CN108929324A - 新型1,1-环丙基二酰胺衍生物的制备与应用 - Google Patents
新型1,1-环丙基二酰胺衍生物的制备与应用 Download PDFInfo
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Abstract
本发明新型1,1‑环丙基二酰胺衍生物的制备与应用，涉及新的具有式(I)的1,1‑环丙基二酰胺衍生物及其盐、包括可药用盐，其中R1、R2、R3、R4、R5和X、Z、L在本文被定义。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，其在治疗癌症和HIV等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。
Description
技术领域
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。
发明内容
(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、，其中R6 选自H、卤素、C1-C6烷烃, C3-C7 环烷烃, C1-C8烷氧基,
C1-C8 alkoxyalkyl, C1-C8卤代烷烃, -CN, COR7, -B(OR7)2、、、、、、、、、、烯基、炔
基、杂环基、芳基、杂芳环，其中R7和R8分别是氢基、烃基、环烷基、杂原子环烷基、芳基或杂芳
环。
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1 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-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 (13.01 g, 100 mmol)溶于150 mL乙酸异丙酯中降温至0℃后滴加二氯亚砜（12.5 g, 105 mmol）。滴加完毕升至室温搅拌6小时。滴加苯胺 (110 mmol)与三乙胺(15.29 mL, 110 mmol)的乙酸异丙酯（40 mL）溶液约1小时，继续搅拌2小时。反应液入乙酸乙酯（500mL）稀释, 1 N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%。1H NMR (400MHz, DMSO-d6) δ 13.10 (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 (60 mmol),EDCI (45 mmol), HOBt (36 mmol), DIEA (60 mmol) 和DMF (30 mL)，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%。1H NMR (400 MHz, DMSO-d6) δ 10.27 (s, 1H),9.68 (s, 1H), 7.60 (d, J = 7.9 Hz, 2H), 7.30 (t, J = 7.8 Hz, 2H), 7.19 (d, J= 8.4 Hz, 2H), 7.05 (t, J = 7.4 Hz, 1H), 6.50 (d, J = 8.4 Hz, 2H), 4.91 (s,2H), 1.45 (d, J = 3.6 Hz, 4H); 13C NMR (101 MHz, DMSO) δ 168.94, 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 (586 mg, 2 mmol)溶于20 mL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 (11 mg, 0.05 mmol)、 BINAP (62 mg, 0.1 mmol) 和Cs2CO3 (978 mg,3 mmol)，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%。1H NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H), 9.89 (s, 1H), 9.52 (s, 1H), 8.73 (s, 1H), 7.78 (d, J =8.7 Hz, 2H), 7.62 (d, J = 8.0 Hz, 2H), 7.53 (d, J = 8.6 Hz, 2H), 7.30 (t, J =7.9 Hz, 2H), 7.06 (t, J = 7.4 Hz, 1H), 6.57 (s, 1H), 4.72 (p, J = 8.9 Hz,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); 13C NMR (101 MHz, DMSO) δ 168.31, 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-HRMS m/z calcd for C31H34N7O3 + 552.2718, found 552.2718 [M +H]+。
实施例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)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%,1H NMR (400 MHz, DMSO-d6) δ 13.51 (s,1H), 11.27 (s, 1H), 8.15 (td, J = 8.0, 2.0 Hz, 1H), 7.27 (ddd, J = 11.4, 7.9,1.8 Hz, 1H), 7.13 (tdd, J = 13.3, 7.7, 3.7 Hz, 2H), 1.56 (h, J = 4.0 Hz, 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%。1H NMR (400 MHz, DMSO-d6) δ 11.16 (s,1H), 9.40 (s, 1H), 8.04 (td, J = 7.8, 2.4 Hz, 1H), 7.33 – 7.22 (m, 1H), 7.20– 7.09 (m, 4H), 6.53 (d, J = 8.4 Hz, 2H), 4.99 (s, 2H), 1.66 – 1.53 (m, 4H);13C NMR (101 MHz, DMSO) δ 170.14, 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%。1H NMR (400 MHz, DMSO-d6) δ 10.84 (s,1H), 9.75 (s, 1H), 9.55 (s, 1H), 8.74 (s, 1H), 7.96 (td, J = 7.8, 3.7 Hz,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 = 8.9 Hz, 1H), 3.05 (d, J = 10.6 Hz, 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); 13C NMR (101 MHz, DMSO) δ 169.44, 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-HRMS m/z calcd for C31H33FN7O3 + 570.2623, found570.2628 [M + H]+. HPLC purity 99%。
实施例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-(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%。1H NMR (400 MHz, DMF-d7) δ 10.34 (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, 2.3 Hz, 1H), 7.53 (d, J = 8.7 Hz, 2H), 7.41 – 7.28 (m, 2H), 6.89 (td, J= 8.5, 2.6 Hz, 1H), 6.57 (s, 1H), 4.72 (p, J = 8.9 Hz, 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); 13C NMR (101 MHz, DMSO) δ 168.93, 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-HRMS m/z calcdfor C31H33FN7O3 + 570.2623, found 570.2627 [M + H]+. HPLC purity 99%。
实施例4 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-(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%。1H NMR (400 MHz, DMSO-d6) δ 10.14 (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 = 8.9 Hz, 2H), 7.15 (t, J = 8.9 Hz, 2H), 6.57 (s,1H), 4.72 (p, J = 8.9 Hz, 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); 13C NMR (101 MHz, 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-HRMS m/z calcd for C31H33FN7O3 + 570.2623, found 570.2622 [M + H]+. HPLC purity 99%。
实施例5 N-(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%。1H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H),9.84 (s, 1H), 9.51 (s, 1H), 8.73 (s, 1H), 7.87 (t, J = 2.1 Hz, 1H), 7.83 –7.74 (m, 2H), 7.52 (dd, J = 8.7, 3.6 Hz, 3H), 7.32 (t, J = 8.1 Hz, 1H), 7.12(dd, J = 8.0, 2.0 Hz, 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); 13C NMR (101 MHz, DMSO) δ 168.98, 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-HRMS m/z calcd for C31H33ClN7O3 + 586.2328, found 586.2326 [M+ H]+. HPLC purity 98%。
实施例6 N-(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%。1H NMR (400 MHz, DMSO-d6) δ 10.25 (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 = 8.7 Hz, 2H), 7.40 – 7.31 (m, 2H), 6.57 (s, 1H), 4.85 –4.63 (m, 1H), 3.05 (d, J = 10.3 Hz, 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); 13C NMR (101 MHz, 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-HRMS m/z calcd for C31H33ClN7O3 + 586.2328,found 586.2331 [M + H]+. HPLC purity 99%。
实施例7 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-(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%。1H NMR (400 MHz, DMSO-d6) δ 10.10 (s, 1H),9.87 (s, 1H), 9.51 (s, 1H), 8.73 (s, 1H), 7.85 – 7.70 (m, 2H), 7.52 (d, J =8.9 Hz, 2H), 7.49 – 7.36 (m, 2H), 7.18 (t, J = 7.8 Hz, 1H), 6.88 (d, J = 7.5Hz, 1H), 6.58 (s, 1H), 4.72 (p, J = 9.0 Hz, 1H), 3.05 (d, J = 10.4 Hz, 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); 13C NMR (101 MHz, DMSO) δ 168.28, 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-HRMS m/z calcd for C32H36N7O3 + 566.2874, found566.2879 [M + H]+. HPLC purity 99%。
实施例8 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-(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%。1H NMR (400 MHz, DMSO-d6) δ 10.04 (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, 8.6 Hz, 4H), 7.11 (d, J = 8.2 Hz, 2H), 6.58 (s, 1H), 4.72 (p, J = 8.9Hz, 1H), 3.05 (d, J = 10.4 Hz, 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); 13C NMR (101 MHz,DMSO) δ 168.70, 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-HRMS m/z calcd forC32H36N7O3 + 566.2874, found 566.2879 [M + H]+. HPLC purity 99%。
实施例9 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-(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%。1H NMR (400 MHz, DMSO-d6) δ 10.44 (s, 1H),9.87 (s, 1H), 9.52 (s, 1H), 8.73 (s, 1H), 8.17 (s, 1H), 7.86 (d, J = 8.2 Hz,1H), 7.78 (d, J = 8.4 Hz, 2H), 7.62 – 7.49 (m, 3H), 7.40 (d, J = 7.7 Hz, 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); 13C NMR (101 MHz,DMSO) δ 168.68, 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-HRMS m/z calcd for C32H33F3N7O3 + 620.2591, found 620.2593 [M + H]+.HPLC purity 99%。
实施例10 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-(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%。1H NMR (400 MHz, DMSO-d6) δ 10.53 (s, 1H),9.83 (s, 1H), 9.51 (s, 1H), 8.73 (s, 1H), 7.87 (d, J = 8.4 Hz, 2H), 7.80 –7.75 (m, 2H), 7.67 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.7 Hz, 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); 13C NMR (101 MHz, 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-HRMS m/z calcd for C32H33F3N7O3 +620.2591, found 620.2588 [M + H]+. HPLC purity 99%。
实施例11 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-(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%。1H NMR (400 MHz, DMSO-d6) δ 10.14 (s, 1H),9.83 (s, 1H), 9.51 (s, 1H), 8.73 (s, 1H), 7.77 (dd, J = 9.7, 2.7 Hz, 3H),7.52 (d, J = 9.0 Hz, 2H), 7.40 – 7.30 (m, 1H), 7.25 – 7.14 (m, 2H), 6.64 (dq,J = 6.2, 2.7 Hz, 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); 13C NMR (101 MHz, DMSO) δ 168.72, 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-HRMS m/z calcd for C32H36N7O4 + 582.2823, found582.2827 [M + H]+. HPLC purity 99%。
实施例12 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-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%。1H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1H),9.93 (s, 1H), 9.51 (s, 1H), 8.73 (s, 1H), 7.78 (d, J = 8.9 Hz, 2H), 7.63 –7.46 (m, 4H), 6.95 – 6.82 (m, 2H), 6.57 (s, 1H), 4.73 (q, J = 8.8 Hz, 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); 13C NMR (101 MHz, DMSO) δ 168.69, 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-HRMS m/z calcd for C32H36N7O4 + 582.2823, found582.2824 [M + H]+. HPLC purity 99%。
实施例13 N-(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%。1H NMR (400 MHz, DMSO-d6) δ 10.46 (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 = 8.9 Hz, 2H), 7.53 (t, J = 6.1 Hz, 4H), 6.57 (s, 1H), 4.72 (p, J= 9.0 Hz, 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); 13C NMR (101 MHz, DMSO) δ 169.21, 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-HRMS m/z calcd for C32H33N8O3 +577.2670, found 577.2666 [M + H]+. HPLC purity 99%。
实施例14 N-(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%。1H NMR (400 MHz, DMSO-d6) δ 10.60 (s, 1H),9.80 (s, 1H), 9.51 (s, 1H), 8.73 (s, 1H), 7.85 (d, J = 8.8 Hz, 2H), 7.77 (d,J = 8.9 Hz, 4H), 7.52 (d, J = 8.9 Hz, 2H), 6.57 (s, 1H), 4.72 (p, J = 8.9 Hz,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, 3.2 Hz, 4H); 13C NMR (101 MHz, DMSO) δ 169.20,168.01, 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-HRMS m/z calcd for C32H33N8O3 + 577.2670, found577.2668 [M + H]+. HPLC purity 99%。
实施例15 3-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%。1H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H),9.89 (s, 1H), 9.51 (s, 1H), 8.73 (s, 1H), 8.34 (t, J = 1.9 Hz, 1H), 7.89 (dd,J = 8.1, 2.2 Hz, 1H), 7.77 (d, J = 8.6 Hz, 2H), 7.66 (dt, J = 7.8, 1.4 Hz,1H), 7.54 (d, J = 8.6 Hz, 2H), 7.45 (t, J = 7.9 Hz, 1H), 6.57 (s, 1H), 4.72(p, J = 8.9 Hz, 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); 13C NMR (101 MHz,DMSO) δ 169.06, 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-HRMS m/z calcd for C33H36N7O5 + 610.2772, found 610.2774 [M + H]+. HPLC purity99%。
实施例16 4-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%。1H NMR (400 MHz, DMSO-d6) δ 10.55 (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 = 8.7 Hz, 2H), 6.56 (s, 1H), 4.72 (p, J = 8.9 Hz,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); 13C NMR (101 MHz, DMSO) δ 168.60,167.83, 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-HRMS m/z calcd for C33H36N7O5 + 610.2772,found 610.2771 [M + H]+. HPLC purity 99%。
实施例17 N-(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%。1H NMR (400 MHz, DMSO-d6) δ 10.51 (s,1H), 9.86 (s, 1H), 9.51 (s, 1H), 8.73 (s, 1H), 8.27 (d, J = 2.6 Hz, 1H), 7.91(dd, J = 8.8, 2.5 Hz, 1H), 7.77 (d, J = 8.9 Hz, 2H), 7.66 (d, J = 8.8 Hz,1H), 7.53 (d, J = 8.8 Hz, 2H), 6.57 (s, 1H), 4.72 (p, J = 8.9 Hz, 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); 13C NMR (101 MHz, DMSO) δ 169.21, 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-HRMS m/z calcd for C32H32ClF3N7O3 + 654.2202, found 654.2203 [M+ H]+. HPLC purity 99%。
实施例18 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
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%。1H NMR (400 MHz, DMSO-d6) δ 13.12 (s, 1H), 10.69 (s,1H), 7.97 (t, J = 2.0 Hz, 1H), 7.50 (dt, J = 7.5, 1.9 Hz, 1H), 7.39 – 7.15(m, 2H), 1.42 (s, 4H); 13C NMR (101 MHz, DMSO) δ 174.03, 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(2.92 g, 10 mmol)悬浮于80mL的1,4-二氧六环中，加入对苯二胺(2.18 g, 20 mmol)、Pd(OAc)2 (56 mg,0.25 mmol)、 BINAP (311 mg, 0.5 mmol) 和Cs2CO3 (4.89 g, 15 mmol)，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%。1H NMR (400 MHz, DMSO-d6) δ 9.01 (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 (511 mg, 1.5 mmol)、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 (547 mg, 1.5mmol)、EDCI (431 mg, 2.25 mmol)、HOBt (243 mg, 1.8 mmol)、DIEA (388 mg, 3 mmol)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%。1H NMR (400 MHz, DMSO-d6) δ 10.27 (s, 1H), 9.84 (s,1H), 9.50 (s, 1H), 8.73 (s, 1H), 8.00 (d, J = 2.2 Hz, 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 =8.9 Hz, 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), 13C NMR (101 MHz, DMSO) δ 168.50, 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-HRMS m/z calcd for C31H33BrN7O3 + 630.1823,found 630.1817 [M + H]+. HPLC purity 99%。
实施例19 N-(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%。1H NMR (400 MHz, DMSO-d6) δ 10.24 (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 = 9.0 Hz, 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); 13C NMR (101 MHz, DMSO) δ 168.35, 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-HRMS m/z calcd for C31H33BrN7O3 + 630.1823, found 630.1818 [M + H]+. HPLCpurity 97%。
实施例20 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
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%。1H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 9.70 (s, 1H),9.26 (s, 1H), 7.43 – 7.34 (m, 2H), 7.20 (d, J = 8.4 Hz, 2H), 6.79 – 6.68 (m,2H), 6.59 – 6.48 (m, 2H), 4.91 (s, 2H), 1.45 (s, 4H); 13C NMR (101 MHz, DMSO)δ 168.76, 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(586 mg, 2 mmol)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(2 mmol)、Pd(OAc)2 (11 mg, 0.05 mmol)、 BINAP (62 mg, 0.1 mmol) 和Cs2CO3(1.63g, 3 mmol)，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%。1H NMR (400 MHz, 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, 2.9 Hz, 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 = 8.8 Hz, 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); 13C NMR(101 MHz, DMSO) δ 168.66, 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-HRMS m/z calcd forC31H34N7O4 + 568.2667, found 568.2668 [M + H]+. HPLC purity 99%。
实施例21 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-(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%。1H NMR (400 MHz, DMSO-d6) δ 10.06 (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 = 8.7 Hz, 2H), 7.20 (t, J = 2.1 Hz, 1H), 7.07 (t, J = 8.0 Hz, 1H),7.03 – 6.96 (m, 1H), 6.57 (s, 1H), 6.47 (dd, J = 7.9, 2.4 Hz, 1H), 4.85 –4.65 (m, 1H), 3.05 (d, J = 10.1 Hz, 6H), 2.50 (s, 2H), 2.04 – 1.86 (m, 4H),1.76 – 1.58 (m, 2H), 1.51 – 1.42 (m, 4H); 13C NMR (101 MHz, DMSO) δ 168.69,168.58, 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-HRMS m/z calcd for C31H34N7O4 +568.2667, found 568.2663 [M + H]+. HPLC purity 99%。
实施例22 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
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 (4.91 g, 22 mmol)悬浮于40mL四氢呋喃中，滴加二氯亚砜(2.86 g, 24 mmol)后室温搅拌3小时。50 mL加入3-氟-4-硝基苯胺(3.12 g, 20 mmol)的二氯甲烷溶液和DIPEA (3.88 g, 30 mmol)后搅拌过夜。减压蒸去溶剂后加入200 mL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 (80/80/32 mL)混合溶剂中，加入铁粉(5.6 g, 100 mmol)、氯化铵(16 g, 300 mmol)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*100 mL，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2.74 g棕色固体，产率41%。1H NMR (400 MHz, DMSO-d6) δ 10.14 (s, 1H), 9.78 (s, 1H), 7.70 –7.56 (m, 2H), 7.41 (dd, J = 13.5, 2.3 Hz, 1H), 7.21 – 7.10 (m, 2H), 7.04 (dd,J = 8.5, 2.3 Hz, 1H), 6.70 (dd, J = 10.1, 8.6 Hz, 1H), 4.95 (s, 2H), 1.44 (s,4H); 13C NMR (101 MHz, DMSO) δ 168.74, 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(586 mg, 2 mmol)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 (663 mg, 2 mmol)、Pd(OAc)2 (11 mg, 0.05 mmol)、 BINAP (62 mg, 0.1 mmol) 和Cs2CO3 (978 mg, 3 mmol)，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%。1H NMR (400MHz, DMSO-d6) δ 10.16 (s, 1H), 10.06 (s, 1H), 8.81 (s, 1H), 8.69 (s, 1H),7.78 (t, J = 9.0 Hz, 1H), 7.72 – 7.60 (m, 3H), 7.34 (dd, J = 8.7, 2.3 Hz,1H), 7.19 – 7.09 (m, 2H), 6.55 (s, 1H), 4.66 (p, J = 8.7 Hz, 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). 13C NMR (101 MHz, DMSO) δ 168.10, 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-HRMS m/z calcd for C31H32F2N7O3 + 588.2529, found 588.2531 [M + H]+.HPLC purity 97%。
实施例23 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
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 (500 mg, 1.71mmol)悬浮于20mL的1,4-二氧六环中，加入2-氨基-5-硝基吡啶(356 mg, 2.56 mmol)、Pd(OAc)2 (9.6 mg, 0.043 mmol)、 BINAP (53 mg, 0.09 mmol) 和Cs2CO3 (834 mg, 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%。1H NMR (400 MHz, Chloroform-d) δ 9.29 (d, J = 2.7 Hz, 1H), 8.90 (s, 1H), 8.66 (d, J = 9.3 Hz, 1H), 8.47(dd, J = 9.4, 2.8 Hz, 1H), 7.26 (s, 1H), 6.55 (s, 1H), 4.84 (p, J = 8.9 Hz,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(204 mg, 0.5 mmol)悬浮于10 mL乙醇中，加入氯化亚锡二水合物(1.25 g,11 mmol)后回流4小时。将反应液冷却至室温，加入100 mL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105 mg棕色固体，产率57%。1H NMR (400 MHz, Chloroform-d) δ 8.68 (s, 1H), 8.24 (d, J = 8.8Hz, 1H), 8.01 (s, 1H), 7.85 (d, J = 2.9 Hz, 1H), 7.11 (dd, J = 8.7, 2.9 Hz,1H), 6.42 (s, 1H), 4.77 (p, J = 8.9 Hz, 1H), 3.15 (s, 6H), 2.66 – 2.51 (m,2H), 2.12 – 1.96 (m, 4H), 1.79 – 1.61 (m, 2H); 1 13C NMR (101 MHz, 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(375 mg, 1.68 mmol)、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 (510 mg, 1.4mmol)、EDCI (403 mg, 2.1 mmol)、HOBt (227 mg, 1.68 mmol)和DIEA (362 mg, 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556 mg目标产物。棕色固体，产率70%。1H NMR (400 MHz, DMSO-d6) δ 10.16 (s,1H), 10.06 (s, 1H), 9.77 (s, 1H), 8.82 (s, 1H), 8.55 (d, J = 2.6 Hz, 1H),8.30 (d, J = 9.0 Hz, 1H), 7.99 (dd, J = 9.0, 2.7 Hz, 1H), 7.65 (dd, J = 8.9,5.0 Hz, 2H), 7.15 (t, J = 8.9 Hz, 2H), 6.63 (s, 1H), 4.74 (p, J = 8.8 Hz,1H), 3.05 (d, J = 9.5 Hz, 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); 13C NMR (101 MHz, DMSO) δ 168.32, 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-HRMS m/z calcd for C30H32FN8O3 + 571.2576, found571.2580 [M + H]+. HPLC purity 99%。
实施例24 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-8-环戊基-5-甲基吡啶并[2,3-d]嘧啶-7(8H)-酮(200 mg, 0.76 mmol)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(0.76 mmol)、Pd(OAc)2 (5 mg, 0.02 mmol)、 BINAP (28 mg, 0.04 mmol) 和Cs2CO3 (370 mg, 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%。1H NMR (400 MHz, DMSO-d6) δ 10.10 (s,1H), 9.96 (d, J = 11.1 Hz, 2H), 8.79 (s, 1H), 7.77 – 7.48 (m, 6H), 7.30 (t, J= 7.8 Hz, 2H), 7.06 (t, J = 7.4 Hz, 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)；13C NMR (101 MHz, DMSO) δ 168.33,168.15, 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-HRMS m/z calcd for C30H31N6O3 +523.2452, found 523.2451 [M + H]+。
实施例25 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-（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%。1H NMR (400 MHz, DMSO-d6) δ 10.76 (s,1H), 9.98 (s, 1H), 9.83 (s, 1H), 8.80 (s, 1H), 7.99 – 7.88 (m, 1H), 7.68 (d,J = 8.7 Hz, 2H), 7.53 (d, J = 8.9 Hz, 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)；13C NMR(101 MHz, DMSO) δ 169.51, 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-HRMS m/z calcd for C30H30FN6O3 + 541.2358, found541.2354 [M + H]+。
实施例26 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-（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%。1H NMR (400 MHz, DMSO-d6) δ 10.31 (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, 2.6 Hz, 1H), 6.17 (d, J = 1.3 Hz, 1H), 5.84(t, J = 8.9 Hz, 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)；13C NMR (101MHz, DMSO) δ 168.45, 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-HRMS m/z calcd for C30H30FN6O3 + 541.2358, found541.2354 [M + H]+。
实施例27 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-（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%。1H NMR (400 MHz, DMSO-d6) δ 10.09 (s,1H), 10.00 (s, 1H), 9.95 (s, 1H), 8.80 (s, 1H), 7.68 – 7.61 (m, 4H), 7.57 (d,J = 8.8 Hz, 2H), 7.14 (t, J = 8.9 Hz, 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 = 7.9 Hz, 2H), 1.81 – 1.70 (m,2H), 1.63 – 1.54 (m, 2H), 1.49 – 1.41 (m, 4H)；13C NMR (101 MHz, 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-HRMS m/z calcdfor C30H30FN6O3 + 541.2358, found 541.2354 [M + H]+。
实施例28 N-(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%。1H NMR (400 MHz, DMSO-d6) δ 10.26 (s,1H), 9.94 (d, J = 9.3 Hz, 2H), 8.79 (s, 1H), 7.86 (d, J = 2.1 Hz, 1H), 7.65(d, J = 8.7 Hz, 2H), 7.57 (d, J = 8.8 Hz, 2H), 7.52 (dd, J = 8.1, 1.9 Hz,1H), 7.32 (t, J = 8.1 Hz, 1H), 7.11 (dd, J = 7.9, 2.1 Hz, 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)；13C NMR (101MHz, DMSO) δ 168.50, 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-HRMS m/z calcd for C30H30ClN6O3 + 557.2062,found 557.2055 [M + H]+。
实施例29 N-(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%。1H NMR (400 MHz, DMSO-d6) δ 10.20 (s,1H), 9.94 (s, 2H), 8.79 (s, 1H), 7.70 – 7.61 (m, 4H), 7.57 (d, J = 8.8 Hz,2H), 7.43 – 7.28 (m, 2H), 6.17 (s, 1H), 5.84 (t, J = 8.9 Hz, 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)；13C NMR (101 MHz, DMSO) δ 168.39, 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-HRMS m/z calcd for C30H30ClN6O3 + 557.2062, found 557.2055 [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%。1H NMR (400 MHz, DMSO-d6) δ 10.29 (s,1H), 9.98 (s, 1H), 9.95 (s, 1H), 8.79 (s, 1H), 8.32 (d, J = 2.4 Hz, 1H), 7.88(dd, J = 8.1, 2.1 Hz, 1H), 7.69 – 7.55 (m, 5H), 7.45 (t, J = 7.9 Hz, 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)；13C NMR (101 MHz, DMSO) δ 168.58, 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-HRMS m/z calcd for C32H33N6O5 + 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%。1H NMR (400 MHz, DMSO-d6) δ 10.49 (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 = 8.9 Hz, 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)；13C NMR (101 MHz, DMSO) δ 168.58, 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-HRMS m/z calcd for C32H33N6O5 + 581.2507, found581.2503 [M + H]+。
实施例32 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-(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%。1H NMR (400 MHz, DMSO-d6) δ 10.05 (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 = 7.8 Hz, 1H), 6.88 (d, J = 7.5 Hz, 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)；13C NMR (101 MHz, 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-HRMS m/z calcd for C31H33N6O3 +537.2609, found 537.2603 [M + H]+。
实施例33 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-(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%。1H NMR (400 MHz, DMSO-d6) δ 10.01 (d,J = 6.0 Hz, 2H), 9.96 (s, 1H), 8.80 (s, 1H), 7.66 (d, J = 8.7 Hz, 2H), 7.58(d, J = 8.8 Hz, 2H), 7.50 (d, J = 8.1 Hz, 2H), 7.11 (d, J = 8.1 Hz, 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)；13C NMR(101 MHz, DMSO) δ 168.23, 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-HRMS m/z calcd forC31H33N6O3 + 537.2609, found 537.2603 [M + H]+。
实施例34 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-(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%。1H NMR (400 MHz, DMSO-d6) δ 10.48 (s,1H), 9.95 (s, 1H), 9.90 (s, 1H), 8.79 (s, 1H), 7.86 (d, J = 8.4 Hz, 2H), 7.71– 7.54 (m, 6H), 6.17 (d, J = 1.3 Hz, 1H), 5.84 (t, J = 8.9 Hz, 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)；13C NMR (101 MHz, DMSO) δ 168.61, 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-HRMS m/z calcd forC31H30F3N6O3 + 591.2326, found 591.2322 [M + H]+。
实施例35 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-(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%。1H NMR (400 MHz, DMSO-d6) δ 10.48 (s,1H), 9.95 (s, 1H), 9.90 (s, 1H), 8.79 (d, J = 1.6 Hz, 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)；13C NMR (101 MHz, DMSO) δ 168.65, 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-HRMS m/z calcdfor C31H30F3N6O3 + 591.2326, found 591.2322 [M + H]+。
实施例36 N-(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%。1H NMR (400 MHz, DMSO-d6) δ 10.42 (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)；13C NMR (101 MHz, DMSO) δ 168.73, 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-HRMS m/z calcd for C31H30N7O3 + 548.2405, found548.2402 [M + H]+。
实施例37 N-(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%。1H NMR (400 MHz, DMSO-d6) δ 10.56 (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 = 9.0 Hz, 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, 3.1 Hz, 4H)；13C NMR (101 MHz, DMSO) δ 168.70,167.62, 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-HRMS m/z calcd for C31H30N7O3 + 548.2405, found548.2402 [M + H]+。
实施例38 N-(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%。1H NMR (400 MHz, DMSO-d6) δ 10.48 (s,1H), 9.95 (s, 2H), 8.79 (s, 1H), 8.26 (d, J = 2.5 Hz, 1H), 7.91 (dd, J = 8.8,2.5 Hz, 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)；13C NMR (101 MHz, DMSO) δ 168.73,167.35, 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-HRMS m/z calcd for C31H29ClF3N6O3 + 625.1936, found 625.1931 [M + H]+。
实施例39 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-(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%。1H NMR (400 MHz, DMSO-d6) δ 10.01 (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 = 2.5 Hz, 1H), 7.07 (t, J = 8.0 Hz, 1H), 6.98 (d, J = 7.5 Hz,1H), 6.47 (dd, J = 8.0, 2.3 Hz, 1H), 6.17 (s, 1H), 5.84 (p, J = 8.9 Hz, 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)；13C NMR (101 MHz, DMSO) δ 168.30,168.12, 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-HRMS m/z calcd for C30H31N6O4 +539.2401, found 539.2398 [M + H]+。
实施例40 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(2.0 g, 7.6 mmol)悬浮于50mL的1,4-二氧六环中，加入对苯二胺(1.6 g, 15.2 mmol)、Pd(OAc)2 (42.6 mg, 0.2mmol)、 BINAP (236.0 mg, 0.4 mmol) 和Cs2CO3 (1.6 g, 11.4 mmol)，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(100 mg,0.30 mmol), 1–((3-氰基苯基)氨基甲酰基)环丙烷-1-羧酸(0.33 mmol)、EDCI (85.73mg, 0.45 mmol)、HOBt (60.43 mg, 0.45 mmol)、DIEA (0.1 mL, 0.60 mmol) 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%。1H NMR (400 MHz, DMSO-d6) δ 10.23 (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, 2.1 Hz, 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)；13C NMR (101MHz, DMSO) δ 168.56, 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-HRMS m/z calcd for C31H32N7O4 + 566.2510, found 566.2508 [M + H]+。
实施例41 N-(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%。1H NMR (400 MHz, DMSO-d6) δ 10.41 (s,1H), 9.99 (s, 1H), 9.96 (s, 1H), 8.79 (s, 1H), 7.93 (s, 1H), 7.78 (dd, J =50.9, 8.5 Hz, 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)；13C NMR (101 MHz, DMSO)δ 168.55, 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-HRMS m/z calcd for C31H32N7O4 +566.2510, found 566.2508 [M + H]+。
实施例42 N-(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%。1H NMR (400 MHz, DMSO-d6) δ 10.24 (s,1H), 9.95 (s, 1H), 9.93 (s, 1H), 8.79 (s, 1H), 8.00 (d, J = 2.2 Hz, 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)；13C NMR (101 MHz, DMSO) δ 168.48, 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-HRMS m/z calcd for C30H30BrN6O3 + 601.1557,found 601.1551 [M + H]+。
实施例43 N-(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%。1H NMR (400 MHz, DMSO-d6) δ 10.20 (s,1H), 9.94 (s, 2H), 8.80 (s, 1H), 7.71 – 7.43 (m, 8H), 6.18 (s, 1H), 5.84 (t,J = 8.9 Hz, 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)；13C NMR (101 MHz,DMSO) δ 168.37, 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-HRMS m/z calcd for C30H30BrN6O3 +601.1557, found 601.1551 [M + H]+。
实施例44 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-(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%。1H NMR (400 MHz, DMSO-d6) δ 10.11 (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 = 8.9 Hz, 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)；13C NMR(101 MHz, DMSO) δ 168.24, 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-HRMS m/z calcd for C31H33N6O4 + 553.2558, found 553.2257 [M + H]+。
实施例45 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-(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%。1H NMR (400 MHz, DMSO-d6) δ 10.08 (s,1H), 9.95 (s, 1H), 9.88 (s, 1H), 8.80 (s, 1H), 7.70 – 7.53 (m, 4H), 7.50 (d,J = 8.9 Hz, 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)；13C NMR (101 MHz, 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-HRMS m/z calcd for C31H33N6O4 + 553.2558,found 553.2257 [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3×103 cells/0.1 mL/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Microplate reader (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。
Claims (10)
1.1,1-环丙基二酰胺衍生物及其可药用盐
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、，其中R6 选自H、卤素、C1-C6烷烃, C3-C7 环烷烃, C1-C8烷氧基,
C1-C8烷氧烷基, C1-C8卤代烷烃, -CN, COR7, -B(OR7)2、、、、、、、、、、烯基、炔
基、杂环基、芳基、杂芳环，其中R7和R8分别是氢基、烃基、环烷基、杂原子环烷基、芳基或杂芳
环。
2.根据权利要求1 的式 (I) 化合物，R1选自环戊基；R2选自、；R3、R4、R5分
别独自选自H，F、Cl、Br、CN、OH、C(O)NH2、CH3、OCH3、CF3、C(O) CH3；L 是价键；X1、X2和X3各自独
立选自CH、N、CCH3；Z选自N、CR6、，其中R6 选自H、。
3.治疗癌和HIV等疾病的方法，所述方法包括给需要其的个体施用根据权利要求1-2的任意一项的化合物或其前药或包含式I 化合物或其前药及药学上可接受的赋形剂的药物组合物。
4.如权利要求3 中所述的治疗方法，其中所述疾病、障碍或综合征是在个体中过度增殖性的，选自HIV、癌症与炎症，其中个体是包括人和动物。
5.如权利要求3所述的应用，其特征在于，在所述药物组合物中，所述通式（I）所示的化合物的含量为0.001 ～ 99.9wt％。
6.如权利要求2所述的应用，其特征在于，所述药物组合物的日给药量为通式（I）所示的化合物以0.001 ～ 50mg/kg 的量被使用。
7.根据权利要求1 至2 的任意一项的化合物，用于如本文所述的疾病状态的预防或治疗。
8.根据权利要求1 至2 的任意一项的化合物用于药物制备的用途，其中所述药物是用于本文定义的任意一种或多种用途。
9.药物组合物，包含上述权利要求任一项的化合物或其可药用盐以及包含可药用的载体或赋形剂。
10.在需要其治疗的患者中治疗癌症的方法，该方法包括有效量的上述权利要求任一项的化合物或其可药用盐。
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