CN114502559B - 二氢咪唑并嘧啶并嘧啶酮类化合物 - Google Patents
二氢咪唑并嘧啶并嘧啶酮类化合物 Download PDFInfo
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- CN114502559B CN114502559B CN202080070915.3A CN202080070915A CN114502559B CN 114502559 B CN114502559 B CN 114502559B CN 202080070915 A CN202080070915 A CN 202080070915A CN 114502559 B CN114502559 B CN 114502559B
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Classifications
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- C07—ORGANIC CHEMISTRY
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- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
- C07D487/14—Ortho-condensed systems
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
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- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
式I的二氢咪唑并嘧啶并嘧啶酮类化合物,或其可药用盐,或前药。该类化合物是Wee1激酶抑制剂,可用于治疗由Wee1活性异常而导致的疾病。
Description
技术领域
本发明属于药物化学领域。本发明特别涉及8,9-二氢咪唑[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮类化合物,及其作为治疗上有效的Wee1激酶抑制剂,和抗癌药物的应用。
背景技术
真核细胞的生长、增殖的过程包括母细胞通过准确复制其包括遗传信息的基因组,通过细胞染色体的有丝***产生两个相同的子细胞。这种细胞的增殖、***过程被称为细胞周期(cell cycle),这包括了细胞从一次***完成开始,到下一次***完成的整个过程。细胞周期包括四个生长阶段,有丝***后的蛋白质,RNA等大量合成的G1期,DNA合成复制的S期,有丝***前的准备阶段G2期和细胞进行有丝***的M期。细胞根据细胞状况和需要决定通过细胞周期进行***增殖,或停止。细胞增殖,***必须保持其遗传信息的完整和正确。是否进入细胞周期的下一阶段直至完成整个细胞周期是通过在细胞周期过程中的多个检验点(checkpoint)来保障并完成的。
在细胞周期的整个过程中有多个细胞周期检验点(cell cycle checkpoint)存在。每个细胞周期检验点都包括非常复杂的***和由多个因子组成。在G1期内的检验点通过检验细胞内外的状态来决定是否进入细胞周期,从而决定细胞是否进入S期DNA合成。G1检验点是个复杂的***,其中包括著名的CDK4/CDK6。另一个重要的检验点在细胞完成了DNA复制(S期)进入细胞生长期(G2期),即所谓的G2-M检验点。这个检验点检验细胞合成DNA后是否有DNA损伤或缺损,从而决定细胞是否进行下面染色体分离的有丝***(M-期)。这一阶段的细胞周期检验点包括了复杂的激酶Cdk1复合体包括Cyclin-B-cdc2(Nurse,P.,1990,Nature 344,503-508)。Cdk1的活化导致有丝***的起始,其随后的失活伴随着有丝***的完成。Cdk1的活性是通过cdc2结合细胞周期蛋白A(Cyclin-A)或细胞周期蛋白B(Cyclin-B)以及其磷酸化来调节的。比如,细胞周期蛋白B-Cdk1复合物的激活能使细胞有丝***(Lindqvist,A.等,2009,The Journal of cell biology 185,193-202)。Cdc2在细胞进入有丝***前通过磷酸化维持在无活性的状态。其磷酸化状态是通过络氨酸激酶Wee1等来实现的。另外,还有M期细胞周期检验点。
Wee1磷酸化Cdk1上的酪氨酸15(Y15)从而抑制Cdk1的活性(McGowan,C.H.等,1993,The EMBO journal 12,75-85;Parker,L.L.等,1992,Science 257,1955-1957)。因此,Wee1是Cdk1活性的关键抑制性调节剂,在G2-M期检测点起重要作用,保证当DNA复制完成后在DNA没有损伤的情况下进入有丝***(O’Connell等,1997,The EMBO journal 16,545-554)。Wee1的丧失或失活可以导致过早进入有丝***,引起有丝***的失败和细胞死亡(Stumpff,J.等,2004,Curr Biol 14,2143-2148)。一些肿瘤细胞的G1期细胞周期检验点有功能缺陷,依赖G2-M期检测点来保障细胞周期的进行(Sancar,A.等,2004,Annualreview of biochemistry 73,39-85)。在这些癌细胞中由于p53蛋白功能的缺失,丧失Wee1表达或抑制Wee1的活性会导致G2-M期检验点的丧失,使肿瘤细胞对DNA损伤非常敏感,这个敏感化在丧失G1期检验点能力的肿瘤细胞中尤其突出(Wang,Y.等,2004,Cancer biology&therapy 3,305-313)。
综上所述,抑制Wee1的活性可以有选择性促使细胞周期检验点有缺陷的癌细胞死亡;同时,对细胞周期检验点正常的正常细胞则作用甚小。因此,Wee1的抑制剂有可能用于癌症及其它细胞增殖病症的治疗的靶向药物。
另外,由于抑制Wee1活性使细胞对DNA损伤的敏感度提高,Wee1抑制剂可以和造成DNA损伤或抑制DNA修复机制有关的抗癌药物联合使用,这包括和PARP抑制剂奥拉帕尼(olaparib)、Niraparib、Rucaparib和Talazoparib;HDAC抑制剂伏立诺他、罗咪地辛、帕比司他和贝利司他等等用于治疗癌症或其它细胞增殖病症。Wee1抑制剂还可能和其他与细胞***细胞周期检测点有关的抗癌药物的联合共用,包括Chk1/2抑制剂,CDK4/6抑制剂如帕博西尼,ATM/ATR抑制剂等等用于治疗癌症等病症。
Karnak等人(Clin Cancer Res,2014,20(9):5085-5096)的研究表明Wee1抑制剂AZD1775和PARP抑制剂olaparib联合使用可对放射治疗胰腺癌增敏。其结果证实了Wee1抑制剂和PARP抑制剂联合使用治疗胰腺癌可增敏放射疗效,支持了Wee1抑制使细胞对PARP抑制剂增敏的假设-通过抑制DNA修复和G2检验点功能对辐射治疗增敏,最终可导致未修复的损伤的DNA的积累直至细胞死亡。
另外,有报道(BMC Cancer,2015,15:462)将Wee1抑制剂MK1775和Chk1/2抑制剂AZD7762联合使用用于恶性黑素瘤细胞和异种移植模型中。结果显示,在Wee1和Chk1/2抑制剂的联合使用可协同单一药物的抑制效果,从而降低肿瘤细胞的增殖能力及激活了细胞凋亡机制;在异种移植模型中二者的联合使用可更好地抑制肿瘤生长。
AZD1775是第一个在临床前模型中具有单药抗肿瘤活性的Wee1激酶抑制剂。I期临床研究显示出AZD1775对携带BRCA突变的实体瘤患者的单药疗效,并通过配对肿瘤活检发现跟靶向有关的变化和DNA损伤应答证实了其Wee1激酶抑制机制(J Clin Oncol,2015,33:3409-3415)。在AZD1775总共入组200多患者的一个临床I期中,研究了其在治疗晚期实体瘤患者的单药疗效和与吉西他滨、顺铂或卡铂联用的疗效,显示了其在一定的剂量下不管是单药还是与化药联用都是安全且可耐受的。在176例可评估疗效的患者中,94(53%)具有作为最佳应答的稳定疾病,以及17(10%)有部分应答。重要的是,AZD1775在TP53突变患者(n=19)的应答率为21%,而在TP53野生型患者(n=33)的应答率为12%,展现出其对TP53突变患者的巨大潜力(J Clin Oncol,2016 Sep 6,pii:JCO675991)。
已有多种激酶抑制剂公开,例如,WO2012161812公开了三环化合物作为Wee1激酶抑制剂物;WO2005021551公开了四环嘧啶或吡啶化合物作为蛋白激酶抑制剂;WO2018090939公开了二氢咪唑并嘧啶并嘧啶酮类化合物作为Wee1激酶抑制剂物。
发明内容
如结构式I(包括式Ia、Ib和Ic)所示,本发明提供了新颖的8,9-二氢咪唑[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮类化合物作为激酶抑制剂,特别是Wee1激酶抑制剂。
本发明还提供了包含一个有效量的式I(包括式Ia、Ib和Ic)化合物的药用组合物,用来治疗癌症。
在一具体实施例中,所述药用组合物还可含有一种或多种可药用载体或稀释剂,用来治疗癌症。
在一具体实施例中,所述药用组合物还可含有至少一种已知的抗癌药物或所述抗癌药物的可药用盐,用来治疗癌症。
本发明也涉及到式I(包括式Ia、Ib和Ic)的新颖化合物的制备方法。
具体实施方式
如式I(包括式Ia、Ib和Ic)所示,本发明发现新颖的8,9-二氢咪唑[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮类化合物作为激酶抑制剂,特别是Wee1激酶抑制剂。
具体来说,本发明提供下式I所示的化合物或其立体异构体、其可药用盐或前药:
式中,R1和R2独立为卤素;R3为卤素、C1-4烷基或C1-4烷氧基;R4和R6各自独立为H或C1-4烷基;R5为H或C1-4烷基;R7为H、卤素、C1-4烷基或C1-4烷氧基;和X为CH或N;
其中,所述式I化合物不包括下述化合物:
6-(2-氯-6-氟苯基)-2-((3-氟-4-((3R,5S)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3-氯-4-((3R,5S)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3-甲基-4-((3R,5S)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((4-((3S,5R)-4-异丙基-3,5-二甲基哌嗪-1-基)-3-甲基苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氟-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氯-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-甲基-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-甲基-4-((3S,5R)-4-异丙基-3,5-二甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3,5-二氯-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;和
6-(2,6-二氯苯基)-2-((3-氯-5-甲基-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮。
式I优选的实施方案中,R1和R2均为氯。
式I优选的实施方案中,R3为卤素、甲基或乙基。
式I优选的实施方案中,R7为H、卤素、甲基或甲氧基。
式I优选的实施方案中,R4和R6各自独立为H或甲基。
式I优选的实施方案中,R5为H、甲基或甲基-d3。
式I优选的实施方案中,当X为N时,R4、R5和R6不同时为H;优选地,R4和R6为C1-4烷基,R5为H或C1-4烷基;更为优选地,R4和R6为甲基,R5为H、甲基或甲基-d3。
式I优选的实施方案中,式I化合物为具有下式Ia所示结构的化合物或其立体异构体、其可药用盐或前药:
式中,R1和R2独立为卤素;R3为卤素或C1-4烷基;R7为H、卤素、C1-4烷基或C1-4烷氧基;R4和R6各自独立为C1-4烷基;R5为H或C1-4烷基;
其中,所述式Ia化合物不包括下述化合物:
6-(2-氯-6-氟苯基)-2-((3-氟-4-((3R,5S)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2--a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3-氯-4-((3R,5S)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3-甲基-4-((3R,5S)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((4-((3S,5R)-4-异丙基-3,5-二甲基哌嗪-1-基)-3-甲基苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氟-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氯-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-甲基-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-甲基-4-((3S,5R)-4-异丙基-3,5-二甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3,5-二氯-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;和
6-(2,6-二氯苯基)-2-((3-氯-5-甲基-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮。
式Ia优选的实施方案中,R1和R2均为氯。
式Ia优选的实施方案中,R3为卤素、甲基或乙基。
式Ia优选的实施方案中,R7为H、卤素、甲基或甲氧基。
式Ia优选的实施方案中,R4和R6各自独立为甲基。
式Ia优选的实施方案中,R5为H、甲基或甲基-d3。
式Ia优选的实施方案中,R1和R2均为氯;R3为卤素、甲基或乙基;R4和R6各自独立为甲基;R5为H、甲基或甲基-d3;R7为H。更优选地,R1和R2均为氯;R3为甲基或乙基;R4和R6各自独立为甲基;R5为H、甲基或甲基-d3;R7为H。
式Ia优选的实施方案中,R1和R2均为氯;R3为甲基或乙基;R4和R6各自独立为甲基;R5为甲基或甲基-d3;R7为卤素、甲基或甲氧基。
式I优选的实施方案中,式I化合物为具有下式Ib所示结构的化合物或其立体异构体、其可药用盐或前药:
式中,R1和R2独立为卤素;R3为C1-4烷基;R4和R6各自独立为C1-4烷基;R5为H或C1-4烷基,且该烷基至少含有3个氘(D)。
式Ib优选的实施方案中,R1和R2均为氯。
式Ib优选的实施方案中,R3为甲基或乙基。
式Ib优选的实施方案中,R4和R6各自独立为甲基。
式Ib优选的实施方案中,R5为H或甲基-d3。
式Ib优选的实施方案中,R1和R2均为氯;R3为甲基或乙基;R4和R6各自独立为甲基;R5为H或甲基-d3。
式I优选的实施方案中,式I化合物为具有下式Ic所示结构的化合物或其立体异构体、其可药用盐或前药:
式Ic中,R1和R2独立为卤素;R3为卤素、C1-4烷基或C1-4烷氧基;R5为H或C1-4烷基;R7为H、卤素、C1-4烷基或C1-4烷氧基。
式Ic优选的实施方案中,R1和R2均为氯。
式Ic优选的实施方案中,R3为卤素、甲基或乙基,更优选为F、Cl或甲基。
式Ic优选的实施方案中,R7为H、卤素、甲基或乙基,更优选为H、F、Cl或甲基。
式Ic优选的实施方案中,R5为C1-4烷基。更优选地,R5为甲基或甲基-d3。
式Ic优选的实施方案中,R1和R2均为卤素;R3为卤素或C1-4烷基;R5为C1-4烷基;R7为H或卤素。
式Ic优选的实施方案中,R1和R2均为氯;R3为卤素、甲基或乙基;R5为甲基或甲基-d3;R7为H、卤素、甲基或乙基。
式I优选的化合物包括但不限于:
本发明化合物可能作为立体异构体,包括旋光异构体存在。本发明包括所有立体异构体和这样的立体异构体的外消旋混合物,以及可以根据本领域技术人员众所周知的方法分离出来的单独的对映体。
可药用盐的例子包括无机和有机酸盐,例如盐酸盐、氢溴酸盐、磷酸盐、硫酸盐、柠檬酸盐、乳酸盐、酒石酸盐、马来酸盐、富马酸盐、扁桃酸盐和草酸盐;以及与碱例如钠羟基、三(羟基甲基)氨基甲烷(TRIS,氨丁三醇)和N-甲基葡糖胺形成的无机和有机碱盐。
本发明化合物的前药的实施例包括含有羧酸的化合物的简单酯(例如依据本领域已知方法通过与C1-4醇缩合而获得的酯);含有羟基的化合物的酯(例如依据本领域已知方法通过与C1-4羧酸、C3-6二酸或其酸酐例如琥珀酸酐和富马酸酐缩合而获得的酯);含有氨基的化合物的亚胺(例如依据本领域已知方法通过与C1-4醛或酮缩合而获得的亚胺);含有氨基的化合物的氨基甲酸酯,例如Leu等人(J.Med.Chem.42:3623-3628(1999))和Greenwald等人(J.Med.Chem.42:3657-3667(1999))描述的那些酯;含有醇的化合物的醛缩醇或酮缩醇(例如依据本领域已知方法通过与氯甲基甲基醚或氯甲基乙基醚缩合而获得的那些缩醇)。
本发明化合物可使用本领域技术人员已知的方法或本发明新方法制得。具体来说,具有式I(包括式Ia、Ib和Ic)的本发明化合物可如反应方案1中的反应实施例所示制得。6-(2,6-二氯苯基)-2-(甲硫基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮和间氯过氧苯甲酸在二氯甲烷中室温反应,得到产物6-(2,6-二氯苯基)-2-(甲亚磺酰基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮和6-(2,6-二氯苯基)-2-(甲磺酰基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮。6-(2,6-二氯苯基)-2-(甲亚磺酰基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮和6-(2,6-二氯苯基)-2-(甲磺酰基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮的混合产物和(2S,6R)-4-(4-氨基-2-甲基苯基)-2,6-二甲基哌嗪-1-甲酸叔丁基酯在三氟乙酸存在下在乙腈中室温反应,得到产物(2S,6R)-4-(4-((6-(2,6-二氯苯基)-5-氧代-5,6,8,9-四氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-2-基)氨基)-2-甲基苯基)-2,6-二甲基哌嗪-1-甲酸叔丁基酯。(2S,6R)-4-(4-((6-(2,6-二氯苯基)-5-氧代-5,6,8,9-四氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-2-基)氨基)-2-甲基苯基)-2,6-二甲基哌嗪-1-甲酸叔丁基酯和氯化氢甲醇溶液在甲醇中室温反应,得到目标化合物6-(2,6-二氯苯基)-2-((4-((3S,5R)-3,5-二甲基哌嗪-1-基)-3-甲基苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮。
反应方案1
其它相关化合物可采用类似反应方案1所示的方法制得。用4-((3S,5R)-3,5-二甲基-4-(甲基-d3)哌嗪-1-基)-3-甲基苯胺替代(2S,6R)-4-(4-氨基-2-甲基苯基)-2,6-二甲基哌嗪-1-甲酸叔丁基酯,可制得目标化合物6-(2,6-二氯苯基)-2-((4-((3S,5R)-3,5-二甲基-4-(甲基-d3)哌嗪-1-基)-3-甲基苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮。用3-溴-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯胺替代(2S,6R)-4-(4-氨基-2-甲基苯基)-2,6-二甲基哌嗪-1-甲酸叔丁基酯,可制得目标化合物2-((3-溴-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-6-(2,6-二氯苯基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮。用3-氟-5-甲基-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯胺替代(2S,6R)-4-(4-氨基-2-甲基苯基)-2,6-二甲基哌嗪-1-甲酸叔丁基酯,可制得目标化合物6-(2,6-二氯苯基)-2-((3-氟-5-甲基-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮。用3-甲基-4-((3S,5S)-3,4,5-三甲基哌嗪-1-基)苯胺替代(2S,6R)-4-(4-氨基-2-甲基苯基)-2,6-二甲基哌嗪-1-甲酸叔丁基酯,可制得目标化合物6-(2,6-二氯苯基)-2-((3-甲基-4-((3S,5S)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮。用3-甲基-4-(哌啶-4-基)苯胺替代(2S,6R)-4-(4-氨基-2-甲基苯基)-2,6-二甲基哌嗪-1-甲酸叔丁基酯,可制得目标化合物6-(2,6-二氯苯基)-2-((3-甲基-4-(哌啶-4-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮。用3-甲基-4-(1-甲基-4-哌啶)苯胺替代(2S,6R)-4-(4-氨基-2-甲基苯基)-2,6-二甲基哌嗪-1-甲酸叔丁基酯,可制得目标化合物6-(2,6-二氯苯基)-2-((3-甲基-4-(1-甲基哌啶-4-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮。用3-氟-5-甲基-4-(1-甲基哌啶-4-基)苯胺替代(2S,6R)-4-(4-氨基-2-甲基苯基)-2,6-二甲基哌嗪-1-甲酸叔丁基酯,可制得目标化合物6-(2,6-二氯苯基)-2-((3-氟-5-甲基-4-(1-甲基哌啶-4-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮。
本发明的一个重要方面是发现了式I(包括式Ia、Ib和Ic)化合物是激酶抑制剂,特别是Wee1激酶抑制剂,有很好的活性。因此,这些化合物可用于治疗Wee1相关疾病,即Wee1介导的疾病,例如癌症。本文中,Wee1介导的疾病指为其治疗或预防需抑制Wee1活性的疾病。
本发明还包括给动物施用有效量的式I(包括式Ia、Ib和Ic)化合物或其立体异构体、其可药用盐或前药的治疗方法。其中所述治疗方法用于治疗激酶相关疾病,特别是Wee1激酶相关疾病,例如癌症。可由本发明的方法或药物组合物治疗或预防的这类疾病包括但不限于肝癌、黑素瘤、霍奇金病、非霍奇金淋巴瘤、急性淋巴白血病、慢性淋巴白血病、多发性骨髓瘤、成神经细胞瘤、乳腺癌、卵巢癌、肺癌、维尔姆斯瘤、子***、睾丸癌、软组织肉瘤、原发性巨球蛋白血症、膀胱癌、慢性粒细胞白血病、原发性脑癌、恶性黑素瘤、小细胞肺癌、胃癌、结肠癌、恶性胰腺胰岛瘤、恶性类癌性癌症、绒毛膜癌、蕈樣肉芽腫、头颈癌、骨原性肉瘤、胰腺癌、急性粒细胞白血病、毛细胞白血病、横纹肌肉瘤、卡波西肉瘤、泌尿生殖***肿瘤病、甲状腺癌、食管癌、恶性高钙血症、子宫颈增生症、肾细胞癌、子宫内膜癌、真性红细胞增多症、特发性血小板增多症、肾上腺皮质癌、皮肤癌和***癌。
本发明也包括用于治疗或预防因激酶(特别是Wee1)活性异常而引起的其他疾病,例如神经病学或神经精神疾病或病症,例如抑郁症患者。
在实施本发明治疗方法时,给有一种或多种这些症状的病人施用有效量的药物制剂。所述药物制剂含有有效治疗浓度的式I(包括式Ia、Ib和Ic)化合物或其立体异构体、其可药用盐或前药,被配制成用于口服、静脉注射、局部或外用给药的形式,用于治疗癌症和其他疾病。给药量是有效地改善或消除一个或多个病症的药量。对于特定疾病的治疗,有效量是足以改善或以某些方式减轻与疾病有关的症状的药量。这样的药量可作为单一剂量施用,或者可依据有效的治疗方案给药。给药量也许可治愈疾病,但是给药通常是为了改善疾病的症状。一般需要反复给药来实现所需的症状改善。
在另一个实施方案中提供了一种药用组合物,其中含有激酶抑制剂的式I(包括式Ia、Ib和Ic)化合物或其立体异构体、其可药用盐与可药用载体。
本发明另一个实施方案涉及能有效地治疗癌症的药用组合物,其中包含激酶抑制剂的式I(包括式Ia、Ib和Ic)化合物,或其立体异构体、其可药用盐或前药,与至少一种已知的抗癌药物或抗癌药物的可药用盐联合共用。特别是和其他与DNA损伤和修复机理有关的抗癌药物的联合共用,包括PARP抑制剂奥拉帕尼、Niraparib、Rucaparib、Talazoparib和Senaparib;HDAC抑制剂伏立诺他、罗咪地辛、帕比司他和贝利司他;等等。以及和其他与细胞***检测点有关的抗癌药物的联合共用,包括Chk1/2抑制剂,CDK4/6抑制剂如帕博西尼,ATM/ATR抑制剂等等。其他可用于抗癌联合治疗的已知抗癌药物包括但不限于烷化剂例如白消安、马法兰、苯丁酸氮芥、环磷酰胺、异环磷酰胺、替莫唑胺、苯达莫司汀、顺铂、丝裂霉素C、博莱霉素和卡铂;拓扑异构酶I抑制剂例如喜树碱、伊立替康和托泊替康;拓扑异构酶II抑制剂例如阿霉素、表阿霉素、阿克拉霉素、米托蒽醌、甲基羟基玫瑰树碱和铭托泊普;RNA/DNA抗代谢物例如5-氮杂胞苷、吉西他滨、5-氟尿嘧啶和甲氨蝶呤;DNA抗代谢物例如5-氟-2′-去氧尿苷、氟达拉滨,奈拉滨、阿糖胞苷、普拉曲沙、培美曲塞、羟基脲和硫代鸟嘌呤;抗有丝***剂例如秋水仙碱、长春碱、长春新碱、长春瑞滨、紫杉醇,伊沙匹隆、卡巴他赛和多西他赛;抗体例如单抗,帕尼单抗、耐措妥珠单抗、纳武单抗、派姆单抗、雷莫芦单抗、贝伐珠单抗、帕妥珠单抗、曲妥珠单抗、西妥昔单抗、奥滨尤妥珠单抗、奥法木单抗、利妥昔单抗、阿仑单抗、替伊莫单抗、托西莫单抗、本妥昔单抗、达雷木单抗、埃罗妥珠单抗、T-DM1、Ofatumumab、Dinutuximab、Blinatumomab、易普利姆玛、阿瓦斯丁、赫赛汀和美罗华;激酶抑制剂例如伊马替尼、吉非替尼、厄洛替尼、奥斯替尼、阿法替尼、赛立替尼、艾乐替尼、克唑替尼、埃罗替尼、拉帕替尼、索拉非尼、瑞格非尼、维罗非尼、达拉非尼、阿柏西普、舒尼替尼、尼罗替尼、达沙替尼、博舒替尼、普拉替尼、依鲁替尼、卡博替尼、乐伐替尼、凡德他尼、曲美替尼、卡比替尼、阿昔替尼、替西罗莫司、Idelalisib、帕唑帕尼、特癌适和依维莫司。其他可用于抗癌组合治疗的已知抗癌药物包括他莫昔芬、来曲唑、氟维司群、米托胍腙、奥曲肽、视黄酸、砒霜、唑来膦酸、硼替佐米、卡非佐米、Ixazomib、维莫德吉、索尼德吉、狄诺塞麦、萨力多胺、来那度胺、Venetoclax、Aldesleukin(重组人白介素-2)和Sipueucel-T(***癌治疗疫苗)。
在实施本发明的方法时,本发明化合物与至少一种已知的抗癌药物可作为单一的药用组合物一起给药。另外,本发明化合物也可与至少一种已知抗癌药分开给药。在一个实施方案,本发明化合物和至少一种已知的抗癌药差不多同时给药,即所有的药物同时施用或陆续施用,只要化合物在血液中同时达到治疗浓度即可。在另外一个实施方案,本发明的化合物和至少一种已知的抗癌药根据各自的剂量方案给药,只要化合物在血液中达到治疗浓度即可。
本发明的另一个实施方案,是一种由所述化合物组成的能有效的抑制肿瘤的,作为激酶抑制剂的生物耦合物。这个能抑制肿瘤的生物耦合物由所述化合物与至少一种已知的有医疗作用的抗体,如赫赛汀或美罗华,或生长素,如DGF或NGF,或细胞激素,如白细胞介素2或4,或任意能与细胞表面结合的分子组成。该抗体与其他分子能把所述化合物递送到其靶点,使之成为有效的抗癌药物。此生物耦合物也可以提高有医疗作用的抗体,如赫赛汀或美罗华的抗癌效果。
本发明的另一实施例涉及一种能有效的抑制肿瘤的药用组合物,包含式I(包括式Ia、Ib和Ic)所示的激酶抑制剂,或其可用药盐或前药,与放射疗法联合治疗。在此实施例,本发明化合物与放射治疗可在相同时间或不同时间给药。
本发明的另一实施例涉及一种能有效的用于癌症手术后治疗的药用组合物,包含式I(包括式Ia、Ib和Ic)所示的激酶抑制剂,或其立体异构体、其可用药盐或前药。本发明还涉及用手术切除肿瘤,然后用本发明的药用组合物治疗该哺乳动物的癌症的治疗方法。
本发明的药用组合物包括所有本发明化合物的含有量能有效地实现其预期目标的药品制剂。虽然每个人的需求各不相同,本领域技术人员可确定药品制剂中每个部分的最佳剂量。一般情况下,所述化合物,或其可用药盐,对哺乳动物每天口服给药,药量按照约0.0025到50毫克/公斤体重。但最好是每公斤口服给药约0.01到10毫克/公斤。如果也施用一个已知的抗癌药物,其剂量应可有效地实现其预期的目的。这些已知的抗癌药物的最佳剂量是本领域技术人员所熟知的。
单位口服剂量可以包括约0.01到50毫克,最好是约0.1到10毫克的本发明化合物。单位剂量可给予一次或多次,每天为一片或多片,每片含有约0.1到50毫克,合宜地约0.25到10毫克的本发明化合物或其溶剂化物。
在外用制剂中,本发明化合物的浓度可以是每克载体约0.01到100毫克。
本发明化合物可作为未加工药品给药。本发明化合物也可以作为含有可药用载体(包括辅料和助剂)的一个合适的药物制剂的一部分给药。这些可药用载体有利于把化合物加工成可药用的药物制剂。优选的药物制剂,特别是那些口服的和优选的给药方式类型,如片剂,锭剂和胶囊,以及适合于注射或口服的溶液,包含约0.01%到99%,最好从约0.25%到75%的活性化合物以及辅料。
本发明的范围也包括本发明化合物的无毒性可药用盐。酸加成盐由混合一个无毒性可药用酸溶液和本发明的化合物溶液而形成。所述酸例如盐酸,富马酸,马来酸,琥珀酸,乙酸,柠檬酸,酒石酸,碳酸,磷酸,草酸等。碱加成盐由混合一个无毒性可药用碱溶液和本发明的化合物溶液而形成。所述碱例如氢氧化钠,氢氧化钾,氢胆碱,碳酸钠,三羟甲基氨基甲烷,N-甲基-葡萄糖胺等。
本发明的药物制剂可以给予任何哺乳动物,只要他们能获得本发明化合物的治疗效果。在这些哺乳动物中最为重要的是人类和兽医动物,虽然本发明不打算如此受限。
本发明的药物制剂可通过任何途径给药以达到其预期目的。例如,可以通过肠外,皮下,静脉,肌肉,腹腔内,透皮,口腔,鞘内,颅内,鼻腔或外用途径给药。作为替代或并行地,可以通过口服给药。药的剂量将根据病人的年龄,健康与体重,并行治疗的种类,治疗的频率,以及所需治疗效益来决定。
本发明的药物制剂可用已知的方式制造。例如,由传统的混合,制粒,制锭,溶解,或冷冻干燥过程制造。制造口服制剂时,可结合固体辅料和活性化合物,选择性研磨混合物。如果需要或必要时加入适量助剂后,加工颗粒混合物,获得片剂或锭剂芯。
合适的辅料特别是填料,例如糖类如乳糖或蔗糖,甘露醇或山梨醇;纤维素制剂和/或钙磷酸盐,例如磷酸三钙或磷酸氢钙;以及粘结剂,例如淀粉糊,包括玉米淀粉,小麦淀粉,大米淀粉,马铃薯淀粉,明胶,黄芪胶,甲基纤维素,羟丙基甲基纤维素,羧甲基纤维素钠,和/或聚乙烯吡咯烷酮。如果需要,可增加崩解剂,比如上面提到的淀粉,以及羧甲基淀粉,交联聚乙烯吡咯烷酮,琼脂,或褐藻酸或其盐,如海藻酸钠。辅助剂特别是流动调节剂和润滑剂,例如,硅石,滑石,硬脂酸或其盐,如硬脂酸镁或硬脂酸钙,和/或聚乙二醇。如果需要,可以给锭剂核芯提供可以抵抗胃液的合适包衣。为此,可以应用浓缩糖类溶液。这个溶液可以含有***树胶,滑石,聚乙烯吡咯烷酮,聚乙二醇和/或二氧化钛,漆溶液和合适的有机溶剂或溶剂混合物。为了制备耐胃液的包衣,可使用适当的纤维素溶液,例如醋酸纤维素邻苯二甲酸或羟丙基甲基纤维素邻苯二甲酸。可向药片或锭剂核芯的包衣加入染料或色素。例如,用于识别或为了表征活性成分剂量的组合。
其他可口服的药物制剂包括明胶制成的压接式胶囊,以及用明胶和甘油或山梨醇等增塑剂制成的密封软胶囊。该压接式胶囊可含有颗粒形式的活性化合物,与填料例如乳糖;粘结剂例如淀粉;和/或润滑剂例如滑石粉或硬脂酸镁,以及稳定剂混合而成。在软胶囊,活性化合物最好是溶解或悬浮在适当的液体例如油脂或液体石蜡中,其中可加入稳定剂。
合适于肠外给药的制剂包括活性化合物的水溶液,如水溶性盐的溶液和碱性溶液。此外,可施用适当的活性化合物的油性注射悬浮液。合适的亲脂性溶剂或载体包括油脂例如香油,合成脂肪酸酯例如油酸乙酯或甘油三酯或聚乙二醇400,或氢化蓖麻油,或环糊精。水性注射悬浮液可含有增加悬浮液黏度的物质,例如羧甲基纤维素钠,山梨醇,和/或葡聚糖。也可以含有悬浮稳定剂。
按照本发明的一个方面,本发明的化合物采用外用和肠外配方,并用于治疗皮肤癌。
本发明的外用制剂可通过优选合适的载体来制成油剂,霜剂,乳液剂,药膏等。合适的载体包括植物或矿物油,白矿油(白软石蜡),支链脂肪或油脂,动物脂肪和高分子醇(大于C12)。优选的载体是活性成分能溶解在其中的那些载体。也可包括乳化剂,稳定剂,保湿剂和抗氧化剂,以及如果需要的话,给予颜色或香味的试剂。此外,这些外用制剂可包含透皮渗透增强剂。这种增强剂的例子可参见美国专利号3,989,816和4,444,762。
霜剂优选用矿物油,自乳化蜂蜡和水的混合物配制,与溶解于少量油例如杏仁油的活性成分混合而成。一个典型的霜剂例子包括约40份水,20份蜂蜡,40份矿物油和1份杏仁油。
药膏可以这样配制,将含有活性成分的植物油例如杏仁油和温热的软石蜡混合,然后使该混合物冷却。一个典型的药膏例子包括约30%重量的杏仁油和70%重量的白软石蜡。
本发明也涉及应用本发明的化合物制备治疗对抑制激酶(特别是Wee1)活性有效果的临床病症的药物。这些药物可包括上述药用组合物。
下列实施例是举例说明,而不是限制本发明的方法和制剂。其他对于本领域技术人员来说是显而易见的,和在临床治疗中通常会遇到的对各种条件和参数的适当修改和改进,都在本发明的精神和范围内。
实施例
一般性说明
所用试剂均是商品品质,溶剂均按照标准方法干燥纯化。使用电喷雾的单四级杆质谱仪(平台II,安捷伦6110)分析质谱样品。使用Brücker Ascend 400核磁仪在400MHz记录1H NMR光谱,化学位移记录为以TMS作为内标(0.00ppm)从低场始以ppm为单位,耦合常数J值以Hz为单位。
实施例1
6-(2,6-二氯苯基)-2-((4-((3S,5R)-3,5-二甲基哌嗪-1-基)-3-甲基苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮
A)(2S,6R)-4-(4-氨基-2-甲基苯基)-2,6-二甲基哌嗪-1-甲酸叔丁基酯的制备
a)(3S,5R)-3,5-二甲基-1-(2-甲基-4-硝基)哌嗪的制备:向1-氟-2-甲基-4-硝基苯(25g,161.16mmol)的DMSO(500mL)溶液中加入碳酸钾(66.82g,483.48mmol)和(2S,6R)-2,6-二甲基哌嗪(21.53g,188.56mmol)。该混合物在100℃搅拌6小时后,加入水(2.5L),用乙酸乙酯(1L×3)萃取。合并收集的有机相用饱和食盐水(1L×2)洗,用无水硫酸钠干燥,过滤,滤液减压浓缩得到目标产物(38g,棕色油状物,94.58%收率)。
b)(2S,6R)-2,6-二甲基-4-(2-甲基-4-硝基苯基)哌嗪-1-甲酸叔丁基酯的制备:向(3S,5R)-3,5-二甲基-1-(2-甲基-4-硝基)哌嗪(38g,152.42mmol)的二氯甲烷(380mL)溶液中加入N,N-二异丙基乙胺(29.55g,228.63mmol,39.82mL)和二碳酸二叔丁酯(39.92g,182.91mmol,42.02mL)。该混合物在25℃搅拌24小时后,LCMS检测显示还有19.4%的原料(3S,5R)-3,5-二甲基-1-(2-甲基4-硝基)哌嗪剩余。向该混合物中加入N,N-二异丙基乙胺(15.76g,121.94mmol,21.24mL)和二碳酸二叔丁酯(16.63g,76.21mmol,17.51mL),该混合物继续在室温下搅拌12小时。该反应混合物减压浓缩得到粗产品,经硅胶柱层析纯化得到目标产物(45g,128.78mmol,黄色固体,84.49%收率)。
LC-MS(ESI):m/z(M-55)+294.2。1H NMR(400MHz,CDCl3):δ8.08-8.05(m,2H),7.06-7.04(m,1H),4.29(t,J=5.2Hz,2H),3.06(d,J=11.6Hz,1H),2.88(dd,J=4.0,11.6Hz,2H),2.48(s,3H),1.51(s,9H),1.46(s,3H),1.44(s,3H)。
c)(2S,6R)-4-(4-氨基-2-甲基苯基)-2,6-二甲基哌嗪-1-甲酸叔丁基酯的制备:向(2S,6R)-2,6-二甲基-4-(2-甲基-4-硝基苯基)哌嗪-1-甲酸叔丁基酯(25g,71.55mmol)在甲醇(250mL)的溶液中加入钯碳(5g,2.86mol,10%纯度),在氢气(25psi)气氛下,该反应混合物在25℃下搅拌12小时,过滤,滤液在减压下浓缩得到目标产物(22.5g,70.44mmol,棕色油状物,98.45%收率)。LC-MS(ESI):m/z(M+1)+320.0。
B)6-(2,6-二氯苯基)-2-((4-((3S,5R)-3,5-二甲基哌嗪-1-基)-3-甲基苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮的制备
a)6-(2,6-二氯苯基)-2-(甲亚磺酰基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮和6-(2,6-二氯苯基)-2-(甲磺酰基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮的制备:在0℃下,向6-(2,6-二氯苯基)-2-(甲硫基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮(24.7g,64.96mmol)的二氯甲烷(250mL)溶液中加入间氯过氧苯甲酸(28.02g,129.91mmol,80%纯度)。该混合物在25℃下搅拌2小时后,在0℃下,加入水(100mL)淬灭反应,然后加入二氯甲烷(100mL)稀释,依次用水(100mL×2)、碳酸氢钠水溶液(100mL×2)、亚硫酸钠水溶液(5wt%,100mL×2)和饱和食盐水(100mL×2)洗,有机相用无水硫酸钠干燥,过滤,滤液减压浓缩得到的粗产物用甲基叔丁基醚(40mL)洗,得到混合的目标产物(19.2g,黄色固体)。LC-MS(ESI):m/z(M+1)+395.8;(M+1)+411.8。
b)(2S,6R)-4-(4-((6-(2,6-二氯苯基)-5-氧代-5,6,8,9-四氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-2-基)氨基)-2-甲基苯基)-2,6-二甲基哌嗪-1-甲酸叔丁基酯的制备:向(2S,6R)-4-(4-氨基-2-甲基苯基)-2,6-二甲基哌嗪-1-甲酸叔丁基酯(15.3g,47.90mmol)和三氟乙酸(148.94mg,1.31mmol,96.72uL)的乙腈(153mL)溶液中加入上述制备的6-(2,6-二氯苯基)-2-(甲亚磺酰基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮和6-(2,6-二氯苯基)-2-(甲磺酰基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮的混合物(17.28g)。该混合物在25℃下搅拌2小时后,过滤,滤饼减压干燥,用乙腈(200mL)和甲醇(200mL)洗,得到目标产物(15g,22.84mmol,黄色固体,52.45%收率)。LC-MS(ESI):m/z(M+1)+651.2。1H NMR(400MHz,CDCl3):δ8.83(s,1H),7.49-7.45(m,4H),7.39-7.37(m,1H),7.05-7.03(d,J=8.4Hz,1H),4.24(t,J=4.8Hz,4H),4.03(t,J=9.2Hz,2H),2.93-2.82(m,4H),2.44(s,3H),3.12(s,9H),1.46(s,3H),1.44(s,3H)。
c)6-(2,6-二氯苯基)-2-((4-((3S,5R)-3,5-二甲基哌嗪-1-基)-3-甲基苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮的制备:在0℃下,向(2S,6R)-4-(4-((6-(2,6-二氯苯基)-5-氧代-5,6,8,9-四氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-2-基)氨基)-2-甲基苯基)-2,6-二甲基哌嗪-1-甲酸叔丁基酯(8.24g,12.54mmol)的甲醇(63mL)溶液中加入氯化氢甲醇溶液(4M,62.72mL)。该混合物在25℃下搅拌24小时后,减压浓缩,加入水(200mL)溶解该残留物,用碳酸氢钠水溶液将其pH调至8。混合物过滤,滤饼用水(50mL)洗,减压干燥,用乙腈(40mL)洗,过滤,得到的滤饼减压干燥得到的产物悬浮在水(100mL)和甲醇(20mL)溶剂中,冻干得到目标化合物(6.2g,11.10mmol,黄色固体,88.50%收率)。LC-MS(ESI):m/z(M+1)+551.2。1H NMR(400MHz,DMSO-d6):δ10.31-10.24(m,1H),8.67(s,1H),7.68-7.45(m,5H),6.98(d,J=8.4Hz,1H),4.17(d,J=7.2Hz,2H),3.82(t,J=9.2Hz,2H),3.06(s,2H),2.94(d,J=10.8Hz,2H),2.33-2.25(m,5H),1.07(s,3H),1.05(s,3H)。
实施例2
6-(2,6-二氯苯基)-2-((4-((3S,5R)-3,5-二甲基-4-(甲基-d3)哌嗪-1-基)-3-甲基苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮
a)(2S,6R)-2,6-二甲基-1-(甲基-d3)-4-(2-甲基-4-硝基)哌嗪的制备:向(3S,5R)-3,5-二甲基-1-(2-甲基-4-硝基)哌嗪(2g,8.02mmol)的N,N-二甲基甲酰胺(15mL)的溶液中加入钠氢(385.03mg,9.63mmol,60%纯度)。该混合物在0℃下搅拌25小时后,向该混合物中加入三氘代碘甲烷(1.16g,8.02mmol,499.09uL),在0℃下搅拌2小时。在0℃下向反应液中加入碳酸氢钠水溶液(30mL)淬灭反应,用乙酸乙酯萃取(50mL×3),用无水硫酸钠干燥,过滤,滤液减压浓缩得到目标粗产物(1.5g,黄绿色固体)。LC-MS(ESI):m/z(M+1)+267.1。1H NMR(400MHz,CDCl3):δ8.04-8.01(m,2H),6.96(d,J=12.0Hz,1H),3.10(d,J=12Hz,2H),2.65(t,J=12Hz,2H),2.45-2.43(m,2H),2.36(s,3H),1.16-1.15(d,J=4.0Hz,6H)。
b)4-((3S,5R)-3,5-二甲基-4-(甲基-d3)哌嗪-1-基)-3-甲基苯胺的制备:在氮气保护下,向(2S,6R)-2,6-二甲基-1-(甲基-d3)-4-(2-甲基-4-硝基)哌嗪(1.5g,5.63mmol)的甲醇(5mL)溶液中加入钯碳(281.58umol,10%纯度),得到的混悬液抽真空用氢气净化多次。该混合物在氢气(15psi)气氛下在25℃下搅拌12小时,将反应混合物过滤,滤液减压浓缩得到目标粗产物(1.3g,黑色固体)。LC-MS(ESI):m/z(M+1)+237.1。
c)6-(2,6-二氯苯基)-2-((4-((3S,5R)-3,5-二甲基-4-(甲基-d3)哌嗪-1-基)-3-甲基苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮的制备:向4-((3S,5R)-3,5-二甲基-4-(甲基-d3)哌嗪-1-基)-3-甲基苯胺(459.32mg,1.94mmol)和制备的6-(2,6-二氯苯基)-2-(甲亚磺酰基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮和6-(2,6-二氯苯基)-2-(甲磺酰基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮的混合物(700mg,粗品)的乙腈(5mL)溶液中加入三氟乙酸(20.14mg,0.177mmol,13.08uL)。该混合物在20-25℃下搅拌2小时后,过滤,滤液减压浓缩得到粗产物,经反相HPLC纯化,得到目标化合物(56.89mg,100.00μmol,黄色固体,5.66%收率)。LC-MS(ESI):m/z(M+1)+568.0。1H NMR(400MHz,CDCl3):δ8.81(s,1H),7.49(d,J=3.8Hz,3H),7.41-7.34(m,3H),7.02(d,J=4.2Hz,1H),4.25-4.21(m,2H),4.02(t,J=8.0Hz,2H),2.95(d,J=6.0Hz 2H),2.62(t,J=6.0Hz,2H),2.46-2.41(m,2H),2.34(s,6H),1.15(d,J=6.4Hz,6H)。
参照实施例1或2的方法可制备获得下述实施例3-13的化合物。
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实施例14
应用Wee1激酶(人源)检测法测定本发明化合物对Wee1激酶的酶活性的抑制效应
在含20mM Tris/HCl pH 8.5,0.2mM EDTA,500μM LSNLYHQGKFLQTFCGSPLYRRR,10mM醋酸镁和10μM[γ-33p]-ATP的反应液中加入Wee1激酶(人源)孵育,而后加入50倍浓度的溶于100%DMSO中的待测化合物储液至终浓度10μM,混匀,按1∶3和1∶10比例分别进行连续系列稀释至10个浓度(最后一个浓度为DMSO阴性对照):10μM,3μM,1μM,0.3μM,0.1μM,0.03μM,0.01μM,0.003μM,0.001μM,0μM。加入Mg/ATP混合物启动反应,在室温下孵育40分钟后,加入磷酸溶液至终浓度0.5%淬灭反应。取10μL反应液滴到P30滤纸上用0.425%磷酸溶液洗4次之后用甲醇洗1次,干燥,液闪计数。每个化合物样品一式二份重复。实验阴性对照为缺少Wee1酶的所有组成部分,阳性为加入30%磷酸终止反应。表1列出了化合物的Wee1激酶抑制数据(IC50)。
表1
实施例 | 1 | 2 | 8 | 9 | 12 | 13 | E64* | E70* | E77* |
IC50(nM) | 37 | 21 | 30 | 23 | 23 | 26 | 30 | 48 | 23 |
*注:E64、E70和E77分别为WO 2018/090939中实施例64、70和77的化合物。
因此,经Wee1激酶(人源)检测法测定,本发明化合物(实施例1-13)对Wee1激酶酶活性有好的抑制效应。
实施例15
应用CCK-8检测法测定本发明化合物对LoVo细胞增长的抑制作用
将新复苏的LoVo细胞培养传代至第三代后,且生长状态良好、融合度90%左右,开始用于实验。用胰酶消化LoVo细胞,800rpm离心5min,弃上清,用新鲜培基重悬,并计数,以6000个细胞每孔密度接种至96孔细胞培养板,置于37℃ 5%CO2培养箱培养过夜。待测化合物母液用DMSO按1∶3和1∶10比例分别进行连续系列稀释至8个浓度(最后一个浓度为DMSO阴性对照):10μM,3.3μM,1μM,0.33μM,0.1μM,0.033μM,0.01μM,0μM(DMSO终浓度为1‰)。每个浓度取5μL加入到120μL培基(25倍稀释),振荡混匀。取培养过夜的细胞,除去培养基,每孔加入195μL新鲜培基,再分别加入5μL稀释好的含相应浓度受试物的培基,随后将培养板置于37℃ 5%CO2培养箱培养3d。除去原液,每孔加90μL的新鲜无血清1640培养基后,再每孔加10μL CCK-8检测试剂,继续培养2h后,置于多功能读数仪读取450/650nm波长的吸光值(OD值)。用软件Graph Pad Prism 5.0分析数据,化合物对细胞增值的抑制活性以细胞存活率和化合物浓度为坐标绘图。IC50值以S形剂量反应曲线方程拟合,曲线方程为:Y=100/(1+10^(LogC-LogIC50)),其中C是化合物浓度。
表2汇总了化合物对LoVo细胞增长的抑制作用数据(IC50)。
表2
实施例 | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 |
IC50(μM) | 0.126 | 0.158 | 0.219 | 0.222 | 0.124 | 0.114 | 0.137 | 0.163 |
实施例 | 9 | 10 | 11 | 12 | 13 | E47* | E51* | E64* |
IC50(μM) | 0.533 | 0.220 | 0.175 | 0.078 | 0.073 | 0.384 | 0.359 | 0.421 |
实施例 | E70* | E77* | E78* | E114* | E137* | |||
IC50(μM) | 0.557 | 0.166 | 0.204 | 0.662 | 0.757 |
*注:E47、E51、E64、E70、E77、E78、E114和E137分别为WO 2018/090939中实施例47、51、64、70、77、78、114和137的化合物。
表2的结果显示,与R3和R7均为H的化合物E64相比,R3和R7之一或两者均不为H的化合物2-8具有明显更低的IC50值。与R3为F、R7为H的化合物E70相比,R3或R7之一为烷基或溴的化合物2-8也具有明显更低的IC50值。与R3为甲基、R7为H的化合物E70相比,R3和R7为烷基、烷氧基和F的化合物5-7也具有明显更低的IC50值。与R3和R7均为H的化合物E114相比,R3和R7之一或两者均不为H的化合物9-13具有明显更低的IC50值。
因此,经CCK-8检测法测定,本发明化合物(实施例1-13)对LoVo细胞增长有好的抑制作用。
实施例16
应用CCK-8检测法测定本发明化合物对NCI-H1299细胞增长的抑制作用
将新复苏的NCI-H1299细胞培养传代至第三代后,且生长状态良好、融合度90%左右,开始用于实验。用胰酶消化NCI-H1299细胞,800rpm离心5min,弃上清,用新鲜培基重悬,并计数,以1000个细胞每孔密度接种至96孔细胞培养板,置于37℃5%CO2培养箱培养过夜。待测化合物母液用DMSO按1∶3和1∶10比例分别进行连续系列稀释至8个浓度(最后一个浓度为DMSO阴性对照):10μM,3.3μM,1μM,0.33μM,0.1μM,0.033μM,0.01μM,0μM(DMSO终浓度为1‰)。每个浓度取5μL加入到120μL培基(25倍稀释),振荡混匀。取培养过夜的细胞,除去培养基,每孔加入195μL新鲜培基,再分别加入5μL稀释好的含相应浓度受试物的培基,随后将培养板置于37℃、5%CO2培养箱培养3d。除去原液,每孔加90μL的新鲜无血清1640培养基后,再每孔加10μL CCK-8检测试剂,继续培养2h后,置于多功能读数仪读取450/650nm波长的吸光值(OD值)。用软件Graph Pad Prism 5.0分析数据,化合物对细胞增值的抑制活性以细胞存活率和化合物浓度为坐标绘图。IC50值以S形剂量反应曲线方程拟合,曲线方程为:Y=100/(1+10^(LogC-LogIC50)),其中C是化合物浓度。
表3汇总了化合物对NCI-H1299细胞增长的抑制作用数据(IC50)。
表3
实施例 | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 |
IC50(μM) | 0.071 | 0.123 | 0.382 | 0.838 | 0.182 | 0.140 | 0.209 | 0.214 |
实施例 | 9 | 10 | 11 | 12 | 13 | E47* | E51* | E64* |
IC50(μM) | 0.940 | 0.204 | 0.166 | 0.079 | 0.085 | 0.574 | 0.396 | 0.315 |
实施例 | E70* | E77* | E78* | E114* | E137* | |||
IC50(μM) | 0.398 | 0.122 | 0.151 | 0.465 | 0.364 |
*注:E47、E51、E64、E70、E77、E78、E114和E137分别为WO 2018/090939中实施例47、51、64、70、77、78、114和137的化合物。
因此,经CCK-8检测法测定,本发明化合物(实施例1-13)对NCI-H1299细胞增长有好的抑制作用。
虽然已经充分地描述了本发明,但是本领域技术人员应当理解,可在不影响本发明范围或其任何实施方案的情况下,在广泛且等同的条件、制剂和其它参数范围内进行相同实施。本文所引用的所有专利、专利申请和出版物都全文引入本文以供参考。
Claims (11)
1.下式Ia所示结构的化合物或其可药用盐:
式中,R1和R2均为氯;R3为甲基;R7为氟或甲基;R4和R6各自独立为甲基;R5为甲基。
2.具有下式Ib所示结构的化合物或其可药用盐:
式中,R1和R2均为氯;R3为甲基;R4和R6各自独立为甲基;R5为H。
3.具有下式Ic所示结构的化合物或其可药用盐:
式Ic中,R1和R2均为氯;R3为氟、氯或甲基;R5为甲基;R7为H或氟。
4.如权利要求3所述的化合物或其可药用盐,其特征在于,所述化合物选自:
5.权利要求1-4中任一项所述的化合物或其可药用盐在制备治疗或预防Wee1介导的疾病的药物中的用途。
6.权利要求5的用途,其中,所述疾病是癌症。
7.权利要求6的用途,其中,所述癌症选自肝癌、黑素瘤、霍奇金病、非霍奇金淋巴瘤、急性淋巴白血病、慢性淋巴白血病、多发性骨髓瘤、成神经细胞瘤、乳腺癌、卵巢癌、肺癌、维尔姆斯瘤、子***、睾丸癌、软组织肉瘤、原发性巨球蛋白血症、膀胱癌、慢性粒细胞白血病、原发性脑癌、胃癌、结肠癌、恶性胰腺胰岛瘤、恶性类癌性癌症、绒毛膜癌、蕈样肉芽肿、头颈癌、骨原性肉瘤、胰腺癌、急性粒细胞白血病、毛细胞白血病、横纹肌肉瘤、卡波西肉瘤、泌尿生殖***肿瘤、甲状腺癌、食管癌、恶性高钙血症、肾细胞癌、子宫内膜癌、真性红细胞增多症、特发性血小板增多症、肾上腺皮质癌、皮肤癌和***癌。
8.权利要求6的用途,其中,所述癌症选自恶性黑素瘤、小细胞肺癌和子宫颈增生症。
9.一种药用组合物,包括权利要求1-4中任一项所述的化合物或其可药用盐与可药用载体。
10.权利要求9的药用组合物,其中所述组合物还含有至少一种已知的抗癌药物或其可药用盐。
11.如权利要求10所述的药用组合物,其中所述抗癌药物选自:白消安、马法兰、苯丁酸氮芥、环磷酰胺、异环磷酰胺、替莫唑胺、苯达莫司汀、顺铂、丝裂霉素C、博莱霉素、卡铂、喜树碱、伊立替康、托泊替康、阿霉素、表阿霉素、阿克拉霉素、米托蒽醌、甲基羟基玫瑰树碱、铭托泊普、5-氮杂胞苷、吉西他滨、5-氟尿嘧啶、甲氨蝶呤、5-氟-2'-去氧尿苷、氟达拉滨、奈拉滨、阿糖胞苷、普拉曲沙、培美曲塞、羟基脲、硫代鸟嘌呤、秋水仙碱、长春碱、长春新碱、长春瑞滨、紫杉醇、伊沙匹隆、卡巴他赛、多西他赛、单抗、帕尼单抗、耐措妥珠单抗、纳武单抗、派姆单抗、雷莫芦单抗、贝伐珠单抗、帕妥珠单抗、曲妥珠单抗、西妥昔单抗、奥滨尤妥珠单抗、奥法木单抗、利妥昔单抗、阿仑单抗、替伊莫单抗、托西莫单抗、本妥昔单抗、达雷木单抗、埃罗妥珠单抗、T-DM1、Ofatumumab、Dinutuximab、Blinatumomab、易普利姆玛、阿瓦斯丁、赫赛汀、美罗华、伊马替尼、吉非替尼、厄洛替尼、奥斯替尼、阿法替尼、赛立替尼、艾乐替尼、克唑替尼、埃罗替尼、拉帕替尼、索拉非尼、舒尼替尼、尼罗替尼、达沙替尼、帕唑帕尼、特癌适、依维莫司、伏立诺他、罗咪地辛、帕比司他、贝利司他、他莫昔芬、来曲唑、氟维司群、米托胍腙、奥曲肽、视黄酸、砒霜、唑来膦酸、硼替佐米、卡非佐米、Ixazomib、维莫德吉、索尼德吉、狄诺塞麦、萨力多胺、来那度胺、Venetoclax、Aldesleukin、Sipueucel-T、帕博西尼、奥拉帕尼、Niraparib,Rucaparib、Talazoparib和Senaparib。
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