CN110139856A - Vista和pd-1通路的双重抑制剂 - Google Patents
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- CN110139856A CN110139856A CN201780078731.XA CN201780078731A CN110139856A CN 110139856 A CN110139856 A CN 110139856A CN 201780078731 A CN201780078731 A CN 201780078731A CN 110139856 A CN110139856 A CN 110139856A
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Abstract
本公开涉及3‑取代的1，2，4‑噁二唑化合物及其衍生物，其可用作T细胞活化的V结构域免疫球蛋白阻抑剂(VISTA)的抑制剂或用作VISTA和程序性细胞死亡1(PD‑1)信号传导通路的双重抑制剂。本公开还涉及通过抑制由VISTA及其配体、PD‑1、PD‑L1和/或PD‑L2诱导的免疫阻抑信号来治疗病症。
Description
相关申请
本申请要求2016年10月20日提交的印度临时申请第201641035996号的权益，该申请的说明书由此以引用方式全文并入本文。
技术领域
本公开涉及包含3-取代的1，2，4-噁二唑化合物及其衍生物的药物组合物，所述药物组合物可用作VISTA抑制剂或用作VISTA和PD-1(例如，PD-1、PD-L1或PD-L2)通路的双重抑制剂。
背景技术
哺乳动物的免疫系统维持在免疫反应期间和之后通过各种调节机制控制淋巴细胞的活化和失活间的稳态的能力。在这些机制中，存在在需要时特异性调节免疫反应的机制。
T细胞活化的V结构域免疫球蛋白阻抑剂(VISTA或PD-1H)是约60 kDa的I型Ig膜蛋白，其具有不常见的半胱氨酸残基分布，并且是CD28蛋白质家族的成员。VISTA是一种阴性检查点调节剂，其直接抑制T细胞活化。VISTA蛋白质的结构包含细胞外IgV结构域和随后的茎干区、跨膜区和细胞内尾部。细胞内尾部含有可以结合蛋白激酶C的酪氨酸残基。VISTA主要在造血组织(例如，脾、淋巴结和外周血)或含有大量浸润性白细胞的组织中表达。VISTA既作为抗原呈递细胞上的T细胞受体的配体，又作为T细胞活化期间的共抑制受体。报道的VISTA的相互作用包括与其自身、VSIG8和VSIG3的同源性相互作用。
PD-1(或程序性细胞死亡1或PDCD1)是～55kDa的I型膜糖蛋白，并且是CD28超家族的受体，其通过与特异性配体相互作用负向调节T细胞抗原受体信号传导，并且被认为在维持自身耐受性方面发挥重要作用。PD-1蛋白质的结构包含胞外IgV结构域以及随后的跨膜区和细胞内尾部。细胞内尾部含有位于基于免疫受体酪氨酸的抑制基序和基于免疫受体酪氨酸的开关基序中的两个磷酸化位点，这表明PD-1负向调节TCR信号。另外，PD-1在活化的T细胞、B细胞和巨噬细胞的表面上表达(Y.Agata等，Int.Immunol.1996，8：765)，这表明与CTLA-4[(细胞毒性T淋巴细胞抗原4)，也称为CD152(分化簇152)，它是一种在免疫系统中也起重要调节作用的蛋白质]相比，PD-1更广泛地负向调节免疫反应。
将由T细胞表达的抑制性受体PD-1阻断可以克服免疫抗性。PD-1是由活化T细胞表达的关键免疫检查点受体，它介导免疫抑制。PD-1主要在外周组织中起作用，其中T细胞可能遇到免疫抑制性PD-1配体PD-L1(B7-H1)和PD-L2(B7-DC)，它们由肿瘤细胞、基质细胞或两者表达。抑制PD-1和PD-L1之间的相互作用可以增强体外T细胞反应并介导临床前抗肿瘤活性(S.L.Topalian等，N.Engl.J.Med.2012，366(26)：2443-2454)。
VISTA和PD-1均作为抑制T细胞活化的免疫检查点蛋白。VISTA和PD-1/PD-L1通路非冗余地调节T细胞反应。VISTA和PD-1涉及免疫反应的几乎各个方面，包括自身免疫、肿瘤免疫、感染免疫、移植免疫和免疫特权。PD-1在调节对癌症、过敏和慢性病毒感染的免疫反应中起关键作用(J.R.Brahmer等，N.Engl.J.Med.2012，366(26)：2455-2465)。
实际上，T细胞和B细胞亚群中的功能性“耗竭”(免疫功能障碍)是慢性病毒感染(例如乙型肝炎和丙型肝炎病毒及HIV病毒)的良好描述的特征。最初描述了长期感染淋巴细胞脉络丛脑膜炎病毒克隆13的小鼠中的CD8T细胞的T细胞耗竭。在淋巴细胞脉络丛脑膜炎病毒小鼠模型中，通过T细胞抗原受体进行的重复抗原刺激驱动T细胞抑制性受体(包括程序性细胞死亡-1(PD-1)和淋巴细胞活化基因-3(LAG-3))在病毒特异性CD8 T细胞上的持续表达(J.Illingworth等，J.Immunol.2013，190(3)：1038-1047)。已知肿瘤细胞和病毒(包括HCV和HIV)感染的细胞利用PD-1信号传导通路(产生免疫抑制)以逃避宿主T细胞的免疫监视。VISTA是在肿瘤内的白细胞上表达的PD-L1样配体，使其成为引人注目的抗癌靶标(J.L.Lines等，Cancer Res.2014，74(7)：1924-1932)。破坏VISTA和PD-1(例如，PD-1、PD-L1或PD-L2)通路增强自身免疫并抑制肿瘤生长(J.Liu等，Proc.Natl.Acad.Sci.USA 2015，112(21)：6682-6687)。
国际申请WO2011161699和WO2012168944报道了衍生自PD-1胞外域的肽及其衍生物，其能够抑制程序性细胞死亡1(PD-1)信号传导通路。此外，WO2013144704和WO2013132317分别报道了环肽和拟肽化合物作为能够抑制PD-1蛋白的治疗剂。WO2015033299和WO2015033301分别报道了1，2，4-噁二唑和1，3，4-噁二唑化合物作为能够抑制PD-1蛋白的治疗剂。
由于上述原因，还需要VISTA的免疫调节剂。还需要VISTA和PD-1(例如，PD-1、PD-L1或PD-L2)通路的更有效的累加或协同免疫调节剂。
发明内容
本公开涉及使用3-取代的1，2，4-噁二唑化合物或其立体异构体或其药学上可接受的盐调节VISTA的方法。在某些实施方案中，本公开涉及使用3-取代的1，2，4-噁二唑化合物或其立体异构体或其药学上可接受的盐调节VISTA和PD-1(例如，PD-1、PD-L1或PD-L2)通路的方法。
在一个方面，本公开提供调节细胞中由T细胞活化的V结构域免疫球蛋白阻抑剂(VISTA)活性介导的免疫反应的方法，该方法包括使细胞与式(I)化合物或其药学上可接受的盐接触：
其中：
G代表氢或(C1-C6)烷基；
Ra代表被-OH、-C(O)NRxRy、-NRxRy、胍基、羧酸、杂芳基或芳基-OH取代的(C1-C6)烷基；
Ra’代表氢；或者Ra和Ra’与它们所附接的原子结合在一起形成5至6元环；
Rb代表(C1-C6)烷基，其任选地被-OH、-C(O)NRxRy、-NRxRy、羧酸或杂芳基取代；其中所述杂芳基任选地被羟基进一步取代；
Rc代表氢；或者Rb和Rc与它们所附接的原子结合在一起形成5至6元环；
Rd代表H，被-OH、-NRxRy或羧酸取代的(C1-C6)烷基；
Re代表氢；或者Rd和Re与它们所附接的原子结合在一起形成任选地含有1至3个选自O、NH或S的杂原子的5至6元环；且
Rx和Ry独立地代表氢、(C1-C6)烷基、(C2-C6)酰基或(C1-C6)环烷基；或者Rx和Ry与它们所附接的原子结合在一起形成5至6元环。
在本文公开的方法的一些实施方案中，免疫反应进一步由程序性细胞死亡1(PD-1)信号传导通路(例如，PD-1、PD-L1或PD-L2)介导。
在另一方面，本公开涉及包含式(I)化合物、药学上可接受的盐或立体异构体的药物组合物，以及制备这种组合物的方法。
在另一方面，本公开提供了式(I)的3-取代的1，2，4-噁二唑化合物和衍生物、其药学上可接受的盐和立体异构体的用途，它们能够压制和/或抑制T细胞活化的V结构域免疫球蛋白阻抑剂(VISTA)活性。在某些实施方案中，本公开提供了式(I)的3-取代的1，2，4-噁二唑化合物和衍生物、其药学上可接受的盐和立体异构体的用途，它们能够压制和/或抑制VISTA和程序性细胞死亡1(PD-1)(例如，PD-1、PD-L1或PD-L2)信号传导通路。例如，这些化合物可用于治疗以VISTA的异常或非所需活性为特征或以VISTA和PD-1(例如，PD-1、PD-L1或PD-L2)通路的异常或非所需活性为特征的一种或多种疾病。
具体实施方式
本公开提供作为可用于通过包括抑制由VISTA诱导的免疫阻抑信号的免疫增强作用治疗病症的治疗剂的3-取代的1，2，4-噁二唑化合物及其衍生物，以及使用它们的疗法。在某些实施方案中，本公开提供作为可用于通过包括抑制由PD-1、PD-L1、PD-L2和/或VISTA诱导的免疫阻抑信号的免疫增强作用治疗病症的治疗剂的3-取代的1，2，4-噁二唑化合物及其衍生物，以及使用它们的疗法。
提供每个实施方案是为了解释说明本公开，而不是限制本公开。实际上，本领域技术人员应该了解，可以在不脱离本公开的范围或精神的情况下对本公开作出各种修改和变化。例如，作为一个实施方案的部分阐明或描述的特征可以用在另一个实施方案上，以产生又一个实施方案。因此，希望本公开涵盖属于随附权利要求书和其等效物的范围内的这些修改和变化。本公开的其它目的、特征和方面在以下详细描述中公开，或者可以从以下详细描述中得出。本领域普通技术人员应理解，本讨论仅是示例性实施方案的描述，而不应被解释为限制本公开的更广泛方面。
治疗方法
T细胞活化的V结构域免疫球蛋白阻抑剂(VISTA)的作用是作为抑制T细胞活化的免疫检查点蛋白。VISTA主要在造血细胞上表达。
VISTA和程序性细胞死亡蛋白1(PD-1)蛋白质均作为抑制T细胞活化的免疫检查点蛋白。VISTA和PD-1/PD-L1通路非冗余地调节T细胞反应。VISTA和PD-1(例如，PD-1、PD-L1或PD-L2)通路涉及许多疾病和病症，并且已知VISTA和PD-1(例如，PD-1、PD-L1或PD-L2)调节各种免疫反应。许多研究已经寻求通过靶向VISTA通路或PD-1(例如，PD-1、PD-L1或PD-L2)通路来激活免疫反应，从而为某些疾病如癌症和自身免疫病症提供治疗。例如，使用VISTA和PD-L1的特异性单克隆抗体的组合治疗在结肠癌模型中实现协同治疗功效，显示肿瘤消退和提高的存活率(J.Liu等，Proc.Natl.Acad.Sci.USA 2015，112(21)：6682-6687)。PD-1活性还与自身免疫疾病如红斑狼疮、幼年特发性关节炎和过敏性脑脊髓炎有关。
在一些实施方案中，本公开提供了本公开的式(I)化合物用于抑制VISTA的用途。
在某些实施方案中，本公开提供了式(I)化合物用于调节细胞中由VISTA活性和PD-1通路(例如，PD-1、PD-L1或PD-L2)介导的免疫反应的用途。
在某些实施方案中，本公开提供调节细胞中由VISTA活性介导的免疫反应的方法，该方法包括使细胞与式(I)化合物或其药学上可接受的盐接触：
其中：
G代表氢或(C1-C6)烷基；
Ra代表被-OH、-C(O)NRxRy、-NRxRy、胍基、羧酸、杂芳基或芳基-OH取代的(C1-C6)烷基；
Ra’代表氢；或者Ra和Ra’与它们所附接的原子结合在一起形成5至6元环；
Rb代表(C1-C6)烷基，其任选地被-OH、-C(O)NRxRy、-NRxRy、羧酸或杂芳基取代；其中所述杂芳基任选地被羟基进一步取代；
Rc代表氢；或者Rb和Rc与它们所附接的原子结合在一起形成5至6元环；
Rd代表H，被-OH、-NRxRy或羧酸取代的(C1-C6)烷基；
Re代表氢；或者Rd和Re与它们所附接的原子结合在一起形成任选地含有1至3个选自O、NH或S的杂原子的5至6元环；且
Rx和Ry独立地代表氢、(C1-C6)烷基、(C2-C6)酰基或(C1-C6)环烷基；或者Rx和Ry与它们所附接的原子结合在一起形成5至6元环。
在式(I)的某些实施方案中，G代表氢或甲基。在一些实施方案中，G代表氢。
在某些实施方案中，Ra代表-(CH2)2C(O)OH或(C1-C4)烷基，其中(C1-C4)烷基被-OH、-C(O)NRxRy、-NRxRy、胍基、杂芳基或芳基-OH取代。在式(I)的某些实施方案中，Ra代表被-OH、-NH2、-NH-C(＝NH)-NH2、羧酸、咪唑基或对-OH(苯基)取代的(C1-C4)烷基；且Ra’是氢。在式(I)的其它实施方案中，Ra代表被-OH、-NH2、-NH-C(＝NH)-NH2、咪唑基或对-OH(苯基)取代的(C1-C4)烷基；且Ra’是氢。在一些实施方案中，Ra代表-CH2OH、-CH(CH3)OH、-CH2-(对-OH(苯基))、-(CH2)4-NH2、-CH2(咪唑基)或-(CH2)3-NH-C(＝NH)-NH2。在其它实施方案中，Ra代表-CH2OH、-CH(CH3)OH、-CH2-(对-OH(苯基))、-(CH2)4-NH2、-(CH2)2C(O)OH、-(CH2)2C(O)NH2、-CH2(咪唑基)或-(CH2)3-NH-C(＝NH)-NH2。在某些实施方案中，Ra代表-CH2OH或-CH(CH3)OH。在一些实施方案中，Ra代表-CH2OH。
或者，在某些实施方案中，Ra和Ra’与它们所附接的原子结合在一起形成环戊基或环己基环。
在其它实施方案中，Rb代表-CH2C(O)OH或-(C1-C6)烷基，其中(C1-C6)烷基任选地被-OH、-C(O)NRxRy或杂芳基取代，其中所述杂芳基任选地被羟基进一步取代。在某些实施方案中，Rb代表任选地被-OH、-C(O)NH2、羧酸、吲哚基或-C(O)NH-((C1-C6)烷基)取代的(C1-C4)烷基；且Rc代表氢。在一些实施方案中，Rb代表任选地被-OH、-C(O)NH2、吲哚基或-C(O)NH-((C1-C6)烷基)取代的(C1-C4)烷基；且Rc代表氢。在一些实施方案中，Rb代表异丙基、仲丁基、-CH2OH、-CH2C(O)NH2、-(CH2)2C(O)NH2、-(CH2)4-NH(COCH3)、-CH2C(O)OH、-(CH2)2C(O)OH、-CH2(吲哚基)、-CH2C(O)NH(己基)或-(CH2)2C(O)NH(己基)。在其它实施方案中，Rb代表异丙基、仲丁基、-CH2OH、-CH2C(O)NH2、-(CH2)2C(O)NH2、-(CH2)4-NH(COCH3)、-CH2C(O)OH、-CH2(吲哚基)、-CH2C(O)NH(己基)或-(CH2)2C(O)NH(己基)。在某些实施方案中，Rb代表-CH2C(O)NH2或-CH2C(O)OH。在一些实施方案中，Rb代表-CH2C(O)NH2。
或者，在某些实施方案中，Rb和Rc与它们所附接的原子结合在一起形成吡咯烷环。
在某些实施方案中，Rd代表被-OH、-NH2或-C(O)OH取代的(C1-C4)烷基；且Re代表氢。在其它实施方案中，Rd代表-CH2OH、-CH(CH3)OH、-(CH2)4-NH2或-(CH2)2C(O)OH。在一些实施方案中，Rd代表-CH2OH或-CH(CH3)OH。在某些实施方案中，Rd代表-CH(CH3)OH。
或者，在某些实施方案中，Rd和Re与它们所附接的原子结合在一起形成吡咯烷环。
在式(I)的其它实施方案中，
G代表氢或(C1-C6)烷基；
Ra代表-(CH2)2C(O)OH或(C1-C4)烷基，其中(C1-C4)烷基被-OH、-NRxRy、胍基、杂芳基或芳基-OH取代；
Ra’代表氢；或者Ra和Ra’与它们所附接的原子结合在一起形成5至6元环；
Rb代表-CH2C(O)OH或-(C1-C6)烷基，其中(C1-C6)烷基任选地被-OH、-C(O)NRxRy或杂芳基取代；其中所述杂芳基任选地被羟基进一步取代；
Rc代表氢；或者Rb和Rc与它们所附接的原子结合在一起形成5至6元环；
Rd代表H，被-OH、-NRxRy或羧酸取代的-(C1-C6)烷基；
Re代表氢；或者Rd和Re与它们所附接的原子结合在一起形成任选地含有1至3个选自O、NH或S的杂原子的5至6元环；且
Rx和Ry独立地代表氢、(C1-C6)烷基或(C2-C6)酰基。
在式(I)的一些实施方案中，
G代表氢或甲基；
Ra代表-CH2OH、-CH(CH3)OH、-CH2-(对-OH(苯基))、-(CH2)4-NH2、-CH2(咪唑基)或-(CH2)3-NH-C(＝NH)-NH2；
Ra’代表氢；或者Ra和Ra’与它们所附接的原子结合在一起形成环戊基或环己基环；
Rb代表异丙基、仲丁基、-CH2OH、-CH2C(O)NH2、-(CH2)2C(O)NH2、-(CH2)4-NH(COCH3)、-CH2C(O)OH、-(CH2)2C(O)OH、-CH2(吲哚基)、-CH2C(O)NH(己基)或-(CH2)2C(O)NH(己基)；
Rc代表氢；或者Rb和Rc与它们所附接的原子结合在一起形成吡咯烷环；
Rd代表-CH2OH、-CH(CH3)OH、-(CH2)4-NH2或-(CH2)2C(O)OH；且
Re代表氢；或者Rd和Re与它们所附接的原子结合在一起形成吡咯烷环。
在式(I)的某些实施方案中，
G代表氢或甲基；
Ra代表-CH2OH、-CH(CH3)OH、-CH2-(对-OH(苯基))、-(CH2)4-NH2、-(CH2)2COOH、-CH2(咪唑基)或-(CH2)3-NH-C(＝NH)-NH2；
Ra’代表氢；或者Ra和Ra’与它们所附接的原子结合在一起形成环戊基或环己基环；
Rb代表异丙基、仲丁基、-CH2OH、-CH2C(O)NH2、-(CH2)2C(O)NH2、-(CH2)4-NH(COCH3)、-CH2C(O)OH、-CH2(吲哚基)、-CH2C(O)NH(己基)或-(CH2)2C(O)NH(己基)；
Rc代表氢；或者Rb和Rc与它们所附接的原子结合在一起形成吡咯烷环；
Rd代表-CH2OH、-CH(CH3)OH、-(CH2)4-NH2或-(CH2)2C(O)OH；且
Re代表氢；或者Rd和Re与它们所附接的原子结合在一起形成吡咯烷环。
在某些实施方案中，Ra代表-CH2OH或-CH(CH3)OH，Rb代表-CH2C(O)NH2或-CH2C(O)OH，且Rd代表-CH2OH或-CH(CH3)OH。在一些实施方案中，Ra代表-CH2OH或-CH(CH3)OH，Rb代表-CH2C(O)NH2，且Rd代表-CH(CH3)OH。在其它实施方案中，Ra代表-CH2OH，Rb代表-CH2C(O)NH2，且Rd代表-CH(CH3)OH。在一些实施方案中，Ra代表-CH(CH3)OH，Rb代表-CH2C(O)NH2，且Rd代表-CH2OH。
在某些实施方案中，当Rd代表-CH2OH时，Ra不是-CH2-(对-OH(苯基))。
在本文公开的方法和组合物的某些实施方案中，所述化合物、其药学上可接受的盐或立体异构体选自：
表1
在本文公开的方法和组合物的一些实施方案中，所述化合物、其药学上可接受的盐或立体异构体选自：
表2
在本文公开的方法和组合物的某些实施方案中，所述化合物、其药学上可接受的盐或立体异构体选自：
表3
在本文公开的方法和组合物的某些实施方案中，Ra代表氨基酸残基的侧链。在一些实施方案中，Rb代表氨基酸残基的侧链。在某些实施方案中，Rd代表氨基酸残基的侧链。在某些实施方案中，Ra、Rb和Rd各自代表氨基酸残基的侧链。
氨基酸残基在本领域中应理解为意指在α、β或γ碳位置上被氨基(-NH2)基团取代的羧酸。在-CO-Aaa基团中，氨基酸残基Aaa通过羰基碳和氨基酸残基的氨基之间的共价键与羰基CO连接。在优选的实施方案中，氨基酸是α-氨基酸，并且氨基酸残基Aaa通过羰基碳和氨基酸残基的α-氨基之间的共价键与羰基CO连接。
根据上述实施方案中的任一个，在某些实施方案中，一个、多于一个或所有氨基酸残基为D氨基酸残基。在某些实施方案中，一个、多于一个或所有氨基酸残基侧链对应于D氨基酸残基的立体化学。
在某些实施方案中，一个、多于一个或所有氨基酸残基为L氨基酸残基。在某些实施方案中，一个、多于一个或所有氨基酸残基侧链对应于L氨基酸残基的立体化学。
在本文公开的方法和组合物的某些实施方案中，化合物可以是式(I)化合物的前药，例如，其中母体化合物中的羟基以酯或碳酸酯形式存在或母体化合物中的羧酸以酯形式存在。在另一个实施方案中，前药在体内代谢成活性母体化合物(例如，酯被水解成相应的羟基或羧酸)。
在本文公开的方法和组合物的某些实施方案中，本公开的化合物还可以在组成这些化合物的原子的一个或多个处包含非自然比例的原子同位素。例如，本公开还包括本公开的同位素标记变型，它们与本文中列举的化合物相同，只不过化合物的一个或多个原子被原子质量或质量数不同于通常在自然界中发现的主要原子质量或质量数的原子替代。任何特定原子或元素的所有同位素均涵盖于本公开的化合物及其用途的范围内。可以掺入本公开的化合物中的示例性同位素包括氢、碳、氮、氧、磷、硫、氟、氯和碘的同位素，诸如2H(“D”)、3H、11C、13C、14C、13N、15N、15O、17O、18O、35S、18F、36C1、123I和125I。本公开的同位素标记化合物一般可以通过按照类似于下文中的方案及/或实施例中所公开的程序，用同位素标记试剂代替非同位素标记试剂来制备。
在本文公开的方法的一些实施方案中，免疫反应进一步由程序性细胞死亡1(PD-1)信号传导通路介导。
使用方法
在某些实施方案中，本公开提供了调节细胞中由VISTA活性介导的免疫反应的方法，该方法包括使细胞与根据任何以上实施方案的式(I)化合物或其药学上可接受的盐接触。在一些实施方案中，本公开提供了调节细胞中由PD-1通路(例如，PD-1、PD-L1或PD-L2)和VISTA活性介导的免疫反应的方法，该方法包括使细胞与根据任何以上实施方案的式(I)化合物或其药学上可接受的盐接触。
在某些实施方案中，本公开提供了式(I)化合物用于制备例如用于治疗癌症、免疫失调、免疫缺陷病症、炎性病症、感染性疾病和移植排斥的药物的用途。
根据上述实施方案中的任一个，在某些实施方案中，接触细胞发生在有需要的受试者中，从而治疗选自癌症、免疫失调、免疫缺陷病症、炎性病症、感染性疾病和移植排斥的疾病或病症。
在某些实施方案中，本公开提供治疗癌症的方法，其中该方法包括向有需要的受试者施用治疗有效量的式(I)化合物。
在某些实施方案中，本公开提供了通过向有需要的受试者施用治疗有效量的式(I)化合物来抑制肿瘤细胞生长和/或转移的方法。
代表性肿瘤细胞包括诸如但不限于下列各项的癌症的细胞：胚细胞瘤(例如，胶质母细胞瘤)、乳腺癌(例如，乳腺癌、原发性导管癌、三阴性乳腺癌、雌激素受体阳性(ER+)、孕酮受体阳性(PR+)和/或人表皮生长因子受体2阳性(HER2+))、上皮癌(例如癌)、结肠癌、肺癌(例如，小细胞肺癌、非小细胞肺癌(NSCLC)、肺腺癌和肺鳞状细胞癌)、黑素瘤(例如，皮肤黑素瘤、眼黑素瘤、皮肤或眼内噁性黑素瘤和淋巴结相关黑素瘤)、前列腺癌(例如前列腺腺癌)、肾癌(例如，肾细胞癌(RCC)和肾癌)、骨癌(例如，骨肉瘤)、胰腺癌(例如，胰脏腺癌)、皮肤癌、头颈部癌症(例如，头颈部鳞状细胞癌)、子宫癌、卵巢癌症(例如，卵巢癌)、结直肠癌(例如微卫星不稳定性高级结直肠癌和结直肠腺癌)、直肠癌、肛门癌、腹膜癌、胃部癌症(例如，胃癌和胃肠癌)、睾丸癌、输卵管癌、子宫内膜癌、宫颈癌(例如，子宫颈癌)、阴道癌(例如阴道癌)、外阴癌(例如外阴癌)、食道癌、小肠癌、内分泌系统癌症、甲状腺癌(如甲状腺癌症)、甲状旁腺癌、肾上腺癌、肉瘤(例如，软组织肉瘤和卡波西(Kaposi′s)肉瘤)、尿道癌、阴茎癌、慢性或急性白血病(例如，急性髓性白血病、慢性髓性白血病、急性成淋巴细胞性白血病、慢性淋巴细胞白血病、毛细胞白血病和慢性成髓细胞性白血病)、儿童实体瘤、霍奇金淋巴瘤(HL)(例如，淋巴细胞富集型(LRCHL)、结节性硬化症(NSHL)、混合细胞性(MCHL)和淋巴细胞消减型(LDHL))、B细胞淋巴瘤(例如弥漫性大B细胞淋巴瘤(DLBCL))、非霍奇金淋巴瘤(NHL)(例如，低级/卵泡非霍奇金淋巴瘤、小淋巴细胞(SL)NHL、中级/滤泡性NHL、中级弥漫性NHL、高级成免疫细胞性NHL、高级成淋巴细胞性NHL、高级小型非裂解细胞性NHL、肿瘤巨大NHL、伯基特氏淋巴瘤(Burkitt’s lymphoma)、套细胞淋巴瘤)、AIDS相关淋巴瘤、皮肤T细胞淋巴瘤(如蕈样真菌病)和华氏巨球蛋白血症(Waldenstrom′s Macroglobulinemia)、移植后淋巴组织增生性疾病(PTLD)、淋巴细胞性淋巴瘤、原发性CNS淋巴瘤和T细胞淋巴瘤)、间皮瘤、胸腺癌、骨髓瘤(例如，多发性骨髓瘤)、膀胱癌症(如膀胱癌)、输尿管癌、肾盂癌、肝癌(如肝细胞癌、肝癌、肝细胞瘤)、胰腺癌、移植后淋巴组织增生性疾病(PTLD)、中枢神经系统(CNS)肿瘤、肿瘤血管生成、脊髓轴肿瘤、脑干胶质瘤、垂体腺瘤、表皮样癌、唾液腺癌、鳞状细胞癌、与母斑细胞病相关的异常血管增生、水肿(例如与脑肿瘤相关的水肿)、梅格氏综合症(Meigs’syndrome)、梅克尔细胞癌(Merkel cell carcinoma)、环境诱发的癌症(包括由石棉诱发的癌症)以及所述癌症的组合。
在其它实施方案中，例如，肿瘤细胞可以包括选自下列各项的癌症的细胞：前列腺癌、黑素瘤、乳腺癌、结肠癌、前列腺癌、肺癌、肾癌、胰腺癌、胃癌、膀胱癌、食道癌、间皮瘤、甲状腺癌、胸腺癌、肉瘤、胶质母细胞瘤、慢性或急性白血病、淋巴瘤、骨髓瘤、梅克尔细胞癌、上皮癌、结直肠癌、阴道癌、宫颈癌、卵巢癌和头颈癌。
在其它实施方案中，例如，肿瘤细胞可以包括选自下列各项的癌症的细胞：黑素瘤、三阴性乳腺癌、非小细胞肺癌、肾细胞癌、胰腺癌、胃癌、膀胱癌、间皮瘤、霍奇金淋巴瘤、宫颈癌、卵巢癌和头颈部鳞状细胞癌。
在一些实施方案中，肿瘤细胞和/或受试者未接受过免疫肿瘤学治疗。免疫肿瘤学利用受试者的免疫系统来帮助对抗癌症。例如，免疫肿瘤学疗法包括但不限于艾佐珠单抗(atezolizumab)(靶向PD-L1的人单克隆抗体)、阿维罗单抗(avelumab)(靶向PD-L1的人单克隆抗体)、本妥昔单抗(brentuximab vedotin)(靶向CD30的抗体-药物缀合物)、利妥昔单抗(rituximab)(靶向CD20的抗体)、杜伐鲁单抗(durvalamab)(靶向PD-L1的人单克隆抗体)、易普利单抗(ipilimumab)(靶向CTLA-4的人单克隆抗体)、尼维单抗(nivolumab)(靶向PD-L1的人单克隆抗体)、培罗珠单抗(pembrolizumab)(也称为拉姆布罗力珠单抗(1ambrolizumab)，靶向PD-L1的人单克隆抗体)、曲利木单抗(tremelimumab)(靶向CTLA-4的人单克隆抗体)、CT-011(靶向PD-1的抗体)、MDX-1106(靶向PD-1的抗体)、MK-3475(靶向PD-1的抗体)、YW243.55.S70(靶向PD-L1的抗体)、MPDL3280A(靶向PD-L1的抗体)、MDX-1105(靶向PD-L1的抗体)和MEDI4736(靶向PD-L1的抗体)。在一些实施方案中，免疫肿瘤学疗法选自抗CTLA-4抗体、抗PD-1抗体、抗PD-L1抗体、抗PD-L2抗体、抗TIGIT抗体(例如，WO 2015/009856中公开的抗体)。
在其它实施方案中，生物样品包含癌症的肿瘤细胞，其中已经通过测试该类型的代表性肿瘤的样品或通过测试患者自身的肿瘤证明了对免疫检查点疗法的响应。在一些实施方案中，癌症已对抗PD1疗法产生反应，例如，通过测试该类型的代表性肿瘤的样品。例如，癌症可以包括非小细胞肺癌(NSCLC)、黑素瘤、肾细胞癌(RCC)、膀胱癌、霍奇金淋巴瘤和头颈部鳞状细胞癌。
在一些实施方案中，生物样品包含对一种或多种PD-1拮抗剂具有难治性或抗性的肿瘤细胞。在其它实施方案中，肿瘤细胞对一种或多种PD-1拮抗剂具有难治性或抗性，同时保持对PD-1(例如PD-1、PD-L1或PD-L2)通路的活性。
在某些实施方案中，生物样品包含癌症的肿瘤细胞，其中VISTA在不存在PD-L1和PD-L2的情况下表达。在一些实施方案中，生物样品包含肿瘤细胞、基质和免疫浸润。例如，在其中VISTA在没有PD-L1和PD-L2的情况下表达的一些实施方案中，生物样品包含癌症如小细胞肺癌、多发性骨髓瘤、膀胱癌、原发性导管癌、卵巢癌、霍奇金淋巴瘤、胃癌、急性髓性白血病和胰腺癌的肿瘤细胞。
在其它实施方案中，生物样品包含癌症的肿瘤细胞，其中VISTA和PD-L1表达没有相关性。例如，生物样品可以包括癌症(例如子宫内膜癌、卵巢癌、霍奇金淋巴瘤、非霍奇金淋巴瘤以及慢性或急性白血病，包括急性髓性白血病、慢性髓性白血病、急性成淋巴细胞性白血病、慢性淋巴细胞白血病、淋巴细胞性淋巴瘤和多发性骨髓瘤)的肿瘤细胞。
在其它实施方案中，生物样品包含癌症的肿瘤细胞，其中所述肿瘤细胞表达VISTA和PD-L1。例如，肿瘤细胞包括癌症如前列腺腺癌、肺腺癌、肺鳞状细胞癌、胰腺癌、乳腺癌和结直肠腺癌的细胞。在某些实施方案中，肿瘤细胞来自乳腺癌。在一些实施方案中，肿瘤细胞来自选自三阴性乳腺癌、雌激素受体阳性(ER+)、孕酮受体阳性(PR+)和/或人表皮生长因子受体2(HER2+)的乳腺癌。在其它实施方案中，肿瘤细胞来自PAM50+乳腺癌测定小组(Parker，J.S.等，J.Clin.Oncol.，2009，27(8)：1160-1167)，选自luminal A、luminal B、HER2富集型、基底样和正常样的乳腺癌。
在一些实施方案中，生物样品包括癌症的肿瘤细胞，其中肿瘤清除依赖于髓样细胞、自然杀伤(NK)细胞或NKT细胞。在其它实施方案中，生物样品包含癌症的肿瘤细胞，其中清除依赖于CD8+T细胞。例如，癌症可以包括三阴性乳腺癌、微卫星不稳定性高级结直肠癌、胃癌、间皮瘤、胰腺癌和宫颈癌。
在一些实施方案中，生物样品包含来自癌症的一个或多个细胞。
本公开的其它实施方案提供通过抑制VISTA来治疗感染的方法。
本公开的其它实施方案提供通过阻断PD-1通路和抑制VISTA(例如抑制由PD-1、PD-L1或PD-L2和/或VISTA诱导的免疫阻抑信号)来治疗感染的方法，其中该方法包括向有需要的受试者施用治疗有效量的式(I)化合物。
在某些实施方案中，本公开提供了本公开的化合物用于制备用来治疗感染性疾病的药物的用途，以及施用治疗有效量的式(I)化合物以治疗感染性疾病的方法。
在一些实施方案中，感染性疾病为细菌感染、病毒感染、真菌感染或寄生虫感染，以及施用治疗有效量的式(I)化合物以治疗细菌感染、病毒感染、真菌感染或寄生虫感染的方法。
在一些实施方案中，例如，细菌感染可以由选自下列的至少一种细菌引起：炭疽、杆菌(Bacilli)、博德特氏菌(Bordetella)、疏螺旋体(Borrelia)、肉毒杆菌、布鲁氏菌(Brucella)、伯克霍尔德菌(Burkholderia)、弯曲杆菌(Campylobacter)、衣原体(Chlamydia)、霍乱、梭菌(Clostridium)、球菌(Conococcus)、棒状杆菌(Corynebacterium)、白喉、肠杆菌(Enterobacter)、肠球菌(Enterococcus)、欧文氏菌(Erwinia)、埃希氏杆菌(Escherichia)、弗朗西斯氏菌(Francisella)、嗜血杆菌(Haemophilus)、螺杆菌(Heliobacter)、克雷伯氏菌(Klebsiella)、军团杆菌(Legionella)、钩端螺旋体(Leptospira)、钩端螺旋体病、李斯特菌(Listeria)、莱姆病(Lyme′s disease)、脑膜炎球菌(meningococcus)、分支杆菌(Mycobacterium)、支原体、奈瑟氏菌(Neisseria)、巴斯德菌(Pasteurella)、暗杆菌(Pelobacter)、瘟疫、肺炎球菌(Pneumonococcus)、变形杆菌(Proteus)、假单胞菌(Pseudomonas)、立克次氏体(Rickettsia)、沙门氏菌(Salmonella)、沙雷氏菌(Serratia)、志贺氏菌(Shigella)、葡萄球菌(Staphylococcus)、链球菌(Streptococcus)、破伤风、密螺旋体(Treponema)、弧菌(Vibrio)、耶尔森氏菌(Yersinia)和黄单胞菌(Xanthomonas)。
在其它实施方案中，例如，病毒感染可以由选自下列的至少一种病毒引起：腺病毒科(Adenoviridae)、头瘤病毒科(Papillomaviridae)、多瘤病毒科(Polyomaviridae)、疱疹病毒科(Herpesviridae)、痘病毒科(Poxviridae)、嗜肝DNA病毒科(Hepadnaviridae)、细小病毒科(Parvoviridae)、星状病毒科(Astroviridae)、杯状病毒科(Caliciviridae)、小核糖核酸病毒科(Picornaviridae)、冠状病毒科(Coronoviridae)、黄病毒科(Flaviviridae)、逆转录病毒科(Retroviridae)、披膜病毒科(Togaviridae)、沙粒病毒科(Arenaviridae)、布尼亚病毒科(Bunyaviridae)、丝状病毒科(Filoviridae)、正粘病毒科(Orthomyxoviridae)、副粘病毒科(Paramyxoviridae)、弹状病毒科(Rhabdoviridae)和呼肠孤病毒科(Reoviridae)。在某些实施方案中，病毒可以是虫媒病毒性脑炎病毒、腺病毒、单纯疱疹病毒I型、单纯疱疹病毒2型、水痘-带状疱疹病毒、爱泼斯坦-巴尔(Epstein-barr)病毒、巨细胞病毒、8型疱疹病毒、乳头瘤病毒、BK病毒、冠状病毒、艾柯病毒(echovirus)、JC病毒、天花、乙型肝炎、博卡病毒(bocavirus)、细小病毒B19、星状病毒、诺沃克病毒(Norwalk virus)、柯萨奇病毒(coxsackievirus)、甲型肝炎、脊髓灰质炎病毒、鼻病毒、严重急性呼吸综合症病毒、丙型肝炎、黄热病、登革热病毒、西尼罗河病毒(West Nilevirus)、风疹、E型肝炎、人类免疫缺陷病毒(HIV)、人类T细胞嗜淋巴细胞病毒(HTLV)、流感、鸟粪病毒、胡宁病毒(Junin virus)、拉沙病毒(Lassa virus)、马丘波病毒(Machupovirus)、萨比亚病毒(Sabia virus)、克里米亚-刚果出血热病毒、埃博拉病毒(ebolavirus)、马尔堡病毒(Marburg virus)、麻疹病毒、软疣病毒、腮腺炎病毒、副流感病毒、呼吸道合胞病毒、人偏肺病毒、亨德拉病毒(Hendra virus)、尼帕病毒(Nipah virus)、狂犬病、丁型肝炎、轮状病毒、环状病毒、科罗拉多壁虱热病毒(coltivirus)、牛痘病毒和班纳病毒(Banna virus)。
在其它实施方案中，例如，真菌感染可以选自鹅口疮、曲霉属真菌(Aspergillus)(烟曲霉(fumigatus)、黑曲霉(niger)等)、皮肤芽生霉菌(Blastomyces dermatitidis)、念珠菌(Candida)(白色念珠菌(albicans)、克柔念珠菌(krusei)、光滑念珠菌(glabrata)、热带念珠菌(tropicalis)等)、粗球孢子菌(Coccidioides immitis)、隐球菌(新型隐球菌(neoformans)等)、荚膜组织胞浆菌(Histoplasma capsulatum)、毛霉目(Mucorales)(毛霉属(mucor)、犁头霉属(absidia)、根霉属(rhizophus))、巴西副球孢子菌(Paracoccidioides brasiliensis)、孢子丝菌病、申克氏孢子丝菌(Sporothrixschenkii)、接合菌病、着色芽生菌病、洛博真菌病(lobomycosis)、足分支菌病、甲真菌病、毛孢子菌花斑癣(piedra pityriasis versicolor)、胡须癣(tinea barbae)、头癣(tineacapitis)、体癣(tinea corporis)、股癣(tinea cruris)、黄癣(tinea favosa)、黑癣(tinea nigra)、足癣(tinea pedis)、耳霉菌病、暗色丝孢霉病(phaeohyphomycosis)和鼻孢子虫病。
在一些实施方案中，例如，寄生虫感染可以由选自下列的至少一种寄生虫引起：棘变形虫属(Acanthamoeba)、微小巴贝斯虫(Babesia microti)、结肠小袋纤毛虫(Balantidium coli)、溶组织内阿米巴(Entamoeba hystolytica)、兰伯氏贾第虫(Giardialamblia)、鼠隐孢子虫(Cryptosporidium muris)、冈比亚锥虫(Trypanosomatidagambiense)、罗氏锥虫(Trypanosomatida rhodesiense)、布氏锥虫(Trypanosomabrucei)、克氏锥虫(Trypanosoma cruzi)、墨西哥利什曼原虫(Leishmania mexicana)、巴西利什曼原虫(Leishmania braziliensis)、热带利什曼原虫(Leishmania tropica)、杜氏利什曼原虫(Leishmania donovani)、刚地弓形虫(Toxoplasma gondii)、间日疟原虫(Plasmodium vivax)、卵形疟原虫(Plasmodium ovale)、三日疟原虫(Plasmodiummalariae)、镰状疟原虫(Plasmodium falciparum)、卡氏肺孢子虫(Pneumocystiscarinii)、阴道毛滴虫(Trichomonas vaginalis)、黑头组织滴虫(Histomonasmeleagridis)、侧尾腺纲(Secementea)、毛首鞭形线虫(Trichuris trichiura)、人蛔虫(Ascaris lumbricoides)、蠕形住肠线虫(Enterobius vermicularis)、十二指肠钩虫(Ancylostoma duodenale)、福氏耐格里变形虫(Naegleria fowleri)、美洲钩虫(Necatoramericanus)、巴西日圆线虫(Nippostrongylus brasiliensis)、粪类圆线虫(Strongyloides stercoralis)、班氏吴策线虫(Wuchereria bancrofti)、麦地那龙线虫(Dracunculus medinensis)、血吸虫、肝吸虫、肠吸虫、肺吸虫、曼氏血吸虫(Schistosomamansoni)、埃及血吸虫(Schistosoma haematobium)、日本血吸虫(Schistosomajaponicum)、肝片吸虫(Fasciola hepatica)、大片吸虫(Fasciola gigantica)、异形异形吸虫(Heterophyes heterophyes)和卫氏并殖吸虫(Paragonimus westermani)。
生物标记物筛选
可以获取受关注组织(例如肿瘤组织)的基因表达谱，并且可以基于基因表达谱选择治疗性治疗。换句话说，如果抗肿瘤剂通过抑制特定癌蛋白起作用，那么可能需要在尝试用该抗肿瘤剂治疗癌症之前知道特定的癌症是否表达该致癌基因。可以以许多方式评估特定基因的表达。可以确定基因转录物的水平或编码的蛋白质的水平。蛋白质的存在可以通过诸如抗体结合、质谱法和双向凝胶电泳法等方法直接测定，或通过检测蛋白质的活性(无论是生物化学活性还是对另一种蛋白质水平或一种或多种基因的表达水平的影响)间接测定。
目前使用许多方法测量基因表达。在一些实施方案中，这些方法使用聚合酶链反应(PCR)技术，其细节提供于颁予Mullis等的美国专利第4,683,195号、美国专利第4,683,202号和美国专利第4,965,188号，所述专利均通过引用整体并入本文中。在其它实施方案中，方法利用与DNA片段杂交的探针对转录物进行数字检测，所述DNA片段连接至一串独特的有色荧光团(也称为分子条形码)。
方法还包括比较基因组杂交(CGH)；荧光原位杂交(FISH)；免疫组织化学(包含IHC)；以及下一代测序(NGS)和其它评估DNA水平的分子分析技术(如基因组阵列)、RNA定量、蛋白质组测定等。
如本文中所用，“标签”是基因或生物标记物的限定亚群的表达模式。
如本文中所用，“高免疫标签阳性”样品代表特定类型免疫细胞(例如细胞毒性T细胞)的免疫细胞肿瘤浸润。
例如，在本文公开的治疗癌症的某些方法中，该方法可以包括确定包含肿瘤细胞的生物样品是否表达(或相对于该组织类型的正常组织过度表达)生物标记物如VISTA、PD-L1或PD-L2。类似地，该方法可以包括确定生物样品是否是VISTA阳性、骨髓标签阳性、天然杀伤标签阳性和/或高度免疫标签阳性。可以对患者的肿瘤进行活组织检查以获取用于测试的样品，但是也可以通过任何其它合适的方式获取样品，例如通过鉴定受试者血流中的脱落或转移性肿瘤细胞或核酸。在一些实施方案中，可以在患者体内原位测试样品。或者，样品可以是血液样品，并且确定肿瘤是否过度表达标记物可以包括测量血液样品中标记物的水平以确定该水平是否指示标记物的正常表达或标记物的高表达。
在一些实施方案中，生物样品可以表现出VISTA和免疫系统活化的其它标记物的高表达。例如，生物样品可以表现出某个标签，例如，具有高免疫标签阳性。在其它实施方案中，则可以用式(I)化合物治疗表现出特定基因标签的患者。
在一些实施方案中，然后可以用本文公开的化合物治疗表现出例如VISTA、PD-L1和/或PD-L2的高表达的患者。
因此，本文提供了调节受试者的免疫反应的方法，其包括
a)确定来自受试者的生物样品是否过度表达VISTA、PD-L1和/或PD-L2；和
b)如果样品过度表达VISTA、PD-L1和/或PD-L2，则使受试者与如本文所公开的式(I)化合物接触。
在一些实施方案中，本文提供了调节受试者的免疫反应的方法，其包括
a)确定来自受试者的生物样品是否过度表达VISTA；以及
b)如果样品过度表达VISTA，则使受试者与如本文所公开的式(I)化合物接触。
在一些实施方案中，该方法还包括确定样品是否还过度表达PD-L1或PD-L2。在其它实施方案中，本文公开的方法还包括确定样品是否也过度表达免疫系统活化的标记物。在某些实施方案中，样品包含一个或多个肿瘤细胞。
评估基因表达的另一个应用是开发伴随诊断(CDx)工具，用于确定药物或其它治疗剂是否将有益于具有受该基因的活性调节的疾病或病状的受试者。CDx可以指导药物仅用于具有受治疗影响的基因、基因标签或蛋白质的患者，并且可以是经FDA批准的治疗中的必需要素。受试者受益于不是不会对疾病(例如某种癌症)产生有益效果的处方药物，并且允许医生基于患者状况定制对患者的治疗。因此，最重要的是CDx在分析和临床上经过验证，以最大程度地减少任何假阳性或阴性效应。因此，CDx测试经常与药物开发同时开展。有效的CDx必须与所评估的疾病或病状具有高度且可再现的相关性。
在某些实施方案中，本文提供了确定用式(I)化合物调节受试者的免疫反应的可能性的方法，该方法包括：
a)从受试者获取或提供生物样品；
b)测量受试者样品中VISTA的量或活性；以及
c)将测得的量或活性与对照样品中VISTA的量或活性进行比较，
其中受试者样品中VISTA的量或活性相对于对照样品显著增加表明受试者更可能对式(I)化合物有反应，并且
其中受试者样品中VISTA的量或活性类似于或低于对照样品表明受试者不太可能对式(I)化合物有反应。
在其它实施方案中，本文提供了确定用式(I)化合物调节受试者的免疫反应的可能性的方法，该方法包括：
a)从受试者获取或提供生物样品；
b)测量受试者样品中VISTA的量或活性；以及
c)将测得的量或活性与对照样品中VISTA的量或活性进行比较，
其中受试者样品中VISTA的活性类似于或低于对照样品表明受试者更可能对式(I)化合物有反应，并且
其中受试者样品中VISTA的量或活性高于对照样品表明受试者不太可能对式(I)化合物有反应。
在某些实施方案中，对照样品在受试者接受式(I)化合物之前获取，并且受试者样品在受试者接受式(I)化合物之后获取。
在某些实施方案中，生物样品选自血清、全血、血浆、尿液、细胞(例如肿瘤细胞)、细胞系、手术切除的肿瘤组织和组织活检物。在一些实施方案中，样品选自全血或组织活检物。在某些实施方案中，样品包含来自受试者的生物标记物，例如VISTA、PD-L1和/或PD-L2。在其它实施方案中，受试者显示特定基因标签作为生物标记物。在其它实施方案中，基因标签包括VISTA表达。在一些实施方案中，受试者患有本文所述的癌症。在一些实施方案中，该方法还包括：如果确定受试者可能对式(I)化合物有反应，则推荐、开出或施用式(I)化合物，或者如果确定受试者不太可能对式(I)化合物有反应，则施用除式(I)化合物以外的疗法。在一些实施方案中，肿瘤细胞来自选自乳腺癌、结肠癌、肺癌、黑色素瘤、前列腺癌和肾癌的癌症。
在某些实施方案中，对照样品是来自受试者或患者所属的相同物种的成员的样品，或甚至是来自相同受试者的健康组织样品。对照样品可以包含细胞或不包含细胞。对照样品可以包含已知对式(I)的化合物有反应或无反应的癌细胞。
在某些实施方案中，使用与蛋白质特异性结合的试剂检测VISTA的量。在某些实施方案中，试剂选自抗体、抗体衍生物和抗体片段。在某些实施方案中，通过检测转录的多核苷酸或其部分在样品中的存在来评估VISTA表达。在某些实施方案中，转录的多核苷酸是mRNA或cDNA。在某些实施方案中，检测还包括扩增转录的多核苷酸。在某些实施方案中，通过鉴定在严格杂交条件下与生物标记物核酸或其部分退火的核酸来检测转录的多核苷酸。在其它实施方案中，检测作为生物标记物的基因标签可以基于包括但不限于下一代测序(NGS)、杂交和数字检测的方法。例如，多重测序是一种NGS方法，它使用平行测序和独特的索引标签，允许同时分析合并的样品。数字检测依赖于离散单元进行测量，而不是依赖于信号的相对水平。例如，通过与连接至一串独特的有色荧光团(分子条形码)的DNA片段杂交的探针检测转录物，并且通过计算检测到特定分子条形码的次数来量化样品中转录物的总数量。
如果VISTA的量大于或小于正常水平的程度为大于用于评估量的测定的标准误差的量和优选为该量的至少约0.2倍、0.3倍、0.4倍、0.5倍、0.6倍、0.7倍、0.8倍、0.9倍、1倍、1.5倍、2倍、2.5倍、3倍、3.5倍、4倍、5倍、6倍、7倍、8倍、9倍或10倍，则受试者中的VISTA表达分别“显著”高于或低于标记物的正常水平。或者，如果VISTA的量比VISTA的正常量高或低至少约为2倍且优选至少约3、4或5倍，则可认为受试者中VISTA的量“显著”高于或低于正常量。这种“显著性”还可以应用于本文所述的任何测量参数，例如表达、抑制、细胞毒性、细胞生长等。
除非此处另有说明，否则术语“抗体”广泛地包括抗体的天然存在的形式(例如IgG、IgA、IgM、IgE)和重组抗体，例如单链抗体、嵌合和人源化抗体及多特异性抗体，以及所有前述抗体的片段和衍生物，该片段和衍生物至少具有抗原结合位点。抗体衍生物可以包含与抗体缀合的蛋白质或化学部分。
如本文所用的术语“抗体”还包括抗体的“抗原结合部分”(或简称“抗体部分”)。如本文所用，术语“抗原结合部分”是指抗体的一个或多个片段，其保留与抗原特异性(例如，生物标记多肽或其片段)结合的能力。已经显示抗体的抗原结合功能可以通过全长抗体的片段执行。
术语“对照”是指适合于提供与测试样品中的表达产物的比较的任何参考标准。在某些实施方案中，对照包括获取“对照样品”，检测该对照样品中的表达产物水平并与测试样品中的表达产物水平进行比较。这样的对照样品可以包含任何合适的样品，包括但不限于来自对照受试者的具有已知结果的样品(可以是储存样品或先前的样品测量值)；从受试者分离的正常组织或细胞、从受试者分离的原代细胞/组织的培养物、从受试者的相同器官或身体位置获取的邻近的正常细胞/组织、从正常受试者分离的组织或细胞样品或从保藏所获取的原代细胞/组织。在某些实施方案中，对照可以包含来自任何合适来源的参考标准表达产物水平，包括但不限于持家基因、来自正常组织(或其它先前分析的对照样品)的表达产物水平范围、来自一组患者的测试样品中的先前测定的表达产物水平范围或者具有某种结果或接受某种治疗的一组患者。本领域技术人员将理解，这些对照样品和参考标准表达产物水平可以组合地用作本发明方法中的对照。
VISTA的“正常”表达水平是不需要免疫反应调节的受试者(例如，人类患者)的细胞中的VISTA表达水平。生物标记物的“过表达”或“显著更高的表达水平”是指测试样品中的表达水平高于用于评估表达的测定的标准误差，并且优选比对照样品(例如，来自不需要免疫调节的健康受试者的样品，或来自从相同受试者获取的健康组织样品)中VISTA的表达活性或水平和优选若干对照样品中生物标记物的平均表达水平高至少约10％，且更优选高约1.2、1.3、1.4、1.5、1.6、1.7、1.8、1.9、2.0、2.1、2.1、2.2、2.3、2.4、2.5、2.6、2.7、2.8、2.9、3、3.5、4、4.5、5、5.5、6、6.5、7、7.5、8、8.5、9、9.5、10、10.5、11、12、13、14、15、16、17、18、19、20倍或更多倍。生物标记物的“显著更低的表达水平”是指测试样品中的表达水平比对照样品(例如，来自不需要免疫调节的健康受试者的样品)中生物标记物的表达水平和优选若干对照样品中生物标记物的平均表达水平低至少约10％，且更优选低约1.2、1.3、1.4、1.5、1.6、1.7、1.8、1.9、2.0、2.1、2.1、2.2、2.3、2.4、2.5、2.6、2.7、2.8、2.9、3、3.5、4、4.5、5、5.5、6、6.5、7、7.5、8、8.5、9、9.5、10、10.5、11、12、13、14、15、16、17、18、19、20倍或更多倍。
用于检测或测定VISTA基因的存在或水平的术语“样品”通常是全血、血浆、血清、唾液、尿液、粪便(例如排泄物)、眼泪和任何其它体液(例如，如上文在“体液”的定义下所描述)，或组织样品(例如，活组织切片)，如小肠、结肠样品或手术切除组织。在一些实施方案中，所公开的方法还包括在检测或测定VISTA基因的存在或水平之前从受试者获取样品。
施用方法
本公开的化合物可以作为单一药物(单一疗法)使用或与一种或多种其它药剂联合使用(联合疗法)。化合物可以单独使用，或优选在药物组合物中使用，其中化合物与一种或多种药学上可接受的物质混合。
药物组合物可以通过口服或吸入途径施用，或通过肠胃外给药途径施用。例如，组合物可以口服、通过静脉内输注、局部、腹膜内、膀胱内、鞘内或作为栓剂施用。肠胃外施用的实例包括但不限于关节内(在关节中)、静脉内、肌肉内、皮内、腹膜内和皮下途径。合适的液体组合物可以是水性或非水性等渗无菌注射溶液并且可以含有抗氧化剂、缓冲剂、抑菌剂和使制剂与预期接受者的血液等渗的溶质，以及可包括悬浮剂、增溶剂、增稠剂、稳定剂和防腐剂的水性和非水性无菌混悬液。口服施用、肠胃外施用、皮下施用和静脉内施用是优选的施用方法。
本公开化合物的剂量根据患者的年龄、体重或症状以及化合物的效力或治疗功效、给药方案和/或治疗时间而变化。通常，合适的施用途径可以包括例如口服、滴眼、直肠、经粘膜、局部或肠道施用；肠胃外递送，包括肌肉内、皮下、髓内注射，以及鞘内、直接心室内、静脉内、腹膜内、鼻内或眼内注射。本公开的化合物可以以每剂量方案0.5mg或1mg至500mg、1g或2g的量施用。剂量可以每周施用一次、每三天施用一次、每两天施用一次、每天施用一次、每天施用两次、每天施用三次或更频繁地施用。在替代实施方案中，在某些成人中，化合物可以通过静脉内施用连续施用由医生指定的一段时间。由于剂量受各种条件的影响，因此在某些情况下可以使用小于或大于所考虑的剂量范围的量。医生可以容易地确定接受治疗处理的患者的合适剂量。
组合治疗
本公开的化合物可以与一种或多种其它药物组合施用以(1)补充和/或增强式(I)化合物的作用；(2)调节药效学、改善吸收或减少式(I)化合物的剂量；和/或(3)减少或减轻式(I)化合物的副作用。如本文所用，短语“联合施用”是指以任何形式施用两种或更多种不同治疗化合物，以使得在施用第二种化合物的同时，先前施用的治疗化合物在体内仍然有效(例如，两种化合物在患者中同时有效，可以包括两种化合物的协同作用)。例如，不同的治疗化合物可以在相同制剂中施用或在不同制剂中同时或依序施用。在某些实施方案中，不同的治疗化合物可以彼此间隔1小时、12小时、24小时、36小时、48小时、72小时或一周施用。因此，接受这种治疗的个体可受益于不同治疗化合物的组合效果。各化合物可以通过相同或不同的途径和相同或不同的方法施用。在一些实施方案中，联合疗法的组合效果可通过免疫效应检测。
其它药物的剂量可以是临床使用的剂量，或者可以是改变的剂量，使得该剂量在与本公开的化合物组合施用时是有效的。本公开的化合物与其它药物的比例可以根据待给药的受试者的年龄和体重、施用方法、施用时间、待治疗的病症、症状及其组合而变化。例如，基于1质量份本公开的化合物，其它药物的使用量可以是0.01至100质量份。
联合疗法可用于治疗本文讨论的任何疾病。在某些实施方案中，本公开的式(I)化合物可以与另一种治疗剂(例如抗癌剂、抗病毒剂、细胞因子或免疫激动剂)联合施用。在一些实施方案中，另一种治疗剂选自CTLA-4拮抗剂、PD-1拮抗剂、PD-L1拮抗剂或PD-L2拮抗剂以及EGFR拮抗剂。
组合治疗用药剂
在某些实施方案中，式(I)的化合物可以与另一种治疗剂联合施用，例如，
1)醛固酮合酶抑制剂；
2)ALK抑制剂；细胞凋亡诱导剂；
3)芳香酶抑制剂；
4)CART细胞(例如，靶向CD19的CART细胞)；
5)BCR-ABL抑制剂；
6)BRAF抑制剂；
7)CDK4/6抑制剂；
8)CEACAM(例如，CEACAM-1、CEACAM-3和/或CEACAM-5)抑制剂；
9)c-KIT抑制剂；
10)c-MET抑制剂；
10)cRAP抑制剂；
11)CTLA4抑制剂；
12)细胞色素P450抑制剂(例如，CYP17抑制剂)；
13)EGF抑制剂；
14)ERK1/2ATP抑制剂；
15)FGF抑制剂(例如，FGFR2或FGFR4抑制剂)；
16)Flt3抑制剂(例如，FLK2/STK1)；
17)P-糖蛋白1抑制剂；
18)HDAC抑制剂；
19)HDM2抑制剂；
20)HER3抑制剂；
21)组胺释放抑制剂；
22)HSP90抑制剂；
23)IAP抑制剂；
24)IDH抑制剂；
25)IDO抑制剂；
26)IGF-1R抑制剂；
27)铁螯合剂；
28)Janus抑制剂；
29)LAG-3抑制剂；
30)M-CSF抑制剂；
31)MEK抑制剂；
32)mTOR抑制剂；
33)p53抑制剂(例如，p53/Mdm2相互作用的抑制剂)；
34)PDGFRβ抑制剂；
35)PKC抑制剂；
36)PI3K抑制剂；
37)PIM抑制剂；
38)PRLR抑制剂；
39)Raf激酶C抑制剂；
40)平滑(SMO)受体抑制剂；
41)生长抑素激动剂和/或生长激素释放抑制剂；
42)转导调节剂和/或血管生成抑制剂；
43)VEGFR-2抑制剂(例如，FLK-1/KDR)；
44)酪氨酸激酶抑制剂(例如，CSF-1R酪氨酸激酶)；
45)Wnt信号传导抑制剂；
46)Bcl-2抑制剂；
47)Mcl-1抑制剂；
48)BTK抑制剂；
49)双活性分子如CUDC-907(PI3K/HDAC双重抑制剂)；和
50)BET溴结构域抑制剂。
适合与本文公开的化合物和组合物联合施用的其它治疗剂已在例如以下出版物中描述：WO2016/100882；WO2016/054555；WO2016/040892；WO2015/097536；WO2015/088847；WO2015/069770；WO2015/026634；WO 2015/009856；EP 1377609B1；Antonia等，Clin.CancerRes.201420：6258-6268；和Melero等，Nature Reviews Cancer 2015 15：457-472。每个出版物通过引用整体并入本文中。
例如，在涉及癌症治疗的本公开的方法中，本公开的化合物可以与另一种化学治疗剂一起作为单一药物组合物或作为不同药物组合物的组合使用。化学治疗剂的非限制性实例包括烷基化剂、亚硝基脲剂、抗代谢物、抗癌抗生素、植物源生物碱、拓扑异构酶抑制剂、激素药物、激素拮抗剂、白细胞减少症(中性粒细胞减少症)治疗药物、血小板减少症治疗药物、止吐剂、芳香酶抑制剂、P-糖蛋白抑制剂、铂络合物衍生物、其它免疫治疗药和其它抗癌药。
可以联合施用的示例性细胞毒性剂包括抗微管剂、拓扑异构酶抑制剂、抗代谢物、有丝分裂抑制剂、烷化剂、蒽环霉素、长春花生物碱、嵌入剂、能够干扰信号转导通路的试剂、细胞凋亡促进剂、蛋白酶体抑制剂和辐射(例如，局部或全身照射)。
其它治疗剂的非限制性实例包括但不限于肽、多肽、蛋白质、融合蛋白、核酸分子、小分子、模拟剂、合成药物、无机分子和有机分子。
药物组合物可以含有或联合疗法可以包括其它相容的试剂，例如，化学治疗剂、细胞因子疗法、干扰素疗法(例如，干扰素-α、干扰素-β或干扰素-γ；干扰素α-2a；干扰素-d-2b；干扰素α-m；干扰素α-n3；干扰素β-Ia；和干扰素γ-Ib)、白细胞介素疗法(例如，IL-1、IL-2、IL-2Rβ、IL-2Rγ、IL-3、IL-7、IL7Rα、IL-11、IL-12、IL-15和IL-21)、分化簇(CD)蛋白(例如，CD2、CD4、CD7、CD8α、CD8β、CD11a/CD18、CD11b、CD11c、CD11d、CD18、CD19、CD19a、CD20、CD27、CD28、CD29、CD30、CD40、CD40L、CD49a、CD49D、CD49f、CD69、CD84、CD96、CD100、CD103、CD137、CD160、CD226、CD229、CD278)、MHC I类分子的共刺激调节剂(例如，激动剂(例如，激动性抗体或其抗原结合片段，或可溶性融合物))、TNF受体蛋白、免疫球蛋白样蛋白、Toll配体受体、CD83配体、细胞因子受体、整合素、信号传导淋巴细胞激活分子(SLAM蛋白)、活化NK细胞受体、抗体疗法、病毒疗法、基因疗法或其组合。
可以与本公开的化合物联合施用的化学治疗剂和其它治疗剂包括但不限于：阿比特龙、紫杉醇(abraxane)、醋葡醛内酯、阿西维辛(acivicin)、阿克拉霉素(aclacinomysin)、阿替米得(actimid)、放线菌素、阿柏西普(aflibercept)、阿地白介素(aldesleukin)、醒磷酰胺糖苷(aldophosphamide glycoside)、阿来替尼(alectinib)、阿仑膦酸钠(alendronate)、阿利维A酸(alitretinoin)、六甲蜜胺(altretamine)、氨鲁米特(aminoglutethimide)、氨基乙酰丙酸、氨蝶呤、安吖嗪、阿那曲唑(anastrozole)、安西他滨(ancitabine)、血管抑制素、血管酶、蛇形菌素(anguidine)、安沙霉素(ansamitocin)、安曲霉素(anthramycin)、抗凝血酶III、阿帕替尼(apatinib)、阿拉伯糖苷、卡铂(arboplatin)、天冬酰胺酶、安曲霉素、阿西替尼(axitinib)、阿扎胞苷、重氮丝氨酸、阿扎替派(azetepa)、阿佐霉素(azotomycin)、6-氮杂尿苷、巴瑞替尼(baricitinib)、巴马司他(batimastat)、苯达莫司汀(bendamustine)、苯美替尼(benimetinib)、苯佐替派(benzodopa)、倍曲布西(bestrabucil)、蓓萨罗丁(bexarotene)、比卡鲁胺(bicalutamide)、比生群(bisantrene)、博来霉素(bleomycin)、硼替佐米(bortezomib)、博舒替尼(bosutinib)、布列奎钠(brequinar)、布立尼布(brivanib)、苔藓抑素(bryostatin)、溴匹立明(bropirimine)、布拉他辛(bullatacin)、布拉他辛酮(bullatacinone)、布舍瑞林(buserelin)、白消安(busulfan)、放线菌素、卡里奇霉素(calicheamicin)、卡里司汀(callystatin)、卡鲁睾酮(calusterone)、洋红霉素(caminomycin)、喜树碱(campothecin)、卡培他滨(capecitabine)、卡拉比辛(carabicin)、卡铂、卡波醌(carboquone)、卡非佐米(carfilzomib)、卡莫氟(carmofur)、卡莫司汀(carmustine)、卡柔比星(carubicin)、卡泽来新(carzelesin)、嗜癌菌素(carzinophilin)、西地芬戈(cedefingol)、西地尼布(cediranib)、萘氮芥(chlomaphazine)、苯丁酸氮芥(chlorambucil)、氯喹(chloroquine)、氯佐星(chlorozotocin)、胆磷酰胺(cholophosphamide)、色霉素、西罗霉素(cirolemycin)、顺铂、顺二氯二胺铂(II)、顺铂、克拉屈滨(cladribine)、氯屈膦酸(clodronate)、考比替尼(cobimetinib)、秋水仙碱、克雷斯托(crisnatol)、克唑替尼(crizotinib)、隐藻素1(cryptophycin 1)、隐藻素8(cryptophycin 8)、环磷酰胺、环丙孕酮(cyproterone)、阿糖胞苷、细胞松弛素B、胞嘧啶阿拉伯糖苷、达拉非尼(dabrafenib)、达卡巴嗪(dacarbazine)、更生霉素(dactinomycin)、丹诺普韦(danoprevir)、达沙替尼(dasatinib)、地吖醌(diaziquone)、二溴甘露醇、柔红霉素(daunorubicin)、地西他滨(decitabine)、地磷酰胺(defofamine)、地加瑞克(degarelix)、1-去氢睾酮、德拉佐米(delanzomib)、地美可辛(demecolcine)、去甲氧绿胶霉素(demethoxyviridin)、地尼白介素(denileukin)、得尼考辛(denenicokin)、二甲叶酸(denopterin)、脱乙酰拉维霉素(desacetylrayidomycin)、地托比星(detorubicin)、地塞米松(dexamethasone)、右奥马铂(dexormaplatin)、地扎胍宁(dezaguanine)、地吖醌、6-重氮-5-氧代-L-正亮氨酸、二氯乙酸盐、二脱氧尿苷、双烯雌酚(dienestrol)、已烯雌酚(diethylstilbestrol)、迪非替拓(diftitox)、二氟甲基鸟氨酸、二羟蒽二酮、地那西利(dinaciclib)、多西他赛(docetaxel)、多拉司他汀(dolastatin)、多韦替尼(dovitinib)、去氧氟尿苷、多柔比星(doxorubicin)、强力霉素(doxycycline)、屈洛昔芬(droloxifene)、屈他雄酮(dromostanolone)、达佐霉素(duazomycin)、达卡霉素(duocarmycin)、达内霉素(dynemicin)、依达曲沙(edatrexate)、依氟鸟氨酸(eflomithine)、依利醋铵(elliptiniumacetate)、五加素(eleutherobin)、依米丁(emetine)、埃西罗莫司(emsirolimus)、恩克芬尼(encorafenib)、恩洛铂(enloplatin)、依诺他滨(enocitabine)、恩普氨酯(enpromate)、依匹哌啶(epipropidine)、表柔比星(epirubicin)、埃博霉素(epithilone)、环硫雄醇(epitiostanol)、厄布洛唑(erbuloZole)、伊莫德吉(erismodegib)、厄洛替尼(erlotinib)、依索比星(esorubicin)、埃斯波霉素(esperamicin)、雌二醇、雌莫司汀(estramustine)、依他硝唑(etanidazole)、溴化乙锭、2-乙酰肼、依替膦酸盐(etidronate)、依托格鲁(etoglucid)、依托泊苷(etoposide)、依维莫司(everolimus)、依西美坦(exemestane)、法曲唑(fadrozole)、法扎拉滨(fazarabine)、芬维A胺(fenretinide)、非格司亭(filgrastim)、氟尿苷(floxuridine)、氟达拉滨(fludarabine)、氟氢可的松(fludrocortisone)、氟尿嘧啶、氟甲睾酮(fluoxymesterone)、氟西他滨(flurocitabine)、氟他胺(flutamide)、foretinib(氟瑞替尼)、福美司坦(formestane)、磷喹酮(fosquidone)、福莫司汀(fotemustine)、亚叶酸(frolinic acid)、加西托星(gacytosine)、硝酸镓、加仑色替(galunisertib)、加多替尼(gandotinib)、吉非替尼(gefitinib)、格尔德霉素(geldanamycin)、吉西他滨(gemcitabine)、染料木黄酮(genistein)、糖皮质激素、戈舍瑞林(goserelin)、短杆菌肽D(gramicidin D)、除莠霉素(herbimycin)、西托诺(hiltonol)、4-羟基他莫昔芬(4-hydroxytamoxifen)、羟基脲、伊班膦酸盐(ibandronate)、伊达比星(idarubicin)、异环磷酰胺(ifosfamide)、伊莫福新(ilmofosine)、伊马替尼(imatinib)、咪喹莫特(imiquimod)、英丙舒凡(improsulfan)、吲哚莫德(indoximod)、干扰素、异丙铂(iproplatin)、伊立替康(irinotecan)、伊诺替康(ironotecan)、伊沙佐米(ixazomib)、酮替芬(keoxifene)、拉派瑞伐(laherparepvec)、拉美替德(lameotide)、拉帕替尼(lapatinib)、来那度胺(lenalidomide)、来他替尼(lestaurtinib)、来曲唑(letrozole)、甲酰四氢叶酸(leucovorin)、亮丙瑞林(leuprolide)、香菇多糖(lentinan)、左旋咪唑(levamisole)、利罗唑(liarozole)、利多卡因(lidocaine)、利尼法尼(linifanib)、洛美曲(lometrexo)、洛莫司汀(lomustine)、氯尼达明(1onidamine)、洛索蒽醌(losoxantrone)、麻西罗霉素(marcellomycin)、马利佐米(marizomib)、马赛替尼(masitinib)、马索罗酚(masoprocol)、美登素(maytansyne)、美登醇(maytansinol)、氮芥(mechlorethamine)、盐酸氧氮芥、甘露莫司汀(mannomustine)、甲羟孕酮(medroxyprogesterone)、甲地孕酮(megestrol)、美仑孕酮(melengestrol)、美诺立尔(menogaril)、美法仑(melphalan)、美雄烷(mepitiostane)、巯嘌呤、美司钠(mesna)、二甲双胍(metformin)、甲氨蝶呤(methotrexate)、氯苯氨啶(metoprine)、美曲多巴(meturedopa)、光神霉素(mithramycin)、二溴甘露醇(mitobronitol)、米托胍腙(mitoguazone)、二溴卫矛醇(mitolactol)、丝裂霉素、米托司培(mitosper)、米托坦(mitotane)、米托蒽醌(mitoxantrone)、莫托替尼(momelotinib)、莫坦尼(montanide)、莫哌达醇(mopidamol)、莫特塞尼(motesanib)、莫托利莫(motolimod)、霉酚酸、米洛塔格(mylotarg)、nab-紫杉醇、长春瑞滨(navelbine)、来那替尼(neratinib)、尼罗替尼(nilotinib)、尼罗米特(nilutamide)、尼莫司汀(nimustine)、硝曲新(nitracrine)、诺考达唑(nocodazole)、诺加霉素(nogalamycin)、米托恩醌(novantrone)、新恩比兴(novembichin)、奥比珠单抗(obinutuzumab)、奥曲肽(octreotide)、橄榄霉素、奥那司酮(onapristone)、奥马铂(ormaplatin)、奥沙利铂(oxaliplatin)、紫杉醇、帕曲替尼(pacritinib)、帕博西尼(palbociclib)、帕米膦酸(pamidronate)、水鬼蕉碱(pancratistatin)、帕比司他(panobinostat)、帕唑帕尼(pazopanib)、哌加他尼(pegaptanib)、培门冬酶(pegaspargase)、聚乙二醇非格司亭(pegfilgrastim)、聚乙二醇干扰素α-2b、培利替尼(pelitinib)、培美曲塞(pemetrexed)、喷司他丁(pentostatin)、N4-戊氧羰基-5-脱氧-5-氟胞苷、培来霉素(peplomycin)、哌立福辛(perifosine)、苯来美特(phenamet)、苯芥胆甾醇(phenesterine)、匹色替尼(pimasertib)、哌泊溴烷(pipobroman)、哌泊舒凡(piposulfan)、吡柔比星(pirarubicin)、普卡霉素(plicamycin)、足叶草酸(podophyllinicacid)、聚苯丙生(polifeprosan)、泊马度胺(pomalidomide)、卟菲尔钠(porfimer)、泊非霉素(porfromycin)、甲基丝裂霉素(potfiromycin)、泼尼莫司汀(prednimustine)、普鲁卡因(procaine)、丙卡巴肼(procarbazine)、普萘洛尔(propranolol)、蝶罗呤(pteropterin)、嘌呤霉素(puromycin)、三铁阿霉素(quelamycin)、雷替曲塞(raltitrexed)、雷洛昔芬(raloxifene)、雷莫司汀(ranimustine)、雷帕霉素(rapamycin)、拉维霉素(ravidomycin)、雷左生(razoxane)、瑞格拉菲尼(regorafenib)、利塞膦酸盐(risedronate)、瑞喹莫德(resiquimod)、利妥昔单抗、罗多比星(rodorubicin)、罗谷亚胺(rogletimide)、杆孢菌素(roridin)、鲁索替尼(ruxolitinib)、沙芬戈(saringol)、匍枝珊瑚醇(sarcodictyin)、司美替尼(selumetinib)、司马沙尼(semaxanib)、司莫司汀(semustine)、西马莫德(simapimod)、辛曲秦(simtrazene)、西罗莫司(sirolimus)、西佐喃(sizofiran)、索拉菲尼(sorafenib)、司帕磷酸(sparfosate)、司帕霉素(sparsomycin)、锗螺胺(spirogermanium)、螺莫司汀(spiromustine)、螺铂(spiroplatin)、软海绵素(spongistatin)、链褐霉素(streptonigrin)、链脲菌素(streptozocin)、磺氯苯脲(sulofenur)、舒尼替尼(sunitinib)、苏拉明(suramin)、他利霉素(talisomycin)、他莫昔芬(tamoxifen)、泰利莫吉(talimogene)、塔索替尼(tasocitinib)、紫杉醇(taxol)、替加氟(tegafur)、替拉替尼(telatinib)、替洛蒽醌(Teloxantrone)、替莫泊芬(temoporfin)、替莫唑胺(temozolomide)、替西罗莫司(temsirolimus)、替尼泊苷(teniposide)、细交链抱菌酮酸(tenuazonic acid)、替罗昔隆(teroxirone)、睾内酯(testolactone)、睾酮、丁卡因(tetracaine)、泽西他滨(tezacitibine)、萨利多胺(thalidomide)、硫咪嘌呤(thiamiprine)、硫鸟嘌呤、塞替派(thiotepa)、噻唑呋林(tiazofurin)、替鲁膦酸盐(tiludronate)、替拉扎明(tirapazamine)、替他洛辛(titanocene)、替氟扎尼(tivozanib)、托赛拉尼(toceranib)、托法替尼(tofacitinib)、拓扑异构酶抑制剂RFS 2000、拓扑替康(topotecan)、托瑞米芬(toremifene)、拓扎色替(tozasertib)、曲美替尼(trametinib)、曲妥珠单抗、三亚胺醌、维甲酸(tretinoin)、2，2’，2”-三氯三乙胺、三亚乙基三聚氰胺、三亚乙基磷酰胺、三亚乙基硫代磷酰胺、曲洛司坦(trilostane)、三羟甲基三聚氰胺、曲美沙特(trimetrexate)、曲普瑞林(triptorelin)、曲洛磷胺(trofosfamide)、杀结核菌素(tubercidin)、妥维尼布(tuvizanib)、乌拉莫司汀(uracil mustard)、乌苯美司(ubenimex)、优瑞多帕(uredopa)、尿烷、凡德他尼(vandetanib)、伐普肽(vapreotide)、尼达尼布(vargatef)、瓦他拉尼(vatalanib)、维莫非尼(vemurafenib)、维拉曲新(verracurin)、维替泊芬(verteporfin)、长春花碱(vinblastine)、长春新碱(vincristine)、长春地辛(vindesine)、长春匹定(vinepidine)、长春甘酯(vinglycinate)、长春罗新(vinleurosine)、长春瑞滨(vinorelbine)、长春罗定(vinrosidine)、长春利定(vinzolidine)、伏氯唑(vorozole)、维莫德吉(vismodegib)、卡培他滨(xeloda)、凡德他尼(zactima)、折尼铂(zeniplatin)、净司他丁(zinostatin)、阿柏西普(Ziv-aflibercept)、唑来膦酸(zoledronate)和佐柔比星(zorubicin)。
在某些实施方案中，示例性化学治疗剂包括但不限于：细胞因子如ABT-869、ACP-196、ADXS11-001、ADXS31-142、AEE788、AG-490、AM0010、AMN-107、AMP-224、AMP-514、AP24534、ARRY-142886、AST-6、AZD1480、AZD4547、AZD6094、AZD6244、AZD8055、AZD9291、B7-H3、BAFFR、4-1BB、BEZ235、BGT 226、BHG712、BIBF 1120、BIBW2992、BIX 02188、BJG398、BKM-120、BMS-599626、BMS-690154、BMS-777607、BMS-911543、BMS-936558、BMS-936559、BMS-986016、BRAF-V600E、BTLA、BUW078、BYL719、CAL-101、CAL-263、CBI-TMI、CC-1065、CC-4047、CC-5013、CDS、CDX-1127、CEACAM1、CEP-701、CEP-11981、CGM097、Chi Lob7/4、CI-1040、CO-1686、CP-673451、CP-870，893、CpG 7909、CPT-11、CRTAM、CT-011、CTL019、CTLA-4、CUDC-101、CYC116、CYT 387、DCC-2036、DNAM1、E6201、E7080、EGF816、FOLFOX6、G02443714、G-38963、GADS、GC1008、G-CSF、GDC-0032、GDC-0973、GDC-0980、GITR、GM-CSF、GR-MD-02、GSK1059615、GVAX、HVEM(LIGHTR)、IA4、ICAM-1、ICOS、IMC-TR1、IMP321、INC280、INC424、INCB18424、INCB024360、INCB028050、IPH2012、IPI926、IRX-2、ISA 51VG、ITGA4、ITGA6、ITGAD、ITGAE、ITGAL、ITGAM、ITGAX、ITGB 1、ITGB2、ITGB7、JNJ-26483327、Ki8751、KIRDS2、KU-0063794、KW-289LAT、LBH589、LCL161、LGH447、LTBR、LDK378、LEE011、LGX818、LIGHT、LJM716、LY117018、LY2157299、LY294002、LY2940680、M-CSF、MARTI、MDX-1105、MDX-1106、MEDI0562、MEDI4736、MEDI4737、MEDI6383、MEDI6469、MEK162、MG-132、MGCD265、MK-3475、MK-4166、MM-121、MOXR0916、MP470、MPDL3280A、MSB-0010718C、NKG2C、NKG2D、NKp30、NKp44、NKp46、NKp80(KLRF1)、NY-ESO-1、ODC-0879、ODC-0980、ONX-0912、ODC-0941、OSI-027、OSI-930、OSK-1120212、OSK2118436、OSK 2126458、OX40、P529、PAG/Cbp、PD153035、PD173074、PD0325901、PF-299804、PF-02341066、PF-04217903、PF-046915032、PF-05082566、PD98059、Poly(I：C)、PKI-587、PLX4032、PLX4720、PSGL1、PSK、PX-886、Rad-001、RAF265、rHIgM12B7、R07204、RO4987655、RO6895882、RO7009789、SAR 245408、SAR 245409、SB-1317、SB-1518、SB-1578、SELPLG、SF1126、SGX523、SLAM、SLAMF4、SLAMF6、SLAMF7、SLAML_BLAME、SLP-76、SU5402、T2毒素、TEW 7197、TGN1412、TNFR2、TRANCE/RANKL、TriMix-DC、TRP-2、TRX518、TSU-68、VLA1、VLA-6、WYE-354、WZ3146、WZ4002、WZ8040、XL-147、XL-184、XL-228、XL-281、XL-647、XL-756、XL-765、XL-880、钇90/MX-DTPA和YW243.55.S70。
可以与本文公开的化合物联合使用的示例性紫杉醇试剂包括但不限于纳米颗粒白蛋白结合型紫杉醇(ABRAXANE，由Abraxis Bioscience销售)、二十二碳六烯酸结合型紫杉醇(DHA-紫杉醇、Taxoprexin，由Protarga销售)、聚谷氨酸结合型紫杉醇(PG-紫杉醇、paclitaxel poliglumex、CT-2103、XYOTAX，由Cell Therapeutic销售)，肿瘤活化前药(TAP)、ANG 105(与三分子紫杉醇结合的Angiopep-2，由ImmunoGen销售)、紫杉醇-EC-1(与erbB2识别肽EC-1结合的紫杉醇；参见Li等，Biopolymers(2007)87：225-230)以及葡萄糖缀合型紫杉醇(例如，2’紫杉醇甲基2-吡喃葡萄糖基琥珀酸酯，参见Liu等，Bioorganic&Medicinal Chemistry Letters(2007)17：617-620)。
在某些实施方案中，示例性化学治疗剂包括但不限于：
1)(S)-N-((S)-1-环己基-2-((S)-2-(4-(4-氟苯甲酰基)噻唑-2-基)吡咯烷-1-基)-2-氧代乙基)-2-(甲基氨基)丙酰胺；
2)((1R，9S，12S，15R，16E，18R，19R，21R，23S，24E，26E，28E，30S，32S，35R)-1，18-二羟基-12-{(1R)-2-[(1S，3R，4R)-4-(2-羟基乙氧基)-3-甲氧基环己基]-1-甲基乙基}-19，30二甲氧基-15，17，21，23，29，35-六甲基-11，36-二氧杂-4-氮杂三环并[30.3.1.04，9]三十六碳-16，24，26，28-四烯-2，3，10，14，20-五酮)；
3)(S)-1-(4-氯苯基)-7-异丙氧基-6-甲氧基-2-(4-{甲基-[4-(4-甲基-3-氧代哌嗪-1-基)-反式-环己基甲基]-氨基}苯基)-1，4-二氢-2H-异喹啉-3-酮；
4)N-(4-((1R，3S，5S)-3-氨基-5-甲基环己基)吡啶-3-基)-6-(2，6-二氟苯基)-5-氟吡啶甲酰胺；
5)如U.S.8,735,551中所述的抗HER3单克隆抗体或其抗原结合片段，其包含SEQID NO：141的VH和SEQ ID NO：140的VL；
6)(E)-N-羟基-3-(4-(((2-(2-甲基-1H-吲哚-3-基)乙基)氨基)甲基)苯基)丙烯酰胺；
7)(3R)-3-环戊基-3-[4-(7H-吡咯并-[2，3-d]嘧啶-4-基)-1H-吡唑-1-基]丙腈；和/或
8)8-(2，6-二氟-3，5-二甲氧基-苯基)-喹喔啉-5-羧酸(4-二甲基氨基甲基-1H-咪唑-2-基)-酰胺。
在其它实施方案中，示例性化学治疗剂包括但不限于：
1)3-(1H-吲哚-3-基)-4-[2-(4-甲基-1-哌嗪基)-4-喹唑啉基]-1H-吡咯-2，5-二酮；
2)5-(2，4-二羟基-5-异丙基苯基)-N-乙基-4-(4-(吗啉代甲基)苯基)异噁唑-3-甲酰胺；
3)2-甲基-2-(4-(3-甲基-2-氧代-8-(喹啉-3-基)-2，3-二氢-1H-咪唑并[4，5-c]喹啉-1-基)苯基)丙腈(达托利塞(dactolisib))；
4)化合物D(CYP17抑制剂)；
5)4-[3，5-双(三-羟基苯基)-1H-1，2，4-三唑-1-基]-苯甲酸(地拉罗司(defeasirox))；
6)4，4′-(1H-1，2，4-三唑-1-基亚甲基)双苄腈(来曲唑)；
7)(4S，5R)-3-(2′-氨基-2-吗啉代-4′-(三氟甲基)-[4，5′-联嘧啶]-6-基)-4-(羟甲基)-5-甲基噁唑烷-2-酮；
8)(S)-5-(5-氯-1-甲基-2-氧代-1，2-二氢吡啶-3-基)-6-(4-氯苯基)-2-(2，4-二甲氧基嘧啶-5)基)-1-异丙基-5，6-二氢吡咯并[3，4-d]咪唑-4-(1H)-酮；
9)4-[(4-甲基-1-哌嗪基)甲基]-N-[4-甲基-3-[[4-(3-吡啶基)-2-嘧啶基]氨基]苯基]-甲磺酸酯-苯甲酰胺；
10)4-[(R)-6，7-二氢-5H-吡咯并[1，2-c]咪唑-5-基]-3-氟苄腈(奥罗司他(osilodrostat))；
11)N-[6-[(2R，6S)-2，6-二甲基-4-吗啉基]-3-吡啶基]-2-甲基-4′(三氟甲氧基)-[1，1′-联苯]-3-甲酰胺二磷酸盐(磷酸索尼德吉(sonidegib))；
12)(R)-2-(5-(4-(6-苄基-4，5-二甲基哒嗪-3-基)-2-甲基哌嗪-1-基)吡嗪-2-基)丙-2-醇；
13)化合物M(PRLR的人单克隆抗体)；
14)2-(2′，3-二甲基-[2，4′-联吡啶]-5-基)-N-(5-(吡嗪-2-基)吡啶-2-基)乙酰胺；
15)7-环戊基-N，N-二甲基-2-((5-((1R，6S)-9-甲基-4-氧代-3，9-二氮杂双环[4.2.1]壬-3-基)吡啶-2-基)氨基)-7H-吡咯并[2，3-d]嘧啶-6-甲酰胺；
16)化合物P(FGFR2和/或FGFR4抗体药物缀合物，mAb 12425)；
17)化合物Q(M-CSF的Fab单克隆抗体)；
18)N-[(9S，10R，11R，13R)-2，3，10，11，12，13-六氢-10-甲氧基-9-甲基-1-氧代-9，13-环氧-1H，9H-二吲哚并[1，2，3m]吡咯并[3，4-j][1，7]苯并二氮杂环壬四烯-11-基]-N-甲基-苯甲酰胺(米哚妥林(midostaurin))；
19)1-甲基-5-((2-(5-(三氟甲基)-1H-咪唑-2-基)吡啶-4-基)氧基)-N-(4-(三氟甲基)苯基)-1H-苯并[d]咪唑-2-胺；
20)环((4R)-4-(2-氨基乙基氨甲酰基氧基)-L-脯氨酰基-L-苯基甘氨酰基-D-色氨酰基-L-赖氨酰基-4-0-苄基-L-酪氨酰基-L-苯丙氨酰基-)(帕瑞肽二天冬氨酸盐)；
21)1-氨基-5-氟-3-[6-(4-甲基-1-哌嗪基)-1H-苯并咪唑-2-基]-2(1H)-喹啉酮(多韦替尼)；
22)8-(6-甲氧基-吡啶-3-基)-3-甲基-1-(4-哌嗪-1-基-3-三氟甲基-苯基)-1，3-二氢咪唑并[4，5-c]喹啉-2-酮；
23)N6-(2-异丙氧基-5-甲基-4-(1-甲基哌啶-4-基)苯基)-N4-(2-(异丙基磺酰基)苯基)-1H-吡唑并[3，4-d]嘧啶-4，6-二胺；
24)3-(4-(4-((5-氯-4-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)-5-氟-2-甲基苯基)哌啶-1-基]硫杂环丁烷-1，1-二氧化物；
25)5-氯-N2-(2-氟-5-甲基-4-(1-(四氢-2H-吡喃-4-基)哌啶-4-基)苯基)-N4-(5-甲基-1H-)-吡唑-3-基)嘧啶-2，4-二胺；
26)5-氯-N2-(4-(1-乙基哌啶-4-基)-2-氟-5-甲基苯基)-N4-(5-甲基-1H-吡唑-3-基)嘧啶-2，4-二胺；
27)6-[(2S，4R，6E)-4-甲基-2-(甲基氨基)-3-氧代-6-辛烯酸]环孢素D(Amdray、PSC833、[3′-脱氧-3′-氧代-MeBmt]1-[Val]2-环孢菌素(戊司泊达(valspodar)))；
28)N-(4-氯苯基)-4-(4-吡啶甲基)-1-酞嗪胺琥珀酸盐(瓦他拉尼琥珀酸盐)；
29)化合物CC(IDH抑制剂)；
30)(R)-N-(4-(氯二氟甲氧基)苯基)-6-(3-羟基吡咯烷-1-基)-5-(1H-吡唑-5-基)烟酰胺；
31)化合物EE(cRAF抑制剂)；
32)化合物FF(ERK1/2ATP竞争性抑制剂)；和
33)4-((2-(((1R，2R)-2-羟基环己基)氨基)苯并[d]噻唑-6-基)氧基)-N-甲基吡啶甲酰胺。参见例如WO2016/100882，其以引用方式整体并入本文中。
在某些实施方案中，用于联合施用的示例性治疗剂是单克隆抗体或其片段(参见例如Bolliger(1993)Proc.Natl.Acad.Sci.USA 90：6444-6448；Poljak(1994)Structure2：1121-1123)。这些治疗性单克隆抗体和/或其片段包括但不限于抗LAG-3单克隆抗体、抗PD-1抗体、抗PD-L1抗体、抗PD-L2抗体、抗TIM-3抗体、抗CTLA-4抗体、抗TIGIT抗体、抗OX40抗体、抗GITR抗体、阿达木单抗(adalimumab)、阿法替尼(afatinib)、阿夫珠单抗(afutuzumab)、阿仑单抗(alemtuzumab)、艾佐珠单抗、阿维罗单抗、阿西替尼、巴利昔单抗(basiliximab)、巴维昔单抗(bavituximab)、贝利木单抗(belimumab)、贝伐单抗(bevacizumab)、本妥昔单抗、卡那单抗(canakinumab)、塞妥珠单抗(certolizumab)、西妥昔单抗、达利珠单抗(daclizumab)、地诺单抗(denosumab)、杜伐鲁单抗、依库珠单抗(eculizumab)、依法利珠单抗(efalizumab)、艾罗珠单抗(elotuzumab)、福坦替尼(fostamatinib)、吉妥珠单抗奥佐米星(gemtuzumab ozogamicin)、戈利木单抗(golimumab)、替伊莫单抗(ibritumomab tiuxetan)、英夫利昔单抗(infliximab)、易普利单抗、拉姆布罗力珠单抗、拉帕替尼、乐伐替尼(lenvatinib)、利瑞单抗(lirilumab)、莫加木珠单抗(mogamulizumab)、莫维珠单抗(motavizumab)、木利替尼(mubritinib)、那他珠单抗(natalizumab)、尼维单抗、奥比珠单抗、奥法木单抗(ofatumumab)、奥马珠单抗(omalizumab)、帕利珠单抗(palivizumab)、帕尼单抗(panitumumab)、哌加他尼、培罗珠单抗、帕妥珠单抗(pertuzumab)、普利珠单抗(pidilizumab)，雷珠单抗(ranibizumab)、瑞西库单抗(raxibacumab)、利妥木单抗(rilotumumab)、利妥昔单抗、托西珠单抗(tocilizumab)、托西莫单抗(tositumomab)-I-13、曲妥珠单抗、曲利木单抗、厄瑞鲁单抗(urelumab)、优特克单抗(ustekinumab)和法利单抗(varlilumab)。
组合疗法还可以包括施用双特异性抗体。双特异性抗体可用于靶向两种不同的抗原。例如，已使用抗Fc受体/抗肿瘤抗原(例如，Her-2/neu)双特异性抗体将巨噬细胞靶向肿瘤部位。该靶向可以更有效地激活肿瘤特异性反应。这些反应的T细胞臂将通过使用PD-1阻断来增强。或者，可以通过使用结合肿瘤抗原和树突细胞特异性细胞表面标记物的双特异性抗体将抗原直接递送至DC。
可用于激活宿主免疫反应的其它抗体可与本文所述的组合疗法组合使用。这些包括树突细胞表面上的分子，其激活DC功能和抗原呈递。抗CD40抗体能够有效替代T细胞辅助活性(Ridge，J.等(1998)Nature 393：474-478)并且可以与PD-1抗体联合使用(Ito，N.等(2000)Immunobiology 201(5)527-40)。T细胞共刺激分子如CTLA-4(例如，美国专利第5,811,097号)、OX-40(Weinberg，A.等(2000)Immunol 164：2160-2169)、4-1BB(Melero，I.等(1997)Nature Medicine 3：682-685(1997)和ICOS(Hutloff，A.等(1999)Nature 397：262-266)的抗体也可以实现增加的T细胞活化水平。
适用于本文所述的组合物和联合方法的免疫调节剂和疗法包括但不限于：抗T细胞受体抗体，如抗CD3抗体(例如，Nuvion(Protein Design Labs)、OKT3(Johnson&Johnson)或抗CD20抗体Rituxan(IDEC))、抗CD52抗体(例如，CAMPATH 1H(Ilex))、抗CDlla抗体(例如，Xanelim(Genentech))；抗细胞因子或抗细胞因子受体抗体和拮抗剂，如抗IL-2受体抗体(赛尼哌(Zenapax)(Protein Design Labs))、抗IL-6受体抗体(例如，MRA(Chugai))和抗IL-12种抗体(CNT01275(Janssen))、抗TNFα抗体(Remicade(Janssen))或TNF受体拮抗剂(Enbrel(Immunex))、抗IL-6抗体(BE8(Diaclone)和西托昔单抗(siltuximab)(CNT032(Centocor))；以及免疫特异性结合肿瘤相关抗原的抗体(例如，曲妥珠单抗(Genentech))。
本文公开的组合疗法可以进一步与免疫原性剂如癌细胞、纯化的肿瘤抗原(包括重组的蛋白质、肽和碳水化合物分子)、细胞和用编码免疫刺激细胞因子的基因转染的细胞(He等(2004)J.Immunol.173：4919-28)组合。可以使用的肿瘤疫苗的非限制性实例包括黑素瘤抗原的肽，例如gp100、MAGE抗原、Trp-2、MARTI和/或酪氨酸酶的肽，或被转染以表达细胞因子GM-CSF的肿瘤细胞。
本文公开的化合物可以与肿瘤中表达的重组蛋白和/或肽的集合联合使用，以产生对这些蛋白质的免疫反应。这些蛋白质通常被免疫系统视为自身抗原，因此对它们具有耐受性。肿瘤抗原还可以包括蛋白质端粒酶，它是合成染色体端粒所必需的，并且在超过85％的人类癌症中和仅少数体细胞组织中表达(Kim，N等(1994)Science 266：2011-2013)。(可以通过各种手段使这些体细胞组织免受免疫攻击)。肿瘤抗原还可以是在癌细胞中表达的“新抗原”(由于体细胞突变改变蛋白质序列或在两个不相关的序列之间产生融合蛋白(即费城染色体(Philadelphia chromosome)中的bcr-abl)，或是来自B细胞肿瘤的独特型。
本文公开的化合物可以与疫苗接种方案组合。已经设计出许多针对肿瘤疫苗接种的实验策略(参见Rosenberg，S.，2000，Development of Cancer Vaccines，ASCOEducational Book Spring：60-62；Logothetis，C.，2000，ASCO Educational BookSpring：300-302；Khayat，D.2000，ASCO Educational Book Spring：414-428；Foon，K.2000，ASCO Educational Book Spring：730-738；还参见DeVita，V.等(编辑)，1997，Cancer：Principles and Practice of Oncology第五版中的Restifo，N.和Sznol，M.，Cancer Vaccines，第61章，第3023-3043页)。在这些策略的其中一个中，使用自体或同种异体肿瘤细胞制备疫苗。已证明这些细胞疫苗在肿瘤细胞被转导以表达GM-CSF时最有效。GM-CSF已被证明是有关肿瘤疫苗接种的抗原呈递的有效活化剂(Dranoff等(1993)Proc.Natl.Acad.Sci.U.S.A.90：3539-43)。在一些实施方案中，使用由噁性浆细胞产生的免疫球蛋白独特型进行疫苗接种。其它治疗性疫苗包括但不限于sipuleucel-T、gp100疫苗、HPV-16疫苗接种和GVAX胰腺疫苗。
其它肿瘤疫苗可以包括来自涉及人类癌症的病毒(例如人乳头瘤病毒(HPV)、肝炎病毒(HBV和HCV)、卡波西氏疱疹肉瘤病毒(KHSV)和黑素瘤优先表达抗原(PRAME))的蛋白质。在某些实施方案中，疫苗选自病毒载体疫苗、细菌疫苗、细胞疫苗、DNA疫苗、RNA疫苗、肽疫苗或蛋白质疫苗。参见例如Jeffrey Schlom，″Therapeutic Cancer Vaccines：CurrentStatus and Moving Forward，″J Natl Cancer Inst；104∶599-613(2012)。可以与PD-1阻断联合使用的另一种形式的肿瘤特异性抗原是从肿瘤组织本身分离出的纯化热休克蛋白(HSP)。这些热休克蛋白含有来自肿瘤细胞的蛋白质片段，并且这些HSP在递送至抗原呈递细胞时非常有效地引发肿瘤免疫(Suot，R和Srivastava，P(1995)Science 269：1585-1588；Tamura，Y.等(1997)Science 278：117-120)。
可以与本文公开的化合物联合施用的示例性药剂包括治疗性癌症疫苗或过继性T细胞疗法。在某些实施方案中，治疗性癌症疫苗是树突细胞疫苗。树突细胞疫苗可以由自体树突细胞和/或同种异体树突细胞组成。在某些实施方案中，自体或同种异体的树突细胞在施用给受试者之前加载癌抗原。在某些实施方案中，自体或同种异体的树突细胞通过直接施用给受试者来加载癌抗原。在某些实施方案中，过继性T细胞疗法包括自体和/或同种异体T细胞。在某些实施方案中，自体和/或同种异体T细胞靶向肿瘤抗原。
在某些实施方案中，癌症疫苗的非限制性实例包括肿瘤细胞疫苗、抗原疫苗、树突细胞疫苗、DNA疫苗和载体疫苗。抗原疫苗通过使用一种或多种抗原(如肽)来增强免疫系统。抗原疫苗可以对某种类型的癌症具有特异性，因为每种肿瘤类型可以通过特定的抗原谱来鉴定。树突细胞疫苗通常是自体疫苗，并且通常必须针对每个受试者单独制备。树突疫苗的非限制性实例是Sipuleucel-T和DCvax。为了制备DNA疫苗，可以将载体工程化为含有可以注射到受试者中以使DNA被细胞摄取的特定DNA。一旦细胞摄取DNA，DNA将对细胞发出指令以产生特异性抗原，然后可以激发所需的免疫反应。
胰腺癌
可以与本文公开的化合物联合用于治疗胰腺癌的示例性药剂包括但不限于：TAXOL，它是一种白蛋白稳定型纳米颗粒紫杉醇制剂(例如ABRAXANE)或脂质体紫杉醇制剂)；吉西他滨(例如单独或与AXP107-11组合的吉西他滨)；其它化学治疗剂如奥沙利铂、5-氟尿嘧啶、卡培他滨、卢比替康(rubitecan)、盐酸表柔比星、NC-6004、顺铂、多西他赛(例如TAXOTERE)、丝裂霉素C、异环磷酰胺；干扰素；酪氨酸激酶抑制剂(例如，EGFR抑制剂(例如，厄洛替尼、帕尼单抗、西妥昔单抗、尼妥珠单抗)；HER2/neu受体抑制剂(例如曲妥珠单抗)；双激酶抑制剂(例如，博舒替尼、塞卡替尼(saracatinib)、拉帕替尼、凡德他尼)；多激酶抑制剂(例如，索拉非尼、舒尼替尼、XL184、帕唑帕尼)；VEGF抑制剂(如贝伐单抗、AV-951、布立尼布)；放射免疫疗法(例如XR303)；癌症疫苗(例如GVAX、生存素肽)；COX-2抑制剂(例如塞来昔布)；IGF-1受体抑制剂(例如，AMG 479、MK-0646)；mTOR抑制剂(例如依维莫司；替西罗莫司)；IL-6抑制剂(例如CNTO 328)；细胞周期蛋白依赖性激酶抑制剂(例如，P276-00、UCN-01)；能量代谢改变导向(AEMD)化合物(例如，CPI-613)；HDAC抑制剂(例如，伏立诺他)；TRAIL受体2(TR-2)激动剂(例如，考那木单抗)；MEK抑制剂(例如，AS703026、司美替尼、GSK1120212)；Raf/MEK双激酶抑制剂(例如，R05126766)；Notch信号传导抑制剂(例如，MK0752)；单克隆抗体-抗体融合蛋白(例如L19IL2)；姜黄素；HSP90抑制剂(例如，坦螺旋霉素(tanespimycin)、STA-9090)；riL-2；地尼白介素(denileukin diftitox)；拓扑异构酶1抑制剂(例如伊立替康、PEP02)；他汀类(如辛伐他汀)；因子VIla抑制剂(例如，PCI-27483)；AKT抑制剂(例如，RX-0201)；缺氧活化前药(例如，TH-302)；二甲双胍盐酸盐、γ-分泌酶抑制剂(例如，R04929097)；核糖核苷酸还原酶抑制剂(例如3-AP)；免疫毒素(例如HuC242-DM4)；PARP抑制剂(例如，KU-0059436、维利帕尼)；CTLA-4抑制剂(例如，CP-675,206、易普利单抗)；AdVtk疗法；蛋白酶体抑制剂(例如硼替佐米(Velcade)、NPI-0052)；噻唑烷二酮(例如吡格列酮)；NPC-1C；Aurora激酶抑制剂(例如R763/AS703569)、CTGF抑制剂(例如FG-3019)；siG 12D LODER；和放射疗法(例如，螺旋断层放疗、立体定向放射、质子疗法)、手术及其组合。
小细胞肺癌
可以与本文公开的化合物联合用于治疗小细胞肺癌的示例性药剂包括但不限于：依托泊苷、卡铂、顺铂、伊立替康、托泊替康、吉西他滨、脂质体SN-38、苯达莫司汀、替莫唑胺、贝洛替康、NK012、FR901228、夫拉平度(flavopiridol)；酪氨酸激酶抑制剂(例如，EGFR抑制剂(例如厄洛替尼、吉非替尼、西妥昔单抗、帕尼单抗)；多激酶抑制剂(例如索拉非尼，舒尼替尼)；VEGF抑制剂(例如贝伐单抗、凡德他尼)；癌症疫苗(例如GVAX)；Bcl-2抑制剂(例如、奥利默森钠、ABT-263)；蛋白酶体抑制剂(例如硼替佐米(Velcade)、NPI-0052)、紫杉醇或紫杉醇剂；多西他赛；IGF-1受体抑制剂(例如，AMG 479)；HGF/SF抑制剂(例如，AMG 102、MK-0646)；氯喹；Aurora激酶抑制剂(例如，MLN8237)；放射免疫疗法(例如，TF2)；HSP90抑制剂(例如，坦螺旋霉素、STA-9090)；mTOR抑制剂(例如依维莫司)；Ep-CAM/CD3双特异性抗体(例如，MT110)；CK-2抑制剂(例如，CX-4945)；HDAC抑制剂(例如，贝利司他)；SMO拮抗剂(例如，BMS833923)；肽癌症疫苗和放射疗法(例如，调强放射治疗(IMRT)、大分割放射治疗、缺氧引导放射治疗)、手术及其组合。
非小细胞肺癌
可以与本文公开的化合物联合用于治疗非小细胞肺癌的示例性药剂包括但不限于：长春瑞滨、顺铂、多西他赛、培美曲塞二钠、依托泊苷、吉西他滨、卡铂、脂质体SN-38、TLK286、替莫唑胺、托泊替康、培美曲塞二钠、阿扎胞苷、伊立替康、替加氟米拉-奥替拉西(tegafurgimeracil-oteracil)钾、沙帕西他滨(sapacitabine))；酪氨酸激酶抑制剂(例如，EGFR抑制剂(例如，厄洛替尼、吉非替尼、西妥昔单抗、帕尼单抗、勒妥木单抗(necitumumab)、PF-00299804、尼妥珠单抗、R05083945)、MET抑制剂(例如，PF-02341066、ARQ 197)、PI3K激酶抑制剂(例如，XL147、GDC-0941)、Raf/MEK双激酶抑制剂(例如，R05126766)、PI3K/mTOR双激酶抑制剂(例如，XL765)、SRC抑制剂(例如达沙替尼)、双重抑制剂(例如，BIBW 2992、GSK1363089、ZD6474、AZD0530、AG-013736、拉帕替尼、MEHD7945A、利尼法尼)、多激酶抑制剂(例如，索拉非尼、舒尼替尼、帕唑帕尼、AMG 706、XL184、MGCD265、BMS-690514、R935788)、VEGF抑制剂(例如，恩度(endostar)、内皮抑素、贝伐单抗、西地尼布)、BIBF 1120、阿西替尼、tivozanib、AZD2171)、癌症疫苗(例如，BLP25脂质体疫苗、GVAX、表达L523S蛋白的重组DNA和腺病毒)、Bcl-2抑制剂(例如，奥利默森钠)、蛋白酶体抑制剂(例如硼替佐米、卡非佐米、NPI-0052、伊沙佐米)、紫杉醇或紫杉醇剂、多西他赛、IGF-1受体抑制剂(例如，西妥木单抗、MK-0646、OSI906、CP-751，871、BIIB022)、羟氯喹、HSP90抑制剂(例如，坦螺旋霉素、STA-9090、AUY922、XL888)、mTOR抑制剂(例如依维莫司、替西罗莫司、利达氟莫司(ridaforolimus))、Ep-CAM/CD3双特异性抗体(例如，MT110)、CK-2抑制剂(例如，CX-4945)、HDAC抑制剂(例如，MS 275、LBH589、伏立诺他、丙戊酸、FR901228)、DHFR抑制剂(例如，普拉曲沙(pralatrexate))、类视色素(例如，贝沙罗汀、维甲酸)、抗体-药物缀合物(例如，SGN-15)、双膦酸盐(例如，唑来膦酸)、癌症疫苗(例如，belagenpumatucel-L)、低分子量肝素(LMWH)(例如，亭扎肝素、依诺肝素)、GSK1572932A、褪黑激素、塔拉妥芬(talactoferrin)、地美司钠、拓扑异构酶抑制剂(例如氨柔比星、依托泊苷、卡瑞汀)、奈非那韦、西仑吉肽、ErbB3抑制剂(例如MM-121、U3-1287)、生存素抑制剂(例如YM155、LY2181308)、艾日布林(eribulin、)甲磺酸盐、COX-2抑制剂(例如塞来昔布)、培非格司亭(pegfilgrastim)、Polo样激酶1抑制剂(例如，BI 6727)、TRAIL受体2(TR-2)激动剂(例如，CS-1008)、CNGRC肽-TNFα缀合物、二氯乙酸酯(DCA)、HGF抑制剂(例如SCH 900105)、SAR240550、PPAR-γ激动剂(例如CS-7017)、γ-分泌酶抑制剂(例如，R04929097)、表观遗传治疗(例如，5-阿扎胞苷)、硝化甘油、MEK抑制剂(例如，AZD6244)、细胞周期蛋白依赖性激酶抑制剂(例如，UCN-01)、胆固醇-Fus1、抗微管蛋白剂(例如，E7389)、法尼基-OH转移酶抑制剂(例如，洛那法尼(lonafarnib))、免疫毒素(例如，BB-10901、SS1(dsFv)PE38)、磺达肝素、血管破坏剂(例如，A VE8062)、PD-L1抑制剂(例如，MDX-1105、MDX-1106)、β-葡聚糖、NGR-hTNF、EMD 521873、MEK抑制剂(例如，GSK1120212)、埃博霉素类似物(例如伊沙匹隆)、驱动蛋白-纺锤体抑制剂(例如，4SC-205)、端粒靶向剂(例如，KML-001)、P70通路抑制剂(例如，LY2584702)、AKT抑制剂(例如，MK-2206)、血管生成抑制剂(例如，来那度胺)、Notch信号传导抑制剂(例如，OMP-21M18)、放射疗法、手术及其组合。
卵巢癌
可以与本文公开的化合物联合用于治疗卵巢癌的示例性药剂包括但不限于：化学治疗剂(例如，紫杉醇或紫杉醇剂；多西他赛；卡铂；吉西他滨；多柔比星；托泊替康；顺铂；伊立替康、TLK286、异环磷酰胺、奥拉帕尼、奥沙利铂、美法仑、培美曲塞二钠、SJG-136、环磷酰胺、依托泊苷、地西他滨)；胃饥饿素拮抗剂(例如，AEZS-130)、免疫疗法(例如，APC8024、奥戈伏单抗(oregovomab)、OPT-821)、酪氨酸激酶抑制剂(例如，EGFR抑制剂(例如厄洛替尼)、双重抑制剂(例如E7080)、多激酶抑制剂(例如，AZD0530、JI-101、索拉非尼、舒尼替尼、帕唑帕尼)、ON 01910.Na)、VEGF抑制剂(例如，贝伐单抗、BIBF 1120、西地尼布、AZD2171)、PDGFR抑制剂(例如IMC-303)、紫杉醇、拓扑异构酶抑制剂(例如，卡瑞汀、伊立替康)、HDAC抑制剂(例如丙戊酸盐、伏立诺他)、叶酸受体抑制剂(例如，法妥珠单抗(farletuzumab))、血管生成素抑制剂(例如，AMG 386)、埃博霉素类似物(例如伊沙匹隆)、蛋白酶体抑制剂(例如卡非佐米)、IGF-1受体抑制剂(例如，OSI 906、AMG 479)、PARP抑制剂(例如，维利帕尼、AG014699、依尼帕尼、MK-4827)、Aurora激酶抑制剂(例如，MLN8237、ENMD-2076)、血管生成抑制剂(例如来那度胺)、DHFR抑制剂(例如，普拉曲沙)、放射免疫治疗剂(例如，Hu3S 193)、他汀类(例如，洛伐他汀)、拓扑异构酶1抑制剂(例如，NKTR-102)、癌症疫苗(例如，p53合成长肽疫苗、自体OC-DC疫苗)、mTOR抑制剂(例如，替西罗莫司、依维莫司)、BCR/ABL抑制剂(例如伊马替尼)、ET-A受体拮抗剂(例如，ZD4054)、TRAIL受体2(TR-2)激动剂(例如，CS-1008)、HGF/SF抑制剂(例如，AMG102)、EGEN-001、Polo样激酶1抑制剂(例如，BI 6727)、γ-分必酶抑制剂(例如，R04929097)、Wee-1抑制剂(例如，MK-1775)、抗微管蛋白剂(例如，长春瑞滨、E7389)、免疫毒素(例如，地尼白介素)、SB-485232、血管破坏剂(例如，AVE8062)、整联蛋白抑制剂(例如，EMD 525797)、驱动蛋白-纺锤体抑制剂(例如，4SC-205)、瑞复美(revlimid)、HER2抑制剂(例如，MGAH22)、ErrB3抑制剂(例如，MM-121)、放射疗法；及其组合。
骨髓瘤
可以与本文公开的化合物联合施用以治疗骨髓瘤的示例性药剂包括但不限于：沙利度胺类似物(例如来那度胺)、HSCT(Cook，R.(2008)J Manag Care Pharm.14(7增刊)：19-25)、抗TIM-3抗体(Hallett，WHD等(2011)J of American Society for Blood and MarrowTransplantation 17(8)：1133-145)、肿瘤抗原致敏的树突细胞、肿瘤细胞和树突细胞的融合物(例如，电融合)或使用由噁性浆细胞产生的免疫球蛋白独特型进行疫苗接种(综述于Yi，Q.(2009)Cancer J.15(6)：502-10)。
肾细胞癌
可以与本文公开的化合物联合施用以治疗肾细胞癌的示例性药剂包括但不限于：白细胞介素-2或干扰素-α、靶向剂(例如，VEGF抑制剂如VEGF的单克隆抗体，例如贝伐单抗(Rini，B.I.等(2010)J.Clin.Oncol.28(13)：2137-2143))；VEGF酪氨酸激酶抑制剂，如舒尼替尼、索拉非尼、阿西替尼和帕唑帕尼(综述于Pal S.K.等(2014)Clin.Advances inHematology&Oncology 12(2)：90-99))；RNAi抑制剂，或VEGF信号传导的下游介导物的抑制剂，例如哺乳动物雷帕霉素靶蛋白(mTOR)抑制剂，例如依维莫司和替西罗莫司(Hudes，G.等(2007)N.Engl.J.Med.356(22)：2271-2281；Motzer，R.J.等(2008)Lancet 372：449-456)。
慢性髓性白血病
可以与本文公开的化合物联合施用以治疗慢性髓性白血病(CML)的示例性药剂包括但不限于：化学治疗剂(例如，阿糖胞苷、羟基脲、氯法拉滨、美法仑、硫噻吩、氟达拉滨、白消安、依托泊苷、虫草素、喷司他丁、卡培他滨、阿扎胞苷、环磷酰胺、克拉屈滨、拓扑替康)、酪氨酸激酶抑制剂(例如，BCR/ABL抑制剂(例如，伊马替尼、尼罗替尼)、双重抑制剂(例如，达沙替尼、博舒替尼)、多激酶抑制剂(例如，DCC-2036、普纳替尼、索拉非尼、舒尼替尼、RGB-286638))、干扰素α、类固醇、细胞凋亡剂(例如，高三尖杉酯碱(omacetaxinemepesuccinat))、免疫疗法(例如，同种异体CD4+记忆Th1样T细胞/微粒结合型抗CD3/抗CD28、自体细胞因子诱导型杀伤细胞(CIK)、AHN-12)、CD52靶向剂(例如，阿仑单抗)、HSP90抑制剂(例如，坦螺旋霉素、STA-9090、AUY922、XL888)、mTOR抑制剂(例如依维莫司)、SMO拮抗剂(例如，BMS 833923)、核糖核苷酸还原酶抑制剂(例如3-AP)、JAK-2抑制剂(例如INCB018424)、羟氯喹、类视色素(例如芬维A胺)、细胞周期蛋白依赖性激酶抑制剂(例如UCN-01)、HDAC抑制剂(例如贝利司他、伏立诺他、JNJ-26481585)、PARP抑制剂(例如，维利帕尼)、MDM2拮抗剂(例如，R05045337)、Aurora B激酶抑制剂(例如，TAK-901)、放射免疫疗法(例如，锕-225标记的抗CD33抗体HuM195)、Hedgehog抑制剂(例如，PF-04449913)、STAT3抑制剂(例如，OPB-31121)、KB004、癌症疫苗(例如，AG858)、骨髓移植、干细胞移植、放射疗法及其组合。
慢性淋巴细胞性白血病
可以与本文公开的化合物联合施用以治疗慢性淋巴细胞性白血病(CLL)的示例性药剂包括但不限于：化学治疗剂(例如，氟达拉滨、环磷酰胺、多柔比星、长春新碱、苯丁酸氮芥、苯达莫司汀、苯丁酸氮芥、白消安、吉西他滨、美法仑、喷司他丁、米托蒽醌、5-氮杂胞苷、培美曲塞二钠)、酪氨酸激酶抑制剂(例如，EGFR抑制剂(例如厄洛替尼)、BTK抑制剂(例如PCI-32765)、多激酶抑制剂(例如MGCD265、RGB-286638))、CD-20靶向剂(例如利妥昔单抗、奥法木单抗、R05072759、LFB-R603)、CD52靶向剂(例如阿仑单抗)、泼尼松龙、达贝泊汀α、来那度胺、Bcl-2抑制剂(例如ABT-263)、免疫疗法(例如，同种异体CD4+记忆Th1样T细胞/微粒结合型抗CD3/抗CD28、自体细胞因子诱导型杀伤细胞(CIK))、HDAC抑制剂(例如伏立诺他、丙戊酸、LBH589、JNJ-26481585、AR-42)、XIAP抑制剂(例如，AEG35156)、CD-74靶向剂(例如，米拉珠单抗)、mTOR抑制剂(例如依维莫司)、AT-101、免疫毒素(例如，CAT-8015、抗Tac(Fv)-PE38(LMB-2))、CD37靶向剂(例如，TRU-5016)、放射免疫疗法(例如，131-托西莫单抗)、羟氯喹、哌立福辛、SRC抑制剂(例如达沙替尼)、沙利度胺、PI3Kδ抑制剂(例如，CAL-101)、类视色素(例如，芬维A胺)、MDM2拮抗剂(例如，R05045337)、普乐沙福(plerixafbr)、Aurora激酶抑制剂(例如，MLN8237、TAK-901)、蛋白酶体抑制剂(例如硼替佐米)、CD-19靶向剂(例如，MEDI-551、MOR208)、MEK抑制剂(例如ABT-348)、JAK-2抑制剂(例如，INCB018424)、缺氧活化型前药(例如，TH-302)、紫杉醇或紫杉醇剂、HSP90抑制剂、AKT抑制剂(例如，MK2206)、HMG-CoA抑制剂(例如辛伐他汀)、GNKG 186、放射疗法、骨髓移植、干细胞移植及其组合。
急性淋巴细胞性白血病
可以与本文公开的化合物联合施用以治疗急性淋巴细胞性白血病(ALL)的示例性药剂包括但不限于：化学治疗剂(例如，泼尼松龙、地塞米松、长春新碱、天冬酰胺酶、柔红霉素、环磷酰胺、阿糖胞苷、依托泊苷、硫鸟嘌呤、巯基嘌呤、氯法拉滨、脂质体安那霉素、白消安、依托泊苷、卡培他滨、地西他滨、阿扎胞苷、托泊替康、替莫唑胺)、酪氨酸激酶抑制剂(例如BCR/ABL抑制剂(例如伊马替尼、尼罗替尼)、ON 01910.Na、多激酶抑制剂(例如，索拉非尼))、CD-20靶向剂(例如利妥昔单抗)、CD52靶向剂(例如阿仑单抗)、HSP90抑制剂(例如STA-9090)、mTOR抑制剂(例如依维莫司、雷帕霉素)、JAK-2抑制剂(例如，INCB018424)、HER2/neu受体抑制剂(例如曲妥珠单抗)、蛋白酶体抑制剂(例如硼替佐米)、甲氨蝶呤、天冬酰胺酶、CD-22靶向剂(例如，依帕珠单抗、伊诺珠单抗(inotuzumab))、免疫疗法(例如，自体细胞因子诱导型杀伤细胞(CIK)、AHN-12)、兰妥莫单抗(blinatumomab)、细胞周期蛋白依赖性激酶抑制剂(例如，UCN-01)、CD45靶向剂(例如BC8)、MDM2拮抗剂(例如，R05045337)、免疫毒素(例如CAT-8015、DT2219ARL)、HDAC抑制剂(例如，JNJ-26481585)、JVRS-100、紫杉醇或紫杉醇剂、STAT3抑制剂(例如，OPB-31121)、PARP抑制剂(例如维利帕尼)、EZN-2285、骨髓移植、干细胞移植、放射疗法及其组合。
急性髓性白血病
可以与本文公开的化合物联合施用以治疗急性髓性白血病(AML)的示例性药剂包括但不限于：化学治疗剂(例如，阿糖胞苷、柔红霉素、伊达比星、氯法拉滨、地西他滨、伏沙罗新(vosaroxin)、阿扎胞苷、氯法拉滨、利巴韦林、CPX-351、苏消安(treosulfan)、艾西拉滨(elacytarabine)、阿扎胞苷)、酪氨酸激酶抑制剂(如BCR/ABL抑制剂(例如伊马替尼、尼罗替尼)、ON 01910.Na、多激酶抑制剂(例如米哚妥林、SU 11248、奎扎替尼(quizartinib)、索拉非尼(sorafinib)))、免疫毒素(例如，吉妥珠单抗奥佐米星)、DT388IL3融合蛋白、HDAC抑制剂(例如伏立诺他、LBH589)、普乐沙福、mTOR抑制剂(例如依维莫司)、SRC抑制剂(例如达沙替尼)、HSP90抑制剂(例如，STA-9090)、类视色素(例如，贝沙罗汀)、Aurora激酶抑制剂(例如，BI 811283)、JAK-2抑制剂(例如，INCB018424)、Polo样激酶抑制剂(例如，BI 6727)、塞那生(cenersen)、CD45靶向剂(例如，BC8)、细胞周期蛋白依赖性激酶抑制剂(例如，UCN-01)、MDM2拮抗剂(例如，R05045337)、mTOR抑制剂(例如依维莫司)、LY573636-钠、ZRx-101、MLN4924、来那度胺、免疫疗法(例如，AHN-12)、组胺二盐酸盐、骨髓移植、干细胞移植、放射疗法及其组合。
多发性骨髓瘤
可以与本文公开的化合物联合施用以治疗多发性骨髓瘤的示例性药剂包括但不限于：化学治疗剂(例如，美法仑、氨磷汀、环磷酰胺、多柔比星、氯法拉滨、苯达莫司汀、氟达拉滨、阿霉素、SyB L-0501)、沙利度胺、来那度胺、地塞米松、泼尼松、泊马度胺、蛋白酶体抑制剂(例如硼替佐米、卡非佐米、伊沙佐米)、癌症疫苗(例如GVAX)、CD-40靶向剂(例如SGN-40、CHIR-12.12)、哌立福辛、唑来膦酸、免疫疗法(例如MAGE-A3、NY-ES0-1、HuMax-CD38)、HDAC抑制剂(例如伏立诺他、LBH589、AR-42)、阿普利定(aplidin)、细胞周期蛋白依赖性激酶抑制剂(例如，PD-0332991、地那西利)、三氧化二砷、CB3304、HSP90抑制剂(例如KW-2478)、酪氨酸激酶抑制剂(例如EGFR抑制剂(例如西妥昔单抗)、多激酶抑制剂(例如AT9283))、VEGF抑制剂(例如贝伐单抗)、普乐沙福、MEK抑制剂(例如AZD6244)、IPH2101、阿托伐他汀、免疫毒素(例如BB-10901)、NPI-0052、放射免疫治疗(例如，钇Y 90替伊莫单抗)、STAT3抑制剂(例如，OPB-31121)、MLN4924、Aurora激酶抑制剂(例如，ENMD-2076)、IMGN901、ACE-041、CK-2抑制剂(例如，CX-4945)、骨髓移植、干细胞移植、放射疗法及其组合。
前列腺癌
可以与本文公开的化合物联合施用以治疗前列腺癌的示例性药剂包括但不限于：化学治疗剂(例如，多西他赛、卡铂、氟达拉滨)、阿比特龙、激素疗法(例如，氟他胺、比卡鲁胺、尼鲁米特、环丙孕酮乙酸盐、酮康唑、氨鲁米特、阿巴瑞克、地加瑞克、亮丙瑞林、戈舍瑞林、曲普瑞林、布舍瑞林)、酪氨酸激酶抑制剂(例如，双激酶抑制剂(例如拉帕尼布(lapatanib))、多激酶抑制剂(例如索拉非尼、舒尼替尼))、VEGF抑制剂(例如贝伐单抗)、TAK-700、癌症疫苗(例如，BPX-101、PEP223)、来那度胺、TOK-001、IGF-1受体抑制剂(例如，西妥木单抗)、TRC105、Aurora A激酶抑制剂(例如，MLN8237)、蛋白酶体抑制剂(例如，硼替佐米)、OGX-011、放射免疫疗法(例如，HuJ591-GS)、HDAC抑制剂(例如丙戊酸、SB939、LBH589)、羟氯喹、mTOR抑制剂(例如依维莫司)、乳酸多韦替尼、二引哚基甲烷、依非韦仑、OGX-427、染料木黄酮、IMC-303、巴非替尼(bafetinib)、CP-675,206、放射疗法、手术或其组合。
霍奇金淋巴瘤
可以与本文公开的化合物联合用于治疗霍奇金淋巴瘤的示例性药剂包括但不限于：化学治疗剂，例如多柔比星(阿霉素)、博来霉素(Blenoxane)、长春碱(Velban、Velsar)、达卡巴嗪、依托泊苷(Toposar、VePesid)、环磷酰胺(Cytoxan、Neosar)、长春新碱(VincasarPFS、Oncovin)、丙卡巴肼(Matulane)、泼尼松、异环磷酰胺(Ifex)、卡铂(Paraplatin)、氮芥、苯丁酸氮芥、甲泼尼龙(Solu-Medrol)、阿糖胞苷(Cytosar-U)、顺铂(Platinol)、吉西他滨(Gemzar)、长春瑞滨(Navelbine)、奥沙利铂(Eloxatin)、洛莫司汀、米托蒽醌、卡莫司汀、美法仑、苯达莫司汀、来那度胺和长春瑞滨，它们单独或组合使用；本妥昔单抗(Adcetris-CD30抗体药物缀合物)；碘131-CHT25抗体缀合物；HDAC抑制剂(例如伏立诺他)；m-TOR抑制剂(例如，依维莫司、替西罗莫司)；PI3K抑制剂(例如，CAL-101、BAY80-6946、TGR-1202、BKM-120、AMG-319)；JAK/STAT通路抑制剂；Bcl-2抑制剂(例如，维奈托克(venetoclax))；Mcl-1抑制剂；多激酶抑制剂如BAY 43-9006(索拉非尼)；蛋白酶体抑制剂(例如硼替佐米(Velcade)、NPI-0052)；PI3K/HDAC双重靶向抑制剂(例如，CUDC-907)；NF-kB抑制剂；抗PD-1抗体(例如，尼维单抗、培罗珠单抗)；抗CTLA-4抗体(例如，易普利单抗)；抗CD-20抗体(例如利妥昔单抗)；抗CD40抗体；抗CD80抗体；和放射疗法(例如，螺旋断层放疗、立体定向放射、质子疗法)、手术及其组合。
非霍奇金淋巴瘤
可以与本文公开的化合物联合用于治疗非霍奇金淋巴瘤的示例性药剂包括但不限于：化学治疗剂，例如多柔比星(阿霉素)、博来霉素(Blenoxane)、长春碱(Velban、Velsar)、达卡巴嗪、依托泊苷(Toposar、VePesid)、环磷酰胺(Cytoxan、Neosar)、长春新碱(Vincasar PFS、Oncovin)、丙卡巴肼(Matulane)、泼尼松、异环磷酰胺(Ifex)、卡铂(Paraplatin)、氮芥、苯丁酸氮芥、甲泼尼龙(Solu-Medrol)、阿糖胞苷(Cytosar-U)、顺铂(Platinol)、吉西他滨(Gemzar)、长春瑞滨(Navelbine)、奥沙利铂(Eloxatin)、洛莫司汀、米托蒽醌、甲氨蝶呤、卡莫司汀、美法仑、苯达莫司汀、来那度胺和长春瑞滨，它们单独或组合使用；酪氨酸激酶抑制剂(例如，EGFR抑制剂(例如，厄洛替尼、帕尼单抗、西妥昔单抗、尼妥珠单抗)；HDAC抑制剂(例如伏立诺他)；IRAK-4抑制剂；HSP90抑制剂(例如，坦螺旋霉素、STA-9090、CUDC-305)；m-TOR抑制剂(例如，依维莫司、替西罗莫司)；PI3K抑制剂(例如，CAL-101、BAY80-6946、TGR-1202、BKM-120、AMG-319)；JAK/STAT通路抑制剂；AKT抑制剂(例如，RX-0201)；Bcl-2抑制剂(例如，维奈托克)；Mcl-1抑制剂；多激酶抑制剂如BAY 43-9006(索拉非尼)；蛋白酶体抑制剂(例如，硼替佐米(Velcade)、NPI-0052)；PI3K/HDAC双重靶向抑制剂(例如，CUDC-907)；NF-kB抑制剂；BTK抑制剂(例如依鲁替尼)；BET溴结构域抑制剂；抗PD-1抗体(例如，尼维单抗、培罗珠单抗)；抗CTLA-4抗体(例如，易普利单抗)；抗CD-20抗体(例如利妥昔单抗)；抗CD40抗体；抗CD80抗体；和放射疗法(例如，螺旋断层放疗、立体定向放射、质子疗法)、手术及其组合。
在某些实施方案中，本公开的式(I)化合物可以与癌症治疗的非化学方法联合施用。在另一个实施方案中，本公开的式(I)化合物可以与放射疗法联合施用。在另一个实施方案中，本公开的式(I)化合物可以与手术、热消融、聚焦超声疗法、冷冻疗法或这些方法的任何组合联合施用。
在某些实施方案中，本公开的不同化合物可以与本公开的一种或多种其它化合物联合施用。此外，这些组合可以与其它治疗剂(如适用于治疗癌症、免疫或神经疾病的其它药剂，例如上文确定的药剂)联合施用。在某些实施方案中，将一种或多种其它化学治疗剂与本公开的式(I)化合物联合施用提供协同效应。在某些实施方案中，联合施用一种或多种其它化学治疗剂提供累加效应。
药物组合物
在某些实施方案中，本公开提供一种药物组合物，其包含本文公开的式(I)化合物，所述化合物任选地与药学上可接受的载体或稀释剂混合。
本公开还提供了用于将公开的式(I)化合物配制成用于药物施用的方法。
本公开的组合物和方法可用于治疗有此需要的个体。在某些实施方案中，个体是哺乳动物，例如人或非人哺乳动物。当施用给动物(如人类)时，组合物或化合物优选作为包含例如本公开的式(I)化合物和药学上可接受的载体的药物组合物施用。药学上可接受的载体是本领域公知的，并且包括例如水溶液如水或生理缓冲盐水，或者其它溶剂或媒介物如二醇、甘油、油(如橄榄油)或可注射有机酯。在一个优选实施方案中，当这些药物组合物用于人类施用时，特别是用于侵入性施用途径(即，规避透过上皮屏障转运或扩散的途径，如注射或植入)时，水溶液是无热原的，或大体上无热原。可以选择赋形剂以例如实现药剂的延迟释放或选择性地靶向一种或多种细胞、组织或器官。药物组合物可以是剂量单位形式，例如片剂、胶囊(包括易开胶囊和明胶胶囊)、颗粒剂、复水亲液物、粉剂、溶液剂、糖浆剂、栓剂、注射剂等。组合物还可以存在于透皮递送系统(例如皮肤贴剂)中。组合物还可以存在于适于局部施用的溶液(例如滴眼剂)中。
药学上可接受的载体可以含有生理上可接受的试剂，其用于例如稳定化合物(如本公开的式(I)化合物)、增加其溶解度或增加其吸收。这些生理上可接受的试剂包括例如碳水化合物(如葡萄糖、蔗糖或葡聚糖)、抗氧化剂(如抗坏血酸或谷胱甘肽)、螯合剂、低分子量蛋白质或其它稳定剂或赋形剂。药学上可接受的载体(包括生理上可接受的试剂)的选择取决于例如组合物的施用途径。药物组合物的制剂可以是自乳化药物递送系统或自微乳化药物递送系统。药物组合物(制剂)还可以是脂质体或其它聚合物基质，其中可以掺入例如本公开的式(I)化合物。例如，包含磷脂或其它脂质的脂质体是无毒的、生理上可接受的和可代谢的载体，其制备和施用相对简单。
本文使用的短语“药学上可接受的”是指那些在合理医学判断的范围内适用于与人类和动物的组织接触而无过度的毒性、刺激性、过敏反应或与合理的效益/风险比相称的其它问题或并发症的化合物、材料、组合物和/或剂型。
本文所用的短语“药学上可接受的载体”是指药学上可接受的物质、组合物或媒介物，诸如液体或固体填充剂、稀释剂、赋形剂、溶剂或封装材料。每种载体必须是可接受的，其含义为与制剂的其它成分相容并且不有害于患者。可以作为药学上可接受的载体的物质的一些实例包括：(1)糖类，如乳糖、葡萄糖和蔗糖；(2)淀粉，如玉米淀粉和马铃薯淀粉；(3)纤维素及其衍生物，如羧甲基纤维素钠、乙基纤维素和醋酸纤维素；(4)黄蓍胶粉末；(5)麦芽；(6)明胶；(7)滑石；(8)赋形剂，如可可脂和栓剂蜡；(9)油，如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油和豆油；(10)二醇，如丙二醇；(11)多元醇，如甘油、山梨糖醇、甘露醇和聚乙二醇；(12)酯类，如油酸乙酯和月桂酸乙酯；(13)琼脂；(14)缓冲剂，如氢氧化镁和氢氧化铝；(15)藻酸；(16)无热原水；(17)等渗盐水；(18)林格氏溶液(Ringer′s solution)；(19)乙醇；(20)磷酸盐缓冲溶液；和(21)药物制剂中使用的其它无毒相容物质。
药物组合物(制剂)可以通过多种施用途径施用给受试者，包括例如口服(例如，作为在水性或非水性溶液或悬浮液中的浸液、片剂、胶囊(包括易开胶囊和明胶胶囊)、大丸剂、粉剂、颗粒剂、敷用于舌头的糊剂)；通过口腔粘膜吸收(例如，舌下)；经肛门、直肠或阴道(例如，作为阴道栓、乳霜或泡沫)；肠胃外(包括作为例如无菌溶液或混悬液经肌肉内、静脉内、皮下或鞘内)；经鼻；腹膜内；皮下；透皮(例如作为贴在皮肤上的贴剂)；和局部(例如，作为涂抹在皮肤上的乳霜、软膏或喷雾剂，或作为滴眼剂)。化合物也可以被配制成用于吸入。在某些实施方案中，化合物可以简单地溶解或悬浮在无菌水中。适当的施用途径及其适用的组合物的细节可见于例如美国专利第6,110,973号、5,763,493号、5,731,000号、5,541,231号、5,427,798号、5,358,970号和4,172,896号，以及其中引用的专利。
所述制剂可以方便地以单位剂型提供，并且可以通过药学领域中熟知的任何方法来制备。可以与载体材料组合以产生单一剂型的活性成分的量将根据所治疗的宿主和具体施用模式而变化。可以与载体材料组合以产生单一剂型的活性成分的量通常是产生治疗效果的化合物的量。通常，以百分之百计，该量为约1％至约99％的活性成分，优选约5％至约70％，最优选约10％至约30％。
这些制剂或组合物的制备方法包括将活性化合物如本公开的式(I)化合物与载体和任选的一种或多种辅助成分结合的步骤。通常，制剂是通过使本公开的化合物与液体载体或微细固体载体或两者均匀和紧密地结合且然后在必要时使产品成型来制备。
适合于口服施用的本公开的制剂可以呈胶囊(包括易开胶囊和明胶胶囊)、扁囊剂、丸剂、片剂、锭剂(使用调味基质，通常是蔗糖和阿拉伯胶或黄蓍胶)、亲液物、粉剂、颗粒剂形式或为在水性或非水性液体中的溶液或混悬液形式或为水包油型或油包水型乳剂形式，或为酏剂或糖浆剂形式，或为软锭剂形式(使用惰性基质，诸如明胶和甘油，或蔗糖和阿拉伯胶)和/或为漱口剂形式等，它们各自包含预定量的本公开的化合物作为活性成分。组合物或化合物还可以作为大丸剂、药糖剂或糊剂施用。
为了制备用于口服施用的固体剂型(胶囊(包括易开胶囊和明胶胶囊)、片剂、丸剂、糖包衣片、粉剂、颗粒剂等)，将活性成分与一种或多种药学上可接受的载体混合，诸如柠檬酸钠或磷酸二钙和/或任何如下成分：(1)填充剂或增量剂，如淀粉、乳糖、蔗糖、葡萄糖、甘露糖醇和/或硅酸；(2)粘合剂，如(例如)羧甲基纤维素、藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和/或阿拉伯胶；(3)保湿剂，如甘油；(4)崩解剂，如琼脂、碳酸钙、马铃薯或木薯淀粉、藻酸、某些硅酸盐和碳酸钠；(5)溶解阻滞剂，如石蜡；(6)吸收加速剂，如季铵化合物；(7)湿润剂，如(例如)鲸蜡醇和单硬脂酸甘油酯；(8)吸收剂，如高岭土和膨润土；(9)润滑剂，如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠及其混合物；(10)络合剂，如改性和未改性环糊精；和(11)着色剂。就胶囊(包括易开胶囊和明胶胶囊)、片剂和丸剂而言，药物组合物还可以包含缓冲剂。使用诸如乳糖或奶糖以及高分子量聚乙二醇等赋形剂时，相似类型的固体组合物还可以在软质和硬质填充明胶胶囊中用作填充剂。
可以通过任选与一种或多种辅助成分一起压制或模制来制备片剂。可以使用粘合剂(例如，明胶或羟丙基甲基纤维素)、润滑剂、惰性稀释剂、防腐剂、崩解剂(例如，羟乙酸淀粉钠或交联羧甲基纤维素钠)、表面活性剂或分散剂来制备压制片剂。模制片剂可以通过在适当的机器中模制被惰性液体稀释剂润湿的粉末状化合物的混合物而制成。
可以任选地对药物组合物的片剂和其它固体剂型如糖包衣片、胶囊(包括易开胶囊和明胶胶囊)、丸剂和颗粒剂刻痕，或使用制药领域中熟知的包衣和壳层如肠溶衣和其它包衣制备。它们还可以使用例如不同比例的羟丙基甲基纤维素(以提供所需的释放曲线)、其它聚合物基质、脂质体和/或微球体进行配制，以便提供其中的活性成分的缓慢或控制释放。可以通过例如滤过细菌截留过滤器或通过以可以在使用前立即溶解在无菌水或一些其它无菌可注射介质中的无菌固体组合物形式掺入灭菌剂而将它们灭菌。这些组合物还可以任选地含有遮光剂，并且可以是仅仅或优选在肠道的一定部位任选地以延迟方式释放活性成分的组合物。可使用的包埋组合物的实例包括聚合物物质和蜡。在适当的时候，活性成分还可以呈含有一种或多种上述赋形剂的微囊封形式。
可用于口服的液体剂型包括药物学上可接受的乳剂、复水亲液物、微乳剂、溶液剂、混悬剂、糖浆剂和酏剂。除活性成分以外，液体剂型还可以包含本领域中常用的惰性稀释剂，如(例如)水或其它溶剂、环糊精和其衍生物；增溶剂和乳化剂，如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苄酯、丙二醇、1，3-丁二醇、油类(特别是棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油和芝麻籽油)、甘油、四氢糠醇、聚乙二醇和山梨糖醇酐脂肪酸酯及其混合物。
除了惰性稀释剂，口服组合物还可以包括佐剂，诸如润湿剂、乳化剂和悬浮剂、甜味剂、调味剂、着色剂、芳香剂和防腐剂。
除了活性化合物以外，混悬剂还可以含有悬浮剂，例如乙氧基化异硬脂醇、聚氧乙烯山梨糖醇和山梨糖醇酐酯、微晶纤维素、偏氢氧化铝、膨润土、琼脂和黄蓍胶及其混合物。
用于直肠、阴道或尿道施用的药物组合物的制剂可以呈栓剂形式，其可以通过将一种或多种活性化合物与一种或多种合适的无刺激性赋形剂或载体(包括例如可可脂、聚乙二醇、栓剂蜡或水杨酸酯)混合来制备，并且在室温下为固体，而在体温下为液体，因此在直肠或阴道腔内融化并释放活性化合物。
用于施用到口中的药物组合物的制剂可以呈漱口剂、口腔喷雾剂或口用软膏的形式。
可选地或另外，可以将组合物配制成用于经由导管、支架、线材或其它腔内装置递送。通过这些装置递送对于递送至膀胱、尿道、输尿管、直肠或肠道可以尤其有用。
适合于阴道施用的制剂还包括含有本领域已知的适当载体的阴道栓、棉塞、乳霜、凝胶、糊剂、泡沫或喷雾制剂。
用于局部或透皮施用的剂型包括粉剂、喷雾剂、软膏、糊剂、乳霜、洗剂、凝胶、溶液剂、贴剂和吸入剂。可以在无菌条件下将活性化合物与药学上可接受的载体和可能需要的任何防腐剂、缓冲剂或推进剂混合。
除活性化合物外，软膏、糊剂、乳霜和凝胶可以含有赋形剂，例如动物和植物脂肪、油、蜡、石蜡、淀粉、黄蓍胶、纤维素衍生物、聚乙二醇、硅酮、膨润土、硅酸、滑石和氧化锌或其混合物。
除活性化合物外，粉剂和喷雾剂可以含有赋形剂，例如乳糖、滑石、硅酸、氢氧化铝、硅酸钙和聚酰胺粉末或这些物质的混合物。喷雾剂可以另外含有常规推进剂，例如氯氟烃和挥发性未被取代的烃类如丁烷和丙烷。
透皮贴剂具有将本公开化合物受控递送至身体的附加优点。这些剂型可以通过将活性化合物溶解或分散在适当的介质中来制备。还可以使用吸收促进剂来增加化合物透过皮肤的通量。可以通过提供速率控制膜或将化合物分散在聚合物基质或凝胶中来控制该通量的速率。
在本公开的范围内还考虑了眼科制剂、眼用膏剂、粉剂、溶液剂等。示例性眼科制剂描述于美国公开第2005/0080056号、2005/0059744号、2005/0031697号和2005/004074号以及美国专利第6,583,124号中，它们的公开内容以引用方式整体并入本文。如果需要，液体眼科制剂具有与泪液、房水或玻璃体液相似的性质或与这些液体相容。优选的施用途径是局部施用(例如，局部施用如滴眼剂，或通过植入物施用)。
在本公开的范围内还考虑了栓剂。
本文所用的短语“肠胃外施用”和“经胃肠外施用”是指除肠内和局部施用以外的施用方式，通常通过注射进行，并且包括但不限于静脉内、肌肉内、动脉内、鞘内、囊内、眼眶内、心内、皮内、腹膜内、经气管、皮下、表皮下、关节内、囊下、蛛网膜下、脊柱内和胸骨内注射和输注。
适合于肠胃外施用的药物组合物包含与一种或多种药学上可接受的无菌等渗水溶液或非水溶液、分散液、混悬液或乳液或可以在即将使用前重构成无菌可注射溶液或分散液的无菌粉末组合的一种或多种活性化合物，其可以包含抗氧化剂、缓冲剂、抑菌剂、使制剂与预期接受者的血液等渗的溶质或悬浮剂或增稠剂。
可以用于本公开的药物组合物中的适合的水性和非水性载体的实例包括水、乙醇、多元醇(如甘油、丙二醇、聚乙二醇等)和其适合的混合物、植物油如橄榄油，以及可注射有机酯如油酸乙酯。可以通过例如使用包衣材料例如卵磷脂、在分散液的情况下保持所需粒度和使用表面活性剂来保持适当的流动性。
这些组合物还可以包含佐剂如防腐剂、润湿剂、乳化剂和分散剂。可以通过包含各种抗菌剂和抗真菌剂例如对羟基苯甲酸酯、氯丁醇、苯酚山梨酸等来确保防止微生物作用。还可以期望在组合物中包括等渗剂，例如糖、氯化钠等。另外，可注射药物形式的延长吸收可以通过包含延迟吸收的试剂如单硬脂酸铝和明胶来实现。
在某些情况下，为了延长药物的作用，希望减缓来自皮下或肌肉内注射的药物的吸收。这可以通过使用具有不良水溶性的结晶或非晶形材料的液体混悬剂来实现。药物的吸收速率则取决于其溶解速率，而溶解速率可以取决于晶体尺寸和结晶形式。或者，通过将药物溶解或悬浮在油性媒介物中来实现肠胃外施用的药物形式的延迟吸收。
可注射储库剂型是通过形成主题化合物在生物可降解聚合物如聚丙交酯-聚乙交酯中的微胶囊基质而制成。根据药物对聚合物比和所用特定聚合物的性质，可以控制药物释放的速率。其它生物可降解聚合物的实例包括聚(原酸酯)和聚(酸酐)。还通过将药物包埋在与体组织相容的脂质体或微乳剂中来制备储库型可注射制剂。
为了用于本公开的方法，活性化合物可以单独给药或作为药物组合物给药，该药物组合物含有例如与药学上可接受的载体组合的0.1至99.5％(更优选0.5至90％)的活性成分。
还可以通过可充电或可生物降解的装置提供引入方法。近年来，已经开发并在体内测试了各种缓释聚合物装置用于药物(包括蛋白质生物药物)的控制递送。多种生物相容性聚合物(包括水凝胶)，包括可生物降解和不可降解的聚合物，可用于形成用来在特定靶位点持续释放化合物的植入物。
药物组合物中的活性成分的实际剂量水平可以变化，以便获取有效实现针对特定患者、组合物和施用方式的所需治疗反应而对患者无毒的活性成分的量。
所选的剂量水平将取决于多种因素，包括特定化合物的活性或所用化合物或其酯、盐或酰胺的组合、施用途径、施用时间、所用的特定化合物的排泄速率、治疗持续时间、与所用的特定化合物组合使用的其它药物、化合物和/或物质、所治疗的患者的年龄、性别、体重、病情、一般健康状况和既往病史，以及医学领域众所周知的类似因素。
具有本领域普通技术的医生或兽医可以容易地确定和开出治疗有效量的所需药物组合物。例如，医生或兽医可以将药物组合物或化合物的初始剂量确定在低于实现所需治疗效果所需要的水平，并逐渐增加剂量直至实现所需效果。“治疗有效量”是指足以引发所需治疗效果的化合物浓度。通常应理解，化合物的有效量将根据受试者的体重、性别、年龄和病史而变化。影响有效量的其它因素可以包括但不限于患者疾病的严重程度、所治疗的病症、化合物的稳定性以及与本公开的式(I)化合物一起施用的另一种类型的治疗剂(如果需要)。可以通过多次施用药剂递送更大的总剂量。确定功效和剂量的方法是本领域技术人员已知的(Isselbacher等(1996)Harrison′s Principles of Internal Medicine第13版，1814-1882，其以引用方式并入本文)。
通常，在本公开的组合物和方法中使用的活性化合物的合适日剂量将是有效产生治疗效果的最低剂量的化合物量。这种有效剂量通常取决于上述因素。
如果需要，活性化合物的有效日剂量可以作为一个、两个、三个、四个、五个、六个或更多个亚剂量，在一天中以适当的时间间隔任选地以单位剂型分开施用。在本公开的某些实施方案中，活性化合物可以每天施用两次或三次。在优选的实施方案中，活性化合物每天施用一次。
接受该治疗的患者是任何有需要的动物，包括灵长类动物，特别是人类，以及其它哺乳动物如马、牛、猪和绵羊；和一般的家禽和宠物。
湿润剂、乳化剂和润滑剂(诸如十二烷基硫酸钠和硬脂酸镁)以及着色剂、释放剂、包衣剂、甜味剂、调味剂和芳香剂、防腐剂和抗氧化剂也可以存在于组合物中。
药学上可接受的抗氧化剂的实例包括：(1)水溶性抗氧化剂，如抗坏血酸、盐酸半胱氨酸、硫酸氢钠、偏亚硫酸氢钠、亚硫酸钠等；(2)油溶性抗氧化剂，如抗坏血酸棕榈酸酯、丁基化羟苯甲醚(BHA)、丁羟甲苯(BHT)、卵磷脂、没食子酸丙酯、α-生育酚等；和(3)金属螯合剂，如柠檬酸、乙二胺四乙酸(EDTA)、山梨糖醇、酒石酸、磷酸等。
除非另有规定，否则本文所使用的所有技术和科技术语具有如本文标的物所属技术领域的技术人员通常所理解的相同含义。如本文中所用，提供以下定义以便于理解本公开。
术语“酰基”是本领域公认的并且是指由通式烃基C(O)-，优选烷基C(O)-表示的基团。酰基包括-C(O)CH3、-C(O)CH2CH3等。
“烷基”或“烷烃”是完全饱和的直链或支链非芳族烃。通常，除非另外定义，否则直链或支链烷基具有1至约20个碳原子，优选1至约10个碳原子。直链和支链烷基的实例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、戊基、己基、戊基和辛基。C1-C6直链或支链烷基也称为“低级烷基”。烷基可以在化合价允许的一个或多个位置任选地被取代。这些任选的取代基包括，例如，卤素、叠氮化物、烷基、芳烷基、烯基、炔基、环烷基、羟基、烷氧基、氨基、硝基、巯基、亚氨基、酰胺基、膦酸酯、次膦酸酯、羰基、羧基、甲硅烷基、醚、烷硫基、磺酰基、磺酰胺基、酮、醛、酯、杂环基、芳族或杂芳族部分、-CF3、-CN等。
本文所用的术语“芳基”包括被取代或未取代的单环芳族基团，其中每个环原子是碳。优选地，该环是5元至7元环，更优选是6元环。术语“芳基”还包括具有两个或更多个环的多环系统，其中两个相邻环共用两个或更多个碳，其中至少一个环是芳族环，例如，其它环可以是环烷基、环烯基、环炔基、芳基、杂芳基和/或杂环基。芳基包括苯、萘、菲、苯酚、苯胺等。
“环烷基”是完全饱和的环烃。“环烷基”包括单环和双环。通常，除非另外定义，否则单环环烷基具有3至约10个碳原子，更通常具有3至8个碳原子。双环环烷基的第二个环可选自饱和、不饱和和芳族环。环烷基包括双环分子，其中两个环之间共有一个、两个或三个或更多个原子。术语“稠合环烷基”是指双环环烷基，其中每个环与另一个环共享两个相邻的原子。稠合双环环烷基的第二个环可选自饱和、不饱和和芳族环。“环烯基”是含有一个或多个双键的环烃。环烷基可以在化合价允许的一个或多个位置被本文所述的任何任选的取代基取代。环烷基包括但不限于环丙基、环丁基、环戊基和环己基。
如本文中所用，术语“羧基”或“羧酸”是指由式-CO2H表示的基团。术语“羧酸根”是指由式-(CO2)-表示的基团。
如本文中所用，术语“胍基”是指NH-C(＝NH)-NH2基团。
术语“杂芳基(heteroaryl)”和“杂芳基(hetaryl)”包括被取代或未取代的非芳族单环结构，优选5至7元环，更优选5至6元环，其环结构包括至少一个杂原子，优选一至四个杂原子，更优选一个或两个杂原子。术语“杂芳基(heteroaryl)”和“杂芳基(hetaryl)”还包括具有两个或更多个环的多环系统，其中两个相邻环共用两个或更多个碳，其中至少一个环是杂芳族环，例如，其它环可以是环烷基、环烯基、环炔基、芳基、杂芳基和/或杂环基。杂芳基包括，例如，吡咯、呋喃、噻吩、咪唑、噁唑、噻唑、吡唑、吡啶、吡嗪、哒嗪、吲哚、1，2，4-噁二唑、1，2，4-噻二唑、1，3，4-噁二唑、1，3，4-噻二唑、苯并咪唑、嘧啶等。杂芳基可以在化合价允许的一个或多个位置被本文所述的任何任选的取代基取代。
本文所用的术语“杂原子”是指除碳或氢以外的任何元素的原子。优选的杂原子是氮、氧和硫。
术语“杂环基”、“杂环”和“杂环状”是指被取代或未取代的非芳族环结构，优选3至10元环，更优选3至7元环，其环结构包括至少一个杂原子，优选一至四个杂原子，更优选一个或两个杂原子。术语“杂环基”和“杂环”还包括具有两个或更多个环的多环系统，其中两个相邻环共用两个或更多个碳，其中至少一个环是杂环，例如，其它环可以是环烷基、环烯基、环炔基、芳基、杂芳基和/或杂环基。杂环基包括例如哌啶、哌嗪、吡咯烷、吗啉、氮杂环庚烷、氮杂环丁烷、2，3-二氢苯并[b][1，4]二噁英、四氢-2H-吡喃、内酯、内酰胺等。杂环基可以在化合价允许的情况下任选地被取代。
如本文中所用，术语“羟基(hydroxy)”或“羟基(hydroxyl)”是指-OH基团。
当与化学部分(如酰基、酰氧基、烷基、烯基、炔基或烷氧基)结合使用时，术语“低级”意在包括取代基中具有十个或更少非氢原子，优选六个或更少非氢原子的基团。例如，“低级烷基”是指含有10个或更少碳原子(优选6个或更少)的烷基。在某些实施方案中，本文所定义的酰基、酰氧基、烷基、烯基、炔基或烷氧基取代基分别是低级酰基、低级酰氧基、低级烷基、低级烯基、低级炔基或低级烷氧基，无论它们单独出现还是与其它取代基组合出现，例如在羟基烷基和芳烷基的叙述中(在此情况下，例如，当计数烷基取代基中的碳原子时，不计数芳基内的原子)。
术语“被取代的”是指具有取代主链的一个或多个碳上的氢的取代基的部分。应当理解，“取代”或“被......取代”包括隐含的条件，即这种取代符合被取代原子和取代基的允许的化合价，并且取代产生稳定的化合物，例如，该化合物不会自发地通过例如重排、环化、消去等进行转化。如本文中所用，术语“被取代的”意图包括有机化合物的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、芳族和非芳族取代基。对于合适的有机化合物，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，杂原子如氮可以具有氢取代基和/或本文所述的有机化合物的满足杂原子化合价的任何可允许的取代基。取代基可以包括本文所述的任何取代基，例如，卤素、羟基、羰基(如羧基、烷氧基羰基、甲酰基或酰基)、硫代羰基(如硫代酯、硫代乙酸酯或硫代甲酸酯)、烷氧基、磷酰基、磷酸酯、膦酸酯、次膦酸酯、氨基、酰胺基、脒、亚胺、氰基、硝基、叠氮基、巯基、烷硫基、硫酸酯、磺酸酯、氨磺酰基、磺酰胺基、磺酰基、杂环基、芳烷基或芳族或杂芳族部分。本领域技术人员将理解，取代基本身可以视情况被取代。除非特别说明为“未取代的”，否则在本文中提及化学部分应理解为包括取代的变体。例如，提及“芳基”基团或部分隐含地包括取代的和未取代的变体。
如本文中所用，“预防”病症或疾病的治疗剂是指一种化合物，其在统计样品中相对于未经治疗的对照样品减少治疗样品中病症或疾病的发生，或相对于未经治疗的对照样品延迟病症或疾病的一种或多种症状的发作或降低其严重程度。
术语“治疗”包括预防性和/或治疗性治疗。术语“预防性或治疗性”治疗是本领域公认的，并且包括向宿主施用一种或多种主题组合物。如果治疗是在临床表现出不想要的病状(例如，宿主动物的疾病或其它不想要的状态)之前施用，那么它是预防性的(即，它使宿主免于发展不想要的病状)，而如果治疗是在表现出不想要的状况之后施用，那么它是治疗性的(即，它旨在减少、改善或稳定现有的不想要的状况或其副作用)。
术语“前药”旨在涵盖在生理条件下转化为本公开的治疗活性剂(例如，式(I)化合物)的化合物。制备前药的常用方法是包括一个或多个选定的部分，它们在生理条件下水解以显示所需的分子。在其它实施方案中，前药通过宿主动物的酶活性转化。例如，酯或碳酸酯(例如，醇或羧酸的酯或碳酸酯)是本公开的优选前药。在某些实施方案中，上述制剂中的一些或全部式(I)化合物可以用合适的相应前药替代，例如其中母体化合物中的羟基以酯或碳酸酯形式存在或母体化合物中的羧酸以酯形式存在。
如本文中所用，术语“包含(comprise)”或“包含(comprising)”通常以包括的含义使用，也就是说允许存在一种或多种另外的(未指定的)特征或组分。
如本文中所用，术语“包括”以及其它形式，例如“包括(include)”、“包括(includes)”和“包括(included)”不是限制性的。
如本文中所用，术语“氨基酸”是指同时含有氨基和羧基的分子，并且包括其盐、酯、其各种盐的组合以及互变异构形式。在溶液中，在中性pH下，氨基酸的氨基和酸基可以交换质子而形成总体上中性的双电离实体，其被确定为两性离子。在一些实施方案中，氨基酸是α-氨基酸、β-氨基酸、γ-氨基酸或6-氨基酸，包括其立体异构体和外消旋体。如本文中所用，术语“L-氨基酸”表示在α-碳周围具有左旋构型的α-氨基酸，即具有L构型的通式CH(COOH)(NH2)-(侧链)的羧酸。术语“D-氨基酸”类似地表示通式CH(COOH)(NH2)-(侧链)的羧酸，其在α-碳周围具有右旋构型。L-氨基酸的侧链可以包括天然存在的和非天然存在的部分。非天然存在的(即，非天然)氨基酸侧链是在例如氨基酸类似物中用于代替天然存在的氨基酸侧链的部分。
如本文所用的“氨基酸残基”是指与母体氨基酸具有结构相似性的部分。氨基酸残基可以通过残基的氨基或残基的羧酸酯基共价结合至另一个化学部分(即，-NH2或-OH的氢原子被连接至另一个化学部分的键取代)。
氨基酸包括大多数生物有机体在蛋白质合成中使用的二十种标准氨基酸。非天然氨基酸残基可以选自但不限于α和α-二取代氨基酸、N-烷基氨基酸和被低级烷基、芳烷基、羟基、芳基、芳氧基、杂芳烷基或酰基取代的天然氨基酸。
例如，赖氨酸可以被取代而形成非天然氨基酸，例如，在其侧链的碳原子上被取代，或者通过其末端NH2基团的单-或二烷基化(例如，其中赖氨酸侧链的氨基与其取代基连接一起形成杂环，例如哌啶或吡咯烷)。在另一个实例中，赖氨酸侧链的末端氨基可以如在卡培霉定(capreomycidine)中一样与氨基酸主链形成环。赖氨酸的其它非天然衍生物包括高赖氨酸和去甲赖氨酸。赖氨酸的侧链可以替代地被第二个氨基取代。在另一个实例中，赖氨酸侧链的烷基部分可以并入碳环结构中以形成半刚性类似物，例如环己基或环戊基。
在整个说明书和权利要求书中，式(I)化合物中提及的“L-苏氨酸残基”和/或“L-苏氨酸的侧链”和/或其制备可以由下式中的任何一个表示。
在某些实施方案中，非天然氨基酸可以是具有一个或多个双键的天然氨基酸的衍生物。
在其它示例性实施方案中，在苏氨酸中，β-甲基可以被乙基、苯基或其它高级烷基取代。在组氨酸中，咪唑部分可以被取代，或者侧链的亚烷基主链可以被取代。
非天然氨基酸的其它实例包括高丝氨酸和天然氨基酸的同源物。
在其它示例性实施方案中，非天然氨基酸可以在α位烷基化(例如，甲基化)。
非天然氨基酸的其它实例包括α，β-脱氢氨基酸类似物和β，γ-脱氢氨基酸类似物。
其它示例性氨基酸包括青霉胺和β-甲氧基缬氨酸。
非天然氨基酸的其它实例包括其中侧链包含氨基、烷基氨基、酰基氨基、-COO-烷基、环烷基、杂环基、杂芳基、胍基、(环烷基)烷基、(杂环基)烷基和(杂芳基)烷基的氨基酸。
“修饰的N端氨基”和“修饰的C端羧基”意指氨基或羧基被改变。
N端氨基的修饰优选具有通式-NRxRy；其中Rx是氢或烷基，Ry是烷基、烯基、-C(＝NH)NH2、炔基或酰基。
N端修饰的实例包括但不限于乙酰化、甲酰化或鸟苷酸化的N末端。
C端羧基的修饰优选具有通式CORz(Rz取代最后一个氨基酸的羟基)；其中Rz是-NRbRc、烷氧基、氨基或酰亚胺。例如，C末端可以被酯化或酰胺化。
本公开包括本公开化合物的药学上可接受的盐及其在本公开的组合物和方法中的用途。在某些实施方案中，本公开所预期的盐包括但不限于烷基、二烷基、三烷基或四烷基铵盐。在某些实施方案中，本公开所预期的盐包括但不限于L-精氨酸、苯乙苄胺(benenthamine)、苄星青霉素、甜菜碱、氢氧化钙、胆碱、癸醇、二乙醇胺、二乙胺、2-(二乙基氨基)乙醇、乙醇胺、乙二胺、N-甲基葡糖胺、海巴明(hydrabamine)、1H-咪唑、锂、L-赖氨酸、镁、4-(2-羟乙基)吗啉、哌嗪、钾、1-(2-羟乙基)吡咯烷、钠、三乙醇胺、氨丁三醇和锌盐。在某些实施方案中，本公开所预期的盐包括但不限于Na、Ca、K、Mg、Zn或其它金属盐。
药学上可接受的酸加成盐还可以作为各种溶剂化物存在，例如与水、甲醇、乙醇、二甲基甲酰胺等的溶剂化物。还可以制备这些溶剂化物的混合物。这种溶剂化物的来源可以是结晶溶剂、在制备或结晶的溶剂中固有的或是这种溶剂偶然形成的。
“药学上可接受的”意指可用于制备通常安全、无毒并在生物学上或其它方面适用的药物组合物的物质，并且包括对于兽用和人类药物使用而言可接受的物质。
术语“立体异构体”是指例如本公开化合物的任何对映异构体、非对映体或几何异构体。当本公开的化合物是手性时，它们可以以外消旋或光学活性形式存在。由于根据本公开的化合物的外消旋体或立体异构体的药物活性可能不同，因此可能需要使用富集其中一种对映体的化合物。在这些情况下，最终产物或甚至中间体可以通过本领域技术人员已知的化学或物理方法分离成对映体化合物，或甚至在合成中原样使用。在外消旋胺的情况下，通过使混合物与光学活性拆分剂反应形成非对映体。合适的拆分剂的实例是光学活性酸，例如R和S型酒石酸、二乙酰基酒石酸、二苯甲酰基酒石酸、扁桃酸、苹果酸、乳酸、合适的N-保护型氨基酸(例如N-苯甲酰脯氨酸或N-苯磺酰脯氨酸)，或各种光学活性的樟脑磺酸。借助于光学活性拆分剂(例如，固定在硅胶上的二硝基苯甲酰苯基甘氨酸、三乙酸纤维素或其它碳水化合物衍生物或手性衍生的甲基丙烯酸酯聚合物)的色谱对映体拆分也是有利的。
在某些实施方案中，本公开的化合物可以是外消旋的。在某些实施方案中，本公开的化合物可以富集一种对映体。例如，本公开的式(I)化合物可以具有大于30％ee、40％ee、50％ee、60％ee、70％ee、80％ee、90％ee或甚至95％ee或更大的ee。在某些实施方案中，本公开的化合物可以具有多于一个立构中心。在某些这样的实施方案中，本公开的化合物可以富集一种或多种非对映体。例如，本公开的式(I)化合物可以具有大于30％de、40％de、50％de、60％de、70％de、80％de、90％de或甚至95％de或更大的de。
术语“受试者”包括哺乳动物(尤其是人)和其它动物如家畜(例如家养宠物，包括猫和狗)和非家畜(例如野生动物)。
在整个说明书和权利要求书中，通过下表中指定的常规三字母缩写标识天然存在的氨基酸(L型)。
表4(氨基酸编码)
| 名称 | 3字母编码 | 名称 | 3字母编码 |
| 丙氨酸 | Ala | 赖氨酸 | Lys |
| 精氨酸 | Arg | 甲硫氨酸 | Met |
| 天冬酰胺 | Asn | 苯丙氨酸 | Phe |
| 天冬氨酸 | Asp | 脯氨酸 | Pro |
| 谷氨酸 | Glu | 丝氨酸 | Ser |
| 谷氨酰胺 | Gln | 苏氨酸 | Thr |
| 组氨酸 | His | 酪氨酸 | Tyr |
| 异亮氨酸 | Ile | 缬氨酸 | Val |
用于制备本发明化合物的合成程序描述于WO2016142833 A1和WO2015033299 A1中。
实施例1：在重组PD-L1/PD-L2存在下的小鼠脾细胞增殖拯救
使用重组小鼠PD-L1(rm-PDL-1，目录号：1019-B7-100；R&D Systems)作为PD-L1的来源。
要求：
从6-8周龄C57BL6小鼠收获的小鼠脾细胞；RPMI 1640(GIBCO，目录号11875)；高糖DMEM(GIBCO，目录号D6429)；胎牛血清[Hyclone，目录号SH30071.03]；青霉素(10000单位/mL)-链霉素(10,000μg/mL)液体(GIBCO，目录号15140-122)；MEM丙酮酸钠溶液100mM(100x)液体(GIBCO，目录号11360)；非必需氨基酸(GIBCO，目录号11140)；L-谷氨酰胺(GIBCO，目录号25030)；抗CD3抗体(eBiosciences-16-0032)；抗CD28抗体(eBiosciences-16-0281)；ACK裂解缓冲液(1mL)(GIBCO，目录号-A10492)；Histopaque(密度-1.083gm/mL)(SIGMA10831)；台盼蓝溶液(SIGMA-T8154)；2mL Norm Ject Luer Lock注射器-(Sigma 2014-12)；40μm尼龙细胞过滤器(BD FALCON 35230)；血细胞计数器(Bright line-SIGMA Z359629)；FACS缓冲液(PBS/0.1％BSA)：含0.1％牛血清白蛋白(BSA)(SIGMA A7050)和叠氮化钠(SIGMA 08591)的磷酸盐缓冲盐水(PBS)pH 7.2(HiMedia TS1006)；5mM CFSE原液：通过用180μL二甲基亚砜(DMSO C2H6SO，SIGMA-D-5879)稀释冻干CFSE制备CFSE原液，并将其等分到试管中以供进一步使用。将使用浓度从10μM滴定至1μM。(eBioscience-650850-85)；0.05％胰蛋白酶和0.02％EDTA(SIGMA 59417C)；96孔格式ELISA板(Corning CLS3390)；BD FACScaliber(E6016)；重组小鼠B7-H1/PDL1 Fc嵌合体(rm-PD-L1，目录号：1019-B7-100)。
方案
脾细胞制备和培养：
通过在40μm细胞过滤器中捣碎小鼠脾脏收获在50mL falcon管中的脾细胞在室温下用1mL ACK裂解缓冲液进一步处理5分钟。用9mL RPMI完全培养基洗涤后，将细胞再悬浮于15mL管中的3mL1xPBS中。将3mL Histopaque小心地添加到该管的底部而不扰动上层的脾细胞悬浮液。在室温下以800xg离心20分钟后，小心地收集不透明的脾细胞层而不扰动/混合各层。用冷的1xPBS洗涤脾细胞两次，然后使用台盼蓝排除法进行总细胞计数，并进一步用于基于细胞的测定。
在RPMI完全培养基(RPMI+10％胎牛血清+1mM丙酮酸钠+10,000单位/mL青霉素和10,000μg/mL链霉素)中培养脾细胞，并在含有5％CO2的CO2培养箱中维持在37℃下。
CFSE增殖测定：
CFSE是一种被动扩散到细胞中并与细胞内蛋白质结合的染料。在预热的1xPBS/0.1％BSA溶液中，将1×106个细胞/mL收获的脾细胞用5μM CFSE在37℃下处理10分钟。使用5体积的冰冷培养基将过量的CFSE淬灭至细胞中并在冰上培养5分钟。用冰冷的完全RPMI培养基进一步洗涤CFSE标记的脾细胞三次。将CFSE标记的1×105个脾细胞添加到含有MDA-MB231细胞(在高糖DMEM培养基中培养的1×105个细胞)或重组人PDL-1(100ng/mL)和测试化合物的孔中。用抗小鼠CD3和抗小鼠CD28抗体(各自为1μg/mL)刺激脾细胞，并将培养物在37℃下以5％CO2进一步培养72小时。收获细胞并用冰冷的FACS缓冲液洗涤三次，并通过使用488nm激发和521nm发射滤光片的流式细胞术分析增殖％。
数据编译、处理和推理：
使用细胞任务FACS程序分析脾细胞增殖百分比，并且在扣除％背景增殖％值并将受刺激的脾细胞增殖(阳性对照)％归一化为100％后评估由化合物产生的脾细胞增殖拯救的百分比。
受刺激的脾细胞：脾细胞+抗CD3/CD28刺激
背景增殖：脾细胞+抗CD3/CD28刺激+PD-L1
化合物增殖：脾细胞+抗CD3/CD28刺激+PD-L1+化合物
通过将所需浓度的化合物在配体(PDL-1)的存在下添加到受抗CD3/CD28刺激的脾细胞中来检测化合物效果。
示例性测定数据示于表5中。
实施例2：在重组VISTA存在下的小鼠脾细胞增殖拯救
要求：
媒介物：Milli Q水；RPMI 1640(GIBCO，目录号11875)；胎牛血清[Hyclone，目录号SH30071.03]；青霉素(10000单位/ml)-链霉素(10,000μg/ml)液体(GIBCO，目录号15140-122)；MEM丙酮酸钠溶液100mM(100x)液体(GIBCO，目录号11360)；非必需氨基酸(GIBCO，目录号11140)；L-谷氨酰胺(GIBCO，目录号25030)；重组人VISTA(rhGi24 VISTA/B7-H5 Fc嵌合体(R&D systems，目录号：7126-B7)；抗h/m Gi24/VISTA/B7-H5纯化小鼠单克隆IgG2B(R&D systems，目录号：MAB7126)；小鼠IgG2B同型对照(R&D Systems目录号：MAB 004)；抗人CD3抗体(eBiosciences-16-0039)；抗人CD28抗体(eBiosciences-16-0289)；Histopaque(密度-1.077gm/ml)(SIGMA 1077)；台盼蓝溶液(SIGMA-T8154)；血细胞计数器(Brightline-SIGMA Z359629)；含磷酸盐缓冲盐水(PBS)pH 7.2的FACS缓冲液；含有0.1％牛血清白蛋白(BSA)(SIGMA A7050)和叠氮化钠(SIGMA 08591)的(HiMedia TS1006)；96孔格式ELISA板(Corning 3599)；96孔格式ELISA板(Corning 3361)；BD FACS caliber(E6016)；离心机(Eppendorf 5810R)；人IFN-γ双组ELISA试剂盒(R&D Systems；目录号：DY-285)。
方案
人PBMC IFN-γ释放测定
用重组人VISTA(2.5μg/ml)和抗人CD3(2.5μg/ml)预包被96孔细胞培养板，并在4℃下储存过夜。将抗人VISTA和同种型对照抗体与VISTA一起包被或在第二天培养30分钟，然后加入细胞中。第二天，用1x PBS洗涤平板，然后与测试化合物一起培养30分钟。将分离的PBMC(0.1×106个细胞/孔)和抗人CD28抗体(1μg/ml)加入孔中。将培养物在37℃下以5％CO2进一步培养72小时。培养72小时后，在4℃下以200g×5min短暂离心后收集细胞培养上清液，并按照制造商的方案(R&D Systems；DY-285)加以处理以通过ELISA处理测量人IFN-γ。
简言之，在包被缓冲液中用100μl/孔捕获抗体包被96孔ELISA板，并在4℃下培养过夜。将平板用洗涤缓冲液洗涤五次，并在室温下进一步用200μl的1x分析稀释剂封闭1小时。在洗涤步骤后，将100μl细胞培养上清液加入孔中，并在室温下进一步培养2小时。还包括适当的标准品。在洗涤步骤后，将平板与100μl/孔检测抗体一起培养1小时。重复洗涤步骤，并将平板与100μl/孔亲和素-HRP一起培养30分钟。将平板用洗涤缓冲液洗涤四次，随后用100μl/孔底物溶液培养15分钟。向每个孔中加入50μl终止溶液，并使用Gen52.05版在450nm下读板。利用ΔOD值计算浓度。绘制吸光度值相对于标准品的曲线图，并使用GraphPad Prism软件测定IFN-γ的浓度。每个实验条件重复进行三次。
在上述分析中筛选本发明化合物，并且结果汇总于表5中。所选择的本发明化合物的IFN-γ释放拯救百分比列于下文，其中“A”是指具有超过70％的IFN-γ释放拯救的化合物，“B”是指具有50％至69.9％的IFN-γ释放拯救的化合物，且“C”是指具有少于50％的IFN-γ释放拯救的化合物。
表5：
Claims (56)
1.一种调节细胞中由T细胞活化的V结构域免疫球蛋白阻抑剂(VISTA)活性介导的免疫反应的方法，其包括使所述细胞与式(I)化合物或其药学上可接受的盐接触：
其中：
G代表氢或(C1-C6)烷基；
Ra代表被-OH、-C(O)NRxRy、-NRxRy、胍基、羧酸、杂芳基或芳基-OH取代的(C1-C6)烷基；
Ra’代表氢；或者Ra和Ra’与它们所附接的原子结合在一起形成5至6元环；
Rb代表(C1-C6)烷基，其任选地被-OH、-C(O)NRxRy、-NRxRy、羧酸或杂芳基取代；其中所述杂芳基任选地被羟基进一步取代；
Rc代表氢；或者Rb和Rc与它们所附接的原子结合在一起形成5至6元环；
Rd代表H，被-OH、-NRxRy或羧酸取代的(C1-C6)烷基；
Re代表氢；或者Rd和Re与它们所附接的原子结合在一起形成任选地含有1至3个选自O、NH或S的杂原子的5至6元环；且
Rx和Ry独立地代表氢、(C1-C6)烷基、(C2-C6)酰基或(C1-C6)环烷基；或者Rx和Ry与它们所附接的原子结合在一起形成5至6元环。
2.根据权利要求1所述的方法，其中G代表氢或甲基。
3.根据权利要求1或2所述的方法，其中G代表氢。
4.根据权利要求1至3中任一项所述的方法，Ra代表-(CH2)2C(O)OH或(C1-C4)烷基，其中(C1-C4)烷基被-OH、-C(O)NRxRy、-NRxRy、胍基、杂芳基或芳基-OH取代。
5.根据权利要求1至3中任一项所述的方法，其中Ra代表被-OH、-NH2、-NH-C(＝NH)-NH2、羧酸、咪唑基或对-OH(苯基)取代的(C1-C4)烷基；且Ra’是氢。
6.根据权利要求1至5中任一项所述的方法，其中Ra代表被-OH、-NH2、-NH-C(＝N)-NH2、咪唑基或对-OH(苯基)取代的(C1-C4)烷基；且Ra’是氢。
7.根据权利要求1至3或5中任一项所述的方法，其中Ra代表-CH2OH、-CH(CH3)OH、-CH2-(对-OH(苯基))、-(CH2)4-NH2、-(CH2)2C(O)OH、-(CH2)2C(O)NH2、-CH2(咪唑基)或-(CH2)3-NH-C(＝NH)-NH2。
8.根据权利要求1至3或7中任一项所述的方法，其中Ra代表-CH2OH、-CH(CH3)OH、-CH2-(对-OH(苯基))、-(CH2)4-NH2、-CH2(咪唑基)或-(CH2)3-NH-C(＝NH)-NH2。
9.根据权利要求1至8中任一项所述的方法，其中Ra代表-CH2OH或-CH(CH3)OH。
10.根据权利要求9所述的方法，其中Ra代表-CH2OH。
11.根据权利要求1至3中任一项所述的方法，其中Ra和Ra’与它们所附接的原子结合在一起形成环戊基或环己基环。
12.根据权利要求1至11中任一项所述的方法，其中Rb代表-CH2C(O)OH或(C1-C6)烷基，其中(C1-C6)烷基任选地被-OH、-C(O)NRxRy或杂芳基取代，其中所述杂芳基任选地被羟基进一步取代。
13.根据权利要求1至11中任一项所述的方法，其中Rb代表任选地被-OH、-C(O)NH2、羧酸、吲哚基或-C(O)NH-((C1-C6)烷基)取代的(C1-C4)烷基；且Rc代表氢。
14.根据权利要求1至11中任一项所述的方法，其中Rb代表任选地被-OH、-C(O)NH2、吲哚基或-C(O)NH-((C1-C6)烷基)取代的(C1-C4)烷基；且Rc代表氢。
15.根据权利要求1至11或13中任一项所述的方法，其中Rb代表异丙基、仲丁基、-CH2OH、-CH2C(O)NH2、-(CH2)2C(O)NH2、-(CH2)4-NH(COCH3)、-CH2C(O)OH、-(CH2)2C(O)OH、-CH2(吲哚基)、-CH2C(O)NH(己基)或-(CH2)2C(O)NH(己基)。
16.根据权利要求1至15中任一项所述的方法，其中Rb代表异丙基、仲丁基、-CH2OH、-CH2C(O)NH2、-(CH2)2C(O)NH2、-(CH2)4-NH(COCH3)、-CH2C(O)OH、-CH2(吲哚基)、-CH2C(O)NH(己基)或-(CH2)2C(O)NH(己基)。
17.根据权利要求1至13、15或16中任一项所述的方法，其中Rb代表-CH2C(O)NH2或-CH2C(O)OH。
18.根据权利要求17所述的方法，其中Rb代表-CH2C(O)NH2。
19.根据权利要求1至11中任一项所述的方法，其中Rb和Rc与它们所附接的原子结合在一起形成吡咯烷环。
20.根据权利要求1至19中任一项所述的方法，其中Rd代表被-OH、-NH2或-C(O)OH取代的(C1-C4)烷基；且Re代表氢。
21.根据权利要求1至20中任一项所述的方法，其中Rd代表-CH2OH、-CH(CH3)OH、-(CH2)4-NH2或-CH2C(O)OH。
22.根据权利要求21所述的方法，其中Rd代表-CH2OH或-CH(CH3)OH。
23.根据权利要求22所述的方法，其中Rd代表-CH(CH3)OH。
24.根据权利要求1至19中任一项所述的方法，其中Rd和Re与它们所附接的原子结合在一起形成吡咯烷环。
25.根据权利要求1所述的方法，其中：
G代表氢或(C1-C6)烷基；
Ra代表-(CH2)2C(O)OH或(C1-C4)烷基，其中(C1-C4)烷基被-OH、-NRxRy、胍基、杂芳基或芳基-OH取代；
Ra’代表氢；或者Ra和Ra’与它们所附接的原子结合在一起形成5至6元环；
Rb代表-CH2C(O)OH或-(C1-C6)烷基，其中(C1-C6)烷基任选地被-OH、-C(O)NRxRy或杂芳基取代；其中所述杂芳基任选地被羟基进一步取代；
Rc代表氢；或者Rb和Rc与它们所附接的原子结合在一起形成5至6元环；
Rd代表H，被-OH、-NRxRy或羧酸取代的-(C1-C6)烷基；
Re代表氢；或者Rd和Re与它们所附接的原子结合在一起形成任选地含有1至3个选自O、NH或S的杂原子的5至6元环；且
Rx和Ry独立地代表氢、(C1-C6)烷基或(C2-C6)酰基。
26.根据权利要求1所述的方法，其中：
G代表氢或甲基；
Ra代表-CH2OH、-CH(CH3)OH、-CH2-(对-OH(苯基))、-(CH2)4-NH2、-CH2(咪唑基)或-(CH2)3-NH-C(＝NH)-NH2；
Ra’代表氢；或者Ra和Ra’与它们所附接的原子结合在一起形成环戊基或环己基环；
Rb代表异丙基、仲丁基、-CH2OH、-CH2C(O)NH2、-(CH2)2C(O)NH2、-(CH2)4-NH(COCH3)、-CH2C(O)OH、-(CH2)2C(O)OH、-CH2(吲哚基)、-CH2C(O)NH(己基)或-(CH2)2C(O)NH(己基)；
Rc代表氢；或者Rb和Rc与它们所附接的原子结合在一起形成吡咯烷环；
Rd代表-CH2OH、-CH(CH3)OH、-(CH2)4-NH2或-(CH2)2C(O)OH；且
Re代表氢；或者Rd和Re与它们所附接的原子结合在一起形成吡咯烷环。
27.根据权利要求1所述的方法，其中：
G代表氢或甲基；
Ra代表-CH2OH、-CH(CH3)OH、-CH2-(对-OH(苯基))、-(CH2)4-NH2、-(CH2)2COOH、-CH2(咪唑基)或-(CH2)3-NH-C(＝NH)-NH2；
Ra’代表氢；或者Ra和Ra’与它们所附接的原子结合在一起形成环戊基或环己基环；
Rb代表异丙基、仲丁基、-CH2OH、-CH2C(O)NH2、-(CH2)2C(O)NH2、-CH2C(O)OH、-(CH2)4-NH(COCH3)、-CH2(吲哚基)、-CH2C(O)NH(己基)或-(CH2)2C(O)NH(己基)；
Rc代表氢；或者Rb和Rc与它们所附接的原子结合在一起形成吡咯烷环；
Rd代表-CH2OH、-CH(CH3)OH、-(CH2)4-NH2或-(CH2)2C(O)OH；且
Re代表氢；或者Rd和Re与它们所附接的原子结合在一起形成吡咯烷环。
28.根据权利要求25至27中任一项所述的方法，其中Ra代表-CH2OH或-CH(CH3)OH，Rb代表-CH2C(O)NH2或-CH2C(O)OH，且Rd代表-CH2OH或-CH(CH3)OH。
29.根据权利要求28所述的方法，其中Ra代表-CH2OH或-CH(CH3)OH，Rb代表-CH2C(O)NH2，且Rd代表-CH(CH3)OH。
30.根据权利要求28所述的方法，其中Ra代表-CH2OH，Rb代表-CH2C(O)NH2，且Rd代表-CH(CH3)OH。
31.根据权利要求28所述的方法，其中Ra代表-CH(CH3)OH，Rb代表-CH2C(O)NH2，且Rd代表-CH2OH。
32.根据权利要求1所述的方法，其中所述化合物选自下表：
33.根据权利要求1所述的方法，其中所述化合物选自下表：
34.根据权利要求1至33中任一项所述的方法，其中所述免疫反应进一步由程序性细胞死亡1(PD-1)信号传导通路介导。
35.根据权利要求1至34中任一项所述的方法，其中接触所述细胞发生在有需要的受试者中，从而治疗选自癌症、免疫失调、免疫缺陷病症、炎性病症、感染性疾病和移植排斥的疾病或病症。
36.根据权利要求35所述的方法，其中所述疾病或病症是癌症。
37.根据权利要求1至34所述的方法，其中疾病或病症的治疗包括抑制肿瘤细胞生长和/或转移。
38.根据权利要求37所述的方法，其中所述肿瘤细胞来自选自下列各项的癌症：小细胞肺癌、多发性骨髓瘤、膀胱癌、原发性导管癌、卵巢癌、霍奇金淋巴瘤、胃癌、急性髓性白血病和胰腺癌。
39.根据权利要求37所述的方法，其中所述肿瘤细胞来自选自下列各项的癌症：胚细胞瘤、乳腺癌、上皮癌、结肠癌、肺癌、黑素瘤、前列腺癌、肾癌、骨癌、胰腺癌、皮肤癌、头颈部癌症、子宫癌、卵巢癌、结直肠癌、直肠癌、肛门癌、腹膜癌、胃癌、睾丸癌、输卵管癌、子宫内膜癌、宫颈癌、阴道癌、外阴癌、食道癌、小肠癌、内分泌系统癌、甲状腺癌、甲状旁腺癌、肾上腺癌、肉瘤、尿道癌、阴茎癌、慢性或急性白血病、儿童实体瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、间皮瘤、胸腺癌、骨髓瘤、膀胱癌、输尿管癌、肾盂癌、肝癌、胰腺癌、移植后淋巴组织增生性病症(PTLD)、中枢神经系统(CNS)肿瘤、肿瘤血管生成、脊髓轴肿瘤、脑干胶质瘤、垂体腺瘤、表皮样癌、唾液腺癌、鳞状细胞癌、与母斑细胞病相关的异常血管增生、水肿(如与脑肿瘤相关的水肿)、梅格氏综合症、梅克尔细胞癌和环境诱发的癌症。
40.根据权利要求35所述的方法，其中所述疾病或病症是感染性疾病。
41.根据权利要求40所述的方法，其中所述感染性疾病为细菌感染、病毒感染、真菌感染或寄生虫感染。
42.根据权利要求35所述的方法，其中所述感染性疾病选自：至少一种细菌，其选自炭疽、杆菌(Bacilli)、博德特氏菌(Bordetella)、疏螺旋体(Borrelia)、肉毒杆菌、布鲁氏菌(Brucella)、伯克霍尔德菌(Burkholderia)、弯曲杆菌(Campylobacter)、衣原体(Chlamydia)、霍乱、梭菌(Clostridium)、球菌(Conococcus)、棒状杆菌(Corynebacterium)、白喉、肠杆菌(Enterobacter)、肠球菌(Enterococcus)、欧文氏菌(Erwinia)、埃希氏杆菌(Escherichia)、弗朗西斯氏菌(Francisella)、嗜血杆菌(Haemophilus)、螺杆菌(Heliobacter)、克雷伯氏菌(Klebsiella)、军团杆菌(Legionella)、钩端螺旋体(Leptospira)、钩端螺旋体病、李斯特菌(Listeria)、莱姆病(Lyme′s disease)、脑膜炎球菌(meningococcus)、分支杆菌(Mycobacterium)、支原体、奈瑟氏菌(Neisseria)、巴斯德菌(Pasteurella)、暗杆菌(Pelobacter)、瘟疫、肺炎球菌(Pneumonococcus)、变形杆菌(Proteus)、假单胞菌(Pseudomonas)、立克次氏体(Rickettsia)、沙门氏菌(Salmonella)、沙雷氏菌(Serratia)、志贺氏菌(Shigella)、葡萄球菌(Staphylococcus)、链球菌(Streptococcus)、破伤风、密螺旋体(Treponema)、弧菌(Vibrio)、耶尔森氏菌(Yersinia)和黄单胞菌(Xanthomonas)；至少一种病毒，其选自虫媒病毒性脑炎病毒、腺病毒、单纯疱疹病毒I型、单纯疱疹病毒2型、水痘-带状疱疹病毒、爱泼斯坦-巴尔(Epstein-barr)病毒、巨细胞病毒、8型疱疹病毒、乳头瘤病毒、BK病毒、冠状病毒、艾柯病毒(echovirus)、JC病毒、天花、乙型肝炎、博卡病毒(bocavirus)、细小病毒B19、星状病毒、诺沃克病毒(Norwalk virus)、柯萨奇病毒(coxsackievirus)、甲型肝炎、脊髓灰质炎病毒、鼻病毒、严重急性呼吸综合症病毒、丙型肝炎、黄热病、登革热病毒、西尼罗河病毒(West Nile virus)、风疹、E型肝炎、人类免疫缺陷病毒(HIV)、人类T细胞嗜淋巴细胞病毒(HTLV)、流感、鸟粪病毒、胡宁病毒(Junin virus)、拉沙病毒(Lassa virus)、马丘波病毒(Machupo virus)、萨比亚病毒(Sabia virus)、克里米亚-刚果出血热病毒、埃博拉病毒(ebola virus)、马尔堡病毒(Marburg virus)、麻疹病毒、软疣病毒、腮腺炎病毒、副流感病毒、呼吸道合胞病毒、人偏肺病毒、亨德拉病毒(Hendra virus)、尼帕病毒(Nipah virus)、狂犬病、丁型肝炎、轮状病毒、环状病毒、科罗拉多壁虱热病毒(coltivirus)、牛痘病毒和班纳病毒(Banna virus)；真菌感染，其选自鹅口疮、曲霉属真菌(Aspergillus)(烟曲霉(fumigatus)、黑曲霉(niger)等)、皮肤芽生霉菌(Blastomyces dermatitidis)、念珠菌(Candida)(白色念珠菌(albicans)、克柔念珠菌(krusei)、光滑念珠菌(glabrata)、热带念珠菌(tropicalis)等)、粗球孢子菌(Coccidioides immitis)、隐球菌(新型隐球菌(neoformans)等)、荚膜组织胞浆菌(Histoplasma capsulatum)、毛霉目(Mucorales)(毛霉属(mucor)、犁头霉属(absidia)、根霉属(rhizophus))、巴西副球孢子菌(Paracoccidioides brasiliensis)、孢子丝菌病、申克氏孢子丝菌(Sporothrixschenkii)、接合菌病、着色芽生菌病、洛博真菌病(lobomycosis)、足分支菌病、甲真菌病、毛孢子菌花斑癣(piedra pityriasis versicolor)、胡须癣(tinea barbae)、头癣(tineacapitis)、体癣(tinea corporis)、股癣(tinea cruris)、黄癣(tinea favosa)、黑癣(tinea nigra)、足癣(tinea pedis)、耳霉菌病、暗色丝孢霉病(phaeohyphomycosis)和鼻孢子虫病；和至少一种寄生虫，其选自棘变形虫属(Acanthamoeba)、微小巴贝斯虫(Babesiamicroti)、结肠小袋纤毛虫(Balantidium coli)、溶组织内阿米巴(Entamoebahystolytica)、兰伯氏贾第虫(Giardia lamblia)、鼠隐孢子虫(Cryptosporidium muris)、冈比亚锥虫(Trypanosomatida gambiense)、罗氏锥虫(Trypanosomatida rhodesiense)、布氏锥虫(Trypanosoma brucei)、克氏锥虫(Trypanosoma cruzi)、墨西哥利什曼原虫(Leishmania mexicana)、巴西利什曼原虫(Leishmania braziliensis)、热带利什曼原虫(Leishmania tropica)、杜氏利什曼原虫(Leishmania donovani)、刚地弓形虫(Toxoplasma gondii)、间日疟原虫(Plasmodium vivax)、卵形疟原虫(Plasmodiumovale)、三日疟原虫(Plasmodium malariae)、镰状疟原虫(Plasmodium falciparum)、卡氏肺孢子虫(Pneumocystis carinii)、阴道毛滴虫(Trichomonas vaginalis)、黑头组织滴虫(Histomonas meleagridis)、侧尾腺纲(Secementea)、毛首鞭形线虫(Trichuristrichiura)、人蛔虫(Ascaris lumbricoides)、蠕形住肠线虫(Enterobiusvermicularis)、十二指肠钩虫(Ancylostoma duodenale)、福氏耐格里变形虫(Naegleriafowleri)、美洲钩虫(Necator americanus)、巴西日圆线虫(Nippostrongylusbrasiliensis)、粪类圆线虫(Strongyloides stercoralis)、班氏吴策线虫(Wuchereriabancrofti)、麦地那龙线虫(Dracunculus medinensis)、血吸虫、肝吸虫、肠吸虫、肺吸虫、曼氏血吸虫(Schistosoma mansoni)、埃及血吸虫(Schistosoma haematobium)、日本血吸虫(Schistosoma japonicum)、肝片吸虫(Fasciola hepatica)、大片吸虫(Fasciolagigantica)、异形异形吸虫(Heterophyes heterophyes)和卫氏并殖吸虫(Paragonimuswestermani)。
43.一种调节受试者的免疫反应的方法，其包括
a)确定来自受试者的生物样品是否过度表达VISTA；和
b)如果所述样品过度表达VISTA，则使所述受试者与如权利要求1至33中任一项所限定的化合物接触。
44.根据权利要求43所述的方法，其进一步包括确定所述样品是否过度表达PD-L1或PD-L2，以及如果所述样品过度表达VISTA和PD-L1或PD-L2，则使所述受试者与所述化合物接触。
45.根据权利要求43或44所述的方法，其中所述生物样品选自全血、血浆、血清、细胞(例如，肿瘤细胞)、唾液、尿液、粪便和组织。
46.根据权利要求43至45中任一项所述的方法，其中所述受试者患有癌症，并且任选地，所述样品包含来自所述癌症的一个或多个细胞。
47.根据权利要求43至45中任一项所述的方法，其中所述受试者患有选自细菌感染、病毒感染、真菌感染和寄生虫感染的感染性疾病。
48.根据权利要求43至47中任一项所述的方法，其中在所述受试者接受式(I)化合物之前获取所述对照样品，并在所述受试者接受式(I)化合物之后获取所述受试者样品。
49.一种药物组合物，其包含药学上可接受的载体或赋形剂和至少一种式(I)的化合物、其药学上可接受的盐或其立体异构体：
其中：
G代表氢或(C1-C6)烷基；
Ra代表被-OH、-C(O)NRxRy、-NRxRy、胍基、羧酸、杂芳基或芳基-OH取代的(C1-C6)烷基；
Ra’代表氢；或者Ra和Ra’与它们所附接的原子结合在一起形成5至6元环；
Rb代表(C1-C6)烷基，其任选地被-OH、-C(O)NRxRy、-NRxRy、羧酸或杂芳基取代；其中所述杂芳基任选地被羟基进一步取代；
Rc代表氢；或者Rb和Rc与它们所附接的原子结合在一起形成5至6元环；
Rd代表H，被-OH、-NRxRy或羧酸取代的(C1-C6)烷基；
Re代表氢；或者Rd和Re与它们所附接的原子结合在一起形成任选地含有1至3个选自O、NH或S的杂原子的5至6元环；且
Rx和Ry独立地代表氢、(C1-C6)烷基、(C2-C6)酰基或(C1-C6)环烷基；或者Rx和Ry与它们所附接的原子结合在一起形成5至6元环。
50.根据权利要求49所述的药物组合物，其进一步包含抗癌剂、化疗剂或抗增殖化合物中的至少一种。
51.一种治疗癌症的方法，其包括向有需要的受试者施用治疗有效量的根据权利要求49所述的药物组合物。
52.根据权利要求45所述的方法，其中所述肿瘤细胞来自选自乳腺癌、结肠癌、肺癌、黑色素瘤、前列腺癌和肾癌的癌症。
53.根据权利要求45所述的方法，其中所述肿瘤细胞来自选自下列各项的癌症：胚细胞瘤、乳腺癌、上皮癌、结肠癌、肺癌、黑素瘤、前列腺癌、肾癌、骨癌、胰腺癌、皮肤癌、头颈部癌症、子宫癌、卵巢癌、结直肠癌、直肠癌、肛门癌、腹膜癌、胃癌、睾丸癌、输卵管癌、子宫内膜癌、宫颈癌、阴道癌、外阴癌、食道癌、小肠癌、内分泌系统癌、甲状腺癌、甲状旁腺癌、肾上腺癌、肉瘤、尿道癌、阴茎癌、慢性或急性白血病、儿童实体瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、间皮瘤、胸腺癌、骨髓瘤、膀胱癌、输尿管癌、肾盂癌、肝癌、胰腺癌、移植后淋巴组织增生性病症(PTLD)、中枢神经系统(CNS)肿瘤、肿瘤血管生成、脊髓轴肿瘤、脑干胶质瘤、垂体腺瘤、表皮样癌、唾液腺癌、鳞状细胞癌、与母斑细胞病相关的异常血管增生、水肿(如与脑肿瘤相关的水肿)、梅格氏综合症、梅克尔细胞癌和环境诱发的癌症。
54.一种治疗感染性疾病的方法，其包括向有需要的受试者施用治疗有效量的根据权利要求49所述的药物组合物。
55.根据权利要求54所述的方法，其中所述感染性疾病为细菌感染、病毒感染、真菌感染或寄生虫感染。
56.根据权利要求54所述的方法，其中所述感染性疾病选自：至少一种细菌，其选自炭疽、杆菌、博德特氏菌、疏螺旋体、肉毒杆菌、布鲁氏菌、伯克霍尔德菌、弯曲杆菌、衣原体、霍乱、梭菌、球菌、棒状杆菌、白喉、肠杆菌、肠球菌、欧文氏菌、埃希氏杆菌、弗朗西斯氏菌、嗜血杆菌、螺杆菌、克雷伯氏菌、军团杆菌、钩端螺旋体、钩端螺旋体病、李斯特菌、莱姆病、脑膜炎球菌、分支杆菌、支原体、奈瑟氏菌、巴斯德菌、暗杆菌、瘟疫、肺炎球菌、变形杆菌、假单胞菌、立克次氏体、沙门氏菌、沙雷氏菌、志贺氏菌、葡萄球菌、链球菌、破伤风、密螺旋体、弧菌、耶尔森氏菌和黄单胞菌；至少一种病毒，其选自虫媒病毒性脑炎病毒、腺病毒、单纯疱疹病毒I型、单纯疱疹病毒2型、水痘-带状疱疹病毒、爱泼斯坦-巴尔病毒、巨细胞病毒、8型疱疹病毒、乳头瘤病毒、BK病毒、冠状病毒、艾柯病毒、JC病毒、天花、乙型肝炎、博卡病毒、细小病毒B19、星状病毒、诺沃克病毒、柯萨奇病毒、甲型肝炎、脊髓灰质炎病毒、鼻病毒、严重急性呼吸综合症病毒、丙型肝炎、黄热病、登革热病毒、西尼罗河病毒、风疹、E型肝炎、人类免疫缺陷病毒(HIV)、人类T细胞嗜淋巴细胞病毒(HTLV)、流感、鸟粪病毒、胡宁病毒、拉沙病毒、马丘波病毒、萨比亚病毒、克里米亚-刚果出血热病毒、埃博拉病毒、马尔堡病毒、麻疹病毒、软疣病毒、腮腺炎病毒、副流感病毒、呼吸道合胞病毒、人偏肺病毒、亨德拉病毒、尼帕病毒、狂犬病、丁型肝炎、轮状病毒、环状病毒、科罗拉多壁虱热病毒、牛痘病毒和班纳病毒；真菌感染，其选自鹅口疮、曲霉属真菌(烟曲霉、黑曲霉等)、皮肤芽生霉菌、念珠菌(白色念珠菌、克柔念珠菌、光滑念珠菌、热带念珠菌等)、粗球孢子菌、隐球菌(新型隐球菌等)、荚膜组织胞浆菌、毛霉目(毛霉属、犁头霉属、根霉属)、巴西副球孢子菌、孢子丝菌病、申克氏孢子丝菌、接合菌病、着色芽生菌病、洛博真菌病、足分支菌病、甲真菌病、毛孢子菌花斑癣、胡须癣、头癣、体癣、股癣、黄癣、黑癣、足癣、耳霉菌病、暗色丝孢霉病和鼻孢子虫病；和至少一种寄生虫，其选自棘变形虫属、微小巴贝斯虫、结肠小袋纤毛虫、溶组织内阿米巴、兰伯氏贾第虫、鼠隐孢子虫、冈比亚锥虫、罗氏锥虫、布氏锥虫、克氏锥虫、墨西哥利什曼原虫、巴西利什曼原虫、热带利什曼原虫、杜氏利什曼原虫、刚地弓形虫、间日疟原虫、卵形疟原虫、三日疟原虫、镰状疟原虫、卡氏肺孢子虫、阴道毛滴虫、黑头组织滴虫、侧尾腺纲、毛首鞭形线虫、人蛔虫、蠕形住肠线虫、十二指肠钩虫、福氏耐格里变形虫、美洲钩虫、巴西日圆线虫、粪类圆线虫、班氏吴策线虫、麦地那龙线虫、血吸虫、肝吸虫、肠吸虫、肺吸虫、曼氏血吸虫、埃及血吸虫、日本血吸虫、肝片吸虫、大片吸虫、异形异形吸虫和卫氏并殖吸虫。
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| AU2017345500A1 (en) | 2019-05-23 |
| JP7189870B2 (ja) | 2022-12-14 |
| NZ753204A (en) | 2023-09-29 |
| JP2022191239A (ja) | 2022-12-27 |
| EP3529235A4 (en) | 2020-07-08 |
| BR112019007872A2 (pt) | 2019-07-02 |
| JP2019532083A (ja) | 2019-11-07 |
| MX2023007973A (es) | 2023-07-18 |
| IL266042A (en) | 2019-06-30 |
| WO2018073754A1 (en) | 2018-04-26 |
| US20200061030A1 (en) | 2020-02-27 |
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| EP3529235A1 (en) | 2019-08-28 |
| SG10202010584XA (en) | 2020-12-30 |
| AU2017345500B2 (en) | 2022-03-10 |
| IL287518A (en) | 2021-12-01 |
| EA201990997A1 (ru) | 2019-08-30 |
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