CN117003736A - 3-氨基吡嗪-2-甲酰胺类靶向蛋白水解嵌合体及其制备方法、药物组合物和应用 - Google Patents
3-氨基吡嗪-2-甲酰胺类靶向蛋白水解嵌合体及其制备方法、药物组合物和应用 Download PDFInfo
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- CN117003736A CN117003736A CN202311279883.XA CN202311279883A CN117003736A CN 117003736 A CN117003736 A CN 117003736A CN 202311279883 A CN202311279883 A CN 202311279883A CN 117003736 A CN117003736 A CN 117003736A
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- 238000001959 radiotherapy Methods 0.000 description 1
- 239000003642 reactive oxygen metabolite Substances 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
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Abstract
本发明属于化药技术领域,具体涉及一种3‑氨基吡嗪‑2‑甲酰胺类靶向蛋白水解嵌合体及其制备方法、药物组合物和应用。该3‑氨基吡嗪‑2‑甲酰胺类靶向蛋白水解嵌合体中Linker为任一化学上可行的连接结构。本发明制备过程简单易行,制备得到的蛋白水解靶向嵌合体或其在药学上可接受的盐具有高效靶向降解ATR的效果,且具有较高选择性,有望解决耐药等问题,具有广阔的应用前景;同时,PROTAC技术也为蛋白功能研究提供了方法,对药物开发具有指导意义。
Description
技术领域
本发明属于化药技术领域,具体涉及一种3-氨基吡嗪-2-甲酰胺类靶向蛋白水解嵌合体及其制备方法、药物组合物和应用。
背景技术
DNA损伤类型包括点突变、缺失、插入、DNA单链断裂(single-stranded DNA,ssDNA)、DNA双链断裂等。一般来说,造成DNA损伤的原因主要分为两种:一种是由 DNA复制错误、细胞内代谢副产物产生的活性氧等引起的内源性损伤;另一种是由外部刺激如电离辐射、紫外线、诱变化学物质等引起的外源性损伤。为维持DNA复制的准确性,确保基因可以准确的表达和遗传,细胞进化出了复杂的DNA损伤应答(DNA damage response, DDR),这是一个复杂的信号网络用于DNA 损伤的识别和修复。
DNA损伤会造成基因组不稳定和基因突变,与肿瘤的发生发展有密切关系。而开发针对DNA损伤应答的药物,一直是抗肿瘤药物研发的重要策略之一。但是DDR在抗肿瘤治疗中是一把“双刃剑”,一方面,激活该信号网络可以修复DNA损伤,抑制原癌基因、抑癌基因突变等导致的肿瘤;另一方面,抑制该信号网络可以使肿瘤对放、化疗等敏感,从而提高抗肿瘤效果。尽管已经有多种药物用于抗肿瘤的临床治疗,但是靶点选择和机制研究仍是DDR在抗肿瘤药物研发和临床实践中的重点和难点。
发明内容
本发明的目的是解决现有技术的不足,提供一种3-氨基吡嗪-2-甲酰胺类靶向蛋白水解嵌合体及其制备方法、药物组合物和应用,具体采用以下的技术方案:
一种3-氨基吡嗪-2-甲酰胺类靶向蛋白水解嵌合体,其结构式如式I所示:
式I,其中X为C=O或CH2,Linker为任一化学上可行的连接结构。
本发明基于PROTAC技术原理,利用体内的泛素-蛋白酶体系统来实现靶蛋白的选择性降解,在基础研究以及新药研发中具有显著优势。此外,本发明的发明人在大量研究中发现,上述3-氨基吡嗪-2-甲酰胺类靶向蛋白水解嵌合体或其在药学上可接受的盐能够应用在制备治疗和/或预防癌药物中,可以作为治疗癌症的药物组合物的活性成分,在蛋白水平能够有效降解恶性肿瘤细胞中的ATR,在细胞水平能够显著抑制恶性肿瘤细胞增殖。该药物组合物包含一种或多种药学上可接受的赋形剂,上述药物组合物的剂型为药学上可接受的任一剂型,还可以应用在作为靶向降解ATR药物中。
上述癌症药物优选用于急性髓性白血病的治疗中。
作为进一步优选的实施方式,Linker为饱和脂肪链、不饱和脂肪链或脂肪酸链。
作为进一步优选的实施方式,3-氨基吡嗪-2-甲酰胺类靶向蛋白水解嵌合体的分子结构如式II所示:
式II;
其中,X=CO或X=CH2,n取2,3,4,5,6,7中任一正整数。
作为进一步优选的实施方式,3-氨基吡嗪-2-甲酰胺类靶向蛋白水解嵌合体的结构如下所示:
。
本发明还提供了一种上述3-氨基吡嗪-2-甲酰胺类靶向蛋白水解嵌合体或其药学上可接受的盐的制备方法,其制备路线如下所示:
;
上述路线中合成路线如下:
;
中间体2的合成路线如下:
;
中间体3的合成路线如下:
;
中间体4的合成路线如下:
。
本发明还提供了一种药物组合物,药物组合物包括一种或多种药学上可接受的赋形剂或载体;上述赋形剂包括碳水化合物、聚合物、脂质或矿物中的至少一种。
本发明的有益效果为:本发明制备过程简单易行,制备得到的蛋白水解靶向嵌合体或其在药学上可接受的盐具有高效靶向降解ATR的效果,且具有较高选择性。本发明基于PROTAC技术原理,合成并筛选评价了一系列结构新颖的PROTAC化合物,开发了新型靶向ATR的PROTAC降解剂化合物;其可以选择性的利用泛素-蛋白酶体系统诱导ATR蛋白的靶向降解,并抑制其下游信号通路,在细胞水平上能够通过对ATR的选择性降解实现良好的抗肿瘤作用;在动物水平,小鼠皮下荷瘤模型以及原位肿瘤模型证明化合物可以抑制体内AML细胞的增殖,且安全性较好。
附图说明
图1所示为化合物8i以浓度依赖方式降解细胞系中的ATR蛋白水平试验结果图;
图2所示为化合物8i抑制小鼠体外MV-4-11细胞移植瘤模型试验结果。
具体实施方式
以下将结合实施例和附图对本发明的构思、具体结构及产生的技术效果进行清楚、完整的描述,以充分地理解本发明的目的、方案和效果。
PROTAC分子设计与化合物的合成
ATR 属于磷脂酰肌醇3-激酶(PI3-K) 家族中的丝氨酸-苏氨酸激酶, 在DNA损伤之后激活细胞应答, 阻止细胞周期并修复DNA, 从而避免细胞凋亡。它是由2644 个氨基酸组成, 在其N端存在着ATR相互作用蛋白(ATR interacting protein, ATRIP) 结构域, 这是ATR激酶激活的重要区域。在它的C端有下游蛋白磷酸化的激酶结构域, 能够将靶蛋白如细胞周期检测点激酶1(CHK1) 等丝氨酸或苏氨酸磷酸化。ATR 激酶激活后可通过多种信号调控细胞生物过程, 包括细胞周期阻滞、抑制复制起点、促进脱氧核苷酸合成、启动复制叉以及修复DNA双链断裂。因此,发明人设想基于能够结合ATR结构域的配体合成和筛选出PROTAC分子。筛选出的PROTAC分子能够有效诱导ATR蛋白的降解,抑制ATR的激酶活性,抑制DNA损伤的修复,发挥抗肿瘤细胞效果。
本发明基于ATR具有一定抑制活性的小分子抑制剂出发,结合已发表的结合模型,我们设计了一系列靶向ATR的PROTAC降解剂分子库,并且在细胞水平和蛋白水平以及动物水平上抑制急性髓性白血病模型的生长。
3-氨基吡嗪-2-甲酰胺类靶向蛋白水解嵌合体化合物8a-8l的合成路线如下:
;
中间体2的合成
;
中间体2的中文名称为:3-氨基-6-溴-N-苯基吡嗪-2-甲酰胺
具体具体制备步骤如下:
向1(2.18 g,10.0 mmol)的DMF(65 mL)溶液中依次加入苯胺(0.930 g,10.0mmol),HBTU(4.55 g,12.0 mmol),DIEA(5.95 mL,36.0 mmol)。将混合物在25°C下搅拌12小时。然后将混合物用EtOAc(150 mL)稀释并用饱和NaCl溶液(100 mL)洗涤,用Na2SO4干燥并在减压下浓缩。浓缩物通过硅胶柱进行柱层析纯化(PE:EtOAc = 9:1),得到化合物2(2.26mg,77%),为黄色胶状化合物。
其检测结果如下:
IR (KBr): 3434, 3341, 1661, 1591, 1523, 1437, 752 cm-1.1H NMR (400MHz, Chloroform-d) δ 9.46 (s, 1H), 8.26 (s, 1H), 7.67 (d,J= 8.0 Hz, 2H), 7.38(t,J= 7.8 Hz, 2H), 7.16 (t,J= 7.4 Hz, 1H).13C NMR (100 MHz, Chloroform-d) δ162.9, 154.2, 149.4, 137.1, 129.1, 125.6, 124.8, 123.0, 120.1. HRMS (ESI) 预测值:C11H9BrN4NaO+[M+Na]+: 314.8952, 实测值:314.9847。
中间体3的合成
中间体3的中文名称为:4-(5-氨基-6-(苯基氨基甲酰基)吡嗪-2-基)苯甲酸
具体制备步骤如下:
向2(1.17 g,4.00 mmol)的1,4-二氧六环/水(20.0 / 20.0 mL)溶液中加入对溴苯甲酸(664 mg,4.00 mmol),Pd(PPh3)4(462 mg,0.400 mmol)和Na2CO3(1.02 g,9.60mmol)。将混合物用氩气保护,在90 ℃下搅拌12小时。然后将混合物用EtOAc(150 mL)稀释并用饱和NaCl溶液(120 mL)洗涤,用Na2SO4干燥并减压浓缩。浓缩物通过硅胶柱进行柱层析纯化(二氯甲烷:甲醇=50:1),得到黄色固体化合物3(1.23 g,92%)。
其检测结果如下:
IR (KBr): 3409, 3164, 1690, 1357, 1269, 1191, 1122 cm-1.1H NMR (400MHz, DMSO-d 6) δ 10.43 (s, 1H), 9.00 (s, 1H), 8.35 (d,J= 8.1 Hz, 2H), 8.04 (d,J= 7.9 Hz, 2H), 7.83 (d,J= 8.1 Hz, 4H), 7.40 (t,J= 7.8 Hz, 2H), 7.17 (t,J=7.4 Hz, 1H).13C NMR (100 MHz, DMSO-d 6) δ 167.6, 164.4, 154.5, 145.1, 139.4,137.8, 137.4, 130.0, 129.7, 128.6, 126.9, 125.5, 124.2, 121.2. HRMS (ESI) 预测值:C18H14N4NaO3 +[M+Na]+: 357.0958, 实测值:357.0961。
中间体4的合成
中间体4的中文名称为:4-(4-(5-氨基-6-(苯基氨基甲酰基)吡嗪-2-基)苯甲酰基)哌嗪-1-羧酸叔丁酯
具体制备步骤如下:
向3(200 mg,0.598 mmol)的DMF(5.00 mL)溶液中加入1-Boc-哌嗪(111 mg,0.598mmol),EDCI(172 mg,0.897 mmol),HOBt(97.0 mg,0.718 mmol)和DIEA(231 mg,1.79mmol)。将混合物在25°C下搅拌8小时。然后将混合物用EtOAc(50 mL)稀释并用饱和NaCl溶液(50 mL)洗涤,用Na2SO4干燥并在减压下浓缩。浓缩物通过硅胶柱进行柱层析纯化(二氯甲烷:甲醇=80:1),得到化合物4(255 mg,85%),为黄色固体。
其检测结果如下:
IR (KBr): 3372, 1690, 1634, 1545, 1439 cm-1.1H NMR (400 MHz, DMSO-d 6)δ 10.43 (s, 1H), 8.98 (s, 1H), 8.31 (d,J= 8.0 Hz, 2H), 7.95 – 7.67 (m, 4H),7.53 (d,J= 8.0 Hz, 2H), 7.41 (t,J= 7.8 Hz, 2H), 7.17 (t,J= 7.4 Hz, 1H), 3.61(s, 8H), 1.42 (s, 9H).13C NMR (100 MHz, DMSO-d 6) δ 169.0, 164.5, 154.4, 153.8,144.8, 137.9, 137.6, 136.9, 135.2, 128.6, 127.5, 125.6, 124.2, 124.1, 121.1,79.2, 28.0. HRMS (ESI) 预测值:C27H30N6NaO4 +[M+Na]+: 525.2221, 实测值:525.2223。
实施例1
3-氨基吡嗪-2-甲酰胺类靶向蛋白水解嵌合体
(1)化合物8a的制备,其制备路线如下:
化合物8a的结构如下:
;其中文名称为:3-氨基-6-(4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基氨基)-3-氧代丙基)哌嗪-1-羰基)苯基)-N-苯基吡嗪-2-甲酰胺
7a中文名称为:3-溴-N-(2-(2,6-二氧哌啶-3-基)-1,3-二氧哌啶-4-基)丙烯酰胺
在6a (514 mg, 3.00 mmol)中加入干THF (5 mL)至15 (273 mg, 1.00 mmol)的溶液。反应加热回流6 h,浓缩反应混合物,用二氯甲烷萃取残渣。有机层用饱和NaHCO3洗涤,Na2SO4干燥。用硅胶柱层析纯化(二氯甲烷:甲醇= 60:1)得到化合物7a (290 mg, 71%)为白色固体。
其检测结果如下:
M.p. 180.6-181.7°C; IR (KBr): 3354, 3208, 3100, 1767, 1697, 1617,1521, 1476, 1398, 1352, 1330, 1205, 1144, 1059, 1021, 745, 686 cm-1 . 1H NMR(400 MHz, CDCl3) δ 9.47 (s, 1H), 8.83 (d,J= 8.5 Hz, 1H), 8.27 (s, 1H), 7.74(t,J= 7.9 Hz, 1H), 7.58 (d,J= 7.3 Hz, 1H), 4.96 (dd,J= 12.1, 5.3 Hz, 1H),3.70 (t,J= 6.5 Hz, 2H), 3.06 (t,J= 6.5 Hz, 2H), 2.96 – 2.87 (m, 1H), 2.85 –2.74 (m, 2H), 2.17 (dt,J= 8.4, 5.2 Hz, 1H).13C NMR (100 MHz, CDCl3) δ 170.8,169.2, 169.0, 167.9, 166.7, 137.4, 136.7, 131.2, 125.5, 119.1, 115.7, 49.5,40.9, 31.5, 26.1, 22.8. HRMS (ESI) 预测值:C16H15BrN3O5 +[M+H]+: 408.0190, 实测值:408.0191.
具体制备步骤如下:
向化合物4(0.15 mg,0.30 mmol)的二氯甲烷(3.0 mL)溶液中加入TFA(2.00 mL),并在室温下搅拌2小时。将混合物减压浓缩,得到黄色固状粗中间化合物;将上述粗中间体化合物溶于DMF(3.0 mL)中;然后向所得溶液中加入7a(0.12 g,0.300 mmol),DIEA(0.190g,1.5 mmol),将混合物在室温下搅拌12小时,然后将混合物用EtOAc(80 mL)稀释并用饱和NaCl溶液(50 mL)洗涤,用Na2SO4干燥,过滤并在减压下浓缩;浓缩物通过硅胶柱层析纯化(二氯甲烷:甲醇= 80:1),得到化合物8a(120 mg,56%),为黄色固体。
其检测结果如下:
IR (KBr): 3421, 1701, 1607, 1546, 1197 cm-1.1H NMR (400 MHz, DMSO-d 6)δ 11.18 (s, 1H), 10.53 – 10.34 (m, 2H), 8.96 (s, 1H), 8.57 (d,J= 8.4 Hz, 1H),8.29 (d,J= 8.0 Hz, 2H), 7.87 – 7.75 (m, 5H), 7.60 (dd,J= 7.3, 0.8 Hz, 1H),7.55 – 7.46 (m, 2H), 7.44 – 7.35 (m, 2H), 7.20 – 7.12 (m, 1H), 5.16 (dd,J=12.7, 5.5 Hz, 1H), 3.71 (s, 4H), 2.92 (ddd,J= 16.9, 13.7, 5.4 Hz, 1H), 2.74 –2.64 (m, 4H), 2.62 – 2.46 (m, 6H), 2.09 (dp,J= 10.4, 3.1 Hz, 1H).13C NMR (100MHz, DMSO-d 6) δ 172.7, 171.3, 169.8, 168.6, 167.5, 166.7, 164.4, 154.4,144.8, 137.8, 137.6, 136.8, 136.5, 136.0, 135.4, 131.5, 128.6, 127.4, 126.4,125.6, 124.2, 124.0, 121.1, 118.2, 116.7, 53.1, 52.2, 48.9, 33.7, 30.9, 22.0.HRMS (ESI) 预测值:C38H35N9NaO7 +[M+Na]+: 752.2552, 实测值:752.2547。
(2)化合物8b的制备,其制备路线如下:
化合物8b的结构如下:
;其中文名称为:3-氨基-6-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)-4-氧代丁基)哌嗪-1-羰基)苯基)-N-苯基吡嗪-2-甲酰胺
化合物7b中文名称为:4-溴-N-(2-(2,6-二氧哌替啶-3-基)- 1,3 -二氧哌替啶-4-基)丁酰胺;化合物7b的合成方法同7a,只需将溴代丙酰氯替换为溴代丁酰氯其余相同,得到化合物7b (67%) 白色固体。
其检测结果如下:
M.p. 182.8-183.7°C; IR (KBr): 3349, 3209, 3099, 1760, 1685, 1632,1483, 1410, 1325, 1310, 1222, 1103, 1060, 741, 695 cm-1.1H NMR (400 MHz,CDCl3) δ 9.44 (s, 1H), 8.80 (d,J= 8.5 Hz, 1H), 8.31 (s, 1H), 7.72 (t,J= 7.9Hz, 1H), 7.56 (d,J= 7.3 Hz, 1H), 4.96 (dd,J= 12.2, 5.4 Hz, 1H), 3.53 (t,J=6.3 Hz, 2H), 2.97 – 2.85 (m, 1H), 2.84 – 2.74 (m, 2H), 2.68 (t,J= 7.1 Hz,2H), 2.29 (p,J= 6.7 Hz, 2H), 2.22 – 2.15 (m, 1H).13C NMR (100 MHz, CDCl3) δ171.0, 170.9, 169.2, 168.0, 166.8, 137.7, 136.6, 131.2, 125.4, 118.8, 115.5,49.4, 35.8, 32.9, 31.5, 27.7, 22.8. HRMS (ESI) 预测值:C17H17BrN3O5 +[M+H]+:422.0346, 实测值:422.0344。
具体制备步骤如下:
按照化合物8a的制备方法,将7a替换为7b,其余操作相同,得到了目标化合物8b。硅胶柱层析纯化(二氯甲烷:甲醇= 60:1)得到的化合物8b(61%),为黄色固体。
其检测结果如下:
IR (KBr): 3424, 1709, 1601, 1523, 1206 cm-1.1H NMR (400 MHz, DMSO-d 6)δ 11.16 (s, 1H), 10.42 (s, 1H), 9.71 (s, 1H), 8.96 (s, 1H), 8.49 (d,J= 8.4Hz, 1H), 8.29 (d,J= 8.1 Hz, 2H), 7.84 – 7.74 (m, 5H), 7.62 (d,J= 7.3 Hz, 1H),7.48 (d,J= 8.3 Hz, 2H), 7.40 (t,J= 7.8 Hz, 2H), 7.16 (t,J= 7.4 Hz, 1H), 5.15(dd,J= 12.7, 5.5 Hz, 1H), 3.51 (s, 4H), 2.90 (ddd,J= 16.6, 13.6, 5.3 Hz, 1H),2.66 – 2.51 (m, 4H), 2.39 (t,J= 7.0 Hz, 6H), 2.11 – 2.02 (m, 1H), 1.82 (q,J=7.1 Hz, 2H)。13C NMR (100 MHz, DMSO-d 6) δ 173.2, 172.5, 170.2, 169.1, 168.2,165.0, 145.3, 138.3, 138.1, 137.1, 136.6, 135.9, 131.9, 129.1, 127.9, 126.0,124.7, 124.5, 121.6, 118.7, 117.3, 70.2, 57.2, 49.4, 41.5, 41.3, 41.1, 40.9,40.1, 39.9, 39.7, 39.5, 39.3, 39.1, 39.0, 38.9, 38.8, 38.6, 38.6, 38.5, 38.4,38.2, 35.0, 29.5, 22.5, 22.4. HRMS (ESI) 预测值:C39H37N9NaO7 +[M+Na]+: 766.2708,实测值:766.2711。
(3)化合物8c的制备,其制备路线如下:
化合物8c的结构如下:
;其中文名称为3-氨基-6-(4-(4-(4-(5-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)-5-氧代戊基)哌嗪-1-羰基)苯基)-N-苯基吡嗪-2-甲酰胺
化合物7c中文名称为:5-溴-N-(2-(2,6-二氧哌啶-3-基)-1,3-二氧哌啶-4-基)戊胺。化合物7c的合成方法同7a,只需将溴代丙酰氯替换为溴代戊酰氯其余相同,得到化合物7c (67%) 白色固体。
其检测结果如下:
M.p. 183.3-184.1°C; IR (KBr): 3352, 3215, 3103, 1765, 1681, 1652,1454, 1428, 1310, 1303, 1211, 1115, 1051, 737, 683 cm-1.1H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 8.34 (d,J= 8.3 Hz, 1H), 7.71 (dd,J= 8.4, 7.3 Hz, 1H),7.50 (d,J= 7.2 Hz, 1H), 5.04 (dd,J= 12.7, 5.4 Hz, 1H), 3.46 (t,J= 6.6 Hz,2H), 2.79 (ddd,J= 16.7, 13.7, 5.3 Hz, 1H), 2.56 – 2.46 (m, 1H), 2.45 – 2.39(m, 3H), 1.99 – 1.94 (m, 1H), 1.78 – 1.73 (m, 1H), 1.68 – 1.59 (m, 2H).13C NMR(100 MHz, CDCl3) δ 171.7, 170.9, 169.3, 168.0, 166.8, 137.8, 136.7, 131.2,125.4, 118.7, 115.4, 49.4, 36.9, 33.1, 32.0, 31.5, 23.8, 22.8. HRMS (ESI) 预测值:C18H19BrN3O5 +[M+H]+: 436.0503, 实测值:436.0504。
具体制备步骤如下:
按照化合物8a的制备方法,将7a替换为7c,其余操作相同,得到了目标化合物8c。硅胶柱层析纯化(二氯甲烷:甲醇= 60:1)得到化合物8c(72%),为黄色固体。
其检测结果如下:
IR (KBr): 3431, 1711, 1602, 1531, 1204 cm-1.1H NMR (400 MHz, DMSO-d 6)δ 11.26 – 11.12 (m, 1H), 10.42 (d,J= 5.1 Hz, 1H), 9.70 (d,J= 5.2 Hz, 1H),8.96 (d,J= 5.2 Hz, 1H), 8.49 (t,J= 7.3 Hz, 1H), 8.29 (d,J= 6.9 Hz, 2H), 7.91– 7.68 (m, 5H), 7.61 (d,J= 6.5 Hz, 1H), 7.48 (d,J= 6.9 Hz, 2H), 7.39 (q,J=7.1 Hz, 2H), 7.16 (t,J= 7.1 Hz, 1H), 5.16 (dd,J= 13.0, 6.3 Hz, 1H), 3.61 –3.36 (m, 4H), 2.88 (d,J= 15.6 Hz, 1H), 2.61 (d,J= 18.0 Hz, 4H), 2.43 – 2.36(m, 6H), 2.14 – 2.01 (m, 1H), 1.80 (q,J= 7.0 Hz, 2H), 1.29 – 1.20 (m, 2H).13CNMR (100 MHz, DMSO-d 6) δ 172.8, 172.0, 169.8, 168.7, 167.8, 166.7, 164.5,154.4, 144.9, 137.9, 137.6, 136.8, 136.6, 136.2, 135.4, 131.4, 128.6, 127.4,126.1, 125.6, 124.2, 124.1, 121.1, 118.3, 116.8, 56.8, 52.7, 48.9, 34.6,31.0, 22.0, 21.9. HRMS (ESI) 预测值:C40H39N9NaO7 +[M+Na]+: 780.2865, 实测值:780.2867。
(4)化合物8d的制备,其制备路线如下:
化合物8d的结构如下:
;其中文名称为:3-氨基-6-(4-(4-(6-(2-(2,6-二氧嘧啶-3-基)-1,3-二氧嘧啶异吲哚-4-基)氨基)-6-氧己基)哌嗪-1-羰基)苯基-N-苯吡嗪-2-羧酰胺/>
化合物7d的中文名称为:5-溴-N-(2-(2,6-二氧哌啶-3-基)-1,3-二氧哌啶-4-基)己胺。化合物7d的合成方法同7a,只需将溴代丙酰氯替换为溴代己酰氯其余相同,得到化合物7d (67%)白色固体。
其检测结果如下:
M.p. 183.7-184.6°C; IR (KBr): 3355, 3210, 3101, 1758, 1677, 1659,1457, 1438, 1321, 1313, 1205, 1109, 1047, 750, 682 cm-1.1H NMR (400 S10 MHz,CDCl3) δ 9.41 (s, 1H), 8.81 (d,J= 8.6 Hz, 1H), 8.58 (s, 1H), 7.71 (t,J= 7.8Hz, 1H), 7.54 (d,J= 7.4 Hz, 1H), 5.07 – 4.88 (m, 1H), 3.41 (t,J= 6.5 Hz, 2H),2.96 – 2.88 (m, 1H), 2.84 – 2.74 (m, 2H), 2.48 (t,J= 7.4 Hz, 2H), 2.24 – 2.11(m, 1H), 1.91 (p,J= 7.2 Hz, 2H), 1.77 (t,J= 7.7 Hz, 2H), 1.54 (q,J= 7.9 Hz,2H). 13C NMR (100 MHz, CDCl3) δ 172.0, 171.1, 169.2, 168.10, 166.7, 137.8,136.5, 131.08, 125.3, 118.5, 115.3, 49.2, 37.6, 33.5, 32.4, 31.4, 27.6, 24.3,22.7. HRMS (ESI) 预测值:C19H21BrN3O5 +[M+H]+: 450.0659, 实测值:450.0660。
具体制备步骤如下:
按照化合物8a的制备方法,将7a替换为7d,其余操作相同,得到了目标化合物8d。硅胶柱层析纯化(二氯甲烷:甲醇= 60:1)得到的化合物8d(67%)为黄色固体。
其检测结果如下:
IR (KBr): 3425, 3335, 1703, 1605, 1531, 1202 cm-1.1H NMR (400 MHz,DMSO-d 6) δ 11.18 (s, 1H), 10.42 (s, 1H), 9.68 (s, 1H), 8.97 (s, 1H), 8.49 (d,J= 8.4 Hz, 1H), 8.29 (d,J= 8.0 Hz, 2H), 7.81 (dd,J= 18.7, 10.6 Hz, 5H), 7.60(d,J= 7.3 Hz, 1H), 7.49 (d,J= 8.1 Hz, 2H), 7.40 (t,J= 7.8 Hz, 2H), 7.17 (t,J=7.4 Hz, 1H), 5.16 (dd,J= 12.8, 5.5 Hz, 1H), 3.58 (d,J= 44.5 Hz, 4H), 2.91(ddd,J= 16.7, 13.5, 5.3 Hz, 1H), 2.69 – 2.47 (m, 4H), 2.45 – 2.26 (m, 6H),2.08 (ddd,J= 11.1, 6.1, 3.5 Hz, 1H), 1.65 (p,J= 7.4 Hz, 2H), 1.48 (dq,J=14.9, 7.3, 6.8 Hz, 2H), 1.35 (q,J= 7.9 Hz, 2H).13C NMR (100 MHz, DMSO-d 6) δ173.2, 172.4, 170.2, 169.1, 168.2, 167.1, 164.9, 154.9, 145.3, 138.3, 138.1,137.2, 137.0, 136.6, 135.9, 131.9, 129.1, 127.9, 126.6, 126.0, 124.6, 124.5,121.5, 118.7, 117.3, 58.0, 55.4, 53.2, 49.4, 37.0, 31.4, 26.9, 26.4, 25.2,22.5. HRMS (ESI) 预测值:C41H41N9NaO7 +[M+Na]+: 794.3021, 实测值:794.3024。
(5)化合物8e的制备,其制备路线如下:
化合物8e的结构如下:
;其中文名称为3-氨基-6-(4-(4-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)-7-氧代庚基)哌嗪-1-羰基)苯基)-N-苯基吡嗪-2-甲酰胺
化合物7e的中文名称为:5-溴-N-(2-(2,6-二氧哌啶-3-基)-1,3-二氧哌啶-4-基)庚胺。化合物7d的合成方法同7a,只需将溴代丙酰氯替换为溴代庚酰氯其余相同,得到化合物7d (67%)白色固体。
其检测结果如下:
M.p. 184.2-185.0°C; IR (KBr): 3344, 3223, 3113, 1769, 1666, 1643,1471, 1429, 1320, 1301, 1217, 1141, 1025, 747, 696 cm-1.1H NMR (400 MHz,CDCl3) δ 9.40 (s, 1H), 8.81 (d,J= 8.5 Hz, 1H), 8.47 (s, 1H), 7.71 (dd,J= 8.5,7.3 Hz, 1H), 7.54 (d,J= 7.3 Hz, 1H), 5.09 – 4.88 (m, 1H), 3.40 (t,J= 6.8 Hz,2H), 2.96 – 2.85 (m, 1H), 2.84 – 2.73 (m, 2H), 2.46 (t,J= 7.5 Hz, 2H), 2.16(ddd,J= 8.3, 6.3, 4.1 Hz, 1H), 1.88 (q,J= 7.1 Hz, 2H), 1.81 – 1.71 (m, 2H),1.54 – 1.38 (m, 4H).13C NMR (100 MHz, CDCl3) δ 172.3, 171.0, 169.3, 168.1,166.8, 137.9, 136.6, 131.2, 125.4, 118.6, 115.4, 49.4, 37.9, 33.9, 32.6,31.5, 28.3, 27.9, 25.1, 22.8. HRMS (ESI) 预测值:C20H23BrN3O5 +[M+H]+: 464.0816,实测值:464.0815。
具体制备步骤如下:
按照化合物8a的制备方法,将7a替换为7e,其余操作相同,得到了目标化合物8e。硅胶柱层析纯化(二氯甲烷:甲醇= 60:1)得到的化合物8e(62%)为黄色固体。
其检测结果如下:
IR (KBr): 3422, 3348, 2929, 1705, 1599, 1528, 1196 cm-1.1H NMR (400MHz, DMSO-d 6) δ 11.16 (s, 1H), 10.40 (s, 1H), 9.67 (s, 1H), 8.95 (s, 1H),8.47 (d,J= 8.4 Hz, 1H), 8.28 (d,J= 8.0 Hz, 2H), 7.87 – 7.70 (m, 5H), 7.59 (d,J= 7.3 Hz, 1H), 7.48 (d,J= 8.0 Hz, 2H), 7.39 (t,J= 7.7 Hz, 2H), 7.15 (t,J=7.4 Hz, 1H), 5.14 (dd,J= 12.7, 5.4 Hz, 1H), 3.56 (d,J= 46.0 Hz, 4H), 2.95 –2.84 (m, 1H), 2.67 – 2.49 (m, 4H), 2.48 – 2.26 (m, 7H), 2.07 (td,J= 7.6, 6.8,3.0 Hz, 1H), 1.62 (p,J= 7.2 Hz, 2H), 1.51 – 1.40 (m, 2H), 1.32 (dt,J= 10.0,5.7 Hz, 4H).13C NMR (100 MHz, DMSO-d 6) δ 172.7, 172.0, 169.8, 168.7, 167.7,166.6, 164.5, 154.4, 144.8, 137.9, 137.6, 136.8, 136.6, 136.1, 135.3, 131.4,128.6, 127.4, 126.2, 125.6, 124.2, 124.1, 121.1, 118.3, 116.9, 57.5, 52.5,48.9, 36.5, 31.0, 28.4, 26.6, 24.7, 22.1, 22.0. HRMS (ESI) 预测值:C42H43N9NaO7 +[M+Na]+: 808.3178, 实测值: 808.3181。
(6)化合物8f的制备,其制备路线如下:
化合物8f的结构如下:
;其中文名称为3-氨基-6-(4-(4-(4-(8-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)-8-氧代辛基)哌嗪-1-羰基)苯基)-N-苯基吡嗪-2-甲酰胺/>
化合物7f的中文名称为:5-溴-N-(2-(2,6-二氧哌啶-3-基)-1,3-二氧哌啶-4-基)辛胺。7f的合成方法同7a,只需将溴代丙酰氯替换为溴代辛酰氯其余相同,得到化合物7f(67%) 白色固体。
其检测结果如下:
M.p. 185.2-186.1°C; IR (KBr): 3347, 3231, 3124, 1729, 1673, 1652,1491, 1447, 1336, 1314, 1240, 1127, 1052, 729, 683 cm-1.1H NMR (400 MHz,CDCl3) δ 9.41 (s, 1H), 8.84 (dd,J= 8.5, 0.8 Hz, 1H), 8.09 (s, 1H), 7.72 (dd,J= 8.5, 7.3 Hz, 1H), 7.55 (dd,J= 7.3, 0.8 Hz, 1H), 5.12 – 4.79 (m, 1H), 3.41(t,J= 6.8 Hz, 2H), 2.98 – 2.89 (m, 1H), 2.86 – 2.71 (m, 2H), 2.46 (t,J= 7.5Hz, 2H), 2.23 – 2.14 (m, 1H), 1.86 (p,J= 6.8 Hz, 2H), 1.76 (p,J= 7.4 Hz, 2H),1.50 – 1.35 (m, 6H).13C NMR (100 MHz, CDCl3) δ 172.2, 170.9, 169.2, 168.0,166.7, 137.8, 136.5, 131.1, 125.3, 118.5, 115.3, 49.3, 37.8, 33.8, 32.5,31.4, 28.2, 27.8, 25.0, 22.7. HRMS (ESI) 预测值:C21H25BrN3O5 +[M+H]+: 478.0972,实测值: 478.0973。
具体制备步骤如下:
按照化合物8a的制备方法,将7a替换为7f,其余操作相同,得到了目标化合物8f。硅胶柱层析纯化(二氯甲烷:甲醇= 60:1)得到化合物8f(66%),为黄色固体。
其检测结果如下:
IR (KBr): 3423, 1705, 1623, 1578, 1217 cm-1.1H NMR (400 MHz, DMSO-d 6)δ 11.18 (s, 1H), 10.41 (s, 1H), 9.67 (s, 1H), 8.96 (s, 1H), 8.48 (d,J= 8.4Hz, 1H), 8.35 – 8.26 (m, 2H), 7.88 – 7.69 (m, 5H), 7.60 (d,J= 7.2 Hz, 1H),7.52 – 7.46 (m, 2H), 7.44 – 7.37 (m, 2H), 7.20 – 7.13 (m, 1H), 5.15 (dd,J=12.8, 5.4 Hz, 1H), 3.63 (s, 4H), 2.91 (ddd,J= 16.8, 13.6, 5.3 Hz, 1H), 2.69 –2.47 (m, 4H), 2.44 – 2.22 (m, 6H), 2.08 (ddq,J= 12.9, 5.8, 3.6, 2.4 Hz, 1H),1.62 (p,J= 7.1 Hz, 2H), 1.43 (q,J= 7.3 Hz, 2H), 1.37 – 1.26 (m, 6H).13C NMR(100 MHz, DMSO-d 6) δ 173.2, 172.5, 170.2, 169.1, 168.2, 167.1, 164.9, 154.9,145.3, 138.3, 138.1, 137.2, 137.0, 136.6, 135.9, 131.9, 129.1, 127.9, 126.6,126.0, 124.7, 124.5, 121.5, 118.7, 117.3, 58.1, 55.4, 53.3, 49.4, 37.0, 31.4,29.1, 28.9, 27.2, 26.6, 25.2, 22.6, 22.5. HRMS (ESI) 预测值:C43H45N9NaO7 +[M+Na]+:822.3334, 实测值: 822.3336。
(7)化合物8g的制备,其制备路线如下:
化合物8g的结构如下:
;其中文名称为:3-氨基-6-(4-(4-(3-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基氨基)-3-氧代丙基)哌嗪-1-羰基)苯基)-N-苯基吡嗪-2-甲酰胺
7g的中文名称为:3-溴-N-(2-(2,6-二氧哌啶-3-基)-1,3-二氧哌啶-4-基)丙烯酰胺
将6b (514 mg, 3.00 mmol)中溶解于干燥的THF (5 mL)中,缓慢加入溴代丙酰氯(273 mg, 1.00 mmol)的溶液。反应加热回流6 h,浓缩反应混合物,用二氯甲烷萃取残渣。有机层用饱和NaHCO3洗涤,Na2SO4干燥。用硅胶柱层析纯化(二氯甲烷:甲醇= 60:1)得到化合物7g (290 mg, 71%)为白色固体。
其检测结果如下:
M.p. 180.6-181.7°C; IR (KBr): 3354, 3208, 3100, 1767, 1697, 1617,1521, 1476, 1398, 1352, 1330, 1205, 1144, 1059, 1021, 745, 686 cm-1.1H NMR(400 MHz, CDCl3) δ 9.47 (s, 1H), 8.83 (d,J= 8.5 Hz, 1H), 8.27 (s, 1H), 7.74(t,J= 7.9 Hz, 1H), 7.58 (d,J= 7.3 Hz, 1H), 4.96 (dd,J= 12.1, 5.3 Hz, 1H),3.70 (t,J= 6.5 Hz, 2H), 3.06 (t,J= 6.5 Hz, 2H), 2.96 – 2.87 (m, 1H), 2.85 –2.74 (m, 2H), 2.17 (dt,J= 8.4, 5.2 Hz, 1H).13C NMR (100 MHz, CDCl3) δ 170.8,169.2, 169.0, 167.9, 166.7, 137.4, 136.7, 131.2, 125.5, 119.1, 115.7, 49.5,40.9, 31.5. HRMS (ESI) 预测值:C16H17BrN3O5 +[M+H]+: 394.0190, 实测值: 394.0191。
具体制备步骤如下:
按照化合物8a的制备方法,将7a替换为7g,其余操作相同,得到了目标化合物8g。硅胶柱层析纯化(二氯甲烷:甲醇= 40:1)得到化合物8g(64%),为黄色固体。
其检测结果如下:
IR (KBr): 3421, 1670, 1601, 1544, 1203 cm-1.1H NMR (400 MHz, DMSO-d 6)δ 11.06 (s, 1H), 10.42 (s, 1H), 9.93 (s, 1H), 8.96 (s, 1H), 8.29 (d,J= 8.0Hz, 2H), 7.90 – 7.72 (m, 5H), 7.51 (td,J= 7.9, 4.8 Hz, 4H), 7.40 (t,J= 7.8Hz, 2H), 7.16 (t,J= 7.4 Hz, 1H), 5.17 (dd,J= 13.3, 5.1 Hz, 1H), 4.47 – 4.30(m, 2H), 3.78 – 3.38 (m, 4H), 2.93 (ddd,J= 18.0, 13.6, 5.4 Hz, 1H), 2.77 –2.53 (m, 6H), 2.33 (qd,J= 13.2, 4.4 Hz, 4H), 2.11 – 2.00 (m, 1H).13C NMR (100MHz, DMSO-d 6) δ 172.8, 171.1, 170.2, 168.7, 167.8, 164.5, 154.4, 144.8,137.9, 137.6, 136.8, 135.4, 133.7, 133.7, 132.6, 128.7, 128.6, 127.4, 125.6,125.1, 124.2, 124.1, 121.1, 119.0, 54.9, 52.5, 51.5, 46.5, 33.5, 31.2, 22.7.HRMS (ESI) 预测值:C38H37N9NaO6 +[M+Na]+: 738.2759, 实测值: 738.2761。
(8)化合物8h的制备,其制备路线如下:
化合物8h的结构如下:
;其中文名称为:3-氨基-6-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-4-氧代丁基)哌嗪-1-羰基)苯基)-N-苯基吡嗪-2-甲酰胺
7h的中文名称为:5-溴-N-(2-(2,6-二氧哌啶-3-基)- 1-氧异吲哚-4-基)丁胺。化合物7h的合成方法同7g,只需将溴代丙酰氯替换为溴代丁酰氯其余相同,得到化合物7h(65%) 白色固体。
其检测结果如下:
M.p. 265.6-266.4 °C; IR (KBr): 3330, 3095, 2937, 1734, 1685, 1653,1606, 1537, 1463, 1435, 1355, 1237, 1209, 1195, 1153, 844, 751 cm-1 . 1H NMR(400 MHz, DMSO-d6) δ 11.02 (s, 1H), 9.82 (s, 1H), 7.82 (dd,J= 7.0, 1.9 Hz,1H), 7.57 – 7.40 (m, 2H), 5.15 (dd,J= 13.3, 5.1 Hz, 1H), 4.65 – 4.25 (m, 2H),3.63 (dt,J= 41.8, 6.3 Hz, 2H), 2.92 (ddd,J= 17.3, 13.6, 5.4 Hz, 1H), 2.61(dt,J= 17.0, 3.4 Hz, 1H), 2.43 – 2.28 (m, 3H), 2.03 (ddd,J= 9.8, 5.2, 2.6 Hz,1H), 1.81 (ddt,J= 48.1, 14.9, 7.0 Hz, 4H). 13C NMR (100 MHz, DMSO-d6) δ173.3, 171.5, 171.4, 168.3, 134.2, 133.2, 129.1, 125.7, 119.5, 52.0, 46.9,45.6, 35.2, 32.2, 32.0, 31.7, 24.1, 23.1. HRMS (ESI) 预测值:C17H19BrN3O4 +[M+H]+:408.0700, 实测值:408.0701。
具体制备步骤如下:
按照化合物8a的制备方法,将7a替换为7h,其余操作相同,得到了目标化合物8h。硅胶柱层析纯化(二氯甲烷:甲醇= 40:1)得到化合物8h(68%),为黄色固体。
其检测结果如下:
IR (KBr): 3425, 1679, 1606, 1531, 1206 cm-1.1H NMR (400 MHz, DMSO-d 6)δ 11.02 (s, 1H), 10.41 (s, 1H), 9.82 (s, 1H), 8.96 (s, 1H), 8.35 – 8.23 (m,2H), 7.94 – 7.80 (m, 3H), 7.75 (s, 2H), 7.49 (dd,J= 7.9, 2.8 Hz, 4H), 7.45 –7.36 (m, 2H), 7.21 – 7.13 (m, 1H), 5.14 (dd,J= 13.2, 5.1 Hz, 1H), 4.48 – 4.29(m, 2H), 3.62 (s, 4H), 2.92 (ddd,J= 17.9, 13.5, 5.5 Hz, 1H), 2.65 – 2.57 (m,1H), 2.51 (d,J= 2.0 Hz, 1H), 2.48 – 2.28 (m, 8H), 2.07 – 1.99 (m, 1H), 1.89 –1.70 (m, 2H).13C NMR (100 MHz, DMSO-d 6) δ 173.3, 171.7, 171.5, 169.1, 168.3,165.0, 154.9, 145.3, 138.3, 138.1, 137.3, 135.9, 134.3, 134.1, 133.1, 129.1,127.9, 126.0, 125.6, 124.7, 124.6, 121.6, 119.4, 57.6, 52.0, 47.0, 34.2,31.7, 23.1, 22.6. HRMS (ESI) 预测值:C39H39N9NaO6 +[M+Na]+: 752.2916, 实测值:752.2913。
(9)化合物8i的制备,其制备路线如下:
化合物8i的结构如下:
;其中文名称为:3-氨基-6-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-5-氧代戊基)哌嗪-1-羰基)苯基)-N-苯基吡嗪-2-甲酰胺
化合物7i的中文名称为:5-溴-N-(2-(2,6-二氧哌啶-3-基)- 1-氧异吲哚-4-基)戊胺。化合物7i的合成方法同7g,只需将溴代丙酰氯替换为溴代戊酰氯其余相同,得到化合物7i (62%) 白色固体。
其检测结果如下:
M.p. 265.6-266.4 °C; IR (KBr): 3330, 3095, 2937, 1734, 1685, 1653,1606, 1537, 1463, 1435, 1355, 1237, 1209, 1195, 1153, 844, 751 cm-1 . 1H NMR(400 MHz, DMSO-d6) δ 11.02 (s, 1H), 9.82 (s, 1H), 7.82 (dd,J= 7.0, 1.9 Hz,1H), 7.57 – 7.40 (m, 2H), 5.15 (dd,J= 13.3, 5.1 Hz, 1H), 4.65 – 4.25 (m, 2H),3.63 (dt,J= 41.8, 6.3 Hz, 2H), 2.92 (ddd,J= 17.3, 13.6, 5.4 Hz, 1H), 2.61(dt,J= 17.0, 3.4 Hz, 1H), 2.43 – 2.28 (m, 3H), 2.03 (ddd,J= 9.8, 5.2, 2.6 Hz,1H), 1.81 (ddt,J= 48.1, 14.9, 7.0 Hz, 4H). 13C NMR (100 MHz, DMSO-d6) δ173.3, 171.5, 171.4, 168.3, 134.2, 133.2, 129.1, 125.7, 119.5, 52.0, 46.9,45.6, 35.2, 32.2, 32.0, 31.7, 24.1, 23.1, 22.9. HRMS (ESI) 预测值:C18H21BrN3O4 +[M+H]+: 422.0710, 实测值:422.0711.
具体制备步骤如下:
按照化合物8a的制备方法,将7a替换为7i,其余操作相同,得到了目标化合物8i。硅胶柱层析纯化(二氯甲烷:甲醇= 40:1)得到化合物8i(60%),为黄色固体。
其检测结果如下:
IR (KBr): 3426, 2927, 1672, 1599, 1528, 1438, 1196 cm-1.1H NMR (400MHz, DMSO-d 6) δ 11.03 (s, 1H), 10.41 (s, 1H), 9.78 (s, 1H), 8.96 (s, 1H),8.28 (d,J= 8.2 Hz, 2H), 7.96 – 7.69 (m, 5H), 7.55 – 7.44 (m, 4H), 7.39 (t,J=7.9 Hz, 2H), 7.15 (t,J= 7.4 Hz, 1H), 5.16 (dd,J= 13.3, 5.1 Hz, 1H), 4.48 –4.30 (m, 2H), 3.57 (d,J= 51.8 Hz, 4H), 2.98 – 2.86 (m, 1H), 2.61 (ddd,J=17.3, 4.4, 2.4 Hz, 1H), 2.49 – 2.25 (m, 9H), 2.03 (ddq,J= 10.4, 5.4, 3.2, 2.7Hz, 1H), 1.63 (p,J= 7.3 Hz, 2H), 1.49 (p,J= 7.4 Hz, 2H).13C NMR (100 MHz,DMSO-d 6) δ 173.3, 171.8, 171.5, 169.2, 168.3, 164.9, 154.9, 145.3, 138.3,138.1, 137.3, 135.8, 134.3, 134.1, 133.1, 129.1, 127.9, 126.0, 125.7, 124.7,124.6, 121.6, 119.4, 57.8, 53.3, 52.0, 47.0, 36.1, 31.7, 26.2, 23.5, 23.1.HRMS (ESI) 预测值:C40H41N9NaO6 +[M+Na]+: 766.3072, 实测值:766.3072。
(10)化合物8J的制备,其制备路线如下:
化合物8J的结构如下:
;其中文名称为:3-氨基-6-(4-(4-(4-(6-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-6-氧代己基)哌嗪-1-羰基)苯基)-N-苯基吡嗪-2-甲酰胺/>
化合物7j的中文名称为:5-溴-N-(2-(2,6-二氧哌啶-3-基)- 1-氧异吲哚-4-基)己胺。化合物7j的合成方法同7g,只需将溴代丙酰氯替换为溴代己酰氯其余相同,得到化合物7j (61%) 白色固体。
其检测结果如下:
M.p. 279.8-280.5 °C; IR (KBr): 3332, 3094, 2939, 1736, 1688, 1651,1601, 1535, 1465, 1435, 1353, 1236, 1208, 1194, 1156, 847, 748 cm-1. 1H NMR(400 MHz, DMSO-d6) δ 11.02 (s, 1H), 9.79 (s, 1H), 7.80 (dd,J= 7.0, 1.9 Hz,1H), 7.64 – 7.40 (m, 2H), 5.15 (dd,J= 13.3, 5.1 Hz, 1H), 4.52 – 4.24 (m, 2H),3.55 (t,J= 6.6 Hz, 2H), 2.92 (ddd,J= 17.2, 13.6, 5.4 Hz, 1H), 2.61 (dt,J=15.4, 2.8 Hz, 1H), 2.35 (dt,J= 12.5, 5.9 Hz, 3H), 2.03 (dtd,J= 10.4, 5.2, 2.6Hz, 1H), 1.90 – 1.79 (m, 2H), 1.64 (p,J= 7.4 Hz, 2H), 1.44 (tt,J= 9.5, 6.1Hz, 2H). 13C NMR (100 MHz, DMSO-d6) δ 172.8, 171.1, 171.0, 167.8, 133.7,132.7, 128.6, 125.3, 119.0, 51.5, 46.5, 35.6, 35.1, 32.0, 31.2, 27.2, 24.2,22.6. HRMS (ESI) 预测值:C19H23BrN3O4 +[M+H]+: 436.0866, 实测值:436.0867。
其具体制备步骤如下:
按照化合物8a的制备方法,将7a替换为7j,其余操作相同,得到了目标化合物8j。硅胶柱层析纯化(二氯甲烷:甲醇= 40:1)得到化合物8j(64%),为黄色固体。
其检测结果如下:
IR (KBr): 3421, 1687, 1603, 1525, 1199 cm-1.1H NMR (400 MHz, DMSO-d 6)δ 11.03 (s, 1H), 10.42 (s, 1H), 9.79 (s, 1H), 8.97 (s, 1H), 8.35 – 8.24 (m,2H), 7.89 – 7.67 (m, 5H), 7.56 – 7.45 (m, 4H), 7.43 – 7.35 (m, 2H), 7.22 –7.12 (m, 1H), 5.15 (dd,J= 13.3, 5.1 Hz, 1H), 4.45 – 4.29 (m, 2H), 3.62 (s,4H), 2.92 (ddd,J= 17.3, 13.6, 5.4 Hz, 1H), 2.61 (dt,J= 17.0, 3.5 Hz, 1H),2.51 – 2.50 (m, 1H), 2.35 (tt,J= 13.1, 6.5 Hz, 8H), 2.03 (dtt,J= 14.0, 5.8,3.0 Hz, 1H), 1.63 (p,J= 7.5 Hz, 2H), 1.48 (d,J= 8.9 Hz, 2H), 1.35 (td,J= 8.3,3.8 Hz, 2H).13C NMR (100 MHz, DMSO-d 6) δ 172.8, 171.3, 171.0, 168.7, 167.8,164.5, 154.4, 144.8, 137.9, 137.6, 136.8, 133.8, 133.6, 132.6, 128.6, 127.4,125.6, 125.2, 124.2, 124.1, 121.1, 119.0, 51.5, 46.5, 35.7, 31.2, 26.5, 25.0,22.7. HRMS (ESI) 预测值:C41H43N9NaO6 +[M+Na]+: 780.3229, 实测值: 780.3231。
(11)化合物8k的制备,其制备路线如下:
化合物8k的结构如下:
;其中文名称为:3-氨基-6-(4-(4-(4-(6-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-7-氧代庚基)哌嗪-1-羰基)苯基)-N-苯基吡嗪-2-甲酰胺
化合物7k的中文名称为:5-溴-N-(2-(2,6-二氧哌啶-3-基)- 1-氧异吲哚-4-基)庚胺,化合物7k的合成方法同7g,只需将溴代丙酰氯替换为溴代庚酰氯其余相同,得到化合物7k (67%) 白色固体。
其检测结果如下:
M.p. 275.2-275.9 °C; IR (KBr): 3330, 3095, 2937, 1737, 1689, 1653,1600, 1535, 1464, 1433, 1353, 1239, 1207, 1195, 1157, 849, 747 cm-1 . 1H NMR(400 MHz, DMSO-d6) δ 11.02 (s, 1H), 9.80 (s, 1H), 7.81 (dd,J= 7.0, 2.0 Hz,1H), 7.70 – 7.37 (m, 2H), 5.15 (dd,J= 13.3, 5.1 Hz, 1H), 4.55 – 4.17 (m, 2H),3.54 (t,J= 6.7 Hz, 2H), 3.02 – 2.82 (m, 1H), 2.61 (ddd,J= 17.3, 4.5, 2.3 Hz,1H), 2.36 (q,J= 6.9, 6.3 Hz, 3H), 2.03 (dddd,J= 10.6, 5.5, 3.3, 2.8 Hz, 1H),1.81 (p,J= 6.8 Hz, 2H), 1.62 (p,J= 7.4 Hz, 2H), 1.49 – 1.25 (m, 4H). 13C NMR(100 MHz, DMSO-d6) δ 173.3, 171.8, 171.5, 168.3, 134.2, 133.1, 129.1, 125.8,119.5, 52.0, 47.0, 36.1, 35.6, 32.6, 31.7, 28.2, 27.7, 25.4, 23.1. HRMS (ESI)预测值:C20H25BrN3O4 +[M+H]+: 450.1023, 实测值: 450.1025。
具体制备步骤如下:按照化合物8a所述的方法,得到了目标化合物8k。硅胶柱层析纯化(二氯甲烷:甲醇= 40:1)得到化合物8k(60%, 黄色固体)。
其检测结果如下:
IR (KBr): 3425, 1700, 1605, 1535, 1200 cm-1.1H NMR (400 MHz, DMSO-d 6)δ 11.03 (s, 1H), 10.42 (s, 1H), 9.79 (s, 1H), 8.97 (s, 1H), 8.35 – 8.24 (m,2H), 7.89 – 7.67 (m, 5H), 7.56 – 7.45 (m, 4H), 7.43 – 7.35 (m, 2H), 7.22 –7.12 (m, 1H), 5.15 (dd,J= 13.3, 5.1 Hz, 1H), 4.45 – 4.29 (m, 2H), 3.62 (s,4H), 2.92 (ddd,J= 17.3, 13.6, 5.4 Hz, 1H), 2.61 (dt,J= 17.0, 3.5 Hz, 1H),2.51 – 2.50 (m, 1H), 2.35 (tt,J= 13.1, 6.5 Hz, 8H), 2.03 (dtt,J= 14.0, 5.8,3.0 Hz, 1H), 1.63 (p,J= 7.5 Hz, 2H), 1.48 (d,J= 8.9 Hz, 2H), 1.29-1.35 (m,J=8.3, 3.8 Hz, 4H).13C NMR (100 MHz, DMSO-d 6) δ 172.8, 171.3, 171.0, 168.7,167.8, 164.5, 154.4, 144.8, 137.9, 137.6, 136.8, 133.8, 133.6, 132.6, 128.6,127.4, 125.6, 125.2, 124.2, 124.1, 121.1, 119.0, 51.5, 46.5, 35.7, 31.2,26.5, 26.1, 25.0, 22.7. HRMS (ESI) 预测值:C42H46N9O6 +[M+H]+: 772.8870, 实测值:772.8871。
(12)化合物8l的制备,其制备路线如下:
化合物8l的结构如下:
;其中文名称为:3-氨基-6-(4-(4-(4-(6-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-8-氧代辛基)哌嗪-1-羰基)苯基)-N-苯基吡嗪-2-甲酰胺
化合物7l的中文名称为:5-溴-N-(2-(2,6-二氧哌啶-3-基)-1-氧异吲哚-4-基)辛胺。化合物7l的合成方法同7g,只需将溴代丙酰氯替换为溴代辛酰氯其余相同,得到化合物7l (69%) 白色固体。
其检测结果如下:
M.p. 275.2-275.9 °C; IR (KBr): 3330, 3095, 2937, 1737, 1689, 1653,1600, 1535, 1464, 1433, 1353, 1239, 1207, 1195, 1157, 849, 747 cm-1 . 1H NMR(400 MHz, DMSO-d6) δ 11.02 (s, 1H), 9.80 (s, 1H), 7.81 (dd,J= 7.0, 2.0 Hz,1H), 7.70 – 7.37 (m, 2H), 5.15 (dd,J= 13.3, 5.1 Hz, 1H), 4.55 – 4.17 (m, 2H),3.54 (t,J= 6.7 Hz, 2H), 3.02 – 2.82 (m, 1H), 2.61 (ddd,J= 17.3, 4.5, 2.3 Hz,1H), 2.36 (q,J= 6.9, 6.3 Hz, 3H), 2.03 (dddd,J= 10.6, 5.5, 3.3, 2.8 Hz, 1H),1.81 (p,J= 6.8 Hz, 2H), 1.62 (p,J= 7.4 Hz, 2H), 1.49 – 1.25 (m, 6H). 13C NMR(100 MHz, DMSO-d6) δ 173.3, 171.8, 171.5, 168.3, 134.2, 133.1, 129.1, 125.8,119.5, 52.0, 47.0, 36.1, 35.6, 32.6, 31.7, 28.2, 27.7, 25.4, 23.1. HRMS (ESI)预测值:C20H25BrN3O4 +[M+H]+: 464.1033, 实测值: 464.1035.
具体制备步骤如下:
按照化合物8a的制备方法,将7a替换为7l,其余操作相同,得到了目标化合物8l。硅胶柱层析纯化(二氯甲烷:甲醇= 40:1)得到化合物8l(65%, 黄色固体)。
其检测结果如下:
IR (KBr): 3415, 1680, 1635, 1525, 1205 cm-1.1H NMR (400 MHz, DMSO-d 6)δ 11.03 (s, 1H), 10.42 (s, 1H), 9.79 (s, 1H), 8.97 (s, 1H), 8.35 – 8.24 (m,2H), 7.89 – 7.67 (m, 5H), 7.56 – 7.45 (m, 4H), 7.43 – 7.35 (m, 2H), 7.22 –7.12 (m, 1H), 5.15 (dd,J= 13.3, 5.1 Hz, 1H), 4.45 – 4.29 (m, 2H), 3.62 (s,4H), 2.92 (ddd,J= 17.3, 13.6, 5.4 Hz, 1H), 2.61 (dt,J= 17.0, 3.5 Hz, 1H),2.51 – 2.50 (m, 1H), 2.35 (tt,J= 13.1, 6.5 Hz, 8H), 2.03 (dtt,J= 14.0, 5.8,3.0 Hz, 1H), 1.63 (p,J= 7.5 Hz, 2H), 1.48 (d,J= 8.9 Hz, 2H),1.51 – 1.40 (m,2H), 1.32 (dt,J= 10.0, 5.7 Hz, 4H).13C NMR (100 MHz, DMSO-d 6) δ 172.8, 171.3,171.0, 168.7, 167.8, 164.5, 154.4, 144.8, 137.9, 137.6, 136.8, 133.8, 133.6,132.6, 128.6, 127.4, 125.6, 125.2, 124.2, 124.1, 121.1, 119.0, 51.5, 46.5,35.7, 31.2, 26.5, 26.1, 25.0, 22.7, 22.1 HRMS (ESI) 预测值:C43H48N9O6 +[M+H]+:785.9060, 实测值: 785.9063。
实施例2
化合物的性能试验
通过Western Blot实验对上述PROTAC分子在MV-4-11细胞中进行ATR蛋白的降解能力评价。将不同浓度(0.1 μM和0.5 μM)的PROTAC分子与MV-4-11细胞共同孵育24 h后,检测细胞中ATR蛋白的表达情况,并利用ImageJ软件进行量化,结果如表1所示。可以看到,长度为5或6个碳链的linker构成的PROTAC降解作用较强。
表1. 化合物结构以及降解能力评价
++++:>60;+++:40-60;++:20-40;+:0-20
实施例3
化合物8i不同细胞系的杀伤性评估
进一步的,利用CCK-8方法检测化合物8i 多种类型的不同细胞系的杀伤性评估,检测其抗肿瘤细胞的增殖活性。以ATR激酶抑制剂作为对照,将不同浓度的化合物化合物8i与肿瘤细胞共同孵育以后,测定吸光度值,计算IC50, 结果如表2所示。可以看到化合物对白血病细胞的杀伤作用较为显著,这也表明得到的PROTAC分子是一个高选择性的新型PROTAC分子。
表2. 化合物8i对不同肿瘤细胞的抑制作用
++++:0~5 ;+++:5~10;++:10~20 ;+:20~40.
接下来通过小鼠移植瘤模型评价化合物8i对小鼠体内肿瘤细胞生长的影响。与对照组相比,化合物8i处理后小鼠的生存状态良好,连续给药17天对小鼠体重几乎无影响(图2)。化合物8i能明显抑制肿瘤生长,肿瘤的生长速度低于对照组,肿瘤重量明显降低(图2)。因此,化合物8i能够显著抑制小鼠体内AML细胞的生长,无明显毒副作用。
以上所述,只是本发明的较佳实施例而已,本发明并不局限于上述实施方式,只要其以相同的手段达到本发明的技术效果,都应属于本发明的保护范围。在本发明的保护范围内其技术方案和/或实施方式可以有各种不同的修改和变化。
Claims (10)
1.一种3-氨基吡嗪-2-甲酰胺类靶向蛋白水解嵌合体,其特征在于,其结构式如式I所示:
式I,其中X为CH2,Linker为任一化学上可行的连接结构。
2.根据权利要求1所述的3-氨基吡嗪-2-甲酰胺类靶向蛋白水解嵌合体,其特征在于,Linker为饱和脂肪链、不饱和脂肪链或脂肪酸链。
3.根据权利要求1所述的3-氨基吡嗪-2-甲酰胺类靶向蛋白水解嵌合体,其特征在于,所述3-氨基吡嗪-2-甲酰胺类靶向蛋白水解嵌合体的分子结构如式II所示:
式II,
其中,X为CH2,n取2,3,4,5,6,7中任一正整数。
4.根据权利要求3所述的3-氨基吡嗪-2-甲酰胺类靶向蛋白水解嵌合体,其特征在于,所述3-氨基吡嗪-2-甲酰胺类靶向蛋白水解嵌合体的分子结构如式II所示:
式II,
其中,X为C=O,n取2,3,4,5,6,7中任一正整数。
5.根据权利要求1所述的3-氨基吡嗪-2-甲酰胺类靶向蛋白水解嵌合体,其特征在于,所述3-氨基吡嗪-2-甲酰胺类靶向蛋白水解嵌合体的结构如下所示:
。
6.一种权利要求1-5任一项所述的3-氨基吡嗪-2-甲酰胺类靶向蛋白水解嵌合体的制备方法,其特征在于,其制备路线为如下所示:
。
7.一种权利要求1-5任一项所述的3-氨基吡嗪-2-甲酰胺类靶向蛋白水解嵌合体或其在药学上可接受的盐在制备治疗和/或预防癌药物中的应用。
8.根据权利要求7所述的应用,其特征在于,癌症为急性髓性白血病。
9.一种权利要求1-5任一项所述的3-氨基吡嗪-2-甲酰胺类靶向蛋白水解嵌合体在制备作为靶向ATR降解中的应用。
10.一种药物组合物,其特征在于,以权利要求1-5任一项所述的3-氨基吡嗪-2-甲酰胺类靶向蛋白水解嵌合体或其在药学上可接受的盐为主要活性成分。
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