CN117396208A - 细胞周期蛋白依赖性激酶4/6(cdk4/6)和ikzf2(helios)的小分子降解剂及其使用方法 - Google Patents
细胞周期蛋白依赖性激酶4/6(cdk4/6)和ikzf2(helios)的小分子降解剂及其使用方法 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/545—Heterocyclic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Enzymes And Modification Thereof (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
本申请提供了双功能化合物,其作为细胞周期蛋白依赖性激酶4(CDK4)、细胞周期蛋白依赖性激酶6(CDK6)和Ikaros家族锌指2(IKZF2)(也称为Helios)的诱导蛋白降解部分。还公开了用于治疗受CDK4、CDK6和IKZF2调节的病症的方法。
Description
相关申请
根据35U.S.C.§119(e),本申请要求2021年7月16日提交的美国临时申请号63/222,646的权益,将其通过引用整体并入本文。
政府支持
本公开是在美国国立卫生研究院授予的项目号为R01 CA218278的政府资助下完成的。政府在本公开中拥有某些权利。
背景
Helios(IKZF2),IKZF锌指转录因子家族(IKZF)的成员,是T细胞活性和功能的关键调节因子。Helios的基因缺失导致抗肿瘤免疫反应增强(Kim et al.,Science 350:334-339(2015))。值得注意的是,Helios在调节性T细胞中高度表达(Elkord et al.,ExpertOpin.Biol.Ther.12:1423-1425(2012)),调节性T细胞是限制效应T细胞的活性的T细胞亚群。调节性T细胞(Treg)中Helios的选择性缺失导致抑制活性的丧失和效应T细胞功能的获得(Najagawa et al.,Proc.Natl.Acad.Sci.USA 113:6248-6253(2016);Yates et al.,Proc.Natl.Acad.Sci.USA 115:2162-2167(2018))。因此,Helios是限制Treg的T细胞效应功能的关键因子。
据报道,Helios的表达在“衰竭”(exhausted)T细胞中、在慢性病毒感染(Crawfordet al.,Immunity 40:289-302(2014),Doering et al.,Immunity 371130-1144(2012);Scott-Browne et al.,Immunity 45:1327-1340(2016))和肿瘤(Martinez et al.,Immunity 42:265-278(2015);Mognol et al.,Proc.Natl.Acad.Sci.USA 114:E2776-E2785(2017);Pereira et al.,J.Leukoc.Biol.102:601-615(2017);Singer et al.,Cell166:1500-1511(2016);Schietinger et al.,Immunity 45:389-401(2016))二者的环境中以及在功能失调的嵌合抗原受体(CAR)T细胞(Long et al.,Nat.Med.21:581-590(2015))中均上调。在几种血液***恶性肿瘤中,包括T细胞白血病和淋巴瘤,已经报道了Helios和各种剪接同种型的过表达或异常表达(Nakase et al.,Exp.Hematol.30:313-317(2002);Tabayashi et al.,Cancer Sci.98:182-188(2007);Asanuma et al.,Cancer Sci.104:1097-1106(2013))。此外,在混合谱系白血病(MLL)驱动的髓系白血病模型中敲除Helios可有效抑制增殖及增加细胞死亡(Park et al.,J.Clin.Invest.125:1286-1298(2015);Parket al.,Cell Stem Cell 24:153-165(2019))。
细胞周期蛋白依赖性激酶(CDK)整合多种信号通路来控制细胞周期或基因转录。CDK1、CDK2、CDK4和CDK6是驱动细胞周期转变的关键酶。例如,CDK1是有丝***进程的关键决定因素,CDK2调节S期的DNA复制,和CDK4/6通过Rb蛋白上的磷酸化激活参与细胞周期控制的基因的表达,驱动细胞周期从G0或G1到S期。已证明CDK4/6抑制剂对T细胞具有有效的免疫刺激作用,在离体人T细胞和多种体内鼠肿瘤模型中均如此。CDK7、CDK9和CDK12调节转录,而不是直接促进细胞周期。CDK7是负责调节转录起始的TFIIH复合物的酶组分,而CDK9和CDK12调节转录延伸和加工。
已显示CDK的去调节(deregulation)对细胞状态具有显著影响,并且经常被鉴定为致癌的。已经鉴定了许多选择性或泛CDK小分子抑制剂,然而,由于无法实现高的全身药物浓度,大多数已知的抑制剂未能通过在临床试验。最近,三种CDK4/6抑制剂,阿贝西利、帕博西尼和瑞博西尼,已显示与激素疗法联合治疗激素受体(HR)阳性/人表皮生长因子受体2(HER-2)阴性的转移性乳腺癌的临床用途。
概述
本公开的第一方面涉及具有由式(I)表示的结构的双功能化合物:
或其药学上可接受的盐或立体异构体,其中靶向配体结合CDK4和/或CDK6,接头包含亚烷基链或聚乙二醇链。
本公开的另一方面涉及药物组合物,其包括治疗有效量的式(I)的双功能化合物或其药学上可接受的盐或立体异构体,以及药学上可接受的载体。在一些实施方案中,药物组合物为固体形式。在一些实施方案中,药物组合物为片剂或胶囊剂形式。在一些实施方案中,药物组合物为液体形式。
本公开的另一方面涉及式(I)的双功能化合物及其药学上可接受的盐和立体异构体的制备方法。
本公开的又一方面涉及治疗以CDK4和/或CDK6和Helios的异常活性为特征的疾病或病症的方法,包括向有此需要的受试者施用治疗有效量的式(I)双功能化合物或其药学上可接受的盐或立体异构体。在一些实施方案中,疾病或病症是癌症。在一些实施方案中,癌症被表征为实体瘤。在一些实施方案中,癌症选自乳腺癌、脑癌、子宫内膜癌、头颈癌、胃肠癌、肺癌、卵巢癌、***癌、子宫癌、肝细胞癌、脂肪肉瘤和黑色素瘤。在一些实施方案中,癌症是血液***癌症。在一些实施方案中,血液***癌症选自白血病、淋巴瘤和骨髓瘤。
本公开的又一个方面涉及降低细胞中CDK4和/或CDK6和Helios水平的方法(无论是在体外还是在体内),其包括使细胞与有效量的式(I)双功能化合物或其药学上可接受的盐或立体异构体接触。
已证明CDK4/6抑制剂对T细胞具有有效的免疫刺激作用,在离体人T细胞和多种体内小鼠肿瘤模型中均如此。未证明先前的CDK4/6抑制剂可诱导Helios降解。已证明先前Helios的小分子降解剂可使无能和抑制表型的调节性T细胞不稳定。本公开的双功能化合物可以对CRL4(CRBN)E3连接酶复合物进行重新编程,以靶向Helios、CDK4和/或CDK6使其被泛素化并随后被蛋白酶体降解,且从而促进抗肿瘤免疫。它们也可以与现有的免疫疗法如免疫检查点抑制剂(例如,抗PD-1、抗PD-L1)或细胞疗法(例如,CAR-T细胞)结合使用。
虽然无意受任何特定操作理论所束缚,但据信通过引起Helios的降解,本公开的双功能化合物可通过将调节性T细胞转化为效应T细胞,并通过拯救衰竭T细胞或CAR-T细胞的效应T细胞功能来增强抗肿瘤免疫反应。此外,据信本公开的化合物通过抗增殖和免疫调节作用的组合来发挥其治疗(例如,抗癌)作用或益处。从机制上讲,所公开的化合物被认为通过与cereblon(CRBN)形成“分子胶”来诱导Helios的降解。
分子胶化合物诱导蛋白质-蛋白质相互作用,其在泛素连接酶的背景下导致蛋白质降解(Stanton et al.,Science 359:eaao5902(2018))。与靶向蛋白水解的嵌合分子(PROTAC)不同,分子胶化合物是小分子(也称为小分子降解剂),其诱导E3泛素连接酶的底物受体和靶蛋白之间的相互作用,导致靶标的蛋白水解。诱导靶标蛋白水解的分子胶的实例包括IMiD(免疫调节药物;例如,沙利度胺),其在底物(例如,IKZF1/3)和cereblon(Cullin-RING泛素连接酶4(CRL4)的底物受体(也称为DCAF))之间产生新的相互作用(denBesten and Lipford,Nat.Chem.Biol.16(11):1157-1158(2020))。与传统的酶抑制剂不同,这些分子胶降解剂以亚化学计量的方式催化先前无法触及的靶标的快速耗竭(Chopraet al.,Drug Discov.Today.Technol.31:5–13(2019))。虽然分子胶降解剂非常可取,但只是偶然发现的。可用于识别或设计这些化合物的策略是有限的(Slabicki et al.,NatureDOI:10.1038/s41586-020-2374-x(2020))。
在本公开的上下文中,式(I)的化合物在其将将泛素连接酶(在本例中为CRBN)募集到靶蛋白(在本例中为Helios)的意义上发挥分子胶的作用,来充当靶向蛋白降解的催化剂。在这样做的过程中,这些化合物被认为会改变CRBN的底物结合位点,使靶蛋白成为新底物(Burslem et al.,Chem.Rev.117:11269-11301(2017))。泛素化步骤后分子胶的解离使其能够随后作用于靶蛋白的不同分子(Che et al.,Bioorg.Med.Chem.Lett.28:2585-2592(2018))。
如本文工作实施例所示,式(I)的双功能化合物(本文也称为降解剂)促进CDK4、CDK6和Helios的共降解,同时基本上保留了其他CDK和IKZF同种型。因此,本公开的双功能化合物可作为CDK4、CDK6和Helios敲除的一套新的化学工具,其举例说明了广泛适用的获得对非选择性结合配体具有选择性的降解剂的方法,并可能为CDK4、CDK6和Helios介导的疾病和病症(如癌症、神经退行性疾病和自身免疫性疾病)提供有效的治疗。
附图简要说明
图1A是用1μM指示(DKY709和Ia-1到Ia-8)化合物处理4小时的Jurkat细胞的一组免疫印迹,其显示了每种化合物的Ikaros、Helios、CDK4、CDK6和微管蛋白的水平。
图1B是用Helios降解剂DKY709、三重降解剂Ia-8和配对的阴性对照化合物17处理4小时的Jurkat细胞的一组免疫印迹,其显示了每种化合物在0.1μM和1μM时的Ikaros、Helios、CDK4、CDK6和微管蛋白的水平。
图2是用0.1μM和1μM指示化合物(帕博西尼、DKY709、Ia-8和17)处理16小时的Jurkat细胞的一组免疫印迹。
图3A是用100nM指示化合物(帕博西尼、DKY709、18、Ia-6、16、Ia-8和17)处理Jurkat细胞24h后,使用碘化丙啶(PI)染色的一组直方图和DNA含量的定量。
图3B是在处理Jurkat细胞3d后通过CellTiterGlo评估的指示化合物(帕博西尼、Ia-8和17)的归一化发光与浓度(log[抑制剂],M)的图。
图4是对于指示化合物,在用a-CD3/CD28进行TCR刺激时Jurkat细胞中[IL2]的图。
详述
除非另有定义,本文使用的所有技术和科学术语具有与本文主题所属领域的技术人员通常理解的含义相同的含义。如说明书和所附权利要求书中所使用的,除非有相反的说明,以下术语具有所指示的含义,以便于理解本公开。
如本说明书和所附权利要求中使用的,单数形式“一个/种(a,an),所述/该(the)”包括复数指代对象,除非上下文另有明确规定。因此,例如,提及“一种组合物”包括两种或更多种这种组合物的混合物,提及“一种抑制剂”包括两种或更多种这种抑制剂的混合物,等等。
除非另有说明,术语“约”是指由术语“约”修饰的特定值的10%以内(例如,5%、2%或1%以内)。
过渡术语“comprising(包含)”,与“including(包括)”、“containing(含有)”或“以……为特征”同义,是包含性的或开放式的,并且不排除其他未述及的要素或方法步骤。相比之下,过渡短语“由……组成”排除了权利要求中未指定的任何要素、步骤或成分。过渡短语“主要由……组成”将权利要求的范围限制为指定材料或步骤“以及实质上不影响所声称的公开内容的基本和新特征的材料或步骤”。
关于本公开的化合物,并且在本文使用下列术语来进一步描述它们的程度上,适用以下定义。
如本文所用,术语“烷基”是指饱和的直链或支链单价烃基。在一个实施方案中,在式(I)化合物中的任何特定基团未被另行定义的程度上,烷基是C1-C18基团。在其他实施方案中,烷基为C0-C6、C0-C5、C0-C3、C1-C12、C1-C8、C1-C6、C1-C5、C1-C4或C1-C3基团(其中C0烷基是指键)。烷基的实例包括甲基、乙基、1-丙基、2-丙基、异丙基、1-丁基、2-甲基-1-丙基、2-丁基、2-甲基-2-丙基、1-戊基、正戊基、2-戊基、3-戊基、2-甲基-2-丁基、3-甲基-2-丁基、3-甲基-1-丁基、2-甲基-1-丁基、1-己基、2-己基、3-己基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、3-甲基-3-戊基、2-甲基-3-戊基、2,3-二甲基-2-丁基、3,3-二甲基-2-丁基、庚基、辛基、壬基、癸基、十一烷基和十二烷基。在一些实施方案中,烷基是C1-C3烷基。
如本文所用,术语“亚烷基”是指将分子的其余部分连接到一个基团的直链或支链二价烃链,其仅由碳和氢组成,不含不饱和键并且具有1个至12个碳原子,例如亚甲基、亚乙基、亚丙基、正亚丁基等。在一些实施方案中,亚烷基链或二价亚烷基链可以被至少一个其他基团中断和/或终止(在一个或两个末端)。在一些实施方案中,亚烷基链或二价亚烷基链可以被–O–、–S–、–N(R')–、–C≡C–、–C(O)–、–C(O)O–、–OC(O)–、–OC(O)O–、–C(NOR')–、–C(O)N(R')–、–C(O)N(R')C(O)–、–C(O)N(R')C(O)N(R')–、–N(R')C(O)–、–N(R')C(O)N(R')–、–N(R')C(O)O–、–OC(O)N(R')–、–C(NR')–、–N(R')C(NR')–、–C(NR')N(R')–、–N(R')C(NR')N(R')–、–OB(Me)O–、–S(O)2–、–OS(O)–、–S(O)O–、–S(O)–、–OS(O)2–、–S(O)2O–、–N(R')S(O)2–、–S(O)2N(R')–、–N(R')S(O)–、–S(O)N(R')–、–N(R')S(O)2N(R')–、–N(R')S(O)N(R')–、C3-C12碳环烯(carbocyclene)、3元至12元杂环烯、5元至12元杂芳烯中的至少一种或其任意组合中断和/或终止(在一个或两个末端),其中R'是H或C1-C6烷基,其中中断基团和一个或两个终止基团可以相同或不同。在式(I)化合物中任何特定基团未另行定义的程度上,亚烷基链可以通过单个键连接到分子的其余部分,并通过单个键连接到基团。在一些实施方案中,亚烷基含有1个至8个碳原子(C1-C8亚烷基)。在其他实施方案中,亚烷基含有1个至5个碳原子(C1-C5亚烷基)。在其他实施方案中,亚烷基含有1个至4个碳原子(C1-C4亚烷基)。在其他实施方案中,亚烷基含有1个至3个碳原子(C1-C3亚烷基)。在其他实施方案中,亚烷基含有1个至2个碳原子(C1-C2亚烷基)。在其他实施方案中,亚烷基含有1个碳原子(C1亚烷基)。
如本文所用,术语“烯基”是指具有至少一个碳-碳双键的直链或支链单价烃基。在式(I)化合物中任何特定基团未另行定义的程度上,烯基包括具有“顺式”和“反式”方向,或者可替换地“E”和“Z”方向的基团。在一个实例中,烯基是C2-C18基团。在其他实施方案中,烯基是C2-C12、C2-C10、C2-C8、C2-C6或C2-C3基团。实例包括乙烯基(ethenyl)或乙烯基(vinyl)、丙-1-烯基、丙-2-烯基、2-甲基丙-1-烯基、丁-1-烯基、丁-2-烯基、丁-3-烯基、丁-1,3-二烯基、2-甲基丁-1,3-二烯、己-1-烯基、己-2-烯基、己-3-烯基、己-4-烯基和己-1,3-二烯基。
如本文所使用的术语“烷氧基(alkoxyl)”或“烷氧基(alkoxy)”是指如上所述的烷基,其上连接有氧自由基,氧自由基是连接点。代表性的烷氧基包括甲氧基、乙氧基、丙氧基、叔丁氧基等。“醚”是由氧共价连接的两个烃。因此,使烷基成为醚的烷基的取代基是或类似于烷氧基,例如可以用-O-烷基、–O-烯基和-O-炔基中的一种表示。
如本文所用,术语“亚烷氧基(alkoxylene)”是指通式(–O-CnH2n–)的饱和单价脂肪族基团,其中n表示整数(例如,1、2、3、4、5、6或7),并且包括直链和支链基团。在式(I)化合物中任何特定基团未另行定义的程度上,亚烷氧基链可以通过单个键连接到分子的其余部分,并通过单个键连接到基团。在一些实施方案中,亚烷氧基含有1个至3个碳原子(–O-C1-C3亚烷氧基)。在其他实施方案中,亚烷氧基含有1个至5个碳原子(–O-C1-C5亚烷氧基)。
如本文所用,术语“卤素”(或“卤代”或“卤化物”)是指氟、氯、溴或碘。
如本文所用,术语“环基”广义上是指单独使用或作为较大部分的一部分的任何基团,其含有饱和、部分饱和或芳环体系,例如,碳环基(环烷基、环烯基)、杂环基(杂环烷基、杂环烯基)、芳基和杂芳基。在式(I)化合物中任何特定基团未另行定义的程度上,环基可以具有一个或更多个(例如,稠合的)环***。因此,例如,环基可以含有一个或更多个碳环基、杂环基、芳基或杂芳基。
如本文所用,术语“碳环”(也称为“碳环基”)是指单独使用或作为较大部分的一部分的基团,其含有饱和的、部分不饱和的或具有3个至20个碳原子芳环体系,其是单独的或较大部分的一部分(例如,烷碳环基团)。在式(I)化合物中任何特定基团未另行定义的程度上,术语碳环基包括单环、双环、三环、稠合环、桥接环和螺环体系及其组合。在一个实施方案中,碳环基包括3个至15个碳原子(C3-C15)。在一个实施方案中,碳环基包括3个至12个碳原子(C3-C12)。在另一个实施方案中,碳环基包括C3-C8、C3-C10或C5-C10。在另一个实施方案中,碳环基作为单环,包括C3-C8、C3-C6或C5-C6。在一些实施方案中,作为二环的碳环基包括C7-C12。在一些实施方案中,作为螺环体系的碳环基包括C5-C12。单环碳环基的代表性实例包括环丙基、环丁基、环戊基、1-环戊-1-烯基、1-环戊-2-烯基、1-环戊-3-烯基、环己基、氘代环己基、1-环己基-1-烯基、1-环己基-2-烯基、1-环己基-3-烯基、环己二烯基、环庚基、环辛基、环壬基、环癸基、环十一烷基、苯基和环十二烷基;具有7个至12个环原子的双环碳环基包括[4,3]、[4,4]、[4,5]、[5,5]、[5,6]或[6,6]环体系,例如双环[2.2.1]庚烷、双环[2.2.2]辛烷、萘和双环[3.2.2]壬烷。螺碳环基的代表性实例包括螺[2.2]戊烷、螺[2.3]己烷、螺[2.4]庚烷、螺[2.5]辛烷和螺[4.5]癸烷。术语碳环基包括如本文所述的芳基环体系。术语碳环基还包括环烷基环(例如,饱和或部分不饱和的单碳环基、双碳环基或螺旋碳环基)。术语碳环基团还包括与一个或更多个(例如1、2或3个)不同环基团(例如芳环或杂环)稠合的碳环,其中自由基或连接点在碳环上。
因此,术语碳环也包括碳环烷基,如本文所用,其是指式-Rc-碳环基的基团,其中Rc是亚烷基链。术语碳环也包括碳环烷氧基,如本文所用,其指通过式–O-Rc-碳环基的氧原子键合的基团,其中Rc是亚烷基链。
如本文所用,术语“杂环基”是指单独使用或作为较大部分的一部分的“碳环基”,含有饱和、部分不饱和或芳环体系,其中一个或更多个(例如1、2、3或4个)碳原子被杂原子(例如O、N、N(O)、S、S(O)或S(O)2)取代。术语杂环基包括单环、双环、三环、稠合环、桥接环和螺环体系及其组合。在式(I)化合物中任何特定基团未另行定义的程度上,在一些实施方案中,杂环基是指3元至15元杂环体系。在一些实施方案中,杂环基是指3元至12元杂环体系。在一些实施方案中,杂环基是指饱和环体系,例如3元至12元饱和杂环体系。在一些实施方案中,杂环基是指杂芳环体系,例如5元至14元杂芳环体系。术语杂环基还包括C3-C8杂环烷基,其是含有3个至8个碳和一个或更多个(1、2、3或4)杂原子的饱和或部分不饱和的单环、双环或螺环体系。
在一些实施方案中,杂环基包括3个至12个环原子,并且包括单环、双环、三环和螺环体系,其中环原子是碳,并且1个至5个环原子是杂原子,例如氮、硫或氧。在一些实施方案中,杂环基包括具有一个或更多个选自氮、硫或氧的杂原子的3元至7元单环。在一些实施方案中,杂环基包括具有一个或更多个选自氮、硫或氧的杂原子的4元至6元单环。在一些实施方案中,杂环基包括3元单环。在一些实施方案中,杂环基包括4元单环。在一些实施方案中,杂环基包括5元至6元单环。在一些实施方案中,杂环基包括0个至3个双键。在任一前述实施方案中,杂环基包括1个、2个、3个或4个杂原子。任何氮或硫杂原子可任选地被氧化(例如,NO、SO、SO2),且任何氮杂原子可任选地被季铵化(例如,[NR4]+Cl-、[NR4]+OH-)。杂环基的代表性实例包括环氧乙烷基、吖丙啶基、thiiranyl、氮杂环丁烷基、氧杂环丁基、硫杂环丁基、1,2-二硫杂环丁烷基、1,3-二硫杂环丁基、吡咯烷基、二氢-1H-吡咯基、二氢呋喃基、四氢吡喃基、二氢噻吩基、四氢噻吩基、咪唑烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、1,1-二氧代硫代吗啉基、二氢吡喃基、四氢吡喃基、六氢硫代吡喃基、六氢嘧啶基、噁嗪烷基、噻嗪基、噻噁烷基、高哌嗪基、高哌啶基、氮杂环庚基、氧杂环庚基、硫杂环庚基、氧氮杂卓基(oxazepinyl)、氧杂氮杂环庚基(oxazepanyl)、二氮杂环庚基、1,4-二氮杂环庚烷基、二氮杂卓基、硫氮杂卓基、硫氮杂环庚基、四氢硫吡喃基、噁唑烷基、噻唑烷基、异噻唑烷基、1,1-二氧代异噻唑烷二壬基、噁唑烷二壬基、咪唑烷二壬基、4,5,6,7-四氢[2H]吲唑基、四氢苯并咪唑基、4,5,6,7-四氢苯并[d]咪唑基、1,6-二氢咪唑并[4,5-D]吡咯并[2,3-b]吡啶基、噻嗪基、苯硫基、噁嗪基、噻二嗪基、噁二嗪基、二噻嗪基、二恶嗪基、氧杂噻嗪基、硫杂三嗪基(thiatriazinyl)、氧杂三嗪基、二噻二嗪基、咪唑啉基、二氢嘧啶基、四氢嘧啶基、1-吡咯啉基、2-吡咯啉基、3-吡咯啉基、二氢吲哚基、硫杂吡喃基、2H-吡喃基、4H-吡喃基、二恶烷基、1,3-二氧戊环基、吡唑啉基、吡唑烷基、二噻烷基、二硫代戊基、嘧啶壬基、嘧啶二酮基、嘧啶-2,4-二酮基、哌嗪壬基、哌嗪二壬基、吡唑烷基咪唑啉基、3-氮杂双环[3.1.0]己烷基、3,6-二氮杂双环[3.1.1]庚烷基、6-氮杂双环[3.1.1]庚烷基、3-氮杂双环[3.1.1]庚烷基、3-氮杂双环[4.1.0]庚烷基、氮杂双环[2.2.2]己基、2-氮杂双环[3.2.1]辛烷基、8-氮杂双环[3.2.1]辛烷基、2-氮杂双环[2.2.2]辛烷基、8-氮杂双环[2.2.2]辛烷基、7-氧杂双环[2.2.1]庚烷、氮杂螺[3.5]壬基、氮杂螺[2.5]辛烷基、氮杂螺[4.5]癸烷基、1-氮杂螺[4.5]癸-2-酮基、氮杂螺[5.5]十一烷基、四氢吲哚基、八氢吲哚基、四氢异吲哚基、四氢吲唑基、1,1-二氧代六氢硫代吡喃基。含有硫或氧原子及1个至3个氮原子的5元杂环基的实例为噻唑基(包括噻唑-2-基和噻唑-2-基N-氧化物)、噻二唑基(包括1,3,4-噻二唑-5-基和1,2,4-噻二唑-5-基)、恶唑基(例如恶唑-2-基)和恶二唑基(例如1,3,4-恶二唑-5-基和1,2,4-恶二唑-5-基)。含有2个至4个氮原子的实例5元环杂环基包括咪唑基,例如咪唑-2-基;***基,例如1,3,4-***-5-基;1,2,3-***-5-基、1,2,4-***-5基和四唑基,例如1H-四唑-5-基。苯并稠合5元杂环基的代表性实例是苯并恶唑-2-基、苯并噻唑-2-基和苯并咪唑-2-基。实例6元杂环基含有1个至3个氮原子和任选的硫或氧原子,例如吡啶基,如吡啶-2-基、吡啶-3-基和吡啶-4-基;嘧啶基,例如嘧啶-2-基和嘧啶-4-基;三嗪基,如1,3,4-三嗪-2-基和1,3,5-三嗪-4-基;哒嗪基,特别是哒嗪-3-基和吡嗪基。吡啶N-氧化物和哒嗪N-氧化物以及吡啶基、嘧啶-2-基、嘧啶-4-基、哒嗪基和1,3,4-三嗪-2-基是杂环基的其他实例。在一些实施方案中,杂环基包括稠合到一个或更多个(例如,1、2或3个)不同环状基团(例如,碳环或杂环)的杂环,其中自由基或连接点位于杂环上,并且在一些实施方案中,其中连接点是包含在杂环中的杂原子。
因此,术语“杂环”包括N-杂环基,如本文所用,N-杂环基指含有至少一个氮的杂环基,并且其中杂环基与分子的其余部分的连接点是通过杂环基中的氮原子。N-杂环基的代表性实例包括1-吗啉基、1-哌啶基、1-哌嗪基、1-吡咯烷基、吡唑烷基、咪唑啉基和咪唑烷基。术语杂环还包括C-杂环基,如本文所用,C-杂环基指含有至少一种杂原子的杂环基,并且其中杂环基与分子的其余部分的连接点是通过杂环基中的碳原子。C-杂环基的代表性实例包括2-吗啉基、2-或3-或4-哌啶基、2-哌嗪基和2-或3-吡咯烷基。术语杂环还包括杂环烷基,如上所公开的,杂环烷基是指式-Rc-杂环基的基团,其中Rc是亚烷基链。术语杂环还包括杂环烷氧基,如本文所用,其指通过式-O-Rc-杂环基的氧原子键合的自由基,其中Rc是亚烷基链。
如本文所用,单独使用或作为较大部分的一部分使用的术语“芳基”(例如,“芳烷基”,其中烷基上的末端碳原子是连接点,例如苄基,“芳烷氧基”,其中氧原子是连接点,或“芳氧基烷基”,其中连接点在芳基上)是指包括单环、双环或三环碳环体系的基团,其包括稠合环,其中体系中至少一个环是芳香族的。在式(I)化合物中未对任何特定基团另行定义的程度上,在一些实施方案中,芳烷氧基是苯甲酰氧基。术语“芳基”可以与术语“芳环”互换使用。在一个实施方案中,芳基包括具有6个至18个碳原子的基团。在另一个实施方案中,芳基包括具有6个至10个碳原子的基团。芳基的实例包括苯基、萘基、蒽基、联苯基、菲基、naphthacenyl、1,2,3,4-四氢萘基、1H-茚基、2,3-二氢-1H-茚基、萘啶基(naphthyridinyl)等,它们可被本文所述的一个或更多个取代基取代或独立取代。一种特殊的芳基是苯基。在一些实施方案中,芳基包括稠合到一个或更多个(例如,1、2或3个)不同环状基团(例如,碳环或杂环)的芳环,其中自由基或连接点在芳环上。任何芳基的能够使双键不同定位的结构被认为包括任一个及所有的此类共振结构。
因此,术语芳基包括芳烷基(例如,苄基),如上所述,芳烷基是指式-Rc-芳基的基团,其中Rc是亚烷基链,例如亚甲基或亚乙基。在一些实施方案中,芳烷基是任选地取代的苄基。术语芳基还包括芳烷氧基,如本文所用,其是指通过式-O-Rc-芳基的氧原子键合的基团,其中Rc是亚烷基链,例如亚甲基或亚乙基。
如本文所用,单独使用或作为较大部分的一部分使用的术语“杂芳基”,例如,“杂芳基烷基(heteroarylalkyl)”(也称为“杂芳烷基(heteroaralkyl)”)或“杂芳基烷氧基(heteroarylalkoxy)”(也称“杂芳烷氧基(heteroaralkoxy)”)是指具有5个至14个环原子的单环、双环或三环环体系,其中至少一个环是芳香族的并且含有至少一个杂原子。在一个实施方案中,杂芳基包括5元至6元单环芳族基团,其中一个或更多个环原子为独立地被任选地取代的氮、硫或氧。在另一实施方案中,杂芳基包括5-6元单环芳族基团,其中一个或多个环原子是氮、硫或氧。杂芳基的代表性实例包括噻吩基、呋喃基、咪唑基、吡唑基、噻唑基、异噻唑基、噁唑基、异恶唑基、***基、噻二唑基、恶二唑基、四唑基、噻***基、恶***基、吡啶基、嘧啶基、咪唑吡啶基、吡嗪基、哒嗪基、三嗪基、四嗪基、四唑并[1,5-b]哒嗪基、嘌呤基、脱氮嘌呤基、苯并恶唑基、苯并呋喃基、苯并噻唑基、苯并噻二唑基、苯并***基、苯并咪唑基、吲哚基、1,3-噻唑-2-基、1,3,4-***-5-基、1,3,4-恶唑-5-基、1,2,4-恶二唑-5-基、1,3,4-噻二唑-5-基、1H-四唑-5-基、1,2,3-***-5-基和吡啶-2-基N-氧化物。术语“杂芳基”还包括其中杂芳基稠合到一个或更多个环状(例如,碳环基或杂环基)环的基团,其中自由基或连接点在杂芳基环上。非限制性实例包括吲哚基、吲哚嗪基、异吲哚基、苯并噻吩基、苯并苯硫基、亚甲二氧苯基、苯并呋喃基、二苯并呋喃基、吲唑基、苯并咪唑基、苯并二恶唑基、苯并噻唑基、喹啉基、异喹啉基、噌嗪基、酞嗪基、喹唑啉基、喹喔啉基、4H-喹啉基、咔唑基、吖啶基、吩嗪基、吩噻嗪基、吩恶嗪基、四氢异喹啉基和吡啶并[2,3-b]-1,4-恶嗪-3(4H)-酮。杂芳基可以是单环的、双环的或三环的。在一些实施方案中,杂芳基包括稠合到一个或更多个(例如,1、2或3个)不同环状基团(例如,碳环或杂环)的杂芳基环,其中自由基或连接点位于杂芳环上,并且在一些实施方案中,其中连接点是包含在杂环中的杂原子。任何杂芳基的能够使双键不同定位的结构被认为包括任一个及所有的此类共振结构。
因此,术语杂芳基还包括N-杂芳基,其如本文所用是指,含有至少一个氮的如上所述且包含至少一个氮原子的杂芳基,并且其中杂芳基与分子其余部分的连接点是通过杂芳基中的氮原子。术语杂芳基还包括C-杂芳基,其如本文所用是指如上所述的杂芳基,并且其中杂芳基与分子的其余部分的连接点是通过杂芳基中的碳原子。术语杂芳基还包括杂芳基烷基,其如上所述是指式--Rc-杂芳基的基团,其中Rc是如上所述的亚烷基链。术语杂芳基还包括杂芳烷氧基(heteroaralkoxy)(或杂芳基烷氧基(heteroarylalkoxy))基团,其如本文所用是指通过式--O--Rc-杂芳基的氧原子键合的基团,其中Rc是如上所定义的亚烷基链。
除非另有说明,并且在未对任何特定基团进一步定义的程度上,本文所述的任何基团均可被取代或不被取代。如本文所用,术语“取代的”广义地指所有允许的取代基,其隐含的条件是,这种取代基符合被取代原子和取代基的允许价,并且这种取代基生成稳定的化合物,即不会自发发生重排、环化、消除等变换的化合物。代表性取代基包括卤素、羟基和含有任意数目碳原子(例如1个至14个碳原子)的以线性、支链或环状结构形式分组的任何其他有机基团,并且其可包括一个或更多个(例如,1、2、3或4)杂原子,例如氧、硫和氮。
在未对任何特定基团另行定义的程度上,取代基的代表性实例因此可包括烷基、取代的烷基(例如,C1-C6、C1-C5、C1-C4、C1-C3、C1-C2、C1)、烷氧基(例如,C1-C6、C1-C5、C1-C4、C1-C3、C1-C2、C1)、取代的烷氧基(例如,C1-C6、C1-C5、C1-C4、C1-C3、C1-C2、C1)、卤代烷基(例如CF3)、烯基(例如C2-C6、C2-C5、C2-C4、C2-C3、C2)、取代的烯基(例如,C2-C6、C2-C5、C2-C4、C2-C3、C2)、炔基(例如,C2-C6、C2-C5、C2-C4、C2-C3、C2)、取代的炔基(例如,C2-C6、C2-C5、C2-C4、C2-C3、C2)、环(例如,C3-C12、C5-C6)、取代的环(例如,C3-C12、C5-C6)、碳环(例如,C3-C12、C5-C6)、取代的碳环(例如,C3-C12、C5-C6)、杂环(例如C3-C12,C5-C6)、取代的杂环(例如,C3-C12、C5-C6)、芳基(例如苄基和苯基)、取代的芳基(例如取代的苄基或苯基)、杂芳基(例如吡啶基或嘧啶基)、取代的杂芳基(例如取代的吡啶基或嘧啶基)、芳烷基(例如苄基)、取代的芳烷基(例如取代的苄基)、卤代、羟基、芳氧基(例如C6-C12、C6)、取代的芳氧基(例如C6-C12、C6)、硫代烷基(例如C1-C6)、取代的硫代烷基(例如C1-C6)、芳硫基(例如C6-C12、C6)、取代的芳硫基(例如C6-C12、C6)、氰基、羰基、取代的羰基、羧基、取代的羧基、氨基、取代的氨基、酰胺基、取代的酰胺基、硫代、取代的硫代、亚磺酰基、取代的亚磺酰基、磺酰基、取代的磺酰基、亚磺酰胺、取代的亚磺酰胺、磺酰胺、取代的磺酰胺、尿素、取代的尿素、氨基甲酸酯、取代的氨基甲酸酯、氨基酸和肽基。
锌指转录因子Helios对于维持调节性T细胞的身份、无能表型和抑制活性至关重要[PMID:26472910,27185917,29440380],且Helios的急性药理学降解可使离体调节性T细胞不稳定[PMID:34035522]。另外,鉴于细胞周期蛋白依赖性激酶4/6(CDK4/6)在调节细胞周期进程中的重要作用,已经发现CDK4/6的抑制剂具有有效的抗增殖作用[PMID:27030077,29935901,26658964]。最近,还发现这些CDK4/6抑制剂具有免疫调节作用,包括直接促进T细胞活性[PMID:29101163]、增强记忆性T细胞的形成[PMID:33941591]、调控调节性T细胞增殖[PMID:28813415]和调节肿瘤细胞免疫原性[PMID:28813415,29160310,30388455]。因此,靶向Helios和CDK4/6二者可能对减少肿瘤细胞增殖和促进抗肿瘤免疫反应有深远影响。
本公开的第一方面涉及具有由式(I)表示的结构的双功能化合物:
或其药学上可接受的盐或立体异构体,其中靶向配体结合CDK4和/或CDK6,接头包含亚烷基链或聚乙二醇链。
靶向配体代表与CDK4和/或CDK6结合的部分。在一些实施方案中,靶向配体来源于帕博西尼、瑞博西尼或阿贝西利。帕博西尼的衍生物在本领域是已知的,并且例如在美国专利号6,936,612、7,456,168、10,723,730和RE47739中进行了描述。瑞博西尼的衍生物在本领域是已知的,并且例如在美国专利号8,324,225、8,415,355、8,685,980、8,962,630、9,193,732、9,416,136、9,868,739和10,799,506中进行了描述。阿贝西利的衍生物在本领域是已知的,并且例如在美国专利号7,855,221中进行了描述。
在一些实施方案中,靶向配体由以下结构中的任一种表示:
因此,在一些实施方案中,双功能化合物具有由式(Ia)、式(Ib)或式(Ic)表示的结构:
或其药学上可接受的盐或立体异构体。
在一些实施方案中,接头包含亚烷基链(例如,具有1个至20个亚烷基单元)。在一些实施方案中,接头包含1个至6个亚烷基单元。在一些实施方案中,亚烷基链或二价亚烷基链可以被–O–、–S–、–N(R')–、–C≡C–、–C(O)–、–C(O)O–、–OC(O)–、–OC(O)O–、–C(NOR')–、–C(O)N(R')–、–C(O)N(R')C(O)–、–C(O)N(R')C(O)N(R')–、–N(R')C(O)–、–N(R')C(O)N(R')–、–N(R')C(O)O–、–OC(O)N(R')–、–C(NR')–、–N(R')C(NR')–、–C(NR')N(R')–、–N(R')C(NR')N(R')–、–OB(Me)O–、–S(O)2–、–OS(O)–、–S(O)O–、–S(O)–、–OS(O)2–、–S(O)2O–、–N(R')S(O)2–、–S(O)2N(R')–、–N(R')S(O)–、–S(O)N(R')–、–N(R')S(O)2N(R')–、–N(R')S(O)N(R')–、C3-C12碳环烯、3元至12元杂环烯、5元至12元杂芳烯中的至少一种或其任意组合中断和/或终止(在一个或两个末端),其中R'是H或C1-C6烷基,其中中断基团和一个或两个终止基团可以相同或不同。
在一些实施方案中,亚烷基链被-O-或-NH-中的至少一个中断和/或终止(在一个或两个末端)。
在其他实施方案中,接头包含聚乙二醇链。聚乙二醇链可以用–S–、–N(R')–、–C≡C–、–C(O)–、–C(O)O–、–OC(O)–、–OC(O)O–、–C(NOR')–、–C(O)N(R')–、–C(O)N(R')C(O)–、–C(O)N(R')C(O)N(R')–、–N(R')C(O)–、–N(R')C(O)N(R')–、–N(R')C(O)O–、–OC(O)N(R')–、–C(NR')–、–N(R')C(NR')–、–C(NR')N(R')–、–N(R')C(NR')N(R')–、–OB(Me)O–、–S(O)2–、–OS(O)–、–S(O)O–、–S(O)–、–OS(O)2–、–S(O)2O–、–N(R')S(O)2–、–S(O)2N(R')–、–N(R')S(O)–、–S(O)N(R')–、–N(R')S(O)2N(R')–、–N(R')S(O)N(R')–、C3-12碳环烯、3元至12元杂环烯、5元至12元杂芳烯中的至少一个或其任意组合终止(在一个或两个末端),其中R'是H或C1-C6烷基,其中一个或两个终止基团可以相同或不同。
在一些实施方案中,聚乙二醇链在一个或两个末端终止于-O-或-NH-中的至少一个。在一些实施方案中,接头包含1个至3个乙二醇单元。在一些实施方案中,接头是以下结构中的任一种: 在一些实施方案中,接头在3-位(间位)处连接到苯基。在一些实施方案中,接头在4-位(对位)处连接到苯基。
术语“结合”当涉及靶向配体与两个靶向蛋白(在本公开中为CDK4和/或CDK6)之间的相互作用时,通常是指具有优先性(在本文中也称为“选择性”)的分子间相互作用,因为靶向配体与存在于细胞中的其他蛋白(包括其他CDK同种型)的结合实质上更少并且功能上不重要,至少从降解的角度来看是这样。术语“选择性的”和“选择性”是指双功能化合物区分分子靶标的能力。本文所述的选择性双CDK4/6降解剂可能具有的针对CDK4/6活性的DC50(半数最大降解浓度)比针对CDK1、CDK2、CDK7、CDK8、CDK9、CDK11、CDK12、CDK13、CDK14中的一种或更多种和其他激酶的DC50低至少约1、2、3、4、5、6、7、8、9或10倍。因此,尽管本公开的各种双功能化合物以相似或更低的亲和力与其他CDK蛋白结合,但它们显示出对CDK4/6的选择性降解。
术语“结合”当涉及连接到式(I)中与靶向配体相对的接头上的基团与E3泛素连接酶之间的相互作用时,通常是指分子间相互作用,该相互作用可能或可能不表现出等于或超过靶向配体和靶蛋白之间的亲和力的亲和力水平,但其中该亲和力足以募集连接酶以实现靶向降解和靶蛋白的选择性降解。
术语“结合”当涉及连接到式(I)中与靶向配体相对的接头上的基团与Helios之间的相互作用时,通常是指充当分子胶的化合物,在这个意义上,这些化合物将泛素连接酶(在本例中为CRBN)募集到靶蛋白(在本例中为Helios)上,以充当靶向蛋白降解的催化剂。
本公开的代表性双功能化合物如下:
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或其药学上可接受的盐或立体异构体。
式(I)的双功能化合物可以是游离酸或游离碱或药学上可接受的盐的形式。如本文所用,在盐的上下文中,术语“药学上可接受的”是指不消除化合物的生物活性或性质并且相对无毒的化合物的盐,即,盐形式的化合物可以施用于受试者,而不会引起不良的生物学效应(如头晕或胃部不适)或以有害的方式与含有它的组合物的任何其他组分相互作用。术语“药学上可接受的盐”是指通过本公开化合物与合适的酸或碱反应而获得的产品。本公开化合物的药学上可接受的盐的实例包括那些来源于合适的无机碱的盐如Li盐、Na盐、K盐、Ca盐、Mg盐、Fe盐、Cu盐、Al盐、Zn盐和Mn盐。药学上可接受的无毒酸加成盐的实例是氨基与无机酸形成的盐,如盐酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、硫酸盐、硫酸氢盐、磷酸盐、异烟酸盐、乙酸盐、乳酸盐、水杨酸盐、枸橼酸盐、酒石酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、琥珀酸盐、马来酸盐、龙胆酸盐、富马酸盐、葡糖酸盐、葡糖醛酸盐、糖酸盐、甲酸盐、苯甲酸盐、谷氨酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、4-甲基苯磺酸盐或对甲苯磺酸盐等。本公开的某些化合物可以与各种有机碱如赖氨酸、精氨酸、胍、二乙醇胺或二甲双胍形成药学上可接受的盐。
式(I)的双功能化合物可以具有至少一个手性中心,且因此可以是立体异构体的形式,其如本文所用,包括个体化合物的所有异构体,不同之处仅在于它们的原子在空间的取向。术语立体异构体包括镜像异构体(包括化合物的(R-)或(S-)构型的对映异构体)、化合物的镜像异构体混合物(对映异构体的物理混合物和外消旋物或外消旋混合物)、化合物的几何(顺式/反式或E/Z,R/S)异构体和具有一个以上手性中心且互不为镜像的化合物异构体(非对映异构体)。化合物的手性中心可能在体内发生差向异构化;因此,对于这些化合物来说,施用其(R-)形式的化合物被认为等同于施用其(S-)形式的化合物。因此,本公开的化合物可以以单个异构体形式且基本上不含其它异构体的形式制造和使用,或者以各种异构体的混合物形式制造和使用,例如,立体异构体的外消旋混合物。
在一些实施方案中,式(I)的双功能化合物是同位素衍生物,因为它具有至少一个所期望的原子的同位素取代,其量高于该同位素的天然丰度,即被富集。在一个实施方案中,化合物包括氘或多个氘原子。用较重的同位素如氘(即2H)取代,由于其代谢稳定性较高,例如体内半衰期增加或剂量要求减少,可能具有某些治疗优势,且因此在某些情况下可能是有利的。
此外,式(I)的双功能化合物包括使用N-氧化物、结晶形式(也称为多晶型物)、具有相同类型活性的化合物的活性代谢物、互变异构体和非溶剂化形式以及使用药学上可接受溶剂(如水、乙醇等)的溶剂化形式。本文提出的偶联物的溶剂化形式也应认为被本文公开。
合成方法
在一些实施方案中,本公开涉及制造式(I)的双功能化合物或其药学上可接受的盐或立体异构体的方法。从广义上讲,该化合物或其药学上可接受的盐或立体异构体可以通过已知适用于制备化学相关化合物的任何工艺来制备。结合各种工作实施例中描述的合成方案,可以更好地理解本公开的化合物,且这些方案说明了可以制备本公开化合物的非限制性方法。
药物组合物
本公开的另一方面涉及药物组合物,其包括治疗有效量的式(I)双功能化合物或其药学上可接受的盐或立体异构体,以及药学上可接受的载体。术语“药学上可接受的载体”,如本领域所知,是指适用于向哺乳动物施用本公开的化合物的药学上可接受的材料、组合物或媒介物。合适的载体可包括,例如,液体(水性和非水性均可,及其组合)、固体、包封材料、气体及其组合(例如,半固体)和气体,其功能是将化合物从一个器官或身体的一部分携带或运输到另一个器官或身体的另一部分。载体是“可接受的”,即在生理上是惰性的且与制剂的其他成分相容,并且对受试者或患者无害。根据制剂的类型,组合物还可以包括一种或更多种药学上可接受的赋形剂。
从广义上讲,式(I)双功能化合物及其药学上可接受的盐和立体异构体可根据常规制药实践,例如常规混合、溶解、制粒、糖衣丸制造、粉碎、乳化、封装、包封和压片工艺,配制成给定类型的组合物(参见,例如,Remington:The Science and Practice of Pharmacy(20th ed.),ed.A.R.Gennaro,Lippincott Williams&Wilkins,2000和Encyclopedia ofPharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,MarcelDekker,New York)。制剂的类型取决于施用方式,其可以包括肠内(例如,口服、含服、舌下和直肠)、肠胃外(例如,皮下(s.c.)、静脉内(i.v.)、肌内(i.m.)和胸骨内注射,或输注技术、眼内、动脉内、髓内、鞘内、心室内、经皮、皮内、***内、腹膜内、粘膜、鼻、气管内滴注、支气管滴注和吸入)和外用(例如,经皮的)。一般来说,最合适的施用途径将取决于多种因素,包括,例如,剂的性质(例如,其在胃肠道环境中的稳定性)和/或受试者的状况(例如,受试者是否能够耐受口服施用)。例如,胃肠外(例如,静脉内)施用也可能是有利的,因为例如在单剂量治疗和/或急性不适的情况下,化合物可以相对快速地施用。
在一些实施方案中,双功能化合物被配制成用于口服或静脉内施用(例如,全身静脉内注射)。
因此,本公开的双功能化合物可以配制成固体组合物(例如,粉剂、片剂、分散颗粒、胶囊、扁囊剂和栓剂)、液体组合物(例如,溶解该化合物的溶液、分散该化合物固体颗粒的悬浮液、乳剂和含有脂质体的溶液、胶束或纳米颗粒、糖浆和酏剂);半固体组合物(例如,凝胶、混悬剂和乳膏);和气体(例如,气溶胶组合物的推进剂)。还可将化合物配制用于速释、中速释放或缓释。
口服的固体剂型包括胶囊、片剂、丸剂、散剂和颗粒。在这类固体剂型中,活性化合物与载体如柠檬酸钠或磷酸二钙以及其他的载体或赋形剂例如a)填充剂或增量剂(extender)如淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸,b)粘合剂如甲基纤维素、微晶纤维素、羟丙基甲基纤维素、羧甲基纤维素、羧甲基纤维素钠、海藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和***胶,c)保湿剂如甘油,d)崩解剂如交联聚合物(如交联聚乙烯吡咯烷酮(交聚维酮)、交联羧甲基纤维素钠(交联羧甲基纤维素钠)、羟基乙酸淀粉钠、琼脂、碳酸钙、马铃薯或木薯淀粉、藻酸、某些硅酸盐和碳酸钠,e)溶液阻滞剂如石蜡,f)吸收促进剂如季铵化合物,g)润湿剂例如,如鲸蜡醇和单硬脂酸甘油酯,h)吸收剂如高岭土和膨润土,和i)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)混合。在胶囊剂、片剂和丸剂的情况下,剂型还可以包括缓冲剂。类似类型的固体组合物也可以用作使用如乳糖(lactose或milk sugar)以及高分子量聚乙二醇等赋形剂的软填充和硬填充明胶胶囊的填充物。片剂、糖衣丸、胶囊、丸剂和颗粒的固体剂型可以用肠溶衣和其他包衣等包衣和壳来制备。它们还可含有遮光剂。
在一些实施方案中,本公开的双功能化合物可以被配制成硬明胶或软明胶胶囊。可以使用的代表性赋形剂包括预胶化淀粉、硬脂酸镁、甘露醇、硬脂酰富马酸钠、无水乳糖、微晶纤维素和交联羧甲基纤维素钠。明胶壳可包括明胶、二氧化钛、氧化铁和着色剂。
用于口服施用的液体剂型包括溶液、混悬剂、乳剂、微乳剂、糖浆和酏剂。除化合物外,液体剂型可含有本领域常用的水性或非水性载体(取决于化合物的溶解度),例如,例如水或其他溶剂、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、二甲基甲酰胺、油(特别是棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油和芝麻油)、甘油、四氢糠醇、聚乙二醇和山梨醇酐脂肪酸酯及其混合物。口服组合物还可以包括赋形剂,例如润湿剂、助悬剂、着色剂、甜味剂、调味剂和芳香剂。
可注射制剂可包括无菌水溶液或含油混悬剂。它们可以根据标准技术使用合适的分散剂或湿润剂和助悬剂来配制。无菌可注射制剂也是在无毒的肠外可接受稀释剂或溶剂中的无菌可注射溶液、混悬剂或乳剂,如溶于1,3-丁二醇的溶液。可以使用的可接受的载体和溶剂是水、林格氏溶液、U.S.P.和等渗氯化钠溶液。此外,通常使用无菌的固定油作为溶剂或悬浮介质。为此,可以使用任何温和的固定油,其包括合成的单甘油酯或二甘油酯。此外,脂肪酸(如油酸)用于制备注射剂。将注射制剂灭菌,例如,通过细菌截留过滤器过滤,或通过将灭菌剂以掺入无菌固体组合物形式中,可在使用前将该无菌固体组合物溶解或分散于无菌水或其他无菌注射介质中。可通过减慢化合物的吸收来延长其作用,其可通过使用具有较差水溶性的液体悬浮液或结晶或无定形材料来实现。延长从肠胃外施用的制剂中吸收化合物也可以通过将化合物悬浮在油性溶媒中来实现。
在某些实施方案中,式(I)的双功能化合物可以以局部而非全身的方式施用,例如,通过将偶联物通常以贮库制剂或缓释制剂形式直接注射到器官中。在具体实施方案中,长效制剂通过植入(例如皮下或肌内)或肌内注射施用。可注射的长效剂型通过使化合物在可生物降解聚合物(例如,聚乳酸–聚乙醇酸、聚原酸酯和聚酸酐)中形成微囊基质来制造。化合物的释放速率可以通过改变化合物与聚合物的比例和所采用的特定聚合物的性质来控制。可注射的长效制剂还通过将化合物包封在与身体组织相容的脂质体或微乳剂中制备。此外,在其他实施方案中,化合物在靶向药物递送***中递送,例如,在用器官特异性抗体包被的脂质体中递送。在这样的实施方案中,脂质体靶向器官并被器官选择性地摄取。
双功能化合物可以被配制成用于含服或舌下施用,其实例包括片剂、含片和凝胶。
双功能化合物可以被配制成吸入施用。适合吸入施用的各种形式包括气雾剂、喷雾或散剂。药物组合物可以使用合适的推进剂(例如,二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、二氧化碳或其他合适的气体)以气雾剂喷雾的形式从加压包装或雾化器中递送。在一些实施方案中,加压气雾剂的剂量单位可以通过提供阀门以输送计量的量来确定。在一些实施方案中,包括明胶的胶囊和药筒(例如,用于吸入器或吹药器)可以被配制含有该化合物和合适的粉基如乳糖或淀粉的粉末混合物。
式(I)的双功能化合物可以被配制用于表面施用,如本文所用,是指将制剂皮内施用至表皮。这些类型的组合物通常以软膏剂、糊剂、霜剂、洗剂、凝胶、溶液和喷雾剂的形式存在。
用于配制表面施用的组合物的载体的代表性实例包括溶剂(例如,醇、多元醇、水)、霜剂、洗剂、软膏剂、油、膏药、脂质体、粉剂、乳剂、微乳剂和缓冲液(例如,低渗或缓冲盐水)。例如,可以使用饱和或不饱和脂肪酸如硬脂酸、棕榈酸、油酸、棕榈油酸、鲸蜡醇或油醇来配制霜剂。霜剂还可含有非离子表面活性剂,如硬脂酸聚烃氧(40)酯。
在一些实施方案中,表面制剂还可以包括赋形剂,其实例是渗透促进剂。这些制剂能够将具有药理活性的化合物通过角质层运输和到表皮或真皮中,优选全身吸收很少或没有。已经对多种化合物在提高药物的皮肤渗透速率方面的有效性进行了评估。参见,例如,Percutaneous Penetration Enhancers,Maibach H.I.和Smith H.E.(eds.),CRC Press,Inc.,Boca Raton,Fla.(1995)(其调查了各种皮肤渗透增强剂的使用和测试)和Buyuktimkin et al.,Chemical Means of Transdermal Drug Permeation Enhancementin Transdermal和Topical Drug Delivery Systems,Gosh T.K.,Pfister W.R.,Yum S.I.(Eds.),Interpharm Press Inc.,Buffalo Grove,Ill.(1997)。渗透增强剂的代表性实例包括甘油三酯(例如,大豆油)、芦荟组合物(例如,芦荟凝胶(aloe-vera gel))、乙醇、异丙醇、辛基苯基聚乙二醇(octylphenylpolyethylene glycol)、油酸、聚乙二醇400、丙二醇、N-癸基甲基亚砜、脂肪酸酯(例如,肉豆蔻酸异丙酯、月桂酸甲酯、甘油单油酸酯和丙二醇单油酸酯)和N-甲基吡咯烷酮。
可包括在表面制剂以及其他类型的制剂中的其他赋形剂的代表性实例(在它们相容的程度上)包括防腐剂、抗氧化剂、保湿剂、润肤剂、缓冲剂、增溶剂、皮肤保护剂和表面活性剂。合适的防腐剂包括醇类、季胺类、有机酸类、苯甲酸酯类和酚类。合适的抗氧化剂包括抗坏血酸及其酯、亚硫酸氢钠、丁基羟基甲苯、丁基羟基茴香醚、生育酚以及螯合剂如EDTA和柠檬酸。合适的保湿剂包括甘油、山梨醇、聚乙二醇、尿素和丙二醇。合适的缓冲剂包括柠檬酸、盐酸和乳酸缓冲液。合适的增溶剂包括季铵盐酸盐、环糊精类、苯甲酸苄酯、卵磷脂和聚山梨醇酯。合适的皮肤保护剂包括维生素E油、尿囊素(allantoin)、二甲基硅油、甘油、凡士林和氧化锌。
透皮制剂通常采用透皮递送装置和透皮递送贴片,其中化合物被配制成溶于和/或分散于聚合物或粘合剂中的亲脂性乳液或缓冲水溶液。贴剂可以被构建为用于连续、脉冲式(pulsatile)或按需递送药剂。化合物的透皮递送可以通过离子电渗贴剂实现。透皮贴剂可以提供化合物的受控递送,其中通过使用速率控制膜或通过将化合物截留在聚合物基质或凝胶中来减缓吸收率。吸收促进剂可用于增加吸收,其实例包括有助于通过皮肤的可吸收药学上可接受的溶剂。
眼科制剂包括滴眼液。用于直肠施用的制剂包括灌肠剂、直肠凝胶、直肠泡沫剂、直肠气雾剂和保留灌肠剂,其可含有常规栓剂基质如可可油或其他甘油酯,以及合成聚合物如聚乙烯吡咯烷酮、PEG等。用于直肠或***施用的组合物也可以被配制成栓剂,其可以通过将化合物与合适的非刺激性载体和赋形剂如可可油、脂肪酸甘油酯的混合物、聚乙二醇、栓剂蜡及其组合混合来制备,所有这些化合物在环境温度下是固体,但在体温下是液体,且因此在直肠或***腔中融化并释放化合物。
剂量
如本文所用,术语“治疗有效量”是指式(I)的双功能化合物或药学上可接受的盐或其立体异构体或包括式(I)的双功能化合物或其药学上可接受的盐或立体异构体的组合物,在患有以CDK4/6和Helios的任何一种或更多种的异常活性为特征或由其介导的疾病或病症的特定患者中有效地产生所需的治疗反应的量。因此,术语“治疗有效量”包括本公开的双功能化合物或其药学上可接受的盐或立体异构体的量,当施用该量时,诱导待治疗的疾病或病症的积极改变,或足以防止疾病或病症的发展或进展,或在某种程度上减轻受试者中正在治疗的疾病或病症的一种或更多种症状,或仅杀死或抑制病变(如神经母细胞瘤)细胞的生长,或减少病变细胞中CDK4/6和Helios的量。
双功能化合物的每日总剂量及其用法可以根据标准医疗实践决定,例如,由主治医师使用合理的医学判断来决定。任何特定受试者的具体治疗有效剂量可能取决于多种因素,其包括待治疗的疾病或病症及其严重程度(例如,其现状);受试者的年龄、体重、总体健康状况、性别和饮食;所用特定化合物的施用时间、施用途径和***率;治疗的持续时间;与双功能化合物联合或同时使用的药物;以及医学界公知的类似因素(参见,例如,Goodmanand Gilman's,The Pharmacological Basis of Therapeutics,10th Edition,A.Gilman,J.Hardman and L.Limbird,eds.,McGraw-Hill Press,155-173,2001)。
式(I)的双功能化合物及其药学上可接受的盐和立体异构体可能在宽剂量范围内有效。在一些实施方案中,每日总剂量(例如,对于成年人)的范围可以是约0.001mg至约1600mg、0.01mg至约1600mg、0.01mg至约500mg、约0.01mg至约100mg、约0.5mg至约100mg、每天约1mg至约100mg-400mg、每天约1mg至约50mg、和每天约5mg至约40mg,且在其他实施方案中每天约10mg至约30mg。根据化合物每天施用的次数,可以配制含有所需剂量的单个剂量。作为实例,可以用约1mg至约200mg的双功能化合物(例如,1mg、2mg、2.5mg、3mg、4mg、5mg、10mg、15mg、20mg、25mg、50mg、100mg、150mg和200mg)来配制胶囊。在一些实施方案中,可以根据化合物每天施用的次数配制含有所需剂量的单个剂量。
使用方法
在一些方面,本公开涉及治疗涉及异常(例如,功能障碍或失调)CDK4/6和/或Helios活性的疾病或不适的方法,其需要向有需要的受试者施用治疗有效量的式(I)双功能化合物或其药学上可接受的盐或立体异构体。在一些实施方案中,本公开涉及降低细胞中CDK4和/或CDK6和Helios水平的方法,无论是在体外还是在体内,其包括使细胞与式(I)的双功能化合物接触。
疾病或不适由CDK4/6和/或Helios的异常活性表征或介导(例如,相对于非病理状态,CDK4/6或Helios水平升高或以其他方式表现的CDK4/6及/或Helios功能异常)。“疾病”通常被认为是受试者的健康状态,其中受试者不能维持体内稳态,并且其中如果疾病没有改善,则受试者的健康继续恶化。相比之下,受试者的“不适”是受试者能够维持体内稳态的健康状况,但是受试者的健康状态不如没有不适时的健康状态好。如果不进行治疗,不适不一定导致动物的健康状况的进一步下降。在一些实施方案中,式(I)的化合物可用于治疗细胞增殖性疾病和不适(例如,癌症或良性肿瘤)。如本文所用,术语“细胞增殖性疾病或不适”是指以细胞生长失调或异常或两者兼有为特征的状况,包括非癌性疾病如赘生物、癌前疾病、良性肿瘤和癌症。
如本文所用,术语“受试者”(或“患者”)包括易患或患有所述疾病或不适的动物界所有成员。在一些实施方案中,受试者是哺乳动物,例如,人类或非人类哺乳动物。该方法也适用于伴侣动物,如狗和猫,以及家畜,如牛、马、绵羊、山羊、猪和其他家养和野生动物。根据本公开,“需要”治疗的受试者可能“患有或疑似患有”特定的疾病或不适,可能已经被确诊或以其他方式表现出足够数量的危险因素或足够数量的体征或症状或其组合,使得医学专业人员可以诊断或怀疑受试者患有该疾病或不适。因此,患有和疑似患有特定疾病或不适的受试者不一定是两个不同的群体。
可以用本公开的化合物治疗的非癌性(例如,细胞增殖性)疾病或不适的示例性类型包括炎性疾病和状况、自身免疫性疾病、神经退行性疾病、心脏病、病毒性疾病、慢性和急性肾脏疾病或损伤、代谢性疾病以及过敏性和遗传性疾病。
具体的非癌性疾病和不适的代表性实例包括类风湿性关节炎、斑秃、淋巴组织增生性疾病、自身免疫性血液病(例如,溶血性贫血、再生障碍性贫血、无汗性外胚层发育不良、单纯红细胞性贫血和特发性血小板减少症)、胆囊炎、肢端肥大症、类风湿性脊柱炎、骨关节炎、痛风、硬皮病、脓毒症、脓毒性休克、泪腺炎、冷吡啉相关的周期性综合征(CAPS)、内毒素性休克、子***、革兰氏阴性脓毒症、干燥性角膜结膜炎、中毒性休克综合征、哮喘、成人呼吸窘迫综合征、慢性阻塞性肺疾病、慢性肺部炎症、慢性移植物排斥、化脓性汗腺炎、炎性肠病、克罗恩病、贝赫切特综合征、***性红斑狼疮、肾小球肾炎、多发性硬化症、青少年糖尿病、自身免疫性葡萄膜炎、自身免疫性血管炎、甲状腺炎、阿狄森病、扁平苔癣、阑尾炎、大疱性天疱疮、寻常型天疱疮、落叶性天疱疮、副肿瘤性天疱疮、重症肌无力、A型免疫球蛋白肾病、桥本病、干燥综合征、白癜风、韦格纳肉芽肿、肉芽肿性***、自身免疫性***、结节病、风湿性心脏炎、强直性脊柱炎、格雷夫症、自身免疫性血小板减少性紫癜、银屑病、银屑病性关节炎、湿疹、疱疹样皮炎、溃疡性结肠炎、胰腺纤维化、肝炎、肝纤维化、CD14介导的脓毒症、非CD14介导的脓毒症、急性和慢性肾病、肠易激综合征、发热(pyresis)、再狭窄、***、中风和缺血性损伤、神经创伤、急性和慢性疼痛、过敏性鼻炎、过敏性结膜炎、慢性心力衰竭、充血性心力衰竭、急性冠脉综合征、恶病质、疟疾、麻风病、利什曼病、莱姆病、赖特综合征、急性滑膜炎、肌肉变性、滑囊炎、肌腱炎、腱鞘炎、椎间盘突出、破裂或脱出综合征、骨硬化症、鼻窦炎、血栓形成、矽肺、肺肉瘤病、骨吸收疾病如骨质疏松症、纤维肌痛、AIDS和其他病毒性疾病如带状疱疹、单纯疱疹I型或II型、流感病毒和巨细胞病毒、I型和II型糖尿病、肥胖症、胰岛素抗药性和糖尿病视网膜病变、22q11.2缺失综合征、天使人综合征、卡纳万病、乳糜泻、Charcot-Marie-Tooth病、色盲、猫哭症、唐氏综合征、囊性纤维化、杜氏肌营养不良、血友病、克氏综合征、多发性神经纤维瘤、苯丙酮尿症、普拉德-威利综合征、镰状细胞病、泰-萨克斯病、特纳综合征、尿素循环障碍、地中海贫血、耳炎、胰腺炎、腮腺炎、心包炎、腹膜炎、咽炎、胸膜炎、静脉炎、肺炎、葡萄膜炎、多发性肌炎、直肠炎、间质性肺纤维化、皮肌炎、动脉粥样硬化、动脉硬化、肌萎缩侧索硬化、社交不能、静脉曲张病、***炎、抑郁症和婴儿猝死综合征。
在一些实施方案中,双功能化合物可用于治疗神经退行性疾病和不适。如本文所用,术语“神经退行性疾病和病症”是指以神经细胞进行性变性或死亡为特征的状况,或两者兼而有之,其包括运动问题(共济失调)或精神功能问题(痴呆)。此类疾病和不适的代表性实例包括阿尔茨海默氏病(AD)和与AD相关的痴呆、帕金森病(PD)和与PD相关的痴呆、朊蛋白病、运动神经元病(MND)、亨廷顿病(HD)、皮克氏综合征、脊髓小脑性共济失调(SCA)、脊髓性肌萎缩症(SMA)、原发性进行性失语(PPA)、肌萎缩侧索硬化(ALS)、外伤性脑损伤(TBI)、多发性硬化(MS)、痴呆(例如,血管性痴呆(VaD)、路易体痴呆(LBD)、语义性痴呆和额颞叶痴呆(FTD)。
在一些实施方案中,双功能化合物可用于治疗自身免疫性疾病和不适。如本文所用,术语“自身免疫性疾病”是指免疫***产生攻击正常身体组织的抗体的状况。此类疾病的代表性实例包括干燥综合征、桥本甲状腺炎、类风湿性关节炎、青少年(1型)糖尿病、多发性肌炎、硬皮病、阿狄森病、包括***性红斑狼疮的狼疮、白癜风、恶性贫血、肾小球肾炎、肺纤维化、乳糜泻病、风湿性多肌痛、多发性硬化、强直性脊柱炎、斑秃、血管炎和颞动脉炎。
在其他实施方案中,这些方法涉及治疗患有癌症的受试者。从广义上讲,本公开的双功能化合物可有效治疗癌症(包括原发性和转移性肿瘤的实体瘤)、肉瘤、黑色素瘤和血癌(影响血液包括淋巴细胞、骨髓和/或***的癌症),如白血病、淋巴瘤和多发性骨髓瘤。包括成人肿瘤/癌症和儿童肿瘤/癌症。癌症可以是血管化的,或基本上尚未血管化的或非血管化的肿瘤。
癌症的代表性实例包括肾上腺皮质癌、AIDS相关癌症(例如,卡波西氏和AIDS相关淋巴瘤)、阑尾癌、儿童癌症(例如,儿童小脑星形细胞瘤、儿童脑星形细胞瘤)、基底细胞癌、皮肤癌(非黑色素瘤)、胆道癌、肝外胆管癌、肝内胆管癌、膀胱癌(bladder cancer)、膀胱癌(urinary bladder cancer)、脑癌(例如,胶质瘤和胶质母细胞瘤如脑干胶质瘤、妊娠滋养细胞肿瘤神经胶质瘤、小脑星形细胞瘤、脑星形细胞瘤/恶性神经胶质瘤、室管膜瘤、髓母细胞瘤、幕上原始神经外胚层肿瘤(supratentorial primitive neuroectodermal tumor)、视通路和下丘脑胶质瘤)、乳腺癌、支气管腺瘤/类癌、类癌瘤、神经***癌(例如,中枢神经***癌症、中枢神经***淋巴瘤)、***、慢性骨髓增生性疾病、结直肠癌(例如,结肠癌、直肠癌)、淋巴样肿瘤、蕈样真菌病(mycosis fungoides)、Sezary综合征、子宫内膜癌、食管癌、颅外胚细胞瘤、性腺外胚细胞瘤、肝外胆管癌、眼癌、眼内黑素瘤、视网膜母细胞瘤、胆囊癌、胃肠癌(例如,胃癌、小肠癌、胃肠道类癌瘤、胃肠道间质瘤(GIST))、胆管癌、胚细胞瘤、卵巢胚细胞瘤、头颈癌、神经内分泌肿瘤、霍奇金淋巴瘤、Ann Arbor III期和IV期儿童非霍奇金淋巴瘤、ROS1阳性难治性非霍奇金淋巴瘤、白血病、淋巴瘤、多发性骨髓瘤、下咽癌、眼内黑素瘤、眼癌、胰岛细胞瘤(内分泌胰腺)、肾癌(例如,肾母细胞瘤、肾细胞癌)、肝癌、肺癌(例如,非小细胞肺癌和小细胞肺癌)、ALK阳性间变性大细胞淋巴瘤、ALK阳性晚期恶性实体瘤、华氏巨球蛋白血症、黑色素瘤、眼内(眼)黑色素瘤、梅克尔细胞癌、间皮瘤、颈部原发灶隐匿转移性鳞癌、多发性内分泌腺瘤(MEN)、骨髓增生异常综合征、骨髓增生异常/骨髓增生性疾病、鼻咽癌、神经母细胞瘤、口腔癌(oral cancer)(例如,口癌、唇癌、口腔癌(oralcavity cancer)、舌癌、口咽癌、咽喉癌、喉癌)、卵巢癌(例如,卵巢上皮癌、卵巢胚细胞瘤、低度恶性潜能卵巢肿瘤)、胰腺癌、胰岛细胞胰腺癌、鼻旁窦和鼻腔癌、甲状旁腺癌、***癌、咽癌、嗜铬细胞瘤、松果体母细胞瘤、转移性间变性甲状腺癌、未分化甲状腺癌、***状甲状腺癌、垂体瘤、浆细胞肿瘤/多发性脊髓瘤、胸膜肺母细胞瘤、***癌、视网膜母细胞瘤、横纹肌肉瘤、唾液腺癌、子宫癌(例如,子宫内膜癌、子宫肉瘤、子宫体癌)、鳞状细胞癌、睾丸癌、胸腺瘤、胸腺癌、甲状腺癌、幼年黄色肉芽肿、肾盂和输尿管及其他泌尿器官的移行细胞癌、尿道癌、妊娠滋养细胞肿瘤、***癌、外阴癌、肝母细胞瘤、横纹肌样瘤和肾母细胞瘤。
可以用本公开的双功能化合物治疗的肉瘤包括软组织癌和骨癌二者,其代表性实例包括骨肉瘤或成骨肉瘤(骨)(例如,尤文氏肉瘤)、软骨肉瘤(软骨)、平滑肌肉瘤(平滑肌)、横纹肌肉瘤(骨骼肌)、间皮性肉瘤或间皮瘤(体腔的膜状内衬)、纤维肉瘤(纤维组织)、血管肉瘤或血管内皮瘤(血管)、脂肪肉瘤(脂肪组织)、神经胶质瘤或星形细胞瘤(在脑中发现的神经源性***)、粘液肉瘤(原始胚胎***)和间叶瘤或混合性中胚层肿瘤(混合***类型)和组织细胞肉瘤(免疫学癌症)。
在一些实施方案中,本公开的方法涉及治疗患有血液***、肝、脑、肺、结肠、胰腺、***、卵巢、乳腺、皮肤和子宫内膜的细胞增殖性疾病或不适的受试者。
如本文所用,“血液***的细胞增殖性疾病或病症”包括淋巴瘤、白血病、骨髓肿瘤、肥大细胞肿瘤、骨髓发育不良、良性单克隆丙球蛋白病、淋巴瘤样丘疹病、真性红细胞增多症、慢性粒细胞白血病、特发性骨髓外化生和原发性血小板增多症。因此,血液***癌症的代表性实例可包括多发性骨髓瘤、淋巴瘤(包括T细胞淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤(弥漫性大B细胞淋巴瘤(DLBCL))、滤泡性淋巴瘤(FL)、套细胞淋巴瘤(MCL)和ALK+间变性大细胞淋巴瘤(例如,选自弥漫性大B细胞淋巴瘤(例如,生发中心B细胞样弥漫性大B细胞淋巴瘤或活化B细胞样弥漫性大B细胞淋巴瘤)的B细胞非霍奇金淋巴瘤)、伯基特淋巴瘤/白血病、套细胞淋巴瘤、纵隔(胸腺)大B细胞淋巴瘤、滤泡性淋巴瘤、边缘区淋巴瘤、淋巴浆细胞淋巴瘤/华氏巨球蛋白血症、转移性胰腺癌、难治性B细胞非霍奇金淋巴瘤和复发性B细胞非霍奇金淋巴瘤、儿童淋巴瘤,以及淋巴细胞和皮肤来源的淋巴瘤,例如,小淋巴细胞淋巴瘤、白血病,包括儿童白血病、毛细胞白血病、急性淋巴细胞白血病、急性髓细胞白血病、急性骨髓性白血病(例如,急性单核细胞白血病)、慢性淋巴细胞白血病、小淋巴细胞白血病、慢性粒细胞白血病、慢性髓细胞性白血病和肥大细胞白血病、骨髓肿瘤和肥大细胞肿瘤。
如本文所用,“肝脏的细胞增殖性疾病或病症”包括影响肝脏的所有形式的细胞增殖性病症。肝脏的细胞增殖性病症可以包括肝癌(例如,肝细胞癌、肝内胆管癌和肝母细胞瘤)、肝脏癌前病变或癌前状态、肝脏良性生长或病变和肝脏恶性生长或病变,以及肝脏之外的身体组织和器官的转移性病变。肝脏的细胞增殖性病症可以包括肝脏的增生、化生和发育异常。
如本文所用,“脑细胞增殖性疾病或病症”包括影响脑的所有形式的细胞增殖性病症。脑细胞增殖性病症可以包括脑癌(例如,胶质瘤、胶质母细胞瘤、脑膜瘤、垂体腺瘤、前庭神经鞘瘤和原始神经外胚层瘤(髓母细胞瘤))、脑癌前病变或癌前状态、脑良性生长或病变和脑恶性生长或病变以及除脑以外的身体组织和器官的转移性病变。脑的细胞增殖性病症可以包括脑增生、化生和发育异常。
如本文所用,“肺细胞增殖性疾病或病症”包括影响肺细胞的所有形式的细胞增殖性病症。肺细胞增殖性疾病包括肺癌、肺癌前病变或癌前状态、肺良性生长或病变、肺增生、化生和发育异常,以及除肺以外的身体组织和器官的转移性病变。肺癌包括所有形式的肺部癌症,例如,恶性肺肿瘤、原位癌、典型类癌瘤和非典型类癌瘤。肺癌包括小细胞肺癌(“SLCL”)、非小细胞肺癌(“NSCLC”)、腺癌、小细胞癌、大细胞癌、鳞状细胞癌和间皮瘤。肺癌可以包括“瘢痕癌”、支气管肺泡癌、巨细胞癌、梭形细胞癌和大细胞神经内分泌癌。肺癌还包括具有组织学和超微结构异质性(例如,混合细胞类型)的肺肿瘤。在一些实施方案中,本公开的化合物可用于治疗非转移性或转移性肺癌(例如,NSCLC、ALK阳性NSCLC、携带ROS1重排的NSCLC、肺腺癌和肺鳞癌)。
如本文所用,“结肠细胞增殖性疾病或病症”包括影响结肠细胞的所有形式的细胞增殖性病症,包括结肠癌、结肠癌前病变或癌前状态、结肠腺瘤性息肉和结肠异时性病变。结肠癌包括散发性和遗传性结肠癌、恶性结肠肿瘤、原位癌、典型类癌瘤和非典型类癌瘤、腺癌、鳞状细胞癌和鳞状细胞癌。结肠癌可能与遗传性综合征有关,如遗传性非息肉病性结直肠癌、家族性腺瘤性息肉病、MYH相关息肉病、加德纳综合征、黑斑息肉综合征(Peutz-Jeghers syndrome)、特科特综合征和青少年息肉病。结肠细胞增殖性病症也可能以结肠增生、化生和发育异常为特征。
如本文所用,“胰腺细胞增殖性疾病或病症”包括影响胰腺细胞的所有形式的细胞增殖性病症。胰腺细胞增殖性病症包括胰腺癌、胰腺癌前病变或癌前状态、胰腺增生、胰腺发育异常、胰腺良性生长或病变、和胰腺恶性生长或病变,以及胰腺之外的身体组织和器官的转移性病变。胰腺癌包括所有形式胰腺的癌症,包括导管腺癌、腺鳞状癌、多形性巨细胞癌、粘液腺癌、破骨细胞样巨细胞癌、粘液囊腺癌、腺泡癌、未分类的大细胞癌、小细胞癌、胰母细胞瘤、***状肿瘤、粘液囊腺瘤、***状囊性肿瘤和浆液囊腺瘤,以及具有组织学和超微结构异质性(例如,混合细胞)的胰腺肿瘤。
如本文所用,“***细胞增殖性疾病或病症”包括影响***的所有形式的细胞增殖性病症。***细胞增殖性病症可包括***癌、***癌前病变或癌前状态、***良性生长或病变、和***恶性生长或病变,以及***之外的身体组织和器官的转移性病变。***细胞增殖性病症包括***增生、化生和发育异常。
如本文所用,“卵巢细胞增殖性疾病或病症”包括影响卵巢细胞的所有形式的细胞增殖性病症。卵巢细胞增殖性病症包括卵巢癌前病变或癌前状态、卵巢良性生长或病变、卵巢癌,和卵巢之外的身体组织和器官的转移性病变。卵巢细胞增殖性不适可包括卵巢增生、化生和发育异常。
如本文所用,“乳腺细胞增殖性疾病或不适”包括影响乳腺细胞的所有形式的细胞增殖性不适。乳腺细胞增殖性不适包括乳腺癌、乳腺癌前病变或癌前状态、乳腺良性生长或病变和乳腺之外的身体组织和器官的转移性病变。乳腺细胞增殖性不适可包括乳腺增生、化生和发育异常。
如本文所用,“皮肤细胞增殖性疾病或病症”包括影响皮肤细胞的所有形式的细胞增殖性病症。皮肤细胞增殖性病症包括皮肤癌前病变或癌前状态、皮肤良性生长或病变、皮肤恶性黑色素瘤或其他恶性生长或病变和皮肤之外的身体组织和器官的转移性病变。皮肤细胞增殖性病症可以包括皮肤增生、化生和发育异常。
如本文所用,“子宫内膜细胞增殖性疾病或病症”包括影响子宫内膜细胞的所有形式的细胞增殖性病症。子宫内膜细胞增殖性病症包括子宫内膜癌前病变或癌前状态、子宫内膜良性生长或病变、子宫内膜癌和子宫内膜之外的身体组织和器官的转移性病变。子宫内膜细胞增殖性病症可以包括子宫内膜增生、化生和发育异常。
在一些实施方案中,疾病或病症是癌症。在一些实施方案中,癌症被表征为实体瘤。在一些实施方案中,癌症选自乳腺癌、脑癌、子宫内膜癌、头颈癌、胃肠癌、肺癌、卵巢癌、***癌、子宫癌、肝细胞癌、脂肪肉瘤和黑色素瘤。在一些实施方案中,癌症是血液***癌症。在一些实施方案中,血液***癌症选自白血病、淋巴瘤和骨髓瘤。
式(I)的双功能化合物可以作为单一疗法或通过联合疗法的方式施用于患者,例如癌症患者。治疗可以是“一线(front/first-line)的”,即,作为既往未接受过抗癌治疗方案的患者的初始治疗,无论是单独使用还是与其他治疗联合使用;或“二线的”,作为既往接受过抗癌治疗方案的患者的治疗,无论是单独使用还是与其他治疗联合使用;或作为“三线”、“四线”等治疗,无论是单独使用还是与其他治疗联合使用。治疗也可以对既往治疗不成功或部分成功但对特定治疗不耐受的患者进行。治疗也可以作为辅助治疗给予,即,在目前未检出疾病或在手术切除肿瘤后的患者中预防癌症复发。因此,在一些实施方案中,可以将双功能化合物施用于接受过另一种治疗如化疗、放射免疫治疗、手术治疗、免疫治疗、放射治疗、靶向治疗或其任意组合的患者。
本公开的方法可能需要以单剂量或多剂量(例如,1、2、3、4、5、6、7、8、10、15、20或更多剂量)向患者施用式(I)的双功能化合物或其药物组合物。例如,施用频率的范围可以从每天一次到大约每八周一次。在一些实施方案中,施用频率的范围为约每天一次,持续1、2、3、4、5或6周,而在其他实施方案中,需要28天的周期,其包括每日施用,持续3周(21天),随后是7天的“停药期”。在其他实施方案中,双功能化合物可以在两天半的疗程内每天给药两次(BID)(总共5剂)或在两天的疗程内每天给药一次(QD)(总共2剂)。在其他实施方案中,双功能化合物可以在五天的疗程内每天给药一次(QD)。
联合疗法
式(I)的双功能化合物与至少一种其他活性剂,例如抗癌剂或抗癌方案结合或同时使用,以治疗疾病和病症。在一些实施方案中,式(I)的双功能化合物可以与现有的免疫疗法结合使用,如免疫检查点抑制剂(例如,抗PD-1或抗PD-L1)或细胞疗法(例如,CAR-T细胞)。在本上下文中,术语“组合”和“同时”是指剂通过同一剂型或分开的剂型,以及通过相同或不同的施用方式,或依次地,例如作为同一方案的一部分或通过连续的治疗方案共同施用,其包括基本上同时施用。因此,如果顺序给药,在开始施用第二种化合物时,在某些情况下,两种化合物中的第一种在治疗部位的有效浓度下仍然是可检测到的。可以确定顺序和时间间隔,以便它们可以共同作用(例如,协同作用)以提供比以其他方式施用更大的益处。例如,可以同时或在不同的时间点以任何顺序依次施用治疗剂;然而,如果不同时施用,它们可以在足够接近的时间内施用,以提供所需的治疗效果,这可以是协同的方式。因此,这些术语不限于在完全相同的时间施用活性剂。
在一些实施方案中,治疗方案可以包括施用式(I)的双功能化合物与一种或更多种已知用于治疗疾病或病症(例如,癌症)的其他治疗剂的组合。其他抗癌治疗剂的剂量可以与已知或推荐的剂量相同或甚至更低。参见Hardman et al.,eds.,Goodman&Gilman'sThe Pharmacological Basis of Therapeutics,10th ed.,McGraw-Hill,New York,2001;Physician's Desk Reference 60th ed.,2006。例如,可适于与双功能化合物组合使用的抗癌剂是本领域已知的。参见,例如,美国专利9,101,622(其第5.2节)和美国专利9,345,705B2(其第12-18列)。其他活性剂和治疗方案的代表性实例包括放射疗法、化学疗法(例如,有丝***抑制剂、血管生成抑制剂、抗激素、自噬抑制剂、烷化剂、嵌入抗生素、生长因子抑制剂、抗雄激素、信号转导途径抑制剂、抗微管剂、铂配位复合物、HDAC抑制剂、蛋白酶体抑制剂和拓扑异构酶抑制剂)、免疫调节剂、治疗性抗体(例如,单特异性和双功能抗体)和CAR-T疗法。
在一些实施方案中,式(I)的双功能化合物和其他的(例如,抗癌)治疗剂可以间隔少于5分钟、间隔少于30分钟、间隔少于1小时、间隔约1小时、间隔约1小时至约2小时、间隔约2小时至约3小时、间隔约3小时至约4小时、间隔约4小时至约5小时、间隔约5小时至约6小时、间隔约6小时至约7小时、间隔约7小时至约8小时、间隔约8小时至约9小时、间隔约9小时至约10小时、间隔约10小时至约11小时、间隔约11小时至约12小时、间隔约12小时至18小时、间隔18小时至24小时、间隔24小时至36小时、间隔36小时至48小时、间隔48小时至52小时、间隔52小时至60小时、间隔60小时至72小时、间隔72小时至84小时、间隔84小时至96小时或间隔96小时至120小时施用。两种或更多种(例如,抗癌)治疗剂可以在同一患者就诊中施用。
在一些涉及癌症治疗的实施方案中,循环施用式(I)的双功能化合物和其他的抗癌剂或治疗剂。循环疗法包括施用一种抗癌治疗剂一段时间,然后施用第二种抗癌治疗剂一段时间,并重复这种顺序施用,即循环,以减少对一种或两种抗癌治疗剂的耐药性的发生,避免或减少一种或两种抗癌治疗剂的副作用,和/或提高治疗的疗效。在一个实例中,循环疗法包括在一段时间内施用第一种抗癌治疗剂,然后在一段时间内施用第二种抗癌治疗剂,任选地,然后在一段时间内施用第三种抗癌治疗剂等,并重复这种顺序施用,即循环,以减少发生对一种抗癌治疗剂的耐药性,避免或减少一种抗癌治疗剂的副作用,和/或提高抗癌治疗剂的疗效。
在一些实施方案中,根据所治疗的特定癌症,本公开的化合物可以与至少一种其他抗癌剂组合使用,如紫杉醇(例如,卵巢癌、乳腺癌、肺癌、卡波西肉瘤、***和胰腺癌)、拓扑替康(例如,卵巢癌和肺癌)、伊立替康(例如,结肠癌和小细胞肺癌)、依托泊苷(例如,睾丸癌、肺癌、淋巴瘤和非淋巴细胞白血病)、长春新碱(例如,白血病)、亚叶酸(例如,结肠癌)、六甲蜜胺(例如,卵巢癌)、柔红霉素(例如,急性髓细胞性白血病(AML)、急性淋巴细胞性白血病(ALL)、慢性髓细胞性白血病(CML)和卡波西肉瘤)、曲妥珠单抗(例如,乳腺癌、胃癌和食道癌)、利妥昔单抗(例如,非霍奇金淋巴瘤)、西妥昔单抗(例如,结直肠癌、转移性非小细胞肺癌和头颈癌)、帕妥珠单抗(例如,转移性HER2阳性乳腺癌)、阿仑单抗(例如,慢性淋巴细胞白血病(CLL)、皮肤T细胞淋巴瘤(CTCL)和T细胞淋巴瘤)、帕尼单抗(例如,结肠癌和直肠癌)、他莫昔芬(例如,乳腺癌)、氟维司群(例如,乳腺癌)、来曲唑(例如,乳腺癌)、依西美坦(例如,乳腺癌)、阿扎胞苷(例如,骨髓增生异常综合征)、丝裂霉素C(例如,胃肠癌、***癌和乳腺癌)、放线菌素(例如,肾母细胞瘤、横纹肌肉瘤、尤文氏肉瘤、滋养层肿瘤、睾丸癌和卵巢癌)、埃罗替尼(例如,非小细胞肺癌和胰腺癌)、索拉非尼(例如,肾癌和肝癌)、替西莫司(例如,肾癌)、硼替佐米(例如,多发性骨髓瘤和套细胞淋巴瘤)、培门冬酶(例如,急性淋巴细胞白血病)、卡博替尼(例如,肝细胞癌、甲状腺髓样癌和肾细胞癌)、派姆单抗(例如,***、胃癌、肝细胞癌、霍奇金淋巴瘤、黑色素瘤、默克尔细胞癌、非小细胞肺癌、尿路上皮癌和头颈部鳞状细胞癌)、纳武单抗(例如,结直肠癌、肝细胞癌、黑色素瘤、非小细胞肺癌、肾细胞癌、小细胞肺癌、尿路上皮癌)、瑞戈非尼(例如,结直肠癌、胃肠道间质瘤和肝细胞癌)、西米普利单抗(例如,皮肤鳞状细胞癌(CSCC))、阿维鲁单抗(例如,默克尔细胞癌、尿路上皮癌和肾细胞癌)、德瓦鲁单抗(例如,膀胱癌和肺癌)、阿特珠单抗(例如,尿路上皮癌、非小细胞肺癌(NSCLC)、三阴性乳腺癌(TNBC)、小细胞肺癌(SCLC)和肝细胞癌(HCC))和伊匹单抗(例如,黑色素瘤、非小细胞肺癌(NSCLC)、小细胞肺癌(SCLC)、膀胱癌、***癌)。
药物试剂盒
本双功能化合物和/或含有它们的组合物可以被组装到试剂盒或制药***中。根据本公开的这一方面,试剂盒或制药***包括载体或包装,例如盒子、纸箱、管或类似物,其中紧密封闭有一个或更多个容器,例如小瓶、管、安瓿或瓶子,其含有式(I)的双功能化合物或其药物组合物。本公开的试剂盒或制药***还可能包括使用双功能化合物和组合物的印刷说明书。
实施例
本公开的这些和其他方面将在考虑以下实施例后得到进一步理解,这些实施例旨在示例本公开的某些特定实施方案,但不旨在限制权利要求书限定的范围。
一般方法
除非另有说明,否则使用从商业供应商处收到的试剂和溶剂。使用采用AcquityBEH C18色谱柱(2.1x50mm,1.7μm粒径)的/>Acquity超高效液相色谱/质谱(UPLC/MS)***监测所有反应。UPLC方法A:溶剂梯度=0min时90% A,1.8min时5% A;方法B:溶剂梯度=0min时85% A,1.8min时1% A;溶剂A=H2O中0.1%甲酸;溶剂B=乙腈中0.1%甲酸;流速:0.6mL/min。反应产物的纯化通过使用带有Teledyne ISCO/>正相二氧化硅快速柱的/>Rf的快速色谱法进行;或采用使用SunFireTM C18柱(19x100mm,5μm粒径)的/>高效液相色谱(HPLC)***:溶剂梯度H2O中0%至99%乙腈(0.035%三氟乙酸(TFA)作为添加剂);流速:20mL/min,或采用使用SunFireTM C18柱(30x250mm,5μm粒径)的/>高效液相色谱(HPLC)***:溶剂梯度H2O中0%至99%乙腈(0.035% TFA作为添加剂);流速:40mL/min。所有化合物的纯度超过95%,并用/>UPLC***分析。使用Bruker Avance III光谱仪(500MHz用于1H,125MHz用于13C)获得1H NMR和13C NMR光谱。对于1H NMR,报道了相对于氘代甲醇(δ=3.31)或二甲基亚砜(DMSO)(δ=2.50)的化学位移。以ppm(δ)为单位给出光谱,并且br=宽峰,s=单峰,d=二重峰,t=三重峰,q=四重峰,m=多重峰,且以赫兹单位报告耦合常数(J)。
实施例1:一般合成路线。
可根据上述一般合成路线制备化合物Ia-1至Ia-8,使用合适的羟基苯甲醛,例如4-羟基苯甲醛8或3-羟基苯甲醛,合适的二溴或二氯化合物,例如9a至9e,和如以下实施例2中所述中间体7。实施例3中描述了Ia-8的示例性合成。
实施例2:中间体7的合成。
3-(5-溴-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(3)。
将碳酸钾(2.29g,16.57mmol)加到N,N-二甲基甲酰胺(DMF,18.4mL,0.30M)中4-溴代-2-(溴甲基)苯甲酸甲酯1(1.70g,5.52mmol)和3-氨基哌啶-2,6-二酮盐酸盐2(1g,6.08mmol)溶液中,并在70℃下搅拌17h。真空浓缩反应混合物,并向残留物中加水,得到沉淀,将其通过重力过滤收集并干燥得到固体的标题化合物(1.5g,84%收率)。LC-MS(ES+):322.9m/z[M+H]+.
4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)-3,6-二氢吡啶-1(2H)-羧
酸叔丁酯(5)。
在氮气氛下,将3-(5-溴-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮3(1.5g,4.64mmol)和4-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯4(1.87g,6.03mmol)溶解在DMF(30mL,0.155M)中。加入Pd(dppf)Cl2-CH2Cl2(189mg,0.232mmol)和磷酸钾(K3PO4,1.182g,5.57mmol),并将反应混合物在100℃下搅拌15h。冷却至室温后,用EtOAc稀释反应混合物。用水2x、盐水洗涤有机层,用Na2SO4干燥,过滤,并真空浓缩。纯化(SiO2:己烷中0%-100%二氯甲烷)提供浅棕色固体的标题化合物(1.5g,76%)。LC-MS(ES+):426.2m/z[M+H]+.
4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)哌啶-1-羧酸叔丁酯(6)。
在装有搅拌棒的100mL圆底烧瓶中,在氮气氛下,将4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯5(1.5g,3.53mmol)溶解在DMF(20mL,0.18M)中。加入钯碳(10wt%,375mg,0.10当量),烧瓶配备有H2气球并用H2冲洗。在室温H2气氛下搅拌20小时后,将反应混合物用硅藻土过滤以去除Pd催化剂,并用DMF冲洗。将滤液真空浓缩,得到灰白色固体的标题化合物(1.51g,99%),将其结转而无需纯化。LC-MS 372.1m/z[M+H–tBu]+,328.11m/z[M+H–Boc]+.
3-(1-氧代-5-(哌啶-4-基)异吲哚啉-2-基)哌啶-2,6-二酮盐酸盐(7)。
将二恶烷(10mL)中的4M HCl加入到4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)哌啶-1-羧酸叔丁酯6(1.51g,3.53mmol)的CH2Cl2溶液(10mL,0.35M)中,并在室温下搅拌12h。将反应混合物真空浓缩,得到固体的标题化合物(1.156g,90%),将其结转而无需纯化。1H NMR(500MHz,DMSO-d6)δ10.98(s,1H),8.95(d,J=9.7Hz,1H),8.88–8.72(m,1H),7.70(d,J=7.9Hz,1H),7.46(s,1H),7.41–7.34(m,1H),5.11(dd,J=13.3,5.1Hz,1H),4.45(d,J=17.3Hz,1H),4.32(d,J=17.3Hz,1H),3.44–3.36(m,2H),3.04–2.88(m,4H),2.63–2.57(m,1H),2.39(ddd,J=13.3,4.5Hz,1H),2.03–1.85(m,5H).LC-MS(ES+):328.05m/z[M+H]+.
实施例3:(Ia-8)的合成。
3-(5-(1-(4-(2-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙氧基)苄基)哌啶-4-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(Ia-8)
4-(2-溴乙氧基)苯甲醛(10a)。
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将碳酸钾(410mg,2.96mmol)加入4-羟基苯甲醛8(302mg,2.47mmol)的DMF溶液(10mL,0.25M)中,并在室温搅拌10min。通过注射器加入1,2-二溴乙烷9a,并将反应混合物在室温下搅拌15h。用乙酸乙酯(EtOAc)提取反应混合物,用NH4Cl饱和水溶液(satd aq)、水2x和盐水洗涤。收集有机层,用Na2SO4干燥,过滤,并真空浓缩。用硅胶快速色谱法纯化,得到黄色固体的标题化合物(376mg,67%收率)。LC-MS(ES+):228.9m/z[M+H]+.
4-(2-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧
啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙氧基)苯甲醛(12a)。
将N,N-二异丙基乙胺(DIPEA,440μL,2.52mmol)加入苯甲醛10a(376mg,0.839mmol)和帕博西尼11(250mg,1.09mmol)的DMF溶液(4mL,0.21M)中4-(2-溴乙氧基)中,并在80℃搅拌15h。冷却至室温后,用EtOAc提取反应混合物,用水2x、盐水洗涤,用Na2SO4干燥,过滤,并真空浓缩。通过硅胶快速色谱法(0%–80% EtOAc/CH2Cl2,然后0%–20% MeOH/CH2Cl2)纯化,得到黄色固体的标题化合物(310mg,62%)。LC-MS(ES+):596.23m/z[M+H]+,298.68m/z[M+2H]2+.
3-(5-(1-(4-(2-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并
[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙氧基)苄基)哌啶-4-基)-1-氧代异吲哚
啉-2-基)哌啶-2,6-二酮(Ia-8)。
将三乙酰氧基硼氢化钠(NaBH(OAc)3,64mg,0.300mmol)加入溶于4:1DMF/CH2Cl2(3mL,0.05M)的4-(2-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙氧基)苯甲醛12a(89.5mg,0.150mmol)和3-(1-氧代-5-(哌啶-4-基)异吲哚啉-2-基)哌啶-2,6-二酮盐酸盐7(59mg,0.180mmol)溶液中。通过硅胶快速色谱法(0%–80%EtOAc/CH2Cl2,然后0%–20% MeOH/CH2Cl2)纯化,得到黄色固体的标题化合物(5.1mg)。1H NMR(500MHz,DMSO-d6)δ10.97(s,1H),10.08(s,1H),8.94(s,1H),8.05(d,J=3.0Hz,1H),7.84(d,J=9.0Hz,1H),7.63(d,J=7.9Hz,1H),7.49–7.45(m,2H),7.39(d,J=8.0Hz,1H),7.23(t,J=8.4Hz,2H),6.92(d,J=8.5Hz,2H),5.81(p,J=8.5Hz,1H),5.09(dd,J=13.3,5.1Hz,1H),4.41(d,J=17.2Hz,1H),4.28(d,J=17.4Hz,1H),4.12(t,J=5.7Hz,2H),3.18–3.16(m,3H),2.95–2.86(m,4H),2.77(t,J=5.6Hz,2H),2.69–2.64(m,4H),2.62–2.56(m,2H),2.43–2.36(m,4H),2.30(s,2H),2.26–2.21(m,2H),2.20–2.16(m,2H),2.09–2.03(m,2H),2.01–1.95(m,2H),1.89–1.84(m,2H),1.80–1.74(m,4H),1.72–1.67(m,2H),1.61–1.55(m,2H).LC-MS(ES+):907.48m/z[M+H]+,454.44m/z[M+2H]2+.
实施例4:(Ia-1)的合成。
3-(5-(1-(3-(2-(2-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙氧基)乙氧基)苄基)哌啶-4-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(Ia-1)。
根据实施例1制备标题化合物。1H NMR(500MHz,DMSO-d6)δ10.96(s,1H),10.08(s,1H),8.94(s,1H),8.03(d,J=2.8Hz,1H),7.84(d,J=9.0Hz,1H),7.61(d,J=7.8Hz,1H),7.46(s,1H),7.44(dd,J=9.1,2.8Hz,1H),7.37(d,J=7.9Hz,1H),7.23(t,J=8.0Hz,1H),6.94–6.87(m,2H),6.83(dd,1H),5.81(p,J=8.8Hz,1H),5.08(dd,J=13.3,5.0Hz,1H),4.39(d,J=17.2Hz,1H),4.26(d,J=17.2Hz,1H),4.12–4.07(m,2H),3.77–3.72(m,2H),3.63(t,J=5.6Hz,2H),3.47(s,2H),3.15–3.09(m,4H),2.95–2.85(m,3H),2.64–2.54(m,8H),2.42(s,3H),2.37(dd,J=13.2,4.5Hz,1H),2.30(s,3H),2.27–2.19(m,2H),2.09–1.94(m,3H),1.90–1.83(m,2H),1.81–1.64(m,6H),1.62–1.53(m,2H).LC-MS(ES+):951.54m/z[M+H]+,476.48m/z[M+2H]2+.
实施例5:(Ia-2)的合成。
3-(5-(1-(4-(2-(2-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙氧基)乙氧基)苄基)哌啶-4-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(Ia-2)。
根据实施例1制备标题化合物。1H NMR(500MHz,DMSO-d6)δ10.97(s,1H),10.09(s,1H),8.94(s,1H),8.04(d,J=2.9Hz,1H),7.84(d,J=9.0Hz,1H),7.62(d,J=7.9Hz,1H),7.48–7.42(m,2H),7.37(d,J=7.8Hz,1H),7.33–7.20(m,2H),6.93(d,J=8.1Hz,2H),5.81(p,J=8.8Hz,1H),5.09(dd,J=13.3,5.1Hz,1H),4.40(d,J=17.2Hz,1H),4.27(d,J=17.2Hz,1H),4.14–4.05(m,2H),3.76–3.72(m,2H),3.69–3.42(m,4H),3.21–2.84(m,7H),2.74–2.54(m,8H),2.42(s,3H),2.40–2.33(m,1H),2.30(s,3H),2.28–2.18(m,3H),2.02–1.94(m,1H),1.93–1.68(m,9H),1.62–1.53(m,2H).LC-MS(ES+):951.56m/z[M+H]+,476.48m/z[M+2H]2+.
实施例6:(Ia-3)的合成。
3-(5-(1-(3-(2-(2-(2-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙氧基)乙氧基)乙氧基)苄基)哌啶-4-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(Ia-3)。
根据实施例1制备标题化合物。1H NMR(500MHz,DMSO-d6)δ10.97(s,1H),10.08(s,1H),8.94(s,1H),8.02(d,J=2.9Hz,1H),7.84(d,J=9.0Hz,1H),7.61(d,J=7.8Hz,1H),7.46(s,1H),7.42(dd,J=9.1,3.0Hz,1H),7.36(d,J=7.9Hz,1H),7.23(t,J=8.0Hz,1H),6.91–6.88(m,2H),6.83(dd,J=8.1,2.3Hz,1H),5.83–5.78(m,1H),5.09(dd,J=13.3,5.1Hz,1H),4.39(d,J=17.2Hz,1H),4.27(d,J=17.2Hz,1H),4.08(dd,J=5.5,3.7Hz,2H),3.76(dd,J=5.5,3.7Hz,2H),3.62–3.59(m,3H),3.58–3.54(m,6H),3.13–3.10(m,4H),2.92–2.89(m,2H),2.59–2.53(m,8H),2.42(s,3H),2.30(s,3H),1.90(s,3H),1.78–1.67(m,8H),1.59–1.54(m,3H).LC-MS(ES+):995.58m/z[M+H]+,498.47m/z[M+2H]2+.
实施例7:(Ia-4)的合成。
3-(5-(1-(4-(2-(2-(2-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙氧基)乙氧基)乙氧基)苄基)哌啶-4-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(Ia-4)。
根据实施例1制备标题化合物。1H NMR(500MHz,DMSO-d6)δ10.97(s,1H),10.16(s,1H),8.95(s,1H),8.02(s,1H),7.88(d,J=8.5Hz,1H),7.65(d,J=7.8Hz,1H),7.60–7.51(m,2H),7.47(d,J=7.6Hz,1H),7.41(s,1H),7.33(d,J=7.6Hz,1H),7.02(d,J=8.4Hz,2H),5.81(p,J=8.8Hz,1H),5.08(dd,J=13.2,5.0Hz,1H),4.41(d,J=17.3Hz,1H),4.28(d,J=17.3Hz,1H),4.16–4.10(m,2H),3.80–3.74(m,3H),3.65–3.57(m,6H),3.23–3.08(m,5H),3.04(q,J=7.2Hz,3H),3.00–2.85(m,4H),2.63–2.55(m,2H),2.41(s,4H),2.30(s,3H),2.27–2.05(m,5H),1.99–1.84(m,6H),1.79–1.72(m,2H),1.59–1.54(m,2H).LC-MS(ES+):995.58m/z[M+H]+,498.48m/z[M+2H]2+.
实施例8:(Ia-5)的合成。
3-(5-(1-(3-(4-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)丁氧基)苄基)哌啶-4-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(Ia-5)。
根据实施例1制备标题化合物。1H NMR(500MHz,DMSO-d6)δ10.97(s,1H),10.08(s,1H),8.94(s,1H),8.04(d,J=2.8Hz,1H),7.84(d,J=9.0Hz,1H),7.62(d,J=7.8Hz,1H),7.48–7.43(m,2H),7.38(d,J=7.8Hz,1H),7.23(t,J=7.8Hz,1H),6.93–6.87(m,2H),6.82(d,J=7.1Hz,1H),5.81(p,J=8.8Hz,1H),5.09(dd,J=13.3,5.1Hz,1H),4.40(d,J=17.2Hz,1H),4.27(d,J=17.2Hz,1H),4.05–3.96(m,3H),3.17–3.12(m,4H),2.99–2.84(m,3H),2.61–2.52(m,4H),2.44–2.35(m,7H),2.30(s,3H),2.27–2.17(m,4H),1.98–1.94(m,1H),1.90–1.83(m,3H),1.79–1.71(m,8H),1.65–1.56(m,5H).LC-MS(ES+):935.53m/z[M+H]+,468.45m/z[M+2H]2+.
实施例9:(Ia-6)的合成。
3-(5-(1-(4-(4-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)丁氧基)苄基)哌啶-4-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(Ia-6)。
根据实施例1制备标题化合物。1H NMR(500MHz,DMSO-d6)δ10.97(s,1H),10.09(s,1H),8.94(s,1H),8.05(d,J=2.8Hz,1H),7.84(d,J=9.0Hz,1H),7.63(d,J=7.8Hz,1H),7.50–7.43(m,2H),7.38(d,J=7.8Hz,1H),7.28(s,2H),6.92(d,J=6.7Hz,2H),5.81(p,J=8.7Hz,1H),5.09(dd,J=13.3,5.1Hz,1H),4.41(d,J=17.3Hz,1H),4.28(d,J=17.2Hz,1H),4.05–3.94(m,3H),3.16(s,4H),3.04–2.85(m,3H),2.62–2.53(m,4H),2.46–2.35(m,7H),2.34–2.19(m,7H),2.01–1.96(m,1H),1.87(s,3H),1.82–1.53(m,13H).LC-MS(ES+):935.54m/z[M+H]+,468.46m/z[M+2H]2+.
实施例10:(Ia-7)的合成。
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3-(5-(1-(4-(2-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙氧基)苄基)哌啶-4-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(Ia-7)。
根据实施例1制备标题化合物。1H NMR(500MHz,DMSO-d6)δ10.97(s,1H),10.08(s,1H),8.95(s,1H),8.04(d,J=2.6Hz,1H),7.84(d,J=9.0Hz,1H),7.62(d,J=7.8Hz,1H),7.48–7.43(m,2H),7.38(d,J=7.9Hz,1H),7.21(d,J=8.1Hz,2H),6.87(d,J=8.3Hz,2H),5.82(p,J=8.8Hz,1H),5.09(dd,J=13.3,5.1Hz,1H),4.40(d,J=17.2Hz,1H),4.27(d,J=17.2Hz,1H),3.94(t,J=6.3Hz,2H),3.16–3.12(m,4H),2.95–2.86(m,3H),2.59(d,J=16.9Hz,2H),2.42(s,3H),2.38(dd,J=13.4,4.7Hz,1H),2.35–2.28(m,6H),2.28–2.20(m,3H),2.05–1.95(m,3H),1.92–1.85(m,3H),1.78–1.67(m,8H),1.60–1.55(m,2H),1.51–1.41(m,5H),1.39–1.34(m,2H).LC-MS(ES+):963.60m/z[M+H]+,482.50m/z[M+2H]2+.
实施例11:合成(16)。
4-(2-(1-甲基-2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)哌啶-1-羧酸叔丁
酯(14)。
将碳酸钾加入溶于DMF(12mL,0.07M)的4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)哌啶-1-羧酸叔丁酯6(350mg,0.819mmol)溶液中,并在室温下搅拌10min。加入甲基碘(0.080mL,1.23mmol)并在室温下搅拌6h。用EtOAc稀释反应混合物,并用水2x和盐水洗涤。用Na2SO4干燥有机层,过滤,并真空浓缩。纯化(SiO2:己烷中的0%-100%EtOAc)得到了标题化合物(340mg,94%)。LC-MS(ES+):386.14m/z[M+H–tBu]+,342.15m/z[M+H–Boc]+.
1-甲基-3-(1-氧代-5-(哌啶-4-基)异吲哚啉-2-基)哌啶-2,6-二酮盐酸盐(15)。
将二恶烷(4mL)中的4M HCl加入溶于CH2Cl2(4mL)的4-(2-(1-甲基-2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)哌啶-1-羧酸叔丁酯14(340mg,0.77mmol)溶液中,并在室温下搅拌12h。将反应混合物真空浓缩,得到固体的标题化合物(278mg,91%),将其结转而无需纯化。1H NMR(500MHz,DMSO-d6)δ9.14–9.01(m,2H),7.70(d,J=7.5Hz,1H),7.46(s,1H),7.37(s,1H),5.17(dd,J=12.8,4.2Hz,1H),4.44(d,J=17.1Hz,1H),4.31(d,J=17.0Hz,1H),3.36(d,J=11.2Hz,2H),3.03–2.94(m,7H),2.76(d,J=16.7Hz,1H),2.43–2.34(m,1H),2.02–1.90(m,5H).LC-MS(ES+):342.1m/z[M+H]+.
3-(5-(1-(4-(4-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并
[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)丁氧基)苄基)哌啶-4-基)-1-氧代异吲哚
啉-2-基)-1-甲基哌啶-2,6-二酮(16)。
根据实施例3中所述的方法对1-甲基-3-(1-氧代-5-(哌啶-4-基)异吲哚啉-2-基)哌啶-2,6-二酮盐酸盐15和4-(4-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)丁氧基)苯甲醛12b进行还原胺化以得到标题化合物。1H NMR(500MHz,DMSO-d6)δ10.97(s,1H),10.08(s,1H),8.94(s,1H),8.05(d,J=3.0Hz,1H),7.84(d,J=9.0Hz,1H),7.63(d,J=7.9Hz,1H),7.49–7.45(m,2H),7.39(d,J=8.0Hz,1H),7.23(t,J=8.4Hz,2H),6.92(d,J=8.5Hz,2H),5.81(p,J=8.5Hz,1H),5.09(dd,J=13.3,5.1Hz,1H),4.41(d,J=17.2Hz,1H),4.28(d,J=17.4Hz,1H),4.12(t,J=5.7Hz,2H),3.19–3.15(m,4H),2.97–2.86(m,5H),2.77(t,J=5.6Hz,2H),2.69–2.56(m,7H),2.42–2.36(m,4H),2.30(s,3H),2.26–2.21(m,2H),2.18(s,2H),2.09–2.03(m,2H),2.01–1.95(m,2H),1.89–1.84(m,2H),1.81–1.53(m,11H).LC-MS(ES+):949.6m/z[M+H]+,475.5m/z[M+2H]2+.
实施例12:(17)的合成。
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3-(5-(1-(4-(2-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙氧基)苄基)哌啶-4-基)-1-氧代异吲哚啉-2-基)-1-甲基哌啶-2,6-二酮(17)。
根据实施例3中所述的方法对1-甲基-3-(1-氧代-5-(哌啶-4-基)异吲哚啉-2-基)哌啶-2,6-二酮盐酸盐15和12a进行还原胺化,得到标题化合物。1H NMR(500MHz,DMSO-d6)δ10.08(s,1H),8.95(s,1H),8.05(d,J=3.0Hz,1H),7.84(d,J=9.0Hz,1H),7.64(d,J=7.8Hz,1H),7.50–7.45(m,2H),7.39(d,J=7.9Hz,1H),7.24(d,J=8.1Hz,2H),6.92(d,J=8.1Hz,2H),5.81(p,J=8.8Hz,1H),5.16(dd,J=13.4,5.1Hz,1H),4.41(d,J=17.2Hz,1H),4.27(d,J=17.1Hz,1H),4.12(t,J=5.7Hz,2H),3.45(s,2H),3.17(t,J=5.1Hz,4H),3.00(s,3H),2.95(d,J=5.5Hz,2H),2.77(d,J=5.2Hz,3H),2.73(d,J=3.8Hz,1H),2.66(t,J=5.0Hz,4H),2.42(s,3H),2.40–2.35(m,1H),2.30(s,3H),2.24(t,J=9.7Hz,2H),2.02–1.97(m,2H),1.88(q,J=8.5,7.4Hz,2H),1.76(d,J=9.3Hz,5H),1.70(d,J=11.8Hz,1H),1.57(q,J=6.0Hz,2H),1.23(d,J=2.8Hz,1H).LC-MS(ES+):920.51m/z[M+H]+.
实施例13:Ia-1至Ia-8对CDK4、CDK6和Helios的共降解
如图1A所示,用所示化合物(DKY709和Ia-1至Ia-8)处理4h的Jurkat细胞的免疫印迹显示CDK4、CDK6和Helios的共降解,同时保留了Ikaros,证明了重新定向双功能降解分子的E3连接酶结合组分的新底物特异性的可行性。DKY709(3-(5-(1-苄基哌啶-4-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮)的结构如下所示:
实施例14:Ia-8对CDK4、CDK6和Helios的共降解
图1B示出了,用1μM的指示化合物(DKY709、三重降解剂Ia-8和配对的阴性对照化合物17)处理4h的Jurkat细胞的免疫印迹。亲代Helios降解剂DKY709仅诱导Helios的降解,但不影响CDK4或CDK6的丰度,而三重降解剂Ia-8诱导Jurkat细胞中CDK4、CDK6和Helios的降解,但不诱导Ikaros的降解。阴性对照化合物17无降解活性。
实施例15:CDK4、CDK6、Helios和磷酸化Rb的蛋白丰度
如图2所示(用1μM指示化合物处理16h的Jurkat细胞的免疫印迹),帕博西尼(CDK4/6抑制剂)降低了磷酸化Rb的水平,而不影响Helios、CDK4或CDK6的蛋白丰度,而DKY709诱导Helios降解,而不影响磷酸化Rb的水平。Ia-8诱导Helios、CDK4和CDK6的三重降解,并降低磷酸化Rb的水平,而阴性对照化合物17的影响最小。
实施例16:诱导G1停滞
如图3A所示(用100nM指示化合物处理24h的Jurkat细胞的DNA含量的碘化丙锭染色),帕博西尼(而不是DKY709)诱导G1停滞,而18和Ia-8诱导G1停滞,而阴性对照化合物17不诱导G1停滞。18(N-(4-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)丁基)-2-((2-(1-甲基-2,6-二氧代哌啶-3-基)-1,3-二氧代吲哚啉-4-基)氨基)乙酰胺)的结构如下所示:
实施例17:抗增殖活性的测量
如图3B所示,以指示化合物的剂量曲线处理Jurkat细胞3d,并通过CellTiter-Glo对细胞增殖进行定量,显示阴性对照化合物17的抗增殖活性(244nM)低于Ia-8(166nM)。
实施例18:CDK4-CDK6-Helios共降解促进IL-2分泌
通过ELISA对用1μM指示化合物预处理24h,且然后用TCR刺激18h的Jurkat细胞的IL-2水平进行定量。结果以平均值±SD表示,见图4(未经处理,n=3;其他条件,n=4)(*p<0.05)。来那度胺和DKY709处理均导致IL-2分泌升高,但未达到统计学意义。虽然用CDK4/CDK6选择性降解剂处理,19具有与帕博西尼相似的活性,但CDK4/CDK6/Ikaros/Aiolos降解剂18诱导甚至更多的IL-2分泌。值得注意的是,用CDK4/CDK6/Helios三重降解剂Ia-8处理诱导IL2水平升高,其与18相当,而无活性化学对照化合物17的活性与帕博西尼相似。19(N-(4-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)丁基)-2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代吲哚啉-4-基)氧基)乙酰胺)的结构如下所示:
所有专利出版物和非专利出版物都表明了本公开所属领域技术人员的技术水平。所有这些出版物(包括所引用的其任何特定部分)在此通过引用并入,其程度与每个单独的出版物被具体和单独指示为通过引用并入相同。
虽然已经参照特定实施方案描述了本公开,但是应理解,这些实施方案仅仅是本公开的原理和应用的示例。因此,应当理解,在不脱离由所附权利要求书限定的本公开的精神和范围情况下,可以对这些示例性实施方案进行诸多修改,并且可以设计其他安排。
Claims (23)
1.一种具有由式(I)表示的结构的双功能化合物:
或其药学上可接受的盐或立体异构体,其中所述靶向配体结合CDK4和/或CDK6,且接头包含亚烷基链或聚乙二醇链。
2.根据权利要求1所述的双功能化合物,其具有由式(Ia)、式(Ib)或式(Ic)表示的结构:
或其药学上可接受的盐或立体异构体。
3.根据权利要求1所述的双功能化合物,其中所述接头包含亚烷基链。
4.根据权利要求3所述的双功能化合物,其中所述亚烷基链在一个或两个末端被-O-或-NH-中的至少一个中断和/或终止。
5.根据权利要求1所述的双功能化合物,其中所述接头包含1个至6个亚烷基单元。
6.根据权利要求1所述的双功能化合物,其中所述接头包含聚乙二醇链。
7.根据权利要求6所述的双功能化合物,其中所述接头在一个或两个末端被-O-或-NH-中的至少一个终止。
8.根据权利要求6所述的双功能化合物,其中所述接头包含2个至3个乙二醇单元。
9.根据权利要求1所述的双功能化合物,其中所述接头是以下结构中的任何一种:
10.根据权利要求1所述的双功能化合物,其中所述接头在3-位(间位)处连接到苯基上。
11.根据权利要求1所述的双功能化合物,其中所述接头在4-位(对位)处连接到苯基上。
12.根据权利要求1所述的双功能化合物,其是:
或其药学上可接受的盐或立体异构体。
13.一种药物组合物,其包含治疗有效量的权利要求1所述的双功能化合物或其药学上可接受的盐或立体异构体,以及药学上可接受的载体。
14.根据权利要求13所述的药物组合物,其为固体形式。
15.根据权利要求14所述的药物组合物,其为片剂或胶囊剂形式。
16.根据权利要求13所述的药物组合物,其为液体形式。
17.一种治疗以CDK4和/或CDK6和Helios的异常活性为特征的疾病或病症的方法,其包括向有此需要的受试者施用治疗有效量的权利要求1所述的双功能化合物或其药学上可接受的盐或立体异构体。
18.根据权利要求17所述的方法,其中所述疾病或病症是癌症。
19.根据权利要求18所述的方法,其中所述癌症被表征为实体瘤。
20.根据权利要求18所述的方法,其中所述癌症选自乳腺癌、脑癌、子宫内膜癌、头颈癌、胃肠癌、肺癌、卵巢癌、***癌、子宫癌、肝细胞癌、脂肪肉瘤和黑色素瘤。
21.根据权利要求18所述的方法,其中所述癌症是血液***癌症。
22.根据权利要求21所述的方法,其中所述血液***癌症选自白血病、淋巴瘤和骨髓瘤。
23.一种降低细胞中CDK4和/或CDK6以及Helios水平的方法,无论是在体外还是在体内,其包括使所述细胞与权利要求1所述的双功能化合物接触。
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