CN109843866A - 靶向yap1与oct4的相互作用的yap1抑制剂 - Google Patents
靶向yap1与oct4的相互作用的yap1抑制剂 Download PDFInfo
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- CN109843866A CN109843866A CN201780063922.9A CN201780063922A CN109843866A CN 109843866 A CN109843866 A CN 109843866A CN 201780063922 A CN201780063922 A CN 201780063922A CN 109843866 A CN109843866 A CN 109843866A
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Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/14—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being saturated and containing rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C251/02—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups
- C07C251/24—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to carbon atoms of six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/57—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and carboxyl groups, other than cyano groups, bound to the carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/24—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a ring other than a six-membered aromatic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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Abstract
转录共激活因子YAP1与转录因子Oct4的结合诱导Sox2,Sox2是来自非小细胞肺癌的干细胞样细胞自我更新所必需的转录因子。YAP1的WW结构域与Oct4的PPxY基序结合以诱导Sox2。递送与WW结构域相应的肽可阻止Sox2和干性的诱导。类似地,PPxY基序的肽和模拟物将能够抑制干性。公开了影响Yap1:Oct4相互作用的化合物。
Description
相关申请的交叉引用
本申请要求2016年9月18日提交的美国临时申请62/396,190和2016年9月19日提交的美国临时申请62/396,383的优先权权益,这两件临时申请的全部内容以引用的方式并入本文。
背景技术
肺癌在美国是癌症相关死亡率的主要原因(Siegel R等人,癌症统计,2013。CACancer J Clin.2013;63(1):11-30),这其中大多数(85%)是由非小细胞肺癌(NSCLC)造成的。通过手术治疗早期疾病患者,但有约30-60%会发生导致死亡的复发性肿瘤(DemicheliR等人,复发动态不依赖于复发部位。Breast Cancer Res.2008;10(5):R83;Demicheli R等人,非小细胞肺癌的复发动态:手术对转移发展的影响。J Thorac Oncol.2012;7(4):723-30;Senthi S等人,早期非小细胞肺癌的立体定向消融放射治疗后疾病复发的模式:回顾性分析。Lancet Oncol.2012;13(8):802-9)。虽然化学治疗剂如吉西他滨、铂化合物和紫杉烷在有限的程度上提高了存活率,但由于复发更具侵袭性、抗药性的肿瘤原因,总体存活率仍然很低(Seve P等人,非小细胞肺癌中的化学抗性。Curr Med Chem AnticancerAgents.2005;5(1):73-88;Lara PN,Jr.等人,一线化学治疗后的非小细胞肺癌进展。CurrTreat Options Oncol.2002;3(1):53-8)。即使是对EGFR抑制剂如埃罗替尼反应良好的携带EGFR突变的患者也最终会产生抗药性并死于疾病(Brugger W等人,EGFR-TKI抗性非小细胞肺癌(NSCLC):新发展及对未来治疗的启示。Lung Cancer.2012;77(1):2-8)。已经假设肿瘤启动细胞或癌症干细胞样细胞可能促成肿瘤的启动、进展、转移和复发(Patel P等人,癌症干细胞、肿瘤休眠和转移。Front Endocrinol(Lausanne).2012;3:125;Allan AL等人,肿瘤休眠和癌症干细胞:对乳腺癌转移的生物学和治疗的启示。Breast Dis.2006;26:87-98;Giancotti FG.控制转移性休眠和再激活的机制。Cell.2013;155(4):750-64;Lee N等人,黑素瘤干细胞和转移:模拟造血细胞转运?Lab Invest.2014;94(1):13-30),并且这一观点在肺癌领域中获得了重大关注(Peacock CD等人,癌症干细胞与肺癌的个体发生。J ClinOncol.2008;26(17):2883-9;Singh S等人,肺癌干细胞:分子特征和治疗靶点。MolAspects Med.2013.Epub 2013/09/11.doi:10.1016/j.mam.2013.08.003;Koren A等人,肺癌干细胞:生物学和临床前景。Cell Oncol(Dordr).2013;36(4):265-75;Lundin A等人,肺癌干细胞:进展和前景。Cancer Lett.2013;338(1):89-93;Morrison BJ等人,肺癌启动细胞:癌症治疗的新颖靶点。Target Oncol.2013;8(3):159-72;Leeman KT等人,组织稳态和疾病中的肺干细胞和祖细胞。Curr Top Dev Biol.2014;107:207-33;Sutherland KD等人,突变体K-Ras-诱导的小鼠肺腺癌的多种起源细胞。Proc Natl Acad Sci U S A.2014.Epub2014/03/04;Wang J等人,肺癌干细胞及对未来治疗的启示。Cell BiochemBiophys.2014.Epub 2014/02/20.doi:10.1007/s12013-014-9844-4;Lau AN等人,肿瘤繁殖细胞和Yap/Taz活性促成肺部肿瘤进展和转移。Embo J.2014;33(5):468-81)。在这种背景下,我们的研究已表明,河马(Hippo)信号传导通路的致癌成分YAP1促成干细胞样细胞的自我更新和血管拟态。
经典的河马信号传导级联导致激酶Lats1/2和Mst1/2的激活,所述激酶使YAP1或其直系同源TAZ磷酸化,导致它们的细胞质隔离和/或降解(Yu FX等人,河马通路:调节剂和调节。Genes Dev.2013;27(4):355-71;Zhao B等人,器官大小控制、组织再生和干细胞自我更新中的河马通路。Nat Cell Biol.2011;13(8):877-83)。河马通路的失活导致YAP1的激活及核转位,其中YAP1主要与TEAD家族转录因子结合以促进细胞增殖(Mizuno T等人,YAP通过上调细胞周期促进基因的转录诱导恶性间皮瘤细胞增殖。Oncogene.2012;31(49):5117-22;Mao B等人,SIRT1调节肝细胞癌中YAP2介导的细胞增殖和化学抗性。Oncogene.2013.Epub 2013/04/02.doi:10.1038/onc.2013.88)。在多种肿瘤类型中YAP1水平升高,并且已发现YAP1促成包括胰腺和肺部癌症在内的多种癌症的发生和进展。YAP1可与另外的转录因子物理相互作用以促进细胞增殖、血管生成和癌症转移。在这种背景下,我们的研究已表明,YAP1与Oct4转录因子物理相互作用以诱导另一种胚胎干细胞转录因子Sox2。这种相互作用通过YAP1的WW结构域和Oct4的PPxY基序发生。我们已发现,Oct4-YAP1相互作用的破坏可阻止来自肺癌细胞系的干细胞样侧群细胞的自我更新,并且可阻止血管拟态。因此所需要的是破坏Oct4-YAP1相互作用的组合物及方法,这将具有抗癌作用,因为这类试剂会阻止自我更新、细胞增殖和潜在的血管生成。本文公开的组合物及方法即针对这些及其它需求。
发明内容
根据如本文具体实施和广泛描述的公开物质及方法的目的,一方面所公开的主题涉及化合物、组合物以及制备和使用化合物和组合物的方法。在具体方面,所公开的主题涉及癌症治疗和抗癌化合物。更具体地,本文公开的主题涉及YAP1的抑制剂。
另外的优点部分地将在随后的描述中予以阐述,并且部分地可从所述描述中显而易见,或者可通过下述方面的实践而了解。将借助于所附权利要求中特别指出的要素及组合来实现和获得下述优点。要理解的是,前面的一般性描述和以下的详细描述都只是示例性和解释性而非限制性的。
附图说明
结合在本说明书中并构成其一部分的附图示出下述的若干方面。
图1是拟肽类似物的总结示意图。
图2是示出SR1-083的C-末端变体的合成的示意图。
图3是有效C-末端改性的SR1-083类似物的总结示意图。
图4是示出基于SR1-119的C-末端变体的示意图。
图5是SR1-119的有效C-末端变体的总结示意图。
图6是示出进一步N-末端改性的SR1-119类似物(基于SR1-083的系列)的示意图。
图7是有效N-末端改性的SR1-119类似物(SR1-083系列)的总结示意图。
图8是有效类似物的总结示意图。
图9是有效类似物的总结示意图。
图10是用于SAR验证的SR1-083的N-末端变体的进一步合成的示意图。
图11是示出高优先级和中等优先级NCI化合物对YAP1和Oct4共定位的破坏的一组细胞显微照片。双免疫荧光实验示出了Oct4和YAP1的共定位。用指示的化合物处理细胞48小时,并按照Bora-Singhal等人在Stem Cells,2015,33(6):1705-18中描述的方案进行双免疫荧光实验。Oct4和YAP1的共定位在合并图像中示为黄或橙颜色。这被初始NCI命中所抑制,如通过共定位实验中黄/橙颜色的减少所示。插图示出了放大的细胞核。
图12是示出高优先级和中等优先级NCI化合物对YAP1和Oct4共定位的破坏的一组细胞显微照片。双免疫荧光实验示出了Oct4和YAP1的共定位。用指示的化合物处理细胞48小时,并按照Bora-Singhal等人在Stem Cells,2015,33(6):1705-18中描述的方案进行双免疫荧光实验。Oct4和YAP1的共定位在合并图像中示为黄或橙颜色。这被初始NCI命中所抑制,如通过共定位实验中黄/橙颜色的减少所示。插图示出了放大的细胞核。
图13是示出如通过PLA所示NCI化合物和拟肽对YAP1和Oct4相互作用的破坏的一组细胞显微照片。采用Bora-Singhal等人,2015中描述的方案,进行邻近连接测定以进一步检测Oct4与YAP1的相互作用。每个红点为相互作用的焦点。邻近连接测定示出NCI命中破坏了H1650细胞中的Oct4-YAP1相互作用,如通过红点的缺失或减少所确定。用化合物处理细胞48小时。
图14是示出如通过PLA所示NCI化合物和拟肽对YAP1和Oct4相互作用的破坏的一组细胞显微照片。邻近连接测定用于测试化合物是否能抑制无关转录因子TEAD2与YAP1的结合。TEAD2通过TEAD结合结构域而不是YAP1的WW结构域与YAP1结合。使用针对YAP1和TEAD2的抗体的邻近连接测定显示,相同的NCI化合物不破坏YAP1与TEAD2的结合。用指示剂量的化合物处理细胞48小时。这基本上是显示药物破坏OCt4-YAP1相互作用的特异性的对照实验。
图15是示出如通过IP-WB所检测拟肽化合物SR2-022、SR2-030和SR2-033减少YAP1-Oct4相互作用的一组凝胶图像。进行免疫沉淀-蛋白质印迹实验以评估指示的化合物是否能破坏Oct4与YAP1的结合。采用Bora-Singhal等人,2015中描述的方案进行IP-蛋白质印迹。基本上,用5μM的指示化合物处理细胞72小时。由细胞制备裂解物,并用针对OCt4的抗体或对照IgG进行免疫沉淀。通过聚丙烯酰胺凝胶使裂解物以及免疫沉淀物重新溶解,并使用针对YAP1的抗体进行蛋白质印迹。可以看出,在来自未反应的细胞的IP中有大量与Oct4缔合的YAP1(对照泳道,Oct4IP中);相互作用在A549细胞中被药物完全消除,并且在H1650细胞中显著减少。这表明所述化合物可破坏Oct4与YAP1的相互作用。
图16是示出在腺癌细胞中SR-2033减少Sox2蛋白质表达的一组凝胶图像。
图17是示出在H165和A549细胞中化合物SR2-046、SR2-051和SR2-052减少Sox2、c-Myc表达的一组凝胶图像。用指示的化合物处理细胞72小时。蛋白质印迹显示,在用10uM药物处理72小时后,H1650细胞中和A549细胞中的Sox2表达减少。C-myc和磷酸二酯酶激酶2的水平也有减少。采用我们如Bora-Singhal等人,2015发表的标准方案进行蛋白质印迹。
图18是示出在球体形成测定中选定化合物抑制自我更新的一组细胞显微照片。通过球体形成测定来测量干细胞样侧群(SP)细胞的自我更新。基本上,如我们发表中描述的那样,通过基于Hoechst 33342染料排除的流式细胞术对侧群细胞进行分选。使分离的SP细胞在低粘附板上的干细胞选择性培养基中生长10天(Singh和Chellappan,2012,Bora-Singhal等人,2015等)。可通过在这些条件下球体的形成来评估干细胞样细胞的自我更新能力;非干细胞不能自我更新和形成球体。包含指示的破坏剂显著减少了球体的数量,而标准的化学治疗药物顺铂没有效果。
图19是示出如通过球体形成测定所示3个命中抑制H1650SP细胞自我更新的图示。测定进行10天,并对直径大于50μm的球体的数量进行计数。指示的药物能显著抑制自我更新。
图20是示出如通过球体形成测定所示PPxY模拟化合物抑制自我更新的图示。测定进行10天,并对直径大于50μm的球体的数量进行计数。指示的药物能显著抑制自我更新。
图21是示出如通过球体形成测定所示化合物抑制自我更新的图示。测定进行10天,并对直径大于50μm的球体的数量进行计数。指示的药物能显著抑制自我更新。
图22是示出如通过采用标准方案的MTT测定所评估的指示的化合物降低A549和H1650细胞活力的能力的一组图示。用指示剂量的药物处理细胞72小时并进行MTT测定。药物显著降低A549和H1650细胞活力。
图23是示出实验结果的一组图示,所述实验检查应用药物将细胞处理多长时间以降低活力。用药物处理细胞24小时(亮条);除去药物,并使细胞在常规生长培养基中再生长48小时。平行地,将细胞用药物连续处理72小时(暗条)。可以看出,用药物处理24小时可降低细胞活力,与连续处理72小时相当。
图24示出如通过MTT测定所测量,YAP1抑制剂降低鳞状细胞癌细胞系(来自肺)的活力。用指示剂量的药物处理细胞96小时。
图25示出如通过MTT测定所测量,YAP1抑制剂降低鳞状细胞癌细胞系(来自肺)的活力。用指示剂量的药物处理两种不同的细胞系96小时。
图26示出在选定化合物的存在下测定H1650细胞的粘附无关生长的照片。癌细胞的一个特征是它们能以粘附无关的方式生长。它们不需要来自粘附于基质的存活信号。可通过使细胞在软琼脂中生长来测量以粘附无关的方式生长的能力。持续33天测试YAP1抑制剂遏制H1650肺腺癌细胞在软琼脂中粘附无关生长的能力,每三天添加新的药物等分试样。采用标准方案。
图27示出在选定化合物的存在下测定H1703细胞的粘附无关生长的照片。癌细胞的一个特征是它们能以粘附无关的方式生长。它们不需要来自粘附于基质的存活信号。可通过使细胞在软琼脂中生长来测量以粘附无关的方式生长的能力。持续33天测试YAP1抑制剂遏制H1703肺鳞状细胞癌在软琼脂中粘附无关生长的能力,每三天添加新的药物等分试样。采用标准方案。
图28是研究化合物对共培养物的影响的示意图。肿瘤基质中存在的癌症相关性成纤维细胞(CAF)促进肿瘤的生长并赋予对各种药物的抗性。这项实验用于测试YAP1抑制剂是否即使在CAF存在时也能消除癌细胞。用市售的细胞追踪红染料标记H1650细胞,并用细胞追踪绿染料标记CAF。可将细胞在一起培养,并通过免疫荧光显微镜可视化。此共培养系统用于评估YAP1抑制剂是否即使在CAF存在下也能选择性地杀灭癌细胞。
图29示出来自与原发性肺癌相关性成纤维细胞共培养的H1650细胞的结果。肿瘤基质中存在的癌症相关性成纤维细胞(CAF)促进肿瘤的生长并赋予对各种药物的抗性。这项实验用于测试YAP1抑制剂是否即使在CAF存在时也能消除癌细胞。用市售的细胞追踪红染料标记H1650细胞,并用细胞追踪绿染料标记CAF。可将细胞在一起培养,并通过免疫荧光显微镜可视化。此共培养系统用于评估YAP1抑制剂是否即使在CAF存在下也能选择性地杀灭癌细胞。
当与癌症相关性成纤维细胞(CAF,染绿色)共培养时,拟肽化合物和NCI命中消除H1650癌细胞(染红色)。治疗后24小时或48小时将药物的效果可视化。CAF赋予对药物的抗性,并且这项实验表明,即使当存在来自CAF的存活信号时,YAP1抑制剂也能起作用。进一步地,CAF的影响甚微,它们是相对正常的细胞。
图30示出确认的化合物抑制顺铂不敏感性SP细胞的自我更新。癌症干细胞的一个特征是它们的抗药性。顺铂的存在有助于来自H1650细胞的SP细胞形成球体;干细胞样SP细胞可在干细胞选择性培养基中和在低粘附板上自我更新并形成球体,即使存在5uM顺铂也如此(右上图像)。解离顺铂不敏感性球体并将它们用2uM的YAP1抑制剂处理完全抑制了自我更新,如通过球体的消失所示。相比之下,解离顺铂不敏感性细胞并再次用顺铂进行自我更新测定则允许自我更新和集落形成。表明YAP抑制剂可有效消除顺铂不敏感性干细胞样细胞。
图31示出YAP1抑制剂降低甲氨蝶呤不敏感性H146SLCL细胞的自我更新能力。类似的实验中,YAP1抑制剂抑制了对甲氨蝶呤不敏感的小细胞肺癌细胞的球体形成。2.5uM甲氨蝶呤的存在有助于来自H146小细胞肺癌细胞的SP细胞形成球体;干细胞样细胞可在干细胞选择性培养基中和在低粘附板上自我更新并形成球体,即使存在2.5uM甲氨蝶呤也如此。解离甲氨蝶呤不敏感性球体并将它们用2uM的YAP1抑制剂处理完全抑制了自我更新,如通过球体的消失所示。相比之下,解离甲氨蝶呤不敏感性细胞并再次用甲氨蝶呤进行自我更新测定则允许自我更新和集落形成。表明YAP抑制剂可有效消除甲氨蝶呤不敏感性干细胞样细胞。
图32示出确认的化合物可在EGFR抑制剂抗性细胞中诱导细胞毒性。EGFR抑制剂如埃罗替尼和吉非替尼对抗EGFR突变肺腺癌是有效的。患者总是对这些抑制剂产生抗性。埃罗替尼抗性的HCC827细胞(HCC827-ER)和吉非替尼抗性PC-9细胞(PC-9GR)表达较高的Sox2和YAP1水平。如通过MTT测定所测量,YAP抑制剂可有效降低EGFR-I敏感性亲本细胞以及抗性细胞的活力(ER=埃罗替尼抗性细胞;GR=吉非替尼抗性细胞)。
图33是示出确认的化合物降低H1975(RGFR T790M突变)肺腺癌细胞的活力的图示。H1975是对EGFR抑制剂如埃罗替尼和吉非替尼抗性的EGFR突变细胞系。如通过MTT测定所示,YAP1抑制剂可有效降低这些细胞的活力。药物治疗持续72小时。
图34含有示出确认的化合物抑制多种肺癌细胞中的Sox2表达的图示。较早期的研究已表明,YAP1调节Sox2的表达,对Oct4和Nanog转录因子影响甚微。RT-PCR实验表明,在72小时治疗后,PPxY模拟物可抑制Sox2 mRNA的表达,但对Oct4和Nanog mRNA的表达影响甚微。在H1650(肺腺癌)、H1703(鳞状细胞癌)和H146(小细胞肺癌)细胞系中得到类似的结果。
图35含有示出确认的化合物抑制肺癌细胞中的HK2和PDK2 mRNA表达的图示。这些基因的抑制可能是YAP1抑制剂抑制细胞增殖和降低活力的机制。我们测试了这些基因(HK2和PKD2),因为它们在其启动子上具有Sox2结合位点,并且似乎受Sox2调节。如通过RT-PCR所示,用药物治疗72小时减少了己糖激酶2和丙酮酸脱氢酶激酶2的表达。
图36含有示出某些化合物抑制肺癌细胞中的PD-L1表达但不抑制CTGF(TREAD2靶标)表达的图示。YAP1可能调节PD-L1的表达。如通过RT-PCR所示,在72小时治疗后,YAP1抑制剂在转录水平上抑制PD-L1。TEAD-2靶基因CTGF的表达不受这些药物影响。
图37含有示出某些化合物抑制肺癌细胞中的纤连蛋白表达的图示。较早期的研究已表明,间充质基因如纤连蛋白和波形蛋白是YAP1的靶标。已知它们通过促进上皮-间充质转变而促进癌症的进展和转移。RT-PCR实验表明,在72小时治疗后,YAP1抑制剂可抑制这些基因的表达。
图38含有示出某些化合物通过Huvec减少基质胶中的小管形成的细胞显微照片。研究表明YAP1在血管生成中起作用。血管生成对于肿瘤生长是必要的,并且抑制血管生成是公认的实体肿瘤治疗策略。结果表明,在18-24小时治疗后,YAP1抑制剂可通过基质胶中的HUVEC抑制血管生成小管的形成。
图39是示出对用SR2-033处理的A549细胞进行细胞因子阵列实验的结果的图示。细胞因子阵列实验表明,YAP1抑制剂改变了分泌细胞因子的水平。这个数据是关于A549肺腺癌细胞的。
图40是示出对用SR2-033处理的A549细胞进行细胞因子阵列实验的结果的图示。细胞因子阵列实验表明,YAP1抑制剂改变了分泌细胞因子的水平。这个数据是关于原发性癌症相关性成纤维细胞的。
具体实施方式
通过参考以下对所公开的主题的具体方面及其中包括的实施例的详细描述可以更容易地理解本文所述的物质、化合物、组合物及方法。
在公开和描述本发明的物质、化合物、组合物及方法之前要理解的是,下述方面不限于具体的合成方法或具体的试剂,因为这些当然可有所变化。还要理解的是,本文使用术语的目的仅是描述特定的方面,并不旨在具有限制意义。
另外,贯穿本说明书引用了各种出版物。这些出版物的全部公开内容特此以引用的方式并入本申请中,以便更全面地描述所公开的内容所属领域的技术状态。所公开的参考文献也就它们当中所含有的赖以引用的句子中讨论的内容单独和具体地以引用的方式并入本文。
一般定义
在本说明书和随后的权利要求中将参考许多术语,这些术语将被定义为具有以下含义:
贯穿说明书和权利要求的词语“包含”(comprise/comprising/comprises)意指包括但不限于,并且不旨在排除例如其它添加剂、组分、整体或步骤。
如说明书和所附权利要求中所用,单数形式“一个(种)”和“该(所述)”包括复数指代项,除非上下文明确另有规定。因此,例如提到“组合物”包括两种或更多种这类组合物的混合物,提到“抑制剂”包括两种或更多种这类抑制剂的混合物,等等。
“任选的”或“任选地”意指随后描述的事件或情况可以发生或可以不发生,并且该描述包括事件或情况发生的实例以及其不发生的实例。
尽管陈述本公开的宽广范围的数值范围和参数是近似值,但尽可能精确地报告具体实施例中列举的数值。然而,任何数值内在地含有一定的误差,这些误差是由其各自的测试测量中存在的标准偏差必然引起的。此外,当本文列举变化范围的数值时,预期可使用这些值的任意组合,包括所述的值。此外,范围在本文中可以被表示为从“约”一个特定值和/或至“约”另一个特定值。当表达这样的范围时,另一方面包括从该一个特定值和/或至该另一特定值。类似地,当通过使用先行词“约”将值表示为近似值时,将要理解的是,该特定值构成另一方面。进一步要理解的是,范围的每个端点相对于另一端点和独立于另一端点都是重要的。除另有说明外,术语“约”意指不超出由术语“约”修饰的特定值5%(例如,不超出特定值2%或1%)。
所谓“减少”(reduce/reducing/reduction)意思是事件或特征(例如,肿瘤生长、转移)的减低。要理解的是,这通常是与某个标准或期望值相比,换言之,其是相对的,但并不总是需要提到标准或相对值。例如,“减少肿瘤生长”意指相对于标准或对照减少肿瘤细胞的数量。
所谓“预防”(prevent/preventing/prevention)意思是使特定事件或特征停止,稳定或延迟特定事件或特征的发展或进展,或者使特定事件或特征将会发生的可能性最小化。预防不需要与对照进行比较,因为其通常比例如减少更绝对。如本文所用,某事物可能被减少但不能被预防,但被减少的某事物也可能被预防。同样,某事物可能被预防但不能被减少,但被预防的某事物也可能被减少。要理解的是,在使用减少或者使用预防的情况下,除特别另指出外,也明确公开了另一词语的使用。
如本文所用,“治疗”是指获得有益或所需的临床结果。有益或所需的临床结果包括但不限于以下中的任何一者或多者:减轻一种或多种症状(如肿瘤生长或转移)、降低癌症的程度、稳定(即,不恶化)癌症的状态、预防或延迟癌症的扩散(例如,转移)、延迟癌症的发生或复发、延迟或减缓癌症进展、改善癌症状态和缓解(无论是部分还是完全)。
术语“患者”优选是指需要用抗癌剂治疗或出于任何目的治疗的人,更优选是需要这种治疗来治疗癌症或癌前病状或病变的人。然而,术语“患者”也可指需要用抗癌剂治疗或需要治疗的非人类动物,优选哺乳动物,如狗、猫、马、母牛、猪、绵羊,以及非人灵长类动物,等等。
要理解的是,贯穿本说明书的标示“第一”和“第二”仅用于帮助区分所公开的主题的各种组分及各个步骤。标示“第一”和“第二”并不旨在暗示由这些术语修饰的组分或步骤的任何特定顺序、数量、优先性或重要性。
化学定义
如本文所用,术语“组合物”旨在涵盖包含指定量的指定成分的产品,以及直接或间接由指定量的指定成分的组合产生的任何产品。
说明书和最后的权利要求中提到组合物中特定元素或组分的重量份指示在组合物或制品中以重量份表示的该元素或组分与任何其它元素或组分之间的重量关系。因此,在含有2重量份组分X和5重量份组分Y的混合物中,X和Y以2:5的重量比存在,并且不管混合物中是否含有另外的组分时都以这样的比例存在。
除明确有相反的规定外,组分的重量百分比(重量%)是基于包括该组分的制剂或组合物的总重量。
如本文所用,术语“取代的”预期包括有机化合物所有可允许的取代基。在广义方面,可允许的取代基包括有机化合物的无环和环状、支链和非支链、碳环和杂环以及芳族和非芳族取代基。例示的取代基包括例如下述的那些。对于适当的有机化合物,可允许的取代基可以是一个或多个,并且相同或不同。出于本公开的目的,杂原子如氮可具有氢取代基和/或本文所述的满足杂原子价态的有机化合物的任何可允许的取代基。本公开并不旨在以任何方式受限于有机化合物的可允许的取代基。另外,术语“取代”或“被…取代”包括隐含的条件,即这种取代符合被取代的原子和取代基的允许价态,并且所述取代产生稳定的化合物,例如不会诸如通过重排、环化、消除等自发地经历转化的化合物。
如本文所用的术语“脂族”是指非芳族烃基团,并且包括支链和非支链的烷基、烯基或炔基。
如本文所用的术语“烷基”是1至24个碳原子的支链或非支链饱和烃基团,如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊基、己基、庚基、辛基、壬基、癸基、十二烷基、十四烷基、十六烷基、二十烷基、二十四烷基等。烷基也可以是取代的或未取代的。如下所述,烷基可以被一个或多个包括但不限于烷基、卤代烷基、烷氧基、烯基、炔基、芳基、杂芳基、醛、氨基、羧酸、酯、醚、卤族、羟基、酮、硝基、甲硅烷基、磺基-氧代、磺酰基、砜、亚砜或巯基的基团取代。
符号An在本文中仅用作下面的定义中的通用取代基。
如本文所用的术语“烷氧基”是通过单个末端醚键结合的烷基;也就是说,“烷氧基”基团可被定义为—OA1,其中A1是如上所定义的烷基。
如本文所用的术语“烯基”是结构式含有至少一个碳-碳双键的2至24个碳原子的烃基团。不对称结构如(A1A2)C=C(A3A4)旨在包括E和Z异构体两者。这可以在其中存在不对称烯烃的本文的结构式中予以推测,或者可通过键符号C=C明确指出。如下所述,烯基可以被一个或多个包括但不限于烷基、卤代烷基、烷氧基、烯基、炔基、芳基、杂芳基、醛、氨基、羧酸、酯、醚、卤族、羟基、酮、硝基、甲硅烷基、磺基-氧代、磺酰基、砜、亚砜或巯基的基团取代。
如本文所用的术语“炔基”是结构式含有至少一个碳-碳三键的2至24个碳原子的烃基团。如下所述,炔基可以被一个或多个包括但不限于烷基、卤代烷基、烷氧基、烯基、炔基、芳基、杂芳基、醛、氨基、羧酸、酯、醚、卤族、羟基、酮、硝基、甲硅烷基、磺基-氧代、磺酰基、砜、亚砜或巯基的基团取代。
如本文所用的术语“芳基”是含有任何碳基芳族基团的基团,包括但不限于苯、萘、苯基、联苯、苯氧基苯等。术语“杂芳基”被定义为含有芳族基团的基团,所述芳族基团具有至少一个结合在芳族基团的环内的杂原子。杂原子的实例包括但不限于氮、氧、硫和磷。包括在术语“芳基”中的术语“非杂芳基”定义了含有不含杂原子的芳族基团的基团。芳基和杂芳基可以是取代或未取代的。如本文所述,芳基和杂芳基可以被一个或多个包括但不限于烷基、卤代烷基、烷氧基、烯基、炔基、芳基、杂芳基、醛、氨基、羧酸、酯、醚、卤族、羟基、酮、硝基、甲硅烷基、磺基-氧代、磺酰基、砜、亚砜或巯基的基团取代。术语“联芳基”是特定类型的芳基,并且包括在芳基的定义中。联芳基是指经由稠环结构结合在一起(如萘)或经由一个或多个碳-碳键连接(如联苯)的两个芳基。
如本文所用的术语“环烷基”是由至少三个碳原子组成的非芳族碳基环。环烷基的实例包括但不限于环丙基、环丁基、环戊基、环己基等。术语“杂环烷基”是如上所定义的环烷基,其中环的至少一个碳原子被诸如但不限于氮、氧、硫或磷的杂原子取代。环烷基和杂环烷基可以是取代或未取代的。如本文所述,环烷基和杂环烷基可以被一个或多个包括但不限于烷基、烷氧基、烯基、炔基、芳基、杂芳基、醛、氨基、羧酸、酯、醚、卤族、羟基、酮、硝基、甲硅烷基、磺基-氧代、磺酰基、砜、亚砜或巯基的基团取代。
如本文所用的术语“环烯基”是由至少三个碳原子组成并且含有至少一个双键即C=C的非芳族碳基环。环烯基的实例包括但不限于环丙烯基、环丁烯基、环戊烯基、环戊二烯基、环己烯基、环己二烯基等。术语“杂环烯基”是一类如上所定义的环烯基,其中环的至少一个碳原子被诸如但不限于氮、氧、硫或磷的杂原子取代。环烯基和杂环烯基可以是取代或未取代的。如本文所述,环烯基和杂环烯基可以被一个或多个包括但不限于烷基、烷氧基、烯基、炔基、芳基、杂芳基、醛、氨基、羧酸、酯、醚、卤族、羟基、酮、硝基、甲硅烷基、磺基-氧代、磺酰基、砜、亚砜或巯基的基团取代。
术语“环状基团”在本文中用来指芳基、非芳基(即,环烷基、杂环烷基、环烯基和杂环烯基)或这两者。环状基团具有一个或多个可以是取代或未取代的环体系。环状基团可含有一个或多个芳基、一个或多个非芳基,或者一个或多个芳基和一个或多个非芳基。
如本文所用的术语“醛”由式—C(O)H表示。贯穿本说明书的“C(O)”是C=O的简写符号。
如本文所用的术语“胺”或“氨基”由式NA1A2A3表示,其中A1、A2和A3可独立地为氢、上述烷基、卤代烷基、烯基、炔基、芳基、杂芳基、环烷基、环烯基、杂环烷基或杂环烯基。
如本文所用的术语“羧酸”由式—C(O)OH表示。如本文所用的“羧酸根”由式—C(O)O-表示。
如本文所用的术语“酯”由式—OC(O)A1或—C(O)OA1表示,其中A1可以是上述烷基、卤代烷基、烯基、炔基、芳基、杂芳基、环烷基、环烯基、杂环烷基或杂环烯基。
如本文所用的术语“醚”由式A1OA2表示,其中A1和A2可独立地为上述烷基、卤代烷基、烯基、炔基、芳基、杂芳基、环烷基、环烯基、杂环烷基或杂环烯基。
如本文所用的术语“酮”由式A1C(O)A2表示,其中A1和A2可独立地为上述烷基、卤代烷基、烯基、炔基、芳基、杂芳基、环烷基、环烯基、杂环烷基或杂环烯基。
如本文所用的术语“卤族”(halide)是指卤素氟、氯、溴和碘。
如本文所用的术语“羟基”由式—OH表示。
如本文所用的术语“硝基”由式—NO2表示。
如本文所用的术语“氰基”由式—CN表示。
如本文所用的术语“叠氮基”由式–N3表示。
术语“磺酰基”在本文中用来指由式--S(O)2A1表示的磺基-氧代基团,其中A1可以是氢、上述烷基、卤代烷基、烯基、炔基、芳基、杂芳基、环烷基、环烯基、杂环烷基或杂环烯基。
如本文所用的术语“磺酰氨基”或“磺酰胺”由式--S(O)2NH2表示。
如本文所用的术语“巯基”由式--SH表示。
要理解的是,本文提供的化合物可含有手性中心。这类手性中心可呈(R-)或(S-)构型。本文提供的化合物可以是对映体纯的,或者是非对映体或对映体混合物。要理解的是,本文提供的化合物的手性中心可在体内经历差向异构化。如此,本领域技术人员将会认识到,对于在体内经历差向异构化的化合物来说,施用其(R-)形式的化合物等同于施用其(S-)形式的化合物。
如本文所用,基本上纯意指足够同质,以至于看起来不含容易通过本领域技术人员用来评估这种纯度的标准分析方法测定可检测到的杂质,这些标准分析方法如薄层色谱法(TLC)、核磁共振(NMR)、凝胶电泳、高效液相色谱(HPLC)和质谱法(MS)、气相色谱质谱法(GC-MS)等,或者足够纯,以至于进一步纯化不会可检测地改变物质的物理和化学性质,如酶活性和生物活性。将化合物纯化以产生基本上化学纯的化合物的传统及现代方法都是本领域技术人员已知的。然而,基本上化学纯的化合物可以是立体异构体的混合物。
除有相反的规定外,化学键仅显示为实线而不是楔形或虚线的化学式涵盖每种可能的异构体,例如每种对映体、非对映体和内消旋化合物,以及异构体的混合物,如外消旋或部分消旋(scalemic)混合物。
“药学上可接受的”组分是适合人和/或动物使用而没有不适当的不良副作用(如毒性、刺激性和过敏反应)且与合理的利益/风险比相称的组分。
“药学上可接受的盐”是指在药学上是可接受的并且具有所需药理学性质的盐。这类盐包括在化合物中存在的酸性质子能够与无机或有机碱反应的情况下可形成的盐。合适的无机盐包括与碱金属例如钠、钾、镁、钙和铝形成的那些。合适的有机盐包括与有机碱形成的那些,所述有机碱如胺碱,例如乙醇胺、二乙醇胺、三乙醇胺、氨丁三醇、N-甲基葡糖胺等。这类盐还包括用无机酸(例如,盐酸和氢溴酸)和有机酸(例如,乙酸、柠檬酸、马来酸,以及烷烃-磺酸和芳烃-磺酸,如甲磺酸和苯磺酸)形成的酸加成盐。当存在两个酸性基团时,药学上可接受的盐可以是单酸单盐或二盐;类似地,在存在多于两个酸性基团的情况下,一些或所有这类基团可以被转化成盐。
“药学上可接受的赋形剂”是指常规上可用于制备药物组合物的赋形剂,其通常是安全、无毒且合乎需要的,并且包括可接受用于兽医用途以及用于人类药物用途的赋形剂。这类赋形剂可以是固体、液体、半固体,或者在气溶胶组合物的情况下是气态的。
“药学上可接受的载体”是用于将所公开的化合物递送给患者的载体,如溶剂、助悬剂或媒介物。载体可以是液体或固体,并且在选择时要考虑拟用的施用方式。脂质体也是药物载体。如本文所用,“载体”包括任何及所有溶剂、分散介质、媒介物、包衣、稀释剂、抗菌剂和抗真菌剂、等渗剂和吸收延迟剂、缓冲剂、载体溶液、混悬液、胶体等。这类介质和试剂用于药物活性物质的用途在本领域中是众所周知的。除了任何常规介质或试剂与活性成分不相容的情况外,其在治疗组合物中的用途是可被考虑的。
如本文所用的术语“治疗有效量”意指研究人员、兽医、医生或其他临床医师谋求在组织、系统、动物或人中引起生物反应或药物反应的活性化合物或药剂量。关于癌症或其它有害的细胞增殖,有效量包括足以使肿瘤缩小和/或降低肿瘤生长速率(如抑制肿瘤生长)或者防止或延迟其它有害细胞增殖的量。在一些实施方案中,有效量是足以延迟发展的量。在一些实施方案中,有效量是足以防止或延迟发生和/或复发的量。可一剂或多剂施用有效量。在癌症的情况下,药物或组合物的有效量可:(i)减少癌细胞的数量;(ii)减小肿瘤尺寸;(iii)在一定程度上抑制、延缓、减慢并且优选阻止癌细胞浸润到外周器官当中;(iv)抑制(即,在一定程度上减慢并且优选阻止)肿瘤转移;(v)抑制肿瘤生长;(vi)预防或延迟肿瘤的发生和/或复发;和/或(vii)在一定程度上缓解与癌症相关的一种或多种症状。
如本文所述的化合物或组合物用于治疗哺乳动物受试者的有效量可包括约0.1至约1000mg/Kg受试者体重/天,如约1至约100mg/Kg/天,特别是约10至约100mg/Kg/天。剂量可以是急性的或慢性的。所公开的组合物剂量的宽范围被认为是既安全又有效的。
现在将详细参考所公开的物质、化合物、组合物、制品和方法的具体方面,其实例在所附实施例和附图中示出。
化合物
本文公开了式I的化合物。
其中,
X是C(O)、S(O)或SO2;
Y是CH、CR6或N;
Z是CH2、CR6R7或NH;
R1是C1-C8烷基、C1-C8烯基、C1-C8炔基、C1-C8烷氧基、C1-C8杂烷基、C3-C6环烷基、C3-C6杂环烷基、芳基或杂芳基,其中的任一者任选被一个或多个羰基(C=O)、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、氨基、-NR6R7、-C(O)NR6R7、C1-C6烷基羟基、C3-C6环烷基、C3-C6杂环烷基、芳基、杂芳基、卤代、羟基、巯基、氰基、硝基或放射标记同位素(例如,18F、11C)取代;
R2是氨基、羟基、C1-C8烷基、C1-C8烯基、C1-C8炔基、C1-C8烷氧基、C1-C8杂烷基、C3-C6环烷基、C3-C6杂环烷基、芳基或杂芳基,其中的任一者任选被一个或多个羰基(C=O)、羧基(-CO2-)、酯(CO2R6)、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、氨基、-NR6R7、-C(O)NR6R7、C1-C6烷基C3-6环烷基、C3-C6环烷基、C3-C6杂环烷基、芳基、杂芳基、C1-6烷基芳基、卤代、羟基、巯基、氰基、硝基或放射标记同位素(例如,18F、11C)取代;
每个R3独立地为氢、卤素、OH、C1-C8烷基、C1-C8烷氧基、芳基、O-芳基、杂芳基、O-杂芳基、O-CH2芳基或O-CH2杂芳基;且
R6和R7独立地选自氢、C1-C8烷基、C1-C8烯基、C1-C8炔基、C1-C8烷氧根(alkoxide)、C1-C8羧酸根(carboxylate)、C1-C8卤代烷基、C1-C8卤代烯基、C1-C8卤代炔基、C3-C6环烷基、C3-C6杂环烷基、芳基、C1-C3烷基杂芳基或杂芳基;其中的任一者任选被卤素取代;且n是1-5。
在式I的优选实例中,Z是CH2。
在一些实施方案中,当X是C(O)时,所述化合物可具有式I-A
在一些实例中,当X是S(O)时,所述化合物可具有式I-B
在一些实例中,当X是SO2时,所述化合物可具有式I-C
在一些实施方案中,当Y是CH且X是C(O)时,所述化合物可具有式I-D
在一些实例中,当Y是CH且X是S(O)时,所述化合物可具有式I-E
在一些实例中,当Y是CH且X是SO2时,所述化合物可具有式I-F
在一些实施方案中,当Y是N且X是C(O)时,所述化合物可具有式I-G
在一些实例中,当Y是N且X是S(O)时,所述化合物可具有式I-H
在一些实例中,当Y是N且X是SO2时,所述化合物可具有式I-I
在一些实施方案中,当Y是CH且X是C(O)时,所述化合物可具有式I-J
在一些实例中,当Y是CH且X是S(O)时,所述化合物可具有式I-K
在一些实例中,当Y是CH且X是SO2时,所述化合物可具有式I-L
还涵盖式I-A-I-L,其中n=1,且R3也在2、3、5或6位上。
本文还公开了式II的化合物。
其中,
R1是氢、C1-C8烷基、C1-C8烯基、C1-C8炔基、C1-C8烷氧基、C1-C8杂烷基、C3-C6环烷基、C3-C6杂环烷基、芳基或杂芳基,其中的任一者任选被一个或多个羰基(C=O)、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、氨基、-NR6R7、-C(O)NR6R7、C1-C6烷基羟基、C3-C6环烷基、C3-C6杂环烷基、芳基、杂芳基、卤代、羟基、巯基、氰基、硝基或放射标记同位素(例如,18F、11C)取代;
R2是氨基、羟基、C1-C8烷基、C1-C8烯基、C1-C8炔基、C1-C8烷氧基、C1-C8杂烷基、C3-C6环烷基、C3-C6杂环烷基、芳基或杂芳基,其中的任一者任选被一个或多个羰基(C=O)、羧基(-CO2-)、酯(CO2R6)、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、氨基、-NR6R7、-C(O)NR6R7、C1-C6烷基C3-6环烷基、C3-C6环烷基、C3-C6杂环烷基、芳基、杂芳基、C1-6烷基芳基、卤代、羟基、巯基、氰基、硝基或放射标记同位素(例如,18F、11C)取代;
每个R3独立地为氢、卤素、OH、C1-C8烷基、C1-C8烷氧基、芳基、O-芳基、杂芳基、O-杂芳基、O-CH2芳基或O-CH2杂芳基;且
R6和R7独立地选自氢、C1-C8烷基、C1-C8烯基、C1-C8炔基、C1-C8烷氧根、C1-C8羧酸根、C1-C8卤代烷基、C1-C8卤代烯基、C1-C8卤代炔基、C3-C6环烷基、C3-C6杂环烷基、芳基、C1-C3烷基杂芳基或杂芳基;其中的任一者任选被卤素取代;且n是1-5。
本文还公开了式III的化合物
其中,
X是C(O)、S(O)或SO2;
Y是CH、CR6或N;
Z是CH2、CR6R7或NH;
W是氰基、C2-C4炔烃或者三唑、四唑或噁唑(oxaxole),其任选被一个或多个羰基(C=O)、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、氨基、-NR6R7、-C(O)NR6R7、C1-C6烷基羟基、C3-C6环烷基、C3-C6杂环烷基、芳基、杂芳基、卤代、羟基、巯基、氰基、硝基或放射标记同位素(例如,18F、11C)取代;
R1是C1-C8烷基、C1-C8烯基、C1-C8炔基、C1-C8烷氧基、C1-C8杂烷基、C3-C6环烷基、C3-C6杂环烷基、芳基或杂芳基,其中的任一者任选被一个或多个羰基(C=O)、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、氨基、-NR6R7、-C(O)NR6R7、C1-C6烷基羟基、C3-C6环烷基、C3-C6杂环烷基、芳基、杂芳基、卤代、羟基、巯基、氰基、硝基或放射标记同位素(例如,18F、11C)取代;
R2是氨基、羟基、C1-C8烷基、C1-C8烯基、C1-C8炔基、C1-C8烷氧基、C1-C8杂烷基、C3-C6环烷基、C3-C6杂环烷基、芳基或杂芳基,其中的任一者任选被一个或多个羰基(C=O)、羧基(-CO2-)、酯(CO2R6)、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、氨基、-NR6R7、-C(O)NR6R7、C1-C6烷基C3-6环烷基、C3-C6环烷基、C3-C6杂环烷基、芳基、杂芳基、C1-6烷基芳基、卤代、羟基、巯基、氰基、硝基或放射标记同位素(例如,18F、11C)取代;
每个R3独立地为氢、卤素、OH、C1-C8烷基、C1-C8烷氧基、芳基、O-芳基、杂芳基、O-杂芳基、O-CH2芳基或O-CH2杂芳基;且
R6和R7独立地选自氢、C1-C8烷基、C1-C8烯基、C1-C8炔基、C1-C8烷氧根、C1-C8羧酸根、C1-C8卤代烷基、C1-C8卤代烯基、C1-C8卤代炔基、C3-C6环烷基、C3-C6杂环烷基、芳基、C1-C3烷基杂芳基或杂芳基;其中的任一者任选被卤素取代;且n是1-5。
在式I-A至I-L、II和III中的任一者中,R1、R2、R3、R6和R7可如本文中进一步所定义。
在优选的实例中,Y是CH。在其它实例中,Y是N。
在优选的实例中,Z是CH2。在其它实例中,Z是NH。
在具体的实例中,R1可以是C1-C8烷氧基。在其它实例中,R1可以是OtBu。在其它实例中,R1可以是苯基。仍在其它实例中,R1可以是被芳基取代的C1-C3烷基,例如(CH2)1-3Ph,其中所述芳基任选被一个或多个C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、氨基、卤代、羟基、巯基、氰基、硝基或放射标记同位素取代。仍在其它实例中,R1可以是CH2Ph。在其它实例中,R1可以是CH2CH2Ph。仍在其它实例中,R1可以是CH2CH2CH2Ph。在进一步的实例中,R1可以是CH(CH2)Ph或C(CH3)2Ph。还在进一步的实例中,R1可以是CH2CH(Ph)2。在其它实例中,R1可以是CH2CH2Ph,其中所述苯基被一个或多个C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、氨基、卤代、羟基、巯基、氰基、硝基或放射标记同位素取代。在进一步的实例中,R1是被苯基取代的C1-3烷基,所述苯基被一个或多个卤素、甲氧基、乙氧基、丙氧基、氰基和CF3取代。在进一步的实例中,R1是被苯基取代的C1-3烷基,所述苯基被二氧杂环戊烯取代。
仍在其它实例中,R1可以是被芳基取代的C1-3烯基,例如CH=CHPh,其中所述芳基任选被一个或多个C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、氨基、卤代、羟基、巯基、氰基、硝基或放射标记同位素取代。在其它实例中,R1可以是CH=CHPh。在其它实例中,R1可以是CH=CHPh,其中所述苯基被一个或多个C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、氨基、卤代、羟基、巯基、氰基、硝基或放射标记同位素取代。在进一步的实例中,R1可以是吡啶。
在具体的实例中,R1可以是C1-C8杂烷基,如-CH2O-、OCH2-、-NHCH2-、-CH2NH-、-CH2CH2O-、OCH2CH2-、-NHCH2CH2-和-CH2CH2NH-。
在进一步的实例中,R1可以是C3-6杂环烷基,例如吡咯烷、哌啶(piperadine)、哌嗪,其可任选被一个或多个C=O、C1-6烷基和芳基取代。在一些实例中,R1可以是被C(O)CH3取代的吡咯烷。
在具体的实例中,R2可以是OMe或OH。在其它实例中,R2可以是未取代的氨基。在其它实例中,R2可以是被C1-C6烷基取代的氨基,具体实例包括NH甲基、NH乙基、NH丙基和NH异丙基。在其它实例中,R2可以是被C3-C6环烷基取代的氨基,具体实例包括NH环丙基、NH环丁基、NH环戊基和NH环己基。在其它实例中,R2可以是被C1-C6烷基C3-6环烷基取代的氨基,具体实例包括NHCH2环丙基、NHCH2环丁基、NHCH2环戊基和NHCH2环己基。
在具体的实例中,R3可以是氢。在其它实例中,R3可以是OH。在进一步的实例中,R3可以是O苄基。在具体的实例中,R3在4位。在其它实例中,R3在2、3、5或6位。
在优选的实例中,n是1。在其它实例中,n是2、3、4或5。
还公开了具有式IV的化合物
其中
R4是氢、卤代、羟基、氰基、硝基、氨基、C1-C8烷基、C1-C8烯基、C1-C8炔基、C1-C8烷氧基、C1-C8杂烷基、C3-C6环烷基、C3-C6杂环烷基、芳基(稠合或侧位)或杂芳基(稠合或侧位),其中的任一者任选被一个或多个羰基(C=O)、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、氨基、-NR6R7、-C(O)NR6R7、C1-C6烷基羟基、C3-C6环烷基、C3-C6杂环烷基、芳基、杂芳基、卤代、羟基、巯基、氰基、硝基或放射标记同位素(例如,18F、11C)取代。
在式IV的具体实例中,R4是OH、F、Cl、Br或CN。
还公开了具有式V的化合物。
其中
R5是氢、卤代、羟基、氰基、硝基、氨基、C1-C8烷基、C1-C8烯基、C1-C8炔基、C1-C8烷氧基、C1-C8杂烷基、C3-C6环烷基、C3-C6杂环烷基、芳基(稠合或侧位)或杂芳基(稠合或侧位),其中的任一者任选被一个或多个羰基(C=O)、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、氨基、-NR6R7、-C(O)NR6R7、C1-C6烷基羟基、C3-C6环烷基、C3-C6杂环烷基、芳基、杂芳基、卤代、羟基、巯基、氰基、硝基或放射标记同位素(例如,18F、11C)取代;且
R8是氢、卤代、羟基、氰基、硝基、氨基、C1-C8烷基、C1-C8烯基、C1-C8炔基、C1-C8烷氧基、C1-C8杂烷基、C3-C6环烷基、C3-C6杂环烷基、芳基(稠合或侧位)或杂芳基(稠合或侧位),其中的任一者任选被一个或多个羰基(C=O)、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、氨基、-NR6R7、-C(O)NR6R7、C1-C6烷基羟基、C3-C6环烷基、C3-C6杂环烷基、芳基、杂芳基、卤代、羟基、巯基、氰基、硝基或放射标记同位素(例如,18F、11C)取代。
在式V的具体实例中,R5在苯基环的3位。在具体的实例中,R5是OH、F、Cl、Br或CN。在其它实例中,R5是C1-C6烷基或C1-C6烷氧基。在具体的实例中,R5是稠合苯基。在具体的实例中,R5是苯基。
在具体的实例中,R8在苯基环的2位。在其它实例中,R8在苯基环的3位。在具体的实例中,R8是羟基、F、Cl或Br。在具体的实例中,R8是苯基或苄基。
方法
本文进一步提供治疗或预防受试者的癌症的方法,包括对受试者施用有效量的如本文公开的化合物或组合物。所述方法可进一步包括施用第二化合物或组合物,举例如抗癌剂或抗炎剂。另外,所述方法可进一步包括对受试者施用有效量的电离辐射。
本文还提供杀灭肿瘤细胞的方法。所述方法包括使肿瘤细胞与有效量的如本文公开的化合物或组合物接触。所述方法可进一步包括对受试者施用第二化合物或组合物(例如,抗癌剂或抗炎剂)或者施用有效量的电离辐射。
本文还提供肿瘤放射治疗的方法,包括使肿瘤与有效量的如本文公开的化合物或组合物接触,并用有效量的电离辐射照射肿瘤。
还公开了治疗患者的肿瘤病症的方法。在一个实施方案中,对患有肿瘤病症并且需要对其进行治疗的患者施用有效量的一种或多种本文公开的化合物或组合物。所公开的方法可任选包括确认需要或可能需要治疗肿瘤病症的患者。患者可以是人或其他哺乳动物,如灵长类动物(猴子、黑猩猩、猿等)、狗、猫、母牛、猪或马,或患有肿瘤病症的其他动物。肿瘤病症包括但不限于肛门、胆管、膀胱、骨骼、骨髓、肠(包括结肠和直肠)、乳房、眼睛、胆囊、肾脏、口、喉、食道、胃、睾丸、子宫颈、头部、颈部、卵巢、肺、间皮瘤、神经内分泌、阴茎、皮肤、脊髓、甲状腺、阴道、外阴、子宫、肝脏、肌肉、胰腺、前列腺、血细胞(包括淋巴细胞及其它免疫系统细胞)和大脑的癌症和/或肿瘤。治疗涵盖的具体癌症包括癌(carcinoma)、卡波西氏肉瘤、黑素瘤、间皮瘤、软组织肉瘤、胰腺癌、肺癌、白血病(急性淋巴母细胞性、急性髓细胞性、慢性淋巴细胞性、慢性髓细胞性等)和淋巴瘤(霍奇金氏和非霍奇金氏)及多发性骨髓瘤。
根据本文公开的方法可治疗的癌症的其它实例有肾上腺皮质癌、肾上腺皮质癌、小脑星形细胞瘤、基底细胞癌、胆管癌、膀胱癌、骨癌、脑肿瘤、乳腺癌、伯基特淋巴瘤、类癌肿瘤、中枢神经系统淋巴瘤、宫颈癌、慢性骨髓增生病症、结肠癌、皮肤T细胞淋巴瘤、子宫内膜癌、室管膜瘤、食道癌、胆囊癌、胃(gastric/stomach)癌、胃肠道类癌肿瘤、生殖细胞肿瘤、胶质瘤、毛细胞白血病、头颈癌、肝细胞(肝)癌、下咽癌、下丘脑和视觉通路胶质瘤、眼内黑素瘤、视网膜母细胞瘤、胰岛细胞癌(内分泌胰腺)、喉癌、唇和口腔癌、肝癌、髓母细胞瘤、梅克尔细胞癌、伴有隐匿性蕈样真菌病的鳞状颈癌、骨髓增生异常综合征、骨髓性白血病、鼻腔和副鼻窦癌、鼻咽癌、神经母细胞瘤、非小细胞肺癌、口腔癌、口咽癌、骨肉瘤、卵巢癌、胰腺癌、副鼻窦和鼻腔癌、甲状旁腺癌、阴茎癌、嗜铬细胞瘤、松果体母细胞瘤和幕上原始神经外胚层肿瘤、垂体肿瘤、浆细胞肿瘤/多发性骨髓瘤、胸膜肺母细胞瘤、前列腺癌、直肠癌、肾细胞(肾)癌、视网膜母细胞瘤、横纹肌肉瘤、唾液腺癌、尤文氏肉瘤、软组织肉瘤、塞扎里综合征、皮肤癌、小细胞肺癌、小肠癌、幕上原始神经外胚层肿瘤、睾丸癌、胸腺癌、胸腺瘤、甲状腺癌、肾盂和输尿管的移行细胞癌、滋养细胞肿瘤、尿道癌、子宫癌、阴道癌、外阴癌、瓦尔登斯特伦巨球蛋白血症和威尔姆氏肿瘤。
在一些方面公开了通过对受试者施用至少一种如本文公开的化合物或组合物和至少一种癌症免疫治疗剂的组合来治疗受试者的肿瘤或肿瘤转移的方法。可单独或者与癌症免疫治疗剂组合施用所公开的化合物。受试者可在外科手术干预以去除全部或部分肿瘤之前、期间或之后接受治疗组合物。可经由以下方式完成施用:直接浸泡;全身或局部静脉内注射(i.v.)、腹膜内注射(i.p.)、皮下注射(s.c.)、肌肉内注射(i.m.)或直接注射到肿瘤块当中;和/或通过口服施用适当的制剂。
在具体的实例中,癌症的类型是肺癌。
施用
可顺序或同时以分开或组合的药物制剂施用所公开的化合物。当将一种或多种所公开的化合物与第二治疗剂组合使用时,每种化合物的剂量可与该化合物被单独使用时的剂量相同或不同。本领域技术人员将会很容易地确定适当的剂量。
关于本发明化合物的术语“施用”及其变化形式(例如,“施用”化合物)意指将化合物或化合物的前药引入到需要治疗的动物的系统当中。当与一种或多种其它活性剂(例如,细胞毒性剂等)组合提供本发明的化合物或其前药时,“施用”及其变化形式各自被理解为包括同时和顺序引入化合物或其前药及其它试剂。
可通过本领域技术人员目前或将来可能已知的任意合适的方法和技术来完成体内施加所公开的化合物和含有它们的组合物。例如,可按生理学或药学上可接受的形式配制所公开的化合物,并通过本领域中已知的任意合适的途径进行施用,包括例如口服、经鼻、经直肠、局部和肠胃外途径施用。如本文所用,术语肠胃外包括皮下、真皮内、静脉内、肌肉内、腹膜内和胸骨内施用,如通过注射。所公开的化合物或组合物的施用可以是单次施用,或者是以本领域技术人员可以很容易地确定的连续或不同的间隔施用。
也可以利用脂质体技术、缓释胶囊、可植入泵和可生物降解的容器来施用本文公开的化合物和包含它们的组合物。这些递送方法可有利地在延长的时间段内提供均匀的剂量。也可以将化合物以其盐衍生物形式或结晶形式施用。
可根据制备药学上可接受的组合物的已知方法配制本文公开的化合物。在本领域技术人员众所周知并且容易获得的许多来源中有对制剂的详细描述。例如,E.W.Martin的Remington’s Pharmaceutical Science(1995)描述了可与所公开的方法结合使用的制剂。一般来说,可配制本文公开的化合物,使得有效量的化合物与合适的载体组合,以便促进化合物的有效施用。所使用的组合物也可以呈多种形式。这些包括例如固体、半固体和液体剂型,如片剂、丸剂、粉末、液体溶液或悬浮液、栓剂、可注射及可输注溶液和喷雾剂。优选的形式取决于预期的施用模式和治疗应用。组合物还优选包括本领域技术人员已知的常规药学上可接受的载体和稀释剂。与所述化合物一起使用的载体或稀释剂的实例包括乙醇、二甲基亚砜、甘油、氧化铝、淀粉、盐水以及等效的载体和稀释剂。为了给所需的治疗处理提供这类剂量施用,基于包括载体或稀释剂在内的组合物的总重量,本文公开的组合物可有利地包含约0.1%与99%之间且特别是1%与15%之间的总重量的一种或多种主题化合物。
适合施用的制剂包括例如无菌注射水溶液,其可含有抗氧化剂、缓冲剂、抑菌剂和使制剂与预期接受者的血液等渗的溶质;以及水性和非水性无菌悬浮液,其可包括助悬剂和增稠剂。制剂可存在于单位剂量或多剂量容器中,例如密封的安瓿和小瓶中,并且在使用之前可储存在仅需无菌液体载体(例如注射用水)条件的冷冻干燥(冻干)条件下。可由无菌粉末、颗粒、片剂等制备临时注射溶液和悬浮液。应当理解的是,除了上面特别提到的成分之外,考虑到所述及的制剂的类型,本文公开的组合物还可包括本领域中常规的其它试剂。
可通过与细胞直接接触或经由载体方法将本文公开的化合物和包含它们的组合物递送到细胞中。将化合物和组合物递送到细胞中的载体方法是本领域中已知的,包括例如将组合物包封在脂质体部分中。将本文公开的化合物和组合物递送到细胞中的另一种方法包括使化合物与目标是递送至靶细胞的蛋白质或核酸连接。6,960,648号美国专利以及20030032594和20020120100号美国申请公布公开了可与另一种组合物偶联并允许该组合物跨生物膜易位的氨基酸序列。20020035243号美国申请公布也描述了用于跨细胞膜转运生物部分以进行细胞内递送的组合物。也可使化合物结合到聚合物当中,其实例包括用于颅内肿瘤的聚(D-L丙交酯-共-乙交酯)聚合物;20:80摩尔比的聚[双(对羧基苯氧基)丙烷:癸二酸](如在GLIADEL中使用的);软骨素;甲壳素;和壳聚糖。
为了治疗肿瘤病症,可与其它抗肿瘤或抗癌物质和/或与放射治疗和/或光动力治疗和/或与用以去除肿瘤的外科手术治疗组合对需要治疗的患者施用本文公开的化合物。可在与给予本文公开的化合物相同或不同的时间给予这些其它物质或治疗。例如,本文公开的化合物可分别与以下物质组合使用:有丝分裂抑制剂如紫杉醇或长春碱、烷化剂如环磷酰胺或异环磷酰胺、抗代谢物如5-氟尿嘧啶或羟基脲、DNA嵌入剂如阿霉素或博莱霉素、拓扑异构酶抑制剂如依托泊苷或喜树碱、抗血管生成剂如血管抑制素、抗雌激素如他莫昔芬和/或其它抗癌药物或抗体举例如GLEEVEC(Novartis Pharmaceuticals Corporation)和HERCEPTIN(Genentech,Inc.)。
许多肿瘤和癌症在肿瘤或癌细胞中存在有病毒基因组。例如,爱泼斯坦-巴尔病毒(EBV)与许多哺乳动物恶性肿瘤相关。本文公开的化合物也可单独使用,或者与抗癌剂或抗病毒剂如更昔洛韦、叠氮胸苷(AZT)、拉米夫定(3TC)等组合使用,以治疗被可引起细胞转化的病毒感染的患者和/或治疗患有与在细胞中存在病毒基因组相关的肿瘤或癌症的患者。本文公开的化合物也可与基于病毒的肿瘤疾病治疗组合使用。例如,所述化合物可与突变型单纯疱疹病毒一起用于治疗非小细胞肺癌(Toyoizumi等人,“Combined therapy withchemotherapeutic agents and herpes simplex virus type IICP34.5mutant(HSV-1716)in human non-small cell lung cancer,”Human Gene Therapy,1999,10(18):17)。
可通过本领域技术人员目前或将来可能已知的任意合适的治疗方法和技术来实现化合物和/或含有它们的组合物的治疗应用。进一步地,本文公开的化合物和组合物可用作制备其它有用的化合物和组合物的起始物质或中间体。
可在一个或多个解剖部位局部施用本文公开的化合物和组合物,如在有害的细胞生长部位(如肿瘤部位或良性皮肤赘生物,例如对肿瘤或皮肤赘生物注射或局部施加),任选与药学上可接受的载体如惰性稀释剂组合施用。可全身性施用本文公开的化合物和组合物,如静脉内或口服施用,任选与药学上可接受的载体如惰性稀释剂或用于口服递送的可吸收食用载体组合施用。它们可被包裹在硬壳或软壳明胶胶囊中,可被压制成片剂,或者可直接与患者饮食的食物掺合。对于口服治疗施用,可将活性化合物与一种或多种赋形剂组合,并以可摄入的片剂、口含片、锭剂、胶囊、酏剂、悬浮液、糖浆、薄饼、气溶胶喷雾剂等的形式使用。
片剂、锭剂、丸剂、胶囊等还可含有以下物质:粘合剂,如黄蓍胶、阿拉伯胶、玉米淀粉或明胶;赋形剂,如磷酸二钙;崩解剂,如玉米淀粉、马铃薯淀粉、海藻酸等;润滑剂,如硬脂酸镁;并且可添加甜味剂如蔗糖、果糖、乳糖或阿斯巴甜或调味剂如薄荷、冬青油或樱桃调料。当单位剂型是胶囊时,其除了上述类型的物质外还可含有液体载体,如植物油或聚乙二醇。可存在各种其它物质作为包衣,或者以另外的方式改变固体单位剂型的物理形式。例如,片剂、丸剂或胶囊可用明胶、蜡、虫胶或糖等进行包衣。糖浆或酏剂可含有活性化合物、作为甜味剂的蔗糖或果糖、作为防腐剂的对羟基苯甲酸甲酯和对羟基苯甲酸丙酯、染料和调料如樱桃或橙子香味料。当然,用于制备任何单位剂型的任何物质都应该是药学上可接受的,并且在用量上基本无毒。此外,可将活性化合物掺合到缓释制剂和装置当中。
可通过输注或注射静脉内、肌肉内或腹膜内施用本文公开的化合物和组合物,包括其药学上可接受的盐、水合物或类似物。可任选与无毒表面活性剂混合,在水中制备活性剂或其盐的溶液。也可在甘油、液体聚乙二醇、三醋精及其混合物中以及在油中制备分散体。在普通的储存和使用条件下,这些制剂可含有防腐剂以阻止微生物的生长。
适合注射或输注的药物剂型可包括无菌水溶液或分散体,或包含活性成分的无菌粉末,其适于临时制备无菌可注射或可输注溶液或分散体,任选包封在脂质体中。最终剂型在制造和储存条件下应该是无菌、流动和稳定的。液体载体或媒介物可以是溶剂或液体分散介质,包含例如水、乙醇、多元醇(例如,甘油、丙二醇、液体聚乙二醇等)、植物油、无毒甘油酯及其合适的混合物。可例如通过形成脂质体、通过在分散体的情况下保持所需的粒度或通过使用表面活性剂来保持适当的流动性。任选地,可通过各种其它抗菌剂和抗真菌剂例如对羟基苯甲酸酯、氯丁醇、苯酚、山梨酸、硫柳汞等来防止微生物的作用。在许多情况下,优选包括等渗剂,例如糖、缓冲液或氯化钠。可通过包含延迟吸收的试剂例如单硬脂酸铝和明胶来延长可注射组合物的吸收。
通过在适当的溶剂中以所需的量将本文公开的化合物和/或试剂根据需要与上面列举的各种其它成分掺合,接着进行过滤灭菌,由此制备无菌可注射溶液。在用于制备无菌可注射溶液的无菌粉末的情况下,优选的制备方法是真空干燥和冷冻干燥技术,其产生活性成分的粉末加上先前无菌过滤的溶液中存在的任何另外的所需成分。
对于局部施用,可按液体或固体的形式施加本文公开的化合物和试剂。然而,通常可取的是将它们作为与皮肤病学上可接受的载体(其可以是固体或液体)组合的组合物局部施用于皮肤。可以对受试者的皮肤局部施加本文公开的化合物和试剂及组合物,以减小恶性或良性赘生物的尺寸(并且可包括将其完全去除)或者治疗感染部位。可将本文公开的化合物和试剂直接施加于赘生物或感染部位。优选地,以制剂如软膏、乳膏、洗剂、溶液、酊剂等形式将化合物和试剂施加于赘生物或感染部位。也可使用将药理学物质递送至病变皮肤的药物递送系统,如5,167,649号美国专利中描述的药物递送系统。
有用的固体载体包括细碎的固体,如滑石、粘土、微晶纤维素、二氧化硅、氧化铝等。有用的液体载体包括水、醇或二醇或水-醇/二醇共混物,其中化合物可任选借助于无毒表面活性剂以有效水平溶解或分散。可添加佐剂如香料和另外的抗微生物剂以优化给定用途的性能。可将所得到的液体组合物自用于浸渍绷带及其它敷料的吸收垫施加,或者使用例如泵型或气溶胶喷雾器喷洒到受感染的区域上。
也可将增稠剂如合成聚合物、脂肪酸、脂肪酸盐和酯、脂肪醇、改性纤维素或改性矿物质与液体载体一起使用,以形成用于直接对使用者的皮肤施加的可涂抹的糊剂、凝胶、软膏、皂等。4,608,392号美国专利;4,992,478号美国专利;4,559,157号美国专利;和4,820,508号美国专利中公开了可用于向皮肤递送化合物的有用的皮肤病学组合物的实例。
可通过比较本文公开的化合物和试剂及药物组合物在动物模型中的体外活性和体内活性来确定其有用剂量。将在小鼠及其他动物中的有效剂量外推至人的方法是本领域中已知的;例如参见4,938,949号美国专利。
还公开了包含本文公开的化合物与药学上可接受的载体相组合的药物组合物。包含一定量化合物的适于口服、局部或肠胃外施用的药物组合物构成优选的方面。对患者、特别是人施用的剂量应足以在合理的时间范围内在患者中获得治疗反应而没有致命毒性,并且优选不引起超过可接受水平的副作用或发病率。本领域技术人员将会认识到,剂量将取决于多种因素,包括受试者的状态(健康状况)、受试者的体重、同步治疗(如果有的话)的种类、治疗的频率、治疗比率以及病理状况的严重程度和阶段。
为了治疗肿瘤病症,可在其它抗肿瘤或抗癌剂或物质(例如,化学治疗剂、免疫治疗剂、放射治疗剂、细胞毒性剂等)和/或放射治疗和/或用以去除肿瘤的外科手术治疗之前、继其之后或与其组合施用本文公开的化合物和试剂及组合物。例如,本文公开的化合物和试剂及组合物可用于治疗癌症的方法,其中分别要用或者正用或已用以下物质治疗患者:有丝分裂抑制剂如紫杉醇或长春碱、烷化剂如环磷酰胺或异环磷酰胺、抗代谢物如5-氟尿嘧啶或羟基脲、DNA嵌入剂如阿霉素或博莱霉素、拓扑异构酶抑制剂如依托泊苷或喜树碱、抗血管生成剂如血管抑制素、抗雌激素如他莫昔芬和/或其它抗癌药物或抗体举例如GLEEVEC(Novartis Pharmaceuticals Corporation)和HERCEPTIN(Genentech,Inc.)。可在与给予本文公开的化合物相同或不同的时间给予这些其它物质或放射治疗。其它合适化学治疗剂的实例包括但不限于六甲蜜胺、博莱霉素、硼替佐米(VELCADE)、白消安、亚叶酸钙、卡培他滨、卡铂、卡莫司汀、苯丁酸氮芥、顺铂、克拉屈滨、克立他酶(crisantaspase)、环磷酰胺、阿糖胞苷、达卡巴嗪、更生霉素、道诺霉素、多西他赛、多柔比星、表柔比星、依托泊苷、氟达拉滨、氟尿嘧啶、吉非替尼(IRESSA)、吉西他滨、羟基脲、伊达比星、异环磷酰胺、伊马替尼(GLEEVEC)、伊立替康、脂质体多柔比星、洛莫司汀、美法仑、巯基嘌呤、甲氨蝶呤、丝裂霉素、米托蒽醌、奥沙利铂、紫杉醇、喷司他丁、丙卡巴肼、雷替曲塞、链脲菌素、替加氟-尿嘧啶、替莫唑胺、噻替派、硫鸟嘌呤(tioguanine/thioguanine)、拓扑替康、曲奥舒凡、长春碱、长春新碱、长春地辛、长春瑞滨。在例示性实施方案中,化学治疗剂是美法仑。合适的免疫治疗剂的实例包括但不限于阿仑单抗、西妥昔单抗(ERBITUX)、吉妥珠单抗、碘131托西莫单抗、利妥昔单抗、曲妥珠单抗(赫赛汀,HERCEPTIN)。细胞毒性剂包括例如放射性同位素(例如,I131、I125、Y90、P32等)以及细菌、真菌、植物或动物来源的毒素(例如,蓖麻毒素、肉毒杆菌毒素、炭疽毒素、黄曲霉毒素、水母毒液(例如,箱型水母)等)。还公开了治疗肿瘤病症的方法,包括在施用化学治疗剂、免疫治疗剂、放射治疗剂或放射治疗之前、继其之后和/或与其组合施用有效量的本文公开的化合物和/或试剂。
试剂盒
进一步提供了用于实施本发明方法的试剂盒。所谓“试剂盒”是指包含至少一种试剂(例如,表1中所述的任一化合物)的产品(例如,包装或容器)。可将试剂盒作为用于执行本发明方法的单元来推广、分发或销售。另外,试剂盒可含有描述试剂盒及其使用方法的包装插页。可将任何或所有的试剂盒试剂提供在保护它们免受外部环境影响的容器如密封容器或小袋内。
为了给所需的治疗处理提供这类剂量施用,在一些实施方案中,基于包括载体或稀释剂在内的组合物的总重量,本文公开的药物组合物可包含约0.1%与45%之间且特别是1%与15%之间的总重量的一种或多种所述化合物。例示地,施用的活性成分的剂量水平可以是:静脉内,0.01至约20mg/kg动物(体)重;腹膜内,0.01至约100mg/kg动物(体)重;皮下,0.01至约100mg/kg动物(体)重;肌肉内,0.01至约100mg/kg动物(体)重;口服0.01至约200mg/kg动物(体)重,且优选约1至100mg/kg动物(体)重;鼻内滴注,0.01至约20mg/kg动物(体)重;以及气溶胶,0.01至约20mg/kg动物(体)重。
还公开了包含组合物的试剂盒,所述组合物包含在一个或多个容器中的本文公开的化合物。所公开的试剂盒可任选包括药学上可接受的载体和/或稀释剂。在一个实施方案中,试剂盒包括如本文所述的一种或多种其它组分、助剂或佐剂。在另一实施方案中,试剂盒包括一种或多种抗癌剂,如本文所述的那些试剂。在一个实施方案中,试剂盒包括描述如何施用试剂盒的化合物或组合物的说明书或包装材料。试剂盒的容器可以是任意合适材质的,例如玻璃、塑料、金属等,并且有任意合适的尺寸、形状或构造。在一个实施方案中,将本文公开的化合物和/或试剂以固体如片剂、丸剂或粉末形式提供在试剂盒中。在另一实施方案中,将本文公开的化合物和/或试剂以液体或溶液提供在试剂盒中。在一个实施方案中,试剂盒包括安瓿或注射器,其含有液体或溶液形式的本文公开的化合物和/或试剂。
实施例
下面列举以下实施例以说明根据所公开主题的方法和结果。这些实施例并不旨在囊括本文公开的主题的所有方面,而是说明代表性的方法和结果。这些实施例并不旨在排除本发明的等同方案和变化方案,这些对于本领域技术人员来说是显而易见的。
已经尽力确保数字(例如,数量、温度等)的准确性,但应考虑到有一定的误差和偏差。除另指出外,份数是重量份,温度以℃表示或者是处于环境温度,并且压力处于或接近大气压力。反应条件有许多变化及组合,例如组分浓度、温度、压力及其它反应范围和条件,这些可用于优化由所述方法得到的产物纯度和收率。优化这类方法条件将仅需进行合理且常规的实验。
哌啶衍生物:
基于哌啶乙酸核心制备一系列基于OCT4PPPY肽序列的模拟物的酪氨酸衍生物。通过与不同的氨基酸和酯偶联制备一组酰胺,如SR1-082和SR1-083。Boc基团脱保护得到NH哌啶,其经酰化得到脯氨酰基衍生物SR1-086和SR1-088。
(S)-4-(2-((3-(4-(苄氧基)苯基)-1-甲氧基-1-氧代丙烷-2-基)氨基)-2-氧代乙基)哌啶-1-羧酸叔丁酯(SR1-083)。在室温下将DIEA(0.472mL,2.713mmol)和HATU(0.563g,1.48mmol)添加到2-(1-Boc-哌啶-4-基)乙酸(0.300g,1.233mmol)在无水DMF(7mL)中的溶液里。搅拌3分钟后,将H-Tyr(bzl)-OH·HCl(0.476g,1.480mmol)添加到混合物中并搅拌21h。在减压下除去溶剂,并将所得胶状物溶解在EtOAc(30mL)中。将有机相用1N HCl(2×20mL)洗涤,接着用饱和NaHCO3(2×20mL)洗涤。使用EtOAc/己烷(40:60-100:0)作为洗脱液,通过快速柱色谱法纯化,得到SR1-083,为白色泡沫状物(0.602g,96%)。HPLC:>97%[tR=5.8分钟,80%MeOH,20%水(含0.1%TFA),20分钟]。1H NMR(400MHz,CDCl3-d)δ7.49–7.30(m,5H),7.00(d,J=8.7Hz,2H),6.89(d,J=8.7Hz,2H),5.85(d,J=7.9Hz,1H),5.03(s,2H),4.87(dt,J=8.0,5.9Hz,1H),4.06(dq,J=13.2,2.4Hz,2H),3.73(s,3H),3.05(qd,J=14.0,5.9Hz,2H),2.74–2.62(m,2H),2.08(d,J=7.1Hz,2H),1.97–1.70(m,2H),1.60(m,2H),1.44(s,9H),1.09(m,2H)。HRMS(ESI+):m/z C29H38N2O6(M+H)+511.2794;m/zC29H38N2O6Na(M+Na)+533.2613。HPLC–MS(ESI+):m/z 533.3[90%,(M+Na)+]。
(S)-2-(2-(1-(乙酰基-L-脯氨酰基)哌啶-4-基)乙酰胺基)-3-(4-(苄氧基)苯基)-丙酸甲酯(SR1-087)。在室温下将HCl溶液(3mL,在二噁烷中4N)添加到哌啶甲酯SR1-083(0.300g,0.507mmol)中。搅拌2h后,将反应混合物在减压下浓缩,得到白色半固体,然后将其溶解在无水DMF(5mL)中。向混合物中添加DIEA(0.307mL,1.761mmol)、HATU(0.268g,0.704mmol)和Ac-Pro-OH(0.110g,0.704mmol)。将混合物搅拌20h并在减压下蒸发。将所得残留物溶解在EtOAc(30mL)中。将有机相用1N HCl(2×20mL)洗涤,接着用饱和NaHCO3(2×20mL)洗涤。使用MeOH/DCM(0:100-10:90)作为洗脱液,通过快速柱色谱法纯化,得到SR1-087,为白色泡沫状物(0.223g,69%,2步)。HPLC:>99%[tR=18.8分钟,在水中10-95%MeOH(含0.1%TFA),20分钟]。1H NMR(400MHz,CDCl3-d)δ7.51–7.27(m,5H),7.02(m,2H),6.90(m,2H),6.19(bs,0.5H),5.84(bs,0.5H),5.03(s,2H),4.85(m,2H),4.52(bs,1H),3.94(m,1H),3.72(m,4H),3.56(bs,1H),3.23–2.90(m,3H),2.82–2.32(m,3H),2.13(m,6H),1.94(m,1H),1.80–1.51(m,2H),1.46(m,1H),1.14(bs,1H)。HRMS(ESI+):m/z C31H39N3O6(M+H)+550.2903;m/z C31H39N3O6Na(M+Na)+572.2716。HPLC–MS(ESI+):m/z 550.4[100%,(M+H)+],572.2[80%,(M+Na)+]。
(2-(1-(乙酰基-L-脯氨酰基)哌啶-4-基)乙酰基)-L-酪氨酸甲酯(SR1-088)。将苄基醚甲酯SR1-087(0.030g,0.055mmol)溶解在MeOH(2.5mL)中并用氩气吹扫。添加碳载钯(10%,0.008g,0.15g/mol)并用H2(气囊)吹扫。将混合物在H2下搅拌20h并通过硅藻土过滤,用MeOH/DCM冲洗滤床。将滤液在减压下蒸发,得到SR1-088,为白色泡沫状物(0.25g,定量收率)。HPLC:>99%[tR=6.9分钟,40%MeOH,60%水(含0.1%TFA),20分钟]。1H NMR(400MHz,CDCl3-d)δ6.91(d,J=8.3Hz,1H),6.76(d,J=8.1Hz,1H),6.44(d,J=8.0Hz,0.5H),6.20(d,J=8.2Hz,0.5H),4.93–4.70(m,2H),4.44(m,1H),3.92–3.76(m,1H),3.72(m,4H),3.55(m,1H),3.39(m,1H),3.19–2.92(m,2H),2.84(m,1H),2.50(m,1H),2.11(m,4H),2.04–1.75(m,4H),1.60(m,1H),1.53–1.39(m,2H),1.36–1.19(m,1H),1.15–0.81(m,2H)。HRMS(ESI+):m/z C24H33N3O6(M+H)+460.2437;m/z C24H33N3O6Na(M+Na)+482.2253。HPLC–MS(ESI+):m/z460.4[100%,(M+H)+],919.4[30%,(2M+H)+]。
(S)-4-(2-((1-甲氧基-1-氧代-3-苯基丙烷-2-基)氨基)-2-氧代乙基)哌啶-1-羧酸叔丁酯(SR1-082)。使用H-Phe-OH·HCl(0.300g,1.233mmol)作为起始物质,按与SR1-083相同的方式制备酰胺SR1-082(0.491g,98%)。HPLC:>97%[tR=6.9分钟,70%MeOH,30%水(含0.1%TFA),20分钟]。1H NMR(400MHz,CDCl3-d)δ7.33–7.19(m,3H),7.11–7.04(m,2H),5.90(d,J=7.9Hz,1H),4.91(m,1H),4.03(m,2H),3.73(d,3H),3.16(dd,J=13.9,5.6Hz,1H),3.04(dd,J=13.9,6.5Hz,1H),2.65(m,2H),2.07(dd,J=7.1,4.6Hz,2H),1.88(m,1H),1.61(m,1H),1.52(m,1H),1.44(s,9H),1.14–0.96(m,2H)。HRMS(ESI+):m/z C22H32N2O5Na(M+Na)+427.2202;m/z C22H32N2O5K(M+K)+443.1946HPLC–MS(ESI+):m/z 427.3[100%,(M+Na)+]。
(2-(1-(乙酰基-L-脯氨酰基)哌啶-4-基)乙酰基)-L-苯丙氨酸甲酯(SR1-086)。通过与制备SR1-087所用相同的方法由SR1-082(0.200g,0.494mmol)制备酰胺SR1-086(0.106g,48%,2步)。HPLC:>99%[tR=7.8分钟,50%MeOH,50%水(含0.1%TFA),20分钟]。1H NMR(400MHz,DMSO-d6)δ8.31(m,1H),7.33–7.15(m,5H),4.87(m,0.4H),4.72(m,0.6H),4.51(m,1H),4.28–4.08(m,1H),3.94–3.71(m,1H),3.61(s,3H),3.49(t,J=6.6Hz,1H),3.05(d,J=14.0Hz,1H),3.94(m,1H),2.84(dd,J=13.8,10.2Hz,1H),2.45(m,1H),2.34–2.03(m,2H),1.98(d,J=7.2Hz,2H),1.93(s,2H),1.87(m,1H),1.79(m,3H),1.71(m,1H),1.64(m,0.5H),1.49(m,0.5H),1.41–1.21(m,1H),1.21–0.92(m,1H),0.92–0.74(m,1H)。HRMS(ESI+):m/z C24H33N3O5(M+H)+444.2488;m/z C24H33N3O5Na(M+Na)+466.2301。HPLC–MS(ESI+):m/z 444.2[100%,(M+H)+],466.2[30%,(M+Na)+],909.4[45%(2M+Na)+]。
哌嗪衍生物:
如衍生物SR1-099和SR1-100中所示,PPPY模拟物的中心哌啶基核心被哌嗪置换。SR1-099和SR1-100的合成如上图所示,由4-Boc哌嗪-1-乙酸开始,首先用氨基酸衍生物形成酰胺以制备SR1-089和SR1-090。进行Boc脱保护,接着用Fmoc脯氨酰基衍生物酰化,进一步进行Fmoc脱保护和乙酰化,得到PPPY模拟物SR1-099和SR1-100。酪氨酰苄基可如SR1-100转化成SR1-101中所示的那样被脱保护。
(S)-4-(2-((3-(4-(苄氧基)苯基)-1-甲氧基-1-氧代丙烷-2-基)氨基)-2-氧代乙基)哌嗪-1-羧酸叔丁酯(SR1-090)。在室温下将DIEA(0.534mL,3.065mmol)和HATU(0.560g,1.472mmol)添加到4-N-Boc-哌嗪乙酸(0.300g,1.223mmol)在无水DMF(7mL)中的溶液里并搅拌3分钟。将H-Tyr(bzl)-OMe·HCl添加到混合物里,搅拌18h并在减压下浓缩。将所得残留物溶解在EtOAc中,并用饱和NH4OH(2×20mL)和饱和NaHCO3(2×20mL)洗涤。使用EtOAc/己烷(1:1-100:0)作为洗脱液,通过快速柱色谱法纯化,得到SR1-090,为白色泡沫状物(0.569g,91%)。HPLC:>98%[tR=9.6分钟,60%MeOH,40%水(含0.1%TFA),20分钟]。1HNMR(400MHz,DMSO-d6)δ7.90(d,J=8.1Hz,1H),7.47–7.28(m,5H),7.11(d,J=8.6Hz,2H),6.96–6.89(m,2H),5.06(s,2H),4.54(td,J=8.7,5.2Hz,1H),3.64(s,3H),3.24(m,4H),3.03(dd,J=13.9,5.2Hz,1H),2.96(m,1H),2.91(m,1H),2.83(d,J=15.5Hz,1H),2.30–2.11(m,4H)。HRMS(ESI+):m/z C28H37N3O6(M+H)+512.2748;m/z C28H37N3O6Na(M+Na)+534.2568。HPLC–MS(ESI+):m/z 512.4[100%,(M+H)+]。
(S)-2-(2-(4-(乙酰基-L-脯氨酰基)哌嗪-1-基)乙酰胺基)-3-(4-(苄氧基)苯基)-丙酸甲酯(SR1-100)。在室温下将HCl溶液(4mL,在二噁烷中4N)滴加到SR1-090(0.350g,0.684mmol)里并搅拌3h。将所得残留物溶解在无水DMF(2mL)中,并添加到DIEA(0.357mL,2.052mmol)、HATU(0.312g,0.821mmol)和Fmoc-Pro-OH(0.278g,0.821mmol)在DMF(5mL)中的混合物里。搅拌16h后,将反应混合物在减压下蒸发。将所得残留物溶解在EtOAc中,并用饱和NH4OH(2×25mL)和饱和NaHCO3(2×25mL)洗涤。使用MeOH/DCM(0%-10%)作为洗脱液,通过快速柱色谱法纯化,得到SR1-094(Fmoc-Pro-哌嗪乙酸Tyr(bzl)-OMe),为白色泡沫状物(0.452g,91%)。HPLC:>92%[tR=6.4分钟,50%MeOH,50%水(含0.1%TFA),20分钟]。1H NMR(400MHz,DMSO-d6)δ7.93(dd,J=8.1,5.2Hz,1H),7.88(m,2H),7.65(dd,J=10.2,7.3Hz,1H),7.56(J=13.8,7.5Hz,1H),7.44–7.23(m,9H),7.10(m,2H),6.90(m,2H),5.03(s,1H),4.99(s,1H),4.67–4.56(m,1H),4.52(m,1H),4.30–4.06(m,3H),3.62(s,3H),3.50–3.34(m,4H),3.01(m,1H),2.92(m,2H),2.81(m,1H),2.31(m,2H),2.26–2.02(m,4H),1.76(m,4H)。HRMS(ESI+):m/z C43H47N4O7(M+H)+731.5639。HPLC–MS(ESI+):m/z 731.4[100%,(M+H)+]。
在室温下将二乙胺(0.269mL,2.600mmol)添加到SR1-094(380g,0.519mmol)在THF(5mL)中的混合物里。搅拌反应4h并将溶剂蒸发。将所得胶状物溶解在DCM(5mL)中,并添加吡啶(0.210mL,2.595mmol)和乙酸酐(0.245mL,2.595)。将混合物在室温下搅拌16h并蒸发。使用MeOH/DCM(5%-10%)作为洗脱液,通过快速柱色谱法纯化,得到SR1-100,为白色泡沫状物(0.052g,18%)。(注意:纯化期间粗混合物在柱中部分固化,并且大量的SR1-100是与杂质共洗脱得到的。仅将纯物质带入下一步)。将上述苄醚SR1-100(0.052,0.094mmol)溶解在MeOH(1.5mL)中并用氩气吹扫。添加碳载钯(10%,0.015g,0.15/mmol),并将混合物用H2(气囊)吹扫。搅拌反应20h,通过硅藻土过滤并在减压下浓缩。使用MeOH/DCM(3%-12%)作为洗脱液,通过快速柱色谱法纯化,得到SR1-101,为白色泡沫状物(0.035g,81%)。HPLC:>97%[tR=12.2分钟,在水中10-95%MeOH(含0.1%TFA),20分钟1H NMR(400MHz,DMSO-d6)δ9.25(s,1H),7.89(t,J=7.7Hz,1H),6.97(d,J=8.5Hz,2H),6.65(d,J=8.5Hz,2H),4.88(dd,J=8.6,3.7Hz,0.3H),4.70(dd,J=8.6,3.7Hz,0.7H),4.49(m,1H),3.62(s,3H),3.56–3.34(m,4H),3.26(m,2H),3.00–2.80(m,4H),2.42(m,1H),2.31(m,1H),2.28–2.04(m,4H),1.92(s,2H),1.89–1.60(m,3H)。HRMS(ESI+):m/z C23H33N4O6(M+H)+461.2388;m/zC23H32N4O6Na(M+Na)+483.2205。HPLC–MS(ESI+):m/z 461.2[70%,(M+H)+]。
(S)-4-(2-((1-甲氧基-1-氧代-3-苯基丙烷-2-基)氨基)-2-氧代乙基)哌嗪-1-羧酸叔丁酯(SR1-089)。按照与SR1-090报道相同的方法由H-Phe-OMe(0.300g,1.228mmol)制备SR1-089(0.463g,93%)。HPLC:>99%[tR=4.3分钟,55%MeOH,45%水(含0.1%TFA),20分钟]。1H NMR(400MHz,DMSO-d6)δ7.94(d,J=8.3Hz,1H),7.26(m,2H),7.19(m,3H),4.59(ddd,J=9.4,8.2,5.2Hz,1H),3.63(s,3H),3.27–3.14(m,4H),3.09(dd,J=13.8,5.1Hz,1H),3.01(d,J=9.4Hz,1H),2.99–2.75(m,2H),2.26–2.09(m,4H),1.37(s,9H)。HRMS(ESI+):m/z C21H31N3O5(M+H)+406.2326;m/z C21H31N3O5Na(M+Na)+428.2147。HPLC–MS(ESI+):m/z406.2[100%,(M+H)+]。
通过制备SR1-094所用的方法由SR1-089(0.300g,0.740mmol)得到SR1-093(Fmoc-Pro-哌嗪乙酸-Phe-OMe),为白色泡沫状物(0.441g,96%)。HPLC:87%&13%(两种非对映体)[tR=6.4分钟和5.2分钟,70%MeOH,30%水(含0.1%TFA),20分钟]。1H NMR(400MHz,DMSO-d6)δ7.98(t,J=8.7Hz,1H),7.88(m,3H),7.65(m,2H),7.58(m,1H),7.40(m,3H),7.35–7.15(m,4H),4.61(m,2H),4.31–4.01(m,3H),3.63(s,3H),3.50–3.37(m,4H),3.30–3.14(m,2H),3.08(m,1H),3.01(m,1H),2.92(m,1H),2.86–2.70(m,1H),2.32(m,1H),2.17(m,3H),1.78(m,4H)。HRMS(ESI+):m/z C36H40N4O6(M+H)+625.3008;m/z C36H40N4O6Na(M+Na)+647.2829。HPLC–MS(ESI+):m/z 625.3[100%,(M+H)+]。
(2-(4-(乙酰基-L-脯氨酰基)哌嗪-1-基)乙酰基)-L-苯丙氨酸甲酯(SR1-099)。按照与SR1-100报道相同的方法由SR1-093(0.410g,0.656mmol)制备酰胺SR1-099(0.078g,27%)。HPLC:>98%[tR=13.9分钟,在水中10-95%MeOH(含0.1%TFA),20分钟]。1H NMR(400MHz,DMSO-d6)δ8.01(dd,J=8.2,6.6Hz,1H),7.29(m,2H),7.21(m,3H),4.89(dd,J=8.6,2.8Hz,0.3H),4.72(dd,J=8.6,3.7Hz,0.7H),4.61(m,1H),3.65(s,3H),3.57–3.35(m,4H),3.28(m,2H),3.11(dd,J=13.8,5.1Hz,1H),3.03(dd,J=9.9,3.6Hz,1H),2.963(m,1H),2.85(m,1H),2.44(m,1H),2.32(m,1H),2.26–2.06(m,3H),1.94(s,2H),1.88(m,1H),1.79(m,1H),1.73(s,1H),1.73(m,1H)。HRMS(ESI+):m/z C23H32N4O5(M+H)+445.2440;m/zC23H32N4O5Na(M+Na)+467.2259。HPLC–MS(ESI+):m/z 445.4[100%,(M+H)+]。
可由哌啶SR1-109(通过Boc衍生物SR1-083的脱保护制备)来制备一组PPPY模拟物。如上图所示,通过用一系列酰基和烷基卤化物进行烷基化或酰化来制备一组PPPY模拟物。如下面的实施例中所示,甲酯基团可被进一步转化成酰胺或水解为其相应的羧酸。
(S)-3-(4-(苄氧基)苯基)-2-(2-(哌啶-4-基)乙酰胺基)丙酸甲酯盐酸盐(SR1-085)。在室温下将HCl溶液(3mL,在二噁烷中4N)缓慢添加到SR1-083(0.300g,0.587mmol)中并搅拌2h。将混合物在减压下浓缩,得到SR2-085(0.262g,99%),为白色固体。HPLC:>99%[tR=4.7分钟,60%MeOH,40%水(含0.1%TFA),20分钟]。1H NMR(400MHz,DMSO-d6)δ8.68(s,1H),8.46(s,1H),8.35(d,J=8.7Hz,1H),7.45–7.34(m,4H),7.32(m,1H),7.11(d,J=8.7Hz,2H),6.90(d,J=8.7Hz,2H),5.04(s,2H),4.43(ddd,J=10.1,8.0,5.2Hz,1H),3.58(s,3H),3.21–3.05(m,2H),2.96(dd,J=13.8,5.2Hz,1H),2.76(m,3H),2.00(m,2H),1.80(m,1H),1.62(m,1H),1.43(m,1H),1.32–1.09(m,2H)。HRMS(ESI+):m/z C24H30N2O4(M+H)+411.2270;m/z C24H30N2O4Na(M+Na)+433.2089。HPLC–MS(ESI+):m/z 411.3[100%,(M+H)+]。
一般方法A:SR1-083的N-末端变体的合成。
在氩气下将胺盐SR1-085(0.055mmol)溶解在DCM(1.5mL)中并添加DIEA/NEt3或吡啶(0.167mmol)。向此混合物中添加相应的烷基卤化物或取代的羰基卤化物(0.067mmol),在室温下搅拌14-20h并在减压下浓缩。将所得残留物通过柱色谱法直接纯化。
(S)-2-(2-(1-乙酰基哌啶-4-基)乙酰胺基)-3-(4-(苄氧基)苯基)丙酸甲酯(SR1-116)。采用方法A,由SR1-085(0.025g,0.056mmol)、乙酰氯(8μL,0.084mmol)和吡啶(13.5μL,0.167mmol)制备N-乙酰基衍生物SR1-116(0.025g,98%)。HPLC:>99%[tR=10.24分钟,60%MeOH,40%水(含0.1%TFA),20分钟]。1H NMR(400MHz,DMSO-d6)δ8.25(d,J=8.0Hz,1H),7.42(m,2H),7.36(m,2H),7.31(m,1H),7.11(d,J=8.2Hz,2H),6.90(m,2H),5.04(s,2H),4.43(m,1H),4.22(m,1H),3.65(m,1H),3.58(s,3H),2.96(dd,J=13.8,5.2Hz,1H),2.86(m,1H),2.75(dd,J=13.4,10.6Hz 1H),2.36(m,1H),1.93(m,5H),1.71(m,1H),1.47(m,1H),1.28(m,1H),1.04–0.63(m,2H)。HRMS(ESI+):m/z C26H32N2O4(M+H)+453.2395;m/zC26H32N2O4Na(M+Na)+475.2203。HPLC–MS(ESI+):m/z 453.3[100%,(M+H)+],475.3[40%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-2-(2-(1-苄基哌啶-4-基)乙酰胺基)丙酸甲酯(SR1-117)。采用一般方法A,由SR1-085(0.025g,0.056mmol)、苄基氯(8μL,0.067mmol)和三乙胺(23μL,0.167mmol)制备N-苄基衍生物SR1-117(0.026g,93%)。HPLC:>95%[tR=7.79分钟,60%MeOH,40%水(含0.1%TFA),20分钟]。1H NMR(400MHz,CDCl3-d)δ7.57(bs,1H),7.49–7.28(m,10H),7.01(d,J=8.6Hz,1H),6.89(d,J=8.7Hz,1H),6.12(s,0.7H),5.92(s,0.3H),5.03(s,2H),4.85(dt,J=8.0,6.0Hz,0.2H),4.78(td,J=7.4,5.5Hz,0.8H),4.28(bs,0.4H),4.06(bs,1.6H),3.69(s,1H),3.36(m,1H),3.06(dd,J=14.1,5.5Hz,1H),2.96(dd,J=14.2,7.1Hz,1H),2.56(m,1H),2.24–2.07(m,2H),2.07–1.89(m,3H),1.78(m,2H),1.65(m,1H)。HRMS(ESI+):m/z C31H36N2O4(M+H)+501.2740;m/zC31H36N2O4Na(M+Na)+523.2559。HPLC–MS(ESI+):m/z 501.3[95%,(M+H)+]。
(S)-2-(2-(1-苯甲酰基哌啶-4-基)乙酰胺基)-3-(4-(苄氧基)苯基)丙酸甲酯(SR1-118)。采用一般方法A,由SR1-085(0.025g,0.056mmol)、苯甲酰氯(8μL,0.067mmol)和三乙胺(23μL,0.167mmol)制备N-苯甲酰基衍生物SR1-118(0.028g,97%)。HPLC:>95%[tR=6.5分钟,70%MeOH,30%水(含0.1%TFA),20分钟]。1H NMR(400MHz,DMSO-d6)δ8.25(d,J=8.0Hz,1H),7.54–7.25(m,10H),7.10(d,J=8.7Hz,2H),6.86(bs,2H),4.98(bs,2H),4.44(ddd,J=10.3,8.0,5.1Hz,1H),4.34(bs,1H),3.58(s,3H),3.42(m,1H),3.06–2.83(m,2H),2.82–2.54(m,2H),1.98(m,2H),1.77(m,1H),1.67–1.16(m,2H),1.07–0.86(m,2H)。RMS(ESI+):m/z C31H34N2O5(M+H)+515.2544;m/z C31H34N2O5Na(M+Na)+537.2353。HPLC–MS(ESI+):m/z515.3[95%,(M+H)+],537.3[30%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-2-(2-(1-(3-苯基丙酰基)哌啶-4-基)乙酰胺基)丙酸甲酯(SR1-119)。采用一般方法A,由SR1-085(0.025g,0.056mmol)、3-苯基丙酰氯(10μL,0.067mmol)和三乙胺(23μL,0.167mmol)制备N-苯基丙酰基衍生物SR1-119(0.028g,92%)。HPLC:>98%[tR=10.8分钟,70%MeOH,30%水(含0.1%TFA),20分钟]。1H NMR(400MHz,CDCl3-d)δ7.44–7.35(m,4H),7.35–7.25(m,3H),7.25–7.15(m,3H),7.00(d,J=8.7Hz,2H),6.89(d,J=8.7Hz,2H),5.94(d,J=7.9Hz,1H),5.03(s,2H),4.90–4.78(m,1H),3.73(s,3H),3.09(dd,J=14.1,5.7Hz,1H),3.03–2.88(m,5H),2.83–2.47(m,4H),2.04(d,J=6.9Hz,2H),2.02–1.92(m,1H),1.64(dd,J=26.6,13.2Hz,2H),0.94(bs,2H)。HRMS(ESI+):m/z C33H39N2O5(M+H)+543.2841;m/z C33H38N2O5Na(M+Na)+565.2659。HPLC–MS(ESI+):m/z543.3[100%,(M+H)+],565.4[50%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-2-(2-(1-(3-甲基丁酰基)哌啶-4-基)乙酰胺基)-丙酸甲酯(SR1-121)。采用一般方法A,由SR1-085(0.025g,0.056mmol)、异戊酰氯(11μL,0.087mmol)和三乙胺(23μL,0.167mmol)制备N-甲基丁酰基衍生物SR1-121(0.032g,96%)。HPLC:>99%[tR=8.0分钟,70%MeOH,30%水(含0.1%TFA),20分钟]。1H NMR(400MHz,CDCl3-d)δ7.46–7.30(m,5H),7.00(d,J=8.6Hz,2H),6.89(d,J=8.6Hz,2H),5.88(d,J=8.0Hz,1H),5.03(s,2H),4.86(dt,J=8.0,5.9Hz,1H),4.70–4.0(m,2H),3.73(s,3H),3.09(dd,J=14.1,5.7Hz,1H),3.01(dd,J=14.1,6.2Hz,1H),2.90–2.62(m,2H),2.21(d,J=7.0Hz,2H),2.17–1.95(m,4H),1.77–1.62(m,2H),1.15–1.00(m,1.5H),0.99–0.92(m,6.5H)。HRMS(ESI+):m/z C29H39N2O5(M+H)+495.2846;m/z C29H38N2O5Na(M+Na)+517.2655。HPLC–MS(ESI+):m/z 495.3[100%,(M+H)+],517.3[30%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-2-(2-(1-(2-苯乙酰基)哌啶-4-基)乙酰胺基)-丙酸甲酯(SR1-122)。采用一般方法A,由SR1-085(0.032g,0.072mmol)、苯乙酰氯(12μL,0.093mmol)和三乙胺(30μL,0.215mmol)制备N-苯乙酰基衍生物SR1-122(0.033g,87%)。HPLC:>98%[tR=7.9分钟,70%MeOH,30%水(含0.1%TFA),20分钟]。1H NMR(400MHz,DMSO-d6)δ8.22(d,J=8.0Hz,1H),7.44–7.23(m,7H),7.24–7.14(m,3H),7.10(d,J=8.2Hz,2H),6.88(d,J=8.5Hz,2H),5.03(s,2H),4.43(m,1H),4.26(m,1H),3.91–3.72(m,1H),3.64(s,2H),3.58(s,3H),2.94(dd,J=13.9,5.0Hz,1H),2.92–2.80(m,1H),2.74(dd,J=13.8,10.1Hz,1H),2.44–2.31(m,1H),1.91(d,J=7.2Hz,2H),1.78–1.64(m,1H),1.51–1.37(m,1H),1.32–1.20(m,1H),0.91–0.61(m,2H)。HRMS(ESI+):m/z C32H36N2O5(M+H)+529.2687;m/zC32H36N2O5Na(M+Na)+551.2508。HPLC–MS(ESI+):m/z 529.3[80%,(M+H)+],551.3[100%,(M+Na)+]。
(S)-2-(2-(1-丙烯酰基哌啶-4-基)乙酰胺基)-3-(4-(苄氧基)苯基)丙酸甲酯(SR1-123)。采用一般方法A,由SR1-085(0.030g,0.067mmol)、丙烯酰氯(7uL,0.087mmol)和三乙胺(28μL,0.201mmol)制备N-丙烯酰基衍生物SR1-123(0.030g,96%)。HPLC:>99%[tR=4.6分钟,70%MeOH,30%水(含0.1%TFA),20分钟]。1H NMR(400MHz,氯仿-d)δ7.46–7.29(m,5H),7.00(d,J=8.5Hz,2H),6.93–6.86(m,2H),6.55(dd,J=17.0,10.6Hz,1H),6.25(dd,J=16.8,1.9Hz,1H),5.86(d,J=7.9Hz,1H),5.66(dd,J=10.6,1.9Hz,1H),5.03(s,2H),4.86(m,1H),4.49–4.02(m,2H),3.74(s,3H),3.10(dd,J=14.1,5.7Hz,1H),3.06–2.96(m,1H),2.93–2.54(m,2H),2.14–1.96(m,2H),1.89(m,1H),1.78–1.61(m,2H),1.19–1.01(m,2H)。HRMS(ESI+):m/z C27H32N2O5(M+H)+465.2376;m/z C27H32N2O5Na(M+Na)+487.2192。HPLC–MS(ESI+):m/z 465.3[50%,(M+H)+],487.3[100%,(M+Na)+]。
(S)-4-(2-((3-(4-(苄氧基)苯基)-1-甲氧基-1-氧代丙烷-2-基)氨基)-2-氧代乙基)哌啶-1-羧酸苄酯(SR1-130)。采用一般方法A,由SR1-085(0.030g,0.067mmol)、氯甲酸苄酯(13μL,0.087mmol)和三乙胺(28μL,0.201mmol)制备氨基甲酸N-苄酯衍生物SR1-130(0.024g,66%)。HPLC:>99%[tR=4.4分钟,80%MeOH,20%水(含0.1%TFA),20分钟]。1HNMR(400MHz,CDCl3-d)δ7.46–7.29(m,10H),6.99(d,J=8.7Hz,2H),6.89(d,J=8.7Hz,2H),5.83(d,J=8.3Hz,1H),5.11(s,2H),5.02(s,2H),4.86(m,1H),4.15(m,2H),3.73(s,3H),3.09(dd,J=13.7,5.6Hz,1H),3.01(dd,J=14.2,6.1Hz,1H),2.75(m,2H),2.08(dd,J=6.9,1.8Hz,2H),1.94(m,1H),1.62(m,2H),1.11(m,2H)。HRMS(ESI+):m/z C32H36N2O6(M+H)+545.2645;m/z C32H36N2O6Na(M+Na)+567.2462。HPLC–MS(ESI+):m/z 545.4[60%,(M+H)+],567.3[100%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-2-(2-(1-甲基哌啶-4-基)乙酰胺基)丙酸甲酯(SR1-110)。采用一般方法A,由SR1-085(0.030g,0.067mmol)、甲基碘(2.5当量,10μL)和K2CO3(5当量,0.046g)及作为溶剂的DMF(1.2mL)制备N-甲基衍生物SR1-110(0.014g,49%,与N,N’-二甲基化副产物分离)。HPLC:>97%[tR=11.3分钟,50% MeOH,50%水(含0.1%TFA),20分钟]。1H NMR(400MHz,DMSO-d6)δ8.35(d,J=7.9Hz,1H),7.45–7.28(m,5H),7.11(d,J=8.6Hz,2H),6.90(d,J=8.7Hz,2H),5.04(s,3H),4.43(ddd,J=9.9,7.9,5.2Hz,1H),3.58(s,3H),3.34–3.20(m,2H),2.96(dd,J=13.8,5.2Hz,1H),2.86–2.73(m,3H),2.66(s,3H),1.99(dd,J=7.2,2.3Hz,2H),1.74(m,1H),1.66(m,1H),1.50(m,2H),1.40–1.15(m,2H)。HRMS(ESI+):m/z C25H32N2O4(M+H)+425.2423;m/z C25H32N2O4Na(M+Na)+447.2240。HPLC–MS(ESI+):m/z 425.3[100%,(M+H)+]。
SR1-083的C-末端变体的合成。
(S)-4-(2-((1-氨基-3-(4-(苄氧基)苯基)-1-氧代丙烷-2-基)氨基)-2-氧代乙基)哌啶-1-羧酸叔丁酯(SR1-136)。在室温下将氨(1.25mL,30%水溶液)与MeOH(1.25mL)预混合并添加到SR1-083(0.050g,0.098mmol)中。将混合物搅拌4h,并在减压下除去溶剂。使用MeOH/DCM(3:97-1:9)作为洗脱液,通过快速柱色谱法纯化,得到SR1-136,为白色固体(0.033g,68%)。HPLC:>99%[tR=7.4分钟,70% MeOH,30%水(含0.1%TFA),20分钟]。1HNMR(400MHz,DMSO-d6)δ7.93(d,J=8.7Hz,1H),7.50–7.25(m,5H),7.13(d,J=8.6Hz,2H),7.01(m,1H),6.88(d,J=8.7Hz,2H),5.02(s,2H),4.42(ddd,J=10.6,8.7,4.3Hz,1H),3.78(m,2H),2.93(dd,J=13.8,4.3Hz,1H),2.61(dd,J=13.8,10.5Hz,1H),2.5(m,2H),1.97–1.84(m,2H),1.70–1.49(m,1H),1.36(s,9H),1.24–1.05(m,1H),0.93–0.65(m,2H)。HRMS(ESI+):m/z C28H37N3O5Na(M+Na)+518.2611;m/z C28H37N3O5K(M+K)+534.2358。HPLC–MS(ESI+):m/z 518.3[70%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-2-(2-(1-(叔丁氧羰基)哌啶-4-基)乙酰胺基)-丙酸(SR1-152)。将甲酯SR1-083(0.025g,0.049mmol)溶解在MeOH(1mL)中,并将氢氧化钠(0.50mL 2N水溶液,20当量)添加到混合物里。搅拌反应1.5h并在减压下浓缩。将所得水层用水(3mL)稀释,并用Et2O(2×15mL)洗涤。将水层用1N HCl酸化(至pH~3.0),然后用EtOAc(2×20mL)萃取。将合并的有机层干燥(Na2SO4)并蒸发,得到SR1-152,为白色半固体(0.024g,98%)。HPLC:>99%[tR=9.5分钟,70%MeOH,30%水(含0.1%TFA),20分钟]。1HNMR(400MHz,DMSO-d6)δ12.62(bs,1H),8.08(d,J=8.3Hz,1H),7.47–7.23(m,5H),7.11(d,J=8.6Hz,2H),6.88(d,J=8.6Hz,2H),5.02(s,3H),4.38(ddd,J=10.3,8.2,4.6Hz,1H),3.78(m,3H),2.98(dd,J=13.9,4.6Hz,1H),2.70(dd,J=13.8,10.4Hz,1H),2.67–2.49(m,2H),1.92(d,J=7.2Hz,2H),1.62(d,J=3.6Hz,1H),1.42(m,1H),1.34(s,9H),1.21(m,1H),0.94–0.70(m,2H)。HRMS(ESI+):m/z C28H36N2O6(M)+496.2581;m/z C28H36N2O6Na(M+Na)+519.2444。HPLC–MS(ESI+):m/z 519.3[50%,(M+Na)+],m/z 441.2[100%,(M-t-Bu+1)]+。
(S)-4-(2-((3-(4-羟苯基)-1-甲氧基-1-氧代丙烷-2-基)氨基)-2-氧代乙基)哌啶-1-羧酸叔丁酯(SR1-153)。将苄醚SR1-083(0.030g,0.059mmol)溶解在MeOH(1.5mL)中并用氩气吹扫。将碳载钯(10%,0.009g,0.15g/mmol)添加到混合物里,用H2(气囊)吹扫,并在室温下搅拌2h。将悬浮液通过硅藻土过滤,并用MeOH/DCM冲洗滤床。将滤液在减压下蒸发,得到SR1-153(0.025g,定量收率),为白色泡沫状物。HPLC:>98%[tR=5.0分钟,60%MeOH,40%水(含0.1% TFA),20分钟]。1H NMR(400MHz,氯仿-d)δ6.93(d,J=8.5Hz,2H),6.75(d,J=8.5Hz,2H),5.98(d,J=8.1Hz,1H),4.91–4.81(m,1H),4.00(m,2H),3.73(d,J=1.9Hz,3H),3.11(dd,J=14.1,5.4Hz,1H),2.91(dd,J=14.1,7.3Hz,1H),2.62(m,2H),2.15–1.96(m,2H),1.84(m,1H),1.61–1.48(m,1H),1.45-143(m,1H,overlap with t-Bu),1.44(d,J=2.0Hz,9H),0.99(s,2H)。HRMS(ESI+):m/z C22H32N2O6Na(M+Na)+443.2143;m/z C22H32N2O6K(M+K)+459.1878。HPLC–MS(ESI+):m/z 443.3[90%,(M+Na)+],m/z 365.2[100%,(M-t-Bu+1)]+。
一般方法B:SR1-083的C-末端酰胺变体的合成。
将甲酯SR1-083(0.050-0.100g,0.098-0.196mmol)置于密封的微波小瓶(大小为2.5mL)中,并将其溶于选定的烷基胺(1.0mL)。将混合物在90-100℃下加热20-36h并使之冷却到室温。将混合物在减压下蒸发,并将所得残留物溶解在EtOAc(25mL)中。将有机层用1NHCl(3×15mL)洗涤并蒸发。使用MeOH/DCM(0:100-10:100)或EtOAc/己烷(4:6-100:0)作为洗脱液,通过快速柱色谱法纯化,得到以下C-末端酰胺化的产物。
(S)-4-(2-((1-(苄氨基)-3-(4-(苄氧基)苯基)-1-氧代丙烷-2-基)氨基)-2-氧代乙基)哌啶-1-羧酸叔丁酯(SR1-160)。根据使用苄胺的一般方法B,由SR1-083(0.050g,0.097mmol)得到SR1-160,为白色泡沫状物(0.046g,80%)。HPLC:>99%[tR=5.4分钟,80%MeOH,20%水(含0.1%TFA),20分钟]。11H NMR(400MHz,DMSO-d6)δ8.48(t,J=6.0Hz,1H),8.08(d,J=8.6Hz,1H),,7.47–7.41(m,2H),7.38(ddd,J=7.9,6.9,1.1Hz,2H),7.35–7.30(m,1H),7.29(d,J=1.6Hz,1H),7.27(t,J=1.1Hz,1H),7.26–7.19(m,1H),7.19–7.12(m,4H),6.89(d,J=8.7Hz,1H),5.04(s,2H),4.54(ddd,J=10.0,8.6,4.9Hz,1H),4.27(d,J=5.9Hz,2H),3.79(m,2H),2.95(dd,J=13.5,4.9Hz,1H),2.68(dd,J=13.6,10.3Hz,1H),2.60–2.52(m,2H),2.02–1.87(m,2H),1.62(m,1H),1.39(m,1H),1.37(s,9H),1.29–1.12(m,1H),0.97–0.71(m,2H)。HRMS(ESI+):m/z C35H44N3O5(M+H)+586.3266;m/z C35H43N3O5Na(M+Na)+608.3084。HPLC–MS(ESI+):m/z 608.2[50%,(M+Na)+]。
(S)-4-(2-((3-(4-(苄氧基)苯基)-1-(异丙基氨基)-1-氧代丙烷-2-基)氨基)-2-氧代乙基)哌啶-1-羧酸叔丁酯(SR1-167)。根据使用异丙胺的一般方法B,由SR1-083(0.100g,0.195mmol)得到SR1-167,为泡沫状物(0.053g,50%),并且回收起始物质(0.036g,36%)。HPLC:>99%[tR=4.5分钟,80%MeOH,20%水(含0.1%TFA),20分钟]。1HNMR(400MHz,氯仿-d)δ7.45–7.27(m,5H),7.12(d,J=8.6Hz,2H),6.89(d,J=8.6Hz,2H),6.52(bs,1H),5.59(bs,1H),5.03(s,2H),4.51(m,1H),4.05(m,2H),3.93(m,1H),3.02(ddd,J=13.7,6.3,1.6Hz,1H),2.87(dd,J=13.6,8.5Hz,1H),2.66(m,2H),2.16–2.05(m,2H),1.96–1.85(m,1H),1.66–1.52(m,2H),1.44(s,9H),1.16–1.08(m,1H),1.05(s,1H),1.03(s,1H),0.95(s,1H),0.93(s,1H)。HRMS(ESI+):m/z C31H44N3O5(M+H)+538.3275;m/zC31H43N3O5Na(M+Na)+560.3093。HPLC–MS(ESI+):m/z 457.4[40%(M+H)+],m/z 560.4[80%,(M+Na)+]。
(S)-4-(2-((3-(4-(苄氧基)苯基)-1-(环丙基氨基)-1-氧代丙烷-2-基)氨基)-2-氧代乙基)哌啶-1-羧酸叔丁酯(SR1-168)。根据使用环丙胺连同作为共溶剂的DMF(1mL)的一般方法B,由SR1-083(0.100g,0.195mmol)得到SR1-168,为泡沫状物(0.052g,50%),并且回收起始物质(0.014g,14%)。HPLC:>99%[tR=11.2分钟,70%MeOH,30%水(含0.1%TFA),20分钟]。1H NMR(400MHz,DMSO-d6)δ8.03(d,J=4.2Hz,1H),7.99(d,J=8.7Hz,1H),7.47–7.27(m,5H),7.11(d,J=8.7Hz,2H),6.88(d,J=8.7Hz,2H),5.03(s,2H),4.39(m,1H),3.79(m,2H),2.83(dd,J=13.6,5.0Hz,1H),2.71–2.51(m,4H),1.92(m,2H),1.61(m,1H),1.45–1.37(m,1H),1.36(s,9H),1.29–1.12(m,1H),0.84(m,2H),0.66–0.53(m,2H),0.44–0.25(m,2H)。HRMS(ESI+):m/z C31H42N3O5(M+H)+536.3112;m/z C31H41N3O5Na(M+Na)+558.2939。HPLC–MS(ESI+):m/z 536.4[100%(M+H)+],m/z 558.4[80%,(M+Na)+]。
(S)-4-(2-((3-(4-(苄氧基)苯基)-1-((环丙基甲基)氨基)-1-氧代丙烷-2-基)氨基)-2-氧代乙基)哌啶-1-羧酸叔丁酯(SR1-172)。根据使用环丙烷甲胺的一般方法B,由SR1-083(0.075g,0.147mmol)得到SR1-172,为泡沫状物(0.068g,84%)。HPLC:>95%[tR=7.9分钟,75%MeOH,25%水(含0.1%TFA),20分钟]。1H NMR(400MHz,DMSO-d6)δ8.11–7.93(m,2H),7.47–7.27(m,5H),7.14(d,J=8.6Hz,2H),6.89(d,J=8.7Hz,2H),5.04(s,2H),4.48(ddd,J=10.2,8.9,4.7Hz,1H),3.90–3.69(m,2H),2.99–2.85(m,3H),2.69–2.52(m,3H),2.03–1.84(m,2H),1.62(m,1H),1.37–1.50(m,1H),1.37(s,9H),1.19(m,2H),0.98–0.80(m,1H),0.78(m,0.5H),0.67–0.57(m,0.5H),0.44–0.33(m,2H),0.20–0.08(m,2H)。HRMS(ESI+):m/z C32H44N3O5(M+H)+550.3283;m/z C32H43N3O5Na(M+Na)+572.3108。HPLC–MS(ESI+):m/z 550.4[40%(M+H)+],m/z 495.2[60%,(M-t-Bu+1)+]。
(S)-4-(2-((3-(4-(苄氧基)苯基)-1-(环戊基氨基)-1-氧代丙烷-2-基)氨基)-2-氧代乙基)哌啶-1-羧酸叔丁酯(SR1-174)。根据使用环戊胺的一般方法B,由SR1-083(0.075g,0.147mmol)得到SR1-174,为泡沫状物(0.067g,81%)。HPLC:>99%[tR=5.8分钟,80%MeOH,20%水(含0.1%TFA),20分钟]。1H NMR(400MHz,DMSO-d6)δ7.96(d,J=8.7Hz,1H),7.87(d,J=7.3Hz,1H),7.46–7.41(m,2H),7.41–7.35(m,2H),7.34–7.29(m,1H),7.13(d,J=8.6Hz,2H),6.88(d,J=8.7Hz,2H),5.03(s,2H),4.46(td,J=9.4,5.0Hz,1H),3.94(m,1H),3.80(m,2H),2.82(dd,J=13.7,5.1Hz,1H),2.68–2.53(m,3H),2.01–1.86(m,2H),1.83–1.66(m,2H),1.66–1.43(m,5H),1.42–1.35(m,2H),1.36(s,9H),1.30–1.11(m,2H),0.95–0.70(m,2H)。HRMS(ESI+):m/z C33H46N3O5(M+H)+564.3432;m/z C33H45N3O5Na(M+Na)+586.3248。HPLC–MS(ESI+):m/z 564.4[90%(M+H)+],m/z 586.4[100%,(M+Na)+]。
(S)-4-(2-((3-(4-(苄氧基)苯基)-1-(甲氨基)-1-氧代丙烷-2-基)氨基)-2-氧代乙基)哌啶-1-羧酸叔丁酯(SR1-177)。根据使用40%甲胺水溶液的一般方法B,由SR1-083(0.040g,0.073mmol)得到SR1-177,为白色泡沫状物(0.032g,80%)。HPLC:>99%[tR=9.1分钟,70%MeOH,30%水(含0.1%TFA),20分钟]。1H NMR(400MHz,DMSO-d6)δ7.99(d,J=8.7Hz,1H),7.88(d,J=4.7Hz,1H),7.45–7.39(m,2H),7.36(m,2H),7.33–7.28(m,1H),7.11(d,J=8.6Hz,2H),6.87(d,J=8.7Hz,2H),5.02(s,2H),4.46–4.35(m,1H),3.77(m,2H),2.89(dd,J=13.7,4.5Hz,1H),2.68–2.58(m,1H),2.55(d,J=4.5Hz,3H),2.55–2.45(m,2H),1.98–1.86(m,2H),1.67–1.50(m,1H),1.4.0-1.34(m,1H),1.35(s,9H),1.19–1.02(m,1H),0.79(m,2H)。HRMS(ESI+):m/z C29H40N3O5(M+H)+510.2945;m/z C29H39N3O5Na(M+Na)+532.2771。HPLC–MS(ESI+):m/z 510.4[100%(M+H)+],m/z 532.4[50%,(M+Na)+]。
(S)-4-(2-((3-(4-(苄氧基)苯基)-1-(环丁基氨基)-1-氧代丙烷-2-基)氨基)-2-氧代乙基)哌啶-1-羧酸叔丁酯(SR1-178)。根据使用环丁胺的一般方法B,由SR1-083(0.040g,0.073mmol)得到SR1-178,为泡沫状物(0.068g,79%)。HPLC:>99%[tR=2.6分钟,75%MeOH,25%水(含0.1%TFA),20分钟]。1H NMR(400MHz,DMSO-d6)δ8.17(d,J=7.8Hz,1H),7.96(d,J=8.7Hz,1H),7.45–7.39(m,2H),7.39–7.33(m,2H),7.33–7.28(m,1H),7.10(d,J=8.7Hz,2H),6.87(d,J=8.7Hz,2H),5.02(s,2H),4.40(ddd,J=10.1,8.6,4.9Hz,1H),4.21–4.05(m,1H),3.87–3.66(m,2H),2.82(dd,J=13.7,4.9Hz,1H),2.65–2.50(m,3H),2.18–2.02(m,2H),1.99–1.68(m,4H),1.58(m,3H),1.44–1.35(m,1H),1.35(s,9H),1.28–1.03(m,1H),0.94–0.68(m,2H)。HRMS(ESI+):m/z C32H44N3O5(M+H)+550.3280;m/zC32H43N3O5Na(M+Na)+572.3104。HPLC–MS(ESI+):m/z 550.4[100%(M+H)+],m/z 572.4[80%,(M+Na)+]。
(S)-4-(2-((3-(4-(苄氧基)苯基)-1-(环己基氨基)-1-氧代丙烷-2-基)氨基)-2-氧代乙基)哌啶-1-羧酸叔丁酯(SR1-181)。根据使用环己胺的一般方法B,由SR1-083(0.050g,0.098mmol)得到SR1-181,为白色泡沫状物(0.051g,93%)。HPLC:>99%[tR=5.6分钟,80%MeOH,20%水(含0.1%TFA),20分钟]。1H NMR(400MHz,DMSO-d6)δ7.96(d,J=8.8Hz,1H),7.79(d,J=7.9Hz,1H),7.43(dt,J=6.1,1.6Hz,2H),7.41–7.35(m,2H),7.35–7.29(m,1H),7.13(d,J=8.7Hz,2H),6.88(d,J=8.7Hz,2H),5.03(s,2H),4.47(td,J=9.3,4.9Hz,1H),3.91–3.68(m,2H),3.54–3.42(m,1H),2.83(dd,J=13.7,4.9Hz,1H),2.69–2.52(m,3H),2.00–1.84(m,2H),1.77–1.48(m,6H),1.37–1.44(m,1H),1.37(d,9H),1.30–0.98(m,6H),0.97–0.71(m,2H)。HRMS(ESI+):m/z C34H48N3O5(M+H)+578.3575;m/z C34H47N3O5Na(M+Na)+600.3393。HPLC–MS(ESI+):m/z 578.5[70%(M+H)+],m/z 600.4[40%,(M+Na)+]。
SR1-119的C末端类似物
SR1-119的C-末端变体的合成。
(S)-3-(4-(苄氧基)苯基)-2-(2-(1-(3-苯基丙酰基)哌啶-4-基)乙酰胺基)丙酸(SR2-022)。将甲酯SR1-119(0.050g,0.092mmol)溶解在MeOH(1mL)中,并将氢氧化钠(1.0mL2N水溶液)添加到混合物中。在室温下搅拌反应1.5h并在减压下浓缩。将所得水层用水(3mL)稀释,并用Et2O(2×15mL)洗涤。将水层用1N HCl酸化(至pH~3.0),然后用EtOAc(2×20mL)萃取。将合并的有机层干燥(Na2SO4)并将溶剂蒸发,得到SR2-022,为白色半固体(0.046g,94%)。HPLC:>98%[tR=6.3分钟,70%MeOH,30%水(含0.1%TFA),20分钟]。1HNMR(400MHz,DMSO-d6)δ12.58(bs,1H),8.08(d,J=8.2Hz,1H),7.48–7.29(m,5H),7.28–7.14(m,5H),7.11(d,J=8.6Hz,2H),6.88(d,J=8.6Hz,2H),5.02(s,2H),4.38(td,J=9.3,8.7,4.1Hz,1H),4.26(m,1H),3.76–3.59(m,1H),2.98(dd,J=13.9,4.6Hz,1H),2.87–2.62(m,5H),2.62–2.51(m,1H),2.45–2.30(m,1H),1.92(d,7.2Hz,2H),1.69(m,1H),1.44(m,1H),1.31–1.19(m,2H),0.92–0.67(m,2H)。HRMS(ESI+):m/z C32H37N2O5(M+H)+529.2690;m/zC32H36N2O5Na(M+Na)+551.2504。HPLC–MS(ESI+):m/z 529.3[40%(M+H)+],m/z 551.3[40%,(M+Na)+],HPLC–MS(ESI-):m/z 527.3[100%(M-H)-]。
(S)-3-(4-(苄氧基)苯基)-2-(2-(1-(3-苯基丙酰基)哌啶-4-基)乙酰胺基)丙酰胺(SR2-021)。在室温下将氨(30%水溶液,1.25mL)与MeOH(1.25mL)预混合并添加到SR1-119(0.050g,0.092mmol)中。将混合物搅拌4h并在减压下除去溶剂。使用MeOH/DCM(3:97-10:90),通过快速柱色谱法纯化残留物,得到SR2-021,为白色固体(0.033g,69%)。HPLC:>99%[tR=6.2分钟,70%MeOH,30%水(含0.1%TFA),20分钟]。1H NMR(400MHz,DMSO-d6)δ7.93(d,J=8.6Hz,1H),7.50–7.28(m,6H),7.22(m,5H),7.12(d,J=8.5Hz,2H),7.01(s,1H),6.87(d,J=8.7Hz,2H),5.04–4.97(m,2H),4.40(td,J=8.6,7.8,3.7Hz,1H),4.24(m,1H),3.67(m,1H),2.92(dd,J=13.8,4.5Hz,1H),2.76(m,3H),2.61(m,1H),2.54(m,2H),2.44–2.29(m,1H),1.90(dd,J=7.3,4.2Hz,2H),1.65(m,1H),1.37(m,1H),1.16(m,1H),0.87–0.61(m,2H)。HRMS(ESI+):m/z C32H38N3O4(M+H)+528.2862;m/z C32H37N3O4Na(M+Na)+550.2681。HPLC–MS(ESI+):m/z 528.3[100%(M+H)+],m/z 550.3[90%,(M+Na)+]。
(2-(1-(3-苯基丙酰基)哌啶-4-基)乙酰基)-L-酪氨酸甲酯(SR2-014)。将苄醚SR2-014(0.020g,0.037mmol)溶解在MeOH(1.5mL)中并用氩气吹扫。将碳载钯(10%,0.005g,0.15g/mmol)添加到混合物中并用H2(气囊)吹扫。在室温下搅拌2h后,将悬浮液通过硅藻土过滤,并用MeOH/DCM冲洗滤床。将滤液在减压下蒸发,得到SR2-014(0.015g,90%),为白色泡沫状物。HPLC:>98%[tR=2.6分钟,70%MeOH,30%水(含0.1%TFA),20分钟]。1H NMR(400MHz,CDCl3-d)δ7.27(m,3H),7.24–7.16(m,3H),6.94(d,J=8.5Hz,2H),6.77(dd,J=8.3Hz,2H),5.84(d,J=8.1Hz,1H),4.91–4.81(m,1H),4.44(m,1H),3.75(m,4H),3.14(dd,J=13.8,5.2Hz,1H),3.02–2.73(m,4H),2.70–2.20(m,3H),2.14–2.02(m,1H),1.94(m,2H),1.65–1.34(m,1H),1.25(d,1H),0.97–0.73(m,2H)。HRMS(ESI+):m/z C26H33N2O5(M+H)+453.2386;m/z C26H32N2O5Na(M+Na)+475,2204。HPLC–MS(ESI+):m/z 453.2[80%(M+H)+],m/z 475.2[100%,(M+Na)+],HPLC–MS(ESI-):m/z 451.2[100%(M-H)-]。
一般方法C:SR1-119的C-末端酰胺变体的合成。
将甲酯SR1-119(0.050-0.100g,0.092-0.184mmol)置于密封的微波小瓶(2.5mL)中,并将其溶于选定的烷基胺(1.0mL)。将混合物在90-100℃下加热20-36h,然后冷却到室温。将混合物在减压下蒸发,并将所得残留物溶解在EtOAc(25mL)中。将有机层用1N HCl(3×15mL)洗涤并蒸发。使用MeOH/DCM(0:100-10:90)或EtOAc/己烷(4:6-100:0)作为洗脱液,通过快速柱色谱法纯化,得到相应的C-末端酰胺化的产物。
(S)-3-(4-(苄氧基)苯基)-N-异丙基-2-(2-(1-(3-苯基丙酰基)哌啶-4-基)乙酰胺基)丙酰胺(SR2-001)。
采用一般方法C,由SR1-119(0.050g,0.092mmol)、异丙胺和作为共溶剂的DMF得到酰胺SR2-001,为泡沫状物(0.039g,74%)。HPLC:>98%[tR=5.1分钟,50%MeOH,50%水(含0.1%TFA),20分钟]。HRMS(ESI+):m/z C35H44N3O4(M+H)+570.3337;m/z C35H43N3O4Na(M+Na)+592.3151。HPLC–MS(ESI+):m/z 570.4[100%(M+H)+],m/z 592.3[100%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-N-环己基-2-(2-(1-(3-苯基丙酰基)哌啶-4-基)乙酰胺基)丙酰胺(SR2-003)。采用一般方法C,由SR1-119(0.050g,0.092mmol)、环己胺得到酰胺SR2-003,为白色泡沫状物(0.048g,83%)。HPLC:>98%[tR=5.8分钟,80%MeOH,20%水(含0.1%TFA),20分钟]。HRMS(ESI+):m/z C38H48N3O4(M+H)+610.3629;m/z C38H47N3O4Na(M+Na)+632.3451。HPLC–MS(ESI+):m/z 632.4[100%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-N-环丙基-2-(2-(1-(3-苯基丙酰基)哌啶-4-基)乙酰胺基)丙酰胺(SR2-015)。采用一般方法C,由SR1-119(0.050g,0.092mmol)、环丙胺和作为共溶剂的DMF得到酰胺SR2-015,为白色泡沫状物(0.034g,65%(分离的))。HPLC:>99%[tR=3.0分钟,20%MeOH,80%水(含0.1%TFA),20分钟]。1H NMR(400MHz,DMSO-d6)δ8.17–7.87(m,7H),7.47–7.28(m,2H),7.27–7.12(m,3H),7.09(d,J=8.1Hz,2H),6.86(d,J=8.7Hz,2H),5.02(s,J=1.8Hz,1H),4.99(s,1H),4.36(td,J=10.4,8.6,3.5Hz,1H),4.24(m,1H),3.68(m,4H),2.91–2.69(m,4H),2.67–2.50(m,1H),2.46–2.29(m,1H),2.01–1.83(m,2H),1.69(m,1H),1.40(m,1H),1.19(m,1H),0.89–0.66(m,1H),0.65–0.55(m,2H),0.47(m,1H),0.38(m,1H),0.35–0.25(m,1H)。HRMS(ESI+):m/z C35H42N3O4(M+H)+568.3171;m/zC35H41N3O4Na(M+Na)+590.2988。HPLC–MS(ESI+):m/z 568.2[80%(M+H)+],m/z 590.4[70%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-N-环丁基-2-(2-(1-(3-苯基丙酰基)哌啶-4-基)乙酰胺基)丙酰胺(SR2-016)。采用一般方法C,由SR1-119(0.050g,0.092mmol)和环丁胺得到酰胺SR2-016,为白色固体(0.044g,82%)。HPLC:>99%[tR=11.5分钟,20%MeOH,70%水(含0.1%TFA),20分钟]。1H NMR(400MHz,DMSO-d6)δ8.18(d,J=7.9Hz,1H),7.98(d,J=8.6Hz,1H),7.48–7.29(m,6H),7.29–7.14(m,4H),7.12(d,J=8.0Hz,2H),6.88(d,J=8.7Hz,2H),5.04(s,1H),5.01(s,1H),4.47–4.35(m,1H),4.25(m,1H),4.15(m,1H),3.69(m,1H),2.88–2.73(m,4H),2.69–2.52(m,3H),2.46–2.29(m,1H),2.11(dtd,J=14.0,7.3,3.2Hz,2H),2.00–1.73(m,4H),1.72–1.51(m,3H),1.40(m,1H),1.30–1.12(m,1H),0.94–0.64(m,2H)。HRMS(ESI+):m/z C36H44N3O4(M+H)+582.3327;m/z C36H43N3O4Na(M+Na)+604.3144。HPLC–MS(ESI+):m/z 582.4[70%(M+H)+],m/z 604.3[80%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-N-环戊基-2-(2-(1-(3-苯基丙酰基)哌啶-4-基)乙酰胺基)丙酰胺(SR2-017)。采用一般方法C,由SR1-119(0.050g,0.092mmol)和环戊胺得到酰胺SR2-017,为白色固体(0.043g,80%)。HPLC:>98%[tR=4.9分钟,80%MeOH,20%水(含0.1%TFA),20分钟]。1H NMR(400MHz,DMSO-d6)δ7.97(d,J=8.6Hz,1H),7.88(m,1H),7.47–7.29(m,5H),7.29–7.14(m,5H),7.12(d,J=7.3Hz,2H),6.88(d,J=8.7Hz,2H),5.04(m,1H),5.01(m,1H),4.45(m,1H),4.26(m,1H),3.93(m,1H),3.77–3.62(m,1H),2.79(m,4H),2.71–2.52(m,3H),2.47–2.31(m,1H),2.01–1.86(m,2H),1.83–1.65(m,2H),1.65–1.32(m,7H),1.25(m,2H),0.78(m,2H)。HRMS(ESI+):m/z C37H46N3O4(M+H)+596.3484;m/zC37H45N3O4Na(M+Na)+618.3302。HPLC–MS(ESI+):m/z 596.4[80%(M+H)+],m/z 618.2[80%,(M+Na)+]。
(S)-N-苄基-3-(4-(苄氧基)苯基)-2-(2-(1-(3-苯基丙酰基)哌啶-4-基)乙酰胺基)丙酰胺(SR2-018)。采用一般方法C,由SR1-119(0.050g,0.092mmol)和苄胺得到酰胺SR2-018,为白色泡沫状物(0.046g,81%)。HPLC:>98%[tR=4.3分钟,70%MeOH,30%水(含0.1%TFA),20分钟]。1H NMR(400MHz,DMSO-d6)δ8.47(t,J=6.0Hz,1H),8.06(d,J=8.5Hz,1H),7.46–7.08(m,17H),6.87(d,J=8.7Hz,2H),5.03(s,1H),5.00(m,1H),4.51(m,1H),4.33–4.17(m,3H),3.67(m,1H),2.93(m,1H),2.85–2.71(m,3H),2.66(dd,J=13.6,10.1Hz,1H),2.61–2.50(m,J=7.8Hz,2H),2.45–2.27(m,1H),2.02–1.83(m,2H),1.74–1.59(m,1H),1.39(m,1H),1.26–1.12(m,1H),0.90–0.62(m,2H)。HRMS(ESI+):m/z C39H44N3O4(M+H)+618.3328;m/z C39H43N3O4Na(M+Na)+640.3146。HPLC–MS(ESI+):m/z 618.2[40%(M+H)+],m/z640.2[100%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-N-(环丙基甲基)-2-(2-(1-(3-苯基丙酰基)哌啶-4-基)乙酰胺基)丙酰胺(SR2-019)。采用一般方法C,由SR1-119(0.050g,0.092mmol)和环丙烷甲胺得到酰胺SR2-019,为白色泡沫状物(0.040g,75%)。HPLC:>99%[tR=9.2分钟,70%MeOH,30%水(含0.1%TFA),20分钟]。1H NMR(400MHz,DMSO-d6)δ8.16–7.96(m,2H),7.47–7.30(m,4H),7.30–7.16(m,6H),7.14(d,J=7.6Hz,2H),6.88(d,J=8.7Hz,2H),5.04(s,1H),5.01(s,1H),4.53–4.41(m,1H),4.25(m,1H),3.76–3.63(m,1H),3.31(m,2H),3.01–2.83(m,3H),2.77(m,2H),2.63(dd,J=13.8,10.3Hz,1H),2.58–2.52(m,1H),2.47–2.29(m,1H),2.02–1.83(m,2H),1.67(m,1H),1.40(m,1H),1.21(m,1H),0.94–0.56(m,3H),0.46–0.34(m,2H),0.22–0.05(m,2H)。HRMS(ESI+):m/z C36H44N3O4(M+H)+582.3317;m/zC36H43N3O4Na(M+Na)+604.3139。HPLC–MS(ESI+):m/z 582.4[90%(M+H)+],m/z 604.48[100%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-N-甲基-2-(2-(1-(3-苯基丙酰基)哌啶-4-基)乙酰胺基)丙酰胺(SR2-020)。采用一般方法C,由SR1-119(0.050g,0.092mmol)和甲胺(在水中40%)得到酰胺SR2-020,为白色固体(0.033g,66%)。HPLC:>99%[tR=6.7分钟,70%MeOH,30%水(含0.1%TFA),20分钟]。1H NMR(400MHz,DMSO-d6)δ8.02(d,J=8.4Hz,1H),7.90(d,J=5.1Hz,1H),7.48–7.27(m,6H),7.27–7.15(m,4H),7.12(d,J=8.1Hz,2H),6.88(d,J=8.7Hz,2H),5.04(s,1H),5.01(s,1H),4.47–4.37(m,1H),4.31–4.21(m,1H),3.68(m,1H),2.90(dd,J=14.2,4.2Hz,1H),2.86–2.71(m,3H),2.62(m,1H),2.57(d,J=4.7Hz,2H,N-甲基的主要旋转异构体),2.59–2.55(m,1H),2.53(d,J=4.7Hz,1H,N-甲基的次要旋转异构体),2.54–2.52(m,1H),2.46–2.30(m,1H),2.00–1.84(m,2H),1.73–1.59(m,1H),1.39(m,1H),1.25–1.10(m,1H),0.92–0.62(m,2H)。HRMS(ESI+):m/z C33H40N3O4(M+H)+542.3015;m/zC33H39N3O4Na(M+Na)+564.2834。HPLC–MS(ESI+):m/z 542.2[90%(M+H)+],m/z 564.3[100%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-N-异丙基-2-(2-(1-(2-苯乙酰基)哌啶-4-基)乙酰胺基)丙酰胺(SR2-012)。采用一般方法C,由SR1-119(0.050g,0.092mmol)、异丙胺和作为共溶剂的DMF(1:1)得到酰胺SR2-012,为白色泡沫状物(0.051g,96%)。HPLC:>98%[tR=5.7分钟,50%MeOH,50%水(含0.1%TFA),20分钟]。HRMS(ESI+):m/z C34H42N3O4(M+H)+556.3172;m/z C34H41N3O4Na(M+Na)+578.2989。HPLC–MS(ESI+):m/z 556.2[80%(M+H)+],m/z 578.2[100%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-N-环己基-2-(2-(1-(2-苯乙酰基)哌啶-4-基)乙酰胺基)丙酰胺(SR1-013)。采用一般方法C,由SR1-119(0.050g,0.092mmol)和环己胺得到酰胺SR2-013,为白色泡沫状物(0.032g,57%)。HPLC:>98%[tR=5.1分钟,80% MeOH,20%水(含0.1% TFA),20分钟]。HRMS(ESI+):m/z C37H46N3O4(M+H)+596.3475;m/z C37H45N3O4Na(M+Na)+618.3297。HPLC–MS(ESI+):m/z 596.2[50%(M+H)+],m/z 618.4[100%,(M+Na)+]。
一般方法D:SR1-119的N-末端改性类似物的合成
在氩气下将胺盐SR1-085(0.050g,0.112mmol,1当量)溶解在DMF(1.5-2.0mL)中,并添加DIEA(2.0当量)、HATU(1.2当量)和相应的丙酸(1.2当量)。将混合物在室温下搅拌18-24h并在减压下浓缩。将所得稠油状物溶解在EtOAc中,并用1N HCl(2×20mL)和饱和NaHCO3水溶液(2×20mL)洗涤。将有机层干燥(Na2SO4)并蒸发。使用MeOH/DCM(0:100-10:90)作为洗脱液,通过快速柱色谱法纯化,得到相应的N-末端酰胺化的产物。
(S)-3-(4-(苄氧基)苯基)-2-(2-(1-(3-(4-氯苯基)丙酰基)哌啶-4-基)乙酰胺基)丙酸甲酯(SR2-004)。采用一般方法D,由3-(4-氯苯基)丙酸(0.020g,0.109mmol,1.2当量)得到酰胺SR2-004,为白色泡沫状物(0.037g,71%)。HPLC:>97%[tR=4.9分钟,80%MeOH,20%水(含0.1%TFA),20分钟]。11H NMR(400MHz,CDCl3-d)δ7.47–7.30(m,5H),7.24(d,J=8.4Hz,2H),7.14(d,J=8.6Hz,2H),6.99(d,J=8.7Hz,2H),6.89(d,J=8.7Hz,2H),5.83(d,J=7.9Hz,1H),5.03(s,2H),4.86(dt,J=7.9,5.9Hz,1H),4.73–4.44(m,1H),3.84–3.60(m,1H),3.73(s,3H),3.09(dd,J=14.0,5.7Hz,1H),3.01(dd,J=14.1,6.1Hz,,1H),2.97–2.87(m,2H),2.57(t,J=7.7Hz,2H),2.57–2.31(m,1H),2.28–1.87(m,4H),1.64(m,2H),1.15–0.72(m,2H)。HRMS(ESI+):m/z C33H38ClN2O5(M+H)+577.2480;m/z C33H37ClN2O5Na(M+Na)+599.2297。HPLC–MS(ESI+):m/z 577.2[40%(M+H)+],m/z 599.2[100%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-2-(2-(1-(3-(2-甲氧基苯基)丙酰基)哌啶-4-基)乙酰胺基)丙酸甲酯(SR2-006)。采用一般方法D,由3-(2-甲氧基苯基)丙酸(0.024g,0.134mmol,1.2当量)得到酰胺SR2-006,为白色泡沫状物(0.059g,92%)。HPLC:>96%[tR=4.9分钟,70%MeOH,30%水(含0.1%TFA),20分钟]。1H NMR(400MHz,CDCl3-d)δ7.49–7.29(m,5H),7.22–7.14(m,2H),6.99(d,J=8.7Hz,2H),6.95–6.80(m,4H),5.81(d,J=7.9Hz,1H),5.03(d,J=2.3Hz,2H),4.91–4.81(m,1H),4.75–4.27(m,1H),3.81(s,3H),3.78–3.50(m,1H),3.73(s,3H),3.09(dd,J=14.2,5.7Hz,1H),3.02(dd,J=14.1,6.0Hz,1H),2.94(t,J=8.0Hz,2H),2.93–2.75(m,1H),2.61(dd,J=9.3,6.7Hz,2H),2.61–2.39(m,1H),2.05(d,J=4.8Hz,2H),2.00–1.76(m,1H),1.74–1.59(m,2H),1.17–0.74(m,2H)。HRMS(ESI+):m/zC34H41N2O6(M+H)+573.2949;m/z C34H40N2O6Na(M+Na)+595.2767。HPLC–MS(ESI+):m/z 573.2[80%(M+H)+],m/z 595.2[100%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-2-(2-(1-(3-(4-乙氧基苯基)丙酰基)哌啶-4-基)乙酰胺基)丙酸甲酯(SR2-007)。采用一般方法D,由3-(4-乙氧基苯基)丙酸(0.026g,0.134mmol,1.2当量)得到酰胺SR2-007,为白色泡沫状物(0.046g,72%)。HPLC:>96%[tR=10.4分钟,75%MeOH,25%水(含0.1%TFA),20分钟]。1H NMR(400MHz,DMSO-d6)δ8.24(d,J=8.0Hz,1H),7.47–7.25(m,5H),7.14–7.05(m,4H),6.89(d,J=8.4Hz,2H),6.78(dd,J=8.6,4.1Hz,2H),5.03(s,1H),5.00(m,1H),4.48–4.37(m,1H),4.30–4.19(m,1H),3.98–3.89(m,2H),3.81–3.63(m,1H),3.58(s,3H),2.95(dd,J=13.7,5.1Hz,1H),2.88–2.73(m,1H),2.72–2.63(m,2H),2.50(m,2H),2.42–2.29(m,1H),1.93(d,J=7.2Hz,2H),1.82–1.61(m,1H),1.44(m,1H),1.31–1.24(m,4H),0.95–0.71(m,2H)。HRMS(ESI+):m/z C35H42N2O6(M+H)+587.3107;m/z C35H42N2O6Na(M+Na)+609.2932。HPLC–MS(ESI+):m/z 587.2[90%(M+H)+],m/z609.2[100%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-2-(2-(1-(3-(4-氟苯基)丙酰基)哌啶-4-基)乙酰胺基)丙酸甲酯(SR2-008)。采用一般方法D,由3-(4-氟苯基)丙酸(0.023g,0.134mmol,1.2当量)得到酰胺SR2-008,为白色泡沫状物(0.059g,93%)。HPLC:>95%[tR=6.1分钟,75%MeOH,25%水(含0.1%TFA),20分钟]。1H NMR(400MHz,CDCl3-d)δ7.48–7.30(m,5H),7.19–7.12(m,2H),6.99(d,J=8.6Hz,2H),6.96(t,J=8.7Hz,2H),6.89(d,J=8.7Hz,2H),5.83(d,J=7.9Hz,1H),5.03(s,2H),4.85(dt,J=8.0,5.9Hz,1H),4.78–4.28(m,1H),3.73(s,1H),3.80–3.42(m,1H),3.09(dd,J=14.1,5.7Hz,1H),3.01(dd,J=14.1,6.2Hz,1H),2.92(t,J=7.7Hz,2H),2.92–2.74(m,1H),2.65–2.26(m,3H),2.15–1.86(m,3H),1.75–1.54(m,2H),1.15–0.68(m,2H)。19F NMR(376MHz,CDCl3-d)δ-117.27(ddd,J=14.1,8.9,5.4Hz)。HRMS(ESI+):m/z C33H38FN2O5(M+H)+561.2753;m/z C33H37FN2O5Na(M+Na)+583.2573。HPLC–MS(ESI+):m/z 561.2[60%(M+H)+],m/z 583.2[100%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-2-(2-(1-(3-(4-(三氟甲基)苯基)丙酰基)-哌啶-4-基)乙酰胺基)丙酸甲酯(SR2-009)。采用一般方法D,由3-(4-三氟苯基)丙酸(0.029g,0.134mmol,1.2当量)得到酰胺SR2-009,为白色泡沫状物(0.066g,97%)。HPLC:>99%[tR=4.9分钟,80%MeOH,20%水(含0.1%TFA),20分钟]。1H NMR(400MHz,DMSO-d6)δ8.25(d,J=8.0Hz,1H),7.61(dd,J=7.9,5.4Hz,2H),7.49–7.26(m,7H),7.12(d,J=8.6Hz,2H),6.90(d,J=8.2Hz,2H),5.05(s,1H),5.03(s,1H),4.45(dt,J=8.9,4.6Hz,1H),4.27(m,1H),3.81–3.67(m,1H),3.60(s,3H),2.97(dd,J=13.8,5.1Hz,1H),2.87(td,J=7.5,4.0Hz,2H),2.76(dd,J=13.9,10.2Hz,1H),2.69–2.53(m,2H),2.50(m,1H),2.47–2.27(m,1H),1.95(d,J=7.1Hz,2H),1.72(m,1H),1.47(m,1H),1.39–1.19(m,1H),0.98–0.70(m,2H)。19FNMR(376MHz,DMSO-d6)δ-60.70(d,J=3.2Hz)。HRMS(ESI+):m/z C34H38F3N2O5(M+H)+611.2718;m/z C34H37F3N2O5Na(M+Na)+633.2537。HPLC–MS(ESI+):m/z 611.2[70%(M+H)+],m/z 633.2[100%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-2-(2-(1-(3-(3-氟苯基)丙酰基)哌啶-4-基)乙酰胺基)丙酸甲酯(SR2-010)。采用一般方法D,由3-(3-氟苯基)丙酸(0.023g,0.134mmol,1.2当量)得到酰胺SR2-010,为白色泡沫状物(0.060g,95%)。HPLC:>99%[tR=9.5分钟,70%MeOH,30%水(含0.1%TFA),20分钟]。1H NMR(400MHz,氯仿-d)δ7.47–7.29(m,5H),7.25–7.19(m,1H),6.99(m,3H),6.94–6.84(m,4H),5.81(d,J=7.9Hz,1H),5.03(s,2H),4.86(dt,J=7.9,5.9Hz,1H),4.77–4.36(m,1H),3.86–3.54(m,1H),3.74(s,3H),3.09(dd,J=14.0,5.7Hz,1H),3.01(dd,J=14.1,6.1Hz,1H),3.00–2.88(m,3H),2.64–2.57(m,3H),2.12–1.75(m,3H),1.73–1.56(m,2H),1.19–0.78(m,2H)。19F NMR(376MHz,CDCl3-d)δ-113.45–113.57(m)。HRMS(ESI+):m/z C33H38FN2O5(M+H)+561.2754;m/z C33H37FN2O5Na(M+Na)+583.2581;HPLC–MS(ESI+):m/z 561.2[50%(M+H)+],m/z 583.2[100%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-2-(2-(1-(3,3-二苯基丙酰基)哌啶-4-基)乙酰胺基)丙酸甲酯(SR2-029)。采用一般方法D,由3-(3,3-二苯基)丙酸(0.030g,0.134mmol,1.2当量)得到酰胺SR2-029,为白色泡沫状物(0.063g,91%)。HPLC:>99%[tR=5.6分钟,80%MeOH,20%水(含0.1%TFA),20分钟]。1H NMR(400MHz,DMSO-d6)δ8.25(d,J=8.0Hz,1H),7.45–7.39(m,2H),7.39–7.19(m,11H),7.18–7.08(m,4H),6.90(dd,J=8.7,3.3Hz,2H),5.04(s,2H),4.53–4.37(m,2H),4.18(m,1H),3.91(m,1H),3.59(s,3H),3.16–3.03(m,1H),3.05–2.90(m,2H),2.89–2.65(m,2H),2.34(m,1H),1.91(d,J=7.2Hz,2H),1.78–1.58(m,1H),1.49–1.36(m,1H),1.35–1.12(m,1H),0.94–0.55(m,2H)。HRMS(ESI+):m/z C39H43N2O5(M+H)+619.3157;m/z C39H42N2O5Na(M+Na)+641.2979;HPLC–MS(ESI+):m/z 619.2[60%(M+H)+],m/z 641.2[100%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-2-(2-(1-(3-(3,4-二氯苯基)丙酰基)哌啶-4-基)乙酰胺基)丙酸甲酯(SR2-030)。采用一般方法D,由3-(3,4-二氯苯基)丙酸(0.029g,0.134mmol,1.2当量)得到酰胺SR2-030,为白色泡沫状物(0.060g,88%)。HPLC:>98%[tR=6.4分钟,80%MeOH,20%水(含0.1%TFA),20分钟]。1H NMR(400MHz,DMSO-d6)δ8.24(d,J=8.0Hz,1H),7.54–7.45(m,2H),7.44–7.25(m,5H),7.22(m,1H),7.11(d,J=8.5Hz,2H),6.89(d,J=7.7Hz,2H),5.03(s,1H),5.01(s,1H),4.43(td,J=9.5,9.1,4.7Hz,1H),4.30–4.19(m,1H),3.80–3.63(m,1H),3.58(s,3H),2.96(dd,J=13.8,5.1Hz,1H),2.90–2.70(m,4H),2.66(m,1H),2.61–2.52(m,1H),2.45–2.29(m,1H),1.94(d,J=7.1Hz,2H),1.80–1.61(m,1H),1.53–1.38(m,1H),1.36–1.19(m,1H),1.02–0.62(m,2H)。HRMS(ESI+):m/z C33H37Cl2N2O5(M+H)+611.2048;m/z C33H36N2O5Na(M+Na)+633.1876;HPLC–MS(ESI+):m/z 611.2[50%(M+H)+],m/z633.2[100%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-2-(2-(1-(3-(对甲苯基)丙酰基)哌啶-4-基)乙酰胺基)丙酸甲酯(SR2-031)。采用一般方法D,由3-(对甲苯基)丙酸(0.022g,0.134mmol,1.2当量)得到酰胺SR2-031,为白色泡沫状物(0.054g,87%)。HPLC:>98%[tR=4.8分钟,80%MeOH,20%水(含0.1%TFA),20分钟]。1H NMR(400MHz,DMSO-d6)δ8.24(d,J=8.0Hz,1H),7.46–7.24(m,5H),7.11(d,J=8.7Hz,2H),7.08–6.99(m,4H),6.89(d,J=8.6Hz,2H),5.03(s,1H),5.00(s,1H),4.43(ddd,J=10.5,8.2,5.2Hz,1H),4.32–4.18(m,1H),3.77–3.63(m,1H),3.58(s,3H),2.95(dd,J=13.8,5.0Hz,1H),2.87–2.64(m,5H),2.51(m,1H),2.45–2.30(m,1H),2.22(s,3H),1.93(d,J=7.2Hz,2H),1.83–1.56(m,1H),1.54–1.36(m,1H),1.33–1.17(m,1H),0.93–0.66(m,2H)。HRMS(ESI+):m/z C34H41N2O5(M+H)+557.3002;m/zC34H40N2O5Na(M+Na)+579.2825;HPLC–MS(ESI+):m/z 557.2[60%(M+H)+],m/z 579.2[100%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-2-(2-(1-(3-(3-氯苯基)丙酰基)哌啶-4-基)乙酰胺基)丙酸甲酯(SR2-032)。采用一般方法D,由3-(3-氯苯基)丙酸(0.025g,0.134mmol,1.2当量)得到酰胺SR2-032,为白色泡沫状物(0.052g,81%)。HPLC:>98%[tR=4.9分钟,80%MeOH,20%水(含0.1%TFA),20分钟]。1H NMR(400MHz,DMSO-d6)δ8.24(d,J=8.0Hz,1H),7.46–7.32(m,4H),7.32–7.28(m,2H),7.26(dd,J=7.6,3.8Hz,1H),7.23–7.14(m,2H),7.11(d,J=8.6Hz,2H),6.89(d,J=8.5Hz,2H),5.04(s,1H),5.02(m,1H),4.43(ddd,J=12.9,9.7,5.0Hz,1H),4.31–4.21(m,1H),3.79–3.64(m,1H),3.58(s,3H),2.95(dd,J=13.8,5.1Hz,1H),2.88–2.69(m,5H),2.63–2.51(m,1H),2.45–2.28(m,1H),1.93(d,J=7.3Hz,2H),1.80–1.58(m,1H),1.54–1.39(m,1H),1.35–1.17(m,1H),0.94–0.70(m,2H)。HRMS(ESI+):m/z C33H38ClN2O5(M+H)+577.2454;m/z C33H37ClN2O5Na(M+Na)+599.2274HPLC–MS(ESI+):m/z 577.2[50%(M+H)+],m/z 599.2[100%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-2-(2-(1-(3-(4-氰基苯基)丙酰基)哌啶-4-基)乙酰胺基)丙酸甲酯(SR2-033)。采用一般方法D,由3-(4-氰基苯基)丙酸(0.024g,0.134mmol,1.2当量)得到酰胺SR2-033,为白色泡沫状物(0.055g,87%)。HPLC:>99%[tR=4.1分钟,75%MeOH,25%水(含0.1%TFA),20分钟]。1H NMR(400MHz,DMSO-d6)δ8.26(d,J=8.0Hz,1H),7.71(dd,J=8.3,6.5Hz,2H),7.47–7.27(m,7H),7.12(d,J=8.7Hz,2H),6.90(d,J=7.8Hz,2H),5.04(s,1H),5.01(m,1H),4.50–4.38(m,1H),4.31–4.20(m,1H),3.81–3.64(m,1H),3.59(s,3H),2.97(dd,J=13.8,5.0Hz,1H),2.90–2.70(m,4H),2.69–2.54(m,2H),2.47–2.30(m,1H),1.95(d,J=7.2Hz,2H),1.82–1.63(m,1H),1.52–1.42(m,1H),1.40–1.20(m,1H),0.96–0.70(m,2H)。HRMS(ESI+):m/z C34H38N3O5(M+H)+568.2793;m/z C34H37N3O5Na(M+Na)+590.2618;HPLC–MS(ESI+):m/z 568.2[50%(M+H)+],m/z 599.2[100%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-2-(2-(1-(3-(3,4,5-三甲氧基苯基)丙酰基)哌啶-4-基)乙酰胺基)丙酸甲酯(SR2-034)。采用一般方法D,由3-(3,4,5-三甲氧基苯基)丙酸(0.032g,0.134mmol,1.2当量)得到酰胺SR2-034,为白色泡沫状物(0.052g,85%)。HPLC:>99%[tR=7.3分钟,70%MeOH,30%水(含0.1%TFA),20分钟]。1H NMR(400MHz,DMSO-d6)δ8.24(d,J=8.0Hz,1H),7.46–7.25(m,5H),7.11(d,J=8.7Hz,2H),6.89(d,J=8.6Hz,2H),6.51(s,2H),5.03(s,1H),5.00(m,1H),4.43(ddd,J=13.0,9.8,5.1Hz,1H),4.34–4.21(m,1H),3.79–3.67(m,1H),3.72(s,6H),3.58(s,3H),3.57(s,3H),2.95(dd,J=13.9,5.1Hz,1H),2.89–2.79(m,1H),2.79–2.63(m,4H),2.64–2.49(m,1H),2.45–2.30(m,1H),1.94(d,J=7.1Hz,2H),1.84–1.61(m,1H),1.52–1.40(m,1H),1.37–1.17(m,1H),0.93–0.68(m,2H)。HRMS(ESI+):m/z C36H45N2O8(M+H)+633.3162;m/z C36H44N2O8Na(M+Na)+655.2980;HPLC–MS(ESI+):m/z 633.2[70%(M+H)+],m/z 655.2[100%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-2-(2-(1-(3-(邻甲苯基)丙酰基)哌啶-4-基)乙酰胺基)丙酸甲酯(SR2-035)。采用一般方法D,由3-(2-甲基苯基)丙酸(0.022g,0.134mmol,1.2当量)得到酰胺SR2-035,为白色泡沫状物(0.047g,74%)。HPLC:>99%[tR=7.9分钟,75%MeOH,25%水(含0.1%TFA),20分钟]。1H NMR(400MHz,DMSO-d6)δ8.26(d,J=8.0Hz,1H),7.47–7.28(m,5H),7.23–7.04(m,6H),6.90(d,J=7.4Hz,2H),5.05(s,1 1H),5.02(m,1H),4.44(ddd,J=13.2,9.9,5.0Hz,1H),4.33–4.25(m,1H),3.81–3.66(m,1H),3.60(s,3H),2.97(dd,J=13.8,4.6Hz,1H),2.88–2.75(m,3.5H),2.75–2.64(m,1.5H),2.54(m,1H),2.47–2.35(m,1H),2.26(s,3H),1.95(d,J=7.1Hz,2H),1.82–1.61(m,1H),1.54–1.39(m,1H),1.36–1.20(m,1H),0.95–0.65(m,2H)。HRMS(ESI+):m/z C34H41N2O5(M+H)+557.3006;m/zC34H40N2O5Na(M+Na)+579.2822;HPLC–MS(ESI+):m/z 557.2[80%(M+H)+],m/z 579.2[100%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-2-(2-(1-(3-(间甲苯基)丙酰基)哌啶-4-基)乙酰胺基)丙酸甲酯(SR2-036)。采用一般方法D,由3-(3-甲基苯基)丙酸(0.022g,0.134mmol,1.2当量)得到酰胺SR2-036,为白色泡沫状物(0.046g,74%)。HPLC:>99%[tR=7.5分钟,75%MeOH,25%水(含0.1%TFA),20分钟]。1H NMR(400MHz,DMSO-d6)δ8.26(d,J=8.0Hz,1H),7.37(m,5H),7.15(m,1H),7.12(d,J=8.5Hz,2H),7.06–6.95(m,3H),6.90(d,J=8.6Hz,2H),5.05(s,1H),5.02(s,1H),4.44(ddd,J=13.3,4.7,2.5Hz,1H),4.33–4.24(m,1H),3.79–3.67(m,1H),3.60(s,3H),2.97(dd,J=13.9,5.1Hz,1H),2.89–2.65(m,5H),2.63–2.52(m,1H),2.41(m,1H),2.25(s,3H),1.95(d,J=7.2Hz,2H),1.79–1.63(m,1H),1.54–1.37(m,1H),1.34–1.20(m,1H),0.94–0.71(m,2H)。HRMS(ESI+):m/z C34H41N2O5(M+H)+557.3009;m/z C34H40N2O5Na(M+Na)+579.2826;HPLC–MS(ESI+):m/z 557.2[60%(M+H)+],m/z579.2[100%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-2-(2-(1-(4-(4-甲氧基苯基)-4-氧代丁酰基)哌啶-4-基)乙酰胺基)丙酸甲酯(SR2-037)。采用一般方法D,由3-(4-甲氧基苄基)丙酸(0.028g,0.134mmol,1.2当量)得到酰胺SR2-037,为白色泡沫状物(0.061g,91%)。HPLC:>98%[tR=5.0分钟,75%MeOH,25%水(含0.1%TFA),20分钟]。1H NMR(400MHz,DMSO-d6)δ8.28(d,J=8.0Hz,1H),7.94(dd,J=8.8,1.9Hz,2H),7.41(d,J=7.0Hz,2H),7.38–7.24(m,3H),7.12(dd,J=8.6,3.8Hz,2H),7.07–7.00(m,2H),6.90(t,J=8.2Hz,2H),5.04(s,2H),4.50–4.39(m,1H),4.25–4.16(m,1H),3.88–3.74(m,1H),3.83(s,3H),3.59(s,3H),3.11(m,2H),2.97(dd,J=13.8,5.1Hz,1H),2.92–2.83(m,1H),2.76(dd,J=13.8,10.3Hz,1H),2.70–2.55(m,2H),2.46–2.25(m,1H),1.97(d,J=7.2Hz,2H),1.80–1.65(m,1H),1.49(m,1H),1.40–1.17(m,1H),1.11–0.70(m,2H)。HRMS(ESI+):m/z C35H41N2O7(M+H)+601.2900;m/z C35H40N2O7Na(M+Na)+623.2723;HPLC–MS(ESI+):m/z 601.2[30%(M+H)+],m/z 623.2[100%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-2-(2-(1-新戊酰基哌啶-4-基)乙酰胺基)丙酸甲酯(SR2-039)。采用一般方法D,由三甲基乙酸(0.014g,0.134mmol,1.2当量)得到酰胺SR2-039,为白色泡沫状物(0.043g,78%)。HPLC:>99%[tR=8.5分钟,70%MeOH,30%水(含0.1%TFA),20分钟]。1H NMR(400MHz,DMSO-d6)δ8.26(d,J=8.0Hz,1H),7.47–7.40(m,2H),7.42–7.34(m,2H),7.36–7.27(m,1H),7.13(d,J=8.6Hz,2H),6.91(d,J=8.6Hz,2H),5.05(s,2H),4.46(ddd,J=10.2,8.0,5.1Hz,1H),4.15(m,2H),3.60(s,3H),2.98(dd,J=13.9,5.0Hz,1H),2.76(dd,J=13.8,10.3Hz,1H),2.73–2.58(m,2H),1.96(d,J=7.2Hz,2H),1.84–1.68(m,1H),1.55–1.44(m,1H),1.35–1.26(m,1H),1.15(s,9H),1.00–0.72(m,2H)。HRMS(ESI+):m/z C29H39N2O5(M+H)+495.2853;m/z C29H38N2O5Na(M+Na)+517.2671;HPLC–MS(ESI+):m/z 495.2[50%(M+H)+],m/z 517.2[100%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-2-(2-(1-(3,3-二甲基丁酰基)哌啶-4-基)乙酰胺基)丙酸甲酯(SR2-040)。采用一般方法D,由叔丁基乙酸(0.017μL,0.134mmol,1.2当量)得到酰胺SR2-040,为白色泡沫状物(0.051g,90%)。HPLC:>98%[tR=10.1分钟,70%MeOH,30%水(含0.1%TFA),20分钟]。1H NMR(400MHz,DMSO-d6)δ8.24(d,J=8.0Hz,1H),7.43(m,2H),7.37(m,2H),7.34–7.26(m,1H),7.12(d,J=8.2Hz,2H),6.90(d,J=8.7Hz,2H),5.04(s,2H),4.50–4.38(m,1H),4.32(m,1H),3.91–3.71(m,1H),3.59(s,3H),2.96(dd,J=13.8,5.1Hz,1H),2.91–2.79(m,1H),2.75(dd,J=13.8,10.2Hz,1H),2.45–2.28(m,1H),2.24–2.08(m,2H),1.96(dd,J=7.6,5.3Hz,2H),1.81–1.64(m,1H),1.55–1.41(m,1H),1.37–1.20(m,1H),0.95(s,4.5H),0.93(s,4.5),0.93–0.69(m,2H)。HRMS(ESI+):m/z C30H41N2O5(M+H)+509.3016;m/z C30H40N2O5Na(M+Na)+531.2839;HPLC–MS(ESI+):m/z 509.4[40%(M+H)+],m/z531.2[100%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-2-(2-(1-((S)-2-苯基丙酰基)哌啶-4-基)乙酰胺基)丙酸甲酯(SR2-041)。采用一般方法D,由(S)-(+)-2-苯基丙酸(0.018μL,0.134mmol,1.2当量)得到酰胺SR2-041,为白色泡沫状物(0.054g,89%)。HPLC:>99%(88:11两种异构体(S:R))[tR=8.2和8.8分钟,70%MeOH,30%水(含0.1%TFA),20分钟]。1H NMR(400MHz,DMSO-d6)δ8.24(d,J=8.0Hz,0.4H),8.16(d,J=7.9Hz,0.6H),7.51–7.16(m,10H),7.10(d,J=8.7Hz,1H),7.06(d,J=8.7Hz,1H),6.88(d,J=8.7Hz,1H),6.85(d,J=8.6Hz,1H),5.04(s,2H),4.47–4.20(m,2H),4.11–3.92(m,1H),3.79(m,1H),3.58(s,1.0H),3.56(s,2H),2.92(m,0.7H),2.88–2.76(m,0.3H),2.76–2.63(m,1H),2.63–2.51(m,1H),2.48–2.26(m,1H),1.96(d,J=7.2Hz,2H),1.74(d,J=7.4Hz,1H),1.71–1.57(m,1H),1.49–1.35(m,1H),1.24(d,6.8Hz,1.5H),1.22(d,6.7Hz,1.5H),1.09–0.89(m,1H),0.89–0.54(m,0.6H),0.15–-0.07(m,0.4H)。HRMS(ESI+):m/z C33H39N2O5(M+H)+543.2860;m/z C33H38N2O5Na(M+Na)+565.2683;HPLC–MS(ESI+):m/z 543.2[40%(M+H)+],m/z 565.2[100%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-2-(2-(1-((R)-2-苯基丙酰基)哌啶-4-基)-乙酰胺基)丙酸甲酯(SR2-056)。采用一般方法D,由(R)-(+)-2-苯基丙酸(0.020g,0.134mmol,1.2当量)得到酰胺SR2-056,为白色泡沫状物(0.052g,86%)。HPLC:>99%(95:4.5两种异构体(R:S))[tR=8.6和9.0分钟,70%MeOH,30%水(含0.1%TFA),20分钟]。1H NMR(400MHz,DMSO-d6)δ8.25(d,J=7.9Hz,0.4H),8.16(d,J=8.0Hz,0.6H),7.50–7.25(m,6H),7.25–7.15(m,4H),7.14–7.03(m,2H),6.94–6.82(m,2H),5.04(s,2H),4.48–4.21(m,2H),4.08–3.94(m,1H),3.87–3.71(m,1H),3.57(s,1H),3.55(s,2H),3.01–2.63(m,2H),2.62–2.48(m,1H),2.46–2.30(m,1H),1.95(d,J=7.1Hz,1H),1.74(d,J=6.3Hz,1H),1.72–1.57(m,2H),1.50–1.33(m,0.5H),1.23(m,3H),1.19–1.11(m,0.5H),1.10–0.76(m,1H),0.73–0.50(m,0.5H),0.15–-0.07(m,0.5H)。HRMS(ESI+):m/z C33H39N2O5(M+H)+543.2866;m/z C33H38N2O5Na(M+Na)+565.2684;HPLC–MS(ESI+):m/z 543.3[30%(M+H)+],m/z 565.3[100%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-2-(2-(1-(3-(3-(三氟甲基)苯基)丙酰基)-哌啶-4-基)乙酰胺基)丙酸甲酯(SR2-042)。采用一般方法D,由3-(3-三氟甲基苯基)丙酸(0.029g,0.134mmol,1.2当量)得到酰胺SR2-042,为白色泡沫状物(0.061g,91%)。HPLC:>99%[tR=11.3分钟,70%MeOH,30%水(含0.1%TFA),20分钟]。1H NMR(400MHz,DMSO-d6)δ8.25(d,J=8.0Hz,1H),7.58(d,J=4.7Hz,1H),7.55–7.44(m,3H),7.44–7.24(m,5H),7.11(d,J=8.7Hz,2H),6.89(d,J=8.6Hz,2H),5.04(s,1H),5.01(s,1H),4.43(ddd,J=13.1,10.0,5.2Hz,1H),4.31–4.19(m,1H),3.80–3.67(m,1H),3.58(s,3H),2.96(dd,J=13.8,5.1Hz,1H),2.91–2.70(m,4H),2.70–2.52(m,2H),2.47–2.29(m,1H),1.93(d,J=7.2Hz,2H),1.82–1.59(m,1H),1.53–1.40(m,1H),1.35–1.17(m,1H),0.97–0.67(m,2H)。19F NMR(376MHz,DMSO-d6)δ-60.90。HRMS(ESI+):m/z C34H38F3N2O5(M+H)+611.2739;m/z C34H37F3N2O5Na(M+Na)+633.2559;HPLC–MS(ESI+):m/z 611.2[60%(M+H)+],m/z 633.2[100%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-2-(2-(1-(3-(4-异丙基苯基)丙酰基)哌啶-4-基)乙酰胺基)丙酸甲酯(SR2-043)。采用一般方法D,由3-(4-异丙基苯基)丙酸(0.026g,0.134mmol,1.2当量)得到酰胺SR2-043,为白色泡沫状物(0.064g,98%)。HPLC:>98%[tR=10.5分钟,75%MeOH,25%水(含0.1%TFA),20分钟]。1H NMR(400MHz,DMSO-d6)δ8.22(d,J=8.0Hz,1H),7.34(m,5H),7.11–7.07(m,6H),6.87(d,J=8.6Hz,2H),5.02(s,1H),4.99(s,1H),4.42(dt,J=9.5,4.7Hz,1H),4.30–4.17(m,1H),3.77–3.62(m,1H),3.57(s,3H),2.94(dd,J=13.8,5.1Hz,1H),2.85–2.62(m,6H),2.59–2.49(m,1H),2.44–2.27(m,1H),1.92(d,J=7.2Hz,2H),1.79–1.59(m,1H),1.51–1.34(m,1H),1.31–1.19(m,1H),1.17–1.11(m,6H),0.93–0.68(m,2H)。HRMS(ESI+):m/z C36H45N2O5(M+H)+585.3327;m/z C36H44N2O5Na(M+Na)+607.3135;HPLC–MS(ESI+):m/z 585.2[40%(M+H)+],m/z 607.2[100%,(M+Na)+]。
(S)-2-(2-(1-(3-(苯并[d][1,3]二氧杂环戊烯-5-基)丙酰基)哌啶-4-基)乙酰胺基)-3-(4-(苄氧基)苯基)丙酸甲酯(SR2-044)。采用一般方法D,由3-(3,4-亚甲二氧基苯基)丙酸(0.026g,0.134mmol,1.2当量)得到酰胺SR2-044,为白色泡沫状物(0.059g,89%)。HPLC:>98%[tR=7.8分钟,70%MeOH,30%水(含0.1%TFA),20分钟]。1H NMR(400MHz,DMSO-d6)δ8.25(d,J=8.0Hz,1H),7.46–7.26(m,5H),7.11(d,J=8.6Hz,2H),6.89(d,J=8.7Hz,2H),6.81(dd,J=4.8,1.7Hz,1H),6.77(dd,J=7.8,4.4Hz,1H),6.65(ddd,J=8.0,3.7,1.7Hz,1H),5.93(1,1H),5.92(s,1H),5.04(s,1H),5.02(s,1H),4.43(dt,J=9.2,4.6Hz,1H),4.31–4.22(m,1H),3.80–3.65(m,1H),3.59(s,3H),2.96(dd,J=13.8,5.1Hz,1H),2.88–2.63(m,4H),2.52(m,2H),2.47–2.32(m,1H),1.94(d,J=7.2Hz,2H),1.77–1.64(m,1H),1.50–1.39(m,1H),1.35–1.19(m,1H),0.96–0.67(m,2H)。HRMS(ESI+):m/z C34H39N2O7(M+H)+587.2755;m/z C34H38N2O7Na(M+Na)+609.2575;HPLC–MS(ESI+):m/z 587.4[40%(M+H)+],m/z609.2[100%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-2-(2-(1-(2-甲基-2-苯基丙酰基)哌啶-4-基)乙酰胺基)丙酸甲酯(SR2-045)。采用一般方法D,由2-甲基-2-苯基丙酸(0.022g,0.134mmol,1.2当量)得到酰胺SR2-045,为白色泡沫状物(0.058g,93%)。HPLC:>99%[tR=4.1分钟,80%MeOH,20%水(含0.1%TFA),20分钟]。1H NMR(500MHz,DMSO-d6,65℃)δ7.97(d,J=8.0Hz,1H),7.44(d,J=7.3Hz,2H),7.39(t,J=7.5Hz,2H),7.37–7.29(m,3H),7.22(d,J=7.4Hz,1H),7.18(d,J=7.9Hz,2H),7.08(d,J=8.6Hz,2H),6.87(d,J=8.6Hz,2H),5.06(s,2H),4.44(ddd,J=9.6,7.8,5.3Hz,1H),4.00–3.64(m,1H),3.58(s,3H),3.43–3.20(m,1H),2.95(dd,J=14.0,5.4Hz,1H),2.77(dd,J=13.9,9.6Hz,1H),2.46(m,2H),1.89(d,J=7.1Hz,2H),1.69–1.56(m,1H),1.42(s,6H),1.32–1.12(m,2H),0.67(m,2H)。HRMS(ESI+):m/zC34H41N2O5(M+H)+557.3022;m/z C34H40N2O5Na(M+Na)+579.2840;HPLC–MS(ESI+):m/z 557.4[50%(M+H)+],m/z 579.2[100%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-2-(2-(1-(4-苯基丁酰基)哌啶-4-基)乙酰胺基)-丙酸甲酯(SR2-046)。采用一般方法D,由4-苯基丁酸(0.022g,0.134mmol,1.2当量)得到酰胺SR2-046,为白色泡沫状物(0.058g,93%)。HPLC:>98%[tR=6.5分钟,75%MeOH,25%水(含0.1%TFA),20分钟]。1H NMR(400MHz,DMSO-d6)δ8.26(d,J=8.0Hz,1H),7.47–7.41(m,2H),7.40–7.35(m,2H),7.34–7.24(m,3H),7.17(m,3H),7.13(d,J=8.2Hz,2H),6.90(dd,J=8.6,2.1Hz,2H),5.06(s,1H),5.04(s,1H),4.46(ddd,J=10.2,8.0,5.1Hz,1H),4.33–4.23(m,1H),3.76–3.62(m,1H),3.60(s,3H),2.98(ddd,J=14.0,5.4,1.8Hz,1H),2.92–2.64(m,2H),2.61–2.53(m,2H),2.47–2.35(m,1H),2.34–2.15(m,2H),2.01–1.92(m,2H),1.82–1.65(m,3H),1.48(d,J=13.2Hz,1H),1.34–1.22(m,1H),1.00–0.71(m,2H)。HRMS(ESI+):m/zC34H41N2O5(M+H)+557.3018;m/z C34H40N2O5Na(M+Na)+579.2834;HPLC–MS(ESI+):m/z 557.3[80%(M+H)+],m/z 579.2[100%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-2-(2-(1-异烟酰基哌啶-4-基)乙酰胺基)丙酸甲酯(SR2-050)。采用一般方法D,由异烟酸(0.016g,0.134mmol,1.2当量)得到酰胺SR2-050,为白色泡沫状物(0.051g,88%)。HPLC:>98%[tR=4.4分钟,60%MeOH,40%水(含0.1%TFA),20分钟]。1H NMR(400MHz,DMSO-d6)δ8.63(d,J=5.9Hz,1H),8.27(d,J=8.0Hz,1H),7.44–7.27(m,7H),7.11(dd,J=8.3,6.0Hz,2H),6.86(dd,J=22.5,8.2Hz,2H),5.02(s,1H),4.95(s,1H),4.45(m,1H),4.41–4.27(m,1H),3.58(s,3H),3.30(m,1H),3.02–2.86(m,2H),2.75(dd,J=13.9,10.1Hz,1H),2.72–2.61(m,1H),1.98(d,J=6.1Hz,2H),1.89–1.71(m,1H),1.65–1.53(m,1H),1.45–1.34(m,1H),1.29–1.17(m,1H),1.14–0.84(m,2H)。HRMS(ESI+):m/z C30H34N3O5(M+H)+516.2504;m/z C30H33N3O5Na(M+Na)+538.2316;HPLC–MS(ESI+):m/z 516.2[100%(M+H)+]。
(S)-3-(4-(苄氧基)苯基)-2-(2-(1-(4-((叔丁氧羰基)氨基)苯甲酰基)哌啶-4-基)乙酰胺基)丙酸甲酯(SR2-051)。采用一般方法D,由4-(Boc-氨基)苯甲酸(0.032g,0.134mmol,1.2当量)得到酰胺SR2-051,为白色泡沫状物(0.068g,96%)。HPLC:>98%[tR=5.7分钟,75%MeOH,25%水(含0.1%TFA),20分钟]。1H NMR(400MHz,DMSO-d6)δ8.63(d,J=5.9Hz,1H),8.27(d,J=8.0Hz,1H),7.44–7.27(m,7H),7.11(dd,J=8.3,6.0Hz,2H),6.86(dd,J=22.5,8.2Hz,2H),5.02(s,1H),4.95(s,1H),4.45(m,1H),4.41–4.27(m,1H),3.58(s,3H),3.30(m,1H),3.02–2.86(m,2H),2.75(dd,J=13.9,10.1Hz,1H),2.72–2.61(m,1H),1.98(d,J=6.1Hz,2H),1.89–1.71(m,1H),1.65–1.53(m,1H),1.45–1.34(m,1H),1.29–1.17(m,1H),1.14–0.84(m,2H)。HRMS(ESI+):m/z C36H44N3O7(M+H)+630.;3184m/z C36H43N3O7Na(M+Na)+652.3001;HPLC–MS(ESI+):m/z 630.4[100%(M+H)+],m/z 652.3[90%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-2-(2-(1-(2-(4-((叔丁氧羰基)氨基)苯基)乙酰基)哌啶-4-基)乙酰胺基)丙酸甲酯(SR2-052)。采用一般方法D,由4-(Boc-氨基)苯乙酸(0.034g,0.134mmol,1.2当量)得到酰胺SR2-052,为白色泡沫状物(0.058g,81%)。HPLC:>96%[tR=6.0分钟,75%MeOH,25%水(含0.1%TFA),20分钟]。1H NMR(400MHz,DMSO-d6)δ9.27(s,1H),8.23(d,J=7.8Hz,1H),7.46–7.23(m,7H),7.10(d,J=8.6Hz,2H),7.05(dd,J=8.5,4.6Hz,1H),6.88(d,J=8.6Hz,2H),5.03(s,2H),4.48–4.35(m,1H),4.29–4.19(m,1H),3.79(m,1H),3.57(s,3H),3.58–3.49(m,2H),3.29(m,1H),2.94(dd,J=13.9,5.1Hz,1H),2.90–2.79(m,1H),2.74(dd,J=13.8,10.1Hz,1H),2.66(m,1H),2.46–2.35(m,1H),1.91(d,J=7.1Hz,2H),1.80–1.61(m,1H),1.44(s,9H),1.33–1.20(m,2H),0.91–0.65(m,2H)。HRMS(ESI+):m/zC37H46N3O7(M+H)+644.3337m/z C37H45N3O7Na(M+Na)+666.3156;HPLC–MS(ESI+):m/z 644.4[50%(M+H)+],m/z 666.2[80%,(M+Na)+]。
(S)-2-(2-(1-(4-氨基苯甲酰基)哌啶-4-基)乙酰胺基)-3-(4-(苄氧基)苯基)-丙酸甲酯(SR2-057)。将SR2-051(0.032g,0.508mmol)溶解在DCM(1mL)中,并在室温下添加HCl(在二噁烷中4N,2.0mL)。将混合物搅拌3h并浓缩。将所得残留物溶解在EtOAc(1×15mL)中,并用饱和NaHCO3(1×10mL)洗涤。将有机层用EtOAc(1×10mL)萃取。将合并的有机层干燥(Na2SO4)并蒸发。使用MeOH/DCM(0:100-10:90)作为洗脱液,通过快速柱色谱法纯化,得到SR2-057,为白色固体(0.026g,96%)。HPLC:>97%[tR=5.0分钟,60%MeOH,40%水(含0.1%TFA),20分钟]。1H NMR(400MHz,DMSO-d6)δ8.22(d,J=8.0Hz,1H),7.46–7.34(m,4H),7.34–7.28(m,1H),7.12(d,J=8.6Hz,2H),7.07(d,J=8.5Hz,2H),6.89(d,J=8.7Hz,2H),6.54(d,J=8.5Hz,2H),5.43(s,2H),5.02(s,2H),4.47(ddd,J=10.0,8.0,5.2Hz,1H),4.09–3.90(m,1H),3.60(s,3H),3.29–3.23(m,1H),2.98(dd,J=13.8,5.1Hz,1H),2.78(dd,J=13.9,10.1Hz,1H),2.73–2.64(m,1H),2.50(m,1H),2.00(d,J=7.2Hz,2H),1.85–1.68(m,1H),1.49(m,1H),1.35(m,1H),1.15–0.85(m,2H)。HRMS(ESI+):m/z C31H36N3O5(M+H)+530.2661m/z C31H35N3O5Na(M+Na)+552.2475;HPLC–MS(ESI+):m/z 530.2[100%(M+H)+],m/z552.2[40%,(M+Na)+]。
(S)-2-(2-(1-(2-(4-氨基苯基)乙酰基)哌啶-4-基)乙酰胺基)-3-(4-(苄氧基)-苯基)丙酸甲酯(SR2-058)。通过与制备SR2-057所用相同的方法,由SR2-052(0.040g,0.062mmol)得到苯胺SR2-058,为白色固体(0.031g,92%)。HPLC:>96%[tR=11.5分钟,50%MeOH,50%水(含0.1%TFA),20分钟]。1H NMR(400MHz,DMSO-d6)δ8.18(d,J=7.9Hz,1H),7.41(m,2H),7.36(m,2H),7.33–7.25(m,1H),7.10(d,J=8.7Hz,2H),6.89(d,J=8.6Hz,2H),6.83(dd,J=8.4,2.4Hz,2H),6.47(d,J=8.3Hz,2H),5.04(s,2H),4.86(s,2H),4.43(td,J=8.39,4.8Hz,1H),4.29–4.19(m,1H),3.86–3.72(m,1H),3.58(s,3H),3.43(bs,2H),2.94(dd,J=14.0,5.1Hz,1H),2.90–2.63(m,2H),2.45–2.28(m,1H),1.91(d,J=7.2Hz,2H),1.77–1.56(m,1H),1.53–1.36(m,1H),1.33–1.20(m,1H),0.92–0.60(m,2H)。HRMS(ESI+):m/z C32H38N3O5(M+H)+544.2818m/z C32H37N3O5Na(M+Na)+566.2634;HPLC–MS(ESI+):m/z 544.2[100%(M+H)+],m/z 566.2[50%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-2-(2-(1-(3-(3,5-二氯苯基)丙酰基)哌啶-4-基)乙酰胺基)丙酸甲酯(SR2-106)。采用一般方法D,由3-(3,5-二氯苯基)丙酸(0.029g,0.134mmol,1.2当量)得到酰胺SR2-106,为白色泡沫状物(0.066g,96%)。HPLC:>98%[tR=7.0分钟,80%MeOH,20%水(含0.1%TFA),20分钟]。1H NMR(500MHz,DMSO-d6)δ8.23(dd,J=7.9,1.7Hz,1H),7.45–7.31(m,5H),7.31–7.28(m,3H),7.11(d,J=8.6Hz,2H),6.89(d,J=8.5Hz,2H),5.04(s,1H),5.02(s,1H),4.44(m,1H),4.25(m,1H),3.80–3.66(m,1H),3.58(s,3H),2.96(dd,J=13.9,5.1Hz,1H),2.89–2.72(m,4H),2.68–2.51(m,2H),2.46–2.33(m,1H),1.94(d,J=7.1Hz,2H),1.79–1.64(m,1H),1.49–1.42(m,1H),1.36–1.19(m,1H),0.97–0.65(m,2H)。HRMS(ESI+):m/z C33H36Cl2N2O5(M)+610.2001;m/z C33H36Cl2N2O5Na(M+Na)+633.1889;HPLC–MS(ESI+):m/z 633.2[100%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-2-(2-(1-(3-(3-溴苯基)丙酰基)哌啶-4-基)乙酰胺基)丙酸甲酯(SR2-107)。采用一般方法D,由3-(3-溴苯基)丙酸(0.031g,0.134mmol,1.2当量)得到酰胺SR2-107,为白色泡沫状物(0.068g,97%)。HPLC:>97%[tR=4.9分钟,80%MeOH,20%水(含0.1%TFA),20分钟]。1H NMR(500MHz,DMSO-d6)δ8.22(d,J=8.0Hz,1H),7.45–7.37(m,3H),7.35(m,3H),7.30(m,1H),7.21(m,2H),7.11(d,J=8.6Hz,2H),6.89(d,J=8.6Hz,2H),5.04(s,1H),5.02(s,1H),4.43(ddd,J=13.3,10.2,5.2Hz,1H),4.32–4.21(m,1H),3.81–3.62(m,1H),3.58(s,3H),2.96(dd,J=13.8,5.1Hz,1H),2.90–2.70(m,4H),2.64–2.50(m,2H),2.47–2.33(m,1H),1.94(d,J=7.2Hz,2H),1.71(m,1H),1.45(m,1H),1.35–1.21(m,1H),0.94–0.68(m,2H)。HRMS(ESI+):m/z C33H38BrN2O5(M+H)+621.1959;m/zC33H37BrN2O5Na(M+Na)+643.1774;HPLC–MS(ESI+):m/z 621.2[40%,(M+H)+],m/z 643.2[100%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-2-(2-(1-(3-(3,4-di氟苯基)丙酰基)哌啶-4-基)乙酰胺基)丙酸甲酯(SR2-109)。采用一般方法D,由3-(3,4-二氟苯基)丙酸(0.025g,0.134mmol,1.2当量)得到酰胺SR2-109,为白色泡沫状物(0.058g,90%)。HPLC:>99%[tR=12.6分钟,70%MeOH,30%水(含0.1%TFA),20分钟]。1H NMR(500MHz,DMSO-d6)δ8.22(d,J=8.0Hz,1H),7.40(m,2H),7.35(m,2H),7.32–7.23(m,3H),7.11(d,J=8.6Hz,2H),7.04(m,1H),6.89(d,J=7.6Hz,2H),5.03(s,1H),5.01(m,1H),4.44(ddd,J=10.1,8.0,5.1Hz,1H),4.31–4.21(m,1H),3.72(m,1H),3.58(s,3H),2.96(dd,J=13.8,5.1Hz,1H),2.88–2.70(m,4H),2.64–2.50(m,2H),2.45–2.32(m,1H),1.94(d,J=7.2Hz,2H),1.78–1.63(m,1H),1.51–1.40(m,1H),1.36–1.20(m,1H),0.95–0.71(m,2H)。HRMS(ESI+):m/z C33H37F2N2O5(M)+578.2592;m/z C33H36F2N2O5Na(M+Na)+601.2481;HPLC–MS(ESI+):m/z 579.2[30%,(M+H)+],m/z 601.2[100%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-2-(2-(1-(3-(4-溴苯基)丙酰基)哌啶-4-基)乙酰胺基)丙酸甲酯(SR2-110)。采用一般方法D,由3-(4-溴苯基)丙酸(0.031g,0.134mmol,1.2当量)得到酰胺SR2-110,为白色泡沫状物(0.055g,79%)。HPLC:>99%[tR=9.4分钟,75%MeOH,25%水(含0.1%TFA),20分钟]。1H NMR(500MHz,DMSO-d6)δ8.25(d,J=8.0Hz,1H),7.46–7.40(m,4H),7.39–7.35(m,2H),7.34–7.27(m,1H),7.19(dd,J=8.4,6.9Hz,2H),7.13(d,J=8.6Hz,2H),6.91(d,J=8.6Hz,2H),5.06(s,1H),5.04(s,1H),4.46(ddd,J=10.0,8.1,4.7Hz,1H),4.33–4.21(m,1H),3.73(m,1H),3.61(s,3H),2.98(dd,J=13.8,5.1Hz,1H),2.90–2.71(m,4H),2.65–2.52(m,2H),2.49–2.37(m,1H),1.96(d,J=7.2Hz,2H),1.81–1.67(m,1H),1.47(d,J=13.0Hz,1H),1.37–1.22(m,1H),0.96–0.70(m,2H)。HRMS(ESI+):m/z C33H37BrN2O5(M+H)+621.1951;m/z C33H37BrN2O5Na(M+Na)+643.1767;HPLC–MS(ESI+):m/z622.0[80%,(M+H)+],m/z 643.2[100%,(M+Na)+]。
一般方法E:N-末端亚磺酰胺和磺酰胺的合成
在氩气下将胺SR1-085(0.050g,0.112mmol,1当量)溶解在DCM(1.5-2.0mL)中。向溶液中添加三乙胺(0.336mmol,0.047mL,3.0当量)和相应的亚磺酰氯或磺酰氯(1.2当量)。将混合物在室温下搅拌18-24h并在减压下浓缩。将所得稠油状物溶解在EtOAc中,并用饱和NH4Cl(2×15mL)洗涤。将有机层干燥(Na2SO4)并蒸发。使用MeOH/DCM(0:10-1:9)作为洗脱液,通过快速柱色谱法纯化,得到相应的N-末端亚磺酰基和磺酰基产物。
(S)-3-(4-(苄氧基)苯基)-2-(2-(1-(吡啶-3-基磺酰基)哌啶-4-基)乙酰胺基)-丙酸甲酯(SR2-075)。采用一般方法E,由哌啶-3-磺酰氯(0.024g,0.134mmol,1.2当量)得到磺酰胺SR2-075,为白色泡沫状物(0.045g,73%)。HPLC:>98%[tR=3.8分钟,70%MeOH,30%水(含0.1%TFA),20分钟]。1H NMR(500MHz,DMSO-d6)δ8.86(m,2H),8.22(d,J=8.0Hz,1H),8.09(dt,J=8.0,1.9Hz,1H),7.64(ddd,J=8.0,4.8,0.8Hz,1H),7.43(m,2H),7.38(m,2H),7.32(m,2H),7.09(d,J=8.6Hz,2H),6.88(d,J=8.7Hz,2H),5.04(s,1H),4.42(ddd,J=10.1,8.0,5.2Hz,1H),3.57(s,3H),3.54(m,2H),2.94(dd,J=13.9,5.1Hz,1H),2.73(dd,J=13.9,10.1Hz,1H),2.30–2.19(m,2H),1.93(dd,J=7.1,2.0Hz,2H),1.56–1.42(m,2H),1.40–1.21(m,1H),1.13–0.92(m,2H)。HRMS(ESI+):m/z C29H34N3O6S(M+H)+552.2173;m/zC29H33N3O6SNa(M+Na)+574.1985HPLC–MS(ESI+):m/z 552.2[100%(M+H)+],m/z 574.2[50%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-2-(2-(1-(苯基磺酰基)哌啶-4-基)乙酰胺基)-丙酸甲酯(SR3-078)。采用一般方法E,由苯磺酰氯(0.017μL,0.134mmol,1.2当量)得到磺酰胺SR2-078,为白色泡沫状物(0.060g,97%)。HPLC:>98%[tR=4.7分钟,70%MeOH,30%水(含0.1%TFA),20分钟]。1H NMR(500MHz,DMSO-d6)δ8.21(d,J=8.0Hz,1H),7.67(m,3H),7.59(m,2H),7.44(m,2H),7.38(m,2H),7.33(m,1H),7.09(d,J=8.6Hz,2H),6.87(d,J=8.7Hz,2H),5.04(s,2H),4.42(ddd,J=10.1,8.0,5.1Hz,1H),3.57(s,3H),3.52(m,2H),2.95(dd,J=13.9,5.1Hz,1H),2.73(dd,J=13.8,10.2Hz,1H),2.11(m,2H),1.92(d,J=7.0Hz,2H),1.56–1.37(m,2H),1.32(dd,J=12.8,3.1Hz,1H),1.13–0.93(m,2H)。HRMS(ESI+):m/zC30H35N2O6S(M+H)+551.2214;m/z C30H34N2O6SNa(M+Na)+573.2040HPLC–MS(ESI+):m/z 551.2[50%(M+H)+],m/z 573.2[100%,(M+Na)+]。
(2S)-3-(4-(苄氧基)苯基)-2-(2-(1-(叔丁基亚磺酰基)哌啶-4-基)乙酰胺基)-丙酸甲酯(SR3-079)。采用一般方法E,由叔丁基亚磺酰氯(0.017μL,0.134mmol,1.2当量)得到磺酰胺SR2-079,为白色泡沫状物(0.041g,71%)。HPLC:>98%[tR=7.6分钟,70%MeOH,30%水(含0.1%TFA),20分钟]。1H NMR(500MHz,DMSO-d6)δ8.21(d,J=8.0Hz,1H),7.67(m,3H),7.59(m,2H),7.44(m,2H),7.38(m,2H),7.33(m,1H),7.09(d,J=8.6Hz,2H),6.87(d,J=8.7Hz,2H),5.04(s,2H),4.42(ddd,J=10.1,8.0,5.1Hz,1H),3.57(s,3H),3.52(m,2H),2.95(dd,J=13.9,5.1Hz,1H),2.73(dd,J=13.8,10.2Hz,1H),2.11(m,2H),1.92(d,J=7.0Hz,2H),1.56–1.37(m,2H),1.32(dd,J=12.8,3.1Hz,1H),1.13–0.93(m,2H)。HRMS(ESI+):m/z C28H39N2O5S(M+H)+515.2585;m/z C28H38N2O5SNa(M+Na)+537.2406HPLC–MS(ESI+):m/z515.2[40%(M+H)+],m/z 537.2[100%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-2-(2-(1-(苄基磺酰基)哌啶-4-基)乙酰胺基)-丙酸甲酯(SR2-082)。采用一般方法E,由α-甲苯磺酰氯(0.026g,0.134mmol,1.2当量)得到磺酰胺SR2-082,为白色泡沫状物(0.046g,73%)。HPLC:>98%[tR=7.1分钟,70%MeOH,30%水(含0.1%TFA),20分钟]。1H NMR(400MHz,DMSO-d6)δ8.24(d,J=8.0Hz,1H),7.46–7.27(m,10H),7.10(d,J=8.2Hz,2H),6.88(d,J=8.3Hz,2H),5.02(s,2H),4.43(td,J=9.3,5.3Hz,1H),4.31(s,2H),3.58(s,3H),3.51–3.23(m,2H),2.95(dd,J=13.9,5.1Hz,1H),2.74(dd,J=13.8,10.1Hz,1H),2.65–2.39(m,2H),1.95(d,J=7.3Hz,2H),1.49(d,J=13.4Hz,2H),1.34–1.20(m,1H),1.08–0.78(m,2H)。HRMS(ESI+):m/z C31H37N2O6S(M+H)+565.2374;m/zC31H36N2O6SNa(M+Na)+587.2198HPLC–MS(ESI+):m/z 587.2[100%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-2-(2-(1-(苯乙基磺酰基)哌啶-4-基)乙酰胺基)-丙酸甲酯(SR2-083)。采用一般方法E,由2-苯基乙磺酰氯(0.027g,0.134mmol,1.2当量)得到磺酰胺SR2-083,为白色泡沫状物(0.049g,76%)。HPLC:>99%[tR=11.6分钟,70%MeOH,30%水(含0.1%TFA),20分钟]。1H NMR(400MHz,DMSO-d6)δ8.26(d,J=8.0Hz,1H),7.45–7.40(m,2H),7.40–7.34(m,2H),7.34–7.25(m,5H),7.22(m,1H),7.13(d,J=8.6Hz,2H),6.91(d,J=8.6Hz,2H),5.04(s,2H),4.46(ddd,J=10.0,7.9,5.0Hz,1H),3.60(s,3H),3.58–3.45(m,2H),3.29–3.20(m,2H),3.02–2.86(m,3H),2.80–2.62(m,3H),1.99(d,J=7.2Hz,2H),1.70–1.51(m,1H),1.45–1.30(m,2H),1.14–0.91(m,2H)。HRMS(ESI+):m/z C32H39N2O6S(M+H)+579.2530;m/z C32H38N2O6SNa(M+Na)+601.2354HPLC–MS(ESI+):m/z 601.2[100%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-2-(2-(1-(甲基磺酰基)哌啶-4-基)乙酰胺基)-丙酸甲酯(SR2-089)。采用一般方法E,由甲磺酰氯(0.011μL,0.134mmol,1.2当量)得到磺酰胺SR2-089,为白色泡沫状物(0.043g,79%)。HPLC:>97%[tR=5.9分钟,70%MeOH,30%水(含0.1%TFA),20分钟]。1H NMR(500MHz,DMSO-d6)δ8.28(d,J=7.9Hz,1H),7.45–7.41(m,2H),7.41–7.35(m,2H),7.34–7.30(m,1H),7.13(d,J=8.6Hz,2H),6.91(d,J=8.7Hz,2H),5.04(s,2H),4.46(ddd,J=10.1,8.0,5.1Hz,1H),3.60(s,3H),3.44(m,2H),2.98(dd,J=13.8,5.1Hz,1H),2.80(s,3H),2.79–2.73(m,1H),2.65–2.53(m,2H),2.01(dd,J=7.1,1.5Hz,2H),1.68–1.55(m,2H),1.44–1.36(m,1H),1.16–0.97(m,2H)。HRMS(ESI+):m/z C25H33N2O6S(M+H)+489.2063;m/z C25H32N2O6SNa(M+Na)+511.1879HPLC–MS(ESI+):m/z 511.2[100%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-2-(2-(1-((3,4-二氯苯乙基)磺酰基)哌啶-4-基)乙酰胺基)丙酸甲酯(SR2-112)。采用一般方法E,由2-(3,4-二氯苯基)乙烷-1-磺酰氯(0.037g,0.134mmol,1.2当量)得到磺酰胺SR2-112,为白色泡沫状物(0.023g,32%)。HPLC:>97%[tR=6.9分钟,75%MeOH,25%水(含0.1%TFA),20分钟]。1H NMR(500MHz,DMSO-d6)δ8.29–8.23(m,1H),7.60(d,J=2.0Hz,1H),7.53(d,J=8.3Hz,1H),7.45–7.26(m,6H),7.11(d,J=8.5Hz,2H),6.89(d,J=8.6Hz,2H),5.04(s,1H),5.02(s,1H),4.45(ddd,J=10.1,7.9,5.1Hz,1H),3.59(s,3H),3.55–3.43(m,2H),3.33–3.25(m,2H),3.01–2.86(m,3H),2.82–2.64(m,3H),1.98(d,J=7.2Hz,2H),1.63(m,0.5H),1.57–1.49(m,0.5H),1.40–1.18(m,1.5H),1.10–0.83(m,2H)。HRMS(ESI+):m/z C32H36Cl2N2O6S(M)+646.1671;HPLC–MS(ESI+):m/z 669.0[100%,(M+Na)+]。
含环己基乙酸的N-末端变体的合成
(S)-3-(4-(苄氧基)苯基)-2-(2-((1r,4S)-4-((叔丁氧羰基)氨基)环己基)乙酰胺基)丙酸甲酯(SR2-087)。通过按照用于制备SR1-083的方法,由反式-4-(Boc-氨基)环己烷乙酸(0.400g,1.554mmol,1.2当量)得到酰胺SR2-087,为白色泡沫状物(0.674g,83%)。HPLC:>99%[tR=10.3分钟,70%MeOH,30%水(含0.1%TFA),20分钟]。1H NMR(400MHz,DMSO-d6)δ8.17(d,J=8.0Hz,1H),7.46–7.26(m,5H),7.10(d,J=8.6Hz,2H),6.88(d,J=8.6Hz,2H),6.61(d,J=8.1Hz,1H),5.02(s,2H),4.41(ddd,J=9.9,7.8,5.1Hz,1H),3.57(s,3H),3.16–3.00(m,1H),2.94(dd,J=13.8,5.1Hz,1H),2.75(dd,J=13.8,10.0Hz,1H),1.89(d,J=7.1Hz,2H),1.73–1.57(m,2H),1.51(m,1H),1.46–1.26(m,2H),1.34(s,9H),1.03(dd,J=17.9,7.6Hz,2H),0.90–0.70(m,2H)。HRMS(ESI+):m/z C30H41N2O6(M+H)+525.2958;m/z C30H40N2O6Na(M+Na)+547.2784,实测值547.2793;HPLC–MS(ESI+):m/z 547.2[100%,(M+Na)+]。
(S)-2-(2-反式-4-氨基环己基)乙酰胺基)-3-(4-(苄氧基)苯基)丙酸甲酯盐酸盐(SR2-088)。通过按照用于制备SR1-087的方法,由SR2-087(0.365g,0.695mmol)得到胺盐SR2-088,为白色泡沫状物(0.280g,88%)。HPLC:>97%[tR=10.8分钟,50%MeOH,50%水(含0.1%TFA),20分钟]。1H NMR(500MHz,DMSO-d6)δ8.24(d,J=7.9Hz,1H),7.81(s,3H),7.44–7.40(m,2H),7.40–7.35(m,2H),7.33–7.28(m,1H),7.11(d,J=8.6Hz,2H),6.89(d,J=8.6Hz,2H),5.04(s,2H),4.41(ddd,J=9.9,7.9,5.2Hz,1H),3.58(s,3H),2.94(dd,J=13.8,5.2Hz,1H),2.91–2.82(m,1H),2.76(dd,J=13.9,9.9Hz,1H),1.95–1.90(m,2H),1.88–1.80(m,2H),1.64–1.54(m,1H),1.54–1.42(m,2H),1.29–1.11(m,2H),0.98–0.79(m,2H)。HRMS(ESI+):m/z C25H34N2O4(M+H)+425.2447;m/z C25H33N2O4Na(M+Na)+447.2288;HPLC–MS(ESI+):m/z 425.2[100%,(M+H)+]。
(S)-3-(4-(苄氧基)苯基)-2-(2-反式-4-(3-苯基丙酰胺基)环己基)-乙酰胺基)丙酸甲酯(SR2-090)。采用一般方法E,由3-苯基丙酰氯(0.019μL,0.130mmol,1.2当量)得到酰胺SR2-090,为白色泡沫状物(0.054g,90%)。HPLC:>98%[tR=10.9分钟,70%MeOH,30%水(含0.1%TFA),20分钟]。1H NMR(500MHz,DMSO-d6)δ8.21(d,J=7.9Hz,1H),7.63(d,J=7.9Hz,1H),7.45–7.40(m,2H),7.39–7.35(m,2H),7.34–7.28(m,1H),7.29–7.21(m,3H),7.20–7.15(m,2H),7.12(d,J=8.7Hz,2H),6.90(d,J=8.7Hz,2H),5.04(s,2H),4.43(ddd,J=10.0,7.9,5.1Hz,1H),3.59(s,3H),3.41(m,1H),2.96(dd,J=13.9,5.2Hz,1H),2.81–2.74(m,3H),2.30(dd,J=8.7,6.9Hz,2H),1.92(dd,J=7.2,4.0Hz,2H),1.70–1.60(m,2H),1.59–1.51(m,1H),1.51–1.41(m,1H),1.42–1.32(m,1H),1.09–0.93(m,2H),0.94–0.74(m,2H)。HRMS(ESI+):m/z C34H41N2O5(M+H)+557.3013;m/z C34H40N2O5Na(M+Na)+579.2831;HPLC–MS(ESI+):m/z 579.2[100%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-2-(2-反式-4-(2-苯基乙酰胺基)环己基)-乙酰胺基)丙酸甲酯(SR2-091)。采用一般方法E,由苯乙酰氯(0.017μL,0.130mmol,1.2当量)得到酰胺SR2-091,为白色固体(0.042g,72%)。HPLC:>97%[tR=15.6分钟,65%MeOH,35%水(含0.1%TFA),20分钟]。1H NMR(500MHz,DMSO-d6)δ8.19(d,J=8.0Hz,1H),7.89(d,J=7.9Hz,1H),7.42–7.38(m,2H),7.37–7.33(m,2H),7.33–7.15(m,6H),7.10(d,J=8.6Hz,2H),6.88(d,J=8.7Hz,2H),5.02(s,2H),4.41(ddd,J=10.1,7.9,5.1Hz,1H),3.58(s,3H),3.41–3.33(m,1H),3.32(s,2H),2.94(dd,J=13.8,5.1Hz,1H),2.75(dd,J=13.8,10.0Hz,1H),1.90(dd,J=7.2,4.6Hz,2H),1.73–1.62(m,2H),1.60–1.51(m,1H),1.52–1.41(m,1H),1.37(m,1H),1.15–0.95(m,2H),0.92–0.74(m,2H)。HRMS(ESI+):m/z C33H39N2O5(M+H)+543.2863;m/z C33H38N2O5Na(M+Na)+565.2677;HPLC–MS(ESI+):m/z 543.4[60%,(M+H)+],m/z 565.2[100%,(M+Na)+]。
(S)-2-(2-反式-4-苯甲酰胺基环己基)乙酰胺基)-3-(4-(苄氧基)苯基)-丙酸甲酯(SR2-092)。采用一般方法E,由苄基氯(0.015μL,0.130mmol,1.2当量)得到酰胺SR2-092,为白色固体(0.051g,89%)。HPLC:>97%[tR=4.7分钟,75%MeOH,25%水(含0.1%TFA),20分钟]。1H NMR(500MHz,DMSO-d6)δ8.21(d,J=8.0Hz,1H),8.15(d,J=8.0Hz,1H),7.82–7.79(m,2H),7.53–7.46(m,1H),7.45–7.33(m,4H),7.32–7.22(m,3H),7.12(d,J=8.6Hz,2H),6.89(d,J=8.7Hz,2H),5.01(s,2H),4.45(ddd,J=10.2,8.0,5.0Hz,1H),3.74–3.61(m,1H),3.59(s,3H),2.97(dd,J=13.8,5.1Hz,1H),2.76(dd,J=13.8,10.2Hz,1H),1.93(dd,J=7.1,4.0Hz,2H),1.80–1.68(m,2H),1.62–1.53(m,1H),1.55–1.40(m,1H),1.41–1.31(m,1H),1.32–1.14(m,2H),0.98–0.78(m,2H)。HRMS(ESI+):m/z C32H36N2O5(M+H)+529.2698;m/zC32H36N2O5Na(M+Na)+551.2514;HPLC–MS(ESI+):m/z 529.8[70%,(M+H)+],m/z 551.2[100%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-2-(2-反式-4-(3-(3,4-二氯苯基)丙酰胺基)-环己基)乙酰胺基)丙酸甲酯(SR2-093)。通过按照用于制备SR1-083的方法,由3-(3,4-二氯苯基)丙酸(0.028g,0.130mmol,1.2当量)得到酰胺SR2-093,为白色固体(0.059g,87%)。HPLC:>97%[tR=6.2分钟,80%MeOH,20%水(含0.1%TFA),20分钟]。1H NMR(500MHz,DMSO-d6)δ8.19(d,J=8.0Hz,1H),7.63(d,J=7.9Hz,1H),7.49(d,J=8.2Hz,1H),7.44–7.38(m,3H),7.38–7.32(m,2H),7.32–7.27(m,1H),7.16(dd,J=8.2,2.1Hz,1H),7.11(d,J=8.6Hz,2H),6.88(d,J=8.6Hz,2H),5.02(s,2H),4.41(ddd,J=10.0,7.9,5.1Hz,1H),3.58(s,3H),3.43–3.33(m,1H),2.94(dd,J=13.8,5.2Hz,1H),2.80–2.73(m,3H),2.29(t,J=7.5Hz,2H),1.90(dd,J=7.1,4.4Hz,2H),1.70–1.57(m,2H),1.57–1.49(m,1H),1.49–1.32(m,2H),1.07–0.90(m,2H),0.92–0.73(m,2H)。HRMS(ESI+):m/z C34H39Cl2N2O5(M+H)+625.2221;m/zC34H38Cl2N2O5Na(M+Na)+647.2039;HPLC–MS(ESI+):m/z 647.2[40%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-2-(2-反式-4-(3-(4-氰基苯基)丙酰胺基)-环己基)乙酰胺基)丙酸甲酯(SR2-094)。通过按照用于制备SR1-083的方法,由3-(4-氰基苯基)丙酸(0.023g,0.130mmol,1.2当量)得到酰胺SR2-094,为白色固体(0.061g,97%)。HPLC:>97%[tR=6.6分钟,70%MeOH,30%水(含0.1%TFA),20分钟]。]。1H NMR(500MHz,DMSO-d6)δ8.16(d,J=7.9Hz,1H),7.72(d,J=8.3Hz,2H),7.61(d,J=7.9Hz,1H),7.45–7.34(m,6H),7.33–7.28(m,1H),7.13(d,J=8.6Hz,2H),6.91(d,J=8.7Hz,2H),5.05(s,2H),4.45(ddd,J=9.9,7.9,5.2Hz,1H),3.60(s,3H),3.47–3.36(m,1H),2.97(dd,J=13.9,5.2Hz,1H),2.88(t,J=7.6Hz,2H),2.79(dd,J=13.9,9.9Hz,1H),2.35(t,J=7.6Hz,2H),1.93(dd,J=7.1,3.5Hz,2H),1.70–1.61(m,2H),1.61–1.53(m,1H),1.52–1.37(m,2H),1.09–0.95(m,2H),0.94–0.77(m,2H)。HRMS(ESI+):m/z C35H40N3O5(M+H)+582.2958;m/z C35H39N3O5Na(M+Na)+604.2776;HPLC–MS(ESI+):m/z 582.4[30%,(M+H)+],m/z 604.2[100%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-2-(2-反式-4-(2-(3,4-二氯苯基)乙酰胺基)-环己基)乙酰胺基)丙酸甲酯(SR2-100)。通过按照用于制备SR1-083的方法,由3-(3,4-二氯苯基)乙酸(0.027g,0.130mmol,1.2当量)得到酰胺SR2-100,为白色固体(0.058g,88%)。HPLC:>97%[tR=4.9分钟,80%MeOH,20%水(含0.1%TFA),20分钟]。1H NMR(500MHz,DMSO-d6)δ8.21(d,J=7.9Hz,1H),7.96(d,J=7.9Hz,1H),7.53(d,J=8.3Hz,1H),7.49(d,J=2.0Hz,1H),7.44–7.39(m,2H),7.39–7.34(m,2H),7.34–7.28(m,1H),7.21(dd,J=8.2,2.1Hz,1H),7.12(d,J=8.6Hz,2H),6.90(d,J=8.7Hz,2H),5.03(s,2H),4.43(ddd,J=10.0,7.9,5.1Hz,1H),3.59(s,3H),3.38(s,2H),2.96(dd,J=13.8,5.1Hz,1H),2.77(dd,J=13.8,10.0Hz,1H),1.92(dd,J=7.1,5.0Hz,2H),1.73–1.63(m,2H),1.60–1.52(m,1H),1.53–1.42(m,1H),1.42–1.33(m,1H),1.19–0.98(m,2H),0.95–0.72(m,2H)。HRMS(ESI+):m/zC33H36Cl2N2O5(M)+610.1999;m/z C33H36Cl2N2O5Na(M+Na)+633.1890;HPLC–MS(ESI+):m/z633.1[80%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-2-(2-反式-4-(2-(4-氰基苯基)乙酰胺基)环己基)-乙酰胺基)丙酸甲酯(SR2-108)。通过按照用于制备SR1-083的方法,使用(4-氰基苯基)乙酸(0.021g,0.130mmol,1.2当量)得到酰胺SR2-108,为白色固体(0.059g,96%)。HPLC:>98%[tR=5.6分钟,70%MeOH,30%水(含0.1%TFA),20分钟]。1H NMR(500MHz,DMSO-d6)δ8.19(d,J=8.0Hz,1H),7.99(d,J=7.8Hz,1H),7.72(d,J=8.3Hz,2H),7.44–7.37(m,4H),7.37–7.33(m,2H),7.32–7.26(m,1H),7.10(d,J=8.6Hz,2H),6.88(d,J=8.7Hz,2H),5.01(s,2H),4.41(ddd,J=10.1,7.9,5.1Hz,1H),3.58(s,3H),3.45(s,2H),3.36(m,1H),2.94(dd,J=13.8,5.1Hz,1H),2.75(dd,J=13.8,10.0Hz,1H),1.90(dd,J=7.1,4.8Hz,2H),1.74–1.64(m,2H),1.54(m,1H),1.53–1.41(m,1H),1.41–1.31(m,1H),1.16–0.97(m,2H),0.93–0.74(m,2H)。HRMS(ESI+):m/z C34H38N3O5(M+H)+568.2802;m/z C34H37N3O5Na(M+Na)+590.2620;HPLC–MS(ESI+):m/z 568.2[100%,(M+H)+],m/z 590.2[100%,(M+Na)+]。
含D-酪氨酸的类似物的合成
(R)-3-(4-(苄氧基)苯基)-2-(2-(1-(3-(3,4-二氯苯基)丙酰基)哌啶-4-基)乙酰胺基)丙酸甲酯(SR2-134)。采用一般方法D,由3-(3,4-二氯苯基)丙酸(0.029g,0.134mmol,1.2当量)和SR2-132(SR1-085的对映体,其制备方式与SR1-085相同)得到酰胺SR2-134,为白色泡沫状物(0.140g,97%)。HPLC:>98%[tR=6.4分钟,80%MeOH,20%水(含0.1%TFA),20分钟]。HRMS(ESI+):m/z C33H37Cl2N2O5(M+H)+611.2081;m/z C33H36Cl2N2O5Na(M+Na)+633.1899实测值633.1899;HPLC–MS(ESI+):m/z 633.2[100%,(M+Na)+]。
(R)-3-(4-(苄氧基)苯基)-2-(2-(1-(3-(4-氰基苯基)丙酰基)哌啶-4-基)乙酰胺基)丙酸甲酯(SR2-135)。采用方法D,由3-(4-氰基苯基)丙酸(0.024g,0.134mmol,1.2当量)和SR2-132(0.050g,0.112mmol)得到酰胺SR2-135,为白色泡沫状物(0.063g,99%)。1H NMR(500MHz,DMSO-d6)δ8.25(d,J=8.0Hz,1H),7.55–7.48(m,2H),7.47–7.35(m,5H),7.34–7.29(m,1H),7.24(dd,J=8.7,7.2Hz,1H),7.13(d,J=8.6Hz,2H),6.91(dd,J=8.6,1.9Hz,2H),5.06(s,1H),5.04(s,1H),4.46(ddd,J=13.2,10.2,5.2Hz,1H),4.32–4.21(m,1H),3.82–3.70(m,1H),3.61(s,3H),2.98(dd,J=13.8,5.1Hz,1H),2.89–2.74(m,4H),2.68–2.53(m,2H),2.47–2.35(m,1H),1.96(d,J=7.2Hz,2H),1.83–1.64(m,1H),1.48(m,1H),1.37–1.27(m,1H),0.97–0.68(m,2H)。HPLC:>97%[tR=6.5分钟,70%MeOH,30%水(含0.1%TFA),20分钟]。HRMS(ESI+):m/z C34H38N3O5(M+H)+568.2805;m/z C34H37N3O5Na(M+Na)+590.2628;HPLC–MS(ESI+):m/z 568.2[40%(M+H)+],m/z 599.2[100%,(M+Na)+]。
(R)-3-(4-(苄氧基)苯基)-2-(2-(1-(3-苯基丙酰基)哌啶-4-基)乙酰胺基)丙酸甲酯(SR3-138)。采用一般方法A,由3-苯基丙酰氯(0.020μL,0.134mmol,1.2当量)和SR2-132(0.050g,0.112mmol)制备N-苯基丙酰基衍生物SR3-138(0.059g,97%)。HPLC:>99%[tR=9.6分钟,70%MeOH,30%水(含0.1%TFA),20分钟]。1H NMR(500MHz,DMSO-d6)δ8.25(d,J=8.0Hz,1H),7.43(dd,J=12.2,7.2Hz,2H),7.40–7.35(m,2H),7.32(m,1H),7.29–7.20(m,4H),7.21–7.15(m,1H),7.13(d,J=8.3Hz,2H),6.91(d,J=8.6Hz,2H),5.06(s,1H),5.04(s,1H),4.46(ddd,J=12.8,9.8,4.8Hz,1H),4.35–4.25(m,1H),3.80–3.69(m,1H),3.61(s,3H),2.98(dd,J=13.8,5.1Hz,1H),2.91–2.72(m,4H),2.67–2.52(m,2H),2.48–2.35(m,1H),1.96(d,J=7.2Hz,2H),1.81–1.64(m,1H),1.51–1.43(m,1H),1.35–1.23(m,1H),0.95–0.71(m,2H)。HRMS(ESI+):m/z C33H38N2O5(M+H)+543.2853;m/z C33H38N2O5Na(M+Na)+565.2682。HPLC–MS(ESI+):m/z 543.4[30%,(M+H)+],565.2[100%,(M+Na)+]。
(R)-3-(4-(苄氧基)苯基)-2-(2-(1-(3-苯基丙酰基)哌啶-4-基)乙酰胺基)丙酸(SR2-148)。通过与制备SR2-022所用相同的方法,由甲酯SR3-138(27.0mg)制备羧酸SR2-148(25.0mg,95%),其分离为白色泡沫状物。HPLC:>98%[tR=4.4分钟,70%MeOH,30%水(含0.1%TFA),20分钟]。1H NMR(500MHz,DMSO-d6)δ12.63(bs,1H),8.10(d,J=8.3Hz,1H),7.47–7.34(m,4H),7.33–7.29(m,1H),7.28–7.20(m,4H),7.18(m,1H),7.14(d,J=8.5Hz,2H),6.91(d,J=8.6Hz,2H),5.06(s,1H),5.03(s,1H),4.41(ddd,J=9.7,6.0,4.1Hz,1H),4.34–4.22(m,1H),3.78–3.66(m,1H),3.01(dd,J=14.3,3.6Hz,1H),2.89–2.69(m,4H),2.64–2.51(m,2H),2.47–2.34(m,1H),1.95(d,J=7.2Hz,2H),1.81–1.64(m,1H),1.54–1.38(m,1H),1.34–1.20(m,1H),0.93–0.71(m,2H)。HRMS(ESI+):m/z C32H37N2O5(M+H)+529.2698;m/z C32H36N2O5Na(M+Na)+551.2514。HPLC–MS(ESI+):m/z 529.2[80%(M+H)+],m/z 551.2[100%,(M+Na)+],HPLC–MS(ESI-):m/z 527.3[100%(M-H)-]。
含Tyr(OMe)的衍生物的合成
(S)-2-(2-(1-(3-(3,4-二氯苯基)丙酰基)哌啶-4-基)乙酰胺基)-3-(4-甲氧基苯基)丙酸甲酯(SR2-136)。采用一般方法D,由(S)-3-(4-甲氧基苯基)-2-(2-(哌啶-4-基)乙酰胺基)丙酸甲酯的HCl盐(0.100g,0.269mmol)和3-(3,4-二氯苯基)丙酸(0.071g,0.323mmol,1.2当量)得到酰胺SR2-136,为白色泡沫状物(0.140g,97%)。HPLC:>94%[tR=6.5分钟,70%MeOH,30%水(含0.1%TFA),20分钟]。1H NMR(500MHz,DMSO-d6)δ8.24(d,J=8.0Hz,1H),7.55–7.50(m,2H),7.25(dt,J=8.4,2.5Hz,1H),7.12(d,J=8.5Hz,2H),6.82(d,J=8.5Hz,2H),4.49–4.40(m,1H),4.30–4.20(m,1H),3.80–3.70(m,1H),3.71(s,1.5H),3.68(s,1.5H),3.60(s,3H),2.97(dd,J=13.8,5.1Hz,1H),2.89–2.73(m,4H),2.68–2.53(m,2H),2.47–2.36(m,1H),1.96(d,J=7.6Hz,2H),1.81–1.66(m,1H),1.54–1.43(m,1H),1.36–1.22(m,1H),0.97–0.66(m,2H)。HRMS(ESI+):m/z C27H33Cl2N2O5(M+H)+535.1757;m/zC27H32Cl2N2O5Na(M+Na)+557.1582;HPLC–MS(ESI+):m/z 535.2[30%(M+H)+],m/z 557.2[100%,(M+Na)+]。
(S)-2-(2-(1-(3-(4-氰基苯基)丙酰基)哌啶-4-基)乙酰胺基)-3-(4-甲氧基-苯基)丙酸甲酯(SR2-137)。采用一般方法D,由(S)-3-(4-甲氧基苯基)-2-(2-(哌啶-4-基)乙酰胺基)丙酸甲酯的HCl盐(0.100g,0.269mmol)和3-(4-氰基苯基)丙酸(0.071g,0.323mmol,1.2当量)得到酰胺SR2-136,为白色泡沫状物(0.140g,97%)。HPLC:>98%[tR=4.7分钟,60%MeOH,40%水(含0.1%TFA),20分钟]。1H NMR(500MHz,DMSO-d6)δ8.25(d,J=8.0Hz,1H),7.74(dd,J=8.3,2.4Hz,2H),7.46(dd,J=8.2,2.5Hz,2H),7.13(d,J=8.5Hz,2H),6.83(d,J=8.5Hz,2H),4.45(m,1H),4.25(m,1H),3.84–3.70(m,1H),3.72(s,1.5H),3.68(s,1.5H),3.61(s,3H),2.98(dd,J=13.8,5.1Hz,1H),2.93–2.81(m,3H),2.77(dd,J=13.8,10.1Hz,1H),2.67–2.58(m,2H),2.48–2.35(m,1H),1.96(d,J=7.2Hz,2H),1.81–1.68(m,1H),1.54–1.43(m,1H),1.37–1.21(m,1H),0.99–0.70(m,2H)。HRMS(ESI+):m/zC28H34N3O5(M+H)+492.2494;m/z C28H33N3O5Na(M+Na)+514.2317;HPLC–MS(ESI+):m/z 492.2[80%(M+H)+],m/z 514.2[100%,(M+Na)+]。
(S)-3-(4-甲氧基苯基)-2-(2-(1-(3-苯基丙酰基)哌啶-4-基)乙酰胺基)-丙酸甲酯(SR2-139)。采用一般方法D,由(S)-3-(4-甲氧基苯基)-2-(2-(哌啶-4-基)乙酰胺基)丙酸甲酯的HCl盐(0.100g,0.269mmol)和3-苯基丙酰氯(0.048μL,0.323mmol,1.2当量)得到酰胺SR2-139,为白色泡沫状物(0.101g,81%)。HPLC:>99%[tR=4.7分钟,70%MeOH,30%水(含0.1%TFA),20分钟]。1H NMR(500MHz,DMSO-d6)δ8.24(d,J=8.0Hz,1H),7.32–7.21(m,4H),7.18(td,J=7.0,1.8Hz,1H),7.13(d,J=8.5Hz,2H),6.83(d,J=8.2Hz,2H),4.45(ddd,J=12.7,9.6,4.7Hz,1H),4.33–4.22(m,1H),3.83–3.70(m,1H),3.72(s,1.5H),3.67(s,1.5H),3.61(s,3H),2.98(dd,J=13.8,5.2Hz,1H),2.90–2.73(m,4H),2.57(td,J=7.5,3.1Hz,2H),2.48–2.35(m,1H),1.95(d,J=7.5Hz,2H),1.80–1.65(m,1H),1.51–1.44(m,1H),1.34–1.22(m,1H),0.95–0.71(m,2H)。HRMS(ESI+):m/z C27H35N2O5(M+H)+467.2536;m/zC27H34N2O5Na(M+Na)+489.2362;HPLC–MS(ESI+):m/z 467.2[50%(M+H)+],m/z 489.2[100%,(M+Na)+]。
(S)-3-(4-甲氧基苯基)-2-(2-(1-(3-苯基丙酰基)哌啶-4-基)乙酰胺基)丙酸(SR2-149)。通过按照与制备SR2-022所用相同的方法,由甲酯SR2-139(0.050g,0.107mmol)制备羧酸SR2-149(0.048g,98%)。HPLC:>99%[tR=3.7分钟,70%MeOH,30%水(含0.1%TFA),20分钟]。1H NMR(500MHz,DMSO-d6)δ12.42(bs,1H),8.07(d,J=8.3Hz,1H),7.32–7.20(m,4H),7.17(m,1H),7.13(d,J=8.6Hz,2H),6.82(d,J=8.2Hz,2H),4.44–4.34(m,1H),4.25(m,1H),3.79–3.67(m,1H),3.71(s,1.5H),3.66(s,1..5H),3.00(dd,J=13.8,4.6Hz,1H),2.88–2.67(m,4H),2.56(td,J=7.5,3.0Hz,2H),2.47–2.33(m,1H),1.94(d,J=7.2Hz,2H),1.78–1.65(m,1H),1.52–1.39(m,1H),1.32–1.19(m,1H),0..94–0.69(m,2H)。HRMS(ESI+):m/z C26H33N2O5(M+H)+453.2383;m/z C26H32N2O5Na(M+Na)+475.2207;HPLC–MS(ESI+):m/z453.2[50%(M+H)+],m/z 475.2[100%,(M+Na)+]。
脲衍生物的合成
(S)-4-(3-(3-(4-(苄氧基)苯基)-1-甲氧基-1-氧代丙烷-2-基)脲基)哌啶-1-羧酸叔丁酯(SR2-127)。将胺盐H-Tyr(OBn)OMe·HCl(6.215mmol,,2.00g)溶解在THF(40mL)中。向此溶液中添加三乙胺(28.645mmol,2.60mL)和氯甲酸4-硝基苯酯(9.323mmol,1.879g)。将所得混合物在室温下搅拌5h。在减压下除去溶剂,并将所得残留物溶解在DCM(30mL)中。将有机层用水(2×20mL)洗涤并蒸发,得到SR2-126,为白色固体,其不经进一步纯化直接用于下一步。将SR2-126溶解在DMF(20mL)中并添加1-Boc-4-氨基哌啶(9.322mmol,1.867g)。将混合物在80℃下加热16h并在减压下浓缩。将所得残留物溶解在EtOAc(50mL)中,并用饱和NH4Cl(3×25mL)洗涤。使用MeOH/DCM(0-10%)作为洗脱液,通过快速柱色谱法纯化,得到SR2-127,为白色泡沫状物(1.953g,61%)。1H NMR(500MHz,DMSO-d6)δ7.44(m,2H),7.40(m,2H),7.33(m,1H),7.06(d,J=8.6Hz,2H),6.93(d,J=8.6Hz,2H),6.14(d,J=7.8Hz,1H),6.02(d,J=8.2Hz,1H),5.07(s,2H),4.35(td,J=7.9,5.6Hz,1H),3.75(m,2H),3.59(s,3H),3.55–3.43(m,1H),2.89(dd,J=9.8,4.0Hz,1H),2.89–2.76(m,2H),2.82(dd,J=13.8,7.7Hz,1H),1.72–1.63(m,2H),1.39(s,9H),1.21–1.06(m,2H)。HRMS(ESI+):m/z C28H38N3O6(M+H)+512.2745;m/z C28H37N3O6Na(M+Na)+534.2567;HPLC–MS(ESI+):m/z 512.3[60%(M+H)+],m/z 534.3[100%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-2-(3-(哌啶-4-基)脲基)丙酸甲酯盐酸盐(SR2-140)。将N-Boc-哌啶SR2-127(0.603mmol,0.309g)溶解在4N HCl/二噁烷(3.5mL)中,并在室温下搅拌2h。将混合物在减压下浓缩,得到SR2-140,为白色固体(0.267g,99%)。
(S)-3-(4-(苄氧基)苯基)-2-(3-(1-(3-(3,4-二氯苯基)丙酰基)哌啶-4-基)脲基)丙酸甲酯(SR2-141)。采用一般方法D,由胺盐SR2-140(0.050g,0.112mmol)和3-(3,4-二氯苯基)丙酸(0.029g,0.134mmol,1.2当量)得到酰胺SR2-141,为白色泡沫状物(0.048g,66%)。HPLC:>98%[tR=6.0分钟,70%MeOH,30%水(含0.1%TFA),20分钟]。1H NMR(500MHz,DMSO-d6)δ7.55(bs,1H),7.52(d,J=8.2Hz,1H),7.46–7.42(m,2H),7.39(m,2H),7.33(m,1H),7.25(dd,J=8.4,2.0Hz,1H),7.06(d,J=8.6Hz,2H),6.92(d,J=8.6Hz,2H),6.15(d,J=7.8Hz,1H),6.04(dd,J=8.2,2.7Hz,1H),5.07(s,2H),4.35(td,J=7.9,5.6Hz,1H),4.10(m,1H),3.78–3.69(m,1H),3.59(s,3H),3.57–3.49(m,1H),3.12–3.01(m,1H),2.89(dd,J=13.8,5.6Hz,1H),2.86–2.72(m,4H),2.68–2.60(m,2H),1.77–1.64(m,2H),1.27–1.04(m,2H)。HRMS(ESI+):m/z C32H36Cl2N3O5(M+H)+612.2024;m/z C32H35Cl2N3O5Na(M+Na)+634.1849;HPLC–MS(ESI+):m/z 634.2[80%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-2-(3-(1-(3-(4-氰基苯基)丙酰基)哌啶-4-基)脲基)-丙酸甲酯(SR2-142)。采用一般方法D,由胺盐SR2-140(0.050g,0.112mmol)和3-(4-氰基苯基)丙酸(0.029g,0.134mmol,1.2当量)得到酰胺SR2-142,为白色泡沫状物(0.049g,77%)。HPLC:>99%[tR=6.4分钟,70%MeOH,30%水(含0.1%TFA),20分钟]。1H NMR(500MHz,DMSO-d6)δ7.74(d,J=8.2Hz,2H),7.49–7.42(m,4H),7.39(td,J=7.5,1.6Hz,2H),7.35–7.31(m,1H),7.06(d,J=8.6Hz,2H),6.92(d,J=8.6Hz,2H),6.15(d,J=7.7Hz,1H),6.03(dd,J=8.2,2.5Hz,1H),5.07(s,2H),4.35(td,J=7.8,5.6Hz,1H),4.10(m,1H),3.72(m,1H),3.59(s,3H),3.57–3.49(m,1H),3.06(td,J=14.6,3.7Hz,1H),2.94–2.85(m,3H),2.82(dd,J=13.8,7.7Hz,1H),2.77(dt,J=14.0,7.3Hz,1H),2.71–2.61(m,2H),1.76–1.64(m,2H),1.24–1.02(m,2H)。HRMS(ESI+):m/z C32H37N4O5(M+H)+569.2757;m/z C32H36N4O5Na(M+Na)+591.2577;HPLC–MS(ESI+):m/z 569.2[30%,(M+H)+];m/z 591.2[100%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-2-(3-(1-(3-苯基丙酰基)哌啶-4-基)脲基)-丙酸甲酯(SR2-143)。通过按照一般方法D,由胺盐SR2-140(0.050g,0.112mmol)和3-苯基丙酸(0.029g,0.134mmol,1.2当量)得到酰胺SR2-143,为白色泡沫状物(0.048g,79%)。HPLC:>99%[tR=4.7分钟,70%MeOH,30%水(含0.1%TFA),20分钟]。1H NMR(500MHz,DMSO-d6)δ7.44(d,J=7.6Hz,2H),7.39(td,J=7.6,2.2Hz,2H),7.36–7.30(m,1H),7.31–7.21(m,4H),7.18(m,1H),7.06(d,J=8.3Hz,2H),6.93(d,J=8.2Hz,2H),6.13(d,J=7.7Hz,1H),6.04(dd,J=7.9,2.6Hz,1H),5.07(s,2H),4.35(m,1H),4.12(m,1H),3.75–3.66(m,1H),3.59(s,3H),3.53(m,1H),3.05(dd,J=14.3,10.8Hz,1H),2.89(dd,J=13.8,5.6Hz,1H),2.85–2.71(m,4H),2.65–2.56(m,2H),1.73–1.63(m,2H),1.22–0.97(m,2H)。HRMS(ESI+):m/zC32H38N3O5(M+H)+544.2814;m/z C32H37N3O5Na(M+Na)+566.2633;HPLC–MS(ESI+):m/z 544.2[30%,(M+H)+];m/z 566.2[100%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-2-(3-(1-(3-苯基丙酰基)哌啶-4-基)脲基)丙酸(SR2-147)。通过按照对于SR2-022的合成报道的方法,由SR2-143得到羧酸SR2-147,为白色泡沫状物(0.031g,80%)。1H NMR(500MHz,DMSO-d6)δ12.10(bs,1H),8.20(d,J=2.2Hz,2H),7.45–7.33(m,4H),7.33–7.21(m,5H),7.20–7.12(m,1H),7.04(d,J=8.4Hz,2H),6.90(dd,J=8.3,4.8Hz,2H),5.06(d,J=4.5Hz,2H),4.49–4.35(m,1H),4.26(t,J=4.5Hz,1H),3.89–3.69(m,2H),2.95–2.76(m,5H),2.60(dd,J=8.8,6.7Hz,2H),2.49–2.36(m,1H),1.99–1.86(m,1H),1.86–1.69(m,1H),1.25–1.08(m,2H)。HPLC:>96%[tR=4.9分钟,75%MeOH,25%水(含0.1%TFA),20分钟]。HRMS(ESI+):m/z C31H36N3O5(M+H)+530.2648;m/z C31H35N3O5Na(M+Na)+552.2480;HPLC–MS(ESI+):m/z 530.2[30%,(M+H)+];m/z 552.2[40%,(M+Na)+]。
(2-(1-(3-(4-氰基苯基)丙酰基)哌啶-4-基)乙酰基)-L-酪氨酸甲酯(SR2-150)。通过按照用于制备SR2-014的方法,由苄醚SR2-142(0.019g,0.033mmol)得到酚SR2-150,为白色泡沫状物(0.014g,87%)。HPLC:>96%[tR=4.6分钟,50%MeOH,50%水(含0.1%TFA),20分钟]。1H NMR(500MHz,DMSO-d6)δ9.23(s,1H),8.22(dd,J=7.9,4.6Hz,1H),7.74(dd,J=8.2,1.9Hz,2H),7.46(d,J=7.4Hz,2H),6.99(d,J=8.2Hz,2H),6.65(d,J=8.4Hz,2H),4.45–4.36(m,1H),4.32–4.23(m,1H),3.76(m,1H),3.60(s,3H),2.97–2.81(m,4H),2.79–2.68(m,1H),2.68-2.58(m,2H),2.46–2.36(m,1H),2.00–1.93(m,2H),1.81–1.69(m,1H),1.55–1.44(m,1H),1.37(m,1H),0.98–0.73(m,2H)。HRMS(ESI+):m/z C27H32N3O5(M+H)+478.2343;m/z C27H31N3O5Na(M+Na)+500.2161;HPLC–MS(ESI-):m/z 476.2[100%,(M-H)-];m/z 500.2[20%,(M+Na)+]。
(2-(1-(3-(3,4-二氯苯基)丙酰基)哌啶-4-基)乙酰基)-L-酪氨酸甲酯(SR2-151)。通过按照用于制备SR2-014的方法,由苄醚SR2-030(0.019g,0.033mmol)得到酚SR2-151,为白色泡沫状物(0.011g,98%)。HPLC:>97%[tR=9.5分钟,40%MeOH,60%水(含0.1%TFA),20分钟]。1H NMR(500MHz,DMSO-d6)δ9.23(s,1H),8.22(dd,J=7.9,4.6Hz,1H),7.57–7.48(m,1H),7.32–7.20(m,1H),7.18(m,1H),6.99(d,J=8.0Hz,2H),6.65(d,J=8.0Hz,2H),4.41(m,1H),4.33–4.24(m,1H),3.76(m,1H),3.60(s,3H),2.97–2.67(m,6H),2.67–2.54(m,1H),2.47–2.35(m,1H),2.04–1.91(m,2H),1.83–1.68(m,1H),1.54–1.44(m,1H),1.42–1.28(m,1H),0.96–0.75(m,2H)。HRMS(ESI+):m/z C26H31Cl2N2O5(M+H)+521.1612;m/z C26H30Cl2N2O5Na(M+Na)+543.1429;HPLC–MS(ESI+):m/z 521.4[40%,(M+H)-];m/z543.0[100%,(M+Na)+]。
C-末端羧酸衍生物的合成
一般方法F:C-末端甲酯的水解:将选定的甲酯衍生物(0.020-0.050g,0.045-0.092mmol)溶解在MeOH(1mL)中,并将2N NaOH水溶液(1.0mL,20mmol)添加到混合物里。在室温下搅拌反应1.5h并在减压下浓缩。将所得水层用水(3mL)稀释,并用Et2O(2×15mL)洗涤。将水层用1N HCl酸化(pH~3.0),然后用EtOAc(2×20mL)萃取。将合并的有机层经无水(Na2SO4)干燥并蒸发,得到相应的羧酸衍生物,为白色半固体或泡沫状物(92-99%收率)。
(S)-3-(4-(苄氧基)苯基)-2-(2-(1-(2-苯乙酰基)哌啶-4-基)乙酰胺基)丙酸(SR2-118)。采用一般方法F,由甲酯SR1-122(0.024g,0.045mmol)得到羧酸SR2-118,为白色泡沫状物(0.023g,99%)。HPLC:>97%[tR=5.3分钟,70%MeOH,30%水(含0.1%TFA),20分钟]。1H NMR(500MHz,DMSO-d6)δ12.60(bs,1H),8.07(d,J=8.3Hz,1H),7.41(dd,J=7.2,5.4Hz,2H),7.35(td,J=7.5,2.3Hz,2H),7.32–7.24(m,3H),7.19(td,J=7.0,2.6Hz,3H),7.11(d,J=7.1Hz,1H),6.88(d,J=8.6Hz,1H),5.03(s,2H),4.42–4.31(m,1H),4.30–4.19(m,1H),3.87–3.74(m,1H),3.64(s,2H),2.97(ddd,J=13.9,4.6,2.0Hz,1H),2.91–2.80(m,1H),2.71(dd,J=13.9,10.3Hz,1H),2.46–2.31(m,1H),1.91(d,J=7.1Hz,2H),1.78–1.64(m,1H),1.52–1.37(m,1H),1.32–1.19(m,1H),0.90–0.63(m,2H)。HRMS(ESI+):m/zC31H35N2O5(M+H)+515.2533;m/z C31H34N2O5Na(M+Na)+537.2349;HPLC–MS(ESI+):m/z 515.2[80%,(M+H)-];m/z 537.2[100%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-2-(2-(1-(3-(3,4-二氯苯基)丙酰基)哌啶-4-基)乙酰胺基)丙酸(SR2-113)。采用一般方法F,由甲酯SR2-030(0.030g,0.049mmol)得到羧酸SR2-113,为白色泡沫状物(0.028g,96%)。HPLC:>97%[tR=11.3分钟,70%MeOH,30%水(含0.1%TFA),20分钟]。1H NMR(500MHz,DMSO-d6)δ12.47(bs,1H),8.09(d,J=8.3Hz,1H),7.54–7.47(m,2H),7.45–7.34(m,4H),7.33–7.28(m,1H),7.23(td,J=7.9,2.1Hz,1H),7.13(d,J=8.6Hz,2H),6.90(dd,J=8.6,2.0Hz,2H),5.05(s,1H),5.02(s,1H),4.45–4.36(m,1H),4.31–4.20(m,1H),3.81–3.64(m,1H),3.00(dd,J=13.9,4.6Hz,1H),2.89–2.69(m,4H),2.67–2.53(m,2H),2.47–2.34(m,1H),1.95(d,J=7.2Hz,2H),1.78–1.65(m,1H),1.52–1.43(m,1H),1.37–1.21(m,1H),0.97–0.70(m,2H)。HRMS(ESI+):m/z C32H35Cl2N2O5(M+H)+597.1909;m/z C32H34Cl2N2O5Na(M+Na)+619.1734;HPLC–MS(ESI+):m/z 619.2[60%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-2-(2-(1-(3-(4-氰基苯基)丙酰基)哌啶-4-基)乙酰胺基)丙酸(SR2-114)。采用一般方法F,由甲酯SR2-033(0.023g,0.041mmol)得到羧酸SR2-114,为白色泡沫状物(0.022g,98%)。HPLC:>97%[tR=5.9分钟,65%MeOH,35%水(含0.1%TFA),20分钟]。1H NMR(500MHz,DMSO-d6)δ12.64(s,1H),8.11(d,J=8.3Hz,1H),7.72(t,J=8.2Hz,2H),7.50–7.23(m,7H),7.14(d,J=8.6Hz,2H),6.91(d,J=7.6Hz,2H),5.05(s,1H),5.03(s,1H),4.46–4.36(m,1H),4.31–4.22(m,1H),3.81–3.65(m,1H),3.01(dd,J=13.9,4.6Hz,1H),2.93–2.79(m,3H),2.74(dd,J=13.8,10.3Hz,1H),2.69–2.53(m,2H),2.48–2.36(m,1H),1.95(d,J=7.2Hz,2H),1.78–1.68(m,1H),1.53–1.41(m,1H),1.35–1.24(m,1H),0.98–0.71(m,2H)。HRMS(ESI+):m/z C33H36N3O5(M+H)+554.2648;m/z C33H35N3O5Na(M+Na)+576.2463;HPLC–MS(ESI+):m/z 554.2[50%,(M+H)+];m/z 576.2[60%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-2-(2-(1-(3,3-二苯基丙酰基)哌啶-4-基)乙酰胺基)-丙酸(SR2-115)。采用一般方法F,由甲酯SR2-029(0.053g,0.086mmol)得到羧酸SR2-115,为白色泡沫状物(0.051g,98%)。HPLC:>98%[tR=6.0分钟,75%MeOH,25%水(含0.1%TFA),20分钟]。1H NMR(500MHz,DMSO-d6)δ12.56(bs,1H),8.02(dd,J=8.3,3.3Hz,1H),7.39–7.32(m,3H),7.33–7.25(m,2H),7.27–7.13(m,8H),7.12–7.03(m,4H),6.86–6.79(m,2H),4.97(s,2H),4.41(td,J=7.4,3.4Hz,1H),4.37–4.28(m,1H),4.17–4.03(m,1H),3.92–3.76(m,1H),3.11–2.88(m,3H),2.74(dd,J=20.1,7.7Hz,1H),2.66(ddd,J=14.0,10.2,4.1Hz,1H),2.35–2.19(m,1H),1.83(d,J=7.2Hz,2H),1.70–1.51(m,1H),1.45–1.28(m,1H),1.26–1.09(m,1H),0.83–0.52(m,2H)。HRMS(ESI+):m/z C38H41N2O5(M+H)+605.3005;m/zC38H40N2O5Na(M+Na)+627.2827;HPLC–MS(ESI+):m/z 605.2[80%,(M+H)+];m/z 627.2[100%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-2-(2-(1-(3-(3-氯苯基)丙酰基)哌啶-4-基)乙酰胺基)丙酸(SR2-116)。采用一般方法F,由甲酯SR2-032(0.030g,0.052mmol)得到羧酸SR2-116,为白色泡沫状物(0.027g,92%)。HPLC:>99%[tR=3.1分钟,70%MeOH,30%水(含0.1%TFA),20分钟]。1H NMR(500MHz,DMSO-d6)δ12.61(bs,1H),8.07(d,J=8.3Hz,1H),7.45–7.32(m,4H),7.28(m,3H),7.19(m,2H),7.12(d,J=8.2Hz,2H),6.88(d,J=8.2Hz,2H),5.03(s,1H),5.01(s,1H),4.44–4.32(m,1H),4.29–4.16(m,1H),3.80–3.64(m,1H),2.98(dd,J=13.9,4.6Hz,1H),2.87–2.66(m,4H),2.63–2.52(m,1H),2.44–2.19(m,2H),1.93(d,J=7.2Hz,2H),1.78–1.63(m,1H),1.51–1.36(m,1H),1.35–1.19(m,1H),0.98–0.64(m,2H)。HRMS(ESI+):m/z C32H36ClN2O5(M+H)+563.2298;m/z C32H35ClN2O5Na(M+Na)+585.2135;HPLC–MS(ESI+):m/z 563.2[40%,(M+H)+];m/z 585.2[70%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-2-(2-(1-(3-(3-氟苯基)丙酰基)哌啶-4-基)乙酰胺基)丙酸(SR2-117)。采用一般方法F,由甲酯SR2-010(0.051g,0.091mmol)得到羧酸SR2-117,为白色泡沫状物(0.049g,98%)。HPLC:>97%[tR=7.8分钟,70%MeOH,30%水(含0.1%TFA),20分钟]。1H NMR(500MHz,DMSO-d6)δ12.54(bs,1H),8.08(d,J=8.3Hz,1H),7.45–7.36(m,2H),7.35(td,J=7.5,2.2Hz,1H),7.32–7.19(m,3H),7.11(d,J=8.2Hz,2H),7.10–7.00(m,2H),7.00–6.92(m,1H),6.88(d,J=8.2Hz,2H),5.03(s,1H),5.01(s,1H),4.39(td,J=9.3,4.6Hz,1H),4.30–4.16(m,1H),3.72(m,1H),2.98(m,1H),2.89–2.66(m,4H),2.64–2.50(m,2H),2.46–2.23(m,1H),1.93(d,J=7.1Hz,2H),1.77–1.62(m,1H),1.50–1.40(m,1H),1.36–1.07(m,1H),0.96–0.63(m,2H)。19F NMR(471MHz,DMSO-d6)δ-113.91(d,J=8.9Hz)。HRMS(ESI+):m/z C32H35FN2O5(M+H)+547.2597;m/z C32H35FN2O5Na(M+Na)+569.2421;HPLC–MS(ESI+):m/z 547.3[80%,(M+H)+];m/z 569.2[80%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-2-(2-(1-(3-(4-氯苯基)丙酰基)哌啶-4-基)乙酰胺基)丙酸(SR2-119)。采用一般方法F,由甲酯SR2-004(0.020g,0.035mmol)得到羧酸SR2-119,为白色泡沫状物(0.019g,98%)。HPLC:>97%[tR=6.6分钟,75%MeOH,25%水(含0.1%TFA),20分钟]。1H NMR(500MHz,DMSO-d6)δ12.61(bs,1H),8.06(d,J=8.3Hz,1H),7.40(dd,J=13.2,7.1Hz,2H),7.37–7.32(m,2H),7.32–7.26(m,3H),7.23(m,2H),7.11(d,J=8.6Hz,2H),6.88(d,J=8.5Hz,2H),5.03(s,1H),5.01(s,1H),4.43–4.34(m,2H),4.28–4.17(m,1H),3.77–3.64(m,1H),2.98(dd,J=13.9,4.6Hz,1H),2.86–2.65(m,4H),2.61–2.50(m,2H),2.45–2.32(m,1H),1.93(d,J=7.2Hz,2H),1.77–1.63(m,1H),1.50–1.39(m,1H),1.31–1.20(m,1H),0.95–0.66(m,2H)。HRMS(ESI+):m/z C32H36ClN2O5(M+H)+563.2297;m/zC32H35ClN2O5Na(M+Na)+585.2125;HPLC–MS(ESI+):m/z 563.2[80%,(M+H)+];m/z 585.2[80%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-2-(2-(1-(3-(4-氟苯基)丙酰基)哌啶-4-基)乙酰胺基)丙酸(SR2-120)。采用一般方法F,由甲酯SR2-008(0.048g,0.085mmol)得到羧酸SR2-120,为白色泡沫状物(0.046g,98%)。HPLC:>99%[tR=8.5分钟,70%MeOH,30%水(含0.1%TFA),20分钟]。1H NMR(500MHz,DMSO-d6)δ12.62(bs,1H),8.07(d,J=8.3Hz,1H),7.36(m,4H),7.27–7.19(m,3H),7.11(d,J=8.6Hz,2H),7.06(dd,J=9.1,6.7Hz,2H),6.88(d,J=8.6Hz,2H),5.03(s,1H),5.01(s,1H),4.39(m,1H),4.31–4.17(m,1H),3.78–3.59(m,1H),2.98(dd,J=13.9,4.6Hz,1H),2.87–2.61(m,4H),2.53(m,1H),2.43–2.20(m,2H),1.93(d,J=7.2Hz,2H),1.76–1.57(m,1H),1.50–1.35(m,1H),1.34–1.11(m,1H),0.95–0.59(m,2H)。HRMS(ESI+):m/z C32H35FN2O5(M+H)+547.2599;m/z C32H35FN2O5Na(M+Na)+569.2410;HPLC–MS(ESI+):m/z 547.3[60%,(M+H)+];m/z 569.2[70%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-2-(2-(1-(3-(邻甲苯基)丙酰基)哌啶-4-基)乙酰胺基)-丙酸(SR2-121)。采用一般方法F,由甲酯SR2-035(0.025g,0.045mmol)得到羧酸SR2-121,为白色泡沫状物(0.024g,99%)。HPLC:>99%[tR=10.3分钟,70%MeOH,30%水(含0.1%TFA),20分钟]。1H NMR(500MHz,DMSO-d6)δ12.60(bs,1H),8.08(d,J=8.2Hz,1H),7.45–7.24(m,5H),7.16–7.00(m,6H),6.88(d,J=8.3Hz,2H),5.03(s,1H),5.00(s,1H),4.38(m,1H),4.27(m,1H),3.70(m,1H),3.02–2.92(m,1H),2.88–2.58(m,4H),2.58–2.49(m,1H),2.48–2.29(m,2H),2.24(s,3H),1.93(d,J=7.1Hz,2H),1.71(m,1H),1.51–1.39(m,1H),1.35–1.23(m,1H),0.91–0.69(m,2H)。HRMS(ESI+):m/z C33H39N2O5(M+H)+543.2845;m/zC33H38N2O5Na(M+Na)+565.2660;HPLC–MS(ESI+):m/z 543.2[100%,(M+H)+];m/z 565.3[90%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-2-(2-(1-(3-(4-乙氧基苯基)丙酰基)哌啶-4-基)乙酰胺基)丙酸(SR2-122)。采用一般方法F,由甲酯SR2-007(0.045g,0.078mmol)得到羧酸SR2-122,为白色泡沫状物(0.044g,97%)。HPLC:>95%[tR=6.5分钟,70%MeOH,30%水(含0.1%TFA),20分钟]。1H NMR(500MHz,DMSO-d6)δ12.62(bs,1H),8.09(d,J=8.3Hz,1H),7.48–7.25(m,5H),7.19–7.06(m,4H),6.91(d,J=8.2Hz,2H),6.80(dd,J=8.3,5.0Hz,2H),5.06(s,1H),5.03(s,1H),4.48–4.36(m,1H),4.27(m,1H),3.97(q,J=6.8Hz,2H),3.83–3.66(m,1H),3.01(dd,J=13.8,4.6Hz,1H),2.91–2.79(m,1H),2.78–2.61(m,3H),2.55–2.35(m,3H),1.97–1.92(m,2H),1.81–1.64(m,1H),1.56–1.39(m,1H),1.30(t,J=7.0,3H),1.25(m,1H),1.03–0.71(m,2H)。HRMS(ESI+):m/z C34H40N2O6(M+H)+573.2957;m/zC34H40N2O6Na(M+Na)+595.2770;HPLC–MS(ESI+):m/z 573.2[95%,(M+H)+];m/z 595.2[100%,(M+Na)+]。
C-末端酰胺衍生物的合成:
(S)-3-(4-(苄氧基)苯基)-2-(2-(1-(3-(3,4-二氯苯基)丙酰基)哌啶-4-基)乙酰胺基)-N-异丙基丙酰胺(SR2-153)。通过采用一般方法B,由甲酯SR2-030(0.040g,0.065mmol)得到酰胺SR2-153,为白色泡沫状物(0.026g,63%)。HPLC:>95%[tR=12.9分钟,75%MeOH,25%水(含0.1%TFA),20分钟]。1H NMR(500MHz,DMSO-d6)δ7.87(d,J=8.7Hz,1H),7.71(dd,J=7.6,5.1Hz,1H),7.47–7.40(m,2H),7.39–7.20(m,5H),7.16(td,J=8.3,2.1Hz,1H),7.06(d,J=8.2Hz,2H),6.82(dd,J=8.6,2.9Hz,2H),4.97(s,1H),4.95(s,1H),4.42–4.32(m,1H),4.23–4.13(m,1H),3.78–3.58(m,2H),2.83–2.66(m,4H),2.53(m,3H),2.38–2.27(m,1H),1.94–1.78(m,2H),1.72–1.54(m,1H),1.49–1.32(m,1H),1.12(m,1H),0.97(d,J=6.6Hz,3H),0.91(d,J=6.7,3H),0.88–0.48(m,2H)。HRMS(ESI+):m/zC35H42Cl2N3O4(M+H)+638.2543;m/z C35H41Cl2N3O4Na(M+Na)+660.2363;HPLC–MS(ESI+):m/z639.2[30%,(M+H)+]。
(S)-3-(4-(苄氧基)苯基)-N-(环丙基甲基)-2-(2-(1-(3-(3,4-二氯苯基)丙酰基)哌啶-4-基)乙酰胺基)丙酰胺(SR2-154)。通过采用一般方法B,由甲酯SR2-030(0.020g,0.032mmol)得到SR2-154,为白色泡沫状物(0.017g,80%)。HPLC:>96%[tR=8.3分钟,75%MeOH,25%水(含0.1%TFA),20分钟]。1H NMR(500MHz,DMSO-d6)δ8.04–7.94(m,2H),7.50(m,2H),7.45–7.28(m,5H),7.22(td,J=8.6,2.0Hz,1H),7.14(d,J=8.5Hz,2H),6.89(dd,J=8.6,3.0Hz,2H),5.04(s,1H),5.01(s,1H),4.47(m,1H),4.28–4.19(m,1H),3.77–3.63(m,1H),2.99–2.92(m,2H),2.89(dd,J=13.7,4.6Hz,1H),2.86–2.71(m,3H),2.69–2.51(m,3H),2.45–2.33(m,1H),2.00–1.86(m,2H),1.76–1.59(m,1H),1.42(m,1H),1.27–1.12(m,1H),0.97–0.65(m,3H),0.37(dd,J=8.0,1.8Hz,2H),0.16–0.09(m,2H)。HRMS(ESI+):m/zC36H42Cl2N3O4(M+H)+650.2554;m/z C36H41Cl2N3O4Na(M+Na)+672.2373;HPLC–MS(ESI+):m/z650.2[30%,(M+H)+]。
(S)-3-(4-(苄氧基)苯基)-2-(2-(1-(3-(4-氰基苯基)丙酰基)哌啶-4-基)乙酰胺基)-N-异丙基丙酰胺(SR2-155)。采用一般方法B,由甲酯SR2-033(0.040g,0.070mmol)得到酰胺SR2-155,为白色泡沫状物(0.021g,51%)。HPLC:>97%[tR=7.0分钟,70%MeOH,30%水(含0.1%TFA),20分钟]。1H NMR(500MHz,DMSO-d6)δ7.96(d,J=8.7Hz,1H),7.79(dd,J=7.6,5.3Hz,1H),7.72(dd,J=10.3,8.0Hz,2H),7.48–7.34(m,6H),7.34–7.29(m,1H),7.13(d,J=8.6Hz,2H),6.91–6.87(m,2H),5.05(s,1H),5.01(s,1H),4.44(m,1H),4.32–4.19(m,1H),3.87–3.64(m,2H),2.93–2.77(m,4H),2.71–2.54(m,3H),2.47–2.36(m,1H),2.02–1.85(m,2H),1.79–1.62(m,1H),1.49–1.39(m,1H),1.31–1.14(m,1H),1.04(d,J=6.7Hz,3H),0.98(d,J=6.5Hz,3H),0.93–0.67(m,2H)。HRMS(ESI+):m/z C36H43N4O4(M+H)+595.3277;m/zC36H42N4O4Na(M+Na)+617.3101;HPLC–MS(ESI+):m/z 595.4[60%,(M+H)+];m/z 617.4[100%,(M+Na)+]。
(S)-3-(4-(苄氧基)苯基)-2-(2-(1-(3-(4-氰基苯基)丙酰基)哌啶-4-基)乙酰胺基)-N-(环丙基甲基)丙酰胺(SR2-156)。采用一般方法B,由甲酯SR2-033(0.040g,0.070mmol)得到酰胺SR2-156,为白色泡沫状物(0.026g,68%)。HPLC:>97%[tR=4.5分钟,75%MeOH,25%水(含0.1%TFA),20分钟]。11H NMR(500MHz,DMSO-d6)δ8.05–7.96(m,2H),7.71(dd,J=10.9,8.0Hz,2H),,7.48–7.27(m,7H),7.14(d,J=8.5Hz,2H),6.88(d,J=6.8Hz,2H),5.04(s,1H),5.00(s,1H),4.47(m,1H),4.30–4.18(m,1H),3.77–3.62(m,1H),2.99–2.74(m,6H),2.70–2.53(m,3H),2.47–2.32(m,1H),2.03–1.86(m,2H),1.76–1.62(m,1H),1.42(m,1H),1.28–1.13(m,1H),0.96–0.65(m,3H),0.37(dd,J=8.1,1.8Hz,2H),0.15–0.08(m,2H)。HRMS(ESI+):m/z C37H43N4O4(M+H)+607.3286;m/z C37H42N4O4Na(M+Na)+629.3106;HPLC–MS(ESI+):m/z 607.2[70%,(M+H)+];m/z 629.2[50%,(M+Na)+]。
C-末端噁唑衍生物的合成
由衍生自氨基酸的噁唑制备一系列C-末端噁唑。一个实施例示于上图中。Boc-Tyr(OBn))Su与炔丙基胺反应得到炔丙基酰胺SR2-160。炔丙基酰胺的金(III)催化环化(Hashmi,A.S.K.等人,Org Lett.2004 6(23):4391-4394)得到噁唑SR2-162。如下面所例示的那样,胺SR2-162充当用酰基哌啶PPP替代物进行酰化的重要结构单元。
(S)-(3-(4-(苄氧基)苯基)-1-氧代-1-(丙-2-炔-1-基氨基)丙烷-2-基)-氨基甲酸叔丁酯(SR2-160)。在氩气和室温下将琥珀酰亚胺酯Boc-Tyr(OBn)OSu(1.00g,2.134mmol)溶解在无水THF(20mL)中。将炔丙基胺(0.136mL,2.134mmol)添加到混合物中,然后将混合物搅拌21h。将反应混合物在减压下浓缩并重新溶解在EtOAc(50mL)中。随后将此溶液用1N HCl(2×25mL)和饱和NaHCO3(2×25mL)洗涤并浓缩,得到炔丙基酰胺SR2-160,为白色固体(0.851g,97%)。1H NMR(500MHz,DMSO-d6)δ8.36(t,J=5.6Hz,1H),7.43(d,J=7.0Hz,2H),7.39(t,J=7.4Hz,2H),7.36–7.29(m,1H),7.17(d,J=8.3Hz,2H),6.91(d,J=8.2Hz,2H),5.06(s,2H),4.07(td,J=9.4,4.4Hz,1H),3.87(dd,J=5.6,2.5Hz,2H),3.13(t,J=2.6Hz,1H),2.85(dd,J=13.8,4.5Hz,1H),2.65(dd,J=13.8,10.1Hz,1H),1.30(s,9H)。HRMS(ESI+):m/z C24H29N2O4(M+H)+409.2132;m/z C24H28N2O4Na(M+Na)+431.1953;HPLC–MS(ESI+):m/z 431.2[100%,(M+Na)+];m/z 839.2[30%,(2M+Na)+]。
(S)-(2-(4-(苄氧基)苯基)-1-(5-甲基噁唑-2-基)乙基)氨基甲酸叔丁酯(SR2-162)。在氩气下将炔丙基酰胺SR2-160(0.200g,0.489mmol)溶解在乙腈(3.5mL)中并添加氯化金(III)(0.015g,0.049mmol)。将混合物在50℃下加热24h,通过硅藻土过滤并用EtOAc冲洗滤床。将合并的滤液干燥(Na2SO4)并将溶剂蒸发。使用EtOAc/己烷(1:9-2:8)作为洗脱液,通过快速柱色谱法纯化,得到SR2-162,为白色固体(0.096g,50%)。1H NMR(500MHz,DMSO-d6)δ7.49(dt,J=6.2,1.5Hz,1H),7.47–7.41(m,2H),7.41–7.35(m,1H),7.17(d,J=8.4Hz,2H),6.95(m,2H),6.79(s,1H),5.11(s,2H),4.78(td,J=8.3,5.8Hz,1H),3.91(t,J=6.3Hz,2H),3.13(dd,J=13.8,6.1Hz,1H),2.97(dd,J=13.8,9.4Hz,1H),2.31(s,3H),1.37(s,9H)。HRMS(ESI+):m/z C24H29N2O4(M+H)+409.2134;m/z C24H28N2O4Na(M+Na)+431.1945;HPLC–MS(ESI+):m/z 409.3[70%,(M+H)+];m/z 431.2[100%,(M+Na)+]。
(S)-2-(4-(苄氧基)苯基)-1-(5-甲基噁唑-2-基)乙-1-胺盐酸盐(SR2-171)。通过与制备SR1-085所用相同的方法由SR2-162(0.083g,0.203mmol)得到胺盐SR2-171(70mg,定量收率),为白色半固体。胺盐SR2-171不经进一步纯化即使用。
(S)-N-(2-(4-(苄氧基)苯基)-1-(5-甲基噁唑-2-基)乙基)-2-(1-(3-(3,4-二氯苯基)-丙酰基)哌啶-4-基)乙酰胺(SR2-176)。采用一般方法D,由SR2-171(0.023g,0.067mmol)和3-(3,4-二氯苯基)丙酸(0.028g,0.080mmol,1.2当量)得到噁唑SR2-176,为白色泡沫状物(0.024g,57%)。HPLC:>94%[tR=7.1分钟,80%MeOH,20%水(含0.1%TFA),20分钟]。1H NMR(500MHz,DMSO-d6)δ8.39(d,J=8.7Hz,1H),7.55–7.48(m,2H),7.46–7.34(m,4H),7.34–7.28(m,1H),7.24(m,1H),7.15–7.12(m,2H),6.90(dd,J=8.7,2.3Hz,2H),6.76(d,J=1.4Hz,1H),5.18–5.08(m,1H),5.05(s,1H),5.02(s,1H),4.31–4.22(m,1H),3.78–3.63(m,1H),3.12(dd,J=13.9,5.6Hz,1H),2.96–2.86(m,1H),2.79(m,3H),2.68–2.54(m,2H),2.47–2.37(m,1H),2.26(d,J=1.3Hz,3H),1.94(dd,J=7.1,2.2Hz,2H),1.78–1.62(m,1H),1.43(m,1H),1.26(m,1H),0.97–0.67(m,2H)。HRMS(ESI+):m/z C35H38Cl2N3O4(M+H)+;634.2235;m/z计算值C35H37Cl2N3O4Na(M+Na)+656.2050;HPLC–MS(ESI+):m/z 634.2[40%,(M+H)+]。
(S)-N-(2-(4-(苄氧基)苯基)-1-(5-甲基噁唑-2-基)乙基)-2-(1-(3-(4-氰基苯基)-丙酰基)哌啶-4-基)乙酰胺(SR2-177)。采用一般方法D,由SR2-171(0.023g,0.067mmol)和3-(4-氰基苯基)丙酸(0.024g,0.080mmol,1.2当量)得到噁唑SR2-177,为白色泡沫状物(0.023g,59%)。HPLC:>95%[tR=4.4分钟,75%MeOH,25%水(含0.1%TFA),20分钟]。1H NMR(500MHz,DMSO-d6)δ8.39(dd,J=8.9Hz,1H),7.74–7.69(m,2H),7.48–7.34(m,6H),7.32(dd,J=7.0,2.2Hz,1H),7.13(d,J=8.6Hz,2H),6.90(dd,J=8.6,1.7Hz,2H),6.76(d,J=1.4Hz,1H),5.18–5.08(m,1H),5.05(s,1H),5.02(s,1H),4.26(m,1H),3.83–3.62(m,1H),3.12(dd,J=13.8,5.6Hz,1H),2.99–2.75(m,4H),2.72–2.54(m,2H),2.47–2.35(m,1H),2.26(d,J=1.3Hz,3H),1.94(dd,J=7.4,3.0Hz,2H),1.77–1.61(m,1H),1.47–1.38(m,1H),1.31–1.15(m,1H),0.97–0.65(m,2H)。HRMS(ESI+):m/z C36H39N4O4(M+H)+;591.2961;m/z C36H38N4O4Na(M+Na)+613.2786;HPLC–MS(ESI+):m/z 591.2[100%,(M+H)+];m/z 613.2[30%,(M+Na)+]。
(S)-N-(2-(4-(苄氧基)苯基)-1-(5-甲基噁唑-2-基)乙基)-2-(1-(3-(4-乙氧基苯基)丙酰基)哌啶-4-基)乙酰胺(SR2-178)。采用一般方法D,由SR2-171(0.023g,0.067mmol)和3-(4-乙氧基苯基)丙酸(0.026g,0.080mmol,1.2当量)得到噁唑SR2-178,为白色泡沫状物(0.028g,70%)。HPLC:>96%[tR=7.9分钟,75%MeOH,25%水(含0.1%TFA),20分钟]。1H NMR(500MHz,DMSO-d6)δ8.39(d,J=8.8Hz,1H),7.47–7.34(m,4H),7.32(dt,J=8.0,3.6Hz,1H),7.15–7.09(m,4H),6.89(d,J=8.2Hz,2H),6.82–6.77(m,2H),6.75(d,J=1.2Hz,1H),5.17–5.09(m,1H),5.05(s,1H),5.02(s,1H),4.27(m,1H),3.97(q,J=6.8Hz,2H),3.70(m,1H),3.12(dd,J=13.8,5.6Hz,1H),2.95–2.86(m,1H),2.81(m,1H),2.75–2.61(m,3H),2.58–2.51(m,1H),2.49–2.33(m,1H),2.26(d,J=1.2Hz,3H),1.93(d,J=7.1Hz,2H),1.78–1.62(m,1H),1.41(m,1H),1.30(td,J=7.0,2.2Hz,3H),1.23(d,J=10.3Hz,1H),0.93–0.67(m,2H)。HRMS(ESI+):m/z C37H44N3O5(M+H)+;610.3280;m/z C37H43N3O5Na(M+Na)+632.3096;HPLC–MS(ESI+):m/z 610.2[90%,(M+H)+];m/z 632.2[40%,(M+Na)+]。
四唑类似物的合成
如上图中的实施例所示,由来自氨基酸衍生物的腈制备一系列C-末端四唑衍生物。通过用N-乙氧羰基-2-乙氧基-1,2-二氢喹啉(EEDQ)和碳酸氢铵处理由Fmoc-Tyr(Bzl)OH制备酰胺SR2-161(Nozaki,S.,Bull.Chem.Soc.Jpn.,1988,61:2647-2648),接着进行三氟甲磺酸酐脱水(Sureshbabu,V.V.,Tetrahedron Lett.,2007,48:7038-7041),得到腈SR2-165。去掉Fmoc基团得到胺SR3-018,继而用取代的苯基丙酰基哌啶乙酸衍生物将其酰化,得到具有C-末端腈基团的PPPY。通过由Sharpless开发的条件(叠氮化钠和溴化锌)来实现使用这些腈形成四唑SR2-173(Demko D.P.,Org Lett.,2002,4,2525-2527),,得到带有C-末端四唑基团的目标PPPY模拟物。
(S)-(1-氨基-3-(4-(苄氧基)苯基)-1-氧代丙烷-2-基)氨基甲酸(9H-芴-9-基)甲酯(SR2-161)*。在氩气和室温下将氨基酸Fmoc-Tyr(Bzl)-OH(1.00g,2.026mmol)溶解在CHCl3(10mL)中。向此溶液中添加N-乙氧羰基-2-乙氧基-1,2-二氢喹啉(EEDQ)(0.551g,2.228mmol)和碳酸氢铵(0.480g,6.078mmol),并将所得混合物搅拌20h。将混合物在减压下浓缩,并将所得白色固体溶解在EtOAc(50mL)中。将溶液用水(30mL)洗涤,接着用饱和NaHCO3(30mL)洗涤。将分离的有机层干燥(Na2SO4)浓缩,得到SR2-161,为白色固体(0.937g,95%)。HPLC–MS(ESI+):m/z 493.2[30%,(M+H)+];m/z 515.2[90%,(M+Na)+]。*-文献报道:Bull.Chem.Soc.,Jpn,1988,61,2647。
(S)-(2-(4-(苄氧基)苯基)-1-氰乙基)氨基甲酸(9H-芴-9-基)甲酯(SR2-165)。在氩气下将酰胺SR2-161(0.990g,2.012mmol)溶解在吡啶(6mL)中,并将溶液冷却到0℃。将三氟甲磺酸酐(0.508mL,3.018mmol)滴加到混合物中,并在0℃下搅拌3h。用水(1mL)淬灭反应并在真空下蒸发溶剂。将残留物用EtOAc(50mL)稀释,并用10%KHSO4水溶液(1×30mL)洗涤。将有机层干燥(Na2SO4)并在减压下蒸发。使用MeOH/DCM(0:100-10:90)作为洗脱液,通过快速柱色谱法纯化,得到SR2-165,为白色固体(0.848g,89%)。1H NMR(500MHz,DMSO-d6)δ8.24(d,J=8.1Hz,1H),7.90(d,J=7.6Hz,2H),7.64(dd,J=7.6,4.8Hz,2H),7.50–7.36(m,6H),7.36–7.29(m,3H),7.21(d,J=8.1Hz,2H),6.94(d,J=8.2Hz,2H),5.05(s,2H),4.65(q,J=8.0Hz,1H),4.41–4.30(m,2H),4.21(t,J=6.8Hz,1H),3.07–2.93(m,2H)。HPLC–MS(ESI+):m/z 497.2[100%,(M+Na)+]。
(S)-2-氨基-3-(4-(苄氧基)苯基)丙腈(SR3-018)。将二乙胺(1.0mL)添加到腈SR2-165(0.201g,0.421mmol)在DCM(2.5mL)中的溶液里,并在室温下搅拌3h。在减压下除去挥发物,并使用MeOH/DCM(0:10-10:90)作为洗脱液,通过快速柱色谱法纯化所得稠油状物,得到SR3-018,为白色固体(0.081g,76%)。1H NMR(500MHz,DMSO-d6)δ7.47–7.43(m,1H),7.42–7.37(m,1H),7.36–7.30(m,0H),7.20(d,J=8.6Hz,1H),6.96(d,J=8.6Hz,1H),5.08(s,1H),3.88(s,1H),2.87(dd,J=13.5,6.4Hz,0H),2.80(dd,J=13.5,8.5Hz,1H),2.38–2.27(m,1H)。HPLC–MS(ESI+):m/z 253.2[100%,(M+H)+];m/z 505.3[30%,(2M+H)+]。
(S)-N-(2-(4-(苄氧基)苯基)-1-氰乙基)-2-(1-(3-(4-乙氧基苯基)丙酰基)哌啶-4-基)乙酰胺(SR3-020)。将2-(1-(3-(4-乙氧基苯基)丙酰基)哌啶-4-基)乙酸(0.059g,0.186mmol)溶解在DMF(2mL)中,并且添加HATU(0.071g,0.185mmol)和DIEA(0.081mL,0.465mmol)。搅拌5分钟后,将SR3-018(0.054g,0.186mmol)添加到混合物里,并继续搅拌12h。将混合物在减压下浓缩,并将所得稠油状物溶解在EtOAc(30mL)中。将有机层依次用1NHCl(2×20mL)和饱和NaHCO3(2×20mL)洗涤并蒸发。使用MeOH/DCM(0:10-9:1)作为洗脱液,通过快速柱色谱法纯化,得到SR3-020,为白色固体(0.064g,75%)。1H NMR(500MHz,DMSO-d6)δ8.64(d,J=7.9Hz,1H),7.43(t,J=8.3Hz,2H),7.38(t,J=7.4Hz,2H),7.35–7.29(m,1H),7.21(d,J=8.6Hz,2H),7.11(dd,J=8.5,3.5Hz,2H),6.95(d,J=8.6Hz,2H),6.80(dd,J=8.5,3.3Hz,2H),5.07(s,1H),5.05(s,1H),4.91(dt,J=12.1,7.9,7.4Hz,1H),4.30(m,1H),3.97(q,J=6.9Hz,2H),3.80–3.68(m,1H),3.05(dd,J=13.6,6.8Hz,1H),2.94(dd,J=13.6,9.0Hz,1H),2.86(m,1H),2.75–2.66(m,2H),2.57–2.52(m,2H),2.48–2.34(m,1H),1.99(m,2H),1.82–1.68(m,1H),1.45(m,1H),1.37–1.20(m,1H),1.30(t,J=7.0Hz,3H),0.99–0.70(m,2H)。HPLC–MS(ESI+):m/z 554.3[100%,(M+H)+];m/z 576.2[40%,(M+Na)+]
(S)-N-(2-(4-(苄氧基)苯基)-1-(2H-四唑-5-基)乙基)-2-(1-(3-(4-乙氧基苯基)丙酰基)哌啶-4-基)乙酰胺(SR3-023)。将腈SR3-020(0.058g,0.105mmol)和ZnBr2(0.035g,0.157mmol)溶解在异丙醇:水的2:1混合物(2mL)中。将叠氮化钠(0.041g,0.630mmol)添加到混合物中,然后将混合物在100℃下回流24h。将反应混合物用EtOAc(25mL)和3N HCl(15mL)稀释并分离各层。将水层用EtOAc(1×25mL)萃取,并将合并的有机层蒸发。使用MeOH/DCM(0:10-9:1)作为洗脱液,通过快速柱色谱法纯化,得到SR3-023,为白色泡沫状物(0.062g,98%)。HPLC:>97%[tR=6.0分钟,75%MeOH,25%水(含0.1%TFA),20分钟]。1H NMR(500MHz,DMSO-d6)δ8.52(s,1H),7.47–7.34(m,4H),7.34–7.29(m,1H),7.15(d,J=8.9Hz,2H),7.11(dd,J=8.4,4.7Hz,2H),6.90(d,J=8.2Hz,2H),6.80(dd,J=8.4,5.5Hz,2H),5.47–5.30(m,2H),5.05(s,1H),5.01(s,1H),4.26(m,1H),3.97(q,J=6.8Hz,2H),3.75–3.62(m,1H),3.21(dd,J=13.6,4.9Hz,1H),3.08–2.93(m,1H),2.88–2.74(m,1H),2.71(td,J=7.7,2.7Hz,2H),2.62–2.45(m,2H),2.48–2.32(m,1H),1.95(d,J=7.3Hz,2H),1.76–1.63(m,1H),1.38(d,J=13.1Hz,1H),1.30(t,J=6.9Hz,3H),1.26–1.16(m,1H),0.94–0.66(m,2H)。HRMS(ESI+):m/z C34H41N6O4(M+H)+;597.3190;m/z C34H40N6O4Na(M+Na)+619.2997;HPLC–MS(ESI+):m/z 597.2[100%,(M+H)+];m/z 619.2[30%,(M+Na)+]。
(S)-N-(2-(4-(苄氧基)苯基)-1-氰乙基)-2-(1-(3-(3,4-二氯苯基)丙酰基)-哌啶-4-基)乙酰胺(SR2-019)。按照与制备SR3-020所用相同的方法,由SR3-018(0.039g,0.155mmol)和2-(1-(3-(3,4-二氯苯基)丙酰基)哌啶-4-基)乙酸(0.064g,0.186mmol)得到腈SR2-019,为白色泡沫状物(0.077g,86%)。HPLC–MS(ESI+):m/z 578.2[100%,(M+H)+]。1HNMR(500MHz,DMSO-d6)δ8.64(d,J=8.0Hz,1H),7.56–7.47(m,2H),7.43(dd,J=10.2,7.4Hz,2H),7.37(t,J=7.4Hz,2H),7.32(t,J=7.5Hz,1H),7.26–7.23(m,1H),7.21(d,J=8.3Hz,2H),6.95(d,J=8.2Hz,2H),5.07(s,1H),5.05(s,1H),4.96–4.85(m,1H),4.33–4.25(m,1H),3.85–3.70(m,1H),3.05(dd,J=13.7,6.8Hz,1H),2.94(dd,J=13.6,9.0Hz,1H),2.90–2.82(m,1H),2.81–2.75(m,2H),2.69–2.53(m,2H),2.48–2.34(m,1H),2.03–1.95(m,2H),1.85–1.69(m,1H),1.46(d,J=13.1Hz,1H),1.40–1.26(m,1H),1.00–0.72(m,2H)。
(S)-N-(2-(4-(苄氧基)苯基)-1-(2H-四唑-5-基)乙基)-2-(1-(3-(3,4-二氯苯基)-丙酰基)哌啶-4-基)乙酰胺(SR3-034)。通过与制备SR3-023所用相同的方法,由腈SR2-019(0.067g,0.119mmol)、ZnBr2(0.035g,0.157mmol)和NaN3(0.046g,0.714mmol)得到四唑SR2-034,为白色泡沫状物(0.071g,96%)。HPLC:>97%[tR=9.1分钟,75%MeOH,25%水(含0.1%TFA),20分钟]。11H NMR(500MHz,DMSO-d6)δ8.53(d,J=8.3Hz,1H),7.54–7.48(m,2H),7.46–7.29(m,5H),7.23(td,J=8.0,2.1Hz,1H),7.14(d,J=8.2Hz,2H),6.91(d,J=6.8Hz,2H),5.37(m,1H),5.05(s,1H),5.02(s,1H),4.26(m,1H),3.72(m,1H),3.23(dd,J=13.8,5.7Hz,1H),3.01(dd,J=13.8,9.9Hz,1H),1.99–1.93(m,3H),1.77–1.61(m,1H),1.45–1.32(m,1H),1.28–1.19(m,2H),0.94–0.61(m,3H)。HRMS(ESI+):m/z C32H35Cl2N6O3(M+H)+;621.2144;m/z C32H34Cl2N6O3Na(M+Na)+643.1957;HPLC–MS(ESI+):m/z 621.2[40%,(M+H)+];m/z 619.0[30%,(M-Na)-]。
在固相上合成SR3-032
为制备同时含有四唑和腈基团的PPPY模拟物,采用上图所示的途径。由腈SR2-165制备Fmoc四唑SR2-173。然后通过四唑的氯-三苯甲基保护将此附着于树脂(Gunn,S.J.等人,Synlett,2007,2643-2646),得到SR3-030。去掉Fmoc基团,接着用2-(1-(3-(4-氰基苯基)丙酰基)哌啶-4-基)乙酸进行酰化,得到树脂结合的SR3-032。通过用三氟乙酸处理树脂结合的SR3-032得到所需的含腈PPPY模拟物SR3-032。
(S)-(2-(4-(苄氧基)苯基)-1-(1H-四唑-5-基)乙基)氨基甲酸(9H-芴-9-基)甲酯(SR2-173)。通过与制备SR3-023所用相同的方法,由SR2-165得到四唑SR2-173,为白色泡沫状物(0.072g,94%)。1H NMR(500MHz,DMSO-d6)δ8.12(bs,1H),7.88(d,J=7.6Hz,2H),7.63(dd,J=7.6,3.1Hz,2H),7.44–7.33(m,7H),7.33–7.26(m,2H),7.15(d,J=8.2Hz,2H),6.86(d,J=8.2Hz,2H),,5.13–5.01(m,1H),4.98(s,2H),4.28–4.06(m,1H),3.26–3.13(m,1H),3.12–3.01(m,1H)。HPLC–MS(ESI+):m/z 518.2[100%,(M+H)+];m/z 540.3[70%,(M+Na)+];m/z 516.3[60%,(M-H)-]。
固相方案
树脂结合的Fmoc-四唑SR3-030。将2-氯三苯甲基氯树脂(0.386g,0.744mmol,1.1当量/g装载量)在DCM(5mL)中的悬浮液搅动1h。排出溶剂,并将SR2-173(0.220g,0.425mmol)和DIEA(0.259L,1.487mmol)在1:1DMF/DCM(5mL)中的溶液添加到树脂中。将混合物在室温下缓慢搅拌6h并将溶液排出。将树脂依次用DMF(3×3mL)、DCM(3×mL)和己烷(3×3mL)洗涤,并在高真空下干燥,得到树脂结合产物SR3-030并直接用于下一步。
树脂结合的SR3-032。向Fmoc-四唑结合树脂SR3-030中添加哌啶在DMF(3mL)中的20%溶液并搅拌20分钟。将溶液排出,并用DMF(3×3mL)和DCM(3×3mL)洗涤树脂。向树脂中添加HATU(0.323g,0.850mmol)、DIEA(0.296mL,1.700mmol)和2-(1-(3-(4-氰基苯基)丙酰基)哌啶-4-基)乙酸(0.255g,0.850mmol),并将所得混合物缓慢搅拌10h。将溶剂排出,将树脂依次用DMF(3×3mL)和DCM(3×3mL)及MeOH(1×3mL)洗涤,并在高真空下干燥,得到树脂结合的SR3-032并直接用于下一步
(S)-N-(2-(4-(苄氧基)苯基)-1-(2H-四唑-5-基)乙基)-2-(1-(3-(4-氰基苯基)-丙酰基)哌啶-4-基)乙酰胺(SR3-032)。通过与TFA/H2O(95:5)的溶液一起搅拌2h实现从树脂结合的SR3-032中裂解SR3-032。将悬浮液通过棉塞过滤并用DCM冲洗残留物。将合并的有机层在减压下蒸发,得到胶状残留物,然后将其溶解在EtOAc中。将此溶液用水(1×10mL)洗涤并蒸发,得到灰白色固体。使用MeOH/DCM(0-15%)作为洗脱液,通过快速柱色谱法纯化,得到SR3-032,为白色固体(26mg,11%)。HPLC:>95%[tR=3.9分钟,70%MeOH,30%水(含0.1%TFA),20分钟]。1H NMR(500MHz,DMSO-d6)δ8.51(d,J=8.3Hz,1H),7.72(t,J=8.2Hz,2H),7.51–7.29(m,7H),7.14(d,J=8.3Hz,2H),6.90(d,J=8.2Hz,2H),5.42–5.31(m,1H),5.04(s,1H),5.01(s,1H),4.25(m,1H),3.71(dd,J=23.6,13.4Hz,1H),3.22(dd,J=13.8,5.7Hz,1H),3.00(dd,J=13.7,9.9Hz,1H),2.85(m,3H),2.68–2.54(m,2H),2.48–2.33(m,1H),1.96(d,J=7.3Hz,2H),1.78–1.65(m,1H),1.40(d,J=13.0Hz,1H),1.27–1.19(m,1H),0.93–0.69(m,2H)。HRMS(ESI+):m/z C33H36N7O3(M+H)+;578.2872;m/z C33H35N7O3Na(M+Na)+600.2680;HPLC–MS(ESI+):m/z 576.3[100%,(M+H)+]。
N-末端丙酰胺的合成。
(S,E)-3-(4-(苄氧基)苯基)-2-(2-(1-(3-(3,4-二氯苯基)丙烯酰基)哌啶-4-基)乙酰胺基)丙酸甲酯(SR3-001)。采用一般方法D,由(E)-(3,4-二氯苯基)丙烯酸(0.029g,0.134mmol)和胺盐SR1-085(0.050g,0.112mmol)得到酰胺SR3-001,为白色泡沫状物(0.061g,90%)。HPLC:>99%[tR=7.8分钟,80%MeOH,20%水(含0.1%TFA),20分钟]。1HNMR(500MHz,DMSO-d6)δ8.27(d,J=7.9Hz,1H),8.14–8.08(m,1H),7.70(t,J=9.1Hz,1H),7.64(dd,J=11.1,8.3Hz,1H),7.48–7.28(m,7H),7.14(d,J=8.3Hz,2H),6.92(d,J=8.7Hz,2H),5.06(bs,2H),4.46(m,1H),4.41–4.29(m,1H),4.29–4.14(m,1H),3.61(s,3H),2.98(m,2H),2.79(td,J=14.0,11.7,5.3Hz,1H),2.67–2.53(m,1H),2.01(dd,J=7.0,3.7Hz,2H),1.92–1.74(m,1H),1.66–1.45(m,1H),1.39(m,1H),1.09–0.83(m,2H)。HRMS(ESI+):m/z C33H35Cl2N2O5(M+H)+;609.1899;m/z C33H34Cl2N2O5Na(M+Na)+631.1756;HPLC–MS(ESI+):m/z 609.2[40%,(M+H)+]。
(S,E)-3-(4-(苄氧基)苯基)-2-(2-(1-(3-(4-氰基苯基)丙烯酰基)哌啶-4-基)乙酰胺基)丙酸甲酯(SR3-002)。采用一般方法D,由反式-4-氰基肉桂酸(0.023g,0.134mmol)和胺盐SR1-085(0.050g,0.112mmol)得到酰胺SR3-002,为白色泡沫状物(0.059g,94%)。HPLC:>98%[tR=5.2分钟,75%MeOH,25%水(含0.1%TFA),20分钟]。1H NMR(500MHz,DMSO-d6)δ8.27(d,J=7.9Hz,1H),7.92(dd,J=13.6,8.1Hz,2H),7.85(dd,J=12.1,8.1Hz,2H),7.54–7.40(m,4H),7.39–7.34(m,2H),7.31(t,J=7.2Hz,1H),7.14(d,J=8.2Hz,2H),6.92(d,J=8.5Hz,2H),5.06(bs,2H),4.46(dt,J=8.7,4.1Hz,1H),4.41–4.32(m,1H),4.28–4.11(m,1H),3.61(s,3H),3.00(dd,J=19.9,12.3Hz,2H),2.83–2.74(m,1H),2.68–2.53(m,1H),2.04–1.96(m,2H),1.84–1.74(m,1H),1.64–1.53(m,1H),1.53–1.35(m,1H),1.12–0.81(m,2H)。HRMS(ESI+):m/z C34H36N3O5(M+H)+;566.2651;m/z C34H35N3O5Na(M+Na)+588.2472;HPLC–MS(ESI+):m/z 566.2[70%,(M+H)+]。
(S,E)-3-(4-(苄氧基)苯基)-2-(2-(1-(3-(4-乙氧基苯基)丙烯酰基)哌啶-4-基)乙酰胺基)丙酸甲酯(SR3-003)。采用一般方法D,由4-乙氧基肉桂酸(0.026g,0.134mmol)和胺盐SR1-085(0.050g,0.112mmol)得到酰胺SR3-003,为白色泡沫状物(0.062g,95%)。1HNMR(500MHz,DMSO-d6)δ8.27(d,J=8.0Hz,1H),7.68–7.58(m,2H),7.44(d,J=7.1Hz,2H),7.41–7.35(m,3H),7.32(m,1H),7.14(d,J=8.6Hz,2H),7.12–7.01(m,1H),6.95–6.89(m,4H),5.07(s,2H),4.46(dd,J=14.4,7.2Hz,2H),4.39(m,1H),4.29–4.10(m,1H),4.06(q,J=6.9Hz,2H),3.61(s,3H),3.03–2.88(m,2H),2.78(dd,J=13.8,10.0Hz,1H),2.64–2.53(m,1H),2.00(d,J=7.2Hz,2H),1.88–1.72(m,1H),1.65–1.51(m,1H),1.45(m,1H),1.33(t,J=7.0Hz,3H),1.07–0.80(m,3H)。HPLC:>98%[tR=8.4分钟,75%MeOH,25%水(含0.1%TFA),20分钟]。HRMS(ESI+):m/z C35H41N2O6(M+H)+;585,2962;m/z C35H40N2O6Na(M+Na)+607.2784;HPLC–MS(ESI+):m/z 585.2[100%,(M+H)+]。
(S,E)-3-(4-(苄氧基)苯基)-2-(2-(1-(3-(4-氟苯基)丙烯酰基)哌啶-4-基)乙酰胺基)丙酸甲酯(SR3-021)。采用一般方法D,由4-氟肉桂酸(0.031g,0.187mmol)和胺盐SR1-085(0.050g,0.112mmol)得到酰胺SR3-021,为白色泡沫状物(0.077g,88%)。HPLC:>98%[tR=7.1分钟,75%MeOH,25%水(含0.1%TFA),20分钟]。1H NMR(500MHz,DMSO-d6)δ8.27(d,J=8.0Hz,1H),7.78(m,2H),7.50–7.40(m,3H),7.39–7.34(m,2H),7.34–7.28(m,1H),7.27–7.16(m,3H),7.14(d,J=8.6Hz,2H),6.92(d,J=8.7Hz,2H),5.06(s,2H),4.53–4.41(m,1H),4.42–4.30(m,1H),4.29–4.11(m,1H),3.61(s,3H),3.07–2.88(m,3H),2.86–2.72(m,1H),2.68–2.53(m,1H),2.00(d,J=6.9Hz,2H),1.91–1.73(m,1H),1.64–1.52(m,1H),1.51–1.32(m,1H),1.08–0.80(m,2H)。19F NMR(471MHz,DMSO-d6)δ-111.70。HRMS(ESI+):m/zC33H36FN2O5(M+H)+559.2598;m/z C33H35FN2O5Na(M+Na)+581.2414;HPLC–MS(ESI+):m/z 559.2[60%,(M+H)+];m/z.581.3[50%(M+Na)+]。
(S,E)-3-(4-(苄氧基)苯基)-2-(2-(1-(3-(3,4-二氯苯基)丙烯酰基)哌啶-4-基)乙酰胺基)丙酸(SR3-010)。采用一般方法E,由甲酯SR3-001(0.026g,0.043mmol)得到羧酸SR3-010,为白色泡沫状物(0.023g,90%)。HPLC:>99%[tR=6.6分钟,80%MeOH,20%水(含0.1%TFA),20分钟]。1H NMR(500MHz,DMSO-d6)δ12.66(bs,1H),8.14–8.08(m,2H),7.73–7.67(m,1H),7.63(dd,J=12.3,8.4Hz,1H),7.50–7.26(m,6H),7.15(d,J=8.3Hz,2H),6.92(d,J=8.3Hz,2H),5.06(s,2H),4.48–4.30(m,2H),4.27–4.11(m,1H),3.09–2.90(m,2H),2.83–2.68(m,1H),2.65–2.53(m,1H),2.05–1.94(m,2H),1.89–1.74(m,1H),1.64–1.53(m,1H),1.52–1.32(m,1H),1.10–0.70(m,2H)。HRMS(ESI+):m/z C33H33Cl2N2O5(M+H)+;595.1757;m/z C33H32Cl2N2O5Na(M+Na)+617.1571;HPLC–MS(ESI+):m/z 595.2[60%,(M+H)+];HPLC–MS(ESI-):m/z.593.2[20%(M-H)-]。
(S,E)-3-(4-(苄氧基)苯基)-2-(2-(1-(3-(4-氰基苯基)丙烯酰基)哌啶-4-基)乙酰胺基)丙酸(SR3-011)。采用一般方法E,由甲酯SR3-002(0.024g,0.042mol)得到羧酸SR3-011,为白色泡沫状物(0.019g,83%)。HPLC:>97%[tR=4.5分钟,75%MeOH,25%水(含0.1%TFA),20分钟]。1H NMR(500MHz,DMSO-d6)δ12.65(bs,1H),8.12(d,J=8.2Hz,1H),7.91(dd,J=14.8,8.1Hz,2H),7.85(dd,J=13.4,8.1Hz,2H),7.53–7.40(m,4H),7.37(t,J=7.4Hz,2H),7.31(t,J=7.3Hz,1H),7.15(d,J=8.3Hz,2H),6.92(d,J=8.6Hz,2H),5.06(s,2H),4.47–4.30(m,2H),4.26–4.12(m,1H),3.06–2.94(m,2H),2.80–2.68(m,1H),2.66–2.53(m,1H),2.04–1.96(m,2H),1.90–1.72(m,1H),1.68–1.52(m,1H),1.51–1.31(m,1H),1.09–0.72(m,2H)。HRMS(ESI+):m/z C33H34N3O5(M+H)+552.2483;m/z C33H33N3O5Na(M+Na)+574.2300;HPLC–MS(ESI+):m/z 552.2[60%,(M+H)+];HPLC–MS(ESI-):m/z.551.0[20%(M-H)-]。
(S,E)-3-(4-(苄氧基)苯基)-2-(2-(1-(3-(4-乙氧基苯基)丙烯酰基)哌啶-4-基)乙酰胺基)丙酸(SR3-012)。采用一般方法E,由甲酯SR3-003(0.025g,0.043mol)得到羧酸SR3-012,为白色泡沫状物(0.020g,83%)。HPLC:>97%[tR=6.8分钟,75%MeOH,25%水(含0.1%TFA),20分钟]。1H NMR(500MHz,DMSO-d6)δ12.65(bs,1H),8.11(d,J=8.3Hz,1H),7.63(dt,J=8.3,4.8Hz,2H),7.49–7.41(m,3H),7.41–7.38(m,1H),7.38–7.34(m,1H),7.32(m,1H),7.15(d,J=8.7Hz,2H),7.12–7.02(m,1H),6.97–6.97(m,2H),6.92(d,J=8.7Hz,2H),5.06(s,2H),4.46–4.30(m,2H),4.26–4.06(m,1H),4.06(q,J=7.8,7.1Hz,2H),3.01(dd,J=13.9,4.6Hz,1H),2.95(m,1H),2.75(dd,J=13.8,10.2Hz,1H),2.65–2.53(m,1H),1.99(d,J=7.2Hz,2H),1.80(m,1H),1.56(m,1H),1.48–1.36(m,1H),1.33(t,J=7.0Hz,3H),1.10–0.79(m,2H)。HRMS(ESI+):m/z C34H39N2O6(M+H)+571.2810;m/z C34H38N2O6Na(M+Na)+593.2618;HPLC–MS(ESI+):m/z 571.2[60%,(M+H)+];HPLC–MS(ESI-):m/z.569.2[80%(M-H)-]。
(S,E)-3-(4-(苄氧基)苯基)-2-(2-(1-(3-(4-氟苯基)丙烯酰基)哌啶-4-基)乙酰胺基)丙酸(SR3-027)。采用一般方法E,由甲酯SR3-021(0.030g,0.054mol)得到羧酸SR3-027,为白色泡沫状物(0.025g,87%)。HPLC:>98%[tR=4.6分钟,75%MeOH,25%水(含0.1%TFA),20分钟]。1H NMR(500MHz,DMSO-d6)δ12.64(bs,1H),8.11(d,J=8.3Hz,1H),7.83–7.71(m,2H),7.48–7.41(m,3H),7.39–7.34(m,2H),7.34–7.27(m,1H),7.27–7.18(m,3H),7.15(d,J=8.6Hz,2H),6.92(d,J=8.7Hz,2H),5.06(s,2H),4.45–4.30(m,2H),4.25–4.10(m,1H),3.05–2.94(m,2H),2.81–2.68(m,1H),2.67–2.53(m,1H),1.99(d,J=7.1Hz,2H),1.87–1.74(m,1H),1.65–1.52(m,1H),1.49–1.30(m,1H),1..08–0.76(m,2H)。HRMS(ESI+):m/z C32H34FN2O5(M+H)+545.2460;m/z C32H33FN2O5Na(M+Na)+567.2262;HPLC–MS(ESI+):m/z 545.2[60%,(M+H)+];HPLC–MS(ESI-):m/z.543.2[100%(M-H)-]。
NCI 41092系列的合成
采用上面所示的方法制备一系列硝基咪唑取代的烯烃作为OCT4-YAP1破坏剂。
缩合反应的一般程序
在微波管(5mL)中混合5-甲基-4-硝基咪唑(0.200g,1.573mmol)和相应的醛(3.934mmol,2.5当量)。在氩气下将哌啶(0.031mL,0.315mmol,0.2当量)添加到混合物中并密封小瓶。将混合物在150℃下加热30分钟。将所得固体混合物在水(1×5mL)和乙醇(1×5mL)或DCM/己烷(1:9比例,3×5mL)*中研磨。倾析上清液,并将固体分离为纯产物。(*当水/乙醇系统不利于沉淀时用于粗产物)。
(E)-5-(2-(萘-2-基)乙烯基)-4-硝基-1H-咪唑(SR2-048)。通过按照上面的一般程序,使用2-萘甲醛(0.614g,3.934mmol)得到烯烃SR2-048,为亮黄色固体(0.186g,45%)。HPLC:>99%[tR=5.6分钟,70%MeOH,30%水(含0.1%TFA),20分钟]。1H NMR(400MHz,DMSO-d6)δ13.68(bs,1H),8.05–8.02(bs,1H),8.00(m,1H),7.98(bs,0.5H),7.96(bs,0.5H),7.94(m,1.5H),7.92(m,0.5H),7.82(d,J=1.8Hz,0.5H),7.80(s,0.5H),7.80(s,0.3H),7.76(s,0..7H),7.65(s,0.6H),7.61(s,0.4H),7.54(m,2H)。HRMS(ESI+):m/z C15H12N3O2(M+H)+266.0922;m/z C15H11N3O2Na 288.0738。HPLC–MS(ESI+):m/z 266.2[40%,(M+H)+],553.2[100%,(2M+Na)+]。
(E)-5-(4-异丙基苯乙烯基)-4-硝基-1H-咪唑(SR2-054)。通过按照上面的一般程序,使用4-异丙基苯甲醛(0.607mL,3.934mmol)得到烯烃SR2-054,为亮黄色固体(0.296g,73%)。HPLC:>99%[tR=8.5分钟,70%MeOH,30%水(含0.1%TFA),20分钟]。1H NMR(400MHz,DMSO-d6)δ13.57(bs,1H),7.89(m,1H),7.61(s,0.4H),7.57(s,0.6H),7.52(s,1H),7.50(s,1H),7.46(s,0.6H),7.41(s,0.4H),7.32(1,1H),7.30(s,1H),2.90(h,J=6.9Hz,1H),1.21(s,3H),1.19(s,3H)。HRMS(ESI+):m/z C14H16N3O2(M+H)+258.1242;m/zC14H15N3O2Na(M+Na)+280.1052。HPLC–MS(ESI+):m/z 258.2[40%,(M+H)+],537.3[100%,(2M+Na)+]。
(E)-5-(3-氟苯乙烯基)-4-硝基-1H-咪唑SR2-055)。通过按照上面的一般程序,使用3-氟苯甲醛(0.413mL,3.934mmol)得到烯烃SR2-055,为亮黄色固体(0.220g,60%)。HPLC:>99%[tR=7.2分钟,60%MeOH,40%水(含0.1%TFA),20分钟]。1H NMR(400MHz,DMSO-d6)δ13.66(bs,1H),7.93(s,1H),7.69(s,0.5H),7.65(s,0.5H),7.54–7.39(m,4H),7.21(td,J=8.7,2.5Hz,1H)。19F NMR(376MHz,DMSO-d6)δ-112.71(td,J=9.3,6.1Hz)。HRMS(ESI+):m/z C11H9FN3O2(M+H)+234.0676;m/z C11H8FN3O2Na(M+Na)+256.0488。HPLC–MS(ESI+):m/z234.1[40%,(M+H)+],489.1[100%,(2M+Na)+]。
(E)-4-(2-(4-硝基-1H-咪唑-5-基)乙烯基)苯甲腈(SR2-067)。通过按照上面的一般程序,使用4-氰基苯甲醛(0.517g,3.934mmol)得到烯烃SR2-067,为橙颜色固体(0.134g,36%)。HPLC:>99%[tR=6.9分钟,50%MeOH,50%水(含0.1%TFA),20分钟]。1H NMR(400MHz,DMSO-d6)δ13.69(bs,1H),7.94(s,1H),7.88(s,1H),7.86(s,1H),7.82–7.73(m,3H),7.49(d,J=16.7Hz,1H)。HRMS(ESI+):m/z C12H9N4O2(M+H)+241.0718;m/z C12H8N4O2Na(M+Na)+263.0532。HPLC–MS(ESI+):m/z 241.2[100%,(M+H)+],503.2[80%,(2M+Na)+]。
(E)-5-(4-异丁基苯乙烯基)-4-硝基-1H-咪唑SR2-068)。通过按照上面的一般程序,使用4-异丁基苯甲醛(0.638g,3.934mmol)得到烯烃SR2-068,为黄色固体(0.223g,52%)。HPLC:>99%[tR=4.9分钟,20%MeOH,80%水(含0.1%甲酸),20分钟]。1H NMR(400MHz,DMSO-d6)δ13.55(bs,1H),7.90(b,1H),7.61(d,J=16.7Hz,1H),7.51(d,J=8.2Hz,2H),7.45(d,J=16.8Hz,1H),7.24(d,J=8.2Hz,2H),2.53(s,1H),2.47(s,1H),1.85(h,J=7.1Hz,1H),0.88(s,3H),0.86(s,3H)。HRMS(ESI+):m/z C15H18N3O2(M+H)+272.1397;m/z C15H17N3O2Na(M+Na)+294.2109。HPLC–MS(ESI+):m/z 272.2[30%,(M+H)+],565.3[100%,(2M+Na)+]。
(E)-5-(2-([1,1'-联苯]-4-基)乙烯基)-4-硝基-1H-咪唑(SR2-069)。通过按照上面的一般程序,使用4-联苯基甲醛(0.717g,3.934mmol)得到烯烃SR2-069,为黄色固体(0.381g,83%)。HPLC:>99%[tR=9.1分钟,70%MeOH,30%水(含0.1%TFA),20分钟]。1HNMR(400MHz,DMSO-d6)δ13.63(bs,1H),7.92(b,1H),7.75(d,J=8.4Hz,2H),7.73–7.69(m,3H),7.67(d,J=10.5Hz,2H),7.51(d,J=10.5Hz,1H),7.47(m,2H),7.38(m,1H)。HRMS(ESI+):m/z C17H14N3O2(M+H)+292.1080;m/z C17H13N3O2Na(M+Na)+314.0893。HPLC–MS(ESI+):m/z605.2[100%,(2M+Na)+];(ESI-):m/z 290.1[100%,(M-H)-]。
(E)-5-(4-溴苯乙烯基)-4-硝基-1H-咪唑(SR2-071)。通过按照上面的一般程序,使用4-溴苯甲醛(0.437g,2.360mmol,1.5当量)得到烯烃SR2-071,为砖红色固体(0.322g,70%)。HPLC:>99%[tR=5.3分钟,70%MeOH,30%水(含0.1%TFA),20分钟]。1H NMR(400MHz,DMSO-d6)δ13.62(bs,1H),7.92(s,1H),7.65(d,J=15.9Hz,1H),7.62(d,J=8.6Hz,2H),7.54(d,J=8.5Hz,2H),7.40(d,J=16.7Hz,1H)。HRMS(ESI+):m/z C11H9BrN3O2(M+H)+293.9869;m/z C11H8BrN3O2Na(M+Na)+315.9690。HPLC–MS(ESI+):m/z 294.0[40%,(M+H)+],611.0[100%,(2M+Na)+];(ESI-):m/z 292.0[100%,(M-H)-]。
(E)-4-硝基-5-(4-丙氧基苯乙烯基)-1H-咪唑(SR2-072)。通过按照上面的一般程序,使用4-丙氧基苯甲醛(0.373mL,2.360mmol,1.5当量)得到烯烃SR2-072,为亮黄色固体(0.353g,82%)。HPLC:>99%[tR=14.2分钟,60%MeOH,40%水(含0.1%甲酸),20分钟]。1HNMR(400MHz,DMSO-d6)δ13.50(bs,1H),7.86(s,1H),7.52(d,J=8.8Hz,2H),7.50(d,J=16.7Hz,1H),7.40(d,J=16.8Hz,1H),6.98(d,J=8.8Hz,2H),3.95(t,J=6.5Hz,2H),1.72(qt,J=7.1Hz,2H),0.97(t,J=7.4Hz,3H)。HRMS(ESI+):m/z C14H16N3O3(M+H)+274.1190;m/z C14H15N3O3Na(M+Na)+296.1003。HPLC–MS(ESI+):m/z 274.2[30%,(M+H)+],569.2[100%,(2M+Na)+];(ESI-):m/z 272.2[100%,(M-H)-]。
(E)-4-(2-(4-硝基-1H-咪唑-5-基)乙烯基)苯酚(SR2-073)。通过按照上面的一般程序,使用4-羟基苯甲醛(0.288g,2.360mmol,1.5当量)得到烯烃SR2-073,为砖红色固体(0.352g,96%)。HPLC:>99%[tR=9.2分钟,40%MeOH,60%水(含0.1%甲酸),20分钟]。1HNMR(400MHz,DMSO-d6)δ13.14(bs,1H),9.89(bs,1H),7.81(s,1H),7.45(d,J=15.8Hz,1H),7.42(d,J=8.7Hz,2H),7.36(d,J=16.7Hz,1H),6.81(d,J=8.6Hz,2H)。HRMS(ESI+):m/zC11H10N3O3(M+H)+232.0723;m/z C11H9N3O3Na(M+Na)+254.0536。HPLC–MS(ESI+):m/z 232.2[80%,(M+H)+],485.1[100%,(2M+Na)+];(ESI-):m/z 230.2[90%,(M-H)-]。
(E)-2-(4-(2-(4-硝基-1H-咪唑-5-基)乙烯基)苯基)吡啶(SR2-074)。通过按照上面的一般程序,使用4-(2-吡啶基)苯甲醛(0.432g,2.360mmol,1.5当量)得到烯烃SR2-074,为亮黄色固体(0.331g,72%)。HPLC:>97%[tR=5.8分钟,55%MeOH,45%水(含0.1%甲酸),20分钟]。1H NMR(400MHz,DMSO-d6)δ13.63(bs,1H),8.67(ddd,J=4.8,1.9,0.9Hz,1H),8.17(d,J=8.4Hz,2H),8.01(d,J=8.1Hz,1H),7.92(s,1H),7.89(td,J=7.7,1.9Hz,1H),7.72(d,J=16.7Hz,1H),7.71(d,J=8.4Hz,2H),7.51(d,J=16.7Hz,1H),7.36(ddd,J=7.4,4.7,1.1Hz,1H)。HRMS(ESI+):m/z C16H13N4O2(M+H)+293.1041;m/z C16H12N4O2Na(M+Na)+315.0851。HPLC–MS(ESI+):m/z 293.1[100%,(M+H)+],485.1[20%,(2M+Na)+];(ESI-):m/z291.2[100%,(M-H)-]。
NCI 111847系列的合成
采用上面所示的方法,由取代的邻羟基芳胺和取代的芳醛制备一系列取代的亚胺,作为OCT4-YAP1破坏剂。
用于亚胺衍生物的一般程序。将2-氨基苯酚(0.156g,1..427mmol,1当量)和相应的醛(200mg,1.427mmol,1当量)溶解在MeOH(3mL)中。将混合物在82℃下回流3.5h,并使之冷却到室温。向所得固体混合物中添加DCM(1-2mL),直到固体完全溶解。将混合物与己烷一起研磨(10-15mL,伴随声处理添加,直到沉淀完成),得到纯亚胺产物。
(E)-2-氟-6-(((2-羟苯基)亚氨基)甲基)苯酚(SR2-059)。通过按照上面用于亚胺衍生物的一般程序,使用3-氟-2-羟基苯甲醛(0.200g,1.427mmol,1.0当量)得到亚胺SR2-059,为亮橙色固体(0.282g,86%)。HPLC:>99%[tR=5.8分钟,40%MeOH,60%水(含0.1%甲酸),20分钟]。1H NMR(400MHz,DMSO-d6)δ9.96(s,1H),9.05(d,J=1.1Hz,1H),7.45(dd,J=7.9,1.6Hz,1H),7.40(dt,J=7.9,1.2Hz,1H),7.32(ddd,J=11.7,8.0,1.5Hz,1H),7.14(ddd,J=8.7,7.3,1.6Hz,1H),6.97(dd,J=8.2,1.3Hz,1H),6.89(dd,J=7.5,1.4Hz,1H),6.88–6.81(m,1H)。19F NMR(376MHz,DMSO-d6)δ-138.07(dd,J=11.5,4.6Hz)。HRMS(ESI+):m/z C13H11FNO2(M+H)+232.0769;m/z C13H10FNO2Na(M+Na)+254.0579。HPLC–MS(ESI+):m/z232.2[30%,(M+H)+],487.1[20%,(2M+Na)+];(ESI-):m/z 230.1[30%,(M-H)-]。
(E)-2-乙氧基-6-(((2-羟苯基)亚氨基)甲基)苯酚(SR2-060)。通过按照上面用于亚胺衍生物的一般程序,使用3-乙氧基水杨醛(0.200g,1.205mmol,1.0当量)得到亚胺SR2-060,为亮红色固体(0.208g,67%)。HPLC:>99%[tR=7.4分钟,40%MeOH,60%水(含0.1%甲酸),20分钟]。1H NMR(400MHz,DMSO-d6)δ9.80(s,1H),8.96(s,1H),7.38(dd,J=7.9,1.6Hz,1H),7.18(dd,J=7.9,1.5Hz,1H),7.13(ddd,J=8.1,7.3,1.6Hz,1H),7.06(dd,J=8.0,1.5Hz,1H),6.96(dd,J=8.1,1.4Hz,1H),6.88(td,J=7.6,1.4Hz,1H),6.83(t,J=7.9Hz,1H),4.06(q,J=7.0Hz,2H),1.35(t,J=6.9Hz,3H)。HRMS(ESI+):m/z C15H16NO3(M+H)+258.1128;m/z C15H15NO3Na(M+Na)+280.0945。HPLC–MS(ESI-):m/z 257.1[40%,(M-H)-]。
(E)-2-(((2-羟苯基)亚氨基)甲基)-6-甲基苯酚(SR2-061)。通过按照上面用于亚胺衍生物的一般程序,使用2-羟基-3-甲基苯甲醛(0.200g,1.469mmol,1.0当量)得到亚胺SR2-061,为亮橙色固体(分离0.136g,41%)。HPLC:>99%[tR=6.4分钟,55%MeOH,45%水(含0.1%甲酸),20分钟]。1H NMR(400MHz,DMSO-d6)δ9.76(s,1H),8.94(s,1H),7.40(dd,J=7.7,1.7Hz,1H),7.36(dd,J=7.9,1.6Hz,1H),7.26(ddd,J=7.4,1.7,0.9Hz,1H),7.14–7.08(m,1H),6.95(dd,J=8.1,1.4Hz,1H),6.90–6.80(m,2H),2.19(s,3H)。HRMS(ESI+):m/zC14H14NO2(M+H)+228.1021;m/z C14H13NO2Na(M+Na)+250.0851。
(E)-2-溴-6-(((2-羟苯基)亚氨基)甲基)苯酚(SR2-062)。通过按照上面用于亚胺衍生物的一般程序,使用3-溴-2-羟基苯甲醛(0.200g,0.995mmol,1.0当量)得到亚胺SR2-062,为亮红色固体(0.183g,63%)。HPLC:>99%[tR=6.9分钟,50%MeOH,50%水(含0.1%甲酸),20分钟]。1H NMR(400MHz,DMSO-d6)δ10.06(s,1H),9.05(s,1H),7.68(dd,J=7.8,1.6Hz,1H),7.56(dd,J=7.8,1.6Hz,1H),7.49(dd,J=8.0,1.6Hz,1H),7.18–7.12(m,1H),6.98(dd,J=8.2,1.3Hz,1H),6.93–6.87(m,1H),6.80(t,J=7.8Hz,1H)。HRMS(ESI+):m/zC13H11BrNO2(M+H)+291.9972;m/z C13H10BrNO2Na(M+Na)+313.9777。
(E)-2-氯-6-(((2-羟苯基)亚氨基)甲基)苯酚(SR2-063)。通过按照上面用于亚胺衍生物的一般程序,使用3-氯-2-羟基苯甲醛(0.200g,1.227mmol,1.0当量)得到亚胺SR2-063,为亮橙色固体(0.251g,80%)。HPLC:>99%[tR=4.2分钟,50%MeOH,50%水(含0.1%甲酸),20分钟]。1H NMR(400MHz,DMSO-d6)δ10.06(s,1H),9.07(s,1H),7.54(s,1H),7.52(s,1H),7.49(dd,J=8.0,1.6Hz,1H),7.15(ddd,J=8.5,7.3,1.6Hz,1H),6.98(dd,J=8.2,1.4Hz,1H),6.94–6.82(m,2H)。HRMS(ESI+):m/z C13H11ClNO2(M+H)+248.0476;m/zC13H10ClNO2Na(M+Na)+270.0273。
(E)-1-((苯基亚氨基)甲基)萘-2-醇(SR2-076)。通过按照上面用于亚胺衍生物的一般程序,使用2-羟基-1-萘甲醛(0.200g,1.162mmol,1.0当量)和苯胺(0.106g,1.162mmol,1.0当量)得到亚胺SR2-076,为黄色固体(0.182g,63%)。HPLC:>99%[tR=8.0分钟,70%MeOH,30%水(含0.1%甲酸),20分钟]。1H NMR(400MHz,DMSO-d6)δ9.64(s,1H),8.48(d,J=8.4Hz,1H),7.91(d,J=9.2Hz,1H),7.77(dd,J=7.9,1.3Hz,1H),7.63(dd,J=8.5,1.2Hz,2H),7.55–7.45(m,3H),7.36–7.26(m,2H),6.97(d,J=9.2Hz,1H)。HRMS(ESI+):m/z C17H14NO(M+H)+248.1076;m/z C17H13NONa(M+Na)+270.0912。HPLC–MS(ESI+):m/z 248.2[100%,(M+H)+],517.2[70%,(2M+Na)+]。
(E)-1-((间甲苯基亚氨基)甲基)萘-2-醇(SR2-077)。通过按照上面用于亚胺衍生物的一般程序,使用2-羟基-1-萘甲醛(0.200g,1.162mmol,1.0当量)和间甲苯(0.126mL,1.162mmol,1.0当量)得到亚胺SR2-077,为黄色固体(0.147g,49%)。HPLC:>99%[tR=11.2分钟,70%MeOH,30%水(含0.1%甲酸),20分钟]。1H NMR(400MHz,DMSO-d6)δ9.61(s,1H),8.46(d,J=8.5Hz,1H),7.89(d,J=9.3Hz,1H),7.76(d,J=7.8Hz,1H),7.55–7.49(m,1H),7.47(s,1H),7.42–7.29(m,3H),7.11(d,J=7.2Hz,1H),6.95(d,J=9.2Hz,1H),2.38(s,3H)。HRMS(ESI+):m/z C17H14NO(M+H)+248.1076;m/z C17H13NONa(M+Na)+270.0912。HRMS(ESI+):m/z C18H16NO(M+H)+262.1232;m/z C18H15NONa(M+Na)+284.1052。HPLC–MS(ESI+):m/z262.2[100%,(M+H)+],545.3[90%,(2M+Na)+]。
(E)-1-(((3-氟苯基)亚氨基)甲基)萘-2-醇(SR2-080)。通过按照上面用于亚胺衍生物的一般程序,使用2-羟基-1-萘甲醛(0.200g,1.162mmol,1.0当量)和3-氟苯胺(0.112mL,1.162mmol,1.0当量)得到亚胺SR2-080,为黄色固体(0.217g,70%)。HPLC:>99%[tR=9.6分钟,70%MeOH,30%水(含0.1%甲酸),20分钟]。1H NMR(400MHz,DMSO-d6)δ9.65(s,1H),8.51(d,J=8.4Hz,1H),7.94(d,J=9.2Hz,1H),7.79(d,J=7.8Hz,1H),7.65(dt,J=10.8,2.3Hz,1H),7.54(t,J=7.5Hz,1H),7.49(dd,J=8.2,6.7Hz,1H),7.44–7.31(m,2H),7.12(td,J=8.3,2.0Hz,1H),7.01(d,J=9.2Hz,1H)。HRMS(ESI+):m/z C17H14NO(M+H)+248.1076;m/z C17H13NONa(M+Na)+270.0912。HRMS(ESI+):m/z C17H13FNO(M+H)+266.0982;m/z C17H12FNONa(M+Na)+288.0797。HPLC–MS(ESI+):m/z262.2[90%,(M+H)+],545.3[20%,(2M+Na)+]。
(E)-1-(((2-苄基苯基)亚氨基)甲基)萘-2-醇(SR2-084)。通过按照上面用于亚胺衍生物的一般程序,使用2-羟基-1-萘甲醛(0.200g,1.162mmol,1.0当量)和2-苄胺(0.213g,1.162mmol,1.0当量)得到亚胺SR2-084,为黄色固体(0.371g,95%)。HPLC:>99%[tR=8.4分钟,80%MeOH,20%水(含0.1%甲酸),20分钟]。1H NMR(500MHz,DMSO-d6)δ9.60(d,J=2.6Hz,1H),8.47(d,J=8.4Hz,1H),7.94(d,J=9.2Hz,1H),7.80(dd,J=8.0,1.3Hz,1H),7.73(dd,J=8.1,1.1Hz,1H),7.53(ddd,J=8.4,6.9,1.4Hz,1H),7.39(td,J=7.6,1.7Hz,1H),7.37–7.30(m,2H),7.29–7.25(m,2H),7.25–7.19(m,3H),7.17–7.11(m,1H),7.05(d,J=9.1Hz,1H),4.14(s,2H)。HRMS(ESI+):m/z C24H20NO(M+H)+338.1544;m/zC24H19NONa(M+Na)+360.1350。HPLC–MS(ESI+):m/z 338.2[80%,(M+H)+],360.2[60%,(M+Na)+],697.3[50%,(2M+Na)+]。
(E)-1-(((3-羟苯基)亚氨基)甲基)萘-2-醇(SR2-085)。通过按照上面用于亚胺衍生物的一般程序,使用2-羟基-1-萘甲醛(0.200g,1.162mmol,1.0当量)和3-氨基苯酚(0.127g,1.162mmol,1.0当量)得到亚胺SR2-085,为黄色固体(0.288g,94%)。HPLC:>99%[tR=3.9分钟,70%MeOH,30%水(含0.1%甲酸),20分钟]。1H NMR(400MHz,DMSO-d6)δ9.69(s,1H),9.54–9.49(m,1H),8.42(d,J=8.5Hz,1H),7.86(d,J=9.2Hz,1H),7.73(dd,J=8.0,1.3Hz,1H),7.48(ddd,J=8.3,6.9,1.5Hz,1H),7.29(t,J=7.4Hz,1H),7.24(t,J=8.0Hz,1H),7.02(dd,J=7.9,2.0Hz,1H),6.94(t,J=2.2Hz,1H),6.92(d,J=9.2Hz,1H),6.69(dd,J=8.1,2.3Hz,1H)。HRMS(ESI+):m/z C17H14NO2(M+H)+264.1023;m/z C17H13NO2Na(M+Na)+286.0831。HPLC–MS(ESI+):m/z 264.2[100%,(M+H)+],549.2[50%,(2M+Na)+];(ESI-):m/z 262.1[80%,(M-H)-]。
(E)-1-(((4-羟基-[1,1'-联苯]-3-基)亚氨基)甲基)萘-2-醇(SR2-086)。通过按照上面用于亚胺衍生物的一般程序,使用2-羟基-1-萘甲醛(0.200g,1.162mmol,1.0当量)和2-氨基-3-苯基苯酚(0.215g,1.162mmol,1.0当量)得到亚胺SR2-086,为黄色固体(0.373g,95%)。HPLC:>99%[tR=5.1分钟,80%MeOH,20%水(含0.1%甲酸),20分钟]。1HNMR(400MHz,DMSO-d6)δ10.43(s,1H),9.60(d,J=9.4Hz,1H),8.43(d,J=8.4Hz,1H),8.16(d,J=2.1Hz,1H),7.78(d,J=9.5Hz,1H),7.73(m,2H),7.65(dd,J=7.9,1.4Hz,1H),7.44(m,3H),7.38(dd,J=8.4,2.1Hz,1H),7.34–7.27(m,1H),7.24(t,J=7.4Hz,1H),7.04(d,J=8.4Hz,1H),6.76(d,J=9.4Hz,1H)。HRMS(ESI+):m/z C23H18NO2(M+H)+340.1332;m/zC23H17NO2Na(M+Na)+462.1146。HPLC–MS(ESI+):m/z 340.2[100%,(M+H)+],701.3[10%,(2M+Na)+];(ESI-):m/z 338.2[50%,(M-H)-]。
化合物在体外YAP1:OCT4ELISA结合测定中的活性
在YAP1:OCT4结合测定中测定选定的化合物。表1中给出了结果。
表1:
ID | IC<sub>50</sub>结合测定 |
SR1-083 | ++ |
SR1-090 | + |
SR1-094 | + |
SR1-117 | + |
SR1-118 | ++ |
SR1-119 | ++ |
SR1-122 | ++ |
SR1-152 | ++ |
SR1-167 | ++ |
SR2-004 | +++ |
SR2-006 | ++ |
SR2-007 | ++ |
SR2-008 | ++ |
SR2-009 | ++ |
SR2-010 | +++ |
SR2-015 | ++ |
SR2-016 | ++ |
SR2-019 | ++ |
SR2-022 | +++ |
SR2-029 | +++ |
SR2-030 | +++ |
SR2-032 | +++ |
SR2-033 | +++ |
SR2-036 | ++ |
SR2-046 | +++ |
SR2-051 | +++ |
SR2-052 | +++ |
SR2-106 | +++ |
SR2-107 | +++ |
SR2-113 | +++ |
SR2-114 | +++ |
SR2-117 | +++ |
SR2-120 | +++ |
SR2-122 | +++ |
+:IC50(YAP1:OCT4破坏)>10μM;
++:IC50(YAP1:OCT4破坏)1至10μM
+++:IC50(YAP1:OCT4破坏)<10μM
对于本领域技术人员来说,本发明的明显和固有的其它优点将是显而易见的。将要理解的是,某些特征及子组合具有实用性,并且可以在不参考其它特征及子组合的情况下采用。这由权利要求所涵盖并且在权利要求的范围内。由于在不脱离本发明范围的情况下,可由本发明构成许多可能的实施方案,因此要理解的是,本文阐述或附图中所示的所有内容应被解释为说明性的而不具有限制意义。
Claims (28)
1.一种具有式I的化合物
其中,
X是C(O)、S(O)或SO2;
Y是CH、CR6或N;
Z是CH2、CR6R7或NH;
R1是C1-C8烷基、C1-C8烯基、C1-C8炔基、C1-C8烷氧基、C1-C8杂烷基、C3-C6环烷基、C3-C6杂环烷基、芳基或杂芳基,其中的任一者任选被一个或多个羰基(C=O)、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、氨基、-NR6R7、-C(O)NR6R7、C1-C6烷基羟基、C3-C6环烷基、C3-C6杂环烷基、芳基、杂芳基、卤代、羟基、巯基、氰基、硝基或放射标记同位素取代;
R2是氨基、羟基、C1-C8烷基、C1-C8烯基、C1-C8炔基、C1-C8烷氧基、C1-C8杂烷基、C3-C6环烷基、C3-C6杂环烷基、芳基或杂芳基,其中的任一者任选被一个或多个羰基(C=O)、羧基(-CO2-)、酯(CO2R6)、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、氨基、-NR6R7、-C(O)NR6R7、C1-C6烷基C3-6环烷基、C3-C6环烷基、C3-C6杂环烷基、芳基、杂芳基、C1-6烷基芳基、卤代、羟基、巯基、氰基、硝基或放射标记同位素取代;
每个R3独立地为氢、卤素、OH、C1-C8烷基、C1-C8烷氧基、芳基、O-芳基、杂芳基、O-杂芳基、O-CH2芳基或O-CH2杂芳基;且
R6和R7独立地选自氢、C1-C8烷基、C1-C8烯基、C1-C8炔基、C1-C8烷氧根、C1-C8羧酸根、C1-C8卤代烷基、C1-C8卤代烯基、C1-C8卤代炔基、C3-C6环烷基、C3-C6杂环烷基、芳基、C1-C3烷基杂芳基或杂芳基;其中的任一者任选被卤素取代;且n是1-5。
2.一种具有式II的化合物
其中,
R1是氢、C1-C8烷基、C1-C8烯基、C1-C8炔基、C1-C8烷氧基、C1-C8杂烷基、C3-C6环烷基、C3-C6杂环烷基、芳基或杂芳基,其中的任一者任选被一个或多个羰基(C=O)、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、氨基、-NR6R7、-C(O)NR6R7、C1-C6烷基羟基、C3-C6环烷基、C3-C6杂环烷基、芳基、杂芳基、卤代、羟基、巯基、氰基、硝基或放射标记同位素取代;
R2是氨基、羟基、C1-C8烷基、C1-C8烯基、C1-C8炔基、C1-C8烷氧基、C1-C8杂烷基、C3-C6环烷基、C3-C6杂环烷基、芳基或杂芳基,其中的任一者任选被一个或多个羰基(C=O)、羧基(-CO2-)、酯(CO2R6)、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、氨基、-NR6R7、-C(O)NR6R7、C1-C6烷基C3-6环烷基、C3-C6环烷基、C3-C6杂环烷基、芳基、杂芳基、C1-6烷基芳基、卤代、羟基、巯基、氰基、硝基或放射标记同位素取代;
每个R3独立地为氢、卤素、OH、C1-C8烷基、C1-C8烷氧基、芳基、O-芳基、杂芳基、O-杂芳基、O-CH2芳基或O-CH2杂芳基;且
R6和R7独立地选自氢、C1-C8烷基、C1-C8烯基、C1-C8炔基、C1-C8烷氧根、C1-C8羧酸根、C1-C8卤代烷基、C1-C8卤代烯基、C1-C8卤代炔基、C3-C6环烷基、C3-C6杂环烷基、芳基、C1-C3烷基杂芳基或杂芳基;其中的任一者任选被卤素取代;且n是1-5。
3.一种具有式III的化合物
其中,
X是C(O)、S(O)或SO2;
Y是CH、CR6或N;
Z是CH2、CR6R7或NH;
W是氰基、C2-C4炔烃或者三唑、四唑或噁唑,其任选被一个或多个羰基(C=O)、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、氨基、-NR6R7、-C(O)NR6R7、C1-C6烷基羟基、C3-C6环烷基、C3-C6杂环烷基、芳基、杂芳基、卤代、羟基、巯基、氰基、硝基或放射标记同位素取代;
R1是C1-C8烷基、C1-C8烯基、C1-C8炔基、C1-C8烷氧基、C1-C8杂烷基、C3-C6环烷基、C3-C6杂环烷基、芳基或杂芳基,其中的任一者任选被一个或多个羰基(C=O)、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、氨基、-NR6R7、-C(O)NR6R7、C1-C6烷基羟基、C3-C6环烷基、C3-C6杂环烷基、芳基、杂芳基、卤代、羟基、巯基、氰基、硝基或放射标记同位素取代;
R2是氨基、羟基、C1-C8烷基、C1-C8烯基、C1-C8炔基、C1-C8烷氧基、C1-C8杂烷基、C3-C6环烷基、C3-C6杂环烷基、芳基或杂芳基,其中的任一者任选被一个或多个羰基(C=O)、羧基(-CO2-)、酯(CO2R6)、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、氨基、-NR6R7、-C(O)NR6R7、C1-C6烷基C3-6环烷基、C3-C6环烷基、C3-C6杂环烷基、芳基、杂芳基、C1-6烷基芳基、卤代、羟基、巯基、氰基、硝基或放射标记同位素取代;
每个R3独立地为氢、卤素、OH、C1-C8烷基、C1-C8烷氧基、芳基、O-芳基、杂芳基、O-杂芳基、O-CH2芳基或O-CH2杂芳基;且
R6和R7独立地选自氢、C1-C8烷基、C1-C8烯基、C1-C8炔基、C1-C8烷氧根、C1-C8羧酸根、C1-C8卤代烷基、C1-C8卤代烯基、C1-C8卤代炔基、C3-C6环烷基、C3-C6杂环烷基、芳基、C1-C3烷基杂芳基或杂芳基;其中的任一者任选被卤素取代;且n是1-5。
4.如前述权利要求中任一项所述的化合物,其中Z是CH2。
5.如前述权利要求中任一项所述的化合物,其中Z是NH。
6.如前述权利要求中任一项所述的化合物,其中Y是CH2。
7.如前述权利要求中任一项所述的化合物,其中Y是N。
8.如前述权利要求中任一项所述的化合物,其中X是C(O)。
9.如前述权利要求中任一项所述的化合物,其中X是SO2。
10.如前述权利要求中任一项所述的化合物,其中R1是C1-C8烷氧基。
11.如前述权利要求中任一项所述的化合物,其中R1是苯基。
12.如前述权利要求中任一项所述的化合物,其中R1是被芳基取代的C1-3烷基,其中所述芳基任选被一个或多个C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、氨基、卤代、羟基、巯基、氰基、硝基或放射标记同位素取代。
13.如前述权利要求中任一项所述的化合物,其中R1是CH2CH2Ph、CH2CH2CH2Ph、CH(CH2)Ph、C(CH3)2Ph或CH2CH(Ph)2。
14.如前述权利要求中任一项所述的化合物,其中R1是CH2CH2Ph,其中所述苯基被一个或多个C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、氨基、卤代、羟基、巯基、氰基、硝基或放射标记同位素取代。
15.如前述权利要求中任一项所述的化合物,其中R1是被苯基取代的C1-3烷基,所述苯基被一个或多个卤素、甲氧基、乙氧基、丙氧基、氰基和CF3取代,或者R1是被苯基取代的C1-3烷基,所述苯基被二氧杂环戊烯取代。
16.如前述权利要求中任一项所述的化合物,其中R1是被芳基取代的C1-3烯基,其中所述芳基任选被一个或多个C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、氨基、卤代、羟基、巯基、氰基、硝基或放射标记同位素取代。
17.如前述权利要求中任一项所述的化合物,其中R1是CH=CHPh,其中所述苯基被一个或多个C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、氨基、卤代、羟基、巯基、氰基、硝基或放射标记同位素取代。
18.如前述权利要求中任一项所述的化合物,其中R1是C1-C8杂烷基、C3-C6杂环烷基,其任选被一个或多个C=O、C1-6烷基和芳基取代。
19.如前述权利要求中任一项所述的化合物,其中R1是被C(O)CH3取代的吡咯烷。
20.如前述权利要求中任一项所述的化合物,其中R2是OMe或OH。
21.如前述权利要求中任一项所述的化合物,其中R2是未取代的氨基、被C1-C6烷基取代的氨基、被C3-C6环烷基取代的氨基或被C1-C6烷基C3-6环烷基取代的氨基。
22.如前述权利要求中任一项所述的化合物,其中R3是氢或OH。
23.如前述权利要求中任一项所述的化合物,其中R3是O苄基。
24.一种药物组合物,其包含治疗有效量的前述权利要求中任一项所述的化合物和药物载体及任选的抗癌剂或抗炎剂。
25.一种治疗有需要的受试者的癌症的方法,包括:对所述受试者施用权利要求1-23中任一项所述的化合物。
26.如权利要求25所述的方法,其中所述癌症选自膀胱癌、脑癌、乳腺癌、结直肠癌、宫颈癌、胃肠癌、泌尿生殖系统癌、头颈癌、卵巢癌、胰腺癌、前列腺癌、肾癌、皮肤癌和睾丸癌。
27.如权利要求25所述的方法,其中所述癌症是肺癌。
28.一种杀灭受试者的肿瘤细胞的方法,包括使所述细胞与权利要求1-23中任一项所述的化合物接触。
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US62/396,383 | 2016-09-19 | ||
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ZA201902346B (en) | 2020-08-26 |
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