C NMR谱图符合文献报告的那些。16
Fmoc-Hyp(OWang)-O烯丙基
将Wang树脂(12.1g,1.1mmol/g负载,13.3mmol,1eq)在玻璃反应容器中用DCM(90mL)溶胀,并冷却至4℃。添加三氯乙腈(20mL,200mmol,15eq),然后经3分钟以3部分添加DBU(3mL,20mmol,1.5eq),在各添加之间手动振荡反应容器。使反应容器在4℃下摇摆1小时,然后在室温下用DCM,DMSO,THF洗涤,然后用DCM洗涤两次。17然后添加Fmoc-Hyp(OH)-O烯丙基(26.15g,66.5mmol,5eq)的DCM(40mL)和THF(40mL)溶液,并振荡30分钟,然后用DCM洗涤两次,用DCM洗涤三次,然后用MeOH然后DCM洗涤两次。浓缩最初的DCM洗涤液,并柱层析(33%至80% EtOAc)纯化,以回收Fmoc-Hyp(OH)-O烯丙基原料(21.51g,54.67mmol,82%)。将树脂在空气中干燥,然后在真空下干燥,提供15.5g的Fmoc-Hyp(OWang)-O烯丙基。18基于质量的增加来估测树脂的负载为0.53mmol/g。
固相合成一般方法A
将Fmoc-Hyp(OWang)-O烯丙基树脂(1eq)在DMF中溶胀,然后与20%哌啶在DMF中反应30分钟。然后将树脂用哌啶洗涤一次,和与20%哌啶再次反应30分钟,以确保完全去保护。然后将树脂用DMF洗涤两次和用MeOH然后DCM洗涤一次。然后将所得游离胺与3-甲基-5-异唑乙酸(4eq)、PyBOP(4eq)HOBt(4eq)和DIPEA(7eq)在DMF中偶联4小时。然后将树脂用DMF洗涤三次和用MeOH然后DCM洗涤两次。然后将树脂用新蒸馏的DCM溶胀,和与Pd(PPh3)4(0.1eq)和PhSiH3(10eq)反应30分钟。然后将树脂用DCM洗涤一次,并再次与Pd(PPh3)4(0.1eq)和PhSiH3(10eq)在蒸馏的DCM中反应30分钟,然后将树脂用DMF洗涤两次和用MeOH然后DCM洗涤一次。然后将所得羧酸与适当的胺(或适当胺的盐)、RNH2(4eq)和PyBOP(4eq)、HOBt(4eq)和DIPEA(游离胺7eq,胺盐8eq)在DMF中偶联4小时。然后将树脂用DMF洗涤五次,用MeOH洗涤三次和用DCM洗涤五次。然后将树脂与20% TFA在DCM中反应2小时。然后沥干反应混合物,并用DCM洗涤树脂。减压下浓缩和通过柱层析(在MeOH/DCM中1%至10%0.5MNH3或在DCM中1%至10% MeOH)纯化提供预期的VHL配体。
固相合成一般方法B
简而言之,将Fmoc-Hyp-(OWang)-O烯丙基树脂(1eq)用新蒸馏的DCM溶胀,和与Pd(PPh3)4(0.1eq)和PhSiH3(10eq)反应30分钟。然后将树脂用DCM洗涤一次,并再次与Pd(PPh3)4(0.1eq)和PhSiH3(10eq)在蒸馏的DCM中反应30分钟,然后将树脂用DMF洗涤两次和用MeOH然后DCM洗涤一次。然后将所得羧酸与4-氯苄基胺(4eq)、PyBOP(4eq)、HOBt(4eq)和DIPEA(7eq)在DMF中偶联4小时。然后将树脂与20%哌啶在DMF中反应30分钟。然后将树脂用DMF洗涤一次,并再次与20%哌啶反应30分钟,以确保完全去保护。然后将树脂与适当的羧酸(RCO2H、4eq)、PyBOP(4eq)、HOBt(4eq)和DIPEA(7eq)在DMF中偶联4小时。然后将树脂用DMF洗涤4次和用甲醇然后DCM洗涤两次。然后将树脂与20%TFA在DCM中反应2小时。然后沥干反应混合物,并用DCM洗涤树脂。减压下进行浓缩和通过柱层析(在MeOH/DCM中1%至10%0.5M NH3或在DCM中1%至10% MeOH)纯化提供预期的VHL配体。产率基于树脂负载,树脂负载基于其质量变化来估测。
叔丁基4-(甲氧基(甲基)氨甲酰基)苄基氨基甲酸酯(Boc-Amb-N(OMe)Me)
将Boc-Amb-OH(2.55g,10.16mmol,1eq)溶解于DCM(68mL)中,并在冰浴中冷却至4℃。添加EDC(2.34g,12.2mmol,1.2eq)、HOBt(1.65g,12.2mmol,1.2eq)和DIPEA(6.2mL,35.6mmol,3.5eq)。将溶液搅拌30分钟,然后添加盐酸N,O-二甲基羟基胺(1.09g,11.2mmol,1.1eq)。将溶液缓慢升温至室温,并在21小时后倒入盐水中——与少量氯仿一起,从而破坏所得乳液。分离后,用EtOAc萃取水层两次。将组合的有机层在硫酸钠上干燥,过滤和浓缩。通过柱层析(40至75% EtOAc/己烷)纯化提供无色油(2.45g,8.33mmol,82%)。1H NMR(500MHz,CDCl3)δ7.65(d,J=8.2Hz,2H),7.31(d,J=8.1Hz,2H),4.88(s,1H),4.36(d,J=5.1Hz,2H),3.55(s,3H),3.35(d,J=4.7Hz,3H),1.47(s,9H)。13C NMR(126MHz,CDCl3)δ169.77,156.04,141.79,133.21,128.76,127.03,79.87,61.20,44.50,33.88,28.55。MS(ESI)295.2(M+H)。
叔丁基4-甲酰基苄基氨基甲酸酯(Boc-Amb-H)
将Boc-Amb-N(OMe)Me(2.45g,8.33mmol,1eq)溶解于THF(83mL)中,并在干冰/丙酮浴中冷却至-78℃。经5分钟以2部分添加氢化铝锂(0.41g,10.83mmol,1.3eq)。50分钟后,使悬浮液在冰浴中升温至4℃。3.5小时后,通过TLC(在10%硫酸氢钾和EtOAc,50% EtOAc/己烷中微型检查(mini workup))认定反应完全,并通过在4℃下缓慢添加10%硫酸氢钾淬灭反应。将混合物升温至室温,并搅拌30分钟。在减压下去除大部分THF,并将混合物用水稀释和用EtOAc萃取三次。将组合的有机层用盐水洗涤一次,在硫酸钠上干燥,过滤和浓缩。通过柱层析(40至50% EtOAc/己烷)纯化提供Boc-Amb-H,为白色固体(1.66g,7.1mmol,85%)。1H NMR(500MHz,CDCl3)δ9.96(s,1H),7.81(d,J=8.2Hz,2H),7.41(d,J=8.0Hz,2H),5.12(s,1H),4.37(d,J=5.6Hz,2H),1.44(s,9H)。13C NMR(126MHz,CDCl3)δ191.94,156.03,146.30,135.62,130.14,127.78,79.92,44.44,28.46。MS(ESI)235.9(M+H),180.2(M-tBu)。
叔丁基4-(唑-5-基)苄基氨基甲酸酯
在室温下将碳酸钾(0.13g,0.94mmol,1.2eq)和甲苯磺酰基甲基异腈(0.184g,0.94mmol,1.2eq)添加至MeOH(7.8mL)。将圆底烧瓶装配回流冷凝器并加热至45℃。15分钟后,添加Boc-Amb-H(0.1835g,0.78mmol,1eq),并将混合物加热至75℃3小时,然后冷却至室温。在减压下去除MeOH,并将粗料重新悬浮在EtOAc和饱和碳酸钠与水的1:2混合物中,并分离。然后用EtOAc萃取水层一次。将组合的有机层在硫酸钠上干燥,过滤和浓缩。通过柱层析(20至35% EtOAc/己烷)纯化提供白色固体。1H NMR(400MHz,CDCl3)δ7.91(s,1H),7.62(d,J=8.3Hz,2H),7.35(ob d,2H),7.34(ob s,1),4.88(s,1H),1.47(s,9H)。13C NMR(126MHz,CDCl3)δ156.02,151.40,150.47,139.78,128.01,126.84,124.67,121.47,79.68,44.38,28.47。MS(ESI)275.5(M+H)。
(4-(唑-5-基)苯基)甲胺三氟乙酸盐
在室温下向叔丁基4-(唑-5-基)苄基氨基甲酸酯(1.09g)的DCM(40mL)溶液添加TFA(4mL)。将溶液搅拌16小时并在减压下浓缩,以生成(4-(/>唑-5-基)苯基)甲胺的三氟乙酸盐(1.984g),为乳白色固体,其不经进一步纯化进行使用。1HNMR(400MHz,MeOD)δ8.29(s,1H),7.83(d,J=8.4Hz,2H),7.60(s,1H),7.56(d,J=8.5Hz,2H),4.16(s,2H)。MS(ESI)175.3(M-CF3CO2 -)。
(2S,4R)-N-(3-氯苄基)-4-羟基-1-(2-(3-甲基异唑-5-基)乙酰基)吡咯烷-2-羧酰胺(VL4)/>
根据一般方法F合成VL4,为白色固体。1H NMR(500MHz,MeOD):δ8.684(1H,s);7.33-7.23(4H,m);6.24(1H,s);4.56-4.53(1H,t,J=8Hz);4.51-4.50(1H,m);4.39-4.37(2H,m);3.96-3.92(2H,m);3.81-3.3.78(1H,dd,J=9Hz,4Hz);3.64-3.62(1H,m);2.28-2.24(4H,m);2.09-2.04(1H,m).13C NMR(125MHz,MeOD):δ174.56,168.67,167.68,161.58,142.25,135.35,131.04,128.43,128.19,126.76,105.37,70.86,60.78,56.96,43.60,39.33,33.90,11.21。MS(ESI)378.2(M+H)。
(2S,4R)-4-羟基-N-(4-羟基苯乙基)-1-(2-(3-甲基异唑-5-基)乙酰基)吡咯烷-2-羧酰胺(VL2)
根据一般方法F合成VL2。1H NMR(500MHz,MeOD)d 8.33&8.13(由于旋转异构体,两者s,1H),7.02(d,J=8.3Hz,2H),6.69&6.65(由于旋转异构体,两者d,J=8.3Hz,2H),6.22&6.10(由于旋转异构体,两者s,1H),4.43(d,J=7.7Hz,2H),3.89(d,J=4.7Hz,2H),3.74(dd,J=11.0,4.3Hz,1H),3.57(d,J=11.0Hz,1H),3.42-3.36(m,2H),2.73-2.63(m,2H),2.25(s,3H),2.16-2.12(m,1H),1.96-1.91(m,1H)。13C NMR(星号表示次要旋转异构体的信号,125MHz,MeOD)d 174.2,174.1,*173.9,*173.8,*169.0,168.6,167.6,*167.4,161.6,*161.5,*157.0,156.9,*131.2,130.8,*116.2,116.1,*105.6,105.4,70.7,*69.2,*61.0,*60.9,60.7,60.6,56.9,*56.2,42.4,42.3,*42.0,*41.9,41.5,39.3,35.5,*35.3,33.9,*32.9,11.2。MS(ESI)[M+H]374.1,[2M+Na]769.6。
(2S,4R)-4-羟基-N-甲基-1-(2-(3-甲基异唑-5-基)乙酰基)吡咯烷-2-羧酰胺(VL26)
根据一般方法F合成VL26,并将其分离,为无色油(28mg,0.105mmol,80%)。1H NMR(500MHz,MeOD)δ6.23(s,1H),4.47(dt,J=16.3,5.2Hz,2H),3.91(d,J=5.7Hz,2H),3.78(dd,J=10.9,4.2Hz,1H),3.61(dd,J=11.0,1.8Hz,1H),2.73(s,3H),2.26-2.18(m,4H),2.05(dd,J=8.3,4.7Hz,1H)。13C NMR(126MHz,MeOD)δ174.82,168.66,167.67,161.58,105.40,70.79,60.67,56.91,39.30,33.89,26.35,11.20。MS(ESI)291.1(M+Na),268.7(M+H)。
VL34
根据固相合成一般方法A由Fmoc-Hyp(OWang)-O烯丙基(0.3mmol)合成VL34。将其分离,为白色固体(14.7mg)。1H NMR(400MHz,MeOD)δ7.31(dd,J=5.9,5.1Hz,4H),7.27-7.17(m,1H),6.23(s,1H),4.55(t,J=8.0Hz,1H),4.50(s,1H),4.39(s,2H),3.92(d,J=1.8Hz,2H),3.80(dd,J=10.9,4.3Hz,1H),3.61(dd,J=7.3,5.5Hz,1H),2.33-2.19(m,4H),2.12-2.03(m,1H)。13CNMR(101MHz,MeOD)δ174.29,168.68,167.68,161.60,139.73,129.51,128.40,128.14,105.36,70.84,60.73,56.97,44.05,39.36,33.95,11.21.MS(ESI)344.3(M+H),366.2(M+Na)。
VL28
根据固相合成一般方法A由Fmoc-Hyp(OWang)-O烯丙基(0.3mmol)合成VL28。将其分离,为黄色固体(19.1mg)。1H NMR(500MHz,MeOD)δ8.66(t,J=5.5Hz,1H),7.48-7.34(m,2H),7.31-7.21(m,2H),6.23(s,1H),4.58(t,J=8.0Hz,1H),4.48(qd,J=15.8,5.9Hz,3H),3.99-3.87(m,2H),3.80(dd,J=10.9,4.3Hz,1H),3.66-3.60(m,1H),2.31-2.22(m,4H),2.09(ddd,J=13.0,8.2,4.7Hz,1H)。13C NMR(126MHz,MeOD)δ174.60,168.72,167.65,161.59,136.79,134.01,130.29,130.08,129.67,128.21,105.37,70.84,60.74,56.96,42.08,39.34,33.95,11.22。MS(ESI)378.3(M+H)。
VL21
利用固相合成一般方法A由Fmoc-Hyp(OWang)-O烯丙基(0.2mmol)合成VL21。将其分离,为白色固体(15.9mg)。1H NMR(500MHz,MeOD)δ8.65(s,1H),7.32-7.26(m,4H),6.22(s,1H),4.58-4.47(m,2H),4.43-4.32(m,2H),3.92(d,J=4.2Hz,2H),3.80(dd,J=10.9,4.3Hz,1H),3.66-3.58(m,1H),2.30-2.22(m,4H),2.08(dd,J=8.3,4.7Hz,1H)。13C NMR(126MHz,MeOD)δ174.48,168.71,167.66,161.60,138.67,133.85,129.99,129.53,105.37,70.85,60.80,56.99,43.45,39.33,33.95,11.20。MS(ESI)378.4(M+H)。
VL20
利用固相合成一般方法A由Fmoc-Hyp(OWang)-O烯丙基(0.15mmol)合成VL20。将其分离,为白色固体(9.9mg)。1H NMR(400MHz,MeOD)δ8.64(t,J=5.6Hz,1H),7.37-7.26(m,2H),7.07-6.99(m,2H),6.23(s,1H),4.57-4.47(m,2H),4.37(dd,J=8.4,5.8Hz,2H),3.93(d,J=3.0Hz,2H),3.80(dd,J=11.0,4.2Hz,1H),3.66-3.58(m,1H),2.28-2.22(m,4H),2.08(dd,J=8.3,4.7Hz,1H)。13C NMR(126MHz,MeOD)δ174.31,168.69,167.67,163.44(d,J=243.5Hz),161.60,135.78,130.27(d,J=8.1Hz),116.09(d,J=21.6Hz),105.37,70.85,60.75,56.99,43.32,39.33,33.95,11.20。MS(ESI)362.3(M+H)。
VL29
根据固相合成一般方法A由Fmoc-Hyp(OWang)-O烯丙基(0.3mmol)合成VL29。将其分离,为淡黄色固体(16.4mg)。1H NMR(400MHz,MeOD)δ7.45(dq,J=9.0,2.2Hz,2H),7.23(d,J=8.5Hz,2H),6.22(s,1H),4.58-4.47(m,2H),4.35(dt,J=18.9,15.4Hz,2H),3.92(d,J=2.6Hz,2H),3.80(dd,J=10.9,4.2Hz,1H),3.63(d,J=11.0Hz,1H),2.30-2.21(m,4H),2.11-2.02(m,1H)。13CNMR(101MHz,MeOD)δ174.41,168.71,167.66,161.61,139.15,132.55,130.32,121.77,105.37,70.85,60.75,56.99,43.37,39.33,33.94,11.22。MS(ESI)424.1(M+H)。
VL31
根据固相合成一般方法A由Fmoc-Hyp(OWang)-O烯丙基(0.3mmol)合成VL31。将其分离,为白色固体(19.8mg)。1H NMR(500MHz,MeOD)δ8.56(s,1H),7.35(d,J=8.2Hz,2H),7.22(d,J=8.2Hz,2H),6.24(s,1H),4.53(dd,J=18.3,10.3Hz,2H),4.36(d,J=5.7Hz,2H),3.92(d,J=3.0Hz,2H),3.80(dd,J=10.9,4.2Hz,1H),3.62(d,J=11.1Hz,1H),2.29-2.21(m,4H),2.12-2.02(m,1H),1.29(d,J=7.9Hz,9H)。13C NMR(126MHz,MeOD)δ174.29,168.67,167.68,161.59,151.18,136.67,128.19,126.39,105.38,70.83,60.77,56.97,43.88,39.37,35.28,33.95,31.79,31.74,11.23。MS(ESI)400.5(M+H)。
VL47
根据固相合成一般方法A由Fmoc-Hyp(OWang)-O烯丙基(0.156mmol)合成VL47。将其分离,为白色固体(9.1mg)。1H NMR(500MHz,MeOD)δ7.22(dd,J=8.4,3.9Hz,2H),6.86(dd,J=8.8,2.2Hz,2H),6.22(s,1H),4.63-4.45(m,2H),4.37-4.26(m,2H),3.92(d,J=2.6Hz,2H),3.83-3.70(m,4H),3.61(d,J=11.2Hz,1H),2.28-2.20(m,4H),2.06(ddd,J=13.0,8.1,4.7Hz,1H)。13CNMR(126MHz,MeOD)δ174.13,168.66,167.68,161.60,160.39,131.67,129.76,114.89,105.37,70.83,60.74,56.97,55.67,43.57,39.34,33.95,11.21。MS(ESI)374.5(M+H)。
VL35
根据固相合成一般方法A由Fmoc-Hyp(OWang)-O烯丙基(0.156mmol)合成VL35。将其分离,为白色固体(14.1mg)。1H NMR(500MHz,DMSO)δ7.90-7.85(m,2H),7.39(d,J=8.4Hz,2H),6.23(s,1H),5.17(s,1H),4.37(dd,J=17.9,10.4Hz,4H),3.88(s,2H),3.84(s,3H),3.70(dd,J=10.5,4.6Hz,1H),3.47(dd,J=10.4,2.5Hz,1H),2.20(d,J=10.2Hz,3H),2.11-2.03(m,1H),1.92(ddd,J=12.5,7.2,4.9Hz,1H)。13C NMR(126MHz,DMSO)δ171.66,166.66,166.10,165.66,159.35,145.22,129.08,127.99,127.06,103.94,68.62,58.76,55.20,52.02,41.49,38.17,32.73,10.95.MS(ESI)402.6(M+H)。
VL48
根据固相合成一般方法A由Fmoc-Hyp(OWang)-O烯丙基(0.156mmol)合成VL48。将其分离,为白色固体(11.4mg)。1H NMR(400MHz,MeOD)δ8.28-8.05(m,2H),7.55(d,J=8.8Hz,2H),6.23(s,1H),4.64-4.36(m,4H),3.94(d,J=3.8Hz,2H),3.81(dd,J=10.9,4.2Hz,1H),3.65(dt,J=11.0,1.7Hz,1H),2.34-2.21(m,4H),2.09(td,J=8.5,4.2Hz,1H)。13CNMR(101MHz,MeOD)δ174.70,168.79,167.65,161.63,148.48,147.72,129.13,124.56,105.40,70.88,60.79,57.03,43.41,39.32,33.94,11.20。MS(ESI)389.3(M+H),411.4(M+Na)。
VL88
根据固相合成一般方法A由Fmoc-Hyp(OWang)-O烯丙基(0.156mmol)合成VL88。将其分离,为清澈油(8.0mg)。1H NMR(500MHz,MeOD)δ8.77(s,1H),7.58(dd,J=88.0,8.1Hz,4H),6.23(d,J=4.4Hz,1H),4.61-4.33(m,4H),3.93(d,J=9.7Hz,2H),3.83-3.74(m,1H),3.63(dd,J=10.4,9.0Hz,1H),2.33-2.27(m,1H),2.26(d,J=3.7Hz,3H),2.15-2.03(m,1H)。13C NMR(126MHz,MeOD)δ175.33,168.76,167.64,161.61,145.83,133.39,129.12,119.74,111.79,105.28,70.87,70.87,59.32,57.02,43.61,38.79,33.94,11.21,11.19。MS(ESI)391.2(M+Na)。
VL95
根据固相合成一般方法A由Fmoc-Hyp(OWang)-O烯丙基(0.156mmol)合成VL95。将其分离,为白色固体(23mg)。1H NMR(400MHz,MeOD)δ8.71(s,1H),7.96-7.91(m,2H),7.43(d,J=8.5Hz,2H),6.22(s,1H),4.56(t,J=8.0Hz,1H),4.49(ddd,J=18.6,8.6,4.1Hz,3H),3.91(s,2H),3.80(dd,J=10.9,4.2Hz,1H),3.65-3.58(m,1H),2.58(d,J=1.6Hz,3H),2.28-2.22(m,4H),2.10(dd,J=8.3,4.7Hz,1H)。13C NMR(101MHz,MeOD)δ200.08,174.34,168.43,167.36,161.39,145.50,136.96,129.62,128.28,105.26,70.65,60.57,56.83,43.72,39.14,33.87,26.73,11.30。MS(ESI)386.0(M+H)。
VL111
根据固相合成一般方法A由Fmoc-Hyp(OWang)-O烯丙基(0.2mmol)合成VL111。将其分离,为白色固体(18.2mg)。1H NMR(500MHz,MeOD)δ8.23(s,1H),7.68(d,J=8.1Hz,2H),7.49(s,1H),7.41(d,J=8.1Hz,2H),6.23(s,1H),4.59-4.37(m,4H),3.93(d,J=3.4Hz,2H),3.81(dd,J=10.9,4.1Hz,1H),3.63(d,J=11.0Hz,1H),2.32-2.17(m,4H),2.09(ddd,J=13.0,8.0,4.6Hz,1H)。13C NMR(126MHz,MeOD)δ174.43,168.72,167.67,161.60,153.14,152.75,140.78,129.06,127.74,125.61,121.81,105.37,70.86,60.78,57.00,43.72,39.35,33.96,11.20。MS(ESI)411.3(M+H)。
VL116右手区段(代表性方法B合成)
2-(三甲基甲硅烷基)乙基4-溴苄基氨基甲酸酯
将盐酸4-溴苄基胺(354mg,1.59mmol,1eq)溶解于DMF(6.4mL)和水(2.1mL)中,并在室温下搅拌。然后添加三乙胺(0.33mL,2.39mmol,1.5eq)和TeocOSu(454mg,1.75mmol,1.1eq)。12小时后,将混合物用EtOAc稀释,用1M HCl、饱和碳酸氢钠、水和盐水洗涤。然后将有机层在硫酸钠上干燥,过滤,并在减压下浓缩。通过柱层析(10至20% EtOAc/己烷)纯化提供无色油(0.4158g,1.26mmol,79%)。1H NMR(500MHz,CDCl3)δ7.48-7.43(m,2H),7.17(d,J=8.1Hz,2H),4.94(s,1H),4.31(d,J=6.0Hz,2H),4.23-4.15(m,2H),1.04-0.93(m,2H),0.04(s,9H)。13C NMR(126MHz,CDCl3)δ156.91,137.95,131.88,129.32,121.43,63.53,44.53,17.92,-1.32。MS(ESI)354.1(M+H)。
2-(三甲基甲硅烷基)乙基4-(4-甲基噻唑-5-基)苄基氨基甲酸酯
将2-(三甲基甲硅烷基)乙基4-溴苄基氨基甲酸酯(132mg,0.4mmol,1eq)、4-甲基噻唑-5-羧酸(114.5mg,0.8mmol,2eq)、四丁基氯化铵水合物(118mg,0.4mmol,1eq)、碳酸铯(196mg,0.6mmol,1.5eq)和Pd(P(tBu)3)2(40.8mg,0.08mmol,0.2eq)溶解于DMF(4mL)中。1在微波反应器中将反应加热至170℃16分钟。然后将混合物冷却至室温,用EtOAc稀释和用盐水洗涤三次,用饱和碳酸氢钠、水然后盐水洗涤一次。将有机层在硫酸钠上干燥,过滤并在减压下浓缩。通过柱层析(10至35% EtOAc/己烷)纯化提供无色油(61.7mg,0.177mmol,44%)。1H NMR(400MHz,CDCl3)δ8.67(s,1H),7.43-7.37(m,2H),7.34(d,J=8.1Hz,2H),5.09(s,1H),4.39(d,J=6.0Hz,2H),4.28-4.02(m,2H),2.52(s,3H),1.10-0.90(m,2H),0.14--0.09(m,9H)。13C NMR(101MHz,CDCl3)δ156.98,150.42,148.66,138.76,131.67,131.18,129.66,127.89,63.46,44.71,17.90,16.18,-1.34。MS(ESI)349.0(M+H)。
(4-(4-甲基噻唑-5-基)苯基)甲胺
将2-(三甲基甲硅烷基)乙基4-(4-甲基噻唑-5-基)苄基氨基甲酸酯(51.8mg,0.149mmol,1eq)在室温下溶解在乙腈(6mL)中。添加四丁基氟化铵在THF(0.45mL,0.45mmol,3eq)中的1摩尔溶液,并将溶液搅拌24小时。在减压下浓缩混合物。通过柱层析(0.5至4%0.5N NH3(MeOH)/DCM)纯化提供淡黄色油(27.2mg,0.133mmol,89%)。1H NMR(500MHz,MeOD)δ8.87(s,1H),7.44(s,4H),3.85(s,2H),2.47(s,3H)。13C NMR(126MHz,MeOD)δ152.77,149.07,143.63,133.42,131.46,130.49,129.05,46.23,15.79。MS(ESI)205.0(M+H)。
替代途径:
4-溴苄腈(5.1g,28mmol,1eq)、4-甲基噻唑(5.56g,56mmol,2eq)、乙酸钾(5.5g,56mmol,2eq)、乙酸钯(II)(63mg,0.28mmol,1mol%)溶解于二甲基乙酰胺中,并在氩气下搅拌。(CITE JOC,2009,74,1179)将混合物加热至150℃并搅拌19小时,然后用500mL EtOAc稀释,和用300mL水洗涤四次。然后将第一洗涤液用300mL EtOAc反萃取,然后用100mL水洗涤四次。将组合的有机层在硫酸钠上干燥,过滤和在真空下浓缩,以提供米色固体(5.55g,27.7mmol,99%),其符合报告的谱图数据。[8]然后将固体溶解于MeOH(280mL)中,并冷却至4℃。添加氯化钴(9.9g,41.6mmol,1.5eq),然后缓慢逐部分添加硼氢化钠(5.2g,139mmol,5eq)——其通过剧烈鼓泡实现。90分钟后,通过添加水和氢氧化铵淬灭反应。混合物用氯仿萃取四次,并通过柱层析(10至30%0.5M NH3(MeOH)/DCM)纯化,以提供较深色油(4.12g,20.2mmol,73%)。
一般溶液相合成
(2S,4R)-烯丙基4-(叔丁氧基)吡咯烷-2-羧酸酯
将(2S,4R)-1-((9H-芴-9-基)甲基)2-烯丙基4-(叔丁氧基)吡咯烷-1,2-二羧酸酯(7.0g,15.57mmol,1eq)溶解于DCM(156mL)中,并冷却至4℃。添加三(2-氨基乙基)胺(5.8mL,38.9mmol,2.5eq),并将溶液在4℃下搅拌1小时和在室温下搅拌4.5小时。然后将混合物与硅胶(约20g)混合,并在减压下浓缩,和通过柱层析(1至5%0.5N NH3(MeOH)/DCM)纯化,以提供不透明油(3.44g,15.1mmol,97%)。1HNMR(400MHz,MeOH)δ6.03-5.88(m,1H),5.25(dq,J=17.2,1.8Hz,1H),5.09(dq,J=10.5,1.6Hz,1H),4.33-4.23(m,1H),4.06(dt,J=5.1,1.6Hz,2H),3.86(t,J=8.0Hz,1H),3.18(dd,J=11.4,5.7Hz,1H),2.70(dd,J=11.4,3.8Hz,1H),2.00(dd,J=8.0,5.0Hz,2H),1.19(s,9H)。13C NMR(101MHz,MeOH)δ175.89,138.93,114.88,74.93,72.93,63.97,59.77,55.44,40.18,28.65。MS(ESI)228.0(M+H)。
(2S,4R)-烯丙基4-(叔丁氧基)-1-(2-(3-甲基异唑-5-基)乙酰基)吡咯烷-2-羧酸酯
将(2S,4R)-烯丙基4-(叔丁氧基)吡咯烷-2-羧酸酯(0.148g,0.65mmol,1eq)溶解于DMF(6.5mL)中,并冷却至4℃。添加2-(3-甲基异唑-5-基)乙酸(0.12g,0.85mmol,1.3eq)、EDC(0.163g,0.85mmol,1.3eq)、HOBt(0.123g,0.91mmol,1.4eq)、和DIPEA(0.283mL、1.63mmol,2.5eq),并使溶液缓慢升温至室温。12小时后,将混合物倒入盐水中,并用EtOAc萃取四次。将有机层在硫酸钠上干燥,过滤并在减压下浓缩。通过柱层析(1至3%MeOH/DCM)纯化提供淡黄色油(0.2008g,0.573mmol,88%)。1H NMR(500MHz,CDCl3)δ6.17(s,1H),5.95-5.85(m,1H),5.29(ddd,J=13.8,11.7,1.3Hz,2H),4.69-4.55(m,3H),4.40-4.32(m,1H),3.84-3.75(m,3H),3.37(dd,J=10.0,4.7Hz,1H),2.27(s,3H),2.15(ddd,J=18.5,12.0,5.9Hz,2H),1.18(s,9H)。13C NMR(126MHz,CDCl3)δ171.87,165.94,165.63,160.30,131.84,118.72,104.04,74.53,69.55,65.98,57.96,54.53,37.31,33.58,28.35,11.62。MS(ESI)351.5(M+H)。
(2S,4R)-4-(叔丁氧基)-1-(2-(3-甲基异唑-5-基)乙酰基)吡咯烷-2-羧酸
将(2S,4R)-烯丙基4-(叔丁氧基)-1-(2-(3-甲基异唑-5-基)乙酰基)吡咯烷-2-羧酸酯(1.67g,4.77mmol,1eq)在室温下溶解于THF(48mL)中。然后添加Pd(PPh3)4(0.55g,0.48mmol,0.1eq)和吗啉(4.2mL,48mmol,10eq)。35分钟后,将溶液在减压下浓缩,重新溶解于DCM中,并用1M HCl(aq)洗涤四次。然后将水层用DCM反萃取一次。将组合的有机层然后在硫酸钠上干燥,过滤并在减压下浓缩。通过柱层析(1至20% MeOH/DCM)纯化提供黄色固体(1.27g,4.1mmol,86%)。1H NMR(500MHz,MeOH)δ6.23(s,1H),4.47(t,J=6.0Hz,2H),3.94-3.80(m,3H),3.48(dd,J=10.6,3.8Hz,1H),2.28-2.11(m,5H),1.21(s,9H)。13C NMR(126MHz,MeOH)δ175.53,168.41,167.68,161.59,105.25,75.57,71.00,59.36,55.81,38.49,33.88,28.48,11.20。MS(ESI)311.2(M+H)。
一般方法B代表性程序(具有羟基保护):VL116
(2S,4R)-4-(叔丁氧基)-1-(2-(3-甲基异唑-5-基)乙酰基)-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺
将(2S,4R)-4-(叔丁氧基)-1-(2-(3-甲基异唑-5-基)乙酰基)吡咯烷-2-羧酸(53.7mg,0.173mmol,1.3eq)、(4-(4-甲基噻唑-5-基)苯基)甲胺(27.2mg,0.133mmol,1eq)、EDC(33.2mg,0.173mmol,1.3eq)、和HOBt(23.4mg,0.173mmol,1.3eq)在4℃下溶解于DMF(3.5mL)中。添加DIPEA(0.07mL,0.4mmol,3eq),并使溶液缓慢升温至室温。19小时后,将混合物倒入盐水中,并用EtOAc萃取四次。将有机层用硫酸钠干燥,过滤并在减压下浓缩。通过柱层析(1至5% MeOH/DCM)纯化提供无色油(58.1mg,0.117mmol,88%)。1H NMR(400MHz,CDCl3)δ8.67(s,1H),7.42-7.27(m,5H),6.06(s,1H),4.69(dd,J=8.4,2.6Hz,1H),4.59-4.35(m,3H),3.82-3.71(m,3H),3.34(dd,J=9.9,6.3Hz,1H),2.59-2.46(m,4H),2.25(s,3H),1.91(dd,J=8.2,4.4Hz,1H),1.25-1.14(m,9H)。13C NMR(101MHz,CDCl3)δ170.70,167.35,165.30,160.24,150.42,148.59,138.09,131.74,131.05,129.66,127.85,104.19,74.48,70.02,59.12,54.20,43.25,35.59,33.49,28.38,16.19,11.57。MS(ESI)497.4(M+H)。
(2S,4R)-4-羟基-1-(2-(3-甲基异唑-5-基)乙酰基)-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺(VL116)
将(2S,4R)-4-(叔丁氧基)-1-(2-(3-甲基异唑-5-基)乙酰基)-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺(58.1mg,0.117mmol)溶解于DCM(8mL)中。添加TFA(2mL,20%vol/vol),并将溶液在室温下搅拌12小时,然后将其在减压下浓缩。通过柱层析(1至10%0.5N NH3(MeOH)/DCM)纯化提供无色油(28.4mg,0.065mmol,56%)。1H NMR(400MHz,MeOH)δ8.87(d,J=2.1Hz,1H),7.50-7.34(m,4H),6.23(s,1H),4.57(t,J=8.0Hz,1H),4.54-4.38(m,3H),3.93(d,J=2.4Hz,2H),3.81(dd,J=10.9,4.3Hz,1H),3.63(dd,J=7.2,5.5Hz,1H),2.46(d,J=8.8Hz,3H),2.33-2.20(m,4H),2.10(ddd,J=13.1,8.2,4.7Hz,1H)。13CNMR(101MHz,MeOH)δ174.43,168.71,167.66,161.58,152.83,149.04,140.14,133.39,131.56,130.43,128.88,105.39,70.86,60.78,57.00,43.65,39.36,33.96,15.81,11.22。MS(ESI)441.3(M+H)。
一般方法A代表性程序:VL133
(2S,4R)-4-羟基-1-(2-(3-甲基异唑-5-基)乙酰基)吡咯烷-2-羧酸
将(2S,4R)-4-(叔丁氧基)-1-(2-(3-甲基异唑-5-基)乙酰基)吡咯烷-2-羧酸(124.9mg,0.4mmol,1eq)在室温下溶解于DCM(18mL)中。添加TFA(2mL、10%),并将溶液搅拌12小时。然后将其在减压下浓缩,并通过柱层析(4至20% MeOH/DCM)纯化,以提供黄色油(99.7mg,0.39mmol,98%)。1H NMR(500MHz,MeOD)δ6.24(s,1H),4.55-4.46(m,2H),3.89(d,J=28.3Hz,2H),3.77(dd,J=10.9,4.3Hz,1H),3.62(d,J=11.0Hz,1H),2.36-2.22(m,4H),2.10(ddd,J=13.1,8.0,4.8Hz,1H)。13C NMR(126MHz,CDCl3)δ175.33,168.51,167.61,161.61,105.28,70.86,59.33,56.60,38.78,33.85,11.20。MS(ESI)255.1(M+H)。
(2S,4R)-N-(4-(1H-吡咯-3-基)苄基)-4-羟基-1-(2-(3-甲基异唑-5-基)乙酰基)吡咯烷-2-羧酰胺(VL133)/>
将(2S,4R)-4-羟基-1-(2-(3-甲基异唑-5-基)乙酰基)吡咯烷-2-羧酸(52.6mg,0.207mmol,1.3eq)、(4-(1H-吡咯-3-基)苯基)甲胺(27.3mg,0.159mmol,1eq)、EDC(39.7mg,0.207mmol,1.3eq)和HOBt(28mg,0.207mmol,1.3eq)溶解于DMF(4.1mL)中,并冷却至4℃。添加DIPEA(0.083mL,0.477mmol,3eq),并使溶液缓慢升温至室温。16小时后,将混合物倒入半饱和氯化钠(含水),并用EtOAc萃取三次。将有机层在硫酸钠上干燥,过滤并在减压下浓缩。通过柱层析(1至10%0.5N NH3(MeOH)/DCM)纯化提供灰白色固体(41.5mg,0.102mmol,64%)。1HNMR(400MHz,DMSO)δ8.40(d,J=6.0Hz,1H),7.52-7.39(m,2H),7.22-7.12(m,3H),6.82-6.72(m,1H),6.41(d,J=1.7Hz,1H),6.24(s,1H),5.17(d,J=3.9Hz,1H),4.31(ddd,J=17.1,13.7,6.4Hz,4H),3.88(s,2H),3.75-3.65(m,1H),3.52-3.41(m,1H),2.18(d,J=18.0Hz,3H),2.12-1.99(m,1H),1.94-1.85(m,1H)。13C NMR(101MHz,DMSO)δ171.36,166.69,165.54,159.38,135.66,134.68,127.20,124.21,123.00,118.86,114.71,105.22,103.99,68.61,58.76,55.18,41.63,38.27,32.78,11.00。MS(ESI)431.5(M+Na)。
进一步的参考文献参见下列文章和其中应用的参考文献:
(1)Buckley DL等.J.Am.Chem.Soc 2012,134,4465-4468.
(2)Van Molle I等.A Chemistry&Biology 2012,19,1300-1312
(3)Buckley,D Angew.Chem.Int.Ed.,2012,51,11463-11467
(4)Buckley,D.L等.Angew.Chem.2012,124,11630-11634。
实施例第二组
VL50
根据固相合成一般方法B由Fmoc-Hyp(OWang)-O烯丙基树脂(0.156mmol)合成VL50。将其分离,为白色固体(29.8mg,0.084mmol,54%)。1H NMR(400MHz,CD3OD):δ7.34-7.27(m,4H);5.43-5.35(m,4H);3.81-3.78(dd,J=8Hz,4Hz,1H);3.61-3.57(m,1H);2.65-2.61(m,2H);2.57-2.51(m,2H);2.28-2.21(m,1H);2.08-2.02(m,1H)。13C NMR(100MHz,CD3OD):δ177.53,174.74,173.76,138.75,133.76,129.96,129.49,70.71,60.55,56.47,43.25,39.33,30.97,30.64。MS(ESI)354.2(M+H)。
VL52
根据固相合成一般方法B由Fmoc-Hyp(OWang)-O烯丙基树脂(0.156mmol)合成VL52。将其分离,为白色固体(7.7mg,0.021mmol,14%)。1H NMR(500MHz,CD3OD):δ7.41(d,J=2Hz,1H);7.30(s,4H);6.35-6.34(dd,J=3Hz,2Hz,1H);6.26-6.25(d,J=3Hz,1H);4.49-4.32(m,4H);3.82-3.73(m,3H);3.65-2.62(m,1H);2.23-2.22(m,1H);2.09-2.06(m,1H).13CNMR(125MHz,CD3OD):δ174.54,170.58,149.67,143.24,138.68,133.84,129.98,129.53,111.50,108.98,70.88,60.75,56.95,43.31,39.24,35.58。MS(ESI)365.2(M+H),385.3(M+Na)。
VL73
根据固相合成一般方法B由Fmoc-Hyp(OWang)-O烯丙基树脂(0.18mmol)合成VL73。将其分离,为清澈油(38.9mg,0.099mmol,55%).1H NMR(500MHz,CD3OD)δ7.51-6.99(m,8H),4.72(t,J=8.2,1H),4.55-4.33(m,3H),3.60(dd,J=3.7,11.3,1H),3.19(dd,J=1.5,11.3,1H),2.36-2.25(m,1H),2.21-2.03(m,1H).13C NMR(126MHz,CD3OD)δ174.03,169.66,138.62,137.31,133.87,132.12,130.92,130.48,129.98,129.56,129.16,128.53,70.64,60.38,43.39,39.25,24.21。MS(ESI)395.3(M+H)。
VL64
根据固相合成一般方法B由Fmoc-Hyp(OWang)-O烯丙基树脂(0.156mmol)合成VL64。将其分离,为白色固体(27.5mg,0.077mmol,49%).1H NMR(500MHz,CD3OD)δ7.66-7.59(m,2H),7.54-7.22(m,7H),4.75(t,J=8.6,1H),4.55-4.33(m,3H),3.85(dd,J=3.0,11.5,1H),3.43(d,J=11.5,1H),2.38-2.26(m,1H),2.14-2.05(m,1H).13C NMR(126MHz,CD3OD)δ174.72,172.78,138.73,137.14,133.83,131.74,129.93,129.55,129.49,128.56,71.04,60.85,59.80,43.34,39.28。MS(ESI)359.1(M+H)。
VL69
根据固相合成一般方法B由Fmoc-Hyp(OWang)-O烯丙基树脂(0.156mmol)合成VL69。将其分离,为白色固体(26.1mg,0.62mmol,40%)。1H NMR(500MHz,DMSO)δ7.30(dt,J=8.2,25.1,4H),7.20(dd,J=1.7,8.3,1H),7.13(d,J=1.7,1H),7.01(d,J=8.4,1H),4.98(s,1H),4.56(t,J=8.6,1H),4.29(d,J=2.6,2H),3.76(dd,J=15.5,30.6,7H),3.36(d,J=11.1,1H),2.14(dd,J=7.7,12.8,1H),1.96-1.83(m,1H)。13C NMR(126MHz,DMSO)δ171.91,168.82,150.39,148.08,138.70,131.10,128.68,128.09,121.00,111.44,110.75,99.56,68.90,59.33,59.30,58.68,55.57,41.17,38.01。MS(ESI)418.8(M+H)。
VL70
根据固相合成一般方法B由Fmoc-Hyp(OWang)-O烯丙基树脂(0.156mmol)合成VL70。将其分离,为无色油(31.1mg,0.083mmol,53%).1H NMR(500MHz,CD3OD)δ7.38-7.17(m,6H),6.85-6.73(m,2H),4.76(t,J=8.5,1H),4.53-4.31(m,3H),3.85(dd,J=3.2,11.6,1H),3.37(d,J=11.6,1H),2.50-2.24(m,1H),2.08(ddd,J=4.3,9.1,13.3,1H).13C NMR(126MHz,CD3OD)δ174.72,172.14,145.18,138.67,133.87,132.18,129.97,129.56,128.80,122.39,118.87,117.94,71.01,60.29,58.54,43.40,39.40。MS(ESI)374.5(M+H)。
VL71
根据固相合成一般方法B由Fmoc-Hyp(OWang)-O烯丙基树脂(0.156mmol)合成VL71。将其分离,为无色油(31.1mg,0.080mmol,51%)。1H NMR(500MHz,CD3OD)δ7.40-7.32(m,4H),7.24(t,J=7.6,1H),7.09(d,J=7.9,1H),7.03(d,J=7.1,1H),4.74(t,J=8.2,1H),4.59-4.33(m,3H),3.54(d,J=11.0,1H),3.20(d,J=11.2,1H),2.35(dd,J=8.7,12.4,1H),2.26(s,3H),2.14(dd,J=4.3,9.3,1H)。13C NMR(126MHz,CD3OD)δ174.37,172.44,140.91,139.29,138.69,133.84,129.93,129.55,128.37,124.30,121.45,120.64,70.73,60.11,43.36,39.44,13.89。MS(ESI)388.1,390.3(M+H)。
VL72
根据固相合成一般方法B由Fmoc-Hyp(OWang)-O烯丙基树脂(0.156mmol)合成VL72。将其分离,为黄色油(31.3mg,0.084mmol,54%)。1H NMR(500MHz,CD3OD)δ7.48(d,J=8.3,2H),7.30(s,4H),6.79(d,J=8.3,2H),4.79-4.69(m,1H),4.53-4.29(m,3H),3.95-3.83(m,1H),3.54(d,J=11.4,1H),2.35-2.24(m,1H),2.07(ddd,J=3.9,10.1,13.5,1H)。13C NMR(126MHz,CD3OD)δ175.03,173.02,149.95,138.75,133.80,130.79,129.91,129.54,126.23,115.89,71.16,61.03,60.12,43.31,39.16。MS(ESI)375.0(M+H)。
VL74
根据固相合成一般方法B由Fmoc-Hyp(OWang)-O烯丙基树脂(0.18mmol)合成VL74。将其分离,为白色固体(36.3mg,0.092mmol,51%).1H NMR(500MHz,CD3OD)δ7.67-7.56(m,2H),7.52-7.44(m,2H),7.34-7.28(m,4H),4.74(dd,J=7.7,9.6,1H),4.55-4.30(m,3H),3.85(dd,J=3.5,11.4,1H),3.42(d,J=11.4,1H),2.37-2.28(m,1H),2.15-2.05(m,1H)。13CNMR(126MHz,CD3OD)δ174.59,171.54,138.69,137.75,135.66,133.84,130.38,129.92,129.70,129.55,71.04,60.92,59.75,43.34,39.29。MS(ESI)394.6(M+H)。
VL75
根据固相合成一般方法B由Fmoc-Hyp(OWang)-O烯丙基树脂(0.18mmol)合成VL75。将其分离,为白色固体(25.0mg,0.066mmol,37%)。1H NMR(500MHz,CD3OD)δ7.64-6.87(m,8H),4.73(dd,J=7.7,9.6,1H),4.54-4.31(m,3H),3.84(dd,J=3.5,11.5,1H),3.42(d,J=11.4,1H),2.33(ddd,J=1.6,7.6,13.0,1H),2.13-2.05(m,1H)。13C NMR(126MHz,CD3OD)δ174.64,171.20,163.83(d,J=246.5),139.35,138.72,133.86,131.60,129.94,129.56,124.51,118.51(d,J=21.3),115.56(d,J=23.4),71.02,60.94,59.70,43.47,39.31。MS(ESI)377.4(M+H)。
VL76
根据固相合成一般方法B由Fmoc-Hyp(OWang)-O烯丙基树脂(0.18mmol)合成VL76。将其分离,为白色固体(29.6mg,0.067mmol,38%)。1H NMR(400MHz,CD3OD)δ7.82(s,1H),7.70-7.58(m,2H),7.40(t,J=7.9,1H),7.36-7.18(m,4H),4.73(dd,J=7.9,9.4,1H),4.53-4.31(m,3H),3.82(dt,J=5.2,10.4,1H),3.40(d,J=11.4,1H),2.33(dd,J=7.6,13.2,1H),2.09(ddd,J=4.1,9.7,13.7,1H)。13C NMR(101MHz,CD3OD)δ174.53,170.95,139.22,138.68,134.68,133.85,131.56,131.44,129.92,129.56,127.31,123.35,71.02,60.90,59.70,43.33,39.31。MS(ESI)439.4(M+H)。
VL77
根据固相合成一般方法B由Fmoc-Hyp(OWang)-O烯丙基树脂(0.18mmol)合成VL77。将其分离,为白色固体(31.0mg,0.081mmol,45%)。1H NMR(500MHz,DMSO)δ8.07(t,J=1.4,1H),8.01-7.95(m,1H),7.93-7.88(m,1H),7.69(t,J=7.8,1H),7.40-7.23(m,4H),4.56(dd,J=8.3,16.4,1H),4.30(dd,J=8.1,15.4,3H),3.79(dd,J=3.6,11.0,1H),3.24(d,J=11.0,1H),2.23-2.15(m,1H),1.92(ddd,J=4.2,9.3,13.2,1H)。13C NMR(126MHz,DMSO)δ171.51,167.29,138.64,137.27,133.88,132.29,131.16,131.08,129.73,128.68,128.15,118.25,111.40,68.82,59.39,59.36,58.28,38.19。MS(ESI)383.8(M+H)。
VL79
根据固相合成一般方法B由Fmoc-Hyp(OWang)-O烯丙基树脂(0.18mmol)合成VL79。将其分离,为白色固体(34.9mg,0.090mmol,50%)。1H NMR(500MHz,CD3OD)δ7.41-7.15(m,6H),7.08-6.90(m,2H),4.73(dd,J=7.7,9.6,1H),4.54-4.31(m,3H),3.87-3.74(m,4H),3.43(d,J=11.5,1H),2.37-2.27(m,1H),2.14-2.05(m,1H)。13C NMR(126MHz,CD3OD)δ174.72,172.59,161.07,138.72,138.40,133.83,130.67,129.93,129.56,120.58,117.52,113.77,71.01,60.82,59.80,55.87,43.33,39.29。MS(ESI)389.0(M+H)。
VL80
根据固相合成一般方法B由Fmoc-Hyp(OWang)-O烯丙基树脂(0.18mmol)合成VL80。将其分离,为白色固体(41.2mg,0.110mmol,61%)。1H NMR(500MHz,CD3OD)δ7.36-6.76(m,8H),4.72(dd,J=7.8,9.4,1H),4.53-4.31(m,3H),3.82(dd,J=3.5,11.6,1H),3.45(d,J=11.6,1H),2.34-2.27(m,1H),2.14-2.03(m,1H)。13C NMR(126MHz,CD3OD)δ174.81,172.77,158.73,138.74,138.36,133.83,130.64,129.93,129.56,119.39,118.62,115.26,71.01,60.81,59.80,43.46,39.24。MS(ESI)375.4(M+H)。
VL81
根据固相合成一般方法B由Fmoc-Hyp(OWang)-O烯丙基树脂(0.18mmol)合成VL81。将其分离,为无色油(42.9mg,0.091mmol,50%)。1H NMR(500MHz,CD3OD)δ7.77-7.27(m,6H),7.04(d,J=8.3,1H),4.71(t,J=8.2,1H),4.56-4.30(m,3H),3.59(dd,J=3.7,11.2,1H),3.17(d,J=11.3,1H),2.37-2.25(m,1H),2.19-2.09(m,1H)。13C NMR(126MHz,CD3OD)δ173.87,169.41,138.18,137.15,133.71,130.60,130.36,130.00,129.69,129.56,129.40,120.48,70.62,69.41,60.48,43.53,39.23。MS(ESI)472.1(M+H)。
VL96
根据固相合成一般方法B由Fmoc-Hyp(OWang)-O烯丙基树脂(0.155mmol)合成VL96。将其分离,为淡黄色油(36.6mg,0.102mmol,66%)。1H NMR(500MHz,CD3OD)δ8.81(s,1H),8.66(dd,J=4.6,1.5Hz,2H),7.60(dd,J=4.5,1.6Hz,2H),7.32-7.25(m,4H),4.70(dd,J=9.3,7.9Hz,1H),4.46(dd,J=15.3,6.3Hz,1H),4.39(s,1H),4.33(dd,J=15.4,5.5Hz,1H),3.78(dd,J=11.4,3.5Hz,1H),3.27(dt,J=3.2,1.6Hz,1H),2.31(dd,J=13.2,7.6Hz,1H),2.08(ddd,J=13.5,9.6,4.2Hz,1H)。13C NMR(126MHz,CD3OD)δ174.32,169.63,150.65,145.83,138.68,133.88,129.96,129.56,123.32,70.99,60.88,59.33,43.49,39.33。MS(ESI)360.5(M+H)。
VL112
根据固相合成一般方法A由Fmoc-Hyp(OWang)-O烯丙基树脂(0.2mmol)合成VL112。将其分离,为乳白色固体(22.6mg,0.055mmol,28%)。1H NMR(500MHz,CD3OD)δ7.98(d,J=7.1Hz,3H),7.46(d,J=8.0Hz,2H),7.28(s,1H),6.23(s,1H),4.62-4.39(m,4H),3.93(d,J=2.9Hz,2H),3.81(dd,J=10.9,4.1Hz,1H),3.64(d,J=11.0Hz,1H),2.33-2.17(m,4H),2.15-2.04(m,1H)。13C NMR(126MHz,CD3OD)δ174.50,168.72,167.68,163.41,161.60,142.96,140.75,129.45,128.96,127.53,127.15,105.36,70.87,60.78,56.99,43.72,39.36,33.95,11.20。MS(ESI)410.9(M+H)。
VL115
根据一般方法B合成VL115。1H NMR(500MHz,CD3OD)δ8.87(s,1H),7.46-7.40(m,2H),7.36(dd,J=8.8,4.3Hz,2H),6.20(s,1H),4.55(t,J=8.0Hz,1H),4.50(d,J=6.3Hz,1H),4.48-4.42(m,2H),3.92(d,J=4.5Hz,2H),3.80(dd,J=10.9,4.3Hz,1H),3.62(d,J=11.0Hz,1H),2.48(d,J=10.2Hz,3H),2.31-2.21(m,4H),2.08(ddd,J=13.0,8.2,4.7Hz,1H)。13C NMR(126MHz,CD3OD)δ174.48,168.60,167.70,161.57,152.92,149.26,140.81,133.50,133.09,130.13,129.24,129.09,128.34,105.35,70.86,60.75,56.95,43.81,39.38,33.92,15.87,11.23。MS(ESI)441.4(M+H)。
VL154
根据一般方法B合成VL154。1H NMR(500MHz,CD3OD)δ8.95(s,1H),8.44(t,J=5.6,1H),7.84(d,J=8.2,2H),7.70(d,J=1.9,1H),7.35(d,J=8.2,2H),6.19(s,1H),4.56(t,J=7.9,1H),4.51(s,1H),4.43(d,J=5.7,2H),3.87(s,2H),3.78(dd,J=10.9,4.3,1H),3.58(d,J=10.8,1H),2.24(obscured s,4H),2.16-2.07(m,1H);13C NMR(126MHz,CD3OD)δ176.66,170.98,169.94,164.15,159.72,157.62,142.33,136.89,131.58,130.33,117.00,108.05,73.36,63.27,59.60,46.75,41.78,36.80,14.39;TLC:(EtOAC)Rf=0.5;LRMS(ESI)427.6(M+H)+。
VL155
根据一般方法B合成VL155。1H NMR(500MHz,CD3OD)δ8.87(d,J=5.2,1H),8.54(t,J=5.7,1H),8.07(s,1H),7.56(d,J=8.2,2H),7.36(d,J=8.2,2H),6.20(s,1H),4.56(t,J=8.0,1H),4.51(s,1H),4.42(qd,J=5.5,15.5,2H),3.78(dt,J=9.2,18.5,1H),3.60(d,J=11.1,1H),2.28-2.21(m,4H),2.10(ddd,J=4.7,8.0,13.0,1H);13C NMR(126MHz,CD3OD)δ176.72,171.03,169.98,164.12,142.98,142.96,133.45,132.34 131.86,130.07,108.02,100.0,73.37,63.29,59.60,46.52,41.81,36.74,14.27。TLC:(EtOAC)Rf=0.5;LRMS(ESI)427.4(M+H)+。
VL118
根据一般方法A合成VL118。1H NMR(500MHz,CD3OD)δ7.37-7.31(m,2H),7.27(d,J=7.7Hz,1H),7.22(d,J=7.5Hz,1H),6.74-6.68(m,1H),6.20(s,1H),6.14(dd,J=3.5,1.8Hz,1H),6.10-6.05(m,1H),4.55(t,J=8.0Hz,1H),4.49(s,1H),4.45-4.39(m,2H),3.89(t,J=8.4Hz,1H),3.79(dd,J=10.9,4.3Hz,1H),3.67-3.55(m,5H),2.26-2.22(m,4H),2.07(ddd,J=13.0,8.1,4.7Hz,1H)。13C NMR(126MHz,CD3OD)δ174.35,168.57,167.66,161.57,139.94,135.44,135.24,129.58,128.35,128.22,126.62,124.93,109.56,108.54,105.37,70.84,60.72,56.91,44.04,39.36,35.34,33.88,11.23。MS(ESI)422.8(M+H)。
VL119
根据一般方法A合成VL119。1H NMR(500MHz,CD3OD)δ7.38-7.30(m,4H),6.76-6.67(m,1H),6.23(s,1H),6.10(dd,J=3.5,1.8Hz,1H),6.09-6.05(m,1H),4.56(t,J=8.1Hz,1H),4.51(s,1H),4.47-4.39(m,2H),3.93(d,J=3.0Hz,2H),3.81(dd,J=10.9,4.3Hz,1H),3.63(q,J=5.8Hz,4H),2.31-2.22(m,4H),2.10(ddd,J=13.0,8.1,4.7Hz,1H)。13C NMR(101MHz,~1:1CD3OD:CDCl3)δ172.63,167.39,166.19,160.68,136.80,132.70,129.06,128.99,127.75,124.09,108.75,107.93,104.62,69.88,59.64,56.15,43.36,37.98,35.19,33.53,11.37。MS(ESI)423.6(M+H)。
VL131
根据一般方法B合成VL131。1H NMR(400MHz,CD3OD)δ9.02(d,J=5.2Hz,1H),8.02(d,J=8.4Hz,2H),7.41(d,J=8.4Hz,2H),6.17(s,1H),4.52-4.38(m,4H),3.84(s,2H),3.76(dd,J=10.8,4.3Hz,1H),3.56(d,J=9.5Hz,1H),2.30-2.18(m,4H),2.14(td,J=8.1,3.9Hz,1H)。13C NMR(101MHz,CD3OD)δ173.25,167.86,167.57,166.44,166.18,160.85,142.53,128.33,128.14,125.56,104.77,70.04,59.87,56.31,43.52,38.30,33.60,11.39。MS(ESI)413.3(M+H)。
VL138
根据一般方法B合成VL138。1H NMR(400MHz,CD3OD)δ7.42(d,J=8.2Hz,2H),7.32-7.24(m,2H),6.24(s,1H),4.69-4.33(m,5H),3.94(d,J=3.0Hz,1H),3.82(dd,J=10.9,4.3Hz,1H),3.64(d,J=11.1Hz,1H),2.38(s,3H),2.31-2.24(m,4H),2.23(s,3H),2.10(ddd,J=13.1,8.2,4.7Hz,1H)。13C NMR(126MHz,CD3OD)δ174.41,168.72,167.67,166.87,161.59,160.02,139.46,130.38,129.37,128.89,117.72,105.38,70.87,60.78,57.01,43.74,39.37,33.97,11.38,11.20,10.66。MS(ESI)438.6(M+H)。
VL139
根据一般方法B合成VL139。1H NMR(400MHz,~1:1CD3OD:CDCl3)δ7.89(s,2H),7.49(d,J=8.1Hz,2H),7.28(d,J=7.9Hz,2H),6.20(s,1H),4.54(dd,J=17.4,9.5Hz,2H),4.39(d,J=5.3Hz,2H),3.93-3.46(m,4H),2.32-2.16(m,4H),2.16-2.05(m,1H)。13C NMR(126MHz,~1:1CD3OD:CDCl3)δ173.80,168.23,167.21,161.29,137.35,132.66,129.24,128.77,126.60,126.48,105.16,70.53,60.42,56.73,43.71,39.00,33.85,11.30。MS(ESI)410.0(M+H)。
VL152
根据一般方法B合成VL152。1H NMR(400MHz,CD3OD)δ7.38(d,J=8.2Hz,2H),7.25(d,J=8.2Hz,2H),6.17(d,J=55.2Hz,1H),4.65-4.30(m,4H),4.05-3.72(m,3H),3.64(d,J=11.1Hz,1H),2.32-2.19(m,10H),2.10(ddd,J=13.1,8.2,4.7Hz,1H)。13C NMR(101MHz,CD3OD)δ174.37,168.72,167.67,161.59,143.18,138.27,132.85,130.54,129.12,128.64,105.40,70.86,60.78,57.01,43.80,39.38,33.96,11.21,11.07。MS(ESI)438.5(M+H)。
VL158
根据一般方法B合成VL158。1H NMR(500MHz,CD3OD)δ8.03(s,1H),7.62(t,J=8.7Hz,2H),7.43(d,J=6.6Hz,1H),7.33(t,J=6.5Hz,2H),6.19(s,1H),4.62-4.48(m,2H),4.48-4.32(m,2H),3.93-3.68(m,3H),3.58(s,1H),2.29-2.19(m,4H),2.11(ddd,J=13.0,8.0,4.8Hz,1H)。13C NMR(126MHz,CD3OD)δ173.59,168.01,166.92,161.11,138.84,135.95,130.48,129.06,128.64,125.89,116.23,105.04,70.35,60.24,56.60,43.56,38.76,33.78,11.33。MS(ESI)410.1(M+H)。
VL160
根据一般方法B合成VL160。1H NMR(500MHz,CD3OD)δ7.68(d,J=8.1Hz,2H),7.63(s,1H),7.33(d,J=8.0Hz,2H),6.63(s,1H),6.19(s,1H),4.54(t,J=8.0Hz,1H),4.47(s,1H),4.38(d,J=4.6Hz,2H),3.89(d,J=3.1Hz,2H),3.78(dd,J=10.9,4.3Hz,1H),3.60(d,J=11.1Hz,1H),2.28-2.14(m,4H),2.06(ddd,J=13.0,8.1,4.7Hz,1H)。13C NMR(126MHz,CD3OD)δ174.32,168.69,167.67,161.61,139.59,132.31,129.33,128.86,127.00,126.87,105.49,105.38,70.84,60.78,56.97,43.80,39.35,33.95,11.19。MS(ESI)409.2(M+H),431.8(M+Na)。
(2S,4R)-(9H-芴-9-基)甲基4-(叔丁氧基)-2-((4-氯苄基)氨甲酰基)吡咯烷-1-羧酸酯
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将Fmoc-Hyp(OtBu)-OH(1.23g,3mmol,1eq)溶解于DCM(15mL)中,并冷却至4℃。然后添加EDC(0.69g,3.6mmol,1.2eq)和HOBt(0.49g,3.6mmol,1.2eq)。20分钟后,添加4-氯苄基胺(0.48mL,3.9mmol,1.3eq),并使溶液缓慢升温至室温。15小时后,将混合物用EtOAc稀释和用1M HCl、碳酸氢钠、水和盐水洗涤。将有机层用硫酸钠干燥,过滤和浓缩。通过柱层析(25至100% EtOAc/己烷)纯化提供白色泡沫(1.42g,2.66mmol,89%)。1H NMR(400MHz,CDCl3)δ7.77(d,J=7.2Hz,2H),7.57(s,2H),7.40(t,J=7.3Hz,2H),7.31(t,J=7.3Hz,2H),7.17(dd,J=27.2,19.5Hz,4H),4.58-3.94(m,7H),3.60(d,J=6.7Hz,1H),3.31(d,J=6.6Hz,1H),2.50(s,1H),1.96(s,1H),1.28-1.10(m,9H)。13C NMR(101MHz,CDCl3)δ171.54,156.13,143.74,141.32,136.81,133.02,128.79,128.71,127.83,127.12,125.04,120.07,74.15,69.63,67.87,59.17,53.26,47.10,42.72,36.34,28.31。MS(ESI)534.8(M+H)。
(2S,4R)-4-(叔丁氧基)-N-(4-氯苄基)吡咯烷-2-羧酰胺
将(2S,4R)-(9H-芴-9-基)甲基4-(叔丁氧基)-2-((4-氯苄基)氨甲酰基)吡咯烷-1-羧酸酯(0.5g,0.94mmol,1eq)溶解于DCM(15mL)中,并冷却至4℃。缓慢逐滴添加三(2-氨基乙基)胺(0.35mL,2.34mmol,2.5eq)。30分钟后,使反应升温至室温,并再搅拌14小时。将其直接负载到硅胶柱上,并通过柱层析(1至7%0.5N甲醇氨/DCM)纯化,以提供白色固体(0.2871g,0.92mmol,98%)。1H NMR(400MHz,CD3OD)δ7.27(dd,J=20.1,8.4Hz,4H),4.35(s,2H),4.22(s,1H),3.84(t,J=8.0Hz,1H),3.08(dd,J=11.4,5.1Hz,1H),2.76(dd,J=11.4,2.8Hz,1H),2.14-1.98(m,1H),1.97-1.81(m,1H),1.17(s,9H)。13C NMR(126MHz,CD3OD)δ176.48,138.81,133.83,130.00,129.52,74.76,73.37,60.80,55.61,43.04,40.76,28.67。
一般方法C:代表性程序:VL156
将1H-咪唑-1-基乙酸(20.6mg,0.163mmol,1.3eq)、EDC(31.2mg,0.163mmol,1.3eq)和HOBt(22mg,0.163mmol,1.3eq)在室温下溶解于1打兰小瓶中的DCM(2.5mL)和DMF(0.4mL)中。搅拌15分钟后,添加DIPEA(0.055mL,0.313mmol,2.5eq),然后在再30分钟后添加(2S,4R)-4-(叔丁氧基)-N-(4-氯苄基)吡咯烷-2-羧酰胺(38.9mg,0.125mmol,1eq)。将混合物搅拌14小时,然后用EtOAc稀释和用盐水洗涤。将有机层在硫酸钠上干燥,过滤和浓缩。通过柱层析(1至10%MeOH/DCM)纯化提供白色固体,其直接用于后续步骤。1H NMR(400MHz,CD3OD)δ7.65(s,1H),7.28(td,J=10.9,8.4Hz,4H),7.06(d,J=43.6Hz,2H),4.99(dd,J=38.1,17.1Hz,2H),4.51(t,J=6.6Hz,2H),4.35(q,J=15.4Hz,2H),3.86(dd,J=10.2,5.6Hz,1H),3.45(dd,J=10.3,4.1Hz,1H),2.22-2.02(m,2H),1.21(d,J=13.8Hz,9H)。MS(ESI)419.7(M+H)。
将白色固体在室温下溶解于DCM(9mL)中。添加TFA(1mL),并将混合物搅拌12小时并浓缩。通过柱层析(1至20%0.5N甲醇氨/DCM)纯化提供白色固体(39.8mg,0.11mmol,经2步88%。1H NMR(400MHz,CD3OD)δ8.73(s,1H),7.47(d,J=16.9Hz,2H),7.26(s,4H),5.25(dd,J=37.5,16.9Hz,2H),4.56(t,J=7.9Hz,2H),4.44-4.27(m,2H),3.82(dd,J=10.8,4.1Hz,1H),3.63(d,J=10.8Hz,1H),2.36-2.22(m,1H),2.07(ddd,J=13.1,8.3,4.6Hz,1H)。13C NMR(126MHz,CD3OD)δ174.14,166.34,138.56,138.20,133.87,129.97,129.49,124.55,121.47,70.94,61.00,55.75,51.33,43.35,39.21。MS(ESI)364.8(M+H)。
VL120
根据一般方法C合成VL120。1H NMR(500MHz,CD3OD)δ8.67(d,J=1.2Hz,1H),7.36(s,1H),7.29(d,J=9.2Hz,4H),4.62-4.47(m,2H),4.47-4.24(m,2H),3.87(ddd,J=18.3,15.1,10.8Hz,3H),3.66(d,J=11.0Hz,1H),2.37-2.20(m,1H),2.07(ddd,J=13.1,8.4,4.6Hz,1H)。13C NMR(126MHz,CD3OD)δ174.56,169.45,138.62,135.15,133.89,129.98,129.72,129.52,118.80,70.89,60.70,56.84,43.35,39.46,31.70。MS(ESI)362.3(M+H)。
VL157
根据一般方法C合成VL157。1H NMR(500MHz,CD3OD)δ7.49(s,1H),7.39(s,1H),7.34-7.22(m,4H),4.52(t,J=8.1Hz,1H),4.50-4.45(m,1H),4.37(dt,J=22.8,15.4Hz,2H),3.87-3.80(m,3H),3.77(dd,J=11.0,4.2Hz,1H),3.66-3.52(m,3H),2.30-2.18(m,1H),2.04(ddd,J=13.1,8.3,4.7Hz,1H)。13C NMR(126MHz,CD3OD)δ174.67,172.70,140.18,138.71,133.81,131.62,129.95,129.51,115.17,70.91,60.65,56.93,43.29,39.28,38.76,31.51。MS(ESI)377.0(M+H)。
VL173
根据一般方法C合成VL173。1H NMR(400MHz,CDCl3/CD3OD)δ7.63-7.53(m,3H);7.49(d,J=7.6Hz,1H);7.26(q,J=8.3Hz,4H);4.60-4.51(m,2H);4.42-4.32(m,2H);3.84-3.75(m,3H);3.59(d,J=11.3Hz,1H);3.42-3.32(m,1H);2.29-2.19(m,1H);2.17-2.08(m,1H)。13C NMR(100MHz,CDCl3/CD3OD)δ173.4,170.7,137.4,136.8,134.8,133.6,131.1,129,9,129.3,129.0,119.2,112.7,70.1,59.8,56.3,43.0,41.1,38.4。TLC(10% MeOH,在CH2Cl2中),Rf 0.38(UV,CAM),MS(ESI+):计算C21H21N3O3Cl[M+H]+398.1,发现398.2。
叠氮乙酸
在室温(rt)下向叠氮乙酸乙酯(530mg,4.107mmol)的THF-H2O(12mL/12mL)溶液添加LiOH·H2O(345mg,8.214mmol)。将反应混合物在室温下搅拌17H,蒸发,并用H2O(10mL)稀释,冷却至0℃,和用1N-HCl调节至pH 4。将所得混合物用二乙醚萃取两次,用盐水洗涤,在无水Na2SO4上干燥,和蒸发。通过在硅胶上的短柱层析(最初用100%己烷洗脱,逐级变化至己烷中2%乙酸乙酯)纯化浓缩物,以提供叠氮乙酸1(372mg,89%),为淡黄色油。1H NMR(500MHz,CDCl3)δ9.73(brs,1H),3.97(s,2H)。13C NMR(125MHz,CD3OD)d 174.2,50.0。
(2S,4R)-1-(2-叠氮乙酰基)-4-(叔丁氧基)-N-(4-氯苄基)吡咯烷-2-羧酰胺
在室温下向叠氮乙酸(32mg,0.315mmol)的CH2Cl2-DMF(1.5mL/1.5mL))溶液添加(2S,4R)-4-(叔丁氧基)-N-(4-氯苄基)吡咯烷-2-羧酰胺(93mg,0.300mmol)、DIPEA(0.19mL,1.080mmol)、和HOBt(48mg,0.360mmol)。将混合物冷却至0℃,然后在0℃下向混合物添加EDC(69mg,0.360mmol)。使反应混合物升温至室温,在室温下搅拌17h,并冷却至0℃。所得混合物用H2O(5mL)终止,并用乙酸乙酯萃取两次。将组合的萃取物用盐水洗涤,在无水Na2SO4上干燥,过滤,和蒸发。通过在硅胶上的柱层析(最初用己烷中的5%乙酸乙酯洗脱,逐级变化至己烷中的40%乙酸乙酯)纯化浓缩物,以提供偶合的产物(110mg,93%)。1H NMR(400MHz,CDCl3)δ7.31(brs,1H),7.27(d,J=8.5Hz,2H),7.18(d,J=8.5Hz,2H),4.66(dd,J=8.4,2.2Hz,1H),4.58-4.52(m,1H),4.41(dd,J=15.1,6.1Hz,1H),4.30(dd,J=15.1,5.8Hz,1H),3.87(dd,J=16.0,16.0Hz,1H),3.84(dd,J=16.0,16.0Hz,1H),3.61(dd,J=9.8,7.0Hz,1H),3.14(dd,J=9.8,6.4Hz,1H),2.50(ddd,J=12.6,6.3,2.3Hz,1H),1.86(dt,J=12.6,8.2Hz,1H),1.19(s,9H)。13C NMR,100MHz,CDCl3)δ170.3,167.4,162.5,136.5,133.1,128.8,128.7,74.3,69.9,59.0,52.7,50.9,42.8,36.4,35.1,31.4,28.2。MS(ESI)[M+H]+394.3。
(2S,4R)-4-(叔丁氧基)-N-(4-氯苄基)-1-(2-(4-(甲氧基甲基)-1H-1,2,3-三唑-1-基)乙酰基)吡咯烷-2-羧酰胺
在室温下向甲基炔丙基醚(7mg,0.067mmol)和(2S,4R)-1-(2-叠氮乙酰基)-4-(叔丁氧基)-N-(4-氯苄基)吡咯烷-2-羧酰胺(25mg,0.0636mmol)在t-BuOH-H2O(1:1,1mL)和THF(1mL)中的溶液中添加CuSO4·5H2O(1.5mg,0.006mmol)和抗坏血酸钠(在H2O中1.0M,2滴)。将反应混合物在室温下搅拌19h,并蒸发。剩余物用H2O(5mL)稀释,并将混合物用乙酸乙酯萃取三次。将组合的萃取物用盐水洗涤,在Na2SO4上干燥,过滤,和浓缩。通过在硅胶上的快速层析纯化粗剩余物,以提供预期的三唑(25mg,85%)。1H NMR(500MHz,CD3OD)d 7.91(s,1H),7.30-7.22(m,4H),5.43(d,J=16.8Hz,1H),5.34(d,J=16.7Hz,1H),4.54(s,2H),4.53-4.49(m,2H),4.37(d,J=15.4Hz,1H),4.31(d,J=15.4Hz,1H),3.90(dd,J=10.3,5.6Hz,1H),3.49(dd,J=10.4,4.3Hz,1H),3.37(s,3H),2.19-2.13(m,1H),2.11-2.07(m,1H),1.22(s,9H)。13C NMR(星号表示次要旋转异构体的信号,125MHz,CD3OD)d174.1,*173.4,*166.9,166.7,145.7,*138.6,138.5,*134.2,133.8,*130.4,129.9,*129.7,129.5,126.7,75.6,*75.5,71.1,*69.2,66.3,*66.2,60.8,*60.3,58.4,*58.3,*55.5,54.8,52.6,*51.9,*43.7,43.3,*41.1,38.7,28.5。MS(ESI)[M+H]+464.2。
VL141
在0℃下向相应叔丁醚(22mg,0.0475mmol)在CH2Cl2(1.5mL)中的搅拌溶液添加TFA(0.2mL)。将反应混合物在室温下搅拌12h并浓缩。将剩余物在硅胶上层析(最初用100%CH2Cl2洗脱,逐级变化至CH2Cl2中7% CH3OH),以提供5(18.5mg,96%)。1H NMR(500MHz,CD3OD/CDCl3=2:1)d 8.83&8.46(由于旋转异构体,两者t,J=5.7Hz,1H),7.85&7.76(由于旋转异构体,两者s,1H),7.23(d,J=8.5Hz,2H),7.18(d,J=8.5Hz,2H),5.36(d,J=16.6Hz,1H),5.27(d,J=16.6Hz,1H),4.54(s,2H),4.54-4.50(m,2H),4.33&4.32(由于旋转异构体,两者s,2H),3.77(dd,J=10.8,4.2Hz,1H),3.60(d,J=10.8Hz,1H),3.37&3.36(由于旋转异构体,两者s,3H),2.26-2.21(m,1H),2.09-2.04(m,1H)。13C NMR(星号表示次要旋转异构体的信号,125MHz,CD3OD/CDCl3=2:1)d*173.4,173.3,*166.2,165.9,145.2,137.5,*133.9,133.5,129.9,129.4,129.1,126.0,*125.9,70.4,*68.5,66.0,*65.9,*60.4,60.3,58.4,*58.3,*56.1,55.4,52.2,*51.5,*43.2,43.1,*41.1,38.4。MS(ESI)[M+H]+408.3。TLC(10% MeOH,在CH2Cl2中),Rf 0.48(UV,CAM)。
VL167
根据一般方法C合成VL167。1H NMR(500MHz,CDCl3)d 7.86(s,1H),7.71(d,J=9.5Hz,1H),7.61(d,J=7.4Hz,2H),7.56(d,J=7.6Hz,1H),7.51(d,J=7.6Hz,1H),7.42(dd,J=7.4,7.4Hz,2H),7.38-7.30(m,2H),7.30-7.26(m,3H),4.66-4.42(m,2H),4.42-4.27(m,2H),3.85(dd,J=11.4,3.5Hz,1H),3.49(d,J=11.4Hz,1H),2.33-2.29(m,1H),2.15-2.09(m,1H)。13C NMR(星号表示次要旋转异构体的信号,125MHz,CDCl3)d 172.5,170.6,162.7,140.7,139.3,136.4,135.6,131.9,128.2,*128.1,128.0,127.9,127.6,*127.5,126.8,126.1,*126.0,125.2,125.1,68.9,*67.4,*60.2,58.7,57.8,41.5,*39.5,37.2,35.2,30.0。MS(ESI)[M+H]+435.5。
VL216
根据一般方法C合成VL216。
(2S,4R)-(9H-芴-9-基)甲基4-(叔丁氧基)-2-((4-(唑-5-基)苄基)氨甲酰基)吡咯烷-1-羧酸酯
向具有搅拌棒的圆底烧瓶装载(2S,4R)-1-(((9H-芴-9-基)甲氧基)羰基)-4-(叔丁氧基)吡咯烷-2-羧酸(0.587、1.4mmol 1.0当量)、EDC(380mg,2.0mmol,1.4当量)、HOBt(310mg,2.0mmol,1.4当量)和(4-(唑-5-基)苯基)甲胺(250mg,1.4mmol,1.0当量)。在搅18h后,将反应用25ml DCM稀释,并用柠檬酸(2×50mL)和饱和NaHCO3(2×50mL)洗涤。将有机层用Na2SO4干燥,浓缩,然后通过硅胶层析(DCM至2% MeOH(0,5N NH3)纯化,以生成515mg(65%产率)产物,为粘性油。1HNMR(400MHz,CDCl3)δ7.89(s,1H),7.85-7.70(m,2H),7.68-7.49(m,4H),7.47-7.37(m,2H),7.35-7.20(m,5H),4.54-4.35(m,4H),4.35-4.14(m,2H),3.72-3.58(m,1H),3.49-3.27(m,1H),2.53(s,1H),2.00(dd,J=8.1,20.2,1H),1.25(s,9H);TLC:(9:1DCM:MeOH(0.5N NH3))Rf=0.5;LRMS(ESI)565.9(M+H)+。/>
(2S,4R)-1-(3-乙氧基苯甲酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺
向36mL DCM中的(2S,4R)-(9H-芴-9-基)甲基4-(叔丁氧基)-2-((4-(唑-5-基)苄基)氨甲酰基)吡咯烷-1-羧酸酯(2,5g,3.61mmol,1.0当量)装载三(2-氨基乙基)胺mol,9.0mmol,2.5当量)。(400,在搅拌3h后,将混浊的混合物用硅胶稀释并浓缩。然后将物质干燥,负载于硅胶柱,并纯化(DCM至5% MeOH(0.5N NH3)在DCM中),以生成820mg(67%产率),为白色固体。1H NMR(501MHz,CDCl3)δ8.02(s,1H),7.90(s,1H),7.60(d,J=8.1,2H),7.33-7.29(m,3H),4.44(d,J=6.1,2H),4.21-4.07(m,1H),3.97(dd,J=7.2,8.7,1H),2.87(d,J=11.6,1H),2.80(dd,J=4.3,11.6,1H),2.17(dd,J=10.2,12.4,1H),2.11-1.94(m,1H),1.16(s,9H);13C NMR(126MHz,CDCl3)δ174.88,151.27,150.40,139.33,128.07,126.79,124.63,121.43,73.65,72.30,59.95,54.97,42.51,39.27,28.38;TLC:(9:1DCM:MeOH(0.5NNH3))Rf=0.42;LRMS(ESI)344.2(M+H)+。
1H NMR(400MHz,CD3OD)δ7.42-7.28(m,4H),7.28-7.12(m,2H),7.10-6.77(m,2H),4.71(dt,J=30.7,15.3Hz,1H),4.58-4.30(m,3H),4.18-3.92(m,2H),3.87-3.77(m,1H),3.44(d,J=11.4Hz,1H),2.38-2.24(m,1H),2.15-2.03(m,1H),1.55-1.23(m,3H)。13C NMR(126MHz,CD3OD)δ174.72,172.63,160.34,138.72,138.35,133.82,130.65,130.11,129.92,129.55,120.47,118.08,114.27,113.89,71.01,64.71,60.81,59.80,43.33,39.29,15.09。MS(ESI)403.2(M+H)。
一般方法D:代表性程序:VL217
(2S,4R)-4-(叔丁氧基)-1-(3-乙氧基苯甲酰基)-N-(4-(唑-5-基)苄基)吡咯烷-2-羧酰胺
将3-乙氧基苯甲酸(13.3mg,0.08mmol,1eq)、EDC(16.9mg,0.088mmol,1.1eq)和HOBt(11.9mg,0.88mmol,1.1eq)在室温下溶解于DCM(0.8mL)中。添加DIPEA(0.0279mL,0.16mmol,2eq),然后(2S,4R)-4-(叔丁氧基)-N-(4-(唑-5-基)苄基)吡咯烷-2-羧酰胺(33.0mg,0.096mmol,1.2eq)。将溶液搅拌21小时,然后用EtOAc稀释和用10%柠檬酸、饱和碳酸氢钠和盐水洗涤。将有机层在硫酸钠上干燥,过滤和浓缩。通过柱层析(1至5% MeOH/DCM)纯化提供无色油(36.1mg,0.073mmol,92%)。1H NMR(400MHz,CDCl3)δ7.90(s,1H),7.61(dd,J=16.6,6.9Hz,3H),7.38-7.27(m,4H),6.98(dd,J=16.0,6.4Hz,3H),4.92(dd,J=8.3,4.7Hz,1H),4.48(d,J=6.0Hz,2H),4.43-4.31(m,1H),4.03(q,J=7.0Hz,2H),3.61(dd,J=10.9,5.7Hz,1H),3.31(dd,J=10.9,4.4Hz,1H),2.73-2.55(m,1H),2.05-1.92(m,1H),1.40(t,J=7.0Hz,3H),1.13(s,9H)。MS(ESI)492.4(M+H)。
VL217
将(2S,4R)-4-(叔丁氧基)-1-(3-乙氧基苯甲酰基)-N-(4-(唑-5-基)苄基)吡咯烷-2-羧酰胺(36.1mg,0.073mmol,1eq)在室温下溶解于DCM(9mL)中。添加TFA(1mL)并将溶液搅拌13小时,然后浓缩。通过柱层析(1至10% MeOH/DCM)纯化提供无色油(22.9mg,0.053mmol,72%)。1H NMR(400MHz,CD3OD)δ8.24(d,J=12.0Hz,1H),7.65(dd,J=28.0,8.3Hz,2H),7.47(dd,J=18.8,10.6Hz,3H),7.23(ddd,J=9.4,4.6,4.1Hz,3H),7.09-6.87(m,2H),4.75(dd,J=9.6,7.7Hz,1H),4.48(dd,J=49.7,15.5Hz,3H),4.06(q,J=7.0Hz,2H),3.84(dd,J=11.5,3.5Hz,1H),3.44(d,J=11.5Hz,1H),2.42-2.29(m,1H),2.21-2.05(m,1H),1.36(dt,J=24.0,7.0Hz,3H)。13C NMR(101MHz,CD3OD)δ174.78,172.66,160.35,153.14,152.74,140.85,138.38,130.66,129.00,127.71,125.62,121.77,120.50,118.08,114.30,71.02,64.71,60.85,59.82,43.72,39.32,
(2S,4R)-叔丁基4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨甲酰基)吡咯烷-1-羧酸酯
将(2S,4R)-1-(叔丁氧基羰基)-4-羟基吡咯烷-2-羧酸(366mg,1.58mmol,1当量)溶解于15mL DMF中,并添加EDC(380mg,2.0mmol 1.3当量)、和HOBt(310mg,2.0mmol,1.5当量),在搅拌5分钟后,添加(4-(4-甲基噻唑-5-基)苯基)甲胺(325mg,1.58mmol,1当量)。在搅拌15h后,将反应用25mL EtOAc稀释,和用25mL盐水(2X)然后25mL饱和NaHCO3(2X)洗涤。将有机层浓缩,以生成650mg(98%产率)产物,为黄色油。1H NMR(400MHz,CDCl3)δ8.67(s,1H),7.43-7.29(m,4H),4.49(d,J=16.7Hz,4H),3.51(dd,J=11.0,4.7Hz,2H),2.61-2.45(m,4H),2.03(d,J=7.4Hz,2H),1.42(s,9H).TLC:(9:1DCM:MeOH(0.5NNH3))Rf=0.20;MS(ESI)417.5(M+H)+。
(2S,4R)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺
向圆底烧瓶中的(2S,4R)-叔丁基4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨甲酰基)吡咯烷-1-羧酸酯(650mg,1.40mmol,1当量)装载二烷中的9mL 4M HCL(36mmol,26当量)。将反应搅拌1h,然后鼓充N2 1h,并将挥发物通过真空去除。将所得粘性油溶解于水中洗涤,和用50mL EtOAC洗涤。然后水层用1M NaOH碱化至pH 12,然后用50mL EtOAC(3×)萃取。将有机层干燥并浓缩,以生成250mg(79%产率)产物,为棕色粘性油。1H NMR(501MHz,CDCl3)δ8.66(s,1H),8.18(t,J=6.0,1H),7.38(d,J=8.1,2H),7.30(d,J=8.1,2H),4.48-4.37(m,3H),4.08(t,J=8.4,1H),3.02(d,J=13.3,1H),2.79(dd,J=3.2,12.3,1H),2.51(s,3H),2.33(dd,J=8.6,13.9,1H),2.03-1.87(m,1H);13C NMR(126MHz,CDCl3)δ174.89,150.35,148.46,138.30,131.54,130.95,129.51,127.92,72.90,59.72,55.35,42.53,39.98,16.06;TLC:(9:1DCM:MeOH)Rf=0.1;LRMS(ESI)317.4(M+H)+。
一般方法E:代表性程序:VL219
VL219
将3-乙氧基苯甲酸(17mg,0.1mmol,1当量)溶解于中1mL 10:1DCM:DMF并添加EDC(25mg,0.13mmol 1.3当量)和HOBt(21mg,0.13mmol,1.3当量)。搅拌5分钟后,添加(2S,4R)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺(31mg,0.095mmol,1当量)。搅拌18h后,将反应用15mL EtOAc稀释和用25mL 10%含水柠檬酸和25mL饱和NaHCO3洗涤。将有机层用Na2SO4干燥并通过真空浓缩。通过硅胶层析(DCM至9% MeOH(0.5N NH3)在DCM中)纯化所得油,以生成25mg(56%产率)产物,为白色固体。1H NMR(501MHz,CD3OD)δ8.87(s,1H),7.51-7.42(m,4H),7.37(t,J=8.1,1H),7.23-7.14(m,2H),7.05(dd,J=2.2,8.4,1H),4.79(dd,J=7.7,9.5,1H),4.63-4.40(m,3H),4.08(q,J=7.0,2H),3.86(dt,J=3.8,7.6,1H),3.47(d,J=11.5,1H),2.47(s,3H)2.36(dd,J=7.6,13.2,1H),2.14(ddd,J=5.3,10.2,16.4,1H),1.41(t,J=7.0,3H);13C NMR(126MHz,CD3OD)δ174.74,172.64,160.34,152.78,149.05,140.21,138.40,133.39,131.55,130.65,130.44,128.83,120.49,118.07,114.32,71.02,64.71,60.83,59.81,43.67,39.30,15.79,15.06;TLC:(9:1DCM:MeOH(0.5N NH3))Rf=0.25;LRMS(ESI)466.1(M+H)+。
VL210
根据一般方法D合成VL210。1H NMR(500MHz,CD3OD)δ8.23(s,1H),7.82(t,J=1.7,1H),7.73-7.58(m,4H),7.49-7.33(m,4H),4.76(dd,J=7.6,9.6,1H),4.59-4.32(m,3H),3.84(dd,J=3.5,11.4,1H),3.41(d,J=11.3,1H),2.43-2.30(m,1H),2.18-2.07(m,1H);13CNMR(126MHz,CD3OD)δ173.14,169.54,151.35,139.41,137.87,133.28,130.18,130.01,127.92,127.61,126.31,125.93,124.23,121.93,120.36,69.62,59.53,58.30,42.31,37.95;LRMS(ESI)471.5(M+H)+。
VL224
根据一般方法E合成VL224。1H NMR(501MHz,CD3OD)δ8.87(s,1H),7.83(d,J=1.5,1H),7.67(d,J=7.1,1H),7.61(d,J=6.7,1H),7.48-7.36(m,5H),4.77(t,J=8.5,1H),4.60-4.39(obscured m,3H),3.90-3.78(m,1H),3.42(d,J=11.4,1H),2.47(s,3H),2.41-2.30(m,1H),2.19-2.06(m,1H);13C NMR(126MHz,CD3OD)δ173.15,169.55,151.41,147.64,138.77,137.85,133.26,132.78,131.98,130.16,130.02,129.05,127.43,125.91,121.93,69.64,59.53,58.32,42.27,37.94,14.41;TLC:(9:1DCM:MeOH(0.5N NH3))Rf=0.7;LRMS(ESI)499.8(M+H)+。
VL215
根据一般方法D合成VL215。1H NMR(501MHz,CD3OD)δ8.24(dd,J=13.4,7.1Hz,1H),7.87-7.58(m,3H),7.58-7.31(m,4H),7.16(s,1H),4.73(d,J=7.8Hz,1H),4.63-4.50(m,1H),4.49-4.29(m,2H),3.80(d,J=10.5Hz,1H),3.60(s,1H),2.31(s,1H),2.17(s,1H)。13CNMR(126MHz,CD3OD)δ179.37,169.61,153.12,152.75,140.72,138.21,137.16,133.72,130.38,129.70,129.40,129.08,127.76,125.63,121.80,70.64,60.46,58.42,43.80,39.27。MS(ESI)504.2(M+H)。
VL228
根据一般方法E合成VL228。NMR(400MHz,CD3OD)δ8.88(d,J=9.3Hz,1H),7.75(d,J=1.9Hz,1H),7.48(ddd,J=13.9,8.4,4.1Hz,5H),7.17(d,J=8.3Hz,1H),4.74(t,J=8.2Hz,1H),4.63-4.33(m,3H),3.61(dd,J=11.3,3.8Hz,1H),3.18(d,J=11.3Hz,1H),2.49(d,J=9.6Hz,3H),2.33(ddd,J=7.8,4.8,2.1Hz,1H),2.19(ddd,J=11.9,7.8,4.6Hz,1H)。13CNMR(126MHz,CD3OD)δ173.93,169.45,152.84,149.07,140.11,138.21,137.17,133.73,131.62,130.53,130.48,130.39,129.52,129.41,128.93,70.65,60.48,58.39,43.75,39.26,15.81。MS(ESI)534.4(M+H)。
VL177
根据一般方法D合成VL177。1H NMR(500MHz,CDCl3/CD3OD)δ7.89(s,1H);7.84(s,1H);7.80-7.75(m,2H);7.69(d,J=7.8Hz,1H);7.57-7.48(m,3H);7.31(d,J=8.1Hz,2H);4.76(t,J=8.3Hz,1H);4.49-4.39(m,3H);3.72(dd,J=11.2,3.5Hz,1H);3.36(d,J=11.2Hz,1H);2.93(s,1H);2.31(ddd,J=13.2,8.8,4.4Hz,1H);2.21(dd,J=13.5,7.8Hz,1H)。13C NMR(125MHz,CDCl3/CD3OD)δ171.8,169.0,151.5,150.6,138.9,137.0,133.9,131.9,131.3,129.5,128.1,126.7,124.7,121.1,117.9,112.7,69.9,59.3,58.5,43.3,37.4。TLC(10% MeOH,在CH2Cl2中),Rf 0.17(UV,CAM),MS(ESI+):计算C23H21N4O4[M+H]+417.2,发现417.1。
VL226
根据一般方法E合成VL226。1H NMR(500MHz,CDCl3/CD3OD)δ8.65(s,1H);7.84(s,1H);7.74(dd,J=13.3,7.8Hz,2H);7.53(t,J=7.8Hz,1H);7.40-7.28(m,5H);4.92(t,J=8.1Hz,1H);4.53(s,1H);4.48(d,J=5.9Hz,2H);3.72(dd,J=11.3,3.5Hz,1H);3.52-3.44(m,1H);2.85(br s,1H);2.67-2.56(m,1H);2.48(s,3H);2.21(dd,J=13.5,7.8Hz,1H)。13CNMR(125MHz,CDCl3/CD3OD)δ170.8,169.4,150.5,148.6,138.0,137.0,134.1,131.9,131.4,129.7,129.6,127.0,118.0,113.0,70,4,59.1,58.6,43.5,36.8,16.2。TLC(10% MeOH,在CH2Cl2中),Rf 0.32(UV,CAM),MS(ESI+):计算C24H23N4O3S[M+H]+447.2,发现447.0。
VL211
根据一般方法D合成VL211。1H NMR(500MHz,CD3OD)δ8.11(s,1H),7.58(dd,J=2.3,8.2,2H),7.42-7.30(m,3H),7.16(t,J=7.9,1H),6.96(d,J=7.7,1H),6.92(s,1H),6.80(dd,J=2.3,8.1,1H),4.65(t,J=8.6,1H),4.47-4.26(m,3H),3.71(dt,J=4.0,8.0,1H),3.36(d,J=11.6,1H),2.32-2.16(m,1H),2.08-1.94(m,1H);13C NMR(126MHz,CD3OD)δ174.74,172.77,158.71,153.14,152.70,140.83,138.38,130.62,128.98,127.69,125.62,121.75,119.39,118.61,115.27,71.01,60.77,59.79,43.73,39.25;TLC:(9:1DCM:MeOH Rf=0.15;LRMS(ESI)408.3(M+H)+。
VL225
根据一般方法E合成Vl225。1H NMR(501MHz,CD3OD)δ8.86(s,1H),7.49-7.34(m,4H),7.27(t,J=7.8,1H),7.11-7.00(m,2H),6.93-6.84(m,1H),4.77(t,J=8.5,1H),4.57-4.38(m,3H),3.84(dd,J=3.3,11.5,1H),3.47(d,J=11.5,1H),2.46(S,3H)2.34(dd,J=7.1,12.5,1H),2.18-2.06(m,1H);13C NMR(126MHz,CD3OD)δ173.35,171.36,157.31,151.39,147.62,138.81,136.95,130.12,129.21,129.04,127.62,127.41,117.97,117.19,113.84,69.61,59.37,58.41,42.24,37.85,14.37;TLC:(9:1DCM:MeOH)Rf=0.3;LRMS(ESI)437.0(M+H)+。
VL178
根据一般方法D合成VL178。1H NMR(400MHz,CD3OD)δ8.84(t,J=5.9,1H),8.26(d,J=5.9,1H),7.73(d,J=8.3,2H),7.55-7.45(m,3H),7.06(t,J=7.8,1H),6.86-6.76(m,1H),6.68(d,J=7.3,1H),4.75(t,J=8.4,1H),4.66-4.35(m,3H),3.55(dd,J=3.5,11.6,1H),3.24(d,J=11.4,1H),2.41-2.26(m,1H),2.21-2.10(m,4H);13C NMR(126MHz,CD3OD)δ173.21,172.03,151.32,145.03,139.46,137.30,130.95,127.61,126.53,126.29,124.22,123.96,120.35,116.31,115.97,74.46,69.35,58.72,42.46,38.02,23.61;LRMS(ESI)420.4(M+H)+。
VL229
将(2S,4R)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺(24mg,0.0756mmol,1eq)、3-氨基-2-甲基苯甲酸(13mg,0.083mmol,1.1eq)、EDC(16mg,0.083mmol,1.1eq)和HOBt(11mg,0.083mmol,1.1eq)在室温下溶解于DMF(0.76mL)中。添加DIPEA(0.02mL,0.113mmol,1.5eq),并将溶液搅拌17小时。然后溶液在1M NaOH和EtOAc之间分配,分离,并再用EtOAc萃取两次。将组合的有机层在硫酸钠上干燥,过滤和浓缩。通过柱层析(1至10%0.5N甲醇氨/DCM)纯化提供白色固体(20.5mg,0.045mmol,60%)。1H NMR(501MHz,CD3OD)δ8.87(t,J=6.6Hz,1H),7.45(dt,J=20.5,7.7Hz,4H),7.03(t,J=7.6Hz,1H),6.78(d,J=7.8Hz,1H),6.65(s,1H),4.74(t,J=8.1Hz,1H),4.67-4.34(m,3H),3.53(d,J=11.3Hz,1H),3.21(d,J=9.3Hz,1H),2.48(d,J=3.1Hz,3H),2.32(d,J=7.6Hz,1H),2.14(dd,J=31.4,20.5Hz,4H)。13C NMR(126MHz,CD3OD)δ174.56,173.67,152.89,152.81,149.04,147.80,140.23,138.57,133.44,131.54,130.46,128.86,127.83,117.01,116.36,70.77,69.66,60.09,43.70,39.41,15.81,13.92。MS(ESI)450.6(M+H),473.4(M+Na)。
进一步的参考文献参见下列文章和其中引用的参考文献:
(1)Buckley DL等.J.Am.Chem.Soc 2012,134,4465-4468.
(2)Van Molle I等.A Chemistry&Biology 2012,19,1300-1312
(3)Buckley,D Angew.Chem.Int.Ed.,2012,51,11463-11467
(4)Buckley,D.L等.Angew.Chem.2012,124,11630-11634。
实施例——亲和力表II的化合物165-266
下列化合物根据所述一般方法合成,通过标准层析法纯化,并具有与预期结构一致的1H和13C NMR和MS数据。
VL165:
根据一般方法B合成VL165。
VL168&169
利用来自Surya Prakash,G.K.;Mandal,M.;Olah,G.A.Angew.Chem.Int.Ed.2001,40,589-690的程序合成手性RHS胺区段。
VL168
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根据一般方法F合成VL168。
VL169
根据一般方法F合成VL169。
VL174
VL174一般方法C
VL175:一般方法C
VL170:一般方法C
VL190:一般方法B
VL191:一般方法B
VL182:一般方法B
VL183:一般方法B
VL184:一般方法C
VL185:一般方法C
VL187:一般方法B
VL188:一般方法B
VL189:一般方法B
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VL192-VL205:固相合成一般方法B
VL206:一般方法C
VL207一般方法C
VL212一般方法C
VL214一般方法C
VL218一般方法C
VL220一般方法C
VL221一般方法C
VL222一般方法C
VL255一般方法C
VL256一般方法E
VL213:一般方法C
VL223:一般方法D
VL230:一般方法D
VL231:一般方法E
VL238:一般方法B
VL240:一般方法E
VL241:一般方法B
VL242:一般方法E
VL243:一般方法E
VL244:一般方法B
VL245:一般方法E
将3-羟基-2-甲基苯甲酸(26.3mg,0.173mmol,1.1eq)、EDC(33.2mg)和HOBt(23.4mg)在4℃下溶解于DCM(0.8mL)和DMF(0.1mL)中。10分钟后,添加(2S,4R)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺(0.5mL在DCM中的100mg/mL溶液),并使混合物升温至室温。21小时后,将混合物用10mL半饱和氯化钠稀释,并用10mL EtOAc萃取三次。将组合的有机层在硫酸钠上干燥,过滤和浓缩。通过柱层析(1至10% MeOH/DCM)纯化提供白色固体(29.2mg,0.0647,41%)。1H NMR(400MHz,MeOD)δ8.93-8.82(m,1H),7.55-7.36(m,4H),7.10(t,J=7.8Hz,1H),6.83(dd,J=10.3,7.9Hz,2H),4.76(t,J=8.4Hz,1H),4.66-4.38(m,3H),3.56(dd,J=11.6,3.6Hz,1H),3.22(d,J=11.6Hz,1H),2.54-2.47(m,3H),2.41-2.31(m,1H),2.19(dt,J=11.3,10.9Hz,4H)。13C NMR(126MHz,MeOD)δ174.50,173.09,157.22,152.89,152.80,149.01,140.21,139.18,133.42,131.52,130.44,128.85,127.94,117.84,116.42,70.73,69.62,60.12,43.69,39.38,15.79,12.70。MS(ESI)452.5(M+H)。
VL247:一般方法C
VL248:一般方法E
VL249:一般方法E
VL250:一般方法E
VL253:一般方法C
VL254:一般方法C
VL257:一般方法C
VL258:一般方法C
VL259:一般方法C
VL260:一般方法E
VL261:一般方法E
VL262:一般方法E
VL263:一般方法E
VL264:一般方法E
VL265:一般方法E
VL251
(2S,4R)-1-((S)-2-((S)-2-乙酰氨基-4-甲基戊酰氨基)丙酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺
叔丁基((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-基)-1-氧代丙烷-2-基)氨基甲酸酯
将Boc-Ala-OH(189mg,1.0-mmol)溶解于10mL DCM中并装载EDC(248mg,1.2mmol)、和HOBt(202mg,1.3mmol),搅拌5分钟后,添加(2S,4R)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(carboxamide)(317mg,1.0mmol)。搅拌18h后,将反应用10mL DCM稀释和用10mL 10%含水柠檬酸然后5mL饱和NaHCO3洗涤。将混合物浓缩并通过硅胶层析纯化(DCM/MeOH梯度),以生成210mg(43%产率)产物,为白色固体。1H NMR(501MHz,CDCl3)δ8.65(s,1H),7.58(s,1H),7.31(d,J=8.1,2H),7.26(d,J=8.0,2H),5.44(d,J=7.4,1H),4.66(t,J=7.6,1H),4.52(s,1H),4.39(m,3H),3.78(d,J=10.9,1H),3.59(d,J=7.0,1H),2.47(s,3H),2.30(s,1H),2.10(s,1H),1.54-1.31(m,9H),1.26(d,J=6.9,3H);13C NMR(126MHz,CDCl3)δ173.1,171.2,155.5,150.5,148.2,138.2,130.7,129.4,127.6,80.1,70.1,58.8,55.2,48.0,42.3,36.5,28.3,18.0,16.0;LRMS(ESI)489.4(M+H)+。
VL251
(2S,4R)-1-((S)-2-((S)-2-乙酰氨基-4-甲基戊酰氨基)丙酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺
将Boc-Ala-Hyp-苄基噻唑(116mg,0.225mmol)溶解于1mL DCM中并装载2.3mL二烷中的4M HCL。搅拌1小时后,将氮气通入混合物15分钟,并通过旋转蒸发器去除剩余挥发物。然后将所得泡沫溶解于中5mL 1:1DCM:DMF并装载EDC(56mg,0.29mmol)、HOBt(45mg,0.29mmol),和添加Ac-Leu-OH(43mg,0.25mmol)。搅拌5分钟后,添加三乙胺。搅拌18h后,将反应用10mL EtOAc稀释和用10mL 10%含水柠檬酸然后5mL饱和NaHCO3洗涤。然后用2×10mL DCM反萃取水层。将有机层组合,并将混合物浓缩并通过硅胶层析(DCM/MeOH梯度)纯化,以生成35mg(29%产率)产物,为白色固体。1H NMR(501MHz,CDCl3)δ8.68(s,1H),8.05(s,1H),7.70(s,1H),7.36(d,J=7.3,2H),7.28(d,J=8.6,2H),6.50(s,1H),4.85-4.73(m,2H),4.68(s,1H),4.59(s,1H),4.40(d,J=32.4,2H),3.84(d,J=10.7,1H),3.70(d,J=10.5,1H),2.51(s,3H),2.30(s,1H),2.21(s,1H),1.85(s,3H),1.59(s,1H),1.50(s,2H),1.34(d,J=6.7,3H),0.86(t,J=6.7,6H);13C NMR(126MHz,CDCl3)δ172.1,172.0,171.2,170.8,150.4,148.4,138.1,129.5,129.4,127.8,110.0,70.36,58.9,55.5,51.8,46.9,43.1,41.8,36.9,24.7,23.2,23.1,21.8,17.9,16.0;LRMS(ESI)545.1(M+H)+。
VL252
(2S,4R)-1-((S)-2-((S)-2-氨基-4-甲基戊酰氨基)丙酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺
将Boc-Ala-Hyp-苄基噻唑(116mg,0.225mmol)溶解于1mL DCM中并添加2.3mL二烷中的4M HCL。搅拌1小时后,将氮气通入混合物15分钟,并通过旋转蒸发器去除剩余挥发物。然后将所得泡沫溶解于5mL 1:1DCM:DMF中并装载EDC(56mg,0.29mmol)、HOBt(45mg,0.29mmol),和添加Boc-Leu-OH(62mg,0.25mmol)。搅拌5分钟后,添加三乙胺。搅拌18h后,将反应用10mL EtOAc稀释和用10mL 10%含水柠檬酸然后5mL饱和NaHCO3洗涤。组合有机层,并将混合物浓缩,以生成55mg(40%产率)产物,为白色固体。LRMS(ESI)602.0(M+H)+。在通过质谱法确认后,将产物溶解于2mL 1:1DCM:MeOH中并装载3mL二/>烷中的4M HCl。搅拌45分钟后,用5ml甲醇中的0,5N氨淬灭反应。将溶剂蒸发并通过硅胶层析(梯度为DCM/MeOH(0.5N NH3)纯化,以生成50mg纯产物,为白色固体。1H NMR(501MHz,CDCl3)δ8.25(s,1H),6.91(dd,J=7.3,18.0,4H),4.17(d,J=7.5,2H),4.06(d,J=22.4,2H),3.95(d,J=15.3,1H),3.56-3.42(m,2H),3.24(d,J=7.8,1H),2.05(s,3H),1.86-1.77(m,1H),1.77-1.65(m,1H),1.35-1.19(m,2H),1.13(s,1H),0.93(d,J=6.8,3H),0.50(dd,J=6.3,9.8,6H);13CNMR(126MHz,CDCl3)δ171.6,171.5,150.3,147.7,137.9,131.4,130.1,129.0,127.3,109.9,69.7,58.6,55.11,46.9,42.5,36.7,24.1,22.4,22.2,16.2,15.3;LRMS(ESI)502.0(M+H)+。
VL253:一般方法C
VL254:一般方法C
VL257:一般方法C
VL258:一般方法C
VL259:一般方法C
VL260:一般方法E
VL261:一般方法E
VL262:一般方法E
VL263:一般方法E
VL264:一般方法E
VL265:一般方法E
图15的化合物的实施例
下列程序用于合成和/或表征所示的根据本发明所述的化合物
LCMS方法:
分析在40℃下、Acquity UPLC BEH C18柱(50mm×2.1mm内径1.7μm填料直径(packing diameter))上进行。
所用溶剂是:
A=0.1%v/v甲酸水溶液。
B=0.1%v/v甲酸的乙腈溶液。
所用梯度如下:
UV检测是波长210nm至350nm的平均化信号,并且质谱在利用交替扫描正负模式电喷雾电离化的质谱仪上进行记录。
如下示例化合物当通过质量导向自动制备型HPLC进行纯化时所用的流动相和梯度。
质量导向自动制备型HPLC(甲酸改性剂)
HPLC分析在环境温度下在Sunfire C18柱(150mm×30mm内径,5μm填料直径)上进行。
所用溶剂是:
A=0.1%v/v甲酸水溶液。
B=0.1%v/v甲酸的乙腈溶液。
质量导向自动制备型HPLC(三氟乙酸改性剂)
HPLC分析在环境温度下在Sunfire C18柱(150mm×30mm内径,5μm填料直径)上进行。
所用溶剂是:
A=0.1%v/v三氟乙酸水溶液。
B=0.1%v/v三氟乙酸的乙腈溶液。
质量导向自动制备型HPLC(碳酸氢铵改性剂)
HPLC分析在环境温度下在XBridge C18柱(150mm×30mm内径,5μm填料直径)上进行。
所用溶剂是:
A=10mM碳酸氢铵的水溶液,用氨溶液调节至pH 10。
B=乙腈。
对于每个质量导向自动制备型纯化,与所用改性剂无关,所用梯度取决于分析LCMS中记录的进行纯化的具体化合物的保留时间,如下:
对于分析LCMS保留时间在0.6分钟以下的化合物,应用下列梯度:
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对于分析LCMS保留时间在0.6和0.9分钟之间的化合物,应用下列梯度:
对于分析LCMS保留时间在0.9和1.2分钟之间的化合物,应用下列梯度:
对于分析LCMS保留时间在1.2和1.4分钟之间的化合物,应用下列梯度:
UV检测是波长210nm至350nm的平均化信号,并且质谱在应用交替扫描正负模式电喷雾电离化的质谱仪上进行记录。
化学名称利用来自Advanced Chemistry Development,Inc.的ACD Name Proversion 6.02生成。
实施例
(2S,4R)-1-(2-乙氧基苯甲酰基)-4-羟基-N-(4-(唑-5-基)苄基)吡咯烷-2-羧酰胺
将2-乙氧基苯甲酸(可购自例如Aldrich)(29mg,0.17mmol)、(2S,4R)-4-羟基-N-(4-(唑-5-基)苄基)吡咯烷-2-羧酰胺(50mg,0.17mmol)和DIPEA(0.061mL,0.35mmol)在DMF(1mL)中的溶液用HATU(80mg,0.21mmol)处理,并将混合物在环境温度下搅拌2小时。然后产物通过质量导向自动制备型HPLC(甲酸改性剂)进行纯化,以提供标题化合物(38mg,0.087mmol,50%产率)。LCMS RT=0.72min,ES+ve m/z 436[M+H]+。
利用与(2S,4R)-1-(2-乙氧基苯甲酰基)-4-羟基-N-(4-(唑-5-基)苄基)吡咯烷-2-羧酰胺类似的方法,制备下列化合物:/>
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(S)-1-((2S,4R)-4-羟基-2-((4-(唑-5-基)苄基)氨甲酰基)吡咯烷-1-基)-1-氧代丙烷-2-基乙酸酯和(2S,4R)-4-羟基-1-((S)-2-羟基丙酰基)-N-(4-(/>唑-5-基)苄基)吡咯烷-2-羧酰胺
将(2S,4R)-4-羟基-N-(4-(唑-5-基)苄基)吡咯烷-2-羧酰胺盐酸(60mg,0.19mmol)和(S)-2-乙酰氧基丙酸(可购自例如Aldrich)(25mg,0.19mmol)在DMF(1.2mL)中的搅拌混合物用DIPEA(0.13mL,0.74mmol),然后用HATU(85mg,0.22mmol)处理,并将混合物在环境温度下搅拌30分钟。然后将一半反应混合物通过质量导向自动制备型HPLC(甲酸改性剂)进行纯化,以提供(S)-1-((2S,4R)-4-羟基-2-((4-(/>唑-5-基)苄基)氨甲酰基)吡咯烷-1-基)-1-氧代丙烷-2-基乙酸酯(21mg,0.052mmol,28%产率)。LCMS RT=0.58min,ES+ve m/z 402[M+H]+。
将剩余一半反应混合物用氨(在甲醇中的2M溶液)(2mL)处理,密封和静置1天。然后蒸发溶液至干燥,并将产物通过质量导向自动制备型HPLC(甲酸改性剂)进行纯化,以提供(2S,4R)-4-羟基-1-((S)-2-羟基丙酰基)-N-(4-(唑-5-基)苄基)吡咯烷-2-羧酰胺(18mg,0.050mmol,27%产率)。LCMS RT=0.53min,ES+ve m/z 360[M+H]+。
(2S,4R)-苄基4-羟基-1-(2-(3-甲基异唑-5-基)乙酰基)吡咯烷-2-羧酸酯
2-(3-甲基异唑-5-基)乙酸(可购自例如Aldrich)(0.91g,6.4mmol)和(2S,4R)-苄基4-羟基吡咯烷-2-羧酸酯,盐酸盐(1.67g,6.5mmol)在DMF(9mL)中的冰冷却混合物用DIPEA(3.4mL、19mmol),然后用HATU(2.56g,6.7mmol)处理20分钟。将混合物搅拌并冷却30分钟,然后在环境温度下过夜。然后将混合物用饱和碳酸氢钠水溶液(50mL)处理,用二氯甲烷(4×60mL)萃取,并将组合的有机相经疏水玻璃料过滤,并蒸发至干燥。产物利用二氯甲烷中0%至15%甲醇的梯度洗脱、通过快速层析(100g柱体)纯化,以提供标题化合物(2.3g,6.7mmol,定量)。LCMS RT=0.75min,ES+ve m/z 345[M+H]+。
(2S,4R)-N-((3,4-二氢-2H-苯并[b][1,4]嗪-2-基)甲基)-4-羟基-1-(2-(3-甲基异/>唑-5-基)乙酰基)吡咯烷-2-羧酰胺
将(2S,4R)-4-羟基-1-(2-(3-甲基异唑-5-基)乙酰基)吡咯烷-2-羧酸(90mg,0.35mmol)、(3,4-二氢-2H-苯并[b][1,4]/>嗪-2-基)甲胺(可购自例如Fluorochem)(58mg,0.35mmol)和DIPEA(0.155mL,0.89mmol)在DMF(2mL)中的溶液用HATU(139mg,0.37mmol)处理并搅拌1小时。产物通过质量导向自动制备型HPLC(甲酸改性剂)进行纯化,以提供标题化 合物(84mg,0.21mmol,60%产率)LCMS RT=0.61min,ES+ve m/z 401[M+H]+。
(2S,4R)-N-(4-氯苄基)-4-羟基-1-(2-(3-甲基异唑-5-基)乙酰基)吡咯烷-2-羧酰胺
将(4-氯苯基)甲胺(可购自例如Aldrich)(0.021mL,0.17mmol)和(2S,4R)-4-羟基-1-(2-(3-甲基异唑-5-基)乙酰基)吡咯烷-2-羧酸(40mg,0.16mmol)在DMF(1mL)中的溶液用DIPEA(0.082mL,0.47mmol)然后用HATU(66mg,0.17mmol)处理,并将混合物在环境温度下搅拌2小时。产物通过质量导向自动制备型HPLC(甲酸改性剂)进行纯化,以提供标题化 合物(24mg,0.064mmol,40%产率)。LCMS RT=0.73min,ES+ve m/z 378[M+H]+。
(2S,4R)-4-羟基-1-(2-(3-甲基异唑-5-基)乙酰基)-N-(4-(2-氧代-2,3-二氢苯并[d]/>唑-5-基)苄基)吡咯烷-2-羧酰胺
将(2S,4R)-4-羟基-1-(2-(3-甲基异唑-5-基)乙酰基)吡咯烷-2-羧酸(60mg,0.24mmol)和5-(4-(氨基甲基)苯基)苯并[d]/>唑-2(3H)-酮,盐酸盐(65mg,0.24mmol)在DMF(1.6mL)中的混合物用DIPEA(0.124mL,0.71mmol)和HATU(99mg,0.26mmol)处理,并将混合物搅拌30分钟。然后产物通过质量导向自动制备型HPLC(甲酸改性剂)进行纯化,以提供标题化合物(64mg,0.13mmol,57%产率)。LCMS RT=0.70min,ES+ve m/z 477[M+H]+。
(2S,4R)-N-(1-(苯并呋喃-2-基)乙基)-4-羟基-1-(2-(3-甲基异唑-5-基)乙酰基)吡咯烷-2-羧酰胺
(2S,4R)-4-羟基-1-(2-(3-甲基异唑-5-基)乙酰基)吡咯烷-2-羧酸(90mg,0.35mmol)、1-(苯并呋喃-2-基)乙胺(可购自例如Enamine)(57mg,0.35mmol)和DIPEA(0.155mL,0.89mmol)在DMF(2mL)中的搅拌溶液用HATU(139mg,0.37mmol)处理。1小时后,产物通过质量导向自动制备型HPLC(甲酸改性剂)进行纯化,以提供标题化合物(91mg,0.21mmol,65%产率)LCMS RT=0.79min,ES+ve m/z398[M+H]+。
(2S,4R)-N-([1,1'-二苯基]-4-基甲基)-4-羟基-1-(2-(3-甲基异唑-5-基)乙酰基)吡咯烷-2-羧酰胺
将(2S,4R)-4-羟基-1-(2-(3-甲基异唑-5-基)乙酰基)吡咯烷-2-羧酸(30mg,0.12mmol)和[1,1'-联苯基]-4-基甲胺(可购自例如Aldrich)(22mg,0.12mmol)在DMF(0.8mL)中的搅拌混合物用DIPEA(0.08mL,0.47mmol),然后用HATU(49mg,0.13mmol)处理,并将混合物在环境温度下搅拌30分钟。产物通过质量导向自动制备型HPLC(甲酸改性剂)进行纯化,以提供标题化合物(40mg,81%产率)。LCMS RT=0.86min,ES+ve m/z 420[M+H]+。
利用与(2S,4R)-N-([1,1'-联苯基]-4-基甲基)-4-羟基-1-(2-(3-甲基异唑-5-基)乙酰基)吡咯烷-2-羧酰胺类似的方法,制备下列化合物:/>
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(2S,4R)-1-((S)-2-乙酰氨基丙酰基)-4-羟基-N-苯乙基吡咯烷-2-羧酰胺
将(2S,4R)-1-((S)-2-乙酰氨基丙酰基)-4-羟基吡咯烷-2-羧酸(24mg,0.10mmol)和2-苯基乙胺(可购自例如Aldrich)(0.012mL,0.10mmol)在DMF(0.8mL)中的搅拌混合物用DIPEA(0.07mL,0.39mmol),然后用HATU(45mg,0.12mmol)处理,并将混合物在环境温度下搅拌30分钟。产物通过质量导向自动制备型HPLC(甲酸改性剂)进行纯化,以提供标题化合物(25mg,72%产率)。LCMS RT=0.56min,ES+ve m/z 348[M+H]+。
利用与(2S,4R)-1-((S)-2-乙酰氨基丙酰基)-4-羟基-N-苯乙基吡咯烷-2-羧酰胺类似的方法,制备下列化合物:
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(S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨甲酰基)吡咯烷-1-基)-1-氧代丙烷-2-基乙酸酯&(2S,4R)-1-乙酰基-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺
(2S,4R)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺,盐酸盐(31mg,0.088mmol)和(S)-2-乙酰氧基丙酸(可购自例如Aldrich)(8μL,0.09mmol)在DMF(0.8mL)中的冰冷却混合物用DIPEA(0.074mL,0.42mmol)处理。然后经10分钟逐部分添加HATU(34mg,0.088mmol),并将混合物在环境温度下搅拌1小时。将产物分离并通过质量导向自动制备型HPLC(甲酸改性剂)纯化,以提供(S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨甲酰基)吡咯烷-1-基)-1-氧代丙烷-2-基乙酸酯(15mg,0.035mmol,41%产率)LCMS RT=0.64min,ES+ve m/z 432[M+H]+和(2S,4R)-1-乙酰基-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺(9mg,0.025mmol,30%产率)LCMS RT=0.57min,ES+vem/z 360[M+H]+。
(2S,4R)-1-(2-(氰基甲基)苯甲酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺
将(2S,4R)-4-羟基-N-(4-(噻唑-5-基)苄基)吡咯烷-2-羧酰胺(50mg,0.17mmol)和2-(氰基甲基)苯甲酸(可购自例如Aldrich)(29mg,0.18mmol)在DMF(0.7mL)中的搅拌混合物用DIPEA(0.086mL,0.49mmol),然后用HATU(69mg,0.18mmol)处理,并将混合物在环境温度下搅拌10分钟。产物通过质量导向自动制备型HPLC(甲酸改性剂)进行纯化,以提供标 题化合物(31mg,0.067mmol,41%产率)。LCMS RT=0.73min,ES+ve m/z 461[M+H]+。
利用与(2S,4R)-1-(2-(氰基甲基)苯甲酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺类似的方法,制备下列化合物:
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3-(2-(2-(2-(3-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨甲酰基)吡咯烷-1-羰基)苯氧基)乙氧基)乙氧基)乙氧基)丙酸
(2S,4R)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺,盐酸盐(682mg,2.2mmol)、3-((14,14-二甲基-12-氧代-3,6,9,13-四氧杂五癸基)氧)苯甲酸(778mg,2.0mmol)、DIPEA(1.36mL,7.8mmol)在DMF(12mL)中的冰冷却混合物用HATU(817mg,2.2mmol)处理。使混合物升温至环境温度并搅拌30分钟,然后用水(70mL)处理,并用乙酸乙酯(3×70mL)萃取。将组合的有机相用饱和碳酸氢钠水溶液(100mL)、水(100mL)、盐水(100mL)洗涤,在硫酸镁上干燥,过滤,并蒸发至干燥。将粗产物溶解于二氯甲烷(6mL)中并用TFA(2.0mL)处理。1小时后,将反应混合物蒸发至干燥,并应用从水(+0.1%甲酸)中10至95%乙腈(+0.1%甲酸)的梯度洗脱通过快速层析(60g C18柱体)纯化产物,以提供标题化 合物(568mg,45%产率)。LCMS RT=0.73min,ES+ve m/z 642[M+H]+。
(2S,4R)-4-羟基-1-(3-(2-甲氧基乙氧基)苯甲酰基)-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺
将(2S,4R)-4-羟基-1-(3-羟基苯甲酰基)-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺(55mg,0.13mmol)和碳酸钾(55mg,0.40mmol)在DMF(0.8mL)中的混合物用1-溴-2-甲氧基乙烷(可购自例如Aldrich)(0.024mL,0.25mmol)处理并在50℃下搅拌2.5小时。添加另外的1-溴-2-甲氧基乙烷(0.024mL,0.25mmol)并将混合物在50℃下搅拌过夜。产物通过质量导向自动制备型HPLC(甲酸改性剂)进行纯化,以提供标题化合物(41mg,0.083mmol,66%产率)LCMS RT=0.74min,ES+ve m/z496[M+H]+
(2S,4R)-4-羟基-1-(3-(2-(2-甲氧基乙氧基)乙氧基)苯甲酰基)-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺
将(2S,4R)-4-羟基-1-(3-羟基苯甲酰基)-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺(55mg,0.13mmol)和碳酸钾(55mg,0.40mmol)在DMF(0.8mL)中的混合物用1-溴-2-(2-甲氧基乙氧基)乙烷(可购自例如Aldrich)(0.034mL,0.25mmol)处理,并使反应在50℃下搅拌2.5小时。添加另外的1-溴-2-(2-甲氧基乙氧基)乙烷(0.034mL,0.25mmol)并将混合物在50℃下搅拌过夜。通过质量导向自动制备型HPLC(甲酸改性剂)产物进行纯化,以提供标题化合物(40mg,0.074mmol,59%产率)LCMS RT=0.74min,ES+ve m/z 540[M+H]+。
(2S,4R)-1-((S)-2-((S)-2-乙酰氨基-4-甲基戊酰氨基)丙酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺
将(2S,4R)-1-((S)-2-氨基丙酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺,盐酸盐(50mg,0.12mmol)和(S)-2-乙酰氨基-4-甲基戊酸(可购自例如Aldrich)(22mg,0.12mmol)在DMF(0.7mL)中的搅拌混合物用DIPEA(0.062mL,0.35mmol),然后用HATU(49mg,0.13mmol)处理,并将混合物在环境温度下搅拌10分钟。产物通过质量导向自动制备型HPLC(甲酸改性剂)进行纯化,以提供标题化合物(42mg,0.077mmol,66%产率)。LCMS RT=0.68min,ES+ve m/z 544[M+H]+。
(2S,4R)-1-((S)-2-乙酰氨基-3-甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺
将叔丁基((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨甲酰基)吡咯烷-1-基)-3-甲基-1-氧代丁-2-基)氨基甲酸酯(120mg,0.23mmol)的二氯甲烷(2mL)溶液用在1,4-二烷(1mL)中的4M盐酸处理。将混合物在环境温度下搅拌30分钟,然后蒸发至干燥。将剩余物溶解于DMF(1mL)中并用三乙胺(0.08mL,0.58mmol),然后乙酸酐(0.02mL,0.21mmol)处理,并将混合物在环境温度下搅拌1小时。产物通过质量导向自动制备型HPLC(甲酸改性剂)进行纯化,以提供标题化合物(53mg,49%产率)。LCMS RT=0.65min,ES+vem/z 460[M+H]+。/>
利用与(2S,4R)-1-((S)-2-乙酰氨基-3-甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺类似的方法,制备下列化合物:
(2S,4R)-1-((S)-2-(3-乙氧基-N-甲基苯甲酰氨基)丙酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺
将(2S,4R)-4-羟基-1-((S)-2-(甲基氨基)丙酰基)-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺(20mg,0.05mmol)、DIPEA(0.043mL,0.25mmol)和3-乙氧基苯甲酸(可购自例如Aldrich)(8mg,0.05mmol)在DMF(1mL)中的混合物用HATU(19mg,0.05mmol)处理,并将混合物搅拌20分钟。通过质量导向自动制备型HPLC(甲酸改性剂)纯化产物,以提供标 题化合物(14mg,0.025mmol,50%产率)。LCMS RT=0.82min,ES+ve m/z 551[M+H]+。
(2S,4R)-4-羟基-1-((S)-2-(3-甲氧基丙酰氨基)丙酰基)-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺
将(2S,4R)-1-((S)-2-氨基丙酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺,盐酸盐(107mg,0.25mmol)、3-甲氧基丙酸(可购自例如Aldrich)(0.028mL,0.30mmol)和DIPEA(0.2mL,1.15mmol)在干燥DMF(3mL)中的混合物溶液用HATU(115mg,0.30mmol)处理。将混合物在环境温度下搅拌30分钟。将混合物负载到甲醇预处理的氨基丙基固相萃取柱体(2g)上,其用甲醇(3个柱体积)洗脱。将所得洗脱液蒸发至干燥,并且产物通过质量导向自动制备型HPLC(甲酸改性剂)进行纯化,以提供标题化合物(57mg,0.12mmol,48%产率)。LCMS RT=0.62min,ES+ve m/z 475[M+H]+。
(2S,4R)-4-羟基-1-(2-(3-甲氧基丙酰氨基)-2-甲基丙酰基)-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺
将(2S,4R)-1-(2-氨基-2-甲基丙酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺(95mg,0.24mmol)、3-甲氧基丙酸(0.028mL,0.30mmol)和DIPEA(0.2mL、1.15mmol)在干燥DMF(3mL)中的混合物溶液用HATU(115mg,0.30mmol)处理,并将混合物在环境温度下搅拌30分钟。将混合物负载到甲醇预处理的氨基丙基固相萃取柱体(NH2)上,其用甲醇(3个柱体积)洗脱。将所得洗脱液蒸发至干燥,并且产物通过质量导向自动制备型HPLC(甲酸改性剂)进行纯化,以提供标题化合物(45mg,0.09mmol,37%产率)。LCMS RT=0.68min,ES+ve m/z 489[M+H]+。
(2S,4R)-4-羟基-1-((S)-2-(2-甲氧基乙酰氨基)-3-甲基丁酰基)-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺
将(2S,4R)-1-((S)-2-氨基-3-甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺,盐酸盐(20mg,0.044mmol)、2-甲氧基乙酸(3μL,0.039mmol)和DIPEA(0.035mL,0.20mmol)在DMF(1mL)中的混合物用HATU(18mg,0.047mmol)处理,并在环境温度下搅拌30分钟。产物通过质量导向自动制备型HPLC(甲酸改性剂)进行纯化,以提供标题化 合物(14mg,0.029mmol,73%产率)。LCMS RT=0.70min,ES+ve m/z 489[M+H]+。
(2S,4R)-4-羟基-1-((S)-2-(2-甲氧基-N-甲基乙酰氨基)-3-甲基丁酰基)-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺
将(2S,4R)-4-羟基-1-((S)-3-甲基-2-(甲基氨基)丁酰基)-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺,盐酸盐(19mg,0.041mmol)、2-甲氧基乙酸(3μL,0.039mmol)和DIPEA(0.035mL,0.20mmol)在DMF(1mL)中的混合物用HATU(18mg,0.047mmol)处理,并在环境温度下搅拌30分钟。产物通过质量导向自动制备型HPLC(甲酸改性剂)进行纯化,以提供标题化合物(16mg,0.032mmol,81%产率)。LCMS RT=0.70min,ES+ve m/z 503[M+H]+。
(2S,4R)-1-((S)-2-(N,3-二甲基氧杂环丁烷-3-羧酰胺基)丙酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺
将(2S,4R)-4-羟基-1-((S)-2-(甲基氨基)丙酰基)-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺(15mg,0.037mmol)、DIPEA(0.032mL,0.18mmol)和3-甲基氧杂环丁烷-3-羧酸(可购自例如Fluorochem)(3μL,0.037mmol)在DMF(1mL)中的混合物用HATU(14mg,0.037mmol)处理,并将混合物搅拌1小时。通过质量导向自动制备型HPLC(甲酸改性剂)纯化产物,以提供标题化合物(9mg,0.019mmol,51%产率)。LCMS RT=0.62min,ES+ve m/z 501[M+H]+。
(2S,4R)-4-羟基-1-((S)-2-(3-甲基氧杂环丁烷-3-羧酰胺基)丙酰基)-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺
将(2S,4R)-1-((S)-2-氨基丙酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺(21mg,0.043mmol)、DIPEA(0.043mL,0.25mmol)和3-甲基氧杂环丁烷-3-羧酸(可购自例如Fluorochem)(6mg,0.05mmol)在DMF(2mL)中的搅拌混合物用HATU(19mg,0.05mmol)处理并搅拌30分钟。通过质量导向自动制备型HPLC(甲酸改性剂)纯化产物,以提供标题化合物(14mg,0.029mmol,60%产率)。LCMS RT=0.59min,ES+ve m/z 487[M+H]+。
(2S,4R)-1-((S)-2-(3-乙氧基苯甲酰氨基)丙酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺
将3-乙氧基苯甲酸(可购自例如Aldrich)(20mg,0.12mmol)和(2S,4R)-1-((S)-2-氨基丙酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺,盐酸盐(56mg,0.13mmol)在DMF(3.2mL)中的搅拌混合物用DIPEA(0.063mL,0.36mmol),然后用HATU(50mg,0.13mmol)处理,并将混合物在环境温度下搅拌30分钟。然后产物通过质量导向自动制备型HPLC(甲酸改性剂)进行纯化,以提供标题化合物(36mg,0.067mmol,56%产率)。LCMS RT=0.80min,ES+ve m/z 537[M+H]+。
(2S,4R)-N-((1H-吲哚-3-基)甲基)-4-羟基-1-((S)-2-(1-氧代异吲哚啉-2-基)丙酰基)吡咯烷-2-羧酰胺
将(2S,4R)-4-羟基-1-((S)-2-(1-氧代异吲哚啉-2-基)丙酰基)吡咯烷-2-羧酸(10mg,0.031mmol)、DIPEA(0.038mL,0.22mmol)和(1H-吲哚-3-基)甲胺(可购自例如Fluorochem)(6mg,0.041mmol)在DMF(0.8mL)中的溶液用HATU(15mg,0.039mmol)处理并搅拌1小时。通过质量导向自动制备型HPLC(甲酸改性剂)纯化产物,以提供标题化合物(3.1mg,6.9μmol,22%产率)。LCMS RT=0.75min,ES+ve m/z447[M+H]+。
(2S,4R)-N-((R)-2,3-二氢苯并呋喃-3-基)-4-羟基-1-((S)-2-(1-氧代异吲哚啉-2-基)丙酰基)吡咯烷-2-羧酰胺&(2S,4R)-N-((S)-2,3-二氢苯并呋喃-3-基)-4-羟基-1-((S)-2-(1-氧代异吲哚啉-2-基)丙酰基)吡咯烷-2-羧酰胺
将2,3-二氢苯并呋喃-3-胺(可购自例如Chem-Impex International,Inc.)(13mg,0.094mmol)和(2S,4R)-4-羟基-1-((S)-2-(1-氧代异吲哚啉-2-基)丙酰基)吡咯烷-2-羧酸(25mg,0.079mmol)在DMF(0.8mL)中的混合物用DIPEA(0.055mL,0.31mmol),然后HATU(33mg,0.086mmol)处理,并将混合物在环境温度下搅拌30分钟。产物混合物通过质量导向自动制备型HPLC(甲酸改性剂)进行纯化,以提供标题化合物:异构体1(第一个洗脱)(12mg,0.027mmol,35%产率)。LCMS RT=0.73min,ES+ve m/z 436[M+H]+。异构体2(第二个洗脱)(13mg,0.030mmol,38%产率)。LCMS RT=0.74min,ES+ve m/z 436[M+H]+。
利用与(2S,4R)-N-(2,3-二氢苯并呋喃-3-基)-4-羟基-1-((S)-2-(1-氧代异吲哚啉-2-基)丙酰基)吡咯烷-2-羧酰胺的两种非对映立体异构体类似的方法,制备下列化合物:
(2S,4R)-4-羟基-N-(2-羟基-4-(4-甲基噻唑-5-基)苄基)-1-((S)-3-甲基-2-(1-氧代异吲哚啉-2-基)丁酰基)吡咯烷-2-羧酰胺
将(2S,4R)-4-羟基-N-(2-羟基-4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺,盐酸盐(125mg,0.34mmol)和(S)-3-甲基-2-(1-氧代异吲哚啉-2-基)丁酸(83mg,0.36mmol)在DMF(1.6mL)中的混合物用DIPEA(0.24mL,1.4mmol)和HATU(140mg,0.37mmol)处理,并将混合物在环境温度下搅拌30分钟。产物通过质量导向自动制备型HPLC(甲酸改性剂)进行纯化,以提供标题化合物(120mg,0.22mmol,65%产率)。LCMS RT=0.81min,ES+ve m/z 549[M+H]+。
(2S,4R)-4-羟基-N-(2-羟基-4-(4-甲基噻唑-5-基)苄基)-1-((R)-3-甲基-2-(1-氧代异吲哚啉-2-基)丁酰基)吡咯烷-2-羧酰胺
将(2S,4R)-4-羟基-N-(2-羟基-4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺,盐酸盐(65mg,0.18mmol)和(R)-3-甲基-2-(1-氧代异吲哚啉-2-基)丁酸(43mg,0.19mmol)在DMF(1.6mL)中的混合物用DIPEA(0.123mL,0.70mmol)和HATU(74mg,0.19mmol)处理,并将混合物在环境温度下搅拌30分钟。产物通过质量导向自动制备型HPLC(甲酸改性剂)进行纯化,以提供标题化合物(64mg,0.12mmol,66%产率)。LCMS RT=0.80min,ES+ve m/z 549[M+H]+。
叔丁基((S)-1-((2R,4S)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨甲酰基)吡咯烷-1-基)-1-氧代丙烷-2-基)(甲基)氨基甲酸酯
将(S)-2-((叔丁氧基羰基)(甲基)氨基)丙酸(115mg,0.57mmol)和(2R,4S)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺,盐酸盐(200mg,0.57mmol)在DMF(0.7mL)中的搅拌混合物用DIPEA(0.4mL,2.3mmol),然后用HATU(215mg,0.57mmol)处理,并将混合物在环境温度下搅拌30分钟。产物通过质量导向自动制备型HPLC(甲酸改性剂)进行纯化,以提供标题化合物(146mg,0.29mmol,51%产率)。LCMS RT=0.84min,ES+ve m/z 503[M+H]+。
(2S,4R)-4-羟基-1-((S)-2-(3-甲氧基-N-甲基丙酰氨基)丙酰基)-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺
将(2S,4R)-4-羟基-1-((S)-2-(甲基氨基)丙酰基)-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺(50mg,0.12mmol)和3-甲氧基丙酸(可购自例如Aldrich)(0.013mL,0.14mmol)在DMF(0.8mL)中的搅拌混合物用DIPEA(0.087mL,0.50mmol),然后用HATU(52mg,0.14mmol)处理。将混合物在环境温度下搅拌30分钟。产物通过质量导向自动制备型HPLC(甲酸改性剂)进行纯化,以提供标题化合物(43mg,71%产率)。LCMS RT=0.61min,ES+vem/z 489[M+H]+。
(2S,4R)-4-羟基-1-((S)-2-((2-甲氧基乙基)(甲基)氨基)丙酰基)-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺
将1-溴-2-甲氧基乙烷(可购自例如Aldrich)(0.013mL,0.14mmol)和(2S,4R)-4-羟基-1-((S)-2-(甲基氨基)丙酰基)-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺(50mg,0.12mmol)在DMF(0.8mL)中的搅拌混合物用DIPEA(0.054mL,0.31mmol)处理,并将混合物在85℃下搅拌18小时。将反应混合物冷却,并且产物通过质量导向自动制备型HPLC(碳酸氢铵改性剂)进行纯化,以提供标题化合物(44mg,77%产率)。LCMS RT=0.51min,ES+vem/z 461[M+H]+。
(2S,4R)-4-羟基-1-((S)-4-(2-甲氧基乙酰基)吗啉-3-羰基)-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺
将(2S,4R)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)-1-((S)-吗啉-3-羰基)吡咯烷-2-羧酰胺,盐酸盐(19mg,0.041mmol)、2-甲氧基乙酸(3μL,0.039mmol)和DIPEA(0.035mL,0.20mmol)在DMF(1mL)中的混合物用HATU(18mg,0.047mmol)处理,并在环境温度下搅拌30分钟。产物通过质量导向自动制备型HPLC(甲酸改性剂)进行纯化,以提供标题化 合物(13mg,0.026mmol,66%产率)。LCMS RT=0.60min,ES+ve m/z 503[M+H]+。
(2S,4R)-N-(4-(2,4-二甲基噻唑-5-基)苄基)-4-羟基-1-(2-(3-甲基异唑-5-基)乙酰基)吡咯烷-2-羧酰胺
将(2S,4R)-N-(4-(2,4-二甲基噻唑-5-基)苄基)-4-羟基吡咯烷-2-羧酰胺(30mg,0.09mmol)和2-(3-甲基异唑-5-基)乙酸(可购自例如Aldrich)(13mg,0.09mmol)在DMF(0.8mL)中的搅拌混合物用DIPEA(0.063mL,0.36mmol),然后用HATU(41mg,0.11mmol)处理,并在环境温度下搅拌30分钟。产物通过质量导向自动制备型HPLC(甲酸改性剂)进行纯化,以提供标题化合物(26mg,63%产率)。LCMS RT=0.66min,ES+ve m/z 455[M+H]+。
(2S,4R)-1-((S)-2-乙酰氨基丙酰基)-N-(4-(2,4-二甲基噻唑-5-基)苄基)-4-羟基吡咯烷-2-羧酰胺
将(2S,4R)-N-(4-(2,4-二甲基噻唑-5-基)苄基)-4-羟基吡咯烷-2-羧酰胺(30mg,0.09mmol)和(S)-2-乙酰氨基丙酸(可购自例如Aldrich)(12mg,0.09mmol)在DMF(0.8mL)中的搅拌混合物用DIPEA(0.063mL,0.36mmol),然后用HATU(41mg,0.11mmol)处理,并将混合物在环境温度下搅拌30分钟。产物通过质量导向自动制备型HPLC(甲酸改性剂)进行纯化,以提供标题化合物(30mg,75%产率)。LCMS RT=0.58min,ES+ve m/z 445[M+H]+。
(2S,4R)-N-(4-溴苄基)-1-(3-乙氧基苯甲酰基)-4-羟基吡咯烷-2-羧酰胺
将(2S,4R)-1-(3-乙氧基苯甲酰基)-4-羟基吡咯烷-2-羧酸(73mg,0.26mmol)和(4-溴苯基)甲胺,盐酸盐(可购自例如Aldrich)(58mg,0.26mmol)在DMF(0.5mL)中的冰冷却混合物用DIPEA(0.145mL,0.83mmol)的DMF(1mL)溶液,然后用HATU(105mg,0.28mmol)处理,并在环境温度下搅拌过夜。然后产物通过质量导向自动制备型HPLC(甲酸改性剂)进行纯化,以提供标题化合物(62mg,53%产率)。LCMS RT=0.90min,ES+ve m/z 447,449[M+H]+。
(2S,4R)-N-([1,1'-联苯基]-4-基甲基)-1-(3-乙氧基苯甲酰基)-4-羟基吡咯烷-2-羧酰胺
将(2S,4R)-1-(3-乙氧基苯甲酰基)-4-羟基吡咯烷-2-羧酸(30mg,0.11mmol)和[1,1'-联苯基]-4-基甲胺(可购自例如Aldrich)(20mg,0.11mmol)在DMF(0.8mL)中的混合物用DIPEA(0.075mL,0.43mmol),然后用HATU(45mg,0.12mmol)处理,并在环境温度下搅拌30分钟。产物通过质量导向自动制备型HPLC(甲酸改性剂)进行纯化,以提供标题化合物(26mg,55%产率)。LCMS RT=0.98min,ES+ve m/z445[M+H]+。
利用与(2S,4R)-N-([1,1'-联苯基]-4-基甲基)-1-(3-乙氧基苯甲酰基)-4-羟基吡咯烷-2-羧酰胺类似的方法,制备下列化合物:
(2S,4R)-4-羟基-1-(2-(3-甲氧基丙酰氨基)乙酰基)-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺
将(2S,4R)-1-(2-氨基乙酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺(134mg,0.33mmol)和3-甲氧基丙酸(可购自例如Aldrich)(37mg,0.36mmol)在DMF(0.8mL)中的混合物用DIPEA(0.23mL、1.3mmol),然后用HATU(136mg,0.36mmol)处理,并在环境温度下搅拌30分钟。产物通过质量导向自动制备型HPLC(甲酸改性剂)进行纯化,以提供标题化合物(36mg,24%产率)。LCMS RT=0.56min,ES+ve m/z 461[M+H]+。
(2S,4R)-1-((S)-3,3-二甲基-2-(3-甲基氧杂环丁烷-3-羧酰胺基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺
将(2S,4R)-1-((S)-2-氨基-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺,盐酸盐(20mg,0.04mmol)和3-甲基氧杂环丁烷-3-羧酸(可购自例如Chemgenx)(5mg,0.04mmol)在DMF(0.6mL)中的搅拌混合物用DIPEA(0.03mL,0.17mmol),然后用HATU(20mg,0.05mmol)处理,并将混合物在环境温度下搅拌1小时。产物通过质量导向自动制备型HPLC(甲酸改性剂)进行纯化,以提供标题化合物(18mg,80%产率)。LCMS RT=0.76min,ES+ve m/z 529[M+H]+。
利用与(2S,4R)-1-((S)-3,3-二甲基-2-(3-甲基氧杂环丁烷-3-羧酰胺基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺类似的方法,制备下列化合物:
(S)-N-((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁烷-2-基)吗啉-3-羧酰胺盐酸盐
将(2S,4R)-1-((S)-2-氨基-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺(40mg,0.086mmol)和(S)-4-(叔丁氧基羰基)吗啉-3-羧酸(可购自例如AstatecH,Inc.)(20mg,0.086mmol)在DMF(0.6mL)中的混合物用DIPEA(0.06mL,0.35mmol),然后用HATU(40mg,0.10mmol)处理,并在环境温度下搅拌1小时。产物通过质量导向自动制备型HPLC(甲酸改性剂)进行纯化,以提供中间体Boc-保护的产物。然后将中间体溶解于二氯甲烷(1mL)和甲醇(0.5mL)的混合物中,并用1,4-二烷(0.4mL,1.6mmol)中的4M盐酸处理,在环境温度下搅拌1小时后,将混合物蒸发至干燥,以提供标题化合物(31mg,62%产率)。LCMS RT=0.60min,ES+ve m/z 544[M+H]+。
利用与(S)-N-((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁烷-2-基)吗啉-3-羧酰胺盐酸盐类似的方法,制备下列化合物:
叔丁基4-((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨甲酰基)吡咯烷-1-基)-1-氧代丙烷-2-基)哌嗪-1-羧酸酯&叔丁基4-((R)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨甲酰基)吡咯烷-1-基)-1-氧代丙烷-2-基)哌嗪-1-羧酸酯
将(2S,4R)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺,盐酸盐(100mg,0.28mmol)和2-(4-(叔丁氧基羰基)-2-氧代哌嗪-1-基)丙酸(85mg,0.31mmol)在DMF(0.8mL)中的搅拌混合物用DIPEA(0.20mL,1.13mmol),然后用HATU(129mg,0.34mmol)处理,然后在环境温度下搅拌30分钟。产物通过质量导向自动制备型HPLC(碳酸氢铵改性剂)进行纯化,以提供标题化合物:异构体1(第一洗脱)(48mg,30%产率)。LCMS RT=0.85min,ES+ve m/z 572[M+H]+。异构体2(第二洗脱)(51mg,32%产率)。LCMS RT=0.86min,ES+vem/z 572[M+H]+。
(2S,4R)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)-1-((S)-2-(哌嗪-1-基)丙酰基)吡咯烷-2-羧酰胺,盐酸盐&(2S,4R)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)-1-((R)-2-(哌嗪-1-基)丙酰基)吡咯烷-2-羧酰胺,盐酸盐
将叔丁基4-(1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨甲酰基)吡咯烷-1-基)-1-氧代丙烷-2-基)哌嗪-1-羧酸酯(48mg,0.08mmol)的异构体1和异构体2分别溶解于二氯甲烷(0.3mL)和甲醇(0.1mL)的混合物中,并分别用1,4-二烷(0.3mL、1.2mmol)中的4M盐酸处理。在环境温度下搅拌1小时后,将反应混合物蒸发至干燥,以提供标题化合物为盐酸盐。异构体1(42mg,99%产率)。LCMS RT=0.62min,ES+ve m/z 472[M+H]+。异构体2(42mg,99%产率)。LCMS RT=0.60min,ES+ve m/z 472[M+H]+。
(S)-N-((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁烷-2-基)-4-(2-甲氧基乙基)吗啉-2-羧酰胺
将1-溴-2-甲氧基乙烷(4μL,0.04mmol)、(S)-N-((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁烷-2-基)吗啉-2-羧酰胺,盐酸盐(20mg,0.04mmol)和DIPEA(0.019mL,0.11mmol)在DMF(0.5mL)中的混合物在85℃下搅拌6小时。冷却产物通过质量导向自动制备型HPLC(碳酸氢铵改性剂)进行纯化,以提供标题化合物(9mg,41%产率)。LCMS RT=0.88min,ES+ve m/z 602[M+H]+。
利用与(S)-N-((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁烷-2-基)-4-(2-甲氧基乙基)吗啉-2-羧酰胺类似的方法,制备下列化合物:
甲基4-(((S)-1-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨甲酰基)吡咯烷-1-基)-1-氧代丙烷-2-基)氨基)-4-甲基-1-氧代戊烷-2-基)氨基)-4-氧代丁酸酯
将(2S,4R)-1-((S)-2-((S)-2-氨基-4-甲基戊酰氨基)丙酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺,盐酸盐(102mg,0.19mmol)、DIPEA(0.165mL,0.95mmol)和4-甲氧基-4-氧代丁酸(可购自例如Aldrich)(25mg,0.19mmol)在DMF(2mL)中的混合物用HATU(64mg,0.17mmol)处理,并将混合物在环境温度下搅拌20分钟。添加盐水(10mL),并将产物用乙酸乙酯(20mL)萃取。有机相用盐水(2×20mL)洗涤,利用疏水玻璃料干燥,并蒸发至干燥。应用水(+0.1%甲酸)中的5%至70%乙腈(+0.1%甲酸)的梯度洗脱通过反相硅胶上的层析纯化产物,以提供标题化合物(73mg,0.12mmol,63%产率)。LCMS RT=0.74min,ES+ve m/z616[M+H]+。
4-(3-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨甲酰基)吡咯烷-1-羰基)苯氧基)丁酸(
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将叔丁基4-(3-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨甲酰基)吡咯烷-1-羰基)苯氧基)丁酸酯(130mg,0.22mmol)的二氯甲烷(3mL)溶液用TFA(0.5mL,6.5mmol)处理,并在环境温度下搅拌5小时。将溶剂蒸发至干燥,并且产物通过质量导向自动制备型HPLC(甲酸改性剂)进行纯化,以提供标题化合物(65mg,0.12mmol,55%产率)。LCMS RT=0.70min,ES+ve m/z 524[M+H]+。
4-(((S)-1-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨甲酰基)吡咯烷-1-基)-1-氧代丙烷-2-基)氨基)-4-甲基-1-氧代戊烷-2-基)氨基)-4-氧代丁酸
将甲基4-(((S)-1-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨甲酰基)吡咯烷-1-基)-1-氧代丙烷-2-基)氨基)-4-甲基-1-氧代戊烷-2-基)氨基)-4-氧代丁酸酯(73mg,0.12mmol)的甲醇(3mL)溶液用含水氢氧化钠(2M,0.6mL,1.2mmol)处理,并将混合物在环境温度下搅拌2小时。将混合物蒸发至干燥,并应用在水(+0.1%甲酸)中的5%至60%乙腈(+0.1%甲酸)的梯度洗脱、通过反相硅胶上的层析纯化产物,以提供标题化 合物(53mg,0.088mmol,74%产率)。LCMS RT=0.69min,ES+ve m/z 602[M+H]+。
(2S,4R)-4-羟基-1-((S)-2-((S)-2-(2-甲氧基乙酰氨基)-4-甲基戊酰氨基)丙酰基)-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺
将(2S,4R)-1-((S)-2-((S)-2-氨基-4-甲基戊酰氨基)丙酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺,盐酸盐(30mg,0.056mmol)、2-甲氧基乙酸(可购自例如Aldrich)(4.3uL,0.056mmol)和DIPEA(0.05mL,0.29mmol)在DMF(1mL)中的混合物用HATU(25mg,0.066mmol)处理,并在环境温度下搅拌30分钟。产物通过质量导向自动制备型HPLC(甲酸改性剂)进行纯化,以提供标题化合物(18mg,0.031mmol,56%产率)。LCMS RT=0.73min,ES+ve m/z 574[M+H]+。
(2S,4R)-4-羟基-1-((S)-2-((S)-2-(3-甲氧基丙酰氨基)-4-甲基戊酰氨基)丙酰基)-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺
将(2S,4R)-1-((S)-2-((S)-2-氨基-4-甲基戊酰氨基)丙酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺,盐酸盐(30mg,0.056mmol)、3-甲氧基丙酸(可购自例如Aldrich)(5.2uL,0.056mmol)和DIPEA(0.05mL,0.29mmol)在DMF(1mL)中的混合物,并在环境温度下搅拌30分钟。产物通过质量导向自动制备型HPLC(甲酸改性剂)进行纯化,以提供标题化合物(20mg,0.034mmol,61%产率)。LCMS RT=0.72min,ES+ve m/z 588[M+H]+。
(2S,4R)-1-(6-氰基吡啶-2-基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺
将(2S,4R)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺,盐酸盐(58mg,0.16mmol)和6-氟甲基吡啶腈(可购自例如Aldrich)(20mg,0.16mmol)在DMSO(1mL)中的混合物用DIPEA(0.10mL,0.57mmol)处理,密封,并在Biotage“Initiator”微波中在100℃下加热60分钟。通过质量导向自动制备型HPLC(甲酸改性剂)纯化产物,以提供标题化合 物(23mg,0.055mmol,34%产率)。LCMS RT=0.74min,ES+ve m/z 420[M+H]+。
中间体
4-(唑-5-基)苄腈
将4-甲酰基苄腈(可购自例如Aldrich)(5.32g,41mmol)、1-((异氰基甲基)磺酰基)-4-甲基苯(可购自例如Aldrich)(8.83g,45mmol)和碳酸钾(7.3g,53mmol)在甲醇(200mL)中的混合物在环境温度下搅拌80分钟。然后将混合物蒸发至干燥;剩余物用饱和碳酸氢钠水溶液(100mL)处理,并用二氯甲烷(3×100mL)萃取。组合的有机相用盐水(75mL)洗涤,经过疏水玻璃料,然后蒸发至干燥,以提供标题化合物(7.19g,42mmol,定量)。LCMS RT=0.48min,ES+ve m/z 171[M+H]+。
(4-(唑-5-基)苯基)甲胺
在氮气气氛下,将4-(唑-5-基)苄腈(900mg,5.29mmol)和氯化钴(II)六水合物(可购自例如Aldrich)(1.8g,7.9mmol)在甲醇(50mL)中的冰冷却混合物用硼氢化钠(1g,26mmol)经5分钟逐部分处理。将混合物搅拌30分钟,然后用水(50mL)和浓缩含水氨(20mL)处理。将混合物用氯仿(3×150mL)萃取,组合的有机相蒸发至干燥,并且应用在二氯甲烷(+0.1%三乙胺)中的0%至30%甲醇的梯度洗脱、通过在硅胶上进行层析来纯化产物,以提供标题化合物(580mg,3.3mmol,63%产率)。LCMS RT=0.35min,ES+ve m/z 175[M+H]+。
(2S,4R)-叔丁基4-羟基-2-((4-(唑-5-基)苄基)氨甲酰基)吡咯烷-1-羧酸酯
向在干燥DMF(20mL)中的(2S,4R)-1-(叔丁氧基羰基)-4-羟基吡咯烷-2-羧酸(0.66g,2.9mmol)的搅拌溶液添加(4-(唑-5-基)苯基)甲胺(0.5g,2.87mmol)和DIPEA(1mL,5.7mmol)。然后冰冷却该溶液,并添加HATU(1.09g,2.9mmol)。将反应混合物再搅拌并冷却1小时,然后用水(30mL)处理,并用乙酸乙酯(3×100mL)萃取。将组合的有机相用饱和碳酸氢钠水溶液(60mL)、盐水(60mL)洗涤,在硫酸镁上干燥,过滤,并蒸发至干燥。应用二氯甲烷中0%至25%甲醇的梯度洗脱、通过在硅胶上进行层析来纯化产物,以提供标题化合物(758mg,1.96mmol,68%产率)。LCMS RT=0.73min,ES+ve m/z 388[M+H]+。
(2S,4R)-4-羟基-N-(4-(唑-5-基)苄基)吡咯烷-2-羧酰胺,盐酸盐
将(2S,4R)-叔丁基4-羟基-2-((4-(唑-5-基)苄基)氨甲酰基)吡咯烷-1-羧酸酯(2.74g,7.1mmol)在甲醇(10mL)和二氯甲烷(15mL)中的溶液用盐酸(4M,在1,4-二/>烷中)(8.8mL,35mmol)处理,并将混合物在环境温度下搅拌24小时。将混合物蒸发至干燥。将剩余物悬浮在甲醇中,过滤和在真空下干燥,以提供标题化合物(2.24g,6.9mmol,98%产率)。LCMS RT=0.44min,ES+ve m/z 288[M+H]+。
(2S,4R)-叔丁基2-((4-溴苄基)氨甲酰基)-4-羟基吡咯烷-1-羧酸酯
将(2S,4R)-1-(叔丁氧基羰基)-4-羟基吡咯烷-2-羧酸(可购自例如Aldrich)(7.95g,34mmol)和(4-溴苯基)甲胺(可购自例如Fluorochem)(6.4g,34mmol)在DMF(200mL)中的冰冷却混合物用DIPEA(18mL、103mmol),然后用HATU(14.4g,38mmol)处理,并将混合物在环境温度下搅拌30分钟。将混合物用水(200mL)处理,并用乙酸乙酯(2×200mL)萃取。将组合的有机相用饱和碳酸氢钠水溶液(2×300mL)、水(100mL)、盐水(200mL)洗涤,在硫酸镁上干燥,并蒸发至干燥。应用二氯甲烷中0%至10%甲醇的梯度洗脱、通过快速层析(750g硅胶柱体)纯化产物,以提供标题化合物(12.9g,94%产率)。LCMS RT=0.87min,ES+ve m/z401[M+H]+。
(2S,4R)-叔丁基4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨甲酰基)吡咯烷-1-羧酸酯
在氮气气氛下,将(2S,4R)-叔丁基2-((4-溴苄基)氨甲酰基)-4-羟基吡咯烷-1-羧酸酯(12.9g,32mmol)、4-甲基噻唑(可购自例如Aldrich)(5.9mL,65mmol)、乙酸钯(II)(可购自例如Aldrich)(0.145g,0.65mmol)和乙酸钾(6.34g,65mmol)在N-甲基-2-吡咯烷酮(80mL)中的混合物在120℃下搅拌18小时。冷却至环境温度后,添加水(100ml),并将产物用乙酸乙酯(4×300mL)萃取。将组合的有机相用盐水(5×200mL)洗涤,在硫酸镁上干燥,并蒸发至干燥。应用二氯甲烷中0%至10%甲醇的梯度洗脱、通过快速层析(750g硅胶柱体)纯化产物,以提供标题化合物(8.0g,59%产率)。LCMS RT=0.75min,ES+ve m/z 418[M+H]+。
(2S,4R)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺,盐酸盐
将(2S,4R)-叔丁基4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨甲酰基)吡咯烷-1-羧酸酯(8g,19mmol)在甲醇(30mL)和二氯甲烷(20mL)混合物中的溶液用1,4-二烷(8mL,32mmol)中的4M盐酸处理。将混合物在环境温度下搅拌2小时。溶剂蒸发至干燥,并将剩余物在二氯甲烷中研磨,过滤和在真空下干燥,以提供标题化合物(6.7g,99%产率)。LCMS RT=0.51min,ES+ve m/z 318[M+H]+。
(2S,4R)-1-(3-乙氧基苯甲酰基)-4-羟基吡咯烷-2-羧酸
将3-乙氧基苯甲酸(可购自例如Aldrich)(4g,24mmol)溶解于亚硫酰氯(24mL,329mmol)中并在60℃下搅拌1小时,然后在50℃下搅拌18小时。冷却至环境温度后,将混合物蒸发至干燥,并将剩余物用二乙醚(5mL)处理。然后将混合物冰冷却,并用(2S,4R)-4-羟基吡咯烷-2-羧酸,盐酸盐(可购自例如Aldrich)(4.44g,27mmol)在1M含水氢氧化钠(27mL,27mmol)中的溶液处理。使反应升温至环境温度并搅拌18小时。将混合物分离;水相用二乙醚洗涤,然后用2M含水盐酸酸化。产物在二乙醚(2×70mL)中萃取,并将组合的醚相蒸发至干燥。应用10至30%乙腈(+0.1%甲酸)的水(+0.1%甲酸)溶液的梯度洗脱、通过快速层析(340g C18柱体)纯化产物,以提供标题化合物(3.5g,52%产率)。LCMS RT=0.55min,ES+vem/z 280[M+H]+。
(2S,4R)-苄基1-((S)-2-乙酰氨基丙酰基)-4-羟基吡咯烷-2-羧酸酯
将(S)-2-乙酰氨基丙酸(可购自例如Aldrich)(2.80g,21mmol)和(2S,4R)-苄基4-羟基吡咯烷-2-羧酸酯,盐酸盐(可购自例如Aldrich)(5g,19mmol)在DMF(5mL)中的冰冷却混合物用DIPEA(14mL,78mmol),然后HATU(8.11g,21mmol)经10min处理。将混合物升温至环境温度并搅拌1小时,然后用饱和碳酸氢钠水溶液(30mL)处理并搅拌5min。然后将混合物用乙酸乙酯(3×100mL)萃取,并将组合的有机相用水(100mL)、盐水(100mL)洗涤,在硫酸镁上干燥,并蒸发至干燥。应用二氯甲烷中0至10%甲醇的梯度洗脱、通过快速层析(330g硅胶柱体)纯化产物,以提供标题化合物(2.0g,31%产率)。LCMS RT=0.63min,ES+ve m/z 335[M+H]+。
(2S,4R)-1-((S)-2-乙酰氨基丙酰基)-4-羟基吡咯烷-2-羧酸
将(2S,4R)-苄基-1-((S)-2-乙酰氨基丙酰基)-4-羟基吡咯烷-2-羧酸酯(2g,6.0mmol)的乙醇(10mL)溶液在氮气气氛下添加至包含钯碳(palladium on carbon)(1.27g,1.2mmol)(10%,Degussa类型)的烧瓶。烧瓶充氢气,并且将溶液在环境温度下搅拌2小时。通过经过硅藻土过滤除去催化剂,并在减压下蒸发滤液,以提供标题化合物(1.37g,94%产率)。LCMS RT=0.28min,ES+ve m/z 244[M+H]+。
(2S,4R)-4-羟基-1-(2-(3-甲基异唑-5-基)乙酰基)吡咯烷-2-羧酸
在氮气气氛下,将(2S,4R)-苄基4-羟基-1-(2-(3-甲基异唑-5-基)乙酰基)吡咯烷-2-羧酸酯(2.3g,6.7mmol)的乙醇(60mL)溶液添加至钯碳(0.071g,0.67mmol)(10%,Degussa类型),然后在氢气气氛下搅拌。2小时后,经过硅藻土过滤混合物。将滤液蒸发至干燥,并将剩余物与环己烷研磨,和在真空下干燥,以提供白色固体。通过质量导向自动制备型HPLC(TFA改性剂)纯化产物,以提供标题化合物(650mg,2.6mmol,38%产率)。LCMS RT=0.38min,ES+ve m/z 255[M+H]+。
(2S,4R)-甲基4-羟基-1-((S)-2-(1-氧代异吲哚啉-2-基)丙酰基)吡咯烷-2-羧酸酯
将(2S,4R)-甲基4-羟基吡咯烷-2-羧酸酯,盐酸盐(可购自例如Aldrich)(1.77g,9.8mmol)和(S)-2-(1-氧代异吲哚啉-2-基)丙酸(2g,9.8mmol)在DMF(4mL)中的混合物用DIPEA(5.11mL,29mmol),然后用HATU(4.08g,10.7mmol)处理,并在环境温度下搅拌30分钟。将混合物用饱和碳酸氢钠水溶液(100mL)处理,并用乙酸乙酯(2×200mL)萃取。将组合的有机相用水(100mL)、盐水(100mL)洗涤,在硫酸镁上干燥,并蒸发至干燥。应用10%至50%乙腈(+0.1%甲酸)的水(+0.1%甲酸)溶液的梯度洗脱、通过快速层析(120g C18柱体)纯化产物,以提供标题化合物(1.0g,31%产率)。LCMS RT=0.60min,ES+ve m/z 333[M+H]+。
(2S,4R)-4-羟基-1-((S)-2-(1-氧代异吲哚啉-2-基)丙酰基)吡咯烷-2-羧酸
将(2S,4R)-甲基4-羟基-1-((S)-2-(1-氧代异吲哚啉-2-基)丙酰基)吡咯烷-2-羧酸酯(1g,3.0mmol)的甲醇(2mL)溶液用2M含水氢氧化钠(5mL,10mmol)处理,并将混合物在环境温度下搅拌2小时,然后用2M含水盐酸(6mL)酸化。然后将混合物蒸发至约原体积的一半,然后冰冷却。将所得沉淀物滤出,并在真空下干燥,以提供标题化合物(615mg,64%产率)。LCMS RT=0.51min,ES+ve m/z 319[M+H]+。
甲基3-(4-(叔丁氧基)-4-氧代丁氧基)苯甲酸酯
将3-羟基苯甲酸甲酯(可购自例如Aldrich)(1g,6.6mmol)和K2CO3(1.82g,13.2mmol)的DMF(10mL)溶液用叔丁基4-溴丁酸酯(可购自例如Aldrich)(2.2g,9.9mmol)处理,并将混合物在60℃下搅拌16小时。再添加等份的K2CO3(1.82g,13.2mmol)和叔丁基4-溴丁酸酯(2.2g,9.9mmol),并将混合物在60℃下再加热6小时。将混合物冷却至环境温度,并在乙酸乙酯(50mL)和水(50mL)之间分配。有机相用盐水(2×50mL)洗涤,干燥(疏水玻璃料),并蒸发至干燥。应用0%至100%甲基叔丁基醚的环己烷溶液的梯度洗脱、通过在硅胶上进行层析来纯化产物,以提供标题化合物(1.4g,4.8mmol,72%产率)。LCMS RT=1.26min,ES+ve m/z 312[M+H]+。
3-(4-(叔丁氧基)-4-氧代丁氧基)苯甲酸
将甲基3-(4-(叔丁氧基)-4-氧代丁氧基)苯甲酸酯(1.4g,4.8mmol)和含水氢氧化钠(2M,4.8mL,9.6mmol)在甲醇(10mL)中的混合物在环境温度下搅拌5小时。将甲醇在减压下去除(不加热),并且将水相用饱和含水柠檬酸酸化至pH 3。产物用乙酸乙酯(60mL)萃取,并且有机萃取相用盐水(20mL)洗涤,利用疏水玻璃料干燥,并蒸发至干燥。应用0%至25%甲醇的二氯甲烷溶液的梯度洗脱、通过在硅胶上进行层析来纯化产物,以提供标题化合物(625mg,2.2mmol,47%产率)。LCMS RT=1.06min,ES+ve m/z 279[M-H]-。
甲基3-((14,14-二甲基-12-氧代-3,6,9,13-四氧杂五癸基)氧)苯甲酸酯
将叔丁基3-(2-(2-(2-羟基乙氧基)乙氧基)乙氧基)丙酸酯(可购自例如Aldrich)(2.0g,7.2mmol)、三苯基膦(2.3g,8.6mmol)和甲基3-羟基苯甲酸酯(可购自例如Aldrich)(1.2g,7.9mmol)在THF(40mL)中的冰冷却混合物用偶氮二羧酸二异丙酯(1.68mL,8.6mmol)经5分钟逐滴处理。将混合物升温至环境温度并搅拌18小时。然后将混合物蒸发至干燥,并应用0至100%甲基叔丁基醚的环己烷溶液的梯度洗脱、通过快速柱层析法(100g硅胶柱体)经40分钟纯化,以提供标题化合物(2.53g,85%产率)。LCMS RT=1.14min,ES+ve m/z 430[M+NH4]+。
3-((14,14-二甲基-12-氧代-3,6,9,13-四氧杂五癸基)氧)苯甲酸
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将甲基3-((14,14-二甲基-12-氧代-3,6,9,13-四氧杂五癸基)氧)苯甲酸酯(2.53g,4.9mmol)的甲醇(25mL)溶液用1M氢氧化钠(0.3g,7.6mmol)的水(7mL)溶液处理,并将混合物在环境温度下搅拌1小时。缓慢添加乙酸(0.45mL,7.9mmol),并将混合物蒸发至干燥,并应用0%至15%甲醇的二氯甲烷(+1%三乙胺)溶液的梯度洗脱、通过快速层析(100g硅胶柱体)纯化,以提供标题化合物(1.37g,70%产率)。LCMS RT=0.99min,ES+ve m/z 399[M+H]+。
叔丁基((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨甲酰基)吡咯烷-1-基)-3-甲基-1-氧代丁烷-2-基)氨基甲酸酯
将(2S,4R)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺,盐酸盐(125mg,0.35mmol)和(S)-2-((叔丁氧基羰基)氨基)-3-甲基丁酸(可购自例如Aldrich)(77mg,0.35mmol)在DMF(0.9mL)中的搅拌混合物用DIPEA(0.22mL、1.3mmol),然后用HATU(134mg,0.35mmol)处理,并将混合物在环境温度下搅拌1小时。产物通过质量导向自动制备型HPLC(甲酸改性剂)进行纯化,以提供标题化合物(120mg,72%产率)。LCMS RT=0.87min,ES+ve m/z 517[M+H]+。
利用与叔丁基-((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨甲酰基)吡咯烷-1-基)-3-甲基-1-氧代丁烷-2-基)氨基甲酸酯类似的方法,制备下列化合物:
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(2S,4R)-1-(2-氨基乙酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺
将(2S,4R)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺,盐酸盐(100mg,0.28mmol)和2-((叔丁氧基羰基)氨基)乙酸(可购自例如Aldrich)(49mg,0.28mmol)在DMF(3mL)中的搅拌混合物用DIPEA(0.20mL,1.1mmol),然后用HATU(118mg,0.31mmol)处理,并将混合物在环境温度下搅拌30分钟。添加水(20ml),并将产物用乙酸乙酯(3×20mL)萃取。将组合的有机相用饱和碳酸氢钠水溶液(20mL)、水(20mL)、盐水(20mL)洗涤,经过疏水玻璃料过滤,并蒸发至干燥。然后将剩余物溶解于二氯甲烷(3mL)中,并用TFA(1mL,13mmol)处理。在环境温度下搅拌10分钟后,将反应混合物蒸发至干燥。剩余物溶解于最少量甲醇中,然后负载到预处理(甲醇)氨基丙基固相萃取柱体(5g)上。柱用甲醇(3volumes)洗脱,并且将包含产物的馏分蒸发至干燥,以提供标题化合物(104mg,99%产率)。LCMS RT=0.44min,ES+ve m/z 375[M+H]+。
(2S,4R)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)-1-((S)-吗啉-3-羰基)吡咯烷-2-羧酰胺
将(S)-叔丁基3-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨甲酰基)吡咯烷-1-羰基)吗啉-4-羧酸酯(115mg,0.22mmol)的二氯甲烷(0.5mL)溶液用TFA(0.5mL)处理,并将反应混合物在环境温度下搅拌1小时。将混合物蒸发至干燥,然后将剩余物溶解于最少量甲醇:二氯甲烷(1:1)混合物中,并负载到预处理(甲醇)氨基丙基固相萃取柱体(2g)上。柱用甲醇(3体积)洗脱,并且将包含产物的馏分在减压下蒸发,以提供标题化合物(89mg,94%产率)。LCMS RT=0.47min,ES+ve m/z 431[M+H]+。
(2S,4R)-4-羟基-1-((S)-3-甲基-2-(甲基氨基)丁酰基)-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺,盐酸盐
将(2S,4R)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺,盐酸盐(100mg,0.28mmol)、(S)-2-((叔丁氧基羰基)(甲基)氨基)-3-甲基丁酸(可购自例如Aldrich)(65mg,0.28mmol)和DIPEA(0.247mL、1.41mmol)在DMF(2mL)中的混合物用HATU(118mg,0.31mmol)处理,并在环境温度下搅拌30分钟。将Boc保护的中间体通过质量导向自动制备型HPLC(甲酸改性剂)进行纯化。将纯化的中间体溶解于甲醇:二氯甲烷(1:1.3mL)中,用盐酸的1,4-二烷(4M,3mL,12mmol)溶液处理,并静置1小时。然后将混合物蒸发至干燥,以提供标题化合物(107mg,0.23mmol,81%产率)。LCMS RT=0.55min,ES+ve m/z 431[M+H]+。
(2S,4R)-1-((S)-2-氨基-3-甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺,盐酸盐
将叔丁基((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨甲酰基)吡咯烷-1-基)-3-甲基-1-氧代丁烷-2-基)氨基甲酸酯(287mg,0.56mmol)的THF(5mL)溶液用4M盐酸的1,4-二烷(10mL)溶液处理,并在环境温度下搅拌2小时。将混合物蒸发至干燥,以提供标题化合物(224mg,0.49mmol,定量)。LCMS RT=0.55min,ES+ve m/z 417[M+H]+。
(2S,4R)-1-((S)-2-氨基-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺,盐酸盐
将(2S,4R)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺,盐酸盐(70mg,0.20mmol)和(S)-2-((叔丁氧基羰基)氨基)-3,3-二甲基丁酸(可购自例如Fluka)(50mg,0.22mmol)在DMF(1mL)中的搅拌混合物用DIPEA(0.14mL,0.79mmol),然后用HATU(90mg,0.24mmol)处理,并在环境温度下搅拌30分钟。产物通过质量导向自动制备型HPLC(甲酸改性剂)进行纯化,以提供中间体boc-保护的产物。然后将中间体溶解于二氯甲烷(0.5mL)和甲醇(0.1mL)混合物中,并用4M盐酸的1,4-二烷(0.25mL,1,0mmol)溶液处理,在环境温度下搅拌1小时后,将反应混合物蒸发至干燥,并将剩余物与二氯甲烷一起研磨成固体,并在真空下干燥,以提供标题化合物(76mg,82%产率)。LCMS RT=0.58min,ES+ve m/z 431[M+H]+。/>
(2S,4R)-1-((S)-2-((S)-2-氨基-4-甲基戊酰氨基)丙酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺,盐酸盐
将(2S,4R)-1-((S)-2-氨基丙羡酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺,盐酸盐(507mg,1.2mmol)、DIPEA(0.868mL,4.97mmol)和(S)-2-((叔丁氧基羰基)氨基)-4-甲基戊酸(可购自例如Aldrich)(230mg,0.99mmol)在DMF(5mL)中的混合物溶液用HATU(416mg,1.1mmol)处理,并在环境温度下搅拌2小时。添加水(50mL),并将产物用乙酸乙酯(50mL)萃取。有机相用盐水(2×50mL)洗涤,利用疏水玻璃料干燥,并蒸发至干燥。剩余物溶解于甲醇:二氯甲烷(1:1.15mL)中,用盐酸的1,4-二烷(4M,5mL,20mmol)溶液处理,并在环境温度下搅拌3小时。将混合物蒸发至干燥,并将剩余物悬浮在二氯甲烷(10mL)中,超声处理,过滤,并在真空下干燥,以提供标题化合物(280mg,0.56mmol,56%产率)。LCMS RT=0.55min,ES+ve m/z 502[M+H]+。
(2S,4R)-叔丁基2-((4-(2,4-二甲基噻唑-5-基)苄基)氨甲酰基)-4-羟基吡咯烷-1-羧酸酯
在氮气气氛下,将(2S,4R)-叔丁基2-((4-溴苄基)氨甲酰基)-4-羟基吡咯烷-1-羧酸酯(200mg,0.50mmol)、2,4-二甲基噻唑(可购自例如Avocado)(113mg,1.0mmol)、乙酸钯(II)(可购自例如Aldrich)(2mg,10μmol)和乙酸钾(98mg,1.0mmol)在N-甲基-2-吡咯烷酮(2mL)中的混合物在120℃下搅拌18小时。将冷却混合物用水(25ml)处理,并将产物用乙酸乙酯(4×30mL)萃取。将组合的有机相用盐水(5×20mL)洗涤,经过疏水玻璃料过滤,并蒸发至干燥。产物通过质量导向自动制备型HPLC(甲酸改性剂)进行纯化,以提供标题化合物(142mg,66%产率)。LCMS RT=0.77min,ES+ve m/z 432[M+H]+。
(2S,4R)-N-(4-(2,4-二甲基噻唑-5-基)苄基)-4-羟基吡咯烷-2-羧酰胺,盐酸盐
将(2S,4R)-叔丁基2-((4-(2,4-二甲基噻唑-5-基)苄基)氨甲酰基)-4-羟基吡咯烷-1-羧酸酯(142mg,0.33mmol)在甲醇(0.5mL)和二氯甲烷(1.5mL)混合物中的溶液用4M盐酸的1,4-二烷(0.63mL,2.5mmol)溶液处理,并在环境温度下搅拌2小时。蒸发溶剂至干燥,并将剩余物与二乙醚一起研磨至固体,并在真空下干燥,以提供标题化合物(120mg,99%产率)。LCMS RT=0.49min,ES+ve m/z 332[M+H]+。
(S)-3-甲基-2-(3-甲基-2,5-二氧代-2,5-二氢-1H-吡咯-1-基)丁酸
将3-甲基呋喃-2,5-二酮(可购自例如Aldrich)(0.12mL,1.3mmol)和(S)-2-氨基-3-甲基丁酸(可购自例如Apollo Scientific)(150mg,1.3mmol)在乙酸(1mL)中的混合物密封,并在Biotage“Initiator”微波中、在120℃下加热1小时。将混合物蒸发至干燥,以提供标题化合物(253mg,94%产率)。LCMS RT=0.75min,ES+ve m/z 212[M+H]+
苄基2-(3-氧代吗啉基)丙酸酯
在氮气气氛下,将吗啉-3-酮(可购自例如Aldrich)(100mg,1.0mmol)在DMF(2mL)中的冰冷却溶液用氢化钠(60%w/w,在矿物油中)(40mg,1.0mmol)处理。5分钟后,添加2-溴丙酸苄酯(可购自例如Aldrich)(240mg,1.0mmol),并将混合物搅拌并冷却30分钟,然后在环境温度下再搅拌18小时。将反应混合物小心地用饱和碳酸氢钠水溶液(10mL)处理,然后用乙酸乙酯(2×40mL)萃取。将组合的有机相用盐水(25mL)洗涤,经过疏水玻璃料过滤,并蒸发至干燥。产物通过质量导向自动制备型HPLC(甲酸改性剂)进行纯化,以提供标题化合 物(105mg,40%产率)。LCMS RT=0.80min,ES+ve m/z 264[M+H]+。
2-(3-氧代吗啉基)丙酸
在氮气气氛下,将苄基2-(3-氧代吗啉基)丙酸酯(90mg,0.34mmol)的乙醇(3mL)溶液添加至包含钯碳(36mg,0.034mmol)(10%,Degussa类型)的烧瓶。然后烧瓶充氢气,并将混合物在环境温度下搅拌1小时。通过经过硅藻土过滤除去催化剂,并在减压下蒸发滤液,以提供标题化合物(55mg,93%产率)。LCMS RT=0.33min,ES+ve m/z 174[M+H]+。
叔丁基4-(1-(苄氧基)-1-氧代丙烷-2-基)-3-氧代哌嗪-1-羧酸酯
在氮气气氛下,将叔丁基3-氧代哌嗪-1-羧酸酯(可购自例如Aldrich)(200mg,1.0mmol)在DMF(4mL)中的冰冷却溶液用氢化钠(60%w/w,在矿物油中)(44mg,1.1mmol)处理。5分钟后,添加2-溴丙酸苄酯(可购自例如Aldrich)(255mg,1.05mmol)。将混合物在0℃下搅拌30分钟,然后在环境温度下再搅拌18小时。将混合物小心地用饱和碳酸氢钠水溶液(20mL)处理,然后用乙酸乙酯(2×40mL)萃取。将组合的有机相用盐水(25mL)洗涤,经过疏水玻璃料过滤,并蒸发至干燥。应用0%至100%乙酸乙酯的环己烷溶液的梯度洗脱、通过快速柱层析(20g硅胶柱体)纯化产物,以提供标题化合物(230mg,64%产率)。LCMS RT=1.05min,ES+ve m/z 363[M+H]+。
2-(4-(叔丁氧基羰基)-2-氧代哌嗪-1-基)丙酸
在氮气气氛下,将叔丁基4-(1-(苄氧基)-1-氧代丙烷-2-基)-3-氧代哌嗪-1-羧酸酯(230mg,0.64mmol)的乙醇(3mL)溶液添加至包含钯碳(68mg,0.063mmol)(10%,Degussa类型)的烧瓶。烧瓶充氢气,并将混合物在环境温度下搅拌1小时。通过经过硅藻土过滤除去催化剂,并在减压下蒸发滤液,以提供标题化合物(171mg,99%产率)。LCMS RT=0.62min,ES+ve m/z 290[M+H]+。
叔丁基4-(2-氧代-2,3-二氢苯并[d]唑-5-基)苄基氨基甲酸酯
在氮气气氛下,将(4-(((叔丁氧基羰基)氨基)甲基)苯基)硼酸(可购自例如Aldrich)(387mg,1.54mmol)、5-溴苯并[d]唑-2(3H)-酮(可购自例如Aldrich)(300mg,1.40mmol)和碳酸钠(446mg,4.21mmol)在DMF(4mL)中的混合物用二氯[1,1'-双(二苯基膦)二茂铁]钯(II)(可购自例如Aldrich)(72mg,0.098mmol)处理,然后密封,并在Biotage“Initiator”微波中在110℃下加热1hr。将冷却产物混合物用二氯甲烷(50mL)和水(10mL)处理。将混合物分离,并将有机部分蒸发至干燥。产物通过质量导向自动制备型HPLC(甲酸改性剂)进行纯化,以提供标题化合物(178mg,0.52mmol,37%产率)。LCMS RT=1.03min,ES+ve m/z 341[M+H]+。
5-(4-(氨基甲基)苯基)苯并[d]唑-2(3H)-酮,盐酸盐
将叔丁基4-(2-氧代-2,3-二氢苯并[d]唑-5-基)苄基氨基甲酸酯(130mg,0.38mmol)的THF(10mL)溶液用盐酸(4M,在1,4-二/>烷中)(1mL,4mmol)处理,并将混合物在环境温度下搅拌过夜。将混合物用二乙醚(40mL)处理;将所得沉淀物滤出,并在真空下干燥,以提供标题化合物(87mg,0.31mmol,82%产率)。LCMS RT=0.49min,ES+ve m/z 241[M+H]+。
(2S,4R)-4-羟基-1-(3-羟基苯甲酰基)-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺
将(2S,4R)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺,盐酸盐(217mg,0.61mmol)、3-羟基苯甲酸(85mg,0.61mmol)和DIPEA(0.321mL,1.84mmol)在DMF(4mL)中的冰冷却溶液用HATU(240mg,0.63mmol)经1分钟逐部分处理,然后在环境温度下搅拌1小时。将混合物用饱和碳酸氢钠水溶液(20mL)处理,并用乙酸乙酯(3×20mL)萃取。将组合的有机相用盐水(3×30mL)洗涤,经过疏水玻璃料过滤,然后蒸发至干燥。应用0至25%甲醇的二氯甲烷溶液的梯度洗脱、通过快速层析(50g硅胶柱体)纯化产物,以提供标题化合物(234mg,0.53mmol,87%产率)。LCMS RT=0.49min,ES+ve m/z 241[M+H]+。
(S)-2-(1-氧代异吲哚啉-2-基)丙酸
将苯二甲醛(可购自例如Aldrich)(4g,30mmol)和(S)-2-氨基丙酸(可购自例如Aldrich)(2.39g,27mmol)在乙腈(150mL)中的混合物在回流下加热5hr,然后使其冷却至环境温度,并静置过夜。将所得晶体沉淀物滤出,用乙腈洗涤,并在真空下干燥,以提供标题化 合物(4.46g,22mmol,73%产率)。LCMS RT=0.59min,ES+ve m/z 206[M+H]+。
利用与(S)-2-(1-氧代异吲哚啉-2-基)丙酸类似的方法,制备下列化合物:
乙基2-(5-甲氧基-1-氧代异吲哚啉-2-基)-3-甲基丁酸酯
在氮气气氛下,将5-甲氧基异吲哚啉-1-酮(可购自例如Chem Impex)(105mg,0.64mmol)在DMF(2.5mL)中的冰冷却溶液用氢化钠(60%w/w,在矿物油中)(31mg,0.77mmol)处理。将混合物升温至环境温度,用乙基2-溴-3-甲基丁酸酯(可购自例如ΑlfaAesar)(135mg,0.64mmol)处理,在环境温度下搅拌2小时,然后加热至70℃再18小时。然后将混合物冰冷却,并用另外的氢化钠(60%w/w,在矿物油中)(31mg,0.77mmol),然后乙基2-溴-3-甲基丁酸酯(135mg,0.64mmol)处理,并在70℃下再搅拌24小时。然后将冷却混合物小心地用饱和含水氯化铵(20mL)处理,并将产物用乙酸乙酯(2×25mL)萃取。将组合的有机相用水(20mL)、盐水(20mL)洗涤,经过疏水玻璃料过滤,并蒸发至干燥。应用0%至50%乙酸乙酯的环己烷溶液的梯度洗脱、通过快速层析(20g硅胶柱体)纯化产物,以提供标题化合物(44mg,23%产率)。LCMS RT=1.01min,ES+ve m/z 292[M+H]+
乙基2-(6-甲氧基-1-氧代异吲哚啉-2-基)-3-甲基丁酸酯
在氮气气氛下,将6-甲氧基异吲哚啉-1-酮(可购自例如Astatech)(105mg,0.64mmol)在DMF(2.5mL)中的冰冷却溶液用氢化钠(60%w/w,在矿物油中)(31mg,0.77mmol)处理,并使混合物升温至环境温度。然后将混合物用乙基2-溴-3-甲基丁酸酯(可购自例如Αlfa Aesar)(135mg,0.64mmol)处理,并将混合物搅拌18小时,然后小心地用饱和含水氯化铵(20mL)处理。产物用乙酸乙酯(2×25mL)萃取,并将组合的有机相用水(20mL)、盐水(20mL)洗涤,经过疏水玻璃料过滤,并蒸发至干燥。应用0至50%乙酸乙酯的环己烷溶液的梯度洗脱、通过快速层析(20g硅胶柱体)纯化产物,以提供标题化合物(40mg,21%产率)。LCMS RT=1.03min,ES+ve m/z 292[M+H]+
2-(6-甲氧基-1-氧代异吲哚啉-2-基)-3-甲基丁酸
将乙基2-(6-甲氧基-1-氧代异吲哚啉-2-基)-3-甲基丁酸酯(40mg,0.14mmol)的乙醇(0.4mL)溶液用2M含水氢氧化钠(0.20mL,0.41mmol)处理,并将混合物在环境温度下搅拌2小时。将反应混合物蒸发至干燥,用水(10mL)处理,并用2M含水盐酸酸化至pH 3。产物用乙酸乙酯(2×10mL)萃取,并将组合的有机相经过疏水玻璃料过滤,并蒸发至干燥,以提供标题化合物(34mg,94%产率)。LCMS RT=0.80min,ES+ve m/z 264[M+H]+。
2-(5-甲氧基-1-氧代异吲哚啉-2-基)-3-甲基丁酸
将乙基2-(5-甲氧基-1-氧代异吲哚啉-2-基)-3-甲基丁酸酯(40mg,0.14mmol)的乙醇(0.4mL)溶液用2M含水氢氧化钠(0.20mL,0.41mmol)处理,并将混合物在环境温度下搅拌2小时。然后将混合物蒸发至干燥;剩余物用水(10mL)处理并用2M含水盐酸酸化至pH 3。产物用乙酸乙酯(2×10mL)萃取,并将组合的有机相经过疏水玻璃料过滤,并蒸发至干燥,以提供标题化合物(33mg,93%产率)。LCMS RT=0.76min,ES+ve m/z 264[M+H]+。
乙基2-(7-氯-1-氧代异吲哚啉-2-基)-3-甲基丁酸酯
在氮气气氛下,将7-氯异吲哚啉-1-酮(可购自例如JW Pharm)(150mg,0.90mmol)在DMF(2.5mL)中的冰冷却溶液用氢化钠(60%w/w,在矿物油中)(50mg,1.25mmol)处理。使混合物升温至环境温度,然后用乙基2-溴-3-甲基丁酸酯(可购自例如Αlfa Aesar)(187mg,0.90mmol)处理并搅拌5小时。然后将混合物冰冷却,用另外的氢化钠(60%w/w,在矿物油中)(50mg,1.25mmol)和乙基2-溴-3-甲基丁酸酯(187mg,0.90mmol)处理,并将混合物在环境温度下再搅拌24小时。然后将混合物小心地用饱和含水氯化铵(20mL)处理,并将产物用乙酸乙酯(2×25mL)萃取。将组合的有机相用水(20mL)、盐水(20mL)洗涤,经过疏水玻璃料过滤,并蒸发至干燥。应用0至50%乙酸乙酯的环己烷溶液的梯度洗脱、通过快速层析(20g硅胶柱体)纯化产物,以提供标题化合物(40mg,15%产率)。LCMS RT=1.07min,ES+ve m/z 296[M+H]+。
2-(7-氯-1-氧代异吲哚啉-2-基)-3-甲基丁酸
将乙基2-(7-氯-1-氧代异吲哚啉-2-基)-3-甲基丁酸酯(40mg,0.14mmol)的乙醇(0.4mL)溶液用2M含水氢氧化钠(0.22mL,0.45mmol)处理,并将混合物在环境温度下搅拌2小时。然后将混合物蒸发至干燥,用水(10mL)处理,然后用2M含水盐酸酸化至pH 3。产物用乙酸乙酯(2×10mL)萃取,并将组合的有机相经过疏水玻璃料过滤,并蒸发至干燥,以提供标题化合物(34mg,94%产率)。LCMS RT=0.82min,ES+ve m/z 268[M+H]+。
2-羟基-4-(4-甲基噻唑-5-基)苄腈
在氮气气氛下,将4-溴-2-羟基苄腈(可购自例如Fluorochem)(15g,76mmol)、4-甲基噻唑(可购自例如Aldrich)(14mL、152mmol)、乙酸钾(14.9g,152mmol)和乙酸钯(II)(0.34g,1.52mmol)在1-甲基-2-吡咯烷酮(125mL)中的混合物在110℃下加热3小时。然后将混合物冷却至50℃,倒入水(300mL)中,并用乙酸乙酯(3×350mL)萃取。将组合的有机部分过滤,然后将滤液用盐水(3×400mL)洗涤,经过疏水玻璃料过滤,并蒸发至干燥。剩余物从甲苯然后二乙醚重新蒸发,然后在甲醇中浆化,以沉淀黄色固体,将其滤出。将滤液蒸发至干燥并在冰冷却甲醇中浆化,以提供第二批黄色固体。将组合的固体在真空下干燥,以提供标题化合物(12g,56mmol,73%产率)。LCMS RT=0.75min,ES+ve m/z 217[M+H]+。
2-(氨基甲基)-5-(4-甲基噻唑-5-基)苯酚
将2-羟基-4-(4-甲基噻唑-5-基)苄腈(12g,56mmol)在THF(550mL)中的冰冷却溶液用氢化铝锂(1M,在THF中,140mL,140mmol)经5分钟逐滴处理。然后将所得混合物在50℃下加热30分钟,并添加另外的氢化铝锂(1M,THF中,20mL,20mmol)。再30分钟后,将混合物在冰浴中冷却并小心地用水(14mL),然后用含水氢氧化钠(4M,42mL,168mmol)和最后用水(14mL)处理。静置3天后,将混合物过滤,并将过滤的固体用THF洗涤。将组合的滤液蒸发至干燥,并将剩余物在二氯甲烷中:甲醇(4:1)中与硅藻土(约20g)一起浆化并过滤。将过滤的固体用二氯甲烷/甲醇(4:1)洗涤三次,并将组合的滤液蒸发至干燥。应用0至15%甲醇的二氯甲烷(+1%三乙胺)溶液的梯度洗脱、通过快速层析(330g硅胶柱体)纯化产物,以提供标 题化合物(6.2g,28mmol,51%产率)。LCMS RT=0.41min,ES+ve m/z 221[M+H]+。
(2S,4R)-叔丁基4-羟基-2-((2-羟基-4-(4-甲基噻唑-5-基)苄基)氨甲酰基)吡咯烷-1-羧酸酯
将2-(氨基甲基)-5-(4-甲基噻唑-5-基)苯酚(3.05g,13.8mmol)和(2S,4R)-1-(叔丁氧基羰基)-4-羟基吡咯烷-2-羧酸(2.94mL、13.8mmol)在DMF(35mL)中的冰冷却溶液用DIPEA(7.25mL,42mmol)然后HATU(5.79g,15.2mmol)处理,并将混合物在环境温度下搅拌1小时。将混合物用饱和碳酸氢钠水溶液(50mL)处理,并用乙酸乙酯(3×80mL)萃取。将组合的有机相用盐水(60mL)洗涤,经过疏水玻璃料过滤,并蒸发至干燥。应用0至15%甲醇的二氯甲烷溶液的梯度、通过快速层析(330g硅胶柱体)纯化产物,以提供标题产物(4.8g,11mmol,80%产率)。LCMS RT=0.76min,ES+ve m/z 434[M+H]+。
(2S,4R)-4-羟基-N-(2-羟基-4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺,盐酸盐
将(2S,4R)-叔丁基4-羟基-2-((2-羟基-4-(4-甲基噻唑-5-基)苄基)氨甲酰基)吡咯烷-1-羧酸酯(4.8g,11mmol)在二氯甲烷:甲醇20:1(50mL)中的溶液用盐酸(4M,在1,4-二烷中)(35mL,140mmol)处理,并将混合物搅拌过夜在环境温度下。然后将混合物蒸发至干燥,并将残留固体悬浮在二氯甲烷中并过滤。过滤的固体再用二氯甲烷洗涤,并在真空下干燥,以提供标题化合物(4g,10.8mmol,98%产率)。LCMS RT=0.46min,ES+ve m/z 334[M+H]+。
(2S,4R)-1-((S)-2-氨基丙酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺,盐酸盐
将(2S,4R)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺,盐酸盐(100mg,0.28mmol)、(S)-2-((叔丁氧基羰基)氨基)丙酸(可购自例如Aldrich)(64mg,0.34mmol)和DIPEA(0.197mL,1.13mmol)在干燥DMF(3mL)中的搅拌混合物用HATU(129mg,0.34mmo)处理,并在环境温度下搅拌30分钟。然后将混合物在乙酸乙酯(30mL)和水(30mL)之间分配,并将有机相用盐水(30mL)洗涤,干燥(疏水玻璃料),并蒸发至干燥。将剩余物溶解于甲醇中,并添加至甲醇预处理的氨基丙基固相萃取柱体(2g),用甲醇洗脱(3个柱体积)。将所得洗脱液蒸发至干燥,并将剩余物溶解于二氯甲烷:甲醇(1:1.8mL)中,并用盐酸(4M,在1,4-二烷中)(1mL,4mmol)处理。将混合物在环境温度下搅拌16小时,然后蒸发至干燥,以提供标题化合物(107mg,0.25mmol,89%产率)。LCMS RT=0.51min,ES+ve m/z 389[M+H]+。
(2S,4R)-1-(2-氨基-2-甲基丙酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺
将(2S,4R)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺,盐酸盐(100mg,0.28mmol)、2-((叔丁氧基羰基)氨基)-2-甲基丙酸(可购自例如Aldrich)(69mg,0.34mmol)和DIPEA(0.197mL、1.13mmol)在干燥DMF(3mL)中的混合物溶液用HATU(129mg,0.34mmol)处理,在环境温度下搅拌30分钟,然后在乙酸乙酯(30mL)和水(30mL)之间分配。将有机相用盐水(30mL)洗涤,干燥(疏水玻璃料),并蒸发至干燥。将剩余物溶解于甲醇中,并添加至甲醇预处理的氨基丙基固相萃取柱体(2g),用甲醇洗脱。将所得洗脱液蒸发至干燥,并将剩余物溶解于二氯甲烷:甲醇(1:1.8mL)中,并用在1,4-二烷中的4M盐酸(1mL,4mmol)处理。将反应混合物在环境温度下搅拌16小时,然后蒸发至干燥。将剩余物悬浮在二氯甲烷(4mL)中,并用TFA(1mL)处理,并将混合物在环境温度下搅拌4小时。将混合物蒸发至干燥,并将剩余物溶解于甲醇中和添加至甲醇预处理的磺酸固相萃取柱体(2g),并用甲醇(3个柱体积)然后用氨的甲醇(2M,3个柱体积)溶液洗脱。将包含产物的馏分蒸发至干燥,以提供标题化合物(95mg,0.24mmol,84%产率)。LCMS RT=0.53min,ES+ve m/z 403[M+H]+。
(2S,4R)-4-羟基-1-((S)-2-(甲基氨基)丙酰基)-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺
将(2S,4R)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺,盐酸盐(120mg,0.34mmol)和(S)-2-((叔丁氧基羰基)(甲基)氨基)丙酸(可购自例如Aldrich)(76mg,0.37mmol)在DMF(2mL)中的搅拌混合物用DIPEA(0.24mL,1.36mmol)然后用HATU(155mg,0.41mmol)处理,并将混合物在环境温度下搅拌30分钟。将粗产物通过质量导向自动制备型HPLC(甲酸改性剂)进行纯化,以提供中间体Boc-保护的产物。将中间体悬浮在二氯甲烷(0.5mL)中,并用TFA(0.5mL)处理。将混合物在环境温度下搅拌1小时,然后蒸发至干燥。将剩余物溶解于最少量的甲醇:二氯甲烷(1:1)混合物中,然后负载到预处理(甲醇)氨基丙基固相萃取柱体(5g)上。将柱用甲醇(3体积)洗脱,并且将包含产物的馏分组合,并蒸发至干燥,以提供标题化合物(103mg,75%产率)。LCMS RT=0.47min,ES+ve m/z 403[M+H]+。
(2S,4R)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)-1-((S)-吗啉-3-羰基)吡咯烷-2-羧酰胺,盐酸盐
将(2S,4R)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺,盐酸盐(100mg,0.28mmol)、(S)-4-(叔丁氧基羰基)吗啉-3-羧酸(可购自例如Astatech)(65mg,0.28mmol)和DIPEA(0.247mL、1.41mmol)在DMF(2mL)中的混合物用HATU(118mg,0.311mmol)处理,并在环境温度下搅拌30分钟。将Boc保护的中间体通过质量导向自动制备型HPLC(甲酸改性剂)进行纯化。将中间体溶解于甲醇:二氯甲烷(1:1.3mL)中,用盐酸的1,4-二烷溶液(4M,3mL,12mmol)处理,并静置1小时。将混合物蒸发至干燥,以提供标题化合物(110mg,0.24mmol,83%产率)。LCMS RT=0.50min,ES+ve m/z 431/432[M+H]+。
叔丁基4-(3-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨甲酰基)吡咯烷-1-羰基)苯氧基)丁酸酯
将3-(4-(叔丁氧基)-4-氧代丁氧基)苯甲酸(95mg,0.34mmol)、(2S,4R)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺,盐酸盐(100mg,0.28mmol)和DIPEA(0.2mL,1.15mmol)在干燥DMF(3mL)中的混合物溶液用HATU(129mg,0.34mmol)处理,并将混合物在环境温度下搅拌30分钟。将混合物添加至氨基丙基固相萃取柱体,并用甲醇(3个柱体积)洗脱。将所得洗脱液蒸发至干燥,并且产物通过质量导向自动制备型HPLC(甲酸改性剂)进行纯化,以提供标题化合物(130mg,0.22mmol,79%产率)。LCMS RT=0.98min,ES+vem/z 580[M+H]+。
实施例——结合雌激素受体的VHL普罗太克(雌激素普罗太克)
简称:
DCM:二氯甲烷。
DIPEA:N,N-二异丙基乙基胺。
DMF:N,N-二甲基甲酰胺。
HATU:2-(7-氮杂-1H-苯并三唑-1-基)-1,1,3,3-四甲基脲六氟磷酸盐。
HPLC:高效液相色谱。
LCMS:液相色谱-质谱
Min:分钟。
RT:保留时间。
tBu:叔丁醇盐。
TFA:三氟乙酸。
THF:四氢呋喃。
LCMS方法:
分析在40℃下在Acquity UPLC BEH C18柱(50mm×2.1mm内径1.7μm填料直径)上进行。
所用溶剂是:
A=0.1%v/v甲酸水溶液。
B=0.1%v/v甲酸的乙腈溶液。
所用梯度如下:
UV检测是波长210nm至350nm的平均化信号,并且在应用交替扫描正负模式电喷雾电离的质谱仪上记录质谱。
如下示例化合物当通过质量导向自动制备型HPLC进行纯化时所用的流动相和梯度。
质量导向自动制备型HPLC(甲酸改性剂)
HPLC分析在环境温度下在Sunfire C18柱(150mm×30mm内径,5μm填料直径)上进行。
所用溶剂是:
A=0.1%v/v甲酸水溶液。
B=0.1%v/v甲酸的乙腈溶液。
质量导向自动制备型HPLC(三氟乙酸改性剂)
HPLC分析在环境温度下在Sunfire C18柱(150mm×30mm内径,5μm填料直径)上进行。
所用溶剂是:
A=0.1%v/v三氟乙酸水溶液。
B=0.1%v/v三氟乙酸的乙腈溶液。
质量导向自动制备型HPLC(碳酸氢铵改性剂)
HPLC分析在环境温度下在XBridge C18柱(150mm×30mm内径,5μm填料直径)上进行。
所用溶剂是:
A=10mM碳酸氢铵水溶液,用氨溶液调节至pH 10。
B=乙腈。
对于各个质量导向自动制备型纯化,不管所用改性剂如何,所用梯度取决于分析LCMS中记录的进行纯化的具体化合物的保留时间,如下:
对于分析LCMS保留时间在0.6分钟以下的化合物,应用下列梯度:
对于分析LCMS保留时间在0.6和0.9分钟之间的化合物,应用下列梯度:
对于分析LCMS保留时间在0.9和1.2分钟之间的化合物,应用下列梯度:
对于分析LCMS保留时间在1.2和1.4分钟之间的化合物,应用下列梯度:
对于分析LCMS保留时间大于1.4分钟(LCMS方法A)或大于3.6分钟(LCMS方法B)的化合物,应用下列梯度:
UV检测是波长210nm至350nm的平均化信号,并且在应用交替扫描正负模式电喷雾电离的质谱仪上记录质谱。
化学名称利用来自Advanced Chemistry Development,Inc.的ACD Name Proversion 6.02生成。
8R,9S,13S,14S,17S)-3,17-双(甲氧基甲氧基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-6-酮
(8R,9S,13S,14S,17S)-3,17-双(甲氧基甲氧基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-6-酮可根据Xiang-Rong Jiang,J.Walter Sowell,Bao Ting Zhu,Steroids,2006,71,334-342.(doi:10.1016/j.steroids.2005.11.008)描述的方法制备。
15-溴-1-苯基-2,5,8,11-四氧杂十五烷
在0℃下,向氢化钠——60%w/w,在矿物油中(0.250g,6.24mmol)——在DMF(2mL)中的悬浮液添加2-(2-(2-(苄氧基)乙氧基)乙氧基)乙醇(1g,4.16mmol)(可购自例如Fluorochem)在DMF(2mL)中的溶液。搅拌25分钟后,将溶解于中DMF(2mL)的1,4-二溴丁烷(可购自例如Aldrich)(4.04g,18.73mmol)逐滴添加至混合物。将反应在氮气气氛下搅拌2.5小时。添加再一等份的氢化钠——60%w/w,在矿物油中(0.250g,6.24mmol),并将反应在0℃下搅拌30分钟。使反应升温至室温并搅拌30分钟。添加最后一个等份的氢化钠——60%w/w,在矿物油中(0.250g,6.24mmol),并将反应在室温下搅拌2小时,然后静止周末。经过硅藻土过滤反应混合物,并用DCM洗涤固体。将滤液在DCM(30mL)和水(30mL)之间分配。有机萃取物用盐水(2×30mL)洗涤,利用疏水玻璃料干燥,并在减压下浓缩。应用0%至100%甲基叔丁基醚的环己烷溶液的梯度洗脱、通过在硅胶上进行层析来纯化产物,以提供标题化合物(711mg,1.89mmol,46%产率)。LCMS RT=1.16min,ES+ve m/z 375.2/377.1[M+H]+。
15-碘-1-苯基-2,5,8,11-四氧杂十五烷
将15-溴-1-苯基-2,5,8,11-四氧杂十五烷(711mg,1.894mmol)和碘化钠(568mg,3.79mmol)在丙酮(10mL)中的混合物在回流条件下加热4小时。将反应冷却至室温。经过硅藻土过滤混合物并用丙酮洗涤固体。将溶剂在减压下去除。剩余物溶解于乙酸乙酯(30mL)中并用水(30mL)和盐水(2×30mL)洗涤。有机萃取物利用疏水玻璃料干燥并在减压下浓缩,以提供标题化合物(759mg,1.797mmol,95%产率)。LCMS RT=1.23min,ES+ve m/z 440.0[M+NH4]+。
(7S,8R,9S,13S,14S,17S)-3,17-双(甲氧基甲氧基)-13-甲基-7-(1-苯基-2,5,8,11-四氧杂十五烷-15-基)-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-6-酮
将KOtBu的THF(1M,1.282mL,1.282mmol)溶液添加至(8R,9S,13S,14S,17S)-3,17-双(甲氧基甲氧基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-6-酮(240mg,0.641mmol)在无水THF(2mL)中的冷却溶液(0℃)。将反应混合物在0℃下搅拌45分钟,然后冷却至-78℃。逐滴添加15-碘-1-苯基-2,5,8,11-四氧杂十五烷(789mg,1.868mmol)在THF(1mL)中的溶液。将溶液在-78℃下搅拌2分钟,使其升温至0℃,并在该温度下搅拌1.5小时。将反应在水(30mL)和乙酸乙酯(30mL)之间分配。有机萃取物利用疏水玻璃料干燥,并在减压下浓缩。应用0%至100%乙酸乙酯的环己烷溶液的梯度洗脱、通过在硅胶上进行层析来纯化产物,以提供标题化合物(234mg,0.350mmol,55%产率)。LCMS RT=1.48min,ES+ve m/z 669.3[M+H]+,686.4[M+NH4]+。
(7S,8R,9S,13S,14S,17S)-3,17-二羟基-13-甲基-7-(1-苯基-2,5,8,11-四氧杂十五烷-15-基)-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-6-酮
将HCl(6M,2.3mL,13.80mmol)水溶液添加至(7S,8R,9S,13S,14S,17S)-3,17-双(甲氧基甲氧基)-13-甲基-7-(1-苯基-2,5,8,11-四氧杂十五烷-15-基)-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-6-酮(234mg,0.350mmol)在THF(2.3mL)中的溶液。将反应混合物在室温下搅拌16小时。添加水(30mL),并将产物用乙酸乙酯(50mL)萃取。有机萃取物用盐水(2×30mL)洗涤,利用疏水玻璃料干燥,并在减压下浓缩,以提供标题化合物(200mg,0.344mmol,98%产率)。LCMS RT=1.07min,ES+ve m/z 581.3[M+H]+,598.3[M+NH4]+。
(7R,8R,9S,13S,14S,17S)-13-甲基-7-(1-苯基-2,5,8,11-四氧杂十五烷-15-基)-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-3,17-二醇
将三乙基硅烷(可购自例如Aldrich)(0.550mL,3.44mmol)添加至(7S,8R,9S,13S,14S,17S)-3,17-二羟基-13-甲基-7-(1-苯基-2,5,8,11-四氧杂十五烷-15-基)-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-6-酮(200mg,0.344mmol)在TFA(2mL,26.0mmol)中的溶液。将反应在室温下在氮气气氛下搅拌16小时。将混合物在乙酸乙酯(30mL)和盐水(30mL)之间分配。有机萃取物用盐水(2×30mL)洗涤,利用疏水玻璃料干燥,并在减压下浓缩。将剩余物溶解于MeOH(5mL)中,并用含水NaOH(2M,5mL,10.00mmol)处理。将反应混合物在室温下搅拌3小时。在减压下去除溶剂。将剩余物在乙酸乙酯(30mL)和10%柠檬酸溶液(30mL)之间分配。有机萃取物用盐水(30mL)洗涤,利用疏水玻璃料干燥,并在减压下浓缩。应用5%至95%乙腈(+0.1%甲酸)的水(+0.1%甲酸)溶液的梯度洗脱、通过反相层析纯化产物,以提供标题化合物(150mg,0.265mmol,77%产率)。LCMS RT=1.18min,ES+ve m/z 567.3[M+H]+,584.3[M+NH4]+。
15-((7R,8R,9S,13S,14S,17S)-3,17-双(甲氧基甲氧基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-7-基)-1-苯基-2,5,8,11-四氧杂十五烷
在小瓶中装载在THF(10mL)中的(7R,8R,9S,13S,14S,17S)-13-甲基-7-(1-苯基-2,5,8,11-四氧杂十五烷-15-基)-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-3,17-二醇(150mg,0.265mmol)和DIPEA(0.555mL,3.18mmol)。将小瓶密封,使溶液冷却至0℃,并添加氯(甲氧基)甲烷(可购自例如Aldrich)(0.2mL,2.63mmol)。将反应混合物升温至室温,搅拌1小时,并在70℃下加热40小时。将反应冷却至室温。将反应在乙酸乙酯(100mL)和水(100mL)之间分配。有机萃取物用盐水(2×50mL)洗涤,利用疏水玻璃料干燥并在减压下浓缩。应用0%至100%甲基叔丁基醚的环己烷溶液的梯度洗脱、通过在硅胶上进行层析来纯化产物,以提供标题化合物(122mg,0.186mmol,70%产率)。LCMS RT=1.60min,ES+ve m/z 672.5[M+NH4]+。
2-(2-(2-(4-((7R,8R,9S,13S,14S,17S)-3,17-双(甲氧基甲氧基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-7-基)丁氧基)乙氧基)乙氧基)乙醇
将15-((7R,8R,9S,13S,14S,17S)-3,17-双(甲氧基甲氧基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-7-基)-1-苯基-2,5,8,11-四氧杂十五烷(115mg,0.176mmol)和10%w/w钯碳(100mg,0.094mmol)在乙醇(4mL)中的混合物在室温下在氢气气氛下搅拌1.5小时。经过硅藻土过滤钯碳,并在减压下蒸发滤液。将剩余物在乙酸乙酯(15mL)和盐水(15mL)之间分配。有机萃取物利用疏水玻璃料干燥并在减压下浓缩,以提供标题化合物(81mg,0.143mmol,82%产率)。LCMS RT=1.36min,ES+ve m/z 582.4[M+NH4]+。
叔丁基16-((7R,8R,9S,13S,14S,17S)-3,17-双(甲氧基甲氧基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-7-基)-3,6,9,12-四氧杂十六烷-1-酸酯
将氢化钠——60%w/w,在矿物油中(10mg,0.250mmol)——添加至2-(2-(2-(4-((7R,8R,9S,13S,14S,17S)-3,17-双(甲氧基甲氧基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-7-基)丁氧基)乙氧基)乙氧基)乙醇(81mg,0.143mmol)在DMF(2mL)中的冷却溶液(0℃)。将反应在该温度下搅拌10分钟,并添加叔丁基2-溴乙酸酯(可购自例如Aldrich)(32μL,0.217mmol)。将反应在0℃下搅拌1小时并在室温下再搅拌2小时。将反应混合物在乙酸乙酯(30mL)和水(30mL)之间分配。将有机层用盐水(30mL)洗涤,干燥(疏水玻璃料)并在减压下浓缩。应用0%至100%甲基叔丁基醚的环己烷溶液的梯度洗脱、通过在硅胶上进行层析来纯化产物,以提供标题化合物(60mg,0.088mmol,62%产率)。LCMS RT=1.57min,ES+ve m/z 696.5[M+NH4]+。
16-((7R,8R,9S,13S,14S,17S)-3,17-二羟基-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-7-基)-3,6,9,12-四氧杂十六烷-1-酸
将叔丁基16-((7R,8R,9S,13S,14S,17S)-3,17-双(甲氧基甲氧基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-7-基)-3,6,9,12-四氧杂十六烷-1-酸酯(133mg,0.196mmol)溶解于THF(1.5mL)中,并用含水HCl(6M,1.5mL,9.00mmol)处理。将反应混合物在室温下搅拌8小时。将反应混合物直接通过质量导向自动制备型HPLC(甲酸改性剂)进行纯化,以提供标题化合物(60mg,0.112mmol,57%产率)。LCMS RT=0.89min,ES+ve m/z 535.3[M+H]+,552.3[M+NH4]+。
(2S,4R)-1-((S)-19-((7R,8R,9S,13S,14S,17S)-3,17-二羟基-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-7-基)-2-异丙基-4-氧代-6,9,12,15-四氧杂-3-氮杂十九烷-1-酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺
将HATU(16mg,0.042mmol)添加至(2S,4R)-1-((S)-2-氨基-3-甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺,盐酸盐(25mg,0.055mmol)、16-((7R,8R,9S,13S,14S,17S)-3,17-二羟基-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-7-基)-3,6,9,12-四氧杂十六烷-1-酸(15mg,0.028mmol)和DIPEA(0.05mL,0.286mmol)在DMF(1mL)中的混合物。将反应在室温下搅拌30分钟。将反应混合物直接通过质量导向自动制备型HPLC(甲酸改性剂)进行纯化,以提供标题化合物(20mg,0.021mmol,76%产率)。LCMS RT=0.99min,ES+ve m/z933.3[M+H]+。
(2S,4R)-1-((S)-2-(叔丁基)-19-((7R,8R,9S,13S,14S,17S)-3,17-二羟基-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-7-基)-4-氧代-6,9,12,15-四氧杂-3-氮杂十九烷-1-酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺
将HATU(22mg,0.058mmol)添加至(2S,4R)-1-((S)-2-氨基-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺,盐酸盐(25mg,0.054mmol)、16-((7R,8R,9S,13S,14S,17S)-3,17-二羟基-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-7-基)-3,6,9,12-四氧杂十六烷-1-酸(23mg,0.043mmol)和DIPEA(0.040mL,0.229mmol)在DMF(1mL)中的混合物。将反应在室温下搅拌10分钟。将反应混合物直接通过质量导向自动制备型HPLC(甲酸改性剂)进行纯化,以提供标题化合物(26mg,0.027mmol,64%产率)。LCMS RT=1.02min,ES+ve m/z 947.8[M+H]+。
((2-(2-(4-溴丁氧基)乙氧基)乙氧基)甲基)苯
在0℃下向氢化钠——60%w/w,在矿物油中(0.92g,22.9mmol)——在DMF(5mL)中的悬浮液添加2-(2-(苄氧基)乙氧基)乙醇(可购自例如Aldrich)(2.74mL,15.29mmol)在DMF(5mL)中的溶液。搅拌25min后,将溶解于DMF(5mL)中的1,4-二溴丁烷(可购自例如Aldrich)(14.9g,68.8mmol)逐滴添加至混合物。使反应升温至环境温度,并在氮气气氛下搅拌2.5小时。添加再一等份的氢化钠——60%w/w,在矿物油中(0.92g,22.9mmol),并将反应在0℃下搅拌30分钟和在环境温度下搅拌30分钟。添加最后一个等份的氢化钠——60%w/w,在矿物油中(0.92g,22.9mmol),并使反应在环境温度下搅拌2小时,然后静置过夜。经过硅藻土过滤反应混合物并用DCM洗涤固体。将滤液在DCM(30mL)和水(30mL)之间分配。有机萃取物用盐水(2×30mL)洗涤,利用疏水玻璃料干燥,并在减压下浓缩。应用0%至80%甲基叔丁基醚的环己烷溶液的梯度洗脱、通过在硅胶上进行层析来纯化产物,以提供标题化合物(3g,9.06mmol,59%产率)。LCMS RT=1.19min,ES+ve m/z331.2/333.2[M+H]+。
((2-(2-(4-碘丁氧基)乙氧基)乙氧基)甲基)苯
将((2-(2-(4-溴丁氧基)乙氧基)乙氧基)甲基)苯(3g,9.06mmol)和碘化钠(2.72g,18.11mmol)在丙酮(10mL)中的混合物在回流条件下加热3小时。使反应冷却至室温。经过硅藻土过滤混合物并用丙酮洗涤固体。将溶剂在减压下去除,并将剩余物溶解于乙酸乙酯(30mL)中并用水(30mL)和盐水(2×30mL)洗涤。有机萃取物利用疏水玻璃料干燥并在减压下浓缩。应用0%至50%甲基叔丁基醚的环己烷溶液的梯度洗脱、通过在硅胶上进行层析来纯化产物,以提供标题化合物(3.1g,8.2mmol,90%产率)。LCMS RT=1.25min,ES+vem/z 379.2[M+H]+。
(7S,8R,9S,13S,14S,17S)-7-(4-(2-(2-(苄氧基)乙氧基)乙氧基)丁基)-3,17-双(甲氧基甲氧基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-6-酮
将KOtBu的THF(1M,3.2 mL,3.2 mmol)溶液添加至(8R,9S,13S,14S,17S)-3,17-双(甲氧基甲氧基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-6-酮(600 mg,1.6 mmol)在无水THF(6 mL)中的冷却溶液(0℃)。将反应混合物在0℃下搅拌45分钟,然后冷却至-78℃。逐滴添加((2-(2-(4-碘丁氧基)乙氧基)乙氧基)甲基)苯(910 mg,2.4 mmol)在THF(3 mL)中的溶液。将溶液在-78℃下搅拌2分钟,然后使其升温至0℃并在该温度下搅拌1.5小时。将反应在水(30 mL)和乙酸乙酯(30 mL)之间分配。将有机萃取物分离,利用疏水玻璃料干燥并在减压下浓缩。应用0%至50%乙酸乙酯的环己烷溶液的梯度洗脱、通过在硅胶上进行层析来纯化产物,以提供标题化合物(450 mg,0.72 mmol,45%产率)。LCMS RT=1.49 min,ES+ve m/z 625.5[M+H]+。
(7S,8R,9S,13S,14S,17S)-7-(4-(2-(2-(苄氧基)乙氧基)乙氧基)丁基)-3,17-二羟基-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-6-酮
将HCl(6M,4.6 mL,27.6 mmol)的水溶液添加至(7S,8R,9S,13S,14S,17S)-7-(4-(2-(2-(苄氧基)乙氧基)乙氧基)丁基)-3,17-双(甲氧基甲氧基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-6-酮(470 mg,0.752 mmol)在THF(4.6 mL)中的溶液。将反应混合物在室温下搅拌18小时。添加水(30 mL),并将产物用乙酸乙酯(50 mL)萃取。有机萃取物用盐水(2×30 mL)洗涤,利用疏水玻璃料干燥并在减压下浓缩,以提供标题化合物(390 mg,0.727 mmol,97%产率)。LCMS RT=1.08 min,ES+ve m/z 537.2[M+H]+,554.2[M+NH4]+。(7R,8R,9S,13S,14S,17S)-7-(4-(2-(2-(苄氧基)乙氧基)乙氧基)丁基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-3,17-二醇
将三乙基硅烷(可购自例如Aldrich)1.161mL,7.27mmol)添加至(7S,8R,9S,13S,14S,17S)-7-(4-(2-(2-(苄氧基)乙氧基)乙氧基)丁基)-3,17-二羟基-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-6-酮(390mg,0.727mmol)在TFA(4.2mL,54.5mmol)中的溶液。将反应在室温下在氮气气氛下搅拌18小时。将混合物在乙酸乙酯(50mL)和盐水(50mL)之间分配。有机萃取物用盐水(2×30mL)、饱和碳酸氢钠(30mL)洗涤,利用疏水玻璃料干燥并在减压下浓缩。将剩余物溶解于中MeOH(10mL),并用含水NaOH(2M,5mL,10.0mmol)处理。将反应混合物在室温下搅拌1小时。在减压下去除溶剂。将剩余物在乙酸乙酯(30mL)和含水HCl溶液(1M,20mL)之间分配。有机萃取物用盐水(20mL)洗涤,利用疏水玻璃料干燥并在减压下浓缩。应用5%至95%乙腈(+0.1%甲酸)的水(+0.1%甲酸)溶液的梯度洗脱、通过反相层析纯化产物,以提供标题化合物(270mg,0.517mmol,71%产率)。LCMS RT=1.18min,ES+ve m/z 523.5[M+H]+,540.5[M+NH4]+。
(7R,8R,9S,13S,14S,17S)-7-(4-(2-(2-(苄氧基)乙氧基)乙氧基)丁基)-3,17-双(甲氧基甲氧基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲
将氯(甲氧基)甲烷(可购自例如Aldrich)(0.390mL,5.14mmol)添加至(7R,8R,9S,13S,14S,17S)-7-(4-(2-(2-(苄氧基)乙氧基)乙氧基)丁基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-3,17-二醇(270mg,0.517mmol)和DIPEA(1.083mL,6.20mmol)在THF(16mL)中的冷却(0℃)溶液。将反应混合物升温至室温,搅拌1小时,然后在70℃下加热40小时。将反应混合物冷却至0℃,添加另外的DIPEA(0.271mL,1.550mmol)和氯(甲氧基)甲烷(0.098mL,1.291mmol)。将反应加热至70℃并再搅拌24小时。将反应冷却至室温,并且在乙酸乙酯(100mL)和水(100mL)之间分配。有机萃取物用盐水(2×50mL)洗涤,利用疏水玻璃料干燥并在减压下浓缩。应用0%至100%甲基叔丁基醚的环己烷溶液的梯度洗脱、通过在硅胶上进行层析来纯化产物,以提供标题化合物(220mg,0.36mmol,70%产率)。LCMS RT=1.62min,ES+ve m/z 628.6[M+NH4]+。
2-(2-(4-((7R,8R,9S,13S,14S,17S)-3,17-双(甲氧基甲氧基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-7-基)丁氧基)乙氧基)乙醇
将(7R,8R,9S,13S,14S,17S)-7-(4-(2-(2-(苄氧基)乙氧基)乙氧基)丁基)-3,17-双(甲氧基甲氧基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲(220mg,0.36mmol)和10%w/w钯碳(100mg,0.094mmol)在乙醇(4mL)中的混合物在室温下在氢气气氛下搅拌1小时。将钯碳经过硅藻土过滤,用乙醇(50ml)洗涤,并将滤液在减压下蒸发,以提供标题化合物(186mg,0.357mmol,99%产率)LCMS RT=1.36min,ES+ve m/z 521.5[M+H]+,538.5[M+NH4]+。
叔丁基2-(2-(2-(4-((7R,8R,9S,13S,14S,17S)-3,17-双(甲氧基甲氧基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-7-基)丁氧基)乙氧基)乙氧基)乙酸酯
将氢化钠——60%w/w矿物油(25.0mg,0.625mmol)——添加至2-(2-(4-((7R,8R,9S,13S,14S,17S)-3,17-双(甲氧基甲氧基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-7-基)丁氧基)乙氧基)乙醇(186mg,0.357mmol)在DMF(4.5mL)中的冷却溶液(0℃)。将反应在0℃下搅拌10分钟,并添加叔丁基2-溴乙酸酯(可购自例如Aldrich)(79μL,0.536mmol)。将反应在0℃下搅拌1小时并在室温下再搅拌6小时。使反应冷却至0℃,并添加另外的氢化钠——60%w/w,在矿物油中(15.72mg,0.393mmol)——然后叔丁基2-溴乙酸酯(0.053mL,0.357mmol)。将反应在室温下再搅拌18小时。将反应混合物在乙酸乙酯(30mL)和水(30mL)之间分配。将有机层分离,用盐水(30mL)洗涤,利用疏水玻璃料干燥并在减压下浓缩。应用0%至100%甲基叔丁基醚的环己烷溶液的梯度洗脱、通过在硅胶上进行层析来纯化产物,以提供标题化合物(90mg,0.142mmol,40%产率)。LCMS RT=1.56min,ES+ve m/z 652.6[M+NH4]+,657.5[M+Na]+。
2-(2-(2-(4-((7R,8R,9S,13S,14S,17S)-3,17-二羟基-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-7-基)丁氧基)乙氧基)乙氧基)乙酸
将叔丁基2-(2-(2-(4-((7R,8R,9S,13S,14S,17S)-3,17-双(甲氧基甲氧基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-7-基)丁氧基)乙氧基)乙氧基)乙酸酯(80mg,0.126mmol)溶解于THF(1mL)中,并用含水HCl(6M,1mL,6.0mmol)处理。将反应混合物在室温下搅拌4小时。将反应混合物通过质量导向自动制备型HPLC(甲酸改性剂)直接进行纯化,以提供标题化合物(23mg,0.047mmol,37%产率)。LCMS RT=0.89min,ES+ve m/z 491.4[M+H]+。
(2S,4R)-1-((S)-16-((7R,8R,9S,13S,14S,17S)-3,17-二羟基-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-7-基)-2-异丙基-4-氧代-6,9,12-三氧杂-3-氮杂十六烷-1-酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺
将HATU(12mg,0.03mmol)添加至(2S,4R)-1-((S)-2-氨基-3-甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺,盐酸盐(23mg,0.05mmol)、2-(2-(2-(4-((7R,8R,9S,13S,14S,17S)-3,17-二羟基-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-7-基)丁氧基)乙氧基)乙氧基)乙酸(10mg,0.02mmol)和DIPEA(0.04mL,0.20mmol)在DMF(0.8mL)中的混合物。将反应在室温下搅拌30min。将反应混合物通过质量导向自动制备型HPLC(甲酸改性剂)直接进行纯化,以提供标题化合物(15mg,0.017mmol,84%产率)。LCMS RT=0.98min,ES+ve m/z889.7[M+H]+。
18-溴-1-苯基-2,5,8,11,14-五氧杂十八烷
在0℃下向氢化钠——60%w/w,在矿物油中(0.85g,21.3mmol)——在DMF(8mL)中的悬浮液添加1-苯基-2,5,8,11-四氧杂十三烷-13-醇(可购自例如TCI Europe FineChemicals)(4.0g,14.2mmol)在DMF(8mL)中的溶液。搅拌25分钟后,将溶解于DMF(8mL)中的1,4-二溴丁烷(可购自例如Aldrich)(7.62mL,63.8mmol)逐滴添加至混合物。使反应升温至室温并在氮气气氛下搅拌30分钟。添加再一等份的氢化钠——60%w/w,在矿物油中(0.85g,21.3mmol),并将反应在室温下搅拌过夜。添加另一等份的氢化钠——60%w/w,在矿物油中(0.85g,21.3mmol),并将反应在室温下搅拌2小时。添加最后一个等份的氢化钠——60%w/w,在矿物油中(0.43g,10.6mmol),并将反应在室温下搅拌1小时。经过硅藻土过滤反应混合物并用DCM洗涤固体。将滤液在DCM(50mL)和水(50mL)之间分配。有机萃取物用盐水(2×50mL)洗涤,利用疏水玻璃料干燥并在减压下浓缩。应用0%至85%甲基叔丁基醚的环己烷溶液的梯度洗脱、通过在硅胶上进行层析来纯化产物,以提供标题化合物(3.93g,9.37mmol,63%产率)。LCMS RT=1.16min,ES+ve m/z 419.3/421.2[M+H]+。
18-碘-1-苯基-2,5,8,11,14-五氧杂十八烷
将18-溴-1-苯基-2,5,8,11,14-五氧杂十八烷(2.08g,4.91mmol)和碘化钠(1.47g,9.82mmol)在丙酮(10mL)中的混合物在回流条件下加热3小时。将反应冷却至室温,经过硅藻土过滤,并将固体用丙酮洗涤。在减压下去除溶剂。将剩余物溶解于乙酸乙酯(30mL)中,和用水(30mL)和盐水(2×30mL)洗涤。有机萃取物利用疏水玻璃料干燥并在减压下浓缩,以提供标题化合物(759mg,1.80mmol,95%产率).LCMS RT=1.21min,ES+ve m/z467.0[M+H]+,484.0[M+NH4]+。
(7S,8R,9S,13S,14S,17S)-3,17-双(甲氧基甲氧基)-13-甲基-7-(1-苯基-2,5,8,11,14-五氧杂十八烷-18-基)-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-6-酮
将KOtBu的THF(1M,5.34mL,5.34mmol)溶液添加至(8R,9S,13S,14S,17S)-3,17-双(甲氧基甲氧基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-6-酮(1g,2.67mmol)在无水THF(10mL)中的冷却溶液(0℃)。将反应混合物在0℃下搅拌45分钟,然后冷却至-78℃。逐滴添加18-碘-1-苯基-2,5,8,11,14-五氧杂十八烷(1.87g,4.01mmol)的THF(5mL)溶液。将溶液在-78℃下搅拌2分钟,使其升温至0℃并在该温度下搅拌1.5小时。将反应在水(50mL)和乙酸乙酯(2×50mL)之间分配。有机萃取物利用疏水玻璃料干燥并在减压下浓缩。应用0%至100%乙酸乙酯的环己烷溶液的梯度洗脱、通过在硅胶上进行层析来纯化产物,以提供标题化合物(883mg,1.24mmol,46%产率)。LCMS RT=1.47min,ES+ve m/z 713.5[M+H]+。
(7S,8R,9S,13S,14S,17S)-3,17-二羟基-13-甲基-7-(1-苯基-2,5,8,11,14-五氧杂十八烷-18-基)-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-6-酮
将HCl(6M,9.2mL,55.2mmol)的水溶液添加至(7S,8R,9S,13S,14S,17S)-3,17-双(甲氧基甲氧基)-13-甲基-7-(1-苯基-2,5,8,11,14-五氧杂十八烷-18-基)-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-6-酮(883mg,1.24mmol)在THF(9.2mL)中的溶液。将反应混合物在室温下搅拌18小时。添加水(30mL),并将产物用乙酸乙酯(50mL)萃取。有机萃取物用盐水(2×30mL)洗涤,利用疏水玻璃料干燥并在减压下浓缩,以提供标题化合物(772mg,1.23mmol,99%产率)。LCMS RT=1.06min,ES+ve m/z 625.3[M+H]+,642.3[M+NH4]+。
(7R,8R,9S,13S,14S,17S)-13-甲基-7-(1-苯基-2,5,8,11,14-五氧杂十八烷-18-基)-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-3,17-二醇
将三乙基硅烷(可购自例如Aldrich)(2.0mL、12.9mmol)添加至(7S,8R,9S,13S,14S,17S)-3,17-二羟基-13-甲基-7-(1-苯基-2,5,8,11,14-五氧杂十八烷-18-基)-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-6-酮(830mg,1.29mmol)在TFA(8.5mL、110mmol)中的溶液。将反应在室温下在氮气气氛下搅拌16小时。将混合物在乙酸乙酯(50mL)和盐水(50mL)之间分配。有机萃取物用盐水(2×50mL)、饱和碳酸氢钠(50mL)洗涤,利用疏水玻璃料干燥并在减压下浓缩。将剩余物溶解于MeOH(10mL)中,并用含水NaOH(2M,10mL,20.0mmol)处理。将反应混合物在室温下搅拌1小时。在减压下去除溶剂。将剩余物在乙酸乙酯(40mL)和1M HCl溶液(20mL)之间分配。有机萃取物用盐水(20mL)洗涤,利用疏水玻璃料干燥并在减压下浓缩。应用5%至90%乙腈(+0.1%甲酸)的水(+0.1%甲酸)溶液的梯度洗脱、通过反相层析纯化产物,以提供标题化合物(375mg,0.614mmol,47%产率)。LCMSRT=1.17min,ES+ve m/z 611.5[M+H]+,628.6[M+NH4]+。
18-((7R,8R,9S,13S,14S,17S)-3,17-双(甲氧基甲氧基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-7-基)-1-苯基-2,5,8,11,14-五氧杂十八烷
将氯(甲氧基)甲烷(可购自例如Aldrich)(0.5mL,6.58mmol)添加至(7R,8R,9S,13S,14S,17S)-13-甲基-7-(1-苯基-2,5,8,11,14-五氧杂十八烷-18-基)-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-3,17-二醇(375mg,0.614mmol)和DIPEA(1.5mL,8.59mmol)在THF(20mL)中的冷却(0℃)溶液。将反应混合物升温至室温,搅拌1小时,并在70℃下加热72小时。使反应冷却至室温。将反应在乙酸乙酯(100mL)和水(100mL)之间分配。有机萃取物用盐水(2×50mL)洗涤,利用疏水玻璃料干燥并在减压下浓缩。应用0%至100%甲基叔丁基醚的环己烷溶液的梯度洗脱、通过在硅胶上进行层析来纯化产物,以提供标题化合物(357mg,0.51mmol,72%产率)。LCMS RT=1.60min,ES+ve m/z 716.7[M+NH4]+,721.7[M+Na]+。
16-((7R,8R,9S,13S,14S,17S)-3,17-双(甲氧基甲氧基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-7-基)-3,6,9,12-四氧杂十六烷-1-醇
将18-((7R,8R,9S,13S,14S,17S)-3,17-双(甲氧基甲氧基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-7-基)-1-苯基-2,5,8,11,14-五氧杂十八烷(357mg,0.444mmol)和10%w/w钯碳(157mg,0.148mmol)在乙醇(5mL)中的混合物在室温下在氢气气氛下搅拌1.5小时。经过硅藻土过滤钯碳并在减压下蒸发滤液,以提供标题化合物(300mg,0.41mmol,93%产率)LCMS RT=1.37min,ES+ve m/z 609.6[M+H]+,631.6[M+Na]+。
叔丁基19-((7R,8R,9S,13S,14S,17S)-3,17-双(甲氧基甲氧基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-7-基)-3,6,9,12,15-五氧杂十九烷-1-酸酯
将氢化钠——60%w/w,在矿物油中(30mg,0.75mmol)——添加至16-((7R,8R,9S,13S,14S,17S)-3,17-双(甲氧基甲氧基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-7-基)-3,6,9,12-四氧杂十六烷-1-醇(300mg,0.43mmol)在DMF(5mL)中的冷却溶液(0℃)。将反应在该温度下搅拌10分钟,并添加叔丁基2-溴乙酸酯(0.095mL,0.643mmol)。将反应在0℃下搅拌1小时,然后在室温下再搅拌18小时。将反应混合物在乙酸乙酯(30mL)和水(30mL)之间分配。将水层用另外的乙酸乙酯(2×30mL)萃取,并且将组合的有机层用盐水(2×30mL)洗涤,干燥(疏水玻璃料),并在减压下浓缩。应用0%至100%甲基叔丁基醚的环己烷溶液的梯度洗脱、通过在硅胶上进行层析来纯化产物,以提供标题化合物(177mg,0.245mmol,57%产率)。LCMS RT=1.58min,ES+ve m/z 740.6[M+NH4]+,745.6[M+Na]+。
19-((7R,8R,9S,13S,14S,17S)-3,17-二羟基-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-7-基)-3,6,9,12,15-五氧杂十九烷-1-酸
将叔丁基19-((7R,8R,9S,13S,14S,17S)-3,17-双(甲氧基甲氧基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-7-基)-3,6,9,12,15-五氧杂十九烷-1-酸酯(177mg,0.189mmol)溶解于THF(2mL)中,并用含水HCl(6M,2mL,12.0mmol)处理。将反应混合物在室温下搅拌7小时。将反应混合物通过质量导向自动制备型HPLC(甲酸改性剂)直接进行纯化,以提供标题化合物(64mg,0.111mmol,59%产率)。LCMS RT=0.92min,ES+ve m/z 579.4[M+H]+,596.5[M+NH4]+。
(2S,4R)-1-((S)-22-((7R,8R,9S,13S,14S,17S)-3,17-二羟基-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-7-基)-2-异丙基-4-氧代-6,9,12,15,18-五氧杂-3-氮杂二十二烷-1-酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺
将HATU(16mg,0.04mmol)添加至(2S,4R)-1-((S)-2-氨基-3-甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺,盐酸盐(25mg,0.06mmol)、19-((7R,8R,9S,13S,14S,17S)-3,17-二羟基-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-7-基)-3,6,9,12,15-五氧杂十九烷-1-酸(16mg,0.03mmol)和DIPEA(0.048mL,0.28mmol)在DMF(0.8mL)中的混合物。将反应在室温下搅拌30分钟。将反应混合物通过质量导向自动制备型HPLC(甲酸改性剂)直接进行纯化,以提供标题化合物(17.7mg,0.018mmol,65%产率)。LCMS RT=0.99min,ES+ve m/z 977.4[M+H]+。
(2S,4R)-1-((S)-2-(叔丁基)-22-((7R,8R,9S,13S,14S,17S)-3,17-二羟基-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-7-基)-4-氧代-6,9,12,15,18-五氧杂-3-氮杂二十二烷-1-酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺
将HATU(16mg,0.04mmol)添加至(2S,4R)-1-((S)-2-氨基-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺,盐酸盐(25mg,0.05mmol)、19-((7R,8R,9S,13S,14S,17S)-3,17-二羟基-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-7-基)-3,6,9,12,15-五氧杂十九烷-1-酸(16mg,0.03mmol)和DIPEA(0.048mL,0.28mmol)在DMF(0.8mL)中的混合物。将反应在室温下搅拌30分钟。将反应混合物直接通过质量导向自动制备型HPLC(甲酸改性剂)进行纯化,以提供标题化合物(17.5mg,0.017mmol,63%产率)。LCMS RT=1.03min,ES+ve m/z 991.4[M+H]+。
(7S,8R,9S,13S,14S,17S)-7-(5-(苄氧基)戊基)-3,17-二羟基-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-6-酮
将KOtBu的THF(1M,4.81mL,4.81mmol)溶液添加至(8R,9S,13S,14S,17S)-3,17-双(甲氧基甲氧基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-6-酮(900mg,2.403mmol)在无水THF(10mL)中的冷却溶液(0℃)。将反应混合物在0℃下搅拌45分钟,然后冷却至-78 0℃。逐滴添加(((5-碘戊基)氧)甲基)苯(可按照J.Chem.Soc.,Perkin Trans.1 1990,129-132描述的程序制备)(2.193g,7.21mmol)的THF(0.5mL)溶液。将溶液在-78℃下搅拌2分钟,将其升温至室温并在该温度下搅拌1小时。将反应在水(70mL)和乙酸乙酯(70mL)之间分配。有机萃取物利用疏水玻璃料干燥并在减压下浓缩。应用0%至50%乙酸乙酯的环己烷溶液的梯度洗脱、通过在硅胶上进行层析来纯化中间体。将剩余物溶解于THF(16mL)中并添加含水HCl(6M,16mL,96mmol)。将反应在室温下搅拌16小时。将反应混合物在乙酸乙酯(20mL)和水(20mL)之间分配。将有机萃取物干燥(疏水玻璃料)并在减压下浓缩。应用5%至85%乙腈(+0.1%甲酸)的水(+0.1%甲酸)溶液的梯度洗脱、通过反相层析纯化产物,以提供标题化合物(487mg,1.053mmol,44%产率)。LCMS RT=1.16min,ES+ve m/z 463.4[M+H]+。
(7R,8R,9S,13S,14S,17S)-7-(5-(苄氧基)戊基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-3,17-二醇
将三乙基硅烷(1.681mL,10.53mmol)添加至(7S,8R,9S,13S,14S,17S)-7-(5-(苄氧基)戊基)-3,17-二羟基-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-6-酮(487mg,1.053mmol)在TFA(6mL,78mmol)中的溶液。将反应在室温下在氮气气氛下搅拌16小时。将混合物在乙酸乙酯(30mL)和盐水(30mL)之间分配。有机萃取物用盐水(2×30mL)洗涤,利用疏水玻璃料干燥并在减压下浓缩。将剩余物溶解于MeOH(4mL)中,并用含水NaOH(2M,4mL,8.00mmol)处理。将反应混合物在室温下搅拌3小时。在减压下去除溶剂。将剩余物在乙酸乙酯(30mL)和水(30mL)之间分配。将有机萃取物用盐水(30mL)洗涤,干燥(疏水玻璃料),并在减压下浓缩。应用10%至95%乙腈(+0.1%甲酸)的水(+0.1%甲酸)的梯度洗脱、通过反相层析纯化产物,以提供标题化合物(410mg,0.914mmol,87%产率)。LCMS RT=1.30min,ES+ve m/z 449.1[M+H]+。
(7R,8R,9S,13S,14S,17S)-7-(5-(苄氧基)戊基)-3,17-双(甲氧基甲氧基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲
将氯(甲氧基)甲烷(0.7mL,9.22mmol)添加至(7R,8R,9S,13S,14S,17S)-7-(5-(苄氧基)戊基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-3,17-二醇(410mg,0.914mmol)和DIPEA(2mL、11.45mmol)在THF(8mL)中的溶液。将反应容器密封,置于氮气气氛下,并在70℃下加热2天。使反应冷却至室温。将反应在乙酸乙酯(50mL)和盐水(50mL)之间分配。有机萃取物用盐水(2×50mL)洗涤,利用疏水玻璃料干燥并在减压下浓缩。应用0%至100%甲基叔丁基醚的环己烷溶液的梯度洗脱、通过在硅胶上进行层析来纯化产物,以提供标题化合物(474mg,0.883mmol,97%产率)。LCMS RT=1.72min,ES+ve m/z554.5[M+NH4]+。
5-((7R,8R,9S,13S,14S,17S)-3,17-双(甲氧基甲氧基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-7-基)戊-1-醇
将(7R,8R,9S,13S,14S,17S)-7-(5-(苄氧基)戊基)-3,17-双(甲氧基甲氧基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲(474mg,0.883mmol)和10%w/w钯碳(100mg,0.094mmol)在乙醇(5mL)和甲基叔丁基醚(2mL)中的混合物在室温下在氢气气氛下搅拌1.5小时。经过硅藻土过滤钯,并在减压下浓缩滤液,以提供标题化合物(371mg,0.831mmol,94%产率)。LCMS RT=1.39min,ES+ve m/z447.5[M+H]+(弱电离)。
5-((7R,8R,9S,13S,14S,17S)-3,17-双(甲氧基甲氧基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-7-基)戊基4-甲基苯磺酸酯
将4-甲基苯-1-磺酰氯(400mg,2.098mmol)添加至5-((7R,8R,9S,13S,14S,17S)-3,17-双(甲氧基甲氧基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-7-基)戊-1-醇(371mg,0.831mmol)的吡啶(5mL)溶液。将反应混合物在室温下搅拌20小时。将反应混合物在乙酸乙酯(30mL)和含水HCl(2M,30mL)之间分配。将有机萃取物用饱和Na2CO3(30mL)、盐水(30mL)洗涤,干燥(疏水玻璃料),并在减压下浓缩。应用0%至100%甲基叔丁基醚的环己烷溶液的梯度洗脱、通过在硅胶上进行层析来纯化产物,以提供标题化合物(401mg,0.667mmol,80%产率)。LCMS RT=1.60min,ES+ve m/z623.4[M+Na]+。
叔丁基18-((7R,8R,9S,13S,14S,17S)-3,17-双(甲氧基甲氧基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-7-基)-13-甲基-4,7,10-三氧杂-13-氮杂十八烷-1-酸酯,甲酸盐
在微波小瓶中装载5-((7R,8R,9S,13S,14S,17S)-3,17-双(甲氧基甲氧基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-7-基)戊基4-甲基苯磺酸酯(100mg,0.166mmol)、叔丁基5,8,11-三氧杂-2-氮杂十四烷-14-酸酯(可按照WO2012054110A2描述的程序制备)(145mg,0.499mmol)和DIPEA(0.291mL,1.664mmol)的THF(2mL)溶液。将小瓶密封,并利用真空吹扫将其置于氮气气氛下。将反应在75℃下加热48小时。使反应冷却至室温。将反应混合物直接通过质量导向自动制备型HPLC(甲酸改性剂)进行纯化,以提供标题化合物(102mg,0.133mmol,80%产率)。LCMS RT=1.22min,ES+ve m/z720.6[M+H]+。
18-((7R,8R,9S,13S,14S,17S)-3,17-二羟基-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-7-基)-13-甲基-4,7,10-三氧杂-13-氮杂十八烷-1-酸,甲酸盐
将叔丁基18-((7R,8R,9S,13S,14S,17S)-3,17-双(甲氧基甲氧基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-7-基)-13-甲基-4,7,10-三氧杂-13-氮杂十八烷-1-酸酯,甲酸盐(100mg,0.131mmol)溶解于THF(1mL)中,并用含水HCl(6M、1mL,6.00mmol)处理。将反应在室温下搅拌6小时。将反应混合物通过质量导向自动制备型HPLC(甲酸改性剂)直接进行纯化,以提供标题化合物(24mg,0.039mmol,30%产率)。LCMSRT=0.74min,ES+ve m/z 576.5[M+H]+。
(2S,4R)-1-((S)-2-(叔丁基)-21-((7R,8R,9S,13S,14S,17S)-3,17-二羟基-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-7-基)-16-甲基-4-氧代-7,10,13-三氧杂-3,16-二氮杂二十一烷-1-酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺
将HATU(13mg,0.034mmol)添加至(2S,4R)-1-((S)-2-氨基-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺,盐酸盐(13mg,0.028mmol)、18-((7R,8R,9S,13S,14S,17S)-3,17-二羟基-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-7-基)-13-甲基-4,7,10-三氧杂-13-氮杂十八烷-1-酸,甲酸盐(12mg,0.019mmol)和DIPEA(0.03mL,0.172mmol)在DMF(0.8mL)中的混合物。将反应在室温下搅拌10分钟。将反应混合物直接通过质量导向自动制备型HPLC(甲酸改性剂,然后碳酸铵改性剂)进行两次纯化,以提供标题化合物(13mg,0.013mmol,68%产率)。LCMS RT=0.84min,ES+ve m/z 988.8[M+H]+。
Claims (10)
1.根据下列化学结构的化合物:
其中L是连接体基团,并且
是泛素连接酶结合部分,其中所述连接体基团任选地进一步连接于/>基团。
2.根据下列化学结构的化合物:
其中是泛素连接酶结合部分;
是化学部分(蛋白质靶部分),其结合将要通过泛素连接酶降解的靶蛋白质或多肽,并且直接或通过连接体部分L化学连接于/>基团,或/>可选地是/>基团,其也是泛素连接酶结合部分,其可与/>基团相同或不同并且直接或通过连接体部分连接于/>基团;和
L是连接体部分,其可存在或不存在,并且在存在时,化学地(共价地)连接与或
其药学上可接受的盐、对映体、立体异构体、溶剂化物或多晶型物。
3.根据权利要求2所述的化合物,其中是/>基团。
4.根据权利要求1-3中任一项所述的化合物,其中是根据下列化学结构的基团:
其中R1’是任选取代的C1-C6烷基、任选取代的-(CH2)nOH、任选取代的-(CH2)nSH、任选取代的(CH2)n-O-(C1-C6)烷基、包含环氧化物部分的任选取代的(CH2)n-WCHOCHW-(C0-C6)烷基,其中W独立地不存在或是H、任选取代的-(CH2)nCOOH、任选取代的-(CH2)nC(O)-(C1-C6烷基)、任选取代的-(CH2)nNR1R2、任选取代的-(CH2)nNHC(O)-R1、任选取代的-(CH2)nC(O)-NR1R2、任选取代的-(CH2)nOC(O)-NR1R2、-(CH2O)nH、任选取代的-(CH2)nOC(O)-(C1-C6烷基)、任选取代的-(CH2)nC(O)-O-(C1-C6烷基)、任选取代的-(CH2O)nCOOH、任选取代的-(OCH2)nO-(C1-C6烷基)、任选取代的-(CH2O)nC(O)-(C1-C6烷基)、任选取代的-(OCH2)nNHC(O)-R1、任选取代的-(CH2O)nC(O)-NR1R2、-(CH2CH2O)nH、任选取代的-(CH2CH2O)nCOOH、任选取代的-(OCH2CH2)nO-(C1-C6烷基)、任选取代的-(CH2CH2O)nC(O)-(C1-C6烷基)、任选取代的-(OCH2CH2)nNHC(O)-R1、任选取代的-(CH2CH2O)nC(O)-NR1R2、任选取代的-SO2RS、任选取代的S(O)RS、NO2、CN或卤素(F、Cl、Br,I,优选F或Cl);
R1和R2各自独立地是H或C1-C6烷基,其可任选地用一个或两个羟基或上至三个卤素基团(优选氟)取代;
RS是C1-C6烷基、任选取代的芳基、杂芳基或杂环基团或-(CH2)mNR1R2基团,
X和X’各自独立地是C═O、C═S、-S(O)、S(O)2,(优选X和X’均为C═O);
R2’是任选取代的-(CH2)n-(C=O)u(NR1)v(SO2)w(C1-C6)烷基、任选取代的R1NR2N-(CH2)n-(C=O)u(NR1)v(SO2)wNR1NR2N基团、任选取代的-(CH2)n-(C=O)u(NR1)v(SO2)w-芳基、
任选取代的-(CH2)n-(C=O)u(NR1)v(SO2)w-杂芳基、
任选取代的-(CH2)n-(C=O)vNR1(SO2)w-杂环、
任选取代的-NR1-(CH2)n-C(O)u(NR1)v(SO2)w-C1-C6烷基、
任选取代的-NR1-(CH2)n-C(O)u(NR1)v(SO2)w-NR1NR2N、
任选取代的-NR1-(CH2)n-C(O)u(NR1)v(SO2)w-NR1C(O)R1N、
任选取代的-NR1-(CH2)n-(C=O)u(NR1)v(SO2)w-芳基、
任选取代的-NR1-(CH2)n-(C=O)u(NR1)v(SO2)w-杂芳基或
任选取代的-NR1-(CH2)n-(C=O)vNR1(SO2)w-杂环、
任选取代的-XR2’-C1-C6烷基;
任选取代的-XR2’-芳基;
任选取代的-XR2’-杂芳基;
任选取代的-XR2’-杂环基团;
R3’是任选取代的C1-C6烷基、
任选取代的-(CH2)n-C(O)u(NR1)v(SO2)w-C1-C6烷基、
任选取代的-(CH2)n-C(O)u(NR1)v(SO2)w-NR1NR2N、
任选取代的-(CH2)n-C(O)u(NR1)v(SO2)w-NR1C(O)R1N、
任选取代的-(CH2)n-C(O)u(NR1)v(SO2)w-C(O)NR1R2、
任选取代的-(CH2)n-C(O)u(NR1)v(SO2)w-芳基、
任选取代的-(CH2)n-C(O)u(NR1)v(SO2)w-杂芳基、
任选取代的-(CH2)n-C(O)u(NR1)v(SO2)w-杂环、
任选取代的-NR1-(CH2)n-C(O)u(NR1)v(SO2)w-C1-C6烷基、
任选取代的-NR1-(CH2)n-C(O)u(NR1)v(SO2)w-NR1NR2N、
任选取代的-NR1-(CH2)n-C(O)u(NR1)v(SO2)w-NR1C(O)R1N、
任选取代的-NR1-(CH2)n-C(O)u(NR1)v(SO2)w-芳基、
任选取代的-NR1-(CH2)n-C(O)u(NR1)v(SO2)w-杂芳基、
任选取代的-NR1-(CH2)n-C(O)u(NR1)v(SO2)w-杂环、
任选取代的-O-(CH2)n-(C=O)u(NR1)v(SO2)w-C1-C6烷基、
任选取代的-O-(CH2)n-(C=O)u(NR1)v(SO2)w-NR1NR2N、
任选取代的-O-(CH2)n-(C=O)u(NR1)v(SO2)w-NR1C(O)R1N、
任选取代的-O-(CH2)n-(C=O)u(NR1)v(SO2)w-芳基、
任选取代的-O-(CH2)n-(C=O)u(NR1)v(SO2)w-杂芳基或
任选取代的-O-(CH2)n-(C=O)u(NR1)v(SO2)w-杂环;
任选取代的-(CH2)n-(V)n’-(CH2)n-(V)n’-C1-C6烷基、
任选取代的-(CH2)n-(V)n’-(CH2)n-(V)n’-芳基、
任选取代的-(CH2)n-(V)n’-(CH2)n-(V)n’-杂芳基、
任选取代的-(CH2)n-(V)n’-(CH2)n-(V)n’-杂环’基团、
任选取代的-(CH2)n-N(R1’)(C=O)m’-(V)n’-C1-C6烷基、
任选取代的-(CH2)n-N(R1’)(C=O)m’-(V)n’-芳基、
任选取代的-(CH2)n-N(R1’)(C=O)m’-(V)n’-杂芳基、
任选取代的-(CH2)n-N(R1’)(C=O)m’-(V)n’-杂环基团、
任选取代的-XR3’-C1-C6烷基;
任选取代的-XR3’-芳基;
任选取代的-XR3’-杂芳基;
任选取代的-XR3’-杂环基团;
其中R1N和R2N各自独立地是H、任选地用一个或两个羟基和上至三个卤素基团取代的C1-C6烷基、或任选取代的-(CH2)n-芳基、-(CH2)n-杂芳基或-(CH2)n-杂环基团;
V是O、S或NR1;
R1同上;
R1和R1’各自独立地是H或C1-C3烷基;
XR2’和XR3’各自独立地是任选取代的-CH2)n-、-CH2)n-CH(Xv)=CH(Xv)-(顺式或反式)、-CH2)n-CH≡CH-、-(CH2CH2O)n-或C3-C6环烷基,其中Xv是H、卤素或任选取代的C1-C3烷基;
各m独立地是0、1、2、3、4、5、6;
各m’独立地是0或1;
各n独立地是0、1、2、3、4、5、6;
各n’独立地是0或1;
各u独立地是0或1;
各v独立地是0或1;
各w独立地是0或1;和
其中的R1’、R2’、R3’、X和X’中的任意一个或多个被修饰以直接或通过所述连接体基团共价地结合所述/>基团,或
其药学上可接受的盐、立体异构体、溶剂化物或多晶型物。
5.根据权利要求1-4中任一项所述的化合物,其中和/>在作为/>基团存在时,各自独立地是根据下列化学结构的基团:
其中R1’、R2’和R3’各自与上述权利要求4相同,并且X是C=O、C=S、-S(O)基团或S(O)2基团,并且
其中R1’、R2’和R3’中任意一个或多个被修饰以结合连接体基团,所述连接体基团进一步共价结合于基团,或
其药学上可接受的盐、立体异构体、溶剂化物或多晶型物。
6.根据权利要求5所述的化合物,其中X是C=O。
7.根据权利要求4-6中任一项所述的化合物,其中R1’是羟基或可被代谢成羟基或羧酸基团的基团,使得所述化合物表示活性化合物的前药形式。
8.根据权利要求4-7中任一项所述的化合物,其中R1’是-(CH2)nOH、-(CH2)nSH、(CH2)n-O-(C1-C6)烷基、-(CH2)nCOOH、-(CH2O)nH、任选取代的-(CH2)nOC(O)-(C1-C6烷基)或任选取代的-(CH2)nC(O)-O-(C1-C6烷基),其中n为0或1。
9.根据权利要求4-8中任一项所述的化合物,其中R1’是羧酸基团、羟基或胺基团或包含羧酸基团、羟基或胺基团,所述羟基、羧酸基团或胺基团各自能够进一步被化学修饰以提供与连接体基团的共价连接,所述连接体基团结合基团。
10.根据权利要求4-9中任一项所述的化合物,其中R2’是任选取代的-NR1-T-芳基、任选取代的-NR1-T-杂芳基或任选取代的-NR1-T-杂环,其中R1是H或CH3,优选H;和T是任选取代的-(CH2)n-基团,其中每一个亚甲基可任选地用一个或两个取代基取代,所述取代基可被任选取代;和n为0、1、2或3。
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JP (5) | JP2015508414A (zh) |
KR (3) | KR102204989B1 (zh) |
CN (2) | CN104736569A (zh) |
AU (5) | AU2013207900B2 (zh) |
BR (1) | BR112014017095A2 (zh) |
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