Methyl 1H-indazole-7-carboxylate(3) was obtained by two-step reaction from methyl 2-ni-tro-3-methylbenzoate.3-Halogenated-3(4b~4d) were prepared by halogenation of 3 with POCl3 , Br2 or I2, respectively.3-Fluoro(cyano)-3(4a, 4e) were prepared by fluorination or cyanation of 4d with selectflor or Zn(CN)2.3-Methyl(phenyl)-3(5a, 5b) were obtained by Suzuki coupling of 4d with methylboronic acid or phenylboronic acid catalyzed by Pd(PPh3)4.Indazole derivatives(6a ~6n) were synthesized by N-alkylation of 3, 4a~4c, 4e and 5.Fourteen novel indazole derivatives(7a~7n) were synthesized by aminolysis and deprotection from 6a~6n.The structures were characterized by 1 H NMR and ESI-MS.The results of biological evaluation indicated that seven target molecules dis-played inhibitory activities against PARP-1 with IC50 less than 30 nmol· L-1 .Moreover, the indazoles bearing pyrrolidinyl at 2-position and hydrogen ( 7 e ) or fluorin ( 7 f ) at 3-position displayed inhibitory activities against PARP-1 with IC50 of 4.2 nmol· L-1 and 4.6 nmol· L-1 , respectively.%以3-甲基-2-硝基苯甲酸甲酯为起始原料,经两步反应制得中间体1H-吲唑-7-甲酸甲酯(3);3分别与三氯氧磷、液溴和碘单质反应制得3的3-位卤代产物(4b~4d);4d与氟试剂或氰化锌反应制得3-氟(氰基)-3(4a和4e);4d与苯硼酸或甲基硼酸在四三苯基磷钯催化下反应制得3-甲基(苯基)-3(5a和5b);以氢化钠为碱,3,4a~4c,4e,5分别与4-甲烷磺酰氧基哌啶或3-甲烷磺酰氧基四氢吡咯经缩合反应制得3的2,3-位取代产物(6a~6n);6a~6n在甲醇中氨解,随后采用氯化氢气体脱去Boc保护基合成了14个新型吲唑类PARP-1抑制剂(7a~7n),其结构经1H NMR和ESI-MS表征.生物活性评价结果显示,有7个目标化合物对PARP-1酶活性抑制IC50低于30 nmol·L-1,其中2-(四氢吡咯-4-基)-2H-吲唑-7-甲酰胺(7e)和3-氟-2-(四氢吡咯-4-基)-2H-吲唑-7-甲酰胺(7f)的IC50分别为4.2 nmol·L-1和4.6 nmol·L-1.
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