CN106748892A - 靶向自噬激动剂及其在神经退行性疾病治疗药物中的应用 - Google Patents

靶向自噬激动剂及其在神经退行性疾病治疗药物中的应用 Download PDF

Info

Publication number
CN106748892A
CN106748892A CN201710038351.5A CN201710038351A CN106748892A CN 106748892 A CN106748892 A CN 106748892A CN 201710038351 A CN201710038351 A CN 201710038351A CN 106748892 A CN106748892 A CN 106748892A
Authority
CN
China
Prior art keywords
alkyl
alkoxy
halogen
compound
hydrogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201710038351.5A
Other languages
English (en)
Other versions
CN106748892B (zh
Inventor
欧阳亮
刘博�
张岚
符雷蕾
魏于全
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sichuan University
Original Assignee
Sichuan University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sichuan University filed Critical Sichuan University
Priority to CN201710038351.5A priority Critical patent/CN106748892B/zh
Publication of CN106748892A publication Critical patent/CN106748892A/zh
Priority to PCT/CN2018/072575 priority patent/WO2018133756A1/zh
Application granted granted Critical
Publication of CN106748892B publication Critical patent/CN106748892B/zh
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/30—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by halogen atoms, or by nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/32—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms
    • C07C275/34—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C335/04—Derivatives of thiourea
    • C07C335/16—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton

Abstract

本发明涉及靶向自噬激动剂及其在神经退行性疾病治疗药物中的应用，属于抗神经退行性疾病药学技术领域。本发明解决的技术问题是提供一种作为ULK1激动剂的化合物。该化合物包括如下所示的化合物或其药学上可接受的盐。本发明的化合物或其药学上可接受的盐，可以作为ULK1激动剂，具有一定的抗神经退行性疾病活性。

Description

靶向自噬激动剂及其在神经退行性疾病治疗药物中的应用
技术领域
本发明涉及靶向自噬激动剂及其在神经退行性疾病治疗药物中的应用，属于神经退行性疾病治疗药物发现技术领域。
背景技术
神经退行性疾病(Neurodegenerative disease)是一大脑和脊髓的细胞神经元丧失的疾病状态。典型的神经退行性疾病包括阿尔茨海默病，帕金森病和亨廷顿病等，是中老年人常见的神经系统变性疾病，也是中老年人最常见的锥体外系疾病。目前，以帕金森病为例，我国的患者已逾百万，65岁以上人群患病率为1000/10万，随年龄增高，男性稍多于女性，预计到2030年，我国的患者人数将近500万。该病的主要临床特点：静止性震颤、动作迟缓及减少、肌张力增高、姿势不稳等为主要特征。目前，药物替代治疗仍是现在治疗的主要方法，临床上采用左旋多巴替代治疗，虽然能够缓解大多患者的运动症状，但是不能阻止多巴胺能神经元进行性调亡、坏死，长期使用还存在疗效递减和产生运动障碍等副作用的发生因此，阐明的发病机制以及寻找有效的干预紀点从而研发出早期干预、治疗的药物来延缓的发展具有重要的临床价值和社会意义。
神经退行性疾病临床上主要表现为运动性症状，包括静止性震颤、运动迟缓、肌肉强直和姿势步态异常等，另外，还有一些非运动性的症状，例如便秘，嗅觉失常，抑郁症等。其中以帕金森病为例，黑质多巴胺能神经元变性缺失和路易小体形成为主要病理特征，其中α-突触核蛋白是路易小体的主要成分，也是帕金森病的主要标志物之一。目前研究表明自噬能够有效的促进细胞中已聚集蛋白的清除，因此通过激活自噬可能是一种有潜力的帕金森治疗策略。因此，在帕金森治疗中能够被小分子靶向激活自噬的调控子的发现显得极为迫切。UKL1作为自噬的启动子，显然是一个潜在的靶点。到目前为止还没有任何ULK1的小分子激动剂被发现。
发明内容
本发明解决的技术问题是提供一种作为ULK1激动剂的新化合物。
本发明提供结构式如式Ⅰ或式Ⅱ所示的化合物或其药学上可接受的盐：
其中，R1为R11为氢、烷基、烷氧基或卤素；m为1或2；R2为R21为氢、烷基、烷氧基、卤代烷基或卤素；n为1或2；X为O或S。
本发明还提供上述化合物或其药学上可接受的盐在制备神经退行性疾病治疗药物中的用途
进一步的，所述神经退行性疾病治疗药物优选为抗帕金森药物。
进一步的，所述抗帕金森药物优选为ULK1激动剂类药物，其用途为用于帕金森疾病相关治疗。
本发明还提供一种药物组合物，它是包含有效剂量的上述化合物或其药学上可接受的盐的制剂。
本发明制备的化合物或其药学上可接受的盐，可以作为ULK1激动剂，具有较明显的帕金森治疗效果。
附图说明
图1A为SH-SY5Y细胞用5μM BL-918处理24小时，透射电子显微镜检测自噬小体的图片。
图1B为SH-SY5Y细胞用5μM BL-918处理，检测ULK1,p-ULK1,mAtg13,p-mAtg13,FIP200,Atg101,LC3,Beclin-1和SQSTM1/p62的表达情况。
图1C为ULK复合体的免疫共沉淀图。
图1D为SH-SY5Y细胞转染GFP-LC3和用siRNA-NC或siRNA-ULK1处理后，再用5μMBL-918孵育24小时，使用荧光显微镜观察GFP-LC3的表达图。
图1E为SH-SY5Y细胞转染siRNA-NC或siRNA-ULK1,用5μM BL-918孵育24小时，检测ULK1,p-ULK1,mAtg13,p-mAtg13,FIP200,Atg101,LC3,Beclin-1and SQSTM1/p62的表达水平。
图2A为通过MTT细胞存活实验检测BL-918对MPP+损伤细胞的保护作用图。
图2B为用si-ULK1处理细胞，可以逆转BL-918的保护作用，MTT法测定细胞存活率。
图3A为大鼠游泳和爬杆试验时间的行为学实验。
图3B为大鼠纹状体中多巴胺含量测定。
图3C为神经元中酪氨酸羟化酶的免疫荧光实验。
具体实施方式
本发明提供如式Ⅰ或式Ⅱ所示的化合物：
其中，R1为R11为氢、烷基、烷氧基或卤素；m为1或2；表示苯环上有m个取代基，取代基的位置不限，可以为邻位、间位或者对位；
R2为R21为氢、烷基、烷氧基、卤代烷基或卤素；n为1或2；
X为O或S。
本发明的化学结构通式对手性结构没有要求，可以为R型也可以为S型。优选如式Ⅰ所示的结构，即化学通式为
作为一个优选方案，X为O，R1为R11为氢、烷基、烷氧基或卤素；m为1或2；R2为R21为氢、烷基、烷氧基、卤代烷基或卤素；n为1或2。
进一步优选的，X为O，R1为R11为烷基、烷氧基或卤素；m为1或2；R2为R21为氢、烷基、烷氧基、卤代烷基或卤素；n为1或2。优选的，X为O，R1为R11为烷基、烷氧基或卤素；R2为 R21为氢、C1-C3烷基、烷氧基、卤代C1-C3烷基或卤素。优选的，X为O，R1为R2为 更优选的，X为O，R1为R2为
进一步优选的，X为O，R1为R11为氢、烷基、烷氧基或卤素；m为1或2；R2为R21为氢、烷基、烷氧基、卤代烷基或卤素；n为1或2。优选的，X为O，R1为R11为氢、烷基、烷氧基或卤素；R2为 R21为氢、C1-C3烷基、烷氧基、卤代C1-C3烷基或卤素。更优选的，X为O，R1为R2为 更优选的，X为O，R1为R2为
进一步优选的，X为O，R1为R11为氢、烷基、烷氧基或卤素；m为1或2；R2为R21为氢、烷基、烷氧基、卤代烷基或卤素；n为1或2。优选的，X为O，R1为R111为烷基或烷氧基；R112为烷基或烷氧基；R2为 更优选的，X为O，R1为R2为
作为另一个优选方案，X为S；R1为R11为氢、烷基、烷氧基或卤素；m为1或2；R2为R21为氢、烷基、烷氧基、卤代烷基或卤素；n为1或2。
进一步优选的，X为S，R1为R11为烷基、烷氧基或卤素；m为1或2；R2为R21为氢、烷基、烷氧基、卤代烷基或卤素；n为1或2。优选的，X为S，R1为R11为烷基、烷氧基或卤素；R2为 R21为氢、C1-C3烷基、烷氧基、卤代C1-C3烷基或卤素。更优选的，X为S，R1为R2为 更优选的，X为S，R1为R2为
进一步优选的，X为S，R1为R11为氢、烷基、烷氧基或卤素；m为1或2；R2为R21为氢、烷基、烷氧基、卤代烷基或卤素；n为1或2。优选的，X为S，R1为R11为氢、烷基、烷氧基或卤素；R2为 R21为氢、C1-C3烷基、烷氧基、卤代C1-C3烷基或卤素。更优选的，X为S，R1为R2为 更优选的，X为S，R1为R2为
进一步优选的，X为S，R1为R11为氢、烷基、烷氧基或卤素；m为1或2；R2为R21为氢、烷基、烷氧基、卤代烷基或卤素；n为1或2。优选的，X为S，R1为R111为烷基或烷氧基；R112为烷基或烷氧基；R2为 更优选的，X为S，R1为R2为
下面是本发明的化合物的一些优选结构。
本发明还提供本发明所述的化合物的药学上可接受的盐。所述盐可以为硝酸盐、盐酸盐、硫酸盐或磷酸盐等。
本发明还提供上述化合物或其药学上可接受的盐在制备治疗神经退行性疾病药物中的用途。进一步的，神经退行性疾病优选为帕金森疾病，治疗神经退行性疾病药物为抗帕金森药物。进一步的，所述抗帕金森药物优选为ULK1激动剂类药物，用于帕金森疾病的相关治疗。
本发明还提供一种药物组合物，它是包含有效剂量的上述化合物或其药学上可接受的盐的制剂。可以通过本领域已知的方法可将本发明化合物制成以下形式：片剂、胶囊剂、水性或油性溶液剂、混悬剂、乳剂、乳膏剂、软膏剂、凝胶剂、喷鼻剂、栓剂、用于吸入的细小分散的粉剂或气雾剂或喷雾剂、用于胃肠道外(包括静脉内、肌内或输注)的无菌水性或油性溶液或混悬剂或无菌乳剂。可采用无菌水或水-丙二醇溶液作为溶剂来制备液体制剂，还可将活性组分配制在聚乙二醇水溶液中。用于口服给予的水性溶液可通过将活性组分溶解在水中并按需要加入合适的着色剂、矫味剂、稳定剂和增稠剂来制备。口服使用的水性混悬剂可通过将细小分散的活性组分与粘性物质一道分散在水中，所述粘性物质如为天然合成胶、树脂、甲基纤维素、羧甲基纤维素和其他药剂领域已知的悬浮剂。
药物组合物可为单位剂量形式。在这些形式中，将所述组合物分成含适量活性组分的单位剂量。该单位剂量形式可为包装制剂，包装中包括分隔量的制剂，例如盒装片剂、胶囊剂和在管形瓶或安瓿中的粉剂。单位剂量形式还可为胶囊剂、扁囊剂或片剂或其可为适当数量的任何这些包装形式。
本发明的药物组合物，其活性成分可仅为本发明的化合物，也可与其他抗帕金森化合物组合作为活性成分。
在治疗帕金森的过程中，可采用本发明的药物组合物与其他抗帕金森药进行联合治疗。
在治疗帕金森时，可通过同时、序贯或单独给予各种治疗成分可实现这种联合治疗。此类组合产品应用有效剂量范围内的本发明化合物和准许剂量范围内的其他药学活性剂。
下面结合实施例对本发明的具体实施方式做进一步的描述，并不因此将本发明限制在所述的实施例范围之中。
实施例1化合物1～45的合成
化合物1～12采用如下反应式合成：
Scheme3Reagents and conditions：(a)MeOH，1N NaOH；HCI pH＝3；(b)N-Methylmorpholine，iso-butylchloroformate，THF，-20℃，R1NH2；(c)HCI/MeOH，r.t.；(d)CH2Cl2，TEA，R2NCO or R2NCS，r.t.
中间体3制备
将原料2溶于10ml甲醇中，然后缓慢加入20ml 1N NaOH的水溶液和(Boc)2O(2.18g，10mmol)。室温反应2小时后，用1N HCl溶液调节pH＝4-5。随后用氯仿萃取(3x30ml)，合并有机相，无水硫酸镁干燥得到粗产物。粗产物用硅胶色谱柱纯化，CH2Cl2/MeOH(10：1)作为流动相得到中间体5(955mg，76％)，为白色固体。1H-NMR(400MHz，CDCl3)，δ(ppm)：12.76(1H，s)，7.56(1H，d，J＝8.3Hz)，7.41-7.29(6H，m)，5.10(1H，d，J＝8.3Hz)，1.38(9H，s)。
中间体4a-e合成通法
在-20℃将中间体3(1mol)溶于100ml四氢呋喃中，加入氮甲基吗啉(1mol)和氯甲酰异丁酯(1mol)保温反应半小时后，将苯胺衍生物(1.2mol)缓慢加入反应液中，保温反应2小时后，取100ml 5％的碳酸氢钠水溶液猝灭反应。室温搅拌半小时后，用二氯甲烷萃取(3×50ml)，合并有机相然后用5％的碳酸氢钠水溶液，稀盐酸，水，饱和食盐水洗涤，最后无水硫酸钠干燥。减压浓缩后用，硅胶柱层析纯化，CH2Cl2/MeOH(8：1)作为流动相得到中间体4a-4e，白色固体收率(70-90％)。
中间体(4a)1H-NMR(400MHz,CDCl3),δ(ppm):7.33-7.30(5H,m),7.18-7.03(3H,m),7.03-7.01(2H,m),5.20(1H,m),5.08(1H,m),1.45(3H,d,J＝6.7Hz),1.40(9H,s)；
中间体(4b)1H-NMR(400MHz,CDCl3),δ(ppm):8.16(1H,m),7.81(1H,s),7.40(5H,m),6.81(2H,m),5.67(1H,s),1.43(9H,s)；
中间体(4c)1H-NMR(400MHz,CDCl3),δ(ppm):7.74(1H,d,J＝7.8Hz),7.46-7.35(6H,m),7.18(1H,t,J＝7.2Hz),7.12(1H,d,J＝7.2Hz),7.05(1H,t,J＝7.2Hz),5.87(1H,s),2.01(3H,s),1.43(9H,s)
中间体(4d)1H-NMR(400MHz,CDCl3),δ(ppm):8.42(1H,br s),7.65(1H,d,J＝8.0Hz),7.46(2H,d,J＝7.0Hz),7.37-7.26(4H,m),7.16(1H,t,J＝7.0Hz),7.06(1H,dd,J＝7.8,7.6Hz),5.84(1H,s),1.44(9H,s)；
中间体(4e)1H-NMR(400MHz,CDCl3),δ(ppm):7.33-7.27(5H,m),6.71(1H,d,J＝8.0Hz),6.60(1H,d,J＝1.9Hz),6.50(1H,dd,J＝8.1,1.8Hz),5.79(2H,br s),5.05(1H,brs),3.85(3H,s),3.80(3H,s),3.53(1H,m),3.42(1H,m),2.68(2H,m),1.40(9H,s)；
中间体5a-e合成通法
取5倍量的乙酰氯在零摄氏度下缓慢滴加到110ml甲醇中，并搅拌30min。将中间体4(1eq)缓慢加入反应液中，升至室温后继续反应6-8小时。减压蒸出溶剂，得油状粗品，加入50ml水并用1N NaOH的水溶液体调节pH＝12，并用乙酸乙萃取，合并有机相，无水硫酸钠干燥，减压蒸干溶剂得产物不经纯化直接进行下一步。
中间体(5a)1H-NMR(400MHz,CDCl3),δ(ppm):7.42-7.25(11H,m),5.10(1H,m),4.50(1H,s),1.46(3H,d,J＝6.7Hz)；
中间体(5b)1H-NMR(400MHz,CDCl3),δ(ppm):9.68(1H,s),8.30(1H,m),7.45-7.30(5H,m),6.90-6.81 (2H,m),4.67(1H,s)
中间体(5c)1H-NMR(400MHz,CDCl3),δ(ppm):9.36(1H,s),8.06(1H,d,J＝8.0Hz),7.47(2H,d,J＝8.1Hz),7.40-7.28(3H,m),7.18(2H,m),7.03(1H,td,J＝7.5,1.0Hz),4.69(1H,s),2.27(3H,s),1.94(2H,s)
中间体(5d)1H-NMR(400MHz,CDCl3),δ(ppm):9.49(1H,s),7.86(1H,t,J＝1.9Hz),7.51(1H,ddd,J＝8.0,1.9,1.1Hz),7.41(2H,d,J＝8.0Hz),7.38-7.31(3H,m),7.22(1H,ddd,J＝8.0,1.7,1.2Hz),7.16(1H,t,J＝8.0Hz),4.62(1H,s),1.89(2H,s)
中间体(5e)1H-NMR(400MHz,CDCl3),δ(ppm):7.32-7.28(5H,m),7.08(1H,br s),6.78(1H,d,J＝8.1Hz),6.69-6.65(2H,m),4.48(1H,s),3.86(3H,s),3.83(3H,s),3.51(2H,m),2.75(2H,t,J＝7.1Hz),1.78(4H,s)；
化合物1-45合成通法
取1倍量的中间体5，和1.5倍量的三乙胺在零摄氏度溶于10ml，再缓慢滴加异氰酸酯或异硫氰酸酯，室温反应2小时，过滤并用甲醇洗涤得到产物白色固体，收率60-80％。以下为化合物1-45的核磁检测结果。
化合物1 1H-NMR(400MHz,DMSO-d6),δ(ppm):8.85(1H,d,J＝8.0Hz),8.64(1H,s),7.40(2H,d,J＝7.8Hz),7.33-7.29(2H,m),7.27-7.24(3H,m),7.18-7.14(3H,m),7.10(2H,dd,J＝7.3,1.0Hz),6.92(1H,d,J＝8.1Hz),6.81(1H,d,J＝7.0Hz),5.46(1H,d,J＝8.1Hz),4.92(1H,m),3.68(3H,s),1.39(3H,d,J＝7.0Hz)；13C-NMR(100MHz,DMSO-d6),δ(ppm):169.8,154.8,154.5,144.6,140.5,133.8,128.7,128.7,128.6,128.6,127.8,127.0,127.0,126.1,126.1,119.6,119.6,114.4,114.4,56.7,55.6,48.3,23.2.HRMS(ESI)+calculated for C24H25N3O3,[M+H]+:m/z 404.1974,found 404.1976.
化合物2 1H-NMR(400MHz,DMSO-d6),δ(ppm):8.85(1H,d,J＝8.0Hz),8.48(1H,s),8.12(1H,dd,J＝8.3,1.5Hz),8.02(2H,d,J＝8.1Hz),7.42(2H,d,J＝7.1Hz),7.39(1H,dd,J＝8.0,1.5Hz),7.33(2H,t,J＝7.0Hz),7.28(1H,dt,J＝7.2,1.2Hz),7.23(1H,m),7.21-7.14(3H,m),7.10(2H,dd,J＝7.3,1.0Hz),6.95(1H,td,J＝7.9,1.5Hz),5.50(1H,d,J＝8.1Hz),4.93(1H,m),1.39(3H,d,J＝7.0Hz)；13C-NMR(100MHz,DMSO-d6),δ(ppm):169.6,154.5,144.7,140.1,137.1,129.6,128.7,128.7,128.6,128.6,127.9,127.8,127.2,127.2,127.0,126.1,126.1,123.0,121.7,57.0,48.3,23.2.HRMS(ESI)+calculated forC23H22ClN3O2,[M+H]+:m/z 408.1479,found 408.1473.
化合物3 1H-NMR(400MHz,DMSO-d6),δ(ppm):9.07(1H,s),8.87(1H,d,J＝8.0Hz),7.65(1H,t,J＝2.0Hz),7.40(2H,d,J＝7.7Hz),7.32(2H,d,J＝6.9Hz),7.27(1H,dt,J＝7.2,1.4Hz),7.23(1H,d,J＝8.1Hz),7.20-7.11(5H,m),7.08-7.06(2H,m),6.94(1H,ddd,J＝7.8,2.0,1.0Hz),5.45(1H,d,J＝8.0Hz),4.93(1H,m),1.39(3H,d,J＝7.1Hz)；13C-NMR(100MHz,DMSO-d6),δ(ppm):169.5,154.4,144.6,142.2,140.2,133.7,128.7,128.7,128.6,128.6,127.9,127.0,127.0,126.1,126.1,121.3,117.3,116.4,56.7,48.3,23.1.HRMS(ESI)+calculated for C23H22ClN3O2,[M+H]+:m/z 408.1479,found 408.1473.
化合物4 1H-NMR(400MHz,DMSO-d6),δ(ppm):8.85(1H,d,J＝8.0Hz),8.72(1H,s),7.40(2H,d,J＝7.8,Hz),7.32(2H,t,J＝8.5Hz),7.25(3H,m),7.17-7.14(3H,m),7.10(2H,dd,J＝7.3,1.0Hz),7.00(3H,m),5.46(1H,d,J＝8.1Hz),4.92(1H,m),1.39(3H,d,J＝7.0Hz)；13C-NMR(100MHz,DMSO-d6),δ(ppm):169.7,154.7,144.6,140.5,138.1,130.4,129.6,129.6,128.7,128.7,128.6,128.6,127.8,127.1,127.1,127.0,126.0,126.0,118.0,56.6,48.3,23.2,20.8.HRMS(ESI)+calculated for C24H25N3O2,[M+H]+:m/z388.2025,found 388.2022.
化合物5 1H-NMR(400MHz,DMSO-d6),δ(ppm):8.83(1H,d,J＝8.0Hz),7.88(1H,s),7.41(2H,d,J＝7.3Hz),7.31(2H,t,J＝7.1Hz),7.26-7.14(4H,m),7.10(2H,dd,J＝7.3,1.0Hz),7.00(3H,m),5.45(1H,d,J＝8.1Hz),4.93(1H,m),2.13(6H,s),1.39(3H,d,J＝7.0Hz)；13C-NMR(100MHz,DMSO-d6),δ(ppm):169.9, 155.4,144.7,140.8,136.3,135.7,128.6,128.6,128.5,128.5,128.1,127.7,127.0,126.8,126.8,126.1,126.1,57.1,48.3,23.2,18.7,18.7.HRMS(ESI)+calculated for C25H27N3O2,[M+H]+:m/z 402.2182,found402.2180.
化合物6 1H-NMR(400MHz,DMSO-d6),δ(ppm):9.26(1H,s),8.88(1H,d,J＝8.0Hz),7.57(4H,s),7.41(2H,d,J＝7.1Hz),7.33(2H,t,J＝7.1Hz),7.27(1H,m),7.17(4H,m),7.10(2H,dd,J＝7.3,1.0Hz),5.48(1H,d,J＝8.1Hz),4.93(1H,m),1.39(3H,d,J＝7.0Hz)；13C-NMR(100MHz,DMSO-d6),δ(ppm):169.5,154.3,144.6,144.3,140.2,128.7,128.7,128.6,128.6,127.9,127.0,126.5,126.0,126.0,123.7,121.8,121.5,117.6,56.6,48.3,23.2.HRMS(ESI)+calculated for C24H22F3N3O2,[M+H]+:m/z 442.1742,found442.1742.
化合物7 1H-NMR(400MHz,DMSO-d6),δ(ppm):8.92(2H,s),8.19-7.12(18H,m),5.56(1H,d,J＝6.8Hz),4.96(1H,m),1.41(3H,d,J＝7.0Hz)；13C-NMR(100MHz,DMSO-d6),δ(ppm):169.7,155.0,144.7,140.53,135.4,134.2,128.8,128.7,128.7,128.6,128.6,127.9,127.1,127.1,127.0,126.4,126.2,126.1,126.1,125.9,125.6,122.4,121.7,116.3,56.9,48.3,23.2.HRMS(ESI)+calculated for C27H25N3O2,[M+H]+:m/z424.2025,found 424.2027.
化合物8 1H-NMR(400MHz,DMSO-d6),δ(ppm):10.00(1H,s),8.98(1H,d,J＝8.0Hz),8.36(1H,d,J＝7.8Hz),7.55(2H,d,J＝7.6Hz),7.42(2H,d,J＝7.1Hz),7.34-7.26(5H,m),7.17-7.04(6H,m),6.12(1H,d,J＝7.6Hz),4.93(1H,m),1.39(3H,d,J＝7.0Hz)；13C-NMR(100MHz,DMSO-d6),δ(ppm):179.9,169.1,144.5,139.9,139.7,128.9,128.9,128.7,128.7,128.5,128.5,127.9,127.4,127.4,127.0,126.0,126.0,124.6,123.1,123.1,60.4,55.4,48.4,23.2.HRMS(ESI)+calculated for C23H23N3OS,[M+H]+:m/z 390.1640,found390.1646.
化合物9 1H-NMR(4e00MHz,DMSO-d6),δ(ppm):10.59(1H,s),9.02(1H,d,J＝8.0Hz),8.79(1H,d,J＝7.6Hz),8.35(2H,s),7.75(1H,s),7.45(2H,d,J＝7.8Hz),7.36-7.28(4H,m),7.18-7.14(3H,m),7.10(2H,dd,J＝7.3,1.0Hz),6.09(1H,d,J＝7.6Hz),4.95(1H,m),1.39(3H,d,J＝7.0Hz)；13C-NMR(100MHz,DMSO-d6),δ(ppm):179.9,168.7,144.5,142.2,139.1,131.1,130.7,128.9,128.9,128.7,128.7,128.1,127.4,127.4,127.1,126.6,126.0,126.0,125.0,122.1,116.8,60.5,48.4,23.2.HRMS(ESI)+calculated forC25H21F6N3OS,[M+H]+:m/z 526.1388,found 526.1380.
化合物10 1H-NMR(400MHz,DMSO-d6),δ(ppm):10.26(1H,s),8.58(1H,s),7.74(1H,dd,J＝8.9,8.8Hz),7.51(2H,d,J＝8.0Hz),7.40(2H,t,J＝7.2Hz),7.26-7.34(4H,m),7.05(1H,t,J＝8.4Hz),7.00(1H,d,J＝8.2Hz),6.82(2H,d,J＝8.9Hz),5.69(1H,d,J＝8.0Hz),3.69(3H,s)；13C-NMR(100MHz,DMSO-d6),δ(ppm):170.4,159.3,154.9,154.8,154.5,139.7,133.7,129.0,129.0,128.2,127.3,127.3,126.4,122.6,119.7,119.7,114.4,114.4,111.6,104.7,56.9,55.6.HRMS(ESI)+calculated for C22H19F2N3O3,[M+H]+:m/z412.1473,found 412.1479.
化合物11 1H-NMR(400MHz,DMSO-d6),δ(ppm):10.26(1H,s),8.45(1H,s),8.15(1H,dd,J＝8.4,1.5Hz),8.06(1H,d,J＝7.8Hz),7.75(1H,m),7.54(2H,dd,J＝8.5,1.2Hz),7.41(3H,t,J＝7.5Hz),7.36-7.29(2H,m),7.23(1H,td,J＝7.8,1.4Hz),7.06(1H,t,J＝8.5Hz),6.95(1H,td,J＝7.8,1.5Hz),5.72(1H,d,J＝7.8Hz)；13C-NMR(100MHz,DMSO-d6),δ(ppm):170.2,159.4,154.9,154.5,139.2,136.9,129.6,129.0,129.0,128.3,127.9,127.5,127.5,126.3,123.1,122.5,121.6,111.6,104.7,57.2.HRMS(ESI)+calculated forC21H16ClF2N3O2,[M+H]+:m/z 416.0977,found 416.0975.
化合物12 1H-NMR(400MHz,DMSO-d6),δ(ppm):10.29(1H,s),8.99(1H,s),7.74(1H,m),7.66(1H,d,J＝1.9Hz),7.52(2H,dd,J＝7.6,1.3Hz),7.41(2H,t,J＝7.2Hz),7.35-7.28(2H,m),7.25(1H,t,J＝8.1Hz), 7.19(1H,d,J＝7.8Hz),7.14(1H,d,J＝7.6Hz),7.06(1H,t,J＝8.5Hz),6.96(1H,dd,J＝7.9,2.1Hz),5.69(1H,d,J＝7.8Hz)；13C-NMR(100MHz,DMSO-d6),δ(ppm):170.1,159.3,154.9,154.5,142.1,139.4,133.7,130.8,129.0,129.0,128.3,127.4,127.4,126.3,122.4,121.5,117.3,116.4,111.6,104.8,56.9.HRMS(ESI)+calculated for C21H16ClF2N3O2,[M+H]+:m/z 416.0977,found 416.0975.
化合物13 1H-NMR(400MHz,DMSO-d6),δ(ppm):10.26(1H,s),8.58(1H,s),7.74(1H,dd,J＝8.9,8.8Hz),7.51(2H,d,J＝8.0Hz),7.40(2H,t,J＝7.2Hz),7.26-7.34(4H,m),7.08-7.02(4H,m),5.69(1H,d,J＝8.0Hz),2.21(3H,s)；13C-NMR(100MHz,DMSO-d6),δ(ppm):170.4,159.3,154.9,154.8,139.6,138.0,130.5,129.6,129.6,129.0,129.0,128.2,127.4,127.4,126.4,122.4,118.1,118.1,111.6,104.7,56.9,20.7.HRMS(ESI)+calculated for C22H19F2N3O2,[M+H]+:m/z 396.1524,found 396.1525.
化合物14 1H-NMR(400MHz,DMSO-d6),δ(ppm):10.23(1H,s),7.88(1H,s),7.75(1H,dd,J＝8.9,8.8Hz),7.53(2H,d,J＝7.5Hz),7.40(2H,t,J＝7.3Hz),7.31(2H,m),7.04(5H,m),5.69(1H,d,J＝8.5Hz),2.14(6H,s)；13C-NMR(100MHz,DMSO-d6),δ(ppm):170.5,159.3,155.6,154.9,139.8,136.2,135.8,128.9,128.9,128.1,128.1,127.2,127.2,126.2,122.6,111.6,104.8,57.4,18.7,18.7.HRMS(ESI)+calculated for C23H21F2N3O2,[M+H]+:m/z 410.1680,found 410.1680.
化合物15 1H-NMR(400MHz,DMSO-d6),δ(ppm):10.30(1H,s),9.20(1H,s),7.74(1H,dd,J＝8.9,8.8Hz),7.51(2H,d,J＝8.0Hz),7.40(2H,t,J＝7.2Hz),7.26-7.34(4H,m),7.06(1H,t,J＝8.5Hz),5.69(1H,d,J＝8.0Hz)；13C-NMR(100MHz,DMSO-d6),δ(ppm):170.4,159.3,154.9,154.8,144.2,139.6,129.0,129.0,128.4,127.4,127.4,126.4,124.7,122.4,121.9,121.6,117.7,111.8,104.7,56.9.HRMS(ESI)+calculated for C22H16F5N3O2,[M+H]+:m/z 450.1241,found 450.1240.
化合物16 1H-NMR(400MHz,DMSO-d6),δ(ppm):10.32(1H,s),8.89(1H,s),8.16(1H,d,J＝8.3,Hz),8.06(1H,dd,J＝7.6,1.0Hz),7.89(1H,dd,J＝7.8,1.3Hz),7.77(1H,m),7.71(1H,d,J＝7.9Hz),7.59-7.50(5H,m),7.44-7.39(3H,m),7.36-7.29(2H,m),7.07(1H,t,J＝7.0Hz),5.79(1H,d,J＝7.9Hz)；13C-NMR(100MHz,DMSO-d6),δ(ppm):170.4,159.4,158.0,154.9,139.7,135.3,134.2,129.1,129.1,128.9,128.3,127.4,127.4,126.4,126.3,126.2,125.9,125.6,122.6,122.5,121.6,116.3,111.6,104.7,57.2.HRMS(ESI)+calculated for C25H19F2N3O2,[M+H]+:m/z 432.1524,found 432.1522.
化合物17 1H-NMR(400MHz,DMSO-d6),δ(ppm):10.37(1H,s),9.94(1H,s),8.41(1H,d,J＝7.6Hz),7.70(1H,m),7.55(4H,t,J＝8.9Hz),7.40(2H,t,J＝7.2Hz),7.35-7.28(4H,m),7.12-7.03(2H,m),6.33(1H,d,J＝7.6Hz)；13C-NMR(100MHz,DMSO-d6),δ(ppm):180.3,169.7,159.4,154.9,139.9,138.8,129.0,129.0,128.9,128.9,128.4,127.7,127.7,126.6,124.6,123.1,123.1,122.4,111.6,104.7,60.7.HRMS(ESI)+calculated forC21H17F2N3OS,[M+H]+:m/z 398.1139,found 398.1137.
化合物18 1H-NMR(400MHz,CDCl3),δ(ppm):10.55(1H,s),9.98(1H,s),8.89(1H,d,J＝7.0Hz),8.36(2H,s),7.76(1H,s),7.59(2H,d,J＝7.5Hz),7.44-7.27(5H,m),7.17(3H,dd,J＝7.7,6.8Hz),7.10(1H,td,J＝7.3,1.3Hz),6.24(1H,d,J＝7.6Hz)；13C-NMR(100MHz,DMSO-d6),δ(ppm):180.2,168.9,142.2,138.9,135.9,132.9,130.9,130.8,130.5,128.9,128.9,128.4,127.6,127.6,126.5,126.3,125.9,122.3,122.1,116.9,60.9.HRMS(ESI)+calculated for C23H15F8N3OS,[M+H]+:m/z 534.0886,found 534.0883.
化合物19 1H-NMR(400MHz,DMSO-d6),δ(ppm):9.82(1H,s),8.64(1H,s),7.53(2H,d,J＝7.4Hz),7.40(2H,t,J＝7.7Hz),7.33-7.26(4H,m),7.16(2H,dd,J＝7.7,7.1Hz),7.09(1H,td,J＝7.3,1.3Hz),7.03(1H,d,J＝8.0Hz),6.28(2H,d,J＝9.0Hz),5.64(1H,d,J＝8.0Hz),3.68(3H,s),2.03(3H,s)；13C-NMR(100MHz,DMSO-d6),δ(ppm):169.8,154.9,154.5,140.4,136.0,133.8,132.6,130.8,128.9,128.9,128.1,127.2, 127.2,126.5,126.1,125.7,119.7,119.7,114.4,114.4,57.2,55.6,18.0.HRMS(ESI)+calculated forC23H23N3O3,[M+H]+:m/z 390.1818,found 390.1814.
化合物20 1H-NMR(400MHz,DMSO-d6),δ(ppm):9.83(1H,s),8.49(1H,s),8.15(1H,dd,J＝8.4,1.5Hz),8.11(1H,d,J＝7.9Hz),7.56(2H,d,J＝7.3Hz),7.44-7.37(3H,m),7.35-7.29(2H,m),7.23(1H,td,J＝7.9,1.5Hz),7.17(3H,dd,J＝7.7,6.8Hz),7.09(1H,td,J＝7.3,1.3Hz),6.96(1H,td,J＝7.8,1.5Hz),5.67(1H,d,J＝7.8Hz),2.03(3H,s)；13C-NMR(100MHz,DMSO-d6),δ(ppm):169.7,154.5,139.9,137.0,136.1,132.7,130.8,129.6,128.9,128.2,127.9,127.4,126.5,126.1,125.7,123.1,121.7,121.2,57.5,18.0.HRMS(ESI)+calculated for C22H20ClN3O2,[M+H]+:m/z 394.1322,found 394.1324.
化合物21 1H-NMR(400MHz,DMSO-d6),δ(ppm):9.85(1H,s),9.08(1H,s),7.66(1H,t,J＝2.0Hz),7.54(2H,d,J＝7.8Hz),7.41(2H,t,J＝7.7Hz),7.34-7.26(2H,m),7.24(2H,d,J＝7.9Hz),7.17(3H,dd,J＝7.7,6.8Hz),7.09(1H,td,J＝7.3,1.3Hz),5.64(1H,d,J＝7.8Hz),2.03(3H,s)；13C-NMR(100MHz,DMSO-d6),δ(ppm):169.5,154.5,142.1,140.1,135.9,133.7,132.7,130.8,130.8,128.9,128.9,128.2,127.2,127.2,126.5,126.2,125.7,121.4,117.3,116.4,57.1,18.0.HRMS(ESI)+calculated for C22H20ClN3O2,[M+H]+:m/z394.1322,found 394.1324.
化合物22 1H-NMR(400MHz,DMSO-d6),δ(ppm):9.82(1H,s),8.72(1H,s),7.53(2H,d,J＝7.4Hz),7.40(2H,t,J＝7.7Hz),7.31(2H,t,J＝7.6Hz),7.26(2H,d,J＝8.4Hz),7.09(2H,td,J＝7.3,1.3Hz),7.03(2H,d,J＝8.0Hz),5.64(1H,d,J＝8.0Hz),2.21(3H,s),2.03(3H,s)；13C-NMR(100MHz,DMSO-d6),δ(ppm):169.8,154.8,140.4,138.1,136.0,132.7,130.8,130.5,129.6,129.6,128.9,128.9,128.1,127.2,127.2,126.5,126.1,125.7,118.1,118.1,57.1,20.8,18.0.HRMS(ESI)+calculated for C23H23N3O2,[M+H]+:m/z374.1869,found 374.1865.
化合物23 1H-NMR(400MHz,DMSO-d6),δ(ppm):9.81(1H,s),7.88(1H,s),7.55(2H,d,J＝7.2Hz),7.40(2H,t,J＝7.3Hz),7.32(2H,d,J＝7.5Hz),7.19-7.07(4H,m),7.01(3H,s),5.64(1H,d,J＝7.8Hz),2.14(6H,s),2.03(3H,s)；13C-NMR(100MHz,DMSO-d6),δ(ppm):169.9,155.6,140.5,136.2,136.1,135.8,132.7,130.8,128.9,128.9,128.1,128.1,128.0,127.0,127.0,126.5,126.1,125.7,57.5,18.7,18.0.HRMS(ESI)+calculated forC24H25N3O2,[M+H]+:m/z 388.2025,found 388.2020.
化合物24 1H-NMR(400MHz,DMSO-d6),δ(ppm):9.86(1H,s),9.27(1H,s),7.58-7.54(6H,m),7.40(2H,t,J＝7.7Hz),7.35-7.29(3H,m),7.17(2H,dd,J＝7.7,6.8Hz),7.09(1H,td,J＝7.3,1.3Hz),5.67(1H,d,J＝7.8Hz),2.03(3H,s)；13C-NMR(100MHz,DMSO-d6),δ(ppm):169.8,154.8,144.3,140.4,138.1,136.0,132.7,130.8,128.9,128.9,128.1,127.2,127.2,126.5,126.5,126.1,125.7,121.6,117.7,117.7,57.1,18.0.HRMS(ESI)+calculated for C23H20F3N3O2,[M+H]+:m/z 428.1586,found 428.1590.
化合物25 1H-NMR(400MHz,DMSO-d6),δ(ppm):9.88(1H,s),8.93(1H,s),8.18(2H,d,J＝8.6Hz),8.06(1H,dd,J＝7.7,0.9Hz),7.89(2H,dd,J＝8.0,1.5Hz),7.76(1H,d,J＝7.9Hz),7.62-7.52(5H,m),7.42(3H,m),7.34(2H,m),7.17(2H,dd,J＝7.7,7.1Hz),7.09(1H,td,J＝7.3,1.3Hz),5.73(1H,d,J＝7.8Hz),2.07(3H,s)；13C-NMR(100MHz,DMSO-d6),δ(ppm):169.8,155.1,140.4,136.1,135.4,134.2,132.7,130.9,128.9,128.9,128.8,128.2,127.3,127.3,126.5,126.4,126.3,126.1,126.0,125.7,125.6,122.5,121.7,116.3,57.4,18.0.HRMS(ESI)+calculated for C26H23N3O2,[M+H]+:m/z 410.1869,found410.1870.
化合物26 1H-NMR(400MHz,DMSO-d6),δ(ppm):9.99(1H,s),8.94(1H,s),8.45(1H,d,J＝7.6Hz),7.57(4H,m),7.41(2H,t,J＝7.7Hz),7.35-7.26(4H,m),7.18-7.08(4H,m),6.26(1H,d,J＝7.6Hz),2.03(3H,s)；13C-NMR(100MHz,DMSO-d6),δ(ppm):180.2,169.1,139.9,139.4,135.9,132.9,130.8,128.9,128.9,128.2,127.6,127.6,126.5,126.1,125.9,124.6,123.1,123.1,60.9,18.0.HRMS(ESI)+calculated for C22H21N3OS,[M+H]+:m/z 376.1484,found 376.1486.
化合物27 1H-NMR(400MHz,DMSO-d6),δ(ppm):10.55(1H,s),9.98(1H,s),8.89(1H,d,J＝7.0Hz),8.36(2H,s),7.76(1H,s),7.59(2H,d,J＝7.5Hz),7.44-7.27(5H,m),7.17(3H,dd,J＝7.7,6.8Hz),7.10(1H,td,J＝7.3,1.3Hz),6.24(1H,d,J＝7.6Hz),2.03(3H,s)；13C-NMR(100MHz,DMSO-d6),δ(ppm):180.2,168.9,142.2,138.9,135.9,132.9,130.9,130.8,130.5,128.9,128.9,128.4,127.6,127.6,126.5,126.3,125.9,122.3,122.1,116.9,60.9,18.0.HRMS(ESI)+calculated for C24H19F6N3OS,[M+H]+:m/z512.1231,found512.1233.
化合物28 1H-NMR(400MHz,DMSO-d6),δ(ppm):10.60(1H,s),8.58(1H,s),7.95(1H,s),7.50(3H,m),7.40(2H,t,J＝7.2Hz),7.34-7.26(5H,m),7.01(1H,d,J＝7.9Hz),6.82(2H,d,J＝9.1Hz),5.53(1H,d,J＝7.9Hz),3.69(3H,s)；13C-NMR(100MHz,DMSO-d6),δ(ppm):170.3,155.0,154.6,140.8,139.3,113.6,131.4,129.2,128.4,127.4,126.7,122.1,122.0,119.7,119.7,118.5,114.4,114.4,57.8,55.6.HRMS(ESI)+calculated forC22H20BrN3O3,[M+H]+:m/z 454.0766,found 454.0762.
化合物29 1H-NMR(400MHz,DMSO-d6),δ(ppm):10.61(1H,s),8.44(1H,s),8.14(1H,dd,J＝8.5,1.5Hz),8.07(1H,d,J＝7.7Hz),7.95(1H,s),7.52(3H,d,J＝7.2Hz),7.42(3H,t,J＝7.3Hz),7.36-7.20(4H,m),6.96(1H,td,J＝7.7,1.6Hz),5.53(1H,d,J＝7.8Hz)；13C-NMR(100MHz,DMSO-d6),δ(ppm):170.1,154.6,140.7,138.8,136.9,131.4,129.6,129.2,129.2,128.5,127.5,127.5,126.7,123.2,122.1,121.9,121.6,121.2,118.5,58.1.HRMS(ESI)+calculated for C21H17BrClN3O2,[M+H]+:m/z 458.0271,found 458.0276.
化合物30 1H-NMR(400MHz,DMSO-d6),δ(ppm):10.63(1H,s),8.98(1H,s),7.93(1H,s),7.65(1H,s),7.51(3H,m),7.41(2H,t,J＝7.3Hz),7.35-7.19(5H,m),7.14(1H,d,J＝8.4Hz),6.96(1H,d,J＝7.8Hz),5.51(1H,d,J＝7.8Hz)；13C-NMR(100MHz,DMSO-d6),δ(ppm):169.9,154.6,141.9,140.6,138.9,133.7,131.4,130.8,129.2,129.2,128.5,127.4,127.4,126.8,122.1,122.0,121.5,118.5,117.4,116.5,57.8.HRMS(ESI)+calculated for C21H17BrClN3O2,[M+H]+:m/z 458.0271,found 458.0276.
化合物31 1H-NMR(400MHz,DMSO-d6),δ(ppm):10.60(1H,s),8.58(1H,s),7.95(1H,s),7.50(3H,m),7.40(2H,t,J＝7.2Hz),7.34-7.26(5H,m),7.07-7.00(3H,m),5.53(1H,d,J＝7.9Hz),2.21(3H,s)；13C-NMR(100MHz,CDCl3),δ(ppm):13C-NMR(100MHz,DMSO-d6),δ(ppm):170.3,155.0,154.6,140.8,139.3,113.6,131.4,129.2,128.4,127.4,126.7,122.1,122.0,119.7,119.7,118.5,114.4,114.4,57.8,55.6.HRMS(ESI)+calculated forC22H20BrN3O2,[M+H]+:m/z 438.0817,found 438.0819.
化合物32 1H-NMR(400MHz,DMSO-d6),δ(ppm):10.59(1H,s),7.94(1H,s),7.83(1H,s),7.51(3H,d,J＝7.4Hz),7.41(2H,t,J＝7.3Hz),7.34-7.25(3H,m),7.02(3H,m),5.53(1H,d,J＝8.2Hz),2.14(6H,s)；13C-NMR(100MHz,DMSO-d6),δ(ppm):170.4,155.7,140.7,139.5,136.1,135.8,131.4,129.1,129.1,128.3,128.1,127.2,127.2,126.7,126.2,122.0,121.9,118.5,58.1,18.7,18.7.HRMS(ESI)+calculated for C23H22BrN3O2,[M+H]+:m/z 452.0974,found 452.0975.
化合物33 1H-NMR(400MHz,DMSO-d6),δ(ppm):10.63(1H,s),9.19(1H,s),7.94(1H,s),7.58(4H,s),7.51(3H,m),7.41(2H,t,J＝7.3Hz),7.35(1H,tt,J＝7.4,1.3Hz),7.31-7.26(3H,m),5.54(1H,d,J＝7.8Hz)；13C-NMR(100MHz,DMSO-d6),δ(ppm):169.9,154.5,144.1,140.6,138.9,131.4,129.2,129.2,128.5,127.4,127.4,126.8,126.6,126.4,123.7,122.1,122.0,118.5,117.7,117.7,57.7.HRMS(ESI)+calculated forC22H17BrF3N3O2,[M+H]+:m/z 492.0534,found 492.0530.
化合物34 1H-NMR(400MHz,DMSO-d6),δ(ppm):10.66(1H,s),8.88(1H,s),8.16(1H,s),8.05(1H,dd,J＝7.8,1.0Hz),7.97(1H,t,J＝1.8Hz),7.90(1H,dd,J＝8.1,1.4Hz),7.71(1H,d,J＝7.8Hz),7.58-7.52(6H, m),7.42(3H,m),7.35(1H,tt,J＝7.4,1.3Hz),7.28(2H,m),5.61(1H,d,J＝7.8Hz)；13C-NMR(100MHz,DMSO-d6),δ(ppm):170.2,155.2,140.7,139.2,135.2,134.2,131.4,129.2,129.2,128.9,128.5,127.4,127.4,126.8,126.4,126.3,126.0,125.6,122.6,122.1,122.0,121.6,118.5,116.4,58.0.HRMS(ESI)+calculated for C25H20BrN3O2,[M+H]+:m/z 474.0817,found 474.0815.
化合物35 1H-NMR(400MHz,DMSO-d6),δ(ppm):10.70(1H,s),9.94(1H,s),8.43(1H,d,J＝7.4Hz),7.95(1H,s),7.58-7.26(13H,m),7.11(1H,tt,J＝7.4,1.0Hz),6.17(1H,d,J＝7.4Hz)；13C-NMR(100MHz,DMSO-d6),δ(ppm):180.4,169.5,140.7,139.8,138.4,131.4,129.2,129.2,128.9,128.9,128.6,127.7,127.7,126.8,124.7,123.1,123.1,122.1,122.0,118.5,61.5.HRMS(ESI)+calculated for C21H18BrN3OS,[M+H]+:m/z440.0432,found 440.0430.
化合物36 1H-NMR(400MHz,DMSO-d6),δ(ppm):10.74(1H,s),10.46(1H,s),8.90(1H,d,J＝7.4Hz),8.34(2H,s),7.95(1H,s),7.77(1H,s),7.55-7.50(3H,m),7.42(2H,t,J＝7.1Hz),7.35(1H,t,J＝7.2Hz),7.31-7.26(2H,m),6.17(1H,d,J＝7.2Hz)；13C-NMR(100MHz,DMSO-d6),δ(ppm):180.4,169.0,142.1,140.6,131.9,131.4,130.8,130.5,129.2,129.2,128.7,127.8,127.8,126.9,125.0,122.3,122.1,122.0,118.5,61.6.HRMS(ESI)+calculated for C23H16BrF6N3OS,[M+H]+:m/z 576.0180,found 576.0180.
化合物37 1H-NMR(400MHz,DMSO-d6),δ(ppm):8.60(1H,s),8.44(1H,t,J＝5.4Hz),7.37-7.24(7H,m),6.88(1H,d,J＝8.8Hz),6.81(2H,d,J＝9.0Hz),6.77(2H,d,J＝8.0Hz),6.61(1H,dd,J＝8.1,1.8Hz),5.32(1H,d,J＝8.1Hz),3.68(9H,s),3.27(2H,q,J＝6.8Hz),2.26(2H,t,J＝7.1Hz)；13C-NMR(100MHz,DMSO-d6),δ(ppm):170.7,154.8,154.5,149.0,147.7,140.6,133.8,132.2,128.7,128.7,127.8,127.1,127.1,120.9,120.4,119.6,119.6,114.4,114.4,112.9,112.3,56.8,55.9,55.8,55.6,40.9,34.9.HRMS(ESI)+calculated for C26H29N3O5,[M+H]+:m/z 464.2185,found 464.2180.
化合物38 1H-NMR(400MHz,DMSO-d6),δ(ppm):8.45(2H,s),8.12(1H,d,J＝8.2Hz),7.98(1H,d,J＝7.0Hz),7.40-7.37(3H,m),7.34(2H,t,J＝7.0Hz),7.30-7.27(1H,m),7.22(1H,td,J＝7.8,1.5Hz),6.94(1H,td,J＝7.9,1.5Hz),6.78(1H,d,J＝6.8Hz),6.76(1H,s),6.62(1H,dd,J＝8.2,1.5Hz),5.35(1H,dd,J＝7.8,3.0Hz),3.69(6H,s),3.28(2H,q,J＝6.8Hz),2.63(2H,t,J＝6.9Hz)；13C-NMR(100MHz,DMSO-d6),δ(ppm):170.5,154.4,149.0,147.7,140.1,137.1,132.2,129.6,128.8,128.8,127.9,127.2,127.2,123.0,121.6,121.2,120.9,112.9,112.3,57.1,55.9,55.8,40.9,34.9.HRMS(ESI)+calculatedfor C25H26ClN3O4,[M+H]+:m/z 468.1690,found 468.1692.
化合物39 1H-NMR(400MHz,DMSO-d6),δ(ppm):9.02(1H,s),8.46(1H,s),7.64(1H,s),7.35-7.22(6H,m),7.12(1H,d,J＝7.6Hz),7.08(1H,d,J＝7.4Hz),6.94(1H,d,J＝7.2Hz),6.76(2H,brs),6.60(1H,d,J＝7.4Hz),5.32(1H,d,J＝7.4Hz),3.69(6H,s),3.28(2H,q,J＝6.8Hz),2.62(2H,t,J＝6.9Hz)；13C-NMR(100MHz,DMSO-d6),δ(ppm):170.4,154.4,149.0,147.7,142.2,140.3,133.7,132.1,130.8,128.8,128.8,127.9,127.1,127.1,121.3,120.9,117.2,116.3,112.9,112.3,57.1,55.9,55.8,40.9,34.9.HRMS(ESI)+calculated for C25H26ClN3O4,[M+H]+:m/z 468.1690,found 468.1692.
化合物40 1H-NMR(400MHz,DMSO-d6),δ(ppm):8.68(1H,s),8.44(1H,t,J＝5.5Hz),7.37-7.30(4H,m),7.28-7.22(3H,m),7.02(2H,d,J＝8.3Hz),6.93(1H,d,J＝8.2Hz),6.78(1H,d,J＝6.8Hz),6.76(1H,s),6.60(1H,dd,J＝8.2,1.5Hz),5.32(1H,d,J＝8.0Hz),3.69(3H,s),3.68(3H,s),3.27(2H,q,J＝6.8Hz),2.62(2H,t,J＝6.9Hz),2.20(3H,s)；13C-NMR(100MHz,DMSO-d6),δ(ppm):170.7,154.8,149.0,147.7,140.6,138.2,132.2,130.4,129.6,129.6,128.7,128.7,127.8,127.1,127.1,120.9,118.0,118.0,112.9,112.3,56.8,55.9,55.8,40.9,34.9,20.8.HRMS(ESI)+calculated for C26H29N3O4,[M+H]+:m/z 448.2236,found448.2240.
化合物41 1H-NMR(400MHz,DMSO-d6),δ(ppm):8.44(1H,t,J＝5.4Hz),7.85(1H,s),7.37(2H,d,J＝7.1Hz),7.32(2H,t,J＝7.1Hz),7.26(1H,m),7.05-6.98(4H,m),6.79(1H,d,J＝8.1Hz),6.77(1H,d,J＝1.8Hz),6.62(1H,dd,J＝8.1,1.8Hz),5.33(1H,d,J＝8.1Hz),3.70(3H,s),3.69(3H,s),3.27(2H,q,J＝6.8Hz),2.63(2H,t,J＝7.1Hz),2.12(6H,s)；13C-NMR(100MHz,DMSO-d6),δ(ppm):170.7,155.4,149.1,147.7,140.9,136.3,135.7,132.2,128.6,128.6,128.1,127.6,126.8,126.8,126.1,120.9,112.9,112.3,57.1,55.9,55.8,40.9,34.9,18.7,18.7.HRMS(ESI)+calculated for C27H31N3O4,[M+H]+:m/z462.2393,found462.2396.
化合物42 1H-NMR(400MHz,DMSO-d6),δ(ppm):8.89(1H,s),8.50(1H,t,J＝5.5Hz),8.17(1H,d,J＝8.3Hz),8.04(1H,dd,J＝7.7,0.7Hz),7.88(1H,dd,J＝8.0,1.5Hz),7.64(1H,d,J＝8.0Hz),7.57-7.49(3H,m),7.44-7.33(5H,m),7.30-7.27(1H,m),6.79-6.77(2H,m),6.63(1H,dd,J＝8.2,1.9Hz),5.42(1H,d,J＝8.0Hz),3.69(3H,s),3.68(3H,s),3.31(2H,q,J＝6.8Hz),2.65(2H,t,J＝6.9Hz)；13C-NMR(100MHz,DMSO-d6),δ(ppm):170.3,154.0,149.0,147.7,144.3,140.2,132.1,128.8,128.8,127.9,127.1,127.1,126.5,120.9,117.6,117.6,112.9,112.2,56.8,55.9,55.8,40.9,34.9.HRMS(ESI)+calculatedfor C26H26F3N3O4,[M+H]+:m/z 502.1954,found 502.1950.
化合物43 1H-NMR(400MHz,DMSO-d6),δ(ppm):8.89(1H,s),8.50(1H,t,J＝5.5Hz),8.17(1H,d,J＝8.3Hz),8.04(1H,dd,J＝7.7,0.7Hz),7.88(1H,dd,J＝8.0,1.5Hz),7.64(1H,d,J＝8.0Hz),7.57-7.49(3H,m),7.44-7.33(5H,m),7.30-7.27(1H,m),6.79-6.77(2H,m),6.63(1H,dd,J＝8.2,1.9Hz),5.42(1H,d,J＝8.0Hz),3.69(3H,s),3.68(3H,s),3.31(2H,q,J＝6.8Hz),2.65(2H,t,J＝6.9Hz)；13C-NMR(100MHz,DMSO-d6),δ(ppm):170.6,155.0,149.0,147.7,140.5,135.5,134.2,132.2,128.9,128.8,128.8,127.8,127.1,126.4,126.2,125.9,125.5,122.4,121.7,120.9,116.2,112.9,112.3,57.1,55.9,55.8,40.9,34.9.HRMS(ESI)+calculated for C29H29N3O4,[M+H]+:m/z 484.2236,found484.2240.
化合物44 1H-NMR(400MHz,DMSO-d6),δ(ppm):9.96(1H,s),8.57(1H,t,J＝5.4Hz),8.33(1H,d,J＝7.7Hz),7.54(2H,d,J＝8.3Hz),7.39-7.26(7H,m),7.10(1H,t,J＝7.4Hz),6.78(1H,d,J＝8.4Hz),6.76(1H,d,J＝1.9Hz),6.60(1H,dd,J＝8.2,1.8Hz),5.99(1H,d,J＝7.7Hz),3.69(6H,s),3.28(2H,q,J＝6.8Hz),2.62(2H,t,J＝6.9Hz)；13C-NMR(100MHz,DMSO-d6),δ(ppm):179.9,169.9,149.0,147.7,139.9,139.7,132.1,128.9,128.9,128.7,128.7,127.9,127.3,127.3,124.6,123.1,123.1,120.9,112.9,112.3,60.5,55.9,55.8,40.9,34.9.HRMS(ESI)+calculated for C25H27N3O3S,[M+H]+:m/z 450.1851,found 450.1856.
化合物45 1H-NMR(400MHz,DMSO-d6),δ(ppm):10.55(1H,s),8.76(1H,d,J＝7.6Hz),8.61(1H,t,J＝5.4Hz),8.34(2H,br s),7.75(1H,br s),7.42-7.27(5H,m),6.78(1H,d,J＝8.4Hz),6.76(1H,d,J＝1.9Hz),6.60(1H,dd,J＝8.2,1.8Hz),5.96(1H,d,J＝7.7Hz),3.70(3H,s),3.69(3H,s),3.31(2H,q,J＝6.8Hz),2.64(2H,t,J＝6.9Hz)；13C-NMR(100MHz,DMSO-d6),δ(ppm):179.9,169.6,149.0,147.7,142.2,139.1,132.1,130.8,130.5,128.8,128.8,128.1,1 127.4,127.4,125.0,122.3,120.9,112.9,112.2,60.5,55.9,55.8,40.9,34.9.HRMS(ESI)+calculated for C27H25F6N3O3S,[M+H]+:m/z 586.1599,found 586.1592.
实施例2式Ⅱ化合物的合成通法
式Ⅱ化合物的合成与实施例1类似，仅将原料(R)-苯甘氨酸替换为(S)-苯甘氨酸。以下面化合物46为例。
Scheme2 Reagents and conditions：(a)MeOH，1N NaOH；HCl pH＝3；(b)N-Methylmorpholine，iso-butylchloroformate，THF，-20℃，2，4-difluoroanilie；(c)HCI/MeOH，r.t.；(d)CH2Cl2，TEA，isothiocyanates，r.t
合成方法：将实施例1中的(R)-苯甘氨酸替换为(S)-本甘氨酸，合成方法同实施例1。
试验例1化合物1～46的激酶激动活性及自噬率活性
本实验的目的是检测本发明的化合物对体外ULK1酶激活活性，及对细胞的自噬率活性。
ULK1酶活实验是利用ADP-GloTM Kinase Assay+ULK1Kinase Enzyme System(Promega，Madison，WI，USA)测得，通过GraphPad Prism5 software(San Diego，CA，USA)处理数据，结果见表1。细胞的自噬率活性是通过MDC荧光染色分析实验方法测定。
表1化合物1～46激酶激动活性及自噬率活性
实验结果表明，本发明的化合物均对ULK1具有激动活性及自噬活性，其中，化合物6、化合物15、化合物18、化合物27、化合物36、化合物46的效果较好，最优的，化合物18(记为BL-918)对ULK1具有较强的激动活性及自噬活性。
试验例2化合物18(BL-918)诱导自噬机制研究
为了进一步研究BL-918诱导自噬的分子机制，我们首先利用透射电子显微镜对BL-918处理过得SH-SY5Y细胞进行了观测(图1A)，结果表明BL-918不仅使Beclin-1和LC3-II的表达上调，同时使SQSTM1/p62发生了下调；并且在Bafilomycin A1存在下，LC3-II和SQSTM1/p62发生了明显的聚集(图1B)，以上实验结果表明BL-918加强了自噬流的产生。
由于ULK复合体与自噬小体的形成密切相关，因此我们接下来检测了ULK复合体相关蛋白的表达。BL-918使ULK1和mAtg13的磷酸化上调，并且使ULK复合体上游的负调控因子mTOR发生了去磷酸化。进一步，通过免疫共沉淀实验发现BL-918是ULK复合体的稳定性得到了增强(图1C)。为了验证化合物BL-9184诱导的自噬是否是通过靶向ULK1，siRNA被用于沉默ULK1的表达。我们发现GFP-LC3荧光点基本消失了(图1D，1E)，综上结果表明化合物BL-918激活自噬是通过靶向ULK1激活ULK复合体实现的。
试验例3化合物BL-918的细胞保护活性
为了检测BL-918有诱导的自噬是否具有细胞保护活性。我们建立了MPP+诱导的SH-SY5Y细胞损伤模型，实验结果表明，BL-918能够一定程度上逆转由MPP+诱导的SH-SY5Y细胞的死亡(图2A)。这种保护活性能够被自噬抑制剂3-MA和si-ULK1逆转(图2B)，进一步说明BL-918是通过诱导自噬对细胞产生的保护效应。
试验例4化合物BL-918的体内活性评价
为了检测BL-918在体内的保护活性，我们进而建立了由MPP+诱导的大鼠PD模型。我们测定了大鼠的爬杆和游泳实验的行为学(图3A)。实验结果表明BL-918治疗的大鼠在行为学上显示了明显的改善。并且我们进一步测定了大鼠纹状体的多巴胺水平(图3B)，发现BL-918治疗组一定程度上改善了纹状体多巴胺的下降，并且BL-918能够使纹状体中的酪氨酸羟化酶含量提高(图3C)，并没有表现出明显的毒性。

Claims (14)

1.结构式如式Ⅰ或式Ⅱ所示的化合物或其药学上可接受的盐：
其中，R1为R11为氢、烷基、烷氧基或卤素；m为1或2；
R2为R21为氢、烷基、烷氧基、卤代烷基或卤素；n为1或2；
X为O或S。
2.根据权利要求1所述的化合物或其药学上可接受的盐，其特征在于：结构式如式Ⅰ所示。
3.根据权利要求1或2所述的化合物或其药学上可接受的盐，其特征在于：X为O。
4.根据权利要求3所述的化合物或其药学上可接受的盐，其特征在于：
R1为R11为烷基、烷氧基或卤素；m为1或2；
R2为R21为氢、烷基、烷氧基、卤代烷基或卤素；n为1或2；
优选R1为R11为烷基、烷氧基或卤素；
R2为R21为氢、C1-C3烷基、烷氧基、卤代C1-C3烷基或卤素；
更优选R1为
R2为
更优选R1为R2为
5.根据权利要求3所述的化合物或其药学上可接受的盐，其特征在于：
R1为R11为氢、烷基、烷氧基或卤素；m为1或2；
R2为R21为氢、烷基、烷氧基、卤代烷基或卤素；n为1或2；
优选R1为R11为氢、烷基、烷氧基或卤素；
R2为R21为氢、C1-C3烷基、烷氧基、卤代C1-C3烷基或卤素；
更优选R1为
R2为
更优选R1为R2为
6.根据权利要求3所述的化合物或其药学上可接受的盐，其特征在于：
R1为R11为氢、烷基、烷氧基或卤素；m为1或2；
R2为R21为氢、烷基、烷氧基、卤代烷基或卤素；n为1或2；
优选R1为R111为烷基或烷氧基；R112为烷基或烷氧基；
R2为
更优选R1为
R2为
7.根据权利要求1或2所述的化合物或其药学上可接受的盐，其特征在于：X为S。
8.根据权利要求7所述的化合物或其药学上可接受的盐，其特征在于：
R1为R11为烷基、烷氧基或卤素；m为1或2；
R2为R21为氢、烷基、烷氧基、卤代烷基或卤素；n为1或2；
优选R1为R11为烷基、烷氧基或卤素；
R2为R21为氢、C1-C3烷基、烷氧基、卤代C1-C3烷基或卤素；
更优选R1为
R2为
更优选R1为R2为
9.根据权利要求7所述的化合物或其药学上可接受的盐，其特征在于：
R1为R11为氢、烷基、烷氧基或卤素；m为1或2；
R2为R21为氢、烷基、烷氧基、卤代烷基或卤素；n为1或2；
优选R1为R11为氢、烷基、烷氧基或卤素；
R2为R21为氢、C1-C3烷基、烷氧基、卤代C1-C3烷基或卤素；
更优选R1为
R2为
更优选R1为R2为
10.根据权利要求7所述的化合物或其药学上可接受的盐，其特征在于：
R1为R11为氢、烷基、烷氧基或卤素；m为1或2；
R2为R21为氢、烷基、烷氧基、卤代烷基或卤素；n为1或2；
优选R1为R111为烷基或烷氧基；R112为烷基或烷氧基；
R2为
更优选R1为R2为
11.根据权利要求1所述的化合物或其药学上可接受的盐，其特征在于：所述式Ⅰ化合物为如下化合物：
12.权利要求1～11任一项所述的化合物或其药学上可接受的盐在制备神经退行性疾病治疗药物中的用途。
13.根据权利要求12所述的用途，其特征在于：所述神经退行性疾病治疗药物为抗帕金森药物；优选所述抗帕金森药物为ULK1激动剂类药物。
14.一种药物组合物，其特征在于：它是包含有效剂量的权利要求1～10任一项所述的化合物或其药学上可接受的盐的制剂。
CN201710038351.5A 2017-01-18 2017-01-18 靶向自噬激动剂及其在神经退行性疾病治疗药物中的应用 Active CN106748892B (zh)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN201710038351.5A CN106748892B (zh) 2017-01-18 2017-01-18 靶向自噬激动剂及其在神经退行性疾病治疗药物中的应用
PCT/CN2018/072575 WO2018133756A1 (zh) 2017-01-18 2018-01-15 靶向自噬激动剂及其在神经退行性疾病治疗药物中的应用

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201710038351.5A CN106748892B (zh) 2017-01-18 2017-01-18 靶向自噬激动剂及其在神经退行性疾病治疗药物中的应用

Publications (2)

Publication Number Publication Date
CN106748892A true CN106748892A (zh) 2017-05-31
CN106748892B CN106748892B (zh) 2018-09-18

Family

ID=58943394

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201710038351.5A Active CN106748892B (zh) 2017-01-18 2017-01-18 靶向自噬激动剂及其在神经退行性疾病治疗药物中的应用

Country Status (2)

Country Link
CN (1) CN106748892B (zh)
WO (1) WO2018133756A1 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112057442A (zh) * 2020-08-27 2020-12-11 四川大学 一种硫脲类化合物的抗肌萎缩侧索硬化作用

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024030332A1 (en) * 2022-08-01 2024-02-08 Verge Analytics, Inc. Methods of treating neurological disorders with activators of unc51-like autophagy activating kinase 1 (ulk1)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1443155A (zh) * 2000-06-30 2003-09-17 艾兰制药公司 治疗早老性痴呆的化合物
CN1447789A (zh) * 2000-06-30 2003-10-08 艾兰制药公司 治疗阿尔茨海默氏症的化合物
WO2004022528A2 (en) * 2002-09-09 2004-03-18 Nps Allelix Corp. Arylglycine derivatives and their use as glycine transport inhibitors
WO2004022534A1 (en) * 2002-09-09 2004-03-18 Nps Allelix Corp. Arylglycine derivatives for use as glycine transport inhibitors
US20040077635A1 (en) * 2002-10-02 2004-04-22 Qiao Jennifer X. Lactam-containing diaminoalkyl, beta-aminoacids, alpha-aminoacids and derivatives thereof as factor Xa inhibitors
CN104860924A (zh) * 2008-11-04 2015-08-26 盖尔德马研究及发展公司 黑皮质素受体调节剂、制备它们的方法及其在人用药物和化妆品中的用途

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6221913B1 (en) * 1998-01-21 2001-04-24 Zymogenetics, Inc. Dialkyl ureas as calcitonin mimetics
WO2006063293A2 (en) * 2004-12-07 2006-06-15 Portola Pharmaceuticals, Inc. THIOUREAS AS FACTOR Xa INHIBITORS
WO2006063113A2 (en) * 2004-12-07 2006-06-15 Portola Pharmaceuticals, Inc. Ureas as factor xa inhibitors

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1443155A (zh) * 2000-06-30 2003-09-17 艾兰制药公司 治疗早老性痴呆的化合物
CN1447789A (zh) * 2000-06-30 2003-10-08 艾兰制药公司 治疗阿尔茨海默氏症的化合物
WO2004022528A2 (en) * 2002-09-09 2004-03-18 Nps Allelix Corp. Arylglycine derivatives and their use as glycine transport inhibitors
WO2004022534A1 (en) * 2002-09-09 2004-03-18 Nps Allelix Corp. Arylglycine derivatives for use as glycine transport inhibitors
US20040077635A1 (en) * 2002-10-02 2004-04-22 Qiao Jennifer X. Lactam-containing diaminoalkyl, beta-aminoacids, alpha-aminoacids and derivatives thereof as factor Xa inhibitors
CN104860924A (zh) * 2008-11-04 2015-08-26 盖尔德马研究及发展公司 黑皮质素受体调节剂、制备它们的方法及其在人用药物和化妆品中的用途

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112057442A (zh) * 2020-08-27 2020-12-11 四川大学 一种硫脲类化合物的抗肌萎缩侧索硬化作用

Also Published As

Publication number Publication date
WO2018133756A1 (zh) 2018-07-26
CN106748892B (zh) 2018-09-18

Similar Documents

Publication Publication Date Title
JP6267397B1 (ja) 置換された多環性ピリドン誘導体およびそのプロドラッグを含有する医薬組成物
AU2020341681B2 (en) RIP1 inhibitory compounds and methods for making and using the same
JP7095945B2 (ja) 多環性ピリドン誘導体およびそのプロドラッグ
ES2956087T3 (es) Compuestos inhibidores de RIP1 y métodos para preparar y usar los mismos
JP6323860B2 (ja) キャップ依存的エンドヌクレアーゼ阻害剤及び抗インフルエンザ薬を組み合わせることを特徴とするインフルエンザ治療用医薬
TW402582B (en) Novel delta-amino-gamma-hydroxy-omega-aryl-alkanoic acid amides
CA2848561C (en) Guanidinobenzoic acid compound
CA2874250A1 (en) 7-oxo-thiazolopyridine carbonic acid derivatives and their use in the treatment, amelioration or prevention of a viral disease
PT1689751E (pt) Novas 5,7-diaminopirazolo[4,3-d]pirimidinas com actividade inibidora de pde-5
JPWO2016175224A1 (ja) 置換された多環性ピリドン誘導体およびそのプロドラッグ
CA3226532A1 (en) Lipidated peptide inhibitors of interleukin-23 receptor
CN102659630B (zh) 一种异羟肟酸类化合物及其制备方法和用途
CN106748892B (zh) 靶向自噬激动剂及其在神经退行性疾病治疗药物中的应用
WO2024040768A1 (zh) 5-吡啶-1h-吲唑类化合物、药物组合物和应用
CN108473496A (zh) 杂环化合物及其用途
CN103420980A (zh) 达比加群衍生物
JP6275644B2 (ja) Ｎ−［２−（｛２−［（２Ｓ）−２−シアノピロリジン−１−イル］−２−オキソエチル｝アミノ）−２−メチルプロピル］−２−メチルピラゾロ［１，５−ａ］ピリミジン−６−カルボキサミドの結晶
CN104311503A (zh) 一种制备抗hiv药物利托那韦的方法
CN105960399B (zh) 酶抑制剂环氧酮化合物
CN104781235A (zh) N-[2-{4-[6-氨基-5-(2,4-二氟苯甲酰)-2-氧代吡啶-1(2h)-基]-3,5-二氟苯基}乙基]-l-丙氨酸叔丁酯或其盐、水合物或溶剂合物
CN111960970A (zh) 抗肿瘤化合物
CN103083313A (zh) 一种取代吡咯色原酮类化合物在制备治疗5型磷酸二酯酶相关疾病的药物中的应用
JP2023553417A (ja) Ｅｎｐｐ１阻害剤としてのイミダゾール化合物
US4845284A (en) Substituted 3-nitrobenzenesulfonamides useful as adjuncts in radiation therapy
CN117402156A (zh) 一类酰胺化合物及其制备方法、药物组合物和用途

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant