CN115650958B - 2-氨基嘧啶类化合物及其制备方法、用途和药物组合物 - Google Patents

2-氨基嘧啶类化合物及其制备方法、用途和药物组合物 Download PDF

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CN115650958B
CN115650958B CN202211259227.9A CN202211259227A CN115650958B CN 115650958 B CN115650958 B CN 115650958B CN 202211259227 A CN202211259227 A CN 202211259227A CN 115650958 B CN115650958 B CN 115650958B
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CN115650958A (zh
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蒋晟
肖易倍
叶科
王天雨
张阔军
章翔宇
郑帅
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China Pharmaceutical University
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Abstract

本发明公开了一种2‑氨基嘧啶类化合物及其制备方法、用途和药物组合物，该化合物为结构通式如式Ⅰ所示的化合物或其药学上可接受的盐、互变异构体、内消旋体、外消旋体、立体异构体、前药或溶剂化合物；所述化合物及其药物组合物有望应用于治疗EGFR介导的疾病。

Description

2-氨基嘧啶类化合物及其制备方法、用途和药物组合物
技术领域
本发明涉及一种化合物及其制备方法、用途和药物组合物，尤其涉及一种2-氨基嘧啶类化合物及其制备方法、用途和药物组合物。
背景技术
EGFR(Epidermal Growth Factor Receptor)是表皮生长因子(EGF)细胞增殖和信号传导的受体。EGFR属于ErbB受体家族之一，EGFR也被称作HERl、ErbBl。EGFR是一种糖蛋白，属于酪氨酸激酶型受体，位于细胞膜表面的跨膜受体，分子量为170KDa。EGFR通过与配体EGF和TGFa(transforming growth factorα)结合来激活，进而激活细胞内的激酶通路，引起下游MAPK、Akt以及JNK通路的磷酸化，诱导细胞增殖。
多种癌症都有EGFR过度表达的现象，如肾癌、非小细胞肺癌、前列腺癌、乳腺癌、头颈癌等。EGFR过度表达引起下游信号的异常激活，EGFR与肿瘤细胞的增殖、血管生成、肿瘤侵袭、转移及细胞凋亡的抑制有关。目前约30％～40％的亚洲非小细胞肺癌患者在确诊时携带EGFR突变。
目前小分子的EGFR抑制剂可分为第一代、第二代、第三代和第四代。很多患者在服用第一代EGFR抑制剂几个月就会产生耐药，主要是T790M(苏氨酸替代甲硫氨酸)突变，针对该突变已开发了第二代EGFR抑制剂。第二代EGFR抑制剂考虑需要同时靶向作用于突变和非突变EGFR靶点，因而存在治疗剂量的不足且毒副作用较大的缺点。为了克服上述问题，开第三代EGFR抑制剂，如奥希替尼，它是首个针对EGFR T790M突变的药物。但部分患者再经历9～14个月的治疗后又会出现耐药，主要是因为EGFR C797S突变(半胱氨酸CYS797变为丝氨酸SER797)，奥希替尼的共价结合键无法与靶点半胱氨酸结合，从而导致脱靶。解决其耐药性迫在眉睫，也成为提高非小细胞肺癌患者生存率的最直接手段。目前临床缺乏针对EGFRC797S突变单独用要有效的EGFR抑制剂，因此现在迫切需要开发针对EGFR C797S突变的四代EGFR抑制剂。
发明内容
发明目的：本发明旨在提供一种能有效治疗EGFR介导疾病的2-氨基嘧啶类化合物；本发明的另一目的是提供所述2-氨基嘧啶类化合物的制备方法；本发明的另一目的是提供所述2-氨基嘧啶类化合物在制备具有EGFR抑制活性的抑制剂和抗肿瘤药物中的用途；本发明的另一目的是提供一种含有所述2-氨基嘧啶类化合物的药物组合物。
技术方案：本发明所述的2-氨基嘧啶类化合物，该化合物为结构通式如式Ⅰ所示的化合物或其药学上可接受的盐、互变异构体、内消旋体、外消旋体、立体异构体、前药或溶剂化合物：
其中，n＝0或1；当n＝1时，U为CH，V为CH或N，W为CH或N；当n＝0时，U为N，V为N；X选自O或NH；A选自OR2、SR2、NR2R3、未取代或取代的C6-10的芳基、杂原子数为1-4个的5～10元杂芳基或杂环烷基；且当n＝1时，A不为杂原子数为1-4个的5～10元的杂环烷基；R2选自-NR2- 3R2-4、C3-10环烷基、取代的C1-6烷基、未取代或R2-3取代的C6-10芳基、杂环烷基或杂芳基；R2-3和R2-4独立地选自氢、卤素、硝基、氰基、C1-6烷基、羟基、氨基、-NR2-3-1R2-3-2、-(C＝O)R2-3-3、-(C＝O)NR2-3-4R2-3-5、-NR2-3-6(C＝O)R2-3-7、-(C＝O)OR2-3-8、-O(C＝O)R2-3-9、-S(＝O)2NR2-3-10R2 -3-11、-NR2-3-12S(＝O)2R2-3-13、-S(＝O)2R2-3-14或-P(＝O)R2-3-15R2-3-16；R2-3-1～R2-3-16独立地选自氢、C1-4烷基、C3-10环烷基或C3-10环烷基-(C1-6烷基)-；所述杂原子为N、O或S；R3选自氢或C1-4烷基；R4选自氢、未取代或取代的C1-6烷基、C3-10环烷基或C3-10环烷基-(C1-6烷基)-；R5和R6独立地选自氢、甲基或乙基；R7选自氢、未取代或取代的C1-6烷基、C3-10环烷基或C3-10杂环烷基；R8选自氢、未取代或取代的C1-6烷基。
优选地，当A为取代的C6-10的芳基时，所述取代基选自羟基、氰基、卤素、硝基、C1-6的烷基、C2-8烯基、C2-6炔基、C1-6烷氧基、C6-10芳基氧基、杂芳基氧基、(C3-10环烷基)-氧基、卤代(C1-6烷基)、羟基(C1-6烷基)、氨基(C1-6烷基)、C1-6烷胺基-C1-6烷氧基-、C3-10环烷基、C3-10环烷基-(C1-6烷基)-、C3-10环烷基-(C1-6烷氧基)、-NR1-4R1-5、-(C＝O)R1-6、-(C＝O)NR1-7R1-8、-NR1-9(C＝O)R1-10、-(C＝O)OR1-11、-O(C＝O)R1-12、-S(＝O)2NR1-13R1-14、-NR1-15S(＝O)2R1-16、-S(＝O)2R1-17或-P(＝O)R1-18 R1-19、未取代或R1-1取代的C6-10芳基、C6-10芳基-(C1-6烷基)-、未取代或R1-2取代的C6-10芳基-(C1-6烷氧基)-、杂环烷基、杂环烷基-(C1-6烷基)-、未取代或R1-3取代的杂芳基、杂芳基-(C1-6烷基)-或杂芳基-(C1-6烷氧基)-；所述杂环烷基为杂原子数为1-4个的3-10元杂环烷基；所述杂芳基为杂原子数为1-3个的5-10元杂芳基；R1-1、R1-2和R1-3独立地选自C1-4烷基、羟基(C1-4烷基)-、卤素、氰基、羟基、C1-4烷胺基、C1-4烷氧基或卤代(C1-4烷基)-；R1-4～R1-19独立地选自氢、C1-4烷基、C3-10环烷基或C3-10环烷基-(C1-6烷基)-；
当R2为取代的C1-6烷基时，所述取代基为羟基、氨基、C1-6烷氧基、R2-1S(＝O)2-、R2-2(C＝O)-、C3-10环烷基、C6-10芳基、杂原子数为1-4个的3-10元杂环烷基或杂原子数为1-3个的5-10元杂芳基；
R2-1选自氢、C1-6烷基、C3-6环烷基或C3-6环烷基-(C1-6烷基)-；R2-2选自氢、氨基、羟基、C1-6烷基、C1-6烷氧基、C1-4烷胺基、R2-2-1取代的杂环烷基或杂环烷基-(C1-6烷基)；R2-2-1独立地选自氢、卤素，氰基，羟基、C1-3烷基或C1-3烷氧基；
当R4为取代的C1-6烷基、C3-10环烷基、C3-10环烷基-(C1-6烷基)-时，所述取代基选自卤素、羟基、NR4-1R4-2或氰基；R4-1和R4-2独立地选自氢或C1-6烷基；
当R7为取代的C1-6烷基、C3-10环烷基、C3-10杂环烷基时，所述取代基选自卤素、氰基、羟基、酯基、NR7-1-1R7-1-2、C1-6烷基或C1-6烷氧基；R7-1-1和R7-1-2独立地选自氢或C1-6烷基；
当R8为取代的C1-6烷基时，所述取代基选自卤素，氰基，羟基、NR8-1-1R8-1-2、C1-3烷基或C1-3烷氧基；R8-1-1和R8-1-2独立地选自氢或C1-4烷基。
优选地，R4选自氢、未取代的或R4-1取代的C1-4烷基、C3-6环烷基或C3-6环烷基-(C1-4烷基)；R4-1选自氟、氯、溴、羟基、甲胺、乙胺、二甲胺、二乙胺、正丙胺或氰基；
R5和R6独立地选自氢或甲基；
R7选自氢、未取代或R7-1取代的C1-4烷基、C3-6环烷基或C3-7杂环烷基；R7-1选自卤素，氰基，羟基、酯基、甲氨基、乙胺基、二甲氨基、二乙氨基、丙胺基、甲基、乙基、正丙基、异丙基、甲氧基或乙氧基；
R8选自氢、未取代或R8-1取代的C1-4烷基；R8-1选自卤素、氰基、羟基、甲氨基、乙胺基、二甲氨基、二乙氨基、丙胺基、甲基、乙基、丙基、异丙基、甲氧基或乙氧基。
优选地，当A为取代的C6-10的芳基时，所述取代基选自羟基、氰基、卤素、硝基、C1-4的烷基、C1-4烷氧基、羟基(C1-4烷基)-、氨基(C1-4烷基)-、C3-6环烷基、C3-6环烷基-(C1-4烷基)-、C3-6环烷基-(C1-4烷氧基)-、-NR1-4R1-5、-(C＝O)R1-6、-(C＝O)NR1-7R1-8、-NR1-9(C＝O)R1 -10、-(C＝O)OR1-11、-O(C＝O)R1-12、-(S＝O)2NR1-13R1-14、-NR1-15(S＝O)2R1-16、-(S＝O)2R1-17、-(P＝O)(CH3)2、未取代或R1-1取代的苯基、苯基-(C1-4烷基)-、未取代或R1-2取代的杂环烷基、杂环烷基-(C1-4烷基)-、未取代或R1-3取代的杂芳基、杂芳基-(C1-4烷基)-；R1-1、R1-2和R1-3独立地选自氢、甲基、乙基、羟甲基、羟乙基、氟、氯、溴、氰基、羟基、甲胺基、乙氨基、甲氧基、乙氧基、溴甲基、溴乙基、氯甲基或氯乙基；R1-4～R1-17独立地选自氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、C3-6环烷基或C3-6环烷基-(C1-4烷基)；
当A为OR2、SR2、NR2R3时，R2选自羟基(C1-4烷基)-、氨基(C1-4烷基)-、C1-4烷氧基(C1-4烷基)-、R2-1S(＝O)2(C1-4烷基)-、R2-2(C＝O)(C1-4烷基)-、-NR2-3R2-4、C3-6环烷基、C3-6环烷基-(C1-4烷基)-、未取代的或R2-3取代的苯基、苯基-(C1-4烷基)-、未取代的或R2-4取代的杂环烷基、杂环烷基-(C1-6烷基)-、未取代的或R2-5取代的杂芳基、杂芳基-(C1-4烷基)-；所述杂环烷基为杂原子数为1-4个的3-7元杂环烷基；所述杂芳基为杂原子数为1-3个的5-6元杂芳基；R2-1选自氢、C1-4烷基、C3-6环烷基或C3-6环烷基-(C1-4烷基)-；R2-2选自氢、氨基、羟基、C1-4烷基、C1-4烷氧基、C1-4烷胺基、R2-2-1取代的杂环烷基或杂环烷基-(C1-4烷基)-；R2-2-1独立地选自氢、羟基、甲基、乙基、甲氧基或乙氧基；R2-3～R2-5独立地选自氢、卤素、硝基、氰基、甲基、乙基、丙基、羟基、氨基、-NR2-3-1R2-3-2、-(C＝O)R2-3-3、-(C＝O)NR2-3-4R2-3-5、-NR2-3-6(C＝O)R2 -3-7、-(C＝O)OR2-3-8、-O(C＝O)R2-3-9、-S(＝O)2NR2-3-10R2-3-11、-NR2-3-12S(＝O)2R2-3-13、-S(＝O)2R2-3-14或-P(＝O)R2-3-15R2-3-16；R2-3-1～R2-3-16独立地选自氢、C1-4烷基、C3-6环烷基或C3-6环烷基-(C1-6烷基)-；R3选自氢、甲基或乙基。
优选地，所述A基团选自下列基团中的一种：
优选地，所述化合物为如下任一种结构：
所述的2-氨基嘧啶类化合物的制备方法，其制备过程的反应式为：
其中，P为Cl、Br或I。
含有所述2-氨基嘧啶类化合物的药物组合物，其以该化合物作为活性成分和药学上可接受的载体。
所述2-氨基嘧啶类化合物可应用于制备具有EGFR抑制活性的抑制剂。
所述2-氨基嘧啶类化合物可应用于制备抗肿瘤药物。
有益效果：与现有技术相比，本发明具有如下显著优点：所述2-氨基嘧啶类化合物具有高EGFR激酶选择活性，结构新颖，有望解决目前临床针对EGFR C797S尚无上市抑制剂药物的现状。
具体实施方式
下面结合实施例对本发明的技术方案作进一步说明。
中间体B1～B14如下：
中间体C1～C10如下：
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实施例1
化合物S1的合成反应式及制备过程如下：
步骤1. 4-(4,4,5,5-四甲基-1,3,2-二恶硼烷-2-基)-1H-吡唑(1)的制备
0℃下，向4-溴-1H-吡唑(147mg,1.0mmol)和联硼酸频那醇酯(280mg,1.1mmol)的1,4-二氧六环(6mL)溶液中，加入1,1-双(二苯基膦)二荗铁二氯化钯(37mg,0.05mmol)、醋酸钾(294mg,3.0mmol)，升温至80℃反应10小时后反应完全，加入水(10mL)淬灭反应，用EA萃取三次。合并有机相，有机相用无水硫酸钠干燥，过滤，浓缩后柱层析分离得化合物1(130mg,67％)。ESI-MS m/z:195.1[M+H]+
步骤2. 1-(环丙基磺酰基)-4-(4,4,5,5-四甲基-1,3,2-二恶硼烷-2-基)-1H-吡唑(2)的制备
0℃下，向4-(4,4,5,5-四甲基-1,3,2-二恶硼烷-2-基)-1H-吡唑(1)(194mg,1.0mmol)的THF(6mL)溶液中，加入NaH(48mg,60％,1.2mmol)后移至室温反应1小时，降至0℃，加入环丙基磺酰氯(211mg,1.5mmol)，升温至室温反应4小时后反应完全，用EA萃取三次。合并有机相，有机相用无水硫酸钠干燥，过滤，浓缩后柱层析分离得化合物2(208mg,70％)。ESI-MS m/z:299.1[M+H]+
步骤3.中间体2-(1-(环丙基磺酰基)-1H-吡唑-4-基)嘧啶-4-胺(3)的制备
0℃下，向1-(环丙基磺酰基)-4-(4,4,5,5-四甲基-1,3,2-二恶硼烷-2-基)-1H-吡唑(2)(298mg,1.0mmol)和2-氯嘧啶-4-胺(129mg,1.0mmol)的乙腈(6mL)溶液中，加入二氯二叔丁基-(4-二甲基氨基苯基)磷钯(II)(35.5mg,0.05mmol)、2M碳酸钠水溶液(1mL,2.0mmol)，升温至100℃反应4小时后反应完全，冷却至室温后，用EA萃取三次。合并有机相，有机相用无水硫酸钠干燥，过滤，浓缩后柱层析分离得化合物3(109mg,41％)。ESI-MS m/z:266.1[M+H]+
步骤4. 3-氯-5-异丙基-8-((2R,3S)-2-甲基-3-((甲基磺酰基)甲基)氮杂环丁烷-1-基)异喹啉(4)的合成
0℃下，向(2R,3S)-2-甲基-3-((甲基磺酰基)甲基)氮杂环丁烷(B1)(163mg,1.0mmol)和8-溴-3-氯-5-异丙基异喹啉(C1)(285mg,1.0mmol)的异丙醇(5mL)溶液中，加入TEA(416μL,3.0mmol)，升至95℃反应4小时后反应完全，冷却至室温后，用EA萃取三次。合并有机相，有机相用无水硫酸钠干燥，过滤，浓缩后柱层析分离得化合物4(275mg,75％)。ESI-MS m/z:367.1[M+H]+
步骤5.N-(2-(1-(环丙基甲基)-1H-吡唑-4-基)嘧啶-4-基)-5-异丙基-8-((2R,3S)-2-甲基-3-((甲基磺酰基)甲基)氮杂环丁烷-1-基)异喹啉-3-胺(S1)的合成
0℃下，向3-氯-5-异丙基-8-((2R,3S)-2-甲基-3-((甲基磺酰基)甲基)氮杂环丁烷-1-基)异喹啉(4)(367mg,1.0mmol)和2-(1-(环丙基磺酰基)-1H-吡唑-4-基)嘧啶-4-胺(3)(265mg,1.0mmol)的1,4-二氧六环(5mL)溶液中，加入,Brettphos Pd G3(181mg,0.2mmol)和碳酸铯(326mg,1.0mmol)，升至95℃反应4小时后反应完全，冷却至室温后，用EA萃取三次。合并有机相，有机相用无水硫酸钠干燥，过滤，浓缩后柱层析分离得化合物S1(298mg,50％)。1H NMR(300MHz,DMSO-d6)δ8.99(t,J＝0.5Hz,1H),8.65(d,J＝5.6Hz,1H),8.50–8.39(m,2H),8.13(d,J＝0.5Hz,1H),7.53(d,J＝5.6Hz,1H),7.31(dd,J＝8.5,0.5Hz,1H),6.93–6.80(m,2H),4.04–3.84(m,2H),3.82(dd,J＝9.3,5.7Hz,1H),3.69(hept,J＝6.8Hz,1H),3.33(dd,J＝6.2,2.2Hz,2H),2.94(s,3H),2.90–2.72(m,1H),1.88(p,J＝5.5Hz,1H),1.54(tdd,J＝8.7,5.4,0.7Hz,2H),1.37(d,J＝6.7Hz,3H),1.27–1.09(m,8H)。ESI-MS m/z:596.2[M+H]+
实施例2-76
实施例2-76分别为化合物S2-S76的合成方法，均参照实施例1。
化合物S2：1H NMR(300MHz,DMSO-d6)δ8.95(d,J＝0.5Hz,1H),8.59(d,J＝5.6Hz,1H),8.34(d,J＝0.5Hz,1H),8.24(s,1H),7.64(d,J＝4.2Hz,1H),7.54(d,J＝5.6Hz,1H),7.35–7.20(m,2H),6.89(dd,J＝8.5,0.5Hz,1H),4.05–3.89(m,2H),3.79(dd,J＝9.2,5.6Hz,1H),3.66(hept,J＝6.8Hz,1H),3.33(dd,J＝6.2,2.0Hz,2H),2.94(s,3H),2.89–2.72(m,1H),1.88(p,J＝5.5Hz,1H),1.54(tdd,J＝8.8,5.4,0.6Hz,2H),1.38(d,J＝6.7Hz,3H),1.20(dd,J＝15.0,6.7Hz,6H),1.10(tdd,J＝9.6,5.5,0.7Hz,2H)。ESI-MS m/z:596.2[M+H]+
化合物S3：1H NMR(300MHz,DMSO-d6)δ8.77(d,J＝0.5Hz,1H),8.63–8.50(m,2H),8.46(d,J＝0.6Hz,1H),8.34(d,J＝0.5Hz,1H),7.64(d,J＝4.4Hz,1H),7.54(d,J＝5.6Hz,1H),7.23(d,J＝4.2Hz,1H),4.21–4.03(m,2H),3.93(dd,J＝9.2,5.6Hz,1H),3.79(hept,J＝6.5Hz,1H),3.43–3.26(m,3H),3.01(qt,J＝6.3,5.7Hz,1H),2.94(s,3H),2.42–2.17(m,4H),1.93–1.75(m,2H),1.40–1.27(m,9H)。ESI-MS m/z:611.2[M+H]+
化合物S4：1H NMR(300MHz,DMSO-d6)δ8.98(d,J＝0.5Hz,1H),8.59(d,J＝5.6Hz,1H),8.34(d,J＝0.5Hz,1H),8.23(s,1H),7.69(d,J＝4.4Hz,1H),7.54(d,J＝5.6Hz,1H),7.32(dd,J＝8.5,0.5Hz,1H),7.00–6.88(m,2H),4.10(p,J＝6.6Hz,1H),3.88(dd,J＝9.2,6.8Hz,1H),3.81–3.59(m,2H),3.34(dd,J＝6.2,1.4Hz,2H),3.04(s,3H),2.96(s,3H),2.91–2.74(m,1H),1.33–1.13(m,9H)。ESI-MS m/z:570.2[M+H]+
化合物S5：1H NMR(300MHz,DMSO-d6)δ9.13(t,J＝0.5Hz,1H),8.57(d,J＝5.6Hz,1H),8.39(s,1H),8.29(d,J＝0.5Hz,1H),7.64(d,J＝4.2Hz,1H),7.54(d,J＝5.6Hz,1H),7.25–7.13(m,2H),4.15(p,J＝6.7Hz,1H),3.98(dd,J＝9.2,6.8Hz,1H),3.82(dd,J＝9.2,5.8Hz,1H),3.33(dd,J＝6.2,1.5Hz,2H),2.94(s,3H),2.94–2.72(m,2H),1.88(p,J＝5.5Hz,1H),1.54(tdd,J＝8.7,5.4,0.6Hz,2H),1.48–1.33(m,9H),1.14(tdd,J＝9.7,5.6,0.8Hz,2H)。ESI-MS m/z:597.2[M+H]+
化合物S6：1H NMR(300MHz,DMSO-d6)δ8.78(d,J＝0.5Hz,1H),8.56–8.41(m,2H),8.39–8.31(m,2H),7.59–7.48(m,2H),7.29–7.17(m,1H),6.99(d,J＝5.6Hz,1H),6.83(ddd,J＝7.9,2.1,1.3Hz,1H),5.06–4.91(m,2H),4.20–4.02(m,2H),3.92(dd,J＝9.2,5.6Hz,1H),3.43–3.24(m,2H),3.14(hept,J＝6.5Hz,1H),3.07–2.90(m,1H),2.94(s,3H),1.45–1.26(m,9H)。ESI-MS m/z:518.2[M+H]+
化合物S7：1H NMR(300MHz,DMSO-d6)δ8.96(t,J＝0.5Hz,1H),8.63(d,J＝5.6Hz,1H),8.49(s,1H),8.14–8.01(m,2H),7.53(d,J＝5.6Hz,1H),7.39–7.30(m,1H),6.94–6.83(m,2H),3.98(s,3H),4.03–3.85(m,2H),3.80(dd,J＝9.2,5.8Hz,1H),3.68(dq,J＝13.5,6.7Hz,1H),3.33(dd,J＝6.2,2.2Hz,2H),2.94(s,3H),2.89–2.72(m,1H),1.40(d,J＝6.7Hz,3H),1.20(dd,J＝15.0,6.7Hz,6H)。ESI-MS m/z:506.2[M+H]+
化合物S8：1H NMR(300MHz,DMSO-d6)δ8.97(d,J＝0.5Hz,1H),8.63(d,J＝5.6Hz,1H),8.45(ddd,J＝7.8,2.2,1.2Hz,1H),8.26(s,1H),8.17(t,J＝2.2Hz,1H),8.02(ddd,J＝7.8,2.2,1.2Hz,1H),7.69(t,J＝7.9Hz,1H),7.31(dd,J＝8.5,0.5Hz,1H),7.13(d,J＝5.6Hz,1H),6.94–6.78(m,2H),4.10(p,J＝6.7Hz,1H),3.92(dd,J＝9.2,6.8Hz,1H),3.76(dd,J＝9.3,5.7Hz,1H),3.68(dq,J＝13.5,6.7Hz,1H),3.33(dd,J＝6.1,1.3Hz,2H),2.94(s,3H),2.90–2.72(m,1H),2.46(p,J＝5.5Hz,1H),1.38(d,J＝6.7Hz,3H),1.20(dd,J＝15.0,6.7Hz,6H),1.14–0.91(m,4H)。ESI-MS m/z:606.2[M+H]+
化合物S9：1H NMR(300MHz,DMSO-d6)δ8.78(d,J＝0.5Hz,1H),8.55(d,J＝5.6Hz,1H),8.45(s,1H),8.39–8.31(m,2H),7.93(t,J＝2.2Hz,1H),7.68(ddd,J＝7.8,2.2,1.2Hz,1H),7.22(t,J＝7.8Hz,1H),7.13(d,J＝5.6Hz,1H),6.94(ddd,J＝7.8,2.2,1.2Hz,1H),4.20–4.02(m,2H),3.93(dd,J＝9.3,5.7Hz,1H),3.81(s,3H),3.33(dd,J＝6.1,2.4Hz,2H),3.14(hept,J＝6.5Hz,1H),3.10–2.95(m,1H),2.94(s,3H),1.45–1.26(m,9H)。ESI-MS m/z:533.2[M+H]+
化合物S10：1H NMR(300MHz,DMSO-d6)δ9.13(d,J＝0.6Hz,1H),8.58(d,J＝5.6Hz,1H),8.33–8.26(m,2H),7.60–7.48(m,2H),7.18–7.06(m,3H),6.78(ddd,J＝7.8,2.2,1.2Hz,1H),4.15(p,J＝6.7Hz,1H),3.99(dd,J＝9.2,6.8Hz,1H),3.82(dd,J＝9.3,5.7Hz,1H),3.33(dd,J＝6.3,1.5Hz,2H),2.95(d,J＝1.8Hz,9H),2.93–2.73(m,2H),1.46–1.32(m,9H)。ESI-MS m/z:546.3[M+H]+
化合物S11：1H NMR(300MHz,DMSO-d6)δ8.98(d,J＝0.5Hz,1H),8.65(d,J＝5.6Hz,1H),8.48(t,J＝2.2Hz,1H),8.35(ddd,J＝7.8,2.2,1.2Hz,1H),8.19(s,1H),8.08(ddd,J＝7.8,2.2,1.2Hz,1H),7.69–7.53(m,3H),7.32(dd,J＝8.5,0.5Hz,1H),7.13(d,J＝5.6Hz,1H),6.94(dd,J＝8.5,0.5Hz,1H),6.83(d,J＝0.5Hz,1H),4.11(p,J＝6.7Hz,1H),3.89(dd,J＝9.2,6.8Hz,1H),3.81–3.59(m,2H),3.34(dd,J＝6.2,1.5Hz,2H),2.96(s,3H),2.91–2.74(m,1H),1.33–1.13(m,9H)。ESI-MS m/z:545.2[M+H]+
化合物S12：1H NMR(300MHz,DMSO-d6)δ8.97(d,J＝0.5Hz,1H),8.61(d,J＝5.6Hz,1H),8.46–8.29(m,2H),8.26(s,1H),8.06(ddd,J＝7.8,2.2,1.2Hz,1H),7.69(t,J＝7.8Hz,1H),7.31(dd,J＝8.5,0.5Hz,1H),7.13(d,J＝5.6Hz,1H),6.93–6.79(m,2H),4.10(p,J＝6.7Hz,1H),3.92(dd,J＝9.2,6.9Hz,1H),3.76(dd,J＝9.2,5.8Hz,1H),3.68(dq,J＝13.5,6.8Hz,1H),3.33(dd,J＝6.2,1.3Hz,2H),3.23(s,3H),2.94(s,3H),2.90–2.72(m,1H),1.38(d,J＝6.7Hz,3H),1.20(dd,J＝15.0,6.7Hz,6H)。ESI-MS m/z:580.2[M+H]+
化合物S13：1H NMR(300MHz,DMSO-d6)δ8.98(d,J＝0.5Hz,1H),8.52(d,J＝5.6Hz,1H),8.36–8.24(m,2H),8.28–8.16(m,1H),7.66–7.51(m,2H),7.35–7.19(m,2H),6.88(dd,J＝8.5,0.5Hz,1H),6.78(d,J＝0.5Hz,1H),4.04–3.85(m,2H),3.81(dd,J＝9.2,5.6Hz,1H),3.66(hept,J＝6.8Hz,1H),3.33(dd,J＝6.2,2.2Hz,2H),2.94(s,3H),2.90–2.73(m,1H),2.11(d,J＝13.1Hz,6H),1.37(d,J＝6.7Hz,3H),1.20(dd,J＝15.0,6.7Hz,6H)。ESI-MS m/z:578.2[M+H]+
化合物S14：1H NMR(300MHz,DMSO-d6)δ8.83(d,J＝0.5Hz,1H),8.63–8.53(m,3H),8.20–8.10(m,2H),8.07–7.96(m,2H),7.13(d,J＝5.6Hz,1H),4.24–4.07(m,2H),3.98(dd,J＝9.3,5.7Hz,1H),3.51–3.09(m,5H),3.09–2.92(m,1H),2.94(s,3H),1.56(dd,J＝15.0,6.5Hz,6H),1.38(d,J＝6.7Hz,3H),1.24(t,J＝7.0Hz,3H)。ESI-MS m/z:596.2[M+H]+
化合物S15：1H NMR(300MHz,DMSO-d6)δ8.98(d,J＝0.6Hz,1H),8.58(d,J＝5.6Hz,1H),8.28(s,1H),8.22–8.12(m,2H),8.09–7.98(m,2H),7.33(dd,J＝8.4,0.5Hz,1H),7.13(d,J＝5.6Hz,1H),6.93(dd,J＝8.5,0.5Hz,1H),6.82(d,J＝0.6Hz,1H),4.12(p,J＝6.7Hz,1H),3.89(dd,J＝9.2,6.8Hz,1H),3.81–3.59(m,2H),3.27–2.99(m,4H),2.81(dtd,J＝12.5,6.6,5.8Hz,1H),2.46(p,J＝5.5Hz,1H),1.54–1.39(m,2H),1.37–1.13(m,14H)。ESI-MS m/z:620.2[M+H]+
化合物S16：1H NMR(300MHz,DMSO-d6)δ8.96(d,J＝0.5Hz,1H),8.65(d,J＝5.6Hz,1H),8.49(s,1H),8.27(d,J＝0.5Hz,1H),7.96(d,J＝0.5Hz,1H),7.53(d,J＝5.6Hz,1H),7.34(dd,J＝8.5,0.5Hz,1H),6.94–6.83(m,2H),4.32–4.06(m,2H),4.03–3.86(m,2H),3.80(dd,J＝9.2,5.6Hz,1H),3.69(hept,J＝6.7Hz,1H),3.33(dd,J＝6.2,2.2Hz,2H),2.94(s,3H),2.90–2.73(m,1H),1.47–1.34(m,6H),1.20(dd,J＝15.0,6.7Hz,6H)。ESI-MS m/z:520.2[M+H]+
化合物S17：1H NMR(300MHz,DMSO-d6)δ9.29(s,1H),9.13(d,J＝0.5Hz,1H),8.60(d,J＝5.6Hz,1H),8.33–8.22(m,2H),8.03–7.93(m,2H),7.17–7.08(m,2H),6.94–6.83(m,2H),4.17–3.95(m,2H),3.83(dd,J＝9.2,5.6Hz,1H),3.33(dd,J＝6.1,1.8Hz,2H),2.94(s,3H),2.90–2.65(m,2H),1.46–1.32(m,9H)。ESI-MS m/z:519.2[M+H]+
化合物S18：1H NMR(300MHz,DMSO-d6)δ8.97(d,J＝0.5Hz,1H),8.52(d,J＝5.6Hz,1H),8.28(s,1H),8.07–7.95(m,2H),7.80–7.65(m,2H),7.31(dd,J＝8.5,0.5Hz,1H),7.13(d,J＝5.6Hz,1H),6.93–6.80(m,2H),4.10(p,J＝6.7Hz,1H),3.92(dd,J＝9.2,6.9Hz,1H),3.76(dd,J＝9.2,5.6Hz,1H),3.68(dq,J＝13.5,6.7Hz,1H),3.33(dd,J＝6.2,1.2Hz,2H),2.95(s,3H),2.90–2.73(m,1H),2.07(d,J＝13.1Hz,6H),1.38(d,J＝6.7Hz,3H),1.20(dd,J＝15.0,6.7Hz,6H)。ESI-MS m/z:578.2[M+H]+
化合物S19：1H NMR(300MHz,DMSO-d6)δ8.96(d,J＝0.5Hz,1H),8.78–8.69(m,2H),8.63(d,J＝5.6Hz,1H),8.31–8.22(m,3H),7.53(d,J＝5.6Hz,1H),7.41–7.31(m,1H),6.97–6.82(m,2H),4.06–3.86(m,2H),3.74(dd,J＝9.2,5.6Hz,1H),3.64(dq,J＝13.6,6.8Hz,1H),3.34(dd,J＝6.2,1.2Hz,2H),2.95(s,3H),2.90–2.73(m,1H),1.32(d,J＝6.7Hz,3H),1.20(dd,J＝15.0,6.7Hz,6H)。ESI-MS m/z:503.2[M+H]+
化合物S20：1H NMR(300MHz,DMSO-d6)δ9.08(d,J＝0.5Hz,1H),8.96(t,J＝0.5Hz,1H),8.65–8.52(m,2H),8.43(s,1H),7.52(d,J＝5.6Hz,1H),7.36(dd,J＝8.5,0.5Hz,1H),6.93(dd,J＝8.3,0.5Hz,1H),6.83(t,J＝0.5Hz,1H),4.06–3.86(m,2H),3.79–3.59(m,2H),3.26–2.99(m,4H),2.81(dtd,J＝12.5,6.6,5.7Hz,1H),1.37–1.25(m,6H),1.20(dd,J＝15.0,6.7Hz,6H)。ESI-MS m/z:523.2[M+H]+
化合物S21：1H NMR(300MHz,DMSO-d6)δ9.17(t,J＝0.5Hz,1H),8.65(d,J＝5.6Hz,1H),8.55(s,1H),8.42(d,J＝0.5Hz,1H),8.28(d,J＝0.5Hz,1H),8.13(d,J＝0.5Hz,1H),7.53(d,J＝5.6Hz,1H),7.14(d,J＝0.5Hz,1H),4.10–3.91(m,2H),3.87(dd,J＝9.3,5.7Hz,1H),3.33(dd,J＝6.2,2.6Hz,2H),3.06(hept,J＝6.5Hz,1H),2.94(s,3H),2.90–2.73(m,1H),2.68(p,J＝5.6Hz,1H),1.54(tdd,J＝8.8,5.5,0.8Hz,2H),1.48–1.32(m,9H),1.16(tdd,J＝9.6,5.6,0.8Hz,2H)。ESI-MS m/z:597.2[M+H]+
化合物S22：1H NMR(300MHz,DMSO-d6)δ9.16(t,J＝0.5Hz,1H),8.65(d,J＝5.6Hz,1H),8.52(s,1H),8.42(d,J＝0.5Hz,1H),8.28(d,J＝0.5Hz,1H),8.15(d,J＝0.5Hz,1H),7.53(d,J＝5.6Hz,1H),7.14(d,J＝0.5Hz,1H),4.10–3.91(m,2H),3.87(dd,J＝9.2,5.6Hz,1H),3.43–3.25(m,3H),2.94(s,3H),2.95–2.72(m,2H),2.41–2.16(m,4H),1.93–1.74(m,2H),1.48–1.32(m,9H)。ESI-MS m/z:611.2[M+H]+
化合物S23：1H NMR(300MHz,DMSO-d6)δ8.94(s,1H),8.82(d,J＝0.5Hz,1H),8.66–8.57(m,2H),8.46(s,1H),7.72(td,J＝7.9,2.2Hz,1H),7.59(ddd,J＝7.8,5.1,3.5Hz,1H),7.24(d,J＝5.6Hz,1H),4.22–4.06(m,2H),3.97(dd,J＝9.2,5.6Hz,1H),3.42–3.27(m,2H),3.32–3.16(m,1H),3.07–2.92(m,1H),2.94(s,3H),1.56(dd,J＝15.0,6.5Hz,6H),1.32(d,J＝6.7Hz,3H)。ESI-MS m/z:523.2[M+H]+
化合物S24：1H NMR(300MHz,DMSO-d6)δ8.96(d,J＝0.5Hz,1H),8.62–8.47(m,2H),7.64(d,J＝5.6Hz,1H),7.50(d,J＝5.6Hz,1H),7.36(dd,J＝8.5,0.5Hz,1H),6.99–6.82(m,3H),4.06–3.86(m,5H),3.79–3.59(m,2H),3.34(dd,J＝6.3,1.2Hz,2H),2.95(s,3H),2.90–2.73(m,1H),1.32(d,J＝6.7Hz,3H),1.20(dd,J＝15.0,6.7Hz,6H)。ESI-MS m/z:506.2[M+H]+
化合物S25：1H NMR(300MHz,DMSO-d6)δ9.06(s,1H),8.77(d,J＝0.5Hz,1H),8.58–8.46(m,2H),8.44–8.31(m,2H),8.03–7.92(m,2H),7.46–7.35(m,2H),7.13(d,J＝5.6Hz,1H),4.21–4.03(m,2H),3.93(dd,J＝9.2,5.6Hz,1H),3.41–3.22(m,3H),3.10–2.91(m,7H),1.45–1.26(m,9H)。ESI-MS m/z:596.2[M+H]+
化合物S26：1H NMR(300MHz,DMSO-d6)δ9.13(d,J＝0.5Hz,1H),8.52(d,J＝5.6Hz,1H),8.35–8.26(m,2H),8.04–7.92(m,2H),7.79–7.64(m,2H),7.19–7.08(m,2H),4.14–3.96(m,2H),3.85(dd,J＝9.2,5.8Hz,1H),3.33(dd,J＝6.2,2.1Hz,2H),2.94(s,3H),2.90–2.64(m,2H),2.07(d,J＝13.1Hz,6H),1.46–1.32(m,9H)。ESI-MS m/z:579.2[M+H]+
化合物S27：1H NMR(300MHz,DMSO-d6)δ9.00(d,J＝0.5Hz,1H),8.61(d,J＝5.6Hz,1H),8.41(ddd,J＝7.8,2.2,1.2Hz,1H),8.37–8.25(m,2H),8.06(ddd,J＝7.8,2.2,1.2Hz,1H),7.69(t,J＝7.8Hz,1H),7.44(dd,J＝8.3,0.5Hz,1H),7.23(d,J＝5.6Hz,1H),7.11–7.01(m,1H),6.83(d,J＝0.5Hz,1H),4.06(p,J＝6.7Hz,1H),3.88(dd,J＝9.2,6.8Hz,1H),3.74(dd,J＝9.2,5.7Hz,1H),3.33(dd,J＝6.2,1.2Hz,2H),3.23(s,3H),2.95(s,3H),2.89–2.72(m,1H),2.62(p,J＝5.8Hz,1H),1.38(d,J＝6.7Hz,3H),1.15–0.99(m,2H),0.93–0.77(m,2H)。ESI-MS m/z:578.2[M+H]+
化合物S28：1H NMR(300MHz,DMSO-d6)δ8.77(d,J＝0.5Hz,1H),8.63–8.54(m,2H),8.47–8.40(m,1H),8.37–8.27(m,2H),8.10(s,1H),7.54(d,J＝5.6Hz,1H),4.21–4.02(m,2H),3.93(dd,J＝9.2,5.8Hz,1H),3.43–3.23(m,3H),3.09–2.92(m,1H),2.94(s,3H),1.88(p,J＝5.6Hz,1H),1.42–1.28(m,9H),1.18–0.91(m,4H)。ESI-MS m/z:597.2[M+H]+
化合物S29：1H NMR(300MHz,DMSO-d6)δ9.54(s,1H),9.00(d,J＝0.7Hz,1H),8.61(d,J＝5.6Hz,1H),8.46–8.29(m,2H),8.26(s,1H),8.06(ddd,J＝7.8,2.2,1.2Hz,1H),7.70(t,J＝7.9Hz,1H),7.46(dd,J＝8.5,0.5Hz,1H),7.17–7.06(m,2H),6.82(d,J＝0.5Hz,1H),3.94–3.78(m,2H),3.69(p,J＝6.7Hz,1H),3.66–3.52(m,2H),3.23(s,3H),2.63(q,J＝7.0Hz,2H),2.62–2.47(m,3H),1.31(t,J＝6.9Hz,3H),1.20(d,J＝6.8Hz,6H)。ESI-MS m/z:579.2[M+H]+
化合物S30：1H NMR(300MHz,DMSO-d6)δ8.95(d,J＝0.5Hz,1H),8.52(d,J＝5.6Hz,1H),8.37–8.16(m,3H),7.66–7.50(m,2H),7.30(dd,J＝8.5,0.5Hz,1H),7.13(d,J＝5.6Hz,1H),6.93–6.78(m,2H),4.07–3.91(m,2H),3.82(dd,J＝9.3,5.7Hz,1H),3.68(h,J＝6.8Hz,1H),3.40(dd,J＝6.2,2.6Hz,2H),2.96–2.81(m,1H),2.11(d,J＝13.1Hz,6H),1.38(d,J＝6.7Hz,3H),1.20(dd,J＝15.0,6.7Hz,6H)。ESI-MS m/z:632.2[M+H]+
化合物S31：1H NMR(300MHz,DMSO-d6)δ9.11(s,1H),8.65(d,J＝5.6Hz,1H),8.49(s,1H),8.31(d,J＝0.5Hz,1H),8.08(d,J＝0.5Hz,1H),7.96(s,1H),7.53(d,J＝5.6Hz,1H),7.14(d,J＝0.5Hz,1H),4.17(dd,J＝12.0,3.8Hz,1H),4.10–3.90(m,2H),3.91–3.79(m,2H),3.25–2.98(m,4H),2.91(hept,J＝6.3Hz,1H),2.86–2.71(m,1H),1.52–1.34(m,10H),1.30(t,J＝7.0Hz,3H),0.59–0.43(m,2H),0.30–0.14(m,2H)。ESI-MS m/z:561.3[M+H]+
化合物S32：1H NMR(300MHz,DMSO-d6)δ9.01(t,J＝0.5Hz,1H),8.71(s,1H),8.55(d,J＝5.6Hz,1H),8.15(s,1H),7.87(s,1H),7.54(d,J＝5.6Hz,1H),7.33(dd,J＝8.5,0.5Hz,1H),6.94(dd,J＝8.5,0.5Hz,1H),6.78(t,J＝0.5Hz,1H),4.05–3.88(m,2H),3.77–3.56(m,2H),3.34(dd,J＝6.2,0.9Hz,2H),2.96(s,3H),2.90–2.75(m,1H),2.70(p,J＝5.5Hz,1H),1.49–1.33(m,5H),1.27–1.06(m,8H)。ESI-MS m/z:596.2[M+H]+
化合物S33：1H NMR(300MHz,DMSO-d6)δ8.89(s,1H),8.78(d,J＝0.5Hz,1H),8.52–8.39(m,2H),8.36–8.29(m,2H),7.56(d,J＝5.6Hz,1H),4.21–4.02(m,2H),3.93(dd,J＝9.2,5.8Hz,1H),3.49–3.26(m,3H),3.09–2.94(m,1H),2.94(s,3H),2.73(p,J＝5.5Hz,1H),1.77–1.54(m,4H),1.43–1.29(m,9H)。ESI-MS m/z:598.2[M+H]+
化合物S34：1H NMR(300MHz,DMSO-d6)δ9.00(t,J＝0.5Hz,1H),8.65(s,1H),8.57(d,J＝5.6Hz,1H),8.20(s,1H),7.77(s,1H),7.54(d,J＝5.6Hz,1H),7.32(dd,J＝8.4,0.5Hz,1H),6.93(dd,J＝8.5,0.5Hz,1H),6.81(t,J＝0.5Hz,1H),4.07–3.84(m,2H),3.79–3.59(m,2H),3.38(hept,J＝6.2Hz,1H),3.32–3.00(m,4H),3.00–2.83(m,1H),1.44–1.13(m,18H)。ESI-MS m/z:612.2[M+H]+
化合物S35：1H NMR(300MHz,DMSO-d6)δ9.00–8.94(m,1H),8.66(d,J＝5.6Hz,1H),8.49–8.39(m,2H),8.16(d,J＝0.5Hz,1H),7.53(d,J＝5.6Hz,1H),7.36(dd,J＝8.5,0.5Hz,1H),6.93–6.78(m,2H),3.81(d,J＝10.5Hz,2H),3.67(d,J＝10.6Hz,2H),3.29(s,2H),3.01(q,J＝6.9Hz,2H),2.62(p,J＝5.8Hz,1H),1.88(p,J＝5.5Hz,1H),1.54(tdd,J＝8.7,5.4,0.6Hz,2H),1.30(t,J＝7.0Hz,3H),1.14(s,3H),1.22–1.02(m,4H),0.94–0.78(m,2H)。ESI-MS m/z:608.2[M+H]+
化合物S36：1H NMR(300MHz,DMSO-d6)δ8.97(d,J＝0.5Hz,1H),8.66(d,J＝5.6Hz,1H),8.47(s,1H),8.38(d,J＝0.5Hz,1H),8.15(d,J＝0.5Hz,1H),7.53(d,J＝5.6Hz,1H),7.35–7.26(m,1H),6.93–6.80(m,2H),4.03–3.86(m,2H),3.81(dd,J＝9.3,5.7Hz,1H),3.69(hept,J＝6.8Hz,1H),3.34(d,J＝2.1Hz,1H),3.36–3.19(m,2H),3.15(dq,J＝14.0,7.0Hz,1H),2.94(s,3H),2.89–2.72(m,1H),1.42–1.25(m,6H),1.20(dd,J＝15.0,6.7Hz,6H)。ESI-MS m/z:584.2[M+H]+
化合物S37：1H NMR(300MHz,DMSO-d6)δ9.14(t,J＝0.5Hz,1H),8.71–8.60(m,2H),8.36(d,J＝0.5Hz,1H),8.23(d,J＝0.5Hz,1H),7.97(d,J＝0.5Hz,1H),7.53(d,J＝5.6Hz,1H),7.16(d,J＝0.5Hz,1H),4.36–4.06(m,3H),3.98–3.71(m,6H),3.57(dtd,J＝12.7,6.6,6.0Hz,1H),3.28(hept,J＝6.2Hz,1H),3.16(d,J＝6.0Hz,2H),2.60(ddd,J＝11.6,6.1,5.6Hz,1H),1.50–1.36(m,6H),1.31(d,J＝6.2Hz,6H)。ESI-MS m/z:551.3[M+H]+
化合物S38：1H NMR(300MHz,DMSO-d6)δ9.13(t,J＝0.5Hz,1H),8.59(d,J＝5.6Hz,1H),8.32–8.24(m,2H),7.52(d,J＝5.6Hz,1H),7.17(dd,J＝16.7,1.0Hz,2H),7.09–7.01(m,1H),6.63(dd,J＝4.3,1.5Hz,1H),4.15(p,J＝6.7Hz,1H),3.99(dd,J＝9.2,6.8Hz,1H),3.82(dd,J＝9.3,5.7Hz,1H),3.33(dd,J＝6.2,1.6Hz,2H),2.94(s,3H),2.92–2.73(m,2H),1.84(p,J＝5.5Hz,1H),1.48–1.33(m,9H),1.15–0.89(m,4H)。ESI-MS m/z:596.2[M+H]+
化合物S39：1H NMR(300MHz,DMSO-d6)δ9.14(t,J＝0.5Hz,1H),8.73(s,1H),8.48(d,J＝5.6Hz,1H),8.33(s,1H),8.25(d,J＝0.5Hz,1H),7.56(d,J＝5.6Hz,1H),7.17(d,J＝0.5Hz,1H),4.10–3.91(m,2H),3.87(dd,J＝9.3,5.7Hz,1H),3.33(dd,J＝6.3,2.4Hz,2H),3.01(dq,J＝13.0,6.5Hz,1H),2.94(s,3H),2.89–2.73(m,1H),2.79–2.66(m,1H),1.77–1.54(m,4H),1.48–1.32(m,9H)。ESI-MS m/z:598.2[M+H]+
化合物S40：1H NMR(300MHz,DMSO-d6)δ9.11(s,1H),8.85(d,J＝0.5Hz,1H),8.64–8.53(m,2H),7.71(d,J＝5.6Hz,1H),7.54(d,J＝5.6Hz,1H),7.17(d,J＝5.6Hz,1H),4.01(d,J＝10.5Hz,2H),3.85(d,J＝10.5Hz,2H),3.37–3.11(m,4H),2.67(p,J＝5.5Hz,1H),1.60–1.44(m,8H),1.35–1.17(m,7H),1.18(dd,J＝5.6,1.1Hz,0H),1.12(s,3H)。ESI-MS m/z:626.2[M+H]+
化合物S41：1H NMR(300MHz,DMSO-d6)δ9.00(d,J＝0.5Hz,1H),8.67(s,1H),8.57(d,J＝5.6Hz,1H),7.71(d,J＝5.6Hz,1H),7.54(d,J＝5.6Hz,1H),7.32(dd,J＝8.5,0.5Hz,1H),7.16(d,J＝5.6Hz,1H),6.91(dd,J＝8.5,0.5Hz,1H),6.82(d,J＝0.5Hz,1H),4.10(p,J＝6.7Hz,1H),3.88(dd,J＝9.3,6.8Hz,1H),3.75(dd,J＝9.2,5.6Hz,1H),3.66(hept,J＝6.8Hz,1H),3.34(dd,J＝6.2,1.4Hz,2H),3.05(s,3H),2.96(s,3H),2.90–2.73(m,1H),1.29(d,J＝6.7Hz,3H),1.20(dd,J＝15.0,6.7Hz,6H)。ESI-MS m/z:570.2[M+H]+
化合物S42：1H NMR(300MHz,DMSO-d6)δ9.00(d,J＝0.5Hz,1H),8.67(s,1H),8.57(d,J＝5.6Hz,1H),7.70(d,J＝5.6Hz,1H),7.54(d,J＝5.6Hz,1H),7.32(dd,J＝8.5,0.5Hz,1H),7.16(d,J＝5.6Hz,1H),6.92(dd,J＝8.5,0.5Hz,1H),6.81(t,J＝0.5Hz,1H),4.11(p,J＝6.6Hz,1H),3.88(dd,J＝9.2,6.8Hz,1H),3.75(dd,J＝9.2,5.7Hz,1H),3.65(h,J＝6.7Hz,1H),3.43–3.26(m,3H),2.96(s,3H),2.90–2.73(m,1H),2.39–2.17(m,4H),1.93–1.76(m,2H),1.29(d,J＝6.7Hz,3H),1.20(dd,J＝15.0,6.7Hz,6H)。ESI-MS m/z:610.2[M+H]+
化合物S43：1H NMR(300MHz,DMSO-d6)δ8.83(d,J＝0.5Hz,1H),8.57(d,J＝5.6Hz,1H),8.33(s,1H),7.99(s,1H),7.82(s,1H),7.50(d,J＝5.6Hz,1H),7.13(dd,J＝8.5,0.5Hz,1H),6.96(d,J＝0.5Hz,1H),6.70(dd,J＝8.3,0.5Hz,1H),4.56(h,J＝6.2Hz,1H),4.03–3.87(m,2H),3.86–3.74(m,1H),3.79(s,3H),3.33(dd,J＝6.2,2.1Hz,2H),2.94(s,3H),2.87–2.70(m,1H),1.47–1.27(m,9H)。ESI-MS m/z:522.2[M+H]+
化合物S44：1H NMR(300MHz,DMSO-d6)δ9.14(d,J＝0.6Hz,1H),8.61(s,1H),8.48(d,J＝5.6Hz,1H),8.32–8.23(m,2H),7.56(d,J＝5.6Hz,1H),7.19(d,J＝0.5Hz,1H),4.15(p,J＝6.7Hz,1H),3.98(dd,J＝9.3,6.9Hz,1H),3.82(dd,J＝9.3,5.7Hz,1H),3.45–3.25(m,3H),2.95(s,3H),3.01–2.73(m,2H),2.44–2.19(m,4H),1.87–1.70(m,2H),1.48–1.33(m,9H)。ESI-MS m/z:612.2[M+H]+
化合物S45：1H NMR(300MHz,DMSO-d6)δ8.98(d,J＝0.5Hz,1H),8.64(s,1H),8.57(d,J＝5.6Hz,1H),8.05(d,J＝0.5Hz,1H),7.86(s,1H),7.54(d,J＝5.6Hz,1H),7.32(dd,J＝8.5,0.5Hz,1H),6.92(dd,J＝8.5,0.5Hz,1H),6.82(d,J＝0.5Hz,1H),4.10(p,J＝6.7Hz,1H),3.88(dd,J＝9.3,6.9Hz,1H),3.81–3.59(m,2H),3.34(dd,J＝6.2,1.5Hz,2H),3.05(s,3H),2.96(s,3H),2.90–2.73(m,1H),1.29(d,J＝6.7Hz,3H),1.20(dd,J＝15.0,6.7Hz,6H)。ESI-MS m/z:570.2[M+H]+
化合物S46：1H NMR(300MHz,DMSO-d6)δ8.93(s,1H),8.77(d,J＝0.5Hz,1H),8.57(d,J＝5.6Hz,1H),8.43(t,J＝0.5Hz,1H),8.33(d,J＝0.5Hz,1H),8.03(d,J＝0.5Hz,1H),7.83(s,1H),7.54(d,J＝5.6Hz,1H),4.19–4.02(m,2H),3.93(dd,J＝9.2,5.6Hz,1H),3.33(dd,J＝6.2,2.3Hz,2H),3.05(s,3H),3.16–2.94(m,2H),2.94(s,3H),1.41–1.27(m,9H)。ESI-MS m/z:571.2[M+H]+
化合物S47：1H NMR(300MHz,DMSO-d6)δ9.11(d,J＝0.5Hz,1H),8.61(d,J＝5.6Hz,1H),8.31(d,J＝0.5Hz,1H),8.19(s,1H),7.52(d,J＝5.6Hz,1H),7.29–7.22(m,1H),7.16(d,J＝0.5Hz,1H),7.07(d,J＝4.2Hz,1H),6.70(dd,J＝4.3,1.5Hz,1H),4.14(t,J＝7.0Hz,1H),4.10–3.94(m,2H),3.99–3.80(m,2H),3.76(ddd,J＝11.4,7.0,6.2Hz,1H),3.55–3.39(m,1H),3.44–3.23(m,2H),2.96(d,J＝12.8Hz,6H),2.89–2.72(m,1H),1.41(dd,J＝21.9,6.7Hz,6H)。ESI-MS m/z:586.2[M+H]+
化合物S48：1H NMR(300MHz,DMSO-d6)δ8.99(d,J＝0.5Hz,1H),8.60(d,J＝5.6Hz,1H),8.22(s,1H),7.52(d,J＝5.6Hz,1H),7.35–7.23(m,2H),7.06(d,J＝4.2Hz,1H),6.92–6.83(m,1H),6.83–6.69(m,2H),4.04–3.84(m,2H),3.82(dd,J＝9.2,5.8Hz,1H),3.69(hept,J＝6.8Hz,1H),3.43–3.23(m,3H),2.94(s,3H),2.89–2.72(m,1H),2.33–2.11(m,4H),1.94–1.73(m,2H),1.37(d,J＝6.7Hz,3H),1.20(dd,J＝15.0,6.7Hz,6H)。ESI-MS m/z:609.2[M+H]+
化合物S49：1H NMR(300MHz,DMSO-d6)δ9.93(s,1H),9.00(d,J＝0.5Hz,1H),8.57(d,J＝5.6Hz,1H),8.23(s,1H),7.52(d,J＝5.6Hz,1H),7.37–7.27(m,2H),7.05–6.90(m,2H),6.81(d,J＝0.5Hz,1H),6.53(dd,J＝4.2,1.5Hz,1H),4.20(p,J＝6.6Hz,1H),4.01(dd,J＝12.0,3.8Hz,1H),3.95–3.82(m,1H),3.82–3.59(m,3H),2.80–2.60(m,2H),2.52–2.36(m,4H),1.42–1.24(m,4H),1.20(dd,J＝15.0,6.7Hz,6H),0.77–0.61(m,2H),0.60–0.43(m,2H)。ESI-MS m/z:594.2[M+H]+
化合物S50：1H NMR(300MHz,DMSO-d6)δ8.99(t,J＝0.5Hz,1H),8.58(d,J＝5.6Hz,1H),8.30(s,1H),8.22(s,1H),8.10(s,1H),7.54(d,J＝5.6Hz,1H),7.30(dd,J＝8.3,0.5Hz,1H),6.93–6.78(m,2H),4.04–3.84(m,2H),3.82(dd,J＝9.3,5.7Hz,1H),3.69(hept,J＝6.8Hz,1H),3.43–3.25(m,3H),2.94(s,3H),2.90–2.74(m,1H),2.31–2.09(m,4H),1.90–1.73(m,2H),1.37(d,J＝6.7Hz,3H),1.20(dd,J＝15.0,6.7Hz,6H)。ESI-MS m/z:610.2[M+H]+
化合物S51：1H NMR(300MHz,DMSO-d6)δ8.94(t,J＝0.5Hz,1H),8.59(d,J＝5.6Hz,1H),8.30(d,J＝2.4Hz,2H),8.11(s,1H),7.54(d,J＝5.6Hz,1H),7.36(dd,J＝8.5,0.5Hz,1H),6.93–6.78(m,2H),3.82(d,J＝10.5Hz,2H),3.68(d,J＝10.6Hz,2H),3.42–3.25(m,3H),2.94(s,3H),2.66(p,J＝5.8Hz,1H),2.34–2.12(m,4H),1.94–1.74(m,2H),1.14(s,3H),1.21–1.05(m,2H),0.94–0.78(m,2H)。ESI-MS m/z:608.2[M+H]+
化合物S52：1H NMR(300MHz,DMSO-d6)δ8.83–8.74(m,2H),8.65(d,J＝5.6Hz,1H),8.46–8.31(m,3H),8.17(d,J＝0.5Hz,1H),7.53(d,J＝5.6Hz,1H),4.21–4.02(m,2H),3.93(dd,J＝9.2,5.6Hz,1H),3.43–3.23(m,3H),3.09–2.92(m,1H),2.94(s,3H),2.68(p,J＝5.6Hz,1H),1.54(tdd,J＝8.8,5.5,0.7Hz,2H),1.40–1.26(m,9H),1.14(tdd,J＝9.6,5.6,0.8Hz,2H)。ESI-MS m/z:597.2[M+H]+
化合物S53：1H NMR(300MHz,DMSO-d6)δ8.96(d,J＝0.5Hz,1H),8.59(d,J＝5.6Hz,1H),8.29(d,J＝4.0Hz,2H),8.09(s,1H),7.54(d,J＝5.6Hz,1H),7.31(dd,J＝8.5,0.5Hz,1H),6.94–6.79(m,2H),4.07–3.89(m,2H),3.79(dd,J＝9.2,5.6Hz,1H),3.69(hept,J＝6.8Hz,1H),3.33(dd,J＝6.1,1.8Hz,2H),2.95(s,3H),2.90–2.73(m,1H),1.88(p,J＝5.6Hz,1H),1.37(d,J＝6.7Hz,3H),1.20(dd,J＝15.0,6.7Hz,6H),1.16–0.90(m,4H)。ESI-MS m/z:596.2[M+H]+
化合物S54：1H NMR(300MHz,DMSO-d6)δ8.98(d,J＝0.5Hz,1H),8.59(s,1H),8.48(d,J＝5.6Hz,1H),8.38–8.30(m,2H),7.56(d,J＝5.6Hz,1H),7.31(dd,J＝8.5,0.5Hz,1H),6.90(dd,J＝8.5,0.5Hz,1H),4.11(p,J＝6.7Hz,1H),3.88(dd,J＝9.2,6.8Hz,1H),3.82–3.59(m,2H),3.34(dd,J＝6.2,1.4Hz,2H),2.96(s,3H),2.90–2.75(m,1H),2.73(p,J＝5.5Hz,1H),1.77–1.54(m,4H),1.29(d,J＝6.8Hz,3H),1.20(dd,J＝15.0,6.7Hz,6H)。ESI-MS m/z:597.2[M+H]+
化合物S55：1H NMR(300MHz,DMSO-d6)δ8.96(d,J＝0.5Hz,1H),8.62–8.49(m,2H),8.21(s,1H),7.56(d,J＝5.6Hz,1H),7.32(dd,J＝8.5,0.5Hz,1H),6.98–6.89(m,1H),6.83(d,J＝0.5Hz,1H),4.18(dd,J＝12.0,3.8Hz,1H),4.06–3.86(m,3H),3.80–3.59(m,2H),3.34(dd,J＝6.2,1.0Hz,2H),2.95(s,3H),2.90–2.73(m,1H),1.54–1.38(m,1H),1.29(d,J＝6.7Hz,3H),1.20(dd,J＝15.0,6.7Hz,6H),0.59–0.43(m,2H),0.30–0.14(m,2H)。ESI-MSm/z:547.3[M+H]+
化合物S56：1H NMR(300MHz,DMSO-d6)δ8.99(d,J＝0.5Hz,1H),8.52–8.42(m,2H),8.37(t,J＝0.5Hz,1H),8.28(s,1H),7.56(d,J＝5.6Hz,1H),7.31(dd,J＝8.3,0.5Hz,1H),6.96–6.86(m,1H),4.12(p,J＝6.6Hz,1H),3.89(dd,J＝9.2,6.8Hz,1H),3.82–3.59(m,2H),3.45–3.26(m,3H),2.96(s,3H),2.91–2.74(m,1H),2.42–2.17(m,4H),1.89–1.60(m,2H),1.29(d,J＝6.7Hz,3H),1.20(dd,J＝15.0,6.7Hz,6H)。ESI-MS m/z:611.2[M+H]+
化合物S57：1H NMR(300MHz,DMSO-d6)δ8.99(d,J＝0.5Hz,1H),8.61(d,J＝5.6Hz,1H),8.23(s,1H),7.52(d,J＝5.6Hz,1H),7.37–7.24(m,2H),7.07(d,J＝4.3Hz,1H),6.95(dd,J＝8.5,0.5Hz,1H),6.81(d,J＝0.5Hz,1H),6.67(dd,J＝4.4,1.5Hz,1H),4.06–3.87(m,2H),3.79–3.59(m,2H),3.34(dd,J＝6.2,1.1Hz,2H),2.96(s,3H),2.90–2.72(m,1H),1.84(p,J＝5.5Hz,1H),1.38(d,J＝6.7Hz,3H),1.20(dd,J＝15.0,6.7Hz,6H),1.15–0.89(m,4H)。ESI-MS m/z:595.2[M+H]+
化合物S58：1H NMR(300MHz,DMSO-d6)δ8.97(d,J＝0.5Hz,1H),8.65(d,J＝5.6Hz,1H),8.50–8.41(m,2H),8.16(d,J＝0.5Hz,1H),7.53(d,J＝5.6Hz,1H),7.32(dd,J＝8.5,0.5Hz,1H),6.95–6.80(m,2H),4.07(p,J＝6.7Hz,1H),3.95(dd,J＝9.2,6.8Hz,1H),3.79–3.59(m,2H),3.26–2.99(m,7H),2.92–2.77(m,1H),1.41(d,J＝6.7Hz,3H),1.31(t,J＝7.0Hz,3H),1.20(dd,J＝15.0,6.7Hz,6H)。ESI-MS m/z:584.2[M+H]+
化合物S59：1H NMR(300MHz,DMSO-d6)δ8.97(d,J＝0.5Hz,1H),8.59(d,J＝5.6Hz,1H),8.30(s,1H),8.23(s,1H),8.12(s,1H),7.54(d,J＝5.6Hz,1H),7.31(dd,J＝8.3,0.5Hz,1H),6.93–6.79(m,2H),4.04–3.84(m,2H),3.82(dd,J＝9.2,5.8Hz,1H),3.69(hept,J＝6.8Hz,1H),3.34(d,J＝2.2Hz,1H),3.36–3.18(m,2H),3.15(dq,J＝14.0,7.0Hz,1H),2.94(s,3H),2.89–2.72(m,1H),1.38(d,J＝6.8Hz,3H),1.29(t,J＝6.9Hz,3H),1.20(dd,J＝15.0,6.7Hz,6H)。ESI-MS m/z:584.2[M+H]+
化合物S60：1H NMR(300MHz,DMSO-d6)δ8.99–8.92(m,1H),8.67(d,J＝5.6Hz,1H),8.50(s,1H),8.42(d,J＝0.5Hz,1H),8.16(d,J＝0.5Hz,1H),7.53(d,J＝5.6Hz,1H),7.41–7.31(m,1H),6.94–6.80(m,2H),4.03–3.87(m,2H),3.80(dd,J＝9.2,5.6Hz,1H),3.33(dd,J＝6.2,2.0Hz,2H),2.94(s,3H),2.89–2.72(m,1H),2.64(p,J＝5.8Hz,1H),1.88(p,J＝5.5Hz,1H),1.54(tdd,J＝8.7,5.4,0.6Hz,2H),1.38(d,J＝6.7Hz,3H),1.22–1.03(m,4H),0.93–0.77(m,2H)。ESI-MS m/z:594.2[M+H]+
化合物S61：1H NMR(300MHz,DMSO-d6)δ8.94(d,J＝0.5Hz,1H),8.67(d,J＝5.6Hz,1H),8.50–8.39(m,2H),8.16(d,J＝0.5Hz,1H),7.53(d,J＝5.6Hz,1H),7.31(dd,J＝8.5,0.5Hz,1H),6.95–6.79(m,2H),4.03–3.86(m,2H),3.81(dd,J＝9.2,5.6Hz,1H),3.69(hept,J＝6.8Hz,1H),3.43–3.23(m,3H),2.94(s,3H),2.89–2.72(m,1H),2.40–2.17(m,4H),1.94–1.74(m,2H),1.38(d,J＝6.7Hz,3H),1.20(dd,J＝15.0,6.7Hz,6H)。ESI-MS m/z:610.2[M+H]+
化合物S62：1H NMR(300MHz,DMSO-d6)δ8.83–8.74(m,2H),8.65(d,J＝5.6Hz,1H),8.47–8.39(m,2H),8.35(d,J＝0.5Hz,1H),8.16(d,J＝0.5Hz,1H),7.53(d,J＝5.6Hz,1H),4.21–4.02(m,2H),3.93(dd,J＝9.3,5.7Hz,1H),3.79(hept,J＝6.5Hz,1H),3.43–3.26(m,3H),3.09–2.94(m,1H),2.94(s,3H),2.41–2.16(m,4H),1.93–1.76(m,2H),1.41–1.27(m,9H)。ESI-MS m/z:611.2[M+H]+
化合物S63：1H NMR(300MHz,DMSO-d6)δ8.83–8.75(m,2H),8.65(d,J＝5.6Hz,1H),8.44–8.31(m,3H),8.16(d,J＝0.5Hz,1H),7.53(d,J＝5.6Hz,1H),4.21–4.02(m,2H),3.93(dd,J＝9.3,5.7Hz,1H),3.44–3.28(m,3H),3.33–3.19(m,1H),3.15(dq,J＝14.0,7.0Hz,1H),3.10–2.95(m,1H),2.94(s,3H),1.45–1.26(m,12H)。ESI-MS m/z:585.2[M+H]+
化合物S64：1H NMR(300MHz,DMSO-d6)δ9.93(s,1H),8.77(d,J＝0.5Hz,1H),8.59(t,J＝2.8Hz,2H),8.45(t,J＝0.5Hz,1H),8.32(d,J＝12.9Hz,2H),8.10(s,1H),7.54(d,J＝5.6Hz,1H),3.98(dd,J＝9.1,5.5Hz,2H),3.81(dd,J＝9.2,5.5Hz,2H),3.31(h,J＝6.5Hz,1H),2.66(dh,J＝6.7,5.5Hz,1H),2.57–2.46(m,5H),1.88(p,J＝5.6Hz,1H),1.35(d,J＝6.5Hz,6H),1.16–0.89(m,4H)。ESI-MS m/z:582.2[M+H]+
化合物S65：1H NMR(300MHz,DMSO-d6)δ9.35(s,1H),8.95(d,J＝0.5Hz,1H),8.67(d,J＝5.6Hz,1H),8.50–8.39(m,2H),8.17(d,J＝0.5Hz,1H),7.53(d,J＝5.6Hz,1H),7.35–7.25(m,1H),6.95(dd,J＝8.4,0.5Hz,1H),6.81(d,J＝0.5Hz,1H),3.80(d,J＝10.5Hz,2H),3.77–3.59(m,3H),3.45(d,J＝13.3Hz,1H),2.64(q,J＝6.9Hz,2H),2.47(d,J＝13.3Hz,1H),1.88(p,J＝5.5Hz,1H),1.54(tdd,J＝8.7,5.4,0.6Hz,2H),1.32(t,J＝7.0Hz,3H),1.24–1.06(m,11H)。ESI-MS m/z:609.2[M+H]+
化合物S66：1H NMR(300MHz,DMSO-d6)δ8.78(d,J＝0.5Hz,1H),8.63(d,J＝5.6Hz,1H),8.49(s,1H),8.45–8.29(m,2H),8.16(t,J＝2.2Hz,1H),8.02(ddd,J＝7.8,2.2,1.2Hz,1H),7.69(t,J＝7.8Hz,1H),7.14(d,J＝5.6Hz,1H),4.73(hept,J＝6.4Hz,1H),4.40(p,J＝6.7Hz,1H),4.07(dd,J＝9.2,6.8Hz,1H),3.87(dd,J＝9.2,5.6Hz,1H),3.33(dd,J＝6.2,2.2Hz,2H),3.11–2.94(m,1H),2.94(s,3H),2.46(p,J＝5.5Hz,1H),1.56–1.41(m,8H),1.39(d,J＝6.7Hz,3H),1.09(tdd,J＝9.6,5.5,0.7Hz,2H)。ESI-MS m/z:596.2[M+H]+
化合物S67：1H NMR(300MHz,DMSO-d6)δ8.78(d,J＝0.5Hz,1H),8.58–8.46(m,2H),8.42(d,J＝0.5Hz,1H),8.39–8.26(m,1H),8.28–8.15(m,1H),7.66–7.49(m,2H),7.14(d,J＝5.6Hz,1H),4.72(hept,J＝6.4Hz,1H),4.13–3.97(m,2H),3.88(dd,J＝9.2,5.6Hz,1H),3.33(dd,J＝6.2,1.6Hz,2H),3.08–2.93(m,1H),2.94(s,3H),2.11(d,J＝13.1Hz,6H),1.49(dd,J＝15.0,6.4Hz,6H),1.40(d,J＝6.7Hz,3H)。ESI-MS m/z:568.2[M+H]+
化合物S68：1H NMR(300MHz,DMSO-d6)δ8.79(d,J＝0.5Hz,1H),8.58(d,J＝5.6Hz,1H),8.44(s,1H),8.20–8.10(m,2H),8.09–7.99(m,2H),7.13(d,J＝5.6Hz,1H),6.73(d,J＝0.5Hz,1H),4.37–4.19(m,2H),4.11(dd,J＝9.2,6.8Hz,1H),3.97(dd,J＝9.3,5.7Hz,1H),3.43–3.23(m,2H),3.09–2.94(m,1H),2.95(s,3H),2.46(p,J＝5.5Hz,1H),1.97(dqd,J＝12.1,7.4,5.6Hz,1H),1.77(dqd,J＝11.9,7.4,5.5Hz,1H),1.48(tdd,J＝8.8,5.5,0.7Hz,2H),1.37(dd,J＝11.0,6.6Hz,6H),1.08(tdd,J＝9.5,5.5,0.8Hz,2H),0.96(t,J＝7.4Hz,3H)。ESI-MS m/z:610.2[M+H]+
化合物S69：1H NMR(300MHz,DMSO-d6)δ8.80(d,J＝0.5Hz,1H),8.69–8.61(m,2H),8.42(d,J＝0.5Hz,1H),8.11(d,J＝0.5Hz,1H),7.96(d,J＝0.5Hz,1H),7.53(d,J＝5.6Hz,1H),4.76(hept,J＝6.4Hz,1H),4.29(p,J＝6.6Hz,1H),4.24–4.04(m,2H),4.00–3.83(m,2H),3.43–3.23(m,2H),3.08–2.93(m,1H),2.94(s,3H),1.49(dd,J＝15.0,6.4Hz,6H),1.48–1.34(m,4H),0.61–0.45(m,2H),0.33–0.17(m,2H)。ESI-MS m/z:536.3[M+H]+
化合物S70：1H NMR(300MHz,DMSO-d6)δ8.80(d,J＝0.5Hz,1H),8.76–8.63(m,2H),8.41(d,J＝0.5Hz,1H),8.14(d,J＝0.5Hz,1H),7.53(d,J＝5.6Hz,1H),6.75(d,J＝0.5Hz,1H),4.76(dq,J＝12.7,6.3Hz,1H),4.23(p,J＝6.7Hz,1H),4.09(dd,J＝9.2,6.8Hz,1H),3.92(dd,J＝9.2,5.6Hz,1H),3.43–3.22(m,2H),3.06–2.89(m,1H),2.95(s,3H),1.88(p,J＝5.5Hz,1H),1.61–1.43(m,8H),1.40(d,J＝6.8Hz,3H),1.16(tdd,J＝9.6,5.6,0.9Hz,2H)。ESI-MS m/z:586.2[M+H]+
化合物S71：1H NMR(300MHz,DMSO-d6)δ8.78(d,J＝0.5Hz,1H),8.62(d,J＝5.6Hz,1H),8.45(d,J＝0.5Hz,1H),8.23(s,1H),7.66(s,1H),7.61–7.50(m,2H),5.38(qq,J＝9.0,6.1Hz,1H),4.26(p,J＝6.7Hz,1H),4.17–4.00(m,2H),3.98(dd,J＝9.2,5.8Hz,1H),3.76(dd,J＝12.0,3.8Hz,1H),3.43–3.23(m,2H),3.08–2.93(m,1H),2.94(s,3H),1.51–1.32(m,7H),1.14–0.99(m,2H),0.80–0.64(m,2H)。ESI-MS m/z:590.2[M+H]+
化合物S72：1H NMR(300MHz,DMSO-d6)δ8.73(d,J＝0.5Hz,1H),8.65(d,J＝5.6Hz,1H),8.51(s,1H),8.41(d,J＝0.5Hz,1H),8.16(d,J＝0.5Hz,1H),7.53(d,J＝5.6Hz,1H),6.73(d,J＝0.5Hz,1H),5.45(dddd,J＝15.0,9.0,6.1,2.9Hz,1H),4.30(p,J＝6.7Hz,1H),4.10(dd,J＝9.2,6.8Hz,1H),3.94(dd,J＝9.3,5.7Hz,1H),3.35(p,J＝5.5Hz,1H),3.25–3.01(m,4H),2.95(qt,J＝6.5,5.7Hz,1H),2.43–2.19(m,4H),1.94–1.74(m,2H),1.46(dd,J＝18.7,6.4Hz,6H),1.30(t,J＝7.0Hz,3H)。ESI-MS m/z:668.2[M+H]+
化合物S73：1H NMR(300MHz,DMSO-d6)δ8.79–8.63(m,3H),8.41(d,J＝0.5Hz,1H),8.16(d,J＝0.5Hz,1H),7.53(d,J＝5.6Hz,1H),6.74(d,J＝0.5Hz,1H),4.75(hept,J＝6.3Hz,1H),4.21(p,J＝6.6Hz,1H),4.08(dd,J＝9.3,6.8Hz,1H),3.91(dd,J＝9.2,5.6Hz,1H),3.43–3.22(m,3H),3.06–2.89(m,1H),2.94(s,3H),2.41–2.18(m,4H),1.94–1.74(m,2H),1.49(dd,J＝15.0,6.4Hz,6H),1.39(d,J＝6.7Hz,3H)。ESI-MS m/z:600.2[M+H]+
化合物S74：1H NMR(300MHz,DMSO-d6)δ8.77–8.62(m,2H),8.51(s,1H),8.38(d,J＝0.5Hz,1H),8.16(d,J＝0.5Hz,1H),7.53(d,J＝5.6Hz,1H),6.73(d,J＝0.5Hz,1H),5.45(dddd,J＝15.0,9.0,6.1,2.9Hz,1H),4.28(p,J＝6.7Hz,1H),4.10(dd,J＝9.2,6.7Hz,1H),3.94(dd,J＝9.2,5.6Hz,1H),3.28–2.90(m,7H),1.46(dd,J＝18.4,6.4Hz,6H),1.31(td,J＝7.0,1.6Hz,6H)。ESI-MS m/z:642.2[M+H]+
化合物S75：1H NMR(300MHz,DMSO-d6)δ8.76(d,J＝0.5Hz,1H),8.65(d,J＝5.6Hz,1H),8.53(s,1H),8.41(d,J＝0.5Hz,1H),8.16(d,J＝0.5Hz,1H),7.53(d,J＝5.6Hz,1H),6.73(d,J＝0.5Hz,1H),5.47(qq,J＝9.0,6.1Hz,1H),4.22(p,J＝6.6Hz,1H),4.11(dd,J＝9.3,6.9Hz,1H),3.93(dd,J＝9.3,5.7Hz,1H),3.33(dd,J＝6.2,2.1Hz,2H),3.01(qt,J＝6.7,5.9Hz,1H),2.94(s,3H),1.88(p,J＝5.5Hz,1H),1.60–1.39(m,8H),1.15(tdd,J＝9.6,5.6,0.8Hz,2H)。ESI-MS m/z:640.2[M+H]+
化合物S76：1H NMR(300MHz,DMSO-d6)δ8.83–8.73(m,2H),8.68(d,J＝5.6Hz,1H),8.41(d,J＝0.5Hz,1H),8.15(d,J＝0.5Hz,1H),7.53(d,J＝5.6Hz,1H),6.74(d,J＝0.5Hz,1H),4.37(dtd,J＝11.9,6.5,5.5Hz,1H),4.22(p,J＝6.7Hz,1H),4.09(dd,J＝9.3,6.8Hz,1H),3.92(dd,J＝9.3,5.7Hz,1H),3.43–3.22(m,2H),3.06–2.89(m,1H),2.94(s,3H),2.10–1.78(m,3H),1.54(tdd,J＝8.7,5.4,0.7Hz,2H),1.37(dd,J＝13.0,6.6Hz,6H),1.16(tdd,J＝9.7,5.6,0.8Hz,2H),1.01(t,J＝7.4Hz,3H)。ESI-MS m/z:600.2[M+H]+
实施例77
化合物S77的合成反应式及制备过程如下：
步骤1.(2-((1-(环丙基甲基)-1H-吡唑-4-基)氨基)嘧啶-4-基)氨基甲酸叔丁酯(5)的制备
0℃下，向(2-氯嘧啶-4-基)氨基甲酸叔丁酯(230mg,1.0mmol)和1-(环丙基甲基)-1H-吡唑-4-胺(151mg,1.1mmol)的异丙醇(10mL)溶液中，加入三氟乙酸(77μL,1.0mmol)，升温至90℃反应4小时后反应完全，加入水(10mL)淬灭反应，用EA萃取三次。合并有机相，有机相用无水硫酸钠干燥，过滤，浓缩后柱层析分离得化合物5(294mg,89％)。ESI-MS m/z:331.2[M+H]+
步骤2.中间体N2-(1-(环丙基甲基)-1H-吡唑-4-基)嘧啶-2,4-二胺(6)的制备
0℃下，向(2-((1-(环丙基甲基)-1H-吡唑-4-基)氨基)嘧啶-4-基)氨基甲酸叔丁酯(5)(330mg,1.0mmol)的DCM(2mL)溶液中,加入三氟乙酸(400μL,6.0mmol)，移至室温反应4小时后反应完全，浓缩后得化合物6(196mg,85％)。ESI-MS m/z:231.1[M+H]+
步骤3. 3-氯-5-异丙基-8-((2R,3S)-2-甲基-3-((甲基磺酰基)甲基)氮杂环丁烷-1-基)异喹啉(4)的合成
合成方法已在实施例1中描述
步骤4.N2-(1-(环丙基甲基)-1H-吡唑-4-基)-N4-(5-异丙基-8-((2R,3S)-2-甲基-3-((甲基磺酰基)甲基)氮杂环丁烷-1-基)异喹啉-3-基)嘧啶-2,4-二胺(S77)的合成
0℃下，向3-氯-5-异丙基-8-((2R,3S)-2-甲基-3-((甲基磺酰基)甲基)氮杂环丁烷-1-基)异喹啉(4)(367mg,1.0mmol)和中间体N2-(1-(环丙基甲基)-1H-吡唑-4-基)嘧啶-2,4-二胺(6)(230.3mg,1.0mmol)的1,4-二氧六环(5mL)溶液中，加入,Brettphos Pd G3(181mg,0.2mmol)和碳酸铯(326mg,1.0mmol)，升至95℃反应4小时后反应完全，冷却至室温后，用EA萃取三次。合并有机相，有机相用无水硫酸钠干燥，过滤，浓缩后柱层析分离得化合物S77(275mg,49％)。1H NMR(300MHz,DMSO-d6)δ8.96(t,J＝0.5Hz,1H),8.38–8.26(m,2H),8.21–8.11(m,3H),7.87(s,1H),7.35–7.26(m,1H),6.90(dd,J＝8.5,0.5Hz,1H),6.66(d,J＝5.6Hz,1H),4.18(dd,J＝12.0,3.8Hz,1H),4.03–3.75(m,4H),3.69(hept,J＝6.8Hz,1H),3.33(dd,J＝6.2,2.2Hz,2H),2.94(s,3H),2.89–2.72(m,1H),1.45–1.28(m,4H),1.20(dd,J＝15.0,6.7Hz,6H),0.58–0.42(m,2H),0.30–0.14(m,2H)。ESI-MS m/z:561.3[M+H]+
实施例78-116
实施例78-116分别为化合物S78-S116的合成方法，均参照实施例77。
化合物S78：1H NMR(300MHz,DMSO-d6)δ8.97(d,J＝0.5Hz,1H),8.32–8.19(m,3H),7.33(dd,J＝8.5,0.5Hz,1H),6.97–6.86(m,2H),6.12(d,J＝9.4Hz,1H),4.10(p,J＝6.7Hz,1H),3.88(dd,J＝9.2,6.8Hz,1H),3.81–3.59(m,3H),3.48(dp,J＝6.8,6.0Hz,1H),3.33(dd,J＝6.2,1.4Hz,2H),2.96(s,3H),2.90–2.72(m,2H),1.83–1.64(m,4H),1.61–1.43(m,2H),1.45–1.27(m,2H),1.29(d,J＝6.7Hz,3H),1.20(dd,J＝15.0,6.7Hz,6H)。ESI-MS m/z:539.3[M+H]+
化合物S79：1H NMR(300MHz,DMSO-d6)δ9.75(s,1H),8.97(d,J＝0.5Hz,1H),8.27–8.13(m,2H),7.47–7.32(m,2H),7.30(dd,J＝8.5,0.5Hz,1H),7.24–7.12(m,2H),6.95–6.80(m,3H),4.10(p,J＝6.6Hz,1H),3.92(dd,J＝9.2,6.8Hz,1H),3.77(dd,J＝9.2,5.8Hz,1H),3.66(hept,J＝6.8Hz,1H),3.33(dd,J＝6.2,1.4Hz,2H),2.95(s,3H),2.91–2.74(m,1H),2.07(d,J＝13.1Hz,6H),1.39(d,J＝6.8Hz,3H),1.20(dd,J＝15.0,6.7Hz,6H)。ESI-MS m/z:593.2[M+H]+
化合物S80：1H NMR(300MHz,DMSO-d6)δ9.43(s,1H),9.00–8.94(m,1H),8.27–8.13(m,2H),7.69(d,J＝0.4Hz,4H),7.35–7.25(m,1H),6.95–6.80(m,3H),4.10(p,J＝6.6Hz,1H),3.92(dd,J＝9.3,6.9Hz,1H),3.77(dd,J＝9.2,5.8Hz,1H),3.66(hept,J＝6.8Hz,1H),3.33(dd,J＝6.3,1.2Hz,2H),3.21(s,3H),2.95(s,3H),2.90–2.73(m,1H),1.38(d,J＝6.8Hz,3H),1.20(dd,J＝15.0,6.7Hz,6H)。ESI-MS m/z:595.2[M+H]+
化合物S81：1H NMR(300MHz,DMSO-d6)δ9.13(t,J＝0.5Hz,1H),9.00(s,1H),8.49(s,1H),8.29(d,J＝0.5Hz,1H),8.17(d,J＝5.6Hz,1H),7.73–7.59(m,4H),7.14(d,J＝0.5Hz,1H),6.90(d,J＝5.6Hz,1H),4.15(p,J＝6.7Hz,1H),3.99(dd,J＝9.2,6.8Hz,1H),3.82(dd,J＝9.2,5.6Hz,1H),3.33(dd,J＝6.2,1.6Hz,2H),2.94(s,3H),2.91–2.71(m,2H),2.46(p,J＝5.5Hz,1H),1.54–1.33(m,11H),1.25(dddd,J＝10.1,9.1,5.5,1.4Hz,2H)。ESI-MS m/z:622.2[M+H]+
化合物S82：1H NMR(300MHz,DMSO-d6)δ9.05–8.93(m,2H),8.28–8.13(m,2H),7.74–7.59(m,4H),7.30(dd,J＝8.3,0.5Hz,1H),6.95–6.79(m,3H),4.08–3.89(m,2H),3.79(dd,J＝9.2,5.6Hz,1H),3.66(hept,J＝6.8Hz,1H),3.33(dd,J＝6.2,1.7Hz,2H),2.94(s,3H),2.89–2.72(m,1H),2.46(p,J＝5.5Hz,1H),1.37(d,J＝6.7Hz,3H),1.34–1.07(m,10H)。ESI-MS m/z:621.2[M+H]+
化合物S83：1H NMR(300MHz,DMSO-d6)δ9.58(s,1H),8.98(d,J＝0.5Hz,1H),8.30(s,1H),8.17(d,J＝5.6Hz,1H),7.57(ddd,J＝7.7,1.9,1.2Hz,1H),7.40(dt,J＝13.3,1.9Hz,1H),7.36–7.22(m,2H),7.17(dddd,J＝13.2,7.8,1.9,1.3Hz,1H),6.98–6.86(m,2H),6.83(t,J＝0.5Hz,1H),4.11(p,J＝6.7Hz,1H),3.89(dd,J＝9.2,6.8Hz,1H),3.76(dd,J＝9.2,5.8Hz,1H),3.66(hept,J＝6.8Hz,1H),3.34(dd,J＝6.2,1.5Hz,2H),2.96(s,3H),2.91–2.74(m,1H),2.08(d,J＝13.1Hz,6H),1.34–1.13(m,9H)。ESI-MS m/z:593.2[M+H]+
化合物S84：1H NMR(300MHz,DMSO-d6)δ9.85(s,1H),9.15(d,J＝0.5Hz,1H),8.56(s,1H),8.32(d,J＝0.5Hz,1H),8.17(d,J＝5.6Hz,1H),8.08(ddd,J＝7.8,1.9,1.2Hz,1H),7.75–7.61(m,2H),7.51(t,J＝7.8Hz,1H),7.14(d,J＝0.5Hz,1H),6.91(d,J＝5.6Hz,1H),3.99(dd,J＝9.2,5.6Hz,2H),3.68(dd,J＝9.1,5.5Hz,2H),3.35(d,J＝6.1Hz,2H),3.23(s,3H),2.96(s,3H),2.71(h,J＝6.5Hz,1H),2.60(ddd,J＝11.5,6.1,5.5Hz,1H),1.39(d,J＝6.5Hz,6H)。ESI-MS m/z:582.2[M+H]+
化合物S85：1H NMR(300MHz,DMSO-d6)δ9.61(s,1H),8.97(t,J＝0.5Hz,1H),8.29(s,1H),8.17(d,J＝5.6Hz,1H),8.08(ddd,J＝7.8,1.9,1.2Hz,1H),7.76–7.68(m,1H),7.62(ddd,J＝7.8,1.9,1.3Hz,1H),7.45(t,J＝7.8Hz,1H),7.35–7.25(m,1H),6.95–6.79(m,3H),4.10(p,J＝6.6Hz,1H),3.92(dd,J＝9.2,6.8Hz,1H),3.76(dd,J＝9.2,5.6Hz,1H),3.66(hept,J＝6.8Hz,1H),3.33(dd,J＝6.2,1.3Hz,2H),2.95(s,3H),2.90–2.73(m,1H),2.46(p,J＝5.5Hz,1H),1.38(d,J＝6.8Hz,3H),1.33–1.06(m,10H)。ESI-MS m/z:621.2[M+H]+
化合物S86：1H NMR(300MHz,DMSO-d6)δ9.00(d,J＝0.5Hz,1H),8.24(s,1H),8.21–8.10(m,2H),7.78(d,J＝0.5Hz,1H),7.38–7.25(m,2H),6.94–6.80(m,2H),6.67(d,J＝5.6Hz,1H),4.30(dd,J＝12.9,3.8Hz,1H),4.09(p,J＝6.7Hz,1H),3.92(dd,J＝9.2,6.8Hz,1H),3.86–3.70(m,2H),3.68(dq,J＝13.5,6.8Hz,1H),3.33(dd,J＝6.1,1.3Hz,2H),2.94(s,3H),2.89–2.72(m,1H),1.49–1.31(m,4H),1.20(dd,J＝15.0,6.7Hz,6H),1.12–0.96(m,2H),0.80–0.64(m,2H)。ESI-MS m/z:561.3[M+H]+
化合物S87：1H NMR(300MHz,DMSO-d6)δ10.54(s,1H),9.00(d,J＝0.5Hz,1H),8.31(s,1H),8.26–8.13(m,2H),7.81(s,1H),7.31(dd,J＝8.5,0.5Hz,1H),6.93–6.80(m,2H),6.66(d,J＝5.6Hz,1H),4.04–3.88(m,2H),3.80(dd,J＝9.3,5.7Hz,1H),3.69(hept,J＝6.8Hz,1H),3.33(dd,J＝6.2,1.9Hz,2H),3.05(s,3H),2.94(s,3H),2.89–2.72(m,1H),1.37(d,J＝6.7Hz,3H),1.20(dd,J＝15.0,6.7Hz,6H)。ESI-MS m/z:585.2[M+H]+
化合物S88：1H NMR(300MHz,DMSO-d6)δ10.57(s,1H),9.18(d,J＝0.5Hz,1H),8.60(s,1H),8.29(d,J＝0.5Hz,1H),8.26–8.13(m,2H),7.82(s,1H),7.14(d,J＝0.5Hz,1H),6.66(d,J＝5.6Hz,1H),4.15(p,J＝6.7Hz,1H),3.98(dd,J＝9.3,6.8Hz,1H),3.82(dd,J＝9.2,5.8Hz,1H),3.25–2.98(m,7H),2.99–2.73(m,2H),1.46–1.32(m,9H),1.31(t,J＝6.9Hz,3H)。ESI-MS m/z:600.2[M+H]+
化合物S89：1H NMR(300MHz,DMSO-d6)δ10.57(s,1H),9.03–8.96(m,1H),8.29–8.13(m,3H),7.83(d,J＝0.5Hz,1H),7.32(dd,J＝8.5,0.5Hz,1H),6.93(dd,J＝8.4,0.5Hz,1H),6.82(d,J＝0.5Hz,1H),6.66(d,J＝5.6Hz,1H),4.06–3.87(m,2H),3.74(dd,J＝9.2,5.6Hz,1H),3.65(h,J＝6.7Hz,1H),3.34(dd,J＝6.1,1.0Hz,2H),2.95(s,3H),2.90–2.73(m,1H),2.67(p,J＝5.5Hz,1H),1.33–1.09(m,13H)。ESI-MS m/z:611.2[M+H]+
化合物S90：1H NMR(300MHz,DMSO-d6)δ10.74(s,1H),9.01(d,J＝0.5Hz,1H),8.31(s,1H),8.26–8.13(m,2H),7.81(d,J＝0.5Hz,1H),7.32(dd,J＝8.5,0.5Hz,1H),6.92(dd,J＝8.5,0.5Hz,1H),6.83(t,J＝0.5Hz,1H),6.66(d,J＝5.6Hz,1H),4.11(p,J＝6.7Hz,1H),3.88(dd,J＝9.2,6.8Hz,1H),3.81–3.59(m,2H),3.34(dd,J＝6.2,1.4Hz,2H),3.20(ddt,J＝24.9,14.2,7.1Hz,2H),2.96(s,3H),2.90–2.73(m,1H),1.35–1.13(m,12H)。ESI-MS m/z:599.2[M+H]+
化合物S91：1H NMR(300MHz,DMSO-d6)δ9.35(s,1H),8.81(d,J＝0.5Hz,1H),8.50–8.41(m,2H),8.34(d,J＝0.5Hz,1H),8.27–8.13(m,2H),7.94(s,1H),6.67(d,J＝5.6Hz,1H),4.20–4.02(m,2H),3.92(dd,J＝9.2,5.6Hz,1H),3.47(dt,J＝13.0,6.5Hz,1H),3.33(dd,J＝6.2,2.5Hz,2H),3.09–2.92(m,1H),2.94(s,3H),2.67(p,J＝5.5Hz,1H),1.56–1.41(m,2H),1.41–1.16(m,11H)。ESI-MS m/z:612.2[M+H]+
化合物S92：1H NMR(300MHz,DMSO-d6)δ8.82(d,J＝0.5Hz,1H),8.51(s,1H),8.34(s,2H),8.21–8.10(m,2H),7.79(d,J＝0.5Hz,1H),7.00(s,1H),6.66(d,J＝5.6Hz,1H),4.24–3.85(m,5H),3.33(dd,J＝6.2,1.9Hz,2H),3.15(hept,J＝6.5Hz,1H),3.10–2.93(m,1H),2.94(s,3H),1.45–1.26(m,12H)。ESI-MS m/z:536.3[M+H]+
化合物S93：1H NMR(300MHz,DMSO-d6)δ9.09–8.98(m,2H),8.74(s,1H),8.37(t,J＝0.5Hz,1H),8.26(s,1H),8.17(d,J＝5.6Hz,1H),7.92(d,J＝0.5Hz,1H),7.30(dd,J＝8.5,0.5Hz,1H),6.88(dd,J＝8.5,0.5Hz,1H),6.66(d,J＝5.6Hz,1H),4.10(p,J＝6.7Hz,1H),3.94(dd,J＝9.2,6.9Hz,1H),3.82–3.59(m,2H),3.33(dd,J＝6.2,1.2Hz,2H),2.95(s,3H),2.91–2.74(m,1H),1.88(p,J＝5.5Hz,1H),1.58–1.42(m,2H),1.38(d,J＝6.7Hz,3H),1.27–1.12(m,8H)。ESI-MS m/z:611.2[M+H]+
化合物S94：1H NMR(300MHz,DMSO-d6)δ9.18(t,J＝0.5Hz,1H),9.05(s,1H),8.53(s,1H),8.29(dd,J＝5.1,0.5Hz,2H),8.17(d,J＝5.6Hz,1H),7.92(d,J＝0.5Hz,1H),7.13(d,J＝0.5Hz,1H),6.67(d,J＝5.6Hz,1H),4.15(p,J＝6.7Hz,1H),3.99(dd,J＝9.2,6.8Hz,1H),3.82(dd,J＝9.2,5.6Hz,1H),3.40–3.19(m,3H),3.15(dq,J＝14.0,7.0Hz,1H),2.94(s,3H),2.94–2.73(m,2H),1.46–1.32(m,9H),1.29(t,J＝6.9Hz,3H。ESI-MS m/z:600.2[M+H]+
化合物S95：1H NMR(300MHz,DMSO-d6)δ9.15(s,1H),9.00(d,J＝0.5Hz,1H),8.74(d,J＝0.5Hz,1H),8.35(d,J＝0.5Hz,1H),8.25(s,1H),8.17(d,J＝5.6Hz,1H),7.93(d,J＝0.5Hz,1H),7.30(dd,J＝8.5,0.5Hz,1H),6.88(dd,J＝8.5,0.5Hz,1H),6.66(d,J＝5.6Hz,1H),4.10(p,J＝6.7Hz,1H),3.93(dd,J＝9.3,6.8Hz,1H),3.77(dd,J＝9.2,5.8Hz,1H),3.68(dq,J＝13.6,6.8Hz,1H),3.33(dd,J＝6.3,1.2Hz,2H),3.02(s,3H),2.95(s,3H),2.90–2.73(m,1H),1.39(d,J＝6.7Hz,3H),1.20(dd,J＝15.0,6.7Hz,6H)。ESI-MS m/z:585.2[M+H]+
化合物S96：1H NMR(300MHz,DMSO-d6)δ10.36(s,1H),8.96(d,J＝0.5Hz,1H),8.81(dd,J＝1.4,0.9Hz,1H),8.33–8.25(m,2H),8.17(d,J＝5.6Hz,1H),7.45(t,J＝1.7Hz,1H),7.30(dd,J＝8.3,0.5Hz,1H),6.92–6.82(m,1H),6.66(d,J＝5.6Hz,1H),6.39(dd,J＝1.9,0.9Hz,1H),4.03–3.85(m,2H),3.80(dd,J＝9.2,5.6Hz,1H),3.69(hept,J＝6.7Hz,1H),3.33(dd,J＝6.2,2.1Hz,2H),2.94(s,3H),2.89–2.72(m,1H),1.40(d,J＝6.8Hz,3H),1.20(dd,J＝15.0,6.7Hz,6H)。ESI-MS m/z:507.2[M+H]+
化合物S97：1H NMR(300MHz,DMSO-d6)δ9.14(d,J＝0.6Hz,1H),8.55(s,1H),8.25(d,J＝0.5Hz,1H),8.17(d,J＝5.6Hz,1H),8.09(s,1H),7.33(dd,J＝7.8,1.5Hz,1H),7.25(t,J＝1.5Hz,1H),7.12(d,J＝0.5Hz,1H),6.90(d,J＝5.6Hz,1H),6.45(dd,J＝7.8,1.5Hz,1H),4.10–3.91(m,2H),3.86(dd,J＝9.2,5.6Hz,1H),3.33(dd,J＝6.2,2.6Hz,2H),2.94(s,3H),2.92–2.72(m,2H),1.46–1.32(m,9H)。ESI-MS m/z:508.2[M+H]+
化合物S98：1H NMR(300MHz,DMSO-d6)δ9.00(t,J＝0.5Hz,1H),8.33–8.23(m,3H),8.17(d,J＝5.6Hz,1H),8.07(s,1H),7.82(d,J＝0.5Hz,1H),7.32(dd,J＝8.3,0.5Hz,1H),6.91(dd,J＝8.5,0.5Hz,1H),6.66(d,J＝5.6Hz,1H),4.04–3.86(m,2H),3.89(s,3H),3.78(dd,J＝9.2,5.8Hz,1H),3.68(dq,J＝13.5,6.7Hz,1H),3.33(dd,J＝6.3,2.2Hz,2H),2.95(s,3H),2.92–2.74(m,1H),1.38(d,J＝6.7Hz,3H),1.20(dd,J＝15.0,6.7Hz,6H)。ESI-MSm/z:521.2[M+H]+
化合物S99：1H NMR(300MHz,DMSO-d6)δ8.99(s,1H),8.91(d,J＝0.6Hz,1H),8.74(s,1H),8.47(s,1H),8.17(d,J＝5.6Hz,1H),7.92(d,J＝0.5Hz,1H),7.16(dd,J＝8.5,0.5Hz,1H),6.94(t,J＝0.5Hz,1H),6.78–6.63(m,2H),4.57(dq,J＝12.5,6.2Hz,1H),4.09(p,J＝6.6Hz,1H),3.90(dd,J＝9.2,6.8Hz,1H),3.75(dd,J＝9.2,5.8Hz,1H),3.33(dd,J＝6.2,1.5Hz,2H),2.95(s,3H),2.88–2.71(m,1H),1.88(p,J＝5.5Hz,1H),1.57–1.40(m,7H),1.33(dd,J＝15.0,6.2Hz,6H)。ESI-MS m/z:627.2[M+H]+
化合物S100：1H NMR(300MHz,DMSO-d6)δ8.82(d,J＝0.5Hz,1H),8.47(s,1H),8.41–8.31(m,2H),8.23–8.11(m,3H),7.87(s,1H),6.66(d,J＝5.6Hz,1H),4.27–3.87(m,5H),3.33(dd,J＝6.2,2.4Hz,2H),3.18(hept,J＝6.5Hz,1H),3.10–2.93(m,1H),2.94(s,3H),1.45–1.26(m,12H)。ESI-MS m/z:536.3[M+H]+
化合物S101：1H NMR(300MHz,DMSO-d6)δ8.81(d,J＝0.5Hz,1H),8.30(s,1H),8.15(d,J＝5.6Hz,1H),6.74(d,J＝0.5Hz,1H),6.27(d,J＝5.6Hz,1H),4.72(hept,J＝6.4Hz,1H),4.26(p,J＝6.7Hz,1H),4.16–3.98(m,3H),3.93(dd,J＝9.3,5.7Hz,1H),3.67–3.49(m,4H),3.43–3.23(m,2H),3.07–2.90(m,1H),2.94(s,3H),1.90(ddt,J＝12.9,8.0,5.8Hz,2H),1.81–1.64(m,2H),1.56–1.38(m,9H)。ESI-MS m/z:515.3[M+H]+
化合物S102：1H NMR(300MHz,DMSO-d6)δ8.81(d,J＝0.5Hz,1H),8.29(s,1H),8.15(d,J＝5.6Hz,1H),6.74(d,J＝0.5Hz,1H),6.27(d,J＝5.6Hz,1H),4.73(hept,J＝6.4Hz,1H),4.19(p,J＝6.7Hz,1H),4.15–3.96(m,3H),3.91(dd,J＝9.3,5.7Hz,1H),3.68(ddd,J＝12.2,8.0,5.6Hz,2H),3.52(p,J＝5.5Hz,1H),3.43–3.22(m,2H),3.28(s,3H),2.97(pd,J＝6.5,5.7Hz,1H),2.94(s,3H),1.95(ddt,J＝13.6,8.1,5.6Hz,2H),1.69(ddt,J＝13.5,8.1,5.6Hz,2H),1.49(dd,J＝15.0,6.4Hz,6H),1.39(d,J＝6.8Hz,3H)。ESI-MS m/z:529.3[M+H]+
化合物S103：1H NMR(300MHz,DMSO-d6)δ8.81(d,J＝0.5Hz,1H),8.31(s,1H),8.16(d,J＝5.6Hz,1H),6.74(d,J＝0.5Hz,1H),6.28(d,J＝5.6Hz,1H),5.14(td,J＝3.8,1.7Hz,0H),4.98(td,J＝3.8,1.7Hz,0H),4.70(hept,J＝6.3Hz,1H),4.34–4.18(m,2H),4.10(dd,J＝9.2,6.8Hz,1H),4.07–3.90(m,2H),3.88–3.66(m,2H),3.67–3.47(m,2H),3.43–3.23(m,2H),3.07–2.92(m,1H),2.94(s,3H),1.93–1.65(m,2H),1.49(dd,J＝15.0,6.4Hz,6H),1.39(d,J＝6.7Hz,3H)。ESI-MS m/z:533.2[M+H]+
化合物S104：1H NMR(300MHz,DMSO-d6)δ8.81(d,J＝0.5Hz,1H),8.30(s,1H),8.15(d,J＝5.6Hz,1H),6.74(d,J＝0.5Hz,1H),6.28(d,J＝5.6Hz,1H),4.83–4.64(m,2H),4.60(ddd,J＝4.0,3.3,1.7Hz,1H),4.25(p,J＝6.6Hz,1H),4.10(dd,J＝9.2,6.8Hz,1H),4.05–3.90(m,2H),3.75(ddd,J＝25.1,11.2,1.7Hz,1H),3.69–3.57(m,1H),3.63–3.44(m,2H),3.43–3.22(m,5H),3.07–2.92(m,1H),2.94(s,3H),2.00–1.76(m,2H),1.49(dd,J＝15.0,6.4Hz,6H),1.39(d,J＝6.7Hz,3H)。ESI-MS m/z:547.3[M+H]+
化合物S105：1H NMR(300MHz,DMSO-d6)δ8.81(d,J＝0.5Hz,1H),8.26(s,1H),8.15(d,J＝5.6Hz,1H),6.74(d,J＝0.5Hz,1H),6.28(d,J＝5.6Hz,1H),4.89(d,J＝7.0Hz,1H),4.41–4.18(m,2H),4.10(dd,J＝9.2,6.8Hz,1H),4.00–3.59(m,6H),3.43–3.23(m,2H),3.08–2.92(m,1H),2.94(s,3H),2.00–1.69(m,4H),1.44–1.27(m,9H),0.96(t,J＝7.4Hz,3H)。ESI-MS m/z:561.3[M+H]+
化合物S106：1H NMR(300MHz,DMSO-d6)δ8.82(s,1H),8.41(s,1H),8.27–8.13(m,3H),7.87(s,1H),6.77–6.62(m,2H),4.74(hept,J＝6.4Hz,1H),4.28(p,J＝6.7Hz,1H),4.21–4.04(m,2H),3.97(dd,J＝9.3,5.7Hz,1H),3.89(dd,J＝12.0,3.8Hz,1H),3.33(dd,J＝6.2,2.3Hz,2H),3.08–2.93(m,1H),2.95(s,3H),1.49(dd,J＝15.0,6.4Hz,6H),1.43–1.26(m,4H),0.59–0.43(m,2H),0.33–0.18(m,2H)。ESI-MS m/z:551.3[M+H]+
化合物S107：1H NMR(300MHz,DMSO-d6)δ8.81(d,J＝0.5Hz,1H),8.23(d,J＝5.6Hz,1H),8.15(s,1H),6.77–6.62(m,2H),6.06(d,J＝9.5Hz,1H),4.73(hept,J＝6.4Hz,1H),4.26(p,J＝6.6Hz,1H),4.10(dd,J＝9.2,6.8Hz,1H),3.94(dd,J＝9.3,5.7Hz,1H),3.78–3.61(m,1H),3.46–3.23(m,3H),3.28(s,3H),3.07–2.90(m,1H),2.94(s,3H),1.82–1.62(m,4H),1.59–1.38(m,10H),1.39(d,J＝6.7Hz,3H)。ESI-MS m/z:543.3[M+H]+
化合物S108：1H NMR(300MHz,DMSO-d6)δ8.90–8.81(m,2H),8.38(s,1H),8.27–8.13(m,2H),7.93(s,1H),6.75(d,J＝0.5Hz,1H),6.66(d,J＝5.6Hz,1H),4.72(hept,J＝6.4Hz,1H),4.28(p,J＝6.7Hz,1H),4.10(dd,J＝9.2,6.8Hz,1H),3.93(dd,J＝9.2,5.6Hz,1H),3.33(dd,J＝6.2,2.7Hz,2H),3.08–2.93(m,1H),2.94(s,3H),2.68(p,J＝5.5Hz,1H),1.56–1.41(m,8H),1.38(d,J＝6.8Hz,3H),1.23(dddd,J＝10.0,9.2,5.5,1.2Hz,2H)。ESI-MS m/z:601.2[M+H]+
化合物S109：1H NMR(300MHz,DMSO-d6)δ9.16(s,1H),8.87(d,J＝0.5Hz,1H),8.74(d,J＝1.4Hz,1H),8.44(s,1H),8.17(d,J＝5.6Hz,1H),7.92(d,J＝1.4Hz,1H),6.75–6.62(m,2H),4.70(hept,J＝6.4Hz,1H),4.31(p,J＝6.7Hz,1H),4.10(dd,J＝9.2,5.6Hz,1H),4.00(dd,J＝9.2,6.8Hz,1H),3.34(dd,J＝6.2,1.4Hz,2H),2.99(s,3H),3.05–2.87(m,1H),1.88(p,J＝5.5Hz,1H),1.59–1.42(m,8H),1.39(d,J＝6.7Hz,3H),1.30–1.15(m,2H)。ESI-MS m/z:601.2[M+H]+
化合物S110：1H NMR(300MHz,DMSO-d6)δ9.59(s,1H),8.82(d,J＝0.5Hz,1H),8.46(s,1H),8.17(d,J＝5.6Hz,1H),7.57(ddd,J＝7.8,1.9,1.3Hz,1H),7.41(dt,J＝13.3,1.9Hz,1H),7.29(td,J＝7.8,4.1Hz,1H),7.15(dddd,J＝13.2,7.8,1.8,1.2Hz,1H),6.75(d,J＝0.5Hz,1H),6.67(d,J＝5.6Hz,1H),4.68(h,J＝6.4Hz,1H),4.27(p,J＝6.6Hz,1H),4.11(dd,J＝9.2,6.8Hz,1H),3.98(dd,J＝9.2,5.6Hz,1H),3.33(dd,J＝6.2,2.6Hz,2H),3.05–2.87(m,1H),2.95(s,3H),2.08(d,J＝13.1Hz,6H),1.49(dd,J＝15.0,6.4Hz,6H),1.39(d,J＝6.7Hz,3H)。ESI-MS m/z:583.2[M+H]+
化合物S111：1H NMR(300MHz,DMSO-d6)δ8.95(d,J＝0.5Hz,1H),8.34–8.26(m,2H),8.21(d,J＝5.6Hz,1H),7.32(dd,J＝8.5,0.5Hz,1H),6.91(dd,J＝8.5,0.5Hz,1H),6.67(d,J＝5.6Hz,1H),6.09–5.99(m,1H),4.05–3.86(m,2H),3.92–3.77(m,1H),3.79–3.51(m,5H),3.41–3.26(m,5H),2.95(s,3H),2.94–2.77(m,1H),1.32(d,J＝6.8Hz,3H),1.20(dd,J＝15.0,6.7Hz,6H)。ESI-MS m/z:499.2[M+H]+
化合物S112：1H NMR(300MHz,DMSO-d6)δ8.97(d,J＝0.5Hz,1H),8.38–8.26(m,2H),8.21(d,J＝5.6Hz,1H),7.32(dd,J＝8.3,0.5Hz,1H),6.92(dd,J＝8.5,0.5Hz,1H),6.71–6.60(m,2H),4.18–4.01(m,2H),3.94–3.78(m,2H),3.81–3.59(m,2H),3.33(dd,J＝6.2,1.5Hz,2H),3.02(s,3H),2.96(s,3H),2.90–2.73(m,1H),1.39(s,3H),1.37–1.24(m,6H),1.20(dd,J＝15.0,6.7Hz,6H)。ESI-MS m/z:575.2[M+H]+
化合物S113：1H NMR(300MHz,DMSO-d6)δ8.97(d,J＝0.5Hz,1H),8.33–8.25(m,2H),8.21(d,J＝5.6Hz,1H),7.33(dd,J＝8.5,0.5Hz,1H),6.92(dd,J＝8.5,0.5Hz,1H),6.67(d,J＝5.6Hz,1H),6.53(t,J＝4.6Hz,1H),4.10(p,J＝6.7Hz,1H),3.88(dd,J＝9.2,6.8Hz,1H),3.80–3.60(m,3H),3.53(ddd,J＝12.3,5.4,4.6Hz,1H),3.33(dd,J＝6.2,1.5Hz,2H),3.21(dt,J＝11.0,5.2Hz,2H),3.04(dt,J＝11.1,5.2Hz,2H),2.96(s,3H),2.90–2.73(m,1H),2.29(hept,J＝5.4Hz,1H),2.12(p,J＝5.0Hz,1H),1.31(d,J＝6.7Hz,3H),1.20(dd,J＝15.0,6.7Hz,6H)。ESI-MS m/z:510.3[M+H]+
化合物S114：1H NMR(300MHz,DMSO-d6)δ9.13(d,J＝0.6Hz,1H),8.53(s,1H),8.32–8.19(m,2H),7.20–7.09(m,2H),6.67(d,J＝5.6Hz,1H),4.26–4.06(m,2H),3.98(dd,J＝9.2,6.8Hz,1H),3.91–3.75(m,5H),3.33(dd,J＝6.2,1.6Hz,2H),2.94(s,3H),2.92–2.72(m,2H),1.46–1.32(m,9H)。ESI-MS m/z:498.2[M+H]+
化合物S115：1H NMR(300MHz,DMSO-d6)δ8.80(d,J＝0.5Hz,1H),8.16(d,J＝5.6Hz,1H),7.88(s,1H),6.73(d,J＝0.5Hz,1H),6.29(d,J＝5.6Hz,1H),5.51(qq,J＝9.0,6.1Hz,1H),4.97(td,J＝3.8,1.7Hz,1H),4.34–4.18(m,2H),4.11(dd,J＝9.3,6.9Hz,1H),4.09–3.92(m,2H),3.91–3.67(m,2H),3.69–3.49(m,2H),3.43–3.23(m,2H),3.10–2.93(m,1H),2.94(s,3H),1.84(dddd,J＝13.2,7.9,5.7,4.2Hz,1H),1.80–1.62(m,1H),1.45(dd,J＝11.7,6.4Hz,6H)。ESI-MS m/z:587.2[M+H]+
化合物S116：1H NMR(300MHz,DMSO-d6)δ8.80(s,1H),8.16(d,J＝5.6Hz,1H),7.93(s,1H),6.73(d,J＝0.5Hz,1H),6.29(d,J＝5.6Hz,1H),5.38(qq,J＝9.0,6.1Hz,1H),4.80(ddd,J＝4.0,3.3,1.7Hz,1H),4.65(ddd,J＝4.0,3.3,1.7Hz,1H),4.11(dd,J＝9.2,6.8Hz,1H),4.03–3.87(m,2H),3.76(ddd,J＝25.1,11.2,1.7Hz,1H),3.70–3.47(m,3H),3.43–3.21(m,5H),3.10–2.93(m,1H),2.94(s,3H),1.97–1.78(m,2H),1.45(dd,J＝15.5,6.4Hz,6H)。ESI-MS m/z:601.2[M+H]+
实施例117
EGFRL858R/T790M/C797S激酶抑制活性分析测试方法
实验步骤：将化合物用100％ DMSO溶解并配制成10mM溶液。配制1×Kinasebuffer。化合物浓度梯度的配制：化合物测试起始浓度为5μΜ，3倍稀释，10个浓度，单孔检测。用1×Kinase buffer配制成2.5倍终浓度的激酶溶液。在化合物孔和阳性对照孔分别加10μL的2.5倍终浓度的激酶液；在阴性对照孔中加10μL的1×Kinase buffer。用2000rpm离心30秒，反应板振荡混匀后室温下孵育10分钟。用1×Kinase buffer配制25/15倍终浓度的ATP和Kinase substrate 22混合溶液。加入15μL的25/15倍终浓度的ATP和底物的混合溶液启动反应。将384孔板2000rpm离心30秒，振荡混匀后室温孵育30分钟。停止激酶反应后，2000rpm离心30秒，振荡混匀。用Caliper EZ Reader读取转化率。采用分析软件GraphPadPrism 5的log(inhibitor)vs.response-Variable slope拟合量效曲线，从而得出各个化合物对酶活性的IC50值。所得IC50值如表1所示，从结果可以看出，本发明实施例化合物具有很强的EGFRL858R/T790M/C797S激酶抑制活性。A:IC50<10nM；B:IC50＝10nM-100nM；C:IC50＝100nM-1000nM。
表1 EGFRL858R/T790M/C797S激酶抑制活性
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实施例118
化合物对H-1975(EGFRL858R/T79QM/C797S)细胞系细胞增殖抑制活性通过CCK8方法进行测试。
实验步骤：将细胞计数之后在96孔板中接种100μL细胞悬浮液。在培养箱培养一天，等细胞贴壁后加入相应浓度化合物，将化合物用100％DMSO溶解并配制成1mM溶液，然后用培养基将化合物稀释至所需浓度。在96孔板中加入100μL化合物溶液，吹打均匀。将96孔板放置于细胞培养箱中培养72h后，在96孔板每个孔中加入I00μL Cell Count Kit 8试剂，将96孔板放置于细胞培养箱中培养4h，用酶标仪读取荧光值。采用分析软件GraphPadPrism 7的inhibitor vs.response-Variable slope(four parameters)拟合量效曲线，从而得出各个化合物对酶活性的IC50值。A:IC50<10nM；B:IC50＝10nM-100nM；C:IC50＝100nM-1000nM。
表2实施例化合物对H-1975(EGFRL858R/T790M/C797S)细胞增殖抑制IC50
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Claims (6)

1.一种2-氨基嘧啶类化合物，其特征在于，该化合物为结构通式如式Ⅰ所示的化合物或其药学上可接受的盐：
其中，n＝0，U为N，V为N；
X选自O；
A选自
R4选自取代的C1-6烷基、C3-10环烷基或C3-10环烷基-(C1-6烷基)-，取代基选自卤素；
R5为氢；
R6为甲基；
R7选自氢、未取代的C1-4烷基；
R8选自氢。
2.根据权利要求1所述的2-氨基嘧啶类化合物，其特征在于，所述化合物为如下任一种结构：
3.一种2-氨基嘧啶类化合物，其特征在于，选自如下任一化合物或其药学上可接受的盐：
4.一种含有权利要求1～3任一项所述2-氨基嘧啶类化合物的药物组合物，其特征在于，所述药物组合物以该化合物作为活性成分和药学上可接受的载体。
5.一种权利要求1～3任一项所述2-氨基嘧啶类化合物在制备具有EGFR抑制活性的抑制剂中的应用。
6.一种权利要求1～3任一项所述2-氨基嘧啶类化合物在制备抗肿瘤药物中的应用。
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014210354A1 (en) * 2013-06-28 2014-12-31 Genentech, Inc. Azaindazole compounds as inhibitors of t790m containing egfr mutants
CN115135642A (zh) * 2019-12-23 2022-09-30 缆图药品公司 Egfr突变形式的抑制剂
WO2023025320A1 (zh) * 2021-08-27 2023-03-02 上海翰森生物医药科技有限公司 含氮杂环类衍生物抑制剂、其制备方法和应用
CN116478136A (zh) * 2022-01-17 2023-07-25 苏州浦合医药科技有限公司 2-哌啶基或2-吡唑基取代的嘧啶化合物作为egfr抑制剂

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014210354A1 (en) * 2013-06-28 2014-12-31 Genentech, Inc. Azaindazole compounds as inhibitors of t790m containing egfr mutants
CN115135642A (zh) * 2019-12-23 2022-09-30 缆图药品公司 Egfr突变形式的抑制剂
WO2023025320A1 (zh) * 2021-08-27 2023-03-02 上海翰森生物医药科技有限公司 含氮杂环类衍生物抑制剂、其制备方法和应用
CN115724827A (zh) * 2021-08-27 2023-03-03 上海翰森生物医药科技有限公司 稠环类衍生物抑制剂、其制备方法和应用
CN116478136A (zh) * 2022-01-17 2023-07-25 苏州浦合医药科技有限公司 2-哌啶基或2-吡唑基取代的嘧啶化合物作为egfr抑制剂

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Discovery of BLU-945, a Reversible, Potent, and Wild-Type-Sparing Next-Generation EGFR Mutant Inhibitor for Treatment-Resistant Non-Small-Cell Lung Cancer;Meredith S. Eno等;《Journal of Medicinal Chemistry》;第65卷;第9662-9677页 *

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