CN111683927A - 吲哚胺2,3-双加氧酶的调节剂 - Google Patents
吲哚胺2,3-双加氧酶的调节剂 Download PDFInfo
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- CN111683927A CN111683927A CN201880088842.3A CN201880088842A CN111683927A CN 111683927 A CN111683927 A CN 111683927A CN 201880088842 A CN201880088842 A CN 201880088842A CN 111683927 A CN111683927 A CN 111683927A
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Abstract
提供了式I的IDO1抑制剂化合物及其药学上可接受的盐，它们的药物组合物，它们的制备方法，以及它们在疾病的预防和/或治疗中的使用方法。式I，其中R1是具有式II的基团。
式I
Description
发明领域
公开了用于预防和/或治疗HIV的化合物、方法和药物组合物；包括通过施用治疗有效量的某些吲哚胺2,3-双加氧酶化合物预防AIDS和全身的免疫抑制的进展。还公开了制备此类化合物的方法以及使用所述化合物及其药物组合物的方法。
发明背景
吲哚胺-2,3-双加氧酶1(IDO1)是一种含血红素的酶，其催化色氨酸的吲哚环氧化以生成N-甲酰基犬尿氨酸，该N-甲酰基犬尿氨酸快速地和组成性地转化为犬尿氨酸(Kyn)和一系列下游代谢物。IDO1是该色氨酸代谢的犬尿氨酸途径的限速步骤，并且在炎症的情况下IDO1的表达是可诱导的。诱导IDO1的刺激包括病毒或细菌产物，或与感染、肿瘤或无菌组织损伤有关的炎性细胞因子。Kyn和几种下游代谢物具有免疫抑制作用：Kyn对T细胞和NK细胞具有抗增殖和促凋亡作用(Munn, Shafizadeh等人. 1999, Frumento, Rotondo等人.2002)，而代谢物如3-羟基邻氨基苯甲酸(3-HAA)或3-HAA氧化二聚产物朱红菌素酸(CA)抑制吞噬细胞功能(Sekkai, Guittet等人. 1997)，并诱导免疫抑制性调节性T细胞(Treg)的分化，同时抑制肠道保护性的产生IL-17或IL-22的CD4 + T细胞(Th17和Th22)的分化(Favre, Mold等人. 2010)。除了其它机制以外，IDO1诱导可能在限制主动免疫反应期间的免疫病理学、促进免疫反应的分辨(resolution)以及促进胎儿耐受性中是重要的。然而，在诸如癌症、或慢性病毒或细菌感染等慢性场合中，IDO1活性会阻止肿瘤或病原体的清除，并且如果活性是全身性的，IDO1活性可能会导致全身性免疫功能障碍(Boasso和Shearer2008, Li, Huang等人. 2012)。除了这些免疫调节作用外，还已知IDO1的代谢物(例如Kyn和喹啉酸)具有神经毒性，并在几种神经功能障碍的病况和抑郁症中被发现升高。因此，IDO1是抑制多种适应症的治疗靶标，例如用以促进肿瘤清除，成功清除难治的病毒或细菌感染，减少全身免疫功能障碍（表现为在HIV感染期间的持续的炎症或在脓毒症期间的免疫抑制）和预防或逆转神经学病况。
IDO1和HIV感染中的持续的炎症:
尽管抗逆转录病毒疗法(ART)在抑制HIV复制和减少AIDS相关病况的出现方面取得了成功，但接受ART的HIV感染的患者具有比他们的未感染的对应人群更高的非AIDS发病率和死亡率的出现。这些非AIDS病况包括癌症、心血管疾病、骨质疏松症、肝病、肾病、虚弱和神经认知功能障碍(Deeks 2011)。若干研究表明，非AIDS发病率/死亡率与持续的炎症有关，与对应人群相比其在接受ART的HIV感染的患者中保持升高(Deeks 2011)。因此，猜测尽管ART进行了病毒学抑制，但持续的炎症和免疫功能障碍是这些非AIDS定义事件(NADE)的一个原因。
HIV感染并杀死CD4 + T细胞，特别偏好如驻留在粘膜表面的淋巴组织中的那些CD4 + T细胞那样的细胞(Mattapallil, Douek等人2005)。这些细胞的丧失与对感染的炎症反应相结合，导致宿主与所有病原体(包括HIV本身，但扩展到先前存在的或获得的病毒感染、真菌感染以及皮肤和粘膜表面中的驻留细菌)之间的关系受到干扰。这种功能失调的宿主：病原体关系导致宿主对通常是小问题的过度反应并允许病原体在微生物丛中向外生长。因此，该功能失调的宿主：病原体相互作用会导致炎症加剧，进而导致更严重的功能障碍，从而引发恶性循环。由于炎症被认为会导致非AIDS发病率/死亡率，因此控制改变了的宿主：病原体相互作用的机制是治疗目标。
在未经治疗和治疗的HIV感染以及灵长类SIV感染模型中，IDO1的表达和活性增加(Boasso, Vaccari等人. 2007, Favre, Lederer等人. 2009, Byakwaga, Boum等人.2014, Hunt, Sinclair等人. 2014, Tenorio, Zheng等人. 2014)。如酶底物和产物的血浆水平之比(Kyn/Tryp或K:T比)所示，IDO1活性与其它炎症标志物相关并且是非AIDS发病率/死亡率的最强预测因子之一(Byakwaga, Boum等人. 2014, Hunt, Sinclair等人.2014, Tenorio, Zheng等人. 2014)。此外，与IDO1活性增加对免疫系统的预期影响相一致的特征是HIV和SIV诱导的免疫功能障碍的主要特征，例如对抗原的T细胞增殖反应降低以及全身和肠道隔室中Treg:Th17的失衡(Favre, Lederer等人. 2009, Favre, Mold等人.2010)。因此，我们和其他人猜测IDO1在驱动免疫功能障碍和与非AIDS发病率/死亡率相关的炎症的恶性循环中起作用。因此，我们提议抑制IDO1将在ART抑制的HIV感染的人中减少炎症并降低NADE的风险。
IDO1和HIV以外的持续的炎症
如上所述，与治疗的慢性HIV感染相关的炎症可能是多种终末器官疾病的驱动因素[Deeks 2011]。但是，这些终末器官疾病并非HIV感染所独有，并实际上是在HIV感染人群中较早发生的常见衰老疾病。在未感染的普通人群中，病因不明的炎症是发病率和死亡率的主要相关因素[Pinti, 2016 #88]。实际上，许多炎症标志物是共享的，例如IL-6和CRP。如果，如上面猜测的那样，IDO1通过在GI道或全身组织中诱导免疫功能障碍而在HIV感染人群中引起持续的炎症，那么IDO1也可能会导致炎症并因此在更广泛的人群中导致终末器官疾病。这些与炎症相关的终末器官疾病的例子有心血管疾病、代谢综合征、肝病(NAFLD，NASH)、肾病、骨质疏松症和神经认知障碍。实际上，IDO1途径在文献中与肝病(ItalianAssoc. for the Study of the Liver Conference 2015的Vivoli摘要]、糖尿病[Baban,2010 #89]、慢性肾病[Schefold, 2009 #90]、心血管疾病[Mangge, 2014 #92;Mangge,2014 #91]以及全身性老化和所有原因的死亡率[Pertovaara, 2006 #93]有关。因此，IDO1的抑制可用于减少一般人群的炎症，以减少与炎症和衰老相关的特定终末器官疾病的发生。
IDO1和肿瘤学
IDO表达可在多种人类癌症(例如；黑素瘤、胰腺癌、卵巢癌、AML、CRC、前列腺癌和子宫内膜癌)中检测到，并且与不良预后相关(Munn 2011)。多种免疫抑制作用可归于IDO的作用，包括诱导Treg分化和过度激活，抑制Teff免疫反应和降低的DC功能，所有这些都削弱了免疫识别并促进了肿瘤的生长(Munn 2011)。人脑肿瘤中IDO的表达与存活率降低有关。垂直生长的和转基因的神经胶质瘤小鼠模型证明IDO表达减少与Treg浸润减少以及长期存活率增加之间存在相关性(Wainwright, Balyasnikova等人2012)。在人类黑素瘤中，高比例的肿瘤(36例中的33例)显示出IDO升高，表明在建立特征在于MDSC以Treg依赖性方式扩展、激活和募集的免疫抑制性肿瘤微环境(TME)中的重要作用(Holmgaard, Zamarin等人.2015)。另外，已经在引流淋巴结和肿瘤本身中鉴定了表达宿主IDO的免疫细胞(Mellor和Munn 2004)。因此，肿瘤和宿主来源的IDO均被认为有助于TME的免疫抑制状态。
IDO的抑制是为重建针对癌症的免疫原性反应而提出的首要小分子药物策略之一(Mellor和Munn 2004)。1-甲基色氨酸的d-对映体(D-1MT或indoximod)是第一个进入临床试验的IDO抑制剂。尽管该化合物明确地抑制了IDO的活性，但它是分离的酶的非常弱的抑制剂，并且仍在阐明该化合物的体内作用机理。Incyte的研究者将通过筛选过程获得的命中化合物优化为具有足够的口服暴露的有效且选择性的抑制剂，以证明在小鼠黑素瘤模型中肿瘤生长的延迟(Yue, Douty等人. 2009)。该系列的进一步发展导致INCB204360，其在瞬时转染人或小鼠酶的细胞系中对IDO-1的抑制具有优于IDO-2和TDO的高度选择性(Liu,Shin等人. 2010)。对于内源性地表达IDO1的细胞系和原发性人类肿瘤，观察到相似的效力(IC50s ~ 3-20 nM)。当在DC和初始CD4+CD25- T细胞的共培养物中进行测试时，INCB204360阻断这些T细胞向CD4+FoxP3+ Tregs的转化。最后，当在具有免疫能力的小鼠的同系模型(PAN02胰腺细胞)中进行测试时，口服给药的INCB204360提供了肿瘤生长的显著剂量依赖性的抑制，但对植入免疫缺陷小鼠的同一肿瘤没有影响。相同研究者的其它研究表明，在具有免疫能力的小鼠的另一同系肿瘤模型中，IDO1的抑制与全身性犬尿氨酸水平的抑制以及肿瘤生长的抑制之间存在相关性。基于这些临床前研究，INCB24360进入了治疗转移性黑色瘤的临床试验(Beatty, O'Dwyer等人. 2013)。
鉴于色氨酸的分解代谢在维持免疫抑制中的重要性，因此，并不惊讶的是也已经检测到第二种色氨酸代谢酶TDO2被多种实体瘤(例如膀胱癌和肝癌、黑素瘤)过度表达。对104种人类细胞系的一项调查揭示，20/104具有TDO表达，17/104具有IDO1且16/104表达两者(Pilotte, Larrieu等人. 2012)。类似于IDO1的抑制，对TDO2的选择性抑制可有效逆转过度表达TDO2的肿瘤的免疫抵抗(Pilotte, Larrieu等人. 2012)。这些结果支持TDO2抑制和/或双重TDO2 / IDO1抑制作为改善免疫功能的可行治疗策略。
多项临床前研究已经表明，将IDO-1抑制剂与针对CTLA-4、PD-1和GITR的T细胞检查点调节性mAb结合使用具有重要的，甚至是协同的价值。在每种情况下，在跨越各种鼠类模型的这些研究中均观察到了改善的免疫活性/功能的功效和相关的PD方面(Balachandran, Cavnar等人. 2011, Holmgaard, Zamarin等人. 2013, M. Mautino2014, Wainwright, Chang等人. 2014)。Incyte IDO1抑制剂(INCB204360, epacadostat)已与CTLA4阻滞剂(伊匹木单抗)联用进行了临床测试，但由于联用所见的剂量限制性不良事件，不清楚是否达到了有效剂量。相反，最近发布的一项组合了epacadostat与Merck的PD-1 mAb (派姆单抗)的正在进行的试验的数据表明了该组合的改善的耐受性，从而允许更高剂量的IDO1抑制剂。存在令人鼓舞的跨跃多种肿瘤类型的若干临床反应。然而，尚不清楚这种组合是否比派姆单抗的单药活性有所改善(Gangadhar, Hamid等人. 2015)。类似地，在最近完成了针对晚期肿瘤患者的1a期安全性和PK/PD研究之后，Roche/Genentech正在进行将NGL919/ GDC-0919与PD-L1 (MPDL3280A, Atezo)和OX-40的两种mAb结合使用。
IDO1和慢性感染
IDO1活性会产生犬尿氨酸途径代谢物如Kyn和3-HAA，其至少会损害T细胞、NK细胞和巨噬细胞活性(Munn, Shafizadeh等人. 1999, Frumento, Rotondo等人. 2002) (Sekkai,Guittet等人. 1997, Favre, Mold等人. 2010)。Kyn水平或Kyn/Tryp比在慢性HIV感染(Byakwaga, Boum等人. 2014, Hunt, Sinclair等人. 2014, Tenorio, Zheng等人.2014)、HBV感染(Chen, Li等人. 2009)、HCV感染(Larrea, Riezu-Boj等人. 2007,Asghar, Ashiq等人. 2015)和TB感染(Suzuki, Suda等人. 2012)的场合下升高并与抗原特异性T细胞功能障碍相关(Boasso, Herbeuval等人. 2007, Boasso, Hardy等人. 2008,Loughman和Hunstad 2012, Ito, Ando等人. 2014, Lepiller, Soulier等人. 2015)。因此，认为在这些慢性感染的情况下，IDO1介导的病原体特异性T细胞反应的抑制在感染的持续性中起作用，并且IDO1的抑制可能对促进清除和解决感染具有益处。
IDO1和脓毒症
观察到脓毒症期间IDO1表达和活性升高，并且Kyn或Kyn/Tryp升高的程度对应于疾病严重性增加，包括死亡率增加(Tattevin, Monnier等人. 2010, Darcy, Davis等人.2011)。在动物模型中，对IDO1或IDO1基因敲除的阻断可保护小鼠免受致死剂量的LPS或盲肠结扎/穿孔模型中的死亡的影响(Jung, Lee等人. 2009, Hoshi, Osawa等人. 2014)。脓毒症的特征是在严重病例中的免疫抑制期(Hotchkiss, Monneret等人. 2013)，这可能表明IDO1作为免疫功能障碍的介质的作用，并表明IDO1的药理学抑制可为脓毒症提供临床益处。
IDO1和神经学病症
除了免疫学场合外，IDO1活性还与神经学场合中的疾病相关(在LovelaceNeuropharmacology 2016(Lovelace, Varney等人. 2016)中综述)。犬尿氨酸途径代谢物(例如3-羟基犬尿氨酸和喹啉酸)具有神经毒性，但与互生的具有神经保护作用的代谢物犬尿烯酸或吡啶甲酸平衡。其中已证明犬尿氨酸途径代谢物与疾病相关的神经变性和精神病症包括多发性硬化症、运动神经元病症如肌萎缩性侧索硬化症、亨廷顿氏病、帕金森氏病、阿尔茨海默氏病、重度抑郁症、精神分裂症、厌食症(Lovelace, Varney等人. 2016)。神经学疾病的动物模型已显示出弱的IDO1抑制剂(例如1-甲基色氨酸)对疾病的某些影响，这表明IDO1抑制可能为预防或治疗神经学和精神病症提供临床益处。
因此，将有效平衡上述特性的IDO抑制剂发现为降低非AIDS发病率/死亡率的发生的慢性HIV感染的疾病改良疗法；和/或预防脓毒症的死亡率的疾病改良疗法；和/或增强对HIV、HBV、HCV和其它慢性病毒感染、慢性细菌感染、慢性真菌感染以及对肿瘤的免疫反应的免疫疗法；和/或用于治疗抑郁症或其它神经学/神经精神性病症将是本领域的进步。
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某些IDO1抑制剂公开于美国临时申请62/481,743和62/436,672 (GSK 案号PR66234)。
发明概述
简而言之，在一个方面，本发明公开了式I的化合物或其药学上可接受的盐
式I
其中：
R1是具有式II的基团
式II
其中R5和R6独立地是H或CH3，或R5和R6可以与它们所键合的碳原子连接在一起以形成3-6元环烷基;
R7是含有1-3个选自N和S的杂原子的5或6-元杂环或杂芳基，并任选地被1或2个取代基取代，所述取代基选自F、Cl、CN、OCH3、CF3、环丙基、CONH2、CH2CH2OCH3和CH2OCH3；
R8是5或6-元环烷基或含有O或N的5或6-元杂环，且R8可以任选地被取代基取代，所述取代基选自卤素、OH、C1-3烷基和OCH3；
一个X是氢且另一个代表与Q的连接点；
Q是键、CH2或
，其中Y1代表与R1的连接点且Y2代表与所述化合物的其余部分的连接点；
R2和R3独立地是C10-20烷基；且
R4是氢或C1-4烷基。
在另一个方面，本发明公开了一种用于治疗将从IDO的抑制中受益的疾病或病况的方法。
在另一个方面，本发明公开了包含式I的化合物或其药学上可接受的盐的药物组合物。
在另一个方面，本发明提供了用于治疗的式I的化合物或其药学上可接受的盐。
在另一个方面，本发明提供了用于治疗将从IDO的抑制中受益的疾病或病况的式I的化合物或其药学上可接受的盐。
在另一个方面，本发明提供了式I的化合物或其药学上可接受的盐在制备用于治疗将从IDO的抑制中受益的疾病或病况的药物中的用途。
在另一个方面，本发明公开了一种用于治疗至少部分地由逆转录病毒家族中的病毒介导的患者中的病毒感染的方法，该方法包括向所述患者施用包含式I的化合物或其药学上可接受的盐的组合物。在一些实施方案中，病毒感染由HIV病毒介导。
在另一个方面，本发明的一个具体实施方案提供了一种治疗被HIV感染的对象的方法，该方法包括向该对象施用治疗有效量的式I的化合物或其药学上可接受的盐。
在又另一个方面，本发明的一个具体实施方案提供了一种在具有感染HIV风险的对象中抑制HIV感染的进展的方法，该方法包括向该对象施用治疗有效量的式I的化合物或其药学上可接受的盐。在下文中进一步描述了那些和其它实施方案。
附图简述
图1. 来自中间体C4在大鼠中的口服定量给药(3 mg/kg)的中间体C4的浓度。
图2. 来自前药实施例7在大鼠中的口服定量给药(5 mg/kg)的中间体C4的浓度。
图3. 在大鼠中的来自其口服定量给药的中间体C4的组织分布与来自其前药实施例7的口服定量给药的中间体C4的组织分布的对比。
代表性实施方案的详述
优选地，R5和R6之一是H且另一个是CH3。
优选地，R7是吡啶、噻二唑、嘧啶、吡嗪、哒嗪、三唑或噻唑，其任选地被1或2个取代基取代，所述取代基选自F、Cl、CN、OCH3、CF3、环丙基、CONH2、CH2CH2OCH3和CH2OCH3。更优选地，R7是任选地被Cl取代的吡啶或吡嗪。
优选地，R8是环己基或含有氧的6-元杂环。
最优选地，R1选自：
其中X指示与所述化合物的其余部分的连接点。
优选地，R4是H或甲基。
优选的药物组合物包括单位剂型。优选的单位剂型包括片剂。
预见到，本发明的化合物和组合物将可用于预防和/或治疗HIV；包括预防AIDS和全身的免疫抑制的进展。预期在许多情况下，这种预防和/或治疗将涉及用本发明的化合物与至少一种被认为对这种预防和/或治疗有用的其它药物组合进行治疗。例如，本发明的IDO抑制剂可以与其它免疫疗法例如免疫检查点(PD1、CTLA4、ICOS等)结合使用，并且可能与生长因子或细胞因子疗法(IL21、IL-7等)结合使用。
在治疗HIV中的常见实践是采用超过一种的有效药剂。因此，根据本发明的另一个实施方案，提供了一种用于预防或治疗至少部分地由逆转录病毒家族中的病毒介导的哺乳动物中的病毒感染的方法，该方法包括向已经被诊断出患有所述病毒感染或处于发展所述病毒感染的危险中的哺乳动物施用如式I中所定义的化合物，其中所述病毒为HIV病毒，并且进一步包括施用治疗有效量的一种或多种对HIV病毒具有活性的药剂，其中所述对HIV病毒具有活性的药剂选自核苷酸逆转录酶抑制剂；非核苷酸逆转录酶抑制剂；蛋白酶抑制剂；进入、附着和融合抑制剂；整合酶抑制剂；成熟抑制剂；CXCR4抑制剂；和CCR5抑制剂。此类其它药物的例子是多替拉韦、Bictegravir和Cabotegravir。
“药学上可接受的盐”是指衍生自本领域众所周知的多种有机和无机抗衡离子的药学上可接受的盐，并且仅作为示例包括钠、钾、钙、镁、铵和四烷基铵盐，并且当分子含有碱性官能团时，包括有机或无机酸的盐，例如盐酸盐、氢溴酸盐、酒石酸盐、甲磺酸盐、乙酸盐、马来酸盐和草酸盐。合适的盐包括P. Heinrich Stahl, Camille G. Wermuth (编),Handbook of Pharmaceutical Salts Properties, Selection, and Use；2002中所述的那些。
本发明还包括本文所述化合物的药学上可接受的盐。如本文所用，“药学上可接受的盐”是指所公开的化合物的衍生物，其中母体化合物通过将现有的酸或碱基团转化为其盐形式而被修饰。药学上可接受的盐的实例包括但不限于碱性残基如胺的无机或有机酸盐；酸性残基如羧酸的碱或有机盐；等等。本发明的药学上可接受的盐包括由例如无毒的无机或有机酸形成的母体化合物的常规无毒的盐。本发明的药学上可接受的盐可以通过常规化学方法由含有碱性或酸性基团的母体化合物合成。通常，这些盐可以通过将这些化合物的游离酸或碱形式与化学计量的合适的碱或酸在水中或在有机溶剂中或在两者的混合物中反应来制备；通常，非水介质如乙醚、乙酸乙酯、乙醇、异丙醇或ACN是优选的。
本文所用的短语“药学上可接受的”是指在合理的医学判断范围内，适合于与人类和动物的组织接触而不具有过度的毒性、刺激性、过敏反应或其它问题或并发症，与合理的获益/风险比相称的那些化合物、材料、组合物和/或剂型。
在一个实施方案中，含有式I的化合物或其盐的药物制剂是适于口服或肠胃外施用的制剂。在另一个实施方案中，所述制剂是长效肠胃外制剂。在另一个实施方案中，所述制剂是纳米颗粒制剂。
本发明涉及可用作免疫抑制的新疗法的化合物、组合物和药物组合物。尽管不希望受到任何特定理论的束缚，但认为本发明的化合物能够利用分子氧或活性氧抑制催化I-Trp对N-甲酰基犬尿氨酸的氧化吡咯环裂解反应的酶。
因此，在本发明的另一个实施方案中，提供了一种用于预防和/或治疗HIV的方法；包括预防AIDS和全身的免疫抑制的进展。
实施例
下列实施例用于更充分地描述制造和使用上述发明的方式。应当理解，这些实施例决不用于限制本发明的真正范围，而是出于说明性目的而给出。在下面的实施例和合成方案中，以下缩写具有以下含义。如果未定义缩写，则其具有其被普遍接受的含义。
设备描述
1H NMR谱在Bruker Ascend 400谱仪或Varian 400谱仪上记录。化学位移以百万分率(ppm, δ单位)表达。偶合常数以赫兹(Hz)为单位。分裂模式描述了明显的多重态，并指定为s (单峰)、d (双峰)、t (三重峰)、q (四重峰)、quint (五重峰)、m (多重峰)、br (宽峰)。
在具有SQ检测器的Waters ACQUITY UPLC上使用Waters BEH C18, 2.1 x 50 mm,1.7µm（使用梯度洗脱法）记录分析型低分辨率质谱(MS)。
溶剂A: 0.1%甲酸(FA)水溶液；
溶剂B: 0.1%FA乙腈溶液；
30%B持续0.5 min，随后是30-100%B历经2.5 min。
中间体A的合成
二棕榈酸2-羟基丙烷-1,3-二基酯的制备
向甘油(1.0 g, 0.132 mmol)、吡啶(16.1 mg, 0.132 mmol)在THF (20 mL)中的溶液中加入棕榈酰氯(63.1 mg, 0.329 mmol)，并将混合物在室温搅拌17小时。将反应混合物用DCM (5 mL)稀释，用1 N的HCl水溶液酸化至pH 4~5。分离各层，并将有机层浓缩和通过硅胶色谱法(5%至30%乙酸乙酯/己烷类)纯化以得到作为白色固体的标题化合物(1.7 g, 27%)。1HNMR (400 MHz, CDCl3) δ 4.21 - 4.07 (m, 5H), 2.44 (d, J = 4.7 Hz, 1H), 2.35(t, J = 7.6 Hz, 4H), 1.67 - 1.58 (m, 4H), 1.30 - 1.23 (m, J = 13.4 Hz, 48H),0.88 (t, J = 6.8 Hz, 6H)。C35H68O5的MS (ESI) m/z计算值: 568.51。实测：569.65 (M+1)+。
中间体A
5-((1,3-双(棕榈酰氧基)丙烷-2-基)氧基)-5-氧代戊酸
将二棕榈酸2-羟基丙烷-1,3-二基酯(500 mg, 0.879 mmol)和戊二酸酐(100 mg,0.879 mmol)的混合物在100℃搅拌过夜。将粗产物通过硅胶色谱法(0 ~ 15%的EtOAc在PE中的溶液)纯化以得到作为白色固体的标题化合物(510 mg, 85%)，将其不经纯化地使用。1H NMR (400 MHz, CDCl3): δ 5.26 (m, 1H), 4.31 (dd, J = 11.9, 4.3 Hz, 2H), 4.14(dd, J = 11.9, 5.9 Hz, 2H), 2.44 (t, J = 7.4 Hz, 2H), 2.42 (t, J = 7.4 Hz,2H), 2.31 (t, J = 7.6 Hz, 4H), 1.96 (m, 2H), 1.67 - 1.54 (m, 4H), 1.49 - 1.18(m, 48H), 0.88 (t, J = 6.8 Hz, 6H)。没有发现羧基的质子。
中间体B的合成
4-甲基二氢-2H-吡喃-2,6(3H)-二酮的制备
将3-甲基戊二酸(6.0 g, 41 mmol)和乙酰氯(50 mL)的混合物在70℃搅拌30小时。将反应混合物在减压下浓缩以得到残余物，将其通过在Et2O中重结晶进行纯化以得到作为白色固体的标题产物(2.9 g, 55%收率)。1H NMR (400 MHz, CDCl3) δ 2.91 - 2.87 (m,1H), 2.86 - 2.83 (m, 1H), 2.46 - 2.37 (m, 2H), 2.36 - 2.27 (m, 1H), 1.14 (d,J = 6.4 Hz, 3H)。
中间体B
5-((1,3-双(棕榈酰氧基)丙烷-2-基)氧基)-3-甲基-5-氧代戊酸的制备
将二棕榈酸2-羟基丙烷-1,3-二基酯(9.5 g, 16.75 mmol)和4-甲基二氢-2H-吡喃-2,6(3H)-二酮(2.14 g, 16.75 mmol)的混合物在100℃搅拌过夜。将粗产物通过硅胶色谱法(0 ~ 30%的EtOAc在PE中的溶液)纯化以得到作为白色固体的标题化合物(7.67 g, 66%)。C41H76O8的MS (ESI) m/z计算值：696.55。实测：695.41 (M-1)-。
中间体C的合成
反式-4-((4-溴-2-硝基苯基)(异丁基)氨基)环己烷-1 -醇的制备
将4-溴-1-氟-2-硝基苯(7.4 g, 33.5 mmol)、反式-4-(异丁基氨基)环己烷-1-醇(6.7g, 40.2 mmol)和DIPEA (11.7 mL, 67.0 mmol)在NMP (80 mL)中的混合物在140℃在N2气氛下搅拌6小时。将得到的混合物在EtOAc和H2O之间分配。分离各层并将有机层用盐水洗涤，经Na2SO4干燥，过滤并浓缩以得到粗产物，将其通过快速色谱法(硅胶, 0-20%的EtOAc在PE中的溶液)纯化以得到作为红色油的标题化合物(8.4 g, 67%收率)。C16H23BrN2O3的LCMS(ESI) m/z计算值: 370.09。实测：371.46/373.45 (M/M+2)+。
4-溴-N-(反式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)-N- 异丁基-2-硝基苯
胺的制备
向反式-4-((4-溴-2-硝基苯基)(异丁基)氨基)-环己烷-1-醇(16.2 g, 43.7 mmol)在DCM (100 mL)中的溶液中加入咪唑(5.9 g, 87.4 mmol)和TBSOTf (17.3 g, 65.6 mmol)。在室温搅拌5小时以后，将得到的混合物用H2O淬灭，并用DCM萃取。将有机层用盐水洗涤，经Na2SO4干燥，过滤并浓缩以得到粗产物，将其通过快速色谱法(硅胶, 0-20%的EtOAc在PE中的溶液)纯化以得到标题化合物(20.5 g, 96%收率)。C22H37BrN2O3Si的LCMS (ESI) m/z计算值: 484.18。实测：485.52/487.51 (M/M+2)+。
(E)-3-(4-((反式-4-((叔丁基二甲基甲硅烷基)氧基)环己基) (异丁基)氨基)-
3-硝基苯基)丁-2-烯酸甲酯的制备
将4-溴-N-(反式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)-N- 异丁基-2-硝基苯胺(18.5 g, 38.14 mmol)、(E)-丁-2-烯酸甲酯(11.4 g, 114.4 mmol)、TBAB (2.46 g, 7.6mmol)、Pd(o-MePh3P)4 (1.5 g, 1.91 mmol)和TEA (10.6 mL, 76.28 mmol)在DMF (200mL)中的混合物在100℃在N2气氛下搅拌过夜。将得到的混合物在EtOAc和H2O之间分配。分离各层并将有机层用盐水洗涤，经Na2SO4干燥，过滤并浓缩以得到粗产物，将其通过快速色谱法(硅胶, 0-10%的EtOAc在PE中的溶液)纯化以得到作为黄色油的标题化合物(9.67 g,50%收率)。C27H44N2O5Si的LCMS (ESI) m/z计算值: 504.30。实测：505.69 (M+1)+。
3-(4-((反式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)(异丁基)氨基)-3-硝基
苯基)丁酸甲酯的制备
在-5℃，向(CuHPh3P)6 (288 mg, 0.147 mmol)和(R,S)-PPF-P(tBu)2 (289 mg, 0.535mmol)在甲苯(90 mL)中的混合物中加入PMHS (2.9 mL)和t-BuOH (2.3 mL)，然后引入(E)-3-(4-((反式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)(异丁基)氨基)-3-硝基苯基)丁-2-烯酸甲酯(9.67 g, 19.1 mmol)。在室温搅拌2h以后，将得到的混合物用NaHCO3水溶液淬灭，并用EtOAc萃取。将有机层用盐水洗涤，经Na2SO4干燥，过滤并浓缩以得到粗产物，将其通过快速色谱法(硅胶, 0-10%的EtOAc在PE中的溶液)纯化以得到作为黄色油的标题化合物(8.16 g, 88%收率)。C27H46N2O5Si的LCMS (ESI) m/z计算值: 506.32。实测：507.82 (M+1)+。
(R)-3-(4-((反式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)(异丁基)氨基)-3-
硝基苯基)丁酸的制备
向(R)-3-(3-((5-氯吡嗪-2-基)氨基)-4-((反式-4-羟基环己基)(异丁基)氨基)苯基)丁酸甲酯(3.6 g, 7.09 mmol)在MeOH (30 mL)中的溶液中加入1N的NaOH水溶液(20 mL)。在室温搅拌8h以后，将得到的混合物用1N HCl中和，并用EtOAc萃取。将有机层用盐水洗涤，经Na2SO4干燥并浓缩以得到标题化合物(3.3 g, 94%收率)，将其不经纯化用在下述步骤中。C26H44N2O5Si的LCMS (ESI) m/z计算值: 492.30。实测：493.47 (M+1)+。
(R)-3-(4-((反式-4-((叔丁基二甲基甲硅烷基)氧基)环己基) (异丁基)氨基)-
3-硝基苯基)丁酸叔丁酯的制备
向(R)-3-(4-((反式-4-((叔丁基二甲基甲硅烷基)氧基)-环己基)(异丁基)氨基)-3-硝基苯基)丁酸(3.3 g, 6.70 mmol)在DCM (30 mL)中的溶液中加入2,2,2-三氯乙酰亚氨酸叔丁酯(2.48 g,11.38 mmol)，随后加入BF3•Et2O (0.13 mL, 1.0 mmol)。在室温搅拌40h以后，将反应混合物用NaHCO3水溶液中和。分离各层并将水相用DCM萃取。将合并的有机层用盐水洗涤，经Na2SO4干燥并浓缩以得到粗产物，将其通过快速色谱法(硅胶, 0-20%的EtOAc在PE中的溶液)纯化以得到标题化合物(2.82 g, 77%收率)。C30H52N2O5Si的LCMS(ESI) m/z计算值: 548.36。实测：549.60 (M+1)+。
中间体C
3-(3-氨基-4-((反式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)(异丁基)氨基)苯
基)丁酸叔丁酯的制备
将(R)-3-(4-((反式-4-((叔丁基二甲基甲硅烷基)氧基)-环己基) (异丁基)氨基)-3-硝基苯基)丁酸叔丁酯(2.82 g, 5.13 mmol)和10%Pd/C (846 mg)在EtOAc (30 mL)中的混合物在50℃在H2气氛下搅拌6 h。将得到的混合物穿过硅藻土垫过滤，并将滤液在减压下浓缩以得到粗产物，将其通过快速色谱法(硅胶, 0-20%的EtOAc在PE中的溶液)纯化以得到作为黄色油的标题化合物(1.88 g, 71%收率)。C30H54N2O3Si的LCMS (ESI) m/z计算值:518.39。实测：519.55 (M+1)+。
实施例1的合成
(R)-3-(4-((反式-4-((叔丁基二甲基甲硅烷基)氧基)环己基) (异丁基)氨基)-3-
((6-氯吡啶-3-基)氨基)苯基)丁酸叔丁酯的制备
将3-(3-氨基-4-((反式-4-((叔丁基二甲基甲硅烷基)氧基)环己基) (异丁基)氨基)苯基)丁酸叔丁酯(500 mg, 0.97 mmol)、5-溴-2-氯吡啶(374 mg, 1.94 mmol)、Pd2(dba)3(170 mg, 0.194 mmol)、Xantphos (225 mg, 0.388 mmol)和Cs2CO3 (630 mg, 1.94 mmol)在甲苯(5 mL)中的混合物在100℃在N2气氛下搅拌过夜。将得到的混合物在EtOAc和H2O之间分配。将有机层用盐水洗涤，经Na2SO4干燥，过滤并浓缩以得到粗产物，将其通过快速色谱法(硅胶, 0-10%的EtOAc在PE中的溶液)纯化以得到标题化合物(570 mg, 93%收率)。C35H56ClN3O3Si的LCMS (ESI) m/z计算值: 629.38。实测：630.62/632.61 (M/M+2)+。
(R)-3-(3-((6-氯吡啶-3-基)氨基)-4-((反式-4-羟基环己基)(异丁基)氨基)苯
基)丁酸叔丁酯的制备
向(R)-3-(4-((反式-4-((叔丁基二甲基甲硅烷基)氧基)-环己基) (异丁基)氨基)-3-((6-氯吡啶-3-基)氨基)苯基)丁酸叔丁酯(650 mg, 1.03 mmol)在THF (5 mL)中的溶液中加入TBAF (1N在THF中，5 mL)。在室温搅拌过夜以后，将得到的混合物在EtOAc和H2O之间分配。将有机层用盐水洗涤，经Na2SO4干燥，过滤并浓缩以得到粗产物，将其通过快速色谱法(硅胶, 0-20%的EtOAc在PE中的溶液)纯化以得到标题化合物(450 mg, 84%收率)。C29H42ClN3O3的LCMS (ESI) m/z计算值: 515.29。实测：516.67/518.63 (M/M+2)+。
中间体C2
通过用过量的4N的HCl在二氧杂环己烷中的溶液处理(R)-3-(3-((6-氯吡啶-3-基)氨基)-4-((反式-4-羟基环己基)(异丁基)氨基)苯基)丁酸叔丁酯并除去溶剂，得到(R)-3-(3-((6-氯吡啶-3-基)氨基)-4-(((1r,4R)-4羟基环己基)(异丁基)氨基)-苯基)丁酸。
戊二酸1,3-双(棕榈酰氧基)丙烷-2-基(反式-4-((4-((R)-4-(叔-丁氧基)-4-氧
代丁-2-基)-2-((6-氯吡啶-3-基)氨基)苯基)(异丁基)氨基)环己基)酯的制备
向戊二酸1,3-双(棕榈酰氧基)丙烷-2-基(反式-4-((4-((R)-4-(叔-丁氧基)-4-氧代丁-2-基)-2-((6-氯吡啶-3-基)氨基)苯基)(异丁基)氨基)-环己基)酯(150 mg, 0.29mmol)、5-((1,3-双(棕榈酰氧基)丙烷-2-基)氧基)-5-氧代戊酸(397 mg, 0.58 mmol)和DMAP (35 mg, 0.29 mmol)在DMF (5 mL)中的溶液中加入EDCI (112 mg, 0.58 mmol)。在60℃搅拌17小时以后，将反应混合物在EtOAc和水之间分配并分离各层。将有机层用盐水洗涤，经Na2SO4干燥，在减压下浓缩，得到作为黄色油的标题化合物(70 mg, 20%)。C69H114ClN3O10的MS (ESI) m/z计算值: 1179.82。实测：1181.27/1183.29 (M/M+2)+。
实施例1
(R)-3-(4-((反式-4-((5-((1,3-双(棕榈酰氧基)丙烷-2-基)氧基)-5-氧代戊酰基)氧
基)环己基)(异丁基)氨基)-3-((6-氯吡啶-3-基)氨基)苯基)丁酸的制备
向戊二酸1,3-双(棕榈酰氧基)丙烷-2-基(反式-4-((4-((R)-4-(叔-丁氧基)-4-氧代丁-2-基)-2-((6-氯吡啶-3-基)氨基)苯基)(异丁基)氨基)-环己基)酯(70 mg, 0.1059mmol)在DCM (3 mL)中的溶液中加入TFA (1 mL)，并将混合物在室温搅拌2小时。将反应混合物在减压下浓缩。通过制备型TLC (5%至10%乙酸乙酯/己烷类)纯化，得到作为浅黄色油的标题化合物(37 mg, 55%)。C65H106ClN3O10的MS (ESI) m/z计算值: 1123.76。实测：1124.79/1126.82 (M/M+2)+。
实施例2的合成
(R)-3-(4-((反式-4-((叔丁基二甲基甲硅烷基)氧基)环己基) (异丁基)氨基)-3-
((5-氯吡嗪-2-基)氨基)苯基)丁酸叔丁酯的制备
将(R)-3-(3-氨基-4-((反式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)(异丁基)氨基)苯基)丁酸叔丁酯(500 mg, 0.97 mmol)、2,5-二氯吡嗪(290 mg, 1.94mmol)、Pd2(dba)3(178 mg, 0.194 mmol)、Xantphos (225 mg, 0.388 mmol)和Cs2CO3 (630 mg, 1.94 mmol)在甲苯(5 mL)中的混合物在100℃在N2气氛下搅拌过夜。将得到的混合物在EtOAc和H2O之间分配。分离各层以后，将有机层用盐水洗涤，经Na2SO4干燥，过滤并浓缩以得到粗产物，将其通过快速色谱法(硅胶, 0-30%的EtOAc在PE中的溶液)纯化以得到标题化合物(410 mg,67%收率)。C34H55ClN4O3Si的LCMS (ESI) m/z计算值: 630.37。实测：631.39/633.40 (M/M+2)+。
(R)-3-(3-((5-氯吡嗪-2-基)氨基)-4-((反式-4-羟基环己基)(异丁基)氨基)苯
基)丁酸叔丁酯的制备
向(R)-3-(4-((反式-4-((叔丁基二甲基甲硅烷基)氧基)-环己基) (异丁基)氨基)-3-((5-氯吡嗪-2-基)氨基)苯基)丁酸叔丁酯(410 mg, 0.65 mmol)在THF (3 mL)中的溶液中加入TBAF (1N在THF中，3 mL)。在室温搅拌过夜以后，将得到的混合物在EtOAc和H2O之间分配。将有机层用盐水洗涤，经Na2SO4干燥，过滤并浓缩以得到粗产物，将其通过快速色谱法(硅胶, 0-30%的EtOAc在PE中的溶液)纯化以得到标题化合物(310 mg, 92%收率)。C28H41ClN4O3的LCMS (ESI) m/z计算值: 516.29。实测：517.65/519.62 (M/M+2)+。
与中间体C2的合成类似地得到中间体C3。
(R)-3-(3-((5-氯吡嗪-2-基)氨基)-4-(((1r,4R)-4羟基环己基)(异丁基)氨基)
苯基)丁酸
戊二酸1,3-双(棕榈酰氧基)丙烷-2-基(反式-4-((4-((R)-4-(叔-丁氧基)-4-氧代丁-
2-基)-2-((5-氯吡嗪-2-基)氨基)苯基)(异丁基)氨基)环己基)酯的制备
向(R)-3-(3-((5-氯吡嗪-2-基)氨基)-4-((反式-4-羟基环己基)(异丁基)氨基)苯基)丁酸叔丁酯(120 mg, 0.233 mmol)、5-((1,3-双(棕榈酰氧基)丙烷-2-基)氧基)-5-氧代戊酸(318 mg, 0.466 mmol)和DMAP (614 mg, 0.932 mmol)在DMF (3 mL)中的溶液中加入EDCI (89 mg, 0.466 mmol)，并将混合物在40℃搅拌8 h。将得到的混合物在EtOAc和H2O之间分配。将有机层用盐水洗涤，经Na2SO4干燥，并浓缩以得到粗产物，将其通过快速色谱法(硅胶, 5%至10%乙酸乙酯/己烷类)纯化以得到作为黄色油的标题化合物(50 mg, 18%)。C68H113ClN4O10的MS (ESI) m/z计算值：1180.81。实测：1182.28/1184.30 (M+1)+。
实施例2
(R)-3-(4-((反式-4-((5-((1,3-双(棕榈酰氧基)丙烷-2-基)氧基)-5-氧代戊酰基)氧
基)环己基)(异丁基)氨基)-3-((5-氯吡嗪-2-基)氨基)苯基)丁酸的制备
向戊二酸1,3-双(棕榈酰氧基)丙烷-2-基(反式-4-((4-((R)-4-(叔-丁氧基)-4-氧代丁-2-基)-2-((5-氯吡嗪-2-基)氨基)苯基)-(异丁基)氨基)环己基)酯(50 mg, 0.042mmol)在DCM (3 mL)中的溶液中加入TFA (1 mL)，并将混合物在室温搅拌3 h。将反应混合物在减压下浓缩。通过快速色谱法(硅胶, 5%至30%乙酸乙酯/己烷类)纯化得到作为浅黄色油的标题化合物(30 mg, 63%)。C64H105ClN4O10的MS (ESI) m/z计算值: 1124.75。实测：1126.24/1128.26 (M/M+2)+。
实施例3的合成
3-甲基戊烷二酸1-(1,3-双(棕榈酰氧基)丙烷-2-基) 5-(反式-4-((4-((R)-4-(叔-丁
氧基)-4-氧代丁-2-基)-2-((6-氯吡啶-3-基)氨基)苯基)(异丁基)氨基)环己基)酯的制备
向戊二酸1,3-双(棕榈酰氧基)丙烷-2-基(反式-4-((4-((R)-4-(叔-丁氧基)-4-氧代丁-2-基)-2-((6-氯吡啶-3-基)氨基)苯基)(异丁基)氨基)-环己基)酯(100 mg, 0.194mmol)、5-((1,3-双(棕榈酰氧基)丙烷-2-基)氧基)-3-甲基-5-氧代戊酸(149 mg, 0.213mmol)和DMAP (24 mg, 0.194 mmol)在DCM (5 mL)中的溶液中加入EDCI (75 mg, 0.388mmol)，并将混合物在40℃搅拌过夜。将反应混合物用DCM (5 mL)稀释，加入硅胶，并将混合物在减压下浓缩。通过硅胶色谱法(5%至10%乙酸乙酯/己烷类)纯化，得到作为无色油的标题化合物(190 mg, 82%) ; C70H116ClN3O10的MS (ESI) m/z计算值: 1193.83。
实施例3
(3R)-3-(4-((反式-4-((5-((1,3-双(棕榈酰氧基)丙烷-2-基)氧基)-3-甲基-5-氧代
戊酰基)氧基)环己基)(异丁基)氨基)-3-((6-氯吡啶-3-基)氨基)苯基)丁酸的制备
向5-((1,3-双(棕榈酰氧基)丙烷-2-基)氧基)-3-甲基-5-氧代戊酸(190 mg, 0.159mmol)在DCM (4 mL)中的溶液中加入TFA (2 mL)，并将混合物在室温搅拌5 h。将反应混合物在减压下浓缩。通过制备型TLC (5%至10%乙酸乙酯/己烷类)纯化，得到作为浅黄色固体的标题化合物(138 mg, 76%)。H NMR (400 MHz, CDCl3) δ 8.24 (d, J = 2.9 Hz, 1H),7.42 (dd, J = 8.6, 3.0 Hz, 1H), 7.22 (d, J = 8.6 Hz, 1H), 7.09 (d, J = 8.1Hz, 2H), 6.77 (dd, J = 8.2, 1.8 Hz, 1H), 5.29 - 5.20 (m, 1H), 4.62 - 4.53 (m,1H), 4.33 - 4.24 (m, 2H), 4.17 - 4.09 (m, 2H), 3.27 - 3.17 (m, 1H), 2.93 -2.70 (m, 2H), 2.67 - 2.53 (m, 3H), 2.43 - 2.27 (m, 7H), 2.24 - 2.12 (m, 2H),2.00 - 1.83 (m, 4H), 1.59 (dd, J = 14.1, 7.1 Hz, 4H), 1.50 - 1.38 (m, 3H),1.31 - 1.19 (m, 54H), 0.97 (d, J = 6.5 Hz, 3H), 0.90 - 0.82 (m, 12H)。没有观察到羧基的质子。C66H108ClN3O10的MS (ESI) m/z计算值: 1137.77。实测：1138.57/1140.57(M/M+2)+。
实施例4的合成
3-甲基戊烷二酸1-(1,3-双(棕榈酰氧基)丙烷-2-基) 5-(反式-4-((4-((R)-4-(叔-丁
氧基)-4-氧代丁-2-基)-2-((5-氯吡嗪-2-基)氨基)苯基)(异丁基)氨基)环己基)酯的制备
向(R)-3-(3-((5-氯吡嗪-2-基)氨基)-4-((反式-4-羟基环己基)(异丁基)氨基)苯基)丁酸叔丁酯(80.0 mg, 0.154 mmol)、5-((1,3-双(棕榈酰氧基)丙烷-2-基)氧基)-3-甲基-5-氧代戊酸(119 mg, 0.17 mmol)和DMAP (19 mg, 0.154 mmol)在DCM (3 mL)中的溶液中加入EDCI (58 mg, 0.308 mmol)，并将混合物在40℃rt搅拌过夜。将反应混合物用DCM (5mL)稀释，加入硅胶，并将混合物在减压下浓缩。通过硅胶色谱法(5%至10%乙酸乙酯/己烷类)纯化，得到作为无色油的标题化合物(160 mg, 87%) ; C69H115ClN4O10的MS (ESI) m/z计算值: 1194.83。实测：1196.21/1198.19 (M+1)+。
实施例4
(3R)-3-(4-((反式-4-((5-((1,3-双(棕榈酰氧基)丙烷-2-基)氧基)-3-甲基-5-氧代
戊酰基)氧基)环己基)(异丁基)氨基)-3-((5-氯吡嗪-2-基)氨基)苯基)丁酸的制备
向3-甲基戊烷二酸1-(1,3-双(棕榈酰氧基)丙烷-2-基) 5-(反式-4-((4-((R)-4-(叔-丁氧基)-4-氧代丁-2-基)-2-((5-氯吡嗪-2-基)氨基)苯基)-(异丁基)氨基)环己基)酯(160 mg, 0.133 mmol)在DCM (5 mL)中的溶液中加入TFA (3 mL)，并将混合物在室温搅拌5 h。将反应混合物在减压下浓缩。通过快速色谱法(硅胶, 5%至40%乙酸乙酯/己烷类)纯化，得到作为浅黄色油的标题化合物(68 mg, 44%)。C65H107ClN4O10的MS (ESI) m/z计算值:1138.77。实测：1139.63/1140.63 (M/M+2)+。
中间体D的合成
3,3,5,7-四甲基色满-2-酮的制备
将3,5-二甲基苯酚(5.0 g, 40.93 mmol)和3-甲基丁-2-烯酸甲酯(5.14 g, 45.02mmol)在甲磺酸(10 mL)中的溶液在70℃搅拌过夜。将反应混合物倒入水中，并用EtOAc萃取。将有机层合并并依次用水和盐水洗涤，并经MgSO4干燥。在真空下除去溶剂，并将残余物通过快速色谱法(硅胶, 0~60%的乙酸乙酯在石油醚中的溶液)纯化以得到作为白色固体的标题化合物(8.0 g, 96%收率)。C13H16O2的LCMS (ESI) m/z计算值: 204.12。实测：205.24(M+1)+。
2-(4-羟基-2-甲基丁-2-基)-3,5-二甲基苯酚的制备
在0℃，向3,3,5,7-四甲基色满-2-酮(4.0 g, 19.60 mmol)在THF (180 mL)中的混合物中逐份加入LiAlH4。在室温搅拌1.5 h以后，将反应物用饱和NH4Cl水溶液淬灭并将固体通过过滤除去。将滤液在真空中浓缩并将残余物通过快速色谱法(硅胶, 0~60%的乙酸乙酯在石油醚中的溶液)纯化以得到作为白色固体的标题化合物(900 mg, 23%收率)。C13H20O2的LCMS (ESI) m/z计算值: 208.15。实测：209.2 (M+1)+。
2-(4-((叔丁基二甲基甲硅烷基)氧基)-2-甲基丁-2-基)-3,5-二甲基苯酚的制备
在0℃，向2-(4-羟基-2-甲基丁-2-基)-3,5-二甲基苯酚(900 mg, 4.33 mmol)和咪唑(737 mg, 10.82)在DMF中的溶液中加入TBSCl (974 mg, 6.490)。在室温搅拌2 h以后，将反应混合物倒入水中，并用EtOAc萃取。将有机层合并并依次用水和盐水洗涤，并经MgSO4干燥。在真空下除去溶剂并将残余物通过快速色谱法(硅胶, 0~80%的乙酸乙酯在石油醚中的溶液)纯化以得到作为白色固体的标题化合物(1.12 g, 81%收率)。C19H34O2Si的LCMS (ESI)m/z计算值: 322.23。实测：323.41 (M+1)+。
中间体E的合成
3-甲基戊烷二酸1-(1,3-双(棕榈酰氧基)丙烷-2-基) 5-(2-(4-((叔丁基二甲基甲硅
烷基)氧基)-2-甲基丁-2-基)-3,5-二甲基苯基)酯的制备
向5-((1,3-双(棕榈酰氧基)丙烷-2-基)氧基)-3-甲基-5-氧代戊酸(1.2 g, 1.72mmol)、2-(4-((叔丁基二甲基甲硅烷基)氧基)-2-甲基丁-2-基)-3,5-二甲基苯酚(665 mg,2.07 mmol)和DMAP (210 mg, 1.72 mmol)在DCM (12 mL)中的溶液中加入EDCI (658 mg,3.44 mmol)，并将混合物在室温搅拌17 h。将反应混合物在减压下浓缩以得到残余物，将其通过硅胶色谱法(5%至10%的EtOAc在PE中的溶液)进行纯化以得到标题化合物(1.46 g,85%)。C60H108O9Si的MS (ESI) m/z计算值: 1000.78。实测：1001.82 (M+1)+。
3-甲基戊烷二酸1-(1,3-双(棕榈酰氧基)丙烷-2-基) 5-(2-(4-羟基-2-甲基丁-
2-基)-3,5-二甲基苯基)酯的制备
向3-甲基戊烷二酸1-(1,3-双(棕榈酰氧基)丙烷-2-基) 5-(2-(4-((叔丁基二甲基甲硅烷基)氧基)-2-甲基丁-2-基)-3,5-二甲基苯基)酯(1.3 g, 1.3 mmol)在DCM (10 mL)和MeOH (10 mL)中的溶液中加入10-樟脑磺酸(91 mg, 0.39 mmol)，并将混合物在室温搅拌6h。将反应物用DCM稀释，并将有机相用饱和NaHCO3水溶液和盐水洗涤，经Na2SO4干燥并在减压下浓缩以得到粗产物，将其通过硅胶色谱法(5%至20%的EtOAc在PE中的溶液)纯化以得到作为无色油的标题化合物(1.1 g, 95%)。C54H94O9的MS (ESI) m/z计算值: 886.69。实测：887.83 (M+1)+。
3-甲基戊烷二酸1-(1,3-双(棕榈酰氧基)丙烷-2-基) 5-(3,5-二甲基-2-(2-甲
基-4-氧代丁-2-基)苯基)酯的制备
向3-甲基戊烷二酸1-(1,3-双(棕榈酰氧基)丙烷-2-基) 5-(2-(4-羟基-2-甲基丁-2-基)-3,5-二甲基苯基)酯(1.0 g, 1.13 mmol)和硅藻土(625 mg)在DCM (10 mL)中的混悬液中加入PCC (485 mg, 2.25 mmol)，并将混合物在室温搅拌4小时。将反应物穿过短硅胶垫过滤，用50%乙酸乙酯/己烷类洗脱，并将滤液在减压下浓缩以得到作为黄色油的标题化合物(640 mg, 64%收率)，将其不经纯化用在下述步骤中。
3-(2-((5-((1,3-双(棕榈酰氧基)丙烷-2-基)氧基)-3-甲基-5-氧代戊酰基)氧
基)-4,6-二甲基苯基)-3-甲基丁酸的制备
向3-甲基戊烷二酸1-(1,3-双(棕榈酰氧基)丙烷-2-基) 5-(3,5-二甲基-2-(2-甲基-4-氧代丁-2-基)苯基)酯(449 mg, 0.52 mmol)在丙酮(12 mL)中的溶液中，加入在1:1丙酮/水(共12 mL)中的KMnO4 (122 mg, 0.77 mmol)，并将混合物在室温搅拌15小时。将反应物用水(100 mL)稀释，用1 M HCl酸化至pH ~2，并将水层用乙酸乙酯萃取。将合并的有机层用盐水洗涤, 经Na2SO4干燥并在减压下浓缩以得到粗产物，将其通过硅胶色谱法(10%至30%乙酸乙酯/己烷类)进行纯化以得到标题化合物(216 mg, 46%)。C54H92O10的MS (ESI) m/z计算值: 900.67。实测：901.83 (M+1)+。
实施例5的合成
3-甲基戊烷二酸1-(1,3-双(棕榈酰氧基)丙烷-2-基) 5-(2-(4-(反式-4-(叔-丁氧 基)-4-氧代丁-2-基)-2-((5-氯吡嗪-2-基)氨基)苯基)(异丁基)氨基)环己基)氧基)-2-甲 基-4-氧代丁-2-基)-3,5-二甲基苯基)酯的制备
向3-(2-((5-((1,3-双(棕榈酰氧基)丙烷-2-基)氧基)-3-甲基-5-氧代戊酰基)氧基)-4,6-二甲基苯基)-3-甲基丁酸(156 mg, 0.165 mmol)、2-(4-((叔丁基二甲基甲硅烷基)氧基)-2-甲基丁-2-基)-3,5-二甲基苯酚(60 mg, 0.11 mmol)和DMAP (13 mg, 0.11 mmol)在DCM (3 mL)中的溶液中加入EDCI (42 mg, 0.22 mmol)，并将混合物在室温搅拌过夜。将反应混合物在减压下浓缩并通过硅胶色谱法(5%至20%乙酸乙酯/己烷类)纯化，得到作为无色油的标题化合物(120 mg, 52%) ; C82H131ClN4O12的MS (ESI) m/z计算值: 1398.95。实测：1400.41/1402. 42(M+1)+。
实施例5
(3R)-3-(4-((反式-4-((3-(2-((5-((1,3-双(棕榈酰氧基)丙烷-2-基)氧基)-3-甲基-
5-氧代戊酰基)氧基)-4,6-二甲基苯基)-3-甲基丁酰基)氧基)环己基)(异丁基)氨基)-3-
((5-氯吡嗪-2-基)氨基)苯基)丁酸的制备
向3-甲基戊烷二酸1-(1,3-双(棕榈酰氧基)丙烷-2-基) 5-(2-(4-(反式-4-(叔-丁氧基)-4-氧代丁-2-基)-2-((5-氯吡嗪-2-基)氨基)苯基)(异丁基)氨基)环己基)氧基)-2-甲基-4-氧代丁-2-基)-3,5-二甲基苯基)酯(30 mg, 0.021 mmol)在DCM (2 mL)中的溶液中加入TFA (1 mL)，并将混合物在室温搅拌3小时。将反应混合物在减压下浓缩。通过制备型TLC纯化，得到作为浅黄色油的标题化合物(25 mg, 86%)。1H NMR (400 MHz, CDCl3) δ8.25 - 8.16 (m, 1H), 8.11 (d, J = 1.2 Hz, 1H), 8.07 - 8.02 (m, 1H), 7.89 -7.84 (m, 1H), 7.05 - 7.00 (m, 1H), 6.79 - 6.73 (m, 1H), 6.69 (s, 1H), 6.46(s, 1H), 5.24 - 5.14 (m, 1H), 4.42 - 4.30 (m, 1H), 4.28 - 4.19 (m, 2H), 4.13- 4.03 (m, 2H), 3.25 - 3.17 (m, 1H), 2.70 - 2.63 (m, 3H), 2.58 - 2.38 (m,9H), 2.26 - 2.20 (m, 5H), 2.15 - 2.09 (m, 3H), 1.79 - 1.68 (m, 3H), 1.57 -1.49 (m, 5H), 1.44 (s, 6H), 1.23 - 1.15 (m, 59H), 1.03 (d, J = 6.2 Hz, 3H),0.82 - 0.74 (m, 12H)。没有观察到羧基的质子。C78H123ClN4O12的MS (ESI) m/z计算值：1342.88。实测：1344.60/1346.65 (M+1)+。
中间体E的合成
3-甲基戊烷二酸1-(1,3-双(棕榈酰氧基)丙烷-2-基) 5-(氯甲基)酯的制备
向5-((1,3-双(棕榈酰氧基)丙烷-2-基)氧基)-3-甲基-5-氧代戊酸(2.5 g, 3.59mmol)、水(15 mL)、DCM (15 mL)、NaHCO3 (1.17 g, 14.3 mmol)和正四丁基硫酸氢铵(165mg, 0.359 mmol)的混悬液中加入氯硫酸氯甲酯(580 mg, 3.59 mmol)。将反应物在室温搅拌16 h。分离各层, 将有机层用盐水洗涤，经Na2SO4干燥并浓缩以得到残余物，将其纯化以得到标题化合物(1.65 g, 62%)。C42H77ClO8的MS (ESI) m/z计算值: 744.53。实测：745.61/747.57 (M/M+2)+。
实施例6的合成
3-甲基戊烷二酸1-(1,3-双(棕榈酰氧基)丙烷-2-基) 5-((((R)-3-(3-((6-氯吡啶-3-
基)氨基)-4-(异丁基(四氢-2H-吡喃-4-基)氨基)苯基)丁酰基)氧基)甲基)酯的制备
向3-甲基戊烷二酸1-(1,3-双(棕榈酰氧基)丙烷-2-基) 5-(氯甲基)酯(200 mg,0.269 mmol)、K2CO3 (74 mg, 0.538 mmol)、NaI (4 mg, 0.0269 mmol)在DMSO (5.0 mL)中的混悬液中加入(R)-3-(3-((6-氯吡啶-3-基)氨基)-4-(异丁基(四氢-2H-吡喃-4-基)氨基)苯基)丁酸(120 mg, 0.269 mmol)。在40℃搅拌16 h以后，将反应混合物在EtOAc和水之间分配，并分离各层。将有机层用盐水洗涤，经无水硫酸钠干燥并浓缩以得到残余物，将其通过制备型HPLC进行纯化以得到作为黄色固体的标题化合物(122 mg, 40%收率)。1H NMR(400 MHz, CDCl3) δ 8.20 (d, J = 2.9 Hz, 1H), 7.44 (dd, J = 8.6, 3.0 Hz, 1H),7.23 (d, J = 8.6 Hz, 1H), 7.15 - 7.01 (m, 3H), 6.73 (dd, J = 8.1, 1.9 Hz,1H), 5.74 (d, J = 5.6 Hz, 1H), 5.71 (d, J = 5.6 Hz, 1H), 5.31 - 5.19 (m, 1H),4.38 - 4.22 (m, 2H), 4.22 - 4.07 (m, 2H), 4.02 - 3.86 (m, 2H), 3.36 - 3.11(m, 3H), 2.79 (d, J = 4.9 Hz, 3H), 2.65 (dd, J = 15.5, 6.4 Hz, 1H), 2.55 (dd,J = 15.5, 8.5 Hz, 1H), 2.49 - 2.36 (m, 3H), 2.34 - 2.24 (m, 6H), 1.71 - 1.62(m, 5H), 1.50 - 1.39 (m, 1H), 1.32 - 1.20 (m, 54H), 1.02 (d, J = 6.3 Hz, 3H),0.90 - 0.84 (m, 12H)。C66H108ClN3O11的MS (ESI) m/z计算值:1153.77。实测：1154.61/1156.61 (M/M+2)+。
与中间体C2的合成类似地得到中间体C4。
实施例7的合成
3-甲基戊烷二酸1-(1,3-双(棕榈酰氧基)丙烷-2-基) 5-((((R)-3-(3-((5-氯吡嗪-2- 基)氨基)-4-(异丁基(四氢-2H-吡喃-4-基)氨基)苯基)丁酰基)氧基)甲基)酯的制备
向3-甲基戊烷二酸1-(1,3-双(棕榈酰氧基)丙烷-2-基) 5-(氯甲基)酯(150 mg,0.201 mmol)、K2CO3 (55 mg, 0.402 mmol)、NaI (3 mg, 0.02 mmol)在DMSO (5.0 mL)中的混悬液中加入(R)-3-(3-((5-氯吡嗪-2-基)氨基)-4-(异丁基(四氢-2H-吡喃-4-基)氨基)苯基)丁酸(90 mg, 0.201 mmol)。在40℃搅拌16 h以后，将反应混合物在EtOAc和水之间分配并分离各层。将有机层用盐水洗涤，经无水硫酸钠干燥并浓缩以得到残余物，将其通过制备型HPLC进行纯化以得到作为黄色固体的标题化合物(108 mg, 46%收率)。1H NMR (400MHz, CDCl3) δ 8.40 (s, 1H), 8.18 (dd, J = 11.8, 1.6 Hz, 2H), 7.93 (d, J = 1.3Hz, 1H), 7.13 (d, J = 8.1 Hz, 1H), 6.83 (dd, J = 8.1, 2.0 Hz, 1H), 5.76 (d, J= 5.6 Hz, 1H), 5.72 (d, J = 5.6 Hz, 1H), 5.30 - 5.22 (m, 1H), 4.35 - 4.26 (m,2H), 4.18 - 4.10 (m, 2H), 3.99 - 3.90 (m, 2H), 3.34 - 3.23 (m, 3H), 2.93 -2.76 (m, 3H), 2.71 (dd, J = 15.5, 6.0 Hz, 1H), 2.60 (dd, J = 15.5, 8.9 Hz,1H), 2.48 - 2.36 (m, 3H), 2.34 - 2.24 (m, 6H), 1.77 - 1.61 (m, 5H), 1.49 -1.42 (m, 1H), 1.37 - 1.16 (m, 54H), 1.02 (d, J = 6.3 Hz, 3H), 0.91 - 0.84 (m,12H)。C65H107ClN4O11的MS (ESI) m/z计算值：1154.76。实测：1155.60/1157.59 (M/M+2)+。
与中间体C2的合成类似地得到中间体C5。
IDO1 PBMC RapidFire MS Assay
通过高通量细胞测定，利用犬尿氨酸(通过质谱)和细胞毒性的检测作为终点对本发明的化合物进行测试。为了进行质谱和细胞毒性测定，用人干扰素-γ(IFN-γ) (Sigma-Aldrich Corporation, St. Louis, MO)和来自明尼苏达沙门氏菌（Salmonella minnesota）的脂多糖(LPS)(Invivogen, San Diego, CA)刺激人外周血单核细胞(PBMC)(PB003F; AllCells®, Alameda, CA)以诱导吲哚胺2,3-双加氧酶(IDO1)的表达。具有IDO1抑制特性的化合物减少了细胞通过色氨酸分解代谢途径产生的犬尿氨酸的量。使用CellTiter-Glo®试剂(CTG)(Promega Corporation, Madison, WI)(其基于ATP的发光检测，ATP是代谢活性细胞的指示剂)测量了由于化合物治疗的作用而产生的细胞毒性。
在测定准备中，将测试化合物在DMSO中从1mM或5 mM的典型最高浓度3倍连续稀释，并以0.5 μL铺板在384孔聚苯乙烯透明底部组织培养处理的带盖板(Greiner Bio-One,Kremsmünster, Austria)中以生成11点剂量响应曲线。低对照孔(0％犬尿氨酸或100％细胞毒性)在存在未刺激的(-IFN-γ/-LPS)PBMC的情况下含有0.5 μL DMSO(用于质谱测定)或者在没有细胞的情况下含有0.5 μL DMSO(用于细胞毒性测定)，并且高对照孔(100％犬尿氨酸或0％细胞毒性)在存在刺激的(+IFN-γ/+LPS)PBMC的情况下含有0.5 μL DMSO(用于质谱和细胞毒性测定)。
洗涤PBMC的冷冻原液，并在补充了10%v/v热灭活的胎牛血清(FBS) (ThermoFisher Scientific, Inc., Waltham, MA)和1X青霉素-链霉素抗生素溶液(ThermoFisher Scientific, Inc., Waltham, MA)的RPMI 1640培养基(Thermo FisherScientific, Inc., Waltham, MA)中回收。在补充的RPMI 1640培养基中将细胞稀释至1,000,000个细胞/mL。将50 μL的细胞悬液(用于质谱测定)或单独的培养基(用于细胞毒性测定)添加到先前制备的384孔化合物板上的低对照孔中，分别产生50,000个细胞/孔或0个细胞/孔。将IFN-γ和LPS分别以100 ng/ml和50 ng/ml的终浓度添加到剩余的细胞悬液中，并且将50 μL的刺激的细胞添加到384孔化合物板上的所有剩余的孔中。然后将带盖板置于37oC、5%CO2的增湿培养箱中保持2天。
温育后，将384孔板从培养箱中移出并使其平衡至室温保持30分钟。对于细胞毒性测定，根据制造商的指示制备CellTiter-Glo®，并向每个板孔中添加40 μL。在室温下温育20分钟后，在EnVision® Multilabel Reader (PerkinElmer Inc., Waltham, MA)上读取发光。对于质谱测定，在384孔聚丙烯V形底板(Greiner Bio-One, Kremsmünster,Austria)中，将来自化合物处理的板的每个孔的10 μL上清液添加到40 μL乙腈(含有10 μM内标以进行归一化)中以萃取有机分析物。在以2000 rpm离心10分钟后，将来自乙腈萃取板的每孔的10 μL添加到384孔聚丙烯V形底板中的90 μL无菌蒸馏水中，以在RapidFire 300(Agilent Technologies, Santa Clara, CA)和4000 QTRAP MS (SCIEX, Framingham,MA)上分析犬尿氨酸和内标。使用Agilent Technologies的RapidFire Integrator软件对MS数据进行积分，并对数据进行了归一化以作为犬尿氨酸与内标的比进行分析。
在使用公式100-(100*((U-C2)/(C1-C2)))(其中U是未知值，C1是高(100％犬尿氨酸；0％抑制)对照孔的平均值并且C2是低(0％犬尿氨酸；100％抑制)对照孔的平均值)归一化后，将质谱测定中的剂量响应的数据标绘为IDO1抑制百分比与化合物浓度的关系。在使用公式100-(100*((U-C2)/(C1-C2)))(其中U是未知值，C1是高(0％细胞毒性)对照孔的平均值并且C2是低(100％细胞毒性)对照孔的平均值)归一化后，将细胞毒性测定中的剂量响应的数据标绘为细胞毒性百分比与化合物浓度的关系。
使用方程y=A+((B-A)/(1+(10x/10C)D))(其中A是最小响应，B是最大响应，C是log(XC50)并且D是希尔斜率(Hill slope))进行曲线拟合。将每种测试化合物的结果记录为质谱测定的pIC50值和细胞毒性测定的pCC50值(上面的方程中的-C)。
| PBMC PXC50 | PBMC TOX PXC50 | |
| 实施例1 | 6.8 | <5 |
| 实施例2 | 6.6 | <5 |
| 实施例3 | 5.9 | <5 |
| 实施例4 | 5.1 | <5 |
| 实施例5 | 6.2 | <5 |
| 实施例6 | 5.5 | <5 |
| 实施例7 | 6 | <5 |
| 中间体C2 | 8.7 | <5 |
| 中间体C3 | 8.9 | <5 |
| 中间体C4 | 9 | <5 |
| 中间体C5 | 9.2 | <5 |
在5 mg/kg剂量(100%的溶液(40 mg油酸+ 25mg吐温80 + 2 mL PBS/新鲜)，在0.5mg/mL)的前药的大鼠口服PK研究。
在大鼠中的来自C4的口服定量给药的药物中间体C4的组织分布与来自实施例7的口服定量给药的中间体C4的组织分布
实施例7
Wistar Han大鼠，185-197 g, 雄性, N=8, 购自Beijing Vital River Co. LTD. 资格号: SCXK(J) 2016-0011 11400700240027。禁食过夜并在给药后4小时饲喂。口服：5 mg/kg (10 mL/kg)，通过经口管饲法(N=8)。在1、4、8和24小时4个时间点取样，在每个时间点收集血浆、肝、淋巴结和脾的最终放血。
中间体C4
Wistar Han大鼠，185-197 g, 雄性, N=8，购自Beijing Vital River Co. LTD. 资格号: SCXK(J) 2016-0011 11400700240027。禁食过夜并在给药后4小时饲喂。口服：3 mg/kg(10 mL/kg)，通过经口管饲法(N=8)。在1、4、8和24小时4个时间点取样，在每个时间点收集血浆、肝、淋巴结和脾的最终放血。
在大鼠中的前药口服PK研究
在大鼠中的来自口服定量给药的药物中间体C4的组织分布与来自前药实施例7的口服定量给药的中间体C4的组织分布-总结。
Claims (14)
1.式I的化合物或其药学上可接受的盐
式I
其中：
R1是具有式II的基团
式II
其中R5和R6独立地是H或CH3，或R5和R6可以与它们所键合的碳原子连接在一起以形成3-6元环烷基；
R7是含有1-3个选自N和S的杂原子的5或6-元杂环或杂芳基，并任选地被1或2个取代基取代，所述取代基选自F、Cl、CN、OCH3、CF3、环丙基、CONH2、CH2CH2OCH3和CH2OCH3；
R8是5或6-元环烷基或含有O或N的5或6-元杂环，且R8可以任选地被取代基取代，所述取代基选自卤素、OH、C1-3烷基和OCH3；
一个X是氢且另一个代表与Q的连接点；
Q是键、CH2或
，其中Y1代表与R1的连接点，且Y2代表与所述化合物的其余部分的连接点；
R2和R3独立地是C10-20烷基；且
R4是氢或C1-4烷基。
2.根据权利要求1所述的化合物或盐，其中R5和R6之一是H且另一个是CH3。
3.根据权利要求1或权利要求2所述的化合物或盐，其中R7是吡啶、噻二唑、嘧啶、吡嗪、哒嗪、三唑或噻唑，其任选地被1或2个取代基取代，所述取代基选自F、Cl、CN、OCH3、CF3、环丙基、CONH2、CH2CH2OCH3和CH2OCH3。
4.根据权利要求3中的任一项所述的化合物或盐，其中R7是任选地被Cl取代的吡啶或吡嗪。
5.根据权利要求1-4中的任一项所述的化合物或盐，其中R8是环己基或含有氧的6-元杂环。
6.根据权利要求1所述的化合物或盐，其中R1选自：
其中X指示与所述化合物的其余部分的连接点。
7.根据权利要求1-6中的任一项所述的化合物或盐，其中R4是H或甲基。
8.一种药物组合物，其包含根据权利要求1-7中的任一项所述的化合物或盐。
9.一种用于治疗HIV的方法，所述方法包括施用根据权利要求8所述的药物组合物。
10.权利要求9所述的方法，所述方法进一步包括施用可用于治疗HIV的第二种药剂。
11.权利要求10所述的方法，其中所述第二种药剂选自：核苷酸逆转录酶抑制剂；非核苷酸逆转录酶抑制剂；蛋白酶抑制剂；进入、附着和融合抑制剂；整合酶抑制剂；成熟抑制剂；CXCR4抑制剂；和CCR5抑制剂。
12.权利要求11所述的方法，其中所述第二种药剂是多替拉韦、Bictegravir或Cabotegravir。
13.用于治疗HIV的根据权利要求1-7中的任一项所述的化合物或盐。
14.根据权利要求1-7中的任一项所述的化合物或盐在制备用于治疗HIV的药物中的用途。
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| WO2017051354A1 (en) * | 2015-09-24 | 2017-03-30 | Glaxosmithkline Intellectual Property (No.2) Limited | Modulators of indoleamine 2,3-dioxygenase |
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| WO2017051354A1 (en) * | 2015-09-24 | 2017-03-30 | Glaxosmithkline Intellectual Property (No.2) Limited | Modulators of indoleamine 2,3-dioxygenase |
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