CN119528810B - 喹啉类化合物及其应用 - Google Patents
喹啉类化合物及其应用 Download PDFInfo
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- CN119528810B CN119528810B CN202411798985.7A CN202411798985A CN119528810B CN 119528810 B CN119528810 B CN 119528810B CN 202411798985 A CN202411798985 A CN 202411798985A CN 119528810 B CN119528810 B CN 119528810B
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
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Abstract
本发明涉及药物化学领域，具体涉及一类喹啉类化合物或其药学上可接受的盐、其异构体、其溶剂化物、其组合物及其医药用途。药理试验证明，本发明的喹啉类化合物对KRASG12D‑cRaf有较好的亲和作用。在浓度为10 µM时，本发明的化合物C1、C3、C4、C6、C11、C12、C13、C16、C22和C23对KRASG12D‑cRaf具有一定的抑制作用。尤其是化合物C1和C12对KRASG12D‑cRaf均表现出强抑制作用。
Description
技术领域
本发明涉及药物化学领域，具体涉及一类喹啉类化合物或其药学上可接受的盐、其异构体、其溶剂化物、其药物组合物及其医药用途。
背景技术
RAS是突变频率最高的癌基因之一，其在活性（GTP结合）和非活性（GDP结合）状态循环，发挥了分子开关的作用。RAS是小GTP酶的一种，在细胞正常的生长、发育、增殖和凋亡以及运动的细胞信号传导中发挥了重要的作用。RAS活性主要由鸟嘌呤核苷酸交换因子（GEF）加速GDP解离来促进GTP结合，和GTP酶激活蛋白（GAP）刺激GTP水解驱动RAS进行GDP结合所调节。RAS的三种常见基因分别是：KRAS、HRAS和NRAS，其中KRAS突变最常见，主要发生在胰腺癌和肺癌中，在人类癌症中约占85％。
KRAS分子与GTP结合被激活，与GDP结合会失活。多种KRAS突变导致突变体在癌症中的差异分布。KRAS突变使RAS与GTP结合，不断激活下游信号通路，导致肿瘤的发生与进展。改善KRAS驱动的癌症关键是靶向KRAS突变体和效应蛋白之间相互作用的失调。KRAS突变的高发率以及在很多癌症中的重要作用，使其成为有潜力的药物靶点。但是KRAS表面光滑，没有合适抑制剂结合的口袋，并且KRAS与GTP/GDP的结合亲和力达到皮摩尔水平，因此常被认为是“不可成药靶点”，很难发现靶向KRAS蛋白的抑制剂。靶向KRASG12C药物AMG510与MRTX849的上市，打破了KRAS“不可成药”的观念，也同时推动了靶向KRASG12D抑制剂的研究。KRASG12D突变在胰腺导管腺癌和结肠直肠癌中占主导地位，其结构中的小分子结合位点p110是靶向KRAS的潜在变构调节位点，为靶向KRASG12D的小分子药物开发提供了新的策略。
研究人员基于此研究思路发现了新型喹啉类化合物，其对KARSG12D具有较好的选择性及抗肿瘤细胞增殖活性。
发明内容
本发明解决的技术问题是提供一类新型喹啉类化合物及其药学上可接受的盐、其制备方法、药物组合物以及其应用。
为解决本发明的技术问题，本发明提供如下技术方案：
本发明技术方案的第一方面是提供如通式（I）所示化合物或其药学上可接受的盐、其异构体、其溶剂化物：
式（I）
其中，R为：
优选的，所述R为：或。
本发明技术方案的第二方面是提供包含第一方面所述化合物或其药学上可接受的盐、其异构体、其溶剂化物的药物组合物其药学上可接受的盐与一种或多种药用载体和/或稀释剂的药物组合物，为临床上或药学上可接受的任一剂型，优选为口服制剂或注射剂。其中含有生理有效量的通式（I）所示的化合物0.01g～10g，可以为0.01g、0.015g、0.02g、0.025g、0.03g、0.04g、0.05g、0.1g、0.125g、0.2g、0.25g、0.3g、0.4g、0.5g、0.6g、0.75g、1g、1.25g、1.5g、1.75g、2g、2.5g、3g、4g、5g、6g、7g、8g、9g、10g等。
本发明任一化合物或其药学上可接受的盐、其异构体、其溶剂化物，可以口服或肠胃外给药等方式施用于需要这种治疗的患者。
用于肠胃外给药时，可制成注射剂。制成注射剂时，可采用现有制药领域中的常规方法生产，可选用水性溶剂或非水性溶剂。最常用的水性溶剂为注射用水，也可用0.9％氯化钠溶液或其他适宜的水溶液；常用的非水性溶剂为植物油，主要为供注射用大豆油，其他还有乙醇、丙二醇、聚乙二醇等的水溶液。配制注射剂时，可以不加入附加剂，也可根据药物的性质加入适宜的附加剂，如渗透压调节剂、pH值调节剂、增溶剂、填充剂、抗氧剂、抑菌剂、乳化剂、助悬剂等。用于口服时，可制成常规的固体制剂，如片剂、胶囊剂、丸剂、颗粒剂等；也可制成口服液体制剂，如口服溶液剂、口服混悬剂、糖浆剂等。制成口服制剂时，可以加入适宜的填充剂、粘合剂、崩解剂、润滑剂等。
本发明所述的化合物可以添加药学上可接受的载体制成常见的药用制剂，如片剂、胶囊、粉剂、糖浆、液剂、悬浮剂、针剂，可以加入香料、甜味剂、液体或固体填料或稀释剂等常用药用辅料。
本发明的化合物临床所用剂量为0.01-1000mg/天，也可根据病情的轻重或剂型的不同偏离此范围。
本发明技术方案的第三方面是提供包含第一方面所述化合物或其药学上可接受的盐、其异构体、其溶剂化物以及第二方面所述药物组合物在制备用于抑制细胞中的KRASG12D活性的药物中的应用。
本发明技术方案的第三方面是提供包含第一方面所述化合物或其药学上可接受的盐、其异构体、其溶剂化物以及第二方面所述药物组合物在制备用于治疗KRAS G12D相关癌症的药物中的应用。
所述KRASG12D相关癌症选自：血管肉瘤、纤维肉瘤、横纹肌肉瘤、脂肪肉瘤、粘液瘤、横纹肌瘤、纤维瘤、脂肪瘤、畸胎瘤、肺癌、支气管源性癌、肺泡癌、支气管腺瘤、淋巴瘤、食道癌、胃癌、胰腺癌、结肠直肠癌、小肠癌、大肠癌、直肠癌、肾癌、淋巴瘤、白血病、膀胱和尿道癌、前列腺癌、睾丸癌、肝癌、胆管癌、肝母细胞瘤、肝细胞腺瘤、胆囊癌、胆管癌、骨癌、纤维肉瘤、恶性纤维组织细胞瘤、软骨肉瘤、恶性淋巴瘤、多发性骨髓瘤、恶性巨细胞肿瘤脊索瘤、骨软骨瘤、良性软骨瘤、成软骨细胞瘤、软骨粘液样纤维瘤、神经胶质瘤、生殖细胞瘤、多形性胶质母细胞瘤、少突神经胶质瘤、神经鞘瘤、视网膜母细胞瘤、先天性肿瘤、脊髓神经纤维瘤、子宫内膜癌、恶性畸胎瘤、外阴鳞状细胞癌、输卵管癌、骨髓性白血病、急性成淋巴细胞性白血病、慢性成淋巴细胞性白血病、多发性骨髓瘤、恶性黑素瘤、基底细胞癌、鳞状细胞癌、卡波西肉瘤、脂肪瘤、血管瘤、皮肤纤维瘤。
优选的，所述癌症为肺癌、结肠直肠癌或胰腺癌。
更优选的，所述肺癌为非小细胞肺癌、小细胞肺癌。
或者，更优选的，所述癌症为胰腺癌。
或者，更优选的，所述癌症为结肠直肠癌。
有益技术效果：
本发明的优点在于，
（1）在浓度为10 µM时，本发明的化合物C1、C3、C4、C6、C11、C12、C13、C16、C22和C23对KRASG12D-cRaf具有一定的抑制作用。尤其是化合物C1和C12对KRASG12D-cRaf均表现出强抑制作用。
（2）进一步测试了单浓度抑制效果较好的化合物对KRASG12D-cRaf的IC50值。其中，以C1的活性最好，低至2.04 μM。
（3）本发明设计合成的新型喹啉类化合物对肿瘤细胞均具有一定的生长抑制，IC50值基本在10~30μM左右，其中，C12在4种肿瘤细胞中均表现出良好的抗增殖活性，为抗癌药物的开发奠定了基础。
具体实施方式
下面结合具体实施方式来对本发明作更进一步的说明，以便本领域的技术人员更了解本发明，但并不以此限制本发明。
如无特殊说明，本发明实施例中所涉及的试剂均为市售产品，均可以通过商业渠道购买获得。
本发明的通式（I）化合物可用下述方法制备：
R为：
。
将苯胺（1）与丁二酸二甲酯溶解在甲醇中，在避光条件下发生取代反应，以90%的较高收率生成了苯胺二脂类化合物W1，化合物W1在PPA的催化下发生环化反应，以50%的收率生成了喹啉酮类化合物W2，化合物W2在甲醇和乙腈（1:1）的混合溶剂中，经NaBH4还原，生成了关键中间体羟基喹啉类化合物W3，收率为48%的，化合物W3与亲电试剂发生取代反应得到目标化合物CR1。
实施例1 2-（羟甲基）喹啉- 4-氟苯磺酸酯（C1）的合成:
将苯胺（1）（42.7 mL, 469.0 mmoL）溶于甲醇（50 mL）中，加入乙炔二甲酸二甲酯（86.5 mL, 704.0 mmoL），在室温下反应24 h，TLC检测原料消失（展开剂：乙酸乙酯-石油醚= 1:10）。反应液用减压蒸除溶剂，所得粗品经硅胶柱层析分离（流动相：乙酸乙酯-石油醚= 1:10）纯化得黄色油状苯胺喹啉类化合物W1,将2-(苯氨基)马来酸二甲酯的合成（W1）（25g, 2.4 mmoL）加入PPA（100 g），于25oC，反应3 h，TLC检测原料消失（展开剂：乙酸乙酯-石油醚 = 1:1）。有机相依次用冷的饱和碳酸氢钠溶液，冰水水洗，抽滤，然后用乙醚洗去部分杂质，干燥滤饼，所得粗品经硅胶柱层析分离纯化（流动相：乙酸乙酯-石油醚 = 1:1）得白色固体喹啉酮类化合物W2。将4-氧代-1,4-二氢喹啉-2-羧酸甲酯（W2）（1 g, 4.9 mmoL）溶解在MeOH（50 mL），并在0oC条件下加入NaBH4（1g, 24.6 mmoL）, 此反应于25oC，反应4 h。有机相依次用冰饱和氯化铵水溶液淬灭，乙酸乙酯萃取，饱和氯化钠洗，无水硫酸钠干燥，减压蒸除溶剂，所得粗品经硅胶柱层析分离纯化（流动相：甲醇-二氯甲烷 = 1:15）得白色固体羟基喹啉化合物（W3）。将2-（羟甲基）喹啉-4（1H）-酮（W3）（1 mmoL）溶于乙腈（2 mL）中，缓慢加入无水碳酸钾，氮气保护下缓慢加入亲电试剂4-氟苯磺酰氯，加热回流反应12 h。反应液用水淬灭，二氯甲烷萃取，有机相依次用饱和食盐水洗，无水硫酸镁干燥，过滤，减压旋蒸除溶剂，所得粗品经硅胶柱层析分离（流动相：二氯甲烷：甲醇 = 30：1）纯化得目标化合物（C1）。产物为白色粉末状固体, 产率: 67%, m.p: 85-87oC.1H NMR (800 MHz, Methanol-d 4) δ 8.04 (m, 2H), 7.97 (d,J= 8.4 Hz, 1H), 7.86 – 7.82 (m, 1H), 7.78 – 7.73(m, 1H), 7.59 (s, 1H), 7.55 – 7.50 (m, 1H), 7.37 – 7.30 (m, 2H), 4.87 (s,2H). IR (KBr, cm-1): 554.65, 572.88, 691.89, 763.52, 772.76, 779.27, 842.77,874.24, 965.91, 1052.22, 1069.44, 1158.52, 1192.49, 1383.60, 1494.31,1508.26, 1590.12, 1601.07, 3212.10. HRMS (ESI):m/zcalcd for C16H13FNO4S+[M+H]+:334.0549, found: 334.0531.
实施例2-10中化合物的制备方法同实施例1，区别在于使用不同的亲电试剂，具体每个实施例中使用的亲电试剂在相应实施例中有记载：
实施例2 2-（羟甲基）喹啉-4-（三氟甲基）苯磺酸酯（C3）的合成:
所用亲电试剂为4-三氟甲基苯磺酰氯。产物为白色粉末状固体, 产率: 67%,m.p: 117-119oC.1H NMR (800 MHz, DMSO-d6) δ 8.27 (d, J = 8.3 Hz, 1H), 8.11 (d,J = 8.4 Hz, 1H), 7.98 (t, J = 7.7 Hz, 1H), 7.80 (d, J = 8.1 Hz, 2H), 7.70 (d,J = 8.1 Hz, 3H), 6.94 (s, 1H), 4.85 (s, 2H). IR (KBr, cm-1):429.47, 558.83,604.12, 711.75, 731.70, 750.74, 768.97, 790.09, 852.42, 874.18, 888.40,968.26, 1014.66, 1045.56, 1061.88, 1076.63, 1108.38, 1137.47, 1186.60,1321.75, 1375.87, 1392.53, 1409.41, 1506.70, 1606.59, 3259.01. HRMS (ESI):m/ zcalcd for C16H13F3NO4S+[M+H]+: 384.0517, found: 384.0509.
实施例3（4-（异戊氧基）喹啉）甲醇（C4）的合成:
所用亲电试剂为1-溴代异戊烷。产物为白色粉末状固体, 产率: 67%, m.p: 73-74oC;1H NMR (800 MHz, DMSO-d 6) δ 8.12 – 8.08 (m, 1H), 7.87 (d,J= 8.3 Hz, 1H),7.72 – 7.68 (m, 1H), 7.53 – 7.49 (m, 1H), 7.14 (s, 1H), 5.53 (t,J= 5.9 Hz,1H), 4.68 – 4.65 (m, 2H), 4.29 (t,J= 6.5 Hz, 2H), 1.91 (p,J= 13.4, 6.7 Hz,1H), 1.79 (q,J= 6.6 Hz, 2H), 0.99 (d,J= 6.7 Hz, 6H). IR (KBr, cm-1): 770.98,853.06, 986.31, 1078.53, 1111.79, 1134.27, 1156.41, 1322.62, 1363.41,1429.16, 1471.23, 1508.98, 1569.80, 1590.85, 2870.13, 2931.57, 2956.46,3168.20. HRMS (ESI):m/zcalcd for C15H20NO2 +[M+H]+: 246.1494, found: 246.1479.
实施例4 （4-（4,4,4-三氟丁氧基）喹啉）甲醇（C6）的合成:
所用亲电试剂为1-溴-4,4,4-三氟丁烷。产物为白色粉末状固体, 产率: 67%,m.p: 74-76oC.1H NMR (800 MHz, DMSO-d 6) δ 8.17 (d,J= 8.2 Hz, 1H), 7.88 (d,J=8.4 Hz, 1H), 7.74 – 7.70 (m, 1H), 7.52 (t,J= 7.5 Hz, 1H), 7.12 (s, 1H), 5.56(t,J= 5.9 Hz, 1H), 4.69 – 4.65 (m, 2H), 4.33 (t,J= 6.1 Hz, 2H), 2.61 – 2.53(m, 2H), 2.15 – 2.09 (m, 2H). IR (KBr, cm-1): 616.00, 647.77, 765.69, 835.61,852.50, 981.74, 1012.20, 1048.42, 1083.89, 1113.60, 1150.23, 1192.94,1235.78, 1256.67, 1342.68, 1357.10, 1384.41, 1430.47, 1451.35, 1470.44,1513.54, 1574.17, 1599.64, 1620.25, 2924.98, 3133.89, 3404.36. HRMS (ESI):m/ zcalcd for C14H15F3NO2 +[M+H]+: 286.1055, found: 286.1043.
实施例5 （4-（（3,4-二氯苯基）氧基）喹啉）甲醇（C11）的合成:
所用亲电试剂为3,4-二氯氯苄。产物为白色粉末状固体, 产率: 67%, m.p: 120-123oC.1H NMR (400 MHz, DMSO-d 6) δ 8.17 (d,J= 8.2 Hz, 1H), 7.94 – 7.84 (m, 2H),7.78 – 7.70 (m, 2H), 7.63 – 7.50 (m, 2H), 7.24 (s, 1H), 5.59 (t,J= 4.7 Hz,1H), 5.43 (s, 2H), 4.69 (d,J= 4.4 Hz, 2H). IR (KBr, cm-1): 661.51, 757.10,809.39, 977.30, 1030.54, 1078.70, 1113.85, 1133.77, 1157.65, 1235.17,1350.88, 1372.70, 1402.89, 1425.90, 1472.33, 1510.16, 1569.38, 1597.19,1621.51, 2909.49, 3140.71. HRMS (ESI):m/zcalcd for C17H15Cl2NO2 +[M+H]+:334.0402, found: 334.0392.
实施例6（4-（（3,5-双（三氟甲基）苄基）氧基）喹啉）甲醇（C12）的合成:
所用亲电试剂为3,5-双三氟甲基苄基氯。产物为白色粉末状固体, 产率: 67%,m.p: 124-125oC.1H NMR (800 MHz, DMSO-d 6) δ 8.33 (s, 2H), 8.18 – 8.14 (m, 2H),7.91 (d,J= 8.3 Hz, 1H), 7.74 (t,J= 7.6 Hz, 1H), 7.55 (t,J= 7.5 Hz, 1H), 7.29(s, 1H), 5.62 – 5.60 (m, 3H), 4.70 (d,J= 5.8 Hz, 2H). IR (KBr, cm-1): 683.39,703.71, 765.85, 777.88, 843.81, 890.20, 973.19, 1065.40, 1121.13, 1186.71,1204.75, 1237.95, 1280.30, 1349.80, 1370.87, 1430.20, 1468.74, 1512.46,1572.54, 1599.27, 1621.98, 3397.16. HRMS (ESI):m/zcalcd for C19H14F6NO2 +[M+H]+:402.0929, found: 402.0889.
实施例7（4-（（3-氟苄基）氧基）喹啉）甲醇（C13）的合成:
所用亲电试剂为间氟氯苄。产物为白色粉末状固体, 产率: 67%, m.p: 116-118oC.1H NMR (800 MHz, DMSO-d 6) δ 8.25 – 8.21 (m, 1H), 8.09 (d,J= 8.4 Hz, 1H),8.03 (s, 1H), 7.87 – 7.80 (m, 5H), 7.74 (s, 1H), 7.68 – 7.64 (m, 1H), 5.57(s, 2H), 3.93 (t,J= 5.9 Hz, 2H), 3.11 (s, 2H). IR (KBr, cm-1): 681.89, 760.98,788.20, 843.10, 863.29, 924.93, 978.05, 1023.67, 1042.66, 1085.14, 1116.93,1135.19, 1160.32, 1235.29, 1249.42, 1284.32, 1307.79, 1357.59, 1386.67,1424.87, 1458.62, 1492.14, 1509.84, 1572.29, 1597.58, 1619.43, 2851.69,2923.79, 3195.16. HRMS (ESI):m/zcalcd for C17H15FNO2 +[M+H]+: 284.1087, found:284.1063.
实施例8 2-（羟甲基）喹啉- 3,4,5-三氟苯磺酸酯（C16）的合成:
所用亲电试剂为3,4,5-三氟苯磺酰氯。产物为白色粉末状固体, 产率: 67%,m.p: 106-108oC.1H NMR (800 MHz, DMSO-d 6) δ 8.30 – 8.26 (m, 1H), 8.13 (d,J= 8.5Hz, 1H), 8.01 – 7.97 (m, 1H), 7.71 (t,J= 7.6 Hz, 1H), 7.42 – 7.36 (m, 2H),6.98 (s, 1H), 4.87 (s, 2H). IR (KBr, cm-1): 592.44, 619.10, 683.69, 761.96,774.53, 792.64, 865.18, 880.36, 922.29, 964.71, 1039.86, 1053.90, 1080.35,1178.93, 1327.89, 1351.83, 1370.69, 1420.99, 1441.22, 1506.77, 1524.45,1563.03, 1604.66, 1625.45, 3202.03. HRMS (ESI):m/zcalcd for C16H11F3NO4S+[M+H]+:370.0361, found: 370.0334.
实施例9 2-（羟甲基）喹啉-4-氰基苯磺酸酯（C22）的合成:
所用亲电试剂为4-氰基苯磺酰氯。产物为白色粉末状固体, 产率: 57%, m.p:128-130oC.1H NMR (800 MHz, DMSO-d 6) δ 8.30 (d,J= 8.3 Hz, 1H), 8.18 (d,J= 8.5Hz, 1H), 8.05 – 8.01 (m, 1H), 7.81 (d,J= 8.4 Hz, 2H), 7.75 (d,J= 8.3 Hz, 3H),7.09 – 7.06 (m, 1H), 4.90 (s, 2H). IR (KBr, cm-1): 517.32, 569.63, 635.71,678.39, 755.44, 773.52, 790.25, 812.11, 843.99, 873.45, 889.60, 958.22,966.32, 1016.10, 1035.75, 1068.12, 1090.28, 1147.07, 1180.55, 1190.72,1292.37, 1322.56, 1381.38, 1500.81, 1602.61, 2242.19, 2922.21, 3084.90,3105.65, 3525.70. HRMS (ESI):m/zcalcd for C17H13N2O4S+[M+H]+: 341.0596, found:341.0573.
实施例10 2-（羟甲基）喹啉-4-溴苯磺酸酯（C23）的合成:
所用亲电试剂为4-溴苯磺酰氯。产物为白色粉末状固体, 产率: 73%, m.p: 118-120oC.1H NMR (800 MHz, DMSO-d 6) δ 8.28 (d,J= 8.2 Hz, 1H), 8.16 – 8.12 (m, 1H),7.99 (dd,J= 14.9, 7.9 Hz, 1H), 7.73 – 7.69 (m, 1H), 7.54 (d,J= 8.4 Hz, 2H),7.53 – 7.49 (m, 2H), 6.99 (s, 1H), 4.87 (d,J= 8.0 Hz, 2H). IR (KBr, cm-1):421.72, 533.29, 563.42, 575.37, 604.69, 699.82, 735.05, 760.52, 775.46,828.73, 870.74, 890.78, 967.24, 1010.12, 1022.85, 1048.76, 1153.13, 1176.33,1191.10, 1335.23, 1384.98, 1410.77, 1469.18, 1503.48, 1560.86, 1570.39,1604.60, 1620.46, 2935.93, 3094.62, 3281.08. HRMS (ESI):m/zcalcd forC16H13BrNO4S+[M+H]+: 393.9749, found: 393.9728.
本发明化合物的部分生物活性测试及结果如下：
实验例1：本发明化合物对KRASG12D-cRaf亲和性评价
1.1. 实验方法：
将 0.1 μL 化合物溶液转移到 384 孔板中，测试化合物初始浓度为 1μM，3倍梯度稀释，10个浓度。每孔加入 2.5 μL KRASG12D，1000rpm离心1min，每孔加入2.5 μL cRAF，1000rpm离心1min，25℃孵育15 min。向 384孔板中加入5μL SA-Tb&GST-XL665，1000rpm离心1min，25℃孵育60 min。使用BMG酶标仪读取HTRF信号（665/620 nm）。通过GraphPadPrism软件计算抑制率或IC50值。
1.2. 实验结果
1、单浓度抑制率结果
表1目标化合物对KRASG12D-cRaf亲和性（10 μM）
初步的筛选结果表明，在浓度为10 µM时，本发明的化合物C1、C3、C4、C6、C11、C12、C13、C16、C22和C23对KRASG12D-cRaf具有一定的抑制作用。尤其是化合物C1和C12对KRASG12D-cRaf均表现出强抑制作用。
2、CR系列化合物对KRASG12D-cRaf的IC50值
表2CR系列化合物对KRASG12D-cRaf的IC50值
进一步测试了单浓度抑制效果较好的化合物对KRASG12D-cRaf的IC50值。其中，以C1的活性最好，低至2.04 μM。
实验例2：目标化合物对肿瘤细胞生长抑制作用测定
2.1MTT实验方法
将本发明系列化合物用二甲基亚砜溶解后，用含10%胎牛血清的RPMI-1640培养基配置为1 mg/mL备用，当进行分组给药时，用该培养基进行一定倍数稀释至所需浓度。
NCIH-1385细胞使用含10% 胎牛血清的RPMI-1640培养基培养，每隔2-3 d传代1次。细胞培养箱设置条件为：CO2浓度：5%，温度：37oC，取对数生长期的细胞用于实验。
PANC-1细胞使用含10%胎牛血清的高糖DMEM培养基培养，每隔2-3 d传代1次。细胞培养箱设置条件为：CO2浓度：5%，温度：37oC，取对数生长期的细胞用于实验。
AsPc-1细胞使用含10%胎牛血清的高糖DMEM培养基培养，每隔2-3 d传代1次。细胞培养箱设置条件为：CO2浓度：5%，温度：37oC，取对数生长期的细胞用于实验。
LOVO细胞使用含10%胎牛血清的RPMI-1640培养基培养，每隔2-3 d传代1次。细胞培养箱设置条件为：CO2浓度：5%，温度：37oC，取对数生长期的细胞用于实验。
NCIH-1385细胞、PANC-1细胞、AsPc-1细胞、LOVO细胞（8 × 103个/孔/100 μL）接种于96孔培养板中，孵卵24小时后，加待测量的物质，并继续孵育48小时。将细胞上清吸去后，每孔内加100 μL的含有最终浓为0.5 mg/mL的MTT水溶液，将培养板置于培养箱中继续孵卵4h, 将细胞上清除去后，再加100 μL DMSO，将培养板摇匀后，用酶标仪测出在490 nm处的吸光值(OD)。细胞活性%=给药组OD值/空白组OD值*100%。
2.2测定结果
表3优选化合物抗肿瘤细胞增殖的IC50
注：CDDP为阳性对照药顺铂。
本发明设计合成的新型喹啉类化合物对肿瘤细胞均具有一定的生长抑制，IC50值基本在10~30μM左右，其中，C12在4种肿瘤细胞中均表现出良好的抗增殖活性，为抗癌药物的开发奠定了基础。
Claims (10)
1.通式（I）所示化合物或其药学上可接受的盐,
式（I）
其中，R为：
、、、、、、、
。
2.根据权利要求1所述的化合物或其药学上可接受的盐，其特征在于，所述R为：
或。
3.一种药物组合物，所述药物组合物包含权利要求1-2任一项的所述的化合物或其药学上可接受的盐，以及药学上可接受的载体。
4.权利要求1-2任一项的所述的化合物或其药学上可接受的盐或权利要求3所述的药物组合物在制备用于抑制细胞中的KRASG12D活性的药物中的应用。
5.权利要求1-2任一项的所述的化合物或其药学上可接受的盐或权利要求3所述的药物组合物在制备用于KRASG12D相关癌症的药物中的应用。
6.根据权利要求5所述的应用，其特征在于，所述KRASG12D相关癌症选自：血管肉瘤、横纹肌肉瘤、粘液瘤、横纹肌瘤、纤维瘤、畸胎瘤、肺癌、支气管源性癌、支气管腺瘤、食道癌、胃癌、胰腺癌、结肠直肠癌、小肠癌、大肠癌、直肠癌、肾癌、白血病、膀胱和尿道癌、前列腺癌、睾丸癌、肝癌、胆囊癌、骨癌、恶性纤维组织细胞瘤、软骨肉瘤、恶性淋巴瘤、恶性巨细胞肿瘤脊索瘤、骨软骨瘤、良性软骨瘤、成软骨细胞瘤、软骨粘液样纤维瘤、神经胶质瘤、生殖细胞瘤、多形性胶质母细胞瘤、少突神经胶质瘤、神经鞘瘤、视网膜母细胞瘤、先天性肿瘤、脊髓神经纤维瘤、子宫内膜癌、恶性畸胎瘤、外阴鳞状细胞癌、输卵管癌、恶性黑素瘤、基底细胞癌、鳞状细胞癌、卡波西肉瘤、脂肪瘤、血管瘤。
7.根据权利要求6所述的应用，其特征在于，所述癌症为肺癌、结肠直肠癌或胰腺癌。
8.根据权利要求7所述的应用，其特征在于，所述肺癌为非小细胞肺癌、小细胞肺癌。
9.根据权利要求7所述的应用，其特征在于，所述癌症为胰腺癌。
10.根据权利要求7所述的应用，其特征在于，所述癌症为结肠直肠癌。
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