CN105247072B - 检测和治疗抗药性akt突变体的方法和组合物 - Google Patents
检测和治疗抗药性akt突变体的方法和组合物 Download PDFInfo
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- CN105247072B CN105247072B CN201480023235.0A CN201480023235A CN105247072B CN 105247072 B CN105247072 B CN 105247072B CN 201480023235 A CN201480023235 A CN 201480023235A CN 105247072 B CN105247072 B CN 105247072B
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Abstract
本发明涉及用于鉴定或诊断AKT抑制剂抗性癌症的方法以及用于治疗的方法和组合物。
Description
技术领域
本发明涉及肿瘤生长、肿瘤类型和抗药性的领域。本发明涉及用于肿瘤的抑制剂和诊断标志物,其用于诊断和治疗癌症、抗药性癌症和肿瘤生长的用途。
发明背景
恶性肿瘤(癌)是在美国位居心脏病之后的第二位致死原因(参见例如Boring etal.,CA Cancel J.Clin.43:7(1993))。癌的特征为衍生自正常组织的异常或赘生性细胞的数量增加,所述细胞增殖形成肿瘤块;这些赘生性肿瘤细胞侵入邻近组织;及产生恶性细胞,所述恶性细胞最终经血液或淋巴系统传播到局部淋巴结并经称为转移的过程传播到远处。在癌性状态,细胞在正常细胞不生长的条件下增殖。癌自身表现为多种形式,特征为不同程度的侵袭力和进攻性。
根据癌症类型,患者通常具有可用于他们的几种治疗选项,包括化学疗法、放射和基于抗体的药物。可用于预测来自不同治疗方案的临床后果的诊断方法会使这些患者的临床处置极大地受益。几项研究已经探索了基因表达与鉴定特定癌症类型的关联,例如通过突变特异性测定、微阵列分析、qPCR等来进行。上述方法可用于鉴定并分类由患者呈现的癌症。
Akt是急性转化型逆转录病毒AKT8的原癌基因v-akt的人类同源物。由于它与蛋白激酶A和蛋白激酶C的高度序列同源性,Akt还被称为蛋白激酶B(PKB)并与A和C相关(RAC)。已知存在Akt的三种同工型,即Akt1、Akt2和Akt3,它们表现80%的总同源性(Staal,S.P.(1987)Proc.Natl.Acad.Sci.84:5034;Nakatani,K.(1999)Biochem.Biophys.Res.Commun.257:906;Li et al(2002)Current Topics inMed.Chem.2:939-971;WO 2005/113762)。Akt同工型共享共同的结构域组织,所述结构域组织由在N端的普列克底物蛋白(pleckstrin)同源结构域、激酶催化结构域和在C端的短调节区组成。此外,Akt2和Akt3均显示剪接变体。通过PtdInd(3,4,5)P3募集到细胞膜时,Akt 的同工型Akt1(PKBα)、Akt2(PKBβ)和Akt3(PKBγ)分别在T308、T309和T305被PDK1磷酸化(活化),并且Akt的同工型Akt1、Akt2和Akt3则分别在S473、S474和S472被PDK1磷酸化(活化)。这种磷酸化被认为是通过尚未知的激酶(推定命名为PDK2)发生,尽管PDK1(Balendran,A.,(1999)Curr.Biol.9:393)、自磷酸化(Toker,A.(2000)J.Biol.Chem.275:8271)和整联蛋白连接激酶(ILK)(Delcommenne,M.(1998)Proc.Natl.Acad.Sci.USA,95:11211)已经牵涉该过程。Akt活化需要其在C端疏水基序中的残基Ser 473上磷酸化Brodbeck et al(1999)J.Biol.Chem.274:9133-9136;Coffer et al(1991)Eur.J.Biochem.201:475-481;Alessiet al(1997)Curr.Biol.7:261-269)。虽然Akt的单磷酸化使该激酶活化,但最大的激酶活性则需要双(磷酸化)。
Akt被认为是通过抑制细胞凋亡并增强血管生成与增殖而显示其对癌症的作用(Toker et al.(2006)Cancer Res.66(8):3963-3966)。Akt在多种形式的人类癌症中过度表达,所述癌症包括,但不限于,结肠癌(Zinda et al(2001)Clin.Cancer Res.7:2475)、卵巢癌(Cheng et al(1992)Proc.Natl.Acad.Sci.USA 89:9267)、脑癌(Haas Kogan et al(1998)Curr.Biol.8:1195)、肺癌(Brognard et al(2001)Cancer Res.61:3986)、胰腺癌(Bellacosa et al(1995)Int.J.Cancer 64:280-285;Cheng et al(1996)Proc.Natl.Acad.Sci.93:3636-3641)、前列腺癌(Graff et al(2000)J.Biol.Chem.275:24500)和胃癌(Staal et al(1987)Proc.Natl.Acad.Sci.USA 84:5034-5037)。
因此,具有可用于鉴定和治疗对抗AKT治疗具有抗性的受试者的基于分子的诊断方法和化合物将会是极为有利的。
发明内容
本发明的方法可用于多种背景中,包括例如鉴定、诊断和治疗对AKT抑制剂具有抗性的肿瘤和癌细胞。
一个方面包括用于在癌细胞中检测对AKT抑制剂的治疗效果的抗性的方法,包括在包含AKT1或PRAS40突变的细胞中检测突变的存在,其中突变的存在表明癌细胞已经变得或将会变得对AKT抑制剂具有抗性。
在某些实施方案中,用AKT抑制剂治疗后检测到突变的存在。
在某些实施方案中,所述AKT1突变包含W80。
在某些实施方案中,所述W80突变包含半胱氨酸残基变化。
某些实施方案还包括检测AKT3的表达水平。
在某些实施方案中,还包括检测AKT3的过表达。
在某些实施方案中,所述AKT抑制剂为变构抑制剂(allosteric inhibitor)。
在某些实施方案中,所述变构抑制剂为MK-2206。
某些实施方案包括对癌细胞施用有效量的PI3k或mTOR抑制剂。
在某些实施方案中,所述PRAS40突变包含终止密码子。
在某些实施方案中,所述突变包含178位终止密码子。
在某些实施方案中,所述AKT抑制剂为ATO竞争性抑制剂。
在某些实施方案中,所述AKT抑制剂为GDC-0068或GSK2110183。
在某些实施方案中,所述AKT3表达水平为mRNA表达水平。
在某些实施方案中,使用qRT-PCR或微阵列测量mRNA表达水平。
在某些实施方案中,所述mRNA表达水平的变化增加。
某些实施方案包括施用有效量的选自GDC-0941和GDC-0980的PI3k抑制剂。
某些实施方案包括施用有效量的选自雷帕霉素(rapamyacin)的mTOR抑制剂。
在某些实施方案中,所述癌症选自间皮瘤(mesothelioma)、子宫内膜癌(endometrial)、胰腺癌(pancreatic)、乳腺癌(breast)、肺癌(lung)、卵巢癌(ovarian)、前列腺癌(prostate)、黑素瘤(melanoma)、胃癌(gastric)、结肠癌(colon)、肾癌(renal)、头颈部癌(head and neck)和神经胶质瘤(giloma)。
在某些实施方案中,所述癌症与PTEN突变相关。
在某些实施方案中,所述癌症与PTEN低或缺失状态(low or null status)相关。
在某些实施方案中,所述癌症与AKT突变、过表达或扩增相关。
在某些实施方案中,所述癌症与PI3K突变相关。
在某些实施方案中,所述癌症与Her2/ErbB2扩增相关。
在某些实施方案中,所述癌细胞为循环肿瘤细胞(CTC)。
在某些实施方案中,所述检测还包括通过pCR检测突变。
本文所述任意实施方案或它们的任意组合适用于本文所述任意和所有方法和组合物。
附图简述
图1-2显示在亲代(例如参照细胞)和AKT抑制剂细胞(例如样品细胞)的前列腺癌细胞系(LNCaP细胞)中对AKT抑制剂GDC-0068((S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮)和MK2206(8-[4-(1-氨基环丁基)苯基]-9-苯基-1,2,4-三唑并[3,4-f][1,6]二氮杂萘-3(2H)-酮)的剂量响应曲线。对两种抑制剂的抗性克隆衍生自随时间用升高剂量的AKT抑制剂处理的癌细胞的群。对于GDC-0068,将约10倍较低敏感性的细胞进行克隆。对于MK2206,将约40被较低敏感性的细胞进行克隆。
图3-4显示向癌细胞(LNCaP细胞)给予的AKT抑制剂的Western印迹分析。GDC-0068抗性细胞仍然与抑制剂结合,但GDC-0068在抑制下游pS6(即癌细胞已变得具有抗性)时效力较低。类似地,MK2206抗性细胞丧失由MK2206诱导的pS6的抑制,此外,MK2206未能如其在亲代细胞系中那样抑制Akt磷酸化。通过外显子组测序(exome-seq)分析了抗性克隆和库(pool),并且发现了2个突变,一个位于W80,其突变为半胱氨酸残基,另一个位于具有178位处终止密码子的Akt底物PRAS40。Akt1突变出现在全部MK2206克隆中,而PRAS40突变出现在全部GDC-0068抗性克隆中。
图5显示LNCaP MK2206抗性克隆还获得如RNA测序数据所示的Akt3表达。这说明对AKT抑制剂(例如MK2206)具有抗性的细胞还可具有异常表达的AKT蛋白质,例如AKT3。
如RNA-测序实验所示,亲代LNCaP细胞不表达Akt3,用任一种抑制剂处理的GDC-0068抗性克隆或亲代细胞也不表达Akt3。MK-2206抗性细胞突变Akt1并获得Akt3的表达,从而克服变构抑制剂的抑制效果。
图6显示当用其它AKT抑制剂处理时亲代和对AKT抑制剂具有抗性的LNCap细胞的剂量响应曲线。在GDC-0068和MK-2206均具有抗性的情况下,LNCaP细胞中的Akt抑制剂抗性仍然取决于Akt途径活性。MK2206-抗性细胞仍然对GDC-0068敏感,与靶向ATP位点且等效抑制全部3种Akt的GDC-0068一致。另一方面,GDC-0068-敏感性细胞如GDC-0068那样类似地对MK2206具有抗性,与突变位于Akt的下游一致。
对ATP竞争性抑制剂(例如GDC-0068)具有抗性的癌细胞活化了Akt上位的mTORC1。MK-2206抗性细胞消除了(abrogate)Akt本身的变构抑制, 但仍然对ATP竞争性AKT抑制剂诸如GDC-0068敏感。
图7-8显示卵巢癌细胞对AKT抑制剂处理的结果,例如获得对它们(IGROV1(卵巢的,PI3K突变体O1069W,PTEN杂合型细胞)的抗性后的结果。对GDC0068和MK2206具有抗性的细胞对变构抑制(例如MK2206)抗性相当,而对GDC0068具有抗性的细胞对GDC-0068比对MK2206抗性更强。
图9显示GDC-0941和GDC-0980仍然对全部亲代和抗性IGROV1细胞系均有效。这说明细胞对AKT抑制剂变得具有抗性后患者的癌症可通过给予用于治疗AKT抗性癌症的PI3k或mTOR抑制剂进行治疗。
具体实施方式
本文中所描述或提及的技术和规程一般是本领域技术人员充分了解并使用常规方法所通常采用的,诸如例如记载于下列文献的广泛使用的方法:Sambrook et al.,Molecular Cloning:A Laboratory Manual 3rd.edition(2001)Cold Spring HarborLaboratory Press,Cold Spring Harbor,N.Y.CURRENT PROTOCOLS IN MOLECULARBIOLOGY(F.M.Ausubel,et al.eds.,(2003));丛书METHODS IN ENZYMOLOGY(AcademicPress,Inc.):PCR 2:A PRACTICAL APPROACH(M.J.MacPherson,B.D.Hames andG.R.Taylor eds.(1995)),Harlow and Lane,eds.(1988)ANTIBODIES,A LABORATORYMANUAL,and ANIMAL CELL CULTURE(R.I.Freshney,ed.(1987));OligonucleotideSynthesis(M.J.Gait,ed.,1984);Methods in Molecular Biology,Humana Press;CellBiology:A Laboratory Notebook(J.E.Cellis,ed.,1998)Academic Press;Animal CellCulture(R.I.Freshney),ed.,1987);Introduction to Cell and Tissue Culture(J.P.Mather and P.E.Roberts,1998)Plenum Press;Cell and Tissue Culture:Laboratory Procedures(A.Doyle,J.B.Griffiths,and D.G.Newell,eds.,1993-8)J.Wiley and Sons;Handbook of Experimental Immunology(D.M.Weir andC.C.Blackwell,eds.);Gene Transfer Vectors for Mammalian Cells(J.M.Miller andM.P.Calos,eds.,1987);PCR:The Polymerase Chain Reaction,(Mullis et al.,eds.,1994);Current Protocols in Immunology(J.E.Coligan et al.,eds.,1991);ShortProtocols in Molecular Biology(Wiley and Sons,1999);Immunobiology(C.A.Janewayand P.Travers,1997);Antibodies(P.Finch,1997);Antibodies:A Practical Approach(D.Catty.,ed.,IRL Press, 1988-1989);Monoclonal Antibodies:A PracticalApproach(P.Shepherd and C.Dean,eds.,Oxford University Press,2000);UsingAntibodies:A Laboratory Manual(E.Harlow and D.Lane(Cold Spring HarborLaboratory Press,1999);The Antibodies(M.Zanetti and J.D.Capra,eds.,HarwoodAcademic Publishers,1995);and Cancer:Principles and Practice of Oncology(V.T.DeVita et al.,eds.,J.B.Lippincott Company,1993).
除非另有定义,本文中所使用的技术和科学术语与本领域普通技术人员的通常理解具有相同含义。Singleton et al.,Dictionary of Microbiology and MolecularBiology 2nd ed.,J.Wiley&Sons(New York,N.Y.1994),and March,Advanced OrganicChemistry Reactions,Mechanisms and Structure 4th ed.,John Wiley&Sons(NewYork,N.Y.1992)为本领域技术人员提供本申请中使用的许多术语的一般指导。通过引用的方式将本文中所引用的所有参考文献(包括专利申请和出版物)全部并入本文。
定义
为了解读本说明书,将适用下列定义,并且只要合适,以单数使用的术语也会包括复数,且反之亦然。应当理解的是,本文所使用的专业术语(terminology)仅用于描述具体的实施方案,而非意欲限制。在下文所列出的任何定义与通过引用的方式而并入本文中的任何文献矛盾的情况中,应当以下文所列出的定义为准。
本文中“测试样品”或“样品”是指自感兴趣的受试者获得或衍生的组合物,其含有要例如基于物理、生物化学、化学和/或生理学特征表征和/或鉴定的细胞和/或其它分子实体。在一个实施方案中,该定义涵盖生物起源的血液和其它液体样品及组织样品诸如活组织检查标本或组织培养物或自其衍生的细胞。组织样品的来源可以是固体组织,如来自新鲜的、冷冻的和/或保存的器官或组织样品或活组织检查或吸出物;血液或任何血液成分;体液;和来自受试者妊娠或发育中的任何时间的细胞或血浆。
在另一个实施方案中,该定义包括在其获得后已经以任何方式操作,诸如通过用试剂处理、增溶、或富集某种组分,诸如蛋白质或多核苷酸,或者为了形成切片包埋于半固体或固体基质中的生物学样品。出于本文中的目的,组织样品的“切片”意指组织样品的单一部分或份,例如自组织样品切 割的组织薄片或细胞。
样品包括但不限于原代或培养的细胞或细胞系、细胞上清液、细胞溶胞物、血小板、血清、血浆、玻璃状液、淋巴液、滑液、滤泡液、精液、羊水、乳、全血、尿液、脑脊液、唾液、痰、泪液、汗液、粘液、肿瘤溶胞物和组织培养液及组织提取物诸如均质化组织、肿瘤组织和细胞提取物。
在一个实施方案中,测试样品是临床样品。在另一个实施方案中,在诊断测定法中使用测试样品。在某些实施方案中,自原发性或转移性肿瘤获得测试样品。经常使用组织活组织检查来获得肿瘤组织的代表性部分。可选择地,肿瘤细胞可以已知或认为含有感兴趣的肿瘤细胞的组织或流体形式间接获得。例如,可通过切除、支气管镜检查、细针抽吸、支气管刷检、或自痰、胸膜液或血液获得肺癌病灶的生物学样品。在一个实施方案中,测试样品包含循环肿瘤细胞(CTC),例如来自患者血清的那些CTC。
在一个实施方案中,在用AKT抑制剂治疗之前、期间和/或之后自受试者或患者获得测试样品。在某些实施方案中,癌症转移后获得测试样品。
本文中使用的“参照样品”是指出于比较目的使用的任何样品、标准品、或水平。在一个实施方案中,自相同受试者或患者的身体的健康和/或未患病部分获得参照样品。在另一个实施方案中,自相同受试者或患者的身体的未处理组织和/或细胞获得参照样品。
在某些实施方案中,参照样品包含对AKT抑制剂疗法响应的肿瘤或癌细胞。在某些实施方案中,AKT抑制剂疗法包含GDC-0068、MK2206或GSK2110183。
在某些实施方案中,参照样品是与获得测试样品时不同的一个或多个时间点时获得的来自相同受试者或患者的单一样品或组合的多份样品。例如,在比获得测试样品时更早的时间点时自相同受试者或患者获得参照样品。若在癌症的初始诊断期间获得参照样品,并且后来在癌症变为转移时获得测试样品,则此类参照样品可以是有用的。
在一个实施方案中,在用AKT抑制剂例如GDC-0068、MK2206或GSK2110183治疗之前、期间和之后的各时间点自患者获得CTC,并且检测AKT和PRAS40的突变状态(例如通过pCR、Western或IHC)。
在某些实施方案中,参照样品是来自一个或多个不是受试者或患者的健康个体的组合多份样品。在某些实施方案中,参照样品是来自一个或多个患 有癌症、不是受试者或患者的个体的组合多份样品。在某些实施方案中,参照样品是来自正常组织的合并RNA样品,所述正常组织来自一个或多个不是受试者或患者的个体。在某些实施方案中,参照样品是来自肿瘤组织的合并RNA样品,所述肿瘤组织来自一个或多个患有癌症、不是受试者或患者的个体。
可基于本领域中已知的任何合适的标准,包括但不限于mRNA、cDNA、蛋白质、蛋白质片段和/或基因拷贝数量来测定基因或生物标志的表达水平/量。在某些实施方案中,与第二样品中的表达/量相比,第一样品中基因或生物标志物的表达/量升高。在某些实施方案中,与第二样品中的表达/量相比,第一样品中基因或生物标志物的表达/量降低。在某些实施方案中,第二样品为参照样品。
在某些实施方案中,术语“升高”是指与参照样品相比,通过标准领域已知的方法诸如本文所述方法检测的蛋白或核酸水平总体升高5%、10%、15%、20%、25%、30%、40%、50%、60%、70%、80%、85%、90%、95%、96%、97%、98%、99%或更多。在某些实施方案中,术语升高是指样品的基因或生物标志物的表达水平/量的升高,其中所述升高为参照样品的相应基因或生物标志物的表达水平/量的升高至少约1.25X、1.5X、1.75X、2X、3X、4X、5X、6X、7X、8X、9X、10X、25X、50X、75X或100X。
在某些实施方案中,本文中术语“降低”是指与参照样品相比,通过标准领域已知的方法诸如本文所述方法检测的蛋白或核酸水平总体降低5%、10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、90%、95%、96%、97%、98%、99%或更多。在某些实施方案中,术语升高是指样品的基因或生物标志物的表达水平/量的降低,其中所述降低为参照样品的相应基因或生物标志物的表达水平/量的降低至少约0.9X、0.8X、0.7X、0.6X、0.5X、0.4X、0.3X、0.2X、0.1X、0.05X或0.01X。
术语“标记物”在用于本文时是指与试剂诸如核酸探针或抗体直接或间接偶联或融合,以便于检测它所偶联或融合的试剂的化合物或组合物。标记物可为自身可检测的(例如放射性同位素标记物或荧光标记物),或者在酶标记物的情况中,可催化可检测的底物化合物或组合物的化学改变。
在某些实施方案中,“关联”或“联系”指以任何方式将第一分析或方 案的性能和/或结果与第二分析或方案的性能和/或结果进行比较。例如,可将第一分析或方案的结果用于实施第二分析或方案,和/或,可使用第一分析或方案的结果来决定是否应当实施第二分析或方案。就基因表达分析或方案的实施方案而言,可使用基因表达分析或方案的结果来决定是否应当实施特定治疗方案。
在本文中可互换使用的“多核苷酸”或“核酸”是指任何长度的核苷酸的聚合物,而且包括DNA和RNA。核苷酸可为脱氧核糖核苷酸、核糖核苷酸、经过修饰的核苷酸或碱基和/或它们的类似物,或能由DNA或RNA聚合酶或通过合成反应掺入聚合物的任何底物。多核苷酸可包含经过修饰的核苷酸,诸如甲基化核苷酸及其类似物。
本文中使用的“寡核苷酸”一般是指短的、一般为单链的、一般为合成的多核苷酸,其一般地,但是不必在长度上小于约200个核苷酸。术语“寡核苷酸”和“多核苷酸”并不互相排斥。上文关于多核苷酸的描述同样且完全可适用于寡核苷酸。
“分离的”核酸分子指已经鉴定且与它在多肽核酸的天然来源中通常与之关联的至少一种污染性核酸分子分开的核酸分子。分离的核酸分子不同于在它在自然界中发现的形式或设置。因此,分离的核酸分子区别于从存在于天然细胞中的核酸分子。然而,分离的核酸分子包括包含在通常表达该多肽的细胞中的核酸分子,在所述多肽中,例如,所述核酸分子在与天然细胞的不同的染色体位置。
“引物”一般是指通过与靶序列杂交结合感兴趣的样品中潜在存在的靶标,此后促进与靶标互补的多核苷酸聚合的短的单链多核苷酸,一般具有游离的3'-OH基团。
术语“持家基因”是指一组基因,其编码活性对于细胞功能维持而言必要的蛋白质。这些基因通常类似地存在于所有细胞类型中。
本文中使用的术语“阵列”或“微阵列”是指可杂交阵列元件,优选地多核苷酸探针(例如,寡核苷酸)在基片(substrate)上的有序排布。基片可为固体基片,诸如玻璃载玻片,或半固体基片,诸如硝酸纤维素膜。核苷酸序列可为DNA、RNA或其任何排列(permutation)。
“天然序列”多肽包含与从自然界衍生的多肽具有相同的氨基酸序列的多肽。因此,天然序列多肽可具有来自任何哺乳动物的天然存在的多肽的氨 基酸序列。此类天然序列多肽可从自然界分离或可通过重组或合成手段来生成。术语“天然序列”多肽明确涵盖多肽的天然存在的截短或分泌形式(例如,胞外域序列)、多肽的天然存在的变体形式(例如,可变剪接形式)和天然存在的等位变体。
“分离的”多肽或“分离的”抗体为已经鉴定且由其天然环境的组分分开和/或回收的。其天然环境的污染性组分为将会干扰该多肽的诊断或治疗用途的材料,且可包括酶、激素和其它蛋白质性质或非蛋白质性质的溶质。在某些实施方案中,将多肽纯化至(1)根据Lowry法的测定,以多肽重量计超过95%,或以重量计超过99%,(2)足以通过使用转杯式测序仪获得至少15个残基的N-末端或内部氨基酸序列的程度,或(3)通过在还原性或非还原性条件下的SDS-PAGE,使用考马斯蓝或银染色,达到同质。既然多肽天然环境的至少一种成分将不会存在,那么分离的多肽包括重组细胞内的原位多肽。然而,分离的多肽通常将通过至少一个纯化步骤来制备。
“多肽链”为如下的多肽,其中与非共价相互作用或二硫键相反,通过肽键连接其每个域与其它域。
多肽“变体”意指与相应的天然序列多肽具有至少约80%氨基酸序列同一性的生物学活性多肽。此类变体包括例如如下的多肽,其中在该多肽的N和/或C端添加或删除一个或多个氨基酸(天然存在的氨基酸和/或非天然存在的氨基酸)残基。通常,变体与天然序列多肽会具有至少约80%氨基酸序列同一性,或至少约90%氨基酸序列同一性,或至少约95%或更多的氨基酸序列同一性。变体还包括天然序列的多肽片段(例如,亚序列、截短等),通常具有生物学活性。
本文中使用的术语“蛋白质变体”是指如上文所描述的变体和/或在天然蛋白质序列中包含一处或多处氨基酸突变的蛋白质。任选地,一处或多处氨基酸突变包括氨基酸替代。可通过本领域中公知的多种方法来制备本发明中使用的蛋白质及其变体。可通过蛋白质DNA中的突变来制备蛋白质的氨基酸序列变体。此类变体包括例如蛋白质氨基酸序列内的残基删除、插入或替代。可进行任何删除、插入和替代组合以获得具有期望活性的最终构建物。会对编码变体的DNA进行的突变不得将序列在阅读框外放置,并且优选地,不会创建可生成二级mRNA结构的互补区。
术语“抗体”以最广义使用,并且明确覆盖单克隆抗体(包括全长或完 整的单克隆抗体)、多克隆抗体、多价抗体、自至少两种完整的抗体形成的多特异性抗体(例如,双特异性抗体)和抗体片段(见下文),只要它们展现出期望的生物学活性。
除非另有指示,表述“多价抗体”遍及本说明书用于表示包含三个或更多个抗原结合位点的抗体。多价抗体通常被工程化改造成具有三个或更多个抗原结合位点,并且一般不是天然序列IgM或IgA抗体。
“抗体片段”仅包含完整抗体的一部分,其一般包含完整抗体的抗原结合位点,并且因此保留结合抗原的能力。本定义涵盖的抗体片段的实例包括:(i)Fab片段,其具有VL、CL、VH和CH1域;(ii)Fab’片段,其是在CH1域的C端具有一个或多个半胱氨酸残基的Fab片段;(iii)Fd片段,其具有VH和CH1域;(iv)Fd’片段,其具有VH和CH1域及在CH1域的C端的一个或多个半胱氨酸残基;(v)Fv片段,其具有抗体单臂的VL和VH域;(vi)dAb片段(Ward etal.,Nature 341,544-546(1989)),其由VH域组成;(vii)分离的CDR区;(viii)F(ab’)2片段,即一种包含通过铰链区处的二硫桥连接的两个Fab’片段的二价片段;(ix)单链抗体分子(例如单链Fv;scFv)(Bird et al.,Science 242:423-426(1988);和Huston et al.,PNAS(USA)85:5879-5883(1988));(x)具有两个抗原结合位点的“双抗体”,其包含在同一多肽链中连接的重链可变域(VH)和轻链可变域(VL)(参见例如EP 404,097;WO 93/11161;andHollinger et al.,Proc.Natl.Acad.Sci.USA,90:6444-6448(1993));(xi)“线性抗体”,其包含一对串联的Fd区段(VH-CH1-VH-CH1),它们与互补的轻链多肽一起形成一对抗原结合区(Zapata et al.Protein Eng.8(10):10571062(1995);和美国专利5,641,870)。
本文中使用的术语“单克隆抗体”是指从一群基本上同质的抗体获得的抗体,即构成群体的各个抗体相同,除了可能以极小量存在的可能的突变(例如天然存在的突变)外。因此,修饰语“单克隆”指明抗体不是不同的抗体的混合物的特征。单克隆抗体是高度特异性的,针对单一抗原。在某些实施方案中,单克隆抗体通常包括包含结合靶标的多肽序列的抗体,其中所述靶标结合多肽序列是通过包括从众多多肽序列中选择单一靶物结合多肽序列在内的过程获得的。例如,所述选择过程可为从众多克隆(诸如杂交瘤克隆、噬菌体克隆或重组DNA克隆的集合)选择独特克隆。应当理解的是,可进一步改变选定的靶标结合序列,例如为了提高对靶标的亲和力、将靶标结合序 列人源化、提高其在细胞培养物中的产量、降低其在体内的免疫原性、创建多特异性抗体。与典型的包含针对不同决定簇(表位)的不同抗体的多克隆抗体制备物不同,每种单克隆抗体针对抗原上的单一决定簇。除它们的特异性外,单克隆抗体制备物的优点在于它们通常未受到其它免疫球蛋白的污染。
修饰语“单克隆”指抗体从基本上同质的抗体群获得的特征,不应解释为要求通过任何特定方法来生产抗体。例如,要依照本发明使用的单克隆抗体可通过多种技术来生成,包括例如杂交瘤法(例如,Kohler and Milstein,Nature,256:495-97(1975);Hongo etal.,Hybridoma,14(3):253-260(1995),Harlow et al.,Antibodies:A LaboratoryManual,(Cold Spring Harbor Laboratory Press,2nd ed.1988);Hammerling et al.,in:Monoclonal Antibodies and T-Cell Hybridomas 563-681(Elsevier,N.Y.,1981))、重组DNA法(参见例如,美国专利4,816,567)、噬菌体展示技术(参见例如,Clackson etal.,Nature,352:624-628(1991);Marks et al.,J.Mol.Biol.222:581-597(1991);Sidhuet al.,J.Mol.Biol.338(2):299-310(2004);Lee et al.,J.Mol.Biol.340(5):1073-1093(2004);Fellouse,Proc.Natl.Acad.Sci.USA 101(34):12467-12472(2004);and Lee etal.,J.Immunol.Methods 284(1-2):119-132(2004),和用于在具有部分或整个人免疫球蛋白基因座或编码人免疫球蛋白序列的基因的动物中生成人或人样抗体的技术(参见例如,WO 1998/24893;WO 1996/34096;WO1996/33735;WO 1991/10741;Jakobovits et al.,Proc.Natl.Acad.Sci.USA 90:2551(1993);Jakobovits et al.,Nature 362:255-258(1993);Bruggemann et al.,Year in Immunol.7:33(1993);美国专利5,545,807;5,545,806;5,569,825;5,625,126;5,633,425;and 5,661,016;Marks et al.,Bio/Technology10:779-783(1992);Lonberg et al.,Nature 368:856-859(1994);Morrison,Nature 368:812-813(1994);Fishwild et al.,Nature Biotechnol.14:845-851(1996);Neuberger,Nature Biotechnol.14:826(1996);and Lonberg and Huszar,Intern.Rev.Immunol.13:65-93(1995)。
单克隆抗体在本文中明确包括“嵌合”抗体,其中重链和/或轻链的一部分与衍生自特定物种或属于特定抗体类别或亚类的抗体中的相应序列相同或同源,而链的剩余部分与衍生自另一物种或属于另一抗体类别或亚类的抗体中的相应序列相同或同源,和此类抗体的片段,只要它们展现出期望的生物学活性(美国专利4,816,567和Morrison et al.,Proc.Natl.Acad.Sci.USA 81:6851-6855(1984))。
非人(例如鼠)抗体的“人源化”形式指最低限度包含衍生自非人免疫球蛋白的序列的嵌合抗体。在很大程度上,人源化抗体指人免疫球蛋白(受体抗体)中的高变区残基用具有期望特异性、亲和力、和能力的非人物种(供体抗体)诸如小鼠、大鼠、家兔或非人灵长类动物的高变区残基替换的免疫球蛋白。在有些情况中,将人免疫球蛋白的框架区(FR)残基用相应的非人残基替换。此外,人源化抗体可包含在受体抗体或供体抗体中没有找到的残基。进行这些修饰以进一步改进抗体的性能。通常,人源化抗体会包含至少一个、通常两个基本上整个如下的可变域,其中所有或基本上所有高变环对应于非人免疫球蛋白的高变环,且所有或基本上所有FR是人免疫球蛋白序列的FR。人源化抗体任选还会包含至少部分免疫球蛋白恒定区(Fc),通常是人免疫球蛋白的恒定区。更多细节参见Jones et al.,Nature 321:522-525(1986);Riechmann et al.,Nature 332:323-329(1988);andPresta,Curr.Op.Struct.Biol.2:593-596(1992)。参见例如,Vaswani and Hamilton,Ann.Allergy,Asthma&Immunol.1:105-115(1998);Harris,Biochem.Soc.Transactions23:1035-1038(1995);Hurle and Gross,Curr.Op.Biotech.5:428-433(1994);和美国专利6,982,321和7,087,409。还参见van Dijk and van de Winkel,Curr.Opin.Pharmacol.,5:368-74(2001)。可通过对转基因动物施用抗原来制备人抗体,所述转基因动物已经修饰为响应抗原性考验而生成此类抗体,但是其内源基因座已经丧失能力,例如经免疫的异源小鼠(xenomice)(关于XENOMOUSETM技术,参见例如美国专利6,075,181和6,150,584)。关于经由人B细胞杂交瘤技术生成的人抗体,还参见例如Li et al.,Proc.Natl.Acad.Sci.USA,103:3557-3562(2006)。
“人抗体”为具有与由人生成的抗体的氨基酸序列对应的氨基酸序列和/或使用如本文所公开的用于生成人抗体的任何技术生成的抗体。人抗体的此定义明确排除包含非人抗原结合残基的人源化抗体。可使用本领域中已知的各种技术来生成人抗体。在一个实施方案中,自噬菌体库选择人抗体,其中所述噬菌体库表达人抗体(Vaughan et al.NatureBiotechnology 14:309-314(1996):Sheets et al.PNAS(USA)95:6157-6162(1998));Hoogenboom and Winter,J.Mol.Biol.,227:381(1991);Marks et al.,J.Mol.Biol.,222:581(1991))。还可通过将人免疫球蛋白基因座导入转基因动物,例如已经将内源 免疫球蛋白基因部分或完全灭活的小鼠中来生成人抗体。考验后,观察到人抗体生成,其在所有方面,包括基因重排、装配和抗体全集与人中看到的极其相似。此方法记载于例如美国专利5,545,807;5,545,806;5,569,825;5,625,126;5,633,425;5,661,016,和下列科学出版物中:Marks et al.,Bio/Technology 10:779-783(1992);Lonberg et al.,Nature 368:856-859(1994);Morrison,Nature 368:812-13(1994);Fishwild et al.,NatureBiotechnology 14:845-51(1996);Neuberger,Nature Biotechnology 14:826(1996);Lonberg and Huszar,Intern.Rev.Immunol.13:65-93(1995)。可选择地,可经由永生化生成针对靶抗原的抗体的人B淋巴细胞(此类B淋巴细胞可自个体回收或可已经在体外免疫)来制备人抗体。参见例如Cole et al.,Monoclonal Antibodies and Cancer Therapy,Alan R.Liss,p.77(1985);Boerner et al.,J.Immunol.,147(1):86-95(1991);和美国专利5,750,373。
术语“可变的”是指可变域中的某些部分在抗体间序列差异广泛且用于每种特定抗体对其特定抗原的结合和特异性的事实。然而,变异性并非均匀分布于抗体的整个可变域。它集中于轻链和重链可变域中称作高变区的三个区段。可变域中更加高度保守的部分称作框架区(FR)。天然重链和轻链的可变域各自包含四个FR,它们大多采取β-片层构象,通过形成环状连接且在有些情况中形成β-片层结构一部分的三个高变区连接。每条链中的高变区通过FR非常接近的保持在一起,并与另一条链的高变区一起促成抗体的抗原结合位点的形成(参见Kabat et al.,Sequences of Proteins of Immunological Interest,5thEd.Public Health Service,National Institutes of Health,Bethesda,MD.(1991))。恒定域不直接参与抗体与抗原的结合,但展现出多种效应器功能,诸如抗体依赖性细胞的毒性中抗体的参与。
术语“高变区”、“HVR”或“HV”在用于本文时是指抗体中负责抗原结合的氨基酸残基。例如,术语高变区是指抗体可变域中序列上高度可变和/或形成结构上定义的环的区域。通常,抗体包含六个HVR:三个在VH中(H1、H2、H3),三个在VL中(L1、L2、L3)。在天然抗体中,H3和L3展示这六个HVR的最大多样性,而且认为特别是H3在赋予抗体以精密特异性中发挥独特作用。参见例如Xu et al.,Immunity 13:37-45(2000);Johnson and Wu,inMethods in Molecular Biology 248:1-25(Lo,ed.,Human Press,Totowa,NJ,2003)。事实上,仅由重链组成的天然存在骆驼(camelid)抗体在缺乏轻链 的情况中是有功能的且稳定的。参见例如Hamers-Casterman et al.,Nature363:446-448(1993);Sheriff et al.,Nature Struct.Biol.3:733-736(1996)。
本文中使用且涵盖许多HVR的叙述(delineation)。Kabat互补决定区(CDR)是以序列变异性为基础的且是最常用的(Kabat et al.,Sequences of Proteins ofImmunological Interest,5th Ed.Public Health Service,National Institutes ofHealth,Bethesda,MD.(1991))。Chothia改为指结构环的位置(Chothia and LeskJ.Mol.Biol.196:901-917(1987))。AbM HVR代表Kabat HVR与Chothia结构环之间的折衷,而且被Oxford Molecular的AbM抗体建模软件所使用。“接触”HVR是以对可获得的复合物晶体结构的分析为基础的。下文记录了这些HVR中每一个的残基。
HVR可包含如下“延伸的HVR”:VL中的24-36或24-34(L1)、46-56或50-56(L2)和89-97或89-96(L3)和VH中的26-35(H1)、50-65或49-65(H2)和93-102、94-102或95-102(H3)。对于这些定义中的每一个,可变域残基是依照Kabat等,见上文编号的。
“框架区”或“FR”残基为除如本文中所定义的高变区残基外的那些可变域残基。
术语“如Kabat中的可变域残基编号方式”或“如Kabat中的氨基酸位置编号方式”及其变化形式是指Kabat等,见上文中用于抗体重链可变域或轻链可变域编辑的编号系统。使用此编号系统,实际的线性氨基酸序列可含有较少的或另外的氨基酸,对应于可变域FR或HVR的缩短或插入。例如, 重链可变域可包含H2残基52后的单一氨基酸插入(依照Kabat的残基52a)和重链FR残基82后的插入残基(例如依照Kabat的残基82a、82b和82c等)。给定抗体的Kabat残基编号方式可通过将抗体序列与“标准”Kabat编号序列比对同源区来确定。
贯穿本说明书,Kabat编号系统一般在提及可变域中的残基(大约是轻链残基1-107和重链残基1-113)时使用(例如,Kabat et al.,Sequences of ImmunologicalInterest.5th Ed.Public Health Service,National Institutes of Health,Bethesda,Md.(1991))。“EU编号系统”或“EU索引”一般在提及免疫球蛋白重链恒定区中的残基时使用(例如,在Kabat et al.,Sequences of Proteins of Immunological Interest,5thEd.Public Health Service,National Institutes of Health,Bethesda,MD(1991)中报告的EU索引,通过提及而将其明确并入本文)。除非本文中另有说明,提及抗体可变域中的残基编号指根据Kabat编号系统的残基编号方式。除非本文中另有说明,提及抗体恒定域中的残基编号指根据EU编号系统的残基编号方式。
根据其重链恒定域的氨基酸序列,抗体(免疫球蛋白)可归入不同的类。免疫球蛋白有五大类:IgA、IgD、IgE、IgG和IgM,并且这些中的几种可以进一步分为亚类(同种型),例如IgG1(包括非A和A同种异型)、IgG2、IgG3、IgG4、IgA1和IgA2。将与不同类的免疫球蛋白对应的重链恒定域分别称作α、δ、ε、γ和μ。不同类的免疫球蛋白的亚基结构和三维构造是公知的,并且一般记载于例如Abbas et al.Cellular and Mol.Immunology,4th ed.(W.B.Saunders,Co.,2000)中。抗体可为通过抗体与一种或多种其它蛋白质或肽的共价或非共价联合形成的较大融合分子的一部分。
根据其恒定域的氨基酸序列,来自任何脊椎动物物种的抗体(免疫球蛋白)的“轻链”可归入两种截然不同的型中的一种,称作卡帕(κ)和拉姆达(λ)。
术语“Fc区”用于定义免疫球蛋白重链的C-端区域,其可通过对完整抗体的木瓜蛋白酶消化来生成。Fc区可为天然序列Fc区或变体Fc区。虽然免疫球蛋白重链Fc区的边界可变化,但是人IgG重链Fc区通常定义为自大约位置Cys226处的氨基酸残基或自大约位置Pro230至Fc区的羧基端的区段。Fc区的C端赖氨酸(残基447,依照EU编号系统)可消除,例如在生产或纯化抗体期间,或通过对编码抗体重链的核酸进行重组工程改造来进行。因此,完整抗体组合物可包括所有K447残基都被消除的抗体群、无一 K447残基被消除的抗体群以及具有有和没有K447残基的抗体的混合物的抗体群。免疫球蛋白的Fc区一般包含两个恒定域CH2域和CH3域,而且任选地,包含CH4域。
除非本文另有说明,免疫球蛋白重链中的残基编号方式是如Kabat等,见上文中的EU索引的编号方式。“如Kabat中的EU索引”是指人IgG1EU抗体的残基编号方式。
本文中的“Fc区链”意指Fc区的两条多肽链之一。
人IgG Fc区的“CH2域”(也称为“Cg2”域)通常自约第231位的氨基酸残基延伸至约第340位的氨基酸残基。CH2域的独特之处在于它没有与另一域紧密配对。而是,有两个N-连接的分支的碳水化合物链介于完整天然IgG分子的两个CH2域之间。推测碳水化合物可提供域-域配对的替代且有助于稳定CH2域。Burton,Molec.Immunol.22:161-206(1985)。本文中的CH2域可为天然序列CH2域或变体CH2域。
“CH3域”包含Fc区中CH2域C端的一段残基(即自IgG的约第341位的氨基酸残基至约第447位的氨基酸残基)。本文中的CH3区可为天然序列CH3域或变体CH3域(例如在其一条链中具有引入的“突出”和在其另一条链中具有相应的引入的“穴”的CH3域;参见美国专利5,821,333,通过引用的方式而将其明确并入本文)。可使用此类变体CH3域来生成多特异性(例如双特异性)抗体,如本文中所描述的。
“铰链区”通常定义为自人IgG1的约Glu216或约Cys226至约Pro230的区段(Burton,Molec.Immunol.22:161-206(1985))。其它IgG同种型的铰链区可通过将第一个和最后一个形成重链间S-S键的半胱氨酸残基置于相同位置而与IgG1序列对比。本文中的铰链区可为天然序列铰链区或变体铰链区。变体铰链区的两条多肽链通常保留每条多肽链的至少一个半胱氨酸残基,从而变体铰链区的两条多肽链可形成两条链间的二硫键。本文中优选的铰链区是天然序列人铰链区,例如天然序列人IgG1铰链区。
“功能性Fc区”具有天然序列Fc区的至少一种“效应器功能”。示例性的“效应器功能”包括C1q结合;补体依赖性细胞毒性(CDC);Fc受体结合;抗体依赖性细胞介导的细胞毒性(ADCC);吞噬;细胞表面受体(例如B细胞受体;BCR)下调等。此类效应器功能一般要求Fc区与结合域(例如抗体可变域)联合,而且可使用本领域中已知的用于评估此类抗体效应器功能的多种 测定法来评估。
“天然序列Fc区”包含与在自然界中找到的Fc区的氨基酸序列相同的氨基酸序列。天然序列人Fc区包括天然序列人IgG1Fc区(非A和A同种异型);天然序列人IgG2Fc区;天然序列人IgG3Fc区;和天然序列人IgG4Fc区;以及它们的天然存在变体。
“变体Fc区”包含由于至少一处氨基酸修饰而与天然序列Fc区有所不同的氨基酸序列。在某些实施方案中,变体Fc区与天然序列Fc区相比或与亲本多肽的Fc区相比具有至少一处氨基酸替代,例如在天然序列Fc区中或在亲本多肽的Fc区中的约1处至约10处氨基酸替代,且优选地约1处至约5处氨基酸替代,例如在天然序列Fc区中或在亲本多肽的Fc区中的约1处至约10处氨基酸替代,且优选地约1处至约5处氨基酸替代。本文中的变体Fc区通常会与天然序列Fc区和/或亲本多肽的Fc区具有例如至少约80%的序列同一性,或与它们具有至少约90%的序列同一性,或与它们具有至少约95%或更多的同一性。
抗体“效应器功能”是指那些可归于抗体Fc区(天然序列Fc区或氨基酸序列变体Fc区)且随抗体同种型而变化的生物学活性。抗体效应器功能的实例包括:C1q结合和补体依赖性细胞毒性(CDC);Fc受体结合;抗体依赖性细胞介导的细胞毒性(ADCC);吞噬作用;细胞表面受体(例如B细胞受体)下调;和B细胞活化。
“抗体依赖性细胞介导的细胞毒性”或“ADCC”是指其中结合至某些细胞毒性细胞(例如天然杀伤(NK)细胞、嗜中性粒细胞和巨噬细胞)上存在的Fc受体(FcR)上的分泌型Ig使得这些细胞毒性效应细胞能够特异性结合携带抗原的靶细胞,随后用细胞毒素杀死靶细胞的细胞毒性形式。介导ADCC的主要细胞,即NK细胞,只表达FcγRIII,而单核细胞表达FcγRI、FcγRII和FcγRIII。Ravetch and Kinet,Annu.Rev.Immunol 9:457-92(1991)第464页表3概述了造血细胞上的FcR表达。为了评估感兴趣分子的ADCC活性,可实施体外ADCC测定法,诸如美国专利5,500,362或5,821,337中所描述的。可用于此类测定法的效应细胞包括外周血单个核细胞(PBMC)和天然杀伤(NK)细胞。可选择地,或另外地,可在体内评估感兴趣分子的ADCC活性,例如在动物模型中,诸如Clynes et al.PNAS(USA)95:652-656(1998)中所披露的。
“人效应细胞”为表达一种或多种FcR并行使效应器功能的白细胞。在某些实施方案中,所述细胞至少表达FcγRIII并行使ADCC效应器功能。介导ADCC的人白细胞的实例包括外周血单个核细胞(PBMC)、天然杀伤(NK)细胞、单核细胞、细胞毒性T细胞和嗜中性粒细胞;一般优选PBMC和NK细胞。效应细胞可从其天然来源分离,例如如本文所述从血液或PBMC分离。
“Fc受体”或“FcR”描述结合抗体Fc区的受体。在一些实施方案中,FcR为天然人FcR。在一些实施方案中,FcR为结合IgG抗体的FcR(γ受体),包括FcγRI、FcγRII和FcγRIII亚类的受体,包括那些受体的等位变体和可变剪接形式。FcγRII受体包括FcγRIIA(“活化受体”)和FcγRIIB(“抑制受体”),它们具有相似的氨基酸序列,区别主要在于其胞质域。活化受体FcγRIIA在其胞质域中含有免疫受体基于酪氨酸的活化基序(ITAM)。抑制受体FcγRIIB在其胞质域中含有免疫受体基于酪氨酸的抑制基序(ITIM)。(参见例如,Annu.Rev.Immunol.15:203-234(1997))。FcRs综述于例如Ravetch and Kinet,Annu.Rev.Immunol 9:457-92(1991);Capel et al.,Immunomethods 4:25-34(1994);andde Haas et al.,J.Lab.Clin.Med.126:330-41(1995)中。术语“FcR”在本文中涵盖其它FcR,包括那些未来要鉴定的。
术语“Fc受体”或“FcR”还包括新生儿受体FcRn,其负责将母体IgG转移至胎儿(Guyer et al.,J.Immunol.117:587(1976)and Kim et al.,J.Immunol.24:249(1994))并调节免疫球蛋白稳态。测量对FcRn的结合的方法是已知的(参见例如,Ghetie and Ward.,Immunol.Today 18(12):592-598(1997);Ghetie et al.,Nature Biotechnology,15(7):637-640(1997);Hinton et al.,J.Biol.Chem.279(8):6213-6216(2004);WO 2004/92219(Hinton et al.)。
可测定人FcRn高亲和力结合多肽与人FcRn的体内结合和血清半衰期,例如在表达人FcRn的经转染的人细胞系或转基因小鼠中,或在施用具有变体Fc区的多肽的灵长类中。WO 2000/42072(Presta)描述了对FcR的结合提高或降低的抗体变体。还可见例如Shieldset al.J.Biol.Chem.9(2):6591-6604(2001)。
“补体依赖性细胞毒性”或“CDC”指在存在补体的情况中对靶细胞的溶解。经典补体途径的激活是由补体系统第一组分(C1q)结合其关联抗原所 结合的抗体(适宜亚类的)起始的。为了评估补体激活,可以实施CDC测定法,例如如Gazzano-Santoro et al.,J.Immunol.Methods 202:163(1996)中所描述的。具有改变的Fc区氨基酸序列(具有变体Fc区的多肽)和增强的或减弱的C1q结合能力的多肽变体记载于例如美国专利6,194,551B1和WO1999/51642。还可参见例如Idusogie et al.J.Immunol.164:4178-4184(2000)。
“亲和力成熟的”抗体为在抗体的一个或多个CDR中具有一处或多处改变、导致该抗体对抗原的亲和力与没有那些改变的亲本抗体相比有所改进的抗体。在一个实施方案,亲和力成熟的抗体具有纳摩尔或甚至皮摩尔量级的对靶抗原的亲和力。可通过本领域已知规程来生成亲和力成熟的抗体。Marks et al.Bio/Technology 10:779-783(1992)描述了通过VH和VL域改组进行的亲和力成熟。以下文献记载了CDR和/或框架残基的随机诱变:Barbas et al.Proc Nat.Acad.Sci,USA 91:3809-3813(1994);Schier et al.Gene 169:147-155(1995);Yelton et al.J.Immunol.155:1994-2004(1995);Jackson et al.,J.Immunol.154(7):3310-9(1995);and Hawkins et al,J.Mol.Biol.226:889-896(1992)。
抗体的“功能性抗原结合位点”为能够结合靶抗原的位点。抗原结合位点的抗原结合亲和力不必与衍生抗原结合位点的亲本抗体一样强,但是结合抗原的能力必须使用已知用于评估抗体对抗原结合的多种方法之任一种可测量。此外,本文中的多价抗体的每个抗原结合位点的抗原结合亲和力不需要定量相同。对于本文中的多聚抗体,可使用超速离心分析来评估功能性抗原结合位点的数目。依照此分析方法,组合不同比率的靶抗原与多聚抗体,并且假设不同数目的功能性结合位点,计算复合物的平均分子量。比较这些理论值与获得的实际实验值以评估功能性结合位点的数目。
具有指定抗体的“生物学特征”的抗体为具有所述抗体的一项或多项将其与结合相同抗原的其它抗体区分的生物学特征的抗体。
为了筛选结合抗原上被感兴趣的抗体结合的表位的抗体,可实施常规的交叉阻断测定法,诸如记载于Antibodies,A Laboratory Manual,Cold Spring HarborLaboratory,Ed Harlow and David Lane(1988)的。
术语“拮抗剂”在本文中使用时指能够中和、阻断、抑制、消除、降低或干扰本发明蛋白质活性(包括其对一种或多种受体的结合(在配体的情况中)或对一种或多种配体的结合(在受体的情况中))分子。拮抗剂包括抗体及其抗原结合片段、蛋白质、肽、糖蛋白、糖肽、糖脂、多糖、寡糖、核酸、生物 有机分子、肽模拟物、药剂及其代谢物、转录和翻译控制序列等。拮抗剂还包括本发明蛋白质的小分子抑制剂和融合蛋白、受体分子和衍生物(其特异性结合蛋白质,由此隔绝它对其靶物的结合)、蛋白质的拮抗性变体、针对本发明蛋白质的反义分子、RNA适体和针对本发明蛋白质的核酶。
“阻断性”抗体或“拮抗性”抗体为抑制或降低其所结合的抗原的生物学活性的抗体。某些阻断性抗体或拮抗性抗体实质性或完全抑制抗原的生物学活性。
术语“抗血管生成疗法”是指可用于抑制血管生成的疗法,其包括施用至少一种如本文中所限定的抗血管生成剂。在另一个实施方案中,抗VEGF抗体是贝伐单抗。
本文中使用的术语“免疫抑制剂”是指作用于抑制或掩盖本文中所治疗哺乳动物的免疫系统的物质。这会包括抑制细胞因子生成、下调或抑制自身抗原表达或掩盖MHC抗原的物质。此类药剂的实例包括2-氨基-6-芳基-5-取代的嘧啶(参见美国专利4,665,077);非类固醇抗炎药(NSAID);更昔洛韦(ganciclovir)、他克莫司(tacrolimus)、糖皮质激素诸如皮质醇(cortisol)或醛固酮(aldosterone)、抗炎剂诸如环氧合酶抑制剂、5-脂氧合酶抑制剂、或白三烯受体拮抗剂;嘌呤拮抗剂,诸如硫唑嘌呤(azathioprine)或霉酚酸吗乙酯(mycophenolate mofetil,MMF);烷化剂,诸如环磷酰胺(cyclophosphamide);溴隐亭(bromocryptine);达扎唑(danazol);氨苯砜(dapsone);戊二醛(如美国专利4,120,649中所述,它掩盖MHC抗原);针对MHC抗原和MHC片段的抗独特型抗体;环孢菌素A;类固醇,诸如皮质类固醇或糖皮质类固醇或糖皮质激素类似物,例如泼尼松(prednisone)、甲基泼尼松龙(methylprednisolone)和地塞米松(dexamethasone);二氢叶酸还原酶抑制剂,诸如甲氨蝶呤(methotrexate)(口服或皮下);羟氯喹(hydroxycloroquine);柳氮磺吡啶(sulfasalazine);来氟米特(leflunomide);细胞因子或细胞因子受体抗体,包括抗干扰素-α、-β或-γ抗体、抗肿瘤坏死因子-α抗体(infliximab或adalimumab)、抗TNF-α免疫黏附素(依那西普(etanercept))、抗肿瘤坏死因子-β抗体、抗白介素-2抗体和抗IL-2受体抗体;抗LFA-1抗体,包括抗CD11a和抗CD18抗体;抗L3T4抗体;异源抗淋巴细胞球蛋白;泛T(pan-T)抗体,优选抗CD3或抗CD4/CD4a抗体;含有LFA-3结合域的可溶性肽(1990年7月26日公布的WO 1990/08187);链激酶(streptokinase);TGF-β;链道酶 (streptodornase);来自宿主的RNA或DNA;FK506;RS-61443;脱氧精胍菌素(deoxyspergualin);雷帕霉素(rapamycin);T细胞受体(Cohen et al.,美国专利5,114,721);T细胞受体片段(Offner et al.,Science,251:430-432(1991);WO 1990/11294;Ianeway,Nature,341:482(1989);和WO 1991/01133);以及T细胞受体抗体(EP 340,109),诸如T10B9。
“非类固醇抗炎药”或“NSAID”的实例是乙酰水杨酸、布洛芬(ibuprofen)、萘普生(naproxen)、吲哚美辛(indomethacin)、舒林酸(sulindac)、托美丁(tolmetin),包括它们的盐和衍生物等。
本文中使用的术语“细胞毒剂”是指抑制或阻止细胞的功能和/或引起细胞破坏的物质。该术语意欲包括放射性同位素(例如211At、131I、125I、90Y、 186Re、188Re、153Sm、212Bi、32P和Lu的放射性同位素)、化疗剂和毒素诸如小分子毒素或细菌、真菌、植物或动物源的酶活性毒素,包括其片段和/或变体。
本文中使用的“生长抑制剂”是指在体外和/或在体内抑制细胞生长的化合物或组合物。因此,生长抑制剂可为显著降低处于S期的细胞的百分比的药剂。生长抑制剂的实例包括阻断细胞周期行进(处于与S期不同的位置)的药剂,诸如诱导G1停滞和M期停滞的药剂。经典的M期阻断剂包括长春花类药物(vincas)(长春新碱(vincristine)和长春碱(vinblastine))、和拓扑异构酶II抑制剂诸如多柔比星(doxorubicin)、表柔比星(epirubicin)、柔红霉素(daunorubicin)、依托泊苷(etoposide)和博来霉素(bleomycin)。那些阻滞G1的药剂也溢出进入S期停滞,例如DNA烷化剂类诸如他莫昔芬(tamoxifen)、泼尼松(prednisone)、达卡巴嗪(dacarbazine)、双氯乙基甲胺(mechlorethamine)、顺铂(cisplatin)、甲氨蝶呤(methotrexate)、5-氟尿嘧啶(5-fluorouracil)和阿糖胞苷(ara-C)。更多信息可参见The Molecular Basis of Cancer,Mendelsohn和Israel编,第1章,题目为“Cell cycle regulation,oncogenes,andantineoplastic drugs”,Murakami等(WB Saunders:Philadelphia,1995),尤其是第13页。
“化疗剂”为可用于治疗癌症的化学化合物。化疗剂的实例包括烷化剂类(alkylating agents),诸如塞替派(thiotepa)和环磷酰胺(cyclophosphamide);磺酸烷基酯类(alkyl sulfonates),诸如白消安(busulfan)、英丙舒凡(improsulfan)和哌泊舒凡(piposulfan);氮丙啶类(aziridines),诸如苯 佐替派(benzodepa)、卡波醌(carboquone)、美妥替派(meturedepa)和乌瑞替派(uredepa);乙撑亚胺类(ethylenimines)和甲基蜜胺类(methylamelamines),包括六甲蜜胺(altretamine)、三乙撑蜜胺(triethylenemelamine)、三乙撑磷酰胺(triethylenephosphoramide)、三乙撑硫代磷酰胺(triethylenethiophosphoramide)和三羟甲蜜胺(trimethylolomelamine);番荔枝内酯类(acetogenin)(尤其是布拉他辛(bullatacin)和布拉他辛酮(bullatacinone));δ-9-四氢屈大麻酚(tetrahydrocannabinol)(屈大麻酚(dronabinol),);β-拉帕醌(lapachone);拉帕醇(lapachol);秋水仙素类(colchicines);白桦脂酸(betulinic acid);喜树碱(camptothecin)(包括合成类似物托泊替康(topotecan)CPT-11(伊立替康(irinotecan),)、乙酰喜树碱、东莨菪亭(scopoletin)和9-氨基喜树碱);苔藓抑素(bryostatin);callystatin;CC-1065(包括其阿多来新(adozelesin)、卡折来新(carzelesin)和比折来新(bizelesin)合成类似物);鬼臼毒素(podophyllotoxin);鬼臼酸(podophyllinic acid);替尼泊苷(teniposide);隐藻素类(cryptophycins)(具体是隐藻素1和隐藻素8);多拉司他汀(dolastatin);duocarmycin(包括合成类似物,KW-2189和CB1-TM1);艾榴塞洛素(eleutherobin);pancratistatin;sarcodictyin;海绵抑素(spongistatin);氮芥类(nitrogen mustards),诸如苯丁酸氮芥(chlorambucil)、萘氮芥(chlornaphazine)、胆磷酰胺(cholophosphamide)、雌莫司汀(estramustine)、异环磷酰胺(ifosfamide)、双氯乙基甲胺(mechlorethamine)、盐酸氧氮芥(mechlorethamine oxide hydrochloride)、美法仑(melphalan)、新氮芥(novembichin)、苯芥胆甾醇(phenesterine)、泼尼莫司汀(prednimustine)、曲磷胺(trofosfamide)、尿嘧啶氮芥(uracil mustard);亚硝脲类(nitrosoureas),诸如卡莫司汀(carmustine)、氯脲菌素(chlorozotocin)、福莫司汀(fotemustine)、洛莫司汀(lomustine)、尼莫司汀(nimustine)和雷莫司汀(ranimustine);抗生素类,诸如烯二炔类抗生素(enediyne)(例如加利车霉素(calicheamicin),尤其是加利车霉素γ1I和加利车霉素ωI1(参见例如Agnew,Chem Intl.Ed.Engl.,33:183-186(1994));蒽环类抗生素(dynemicin),包括dynemicin A;埃斯波霉素(esperamicin);以及新制癌素(neocarzinostatin)发色团和相关色蛋白烯二炔类抗生素发色团)、阿克拉霉素(aclacinomycin)、放线菌素(actinomycin)、氨茴霉素(anthramycin)、偶氮丝氨酸(azaserine)、博来霉素(bleomycin)、放线菌素C(cactinomycin)、carabicin、洋红霉素(carminomycin)、嗜癌霉素(carzinophilin)、色霉素(chromomycin)、放线菌素D(dactinomycin)、柔红霉素(daunorubicin)、地托比星(detorubicin)、6-重氮基-5-氧代-L-正亮氨酸、多柔比星(doxorubicin)(包括吗啉代-多柔比星、氰基吗啉代-多柔比星、2-吡咯代-多柔比星、盐酸多柔比星脂质体注射剂和脱氧多柔比星)、表柔比星(epirubicin)、依索比星(esorubicin)、伊达比星(idarubicin)、麻西罗霉素(marcellomycin)、丝裂霉素类(mitomycins)诸如丝裂霉素C、霉酚酸(mycophenolicacid)、诺拉霉素(nogalamycin)、橄榄霉素(olivomycin)、培洛霉素(peplomycin)、potfiromycin、嘌呤霉素(puromycin)、三铁阿霉素(quelamycin)、罗多比星(rodorubicin)、链黑菌素(streptonigrin)、链佐星(streptozocin)、杀结核菌素(tubercidin)、乌苯美司(ubenimex)、净司他丁(zinostatin)、佐柔比星(zorubicin);抗代谢物类,诸如甲氨蝶呤、吉西他滨替加氟(tegafur)卡培他滨(capecitabine)埃博霉素(epothilone)和5-氟尿嘧啶(5-FU);叶酸类似物,诸如二甲叶酸(denopterin)、甲氨蝶呤、蝶酰三谷氨酸(pteropterin)、三甲曲沙(trimetrexate);嘌呤类似物,诸如氟达拉滨(fludarabine)、6-巯基嘌呤(mercaptopurine)、硫咪嘌呤(thiamiprine)、硫鸟嘌呤(thioguanine);嘧啶类似物,诸如安西他滨(ancitabine)、阿扎胞苷(azacitidine)、6-氮尿苷、卡莫氟(carmofur)、阿糖胞苷(cytarabine)、双脱氧尿苷(dideoxyuridine)、去氧氟尿苷(doxifluridine)、依诺他滨(enocitabine)、氟尿苷(floxuridine);雄激素类,诸如卡鲁睾酮(calusterone)、丙酸屈他雄酮(dromostanolone propionate)、表硫雄醇(epitiostanol)、美雄烷(mepitiostane)、睾内酯(testolactone);抗肾上腺类(anti-adrenals),诸如氨鲁米特(aminoglutethimide)、米托坦(mitotane)、曲洛司坦(trilostane);叶酸补充剂,诸如亚叶酸(folinic acid);醋葡醛内酯(aceglatone);醛磷酰胺糖苷(aldophosphamideglycoside);氨基乙酰丙酸(aminolevulinic acid);恩尿嘧啶(eniluracil);安吖啶(amsacrine);bestrabucil;比生群(bisantrene);依达曲沙(edatraxate);地磷酰胺(defofamine);地美可辛(demecolcine);地吖醌(diaziquone);elfornithine;依利醋铵(elliptinium acetate);依托格鲁(etoglucid);硝酸镓;羟脲(hydroxyurea);香菇多糖(lentinan);氯尼达明(lonidainine);美登木素生物碱类(maytansinoids),诸如美登素(maytansine)和安丝菌素(ansamitocin);米托胍腙(mitoguazone);米托蒽醌(mitoxantrone);莫哌达醇 (mopidamol);二胺硝吖啶(nitracrine);喷司他丁(pentostatin);蛋氨氮芥(phenamet);吡柔比星(pirarubicin);洛索蒽醌(losoxantrone);2-乙基酰肼(ethylhydrazide);丙卡巴肼(procarbazine);多糖复合物(JHS Natural Products,Eugene,OR);雷佐生(razoxane);根霉素(rhizoxin);西索菲兰(sizofiran);螺旋锗(spirogermanium);细交链孢菌酮酸(tenuazonic acid);三亚胺醌(triaziquone);2,2’,2”-三氯三乙胺;单端孢菌素类(trichothecenes)(尤其是T-2毒素、疣孢菌素(verrucarin)A、杆孢菌素(roridin)A和蛇行菌素(anguidin));乌拉坦(urethan);长春地辛(vindesine) 达卡巴嗪(dacarbazine);甘露醇氮芥(mannomustine);二溴甘露醇(mitobronitol);二溴卫矛醇(mitolactol);哌泊溴烷(pipobroman);gacytosine;阿糖胞苷(arabinoside)(“Ara-C”);塞替派(thiotepa);类紫杉醇(taxoids),例如帕利他塞(paclitaxel)清蛋白改造的纳米颗粒剂型帕利他塞(ABRAXANETM)和多西他塞(doxetaxel)苯丁酸氮芥(chlorambucil);6-硫鸟嘌呤(thioguanine);巯基嘌呤(mercaptopurine);甲氨蝶呤(methotrexate);铂类似物,诸如顺铂(cisplatin)和卡铂(carboplatin);长春碱(vinblastine)铂;依托泊苷(etoposide)(VP-16);异环磷酰胺(ifosfamide);米托蒽醌(mitoxantrone);长春新碱(vincristine)奥沙利铂(oxaliplatin);亚叶酸(leucovorin);长春瑞滨(vinorelbine)能灭瘤(novantrone);依达曲沙(edatrexate);道诺霉素(daunomycin);氨基蝶呤(aminopterin);伊班膦酸盐(ibandronate);拓扑异构酶抑制剂RFS 2000;二氟甲基鸟氨酸(DMFO);视黄酸类(retinoids),诸如视黄酸(retinoic acid);任何上述物质的药用盐、酸或衍生物;以及两种或更多种上述物质的组合,诸如CHOP(环磷酰胺、多柔比星、长春新碱和泼尼松龙联合疗法的缩写)和FOLFOX(奥沙利铂(ELOXATIN)联合5-FU和亚叶酸的治疗方案的缩写)。
该定义还包括作用为调节、降低、阻断、或抑制可促进癌生长的激素效果的抗激素剂,且常常是系统或全身治疗的形式。它们可为激素本身。实例包括抗雌激素类和选择性雌激素受体调节剂类(SERM),包括例如他莫昔芬(tamoxifen)(包括他莫昔芬)、雷洛昔芬(raloxifene)屈洛昔芬(droloxifene)、4-羟基他莫昔芬、曲沃昔芬(trioxifene)、那洛昔芬(keoxifene)、LY117018、奥那司酮(onapristone)和托瑞米芬(toremifene) 抗孕酮类;雌激素受体下调剂类(ERD);功能为抑制或关闭卵巢的药剂,例如促黄体生成激素释放激素(LHRH)激动剂,诸如醋酸亮丙瑞林(leuprolide acetate)(和)、醋酸戈舍瑞林(goserelinacetate)、醋酸布舍瑞林(buserelin acetate)和曲普瑞林(triptorelin);其它抗雄激素类,诸如氟他米特(flutamide)、尼鲁米特(nilutamide)和比卡米特(bicalutamide);以及抑制在肾上腺中调节雌激素生成的芳香酶的芳香酶抑制剂,诸如例如4(5)-咪唑、氨鲁米特(aminoglutethimide)、醋酸甲地孕酮(megestrol acetate)依西美坦(exemestane)福美坦(formestane)、法倔唑(fadrozole)、伏罗唑(vorozole)来曲唑(letrozole)和阿那曲唑(anastrozole)另外,化疗剂的这种定义包括二膦酸盐类(bisphosphonates),诸如氯膦酸盐(clodronate)(例如或)、依替膦酸钠(etidronate) NE-58095、唑来膦酸/唑来膦酸盐(zoledronicacid/zoledronate) 阿伦膦酸盐(alendronate)帕米膦酸盐(pamidronate)替鲁膦酸盐(tiludronate)或利塞膦酸盐(risedronate)以及曲沙他滨(troxacitabine)(1,3-二氧戊环核苷胞嘧啶类似物);反义寡核苷酸,具体是抑制牵涉异常(abherant)细胞增殖的信号传导途经中的基因表达的反义寡核苷酸,诸如例如PKC-α、Raf、H-Ras和表皮生长因子受体(EGF-R);疫苗,诸如疫苗和基因疗法疫苗,例如疫苗、疫苗和疫苗;拓扑异构酶1抑制剂(例如);rmRH(例如);二甲苯磺酸拉帕替尼(lapatinib ditosylate)(ErbB-2和EGFR双重酪氨酸激酶小分子抑制剂,也称为GW572016);COX-2抑制剂诸如塞来考昔(celecoxib)(4-(5-(4-甲基苯基)-3-(三氟甲基)-1H-吡唑-1-基)苯磺酰胺;以及任何上述物质的药用盐、酸或衍生物。
术语“细胞因子”为由一种细胞群体释放的作为细胞间介导物对另一细胞起作用的蛋白质的通称。此类细胞因子的实例是淋巴因子、单核因子和传统的多肽激素。细胞因子中包括生长激素,诸如人生长激素、N-甲硫氨酰人生长激素和牛生长激素;甲状旁腺素;甲状腺素;胰岛素;胰岛素原;松弛素;松弛素原;糖蛋白激素,诸如促卵泡激素(FSH)、促甲状腺激素(TSH)和黄体生成素(LH);肝生长因子;成纤维细胞生长因子;促乳素;胎盘催乳 激素;肿瘤坏死因子-α和-β;Mullerian抑制物质;小鼠促性腺激素相关肽;抑制素;激活蛋白;血管内皮生长因子(例如VEGF、VEGF-B、VEGF-C、VEGF-D、VEGF-E);胎盘衍生的生长因子(PlGF);血小板衍生的生长因子(PDGF,例如PDGFA、PDGFB、PDGFC、PDGFD);整联蛋白;血小板生成素(TPO);神经生长因子,诸如NGF-α;血小板生长因子;转化生长因子(TGF),诸如TGF-α和TGF-β;胰岛素样生长因子-I和-II;红细胞生成素(EPO);骨诱导因子;干扰素诸如干扰素-α、-β和-γ、集落刺激因子(CSF)诸如巨噬细胞-CSF(M-CSF);粒细胞-巨噬细胞-CSF(GM-CSF);以及粒细胞-CSF(G-CSF);白介素(IL),诸如IL-1、IL-1α、IL-1β、IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-8、IL-9、IL-10、IL-11、IL-12、IL-13、IL-14、IL-15、IL-16、IL-17、IL-18、IL-19、IL-20、IL-30;分泌珠蛋白(secretoglobin)/子宫珠蛋白(uteroglobin);制瘤蛋白M(OSM);肿瘤坏死因子,诸如TNF-α或TNF-β;以及其它多肽因子,包括LIF和kit配体(KL)。本文中使用的术语细胞因子包括来自天然来源或来自重组细胞培养物的蛋白质和天然序列细胞因子的生物学活性等同物。
“受试者”或“患者”意指哺乳动物,其包括但不限于人或非人类哺乳动物,诸如牛、马、犬、羊或猪。在一个实施方案中,所述受试者指人。在另一个实施方案中,所述受试者诊断患有癌症。
为了治疗/处理的目的,“哺乳动物”是指归入哺乳类的任何动物,包括人,家畜和牲畜,以及动物园、运动或宠物动物,诸如犬、马、猫、绵羊、猪、牛等。优选地,所述哺乳动物指人。
“病症”为任何会受益于治疗的状况。这包括慢性和急性病症或疾病,包括那些使哺乳动物倾向于所讨论病症的病理状况。本文中要治疗的病症的非限制性实例包括任何形式的肿瘤、良性和恶性肿瘤;血管化的肿瘤;肥大;白血病和淋巴样恶性肿瘤;神经元、神经胶质、星形胶质细胞、下丘脑和其它腺、巨噬细胞、上皮、基质和囊胚腔病症;以及炎性、血管生成性和免疫学病症,源自不适当的、异常的、过度的和/或病理性的血管化和/或血管通透性的血管病症。
本文中使用的“治疗/处理”是指试图改变所治疗个体或细胞的自然过程的临床干预,并且可为了预防或在临床病理学过程期间实施。治疗的期望效果包括预防疾病的发生或复发、缓解症状、削弱疾病的任何直接或间接病 理学后果、预防转移、减缓疾病进展的速率、改善或减轻疾病状态以及免除或改善预后。在一些实施方案中,使用本发明的方法和组合物来延迟疾病或病症的形成或减缓疾病或病症的进展。
术语“有效量”或“治疗有效量”是指在哺乳动物中有效治疗疾病或病症的药物量。在癌症的情况中,药物的有效量可减少癌细胞数目;缩小肿瘤大小;抑制(即一定程度地减缓,且通常停止)癌细胞浸润到周围器官中;抑制(即一定程度地减缓,且通常停止)肿瘤转移;一定程度地抑制肿瘤生长;和/或一定程度地减轻与病症有关的一种或多种症状。就药物可预防癌细胞生长和/或杀死现有癌细胞的程度而言,其可为细胞抑制的和/或细胞毒性的。对于癌症疗法,体内效力可例如通过评估存活持续时间、疾病进展前时间(TTP)、响应率(RR)、响应的持续时间和/或生命质量来测量。
“减少或抑制”指与参照相比降低或减少活性、功能和/和量。在某些实施方案中,“减少或抑制”意指引起总体降低20%或更多的能力。在另一个实施方案中,“减少或抑制”意指引起总体降低50%或更多的能力。在再一个实施方案中,“减少或抑制”意指引起总体降低75%、85%、90%、95%或更多的能力。减少或抑制可指被治疗的病症的症状、转移瘤的存在或大小、原发肿瘤的大小或血管生成病症中血管的大小或数目。
本文使用的对治疗具有抗性的癌症(细胞和/或肿瘤)包括对治疗不响应和/或降低对治疗产生显著响应(例如,部分响应和/或完全响应)的能力的癌症。抗性可为在治疗方法过程中产生的获得性抗性。在一些实施方案中,所述获得性抗性为耐药性。对治疗的耐药性包括对治疗暂时性和/或可逆性抗性,其在治疗方法间断后能够重新获得对治疗的敏感性。在一些实施方案中,所述获得性抗性为永久性抗性。对治疗永久性抗性包括遗传变化赋予的抗药性。
本文使用的对治疗具有敏感性的癌症包括可响应和/或能够产生显著响应(例如,部分响应和/或完全响应)的癌症。
确定评估获得对治疗的抗性和/或保持对治疗的敏感性的方法是本领域已知的。获得抗性和/或保持敏感性的变化诸如耐药性可通过测定耐药性耐药株的生长进行评估。获得抗性和/或保持敏感性的变化诸如永久性抗性可通过测定耐药性扩大的耐药株的生长进行评估。此外,获得抗性和/或保持敏感性的变化例如可通过评估对治疗的响应(例如,部分响应和完全响应)进 行体内评估。获得抗性和/或保持敏感性的变化可基于个体人群中对治疗的响应的变化,例如部分响应和完全响应的数目。
术语“癌症”和“癌性”是指或描述哺乳动物中特征通常为细胞生长不受调节的生理学状况。癌症的实例包括但不限于癌瘤(carcinoma)、淋巴瘤(lymphoma)、母细胞瘤(blastoma)、肉瘤(sarcoma)和白血病(leukemia)或淋巴样恶性肿瘤(lymphoidmalignancies)。此类癌症的更具体实例包括肾癌(kidney/renal cancer)、乳腺癌(breastcancer)、结肠癌(colon cancer)、直肠癌(rectal cancer)、结肠直肠癌(colorectalcancer)、肺癌(lung cancer)(包括小细胞肺癌(small-cell lung cancer)、非小细胞肺癌(non-small cell lung cancer)、肺的腺癌和肺的鳞癌)、鳞状细胞癌(squamous cellcancer)(例如上皮鳞状细胞癌(epithelial squamous cell cancer))、宫颈癌(cervicalcancer)、卵巢癌(ovarian cancer)、前列腺癌(prostate cancer)、肝癌(liver cancer)、膀胱癌(bladder cancer)、腹膜癌(cancer of the peritoneum)、肝细胞癌(hepatocellular cancer)、胃癌(gastric or stomach cancer)(包括胃肠癌(gastrointestinal cancer))、胃肠基质瘤(gastrointestinal stromal tumors,GIST)、胰腺癌(pancreatic cancer)、头颈癌(head and neck cancer)、成胶质细胞瘤(glioblastoma)、成视网膜细胞瘤(retinoblastoma)、星形细胞瘤(astrocytoma)、泡膜细胞瘤(thecomas)、男性细胞瘤(arrhenoblastomas)、肝瘤(hepatoma)、血液学恶性肿瘤(hematologic malignancies)(包括非何杰金(Hodgkin)氏淋巴瘤(NHL)、多发性骨髓瘤(multiple myeloma)和急性血液学恶性肿瘤(acute hematologic malignancies))、子宫内膜癌或子宫癌(endometrial/uterine carcinoma)、子宫内膜异位症(endometriosis)、纤维肉瘤(fibrosarcomas)、绒毛膜癌(choriocarcinoma)、唾液腺癌(salivary glandcarcinoma)、外阴癌(vulval cancer)、甲状腺癌(thyroid cancer)、食管癌(esophagealcarcinomas)、肝癌(hepatic carcinoma)、肛门癌(anal carcinoma)、阴茎癌(penilecarcinoma)、鼻咽癌(nasopharyngeal carcinoma)、喉癌(laryngeal carcinomas)、卡波西(Kaposi)氏肉瘤、黑素瘤、皮肤癌、许旺氏细胞瘤(Schwannoma)、少突神经胶质瘤(oligodendroglioma)、成神经细胞瘤(neuroblastomas)、横纹肌肉瘤(rhabdomyosarcoma)、骨源性肉瘤(osteogenic sarcoma)、平滑肌肉瘤(leiomyosarcomas)、尿道癌(urinary tract carcinomas)、甲状腺癌(thyroidcarcinomas)、维尔姆斯(Wilm)氏肿瘤、以及B细胞淋巴瘤(包括低级/滤泡性非何杰金氏淋巴瘤(NHL);小淋巴细胞性(SL)NHL;中级/滤 泡性NHL;中级弥漫性NHL;高级成免疫细胞性NHL;高级成淋巴细胞性NHL;高级小无核裂细胞性NHL;贮积病(bulky disease)NHL;套细胞淋巴瘤;AIDS相关淋巴瘤和瓦尔登斯特伦氏(Waldenstrom)巨球蛋白血症);慢性淋巴细胞性白血病(CLL);急性成淋巴细胞性白血病(ALL);毛细胞性白血病;慢性成髓细胞性白血病和移植后淋巴增殖性病症(PTLD);以及与瘢痣病(phakomatoses)、水肿(诸如与脑肿瘤有关的)、和梅格斯氏(Meigs)综合征有关的异常血管增殖。
本文中使用的“肿瘤”是指所有新生物细胞生长和增殖,无论是恶性的或是良性的,以及所有癌前的和癌性的细胞和组织。
所要治疗的新生物病症的实例包括但不限于那些在本文中在术语“癌症”和“癌性”下描述的。经得起用拮抗剂治疗的非赘生性疾病包括但不限于例如不期望的或异常的肥大(hypertrophy)、关节炎(arthritis)、类风湿性关节炎(rheumatoid arthritis)(RA)、银屑病(psoriasis)、银屑病斑块(psoriatic plaque)、结节病(sarcoidosis)、动脉粥样硬化(atherosclerosis)、动脉粥样硬化斑块(atherosclerotic plaque)、由心肌梗塞引起的水肿(edema from myocardial infarction)、糖尿病性和其它增殖性视网膜病包括早产儿视网膜病(retinopathy of prematurity)、晶状体后纤维组织增生(retrolentalfibroplasia)、新血管性青光眼(neovascular glaucoma)、年龄相关黄斑变性(age-related macular degeneration)、糖尿病性黄斑水肿(diabetic macular edema)、角膜新血管形成(corneal neovascularization)、角膜移植片新血管形成(corneal graftneovascularization)、角膜移植片排斥(corneal graft rejection)、视网膜/脉络膜新血管形成(retinal/choroidal neovascularization)、眼角的新血管形成(发红(rubeosis))、眼新血管疾病(ocular neovascular disease)、血管再狭窄(vascularrestenosis)、动静脉畸形(arteriovenous malformations)(AVM)、脑脊膜瘤(meningioma)、血管瘤(hemangioma)、血管纤维瘤(angiofibroma)、甲状腺增生(thyroidhyperplasias)(包括格雷夫斯(Grave)氏病)、角膜和其它组织移植、慢性炎症、肺炎、急性肺损伤/ARDS、败血症(sepsis)、原发性肺动脉高压(primary pulmonary hypertension)、恶性肺积液(malignant pulmonary effusion)、脑水肿(cerebral edema)(例如与急性中风/闭合性头部损伤/外伤有关的)、滑膜炎症(synovial inflammation)、RA中的血管翳(pannus)形成、骨化性肌炎(myositis ossificans)、肥大性骨形成(hypertropic boneformation)、骨关节炎 (osteoarthritis)(OA)、顽固性腹水(refractory ascites)、多囊卵巢病(polycystic ovarian disease)、子宫内膜异位症(endometriosis)、第三空间流体病(3rd spacing of fluid diseases)(胰腺炎、间隔综合征(compartment syndrome)、烧伤、肠病)、子宫纤维瘤(uterine fibroids)、早产(premature labor)、慢性炎症诸如IBD(克罗恩(Crohn)氏病和溃疡性结肠炎)、肾同种异体移植物排斥(renal allograftrejection)、炎性肠病、肾病综合征(nephrotic syndrome)、不期望的或异常的组织块生长(非癌症的)、肥胖症(obesity)、脂肪组织肿块生长(adipose tissue mass growth)、血友病性关节(hemophilic joint)、肥厚性瘢痕(hypertrophic scar)、毛发生长的抑制、奥-韦二氏(Osler-Weber)综合征、脓性肉芽肿晶状体后纤维组织增生(pyogenic granulomaretrolental fibroplasias)、硬皮病(scleroderma)、沙眼(trachoma)、血管粘连(vascular adhesion)、滑膜炎(synovitis)、皮炎(dermatitis)、先兆子痫(preeclampsia)、腹水(ascites)、心包积液(pericardial effusion)(诸如与心包炎(pericarditis)有关的)和胸腔积液(pleural effusion)。
术语“癌症疗法”是指可用于治疗癌症的疗法。术语“抗新生物组合物”是指用于治疗癌症的组合物,所述组合物包含至少一种活性治疗剂,例如,“抗癌剂”。治疗剂(抗癌剂)的实例包括但不限于例如化疗剂、生长抑制剂、细胞毒剂、在放射疗法中使用的药剂、抗血管生成剂、凋亡剂、抗微管蛋白剂、毒素和用于治疗癌症的其它药剂,例如,抗VEGF中和抗体、VEGR拮抗剂、抗HER-2抗体(anti-HER-2)、抗CD20抗体(anti-CD20)、表皮生长因子受体(EGFR)拮抗剂(例如,酪氨酸激酶抑制剂)、HER1/EGFR抑制剂、厄洛替尼(erlotinib)COX-2抑制剂(例如,塞来考昔(celecoxib))、干扰素、细胞因子、与下列靶标ErbB2、ErbB3、ErbB4或VEGF受体中的一种或多种结合的拮抗剂(例如中和性抗体)、血小板衍生的生长因子(PDGF)和/或干细胞因子(SCF)的受体酪氨酸激酶抑制剂(例如,甲磺酸伊马替尼(Novartis))、TRAIL/Apo2以及其它生物活性和有机化学剂等,以及它们的任意组合。
术语“诊断”在本文中用于指鉴定分子或病理状态、疾病或状况,诸如鉴定癌症或指鉴定可能受益于具体治疗方案的癌症患者。在一个实施方案中,诊断是指鉴定肿瘤的具体类型。在再一个实施方案中,诊断是指鉴定受试者中对AKT抑制剂具有抗性的癌细胞。
术语“预后”在本文中用于指预测来自抗癌疗法的临床益处的可能性。
术语“预测”在本文中用于指患者会有利地或不利地响应具体抗癌疗法的可能性。在一个实施方案中,预测涉及那些响应的程度。在一个实施方案中,预测涉及治疗(例如用具体治疗剂进行的治疗)后患者是否会存活或改善且某段时间没有疾病复发和/或患者会这样的概率。
“pAKT分布”是指在给定样品中AKT的活化或磷酸化(“pAKT”)的水平相比于非活化或非磷酸化的AKT水平。在一个实例中,所述样品为肿瘤细胞。pAKT分布可用比例(例如pAKT在肿瘤细胞中的量除以非磷酸化的AKT在相同类型的细胞或在非肿瘤细胞中的量)或减法(例如pAKT在肿瘤细胞中的量减去非磷酸化的AKT在相同类型的细胞或在非肿瘤细胞中的量)的方式来表示。pAKT分布还可以如下方式来表示:通过测量AKT的磷酸化下游靶标(例如pGSK或PRAS40)的量获得的活化途径的水平。“高pAKT分布”是指全部AKT在样品中的活化或磷酸化水平高于基线值。在一个实例中,所述基线值为针对给定细胞类型的pAKT的基本水平。在另一个实例中,所述基线值为在给定样品细胞群体中的pAKT的平均值或平均水平。在另一个实例中,“高pAKT分布”是指当相比于来自相同哺乳动物或患者群体的相同类型的平均正常的、健康的(例如非肿瘤性)细胞而言,过表达或在细胞中具有增多的磷酸化或活化的AKT的肿瘤细胞。所述pAKT分布还可用于与其它标志物(例如PTEN损失(loss)、突变为PI3K、Kras或Braf激酶或FOXO3定位分布)结合以预测AKT抑制剂的效能。
在一个实施方案中,AKT或PRAS40突变状态还可与的其它标志物(例如PTEN状态(例如低或缺失)、突变为PI3K、Kras或Braf激酶或FOXO3定位分布)或HER2状态联合使用以预测AKT抑制剂的效能或癌细胞对AKT抑制剂的抗性。
测量AKT活化水平和pAKT在样品中的量的方法是本领域已知的。例如,可使用免疫沉淀测定诸如AKT活性测定试剂盒(购自San Francisco,CA)。在另一个实例中,可使用Western印迹测定,诸如AKT Western印迹测定试剂盒(购自Cell SignalingTechnology,Danvers,MA)。已知用于测量pAKT水平的其它测定形式包括化学发光关联的免疫吸附测定,参见Cicenas,J,et.al.,“Increased level of phosphorylated aktmeasured by chemiluminescence-linked immunosorbent assay is a predictor ofpoor prognosis in primary breast cancer overexpressing ErbB-2,”BreastCan.Res.,7(4),R394,2005。可使用的其它测定为可获得的,例如获自AlphaScreenSureFire Akt 1(p-Thr308)测定试剂盒(购自Perkin Elmer,Waltham,MA)。
确定PI3K突变的存在的方法是本领域中已知的。例如,使用实时PCR针对在PIK3CA基因中特异性突变(外显子9和20以及H1047R或H1047L突变)的检测的测定是已知的(购自Qiagen,Valencia,CA)。
核酸可为例如基因组DNA、由基因组DNA转录的RNA或由RNA产生的cDNA。核酸可由脊椎动物例如哺乳动物获得。认为核酸“衍生自”具体来源,条件是其直接由该来源获得或其为在该来源中发现的核酸副本。
核酸和氨基酸序列的变异可通过本领域技术人员已知的某些方法来检测。所述方法包括但不限于DNA序列测定;引物延伸测定,包括等位基因特异性核苷酸掺入测定和等位基因特异性引物延伸测定(例如等位基因特异性PCR、等位基因特异性连接酶链反应(LCR)和gap-LCR);等位基因特异性寡核苷酸杂交测定(例如寡核苷酸连接测定);剪切保护测定,其中来自剪切剂的保护用于检测核酸双链体中错配的碱基;MutS蛋白结合分析;电泳分析法,其比较变异的和野生型核酸分子的迁移率;变性梯度凝胶电泳法(DGGE,如在例如Myerset al.(1985)Nature 313:495中);在错配碱基对的RNase剪切的分析;异源双链体DNA的化学或酶剪切的分析;质谱法(例如MALDI-TOF);遗传咬合分析(GBA);5'核酸酶测定(例如);以及采用分子指示标记的测定。这些方法中的某些将在如下作进一步详细地讨论。
靶标核酸中变异的检测可通过使用本领域熟知的技术进行分子克隆和靶标核酸序列测定来完成。可选择地,扩增技术诸如聚合酶链式反应(PCR)可用于直接由来自肿瘤组织的基因组DNA制备来扩增靶标核酸序列。然后可确定所述扩增序列的核酸序列并由此鉴别变异。扩增技术在本领域中是熟知的,例如聚合酶链式反应描述于Saiki et al.,Science 239:487,1988;美国专利4,683,203和4,683,195。
本领域已知的连接酶链反应还可用于扩增靶标核酸序列。参见例如Wu et al.,Genomics 4:560-569(1989)。此外,已知为等位基因特异性PCR的技术还可用于检测变异(例如替换)。参见例如Ruano and Kidd(1989)Nucleic Acids Research 17:8392;McClayet al.(2002)Analytical Biochem.301:200-206。在该技术的某些实施方案中,使用等位基因特异性引物,其中所述引物的3’末端 核苷酸与靶标核酸中的具体变异互补(即能够特异性碱基配对)。如果并未存在具体变异,则不能观察到扩增产物。扩增受阻突变体系(ARMS)还可用于检测变异(例如替换)。ARMS描述于例如欧洲专利申请公开0332435和Newton et al.,Nucleic Acids Research,17:7,1989。
用于检测变异(例如替换)的其它方法包括但不限于(1)等位基因特异性核苷酸掺入测定,诸如单一碱基延伸测定(参见例如Chen et al.(2000)Genome Res.10:549-557;Fan et al.(2000)Genome Res.10:853-860;Pastinen et al.(1997)Genome Res.7:606-614;和Ye et al.(2001)Hum.Mut.17:305-316);(2)等位基因特异性引物延伸测定(参见例如Ye et al.(2001)Hum.Mut.17:305-316;和Shen et al.Genetic Engineering News,vol.23,Mar.15,2003),包括等位基因特异性PCR;(3)5’核酸酶测定(参见例如De La Vegaet al.(2002)BioTechniques 32:S48-S54(描述测定);Ranade et al.(2001)Genome Res.11:1262-1268;和Shi(2001)Clin.Chem.47:164-172);(4)采用分子指示标记的测定(参见例如Tyagi et al.(1998)Nature Biotech.16:49-53;和Mhlanga et al.(2001)Methods 25:463-71);以及(5)寡核苷酸连接测定(参见例如Grossman et al.(1994)Nuc.Acids Res.22:4527-4534;美国专利申请公开2003/0119004A1;PCT国际公开WO01/92579A2;以及美国专利6,027,889)。
还可通过错配检测方法来检测变异。错配为并非100%互补的杂交核酸双链体。总体互补的缺乏可能是由于缺失、插入、倒位(inversions)或替换。错配检测方法的一个实例为错配修复检测(MRD)测定,其描述于例如Faham et al.,Proc.Natl Acad.Sci.USA 102:14717-14722(2005)和Faham et al.,Hum.Mol.Genet.10:1657-1664(2001)中。错配剪切技术的另外的实例为RNase保护方法,其详细描述于Winter et al.,Proc.Natl.Acad.Sci.USA,82:7575,1985和Myers et al.,Science 230:1242,1985中。例如,本发明的方法可包括使用标记的核糖核酸探针,其与人类野生型靶标核酸互补。所述核糖核酸探针和来自组织样品的靶标核酸一起退火(杂交)且随后使用酶核糖核酸酶A消化,所述酶能够检测双链RNA结构的某些错配。如果由核糖核酸酶A检测到错配,则其在错配位点剪切。因此,当退火的RNA制品在电泳凝胶基质上分离时,如果已经检测到错配且由核糖核酸酶A剪切,则会观察到RNA产物,其小于针对核糖核酸探针的全长双链RNA以及mRNA或DNA。核糖核酸探针不需要为所述靶标核酸的全长,但是可为靶标核酸的部分,条件是其涵盖可能具有变异的位置。
以相似的方式,DNA探针可用于检测错配,例如通过酶或化学剪切,参见例如Cotton et al.,Proc.Natl.Acad.Sci.USA,85:4397,1988;和Shenk et al.,Proc.Natl.Acad.Sci.USA,72:989,1975。可选择地,错配可通过在错配的双链体相对于配对的双链体的电泳迁移率中的位移来检测,参见例如Cariello,Human Genetics,42:726,1988。使用核糖核酸探针或DNA探针,被怀疑包括变异的所述靶标核酸可在杂交之前扩增。靶标核酸的变化还可使用Southern杂交来检测,尤其是当所述变化为大片段重排(grossrearrangement),诸如缺失和插入。
对于靶标核酸或周围标记基因的限制性内切酶片段长度多态性(RFLP)探针可用于检测变异例如插入或缺失。插入和缺失还可通过靶标核酸的克隆、序列测定和扩增来检测。单链构象多态性(SSCP)分析还可用于检测等位基因的碱基变化变异。参见例如Oritaet al.,Proc.Natl.Acad.Sci.USA86:2766-2770,1989和Genomics,5:874-879,1989。
本发明的另一个方面提供了可在所述方法中使用的阵列。在一个实施方案中,本发明的阵列包括用于检测变异的单独的核酸分子或核酸分子集合。例如,本发明的阵列可包括一系列分散放置的单独的等位基因特异性寡核苷酸或等位基因特异性寡核苷酸组。用于将核酸附着于固体基质诸如载玻片上的若干技术在本领域中是公知的。一种方法为将含有能够附着于固体基质上的反应性部分的修饰的碱基或类似物掺入至合成的核酸分子中,所述反应性部分诸如氨基、氨基的衍生基团或具有正电荷的另外的基团。然后使得合成的产物与固体基质接触,所述固体基质诸如涂覆有醛基或其它反应基团的载玻片。所述醛基或其它反应基团将形成与扩增产物上的反应性部分的共价连接,其将会共价附着于载玻片上。其它方法诸如使用氨基丙基甲硅烷表面化学的方法在本领域中也是已知的。
任何上述方法的生物样品可使用本领域技术人员已知的某些方法来获得。生物样品可由脊椎动物具体为哺乳动物获得。活组织检查通常用于获得肿瘤组织的代表性切片。可选择地,肿瘤细胞可间接地以已知的或认为含有待研究的肿瘤细胞的组织或液体的形式获得。例如,肺癌病灶的样品可通过切除术、支气管镜检查法、细针抽吸、支气管刷检获得或由痰、胸膜液或血液获得。靶标核酸(或编码的多肽)的变异可由肿瘤样品或其它本体样品诸如 尿、痰或血浆检测。(癌细胞由肿瘤脱落且出现在上述本体样品中。)通过筛选所述本体样品,可针对疾病诸如癌症实现简单的早期诊断。此外,治疗进程可通过针对靶标核酸(或编码的多肽)中的变异来测试所述本体样品而更容易地监测。此外,用于使得针对肿瘤细胞的组织制品富集的方法在本领域中是已知的。例如,所述组织可由石蜡或冷冻切片分离。癌细胞还可由正常细胞通过流式细胞术或激光捕获显微解剖法分离。
AKT激酶抑制剂
已知某些AKT激酶抑制剂为ATP-竞争性抑制剂,由于其能够与ATP竞争结合AKT的活性位点。已知某些AKT激酶抑制剂为不与AKT的活性位点结合的变构抑制剂。AKT抑制剂还可为泛-AKT抑制剂,其中所述抑制剂可抑制AKT-1、AKT-2和AKT-3中两种或更多种的活性。AKT激酶抑制剂可为选择性AKT抑制剂,其中所述抑制剂可抑制AKT-1、AKT-2和AKT-3中一种的活性,而不抑制其它两种的活性。
在一个实施方案中,所述AKT激酶抑制剂为ATP-竞争性抑制剂。在另一个实施方案中,所述ATP-竞争性抑制剂为泛-AKT抑制剂。例如,在某些实施方案中,所述AKT抑制剂为式I的ATP-竞争性、泛-AKT抑制剂及其互变异构体、拆分的对映异构体、拆分的非对映异构体、溶剂化物和盐,所述式I为:
其中,
R1为氢、Me、Et和CF3;
R2为H或Me;R5为H或Me;
A为
其中G为任选被一至四个R9基团取代的苯基或任选被卤素取代的5-6元杂芳基;
R6和R7独立为H、OCH3、(C3-C6环烷基)-(CH2)、(C3-C6环烷基)-(CH2CH2);V-(CH2)0-1,其中V为5-6元杂芳基;W-(CH2)1-2,其中W为任选取代有F、Cl、Br、I、OMe、CF3或Me的苯基;任选取代有C1-C3烷基或O(C1-C3烷基)的C3-C6-环烷基;羟基-(C3-C6-环烷基);氟-(C3-C6-环烷基);CH(CH3)CH(OH)苯基;任选取代有F、OH、C1-C3烷基、环丙基甲基或C(=O)(C1-C3烷基)的4-6元杂环基;或C1-C6-烷基,其任选取代有一个或多个独立选自以下的基团:OH、氧代、O(C1-C6-烷基)、CN、F、NH2、NH(C1-C6-烷基)、N(C1-C6-烷基)2、环丙基、苯基、咪唑基、哌啶基、吡咯烷基、吗啉基、四氢呋喃基、氧杂环丁烷基或四氢吡喃基;或R6和R7与它们连接的氮一起形成4-7元杂环,其任选取代有一个或多个独立选自以下的基团:OH、卤素、氧代、CF3、CH2CF3、CH2CH2OH、O(C1-C3烷基)、C(=O)CH3、NH2、NHMe、N(Me)2、S(O)2CH3、环丙基甲基和C1-C3烷基;
Ra和Rb为H,或者Ra为H且Rb和R6与它们连接的原子一起形成具有一个或两个环氮原子的5-6元杂环;
Rc和Rd为H或Me,或者Rc和Rd与它们连接的原子一起形成环丙基环;
R8为氢、Me、F或OH,或者R8和R6与它们连接的原子一起形成具有一个或两个环氮原子的5-6元杂环;
每个R9独立为卤素、C1-C6-烷基、C3-C6-环烷基、O-(C1-C6-烷基)、CF3、OCF3、S(C1-C6-烷基)、CN、OCH2-苯基、CH2O-苯基、NH2、NH-(C1-C6-烷基)、N-(C1-C6-烷基)2、哌啶基、吡咯烷基、CH2F、CHF2、OCH2F、OCHF2、OH、SO2(C1-C6-烷基)、C(O)NH2、C(O)NH(C1-C6-烷基)和C(O)N(C1-C6-烷基)2;
R10为H或Me;且
m、n和p独立为0或1。
另外的实施方案包括式I的AKT抑制剂,其中R1为甲基;R2、R5和R10为H;G为任选取代有1-3个R9的苯基;R9为卤素、C1-C3烷基、CN、CF3、OCF3、OCH3或OCH2苯基;Rc和Rd为H或甲基;m、n和p为0或1;且R8为H或甲基。
另一个实施方案包括式I的AKT抑制剂,其选自:
2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮二盐酸盐;
(R)-2-氨基-3-(4-氯苯基)-1-((S)-4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)-3-甲基哌嗪-1-基)丙-1-酮二盐酸盐;
(R)-2-氨基-3-(4-氯-3-氟苯基)-1-((S)-4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)-3-甲基哌嗪-1-基)丙-1-酮二盐酸盐;
(R)-2-氨基-3-(4-氯-3-氟苯基)-1-((S)-4-((5R,7R)-7-甲氧基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)-3-甲基哌嗪-1-基)丙-1-酮二盐酸盐;
(S)-3-氨基-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮二盐酸盐;
(R)-2-氨基-3-(4-氯苯基)-1-((S)-4-((S)-7-羟基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)-3-甲基哌嗪-1-基)丙-1-酮;
(R)-2-氨基-3-(4-氯-3-氟苯基)-1-((S)-4-((S)-7-羟基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)-3-甲基哌嗪-1-基)丙-1-酮;
(2R)-2-氨基-3-(4-氯-3-氟苯基)-1-((3S)-4-((5R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)-3-甲基哌嗪-1-基)丙-1-酮;
(2R)-2-氨基-3-(4-氯苯基)-1-(4-(7-羟基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(R)-2-氨基-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-甲氧基苯基)丙-1-酮;
2-(4-氯苯基)-1-((S)-4-((R)-7-羟基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)-3-甲基哌嗪-1-基)-3-(异丙基氨基)丙-1-酮;
2-(4-氯苯基)-1-(4-(7-羟基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮二盐酸盐;
2-(4-氯苯基)-3-(异丙基氨基)-1-(4-(7-甲氧基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮;
2-(4-氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮;
2-(3,4-二氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮;
2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(吡啶-3-基甲基氨基)丙-1-酮;
2-(2,4-二氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮;
2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(戊-3-基氨基)丙-1-酮;
2-(4-氯苯基)-3-((1S,2R)-1-羟基-1-苯基丙-2-基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-((1R,4R)-4-羟基环己基氨基)丙-1-酮;
((3S,4R)-4-(3,4-二氯苯基)吡咯烷-3-基)(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)甲酮;
((3R,4S)-4-(3,4-二氯苯基)吡咯烷-3-基)(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)甲酮;
2-(4-氯苯基)-2-羟基-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮;
4-氨基-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-4-甲基戊-1-酮;
4-氨基-2-(3,4-二氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-4-甲基戊-1-酮;
(4-(4-氯-3-氟苯基)哌啶-4-基)(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)甲酮;
(3-(4-氯苯基)吡咯烷-3-基)(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)甲酮;
1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪 -1-基)-3-(异丙基氨基)-2-对甲苯基丙-1-酮;
1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)-2-(4-甲氧基苯基)丙-1-酮;
3-(乙基氨基)-2-(4-氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
2-(4-氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(甲基氨基)丙-1-酮;
(S)-3-氨基-2-(3,4-二氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
2-(4-氯苯基)-3-(环丙基甲基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
2-(4-氯-3-氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮;
2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(吡咯烷-1-基)丙-1-酮;
(R)-2-氨基-3-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
2-(4-氯苯基)-1-((S)-4-((S)-7-羟基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)-3-甲基哌嗪-1-基)-3-(异丙基氨基)丙-1-酮;
(R)-2-氨基-3-(4-氯苯基)-1-((S)-4-((R)-7-羟基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)-3-甲基哌嗪-1-基)丙-1-酮;
(R)-2-氨基-3-(4-氯-3-氟苯基)-1-((S)-4-((R)-7-羟基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)-3-甲基哌嗪-1-基)丙-1-酮;
2-(4-氯苯基)-1-(4-((5R)-7-羟基-5,7-二甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮;
(R)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮;
(4-(3,4-二氯苯基)哌啶-4-基)(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)甲酮二盐酸盐;
4-(3,4-二氯苯基)吡咯烷-3-基)(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)甲酮二盐酸盐;
1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-2-(4-甲氧基苯基)-3-(吡咯烷-1-基)丙-1-酮;
2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(2,2,2-三氟乙基氨基)丙-1-酮;
3-(叔丁基氨基)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(甲基(四氢-2H-吡喃-4-基)氨基)丙-1-酮;
(S)-2-(4-氯苯基)-3-(环丙基甲基氨基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-2-(5-氯噻吩-2-基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮;
(R)-2-氨基-3-(4-氯苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)-2-(4-(三氟甲基)苯基)丙-1-酮;
4-(1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)-1-氧代丙-2-基)苯甲腈;
(S)-2-(4-氯苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮;
3-(氮杂环丁-1-基)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(3-羟基氮杂环丁-1-基)丙-1-酮;
2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(新戊基氨基)丙-1-酮;
2-(4-溴苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮;
2-(4-氯苯基)-3-(4-氟哌啶-1-基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
2-(4-氯苯基)-3-((S)-3-氟吡咯烷-1-基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
2-(4-氯苯基)-3-(乙基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基(甲基)氨基)丙-1-酮;
2-(4-氯苯基)-3-(4,4-二氟哌啶-1-基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
2-(4-氯苯基)-3-(3,3-二氟吡咯烷-1-基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
2-(4-溴-3-氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮;
(R)-2-氨基-3-(4-氟苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(R)-2-氨基-3-(3,4-二氯苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(R)-2-氨基-3-(3,4-二氟苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(R)-2-(4-氯苯基)-3-(环丙基甲基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-2-(4-氯苯基)-3-(环丙基甲基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
2-(4-氯苯基)-3-((R)-3-氟吡咯烷-1-基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)-2-(4-(三氟甲氧基)苯基)丙-1-酮;
(S)-2-(4-氯苯基)-3-(环丙基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(R)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(3-羟基氮杂环丁-1-基)丙-1-酮;
(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(3-羟基氮杂环丁-1-基)丙-1-酮;
(R)-4-氨基-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-4-甲基戊-1-酮;
(S)-4-氨基-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-4-甲基戊-1-酮;
(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-((R)-吡咯烷-3-基氨基)丙-1-酮;
(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-((S)-吡咯烷-3-基氨基)丙-1-酮;
(S)-3-((R)-1-乙酰基吡咯烷-3-基氨基)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-3-((S)-1-乙酰基吡咯烷-3-基氨基)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-2-(4-溴苯基)-3-(环丙基甲基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(哌啶-4-基氨基)丙-1-酮;
(S)-3-(1-乙酰基哌啶-4-基氨基)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(2-甲氧基乙基氨基)丙-1-酮;
(R)-2-(4-氯苯基)-4-(二甲基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丁-1-酮;
(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(四氢-2H-吡喃-4-基氨基)丙-1-酮;
(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-((1r,4S)-4-羟基环己基氨基)丙-1-酮;
(S)-3-(氮杂环丁-1-基)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(R)-3-(氮杂环丁-1-基)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
2-((S)-2-(4-氯苯基)-3-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-氧代丙基氨基)乙酰胺;
2-((S)-2-(4-氯苯基)-3-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-氧代丙基氨基)-N,N-二甲基乙酰胺;
2-((S)-2-(4-氯苯基)-3-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-氧代丙基氨基)-N-甲基乙酰胺;
(R)-2-(4-溴苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-4-(异丙基氨基)丁-1-酮;
(R)-2-(4-溴苯基)-4-(二甲基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丁-1-酮;
(R)-2-(4-溴苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-4-(异丁基氨基)丁-1-酮;
(R)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-4-((2-甲氧基乙基)(甲基)氨基)丁-1-酮;
(R)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-4-(异丙基氨基)丁-1-酮;
(R)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-4-(3-羟基氮杂环丁-1-基)丁-1-酮;
2-((R)-3-(4-溴苯基)-4-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-4-氧代丁基氨基)-N,N-二甲基乙酰胺;
(R)-2-(4-溴苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-4-(2-羟基乙基氨基)丁-1-酮;
(2R)-2-(4-溴苯基)-4-(2-羟基-1-(四氢-2H-吡喃-4-基)乙基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丁-1-酮;
(R)-2-氨基-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-碘苯基)丙-1-酮;
4-((R)-2-氨基-3-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-氧代丙基)苯甲腈;
(R)-2-氨基-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-(三氟甲基)苯基)丙-1-酮;
(S)-3-(4-乙酰基哌嗪-1-基)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基 -6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(R)-3-(4-乙酰基哌嗪-1-基)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(R)-3-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-2-(甲基氨基)丙-1-酮;
(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-(2-羟基乙基)哌嗪-1-基)丙-1-酮;
(R)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-(2-羟基乙基)哌嗪-1-基)丙-1-酮;
2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(3-甲氧基氮杂环丁-1-基)丙-1-酮;
(R)-2-(4-氯苯基)-4-(环己基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丁-1-酮;
(R)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-4-(四氢-2H-吡喃-4-基氨基)丁-1-酮;
(2R)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-4-(2-羟基丙基氨基)丁-1-酮;
(2R)-2-(4-氯苯基)-4-(2-羟基-1-(四氢-2H-吡喃-4-基)乙基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丁-1-酮;
(2R)-2-(4-氯苯基)-4-(2-羟基-1-苯基乙基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丁-1-酮;
(S)-2-(4-氯苯基)-3-(乙基(四氢-2H-吡喃-4-基)氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(R)-2-(4-溴苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-4-(2-甲氧基乙基氨基)丁-1-酮;
(2R)-2-(4-溴苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-4-(3,3,3-三氟-2-羟基丙基氨基)丁-1-酮;
(R)-2-(4-溴苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-4-((1-羟基环丙基)甲基氨基)丁-1-酮;
2-((R)-3-(4-溴苯基)-4-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-4-氧代丁基氨基)乙酰胺;
(R)-2-(4-溴苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-4-(四氢-2H-吡喃-4-基氨基)丁-1-酮;
(R)-4-(3-(1H-咪唑-1-基)苯基氨基)-2-(4-溴苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丁-1-酮;
(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-吗啉代丙-1-酮;
(R)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-吗啉代丙-1-酮;
(R)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-甲基哌嗪-1-基)丙-1-酮;
(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-甲基哌嗪-1-基)丙-1-酮;
(S)-3-(3-氨基氮杂环丁-1-基)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(R)-3-(3-氨基氮杂环丁-1-基)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-硫吗啉代丙-1-酮;
(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(哌嗪-1-基)丙-1-酮;
(R)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(哌嗪-1-基)丙-1-酮;
(R)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-硫吗啉代丙-1-酮;
(R)-2-(4-氯苯基)-3-(4-氟哌啶-1-基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-2-(4-氯苯基)-3-(4-氟哌啶-1-基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(R)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(3-甲氧基氮杂环丁-1-基)丙-1-酮;
(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(3-甲氧基氮杂环丁-1-基)丙-1-酮;
(S)-2-(3,4-二氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮;
(S)-2-(4-氯苯基)-3-(二甲基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-2-(4-氟-3-(三氟甲基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮;
(S)-2-(3-氟-4-(三氟甲基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮;
(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(甲氧基氨基)丙-1-酮;
(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-甲氧基哌啶-1-基)丙-1-酮;
(R)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-甲氧基哌啶-1-基)丙-1-酮;
(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-羟基哌啶-1-基)丙-1-酮;
(R)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-羟基哌啶-1-基)丙-1-酮;
(S)-3-(4-氨基哌啶-1-基)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(R)-3-(4-氨基哌啶-1-基)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-2-(4-氯苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(四氢-2H-吡喃-4-基氨基)丙-1-酮;
(S)-2-(4-氯苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(甲基(四氢-2H-吡喃-4-基)氨基)丙-1-酮;
(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基(甲基)氨基)丙-1-酮;
(R)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-(甲基磺酰基)哌嗪-1-基)丙-1-酮;
(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-(甲基氨基)哌啶-1-基)丙-1-酮;
(R)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-(甲基氨基)哌啶-1-基)丙-1-酮;
(S)-2-(4-氯-3-(三氟甲氧基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮;
(S)-2-(3-氟-4-(三氟甲氧基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮;
(S)-2-(4-氯-3-(三氟甲基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮;
(R)-2-(4-氯苯基)-3-(4-乙基哌嗪-1-基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-2-(4-氯苯基)-3-(4-乙基哌嗪-1-基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-异丙基哌嗪-1-基)丙-1-酮;
(R)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-异丙基哌嗪-1-基)丙-1-酮;
(R)-2-(4-氯苯基)-3-((S)-3-(二甲基氨基)吡咯烷-1-基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-2-(4-氯苯基)-3-((S)-3-(二甲基氨基)吡咯烷-1-基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-((R)-四氢呋喃-3-基氨基)丙-1-酮;
(S)-2-(4-氯苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-((R)-四氢呋喃-3-基氨基)丙-1-酮;
(S)-2-(4-氯苯基)-3-(2-氟乙基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-2-(4-氟-3-(三氟甲氧基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮;
(S)-2-(3,5-二(三氟甲基)苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮;
(S)-2-(3-氟-4-甲氧基苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮;
4-((R)-2-(4-氯苯基)-3-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-氧代丙基)哌嗪-2-酮;
(R)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-((R)-3-羟基吡咯烷-1-基)丙-1-酮;
(S)-2-(4-氯苯基)-3-(4-(二甲基氨基)哌啶-1-基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(R)-2-(4-氯苯基)-3-(4-(二甲基氨基)哌啶-1-基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-2-(3-氯-5-氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮;
(S)-2-(3-溴-4-甲氧基苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮;
(R)-3-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-2-(哌啶-4-基氨基)丙-1-酮;
(R)-2-(1-乙酰基哌啶-4-基氨基)-3-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
2-((R)-3-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-1-氧代丙-2-基氨基)-N-异丙基乙酰胺;
(R)-3-(4-氯苯基)-2-(二甲基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(R)-3-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-2-(2-吗啉代乙基氨基)丙-1-酮;
(R)-3-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-2-(异丙基氨基)丙-1-酮;
(R)-3-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-2-(四氢-2H-吡喃-4-基氨基)丙-1-酮;
(R)-3-(4-氯苯基)-1-((S)-4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)-3-甲基哌嗪-1-基)-2-(异丙基氨基)丙-1-酮;
2-((R)-3-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-1-氧代丙-2-基氨基)-N,N-二甲基乙酰胺;
(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(1,4-氧氮杂环庚-4-基)丙-1-酮;
(R)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(1,4-氧氮杂环庚-4-基)丙-1-酮;
(R)-2-(4-氯-2-氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮;
(S)-2-(4-氯-2-氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮;
(S)-2-(2-氟-4-(三氟甲基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮;
(S)-2-(4-氯苯基)-3-(环己基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-2-(4-氯苯基)-3-(环己基氨基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-甲氧基环己基氨基)丙-1-酮;
(S)-2-(3-氟-4-(三氟甲氧基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(四氢-2H-吡喃-4-基氨基)丙-1-酮;
(S)-2-(3-氟-4-(三氟甲基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(四氢-2H-吡喃-4-基氨基)丙-1-酮;
(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-((S)-四氢呋喃-3-基氨基)丙-1-酮;
(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-甲基四氢-2H-吡喃-4-基氨基)丙-1-酮;
(R)-3-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-2-(2-(四氢-2H-吡喃-4-基)乙基氨基)丙-1-酮;
(R)-3-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-2-(3,3,3-三氟丙基氨基)丙-1-酮;
(R)-3-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-2-((四氢-2H-吡喃-4-基)甲基氨基)丙-1-酮;
(R)-3-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-2-(异丙基(甲基)氨基)丙-1-酮;
(S)-3-(叔丁基氨基)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(R)-3-(叔丁基氨基)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-2-(4-氯-3-氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-甲基哌嗪-1-基)丙-1-酮;
(R)-2-(4-氯-3-氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-甲基哌嗪-1-基)丙-1-酮;
(S)-2-(4-氯-3-氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-羟基哌啶-1-基)丙-1-酮;
(R)-2-(4-氯-3-氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-吗啉代丙-1-酮;
(R)-2-(4-氯-3-氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-羟基哌啶-1-基)丙-1-酮;
(S)-2-(3-氟-4-(三氟甲氧基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-甲基哌嗪-1-基)丙-1-酮;
(R)-2-(3-氟-4-(三氟甲氧基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-甲基哌嗪-1-基)丙-1-酮;
(S)-3-(环丙基甲基氨基)-2-(3-氟-4-(三氟甲基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-3-(环丙基甲基氨基)-2-(3-氟-4-(三氟甲氧基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)-2-(4-(三氟甲基)苯基)丙-1-酮;
(S)-3-氨基-2-(4-溴苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-3-氨基-2-(4-氯-3-氟苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-2-(4-溴苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(四氢-2H-吡喃-4-基氨基)丙-1-酮;
3-((S)-2-(4-氯苯基)-3-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-氧代丙基氨基)丙酰胺;
3-((S)-2-(4-氯苯基)-3-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-氧代丙基氨基)丙酰胺;
(4-(4-氯苯基)哌啶-4-基)(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)甲酮;
(S)-2-(4-溴苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮;
(S)-3-氨基-2-(4-氯-3-氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-3-氨基-2-(4-溴苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-2-(4-溴苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(四氢-2H-吡喃-4-基氨基)丙-1-酮;
(S)-2-(4-氯-3-氟苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(四氢-2H-吡喃-4-基氨基)丙-1-酮;
(S)-2-(3,4-二氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(四氢-2H-吡喃-4-基氨基)丙-1-酮;
(S)-3-氨基-2-(3,4-二氯苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(R)-2-(3,4-二氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-羟基哌啶-1-基)丙-1-酮;
(S)-2-(3,4-二氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-异丙基哌嗪-1-基)丙-1-酮;
(S)-2-(3-氟-4-(三氟甲氧基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-羟基哌啶-1-基)丙-1-酮;
(R)-2-(3-氟-4-(三氟甲氧基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-羟基哌啶-1-基)丙-1-酮;
(S)-2-(3-氟-4-(三氟甲氧基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-异丙基哌嗪-1-基)丙-1-酮;
(S)-2-(3,5-二氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮;
(S)-3-((R)-3-氨基吡咯烷-1-基)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(R)-3-((R)-3-氨基吡咯烷-1-基)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-2-(4-氯-3-氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-异丙基哌嗪-1-基)丙-1-酮;
(S)-2-(3-氟-4-(三氟甲氧基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-吗啉代丙-1-酮;
(R)-2-(3-氟-4-(三氟甲氧基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-吗啉代丙-1-酮;
(S)-3-(4-乙基哌嗪-1-基)-2-(3-氟-4-(三氟甲氧基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(R)-3-(4-乙基哌嗪-1-基)-2-(3-氟-4-(三氟甲氧基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-3-(4-乙酰基哌嗪-1-基)-2-(3-氟-4-(三氟甲氧基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(R)-3-(4-乙酰基哌嗪-1-基)-2-(3-氟-4-(三氟甲氧基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-2-(3,4-二氯苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(四氢-2H-吡喃-4-基氨基)丙-1-酮;
(S)-2-(4-溴苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮;
(S)-2-(4-氯-3-氟苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮;
(S)-2-(4-氯-3-氟苯基)-3-(环丙基甲基氨基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-3-(二(环丙基甲基)氨基)-2-(4-氯-3-氟苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-2-(4-溴苯基)-3-(环丙基甲基氨基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-2-(4-氯-3-氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(四氢-2H-吡喃-4-基氨基)丙-1-酮;
(S)-2-(4-氯-3-氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮;
(S)-2-(4-溴苯基)-3-((环丙基甲基)(甲基)氨基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-2-(4-氯-3-氟苯基)-3-(环丙基甲基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-3-(环丙基甲基氨基)-2-(3,4-二氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(四氢-2H-吡喃-4-基氨基)-2-(4-(三氟甲氧基)苯基)丙-1-酮;
(R)-2-(4-氯苯基)-3-((3S,5R)-3,5-二甲基哌嗪-1-基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(R)-2-(4-氯苯基)-3-((2S,6R)-2,6-二甲基吗啉代)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-2-(4-氯苯基)-3-((2S,6R)-2,6-二甲基吗啉代)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-2-(4-氯苯基)-3-((3S,5R)-3,5-二甲基哌嗪-1-基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-2-(3-氟-4-(三氟甲基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-羟基哌啶-1-基)丙-1-酮;
(R)-2-(3-氟-4-(三氟甲基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-羟基哌啶-1-基)丙-1-酮;
(S)-2-(3-氟-4-(三氟甲基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-甲基哌嗪-1-基)丙-1-酮;
(R)-2-(3-氟-4-(三氟甲基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-甲基哌嗪-1-基)丙-1-酮;
(S)-2-(3-氟-4-(三氟甲基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-异丙基哌嗪-1-基)丙-1-酮;
(R)-2-(3-氟-4-(三氟甲基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-异丙基哌嗪-1-基)丙-1-酮;
(S)-3-(环丙基甲基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-2-(4-(三氟甲氧基)苯基)丙-1-酮;
(S)-3-氨基-2-(4-溴-3-氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-3-氨基-2-(4-溴-3-氟苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-2-(3,4-二氯苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮;
(S)-2-(4-溴-3-氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮;
(S)-2-(4-溴-3-氟苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮;
(S)-2-(4-溴-3-氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(四氢-2H-吡喃-4-基氨基)丙-1-酮;
(S)-2-(4-溴-3-氟苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(四氢-2H-吡喃-4-基氨基)丙-1-酮;
(S)-2-(4-溴-3-氟苯基)-3-(环丙基甲基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-2-(4-溴-3-氟苯基)-3-(环丙基甲基氨基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-2-(3-氟-4-(三氟甲基)苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮;
(S)-2-(4-溴苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-异丙基哌嗪-1-基)丙-1-酮;
(S)-2-(4-溴苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-羟基哌啶-1-基)丙-1-酮;
(S)-3-(环丙基甲基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-2-(4-(三氟甲基)苯基)丙-1-酮;
(S)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(四氢-2H-吡喃-4-基氨基)-2-(4-(三氟甲基)苯基)丙-1-酮;
(S)-3-(环丙基甲基氨基)-2-(2-氟-4-(三氟甲基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(R)-2-(4-溴-3-氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-羟基哌啶-1-基)丙-1-酮;
(S)-2-(4-溴苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基(甲基)氨基)丙-1-酮;
(S)-3-氨基-2-(4-溴-2-氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-3-氨基-2-(4-溴-2-氟苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-2-(4-溴苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基(甲基)氨基)丙-1-酮;
(S)-2-(4-溴-2-氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮;
(S)-2-(4-溴-2-氟苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮;
(S)-3-氨基-2-(4-氯-2-氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
2-(4-氯苯基)-3-((3S,4R)-4-(二甲基氨基)-3-氟哌啶-1-基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-2-(4-溴-2-氟苯基)-3-(环丙基甲基氨基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-3-(叔丁基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-2-(4-(三氟甲基)苯基)丙-1-酮;
(S)-2-(3-氟-4-(三氟甲氧基)苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(四氢-2H-吡喃-4-基氨基)丙-1-酮;
(S)-2-(3-氟-4-(三氟甲基)苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(四氢-2H-吡喃-4-基氨基)丙-1-酮;
(S)-2-(4-氯-2-氟苯基)-3-(环丙基甲基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-2-(4-溴-2-氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(四氢-2H-吡喃-4-基氨基)丙-1-酮;
(S)-2-(4-氯-2-氟苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(四氢-2H-吡喃-4-基氨基)丙-1-酮;
(S)-2-(4-氯-2-氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(四氢-2H-吡喃-4-基氨基)丙-1-酮;
(S)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(四氢-2H-吡喃-4-基氨基)-2-(4-(三氟甲基)苯基)丙-1-酮;
(S)-3-(环丙基甲基氨基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-2-(4-(三氟甲基)苯基)丙-1-酮;
(S)-2-(4-溴苯基)-3-(叔丁基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-2-(4-氯-3-氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丁基氨基)丙-1-酮;
(S)-2-(4-氯-3-氟苯基)-3-(环戊基甲基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-2-(4-氯-3-氟苯基)-3-(环戊基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-2-(2-氟-4-(三氟甲基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基(甲基)氨基)丙-1-酮;
(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-((2-羟基乙基)(异丙基)氨基)丙-1-酮;
(S)-2-(2-氟-4-(三氟甲基)苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮;
(S)-2-(2-氟-4-(三氟甲基)苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(四氢-2H-吡喃-4-基氨基)丙-1-酮;
(S)-3-氨基-2-(2-氟-4-(三氟甲基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-3-(环丙基甲基氨基)-2-(3-氟-4-(三氟甲基)苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-3-(环丙基甲基氨基)-2-(3-氟-4-(三氟甲氧基)苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-2-(4-溴苯基)-3-(4,4-二甲基环己基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-2-(4-溴苯基)-3-(3,3-二甲基环己基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-2-(4-氯苯基)-3-(4,4-二甲基环己基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-2-(4-氯苯基)-3-(3,3-二甲基环己基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)-2-(噻吩-2-基)丙-1-酮;
(S)-2-(5-溴噻吩-2-基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮;
(S)-2-(5-溴噻吩-2-基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮;
(S)-2-(5-溴噻吩-2-基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(四氢-2H-吡喃-4-基氨基)丙-1-酮;
(R)-2-(5-溴吡啶-2-基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮;
(S)-2-(5-溴吡啶-2-基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮;
(S)-2-(5-溴噻吩-2-基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(四氢-2H-吡喃-4-基氨基)丙-1-酮;
(S)-2-(5-溴噻吩-2-基)-3-(环丙基甲基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-2-(5-氯噻吩-2-基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(四氢-2H-吡喃-4-基氨基)丙-1-酮;
(S)-2-(5-氯噻吩-2-基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮;
(S)-2-(5-氯噻吩-2-基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(四氢-2H-吡喃-4-基氨基)丙-1-酮;
(S)-2-(5-氯噻吩-2-基)-3-(环丙基甲基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;
(S)-2-(5-氯噻吩-2-基)-3-(环丙基甲基氨基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮;以及
它们的盐。
另一个实施方案包括式I的AKT抑制剂,包括以下化合物:
式I化合物的制备
式I化合物可根据美国专利公开2008/0051399(美国专利申请11/773,949,2007年7月5日提交,标题为“Hydroxylated and Methoxylated Pyrimidyl Cyclopentanes asAKT Protein Kinase Inhibitors”)中所述的方法来制备,针对所有目的将其通过引用的方式并入本申请。
式I化合物可逐一制备或作为包括至少2个例如5至1,000个化合物或10至100个化合物的化合物库来制备。式I化合物的库可通过组合的‘分离和混合’方法或通过使用溶液相或固相化学的多重并行合成法来制备。
针对示例说明的目的,方案1-4显示了用于制备式I化合物以及关键中间体的一般方法。本领域技术人员将会认识到可使用其它合成途径。尽管具体起始物质和试剂描述于如下方案中并如下讨论,但是其它起始物质和试剂可容易地替换以提供多种衍生物和/或反应条件。此外,由如下所述的方法 制备的许多化合物可进一步根据本公开使用本领域技术人员公知的常规化学方法来修饰。
方案1
方案1显示制备式I化合物10的方法,其中R1为氢,R2为OH且R5为H。嘧啶2的形成可通过酮酸酯1与硫脲在碱(诸如KOH)的存在下在适当溶剂(诸如乙醇)中的反应来完成。在将化合物2的巯基在标准还原条件(例如兰尼镍和NH4OH)下还原得到化合物3后,可将羟基嘧啶3在标准条件(例如POCl3在DIEA/DCE中)下氯化得到化合物4。然后将化合物4在标准条件(例如MCPBA在适当溶剂诸如CHCl3中)下氧化得到嘧啶-氧化物5。将嘧啶-氧化物用乙酸酐处理得到重排产物6。化合物7通过使得化合物6与适当取代的哌啶在标准SNAr反应条件下反应得到化合物7来获得。将化合物7水解得到化合物8,然后将其脱保护得到中间体9。将哌嗪基环戊二烯并[d]嘧啶9用适当的氨基酸在偶联试剂(诸如HBTU)的存在下进行酰化,接着如果需要进行脱保护,得到式I的化合物10。
方案2
方案2显示制备式I的化合物22、25和27的方法,其中R1、R2和R5为甲基。根据方案2,将(+)-番薄荷酮11用溴进行溴化得到二溴化物12。将二溴化物12用碱(诸如乙醇钠)处理得到番薄荷酸酯(pulegenate)13。将番薄荷酸酯13进行臭氧分解得到酮酸酯(ketoester)14。将酮酸酯14用硫脲在碱(诸如KOH)的存在下在乙醇中处理,接着将巯基在标准条件(例如兰尼镍催化剂在氨水中)下还原得到羟基嘧啶16。将羟基嘧啶16在标准条件(例如POCl3)下氯化得到4-氯嘧啶17。将4-氯嘧啶17用氧化剂(诸如MCPBA或过氧化氢)氧化得到N-氧化物18。将N-氧化物18用乙酸酐重排得到中间体19。使得化合物19与预期的哌嗪根据在方案1中所述的操作反应得到化合物20(其中R5为H)和23(其中R5为Me)。使用HPLC(具有手性固定相)将化合物20和23进行手性分离,然后在用碱(诸如氢氧化锂)处理后进行水解分别得到化合物21和24。在脱保护后,使得化合物21和24分别与适当的氨基酸反应得到化合物22和25。
可选择地,可将化合物24的7-羟基用烷化剂(诸如烷基卤)在碱(诸如NaH或KOH)的存在下进行烷基化得到化合物26,其中R2为Me。在脱保护后,使得化合物26与适当的氨基酸反应得到化合物27。
方案3
方案3显示制备化合物73和74的可选择方法。根据方案3,使用氨合成子将14氨化得到63。使用例如甲酸铵在甲酰胺的存在下在50℃-250℃和/或高压形成嘧啶得到二环单元64。使用例如POCl3或SOCl2活化64得到活化的嘧啶65。在0℃至150℃使用适当保护/取代的哌啶将该离去基团置换得到哌啶66。在-20℃至50℃使用例如间氯过氧苯甲酸(“MCPBA”或“m-CPBA”)或进行氧化得到N-氧化物67。用酰化剂(例如乙酸酐)处理、接着加热(40℃至200℃)引起重排得到68。在0℃至50℃使用例如LiOH或NaOH进行水解得到醇69。使用例如Swern条件、MnO4或吡啶-SO3络合物在适当温度进行氧化得到酮70。使用例如催化手性催化剂在氢、CBS催化剂或硼氢化物还原剂的存在下在手性配体的存在下进行不对称还原得到(R)或(S)立体化学的醇71或72。可选择地,可使用非手性还原剂(例如H2、Pd/C),使得环戊烷单元上的甲基提供面选择性(facial selectivity)以及最终的非对映立体选择性。如果还原得到较弱的非对映立体选择性,则非对映异构体可通过(例如)色谱法、重结晶或衍生化来分离。最终,使用例如酸在0℃至50℃将Boc基团进行脱保护,使用适当官能化的氨基酸进行酰化,且最终将该氨基 酸的胺进行官能化(例如移去任何保护基团、烷基化、还原氨化或酰化以引入新的取代基)得到最终的化合物73和74。
方案4
将手性助剂(例如Evans噁唑烷酮等)引入至化合物(1)可通过标准酰化操作得到结合物(2)来完成。例如,将酸用活化剂(例如COCl2)处理或在胺碱的存在下在-20℃至100℃形成混合酸酐(例如2,2-二甲基丙酰氯),接着用适当的手性助剂(X)处理得到化合物(2)。手性助剂的立体化学和选择可确定新产生的手性中心的立体化学和非对映立体选择性。将化合物(2)用路易斯酸(例如TiCl4)在低温(例如-20℃至-100℃)和胺碱(例如许尼希碱(Hunig’s base))处理,接着使用适当取代的亚铵离子前体(3)在低温处理,得到化合物(4)。可认为所述温度、路易斯酸和手性助剂均影响加成加合物的非对映立体选择性。最终,在温和条件(例如LiOH/H2O,在-10℃至30℃)下进行皂化得到预期的酸(5)。
在另一个实施方案中,所述AKT激酶抑制剂为式II的ATP-竞争性、泛-AKT抑制剂:
及其立体异构体、互变异构体或药用盐,其中:
G为任选取代有一至三个Ra基团的苯基或任选被卤素取代的5-6元杂 芳基;
R1和R1a独立选自H、Me、CF3、CHF2或CH2F;
R2为氢、F或-OH;
R2a为H;
R3为H;
R4为氢或任选取代有F、-OH或-O(C1-C3烷基)的C1-C4烷基;
R5和R5a独立选自H和C1-C4烷基,或者R5和R5a与它们连接的原子一起形成5-6元环烷基或5-6元杂环基,其中所述杂环基具有氧杂原子;
每个Ra独立为卤素、C1-C6-烷基、C3-C6-环烷基、-O-(C1-C6-烷基)、CF3、-OCF3、S(C1-C6-烷基)、CN、-OCH2-苯基、NH2、-NO2、-NH-(C1-C6-烷基)、-N-(C1-C6-烷基)2、哌啶基、吡咯烷基、CH2F、CHF2、-OCH2F、-OCHF2、-OH、-SO2(C1-C6-烷基)、C(O)NH2、C(O)NH(C1-C6-烷基)和C(O)N(C1-C6-烷基)2;且
j为1或2。
另一个实施方案包括AKT抑制剂化合物,其包括:
在一个实施方案中,所述AKT抑制剂为具有上式的选自GDC-0068的化合物及其盐,所述GDC-0068的式为:
式II化合物可根据在WO 2009006567中所述的方法来制备,针对所有目的将其通过引用的方式并入本申请。
在一个实施方案中,所述AKT抑制剂为式III的变构的AKT抑制剂:
其中R1和R2独立为氢、C1-C5烷基、羟基、C1-5烷氧基或氨基;p为1至6的整数;A为5-14个碳的碳环、二环或三环芳族或杂芳族环,其可任选取代有卤素、OH、氨基、二烷基氨基、单烷基氨基、C1-C6-烷基或苯基,上述基团任选取代有卤素、OH、C1-C3烷基或环丙基甲基;且在一个实施方案中A具有下列结构中的一种:
其中D和E独立为-CH或N;
其中R3和R4各自独立为氢、卤素、OH、氨基、二烷基氨基、单烷基 氨基或C1-C6-烷基,上述基团任选取代有卤素、OH、C1-C3烷基或环丙基甲基;
R5为5或6元芳族或杂芳族环,其任选取代有卤素、OH、氨基、二烷基氨基、单烷基氨基或C1-C6-烷基,上述基团任选取代有卤素、OH、C1-C3烷基或环丙基甲基;在一个实施方案中,R5为苯基;
B为芳族环、杂芳族环、碳环或杂环,其具有下式:
其中Q、T、X和Y各自独立选自-CH、-CH2、C=O、N或O;
Z为-CH、-CH2、C=O、N、O或-C=C-;
R6和R7独立选自氢、卤素、羰基和5或6元芳族或杂芳族环,所述环任选取代有卤素、OH、氨基、二烷基氨基、单烷基氨基或C1-C6-烷基,上述基团任选取代有卤素、OH、C1-C3烷基或环丙基甲基;在一个实施方案中,R6或R7为吡啶基,或者R6和R7一起形成5-6元芳族环、杂芳族环、碳环或杂环,其可任选取代有卤素、OH、氨基、二烷基氨基、单烷基氨基或C1-C6-烷基,上述基团任选取代有卤素、OH、C1-C3烷基或环丙基甲基;在一个实施方案中,B具有下列结构中的一种:
其中X、Y、Q、R6和R7如上所述,且X’、Q’和T’为-CH或N。
另一个实施方案包括变构的AKT抑制剂,其具有下式:
其中:a为0或1;b为0或1;m为0、1或2;n为0、1或2;p为0、1或2;r为0或1;s为0或1;
Q选自:-NR7R8、
R1独立选自(C=O)aObC1-C6烷基、(C=O)aOb芳基、C2-C6烯基、C2-C6炔基、(C=O)aOb杂环基、(C=O)aObC3-C6环烷基、CO2H、卤素、CN、OH、ObC1-C6全氟烷基、Oa(C=O)bNR7R8、NRc(C=O)NR7R8、S(O)mRa、S(O)2NR7R8、NRcS(O)mRa、氧代、CHO、NO2、NRc(C=O)ObRa、O(C=O)ObC1-C6烷基、O(C=O)ObC3-C6环烷基、O(C=O)Ob芳基和O(C=O)Ob-杂环基,其中所述烷基、芳基、烯基、炔基、杂环基和环烷基任选取代有一个或多个选自Rz的取代基;
R2独立选自C1-C6烷基、芳基、杂环基、CO2H、卤素、CN、OH和S(O)2NR7R8,其中所述烷基、芳基和杂环基任选取代有一个、两个或三个选自Rz的取代基;
R7和R8独立选自H、(C=O)ObC1-C10烷基、(C=O)ObC3-C8环烷基、(C=O)Ob芳基、(C=O)Ob杂环基、C1-C10烷基、芳基、C2-C10烯基、C2-C10炔基、杂环基、C3-C8环烷基、SO2Ra和(C=O)NRb 2,其中所述烷基、环烷基、芳基、杂环基、烯基和炔基任选取代有一个或多个选自Rz的取代基,或者
R7和R8可与它们连接的氮一起形成单环或二环杂环基,其在每个环具有5-7个成员且任选含有除了氮之外的一个或两个选自N、O和S的额外的杂原子,所述单环或二环杂环基任选取代有一个或多个选自Rz的取代基;
Rz选自:(C=O)rOs(C1-C10)烷基、Or(C1-C3)全氟烷基、(C0-C6)亚烷基-S(O)mRa、氧代、OH、卤素、CN、(C=O)rOs(C2-C10)烯基、(C=O)rOs(C2-C10)炔基、(C=O)rOs(C3-C6)环烷基、(C=O)rOs(C0-C6)亚烷基-芳基、(C=O)rOs(C0-C6)亚烷基-杂环基、(C=O)rOs(C0-C6)亚烷基-N(Rb)2、C(O)Ra、(C0-C6)亚烷基-CO2Ra、C(O)H、(C0-C6)亚烷基-CO2H、C(O)N(Rb)2、S(O)mRa和S(O)2N(Rb)2、NRc(C=O)ObRa、O(C=O)ObC1-C10烷基、O(C=O)ObC3-C8环烷基、O(C=O)Ob芳基和O(C=O)Ob-杂环基,其中所述烷基、烯基、炔基、环烷基、芳基和杂环基任选取代有至多三个选自Rb、OH、(C1-C6)烷氧基、卤素、CO2H、CN、O(C=O)C1-C6烷基、氧代和N(Rb)2的取代基;
Ra为(C1-C6)烷基、(C3-C6)环烷基、芳基或杂环基;且
Rb为氢、(C1-C6)烷基、芳基、杂环基、(C3-C6)环烷基、(C=O)OC1-C6 烷基、(C=O)C1-C6烷基或S(O)2Ra;
Rc选自:H、C1-C6烷基、芳基、C2-C6烯基、C2-C6炔基、杂环基、C3-C8环烷基和C1-C6全氟烷基,其中所述烷基、环烷基、芳基、杂环基、烯基和炔基任选取代有一个或多个选自Rz的取代基;
或其药用盐或立体异构体。
另一个实施方案包括变构的AKT抑制剂,其具有下式:
其中a为0或1;b为0或1;m为0、1或2;n为0、1、2或3;p为0、1或2;r为0或1;s为0或1;u、v、w和x独立选自:CH和N,条件是u、v、w和x中仅一个可为N;
Q选自:-NR5R6,
R1独立选自(C=O)aObC1-C6烷基、(C=O)aOb芳基、C2-C6烯基、C2-C6炔基、(C=O)aOb杂环基、(C=O)aObC3-C6环烷基、CO2H、卤素、CN、OH、ObC1-C6全氟烷基、Oa(C=O)bNR7R8、NRc(C=O)NR7R8、S(O)mRa、S(O)2NR7R8、NRcS(O)mRa、氧代、CHO、NO2、NRc(C=O)ObRa、O(C=O)ObC1-C6烷基、O(C=O)ObC3-C6环烷基、O(C=O)Ob芳基和O(C=O)Ob-杂环基,其中所述烷基、芳基、烯基、炔基、杂环基和环烷基任选取代有一个或多个选自Rz的取代基;
R2独立选自C1-C6烷基、芳基、杂环基、CO2H、卤素、CN、OH和S(O)2NR7R8,其中所述烷基、芳基和杂环基任选取代有一个、两个或三个选自Rz的取代基;
R7和R8独立选自H、(C=O)ObC1-C10烷基、(C=O)ObC3-C8环烷基、(C=O)Ob芳基、(C=O)Ob杂环基、C1-C10烷基、芳基、C2-C10烯基、C2-C10炔基、杂环基、C3-C8环烷基、SO2Ra和(C=O)NRb 2,其中所述烷基、环烷基、芳基、杂环基、烯基和炔基任选取代有一个或多个选自Rz的取代基,或者
R7和R8可与它们连接的氮一起形成单环或二环杂环基,其在每个环具有5-7个成员且任选含有除了氮之外的一个或两个选自N、O和S的额外的杂原子,所述单环或二环杂环基任选取代有一个或多个选自Rz的取代基;
Rz选自:(C=O)rOs(C1-C10)烷基、Or(C1-C3)全氟烷基、(C0-C6)亚烷基-S(O)mRa、氧代、OH、卤素、CN、(C=O)rOs(C2-C10)烯基、(C=O)rOs(C2-C10)炔基、(C=O)rOs(C3-C6)环烷基、(C=O)rOs(C0-C6)亚烷基-芳基、(C=O)rOs(C0-C6)亚烷基-杂环基、(C=O)rOs(C0-C6)亚烷基-N(Rb)2、C(O)Ra、(C0-C6)亚烷基-CO2Ra、C(O)H、(C0-C6)亚烷基-CO2H、C(O)N(Rb)2、S(O)mRa和S(O)2N(Rb)2、NRc(C=O)ObRa、O(C=O)ObC1-C10烷基、O(C=O)ObC3-C8环烷基、O(C=O)Ob芳基和O(C=O)Ob-杂环基,其中所述烷基、烯基、炔基、环烷基、芳基和杂环基任选取代有至多三个选自Rb、OH、(C1-C6)烷氧基、卤素、CO2H、CN、O(C=O)C1-C6烷基、氧代和N(Rb)2的取代基;
Ra为(C1-C6)烷基、(C3-C6)环烷基、芳基或杂环基;且
Rb为氢、(C1-C6)烷基、芳基、杂环基、(C3-C6)环烷基、(C=O)OC1-C6烷基、(C=O)C1-C6烷基或S(O)2Ra;
Rc选自:H、C1-C6烷基、芳基、C2-C6烯基、C2-C6炔基、杂环基、C3-C8环烷基和C1-C6全氟烷基,其中所述烷基、环烷基、芳基、杂环基、烯基和炔基任选取代有一个或多个选自Rz的取代基;
或其药用盐或立体异构体。
另一个实施方案包括变构的AKT抑制剂,其具有下式:
其中a为0或1;b为0或1;m为0、1或2;n为0、1、2或3;p为0、1或2;r为0或1;s为0或1;u、v和x独立选自CH和N;W为化学键、CH或N;
Q选自:-NR5R6、
R1独立选自(C=O)aObC1-C6烷基、(C=O)aOb芳基、C2-C6烯基、C2-C6炔基、(C=O)aOb杂环基、(C=O)aObC3-C6环烷基、CO2H、卤素、CN、OH、ObC1-C6全氟烷基、Oa(C=O)bNR7R8、NRc(C=O)NR7R8、S(O)mRa、S(O)2NR7R8、NRcS(O)mRa、氧代、CHO、NO2、NRc(C=O)ObRa、O(C=O)ObC1-C6烷基、O(C=O)ObC3-C6环烷基、O(C=O)Ob芳基和O(C=O)Ob-杂环基,其中所述烷基、芳基、烯基、炔基、杂环基和环烷基任选取代有一个或多个选自Rz的取代基;
R2独立选自C1-C6烷基、芳基、杂环基、CO2H、卤素、CN、OH和S(O)2NR7R8,其中所述烷基、芳基和杂环基任选取代有一个、两个或三个选自Rz的取代基;
R7和R8独立选自H、(C=O)ObC1-C10烷基、(C=O)ObC3-C8环烷基、(C=O)Ob芳基、(C=O)Ob杂环基、C1-C10烷基、芳基、C2-C10烯基、C2-C10炔基、杂环基、C3-C8环烷基、SO2Ra和(C=O)NRb 2,其中所述烷基、环烷基、芳基、杂环基、烯基和炔基任选取代有一个或多个选自Rz的取代基,或者
R7和R8可与它们连接的氮一起形成单环或二环杂环基,其在每个环具有5-7个成员且任选含有除了氮之外的一个或两个选自N、O和S的额外的杂原子,所述单环或二环杂环基任选取代有一个或多个选自Rz的取代基;
Rz选自:(C=O)rOs(C1-C10)烷基、Or(C1-C3)全氟烷基、(C0-C6)亚烷基-S(O)mRa、氧代、OH、卤素、CN、(C=O)rOs(C2-C10)烯基、(C=O)rOs(C2-C10)炔基、(C=O)rOs(C3-C6)环烷基、(C=O)rOs(C0-C6)亚烷基-芳基、(C=O)rOs(C0-C6)亚烷基-杂环基、(C=O)rOs(C0-C6)亚烷基-N(Rb)2、C(O)Ra、(C0-C6)亚烷基-CO2Ra、C(O)H、(C0-C6)亚烷基-CO2H、C(O)N(Rb)2、S(O)mRa和S(O)2N(Rb)2、NRc(C=O)ObRa、O(C=O)ObC1-C10烷基、O(C=O)ObC3-C8环烷基、O(C=O)Ob芳基和O(C=O)Ob-杂环基,其中所述烷基、烯基、炔基、环烷基、芳基和杂环基任选取代有至多三个选自Rb、OH、(C1-C6)烷氧基、卤素、CO2H、CN、O(C=O)C1-C6烷基、氧代和N(Rb)2的取代基;
Ra为(C1-C6)烷基、(C3-C6)环烷基、芳基或杂环基;且
Rb为氢、(C1-C6)烷基、芳基、杂环基、(C3-C6)环烷基、(C=O)OC1-C6烷基、(C=O)C1-C6烷基或S(O)2Ra;
Rc选自:H、C1-C6烷基、芳基、C2-C6烯基、C2-C6炔基、杂环基、C3-C8环烷基和C1-C6全氟烷基,其中所述烷基、环烷基、芳基、杂环基、烯基和 炔基任选取代有一个或多个选自Rz的取代基;
或其药用盐或立体异构体。
另一个实施方案包括变构的AKT抑制剂,其选自:
及其盐。
在一个实施方案中,所述激酶抑制剂为AKT-1选择性ATP-竞争性抑制剂,且其为式IV化合物:
及其药用盐,其中
Ar选自芳基、取代的芳基、杂芳基和取代的杂芳基;
Q选自环烷基、取代的环烷基、环杂烷基、取代的环杂烷基、芳基、取代的芳基、杂芳基和取代的杂芳基;
R1和R2独立选自氢、烷基、取代的烷基、环烷基、取代的环烷基、杂环烷基、取代的杂环烷基、芳基、取代的芳基、杂芳基和取代的杂芳基;或者R1和R2与R1和R2所连接的氮一起形成选自环杂烷基、取代的环杂烷基、杂芳基和取代的杂芳基的环;
p选自2、3、4和5;且
q为0或1。
式IV化合物包括:
及其盐。
另一个实施方案包括AKT抑制剂,诸如具有下式的哌立福辛(perifosine):
另一个实施方案包括AKT抑制剂,诸如抗-AKT抗体和抗-AKT DNA或RNA。
另一个实施方案包括AKT抑制剂,诸如寡核苷酸,包括反义寡核苷酸,其具有以下序列:5'ccagcccccaccagtccact 3'、5'cgccaaggagatcatgcagc 3'、5'gctgcatgatctccttggcg 3'、5'agatagctggtgacagacag 3'、5'cgtggagagatcatctgagg 3'、5'tcgaaaaggtcaagtgctac 3'、5'tggtgcagcggcagcggcag 3'和5'ggcgcgagcgcgggcctagc3'。
在一个实施方案中,所述激酶抑制剂为式III化合物。在一个实例中,式III化合物包括PI3-k抑制剂。在另一个实例中,式III化合物包括mTOR抑制剂。式III化合物具有下式:
其中,A、B、D和E独立地为-CH或N;
R8和R9一起形成5或6元芳族环、杂芳族环、碳环或杂环,其可为任选取代的。例如,R8和R9与它们连接的式III中的碳一起形成9-10元二环环系。二环环系的实施方案包括下列结构,其中表示式III环中的键:
其中R11和R12独立地选自氢、卤素、OH、氨基、二烷基氨基、单烷基氨基、C1-C6-烷基、-C(=O)O-(CRyRz)n-W或苯基,其任选地取代有卤素、OH、C1-C3烷基或环丙基甲基,其中W为C5-12芳基或杂芳基,Ry和Rz独立地为氢、卤素、-OH或C1-6烷基;或者R11和R12一起形成5-14元芳族环或杂芳族环。例如,R11和R12可与它们连接的碳和上述式III中的环一起形成12-14元三环环系,并且在一个实施方案中具有下列结构:
R’和R”与它们连接N的一起形成5、6或7元杂环,其可任选地取代有卤素、OH、氨基、二烷基氨基、单烷基氨基、C1-C6-烷基,所述杂环具有下列结构中的一种,其还可含有上文所列的取代基:
其中,G和G’独立地为C、O或N;
R10为芳族环或杂芳族环,其具有以下结构:
其中,X、Y、Z和Z’独立地为-CH或N;
R13为氢、卤素、OH、氨基、二烷基氨基、单烷基氨基、C1-C6-烷基或-N-(C=O)-N-R14,其中R14为C1-C6-烷基。R10的一个实例为:
其中,J为-N-(C=O)-N-,且R14为C1-C6-烷基。
式III化合物的实例包括PI3-k抑制剂:
另一个实施方案包括具有下式的mTOR抑制剂、其立体异构体、互变异构体或药用盐:
其中:
A为选自以下的环:吗啉-4-基、3,4-二氢-2H-吡喃-4-基、3,6-二氢-2H-吡喃-4-基、四氢-2H-吡喃-4-基、1,4-氧氮杂环庚-4-基、哌啶-1-基,且任选地取代有1至2个选自以下的取代基:-C(O)ORa、-C(O)NRaRb、-NRaRb、-ORa、-SRa、-S(O)2Rc、-S(O)Rc、-Rc、卤素、-NO2、-CN和-N3,其中Ra和Rb各自独立地选自氢、C1-6烷基、C1-6卤代烷基、C2-6烯基和C3-6环烷基,或者Ra和Rb与各自连接的氮原子一起组合形成3元至6元环,且Rc选自C1-6烷基、C1-6卤代烷基、C2-6烯基、C3-6环烷基;
R1和R2与它们连接的原子组合形成任选取代的吡咯烷、哌啶或高哌啶环,其中所述吡咯烷、哌啶或高哌啶环的氮原子被以下基团取代:
其中E为氢、C6-10芳基、C5-10杂芳基、C3-10环烷基、C3-10杂环烷基、C1-6烷基或C1-6杂烷基;且其中E任选地取代有1至5个选自以下的取代基:卤素、C1-6烷基、-NRdRe、-SRd、-ORd、-C(O)ORd、-C(O)NRdRe、-C(O)Rd、-NRdC(O)Re、-OC(O)Rf、-NRdC(O)NRdRe、-OC(O)NRdRe、-C(=NORd)NRdRe、-NRdC(=N-CN)NRdRe、-NRdS(O)2NRdRe、-S(O)2Rd、-S(O)2NRdRe、-Rf、-NO2、-N3/=O、-CN、-(CH2)1-4-NRdRe、-(CH2)1-4-SRd、-(CH2)1-4-ORd、 -(CH2)1-4-C(O)ORd、-(CH2)1-4-C(O)NRdRe、-(CH2)1-4-C(O)Rd、-(CH2)1-4-NRdC(O)Re、-(CH2)1-4-OC(O)Rf、-(CH2)1-4-NRdC(O)NRdRe、-(CH2)1-4-OC(O)NRdRe、-(CH2)1-4-C(=NORd)NRdRe、-(CH2)1-4-NRdC(=N-CN)NRdRe、-(CH2)1-4-NRdS(O)2NRdRe、-(CH2)1-4-S(O)2Rd、-(CH2)1-4-S(O)2NRdRe、-(CH2)1-4-NO2、-(CH2)1-4-N3或-(CH2)1-4-CN;其中Rd和Re各自独立地选自氢、C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、C3-7环烷基、C3-7杂环烷基、苯基和-(CH2)1-4-苯基,或者Rd和Re,当连接相同氮原子时组合形成3元至6元环;Rf选自C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、C3-7环烷基、C3-7杂环烷基、苯基和-(CH2)1-4-苯基;
F为选自以下的成员:C1-6亚烷基、C2-6亚烯基、C2-6亚炔基和C1-6亚杂烷基;其中F独立地取代有0至3个选自以下的取代基:卤素、-NRgRh、-SRg、-ORg、-C(O)ORg、-C(O)NRgRh、-NRgC(O)Ri、-OC(O)Ri、-NRgC(O)NRgRh、-OC(O)NRgRh、NRgS(O)2NRgRh、-S(O)2Rg、-S(O)2NRgRh、-Ri、-NO2、N3、=O、-CN、-(CH2)1-4-NRgRh、-(CH2)1-4-SRg、-(CH2)1-4-ORg、-(CH2)1-4-C(O)ORg、-(CH2)1-4-C(O)NRgRh、-(CH2)1-4-C(O)Rg、-(CH2)1-4-NRgC(O)Rh、-(CH2)1-4-OC(O)Ri、-(CH2)1-4-NRgC(O)NRgRh、-(CH2)1-4-OC(O)NRgRh、-(CH2)1-4-NRgS(O)2NRgRh、-(CH2)1-4-S(O)2Rg、-(CH2)1-4-S(O)2NRgRh、-(CH2)1-4-NO2、-(CH2)1-4-N3和-(CH2)1-4-CN;其中Rg和Rh各自独立地选自氢、C1-6烷基、C1-6卤代烷基、C1-6杂烷基、C3-7环烷基、C3-7杂环烷基、苯基和-(CH2)1-4-苯基,且任选地Rg和Rh,当连接相同氮原子时组合形成3元至6元环;Ri选自C1-6烷基、C1-6卤代烷基、C3-7环烷基、C3-7杂环烷基、苯基和-(CH2)1-4-苯基;
G为选自以下的成员:-C(O)-、-OC(O)-、-NHC(O)-、-NHC(=NOH)-、-S(O)2-和-NHS(O)2-;
m和p各自独立地为0至1的整数,其中如果m和p均为整数0,则E不为C1-6烷基或C1-6杂烷基;
其中由R1与R2组合形成的吡咯烷、哌啶或高哌啶还取代有0至5个选自以下的取代基:卤素、-NRjRk、-SRj、-ORj、-C(O)ORj、-C(O)NRjRk、-NHC(O)Rj、-OC(O)Rj、-Rm、-CN和=O,其中Rj和Rk各自独立地选自氢、C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、C3-5环烷基和C3-5杂环烷基,且Rj和Rk,当连接相同氮原子时,任选地组合形成3元至6元环;且Rm选 自C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、C3-5环烷基和C3-5杂环烷基;
B选自亚苯基、亚吡啶基(pyridylene)、亚嘧啶基(pyrimidylene)、亚哒嗪基(pyridazinylene)和亚吡嗪基(pyrazinyline)且取代有0至4个选自以下的取代基:卤素、-CN、-N3、-NO2、-C(O)ORn、-C(O)NRnRo、-NRnC(O)Ro、-NRnC(O)NRnRo、-ORn、-NRnRo和Rp;其中Rn和Ro独立地选自氢和C1-4烷基、C1-4卤代烷基、C1-4杂烷基、C3-7环烷基和C3-7杂环烷基,或者当连接相同的氮原子时,Rn和Ro任选地组合形成3元至6元环;Rp为C1-4烷基、C1-4卤代烷基、C3-7环烷基和C3-7杂环烷基,其中位于B的相邻原子上的不包括D基团的任意两个取代基任选地组合形成5元至6元碳环、杂环、芳基环或杂芳基环;且
D为选自以下的成员:-NR3C(O)NR4R5、-NR4R5、-C(O)NR4R5、-OC(O)OR4、-OC(O)NR4R5、-NR3C(=N-CN)NR4R5、-NR3C(=N-OR4)NR4R5、-NR3C(=N-NR4)NR4R5、-NR3C(O)R4、-NR3C(O)OR4、-NR3S(O)2NR4R5和-NR3S(O)2R4,其中R3选自氢、C1-6烷基、C1-6卤代烷基和C2-6烯基;R4和R5各自独立地选自氢、C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、C3-10环烷基、C3-10杂环烷基、C6-10芳基和C5-10杂芳基,且R4和R5,当连接相同的氮原子时,任选地组合形成5元至7元杂环或杂芳基环;且其中R3、R4和R5还取代有0至3个独立地选自以下的取代基:卤素、-NO2、-CN、-NRqRr、-ORq、-SRq、-C(O)ORq、-C(O)NRqRr、-NRqC(O)Rr、-NRqC(O)ORs、-(CH2)1-4-NRqRr、-(CH2)1-4-ORq、-(CH2)1-4-SRq、-(CH2)1-4-C(O)ORq、-(CH2)1-4-C(O)NRqRr、-(CH2)1-4-NRqC(O)Rr、-(CH2)1-4-NRqC(O)ORr、-(CH2)1-4-CN、-(CH2)1-4-NO2、-S(O)Rr、-S(O)2Rr、=O和-Rs;其中Rq和Rr选自氢、C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、C1-6杂烷基、C3-7环烷基、C3-7杂环烷基、C6-10芳基、C5-10杂芳基;且Rs,在每次出现时,独立地选自C1-6烷基、C1-6卤代烷基、C1-6杂烷基、C3-7环烷基、C3-7杂环烷基、C6-10芳基和C5-10杂芳基;且其中D基团与位于B环的相邻原子上的取代基任选地组合形成5元至6元杂环或杂芳基环。
在某些实施方案中:
A为选自以下的环:吗啉-4-基、3,4-二氢-2H-吡喃-4-基、3,6-二氢-2H-吡喃-4-基、四氢-2H-吡喃-4-基、1,4-氧氮杂环庚-4-基、哌啶-1-基,其任选地 被C1-C6烷基取代;
B选自亚苯基和亚嘧啶基;
D为-NR3C(O)NR4R5、-NR4R5、-C(O)NR4R5、-OC(O)OR4、-OC(O)NR4R5、-NR3C(=N-CN)NR4R5、-NR3C(=N-OR4)NR4R5、-NR3C(=N-NR4)NR4R5、-NR3C(O)R4、-NR3C(O)OR4、-NR3S(O)2NR4R5或-NR3S(O)2R4,其中R3为氢或C1-6烷基;R4和R5各自独立地为氢、C1-6烷基、C1-6卤代烷基或C3-10环烷基,或者R4和R5组合形成5元或6元杂环;
R1和R2与它们连接的原子组合形成吡咯烷、哌啶或高哌啶环,其中所述环的氮原子被以下基团取代:
其中E为氢、C6芳基、C5-6杂芳基、C1-6烷基或C5-6杂环烷基;且其中E任选地取代有1至5个选自以下的取代基:卤素、C1-6烷基、-NRdRe、-SRd、-ORd、-C(O)ORd、-C(O)NRdRe、-C(O)Rd、-NRdC(O)Re、-OC(O)Rf、-NRdC(O)NRdRe、-OC(O)NRdRe、-C(=NORd)NRdRe、-NRdC(=N-CN)NRdRe、-NRdS(O)2NRdRe、-S(O)2Rd、-S(O)2NRdRe、-Rf、-NO2、-N3、=O、-CN、-(CH2)1-4-NRdRe、-(CH2)1-4-SRd、-(CH2)1-4-ORd、-(CH2)1-4-C(O)ORd、-(CH2)1-4-C(O)NRdRe、-(CH2)1-4-C(O)Rd、-(CH2)1-4-NRdC(O)Re、-(CH2)1-4-OC(O)Rf、-(CH2)1-4-NRdC(O)NRdRe、-(CH2)1-4-OC(O)NRdRe、-(CH2)1-4-C(=NORd)NRdRe、-(CH2)1-4-NRdC(=N-CN)NRdRe、-(CH2)1-4-NRdS(O)2NRdRe、-(CH2)1-4-S(O)2Rd、-(CH2)1-4-S(O)2NRdRe、-(CH2)1-4-NO2、-(CH2)1-4-N3或-(CH2)1-4-CN;其中Rd和Re各自独立地选自氢、C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、C3-7环烷基、C3-7杂环烷基、苯基和-(CH2)1-4-苯基,或者Rd和Re,当连接相同的氮原子时组合形成3元至6元环;Rf选自C1-6烷基、C1-6卤代烷基、C3-7环烷基、C3-7杂环烷基、苯基和-(CH2)1-4-苯基;
F为C1-6亚烷基;
G为-C(O)-、-OC(O)-、-NHC(O)-、-NHC(=NOH)-、-S(O)2-或-NHS(O)2-;且
m和p独立地为0或1。
另一个实施方案包括mTOR抑制剂化合物,其包括:
另一个实施方案包括mTOR抑制剂雷帕霉素:
另一个实施方案包括具有下式的PI3-k抑制剂化合物或其药用盐:
其中:
R1和R2独立地选自氢、卤素、C1-6烷基、-NRdRe、-SRd、-ORd、-C(O)ORd、-C(O)NRdRe、-C(O)Rd、-NRdC(O)Re、-OC(O)Rf、-NRdC(O)NRdRe、-OC(O)NRdRe、-C(=NORd)NRdRe、-NRdC(=N-CN)NRdRe、-NRdS(O)2NRdRe、-S(O)2Rd、-S(O)2NRdRe、-Rf、-NO2、-N3、=O、-CN、-(CH2)1-4-NRdRe、-(CH2)1-4-SRd、-(CH2)1-4-ORd、-(CH2)1-4-C(O)ORd、-(CH2)1-4-C(O)NRdRe、-(CH2)1-4-C(O)Rd、-(CH2)1-4-NRdC(O)Re、-(CH2)1-4-OC(O)Rf、-(CH2)1-4-NRdC(O)NRdRe、-(CH2)1-4-OC(O)NRdRe、-(CH2)1-4-C(=NORd)NRdRe、-(CH2)1-4-NRdC(=N-CN)NRdRe、-(CH2)1-4-NRdS(O)2NRdRe、-(CH2)1-4-S(O)2Rd、-(CH2)1-4-S(O)2NRdRe、-(CH2)1-4-NO2、-(CH2)1-4-N3或-(CH2)1-4-CN;其中Rd和Re各自独立地选自氢、C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、C3-7环烷基、C3-7杂环烷基、苯基和-(CH2)1-4-苯基,或者Rd和Re,当连接相同的氮原子时组合形成3元至6元环;Rf选自C1-6烷基、C1-6卤代烷基、C3-7环烷基、C3-7杂环烷基、苯基和-(CH2)1-4-苯基;或者
R1和R2与它们连接的原子一起形成稠合的5元至6元杂环基环或杂芳基环,其任选地被氧代、卤素、C1-C3烷基或CF3取代。
实例PI3-k抑制剂包括下列化合物:
在一个实施方案中,所述激酶抑制剂为式V和VI的PI3K激酶抑制剂 或其立体异构体、几何异构体、互变异构体或药用盐:
其中:
R1选自H、F、Cl、Br、I、CN、-(CR14R15)mNR10R11、-C(R14R15)nNR12C(=Y)R10、-(CR14R15)nNR12S(O)2R10、-(CR14R15)mOR10、-(CR14R15)nS(O)2R10、-(CR14R15)nS(O)2NR10R11、-C(OR10)R11R14、-C(=Y)R10、-C(=Y)OR10、-C(=Y)NR10R11、-C(=Y)NR12OR10、-C(=O)NR12S(O)2R10、-C(=O)NR12(CR14R15)mNR10R11、-NO2、-NR12C(=Y)R11、-NR12C(=Y)OR11、-NR12C(=Y)NR10R11、-NR12S(O)2R10、-NR12SO2NR10R11、-SR10、-S(O)2R10、-S(O)2NR10R11、-SC(=Y)R10、-SC(=Y)OR10、C1-C12烷基、C2-C8烯基、C2-C8炔基、C3-C12碳环基、C2-C20杂环基、C6-C20芳基和C1-C20杂芳基;
R2选自H、F、Cl、Br、I、CN、CF3、-NO2、-C(=Y)R10、-C(=Y)OR10、-C(=Y)NR10R11、-(CR14R15)mNR10R11、-(CR14R15)nOR10、-(CR14R15)t-NR12C(=O)(CR14R15)NR10R11、-NR12C(=Y)R10、-NR12C(=Y)OR10、-NR12C(=Y)NR10R11、-NR12SO2R10、OR10、-OC(=Y)R10、-OC(=Y)OR10、-OC(=Y)NR10R11、-OS(O)2(OR10)、-OP(=Y)(OR10)(OR11)、-OP(OR10)(OR11)、SR10、-S(O)R10、-S(O)2R10、-S(O)2NR10R11、-S(O)(OR10)、-S(O)2(OR10)、-SC(=Y)R10、-SC(=Y)OR10、-SC(=Y)NR10R11、C1-C12烷基、C2-C8烯基、C2-C8炔基、C3-C12碳环基、C2-C20杂环基、C6-C20芳基和C1-C20杂芳基;
R3为连接单环杂芳基的碳、连接稠合的二环C3-C20杂环基的碳或连接稠合的二环C1-C20杂芳基的碳,其中所述单环杂芳基、稠合的热换C3-C20杂环基和稠合的二环C1-C20杂芳基任选地取代有一个或多选自以下的基团:F、Cl、Br、I、-CN、-NR10R11、-OR10、-C(O)R10、-NR10C(O)R11、-N(C(O)R11)2、-NR10C(O)NR10R11、-NR12S(O)2R10、-C(=O)OR10、-C(=O)NR10R11、C1-C12烷基和(C1-C12烷基)-OR10;
R10、R11和R12独立地为H、C1-C12烷基、C2-C8烯基、C2-C8炔基、C3-C12碳环基、C2-C20杂环基、C6-C20芳基或C1-C20杂芳基,
或者R10和R11与它们连接的氮一起形成任选地取代有一个或多个独立地选自以下基团的C2-C20杂环:氧代、(CH2)mOR12、NR12R12、CF3、F、Cl、Br、I、SO2R12、C(=O)R12、NR12C(=Y)R12、NR12S(O)2R12、C(=Y)NR12R12、C1-C12烷基、C2-C8烯基、C2-C8炔基、C3-C12碳环基、C2-C20杂环基、C6-C20芳基和C1-C20杂芳基;
R14和R15独立地选自H、C1-C12烷基或-(CH2)n-芳基,
或者R14和R15与它们连接的原子一起形成饱和的或部分不饱和的C3-C12碳环;其中所述烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基任选地取代有一个或多个独立地选自以下的基团:F、Cl、Br、I、CN、CF3、-NO2、氧代、R10、-C(=Y)R10、-C(=Y)OR10、-C(=Y)NR10R11、-(CR14R15)nNR10R11、-(CR14R15)nOR10、-NR10R11、-NR12C(=Y)R10、-NR12C(=Y)OR11、-NR12C(=Y)NR10R11、-(CR14R15)mNR12SO2R10、=NR12、OR10、-OC(=Y)R10、-OC(=Y)OR10、-OC(=Y)NR10R11、-OS(O)2(OR10)、-OP(=Y)(OR10)(OR11)、-OP(OR10)(OR11)、-SR10、-S(O)R10、-S(O)2R10、-S(O)2NR10R11、-S(O)(OR10)、-S(O)2(OR10)、-SC(=Y)R10、-SC(=Y)OR10、-SC(=Y)NR10R11、C1-C12烷基、C2-C8烯基、C2-C8炔基、C3-C12碳环基、C2-C20杂环基、C6-C20芳基和C1-C20杂芳基;
Y为O、S或NR12;
m为0、1、2、3、4、5或6;且
n为1、2、3、4、5或6。
实例PI3-k抑制剂包括下列化合物:
式V和VI化合物的制备
式V和VI化合物可通过包括与化学领域公知的那些方法类似的方法的合成路线进行合成,且包括WO 2006/046031,为了所有目的将其通过引用的方式全部并入本文。起始物质通常是从商业来源诸如Aldrich Chemicals(Milwaukee,WI)获得,或者使用本领域技术人员公知的方法容易地制备(例如,通过通常述于以下文献中的方法制备:Louis F.Fieserand Mary Fieser,Reagents for Organic Synthesis,v.1-19,Wiley,N.Y.(1967-1999ed.),或Beilsteins Handbuch der organischen Chemie,4,Aufl.ed.Springer-Verlag,Berlin,包括增刊(还可经Beilstein在线数据库获得)。
式V和VI化合物可使用用于制备以下物质的规程进行制备:其它噻吩、呋喃、嘧啶(US 6608053;US 6492383;US 6232320;US 6187777;US 3763156;US 3661908;US3475429;US 5075305;US 2003/220365;GB 1393161;WO93/13664);和其它杂环,其制备规程述于:Comprehensive Heterocyclic Chemistry,Editors Katritzky和Rees,PergamonPress,1984。
通过常规方法可将式V和VI化合物转化成药用盐,并且可将盐转化成游离化合物。药用盐的实例包括与无机酸的盐,所述无机酸诸如盐酸、氢溴酸、硫酸、硝酸和磷酸;以及和有机酸的盐,所述有机酸诸如甲磺酸、苯磺酸、甲酸、乙酸、三氟乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、乙磺酸、天冬氨酸和谷氨酸。所述盐可为甲磺酸盐、盐酸盐、磷酸盐、苯磺酸盐或硫酸盐。盐可为单盐或二盐。例如,所述甲磺酸盐可为单甲磺酸盐或二甲磺酸盐。
式V和VI化合物和盐还可以水合物或溶剂化物形式存在。
制备式V和VI化合物中有必要保护中间体的官能团(例如,伯胺或仲胺)。对此种保护的需要取决于远端(remote)官能基的性质和制备方法的条件而改变。合适的氨基保护基包括乙酰基、三氟乙酸基、叔丁氧基羰基(BOC)、 苄基氧基羰基(CBz)和9-芴基亚甲基氧基羰基(Fmoc)。本领域技术人员容易确定对此种保护的需要。对于保护基团及其用途的一般性描述参见T.W.Greene,Protective Groups in Organic Synthesis,John Wiley&Sons,New York,1991。
为了说明性目的,方案5-11显示了用于制备化合物以及关键中间体的一般方法。对于单个反应步骤的更详细描述,参见下文实施例部分。本领域技术人员应当理解的是,其它合成路线可用于合成本发明化合物。虽然特定起始物质和试剂在方案中描述并在下文讨论,但是其它起始物质和试剂可易于替代以得到多种衍生物和/或反应条件。此外,根据本公开内容,可使用本领域技术人员公知的常规化学进一步修饰有下文所述方法制备的多种化合物。
方案5
方案5显示分别由2-羧基酯,3-氨基噻吩和2-氨基,3-羧基酯噻吩试剂,即51和52,制备噻吩并嘧啶中间体55和56的一般方法,其中Hal为Cl、Br或I;且R1、R2和R10如针对式V和VI化合物或其前体或前药所定义。
方案6
方案6显示在碱性条件下在有机溶剂中用吗啉选择性替换来自二卤代噻吩并嘧啶中间体57和58的4-卤化物分别制备2-卤代,4-吗啉代噻吩并嘧啶化合物59和60的一般方法,其中Hal为Cl、Br或I;且R1和R2如针对式V和VI化合物或其前体或前药所定义。
方案7
方案7显示用于衍生化2-卤代,4-吗啉代,6-氢噻吩并嘧啶化合物61和62的6位的一般方法,其中R1为H。用锂化试剂处理61或62除去6位质子,接着加入酰化试剂R10C(O)Z,其中Z为离去基团,诸如卤化物、NHS酯、羧酸酯或二烷基氨基,得到2-卤代,4-吗啉代,6-酰基噻吩并嘧啶化合物 63和64,其中Hal为Cl、Br或I;且R2和R10如针对式V和VI化合物或其前体或前药所定义。用于制备6-甲酰基化合物(R10=H)的R10C(O)Z实例为N,N’-二甲基甲酰胺(DMF)。
方案8
方案8显示2-卤代嘧啶中间体(65和66)与单环杂芳基、稠合的二环杂环基或稠合的二环杂芳基硼酸(R15=H)或硼酸酯(R15=烷基)试剂67进行Suzuki型偶联制备式V和VI的2-取代的(Hy),4-吗啉代噻吩并嘧啶化合物(68和69)的一般方法,其中Hal为Cl、Br或I;且R1和R2如针对式V和VI化合物或其前体或前药所定义。关于Suzuki反应的综述参见:Miyauraet al.(1995)Chem.Rev.95:2457-2483;Suzuki,A.(1999)J.Organomet.Chem.576:147-168;Suzuki,A.in Metal-Catalyzed Cross-Coupling Reactions,Diederich,F.,Stang,P.J.,Eds.,VCH,Weinheim,DE(1998),pp 49-97。钯催化剂可为通常用于Suzuki型交叉偶联的任何钯催化剂,诸如PdCl2(PPh3)2、Pd(PPh3)4、Pd(OAc)2、PdCl2(dppf)-DCM、Pd2(dba)3/Pt-Bu)3(Owens et al(2003)Bioorganic&Med.Chem.Letters 13:4143-4145;Molander et al(2002)Organic Letters 4(11):1867-1870;US 6448433)。
方案9
方案9显示合成炔71的一般方法,所述炔71可用于制备化合物72和73的炔基化衍生物。炔丙基胺71可通过炔丙基溴70与式R10R11NH的胺(其中R10和R11独立地选自H、烷基、芳基和杂芳基,或者R10和R11与它们连接的氮一起形成杂环)在适宜碱(Cs2CO3等)存在下进行反应制备。关于炔基胺和相关合成的综述参见Booker-Milburn,K.I.,ComprehensiveOrganic Functional Group Transformations(1995),2:1039-1074;and Viehe,H.G.,(1967)Angew.Chem.,Int.Ed.Eng.,6(9):767-778。炔71最终可分别与中间体72(X2=溴代或碘代)或73(经Sonogashira偶联)反应得到化合物74和75,其中R2和R3如针对式V和VI化合物或其前体或前药所定义。
方案10
方案10显示合成炔77的一般方法,所述炔77可用于制备化合物72和73炔基化衍生物。偕-二烷基炔丙基胺77可使用由Zaragoza et al(2004)J.Med.Chem.,47:2833描述的方法制备。根据方案6,偕-二烷基氯76(R14和R15独立地为甲基、乙基或其它烷基)可与式R10R11NH的胺(其中R10和R11独立地选自H、烷基、芳基和杂芳基,或者R10和R11与它们连接的氮一起形成杂环)在CuCl和适宜的碱(例如TEA等)存在下反应得到炔77。炔77可分别与中间体72或73(经Sonogashira偶联)反应得到化合物78和79,其中R2和R3如针对式V和VI化合物或其前体或前药所定义。
方案11
方案11显示合成炔81的一般方案,所述炔81可用于制备化合物72和73的炔基化衍生物。丁-3-炔-1-胺81(其中R14和R15独立地为H、烷基、芳基、杂芳基,或者R14和R15与它们连接的碳原子一起形成碳环或杂环)可由炔80(LG=甲苯磺酸酯或其它离去基团)与式R10R11NH的胺(其中R10和R11独立地选自H、烷基、芳基和杂芳基,或者R10和R11与它们连接的氮一起形成杂环)使用由Olomucki M.et al(1960)Ann.Chim.5:845描述的实验方案反应来制备。根据方案5和6提供的描述,炔81最后可分别与中间体72或73(经Sonogashira偶联)反应得到化合物82和83,其中R2和R3如针对式V和VI化合物或其前体或前药所定义。
在上文定义的方法中,胺化步骤和Pd介导的交叉偶联步骤在常规条件下进行。钯催化剂可为通常用于Suzuki型交叉偶联的任何钯催化剂,诸如PdCl2(PPh3)2。还原剂通常为硼氢化物,诸如NaBH(OAc)3、NaBH4或NaCNBH4。
本发明还提供了阻断或减少复发肿瘤生长或复发癌细胞生长的方法。在某些实施方案中,受试者经受或同时经受癌症疗法。本文所述给予其它治疗、药剂或组合疗法阻断或减少复发肿瘤生长或复发癌细胞生长。
RNA构建物
在另一个实施方案中,本文所公开的主题涉及本文所描述的RNAi构建物。RNAi构建物是有用的Akt抑制剂。
药物制剂
散装组合物和各个体计量单位可含有固定量的上述药学活性剂。所述散装组合物是尚未形成个体剂量单位的物质。用作说明的剂量单位是口服剂量单位如片剂、丸剂、胶囊剂等。类似地,本文所描述的通过给予药物组合物治疗患者的方法还意欲涵盖给药散装组合物和个体剂量单位。
药物组合物还包含与本文所述那些等同的同位素标记的化合物,不同的是,一个或多个原子被具有与自然中通常发现的原子量或原子序数不同的原子量或原子序数的原子所替换。如所详细说明的任何具体原子或元素的所有同位素及其用途被考虑在化合物的范围内。可掺入化合物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、3H、11C、13C、 14C、13N、15N、15O、17O、18O、32P、33P、35S、18F、36Cl、123I和125I。某些同位素标记的化合物(例如用3H和14C标记的那些)在化合物和/或底物组织分布测定法中是有用的。氚化的(3H)和碳-14(14C)同位素因其易于制备和可检测性是有用的。此外,用较重同位素诸如氘(2H)的取代可提供由较大代谢稳定性产生的某些治疗学优点(例如增加体内半衰期或减少剂量需要量)并因此在某些情况下可为优选的。正电子发射同位素如15O、13N、11C和18F可用于正电子发射断层扫描(PET)研究以检查底物受体占据。同位素标记的化合物通常可通过以下方法制备:遵循与本文下述方案和/或实施例中所公开的那些操作步骤类似的操作步骤,用同位素标记的试剂替换非同位素标记的试剂。
另一个方面提供了药物组合物,其包含与一种或多种药用载体、助流剂、稀释剂或赋形剂结合的本文所披露的化合物。
适宜的载体、稀释剂和赋形剂是本领域技术人员公知的并包括物质诸如碳水化合物、蜡、水可溶解的和/或可溶胀的聚合物、亲水性或疏水性物质、明胶、油、溶剂、水等。所用的具体载体、稀释剂或赋形剂取决于化合物将适用的方式和目的。溶剂通常基于本领域技术人员认为对给予哺乳动物安全的溶剂(GRAS)来选择。通常,安全溶剂为无毒含水溶剂诸如水和在水中可溶或可混溶的其它无毒溶剂。合适的含水溶剂包括水、乙醇、丙二醇、聚乙二醇(例如PEG 400、PEG 300)等及它们的混合物。所述制剂还可包含一种或 多种缓冲剂、稳定剂、表面活性剂、湿润剂、润滑剂、乳化剂、悬浮剂、防腐剂、抗氧化剂、遮光剂、助流剂、加工助剂、着色剂、增甜剂、芳香剂、矫味剂和其它已知的添加剂以提供药物(即本发明的化合物或其药物组合物)的优美外观或有助于药品(即药剂)的制造。
所述制剂可用常规溶解和混合操作步骤来制备。例如,在一种或多种上面所描述的赋形剂存在下,将散装药物物质(即本发明的化合物或所述化合物的稳定形式(例如与环糊精衍生物或其它已知络合剂的络合物))溶于合适的溶剂中。将化合物典型地配制成药物剂型以提供容易可控的药物剂量并使患者能够顺应开具的用药方案。
供施用的药物组合物(或制剂)可取决于给予药物所用的方法以多种方式来包装。通常,用于分配的物品包括已在其中放置适当形式药物制剂的容器。合适的容器是本领域技术人员公知的并包括物质诸如瓶(塑料的和玻璃的)、小药囊(sachets)、安瓿、塑料袋、金属圆筒(cylinders)等。所述容器还可包括防干扰装置(tamper-proof assemblage)以防止欠慎重地获取包装的内容物。此外,所述容器已在其上放置了描述容器内容物的标签。所述标签还可包括适当的警告。
化合物的药物制剂可针对各种给药路线和类型来制备。例如,可将具有期望纯度的本文所述化合物任选地以冻干的制剂、磨细的粉末或水溶液的形式与药用稀释剂、载体、赋形剂或稳定剂混合(Remington's Pharmaceutical Sciences(1995)18th edition,MackPubl.Co.,Easton,PA)。制剂可通过以下方法来进行:在适当的pH,在环境温度,并以期望的纯度与生理学可接受的载体(即在所用剂量和浓度下对受者无毒的载体)混合。制剂的pH主要取决于化合物的具体用途和浓度,但可为约3至约8。
药物制剂优选地是无菌的。具体地,要用于体内给药的制剂必须是无菌的。此种灭菌易于通过经无菌滤膜的过滤来实现。
药物制剂通常可作为固体组合物、冻干制剂或作为水溶液来储存。
药物制剂将以与良好医学操作规范一致的方式(即量、浓度、时间表、过程、媒介物和给药途径)来配制和给药。该背景中需考虑的因素包括正在治疗的具体病症、正在治疗的具体哺乳动物、个体患者的临床病况、病症的原因、药剂递送部位、给药方法、给药程序安排和医学从业者已知的其它因素。要给予的化合物的“治疗有效量”会受这种考虑约束,并且是预防、改 善或治疗凝血因子介导的病症必需的最小量。此种量优选地在对主体有毒或致使主体对出血明显地更加敏感的量以下。
作为通常建议,口服或肠胃外给药的本文所述化合物的每剂量的起始药学有效量为约0.01-100mg/kg,即约0.1至20mg/kg患者体重/天,典型的所用化合物起始范围是0.3至15mg/kg/天。
可接受的稀释剂、载体、赋形剂和稳定剂在所用剂量和浓度对受者是无毒的,并且包括缓冲剂诸如磷酸盐、柠檬酸盐和其它有机酸;抗氧化剂,其包括抗坏血酸和甲硫氨酸;防腐剂(诸如十八烷基二甲基苄基氯化铵;氯化六甲双铵;氯化苯甲烃铵、氯化苯乙胺;苯酚、丁醇或苄醇;对羟基苯甲酸烷基酯,诸如对羟基苯甲酸甲酯或对羟基苯甲酸丙酯;邻苯二酚;间苯二酚;环己醇;3-戊醇;和间甲酚);低分子量(少于约10个残基)多肽;蛋白质,诸如血清白蛋白、明胶或免疫球蛋白;亲水聚合物,诸如聚乙烯吡咯烷酮;氨基酸,诸如甘氨酸、谷氨酰胺、天冬酰胺、组氨酸、精氨酸或赖氨酸;单糖、二糖和其它碳水化合物,其包括葡萄糖、甘露糖或糊精;螯合剂,诸如EDTA;糖类,诸如蔗糖、甘露醇、海藻糖或山梨醇;成盐的抗衡离子,诸如钠;金属络合物(例如Zn-蛋白质络合物);和/或非离子表面活性剂,诸如TWEENTM、PLURONICSTM或聚乙二醇(PEG)。所述活性药物成分还可在胶体药物递送系统(例如,脂质体、白蛋白微球、微乳剂、纳米粒和纳米囊)或在粗乳剂中,例如,通过凝聚技术或通过界面聚合作用,被裹在所制备的微囊中,例如,分别被裹在羟甲基纤维素或明胶微囊和聚-(甲基丙烯酸酯)微囊中。这些技术公开于Remington's Pharmaceutical Sciences18th edition,(1995)Mack Publ.Co.,Easton,PA.中。
可制备本文所述化合物的持续释放制剂。持续释放制剂的合适的实例包括含化合物的固体疏水性聚合物的半透型基质,所述基质是成形物品的形式,例如,薄膜或微囊。持续释放基质的实例包括聚酯、水凝胶(例如,聚(甲基丙烯酸2-羟乙基酯)或聚(乙烯醇))、聚交酯(US 3773919)、L-谷氨酸和γ-乙基-L-谷氨酸酯的共聚物、不可降解的乙烯-乙酸乙烯酯、可降解的乳酸-甘醇酸共聚物诸如LUPRON DEPOTTM(由乳酸-甘醇酸共聚物和醋酸亮丙瑞林组成的可注射的微球)和聚-D(-)3-羟基丁酸。
药物制剂包括适于本文所详述的给药途径的那些制剂。所述制剂可方便地以单位剂量形式呈现并可通过任何药学领域熟知的方法来制备。技术和制 剂通常可在Remington's Pharmaceutical Sciences 18th Ed.(1995)Mack Publishing Co.,Easton,PA中找到。这些方法包括使活性成分与组成一种或多种附属成分的载体结合的步骤。通常所述制剂通过以下方法制备:均匀并紧密地使活性成分与液体载体或细分的固体载体结合或与两者都结合,然后如果必要使产品成型。
适于口服给药的本文所述化合物的制剂可制成离散单位诸如丸剂、硬或软的例如明胶胶囊、扁胶囊(cachets)、糖锭(troches)、锭剂(lozenges)、含水或含油的混悬剂、可分散的粉末或颗粒、乳剂、糖浆剂或酏剂,其各含有预设量的本文所述化合物。这些制剂可按照用于药物组合物制造的本领域已知的任何方法来制备并且这些制剂可含有一种或多种包括增甜剂、矫味剂、着色剂和防腐剂的试剂,以便提供适口的制剂。压制片剂可通过以下方法来制备:在适宜机器中将任选地与粘合剂、润滑剂、惰性稀释剂、防腐剂、表面活性剂或分散剂混合的自由流动形式(诸如粉末或颗粒)的活性成分压缩。模塑片剂可通过以下方法制备:在适宜机器中模塑以惰性液体稀释剂润湿的粉末状活性成分的混合物。所述片剂可任选地进行包衣或刻线并任选地进行配制,以便提供活性成分从其中缓慢释放或控制释放。
药物制剂的片剂赋形剂可包括:充填剂(或稀释剂),以增加组成片剂的粉末状药物的容量体积;崩解剂,当其被摄入时以促进所述片剂破碎成小碎片,理想地是个体药物粒子,并促进药物的快速溶出和吸收;粘合剂,以确保能以期望的机械强度形成颗粒剂和片剂,并在其已经被压缩后保持片剂在一起,以防止其在包装、运输和日常装卸期间破碎成其组分粉末;助流剂,以改善生产期间组成片剂的粉末的流动性;润滑剂,以确保制造期间压片粉末不粘附到用来压片的设备上。它们改善经过压床的粉末混合物的流动并使当完成的片剂从设备中排出时的摩擦力和破损降到最低;抗粘附剂,其具有与助流剂的那些功能类似的功能,在制造期间减少组成片剂的粉末与用来冲压出片剂形状的机器之间的粘附;矫味剂,其掺合到片剂中以给予其更愉快的味道或掩蔽不愉快的味道;和着色剂,以有助于鉴定和患者顺应性。
含有与适于片剂制造的无毒的可药用的赋形剂混合的活性成分的片剂是可接受的。这些赋形剂可为,例如,惰性稀释剂,诸如碳酸钙或碳酸钠、乳糖、磷酸钙或磷酸钠;成粒和崩解剂,诸如玉米淀粉或藻酸;粘合剂,诸如淀粉、明胶或阿拉伯胶;和润滑剂,诸如硬脂酸镁、硬脂酸或滑石。片剂 可为不包衣的或可为由已知技术包衣(包括微囊化)的,以延迟胃肠道中的崩解和吸收并由此提供历时较长时间的持续作用。例如,可使用单独的或与蜡一起使用的时间延迟物质诸如单硬脂酸甘油酯或二硬脂酸甘油酯。
对于眼睛或其它外部组织(例如口和皮肤)的治疗,所述制剂优选地用作局部软膏或乳膏,其含有一定量的一种或多种活性成分,例如,0.075至20%w/w的活性成分。当以软膏配制时,所述活性成分可与石蜡族或与水可混溶的软膏基质一起使用。可选择地,可将所述活性成分与水包油乳膏基质一起配制在乳膏中。
如果需要,乳膏基质的水相可包括多元醇,即具有两个或更多个羟基的醇,如丙二醇、1,3-丁二醇、甘露醇、山梨醇、甘油和聚乙二醇(包括PEG 400)及它们的混合物。理想地,所述局部制剂可包含增强所述活性成分经皮肤或其它起作用区域的吸收或渗透的化合物。这些皮肤渗透增强剂的实例包括二甲基亚砜和相关的类似物。
乳剂的油相可由已知的成分以已知的方式来组成,其包括至少一种乳化剂与脂肪或油的混合物,或与脂肪和油两者的化合物。优选地,亲水性乳化剂与作为稳定剂的亲脂性乳化剂一起包括在内。合起来,具有或没有一种或多种稳定剂的一种或多种乳化剂组成乳化蜡,并且所述蜡与所述油和脂肪一起构成形成乳膏制剂油性分散相的乳化软膏基质。适于在制剂中使用的乳化剂和乳化稳定剂包括60、80、鲸蜡硬脂醇(cetostearyl alcohol)、苄醇、肉豆蔻醇(myristyl alcohol)、单硬脂酸甘油酯和月桂基硫酸钠。
药物制剂的含水混悬液含有与适于制备含水混悬液的赋形剂混合的活性物质。这些赋形剂包括悬浮剂,诸如羧甲基纤维素钠、交联羧甲纤维素、聚维酮、甲基纤维素、羟基丙基甲基纤维素、藻酸钠、聚乙烯基吡咯烷酮、黄蓍胶和阿拉伯胶;和分散剂或润湿剂,诸如天然存在的磷脂(例如卵磷脂)、亚烷基氧化物与脂肪酸的缩合产物(例如聚氧乙烯硬脂酸酯)、环氧乙烷与长链脂肪醇的缩合产物(例如十七亚乙基氧基鲸蜡醇)、环氧乙烷与由脂肪酸和己糖醇酐衍生的偏酯的缩合产物(例如脱水山梨醇聚氧乙烯醚单油酸酯)。所述含水混悬液还可含有一种或多种防腐剂诸如对羟基苯甲酸乙酯或对羟基苯甲酸正丙酯,一种或多种着色剂,一种或多种矫味剂和一种或多种增甜剂诸如蔗糖和糖精。
药物组合物可为无菌可注射制剂的形式,诸如无菌可注射的含水或油质 混悬液。该混悬液可按照已知的技术使用已在上面提到的那些适宜的分散剂或湿润剂和悬浮剂来配制。所述无菌可注射制剂可为无毒的肠胃外可接受的稀释剂或溶剂中的溶液或混悬液,诸如1,3-丁二醇中的溶液或由冻干粉末制备的溶液。在可接受的媒介物和溶剂之中可使用的是水、林格溶液和等渗的氯化钠溶液。此外,无菌固定油照例可用作溶剂或混悬介质。为此,可使用任何温和的固定油,其包括合成的甘油单酯或甘油二酯。此外,脂肪酸诸如油酸同样可用于可注射制剂的制备。
可与载体材料组合以生产单个剂型的活性成分的量会取决于所治疗的主体和具体的给药模式而改变。例如,意欲对人口服给药的定时释放制剂可含有大约1至1000mg与适当且便利的量的载体物质化合的活性物质,所述载体物质可占总体组合物的约5至约95%(重量:重量)。可制备药物组合物为给药提供可容易测量的量。例如,意欲静脉输注的水溶液可每毫升溶液含有约3至500μg所述活性成分,从而使合适容量的输注能以约30mL/小时的速率进行。
适于肠胃外给药的制剂包括含水的和非水的无菌注射液,其可含有抗氧化剂、缓冲剂、抑菌剂和使所述制剂与预期受者血液等渗的溶质;及含水的和非水的无菌混悬液,其可包括悬浮剂和增稠剂。
适于对眼睛局部给药的制剂还包括滴眼剂,其中所述活性成分溶于或混悬于合适的载体中,尤其用于所述活性成分的含水溶剂。所述活性成分优选地存在于如下这样的制剂中:约0.5至20%w/w浓度,例如约0.5至10%w/w,例如约1.5%w/w。
适于在口中局部给药的制剂包括锭剂,其包含矫味剂中的活性成分,所述矫味剂通常为蔗糖和阿拉伯胶或黄蓍胶;软锭剂,其包含惰性基质中的活性成分,所述惰性基质诸如明胶和甘油,或蔗糖和阿拉伯胶;和漱口剂,其包含合适的液体载体中的所述活性成分。
直肠给药的制剂可作为使用适宜基质的栓剂存在,所述基质包含例如可可脂或水杨酸酯。
适于肺内或鼻腔给药的制剂具有例如0.1至500微米(包括0.1至500微米粒径,增量微米如0.5微米、1微米、30微米、35微米等)粒径,所述制剂通过经鼻通道的快速吸入或通过经口的吸入来给药以便到达肺泡囊。合适的制剂包括所述活性成分的含水溶液或含油溶液。适于气溶胶或干粉给药的 制剂可按照常规方法来制备且可在如下文所述的病症的治疗和预防中与其它治疗剂如此前所用的化合物一起递送。
适于阴道给药的制剂可作为阴道栓剂、棉塞、乳膏剂、凝胶剂、糊剂、泡沫剂或喷雾剂,除所述活性成分之外其应含有本领域已知的应是适当的这些载体。
所述制剂可包装在单位剂量或多个剂量容器中,例如密封的安瓿和小瓶,并可储存在冷冻干燥(冻干)条件下,使用之前仅需加入无菌液体载体,例如水,立即供注射用。临时的注射液和混悬液是从先前所描述的这类无菌粉末、颗粒和片剂制备的。优选的单位剂量制剂是如本文上面所详述含每日剂量或单位每日亚剂量活性成分的那些制剂,或其适当部分的活性成分的那些制剂。
另一个方面还提供了兽用组合物,其因此包含与兽用载体一起使用的至少一种如上文所定义的活性成分。兽用载体是用于给予所述组合物的物质并可为固体、液体或气态物质,所述物质以其它方式是兽医学领域惰性的或可接受的并且是与所述活性成分相容的。这些兽用组合物可以肠胃外给药、口服给药或以任何其它期望的途径给药。
组合疗法
组合疗法可以同时或先后用药方案来给药。当先后给药时,所述组合可在两次或更多次给药中给药。所述组合给药包括使用分开的制剂或单个药物制剂的共给药,和以任一次序的连续给药,其中优选地有两种(或所有)活性剂同时发挥其生物学活性的时间段。
对于任意上述共同给药的药剂,合适的剂量是目前所用的那些剂量并因为新近识别的药剂和其它治疗方法的组合作用(协同作用)可被降低。
化合物可通过任何适于所治疗疾病的途径来给药。合适的途径包括口服、肠胃外(包括皮下、肌内、静脉内、动脉内、吸入、皮内、鞘内、硬膜外和输注技术)、经皮、直肠、经鼻、局部(包括口腔和舌下)、阴道、腹膜内、肺内和鼻内途径。局部给药还可涉及使用经皮给药,诸如透皮贴剂或离子电渗疗法装置。药物制剂在Remington's Pharmaceutical Sciences,18th Ed.,(1995)Mack Publishing Co.,Easton,PA中有论述。其它药物制剂的实例可在Liberman,H.A.and Lachman,L.,Eds.,Pharmaceutical Dosage Forms,Marcel Decker,Vol 3,2nd Ed.,New York,NY中找到。对于局部免疫抑制治疗,可通 过病灶内给药给予所述化合物,其包括灌注或移植前使所述移植物与所述抑制剂接触。应当理解的是,优选的途径可随例如受者的情况而改变。在口服给予化合物的情况下,可将其与药用载体、助流剂或赋形剂一起配制成丸剂、胶囊、片剂等。在肠胃外给予化合物的情况下,如下文所详述的,可将其与药用肠胃外媒介物或稀释剂一起并以单位剂量可注射的形式配制。
治疗人类患者的剂量可为约10至约1000mg化合物。典型的剂量可为约100mg至约300mg所述化合物。可以每日一次(QID)、每日两次(BID)或更频繁地给予剂量,这取决于药物动力学(PK)和药效学(PD)性质,所述性质包括具体化合物的吸收、分布、代谢和排泄。此外,毒性因素可影响剂量和给药方案。当口服给药时,丸剂、胶囊或片剂可在指定的时间段内以每日吞服或较不频繁地吞服。所述给药方案可重复多个治疗循环。
制品
在另一个实施方案中,本发明提供了制品或“试剂盒”,其含有可用于治疗上文所述疾病和病症的化合物。在一个实施方案中,试剂盒包含含有化合物的容器。试剂盒还可在容器上或附随于容器包含标签或药品说明书。术语“药品说明书”用于指习惯上包括在治疗产品商品化包装内的说明书,其含有涉及这些治疗产品使用的有关适应症、用法、用量、给药方法、禁忌症和/或警告的信息。合适的容器包括例如瓶、小瓶、注射器、泡罩包装等。容器可由多种物质诸如玻璃或塑料形成。容器可容纳对治疗所述疾病有效的化合物或其制剂,并可以具有无菌存取口(sterile access port)(例如,容器可为具有可被皮下注射针头刺破的塞子的静脉内注射液袋或小瓶)。组合物中至少一种活性剂为本文所述化合物。标签或药品说明书标明所述组合物用于治疗选择的疾病,诸如癌症。在一个实施方案中,标签或药品说明书标明包含本文所述化合物的组合物可用于治疗由异常细胞生长造成的病症。标签或药品说明书还可标明组合物可用于治疗其它病症。可选择地,或另外地,制品还可包含第二容器,其包含药用缓冲剂,诸如注射用抑菌水(BWFI)、磷酸盐缓冲盐水、林格溶液和葡萄糖溶液。它还可包含从商业或使用者观点期望的其它物质,包括其它缓冲剂、稀释剂、滤器、注射针头和注射器。
在另一个实施方案中,试剂盒适于递送固体口服形式的本文述化合物,诸如片剂或胶囊。这种试剂盒优选地包含若干单位剂量。这些试剂盒可包含具有以其预期使用顺序为导向的剂量的卡片。这种试剂盒的实例为“泡罩包 装”。泡罩包装为包装工业中所公知的并广泛用于包装药物单位剂型。如果需要,可提供记忆辅助器(memory aid),例如以数字、字母或其它标记的形式或用日历插页,其在治疗时间表中指明可给药的日期。
按照一个实施方案,试剂盒可包含(a)其中包含本文所述化合物的第一容器;和任选的(b)其中包含第二药物制剂的第二容器,其中所述第二药物制剂包含具有抗过增殖活性的第二化合物。可选择地,或另外地,所述试剂盒还可包含第三容器,其包含药用缓冲剂,诸如抑菌的注射用水(BWFI)、磷酸盐缓冲盐水、林格溶液和葡萄糖溶液。它还可包含从商业或使用者观点期望的其它物质,包括其它缓冲剂、稀释剂、滤器、注射针头和注射器。
患者的响应可使用表明对患者有益处的任何终点来评估,包括但不限于:(1)一定程度地抑制疾病进展,包括减缓和完全阻滞;(2)缩小病灶尺寸;(3)抑制(即减轻、减缓或完全终止)疾病细胞浸润入临近周围器官和/或组织;(4)抑制(即减轻、减缓或完全终止)疾病扩散;(5)一定程度地减轻与病症有关的一种或多种症状;(6)治疗后无疾病呈现的时间延长;和/或(8)治疗后给定时间点的死亡率降低。
临床益处可通过评估各种终点来测量,例如,一定程度地抑制疾病进展,包括减缓和完全阻滞;减少疾病发作(episode)和/或症状的次数/数量;缩小病灶尺寸;抑制(即减轻、减缓或完全终止)疾病细胞浸润入临近周围器官和/或组织;抑制(即减轻、减缓或完全终止)疾病扩散;降低自身免疫应答,其可以,但不必须导致疾病病灶的退化或消除;一定程度地减轻与病症有关的一种或多种症状;治疗后无疾病呈现的时间延长,例如无进展存活期;增加总体存活期;响应率更高;和/或治疗后给定时间点的死亡率降低。
术语“益处”广义使用并且是指任何期望的效果,明确地包括本文所定义的临床益处。
与一种或多种其它治疗剂“组合”给药包括同时(simultaneous)(同时(concurrent))和/或以任意次序连续(consecutive)给药。
本文使用的术语“同时”是指两种或更多种治疗剂的给药,其中至少部分给药在时间上重叠。因此,同时给药包括这样的给药方案:中断给药一种或多种其它药剂后继续给药一种或多种药剂。
已经确定的是,在一个对AKT抑制剂发生抗性的实施方案中,某些组合针对某些癌症表型提供改善的效果。例如,某些组合针对于PTEN突变、 AKT突变(例如过表达或扩增)、PI3K突变或Her2/ErbB2扩增或突变相关的癌症提供改善的效果。因此,在一个实施方案中,当所述癌症对AKT抑制剂发生抗性时,本文所述某些组合可具体地用于针对这些类型的癌症。
PTEN状态可通过本领域已知的任何合适方式来测量。在一个实例中,使用IHC。可选择地,可使用Western印迹分析。对PTEN的抗体为市售的(Cell Signaling Technology,Beverly,MA,Cascade Biosciences,Winchester,MA)。针对PTEN状态的IHC和Western印迹分析的实例操作描述于Neshat,M.S.et al.Enhanced sensitivity of PTEN-deficienttumors to inhibition of FRAP/mTOR,Proc.Natl Acad.Sci.USA 98,10314–10319(2001)以及Perren,A.,et.al.Immunohistochemical Evidence of Loss of PTEN Expressionin Primary Ductal Adenocarcinomas of the Breast,American Journal ofPathology,Vol.155,No.4,October 1999中。此外,使用本领域已知的技术鉴定与AKT突变、与PI3K突变和与Her2/ErbB2扩增或突变相关的癌症。在一个实例中,使用IHC确定患者或组织样品的PTEN状态,并且对所述样品或患者进行组织学评分(histo score)或HScore。使用公式计算HScore的实例方法为:HScore=(%1+细胞x 1)+(%2+细胞x 2)+(%3+细胞x 3)(参见Shoman,N,et.al,Mod Path(2005)18,250-259)。来自相同患者或一批患者的非癌性组织的平均PTEN HScore可用于确定患者或样品HScore是否低或缺失。在一个实例中,小于200的HScore被认为是低的且对应于PTEN低,而约0的HScore则被认为是缺失的。
包含靶标基因或生物标志物的样品可通过本领域公知的方法获得,并且其适用于特定类型和位置的感兴趣癌症。参见定义部分。例如,癌性病灶的样品可通过切除、支气管镜检查、细针抽吸、支气管刷检、或自痰、胸膜液或血液获得。基因或基因产物可由癌症或肿瘤组织或其它本体样品诸如尿、痰、血清或血浆检测。上述用于检测靶标基因或基因产物的相同技术科适用于其它本体样品。癌细胞从癌症病灶脱落下来并出现在此类本体样品中。通过筛选这些本体样品,可实现对于这些癌症的简单早期诊断。此外,通过对此类本体样品测试靶标基因或基因产物,可更加容易地检测治疗的进程。
对组织制备物富集癌细胞的手段是本领域已知的。例如,可从石蜡或低温保存的切片中分离组织。癌细胞还可通过流式细胞术或激光捕捉显微解剖而与正常细胞分开。这些以及其它从正常细胞中分离癌性细胞是本领域公知 的。如果癌组织被正常细胞高度污染,则检测签名基因(signature gene)或蛋白质表达序型可能更为困难,然而最小化污染和/或假阳性/阴性结果的技术是已知的,其中一些在下文中有述。例如,还可对样品评估生物标志物的存在,所述生物标志物已知与感兴趣的癌细胞相关但与相应的正常细胞无关,反之亦然。
在某些实施方案中,使用免疫组织化学(“IHC”)和染色方案来检验样品中蛋白质的表达。组织切片的免疫组织化学染色已经显示为评估或检测样品中蛋白质存在的可靠方法。免疫组织化学技术利用抗体来探查和原位显现细胞抗原,通常通过显色或荧光方法。
组织样品可用常规方法固定(即进行防腐处理)(参见例如,“Manual ofHistological Staining Method of the Armed Forces Institute of Pathology,”3rdedition(1960)Lee G.Luna,HT(ASCP)Editor,The Blakston Division McGraw-Hill BookCompany,New York;The Armed Forces Institute of Pathology Advanced LaboratoryMethods in Histology and Pathology(1994)Ulreka V.Mikel,Editor,Armed ForcesInstitute of Pathology,American Registry of Pathology,Washington,D.C.)。本领域技术人员应当理解的是,对固定剂的选择取决于对组织是进行组织学染色还是进行其它分析。本领域技术人员还应当理解的是,固定所用时间的长短取决于组织样品的大小和所用的固定剂。例如,中性缓冲的福尔马林、Bouin氏或多聚甲醛可用于固定组织样品。
通常,先将组织样品固定,再通过一组递增系列的乙醇来脱水,浸润,用石蜡或其它切片基质包埋,使组织样品得以切片。可选择地,可对组织进行切片并将所得切片固定。例如,可通过常规方法在石蜡中包埋并处理组织样品(参见例如“Manual of HistologicalStaining Method of the Armed Forces Institute of Pathology",见上文)。可使用的石蜡的实例包括但不限于Paraplast、Broloid和Tissuemay。一旦将组织样品包埋后,可用切片机等对组织进行切片(参见例如“Manual of Histological Staining Method of theArmed Forces Institute of Pathology”,见上文)。关于该规程,例如,切片厚度可为约3至约5微米。一旦切好,可通过数种标准方法将切片贴在载玻片上。载玻片粘合剂的实例包括但不限于硅烷、明胶、聚-L-赖氨酸等。例如,石蜡包埋的切片可粘附在带正电的载玻片和/或涂覆有聚-L-赖氨酸的载玻片上。
如果使用石蜡作为包埋的材料,通常将组织切片脱蜡,然后在水中重新 水合。组织切片可通过多种常规方法脱蜡。例如,可用二甲苯和逐渐递减系列的乙醇(参见例如“Manual of Histological Staining Method of the Armed Forces Institute ofPathology”,见上文)。可选择地,可使用市售非有机脱蜡剂诸如Hemo-De7(CMS,Houston,Texas)。
在某些实施方案中,在样品制备后,可使用IHC来分析组织切片。IHC可与其它技术诸如形态学染色和/或荧光原位杂交组合进行。可利用IHC的两种常用方法,即直接和间接测定法。根据第一种测定法,直接测定抗体对靶标抗原的结合。该直接测定法使用经标记的试剂,诸如荧光标签或酶标记的第一抗体,其可在没有进一步抗体相互作用的情况下显现。在典型的间接测定法中,未偶联的第一抗体与抗原结合,然后经标记的第二抗体与第一抗体结合。若第二抗体与酶标记物偶联,则加入显色或荧光底物以提供抗原的显现。因为若干第二抗体可与第一抗体上的不同表位反应,所以发生了信号放大。
用于免疫组织化学的第一抗体和/或第二抗体通常会用可检测的部分进行标记。有大量标记物可用,通常可将它们分成如下类:
(a)放射性同位素,诸如35S、14C、125I、3H和131I。可使用例如Current Protocols inImmunology,Volumes 1and 2,Coligen et al.,Ed.Wiley-Interscience,New York,NewYork,Pubs.(1991)中所述的技术用放射性同位素标记抗体,并且可使用闪烁计数测量放射性。
(b)胶体金颗粒。
(c)荧光标记物,其包括但不限于稀土元素螯合物(铕螯合物);德克萨斯红(TexasRed);罗丹明;荧光素;丹酰;丽丝胺(Lissamine);伞形酮(umbelliferone);藻红蛋白(phycocrytherin);藻青蛋白(phycocyanin)或市售荧光团,诸如SPECTRUM ORANGE7和SPECTRUM GREEN7和/或任意一种或多种上述标记物的衍生物。例如,可使用CurrentProtocols in Immunology,见上文中披露的技术使荧光标记物与抗体偶联。可使用荧光计定量荧光。
(d)可得到各种酶-底物标记物并且美国专利4,275,149提供了其中一些的综述。所述酶一般催化可使用各种技术测量的显色底物的化学改变(alteration)。例如,酶可催化底物中的颜色变化,所述变化可通过分光光度法测量。可选择地,酶可改变底物的荧光或化学发光。用于定量荧光变化的技术如上文所述。化学发光底物通过化学反应变成电激发的且然后可发射可 测量的光(例如使用化学发光计)或向荧光接受器提供能量。酶标记物的实例包括荧光素酶(例如荧火虫荧光素酶和细菌荧光素酶;美国专利4,737,456);萤光素;2,3-二酞嗪二酮类;苹果酸脱氢酶;尿素酶;过氧化物酶,诸如辣根过氧化物酶(HRPO);碱性磷酸酶(AP);β-半乳糖苷酶;葡萄糖淀粉酶;溶菌酶;糖氧化酶(例如葡萄糖氧化酶、半乳糖氧化酶和葡萄糖-6-磷酸脱氢酶);杂环氧化酶(诸如尿酸酶和黄嘌呤氧化酶);乳过氧化物酶;微过氧化物酶等。用于使酶与抗体偶联的技术描述于O'Sullivan et al.,Methodsfor the Preparation of Enzyme-Antibody Conjugates for use in EnzymeImmunoassay,in Methods in Enzym.(ed.J.Langone&H.Van Vunakis),Academic press,New York,73:147-166(1981)中。
酶-底物组合的实例包括,例如:
(i)辣根过氧化物酶(HRPO)与作为底物的过氧化氢酶,其中过氧化氢酶氧化染料前体(例如邻苯二胺(OPD)或3,3',5,5'-四甲基联苯胺盐酸盐(TMB));
(ii)碱性磷酸酶(AP)与作为显色底物的磷酸对硝基苯基酯;和
(iii)β-D-半乳糖苷酶(β-D-Gal)与显色底物(例如对硝基苯基-β-D-半乳糖苷酶)或荧光底物(例如4-甲基伞形基-β-D-半乳糖苷酶)。
本领域技术人员可利用许多其它酶-底物组合。有关它们的一般性综述参见美国专利4,275,149和4,318,980。有时,将标记物与抗体间接偶联。本领域技术人员了解实现该目的的多种技术。例如,可将抗体与生物素偶联,而且可将上述四大类标记物中的任一种与亲合素偶联,或反之亦然。生物素选择性结合亲合素,由此标记物可与抗体以这种间接方式偶联。可选择地,为了实现标记物与抗体的间接偶联,将抗体与小型半抗原偶联,并将上述不同类型的标记物之一与抗半抗原抗体偶联。由此,可实现标记物与抗体的间接偶联。
在上文讨论的样品制备规程外,可能还需要在IHC之前、期间或之后对组织切片进行进一步的处理。例如,可实施表位修复法,诸如在柠檬酸盐缓冲液中对组织样品进行加热(参见例如Leong et al.Appl.Immunohistochem.4(3):201(1996))。
在任选的封闭步骤后,组织切片在合适条件下暴露于第一抗体足够时间,使得第一抗体结合至组织样品中的靶蛋白抗原。实现这一目的的适宜条 件可通过常规实验来确定。抗体与样品的结合程度通过使用上文讨论的任一种可检测标记物来测定。在某些实施方案中,标记物为酶标记物(例如HRPO),其催化生色底物诸如3,3'-二氨基联苯胺色原体(chromogen)的化学改变。在一个实施方案中,将酶标记物偶联至特异性结合第一抗体的抗体(例如第一抗体为兔多克隆抗体,第二抗体为山羊抗兔抗体)。
可将如此制备的标本放置好并盖上盖玻片。然后进行载玻片评估,例如利用显微镜,并且可采用本领域常规使用的染色强度标准。染色强度标准可如下评估:
表1
染色样式 | 得分 |
在细胞中没有观察到染色。 | 0 |
在超过10%的细胞中检测到微弱/刚刚可察觉的染色。 | 1+ |
在超过10%的细胞中观察到弱至中等的染色。 | 2+ |
在超过10%的细胞中观察到中等至强的染色。 | 3+ |
在一些实施方案中,约1+或更高的染色样式得分为诊断性和/或预兆性的。在某些实施方案中,IHC中约2+或更高的染色样式得分为诊断性和/或预兆性的。在其它实施方案中,约3或更高的染色样式得分为诊断性和/或预兆性的。在一个实施方案中,应当理解的是,当使用IHC检验来自肿瘤或结肠腺瘤的细胞和/或组织,一般在肿瘤细胞和/或组织中确定或评估染色(与可存在于样品中的基质或外围组织正相反)。
在备选方法中,可在足以使抗体-生物标志物复合物形成的条件下使样品接触对所述生物标志物特异性的抗体,然后检测所述复合物。可以多种方式来检测生物标志物的存在,诸如通过Western印迹和ELISA规程,其用于测定极其广泛的组织和样品,包括血浆或血清。可利用多种使用此种测定法的免疫测定技术,参见例如美国专利4,016,043、4,424,279和4,018,653。这些包括非竞争性类型的单位点和双位点或“三明治/夹心式”测定法,以及传统的竞争性结合测定法。这些测定法也包括经标记抗体对靶生物标志物的直接结合。
三明治测定法是最有用且常用的测定法之一。简言之,在一种典型的正向测定法(forward assay)中,将未标记的抗体固定化在固体基片上,使待测试的样品接触所结合的分子。温育足以容许抗体-抗原复合物形成的合适长 度的一段时间后,添加对抗原特异性的、用能够生成可检测信号的报道分子标记的第二抗体并温育足以使另一复合物即抗体-抗原-标记抗体形成的一段时间。洗去任何未反应的物质,并通过由报道分子生成的信号的观察结果来测定抗原的存在。结果可为定性的,即通过可见信号的简单观察,或者可为定量的,即通过与包含已知量生物标志物的对照样品比较。
上述测定法的变化形式包括同时测定法,其中将样品和经标记抗体二者同时添加至所结合的抗体。这些技术是本领域技术人员公知的,包括任何显而易见的微小变化。在一种典型的正向三明治测定法中,具有针对生物标志物的特异性的第一抗体或是共价的或被动的结合至固体表面。所述固体表面典型地为玻璃或聚合酶,最常用的聚合物是纤维素、聚丙烯酰胺、尼龙、聚苯乙烯、聚氯乙烯或聚丙烯。所述固体支持物可为管、珠、微孔板的盘或适于实施免疫测定法的任何其它表面的形式。结合过程是本领域公知的,一般由交联、共价结合或物理吸附组成,清洗聚合物-抗体复合物,为测试样品做好准备。将待测样品的等分试样添加至固相复合物,并在足够时间(例如2-40分钟或过夜,如果更方便的话)与合适条件(例如室温至40℃,诸如25℃至32℃,含两端值)下温育以容许抗体中存在的任何亚基结合。温育期后,将抗体亚基固相清洗并干燥并与对生物标志物的一部分特异性的第二抗体一起温育。所述第二抗体连接用于指示第二抗体对分子标志物结合的报道分子。
一种备选方法涉及将样品中的靶生物标志物固定化,然后将固定化的靶物暴露于未标记的或未用报道分子标记的特异性抗体。取决于靶标的量和报道分子信号的强度,所结合的靶标可为通过用抗体直接标记而可检测的。可选择地,将经标记的、对第一抗体特异性的第二抗体暴露于靶标-第一抗体复合物以形成靶标-第一抗体-第二抗体三元复合物。所述复合物通过报道分子发射的信号来检测。“报道分子”在用于本说明书时指通过其化学本质提供分析上可鉴定的信号从而容许检测抗原所结合抗体的分子。这类测定法中最常用的报道分子是酶、荧光团或含放射性核素的分子(即放射性同位素)和化学发光分子。
在酶免疫测定法的情况中,有酶偶联至第二抗体,一般借助于戊二醛或高碘酸盐(periodate)。然而,正如易于领会的,有极其多种不同偶联技术可供技术人员使用。常用的酶包括辣根过氧化物酶、葡萄糖氧化酶、β-半乳糖 苷酶和碱性磷酸酶等等。与特定酶一起使用的底物一般选择成在被相应的酶水解后生成可检测的颜色变化。合适的酶的实例包括碱性磷酸酶和过氧化物酶。还可采用荧光底物,其生成荧光产物而非上文所述显色底物。在所有情况中,将酶标记的抗体添加至第一抗体-分子标志物复合物,容许结合,然后洗去过量的试剂。然后将含有适宜底物的溶液添加至抗体-抗原-抗体复合物。底物会与第二抗体所连接的酶起反应,给出定性可视信号,其可进一步量化,通常通过分光光度法,以给出样品中存在的生物标志物的量的指示。可选择地,可将荧光化合物(诸如荧光素和罗丹明)化学偶联至抗体而不改变其结合能力。在被特定波长的光照射而激活后,荧光团标记的抗体吸收光能,在分子中诱导激发状态,接着以光学显微镜在视觉上可检测的特征性颜色发光。在EIA中,容许荧光标记的抗体结合至第一抗体-分子标志物复合物。洗去未结合的试剂后,再将剩余的三元复合物暴露于适宜波长的光,所观察到的荧光指示存在感兴趣的分子标志物。免疫荧光和EIA技术都是本领域已完善建立的。然而,还可采用其它报道分子,诸如放射性同位素、化学发光或生物发光分子。
本发明涵盖,上文所述技术还可用于检测一种或多种靶标基因的表达。
所述方法进一步包括检验组织或细胞样品中一种或多种靶标基因的mRNA的存在和/或表达的方案。用于评估细胞中mRNA的方法是公知的,包括例如使用互补DNA探针的杂交测定法(诸如使用经标记的对一种或多种基因特异性的核糖核酸探针的原位杂交、Northern印迹和相关技术,所述基因包括但不限于S100A9、S100A9、Tie-1、Tie-2、CD31、CD34、VEGFR1、VEGFR2、PDGFC、IL-1β、PlGF、HGF、IL-6和LIF)和各种核酸扩增测定法(诸如使用对一种或多种基因特异性的互补引物的RT-PCR,及其它扩增型检测方法,诸如例如分支DNA、SISBA、TMA等)。
可使用Northern、点印迹或PCR分析对来自哺乳动物的组织或细胞样品方便地测定mRNA。例如,RT-PCR测定法(诸如定量PCR测定法)是本领域公知的。在一个示例性实施方案中,用于检测生物学样品中的靶标mRNA的方法包括使用至少一种引物通过逆转录自样品生成cDNA;使用靶标多核苷酸作为有义和反义引物扩增如此生成的cDNA以扩增其中的靶标cDNA;并检测所扩增靶标cDNA的存在。此外,此类方法可包括一个或多个如下步骤,其容许测定生物学样品中靶标mRNA的水平(例如通过同时检验“持家” 基因诸如肌动蛋白家族成员的比较性对照mRNA序列的水平)。任选的是,可测定所扩增靶标cDNA的序列。
任选方法包括通过微阵列技术检验或检测组织或细胞样品中mRNA(诸如靶标mRNA)的方案。使用核酸微阵列,将来自测试和对照组织样品的测试和对照mRNA样品逆转录和标记以生成cDNA探针。然后将所述探针杂交至在固体支持物上固定化的核酸阵列。所述阵列配置成阵列的每个成员的序列和位置是已知的。例如,可将基因选集在固体支持物上形成阵列,所述基因的表达于检测AKT或PRAS40中的突变相关。经标记探针与特定阵列成员的杂交指示衍生该探针的样品表达该基因。疾病组织的差异基因表达分析可提供有价值的信息。微阵列技术利用核酸杂交技术和计算技术在单一实验中评估数以千计基因的mRNA表达序型(expression profile)(参见例如2001年10月11日公布的WO 01/75166;(参见例如美国专利5,700,637、美国专利5,445,934和美国专利5,807,522;Lockart,NatureBiotechnology,14:1675-1680(1996);Cheung,V.G.et al.,Nature Genetics 21(Suppl):15-19(1999),关于阵列制作的讨论)。DNA微阵列是包含基因片段的微型阵列,所述基因片段或是在玻璃或其它基质上直接合成或是点到玻璃或其它基质上。单一阵列中通常呈现数以千计的基因。一个典型的微阵列实验涉及下列步骤:1)自分离自样品的RNA制备荧光标记的靶标;2)将经标记的靶标杂交至微阵列;3)清洗、染色和扫描阵列;4)分析扫描图像;并5)生成基因表达序型。当前使用两种主要类型的DNA微阵列:包含自cDNA制备的PCR产物的基因表达阵列和寡核苷酸(通常25至70聚物)阵列。在形成阵列时,寡核苷酸可为预制并点到表面上的,或者直接在表面上合成的(原位)。
Affymetrix系统是包含通过在玻璃表面上直接合成寡核苷酸而制作的阵列的商品化微阵列系统。探针/基因阵列:寡核苷酸(通常25聚物)通过组合基于半导体的光刻和固相化学合成技术直接合成到玻璃晶片上。每个阵列包含多至400,000种不同寡聚物,每种寡聚物以数以百万计拷贝存在。因为寡核苷酸探针是在阵列上已知位置合成的,所以杂交样式和信号强度可以通过Affymetrix Microarray Suite软件解读成基因身份和相对表达水平。每种基因通过一系列不同寡核苷酸探针呈现在阵列上。每个探针对由完全匹配寡核苷酸和错配寡核苷酸组成。完全匹配探针具有与特定基因精确互补的序列且由此测量该基因的表达。错配探针因中央碱基位置的单一碱基替代而不 同于完全匹配探针,从而扰乱了靶基因转录物的结合。这有助于测定有助于对完全匹配寡聚物测得的信号的背景和非特异性杂交。Microarray Suite软件将错配探针的杂交强度从完全匹配探针的杂交强度中扣除,以确定每个探针集的绝对或特异强度。探针的选择基于Genbank和其它核苷酸库的当前信息。认为其序列识别基因3’末端的独特区域。使用基因芯片杂交炉(GeneChip Hybridization Oven)(“电转”烤炉)来进行多至64个阵列的同时杂交。射流站实施探针阵列的清洗和染色。它是完全自动化的,包括四个模块,每个模块持有一个探针阵列。每个模块经由Microarray Suite软件使用预编程射流方案独立控制。扫描仪是共焦激光荧光扫描仪,其测量由结合至探针阵列的经标记cRNA发射的荧光强度。安装有Microarray Suite软件的计算机工作站控制射流站和扫描仪。Microarray Suite软件可控制多至八个射流站,使用探针阵列的预编程的杂交、清洗和染色方案。该软件还获取杂交强度数据并使用适宜的算法将其转变成每种基因的有/无呼叫(presence/absence call)。最后,该软件通过比较分析来检测各实验间基因表达的变化,并将输出格式化为.txt文件,其可与其它软件程序一起用于进一步的数据分析。
组织或细胞样品中选定的基因或生物标志物的表达还可通过基于功能或活性的测定法来检验。例如,若生物标志物是酶,则可实施本领域已知测定法来测定或检测组织或细胞样品中给定酶活性的存在。
实施例
应当理解的是,本文所述实施例和实施方案仅用于说明目的,本领域技术人员将会根据它们启示进行多种改进或变化并且所述改进或变化包括在本申请和所述权利要求书的精神和范围内。
体外细胞增殖测定
实施例2化合物的组合的体外效能使用CellTiter-发光细胞生存力测定(购于Promega Corp.,Madison,WI)进行测量。这种同种测定方法基于鞘翅目萤光素酶(Coleoptera luciferase)的重组表达(US 5583024;US 5674713;US 5700670)并且基于存在的ATP(代谢活性细胞的指示物)的定量来确定培养物中生存细胞的数目(Crouch et al(1993)J.Immunol.Meth.160:81-88;US6602677)。CellTiter-测定在96或384孔板中进行,使其顺应自动化高通量筛选(HTS)(Cree et al(1995)AntiCancer Drugs 6:398-404)。所述同种测定操作涉及将单一的试剂(CellTiter-Reagent)直接添加至在补充有血清的培 养基中培养的细胞中。洗涤细胞,除去培养基,不需要多次移液步骤。在添加试剂并混合后在10分钟内系统检测到在384孔板中少至15细胞/孔。
同种“加入-混合-测量”板引起细胞溶解和与存在的ATP的量成比例的发光信号的产生。ATP的量直接与培养物中存在的细胞的数目成比例。CellTiter-测定产生了由萤光素酶反应产生的“辉光型(glow-type)”发光信号,取决于细胞类型和所用的培养基,所述发光信号具有通常超过五小时的半衰期。生存的细胞以相对发光单位(RLU)反映。底物甲虫萤光素(Beetle Luciferin)通过重组萤火虫萤光素酶进行氧化脱羧,伴随ATP向AMP的转化和光子的产生。延长的半衰期消除了使用试剂注射器的需要并且为多个板的连续或批量模式处理提供了灵活性。该细胞增殖测定可与各种多孔板如96或384孔板一起使用。数据可通过发光计或CCD照相显像装置记录。发光产量表现为随时间测量的相对光单位(RLU)。
Claims (17)
1.ATP竞争性AKT抑制剂在制备用于治疗包含AKT1突变的前列腺癌细胞的药物中的用途,其中在所述前列腺癌细胞中对变构AKT抑制剂的治疗效果的抗性通过以下方法检测,所述方法包括在包含所述AKT1突变的所述细胞中检测突变的存在,其中所述AKT1突变包括W80变成半胱氨酸的基因突变,其中所述AKT1突变的存在表明所述前列腺癌细胞已经变得或将会变得对所述变构AKT抑制剂具有抗性;
其中所述变构AKT抑制剂为MK2206,其名称为8-[4-(1-氨基环丁基)苯基]-9-苯基-1,2,4-三唑并[3,4-f][1,6]二氮杂萘-3(2H)-酮,且所述ATP竞争性AKT抑制剂为GDC-0068,其具有下式:
2.权利要求1的用途,其中在用所述变构AKT抑制剂处理后检测所述突变的存在。
3.权利要求1的用途,所述方法进一步包括检测AKT3的表达水平。
4.权利要求3的用途,所述方法进一步包括检测AKT3的过表达。
5.权利要求1的用途,所述方法还包括对所述前列腺癌细胞给予有效量的PI3k或mTOR抑制剂。
6.权利要求5的用途,其中所述mTOR抑制剂为雷帕霉素。
7.权利要求3的用途,其中所述AKT3表达水平为mRNA表达水平。
8.权利要求7的用途,其中所述mRNA表达水平使用qRT-PCR或微阵列进行测量。
9.权利要求7的用途,其中所述mRNA表达水平的变化为升高。
10.权利要求1的用途,所述方法还包括给予有效量的选自GDC-0941和GDC-0980的PI3k抑制剂。
11.权利要求1的用途,其中所述前列腺癌细胞与PTEN突变相关。
12.权利要求1的用途,其中所述前列腺癌细胞与PTEN低或缺失状态相关。
13.权利要求1的用途,其中所述前列腺癌细胞与AKT突变、过表达或扩增相关。
14.权利要求1的用途,其中所述前列腺癌细胞与PI3K突变相关。
15.权利要求1的用途,其中所述前列腺癌细胞与Her2/ErbB2扩增相关。
16.权利要求1的用途,其中所述前列腺癌细胞为循环肿瘤细胞。
17.权利要求1的用途,其中所述检测包括通过聚合酶链式反应检测所述突变。
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EP2959014B1 (en) | 2019-11-13 |
CA2901126A1 (en) | 2014-08-28 |
KR20150122198A (ko) | 2015-10-30 |
US20180327860A1 (en) | 2018-11-15 |
JP6669500B2 (ja) | 2020-03-18 |
MX2015010776A (es) | 2015-11-26 |
KR102182488B1 (ko) | 2020-11-24 |
US20160153049A1 (en) | 2016-06-02 |
AR094873A1 (es) | 2015-09-02 |
JP2016510591A (ja) | 2016-04-11 |
JP2019176858A (ja) | 2019-10-17 |
WO2014130923A2 (en) | 2014-08-28 |
US10612100B2 (en) | 2020-04-07 |
EP2959014A2 (en) | 2015-12-30 |
RU2015140573A (ru) | 2017-03-30 |
BR112015020054A2 (pt) | 2017-08-29 |
MX369175B (es) | 2019-10-30 |
WO2014130923A3 (en) | 2015-04-23 |
CN105247072A (zh) | 2016-01-13 |
US9994913B2 (en) | 2018-06-12 |
CA2901126C (en) | 2022-01-25 |
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