CN111836621A - 使用1,2,4-噁二唑化合物调节tigit和pd-1信号传导途径的方法 - Google Patents
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Abstract
本发明涉及调节TIGIT信号传导途径和PD‑1信号传导途径的方法。本发明还包括式(I)化合物、或其立体异构体、或其药学上可接受的盐用于治疗由TIGIT信号传导途径和PD‑1信号传导途径介导的疾病或病症的用途。
Description
相关申请
本申请要求于2018年3月14日提交的印度临时申请号201841009306的权益;其说明书以引用的方式整体并入本文。
技术领域
本发明涉及用于在受试者中调节具有Ig与ITIM结构域(TIGIT)和程序性细胞死亡-1(PD-1)信号传导途径的T细胞免疫受体的方法,其包括施用式(I)化合物或其药学上可接受的盐。
背景技术
利用免疫系统对抗肿瘤的活性的免疫疗法被证明是多种恶性肿瘤的有效治疗方法。实际上,通过基因突变的积累,许多肿瘤表达可以潜在引起特定肿瘤免疫的抗原。但是,肿瘤还可以通过激活负调控途径和检查点诸如PD-1/PD-L1与CTLA-4来抑制这些应答。
TIGIT(具有Ig与ITIM结构域的T细胞免疫受体)为由激活的T细胞、Treg和NK细胞表达的抑制性受体,还称为WUCAM,Vstm3或Vsig9。TIGIT具有免疫球蛋白可变结构域、跨膜结构域和基于免疫受体酪氨酸的抑制性基序(ITIM),并且含有PVR蛋白家族的特征序列元件。已知它与脊髓灰质炎病毒受体(PVR;CD155)并且与nectin2(CD112)相互作用(Stengel等人(2012)Proc.Nat’l Acad.Sci.(USA)19:5399)。TIGIT通过促进成熟的免疫调节性树突状细胞的生成来抑制T细胞激活。TIGIT和其他此类共抑制性分子(例如,CTLA-4、PD-1、Lag3和BTLA)可在逃避肿瘤细胞的免疫监视中发挥作用。实验表明PVR/CD155在黑色素瘤细胞(Inozume等人(2014)J.Invest.Dermatol.134:S121—摘要693)和各种其他肿瘤上过表达。有可能的是,TIGIT/PVR相互作用可通过抑制T细胞和NK细胞的抗肿瘤应答来庇护此类肿瘤细胞免受免疫介导的根除(Stanietsky等人(2009)Proc.Nat’l Acad.Sci.(USA)106:17858和Lozano等人(2012)J.Immunol.188:3869)。已知TIGIT途径负调控NK细胞功能,如由CD155/TIGIT相互作用所致的通过人(Stanietsky等人(2009)Proc.Nat’l Acad.Sci.(USA);106:17858)或小鼠(Stanietsky等人(2013)Eur J Immunol.43:2138)原代NK细胞的杀伤减少所指示。此外,MDSC诱导的NK细胞功能(脱颗粒、IFN-γ生产)的抑制已显示依赖于CD155-TIGIT相互作用和通过TIGIThigh NK细胞观察到的较大功能抑制(Sarhan等人(2016)Cancer Res 2016;76:5696)。其他实验还鉴别了选择性抑制Th1和Th17应答的调节性T细胞(Treg)的TIGIT亚类(Joller等人(2014)Immunity 40:569),表明TIGIT阻滞剂可增强抗肿瘤免疫应答的替代机制。
TIGIT可类似于其他共抑制性受体诸如CTLA-4、PD-1和BTLA起到‘关闭’免疫应答的作用。靶向CTLA-4(伊匹单抗(ipilimumab))和PD-1(纳武单抗(nivolumab)、帕博利珠单抗(pembrolizumab))的抗体已被批准用于治疗人癌症,确认这种治疗方法有效。结合人TIGIT的抗体或其他剂也可用于治疗癌症。在小鼠模型中,PD-L1和TIGIT的抗体阻滞导致CD8<+>T细胞介导的肿瘤排斥的协同增强(Grogan等人(2014)J.Immunol.192(1)增刊203.15;Johnston等人(2014)Cancer Cell 26:1-15)。在黑色素瘤的动物模型中获得了类似结果(Inozume等人(2014)J.Invest.Dermatol.134:S121—摘要693)。
一些实验表明,仅在存在与TIGIT竞争结合PVR/CD155的共激活受体DNAM-1/CD226的情况下,TIGIT阻滞才有效增强抗肿瘤CD8<+>T细胞应答(Johnston等人(2014)CancerCell 26:1-15)。进一步实验阐明了,起双TIGIT和PD-1阻滞作用的mAb(单克隆抗体)增强CD8+T细胞对黑色素瘤的应答并改良PD-1阻滞对于患有晚期黑色素瘤的患者的临床效力(Joe-Marc Chauvin等人,(2015),J Clin Invest.May 1;125(5):2046–2058)。
因此,考虑到尚未对存在在加强免疫相关疾病诸如癌症中结合PD-1阻滞使用TIGIT阻滞进行较多的探索,仍需要开发表现出TIGIT与PD-1信号传导途径的双抑制的有效治疗剂。
发明内容
本发明涉及使用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来调节具有Ig与ITIM结构域(TIGIT)信号传导途径和程序性细胞死亡1(PD-1)信号传导途径的T细胞免疫受体的方法。
在一个方面中,本公开提供了一种在受试者中调节具有Ig与ITIM结构域(TIGIT)信号传导途径和程序性细胞死亡1(PD-1)信号传导途径的T细胞免疫受体的方法,其包括将所述受试者与式(I)化合物、或其立体异构体、或其药学上可接受的盐接触:
其中,
R1表示氢、任选被-OH、-COOH、芳基、杂芳基或芳基-OH取代的-(C1-C6)烷基;
R2表示氢、任选被-OH、-SH、C(O)NH2、-COOH、芳基、杂芳基或芳基-OH取代的-(C1-C6)烷基;
Ra表示氢;或者Ra和R2与它们连接的原子一起形成吡咯烷环;
R3表示氢或由式(I’)表示的基团,
-----表示连接点;
Rb表示氢;或者Rb和Rc与它们连接的原子一起形成吡咯烷环;
Rc表示氢、任选被-OH、-C(O)NH2、COOH、芳基或芳基-OH取代的-(C1-C6)烷基。
附图简述
图1:化合物19在携带CT26肿瘤的小鼠中的抗肿瘤效应
具体实施方式
本发明提供了一种使用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来调节TIGIT信号传导途径和PD-1信号传导途径的方法。本发明还提供了一种用于治疗由TIGIT和PD-1介导的疾病或病症的方法,其包括施用式(I)化合物、或其立体异构体、或其药学上可接受的盐。
每个实施方案均以解释本发明,而非限制本发明的方式提供。实际上,本领域技术人员应该了解,可以在不脱离本发明的范围或精神的情况下对本发明作出各种修改和变化。例如,作为一个实施方案的一部分进行说明或描述的特征可用于另一个实施方案,从而得到再一个实施方案。因此,本发明的旨在覆盖如所附权利要求和它们的等同物的范围内所提供的此类修改和变化。本发明的其他目的、特征和方面在以下详细描述中公开或从以下详细描述中显而易见。本领域普通技术人员将理解,本论述仅仅是示例性实施方案的描述,并且不应被解释为限制本发明的较广泛方面。
在某些实施方案中,本发明提供了一种在受试者中调节具有Ig与ITIM结构域(TIGIT)信号传导途径和程序性细胞死亡1(PD-1)信号传导途径的T细胞免疫受体的方法,其包括将所述受试者与式(I)化合物、或其立体异构体、或其药学上可接受的盐接触:
其中,
R1表示氢、任选被-OH、-COOH、芳基、杂芳基或芳基-OH取代的-(C1-C6)烷基;
R2表示氢、任选被-OH、-SH、C(O)NH2、-COOH、芳基、杂芳基或芳基-OH取代的-(C1-C6)烷基;
Ra表示氢;或者Ra和R2与它们连接的原子一起形成吡咯烷环;
R3表示氢或由式(I’)表示的基团,
-----表示连接点;
Rb表示氢;或者Rb和Rc与它们连接的原子一起形成吡咯烷环;
Rc表示氢、任选被-OH、-C(O)NH2、COOH、芳基或芳基-OH取代的-(C1-C6)烷基。
在某些实施方案中,R1表示氢、任选被-OH、-COOH、苯基、咪唑基或(p-OH)苯基取代的-(C1-C6)烷基。
在某些实施方案中,R1表示任选被-OH、-COOH、咪唑基、苯基或(p-OH)苯基取代的-(C1-C6)烷基。
在某些实施方案中,R1表示任选被-OH、-COOH、咪唑基或(p-OH)苯基取代的-(C1-C6)烷基。
在某些实施方案中,R2表示氢、任选被-OH、-SH、-C(O)NH2、-COOH、苯基、咪唑基或(p-OH)苯基取代的-(C1-C6)烷基。
在某些实施方案中,R2表示氢、任选被-C(O)NH2、苯基或(p-OH)苯基取代的-(C1-C6)烷基。
在某些实施方案中,R2表示氢、任选被-OH、-SH、-COOH、苯基、咪唑基或(p-OH)苯基取代的-(C1-C6)烷基。
在某些实施方案中,R2表示氢、任选被-OH、-COOH、苯基、咪唑基或(p-OH)苯基取代的-(C1-C6)烷基。
在某些实施方案中,Ra表示氢。
在某些实施方案中,Ra和R2与它们连接的原子一起形成吡咯烷环。
在某些实施方案中,R3表示
其中
-----表示连接点;
Rb表示氢;或者Rb和Rc与它们连接的原子一起形成吡咯烷环;
Rc表示氢、任选被-OH、-C(O)NH2、COOH、苯基或(p-OH)苯基取代的-(C1-C6)烷基。
在某些实施方案中,Rb和Rc与它们连接的原子一起形成吡咯烷环。
在某些实施方案中,本发明中所述的化合物由式(IA)化合物表示,
其中,R1、R2、Ra、Rb和Rc如式(I)化合物中所定义。
在某些实施方案中,本发明中所述的化合物由式(IA)化合物、或其立体异构体、或其药学上可接受的盐表示:其中
R1表示任选被-OH、-COOH、咪唑基、苯基或(p-OH)苯基取代的-(C1-C6)烷基;
R2表示氢、被-OH、-SH、-COOH、苯基、咪唑基或(p-OH)苯基取代的-(C1-C6)烷基;
Ra表示氢;或者Ra和R2与它们连接的原子一起形成吡咯烷环;
Rb表示氢;或者Rb和Rc与它们连接的原子一起形成吡咯烷环;并且
Rc表示氢、任选被-OH、-C(O)NH2、-COOH、苯基或(p-OH)苯基取代的-(C1-C6)烷基。
在某些实施方案中,本发明中所述的化合物由式(IA)化合物、或其立体异构体、或其药学上可接受的盐表示:其中R1表示任选被-OH、-COOH、咪唑基或(p-OH)苯基取代的-(C1-C6)烷基;并且R2表示氢、被-OH、-COOH、苯基、咪唑基或(p-OH)苯基取代的-(C1-C6)烷基。
在某些实施方案中,本发明中所述的化合物由式(IB)化合物表示,
其中,R1、R2和Ra如式(I)化合物中所定义。
在某些实施方案中,本发明中所述的化合物由式(IB)化合物、或其立体异构体、或其药学上可接受的盐表示:其中
R1表示任选被-OH或(p-OH)苯基取代的-(C1-C6)烷基;
R2表示氢、被苯基或(p-OH)苯基取代的-(C1-C6)烷基;并且
Ra和R2与它们连接的原子一起形成吡咯烷环。
在某些实施方案中,术语‘芳基’指示苯基。
在某些实施方案中,术语‘杂芳基’指示咪唑。
在某些实施方案中,TIGIT信号传导途径和PD-1信号传导途径的双调节剂为式(I)化合物:
其中,
R1表示氢、任选被-OH、COOH、芳基、杂芳基或芳基-OH取代的-(C1-C6)烷基;
R2表示氢、任选被-OH、-SH、C(O)NH2、-COOH、芳基、杂芳基或芳基-OH取代的-(C1-C6)烷基;
Ra表示氢;或者Ra和R2与它们连接的原子一起形成吡咯烷环;
R3表示氢或由式(I’)表示的基团,
-----表示与–N-Ra基团的连接点;
Rb表示氢;或者Rb和Rc与它们连接的原子一起形成吡咯烷环;
Rc表示氢、被-OH、-C(O)NH2、-COOH、芳基或芳基-OH取代的-(C1-C6)烷基。
在某些实施方案中,本发明提供了一种在受试者中调节具有Ig与ITIM结构域(TIGIT)信号传导途径和程序性细胞死亡1(PD-1)信号传导途径的T细胞免疫受体的方法,其包括将所述受试者与式(I)化合物、或其立体异构体、或其药学上可接受的盐接触:
R1表示氢、-CH2-芳基-OH、-CH2-COOH、-CH2-咪唑基、-(CH2)2-COOH、-CH(CH3)2、-CH2-芳基、-CH(CH3)OH或-CH2(CH)(CH3)2;
R2表示氢、-CH(CH3)OH、-CH2-芳基-OH、-CH2-SH、-CH2-咪唑基、-CH(CH3)2、-(CH2)2-COOH、-(CH2)2-CONH2或-CH2-芳基;
Ra表示氢;或者Ra和R2与它们连接的原子一起形成吡咯烷环;
R3表示氢或由式(I’)表示的基团,
-----表示与–N-Ra基团的连接点;
Rb表示氢;或者Rb和Rc与它们连接的原子一起形成吡咯烷环;
Rc表示氢、-CH2-COOH、-CH(CH3)OH、-CH2-芳基-OH、-CH2-芳基、-(CH2)2-CONH2或-CH(CH3)CH2CH3。
在某些实施方案中,R1表示氢或-CH(CH3)OH。
在某些实施方案中,R2表示-(CH2)2-COOH。
在某些实施方案中,本发明提供了一种在受试者中调节具有Ig与ITIM结构域(TIGIT)信号传导途径和程序性细胞死亡1(PD-1)信号传导途径的T细胞免疫受体的方法,其包括将所述受试者与式(I)化合物、或其立体异构体、或其药学上可接受的盐接触:其中所述化合物为:
或其药学上可接受的盐或立体异构体。
在某些实施方案中,本发明提供了一种在受试者中调节具有Ig与ITIM结构域(TIGIT)信号传导途径和程序性细胞死亡1(PD-1)信号传导途径的T细胞免疫受体的方法,其包括将所述受试者与式(I)化合物、或其立体异构体、或其药学上可接受的盐接触:其中所述化合物为:
或其药学上可接受的盐。
在某些实施方案中,本发明的化合物可为式(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的形式呈现,或者母体化合物中的羧酸以酯的形式呈现。在另一实施方案中,前药在体内被代谢成活性母体化合物(例如,酯被水解成对应羟基或羧酸)。
在某些实施方案中,本发明的化合物还可在组成此类化合物的一个或多个原子处含有非天然比例的原子同位素。例如,本发明还包括本发明的同位素标记变体,其与本文所述的变体相同,但化合物的一个或多个原子被原子质量或质量数与原子的自然界中通常发现的优势原子质量或质量数不同的原子置换。本发明化合物及其用途的范围内涵盖如所指定的任何特定原子或元素的所有同位素。可掺入本发明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、36Cl、123I和125I。本发明同位素标记化合物可一般通过以下与本文下文的方案和/或实施例中所公开类似的程序,或者通过用同位素标记试剂取代非同位素标记试剂来制备。
本发明方法可用于治疗有需要的受试者。在某些实施方案中,个体为哺乳动物,诸如人或非人哺乳动物。当施用于动物诸如人时,所述化合物优选以药物组合物的形式施用,所述药物组合物包含例如本发明化合物和药学上可接受的载体。药学上可接受的载体为本领域中熟知的,并且包括例如水性溶液诸如水或生理缓冲盐水或者其他溶剂或媒介物诸如乙二醇、甘油、油诸如橄榄油或可注射有机酯。在优选实施方案中,当此类药物组合物用于人施用时,特别是用于侵入性施用途径(即,诸如避免通过上皮屏障的运输或扩散的途径,诸如注射或植入)时,水性溶液为无热原的或基本上无热原的。可以选择赋形剂,例如以实现剂的延迟释放或选择性靶向一种或多种细胞、组织或器官。药物组合物可以呈剂量单位形式,诸如片剂、胶囊剂(包括洒胶囊剂和明胶胶囊剂)、颗粒剂、用于重构的冻干剂、散剂、溶液剂、糖浆剂、栓剂、注射剂等。所述组合物也可以存在于透皮递送系统中,例如皮肤贴剂。所述组合物也可以存在于适合局部施用的溶液中,诸如滴眼剂。
本文采用短语“药学上可接受的”指在合理医学判断范围内、适用于与人类和动物组织接触而没有过量毒性、刺激、过敏反应或其他问题或并发症、与合理的利益/风险比相称的那些化合物、材料、组合物和/或剂型。
如本文所用,短语“药学上可接受的载体”意指药学上可接受的材料、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。在与制剂的其他成分相容并且对患者无害的意义上,每种载体必须是“可接受的”。可以用作药学上可接受的载体的材料的一些实例包括:(1)糖,诸如乳糖、葡萄糖和蔗糖;(2)淀粉,诸如玉米淀粉和马铃薯淀粉;(3)纤维素及其衍生物,诸如羧甲基纤维素钠、乙基纤维素和乙酸纤维素;(4)黄芪胶粉;(5)麦芽;(6)明胶;(7)滑石;(8)赋形剂,诸如可可脂和栓剂蜡;(9)油,诸如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油和大豆油;(10)二醇,诸如丙二醇;(11)多元醇,诸如甘油、山梨醇、甘露醇和聚乙二醇;(12)酯,诸如油酸乙酯和月桂酸乙酯;(13)琼脂;(14)缓冲剂,诸如氢氧化镁和氢氧化铝;(15)褐藻酸;(16)无热原质水;(17)等渗盐水;(18)林格氏溶液;(19)乙醇;(20)磷酸盐缓冲溶液;以及(21)药物组合物中采用的其他无毒相容性成分。
在某些实施方案中,本公开提供了一种在受试者中调节具有Ig与ITIM结构域(TIGIT)信号传导途径和程序性细胞死亡1(PD-1)信号传导途径(例如,PD-1、PD-L1或PD-L2)的T细胞免疫受体的方法,其包括向受试者与根据上文实施方案中任一项的式(I)化合物、或其立体异构体、或其药学上可接受的盐接触。
在某些实施方案中,本公开提供了一种调节具有Ig与ITIM结构域(TIGIT)信号传导途径的T细胞免疫受体的方法,其包括将所述受试者本文所公开的化合物19、或其立体异构体、或其药学上可接受的盐接触。
在某些实施方案中,本公开提供了一种调节具有Ig与ITIM结构域(TIGIT)信号传导途径的T细胞免疫受体的方法,其包括将所述受试者本文所公开的化合物20、或其立体异构体、或其药学上可接受的盐接触。
根据前述实施方案中任一项,在某些实施方案中,接触细胞发生在有需要的受试者中,从而治疗选自以下的疾病或病症:癌症、免疫病症、免疫缺陷性病症、炎性病症、感染性疾病和移植排斥。
在某些实施方案中,疾病或病症为癌症。
在某些实施方案中,本公开提供了一种用于抑制肿瘤细胞生长和/或转移的方法,其包括向有需要的受试者施用治疗有效量的TIGIT/PD-1双途径抑制剂。
在某些实施方案中,肿瘤细胞来自选自以下的癌症:小细胞肺部癌症、多发性骨髓瘤、膀胱癌、原发性导管癌、卵巢癌、霍奇金氏淋巴瘤(Hodgkin’s lymphoma)、胃癌、急性髓系白血病和胰腺癌症。
在某些实施方案中,肿瘤细胞来自选自以下的癌症:母细胞瘤、乳腺癌症、上皮癌症、结肠癌症、肺部癌症、黑色素瘤、前列腺癌症、肾脏癌症、骨癌症、胰腺癌症、皮肤癌症、头部或颈部癌症、子宫癌症、卵巢癌症、直肠结肠癌症、直肠癌症、肛门区癌症、腹膜癌症、胃部癌症、睾丸癌症、输卵管癌、子宫内膜癌、宫颈癌症、阴道癌症、外阴癌症、食管癌症、小肠癌症、内分泌系统癌症、甲状腺癌症、甲状旁腺癌症、肾上腺癌症、肉瘤、尿道癌症、阴茎癌症、慢性或急性白血病、儿童期实体肿瘤、霍奇金氏淋巴瘤、非霍奇金氏淋巴瘤、皮肤T细胞淋巴瘤、间皮瘤、胸腺癌、骨髓瘤、膀胱癌症、输尿管癌症、肾盂癌、肝部癌症、胰腺癌症、移植后淋巴组织增生性病症(PTLD)、中枢神经系统肿瘤(CNS)、肿瘤血管生成、脊柱轴肿瘤、脑干胶质瘤、垂体腺瘤、表皮癌症、涎腺癌、鳞状细胞癌症、与斑痣性错构瘤病有关的异常血管增殖、水肿(诸如与脑肿瘤有关的水肿)、麦格氏综合征、梅克尔细胞癌和环境诱导的癌症。
在某些实施方案中,本发明提供了一种用于在受试者中抑制肿瘤细胞生长和/或转移的方法,其包括向有需要的受试者施用TIGIT/PD-1双途径抑制剂。
在某些实施方案中,肿瘤细胞属于选自以下的癌症:小细胞肺部癌症、多发性骨髓瘤、膀胱癌、原发性导管癌、卵巢癌、霍奇金氏淋巴瘤、胃癌、急性髓系白血病和胰腺癌症。
在某些实施方案中,肿瘤细胞属于选自以下的癌症:母细胞瘤、乳腺癌症、上皮癌症、结肠癌症、肺部癌症、黑色素瘤、前列腺癌症、肾脏癌症、骨癌症、胰腺癌症、皮肤癌症、头部或颈部癌症、子宫癌症、卵巢癌症、直肠结肠癌症、直肠癌症、肛门区癌症、腹膜癌症、胃部癌症、睾丸癌症、输卵管癌、子宫内膜癌、宫颈癌症、阴道癌症、外阴癌症、食管癌症、小肠癌症、内分泌系统癌症、甲状腺癌症、甲状旁腺癌症、肾上腺癌症、肉瘤、尿道癌症、阴茎癌症、慢性或急性白血病、儿童期实体肿瘤、霍奇金氏淋巴瘤、非霍奇金氏淋巴瘤、皮肤T细胞淋巴瘤、间皮瘤、胸腺癌、骨髓瘤、膀胱癌症、输尿管癌症、肾盂癌、肝部癌症、胰腺癌症、移植后淋巴组织增生性病症(PTLD)、中枢神经系统肿瘤(CNS)、肿瘤血管生成、脊柱轴肿瘤、脑干胶质瘤、垂体腺瘤、表皮癌症、涎腺癌、鳞状细胞癌症、与斑痣性错构瘤病有关的异常血管增殖、水肿(诸如与脑肿瘤有关的水肿)、麦格氏综合征、梅克尔细胞癌和环境诱导的癌症。
在某些实施方案中,本发明提供用于治疗癌症的方法,其中所述方法包括向有需要的受试者施用TIGIT/PD-1双途径抑制剂。
根据前述实施方案中任一项,在某些实施方案中,TIGIT/PD-1双途径抑制剂为式(I)化合物、或其立体异构体、或其药学上可接受的盐。
根据前述实施方案中任一项,在某些实施方案中,TIGIT/PD-1双途径抑制剂为式(IA)化合物、或其立体异构体、或其药学上可接受的盐。
根据前述实施方案中任一项,在某些实施方案中,TIGIT/PD-1双途径抑制剂为式(IB)化合物、或其立体异构体、或其药学上可接受的盐。
在某些实施方案中,本发明提供了用于治疗由TIGIT介导的癌症的方法,其中所述方法包括向有需要的受试者施用化合物19或20、或其立体异构体、或其药学上可接受的盐。
在某些实施方案中,本发明提供了用于在受试者中抑制肿瘤细胞生长和/或转移的方法,其包括向有需要的受试者施用式(I)化合物或其药学上可接受的盐,其能够抑制具有Ig与ITIM结构域(TIGIT)途径和程序性细胞死亡1(PD1)信号传导途径的T细胞免疫受体。
在某些实施方案中,本发明提供了用于在受试者中抑制肿瘤细胞生长和/或转移的方法,其包括向有需要的受试者施用式(IA)化合物或其药学上可接受的盐,其能够抑制具有Ig与ITIM结构域(TIGIT)途径和程序性细胞死亡1(PD1)信号传导途径的T细胞免疫受体。
在某些实施方案中,本发明提供了用于在受试者中抑制肿瘤细胞生长和/或转移的方法,其包括向有需要的受试者施用式(IB)化合物或其药学上可接受的盐,其能够抑制具有Ig与ITIM结构域(TIGIT)途径和程序性细胞死亡1(PD1)信号传导途径的T细胞免疫受体。
考虑到在激活时TIGIT对CD8+T细胞的上调(Joller等人(2011)J Immunol.186:1338),预期大量癌症适应症对TIGIT阻滞剂有应答。可获得的数据还指示在非小细胞肺部癌症、结肠癌症和黑色素瘤(Chauvin等人(2015)Clin Investig.125:2046;Johnston等人(2014)Cancer Cell.26:923)中的CD8+TIL上、在慢性淋巴细胞白血病(Catakovic等人,(2017)Oncoimmunology 7(1):e1371399)和滤泡性淋巴瘤(Josefsson等人(2018)ClinCancer Res.24:870)的T细胞上以及在急性骨髓性白血病(AML)患者(Kong等人(2016)ClinCancer Res.22:3057)的外周血单核细胞(PBMC)上高水平的TIGIT表达。
本文所公开的代表性肿瘤细胞包括癌症细胞,诸如但不限于:母细胞瘤(例如,胶质母细胞瘤)、乳腺癌症(例如,乳腺癌、原发性导管癌、三阴性乳腺癌症、雌激素受体阳性(ER+)乳腺癌症、孕激素受体阳性(PR+)乳腺癌症和/或人表皮生长因子受体2阳性(HER2+)乳腺癌症)、上皮癌症(例如,上皮癌)、结肠癌症、肺部癌症(例如,小细胞肺部癌症、非小细胞肺部癌症(NSCLC)、肺腺癌和肺鳞状细胞癌)、黑色素瘤(例如,皮肤黑色素瘤、眼部黑色素瘤、皮肤或眼内恶性黑色素瘤和淋巴结相关黑色素瘤)、前列腺癌症(例如,前列腺腺癌)、肾脏癌症(例如,肾细胞癌症(RCC)和肾癌症)、骨癌症(例如,骨肉瘤)、胰腺癌症(例如,胰腺腺癌)、皮肤癌症、头部或颈部癌症(例如,头颈部鳞状细胞癌)、子宫癌症、卵巢癌症(例如,卵巢癌)、直肠结肠癌症(例如,高度微卫星不稳定性直肠结肠癌症和结肠直肠腺癌)、直肠癌症、肛门区癌症、腹膜癌症、胃部癌症(例如,胃癌和胃肠癌症)、睾丸癌症、输卵管癌、子宫内膜癌、宫颈癌症(例如,宫颈癌)、阴道癌症(例如,阴道癌)、外阴癌症(例如,外阴癌)、食管癌症、小肠癌症、内分泌系统癌症、甲状腺癌症(例如,甲状腺癌症)、甲状旁腺癌症、肾上腺癌症、肉瘤(例如,软组织肉瘤和卡波西氏肉瘤)、尿道癌症、阴茎癌症、慢性或急性白血病(例如,急性髓系白血病、慢性髓系白血病、急性淋巴母细胞性白血病、慢性淋巴细胞白血病、毛细胞白血病和慢性骨髓母细胞性白血病)、儿童期实体肿瘤、霍奇金氏淋巴瘤(HL)(例如,淋巴细胞丰富型(LRCHL)、结节硬化型(NSHL)、混合细胞型(MCHL)和淋巴细胞消减型(LDHL))、B细胞淋巴瘤(例如,弥漫大B细胞淋巴瘤(DLBCL))、非霍奇金氏淋巴瘤(NHL)(例如,低级别/滤泡性非霍奇金氏淋巴瘤、小淋巴细胞(SL)NHL、中级别/滤泡性NHL、中级别弥漫NHL、高级别免疫母细胞性NHL、高级别淋巴母细胞性NHL、高级别小非裂细胞NHL、巨大肿块(bulkydisease)NHL、伯基特氏淋巴瘤、套细胞淋巴瘤)、AIDS相关淋巴瘤、皮肤T细胞淋巴瘤(例如,蕈样肉芽肿)和华氏巨球蛋白血症(Waldenstrom’sMacroglobulinemia)、移植后淋巴组织增生性病症(PTLD)、淋巴细胞淋巴瘤、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(例如,膀胱癌)、输尿管癌症、肾盂癌、肝部癌症(例如,肝细胞癌症、肝癌、肝瘤)、胰腺癌症、移植后淋巴组织增生性病症(PTLD)、中枢神经系统肿瘤(CNS)、肿瘤血管生成、脊柱轴肿瘤、脑干胶质瘤、垂体腺瘤、表皮癌症、涎腺癌、鳞状细胞癌症、与斑痣性错构瘤病有关的异常血管增殖、水肿(诸如与脑肿瘤有关的水肿)、麦格氏综合征、梅克尔细胞癌、环境诱导的癌症(包括由石棉诱导的癌症)以及所述癌症的组合。
在其他实施方案中,例如,肿瘤细胞可包括选自以下的癌症的细胞:前列腺癌症、黑色素瘤、乳腺癌症、结肠癌症、前列腺癌症、肺部癌症、肾脏癌症、胰腺癌症、胃癌、膀胱癌症、食道癌症,间皮瘤、甲状腺癌症、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、上皮癌症、直肠结肠癌症、阴道癌症、宫颈癌症、卵巢癌症和头颈部癌症。
在其他实施方案中,例如,肿瘤细胞可包括选自以下的癌症的细胞:黑色素瘤、三阴性乳腺癌症、非小细胞肺部癌症、肾细胞癌、胰腺癌症、胃癌、膀胱癌症、间皮瘤、霍奇金氏淋巴瘤、宫颈癌症、卵巢癌症和头颈部鳞状细胞癌。在其他实施方案中,例如,肿瘤细胞可包括选自以下的癌症的细胞:前列腺癌症、黑色素瘤、乳腺癌症、结肠癌症、前列腺癌症、肺部癌症、肾脏癌症、胰腺癌症、胃癌、膀胱癌症、食道癌症,间皮瘤、甲状腺癌症、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、上皮癌症、直肠结肠癌症、阴道癌症、宫颈癌症、卵巢癌症和头颈部癌症。
在其他实施方案中,例如,肿瘤细胞可包括选自以下的癌症的细胞:黑色素瘤、三阴性乳腺癌症、非小细胞肺部癌症、肾细胞癌、胰腺癌症、胃癌、膀胱癌症、间皮瘤、霍奇金氏淋巴瘤、宫颈癌症、卵巢癌症和头颈部鳞状细胞癌。
在一些实施方案中,肿瘤细胞及/或受试者未接受过免疫肿瘤疗法。免疫肿瘤学使用受试者的免疫系统来帮助对抗癌症。例如,免疫肿瘤疗法包括但不限于:阿特珠单抗(atezolizumab)(靶向PD-L1的人单克隆抗体)、阿维鲁单抗(avelumab)(靶向PD-L1的人单克隆抗体)、维布妥昔单抗(brentuximab vedotin)(靶向CD30的抗体-药物结合物)、利妥昔单抗(rituximab)(靶向CD20的抗体)、度伐鲁单抗(durvalamab)(靶向PD-L1的人单克隆抗体)、伊匹单抗(靶向CTLA-4的人单克隆抗体)、纳武单抗(靶向PD-L1的人单克隆抗体)、帕博利珠单抗(还称为派姆单抗(lambrolizumab),靶向PD-L1的人单克隆抗体)、曲美木单抗(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)。
在另外的实施方案中,本公开提供了一种通过阻滞TIGIT信号传导途径和PD-1信号传导途径,例如抑制由PD-1(例如,PD-1、PD-L1或PD-L2)和TIGIT诱导的免疫抑制信号来治疗感染的方法,其中所述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,以及方法为施用治疗有效量的式(I)化合物,以用于治疗细菌感染、病毒感染、真菌感染或寄生虫感染。
考虑到在激活时TIGIT对CD8+T细胞的上调(Joller等人(2011)J Immunol.186:1338),预期TIGIT阻滞剂在大量感染性疾病中有效。据报道,TIGIT加强由LCMV(Johnston等人(2014)Cancer Cell.26)和HIV(Tauriainen等人(2017)Sci Rep.7:40354)引起的慢性感染中的CD8+T细胞耗竭。
在一些实施方案中,例如,细菌感染可由至少一种选自以下的细菌引起:衣原体(Chlamydia)、杆菌(Bacilli)、博德特菌(Bordetella)、肉毒菌(botulism)、弯曲菌(Campylobacter)、伯克氏菌(Burkholderia)、炭疽菌(anthrax)、霍乱、梭菌(Clostridium)、李斯特菌(Listeria)、淋球菌、棒杆菌(Corynebacterium)、白喉(diptheria)、密螺旋体(Treponema)、布鲁氏菌(Brucella)、肠球菌(Enterococcus)、支原体(Mycoplasma)、疏螺旋体(Borrelia)、欧文氏菌(Erwinia)、埃希氏菌(Escherichia)、弗朗西斯菌(Francisella)、嗜血杆菌(Haemophilus)、螺杆菌(Heliobacter)、克雷伯氏菌(Klebsiella)、黄单胞菌(Xanthomonas)、军团菌(Legionella)、细螺旋体(Leptospira)、细螺旋体病(leptospirosis)、莱姆病(Lyme’s disease)、脑膜炎球菌(meningococcus)、肺炎球菌(Pneumonococcus)、分枝杆菌(Mycobacterium)、奈瑟菌(Neisseria)、弧菌(Vibrio)、巴斯德菌(Pasteurella)、暗杆菌(Pelobacter)、沙雷氏菌(Serratia)、鼠疫、链球菌(Streptococcus)、变形杆菌(Proteus)、肠杆菌(Enterobacter)、假单胞菌(Pseudomonas)、立克次氏体(Rickettsia)、沙门氏菌(Salmonella)、志贺氏菌(Shigella)、葡萄球菌(Staphylococcus)、破伤风和耶尔森氏菌(Yersinia)。
在其他实施方案中,例如,病毒感染可由至少一种选自以下的病毒引起:虫媒病毒性脑炎病毒(arboviral encephalitis virus)、腺病毒、单纯疱疹病毒1型、单纯疱疹病毒2型、水痘-带状疱疹病毒、EB病毒(Epstein-barr virus)、巨细胞病毒、疱疹病毒8型、乳头状瘤病毒、BK病毒、冠状病毒、埃可病毒(echovirus)、JC病毒、天花病毒、乙型肝炎病毒、博卡病毒(bocavirus)、细小病毒(parvovirus)B19、星状病毒(astrovirus)、诺沃克病毒(Norwalk virus)、柯萨奇病毒(coxsackievirus)、甲型肝炎病毒、脊髓灰质炎病毒(poliovirus)、鼻病毒(rhinovirus)、严重急性呼吸综合征病毒、丙型肝炎病毒、黄热病病毒、登革病毒(dengue virus)、西尼罗病毒(West Nile virus)、风疹病毒、戊型肝炎病毒、人免疫缺陷病毒(HIV)、人嗜T淋巴细胞病毒(human T-celllymphotropic virus;HTLV)、流感病毒、瓜纳瑞托病毒(guanarito virus)、胡宁病毒(Junin virus)、拉沙病毒(Lassavirus)、马秋波病毒(Machupo virus)、萨比亚病毒(Sabia virus)、克里米亚-刚果出血热病毒(Crimean-Congo hemorrhagic fever virus)、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(human metapneumovirus)、亨德拉病毒(Hendra virus)、尼帕病毒(Nipah virus)、狂犬病病毒、丁型肝炎病毒、轮状病毒(rotavirus)、环状病毒(orbivirus)、科罗拉多壁虱热病毒(coltivirus)、牛痘病毒和版纳病毒(Banna virus)。
在其他实施方案中,例如,真菌感染可选自:鹅口疮、粗球孢子菌(Coccidioidesimmitis)、皮炎芽生菌(Blastomyces dermatitidis)、耳真菌病、念珠菌(Candida)(白念珠菌、克鲁斯念珠菌、光滑念珠菌、热带念珠菌等)、头癣(tinea capitis)、须癣(tineabarbae)、体癣(tinea corporis)、股癣(tinea cruris)、掌黑癣(tinea nigra)、申克孢子丝菌(Sporothrix schenkii)、接合菌病(zygomycosis)、着色芽生菌病(chromoblastomycosis)、隐球菌(Cryptococcus)(新型隐球菌等)、荚膜组织胞浆菌(Histoplasma capsulatum)、脚湿气(tinea pedis)、巴西副球孢子菌(Paracoccidioidesbrasiliensis)、暗色丝孢霉病(phaeohyphomycosis)、黄癣(tinea favosa)、毛霉菌目(Mucorales)(毛霉属、犁头霉属(absidia)、根霉属(rhizophus))、孢子丝菌病(sporotrichosis)、曲霉属(Aspergillus)(烟曲霉、黑曲霉等)、罗布菌病(lobomycosis)、足菌肿(mycetoma)、甲真菌病(onychomycosis)、毛结节菌病(piedra)、花斑糠疹(pityriasis versicolor)和鼻孢子菌病(rhinosporidiosis)。
在一些实施方案中,例如,寄生虫感染可由至少一种选自以下的寄生虫引起:人蛔虫(Ascaris lumbricoides)、结肠小袋纤毛虫(Balantidium coli)、溶组织内阿米巴(Entamoeba hystolytica)、蓝氏贾第鞭毛虫(Giardia lamblia)、福氏内格里虫(Naegleria fowleri)、美洲钩虫(Necator americanus)、巴西日圆线虫(Nippostrongylusbrasiliensis)、粪类圆线虫(Strongyloides stercoralis)、鼠隐孢子虫(Cryptosporidium muris)、冈比亚锥虫(Trypanosomatida gambiense)、罗德西亚锥虫(Trypanosomatida rhodesiense)、田鼠巴贝虫(Babesia microti)、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)、班氏吴策线虫(Wuchereria bancrofti)、麦地那龙线虫(Dracunculus medinensis)、刚地弓形虫(Toxoplasma gondii)、大片吸虫(Fasciolagigantica)、异形异形吸虫(Heterophyes heterophyes)、间日疟原虫(Plasmodiumvivax)、布氏锥虫(Trypanosoma brucei)、卵形疟原虫(Plasmodium ovale)、三日疟原虫(Plasmodium malariae)、恶性疟原虫(Plasmodium falciparum)、卡氏肺孢子虫(Pneumocystis carinii)、阴道毛滴虫(Trichomonas vaginalis)、火鸡组织滴虫(Histomonas meleagridis)、侧尾腺口纲(Secementea)、毛首鞭形线虫(Trichuristrichiura)、棘阿米巴虫(Acanthamoeba)、蛲虫(Enterobius vermicularis)、十二指肠钩口线虫(Ancylostoma duodenale)、血吸虫(blood flukes)、肝吸虫(liver flukes)、肠吸虫(intestinal flukes)、肺吸虫(lung flukes)、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)和卫氏肺吸虫(Paragonimus westermani)。
在某些实施方案中,本发明提供用于治疗癌症的方法,其中癌症选自:肺部癌症、乳腺癌症、结肠癌症、肾脏癌症、膀胱癌症、甲状腺癌症、前列腺癌症、骨肉瘤和霍奇金氏淋巴瘤。
在某些实施方案中,本发明提供在受试者中调节免疫应答的方法,其包括将过表达具有Ig与ITIM结构域(TIGIT)和PD-L1或PD-L2中至少一个的T细胞免疫受体的受试者的生物样品暴露于式(I)化合物、或其立体异构体、或其药学上可接受的盐。
在某些实施方案中,本发明提供在受试者中调节免疫应答的方法,其包括a)确定受试者的生物样品是否暴露于TIGIT;以及b)如果样品过表达TIGIT,则将受试者与式(I)化合物、或其立体异构体、或其药学上可接受的盐接触。
在某些实施方案中,本发明提供在受试者中调节免疫应答的方法,其还包括:
a)确定样品是否过表达PD-L1或PD-L2;以及
b)如果样品过表达TIGIT和PD-L1或PD-L2,则将受试者与式(I)化合物、或其立体异构体、或药学上可接受的盐接触。
在某些实施方案中,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。
在某些实施方案中,受试者患有癌症,并且任选地,样品包含一种或多种来自癌症的细胞。
在某些实施方案中,受试者具有选自以下的感染性疾病:细菌感染、病毒感染、真菌感染和寄生虫感染。
在某些实施方案中,在受试者已接受式(I)化合物之前获得对照样品,并且在受试者已经接受式(I)化合物之后获得受试者样品。
本发明的化合物可作为单一药物(单一疗法)或与一种或多种其他药物联合(联合疗法)使用。所述化合物可以本身使用,或优选地在将所述化合物与一种或多种药学上可接受的材料混合的药物组合物中使用。
在某些实施方案中,本发明提供用于在受试者中调节由TIGIT信号传导途径和PD-1信号传导途径介导的免疫应答的化合物。
在某些实施方案中,免疫应答被调节成治疗由TIGIT信号传导途径和PD-1信号传导途径介导的疾病或病症。
在某些实施方案中,根据本公开的癌症选自:母细胞瘤、乳腺癌症、上皮癌症、结肠癌症、肺部癌症、黑色素瘤、前列腺癌症、肾脏癌症、骨癌症、胰腺癌症、皮肤癌症、头部或颈部癌症、子宫癌症、卵巢癌症、直肠结肠癌症、直肠癌症、肛门区癌症、腹膜癌症、胃部癌症、睾丸癌症、输卵管癌、子宫内膜癌、宫颈癌症、阴道癌症、外阴癌症、食管癌症、小肠癌症、内分泌系统癌症、甲状腺癌症、甲状旁腺癌症、肾上腺癌症、肉瘤、尿道癌症、阴茎癌症、慢性或急性白血病、儿童期实体肿瘤、霍奇金氏淋巴瘤、非霍奇金氏淋巴瘤、皮肤T细胞淋巴瘤、间皮瘤、胸腺癌、骨髓瘤、膀胱癌症、输尿管癌症、肾盂癌、肝部癌症、胰腺癌症、移植后淋巴组织增生性病症(PTLD)、中枢神经系统肿瘤(CNS)、肿瘤血管生成、脊柱轴肿瘤、脑干胶质瘤、垂体腺瘤、表皮癌症、涎腺癌、鳞状细胞癌症、与斑痣性错构瘤病有关的异常血管增殖、水肿(诸如与脑肿瘤有关的水肿)、麦格氏综合征、梅克尔细胞癌和环境诱导的癌症。
在某些实施方案中,本发明提供了一种式(I)化合物、或其立体异构体、或其药学上可接受的盐,其用于在受试者中调节具有Ig与ITIM结构域(TIGIT)信号传导途径和程序性细胞死亡1(PD-1)信号传导途径的T细胞免疫受体;
其中,
R1表示氢、任选被-OH、-COOH、芳基、杂芳基或芳基-OH取代的-(C1-C6)烷基;
R2表示氢、任选被-OH、-SH、C(O)NH2、-COOH、芳基、杂芳基或芳基-OH取代的-(C1-C6)烷基;
Ra表示氢;或者Ra和R2与它们连接的原子一起形成吡咯烷环;
R3表示氢或由式(I’)表示的基团,
-----表示连接点;
Rb表示氢;或者Rb和Rc与它们连接的原子一起形成吡咯烷环;
Rc表示氢、任选被-OH、-C(O)NH2、COOH、芳基或芳基-OH取代的-(C1-C6)烷基。
在某些实施方案中,本发明提供了一种式化合物(化合物1)、或其立体异构体、或其药学上可接受的盐,其用于在受试者中调节具有Ig与ITIM结构域(TIGIT)信号传导途径和程序性细胞死亡1(PD-1)信号传导途径的T细胞免疫受体。
在某些实施方案中,本发明提供了一种式化合物(化合物2)、或其立体异构体、或其药学上可接受的盐,其用于在受试者中调节具有Ig与ITIM结构域(TIGIT)信号传导途径和程序性细胞死亡1(PD-1)信号传导途径的T细胞免疫受体。
在某些实施方案中,本发明提供了一种式化合物(化合物3)、或其立体异构体、或其药学上可接受的盐,其用于在受试者中调节具有Ig与ITIM结构域(TIGIT)信号传导途径和程序性细胞死亡1(PD-1)信号传导途径的T细胞免疫受体。
在某些实施方案中,本发明提供了一种式化合物(化合物19)、或其立体异构体、或其药学上可接受的盐,其用于在受试者中调节具有Ig与ITIM结构域(TIGIT)信号传导途径和程序性细胞死亡1(PD-1)信号传导途径的T细胞免疫受体。
除非本文中另外指定,否则术语“抗体”广泛涵盖天然存在形式的抗体(例如,IgG、IgA、IgM、IgE)和重组抗体诸如单链抗体、嵌合与人源化抗体和多特异性抗体以及所有前述抗体的片段和衍生物,所述片段和衍生物具有至少一个抗原结合位点。抗体衍生物可包括与抗体结合的蛋白或化学部分。
如本文所用的术语“抗体”还包括抗体的“抗原结合部分”(或简称为“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,其保留特异性结合抗原(例如,生物标志物多肽或其片段)的能力。已显示,抗体的抗原结合功能可通过全长抗体的片段来进行。
术语“对照”是指适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,对照包括获得“对照样品”,从中检测表达产物水平并将其与测试样品的表达产物水平进行比较。此一对照样品可包含任何合适的样品,包括但不限于:结果已知的来自对照受试者的样品(可为储存样品或先前样品测量值);从受试者分离的正常组织或细胞、培养的从受试者分离的原代细胞/组织、从受试者的同一器官或身体位置获得的相邻正常细胞/组织、从正常受试者分离的组织或细胞样品或者从储藏所获得的原代细胞/组织。在某些实施方案中,对照可包括来自任何合适来源(包括但不限于持家基因)的参考标准表达产物水平、来自正常组织(或其他先前分析的对照样品)的表达产物水平范围、来自患者群体的测试样品内的先前测定的表达产物水平范围或者具有某一结果或接受某一治疗的患者集合。本领域技术人员将理解,此类对照样品和参考标准表达产物水平可组合用作本发明方法中的对照。
TIGIT的“正常”表达水平为不需要免疫应答调节的受试者例如人患者的细胞中TIGIT的表达水平。生物标志物的“过表达”或“显著较高的表达水平”是指测试样品中的表达水平大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从同一受试者获得的健康组织样品)中TIGIT的表达活性或水平以及优选若干对照样品中生物标志物的平均表达水平高至少约10%且更优选约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。生物标志物的“显著较低的表达水平”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)中生物标志物的表达水平以及优选若干对照样品中生物标志物的平均表达水平低至少约10%且更优选约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。
用于检测或测定TIGIT基因的存在或水平的术语“样品”通常为全血、血浆、血清、唾液、尿液、粪便(例如,排泄物)、眼泪和任何其他体液(例如,如上文在“体液”的定义下所述)、或组织样品(例如,活检)诸如小肠、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从受试者获得样品,之后检测或测定TIGIT基因的存在或水平。
药物组合物可通过口服或吸入途径或通过肠胃外施用途径来施用。例如,组合物可口服、通过静脉内输注、局部、腹膜内、膀胱内或鞘内施用。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、真皮内、腹膜内和皮下途径。合适的液体组合物可为:水性和非水性等渗无菌注射溶液,其可含有抗氧化剂、缓冲剂、抑菌剂以及使制剂与预期接受者的血液等渗的溶质;以及水性和非水性无菌混悬液,其可包含助悬剂、增溶剂、增稠剂、稳定剂和防腐剂。口服施用、肠胃外施用、皮下施用以及静脉内施用为优选的施用方法。
本发明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。一般而言,合适的施用途径可例如包括口服、滴眼液、直肠、透粘膜、局部或经肠施用;肠胃外递送,包括包括肌肉内、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。可以每个剂量方案0.5mg或1mg至500mg、1g或2g的量施用本发明的化合物。剂量可以每周一次、每三天一次、每两天一次、每天一次、每天两次、每天两次、每天三次或更多次施用。在替代实施方案中,在某些成年人中,化合物可通过静脉内施用持续医师所指定的时间段来连续施用。由于剂量受各种条件影响,所以在某些情况下,可执行小于或大于预期剂量范围的量。医师可容易地为正在接受治疗性治疗的患者确定适当的剂量。
组合疗法
本公开的化合物可与一种或多种其他药物组合施用,(1)以补充和/或增强式(I)化合物的作用;(2)以调节药效学、改良吸收或减少式(I)化合物的剂量;和/或(3)以减少或改善式(I)化合物的副作用。如本文所用,短语“联合施用”是指两种或更多种不同治疗性化合物的任何形式的施用,使得施用了第二化合物同时先前施用的治疗性化合物仍在体内有效(例如,两种化合物同时在患者中有效,其可包括两种化合的协同作用)。例如,不同治疗性化合物可以同一制剂的形式或以单独制剂的形式伴随地或依序施用。在某些实施方案中,不同治疗性化合物可彼此在一小时、12小时、24小时、36小时、48小时、72小时或一周内施用。因此,接受此类治疗的个体可受益于不同治疗性化合物的组合作用。各个化合物可通过相同或不同途径和相同或不同方法来施用。在一些实施方案中,联合疗法的组合作用可通过免疫作用来检测。
另一药物的剂量可为临床上已经使用的剂量,或者可为改变的剂量,使得当与本公开的化合物组合施用时,剂量为有效的。本公开的化合物与另一药物的比率可根据待施用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质量份的本发明的化合物,可以0.01至100质量份的量使用另一药物。
联合疗法可用于治疗本文所讨论的任何疾病。在某些实施方案中,本公开的式(I)化合物可与另一治疗剂例如抗癌剂、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,所述另一治疗剂选自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。
预期TIGIT拮抗剂从TIGIT介导的抑制中拯救NK细胞功能。由于NK细胞通过抗体介导的细胞毒性(ADCC)有助于许多靶向癌细胞表面蛋白的抗体(诸如HER2、EGFR、CD38和CD20抗体)的功效,所以预期TIGIT剂与许多抗癌抗体诸如抗HER2抗体、抗EGFR抗体、抗CD38抗体和抗CD20抗体组合而协同起作用。
组合疗法的剂
在某些实施方案中,式(I)化合物可与另一种治疗剂联合施用,例如,
1)醛固酮合成酶抑制剂;
2)ALK抑制剂;细胞凋亡诱导剂;
3)芳香化酶抑制剂;
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);
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,诸如CUDC-907(双PI3K/HDAC抑制剂);以及
50)BET溴结构域抑制剂。
合适于与本文所公开的化合物和组合物联合施用的额外治疗剂描述于例如以下出版物中:WO2016/100882;WO2016/054555;WO2016/040892;WO2015/097536;WO2015/088847;WO2015/069770;WO2015/026634;WO 2015/009856;EP 1377609B1;Antonia等人,Clin.Cancer Res.2014 20:6258-6268;以及Melero等人,Nature Reviews Cancer 201515:457-472。每个出版物均以引用的方式整体并入本文。
例如,在本公开的针对癌症的治疗的方法中,本公开的化合物可与另一化疗剂联合作为单一药物组合物或不同药物组合物的组合来使用。化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(中性粒细胞减少)治疗药物、血小板减少治疗药物、止吐药物、芳香化酶抑制剂、P-糖蛋白抑制剂、铂络合物衍生物、其他免疫治疗药物和其他抗癌药物。
可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、烷基化剂、蒽环类药物、长春花生物碱、插层剂、能够干扰信号转导途径的剂、促进细胞凋亡的剂、蛋白体抑制剂和放射(例如,局部或全身照射)。
额外治疗剂的非限制性实例包括但不限于肽、多肽、蛋白、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。
联合疗法可包括其他相容剂,例如化疗剂、细胞因子疗法、干扰素疗法(例如,干扰素-α、β或γ;干扰素α-2a;干扰素α-2b;干扰素α-m;干扰素α-n3;干扰素β-Ia;和干扰素γ-Ib)、白介素疗法(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)、共刺激调节剂(例如,MHC I类分子激动剂(例如,激动性抗体或其抗原结合片段或者可溶性融合物))、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、整联蛋白、信号传导淋巴细胞激活分子(SLAM蛋白)、激活NK细胞受体、抗体疗法、病毒疗法、基因疗法或其组合。
可与本公开的化合物联合施用的化疗剂和其他治疗剂包括但不限于:阿比特龙(abiraterone)、abraxane、醋葡醛内酯(aceglatone)、阿西维辛(acivicin)、阿克拉霉素(aclacinomysin)、actimid、放线菌素、阿柏西普(aflibercept)、阿地白介素(aldesleukin)、醛磷酰胺糖苷(aldophosphamideglycoside)艾乐替尼(alectinib)、阿仑膦酸酯、阿曲替诺(alitretinoin)、六甲蜜胺、氨鲁米特(aminoglutethimide)、氨基酮戊酸、氨基喋呤(aminopterin)、安吖啶(amsacrine)、阿那曲唑(anastrozole)、安西他滨(ancitabine)、血管他丁(angiostatin)、angiozyme、安归啶(anguidine)、安丝菌素(ansamitocin)、安曲霉素(anthramycin)、抗凝血酶III、阿帕替尼(apatinib)、阿拉伯糖苷、arboplatin、门冬酰胺酶、authramycin、阿昔替尼(axitinib)、阿扎胞苷、偶氮丝氨酸、阿扎替派(azetepa)、阿佐霉素(azotomycin)、6-氮尿苷、巴瑞替尼、巴马司他(batimastat)、苯达莫司汀(bendamustine)、比美替尼(benimetinib)、苯佐替派(benzodopa)、贝斯特布斯(bestrabucil)、贝沙罗汀(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)、布喹那(brequinar)、布立尼布(brivanib)、苔藓抑素(bryostatin)、溴匹立明(bropirimine)、泡番荔枝辛(bullatacin)、布拉他辛酮(bullatacinone)、布舍瑞林(buserelin)、白消安、放线菌素C、卡奇霉素(calicheamicin)、卡利他汀(callystatin)、卡普睾酮(calusterone)、洋红霉素(caminomycin)、喜树碱、卡培他滨(capecitabine)、卡拉比星(carabicin)、卡铂、卡波醌(carboquone)、卡非佐米(carfilzomib)、卡莫氟、卡莫司汀(carmustine)、卡柔比星(carubicin)、卡折来新(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)、氯脲菌素(chlorozotocin)、氯磷酰胺(cholophosphamide)、色霉素(chromomycin)、西罗霉素(cirolemycin)、顺铂、顺式二氯二胺铂(cisdichlorodiamineplatinum)(II)、顺铂、克拉屈滨(cladribine)、氯膦酸(clodronate)、考比替尼(cobimetinib)、秋水仙碱、克立那托(crisnatol)、克唑替尼(crizotinib)、念珠藻素1、念珠藻素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)、放线菌素D、丹诺瑞韦(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-睾酮脱氢睾酮、地兰佐米(delanzomib)、地美可辛(demecolcine)、脱甲氧绿毛菌素、地尼白介素(denileukin)、得尼考辛(denenicokin)、二甲叶酸(denopterin)、近灰霉素脱乙酰基拉维霉素(desacetyl近灰霉素)、地托比星(detorubicin)、地塞米松(dexamethasone)、奥马铂右奥马铂(dex奥马铂)、地扎胍宁(dezaguanine)、地吖醌、6-重氮-5-氧代-L-正亮氨酸、二氯乙酸盐、脱氧基二脱氧基尿苷、双烯雌酚、二乙基己烯雌酚、diftitox、二氟甲基鸟氨酸、羟基二羟基炭疽菌素二酮(di羟基anthracindione)、dinaciclib、多西他赛(docetaxel)、多拉司他汀(dolastatin)、多韦替尼(dovitinib)、脱氧氟尿苷(doxifluridine)、多柔比星(doxorubicin)、多西环素(doxycycline)、屈洛昔芬(droloxifene)、屈他雄酮(dromostanolone)、达佐霉素(duazomycin)、倍癌霉素(duocarmycin)、dynemicin、依达曲沙(edatrexate)、衣佛鸟氨酸(eflomithine)、依利醋铵(elliptinium acetate)、艾榴塞洛素(eleutherobin)、吐根碱、emsirolimus、康奈非尼(encorafenib)、恩洛铂(enloplatin)、依诺他宾(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)、erismodegib、厄洛替尼(erlotinib)、伊索比星(esorubicin)、埃斯波霉素(esperamicin)、雌二醇(estradiol)、雌莫司汀(estramustine)、依他硝唑(etanidazole)、溴化乙锭、2-乙基酰肼、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)、法倔唑(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、福林替尼(foretinib)、福美坦(formestane)、磷喹酮(fosquidone)、福莫司汀(fotemustine)、亚叶酸(frolinic acid)、加西托星(gacytosine)、硝酸镓、galunisertib、甘多替尼(gandotinib)、吉非替尼(gefitinib)、格尔德霉素(geldanamycin)、吉西他滨(gemcitabine)、染料木素(genistein)、糖皮质激素、戈舍瑞林(goserelin)、短杆菌肽D、除莠霉素(herbimycin)、hiltonol、4-羟基他莫昔芬、羟基脲、伊班膦酸盐(ibandronate)、伊达比星(idarubicin)、异环磷酰胺、依莫福新(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)、依诺替康(ironotecan)、伊沙佐米(ixazomib)、keoxifene、laherparepvec、lameotide、拉帕替尼、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)、利阿唑(liarozole)、利多卡因(lidocaine)、利尼法尼(linifanib)、lometrexo、洛莫司汀(lomustine)、氯尼达明(lonidamine)、洛索蒽醌(losoxantrone)、麻西罗霉素(marcellomycin)、马瑞佐米(marizomib)、马赛替尼(masitinib)、马索罗酚(masoprocol)、maytansyne、美登醇(maytansinol)、氮芥(mechlorethamine)、氮芥氧化物盐酸盐、甘露醇氮芥(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)、巯基嘌呤、美司钠(mesna)、甲福明(metformin)、甲氨蝶呤(methotrexate)、氯苯氨啶(metoprine)、乌瑞替派美妥替哌(met乌瑞替派)、光辉霉素(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)、momelotinib、montanide、莫哌达醇(mopidamol)、莫替沙尼(motesanib)、莫托莫德(motolimod)、霉酚酸(mycophenolicacid)、mylotarg、白蛋白结合型紫杉醇(nab-paclitaxel)、navelbine、来那替尼(neratinib)、尼洛替尼(nilotinib)、尼鲁米特(nilutamide)、尼莫司汀(nimustine)、硝氨吖啶(nitracrine)、诺考达唑(nocodazole)、诺加霉素(nogalamycin)、novantrone、新恩比兴(novembichin)、奥比妥珠单抗(obinutuzumab)、奥曲肽(octreotide)、橄榄霉素(olivomycin)、奥那司酮(onapristone)、奥马铂(ormaplatin)、奥沙利铂(oxaliplatin)、紫杉醇、帕利替尼(pacritinib)、帕博西尼(palbociclib)、帕米膦酸盐(pamidronate)、pancratistatin、帕比司他(panobinostat)、帕唑帕尼(pazopanib)、哌加他尼(pegaptanib)、培门冬酶(pegaspargase)、培非格司亭(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-戊氧基羰基-5-脱氧基-5-氟胞苷、培洛霉素(peplomycin)、哌立福新(perifosine)、蛋氨氮芥(phenamet)、苯芥胆甾醇(phenesterine)、匹马司替(pimasertib)、哌泊溴烷(pipobroman)、哌泊舒凡(piposulfan)、吡柔比星(pirarubicin)、普卡霉素(plicamycin)、鬼臼酸(podophyllinic acid)、聚苯丙生(polifeprosan)、泊马度胺(pomalidomide)、卟吩姆(porfimer)、甲基比裂霉素(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)、近灰霉素(ravidomycin)、雷佐生(razoxane)、瑞戈非尼(regorafenib)、利塞膦酸盐(risedronate)、雷西莫特(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(safingol)、沙克迪因(sarcodictyin)、司美替尼(selumetinib)、司马沙尼(semaxanib)、司莫司汀(semustine)、塞马莫德(simapimod)、辛曲秦(simtrazene)、西罗莫司(sirolimus)、西佐喃(sizofiran)、索拉菲尼(sorafenib)、sparfosate、稀疏霉素(sparsomycin)、锗螺胺(spirogermanium)、螺莫司汀(spiromustine)、螺铂(spiroplatin)、海绵抑素(spongistatin)、链黑菌素(streptonigrin)、链佐星(streptozocin)、磺氯苯脲(sulofenur)、舒尼替尼(sunitinib)、苏拉明(suramin)、他利霉素(talisomycin)、他莫昔芬、talimogene、tasocitinib、红豆杉醇(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)、细交链孢菌酮酸(tenuazonic acid)、替罗昔隆(teroxirone)、睾内酪(testolactone)、睾酮、四卡因(tetracaine)、替扎他滨(tezacitibine)、沙利度胺(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)、二茂钛(titanocene)、tivozanib、托西尼布(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)、陶扎色替(tozasertib)、曲美替尼(trametinib)、曲妥珠单抗(trastuzumab)、三亚胺醌(triaziquone)、tretinoin、2,2’,2”-三氯三乙胺、三亚乙基蜜胺、三亚乙基磷酰胺、三亚乙基硫代磷酰胺(triethylenethiophosphaoramide)、曲洛司坦(trilostane)、三羟甲蜜胺(trimethylolomelamine)、三甲曲沙(trimetrexate)、曲普瑞林(triptorelin)、曲磷胺(trofosfamide)、块菌素(tubercidin)、tuvizanib、乌拉莫司汀(uracil mustard)、乌苯美司(ubenimex)、乌瑞替派(uredopa)、尿烷、凡德他尼(vandetanib)、伐普肽(vapreotide)、vargatef、瓦他拉尼(vatalanib)、维罗非尼(vemurafenib)、verracurin、维替泊芬(verteporfin)、长春碱、长春新碱、长春地辛、长春匹定、长春甘酯、长春罗新、长春瑞滨、长春罗定、长春利定、伏氯唑(vorozole)、维莫德吉(vismodegib)、希罗达(xeloda)、zactima、折尼铂(zeniplatin)、净司他丁(zinostatin)、阿柏西普(Ziv-aflibercept)、唑来膦酸盐(zoledronate)和佐柔比星(zorubicin)。
在某些实施方案中,示例性化疗剂包括但不限于细胞因子诸如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 Lob 7/4、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、ITGB1、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、MK4166、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、OSK 2118436、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。
可与本文所公开的化合物联合使用的示例性紫杉醇剂包括但不限于:纳米粒子白蛋白结合紫杉醇(ABRAXANE,由Abraxis Bioscience销售);二十二碳六烯酸结合紫杉醇(DHA-紫杉醇,Taxoprexin,由Protarga销售);聚谷氨酸盐结合紫杉醇(PG-紫杉醇,paclitaxel poliglumex,CT-2103,XYOTAX,由Cell Therapeutic销售);肿瘤激活的前药(TAP);ANG 105(结合三分子紫杉醇的Angiopep-2,由ImmunoGen销售);紫杉醇-EC-1(结合erbB2识别肽EC-1的紫杉醇;参见Li等人,Biopolymers(2007)87:225-230);以及葡萄糖结合紫杉醇(例如,2’紫杉醇甲基2-吡喃葡萄糖基琥珀酸酯,参见Liu等人,Bioorganic&MedicinalChemistry Letters(2007)17:617-620)。
在某些实施方案中,示例性化疗剂包括但不限于:
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[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-氟吡啶酰胺;
5)抗HER3单克隆抗体或其抗原结合片段,其包含SEQ ID NO:141的VH和SEQ IDNO:140的VL,如U.S.8,735,551中所述;
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-甲酸(4-二甲基氨基甲基-1H-咪唑-2-基)-酰胺。
在其他实施方案中,示例性化疗剂包括但不限于:
1)3-(1H-吲哚-3-基)-4-[2-(4-甲基-1-哌嗪基)-4-喹唑啉基]-1H-吡咯-2,5-二烷;
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(dactolisib);
4)化合物D(CYP17抑制剂);
5)4-[3,5-双(2-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-苯甲腈(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-(羟基甲基)-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]咪唑并咪唑-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]-甲磺酸盐-苯甲酰胺;
10)4-[(R)-6,7-二氢-5H-吡咯并[1,2-c]咪唑-5-基]-3-氟苯甲腈(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’-联苯基]-3-甲酰胺二磷酸盐(磷酸索尼德吉(sonidegib phosphate));
12)(R)-2-(5-(4-(6-苯甲基-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抗体药物结合物,mAb 12425);
17)化合物Q(M-CSF的单克隆抗体或Fab);
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]苯并二氮杂九环-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)-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-苯甲基-L-酪氨酰基-L-苯基丙氨酰基-)(二天冬氨酸帕瑞肽(pasireotide diaspartate));
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)噻丁烷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]环孢菌素D。阿姆德雷(Amdray),PSC833,[3’-脱氧-3’-氧代-MeBmt]l-[Val]2-环孢菌素(伐司扑达(valspodar));
28)N-(4-氯苯基)-4-(4-吡啶基甲基)-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)-N-甲基吡啶酰胺。参见例如WO2016/100882,其以引用的方式整体并入本文。
在某些实施方案中,用于联合施用的示例性治疗剂为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抗体单克隆抗体、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、阿托珠单抗(afutuzumab)、阿仑珠单抗(alemtuzumab)、阿特珠单抗、阿维鲁单抗、阿昔替尼、巴利昔单抗(basiliximab)、巴维昔单抗(bavituximab)、贝利木单抗(belimumab)、贝伐珠单抗(bevacizumab)、本妥昔单抗(brentuximab)、卡那单抗(canakinumab)、塞妥珠单抗(certolizumab)、西妥昔单抗(cetuximab)、达利珠单抗(daclizumab)、地舒单抗(denosumab)、度伐鲁单抗、衣库珠单抗(eculizumab)、依法利珠单抗(efalizumab)、埃罗妥珠单抗(elotuzumab)、福坦替尼(fostamatinib)、吉妥单抗(gemtuzumab ozogamicin)、戈利木单抗(golimumab)、替伊莫单抗(ibritumomab tiuxetan)、英夫利昔单抗(infliximab)、伊匹单抗、派姆单抗、拉帕替尼、乐伐替尼(lenvatinib)、利鲁单抗(lirilumab)、莫加单抗(mogamulizumab)、莫维珠单抗(motavizumab)、木利替尼(mubritinib)、那他珠单抗(natalizumab)、纳武单抗、奥比妥珠单抗、奥法木单抗(ofatumumab)、奥马珠单抗(omalizumab)、帕丽珠单抗(palivizumab)、帕尼单抗(panitumumab)、哌加他尼、帕博利珠单抗、帕妥珠单抗(pertuzumab)、吡地丽珠单抗(pidilizumab)、兰尼单抗(ranibizumab)、瑞西巴库单抗(raxibacumab)、利妥木单抗(rilotumumab)、利妥昔单抗、托珠单抗(tocilizumab)、托西莫单抗(tositumomab)I-13、曲妥珠单抗、曲美木单抗、乌瑞鲁单抗(urelumab)、乌司奴单抗(ustekinumab)和瓦力单抗(varlilumab)。
组合疗法还可包括双特异性抗体的施用。双特异性抗体可用于靶向两种单独的抗原。例如,抗Fc受体/抗肿瘤抗原(例如,Her-2/neu)双特异性抗体已用于靶向到肿瘤部位的巨噬细胞。这种靶向可更有效地激活肿瘤特异性应答。这些应答的T细胞臂将通过使用PD-1阻滞而加强。替代地,可通过使用与肿瘤抗原结合的双特异性抗体和树突状细胞特异性细胞表面标志物将抗原直接递送至DC。
可用于激活宿主免疫应答的其他抗体可与本文所述的组合疗法组合使用。这些包括树突状细胞表面上激活DC功能和抗原呈递的分子。抗CD40抗体能够有效取代T细胞辅助活性(Ridge,J.等人(1998)Nature 393:474-478)并且可与PD-1抗体结合使用(Ito,N.等人(2000)Immunobiology 201(5)527-40)。T细胞共刺激分子的抗体诸如CTLA-4(例如,美国专利号5,811,097)、OX-40(Weinberg,A.等人(2000)Immunol 164:2160-2169)、4-1BB(Melero,I.等人(1997)Nature Medicine 3:682-685(1997),和ICOS(Hutloff,A.等人(1999)Nature 397:262-266)也可提供增加水平的T细胞激活。
合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细胞受体抗体诸如抗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 lH(Ilex))、抗CDlla抗体(例如,Xanelim(Genentech));抗细胞因子或抗细胞因子受体抗体拮抗剂诸如抗IL-2受体抗体(Zenapax(Protein Design Labs))、抗IL-6受体抗体(例如,MRA(Chugai))和抗IL-12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)和司妥昔单抗(siltuximab)(CNT032(Centocor))以及免疫特异性结合肿瘤相关抗原的抗体(例如,trastuzimab(Genentech))。
本文所公开的组合疗法可与免疫源性剂进一步组合,诸如癌性细胞、纯化的肿瘤抗原(包括重组蛋白、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等人(2004)J.Immunol.173:4919-28)。可使用的肿瘤疫苗的非限制性实例包括黑色素抗原的肽,诸如gpl00、MAGE抗原、Trp-2、MARTI和/或酪氨酸酶的肽,或者被转染以表达细胞因子GM-CSF的肿瘤细胞。
本文所公开的化合物可与重组蛋白和/或在肿瘤中表达以生成对这些蛋白的免疫应答的肽的集合结合使用。这些蛋白通常被免疫系统视为自身抗原并且因此对它们耐受。肿瘤抗原还可包括蛋白端粒酶,其为染色体端粒合成所需的并且在多于85%的人癌症中以及仅在有限数目的体细胞组织中表达(Kim,N等人(1994)Science 266:2011-2013)。(可以通过各种方式保护这些体细胞组织免受免疫攻击)。肿瘤抗原还可为在癌细胞中表达的“新抗原”,因为体细胞突变改变了蛋白序列或在两个不相关序列之间形产生融合蛋白(即,费城染色体中的bcr-abl),或者为B细胞肿瘤的独特型。
本文所公开的化合物可与疫苗接种方案组合。已经设计了许多针对肿瘤的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Restifo,N.及Sznol,M.,CancerVaccines,第61章,第3023-3043页,其在DeVita,V.等人(编),1997,Cancer:Principlesand Practice of Oncology.第五版中)。在这些策略中的一个中,使用自体或同种异体肿瘤细胞制备疫苗。当肿瘤细胞经过转导以表达GM-CSF时,这些细胞疫苗显示是最有效的。GM-CSF已显示为用于肿瘤疫苗接种的抗原呈递的有效激活剂(Dranoff等人(1993)Proc.Natl.Acad.Sci.U.S.A.90:3539-43)。在一些实施方案中,使用以由恶性浆细胞产生的免疫球蛋白独特型的疫苗接种。其他治疗性疫苗包括但不限于sipuleucel-T、gp100疫苗、HPV-16疫苗和GVAX胰腺疫苗。
其他肿瘤疫苗可包括来自与人癌症有关的病毒的蛋白,诸如人乳头瘤病毒(HPV)、肝炎病毒(HBV和HCV)、卡波西氏疱疹肉瘤病毒(KHSV)和黑色素瘤中优先表达的抗原(PRAME)。在某些实施方案中,疫苗选自病毒载体疫苗、细菌疫苗、基于细胞的疫苗、DNA疫苗、RNA疫苗、肽疫苗或蛋白疫苗。参见例如,Jeffrey Schlom,“Therapeutic CancerVaccines:Current Status and Moving Forward”,J Natl Cancer Inst;104:599-613(2012)。可与PD-1阻滞结合使用的另一形式的肿瘤特异性抗原为从肿瘤组织本身分离的纯化的热休克蛋白(HSP)。这些热休克蛋白含有来自肿瘤细胞的蛋白片段,并且这些HSP在递送至抗原呈递细胞以引发肿瘤免疫方面高度有效(Suot,R和Srivastava,P(1995)Science269:1585-1588;Tamura,Y.等人(1997)Science 278:117-120)。
可与本文所公开的化合物联合施用的示例性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,治疗性癌症疫苗为树突状细胞疫苗。树突状细胞疫苗可由自体树突状细胞和/或同种异体树突状细胞构成。在某些实施方案中,在向受试者施用之前,自体或同种异体树突状细胞装载有癌症抗原。在某些实施方案中,自体或同种异体树突状细胞通过直接施向肿瘤施用而装载有癌症抗原。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、树突状细胞疫苗、DNA疫苗和基于载体的疫苗。抗原疫苗通过使用一种或多种抗原(诸如,肽)来增强免疫系统。抗原疫苗可对某一类型的癌症具有特异性,因为每种肿瘤类型都可通过特定的抗原图谱来识别。树突状细胞疫苗通常为自体疫苗,并且通常必须针对每个受试者个别制备。树突状疫苗的非限制性实例为Sipuleucel-T和DCvax。对于制备DNA疫苗,可将载体工程化成含有可注射到受试者体内的特定DNA,从而导致DNA被细胞吸收。一旦细胞吸收了DNA,DNA将对细胞进行编程(program)以产生特定抗原,然后可激发所需免疫应答。
胰腺癌症
可与本文所公开的化合物联合用于治疗胰腺癌症的示例性剂包括但不限于:TAXOL、白蛋白稳定的纳米粒子紫杉醇制剂(例如,ABRAXANE)或脂质体紫杉醇制剂);吉西他滨(例如,吉西他滨单独或与AXP107-11组合);其他化疗剂,诸如奥沙利铂、5-氟氟尿嘧啶、卡培他滨、鲁比替康(rubitecan)、表柔比星盐酸盐、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(nimotuzumab));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,索拉菲尼、舒尼替尼、XL184、帕唑帕尼);VEGF抑制剂(例如,贝伐珠单抗、AV-951、布立尼布);放射免疫疗法(例如,XR303);癌症疫苗(例如,GVAX、存活蛋白(survivin)肽);COX-2抑制剂(例如,塞来昔布(celecoxib));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,CNTO328);周期蛋白依赖性激酶抑制剂(例如,P276-00、UCN-01);定向能量代谢改变(AlteredEnergy Metabolism-Directed;AEMD)化合物(例如,CPI-613);HDAC抑制剂(例如,伏立诺他(vorinostat));TRAIL受体2(TR-2)激动剂(例如,可那木单抗(conatumumab));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-毒素连接物(denileukin diftitox);拓扑异构酶1抑制剂(例如,伊立替康、PEP02);斯达汀(statin)(例如,辛伐他汀(simvastatin));因子VIla抑制剂(例如,PCI-27483);AKT抑制剂(例如,RX-0201);低氧激活前药(例如,TH-302);甲福明盐酸盐、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、veliparib);CTLA-4抑制剂(例如,CP-675,206、伊匹单抗);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(pioglitazone));NPC-1C;Aurora激酶抑制剂(例如,R763/AS703569)、CTGF抑制剂(例如,FG-3019);siG 12D LODER;以及放射疗法(例如,断层疗法(tomotherapy)、立体定向放射(stereotacticradiation)、质子疗法)、手术及其组合。
小细胞肺部癌症
可与本文所刚开的化合物联合用于治疗小细胞肺部癌症的示例性剂包括但不限于:依托泊苷、卡铂、顺铂、伊立替康、拓扑替康、吉西他滨、脂质体SN-38、苯达莫司汀、替莫唑胺、贝洛替康(belotecan)、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,索拉菲尼、舒尼替尼);VEGF抑制剂(例如,贝伐珠单抗、凡德他尼);癌症疫苗(例如,GVAX);Bcl-2抑制剂(例如,奥利默森钠(oblimersen sodium)、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(belinostat));SMO拮抗剂(例如,BMS833923);肽癌症疫苗;以及放射疗法(例如,调强放射疗法(IMRT)、大分割放疗(hypofractionatedradiotherapy)、乏氧指导放疗(hypoxia-guidedradiotherapy))、手术及其组合。
非小细胞肺部癌症
可与本文所公开的化合物联合用于治疗非小细胞肺部癌症的示例性剂包括但不限于: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、拓扑替康、培美曲塞二钠、阿扎胞苷、伊立替康、替加氟-吉美拉西-氧嗪酸钾(tegafurgimeracil-oteracilpotassium)、沙巴他滨(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、奈昔妥珠单抗(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,索拉菲尼、舒尼替尼、帕唑帕尼、AMG 706、XL184、MGCD265、BMS-690514、R935788)、VEGF抑制剂(例如,恩度(endostar)、内皮他丁(endostatin)、贝伐珠单抗、西地尼布、BIBF 1120、阿昔替尼、替沃扎尼(tivozanib)、AZD2171)、癌症疫苗(例如,BLP25脂质体疫苗、GVAX、重组DNA和表达L523S蛋白的腺病毒)、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、伊克昔佐米(ixazomid))、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(cixutumumab)、MK-0646、OSI906、CP-751,871、BIIB022)、羟基氯喹、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、地磷莫司(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、tretinoin)、抗体-药物结合物(例如,SGN-15)、双磷酸盐(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(tinzaparin)、依诺肝素)、GSK1572932A、褪黑素、talactoferrin、双美司钠、拓扑异构酶抑制剂(例如,氨柔比星(amrubicin)、依托泊苷、karenitecin)、奈非那韦(nelfinavir)、cilengitide、ErbB3抑制剂(例如,MM-121、U3-1287)、存活蛋白抑制剂(例如,YM155、LY2181308)、甲磺酸艾日布林(eribulin mesylate)、COX-2抑制剂(例如,塞来昔布)、培非格司亭、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结合物、二氯乙酸盐(DCA)、HGF抑制剂(例如,SCH 900105)、SAR240550、PPARγ激动剂(例如,CS-7017)、γ分泌酶抑制剂(例如,R04929097)、表观遗传学疗法(例如,5-阿扎胞苷)、硝酸甘油、MEK抑制剂(例如,AZD6244)、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(fondaparinux)、血管阻断剂(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)、epothilone类似物(例如,伊沙匹隆(ixabepilone))、纺锤体驱动蛋白(kinesin-spindle)抑制剂(例如,4SC-205)、端粒靶向剂(例如,KML-001)、P70途径抑制剂(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。
卵巢癌症
可与本文所公开的化合物联合用于治疗卵巢癌症的示例性剂包括但不限于:化疗剂(例如,紫杉醇或紫杉醇剂;多西他赛;卡铂;吉西他滨;多柔比星;拓扑替康;顺铂;伊立替康、TLK286、异环磷酰胺、奥拉帕利(olaparib)、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);葛瑞林(ghrelin)拮抗剂(例如,AEZS-130)、免疫疗法(例如,APC8024、奥哥伏单抗(oregovomab)、OPT-821)、酪氨酸激酶抑制剂(例如,EGFR抑制剂(例如,厄洛替尼)、双抑制剂(例如,E7080)、多激酶抑制剂(例如,AZD0530、JI-101、索拉菲尼、舒尼替尼、帕唑帕尼)、ON 01910.Na)、VEGF抑制剂(例如,贝伐珠单抗、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,karenitecin、伊立替康)、HDAC抑制剂(例如,丙戊酸盐、伏立诺他)、叶酸盐受体抑制剂(例如,法雷珠单抗(farletuzumab))、血管生成素抑制剂(例如,AMG 386)、epothilone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、AMG479)、PARP抑制剂(例如,veliparib、AG014699、iniparib、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)、斯达汀(例如,洛伐他汀(lovastatin))、拓扑异构酶1抑制剂(例如,NKTR-1 02)、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,AMG 102)、EGEN-001、Polo样激酶1抑制剂(例如,BI 6727)、γ分泌酶抑制剂(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-毒素连接物)、SB-485232、血管阻断剂(例如,A VE8062)、整联蛋白抑制剂(例如,EMD525797)、纺锤体驱动蛋白抑制剂(例如,4SC-205)、revlimid、HER2抑制剂(例如,MGAH22)、ErrB3抑制剂(例如,MM-121)、放射疗法;以及其组合。
骨髓瘤
可与本文所公开的化合物联合施用以治疗骨髓瘤的示例性剂包括但不限于: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等人(2011)J of American Society for Blood andMarrowTransplantation 17(8):1133-145)、肿瘤抗原脉冲的树突状细胞、肿瘤细胞和树突状细胞的融合物(例如,电融合物)或者以由恶性浆细胞产生的免疫球蛋白独特型的疫苗接种(综述于Yi,Q.(2009)Cancer J.15(6):502-10)。
肾细胞癌
可与本文所公开的化合物联合施用以治疗肾细胞癌的示例性剂包括但不限于:白介素-2或干扰素-α、靶向剂(例如,VEGF抑制剂,诸如VEGF的单克隆抗体,例如贝伐珠单抗(Rini,B.I.等人(2010)J.Clin.Oncol.28(13):2137-2143));VEGF酪氨酸激酶抑制剂,诸如舒尼替尼、索拉菲尼、阿昔替尼和帕唑帕尼(综述于Pal S.K.等人(2014)Clin.Advances inHematology&Oncology 12(2):90-99));RNAi抑制剂);或者VEGF信号传导的下游调节剂抑制剂,例如,雷帕霉素的哺乳动物靶标抑制剂(mTOR),例如,依维莫司和替西罗莫司(Hudes,G.等人(2007)N.Engl.J.Med.356(22):2271-2281;Motzer,R.J.等人(2008)Lancet 372:449-456)。
慢性骨髓性白血病
可与本文所公开的化合物联合施用以治疗慢性骨髓性白血病(CML)的示例性剂包括但不限于:化疗剂(例如,阿糖胞苷、羟基脲、氯法拉滨(clofarabine)、美法仑、塞替派、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、尼洛替尼)、双抑制剂(例如,达沙替尼、博舒替尼)、多激酶抑制剂(例如,DCC-2036、普纳替尼(ponatinib)、索拉菲尼、舒尼替尼、RGB-286638))、干扰素α、类固醇、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/微粒结合的抗CD3/抗CD28、自体细胞因子诱导的杀伤细胞(CIK)、AHN-12)、CD52靶向剂(例如,阿仑珠单抗)、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)、羟基氯喹、类视色素(例如,芬维A胺)、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,veliparib)、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。
慢性淋巴细胞白血病
可与本文所公开的化合物联合施用以治疗慢性淋巴细胞白血病(CLL)的示例性剂包括但不限于:化疗剂(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,阿仑珠单抗)、泼尼松龙(prednisolone)、阿法达贝泊汀(darbepoetin alfa)、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/微粒结合抗CD3/抗CD28、自体细胞因子诱导的杀伤细胞(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(milatuzumab))、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)、羟基氯喹、哌立福新、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(plerixafor)、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)、低氧激活前药(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、干细胞移植以及其组合。
急性淋巴细胞白血病
可与本文所公开的化合物联合施用以治疗急性淋巴细胞白血病(ALL)的示例性剂包括但不限于:化疗剂(例如,泼尼松龙、地塞米松、长春新碱、门冬酰胺酶、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(annamycin)、白消安、依托泊苷、卡培他滨、地西他滨、阿扎胞苷、拓扑替康、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、尼洛替尼)、ON 01910.Na、多激酶抑制剂(例如,索拉菲尼))、CD-20靶向剂(例如,利妥昔单抗)、CD52靶向剂(例如,阿仑珠单抗)、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、门冬酰胺酶、CD-22靶向剂(例如,依帕珠单抗(epratuzumab)、英妥珠单抗(inotuzumab))、免疫疗法(例如,自体细胞因子诱导的杀伤细胞(CIK)、AHN-12)、博纳吐单抗(blinatumomab)、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,veliparib)、EZN-2285、骨髓移植、干细胞移植、放射疗法以及其组合。
急性髓系白血病
可与本文所公开的化合物联合施用以治疗急性髓系白血病(AML)的示例性剂包括但不限于:化疗剂(例如,阿糖胞苷、柔红霉素、伊达比星、氯法拉滨、地西他滨、vosaroxin、阿扎胞苷、氯法拉滨、利巴韦林(ribavirin)、CPX-351、苏消安、elacytarabine、阿扎胞苷)、酪氨酸激酶抑制剂(例如,BCR/ABL抑制剂(例如,伊马替尼、尼洛替尼)、ON 01910.Na、多激酶抑制剂(例如,米哚妥林、SU 11248、喹扎替尼(quizartinib)、sorafinib))、免疫毒素(例如,吉妥单抗)、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样激酶激酶抑制剂(例如,BI 6727)、cenersen、CD45靶向剂(例如,BC8)、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、放射疗法以及其组合。
多发性骨髓瘤
可与本文所公开的化合物联合施用以治疗多发性骨髓瘤的示例性剂包括但不限于:化疗剂(例如,美法仑、阿米福汀(amifostine)、环磷酰胺、多柔比星、氯法拉滨、苯达莫司汀、氟达拉滨、阿霉素(adriamycin)、SyB L-0501)、沙利度胺、来那度胺、地塞米松、泼尼松(prednisone)、泊马度胺、蛋白酶体抑制剂(例如,硼替佐米、卡非佐米、伊克昔佐米)、癌症疫苗(例如,GVAX)、CD-40靶向剂(例如,SGN-40、CHIR-12.12)、哌立福新、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)、aplidin、周期蛋白依赖性激酶抑制剂(例如,PD-0332991、迪那西利(dinaciclib))、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,贝伐珠单抗)、普乐沙福、MEK抑制剂(例如,AZD6244)、IPH2101、阿托伐他汀(atorvastatin)、免疫毒素(例如,BB-10901)、NPI-0052、放射免疫治疗剂(例如,钇Y90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、放射疗法以及其组合。
前列腺癌症
可与本文所公开的化合物联合施用以治疗前列腺癌症的示例性剂包括但不限于:化疗剂(例如,多西他赛、卡铂、氟达拉滨)、阿比特龙、激素疗法(例如,酰胺氟他胺、酰胺比卡鲁胺、酰胺尼鲁米特、乙酸环丙孕酮、酮康唑(ketoconazole)、氨基氨鲁米特、阿巴瑞克(abarelix)、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,拉帕替尼(lapatanib))、多激酶抑制剂(例如,索拉菲尼、舒尼替尼))、VEGF抑制剂(例如,贝伐珠单抗)、TAK-700、癌症疫苗(例如,BPX-101、PEP223)、来那度胺、TOK-001、IGF-1抑制剂受体抑制剂(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)、羟基氯喹、mTOR抑制剂(例如,依维莫司)、乳酸多韦替尼、二吲哚基甲烷、依法韦伦(efavirenz)、OGX-427、染料木素、IMC-303、巴氟替尼(bafetinib)、CP-675,206、放射疗法、手术或其组合。
霍奇金氏淋巴瘤
可与本文所公开的化合物联合用于治疗霍奇金氏淋巴瘤的示例性剂包括但不限于:化疗剂诸如多柔比星(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、甲基泼尼松龙(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(单独或以组合的形式);本妥昔单抗维布妥昔单抗(Adcetris,CD30抗体药物结合物);碘131-CHT25抗体药物结合物;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途径抑制剂;Bcl-2抑制剂(例如,维奈托克(venetoclax));Mcl-1抑制剂;多激酶抑制剂诸如BAY 43-9006(索拉菲尼);蛋白酶体抑制剂(例如,硼替佐米(Velcade)、NPI-0052);双PI3K/HDAC靶向抑制剂(例如,CUDC-907);NF-kB抑制剂;抗PD-1抗体(例如,纳武单抗、帕博利珠单抗);抗CTLA-4抗体(例如,伊匹单抗);抗CD-20抗体(例如,利妥昔单抗);抗CD40抗体;抗CD80抗体;以及放射疗法(例如,断层疗法、立体定向放射、质子疗法)、手术及其组合。
非霍奇金氏淋巴瘤
可与本文所公开的化合物联合用于治疗非霍奇金氏淋巴瘤的示例性剂包括但不限于:化疗剂诸如多柔比星(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、甲基泼尼松龙(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(单独或以组合的形式);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途径抑制剂;AKT抑制剂(例如,RX-0201);Bcl-2抑制剂(例如,维奈托克);Mcl-1抑制剂;多激酶抑制剂诸如BAY 43-9006(索拉菲尼);蛋白酶体抑制剂(例如,硼替佐米(Velcade)、NPI-0052);双PI3K/HDAC靶向抑制剂(例如,CUDC-907);NF-kB抑制剂;BTK抑制剂(例如,依鲁替尼(ibrutinib));BET溴结构域抑制剂;抗PD-1抗体(例如,纳武单抗、帕博利珠单抗);抗CTLA-4抗体(例如,伊匹单抗);抗CD-20抗体(例如,利妥昔单抗);抗CD40抗体;抗CD80抗体;以及放射疗法(例如,断层疗法、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)化合物可与癌症治疗的非化学方法联合施用。在另一实施方案中,本公开的式(I)化合物可与放射疗法联合施用。在另一实施方案中,本公开的式(I)化合物可与手术、热消融、聚焦超声疗法、冷冻疗法或这些疗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与本公开的一种或多种其他化合物联合施用。此外,此类组合可与其他治疗剂,诸如合适于治疗癌症、免疫或神经疾病的其他剂,诸如上文确定的剂联合施用。在某些实施方案中,联合施用一种或多种额外化疗剂与本公开的式(I)化合物提供了协同作用。在某些实施方案中,联合施用一种或多种额外化疗剂提供了相加作用。
药物组合物
在某些实施方案中,本公开提供了一种药物组合物,其包含如本文所公开的式(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配制所公开的式(I)化合物以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需要的个体。在某些实施方案中,个体为哺乳动物,诸如人或非人哺乳动物。当施用于动物诸如人时,所述组合物或所述化合物优选以药物组合物的形式施用,所述药物组合物包含例如本公开的式(I)化合物和药学上可接受的载体。药学上可接受的载体为本领域中熟知的,并且包括例如水性溶液诸如水或生理缓冲盐水或者其他溶剂或媒介物诸如乙二醇、甘油、油诸如橄榄油或可注射有机酯。在优选实施方案中,当此类药物组合物用于人施用时,特别是用于侵入性施用途径(即,诸如避免通过上皮屏障的运输或扩散的途径,诸如注射或植入)时,水性溶液为无热原的或基本上无热原的。可以选择赋形剂,例如以实现剂的延迟释放或选择性靶向一种或多种细胞、组织或器官。药物组合物可以呈剂量单位形式,诸如片剂、胶囊剂(包括洒胶囊剂和明胶胶囊剂)、颗粒剂、用于重构的冻干剂、散剂、溶液剂、糖浆剂、栓剂、注射剂等。所述组合物也可以存在于透皮递送系统中,例如皮肤贴剂。所述组合物也可以存在于适合局部施用的溶液中,诸如滴眼剂。
药学上可接受的载体可含有生理上可接受的剂,其起到例如稳定化合物诸如本公开的式(I)化合物、增加其溶解度或增加其吸收的作用。此类生理上可接受的剂包括例如碳水化合物,诸如葡萄糖、蔗糖或葡聚糖;抗氧化剂,诸如抗坏血酸或谷胱甘肽;螯合剂;低分子量蛋白质;或其他稳定剂或赋形剂。药学上可接受的载体(包括生理上可接受的剂)的选择取决于(例如)组合物的施用途径。药物组合物的制备可为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(制备剂)也可为脂质体或其他聚合物基质,其中可以掺入例如本公开的式(I)化合物。脂质体,例如包含磷脂或其他脂质的脂质体,可为制造和施用相对简单的无毒、生理上可接受并且可代谢的载体。
本文采用短语“药学上可接受的”指在合理医学判断范围内、适用于与人类和动物组织接触而没有过量毒性、刺激、过敏反应或其他问题或并发症、与合理的利益/风险比相称的那些化合物、材料、组合物和/或剂型。
如本文所用,短语“药学上可接受的载体”意指药学上可接受的材料、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。在与制剂的其他成分相容并且对患者无害的意义上,每种载体必须是“可接受的”。可以用作药学上可接受的载体的材料的一些实例包括:(1)糖,诸如乳糖、葡萄糖和蔗糖;(2)淀粉,诸如玉米淀粉和马铃薯淀粉;(3)纤维素及其衍生物,诸如羧甲基纤维素钠、乙基纤维素和乙酸纤维素;(4)黄芪胶粉;(5)麦芽;(6)明胶;(7)滑石;(8)赋形剂,诸如可可脂和栓剂蜡;(9)油,诸如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油和大豆油;(10)二醇,诸如丙二醇;(11)多元醇,诸如甘油、山梨醇、甘露醇和聚乙二醇;(12)酯,诸如油酸乙酯和月桂酸乙酯;(13)琼脂;(14)缓冲剂,诸如氢氧化镁和氢氧化铝;(15)褐藻酸;(16)无热原质水;(17)等渗盐水;(18)林格氏溶液;(19)乙醇;(20)磷酸盐缓冲溶液;以及(21)药物组合物中采用的其他无毒相容性成分。
药物组合物(制备剂)可通过多种施用途径中的任一种施用于受试者,所述途径包括例如口服途径(例如,以水性溶液或非水性溶液或混悬液的形式的药水、片剂、胶囊剂(包括洒胶囊剂和明胶胶囊剂)、大丸剂、散剂、颗粒剂、涂敷于舌头的糊剂);通过口腔粘膜吸收途径(例如,舌下);肛门、直肠或阴道途径(例如作为阴道栓剂、乳霜或泡沫);肠胃外途径(包括肌肉内、静脉内、皮下或鞘内,例如作为无菌溶液或混悬剂);鼻腔途径;腹膜内途径;皮下途径;透皮途径(例如作为贴在皮肤上的贴剂);以及局部途径(例如,作为涂敷于皮肤上的乳霜、药膏或喷雾剂或作为滴眼剂)。所述化合物还可以被配制成用于吸入。在某些实施方案中,化合物可简单地溶解或悬浮于无菌水中。适当的施用途径和合适于其的组合物的细节可见于例如美国专利号6,110,973、5,763,493、5,731,000、5,541,231、5,427,798、5,358,970和4,172,896以及其中所引用的专利中。
制剂可方便地以单位剂型呈现并且可通过药学领域中熟知的任何方法来制备。可与载体材料组合以产生单剂型的活性成分的量将根据正治疗的宿主、特定的施用模式而变化。可与载体材料组合以产生单剂型的活性成分的量一般将为产生治疗作用的化合物的量。一般来说,在一百份中,此量的范围将为约1%至约99%活性成分、优选约5%至约70%、最优选约10%至约30%。
制备这些制剂或组合物的方法包括以下步骤:使活性化合物,诸如本公开的式(I)化合物,与载体和任选的一种或多种辅助成分缔合。一般来说,通过将本公开的化合物与液体载体、或精细分开的固体载体、或两者均匀且密切地缔合,然后必要时使产物成形来制备制剂。
适用于口服施用的本公开的制剂可呈以下形式:胶囊剂(包括洒胶囊剂和明胶胶囊剂)、扁囊剂、丸剂、片剂、锭剂(使用经调味的基质,通常为蔗糖和阿拉伯胶或西黄蓍胶)、冻干剂、散剂、颗粒剂或作为在水性液体或非水性液体中的溶液剂或混悬剂、或作为水包油或油包水乳剂、或作为酏剂或糖浆剂、或作为软锭剂(pastille)(使用惰性基质,诸如明胶和甘油,或蔗糖和阿拉伯胶)和/或为漱口剂等,每种均含有预定量的作为活性成分的本公开化合物。组合物或化合物还可以作为大丸剂、糖饵剂(electuary)或糊剂施用。
为了制备口服施用的固体剂型(胶囊剂(包括洒胶囊剂和明胶胶囊剂)、片剂、丸剂、糖锭剂、散剂、颗粒剂等),将所述活性成分与一种或多种药学上可接受的载体(诸如柠檬酸钠或磷酸二钙)和/或以下中的任何一种进行混合:(1)填充剂或增充剂,诸如淀粉、乳糖、蔗糖、葡萄糖、甘露醇、和/或硅酸;(2)粘合剂,例如像,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)湿润剂,诸如甘油;(4)崩解剂,诸如琼脂、碳酸钙、马铃薯或木薯淀粉、藻酸、某些硅酸盐、以及碳酸钠;(5)溶液延迟剂,诸如石蜡;(6)吸收加速剂,诸如季铵化合物;(7)润湿剂,例如像,乙酰醇和单硬脂酸甘油酯;(8)吸收剂,诸如高岭土和膨润土;(9)润滑剂,诸如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、月桂基硫酸钠及其混合物;(10)络合剂,诸如修饰和未修饰的环糊精;以及(11)着色剂。在胶囊剂(包括洒胶囊剂和明胶胶囊剂)、片剂以及丸剂的情况下,所述药物组合物还可以包含缓冲剂。在使用赋形剂(诸如乳糖(lactose)或乳糖(milk sugar))以及高分子量聚乙二醇等的软质和硬质填充的明胶胶囊中还可采用相似类型的固体组合物作为填充剂。
片剂可通过压制或模制来制备,任选地具有一种或多种辅助成分。可使用粘合剂(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(例如羧甲基淀粉钠或交联羧甲基纤维素钠)、表面活性剂或分散剂制备压制片剂。模制片剂可以通过在合适的机器中模制用惰性液体稀释剂湿润的粉末状化合物的混合物来制备。
所述片剂和药物组合物的其他固体剂型,诸如糖锭剂、胶囊剂(包括洒胶囊剂和明胶胶囊剂)、丸剂和颗粒剂,可以任选地用包衣和衣壳(诸如肠溶衣和药物制剂领域中众所周知的其他包衣)刻痕或制备。还可以使用例如提供所需的释放曲线的不同比例的羟丙基甲基纤维素、其他聚合物基质、脂质体和/或微球来配制它们以便使活性成分缓慢或受控释放。可通过例如过滤通过截留细菌的过滤器或通过在使用前即刻掺入为可溶于无菌水或一些其他无菌注射介质的呈无菌固体组合物形式的灭菌剂使它们灭菌。这些组合物还可任选含有遮光剂并且还可为仅在或优先在胃肠道的某一部分任选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质和蜡。所述活性成分还可呈微囊化形式并且适当地具有一种或多种上述赋形剂。
可用于口服施用的液体剂型包括药学上可接受的乳剂、用于重构的冻干剂、微乳剂、溶液剂、混悬剂、糖浆剂和酏剂。除活性成分以外,液体剂型可含有通常在本领域中使用的惰性稀释剂,例如像水或其他溶剂、环糊精及其衍生物、溶解剂和乳化剂诸如乙醇、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(具体地是棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油以及芝麻油)、甘油、四氢糠醇、聚乙二醇和山梨醇酐的脂肪酸酯及其混合物。
除了惰性稀释剂,所述口服组合物还可包含助剂,诸如润湿剂、乳化剂和助悬剂、甜味剂、矫味剂、着色剂、芳香剂和防腐剂。
除活性化合物以外,混悬剂还可含有助悬剂,例如像乙氧基化异硬脂醇、聚氧乙烯山梨醇和脱水山梨糖醇酯、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作为栓剂存在,其可通过将一种或多种活性化合物与一种或多种适合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)混合来制备所述栓剂,并且所述栓剂在室温下为固体,但在体温下为液体并且因此将会在直肠或阴道中熔化并且释放活性化合物。
用于向口施用的药物组合物的制剂可以以漱口剂、或口服喷雾剂或口服药膏的形式呈现。
替代地或另外地,组合物可以被配制成用于通过导管、支架、金属丝或其他腔内装置递送。通过此类装置的递送可能对于递送到膀胱、尿道、输尿管、直肠或肠特别有用。
适用于阴道施用的制剂还包括含有本领域已知的适合的此类载体的阴道栓剂、止血栓、乳霜、凝胶剂、糊剂、泡沫剂或喷雾制剂。
用于局部或经皮施用的剂型包括散剂、喷雾剂、药膏、糊剂、乳霜、洗剂、凝胶剂、溶液剂、贴剂以及吸入剂。可以在无菌条件下将活性化合物与药学上可接受的载体以及与可能需要的任何防腐剂、缓冲剂、或推进剂进行混合。
除活性化合物以外,所述药膏、糊剂、乳双和凝胶剂可含有赋形剂,诸如动物和蔬菜脂肪、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。
除活性化合物以外,散剂和喷雾剂可含有赋形剂诸如乳糖、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。喷雾剂可额外含有常规推进剂,诸如氯氟烃和挥发性未取代的烃(诸如丁烷和丙烷)。
透皮贴剂具有提供本公开的化合物向身体的受控递送的附加优点。此类剂型可通过将活性化合物溶解或分散于适当的介质中来制备。吸收促进剂也可用于增加化合物穿过皮肤的通量。此类通量的速率可通过提供速率控制膜或通过将化合物分散于聚合物基质或凝胶中来控制。
眼科制剂、眼用软膏剂、散剂、溶液等等也涵盖在本公开的范围内。示例性眼科制剂描述于美国公开号2005/0080056、2005/0059744、2005/0031697和2005/004074以及美国专利号6,583,124中,其内容以引用的方式整体并入本文。如果需要的话,液体眼科制剂具有与泪液、房水或玻璃体液类似的性质或与此类液体相容。优选的施用途径为局部性施用(例如,局部施用,例如滴眼剂,或通过植入物施用)。
栓剂也被认为在本公开的范围内。
如本文所用,短语“肠胃外施用”和“肠胃外地施用”意指除了肠内施用和局部施用以外的、通常通过注射进行的施用模式,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、真皮内、腹膜内、经气管、皮下、表皮下、关节内、囊下、蛛网膜下、脊柱内以及胸骨内注射和输注。
适合于肠胃外施用的药物组合物包含一种或多种活性化合物与一种或多种药学上可接受的无菌等渗水性溶液或非水性溶液、分散液、混悬液或乳液,或可在临使用前复原成无菌可注射溶液或分散液的无菌散剂的组合,所述组合可以含有抗氧化剂、缓冲剂、抑菌剂、使制剂与预期受体的血液等渗的溶质、或助悬剂或增稠剂。
可用于本公开的药物组合物中的合适的水性和非水性载体的实例包括水、乙醇、多元醇(诸如甘油、丙二醇、聚乙二醇等等)和其合适的混合物、植物油(诸如橄榄油)和可注射有机酯(诸如油酸乙酯)。适当流动性可例如通过使用包衣材料(诸如卵磷脂),在分散液的情况下通过维持所需粒径和通过使用表面活性剂来维持。
这些组合物也可含有助剂,诸如防腐剂、润湿剂、乳化剂和分散剂。可通过包含各种抗菌剂和抗真菌剂例如尼泊金、三氯叔丁醇、苯酚山梨酸等确保防止微生物的作用。还可合乎需要的是在组合物中包含等渗剂,诸如糖、氯化钠等。另外,可通过包含延迟吸收的剂(诸如单硬脂酸铝和明胶)来实现可注射药物形式的延迟吸收。
在一些情况下,为了延长药物的效果,需要减缓皮下注射或肌肉内注射的药物的吸收。这可通过使用具有低水溶性的结晶或无定形材料的液态混悬剂来实现。药物的吸收速率则取决于其溶解速率,溶解速率进而可取决于晶体大小和晶形。可替代地,通过将药物溶解或混悬于油媒介物中来实现肠胃外施用的药物形式的延迟吸收。
可注射储库式形式是通过在诸如聚乳酸交酯-聚乙交酯等可生物降解聚合物中形成主题化合物的微囊化基质来制备。根据药物与聚合物的比率和所采用的具体聚合物的性质,可控制药物释放的速率。其他可生物降解聚合物的实例包括聚(原酸酯)和聚(酸酐)。也通过将药物截留在与身体组织相容的脂质体或微乳液中来制备储库式可注射制剂。
对于在本公开的方法中使用,活性化合物可以本身或以含有例如0.1%至99.5%(更优选地,0.5%至90%)的活性成分与药学上可接受的载体组合的药物组合物形式给予。
引入的方法也可由可再充电或可生物降解装置提供。近年来,已经开发了各种缓释聚合物装置并在体内进行了测试,以控制药物的递送,包括蛋白质生物药物。包括可生物降解和不可降解的聚合物二者在内的多种生物相容性聚合物(包括水凝胶)可用于形成植入物,以在特定靶标部位缓释化合物。
药物组合物中的活性成分的实际剂量水平可改变以便获得对于特定患者、组合物以及施用模式有效实现所需的治疗反应,而对患者无毒的活性成分的量。
选择的剂量水平将取决于多种因素,包括使用的特定化合物或化合物组合或其酯、盐或酰胺的活性;施用途径;施用时间;所使用的一种或多种特定化合物的排泄速率;治疗的持续时间;与所使用的一种或多种特定化合物组合使用的其他药物、化合物和/或材料;所治疗患者的年龄、性别、体重、状况、一般健康和先前的医疗史;以及在医学领域中熟知的类似因素。
具有本领域普通技术的医师或兽医可容易地确定并开出治疗有效量的所需药物组合物。例如,医师或兽医可在低于实现所需治疗效果所需水平的水平下开始药物组合物或化合物的剂量并逐步增加剂量,直到达到所需效果。“治疗有效量”意指足以引起所需治疗效果的化合物的浓度。通常应理解,化合物的有效量将根据受试者的体重、性别、年龄和医疗史而变化。影响有效量的其他因素可包括但不限于:患者病状的严重程度;所治疗的病症;化合物的稳定性;以及如果需要的话,与本公开的式(I)化合物一起施用的另一类型的治疗剂。可通过多次施用剂来递送较大的总剂量。确定功效和剂量的方法为本领域中的技术人员已知的(Isselbacher等人(1996)Harrison’s Principles of Internal Medicine第13版,1814-1882,以引用的方式并入本文)。
一般来说,在本公开的组合物和方法中使用的活性化合物的合适的日剂量将为化合物有效产生治疗效果的最低剂量的量。这种有效剂量将通常取决于上述因素。
如果需要的话,活性化合物的有效日剂量可任选地以单位剂型以在全天内以适当间隔分开施用的一个、两个、三个、四个、五个、六个或更多个亚剂量来施用。在本公开的某些实施方案中,活性化合物可每天施用两次或三次。在优选的实施方案中,活性化合物将每天施用一次。
接受这种治疗的患者是任何需要的动物,包括灵长类动物,特别是人,以及其他哺乳动物,诸如马、牛、猪和绵羊;以及一般的家禽和宠物。
润湿剂、乳化剂和润滑剂诸如月桂基硫酸钠和硬脂酸镁以及着色剂、释放剂、包衣剂、甜味剂、矫味剂和芳香剂、防腐剂和抗氧化剂也可存在于所述组合物中。
药学上可接受的抗氧化剂的实例包括:(1)水溶性抗氧化剂,诸如抗坏血酸、盐酸半胱氨酸、硫酸氢钠、焦亚硫酸钠、亚硫酸钠等;(2)油溶性抗氧化剂,诸如抗坏血酸棕榈酸酯、丁基化羟基茴香醚(BHA)、丁基化羟基甲苯(BHT)、卵磷脂、没食子酸丙酯、α-生育酚等;和(3)金属螯合剂,诸如柠檬酸、乙二胺四乙酸(EDTA)、山梨糖醇、酒石酸、磷酸等。
定义和缩写:
除非另有定义,否则本文所用的所有技术和科学术语具有相同的含义,并且此类术语的含义在其每次出现时都是独立的并且如本文的标的所属领域的技术人员通常所理解的。尽管如此并且除非另外说明,否则以下定义适用于整个说明书和权利要求书。化学名称、共用名称和化学结构可互换地用于描述相同的结构。如果使用化学结构和化学名称来指称化合物并且在结构与名称之间存在不明确性,则以结构为主。除非另外指示,否则无论术语是单独使用还是与其他术语组合使用,这些定义均适用。因此,“烷基”的定义适用于“烷基”以及“羟烷基”、“卤代烷基”、“--O-烷基”等的“烷基”部分。
除非另外特别说明,否则术语“本发明的一种或多种化合物”包括式(I)、或式(IA)、或式(IB)化合物或者其药学上可接受的盐及其立体异构体。
如本文所用,术语“任选的”或“任选地”意指随后描述的事件或情况可能发生或可能不发生,并且描述包括事件或情况发生的例子和不发生的例子。例如,“任选取代的烷基”是指烷基被取代的事件或情况以及烷基未被取代的事件或情况。
除非特别提及取代基,否则术语“取代的”是指具有取代主链的一个或多个碳原子上的氢的取代基的部分。应理解,“取代”或“被取代的”包括隐含的条件,即此类取代符合取代的原子和取代基的允许化合价,并且取代得到稳定的化合物,例如不自发进行转化(诸如通过重排、环化、消除等)的化合物。如本文所用,术语“取代的”预期包括有机化合物的所有可允许的取代基。在广义方面中,可允许的取代基包括有机化合物的非环状和环状、支化和未支化、碳环和杂环、芳族和非芳族取代基。对于适当的有机化合物,可允许的取代基可以为一个或多个并且为相同或不同的。出于本发明的目的,杂原子(诸如氮)可以具有氢取代基和/或满足杂原子化合价的本文所述有机化合物的任何可允许的取代基。取代基可包括本文所述的任何取代基,例如卤素、羟基、羰基(例如羧基、烷氧基、氧代、氨基、酰胺基、脒、硝基、叠氮基、杂芳基、芳烷基或芳族或杂芳族部分。本领域技术人员将理解,适当时,取代基可本身为取代的。
如本文所用,术语“烷基”是指饱和脂族基团,包括但不限于C1-C10直链烷基或C3-C10支链烷基。优选地,“烷基”是指C1-C6直链烷基或C3-C6支链烷基。最优选地,“烷基”是指C1-C4直链烷基或C3-C8支链烷基。“烷基”的实例包括但不限于甲基、乙基、1-丙基、2-丙基、正丁基、仲丁基、叔丁基、1-戊基、2-戊基、3-戊基、新戊基、1-己基、2-己基、3-己基、1-庚基、2-庚基、3-庚基、4-庚基、1-辛基、2-辛基、3-辛基和4-辛基。“烷基”可为任选取代的。
如本文所用的术语“芳基”包括取代或未取代的单环芳族基团,在所述基团中环的每个原子都为碳。优选地,环为5至7元环,更优选地为6元环。优选地,术语‘芳基’包括苯基。
如本文所用,表述“(p-OH)芳基”意指被羟基(-OH)对位取代的芳基,其中芳基是如上文所定义的。
术语“杂芳基”包括取代或未取代的芳族单环结构,优选地5至7元环,更优选地5至6元环,其环结构包括至少一个杂原子,优选地一至四个杂原子,更优选地一个或两个杂原子。特别地,术语“杂芳基”包括咪唑。杂芳基可如化合价所允许在一个或多个位置处被本文所述的任何任选的取代基取代。
如本文所用,术语“芳烷基”包括通过置换一个或多个氢原子而被一个或多个烷基取代的芳基。
如本文所用,术语“烷氧基”是指–O-芳基,其中芳基如上文所定义。
如本文所用,术语“杂芳基烷基”是指连接至杂芳基的烷基,其中‘烷基’和‘杂芳基’如上文所定义。
如本文所用,“预防”病症或病状的治疗剂是指以下化合物,其在统计学样品中,相对于未治疗对照样品在所治疗样品中降低病症或病状的发生率,或者相对于未治疗对照样品延迟病症或病状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”治疗是本领域认可的,并且包括向宿主施用主题组合物中的一种或多种。如果在临床表现不希望的病状(例如,宿主动物的疾病或其他不希望的状态)之前施用,那么治疗是预防性的(即,其保护宿主免于发展不希望的病状),而如果在表现不希望的病状之后施用,那么治疗是治疗性的(即,其旨在减弱、改善或稳定现有的不希望的病状或其副作用)。
术语“前药”旨在涵盖在生理条件下转化为本发明的治疗活性剂(例如,式(I)化合物)的化合物。用于制备前药的常见方法包括一个或多个选定的部分,这些部分在生理条件下水解以展现所需的分子。在其他实施方案中,前药通过宿主动物的酶促活性转化。例如,酯或碳酸盐(例如,醇或羧酸的酯或碳酸盐)是本发明优选的前药。在某些实施方案中,可以用对应的合适的前药代替上文表示的制剂中的式(I)的化合物的一些或全部,例如其中母体化合物中的羟基以酯形式存在,或母体化合物中存在的碳酸盐或羧酸以酯形式存在。
如本文所用,术语“包含(comprise或comprising)”通常的意思是包括,也就是说允许存在一种或多种附加的(未指定的)特征或组分。
如本文所用,术语“包括(including)”以及其他形式诸如“include”、“includes”和“included”不为限制性的。
在整个说明书和权利要求书中,本发明的化合物和/或其制备中结构上提及的‘L-苏氨酸残基’可通过下式中的任何一个来表示。这种表示可解释为具有类似结构基序的其他化合物。
本发明包括本发明化合物的药学上可接受的盐以及它们在本发明的组合物和方法中的用途。在某些实施方案中,本发明的预期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,本发明的预期盐包括但不限于L-精氨酸、苯乙苄胺、苄星青霉素、甜菜碱、氢氧化钙、胆碱、丹醇、二乙醇胺、二乙胺、2-(二乙氨基)乙醇、乙醇胺、乙二胺、N-甲基葡糖胺、海巴明盐、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,本发明的预期盐包括但不限于Na、Ca、K、Mg、Zn或其他金属盐。
药学上可接受的酸加成盐也可以各种溶剂化物的形式存在,诸如与水、甲醇、乙醇、二甲基甲酰胺等的溶剂化物。也可以制备此类溶剂化物剂的混合物。这类溶剂化物的来源可来自结晶的溶剂,为制备或结晶的溶剂中固有的,或者为偶然引入这类溶剂中的。
术语“立体异构体”是指诸如本发明的化合物的任何对映异构体、非对映异构体或几何异构体。当本发明的化合物为手性的时,它们可以外消旋或旋光形式存在。由于根据本发明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含一种对映体的化合物。在这些情况下,可以通过本领域技术人员已知的化学或物理措施将最终产物甚至中间体分离为对映体化合物,或者甚至就此用于合成中。在外消旋胺的情况下,通过与旋光拆分剂反应,由混合物形成非对映异构体。合适的拆分剂的实例为旋光酸,诸如R和S形式的酒石酸、二乙酰酒石酸、二苯甲酰基酒石酸、扁桃酸、苹果酸、乳酸、合适的N-保护的氨基酸(例如N-苯甲酰脯氨酸或N-苯磺酰脯氨酸)或各种旋光樟脑磺酸。同样有利的是借助旋光拆分剂(例如二硝基苯甲酰基苯基甘氨酸、三乙酸纤维素或碳水化合物的其他衍生物或固定在硅胶上的手性衍生的甲基丙烯酸酯聚合物)的色谱对映体拆分。
在某些实施方案中,本发明的化合物可为外消旋的。在某些实施方案中,本发明的化合物可以富含一种对映体。例如,本发明的化合物可具有大于30%的ee、40%的ee、50%的ee、60%的ee,70%的ee、80%的ee、90%的ee或甚至95%或更高的ee。在某些实施方案中,本发明的化合物可以具有一个以上的立体中心。在某些此类实施方案中,本发明的化合物可以富含一种或多种非对映异构体。例如,本发明的化合物可具有大于30%的de、40%的de、50%的de、60%的de,70%的de、80%的de、90%的de或甚至95%或更高的de。
术语“受试者”包括哺乳动物(特别是人)和其他动物,诸如驯养动物(例如,包括猫和狗的家庭宠物)和非驯养动物(诸如野生动物)。
整个说明书中所用的缩写可以在下文中以其特定含义来概括。
℃(摄氏度);%(百分比);盐水(NaCl溶液);Boc(叔丁氧羰基);DIC:N,N′-二异丙基碳二亚胺;DIPEA(N,N-二异丙基乙胺);DMF(二甲基甲酰胺);EtOH(乙醇);EtOAc(乙酸乙酯);Fmoc(9-芴甲氧羰基);g或gr(克);HOBt(1-羟基苯并三唑);h或hr(小时);HPLC(高效液相色谱);LCMS(液相色谱质谱);mmol(毫摩尔);M(摩尔);μl(微升);mL(毫升);mg(毫克);min(分钟);NaHCO3(碳酸氢钠);NMM(N-甲基吗啉);Na2SO4(硫酸钠);NH2OH.HCl(盐酸羟胺);制备型HPLC(制备型高效液相色谱);TEA/Et3N(三乙胺);TLC(薄层色谱);THF(四氢呋喃);TIPS(三异丙基硅烷);tR(保留时间);等。
实验
分析型HPLC方法:
方法-1:Hilic方法
柱:ZIC-HILLIC(Sequant),C18(4.6X 250mm,5μm)200A°
流量:1.0mL/min;柱温:25.0℃
流动相:A=5mM乙酸铵PH-4.0(乙酸),B=ACN
梯度(时间/B%):0/85、2/85、20/40、20.1/85、30/85。
方法2:DiBoc方法
柱:PhenomenexAeris肽C18(2)100A(250x 4.6mm,3.6μ)
流量:1.0mL/min;柱温:25.0℃
流动相:A=0.1%TFA(Aq),B=ACN
梯度(时间/%B):0/2、2/2、15/70、20/95、25/100、30/100、32/2、42/2
制备型HPLC方法:
在SeQuant ZIC HILIC 200A°柱(10mm×250mm,5μm)上进行制备型HPLC,流速:5.0mL/min。所用的洗脱条件为:缓冲液A:5mmol乙酸铵(用乙酸调整至pH-4),缓冲液B:乙腈,用90%缓冲液B平衡柱,并在20min内通过90%至40%缓冲液B的梯度洗脱。
LCMS在AP1 2000LC/MS/MS三重四极杆(Applied biosystems)以及具有G1315 BDAD的Agilent 1100系列HPLC上使用Mercury MS柱进行,或使用Agilent LC/MSD VL单重四极杆以及具有G1315 B DAD的Agilent 1100系列HPLC使用Mercury MS柱进行,或使用Shimadzu LCMS 2020单重四极杆以及具有SPD-20A DAD的Prominence UFLC系统进行。
实施例1:((S)-2-(3-((S)-1-氨基-2-(4-羟苯基)乙基)-1,2,4-噁二唑-5-基)吡咯烷-1-羰基)-L-天冬氨酸(化合物1)
步骤1a:化合物1b的合成
将氯甲酸乙酯(4.8g,44.4mmol)和NMM(4.5g,44.4mmol)加入化合物1a(10.0g,29.63mmol)在THF(120mL)中的溶液中并在-20℃下搅拌20min。20分钟之后,将25%的氨水(30mL)加入活性混合酸酐中并在0-5℃下搅拌30min。通过TLC分析确认反应完成。将挥发物在减压下蒸发并在水与乙酸乙酯之间分配。先后用NaHCO3溶液、柠檬酸溶液和盐水溶液洗涤有机层。经Na2SO4干燥分离的有机层,将其过滤并在减压下蒸发以得到8.9g化合物1b。LCMS:337.4[M+H]+。
步骤1b:化合物1c的合成
将三氟乙酸酐(TFAA)(14.2g,67.77mmol)加入化合物1b(7.6g,22.59mmol)在吡啶(9.92mL,112.96mmol)中的溶液中并在室温下搅拌2h。通过TLC分析确认反应完成。将挥发物在减压下蒸发并在水与乙酸乙酯之间分配。先后用NaHCO3溶液、柠檬酸和盐水溶液洗涤有机层。经Na2SO4干燥分离的有机层,将其过滤并在减压下蒸发以得到5.5g化合物1c,其直接用于下一步骤。
步骤1c:化合物1d的合成
将盐酸羟胺(1.62g,23.56mmol)、水(9.4mL)和碳酸钾(2.17g,15.7mmol)加入化合物1c(2.5g,7.8mmol)在EtOH(28mL)中的溶液中并在86℃下搅拌4h。通过TLC分析确认反应完成。将挥发物在减压下蒸发并在水与乙酸乙酯之间分配。将有机层用盐水溶液洗涤,经Na2SO4干燥,然后过滤并在减压下蒸发,以得到2.4g化合物1d。LCMS:351.8[M+H]+。
步骤1d:化合物1e的合成
在0℃下向Fmoc-Pro-OH(1.5g,4.5mmol)在DMF(20mL)中的溶液中加入HOBt(1.92g,14.23mmol)和DIC(1.8g,14.23mmol)并搅拌15min。在室温下加入化合物1d(2g,5.7mmol)并继续搅拌1h,然后在室温下搅拌2h。通过TLC分析确认反应完成。将反应混合物用冰水淬灭,将沉淀的白色固体过滤,用水(150mL)洗涤并在减压下干燥。将固体与乙醚(250mL)一起搅拌15min,过滤并干燥,以得到3.2g化合物1e。LCMS:671.1[M+H]+。
步骤1e:化合物1f的合成
在室温下向化合物1e(3.2g,4.7mmol)在乙腈(30ml)中的溶液中添加乙酸(3.2mL)并在90℃下回流12h。通过TLC分析确认反应完成。将挥发物在减压下蒸发,以获得粗半固体,将其用水和乙酸乙酯稀释。先后用NaHCO3溶液、柠檬酸和盐水溶液洗涤有机层。将有机层经Na2SO4干燥,过滤并在减压下蒸发,以得到粗固体,将其用在己烷(50ml)中的10%乙腈稀释并搅拌2h,以得到白色固体。将获得的白色固体过滤并用正戊烷(50mL)洗涤且干燥,以得到0.9g化合物1f。LCMS:653.4[M+H]+。
步骤1f:化合物1g的合成
在0℃下向在DCM中的20%哌啶的溶液(15mL)中加入化合物1f(1.2g,1.83mmol)并在相同温度下搅拌1h。通过TLC分析确认反应完成。将反应混合物在减压下浓缩并用己烷稀释,搅拌且过滤。将过滤的固体溶解于EtOAc中并用饱和NaHCO3溶液、盐水溶液洗涤,经Na2SO4干燥,过滤且蒸发,以得到0.65g化合物1g。LCMS 431.1[M+H]+。
步骤1g:化合物1i的合成
将DIPEA(0.19g,1.5mmol)加入化合物1h(0.74g,1.81mmol,根据下文给出的程序制备)和化合物1g(0.65g,1.5mmol)在EtOH(10mL)中的溶液中并在室温下搅拌3h。将挥发物蒸发并在乙酸乙酯与水之间分配。将有机层用饱和NaHCO3、10%柠檬酸、盐水溶液洗涤,经Na2SO4干燥并在减压下浓缩。将粗化合物通过使用在己烷中的25%乙酸乙酯的中性氧化铝柱色谱来纯化,以得到0.75g化合物1i。LCMS:702.4[M+H]+。
步骤1h:化合物1的合成
向化合物1i(0.75g,1.06mmol)的溶液中加入7.5mL三氟乙酸:TIPS:水的混合物(95:2.5:2.5)并在室温下搅拌2h。将所得反应混合物在减压下蒸发,用乙醚稀释并过滤,以得到0.4g粗化合物1。通过在实验条件下描述的制备型HPLC方法纯化粗固体材料。LCMS:434.3[M+H]+。HPLC RT(min):11.1
化合物1h的合成:
向H-Asp(OtBu)-OtBu(1.0g,3.54mmol)在CH2Cl2(20mL)中的溶液中加入吡啶(0.55g,7.08mmol),并在室温下将溶液搅拌10min。向此混合物中加入氯甲酸4-硝基苯酯(0.86g,4.25mmol)在CH2Cl2(20mL)中的溶液,并在室温下将所得混合物搅拌1h。反应完成(通过TLC确认)之后,将其用CH2Cl2(50mL)稀释并用1.0M硫酸氢钠溶液(50mL×2),接着用1.0M碳酸钠溶液(50mL×2)洗涤。将有机层经Na2SO4干燥,过滤且在减压下蒸发,以得到粗化合物1h,将其通过硅胶柱色谱(洗脱液:0-20%在己烷中的乙酸乙酯)纯化并得到0.75g化合物。
通过与实施例1(化合物1)中描述的类似的程序制备以下化合物,其中反应物、试剂的量、溶剂和反应条件具有适当的变化。下表中总结了化合物的表征数据。
实施例2:4-((S)-2-氨基-2-(5-((S)-吡咯烷-2-基)-1,2,4-噁二唑-3-基)乙基)苯酚(化合物14)
步骤2a:化合物2a的合成
根据实施例1(化合物1)的步骤1a至1c中所述的程序,通过使用Boc-Tyr(tBu)-OH合成化合物2a。
步骤2b:化合物2b的合成
在0℃下向Boc-Pro-OH(0.86g,3.41mmol)在DMF(20mL)中的溶液中加入HOBt(1.4g,10.6mmol)和DIC(1.7mL,10.6mmol)并搅拌30分钟。然后在相同温度下加入化合物2a(1.8g,5.12mmol)并继续搅拌10min,然后在室温下搅拌1h。通过TLC分析确认反应完成。将反应混合物用冰水淬灭,将沉淀的白色固体过滤,用水洗涤并在减压下干燥。将固体与乙醚(50mL)一起搅拌15min,过滤并干燥,以得到1.8g化合物2b。LCMS:549.5[M+H]+。
步骤2c:化合物2c的合成
在室温下向化合物2b(1.8g,3.3mmol)在乙腈(35ml)中的溶液中添加乙酸(1.8mL)并在85℃下回流12h。通过TLC分析确认反应完成。将挥发物在减压下蒸发,以获得粗半固体,将其用水和乙酸乙酯稀释。先后用NaHCO3溶液、柠檬酸溶液和盐水溶液洗涤有机层。将有机层经Na2SO4干燥,过滤并在减压下蒸发,以得到粗品。将粗化合物通过使用在己烷中的20%乙酸乙酯的硅胶柱色谱来纯化,以得到0.5g化合物2c。LCMS:531.3[M+H]+。
步骤2d:化合物14的合成
向化合物2c(0.5g,0.94mmol)的溶液中加入5mL三氟乙酸:TIPS:水的混合物(95:2.5:2.5)并在室温下搅拌2h。将所得反应混合物在减压下蒸发,用乙醚稀释并过滤,以得到0.45g粗化合物14。通过在实验条件下描述的制备型HPLC方法纯化粗固体材料。HPLC(tR,以min为单位):9.99;LCMS:275.4[M+H]+。
通过与实施例2(化合物14)中描述的类似的程序制备以下化合物,其中反应物、试剂的量、溶剂和反应条件具有适当的变化。下表中总结了化合物的表征数据。
本发明的化合物19和20的制备的合成程序描述于WO2016142833A1中。
实施例3:在存在重组PD-L1/PD-L2的情况下小鼠脾细胞增殖的拯救
将重组小鼠PD-L1(rm-PDL-1,目录号:1019-B7-100;R&D Systems)用作PD-L1的来源。
要求:
小鼠脾细胞收获自6-8周龄C57 BL6小鼠;RPMI 1640(GIBCO,目录号11875);DMEM高糖培养基(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裂解液(1mL)(GIBCO,目录号-A10492);Histopaque(密度-1.083gm/mL)(SIGMA 10831);台盼蓝溶液(SIGMA-T8154);2mL Norm Ject鲁尔锁注射器(Sigma 2014-12);40μm尼龙细胞滤网(BD FALCON 35230);血球计数器(Bright line-SIGMA Z359629);FACS缓冲液(PBS/0.1%BSA):具有0.1%牛血清白蛋白(BSA)(SIGMA A7050)和叠氮化钠(SIGMA08591)的磷酸盐缓冲盐水(PBS)pH 7.2(HiMedia TS1006);5mM FSE储备溶液:CFSE储备溶液是通过用180μL二甲基亚砜(DMSO C2H6SO,SIGMA-D-5879)稀释冻干的CFSE来制备并等分到管中以用于进一步使用。工作浓度是从10μM滴定至1μM。(eBioscience-650850-85);0.05%胰蛋白酶和0.02%EDTA(SIGMA 59417C);96孔规格ELISA板(CorningCLS3390);BD FACS caliber(E6016);重组小鼠B7-H1/PDL1 Fc Chimera(rm-PD-L1目录号:1019-B7-100)。
方案
脾细胞制备和培养:
通过在40μm细胞滤网中捣碎小鼠脾来在50mL falcon管中收获脾细胞,在室温下用1mL ACK裂解缓冲液进一步处理5min。在用9mL RPMI完全培养基洗涤之后,将细胞重新悬浮于15mL管中的3mL 1xPBS中。在不干扰覆盖的脾细胞悬浮液的情况下,将3mL Histopaque小心加入到管的底部。在室温下以800xg离心20min之后,在不干扰/混合各层的情况下,收集脾细胞的不透明层。将脾细胞用冷1xPBS洗涤两次,接着使用台盼蓝排除法进行总细胞计数,并且进一步用于基于细胞的测定。
将脾细胞培养于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)中并在37℃下维持在具有5%CO2的CO2培养箱中。
CFSE增殖测定:
CFSE为被动扩散至细胞中并结合细胞内蛋白的染料。在37℃下将1×106细胞/mL收获的脾细胞用5μM在预热的1xPBS/0.1%BSA溶液中的CFSE处理10min。将过量CFSE用5体积冰冷的细胞培养基淬灭并在冰上孵育5min。用冰冷的完全RPMI培养基将CFSE标记的脾细胞再洗涤三次。将CFSE标记的1×105个脾细胞加入至含有MDA-MB231细胞(培养在高糖DMEM培养基中的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1μg/mL)刺激脾细胞,并且将培养物在37℃、5%CO2下进一步孵育72h。收获细胞并用冰冷的FACS缓冲液洗涤三次,并且通过以488nm激发滤片和521nm发射滤片的流式细胞术分析增殖%。
数据编辑、处理和推断:
使用cell quest FACS程序分析脾细胞增殖百分比,并且在扣除背景增殖值%并将刺激的脾细胞增殖%(阳性对照)归一化为100%来估计化合物对脾细胞增殖的拯救百分比。
刺激的脾细胞:脾细胞+抗CD3/CD28刺激
背景增殖:脾细胞+抗CD3/CD28+PD-L1
化合物增殖:脾细胞+抗CD3/CD28+PD-L1+化合物
通过在存在配体(PDL-1)的情况下,将所需浓度的化合物加入到抗CD3/CD28刺激的脾细胞中来检查化合物作用。结果给出在下表中。
实施例–4:在存在重组mPVR的情况下小鼠CD8+T细胞增殖的拯救
试剂:
96孔板,Corning;RPMI,目录号R6504,Sigma;Easy Sep磁体,目录号18000,StemCell;Easy Sep小鼠CD8 T细胞分离试剂盒,目录号19853,Stem Cell;细胞滤网(70μm),目录号431751,Corning;纯化的抗小鼠CD3抗体,目录号100201,Biolegend;重组小鼠PVR,目录号6909-CD-050,R&D Systems;重组小鼠抗TIGIT抗体,目录号142101,Biolegend;FBS,目录号SH30070.03,Hyclone;小鼠IL-2ELISA试剂盒,R&D System目录号DY402;小鼠IFN-γELISA试剂盒R&D Systems目录号DY485;无菌PBS;FicollHistopaque,目录号10831-6X100ML,Sigma
方案:
从6-8周龄的C57BL/6雄性小鼠收集脾。通过缓慢压碎RPMI+10%FBS中的无菌载玻片之间的脾并使其通过70μm滤网来分离脾细胞。将细胞悬浮液在室温下以912xg离心10分钟并舍弃上清液。将脾细胞重新悬浮于RPMI+10%FBS(完全RPMI)中。将重新悬浮的脾细胞覆盖在50ml Tarson管中的Ficoll Histopaque-1083上。将覆盖的细胞在室温下以584xg离心30分钟而不破裂。将透明的血沉棕黄层小心地吸出到无菌PBS中。使用PBS洗涤分离的细胞并重新悬浮在完全RPMI培养基中,以得到约5×107细胞/ml的悬浮液。通过使用EasySep小鼠CD8+T细胞分离试剂盒,根据制造商说明书,分离小鼠CD8+T细胞。
在37℃下用1μg/mL(50μL/孔)纯化的抗小鼠CD3和0.5μg/mL(50ul/孔)重组小鼠PVR Fc嵌合体涂布96孔细胞培养板持续4小时。4小时之后,用无菌PBS洗涤涂布的板。以20万/孔(180μL)浓度将从脾分离的小鼠CD8+T细胞加入到96孔细胞培养板中。将在水或DMSO中制备的各种浓度的测试化合物加入到各自孔(20μL/孔)中,以便使总体积为200μL/孔。将板在37℃CO2培养箱中孵育3天。在第3天,收集细胞上清液,以使用ELISA测定细胞因子水平(IL-2或IFN-γ)。通过使用小鼠IL-2或IFN-γELISA试剂盒,根据制造商说明书分析培养物上清液中IL-2或IFN-γ的量来测量在存在或不存在测试化合物的情况下CD8+T细胞增殖的程度。将重组小鼠抗TIGIT抗体用作阳性对照来测定增加的CD8+T细胞增殖。
数据编辑、处理和推断:
通过使用IL-2ELISA试剂盒测量IL-2水平来分析CD8+T细胞增殖百分比,并且在扣除背景增殖值%并将抗TIGIT抗体刺激的CD8+T细胞增殖%(阳性对照)归一化为100%之后来估计测试化合物对CD8+T细胞的拯救百分比。结果给出在下表中。
实施例–5:化合物19在CT-26同基因(Balb/c雄性)小鼠肿瘤模型中的功效研究
这项研究的目的为评估化合物19在CT26同基因结肠腺癌模型中的抗肿瘤活性。
试剂和材料
细胞系繁殖和接种
CT26细胞系购自ATCC,维持并保存在ADTL-Bangalore细胞系库。将一个小瓶的CT26细胞系解冻并在具有补充有10%FBS(Gibco)、10mM 4-(2-羟乙基)-1-哌嗪乙磺酸(HEPES)、1mM丙酮酸钠、4.5g/L葡萄糖、1%青霉素链霉素(Sigma)和1.5g/L碳酸氢钠的RPMI培养基的T-150cm2烧瓶中复活。将具有细胞密度为25万/ml的CT26细胞的烧瓶在供应有5%二氧化碳的37±1℃培养箱中孵育。在T-150cm2烧瓶中进行细胞扩增,并且将细胞密度维持在20万/烧瓶至120万/烧瓶之间,每隔一天细胞分裂。在分裂的最后一个步骤之后,当细胞达到指数期时,将细胞进行处理以用于注射。将T-150cm2烧瓶中的细胞胰蛋白酶化并转移至50ml管,并且在控制的室温下以1200rpm离心5分钟,以获得细胞团块。舍弃上清液,并且将细胞团块悬浮在培养基中并使用血细胞计数器进行计数。将细胞团块以10×106细胞/ml的最终浓度重新悬浮在RPMI培养基中。为了建立肿瘤,将1×106个细胞(0.1ml细胞悬浮液)皮下注射到小鼠的右侧区域中。
动物的分组和分配
当平均肿瘤体积达到大约30±5mm3时,基于肿瘤体积将动物随机分成五组(G1至G5),每组十只动物(N=10),各自如下文所提及。继续处理14天,之后基于在处理期间观察到的肿瘤体积和体重变化评估总体功效和耐受性。在处理第14天,在最后一次剂量施用之后0.5小时、1小时和4小时杀死所有组的动物。
分组、剂量和给药方案(随机化之后开始给药)
组别 | 化合物 | 剂量 | 频率 | 施用途径 |
1 | 媒介物对照 | 0mg/kg | qd | 口服 |
2 | 抗小鼠PD1抗体 | 10μg/动物 | 每周一次 | I.P |
3 | 抗小鼠TIGIT抗体 | 500μg/动物 | 每周两次 | I.P |
4 | 化合物19 | 10mg/kg | qd | 口服 |
5 | 化合物19 | 30mg/kg | qd | 口服 |
此项研究中任何处理对体重均没有影响,指示在施用的剂量下测试剂的耐受性极好。用化合物19的处理导致剂量依赖性肿瘤生长抑制(在10mg/kg(qd)剂量下为42%并且在30mg/kg(qd)剂量下为53%)。与媒介物处理的动物相比,以30mg/kg(qd)剂量观察到的肿瘤生长抑制百分比为统计学显著的。研究结果用图形表示在图1中。
Claims (61)
1.一种在受试者中调节具有Ig与ITIM结构域(TIGIT)信号传导途径和程序性细胞死亡1(PD-1)信号传导途径的T细胞免疫受体的方法,其包括将所述受试者与式(I)化合物、或其立体异构体、或其药学上可接受的盐接触:
其中,
R1表示氢、任选被-OH、-COOH、芳基、杂芳基或芳基-OH取代的-(C1-C6)烷基;
R2表示氢、任选被-OH、-SH、C(O)NH2、-COOH、芳基、杂芳基或芳基-OH取代的-(C1-C6)烷基;
Ra表示氢;或者Ra和R2与它们连接的原子一起形成吡咯烷环;
R3表示氢或由式(I’)表示的基团,
-----表示连接点;
Rb表示氢;或者Rb和Rc与它们连接的原子一起形成吡咯烷环;
Rc表示氢、任选被-OH、-C(O)NH2、COOH、芳基或芳基-OH取代的-(C1-C6)烷基。
2.如权利要求1所述的方法,其中R1表示氢、任选被-OH、-COOH、苯基、咪唑基或(p-OH)苯基取代的-(C1-C6)烷基。
3.如权利要求1至2中任一项所述的方法,其中R1表示任选被-OH、-COOH、咪唑基、苯基或(p-OH)苯基取代的-(C1-C6)烷基。
4.如权利要求1至3中任一项所述的方法,其中R1表示任选被-OH、-COOH、咪唑基或(p-OH)苯基取代的-(C1-C6)烷基。
5.如权利要求1所述的方法,其中R2表示氢、任选被-OH、-SH、-C(O)NH2、-COOH、苯基、咪唑基或(p-OH)苯基取代的-(C1-C6)烷基。
6.如权利要求1或5中任一项所述的方法,其中R2表示氢、任选被-OH、-SH、-COOH、苯基、咪唑基或(p-OH)苯基取代的-(C1-C6)烷基。
7.如权利要求1、5或6中任一项所述的方法,其中R2表示氢、任选被-OH、-COOH、苯基、咪唑基或(p-OH)苯基取代的-(C1-C6)烷基。
8.如权利要求1所述的化合物,其中Ra和R2与它们连接的原子一起形成吡咯烷环。
10.如权利要求9所述的方法,其中Rb和Rc与它们连接的原子一起形成吡咯烷环。
12.如权利要求11所述的方法,其中
R1表示任选被-OH、-COOH、咪唑基、苯基或(p-OH)苯基取代的-(C1-C6)烷基;
R2表示氢、被-OH、-SH、-COOH、苯基、咪唑基或(p-OH)苯基取代的-(C1-C6)烷基;
Ra表示氢;或者Ra和R2与它们连接的原子一起形成吡咯烷环;
Rb表示氢;或者Rb和Rc与它们连接的原子一起形成吡咯烷环;
Rc表示氢、任选被-OH、-C(O)NH2、-COOH、苯基或(p-OH)苯基取代的-(C1-C6)烷基。
13.如权利要求12所述的方法,其中
R1表示任选被-OH、-COOH、咪唑基或(p-OH)苯基取代的-(C1-C6)烷基;并且R2表示氢、被-OH、-COOH、苯基、咪唑基或(p-OH)苯基取代的-(C1-C6)烷基。
15.如权利要求14所述的方法,其中
R1表示任选被-OH或(p-OH)苯基取代的-(C1-C6)烷基;
R2表示氢、被苯基或(p-OH)苯基取代的-(C1-C6)烷基;
Ra和R2与它们连接的原子一起形成吡咯烷环。
18.如权利要求1-17中任一项所述的方法,其中接触细胞发生在有需要的受试者中,从而调节所述受试者的免疫应答。
19.如权利要求1-17中任一项所述的方法,其中接触细胞发生在有需要的受试者中,从而治疗选自以下的疾病或病症:癌症、免疫病症、免疫缺陷性病症、炎性病症、感染性疾病和移植排斥。
20.如权利要求19所述的方法,其中所述疾病或病症为癌症。
21.一种用于在受试者中抑制肿瘤细胞生长和/或转移的方法,其包括向有需要的所述受试者施用TIGIT/PD-1双途径抑制剂。
22.如权利要求21所述的方法,其中所述肿瘤细胞属于选自以下的癌症:小细胞肺部癌症、多发性骨髓瘤、膀胱癌、原发性导管癌、卵巢癌、霍奇金氏淋巴瘤、胃癌、急性髓系白血病和胰腺癌症。
23.如权利要求21所述的方法,其中所述肿瘤细胞属于选自以下的癌症:母细胞瘤、乳腺癌症、上皮癌症、结肠癌症、肺部癌症、黑色素瘤、前列腺癌症、肾脏癌症、骨癌症、胰腺癌症、皮肤癌症、头部或颈部癌症、子宫癌症、卵巢癌症、直肠结肠癌症、直肠癌症、肛门区癌症、腹膜癌症、胃部癌症、睾丸癌症、输卵管癌、子宫内膜癌、宫颈癌症、阴道癌症、外阴癌症、食管癌症、小肠癌症、内分泌系统癌症、甲状腺癌症、甲状旁腺癌症、肾上腺癌症、肉瘤、尿道癌症、阴茎癌症、慢性或急性白血病、儿童期实体肿瘤、霍奇金氏淋巴瘤、非霍奇金氏淋巴瘤、皮肤T细胞淋巴瘤、间皮瘤、胸腺癌、骨髓瘤、膀胱癌症、输尿管癌症、肾盂癌、肝部癌症、胰腺癌症、移植后淋巴组织增生性病症(PTLD)、中枢神经系统肿瘤(CNS)、肿瘤血管生成、脊柱轴肿瘤、脑干胶质瘤、垂体腺瘤、表皮癌症、涎腺癌、鳞状细胞癌症、与斑痣性错构瘤病有关的异常血管增殖、水肿(诸如与脑肿瘤有关的水肿)、麦格氏综合征、梅克尔细胞癌和环境诱导的癌症。
24.如权利要求19所述的方法,其中所述疾病为感染性疾病。
25.如权利要求24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。
26.如权利要求25所述的方法,其中所述细菌感染为由至少一种选自以下的细菌引起的感染:衣原体、杆菌、博德特菌、肉毒菌、弯曲菌、伯克氏菌、炭疽菌、霍乱、梭菌、李斯特菌、淋球菌、棒杆菌、白喉、密螺旋体、布鲁氏菌、肠球菌、支原体、疏螺旋体、欧文氏菌、埃希氏菌、弗朗西斯菌、嗜血杆菌、螺杆菌、克雷伯氏菌、黄单胞菌、军团菌、细螺旋体、细螺旋体病、莱姆病、脑膜炎球菌、肺炎球菌、分枝杆菌、奈瑟菌、弧菌、巴斯德菌、暗杆菌、沙雷氏菌、鼠疫、链球菌、变形杆菌、肠杆菌、假单胞菌、立克次氏体、沙门氏菌、志贺氏菌、葡萄球菌、破伤风和耶尔森氏菌。
27.如权利要求25所述的方法,其中所述病毒感染为由至少一种选自以下的病毒引起的感染:虫媒病毒性脑炎病毒、腺病毒、单纯疱疹病毒1型、单纯疱疹病毒2型、水痘-带状疱疹病毒、EB病毒、巨细胞病毒、疱疹病毒8型、乳头状瘤病毒、BK病毒、冠状病毒、埃可病毒、JC病毒、天花病毒、乙型肝炎病毒、博卡病毒、细小病毒B19、星状病毒、诺沃克病毒、柯萨奇病毒、甲型肝炎病毒、脊髓灰质炎病毒、鼻病毒、严重急性呼吸综合征病毒、丙型肝炎病毒、黄热病病毒、登革病毒、西尼罗病毒、风疹病毒、戊型肝炎病毒、人免疫缺陷病毒(HIV)、人嗜T淋巴细胞病毒(HTLV)、流感病毒、瓜纳瑞托病毒、胡宁病毒、拉沙病毒、马秋波病毒、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、狂犬病病毒、丁型肝炎病毒、轮状病毒、环状病毒、科罗拉多壁虱热病毒、牛痘病毒和版纳病毒。
28.如权利要求25所述的方法,其中所述真菌感染为由至少一种选自以下的真菌引起的感染:鹅口疮、粗球孢子菌、皮炎芽生菌、耳真菌病、念珠菌(白念珠菌、克鲁斯念珠菌、光滑念珠菌、热带念珠菌等)、头癣、须癣、体癣、股癣、掌黑癣、申克孢子丝菌、接合菌病、着色芽生菌病、隐球菌(新型隐球菌等)、荚膜组织胞浆菌、脚湿气、巴西副球孢子菌、暗色丝孢霉病、黄癣、毛霉菌目(毛霉属、犁头霉属、根霉属)、孢子丝菌病、曲霉属(烟曲霉、黑曲霉等)、罗布菌病、足菌肿、甲真菌病、毛结节菌病、花斑糠疹和鼻孢子菌病。
29.如权利要求25所述的方法,其中所述寄生虫感染为由至少一种选自以下的寄生虫引起的感染:人蛔虫、结肠小袋纤毛虫、溶组织内阿米巴、蓝氏贾第鞭毛虫、福氏内格里虫、美洲钩虫、巴西日圆线虫、粪类圆线虫、鼠隐孢子虫、冈比亚锥虫、罗德西亚锥虫、田鼠巴贝虫、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、班氏吴策线虫、麦地那龙线虫、刚地弓形虫、大片吸虫、异形异形吸虫、间日疟原虫、布氏锥虫、卵形疟原虫、三日疟原虫、恶性疟原虫、卡氏肺孢子虫、阴道毛滴虫、火鸡组织滴虫、侧尾腺口纲、毛首鞭形线虫、棘阿米巴虫、蛲虫、十二指肠钩口线虫、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、肝片吸虫和卫氏肺吸虫。
30.一种在受试者中调节免疫应答的方法,其包括将过表达具有Ig与ITIM结构域(TIGIT)和PD-L1或PD-L2中至少一个的T细胞免疫受体的所述受试者的生物样品暴露于如权利要求1-17中任一项所述的式(I)化合物。
31.一种在受试者中调节免疫应答的方法,其包括:
a)确定受试者的生物样品是否过表达TIGIT;以及
b)如果确定所述生物样品过表达TIGIT,则使所述受试者与如权利要求1-17中任一项所述的式(I)化合物接触。
32.如权利要求31所述的方法,其还包括:
a)确定所述生物样品是否过表达PD-L1或PD-L2;以及
b)如果确定所述生物样品过表达TIGIT和PD-L1或PD-L2,则使所述受试者与如权利要求1-17中任一项所述的式(I)化合物接触。
33.如权利要求30、31或32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。
34.如权利要求30-33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,所述受试者的所述生物样品包含所述癌症的一个或多个细胞。
35.如权利要求30-33中任一项所述的方法,其中所述受试者患有选自以下的感染性疾病:细菌感染、病毒感染、真菌感染和寄生虫感染。
36.如权利要求30-35中任一项所述的方法,其中在所述受试者已接受式(I)化合物之前获得对照样品,并且在所述受试者已经接受式(I)化合物之后获得受试者样品。
37.一种治疗由TIGIT信号传导途径和PD-1信号传导途径介导的疾病或病症的方法,其包括施用治疗有效量的如权利要求1-17中任一项所述的式(I)化合物、或其立体异构体、或其药学上可接受的盐。
38.如权利要求37所述的方法,其中所述疾病或病症选自:癌症、免疫病症、免疫缺陷性病症、炎性病症、感染性疾病和移植排斥。
39.如权利要求38所述的方法,其中所述癌症选自:母细胞瘤、乳腺癌症、上皮癌症、结肠癌症、肺部癌症、黑色素瘤、前列腺癌症、肾脏癌症、骨癌症、胰腺癌症、皮肤癌症、头部或颈部癌症、子宫癌症、卵巢癌症、直肠结肠癌症、直肠癌症、肛门区癌症、腹膜癌症、胃部癌症、睾丸癌症、输卵管癌、子宫内膜癌、宫颈癌症、阴道癌症、外阴癌症、食管癌症、小肠癌症、内分泌系统癌症、甲状腺癌症、甲状旁腺癌症、肾上腺癌症、肉瘤、尿道癌症、阴茎癌症、慢性或急性白血病、儿童期实体肿瘤、霍奇金氏淋巴瘤、非霍奇金氏淋巴瘤、皮肤T细胞淋巴瘤、间皮瘤、胸腺癌、骨髓瘤、膀胱癌症、输尿管癌症、肾盂癌、肝部癌症、胰腺癌症、移植后淋巴组织增生性病症(PTLD)、中枢神经系统肿瘤(CNS)、肿瘤血管生成、脊柱轴肿瘤、脑干胶质瘤、垂体腺瘤、表皮癌症、涎腺癌、鳞状细胞癌症、与斑痣性错构瘤病有关的异常血管增殖、水肿(诸如与脑肿瘤有关的水肿)、麦格氏综合征、梅克尔细胞癌和环境诱导的癌症。
40.如权利要求38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。
41.如权利要求40所述的方法,其中所述感染性疾病选自:至少一种选自炭疽菌、杆菌、博德特菌、疏螺旋体、肉毒菌、布鲁氏菌、伯克氏菌、弯曲菌、衣原体、霍乱、梭菌、淋球菌、棒杆菌、白喉、肠杆菌、肠球菌、欧文氏菌、埃希氏菌、弗朗西斯菌、嗜血杆菌、螺杆菌、克雷伯氏菌、军团菌、细螺旋体、细螺旋体病、李斯特菌、莱姆病、脑膜炎球菌、分枝杆菌、支原体、奈瑟菌、巴斯德菌、暗杆菌、鼠疫、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的细菌;至少一种选自虫媒病毒性脑炎病毒、腺病毒、单纯疱疹病毒1型、单纯疱疹病毒2型、水痘-带状疱疹病毒、EB病毒、巨细胞病毒、疱疹病毒8型、乳头状瘤病毒、BK病毒、冠状病毒、埃可病毒、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、严重急性呼吸综合征病毒、丙型肝炎、黄热病、登革病毒、西尼罗病毒、风疹、戊型肝炎、人免疫缺陷病毒(HIV)、人嗜T淋巴细胞病毒(HTLV)、流感、瓜纳瑞托病毒、胡宁病毒、拉沙病毒、马秋波病毒、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、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、牛痘病毒和版纳病毒的病毒;选自鹅口疮、曲霉属(烟曲霉、黑曲霉等)、皮炎芽生菌、念珠菌(白念珠菌、克鲁斯念珠菌、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、毛霉菌(毛霉属、犁头霉属、根霉属)、巴西副球孢子菌、孢子丝菌病、申克孢子丝菌、接合菌病、着色芽生菌病、罗布菌病、足菌肿、甲真菌病、毛结节菌病、花斑糠疹、须癣、头癣、体癣、股癣、黄癣、掌黑癣、脚湿气、耳真菌病、暗色丝孢霉病和鼻孢子菌病的真菌感染;以及至少一种选自棘阿米巴虫、田鼠巴贝虫、结肠小袋纤毛虫、溶组织内阿米巴、蓝氏贾第鞭毛虫、鼠隐孢子虫、冈比亚锥虫、罗德西亚锥虫、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、恶性疟原虫、卡氏肺孢子虫、阴道毛滴虫、火鸡组织滴虫、侧尾腺口纲、毛首鞭形线虫、人蛔虫、蛲虫、十二指肠钩口线虫、福氏内格里虫、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肺吸虫的寄生虫。
42.如权利要求1-17中任一项所述的化合物,其用于在受试者中调节由TIGIT信号传导途径和PD-1信号传导途径介导的免疫应答。
43.如权利要求42所述的化合物,其中所述免疫应答被调节成治疗由TIGIT信号传导途径和PD-1信号传导途径介导的疾病或病症。
44.如权利要求1-17中任一项所述的化合物,其用于治疗由TIGIT信号传导途径和PD-1信号传导途径介导的疾病或病症。
45.如权利要求43或44所述的化合物,其中所述疾病或病症选自:癌症、免疫病症、免疫缺陷性病症、炎性病症、感染性疾病和移植排斥。
46.如权利要求45所述的化合物,其中所述癌症选自:母细胞瘤、乳腺癌症、上皮癌症、结肠癌症、肺部癌症、黑色素瘤、前列腺癌症、肾脏癌症、骨癌症、胰腺癌症、皮肤癌症、头部或颈部癌症、子宫癌症、卵巢癌症、直肠结肠癌症、直肠癌症、肛门区癌症、腹膜癌症、胃部癌症、睾丸癌症、输卵管癌、子宫内膜癌、宫颈癌症、阴道癌症、外阴癌症、食管癌症、小肠癌症、内分泌系统癌症、甲状腺癌症、甲状旁腺癌症、肾上腺癌症、肉瘤、尿道癌症、阴茎癌症、慢性或急性白血病、儿童期实体肿瘤、霍奇金氏淋巴瘤、非霍奇金氏淋巴瘤、皮肤T细胞淋巴瘤、间皮瘤、胸腺癌、骨髓瘤、膀胱癌症、输尿管癌症、肾盂癌、肝部癌症、胰腺癌症、移植后淋巴组织增生性病症(PTLD)、中枢神经系统肿瘤(CNS)、肿瘤血管生成、脊柱轴肿瘤、脑干胶质瘤、垂体腺瘤、表皮癌症、涎腺癌、鳞状细胞癌症、与斑痣性错构瘤病有关的异常血管增殖、水肿(诸如与脑肿瘤有关的水肿)、麦格氏综合征、梅克尔细胞癌和环境诱导的癌症。
47.如权利要求45所述的化合物,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。
48.如权利要求45所述的化合物,其中所述感染性疾病选自:至少一种选自炭疽菌、杆菌、博德特菌、疏螺旋体、肉毒菌、布鲁氏菌、伯克氏菌、弯曲菌、衣原体、霍乱、梭菌、淋球菌、棒杆菌、白喉、肠杆菌、肠球菌、欧文氏菌、埃希氏菌、弗朗西斯菌、嗜血杆菌、螺杆菌、克雷伯氏菌、军团菌、细螺旋体、细螺旋体病、李斯特菌、莱姆病、脑膜炎球菌、分枝杆菌、支原体、奈瑟菌、巴斯德菌、暗杆菌、鼠疫、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的细菌;至少一种选自虫媒病毒性脑炎病毒、腺病毒、单纯疱疹病毒1型、单纯疱疹病毒2型、水痘-带状疱疹病毒、EB病毒、巨细胞病毒、疱疹病毒8型、乳头状瘤病毒、BK病毒、冠状病毒、埃可病毒、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、严重急性呼吸综合征病毒、丙型肝炎、黄热病、登革病毒、西尼罗病毒、风疹、戊型肝炎、人免疫缺陷病毒(HIV)、人嗜T淋巴细胞病毒(HTLV)、流感、瓜纳瑞托病毒、胡宁病毒、拉沙病毒、马秋波病毒、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、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、牛痘病毒和版纳病毒的病毒;选自鹅口疮、曲霉属(烟曲霉、黑曲霉等)、皮炎芽生菌、念珠菌(白念珠菌、克鲁斯念珠菌、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、毛霉菌(毛霉属、犁头霉属、根霉属)、巴西副球孢子菌、孢子丝菌病、申克孢子丝菌、接合菌病、着色芽生菌病、罗布菌病、足菌肿、甲真菌病、毛结节菌病、花斑糠疹、须癣、头癣、体癣、股癣、黄癣、掌黑癣、脚湿气、耳真菌病、暗色丝孢霉病和鼻孢子菌病的真菌感染;以及至少一种选自棘阿米巴虫、田鼠巴贝虫、结肠小袋纤毛虫、溶组织内阿米巴、蓝氏贾第鞭毛虫、鼠隐孢子虫、冈比亚锥虫、罗德西亚锥虫、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、恶性疟原虫、卡氏肺孢子虫、阴道毛滴虫、火鸡组织滴虫、侧尾腺口纲、毛首鞭形线虫、人蛔虫、蛲虫、十二指肠钩口线虫、福氏内格里虫、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肺吸虫的寄生虫。
49.一种在受试者中调节具有Ig与ITIM结构域(TIGIT)信号传导途径的T细胞免疫受体的方法,其包括将所述受试者与式(I)化合物、或其立体异构体、或其药学上可接受的盐接触:
其中,
R1表示氢、任选被-OH、-COOH、芳基、杂芳基或芳基-OH取代的-(C1-C6)烷基;
R2表示氢、任选被-OH、-SH、C(O)NH2、-COOH、芳基、杂芳基或芳基-OH取代的-(C1-C6)烷基;
Ra表示氢;或者Ra和R2与它们连接的原子一起形成吡咯烷环;
R3表示氢或由式(I’)表示的基团,
-----表示连接点;
Rb表示氢;或者Rb和Rc与它们连接的原子一起形成吡咯烷环;
Rc表示氢、任选被-OH、-C(O)NH2、COOH、芳基或芳基-OH取代的-(C1-C6)烷基。
50.如权利要求49所述的方法,其中R1表示任选被-OH、-COOH、苯基或(p-OH)苯基取代的-(C1-C6)烷基。
51.如权利要求49或50所述的方法,其中R1表示任选被-OH或-COOH取代的-(C1-C6)烷基。
52.如权利要求49所述的方法,其中R2表示氢、任选被-C(O)NH2、-COOH、苯基或(p-OH)苯基取代的-(C1-C6)烷基。
53.如权利要求49或52所述的方法,其中R2表示氢、任选被-C(O)NH2、苯基或(p-OH)苯基取代的-(C1-C6)烷基。
54.如权利要求49所述的化合物,其中Rb和Rc与它们连接的原子一起形成吡咯烷环。
55.一种在受试者中调节具有Ig与ITIM结构域(TIGIT)信号传导途径的T细胞免疫受体的方法,其包括将所述受试者与化合物19、或其立体异构体、或其药学上可接受的盐接触。
56.一种在受试者中治疗由TIGIT介导的癌症的方法,其包括将所述受试者与化合物19或20、或其立体异构体、或其药学上可接受的盐接触。
57.一种式(I)化合物、或其立体异构体、或其药学上可接受的盐,其用于在受试者中调节具有Ig与ITIM结构域(TIGIT)信号传导途径和程序性细胞死亡1(PD-1)信号传导途径的T细胞免疫受体;
其中,
R1表示氢、任选被-OH、-COOH、芳基、杂芳基或芳基-OH取代的-(C1-C6)烷基;
R2表示氢、任选被-OH、-SH、C(O)NH2、-COOH、芳基、杂芳基或芳基-OH取代的-(C1-C6)烷基;
Ra表示氢;或者Ra和R2与它们连接的原子一起形成吡咯烷环;
R3表示氢或由式(I’)表示的基团,
-----表示连接点;
Rb表示氢;或者Rb和Rc与它们连接的原子一起形成吡咯烷环;
Rc表示氢、任选被-OH、-C(O)NH2、COOH、芳基或芳基-OH取代的-(C1-C6)烷基。
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