CN119462648A 四氢吡啶并嘧啶类化合物及其制备方法和应用 （田良良）

四氢吡啶并嘧啶类化合物及其制备方法和氢吡啶并嘧啶类化合物或其药学上可接受的盐述的四氢吡啶并嘧啶类化合物或其药学上可接于制备KRASG12C抑制剂，用于抑制KRAS的G12C2优选为取代或未取代的所述取代基为C1_C4烷基、C1_C4烷氧基；2为氢3为氢4.权利要求1_3任何一项的通式(I)所示的化合物或其药4为取代或未取代的所述取代基为C1_C4烷34为：458.权利要求1_5任何一项的化合物或其药学上可接受的盐或权利要求6所述的药物组合物在制备KRASG12C抑制剂中的9.权利要求1_5任何一项的化合物或其药学上可接受的盐或权利要求6所述的药物组腺癌或结肠癌。6[0001]本发明属于医药技术领域，涉及四氢吡啶并嘧啶类化合具体涉及四氢吡啶并嘧啶类化合物或其药学上可接受的盐及其制备方法和在制备抗肿瘤[0002]RAS是大鼠肉瘤病毒癌基因同源物(ratsarcomaviraloncogenehomolog)的简类产生肉瘤的逆转录病毒分别被命名为Harvey肉瘤病毒(Harveysarcomavirus,Ha_SV)情况下，RAS固有的GTP水解活性和鸟苷酸交换活性均较低，GTPase活化蛋白(GTPase_[0005]KRAS突变在多种癌症中高发，包括结直肠癌(colorectal7[0007]为了克服现有技术的缺陷，本发明提供通式(I)所示的化合物或其药学上可接受[0027]R1为取代或未取代的所述取代基为C1_C4烷基、C1_C4烷氧[0030]R4为取代或未取代的所述取代基为C1_C4烷89[0049]本发明还提供所述四氢吡啶并嘧啶类化合物或其药学上可接受的盐和它们的药物组合物在制备KRASG12C抑制剂[0051]本发明还提供所述四氢吡啶并嘧啶类化合物或其药学上可接受的盐和它们的药和浓缩得粗品，柱层析纯化(DCM/MeOH＝15/1，含1％三乙胺)后得白色固体9.6g，收率啶并[3,4d]嘧啶4基)2(腈甲基)哌嗪1甲酸叔丁酯(4,9.87mmo钠洗、无水硫酸钠干燥和浓缩，所得物经柱层析纯化得类白色固体产物6a～c，收率45~0.82mmol)，200mgPd2(dba)3(0.13mmol)，50mgRuPhos(0.13mmol)，0.63g碳酸铯CNMR556.3036,found:556.3029.158.12,157.02,155.43,146.96,141.51,124.66,123.08,116.82,115.50,112.50,109.29,23.06,19.00.HRMS(ESI)forC31H37N7O3F+[M+H]+calcd:574.294166.19,166.05,162.90,155.27,150.37,146.03,129.86,126.80,124.32,123.42,112.46,23.12,11.85,9.97.HRMS(ESI)forC32H40N7O3+[M+H]+calcd:570.3139.57,134.86,129.34,128.69,125.70,122.15,114.99,111.54,109.98,108.30,68.87,C31H38N7O3+[M+H]+calcd:556.3036,fo47.85,47.41,41.78,29.10,26.21,22.572.2808,found:572.2803.165.66,162.89,150.06,145.32,135.32,131.91,129.85,126.84,122.97,112.27,110.59,12.06,8.19.HRMS(ESI)forC32H40N7O3+[M+H]+calcd:570.1H),1.96_1.69(m,6H).HRMS(ESI)forC32H40N7O2S+[M+H]+calcd:586.2964,found:32H40N7O2S+[M+H]+calcd:586.2964,found:586.3234.C32H40N7O2S+[M+H]+calcd:586.2964,fo(m,1H),1.87_1.60(m,3H).HRMS(ESI)forC32H39FN7O2S+[M+H]+calcd:604.2859,f(ESI)forC32H40N7O2S+[M+H]+calcd:586.2964,fcalcd:572.2808,found:572.3077.forC31H37FN7O2S+[M+H]+calcd:590.2713,(m,1H),1.96_1.77(m,3H).HRMS(ESI)forC33H39FN7O2S+[M+H]+calcd:616.2870,found:616.2855.MF8:calcd:648.2932,found:648.2915.[M+H]+calcd:630.3026,found:630.3012.(ESI)forC33H39FN7O2S+[M+H]found:630.3014..found:612.3106.598.2964,found:598.2951.[0144](7)绘制细胞生长曲线：在GraphPad软件中的GraphPadPrism作图软件中针对抑4.518.660.71Adagrasib5.682.270.9164.037.729.070.685.450.480.972.450.350.423.72物活性优于阳性对照药阿达格拉西布(AdagrasibAdagrasib35.642