CN102245614A - 噻吩并[2,3-d]嘧啶的亚甲基胺以及它们作为腺苷A2a受体拮抗剂的用途 - Google Patents
噻吩并[2,3-d]嘧啶的亚甲基胺以及它们作为腺苷A2a受体拮抗剂的用途 Download PDFInfo
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- CN102245614A CN102245614A CN2009801513045A CN200980151304A CN102245614A CN 102245614 A CN102245614 A CN 102245614A CN 2009801513045 A CN2009801513045 A CN 2009801513045A CN 200980151304 A CN200980151304 A CN 200980151304A CN 102245614 A CN102245614 A CN 102245614A
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- Prior art keywords
- alkyl
- thieno
- pyrimidine
- phenyl
- base
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- -1 Methylene amines Chemical class 0.000 title claims description 36
- DDWBRNXDKNIQDY-UHFFFAOYSA-N thieno[2,3-d]pyrimidine Chemical compound N1=CN=C2SC=CC2=C1 DDWBRNXDKNIQDY-UHFFFAOYSA-N 0.000 title abstract description 3
- 239000002467 adenosine A2a receptor antagonist Substances 0.000 title description 3
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- 125000000217 alkyl group Chemical group 0.000 claims description 77
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 claims description 42
- 238000000034 method Methods 0.000 claims description 38
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 34
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 22
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- 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
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Abstract
本发明涉及一种新的式A噻吩并[2,3-d]嘧啶及其治疗和预防用途,其中R1和R2在说明书中进行了定义。所治疗和/或预防的障碍包括帕金森氏病。
Description
相关专利申请的交叉引用
本专利申请要求于2008年10月13日提交的美国临时专利申请No.61/104,781的权益。藉此为了所有目的将上述相关专利申请的全部公开内容以引用的方式并入本文。
技术领域
本申请涉及新的芳基茚并嘧啶及其治疗和预防用途。所治疗和/或预防的疾病包括可通过拮抗腺苷A2a受体来改善的神经退行性障碍和运动障碍。
背景技术
腺苷A2a受体腺苷是由机体内的所有代谢活性细胞产生的嘌呤核苷酸。腺苷通过四种细胞表面受体亚型(A1、A2a、A2b和A3)发挥其作用,这些亚型属于G蛋白偶联受体超家族(Stiles,G.L.Journal ofBiological Chemistry,1992,267,6451)。A1和A3偶联成抑制型G蛋白,而A2a和A2b偶联成激动型G蛋白。A2a受体主要存在于脑中,在神经元和神经胶质细胞中均有发现(在纹状体和伏隔核中水平最高,于嗅结节、下丘脑和海马等区域中为中等水平至高水平)(Rosin,D.L.;Robeva,A.;Woodard,R.L.;Guyenet,P.G.;Linden,J.Journal ofComparative Neurology,1998,401,163)。
在外周组织中,A2a受体见于血小板、嗜中性粒细胞、血管平滑肌和内皮中(Gessi,S.;Varani,K.;Merighi,S.;Ongini,E.;Bores,P.A.British Journal of Pharmacology,2000,129,2)。纹状体是调节运动活动(特别是通过其起源于黑质的多巴胺能神经元发出的神经支配)的主要脑部区域。纹状体是帕金森氏病(PD)患者中多巴胺能神经元变性的主要靶标。在纹状体内,A2a受体与多巴胺D2受体共区域,从而暗示了脑中腺苷整合和多巴胺信号传导的重要部位(Fink,J.S.;Weaver,D.Ri;Rivkees,S.A.;Peterfreund,R.A.;Pollack,A.E.;Adler,E.M.;Reppert,S.M.Brain Research Molecular Brain Research,1992,14,186)。
神经化学研究已表明,A2a受体的活化可降低D2激动剂对其受体的结合亲和力。这种D2R与A2aR的受体-受体相互作用已在大鼠的纹状体膜制备物(Ferre,S.;con Euler,G.;Johansson,B.;Fredholm,B.B.;Fuxe,K.Proceedings of the National Academy of Sciences I of theUnited States of America,1991,88,7238)中以及在用A2aR和D2RcDNA转染的成纤维细胞系(Salim,H.;Ferre,S.;Dalal,A.;Peterfreund,R.A.;Fuxe,K.;Vincent,J.D.;Lledo,P.M.Journal of Neurochemistty,2000,74,432)中得以阐明。在体内,用A2a拮抗剂药理学阻断A2a受体可在包括小鼠、大鼠和猴在内的多种物种中导致多巴胺能神经毒素MPTP(1-甲基-4-苯基-1,2,3,6-四氢吡啶)诱导的PC中产生有益作用(Ikeda,K.;Kurokawa,M.;Aoyana,S.;Kuwana,Y.Journal ofNeurochemistry,2002,80,262)。
此外,已发现基因阻断A2a功能的A2a敲除小鼠在其暴露于神经毒素MPTP时对运动障碍和神经化学变化不大敏感(Chen,J.F.;Xu,K.;I Petzer,J.P.;Steal,R.;Xu,Y.H.;Beilstein,M.;Sonsalla,P.K.;Castagnoi,K.;Castagnoli,N.,Jr.;Schwarsschild,M.A.Journal ofNeuroscience,2001,121,RC1 43)。
在人类中,已发现腺苷受体拮抗剂茶碱在PD患者中产生有益效果(Mally,J.;Stone,T.W.Journal of the Neurological Sciences,1995,132,129)。与此相一致,最近的流行病学研究已表明,高咖啡因消耗使人不太容易患PD(Ascherio,A.;Zhang,S.M.;Hernan,M.A.;Kawachi,I.;Colditz,G.A.;Speizer,F.E.;Willett,W.C.Annals of Neurology,2001,50,56)。概括地说,腺苷A2a受体阻滞剂可提供一类新的抗震颤麻痹药剂(Impagnatiello,F.;Bastia,E.;Ongini,E.;Monopoli,A.EmergingTherapeutic Targets,2000,4,635)。
A2A受体拮抗剂是用于治疗成瘾的特别有用的疗法。滥用的主要药物(阿片制剂、可卡因、酒精等)可直接或间接调节神经元(特别是含有高水平的A2A腺苷受体的伏隔核中存在的那些)中的多巴胺信号传导。已经显示腺苷信号传导途径可增强依赖性,并且还显示施用A2A受体拮抗剂可减少对成瘾性物质的嗜欲(Ivan Diamond和Lina Yao的“The Critical Role of Adenosine A2A Receptors and Gi βγSubunits inAlcoholism and Addiction;From Cell Biology to Behavior”(The CellBiology of Addiction,2006,第291-316页)以及Stephen P.Hack和Macdonald J.Christie的“Adaptations in Adenosine Signaling in DrugDependence:Therapeutic Implications”,Neurobiology,第15卷,235-274(2003))。还可参见Alcoholism:Clinical and Experimental Research(2007),31(8),1302-1307。
A2A受体拮抗剂可用于治疗注意力缺陷多动障碍(ADHD),因为咖啡因(一种非选择性腺苷拮抗剂)可用于治疗ADHD,并且多巴胺和腺苷神经元之间存在许多相互作用。Clinical Genetics(2000),58(1),31-40以及其中的参考文献。
A2A受体拮抗剂是用于治疗抑郁症的特别有用的疗法。A2A拮抗剂已知可在多种抑郁症模型(包括强迫游泳试验和大鼠悬尾实验)中诱导活跃性。该阳性响应由多巴胺能性传递所介导并且由逃生引导的行为延长引起而不是由运动刺激效果引起。Neurology(2003),61(增刊6)S82-S87。
A2A受体拮抗剂是用于治疗焦虑症的特别有用的疗法。A2A拮抗剂已显示可抑制体内情绪/焦虑反应。Neurobiology of Disease(2007),28(2)197-205。
发明内容
本发明包括式A化合物以及其溶剂化物、水合物和可药用盐,
其中:
R1是环丙基、苯并[1,3]二氧杂环戊烯基,或者R1是苯基,其中所述苯基任选用最多三个独立地选自F、Cl、Br和OCH3的取代基或单个选自如下的取代基取代:OH、OCH2CF3、OC(1-4)烷基、C(1-4)烷基、CHF2、OCF3、CF3和CN;或者R1是任选用一个选自如下的取代基取代的杂芳基:OH,OC(1-4)烷基、CF3、OCF3、Cl、Br、-CN、F、CHF2和C(1-4)烷基;
A1是H或-C(1-4)烷基;
A2是-C(1-4)烷基、-C(1-6)环烷基、-CH2CH2ORa、-CORa、杂芳基、金刚烷基或苯基,其中所述杂芳基或苯基任选用最多三个选自Cl、F、Br、OC(1-4)烷基、OCF3、C(1-4)烷基和和所述C(O)C(1-4)烷基的取代基取代;作为另一种选择,A1和A2可与它们连接的氮合在一起形成选自如下的杂环:
其中:
n为1或2;
Ra是H、CF3、OH、F或C(1-4)烷基;
Rb是H、-C(1-4)烷基或-C(O)C(1-4)烷基;并且
Rc是H或F。
具体实施方式
本发明包括式A化合物以及其溶剂化物、水合物和可药用盐
其中:
R1是环丙基、苯并[1,3]二氧杂环戊烯基,或者R1是苯基,其中所述苯基任选用最多三个独立地选自F、Cl、Br和OCH3的取代基或单个选自如下的取代基取代:OH、OCH2CF3、OC(1-4)烷基、C(1-4)烷基、CHF2、OCF3、CF3和CN;或者R1是任选用一个选自如下的取代基取代的杂芳基:OH,OC(1-4)烷基、CF3、OCF3、Cl、Br、-CN、F、CHF2和C(1-4)烷基;
A1是H或-C(1-4)烷基;
A2是-C(1-4)烷基、-C(1-6)环烷基、-CH2CH2ORa、-CORa、杂芳基、金刚烷基或苯基,其中所述杂芳基或苯基任选用最多三个选自Cl、F、Br、OC(1-4)烷基、OCF3、C(1-4)烷基和C(O)C(1-4)烷基的取代基取代;
作为另一种选择,A1和A2可与它们连接的氮合在一起形成选自如下的杂环:
其中:
n为1或2;
Ra是H、CF3、OH、F或C(1-4)烷基;
Rb是H、-C(1-4)烷基或-C(O)C(1-4)烷基;并且
Rc是H或F。
在本发明的另一个实施例中:
R1是环丙基、呋喃基、噻唑基、噻吩基(thiophenyl)、唑基、异唑基、吡啶基、苯并[1,3]二氧杂环戊烯基、吡咯基、苯并呋喃基、氟代苯基或苯基,其中所述呋喃基、噻唑基、噻吩基、唑基、异唑基、吡啶基、苯并[1,3]二氧杂环戊烯基、吡咯基、苯并呋喃基或苯基任选用OH、OC(1-4)烷基、Cl、Br、-CN、F、CHF2、OCF3、C(1-4)烷基或环丙基取代;
A1是H或-C(1-4)烷基;
A2是-C(1-4)烷基、-C(1-6)环烷基、-CH2CH2ORa、-CORa、杂芳基、金刚烷基或苯基,其中所述杂芳基或苯基任选用最多三个选自Cl、F、Br、OC(1-4)烷基、OCF3、C(1-4)烷基和C(O)C(1-4)烷基的取代基取代;
作为另一种选择,A1和A2可与它们连接的氮合在一起形成选自如下的杂环:
其中:
n为1或2;
Ra是H、CF3、OH、F或C(1-4)烷基;
Rb是H、-C(1-4)烷基或-C(O)C(1-4)烷基;并且
Rc是H或F;
以及其溶剂化物、水合物和可药用盐。
在本发明的另一个实施例中:
R1是环丙基、呋喃基、噻唑基、噻吩基、唑基、异唑基、吡啶基、苯并[1,3]二氧杂环戊烯基、吡咯基、苯并呋喃基、氟代苯基或苯基,其中所述呋喃基、噻唑基、噻吩基、唑基、异唑基、吡啶基、苯并[1,3]二氧杂环戊烯基、吡咯基、苯并呋喃基或苯基任选用OH、OC(1-4)烷基、C1、Br、-CN、F、CHF2、OCF3、C(1-4)烷基或环丙基取代;
A1是H或-C(1-4)烷基;
A2是-C(1-4)烷基、-C(1-6)环烷基、-CH2CH2ORa、-CORa、吡啶基、金刚烷基或苯基,其中所述杂芳基或苯基任选用最多三个选自Cl、F、Br、OC(1-4)烷基、OCF3、C(1-4)烷基和C(O)C(1-4)烷基的取代基取代;
作为另一种选择,A1和A2可与它们连接的氮合在一起形成选自如下的杂环:
其中:
n是1或2
Ra是H、CF3、OH、F或C(1-4)烷基;
Rb是H、-C(1-4)烷基或-C(O)C(1-4)烷基;并且
Rc是H或F;
以及其溶剂化物、水合物和可药用盐。
在本发明的另一个实施例中:
R1是环丙基、呋喃基、噻唑基、噻吩基、唑基、异唑基、吡啶基、苯并[1,3]二氧杂环戊烯基、吡咯基、苯并呋喃基、氟代苯基或苯基,其中所述呋喃基、噻唑基、噻吩基、唑基、异唑基、吡啶基、苯并[1,3]二氧杂环戊烯基、吡咯基、苯并呋喃基、氟代苯基或苯基任选用OH、OCH3、Cl、Br、-CN、F、CHF2、OCF3、CH3、CH2CH3、CH(CH3)2、C(CH3)3或环丙基取代;
A1是H或C(1-4)烷基;
A2是C(1-4)烷基、-CH2CH2OCH3、环丙基、金刚烷基或环己基;
作为另一种选择,A1和A2可与它们连接的氮合在一起形成选自如下的杂环:
其中n是1或2;
以及其溶剂化物、水合物和可药用盐。
在本发明的另一个实施例中:
R1是环丙基、呋喃基(其中所述呋喃基任选用Cl、Br、环丙基、CH3、CH2CH3、CHF2或CH(CH3)2取代)、噻唑基(其中所述噻唑基任选用CH3取代)、噻吩基(其中所述噻吩基任选用C(CH3)3或-CN取代)、唑基、异唑基、吡啶基(其中所述吡啶基用-CN或Cl取代)、苯并[1,3]二氧杂环戊烯基、吡咯基(其中所述吡咯基任选用CH3取代)、苯并呋喃基、氟代苯基(其中所述氟代苯基任选用F取代)或苯基(其中所述苯基任选用CN、Cl、OCH3、CON(CH3)2、CH(CH3)2或OH取代);
A1是H、-CH3或-CH2CH3;
A2是-CH3、-CH2CH3、-CH2CH2OCH3、环丙基、金刚烷基或环己基;
作为另一种选择,A1和A2可与它们连接的氮合在一起形成选自如下的杂环:
其中n是1或2;
以及其溶剂化物、水合物和可药用盐。
本发明的另一个实施例包含选自如下的化合物以及它们的溶剂化物、水合物和可药用盐:
本发明还提供了治疗患有可通过拮抗腺苷A2a受体来改善的病症的受试者的方法,该方法包括给该受试者施用治疗有效剂量的式A化合物。
本发明还提供了预防受试者中可通过拮抗腺苷A2a受体来改善的障碍的方法,该方法包括在预计会引起可通过拮抗该受试者中的腺苷A2a受体来改善的障碍的事件之前或之后,给该受试者施用预防有效剂量的根据权利要求1所述的化合物。
可分离式A化合物并作为游离碱使用。它们也可作为可药用盐分离和使用。
这类盐的例子包括氢溴酸盐、氢碘酸盐、盐酸盐、高氯酸盐、硫酸盐、马来酸盐、富马酸盐、苹果酸盐、酒石酸盐、柠檬酸盐、己二酸盐、苯甲酸盐、扁桃酸盐、甲磺酸盐、羟乙磺酸盐、苯磺酸盐、草酸盐、棕榈酸盐(palmoic)、2-萘磺酸盐、对甲苯磺酸盐、环己烷氨基磺酸盐和葡糖二酸盐。
本发明还提供了包含式A化合物和可药用载体的药物组合物。
可药用载体是本领域技术人员所熟知的,包括但不限于约0.01至约0.1M,优选0.05M的磷酸盐缓冲液或0.8%的盐水。这种可药用载体可以是水性或非水性溶液、悬浮液或乳液。非水性溶剂的例子为丙二醇、聚乙二醇、诸如橄榄油之类的植物油和诸如油酸乙酯之类的注射用有机酯。水性载体包括水、乙醇、醇/水溶液、甘油、包括盐水和缓冲介质的乳液或悬浮液。口服载体可以是酏剂、糖浆剂、胶囊剂、片剂等。典型的固体载体是惰性物质,如乳糖、淀粉、葡萄糖、甲基纤维素、硬脂酸镁、磷酸二钙、甘露醇等。胃肠外用载体包括氯化钠溶液、林格氏葡萄糖、葡萄糖和氯化钠、乳酸林格氏溶液和不挥发油。静脉内用载体包括流体和营养补充物、电解质补充物,如基于林格氏葡萄糖的那些等等。
还可存在防腐剂和其它添加剂,如抗微生物剂、抗氧化剂、螫合剂、惰性气体等。可采用本领域已知的常规技术,根据需要将所有载体与崩解剂、稀释剂、制粒剂、润滑剂、粘合剂等混合。
本发明还提供了治疗患有可通过拮抗腺苷A2a受体来改善的病症的受试者的方法,该方法包括给该受试者施用治疗有效剂量的式A化合物。
在一个实施例中,所述障碍为神经变性障碍或运动障碍。可用本发明药物组合物治疗的障碍的例子包括但不限于帕金森氏病、亨廷顿舞蹈病、多系统萎缩、皮质基底节变性、阿耳茨海默氏病和老年性痴呆。
在一个优选实施例中,所述障碍是帕金森氏病。
如本文所用的,术语“受试者”包括但不限于患有可通过拮抗腺苷A2a受体来改善的障碍的任何动物或经人工修饰的动物。在一个优选的实施例中,受试者是人。
可使用本领域技术人员已知的多种方法中的任一种来实现或实施本发明药物组合物的施用。式A化合物可例如经静脉内、肌内、口服或皮下施用。在一个优选的实施例中,本发明的药物组合物通过口服施用。另外,施用可包括在一段合适的时间周期内将多次剂量给予受试者。这样的给药方案可根据常规方法来确定。
本文所用的药物组合物的“治疗有效剂量”是足以停止、逆转或减缓疾病进程的量。药物组合物的“预防有效剂量”是足以预防疾病,即消除、改善和/或延缓疾病发作的量。用于确定本发明药物组合物的治疗和预防有效剂量的方法是本领域已知的。例如可根据动物实验的结果用数学方法来确定给人施用药物组合物的有效剂量。
在一个实施方案中,所述治疗和/或预防有效剂量是足以递送约0.001mg/kg体重至约200mg/kg体重的式A化合物的剂量。在另一个实施例中,治疗和/或预防有效剂量是足以递送约0.05mg/kg体重至约50mg/kg体重的剂量。更具体地讲,在一个实施例中,口服剂量在每日约0.05mg/kg至约100mg/kg的范围内。在另一个实施例中,口服剂量在每日约0.05mg/kg至约50mg/kg的范围内,并且在进一步的实施例中,在每日约0.05mg/kg至约20mg/kg的范围内。在又一个实施例中,输注剂量的范围为在约数分钟至约数日的周期内约1.0ug/kg/min至约10mg/kg/min的与可药用载体混合的抑制剂。在另一个实施例中,对于局部给药而言,本发明的化合物可与药用载体以约0.001至约0.1的药物/载体比混合。
本发明还提供了在哺乳动物中治疗成瘾的方法,包括施用治疗有效剂量的式A化合物。
本发明还提供了在哺乳动物中治疗ADHD的方法,包括施用治疗有效剂量的式A化合物。
本发明还提供了在哺乳动物中治疗抑郁症的方法,包括施用治疗有效剂量的式A化合物。
本发明还提供了在哺乳动物中治疗焦虑症的方法,包括施用治疗有效剂量的式A化合物。
定义:
术语“Ca-b”(其中a和b是整数,指碳原子的指定数目)指烷基、烯基、炔基、烷氧基或环烷基或指其中烷基作为含有a至b(包括a和b)个碳原子的前缀词根的基的烷基部分。例如,C1-4表示含有1、2、3或4个碳原子的基。
无论是单独使用还是作为取代基的部分使用,术语“烷基”均指饱和的支链或直链单价烃基,其中所述基通过从单个碳原子移除一个氢原子衍生而来。除非具体指出(例如,通过使用诸如“末端碳原子”之类的限制性术语指出),否则取代基变量可处于任何碳原子上。典型的烷基包括但不限于甲基、乙基、丙基、异丙基等等。例子包括C1-8烷基、C1-6烷基和C1-4烷基。
术语“杂芳基”指通过从杂芳环系的环碳原子移除一个氢原子衍生而来的基。典型的杂芳基包括呋喃基、吡咯基、唑基、噻吩基、噻唑基、咪唑基、吡唑基、异唑基、异噻唑基、二唑基、三唑基、噻二唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基、吲嗪基、吲哚基、异吲哚基、吲唑基、苯并咪唑基、苯并噻唑基、嘌呤基、4H-喹嗪基、喹啉基、异喹啉基、噌啉基、酞嗪基、喹唑啉基、喹啉、1,8-萘啶基和蝶啶基等等。
术语“杂环基”指通过从饱和的或部分饱和的杂芳环系的环碳原子或环氮原子移除一个氢原子衍生而来的基。典型的杂环基包括吗啉基、哌啶基、哌嗪基、吡咯烷基和四氢呋喃基等等。
术语“氧代基”指亚甲基可用的取代,其中两个C-H均已被与相同氧相连的键替换。例如,丙酮是氧代基取代的丙烷。
缩写:
在本专利申请说明书以及整个专利申请中,使用了如下缩写。
本发明在其范围内包括本发明化合物的前药。通常,此类前药为化合物的官能化衍生物,其可以在体内容易地转化为所需的化合物。因此,在本发明的治疗方法中,术语“施用”应涵盖使用具体描述的化合物或未具体描述的化合物来治疗多种疾病,而该未具体描述的化合物可在施用给患者后,在体内转化为具体描述的化合物。例如,在“Design of Prodrugs”,H.Bundgaard(编辑),Elsevier,1985中描述了用于选择和制备合适的前药衍生物的常规程序。
如果根据本发明的化合物具有至少一个手性中心,则它们可因此作为对映体存在。如果化合物具有两个或更多个手性中心,则它们可另外还作为非对映体存在。应当理解,所有的这类异构体及其混合物涵盖在本发明的范围内。
如果用于制备根据本发明的化合物的方法产生立体异构体的混合物,则这些异构体可以通过诸如制备色谱之类的常规技术分离。化合物可制备为外消旋形式,或者单独的对映体可通过对映体特异性合成或通过拆分制备。例如,可通过标准的技术将化合物拆分成它们的对映体组分,例如通过用旋光活性酸如(-)-二对甲苯酰基-D-酒石酸和/或(+)-二对甲苯酰基-L-酒石酸成盐而形成非对映体对,然后进行分级结晶和游离碱再生。也可通过形成非对映体酯或酰胺,然后进行色谱分离并移除手性助剂而拆分化合物。作为另一种选择,可用手性HPLC柱拆分化合物。
在制备本发明化合物的任何方法中,可能必需和/或期望保护任何所关注分子上的敏感基团或反应性基团。这可通过常规的保护基来实现,如下列文献中描述的保护基:Protective Groups in Organic Chemistry,J.F.W.McOmie(编辑),Plenum Press,1973和T.W.Greene& P.G.M.Wuts,Protective Groups in Organic Synthesis,John Wiley &Sons,1991。可使用本领域已知的方法在方便的后续阶段移除保护基团。
一般方案:
式A化合物可通过本领域技术人员已知的方法制备。下面的反应方案仅意在给出本发明的实例并且绝不意在限制本发明。
步骤
方案1示出了得到式A化合物的合成路线(路线1和2)。以2-氨基-5-甲基-噻吩-3-甲腈I开始,在碱性条件下与R1-CN(其中R1是如式A中所定义的)缩合,得到氨基嘧啶II。按照路线1,使氨基嘧啶II与二碳酸二叔丁酯[(Boc)2O]在存在4-二甲基氨基吡啶(DMAP)的情况下反应,以得到对应的受保护的胺III。使用1,3-二溴-5,5-二甲基乙内酰脲(DBDMH),甲基噻吩III可经历自由基溴化,然后用三氟乙酸(TFA)去保护而得到溴化物IV。使用A1A2NH(其中A1和A2是如式A中所定义的)完成溴的置换,得到式A化合物。作为另一种选择,按照路线2,氨基嘧啶II可与二氧化硒(SeO2)反应而得到对应的醛V,使用A1A2NH(其中A1和A2是如式A中所定义的)该醛则可经历还原氨化,得到式A化合物。
方案2
方案2示出了获得其中R1=5-氯-呋喃-2-基的式A化合物的合成路线(路线1和2)。按照路线1,以氨基嘧啶VI(如方案1中所述,使2-氨基-5-甲基-噻吩-3-甲腈I与2-糠腈缩合而获得)开始,与N-氯代琥珀酰亚胺(NCS)反应以得到氯代呋喃VII。使氯代呋喃VII与(Boc)2O在存在DMAP的情况下反应而得到对应的受保护的胺VIII。以与方案1中所述相同的方式使化合物VIII溴化、去保护并烷基化而得到其中R1=5-氯-呋喃-2-基的式A化合物。作为另一种选择,按照路线2,氨基嘧啶VI可与二氧化硒(SeO2)反应而得到对应的醛IX,然后使其与NCS反应以得到氯化物X,如方案1所述使用A1A2NH,该氯化物则可经历还原氨化而得到其中R1=5-氯-呋喃-2-基的式A化合物。
方案3
方案3示出了式R1-CN化合物(其中R1是C(1-4)烷基取代的呋喃)的合成路线。方案3还示出了可将任何R1-CO2CH3转化为R1-CN的方式。可使溴代呋喃XI与烷基锌试剂在存在钯催化剂的情况下反应以得到XII。使酯XII(或任何R1-CO2CH3)与氢氧化铵反应而得到对应的酰胺XIII。在吡啶中用POCl3完成该酰胺的脱水,得到所需的杂环腈R1-CN。
方案4
方案5示出了得到式A化合物的合成路线(路线1和2)。以2-氨基-3-氰基噻吩XIV开始,按照箭头所指的路线1,在碱性条件下与R1-CN(其中R1是如式A中所定义的)缩合得到氨基嘧啶XV。然后使氨基嘧啶XV与N-溴代琥珀酰亚胺(NBS)反应,得到溴代噻吩XVI。按照路线1,在钯催化下与乙烯基硼酸二丁酯偶联得到对应的乙烯基加合物XVII。可将XVII中存在的烯烃用AD-混合物二羟基化以得到二醇XVIII,然后用过碘酸氧化该二醇而得到醛XIX。如方案1中所述,使用A1A2NH,醛XIX然后可经历还原氨化而得到式A化合物。作为另一种选择,按照路线2,溴代噻吩XVI可在钯催化下与氨基甲基三氟硼酸钾反应而得到式A化合物。
方案5
方案5示出了可得到A化合物的合成路线。以2-氨基-5-甲基-噻吩-3-甲腈(I)开始,与硫氰酸甲酯在存在酸的情况下反应而形成氨基嘧啶XX。氨基嘧啶XX可与二氧化硒(SeO2)反应而得到对应的醛XXI,使用A1A2NH(其中A1和A2是如式A中所定义的)该醛则可经历还原氨化,得到式XXII化合物。使氨基嘧啶XXII与(Boc)2O在存在DMAP的情况下反应而得到对应的受保护的胺。用钯催化,硫甲基醚官能团可与多种硼酸R1-B(OH)2在存在噻吩-2-甲酸亚铜(CuTC)的情况下发生交叉偶联(其中R1是如式A中所定义的),得到对应的取代的嘧啶XXIV。最后,用TFA去保护得到式A化合物。
实例:
实例1:2-(5-氯-呋喃-2-基)-6-(3,3-二氟-哌啶-1-基甲基)-噻吩并
[2,3-d]嘧啶-4-基胺
实例1:步骤a
2-呋喃-2-基-6-甲基-噻吩并[2,3-d]嘧啶-4-基胺
将叔丁醇钾(325mg,2.9mmol)添加至2-氨基-5-甲基-噻吩-3-甲腈(2.0g,14.5mmol)和2-糠腈(1.3g,14.5mmol)的二烷溶液(7mL)。将所得的混合物在130℃下加热10分钟。将该暗色浆料冷却至室温,用THF稀释,并干燥填充至硅胶上。通过柱层析纯化该物质而得到1.6g的标题化合物。
实例1:步骤b
2-(5-氯-呋喃-2-基)-6-甲基-噻吩并[2,3-d]嘧啶-4-基胺
将固体NCS(916mg,6.9mmol)添加至2-呋喃-2-基-6-甲基-噻吩并[2,3-d]嘧啶-4-基胺(1.4g,6.2mmol)的DMF溶液(25mL)并将该混合物加热至50℃。16小时后,将该混合物冷却至室温用水稀释。滤出沉淀出的固体并真空干燥而得到1.2g的标题化合物,将其无需进一步纯化使用。
实例1:步骤c
[2-(5-氯-呋喃-2-基)-6-甲基-噻吩并[2,3-d]嘧啶-4-基]-双氨基甲酸
叔丁酯
将固体DMAP(29mg,0.2mmol)添加至(Boc)2O(1.3g,5.9mmol)和2-(5-氯-呋喃-2-基)-6-甲基-噻吩并[2,3-d]嘧啶-4-基胺(630mg,2.4mmol)的THF溶液(12mL)。6小时后,用EtOAc稀释该混合物并将有机层用水和盐水洗涤、干燥(Na2SO4)、浓缩,并通过柱层析纯化而得到928mg的标题化合物。
实例1:步骤d
[6-溴甲基-2-(5-氯-呋喃-2-基)-噻吩并[2,3-d]嘧啶-4-基]-双氨基甲
酸叔丁酯
将固体过氧化苯甲酰(34mg,0.1mmol)添加至DBDMH(314mg,1.1mmol)和[2-(5-氯-呋喃-2-基)-6-甲基-噻吩并[2,3-d]嘧啶-4-基]-双氨基甲酸叔丁酯(928mg,2.0mmol)的苯溶液(10mL),并将所得的混合物加热至回流。14小时后,将该混合物冷却至室温、用EtOAc稀释并将有机层用水和盐水洗涤、干燥(Na2SO4)、浓缩,并通过柱层析纯化而得到651mg的标题化合物。
实例1:步骤e
6-溴甲基-2-(5-氯-呋喃-2-基)-噻吩并[2,3-d]嘧啶-4-基胺
将纯TFA(2mL)添加至[6-溴甲基-2-(5-氯-呋喃-2-基)-噻吩并[2,3-d]嘧啶-4-基]-双氨基甲酸叔丁酯(651mg)的CH2Cl2溶液(8mL)。4小时后,添加饱和的NaHCO3水溶液并用EtOAc萃取水相。将合并的有机物用水和盐水洗涤、干燥(Na2SO4)并浓缩而得到369mg的标题化合物,将其无需进一步纯化使用。
实例1:步骤f
2-(5-氯-呋喃-2-基)-6-(3,3-二氟-哌啶-1-基甲基)-噻吩并[2,3-d]嘧
啶-4-基胺
将固体3,3-二氟-哌啶盐酸盐(34mg,0.22mmol)添加至二异丙基乙胺(0.10mL,0.56mmol)和6-溴甲基-2-(5-氯-呋喃-2-基)-噻吩并[2,3-d]嘧啶-4-基胺(50mg,0.14mmol)的THF溶液(1mL)并将该混合物加热至40℃。2小时后,将该混合物用EtOAc稀释并用水和盐水洗涤、干燥(Na2SO4)、浓缩,并通过柱层析纯化而得到31mg的标题化合物。1HNMR(氯仿-d,300MHz):δ=7.23(d,J=3.4Hz,1H),6.99(s,1H),6.34(d,J=3.4Hz,1H),5.31(br.s.,2H),3.86(s,2H),2.75(t,J=11.1Hz,2H),2.57(t,J=5.1Hz,2H),1.73-1.99ppm(m,4H);MS m/e 385(M+H)。
实例2:2-(5-氯-呋喃-2-基)-6-(4-三氟甲基-哌啶-1-基甲基)-噻吩并
[2,3-d]嘧啶-4-基胺
如实例1中所述,用4-三氟甲基-哌啶盐酸盐代替3,3-二氟-哌啶盐酸盐来制备标题化合物。1H NMR(氯仿-d,300MHz):δ=7.23(d,J=3.4Hz,1H),6.96(s,1H),6.34(d,J=3.4Hz,1H),5.28(s,2H),3.75(s,2H),3.02-3.10(m,2H),1.98-2.11(m,3H),1.80-1.91(m,2H),1.61-1.75ppm(m,2H);MS m/e 417(M+H)。
实例3:2-(5-氯-呋喃-2-基)-6-环丙基氨基甲基-噻吩并[2,3-d]嘧啶
-4-基胺
如实例1中所述,用环丙胺代替3,3-二氟-哌啶盐酸盐来合成标题化合物。1H NMR(氯仿-d,300MHz):δ=7.17-7.24(m,1H),6.97(s,1H),6.33(d,J=3.4Hz,1H),5.31(br.s.,2H),4.09(s,2H),2.17-2.30(m,1H),1.58(br.s.,1H),0.37-0.54ppm(m,4H);MS m/e 321(M+H)。
实例4:2-(5-氯-呋喃-2-基)-6-(3-氟-吡咯烷-1-基甲基)-噻吩并
[2,3-d]嘧啶-4-基胺
如实例1中所述,用(S)-3-氟-吡咯烷盐酸盐代替3,3-二氟-哌啶盐酸盐来合成标题化合物。1H NMR(氯仿-d,300MHz):δ=7.22(d,J=3.4Hz,1H),6.98(s,1H),6.33(d,J=3.4Hz,1H),5.33(br.s.,2H),5.04-5.16(m,1H),3.93(s,2H),2.82-2.99(m,3H),2.57-2.69(m,1H),1.99-2.31ppm(m,2H);MS m/e 353(M+H)。
实例5:2-(5-氯-呋喃-2-基)-6-吗啉-4-基甲基-噻吩并[2,3-d]嘧啶-4-
基胺
如实例1中所述,用吗啉代替3,3-二氟-哌啶盐酸盐来合成标题化合物。1H NMR(氯仿-d,300MHz):δ=7.23(d,J=3.8Hz,1H),6.97(s,1H),6.34(d,J=3.8Hz,1H),5.39(br.s.,2H),3.68-3.80(m,6H),2.46-2.61ppm(m,4H);MS m/e 351(M+H)。
实例6:2-(5-氯-呋喃-2-基)-6-(3,3-二氟-吡咯烷-1-基甲基)-噻吩并
[2,3-d]嘧啶-4-基胺
如实例1中所述,用3,3-二氟-吡咯烷盐酸盐代替3,3-二氟-哌啶盐酸盐来合成标题化合物。1H NMR(氯仿-d,300MHz):δ=7.22-7.26(m,1H),7.00(s,1H),6.34(d,J=3.4Hz,1H),5.41(br.s.,2H),3.90(s,2H),3.01(t,J=13.2Hz,2H),2.86(t,J=7.0Hz,2H),2.33ppm(tt,J=14.4,7.1Hz,2H);MS m/e 371(M+H)。
实例7:2-(5-溴-呋喃-2-基)-6-吗啉-4-基甲基-噻吩并[2,3-d]嘧啶-4-
基胺
实例7:步骤a
5-溴-呋喃-2-甲腈
将纯POCl3(0.69mL,7.4mmol)添加至5-溴-呋喃-2-甲酰胺(1.0mg,5.3mmol)的吡啶溶液(13mL)。2小时后,将该混合物冷却至0℃并用浓HCl水溶液调节至pH 4.5。用Et2O萃取该水性混合物并将合并的萃取物用盐水洗涤、干燥(Na2SO4)、浓缩并在无需进一步纯化的情况下使用而得到900mg的标题化合物。
实例7:步骤b
2-(5-氯-呋喃-2-基)-6-(3,3-二氟-吡咯烷-1-基甲基)-噻吩并[2,3-d]
嘧啶-4-基胺
如实例1中所述,用5-溴-呋喃-2-甲腈和吗啉分别代替2-糠腈和3,3-二氟-哌啶盐酸盐来制备标题化合物。1H NMR(氯仿-d,400MHz):δ=7.20(d,J=3.4Hz,1H),6.97(s,1H),6.48(d,J=3.4Hz,1H),5.40(br.s.,2H),3.61-3.86(m,6H),2.40-2.65ppm(m,4H);MS m/e 396(M+H)。
实例8:2-(5-乙基-呋喃-2-基)-6-吗啉-4-基甲基-噻吩并[2,3-d]嘧啶
-4-基胺
将Et2Zn(0.6mL,0.60mmol)的1M THF溶液添加至Pd(dppf)Cl2(10mg,0.01mmol)和2-(5-溴-呋喃-2-基)-6-吗啉-4-基甲基-噻吩并[2,3-d]嘧啶-4-基胺(60mg,0.15mmol)的THF溶液(1.5mL)并使该混合物回流。4小时后,使该混合物冷却并用EtOAc和水小心地稀释。用EtOAc萃取水相并将合并的有机物用水和盐水洗涤、干燥(Na2SO4),并干燥填充至硅胶上。柱层析处理得到33mg的标题化合物。1H NMR(氯仿-d,300MHz):δ=7.19(d,J=3.4Hz,1H),6.95(s,1H),6.17(d,J=3.4Hz,1H),5.32(s,2H),3.68-3.77(m,6H),2.81(q,J=7.5Hz,2H),2.44-2.58(m,4H),1.25-1.34ppm(m,3H);MS m/e 345(M+H)。
实例9:6-(2,6-二甲基-哌啶-1-基甲基)-2-(4-甲基-噻唑-2-基)-噻吩
并[2,3-d]嘧啶-4-基胺
实例9:步骤a
2-(4-甲基-噻唑-2-基)-噻吩并[2,3-d]嘧啶-4-基胺
如实例1所述,用4-甲基-噻唑-2-甲腈和2-氨基-3-氰基噻吩分别代替2-糠腈和2-氨基-5-甲基-噻吩-3-甲腈来制备标题化合物。
实例9:步骤b
6-溴-2-(4-甲基-噻唑-2-基)-噻吩并[2,3-d]嘧啶-4-基胺
实例9:步骤c
2-(4-甲基-噻唑-2-基)-6-乙烯基-噻吩并[2,3-d]嘧啶-4-基胺
将乙烯基硼酸二丁酯(1.0mL,4.7mmol)添加至6-溴-2-(4-甲基-噻唑-2-基)-噻吩并[2,3-d]嘧啶-4-基胺(775mg,2.4mmol)、Pd(dppf)Cl2(196mg,0.2mmol)和K2CO3(650mg,4.7mmol)的二烷(20mL)/水(5mL)溶液并将该混合物加热至80℃。3小时后,冷却该混合物并用EtOAc稀释。将有机相用水和盐水洗涤、干燥(Na2SO4)并干燥填充至硅胶上。柱层析处理得到460mg的标题化合物。
实例9:步骤d
1-[4-氨基-2-(4-甲基-噻唑-2-基)-噻吩并[2,3-d]嘧啶-6-基]-乙烷
-1,2-二醇
将固体MeSO2NH2(162mg,1.7mmol)添加至AD混合物-α(2.4g)的t-BuOH(8mL)/水(8mL)溶液。15分钟后,将所得混合物添加至2-(4-甲基-噻唑-2-基)-6-乙烯基-噻吩并[2,3-d]嘧啶-4-基胺(460mg,1.7mmol)的丙酮悬浮液(8mL)并剧烈搅拌该混合物。18小时后,添加亚硫酸钠(2.5g)并搅拌混合物持续另外30分钟。用EtOAc萃取该混合物并将合并的萃取物用水和盐水洗涤、干燥(Na2SO4)并浓缩而得到350mg的标题化合物,将其无需进一步纯化使用。
实例9:步骤e
4-氨基-2-(4-甲基-噻唑-2-基)-噻吩并[2,3-d]嘧啶-6-甲醛
将固体HIO4(775mg,3.4mmol)添加至1-[4-氨基-2-(4-甲基-噻唑-2-基)-噻吩并[2,3-d]嘧啶-6-基]-乙烷-1,2二醇(350mg,1.1mmol)的THF溶液(20mL)。2小时后,添加饱和的NaHCO3水溶液并用EtOAc萃取水相。将合并的萃取物用水和盐水洗涤、干燥(Na2SO4)并干燥填充至硅胶上。柱层析处理得到113mg的标题化合物。
实例9:步骤f
6-(2,6-二甲基-哌啶-1-基甲基)-2-(4-甲基-噻唑-2-基)-噻吩并[2,3-d]
嘧啶-4-基胺
将固体NaBH(OAc)3(45mg,0.21mmol)添加至4-氨基-2-(4-甲基-噻唑-2-基)-噻吩并[2,3-d]嘧啶-6-甲醛(40mg,0.14mmol)和顺式-2,6-二甲基-哌啶(58μL,0.43mmol)的THF溶液(2mL)并将该混合物加热至45℃。16小时后,使该混合物冷却,用EtOAc稀释、用饱和的NaHCO3水溶液、水和盐水洗涤、干燥(Na2SO4)并干燥填充至硅胶上。柱层析处理得到15mg的标题化合物。1H NMR(丙酮,300MHz):δ=7.29(s,1H),7.13(s,1H),6.87(br.s.,2H),3.96(s,2H),2.43(br.s.,2H),2.34(s,3H),1.38-1.58(m,2H),1.10-1.23(m,4H),1.02ppm(d,J=6.4Hz,6H);MS m/e 374(M+H)。
实例10:6-(2,6-二甲基-哌啶-1-基甲基)-2-(5-异丙基-呋喃-2-基)-
噻吩并[2,3-d]嘧啶-4-基胺
如实例8中所述,用i-PrZnBr和2-(5-溴-呋喃-2-基)-6-(2,6-二甲基-哌啶-1-基甲基)-噻吩并[2,3-d]嘧啶-4-基胺分别代替Et2Zn和2-(5-溴-呋喃-2-基)-6-吗啉-4-基甲基-噻吩并[2,3-d]嘧啶-4-基胺来制备标题化合物。1H NMR(氯仿-d,300MHz):δ=7.17(d,J=3.4Hz,1H),6.95(s,1H),6.14(d,J=3.0Hz,1H),5.34(br.s.,2H),4.13(s,2H),3.12(quin,J=6.9Hz,1H),2.57(br.s.,2H),1.51-1.80(m,6H),1.32(d,J=6.8Hz,6H),1.20ppm(d,J=6.0Hz,6H);MS m/e 385(M+H)。
实例11:6-(2,6-二甲基-哌啶-1-基甲基)-2-(5-乙基-呋喃-2-基)-噻
吩并[2,3-d]嘧啶-4-基胺
如实例8中所述,用2-(5-溴-呋喃-2-基)-6-(2,6-二甲基-哌啶-1-基甲基)-噻吩并[2,3-d]嘧啶-4-基胺代替2-(5-溴-呋喃-2-基)-6-吗啉-4-基甲基-噻吩并[2,3-d]嘧啶-4-基胺来制备标题化合物。1H NMR(氯仿-d,300MHz):δ=7.18(d,J=3.4Hz,1H),6.95(s,1H),6.16(d,J=3.4Hz,1H),5.34(br.s.,2H),4.13(s,2H),2.81(q,J=7.4Hz,2H),2.57(br.s.,2H),1.78(br.s.,4H),1.51-1.70(m,2H),1.23-1.35(m,3H),1.21ppm(d,J=6.0Hz,6H);MS m/e 371(M+H)。
实例12:2-(5-环丙基-呋喃-2-基)-6-(2,6-二甲基-哌啶-1-基甲基)-
噻吩并[2,3-d]嘧啶-4-基胺
将固体环丙基硼酸(31mg,0.36mmol)添加至2-(5-溴-呋喃-2-基)-6-(2,6-二甲基-哌啶-1-基甲基)-噻吩并[2,3-d]嘧啶-4-基胺(60mg,0.14mmol)、Pd(OAc)2(2mg,0.01mmol)、P(Cy)3(5mg,0.02mmol)和K3PO4(104mg,0.49mmol)的甲苯(1mL)/水(0.05mL)悬浮液并将该混合物加热至100℃。4小时后,使该混合物冷却,用EtOAc稀释、用水和盐水洗涤、干燥(Na2SO4)并干燥填充至硅胶上。柱层析处理得到30mg的标题化合物。1H NMR(氯仿-d,300MHz):δ=7.15(d,J=3.4Hz,1H),6.87-6.99(m,1H),6.03(d,J=3.0Hz,1H),5.27(s,2H),4.12(s,2H),2.56(br.s.,2H),2.00-2.11(m,1H),1.58-1.71(m,2H),1.23-1.41(m,4H),1.21(s,3H),1.19(s,3H),0.89-0.99(m,2H),0.79-0.88ppm(m,2H);MS m/e 383(M+H)。
实例13:2-(5-叔丁基-噻吩-2-基)-6-(2,6-二甲基-哌啶-1-基甲基)-
噻吩并[2,3-d]嘧啶-4-基胺
实例13:步骤a
2-(5-叔丁基-噻吩-2-基)-6-甲基-噻吩并[2,3-d]嘧啶-4-基胺
如实例1中所述,用5-叔丁基-噻吩-2-甲腈代替2-糠腈来制备标题化合物。
实例13:步骤b
4-氨基-2-(5-叔丁基-噻吩-2-基)-噻吩并[2,3-d]嘧啶-6-甲醛
将固体SeO2(1.3g,11.6mmol)添加至2-(5-叔丁基-噻吩-2-基)-6-甲基-噻吩并[2,3-d]嘧啶-4-基胺(885mg,2.9mmol)的二烷(20mL)/水(0.2mL)悬浮液并将该混合物加热至100℃。20小时后,将该混合物趁热过滤并用EtOAc稀释。将有机相用水和盐水洗涤、干燥(Na2SO4)并干燥填充至硅胶上。柱层析处理得到521mg的标题化合物。
实例13:步骤c
2-(5-叔丁基-噻吩-2-基)-6-(2,6-二甲基-哌啶-1-基甲基)-噻吩并
[2,3-d]嘧啶-4-基胺
将固体NaBH(OAc)3(124mg,0.59mmol)添加至顺式-2,6-二甲基-哌啶(0.16mL,1.18mmol)和4-氨基-2-(5-叔丁基-噻吩-2-基)-噻吩并[2,3-d]嘧啶-6-甲醛(125mg,0.39mmol)的THF溶液(3mL)并将该混合物加热至45℃。16小时后,冷却该混合物并用EtOAc稀释。将有机层用水和盐水洗涤、干燥(Na2SO4)并干燥填充至硅胶上。柱层析处理得到60mg的标题化合物。1H NMR(氯仿-d,300MHz):δ=7.75(d,J=3.8Hz,1H),6.93(s,1H),6.85(d,J=3.8Hz,1H),5.31(s,2H),4.12(s,2H),2.48-2.64(m,2H),1.53-1.70(m,2H),1.42(s,9H),1.22-1.37(m,4H),1.21(s,3H),1.19ppm(s,3H);MS m/e 415(M+H)。
实例14:2-(5-叔丁基-噻吩-2-基)-6-吗啉-4-基甲基-噻吩并[2,3-d]
嘧啶-4-基胺
如实例13中所述,用吗啉代替顺式-2,6-二甲基-哌啶来制备标题化合物。1H NMR(氯仿-d,300MHz):δ=7.76(d,J=3.8Hz,1H),6.94(s,1H),6.85(d,J=3.8Hz,1H),5.18(s,2H),3.63-3.81(m,6H),2.42-2.62(m,4H),1.42ppm(s,9H);MS m/e 389(M+H)。
实例15:2-(4-甲基-噻唑-2-基)-6-吗啉-4-基甲基-噻吩并[2,3-d]嘧
啶-4-基胺
如实例9中所述,用吗啉代替顺式-2,6-二甲基-哌啶来制备标题化合物。1H NMR(丙酮,300MHz):δ=7.31(s,1H),7.13(s,1H),6.88(br.s.,2H),3.65(s,2H),3.47-3.56(m,4H),2.35-2.40(m,4H),2.34ppm(s,3H);MS m/e 348(M+H)。
实例16:步骤a
异
唑-3-甲酰胺
将固体NaH(油中,60重量%)(425mg,10.6mmol)添加至异唑-3-甲酸(1.0g,8.8mmol)的THF溶液(50mL)。15分钟后,添加纯氯甲酸乙酯(1.0mL,10.6mmol)。45分钟后,添加MeOH(5.0mL,35mmol)中的7N氨溶液。30分钟后,将该混合物用EtOAc稀释、用水和用盐水洗涤、干燥(Na2SO4),并干燥填充至硅胶上。柱层析处理得到600mg的标题化合物。
实例16:步骤b
实例16:步骤c
如实例13所述,用吗啉和异唑-3-甲腈分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1H NMR(丙酮,300MHz):δ=8.68(d,J=1.5Hz,1H),7.33(s,1H),6.83-6.91(m,3H),3.66(s,2H),3.46-3.56(m,4H),2.31-2.43ppm(m,4H);MS m/e 318(M+H)。
实例17:3-[4-氨基-6-(2,6-二甲基-吗啉-4-基甲基)-噻吩并[2,3-d]
嘧啶-2-基]-苄腈
如实例13中所述,用顺式-2,6-二甲基-吗啉和1,3-二氰基苯分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1H NMR(丙酮,300MHz):δ=8.54-8.65(m,2H),7.72(d,J=7.9Hz,1H),7.57(t,J=8.1Hz,1H),7.30(s,1H),6.84(br.s.,2H),3.64(s,2H),3.42-3.58(m,2H),2.62-2.77(m,2H),1.63(t,J=10.7Hz,2H),0.95(s,3H),0.93ppm(s,3H);MS m/e 380(M+H)。
如实例13中所述,用异唑-3-甲腈代替5-叔丁基-噻吩-2-甲腈来制备标题化合物。1H NMR(丙酮,300MHz):δ=8.67(d,J=1.9Hz,1H),7.30(s,1H),6.88(d,J=1.5Hz,1H),6.82(br.s.,2H),3.97(s,2H),2.33-2.51(m,2H),1.42-1.56(m,2H),1.10-1.26(m,4H),1.03ppm(d,J=6.0Hz,6H);MS m/e 344(M+H)。
实例19:2-(5-溴-呋喃-2-基)-6-(2,6-二甲基-哌啶-1-基甲基)-噻吩
并[2,3-d]嘧啶-4-基胺
如实例1中所述,用5-溴-呋喃-2-甲腈和顺式-2,6-二甲基-哌啶分别代替2-糠腈和3,3-二氟-哌啶盐酸盐来制备标题化合物。1H NMR(氯仿-d,400MHz):δ=7.19(d,J=3.4Hz,1H),6.95(s,1H),6.48(d,J=3.7Hz,1H),5.44(br.s.,2H),4.11(s,2H),2.45-2.66(m,2H),1.55-1.70(m,2H),1.26-1.39(m,4H),1.19ppm(d,J=6.1Hz,6H);MS m/e 422(M+H)。
实例20:3-[4-氨基-6-(2-苯基-吡咯烷-1-基甲基)-噻吩并[2,3-d]嘧
啶-2-基]-苄腈
如实例13中所述,用2-苯基-吡咯烷和1,3-二氰基苯分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1HNMR(氯仿-d,400MHz):δ=8.76(t,J=1.5Hz,1H),8.67(dt,J=8.1,1.3Hz,1H),7.69(dt,J=7.6,1.5Hz,1H),7.55(t,J=7.8Hz,1H),7.43-7.50(m,2H),7.31-7.40(m,2H),7.19-7.30(m,1H),6.91(s,1H),5.23(s,2H),3.99(dd,J=14.4,1.5Hz,1H),3.41-3.53(m,2H),3.24-3.35(m,1H),2.35(q,J=8.5Hz,1H),2.14-2.29(m,1H),1.89-2.02(m,1H),1.69-1.89ppm(m,2H);MS m/e 412(M+H)。
实例21:2-(5-异丙基-呋喃-2-基)-6-吗啉-4-基甲基-噻吩并[2,3-d]
嘧啶-4-基胺
实例21:步骤a
5-异丙基-呋喃-2-甲酸甲酯
将异丙基溴化锌的0.5M THF溶液(7.3mL,3.6mmol)添加至5-溴-呋喃-2-甲酸甲酯(250mg,1.2mmol)和Pd(dppf)Cl2(98mg,0.1mmol)的THF溶液(2mL),并将所得的混合物加热至70℃。15小时后,冷却该混合物,添加水并用EtOAc萃取水相。将合并的有机萃取物用水和盐水洗涤、干燥(Na2SO4)、浓缩并通过柱层析纯化而得到150mg的5-异丙基-呋喃-2-甲酸甲酯。按照实例14的步骤b和c获得所需的腈。
实例21:步骤b
5-异丙基-呋喃-2-甲酰胺
将5-异丙基-呋喃-2-甲酸甲酯(150mg,3.9mmol)悬浮于浓NH4OH(5mL)中并剧烈搅拌。16小时后,用水稀释该混合物并用EtOAc萃取水相。将合并的有机萃取物用水和盐水洗涤、干燥(Na2SO4)、浓缩并在无需进一步纯化的情况下使用而得到110mg的标题化合物。
实例21:步骤c
5-异丙基-呋喃-2-甲腈
实例21:步骤d
2-(5-异丙基-呋喃-2-基)-噻吩并[2,3-d]嘧啶-4-基胺
如实例1所述,用4-甲基-噻唑-2-甲腈和2-氨基-3-氰基噻吩分别代替2-糠腈和2-氨基-5-甲基-噻吩-3-甲腈来制备标题化合物。
实例21:步骤e
6-溴-2-(5-异丙基-呋喃-2-基)-噻吩并[2,3-d]嘧啶-4-基胺
如实例9中所述,用2-(5-异丙基-呋喃-2-基)-噻吩并[2,3-d]嘧啶-4-基胺代替2-(4-甲基-噻唑-2-基)-噻吩并[2,3-d]嘧啶-4-基胺来制备标题化合物。
实例21:步骤f
三氟[(吗啉-1-基)甲基]硼酸钾
将固体溴甲基三氟硼酸钾(200mg,1.0mmol)添加至纯吗啉(4mL)并将该混合物加热至80℃。30分钟后真空浓缩该混合物。将所得的固体溶解于K2CO3(138mg,1.0mmol)的丙酮溶液(30mL)并搅拌。30分钟后,滤除不溶解的盐并真空浓缩滤液而得到103mg的标题化合物,将其无需进一步纯化使用。
实例21:步骤g
2-(5-异丙基-呋喃-2-基)-6-吗啉-4-基甲基-噻吩并[2,3-d]嘧啶-4-基
胺
将固体6-溴-2-(5-异丙基-呋喃-2-基)-噻吩并[2,3-d]嘧啶-4-基胺(30mg,0.09mmol)添加至三氟[(吗啉-1-基)甲基]硼酸钾(103mg,0.50mmol)、Pd(OAc)2(1mg,0.004mmol)、Xphos(4mg,0.009mmol)和Cs2CO3(88mg,0.27mmol)的THF(1mL)/水(0.1mL)溶液并使所得的混合物回流。18小时后,使该混合物冷却,用EtOAc稀释、用水和盐水洗涤、干燥(Na2SO4)并干燥填充至硅胶上。柱层析处理得到13mg的标题化合物。1H NMR(氯仿-d,400MHz):δ=7.18(d,J=3.4Hz,1H),6.95(s,1H),6.15(d,J=3.4Hz,1H),5.26(br.s.,2H),3.68-3.79(m,6H),3.07-3.19(m,1H),2.45-2.59(m,4H),1.32ppm(d,J=7.1Hz,6H);MS m/e 359(M+H)。
实例22:2-(5-环丙基-呋喃-2-基)-6-吗啉-4-基甲基-噻吩并[2,3-d]
嘧啶-4-基胺
实例22:步骤a
5-环丙基-呋喃-2-甲酸甲酯
将固体环丙基硼酸(575mg,6.7mmol)添加至5-溴-呋喃-2-甲酸甲酯(980mg,4.8mmol)、Pd(OAc)2(54mg,0.2mmol)、P(Cy)3(135mg,0.5mmol)和K3PO4(3.6g,16.8mmol)的甲苯(22mL)/水(1.1mL)溶液。将所得的混合物加热至90℃。5小时后,将混合物冷却、过滤并用EtOAc萃取。将合并的有机萃取物用水和盐水洗涤、干燥(Na2SO4)、浓缩并通过柱层析纯化而得到650mg的5-环丙基-呋喃-2-甲酸甲酯。
实例22:步骤b
5-环丙基-呋喃-2-甲酰胺
将5-环丙基-呋喃-2-甲酸甲酯(650mg,3.9mmol)悬浮于浓NH4OH(20mL)中并剧烈搅拌。16小时后,用水稀释该混合物并用EtOAc萃取水相。将合并的有机萃取物用水和盐水洗涤、干燥(Na2SO4)、浓缩并在无需进一步纯化的情况下使用而得到550mg的5-环丙基-呋喃-2-甲酰胺。
实例22:步骤c
5-环丙基-呋喃-2-甲腈
将纯POCl3(0.48mL,5.1mmol)添加至5-环丙基-呋喃-2-甲酰胺(550mg,3.6mmol)的吡啶溶液(9mL)。2小时后,将该混合物冷却至0℃并用浓HCl水溶液调节至pH 4.5。用Et2O萃取该水性混合物并将合并的萃取物用盐水洗涤、干燥(Na2SO4)、浓缩并在无需进一步纯化的情况下使用而得到478mg的5-环丙基-呋喃-2-甲腈。
实例22:步骤d
2-(5-环丙基-呋喃-2-基)-6-甲基-噻吩并[2,3-d]嘧啶-4-基胺
如实例1所述,用5-环丙基-呋喃-2-甲腈代替2-糠腈来制备标题化合物。
实例22:步骤e
2-(5-环丙基-呋喃-2-基)-6-吗啉-4-基甲基-噻吩并[2,3-d]嘧啶-4-基
胺
如实例13所述,用吗啉和5-环丙基-呋喃-2-甲腈分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1H NMR(氯仿-d,300MHz):δ=7.16(d,J=3.4Hz,1H),6.95(s,1H),6.03(d,J=3.4Hz,1H),5.29(s,2H),3.62-3.83(m,6H),2.47-2.56(m,4H),1.99-2.12(m,1H),0.90-1.00(m,2H),0.79-0.89ppm(m,2H);MSm/e 357(M+H)。
实例23:3-[4-氨基-6-(2,6-二甲基-哌啶-1-基甲基)-噻吩并[2,3-d]
嘧啶-2-基]-苄腈
如实例13中所述,用1,3-二氰基苯代替5-叔丁基-噻吩-2-甲腈来制备标题化合物。1H NMR(氯仿-d,300MHz):δ=8.77(s,1H),8.68(d,J=7.9Hz,1H),7.70(d,J=7.9Hz,1H),7.56(t,J=7.7Hz,1H),7.00(s,1H),5.25(br.s.,2H),3.74(d,J=2.3Hz,2H),2.80-3.00(m,2H),1.93-2.15(m,2H),1.57-1.78(m,2H),1.19-1.39(m,2H),0.82-0.97ppm(m,6H);MS m/e 378(M+H)。
实例24:6-(2,6-二甲基-哌啶-1-基甲基)-2-(5-甲基-呋喃-2-基)-噻
吩并[2,3-d]嘧啶-4-基胺
将固体甲基硼酸(34mg,0.57mmol)添加至2-(5-溴-呋喃-2-基)-6-(2,6-二甲基-哌啶-1-基甲基)-噻吩并[2,3-d]嘧啶-4-基胺(60mg,0.14mmol)、Pd(dppf)Cl2(11mg,0.01mmol)和K2CO3(79mg,0.57mmol)的二烷(1.6mL)/水(0.4mL)溶液,并将该混合物加热至80℃。6小时后,使该混合物冷却,用EtOAc稀释、用水和盐水洗涤、干燥(Na2SO4)并干燥填充至硅胶上。柱层析处理得到29mg的标题化合物。1H NMR(氯仿-d,300MHz):δ=7.16(d,J=3.4Hz,1H),6.94(s,1H),6.15(d,J=2.3Hz,1H),5.27(br.s.,2H),4.12(s,2H),2.50-2.64(m,2H),2.45(s,3H),1.24-1.39(m,6H),1.20ppm(d,J=6.0Hz,6H);MS m/e 357(M+H)。
实例25:6-吗啉-4-基甲基-2-噻唑-2-基-噻吩并[2,3-d]嘧啶-4-基胺
实例25:步骤a
噻唑-2-甲腈
如实例21中所述,用噻唑-2-甲酸甲酯代替5-异丙基-呋喃-2-甲酸甲酯来制备标题化合物。
实例25:步骤b
6-吗啉-4-基甲基-2-噻唑-2-基-噻吩并[2,3-d]嘧啶-4-基胺
如实例13所述,用吗啉和噻唑-2-甲腈分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1H NMR(氯仿-d,400MHz):δ=7.99(d,J=3.2Hz,1H),7.48(d,J=3.2Hz,1H),7.03(s,1H),5.49(br.s.,2H),3.66-3.80(m,6H),2.46-2.63ppm(m,4H);MSm/e 334(M+H)。
实例26:6-吗啉-4-基甲基-2-噻吩-2-基-噻吩并[2,3-d]嘧啶-4-基胺
如实例13所述,用吗啉和噻吩-2-甲腈分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1H NMR(氯仿-d,300MHz):δ=7.95(dd,J=3.7,1.2Hz,1H),7.41(dd,J=5.0,1.2Hz,1H),7.12(dd,J=5.0,3.7Hz,1H),6.96(s,1H),5.18(br.s.,2H),3.65-3.85(m,6H),2.47-2.65ppm(m,4H);MS m/e 333(M+H)。
实例27:2-(5-氯-呋喃-2-基)-6-(2-甲氧基甲基-吡咯烷-1-基甲基)-
噻吩并[2,3-d]嘧啶-4-基胺
如实例1所述,用(R)-2-甲氧基甲基-吡咯烷代替3,3-二氟-哌啶盐酸盐来制备标题化合物。1H NMR(氯仿-d,300MHz):δ=7.22(d,J=3.4Hz,1H),6.96(s,1H),6.33(d,J=3.4Hz,1H),5.39(s,2H),4.31(d,J=14.3Hz,1H),3.78(d,J=14.3Hz,1H),3.37-3.48(m,2H),3.36(s,3H),3.09(ddd,J=9.1,6.5,3.2Hz,1H),2.73-2.91(m,1H),2.22-2.45(m,1H),1.85-2.01(m,1H),1.53-1.84ppm(m,3H);MS m/e 379(M+H)。
实例28:2-呋喃-2-基-6-吡咯烷-1-基甲基-噻吩并[2,3-d]嘧啶-4-基
胺
如实例13所述,用吡咯烷和4-氨基-2-呋喃-2-基-噻吩并[2,3-d]嘧啶-6-甲醛分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1H NMR(氯仿-d,400MHz):δ=7.59(s,1H),7.25(d,J=3.3Hz,1H),7.06(s,1H),6.54(dd,J=3.3,1.8Hz,1H),5.44(br.s.,2H),3.92(s,2H),2.61-2.74(m,4H),1.85ppm(dt,J=6.8,3.3Hz,4H);MS m/e 301(M+H)。
实例29:6-环丙基氨基甲基-2-呋喃-2-基-噻吩并[2,3-d]嘧啶-4-基
胺
如实例13所述,用环丙胺和4-氨基-2-呋喃-2-基-噻吩并[2,3-d]嘧啶-6-甲醛分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1H NMR(氯仿-d,300MHz):δ=7.60(d,J=0.8Hz,1H),7.25(s,1H),6.99(s,1H),6.55(dd,J=3.5,1.8Hz,1H),5.42(br.s.,2H),4.09(s,2H),2.15-2.32(m,1H),0.33-0.56ppm(m,4H);MS m/e287(M+H)。
实例30:6-吡咯烷-1-基甲基-2-噻吩-2-基-噻吩并[2,3-d]嘧啶-4-基
胺
如实例13所述,用吡咯烷和4-氨基-2-噻吩-2-基-噻吩并[2,3-d]嘧啶-6-甲醛分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1H NMR(氯仿-d,300MHz):δ=7.95(dd,J=3.7,1.2Hz,1H),7.41(dd,J=5.0,1.2Hz,1H),7.11(dd,J=5.0,3.7Hz,2H),5.33(br.s.,2H),3.95(s,2H),2.71(br.s.,4H),1.86ppm(dt,J=6.7,3.2Hz,4H);MS m/e 317(M+H)。
实例31:6-二乙基氨基甲基-2-呋喃-2-基-噻吩并[2,3-d]嘧啶-4-基
胺
如实例13所述,用二乙胺和4-氨基-2-呋喃-2-基-噻吩并[2,3-d]嘧啶-6-甲醛分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1H NMR(氯仿-d,300MHz):δ=7.59(dd,J=1.7,0.9Hz,1H),7.25(dd,J=3.5,0.8Hz,1H),6.96(s,1H),6.54(dd,J=3.4,1.7Hz,1H),5.28(br.s.,2H),3.83(s,2H),2.61(q,J=7.2Hz,4H),1.08ppm(t,J=7.2Hz,6H);MS m/e 303(M+H)。
实例32:6-环己基氨基甲基-2-呋喃-2-基-噻吩并[2,3-d]嘧啶-4-基
胺
如实例13所述,用环己胺和4-氨基-2-呋喃-2-基-噻吩并[2,3-d]嘧啶-6-甲醛分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1H NMR(氯仿-d,300MHz):δ=7.59(d,J=0.8Hz,1H),7.24(d,J=3.4Hz,1H),7.06(s,1H),6.54(dd,J=3.4,1.7Hz,1H),5.44(br.s.,2H),4.05-4.13(m,2H),3.49(s,1H),2.52-2.66(m,1H),2.06(s,2H),1.73(br.s.,2H),1.06-1.35ppm(m,6H);MS m/e 329(M+H)。
实例33:2-呋喃-2-基-6-[(2-甲氧基-乙基氨基)-甲基]-噻吩并[2,3-d]
嘧啶-4-基胺
如实例13所述,用2-甲氧基-乙胺和4-氨基-2-呋喃-2-基-噻吩并[2,3-d]嘧啶-6-甲醛分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1H NMR(氯仿-d,300MHz):δ=7.56-7.61(m,1H),7.25(d,J=3.4Hz,1H),6.98(s,1H),6.54(dd,J=3.4,1.7Hz,1H),5.29(br.s.,2H),4.07(s,2H),3.50-3.57(m,2H),3.37(s,3H),2.81-2.90ppm(m,2H);MS m/e 305(M+H)。
实例34:2-(5-甲基-呋喃-2-基)-6-哌啶-1-基甲基-噻吩并[2,3-d]嘧
啶-4-基胺
实例34:步骤a
4-氨基-2-(5-甲基-呋喃-2-基)-噻吩并[2,3-d]嘧啶-6-甲醛
如实例9中所述,用1-[4-氨基-2-(5-甲基-呋喃-2-基)-噻吩并[2,3-d]嘧啶-6-基]-乙烷-1,2二醇代替1-[4-氨基-2-(4-甲基-噻唑-2-基)-噻吩并[2,3-d]嘧啶-6-基]-乙烷-1,2二醇来制备标题化合物。
实例34:步骤b
2-(5-甲基-呋喃-2-基)-6-哌啶-1-基甲基-噻吩并[2,3-d]嘧啶-4-基胺
如实例13所述,用哌啶和4-氨基-2-(5-甲基-呋喃-2-基)-噻吩并[2,3-d]嘧啶-6-甲醛分别代替顺式-2,6-二甲基-哌啶和4-氨基-2-(5-叔丁基-噻吩-2-基)-噻吩并[2,3-d]嘧啶-6-甲醛来制备标题化合物。1H NMR(氯仿-d,400MHz):δ=7.09(d,J=3.0Hz,1H),6.90(s,1H),6.08(d,J=2.3Hz,1H),5.21(br.s.,2H),3.65(s,2H),2.42(br.s.,4H),2.38(s,3H),1.55(quin,J=5.6Hz,4H),1.39ppm(d,J=5.1Hz,2H);MS m/e 329(M+H)。
实例35:2-(5-溴-呋喃-2-基)-6-吡咯烷-1-基甲基-噻吩并[2,3-d]嘧
啶-4-基胺
如实例13所述,用吡咯烷和5-溴-呋喃-2-甲腈分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1H NMR(氯仿-d,300MHz):δ=7.20(d,J=3.4Hz,1H),7.07(s,1H),6.47(d,J=3.6Hz,1H),5.47(br.s.,2H),3.91(s,2H),2.61-2.74(m,4H),1.85ppm(dt,J=6.7,3.2Hz,4H);MS m/e 380(M+H)。
实例36:2-(5-甲基-呋喃-2-基)-6-(4-甲基-哌嗪-1-基甲基)-噻吩并
[2,3-d]嘧啶-4-基胺
如实例34中所述,用1-甲基-哌嗪代替哌啶来制备标题化合物。1H NMR(氯仿-d,300MHz):δ=7.16(d,J=3.2Hz,1H),6.94(s,1H),6.15(dd,J=3.2,0.9Hz,1H),5.33(br.s.,2H),3.74(s,2H),2.47-2.69(m,8H),2.45(s,3H),2.33ppm(s,3H);MS m/e 344(M+H)。
实例37:6-(1,3-二氢-异吲哚-2-基甲基)-2-(5-甲基-呋喃-2-基)-噻
吩并[2,3-d]嘧啶-4-基胺
如实例34中所述,用2,3-二氢-1H-异吲哚代替哌啶来制备标题化合物。1H NMR(氯仿-d,300MHz):δ=7.20(s,4H),7.17(d,J=3.2Hz,1H),7.03(s,1H),6.11-6.18(m,1H),5.30(br.s.,2H),4.13(s,2H),4.04(s,4H),2.45ppm(s,3H);MS m/e 363(M+H)。
实例38:2-(5-甲基-呋喃-2-基)-6-吗啉-4-基甲基-噻吩并[2,3-d]嘧
啶-4-基胺
如实例34中所述,用吗啉代替哌啶来制备标题化合物。1H NMR(氯仿-d,400MHz):δ=7.17(d,J=3.3Hz,1H),6.95(s,1H),6.15(d,J=2.5Hz,1H),5.27(br.s.,2H),3.61-3.80(m,6H),2.49-2.58(m,4H),2.45ppm(s,3H);MS m/e 331(M+H)。
实例39:2-(5-甲基-呋喃-2-基)-6-吡咯烷-1-基甲基-噻吩并[2,3-d]
嘧啶-4-基胺
如实例34中所述,用吡咯烷代替哌啶来制备标题化合物。1H NMR(氯仿-d,300MHz):δ=7.17(d,J=3.4Hz,1H),7.11(s,1H),6.15(d,J=3.4Hz,1H),5.50(br.s.,2H),3.94(s,2H),2.66-2.80(m,4H),2.44(s,3H),1.86ppm(dt,J=6.4,3.3Hz,4H);MS m/e 315(M+H)。
实例40:1-[4-氨基-2-(5-甲基-呋喃-2-基)-噻吩并[2,3-d]嘧啶-6-基
甲基]-吡咯烷-3-醇
如实例34中所述,用吡咯烷-3-醇代替哌啶来制备标题化合物。1H NMR(氯仿-d,300MHz):δ=7.17(d,J=3.2Hz,1H),6.85-7.02(m,1H),6.06-6.25(m,1H),5.25(br.s.,2H),4.26-4.45(dddd,J=7.0,4.8,2.3,2.3Hz,1H),3.88(s,2H),2.96(td,J=8.6,5.7Hz,1H),2.72-2.79(m,1H),2.59-2.69(m,1H),2.38-2.50(m,1H),2.45(s,3H),2.12-2.30ppm(m,2H);MS m/e 331(M+H)。
实例41:6-(3,4-二氢-1H-异喹啉-2-基甲基)-2-(5-甲基-呋喃-2-基)-
噻吩并[2,3-d]嘧啶-4-基胺
如实例34中所述,用1,2,3,4-四氢-异喹啉代替哌啶来制备标题化合物。1H NMR(氯仿-d,300MHz):δ=7.06-7.23(m,4H),6.95-7.04(m,2H),6.14(dd,J=3.3,0.8Hz,1H),5.35(br.s.,2H),3.91(s,2H),3.74(s,2H),2.91(t,J=5.3Hz,3H),2.82ppm(t,J=5.5Hz,2H);MS m/e377(M+H)。
实例42:2-呋喃-2-基-6-吗啉-4-基甲基-噻吩并[2,3-d]嘧啶-4-基胺
如实例13所述,用吗啉和2-糠腈分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1H NMR(DMSO-d6,300MHz):δ=7.81(s,1H),7.50(s,2H),7.41(s,1H),7.11(d,J=3.4Hz,1H),6.51-6.72(m,1H),3.71(s,2H),3.60(t,J=4.3Hz,4H),2.44ppm(br.s.,4H);MS m/e 317(M+H)。
实例43:2-环丙基-6-吡咯烷-1-基甲基-噻吩并[2,3-d]嘧啶-4-基胺
如实例13所述,用吡咯烷和环丙基腈分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1H NMR(氯仿-d,300MHz):δ=7.07(s,1H),5.59(br.s.,2H),3.92(s,2H),2.59-2.86(m,4H),2.00-2.16(m,1H),1.86(dt,J=6.7,3.3Hz,4H),1.07-1.18(m,2H),0.90-1.02ppm(m,2H);MS m/e 275(M+H)。
实例44:6-(2,6-二甲基-哌啶-1-基甲基)-2-呋喃-2-基-噻吩并[2,3-d]
嘧啶-4-基胺
如实例13所述,用2-糠腈代替5-叔丁基-噻吩-2-甲腈来制备标题化合物。1H NMR(氯仿-d,300MHz):δ=7.59(s,1H),7.25(d,J=3.4Hz,1H),6.95(s,1H),6.55(dd,J=3.4,1.5Hz,1H),5.32(br.s.,2H),4.11(s,2H),2.56(br.s.,2H),1.76(br.s.,2H),1.52-1.70(m,4H),1.21(s,3H),1.19ppm(s,3H);MS m/e 343(M+H)。
实例45:1-(4-氨基-2-呋喃-2-基-噻吩并[2,3-d]嘧啶-6-基甲基)-哌
啶-4-酮
如实例13所述,用4-哌啶酮一水合物盐酸盐和2-糠腈分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1HNMR(氯仿-d,300MHz):δ=7.60(s,1H),7.26(s,1H),7.00(s,1H),6.55(dd,J=3.4,1.5Hz,1H),5.47(s,2H),3.86(s,2H),2.84(t,J=6.0Hz,4H),2.49ppm(t,J=6.0Hz,4H);MS m/e 329(M+H)。
实例46:6-二甲基氨基甲基-2-呋喃-2-基-噻吩并[2,3-d]嘧啶-4-基
胺
如实例13所述,用二甲基胺和2-糠腈的2.0M THF溶液分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1H NMR(氯仿-d,300MHz):δ=7.59(s,1H),7.20-7.33(m,1H),7.12(s,1H),6.55(dd,J=3.4,1.9Hz,1H),5.82(br.s.,2H),3.78(s,2H),2.38ppm(s,6H);MS m/e 275(M+H)。
实例47:2-(3,5-二氟-苯基)-6-吗啉-4-基甲基-噻吩并[2,3-d]嘧啶-4-
基胺
如实例13所述,用吗啉和3,5-二氟-苄腈分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1H NMR(氯仿-d,300MHz):δ=7.87-8.05(m,2H),7.00(s,1H),6.87(tt,J=8.7,2.4Hz,1H),5.23(br.s.,2H),3.59-3.83(m,6H),2.41-2.67ppm(m,4H);MSm/e 363(M+H)。
实例48:2-(3-氯-苯基)-6-(4-氟-哌啶-1-基甲基)-噻吩并[2,3-d]嘧啶
-4-基胺
如实例13所述,用4-氟-哌啶盐酸盐和3-氯-苄腈分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1H NMR(氯仿-d,300MHz):δ=8.44(s,1H),8.31(td,J=4.2,2.1Hz,1H),7.32-7.45(m,2H),6.98(s,1H),5.20(br.s.,2H),4.57-4.90(m,1H),3.76(s,2H),2.57-2.73(m,2H),2.40-2.57(m,2H),1.78-2.05ppm(m,4H);MS m/e 377(M+H)。
实例49:2-(3-氯-苯基)-6-吗啉-4-基甲基-噻吩并[2,3-d]嘧啶-4-基
胺
如实例13所述,用吗啉和3-氯-苄腈分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1H NMR(氯仿-d,300MHz):δ=8.44(s,1H),8.31(dt,J=6.2,2.2Hz,1H),7.33-7.47(m,2H),6.99(s,1H),5.25(br.s.,2H),3.67-3.85(m,6H),2.44-2.63ppm(m,4H);MS m/e 361(M+H)。
实例50:2-(3,4-二氟-苯基)-6-吗啉-4-基甲基-噻吩并[2,3-d]嘧啶-4-
基胺
如实例13所述,用吗啉和3,4-二氟-苄腈分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1H NMR(氯仿-d,300MHz):δ=8.28(ddd,J=11.9,7.9,2.1Hz,1H),8.20(ddd,J=8.7,4.5,1.5Hz,1H),7.15-7.25(m,1H),6.99(s,1H),5.19(br.s.,2H),3.52-3.88(m,6H),2.46-2.62ppm(m,4H);MS m/e 363(M+H)。
实例51:6-(3-氟-吡咯烷-1-基甲基)-2-呋喃-2-基-噻吩并[2,3-d]嘧
啶-4-基胺
如实例13所述,用3-氟-吡咯烷和2-糠腈分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1H NMR(氯仿-d,300MHz):δ=7.60(s,1H),7.25(d,J=3.4Hz,1H),6.99(s,1H),6.55(dd,J=3.4,1.9Hz,1H),5.34(br.s.,2H),5.20-5.32(m,1H),3.92(s,2H),2.93-2.98(m,1H),2.82-2.94(m,2H),2.57-2.68(m,1H),2.06-2.27ppm(m,2H);MS m/e 319(M+H)。
实例52:1-(4-氨基-2-呋喃-2-基-噻吩并[2,3-d]嘧啶-6-基甲基)-哌
啶-4-醇
如实例13所述,用哌啶-4-醇和2-糠腈分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1H NMR(氯仿-d,300MHz):δ=7.60(s,1H),7.25(s,1H),6.99(s,1H),6.55(dd,J=3.4,1.9Hz,1H),5.33(br.s.,2H),3.85(s,2H),2.75(t,J=11.1Hz,2H),2.56(t,J=5.3Hz,2H),1.70-1.99ppm(m,5H);MS m/e 331(M+H)。
实例53:6-(3-氟-吡咯烷-1-基甲基)-2-呋喃-2-基-噻吩并[2,3-d]嘧
啶-4-基胺
如实例13所述,用(S)-3-氟-吡咯烷和2-糠腈分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1H NMR(氯仿-d,300MHz):δ=7.60(s,1H),7.25(d,J=3.4Hz,1H),6.99(s,1H),6.55(dd,J=3.4,1.9Hz,1H),5.34(br.s.,2H),5.20-5.32(m,1H),3.92(s,2H),2.93-2.98(m,1H),2.82-2.94(m,2H),2.57-2.68(m,1H),2.06-2.27ppm(m,2H);MS m/e 319(M+H)。
实例54:6-(3-氟-吡咯烷-1-基甲基)-2-呋喃-2-基-噻吩并[2,3-d]嘧
啶-4-基胺
如实例13所述,用(R)-3-氟-吡咯烷和2-糠腈分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1H NMR(氯仿-d,300MHz):δ=7.60(s,1H),7.25(d,J=3.4Hz,1H),6.99(s,1H),6.55(dd,J=3.4,1.9Hz,1H),5.34(br.s.,2H),5.20-5.32(m,1H),3.92(s,2H),2.93-2.98(m,1H),2.82-2.94(m,2H),2.57-2.68(m,1H),2.06-2.27ppm(m,2H);MS m/e 319(M+H)。
实例55:2-(3,5-二氟-苯基)-6-(4-氟-哌啶-1-基甲基)-噻吩并[2,3-d]
嘧啶-4-基胺
如实例13所述,用4-氟-哌啶盐酸盐和3,5-二氟-苄腈分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1HNMR(氯仿-d,300MHz):δ=7.98(d,J=9.0Hz,2H),6.98(s,1H),6.68-6.93(m,1H),5.20(br.s.,2H),4.60-4.87(m,1H),3.77(s,2H),2.46-2.72(m,4H),1.79-2.10ppm(m,4H);MS m/e 379(M+H)。
实例56:6-(4,4-二氟-哌啶-1-基甲基)-2-呋喃-2-基-噻吩并[2,3-d]
嘧啶-4-基胺
如实例13所述,用4,4-二氟-哌啶盐酸盐和2-糠腈分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1H NMR(氯仿-d,300MHz):δ=7.59(s,1H),7.26(d,J=3.4Hz,1H),6.96(s,1H),6.55(dd,J=3.4,1.5Hz,1H),5.46(s,2H),3.78(s,2H),2.63(t,J=5.5Hz,4H),1.91-2.11(m,4H);MS m/e 351(M+H)。
实例57:6-(3,3-二氟-哌啶-1-基甲基)-2-呋喃-2-基-噻吩并[2,3-d]
嘧啶-4-基胺
如实例13所述,用3,3-二氟-哌啶盐酸盐和2-糠腈分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1H NMR(丙酮,300MHz):δ=7.70(s,1H),7.36(s,1H),7.16(d,J=3.4Hz,1H),6.79(br.s.,2H),6.59(dd,J=3.4,1.9Hz,1H),3.74(s,2H),3.63(br.s.,2H),2.13-2.31(m,2H),1.83(dd,J=12.6,3.6Hz,2H),1.46-1.65ppm(m,2H);MS m/e 351(M+H)。
实例58:2-(3-氟-苯基)-6-硫代吗啉-4-基甲基-噻吩并[2,3-d]嘧啶
-4-基胺
如实例13所述,用硫代吗啉和3-氟-苄腈分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1H NMR(氯仿-d,300MHz):δ=8.24(d,J=7.9Hz,1H),8.10-8.20(m,1H),7.44(td,J=7.9,6.0Hz,1H),7.09-7.20(m,1H),7.01(s,1H),5.22(br.s.,2H),3.80(s,2H),2.79-2.91(m,4H),2.67-2.79ppm(m,4H);MS m/e 362(M+H)。
实例59:2-苯并呋喃-2-基-6-(4-氟代哌啶-1-基甲基)噻吩并[2,3-d]
嘧啶-4-基胺
如实例13所述,用4-氟代哌啶盐酸盐和苯并呋喃-2-甲腈分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1H NMR(氯仿-d,300MHz):δ=7.45-7.74(m,3H),7.30(m,1H),7.20(m,1H),6.94(br.s.,1H),5.28(br.s.,2H),4.66(d,J=48.6Hz,1H),4.46-4.67(m,1H),3.71(s,2H),2.38-2.66(m,4H),1.72-1.94ppm(m,4H);MS m/e 383(M+H)。
实例60:2-(3-氟-苯基)-6-(4-氟-哌啶-1-基甲基)-噻吩并[2,3-d]嘧啶
-4-基胺
如实例13所述,用4-氟代哌啶盐酸盐和3-氟-苄腈分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1H NMR(氯仿-d,300MHz):δ=8.22(d,J=7.9Hz,1H),8.13(m,1H),7.42(td,J=8.0,5.8Hz,1H),7.08-7.19(m,1H),7.02(br.s.,1H),5.22(br.s.,2H),4.74(d,J=48.6Hz,1H),3.79(s,2H),2.65(m,4H),1.80-2.03ppm(m,4H);MS m/e 361(M+H)。
实例61:2-(3-氟-苯基)-6-吗啉-4-基甲基-噻吩并[2,3-d]嘧啶-4-基
胺
如实例13所述,用吗啉和3-氟-苄腈分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1H NMR(氯仿-d,300MHz):δ=8.24(d,J=7.9Hz,1H),8.15(dt,J=10.5,2.1Hz,1H),7.44(td,J=8.0,5.8Hz,1H),7.07-7.22(m,1H),7.03(s,1H),5.23(br.s.,2H),3.69-3.84(m,6H),2.51-2.63ppm(m,4H);MS m/e 345(M+H)。
实例62:3-[4-氨基-6-(3,3-二氟-哌啶-1-基甲基)-噻吩并[2,3-d]嘧啶
-2-基]-苄腈
如实例13所述,用3,3-二氟代哌啶盐酸盐和1,3-二氰基苯分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1H NMR(300MHz,氯仿-D)δppm 8.77(t,J=1.5Hz,1H),8.68(dt,J=7.9,1.5Hz,1H),7.70(dt,J=7.6,1.5Hz,1H),7.56(t,J=7.9Hz,1H),7.04(s,1H),5.27(br s,2H),3.89(s,2H),2.76(t,JHF=11.1Hz,2H),2.55-2.63(m,2H),1.77-1.99(m,4H);MS m/e 386(M+H)。
实例63:4-[4-氨基-6-(3,6-二氢-2H-吡啶-1-基甲基)-噻吩并[2,3-d]
嘧啶-2-基]-苄腈
如实例13所述,用1,2,3,6-四氢吡啶和1,4-二氰基苯分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1HNMR(300MHz,氯仿-D)δppm 8.56(d,J=8.3Hz,2H),7.74(d,J=8.3Hz,2H),7.05(s,1H),5.76-5.84(m,1H),5.62-5.73(m,1H),5.22(brs,2H),3.86(s,2H),3.08-3.13(m,2H),2.66(t,J=5.7Hz,2H),2.17-2.24(m,2H),MS m/e 348(M+H)。
实例64:3-[4-氨基-6-(2,5-二氢-吡咯-1-基甲基)-噻吩并[2,3-d]嘧啶
-2-基]-苄腈
如实例13所述,用3-吡咯啉和1,3-二氰基苯分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1H NMR(300MHz,DMSO-D6)δppm 8.60-8.69(m,2H),7.91-7.99(m,1H),7.70(t,J=7.7Hz,1H),7.60(br s,2H),7.47(s,1H),5.83(s,2H),4.03(s,2H),3.52(s,4H);MS m/e 334(M+H)。
实例65:3-(4-氨基-6-吡咯烷-1-基甲基-噻吩并[2,3-d]嘧啶-2-基)-
苄腈
如实例13所述,用吡咯烷和1,3-二氰基苯分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1H NMR(300MHz,氯仿-D)δppm 8.76(s,1H),8.67(dt,J=7.9,1.3Hz,1H),7.69(dt,J=7.6,1.5Hz,1H),7.55(t,J=7.7Hz,1H),7.03(s,1H),5.32(br s,2H),3.90(s,2H),2.58-2.68(m,4H),1.77-1.89(m,4H);MS m/e 336(M+H)。
实例66:4-[4-氨基-6-(4-氟-哌啶-1-基甲基)-噻吩并[2,3-d]嘧啶-2-
基]-苄腈
如实例13所述,用4-氟代哌啶盐酸盐和1,4-二氰基苯分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1HNMR(300MHz,氯仿-D)δppm 8.55(d,J=8.7Hz,2H),7.74(d,J=8.7Hz,2H),7.01(s,1H),5.25(s,2H),4.74(d,JHF=48.6Hz,1H),3.78(s,2H),2.48-2.69(m,4H),1.85-1.99(m,4H);MS m/e 368(M+H)。
实例67:4-(4-氨基-6-氮杂环庚烷-1-基甲基-噻吩并[2,3-d]嘧啶-2-
基)-苄腈
如实例13所述,用六亚甲基亚胺和1,4-二氰基苯分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1H NMR(300MHz,氯仿-D)δppm 8.55(d,J=8.3Hz,2H),7.74(d,J=8.3Hz,2H),6.98(s,1H),5.24(br s,2H),3.90(s,2H),2.65-2.75(m,4H),1.64(m,8H);MS m/e 364(M+H)。
实例68:3-[4-氨基-6-(3,6-二氢-2H-吡啶-1-基甲基)-噻吩并[2,3-d]
嘧啶-2-基]-苄腈
如实例13所述,用1,2,3,6-四氢吡啶和1,3-二氰基苯分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1HNMR(300MHz,氯仿-D)δppm 8.75(t,J=1.5Hz,1H),8.66(ddd,J=8.1,1.3,1.1Hz,1H),7.69(ddd,J=7.7,1.3,1.1Hz,1H),7.55(t,J=7.7Hz,1H),7.06(s,1H),5.75-5.82(m,1H),5.64-5.71(m,1H),5.39(br s,2H),3.86(s,2H),3.06-3.15(m,2H),2.67(t,J=5.7Hz,2H),2.17-2.24(m,2H);MS m/e 348(M+H)。
如实例13所述,用3-吡咯啉和4-唑甲腈分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1H NMR(300MHz,MeOD)δppm 8.51(s,1H),8.28(s,1H),7.34(s,1H),5.83(s,2H),4.13(s,2H),3.63(s,4H);MS m/e 300(M+H)。
如实例13所述,用1,2,3,6-四氢吡啶和4-唑甲腈分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1H NMR(300MHz,氯仿-D)δppm 8.41(s,1H),7.98(s,1H),7.04(s,1H),5.74-5.83(m,1H),5.64-5.71(m,1H),5.44(br s,2H),3.85(s,2H),3.06-3.12(m,2H),2.65(t,J=5.7Hz,2H),2.15-2.24(m,2H);MS m/e 314(M+H)。
实例71:6-(4-氟-哌啶-1-基甲基)-2-(3-甲氧基-苯基)-噻吩并[2,3-d]
嘧啶-4-基胺
如实例13所述,用4-氟代哌啶盐酸盐和3-甲氧基苄腈分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1HNMR(300MHz,氯仿-D)δppm 8.02(dt,J=7.6,1.3Hz,1H),7.99(dd,J=2.6,1.5Hz,1H),7.37(t,J=7.9Hz,1H),6.96-7.02(m,2H),5.18(brs,2H),4.72(d,JHF=49.0Hz,1H),3.92(s,3H),3.76(s,2H),2.59-2.69(m,2H),2.47-2.57(m,2H),1.85-1.99(m,4H);MS m/e 373(M+H)。
实例72:5-[4-氨基-6-(4-氟-哌啶-1-基甲基)-噻吩并[2,3-d]嘧啶-2-
基]-噻吩-2-甲腈
实例72:步骤a
6-甲基-2-甲硫基-噻吩并[2,3-d]嘧啶-4-基胺
将固体2-氨基-5-甲基噻吩-3-甲腈(6.0g,43.5mmol,1当量)添加至盐酸在1,4-二烷(60mL)中的4M溶液,然后添加硫氰酸甲酯(2.98mL,43.5mmol,1当量)。将所得的悬浮液在压力管中加热至70℃持续24小时。让该混合物冷却至23℃并通过真空过滤收集棕色固体沉淀物。让该固体在EtOAc和饱和NaHCO3水溶液之间分配。用EtOAc萃取水相。将有机萃取物干燥(Na2SO4)、过滤并浓缩,得到棕色固体(5.4g)。通过过滤水相收集收集另外的2.5g的粗产物。将两份6-甲基-2-(甲硫基)噻吩并[2,3-d]嘧啶-4-胺合并并无需进一步纯化使用。
实例72:步骤b
4-氨基-2-甲硫基-噻吩并[2,3-d]嘧啶-6-甲醛
将固体SeO2(12.2g,109.7mmol,3标称当量)添加至6-甲基-2-甲硫基-噻吩并[2,3-d]嘧啶-4-基胺粗产品(7.7g)的二烷(250mL)/水(2mL)悬浮液并加热至回流。23小时后,添加额外的一份二氧化硒(4.1g)并将该混合物继续保持回流。24小时后,通过过滤移除沉淀的固体并浓缩滤液。将该残余固体(17.5g)(由4-氨基-2-甲硫-噻吩并[2,3-d]嘧啶-6-甲醛粗产物组成)无需进一步纯化使用。
实例72:步骤c
6-(4-氟-哌啶-1-基甲基)-2-甲硫基-噻吩并[2,3-d]嘧啶-4-基胺
将固体NaBH(OAc)3(3.1g,14.4mmol)添加至4-氨基-2-甲硫基-噻吩并[2,3-d]嘧啶-6-甲醛粗产物(4.3g)和4-氟代哌啶盐酸盐(2.7g,19.3mmol)的THF溶液(80mL)并将所得的混合物加热至40℃。3天后,TLC分析表明有剩余的醛起始物;添加额外的数份所述胺盐酸盐和三乙酰氧基硼氢化钠(上述量的二分之一)。搅拌3小时后,添加额外的1.5g三乙酰氧基硼氢化钠,从而在40℃下1小时后所述醛消耗完全。通过添加水(3mL)淬灭过量的该氢化物试剂。浓缩该混合物并将残余物在EtOAc和饱和的NaHCO3水溶液之间分配。用EtOAc萃取水相并用饱和的NaCl水溶液洗涤合并的有机萃取物。将该有机相干燥(Na2SO4)、过滤并浓缩,通过快速柱层析(SiO2,60-100%的EtOAc-庚烷梯度)纯化残余物,从而得到782mg的标题化合物。
实例72:步骤d
[6-(4-氟-哌啶-1-基甲基)-2-甲硫基-噻吩并[2,3-d]嘧啶-4-基]-双氨
基甲酸叔丁酯
将固体DMAP(37mg,0.30mmol)添加至6-(4-氟-哌啶-1-基甲基)-2-甲硫基-噻吩并[2,3-d]嘧啶-4-基胺(951mg,3.04mmol)和(Boc)2O(1.7g,7.61mmol)的THF溶液(8mL)并在室温下搅拌该溶液。2.5小时后,浓缩该反应混合物并通过柱层析纯化残余物而得到1.24g的标题化合物。1H NMR(300MHz,氯仿-d)δppm 6.89(s,1H),4.72(dm,JHF=48.6Hz,1H),3.74(s,2H),2.58-2.72(m,5H),2.45-2.56(m,2H),1.84-1.99(m,4H),1.43(s,18H)。
实例72:步骤e
5-[4-氨基-6-(4-氟-哌啶-1-基甲基)-噻吩并[2,3-d]嘧啶-2-基]-噻吩
-2-甲腈
(21):将压力管装上[6-(4-氟-哌啶-1-基甲基)-2-甲硫基-噻吩并[2,3-d]嘧啶-4-基]-双氨基甲酸叔丁酯(54mg,0.11mmol)、5-氰基噻吩-2-硼酸(32mg,0.21mmol)、噻吩-2-甲酸亚铜(40mg,0.212mmol)和Pd(dppf)Cl2(9mg,0.01mmol)。抽空该容器并用氮气吹扫(3个循环),然后添加1,4-二烷(0.5mL)。将该密封管在80℃油浴中加热。在总共反应时间达16小时和22小时后,添加额外的数份硼酸以及铜和钯催化剂(与上述量相同)。总反应时间达2天后,用乙酸乙酯稀释该反应混合物并过滤以除去沉淀的固体。用10%的氢氧化铵水溶液洗涤(3×50mL)并将有机相干燥(Na2SO4)、过滤并浓缩。将残余物用柱层析纯化、溶解于二氯甲烷(3mL)和三氟乙酸(3mL)中并将该混合物在23℃下搅拌20分钟。浓缩该混合物并将残余物在二氯甲烷和饱和的NaHCO3水溶液之间分配。用二氯甲烷萃取水相并将合并的有机萃取物干燥(Na2SO4)、过滤并浓缩。将残余物通过柱层析纯化而得到20mg的标题化合物。1H NMR(300MHz,氯仿-D)δppm 7.87(d,J=3.8Hz,1H),7.60(t,J=4.5Hz,1H),7.08(s,1H),5.37(s,2H),4.76(d,JHF=48.6Hz,1H),3.83(s,2H),2.53-2.77(m,4H),1.86-2.08(m,4H);MS m/e374(M+H)。
实例73:2-[4-氨基-6-(4-氟-哌啶-1-基甲基)-噻吩并[2,3-d]嘧啶-2-
基]-苄腈
如实例85中所述,用2-氰基苯硼酸代替5-氰基噻吩-2-硼酸来制备标题化合物。1H NMR(400MHz,氯仿-D)δppm 8.36(d,J=8.1Hz,1H),7.81(d,J=7.6Hz,1H),7.67(td,J=7.8,1.3Hz,1H),7.48-7.53(m,1H),7.05(s,1H),5.36(s,2H),4.74(d,JHF=48.7Hz,1H),3.79(s,2H),2.47-2.70(m,4H),1.83-2.02(m,4H);MS m/e 368(M+H)。
实例74:3-(4-氨基-6-吗啉-4-基甲基-噻吩并[2,3-d]嘧啶-2-基)-苄
腈
如实例13所述,用吗啉和1,3-二氰基苯分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1H NMR(300MHz,氯仿-D)δppm 8.76(s,1H),8.67(dt,J=7.9,1.5Hz,1H),7.70(dt,J=7.8,1.4Hz,1H),7.55(t,J=7.9Hz,1H),7.03(s,1H),5.34(br s,2H),3.71-3.81(m,6H),2.51-2.63(m,4H);MS m/e 352(M+H)。
实例75:6-吗啉-4-基甲基-2-
唑-2-基-噻吩并[2,3-d]嘧啶-4-基胺
如实例13所述,用吗啉盐酸盐和2-唑甲腈分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1H NMR(300MHz,甲醇-D4)δppm 8.10(s,1H),7.41(s,1H),7.35(s,1H),3.79(s,2H),3.68-3.73(m,4H),2.49-2.59(m,4H);MS m/e 318(M+H)。
实例76:2-苯并[1,3]二氧杂环戊烯-5-基-6-(4-氟-哌啶-1-基甲基)-
噻吩并[2,3-d]嘧啶-4-基胺
如实例85中所述,用3,4-亚甲基二氧基苯硼酸代替5-氰基噻吩-2-硼酸来制备标题化合物。1H NMR(300MHz,氯仿-D)δppm 8.02(dd,J=8.3,1.9Hz,1H),7.92(d,J=1.5Hz,1H),6.94(s,1H),6.89(d,J=8.3Hz,1H),6.02(s,2H),5.18(s,2H),4.72(d,JHF=49.0Hz,1H),3.74(s,2H),2.58-2.68(m,2H),2.46-2.55(m,2H),1.83-2.03(m,4H);MSm/e 387(M+H)。
实例77:3-[4-氨基-6-(7-氮杂-二环[2.2.1]庚-7-基甲基)-噻吩并
[2,3-d]嘧啶-2-基]-苄腈
如实例13所述,用7-氮杂二环[2.2.1]庚烷盐酸盐和1,3-二氰基苯分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1H NMR(400MHz,DMSO-D6)δppm 8.60-8.66(m,2H),7.92(ddd,J=7.7,1.5,1.3Hz,1H),7.69(t,J=7.8Hz,1H),7.55(br s,2H),7.40(s,1H),3.74(s,2H),3.26(s,2H),1.71(d,J=5.9Hz,4H),1.29(d,J=6.6Hz,4H);MS m/e 362(M+H)。
实例78:6-(4-氟-哌啶-1-基甲基)-2-(1-甲基-1H-吡咯-2-基)-噻吩并
[2,3-d]嘧啶-4-基胺
如实例85中所述,用N-甲基吡咯-2-硼酸、频哪醇酯代替5-氰基噻吩-2-硼酸来制备标题化合物。1H NMR(300MHz,氯仿-D)δppm7.05(dd,J=3.8,1.9Hz,1H),6.89(s,1H),6.73(t,J=2.1Hz,1H),6.17(dd,J=3.8,2.6Hz,1H),5.25(br s,2H),4.71(d,JHF=48.6Hz,1H),4.09(s,3H),3.72(s,2H),2.58-2.68(m,2H),2.45-2.53(m,2H),1.84-1.99(m,4H);MS m/e 346(M+H)。
实例79:6-(4-氟-哌啶-1-基甲基)-2-(2-异丙基-苯基)-噻吩并[2,3-d]
嘧啶-4-基胺
如实例85中所述,用2-异丙基苯基硼酸代替5-氰基噻吩-2-硼酸来制备标题化合物。1H NMR(300MHz,氯仿-D)δppm 7.51(d,J=7.2Hz,1H),7.35-7.44(m,2H),7.21-7.28(m,1H),6.99(s,1H),5.36(s,2H),4.73(d,JHF=48.6Hz,1H),3.77(s,2H),3.44(sept,J=6.9Hz,1H),2.49-2.70(m,4H),1.85-2.04(m,4H),1.22(d,J=6.8Hz,6H);MSm/e 385(M+H)。
实例80:6-(3,6-二氢-2H-吡啶-1-基甲基)-2-(3-甲氧基-苯基)-噻吩
并[2,3-d]嘧啶-4-基胺
如实例13所述,用1,2,3,6-四氢吡啶和3-甲氧基苄腈分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1HNMR(300MHz,氯仿-D)δppm 7.98-8.04(m,2H),7.36(t,J=7.9Hz,1H),6.97-7.02(m,2H),5.74-5.82(m,1H),5.63-5.72(m,1H),5.28(br s,2H),3.91(s,3H),3.84(s,2H),3.05-3.14(m,2H),2.65(t,J=5.7Hz,2H),2.14-2.24(m,2H);MS m/e 353(M+H)。
实例81:6-(4-氟-哌啶-1-基甲基)-2-(1H-吡咯-2-基)-噻吩并[2,3-d]
嘧啶-4-基胺
如实例85中所述,用1-(叔丁氧羰基)吡咯-2-硼酸代替5-氰基噻吩-2-硼酸来制备标题化合物。1H NMR(400MHz,氯仿-D)δppm 9.63(br s,1H),7.09(s,2H),6.95(s,1H),6.31-6.38(m,1H),4.77(d,JHF=48.4Hz,1H),3.85(s,2H),2.73(br m,4H),1.96(br m,4H);MSm/e 332(M+H)。
实例82:3-[4-氨基-6-(4-氟-哌啶-1-基甲基)-噻吩并[2,3-d]嘧啶-2-
基]-苄腈
如实例13所述,用4-氟代哌啶盐酸盐和1,3-二氰基苯分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1HNMR(400MHz,氯仿-D)δppm 8.77(s,1H),8.68(d,J=8.1Hz,1H),7.70(dt,J=7.7,1.3Hz,1H),7.56(t,J=7.8Hz,1H),7.00(s,1H),5.26(s,2H),4.73(d,JHF=48.7Hz,1H),3.78(s,2H),2.59-2.69(m,2H),2.48-2.58(m,2H),1.87-1.02(m,4H);MS m/e 368(M+H)。
实例83:3-(4-氨基-6-硫代吗啉-4-基甲基-噻吩并[2,3-d]嘧啶-2-
基)-苄腈
如实例13所述,用硫代吗啉和1,3-二氰基苯分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1H NMR(300MHz,MeOD)δppm 8.61-8.67(m,2H),7.93(ddd,J=7.7,1.3,1.1Hz,1H),7.70(t,J=7.7Hz,1H),7.60(br s,2H),7.45(s,1H),3.78(s,2H),2.69-2.76(m,4H),2.61-2.67(m,4H);MS m/e 368(M+H)。
实例84:2-(3-甲氧基-苯基)-6-吗啉-4-基甲基-噻吩并[2,3-d]嘧啶
-4-基胺
如实例13所述,用吗啉和3-甲氧基苄腈分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1H NMR(300MHz,氯仿-D)δppm 7.97-8.06(m,2H),7.37(t,J=7.9Hz,1H),7.01(dd,J=2.6,0.8Hz,1H),6.98(s,1H),5.27(br s,2H),3.91(s,3H),3.71-3.77(m,6H),2.52-2.57(m,4H);MS m/e 357(M+H)。
实例85:2-(3-甲氧基-苯基)-6-硫代吗啉-4-基甲基-噻吩并[2,3-d]
嘧啶-4-基胺
如实例13所述,用硫代吗啉和3-甲氧基苄腈分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1H NMR(300MHz,氯仿-D)δppm 7.97-8.04(m,2H),7.37(t,J=7.9Hz,1H),7.00(ddd,J=8.1,2.6,0.9Hz,1H),6.95(s,1H),5.26(s,2H),3.91(s,3H),3.76(s,2H),2.76-2.84(m,4H),2.67-2.74(m,4H);MS m/e 373(M+H)。
实例86:6-(3,3-二氟-哌啶-1-基甲基)-2-(3-甲氧基-苯基)-噻吩并
[2,3-d]嘧啶-4-基胺
如实例13所述,用3,3-二氟代哌啶盐酸盐和3-甲氧基苄腈分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1H NMR(300MHz,氯仿-D)δppm 7.97-8.05(m,2H),7.37(t,J=8.1Hz,1H),6.96-7.03(m,2H),5.32(s,2H),3.91(s,3H),3.85(s,2H),2.74(t,JHF=11.1Hz,2H),2.49-2.60(m,2H),1.73-1.98(m,4H);MS m/e 391(M+H)。
实例87:5-[4-氨基-6-(4-氟-哌啶-1-基甲基)-噻吩并[2,3-d]嘧啶-2-
基]-烟腈
如实例85中所述,用3-氰基-5-(4,4,5,5-四甲基-[1,3,2]二氧硼戊环-2-基)吡啶代替5-氰基噻吩-2-硼酸来制备标题化合物。1H NMR(300MHz,DMSO-D6)δppm 9.66(d,J=1.9Hz,1H),9.11(d,J=1.9Hz,1H),8.93(t,J=2.1Hz,1H),7.70(br s,2H),7.47(s,1H),4.72(d,JHF=49.0Hz,1H),3.76(s,2H),2.37-2.67(m,4H),1.66-1.97(m,4H);MS m/e369(M+H)。
实例88:4-[4-氨基-6-(2,5-二氢-吡咯-1-基甲基)-噻吩并[2,3-d]嘧啶
-2-基]-苄腈
如实例13所述,用3-吡咯啉和1,4-二氰基苯分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1H NMR(300MHz,氯仿-D)δppm 8.55(d,J=8.7Hz,2H),7.74(d,J=8.7Hz,2H),7.04(s,1H),5.81(s,2H),5.23(br s,2H),4.09(s,2H),3.61(s,4H);MS m/e 334(M+H)。
实例89:2-(5-氯-呋喃-2-基)-6-(4-氟-哌啶-1-基甲基)-噻吩并[2,3-d]
嘧啶-4-基胺盐酸盐
实例89:步骤a
4-氨基-2-呋喃-2-基-噻吩并[2,3-d]嘧啶-6-甲醛
如实例13中所述,用2-呋喃-2-基-6-甲基-噻吩并[2,3-d]嘧啶-4-基胺(实例1中制备)代替2-(5-叔丁基-噻吩-2-基)-6-甲基-噻吩并[2,3-d]嘧啶-4-基胺来制备标题化合物。
实例89:步骤b
4-氨基-2-(5-氯-呋喃-2-基)-噻吩并[2,3-d]嘧啶-6-甲醛
将固体NCS(196mg,1.5mmol)添加至4-氨基-2-呋喃-2-基-噻吩并[2,3-d]嘧啶-6-甲醛(300mg,1.2mmol)的THF溶液(10mL)并将该混合物加热至50℃。16小时后,将该混合物用EtOAc稀释、用水和盐水洗涤、干燥(Na2SO4)并浓缩而得到325mg的标题化合物,将其无需进一步纯化使用。
实例89:步骤c
2-(5-氯-呋喃-2-基)-6-(4-氟-哌啶-1-基甲基)-噻吩并[2,3-d]嘧啶-4-
基胺盐酸盐
如实例13所述,用4-氟代哌啶盐酸盐和4-氨基-2-(5-氯-呋喃-2-基)-噻吩并[2,3-d]嘧啶-6-甲醛分别代替顺式-2,6-二甲基-哌啶和4-氨基-2-(5-叔丁基-噻吩-2-基)-噻吩并[2,3-d]嘧啶-6-甲醛来制备标题化合物。1H NMR(DMSO-d6,300MHz):δ=7.72(s,1H),7.24(d,J=3.4Hz,1H),6.70(d,J=3.4Hz,1H),4.64(br.s.,2H),3.35(br.s.,1H),3.16(br.s.,4H),2.08ppm(br.s.,4H);MS m/e 367(M+H)。
实例90:2-(5-氯-呋喃-2-基)-6-吡咯烷-1-基甲基-噻吩并[2,3-d]嘧
啶-4-基胺盐酸盐
如实例107所述,用吡咯烷代替4-氟代哌啶盐酸盐来制备标题化合物。1H NMR(DMSO-d6,300MHz):δ=7.65(br.s.,1H),7.18(d,J=3.8Hz,1H),6.67(d,J=3.4Hz,1H),3.99(br.s.,2H),2.68(br.m,4H),1.66-1.89(m,4H);MS m/e 335(M+H)。
实例91:6-(金刚烷-1-基氨基甲基)-2-呋喃-2-基-噻吩并[2,3-d]嘧
啶-4-基胺
如实例13所述,用1-金刚烷胺和2-糠腈分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1H NMR(DMSO-d6,300MHz):δ=9.98(s,1H),8.52(s,1H),8.13(br.s.,2H),7.92(s,1H),7.29(d,J=3.4Hz,1H),6.70(d,J=1.9Hz,1H),4.30(br.s.,2H),1.75-1.91(m,8H),1.69(br.s.,4H),1.57ppm(br.s.,3H);MSm/e 381(M+H)。
实例92:6-(4-氟-哌啶-1-基甲基)-2-呋喃-2-基-噻吩并[2,3-d]嘧啶
-4-基胺盐酸盐
如实例13所述,用4-氟代哌啶盐酸盐和2-糠腈分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1H NMR(DMSO-d6,300MHz):δ=7.93(br.s.,1H),7.72(s,1H),7.24(d,J=3.4Hz,1H),6.70(d,J=3.4Hz,1H),4.64(br.s.,2H),3.35(m.,1H),3.16(br.s.,4H),2.08ppm(br.s.,4H);MS m/e 333(M+H)。
实例93:6-氮杂环庚烷-1-基甲基-2-(5-氯-呋喃-2-基)-噻吩并[2,3-d]
嘧啶-4-基胺
如实例107所述,用六亚甲基亚胺代替4-氟代哌啶盐酸盐来制备标题化合物。1H NMR(DMSO-d6,300MHz):δ=7.74(s,1H),7.24(br.s.,1H),6.79(s,1H),4.61(br.s.,2H),4.50(br.s.,2H),3.38(br.s.,2H),3.13(br.s.,4H),1.84(br.s.,4H),1.63(br.s.,4H);MS m/e 363(M+H)。
实例94:6-(3,3-二氟-吡咯烷-1-基甲基)-2-呋喃-2-基-噻吩并[2,3-d]
嘧啶-4-基胺
如实例13所述,用3,3-二氟-吡咯烷盐酸盐和2-糠腈分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1HNMR(DMSO-d6,300MHz):δ=7.82(s,1H),7.54(s,2H),7.42(s,1H),7.12(d,J=3.4Hz,1H),6.63(dd,J=3.4,1.9Hz,1H),3.88(s,2H),2.97(t,J=13.4Hz,2H),2.80(t,J=7.0Hz,2H),2.13-2.40ppm(m,2H);MSm/e 337(M+H)。
实例95:2-(5-氯-呋喃-2-基)-6-(3,6-二氢-2H-吡啶-1-基甲基)-噻吩
并[2,3-d]嘧啶-4-基胺
如实例107所述,用1,2,3,6-四氢吡啶代替4-氟代哌啶盐酸盐来制备标题化合物。1H NMR(氯仿-d,300MHz):δ=7.22(d,J=3.4Hz,1H),7.00(s,1H),6.33(d,J=3.4Hz,1H),5.73-5.85(m,1H),5.60-5.73(m,1H),5.29(br.s.,2H),3.83(s,2H),3.04-3.15(m,2H),2.64(t,J=5.8Hz,2H),2.14-2.25ppm(m,2H);MS m/e 347(M+H)。
实例96:2-环丙基-6-(3,6-二氢-2H-吡啶-1-基甲基)-噻吩并[2,3-d]
嘧啶-4-基胺
如实例13所述,用1,2,3,6-四氢吡啶和环丙腈分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1H NMR(DMSO-d6,300MHz):δ=7.84(s,1H),5.91(br.s.,1H),5.72(br.s.,1H),4.65(br.s.,2H),3.65(br.s.,2H),3.15(br.s.,2H),2.35(m,2H),2.15(br.s.,2H),1.26(m,1H),1.12ppm(br.s.,4H);MS m/e 287(M+H)。
实例97:2-(5-氯-呋喃-2-基)-6-(2,5-二氢-吡咯-1-基甲基)-噻吩并
[2,3-d]嘧啶-4-基胺
如实例107所述,用3-吡咯啉代替4-氟代哌啶盐酸盐来制备标题化合物。1H NMR(DMSO-d6,300MHz):δ=7.45(s,1H),7.19(d,J=3.0Hz,1H),6.85(s,2H),6.67(d,J=3.0Hz,1H),5.37(s,2H),4.28ppm(br.s.,6H);MS m/e 333(M+H)。
实例98:6-(3,6-二氢-2H-吡啶-1-基甲基)-2-呋喃-2-基-噻吩并
[2,3-d]嘧啶-4-基胺
如实例13所述,用1,2,3,6-四氢吡啶和2-糠腈分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1H NMR(氯仿-d,300MHz):δ=7.60(s,1H),7.25(s,1H),7.00(s,1H),6.55(dd,J=3.4,1.9Hz,1H),5.77(br.s.,1H),5.69(br.s.,1H),5.25(br.s.,2H),3.83(s,2H),2.99-3.16(m,2H),2.64(t,J=5.7Hz,2H),2.12-2.26ppm(m,2H);MS m/e 313(M+H)。
实例99:2-(5-二氟代甲基-呋喃-2-基)-6-(4,4-二氟-哌啶-1-基甲基)-
噻吩并[2,3-d]嘧啶-4-基胺
实例99:步骤a
5-二氟甲基-呋喃-2-甲腈
向Et2NSF3(2.8mL,21.4mmol)和CH2Cl2(10mL)的4℃溶液添加5-甲酰基-呋喃-2-甲腈(2.44g,20.2mmol;W.Hoyle和G.P.Roberts,J.Med.Chem.1973,16,709)在CH2Cl2(10mL)中的溶液。4℃下30分钟后,添加饱和的NaHCO3水溶液,分层并用CH2Cl2萃取水层。将合并的有机层干燥(Na2SO4)并浓缩以得到2.15g的5-二氟甲基-呋喃-2-甲腈,将其无需进一步纯化使用。
实例99:步骤b
2-(5-二氟代甲基-呋喃-2-基)-6-(4,4-二氟-哌啶-1-基甲基)-噻吩并
[2,3-d]嘧啶-4-基胺
如实例13所述,用4,4-二氟代哌啶盐酸盐和5-二氟代甲基-呋喃-2-甲腈分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1H NMR(400MHz,丙酮-d6)δ=7.41(s,1H),7.21(d,J=3.4Hz,1H),7.01(t,J=53.7Hz,1H),6.94-6.99(m,1H),6.92(br.s.,2H),3.87(d,J=1.0Hz,2H),2.66(t,J=5.5Hz,4H),1.95-2.04(m,4H);MS m/e 401(M+H)。
实例100:2-(5-二氟代甲基-呋喃-2-基)-6-(4-氟-哌啶-1-基甲基)-
噻吩并[2,3-d]嘧啶-4-基胺
如实例119所述,用4-氟代哌啶盐酸盐代替4,4-二氟代哌啶盐酸盐来制备标题化合物。1H NMR(400MHz,丙酮-d6)δ=7.39(s,1H),7.20(d,J=3.7Hz,1H),7.01(t,J=53.7Hz,1H),6.94-6.98(m,1H),6.89(br.s.,2H),3.78(d,J=1.2Hz,2H),2.61-2.71(m,2H),2.43-2.52(m,2H),2.08-2.10(m,1H),1.74-1.99(m,4H);MS m/e 383(M+H)。
实例101:2-(5-二氟代甲基-呋喃-2-基)-6-(3,3-二氟-哌啶-1-基甲
基)-噻吩并[2,3-d]嘧啶-4-基胺
如实例119所述,用3,3-二氟代哌啶盐酸盐代替4,4-二氟代哌啶盐酸盐来制备标题化合物。1H NMR(400MHz,丙酮-d6)δ=7.41(s,1H),7.21(d,J=3.7Hz,1H),7.01(t,J=53.7Hz,1H),6.89-6.98(m,3H),3.90(s,2H),2.77(t,J=11.5Hz,2H),2.58(t,J=5.0Hz,2H),1.85-1.98(m,2H),1.71-1.81(m,2H);MS m/e 401(M+H)。
实例102:2-(5-二氟代甲基-呋喃-2-基)-6-(2,6-二甲基-哌啶-1-基甲
基)-噻吩并[2,3-d]嘧啶-4-基胺
如实例119所述,用顺式-2,6-二甲基-哌啶代替4,4-二氟代哌啶盐酸盐来制备标题化合物。1H NMR(400MHz,丙酮-d6)δ=7.40(s,1H),7.19(d,J=3.4Hz,1H),7.00(t,J=53.7Hz,1H),6.93-6.97(m,1H),6.89(br.s.,1H),4.08(s,2H),2.50-2.62(m,2H),1.53-1.67(m,4H),1.27-1.33(m,2H),1.15(d,J=6.4Hz,6H);MS m/e 393(M+H)。
实例103:6-二乙基氨基甲基-2-(5-二氟代甲基-呋喃-2-基)-噻吩并
[2,3-d]嘧啶-4-基胺
如实例119所述,用二乙胺代替4,4-二氟代哌啶盐酸盐来制备标题化合物。1H NMR(300MHz,CDCl3)δ=7.27(s,1H),6.97(s,1H),6.80-6.85(m,1H),6.78(t,J=54.3Hz,1H),6.52(br.s.,2H),3.85(s,2H),2.61(q,J=7.2Hz,4H),1.08(t,J=7.0Hz,6H);MS m/e 353(M+H)。
实例104:2-(2-氯-吡啶-4-基)-6-哌啶-1-基甲基-噻吩并[2,3-d]嘧啶
-4-基胺
如实例13所述,用哌啶和2-氯-异烟腈分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1H NMR(300MHz,DMSO-d6)δ=8.53(d,J=5.3Hz,1H),8.13-8.29(m,2H),7.68(s,2H),7.46(s,1H),3.70(s,2H),2.91-3.11(m,2H),2.29-2.45(m,4H),1.34-1.58(m,4H);MS m/e 360/362(M+H)。
实例105:2-(2-氯-吡啶-4-基)-6-吗啉-4-基甲基-噻吩并[2,3-d]嘧啶
-4-基胺
如实例13所述,用吗啉和2-氯-异烟腈分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1H NMR(300MHz,CDCl3)δ=8.48(d,J=5.3Hz,1H),8.34(s,1H),8.21(dd,J=1.5,5.3Hz,1H),7.05(s,1H),5.36(br.s.,2H),3.70-3.86(m,6H),2.47-2.65(m,4H);MS m/e 362/364(M+H)。
实例106:3-(4-氨基-6-吗啉-4-基甲基-噻吩并[2,3-d]嘧啶-2-基)-
苯酚
如实例13所述,用吗啉和3-羟基-苄腈分别代替顺式-2,6-二甲基-哌啶和5-叔丁基-噻吩-2-甲腈来制备标题化合物。1H NMR(300MHz,丙酮-d6)δ=8.36(br.s.,1H),7.99(s,1H),7.96(d,J=7.9Hz,1H),7.38(s,1H),7.26(t,J=7.7Hz,1H),6.91(dd,J=2.6,7.9Hz,1H),6.74(br.s.,2H),3.76(s,2H),3.64(t,J=4.5Hz,4H),2.38-2.59(m,4H);MSm/e 343(M+H)。
实例107:2-(5-二氟代甲基-呋喃-2-基)-6-吗啉-4-基甲基-噻吩并
[2,3-d]嘧啶-4-基胺
如实例119所述,用吗啉代替4,4-二氟代哌啶盐酸盐来制备标题化合物。1H NMR(400MHz,DMSO-d6)δ=7.63(br.s.,2H),7.43(s,1H),7.19(d,J=3.4Hz,1H),7.16(t,J=53.3Hz,1H),7.02(m,1H),3.72(s,2H),3.59(t,J=4.4Hz,4H),2.44(m,4H);MS m/e 367(M+H)。
生物学测定和活性
腺苷A2a受体的配体结合测定
使用含有人A2a腺苷受体的HEK293细胞的质膜(PerkinElmer,RB-HA2a)和放射性配体[3H]CGS21680(PerkinElmer,NET1021)进行腺苷A2a受体的配体结合测定。在总体积为200μL的96-孔聚丙烯板中,通过顺序加入20μL以1∶20稀释的膜、130μL含有[3H]CGS21680的测定缓冲液(50mM Tris·HCl,pH7.410mM MgCl2,1mM EDTA)、50μL用测定缓冲液稀释的化合物(4x)或溶媒对照来建立测定。通过80mM的NECA测定非特异性结合。在室温下进行2小时的反应,然后滤过在含有0.3%聚乙烯亚胺的50mM Tris·HCl,pH7.4中预先浸渍过的96孔GF/C滤板。然后将滤板用冷的50mM Tris·HCl,pH7.4洗涤5次,干燥并在底部密封。将微板闪烁流体30μL添加至每个孔并密封顶部。将滤板在Packard Topcount上针对[3H]进行计数。在Microsoft Excel和GraphPad Prism程序中分析数据。(Varani,K.;Gessi,S.;Dalpiaz,A.;Borea,P.A.British Journal of Pharmacology,1996,117,1693)
腺苷A2a受体功能测定(A2AGAL2)
开始该功能测定时,将过表达人腺苷A2a受体并且含有cAMP诱导型β-半乳糖苷酶报告基因的冷藏保存的CHO-K1细胞解冻、离心、移除含DMSO的介质,然后与新鲜培养基一起以1万个细胞/孔的浓度接种进透明的组织培养物处理过的384孔板(BD #353961)中。在测定前,将板在37℃、5%CO2、90%相对湿度下培养两天。在功能测定的当天,移除培养基并替换为45uL测定培养基(Hams/F-12改良培养基(Mediatech # 10-080CV),补充有0.1%BSA)。在100%DMSO中稀释测试化合物并以1000x浓度产生11点浓度曲线。在将测定培养基添加至细胞板后,立刻用Cartesian Hummingbird将50nL的适当测试化合物拮抗剂或激动剂对照浓度曲线添加至细胞板。让化合物浓度曲线在室温下在细胞板上孵育大约15分钟,然后添加15nM NECA(Sigma E2387)激动剂测试物(5uL体积)。在每个板上还包括了NECA对照浓度曲线、DMSO/培养基对照和单种剂量的毛喉素(SigmaF3917)。添加后,让细胞板在37℃、5%CO2、90%相对湿度下孵育5.5-6小时。孵育后,移除培养基,用50uL无Ca和Mg的DPBS(Mediatech 21-031-CV)洗涤细胞板1次。向干的孔中,将20uL的1x报告基因裂解缓冲液(Promega E3971(从5x母液稀释于dH2O中))添加至每孔并将板在-20℃下冷冻过夜。对于β-半乳醣苷酶比色测定,将板在室温下解冻并将20μL 2X测定缓冲液(Promega)添加至每孔。在37℃、5%CO2、90%相对湿度下显色1-1.5小时或直到适当的信号出现。添加60μL/孔的1M碳酸钠来终止该比色反应。在SpectraMax酶标仪(Molecular Devices)上于405nm下对板进行计数。在MicrosoftExcel中分析数据并用标准化的macro拟合IC/EC50曲线。
腺苷A1受体功能测定(A1GAL2)
开始该功能测定时,将过表达人腺苷A1受体并且含有cAMP诱导型β-半乳糖苷酶报告基因的冷藏保存的CHO-K1细胞解冻、离心、移除含DMSO的介质,然后与新鲜培养基一起以1万个细胞/孔的浓度接种进透明的组织培养物处理过的384孔板(BD #353961)中。在测定前,将板在37℃、5%CO2、90%相对湿度下培养两天。在功能测定的当天,移除培养基并替换为45uL测定培养基(Hams/F-12改良培养基(Mediatech # 10-080CV),补充有0.1%BSA)。在100%DMSO中稀释测试化合物并以1000x浓度产生11点浓度曲线。在将测定培养基添加至细胞板后,立刻用Cartesian Hummingbird将50nL的适当测试化合物拮抗剂或激动剂对照浓度曲线添加至细胞板。让化合物浓度曲线在室温下在细胞板上孵育大约15分钟,然后添加4nM r-PIA(Sigma P4532)/1uM毛喉素(Sigma F3917)激动剂测试物(5uL体积)。在每个板上还包括了r-PIA在1uM毛喉素中的对照浓度曲线、DMSO/培养基对照和单种剂量的毛喉素。添加后,让细胞板在37℃、5%CO2、90%相对湿度下孵育5.5-6小时。孵育后,移除培养基,用50uL无Ca和Mg的DPBS(Mediatech 21-031-CV)洗涤细胞板1次。向干的孔中,将20uL的1x报告基因裂解缓冲液(Promega E3971(从5x母液稀释于dH2O中))添加至每孔并将板在-20℃下冷冻过夜。对于β-半乳醣苷酶比色测定,将板在室温下解冻并将20μL 2X测定缓冲液(Promega)添加至每孔。在37℃、5%CO2、90%相对湿度下显色1-1.5小时或直到适当的信号出现。添加60μL/孔的1M碳酸钠来终止该比色反应。在SpectraMax酶标仪(Molecular Devices)上于405nm下对板进行计数。在Microsoft Excel中分析数据并用标准化的macro拟合IC/EC50曲线。
A2a测定数据
实例 | A2AGAL2 KiμM | A2A-B KiμM | A1GAL2 KiμM |
1 | ND | ND | ND |
2 | ND | ND | ND |
3 | ND | ND | ND |
4 | ND | ND | ND |
5 | ND | ND | ND |
6 | ND | ND | ND |
7 | 0.0183251 | 0.2024437 | 0.698433 |
8 | 0.0781628 | ND | >0.610098 |
9 | 0.0893717 | ND | 0.296893 |
10 | 0.0173061 | ND | 0.143781 |
11 | 0.0248886 | ND | 0.194133 |
12 | 0.114051 | ND | 0.332659 |
13 | >2.33938 | ND | >0.92747 |
14 | >2.33938 | ND | >0.92747 |
15 | 0.207683 | ND | >0.92747 |
16 | 1.01158 | ND | 0.677954 |
实例 | A2AGAL2 KiμM | A2A-B KiμM | A1GAL2 KiμM |
17 | 0.150349 | ND | 1.07152 |
18 | 0.130227 | ND | 0.504197 |
19 | 0.0120282 | ND | 0.0396187 |
20 | 0.153922 | ND | 0.761553 |
21 | >1.36082 | ND | >0.593882 |
22 | 0.958297 | ND | >1.06832 |
23 | 0.0644614 | ND | 0.463767 |
24 | ND | ND | ND |
25 | 0.245301 | ND | 2.73401 |
26 | ND | 0.207491 | ND |
27 | ND | ND | ND |
28 | 0.0280608 | 0.0144212 | 6.43428 |
29 | 0.0362159 | 0.0933469 | 1.89496 |
30 | 0.114604 | 0.139091 | >10 |
31 | 0.0552332 | 0.13671 | 2.13059 |
32 | 0.168035 | 0.1424839 | 2.47971 |
33 | ND | 0.215824 | ND |
34 | 0.0284053 | 0.0186681 | 0.605759 |
35 | 0.0220141 | 0.0150003 | 0.800018 |
36 | ND | 0.371278 | ND |
37 | ND | ND | ND |
38 | 0.0318713 | 0.0327416 | 1.05439 |
39 | 0.0259478 | 0.0108543 | 0.62044 |
40 | ND | 0.374628 | ND |
41 | 0.202162 | 0.186509 | 3.31971 |
42 | 0.053039 | 0.0880643 | 18.20878 |
43 | 0.403832 | ND | >10 |
44 | 0.00564807 | 0.0013999 | 0.099793 |
45 | 0.229087 | 0.19002 | 2.71894 |
46 | 0.142988 | 0.089002 | 3.55386 |
47 | 0.349301 | ND | 2.30356 |
48 | 0.733331 | ND | 0.85546 |
49 | 0.1166 | ND | 0.785417 |
50 | 0.360662 | ND | 2.89468 |
51 | 0.00979942 | 0.0059007 | 1.33906 |
实例 | A2AGAL2 KiμM | A2A-B KiμM | A1GAL2 KiμM |
52 | 0.297303 | 0.219989 | 4.00313 |
53 | 0.0122999 | 0.0139991 | 0.655843 |
54 | 0.0115001 | 0.0081997 | 0.878214 |
55 | 1.05925 | ND | 3.4135 |
56 | 0.0486968 | 0.0209991 | 2.22844 |
57 | 0.00662369 | 0.0084004 | 0.294036 |
58 | 0.0735868 | ND | 0.331207 |
59 | 0.348097 | ND | 0.63387 |
60 | 0.300331 | ND | 1.25026 |
61 | 0.123254 | ND | 0.616311 |
62 | 0.0502805 | 0.383972 | 1.18114 |
63 | 0.177582 | 0.150003 | 1.63155 |
64 | 0.0834833 | 0.0769662 | 2.06538 |
65 | >10 | 0.0417638 | 0.129449 |
66 | 1.3938 | ND | 8.42753 |
67 | 0.383707 | ND | 8.5546 |
68 | 0.0132556 | 0.377833 | 0.211934 |
69 | 0.238451 | 1.01789 | 3.89493 |
70 | 0.240325 | 0.393007 | 2.96415 |
71 | 0.302831 | ND | 3.22181 |
72 | 0.0913061 | ND | 1.90634 |
73 | 1.02873 | 2.02116 | 5.04778 |
74 | 0.0358674 | 0.0932396 | 1.00531 |
75 | 0.356205 | ND | 3.24639 |
76 | 0.209315 | ND | 0.739605 |
77 | 0.0950167 | 0.0749204 | 2.1737 |
78 | 0.634308 | 0.733162 | 1.59845 |
79 | 1.0361 | 7.41481 | 4.46992 |
80 | 0.102282 | 0.183696 | 1.07696 |
81 | 0.795243 | ND | 3.89135 |
82 | 0.0537527 | 0.443608 | 2.94578 |
83 | 0.0649083 | 0.28132 | 1.77746 |
84 | 0.372649 | ND | 2.98951 |
85 | 0.169239 | 0.659326 | 2.95937 |
86 | 0.0974989 | 0.241824 | 1.80884 |
实例 | A2AGAL2 KiμM | A2A-B KiμM | A1GAL2 KiμM |
87 | 6.62217 | ND | >10 |
88 | 0.0788679 | 0.0759976 | 2.35342 |
89 | 0.0358922 | 0.0019002 | 1.07944 |
90 | 0.0222792 | 0.0037 | 0.712033 |
91 | 0.120531 | 0.0150003 | 1.02991 |
92 | 0.0189496 | 0.0119591 | 0.74114 |
93 | 0.0331971 | 0.0018001 | 1.42495 |
94 | 0.00822622 | ND | 1.23509 |
95 | 0.0107424 | 0.0034002 | 0.187629 |
96 | 0.324639 | 1.61994 | 3.01717 |
97 | 0.0102 | 0.00054 | 0.783069 |
98 | 0.008852 | 0.0203236 | 0.1584335 |
99 | 0.61038 | ND | 17.8238 |
100 | 0.0424326 | ND | 1.67456 |
101 | 0.0425109 | ND | 2.10426 |
102 | 0.0276248 | ND | 0.732487 |
103 | 0.130918 | ND | 2.0917 |
104 | 0.691194 | ND | 3.85923 |
105 | 0.12314 | 0.934114 | 0.875588 |
106 | 0.815831 | ND | 2.43781 |
107 | 0.0304719 | 0.0661454 | 2.70147 |
ND指没有可用的数据
虽然上述说明书教导了本发明的原理,并出于说明的目的提供了实例,但应理解,本发明的实施涵盖落入以下权利要求及其等同物的范围内的所有惯常的变化、改变和/或修改。
藉此将上面说明书中公开的所有出版物全文以引用的方式并入本文。
Claims (20)
1.一种由式A表示的化合物及其溶剂化物、水合物和可药用盐
其中:
R1是环丙基、苯并[1,3]二氧杂环戊烯基或选自苯基、氟代苯基和杂芳基的芳环,其中所述芳环任选用一个选自如下的取代基取代:-OH、OC(1-4)烷基、Cl、Br、-CN、F、CHF2、C(1-4)烷基和环丙基;
A1是H或-C(1-4)烷基;
A2是-C(1-4)烷基、-C(1-6)环烷基、-CH2CH2ORa、-CORa、杂芳基、金刚烷基或苯基,其中所述杂芳基或苯基任选用最多三个选自Cl、F、Br、OC(1-4)烷基、OCF3、C(1-4)烷基和C(O)C(1-4)烷基的取代基取代;
作为另一种选择,A1和A2可与它们连接的氮合在一起形成选自如下的杂环:
其中:
n为1或2;
Ra是H、CF3、OH、F或C(1-4)烷基;
Rb是H、-C(1-4)烷基或-C(O)C(1-4)烷基;并且
Rc是H或F。
4.根据权利要求3所述的化合物及其溶剂化物、水合物和可药用盐,其中
R1是环丙基、呋喃基、噻唑基、噻吩基、唑基、异唑基、吡啶基、苯并[1,3]二氧杂环戊烯基、吡咯基、苯并呋喃基、氟代苯基或苯基,其中所述呋喃基、噻唑基、噻吩基、唑基、异唑基、吡啶基、苯并[1,3]二氧杂环戊烯基、吡咯基、苯并呋喃基、氟代苯基或苯基任选用OH、OCH3、Cl、Br、-CN、F、CHF2、OCF3、CH3、CH2CH3、CH(CH3)2、C(CH3)3或环丙基取代;
A1是H或C(1-4)烷基;
A2是C(1-4)烷基、-CH2CH2OCH3、环丙基、金刚烷基或环己基;
作为另一种选择,A1和A2可与它们连接的氮合在一起形成选自如下的杂环:
其中n是1或2。
5.根据权利要求4所述的化合物及其溶剂化物、水合物和可药用盐,其中
R1是环丙基;呋喃基,其中所述呋喃基任选用Cl、Br、环丙基、CH3、CH2CH3、CHF2或CH(CH3)2取代;噻唑基,其中所述噻唑基任选用CH3取代;噻吩基,其中所述噻吩基任选用C(CH3)3或-CN取代;唑基;异唑基;吡啶基,其中所述吡啶基用-CN或Cl取代;苯并[1,3]二氧杂环戊烯基;吡咯基,中所述吡咯基任选用CH3取代;苯并呋喃基;氟代苯基,其中所述氟代苯基任选用F取代;或苯基,其中所述苯基用CN、Cl、OCH3、CON(CH3)2、CH(CH3)2或OH取代;
A1是H、-CH3或-CH2CH3;
A2是-CH3、-CH2CH3、-CH2CH2OCH3、环丙基、金刚烷基或环己基;
作为另一种选择,A1和A2可与它们连接的氮合在一起形成选自如下的杂环:
其中n是1或2。
7.一种药物组合物,所述药物组合物包含根据权利要求1所述的化合物和可药用载体。
8.一种治疗患有可通过拮抗受试者体内适当细胞中的腺苷A2a受体来改善的障碍的受试者的方法,所述方法包括给予所述受试者治疗有效剂量的根据权利要求1所述的化合物。
9.一种预防可通过拮抗受试者体内合适细胞中的腺苷A2a受体来改善的障碍的方法,所述方法包括在预计会引起可通过拮抗所述受试者体内合适细胞中的腺苷A2a受体来改善的障碍的事件之前或之后,给予所述受试者预防有效剂量的根据权利要求1所述的化合物。
10.根据权利要求8所述的方法,所述方法包括给予所述受试者治疗或预防有效剂量的根据权利要求7所述的药物组合物。
11.根据权利要求9所述的方法,所述方法包括给予所述受试者治疗或预防有效剂量的根据权利要求7所述的药物组合物。
12.根据权利要求8所述的方法,其中所述障碍为神经退行性障碍或运动障碍。
13.根据权利要求8所述的方法,其中所述障碍选自帕金森氏病、亨延顿氏舞蹈病、多系统萎缩症、皮质基底节变性、阿耳茨海默氏病和老年性痴呆。
14.根据权利要求9所述的方法,其中所述障碍为神经退行性障碍或运动障碍。
15.根据权利要求9所述的方法,其中所述障碍选自帕金森氏病、亨延顿氏舞蹈病、多系统萎缩症、皮质基底节变性、阿耳茨海默氏病和老年性痴呆。
16.根据权利要求8所述的方法,其中所述障碍为帕金森氏病。
17.根据权利要求8所述的方法,其中所述障碍为成瘾。
18.根据权利要求8所述的方法,其中所述障碍为注意力缺陷多动障碍(ADHD)。
19.根据权利要求8所述的方法,其中所述障碍为抑郁症。
20.根据权利要求8所述的方法,其中所述障碍为焦虑症。
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US10478108P | 2008-10-13 | 2008-10-13 | |
US61/104781 | 2008-10-13 | ||
US12/479,158 US20100093702A1 (en) | 2008-10-13 | 2009-06-05 | METHYLENE AMINES OF THIENO[2,3-d]PYRIMIDINE AND THEIR USE AS ADENOSINE A2a RECEPTOR ANTAGONISTS |
US12/479158 | 2009-06-05 | ||
PCT/US2009/058705 WO2010045006A1 (en) | 2008-10-13 | 2009-09-29 | Methylene amines of thieno [2,3-d] pyrimidine and their use as adenosine a2a receptor antagonists |
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WO2011022191A1 (en) | 2009-08-21 | 2011-02-24 | The Trustees Of The University Of Pennsylvania | Adamantane analogs |
WO2011101861A1 (en) | 2010-01-29 | 2011-08-25 | Msn Laboratories Limited | Process for preparation of dpp-iv inhibitors |
US9884832B2 (en) * | 2011-12-06 | 2018-02-06 | The Trustees Of The University Of Pennsylvania | Inhibitors targeting drug-resistant influenza A |
CN109311868B (zh) | 2015-12-22 | 2022-04-01 | 尚医治疗有限责任公司 | 用于治疗癌症和炎性疾病的化合物 |
CN110573518A (zh) | 2017-01-26 | 2019-12-13 | 尤拉·S·赞特里佐斯 | 被取代的双环嘧啶基化合物及其组合物和用途 |
IL310023A (en) | 2017-06-21 | 2024-03-01 | SHY Therapeutics LLC | Compounds interacting with the RAS superfamily for the treatment of cancer, inflammation, RAS pathology and fibrotic diseases |
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CN1800186A (zh) * | 2000-05-26 | 2006-07-12 | 先灵公司 | 腺苷A2a受体拮抗剂 |
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IL212173A0 (en) | 2011-06-30 |
EA201170563A1 (ru) | 2011-10-31 |
US20100093702A1 (en) | 2010-04-15 |
ZA201103489B (en) | 2012-11-28 |
AU2009303694A1 (en) | 2010-04-22 |
EP2350092A1 (en) | 2011-08-03 |
PE20110423A1 (es) | 2011-07-08 |
CA2740406A1 (en) | 2010-04-22 |
ECSP11010977A (es) | 2011-05-31 |
KR20110071109A (ko) | 2011-06-28 |
CO6321169A2 (es) | 2011-09-20 |
CL2011000832A1 (es) | 2011-07-15 |
WO2010045006A1 (en) | 2010-04-22 |
JP2012505264A (ja) | 2012-03-01 |
MX2011003962A (es) | 2011-05-03 |
BRPI0920217A2 (pt) | 2015-12-22 |
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