CN105985354A - 嘧啶衍生物、细胞毒性剂、药物组合物及其应用 - Google Patents
嘧啶衍生物、细胞毒性剂、药物组合物及其应用 Download PDFInfo
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- CN105985354A CN105985354A CN201510066655.3A CN201510066655A CN105985354A CN 105985354 A CN105985354 A CN 105985354A CN 201510066655 A CN201510066655 A CN 201510066655A CN 105985354 A CN105985354 A CN 105985354A
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Abstract
一种式(Ⅰ)所示的嘧啶衍生物及其多种晶型体或其药学上可以接受的盐，
Description
PI3K/Akt/mTOR信号通路是细胞信号传导通路中非常重要的一条通路，它对细胞的很多重要生理功能都有调控作用，比如细胞生长、增殖、分化、迁移、存活、血管生成、葡萄糖代谢以及细胞膜的波动等[1,2]。
PI3K激酶是一个复杂的脂酶家族，包括IA型、IB型、II型、III型和IV型(PI3K相关激酶)。IA型PI3k由受体酪氨酸激酶(receptor tyrosine kinases，RTK)激活，包括一个调节亚基p85和一个催化亚基p110，根据催化亚基的不同IA型PI3k分为p110α、β和δ三个亚型。IB型PI3k只有一个p110γ亚型，它包括一个a p110γ催化亚基和一个p101的调节亚基组成，通过G-蛋白偶联受体(G protein-coupled receptor)激活。I型PI3K能够催化磷酸化4,5-磷脂酰肌醇二磷酸盐(phosphatidylinositol(4,5)-bisphosphate，PIP2)3位的羟基生成一个信号分子3，4，5-磷脂酰肌醇三磷酸盐(phosphatidylinositol(3,4,5)-trisphosphate，PIP3)，PIP3能够激活下游的PDK1和Akt激酶实现信号的传导。在细胞内PIP3的浓度还受PTEN(Phosphatase and tensin homolog deleted on chromosome ten)的调控，PTEN的作用是拮抗PI3K对下游通路的激活，它最重要的功能是在磷酸肌醇的3位上起到去磷酸化的作用，使PI3K产生的信号分子PIP3去磷酸化变回PIP3从而反向调节PI3K信号[1,3,4]。II型PI3K包括PI3K-C2α、PI3K-C2β和PI3K-C2γ三个亚型，它能够磷酸化磷脂酰肌醇和4-磷脂酰肌醇磷酸盐但是不能磷酸化4,5-磷脂酰肌醇二磷酸盐(PIP2)[5]。III型PI3K只有一个成员Vps34，它只能磷酸化磷脂酰肌醇生成3-磷脂酰肌醇磷酸盐，在的功能与蛋白质转运和自噬有关[6]。IV型PI3K包含和其他PI3K激酶相似的催化区域，其成员包括mTOR、ATR、ATM、DNA-PK[4,7]。
PI3K信号通路的失调或者异常活跃与许多疾病的发生都有密切的关联。在多种肿瘤中都发现了由于突变导致的p110α过度表达，在超过30％的实体瘤中都发现了编码p110α的PIK3CA基因的突变[7]，在40％卵巢癌和50％的宫颈癌中发现了PIK3CA的突变[8]。P110δ和γ是白细胞信号系统中的关键酶，通过抑制它们的活性能够治疗炎症和自免疫相关的疾病[9]。有证据显示p110β在PTEN缺失导致的肿瘤生成中起着关键的作用，在体内和体外下调编码p110β的PIK3CB基因的表达能抑制PI3K的信号并抑制肿瘤的生长[10]。近些年来，随着人们对PI3K结构功能研究的深入，PI3K在众多疾病中的作用也越来越清楚，PI3K已经成为非常有前景的药物靶点。因此，开发以PI3K为靶点的抑制剂成为药物化学界研究的热点并且已经有大量的PI3K抑制剂被报道出来，已经有不少化合物处于临床研究阶段。目前，已经报道的PI3K抑制剂主要分为以下几类：
一、非选择性的I型PI3K抑制剂
LY294002and wortmannin(结构如式一)是最早的一代非选择性的I型PI3K抑制剂，它们都抑制p110催化亚基。LY294002是礼来公司开发的一类可逆的ATP竞争性的抑制剂，它不但能抑制I型PI3K还能抑制mTOR及DNA-PK。Wortmannin是从真菌中分离出来的天然产物，它通过和p110α的Lys802残基和p110γ的Lys833残基产生共价作用而发挥作用。由于它们的毒副作用、差的药理学性质和缺乏选择性并没有进一步的临床开发[11,12]。
XL147(结构如式一)是新一代的I型PI3K抑制剂，它对p110α、β、δ和γ抑制活性分别为IC50＝39、383、23和36nM并且对VPS34、DNA-PK和mTOR没有抑制活性。在体外肿瘤细胞抑制试验中，XL147能够抑制肿瘤细胞的PI3K信号传导，在临床前的乳腺癌、肺癌、卵巢癌、前列腺癌体内模型中，它能引起肿瘤生长减缓和收缩。XL147已经进入临床试验阶段，在临床阶段将评价其单独用药或者联合用药对实体瘤、淋巴瘤和转移的乳腺癌等多种肿瘤的安全性和有效性[1]。
DGC-0941(结构如式一)是一类口服有效的I型PI3K抑制剂，对p110α、β、δ和γ抑制活性分别为IC50＝3、33、3和75nM并且在细胞中测试抑制AKT磷酸化的试验中IC50＝28nm[11]。GDC-0941能以较低的IC50值抑制U87MG、PC3、SKOV-3、IGROV-1、Detroit 562、HCT116、SNUC2B和LoVo细胞系。GDC-0941在无胸腺小鼠U87MG和IGROV-1移植模型中也有很好的作用。目前，GDC-0941也处于临床研究阶段[13]。
BKM120(结构如式一)是一种有效的I型PI3K抑制剂，对p110α、β、δ和γ抑制活性分别为IC50＝52、166、116和261nM，它对III型和IV型PI3K表现出了较低的抑制活性，对mTO R和其他蛋白激酶比如 HER1、JAK2和PDK1至少有50倍的选择性。BKM120在细胞和肿瘤移植模型中都能够有效降低AKT的磷酸化水平，它还能抑制BCR和细胞趋化性，增加慢性粒细胞白血病细胞对苯达莫司汀和磷酸氟达拉滨的敏感性并且对正常淋巴细胞的毒性小[14]。目前，BKM120治疗急性淋巴细胞白血病、急性髓细胞白血病、与INC424合用治疗骨髓纤维化、与利妥昔单抗合用治疗B细胞淋巴瘤都处在一期临床试验阶段(http://www.clinicaltrials.gov/)。
二、选择性PI3K抑制剂
CAL-101(Idelalisib)(结构如式一)是吉利德公司开发的一类p110δ选择性抑制剂，对p110α、β、δ和γ抑制活性分别为IC50＝820、565、89和2.5nM，其p110α对于其它亚型的选择性在40-300倍之间。它对很多恶性血液疾病比如复发的或者难治愈的慢性粒细胞白血病、急性髓细胞白血病、非霍奇金淋巴瘤以及多发性骨髓瘤在临床上都有很好的效果[1]。2014年7月23日，美国FDA批准了吉利德研发的Idelalisib(商品名：Zydelig)上市，Idelalisib成为第一个上市的PI3K抑制剂。FDA批准了Idelalisib的三个适应症：和利妥昔单抗(Rituxan)联合治疗复发的慢性淋巴细胞白血病(CLL)、作为单药治疗复发性滤泡B细胞、非霍奇金淋巴瘤(FL)和复发性小淋巴细胞淋巴瘤(SLL)。
AS-252424(结构如式一)是一类p110γ选择性抑制剂，它表现出对p110γ以外其它I型PI3K亚型超过300倍的选择性，对p110α、β、δ和γ抑制活性分别为IC50＝935、20000、2000和33nM。它对丝氨酸/苏氨酸和酪氨酸激酶抑制活性低(IC50>10μM，分别为78和79μM)。尽管AS-252424在大鼠中有比较高的清除率(2.3L/kg*h)和比较短的口服半衰期(t1/2＝1h)，但是在硫胶质引起的腹膜炎小鼠模型中口服给药10mg/kg剂量就能减少35％的嗜中性粒细胞的聚集[3]。
PIK-75(结构如式一)是一个p110α选择性抑制剂，对p110α抑制活性为IC50＝0.3nm,对其它PI3K亚型亚的选择性在130–2800倍。在A373、HeLa、A549、MCF7和MCF7ADR-res细胞系抗增殖试验中都表现出了低于微摩尔级的活性，并且在HeLa人宫颈癌移植模型试验中也有效[15]。
TG100-115(结构如式一)是一类选择性的p110δ和γ抑制剂，它对p110α、β、δ和γ抑制活性分别为IC50＝1300、1200、83和235nM。最显著的是它的选择性，它在1μM浓度下对其它136种蛋白激酶的抑制率都在50％以下[3]。在血管内皮生长因子和血小板活化因子参与的心肌梗塞中表现出了很好的抑制水肿和炎症的活性；在缺血性脑伤发生后对组织存活有一个非常重要的促内皮细胞有丝分裂过程，TG100-115对这个过程没有中断作用；已经有报道心肌梗赛动物模型中它在保护心脏和减小梗塞方面极其有效[4]。
三、PI3K/mTOR双重抑制剂
咪唑喹唑啉类化合物NVP-BEZ235(结构如式一)是PI3K/mTOR双重抑制剂，它对p110α、β、δ和γ以及mTOR抑制活性分别为IC50＝4、75、7和5nM以及20.7nm。这个化合物能够通过将细胞周期阻滞在G1期而有效地阻断过于活跃的的PI3K信号，而且它有很好的耐受性。另外，NVP-BEZ235也能抑制p110α的致癌突变(E545K和H1047R)引起的PI3K/mTOR通路的异常激活。它在和传统的细胞毒剂多柔比星和长春新碱联合用药评价其有效性实验中显示出了非常有前景的效果，它用于治疗高级实体瘤和乳腺癌已经处在临床评价阶段[1]。
XL-765(结构如式一)是一个活性在低纳摩尔水平上的PI3K/mTOR双重抑制剂，它对p110α、β、δ和γ以及mTOR抑制活性分别为IC50＝39、113、9和43nM以及157nm。在最近的研究中发现XL-765和诱导自噬药物联合用药能够增加其在胰腺癌中的抗肿瘤活性。XL-765和化疗药物合用已经在临床试验阶段，数据显示病人的终末半衰期在2-15小时之间存在病人间差异性[13]。在小鼠的前列腺癌、乳腺癌、肺癌和卵巢癌等多种人癌细胞移植模型中都观察到了肿瘤生长的停止或者收缩。在单独用药治疗实体瘤的临床一期实验数据显示，在83名病人中有12名病人病情稳定16周或者更多；7名病人病情稳定24周或者更多。其观察到最频繁的的毒副作用是肝脏酶活性增高、皮疹和胃肠道不适[16]。
GDC-0980(结构如式一)是吗啡啉衍生物其做为一种PI3K/mTOR双重抑制剂正处于二期临床研究阶段，它是通过取代GDC-0941上的吲唑环为2-氨基嘧啶合成而来的，这种取代增加了mTOR的抑制活性。GDC-0980对前列腺癌、乳腺癌和肺癌等多种癌细胞系都表现出了很好的活性，但是它对黑色素瘤和胰腺癌活性比较低，这可能跟在这两种肿瘤中是以KRAS和BRAF耐药标记有关。它在PC3和MCF-7 neo/HER2细胞移植模型中都显示出了有效抑制作用[13]。
惠氏发现了一系列三唑嘧啶类化合物，其中PKI-402(结构如式一)是一个p110α/mTOR的双重抑制剂，对p110α和mTOR抑制活性分别为IC50＝1.4nM和1.7nM。在体外细胞实验中PKI-402能够引起细胞凋亡并且显示了很高的抗增殖活性，在很多的肿瘤移植模型中都有抗肿瘤效果[1]。在MDA-MB-361细胞系中研究PKI-402产生抑制效果的机制发现其能在体内和体外抑制Akt Ser473和Thr308的磷酸化，也能抑制Akt下游靶分子的磷酸化；PKI-402MDA-MB-361细胞系凋亡依赖caspase-3通道[13]。
辉瑞公开的PF-04691502(结构如式一)是一种p110α/mTOR的双重抑制剂其对p110α和mTOR抑制活性分别为IC50＝0.57nM和16nM，在p110α突变的SKOV3卵巢癌体内移植模型实验中有很高的有效性，PF-04691502用于治疗实体瘤已经进入临床试验阶段[1]。.
式一 PI3K抑制剂结构
参考文献：
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[11]Timothy A Yap,Michelle D Garrett,Mike I Walton,et al.Targeting the PI3K–AKT–mTOR pathway:progress,pitfalls,and promises[J].Current Opinion in Pharmacology 2008,8:393–412.
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发明内容
本发明的目的是提供嘧啶衍生物、PI3K抑制剂、药物组合物及其在抗肿瘤药物中的应用。
本发明是这样实现的：
式(Ⅰ)所示的嘧啶衍生物及其多种晶型体或其药学上可以接受的盐，
其中，
R1为氢，以C1—C6为取代基的可选取代的芳基，可选取代的C1—C6直链、支链或环状烷基，酰二胺基，以卤素、以可选取代的C1—C6直链、支链、环状烷基为取代基的芳基，以可选取代的C1—C6直链、支链、或环状烷基为取代基的吡啶基，以可选取代的C1—C6直链、支链、或环状烷基为取代基的砜基，以可选取代的C1—C6直链、支链或环状烷基为取代基的磺酰基，以可选取代的C1—C6直链、支链或环状烷基、吡啶基、卤代苯基、胺基、腈基、卤代烷基为取代基的羰基，可选取代的C1—C6直链、支链或环状醇基，酯基，醚基或羧基；
R2为氢，NHR2'或NHCONHR3；
其中，所述R10为H或可选取代的C1—C6直链、支链或环状烷基；所述R2'为H或以C1—C6直链、支链烷基、C3—C6环烷基为取代基的可选取代的酰胺基，以可选取代的C1—C6直链、支链或环状烷基为 取代基的三取代胺基，以一个、两个或三个卤原子为取代基的可选取代的C1—C6直链、支链或环状烷基，C1—C6直链或支链烷氧基，可选取代的C1—C6直链、支链或环状醇基，哌嗪基吡啶基，胺基吡啶基，哌嗪基芳基或卤素为取代基的芳基；其中哌嗪基和胺基为以可选取代的C1—C6直链、支链或环状烷基为取代基的取代哌嗪基和取代胺基；所述R3＝可选取代的C1—C6直链、支链或环状烷基以及可选取代的芳基；
R0为氢、羟基或可选取代的C1—C6直链、支链或环状醇基。
本发明中，式(I)所示的嘧啶衍生物及其多种晶型体或其药学上可以接受的盐，其中，
(1)当R1＝可选取代的芳基，R2＝H时，R0＝—OH或R0'OH，其中，R0'为可选取代的C1—C6直链、支链或环状烷基；
当R1＝可选取代的芳基，R0＝H时，或NHR2'，其中，R10为H或可选取代的C1—C6直链、支链、或环状烷基；R2'＝H或CONHR3；其中，R3＝H，C1—C6直链、支链烷基，C3—C6环烷基，以C1—C6直链或支链烷基为取代基的三取代胺基，一卤代C1—C6直链、支链或环状烷基，二卤代C1—C6直链、支链或环状烷基、三卤代C1—C6直链、支链或环状烷基，-O-R8，R9OH或
其中，
当X＝N时，所述R4＝H、或NHR6，其中，R5、R6独立地为C1—C6直链或支链烷基；
当X＝C时，所述R4＝H、卤素，其中，R7＝H、C1—C6烷基、BOC或
所述R8为可选取代的C1—C6直链、支链或环状烷基；
所述R9为可选取代的C1—C6直链、支链或环状烷基；
(2)当R0＝H，R1＝NHCONHR3'时，R2＝CONHR11，所述R3'、R11各自独立地为H、可选取代的C1—C6直链、支链、或环状烷基；
(3)当R0＝H，R1＝H或C1—C6直链、支链烷基时；R2＝NHCONHR3,R3为可选取代的C1—C6直链、支链或环状烷基；
(4)当R0＝H，R2＝NHCONHR3，且R3为可选取代的C1—C6直链、支链或环状烷基时，R1＝
其中，
所述R11、R20、R21各自独立地为H或可选取代的C1—C6直链、支链或环状烷基；
所述R12、R13、R14a、R16、R18a、R23、R24、R26、R27、R28、R29、R30、R31、R32、R33、R34、各自独立地为可选取代的C1—C6直链、支链或环状烷基；
所述R14为可选取代的C1—C6直链、支链或环状烷基或三卤代C1—C6直链、支链、或环状烷基；
所述R15为可选取代的C1—C12直链、支链、环状烷基或以卤素或C1—C6直链、支链或环状烷基为 取代基的可选取代的芳烃；
所述R18、R19独立地为H、Boc或可选取代的C1—C6直链、支链、环状烷基；
所述Y＝F、Cl、Br或I；
所述Z为F、Cl、Br、I或氢；
本发明中，嘧啶衍生物及其多种晶型体或其药学上可以接受的盐，其中，
(1)当R1＝苄基，R2＝H时，R0为羟基、甲醇、乙醇、丙醇、异丙醇或丁醇；
当R1＝苄基，R0＝H时，NHR2'或NHCONHR3；
其中，
所述R10为H、甲基、乙基、丙基或丁基；
所述R2'＝H或CONHR3；
所述R3＝H、甲基、乙基、丙基、异丙基、丁基、环丙烷基、二甲基乙基胺、氟代乙基、二氟代乙基、三氟代乙基、-O-R8或R9OH；
其中，当X＝N时，所述R4＝H、或NHR6，其中，R5、R6独立地为甲基、乙基、丙基或丁基；
当X＝C时，所述R4＝H、或F，其中，R7＝H、BOC或
所述R8为甲基、乙基、丙基或丁基；
所述R9为甲基、乙基、丙基或丁基；
(2)当R0＝H时，R1＝NHCONHR3’；R2＝CONHR11，所述R3’、R11各自独立地为甲基，乙基、丙基、异丙基或丁基；
(3)当R0＝H时，R1＝H、甲基、乙基、丙基、异丙基或丁基时；R2＝NHCONHR3,R3＝甲基、乙基、丙基、异丙基或丁基；
(4)当R0＝H，R2＝NHCONHR3,R3＝甲基、乙基、丙基、异丙基或丁基时，R1＝
所述R10、R11、R20、R21各自独立地为H或甲基、乙基、丙基、异丙基或丁基；
所述R12、R13、R16、R18a、R23、R24、R26、R27、R28、R29、R30、R31、R32、R33、R34各自独立地为甲基、乙基、丙基、异丙基、丁基、异丁基、环戊基或环己基；
所述R14为甲基、乙基、丙基、异丙基、丁基、一氟代C1-C4直链或支链烷基、二氟代C1-C4直链或支链烷基、三氟代甲基、三氟代乙基、三氟代丙基、三氟代异丙基、三氟代丁基或三氟代异丁基；
所述R15为甲基，乙基，丙基，异丙基，丁基，异丁基，环戊基，环己基，一氟代C1-C4直链、支链、环状烷基，二氟代C1-C4直链、支链、环状烷基，三氟代C1-C4直链、支链、环状烷基，以氟或C1—C4直链、支链、环状烷基为取代基在对位、邻位、间位取代或未取代的苯基；
所述R18、R19独立地为H、甲基、乙基、丙基、异丙基、丁基、异丁基或Boc；
所述Y＝F；
所述Z＝F。
本发明所述的嘧啶衍生物及其多种晶型体或其药学上可以接受的盐，为以下化合物之一：
本发明所述的嘧啶衍生物及其多种晶型体或其药学上可以接受的盐的制备方法，由化合物1制备而成，所述化合物1的制备方法为：
本发明的细胞毒性剂，包含所述的嘧啶衍生物及其多种晶型体或其药学上可以接受的盐。
本发明的药物组合物，包含治疗有效量的所述的的嘧啶衍生物及其多种晶型体或其药学上可以接受的盐以及药学上可接受的载体。
本发明所述的嘧啶衍生物及其多种晶型体或其药学上可以接受的盐在制备细胞毒性剂以及抗肿瘤药物中的应用。
本发明所述的细胞毒性剂在制备针对PI3K激酶异常改变的药物以及抗肿瘤药物中的应用。
本发明所述的药物组合物在制备制备针对PI3K激酶异常改变的药物以及抗肿瘤药物中的应用。
本发明中，化合物1的合成路线如下：
利用化合物1合成脲衍生物包括以下两个步骤：
其中脲的合成通法如下：
将GL-1(94mg，0.2mmol)溶解在2mL无水DCM中并加入三乙胺(61mg，0.6mmol)。混合物在冰盐浴下冷却，加入三光气(30mg，0.1mmol)，继续在冰盐浴下搅拌15min后，5eq胺的无水DCM溶液或者胺的盐酸盐和6eq的三乙胺加入到上述反应液中继续反应过夜。反应中加入水并用DCM萃取，有机相用水和饱和氯化钠洗涤，减压蒸干溶剂，残余物通过柱层析或者制备薄层色谱纯化得到相应的脲衍生 物。
哌啶衍生物的合成路线如下：
利用GL-26制取哌啶衍生物的方式包括如下两种：
过程A
将GL-26(100mg，0.15mmol)悬浮在二氯甲烷中加入1.2eq HATU、相应的酸(1.1eq)和4eq三乙胺，室温下搅拌过夜后，加入饱和碳酸氢钠，DCM萃取。有机相水和饱和氯化钠洗涤，无水硫酸钠干燥，减压浓缩，残余物通过柱层析纯化得相应的哌啶衍生物。
过程B
将GL-26(100mg，0.15mmol)悬浮在无水二氯甲烷中加入3.6eq三乙胺，冰浴下冷却至0℃。然后，将1.1eq酸酐或者酰氯的无水二氯甲烷溶液滴加到反应液中，继续搅拌反应过夜或者TLC监测反应完成后，加入饱和碳酸氢钠，二氯甲烷萃取，有机相用水和饱和氯化钠洗涤，无水硫酸钠干燥，减压浓缩，残余物通过柱层析纯化得相应的哌啶衍生物。
附图说明
图1为试验实施例64的实验流程图。
具体实施方式
实施例1
化合物3-(1-苄基哌啶-4-基)-5-氯-7-吗啡啉基异噁唑[4,5-d]并嘧啶(化合物1)的合成：
第一步：
将N-Boc-4-哌啶甲酸(230mg，1mmol)和CDI(292mg，1.8mmol)混合于三口瓶中，用N2排空空气然后加入2mL无水THF，反应液在环境温度下搅拌1-2h后将硝基甲烷(183mg，3mmol)加到反应体系中再加入DBU(685mg，4.5mmol)。反应液继续搅拌36h后加入乙酸乙酯稀释，再加入6mL 2N HCl溶液，乙酸乙酯萃取，有机相用水洗至中性，再用饱和氯化钠溶液洗三次，无水硫酸钠干燥，减压除去乙酸乙酯得到黄白色产物(130mg，收率96％)，不用纯化直接投下一步。mp 95-97℃.1H NMR(300MHz,CDCl3)δ5.36(s,2H),4.14(d,J＝13.8Hz,2H),2.86-2.76(m,2H),2.64(tt,J＝11.4,3.9Hz,1H),1.90–1.85(m,2H),1.68–1.55(m,2H),1.47(s,9H).ESI-MS:m/z＝172.94[M-Boc+H]+.
第二步：
将化合物1-1(452mg，1.66mmol)和盐酸羟胺(116mg，1.67mmol)以及NaHCO3(140mg，1.67mmol)混合并加入8mL乙醇，所得的悬浊液在50℃下反应过夜。TLC监测反应完成，减压浓缩反应液然后加入水和乙酸乙酯萃取，有机相用水和饱和氯化钠溶液分别洗三次然后用无水硫酸钠干燥，减压蒸干溶剂得黄白色产物1-2(454mg，cis/trans＝6/1，收率95％)，产物不用纯化可直接投下一步。mp 147-149℃.1H NMR(300MHz,DMSO-d6)δ11.62(s,0.11H),11.48(s,0.71H),5.35(s,0.3H),5.33(s,1.7H),3.97(d,J＝12.9Hz,2H),2.93-2.59(m,2H),2.46(tt,J＝11.7,3.6Hz,1H),1.80-1.760(m,1.75H),1.63-1.60(m,0.34H),1.40(s,9H),1.40-1.29(m,2H).ESI-MS:m/z＝187.96[M-Boc+H]+.
第三步：
将上步所得化合物1-2(8.912g，31mmol)溶解在80mL无水乙醚中，缓慢滴加草酰氯单乙酯(3.966mL，36mmol)的无水乙醚溶液，然后反应混合物在室温下搅拌24h，反应液降温，在0℃下滴加三乙胺(3.923g，38.8mmol)。滴完，混合物在室温下搅拌60h后减压浓缩，加入水和乙酸乙酯萃取，有机相用水和饱和氯化钠各洗三次，然后用无水硫酸钠干燥。减压浓缩柱层析得到白色产物1-3(6.614g，收率58％)。mp 59-61℃.1H NMR(300MHz,CDCl3)δ4.52(q,J＝7.2Hz,2H),4.21(d,J＝13.2Hz,2H),3.27(tt,J＝11.7,3.6Hz,1H),2.93-2.85(m,2H),2.03–1.98(m,2H),1.86–1.72(m,2H),1.47(s,9H),1.43(t,J＝7.2Hz,3H).ESI-MS:m/z＝270.05[M-Boc+H]+.
第四步：
将上步所制化合物1-3(151mg，0.41mmol)溶于1mL氨的甲醇溶液并在室温下搅拌3h。减压蒸干溶剂，残余物用甲醇带2次得到白色产物1-4(134mg，收率96％)。mp 184-186℃.1H NMR(300MHz,DMSO-d6)δ8.70(s,1H),8.57(s,1H),4.02(d,J＝12.9Hz,2H),3.38(tt,J＝11.7,3.3Hz,1H),2.95-2.86(m,2H),2.01-1.96(m,2H),1.62–1.49(m,2H),1.41(s,9H).ESI-MS:m/z＝241.04[M-Boc+H]+.
第五步：
将上步所制化合物1-4(85mg，0.25mmol)溶于0.5mL DCM中，加入1.5mL TFA并在室温下搅拌2 h。减压蒸干溶剂，残余物用乙醇带两次以除去残余TFA，得到淡黄色针状晶体1-5(89mg，收率100％)。mp 213-215℃.1H NMR(300MHz,DMSO-d6)δ8.77(brs,2H),8.74(s,1H),8.61(s,1H),3.55(tt,J＝11.4,3.3Hz,1H),3.41-3.37(m,2H),3.14-3.07(m,2H),2.19-2.14(m,2H),1.97-1.83(m,2H).ESI-MS:m/z＝241.04[M+H]+.
第六步：
将上步所制化合物1-5(604mg，1.71mmol)悬浮在乙腈中加入2eq三乙胺在室温下搅拌2h进行解离。乙腈减压蒸干残余物用乙腈带两次以除去残余三乙胺。残余物加入5mL无水乙腈和DIPEA(441mg，3.41mmol)并且降温至0℃，缓慢滴加溴苄(292mg，1.71mmol)的无水乙腈溶液。滴完在室温下搅拌反应，TLC和LC-MS监测反应完成后减压浓缩，然后加入氯仿和饱和碳酸钠溶液，氯仿萃取。有机相柱层析纯化得到淡黄色固体1-6(456mg，收率81％)。mp 134-136℃.1H NMR(300MHz,DMSO-d6)δ8.70(s,1H),8.57(s,1H),7.36–7.22(m,5H),3.52(s,2H),3.16(tt,J＝11.4,3.3Hz,1H),2.91(d,J＝11.7Hz,2H),2.09(t,J＝11.7Hz,2H),1.99-1.95(m,2H),1.79-1.65(m,2H).ESI-MS:m/z＝331.08[M+H]+.
第七步：
将上步所制化合物1-6(73mg，0.22mmol)悬浮在2mL混合溶剂(乙醇:水＝2:1)中并且冷却至0℃。然后加入氯化铵(296mg，5.53mmol)，分批缓慢加入锌粉(145mg，2.22mmol)，室温下搅拌4h。抽滤除去不溶物，滤液蒸干柱层析纯化得到淡黄色固体1-7(52mg，收率78％)。mp 189-191℃.1H NMR(300MHz,DMSO-d6)δ7.69(s,2H),7.36(s,1H),7.36–7.21(m,5H),5.16(s,2H),3.50(s,2H),2.89-2.65(m,2H),2.75(tt,J＝11.7,3.6Hz,1H),2.10-2.01(m,2H),1.92-1.87(m,2H),1.72-1.58(m,2H).ESI-MS:m/z＝301.08[M+H]+.
第八步：
将上步所制化合物1-7(60mg，0.2mmol)溶解在2mL无水THF中，加入三光气(30mg，0.1mmol)，升温回流1h。反应混合物降温至室温，抽滤收集白色沉淀物并用乙酸乙酯或者DCM洗涤得目标化合物1-8(66mg，收率90％)。mp 142-144℃.1H NMR(300MHz,DMSO-d6)δ11.67(s,2H),11.61(s,1H),10.99(s,1H),7.67-7.64(m,2H),7.49–7.47(m,3H),4.35(d,J＝3.9Hz,2H),3.46(d,J＝11.7Hz,2H),3.23-3.12(m,1H),3.03-2.92(m,2H),2.30-2.04(m,4H).ESI-MS:m/z＝327.11[M+H]+.
第九步：
将上步所得化合物1-8(236mg，0.62mmol)和6mL三氯氧磷的混合物升温回流反应24h，然后减压浓缩至干，残余物倒到碎冰中淬灭。水相用6N NaOH水溶液调pH＝8-9，加入乙酸乙酯萃取。有机相用水洗至中性，饱和氯化钠洗三次，无水硫酸钠干燥然后减压蒸干溶剂，残余物溶解在8mL DCM中并用冰盐浴降温，然后加入TEA(90mg，0.89mmol)。将吗啡啉(55mg，0.63mmol)的DCM溶液滴加到上述溶液中并继续搅拌10min。TLC反应完全后加入水，然后用DCM萃取有机相用水和饱和氯化钠洗涤，蒸干溶剂柱层析得到淡黄色固体化合物1(167mg，收率62％)。mp 168-170℃.1H NMR(300MHz,CDCl3)δ7.37–7.23(m,5H),4.21–3.95(m,4H),3.84(t,J＝5.1Hz,4H),3.57(s,2H),3.17-3.07(m,1H),3.02-2.98(m,2H),2.23–1.98(m,6H).ESI-MS:m/z＝414.18[M+H]+.
实施例2
利用化合物1通过Suzuki偶联反应制备如下所示的嘧啶衍生物4-(3-(1-苄基哌啶-4-基)-7-吗啡啉基异噁唑[4,5-d]并嘧啶-5-基)苯胺(GL-1)：
将化合物1(414mg，1mmol)、对氨基苯硼酸频哪醇酯(329mg，1.5mmol)、Pd(Pcy3)2Cl2(37mg，0.05mmol)和CsF(456mg，3mmol)放在三口瓶中，三口瓶排空空气再充入Ar气，重复进行三次，然后将12mL溶剂(NMP:水＝9:1)注射到三口瓶中。反应混合物在Ar气保护下100℃下反应48h后，加入水稀释并用乙酸乙酯萃取，有机相用水和饱和氯化钠洗涤，减压浓缩，残余物通过柱层析得黄色固体化合物GL-1(160mg，产率34％)。mp 118-119℃.1H NMR(300MHz,CDCl3)δ8.26–8.21(m,2H),7.41–7.26(m,5H),6.75–6.70(m,2H),4.14-4.11(m,4H),3.88–3.85(m,6H),3.63(s,2H),3.30-3.13(m,1H),3.07-3.03(m,2H),2.42-2.09(m,6H).ESI-MS:m/z＝471.28[M+H]+.
实施例3
利用GL-1通过脲的合成通法制备1-(4-(3-(1-苄基哌啶-4-基)-7-吗啡啉基异噁唑[4,5-d]并嘧啶-5-基)苯基)-3-甲脲(GL-2)
按上述反应式，GL-2是用相应胺的盐酸盐通过脲的合成通法合成的黄色固体(52mg，收率49％)。 mp 147-149℃.1H NMR(300MHz,DMSO-d6)δ8.79(s,1H),8.23(d,J＝8.7Hz,2H),7.52(d,J＝8.7Hz,2H),7.35–7.25(m,5H),6.08(q,J＝4.8Hz,1H),4.05-4.03(m,4H),3.81-3.78(m,4H),3.54(s,2H),3.17-3.09(m,1H),2.93(d,J＝11.4Hz,2H),2.66(d,J＝4.5Hz,3H),2.22-2.10(m,4H),2.04–1.92(m,2H).ESI-MS:m/z＝528.38[M+H]+.
实施例4
利用GL-1通过脲的合成通法制备1-(4-(3-(1-苄基哌啶-4-基)-7-吗啡啉基异噁唑[4,5-d]并嘧啶-5-基)苯基)-3-乙脲(GL-3)
按上述反应式，GL-3是用相应胺的盐酸盐通过脲的合成通法合成的黄色固体(53mg，收率49％)。mp140-141℃.1H NMR(300MHz,DMSO-d6)δ8.70(s,1H),8.24-8.20(m,2H),7.52-7.48(m,2H),7.35–7.22(m,5H),6.17(t,J＝5.5Hz,1H),4.05-4.02(m,4H),3.80–3.77(m,4H),3.53(s,2H),3.17-3.08(m,3H),2.94-2.90(m,2H),2.22-2.09(m,4H),2.04-1.90(m,2H),1.06(t,J＝7.2Hz,3H).ESI-MS:m/z＝542.39[M+H]+.
实施例5
利用GL-1通过脲的合成通法制备1-(4-(3-(1-苄基哌啶-4-基)-7-吗啡啉基异噁唑[4,5-d]并嘧啶-5-基)苯基)脲(GL-4)
按上述反应式，GL-4是用氨的甲醇溶液通过脲的合成通法合成的黄色固体(46mg，收率50％)。mp204-206℃.1H NMR(300MHz,DMSO-d6)δ8.80(s,1H),8.25–8.22(m,2H),7.54-7.50(m,2H),7.35–7.23(m,5H),5.94(s,2H),4.06-4.03(m,4H),3.81–3.78(m,4H),3.54(s,2H),3.18-3.10(m,1H),2.93(d,J＝11.4Hz,2H),2.23-2.10(m,4H),2.03–1.91(m,2H).ESI-MS:m/z＝514.39[M+H]+.
实施例6
利用GL-1通过脲的合成通法制备1-(4-(3-(1-苄基哌啶-4-基)-7-吗啡啉基异噁唑[4,5-d]并嘧啶-5-基)苯基)-3-(2-(二甲氨基)乙基)脲(GL-5)
按上述反应式，GL-5是用相应的胺通过脲的合成通法合成的黄色固体(70mg，收率67％)。mp 96-98℃. 1H NMR(300MHz,DMSO-d6)δ8.94(s,1H),8.23(d,J＝8.7Hz,2H),7.50(d,J＝8.7Hz,2H),7.35–7.23(m,5H),6.19(t,J＝5.4Hz,1H),4.06-4.03(m,4H),3.81-3.78(m,4H),3.54(s,2H),3.20(q,J＝6.0Hz,2H), 3.15-3.08(m,1H),2.93(d,J＝11.1Hz,2H),2.36(t,J＝6.0Hz,2H),2.20(s,6H),2.20-2.10(m,4H),2.04–1.91(m,2H).ESI-MS:m/z＝585.62[M+H]+.
实施例7
利用GL-1通过脲的合成通法制备1-(4-(3-(1-苄基哌啶-4-基)-7-吗啡啉基异噁唑[4,5-d]并嘧啶-5-基)苯基)-3-异丙基脲(GL-6)
按上述反应式，GL-6是用相应的胺通过脲的合成通法合成的黄色固体(41mg，收率37％)。mp 205-206℃. 1H NMR(300MHz,DMSO-d6)δ8.56(s,1H),8.23(d,J＝8.7Hz,2H),7.49(d,J＝8.7Hz,2H),7.35–7.23(m,5H),6.07(d,J＝7.5Hz,1H),4.06-4.03(m,4H),3.81-3.74(m,5H),3.54(s,2H),3.14(tt,J＝11.1,4.2Hz,1H),2.93(d,J＝11.4Hz,2H),2.22–2.10(m,4H),2.04-1.91(m,2H),1.11(d,J＝6.6Hz,6H).ESI-MS:m/z＝556.38[M+H]+.
实施例8
利用GL-1通过脲的合成通法制备1-(4-(3-(1-苄基哌啶-4-基)-7-吗啡啉基异噁唑[4,5-d]并嘧啶-5-基)苯基)-3-环丙基脲(GL-7)
按上述反应式，GL-7是用相应的胺通过脲的合成通法合成的黄色固体(46mg，收率42％)。mp 220-221℃. 1H NMR(300MHz,DMSO-d6)δ8.58(s,1H),8.23(d,J＝8.7Hz,2H),7.52(d,J＝8.7Hz,2H),7.35–7.24(m,5H),6.45(d,J＝2.7Hz,1H),4.06-4.03(m,4H),3.81-3.78(m,4H),3.54(s,2H),3.18-3.10(m,1H),2.93(d,J＝10.5Hz,2H),2.60-2.53(m,1H),2.22-2.10(m,4H),2.04-1.91(m,2H),0.68–0.62(m,2H),0.44–0.39(m,2H).ESI-MS:m/z＝554.43[M+H]+.
实施例9
利用GL-1通过脲的合成通法制备1-(4-(3-(1-苄基哌啶-4-基)-7-吗啡啉基异噁唑[4,5-d]并嘧啶-5-基)苯基)-3-(2-氟乙基)脲(GL-8)
按上述反应式，GL-8是用相应胺的盐酸盐通过脲的合成通法合成的黄色固体(47mg，收率42％)。mp115-117℃.1H NMR(300MHz,DMSO-d6)δ8.84(s,1H),8.24(d,J＝9.0Hz,2H),7.52(d,J＝8.7Hz,2H),7.35–7.23(m,5H),6.45(t,J＝5.4Hz,1H),4.56(t,J＝4.8Hz,1H),4.40(t,J＝5.1Hz,1H),4.06-4.03(m,4H),3.81-3.78(m,4H),3.54(s,2H),3.47(q,J＝5.4Hz,1H),3.38(q,J＝5.4Hz,1H),3.19-3.09(m,1H),2.93(d,J＝11.1Hz,2H),2.22-2.10(m,4H),2.04–1.92(m,2H).ESI-MS:m/z＝560.38[M+H]+.
实施例10
利用GL-1通过脲的合成通法制备1-(4-(3-(1-苄基哌啶-4-基)-7-吗啡啉基异噁唑[4,5-d]并嘧啶-5-基)苯基)-3-(6-(4-甲基哌嗪-1-基)吡啶-3-基)脲(GL-9)
GL-9是用相应的胺通过脲的合成通法合成的黄色固体(43mg，收率30％)。mp 144-145℃.1H NMR(300MHz,DMSO-d6)δ9.00(s,1H),8.54(s,1H),8.30-8.26(m,2H),8.16(d,J＝3.0Hz,1H),7.71(dd,J＝9.0,2.7Hz,1H),7.58-7.53(m,2H),7.36–7.25(m,5H),6.83(d,J＝9.0Hz,1H),4.06-4.04(m,4H),3.81-3.79(m,4H),3.56(s,2H),3.43–3.40(m,4H),3.20-3.12(m,1H),2.97-2.93(m,2H),2.48-2.45(m,4H),2.26(s,3H),2.26-2.12(m,4H),2.05-1.91(m,2H).ESI-MS:m/z＝689.78[M+H]+.
实施例11
利用GL-1制备1-(4-(3-(1-苄基哌啶-4-基)-7-吗啡啉基异噁唑[4,5-d]并嘧啶-5-基)苯基)-3-(4-((2-(二甲胺基)乙基)(甲基)氨基)苯基)脲(GL-10)
将N1-(2-(二甲胺基)乙基)-N1-甲基-1,4-苯二胺(116mg，0.6mmol)溶解在4mL无水DCM中并加入三乙胺(182mg，1.8mmol)，所得混合物冰盐浴下冷却。将三光气(89mg，0.3mmol)的无水DCM溶液滴加到反应液中并继续在冰盐浴下搅拌15min。然后将GL-1(94mg，0.2mmol)的无水DCM溶液滴加到上述反应液中并搅拌过夜后，加入水，DCM萃取，有机相用水和饱和氯化钠洗涤，减压浓缩，残余物通过柱层析和制备薄层色谱纯化得黄色固体GL-10(50mg，收率36％)。mp 134-135℃.1H NMR(300MHz,DMSO-d6)δ8.81(s,1H),8.33(s,1H),8.27(d,J＝8.7Hz,2H),7.56(d,J＝8.7Hz,2H),7.35–7.24(m,7H),6.66(d,J＝9.3Hz,2H),4.06-4.04(m,4H),3.81-3.79(m,4H),3.54(s,2H),3.37(t,J＝7.2Hz,2H),3.18-3.11(m,1H),2.95-2.91(m,2H),2.86(s,3H),2.38(t,J＝7.2Hz,2H),2,23-2.11(m,4H),2.20(s,6H),2.05–1.93(m,2H).ESI-MS:m/z＝690.54[M+H]+.
实施例12
利用GL-1通过脲的合成通法制备1-(4-(3-(1-苄基哌啶-4-基)-7-吗啡啉基异噁唑[4,5-d]并嘧啶-5-基)苯基)-3-(6-(甲氨基)吡啶-3-基)脲(GL-11)
按上述反应式，GL-11是用相应的胺通过脲的合成通法合成的红色固体(69mg，收率56％)。mp149-150℃.1H NMR(300MHz,DMSO-d6)δ8.91(s,1H),8.29-8.25(m,3H),8.00(d,J＝3.0Hz,1H),7.58–7.50(m,3H),7.36–7.25(m,5H),6.43(d,J＝8.4Hz,1H),6.24(q,J＝4.8Hz,1H),4.07-4.04(m,4H),3.81-3.78(m,
4H),3.55(s,2H),3.19-3.10(m,1H),2.96-2.92(m,2H),2.74(d,J＝5.1Hz,3H),2.23-2.11(m,4H),2.04-1.91(m,2H).ESI-MS:m/z＝620.55[M+H]+.
实施例13
利用GL-1通过脲的合成通法制备1-(4-(3-(1-苄基哌啶-4-基)-7-吗啡啉基异噁唑[4,5-d]并嘧啶-5-基)苯基)-3-(吡啶-3-基)脲(GL-12)
按上述反应式，GL-12是用相应的胺通过脲的合成通法合成的黄色固体(43mg，收率36％)。mp212-213℃.1H NMR(300MHz,DMSO-d6)δ9.14(s,1H),8.97(s,1H),8.62(d,J＝2.4Hz,1H),8.32-8.28(m,2H),8.21(dd,J＝4.8,1.5Hz,1H),7.99-7.95(m,1H),7.61-7.57(m,2H),7.36–7.27(m,6H),4.07-4.04(m,4H),3.82-3.79(m,4H),3.56(s,2H),3.25-3.08(m,1H),3.03-2.82(m,2H),2.16-1.98(m,6H).ESI-MS:m/z＝591.58[M+H]+.
实施例14
利用GL-1通过脲的合成通法制备1-(4-(3-(1-苄基哌啶-4-基)-7-吗啡啉基异噁唑[4,5-d]并嘧啶-5-基)苯基)-3-甲氧基脲(GL-13)
按上述反应式，GL-13是用相应胺的盐酸盐通过脲的合成通法合成的黄色固体(52mg，收率48％)。mp154-155℃.1H NMR(300MHz,DMSO-d6)δ9.61(s,1H),9.09(s,1H),8.27(d,J＝9.0Hz,2H),7.73(d,J＝9.0Hz,2H),7.35–7.23(m,5H),4.06-4.04(m,4H),3.81-3.78(m,4H),3.65(s,3H),3.54(s,2H),3.20-3.11(m,1H),2.93(d,J＝10.8Hz,2H),2.23-2.11(m,4H),2.04–1.93(m,2H).ESI-MS:m/z＝544.33[M+H]+.
实施例15
利用GL-1通过脲的合成通法制备1-(4-(3-(1-苄基哌啶-4-基)-7-吗啡啉基异噁唑[4,5-d]并嘧啶-5-基)苯基)-3-(2-羟乙基)脲(GL-14)
按上述反应式，GL-14是用相应的胺通过脲的合成通法合成的黄色固体(76mg，收率68％)。mp127-129℃.1H NMR(300MHz,DMSO-d6)δ8.83(s,1H),8.26-8.21(m,2H),7.52-7.48(m,2H),7.35–7.23(m,5H),6.27(t,J＝5.4Hz,1H),4.76(t,J＝5.4Hz,1H),4.06–4.03(m,4H),3.81–3.78(m,4H),3.54(s,2H),3.46(q,J＝5.7Hz,2H),3.18(q,J＝5.4Hz,2H),3.15–3.10(m,1H),2.93(d,J＝11.4Hz,2H),2.22-2.10(m,4H),2.04-1.93(m,2H).ESI-MS:m/z＝558.40[M+H]+.
实施例16
利用GL-1通过脲的合成通法制备1-(4-(3-(1-苄基哌啶-4-基)-7-吗啡啉基异噁唑[4,5-d]并嘧啶-5-基)苯基)-3-苯脲(GL-15)
按上述反应式，GL-15是用相应的胺通过脲的合成通法合成的白色固体(61mg，收率52％)。mp201-202℃.1H NMR(300MHz,DMSO-d6)δ8.94(s,1H),8.72(s,1H),8.31-8.28(m,2H),7.60-7.57(m,2H),7.49-7.46(m,2H),7.36–7.23(m,7H),6.99(t,J＝7.5Hz,1H),4.07-4.04(m,4H),3.82-3.79(m,4H),3.54(s,2H),3.18-3.11(m,1H),2.95-2.91(m,2H),2.22-2.11(m,4H),2.05–1.92(m,2H).ESI-MS:m/z＝590.48[M+H]+.
实施例17
利用GL-1通过脲的合成通法制备1-(4-(3-(1-苄基哌啶-4-基)-7-吗啡啉基异噁唑[4,5-d]并嘧啶-5-基)苯基)-3-(4-(4-甲基哌嗪-1-基)苯基)脲(GL-16)
按上述反应式，GL-16是用相应的胺通过脲的合成通法合成的黄色固体(95mg，收率69％)。mp216-218℃.1H NMR(300MHz,DMSO-d6)δ8.84(s,1H),8.45(s,1H),8.28(d,J＝8.7Hz,2H),7.56(d,J＝8.7Hz,2H),7.35–7.24(m,7H),6.89(d,J＝9.0Hz,2H),4.07-4.04(m,4H),3.81-3.79(m,4H),3.54(s,2H),3.19-3.11(m,1H),3.07–3.04(m,4H),2.93(d,J＝11.1Hz,2H),2.47–2.44(m,4H),2.22(s,3H),2.22–2.11(m,4H),2.04-1.93(m,2H).ESI-MS:m/z＝688.44[M+H]+.
实施例18
利用GL-1通过脲的合成通法制备1-(4-(3-(1-苄基哌啶-4-基)-7-吗啡啉基异噁唑[4,5-d]并嘧啶-5-基)苯基)-3-(4-(吡咯烷-1-基)苯基)脲(GL-17)
按上述反应式，GL-17是用相应的胺通过脲的合成通法合成的黄色固体(70mg，收率53％)。mp221-223℃.1H NMR(300MHz,DMSO-d6)δ8.79(s,1H),8.30(s,1H),8.29-8.25(m,2H),7.57-7.54(m,2H),7.36-7.23(m,7H),6.50(d,J＝9.3Hz,2H),4.06-4.04(m,4H),3.81-3.78(m,4H),3.54(s,2H),3.21-3.11(m,5H),2.93(d,J＝11.4Hz,2H),2.23-2.11(m,4H),2.04–1.92(m,6H).ESI-MS:m/z＝659.44[M+H]+.
实施例19
利用GL-1制备4-(4-(3-(4-(3-(1-苄基哌啶-4-基)-7-吗啡啉基异噁唑[4,5-d]并嘧啶-5-基)苯基)脲基)苯基)哌 嗪-1-甲酸叔丁酯(GL-18)
GL-18是用相应的胺通过和GL-10相同方法合成的黄色固体(78mg，收率50％)。mp 156-158℃.1H NMR(300MHz,DMSO-d6)δ8.86(s,1H),8.49(s,1H),8.28(d,J＝9.0Hz,2H),7.58(d,J＝9.0Hz,2H),7.36–7.25(m,7H),6.92(d,J＝9.3Hz,2H),4.07-4.04(m,4H),3.82-3.79(m,4H),3.55(s,2H),3.47-3.44(m,4H),3.19-3.10(m,1H),3.03-2.99(m,4H),2.96-2.92(m,2H),2.23–2.12(m,4H),2.05-1.94(m,2H),1.42(s,9H).ESI-MS:m/z＝774.58[M+H]+.
实施例20
利用GL-18制备1-(4-(3-(1-苄基哌啶-4-基)-7-吗啡啉基异噁唑[4,5-d]并嘧啶-5-基)苯基)-3-(4-(哌嗪-1-基)苯基)脲(GL-19)
将GL-18(45mg，0.058mmol)溶解在0.5mL DCM中，然后加入2mL TFA，室温下搅拌反应2h。减压蒸干溶剂，加入乙醇再减压蒸干，残余物加入DCM和6N NaOH水溶液并萃取。有机相减压浓缩通过柱层析和制备薄层色谱纯化得黄色固体(19mg，收率49％)。mp 156-158℃.1H NMR(300MHz,DMSO-d6)δ9.04(s,1H),8.67(s,1H),8.27(d,J＝8.7Hz,2H),7.57(d,J＝8.7Hz,2H),7.35–7.23(m,7H),6.88(d,J＝9.3Hz,2H),5.52–4.31(brs,1H),4.06-4.03(m,4H),3.81-3.78(m,4H),3.54(s,2H),3.19-3.09(m,1H),3.05-3.02(m,4H),2.94–2.91(m,6H),2.22-2.10(m,4H),2.03–1.93(m,2H).ESI-MS:m/z＝674.51[M+H]+.
实施例21
利用GL-1通过脲的合成通法制备1-(4-(3-(1-苄基哌啶-4-基)-7-吗啡啉基异噁唑[4,5-d]并嘧啶-5-基)苯基)-3-(4-氟苯基)脲(GL-20)
GL-20是用相应的胺通过脲的合成通法合成的黄色固体(68mg，收率45％)。mp 179-181℃.1H NMR(300MHz,DMSO-d6)δ8.95(s,2H),8.77(s,2H),8.29(d,J＝8.7Hz,2H),7.58(d,J＝8.7Hz,2H),7.52–7.45(m,2H),7.36–7.23(m,5H),7.18–7.10(m,2H),4.07-4.04(m,4H),3.82-3.79(m,4H),3.54(s,2H),3.18-3.11(m,1H),2.95-2.92(m,2H),2.23-2.11(m,4H),2.04–1.93(m,2H).ESI-MS:m/z＝608.38[M+H]+.
实施例22
利用GL-1通过脲的合成通法制备1-(4-(3-(1-苄基哌啶-4-基)-7-吗啡啉基异噁唑[4,5-d]并嘧啶-5-基)苯基)-3-(2,2,2-三氟乙基)脲(GL-21)
GL-21是用相应胺的盐酸盐通过脲的合成通法合成的白色固体(81mg，收率54％)。mp 197-198℃.1HNMR(300MHz,DMSO-d6)δ9.02(s,1H),8.28-8.24(m,2H),7.56-7.51(m,2H),7.35–7.23(m,5H),6.80(t,J＝6.6Hz,1H),4.06–4.03(m,4H),3.99-3.90(m,2H),3.81–3.78(m,4H),3.54(s,2H),3.19-3.09(m,1H),2.93(d,J＝11.1Hz,2H),2.10-2.22(m,4H),2.05–1.93(m,2H).ESI-MS:m/z＝596.35[M+H]+.
实施例23
利用GL-1通过脲的合成通法制备1-(4-(3-(1-苄基哌啶-4-基)-7-吗啡啉基异噁唑[4,5-d]并嘧啶-5-基)苯基)-3-(2,2-二氟乙基)脲(GL-22)
GL-22是用相应的胺通过脲的合成通法合成的白色固体(68mg，收率49％)。mp 185-186℃.1H NMR(300MHz,DMSO-d6)δ8.97(s,1H),8.25(d,J＝9Hz,2H),7.52(d,J＝8.7Hz,2H),7.42–7.16(m,5H),6.55(t,J＝6.0Hz,1H),6.27-5.88(m,1H),4.05–4.03(m,1H),3.81–3.78(m,1H),3.62-3.48(m,4H),3.18-3.10(m,1H),2.95-2.91(m,2H),2.10–2.22(m,4H),2.04–1.19(m,2H).ESI-MS:m/z＝578.39[M+H]+.
实施例24
利用GL-1通过制备N-异丙基-4-(5-(4-(3-异丙脲基)苯基)-7-吗啡啉基异噁唑[4,5-d]并嘧啶-3-基)哌啶-1-甲酰胺(GL-23)
将GL-1(80mg，0.17mmol)溶解在2mL无水DCM中并加入三乙胺(52mg，0.51mmol)，混合物在冰浴下冷却。然后加入三光气(31mg，0.1mmol)，继续在冰浴下搅拌反应15min。1-甲基乙胺(50mg，0.85mmol)的无水DCM溶液加到上述反应液中并搅拌过夜。加入水，DCM萃取，有机相减压浓缩，粗品通过柱层析和制备薄层色谱纯化得黄色固体(41mg，收率44％)。mp 223-225℃.1H NMR(300MHz,DMSO-d6)δ8.59(s,1H),8.23(d,J＝8.7Hz,2H),7.48(d,J＝8.7Hz,2H),6.25(d,J＝7.8Hz,1H),6.08(d,J＝7.8Hz,1H),4.09-4.05(m,6H),3.81-3.74(m,6H),3.37-3.31(m,1H),2.91(t,J＝10.8Hz,2H),2.04-1.83(m,4H),1.11(d,J＝3.6Hz,6H),1.09(d,J＝3.6Hz,6H).ESI-MS:m/z＝551.46[M+H]+.
实施例25
N-甲基-4-(5-(4-(3-甲脲基)苯基)-7-吗啡啉基异噁唑[4,5-d]并嘧啶-3-基)哌啶-1-甲酰胺(GL-24)的制备
GL-24是从GL-2的合成过程中分离得到的副产物。mp 174-176℃.1H NMR(300MHz,DMSO-d6)δ8.80(s,1H),8.23(d,J＝8.7Hz,2H),7.51(d,J＝8.7Hz,2H),6.49(q,J＝4.5Hz,1H),6.09(q,J＝4.8Hz,1H),4.06-4.0(m,6H),3.81-3.78(m,4H),3.40-3.32(m,1H),2.94(t,J＝11.7Hz,2H),2.64(d,J＝4.5Hz,3H),2.62(d,J＝4.2Hz,3H),2.07-2.02(m,2H),1.94-1.80(m,2H).ESI-MS:m/z＝495.4[M+H]+.
实施例26
利用GL-1制备1-(4-(3-(1-苄基哌啶-4-基)-7-吗啡啉基异噁唑[4,5-d]并嘧啶-5-基)苯基)-3-甲基硫脲(GL-25)
将GL-1(141mg，0.3mmol)溶解在3mL无水二氧六环中，加入甲基异硫氰酸酯(24mg，0.33mmol)回流反应18h。补加甲基异硫氰酸酯(11mg，0.15mmol)继续回流反应24h。反应液浓缩至干加入水和DCM萃取。有机相用水和饱和氯化钠洗，减压浓缩，残余物通过柱层析和薄层色谱纯化后再用乙醚洗涤产品得黄色固体(44mg，收率30％)。mp 175-177℃.1H NMR(300MHz,DMSO-d6)δ9.78(s,1H),8.30(d,J＝8.7Hz,2H),7.84(s,1H),7.55(d,J＝8.4Hz,2H),7.35–7.23(m,5H),4.06–4.02(m,4H),3.81-3.80(m,4H),3.54(s,2H),3.20–3.10(m,1H),2.95–2.91(m,5H),2.22–1.94(m,6H).ESI-MS:m/z＝544.34[M+H]+.
实施例27
4-(5-(4-(3-甲脲基)苯基)-7-吗啡啉基异噁唑[4,5-d]并嘧啶-3-基)哌啶-1-甲酸叔丁酯(GL-37)和1-甲基-3-(4-(7-吗啡啉-3-(哌啶-4-基)异噁唑[4,5-d]并嘧啶-5-基)苯基)脲双三氟乙酸盐(GL-26)的制备
将GL-1(471mg，1mmol)溶解在4mL DCM中，加入三乙胺(126mg，1.25mmol)。甲氨基甲酰氯(103mg，1.1mmol)的DCM溶液缓慢加到上述混合物中，升温回流反应3d。加入水，DCM萃取，水和饱和氯化钠溶液洗涤有机相，减压浓缩所得残余物通过柱层析纯化得GL-2(447mg，收率71％)。
将GL-2(1.342g，2.54mmol)溶解在40mL DCE中再加入ACE-Cl(2.910g，20.35mmol)，室温下搅拌过夜。反应液浓缩至干，加入甲醇回流反应2h。减压蒸干甲醇得脱苄基成盐酸盐的粗品(1.218g)。向所得粗品中加入50mL DCM和三乙胺(936mg，9.25mmol)并在冰浴下冷却到0℃。将(Boc)2O(618mg，2.83mmol)的DCM溶液滴加到上述反应液中搅拌反应3h。加入水，DCM萃取，有机相用水和饱和氯化 钠洗涤，有机相减压浓缩，柱层析纯化得白色固体GL-37(1.037g，收率76％)。mp 152-154℃.1H NMR(300MHz,DMSO-d6)δ8.77(s,1H),8.22(d,J＝9.0Hz,2H),7.50(d,J＝8.7Hz,2H),6.07(q,J＝4.5Hz,1H),4.06–4.03(m,6H),3.81–3.78(m,4H),3.39(tt,J＝10.8,3.9Hz,1H),3.14-2.86(m,2H),2.66(d,J＝4.8Hz,3H),2.09-1.84(m,4H),1.45(s,9H).ESI-MS:m/z＝538.10[M+H]+.
GL-37(330mg，0.61mmol)溶解在1mL DCM中，加入3mL TFA，室温下搅拌反应2h，减压蒸干，加入EtOH再减压蒸干，重复三次以除去残留三氟乙酸得黄色固体(405mg，收率99％)。mp 211-213℃.1HNMR(300MHz,DMSO-d6)δ8.89(s,1H),8.80-8.76(m,1H),8.61-8.50(m,1H),8.28(d,J＝8.7Hz,2H),7.53(d,J＝8.7Hz,2H),6.21(s,1H),4.07-4.04(m,4H),3.82-3.79(m,4H),3.55(tt,J＝10.8,3.9Hz,1H),3.46-3.41(m,2H),3.22-3.12(m,2H),2.66(s,3H),2.34-2.12(m,4H).ESI-MS:m/z＝438.62[M+H]+.
实施例28
利用GL-26制备1-(4-(3-(1-乙基哌啶-4-基)-7-吗啡啉基异噁唑[4,5-d]并嘧啶-5-基)苯基)-3-甲脲(GL-27)
将GL-26(100mg，0.15mmol)悬浮在乙腈中加入DIPEA(71mg，0.55mmol)，冰盐浴降温，将碘乙烷(29mg，0.18mmol)的乙腈溶液缓慢滴加到反应液中，继续搅拌反应1h，升至室温搅拌反应5h。TLC监测未反应完，在65℃下反应11h，然后回流反应8h。蒸干溶剂加入水，DCM萃取，再在pH＝14条件下用DCM/H2O＝20/1萃取，所得有机相柱层析纯化得黄色固体GL-27(48mg，收率69％)。mp 209-210℃. 1H NMR(300MHz,DMSO-d6)δ8.76(s,1H),8.26–8.20(m,2H),7.54–7.49(m,2H),6.07(q,J＝4.8Hz,1H),4.06–4.03(m,4H),3.81–3.78(m,4H),3.15-3.06(m,1H),2.99-2.95(m,2H),2.66(d,J＝4.8Hz,3H),2.38(q,J＝7.2Hz,2H),2.13-1.90(m,6H),1.04(t,J＝7.2Hz,3H).ESI-MS:m/z＝466.74[M+H]+.
实施例29
利用GL-26制备1-(4-(3-(1-(4-氟苄基)哌啶-4-基)-7-吗啡啉基异噁唑[4,5-d]并嘧啶-5-基)苯基)-3-甲脲(GL-28)
将GL-26(100mg，0.15mmol)悬浮在乙腈中加入DIPEA(71mg，0.55mmol)，室温下搅拌2h。冰盐浴降温，将对氟溴苄(35mg，0.18mmol)的乙腈溶液缓慢滴加到反应液中，继续搅拌反应1h，然后室温下搅拌过夜，TLC监测反应完成。浓缩，加入水，DCM萃取，有机相用水和饱和氯化钠洗涤，减压浓缩，残余物通过柱层析纯化得黄色固体(72mg，收率88％)。mp 164-165℃.1H NMR(300MHz,DMSO-d6)δ8.77(s,1H),8.25–8.21(m,2H),7.54–7.49(m,2H),7.41-7.34(m,2H),7.20–7.12(m,2H),6.08(q,J＝4.2Hz,1H),4.06–4.03(m,4H),3.81–3.78(m,4H),3.52(s,2H),3.13-3.08(m,1H),2.93-2,89(m,2H),2.67(d,J＝4.8 Hz,3H),2.14-2.10(m,4H),2.04-1.91(m,2H).ESI-MS:m/z＝546.44[M+H]+.
实施例30
利用GL-26制备1-甲基-3-(4-(7-吗啡啉-3-(1-(吡啶-3-甲基)哌啶-4-基)异恶唑[4,5-d]并嘧啶-5-基)苯基)脲(GL-29)
将GL-26(100mg，0.15mmol)悬浮在乙腈中加入DIPEA(117mg，0.91mmol)，冰盐浴降温，3-溴甲基吡啶盐酸盐(46mg，0.18mmol)加到反应液中，继续搅拌反应1h，室温下搅拌过夜，TLC监测反应进程。反应液减压浓缩，加入水，DCM萃取，有机相浓缩，柱层析纯化得黄色固体(50mg，收率63％)。mp 146-148℃.1H NMR(300MHz,DMSO-d6)δ8.79(s,1H),8.58–8.53(m,1H),8.52–8.46(m,1H),8.28-8.18(m,2H),7.84-7.7(m,1H),7.57-7.46(m,2H),7.43–7.33(m,1H),6.09(q,J＝4.8Hz,1H),4.19-3.91(m,4H),3.90-3.70(m,4H),3.59(s,2H),3.23-3.05(m,1H),3.04-2.80(m,2H),2.67(d,J＝4.2Hz,3H),2.22–1.92(m,6H).ESI-MS:m/z＝529.65[M+H]+.
实施例31
利用GL-26制备1-甲基-3-(4-(3-(1-(甲磺酰基)哌啶-4-基)-7-吗啡啉基异噁唑[4,5-d]并嘧啶-5-基)苯基)脲(GL-30)
将GL-26(100mg，0.15mmol)悬浮在无水THF中加入三乙胺(76mg，0.75mmol)，冰浴降温，甲磺酰氯(29mg，0.18mmol)的THF溶液缓慢滴加到反应液中，继续搅拌反应1h，室温下反应15h。TLC未反应完全，回流反应6h。抽滤析出的固体，滤液减压浓缩，然后加入水和DCM萃取，有机相和滤饼结合柱层析纯化得白色固体(45mg，收率58％)。mp 261-263℃.1H NMR(300MHz,DMSO-d6)δ8.77(s,1H),8.25-8.22(m,2H),7.53-7.5(m,2H),6.08(q,J＝4.5Hz,1H),4.05-4.04(m,1H),3.82-3.80(m,2H),3.69-3.65(m,2H),3.37-3.30(m,1H),3.05-2.98(m,2H),2.93(s,3H),2.66(d,J＝4.5Hz,3H),2.29-2.25(m,2H),2.09-1.96(m,2H).ESI-MS:m/z＝516.52[M+H]+.
实施例32
利用GL-26制备1-(4-(3-(1-乙酰基-4-基)-7-吗啡啉基异噁唑[4,5-d]并嘧啶-5-基)苯基)-3-甲脲(GL-31)
GL-31是用乙酸酐通过过程B合成得到的土黄色固体(70mg，收率97％)。mp 240-242℃.1H NMR(300MHz,DMSO-d6)δ8.77(s,1H),8.25–8.21(m,2H),7.54-7.49(m,2H),6.08(q,J＝4.8Hz,1H),4.44-4.39(m,1H),4.06–4.03(m,4H),3.96-3.91(m,1H),3.81–3.78(m,4H),3.50-3.39(m,1H),3.35–3.26(m,1H),2.91-2.82(m,1H),2.66(d,J＝4.8Hz,3H),2.22-2.12(m,2H),2.06(s,3H),1.94–1.70(m,2H).ESI-MS:m/z＝480.57 [M+H]+.
实施例33
利用GL-26制备1-甲基-3-(4-(7-吗啡啉-3-(1-烟酰基哌啶-4-基)异噁唑[4,5-d]并嘧啶-5-基)苯基)脲(GL-32)
GL-32是由3-吡啶甲酰氯盐酸盐通过过程B合成得到的黄色固体(58mg，收率72％)。mp 158-160℃. 1H NMR(300MHz,DMSO-d6)δ8.78(s,1H),8.67(dd,J＝4.5,1.5Hz,2H),8.26-8.23(m,2H),7.89(dt,J＝7.8,1.8Hz,1H),7.53-7.48(m,3H),6.08(q,J＝4.8Hz,1H),4.66-4.44(m,1H),4.06–4.03(m,4H),3.82-3.79(m,4H),3.75-3.61(m,1H),3.57-3.48(m,1H),3.46-3.27(m,1H),3.27-3.06(m,1H),2.66(d,J＝4.8Hz,3H),2.39-2.09(m,2H),2.04–1.91(m,2H).ESI-MS:m/z＝543.46[M+H]+.
实施例34
利用GL-26制备1-(4-(3-(1-(4-氟苯甲酰基)哌啶-4-基)-7-吗啡啉基异噁唑[4,5-d]并嘧啶-5-基)苯基)-3-甲脲(GL-33)
GL-33是由对氟苯甲酰氯通过过程B合成得到的白色固体(57mg，收率68％)。mp 174-176℃.1H NMR(300MHz,DMSO-d6)δ8.77(s,1H),8.26-8.23(m,2H),7.55–7.50(m,4H),7.33-7.27(m,2H),6.08(q,J＝4.8Hz,1H),4.67-4.30(m,1H),4.07–4.04(m,4H),3.91–3.61(m,5H),3.60-3.44(m,1H),3.42-3.0(m,2H),2.66(d,J＝4.5Hz,3H),2.36-2.08(m,2H),2.02–1.89(m,2H).ESI-MS:m/z＝560.59[M+H]+.
实施例35
利用GL-26制备1-(4-(3-(1-苯甲酰基哌啶-4-基)-7-吗啡啉基异噁唑[4,5-d]并嘧啶-5-基)苯基)-3-甲脲(GL-34)
GL-34是由苯甲酰氯通过过程B合成得到的黄色固体(77mg，收率95％)。mp 175-177℃.1H NMR(300MHz,DMSO-d6)δ8.77(s,1H),8.26-8.22(m,2H),7.54–7.50(m,2H),7.49-7.42(m,5H),6.08(q,J＝4.5Hz,1H),4.75-4.35(m,1H),4.06–4.03(m,4H),3.91–3.61(m,5H),3.57-3.46(m,1H),3.42-3.0(m,2H),2.66(d,J＝4.5Hz,3H),2.36-2.08(m,2H),2.03–1.91(m,2H).ESI-MS:m/z＝542.70[M+H]+.
实施例36
利用GL-26制备4-(5-(4-(3-甲脲基)苯基)-7-吗啡啉基异噁唑[4,5-d]并嘧啶-3-基)哌啶-1-甲酸甲酯(GL-35)
GL-35由氯甲酸甲酯通过过程B合成得到的白色固体(68mg，收率92％)。mp 228-230℃.1H NMR(300MHz,DMSO-d6)δ8.77(s,1H),8.26-8.20(m,2H),7.54–7.49(m,2H),6.08(q,J＝4.5Hz,1H),4.06–4.03(m,6H),3.81–3.78(m,4H),3.64(s,3H),3.42-3.37(m,1H),3.14-3.05(m,2H),2.66(d,J＝4.8Hz,3H),2.17-2.11(m,2H),1.93–1.80(m,2H).ESI-MS:m/z＝496.45[M+H]+.
实施例37
利用GL-26制备4-(5-(4-(3-甲脲基)苯基)-7-吗啡啉基异噁唑[4,5-d]并嘧啶-3-基)哌啶-1-甲酸异丙酯(GL-36)
GL-36是由氯甲酸异丙酯通过过程B合成得到的白色固体(74mg，收率94％)。mp 228-229℃.1H NMR(300MHz,DMSO-d6)δ8.78(s,1H),8.24-8.20(m,2H),7.53–7.48(m,2H),6.08(q,J＝4.8Hz,1H),4.83(sept,J＝6.3Hz,1H),4.09–4.03(m,6H),3.81–3.78(m,4H),3.44-3.35(m,1H),3.11-3.01(m,2H),2.66(d,J＝4.8Hz,3H),2.13-2.07(m,2H),1.95–1.82(m,2H),1.23(d,J＝6.3Hz,6H).ESI-MS:m/z＝524.37[M+H]+.
实施例38
利用GL-26制备N,N-二甲基-4-(5-(4-(3-甲脲基)苯基)-7-吗啡啉基异噁唑[4,5-d]并嘧啶-3-基)哌啶-1-甲酰胺(GL-38)
GL-38由二甲胺基甲酰氯通过过程B合成得到的白色固体(75mg，收率98％)。mp 152-154℃.1H NMR(300MHz,DMSO-d6)δ8.77(s,1H),8.26-8.21(m,2H),7.53–7.49(m,2H),6.08(q,J＝4.8Hz,1H),4.06–4.03(m,4H),3.81–3.78(m,4H),3.68-3.64(m,2H),3.41-3.30(m,1H),3.89-3.0(m,2H),2.78(s,6H),2.66(d,J＝4.5Hz,3H),2.14-2.09(m,2H),2.02–1.89(m,2H).ESI-MS:m/z＝509.34[M+H]+.
实施例39
利用GL-26制备叔丁基(2-甲基-1-(4-(5-(4-(3-甲脲基)苯基)-7-吗啉基异噁唑[4,5-d]并嘧啶-3-基)哌啶-1-基)-1-氧代丙基-2-基)氨基甲酸酯(GL-39)
GL-39是由GL-26(150mg，0.23mmol)和2-(叔丁氧羰氨基)异丁酸通过过程A合成的黄白色固体(117 mg，收率84％)。mp 180-182℃.1H NMR(300MHz,DMSO-d6)δ8.77(s,1H),8.26-8.21(m,2H),7.53–7.49(m,2H),7.35(s,1H),6.07(q,J＝4.8Hz,1H),4.50-4.54(m,1H),4.06–4.03(m,4H),3.81–3.78(m,4H),3.40-3.37(m,1H),3.24-2.79(m,1H),2.66(d,J＝4.5Hz,3H),2.29-2.03(m,2H),1.97–1.72(m,2H),1.35(s,1H).ESI-MS:m/z＝623.42[M+H]+.
实施例40
利用GL-26制备1-(4-(3-(1-(2-氰乙基)哌啶-4-基)-7-吗啉基异噁唑[4,5-d]并嘧啶-5-基)苯基)-3-甲脲(GL-40)
GL-40是由氰基乙酸通过过程A合成得到的黄色固体(44mg，收率58％)。mp 258-260℃.1H NMR(300MHz,DMSO-d6)δ8.77(s,1H),8.24(d,J＝8.7Hz,2H),7.51(d,J＝8.7Hz,2H),6.07(q,J＝4.8Hz,1H),4.46-4.3(m,1H),4.20-4.04(m,6H),3.90-3.68(m,5H),3.51–3.44(m,1H),3.35–3.27(m,1H),3.01-2.94(m,1H),2.66(d,J＝4.5Hz,3H),2.21-2.17(m,2H),2.08-1.94(m,1H),1.86-1.73(m,1H).ESI-MS:m/z＝505.72[M+H]+.
实施例41
利用GL-26制备1-甲基-3-(4-(7-吗啡啉-3-(1-(2,2,2-三氟乙基)哌啶-4-基)异噁唑[4,5-d]并嘧啶-5-基)苯基)脲(GL-41)
将GL-26(100mg，0.15mmol)悬浮在乙醇中加入DIPEA(71mg，0.55mmol)和三氟甲磺酸三氟乙酯(51mg，0.22mmol)，升温回流反应12h，TLC监测未反应完全，补加DIPEA(23mg，0.18mmol)和三氟甲磺酸三氟乙酯(21mg，0.09mmol)，继续回流反应5h。反应液减压浓缩，加入水，DCM萃取，有机相减压浓缩，柱层析纯化得黄色固体(77mg，收率98％)。mp 229-230℃.1H NMR(300MHz,DMSO-d6)δ8.77(s,1H),8.25-8.21(m,2H),7.54–7.50(m,2H),6.07(q,J＝4.8Hz,1H),4.06–4.03(m,4H),3.81–3.78(m,4H),3.30-3.20(q,J＝10.2Hz,2H),3.18-3.11(m,1H),3.08-3.02(m,2H),2.66(d,J＝4.8Hz,3H),2.63-2.54(m,2H),2.15–2.09(m,2H),2.05-1.92(m,2H).ESI-MS:m/z＝520.41[M+H]+.
实施例42
利用GL-26制备1-甲基-3-(4-(3-(1-(2-(甲砜基)乙基)哌啶-4-基)-7-吗啡啉基异噁唑[4,5-d]并嘧啶-5-基)苯基)脲(GL-42)
将GL-26(100mg，0.15mmol)悬浮在n-BuOH中加入DIPEA(71mg，0.55mmol)、2-甲砜基溴乙烷(41mg，0.22mmol)和NaI(41mg，0.27mmol)，室温下搅拌，TLC监测反应完成，抽滤得苍黄色固 体(70mg，收率85％)。mp 227-228℃.1H NMR(300MHz,DMSO-d6)δ9.23(s,1H),8.22-8.19(m,2H),7.54-7.51(m,2H),6.44(q,J＝4.5Hz,1H),4.06–4.03(m,4H),3.81–3.78(m,4H),3.36–3.32(t,J＝6.3Hz,2H),3.19–3.07(m,1H),3.09(s,3H),3.04-3.0(m,2H),2.78(t,J＝6.6Hz,2H),2.66(d,J＝4.5Hz,3H),2.26-2.19(m,2H),2.12-1.95(m,4H).ESI-MS:m/z＝544.57[M+H]+.
实施例43
利用GL-26制备1-甲基-3-(4-(7-吗啡啉-3-(1-三氟乙酰基哌啶-4-基)异噁唑[4,5-d]并嘧啶-5-基)苯基)脲(GL-43)
GL-26(100mg，0.15mmol)悬浮在乙腈中加入三乙胺解离，所得混合物减压浓缩至干，加入无水DCM，冰盐浴降温，缓慢滴加2eq TFAA。滴完室温下搅拌过夜，TLC监测反应未完成，补加1.2eq TFAA反应液立刻变澄清。反应液加入水，DCM萃取，有机相用水和饱和氯化钠洗涤，柱层析纯化得白色固体(56mg，收率70％)。mp 203-205℃.1H NMR(300MHz,DMSO-d6)δ8.77(s,1H),8.24-8.21(m,2H),7.53-7.50(m,2H),6.07(q,J＝4.8Hz,1H),4.39-4.32(m,1H),4.06–3.98(m,5H),3.81–3.78(m,4H),3.64–3.52(m,2H),3.30–3.22(m,1H),2.66(d,J＝4.5Hz,3H),2.36-2.27(m,2H),2.08-1.86(m,2H).ESI-MS:m/z＝534.59[M+H]+.
实施例44
利用GL-39制备1-(4-(3-(1-(2-氨基-2-甲基丙酰基)哌啶-4-基)-7-吗啡啉基异噁唑[4,5-d]并嘧啶-5-基)苯基)-3-甲脲三氟乙酸盐(GL-44)
GL-39(100mg，0.16mmol)溶解在DCM中加入2mL TFA，室温下搅拌反应2h，浓缩至干加入乙醇，再浓缩并加入石油醚，抽滤析出的固体得黄色产物(107mg，收率100％)。mp 178-180℃.1H NMR(300MHz,DMSO-d6)δ8.88(s,1H),8.24-8.21(m,2H),8.18(s,3H),7.54-7.51(m,2H),6.20(q,J＝4.8Hz,1H),4.49-4.20(m,2H),4.07–4.04(m,4H),3.81–3.79(m,4H),3.61–3.52(m,1H),3.40–3.03(m,2H),2.66(d,J＝4.5Hz,3H),2.24-2.20(m,2H),2.00-1.98(m,2H),1.62(s,6H).ESI-MS:m/z＝523.74[M+H]+.
实施例45
利用GL-26制备N,N-二甲基-2-(4-(5-(4-(3-甲脲基)苯基)-7-吗啡啉基异噁唑[4,5-d]并嘧啶-3-基)哌啶-1-基)乙酰胺(GL-45)
GL-26(100mg，0.15mmol)悬浮在乙腈中，加入DIPEA(71mg，0.55mmol)和2-氯-N,N-二甲基 乙酰胺(25mg，0.21mmol)，室温下搅拌过夜，加入NaI(27mg，0.18mmol)继续搅拌反应10h。减压浓缩，加入水，DCM萃取，有机相用水和饱和氯化钠洗涤，柱层析得黄白色固体(70mg，收率90％)。mp 159-160℃.1H NMR(300MHz,DMSO-d6)δ8.77(s,1H),8.24-8.21(m,2H),7.53-7.50(m,2H),6.07(q,J＝4.5Hz,1H),4.15-3.94(m,4H),3.90–3.66(m,4H),3.20(s,1H),3.16–3.09(m,1H),3.07(s,3H),2.97-2.93(m,2H),2.83(s,3H),2.66(d,J＝4.2Hz,3H),2.33-2.26(m,2H),2.11-1.94(m,4H).ESI-MS:m/z＝523.80[M+H]+.
实施例46
利用GL-26制备2-(4-(5-(4-(3-甲脲基)苯基)-7-吗啡啉基异噁唑[4,5-d]并嘧啶-3-基)哌啶-1-基)乙酰胺(GL-46)
将GL-26(100mg，0.15mmol)悬浮在乙腈中，加入DIPEA(71mg，0.55mmol)和2-碘代乙酰胺(37mg，0.20mmol)，室温下搅拌反应8h。反应液减压浓缩，残余物溶解在氯仿和甲醇中，加入水，氯仿萃取，有机相水和饱和氯化钠洗涤，减压浓缩，抽滤得黄白色固体(86mg，收率100％)。mp 186-188℃. 1H NMR(300MHz,DMSO-d6)δ8.99(s,1H),8.26-8.20(m,2H),7.53-7.50(m,2H),7.24(s,1H),7.13(s,1H),6.25(q,J＝4.8Hz,1H),4.06–4.04(m,4H),3.81–3.78(m,4H),3.15-3.09(m,1H),2.96-2.92(m,4H),2.66(d,J＝4.8Hz,3H),2.35-2.26(m,2H),2.14–1.99(m,4H).ESI-MS:m/z＝495.70[M+H]+.
实施例47
利用GL-26制备1-(4-(3-(1-(2-羟乙基)哌啶-4-基)-7-吗啉基异噁唑[4,5-d]并嘧啶-5-基)苯基)-3-甲脲(GL-47)
将GL-26(100mg，0.15mmol)悬浮在乙醇中，加入DIPEA(71mg，0.55mmol)、NaI(27mg，0.18mmol)和2-溴乙醇(25mg，0.20mmol)，回流反应60h。减压浓缩，加入水，氯仿萃取，萃不干净，在pH＝14下萃取，所得有机相柱层析纯化得黄色固体(50mg，收率69％)。mp 198-199℃.1H NMR(300MHz,DMSO-d6)δ8.77(s,1H),8.24-8.21(m,2H),7.53-7.50(m,2H),6.07(q,J＝4.5Hz,1H),4.41(t,J＝5.1Hz,1H),4.06-4.03(m,4H),3.81–3.78(m,4H),3.54(q,J＝6.0Hz,2H),3.11–3.06(m,1H),3.01-2.97(m,2H),2.66(d,J＝4.8Hz,3H),2.45(t,J＝6.3Hz,2H),2.23-2.16(m,2H),2.11-1.92(m,4H).ESI-MS:m/z＝482.70[M+H]+.
实施例48
利用GL-26制备2-(4-(5-(4-(3-甲脲基)苯基)-7-吗啉基异噁唑[4,5-d]并嘧啶-3-基)哌啶-1-基)乙酰乙酸乙酯(GL-48)
GL-26(100mg，0.15mmol)悬浮在乙腈中，加入DIPEA(71mg，0.55mmol)和溴乙酸乙酯(36mg，0.22mmol)，室温下搅拌反应5h。反应液减压浓缩，加入水，DCM萃取，有机相用水和饱和氯化钠洗涤，浓缩柱层析纯化得黄色固体(66mg，收率84％)。mp 221-223℃.1H NMR(300MHz,DMSO-d6)δ8.77(s,1H),8.25-8.21(m,2H),7.54-7.49(m,2H),6.07(q,J＝4.8Hz,1H),4.11(q,J＝7.2Hz,2H),4.06-4.03(m,4H),3.81–3.78(m,4H),3.29(s,2H),3.17–3.07(m,1H),2.98-2.94(m,2H),2.66(d,J＝4.8Hz,3H),2.48-2.39(m,2H),2.13-1.93(m,4H),1.22(t,J＝7.2Hz,3H).ESI-MS:m/z＝524.45[M+H]+.
实施例49
利用GL-26制备1-(4-(3-(1-(2-甲氧基乙基)哌啶-4-基)-7-吗啉基异噁唑[4,5-d]并嘧啶-5-基)苯基)-3-甲脲(GL-49)
GL-26(100mg，0.15mmol)悬浮在乙醇中，加入DIPEA(71mg，0.55mmol)、NaI(27mg，0.18mmol)和2-甲氧基溴乙烷(27mg，0.20mmol)，回流反应，TLC监测原料不再减少。反应液减压浓缩，加入水，DCM萃取，不能完全萃出产物，再在pH＝14条件下萃取，所得有机相通过柱层析纯化得黄色固体(45mg，收率61％)。mp 208-210℃.1H NMR(300MHz,DMSO-d6)δ8.77(s,1H),8.24-8.21(m,2H),7.53-7.50(m,2H),6.07(q,J＝4.5Hz,1H),4.06-4.03(m,4H),3.81–3.78(m,4H),3.48(t,J＝5.7Hz,2H),3.26(s,3H),3.16–3.09(m,1H),3.03-2.98(m,2H),2.66(d,J＝4.5Hz,3H),2.60-2.50(m,2H),2.27-2.16(m,2H),2.12-1.92(m,4H).ESI-MS:m/z＝496.57[M+H]+.
实施例50
利用GL-48制备2-(4-(5-(4-(3-甲脲基)苯基)-7-吗啉基异噁唑[4,5-d]并嘧啶-3-基)哌啶-1-基)乙酸二三氟乙酸盐(GL-50)
GL-48(110mg，0.21mmol)溶解在MeOH中，加入0.21mL 2N NaOH溶液，回流反应6h。反应液冷却，浓盐酸调pH＝6，加入水，减压浓缩，残余物抽滤，滤饼干燥后在室温下在TFA中搅拌1h。减压蒸干TFA得黄色固体(104mg，收率68％)。mp 240-242℃.1H NMR(300MHz,DMSO-d6)δ10.05(s,1H),8.87(s,1H),8.28-8.25(m,2H),7.54-7.51(m,2H),6.26-6.11(m,1H),5.42(s,2H),4.19(s,2H),4.09-4.02(m,4H),3.82–3.79(m,4H),3.75-3.43(m,3H),3.43-3.19(m,2H),2.66(s,3H),2.47-2.16(m,4H).ESI-MS:m/z＝496.68[M+H]+.
实施例51
利用GL-26制备1-(4-(3-(1-(2-羟基-2-甲基丙酰基)哌啶-4-基)-7-吗啡啉基异噁唑[4,5-d]并嘧啶-5-基)苯基)-3-甲脲(GL-51)
GL-51是由2-羟基异丁酸通过过程A合成得到的黄色固体(75mg，收率95％)。mp 165-167℃.1H NMR(300MHz,DMSO-d6)δ8.78(s,1H),8.25-8.21(m,2H),7.53-7.49(m,2H),6.07(q,J＝4.8Hz,1H),5.44(s,1H),5.12-4.69(m,1H),4.69-4.32(m,1H),4.06–4.03(m,1H),3.81–3.78(m,1H),3.52-3.42(m,1H),3.28-3.05(m,1H),3.05-2.77(m,1H),2.66(d,J＝4.5Hz,3H),2.18-2.12(m,2H),2.06-1.70(m,2H),1.36(s,6H).ESI-MS:m/z＝524.48[M+H]+.
实施例52
利用GL-26制备4-(5-(4-(3-甲脲基)苯基)-7-吗啉基异噁唑[4,5-d]并嘧啶-3-基)-N-吡啶-3-基)哌啶-1-硫代甲酰胺(GL-52)
GL-26(100mg，0.15mmol)悬浮在乙腈中，加入3-异硫氰酸酯基吡啶(50mg，0.37mmol)和DIPEA(28mg，0.22mmol)，回流反应5h。减压浓缩至干，加入水，DCM萃取，有机相用水和饱和氯化钠洗涤，减压浓缩，柱层析纯化得黄色固体(86mg，收率100％)。mp 183-185℃.1H NMR(300MHz,DMSO-d6)δ9.51(s,1H),8.79(s,1H),8.51(d,J＝2.4Hz,1H),8.32-8.30(m,1H),8.28-8.25(m,2H),7.80–7.76(m,1H),7.54-7.51(m,2H),7.37(dd,J＝8.1,4.5Hz,1H),6.09(q,J＝4.5Hz,1H),4.85-4.80(m,2H),4.07–4.04(m,4H),3.82–3.80(m,4H),3.65-3.55(m,1H),3.52-3.44(m,2H),2.67(d,J＝4.8Hz,3H),2.25-1.98(m,4H).ESI-MS:m/z＝574.26[M+H]+.
实施例53
利用GL-26制备1-甲基-3-(4-(7-吗啉-3-(1-三氟甲磺酰基哌啶-4-基)异噁唑[4,5-d]并嘧啶-5-基)苯基)脲(GL-53)
GL-26(137mg，0.21mmol)悬浮在无水THF中，加入DIPEA(96mg，0.74mmol)，冰浴下冷却，将三氟甲磺酰氯(51mg，0.30mmol)的THF溶液滴加到反应液中，继续搅拌反应1h，室温下搅拌过夜，TLC监测反应未完全，升温至40℃反应5h并补加三氟甲磺酰氯(40mg，0.25mmol)。反应液浓缩，加入水，DCM萃取，有机相减压浓缩制备薄层色谱纯化得白色固体(30mg，收率26％)。mp 238-240℃.1HNMR(300MHz,DMSO-d6)δ8.78(s,1H),8.26-8.21(m,2H),7.53-7.50(m,2H),6.08(q,J＝4.8Hz,1H),4.07–4.04(m,4H),3.97-3.93(m,2H),3.81–3.79(m,4H),3.58-3.47(m,3H),2.66(d,J＝4.5Hz,3H),2.35-2.21(m,2H),2.12–1.99(m,2H).ESI-MS:m/z＝570.70[M+H]+.
实施例54
利用GL-26制备1-(4-(3-(1-(2-氯乙酰基)哌啶-4-基)-7-吗啉基异噁唑[4,5-d]并嘧啶-5-基)苯基)-3-甲脲 (GL-54)
GL-54由氯乙酰氯通过过程B合成得到的黄色固体(38mg，收率49％)。mp 157-158℃.1H NMR(300MHz,DMSO-d6)δ8.77(s,1H),8.26-8.21(m,2H),7.54-7.49(m,2H),6.07(d,J＝4.8Hz,1H),4.50-4.36(m,3H),4.06-3.89(m,5H),3.81-3.78(m,1H),3.54-3.44(m,1H),3.39–3.33(m,1H),3.02-2.94(m,1H),2.66(d,J＝4.5Hz,3H),2.16-1.76(m,4H).ESI-MS:m/z＝514.71[M+H]+.
实施例55
利用GL-26制备1-(4-(3-(1-(3,3-二甲基丁酰基)哌啶-4-基)-7-吗啉基异噁唑[4,5-d]并嘧啶-5-基)苯基)-3-甲脲(GL-56)
GL-56由3,3-二甲基丁酸通过过程A合成的白色固体(80mg，收率99％)。mp 153-155℃.1H NMR(300MHz,DMSO-d6)δ8.76(s,1H),8.2–8.20(m,2H),7.52–7.48(m,2H),6.06(q,J＝4.5Hz,1H),4.60-4.47(m,1H),4.13–4.02(m,5H),3.81–3.78(m,4H),3.52-3.40(m,1H),3.31–3.25(m,1H),2.87-2.78(m,1H),2.66(d,J＝4.8Hz,3H),2.30(q,J＝14.1Hz,2H),2.14–1.77(m,4H),1.04(s,9H).ESI-MS:m/z＝536.59[M+H]+.
实施例56
利用GL-26制备1-(4-(3-(1-(3,5-二叔丁基苯甲酰基)哌啶-4-基)-7-吗啉基异噁唑[4,5-d]并嘧啶-5-基)苯基)-3-甲脲(GL-57)
GL-57是由3,5-二叔丁基苯甲酸通过过程A合成的白色固体(66mg，收率67％)。mp 158-159℃.1HNMR(300MHz,DMSO-d6)δ8.75(s,1H),8.27–8.21(m,2H),7.53–7.48(m,3H),7.23(d,J＝1.8Hz,2H),6.06(q,J＝4.8Hz,1H),4.77-4.24(m,1H),4.07–4.04(m,4H),3.82–3.59(m,5H),3.56-3.46(m,1H),3.41–3.02(m,2H),2.66(d,J＝4.5Hz,3H),2.17–1.95(m,4H),1.30(s,18H).ESI-MS:m/z＝654.93[M+H]+。
实施例57
利用GL-26制备1-(4-(3-(1-(3,5-二氟苯甲酰基)哌啶-4-基)-7-吗啉基异噁唑[4,5-d]并嘧啶-5-基)苯基)-3-甲脲(GL-58)
GL-58由3,5-二氟苯甲酸通过过程A合成的黄色固体(60mg，收率81％)。mp 162-164℃.1H NMR(300MHz,DMSO-d6)δ8.77(s,1H),8.26-8.21(m,2H),7.53-7.50(m,2H),7.36(tt,J＝9.6,2.4Hz,1H),7.22–7.19(m,2H),6.07(q,J＝4.5Hz,1H),4.61-4.39(m,1H),4.07-4.04(m,4H),3.82–3.79(m,4H),3.71-3.59(m,1H),3.58-3.47(m,1H),3.40-3.30(m,1H),2.66(d,J＝4.8Hz,3H),2.37-2.06(m,2H),2.04–1.90(m,2H).ESI-MS:m/z＝578.74[M+H]+.
实施例58
利用GL-26制备1-(4-(3-(1-(2-(4-氟苯基)乙酰基)哌啶-4-基)-7-吗啉基异噁唑[4,5-d]并嘧啶-5-基)苯基)-3-甲脲(GL-59)
GL-59由GL-26(86mg，0.13mmol)和对氟苯乙酸通过过程A合成的黄色固体(68mg，收率93％)。mp 138-140℃.1H NMR(300MHz,DMSO-d6)δ8.78(s,1H),8.25–8.20(m,2H),7.54–7.50(m,2H),7.33–7.28(m,2H),7.17–7.09(m,2H),6.08(q,J＝4.8Hz,1H),4.47-4.42(m,1H),4.10-4.03(m,5H),3.81–3.78(m,6H),3.45(tt,J＝11.1,3.6Hz,1H),3.33-3.26(m,1H),2.94-2.87(m,1H),2.66(d,J＝4.5Hz,3H),2.15-2.09(m,2H),1.85-1.72(m,2H).ESI-MS:m/z＝574.91[M+H]+.
实施例59
利用GL-26制备1-甲基-3-(4-(7-吗啡啉-3-(1-(4-(三氟甲基)苯甲酰基)哌啶-4-基)异噁唑[4,5-d]并嘧啶-5-基)苯基)脲(GL-60)
GL-60由GL-26(85mg，0.13mmol)和三氟苯甲酸通过过程A合成的黄白色固体(70mg，收率90％)。mp 208-210℃.1H NMR(300MHz,DMSO-d6)δ8.76(s,1H),8.26–8.23(m,2H),7.84(d,J＝8.1Hz,2H),7.67(d,J＝8.1Hz,2H),7.54–7.49(m,2H),6.07(q,J＝4.5Hz,1H),4.66-4.44(m,1H),4.06–4.07(m,4H),3.82–3.79(m,4H),3.70-3.58(m,1H),3.58-3.49(m,1H),3.43-3.27(m,1H),3.25-3.07(m,1H),2.66(d,J＝4.8Hz,3H),2.38-2.08(m,2H),2.08-1.81(m,2H).ESI-MS:m/z＝610.87[M+H]+.
实施例60
利用化合物1制备(3-(3-(1-苄基哌啶-4-基)-7-吗啉基异噁唑[4,5-d]并嘧啶-5-基)苯基)甲醇(GL-61)
将1(207mg，0.5mmol)、3-羟乙基苯硼酸(114mg，0.75mmol)、Pd(Pcy3)2Cl2(19mg，0.025mmol)和CsF(228mg，1.5mmol)放入三口瓶中，抽真空排气再进Ar气，重复排气进气三次，注射4mL溶剂(NMP/water＝9/1)，在Ar气保护下100℃反应48h。反应液中加入水和乙酸乙酯萃取，有机相水洗再用饱和氯化钠洗三次，减压浓缩，柱层析和制备薄层色谱纯化得黄色固体(44mg，收率18％)。mp 87-89℃. 1H NMR(300MHz,DMSO-d6)δ8.32(s,1H),8.26–8.23(m,1H),7.48-7.43(m,2H),7.35–7.23(m,5H),5.28(t,J＝5.7Hz,1H),4.59(d,J＝5.7Hz,1H),4.08–4.05(m,4H),3.82–3.79(m,4H),3.54(s,2H),3.22-3.12(m,1H),2.95-2.91(m,2H),2.23-1.95(m,6H).ESI-MS:m/z＝486.55[M+H]+.
实施例61
利用化合物1制备3-(3-(1-苄基哌啶-4-基)-7-吗啉基异噁唑[4,5-d]并嘧啶-5-基)苯酚(GL-62)
将1(207mg，0.5mmol)、3-羟基苯硼酸(103mg，0.75mmol)、Pd(Pcy3)2Cl2(19mg，0.025mmol)和CsF(228mg，1.5mmol)置于三口瓶中抽真空排气再进Ar气，重复排气进气三次，注射4mL溶剂(NMP/water＝9/1)，在Ar气保护下100℃反应48h。反应液中加入水和乙酸乙酯萃取，有机相水洗再用饱和氯化钠洗三次，减压浓缩，柱层析和制备薄层色谱纯化得黄色固体(24mg，收率10％)。mp 86-88℃. 1H NMR(300MHz,CDCl3)δ7.93(d,J＝7.8Hz,1H),7.83(s,1H),7.39–7.25(m,5H),6.92(dd,J＝7.8,1.8Hz,1H),4.13–4.10(m,4H),3.87–3.84(m,4H),3.66(s,2H),3.19-3.11(m,3H),2.33–2.11(m,7H).ESI-MS:m/z＝472.31[M+H]+.
实施例62
制备1-(4-(3-(1-苄基哌啶-4-基)-7-吗啡啉基异噁唑[4,5-d]并嘧啶-5-基)苯基)-3-甲脲盐酸盐
将GL-2(528mg,1mmol)溶于10mL无水二氧六环中，加入0.52mL自制的2.3mol/L的氯化氢无水二氧六环溶液，在室温下搅拌过夜，减压蒸干二氧六环，加入10mL无水二氯甲烷超声洗涤，抽滤得白色固体(535mg,收率95％)。mp 255-257℃.ESI-MS:m/z＝528.38[M+H]+.
试验实施例63
本发明的具有式(I)结构的化合物及其药学上可接受的盐，在抗肿瘤方
面有明显的效用，现通过以下药理实验说明：
通过CCK-8检测试剂盒检测化合物对3个肿瘤细胞株(U-87MG,、PC-3和BT-474)的细胞增殖半数抑制浓度IC50值。
1、材料和方法
U-87MG人恶性胶质母细胞瘤细胞株(订购于中科院上海细胞资源中心)
PC-3人前列腺癌细胞株(订购于中科院上海细胞资源中心)
BT-474人乳腺癌细胞株(订购于中科院上海细胞资源中心)
Cell Counting Kit-8(Cat#CK04-13，Dojindo)
96孔培养板(Cat#3599，Corning Costar)
胎牛血清(Cat#10099-141，GIBCO)
培养基(Invitrogen)
台式酶标仪SpectraMax M5Microplate Reader(Molecular Devices)
2、实验步骤
2.1 试剂配制
| 细胞系 | 培养基 |
| U-87MG | EMEM+1mM sodium pyruvate+1.5g/L NaHCO3+10％FBS |
| PC-3 | F12K+10％FBS |
| BT-474 | RPMI1640+10％FBS |
化合物的制备：用DMSO稀释化合物使终浓度为10mM。
2.2 IC50实验(CCK-8检测)
收集对数生长期细胞，计数，用完全培养基重新悬浮细胞，调整细胞浓度至合适浓度(依照细胞密度优化试验结果确定)，接种96孔板，每孔加100μL细胞悬液。细胞在37℃，100％相对湿度，5％CO2培养箱中孵育24小时。用培养基将待测化合物稀释至所设置的相应作用浓度(5X)，按25μL/孔加入到细胞中。化合物作用终浓度从100μM至0μM，4倍梯度稀释，共10个浓度点；或从10μM至0μM，4倍梯度稀释，共10个浓度点。然后将细胞置于37℃，100％相对湿度，5％CO2培养箱中孵育72小时。吸弃培养基，加入含10％CCK-8的完全培养基置于37℃培养箱中孵育2-4小时。轻轻震荡后在SpectraMax M5Microplate Reader上测定450nm波长处的吸光度，以650nm处吸光度作为参比，计算抑制率。
3、数据处理
按下式计算药物对肿瘤细胞生长的抑制率：肿瘤细胞生长抑制率％＝[(Ac-As)/(Ac-Ab)]×100％
As:样品的OA(细胞+CCK-8+待测化合物)
Ac:阴性对照的OA(细胞+CCK-8+DMSO)
Ab:空白对照的OA(培养基+CCK-8+DMSO)
运用软件Graphpad Prism 5并采用计算公式log(inhibitor)vs.normalized response-Variable slope进行IC50曲线拟合并计算出IC50值。
4、实验结果
试验实施例64
式(I)所示化合物作为PIK3抑制剂的作用，通过以下试验说明
应用PI3-Kinase(human)HTRFTM Assay kit检测待测化合物对PI3K delta酶的抑制作用及半数抑制浓度(IC50)。
1、材料和仪器
2104Multilabel Reader(Cat:2104-0010,PerkinElmer)
384well opaque balck plate(Cat.6007270,PerkinElmer)
PI 3-Kinase(human)HTRFTM Assay kit(Cat.33-016,Millipore)
4×Reaction Buffer(Cat.33-002,Millipore)
PIP21mM(Cat.33-004,Millipore)
Stop A(Cat.33-006,Millipore)
Stop B(Cat.33-008,Millipore)
DM A(Cat.33-010,Millipore)
DM B(Cat.33-012,Millipore)
DM C(Cat.33-014,Millipore)
PI3K delta(Cat.14-604,Millipore)
ATP 10mM(cat PV3227,Invitrogen)
DTT 1M(cat D5545,Sigma)
2、试剂配制
2.11×Reaction Buffer
4×Reaction Buffer(Cat.33-002,Millipore)用ddH2O稀释至1×，并加入1M DTT使其终浓度为5mM。每次使用前新鲜配制。例如配制10mL 1×Reaction Buffer，加入2.5mL 4×Reaction Buffer,50μL 1M浓度的DTT和ddH2O 7.45mL。整个实验中，用新鲜配制的1×Reaction Buffer配制ATP工作液，底物和酶混合工作液等。
2.24×化合物工作液
初筛：待测化合物用DMSO溶解至50μM作为储存液，各取2μL加入48μL ddH2O中，得到2μM含4％DMSO的化合物溶液，混匀后各吸取2μL加入18μL 4％DMSO(in ddH2O)得到0.2μM化合物溶液。每个稀释溶液各取5μL加入384孔板中，这样在最后的20μL激酶反应体系中化合物的终浓度就分别是500nM和50nM并含有1％DMSO。
IC50:待测化合物用DMSO溶解至10mM作为储存液，各取2μL加入48μL 1×Reaction Buffer中，得到400000nM含4％DMSO的化合物溶液，混匀后各吸取5μL加入下一个15μL 4％DMSO(in 1×Reaction Buffer)的孔中，依次稀释下去得到10个浓度梯度。每个稀释溶液各取5μL加入384孔板中，这样在最后的20μL激酶反应体系中各个孔的化合物的终浓度就是100000nM、25000nM、6250nM、1562.5nM、390.63nM、97.65nM、24.42nM、6.10nM、1.53nM、0.38nM并含有1％DMSO。10个测定浓度每个浓度为复孔。同时选取CAL-101作为参考化合物，从2μM开始4倍倍比稀释化合物。
2.32×PIP2工作液
用1×reaction buffer配制2×PIP2工作液，使其终浓度为20μM，PIP2的反应终浓度为10μM，例如配制1mL 1x reaction buffer/PIP2工作液，取20μL PIP2加入到980μL 1×reaction buffer中。这个工作液要多配0.1-0.2mL,以满足对照使用和死体积。
2.42×PIP2/激酶工作液
用2×PIP2工作液稀释激酶，激酶工作液的浓度为80ng/well。无激酶对照(可视为100％抑制)即2×PIP2工作液。
2.54×ATP工作液
10mM的ATP用1×reaction buffer稀释至40μM。在20μL激酶反应体系中，ATP的浓度为10μM。例如配制2mL ATP工作液，取8μL 10mM浓度的ATP加入到1992μL 1×reaction buffer中。
2.6终止液
Stop A和Stop B按3：1的比例混合，室温放置至少2小时后才可用，终止液可在室温下稳定12个小时。
2.7检测液
DM C、DM A和DM B按照18：1：1的比例混合，室温放置至少2小时后才可用，检测液可在室温下稳定12个小时。
3、实验流程
实验流程如图1所示。
4、数据分析
计算各孔的Emission Ratio(ER)
Emission Ratio(ER)＝665nm Emission signal/620nm Emission signal
100％抑制对照的平均Emission Ratio记为：ER100 ％
0％抑制对照的平均Emission Ratio记为：ER0 ％
抑制率用以下公式计算：抑制率＝(ERsample-ER0 ％)/(ER100 ％-ER0 ％)×100％
运用软件Graphpad Prism 5进行IC50曲线拟合并计算出IC50值。
5、实验结果
aNT＝no test
Claims (10)
1.一种式(Ⅰ)所示的嘧啶衍生物及其多种晶型体或其药学上可以接受的盐，
其中，
R1为氢，以C1—C6为取代基的可选取代的芳基，可选取代的C1—C6直链、支链或环状烷基，酰二胺基，以卤素、以可选取代的C1—C6直链、支链、环状烷基为取代基的芳基，以可选取代的C1—C6直链、支链、或环状烷基为取代基的吡啶基，以可选取代的C1—C6直链、支链、或环状烷基为取代基的砜基，以可选取代的C1—C6直链、支链或环状烷基为取代基的磺酰基，以可选取代的C1—C6直链、支链或环状烷基、吡啶基、卤代苯基、胺基、腈基、卤代烷基为取代基的羰基，可选取代的C1—C6直链、支链或环状醇基，酯基，醚基或羧基；
R2为氢，NHR2'或NHCONHR3；
其中，所述R10为H或可选取代的C1—C6直链、支链或环状烷基；所述R2'为H或以C1—C6直链、支链烷基、C3—C6环烷基为取代基的可选取代的酰胺基，以可选取代的C1—C6直链、支链或环状烷基为取代基的三取代胺基，以一个、两个或三个卤原子为取代基的可选取代的C1—C6直链、支链或环状烷基，C1—C6直链或支链烷氧基，可选取代的C1—C6直链、支链或环状醇基，哌嗪基吡啶基，胺基吡啶基，哌嗪基芳基或卤素为取代基的芳基；其中哌嗪基和胺基为以可选取代的C1—C6直链、支链或环状烷基为取代基的取代哌嗪基和取代胺基；所述R3＝可选取代的C1—C6直链、支链或环状烷基以及可选取代的芳基；
R0为氢、羟基或可选取代的C1—C6直链、支链或环状醇基。
2.根据权利要求1所述的式(I)所示的嘧啶衍生物及其多种晶型体或其药学上可以接受的盐，其特征在于，
(1)当R1＝可选取代的芳基，R2＝H时，R0＝—OH或R0'OH，其中，R0'为可选取代的C1—C6直链、支链或环状烷基；
当R1＝可选取代的芳基，R0＝H时，或NHR2'，其中，R10为H或可选取代的C1—C6直链、支链、或环状烷基；R2'＝H或CONHR3；其中，R3＝H，C1—C6直链、支链烷基，C3—C6环烷基，以C1—C6直链或支链烷基为取代基的三取代胺基，一卤代C1—C6直链、支链或环状烷基，二卤代C1—C6直链、支链或环状烷基、三卤代C1—C6直链、支链或环状烷基，-O-R8，R9OH或
其中，
当X＝N时，所述R4＝H、或NHR6，其中，R5、R6独立地为C1—C6直链或支链烷基；
当X＝C时，所述R4＝H、卤素，其中，R7＝H、C1—C6烷基、BOC或
所述R8为可选取代的C1—C6直链、支链或环状烷基；
所述R9为可选取代的C1—C6直链、支链或环状烷基；
(2)当R0＝H，R1＝NHCONHR3'时，R2＝CONHR11，所述R3'、R11各自独立地为H、可选取代的C1—C6直链、支链、或环状烷基；
(3)当R0＝H，R1＝H或C1—C6直链、支链烷基时；R2＝NHCONHR3,R3为可选取代的C1—C6直链、支链或环状烷基；
(4)当R0＝H，R2＝NHCONHR3，且R3为可选取代的C1—C6直链、支链或环状烷基时，
其中，
所述R11、R20、R21各自独立地为H或可选取代的C1—C6直链、支链或环状烷基；
所述R12、R13、R14a、R16、R18a、R23、R24、R26、R27、R28、R29、R30、R31、R32、R33、R34、各自独立地为可选取代的C1—C6直链、支链或环状烷基；
所述R14为可选取代的C1—C6直链、支链或环状烷基或三卤代C1—C6直链、支链、或环状烷基；
所述R15为可选取代的C1—C12直链、支链、环状烷基或以卤素或C1—C6直链、支链或环状烷基为取代基的可选取代的芳烃；
所述R18、R19独立地为H、Boc或可选取代的C1—C6直链、支链、环状烷基；
所述Y＝F、Cl、Br或I；
所述Z为F、Cl、Br、I或氢。
3.根据权利要求1所述的嘧啶衍生物及其多种晶型体或其药学上可以接受的盐，其特征在于，
(1)当R1＝苄基，R2＝H时，R0为羟基、甲醇、乙醇、丙醇、异丙醇或丁醇；
当R1＝苄基，R0＝H时，NHR2'或NHCONHR3；
其中，
所述R10为H、甲基、乙基、丙基或丁基；
所述R2'＝H或CONHR3；
所述R3＝H、甲基、乙基、丙基、异丙基、丁基、环丙烷基、二甲基乙基胺、氟代乙基、二氟代乙基、三氟代乙基、-O-R8或R9OH；
其中，当X＝N时，所述R4＝H、或NHR6，其中，R5、R6独立地为甲基、乙基、丙基或丁基；
当X＝C时，所述R4＝H、或F，其中，R7＝H、BOC或
所述R8为甲基、乙基、丙基或丁基；
所述R9为甲基、乙基、丙基或丁基；
(2)当R0＝H时，R1＝NHCONHR3’；R2＝CONHR11，所述R3’、R11各自独立地为甲基，乙基、丙基、异丙基或丁基；
(3)当R0＝H时，R1＝H、甲基、乙基、丙基、异丙基或丁基时；R2＝NHCONHR3,R3＝甲基、乙基、丙基、异丙基或丁基；
(4)当R0＝H，R2＝NHCONHR3,R3＝甲基、乙基、丙基、异丙基或丁基时，
所述R10、R11、R20、R21各自独立地为H或甲基、乙基、丙基、异丙基或丁基；
所述R12、R13、R16、R18a、R23、R24、R26、R27、R28、R29、R30、R31、R32、R33、R34各自独立地为甲基、乙基、丙基、异丙基、丁基、异丁基、环戊基或环己基；
所述R14为甲基、乙基、丙基、异丙基、丁基、一氟代C1-C4直链或支链烷基、二氟代C1-C4直链或支链烷基、三氟代甲基、三氟代乙基、三氟代丙基、三氟代异丙基、三氟代丁基或三氟代异丁基；
所述R15为甲基，乙基，丙基，异丙基，丁基，异丁基，环戊基，环己基，一氟代C1-C4直链、支链、环状烷基，二氟代C1-C4直链、支链、环状烷基，三氟代C1-C4直链、支链、环状烷基，以氟或C1—C4直链、支链、环状烷基为取代基在对位、邻位、间位取代或未取代的苯基；
所述R18、R19独立地为H、甲基、乙基、丙基、异丙基、丁基、异丁基或Boc；
所述Y＝F；
所述Z＝F。
4.根据权利要求1所述的嘧啶衍生物及其多种晶型体或其药学上可以接受的盐，其特征在于，为以下化合物之一：
5.权利要求1所述的嘧啶衍生物及其多种晶型体或其药学上可以接受的盐的制备方法，其特征在于由化合物1制备而成，所述化合物1的制备方法为：
。
6.细胞毒性剂，其特征在于，包含权利要求1-5中任一所述的嘧啶衍生物及其多种晶型体或其药学上可以接受的盐。
7.药物组合物，其特征在于，包含治疗有效量的权利要求1-5中任一所述的的嘧啶衍生物及其多种晶型体或其药学上可以接受的盐以及药学上可接受的载体。
8.权利要求1-5任一所述的嘧啶衍生物及其多种晶型体或其药学上可以接受的盐在制备细胞毒性剂以及抗肿瘤药物中的应用。
9.权利要求6所述的细胞毒性剂在制备针对PI3K激酶异常改变的药物以及抗肿瘤药物中的应用。
10.权利要求7所述的药物组合物在制备制备针对PI3K激酶异常改变的药物以及抗肿瘤药物中的应用。
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| PCT/CN2015/073678 WO2016127455A1 (zh) | 2015-02-09 | 2015-03-05 | 嘧啶衍生物、细胞毒性剂、药物组合物及其应用 |
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| JP2022544063A (ja) * | 2019-07-30 | 2022-10-17 | シァメン バイオタイム バイオテクノロジー シーオー．，エルティーディー． | アデノシン受容体拮抗薬 |
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| WO2008070740A1 (en) * | 2006-12-07 | 2008-06-12 | F.Hoffmann-La Roche Ag | Phosphoinositide 3-kinase inhibitor compounds and methods of use |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109824701A (zh) * | 2019-03-26 | 2019-05-31 | 武汉工程大学 | 一种吡啶并噻唑类化合物及其制备方法和应用 |
| CN109824701B (zh) * | 2019-03-26 | 2021-08-13 | 武汉工程大学 | 一种吡啶并噻唑类化合物及其制备方法和应用 |
| JP2022544063A (ja) * | 2019-07-30 | 2022-10-17 | シァメン バイオタイム バイオテクノロジー シーオー．，エルティーディー． | アデノシン受容体拮抗薬 |
| JP7299411B2 (ja) | 2019-07-30 | 2023-06-27 | シァメン バイオタイム バイオテクノロジー シーオー．，エルティーディー． | アデノシン受容体拮抗薬 |
| EP4006032A4 (en) * | 2019-07-30 | 2023-08-02 | Xiamen Biotime Biotechnology Co., Ltd. | ADENOSIN RECEPTOR ANTAGONIST |
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