CN116535389B - 6-吡啶-3-喹喔啉脲类衍生物及其用途 - Google Patents
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
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- A61P35/02—Antineoplastic agents specific for leukemia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- Y02P20/50—Improvements relating to the production of bulk chemicals
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Abstract
本发明公开了一类6‑吡啶‑3‑喹喔啉脲类衍生物及其用途，属于化学医药领域。本发明提供了式Ⅰ的6‑吡啶‑3‑喹喔啉脲类衍生物及其盐，这些化合物能够高选择性地对毛细血管扩张性共济失调突变激酶进行调节，从而能够用于防治与包括癌症在内的ATM相关的疾病，为抗癌药物的开发提供了新的选择。
Description
技术领域
本发明涉及6-吡啶-3-喹喔啉脲类衍生物及其用途，属于化学医药领域。
背景技术
ATM激酶(ataxia–telangiectasia mutated kinase，共济失调-毛细血管扩张突变激酶)是一种约350kDa的丝氨酸/苏氨酸蛋白激酶，属于高度保守的PIKK(phosphatidylinositol 3kinase-related kinases，磷脂酰肌醇3-激酶PI3K相关激酶)蛋白家族的成员，普遍发现于多种细胞和生物。
未修复的DSB可能直接导致细胞死亡，而修复错误的DSB则导致遗传信息丢失或染色体重排进而影响细胞存活，因此DNA双链断裂被认为是许多不同的DNA损伤类型中危害最大的。ATM是DDR通路中关键的调控激酶，最主要的功能在于响应于DSB信号，参与到DNA的修复(通过HR或NHEJ方式)、细胞周期检查点的激活、染色质的改构、细胞衰老、细胞凋亡等。ATM通常以二聚体的形式存在于正常细胞中；当DNA发生DSB损伤后，染色质中的组蛋白H2AX迅速被磷酸化形成γH2AX，并招募DNA末端连接MRN(MRE11-RAD50-NBS1)复合物到损伤位点，随后ATM蛋白N端的HEAT结构域与NBS1蛋白的C端识别并结合，并通过精氨酸残基与MR复合物(MRE11-RAD50)的相互作用形成稳固的MRN-ATM复合物。在被MRN募集后，ATM通过至少四个残基位点上(Ser367、Ser1893、Ser1981和Ser2996)的自磷酸化以及乙酰转移酶TIP60在Lys3016处的乙酰化而快速激活，从而促进其单体化和激酶活性。
ATM的磷酸化可以激活下游数百个底物，并通过多条信号通路实现对细胞生命活动的调控，主要包括：(1)激活p53并释放促凋亡因子(BAX、NOXA、PUMA等)来介导细胞凋亡；(2)间接或直接磷酸化p53导致其积累，由此磷酸化下游p21并抑制细胞周期依赖性蛋白CDK2导致G1/S阻滞；(3)磷酸化下游关键的细胞周期检查点激酶CHK2，磷酸化细胞周期调节因子CDC25A并诱导其降解，导致DNA合成所需的周期蛋白依赖性激酶2(CDK2)失活，使细胞阻滞在G1期；(4)在G1期激活53BP1(TP53连接蛋白1)来限制DNA的末端切除或磷酸化DNA-PKcs，参与到NHEJ修复方式；(5)在S期或G2期磷酸化CtIP(C-terminal-binding proteininteracting protein)内切酶并招募、激活BRCA1，形成MRN-CtIP-BRCA1复合物促进DNA的末端切除，通过未受损的单链DNA完成HR修复；(6)通过ATM-BRCA1/FANCD2/NBS1/SMC1实现细胞S期周期阻滞；⑦通过ATM-CHK2-CDC25C-CDK1或ATM-BRCA1-cyclin B或ATM-p53-CDC2-cyclin B1信号通路G2/M细胞周期检查点。
结直肠癌(colorectal cancer，CRC)是世界上第三大常见的癌症类型，是造成男性死亡的第四原因(7.6％)和女性死亡的第三原因(8.6％)。其中约72％发生在结肠，28％发生在直肠，从流行病学和病理生理学的角度来看，这两种肿瘤可以归为一类统称为结直肠癌。伊立替康(irinotecan)是一种DNA拓扑异构酶Ⅰ(TOPⅠ)抑制剂，可以在复制叉产生不可逆的DNA单链损伤并崩塌造成致命性的DNA双链损伤从而导致细胞凋亡或死亡，目前是结直肠癌治疗中的一线和二线治疗药物，对胰腺癌、乳腺癌、肺癌等癌症也有一定的疗效。然而，肿瘤自发性或获得性耐药机制的产生，限制了包括伊立替康在内的化疗药物或放疗用于结直肠癌治疗的临床疗效。因此，考虑到ATM在处理DSB方面发挥的重要作用，联用ATM抑制剂与导致DNA损伤的化疗药物(伊立替康、依托泊苷)或放疗方法可能是一种有益于多种肿瘤治疗的合理策略。
开发以ATM激酶为靶点的新型抗癌药物有两个主要的临床应用价值。(1)造成DNA双链断裂是许多已被批准用于临床癌症治疗的化疗药物(如拓扑异构酶I抑制剂伊立替康、拓扑异构酶II抑制剂依托泊苷)以及放射治疗的作用机制，进一步的抑制ATM以干扰DSB修复的机会增强了这些DSB诱导剂介导的细胞毒性和降低了肿瘤细胞的获得性耐药性。(2)在特定DDR缺陷的肿瘤(如BRCA1/2)上单用ATM抑制剂，通过肿瘤细胞对ATM功能的依赖造成显著的细胞毒性。
目前进入临床研究阶段的ATM抑制剂小分子数量较少且进展较慢，这可能与前期缺乏高分辨的ATM晶体结构导致抑制剂的设计受限有关，可能与ATM激酶其他潜在功能的研究不透彻有关，也可能与缺乏合理的联用方案制定标准有关。但是，考虑到ATM在修复DNA双链损伤、调控细胞周期进展、诱导细胞凋亡以维持细胞基因组稳定性方面发挥的关键作用，而且ATM突变和缺陷在多种散发性肿瘤中被发现并伴随着对DNA损伤剂和电离辐射的敏感性，因此研发结构新颖、活性优异、成药性良好的ATM小分子抑制剂对癌症的精准治疗具有十分重要的意义。
发明内容
本发明发现一种新型6-吡啶-3-喹喔啉脲类衍生物及其盐，该化合物能够高选择性地对毛细血管扩张性共济失调突变(ATM)激酶进行调节，从而能够用于防治与包括癌症在内的ATM相关的疾病。
本发明提供了式Ⅰ所示的化合物或其药学上可接受的盐：
其中，
R1选自H、C1～C6烷基；
R2选自C1～C6烷基、C1～C6卤代烷基、C3～C6烯烷基、取代或未取代的3～6元环烷基、取代或未取代的3～6元杂环烷基、取代或未取代的6～10元芳基、取代或未取代的5～10元杂芳基、取代或未取代的R2中，所述3～6元杂环烷基、5～10元杂芳基含有1～2个选自N、S、O中的杂原子；
R2中，所述取代的3～6元环烷基的取代基、取代的3～6元杂环烷基的取代基、取代的6～10元芳基的取代基、取代的5～10元杂芳基的取代基、取代或未取代的的取代基，独立地选自C1～C4烷基、C1～C4卤代烷基、C1～C4烷氧基、C1～C4卤代烷氧基、氨基、羟基、氰基、卤素；
X选自O、S；
L(左端与R3相连，右端与O相连)选自-(CH2)n-、-(CH2)mCHCH3-、-CHCH3(CH2)o-；n选自0～6的整数；m、o独立地选自0～5的整数；
R3选自C1～C6烷基、C1～C6卤代烷基、C1～C6烷氧基、C1～C6卤代烷氧基、NR7R8、取代或未取代的3～6元环烷基、取代或未取代的3～6元杂环烷基、取代或未取代的R3中，所述3～6元杂环烷基含有1～2个选自NR9、S、O中的杂原子；
R3中，所述取代的3～6元环烷基的取代基、取代的3～6元杂环烷基的取代基、取代或未取代的的取代基，独立地选自C1～C4烷基、C1～C4卤代烷基、C1～C4烷氧基、C1～C4卤代烷氧基、氧代基、NR10R11、羟基、氰基、卤素；
R7、R8、R9、R10、R11独立地选自H、C1～C4烷基；
环A(左端与O相连，右端与苯相连)选自：Y1～Y4中，两个选自N，其余两个选自CR4、CR5；或者Y1～Y4中，一个选自N，其余三个选自CR4、CR5、CR6；
R4、R5、R6独立地选自H、C1～C4烷基、C1～C4卤代烷基、C1～C4烷氧基、C1～C4卤代烷氧基、卤素、氰基、氨基、羟基。
在本发明的一些实施例中，R1选自H、C1～C4烷基。
在本发明的一些优选实施例中，R1选自H、甲基。
在本发明的一些实施例中，R2选自C1～C4烷基、C1～C4卤代烷基、C3～C4烯烷基、取代或未取代的3～6元环烷基、取代或未取代的3～6元杂环烷基、取代或未取代的苯基、取代或未取代的5～6元杂芳基、取代或未取代的R2中，所述3～6元杂环烷基、5～6元杂芳基含有1～2个选自N、O中的杂原子；R2中，所述取代的3～6元环烷基的取代基、取代的3～6元杂环烷基的取代基、取代的苯基的取代基、取代的5～6元杂芳基的取代基、取代或未取代的/>的取代基，独立地选自C1～C4烷基、C1～C4氟代烷基、C1～C4烷氧基、C1～C4氟代烷氧基、氨基、羟基、氰基、氟、氯、溴。
在本发明的一些优选实施例中，R2选自C1～C4烷基、C1～C4氟代烷基、C3～C4烯烷基、取代或未取代的3～6元环烷基、取代或未取代的3～6元杂环烷基、取代或未取代的苯基、取代或未取代的5～6元杂芳基、取代或未取代的R2中，所述3～6元杂环烷基、5～6元杂芳基含有1～2个选自N、O中的杂原子；R2中，所述取代的3～6元环烷基的取代基、取代的3～6元杂环烷基的取代基、取代的苯基的取代基、取代的5～6元杂芳基的取代基、取代或未取代的/>的取代基，独立地选自甲基、氟代甲基、甲氧基、氟代甲氧基、氨基、羟基、氰基、氟、氯、溴。
在本发明的一些更优选实施例中，R2选自甲基、乙基、正丙基、异丙基、正丁基、叔丁基、烯丙基、环丙基、环戊基、环己基、
在本发明的一些实施例中，n选自0～5的整数；m、o独立地选自0～4的整数。
在本发明的一些优选实施例中，n选自0～4的整数；m、o独立地选自0或1。
在本发明的一些实施例中，R3选自C1～C4烷基、C1～C4卤代烷基、C1～C4烷氧基、C1～C4卤代烷氧基、NR7R8、取代或未取代的3～6元环烷基、取代或未取代的3～6元杂环烷基、取代或未取代的R3中，所述3～6元杂环烷基含有1～2个选自NR9、O中的杂原子；R3中，所述取代的3～6元环烷基的取代基、取代的3～6元杂环烷基的取代基、取代或未取代的/>的取代基，独立地选自C1～C4烷基、C1～C4氟代烷基、C1～C4烷氧基、C1～C4氟代烷氧基、氧代基、NR10R11、羟基、氰基、氟、氯、溴；R7、R8、R9、R10、R11独立地选自H、甲基、乙基。
在本发明的一些优选实施例中，R3选自C1～C4烷基、C1～C4氟代烷基、C1～C4烷氧基、C1～C4氟代烷氧基、NR7R8、取代或未取代的3～6元环烷基、取代或未取代的3～6元杂环烷基、取代或未取代的的取代基；R3中，所述3～6元杂环烷基选自
R3中，所述取代的3～6元环烷基的取代基、取代的3～6元杂环烷基的取代基、取代或未取代的/>的取代基，独立地选自甲基、氟代甲基、甲氧基、氟代甲氧基、氧代基、NR9R10、羟基、氰基、氟、氯、溴；R7、R8、R9、R10、R11独立地选自H、甲基、乙基。
在本发明的一些更优选实施例中，R3选自异丙基、甲氧基、-N(CH3)2、-N(CH2CH3)2、
在本发明的一些实施例中，环A(左端与O相连，右端与苯相连)选自
在本发明的一些实施例中，R4、R5、R6独立地选自H、C1～C4烷基、C1～C4氟代烷基、C1～C4烷氧基、C1～C4氟代烷氧基、氟、氯、溴、氰基、氨基、羟基。
在本发明的一些优选实施例中，R4、R5、R6独立地选自H、甲基、三氟甲基、氟、氰基。
本发明还提供了一些具体的化合物，其结构式如下：
本发明还提供了一种药物组合物，其由上述化合物及其药学上可接受的盐为活性成分，添加药学上可接受的辅助性成分组成。
本发明还提供了上述化合物及其药学上可接受的盐、上述药物组合物在制备治疗和/或预防ATM相关疾病的药物中的用途。
本发明还提供了上述化合物及其药学上可接受的盐、上述药物组合物在制备ATM激酶抑制剂中的用途。
本发明还提供了上述化合物及其药学上可接受的盐、上述药物组合物联合化疗药物、DDR靶点抑制剂或放疗在制备治疗和/或预防ATM相关疾病的药物中的用途。所述化疗药物包括伊立替康或依托泊苷；所述DDR靶点抑制剂为奥拉帕尼。
本发明还提供了上述化合物及其药学上可接受的盐、上述药物组合物联合化疗药物、DDR靶点抑制剂或放疗在制备ATM激酶抑制剂中的用途。所述化疗药物包括伊立替康或依托泊苷；所述DDR靶点抑制剂为奥拉帕尼。
上述本发明化合物单独用药或联合用药的用途中，所述ATM相关疾病为实体瘤；所述ATM激酶抑制剂用于防治实体瘤。
上述用途中，所述实体瘤包括：结直肠癌、肺癌、乳腺癌、头颈癌、前列腺癌、淋巴瘤、卵巢癌、肾细胞癌、食管癌，白血病、膀胱癌、胃癌、黑色素瘤、尿路上皮癌、脑肿瘤、肝癌、间皮瘤或肝内胆管癌。
术语定义：
本发明提供的化合物和衍生物可以根据IUPAC(国际纯粹与应用化学联合会)或CAS(化学文摘服务社，Columbus，OH)命名系统命名。
术语“烷基”是直链或支链的饱和烃基的基团。C1～C6烷基的实例包括但不限于甲基(C1)、乙基(C2)、正丙基(C3)、异丙基(C3)、正丁基(C4)、叔丁基(C4)、仲丁基(C4)、异丁基(C4)、正戊基(C5)、3-戊基(C5)、戊基(C5)、新戊基(C5)、3-甲基-2-丁基(C5)、叔戊基(C5)和正己基(C6)。
术语“烯烷基”是直链或支链的含有烯基的不饱和烃基的基团。C3～C6烯烷基的实例包括但不限于烯丙基(C3)、1-烯丁基(C4)、2-烯丁基(C4)、1-烯己基(C6)。
术语“环烷基”是指不包含杂原子的饱和的环状烃基，其可以是单环结构，也可以是多环结构(如桥环结构或螺环结构)，例如：环丙烷基(3元)、环己烷基(6元)。
术语“芳基”是指具有共轭的π电子体系的全碳单环或稠环基团，芳基可以是完全芳香族的基团，例如苯基、萘基、蒽基、菲基、芘基等。芳基中的碳原子可以被杂原子取代，杂原子选自硫、氧和/或氮，例如噻吩、呋喃、吡咯、吡啶、喹啉、吲哚等
术语“卤素”是指氟(F)、氯(Cl)、溴(Br)、碘(I)。
术语“药学上可接受的”是指某载体、运载物、稀释剂、辅料，和/或所形成的盐通常在化学上或物理上与构成某药物剂型的其它成分相兼容，并在生理上与受体相兼容。
术语“药学上可接受的盐”是指本发明化合物的有机盐和无机盐，优选无机盐、药学上可接受的无毒的酸形成的盐，包括但不限于，与氨基反应形成的无机酸盐，如盐酸盐、氢溴酸盐、磷酸盐、硫酸盐、高氯酸盐、硝酸盐,有机酸盐如乙酸盐、草酸盐、马来酸盐、酒石酸盐、柠檬酸盐、琥珀酸盐、丙二酸盐、盐酸盐、油酸盐、硬脂酸盐、抗坏血酸盐、甲酸盐、硼酸盐、樟脑酸盐、甲磺酸盐、乙磺酸盐、对甲苯磺酸盐、苹果酸盐等。
本发明所述药学上可接受的辅助性成分，是指除活性成分以外包含在剂型中的物质，所述的辅助性成分如环糊精、精氨酸或葡甲胺。所述的环糊精选自α-环糊精、β-环糊精、γ-环糊精、(C1-4烷基)-α-环糊精、(C1-4烷基)-β-环糊精、(C1-4烷基)-γ-环糊精、(羟基-C1-4烷基)-α-环糊精、(羟基-C1-4烷基)-β-环糊精、(羟基-C1-4烷基)-γ-环糊精、(羧基-C1-4烷基)-α-环糊精、(羧基-C1-4烷基)-β-环糊精、(羧基-C1-4烷基)-γ-环糊精、α-环糊精的糖类醚、β-环糊精的糖类醚、γ-环糊精的糖类醚、α-环糊精的磺丁基醚、β-环糊精的磺丁基醚和γ-环糊精的磺丁基醚。所述的辅助性成分还包含医学上可接受的载体、佐剂或媒剂。可用于药学上可接受的药物组合物还离子交换剂、氧化铝、硬脂酸铝、卵凝脂；缓冲物质包括磷酸盐、甘氨酸、精氨酸、山梨酸等。
有益效果：
本发明提供了一类新型6-吡啶-3-喹喔啉脲类衍生物，这些化合物能够高选择性地对毛细血管扩张性共济失调突变激酶进行调节，从而能够用于防治与包括癌症在内的ATM相关的疾病，为抗癌药物的开发提供了新的选择。
附图说明
图1为化合物A46对伊立替康诱导的ATM信号通路影响的蛋白印迹分析图。
图2为化合物A46联用伊立替康在SW620小鼠模型上的效果图；其中，A为肿瘤体积增长图；B为小鼠体重图；C为肿瘤体积实物图；D为肿瘤重量图。
具体实施方式
下面将结合实施例对本发明的方案进行解释。本领域技术人员将会理解，下面的实施例仅用于说明本发明，而不应视为限定本发明的范围。
实验所用试剂纯度均为分析纯，其中石油醚、乙酸乙酯、二氯甲烷、甲醇、乙醇、三乙胺、四氢呋喃、乙腈、1,4-二氧六环、N,N-二甲基甲酰胺等购买自科伦化工，其他合成的起始原料和氘代试剂(纯度>98％)均可商业购买。薄层色谱所用的GF254硅胶板及拌样用的60～100目硅胶均为山东烟台新诺化工有限公司生产，快速制备过柱机分离使用flash柱购买自月旭科技有限公司。实验所用仪器如表1所示。
表1化学实验仪器汇总
实施例1
7-bromoquinoxalin-2(1H)-one(1-1)
将起始原料2-羟基喹喔啉(14.6g,0.1mol)分散于200ml的冰乙酸中，于0℃下搅拌约3分钟。Br2(17.60g,0.11mol)转移至100ml的滴液漏斗中，维持约0℃的温度，在半小时内完全滴加进上述混悬液体中。黄色的混合液体逐渐升至室温并搅拌过夜，通过点板监测反应已彻底进行后，加入约200ml的冰水形成浑浊的液体。循环水泵抽滤得到滤饼层，并用纯水冲洗三次，于真空干燥箱中60℃过夜，烘干得到19.10g的淡黄色的固体产物，收率约为84％，无需进一步纯化。1H NMR(400MHz,DMSO-d6)δ12.46(s,1H),8.18(s,1H),7.70(d,J＝9.1Hz,1H),7.47–7.42(m,2H)。
7-bromo-2-chloroquinoxaline(1-2)
将中间体1-1(19.00g,0.08mol)置于500ml的茄型瓶中，室温搅拌下加入约100ml的POCl3并逐渐升温到100℃。搅拌约6小时后，萃取后点板监测到反应基本已经完成，待其自然冷却至室温后通过减压浓缩除去绝大部分溶剂得到黑色的油状粘稠液体。在冰浴下，逐渐滴加饱和的NaHCO3的水溶液(约300ml)淬灭残留的溶剂至无明显气泡产生。随后加入约100ml的乙酸乙酯萃取，分液，合并三次乙酸乙酯层并用无水Na2SO4干燥，再次浓缩后加入60～80目粗硅胶拌样得到黑色的干燥粉末。通过快速制备过柱机纯化，浓度梯度为2％的乙酸乙酯/石油醚。浓缩旋干收集的溶液，得到16.60g的中间体1-2，收率为81％。1H NMR(400MHz,DMSO-d6)δ9.04(d,J＝1.3Hz,1H),8.31(s,1H),8.10(d,J＝8.8Hz,1H),8.04(dd,J＝8.9,1.6Hz,1H)。
7-bromoquinoxalin-2-amine(1-3a)
中间体1-2(5.0g,0.02mmol)分散于50ml的氨水中，100℃下在高压釜中密封反应约6小时。反应体系冷却至室温后，打开密封的高压釜，通过抽滤收集到固体产物1-3a。真空干燥箱60℃烘干过夜，得到4.19g的浅黄色固体粉末，收率为91％。1H NMR(400MHz,DMSO-d6)δ8.30(s,1H),7.72–7.61(m,2H),7.44(dd,J＝8.7,2.3Hz,1H),7.18(s,2H)。
7-(6-fluoropyridin-3-yl)quinoxalin-2-amine(1-4a)
将中间体1-3a(4.00g,0.018mol)、2-氟吡啶-5-硼酸酯(4.78g,0.021mol)、PdCl2(dppf)(1.25g,0.001mol)和K2CO3(4.93g,0.036mol)置于100ml的三颈瓶中，加入50ml的1,4-二氧六环/水/乙醇(体积比为7/3/4)。在氮气气氛下，将上述混合物加热至85℃，约6小时后点板监测反应已经完成。将反应冷却至室温后，硅藻土过滤得到滤液并浓缩得到黑色黏稠物，加入适量的60～80目粗硅胶拌样。通过快速制备过柱机纯化，浓度梯度为25％的乙酸乙酯/石油醚。旋干收集的溶液，得到4.07g的黄色中间体1-4a，收率为95％。1H NMR(400MHz,DMSO-d6)δ8.66(d,J＝2.6Hz,1H),8.40(td,J＝8.3,2.7Hz,1H),8.35(s,1H),7.86(d,J＝8.4Hz,1H),7.80(d,J＝2.0Hz,1H),7.67(dd,J＝8.4,2.1Hz,1H),7.31(dd,J＝8.5,2.9Hz,1H),7.10(s,2H)。
7-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)quinoxalin-2-amine(1-5a)
将3-(二甲氨基)丙烷-1-醇(3.43g,0.033mmol)溶于约40ml的DMF中，冰浴下降温搅拌约5分钟后，在0℃左右时缓慢加入NaH固体(1.33g,0.033mmol)。保持反应体系在0℃搅拌约30分钟，缓慢加入中间体1-4a(4.00g,0.017mmol)，随后缓慢升至室温并加热至50℃，搅拌过夜。TLC监测反应结束后，用EtOAc/H2O(体积比1/3)萃取反应液，合并3次萃取收集的乙酸乙酯层，经无水Na2SO4干燥并浓缩，通过快速柱层析纯化得到黄色的中间体1-5a(4.41g)，收率为82％。1H NMR(400MHz,DMSO-d6)δ8.59–8.56(m,1H),8.29(s,1H),8.11(dd,J＝8.5,2.0Hz,1H),7.82(d,J＝8.4Hz,1H),7.72(s,1H),7.62(d,J＝8.4Hz,1H),7.01(s,2H),6.91(d,J＝8.6Hz,1H),4.34(t,J＝6.5Hz,2H),2.47(s,2H),2.24(s,6H),1.91(p,J＝6.7Hz,2H)。
1-cyclohexyl-3-(7-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)quinoxalin-2-yl)urea(A01)
中间体1-5a(100mg,0.31mmol)溶于适量的DMF中，在0℃下加入NaH(18mg,0.46mmol)并搅拌约15分钟。将环己基异氰酸酯(58mg,0.46mmol)在低温下滴加，随后让反应体系自然升至室温并搅拌过夜。TLC监测反应结束后，用EtOAc/H2O(体积比1/3)萃取反应液，合并3次萃取的有机相，无水硫酸钠干燥，减压蒸馏，最终经快速柱层析(溶剂为二氯甲烷/甲醇＝96/4)纯化得目标产物A01。浅黄色固体粉末，收率为81％。1H NMR(400MHz,DMSO-d6)δ10.07(s,1H),8.94(s,1H),8.69(dd,J＝16.2,4.6Hz,2H),8.26–8.19(m,1H),8.00(d,J＝5.4Hz,2H),7.92(d,J＝8.6Hz,1H),6.96(d,J＝8.6Hz,1H),4.40(t,J＝6.1Hz,2H),3.65(s,1H),3.01(s,2H),2.62(s,6H),2.19–2.09(m,2H),1.88(s,2H),1.72(s,2H),1.55(s,1H),1.37(t,J＝8.0Hz,5H).13C NMR(101MHz,DMSO-d6)δ163.00,145.40,139.54,139.45,138.91,138.08,129.23,128.24,125.26,123.13,110.88,63.30,54.35,47.97,42.73,32.51,25.15,24.41,24.21。
实施例2
1-cyclopentyl-3-(7-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)quinoxalin-2-yl)urea(A02)
化合物A02的合成方法与A01相同，用环戊基异氰酸酯替代环己基异氰酸酯即可。淡黄色固体，收率90％。1H NMR(400MHz,DMSO-d6)δ9.98(s,1H),8.86(s,1H),8.66(d,J＝15.7Hz,2H),8.17(d,J＝7.5Hz,1H),7.98(d,J＝13.3Hz,2H),7.90(d,J＝7.4Hz,1H),6.94(d,J＝8.3Hz,1H),4.34(t,J＝6.6Hz,2H),4.09(q,J＝6.6Hz,1H),2.39(s,2H),2.17(s,6H),1.98–1.85(m,4H),1.73(s,2H),1.59(s,4H)。
实施例3
1-(7-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)quinoxalin-2-yl)-3-propylurea(A03)
化合物A03的合成方法与A01相同，用异氰酸丙酯替代环己基异氰酸酯即可。淡黄色固体，收率88％。1H NMR(400MHz,DMSO-d6)δ10.08(s,1H),8.85(s,1H),8.78(s,1H),8.66(d,J＝2.4Hz,1H),8.20(dd,J＝8.7,2.6Hz,1H),8.09(d,J＝1.8Hz,1H),8.00(d,J＝8.6Hz,1H),7.92(dd,J＝8.6,2.0Hz,1H),6.96(d,J＝8.6Hz,1H),4.37(t,J＝6.4Hz,2H),3.24(d,J＝6.5Hz,2H),2.71(q,J＝6.0,4.8Hz,2H),2.42(s,7H),2.00(p,J＝6.6Hz,2H),1.58(q,J＝7.2Hz,2H),0.95(t,J＝7.4Hz,3H).13C NMR(101MHz,DMSO-d6)δ163.16,154.24,148.29,145.37,139.47,139.35,138.91,137.98,137.07,129.18,125.19,123.26,110.87,63.68,55.05,43.92,41.00,25.48,22.73,11.34。
实施例4
1-allyl-3-(7-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)quinoxalin-2-yl)urea(A04)
化合物A04的合成方法与A01相同，用3-异氰酸丙烯替代环己基异氰酸酯即可。淡黄色固体，收率75％。1H NMR(400MHz,DMSO-d6)δ10.14(s,1H),8.84(s,2H),8.61(s,1H),8.14(d,J＝7.2Hz,1H),8.06–7.86(m,3H),6.92(d,J＝8.3Hz,1H),5.96(dd,J＝10.7,5.0Hz,1H),5.24(d,J＝17.2Hz,1H),5.13(d,J＝9.9Hz,1H),4.33(s,2H),3.93(s,2H),2.44–2.35(m,2H),2.18(s,6H),1.95–1.84(m,2H).13C NMR(101MHz,DMSO-d6)δ163.30,154.18,148.22,145.38,139.40,139.35,139.00,137.92,137.13,135.59,129.20,128.00,125.28,123.25,114.95,110.88,64.07,55.57,44.84,41.62,26.37。
实施例5
1-(7-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)quinoxalin-2-yl)-3-isopropyl-urea(A05)
化合物A05的合成方法与A01相同，用异丙基异氰酸酯替代环己基异氰酸酯即可。淡黄色固体，收率92％。1H NMR(400MHz,DMSO-d6)δ9.97(s,1H),8.86(s,1H),8.66(d,J＝2.6Hz,1H),8.58(d,J＝7.4Hz,1H),8.18(dd,J＝8.6,2.6Hz,1H),8.04–7.96(m,2H),7.90(dd,J＝8.6,2.1Hz,1H),6.93(d,J＝8.6Hz,1H),4.35(t,J＝6.5Hz,2H),3.92(h,J＝6.7Hz,1H),2.43(t,J＝7.2Hz,2H),2.21(s,6H),1.90(dd,J＝8.2,5.7Hz,2H),1.24(d,J＝6.5Hz,6H).13C NMR(101MHz,DMSO-d6)δ153.38,148.33,145.46,139.45,139.35,139.01,137.98,137.09,129.19,125.25,123.16,110.83,64.01,55.54,44.81,41.42,26.34,22.77。
实施例6
1-(tert-butyl)-3-(7-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)quinoxalin-2-yl)urea(A06)
化合物A06的合成方法与A01相同，用叔丁基异氰酸酯替代环己基异氰酸酯即可。淡黄色固体，收率85％。1H NMR(400MHz,DMSO-d6)δ9.91(s,1H),8.89(s,1H),8.75(s,1H),8.67(d,J＝2.3Hz,1H),8.22(dd,J＝8.6,2.5Hz,1H),8.01(d,J＝8.4Hz,1H),7.91(dd,J＝10.7,2.1Hz,2H),6.97(d,J＝8.6Hz,1H),4.40(t,J＝6.2Hz,2H),3.08(t,J＝7.9Hz,2H),2.68(s,6H),2.14(dt,J＝13.8,6.3Hz,2H),1.41(s,9H).13C NMR(101MHz,DMSO-d6)δ162.97,152.94,148.44,145.40,139.61,139.28,138.95,138.12,137.06,129.26,128.34,125.27,123.03,110.91,63.17,54.28,50.03,42.56,28.81,24.18。
实施例7
7-bromo-N-methylquinoxalin-2-amine(1-3b)
中间体1-2(10.0g,0.04mmol)置于250ml的茄型瓶中，加入100ml的正丁醇和DIEA(15.89g,0.12mmol)，随后在室温搅拌下加入甲氨盐酸盐固体(3.33g,0.05mmo)。加热混合液体至100℃，约4小时后点板监测反应已经完成。待其冷却至室温，减压浓缩除去绝大部分溶剂，加入适量的60～80目粗硅胶拌样。通过快速制备过柱机纯化，浓度梯度为15％的乙酸乙酯/石油醚。旋干收集的溶液，得到9.11g的浅黄色中间体1-3b，收率为93％。1H NMR(400MHz,DMSO-d6)δ8.28(s,1H),7.82(d,J＝5.1Hz,1H),7.71(d,J＝2.2Hz,1H),7.67(d,J＝8.6Hz,1H),7.41(dd,J＝8.6,2.2Hz,1H),2.90(d,J＝4.8Hz,3H)。
7-(6-fluoropyridin-3-yl)-N-methylquinoxalin-2-amine(1-4b)
采用中间体1-4a的合成方法，以中间体1-3b和2-氟吡啶-5-硼酸酯为原料合成得到。黄色固体，收率为92％。1H NMR(400MHz,DMSO-d6)δ8.68(d,J＝2.6Hz,1H),8.42(td,J＝8.2,2.7Hz,1H),8.29(s,1H),7.88(d,J＝2.0Hz,1H),7.85(d,J＝8.4Hz,1H),7.72(q,J＝4.7Hz,1H),7.65(dd,J＝8.5,2.1Hz,1H),7.30(dd,J＝8.6,2.9Hz,1H),2.93(d,J＝4.7Hz,3H)。
7-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)-N-methylquinoxalin-2-amine(1-5b)
采用中间体1-5a的合成方法，以中间体1-4b和3-(二甲氨基)丙烷-1-醇为原料合成得到。黄色固体，收率为80％。1H NMR(400MHz,DMSO-d6)δ8.59(d,J＝2.6Hz,1H),8.27(s,1H),8.14(dd,J＝8.6,2.6Hz,1H),7.85–7.78(m,2H),7.71–7.65(m,1H),7.61(dd,J＝8.3,2.1Hz,1H),6.90(d,J＝8.6Hz,1H),4.33(t,J＝6.6Hz,2H),2.93(d,J＝4.7Hz,3H),2.42(t,J＝7.2Hz,2H),2.20(s,6H),1.89(p,J＝6.9Hz,2H)。
1-(7-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)quinoxalin-2-yl)-3-ethyl-1-methylurea(A07)
中间体1-5b(100mg,0.30mmol)置于25ml的茄形瓶中，加入无水甲苯(5ml)和DIEA(77mg,0.59mmol)充分溶解后，室温下滴加异氰酸乙酯(32mg,0.44mmol)并升温至100℃。搅拌约5h后，TLC监测反应基本结束，减压浓缩，最终通过快速柱层析(溶剂梯度为二氯甲烷/甲醇＝97/3)纯化得目标产物A07。浅黄色固体粉末，收率为88％。1H NMR(400MHz,DMSO-d6)δ9.07(s,-1H),8.66(s,1H),8.42(t,J＝5.3Hz,1H),8.20(d,J＝8.6Hz,1H),8.12(s,1H),8.02(d,J＝8.5Hz,1H),7.96(d,J＝8.6Hz,1H),6.93(d,J＝8.6Hz,1H),4.35(t,J＝6.4Hz,2H),3.49(s,3H),3.26(dt,J＝13.6,6.9Hz,2H),2.52(s,2H),2.25(s,6H),1.92(p,J＝6.6Hz,2H),1.15(t,J＝7.1Hz,3H).13C NMR(101MHz,DMSO-d6)δ163.26,155.98,150.82,145.41,141.40,138.70,137.99,136.86,128.98,128.04,125.89,123.69,110.90,64.01,55.48,44.69,35.16,32.68,26.22,15.09。
实施例8
1-(7-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)quinoxalin-2-yl)-1-methyl-3-propylurea(A08)
化合物A08的合成方法与A07相同，用异氰酸丙酯替代异氰酸乙酯即可。淡黄色固体，收率为88％。1H NMR(400MHz,DMSO-d6)δ10.08(s,1H),8.85(s,1H),8.78(s,1H),8.66(d,J＝2.4Hz,1H),8.20(dd,J＝8.7,2.6Hz,1H),8.09(d,J＝1.8Hz,1H),8.00(d,J＝8.6Hz,1H),7.92(dd,J＝8.6,2.0Hz,1H),6.96(d,J＝8.6Hz,1H),4.37(t,J＝6.4Hz,2H),3.24(d,J＝6.5Hz,2H),2.71(q,J＝6.0,4.8Hz,2H),2.42(s,7H),2.00(p,J＝6.6Hz,2H),1.58(q,J＝7.2Hz,2H),0.95(t,J＝7.4Hz,3H).13C NMR(101MHz,DMSO-d6)δ163.16,154.24,148.29,145.37,139.47,139.35,138.91,137.98,137.07,129.18,125.19,123.26,110.87,63.68,55.05,43.92,41.00,25.48,22.73,11.34。
实施例9
3-allyl-1-(7-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)quinoxalin-2-yl)-1-methylurea(A09)
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化合物A09的合成方法与A07相同，用3-异氰酸丙烯替代异氰酸乙酯即可。淡黄色固体，收率为83％。1H NMR(400MHz,DMSO-d6)δ10.14(s,1H),8.84(s,2H),8.61(s,1H),8.14(d,J＝7.2Hz,1H),8.06–7.86(m,3H),6.92(d,J＝8.3Hz,1H),5.96(dd,J＝10.7,5.0Hz,1H),5.24(d,J＝17.2Hz,1H),5.13(d,J＝9.9Hz,1H),4.33(s,2H),3.93(s,2H),2.44–2.35(m,2H),2.18(s,6H),1.95–1.84(m,2H).13C NMR(101MHz,DMSO-d6)δ163.30,154.18,148.22,145.38,139.40,139.35,139.00,137.92,137.13,135.59,129.20,128.00,125.28,123.25,114.95,110.88,64.07,55.57,44.84,41.62,26.37。
实施例10
1-(7-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)quinoxalin-2-yl)-3-isopropyl-1-methylurea(A10)
化合物A10的合成方法与A07相同，用异丙基异氰酸酯替代异氰酸乙酯即可。淡黄色固体，收率为95％。1H NMR(400MHz,DMSO-d6)δ9.97(s,1H),8.86(s,1H),8.66(d,J＝2.6Hz,1H),8.58(d,J＝7.4Hz,1H),8.18(dd,J＝8.6,2.6Hz,1H),8.04–7.96(m,2H),7.90(dd,J＝8.6,2.1Hz,1H),6.93(d,J＝8.6Hz,1H),4.35(t,J＝6.5Hz,2H),3.92(h,J＝6.7Hz,1H),2.43(t,J＝7.2Hz,2H),2.21(s,6H),1.90(dd,J＝8.2,5.7Hz,2H),1.24(d,J＝6.5Hz,6H).13C NMR(101MHz,DMSO-d6)δ153.38,148.33,145.46,139.45,139.35,139.01,137.98,137.09,129.19,125.25,123.16,110.83,64.01,55.54,44.81,41.42,26.34,22.77。
实施例11
3-(tert-butyl)-1-(7-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)quinoxalin-2-yl)-1-methylurea(A11)
化合物A11的合成方法与A07相同，用叔丁基异氰酸酯替代异氰酸乙酯即可。淡黄色固体，收率为88％。1H NMR(400MHz,DMSO-d6)δ9.91(s,1H),8.89(s,1H),8.75(s,1H),8.67(d,J＝2.3Hz,1H),8.22(dd,J＝8.6,2.5Hz,1H),8.01(d,J＝8.4Hz,1H),7.91(dd,J＝10.7,2.1Hz,2H),6.97(d,J＝8.6Hz,1H),4.40(t,J＝6.2Hz,2H),3.08(t,J＝7.9Hz,2H),2.68(s,6H),2.14(dt,J＝13.8,6.3Hz,2H),1.41(s,9H).13C NMR(101MHz,DMSO-d6)δ162.97,152.94,148.44,145.40,139.61,139.28,138.95,138.12,137.06,129.26,128.34,125.27,123.03,110.91,63.17,54.28,50.03,42.56,28.81,24.18。
实施例12
3-butyl-1-(7-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)quinoxalin-2-yl)-1-methylurea(A12)
化合物A12的合成方法与A07相同，用异氰酸丁酯替代异氰酸乙酯即可。淡黄色固体，收率为90％。1H NMR(400MHz,DMSO-d6)δ9.02(s,1H),8.65–8.58(m,1H),8.52(t,J＝5.1Hz,1H),8.17–8.11(m,1H),8.02(s,1H),7.98(d,J＝8.6Hz,1H),7.90(d,J＝8.5Hz,1H),6.90(d,J＝8.6Hz,1H),4.33(t,J＝6.4Hz,2H),3.48(s,3H),3.23(q,J＝6.5Hz,2H),2.53(d,J＝7.1Hz,2H),2.27(s,6H),1.98–1.88(m,2H),1.57–1.48(m,2H),1.41–1.29(m,2H),0.90(t,J＝7.3Hz,3H).13C NMR(101MHz,DMSO-d6)δ163.20,155.99,150.67,145.31,141.07,139.52,138.65,137.82,128.92,127.97,125.73,123.47,110.84,63.94,55.39,44.51,32.60,31.40,26.09,19.68,13.71。
实施例13
3-cyclopropyl-1-(7-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)quinoxalin-2-yl)-1-methylurea(A13)
化合物A13的合成方法与A07相同，用环丙基异氰酸酯替代异氰酸乙酯即可。淡黄色固体，收率为90％。1H NMR(400MHz,DMSO-d6)δ9.06(s,1H),8.66(d,J＝2.4Hz,1H),8.35(d,J＝2.8Hz,1H),8.20(dd,J＝8.7,2.5Hz,1H),8.08(d,J＝1.6Hz,1H),8.02(d,J＝8.6Hz,1H),7.96(dd,J＝8.6,1.8Hz,1H),6.93(d,J＝8.6Hz,1H),4.34(t,J＝6.6Hz,2H),3.46(s,3H),2.72(dq,J＝6.9,3.4Hz,1H),2.39(t,J＝7.1Hz,2H),2.18(s,6H),1.88(p,J＝6.8Hz,2H),0.68(dd,J＝6.8,4.6Hz,2H),0.63–0.56(m,2H).13C NMR(101MHz,DMSO-d6)δ163.29,157.12,150.78,145.43,141.55,138.72,137.96,136.89,128.97,125.95,123.62,110.86,64.14,55.67,45.06,32.79,26.58,23.51,6.06。
实施例14
3-cyclopentyl-1-(7-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)quinoxalin-2-yl)-1-methylurea(A14)
化合物A14的合成方法与A07相同，用环戊基异氰酸酯替代异氰酸乙酯即可。淡黄色固体，收率为86％。1H NMR(400MHz,DMSO-d6)δ9.98(s,1H),8.86(s,1H),8.66(d,J＝15.7Hz,2H),8.17(d,J＝7.5Hz,1H),7.98(d,J＝13.3Hz,2H),7.90(d,J＝7.4Hz,1H),6.94(d,J＝8.3Hz,1H),4.34(t,J＝6.6Hz,2H),4.09(q,J＝6.6Hz,1H),2.39(s,2H),2.17(s,6H),1.98–1.85(m,4H),1.73(s,2H),1.59(s,4H)。
实施例15
3-cyclohexyl-1-(7-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)quinoxalin-2-yl)-1-methylurea(A15)
化合物A15的合成方法与A07相同，用环己基异氰酸酯替代异氰酸乙酯即可。淡黄色固体，收率为85％。1H NMR(400MHz,DMSO-d6)δ9.01(s,1H),8.64(d,J＝2.7Hz,1H),8.55(d,J＝7.6Hz,1H),8.17(dd,J＝8.6,2.7Hz,1H),8.01(dd,J＝5.3,3.3Hz,2H),7.97–7.91(m,1H),6.93(d,J＝8.5Hz,1H),4.34(t,J＝6.6Hz,2H),3.61(d,J＝9.9Hz,1H),3.48(s,3H),2.37(t,J＝7.1Hz,2H),2.16(s,6H),1.88(p,J＝8.4,7.3Hz,4H),1.72(dd,J＝9.5,4.9Hz,2H),1.58(d,J＝12.8Hz,1H),1.34(q,J＝10.9Hz,4H),1.23–1.15(m,1H).13C NMR(101MHz,DMSO-d6)δ163.33,155.15,150.76,145.41,140.93,138.87,137.94,129.03,125.87,123.33,110.91,64.18,55.72,49.38,45.12,32.65,32.44,26.65,25.25,24.62。
实施例16
1-(7-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)quinoxalin-2-yl)-1-methyl-3-(4-methylcyclo hexyl)urea(A16)
化合物A16的合成方法与A07相同，用对甲基环己基异氰酸酯替代异氰酸乙酯即可。淡黄色固体，收率为90％。1H NMR(400MHz,DMSO-d6)δ8.99(s,1H),8.60(s,1H),8.40(d,J＝7.3Hz,1H),8.19–8.06(m,1H),8.04–7.92(m,2H),7.89(d,J＝7.4Hz,1H),6.90(d,J＝8.6Hz,1H),4.33(t,J＝6.3Hz,2H),3.46(s,3H),2.49(d,J＝7.3Hz,2H),2.26(s,6H),1.97–1.84(m,4H),1.67(d,J＝12.1Hz,2H),1.34(q,J＝11.1,10.2Hz,3H),1.17(dd,J＝13.8,7.1Hz,1H),0.97(q,J＝11.4Hz,2H),0.86(d,J＝6.3Hz,3H).13C NMR(101MHz,DMSO-d6)δ163.24,155.28,150.73,145.36,140.97,139.50,138.75,137.90,128.97,125.77,123.39,110.87,64.00,55.47,49.75,44.61,33.71,32.66,32.40,31.50,26.20,22.17
实施例17
3-((3s,5s,7s)-adamantan-1-yl)-1-(7-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)quinoxalin-2-yl)-1-methylurea(A17)
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化合物A17的合成方法与A07相同，用金刚烷异氰酸酯替代异氰酸乙酯即可。淡黄色固体，收率为84％。1H NMR(400MHz,Chloroform-d)δ10.30(s,1H),8.80(s,1H),8.51(d,J＝2.5Hz,1H),8.06(d,J＝8.6Hz,1H),7.92(dd,J＝8.6,2.6Hz,1H),7.83–7.74(m,2H),6.88(d,J＝8.6Hz,1H),4.43(t,J＝6.4Hz,2H),3.58(s,3H),2.53(t,J＝7.5Hz,2H),2.32(s,6H),2.15(s,9H),2.07–1.99(m,2H),1.73(d,J＝3.7Hz,6H)。
实施例18
1-(7-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)quinoxalin-2-yl)-3-(4-meth-oxyphenyl)-1-me thylurea(A18)
化合物A18的合成方法与A07相同，用对甲氧基苯异氰酸酯替代异氰酸乙酯即可。淡黄色固体，收率为92％。1H NMR(400MHz,DMSO-d6)δ10.54(s,1H),9.05(s,1H),8.70(d,J＝2.6Hz,1H),8.24(dd,J＝8.7,2.6Hz,1H),8.19(d,J＝2.0Hz,1H),8.07(d,J＝8.6Hz,1H),8.02(d,J＝2.0Hz,1H),7.56–7.48(m,2H),6.94(t,J＝9.0Hz,3H),3.74(s,3H),3.61(s,3H),2.18(s,6H)。
实施例19
1-(7-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)quinoxalin-2-yl)-3-(3-meth-oxyphenyl)-1-me thylurea(A19)
化合物A19的合成方法与A07相同，用间甲氧基苯异氰酸酯替代异氰酸乙酯即可。淡黄色固体，收率为85％。1H NMR(400MHz,DMSO-d6)δ10.63(s,1H),9.04(s,1H),8.70(d,J＝2.5Hz,1H),8.29–8.22(m,1H),8.19(d,J＝1.9Hz,1H),8.07(d,J＝8.5Hz,1H),8.02(dd,J＝8.7,1.9Hz,1H),7.31(t,J＝2.2Hz,1H),7.25(t,J＝8.1Hz,1H),7.17(d,J＝8.1Hz,1H),6.95(d,J＝8.7Hz,1H),6.66(dd,J＝8.1,2.4Hz,1H),4.35(t,J＝6.6Hz,2H),3.76(s,3H),3.61(s,3H),2.38(t,J＝7.2Hz,2H),2.17(s,6H),1.89(t,J＝6.9Hz,2H)。
实施例20
1-(7-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)quinoxalin-2-yl)-1-methyl-3-(3-(trifluoromet hyl)phenyl)urea(A20)
化合物A20的合成方法与A07相同，用间三氟甲基异氰酸苯酯替代异氰酸乙酯即可。淡黄色固体，收率为83％。1H NMR(400MHz,Chloroform-d)δ12.95(s,1H),8.90(s,1H),8.55(d,J＝2.6Hz,1H),8.14(d,J＝8.6Hz,1H),8.09(s,1H),8.00–7.93(m,2H),7.87(dt,J＝8.7,2.6Hz,1H),7.68(d,J＝8.1Hz,1H),7.49(t,J＝7.9Hz,1H),7.37(d,J＝7.9Hz,1H),6.91(d,J＝8.6Hz,1H),4.45(t,J＝6.4Hz,2H),3.73(s,3H),2.56(t,J＝7.5Hz,2H),2.34(s,6H),2.10–2.01(m,2H)。
实施例21
3-(2-chlorophenyl)-1-(7-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)quino-xalin-2-yl)-1-meth ylurea(A21)
化合物A21的合成方法与A07相同，用2-氯苯基异氰酸酯替代异氰酸乙酯即可。淡黄色固体，收率为86％。1H NMR(400MHz,DMSO-d6)δ12.39(s,1H),9.07(s,1H),8.59(d,J＝2.2Hz,1H),8.20(d,J＝7.2Hz,1H),8.15–8.04(m,3H),8.01(dd,J＝8.6,1.6Hz,1H),7.56–7.51(m,1H),7.36(t,J＝7.3Hz,1H),7.18–7.11(m,1H),6.95(d,J＝8.6Hz,1H),4.35(t,J＝6.6Hz,2H),3.63(s,3H),2.41(t,J＝7.1Hz,2H),2.18(d,J＝4.9Hz,7H),1.93–1.85(m,2H)。
实施例22
3-(4-chlorophenyl)-1-(7-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)quino-xalin-2-yl)-1-meth ylurea(A22)
化合物A22的合成方法与A07相同，用对氯苯异氰酸酯替代异氰酸乙酯即可。淡黄色固体，收率为84％。1H NMR(400MHz,DMSO-d6)δ10.73(s,1H),9.06(s,1H),8.71(s,1H),8.31–8.20(m,2H),8.06(q,J＝8.7Hz,2H),7.66(d,J＝8.4Hz,2H),7.40(d,J＝8.4Hz,2H),6.96(d,J＝8.7Hz,1H),4.36(t,J＝6.6Hz,2H),3.62(s,3H),2.41(t,J＝7.2Hz,2H),2.19(s,6H),1.95–1.84(m,2H)。
实施例23
1-(7-(6-(2-(dimethylamino)ethoxy)pyridin-3-yl)quinoxalin-2-yl)-3-isopropyl-1-methylurea(A23)
将2-二甲氨基-1-乙醇(53mg,0.59mmol)在冰浴下溶于DMF(5ml)中，缓慢加入NaH固体(24mg,0.59mmol)后并保持约0℃搅拌约15分钟。加入中间体1-4b(100mg,0.39mmol)，让反应体系逐渐升至室温后再加热至50℃搅拌过夜。TLC监测反应结束后，用EtOAc/H2O(体积比1/3)萃取反应液，合并3次萃取的有机相，经无水Na2SO4干燥并浓缩得到黄色的黏稠的醚粗产品。再次加入无水甲苯(5ml)和DIEA(101mg,0.79mmol)充分溶解粗产品，在室温下滴加异丙基异氰酸酯(69mg,0.79mmol)并升温至100℃。搅拌约5h后，TLC监测反应基本结束，减压浓缩，最终通过快速柱层析(溶剂梯度为二氯甲烷/甲醇＝97/3)纯化得目标产物A23。浅黄色固体，两步反应总收率为76％。1H NMR(400MHz,DMSO-d6)δ9.03(s,1H),8.67(d,J＝2.5Hz,1H),8.33(d,J＝7.3Hz,1H),8.20(dd,J＝8.7,2.6Hz,1H),8.07(d,J＝1.7Hz,1H),8.03(d,J＝8.6Hz,1H),7.96(dd,J＝8.6,1.9Hz,1H),6.94(d,J＝8.6Hz,1H),4.41(t,J＝5.9Hz,2H),3.94(dt,J＝13.6,6.7Hz,1H),3.49(s,3H),2.65(t,J＝5.9Hz,2H),2.22(s,6H),1.21(d,J＝6.6Hz,6H).13C NMR(101MHz,DMSO-d6)δ163.13,155.27,150.86,145.38,141.24,139.61,138.76,138.03,136.79,129.00,128.04,125.87,123.50,110.97,63.61,57.58,45.46,32.67,22.53。
实施例24
1-(7-(6-((1-(dimethylamino)propan-2-yl)oxy)pyridin-3-yl)quinoxalin-2-yl)-3-isopropyl-1-meth ylurea(A24)
化合物A24的合成方法与A23相同，用N,N-二甲基异丙醇胺替代2-二甲氨基-1-乙醇即可。淡黄色固体，两步反应总收率为75％。1H NMR(400MHz,DMSO-d6)δ9.03(s,1H),8.66(d,J＝2.3Hz,1H),8.35(d,J＝7.3Hz,1H),8.18(dd,J＝8.6,2.5Hz,1H),8.08–8.00(m,2H),7.96(dd,J＝8.6,1.7Hz,1H),6.88(d,J＝8.6Hz,1H),5.41(h,J＝6.1Hz,1H),3.93(dq,J＝13.4,6.6Hz,1H),3.48(s,3H),2.58(dd,J＝12.6,7.0Hz,1H),2.39(dd,J＝12.7,5.3Hz,1H),2.21(s,6H),1.29(d,J＝6.2Hz,3H),1.21(d,J＝6.6Hz,6H).13C NMR(101MHz,DMSO-d6)δ162.85,155.25,150.84,145.37,141.17,139.59,138.82,138.06,136.77,128.98,127.80,125.85,123.44,111.36,69.12,63.77,45.75,42.40,32.66,22.53,18.47。
实施例25
3-isopropyl-1-methyl-1-(7-(6-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-yl)quino-xalin-2-yl)urea(A25)
化合物A25的合成方法与A23相同，用2-吡咯烷基乙醇替代2-二甲氨基-1-乙醇即可。淡黄色固体，两步反应总收率为79％。1H NMR(400MHz,DMSO-d6)δ9.03(s,1H),8.66(d,J＝2.5Hz,1H),8.33(d,J＝7.3Hz,1H),8.20(dd,J＝8.6,2.5Hz,1H),8.08–8.00(m,2H),7.96(dd,J＝8.6,1.8Hz,1H),6.94(d,J＝8.6Hz,1H),4.42(t,J＝5.9Hz,2H),3.97–3.88(m,1H),3.49(s,3H),2.81(t,J＝5.9Hz,2H),2.51(d,J＝7.4Hz,4H),1.68(p,J＝3.0Hz,4H),1.21(d,J＝6.6Hz,6H)。
实施例26
3-isopropyl-1-methyl-1-(7-(6-(2-(2-oxopyrrolidin-1-yl)ethoxy)pyridin-3-yl)quinoxalin-2-yl)ur ea(A26)
化合物A26的合成方法与A23相同，用N-羟乙基-2-吡咯烷酮替代2-二甲氨基-1-乙醇即可。淡黄色固体，两步反应总收率为62％。1H NMR(400MHz,DMSO-d6)δ9.03(s,1H),8.66(d,J＝2.4Hz,1H),8.32(d,J＝7.3Hz,1H),8.21(dd,J＝8.6,2.5Hz,1H),8.06(d,J＝1.7Hz,1H),8.02(d,J＝8.6Hz,1H),7.95(dd,J＝8.6,1.8Hz,1H),6.94(d,J＝8.6Hz,1H),4.45(t,J＝5.5Hz,2H),3.93(dq,J＝13.4,6.6Hz,1H),3.58(t,J＝5.5Hz,2H),3.51–3.42(m,5H),2.21(t,J＝8.1Hz,2H),1.91(p,J＝7.5Hz,2H),1.21(d,J＝6.6Hz,6H).13C NMR(101MHz,DMSO-d6)δ174.14,162.85,155.26,150.85,145.31,141.26,139.60,138.66,138.13,136.79,129.00,128.30,125.84,123.54,111.00,63.23,47.16,42.41,41.35,32.70,30.28,22.53,17.64。
实施例27
3-isopropyl-1-methyl-1-(7-(6-(2-(piperidin-1-yl)ethoxy)pyridin-3-yl)quino-xalin-2-yl)urea(A27)
化合物A27的合成方法与A23相同，用2-哌啶基乙醇替代2-二甲氨基-1-乙醇即可。淡黄色固体，两步反应总收率为66％。1H NMR(400MHz,DMSO-d6)δ9.03(s,1H),8.65(d,J＝2.4Hz,1H),8.34(d,J＝7.3Hz,1H),8.18(dd,J＝8.7,2.6Hz,1H),8.06–7.99(m,2H),7.95(dd,J＝8.6,1.9Hz,1H),6.93(d,J＝8.6Hz,1H),4.42(t,J＝6.0Hz,2H),3.93(dq,J＝13.4,6.6Hz,1H),3.48(s,3H),2.68(t,J＝5.9Hz,2H),2.43(s,4H),1.49(p,J＝5.6Hz,4H),1.40–1.33(m,2H),1.22(d,J＝6.6Hz,6H)。
实施例28
3-isopropyl-1-methyl-1-(7-(6-(2-morpholinoethoxy)pyridin-3-yl)quinoxalin-2-yl)urea(A28)
化合物A28的合成方法与A23相同，用2-吗啉基乙醇替代2-二甲氨基-1-乙醇即可。淡黄色固体，两步反应总收率为67％。1H NMR(400MHz,DMSO-d6)δ9.03(s,1H),8.66(d,J＝2.4Hz,1H),8.33(d,J＝7.4Hz,1H),8.20(dd,J＝8.6,2.5Hz,1H),8.06(d,J＝1.5Hz,1H),8.02(d,J＝8.6Hz,1H),7.96(dd,J＝8.6,1.7Hz,1H),6.95(d,J＝8.6Hz,1H),4.44(t,J＝5.8Hz,2H),3.93(dq,J＝13.3,6.6Hz,1H),3.61–3.54(m,4H),3.49(s,3H),2.71(t,J＝5.8Hz,2H),2.49–2.42(m,4H),1.21(d,J＝6.6Hz,6H).13C NMR(101MHz,DMSO-d6)δ163.09,155.28,150.87,145.37,138.74,138.05,136.79,129.00,125.87,123.52,110.98,66.18,63.10,56.92,53.59,32.70,23.30,22.54。
实施例29
3-isopropyl-1-methyl-1-(7-(6-(2-(4-methylpiperazin-1-yl)ethoxy)pyridin-3-yl)-quinoxalin-2-yl)urea(A29)
化合物A29的合成方法与A23相同，用2-N-甲基哌嗪乙醇替代2-二甲氨基-1-乙醇即可。淡黄色固体，两步反应总收率为69％。1H NMR(400MHz,DMSO-d6)δ9.03(s,1H),8.66(d,J＝2.6Hz,1H),8.33(d,J＝7.4Hz,1H),8.20(dd,J＝8.7,2.6Hz,1H),8.06(d,J＝2.0Hz,1H),8.02(d,J＝8.6Hz,1H),7.95(dd,J＝8.6,2.0Hz,1H),6.94(d,J＝8.7Hz,1H),4.42(t,J＝5.9Hz,2H),3.93(h,J＝6.7Hz,1H),3.48(s,3H),2.70(t,J＝5.9Hz,2H),2.51–2.43(m,4H),2.35(s,4H),2.16(s,3H),1.21(d,J＝6.6Hz,6H).13C NMR(101MHz,DMSO-d6)δ163.10,155.27,150.86,145.37,141.24,138.02,136.78,129.00,128.06,125.86,123.51,110.97,63.34,56.42,54.61,52.82,45.58,42.43,32.72,22.54。
实施例30
1-(7-(6-(4-(dimethylamino)butoxy)pyridin-3-yl)quinoxalin-2-yl)-3-isopropyl-1-methylurea(A30)
化合物A30的合成方法与A23相同，用二甲氨丁醇替代2-二甲氨基-1-乙醇即可。淡黄色固体，两步反应总收率为68％。1H NMR(400MHz,DMSO-d6)δ9.03(s,1H),8.65(s,1H),8.33(d,J＝6.8Hz,1H),8.18(d,J＝7.5Hz,1H),8.09–7.99(m,2H),7.94(d,J＝8.2Hz,1H),6.92(d,J＝8.5Hz,1H),4.32(t,J＝5.8Hz,2H),4.00–3.85(m,1H),3.48(s,3H),2.28(t,J＝6.7Hz,2H),2.15(s,6H),1.73(d,J＝6.6Hz,2H),1.55(d,J＝6.6Hz,2H),1.21(d,J＝6.1Hz,6H).13C NMR(101MHz,DMSO-d6)δ163.32,155.26,150.83,145.41,141.19,138.77,137.93,128.98,127.92,125.83,123.45,110.85,65.59,58.61,44.99,42.40,32.68,26.38,23.46,22.53。
实施例31
3-isopropyl-1-methyl-1-(7-(6-((1-methylpyrrolidin-3-yl)oxy)pyridin-3-yl)quino-xalin-2-yl)ure a(A31)
化合物A31的合成方法与A23相同，用3-羟基-1-甲基四氢吡咯替代2-二甲氨基-1-乙醇即可。淡黄色固体，两步反应总收率为65％。1H NMR(400MHz,DMSO-d6)δ9.03(s,1H),8.66(d,J＝2.3Hz,1H),8.36(d,J＝7.3Hz,1H),8.20(dd,J＝8.7,2.5Hz,1H),8.06(d,J＝1.6Hz,1H),8.02(d,J＝8.6Hz,1H),7.96(dd,J＝8.6,1.8Hz,1H),6.92(d,J＝8.6Hz,1H),5.50–5.37(m,1H),3.93(dq,J＝13.2,6.6Hz,1H),3.48(s,3H),2.86(dd,J＝10.6,6.1Hz,1H),2.73(td,J＝13.8,13.3,5.4Hz,2H),2.46–2.39(m,1H),2.37–2.29(m,4H),1.91–1.81(m,1H),1.21(d,J＝6.6Hz,6H).13C NMR(101MHz,DMSO-d6)δ155.27,150.86,145.41,141.23,139.59,138.74,138.06,136.79,129.00,127.99,125.88,123.51,111.31,75.35,61.90,54.53,42.42,41.66,32.70,32.35,22.55。
实施例32
3-isopropyl-1-methyl-1-(7-(6-((1-methylpiperidin-3-yl)oxy)pyridin-3-yl)quino-xalin-2-yl)urea(A32)
化合物A32的合成方法与A23相同，用3-羟基-N-甲基哌啶替代2-二甲氨基-1-乙醇即可。淡黄色固体，两步反应总收率为70％。1H NMR(400MHz,DMSO-d6)δ9.02(s,1H),8.69–8.60(m,1H),8.35(d,J＝7.2Hz,1H),8.22–8.14(m,1H),8.07–7.99(m,2H),7.94(d,J＝8.5Hz,1H),6.90(d,J＝8.6Hz,1H),5.18–5.08(m,1H),3.93(dq,J＝13.2,6.6Hz,1H),3.48(s,3H),2.93(d,J＝9.1Hz,1H),2.57(d,J＝10.5Hz,1H),2.21(s,4H),2.09(s,1H),1.98(d,J＝7.4Hz,1H),1.80–1.69(m,1H),1.62–1.52(m,1H),1.44(d,J＝10.2Hz,1H),1.21(d,J＝6.5Hz,6H).13C NMR(101MHz,DMSO-d6)δ162.52,155.25,150.83,145.35,141.18,139.58,138.74,138.10,128.98,127.97,125.82,123.45,111.32,69.96,58.97,54.79,45.81,42.41,32.67,28.78,22.54。
实施例33
3-isopropyl-1-methyl-1-(7-(6-((1-methylpiperidin-4-yl)oxy)pyridin-3-yl)quino-xalin-2-yl)urea(A33)
化合物A33的合成方法与A23相同，用1-甲基-4-哌啶醇替代2-二甲氨基-1-乙醇即可。淡黄色固体，两步反应总收率为79％。1H NMR(400MHz,DMSO-d6)δ9.03(s,1H),8.65(d,J＝2.1Hz,1H),8.35(d,J＝7.3Hz,1H),8.18(dd,J＝8.6,2.4Hz,1H),8.05(s,1H),8.02(d,J＝8.6Hz,1H),7.95(d,J＝8.6Hz,1H),6.91(d,J＝8.6Hz,1H),5.05(dt,J＝8.6,4.5Hz,1H),3.93(dq,J＝13.3,6.6Hz,1H),3.48(s,3H),2.74–2.62(m,2H),2.19(s,5H),2.00(d,J＝9.7Hz,2H),1.76–1.63(m,2H),1.21(d,J＝6.5Hz,6H).13C NMR(101MHz,DMSO-d6)δ162.61,155.25,150.84,145.38,141.18,139.59,138.79,138.07,136.77,128.99,127.85,125.84,123.44,111.38,52.72,45.76,42.40,32.67,30.68,22.53。
实施例34
3-isopropyl-1-methyl-1-(7-(6-((1,2,2,6,6-pentamethylpiperidin-4-yl)oxy)pyridin-3-yl)quinoxal in-2-yl)urea(A34)
化合物A34的合成方法与A23相同，用五甲基哌啶醇替代2-二甲氨基-1-乙醇即可。淡黄色固体，两步反应总收率为72％。1H NMR(400MHz,DMSO-d6)δ9.03(s,1H),8.68(s,1H),8.39(d,J＝7.1Hz,1H),8.24(d,J＝6.7Hz,1H),8.07(s,1H),8.03(d,J＝8.6Hz,1H),7.97(d,J＝8.5Hz,1H),6.96(d,J＝8.5Hz,1H),5.54(s,1H),4.00–3.84(m,1H),3.49(s,3H),2.68(s,3H),2.29(s,2H),2.17(s,2H),1.55(s,6H),1.43(s,6H),1.21(d,J＝6.5Hz,6H).13CNMR(101MHz,DMSO-d6)δ155.25,150.85,145.41,141.26,139.57,138.62,138.41,136.81,129.03,128.42,125.86,123.60,111.44,42.43,32.70,28.27,22.55,21.05。
实施例35
3-isopropyl-1-methyl-1-(7-(6-(((1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridin-3-yl)quinoxalin-2-yl)urea(A35)
化合物A35的合成方法与A23相同，用托品醇替代2-二甲氨基-1-乙醇即可。淡黄色固体，两步反应总收率为69％。1H NMR(400MHz,DMSO-d6)δ9.03(s,1H),8.65(d,J＝2.4Hz,1H),8.32(d,J＝7.4Hz,1H),8.20(dd,J＝8.6,2.6Hz,1H),8.09–8.01(m,2H),7.96(dd,J＝8.6,1.8Hz,1H),6.89(d,J＝8.6Hz,1H),5.24(t,J＝4.9Hz,1H),3.97–3.87(m,1H),3.49(d,J＝5.8Hz,3H),3.04(s,2H),2.19(s,3H),2.08(dd,J＝10.7,4.0Hz,2H),1.97(s,4H),1.79(d,J＝14.4Hz,2H),1.21(d,J＝6.6Hz,6H)。
实施例36
1-(7-(6-((4-(dimethylamino)cyclohexyl)oxy)pyridin-3-yl)quinoxalin-2-yl)-3-isopropyl-1-meth ylurea(A36)
化合物A36的合成方法与A23相同，用4-二甲氨基环己醇替代2-二甲氨基-1-乙醇即可。淡黄色固体，两步反应总收率为75％。1H NMR(400MHz,DMSO-d6)δ9.03(s,1H),8.65(s,1H),8.35(d,J＝7.0Hz,1H),8.18(d,J＝8.5Hz,1H),8.07–7.99(m,2H),7.95(d,J＝8.5Hz,1H),6.88(d,J＝8.6Hz,1H),4.98(s,1H),3.99–3.89(m,1H),3.74(s,1H),3.48(s,3H),2.32(s,6H),2.17(s,2H),1.93(s,2H),1.51–1.37(m,4H),1.21(d,J＝6.4Hz,6H).13C NMR(101MHz,DMSO-d6)δ155.27,150.84,145.35,141.20,139.60,138.77,138.05,136.76,128.98,125.83,123.43,111.29,72.86,62.17,42.41,40.76,32.71,29.98,25.19,22.53。
实施例37
3-isopropyl-1-methyl-1-(7-(6-((1-methylpyrrolidin-3-yl)methoxy)pyridin-3-yl)quinoxalin-2-yl)urea(A37)
化合物A37的合成方法与A23相同，用1-甲基-3-吡咯烷甲醇替代2-二甲氨基-1-乙醇即可。淡黄色固体，两步反应总收率为68％。1H NMR(400MHz,DMSO-d6)δ9.04(s,1H),8.66(d,J＝2.4Hz,1H),8.31(d,J＝7.4Hz,1H),8.21(dd,J＝8.7,2.6Hz,1H),8.06(d,J＝1.8Hz,1H),8.03(d,J＝8.6Hz,1H),7.96(dd,J＝8.6,1.9Hz,1H),6.96(d,J＝8.6Hz,1H),4.27(qd,J＝10.4,7.1Hz,2H),3.93(dq,J＝13.4,6.6Hz,1H),3.48(s,3H),2.91(t,J＝8.2Hz,1H),2.83(d,J＝6.0Hz,1H),2.78–2.64(m,3H),2.46(s,3H),2.11–2.00(m,1H),1.64(dq,J＝13.2,7.1Hz,1H),1.21(d,J＝6.6Hz,6H).13C NMR(101MHz,DMSO-d6)δ163.14,155.30,150.89,145.37,141.33,138.70,138.09,129.01,128.23,125.87,123.55,110.88,68.20,58.12,54.92,42.43,40.99,36.56,32.73,27.16,22.54。
实施例38
3-isopropyl-1-methyl-1-(7-(6-((1-methylpyrrolidin-2-yl)methoxy)pyridin-3-yl)-quinoxalin-2-yl)urea(A38)
化合物A38的合成方法与A23相同，用1-甲基-2-吡咯烷甲醇替代2-二甲氨基-1-乙醇即可。淡黄色固体，两步反应总收率为65％。1H NMR(400MHz,DMSO-d6)δ9.04(s,1H),8.68(s,1H),8.32(d,J＝7.2Hz,1H),8.23(d,J＝8.5Hz,1H),8.08(s,1H),8.04(d,J＝8.5Hz,1H),7.98(d,J＝8.6Hz,1H),6.98(d,J＝8.6Hz,1H),4.46–4.37(m,1H),4.32(s,1H),3.98–3.89(m,1H),3.49(s,3H),3.09(s,1H),2.86(s,1H),2.49–2.32(m,4H),2.09–1.97(m,1H),1.83–1.61(m,3H),1.21(d,J＝6.5Hz,6H).13C NMR(101MHz,DMSO-d6)δ155.32,150.92,145.38,141.36,139.66,138.71,138.17,136.82,129.03,128.31,125.91,123.59,110.98,56.87,42.42,32.75,27.97,22.55,22.36。
实施例39
3-isopropyl-1-methyl-1-(7-(6-((1-methylpiperidin-3-yl)methoxy)pyridin-3-yl)-quinoxalin-2-yl)urea(A39)
化合物A39的合成方法与A23相同，用1-甲基哌啶-3-甲醇替代2-二甲氨基-1-乙醇即可。淡黄色固体，两步反应总收率为72％。1H NMR(400MHz,DMSO-d6)δ9.02(s,1H),8.62(d,J＝2.3Hz,1H),8.34(d,J＝7.3Hz,1H),8.16(dd,J＝8.6,2.4Hz,1H),8.07–7.98(m,2H),7.96–7.90(m,1H),6.92(d,J＝8.6Hz,1H),4.21(dd,J＝10.5,6.0Hz,1H),4.12(dd,J＝10.3,7.7Hz,1H),3.93(dq,J＝13.4,6.6Hz,1H),3.48(s,3H),2.79(d,J＝9.6Hz,1H),2.61(d,J＝10.7Hz,1H),2.14(s,3H),2.02(d,J＝3.0Hz,1H),1.87(t,J＝10.0Hz,1H),1.81–1.67(m,2H),1.65–1.57(m,1H),1.49(t,J＝11.5Hz,1H),1.21(d,J＝6.6Hz,6H),1.12–0.95(m,1H).13C NMR(101MHz,DMSO-d6)δ163.27,155.23,150.79,145.32,141.12,138.72,137.91,136.75,128.95,127.96,125.79,123.43,110.84,68.50,58.66,55.71,46.42,42.39,35.42,32.66,32.63,26.28,24.23,22.52。
实施例40
3-isopropyl-1-methyl-1-(7-(6-((1-methylpiperidin-2-yl)methoxy)pyridin-3-yl)-quinoxalin-2-yl)urea(A40)
化合物A40的合成方法与A23相同，用1-甲基-2-哌啶甲醇替代2-二甲氨基-1-乙醇即可。淡黄色固体，两步反应总收率为73％。1H NMR(400MHz,DMSO-d6)δ9.03(s,1H),8.66(d,J＝2.4Hz,1H),8.34(d,J＝7.3Hz,1H),8.20(dd,J＝8.7,2.5Hz,1H),8.05(d,J＝1.6Hz,1H),8.02(d,J＝8.6Hz,1H),7.95(dd,J＝8.6,1.8Hz,1H),6.95(d,J＝8.6Hz,1H),4.45(dd,J＝11.3,4.5Hz,1H),4.32(dd,J＝11.2,4.6Hz,1H),3.93(dq,J＝13.4,6.6Hz,1H),3.48(s,3H),2.85(d,J＝10.2Hz,1H),2.41(s,1H),2.34(s,3H),2.18(s,1H),1.82–1.65(m,2H),1.60–1.38(m,3H),1.32–1.24(m,1H),1.21(d,J＝6.6Hz,6H).13C NMR(101MHz,DMSO-d6)δ163.03 155.26,150.84,145.36,141.24,139.59,138.70,138.09,128.99,128.20,125.85,123.53,111.03,67.35,62.19,56.20,42.42,32.70,28.38,24.79,23.22,22.54。
实施例41
3-isopropyl-1-methyl-1-(7-(6-((1-methylpiperidin-4-yl)methoxy)pyridin-3-yl)-quinoxalin-2-yl)urea(A41)
化合物A41的合成方法与A23相同，用1-甲基-4-哌啶甲醇替代2-二甲氨基-1-乙醇即可。淡黄色固体，两步反应总收率为76％。1H NMR(400MHz,Chloroform-d)δ10.04(d,J＝6.7Hz,1H),8.82(s,1H),8.51(d,J＝2.3Hz,1H),8.07(d,J＝8.6Hz,1H),7.92(dd,J＝8.6,2.6Hz,1H),7.82(d,J＝1.7Hz,1H),7.78(dd,J＝8.6,1.9Hz,1H),6.87(d,J＝8.6Hz,1H),4.23(d,J＝6.1Hz,2H),4.10(d,J＝6.6Hz,1H),3.62(s,3H),2.91(d,J＝11.4Hz,2H),2.29(s,3H),2.03–1.93(m,2H),1.86(d,J＝12.5Hz,3H),1.53–1.43(m,2H),1.32(d,J＝6.5Hz,6H).13C NMR(101MHz,Chloroform-d)δ164.25,155.14,150.21,145.67,140.71,138.94,137.73,137.53,129.74,128.73,126.58,123.59,111.48,70.91,55.59,46.59,43.24,35.14,29.26,23.27。
实施例42
3-isopropyl-1-methyl-1-(7-(6-(2-(1-methylpyrrolidin-2-yl)ethoxy)pyridin-3-yl)-quinoxalin-2-yl)urea(A42)
化合物A42的合成方法与A23相同，用N-甲基-2-(2-羟乙基)吡咯烷替代2-二甲氨基-1-乙醇即可。淡黄色固体，两步反应总收率为70％。1H NMR(400MHz,DMSO-d6)δ9.03(s,1H),8.71–8.63(m,1H),8.33(d,J＝7.3Hz,1H),8.20(dd,J＝8.6,2.2Hz,1H),8.10–8.01(m,2H),7.96(d,J＝8.5Hz,1H),6.93(d,J＝8.6Hz,1H),4.37(q,J＝6.4Hz,2H),3.93(dq,J＝13.2,6.6Hz,1H),3.49(s,3H),2.98(s,1H),2.27(s,4H),2.17–2.06(m,2H),1.99–1.87(m,1H),1.67(dq,J＝15.6,7.6Hz,3H),1.56–1.48(m,1H),1.21(d,J＝6.5Hz,6H).13C NMR(101MHz,DMSO-d6)δ163.71,155.76,151.35,145.92,141.73,140.10,138.47,137.27,129.48,128.47,126.35,123.98,111.38,64.07,63.64,56.97,42.89,33.18,33.17,32.60,30.67,23.01,22.15。
实施例43
1-(7-(6-(3-(diethylamino)propoxy)pyridin-3-yl)quinoxalin-2-yl)-3-isopropyl-1-methylurea(A43)
化合物A43的合成方法与A23相同，用3-二乙氨基-1-丙醇替代2-二甲氨基-1-乙醇即可。淡黄色固体，两步反应总收率为78％。1H NMR(400MHz,DMSO-d6)δ9.05(s,1H),8.69(s,1H),8.27(dd,J＝18.5,7.3Hz,2H),8.12–7.92(m,3H),6.97(d,J＝8.4Hz,1H),4.40(s,2H),3.93(d,J＝6.1Hz,1H),3.49(s,3H),2.98(s,6H),2.09(s,2H),1.31–1.04(m,12H).13C NMR(101MHz,DMSO-d6)δ155.79,151.41,145.90,141.88,140.15,139.16,138.61,137.30,129.52,128.73,126.36,124.06,111.40,48.62,46.74,42.89,33.22,23.01。
实施例44
3-isopropyl-1-methyl-1-(7-(6-(3-(pyrrolidin-1-yl)propoxy)pyridin-3-yl)quino-xalin-2-yl)urea(A44)
化合物A44的合成方法与A23相同，用3-吡咯烷-1-丙醇替代2-二甲氨基-1-乙醇即可。淡黄色固体，两步反应总收率为68％。熔点:163℃.1H NMR(400MHz,DMSO-d6)δ9.03(s,1H),8.66(s,1H),8.32(d,J＝7.2Hz,1H),8.25–8.15(m,1H),8.10–8.00(m,2H),7.96(d,J＝8.6Hz,1H),6.94(d,J＝8.6Hz,1H),4.36(t,J＝6.4Hz,2H),4.00–3.88(m,1H),3.48(s,3H),2.64(t,J＝6.7Hz,2H),2.56(s,4H),2.04–1.89(m,2H),1.72(s,4H),1.21(d,J＝6.5Hz,6H).13C NMR(101MHz,DMSO-d6)δ155.29,150.87,145.42,141.27,139.63,138.76,137.98,136.79,129.00,125.86,123.50,110.88,64.07,53.52,52.13,42.39,32.69,27.53,23.04,22.53.HRMS(ESI),m/z:449.2665[M+H+]。
实施例45
3-isopropyl-1-methyl-1-(7-(6-(3-(2-oxopyrrolidin-1-yl)propoxy)pyridin-3-yl)-quinoxalin-2-yl)urea(A45)
化合物A45的合成方法与A23相同，用1-(3-羟丙基)-2-吡咯烷酮替代2-二甲氨基-1-乙醇即可。淡黄色固体，两步反应总收率为66％。1H NMR(400MHz,Chloroform-d)δ10.01(d,J＝6.9Hz,1H),8.82(s,1H),8.50(d,J＝2.5Hz,1H),8.07(d,J＝8.6Hz,1H),7.92(dd,J＝8.6,2.6Hz,1H),7.82(d,J＝2.0Hz,1H),7.77(dd,J＝8.5,2.0Hz,1H),6.88(d,J＝8.6Hz,1H),4.40(t,J＝6.2Hz,2H),4.10(h,J＝6.6Hz,1H),3.62(s,3H),3.47(dt,J＝19.7,7.1Hz,4H),2.39(t,J＝8.1Hz,2H),2.11–2.00(m,4H),1.32(d,J＝6.5Hz,6H).13C NMR(101MHz,Chloroform-d)δ175.16,163.88,155.13,150.19,145.68,140.64,138.92,137.78,137.56,137.42,129.71,126.58,123.61,111.42,63.94,47.54,43.22,40.00,32.51,32.47,31.16,27.12,23.25,18.13。
实施例46
3-isopropyl-1-methyl-1-(7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)quino-xalin-2-yl)ure(A46)
化合物A46的合成方法与A23相同，用1-哌啶丙醇替代2-二甲氨基-1-乙醇即可。淡黄色固体，两步反应总收率为76％。熔点:181℃.1H NMR(400MHz,DMSO-d6)δ9.04(s,1H),8.67(d,J＝2.3Hz,1H),8.31(d,J＝7.4Hz,1H),8.21(dd,J＝8.7,2.5Hz,1H),8.10–8.06(m,1H),8.04(d,J＝8.6Hz,1H),7.97(dd,J＝8.6,1.7Hz,1H),6.94(d,J＝8.6Hz,1H),4.34(t,J＝6.5Hz,2H),3.93(m,6.5Hz,1H),3.49(s,3H),2.40(m,6H),1.91(q,J＝6.6Hz,2H),1.56–1.45(m,4H),1.43–1.33(m,2H),1.21(d,J＝6.5Hz,6H).13C NMR(101MHz,DMSO-d6)δ163.32,155.29,150.89,145.44,141.28,138.80,137.99,136.79,129.01,125.89,123.50,110.90,64.33,55.13,53.99,42.41,32.71,25.95,25.45,24.00,22.54.HRMS(ESI),m/z:463.2821[M+H+]。
实施例47
3-isopropyl-1-methyl-1-(7-(6-(3-morpholinopropoxy)pyridin-3-yl)quinoxalin-2-yl)urea(A47)
化合物A47的合成方法与A23相同，用1-吗啉丙醇替代2-二甲氨基-1-乙醇即可。淡黄色固体，两步反应总收率为71％。1H NMR(400MHz,DMSO-d6)δ9.03(s,1H),8.65(s,1H),8.32(d,J＝7.1Hz,1H),8.19(d,J＝8.6Hz,1H),8.09–7.99(m,2H),7.95(d,J＝8.4Hz,1H),6.93(d,J＝8.5Hz,1H),4.35(t,J＝6.2Hz,2H),3.93(q,J＝6.2Hz,1H),3.59–3.53(m,4H),3.48(s,3H),2.45–2.31(m,6H),1.95–1.85(m,2H),1.21(d,J＝6.3Hz,6H).13C NMR(101MHz,DMSO-d6)δ163.30,155.27,150.86,145.42,141.23,139.62,138.78,137.95,136.78,128.99,127.96,125.85,123.48,110.88,66.21,64.21,54.93,53.36,42.41,32.68,25.66,22.53。
实施例48
3-isopropyl-1-methyl-1-(7-(6-(3-(4-methylpiperazin-1-yl)propoxy)pyridin-3-yl)quinoxalin-2-yl)urea(A48)
化合物A48的合成方法与A23相同，用1-(3-羟丙基)-4-甲基哌嗪替代2-二甲氨基-1-乙醇即可。淡黄色固体，两步反应总收率为73％。1H NMR(400MHz,DMSO-d6)δ9.03(s,1H),8.66(s,1H),8.32(d,J＝7.2Hz,1H),8.20(d,J＝8.5Hz,1H),8.10–8.00(m,2H),7.96(d,J＝8.5Hz,1H),6.93(d,J＝8.6Hz,1H),4.34(t,J＝6.3Hz,2H),3.98–3.87(m,1H),3.49(s,3H),2.50–2.25(m,10H),2.18(s,3H),1.94–1.85(m,2H),1.21(d,J＝6.4Hz,6H).13C NMR(101MHz,DMSO-d6)δ155.28,150.87,145.43,141.26,139.63,137.97,129.00,127.97,125.86,123.49,110.89,64.24,54.55,54.38,52.44,45.45,42.40,32.69,25.96,22.53。
实施例49
3-isopropyl-1-methyl-1-(7-(6-((4-methylpentyl)oxy)pyridin-3-yl)quinoxalin-2-yl)urea(A49)
化合物A49的合成方法与A23相同，用4-甲基-1-戊醇替代2-二甲氨基-1-乙醇即可。淡黄色固体，两步反应总收率为70％。1H NMR(400MHz,DMSO-d6)δ9.03(s,1H),8.65(d,J＝2.3Hz,1H),8.33(d,J＝7.3Hz,1H),8.18(dd,J＝8.7,2.5Hz,1H),8.07–8.00(m,2H),7.95(dd,J＝8.6,1.8Hz,1H),6.92(d,J＝8.6Hz,1H),4.29(t,J＝6.7Hz,2H),3.93(dq,J＝13.3,6.6Hz,1H),3.48(s,3H),1.73(dt,J＝14.8,6.8Hz,2H),1.58(dt,J＝13.3,6.7Hz,1H),1.34–1.26(m,2H),1.21(d,J＝6.6Hz,6H),0.89(d,J＝6.6Hz,6H).13C NMR(101MHz,DMSO-d6)δ163.34,155.26,150.83,145.41,141.18,139.59,138.78,137.92,136.77,128.98,127.89,125.83,123.44,110.84,65.96,42.40,34.69,32.66,27.31,26.43,22.53,22.45。
实施例50
1-(7-(6-(2-cyclohexylethoxy)pyridin-3-yl)quinoxalin-2-yl)-3-isopropyl-1-methylurea(A50)
化合物A50的合成方法与A23相同，用2-环己基乙醇替代2-二甲氨基-1-乙醇即可。淡黄色固体，两步反应总收率为66％。1H NMR(400MHz,DMSO-d6)δ9.03(s,1H),8.66(d,J＝2.5Hz,1H),8.33(d,J＝7.4Hz,1H),8.19(dd,J＝8.7,2.6Hz,1H),8.06(d,J＝1.8Hz,1H),8.03(d,J＝8.6Hz,1H),7.96(dd,J＝8.6,1.9Hz,1H),6.93(d,J＝8.7Hz,1H),4.35(t,J＝6.8Hz,2H),3.93(dq,J＝13.3,6.6Hz,1H),3.49(s,3H),1.74(d,J＝13.0Hz,2H),1.65(p,J＝6.9Hz,5H),1.46(ddt,J＝14.3,7.2,3.7Hz,1H),1.27–1.12(m,9H),1.03–0.90(m,2H).13CNMR(101MHz,DMSO-d6)δ163.33,155.27,145.44,141.23,138.81,137.96,128.99,127.91,125.87,123.47,110.88,63.74,42.42,35.89,34.11,32.74,32.68,26.07,25.74,22.54。
实施例51
3-isopropyl-1-(7-(6-(3-methoxypropoxy)pyridin-3-yl)quinoxalin-2-yl)-1-methylurea(A51)
化合物A51的合成方法与A23相同，用3-甲氧基-1-丙醇替代2-二甲氨基-1-乙醇即可。淡黄色固体，两步反应总收率为70％。1H NMR(400MHz,DMSO-d6)δ9.02(s,1H),8.64(d,J＝2.4Hz,1H),8.33(d,J＝7.3Hz,1H),8.18(dd,J＝8.6,2.5Hz,1H),8.06–7.98(m,2H),7.94(dd,J＝8.6,1.8Hz,1H),6.93(d,J＝8.6Hz,1H),4.36(t,J＝6.5Hz,2H),3.94(dt,J＝13.4,6.7Hz,1H),3.52–3.45(m,5H),3.26(s,3H),1.98(p,J＝6.4Hz,2H),1.21(d,J＝6.6Hz,6H).13CNMR(101MHz,DMSO-d6)δ163.21,155.25,150.81,145.39,141.16,139.57,138.73,137.94,136.76,128.96,127.99,125.81,123.45,110.85,68.63,62.98,57.95,42.42,32.67,32.65,28.77,22.53。
实施例52
3-isopropyl-1-methyl-1-(7-(6-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-3-yl)-quinoxalin-2-yl)ur ea(A52)
化合物A52的合成方法与A23相同，用四氢吡喃-4-醇替代2-二甲氨基-1-乙醇即可。淡黄色固体，两步反应总收率为81％。1H NMR(400MHz,DMSO-d6)δ9.02(s,1H),8.64(d,J＝2.5Hz,1H),8.35(d,J＝7.3Hz,1H),8.17(dd,J＝8.7,2.6Hz,1H),8.05–7.97(m,2H),7.92(dd,J＝8.6,1.9Hz,1H),6.91(d,J＝8.7Hz,1H),5.25(tt,J＝8.8,4.1Hz,1H),3.97–3.85(m,3H),3.55–3.46(m,5H),2.08–1.99(m,2H),1.66(dtd,J＝13.3,9.4,4.1Hz,2H),1.21(d,J＝6.6Hz,6H).13C NMR(101MHz,DMSO-d6)δ162.41,155.23,150.79,145.31,141.14,139.55,138.70,138.10,136.75,128.96,127.97,125.78,123.43,111.36,69.88,69.85,64.79,42.42,32.66,32.63,31.90,22.52。
实施例53
3-isopropyl-1-methyl-1-(7-(6-((tetrahydro-2H-pyran-3-yl)oxy)pyridin-3-yl)-quinoxalin-2-yl)ur ea(A53)
化合物A53的合成方法与A23相同，用3-羟基四氢吡喃替代2-二甲氨基-1-乙醇即可。淡黄色固体，两步反应总收率为75％。1H NMR(400MHz,DMSO-d6)δ9.02(s,1H),8.64(d,J＝2.5Hz,1H),8.33(d,J＝7.3Hz,1H),8.18(dd,J＝8.6,2.6Hz,1H),8.07–7.98(m,2H),7.93(dd,J＝8.7,2.0Hz,1H),6.93(d,J＝8.6Hz,1H),4.30(dd,J＝10.5,6.7Hz,1H),4.21(dd,J＝10.5,8.0Hz,1H),3.93(h,J＝6.7Hz,1H),3.83–3.73(m,2H),3.66(q,J＝7.7Hz,1H),3.55(dd,J＝8.6,5.5Hz,1H),3.48(s,3H),2.69(p,J＝7.1,6.4Hz,1H),2.08–1.97(m,1H),1.67(ddt,J＝12.6,7.7,6.3Hz,1H),1.21(d,J＝6.6Hz,6H).13C NMR(101MHz,DMSO-d6)δ155.26,150.82,145.33,141.21,139.58,138.67,138.02,136.77,128.97,128.16,125.80,123.49,110.82,69.89,67.48,66.89,42.40,38.02,32.67,28.62,22.52。
实施例54
3-isopropyl-1-methyl-1-(7-(6-((tetrahydro-2H-pyran-4-yl)methoxy)pyridin-3-yl)quinoxalin-2-yl)urea(A54)
化合物A54的合成方法与A23相同，用(四氢-2H-吡喃-4-基)甲醇替代2-二甲氨基-1-乙醇即可。淡黄色固体，两步反应总收率为68％。1H NMR(400MHz,DMSO-d6)δ9.03(s,1H),8.66(d,J＝2.1Hz,1H),8.32(d,J＝7.3Hz,1H),8.20(dd,J＝8.6,2.4Hz,1H),8.09–8.00(m,2H),7.99–7.93(m,1H),6.94(d,J＝8.6Hz,1H),4.38(t,J＝6.1Hz,2H),3.93(dq,J＝13.4,6.6Hz,1H),3.88–3.78(m,2H),3.49(s,3H),3.27(d,J＝11.6Hz,2H),1.70(t,J＝4.8Hz,3H),1.63(d,J＝13.2Hz,2H),1.21(d,J＝6.5Hz,6H).13C NMR(101MHz,DMSO-d6)δ163.21,155.25,150.81,145.39,141.16,139.57,138.73,137.94,136.76,128.96,127.99,125.81,123.45,110.85,68.63,62.98,57.95,42.42,32.67,32.65,28.77,22.53。
实施例55
3-isopropyl-1-methyl-1-(7-(6-((tetrahydro-2H-pyran-3-yl)methoxy)pyridin-3-yl)quinoxalin-2-yl)urea(A55)
化合物A55的合成方法与A23相同，用(四氢吡喃-3-基)甲醇替代2-二甲氨基-1-乙醇即可。淡黄色固体，两步反应总收率为70％。1H NMR(400MHz,DMSO-d6)δ9.03(s,1H),8.64(d,J＝2.6Hz,1H),8.33(d,J＝7.4Hz,1H),8.19(dd,J＝8.7,2.7Hz,1H),8.08–7.99(m,2H),7.94(dd,J＝8.6,2.0Hz,1H),6.94(d,J＝8.6Hz,1H),4.23(dd,J＝10.7,5.9Hz,1H),4.16(dd,J＝10.7,7.6Hz,1H),3.98–3.86(m,2H),3.74(dt,J＝11.4,4.0Hz,1H),3.48(s,3H),3.39–3.35(m,1H),3.27(dd,J＝11.1,9.1Hz,1H),2.11–1.99(m,1H),1.84(dt,J＝13.1,4.5Hz,1H),1.60(qt,J＝5.5,2.7Hz,1H),1.56–1.46(m,1H),1.38(ddt,J＝13.0,10.2,5.2Hz,1H),1.21(d,J＝6.6Hz,6H).13C NMR(101MHz,DMSO-d6)δ163.20,155.27,150.85,145.33,141.24,139.60,138.71,138.01,136.77,128.98,125.84,123.50,110.87,69.67,67.50,67.03,42.41,35.27,32.71,25.64,24.62,22.53。
实施例56
1-cyclohexyl-3-(7-(6-fluoropyridin-3-yl)quinoxalin-2-yl)urea(1-6)
将中间体1-4a(3.0g,8.22mmol)溶于30ml的DMF中，在冰浴降温下缓慢加入NaH固体(0.49g,12.32mmol)。在0℃下搅拌约30分钟后，缓慢加入环己基异氰酸酯(1.54g,12.32mmol)。滴加完毕后，让反应体系逐渐升至室温，并搅拌过夜。TLC监测反应结束后，用EtOAc/H2O(体积比1/3)萃取反应液，合并3次萃取的有机相，无水硫酸钠干燥，减压蒸馏，最终经快速柱层析(溶剂梯度为石油醚/乙酸乙酯＝3/2)纯化得中间体1-6。浅黄色固体，收率为85％。1H NMR(400MHz,DMSO-d6)δ10.05(s,1H),8.87(s,1H),8.71(d,J＝12.9Hz,2H),8.45(s,1H),8.03(d,J＝16.2Hz,2H),7.94(s,1H),7.34(s,1H),3.64(s,1H),1.89(s,2H),1.71(s,2H),1.56(s,1H),1.37(s,5H)。
1-cyclohexyl-3-(7-(6-(3-(diethylamino)propoxy)pyridin-3-yl)quinoxalin-2-yl)urea(A56)
将3-二乙氨基-1-丙醇(54mg,0.41mmol)溶于5ml的DMF中，在冰浴降温下缓慢加入NaH固体(16mg,0.41mmol)。在0℃下搅拌约15分钟后，缓慢加入中间体1-6(100mg,0.27mmol)。随后，反应体系自然地升至室温，加热至50℃并搅拌过夜。TLC监测反应结束后，用EtOAc/H2O(体积比1/3)萃取反应液，合并3次萃取的有机相，无水硫酸钠干燥，减压蒸馏，最终经快速柱层析(溶剂梯度为二氯甲烷/甲醇＝96/4)纯化得终产物A56。浅黄色固体，收率为82％。1H NMR(400MHz,DMSO-d6)δ10.05(s,1H),8.91(s,1H),8.71(d,J＝7.4Hz,1H),8.66(d,J＝2.4Hz,1H),8.20(dd,J＝8.6,2.5Hz,1H),7.99(dd,J＝5.1,3.3Hz,2H),7.91(dd,J＝8.7,1.7Hz,1H),6.96(d,J＝8.6Hz,1H),4.39(t,J＝6.2Hz,2H),3.65(s,1H),3.05–2.94(m,4H),2.08(s,2H),1.88(s,2H),1.72(s,2H),1.60–1.52(m,1H),1.44–1.29(m,5H),1.15(t,J＝6.0Hz,6H).13C NMR(101MHz,DMSO-d6)δ163.06,153.36,148.40,145.41,139.53,139.41,138.93,138.06,137.11,129.23,128.19,125.25,123.10,110.87,63.43,48.10,47.99,46.20,45.33,32.51,25.15,24.22,9.43。
实施例57
1-cyclohexyl-3-(7-(6-(3-(pyrrolidin-1-yl)propoxy)pyridin-3-yl)quinoxalin-2-yl)urea(A57)
化合物A57的合成方法与A57相同，用3-吡咯烷-1-丙醇替代2-二甲氨基-1-乙醇即可。淡黄色固体，收率为76％。1H NMR(400MHz,DMSO-d6)δ10.04(s,1H),8.88(s,1H),8.71(d,J＝7.0Hz,1H),8.66(s,1H),8.20(d,J＝8.5Hz,1H),8.00(d,J＝7.2Hz,2H),7.91(d,J＝8.5Hz,1H),6.95(d,J＝8.6Hz,1H),4.38(t,J＝6.2Hz,2H),3.65(s,1H),2.76(d,J＝22.9Hz,6H),2.01(s,2H),1.89(s,2H),1.75(d,J＝20.7Hz,6H),1.55(s,1H),1.35(d,J＝23.1Hz,5H).13C NMR(101MHz,DMSO-d6)δ163.12,145.43,139.53,139.36,138.99,138.05,137.10,129.24,128.15,125.28,123.10,110.88,63.62,53.25,51.75,32.52,25.14,24.23,22.89。
实施例58
1-cyclohexyl-3-(7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)quinoxalin-2-yl)urea(A58)
化合物A58的合成方法与A57相同，用1-哌啶丙醇替代2-二甲氨基-1-乙醇即可。淡黄色固体，收率为75％。1H NMR(400MHz,DMSO-d6)δ10.04(s,1H),8.88(s,1H),8.68(s,2H),8.21(s,1H),8.00(s,2H),7.93(s,1H),6.96(d,J＝7.5Hz,1H),4.38(s,2H),3.66(s,1H),2.86(s,6H),2.10(s,2H),1.89(s,2H),1.62(d,J＝46.5Hz,8H),1.38(s,6H).13C NMR(101MHz,DMSO-d6)δ162.99,153.33,148.39,145.41,139.56,139.36,138.93,138.11,137.11,129.25,128.28,125.28,123.13,110.89,48.00,32.51,25.14,24.23。
实施例59
1-cyclohexyl-3-(7-(6-(3-morpholinopropoxy)pyridin-3-yl)quinoxalin-2-yl)urea(A59)
化合物A59的合成方法与A57相同，用1-吗啉丙醇替代2-二甲氨基-1-乙醇即可。淡黄色固体，收率为86％。1H NMR(400MHz,DMSO-d6)δ10.02(s,1H),8.84(s,1H),8.71(d,J＝7.2Hz,1H),8.66(d,J＝2.3Hz,1H),8.18(dd,J＝8.7,2.5Hz,1H),8.04–7.97(m,2H),7.91(d,J＝8.7Hz,1H),6.94(d,J＝8.6Hz,1H),4.36(t,J＝6.6Hz,2H),3.66(s,1H),3.61–3.54(m,4H),2.43(t,J＝7.1Hz,2H),2.37(s,4H),1.97–1.85(m,4H),1.72(s,2H),1.61–1.54(m,1H),1.40(d,J＝9.2Hz,5H).13C NMR(101MHz,DMSO-d6)δ148.34,145.45,139.48,139.07,137.96,137.05,129.22,127.95,125.28,123.05,110.86,66.18,64.18,54.90,53.33,32.51,25.63,25.13,24.23。
实施例60
7-(2-fluoropyridin-4-yl)-N-methylquinoxalin-2-amine(1-7a)
将中间体1-3b(200mg,0.84mmol)、2-氟-4-吡啶硼酸(142mg,1.01mmol)、PdCl2(dppf)(61mg,0.08mmol)和K2CO3(64mg,1.68mmol)置于25ml的三颈瓶中，加入14ml的1,4-二氧六环/水/乙醇(体积比为7/3/4)。在氮气气氛下，将上述混合物加热至85℃，约4小时后点板监测反应已经完成。将反应冷却至室温后，硅藻土过滤得到滤液并浓缩得到黑色黏稠物，加入适量的60～80目粗硅胶拌样。通过快速制备过柱机纯化，浓度梯度为30％的乙酸乙酯/石油醚。浓缩收集的溶液，得到171mg的黄色中间体1-7a，收率为80％。1H NMR(400MHz,DMSO)δ8.32(d,J＝5.1Hz,2H),8.03(d,J＝2.1Hz,1H),7.87(d,J＝8.3Hz,1H),7.83(dt,J＝5.3,1.8Hz,1H),7.81–7.74(m,2H),7.67(s,1H),2.94(d,J＝4.7Hz,3H)。
1-isopropyl-3-(7-(5-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)quinoxalin-2-yl)urea(A60)
将1-哌啶丙醇(53mg,0.59mmol)在冰浴下溶于DMF(5ml)中，缓慢加入NaH固体(24mg,0.59mmol)后并保持约0℃搅拌约15分钟。加入中间体1-7a(100mg,0.39mmol)，让反应体系逐渐升至室温后再加热至50℃搅拌过夜。TLC监测反应结束后，用EtOAc/H2O(体积比1/3)萃取反应液，合并3次萃取的有机相，经无水Na2SO4干燥并浓缩得到黄色的黏稠的醚粗产品。再次加入无水甲苯(5ml)和DIEA(101mg,0.79mmol)充分溶解粗产品，在室温下滴加异丙基异氰酸酯(69mg,0.79mmol)并升温至100℃。搅拌约5h后，TLC监测反应基本结束，减压浓缩，最终通过快速柱层析(溶剂梯度为二氯甲烷/甲醇＝97/3)纯化得目标产物A60。浅黄色固体，两步反应总收率为68％。1H NMR(400MHz,DMSO-d6)δ9.08(s,1H),8.25(dd,J＝8.0,6.3Hz,2H),8.17(d,J＝1.9Hz,1H),8.08–7.96(m,2H),7.47(dd,J＝5.4,1.6Hz,1H),7.25(d,J＝1.5Hz,1H),4.35(t,J＝6.4Hz,2H),3.93(h,J＝6.6Hz,1H),3.49(s,3H),2.71(m,6H),2.04(t,J＝7.5Hz,2H),1.62(m,4H),1.45(m,2H),1.21(d,J＝6.6Hz,6H).13CNMR(101MHz,DMSO-d6)δ164.10,155.27,151.01,149.16,147.65,142.20,139.49,138.68,129.11,125.80,125.00,115.42,108.22,63.77,54.40,53.13,42.45,32.73,24.12,22.94,22.50。
实施例61
7-(6-fluoro-5-methylpyridin-3-yl)-N-methylquinoxalin-2-amine(1-7b)
中间体1-7b的合成方法与1-7a相同，用2-氟-3-甲基-5吡啶硼酸酯替代2-氟-4-吡啶硼酸即可。黄色固体，收率为75％。1H NMR(400MHz,DMSO)δ8.51–8.44(m,1H),8.36–8.27(m,2H),7.88(d,J＝2.0Hz,1H),7.83(d,J＝8.4Hz,1H),7.70(q,J＝4.7Hz,1H),7.65(dd,J＝8.4,2.1Hz,1H),2.93(d,J＝4.7Hz,3H),2.33(s,3H)。
3-isopropyl-1-methyl-1-(7-(5-methyl-6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)quinoxalin-2-yl)urea(A61)
化合物A61的合成方法与A60相同，用中间体1-7b替代中间体1-7a即可。淡黄色固体，两步反应总收率为81％。1H NMR(400MHz,DMSO-d6)δ9.02(s,1H),8.52–8.42(m,1H),8.25(d,J＝7.4Hz,1H),8.10–7.98(m,3H),7.97–7.89(m,1H),4.35(t,J＝6.4Hz,2H),3.93(h,J＝6.8Hz,1H),3.48(s,3H),2.48–2.29(m,6H),2.23(s,3H),1.89(t,J＝7.0Hz,2H),1.49(p,J＝5.4Hz,4H),1.37(q,J＝6.7,5.8Hz,2H),1.21(d,J＝6.6Hz,6H).13C NMR(101MHz,DMSO-d6)δ155.28,150.83,142.39,141.15,139.64,138.94,137.45,136.72,128.88,127.75,125.79,123.31,120.25,64.17,55.27,54.05,42.39,32.69,26.09,25.53,24.08,22.52。
实施例62
7-(6-fluoro-4-methylpyridin-3-yl)-N-methylquinoxalin-2-amine(1-7c)
中间体1-7c的合成方法与1-7a相同，用2-氟-4-甲基-5吡啶硼酸酯替代2-氟-4-吡啶硼酸即可。黄色固体，收率为72％。1H NMR(400MHz,DMSO)δ8.31(s,1H),8.12(s,1H),7.82(d,J＝8.3Hz,1H),7.70(q,J＝4.8Hz,1H),7.52(d,J＝1.9Hz,1H),7.30(dt,J＝8.4,1.3Hz,1H),7.18(s,1H),2.92(d,J＝4.7Hz,3H),2.33(s,3H)。
3-isopropyl-1-methyl-1-(7-(4-methyl-6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)quinoxalin-2-yl)urea(A62)
化合物A62的合成方法与A60相同，用中间体1-7c替代中间体1-7a即可。淡黄色固体，两步反应总收率为76％。1H NMR(400MHz,DMSO-d6)δ9.07(s,1H),8.33(d,J＝7.4Hz,1H),8.08(s,1H),8.01(d,J＝8.4Hz,1H),7.77(d,J＝1.7Hz,1H),7.63(dt,J＝8.4,1.8Hz,1H),6.79(d,J＝1.8Hz,1H),4.30(t,J＝6.5Hz,2H),3.92(h,J＝6.7Hz,1H),3.48(s,3H),2.38(m,10.4Hz,6H),2.26(s,3H),1.87(p,J＝6.9Hz,2H),1.49(p,J＝5.5Hz,4H),1.37(p,J＝5.7Hz,2H),1.19(d,J＝6.5Hz,6H).13C NMR(101MHz,DMSO-d6)δ163.07,155.24,150.83,147.59,146.59,141.48,139.57,139.10,136.59,130.21,128.93,128.19,126.92,111.17,63.99,55.20,54.03,42.37,32.68,26.08,25.51,24.06,22.51,19.74。
实施例63
7-(6-fluoro-2-methylpyridin-3-yl)-N-methylquinoxalin-2-amine(1-7d)
中间体1-7d的合成方法与1-7a相同，用2-氟-6-甲基-5吡啶硼酸酯替代2-氟-4-吡啶硼酸即可。黄色固体，收率为82％。1H NMR(400MHz,DMSO)δ8.31(s,1H),7.90(t,J＝8.2Hz,1H),7.82(d,J＝8.3Hz,1H),7.70(d,J＝5.0Hz,1H),7.53(d,J＝2.0Hz,1H),7.32(dd,J＝8.3,2.0Hz,1H),7.09(dd,J＝8.3,3.1Hz,1H),2.92(d,J＝4.7Hz,3H),2.42(s,3H)。
3-isopropyl-1-methyl-1-(7-(2-methyl-6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)quinoxalin-2-yl)urea(A63)
化合物A63的合成方法与A60相同，用中间体1-7d替代中间体1-7a即可。淡黄色固体，两步反应总收率为73％。1H NMR(400MHz,DMSO-d6)δ9.06(s,1H),8.31(d,J＝7.4Hz,1H),8.00(d,J＝8.5Hz,1H),7.75(d,J＝1.9Hz,1H),7.68–7.60(m,2H),6.72(d,J＝8.3Hz,1H),4.31(t,J＝6.6Hz,2H),3.92(h,J＝6.7Hz,1H),3.47(s,3H),2.37(m,9H),1.88(p,J＝6.8Hz,2H),1.49(p,J＝5.5Hz,4H),1.37(q,J＝6.4,5.9Hz,2H),1.19(d,J＝6.6Hz,6H).13CNMR(101MHz,DMSO-d6)δ155.25,152.66,150.85,141.44,140.64,139.10,136.46,128.79,128.22,128.18,126.74,107.91,64.02,55.21,54.01,32.66,26.02,25.52,24.09,22.51。
实施例64
7-(6-chloro-5-(trifluoromethyl)pyridin-3-yl)-N-methylquinoxalin-2-amine(1-7e)
中间体1-7e的合成方法与1-7a相同，用2-氟-3-三氟甲基-5吡啶硼酸酯替代2-氟-4-吡啶硼酸即可。黄色固体，收率为70％。1H NMR(400MHz,DMSO)δ9.15(d,J＝2.4Hz,1H),8.66(d,J＝2.4Hz,1H),8.32(s,1H),8.05(d,J＝2.1Hz,1H),7.88(d,J＝8.4Hz,1H),7.77(dd,J＝8.7,2.0Hz,2H),2.94(d,J＝4.7Hz,3H)。
3-isopropyl-1-methyl-1-(7-(6-(3-(piperidin-1-yl)propoxy)-5-(trifluoromethyl)-pyridin-3-yl)quinoxalin-2-yl)urea(A64)
化合物A64的合成方法与A60相同，用中间体1-7e替代中间体1-7a即可。淡黄色固体，两步反应总收率为75％。1H NMR(400MHz,DMSO-d6)δ9.05(s,1H),8.88(d,J＝2.3Hz,1H),8.44(d,J＝2.3Hz,1H),8.22(d,J＝7.4Hz,1H),8.13(s,1H),8.04–7.96(m,2H),4.46(t,J＝6.3Hz,2H),3.92(h,J＝6.7Hz,1H),3.47(s,3H),2.39(t,J＝7.1Hz,2H),2.32(s,4H),1.89(p,J＝6.6Hz,2H),1.47(p,J＝5.4Hz,4H),1.36(q,J＝5.8Hz,2H),1.21(d,J＝6.5Hz,6H).13C NMR(101MHz,DMSO-d6)δ159.56,155.27,150.89,149.50,141.63,139.56,137.23,136.97,135.58,129.02,127.77,125.92,124.26,65.20,54.87,54.02,42.42,32.70,32.67,25.78,25.52,24.04,22.50。
实施例65
6-fluoro-3-(3-(methylamino)quinoxalin-6-yl)picolinonitrile(1-7f)
中间体1-7f的合成方法与1-7a相同，用2-氟-3-三氟甲基-5吡啶硼酸酯替代2-氟-4-吡啶硼酸即可。黄色固体，收率为78％。1H NMR(400MHz,DMSO)δ9.16(d,J＝2.5Hz,1H),8.96(d,J＝2.5Hz,1H),8.31(s,1H),8.03(d,J＝2.1Hz,1H),7.86(d,J＝8.4Hz,1H),7.80–7.71(m,2H),2.94(d,J＝4.7Hz,3H)。
1-(7-(2-cyano-6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)quinoxalin-2-yl)-3-isopropyl-1-methylurea(A65)
化合物A65的合成方法与A60相同，用中间体1-7f替代中间体1-7a即可。淡黄色固体，两步反应总收率为81％。1H NMR(400MHz,DMSO-d6)δ9.11(s,1H),8.27(d,J＝7.4Hz,1H),8.12(dd,J＝11.6,8.6Hz,2H),8.06(d,J＝2.1Hz,1H),7.83(dd,J＝8.5,2.1Hz,1H),7.29(d,J＝8.7Hz,1H),4.37(t,J＝6.6Hz,2H),3.92(h,J＝6.7Hz,1H),3.49(s,3H),2.47–2.31(m,6H),1.93(p,J＝6.8Hz,2H),1.51(p,J＝5.5Hz,4H),1.42–1.34(m,2H),1.20(d,J＝6.6Hz,6H).13CNMR(101MHz,DMSO-d6)δ162.87,155.24,151.13,142.44,141.48,137.23,136.70,134.69,128.92,127.66,127.35,127.07,117.12,116.40,65.29,54.91,53.94,42.40,32.71,25.59,25.41,23.98,22.51。
实施例66
7-(6-chloro-5-fluoropyridin-3-yl)-N-methylquinoxalin-2-amine(1-7g)
中间体1-7g的合成方法与1-7a相同，用2-氟-3-三氟甲基-5吡啶硼酸酯替代2-氟-4-吡啶硼酸即可。黄色固体，收率为86％。1H NMR(400MHz,DMSO)δ8.75(d,J＝2.1Hz,1H),8.42(dd,J＝10.0,2.1Hz,1H),8.30(s,1H),7.96(d,J＝2.1Hz,1H),7.84(d,J＝8.3Hz,1H),7.78–7.72(m,1H),7.69(dd,J＝8.5,2.1Hz,1H),2.93(d,J＝4.8Hz,3H)。
1-(7-(5-fluoro-6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)quinoxalin-2-yl)-3-isopropyl-1-meth ylurea(A66)
化合物A66的合成方法与A60相同，用中间体1-7g替代中间体1-7a即可。淡黄色固体，两步反应总收率为67％。1H NMR(400MHz,DMSO-d6)δ9.09(s,1H),8.47(d,J＝2.0Hz,1H),8.25–8.20(m,1H),8.11(d,J＝7.5Hz,1H),8.06(d,J＝1.8Hz,2H),8.00(d,J＝2.1Hz,1H),4.37(t,J＝6.2Hz,2H),3.93(h,J＝6.7Hz,1H),3.49(s,3H),2.82(m,6H),2.14(m,2H),1.73–1.57(m,4H),1.46(m,2H),1.21(d,J＝6.6Hz,6H).13C NMR(101MHz,DMSO-d6)δ155.41,151.09,150.44,142.21,139.70,138.96,138.70,137.53,135.44,129.05,126.34,125.16,120.06,67.16,54.04,52.97,42.47,42.43,32.85,23.75,22.51。
实施例67
N-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxalin-2-amine(1-8)
中间体1-3b(3g,13mmol)、联硼酸频那醇酯(4.8g,19mmol)、PdCl2(dppf)(0.92g,1.3mmol)和AcOK(2.47g,25mmol)置于250ml的三口圆底烧瓶中，加入约50ml的无水二氧六环为溶剂，在N2氛围下加热至100℃并搅拌约8h。TLC点板监测反应已基本完成，将反应冷却至室温后，硅藻土过滤得到滤液并浓缩得到黑色黏稠物，通过快速制备过柱机纯化(10％的乙酸乙酯/石油醚)，得到2.87g的浅黄色中间体1-8，收率为80％。1H NMR(400MHz,DMSO)δ8.30(s,1H),7.89(d,J＝1.3Hz,1H),7.73(d,J＝8.0Hz,1H),7.64(q,J＝4.8Hz,1H),7.52(dd,J＝8.0,1.4Hz,1H),2.91(d,J＝4.7Hz,3H),1.32(s,12H)。
5-bromo-4-fluoropyridin-2-ol(1-10a)
将5-溴-4-氟吡啶-2-胺(1.0g,5mmol)在冰浴下分散于10ml的水中，再滴加2ml的浓硫酸，保持0℃搅拌10分钟。随后在0℃下逐滴滴加NaNO2水溶液(2M,3ml)，产生大量气泡。在5分钟内滴加完毕，随后让混合物自然升至室温，继续搅拌约5小时，形成黄褐色的浑浊液体。最后，过滤并水洗收集滤饼层，烘干得到约0.9g的棕色中间体1-10a，无需进一步纯化，收率为90％。1H NMR(400MHz,DMSO)δ7.91(d,J＝9.5Hz,1H),6.35(d,J＝11.5Hz,1H)。
5-bromo-4-fluoro-2-(3-(piperidin-1-yl)propoxy)pyridine(1-11a)
将中间体1-10a(0.40g,2mmol)、1-哌啶丙醇(0.45g,3mmol)和PPh3(0.82g,3mmol)溶于15ml的无水THF中，随后在0℃、N2气氛下，将DIAD(0.63g,3mol)缓慢加入到上述混合溶液中，保持0℃搅拌1小时。随后让上述反应液体自然升至室温，搅拌过夜。第二天TLC点板监测反应已完成，加入共60ml的乙酸乙酯/水(体积比1/1)混合液体，萃取三次合并有机相，无水硫酸钠干燥后浓缩，通过快速柱层析纯化得到0.39g的中间体1-11a。米黄色液体，收率为60％。1H NMR(400MHz,DMSO)δ9.42(d,J＝9.9Hz,1H),7.97(d,J＝10.1Hz,1H),5.30(t,J＝6.6Hz,2H),3.35(dt,J＝14.4,6.4Hz,6H),2.87(p,J＝6.8Hz,2H),2.50(p,J＝5.5Hz,4H),2.39(q,J＝6.2Hz,2H)。
1-(7-(4-fluoro-6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)quinoxalin-2-yl)-3-isopropyl-1-meth ylurea(A67)
将中间体1-11a(133mg,0.42mmol)、中间体1-12(100mg,0.35mmol)、PdCl2(dppf)(26mg,0.03mmol)和K2CO3(96mg,0.70mmol)置于25ml三颈瓶中，充分分散于14ml的1,4-二氧六环/水/乙醇(体积比为7/3/4)混合溶剂中。将反应液在N2气氛下加热至100℃，搅拌约5h。TLC点板监测原料基本反应完全，随后用硅藻土过滤得到滤液，减压浓缩即可得到黑色的粗产品。加入无水甲苯充分溶解上述黑色粗产品，在室温下滴加异丙基异氰酸酯(60mg,0.70mmol)，最后将反应混合物加热至100℃搅拌约5小时。通过快速柱层析(二氯甲烷/甲醇＝97/3)纯化，得到淡黄色的终产物A67。两步反应总收率为68％。1H NMR(400MHz,DMSO-d6)δ9.07(d,J＝1.4Hz,1H),8.48(dd,J＝11.1,1.6Hz,1H),8.27(d,J＝7.4Hz,1H),8.04(dd,J＝8.6,1.5Hz,1H),7.95(s,1H),7.79(dt,J＝8.6,1.8Hz,1H),6.89(dd,J＝11.9,1.7Hz,1H),4.35(t,J＝6.6Hz,2H),3.92(h,J＝6.7Hz,1H),3.48(s,3H),2.46–2.28(m,6H),1.90(p,J＝6.8Hz,2H),1.50(p,J＝5.4Hz,4H),1.37(t,J＝6.3Hz,2H),1.20(d,J＝6.6,6H).13C NMR(101MHz,DMSO-d6)δ168.10,165.10,164.98,156.78,155.26,150.90,149.07,141.83,139.27,136.84,133.83,128.69,127.73,126.42,97.66,97.45,65.02,54.98,53.95,42.40,32.68,25.82,25.40,23.29,22.51。
实施例68
5-bromo-6-fluoropyridin-2-amine(1-9b)
将6-氟吡啶-2-胺(6g,0.05mol)分散于100ml的乙腈中，在室温搅拌下缓慢加入N-溴代丁二酰亚胺(11.44g,0.06mol)得到黄色的浑浊液体，保持室温搅拌过夜。TLC点板监测反应已经完成，减压除去溶剂乙腈得到黄色固体，加入约200ml的水打浆，通过过滤、水洗和烘干得到9.81g黄色的中间体1-9b，无需纯化，收率为96％。1H NMR(400MHz,DMSO)δ7.65(dd,J＝9.6,8.5Hz,1H),6.56(s,2H),6.29(dd,J＝8.5,1.7Hz,1H)。
5-bromo-6-fluoropyridin-2-ol(1-10b)
中间体1-10b的合成方法与1-10a相同，用中间体1-9b替代5-溴-4-氟吡啶-2-胺即可。棕色固体，收率为95％。1H NMR(400MHz,DMSO)δ11.69(s,1H),7.99(ddd,J＝9.4,8.3,0.9Hz,1H),6.55(dd,J＝8.4,1.2Hz,1H)。
3-bromo-2-fluoro-6-(3-(piperidin-1-yl)propoxy)pyridine(1-11b)
中间体1-11b的合成方法与1-11a相同，用中间体1-10b替代中间体1-10a即可。米黄色液体，收率为62％。1H NMR(400MHz,DMSO)δ8.09(t,J＝8.9Hz,1H),6.74(d,J＝8.5Hz,1H),4.20(t,J＝6.6Hz,2H),2.31(dt,J＝14.2,6.3Hz,6H),1.83(p,J＝6.8Hz,2H),1.46(p,J＝5.6Hz,4H),1.35(d,J＝5.8Hz,2H)。
1-(7-(2-fluoro-6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)quinoxalin-2-yl)-3-isopropyl-1-meth ylurea(A68)
化合物A68的合成方法与A67相同，用中间体1-11b替代中间体1-11a即可。淡黄色固体，两步反应总收率为82％。1H NMR(400MHz,DMSO-d6)δ9.07(s,1H),8.23(dt,J＝10.4,5.6Hz,2H),8.04(d,J＝8.6Hz,1H),7.97(s,1H),7.82(d,J＝9.0Hz,1H),6.92(d,J＝8.3Hz,1H),4.32(t,J＝6.4Hz,2H),3.92(h,J＝6.7Hz,1H),3.48(s,3H),2.69(m,6H),2.11–1.97(m,2H),1.61(m,5.5Hz,4H),1.44(m,2H),1.20(d,J＝6.6Hz,6H).13C NMR(101MHz,DMSO-d6)δ161.89,159.09,155.31,150.96,144.16,141.89,139.31,136.73,135.22,128.62,127.59,126.26,108.29,108.24,64.89,54.24,53.20,42.39,32.75,32.72,24.23,22.51。
实施例69
3-bromo-2-fluoro-6-(3-(pyrrolidin-1-yl)propoxy)pyridine(1-11c)
中间体1-11c的合成方法与1-11a相同，用中间体1-10b替代中间体1-10a、1-吡咯烷丙醇替代1-哌啶丙醇即可。米黄色液体，收率为72％。1H NMR(400MHz,DMSO)δ8.08(t,J＝8.9Hz,1H),6.74(d,J＝8.5Hz,1H),4.22(t,J＝6.6Hz,2H),2.47(d,J＝7.1Hz,2H),2.40(dt,J＝6.3,3.1Hz,4H),1.86(p,J＝6.9Hz,2H),1.66(p,J＝3.1Hz,4H).
1-(7-(2-fluoro-6-(3-(pyrrolidin-1-yl)propoxy)pyridin-3-yl)quinoxalin-2-yl)-3-isopropyl-1-meth ylurea(A69)
化合物A69的合成方法与A67相同，用中间体1-11c替代中间体1-11a即可。淡黄色固体，两步反应总收率为64％。1H NMR(400MHz,DMSO-d6)δ9.07(s,1H),8.29–8.18(m,2H),8.04(d,J＝8.6Hz,1H),7.97(s,1H),7.86–7.79(m,1H),6.93(d,J＝8.3Hz,1H),4.35(t,J＝6.4Hz,2H),3.92(h,J＝6.7Hz,1H),3.48(s,3H),3.02(m,5H),2.09(t,J＝7.3Hz,2H),1.94–1.77(m,4H),1.20(d,J＝6.5Hz,6H).13C NMR(101MHz,DMSO-d6)δ161.76,161.62,159.07,156.68,155.31,150.96,144.21,144.17,141.91,139.31,136.73,135.22,128.63,127.55,126.26,108.31,64.43,53.31,51.50,42.42,32.74,25.85,22.80,22.51。
体外活性测试
体外活性测试所需的仪器和试剂分别见表2与表3。
表2实验仪器汇总
表3实验试剂汇总
生物实验方法
酶活性筛选实验
ATM、ATR以及其他激酶活性的抑制实验由Eurofins公司提供服务。将每种激酶与相应化合物(明确浓度)在指定的反应溶液中孵育(根据不同激酶的具体需要，pH、浓度不同)。通过添加Mg(n)/ATP混合物来引发反应。在室温下孵育一定时间后，通过添加浓度为0.5％的磷酸来终止反应。将10μL已终止的反应液点到P30滤垫上，并用0.425％磷酸液洗涤4次，每次4min，最后在甲醇中洗涤一次，随后进行干燥和闪烁计数。详细的实验操作可参考网站https://www.eurofinsdiscoveryservices.com。
体外人肝微粒体稳定性实验
在0℃时将1～2μL的待测化合物(浓度1μM)加入188μL的0.1M的PBS缓冲液充分混合均匀，再加入特定的NADPH体系(1mM NADP，5mM浓度为1U/mL的6-磷酸葡萄糖脱氢酶，12μL的浓度为3.3mM的MgCl2)共同孵育。在37℃水浴中预热5分钟后，加入5μL的人肝微粒体(蛋白质浓度：0.5mg/mL)，轻轻混匀继续在37℃水浴中孵育，随后分别在0，5，15，30，45和60分钟6个时间点采集样品并加入400μL含内标SAHA(浓度为20ng/mL)的冰乙腈溶液终止反应。将0分钟待测化合物的浓度定为默认为100％，用LC-MS/MS测定其他时间点化合物浓度并换算为相应的百分比剩余量。使用没有其他蛋白限制的肝脏模型计算预测清除率，将百分剩余量的自然对数值与孵育时间作线性回归线拟合，获得斜率k。待测化合物的体外半衰期T1/2＝-0.693/k；待测化合物的肝微粒体清除率CL(mL·min-1·mg-1)＝0.693/t(min)×V(mL)/M(mg)，V是相应孵育液的体积，M是肝微粒体质量。
表4本发明化合物对ATM的初筛活性、选择性及体外代谢稳定性
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体外酶水平筛选实验表明，本发明化合物对对ATM激酶有良好的抑制活性，且对ATM同家族的ATR激酶抑制活性很弱。
表5化合物对PI3K家族激酶的抑制活性
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体外酶水平筛选实验表明，化合物A10对PI3K家族激酶的抑制活性均较弱，而化合物A12、A15和A21对PI3K家族激酶存在一定的抑制活性，尤其对PI3Kδ的抑制活性明显。
表6化合物A46对癌症常见靶点的激酶选择性
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如表6所示，化合物A46在1μM浓度下仅对PIKK家族的ATM和DNA-PKcs抑制率超过50％，对ATR、mTOR和PI3K家族激酶及其部分突变影响很小。进一步地筛选了化合物A46对DNA-PKcs的IC50，结果表明A46对ATM的选择性倍数约为420倍。总的来说，化合物A46在常见的103种激酶中表现出对ATM的优异选择性。
HCT116细胞克隆形成实验
通过离心收集HCT116细胞，然后用DMED完全培养基再悬浮，并计数。将细胞置于24孔板中，密度为每孔400个细胞。将24孔板置于含5％CO2的培养箱中，并在37℃下培养三天。将预设浓度的化合物与HCT116细胞共同孵育1小时，然后以2Gy照射药物处理的细胞。照射后，将细胞置于培养箱中一周。一周后，除去细胞上清液并用PBS洗涤两次，然后缓慢加入甲醇并在室温下固定20分钟。除去甲醇后，向染料中加入结晶紫染色20min，然后用PBS将其洗掉。随后使用化学发光成像系统拍摄每个孔板的照片，并使用Image J分析克隆实验结果进行定量分析，最终用于计算相应的抑制率和IC50值。
表7化合物对HCT116细胞克隆形成的抑制活性
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表7表明，本发明化合物对辐照诱导的HCT116细胞克隆形成存在明显的抑制效果。
蛋白印迹分析实验
HCT116细胞以每孔3×104个细胞的密度接种在6孔板中。化合物处理后4小时收集MCF-7细胞，并在含有10mM苯基甲磺酰氟(PMSF)的RIPA裂解缓冲液中裂解。在SDS-PAGE电泳仪上分离等量的总蛋白裂解物并转移到PVDF膜上，随后用5％脱脂奶粉封闭2小时，分别加入相应的磷酸化一抗。然后将印迹用PBST缓冲液洗涤三次，并与山羊抗兔IgG HRP标记的二级抗体(1：5000稀释；Earthox)孵育1小时。TBS-T洗涤三次后，用Super ECL Plus超敏发光液浸润后通过化学发光显影仪观察蛋白印迹。
结果见图1，实验表明，优选化合物A46呈浓度依赖性的抑制了伊立替康诱导的ATM信号通路的激活。
Balb/C小鼠体内药代动力学性质研究
称取定量的待测化合物，加2％乙醇，用注射用氯化钠溶液稀释配成1mg·mL-1的溶液待给药。6只雄性Balb/C小鼠(成都达硕实验动物有限公司，许可证号SCXK(川)2019-030)，分别按10mg·kg-1静脉给药、10mg·kg-1口服给药。给药前0min和给药后5min、15min、30min、1h、2h、4h、6h、8h、10h和24h通过心脏穿刺从每只动物身上采集血样约0.2ml并保存在冰箱中(0-4℃)。通过离心(3500rpm，15℃下15分钟)从血液中分离血浆，并将其储存在-40℃的冰箱中。通过LC-MS/MS(岛津UFLC系统；AB Science Qtrap 5500)对所有样品进行测试化合物分析。随后，另配标准浓度的待测化合物溶液，建立其在血浆中的标准曲线。最后整理数据，使用DAS 2.0软件分析药代动力学参数。
表8化合物A46在Balb/c小鼠体内的药代动力学性质
表8的实验结果表明，A46具有较低的血浆清除率、较高的血浆暴露量和最高血浆浓度、合适的半衰期以及优异的口服生物利用度(F＝107.10％)，是一个具有良好药物代谢动力学参数的、适合口服的小分子抑制剂。
SW620裸鼠异种移植模型
本发明使用来自北京华福康生物科学有限公司的6周龄BALB/c裸鼠。收集SW620细胞，用无血清培养基冲洗两次，重新悬浮，并将其通过皮下注射到小鼠右侧腋窝区域(约1×107细胞，总体积0.1mL)。当每只裸鼠的肿瘤体积为100-150mm3时，将动物随机分为不同的治疗组和对照组(5只/组)。给药组伊立替康(40mg/kg)周一给药一次，每周一次；ATM抑制剂每周二、周三、周四同一时间给药一次(20或40mg/kg)，每周三次；周四至周天不给药。监测所有动物的活动、身体状况、体重和肿瘤生长，每三天通过游标卡尺测量肿瘤块的两个垂直直径来计算肿瘤大小。肿瘤体积(单位：mm3)通过公式(a×b2)/2计算，其中“a”是长直径，“b”是短直径(单位：mm)。三周时间结束后，处死小鼠并收集肿瘤组织。本文的动物研究是按照有关实验动物的护理和使用的机构指南进行的。
体内实验的给药方案与药效总结见表9及图2。伊立替康(40mg/kg)单用，约在四天后，肿瘤生长体积开始受到抑制，给药3周后肿瘤重量生长抑制率(TGI)达到69.21％。A46联用伊立替康组3周后同样对肿瘤体积和肿瘤重量有明显抑制，同时A46高剂量组的疗效更明显(A46剂量为20mg/kg时TGI＝77.15％，A46剂量为40mg/kg时，TGI＝85.35％)；高剂量联用组与伊立替康单用组相比有显著性差异(P<0.01)，表明A46在SW620模型上确实有联用协同的抗肿瘤效果；A46两个联用组中，小鼠耐受性良好，无死亡现象，体重下降率不超过12％。AZD0156(20mg/kg)和AZ31(40mg/kg)与伊立替康联用组作为阳性对照，其中AZD0156联用组小鼠体重下降显著，在第八天仅剩一只存活，尽管其肿瘤重量抑制十分显著(TGI＝95.37％)，但数据样本太少而缺乏统计学意义，这一类似状况也有文献报道过(Dou X,SunX,Huang H,et al.Discovery of novel ataxia telangiectasia mutated(ATM)kinasemodulators:Computational simulation,biological evaluation and cancercombinational chemotherapy study[J].European Journal of Medicinal Chemistry,2022,233:114196.)；AZ31联用组小鼠在第11天死亡一只，体重下降率不超过12％，小鼠有一定的耐受性，肿瘤重量生长抑制率与A46低剂量联用组类似(TGI＝77.70％)。总的来说，化合物A46单用和联用组在小鼠体内耐受性较好，同时高剂量联用组在SW620模型中展现更明显的协同抗肿瘤疗效。
表9化合物A46体内给药方案及药效总结
p.o.：口服给药；QD：每周一次；3W：给药共计三周时间；TIW：每周三次，周一Iri(伊立替康)给药后，周二至周四同一时间化合物给药，周五至周天不给药，循环三周结束实验。
Claims (9)
1.式Ⅰ所示化合物或其药学上可接受的盐，其特征在于：结构如下所示：
其中，
R1选自H、甲基；
R2选自C1～C4烷基、C3～C4烯烷基、取代或未取代的3～6元环烷基、取代或未取代的苯基、取代或未取代的R2中，所述取代的3～6元环烷基的取代基、取代的苯基的取代基、取代或未取代的/>的取代基，独立地选自甲基、氟代甲基、甲氧基、氟代甲氧基、氟、氯、溴；
X选自O、S；
L选自-(CH2)n-、-(CH2)mCHCH3-、-CHCH3(CH2)o-；n选自0～4的整数；m、o独立地选自0或1；
R3选自异丙基、甲氧基、-N(CH3)2、-N(CH2CH3)2、
环A选自
R4、R5、R6独立地选自H、C1～C4烷基、C1～C4氟代烷基、氟、氯、溴、氰基。
2.根据权利要求1所述的化合物，其特征在于：
R2选自甲基、乙基、正丙基、异丙基、正丁基、叔丁基、烯丙基、环丙基、环戊基、环己基、
3.根据权利要求1所述的化合物，其特征在于：
R4、R5、R6独立地选自H、甲基、三氟甲基、氟、氰基。
4.根据权利要求1～3任一项所述的化合物，其特征在于：结构式如下：
5.药物组合物，由权利要求1～4任一项所述化合物及其药学上可接受的盐为活性成分，添加药学上可接受的辅助性成分组成。
6.权利要求1～4任一项所述化合物及其药学上可接受的盐、权利要求5所述的药物组合物在制备治疗和/或预防ATM相关疾病的药物中的用途；所述ATM相关疾病为实体瘤。
7.根据权利要求6所述的用途，其特征在于：所述实体瘤包括：结直肠癌、肺癌、乳腺癌、头颈癌、前列腺癌、淋巴瘤、卵巢癌、肾细胞癌、食管癌，白血病、膀胱癌、胃癌、黑色素瘤、尿路上皮癌、脑肿瘤、肝癌、间皮瘤或肝内胆管癌。
8.权利要求1～4任一项所述化合物及其药学上可接受的盐、权利要求5所述的药物组合物联合化疗药物或DDR靶点抑制剂在制备治疗和/或预防ATM相关疾病的药物中的用途；所述化疗药物包括伊立替康或依托泊苷；所述DDR靶点抑制剂为奥拉帕尼；所述ATM相关疾病为实体瘤。
9.根据权利要求8所述的用途，其特征在于：所述实体瘤包括：结直肠癌、肺癌、乳腺癌、头颈癌、前列腺癌、淋巴瘤、卵巢癌、肾细胞癌、食管癌，白血病、膀胱癌、胃癌、黑色素瘤、尿路上皮癌、脑肿瘤、肝癌、间皮瘤或肝内胆管癌。
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