CN102203075B - 二环激酶抑制剂 - Google Patents
二环激酶抑制剂 Download PDFInfo
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- CN102203075B CN102203075B CN200980143219.4A CN200980143219A CN102203075B CN 102203075 B CN102203075 B CN 102203075B CN 200980143219 A CN200980143219 A CN 200980143219A CN 102203075 B CN102203075 B CN 102203075B
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- Prior art keywords
- amino
- pyridine
- amine
- naphthyridines
- piperidines
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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Abstract
本发明提供了在人或动物个体中抑制与肿瘤形成相关的Maloney原病毒整合激酶(PIM激酶)活性的化合物、组合物和方法。在某些实施方案中,所述化合物和组合物有效抑制至少一种PIM激酶的活性。所述化合物和组合物可以单独使用或与至少一种用于治疗丝氨酸/苏氨酸激酶或受体酪氨酸激酶介导的病症例如癌症的其它活性剂联合使用。
Description
相关申请的交叉参引
本申请根据35U.S.C.§119(e)要求2008年9月2日提交的U.S.临时申请61/093,669的优先权,将其整体引入本文作为参考。
技术领域
本发明涉及新化合物和它们的互变异构体和立体异构体,以及其药学上可接受的盐、酯、代谢产物或前药,所述新化合物和药学上可接受的载体的组合物,和所述新化合物单独或与至少一种其它治疗剂联合在预防或治疗癌症中的用途。
背景
Maloney逆转录病毒的感染和宿主细胞基因组中的基因组整合导致小鼠淋巴瘤的发展。Maloney原病毒整合激酶(Provirus Integration ofMaloney Kinase)(PIM-激酶)被认为是常见的原癌基因之一,它能够通过这种逆转录病毒整合事件而被转录性激活(Cuypers HT等,“鼠白血病病毒诱导的T-细胞淋巴瘤生成:在不同染色体域中的原病毒整合”(“Murineleukemia virus-induced T-cell lymphomagenesis:integration of provirusesin a distinct chromosomal region”),Cell 37(1):141-50(1984);Selten G等,“在MuLV诱导的T-细胞淋巴瘤中公认致癌基因Pim-1的原病毒激活”(“Proviral activation of the putative oncogene Pim-1 in MuLV inducedT-cell lymphomas”),EMBO J 4(7):1793-8(1985)),由此确立了该激酶的过度表达与其潜在致癌性之间的关联。序列同源性分析证明存在3种高同源性Pim-激酶(Pim1、2和3),Pim1最初是通过逆转录病毒整合鉴定的原癌基因。另外,过度表达Pim1或Pim2的转基因鼠显示T-细胞淋巴瘤的发生率有所增加(Breuer M等,“在pim-1转基因小鼠中通过化学致癌物导发的高淋巴瘤发生率”(“Very high frequency of lymphoma induction by achemical carcinogen in pim-1 transgenic mice”),Nature 340(6228):61-3(1989)),而c-myc的过度表达与B-细胞淋巴瘤的发生率有关(Verbeek S等,“携有Eμ-myc和Eμ-pim-1转基因的小鼠形成了胎儿期前-B-细胞白血病”(“Mice bearing the E mu-myc and E mu-pim-1transgenes developpre-B-cell leukemia prenatally”),Mol Cell Biol 11(2):1176-9(1991))。因此,这些动物模型确立了造血性恶性肿瘤(malignancies)中Pim过度表达和瘤形成之间具有显著的相关性。除了这些动物模型外,Pim过度表达在多种其他人类恶性肿瘤中也已有报道。Pim1、2和3过度表达常见于多种造血性恶性肿瘤中(Amson R等,“人类原癌基因产物p33pim在胎儿血细胞生成期间以及不同白血病中表达”(“The human protooncogene product p33pimis expressed during fetal hematopoiesis and in diverse leukemias”),PNASUSA 86(22):8857-61(1989);Cohen AM等,“hPim-2基因在人慢性淋巴细胞白血病和非霍奇金淋巴瘤中的表达增加”(“Increased expression of thehPim-2 gene in human chronic lymphocytic leukemia and non-Hodgkinlymphoma”),Leuk Lymph 45(5):951-5(2004),Huttmann A等,“基因表达的特征在于由ZAP-70和CD38表达状态所界定的不同B-细胞慢性淋巴细胞白血病预后亚群”(“Gene expression signatures separate B-cell chroniclymphocytic leukaemia prognostic subgroups defined by ZAP-70 andCD38 expression status”),Leukemia 20:1774-1782(2006)),也常见于***癌中(Dhanasekaran SM等,“***癌中预后生物标记的描述”(“Delineation of prognostic biomarkers in prostate cancer”),Nature412(6849):822-6(2001);Cibull TL等,“***癌发展过程中Pim-1的过度表达”(“Overexpression of Pim-1 during progression of prostaticadenocarcinoma”),J Clin Pathol 59(3):285-8(2006)),而Pim3的过度表达常见于肝细胞癌中(Fujii C等,“肝细胞癌发展中丝氨酸/苏氨酸激酶Pim-3的异常表达及其在人肝细胞瘤细胞系增殖中的作用”(“Aberrant expressionof serine/threonine kinase Pim-3 in hepatocellular carcinoma developmentand its role in the proliferation of human hepatoma cell lines”),Int JCancer 114:209-218(2005)),也常见于胰腺癌中(Li YY等,“Pim-3,一种具有丝氨酸/苏氨酸激酶活性的原癌基因,在人胰腺癌中异常表达以及在人胰腺癌细胞系中磷酸化bad从而阻断bad-介导的细胞凋亡”(“Pim-3,aproto-oncogene with serine/threonine kinase activity,is aberrantlyexpressed in human pancreatic cancer and phosphorylates bad to blockbad-mediated apoptosis in human pancreatic cancer cell lines”),CancerRes 66(13):6741-7(2006))。
Pim1、2和3为丝氨酸/苏氨酸激酶,它们在对生长因子和细胞因子有响应的造血细胞的生存和增殖中发挥正常作用。通过Jak/Stat通路的细胞因子信号导致Pim基因转录的激活和蛋白质的合成。对于激酶Pim活性而言,不需要其它翻译后的修饰。因此,下游信号主要在转录/翻译水平和蛋白周转水平(protein turnover level)上进行控制。Pim激酶的底物包括:细胞凋亡调节剂,例如Bcl-2家族成员BAD(Aho T等,“Pim-1激酶通过在Ser112门控位点对其磷酸化而促进前细胞凋亡Bad蛋白的失活”(″Pim-1kinase promotes inactivation of the pro-apoptotic Bad protein byphosphorylating it on the Ser112 gatekeeper site”),FEBS Letters 571:43-49(2004));细胞周期调节剂,例如p21WFA1/CIP1(Wang Z等,“通过Pim-1激酶进行的细胞周期抑制剂p21Cip1/WAF1的磷酸化”(″Phosphorylationof the cell cycle inhibitor p21 Cip1/WAF1 by Pim- 1kinase,″),BiochimBiophys Acta 1593:45-55(2002));CDC25A(1999);C-TAK(Bachmann M等,“致癌性丝氨酸/苏氨酸激酶Pim-1磷酸化并抑制Cdc25C-相关激酶1(C-TAK1)的活化,Pim-1在G2/M细胞周期限制点处的新作用”(″TheOncogenic Serine/Threonine Kinase Pim-1 Phosphorylates and Inhibits theActivity of Cdc25C-associated Kinase 1(C-TAK1).A novel role for Pim-1 atthe G2/M cell cycle checkpoint,″),J Biol Chem 179:48319-48328(2004));和NuMA(Bhattacharya N等,“Pim-1与有丝***所必需的蛋白复合物之间的联系”(″Pim-1 associates with protein complexes necessary for mitosis,″),Chromosoma 111(2):80-95(2002))和蛋白合成调节剂4EBP1(HammermanPS等,“Pim和Akt癌基因是造血细胞生长和存活的独立调节剂”(“Pim andAkt oncogenes are independent regulators of hematopoietic cell growthand survival”),Blood 105(11):4477-83(2005))。Pim在这些调节剂中的作用与避免细胞凋亡的保护作用以及细胞增殖和生长的促进作用是一致的。因此,Pim在癌症中的过度表达被认为在促进癌细胞存活和增殖中起到了作用,所以,对它们的抑制应该是治疗其过度表达的癌症的有效途径。实际上,多个报道显示,用siRNA击倒Pim的表达导致增殖的抑制和细胞死亡(Dai JM等,“靶向丝氨酸/苏氨酸激酶pim-2的反义寡聚脱氧核苷酸抑制DU-145细胞的增殖”(″Antisense oligodeoxynucleotides targeting theserine/threonine kinase Pim-2 inhibited proliferation of DU-145 cell,″),Acta Pharmacol Sin 26(3):364-8(2005);Fujii等2005;Li等2006)。另外,多种已知癌基因在造血性恶性肿瘤中的突变激活被认为至少部分通过Pim而发挥其作用。例如,pim表达的靶向下调使得被Flt3和BCR/ABL转化的造血细胞的存活受到损害(Adam等,2006)。因此,Pim1、2和3的抑制剂可以用于治疗这些恶性肿瘤。除了在癌症治疗和骨髓增殖性疾病治疗中的可能作用外,此类抑制剂还可能在其他病理情况(例如自身免疫性疾病、***反应以及器官移植排斥综合征)中用于控制免疫细胞的扩张。下列发现支持了这个观点:IL-12和IFN-α导致的Th1 T-辅助细胞分化诱导了Pim1和2的表达(Aho T等,“促进1型T辅助细胞而非2型T辅助细胞分化的细胞因子选择性上调人Pim家族基因的表达”(″Expression of human Pimfamily genes is selectively up-regulated by cytokines promoting T helpertype 1,but not T helper type 2,cell differentiation,″),Immunology 116:82-88(2005))。另外,通过免疫抑制TGF-β在两种细胞类型中能够抑制Pim的表达(Aho等,2005)。这些结果显示,Pim激酶与T-辅助细胞的早期分化过程有关,所述T-辅助细胞能够在自身免疫性疾病、***反应以及组织移植排斥反应中协调免疫应答。
对于能够抑制毛细血管增生、抑制肿瘤生长、治疗癌症、调节细胞周期阻滞和/或抑制分子(例如Pim1、Pim2和Pim3)的化合物以及含有此类化合物的药物制剂以及药物的需求一直存在。对于施用此类化合物、药物制剂和药物至有其需要的患者或个体的方法的需求也存在。
概述
本发明提供式I化合物:
它们的立体异构体、互变异构体和其药学上可接受的盐,其中,
X1、X2、X3、X4、X5和X6独立地选自CR2和N,前提是X1、X2、X3、X4、X5和X6中至少一个但不超过三个是N;
Y选自由氨基、烷氧基、芳基、杂芳基、部分不饱和的环烷基、环烷基和杂环烷基组成的组,其中所述组的每个成员被至多4个取代基取代;
Z1、Z2和Z3独立地选自CR12和N,前提是Z1、Z2和Z3中不超过两个可以是N;
R1选自氢、卤素、羟基、硝基、氰基、SO3H和取代的或未取代的烷基、烯基、炔基、烷氧基、氨基、环烷基、杂环烷基、氨基羰基氧基、氨基磺酰基、氨基磺酰基氧基、氨基磺酰基氨基、脒基、羧基、羧基酯(carboxylester)、(羧基酯)氨基、(羧基酯)氧基、磺酰基、磺酰基氧基、硫代酰基、巯基、烷硫基、芳基、杂芳基、环烷基、杂环烷基、部分饱和的环烷基、芳基氧基、杂芳基氧基、杂环基氧基、环烷基氧基、酰基、酰基氨基和酰基氧基、和部分饱和的环烷基;且
R2和R12每次出现时独立地选自氢、卤素、羟基、硝基、氰基、SO3H和取代的或未取代的烷基、烯基、炔基、烷氧基、氨基、环烷基、杂环烷基、氨基羰基氧基、氨基磺酰基、氨基磺酰基氧基、氨基磺酰基氨基、脒基、羧基、羧基酯、(羧基酯)氨基、(羧基酯)氧基、磺酰基、磺酰基氧基、硫代酰基、巯基、烷硫基、芳基、杂芳基、环烷基、杂环烷基、部分饱和的环烷基、芳基氧基、杂芳基氧基、杂环基氧基、环烷基氧基、酰基、酰基氨基和酰基氧基、和部分饱和的环烷基。
在一些实施方案中,提供了式I化合物或者其立体异构体、互变异构体或药学上可接受的盐,其中X1、X2和X3中不超过两个是N,并且X4、X5和X6中不超过两个是氮。在其它实施方案中,提供了如下式I化合物,其中X2和X4是N,且X1、X3、X5和X6是CR2;或其中X4是N且X1、X2、X3、X5和X6是CR2。在另外实施方案中,提供了如下的新式I化合物,其中Z1是N或CR12且Z2和Z3是CR12;或其中Z1和Z2是N或CR12,且Z3是CR12。
另一实施方案提供式II化合物:
或者其立体异构体、互变异构体或药学上可接受的盐,其中:
其中,
Y选自取代的或未取代的氨基、环己基、环己烯基、哌啶基和哌嗪基;
R1选自未取代的和取代的芳基、杂芳基、烷基、环烷基、氢和卤素;
R3选自氢、卤素、CN、NH2、NHR4、C1-4烷基和C3-4环烷基;
R2和R12每次出现时独立地选自氢、卤素、羟基、硝基、氨基、氰基、SO3H、取代的或未取代的烷基、烯基、炔基、烷氧基、氨基、环烷基、杂环烷基、氨基羰基氧基、氨基磺酰基、氨基磺酰基氧基、氨基磺酰基氨基、脒基、羧基、羧基酯、(羧基酯)氨基、(羧基酯)氧基、磺酰基、磺酰基氧基、硫代酰基、巯基、烷硫基、芳基、杂芳基、环烷基、杂环烷基、部分饱和的环烷基、芳基氧基、杂芳基氧基、杂环基氧基、环烷基氧基、酰基、酰基氨基和酰基氧基、和部分饱和的环烷基;且
R4选自氢、羧基和取代的或未取代的烷基、环烷基、杂环烷基、芳基和杂芳基。
又一实施方案提供式III化合物:
或者其立体异构体、互变异构体或药学上可接受的盐,其中:
Y选自取代的或未取代的氨基、环己基、环己烯基、哌啶基和哌嗪基;
R1选自未取代的和取代的芳基、杂芳基、烷基、环烷基、氢和卤素;且
R2和R12每次出现时独立地选自氢、卤素、羟基、硝基、氨基、氰基、SO3H和取代的或未取代的烷基、烯基、炔基、烷氧基、氨基、环烷基、杂环烷基、氨基羰基氧基、氨基磺酰基、氨基磺酰基氧基、氨基磺酰基氨基、脒基、羧基、羧基酯、(羧基酯)氨基、(羧基酯)氧基、磺酰基、磺酰基氧基、硫代酰基、巯基、烷硫基、芳基、杂芳基、环烷基、杂环烷基、部分饱和的环烷基、芳基氧基、杂芳基氧基、杂环基氧基、环烷基氧基、酰基、酰基氨基和酰基氧基、和部分饱和的环烷基。
又一实施方案提供式IV化合物:
或者其立体异构体、互变异构体或药学上可接受的盐,其中,
Y选自取代的或未取代的氨基、环己基、环己烯基、哌啶基和哌嗪基;
R1选自未取代的和取代的芳基、杂芳基、烷基、环烷基、氢和卤素;
R3选自氢、卤素、CN、NH2、NHR4、C1-4烷基和C3-4环烷基;
每个R2和R12在每次出现时独立地选自氢、卤素、羟基、硝基、氨基、氰基、SO3H和取代的或未取代的烷基、烯基、炔基、烷氧基、氨基、环烷基、杂环烷基、氨基羰基氧基、氨基磺酰基、氨基磺酰基氧基、氨基磺酰基氨基、脒基、羧基、羧基酯、(羧基酯)氨基、(羧基酯)氧基、磺酰基、磺酰基氧基、硫代酰基、巯基、烷硫基、芳基、杂芳基、环烷基、杂环烷基、部分饱和的环烷基、芳基氧基、杂芳基氧基、杂环基氧基、环烷基氧基、酰基、酰基氨基和酰基氧基、和部分饱和的环烷基;且
R4选自氢、羧基和取代的或未取代的烷基、环烷基、杂环烷基、芳基和杂芳基。
在其它实施方案中,提供了式I-IV化合物,其中Y选自由哌啶基、哌嗪基、环己基、吡啶基、嘧啶基和吡嗪基组成的组,其中所述组的每个成员被至多4个取代基取代。在一优选的实施方案中,Y是取代的哌啶基或环己基。
在另外的实施方案中提供了其中R12选自氨基、氢或卤素的式I-IV的化合物。
在本发明的其它方面中,提供了在需要此治疗的人或动物个体中治疗与Maloney原病毒整合激酶(PIM激酶)相关的病症的方法,该方法包括向所述个体施用有效抑制个体中的PIM活性的量的式I、II、III或IV化合物。
在其它方面,本发明提供在需要此治疗的人或动物个体中治疗与PIM相关的病症的方法,该方法包括向所述个体施用有效减少或阻止个体中肿瘤生长的量的式I、II、III或IV化合物。
在另外方面,本发明提供在需要此治疗的人或动物个体中治疗与PIM相关的病症的方法,该方法包括向所述个体施用有效减少或阻止个体中肿瘤生长的量的式I、II、III或IV化合物以及用于治疗癌症的至少一种其它活性剂。
在另外方面,本发明提供治疗组合物,其包含至少一种式I、II、III或IV化合物以及一种或多种用于治疗癌症的其它活性剂,所述活性剂在癌症治疗中是普遍使用的。另外一方面提供了还包含用于治疗癌症的其它活性剂的药物组合物,其中所述的其它活性剂优选选自伊立替康、托泊替康、吉西他滨、5-氟尿嘧啶、亚叶酸、卡铂、顺铂、紫杉烷类、替扎他滨(tezacitabine)、环磷酰胺、长春花生物碱类、伊马替尼(Gleevec)、蒽环类、利妥昔单抗和曲妥珠单抗。
本发明的化合物可用于治疗癌症包括造血性(hematopoietic)恶性肿瘤、癌(例如肺、肝、胰脏、卵巢、甲状腺、膀胱或结肠的癌)、黑色素瘤、骨髓性病症(例如髓样白血病、多发性骨髓瘤和红白血病)、腺瘤(例如结肠绒毛状腺瘤)、肉瘤(例如骨肉瘤)、自身免疫性疾病、***反应和器官移植排斥综合征。
本发明还提供了如本发明的详细说明中所述的组合物、应用方法和制备方法。
详细说明
在一个实施方案中,本发明提供了式I化合物,
它们的立体异构体、互变异构体或其药学上可接受的盐,其中,
X1、X2、X3、X4、X5和X6独立地选自CR2和N,前提是X1、X2、X3、X4、X5和X6中至少一个但不超过三个是N;
Y选自由氨基、烷氧基、芳基、杂芳基、部分不饱和的环烷基、环烷基和杂环烷基组成的组,其中所述组的每个成员被至多4个取代基取代;
Z1、Z2和Z3独立地选自CR12和N,前提是Z1、Z2和Z3中不超过两个可以是N;
R1选自氢、卤素、羟基、硝基、氰基、SO3H和取代的或未取代的烷基、烯基、炔基、烷氧基、氨基、环烷基、杂环烷基、氨基羰基氧基、氨基磺酰基、氨基磺酰基氧基、氨基磺酰基氨基、脒基、羧基、羧基酯、(羧基酯)氨基、(羧基酯)氧基、磺酰基、磺酰基氧基、硫代酰基、巯基、烷硫基、芳基、杂芳基、环烷基、杂环烷基、部分饱和的环烷基、芳基氧基、杂芳基氧基、杂环基氧基、环烷基氧基、酰基、酰基氨基和酰基氧基、和部分饱和的环烷基;且
R2和R12每次出现时独立地选自氢、卤素、羟基、硝基、氰基、SO3H和取代的或未取代的烷基、烯基、炔基、烷氧基、氨基、环烷基、杂环烷基、氨基羰基氧基、氨基磺酰基、氨基磺酰基氧基、氨基磺酰基氨基、脒基、羧基、羧基酯、(羧基酯)氨基、(羧基酯)氧基、磺酰基、磺酰基氧基、硫代酰基、巯基、烷硫基、芳基、杂芳基、环烷基、杂环烷基、部分饱和的环烷基、芳基氧基、杂芳基氧基、杂环基氧基、环烷基氧基、酰基、酰基氨基和酰基氧基、和部分饱和的环烷基。
在优选的实施方案中,提供了式I化合物或者其立体异构体、互变异构体或药学上可接受的盐,其中X1、X2和X3中不超过两个是N,并且X4、X5和X6中不超过两个是氮。在其它实施方案中,提供了式I化合物,其中X2和X4是N,且X1、X3、X5和X6是CR2;或其中X4是N且X1、X2、X3、X5和X6是CR2。在另外实施方案中,提供了新的式I化合物,其中Z1是N或CR12且Z2和Z3是CR12;或其中Z1和Z2是N或CR12,且Z3是CR12。
另一实施方案提供式II化合物:
或者其立体异构体、互变异构体或药学上可接受的盐,其中:
Y选自取代的或未取代的氨基、环己基、环己烯基、哌啶基和哌嗪基;
R1选自未取代的和取代的芳基、杂芳基、烷基、环烷基、氢和卤素;
R3选自氢、卤素、CN、NH2、NHR4、C1-4烷基和C3-4环烷基;
R2和R12每次出现时独立地选自氢、卤素、羟基、硝基、氨基、氰基、SO3H和取代的或未取代的烷基、烯基、炔基、烷氧基、氨基、环烷基、杂环烷基、氨基羰基氧基、氨基磺酰基、氨基磺酰基氧基、氨基磺酰基氨基、脒基、羧基、羧基酯、(羧基酯)氨基、(羧基酯)氧基、磺酰基、磺酰基氧基、硫代酰基、巯基、烷硫基、芳基、杂芳基、环烷基、杂环烷基、部分饱和的环烷基、芳基氧基、杂芳基氧基、杂环基氧基、环烷基氧基、酰基、酰基氨基和酰基氧基、和部分饱和的环烷基;且
R4选自氢、羧基和取代的或未取代的烷基、环烷基、杂环烷基、芳基和杂芳基。
又一实施方案提供式III化合物:
或者其立体异构体、互变异构体或药学上可接受的盐,其中,
Y选自取代的或未取代的氨基、环己基、环己烯基、哌啶基和哌嗪基;
R1选自未取代的和取代的芳基、杂芳基、烷基、环烷基、氢和卤素;且
R2和R12在每次出现时独立地选自氢、卤素、羟基、硝基、氨基、氰基、SO3H和取代的或未取代的烷基、烯基、炔基、烷氧基、氨基、环烷基、杂环烷基、氨基羰基氧基、氨基磺酰基、氨基磺酰基氧基、氨基磺酰基氨基、脒基、羧基、羧基酯、(羧基酯)氨基、(羧基酯)氧基、磺酰基、磺酰基氧基、硫代酰基、巯基、烷硫基、芳基、杂芳基、环烷基、杂环烷基、部分饱和的环烷基、芳基氧基、杂芳基氧基、杂环基氧基、环烷基氧基、酰基、酰基氨基和酰基氧基、和部分饱和的环烷基。
另一实施方案提供式IV化合物:
或者其立体异构体、互变异构体或药学上可接受的盐,其中:
Y选自取代的或未取代的氨基、环己基、环己烯基、哌啶基和哌嗪基;
R1选自未取代的和取代的芳基、杂芳基、烷基、环烷基、氢和卤素;
R3选自氢、卤素、CN、NH2、NHR4、C1-4烷基和C3-4环烷基;
R2和R12每次出现时独立地选自氢、卤素、羟基、硝基、氨基、氰基、SO3H和取代的或未取代的烷基、烯基、炔基、烷氧基、氨基、环烷基、杂环烷基、氨基羰基氧基、氨基磺酰基、氨基磺酰基氧基、氨基磺酰基氨基、脒基、羧基、羧基酯、(羧基酯)氨基、(羧基酯)氧基、磺酰基、磺酰基氧基、硫代酰基、巯基、烷硫基、芳基、杂芳基、环烷基、杂环烷基、部分饱和的环烷基、芳基氧基、杂芳基氧基、杂环基氧基、环烷基氧基、酰基、酰基氨基和酰基氧基、和部分饱和的环烷基;且
R4选自氢、羧基和取代的或未取代的烷基、环烷基、杂环烷基、芳基和杂芳基。
在其它实施方案中,提供了式I-IV化合物,其中Y选自由哌啶基、哌嗪基、环己基、吡啶基、嘧啶基和吡嗪基组成的组,其中该组的每个成员被至多4个取代基取代。在一些实施方案中,Y是取代的哌啶基或环己基。
在另外的实施方案中,提供了式I-IV化合物,其中R12选自氨基、氢和卤素。
在一些优选的实施方案中,提供了式I化合物或者其立体异构体、互变异构体或药学上可接受的盐,所述化合物选自(S)-2-(4-(3-氨基哌啶-1-基)-3-氟-1,7-萘啶-6-基)-6-(噻唑-2-基)吡啶-3-胺、(S)-3-(5-氨基-6-(4-(3-氨基哌啶-1-基)-3-氟-1,7-萘啶-6-基)吡啶-2-基)-4-氟-N-异丙基苯甲酰胺、4-(6-(3-氨基-6-(2,6-二氟苯基)吡啶-2-基)-1,7-萘啶-4-基)-6-甲基吡啶-2-胺、3-(5-氨基-6-(4-(2-氨基-6-甲基吡啶-4-基)-1,7-萘啶-6-基)吡啶-2-基)-4-氟-N-异丙基-苯甲酰胺、(S)-2-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)-6-(噻唑-2-基)吡啶-3-胺、(S)-4-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)-2-(2-氟苯基)嘧啶-5-胺、(R)-2-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)-6-(2,6-二氟苯基)吡啶-3-胺、(R)-3-(5-氨基-6-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)吡啶-2-基)-4-氟-N-异丙基苯甲酰胺、(S)-2-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)-6-(2,6-二氟苯基)吡啶-3-胺、(S)-3-(5-氨基-6-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)吡啶-2-基)-4-氟-N-异丙基苯甲酰胺、(S)-2-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)-6-(2-氟苯基)吡啶-3-胺、(S)-3-(5-氨基-6-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)吡啶-2-基)-4-氟-N-苯基苯甲酰胺、(S)-2-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)-6-(噻吩-2-基)吡啶-3-胺、(S)-6-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)-6′-甲氧基-2,2′-联吡啶-5-胺、(S)-3-(5-氨基-6-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)吡啶-2-基)-N-环己基-4-氟苯甲酰胺、(S)-3-(5-氨基-6-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)吡啶-2-基)-4-氟-N,N-二甲基苯甲酰胺、(S)-2-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)-6-(2,4-二氟苯基)吡啶-3-胺、(S)-2-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)-6-(2,3-二氟苯基)吡啶-3-胺、(S)-2-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)-6-(4-氟苯基)吡啶-3-胺、(S)-2-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)-6-苯基吡啶-3-胺、(S)-3-(5-氨基-6-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)吡啶-2-基)苯磺酰胺、(S)-2-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)-6-(3-(甲基磺酰基)苯基)吡啶-3-胺、(S)-4-(5-氨基-6-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)吡啶-2-基)苯磺酰胺、(S)-2-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)-6-(4-(甲基磺酰基)苯基)吡啶-3-胺、(S)-1-(6-(6-(噻唑-2-基)吡啶-2-基)-1,7-萘啶-4-基)哌啶-3-胺、(S)-1-(6-(6-(2,6-二氟苯基)吡啶-2-基)喹啉-4-基)哌啶-3-胺、(S)-1-(6-(6-(噻唑-2-基)吡啶-2-基)喹啉-4-基)哌啶-3-胺、(S)-1-(6-(4-(2-氟苯基)嘧啶-2-基)喹啉-4-基)哌啶-3-胺、(S)-1-(6-(4-(2,6-二氟苯基)嘧啶-2-基)喹啉-4-基)哌啶-3-胺、(3S,5R)-5-甲基-1-(6-(6-(噻唑-2-基)吡啶-2-基)喹啉-4-基)哌啶-3-胺、(3R,4R)-1-(6-(6-(2,6-二氟苯基)吡啶-2-基)喹啉-4-基)-4-氟哌啶-3-胺、(3R,4R)-4-氟-1-(6-(6-(噻唑-2-基)吡啶-2-基)喹啉-4-基)哌啶-3-胺、(3S,5R)-1-(6-(6-(2,6-二氟苯基)吡啶-2-基)喹啉-4-基)-5-甲基哌啶-3-胺、(3R,4R)-3-氨基-1-(6-(6-(2,6-二氟苯基)吡啶-2-基)喹啉-4-基)哌啶-4-醇和(3R,4R)-3-氨基-1-(6-(6-(噻唑-2-基)吡啶-2-基)喹啉-4-基)哌啶-4-醇。
在其它方面,本发明提供了在需要此治疗的人或动物个体中治疗Maloney原病毒整合激酶(PIM激酶)相关的病症的方法,该方法包括向所述个体施用有效抑制个体中的PIM活性的量的式I、II、III或IV化合物。
在其它方面,本发明提供在需要此治疗的人或动物个体中治疗与PIM相关的病症的方法,该方法包括向所述个体施用有效减少或阻止个体中肿瘤生长的量的式I、II、III或IV化合物。
在另外方面,本发明提供在需要此治疗的人或动物个体中治疗与PIM相关的病症的方法,该方法包括向所述个体施用有效减少或阻止个体中肿瘤生长的量的式I、II、III或IV化合物以及用于治疗癌症的至少一种其它活性剂。
在另外方面,本发明提供治疗组合物,其包含至少一种式I、II、III或IV化合物以及一种或多种用于治疗癌症的其它活性剂,所述其它活性剂在癌症治疗中是普遍使用的。
本发明的化合物可用于治疗癌症包括造血性恶性肿瘤、癌(例如肺、肝、胰脏、卵巢、甲状腺、膀胱或结肠的癌)、黑色素瘤、骨髓性病症(例如髓样白血病、多发性骨髓瘤和红白血病)、腺瘤(例如结肠绒毛状腺瘤)、肉瘤(例如骨肉瘤)、自身免疫性疾病、***反应和器官移植排斥综合征。
在另一方面,本发明涉及抑制个体中的选自Pim1、Pim2和Pim3的至少一种激酶的活性或在需要治疗的人或动物个体中治疗由Pim1、Pim2和Pim3中的至少一种介导的生物学疾病的方法,该方法包括向个体施用有效抑制个体中的所述激酶的量的至少一种式I、II、III或IV化合物。所述治疗化合物可用于治疗需要此类抑制剂的患者(例如患有由异常丝氨酸/苏氨酸激酶受体信号介导的癌症的那些患者)。
本发明还提供如本发明的详细说明中描述的组合物、应用方法和制备方法。
定义
″PIM抑制剂″在本文用于意指就PIM激酶活性而言具有不超过约100μM、更通常不超过约50μM的IC50的化合物,所述值根据后面所述的PIM损耗(depletion)实验测定。
短语″烷基″意指C1-10烷基基团。因此,该短语包括直链烷基基团例如甲基、乙基、丙基、丁基、戊基、己基、庚基、辛基、壬基、癸基、十一烷基、十二烷基等。该短语还包括支链C3-8-烷基基团,包括但不限于-CH(CH3)2、-CH(CH3)(CH2CH3)、-CH(CH2CH3)2、-C(CH3)3、-C(CH2CH3)3、-CH2CH(CH3)2、-CH2CH(CH3)(CH2CH3)、-CH2CH(CH2CH3)2、-CH2C(CH3)3、-CH2C(CH2CH3)3、-CH(CH3)CH(CH3)(CH2CH3)、-CH2CH2CH(CH3)2、-CH2CH2CH(CH3)(CH2CH3)、-CH2CH2CH(CH2CH3)2、-CH2CH2C(CH3)3、-CH2CH2C(CH2CH3)3、-CH(CH3)CH2CH(CH3)2、-CH(CH3)CH(CH3)CH(CH3)2、-CH(CH2CH3)CH(CH3)CH(CH3)(CH2CH3)等。因此,短语烷基基团包括一级烷基基团、二级烷基基团和三级烷基基团。优选的烷基基团包括含有1-6个碳原子的直链和支链烷基基团。
术语″烯基″意指如上所定义的烷基基团,但其包含至少一个不饱和位点,即其中两个相邻的碳原子通过双键相连接。术语″烯基″意指其中两个相邻的碳原子通过叁键相连接的烷基基团。术语′烷氧基″意指式-OR的基团,其中R是如上所定义的烷基。
如文中所用,术语″卤素″或″卤代″意指氯、溴、氟和碘基团。术语″卤代烷基″意指如上所定义的烷基基团,其中该烷基基团中的一个或多个氢原子被一个或多个卤素原子替换。术语″卤代烷基″因此包括单卤代烷基、二卤代烷基、三卤代烷基等。
″氨基″在文中是指基团-NH2。术语″烷基氨基″意指基团-NRR′,其中R和R′各自独立地选自氢和烷基。术语″芳基氨基″在文中是指基团-NR″R′,其中R″是芳基且R′是氢、烷基或芳基。术语″芳烷基氨基″在文中是指基团-NRR′,其中R是芳烷基且R′是氢、烷基、芳基或芳烷基。术语氰基意指基团-CN。术语硝基意指基团-NO2。
术语″烷氧基烷基″意指基团-alk1-O-alk2,其中alk1是烷基或烯基,且alk2是烷基或烯基。术语″芳基氧基烷基″意指基团-烷基-O-芳基。术语″芳烷氧基烷基″意指基团-亚烷基-O-芳烷基,其中芳烷基是芳基烷基。
术语″氨基羰基″在文中是指基团-C(O)-NH2。″取代的氨基羰基″在文中是指基团-C(O)-NRR′,其中R是烷基且R′是氢或烷基。在一些实施方案中,R和R′与它们所连接的N原子一起可以形成″杂环烷基羰基″基团。术语″芳基氨基羰基″在文中是指基团-C(O)-NRR′,其中R是芳基且R′是氢、烷基或芳基。术语″芳烷基氨基羰基″在文中是指基团-C(O)-NRR′,其中R是芳烷基且R′是氢、烷基、芳基或芳烷基。
″氨基磺酰基″在文中是指基团-S(O)2-NH2。″取代的氨基磺酰基″在文中是指基团-S(O)2-NRR′,其中R是烷基且R′是氢或烷基。术语″芳烷基氨基磺酰基芳基″在文中是指基团-芳基-S(O)2-NH-芳烷基。
″羰基″意指二价基团-C(O)-。″羧基″意指-C(=O)-OH。″烷氧基羰基″意指酯-C(=O)-OR,其中R是烷基。″低级烷氧基羰基″意指酯-C(=O)-OR,其中R是C1-4-烷基。″环烷基氧基羰基″意指-C(=O)-OR,其中R是环烷基。
″环烷基″意指单环或多环的碳环烷基取代基。典型的环烷基取代基含有3至8个环碳原子。碳环烷基基团是其中所的环原子都为碳原子的环烷基基团。环烷基基团的示例性实例是环己基、环戊基、环丙基、环丁基等。当与环烷基取代基一起使用时,术语″多环的″在文中是指稠合的和非稠合的烷基环状结构。多环的环烷基基团的示例性实例是八氢-1H-茚、二环[4.2.0]辛烷、二环[3.2.0]庚烷、螺[3.3]庚烷等。术语部分不饱和的环烷基基团意指如上所定义的环烷基基团,其中该环烷基基团的至少两个相邻的碳原子通过双键或叁键相互连接。部分不饱和的环烷基基团的示例性实例包括环戊烯基、环戊炔基、环己烯基、环己炔基等。
文中所用的术语″杂环″或″杂环基团″或“杂环烷基”意指4至10元环***,其中该环***的至少一个但不超过五个成员是选自氮、氧和硫的杂原子。优选的杂环基团是5-或9-元环***,其中该环***的1-3个成员是选自氮、氧和硫的杂原子。应当注意,杂环环***中含有的氮和硫原子可以任选被氧化以及任选被季铵化。还应当理解,文中所用的术语杂环或杂环基团或杂环可以包含单个或多个双键或叁键。杂环基团的示例性实例是哌啶基、1,2,3,4-四氢吡啶、四氢吡喃、3,6-二氢-2H-吡喃、四氢呋喃、哌啶等。
杂环基团可以是未取代的,或被独立地选自下列的取代基单取代、二取代或三取代:羟基、卤素、氧代(C=O)、烷基亚氨基(RN=,其中R是低级烷基或低级烷氧基基团)、氨基、烷基氨基、二烷基氨基、酰基氨基烷基、烷氧基、硫代烷氧基、聚烷氧基(polyalkoxy)、烷基、烯基、烯基、卤素、氰基、硝基、环烷基或卤代烷基。
杂环基团可以在不同位置被连接,这对于有机和/或药物化学领域的技术人员将是显而易见的。
代表性的杂环基团包括咪唑基、吡啶基、哌嗪基、哌啶基、吖丁啶基、噻唑基、呋喃基、***基、苯并咪唑基、苯并噻唑基、苯并唑基、喹啉基、异喹啉基、喹唑啉基、喹喔啉基、酞嗪基、吲哚基、萘啶基(naphthpyridinyl)、吲唑基和喹嗪基。
文中所用的术语″芳基″意指任选取代的具有5-12元环***的单环和多环的芳香基团。芳基基团的示例性实例是苯基、萘基等。文中所用的术语″杂芳基″代表5至12元环状芳香结构,其中1至约6个成员是选自N、O和S的杂原子。杂芳基基团的示例性实例是吡啶基、嘧啶基、噻唑基、吲哚基、咪唑基、二唑基、四唑基、吡嗪基、***基、噻吩基、呋喃基、喹啉基、嘌呤基、苯并噻唑基、苯并吡啶基和苯并咪唑基等。
″任选取代的″或″取代的″意指用单价或二价基团替换一个或多个氢原子。适当的取代基团包括例如羟基、硝基、氨基、亚氨基、氰基、卤素、硫基(thio)、磺酰基、硫代酰氨基、脒基、imidino、氧代、胍基、磺酰氨基、羧基、甲酰基、低级烷基、卤代低级烷基、低级烷基氨基、卤代低级烷基氨基、低级烷氧基、卤代低级烷氧基、低级烷氧基烷基、烷基羰基、氨基羰基、芳基羰基、芳烷基羰基、杂芳基羰基、杂芳烷基羰基、烷硫基、氨基烷基、氰基烷基、芳基等。
取代基团本身可以是被取代的。在取代基团上取代的基团可以是羧基、卤素;硝基、氨基、氰基、羟基、低级烷基、低级烷氧基、氨基羰基、-SR、硫代酰氨基、-SO3H、-SO2R或环烷基,其中R代表性地是氢、羟基或低级烷基。当取代的取代基包含直链基团时,取代可以发生在该链内(例如2-羟基丙基、2-氨基丁基等)或该链末端(例如2-羟基乙基、3-氰基丙基等)。取代的取代基可以是共价键键合的碳或杂原子的直链、支链或环状排布。
应当理解,上面的定义不意欲包括不允许的取代模式(例如被5个氟基团取代的甲基或被另一卤素原子取代的卤素原子)。此类不允许的取代模式是本领域技术人员众所周知的。
对于本领域技术人员显而易见的是,本发明的化合物或它们的立体异构体、以及它们中任何一个的药学上可接受的盐、酯、代谢产物和前药可能进行互变异构化,并因此可能以不同的互变异构体形式存在,在互变异构体中分子的一个原子的质子位移至另一个原子且该分子的所述原子间的化学键因此重排。参见例如March,高等有机化学:反应、机制和结构(Advanced Organic Chemistry:Reactions,Mechanisms and structures),第四版,John Wiley&Sons,第69-74页(1992)。如文中所用,术语″互变异构体″意指通过质子位移产生的化合物,且应当理解,所有的互变异构体形式包括在本发明内,只要它们可以存在。
本发明化合物或它们的互变异构体以及它们中任一个的药学上可接受的盐、酯、代谢产物和前药,可以包含不对称取代的碳原子。此类不对称取代的碳原子可以使得本发明化合物以对映异构体、非对映异构体以及其它立体异构形式存在,它们可以根据绝对立体化学而定义为例如(R)-或(S)-构型。因此,本发明化合物的所有此类可能的异构体、光学纯形式的单一立体异构体、它们的混合物、外消旋混合物(或“外消旋物”)、非对映异构体混合物以及单一非对映异构体均包含在本发明中。本文中所使用的术语“S”和“R”构型根据下面定义:IUPAC 1974 RECOMMENDATIONS FORSECTION E,FUNDAMENTAL STEREOCHEMISTRY,Pure Appl.Chem.45:13-30(1976)。术语α和β用于环状化合物的环位置。参照平面的α-侧为优选的取代基位于较低编号位置的一侧。位于参照平面相反一侧的那些取代基采用β描述符。需要注意的是,该用法与用于环状立体母核的用法有所区别,在环状母核中“α”是指“平面下面”并代表绝对构型。本文中所使用的术语α和β构型根据CHEMICAL ABSTRACTS INDEXGUIDE-APPENDIX IV(1987)第203段定义。
本文中所使用的术语“药学上可接受的盐”是指式I、II、III或IV化合物的非毒性酸盐或碱土金属盐。这些盐可以在式I、II、III或IV化合物进行最后分离和纯化过程中原位制备,或者通过使碱或酸官能团分别与适当的有机或无机酸或者碱反应而分别制备。具有代表性的盐包括但不限于下列:乙酸盐、己二酸盐、藻酸盐、柠檬酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、二葡糖酸盐、环戊烷丙酸盐、十二烷硫酸盐、乙磺酸盐、葡庚糖酸盐(glucoheptanoate)、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、富马酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟基乙磺酸盐、乳酸盐、马来酸盐、甲磺酸盐、烟酸盐、2-萘磺酸盐、草酸盐、扑酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐(phenylproionate)、苦味酸盐、新戊酸盐、丙酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对-甲苯磺酸盐和十一酸盐。此外,碱性含氮基团可以被如下试剂季铵盐化:低级烷基卤化物,例如甲基、乙基、丙基和丁基氯化物、溴化物和碘化物;二烷基硫酸酯,例如二甲基、二乙基、二丁基和二戊基硫酸酯;长链卤化物,例如癸基、十二烷基、十四烷基和十八烷基氯化物、溴化物和碘化物;芳烷基卤化物,例如苄基和苯乙基溴化物等。如此可获得水-或油-溶性或可分散的产物。
本发明还提供氘化形式的上述化合物。如文中所用,“氘化形式”意指其中至少一个氢原子以超过氘存在的天然比例富含同位素氘。通常,所述氢原子富含有至少50%的氘、通常是至少75%的氘,且优选至少约90%的氘。任选地,超过一个氢原子可以被氘替换。例如甲基基团可以通过用氘替换一个氢而被氘化(即,其可以为-CH2D),或它可能使三个氢原子都被氘替换(即,其可以为-CD3)。在每种情况下,D表示至少50%的相应的H作为氘存在。
可以用于形成药学上可接受的酸加成盐的酸的实例包括如下的酸:无机酸,例如盐酸、硫酸和磷酸;和有机酸,例如草酸、马来酸、甲磺酸、琥珀酸和柠檬酸。碱性加成盐可以在式(I)化合物的最后分离和纯化过程中原位制备,或者通过使羧酸基团与适当的碱(例如药学上可接受的金属阳离子的氢氧化物、碳酸盐或碳酸氢盐)反应分别制备,或者与氨或有机伯、仲或叔胺反应制备。药学上可接受的盐包括但不限于:基于碱金属和碱土金属的阳离子,例如钠、锂、钾、钙、镁、铝盐等,以及非毒性铵、季铵和胺阳离子,包括但不限于铵、四甲基铵、四乙基铵、甲胺、二甲胺、三甲胺、三乙胺、乙胺等。用于形成碱加成盐的其它具有代表性的有机胺包括二乙胺、乙二胺、乙醇胺、二乙醇胺、哌嗪等。
本文中所使用的术语“药学上可接受的酯”是指在体内水解的酯,包括那些在人体内易于分解而释放出母体化合物或其盐的酯。适当的酯包括例如衍生自药学上可接受的脂肪族羧酸的那些,所述肪族羧酸特别是烷酸、烯酸、环烷酸和烷二酸,其中每一个烷基或烯基基团最好含有不多于6个碳原子。具体的酯的实例包括甲酸酯、乙酸酯、丙酸酯、丁酸酯、丙烯酸酯和乙基琥珀酸酯。
本文中所使用的术语“药学上可接受的前药”是指本发明化合物的那些前药,它们在良好的医学判断范围内适用于与人类和低等动物的组织接触而不会产生不当的毒性、刺激性、过敏反应等,具有合理的效益/风险比,产生预期的适用效果,如果可能的话,还指本发明化合物的两性离子形式。术语“前药”是指例如通过在血液中水解在体内快速转化而获得上式母体化合物的化合物。详尽的讨论可以参见下列文献:T.Higuchi和V.Stella,作为新型传递***的前药(Pro-drugs as Novel Delivery Systems),A.C.S.专题报告丛书(A.C.S.Symposium Series)的第14卷;Edward B.Roche,ed.,药物设计中的生物可逆载体(Bioreversible Carriers in Drug Design),American Pharmaceutical Association and Pergamon Press,1987,这两篇文献在此引入作为参考。
对于本领域技术人员而言显而易见的是,本发明化合物或它们的互变异构体、前药和立体异构体以及它们中任何一个的药学上可接受的盐、酯和前药,可以在人类或者动物体内或细胞内通过体内代谢过程产生代谢产物。本文中使用的术语“代谢产物”是指给予母体化合物后在个体中产生的任何衍生物。衍生物可以通过在个体中的各种生物化学转化例如氧化、还原、水解或轭合而由母体化合物产生,包括,例如氧化物和去甲基化的衍生物。本发明化合物的代谢产物可以通过本领域中已知的常规技术进行鉴定。参见,例如,Bertolini,G.等,J.Med.Chem.40:2011-2016(1997);Shan,D.等,J.Pharm.Sci.86(7):765-767;Bagshawe K.,Drug Dev.Res.34:220-230(1995);Bodor,N.,Advances in Drug Res.13:224-331(1984);Bundgaard,H.,前药的设计(Design of Prodrugs)(Elsevier Press 1985);和Larsen,I.K.,前药设计和应用,药物设计和开发(Design and Application ofProdrugs,Drug Design and Development)(Krogsgaard-Larsen等编辑.,Harwood Academic Publishers,1991)。应当理解,作为式(I)化合物或它们的互变异构体、前药和立体异构体以及它们中任一个的药学上可接受的盐、酯和前药的代谢产物的各个化合物均包含在本发明范围内。
术语“癌症”是指通过Pim激酶的抑制而能够获得有益治疗的癌症疾病,包括:例如,实体癌症例如癌(例如肺癌、胰腺癌、甲状腺癌、卵巢癌、膀胱癌、乳腺癌、***癌或结肠癌)、黑色素瘤、骨髓性病症(例如髓样白血病、多发性骨髓瘤和红白血病)、腺瘤(例如结肠绒毛状腺瘤)和肉瘤(例如骨肉瘤)。
合成方法
本发明化合物可以通过本领域技术人员已知的方法获得。如流程I中所示,4-氯-6-溴喹啉可以在氯处被胺或有机金属化合物置换,得到4-取代的6-溴喹啉。将所述溴转化为相应的硼酸酯,并与取代的杂芳基卤化物或三氟甲磺酸酯偶联可以得到,6二取代的喹啉I。如果I中的Het2含有卤素或三氟甲磺酸酯前体,则Het2可以通过标准有机金属或胺化方法被进一步修饰。
流程1
流程2显示了获得4,6二取代的喹啉的替代方法。用苄醇置换氯,然后将溴转化为相应的硼酸酯,并与取代的杂芳基卤化物或三氟甲磺酸酯进行Suzuki反应,可以得到4-苄基氧基6-取代的喹啉。苄基脱保护,随后进行三氟甲磺酸化,得到II。三氟甲磺酸酯II在胺化或有机金属偶联条件下反应,得到4,6二取代的喹啉III。
流程2
制备4-羟基6-氯1,7萘啶的路线描述在流程III中。从2-氯-4-甲基-5-硝基吡啶起始,与二甲基甲酰胺二甲基缩醛缩合,随后氧化裂解,得到2-氯-5-硝基异烟醛。用甲基锂和四氯化钛在-50℃化学选择性地将甲基加至醛,随后氧化得到1-(2-氯-5-硝基吡啶-4-基)乙酮。用铁在乙酸中还原硝基,随后进行两步的单甲苯磺酰化,得到N-(4-乙酰基-6-氯吡啶-3-基)-4-硝基苯磺酰胺。与二甲基甲酰胺二甲基缩醛和二异丙基乙胺在DMF中在105℃加热,随后在室温用苯硫酚处理,获得6-氯-1,7-萘啶-4-酚IV。采用标准条件将IV转化为相应的三氟甲磺酸酯或苄醚,得到双官能化的中间体,其可进行流程1和2中所描述的化学转化,从而得到4,6二取代的1,7萘啶V。
流程3
本发明化合物可在体外或体内用于抑制癌细胞的生长。所述化合物可以单独使用,或者在组合物中与药学上可接受的载体或赋形剂一起使用。适当的药学上可接受的载体或赋形剂包括例如处理剂(processing agents)以及药物递送改良剂和增强剂(enhancers),例如,磷酸钙、硬脂酸镁、滑石粉、单糖类、二糖类、淀粉、明胶、纤维素、甲基纤维素、羧基甲基纤维素钠、葡萄糖、羟丙基-β-环糊精、聚乙烯吡咯烷酮、低熔点蜡类、离子交换树脂等以及它们中任何两种或更多种的组合。其它适当的药学上可接受的赋形剂描述于“雷明顿制药科学(Remington′s PharmaceuticalSciences)”,Mack Pub.Co.,New Jersey(1991),在此引入作为参考。
本发明化合物的有效量通常包括足以可检测地(detectably)抑制Pim活性的任何量,所述抑制通过本文中所述的任何实验(assay)进行检测,通过本领域技术人员已知的其它Pim激酶活性实验检测,或者通过测定癌症症状的抑制或缓解检测。
可以与载体物质组合形成单一剂型的活性成分的量取决于待治疗的宿主和具体的施用模式。然而,应当理解,任何特定患者的具体剂量水平取决于各种因素,包括采用的具体化合物的活性、年龄、体重、一般健康情况、性别、饮食、施用时间、施用途径、***速率、药物组合以及正在治疗的特定疾病的严重程度。对于给定条件而言,治疗有效量可以通过常规实验容易地确定,这在普通临床医师的技能和判断范围内。
对于本发明的目的而言,治疗有效剂量通常为以单次剂量或分次剂量施用至宿主的总日剂量,可以是每日0.001至1000mg/kg体重,更优选为每日1.0至30mg/kg体重。单位剂量组合物可以含有用于构成所述日剂量的其约数(submultiples)量。
本发明化合物可以以单位剂量制剂通过口服、胃肠外、舌下施用,通过雾化或吸入喷雾施用,通过直肠或局部施用,所述制剂含有常规无毒药学上可接受的载体、辅助剂以及需要的溶媒。局部施用也可包括透皮施用的应用,例如透皮贴剂或离子电泳装置。本文中使用的术语胃肠外包括皮下注射、静脉注射、肌肉注射、胸骨内注射或输注技术。
注射制剂(例如,无菌注射用水性混悬剂或油性混悬剂)可以根据已知的工艺采用适当的分散剂或润湿剂和助悬剂进行配制。无菌注射用制剂也可以是在无毒胃肠外可接受稀释剂或溶剂中的无菌注射用溶液剂或混悬剂,例如,在1,3-丙二醇中的溶液剂。在可接受的溶媒和溶剂中,可以采用水、林格氏溶液和等渗氯化钠溶液。另外,无菌、不挥发性油通常用作溶剂或混悬介质。为此,可以采用任何刺激性小的不挥发性油,包括合成的单-或二-甘油酯。另外,脂肪酸(例如油酸)也可以用于注射剂的制备。
用于药物直肠施用的栓剂可以通过将药物与适当的无刺激性赋形剂(如可可脂和聚乙二醇)混合而制备,所述赋形剂在常温下是固体,但是在直肠温度下为液体,因而在直肠内熔融并释放药物。
用于口服施用的固体剂型可以包括胶囊、片剂、丸剂、散剂和颗粒剂。在此类固体剂型中,活性化合物可以与至少一种惰性稀释剂(例如蔗糖、乳糖或淀粉)混合。在常规实践中,除了惰性稀释剂外,此类剂型也可以含有其它物质,例如润滑剂,如硬脂酸镁。对于胶囊、片剂和丸剂而言,该剂型也可以含有缓冲剂。片剂和丸剂可以额外地采用肠包衣制备。
用于口服施用的液体剂型可以包括药学上可接受的乳剂、溶液剂、混悬剂、糖浆剂和酏剂,它们含有本领域中常规应用的惰性稀释剂,例如水。此类组合物也可以含有辅助剂,例如润湿剂、乳化剂和助悬剂、环糊精和甜味剂、矫味剂以及芳香剂。
本发明化合物也可以以脂质体的形式施用。如本领域所已知,脂质体通常源自磷脂或其它脂质物质。脂质体是由分散在水性介质中的单-或多-层水合的液晶形成。可以使用能够形成脂质体的任何无毒、生理学上可接受的并且可代谢的脂质。除了本发明化合物外,脂质体形式的本发明组合物还可以含有稳定剂、防腐剂、赋形剂等。优选的脂质为磷脂和磷脂酰胆碱(卵磷脂),它们可以是天然的和合成的。形成脂质体的方法在本领域中是已知的。参见,例如,Prescott,Ed.,细胞生物学方法(Methods in CellBiology),第XIV卷,学术出版社,纽约,N.W.,第33页,et seq.(1976)。
虽然本发明化合物可以作为单一活性药物物质施用,但是它们也可以与一或多种在癌症治疗中应用的其它物质组合使用。本发明化合物也可以与已知的治疗剂以及抗癌物质组合使用,本发明公开的化合物与其它抗癌或化疗物质的组合包含在本发明范围内。此类物质的实例可以参见CancerPrinciples and Practice of Oncology,V.T.Devita和S.Hellman(编辑),第6版(2001年2月15日),Lippincott Williams&Wilkins Publishers。根据药物以及所涉及癌症的特定性质,本领域技术人员能够识别所述物质的哪一种组合是有用的。此类抗癌物质包括但不限于下列:***受体调节剂、雄激素受体调节剂、维甲酸(retinoid)受体调节剂、细胞毒性剂/细胞生长抑制剂、抗增殖剂、异戊二烯基蛋白转移酶抑制剂、HMG-CoA还原酶抑制剂和其它血管生成抑制剂、细胞增殖和存活信号抑制剂、细胞凋亡诱导剂以及干扰细胞周期关键点的物质。本发明化合物也可以与放疗联合应用。
因此,在本发明的一个实施方案中,本发明化合物还可以与已知的抗癌物质组合使用,所述抗癌物质包括例如***受体调节剂、雄激素受体调节剂、维甲酸受体调节剂、细胞毒性剂、抗增殖剂、异戊二烯基蛋白转移酶抑制剂、HMG-CoA还原酶抑制剂、HIV蛋白酶抑制剂、逆转录酶抑制剂及其它血管生成抑制剂。
与本发明化合物组合应用的上述化合物可以以Physicians′DeskReference(PDR)第47版(1993)(该文献在此引入作为参考)所指明的治疗量使用,或者以本领域技术人员所知的治疗有效量使用。
本发明化合物和其它抗癌物质可以以推荐的最大临床剂量或较小剂量施用。本发明组合物中活性化合物的剂量水平可以根据施用的途径、疾病的严重程度以及患者的响应而变化,以获得预期的治疗响应。所述组合可以以各独立的组合物施用,或者以含有两种药物的单一剂型施用。当以组合形式施用时,治疗剂可以制备为各独立的组合物,所述组合物可以在相同时间或不同时间施用,或者治疗剂可以以单一组合物施用。
在一个实施方案中,本发明提供在人类或动物个体中抑制Pim1、Pim2或Pim3的方法。该方法包括将有效量的式I、II、III或IV化合物的任何实施方案的化合物或其药学上可接受的盐施用至有其需要的个体。
通过参考下列实施例可以更容易地理解本发明,下列实施例用于说明而非限定本发明。
实施例
参照下列实施例,优选实施方案的化合物采用本文中所述方法合成,或者采用本领域已知的其它方法合成。
化合物和/或中间体采用配备2695 Separation Module的WatersMillenium色谱***(Milford,MA)通过高效液相色谱法(HPLC)鉴定。分析柱为反相Phenomenex Luna C18-5μ,4.6×50mm,Alltech(Deerfield,IL)。采用梯度洗脱(流速2.5mL/min),通常开始时用5%乙腈/95%水并在10分钟内逐渐过渡至100%乙腈。所有的溶剂均含有0.1%三氟乙酸(TFA)。通过紫外线(UV)吸收于220或254nm检测化合物。HPLC溶剂获自Burdickand Jackson(Muskegan,MI)或Fisher Scientific(Pittsburgh,PA)。
在某些情况下,通过薄层色谱(TLC)采用玻璃或塑料硅胶板例如Baker-Flex Silica Gel 1B2-F柔性板(flexible sheet)测定纯度。TLC结果可以在紫外光下容易地通过视觉检测,或者通过应用众所周知的碘蒸气技术和其它各种染色技术检测。
质谱分析在三种LCMS设备之一上进行:Waters System(Alliance HTHPLC和Micromass ZQ质谱仪;柱:Eclipse XDB-C18,2.1×50mm;梯度:在4分钟内,含有0.05%TFA的5-95%(或35-95%或65-95%或95-95%)乙腈水溶液;流速0.8mL/min;分子量范围200-1500;锥电压(cone Voltage)20V;柱温40℃);另一种Waters System(ACQUITYUPLC***和ZQ 2000***;柱:ACQUITY UPLC HSS-C18,1.8um,2.1×50mm;梯度:在1.3分钟内,含有0.05%TFA的5-95%(或35-95%或65-95%或95-95%)乙腈水溶液;流速1.2mL/min;分子量范围150-850;锥电压20V;柱温50℃);或Hewlett Packard System(Series 1100HPLC;柱:Eclipse XDB-C18,2.1×50mm;梯度:在4分钟内,含有0.05%TFA的5-95%乙腈水溶液;流速0.8mL/min;分子量范围150-850;锥电压50V;柱温30℃)。所有的质量均以质子化的母体离子报告。
采用Varian 300MHz NMR(Palo Alto,CA)对一些化合物进行核磁共振(NMR)分析。波谱参照是TMS或已知化学位移的溶剂。
制备性分离采用Flash 40色谱***和KP-Sil,60A(Biotage,Charlottesville,VA)进行,或者通过快速柱色谱采用硅胶(230-400目)填料进行,或者通过HPLC(采用Waters 2767 Sample Manager,C-18反相柱,30×50mm,流速75mL/min)进行。Flash 40 Biotage***和快速柱色谱的常用溶剂为二氯甲烷、甲醇、乙酸乙酯、己烷、丙酮、氨水(或氢氧化铵)和三乙胺。反相HPLC的常用溶剂为含有0.1%三氟乙酸的各种不同浓度的乙腈和水。
应当理解的是,优选实施方案的有机化合物可以具有互变异构现象。本说明书范围中的化学结构可能只是代表可能的互变异构形式之一,应当理解,优选的实施方案包括所示结构的任何互变异构形式。
应当理解,本发明不受限于为了说明而在本文中提出的实施方案,而是包含上述公开内容范围内其所有的此类形式。
在下面实施例以及整个本申请中,以下缩写具有下列意义。如果未定义,则术语具有其通常被接受的含义。
缩写
DAST | (二乙基氨基)三氟化硫 |
缩写
缩写
TDMSCl | 叔丁基二甲基甲硅烷基氯 |
TEA | 三乙胺 |
THF | 四氢呋喃 |
实施例1
(E)-2-(2-氯-5-硝基吡啶-4-基)-N,N-二甲基乙烯胺的合成
将2-氯-4-甲基-5-硝基吡啶(1.0当量)、25.2mL二甲基甲酰胺二甲基缩醛(2.2当量)的二甲基甲酰胺溶液(0.8M)在95℃下加热18小时。冷却后真空除去挥发物。将粗物质从沸腾的甲醇中重结晶得到(E)-2-(2-氯-5-硝基吡啶-4-基)-N,N-二甲基乙烯胺(70%),为红色固体。1H NMR(CDCl3):δ8.80(s,1H),7.32(d,J=13.2,1H),7.25(s,1H),5.95(d,J=13.2,1H),3.02(bs,6H).
2-氯-5-硝基异烟醛的合成
向(E)-2-(2-氯-5-硝基吡啶-4-基)-N,N-二甲基乙烯胺(1.0当量)的1∶1THF/H2O溶液(0.1M)中分次加入高碘酸钠(3.0当量)。将得到的溶液室温下搅拌6小时,此时将白色固体过滤并用乙酸乙酯冲洗。将全部滤液用NaHCO3(饱和的)、NaCl(饱和的)洗涤,用MgSO4干燥,过滤并浓缩。通过柱色谱法纯化(20%乙酸乙酯/己烷,Rf=0.3),得到2-氯-5-硝基异烟醛(71%)。1HNMR(CDCl3):δ10.51(s,1H),9.25(s,1H),7.75(s,1H).
1-(2-氯-5-硝基吡啶-4-基)乙醇的合成
在氩气气氛下,向烘干的装配有内部温度计的250mL 3颈圆底烧瓶中加入***(180mL)和1.0M在二氯甲烷中的四氯化钛(20.5mL,20.5mmol)。将溶液在CO2(s)/丙酮-78℃浴下冷却,并通过注射器以使内部温度</=-50℃的速度加入1.6M的甲基锂***溶液(12.8mL,20.5mmol)。将得到的阴离子溶液在-50℃下搅拌1小时,此时通过注射器加入2-氯-5-硝基异烟醛(2.54g,13.66mmol)的***溶液(16+4mL),保持内部温度</=-50℃。在-50℃下再搅拌1小时后,将反应物倾入H2O(500mL)中,混合后形成两个淡黄色层。加入***(500mL),分离各层,并将有机层用H2O(250mL)、NaCl(饱和的)(250mL)洗涤,用MgSO4干燥,过滤并浓缩,得到1-(2-氯-5-硝基吡啶-4-基)乙醇(2.76g,100%产率)。LCMS(m/z):203.0(MH+);LC Rt=2.42min.1H NMR(CDCl3):δ8.99(s,1H),7.88(s,1H),5.52(m,1H),1.56(d,J=9.0,3H).
1-(2-氯-5-硝基吡啶-4-基)乙酮的合成
向1-(2-氯-5-硝基吡啶-4-基)乙醇(1.0当量)的二氯甲烷溶液(0.1M)中加入戴斯-马丁氧化剂(Dess-Martin periodinane)(1.8eq.),并将溶液搅拌16小时。将溶液倾入乙酸乙酯(800mL)中,用1∶1 10%Na2S2O3/NaHCO3(饱 和的)(4x)、NaCl(饱和的)洗涤,用MgSO4干燥,过滤并浓缩,得到1-(2-氯-5-硝基吡啶-4-基)乙酮(96%),为黄色固体。LCMS(m/z):201.0(MH+);LC Rt=2.80min.1H NMR(CDCl3):δ9.18(s,1H),7.36(s,1H),2.60(s,3H).
1-(5-氨基-2-氯吡啶-4-基)乙酮的合成
向1-(2-氯-5-硝基吡啶-4-基)乙酮(1.0当量)的醋酸溶液(0.3M)中加入铁(6.0当量)。将溶液剧烈搅拌4小时,此时将其通过硅藻土垫层(9cmx3英寸)过滤,用MeOH然后用乙酸乙酯洗脱。真空除去挥发物,并将粗物质在乙酸乙酯和Na2CO3(饱和的)中分配。将有机层再用Na2CO3(饱和的)(3x)、NaCl(饱 和的)洗涤,用MgSO4干燥,过滤并浓缩,得到1-(5-氨基-2-氯吡啶-4-基)乙酮(87%)。LCMS(m/z):171.0(MH+);LC Rt=2.20min.1H NMR(CDCl3):δ9.18(s,1H),7.36(s,1H),2.60(s,3H).
N-(4-乙酰基-6-氯吡啶-3-基)-4-硝基-N-(4-硝基苯基磺酰基)苯磺酰胺的
合成
向1-(5-氨基-2-氯吡啶-4-基)乙酮(1.0当量)的吡啶溶液(0.26M)中加入4-硝基苯基磺酰氯(3.0当量)。将得到的琥珀色溶液室温下搅拌18小时,此时将其倾入冰中。将得到的固体过滤,用H2O淋洗并泵抽(pumped),得到N-(4-乙酰基-6-氯吡啶-3-基)-4-硝基-N-(4-硝基苯基磺酰基)苯磺酰胺(88%)。LC Rt=4.77min.
N-(4-乙酰基-6-氯吡啶-3-基)-4-硝基苯磺酰胺的合成
向N-(4-乙酰基-6-氯吡啶-3-基)-4-硝基-N-(4-硝基苯基磺酰基)苯磺酰胺(1.0当量)的2∶1 THF/MeOH溶液(0.05M)中加入1M LiOH(aq.)(3.1当量)。将得到的紫色溶液室温下搅拌15小时,此时加入1M HCl(3.1当量)。真空除去挥发物并加入乙酸乙酯(700mL)和H2O(200mL)。分离后将有机层用NaHCO3(饱和的)(200mL)、NaCl(饱和的)(200mL)洗涤,用MgSO4干燥,过滤并浓缩。通过柱色谱法(含有0.1%AcOH的50%乙酸乙酯/己烷,Rf=0.6)纯化,得到N-(4-乙酰基-6-氯吡啶-3-基)-4-硝基苯磺酰胺(84%)。LCMS(m/z):356.0(MH+);LC Rt=3.81min.1H NMR(CDCl3):δ8.89(s,1H),8.32(m,2H),8.06(m,2H),7.62(s,1H),2.60(s,3H).
6-氯-1,7-萘啶-4-酚的合成
在Ar、110℃下,将N-(4-乙酰基-6-氯吡啶-3-基)-4-硝基苯磺酰胺(1.0当量)、二甲基甲酰胺二甲基缩醛(4.8当量)和DIEA(4.8当量)的DMF溶液(0.15M)加热96小时。冷却后,加入苯硫酚(4.9当量)并将溶液室温下搅拌15小时。真空除去挥发物,然后通过硅胶纯化(0-1.5-3-5%MeOH/CH2Cl2),得到6-氯-1,7-萘啶-4-酚(55%)。LC/MS=180.9/182.9(M+H),LC=1.41min
三氟甲磺酸6-氯-1,7-萘啶-4-基酯的合成
将6-氯-1,7-萘啶-4-酚(1.0当量)、二异丙基乙胺(2.0当量)和1,1,1-三氟-N-苯基-N-(三氟甲基磺酰基)甲磺酰胺(1.5当量)的CH2Cl2溶液搅拌16小时。将溶液在EtOAc和Na2CO3(饱和的)之间分配。分离后,将有机层用Na2CO3(饱和的)和NaCl(饱和的)进一步洗涤,用MgSO4干燥,浓缩并通过硅胶色谱法(10-15%EtOAc/己烷洗脱液)纯化,得到三氟甲磺酸6-氯-1,7-萘啶-4-基酯(65%)。LC/MS=131.0/315.0(M+H),LC=4.86min.
(S)-1-(6-氯-1,7-萘啶-4-基)哌啶-3-基氨基甲酸叔丁基酯的合成
将三氟甲磺酸6-氯-1,7-萘啶-4-基酯(1.0当量)、(S)-哌啶-3-基氨基甲酸叔丁基酯(1.0当量)和DIEA(1.5当量)的CH2Cl2溶液(0.3M)在室温下搅拌120小时。将溶液在EtOAc和Na2CO3(饱和的)之间分配。分离后,将有机层用NaCl(饱和的)洗涤,用MgSO4干燥,浓缩并通过硅胶色谱法(EtOAc洗脱液)纯化,得到(S)-1-(6-氯-1,7-萘啶-4-基)哌啶-3-基氨基甲酸叔丁基酯(61%)。LC/MS=363.2(M+H),LC=2.47min.
(S)-1-(6-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊-2-基)-1,7-萘啶-4-基)哌啶
-3-基氨基甲酸叔丁基酯的合成
在135℃、微波下,将(S)-1-(6-氯-1,7-萘啶-4-基)哌啶-3-基氨基甲酸叔丁基酯(1.0当量)、乙酸钾(3.0当量)、双(频哪醇基)二硼(2.0当量)、三环己基膦(0.8当量)和Pd2(dba)3(0.2当量)的二氧六环溶液(0.06M)加热20分钟。将溶液通过1μM HPLC过滤器过滤,浓缩并泵抽,得到(S)-1-(6-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊-2-基)-1,7-萘啶-4-基)哌啶-3-基氨基甲酸叔丁基酯,其被直接使用。LC/MS=373.1(相应的HetB(OH)2的M+H).
(S)-1-(6-氯-3-氟-1,7-萘啶-4-基)哌啶-3-基氨基甲酸叔丁基酯的合成
将1-氯甲基-4-氟-1,4-二氮二环[2.2.2]辛烷双(四氟硼酸盐)(1.0当量)加入到(S)-1-(6-氯-1,7-萘啶-4-基)哌啶-3-基氨基甲酸叔丁基酯(1.0当量)的MeCN溶液(0.14M)中。搅拌18小时后,加入Na2CO3(饱和的)淬灭。将溶液在EtOAc和Na2CO3(饱和的)之间分配,用NaCl(饱和的)进一步洗涤,用MgSO4干燥,浓缩并通过硅胶色谱法(25-50-100%EtOAc/己烷w/0.1%DIEA洗脱液)纯化,得到(S)-1-(6-氯-3-氟-1,7-萘啶-4-基)哌啶-3-基氨基甲酸叔丁基酯(15%),以及回收的(S)-1-(6-氯-1,7-萘啶-4-基)哌啶-3-基氨基甲酸叔丁基酯(55%)。LCMS(m/z):381.1/383.0(MH+);LC Rt=4.20min.
(S)-1-(3-氟-6-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊-2-基)-1,7-萘啶-4-基)
哌啶-3-基氨基甲酸叔丁基酯的合成
在135℃、微波下,将(S)-1-(6-氯-3-氟-1,7-萘啶-4-基)哌啶-3-基氨基甲酸叔丁基酯(1.0当量)、乙酸钾(3.0当量)、双(频哪醇基)二硼(2.0当量)、三环己基膦(0.8当量)和Pd2(dba)3(0.2当量)的二氧六环溶液(0.12M)加热2x15分钟。将溶液通过1μM HPLC过滤器过滤,浓缩并泵抽,得到(S)-1-(3-氟-6-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊-2-基)-1,7-萘啶-4-基)哌啶-3-基氨基甲酸叔丁基酯,其被直接使用。LC/MS=391.2(相应的HetB(OH)2的M+H),LC=2.64min.
4-氯-6-甲基吡啶-2-胺的合成
向10%二氧六环水溶液(0.1M)中加入4,6-二氯吡啶-2-胺(1.0当量)、三甲基环硼氧烷(1.5当量)、Pd(PPh3)4(0.10当量)和K2CO3(3.0当量)。将溶液在油浴中加热至120℃,加热18小时,冷却至室温(原料没有全部耗尽),用EtOAc萃取,用Na2SO4干燥,并浓缩。将粗物质通过SiO2柱色谱法(用5%MeOH/DCM洗脱)纯化,以23%产率得到4-氯-6-甲基吡啶-2-胺,为灰白色固体。LCMS(m/z):143(MH+);LC Rt=1.11min.
6-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊-2-基)吡啶-2-胺的合成
在120℃、微波下,将4-氯-6-甲基吡啶-2-胺(1.0当量)、乙酸钾(3.0当量)、双(频哪醇基)二硼(2.0当量)、三环己基膦(0.075当量)和Pd2(dba)3(0.05当量)的二氧六环溶液(0.12M)加热2x15分钟。将溶液通过1μM HPLC过滤器过滤,浓缩。加入DME并将得到的固体过滤并用CH2Cl2淋洗。将合并的滤液浓缩并泵抽,得到6-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊-2-基)吡啶-2-胺,其被直接使用。LC/MS=153.0(相应的HetB(OH)2的M+H),LC=0.35min.
4-(6-氯-1,7-萘啶-4-基)-6-甲基吡啶-2-胺的合成
在100℃、微波下,将三氟甲磺酸6-氯-1,7-萘啶-4-基酯(1.0当量)、6-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊-2-基)吡啶-2-胺(1.0当量)和Pd(dppf)Cl2-CH2Cl2(0.1当量)的3∶1 DME/2M Na2CO3溶液加热15分钟。冷却后,将溶液在EtOAc和Na2CO3(饱和的)之间分配,进一步用NaCl(饱和的)洗涤,用MgSO4干燥,浓缩并通过硅胶色谱法(2-4%MeOH/CH2Cl2 w/0.1%DIEA洗脱液)纯化,得到叔丁基4-(6-氯-1,7-萘啶-4-基)-6-甲基吡啶-2-胺(17%)。LC/MS=271.0(M+H),LC=1.81min.
6-甲基-4-(6-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊-2-基)-1,7-萘啶-4-基)
吡啶-2-胺的合成
在135℃、微波下,将4-(6-氯-1,7-萘啶-4-基)-6-甲基吡啶-2-基氨基甲酸叔丁基酯(1.0当量)、乙酸钾(3.0当量)、双(频哪醇基)二硼(2.0当量)、三环己基膦(0.8当量)和Pd2(dba)3(0.2当量)的二氧六环溶液(0.06M)加热2x20分钟。将溶液通过1μM HPLC过滤器过滤,浓缩并泵抽,得到6-甲基-4-(6-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊-2-基)-1,7-萘啶-4-基)吡啶-2-胺,其被直接使用。LC/MS=281.1(相应的HetB(OH)2的M+H),LC=1.09min.
2,6二氯-3N-(双Boc氨基)吡啶的合成
将3-氨基-2,6-二氯吡啶(1.0当量)、二碳酸二叔丁酯(2.2当量)和DMAP(0.2当量)的CH2Cl2溶液(0.15M)搅拌16小时。加入硅胶,浓缩后通过硅胶色谱法(10%EtOAc/己烷洗脱液)纯化,得到2,6二氯-3N-(双Boc氨基)吡啶(83%)。LC/MS=363.1(M+H),LC=4.92min.
3-(5-氨基-6-氯吡啶-2-基)-4-氟-N-异丙基苯甲酰胺的合成
在90℃下,将2,6二氯-3N-(双Boc氨基)吡啶(1.0当量)、2-氟-5-(异丙基氨基甲酰基)苯基硼酸(1.0当量)和Pd(dppf)Cl2-CH2Cl2(0.05当量)的3∶1DME/2M Na2CO3溶液加热15小时。冷却后,将溶液在EtOAc和Na2CO3(饱和的)之间分配,进一步用NaCl(饱和的)洗涤,用MgSO4干燥,浓缩并通过硅胶色谱法(30-35%EtOAc/己烷洗脱液)纯化,得到双Boc suzuki产物。将Boc保护的物质用25%TFA/CH2Cl2处理2小时,真空除去挥发物。将粗残留物用EtOAc稀释,用Na2CO3(饱和的)和NaCl(饱和的)洗涤,用MgSO4干燥,过滤并真空除去挥发物,得到3-(5-氨基-6-氯吡啶-2-基)-4-氟-N-异丙基苯甲酰胺(60%)。LC/MS=308.1(M+H),LC=3.15min.
2-氯-6-(2-氟苯基)吡啶-3-胺的合成
在90℃下,将2,6二氯-3N-(双Boc氨基)吡啶(1.0当量)、2-氟苯基硼酸(1.0当量)和Pd(dppf)Cl2-CH2Cl2(0.05当量)的3∶1 DME/2M Na2CO3溶液加热15小时。冷却后,将溶液在EtOAc和Na2CO3(饱和的)之间分配,进一步用NaCl(饱和的)洗涤,用MgSO4干燥,浓缩并通过硅胶色谱法(10%EtOAc/己烷洗脱液)纯化,得到双Boc suzuki产物。将该Boc保护的物质用25%TFA/CH2Cl2处理2小时,真空除去挥发物。将粗残留物用EtOAc稀释,用Na2CO3(饱和的)和NaCl(饱和的)洗涤,用MgSO4干燥,过滤并真空除去挥发物,得到2-氯-6-(2-氟苯基)吡啶-3-胺(57%)。LC/MS=223.0(M+H),LC=3.69min.
2-氯-6-(2,6-二氟苯基)吡啶-3-胺的合成
在90℃下,将2,6二氯-3N-(双Boc氨基)吡啶(1.0当量)、2,6-二氟苯基硼酸(1.0当量)和Pd(dppf)Cl2-CH2Cl2(0.05当量)的3∶1 DME/2MNa2CO3溶液加热15小时。冷却后,将溶液在EtOAc和Na2CO3(饱和的)之间分配,进一步用NaCl(饱和的)洗涤,用MgSO4干燥,浓缩并通过硅胶色谱法(5-10-20%EtOAc/己烷洗脱液)纯化,得到双Boc suzuki产物。将该Boc保护的物质用25%TFA/CH2Cl2处理2小时,真空除去挥发物。将粗残留物用EtOAc稀释,用Na2CO3(饱和的)和NaCl(饱和的)洗涤,用MgSO4干燥,过滤并真空除去挥发物,得到2-氯-6-(2,6-二氟苯基)吡啶-3-胺(15%)。LC/MS=241.0(M+H),LC=3.28min.
2,4-二氯嘧啶-5-胺的合成
将浓度为0.4M的2.4-二氯-5-硝基-嘧啶(1.0eq.)和铁(6.0eq)在乙酸中的非均匀溶液强力搅拌14小时。然后使混合物通过硅藻土垫层,用MeOH洗脱。真空除去挥发物后,将残留物溶解到EtOAc中,用Na2CO3(饱和的)和NaCl(饱和的)洗涤,用MgSO4干燥,过滤并真空除去挥发物,得到2,4-二氯嘧啶-5-胺(80%)。LCMS(m/z):157.0(MH+);LC Rt=1.85min.
2,4二氯-5N-(双Boc氨基)嘧啶的合成
将5-氨基-2,4-二氯嘧啶(1.0当量)、二碳酸二叔丁酯(2.2当量)和DMAP(0.2当量)的CH2Cl2溶液(0.15M)搅拌16小时。加入硅胶,浓缩后通过硅胶色谱法(10%EtOAc/己烷洗脱液)纯化,得到2,4二氯-5N-(双Boc氨基)嘧啶(48%)。LC/MS=364.1(M+H),LC=4.87min.
4-氯-2-(2-氟苯基)嘧啶-5-胺的合成
在90℃下,将2,4二氯-5N-(双Boc氨基)嘧啶(1.0当量)、2-氟苯基硼酸(1.0当量)和Pd(dppf)Cl2-CH2Cl2(0.05当量)的3∶1 DME/2M Na2CO3溶液加热15小时。冷却后,将溶液在EtOAc和Na2CO3(饱和的)之间分配,进一步用NaCl(饱和的)洗涤,用MgSO4干燥,浓缩并通过硅胶色谱法(10%EtOAc/己烷洗脱液)纯化,得到双Boc suzuki产物。将该Boc保护的物质用25%TFA/CH2Cl2处理2小时,真空除去挥发物。将粗残留物用EtOAc稀释,用Na2CO3(饱和的)和NaCl(饱和的)洗涤,用MgSO4干燥,过滤并真空除去挥发物,得到4-氯-2-(2-氟苯基)嘧啶-5-胺(68%)。LC/MS=224.0(M+H),LC=2.71min.
2-氯-6-(噻唑-2-基)吡啶-3-胺的合成
在70℃下,将2,6二氯-3N-(双Boc氨基)吡啶(1.0当量)、(1.0当量)、2-噻唑基-溴化锌(3.5当量)和Pd(dppf)Cl2-DCM(0.10当量)的THF溶液微波处理15min。将反应物通过硅藻土过滤,用EtOAc淋洗,真空下浓缩至干,通过硅胶色谱法纯化得到Boc保护的产物(39%)。将该Boc保护的物质用25%TFA/CH2Cl2处理2小时,真空除去挥发物。将粗残留物用EtOAc稀释,用Na2CO3(饱和的)和NaCl(饱和的)洗涤,用MgSO4干燥,过滤并真空除去挥发物,得到2-氯-6-(噻唑-2-基)吡啶-3-胺。LCMS(m/z):212.1(MH+);LC Rt=2.70min.
方法1
实施例10
(S)-3-(5-氨基-6-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)吡啶-2-基)-4-氟-N-
异丙基苯甲酰胺的合成
在120℃下,将(S)-1-(6-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊-2-基)-1,7-萘啶-4-基)哌啶-3-基氨基甲酸叔丁基酯(1.0当量)、3-(5-氨基-6-氯吡啶-2-基)-4-氟-N-异丙基苯甲酰胺((1.0当量)和Pd(dppf)Cl2-CH2Cl2(0.2当量)的3∶1 DME/2M Na2CO3溶液加热20小时。冷却后,将溶液在EtOAc和Na2CO3(饱和的)之间分配,进一步用NaCl(饱和的)洗涤,用MgSO4干燥,浓缩并通过RP HPLC纯化。冻干后,通过用25%TFA/CH2Cl2处理将Boc基团去保护,浓缩,通过RP-HPLC纯化并冻干,得到(S)-3-(5-氨基-6-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)吡啶-2-基)-4-氟-N-异丙基苯甲酰胺(21%)。LC/MS=500.3(M+H),LC=2.36min.
下面表1中所示的化合物采用上述方法1的方法制备:
表1
(S)-1-(6-(6-氯-3-硝基吡啶-2-基)-1,7-萘啶-4-基)哌啶-3-基氨基甲酸叔丁
基酯的合成
在微波、100℃下,将(S)-1-(6-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊-2-基)-1,7-萘啶-4-基)哌啶-3-基氨基甲酸叔丁基酯(1.0当量)、2.6二氯3-硝基吡啶(1.0当量)和Pd(dppf)Cl2-CH2Cl2(0.15当量)的3∶1 DME/2M Na2CO3溶液加热20分钟。冷却后,将溶液在EtOAc和Na2CO3(饱和的)之间分配,进一步用NaCl(饱和的)洗涤,用MgSO4干燥,浓缩并通过硅胶色谱法(75%EtOAc/己烷洗脱液)纯化,得到(S)-1-(6-(6-氯-3-硝基吡啶-2-基)-1,7-萘啶-4-基)哌啶-3-基氨基甲酸叔丁基酯(20%)。LC/MS=485.1(M+H),LC=3.17min。
(S)-1-(6-(3-氨基-6-氯吡啶-2-基)-1,7-萘啶-4-基)哌啶-3-基氨基甲酸叔丁
基酯的合成
将浓度为0.4M的(S)-1-(6-(6-氯-3-硝基吡啶-2-基)-1,7-萘啶-4-基)哌啶-3-基氨基甲酸叔丁基酯(1.0eq.)和铁(6.0eq)在乙酸中的不均匀溶液强力搅拌14小时。然后使混合物通过硅藻土垫层,用MeOH洗脱。真空除去挥发物后,将残留物溶解到EtOAc中,用Na2CO3(饱和的)和NaCl(饱和的)洗涤,用MgSO4干燥,过滤并真空除去挥发物,得到(S)-1-(6-(3-氨基-6-氯吡啶-2-基)-1,7-萘啶-4-基)哌啶-3-基氨基甲酸叔丁基酯(77%)。LCMS(m/z):455.2(MH+);LC Rt=3.10min.
方法2
实施例19
(S)-2-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)-6-(4-氟苯基)吡啶-3-胺的合
成
在微波、120℃下,将(S)-1-(6-(3-氨基-6-氯吡啶-2-基)-1,7-萘啶-4-基)哌啶-3-基氨基甲酸叔丁基酯(1.0当量)、4-氟苯基硼酸(3.0当量)和Pd(dppf)Cl2-CH2Cl2(0.15当量)的3∶1 DME/2M Na2CO3溶液加热20分钟。冷却后,将溶液在EtOAc和Na2CO3(饱和的)之间分配,进一步用NaCl(饱和的)洗涤,用MgSO4干燥,浓缩并通过RP HPLC纯化。冻干后,通过用25%TFA/CH2Cl2处理,将Boc基团去保护,浓缩,通过RP-HPLC纯化并冻干,得到(S)-2-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)-6-(4-氟苯基)吡啶-3-胺(61%)。LC/MS=415.2(M+H),LC=2.32min.
下面表2中所示的化合物采用上述方法2的方法制备:
表2
(S)-1-(6-溴喹啉-4-基)哌啶-3-基氨基甲酸叔丁基酯的合成
在140℃下,将6-溴-4-氯喹啉(1.0当量)、(S)-哌啶-3-基氨基甲酸叔丁基酯(1.0当量)和DIEA(1.5当量)的NMP溶液(0.1M)加热48小时。冷却后将溶液倾入冰中,并在熔化后将固体过滤,用H2O淋洗并泵抽,得到(S)-1-(6-溴喹啉-4-基)哌啶-3-基氨基甲酸叔丁基酯。LC/MS=406.0/408.0(M+H),LC=2.85min.
(S)-1-(6-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊-2-基)喹啉-4-基)哌啶-3-基
氨基甲酸叔丁基酯的合成
在135℃、微波下,将(S)-1-(6-溴喹啉-4-基)哌啶-3-基氨基甲酸叔丁基酯(1.0当量)、乙酸钾(3.0当量)、双(频哪醇基)二硼(2.0当量)、三环己基膦(0.2当量)和Pd2(dba)3(0.05当量)的二氧六环溶液(0.05M)加热20分钟。将溶液通过1μM HPLC过滤器过滤,浓缩并泵抽,得到(S)-1-(6-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊-2-基)喹啉-4-基)哌啶-3-基氨基甲酸叔丁基酯,其被直接使用。LC/MS=372.1(相应的HetB(OH)2的M+H),LC=2.26min.
三氟甲磺酸6-(噻唑-2-基)吡啶-2-基酯的合成
在100℃、微波下,将2-溴-6-甲氧基吡啶(1.0当量)、0.5M在THF中的2-噻唑-溴化锌(2当量)和Pd(dppf)Cl2-DCM(0.2当量)的THF溶液(0.1M)加热20min。冷却后,将溶液在EtOAc和Na2CO3(饱和的)之间分配,进一步用NaCl(饱和的)洗涤,用MgSO4干燥,浓缩并通过硅胶色谱法(20%EtOAc/己烷洗脱液)纯化,得到2-(6-甲氧基吡啶-2-基)噻唑(73%)。在100℃下,将物质用二氧六环/H2O/HCl(浓)(3∶1∶0.25比例)处理72小时。真空除去挥发物后,将粗羟基吡啶(1.0当量)、二异丙基乙胺(2.0当量)和1,1,1-三氟-N-苯基-N-(三氟甲基磺酰基)甲磺酰胺(1.5当量)的CH2Cl2溶液搅拌16小时。将溶液在EtOAc和Na2CO3(饱和的)之间分配。分离后,将有机层进一步用Na2CO3(饱和的)和NaCl(饱和的)洗涤,用MgSO4干燥,浓缩并通过硅胶色谱法纯化,得到三氟甲磺酸6-(噻唑-2-基)吡啶-2-基酯。
三氟甲磺酸6-(2,6-二氟苯基)吡啶-2-基酯的合成
在110℃下,将2-溴-6-甲氧基吡啶(1.0当量)、2,6二氟苯基硼酸(2当量)和Pd(dppf)Cl2-DCM(0.05当量)的3∶1 DME/2M Na2CO3溶液加热48小时。冷却后,将溶液在EtOAc和Na2CO3(饱和的)之间分配,进一步用NaCl(饱和的)洗涤,用MgSO4干燥,浓缩并通过硅胶色谱法(10-20%EtOAc/己烷洗脱液)纯化,得到Suzuki产物。在100℃下,将物质用二氧六环/H2O/HCl(浓的)(3∶1∶0.25比例)处理72小时。真空除去挥发物后,将粗羟基吡啶(1.0当量)、二异丙基乙胺(2.0当量)和1,1,1-三氟-N-苯基-N-(三氟甲基磺酰基)甲磺酰胺(1.5当量)的CH2Cl2溶液搅拌16小时。将溶液在EtOAc和Na2CO3(饱和的)之间分配。分离后,将有机层进一步用Na2CO3(饱和的)和NaCl(饱 和的)洗涤,用MgSO4干燥,浓缩并通过硅胶色谱法纯化,得到三氟甲磺酸6-(2,6-二氟苯基)吡啶-2-基酯。
方法3
实施例27
(S)-1-(6-(6-(噻唑-2-基)吡啶-2-基)喹啉-4-基)哌啶-3-胺的合成
在微波、100℃下,将(S)-1-(6-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊-2-基)喹啉-4-基)哌啶-3-基氨基甲酸叔丁基酯(1.0当量)、三氟甲磺酸6-(噻唑-2-基)吡啶-2-基酯(1.5当量)和Pd(dppf)Cl2-CH2Cl2(0.15当量)的3∶1 DME/2MNa2CO3溶液加热20分钟。冷却后,将溶液在EtOAc和Na2CO3(饱和的)之间分配,进一步用NaCl(饱和的)洗涤,用MgSO4干燥,浓缩并通过RP HPLC纯化。冻干后,通过用25%TFA/CH2Cl2处理将Boc基团去保护,浓缩,通过RP-HPLC纯化并冻干,得到(S)-1-(6-(6-(噻唑-2-基)吡啶-2-基)喹啉-4-基)哌啶-3-胺(40%)。LC/MS=388.1(M+H),LC=2.02min.
下述表3中所示的化合物采用上述方法3的方法制备:
表3
4-(苄基氧基)-2-氯嘧啶的合成
向冷却的(1-2℃)氢化钠(60%在矿物油中)(1.5当量)的250ml THF混悬液中,滴加苄醇(1.0当量),并在N2下,将混合物搅拌30min。然后同样在1-2℃(内部温度计)下,向混悬液中分次加入(通过注射器,超过1小时)2,4-二氯嘧啶(1.5当量)的THF溶液。在温度<2℃下,将得到的混合物(0.06M)搅拌2.5小时,然后用NH4Cl(饱和的)淬灭并用EtOAc萃取。分离后,将有机层用NaCl(饱和的)洗涤,用Na2SO4干燥,浓缩并通过硅胶色谱法(己烷/DCM洗脱液)纯化,得到4-(苄基氧基)-2-氯嘧啶(24%)。LC/MS=221.0(M+H),LC=3.93min.
(S)-1-(6-(4-(苄基氧基)嘧啶-2-基)-喹啉-4-基)哌啶-3-基氨基甲酸叔丁基
酯的合成
在20ml微波管中,向(S)-1-(6-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊-2-基)喹啉-4-基)哌啶-3-基氨基甲酸叔丁基酯(1.0当量)、4-(苄基氧基)-2-氯嘧啶(2.0当量)和Pd(dppf)Cl2-DCM(0.15当量)的混合物中,加入DME和2MNa2CO3(1.0M)。在微波下,将该管置于125℃反应20min。将得到的混合物在EtOAc和H2O之间分配。分离后,将有机层用NaCl(饱和的)洗涤,用Na2SO4干燥,浓缩并通过反相HPLC纯化,得到(S)-1-(6-(4-(苄基氧基)嘧啶-2-基)喹啉-4-基)哌啶-3-基氨基甲酸叔丁基酯(88%)。LC/MS=512.1(M+H),LC=3.40min.
(S)-1-(6-(6-氧代-1,6-二氢嘧啶-2-基)喹啉-4-基)哌啶-3-基氨基甲酸叔丁
基酯的合成
向(S)-1-(6-(4-(苄基氧基)嘧啶-2-基)喹啉-4-基)哌啶-3-基氨基甲酸叔丁基酯(1.0当量)的4∶1 EtOH/EtOAc溶液(0.6M)中,加入10%钯碳(0.2eq.)。在氢气气氛下,将得到的不均匀溶液搅拌12小时。然后将混合物通过硅藻土垫层过滤,用EtOAc洗脱。真空除去挥发物,得到(S)-1-(6-(6-氧代-1,6-二氢嘧啶-2-基)喹啉-4-基)哌啶-3-基氨基甲酸叔丁基酯(87%)。LCMS(m/z):422.1(MH+);LC Rt=2.14min.
(S)-三氟甲磺酸2-(4-(3-(叔丁氧羰基氨基)哌啶-1-基)喹啉-6-基)嘧啶-4-
基酯的合成
将(S)-1-(6-(6-氧代-1,6-二氢嘧啶-2-基)喹啉-4-基)哌啶-3-基氨基甲酸叔丁基酯(1.0当量)、二异丙基乙胺(2.0当量)和1,1,1-三氟-N-苯基-N-(三氟甲基磺酰基)甲磺酰胺(1.5当量)的CH2Cl2溶液(0.13M)置于105℃微波中,反应3x20min,浓缩并通过硅胶色谱法(80%EtOAc/己烷洗脱液)纯化,得到(S)-三氟甲磺酸2-(4-(3-(叔丁氧羰基氨基)哌啶-1-基)喹啉-6-基)嘧啶-4-基酯(50%)。LC/MS=554.1(M+H),LC=3.62min.
实施例28
(S)-1-(6-(4-(噻唑-2-基)嘧啶-2-基)喹啉-4-基)哌啶-3-胺的合成
将0.5M 2-噻唑-溴化锌的THF溶液(10当量)加入到微波管中的(S)-三氟甲磺酸2-(4-(3-(叔丁氧羰基氨基)哌啶-1-基)喹啉-6-基)嘧啶-4-基酯(1.0当量)(0.045M)和Pd(dppf)Cl2-DCM(0.2当量)中,并将混合物置于微波、100℃条件下,反应10min,通过1μm PTFE HPLC过滤器过滤,用EtOAc洗脱并浓缩。将得到的(S)-1-(6-(4-(噻唑-2-基)嘧啶-2-基)喹啉-4-基)哌啶-3-基氨基甲酸叔丁基酯溶解到25%TFA/DCM(0.011M)中,并放置2小时,浓缩并通过反相HPLC纯化,得到(S)-1-(6-(4-(噻唑-2-基)嘧啶-2-基)喹啉-4-基)哌啶-3-胺(100%)。LC/MS=389.2(M+H),LC=1.97min.
方法4
实施例29
(S)-1-(6-(4-(2,6-二氟苯基)嘧啶-2-基)喹啉-4-基)哌啶-3-胺的合成
在微波管中,向(S)-三氟甲磺酸2-(4-(3-(叔丁氧羰基氨基)哌啶-1-基)喹啉-6-基)嘧啶-4-基酯(1.0当量)的DME溶液中,加入2,6-二氟硼酸(3.0当量)、Pd(dppf)Cl2-DCM(0.2当量)和2M Na2CO3(0.03M),然后将其置于微波中120℃下反应15min。将得到的有机层分离,浓缩并溶解于25%TFA/DCM中(0.023M)。放置约1小时后,将反应混合物浓缩并通过反相HPLC纯化,得到(S)-1-(6-(4-(2,6-二氟苯基)嘧啶-2-基)喹啉-4-基)哌啶-3-胺(100%)。LC/MS=418.2(M+H),LC=2.21min.
下面表4中所示的化合物采用上述方法4的方法制备:
表4
4-(苄基氧基)-6-溴喹啉的合成
向在矿物油中的60%NaH(1.75当量)的DMF溶液(0.5M)中,滴加苄醇(2.5当量)。搅拌30分钟后,加入6-溴-4-氯喹啉(1.0当量)并将溶液在微波、100℃下加热30分钟。冷却后,将溶液在EtOAc和H2O之间分配。分离后,将有机层进一步用H2O(3x)和NaCl(饱和的)洗涤,用MgSO4干燥,浓缩并用己烷研磨,得到4-(苄基氧基)-6-溴喹啉(73%)。LC/MS=314.0/315.9(M+H),LC=2.89min.
4-(苄基氧基)-6-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊-2-基)喹啉的合成
在135℃、微波下,将4-(苄基氧基)-6-溴喹啉(1.0当量)、乙酸钾(3.0当量)、双(频哪醇基)二硼(2.0当量)、三环己基膦(0.2当量)和Pd2(dba)3(0.05当量)的二氧六环溶液(0.05M)加热20分钟。将溶液通过1μM HPLC过滤器过滤,浓缩并泵抽,得到4-(苄基氧基)-6-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊-2-基)喹啉,其被直接使用。LC/MS=362.0/279.9(产物&相应的HetB(OH)2的M+H),LC=3.39min和2.11min(对于相应的Het(B(OH)2)。
2-(6-(4-(苄基氧基)喹啉-6-基)吡啶-2-基)噻唑的合成
在微波、120℃下,将4-(苄基氧基)-6-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊-2-基)喹啉(1.0当量)、三氟甲磺酸6-(噻唑-2-基)吡啶-2-基酯(1.0当量)和Pd(dppf)Cl2-CH2Cl2(0.1当量)的3∶1 DME/2M Na2CO3溶液加热20分钟。冷却后,将溶液在EtOAc和H2O之间分配。分离后,将有机层用NaCl(饱 和的)洗涤,用MgSO4干燥,浓缩并通过硅胶色谱法(EtOAc洗脱液)纯化,得到2-(6-(4-(苄基氧基)喹啉-6-基)吡啶-2-基)噻唑(39%)。LC/MS=396.0(M+H),LC=3.34min.
6-(6-(噻唑-2-基)吡啶-2-基)喹啉-4-酚的合成
向浓度为0.1M的2-(6-(4-(苄基氧基)喹啉-6-基)吡啶-2-基)噻唑(1.0当量)的1∶1 EtOH/EtOAc溶液中,加入10%钯碳(0.1eq.)。将得到的不均匀溶液放置在氢气气氛下,并搅拌72小时。此时将混合物通过硅藻土垫层过滤,用EtOAc洗脱。真空除去挥发物,得到6-(6-(噻唑-2-基)吡啶-2-基)喹啉-4-酚(88%)。LCMS(m/z):305.9(MH+);LC Rt=2.57min.
三氟甲磺酸6-(6-(噻唑-2-基)吡啶-2-基)喹啉-4-基酯的合成
将6-(6-(噻唑-2-基)吡啶-2-基)喹啉-4-酚(1.0当量)、二异丙基乙胺(2.0当量)和1,1,1-三氟-N-苯基-N-(三氟甲基磺酰基)甲磺酰胺(1.5当量)的NMP溶液(0.23M)搅拌72小时。将溶液在EtOAc和Na2CO3(饱和的)之间分配。分离后,将有机层进一步用Na2CO3(饱和的)和NaCl(饱和的)洗涤,用MgSO4干燥,浓缩并通过硅胶色谱法(50%EtOAc/己烷洗脱液)纯化,得到三氟甲磺酸6-(6-(噻唑-2-基)吡啶-2-基)喹啉-4-基酯(47%)。LC/MS=437.9(M+H),LC=4.91min.
4-(苄基氧基)-6-(6-溴吡啶-2-基)喹啉的合成
在微波、100℃下,将4-(苄基氧基)-6-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊-2-基)喹啉(1.0当量)、2,6二溴吡啶(1.0当量)和Pd(dppf)Cl2-CH2Cl2(0.1当量)的3∶1 DME/2M Na2CO3溶液加热20分钟。冷却后,将溶液在EtOAc和H2O之间分配。分离后,将有机层用NaCl(饱和的)洗涤,用MgSO4干燥,浓缩并通过硅胶色谱法(70-90EtOAc/己烷洗脱液)纯化,得到4-(苄基氧基)-6-(6-溴吡啶-2-基)喹啉(36%)。LC/MS=391.1/393.1(M+H),LC=3.36min.
4-(苄基氧基)-6-(6-(2,6-二氟苯基)吡啶-2-基)喹啉的合成
在微波、120℃下,将4-(苄基氧基)-6-(6-溴吡啶-2-基)喹啉(1.0当量)、2,6二氟苯基硼酸(3.0当量)、二异丙基乙胺(3.0当量)和四(三苯基膦)钯(0.1当量)的1∶1甲苯/乙醇溶液加热20分钟。冷却后,将溶液在EtOAc和H2O之间分配。分离后,将有机层用NaCl(饱和的)洗涤,用MgSO4干燥,浓缩并通过硅胶色谱法(60-75EtOAc/己烷洗脱液)纯化,得到4-(苄基氧基)-6-(6-(2,6-二氟苯基)吡啶-2-基)喹啉(74%)。LC/MS=425.1(M+H),LC=3.59min.
6-(6-(2,6-二氟苯基)吡啶-2-基)喹啉-4-酚的合成
向浓度为0.1M的4-(苄基氧基)-6-(6-(2,6-二氟苯基)吡啶-2-基)喹啉(1.0当量)的1∶1EtOH/EtOAc溶液中,加入10%钯碳(0.1eq.)。将得到的不均匀溶液放置在氢气气氛下,并搅拌72小时。此时将混合物通过硅藻土垫层过滤,用EtOAc洗脱。真空除去挥发物,得到6-(6-(2,6-二氟苯基)吡啶-2-基)喹啉-4-酚(70%)。LCMS(m/z):335.0(MH+);LC Rt=3.09min.
三氟甲磺酸6-(6-(2,6-二氟苯基)吡啶-2-基)-喹啉-4-基酯的合成
将6-(6-(2,6-二氟苯基)吡啶-2-基)喹啉-4-酚(1.0当量、二异丙基乙胺(2.0当量)和1,1,1-三氟-N-苯基-N-(三氟甲基磺酰基)甲磺酰胺(1.5当量)的NMP溶液(0.23M)搅拌72小时。将溶液在EtOAc和Na2CO3(饱和的)之间分配。分离后,将有机层进一步用Na2CO3(饱和的)和NaCl(饱和的)洗涤,用MgSO4干燥,浓缩并通过硅胶色谱法(25-35%EtOAc/己烷洗脱液)纯化,得到三氟甲磺酸6-(6-(2,6-二氟苯基)吡啶-2-基)喹啉-4-基酯(72%)。LC/MS=467.0(M+H),LC=5.13min.
反式(+/-)-3-(叔丁氧羰基氨基)-4-羟基哌啶-1-甲酸苄基酯的合成
反式(+/-)-4-(叔丁氧羰基氨基)-3-羟基哌啶-1-甲酸苄基酯的合成
在密封的钢瓶中,将(+/-)7-氧杂-3-氮杂二环[4.1.0]庚烷-3-甲酸苄基酯(1.0当量)在饱和的氢氧化铵水溶液和乙醇中的溶液(1∶1,0.05M溶液)加热至70℃反应5h。通过N2气流除去所有挥发性物质后,加入乙酸乙酯和水进行后处理。将粗的区域异构体混合物3-氨基-4-羟基哌啶-1-甲酸苄基酯和4-氨基-3-羟基哌啶-1-甲酸苄基酯与Boc2O(1.0当量)和三乙胺(1.0当量)在二氯甲烷中(0.1M溶液)反应。室温下搅拌2h后,将反应混合物用二氯甲烷萃取。通过快速柱色谱法(20%至40%EtOAc的己烷溶液,分别以28%,51%)得到极性的(+/-)-3-(叔丁氧羰基氨基)-4-羟基哌啶-1-甲酸苄基酯和非极性的(+/-)-4-(叔丁氧羰基氨基)-3-羟基哌啶-1-甲酸苄基酯。LCMS(m/z):351.1(MH+),Rt=0.81min,LCMS(m/z):351.1(MH+),Rt=0.83min。通过手性HPLC拆分对映体纯的(3S,4S)-3-(叔丁氧羰基氨基)-4-羟基哌啶-1-甲酸苄基酯和(3R,4R)-3-(叔丁氧羰基氨基)-4-羟基哌啶-1-甲酸苄基酯(对于分析而言,Rt分别=6.8min和9.1min;正庚烷∶乙醇=70∶30(v∶v),Chiralpak AD-H prep 250X4.6mm,1mL/min。对于制备分离而言,正庚烷∶乙醇=80∶20(v∶v),Chiralpak AS 50x500mm.,90mL/min)。
(3R,4R)-3-(叔丁氧羰基氨基)-4-(叔丁基二甲基甲硅烷基氧基)哌啶-1-
甲酸苄基酯的合成
向(3R,4R)-3-(叔丁氧羰基氨基)-4-羟基哌啶-1-甲酸苄基酯(1.0当量)的二氯甲烷溶液(0.1M溶液)中顺序地加入咪唑(1.1当量)、DMAP(0.1当量)和TBDMSCl(1.1当量)。将反应混合物在室温下搅拌20h。用二氯甲烷后处理后,将粗物质用硅胶柱色谱法(10%至20%EtOAc的己烷溶液)纯化,得到(3R,4R)-3-(叔丁氧羰基氨基)-4-(叔丁基二甲基甲硅烷基氧基)哌啶-1-甲酸苄基酯(76%)。LCMS(m/z):365.2[(M-Boc)H+];LC Rt=6.05min.
(3R,4R)-4-(叔丁基二甲基甲硅烷基氧基)哌啶-3-基氨基甲酸叔丁基酯
的合成
向浓度为0.1M的(3R,4R)-3-(叔丁氧羰基氨基)-4-(叔丁基二甲基甲硅烷基氧基)哌啶-1-甲酸苄基酯(1.0当量)的1∶1EtOH/EtOAc溶液中,加入10%钯碳(0.1eq.)。将得到的不均匀溶液放置在氢气气氛下,并搅拌72小时。此时将混合物通过硅藻土垫层过滤,用EtOAc洗脱。真空除去挥发物,得到(3R,4R)-4-(叔丁基二甲基甲硅烷基氧基)哌啶-3-基氨基甲酸叔丁基酯(99%)。LCMS(m/z):331.3(MH+).
(3R,4R)-3-(叔丁氧羰基氨基)-4-氟哌啶-1-甲酸苄基酯和(3S,4S)-3-(叔丁
氧羰基氨基)-4-氟哌啶-1-甲酸苄基酯的合成
在-78℃下,向(+/-)-3-(叔丁氧羰基氨基)-4-羟基哌啶-1-甲酸苄基酯(1.0当量)的二氯甲烷溶液(0.3M溶液)中加入DAST。将反应混合物缓慢升温至室温,反应15h。用饱和的碳酸氢钠水溶液淬灭后,加入乙酸乙酯和水进行后处理。通过硅胶柱色谱法得到(+/-)-3-(叔丁氧羰基氨基)-4-氟哌啶-1-甲酸苄基酯(30%EtOAc的己烷溶液,40%)。LCMS(m/z):253.1[(M-Boc)H+];;LC Rt=4.08min。通过手性HPLC拆分对映体纯的(3R,4R)-3-(叔丁氧羰基氨基)-4-氟哌啶-1-甲酸苄基酯和(3S,4S)-3-(叔丁氧羰基氨基)-4-氟哌啶-1-甲酸苄基酯(对于分析而言:Rt分别=9.4min和12.6min;正庚烷∶异丙醇=90∶10(v∶v),Chiralpak AS 250x4.6mm,1mL/min。对于制备分离而言,正庚烷∶异丙醇=90∶10(v∶v),Chiralpak AS50x500mm.,90mL/min)。
(3R,4R)-4-氟哌啶-3-基氨基甲酸叔丁基酯的合成
向浓度为0.1M的(3R,4R)-3-(叔丁氧羰基氨基)-4-氟哌啶-1-甲酸苄基酯(1.0当量)的1∶1EtOH/EtOAc溶液中加入10%钯碳(0.1eq.)。将得到的不均匀溶液放置在氢气气氛下,并搅拌72小时。此时将混合物通过硅藻土垫层过滤,用EtOAc洗脱。真空除去挥发物,得到(3R,4R)-4-氟哌啶-3-基氨基甲酸叔丁基酯(93%)。LCMS(m/z):219.2(MH+),LC Rt=0.45min.
5-甲基吡啶-3-基氨基甲酸叔丁基酯的合成
在r.t.下,向5-甲基吡啶-3-胺(1.0当量)的THF溶液(0.5M)中加入1M双(三甲基甲硅烷基氨基)钠的THF溶液(2.2当量),搅拌15min,然后加入在THF中的二碳酸二叔丁基酯(1.05当量)。在r.t下,将反应物搅拌过夜并浓缩。将浓缩物用0.2M HCl(60mL)和EtOAc处理,并将有机层萃取,用NaHCO3(饱和的)和盐水洗涤,用Na2SO4干燥,过滤并浓缩。将浓缩物通过快速硅胶色谱法(40%EtOAc∶己烷)纯化,得到产物5-甲基吡啶-3-基氨基甲酸叔丁基酯(88%),为黄色固体。LCMS(m/z):209.1(MH+);LC Rt=1.94min.1H NMR(CDCl3)δ8.20(d,1H),8.12(s,1H),7.86(s,1H),6.53(s,1H),2.33(s,3H),1.53(s,9H).
顺式-(+/-)-5-甲基哌啶-3-基氨基甲酸叔丁基酯的合成
在氢化钢瓶中,向5-甲基吡啶-3-基氨基甲酸酯(3g,14mmol)的冰醋酸(50mL)溶液中加入在活性碳上的5%铑(0.5g)和氧化铂(IV)(0.5g)。将混合物密封并在200psi和70℃下氢化48h。将混合物通过硅藻土过滤并浓缩,得到顺式-(+/-)-5-甲基哌啶-3-基氨基甲酸叔丁基酯。LCMS(m/z):215.1(MH+).
方法5
实施例31
(3S,5R)-5-甲基-1-(6-(6-(噻唑-2-基)-吡啶-2-基)喹啉-4-基)哌啶-3-胺的
合成
在微波、150℃下,将(3S,5R)-5-甲基哌啶-3-基氨基甲酸叔丁基酯(1.5当量)和三氟甲磺酸6-(6-(噻唑-2-基)吡啶-2-基)喹啉-4-基酯(1.0当量)和DIEA(2.0当量)的i-PrOH溶液加热(5x20min)。冷却后将物质直接用RP-HPLC纯化。冻干后,用25%TFA/CH2Cl2处理将Boc基团去保护,浓缩,通过RP-HPLC纯化并冻干,得到(3S,5R)-5-甲基-1-(6-(6-(噻唑-2-基)吡啶-2-基)喹啉-4-基)哌啶-3-胺(51%)。LC/MS=402.0(M+H),LC=2.16min.
下面表5中所示的化合物采用上述方法5的方法制备:
表5
实施例37
Pim1 ATP损耗实验(depletion assay)
采用萤火虫荧光素酶(luciferase-luciferin)ATP检测试剂定量测定由激酶催化的磷酰基向肽底物转移所导致的ATP损耗,测定PIM1的活性。将待测化合物溶于100%DMSO,将其直接分布到白色384孔板上,每孔0.5μl。为了开始反应,向每个孔中加入10μl的5nM Pim1激酶和80μM BAD肽(RSRHSSYPAGT-OH)的分析缓冲液(50mM HEPES pH 7.5,5mMMgCl2,1mM DTT,0.05%BSA)。15分钟后,加入10μl的40μM ATP的分析缓冲液。最终的分析浓度为2.5nM PIM1、20μM ATP、40μM BAD肽和2.5%DMSO。反应进行直到约50%的ATP被损耗,然后通过加入20μlKinaseGlo Plus(Promega Corporation)溶液终止反应。将终止的反应物温育10分钟,剩余的ATP在Victor2(Perkin Elmer)上通过荧光测定。通过Pim1 ATP损耗实验对前述实施例化合物进行实验,发现其IC50值如下面的实施例41中所示。IC50(半数最大抑制浓度)表示体外抑制其靶点达50%时所需要的测试化合物的浓度。
实施例38
Pim2 ATP损耗实验
采用萤火虫荧光素酶ATP检测试剂定量测定由激酶催化的磷酰基向肽底物转移所导致的ATP损耗,测定PIM2的活性。将待测化合物溶于100%DMSO,将其直接分布到白色384孔板上,每孔0.5μl。为了开始反应,向每个孔中加入10μl的10nM Pim2激酶和20μM BAD肽(RSRHSSYPAGT-OH)的分析缓冲液(50mM HEPES pH 7.5,5mM MgCl2,1mM DTT,0.05%BSA)。15分钟后,加入10μl的8μM ATP的分析缓冲液。最终分析浓度为5nM PIM2、4μM ATP、10μM BAD肽和2.5%DMSO。反应进行直到约50%的ATP被损耗,然后通过加入20μl KinaseGloPlus(Promega Corporation)溶液终止反应。将终止的反应物温育10分钟,剩余的ATP在Victor2(Perkin Elmer)上通过荧光测定。通过Pim2 ATP损耗实验对前述实施例化合物进行实验,发现其IC50值如下面的实施例41中所示。
实施例39
Pim3 ATP损耗实验
采用萤火虫荧光素酶ATP检测试剂定量测定由激酶催化的磷酰基向肽底物转移所导致的ATP损耗,测定PIM3的活性。将待测化合物溶于100%DMSO,将其直接分布到白色384孔板上,每孔0.5μl。为了开始反应,向每个孔中加入10μl的10nM Pim3激酶和200μM BAD肽(RSRHSSYPAGT-OH)的分析缓冲液(50mM HEPES pH 7.5,5mM MgCl2,1mM DTT,0.05%BSA)。15分钟后,加入10μl的80μM ATP的分析缓冲液。最终分析浓度为5nM PIM1、40μM ATP、100μM BAD肽和2.5%DMSO。反应进行直到约50%的ATP被损耗,然后通过加入20μlKinaseGlo Plus(Promega Corporation)溶液终止反应。将终止的反应物温育10分钟,剩余的ATP在Victor2(Perkin Elmer)上通过荧光测定。通过Pim3 ATP损耗实验对前述实施例化合物进行实验,发现其IC50值如下面的实施例41中所示。
实施例40
细胞增殖实验
将KMS11(人类骨髓瘤细胞系)在补充有10%FBS、丙酮酸钠和抗生素的IMDM中培养。在实验的当天,将细胞以每孔2000个细胞的密度涂布于96孔组织培养板中的相同培养基中,使外侧孔空白。MM1.s(人类骨髓瘤细胞系)在补充有10%FBS、丙酮酸钠和抗生素的RPMI1640中培养。在实验的当天,将细胞以每孔5000个细胞的密度涂布于96孔组织培养板中的相同培养基中,使外侧孔空白。
将在DMSO中提供的测试化合物以需要的终浓度的500倍在DMSO中稀释,然后以终浓度的2倍在培养基中稀释。将相同体积的2×化合物加至96孔板的细胞中,于37℃培养3天。
3天后,将板于室温下平衡,向培养孔中加入等体积的CellTiter-Glow试剂(Promega)。将板短暂震摇,采用光度计测定发光信号。计算在用DMSO单独处理的细胞中所观察到的信号与对照化合物处理的细胞中所观察到的信号的抑制百分比,用于测定测试化合物的EC50值(即,在细胞中获得最大效果的50%所需要的测试化合物的浓度),如下面的实施例41中所示。
实施例41
本发明化合物的IC
50
和EC
50
活性
采用实施例37(Pim1 ATP损耗实验)、38(Pim2 ATP损耗实验)和39(Pim3 ATP损耗实验)的方法,测定前面实施例化合物的IC50浓度,如表6中所示。
采用实施例40(细胞增殖实验)的方法,在KMS11细胞中测定前面实施例化合物的EC50浓度,如表6中所示。
表6
尽管已经例示并描述了示例性实施方案,但是应当理解,这些实施方案可进行各种变化,而不偏离本发明的精神和范围。
Claims (16)
1.式I化合物,
或者其立体异构体或药学上可接受的盐,其中,
X2和X4是N,且X1、X3、X5和X6是CR2;或其中X4是N且X1、X2、X3、X5和X6是CR2;
Y是取代的环己基或取代的哌啶基,其中各自被至多4个选自氨基、卤素、羟基和C1-6烷基的取代基取代;
Z1和Z3独立地选自CR12和N,前提是Z1和Z3中不超过一个是N;
Z2是CR12;
R1是芳基或杂芳基,并任选被下列基团取代:卤素、C1-6烷氧基、磺酰基、磺酰氨基和氨基羰基,其中"芳基"意指具有5-12元环***的单环和多环的芳香基团,"杂芳基"代表5至12元环状芳香结构,其中1至6个成员是选自N、O和S的杂原子;且
R2和R12每次出现时独立地选自氢、卤素、C1-6烷基、C1-6烷氧基和氨基。
2.权利要求1的化合物,其中Z1是N或CR12且Z2和Z3是CR12。
3.权利要求2的化合物,其中Z1是CR12。
4.权利要求3的化合物,其中R12选自氨基、氢或卤素。
5.化合物,其选自(S)-2-(4-(3-氨基哌啶-1-基)-3-氟-1,7-萘啶-6-基)-6-(噻唑-2-基)吡啶-3-胺、(S)-3-(5-氨基-6-(4-(3-氨基哌啶-1-基)-3-氟-1,7-萘啶-6-基)吡啶-2-基)-4-氟-N-异丙基苯甲酰胺、(S)-2-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)-6-(噻唑-2-基)吡啶-3-胺、(S)-4-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)-2-(2-氟苯基)嘧啶-5-胺、(R)-2-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)-6-(2,6-二氟苯基)吡啶-3-胺、(R)-3-(5-氨基-6-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)吡啶-2-基)-4-氟-N-异丙基苯甲酰胺、(S)-2-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)-6-(2,6-二氟苯基)吡啶-3-胺、(S)-3-(5-氨基-6-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)吡啶-2-基)-4-氟-N-异丙基苯甲酰胺、(S)-2-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)-6-(2-氟苯基)吡啶-3-胺、(S)-3-(5-氨基-6-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)吡啶-2-基)-4-氟-N-苯基苯甲酰胺、(S)-2-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)-6-(噻吩-2-基)吡啶-3-胺、(S)-6-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)-6'-甲氧基-2,2'-联吡啶-5-胺、(S)-3-(5-氨基-6-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)吡啶-2-基)-N-环己基-4-氟苯甲酰胺、(S)-3-(5-氨基-6-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)吡啶-2-基)-4-氟-N,N-二甲基苯甲酰胺、(S)-2-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)-6-(2,4-二氟苯基)吡啶-3-胺、(S)-2-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)-6-(2,3-二氟苯基)吡啶-3-胺、(S)-2-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)-6-(4-氟苯基)吡啶-3-胺、(S)-2-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)-6-苯基吡啶-3-胺、(S)-3-(5-氨基-6-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)吡啶-2-基)苯磺酰胺、(S)-2-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)-6-(3-(甲基磺酰基)苯基)吡啶-3-胺、(S)-4-(5-氨基-6-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)吡啶-2-基)苯磺酰胺、(S)-2-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)-6-(4-(甲基磺酰基)苯基)吡啶-3-胺、(S)-1-(6-(6-(噻唑-2-基)吡啶-2-基)-1,7-萘啶-4-基)哌啶-3-胺、(S)-1-(6-(6-(2,6-二氟苯基)吡啶-2-基)喹啉-4-基)哌啶-3-胺、(S)-1-(6-(6-(噻唑-2-基)吡啶-2-基)喹啉-4-基)哌啶-3-胺、(S)-1-(6-(4-(噻唑-2-基)嘧啶-2-基)喹啉-4-基)哌啶-3-胺、(S)-1-(6-(4-(2-氟苯基)嘧啶-2-基)喹啉-4-基)哌啶-3-胺、(S)-1-(6-(4-(2,6-二氟苯基)嘧啶-2-基)喹啉-4-基)哌啶-3-胺、(3S,5R)-5-甲基-1-(6-(6-(噻唑-2-基)吡啶-2-基)喹啉-4-基)哌啶-3-胺、(3R,4R)-1-(6-(6-(2,6-二氟苯基)吡啶-2-基)喹啉-4-基)-4-氟哌啶-3-胺、(3R,4R)-4-氟-1-(6-(6-(噻唑-2-基)吡啶-2-基)喹啉-4-基)哌啶-3-胺、(3S,5R)-1-(6-(6-(2,6-二氟苯基)吡啶-2-基)喹啉-4-基)-5-甲基哌啶-3-胺、(3R,4R)-3-氨基-1-(6-(6-(2,6-二氟苯基)吡啶-2-基)喹啉-4-基)哌啶-4-醇和(3R,4R)-3-氨基-1-(6-(6-(噻唑-2-基)吡啶-2-基)喹啉-4-基)哌啶-4-醇。
6.具有下面式II结构的权利要求1的化合物,
或者其立体异构体或药学上可接受的盐,其中,
Y是取代的哌啶基,其被至多4个选自氨基、卤素、羟基和C1-6烷基的取代基取代;
R1选自未取代的和取代的噻唑基、苯基和吡啶基,其中取代的噻唑基、苯基和吡啶基被选自下列的取代基取代:卤素、C1-6烷氧基、磺酰基、磺酰氨基和氨基羰基;
R3选自氢、卤素和NH2;
且R2和R12如权利要求1中所定义。
7.具有下面式III结构的权利要求1的化合物,
或者其立体异构体或药学上可接受的盐,其中,
Y是取代的哌啶基,其被至多4个选自氨基、卤素、羟基和C1-6烷基的取代基取代;
R1选自未取代的和取代的噻唑基、苯基和吡啶基,其中取代的噻唑基、苯基和吡啶基被选自下列的取代基取代:卤素、C1-6烷氧基、磺酰基、磺酰氨基和氨基羰基;且
R2和R12如权利要求1中所定义。
8.具有下面式IV结构的权利要求1的化合物,
或者其立体异构体或药学上可接受的盐,其中,
Y是取代的哌啶基,其被至多4个选自氨基、卤素、羟基和C1-6烷基的取代基取代;
R1选自未取代的和取代的噻唑基、苯基和吡啶基,其中取代的噻唑基、苯基和吡啶基被选自下列的取代基取代:卤素、C1-6烷氧基、磺酰基、磺酰氨基和氨基羰基;
R3选自氢、卤素和NH2;
且R2和R12如权利要求1中所定义。
9.具有下面式II结构的化合物,其中,
或者其立体异构体或药学上可接受的盐,其中,Y是哌啶基,并且被至多三个选自下列的取代基所取代:甲基、乙基、羟基、氨基、甲氧基、乙氧基和卤素;
R1选自取代的或未取代的噻唑基、苯基和吡啶基,其中取代的噻唑基、苯基和吡啶基被选自下列的取代基取代:卤素、C1-6烷氧基、磺酰基、磺酰氨基和氨基羰基;
R3选自氢、卤素和NH2;
且R2和R12每次出现时独立地选自氢、卤素、C1-6烷基、C1-6烷氧基和氨基。
10.具有下面式III结构的化合物,
或者其立体异构体或药学上可接受的盐,其中,
Y是哌啶基,并且被至多三个选自下列的取代基所取代:甲基、乙基、羟基、氨基、甲氧基、乙氧基和卤素;
R1选自取代的或未取代的噻唑基、苯基和吡啶基,其中取代的噻唑基、苯基和吡啶基被选自下列的取代基取代:卤素、C1-6烷氧基、磺酰基、磺酰氨基和氨基羰基;
且R2和R12每次出现时独立地选自氢、卤素、C1-6烷基、C1-6烷氧基和氨基。
11.具有下面式IV结构的化合物,
或者其立体异构体或药学上可接受的盐,其中,
Y是哌啶基,并且被至多三个选自下列的取代基所取代:甲基、乙基、羟基、氨基、甲氧基、乙氧基和卤素;
R1选自取代的或未取代的噻唑基、苯基和吡啶基,其中取代的噻唑基、苯基和吡啶基被选自下列的取代基取代:卤素、C1-6烷氧基、磺酰基、磺酰氨基和氨基羰基;
R3选自氢、卤素和NH2;
且R2和R12每次出现时独立地选自氢、卤素、C1-6烷基、C1-6烷氧基和氨基。
12.化合物,其选自(S)-2-(4-(3-氨基哌啶-1-基)-3-氟-1,7-萘啶-6-基)-6-(噻唑-2-基)吡啶-3-胺、(S)-3-(5-氨基-6-(4-(3-氨基哌啶-1-基)-3-氟-1,7-萘啶-6-基)吡啶-2-基)-4-氟-N-异丙基苯甲酰胺、(S)-2-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)-6-(噻唑-2-基)吡啶-3-胺、(S)-4-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)-2-(2-氟苯基)嘧啶-5-胺、(R)-2-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)-6-(2,6-二氟苯基)吡啶-3-胺、(R)-3-(5-氨基-6-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)吡啶-2-基)-4-氟-N-异丙基苯甲酰胺、(S)-2-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)-6-(2,6-二氟苯基)吡啶-3-胺、(S)-3-(5-氨基-6-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)吡啶-2-基)-4-氟-N-异丙基苯甲酰胺、(S)-2-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)-6-(2-氟苯基)吡啶-3-胺、(S)-3-(5-氨基-6-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)吡啶-2-基)-4-氟-N-苯基苯甲酰胺、(S)-2-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)-6-(噻吩-2-基)吡啶-3-胺、(S)-6-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)-6'-甲氧基-2,2'-联吡啶-5-胺、(S)-3-(5-氨基-6-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)吡啶-2-基)-N-环己基-4-氟苯甲酰胺、(S)-3-(5-氨基-6-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)吡啶-2-基)-4-氟-N,N-二甲基苯甲酰胺、(S)-2-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)-6-(2,4-二氟苯基)吡啶-3-胺、(S)-2-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)-6-(2,3-二氟苯基)吡啶-3-胺、(S)-2-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)-6-(4-氟苯基)吡啶-3-胺、(S)-2-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)-6-苯基吡啶-3-胺、(S)-3-(5-氨基-6-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)吡啶-2-基)苯磺酰胺、(S)-2-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)-6-(3-(甲基磺酰基)苯基)吡啶-3-胺、(S)-4-(5-氨基-6-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)吡啶-2-基)苯磺酰胺、(S)-2-(4-(3-氨基哌啶-1-基)-1,7-萘啶-6-基)-6-(4-(甲基磺酰基)苯基)吡啶-3-胺、(S)-1-(6-(6-(噻唑-2-基)吡啶-2-基)-1,7-萘啶-4-基)哌啶-3-胺、(S)-1-(6-(6-(2,6-二氟苯基)吡啶-2-基)喹啉-4-基)哌啶-3-胺、(S)-1-(6-(6-(噻唑-2-基)吡啶-2-基)喹啉-4-基)哌啶-3-胺、(S)-1-(6-(4-(2-氟苯基)嘧啶-2-基)喹啉-4-基)哌啶-3-胺、(S)-1-(6-(4-(2,6-二氟苯基)嘧啶-2-基)喹啉-4-基)哌啶-3-胺、(3S,5R)-5-甲基-1-(6-(6-(噻唑-2-基)吡啶-2-基)喹啉-4-基)哌啶-3-胺、(3R,4R)-1-(6-(6-(2,6-二氟苯基)吡啶-2-基)喹啉-4-基)-4-氟哌啶-3-胺、(3R,4R)-4-氟-1-(6-(6-(噻唑-2-基)吡啶-2-基)喹啉-4-基)哌啶-3-胺、(3S,5R)-1-(6-(6-(2,6-二氟苯基)吡啶-2-基)喹啉-4-基)-5-甲基哌啶-3-胺、(3R,4R)-3-氨基-1-(6-(6-(2,6-二氟苯基)吡啶-2-基)喹啉-4-基)哌啶-4-醇和(3R,4R)-3-氨基-1-(6-(6-(噻唑-2-基)吡啶-2-基)喹啉-4-基)哌啶-4-醇。
13.组合物,其包含权利要求1的化合物和用于治疗癌症的至少一种其它活性剂。
14.组合物,其包含权利要求6、7、8、9、10、11或12的化合物和用于治疗癌症的至少一种其它活性剂。
15.药物组合物,其包含有效量的权利要求1的化合物。
16.药物组合物,其包含有效量的权利要求6、7、8、9、10、11或12的化合物。
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Also Published As
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JP5564045B2 (ja) | 2014-07-30 |
WO2010026121A1 (en) | 2010-03-11 |
CN102203075A (zh) | 2011-09-28 |
US20110195980A1 (en) | 2011-08-11 |
AU2009289316A1 (en) | 2010-03-11 |
EA201100426A1 (ru) | 2011-10-31 |
JP2012501312A (ja) | 2012-01-19 |
BRPI0918496A2 (pt) | 2019-09-24 |
CA2735779A1 (en) | 2010-03-11 |
MX2011002367A (es) | 2011-04-04 |
US8735424B2 (en) | 2014-05-27 |
EP2342190A1 (en) | 2011-07-13 |
KR20110058866A (ko) | 2011-06-01 |
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