本发明涉及新型杂环衍生物及其盐、包括可药用盐。包括可药用盐。本发明的化合物可用于治疗hiv及癌症类疾病，包括肺癌，肝癌，乳腺癌，淋巴癌，套细胞淋巴瘤、脂肉瘤、黑素瘤、鳞状细胞食管癌等。本发明的药物组合物能够制成有利于哺乳动物的组织、器官吸收利用的剂型，其在治疗hiv和癌症等增生性疾病具有良好的应用前景。本发明还涉及包含本发明的化合物的药物组合物。
背景技术
肿瘤是人类面临的一个全球性难题，这类致命的疾病所引发的死亡率排在导致人类死亡病因的首位。目前化学药物治疗在解决恶性肿瘤问题中占有非常重要的地位。科学工作者们一直致力于发现高效新型的抗肿瘤药物。在现有技术中，如本发明所示结构新颖的1,1-环丙基二酰胺衍生物的制备与应用尚未报道。
技术实现要素：
(i)的1,1-环丙基二酰胺衍生物及其盐、包括可药用盐：
包括可药用盐。本发明的化合物可用于治疗hiv及癌症类疾病，包括肺癌，肝癌，乳腺癌，淋巴癌，套细胞淋巴瘤、脂肉瘤、黑素瘤、鳞状细胞食管癌等。本发明还涉及使用本发明的化合物或包含本发明的化合物的药物组合物来治疗与其有关的紊乱。
本发明涉及新的具有式
其中：
r1是c3-7烷基；任选被一个选自c1-6烷基和oh的取代基取代的c4-7环烷基；任选被一个选自c1-6烷基、c(ch3)2cn和oh的取代基取代的苯基；任选被一个环丙基或c1-6烷基取代的哌啶基；任选被一个环丙基或c1-6烷基取代的四氢吡喃基；或二环[2.2.1]庚烷基；
r2选自取代或未取代的芳基，取代或未取代的吡啶基，取代或未取代的嘧啶基，取代或未取代的氧化嘧啶基，取代或未取代的吡嗪基，取代或未取代的吡咯基，取代或未取代的吡唑基，取代或未取代的咪唑基，取代或未取代吲哚基，取代或未取代异吲哚基，取代或未取代呋喃基，取代或未取代噻唑基，取代或未取代噁唑啉基，取代或未取代噻吩基；
r3、r4、r5分别独自选自h，f，cl；br；cn；oh；coor9；or9；c(o)n(r9r10)；低级烷烃；o-低级烷烃；nh-低级烷烃；s-低级烷烃；coo-低级烷烃；oc(o)-低级烷烃；c(o)n(r9)-低级烷烃；s(o)2n(r9)-低级烷烃；s(o)n(r9)-低级烷烃；s(o)2-低级烷烃；s(o)-低级烷烃；n(r9)s(o)2-低级烷烃和n(r9)s(o)-低级烷烃；其中每个低级烷烃可被一个或更多f或cl取代；其中r9和r10可各自独立的选自h，f，cl；或低级烷烃，低级环烷烃；或低级烷烃相连接的环烷烃，所有的烷烃可选择被一个或更多的f或cl取代；
l是价键、o、nh、c(o)、c(s)nh2、c(o)nh2、nh2c(o)、nh2c(s)、ch2或s(o)1~2；
x1、x2和x3各自独立选自ch、n、cch3；
z选自n、cr6、
本发明所述新型杂环衍生物可以根据常规药物配制技术与药物载体或赋形剂(例如药学上可接受的载体和赋形剂)混合形成药物制剂。可以将所述新型杂环衍生物作为活性成分混合在任何常用的口服剂型中，所述口服剂型包括片剂、胶囊剂和液体制剂(例如酏剂和混悬剂)，其中包含着色剂、矫味剂、稳定剂和掩盖味道的物质。对于混合口服剂型来说，所述环丙基二酰胺衍生物作为活性成分可以与各种普通片剂材料(例如淀粉、碳酸钙、乳糖、蔗糖和磷酸二钙)混合以助于压片和装入胶囊。可以将所述新型杂环衍生物在药学上可接受的无菌液体载体例如无菌水、无菌有机溶剂或者两者的混合物中溶解或混悬。液体载体可以是适合注射剂的载体，比如生理盐水、丙二醇或者聚乙二醇水溶液。在其他情况下，还可以将微粉化的活性成分分散在淀粉或羧甲基纤维素钠的水溶液中或分散在适当的油(例如花生油)中来制得。液体药物制剂(指无菌溶液或混悬剂)可以用于静脉注射、肌肉注射、腹膜内注射或者皮下注射。
本发明还提供了一种药物组合物，该药物组合物包含至少一种作为活性成分的本发明所述新型杂环衍生物。除此之外，所述药物组合物还可以包含一种或多种无机或有机、固体或液体的药学上可接受的载体或者赋形剂。药物载体和赋形剂可以包括但不限于稀释剂，例如乳糖、葡萄糖、甘露糖和/或甘油；润滑剂；聚乙二醇；粘合剂，例如硅酸铝镁、淀粉、明胶、甲基纤维素、羧甲基纤维素钠和/或聚乙烯吡咯烷酮；并且，如果需要的话，还包括崩解剂，例如淀粉、琼脂、海藻酸或其盐如海藻酸钠；和/或吸附剂、着色剂、防腐剂、稳定剂、矫味剂和甜味剂。
具体实施方式
下面对本发明的各个方面和特点作进一步的描述。
本文所用的缩略语通常为本领域技术人员所熟知的，或者可以是根据基础知识易于理解的。
在本发明化合物的制备中所采用的起始原料是已知的、能够根据已知方法制备的或者可商购获得的。
本发明还涉及新的中间体和/或起始原料。特别优选与实施例中提到的那些相同或者相似的反应条件和新中间体。
中间体和终产物都可以根据常规方法进行后处理和/或纯化，所述常规方法包括调节ph、萃取、过滤、干燥、浓缩、色谱法、研磨、结晶等。
另外，本发明化合物还可以通过本领域已知的各种方法或者本文所述方法的变通方法进行制备。
下列实施例仅用于举例说明本发明，不以任何方式对本发明进行限制。
实施例1n-(4-(7-环戊基-6-(二甲基氨基甲酰基)-7h-吡咯并[2,3-d]嘧啶-2-基)氨基)苯基)-n-苯基环丙烷-1,1-二甲酰胺的合成
步骤1.1：1-(苯基氨基甲酰基)环丙烷-1-羧酸的制备
将环丙烷-1,1-二羧酸(13.01g,100mmol)溶于150ml乙酸异丙酯中降温至0℃后滴加二氯亚砜（12.5g,105mmol）。滴加完毕升至室温搅拌6小时。滴加苯胺(110mmol)与三乙胺(15.29ml,110mmol)的乙酸异丙酯（40ml）溶液约1小时，继续搅拌2小时。反应液入乙酸乙酯（500ml）稀释,1n盐酸和饱和氯化钠洗涤，无水硫酸镁干燥浓缩得粗品。将粗品悬浮于庚烷中充分打浆后过滤干燥得最终产物。白色固体，产率：66%。1hnmr(400mhz,dmso-d6)δ13.10(s,1h),10.60(s,1h),7.63–7.54(m,2h),7.40–7.27(m,2h),7.11–6.99(m,1h),1.42(s,4h)；
步骤1.2：n-(4-氨基苯基)-n-苯基环丙烷-1,1-二甲酰胺的制备
在100ml单口瓶中加入1-(苯基氨基甲酰基)环丙烷-1-羧酸，对苯二胺(60mmol),edci(45mmol),hobt(36mmol),diea(60mmol)和dmf(30ml)，室温搅拌过夜。加入300ml水稀释，乙酸乙酯萃取3*100ml，合并有机相，有机相分别用饱和碳酸氢钠和食盐水洗涤，无水硫酸镁干燥，浓缩得粗品。粗品硅胶柱层析得中间体n-(4-氨基苯基)-n-苯基环丙烷-1,1-二甲酰胺，褐色固体，产率：85%。1hnmr(400mhz,dmso-d6)δ10.27(s,1h),9.68(s,1h),7.60(d,j=7.9hz,2h),7.30(t,j=7.8hz,2h),7.19(d,j=8.4hz,2h),7.05(t,j=7.4hz,1h),6.50(d,j=8.4hz,2h),4.91(s,2h),1.45(d,j=3.6hz,4h);13cnmr(101mhz,dmso)δ168.94,168.62,145.79,139.34,128.99,127.88,123.93,123.14,120.77,114.01,30.93,16.14；
步骤1.3：n-(4-((8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)苯基)-n-苯基环丙烷-1,1-二甲酰胺的合成
将2-氯-7-环戊基-n，n-二甲基-7h-吡咯并[2,3-d]嘧啶-6-甲酰胺(586mg,2mmol)溶于20ml的1,4-二氧六环中，加入n-(4-氨基苯基)-n-苯基环丙烷-1,1-二甲酰胺(2mmol)、pd(oac)2(11mg,0.05mmol)、binap(62mg,0.1mmol)和cs2co3(978mg,3mmol)，抽真空充氩气3次，升温至100℃搅拌过夜。冷却至室温，减压浓缩反应液得粗品。粗品硅胶柱层析得n-(4-((8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)苯基)-n-苯基环丙烷-1,1-二甲酰胺，白色固体，产率：74%。1hnmr(400mhz,dmso-d6)δ10.15(s,1h),9.89(s,1h),9.52(s,1h),8.73(s,1h),7.78(d,j=8.7hz,2h),7.62(d,j=8.0hz,2h),7.53(d,j=8.6hz,2h),7.30(t,j=7.9hz,2h),7.06(t,j=7.4hz,1h),6.57(s,1h),4.72(p,j=8.9hz,1h),3.05(s,6h),2.51–2.44(m,2h),2.04–1.91(m,4h),1.66(q,j=6.6hz,2h),1.52–1.45(m,4h);13cnmr(101mhz,dmso)δ168.31,168.05,162.89,155.47,152.04,151.21,138.74,137.00,132.03,131.43,128.46,123.54,120.99,120.37,118.07,111.32,100.66,56.94,34.48,31.05,29.53,24.14,15.53.esi-hrmsm/zcalcdforc31h34n7o3+552.2718,found552.2718[m+h]+。
实施例2n-(4-(7-环戊基-6-(二甲基氨基甲酰基)-7h-吡咯并[2,3-d]嘧啶-2-基)氨基)苯基)-n-(2-氟苯基)环丙烷-1,1二甲酰胺的合成
步骤2.1：1–((2-氟苯基)氨基甲酰基)环丙烷-1-羧酸的合成
方法同步骤1.1，白色固体，产率：45%,1hnmr(400mhz,dmso-d6)δ13.51(s,1h),11.27(s,1h),8.15(td,j=8.0,2.0hz,1h),7.27(ddd,j=11.4,7.9,1.8hz,1h),7.13(tdd,j=13.3,7.7,3.7hz,2h),1.56(h,j=4.0hz,4h).
步骤2.2：n-(4-氨基苯基)-n-(2-氟苯基)环丙烷-1,1-二甲酰胺的合成
方法同步骤1.2，褐色固体，产率：54%。1hnmr(400mhz,dmso-d6)δ11.16(s,1h),9.40(s,1h),8.04(td,j=7.8,2.4hz,1h),7.33–7.22(m,1h),7.20–7.09(m,4h),6.53(d,j=8.4hz,2h),4.99(s,2h),1.66–1.53(m,4h);13cnmr(101mhz,dmso)δ170.14,169.01,152.43,146.32,126.92,126.67,126.56,125.45,125.37,124.93,124.90,124.02,123.58,115.79,115.60,114.00,29.20,17.67.
步骤2.3：n-(4-(7-环戊基-6-(二甲基氨基甲酰基)-7h-吡咯并[2,3-d]嘧啶-2-基)氨基)苯基)-n-(2-氟苯基)环丙烷-1,1二甲酰胺的合成
方法同步骤1.3，白色固体，产率：79%。1hnmr(400mhz,dmso-d6)δ10.84(s,1h),9.75(s,1h),9.55(s,1h),8.74(s,1h),7.96(td,j=7.8,3.7hz,1h),7.84–7.76(m,2h),7.49(s,1h),7.32–7.25(m,1h),7.23–7.13(m,2h),6.58(s,1h),4.73(p,j=8.9hz,1h),3.05(d,j=10.6hz,6h),2.52–2.43(m,2h),2.04–1.92(m,4h),1.72–1.62(m,4h),1.62–1.54(m,2h);13cnmr(101mhz,dmso)δ169.44,168.56,162.90,155.46,154.77,152.35,152.04,151.21,137.47,131.49,131.26,126.03,125.92,125.31,125.24,124.38,123.82,121.77,118.09,115.36,115.17,111.38,100.64,56.93,34.60,29.55,29.27,24.14,17.00.esi-hrmsm/zcalcdforc31h33fn7o3+570.2623,found570.2628[m+h]+.hplcpurity99%。
实施例3n-(4-(7-环戊基-6-(二甲基氨基甲酰基)-7h-吡咯并[2,3-d]嘧啶-2-基)氨基)苯基)-n-(3-氟苯基)环丙烷-1,1二甲酰胺的合成
类似实施例1，白色固体，产率：76%。1hnmr(400mhz,dmf-d7)δ10.34(s,1h),9.82(s,1h),9.51(s,1h),8.73(s,1h),7.83–7.73(m,2h),7.64(dt,j=11.9,2.3hz,1h),7.53(d,j=8.7hz,2h),7.41–7.28(m,2h),6.89(td,j=8.5,2.6hz,1h),6.57(s,1h),4.72(p,j=8.9hz,1h),3.05(d,j=10.6hz,6h),2.50–2.42(m,2h),2.04–1.88(m,4h),1.75–1.60(m,2h),1.52–1.36(m,4h);13cnmr(101mhz,dmso)δ168.93,168.21,163.65,163.37,161.26,155.95,152.57,151.68,141.21,141.10,137.47,132.58,131.90,130.57,130.48,121.48,118.52,116.31,111.80,110.44,110.23,107.58,107.33,101.17,57.44,35.05,32.01,30.00,24.63,15.88.esi-hrmsm/zcalcdforc31h33fn7o3+570.2623,found570.2627[m+h]+.hplcpurity99%。
实施例4n-(4-(7-环戊基-6-(二甲基氨基甲酰基)-7h-吡咯并[2,3-d]嘧啶-2-基)氨基)苯基)-n-(3-氟苯基)环丙烷-1,1二甲酰胺的合成
类似实施例1，淡黄色固体，产率：80%。1hnmr(400mhz,dmso-d6)δ10.14(s,1h),9.93(s,1h),9.52(s,1h),8.73(s,1h),7.84–7.75(m,2h),7.71–7.59(m,2h),7.54(d,j=8.9hz,2h),7.15(t,j=8.9hz,2h),6.57(s,1h),4.72(p,j=8.9hz,1h),3.05(s,6h),2.51–2.40(m,3h),2.03–1.93(m,4h),1.71–1.58(m,2h),1.54–1.40(m,4h);13cnmr(101mhz,dmso)δ168.82,168.29,163.36,159.89,157.50,155.96,152.56,151.68,137.44,135.65,135.63,132.60,131.89,122.81,122.74,121.37,118.54,115.60,115.38,111.79,101.18,57.44,35.06,31.61,30.00,24.64,15.94.esi-hrmsm/zcalcdforc31h33fn7o3+570.2623,found570.2622[m+h]+.hplcpurity99%。
实施例5n-(3-氯苯基)-n-(4–((7-环戊基-6-(二甲基氨基甲酰基)-7h-吡咯并[2,3-d]嘧啶-2-基)氨基)苯基)环丙烷-1,1二甲酰胺的合成
类似实施例1，白色固体，产率：72%。1hnmr(400mhz,dmso-d6)δ10.30(s,1h),9.84(s,1h),9.51(s,1h),8.73(s,1h),7.87(t,j=2.1hz,1h),7.83–7.74(m,2h),7.52(dd,j=8.7,3.6hz,3h),7.32(t,j=8.1hz,1h),7.12(dd,j=8.0,2.0hz,1h),6.57(s,1h),4.83–4.62(m,1h),3.18–2.96(m,6h),2.50–2.42(m,2h),2.03–1.90(m,4h),1.71–1.59(m,2h),1.51–1.40(m,4h);13cnmr(101mhz,dmso)δ168.98,168.10,163.37,155.95,152.56,151.68,140.87,137.45,133.27,132.61,131.90,130.61,123.59,121.44,120.26,119.03,118.52,111.80,101.17,57.44,35.07,32.03,30.00,24.64,15.89.esi-hrmsm/zcalcdforc31h33cln7o3+586.2328,found586.2326[m+h]+.hplcpurity98%。
实施例6n-(4-氯苯基)-n-(4–((7-环戊基-6-(二甲基氨基甲酰基)-7h-吡咯并[2,3-d]嘧啶-2-基)氨基)苯基)环丙烷-1,1二甲酰胺的合成
类似实施例1，白色固体，产率：80%。1hnmr(400mhz,dmso-d6)δ10.25(s,1h),9.86(s,1h),9.51(s,1h),8.73(s,1h),7.82–7.73(m,2h),7.71–7.65(m,2h),7.53(d,j=8.7hz,2h),7.40–7.31(m,2h),6.57(s,1h),4.85–4.63(m,1h),3.05(d,j=10.3hz,6h),2.53–2.42(m,2h),2.06–1.92(m,4h),1.75–1.62(m,2h),1.53–1.40(m,4h);13cnmr(101mhz,dmso)δ168.86,168.25,163.37,155.96,152.56,151.69,138.32,137.46,132.59,131.90,128.83,127.56,122.34,121.43,118.53,111.80,101.17,57.44,35.12,31.85,30.01,24.64,15.93.esi-hrmsm/zcalcdforc31h33cln7o3+586.2328,found586.2331[m+h]+.hplcpurity99%。
实施例7n-(4–((7-环戊基-6-(二甲基氨基甲酰基)-7h-吡咯并[2,3-d]嘧啶-2-基)氨基)苯基)-n-(间苯甲基)环丙烷-1,1二甲酰胺的合成
类似实施例1，白色固体，产率：57%。1hnmr(400mhz,dmso-d6)δ10.10(s,1h),9.87(s,1h),9.51(s,1h),8.73(s,1h),7.85–7.70(m,2h),7.52(d,j=8.9hz,2h),7.49–7.36(m,2h),7.18(t,j=7.8hz,1h),6.88(d,j=7.5hz,1h),6.58(s,1h),4.72(p,j=9.0hz,1h),3.05(d,j=10.4hz,6h),2.51–2.41(m,2h),2.27(s,3h),2.04–1.92(m,4h),1.72–1.60(m,2h),1.52–1.42(m,4h);13cnmr(101mhz,dmso)δ168.28,168.17,162.91,155.49,152.02,151.23,138.60,137.64,137.03,131.97,131.45,128.30,124.24,121.03,120.92,118.09,117.53,111.33,100.63,56.94,34.65,30.89,29.54,24.14,21.08,15.60.esi-hrmsm/zcalcdforc32h36n7o3+566.2874,found566.2879[m+h]+.hplcpurity99%。
实施例8n-(4–((7-环戊基-6-(二甲基氨基甲酰基)-7h-吡咯并[2,3-d]嘧啶-2-基)氨基)苯基)-n-(对苯甲基)环丙烷-1,1二甲酰胺的合成
类似实施例1，白色固体，产率：63%。1hnmr(400mhz,dmso-d6)δ10.04(s,1h),9.92(s,1h),9.51(s,1h),8.73(s,1h),7.84–7.70(m,2h),7.51(dd,j=11.4,8.6hz,4h),7.11(d,j=8.2hz,2h),6.58(s,1h),4.72(p,j=8.9hz,1h),3.05(d,j=10.4hz,6h),2.52–2.38(m,2h),2.25(s,3h),2.06–1.92(m,4h),1.73–1.60(m,2h),1.54–1.43(m,4h);13cnmr(101mhz,dmso)δ168.70,168.59,163.37,155.96,152.56,151.69,137.47,136.67,133.01,132.52,131.91,129.35,121.43,120.94,118.56,111.80,101.17,57.43,35.16,31.38,30.01,24.64,20.92,16.04.esi-hrmsm/zcalcdforc32h36n7o3+566.2874,found566.2879[m+h]+.hplcpurity99%。
实施例9n-(4–((7-环戊基-6-(二甲基氨基甲酰基)-7h-吡咯并[2,3-d]嘧啶-2-基)氨基)苯基)-n-(3-(三氟甲基)苯基)1,1-二甲酰胺的合成
类似实施例1，白色固体，产率：61%。1hnmr(400mhz,dmso-d6)δ10.44(s,1h),9.87(s,1h),9.52(s,1h),8.73(s,1h),8.17(s,1h),7.86(d,j=8.2hz,1h),7.78(d,j=8.4hz,2h),7.62–7.49(m,3h),7.40(d,j=7.7hz,1h),6.57(s,1h),4.85–4.64(m,1h),3.05(s,6h),2.58–2.40(m,2h),2.05–1.88(m,4h),1.73–1.58(m,2h),1.53–1.40(m,4h);13cnmr(101mhz,dmso)δ168.68,167.50,162.89,155.47,152.03,151.21,139.72,136.96,132.17,131.42,129.62,129.34,129.03,125.48,123.70,122.77,120.92,119.66,118.05,116.41,111.31,100.65,56.94,34.57,31.63,29.51,24.13,15.36.esi-hrmsm/zcalcdforc32h33f3n7o3+620.2591,found620.2593[m+h]+.hplcpurity99%。
实施例10n-(4–((7-环戊基-6-(二甲基氨基甲酰基)-7h-吡咯并[2,3-d]嘧啶-2-基)氨基)苯基)-n-(4-(三氟甲基)苯基)1,1-二甲酰胺的合成
类似实施例1，白色固体，产率：88%。1hnmr(400mhz,dmso-d6)δ10.53(s,1h),9.83(s,1h),9.51(s,1h),8.73(s,1h),7.87(d,j=8.4hz,2h),7.80–7.75(m,2h),7.67(d,j=8.4hz,2h),7.53(d,j=8.7hz,2h),6.57(s,1h),4.89–4.59(m,1h),3.05(s,6h),2.56–2.38(m,2h),2.07–1.89(m,4h),1.74–1.59(m,2h),1.55–1.36(m,4h);13cnmr(101mhz,dmso)δ169.15,168.15,163.37,155.95,152.56,151.68,143.06,137.48,132.60,131.90,126.25,126.21,123.70,121.48,120.46,118.51,111.80,101.17,57.44,35.04,32.16,30.00,24.63,15.96.esi-hrmsm/zcalcdforc32h33f3n7o3+620.2591,found620.2588[m+h]+.hplcpurity99%。
实施例11n-(4–((7-环戊基-6-(二甲基氨基甲酰基)-7h-吡咯并[2,3-d]嘧啶-2-基)氨基)苯基)-n-(3-甲氧基苯基)环丙烷-1,1-二甲酰胺的合成
类似实施例1，白色固体，产率：67%。1hnmr(400mhz,dmso-d6)δ10.14(s,1h),9.83(s,1h),9.51(s,1h),8.73(s,1h),7.77(dd,j=9.7,2.7hz,3h),7.52(d,j=9.0hz,2h),7.40–7.30(m,1h),7.25–7.14(m,2h),6.64(dq,j=6.2,2.7hz,1h),6.57(s,1h),4.82–4.63(m,1h),3.72(s,3h),3.05(s,6h),2.51–2.42(m,2h),2.01–1.91(m,4h),1.73–1.61(m,2h),1.52–1.41(m,4h);13cnmr(101mhz,dmso)δ168.72,168.53,163.37,159.83,155.95,152.57,151.68,140.49,137.48,132.53,131.91,129.72,121.51,118.53,112.95,111.80,109.58,106.40,101.18,57.44,55.45,35.10,31.73,30.01,24.63,15.95.esi-hrmsm/zcalcdforc32h36n7o4+582.2823,found582.2827[m+h]+.hplcpurity99%。
实施例12n-(4–((7-环戊基-6-(二甲基氨基甲酰基)-7h-吡咯并[2,3-d]嘧啶-2-基)氨基)苯基)-n-(4-甲氧基苯基)环丙烷-1,1-二甲酰胺的合成
类似实施例1，白色固体，产率：46%。1hnmr(400mhz,dmso-d6)δ10.00(s,1h),9.93(s,1h),9.51(s,1h),8.73(s,1h),7.78(d,j=8.9hz,2h),7.63–7.46(m,4h),6.95–6.82(m,2h),6.57(s,1h),4.73(q,j=8.8hz,1h),3.72(s,3h),3.05(s,6h),2.50–2.39(m,2h),2.04–1.96(m,4h),1.75–1.54(m,2h),1.57–1.40(m,4h);13cnmr(101mhz,dmso)δ168.69,168.50,163.37,156.01,155.96,152.57,151.69,137.44,132.56,132.20,131.89,122.68,121.32,118.57,114.06,111.79,101.18,57.44,55.61,35.09,31.21,30.01,24.64,16.03.esi-hrmsm/zcalcdforc32h36n7o4+582.2823,found582.2824[m+h]+.hplcpurity99%。
实施例13n-(3-氰基苯基)-n-(4-(7-环戊基-6-(二甲基氨基甲酰基)-7h-吡咯并[2,3-d]嘧啶-2-基)氨基)苯基)环丙烷-1,1二甲酰胺的合成
类似实施例1，黄色固体，产率：79%。1hnmr(400mhz,dmso-d6)δ10.46(s,1h),9.86(s,1h),9.51(s,1h),8.73(s,1h),8.16(s,1h),7.92–7.86(m,1h),7.78(d,j=8.9hz,2h),7.53(t,j=6.1hz,4h),6.57(s,1h),4.72(p,j=9.0hz,1h),3.05(s,6h),2.60–2.37(m,2h),2.06–1.89(m,4h),1.73–1.57(m,2h),1.55–1.43(m,4h);13cnmr(101mhz,dmso)δ169.21,167.95,163.37,155.95,152.57,151.68,140.25,137.47,132.62,131.90,130.44,127.40,125.24,123.52,121.44,119.19,118.53,111.80,111.76,101.18,57.44,35.02,32.10,30.00,24.64,15.92.esi-hrmsm/zcalcdforc32h33n8o3+577.2670,found577.2666[m+h]+.hplcpurity99%。
实施例14n-(4-氰基苯基)-n-(4-(7-环戊基-6-(二甲基氨基甲酰基)-7h-吡咯并[2,3-d]嘧啶-2-基)氨基)苯基)环丙烷-1,1二甲酰胺的合成
类似实施例1，白色固体，产率：68%。1hnmr(400mhz,dmso-d6)δ10.60(s,1h),9.80(s,1h),9.51(s,1h),8.73(s,1h),7.85(d,j=8.8hz,2h),7.77(d,j=8.9hz,4h),7.52(d,j=8.9hz,2h),6.57(s,1h),4.72(p,j=8.9hz,1h),3.05(s,6h),2.51–2.40(m,2h),2.02–1.90(m,4h),1.74–1.60(m,2h),1.47(dt,j=13.8,3.2hz,4h);13cnmr(101mhz,dmso)δ169.20,168.01,163.37,155.94,152.56,151.68,143.77,137.48,133.46,132.59,131.91,121.50,120.52,119.55,118.50,111.80,105.51,101.17,57.43,35.06,32.39,30.00,24.64,15.92.esi-hrmsm/zcalcdforc32h33n8o3+577.2670,found577.2668[m+h]+.hplcpurity99%。
实施例153-甲基-(1-((4-((7-环戊基-6-(二甲基氨基甲酰基)-7h-吡咯并[2,3-d]嘧啶-2-基)氨基)苯基)氨基甲酰基)环丙烷-1-甲酰氨基)苯甲酸酯的合成
类似实施例1，白色固体，产率：62%。1hnmr(400mhz,dmso-d6)δ10.32(s,1h),9.89(s,1h),9.51(s,1h),8.73(s,1h),8.34(t,j=1.9hz,1h),7.89(dd,j=8.1,2.2hz,1h),7.77(d,j=8.6hz,2h),7.66(dt,j=7.8,1.4hz,1h),7.54(d,j=8.6hz,2h),7.45(t,j=7.9hz,1h),6.57(s,1h),4.72(p,j=8.9hz,1h),3.85(s,3h),3.05(s,6h),2.61–2.24(m,2h),2.11–1.93(m,4h),1.70–1.61(m,2h),1.49–1.41(m,4h);13cnmr(101mhz,dmso)δ169.06,168.11,166.57,163.37,155.96,152.57,151.69,139.78,137.42,132.68,131.89,130.32,129.41,125.26,124.55,121.38,121.34,118.53,111.79,101.18,57.44,52.63,35.06,31.99,30.00,24.63,15.89.esi-hrmsm/zcalcdforc33h36n7o5+610.2772,found610.2774[m+h]+.hplcpurity99%。
实施例164-甲基-(1-((4-((7-环戊基-6-(二甲基氨基甲酰基)-7h-吡咯并[2,3-d]嘧啶-2-基)氨基)苯基)氨基甲酰基)环丙烷-1-甲酰氨基)苯甲酸酯的合成
类似实施例1，淡棕色固体，产率：88%。1hnmr(400mhz,dmso-d6)δ10.55(s,1h),9.81(s,1h),9.52(s,1h),8.72(s,1h),7.97–7.88(m,2h),7.85–7.75(m,4h),7.54(d,j=8.7hz,2h),6.56(s,1h),4.72(p,j=8.9hz,1h),3.81(s,3h),3.04(s,6h),2.54–2.40(m,2h),2.00–1.88(m,4h),1.72–1.60(m,2h),1.50–1.46(m,4h);13cnmr(101mhz,dmso)δ168.60,167.83,165.78,162.91,155.49,152.01,151.23,143.35,137.04,132.05,131.44,129.96,124.09,121.08,119.44,118.06,111.33,100.64,56.95,51.80,34.59,31.56,29.53,24.14,15.57.esi-hrmsm/zcalcdforc33h36n7o5+610.2772,found610.2771[m+h]+.hplcpurity99%。
实施例17n-(4-氯-3-(三氟甲基)苯基)-n-(4–((7-环戊基-6-(二甲基氨基甲酰基)-7h-吡咯并[2,3-d]嘧啶-2-基)氨基)苯基)环丙烷-1,1-二甲酰胺
类似实施例1，淡棕色固体，产率：58%。1hnmr(400mhz,dmso-d6)δ10.51(s,1h),9.86(s,1h),9.51(s,1h),8.73(s,1h),8.27(d,j=2.6hz,1h),7.91(dd,j=8.8,2.5hz,1h),7.77(d,j=8.9hz,2h),7.66(d,j=8.8hz,1h),7.53(d,j=8.8hz,2h),6.57(s,1h),4.72(p,j=8.9hz,1h),3.05(s,6h),2.52–2.39(m,2h),2.04–1.87(m,4h),1.70–1.59(m,2h),1.49–1.39(m,4h);13cnmr(101mhz,dmso)δ169.21,167.70,163.37,155.95,152.57,151.68,139.02,137.43,132.70,132.28,131.90,127.06,125.36,124.47,121.33,119.38,118.52,111.79,101.17,57.44,35.01,32.35,29.99,24.63,15.77.esi-hrmsm/zcalcdforc32h32clf3n7o3+654.2202,found654.2203[m+h]+.hplcpurity99%。
实施例18n-(3-溴苯基)-n-(4–((7-环戊基-6-(二甲基氨基甲酰基)-7h-吡咯并[2,3-d]嘧啶-2-基)氨基)苯基)环丙烷-1,1二甲酰胺的合成
步骤18-1类似实施例步骤1-1，得1–((3-溴苯基)氨基甲酰基)环丙烷-1-羧酸的合成
白色固体，产率：76%。1hnmr(400mhz,dmso-d6)δ13.12(s,1h),10.69(s,1h),7.97(t,j=2.0hz,1h),7.50(dt,j=7.5,1.9hz,1h),7.39–7.15(m,2h),1.42(s,4h);13cnmr(101mhz,dmso)δ174.03,167.51,140.83,131.13,126.43,122.14,122.01,118.57,29.38,17.50.
步骤18-2：2-((4-氨基苯基)氨基)-7-环戊基-n，n-二甲基-7h-吡咯并[2,3-d]嘧啶-6-甲酰胺的合成
将2-氯-7-环戊基-n，n-二甲基-7h-吡咯并[2,3-d]嘧啶-6-甲酰胺(2.92g,10mmol)悬浮于80ml的1,4-二氧六环中，加入对苯二胺(2.18g,20mmol)、pd(oac)2(56mg,0.25mmol)、binap(311mg,0.5mmol)和cs2co3(4.89g,15mmol)，抽真空充氩气3次，升温至100℃搅拌过夜。冷却至室温，减压浓缩反应液得粗品。粗品硅胶柱层析得目标产物。灰黄色固体，产率：79%。1hnmr(400mhz,dmso-d6)δ9.01(s,1h),8.64(s,1h),7.73(s,1h),7.53–7.36(m,2h),6.59–6.50(m,4h),4.80–4.58(m,1h),3.05(s,6h),2.48–2.36(m,2h),2.03–1.88(m,4h),1.69–1.53(m,2h).
步骤18-3：n-(3-溴苯基)-n-(4–((7-环戊基-6-(二甲基氨基甲酰基)-7h-吡咯并[2,3-d]嘧啶-2-基)氨基)苯基)环丙烷-1,1二甲酰胺的合成
将1–((3-溴苯基)氨基甲酰基)环丙烷-1-羧酸(511mg,1.5mmol)、2-((4-氨基苯基)氨基)-7-环戊基-n，n-二甲基-7h-吡咯并[2,3-d]嘧啶-6-甲酰胺(547mg,1.5mmol)、edci(431mg,2.25mmol)、hobt(243mg,1.8mmol)、diea(388mg,3mmol)悬浮于10ml的dmf中，室温搅拌过夜。加入水稀释，乙酸乙酯萃取3*30ml，合并有机相。有机相分别用饱和碳酸氢钠和食盐水洗涤，无水硫酸镁干燥、浓缩得粗品。粗品硅胶柱层析得目标产物。白色固体，产率：53%。1hnmr(400mhz,dmso-d6)δ10.27(s,1h),9.84(s,1h),9.50(s,1h),8.73(s,1h),8.00(d,j=2.2hz,1h),7.77(d,j=8.7hz,2h),7.59–7.45(m,3h),7.32–7.21(m,2h),6.57(s,1h),4.72(p,j=8.9hz,1h),3.05(s,6h),2.57–2.38(m,2h),2.06–1.92(m,4h),1.73–1.61(m,2h),1.52–1.42(m,4h),13cnmr(101mhz,dmso)δ168.50,167.62,162.89,155.48,152.03,151.21,140.49,136.98,132.11,131.43,130.41,126.00,122.66,121.24,120.95,118.95,118.05,111.32,100.65,56.94,34.60,31.48,29.52,24.14,15.41.esi-hrmsm/zcalcdforc31h33brn7o3+630.1823,found630.1817[m+h]+.hplcpurity99%。
实施例19n-(4-溴苯基)-n-(4–((7-环戊基-6-(二甲基氨基甲酰基)-7h-吡咯并[2,3-d]嘧啶-2-基)氨基)苯基)环丙烷-1,1二甲酰胺的合成
类似实施例18，白色固体，产率：58%。1hnmr(400mhz,dmso-d6)δ10.24(s,1h),9.85(s,1h),9.51(s,1h),8.73(s,1h),7.84–7.72(m,2h),7.67–7.60(m,2h),7.58–7.45(m,4h),6.58(s,1h),4.72(p,j=9.0hz,1h),3.05(s,6h),2.51–2.41(m,2h),2.09–1.92(m,4h),1.72–1.65(m,2h),1.56–1.43(m,4h);13cnmr(101mhz,dmso)δ168.35,167.72,162.87,155.45,152.08,151.18,138.26,136.95,132.09,131.40,131.25,122.20,120.91,118.02,115.10,111.29,100.68,56.93,35.05,31.43,29.50,24.14,15.41.esi-hrmsm/zcalcdforc31h33brn7o3+630.1823,found630.1818[m+h]+.hplcpurity97%。
实施例20n-(4–((7-环戊基-6-(二甲基氨基甲酰基)-7h-吡咯并[2,3-d]嘧啶-2-基)氨基)苯基)-n-(4-羟基苯基)环丙烷-1,1-二甲酰胺的合成
步骤20-1、20-2类似实施例步骤1-1、1-2，得中间体n-(4-氨基苯基)-n-(4-羟基苯基)环丙烷-1,1-二甲酰胺的合成
灰色固体，产率：50%。1hnmr(400mhz,dmso-d6)δ9.95(s,1h),9.70(s,1h),9.26(s,1h),7.43–7.34(m,2h),7.20(d,j=8.4hz,2h),6.79–6.68(m,2h),6.59–6.48(m,2h),4.91(s,2h),1.45(s,4h);13cnmr(101mhz,dmso)δ168.76,168.60,154.21,145.73,130.55,127.90,123.01,122.91,115.39,114.11,55.34,30.44,16.16.
步骤20-3：n-(4–((7-环戊基-6-(二甲基氨基甲酰基)-7h-吡咯并[2,3-d]嘧啶-2-基)氨基)苯基)-n-(4-羟基苯基)环丙烷-1,1-二甲酰胺的合成
将2-氯-7-环戊基-n，n-二甲基-7h-吡咯并[2,3-d]嘧啶-6-甲酰胺(586mg,2mmol)悬浮于20ml的1,4-二氧六环中，加入n-(4-氨基苯基)-n-(4-羟基苯基)环丙烷-1,1-二甲酰胺(2mmol)、pd(oac)2(11mg,0.05mmol)、binap(62mg,0.1mmol)和cs2co3(1.63g,3mmol)，抽真空充氩气3次，升温至100℃搅拌过夜。冷却至室温，减压浓缩反应液得粗品。粗品硅胶柱层析得目标产物。白色固体，产率：40%。1hnmr(400mhz,dmso-d6)δ10.04(s,1h),9.80(s,1h),9.51(s,1h),9.24(s,1h),8.73(s,1h),7.78(dd,j=9.4,2.9hz,2h),7.60–7.43(m,2h),7.46–7.32(m,2h),6.74–6.67(m,2h),6.57(s,1h),4.72(p,j=8.8hz,1h),3.05(s,6h),2.50–2.43(m,2h),2.04–1.93(m,4h),1.74–1.58(m,2h),1.46(s,4h);13cnmr(101mhz,dmso)δ168.66,168.56,163.38,155.96,154.21,152.56,151.69,137.43,132.54,131.90,130.59,123.02,121.29,118.59,115.33,111.80,101.17,57.44,35.12,31.00,30.02,24.64,16.06.esi-hrmsm/zcalcdforc31h34n7o4+568.2667,found568.2668[m+h]+.hplcpurity99%。
实施例21n-(4–((7-环戊基-6-(二甲基氨基甲酰基)-7h-吡咯并[2,3-d]嘧啶-2-基)氨基)苯基)-n-(3-羟基苯基)环丙烷-1,1二甲酰胺的合成
类似实施例20，白色固体，产率：55%。1hnmr(400mhz,dmso-d6)δ10.06(s,1h),9.84(s,1h),9.52(s,1h),9.38(s,1h),8.73(s,1h),7.84–7.75(m,2h),7.52(d,j=8.7hz,2h),7.20(t,j=2.1hz,1h),7.07(t,j=8.0hz,1h),7.03–6.96(m,1h),6.57(s,1h),6.47(dd,j=7.9,2.4hz,1h),4.85–4.65(m,1h),3.05(d,j=10.1hz,6h),2.50(s,2h),2.04–1.86(m,4h),1.76–1.58(m,2h),1.51–1.42(m,4h);13cnmr(101mhz,dmso)δ168.69,168.58,163.37,157.92,155.95,152.57,151.68,140.26,137.50,132.48,131.90,129.60,121.53,118.54,111.80,111.47,111.12,107.93,101.17,57.44,35.04,31.57,30.01,24.64,16.02.esi-hrmsm/zcalcdforc31h34n7o4+568.2667,found568.2663[m+h]+.hplcpurity99%。
实施例22n-(4-((7-环戊基-6-(二甲基氨基甲酰基)-7h-吡咯并[2,3-d]嘧啶-2-基)氨基)-3-氟苯基)-n-(4-氟苯基)1,1-二甲酰胺的合成
步骤22-1：n-(4-氨基-3-氟苯基)-n-(4-氟苯基)环丙烷-1,1-二甲酰胺的合成
将中间体1–((4-氟苯基)氨基甲酰基)环丙烷-1-羧酸(4.91g,22mmol)悬浮于40ml四氢呋喃中，滴加二氯亚砜(2.86g,24mmol)后室温搅拌3小时。50ml加入3-氟-4-硝基苯胺(3.12g,20mmol)的二氯甲烷溶液和dipea(3.88g,30mmol)后搅拌过夜。减压蒸去溶剂后加入200ml水，乙酸乙酯萃取3*100，合并有机相，有机相分别用水和饱和食盐水洗涤，无水硫酸镁干燥、浓缩得粗品。将粗品悬浮于thf/etoh/h2o(80/80/32ml)混合溶剂中，加入铁粉(5.6g,100mmol)、氯化铵(16g,300mmol)后80℃搅拌6小时。趁热硅藻土过滤，乙酸乙酯洗涤滤饼，分离有机相。水相乙酸乙酯萃取3*100ml，合并有机相，有机相水洗、饱和食盐水洗后无水硫酸镁干燥，减压浓缩得粗品。粗品硅胶柱层析得2.74g棕色固体，产率41%。1hnmr(400mhz,dmso-d6)δ10.14(s,1h),9.78(s,1h),7.70–7.56(m,2h),7.41(dd,j=13.5,2.3hz,1h),7.21–7.10(m,2h),7.04(dd,j=8.5,2.3hz,1h),6.70(dd,j=10.1,8.6hz,1h),4.95(s,2h),1.44(s,4h);13cnmr(101mhz,dmso)δ168.74,168.25,159.90,157.51,151.27,148.93,135.61,135.58,133.07,132.94,128.51,128.42,122.80,122.73,117.70,116.13,116.07,115.59,115.37,109.27,109.04,31.45,15.92.
步骤22-2：n-(4-((7-环戊基-6-(二甲基氨基甲酰基)-7h-吡咯并[2,3-d]嘧啶-2-基)氨基)-3-氟苯基)-n-(4-氟苯基)1,1-二甲酰胺的合成
将2-氯-7-环戊基-n，n-二甲基-7h-吡咯并[2,3-d]嘧啶-6-甲酰胺(586mg,2mmol)悬浮于20ml的1,4-二氧六环中，n-(4-氨基-3-氟苯基)-n-(4-氟苯基)环丙烷-1,1-二甲酰胺(663mg,2mmol)、pd(oac)2(11mg,0.05mmol)、binap(62mg,0.1mmol)和cs2co3(978mg,3mmol)，抽真空充氩气3次，升温至100℃搅拌过夜。冷却至室温，减压浓缩反应液得粗品。粗品硅胶柱层析得565mg目标产物。黄色固体，产率：48%。1hnmr(400mhz,dmso-d6)δ10.16(s,1h),10.06(s,1h),8.81(s,1h),8.69(s,1h),7.78(t,j=9.0hz,1h),7.72–7.60(m,3h),7.34(dd,j=8.7,2.3hz,1h),7.19–7.09(m,2h),6.55(s,1h),4.66(p,j=8.7hz,1h),3.03(s,7h),2.40–2.23(m,2h),1.97–1.85(m,2h),1.85–1.73(m,2h),1.59–1.49(m,2h),1.46(s,4h).13cnmr(101mhz,dmso)δ168.10,168.02,162.89,159.44,157.06,156.05,155.36,152.94,151.94,151.50,135.13,135.03,134.92,131.59,123.97,123.59,123.47,122.42,122.34,115.49,115.08,114.85,111.67,107.86,107.61,100.40,56.70,34.54,31.49,29.83,24.32,15.39.esi-hrmsm/zcalcdforc31h32f2n7o3+588.2529,found588.2531[m+h]+.hplcpurity97%。
实施例23n-(6–((7-环戊基-6-(二甲基氨基甲酰基)-7h-吡咯并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)-n-(4-氟苯基)-1,1-二甲酰胺的合成
步骤23-1：7-环戊基-n，n-二甲基-2–((5-硝基吡啶-2-基)氨基)-7h-吡咯并[2,3-d]嘧啶-6-甲酰胺的合成
将2-氯-7-环戊基-n，n-二甲基-7h-吡咯并[2,3-d]嘧啶-6-甲酰胺(500mg,1.71mmol)悬浮于20ml的1,4-二氧六环中，加入2-氨基-5-硝基吡啶(356mg,2.56mmol)、pd(oac)2(9.6mg,0.043mmol)、binap(53mg,0.09mmol)和cs2co3(834mg,2.56mmol)，抽真空充氩气3次，升温至100℃搅拌过夜。冷却至室温，减压浓缩反应液得粗品。粗品硅胶柱层析得200mg目标产物3-7。黄色固体，产率30%。1hnmr(400mhz,chloroform-d)δ9.29(d,j=2.7hz,1h),8.90(s,1h),8.66(d,j=9.3hz,1h),8.47(dd,j=9.4,2.8hz,1h),7.26(s,1h),6.55(s,1h),4.84(p,j=8.9hz,1h),3.18(s,6h),2.63–2.47(m,2h),2.24–2.02(m,4h),1.90–1.66(m,2h).
步骤23-2：2-((5-氨基吡啶-2-基)氨基)-7-环戊基-n，n-二甲基-7h-吡咯并[2,3-d]嘧啶-6-甲酰胺的合成
将化合物7-环戊基-n，n-二甲基-2–((5-硝基吡啶-2-基)氨基)-7h-吡咯并[2,3-d]嘧啶-6-甲酰胺(204mg,0.5mmol)悬浮于10ml乙醇中，加入氯化亚锡二水合物(1.25g,11mmol)后回流4小时。将反应液冷却至室温，加入100ml乙酸乙酯稀释后分别用饱和碳酸氢钠、水和饱和食盐水洗涤，无水硫酸镁干燥，浓缩得粗品。粗品硅胶柱层析得105mg棕色固体，产率57%。1hnmr(400mhz,chloroform-d)δ8.68(s,1h),8.24(d,j=8.8hz,1h),8.01(s,1h),7.85(d,j=2.9hz,1h),7.11(dd,j=8.7,2.9hz,1h),6.42(s,1h),4.77(p,j=8.9hz,1h),3.15(s,6h),2.66–2.51(m,2h),2.12–1.96(m,4h),1.79–1.61(m,2h);113cnmr(101mhz,cdcl3)δ164.16,154.78,152.06,151.77,145.96,137.27,134.76,131.94,125.06,113.06,112.52,100.99,57.92,35.52,30.21,24.72.
步骤23-3：n-(6–((7-环戊基-6-(二甲基氨基甲酰基)-7h-吡咯并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)-n-(4-氟苯基)-1,1-二甲酰胺的合成
将1–((4-氟苯基)氨基甲酰基)环丙烷-1-羧酸(375mg,1.68mmol)、2-((5-氨基吡啶-2-基)氨基)-7-环戊基-n，n-二甲基-7h-吡咯并[2,3-d]嘧啶-6-甲酰胺(510mg,1.4mmol)、edci(403mg,2.1mmol)、hobt(227mg,1.68mmol)和diea(362mg,2.8mmol)悬浮于10ml的dmf中，室温搅拌过夜。加入水稀释，乙酸乙酯萃取3*30ml，合并有机相。有机相分别用饱和碳酸氢钠和食盐水洗涤，无水硫酸镁干燥、浓缩得粗品。粗品硅胶柱层析得556mg目标产物。棕色固体，产率70%。1hnmr(400mhz,dmso-d6)δ10.16(s,1h),10.06(s,1h),9.77(s,1h),8.82(s,1h),8.55(d,j=2.6hz,1h),8.30(d,j=9.0hz,1h),7.99(dd,j=9.0,2.7hz,1h),7.65(dd,j=8.9,5.0hz,2h),7.15(t,j=8.9hz,2h),6.63(s,1h),4.74(p,j=8.8hz,1h),3.05(d,j=9.5hz,6h),2.50–2.38(m,2h),2.17–1.86(m,4h),1.84–1.60(m,2h),1.54–1.38(m,4h);13cnmr(101mhz,dmso)δ168.32,167.93,162.80,154.33,152.05,150.96,149.21,140.47,135.17,132.24,130.00,129.47,122.28,115.10,114.88,112.17,111.32,100.45,56.98,34.61,31.25,29.67,24.20,15.43.esi-hrmsm/zcalcdforc30h32fn8o3+571.2576,found571.2580[m+h]+.hplcpurity99%。
实施例24n-(4-((8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)苯基)-n-苯基环丙烷-1,1-二甲酰胺的合成
将2-氯-8-环戊基-5-甲基吡啶并[2,3-d]嘧啶-7(8h)-酮(200mg,0.76mmol)悬浮于6ml的1,4-二氧六环中，加入n-(4-氨基苯基)-n-苯基环丙烷-1,1-二甲酰胺(0.76mmol)、pd(oac)2(5mg,0.02mmol)、binap(28mg,0.04mmol)和cs2co3(370mg,1.14mmol)，抽真空充氩气3次，升温至100℃搅拌过夜。冷却至室温，减压浓缩反应液得粗品。粗品硅胶柱层析得目标产物。白色固体，产率：38%。1hnmr(400mhz,dmso-d6)δ10.10(s,1h),9.96(d,j=11.1hz,2h),8.79(s,1h),7.77–7.48(m,6h),7.30(t,j=7.8hz,2h),7.06(t,j=7.4hz,1h),6.17(s,1h),5.94–5.70(m,1h),2.36(s,3h),2.30–2.18(m,2h),2.00–1.86(m,2h),1.82–1.69(m,2h),1.63–1.53(m,2h),1.52–1.41(m,4h)；13cnmr(101mhz,dmso)δ168.33,168.15,162.46,158.71,156.72,155.52,145.28,138.77,135.48,134.50,133.56,128.48,123.59,120.87,120.72,120.45,119.88,117.44,106.85,52.65,31.17,27.51,25.09,16.67,15.58.esi-hrmsm/zcalcdforc30h31n6o3+523.2452,found523.2451[m+h]+。
实施例25n-(4-((8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)苯基)-n-（2-氟苯基）环丙烷-1,1-二甲酰胺的合成
类似实施例24，白色固体，产率：41.7%。1hnmr(400mhz,dmso-d6)δ10.76(s,1h),9.98(s,1h),9.83(s,1h),8.80(s,1h),7.99–7.88(m,1h),7.68(d,j=8.7hz,2h),7.53(d,j=8.9hz,2h),7.31–7.21(m,1h),7.21–7.10(m,2h),6.18(s,1h),5.92–5.77(m,1h),2.36(s,3h),2.30–2.18(m,2h),1.97–1.88(m,2h),1.80–1.69(m,2h),1.67–1.52(m,6h)；13cnmr(101mhz,dmso)δ169.51,168.60,162.47,158.71,156.77,155.53,154.91,152.48,145.33,135.96,132.84,126.03,125.92,125.47,125.39,124.44,124.41,124.03,121.65,119.88,117.53,115.45,115.26,106.93,52.65,29.42,27.55,25.15,17.10,16.71.esi-hrmsm/zcalcdforc30h30fn6o3+541.2358,found541.2354[m+h]+。
实施例26n-(4-((8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)苯基)-n-（3-氟苯基）环丙烷-1,1-二甲酰胺的合成
类似实施例24，白色固体，产率：42.7%。1hnmr(400mhz,dmso-d6)δ10.31(s,1h),9.95(s,1h),9.91(s,1h),8.79(s,1h),7.68–7.54(m,5h),7.41–7.28(m,2h),6.88(td,j=8.4,2.6hz,1h),6.17(d,j=1.3hz,1h),5.84(t,j=8.9hz,1h),2.36(s,3h),2.29–2.20(m,2h),1.97–1.87(m,2h),1.80–1.70(m,2h),1.63–1.54(m,2h),1.50–1.42(m,4h)；13cnmr(101mhz,dmso)δ168.45,167.83,163.20,162.47,160.80,158.71,156.75,155.52,145.32,140.75,140.64,135.48,133.63,130.11,130.02,120.89,119.86,117.45,115.89,110.01,109.80,107.17,106.90,106.85,52.65,31.64,27.52,25.12,16.69,15.46.esi-hrmsm/zcalcdforc30h30fn6o3+541.2358,found541.2354[m+h]+。
实施例27n-(4-((8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)苯基)-n-（4-氟苯基）环丙烷-1,1-二甲酰胺的合成
类似实施例24，黄色固体，产率：28.1%。1hnmr(400mhz,dmso-d6)δ10.09(s,1h),10.00(s,1h),9.95(s,1h),8.80(s,1h),7.68–7.61(m,4h),7.57(d,j=8.8hz,2h),7.14(t,j=8.9hz,2h),6.18(s,1h),5.90–5.75(m,1h),2.36(s,3h),2.30–2.19(m,2h),1.94(q,j=7.9hz,2h),1.81–1.70(m,2h),1.63–1.54(m,2h),1.49–1.41(m,4h)；13cnmr(101mhz,dmso)δ168.35,167.91,162.46,159.45,158.71,157.07,156.74,155.52,145.30,135.44,135.16,135.12,133.61,122.41,122.33,120.78,119.89,117.44,115.13,114.91,106.85,31.19,27.51,25.09,16.67,15.49.esi-hrmsm/zcalcdforc30h30fn6o3+541.2358,found541.2354[m+h]+。
实施例28n-(3-氯苯基)-n-(4-((8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)苯基)环丙烷-1,1-二甲酰胺的合成
类似实施例24，黄色固体，产率：31.7%。1hnmr(400mhz,dmso-d6)δ10.26(s,1h),9.94(d,j=9.3hz,2h),8.79(s,1h),7.86(d,j=2.1hz,1h),7.65(d,j=8.7hz,2h),7.57(d,j=8.8hz,2h),7.52(dd,j=8.1,1.9hz,1h),7.32(t,j=8.1hz,1h),7.11(dd,j=7.9,2.1hz,1h),6.17(s,1h),5.90–5.75(m,1h),2.36(s,3h),2.30–2.18(m,2h),1.97–1.87(m,2h),1.80–1.70(m,2h),1.65–1.54(m,2h),1.51–1.41(m,4h)；13cnmr(101mhz,dmso)δ168.50,167.73,162.47,158.70,156.74,155.52,145.31,140.40,132.82,130.15,123.15,120.85,119.85,118.59,117.45,106.85,52.64,31.65,27.52,25.11,16.69,15.47.esi-hrmsm/zcalcdforc30h30cln6o3+557.2062,found557.2055[m+h]+。
实施例29n-(4-氯苯基)-n-(4-((8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)苯基)环丙烷-1,1-二甲酰胺的合成
类似实施例24，黄色固体，产率：34.8%。1hnmr(400mhz,dmso-d6)δ10.20(s,1h),9.94(s,2h),8.79(s,1h),7.70–7.61(m,4h),7.57(d,j=8.8hz,2h),7.43–7.28(m,2h),6.17(s,1h),5.84(t,j=8.9hz,1h),2.36(s,3h),2.30–2.19(m,2h),1.99–1.87(m,2h),1.82–1.68(m,2h),1.64–1.53(m,2h),1.51–1.42(m,4h)；13cnmr(101mhz,dmso)δ168.39,167.87,162.46,158.70,156.72,155.52,145.29,137.84,135.46,133.61,128.36,127.14,121.91,120.83,119.86,117.44,106.84,52.64,31.45,27.51,25.09,16.67,15.49.esi-hrmsm/zcalcdforc30h30cln6o3+557.2062,found557.2055[m+h]+。
实施例30甲基3-(1-((4-((8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)苯基)氨基甲酰基)1-甲酰胺基)苯甲酸酯
类似实施例24，白色固体，产率：22.7%。1hnmr(400mhz,dmso-d6)δ10.29(s,1h),9.98(s,1h),9.95(s,1h),8.79(s,1h),8.32(d,j=2.4hz,1h),7.88(dd,j=8.1,2.1hz,1h),7.69–7.55(m,5h),7.45(t,j=7.9hz,1h),6.17(s,1h),5.91–5.74(m,1h),3.85(s,3h),2.36(s,3h),2.30–2.19(m,2h),1.93(s,2h),1.80–1.70(m,2h),1.63–1.53(m,2h),1.51–1.42(m,4h)；13cnmr(101mhz,dmso)δ168.58,167.74,166.11,162.47,158.71,156.75,155.52,145.32,139.32,135.42,133.71,129.87,128.96,124.82,124.12,120.96,120.77,119.87,117.44,106.85,52.65,52.19,31.61,27.52,25.12,16.69,15.47.esi-hrmsm/zcalcdforc32h33n6o5+581.2507,found581.2503[m+h]+。
实施例31甲基4-(1-((4-((8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)苯基)氨基甲酰基)1-甲酰胺基)苯甲酸酯
类似实施例24，白色固体，产率：20.7%。1hnmr(400mhz,dmso-d6)δ10.49(s,1h),9.95(s,1h),9.88(s,1h),8.79(s,1h),7.96–7.73(m,4h),7.71–7.53(m,4h),6.17(s,1h),5.83(p,j=8.9hz,1h),3.82(s,3h),2.35(s,3h),2.30–2.18(m,2h),2.00–1.86(m,2h),1.80–1.69(m,2h),1.63–1.53(m,2h),1.52–1.42(m,4h)；13cnmr(101mhz,dmso)δ168.58,167.87,165.83,162.47,158.70,156.73,155.52,145.30,143.43,135.50,133.60,130.01,124.08,120.94,119.84,119.47,117.45,106.85,52.65,51.90,31.80,27.52,25.12,16.69,15.58.esi-hrmsm/zcalcdforc32h33n6o5+581.2507,found581.2503[m+h]+。
实施例32n-(4-((8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)苯基)-n-(间甲苯基)环丙烷-1,1-二甲酰胺的合成
类似实施例24，黄色固体，产率：15.2%。1hnmr(400mhz,dmso-d6)δ10.05(s,1h),9.96(s,2h),8.79(s,1h),7.71–7.53(m,4h),7.49–7.36(m,2h),7.18(t,j=7.8hz,1h),6.88(d,j=7.5hz,1h),6.17(s,1h),5.93–5.73(m,1h),2.36(s,3h),2.30–2.15(m,5h),2.00–1.86(m,2h),1.81–1.68(m,2h),1.65–1.52(m,2h),1.51–1.39(m,4h)；13cnmr(101mhz,dmso)δ168.26,162.47,158.72,156.77,155.53,145.33,138.70,137.70,135.50,133.55,128.36,124.29,120.94,119.87,117.58,117.46,106.86,52.65,31.12,27.54,25.14,21.18,21.15,16.71,15.65.esi-hrmsm/zcalcdforc31h33n6o3+537.2609,found537.2603[m+h]+。
实施例33n-(4-((8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)苯基)-n-(对甲苯基)环丙烷-1,1-二甲酰胺的合成
类似实施例24，浅黄色固体，产率：31.2%。1hnmr(400mhz,dmso-d6)δ10.01(d,j=6.0hz,2h),9.96(s,1h),8.80(s,1h),7.66(d,j=8.7hz,2h),7.58(d,j=8.8hz,2h),7.50(d,j=8.1hz,2h),7.11(d,j=8.1hz,2h),6.18(s,1h),5.92–5.79(m,1h),2.37(s,3h),2.26(s,5h),1.99–1.88(m,2h),1.82–1.70(m,2h),1.66–1.54(m,2h),1.53–1.42(m,4h)；13cnmr(101mhz,dmso)δ168.23,162.46,158.73,156.74,155.54,145.30,136.20,135.49,133.54,132.58,128.88,120.85,120.53,119.90,117.45,106.84,52.66,31.00,27.52,25.11,20.47,16.69,15.60.esi-hrmsm/zcalcdforc31h33n6o3+537.2609,found537.2603[m+h]+。
实施例34n-(4-((8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)苯基)-n-(3-(三氟甲基)苯基)环丙烷-1,1-二甲酰胺的合成
类似实施例24，白色固体，产率：28.8%。1hnmr(400mhz,dmso-d6)δ10.48(s,1h),9.95(s,1h),9.90(s,1h),8.79(s,1h),7.86(d,j=8.4hz,2h),7.71–7.54(m,6h),6.17(d,j=1.3hz,1h),5.84(t,j=8.9hz,1h),2.36(s,3h),2.31–2.19(m,2h),1.98–1.86(m,2h),1.81–1.70(m,2h),1.64–1.53(m,2h),1.52–1.44(m,4h)；13cnmr(101mhz,dmso)δ168.61,167.71,162.42,158.65,156.69,155.48,145.26,142.55,135.43,133.59,125.75,125.71,125.67,123.53,123.21,123.00,120.83,119.98,119.80,117.40,106.80,52.60,31.76,27.46,25.06,16.64,15.47.esi-hrmsm/zcalcdforc31h30f3n6o3+591.2326,found591.2322[m+h]+。
实施例35n-(4-((8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)苯基)-n-(4-(三氟甲基)苯基)环丙烷-1,1-二甲酰胺的合成
类似实施例24，黄色固体，产率：34.8%。1hnmr(400mhz,dmso-d6)δ10.48(s,1h),9.95(s,1h),9.90(s,1h),8.79(d,j=1.6hz,1h),7.86(d,j=8.3hz,2h),7.71–7.53(m,6h),6.17(s,1h),5.91–5.76(m,1h),2.36(s,3h),2.30–2.19(m,2h),1.97–1.87(m,2h),1.80–1.69(m,2h),1.63–1.54(m,2h),1.52–1.43(m,4h)；13cnmr(101mhz,dmso)δ168.65,167.76,162.47,158.70,156.74,155.53,145.31,142.61,135.48,133.64,125.80,125.75,125.72,123.57,123.26,123.06,120.89,120.03,119.84,117.45,113.73,106.85,52.64,31.81,27.51,25.11,16.69,15.52.esi-hrmsm/zcalcdforc31h30f3n6o3+591.2326,found591.2322[m+h]+。
实施例36n-(3-氰基苯基)-n-(4-((8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)苯基)环丙烷-1,1-二甲酰胺的合成
类似实施例24，白色固体，产率13.0%。1hnmr(400mhz,dmso-d6)δ10.42(s,1h),9.94(s,2h),8.79(s,1h),8.15(s,1h),7.94–7.82(m,1h),7.69–7.50(m,6h),6.17(s,1h),5.90–5.76(m,1h),2.36(s,3h),2.29–2.20(m,2h),1.97–1.86(m,2h),1.80–1.69(m,2h),1.64–1.53(m,2h),1.52–1.42(m,4h)；13cnmr(101mhz,dmso)δ168.73,167.57,162.48,158.71,156.77,155.53,145.33,139.80,135.48,133.67,130.01,126.98,124.81,123.09,120.84,119.87,118.75,117.46,111.31,106.86,52.66,31.75,27.53,25.13,16.71,15.49.esi-hrmsm/zcalcdforc31h30n7o3+548.2405,found548.2402[m+h]+。
实施例37n-(4-氰基苯基)-n-(4-((8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)苯基)环丙烷-1,1-二甲酰胺的合成
类似实施例24，白色固体，产率：14.7%。1hnmr(400mhz,dmso-d6)δ10.56(s,1h),9.95(s,1h),9.88(s,1h),8.79(s,1h),7.90–7.72(m,4h),7.69–7.53(m,4h),6.24–6.11(m,1h),5.93–5.73(m,1h),2.36(s,3h),2.23(q,j=9.0hz,2h),2.00–1.85(m,2h),1.81–1.68(m,2h),1.63–1.52(m,2h),1.47(dt,j=10.3,3.1hz,4h)；13cnmr(101mhz,dmso)δ168.70,167.62,162.46,158.70,156.74,155.52,145.31,143.31,135.49,133.63,133.00,120.91,120.08,119.84,119.10,117.45,106.85,105.08,52.65,32.03,27.51,25.11,16.70,15.49.esi-hrmsm/zcalcdforc31h30n7o3+548.2405,found548.2402[m+h]+。
实施例38n-(4-氯-3-(三氟甲基)苯基)-n-(4-((8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]吡啶-2-基)氨基)苯基)环丙烷-1,1-二甲酰胺的合成
类似实施例24，褐色固体，产率：15.2%。1hnmr(400mhz,dmso-d6)δ10.48(s,1h),9.95(s,2h),8.79(s,1h),8.26(d,j=2.5hz,1h),7.91(dd,j=8.8,2.5hz,1h),7.70–7.54(m,5h),6.19–6.14(m,1h),5.89–5.77(m,1h),2.36(s,3h),2.30–2.19(m,2h),1.98–1.86(m,2h),1.80–1.69(m,2h),1.63–1.52(m,2h),1.50–1.41(m,4h)；13cnmr(101mhz,dmso)δ168.73,167.35,162.46,158.71,156.73,155.53,145.30,138.53,135.44,133.72,131.81,126.61,126.31,124.92,124.14,124.04,121.43,120.76,119.87,119.00,118.95,117.44,106.84,52.65,31.93,27.50,25.08,16.67,15.35.esi-hrmsm/zcalcdforc31h29clf3n6o3+625.1936,found625.1931[m+h]+。
实施例39n-(4-((8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)苯基)-n-(3-羟基苯基)环丙烷-1,1-二甲酰胺的合成
类似实施例24，白色固体，产率：10.2%。1hnmr(400mhz,dmso-d6)δ10.01(s,1h),9.94(s,1h),9.91(s,1h),9.37(s,1h),8.79(s,1h),7.68–7.54(m,4h),7.20(d,j=2.5hz,1h),7.07(t,j=8.0hz,1h),6.98(d,j=7.5hz,1h),6.47(dd,j=8.0,2.3hz,1h),6.17(s,1h),5.84(p,j=8.9hz,1h),2.36(s,3h),2.29–2.20(m,2h),1.96–1.88(m,2h),1.79–1.70(m,2h),1.63–1.54(m,2h),1.49–1.43(m,4h)；13cnmr(101mhz,dmso)δ168.30,168.12,162.47,158.71,157.47,156.73,155.53,145.30,139.78,135.51,133.53,129.12,120.94,119.88,117.45,111.07,110.70,107.54,106.86,52.66,31.19,27.52,25.10,16.68,15.58.esi-hrmsm/zcalcdforc30h31n6o4+539.2401,found539.2398[m+h]+。
实施例40n-(3-氨基甲酰基苯基-n-(4-((8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)苯基)环丙烷-1,1-二甲酰胺的合成
步骤40-1：2-((4-氨基苯基)氨基)-8-环戊基-5-甲基吡啶并[2,3-d]嘧啶-7(8h)-酮的合成
将2-氯-8-环戊基-5-甲基吡啶并[2,3-d]嘧啶-7(8h)-酮(2.0g,7.6mmol)悬浮于50ml的1,4-二氧六环中，加入对苯二胺(1.6g,15.2mmol)、pd(oac)2(42.6mg,0.2mmol)、binap(236.0mg,0.4mmol)和cs2co3(1.6g,11.4mmol)，抽真空充氩气3次，升温至100℃搅拌过夜。冷却至室温，减压浓缩反应液得粗品。粗品硅胶柱层析得目标产物1g。灰黄色固体，产率：39.3%；
步骤40-2：n-(3-氨基甲酰基苯基-n-(4-((8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)苯基)环丙烷-1,1-二甲酰胺
将2-((4-氨基苯基)氨基)-8-环戊基-5-甲基吡啶并[2,3-d]嘧啶-7(8h)-酮(100mg,0.30mmol),1–((3-氰基苯基)氨基甲酰基)环丙烷-1-羧酸(0.33mmol)、edci(85.73mg,0.45mmol)、hobt(60.43mg,0.45mmol)、diea(0.1ml,0.60mmol)悬浮于10ml的dmf中，室温搅拌过夜。加入水稀释，乙酸乙酯萃取3*30ml，合并有机相。有机相分别用饱和碳酸氢钠和食盐水洗涤，无水硫酸镁干燥、浓缩得粗品。粗品硅胶柱层析得目标产物。浅黄色固体，产率：52.2%。1hnmr(400mhz,dmso-d6)δ10.23(s,1h),9.99(s,1h),9.95(s,1h),8.80(s,1h),8.13–8.04(m,1h),7.94(s,1h),7.80(dd,j=8.0,2.1hz,1h),7.71–7.53(m,5h),7.41–7.33(m,2h),6.17(s,1h),5.90–5.76(m,1h),2.36(s,3h),2.30–2.16(m,2h),1.99–1.87(m,2h),1.81–1.69(m,2h),1.63–1.54(m,2h),1.53–1.43(m,4h)；13cnmr(101mhz,dmso)δ168.56,168.07,167.78,162.48,158.71,156.76,155.53,145.33,138.80,135.49,134.82,133.59,128.34,123.20,122.40,120.86,120.11,119.87,117.46,113.75,106.86,52.65,31.20,27.54,25.13,16.70,15.69.esi-hrmsm/zcalcdforc31h32n7o4+566.2510,found566.2508[m+h]+。
实施例41n-(4-氨基甲酰基苯基-n-(4-((8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)苯基)环丙烷-1,1-二甲酰胺的合成
类似实施例40，白色固体，产率：68.8%。1hnmr(400mhz,dmso-d6)δ10.41(s,1h),9.99(s,1h),9.96(s,1h),8.79(s,1h),7.93(s,1h),7.78(dd,j=50.9,8.5hz,4h),7.68–7.54(m,4h),7.26(s,1h),6.17(s,1h),5.90–5.75(m,1h),2.36(s,3h),2.30–2.18(m,2h),1.98–1.86(m,2h),1.80–1.70(m,2h),1.63–1.54(m,2h),1.53–1.44(m,4h)；13cnmr(101mhz,dmso)δ168.55,168.07,167.39,162.48,158.71,156.76,155.52,145.32,141.59,135.46,133.64,128.95,128.15,120.91,119.88,119.29,117.42,106.84,52.65,31.66,27.51,25.10,16.69,15.57.esi-hrmsm/zcalcdforc31h32n7o4+566.2510,found566.2508[m+h]+。
实施例42n-(3-溴苯基)-n-(4-((8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)苯基)环丙烷-1,1-二甲酰胺
类似实施例40，白色固体，产率：62.5%。1hnmr(400mhz,dmso-d6)δ10.24(s,1h),9.95(s,1h),9.93(s,1h),8.79(s,1h),8.00(d,j=2.2hz,1h),7.72–7.52(m,5h),7.31–7.20(m,2h),6.17(s,1h),5.91–5.76(m,1h),2.36(s,3h),2.30–2.18(m,2h),1.98–1.86(m,2h),1.80–1.70(m,2h),1.64–1.53(m,2h),1.51–1.41(m,4h)；13cnmr(101mhz,dmso)δ168.48,167.70,162.46,158.71,156.75,155.52,145.31,140.54,135.45,133.66,130.45,126.05,122.69,121.28,120.83,119.86,118.98,117.44,106.85,52.64,31.65,27.52,25.11,16.69,15.46.esi-hrmsm/zcalcdforc30h30brn6o3+601.1557,found601.1551[m+h]+。
实施例43n-(4-溴苯基)-n-(4-((8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)苯基)环丙烷-1,1-二甲酰胺
类似实施例40，白色固体，产率：64.7%。1hnmr(400mhz,dmso-d6)δ10.20(s,1h),9.94(s,2h),8.80(s,1h),7.71–7.43(m,8h),6.18(s,1h),5.84(t,j=8.9hz,1h),2.36(s,3h),2.30–2.19(m,2h),1.98–1.86(m,2h),1.81–1.69(m,2h),1.63–1.53(m,2h),1.50–1.42(m,4h)；13cnmr(101mhz,dmso)δ168.37,167.85,162.47,158.71,156.77,155.53,145.34,138.31,135.46,133.65,131.30,122.27,120.83,119.86,117.45,115.18,106.86,52.68,31.57,27.53,25.13,16.71,15.49.esi-hrmsm/zcalcdforc30h30brn6o3+601.1557,found601.1551[m+h]+。
实施例44n-(4-((8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)苯基)-n-(3-甲氧基苯基)-1,1-二甲酰胺的合成
类似实施例40，黄色固体，产率：52.2%。1hnmr(400mhz,dmso-d6)δ10.11(s,1h),9.95(s,1h),9.92(s,1h),8.80(s,1h),7.71–7.52(m,4h),7.33(s,1h),7.24–7.14(m,2h),6.70–6.59(m,1h),6.21–6.15(m,1h),5.84(t,j=8.9hz,1h),3.72(s,3h),2.36(s,3h),2.30–2.19(m,2h),1.98–1.84(m,2h),1.81–1.68(m,2h),1.65–1.54(m,2h),1.50–1.40(m,4h)；13cnmr(101mhz,dmso)δ168.24,168.13,162.47,159.37,158.70,156.75,155.52,145.32,140.03,135.48,133.57,129.26,120.91,119.86,117.45,112.52,109.13,106.85,105.99,55.00,52.64,31.38,27.52,25.11,16.69,15.51.esi-hrmsm/zcalcdforc31h33n6o4+553.2558,found553.2257[m+h]+。
实施例45n-(4-((8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)苯基)-n-(3-甲氧基苯基)-1,1-二甲酰胺的合成
类似实施例40，黄色固体，产率：84.4%。1hnmr(400mhz,dmso-d6)δ10.08(s,1h),9.95(s,1h),9.88(s,1h),8.80(s,1h),7.70–7.53(m,4h),7.50(d,j=8.9hz,2h),6.92–6.84(m,2h),6.18(s,1h),5.90–5.77(m,1h),3.72(s,3h),2.36(s,3h),2.31–2.18(m,2h),1.98–1.86(m,2h),1.81–1.69(m,2h),1.64–1.52(m,2h),1.51–1.40(m,4h)；13cnmr(101mhz,dmso)δ168.23,168.11,162.46,158.71,156.74,155.58,155.53,145.30,135.43,133.58,131.70,122.27,120.73,119.91,117.44,113.60,106.85,55.16,52.65,30.81,27.51,25.10,16.67,15.59.esi-hrmsm/zcalcdforc31h33n6o4+553.2558,found553.2257[m+h]+。
实施例46：本发明提供的部分实施例化合物的抗肿瘤活性
抗肿瘤活性实验方法
细胞培养浓度为3×103cells/0.1ml/孔，96孔板。培养24小时后加入药物培养24小时后加入药物，药物浓度。同时设置对照组（不加药仅接种细胞）及空白孔（未接种细胞仅加培养基），5%co2，37℃培养箱孵育72小时。使用cck-8(promega,wi)比色法测定细胞数，使用仪器为microplatereader(promega,wi)。
表1为部分化合物在1μm对一些肿瘤细胞的抑制情况。
表2为实施例化合物41对一些肿瘤细胞的抑制情况。
表1
表2
从表2可以看出本发明中实施例化合物41对子宫颈癌hela具有优异的抗肿瘤活性，选择性和特异性。