CN117460736A - 具有多靶标磷酸化酶抑制活性的核苷衍生物及包含其的癌症的预防和治疗用药学组合物 - Google Patents
具有多靶标磷酸化酶抑制活性的核苷衍生物及包含其的癌症的预防和治疗用药学组合物 Download PDFInfo
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Abstract
本发明涉及通过抑制磷酸化酶而用于癌症预防或治疗的核苷衍生物和包含其的药学组合物,所述核苷衍生物对如NTRK1、CSNK1D、DYRK1A、DYRK1B和FLT3的磷酸化酶具有抑制活性,由此对与磷酸化酶直接或间接相关的多种癌细胞表现出抑制活性,因此可用于预防或治疗肺癌、结肠癌、乳腺癌、肝癌、胃癌和前列腺癌等各种癌症。
Description
技术领域
本发明涉及一种核苷衍生物以及包含其的药学组合物,所述核苷衍生物通过抑制磷酸化酶,能够用于癌症预防或治疗。
背景技术
癌症生长的主要原因之一是磷酸化酶(kinase)的突变。蛋白质磷酸化酶通过介导蛋白质的磷酸化在细胞功能中起重要作用。由于它们将腺苷三磷酸(Adenosinetriphosphate,ATP)的末端磷酸基团转移到蛋白质基质上,从而引发信号转导、基因调节、代谢等反应,故磷酸化酶的调节障碍可能与包括癌症在内的多种疾病有关。因此,若以磷酸化酶为标的来开发核苷衍生物,则可用于癌症治疗。
抗癌药的主要问题是抗药性,常见于实行单一疗法的癌症患者。在这种情况下,多重药物疗法策略可以克服抵抗危机。以一个以上的标的为目标的多靶标抑制剂可以阻止癌细胞增殖,其次,通过阻止用于支持肿瘤发生的微观环境,可以超越单靶标抑制剂的效果。
另一方面,ATP的氮碱基通过氢键与铰链区域相互作用,核糖环与糖口袋的极性残基相互作用,而已知的磷酸化酶抑制剂不与糖口袋结合,而是占据铰链区域或疏水性区域。因此,本发明人认识到,在选择性磷酸化酶抑制剂的设计中,不与ATP结合的疏水性口袋是开发抑制剂的重要部位。
因此,本发明人设计了一种核苷磷酸化酶抑制剂,其中,氮碱基与铰链区域形成氢键,并且通过修饰一个疏水性残基(以下化学式1的R1)和另一个疏水性残基(以下化学式1的R2)来占据疏水性口袋。并且,还发现:如ATP的核糖环,糖的极性羟基通过与糖区域形成氢键,使分子紧密贴合,从而增加键合力。此外,评估了通过修饰糖的一部分(以下化学式1的Y)而合成的化合物的磷酸化酶抑制活性,其中,该部分使得在磷酸化酶结构域的三磷酸结合位点形成重要的键。由此,找出对与癌细胞中过表达相关的磷酸化酶NTRK1、DYRK1A、DYRK1B、FLT3、CSNK1D有效的选择性抑制剂,并确认它们表现出优异的抗癌活性,从而完成了本发明。
发明内容
本发明要解决的技术问题
因此,本发明要解决的问题是,提供一种核苷衍生物及包含该核苷衍生物的药学组合物,其通过选择性抑制特定磷酸化酶(Kinase),可用于预防或治疗癌症。
技术方案
用于解决所述问题的本发明的一实施例的核苷衍生物由下述化学式1表示。
<化学式1>
X是氧(O)或硫(S),
R是氢(H)、取代或未取代的C1至C10的烷基(alkyl)或取代或未取代的C6至C20的芳基(aryl)或烷基芳基(alkylaryl),
R1是取代或未取代的C2至C10的杂芳基(heteroaryl)、取代或未取代的C2至C8的烯基(alkenyl)、取代或未取代的C6至C20的芳基(aryl)、取代或未取代的C2至C8的炔基(alkynyl)、氰基(cyano)、酰胺基(amide)或羧基(carboxyl),
R2是卤素(halogen)、取代或未取代的胺基(amine)、或取代或未取代的C6至C20的芳基(aryl)或烷基芳基(alkylaryl),
Y是氢(H)、羟基(hydroxy)、酯基(ester)、烷氧基(alkoxy)、芳基(aryl)、杂芳基(heteroaryl)、杂环烷基(heterocycloalkyl)、环烷基(cycloalkyl)、叠氮基(azide)、胺基(amine)、取代的胺基、尿素(urea)或被酰胺基(amide)取代的烷基(alkyl);或=CZ2,所述Z各自独立地为氢(H)或C2至C8的烷基(alkyl)。
当所述R、R1、R2和Y被取代时,可取代为C1至C6的烷基,C2至C10的杂芳基和磺酰胺基(sulfonamide)中的一种以上。
所述杂芳基可以为呋喃基(furanyl)、苯硫基(thiophenyl)、吡咯基(pyrrolyl)、吡喃基(pyranyl)、吡唑基(pyrazolyl)、吡啶基(pyridinyl)、三唑基(triazolyl)、咪唑基(imidazolyl)、噻唑基(thiazolyl)、嘧啶基(pyrimidinyl)、吡嗪基(pyrazinyl)、哒嗪基(pyridazinyl)、吲哚基(indolyl)、喹啉基(quinolinyl)或嘌呤基(purinyl)。
所述杂环烷基可以为四氢呋喃基(tetrahydrofuranyl)、硫杂环戊基(thiolanyl)、吡咯烷基(pyrrolidinyl)、四氢吡喃基(tetrahydropyranyl)、哌啶基(piperidinyl)、二氧杂环己基(dioxanyl)、吗啉基(morpholino)或四氢嘧啶基(tetrahydropyrimidinyl)。
所述芳基可以为苯基(phenyl)、萘基(naphthalenyl)、蒽基(anthracenyl)或菲基(phenanthrenyl),所述烷基芳基可以为苄基(benzyl)。
所述炔基可以为乙炔基(ethynyl)、丙炔基(propynyl)、丁炔基(butynyl)、戊炔基(pentynyl)、己炔基(hexynyl)、庚炔基(heptynyl)、辛炔基(octynyl)、壬炔基(nonynyl)或癸炔基(decynyl)。
所述烯基可以为乙烯基(ethenyl)、丙烯基(propenyl)、丁烯基(butenyl)、戊烯基(pentenyl)、己烯基(hexenyl)、庚烯基(heptenyl)、辛烯基(octenyl)、壬烯基(nonenyl)或癸烯基(decenyl)。
所述烷基可以为甲基(methyl)、乙基(ethyl)、丙基(propyl)、丁基(butyl)或戊基(pentyl)。
具体地,X可以为硫,R可以为氢,R1可以为呋喃基(furanyl)、苯硫基(thiophenyl)、乙烯基(vinyl)、苯基(phenyl)、硫代吗啉基(Thiomorpholino)苯基、硫代吗啉基二氧苯基、磺酰胺基(sulfonamide)苯基、乙磺酰胺基苯基、乙炔基(ethynyl)、丙炔基(propynyl)、丁炔基(butynyl)、二甲基丁炔(dimethylbutynyl)、环丙基乙炔基(cyclopropylethynyl)、氰基(cyano)、酰胺基(amide)或羧基(carboxy),R2可以为氯(Cl)或胺基(-NH2),Y可以为氢、-CH2OH、-CH2OCOAr、-CH2N3、-CH2NH2、-CH2NHCOAr、-CH2NHCONH2、-CH2N-烷基(CH2N-alkyl)、-CH2N-环烷基(CH2N-cycloalkyl)、-CH2N(CH2CH2)2O或=CH2。
此时,所述“Ar”作为芳基,可以为苯基、氯(chloro)苯基、甲氧基(methoxy)苯基、二甲基(dimethyl)苯基或烟酰基(nicotinyl),所述“烷基(alkyl)”可以为甲基、乙基、丙基、丁基或戊基,所述“环烷基(cycloalkyl)”可以为环丙基(cyclopropyl)、环丁基(cyclobutyl)、环戊基(cyclopentyl)或环己基(cyclohexyl)。
更具体地,本发明的一实施例的核苷衍生物可以以下述化学式1a-1b、2a-2d、3、4a-4d、5、6、7a-7h、8a-8e、9a-9c、10a-10c、11ai-11aiii、11b、12a-12b、13a-13g和14中的一个表示。
<化学式1至14>
所述本发明的核苷衍生物可以以药学上可接受的盐的形式提供。作为盐,可使用药学上接受的多种有机酸或无机酸形成的酸附加盐。
但并不限于此,本发明的核苷衍生物也可以以通过常规方法制备的所有盐、水合物和溶剂化物的形式提供。
如上所述的本发明的核苷衍生物对如NTRK1、CSNK1D、DYRK1A、DYRK1B和FLT3的磷酸化酶(kinase)具有抑制活性(参照实验例1),由此对与磷酸化酶直接或间接相关的多种癌细胞表现出抑制活性(参照实验例2),因此可包含在能够预防或治疗肺癌(Lungcancer)、结肠癌(Colon cancer)、乳腺癌(Breast cancer)、肝癌(Liver cancer)、胃癌(Stomach cancer)和前列腺癌(Prostate cancer)等各种癌症的药学组合物中。
也就是说,本发明的癌症预防或治疗用药学组合物可包含所述核苷衍生物或其药学上可接受的盐,所述癌症可以为选自由肺癌、结肠癌、乳腺癌、肝癌、胃癌和前列腺癌构成的组中的一种以上,所述核苷衍生物或其药学上可接受的盐可具有磷酸化酶抑制活性。
所述药学组合物可全身或局部给药,为进行给药,也可用可常规使用的填充剂、增重剂、粘合剂、润湿剂、崩解剂、表面活性剂等赋形剂(或稀释剂)制剂化。
所述药学组合物的优选给药量取决于患者的状态和体重、疾病程度、药物形态、给药途径和时间等多数因素,但可由本领域技术人员适当选择。此外,给药途径可能会根据患者状态及其严重程度而变化。
其他实施例的具体事项包括在具体实施方式中。
有益效果
根据本发明的实施例的核苷衍生物或其药学上可接受的盐对如NTRK1、CSNK1D、DYRK1A、DYRK1B和FLT3等磷酸化酶(kinase)具有抑制活性,由此对与磷酸化酶直接或间接相关的多种癌细胞表现出抑制活性,因此可用于预防或治疗肺癌(Lung cancer)、结肠癌(Colon cancer)、乳腺癌(Breast cancer)、肝癌(Liver cancer)、胃癌(Stomach cancer)和前列腺癌(Prostate cancer)等各种癌症。
具体实施方式
本说明书中使用的术语是为了说明实施例,并不是为了限制本发明。在本说明书中,“和/或”包括所提及事项的每一个和一个以上的所有组合。另外,除非在句子中特别提及,否则单数形式还包括复数形式。说明书中使用的“包含(comprises)”和/或“包含的(comprising)”不排除除所提及的构成要素外可存在或添加一个以上的其他构成要素。除非另有说明,使用“-”或者“至”表示的数值范围是指将在其前和后所记载的值分别作为下限和上限包含的数值范围。“约”或“大约”是指在其后所记载的数值或数值范围的20%以内的数值或数值范围。
在本说明书中,“预防”是指,在尚未出现症状或疾病但可能患有这些症状或疾病的个体中抑制症状或疾病的发生。
在本说明书中,“治疗”是指,在个体中,(a)抑制症状或疾病的发展(恶化),(b)减轻或改善症状或疾病,或(c)消除症状或疾病。
在本说明书中,“个体”是指,包括通过施用本发明的组合物而具有“预防”或“治疗”症状或疾病的人类在内的动物,特别是哺乳动物。
在本说明书中,所谓“取代的Cn至Cn+m”的化合物,不仅包括取代部分的化合物的所有碳原子数为n至n+m的情况,还包括除取代部分以外的化合物的碳原子数为n至n+m的情况。
以下,通过制备例和实验例详细说明本发明的实施例,但显然,本发明的效果不受以下实验例的限制。
制备例:本发明的核苷衍生物的制备
制备例1:化合物1a-1b和2a-2d的合成
[反应式1]
制备例1-1:7-(3aR,4R,6R,6aS)-6-(((叔丁基二苯基硅烷基)氧基)甲基)-2,2-二
甲基四氢噻吩并[3,4-d][1,3]二氧杂环戊烯-4-基)-4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶
(化合物16)的合成
在无水乙腈中添加4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶(2.6g,9.33mmol)和双(三甲基硅烷基)乙酰胺(BSA,2.5mL,10.27mmol),并置于氮气置换下搅拌10分钟。在该溶液中添加溶于无水乙腈的化合物15(5g,10.27mmol),并滴加三甲基硅烷基三氟甲烷磺酸盐(1.5mL,8.40mmol),在室温下搅拌15分钟后,在80℃条件下进一步搅拌1小时。确认反应终止后,在室温下用乙酸乙酯(700mL)萃取,分离有机层,用饱和碳酸氢钠水溶液和盐水(brine)洗涤,并用无水硫酸镁干燥。减压过滤除去残余固体,减压浓缩后,通过硅胶柱色谱获得化合物16(2.9g,40%)。
1H NMR(CD3OD,500mHz):δ8.46(s,1H),7.87(s,1H),7.64-7.58(m,4H),7.40-7.33(m,4H),7.31-7.28(m,2H),6.24(d,J=2.2Hz,1H),5.10(dd,J=5.5,2.2Hz,1H),4.96(dd,J=5.5,2.1Hz,1H),3.88(dd,J=10.4,7.2Hz,1H),3.81(dd,J=10.4,7.3Hz,1H),3.75(td,J=7.2,2.1Hz,1H),1.55(s,3H),1.28(s,3H),1.04(s,9H);HRMS(ESI-Q-TOF)m/z[M+H]+(C30H34ClIN3O3SSi):计算值(calculated)706.0818,实测值(found)706.0798。
制备例1-2:7-((3aR,4R,6R,6aS)-6-(((叔丁基二苯基硅烷基)氧基)甲基)-2,2-
二甲基四氢噻吩并[3,4-d][1,3]二氧杂环戊烯-4-基)-5-碘-7H-吡咯并[2,3-d]嘧啶-4-胺
(化合物17)的合成
在不锈钢容器(stainless steel bomb)中将化合物16(2.9g,4.11mmol)溶于NH3/t-BuOH(30mL)后,在90℃下搅拌24小时。反应终止后,在室温下对反应溶液进行减压浓缩,并用硅胶柱色谱分离,从而获得化合物17(2.42g,86%)。
1H NMR(CDCl3,500mHz):δ8.22(s,1H),7.64-7.62(m,4H),7.43-7.40(m,2H),7.37-7.33(m,5H),6.21(d,J=2.7Hz,1H),5.88(brs,2H),4.88(dd,J=5.6,2.8Hz,1H),4.78(dd,J=5.6,2.8Hz,1H),3.86-3.79(m,2H),3.77-3.75(m,1H),1.58(s,3H),1.27(s,3H),1.07(s,9H);HRMS(ESI-Q-TOF)m/z[M+H]+(C30H36IN4O3SSi):计算值687.1317,实测值687.1301。
制备例1-3:7-((3aR,4R,6R,6aS)-6-(((叔丁基二苯基硅烷基)氧基)甲基)-2,2-
二甲基四氢噻吩并[3,4-d][1,3]二氧杂环戊烯-4-基)-5-(呋喃-2-基)-7H-吡咯并[2,3-d]
嘧啶-4-胺和7-((3aR,4R,6R,6aS)-6-(((叔丁基二苯基硅烷基)氧基)甲基)-2,2-二甲基四
氢噻吩并[3,4-d][1,3]二氧杂环戊烯-4-基)-5-(噻吩-2-基)-7H-吡咯并[2,3-d]嘧啶-4-
胺(化合物18a/18b)的合成
公知合成法(A):将化合物17(1当量)溶于四氢呋喃后,添加PdCl2(PPh3)2(15mol%)催化剂,进行5分钟的氮气置换。添加2-(三丁基锡烷基)杂芳基(2.5当量)后,在微波炉中,以70℃搅拌1小时。反应结束后,用水和盐水(brine)终止反应,并用乙酸乙酯萃取。分离有机溶剂层,减压浓缩后,用柱层析分离纯物质。
化合物18a为黄色粘性物质,收率为88%。
1H NMR(CDCl3,400mHz):δ8.27(s,1H),7.64-7.61(m,4H),7.47-7.46(m,1H),7.39-7.36(m,3H),7.33-7.29(m,4H),6.45-6.44(m,1H),6.28-6.27(m,2H),5.98(brs,2H),4.95(dd,J=5.9,3.2Hz,1H),4.82(dd,J=5.9,3.2Hz,1H),3.92-3.82(m,2H),3.79-3.75(m,1H),1.59(s,3H),1.28(s,3H),1.05(s,9H);HRMS(ESI-Q-TOF)m/z[M+H]+(C34H39N4O4SSi):计算值627.2456,实测值627.2463。
化合物18b为无色粘性物质,收率为92%。
1H NMR(CDCl3,400mHz):δ8.28(s,1H),7.62-7.59(m,4H),7.37-7.34(m,3H),7.32-7.27(m,4H),7.23(s,1H),7.10-7.07(m,1H),7.00-6.99(m,1H),6.28(d,J=2.7Hz,1H),5.41(brs,2H),4.94(dd,J=5.5,3.2Hz,1H),4.81(dd,J=5.9,3.2Hz,1H),3.91-3.82(m,2H),3.79-3.74(m,1H),1.59(s,3H),1.28(s,3H),1.03(s,9H);HRMS(ESI-Q-TOF)m/z[M+H]+(C34H39N4O3S2Si):计算值643.2227,实测值643.2218。
制备例1-4:(2R,3R,4S,5R)-2-(4-氨基-5-(呋喃-2-基)-7H-吡咯并[2,3-d]嘧啶-
7-基)-5-(羟甲基)四氢噻吩-3,4-二醇和(2R,3R,4S,5R)-2-(4-氨基-5-(噻吩-2-基)-7H-
吡咯并[2,3-d]嘧啶-7-基)-5-(羟甲基)四氢噻吩-3,4-二醇(化合物1a和1b)的合成
公知合成法(B):将化合物18a/18b溶于四氢呋喃后,滴加50%三氟乙酸水溶液,并搅拌12小时。与弱碱性阳离子交换树脂(66自由基(free base))搅拌1小时中和,减压过滤除去残余固体。减压浓缩后,通过硅胶柱色谱分别以75%、81%的收率获得化合物1a/1b。
制备例1-5:化合物19a-19d的合成
公知合成法(C):在化合物17(1当量)中,添加硼酸盐酯、PdCl2(PPh)3(6mol%)、碳酸钠(2当量),溶于氮取代的二甲基甲酰胺/蒸馏水(0.14M/0.36M)后,在微波炉中,以70℃搅拌1小时。用蒸馏水终止反应后,用乙酸乙酯萃取。分离有机溶剂层后,用蒸馏水和盐水(brine)洗涤,减压浓缩后,通过硅胶柱色谱获得化合物19a-d。
7-((3aR,4R,6R,6aS)-6-(((叔丁基二苯基硅烷基)氧基)甲基)-2,2-二甲基四氢噻吩并[3,4-d][1,3]二氧杂环戊烯-4-基)-5-乙烯基-7H-吡咯并[2,3-d]嘧啶-4-胺(化合物19a)。化合物19a为黄色粘性物质,收率为85%。
1H NMR(CD3OD,400mHz):δ8.03(s,1H),7.64(t,J=9.2Hz,4H),7.42-7.39(m,3H),7.37-7.31(m,4H),6.91(dd,J=17.2,10.8Hz,1H),6.21(s,1H),5.44(d,J=17.6Hz,1H),5.20(d,J=10.8Hz,1H),5.07-5.05(m,1H),4.96-4.95(m,1H),3.93-3.89(m,1H),3.86-3.81(m,1H),3.73-3.69(m,1H),1.55(s,3H),1.29(s,3H),1.04(s,9H);HRMS(ESI-Q-TOF)m/z[M+H]+(C32H39N4O3SSi):计算值587.2507,实测值587.2506。
7-((3aR,4R,6R,6aS)-6-(((叔丁基二苯基硅烷基)氧基)甲基)-2,2-二甲基四氢噻吩并[3,4-d][1,3]二氧杂环戊烯-4-基)-5-苯基-7H-吡咯并[2,3-d]嘧啶-4-胺(化合物19b)。化合物19b为无色粘性物质,收率为91%。
1H NMR(CD3OD,400mHz):δ8.11(s,1H),7.62-7.59(m,4H),7.43-7.41(m,3H),7.39-7.33(m,4H),7.29-7.26(m,4H),7.23(s,1H),6.27(d,J=2.7Hz,1H),5.09(dd,J=5.4,2.7Hz,1H),4.96(dd,J=5.5,2.3Hz,1H),3.92-3.82(m,2H),3.75-3.71(m,1H),1.57(s,3H),1.30(s,3H),1.01(s,9H);HRMS(ESI-Q-TOF)m/z[M+H]+(C36H41N4O3SSi):计算值637.2663,实测值637.2646。
4-(4-(4-氨基-7-((3aR,4R,6R,6aS)-6-(((叔丁基二苯基硅烷基)氧基)甲基)-2,2-二甲基四氢噻吩并[3,4-d][1,3]二氧杂环戊烯-4-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)硫代吗啉1,1-二氧化物(化合物19c)。化合物19c为无色粘性物质,收率为89%。
1H NMR(CDCl3,400mHz):δ8.27(s,1H),7.61-7.59(m,4H),7.40-7.34(m,4H),7.32-7.27(m,4H),7.14(s,1H),6.94-6.92(m,2H),6.31(d,J=3.6Hz,1H),5.28(brs,2H),4.99(dd,J=5.9,3.2Hz,1H),4.82(dd,J=5.9,2.7Hz,1H),3.93-3.86(m,4H),3.84-3.82(m,2H),3.79-3.75(m,1H),3.13-3.11(m,4H),1.60(s,3H),1.29(s,3H),1.03(s,9H);HRMS(ESI-Q-TOF)m/z[M+H]+(C40H48N5O5S2Si):计算值770.2861,实测值770.2865。
N-(4-(4-氨基-7-((3aR,4R,6R,6aS)-6-(((叔丁基二苯基硅烷基)氧基)甲基)-2,2-二甲基四氢噻吩并[3,4-d][1,3]二氧杂环戊烯-4-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)乙磺酰胺(化合物19d)。化合物19d为无色粘性物质,收率为87%。
1H NMR(CDCl3,500mHz):δ8.29(s,1H),7.60-7.59(m,4H),7.39-7.34(m,2H),7.32-7.30(m,4H),7.28-7.27(m,2H),7.25-7.24(m,2H),7.20(s,1H),6.66(brs,1H),6.30(d,J=2.9Hz,1H),5.37(brs,2H),4.97(dd,J=5.6,3.0Hz,1H),4.82(dd,J=5.6,2.7Hz,1H),3.90-3.82(m,2H),3.80-3.78(m,1H),3.15(q,J=14.7,7.3Hz,2H),1.60(s,3H),1.39(t,J=7.3Hz,3H),1.29(s,3H),1.02(s,9H);HRMS(ESI-Q-TOF)m/z[M+H]+(C38H46N5O5S2Si):计算值744.2704,实测值744.2698。
制备例1-6:化合物2a-2d的合成
利用所述公知的合成法(B)分别以78%、81%、80%、80%的收率合成了化合物2a-d。
制备例2:化合物3和4a-4d的合成
[反应式2]
制备例2-1:7-((3aR,4R,6R,6aS)-6-(((叔丁基二苯基硅烷基)氧基)甲基)-2,2-
二甲基四氢噻吩并[3,4-d][1,3]二氧杂环戊烯-4-基)-5-((三甲基硅烷基)乙炔基)-7H-吡
咯并[2,3-d]嘧啶-4-胺(化合物20)的合成
公知合成法(D):在化合物17中,添加碘化亚铜(25mol%)、PdCl2(PPh3)2(10mol%)后,添加二甲基甲酰胺-三乙胺(4:1),然后进行5分钟氮气置换。添加相应的炔烃,在微波炉中,以50℃搅拌1小时。用乙酸乙酯和蒸馏水萃取,分离有机层后,用无水MgSO4干燥,通过减压过滤除去残余固体。减压浓缩滤液,通过硅胶层析获得化合物。
化合物20为粘性物质,收率为93%。
1H NMR(CDCl3,500mHz):δ8.24(s,1H),7.65-7.62(m,4H),7.42-7.39(m,3H),7.37-7.34(m,4H),6.19(d,J=2.6Hz,1H),5.73(brs,2H),4.89(dd,J=5.6,2.6Hz,1H),4.78(dd,J=5.6,2.3Hz,1H),3.87-3.84(m,1H),3.79-3.73(m,2H),1.57(s,3H),1.27(s,3H),1.07(s,9H),0.24(s,9H);HRMS(ESI-Q-TOF)m/z[M+H]+(C35H45N4O3SSi2):计算值657.2745,实测值657.2739。
制备例2-2:((3aS,4R,6R,6aR)-6-(4-氨基-5-乙炔基-7H-吡咯并[2,3-d]嘧啶-7-
基)-2,2-二甲基四氢噻吩并[3,4-d][1,3]二氧杂环戊烯-4-基)甲醇(化合物21)的合成
公知合成法(E):将化合物20(0.58g,0.88mmol)溶于无水四氢呋喃(5.8mL)后,添加1M的四正丁基氟化铵(2.64mL,2.64mmol)。将反应溶液在室温下搅拌40分钟后,用氯化铵终止反应。用乙酸乙酯萃取后,分离有机溶剂层,用蒸馏水和盐水(brine)洗涤后,用无水MgSO4干燥,通过减压过滤除去残余固体。减压浓缩后,通过硅胶层析获得化合物21(0.27g,90%)。
1H NMR(CD3OD,500mHz):δ8.12(s,1H),7.78(s,1H),6.27(d,J=3.0Hz,1H),5.14(dd,J=5.3,3.1Hz,1H),4.97(dd,J=5.4,2.2Hz,1H),3.79-3.74(m,2H),3.73(s,1H),3.71-3.68(m,1H),1.58(s,3H),1.32(s,3H);HRMS(ESI-Q-TOF)m/z[M+H]+(C16H19N4O3S):计算值347.1172,实测值347.1168。
制备例2-3:(2R,3R,4S,5R)-2-(4-氨基-5-乙炔基-7H-吡咯并[2,3-d]嘧啶-7-
基)-5-(羟甲基)四氢噻吩-3,4-二醇(化合物3)的合成
公知合成法(F):将化合物21(0.21g,0.60mmol)溶于无水四氢呋喃后,在低温下滴加2N盐酸水溶液(6mL),并在室温下搅拌15小时。反应终止后,用弱碱性阳离子交换树脂(66自由基(free base))搅拌1小时中和。通过减压过滤除去残余固体后,减压浓缩,通过硅胶层析以白色固体获得化合物3(0.13g,72%)。
制备例2-4:化合物22a-22d的合成
通过所述公知合成法(D)合成化合物22a-d。
7-((3aR,4R,6R,6aS)-6-(((叔丁基二苯基硅烷基)氧基)甲基)-2,2-二甲基四氢噻吩并[3,4-d][1,3]二氧杂环戊烯-4-基)-5-(丙-1-炔-1-基)-7H-吡咯并[2,3-d]嘧啶-4-胺(化合物22a)。化合物22a为粘性物质,收率为96%。
1H NMR(CDCl3,400mHz):δ8.22(s,1H),7.66-7.63(m,4H),7.41-7.40(m,2H),7.38-7.34(m,4H),7.30(s,1H),6.20(d,J=2.8Hz,1H),5.74(brs,2H),4.90(dd,J=5.6,2.8Hz,1H),4.80(dd,J=6.0,5.8Hz,1H),3.88(dd,J=10,6.8Hz,1H),3.82-3.75(m,2H),2.07(s,3H),1.58(s,3H),1.28(s,3H),1.08(s,9H);HRMS(ESI-Q-TOF)m/z[M+H]+(C33H39N4O3SSi):计算值599.2507,实测值599.2512。
5-(丙-1-炔-1-基)-7-((3aR,4R,6R,6aS)-6-(((叔丁基二苯基硅烷基)氧基)甲基)-2,2-二甲基四氢噻吩并[3,4-d][1,3]二氧杂环戊烯-4-基)-7H-吡咯并[2,3-d]嘧啶-4-胺(化合物22b)。化合物22b为粘性物质,收率为91%。
1H NMR(CDCl3,500mHz):δ8.22(s,1H),7.65-7.62(m,4H),7.42-7.39(m,2H),7.37-7.34(m,4H),7.30(s,1H),6.19(d,J=2.7Hz,1H),5.68(brs,2H),4.89(dd,J=5.7,2.8Hz,1H),4.79(dd,J=5.6,2.8Hz,1H),3.87-3.85(m,1H),3.80-3.77(m,1H),3.76-3.74(m,1H),2.43(q,J=14.9,7.5Hz,2H),1.57(s,3H),1.27(s,3H),1.23(t,J=7.5Hz,3H),1.06(s,9H);HRMS(ESI-Q-TOF)m/z[M+H]+(C34H41N4O3SSi):计算值613.2663,实测值613.2669。
7-((3aR,4R,6R,6aS)-6-(((叔丁基二苯基硅烷基)氧基)甲基)-2,2-二甲基四氢噻吩并[3,4-d][1,3]二氧杂环戊烯-4-基)-5-(3,3-二甲基丁-1-炔-1-基)-7H-吡咯并[2,3-d]嘧啶-4-胺(化合物22c)。化合物22c为粘性物质,收率为80%。
1H NMR(CDCl3,500mHz):δ8.21(s,1H),7.64(t,J=6.4Hz,4H),7.42-7.40(m,2H),7.38-7.34(m,4H),7.32(s,1H),6.20(d,J=2.6Hz,1H),5.83(brs,2H),4.88(dd,J=5.6,2.7Hz,1H),4.77(dd,J=5.5,2.5Hz,1H),3.87(dd,J=9.7,6.2Hz,1H),3.79-3.73(m,2H),1.57(s,3H),1.31(s,9H),1.26(s,3H),1.07(s,9H);HRMS(ESI-Q-TOF)m/z[M+H]+(C36H45N4O3SSi):计算值641.2976,实测值641.2991。
7-((3aR,4R,6R,6aS)-6-(((叔丁基二苯基硅烷基)氧基)甲基)-2,2-二甲基四氢噻吩并[3,4-d][1,3]二氧杂环戊烯-4-基)-5-(环丙基乙炔基)-7H-吡咯并[2,3-d]嘧啶-4-胺(化合物22d)。化合物22d为粘性物质,收率为92%。
1H NMR(CDCl3,400mHz):δ8.21(s,1H),7.66-7.63(m,4H),7.44-7.40(m,2H),7.39-7.34(m,4H),7.31(s,1H),6.19(d,J=3.2Hz,1H),5.93(brs,2H),4.88(dd,J=5.9,3.2Hz,1H),4.79(dd,J=5.9,2.7Hz,1H),3.89-3.85(m,1H),3.82-3.73(m,2H),1.58(s,3H),1.49-1.44(m,1H),1.27(s,3H),1.07(s,9H),0.92-0.85(m,2H),0.79-0.75(m,2H);HRMS(ESI-Q-TOF)m/z[M+H]+(C35H41N4O3SSi):计算值625.2663,实测值625.2667。
制备例2-5:化合物4a-4d的合成
通过所述公知合成法(B)分别以83%、86%、82%、86%的收率合成化合物4a-d。
制备例3:化合物5和6的合成
[反应式3]
制备例3-1:4-氨基-7-((3aR,4R,6R,6aS)-6-(((叔丁基二苯基硅烷基)氧基)甲
基)-2,2-二甲基四氢噻吩并[3,4-d][1,3]二氧杂环戊烯-4-基)-7H-吡咯并[2,3-d]嘧啶-
5-碳腈(化合物23)的合成
将化合物17(0.42g,0.62mmol)溶于二甲基甲酰胺(5mL)后,添加氰化锌(0.10g,0.92mmol)、Pd(PPh3)4(0.071g,0.06mmol),在微波炉中,以150℃搅拌15分钟。反应结束后,在室温下减压过滤除去残余固体后,减压浓缩。通过硅胶层析获得化合物23(0.29g,82%)。
1H NMR(CDCl3,400mHz):δ8.36(s,1H),7.78(s,1H),7.66-7.62(m,4H),7.45-7.35(m,6H),6.17(d,J=2.4Hz,1H),4.91(dd,J1=2.4Hz,J2=5.6Hz,1H),4.82(d,J=5.6Hz,1H),3.81(s,3H),1.61(s,3H),1.30(s,3H),1.09(s,9H).HRMS(ESI-Q-TOF)m/z[M+H]+(C31H36N5O3SSi):计算值586.2303,实测值586.2311。
制备例3-2:4-氨基-7-((2R,3R,4S,5R)-3,4-二羟基-5-(羟甲基)四氢噻吩-2-
基)-7H-吡咯并[2,3-d]嘧啶-5-碳腈(化合物5)的合成
将化合物23(0.23g,0.42mmol)溶于四氢呋喃(5mL)后,在0℃条件下添加50%三氟乙酸(5mL)水溶液。在室温下搅拌12小时,待反应完结后与甲苯一起蒸发。通过硅胶柱色谱纯化,获得化合物5(0.078g,65%)。
制备例3-3:4-氨基-7-((3aR,4R,6R,6aS)-6-(((叔丁基二苯基硅烷基)氧基)甲
基)-2,2-二甲基四氢噻吩并[3,4-d][1,3]二氧杂环戊烯-4-基)-7H-吡咯并[2,3-d]嘧啶-
5-甲酰胺(化合物24)的合成
将化合物23(0.25g,0.77mmol)溶于乙醇-蒸馏水中,添加盐酸二甲羟胺(0.18g,1.93mmol)和碳酸钾(0.32g,2.32mmol)环流搅拌20小时。减压过滤所得固体,用甲醇洗涤后干燥。化合物24在合成后未经纯化过程,用于下一反应。
制备例3-4:4-氨基-7-((2R,3R,4S,5R)-3,4-二羟基-5-(羟甲基)四氢噻吩-2-
基)-7H-吡咯并[2,3-d]嘧啶-5-甲酰胺(化合物6)的合成
自化合物24起,利用所述公知合成法(F)合成化合物6(105mg,77%(2步骤))。
下表1和表2为分别整理出以下述化学式I表示的化合物的1H NMR和高分辨质谱法(High resolutionmass spectrometry,HRMS)数据的表。
[化学式I]
[表1]
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[表2]
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制备例4:化合物7a-7h的合成
[反应式4]
制备例4-1:化合物25a-25d的合成
将化合物18a、20、23、24(1当量)分别溶于无水四氢呋喃后,添加4-二甲基氨基吡啶(3当量)和二碳酸二叔丁酯(6当量)。将反应溶液在室温下搅拌12小时后,确认反应终止。减压浓缩后,用蒸馏水和乙酸乙酯萃取,分液有机溶剂层后,用无水MgSO4干燥。通过减压过滤除去残余固体后,减压浓缩,分别获得未经纯化的化合物25a-d。
制备例4-2:化合物26a-26d的合成
利用所述公知合成法(E)合成化合物26a-d。
(叔丁氧羰基)(5-(呋喃-2-基)-7-((3aR,4R,6R,6aS)-6-(羟甲基)-2,2-二甲基四氢噻吩并[3,4-d][1,3]二氧杂环戊烯-4-基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基甲酸叔丁酯(化合物26a)。化合物26a为粘性物质,收率为61%。
1H NMR(CDCl3,400mHz):δ8.84(s,1H),7.67(s,1H),7.42(d,J=1.8Hz,1H),6.46-6.43(m,2H),6.23(d,J=3.6Hz,1H),5.28(dd,J=5.5,3.6Hz,1H),4.98(dd,J=5.5,1.3Hz,1H),4.01(s,2H),3.89(s,2H),1.65(s,3H),1.34(s,3H),1.27(s,18H);HRMS(ESI-Q-TOF)m/z[M+H]+(C28H37N4O8S):计算值589.2327,实测值589.2322。
(叔丁氧羰基)(5-呋喃-7-((3aR,4R,6R,6aS)-6-(羟甲基)-2,2-二甲基四氢噻吩并[3,4-d][1,3]二氧杂环戊烯-4-基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基甲酸叔丁基酯(化合物26b)。化合物26b为粘性物质,收率为90%。
1H NMR(CD3OD,400mHz):δ8.78(s,1H),8.30(s,1H),6.46(d,J=2.8Hz,1H),5.21(dd,J=5.6,3.2Hz,1H),5.02(dd,J=5.2,1.2Hz,1H),3.79-3.74(m,3H),3.67(s,1H),1.61(s,3H),1.34(s,21H);HRMS(ESI-Q-TOF)m/z[M+H]+(C26H35N4O7S):计算值547.2221,实测值547.2214。
化合物26c、26d未经纯化过程,用于下一反应。
制备例4-3:化合物27a-27h的合成
公知合成法(G):将化合物26a-d(1当量)溶于二氯甲烷后,在0℃条件下分别添加4-二甲基氨基吡啶(0.08当量)、三乙胺(2.5当量)、苯甲酰氯(1.1当量)。在室温下搅拌15小时后,确认反应终止。用蒸馏水和用乙酸乙酯萃取反应溶液,分离有机溶剂层后,用无水MgSO4干燥。通过减压过滤除去残余固体后,减压浓缩。用硅胶柱色谱纯化获得化合物。
((3aS,4R,6R,6aR)-6-(4-(双(叔丁氧羰基)氨基)-5-(呋喃-2-基)-7H-吡咯并[2,3-d]嘧啶-7-基)-2,2-二甲基四氢噻吩并[3,4-d][1,3]二氧杂环戊烯-4-基)苯甲酸甲酯(化合物27a)。化合物27a通过化合物26a合成,为粘性物质,收率为75%。
1H NMR(CDCl3,400mHz):δ8.87(s,1H),8.03(dd,J=8.6,1.3Hz,2H),7.74(s,1H),7.58-7.54(m,1H),7.44-7.41(m,2H),7.39-7.38(m,1H),6.44(d,J=2.7Hz,1H),6.42-6.40(m,2H),5.25(dd,J=5.4,2.2Hz,1H),5.04(dd,J=5.4,3.2Hz,1H),4.70(dd,J=11.4,7.3Hz,1H),4.50(dd,J=11.4,6.4Hz,1H),4.02(td,J=6.8,3.2Hz,1H),1.64(s,3H),1.34(s,3H),1.29(s,9H),1.26(s,9H);HRMS(ESI-Q-TOF)m/z[M+H]+(C35H41N4O9S):计算值693.2589,实测值693.2585。
((3aS,4R,6R,6aR)-6-(4-(双(叔丁氧羰基)氨基)-5-乙炔基-7H-吡咯并[2,3-d]嘧啶-7-基)-2,2-二甲基四氢噻吩并[3,4-d][1,3]二氧杂环戊烯-4-基)苯甲酸甲酯(化合物27b)。化合物27b通过化合物26b合成,为无色粘性物质,收率为94%。
1H NMR(CDCl3,500mHz):δ8.86(s,1H),8.04-8.02(m,2H),7.70(s,1H),7.58-7.55(m,1H),7.46-7.43(m,2H),6.34(d,J=2.4Hz,1H),5.21(dd,J=5.6,2.4Hz,1H),5.04(dd,J=5.6,3.3Hz,1H),4.66(dd,J=11.4,7.4Hz,1H),4.51(dd,J=11.4,6.4Hz,1H),4.02-3.99(m,1H),3.14(s,1H),1.63(s,3H),1.38(s,18H),1.33(s,3H);HRMS(ESI-Q-TOF)m/z[M+H]+(C33H39N4O8S):计算值651.2483,实测值651.2485。
((3aS,4R,6R,6aR)-6-(4-(双(叔丁氧羰基)氨基)-5-乙炔基-7H-吡咯并[2,3-d]嘧啶-7-基)-2,2-二甲基四氢噻吩并[3,4-d][1,3]二氧杂环戊烯-4-基)甲基4-氯苯甲酸甲酯(化合物27c)。化合物27c通过化合物26b合成,为粘性物质,收率为78%。
1H NMR(CD3OD,500mHz):δ8.80(s,1H),8.04(s,1H),7.99-7.96(m,2H),7.49-7.48(m,2H),6.44(d,J=2.2Hz,1H),5.44(dd,J=5.5,2.2Hz,1H),5.26(dd,J=5.5,2.7Hz,1H),4.65(dd,J=11.3,7.7Hz,1H),4.45(dd,J=11.3,6.6Hz,1H),4.03-4.0(m,1H),3.66(s,1H),1.60(s,3H),1.35(s,3H),1.33(s,18H);HRMS(ESI-Q-TOF)m/z[M+H]+(C33H38ClN4O8S):计算值685.2093,实测值685.2092。
((3aS,4R,6R,6aR)-6-(4-(双(叔丁氧羰基)氨基)-5-乙炔基-7H-吡咯并[2,3-d]嘧啶-7-基)-2,2-二甲基四氢噻吩并[3,4-d][1,3]二氧杂环戊烯-4-基)甲基4-甲氧基苯甲酸甲酯(化合物27d)。化合物27d通过化合物26b合成,为粘性物质,收率为82%。
1H NMR(CDCl3,500mHz):δ8.85(s,1H),7.98-7.97(m,2H),7.71(s,1H),6.92-6.90(m,2H),6.35(d,J=2.3Hz,1H),5.18(dd,J=5.5,2.4Hz,1H),5.02(dd,J=5.5,3.2Hz,1H),4.63(dd,J=11.4,7.3Hz,1H),4.47(dd,J=11.4,6.4Hz,1H),4.01-3.97(m,1H),3.84(s,3H),3.13(s,1H),1.62(s,3H),1.37(s,18H),1.33(s,3H);HRMS(ESI-Q-TOF)m/z[M+H]+(C34H41N4O9S):计算值681.2589,实测值681.2591。
2,6-二甲基苯甲酸((3aS,4R,6R,6aR)-6-(4-(双(叔丁氧羰基)氨基)-5-乙炔基-7H-吡咯并[2,3-d]嘧啶-7-基)-2,2-二甲基四氢噻吩并[3,4-d][1,3]二氧杂环戊烯-4-基)甲酯(化合物27e)。化合物27e通过化合物26b合成,为粘性物质,收率为84%。
1H NMR(CDCl3,400mHz):δ8.84(s,1H),7.64(s,1H),7.21-7.17(m,1H),7.05-7.02(m,2H),6.33(d,J=3.0Hz,1H),5.18(dd,J=6.1,3.0Hz,1H),5.02(dd,J=5.5,3.0Hz,1H),4.64-4.53(m,2H),3.98(td,J=6.7,3.0Hz,1H),3.15(s,1H),2.32(s,6H),1.62(s,3H),1.38(s,18H),1.31(s,3H);HRMS(ESI-Q-TOF)m/z[M+H]+(C35H43N4O8S):计算值679.2796,实测值679.2791。
((3aS,4R,6R,6aR)-6-(4-(双(叔丁氧羰基)氨基)-5-乙炔基-7H-吡咯并[2,3-d]嘧啶-7-基)-2,2-二甲基四氢噻吩并[3,4-d][1,3]二氧杂环戊烯-4-基)异烟酸甲酯(化合物27f)。化合物27f通过化合物26b合成,且未经纯化过程,用于下一反应。
化合物27g、27h分别通过化合物26c、26d合成,且未经纯化过程,用于下一反应。
制备例4-4:化合物7a-7h的合成
公知合成法(H):在化合物27a-h中添加50%甲酸水溶液和四氢呋喃,在室温下搅拌12小时。确认反应终止后,用碱性阳离子交换树脂(66自由基(free base))搅拌1小时并中和溶液。通过减压过滤除去残余固体后,减压浓缩,用硅胶柱色谱纯化,分别以60%、83%、76%、80%、79%、88%(2步骤)、69%(2步骤)、75%(2步骤)的收率获得化合物7a-h。
制备例5:化合物8a-8e的合成
[反应式5]
制备例5-1:化合物28a-28d的合成
将化合物26a-d(1当量)溶于吡啶(15mL/mmol)后,在0℃条件下边搅拌边滴加甲烷磺酰氯(2当量)。在室温下搅拌4小时后,用饱和碳酸氢钠溶液终止反应。并用乙酸乙酯萃取三遍。用无水MgSO4干燥有机溶剂层后,减压过滤,并且将减压浓缩的残留物,未经纯化过程,用于下一反应。将未经纯化的甲磺酰基化合物溶于二甲基甲酰胺(5.5mL/mmol)后,边搅拌边滴加叠氮化钠(3当量)。将反应溶液在60℃下加热2小时。减压浓缩挥发性物质以使其蒸发,并将残留物分液在乙酸乙酯和水中。有机溶剂层用硫酸镁干燥,减压过滤,减压浓缩,分别获得未经纯化的化合物28a-d。化合物28a-d未经纯化过程,用于下一反应。
制备例5-2:化合物29a-29d的合成
在溶于四氢呋喃(27mL/mmol)的化合物28a-d(1当量)中,添加三苯基膦(2当量)后,在室温下搅拌12小时。在反应溶液中添加25%氨水(1.8mL/mmol)后,在65℃下搅拌4小时。蒸发挥发性物质,且对于未经纯化的化合物29a-d而言,未经纯化过程,用于下一反应。
制备例5-3:化合物30a-30e的合成
化合物30a通过29a,化合物30b和30c通过化合物29b,化合物30d和30e通过化合物29d-e,分别以常规合成方法(G)(化合物30a、30b、30d、30e使用苯甲酰氯,化合物30c使用4-甲氧基苯甲酰氯)合成。未经纯化的化合物30a、30d、30e未经纯化过程用于反应,而化合物30b和30c用硅胶柱色谱纯化。
(7-((3aR,4R,6R,6aS)-6-(苯甲酰氨基)-2,2-二甲基四氢噻吩并[3,4-d][1,3]二氧杂环戊烯-4-基)-5-乙炔基-7H-吡咯并[2,3-d]嘧啶-4-基)(叔丁氧基羰基)氨基甲酸叔丁酯(化合物30b)。化合物30b通过化合物26b经3步骤合成,为粘性物质,收率为46%。
1H NMR(CD3OD,500mHz):δ8.81(s,1H),8.14(s,1H),7.82(d,J=7.3Hz,2H),7.54(合并(merged)dd,J1=J2=7.3Hz,1H),7.46(合并(merged)dd,J1=J2=7.8Hz,2H),6.44(d,J=2.6Hz,1H),5.36(dd,J=5.6,2.7Hz,1H),5.12(dd,J=5.6,2.9Hz,1H),3.93-3.91(m,1H),3.86(dd,J=13.5,8.3Hz,1H),3.68(s,1H),3.62(dd,J=13.5,6.6Hz,1H),1.59(s,3H),1.34(s,18H),1.33(s,3H);HRMS(ESI-Q-TOF)m/z[M+H]+(C33H40N5O7S):计算值650.2643,实测值650.2634。
(叔丁氧基羰基)(5-乙炔基-7-((3aR,4R,6R,6aS)-6-((4-甲氧基苯甲酰胺基)甲基)-2,2-二甲基四氢噻吩并[3,4-d][1,3]二氧杂环戊烯-4-基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基甲酸叔丁酯(化合物30c)。化合物30c通过化合物26b经3步骤合成,为粘性物质,收率为52%。
1H NMR(CDCl3,400mHz):δ8.77(s,1H),7.73(s,1H),7.71(d,J=3.6Hz,2H),6.90(d,J=9.1Hz,2H),6.62(brs,1H),6.29(d,J=3.0Hz,1H),5.20(dd,J=5.5,2.4Hz,1H),4.98(dd,J=5.5,3.0Hz,1H),3.89-3.84(m,2H),3.82(s,3H),3.80-3.75(m,1H),3.16(s,1H),1.59(s,3H),1.38(s,18H),1.30(s,3H);HRMS(ESI-Q-TOF)m/z[M+H]+(C34H42N5O8S):计算值680.2749,实测值680.2739。
制备例5-4:化合物8a-8e的合成
化合物8a-e分别通过化合物30a-e以所述公知合成方法(H)合成,收率分别为81%(4步骤)、65%、70%、71%(4步骤)、68%(4步骤)。
下表3和表4为分别整理出以下述化学式II表示的化合物的1H NMR和高分辨质谱法(High resolutionmass spectrometry,HRMS)数据的表。
[化学式II]
[表3]
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[表4]
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制备例6:化合物9a-9c、10a-10c、11ai-11aiii和11b的合成
[反应式6]
制备例6-1:化合物9a-9c的合成
化合物9a-c分别通过化合物28b-d以所述公知合成方法(H)合成。
制备例6-2:化合物10a-10c的合成
将化合物9a-c(1当量)溶于四氢呋喃(5.6mL/mmol)后,添加三苯基膦(2当量),然后将溶液在室温下搅拌12小时。在反应溶液中添加水,在室温下继续搅拌3小时。蒸发挥发性物质,通过硅胶柱色谱法纯化残留物,分别以63%、65%、59%的收率合成化合物10a-c。
制备例6-3:化合物31a-31c合成
边搅拌在无水四氢呋喃(6.6mL/mmol)中溶解化合物29b-d(1当量)的溶液,边滴加三氯乙酰异氰氧化物(1当量),并将反应溶液在室温下搅拌4小时。用水终止反应后,用乙酸乙酯萃取三遍。干燥有机溶液层后,减压过滤,减压浓缩获得的未经纯化的残留物用于下一反应。向未经纯化的化合物中添加氨饱和的甲醇(5mL/mmol),在室温下搅拌3小时。蒸发挥发性物质后,未经纯化的化合物31a-c用于下一反应。
制备例6-4:化合物11ai-11aiii合成
化合物11ai-aiii分别通过化合物31a-c以所述公知合成方法(H)合成,收率分别为55%、60%、52%(2步骤)。
制备例6-5:(叔丁基羰基)(7-((3aR,4R,6R,6aS)-6-((乙基氨基)甲基)-2,2-二甲
基四氢噻吩并[3,4-d][1,3]二氧杂环戊烯-4-基)-5-乙炔基-7H-吡咯并[2,3-d]嘧啶-4-
基)氨基甲酸叔丁酯(化合物32)的合成
将化合物29b(0.05g,0.09mmol)和乙醛(0.08mL)溶于甲醇(0.35mL)后,滴加硼氢化钠和乙酸(4μL)。将反应溶液在室温下搅拌3小时后,用水终止反应。之后,用乙酸乙酯萃取三遍。有机溶剂层用MgSO4干燥后,通过减压过滤和减压浓缩合成未经纯化的化合物32,且未经纯化过程,用于下一反应。
制备例6-6:(2R,3R,4S,5R)-2-(4-氨基-5-乙炔基-7H-吡咯并[2,3-d]嘧啶-7-
基)-5-((乙基氨基)甲基)四氢噻吩-3,4-二醇(化合物11b)的合成
化合物11b通过化合物32以所述公知合成方法(H)合成,收率为30%(2步骤)。
制备例7:化合物12a和12b的合成
[反应式7]
制备例7-1:(叔丁氧羰基)(7-((3aR,4R,6R,6aS)-2,2-二甲基-6-(吗啉基甲基)四
氢噻吩并[3,4-d][1,3]二氧杂环戊烯-4-基)-5-乙炔基-7H-吡咯并[2,3-d]嘧啶-4-基)氨
基甲酸叔丁酯(化合物33)的合成
在将4-甲苯磺酰氯(0.057g,0.30mmol)溶于四氢呋喃(0.3mL)的溶液中,在0℃下添加溶于四氢呋喃的化合物26b(0.15g,0.27mmol)和三乙胺(0.2mL)。将反应溶液在室温下搅拌4小时,用水终止反应。用乙酸乙酯萃取三遍后,用MgSO4干燥所收集的有机溶剂层,减压过滤,减压浓缩,并且将未经纯化的化合物,未经纯化过程,用于下一反应。将未经纯化的甲苯磺酰化合物溶于异丙醇(0.6mL)后,添加吗啉(0.02g,0.23mmol)后,在70℃下环流12小时。减压过滤后,未经纯化过程,用于下一反应。
制备例7-2:(2R,3R,4S,5R)-2-(4-氨基-5-乙炔基-7H-吡咯并[2,3-d]嘧啶-7-
基)-5-(吗啉基甲基)四氢噻吩-3,4-二醇(化合物12a)的合成
化合物12a通过化合物33以所述公知合成方法(H)合成,收率为20%(2步骤)。
制备例7-3:7-((3aR,4R,6aS)-2,2-二甲基-6-甲基四氢噻吩并[3,4-d][1,3]二氧
杂环戊烯-4-基)-5-乙炔基-7H-吡咯并[2,3-d]嘧啶-4-胺(化合物34)的合成
在将化合物26b(0.15g,0.27mmol)溶于二氯甲烷(2.2mL)的溶液中,添加4-二甲基氨基吡啶(0.0004g,0.003mmol)和三乙胺(0.11mL,0.82mmol),并将溶液冷却至0℃。在该溶液中,滴加甲烷磺酰氯(0.03mL,0.41mmol),并将反应溶液在室温下搅拌1小时。用饱和碳酸氢钠溶液终止反应,并用二氯甲烷萃取三遍。用盐水洗涤所收集的有机溶剂层,用MgSO4干燥后,减压过滤,减压浓缩,获得未经纯化的甲磺酰基化合物。在微波瓶中所含的未经纯化的甲磺酰基化合物中添加四氢呋喃(2.5mL)和40%甲胺水溶液(2mL),在60℃下加热5小时。蒸发挥发性物质,通过硅胶柱色谱纯化残留物,获得化合物34(39.6mg,44%)。
1H NMR(CD3OD,400mHz):δ8.11(s,1H),7.35(s,1H),6.33(s,1H),5.52(s,1H),5.46(合并dd,J1=J2=4.8Hz,1H),5.32(s,1H),4.96(dd,J=4.8,0.8Hz,1H),3.73(s,1H),1.50(s,3H),1.33(s,3H);HRMS(ESI-Q-TOF)m/z[M+H]+(C16H17N4O2S):计算值329.1067,实测值329.1064。
制备例7-4:(2R,3R,4S)-2-(4-氨基-5-乙炔基-7H-吡咯并[2,3-d]嘧啶-7-基)-5-
亚甲基四氢噻吩-3,4-二醇(化合物12b)的合成
化合物12b通过化合物34以所述公知合成方法(H)合成,收率为43%。
下表5和表6为分别整理出以下述化学式III和IV化合物表示的化合物的1HNMR和高分辨质谱法(High resolutionmass spectrometry,HRMS)数据的表。
[化学式III和IV]
[表5]
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[表6]
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制备例8:化合物13a-13g的合成
[反应式8]
制备例8-1:(3aR,4S,6aS)-2,2-二甲基四氢噻吩并[3,4-d][1,3]二氧杂环戊烯-
4-醇(化合物37)的合成
将溶于甲醇/四氢呋喃(30mL,9:1)的化合物36(1g,5.74mmol)中,在0℃下滴加硼氢化钠(0.21g,5.74mmol)后,在相同温度下搅拌30分钟,之后,在室温下搅拌30分钟。用水终止反应后,用乙酸乙酯萃取三遍水溶液层。所收集的有机溶剂层用MgSO4干燥,减压过滤,减压浓缩,合成未经纯化的化合物37。对该化合物进行纯化,以能够直接用于下一反应。
制备例8-2:乙酸(3aR,6aS)-2,2-二甲基四氢噻吩并[3,4-d][1,3]二氧杂环戊烯-
4-基酯(化合物38)的合成
边搅拌在二氯甲烷(54mL)中溶解化合物37(5.45g,30.92mmol)的溶液,边添加三乙胺(21.5mL,154.62mmol)后,在0℃条件下添加无水乙酸(5.8mL,61.85mmol)。将反应溶液在室温下搅拌6小时,用饱和碳酸氢钠溶液终止反应后,用乙酸乙酯萃取三遍。干燥所收集的有机溶剂层,减压过滤,减压浓缩。对该化合物进行纯化,以能够直接用于下一反应。
制备例8-3:4-氯-7-((3aR,4R,6aS)-2,2-二甲基四氢噻吩并[3,4-d][1,3]二氧杂
环戊烯-4-基)-5-碘-7H-吡咯并[2,3-d]嘧啶(化合物39)的合成
在氮气环境下,向正在无水乙腈(90mL)中进行搅拌的4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶(7.5g,27.07mmol),添加N,O-双(三甲基硅烷基)乙酰胺(BSA,7.2mL,29.78mmol),在室温下搅拌10分钟,直至形成均质溶液。在这澄清的溶液中添加溶解有化合物38(6.5g,29.78mmol)的无水乙腈(65mL),之后,滴加三甲基硅烷基三氟甲烷磺酸盐(4.3mL,24.36mmol)。将反应溶液在室温下搅拌15分钟,并转移至预先加热至80℃的条件。在80℃下搅拌1小时后,将反应溶液冷却至室温。并且,用乙酸乙酯稀释。用饱和碳酸氢钠洗涤有机溶剂层,并用MgSO4干燥。然后,减压过滤,减压浓缩,用硅胶柱色谱纯化残留物,获得化合物39(5.28g,45%)。
1H NMR(CD3OD,500mHz):δ8.58(s,1H),7.83(s,1H),6.12(s,1H),5.32(t,J=4.8Hz,1H),5.22(合并dd,J1=J2=5.3Hz,1H),3.70(dd,J=12.9,4.4Hz,1H),3.12(合并dd,J1=J2=13Hz,1H),1.53(s,3H),1.32(s,3H);HRMS(ESI-Q-TOF)m/z[M+H]+(C13H14ClIN3O2S):计算值437.9534,实测值437.9523。
制备例8-4:7-((3aR,4R,6aS)-2,2-二甲基四氢噻吩并[3,4-d][1,3]二氧杂环戊
烯-4-基)-5-碘-7H-吡咯并[2,3-d]嘧啶-4-胺(化合物40)的合成
在氨饱和的叔丁醇(35mL)中溶解化合物39(3.5g,7.99mmol)后,装入不锈钢容器并转移至预先加热至90℃的条件,然后在相同温度下搅拌24小时。将装有反应溶液的不锈钢容器放凉至室温,减压浓缩,蒸发溶剂。用硅胶柱色谱纯化残留物,获得化合物40(2.84g,85%)。
1H NMR(CDCl3,500mHz):δ8.25(s,1H),7.12(s,1H),5.89(s,1H),5.65(brs,2H),5.20-5.19(m,1H),5.15(合并dd,J1=J2=5.4Hz,1H),3.63(dd,J=12.8,4.4Hz,1H),3.15(合并dd,J1=J2=12.8Hz,1H),1.56(s,3H),1.32(s,3H);HRMS(ESI-Q-TOF)m/z[M+H]+(C13H16IN4O2S):计算值419.0033,实测值419.0031。
制备例8-5:化合物41a-41g的合成
化合物41a通过化合物40以所述公知合成方法(D)合成。化合物41ai通过化合物41a以所述公知合成方法(E)合成。化合物41b-c通过化合物40以所述公知合成方法(A)合成。化合物41d-e通过化合物40以所述公知合成方法(C)合成。化合物41f-g通过化合物40以所述公知合成方法(A)合成。化合物41a-41g未经纯化过程,用于下一反应。
制备例8-6:化合物13a-13g的合成
化合物13a-13g通过化合物41ai-41g以所述公知合成方法(F)合成,收率分别为70%、80%、75%、69%、65%、71%、69%(2步骤)。
下表7和表8为分别整理出以下述化学式V表示的化合物的1H NMR和高分辨质谱法(High resolutionmass spectrometry,HRMS)数据的表。
[化学式V]
[表7]
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[表8]
制备例9:化合物14的合成
[反应式9]
制备例9-1:(3aR,6R,6aS)-6-(((叔丁基二苯基硅烷基)氧基)甲基)-2,2-二甲基
四氢噻吩并[3,4-d][1,3]二氧杂环戊烯-4-醇(化合物42)的合成
在溶解有化合物15(1.46g,3.00mmol)的二氯甲烷中添加氨饱和叔丁醇,将反应混合物在室温下搅拌4小时。在减压条件下蒸发所述反应混合物。用硅胶柱色谱纯化所述残留物,获得化合物42(1.22g,91%),为无色糖浆。
1H NMR(CDCl3,400mHz):δ7.71-7.68(m,4H),7.48-7.41(m,6H),5.29-5.26(m,1H),4.83-4.78(m,2H),4.33-4.31(brs,1H),3.90-3.87(m,1H),3.76-3.72(m,1H),3.55-3.53(m,1H).
制备例9-2:7-((3aR,4R,6R,6aS)-6-(((叔丁基二苯基硅烷基)氧基)甲基)-2,2-
二甲基四氢噻吩并[3,4-d][1,3]二氧杂环戊烯-4-基)-2,4-二氯-5-碘-7H-吡咯并[2,3-d]
嘧啶(化合物43)的合成
将无水四氢呋喃(50mL)中的化合物42(1.14g,2.57mmol)、2,6-二氯-7-碘-脱氮腺嘌呤(1.21g,3.86mmol)、三苯基膦(1.35g,5.14mmol)的反应混合物冷却至0℃。在所述反应混合物中添加(E)-偶氮二羧酸二异丙酯(1.04g,5.14mmol),并使反应温度缓慢达到室温。将所述反应混合物在室温下搅拌2小时。用饱和碳酸氢钠水溶液中和后,将所述反应混合物分配至乙酸乙酯和水中,并用乙酸乙酯萃取三遍。用无水MgSO4干燥有机溶剂层,过滤后,使其蒸发。用硅胶柱色谱纯化所述残留物,获得化合物43(780.9mg,41%),为黄色糖浆。
1H NMR(CDCl3,400mHz):δ7.68-7.64(m,4H),7.59(s,1H),7.44-7.35(m,6H),6.27-6.27(m,1H),4.88-4.82(m,2H),3.95-3.83(m,3H),1.62(s,3H),1.30(s,3H),1.09(s,9H)。
制备例9-3:7-((3aR,4R,6R,6aS)-6-(((叔丁基二苯基硅烷基)氧基)甲基)-2,2-
二甲基四氢噻吩并[3,4-d][1,3]二氧杂环戊烯-4-基)-2,4-二氯-5-((三甲基硅烷基)乙炔
基)-7H-吡咯并[2,3-d]嘧啶(化合物44)的合成
将混合有DMF(4mL)和三乙胺(1mL)的混合物放入微波瓶后,添加化合物43(153mg,0.206mmol)、碘化铜(4.52mg,0.041mmol)、四(三苯基膦)钯(14.5mg,0.020mmol),用氮气脱气5分钟。在所述反应混合物中添加三甲基硅烷基乙炔(22.3mg,0.22mmol),再用氮气脱气5分钟。将所述反应混合物分配至乙酸乙酯和水中,并用乙酸乙酯萃取三遍后,用无水MgSO4干燥,过滤后,使其蒸发。将所述残留物用硅胶柱色谱纯化,获得化合物44(60.2mg,53%),为黄色糖浆。
1H NMR(CDCl3,400mHz):δ7.69-7.65(m,5H),7.46-7.36(m,6H),6.27-6.26(m,1H),4.85-4.82(m,2H),3.93-3.83(m,3H),1.62(s,3H),1.30(s,3H),1.10(s,9H),0.27(s,9H).HRMS(FAB)m/z[M+H]+(C35H41Cl2N3O3SSi2):实测值710.1863.
制备例9-4:7-((3aR,4R,6R,6aS)-6-(((叔丁基二苯基)氧)甲基)-2,2-二甲基四
氢噻吩并[3,4-d][1,3]二氧杂环戊烯-4-基)-2-氯-5-((三甲基硅烷基)乙炔基)-7H-吡咯
并[2,3-d]嘧啶-4-胺(化合物45)的合成
将化合物44(72mg,0.101mmol)溶于氨饱和叔丁醇,并将所述反应混合物放入不锈钢容器后,转移至预先加热的100℃条件。将所述反应混合物在同一温度下搅拌15小时。冷却不锈钢容器中所含的所述反应混合物,直至室温,之后在减压条件下使其蒸发。用硅胶柱色谱纯化所述残留物,获得化合物45(49.7mg,71%),为无色糖浆。
1H NMR(CDCl3,400mHz):δ7.69-7.65(m,4H),7.45-7.35(m,6H),7.28(s,1H),6.40(brs,1H),6.19-6.19(m,1H),4.87-4.84(m,2H),3.91-3.76(m,3H),1.59(s,3H),1.29(s,3H),1.09(s,9H),0.25(s,9H).HRMS(FAB)m/z[M+H]+(C35H43ClN4O3SSi2):实测值691.2361.
制备例9-5:((3aS,4R,6R,6aR)-6-(4-氨基-2-氯-5-乙炔基-7H-吡咯[2,3-d]嘧
啶-7-基)-2,2-二甲基四氢噻吩并[3,4-d][1,3]二氧杂环戊烯-4-基)甲醇(化合物46)的合
成
在无水四氢呋喃中的化合物45(50.1mg,0.072mmol)中添加1M的四正丁基氟化铵(0.217mL,0.217mmol)和乙酸(0.217mmol),将所述反应混合物在室温下搅拌2小时。用饱和NH4Cl水溶液中和所述反应混合物后,分配至乙酸乙酯和水中,并用乙酸乙酯萃取三遍。用无水MgSO4干燥有机溶剂层,过滤后蒸发。将所述残留物用硅胶柱色谱纯化,获得化合物46(22.3mg,81%),为黄色糖浆。
1H NMR(CDCl3,400mHz):δ7.30(s,1H),6.29(brs,2H),5.99-5.97(m,1H),5.21-5.19(m,1H),4.96-4.94(m,1H),4.01-3.98(m,1H),3.90-3.84(m,2H),3.26(s,1H),1.60(s,3H),1.31(s,3H);LRMS(ESI)m/z[M+H]+(C16H17ClN4O3S):实测值381.1100。
制备例9-6:(2R,3R,4S,5R)-2-(4-氨基-2-氯-5-乙炔基-7H-吡咯并[2,3-d]嘧啶-
7-基)-5-(羟甲基)四氢噻吩-3,4-二醇(化合物14)的合成
在二氯甲烷中的化合物46(20.0mg,0.052mmol)中,在-78℃条件下滴加1M的三氯化硼(0.078mL,0.078mmol)。将所述反应混合物在同一温度下搅拌1小时。将所述反应混合物用磷酸缓冲溶液(pH 7.4)中和后,分配在二氯甲烷和水中,用二氯甲烷萃取三次。用无水MgSO4干燥有机溶剂层,过滤后,使其蒸发。用硅胶柱色谱纯化所述残留物,获得化合物14(14.8mg,83%),为白色固体。
1H NMR(CDCl3,400mHz):δ7.82(s,1H),6.05-6.03(m,1H),4.45-4.42(m,1H),4.25-4.23(m,1H),3.89-3.80(m,2H),3.73(s,1H),3.52-3.44(m,1H);LRMS(ESI)m/z[M+H]+(C13H13ClN4O3S):实测值341.0800。
实验例1:对磷酸化酶的抑制活性评价
为确认在所述制备例中合成的本发明的核苷衍生物对磷酸化酶(kinase)的抑制活性,确认了对与癌细胞中过表达相关的磷酸化酶即NTRK1(神经营养因子酪氨酸激酶受体1型(Neurotrophic tyrosine kinase receptor type 1)或原肌球蛋白受体激酶A(Tropomyosin receptor kinase A))、CSNK1D(酪蛋白激酶1δ(Casein kinase 1 isoformdelta))、DYRK1A(特异性酪氨酸磷酸化调节激酶1A(Dual specificity tyrosine-phosphorylation-regulated kinase 1A))、DYRK1B(特异性酪氨酸磷酸化调节激酶1B(Dual specificity tyrosine-phosphorylation-regulated kinase 1B))和FLT3(酪氨酸蛋白激酶受体(Receptor-type tyrosine-protein kinase)或fms样酪氨酸激酶3(fmslike tyrosine kinase 3)或簇分化抗原135(cluster of differentiation antigen135)(CD135)或胎肝激酶-2(fetal liver kinase-2)(Flk2))的所述核苷衍生物的抑制活性。
抑制的测定方法如下。大多数磷酸化酶是通过将带有磷酸化酶标记的噬菌体在BL21大肠杆菌中在32℃下孵育直至溶菌,然后离心和过滤产生的。并且,其是使用HEK-293细胞产生的。随后,对DNA进行标记以进行qPCR。在链霉亲和素包被珠上搅拌30分钟生物素标记的底物以制备亲和性树脂,然后用缓冲液冲洗(SeaBlock(Pierce),1% BSA,0.05%吐温20,1mM DTT)非特异性结合的底物。
磷酸化酶试验如下:在室温下,将磷酸化酶、底物、亲和性树脂和溶于二甲基亚砜的受试物一起在缓冲液中(20% SeaBlock,0.17×PBS,0.05%吐温20,6mM DTT)搅拌1小时。随后,用缓冲液(1×PBS,0.05%吐温20)洗涤亲和性底物,然后悬浮在洗脱缓冲液(1×PBS,0.05%吐温20,0.5μM非生物素酰化(non-biotinylated affinity ligand)中搅拌。通过qPCR定量磷酸化酶浓度。
下表9是将1μM的化合物1a至14用每种磷酸化酶处理的结果,(-)表示没有效果;(+)表示弱(weak)的抑制活性;(++)表示中等(moderate)的抑制活性;(+++)表示强(strong)的抑制活性;ND表示没有结果(not determined)。
[表9]
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如上述表9所示,可知本发明的核苷衍生物对如NTRK1、CSNK1D、DYRK1A、DYRK1B和FLT3的磷酸化酶普遍具有优异的抑制活性。
实验例2:对癌细胞的抑制活性评价
为了确认在所述制备例中合成的本发明的核苷衍生物的抗癌活性,测量了对A549(肺癌细胞(Lung cancer cells)、HCT116(结肠癌细胞(Colon cancer cells))、MDA-MB-231(乳腺癌细胞(Breast cancer cells))、SK-Hep-1(肝癌细胞(Liver cancer cells))、SNU638(胃癌细胞(Stomach cancer cells))和PC-3(前列腺癌细胞(Prostate cancercells))癌细胞的IC50。
试验方法如下。将细胞静置一天并设置为第0天的对照组。此外,在细胞中加入受试物后静置3天。随后,用1%乙酸和0.4%磺酰罗丹明B染色。将经染色的细胞干燥并溶解在10mM的三羟甲基氨基甲烷(Tris)(pH 10.0)中。在515nm处测定吸光度,通过以下公式获得细胞分裂程度。以细胞分裂(%)=(平均吸光度受试物-平均吸光度第0天)/(平均吸光度对照组-平均吸光度第0天)x100计算后,利用TableCurve2D v5.01(Systat Software Inc.,San Jose,CA,USA)通过非直线回归分析计算。
其结果如下表10。
[表10]
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如上述表10所示,本发明的核苷衍生物对如A549、HCT116、MDA-MB-231、SK-Hep-1、SNU638和PC-3的癌细胞普遍表现出较低的IC50值,因此,可知可用作能够期待抗癌效果的磷酸化酶抑制剂。
Claims (8)
1.一种核苷衍生物或其药学上可接受的盐,其特征在于,
所述核苷衍生物以下述化学式1表示,
<化学式1>
在所述化学式1中,
X是氧或硫,
R是氢、取代或未取代的C1至C10的烷基、或取代或未取代的C6至C20的芳基或烷基芳基,
R1是取代或未取代的C2至C10的杂芳基、取代或未取代的C2至C8的烯基、取代或未取代的C6至C20的芳基、取代或未取代的C2至C8的炔基、氰基、酰胺基、或羧基,
R2是卤素、取代或未取代的胺基、或取代或未取代的C6至C20的芳基或烷基芳基,
Y是氢、羟基、酯基、烷氧基、芳基、杂芳基、杂环烷基、环烷基、叠氮基、胺基、取代的胺基、尿素、或被酰胺基取代的烷基、或=CZ2,所述Z各自独立地为氢或C2至C8的烷基。
2.根据权利要求1所述的核苷衍生物或其药学上可接受的盐,其特征在于,
所述杂芳基是呋喃基、苯硫基、吡咯基、吡喃基、吡唑基、吡啶基、三唑基、咪唑基、噻唑基、嘧啶基、吡嗪基、哒嗪基、吲哚基、喹啉基或嘌呤基,
所述杂环烷基是四氢呋喃基、硫杂环戊基、吡咯烷基、四氢吡喃基、哌啶基、二氧杂环己基、吗啉基或四氢嘧啶基,
所述芳基是苯基、萘基、蒽基或菲基,所述烷基芳基是苄基,
所述炔基是乙炔基、丙炔基、丁炔基、戊炔基、己炔基、庚炔基、辛炔基、壬炔基或癸炔基,
所述烯基是乙烯基、丙烯基、丁烯基、戊烯基、己烯基、庚烯基、辛烯基、壬烯基或癸烯基,
所述烷基是甲基、乙基、丙基、丁基或戊基。
3.根据权利要求1所述的核苷衍生物或其药学上可接受的盐,其特征在于,
R1是呋喃基、苯硫基、乙烯基、苯基、硫代吗啉基苯基、硫代吗啉基二氧苯基、磺酰胺基苯基、乙磺酰胺基苯基、乙炔基、丙炔基、丁炔基、二甲基丁炔基、环丙基乙炔基、氰基、酰胺基或羧基,
R2是氯(Cl)或胺基(-NH2)。
4.根据权利要求1所述的核苷衍生物或其药学上可接受的盐,其特征在于,
Y是氢、-CH2OH、-CH2OCOAr、-CH2N3、-CH2NH2、-CH2NHCOAr、-CH2NHCONH2、-CH2N-烷基、-CH2N-环烷基,-CH2N(CH2CH2)2O或=CH2,
所述“Ar”是苯基、氯苯基、甲氧基苯基、二甲基苯基或烟酰基,所述“烷基”是甲基、乙基、丙基、丁基或戊基,所述“环烷基”是环丙基,环丁基、环戊基或环己基。
5.根据权利要求1所述的核苷衍生物或其药学上可接受的盐,其特征在于,
所述化学式1是下述化学式1a-1b、2a-2d、3、4a-4d、5、6、7a-7h、8a-8e、9a-9c、10a-10c、11ai-11aiii、11b、12a-12b、13a-13g和14中的一个,
<化学式1至14>
6.一种用于预防或治疗癌症的药学组合物,其特征在于,
包含根据权利要求1至5中的任一项所述的核苷衍生物或其药学上可接受的盐。
7.根据权利要求6所述的用于预防或治疗癌症的药学组合物,其特征在于,
所述癌症为选自由肺癌、结肠癌、乳腺癌、肝癌、胃癌和前列腺癌构成的组中的一种以上。
8.根据权利要求6所述的用于预防或治疗癌症的药学组合物,其特征在于,
所述核苷衍生物或其药学上可接受的盐具有磷酸化酶抑制活性。
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