CN105061462B - 含有酰胺的四氢苯并[4,5]噻吩并[2,3‑d]嘧啶类化合物及其应用 - Google Patents
含有酰胺的四氢苯并[4,5]噻吩并[2,3‑d]嘧啶类化合物及其应用 Download PDFInfo
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- CN105061462B CN105061462B CN201510516034.0A CN201510516034A CN105061462B CN 105061462 B CN105061462 B CN 105061462B CN 201510516034 A CN201510516034 A CN 201510516034A CN 105061462 B CN105061462 B CN 105061462B
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- Prior art keywords
- thieno
- methoxv
- phenylsulfanvl
- tetrahydro benzos
- formoxyl
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Landscapes
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- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
本发明属于医药技术领域，涉及含有酰胺的四氢苯并[4,5]噻吩并[2,3‑d]嘧啶类化合物及其作为表皮生长因子受体酪氨酸激酶抑制剂应用，及其制备方法。含有酰胺的四氢苯并[4,5]噻吩并[2,3‑d]嘧啶类化合物和药学上可接受的盐，及其药学上配伍可接受的载体或稀释剂作为表皮生长因子受体酪氨酸激酶抑制剂。其结构通式如下所示：R1、R2分别独立地选自氢、C1‑C4烷基、卤素取代或未取代的苯基、或R1、R2与它们相连的氮原子一起组成吡咯烷基，哌啶基，吗啉基。本发明的这类化合物的合成方法简便，适于工业化生产，生物活性测试显示此类化合物具有抑制表皮生长因子作用,是一种具有抗肿瘤作用的表皮生长因子受体酪氨酸激酶抑制剂。
Description
技术领域
本发明属于医药技术领域，涉及含有酰胺的四氢苯并[4,5]噻吩并[2,3-d]嘧啶类化合物及其作为表皮生长因子受体酪氨酸激酶抑制剂应用，及其制备方法。
背景技术
根据癌细胞的分化程度和形态特征，肺癌可分为非小细胞肺癌和小细胞肺癌。研究发现，肺癌患者中存在着大量的表皮生长因子信号转导的失调和表皮生长因子受体酪氨酸激酶的过度表达。
表皮生长因子受体(EGFR)是具有膜外配体受体结合域和细胞内酪氨酸激酶活性域的一种跨膜蛋白。EGFR有4种类型HER-1、HER-2、HER-3和HER-4，当小分子配体与EGFR结合，使EGFR活化，进而EGFR的酪氨酸激酶区激活，识别蛋白的底物酶,就会将信号传入细胞内，同时EGFR活化后还可激活许多下游信号分子的磷酸化，启动信号转导通路，最终影响细胞存活和细胞增殖。由于受体型酪氨酸激酶主要差异为胞外配体结合区，而胞内的酪氨酸激酶结构域具有较高的同源性，本发明旨在合成胞外配体结合区结合良好的小分子配体，从而抑制胞内酪氨酸激酶活性区，抑制酶的催化活性和酪氨酸自磷酸化，进而抑制细胞周期进程、血管生成和肿瘤的转移等。
现有的表皮生长因子受体酪氨酸激酶抑制剂，如吉非替尼、厄洛替尼、拉帕替尼等，均存在着腹泻、皮疹、瘙痒等皮肤反应，及可能的头痛、心脏QT间期延长和生物利用度降低等。
本发明所述化合物作为全新结构类型的表皮生长因子受体酪氨酸激酶抑制剂，具有结构类型新颖，药效作用明显的特点。可用于治疗或预防与表皮生长因子受体信号转导失调引起的相关疾病如小细胞肺癌，鳞癌，腺癌，大细胞癌，结肠直肠癌、乳腺癌，卵巢癌，肾细胞癌，支气管哮喘，具有良好的应用价值和开发应用前景。
发明内容
本发明所解决的技术问题是提供一种如式I所示的化合物、其前体药物和药物活性代谢物以及其药学上可接受的盐，并提供了其在制备预防和治疗EGFR信号转导失调相关的疾病的药物中的应用。
其中
R1、R2分别独立地选自氢、C1-C4烷基、卤素取代或未取代的苯基、或R1、R2与它们相连的氮原子一起组成吡咯烷基，哌啶基，吗啉基。
优选地，
R1、R2分别独立地选自氢、乙基、苯基、4-氟苯基、4-氯苯基、4-溴苯基，或R1、R2与它们相连的氮原子一起组成吡咯烷基，哌啶基，吗啉基。
“药物可接受的盐”指保留了式I化合物的生物效力和性质，并与合适的非毒性有机或无机酸或有机或无机碱形成的常规酸加成盐或碱加成盐。酸加成盐的实例包括醋酸盐，己二酸盐，藻酸盐，天冬氨酸盐，苯甲酸盐，苯磺酸盐，硫酸氢盐，丁酸盐，柠檬酸盐，樟脑酸盐，樟脑磺酸盐，环戊丙酸盐，二葡萄糖酸盐，十二烷基硫酸盐，乙磺酸盐，富马酸盐，葡庚糖酸盐，甘油磷酸盐，半硫酸盐，庚酸盐，己酸盐，氢氯酸盐，氢溴酸盐，氢碘酸盐，2-羟基乙磺酸盐，乳酸盐，马来酸盐，甲磺酸盐，2-萘磺酸盐，烟酸盐，硝酸盐，草酸盐，扑酸盐，果胶酯酸盐，过硫酸盐，3-苯基丙酸盐，苦味酸盐，新戊酸盐，丙酸盐，琥珀酸盐，硫酸盐，酒石酸盐，硫氰酸盐，甲苯磺酸盐和十一酸盐。碱盐包括铵盐，碱金属盐，例如钠和钾盐，碱土金属盐，例如钙和镁盐，有机碱的盐，例如二环己胺盐，N-甲基-D-葡糖胺盐，和氨基酸的盐，例如精氨酸，赖氨酸等，而且，碱性含氮基团可以用这样的试剂季铵化，例如低级烷基卤化物，如甲基，乙基，丙基和丁基的氯，溴和碘化物；硫酸二烷基酯，如硫酸二甲酯，二乙酯，二丁酯和二戊酯；长链卤化物，如癸基，月桂基，肉豆蔻基和硬脂酰基的氯，溴和碘化物；芳烷基卤化物，如苄基和苯乙基的溴化物等。优选用于生成酸加成盐的酸包括盐酸和醋酸。
“药学上可接受的”如药学上可接受地载体、赋形剂、前体药物等，指药理学上可接受的、并对给药具体化合物的患者基本上无毒性。
“药学活性代谢物”指药学上可接受并有效的式I化合物的代谢产物。
本发明也涉及抑制表皮生长因子受体酪氨酸激酶的药用组合物，该组合物含有式I化合物或衍生物或其药学上适用的酸加成盐以及药学上适用的载体。
本发明化合物可以通过不同的方法给患者服用，例如以胶囊剂或片剂口服，以无菌溶液剂或混悬剂给药，并且在某些情况下，可以以溶液剂形式静脉注射。可以将本发明的游离碱化合物以其药学上适用的酸加成盐形式进行配制和服用。
具体实施方式
反应流程1概括了制备本发明化合物的合成步骤。
反应流程1
以下述实例详细叙述本发明。但是，应当明确，本发明不限于具体叙述的下述实例。
实施例1：4-[2-(4-吗啉基)甲酰基甲氧基苯硫基]-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号01)的制备
步骤A：2-氨基-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺的制备
在250mL三颈瓶中依次加入氰乙酰胺10.1g(120mmol)，单质硫3.8g(120mmol)，环己酮11.8g(120mmol)和无水乙醇38mL，将二乙胺8.8g(120mmol)缓慢滴加至上述混合液，控制温度40～50℃，搅拌反应5h，冷却析晶，抽滤，得棕黄色固体用少量无水乙醇洗2次，自然风干，得黄色固体粉末11.7g，收率49.6％，m.p.:186-188℃。
步骤B：5,6,7,8-四氢苯并噻吩并[2,3-d]嘧啶-4(3H)-酮的制备
将2-氨基-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺11.6g(59.2mmol)和甲酰胺(46.4g，1031mmol)投入250mL茄形瓶中，加热至165℃搅拌回流6h，反应结束后加入异丙醇110mL，搅拌后抽滤，再用异丙醇，水洗各1次，自然风干，得棕黄色固体粉末9.7g，收率80.0％，m.p.:255-257℃。
步骤C：4-氯-5,6,7,8-四氢-1-苯并噻吩并[2,3-d]嘧啶的制备
将5,6,7,8-四氢苯并噻吩并[2,3-d]嘧啶-4(3H)-酮8.7g(42.0mmol)和三氯氧磷70.9g(467.1mmol)投入250mL茄形瓶，加热回流2h，柱层析(石油醚：乙酸乙酯＝2:1)，得黄色固体6.7g，收率70.5％，m.p.:97-99℃。
步骤D：4-(2-甲氧基苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶的制备
将4-氯-5,6,7,8-四氢-1-苯并噻吩并[2,3-d]嘧啶5.0g(22.3mmol)分别与2-甲氧基苯硫酚3.4g(24.5mmol)投入250mL茄形瓶，加入正丁醇64mL，加入三乙胺6.8g(66.9mmol)，加热回流反应1h，冷却析出晶体，抽滤，用水10mL和乙醇10mL各洗涤1次，自然风干后得到黄色结晶粉末6.9g，收率94.5％。m.p.:160-162℃；IR:(KBr,cm-1):2936(s),1643(m),1584(s),1496(s),1415(s),1168(s),1129(s),832(s)；1H-NMR(600MHz,CDCl3):1.92-1.96(m,4H,2×CH2),2.87(s,2H,CH2),3.24(s,2H,CH2),3.79(s,3H,OCH3),7.01-7.07(m,2H,Ar-H),7.49(t,1H,Ar-H,J＝7.9Hz),7.55(dd,1H,Ar-H,J1＝7.5,J2＝1.6Hz),δ8.49(s,1H,Ar-H)；ESI-MS(m/z):329.3([M+H]+)。
步骤E：4-(2-羟基苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶的制备
将4-(2-甲氧基苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶3.3g(9.9mmol)和无水三氯化铝4.0g(29.8mmol)投入250mL茄形瓶，加入甲苯70mL，加热回流搅拌，反应1h后，停止反应，向反应体系中加入水100mL，室温下搅拌3h，抽滤，自然风干，产物经柱层析(甲醇：二氯甲烷＝1:100)得到类白色结晶粉末1.8g，收率58.3％。m.p.:175-176℃；IR:(KBr,cm-1):3421(m),2932(m),1632(m),1596(m),1473(s),1409(s),1384(s),1142(s),830(m)；1H-NMR(400MHz,CDCl3):1.95-1.99(m,4H,CH2),2.90(s,2H,CH2),3.23(s,2H,CH2),6.94(t,J＝8.2Hz,1H),7.17(dd,J1＝8.1,J2＝1.0Hz,1H),7.42(t,J＝7.7Hz,1H),7.49(dd,J1＝7.8,J2＝1.4Hz,1H),δ8.61(s,1H)；ESI-MS(m/z):315.3([M+H]+)。
步骤F：4-[2-(4-吗啉基)甲酰基甲氧基苯硫基]-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号01)的制备
将4-(2-羟基苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶0.5g(1.6mmol)，无水碳酸钾2.2g(15.9mmol)，碘化钾0.1g(0.8mmol)，丙酮50mL和4-氯乙酰基吗啉0.3g(1.8mmol)依次投入100mL茄型瓶中，加热回流搅拌12h，反应完毕后减压蒸除溶剂，然后向剩余物中加入二氯甲烷50mL和水50mL萃取，有机相用100mL饱和NaCl水溶液洗涤1次，收集有机相并用无水硫酸镁干燥30min，过滤，柱层析(甲醇：二氯甲烷＝1:50)分离得到黄色固体0.6g，收率78.6％。m.p.:164-165℃；IR:(KBr,cm-1)3441(m),2943(s),1643(s),1626(s),1557(s),1504(s),1471(s),1436(s),1305(s),1198(s),1115(s),1070(s),977(s),777(s)；1H-NMR(400MHz,CDCl3):δ1.94-1.95(m,4H,2×CH2),2.90(m,2H,CH2),3.13(m,2H,CH2),3.32(t,2H,CH2-N),3.50(t,2H,CH2-N),3.54-3.57(m,2H,CH2-O),3.60-3.62(m,2H,CH2-O),3.65(s,2H,CH2-O),7.20(dd,1H,Ar-H,J1＝8.0Hz,J2＝1.2Hz),7.28-7.32(m,1H,Ar-H),7.35-7.40(m,1H,Ar-H),(dd,1H,Ar-H,J1＝8.0Hz,J2＝1.2Hz),8.45(s,1H,Ar-H)；ESI-MS(m/z):442.4([M+H]+)。
实施例2：4-[2-(1-哌啶基)甲酰基甲氧基苯硫基]-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号02)的制备
参照实例1的方法，制得4-[2-(1-哌啶基)甲酰基甲氧基苯硫基]-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶0.5g，收率85.7％。m.p.:127-129℃；IR:(KBr,cm-1)3426(m),2939(s),2856(s),1642(s),1624(s),1556(s),1506(s),1471(s),1390(s),1309(s),1193(s),1138(s),1070(s),978(s),774(s)；1H-NMR(400MHz,CDCl3):δ1.40-1.52(m,4H,2×CH2),1.55-1.60(m,2H,CH2),1.92-1.97(m,4H,2×CH2),2.89(m,2H,CH2),3.14(m,2H,CH2),3.25(t,2H,CH2-N),3.49(t,2H,CH2-N),3.68(s,2H,CH2-O),7.19(dd,1H,Ar-H,J1＝7.6Hz,J2＝1.6Hz),7.27-7.37(m,2H,Ar-H),7.64(dd,1H,Ar-H,J1＝7.6Hz,J2＝1.6Hz),8.45(s,1H,Ar-H)；ESI-MS(m/z):440.2([M+H]+)。
实施例3：4-(2-二乙胺基甲酰基甲氧基苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号03)的制备
参照实例1的方法，制得4-(2-二乙胺基甲酰基甲氧基苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号03)0.4g，收率72.2％。m.p.:117-119℃；IR:(KBr,cm-1)3428(m),2936(s),1649(s),1559(s),1503(s),1466(s),1390(s),1309(s),1193(s),1136(s),1069(s),974(s),781(s)；1H-NMR(400MHz,CDCl3):δ1.06-1.10(m,6H,2×CH3),1.91-1.96(m,4H,2×CH2),2.88-2.91(m,2H,CH2),3.12-3.15(m,2H,CH2),3.18-3.24(m,2H,CH2-N),3.31-3.36(m,2H,CH2-N),3.66(s,2H,CH2-O),7.19(dd,1H,Ar-H,J1＝8.0Hz,J2＝1.6Hz),7.26-7.30(m,1H,Ar-H),7.33-7.37(m,1H,Ar-H),7.62(dd,1H,Ar-H,J1＝8.0Hz,J2＝1.6Hz),8.45(s,1H,Ar-H)；ESI-MS(m/z):428.2([M+H]+)。
实施例4：4-[2-(1-吡咯烷基)甲酰基甲氧基苯硫基]-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号04)的制备
参照实例1的方法，制得4-[2-(1-吡咯烷基)甲酰基甲氧基苯硫基]-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号04)0.6g，收率80.9％。m.p.:146-147℃；IR:(KBr,cm-1)3432(m),2937(s),2878(m),1646(s),1628(s),1557(s),1506(s),1471(s),1435(s),1391(s),1307(s),1194(s),1070(s),977(s),776(s)；1H-NMR(400MHz,CDCl3):δ1.77-1.88(m,4H,2×CH2),1.91-1.99(m,4H,2×CH2),2.89(m,2H,CH2),3.13(m,2H,CH2),3.32(t,2H,CH2-N),3.43(t,2H,CH2-N),3.60(s,2H,CH2-O),7.19(dd,1H,Ar-H,J1＝7.6Hz,J2＝1.6Hz),7.27-7.36(m,2H,Ar-H),7.66(dd,1H,Ar-H,J1＝7.6Hz,J2＝1.6Hz),8.45(s,1H,Ar-H)；ESI-MS(m/z):426.0([M+H]+)。
实施例5：4-(2-苯胺基甲酰基甲氧基苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号05)的制备
参照实例1的方法，制得4-(2-苯胺基甲酰基甲氧基苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号05)0.3g，收率57.9％。m.p.:187-189℃；IR:(KBr,cm-1)3440(m),3256(d),2936(d),1659(s),1604(s),1552(s),1502(s),1470(s),1390(s),1334(s),1306(s),1194(s),1067(s),974(s),767(m)；1H-NMR(400MHz,CDCl3):δ1.92-1.96(m,4H,2×CH2),2.88-2.90(m,2H,CH2),3.12-3.14(m,2H,CH2),3.69(s,2H,CH2-O),7.08-7.12(m,1H,Ar-H),7.20(dd,1H,Ar-H,J1＝8.0Hz,J2＝1.2Hz),7.25-7.38(m,6H,Ar-H),7.46(dd,1H,Ar-H,J1＝8.0Hz,J2＝1.2Hz),8.37(s,1H,Ar-H),8.53(s,1H,NH)；ESI-MS(m/z):448.1([M+H]+)。
实施例6：4-[2-(4-氟苯胺基)甲酰基甲氧基苯硫基]-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号06)的制备
参照实例1的方法，制得4-[2-(4-氟苯胺基)甲酰基甲氧基苯硫基]-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号06)0.2g，收率39.0％。m.p.:122-124℃；IR:(KBr,cm-1)3275(m),2934(s),1670(s),1556(s),1508(s),1469(s),1436(s),1390(s),1305(s),1197(s),1067(s),974(s),835(s),777(s)；1H-NMR(400MHz,CDCl3):δ1.92-1.96(m,4H,2×CH2),2.89(m,2H,CH2),3.12(m,2H,CH2),3.69(s,2H,CH2-O),6.96(t,2H,Ar-H),7.19-7.29(m,4H,Ar-H),7.34-7.39(m,1H,Ar-H),7.45(dd,1H,Ar-H,J1＝8.0Hz,J2＝1.6Hz),8.32(s,1H,Ar-H),8.56(s,1H,NH)；ESI-MS(m/z):488.1([M+H]+)。
实施例7：4-[3-(4-吗啉基)甲酰基甲氧基苯硫基]-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号07)的制备
参照实例1的方法，制得4-[3-(4-吗啉基)甲酰基甲氧基苯硫基]-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号07)0.5g，收率87.5％。m.p.:117-119℃；IR:(KBr,cm-1)3444(m),2929(s),2857(s),1679(s),1659(s),1591(s),1496(s),1468(s),1416(s),1382(s),1219(s),1112(s),1031(s),831(s),773(s),684(s)；1H-NMR(400MHz,CDCl3):δ1.92-1.96(m,4H,2×CH2),2.87-2.89(m,2H,CH2),3.17-3.19(m,2H,CH2),3.60-3.68(m,8H,2×CH2-N,2×CH2-O),4.72(s,2H,CH2-O),7.06(dd,1H,Ar-H,J1＝7.6Hz,J2＝2.8Hz),7.18(t,1H,Ar-H),7.23(d,1H,Ar-H,J＝8.0Hz),7.39(t,1H,Ar-H),8.53(s,1H,Ar-H)；ESI-MS(m/z):441.9([M+H]+)。
实施例8：4-[3-(1-吡咯烷基)甲酰基甲氧基苯硫基]-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号08)的制备
参照实例1的方法，制得4-[3-(1-吡咯烷基)甲酰基甲氧基苯硫基]-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号08)0.2g，收率30.9％。m.p.:103-105℃；IR:(KBr,cm-1)3422(m),2932(m),2867(s),1678(s),1574(s),1493(s),1407(s),1352(s),1281(s),1227(s),1092(s),829(s),789(s),689(s)；1H-NMR(400MHz,CDCl3):δ1.83-2.00(m,8H,4×CH2),2.88(m,2H,CH2),3.18(m,2H,CH2),3.53(t,4H,CH2-N),4.64(s,2H,CH2-O),7.06(dd,1H,Ar-H,J1＝8.4Hz,J2＝2.0Hz),7.20(t,2H,Ar-H),7.38(t,1H,Ar-H),8.54(s,1H,Ar-H)；ESI-MS(m/z):426.1([M+H]+)。
实施例9：4-(3-苯胺基甲酰基甲氧基苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号09)的制备
参照实例1的方法，制得4-(3-苯胺基甲酰基甲氧基苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号09)0.1g，收率18.3％。m.p.:123-125℃；IR:(KBr,cm-1)3375(s),2929(s),2855(s),1685(s),1603(s),1544(s),1493(s),1444(s),1407(s),1319(s),1226(s),1129(s),832(s),764(s),689(s)；1H-NMR(400MHz,CDCl3):δ1.94-1.96(m,4H,2×CH2),2.88-2.90(m,2H,CH2),3.17-3.19(m,2H,CH2),4.65(s,2H,CH2-O),7.10(dd,1H,Ar-H,J1＝8.4Hz,J2＝2.0Hz),7.16(t,1H,Ar-H),7.28(t,1H,Ar-H),7.36(t,3H,Ar-H),7.44(t,1H,Ar-H),7.58(d,2H,J＝7.6Hz),8.25(s,1H,NH),8.49(s,1H,Ar-H)；ESI-MS(m/z):448.3([M+H]+)。
实施例10：4-[3-(4-氟苯胺基)甲酰基甲氧基苯硫基]-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号10)的制备
参照实例1的方法，制得4-[3-(4-氟苯胺基)甲酰基甲氧基苯硫基]-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号10)0.6g，收率85.1％。m.p.:151-152℃；IR:(KBr,cm-1)3406(s),2944(m),1689(s),1589(s),1509(m),1408(s),1223(s),1058(s),829(s),793(s),687(s)；1H-NMR(400MHz,CDCl3):δ1.92-1.99(m,4H,2×CH2),2.88-2.90(m,2H,CH2),3.17-3.19(m,2H,CH2),4.65(s,2H,CH2-O),7.03-7.10(m,3H,Ar-H),7.25-7.30(m,2H,Ar-H),7.44(t,1H,Ar-H,),7.52-7.57(m,2H,Ar-H),8.23(s,1H,NH),8.51(s,1H,Ar-H)；ESI-MS(m/z):466.1([M+H]+)。
实施例11：4-[4-(4-吗啉基)甲酰基甲氧基苯硫基]-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号11)的制备
参照实例1的方法，制得4-[4-(4-吗啉基)甲酰基甲氧基苯硫基]-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号11)0.6g，收率78.6％。m.p.:141-144℃；IR:(KBr,cm-1)3442(m),2932(s),2857(s),1650(s),1591(s),1492(s),1440(s),1409(s),1380(s),1236(s),1110(s),1031(s),829(s),731(s)；1H-NMR(600MHz,CDCl3):δ1.92-1.96(m,4H,2×CH2),2.87-2.88(m,2H,CH2),3.18-3.19(m,2H,CH2),3.61-3.63(m,2H,CH2-N),3.65-3.66(m,2H,CH2-N),3.68-3.70(m,4H,CH2-O),4.75(s,2H,CH2-O),7.04(d,2H,Ar-H,J＝8.4Hz),7.50(d,2H,Ar-H,J＝8.4Hz),8.52(s,1H,Ar-H)；ESI-MS(m/z):442.0([M+H]+)。
实施例12：4-[4-(1-哌啶基)甲酰基甲氧基苯硫基]-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号12)的制备
参照实例1的方法，制得4-[4-(1-哌啶基)甲酰基甲氧基苯硫基]-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号12)0.6g，收率91.4％。m.p.:84-86℃；IR:(KBr,cm-1)3443(m),2935(s),2855(s),1639(s),1592(s),1493(s),1383(s),1241(s),1178(s),1128(s),1036(m),826(s),727(s)；1H-NMR(400MHz,CDCl3):δ1.58-1.66(m,6H,3×CH2),1.91-1.97(m,4H,2×CH2),2.86-2.88(m,2H,CH2),3.19(brs,2H,CH2),3.50(t,2H,CH2-N),3.58(t,2H,CH2-N),4.73(s,2H,CH2-O),7.04(d,2H,Ar-H,J＝8.4Hz),7.49(d,2H,Ar-H,J＝8.4Hz),8.51(s,1H,Ar-H)；ESI-MS(m/z):440.5([M+H]+)。
实施例13：4-(4-二乙胺基甲酰基甲氧基苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号13)的制备
参照实例1的方法，制得4-(4-二乙胺基甲酰基甲氧基苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号13)0.6g，收率90.8％。m.p.:88-91℃；IR:(KBr,cm-1)3577(s),3489(s),2971(s),2934(s),1647(s),1614(s),1594(s),1494(s),1410(s),1250(s),1078(s),835(s),728(s),616(s)；1H-NMR(400MHz,CDCl3):δ1.16(t,3H,CH3),1.24(t,3H,CH3),1.94(t,4H,CH2),2.87(t,2H,CH2),3.18(t,2H,CH2),3.41(m,4H,2×CH2-N),4.72(s,2H,CH2-O),7.04(d,2H,Ar-H,J＝8.8Hz),7.49(d,2H,Ar-H,J＝8.8Hz),8.52(s,1H,Ar-H)；ESI-MS(m/z):428.2([M+H]+)。
实施例14：4-[4-(1-吡咯烷基)甲酰基甲氧基苯硫基]-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号14)的制备
参照实例1的方法，制得4-[4-(1-吡咯烷基)甲酰基甲氧基苯硫基]-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号14)0.6g，收率83.8％。m.p.:125-127℃；IR:(KBr,cm-1)3556(s),3476(s),2936(s),2882(s),1649(s),1595(s),1494(s),1410(s),1251(s),1175(s),833(s),720(s)；1H-NMR(400MHz,CDCl3):δ1.84-2.02(m,8H,4×CH2),2.87(t,2H,CH2),3.19(t,2H,CH2),3.55(t,4H,2×CH2-N),4.67(s,2H,CH2-O),7.04(d,2H,Ar-H,J＝8.8Hz),7.49(d,2H,Ar-H,J＝8.8Hz),8.52(s,1H,Ar-H)；ESI-MS(m/z):426.1([M+H]+)。
实施例15：4-(4-苯胺基甲酰基甲氧基苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号15)的制备
参照实例1的方法，制得4-(4-苯胺基甲酰基甲氧基苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号15)0.6g，收率77.5％。m.p.:196-198℃；IR:(KBr,cm-1)3374(s),2929(s),1684(s),1599(s),1534(s),1492(s),1438(s),1408(s),1244(d),1180(s),820(s),761(s),695(s)；1H-NMR(400MHz,CDCl3):δ1.94-1.95(m,4H,2×CH2),2.88(s,2H,CH2),3.19(s,2H,CH2),4.68(s,2H,CH2-O),7.10(d,2H,Ar-H,J＝8.8Hz),7.18(t,1H,Ar-H),7.38(t,2H,Ar-H),7.56-7.61(m,4H,Ar-H),8.24(s,1H,NH),8.52(s,1H,Ar-H)；ESI-MS(m/z):448.1([M+H]+)。
实施例16：4-[4-(4-氟苯胺基)甲酰基甲氧基苯硫基]-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号16)的制备
参照实例1的方法，制得1-(7-溴-1,4-二氢噻吩并[3’,2’:5,6]噻喃并[4,3-c]吡唑-3-羰基)-4-(4-乙氧基苯基)哌嗪(化合物编号16)0.6g，收率85.1％。m.p.:195-197℃；IR:(KBr,cm-1)3270(s),2929(s),1680(s),1537(s),1510(d),1412(s),1257(s),1216(s),827(s)；1H-NMR(400MHz,CDCl3):δ1.95(t,4H,2×CH2),2.88(s,2H,CH2),3.19(s,2H,CH2),4.67(s,2H,CH2-O),7.05-7.10(m,4H,Ar-H),7.55-7.58(m,4H,Ar-H),8.22(s,1H,NH),8.52(s,1H,Ar-H)；ESI-MS(m/z):466.2([M+H]+)。
实施例17：4-[4-(4-氯苯胺基)甲酰基甲氧基苯硫基]-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号17)的制备
参照实例1的方法，制得4-[4-(4-氯苯胺基)甲酰基甲氧基苯硫基]-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号17)0.3g，收率41.0％。m.p.:208-210℃；IR:(KBr,cm-1)3262(s),2926(s),1682(s),1593(s),1532(s),1492(s),1413(s),1258(s),1090(s),827(s)；1H-NMR(600MHz,CDCl3):δ1.92-1.95(m,4H,2×CH2),2.86-2.88(m,2H,CH2),3.17-3.19(m,2H,CH2),4.66(s,2H,CH2-O),7.08(d,2H,Ar-H,J＝8.4Hz),7.33(d,2H,Ar-H,J＝8.4Hz),7.56(d,4H,Ar-H,J＝8.4Hz),8.24(s,1H,NH),8.51(s,1H,Ar-H)；ESI-MS(m/z):482.1([M+H]+)。
实施例18：4-[4-(4-溴苯胺基)甲酰基甲氧基苯硫基]-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号18)的制备
参照实例1的方法，制得4-[4-(4-溴苯胺基)甲酰基甲氧基苯硫基]-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号18)0.1g，收率10.0％。m.p.:198-199℃；IR:(KBr,cm-1)3261(s),2925(s),1682(s),1654(s),1531(s),1492(s),1412(s),1255(s),1071(s),813(d)；1H-NMR(400MHz,CDCl3):δ1.95(s,4H,2×CH2),2.88(s,2H,CH2),3.19(s,2H,CH2),4.66(s,2H,CH2-O),7.08(d,2H,Ar-H,J＝8.4Hz),7.47-7.59(m,6H,Ar-H),8.24(s,1H,NH),8.52(s,1H,Ar-H)；ESI-MS(m/z):426.4([M+H]+)。
以上所述，仅是本发明的较佳实施例而已，并非是对本发明作其它形式的限制，任何熟悉本专业的技术人员可能利用上述揭示的技术内容加以变更或改型为等同变化的等效实施例。但是凡是未脱离本发明技术方案内容，依据本发明的技术实质对以上实施例所作的任何简单修改、等同变化与改型，仍属于本发明技术方案的保护范围。
药理实施例
实施例19：
表皮生长因子(EGFR)体外活性测定
按照Mowafy等(Eur.J.Med.Chem,2013,61,132-145)介绍的方法，进行本项测定。
本测定使用的是Kinase-Glo Plus发光激酶检测试剂盒。它通过测量激酶反应后溶剂中ATP的量来评定激酶活性。发光信号强弱与ATP的量成正比而与激酶活性成反比。将测试化合物在10％DMSO中稀释至100μM，然后取出5μl的稀释液加入到50μl的反应中以保证所有反应中DMSO的最终浓度均为1％。所有的酶促反应均在30℃下反应40min。在50μl的反应混合物中包含40mM的三羟甲基氨基甲烷(Tris)，10mM的MgCl2，0.1mg/mL的牛血清白蛋白(BSA)，0.2mg/mL的复合基质(Glu，Tyr)，10μM的ATP和EGFR，并控制pH保持在7.4。在酶促反应结束后，向每个反应中加入50μl的Kinase-Glo Plus发光激酶检测溶剂并随后在室温下培育5min。发光信号通过Tecan公司的无限M1000型酶标仪来测定。
IC50值的测定通过使用ADP-GloTM检测试剂盒来完成。它通过蛋白激酶来测定ADP的生成，在上述试剂盒中伴随激酶反应而生成的ADP会导致发光信号增强。首先，将反应混合物置于96孔板中于30℃下培育30min，随后向其中加入25μl的ADP-GloTM试剂。摇晃该96孔板，然后于室温下继续培育40min。最后加入50μl的激酶检测试剂，随后96孔板的结果通过GloMax酶标仪来读取。空白组的试验方法与样品组完全平行一致。最终，蛋白激酶的活性数值通过减除空白组的数值来进行校正。
按照上述方法，测试本发明代表性化合物与EGFR的结合，IC50值的结果示于表1。
表1
实施例20：A-549细胞增殖测定
按照Stockert等(Acta Histochemica,2012,114(8),785-796)介绍的方法，进行本项测定。
本测定使用MTT法并利用人类肺癌细胞株A549来评价发明代表性化合物的抗肿瘤增值活性。A549细胞株在Dulbecco氏改进的Eagle培养基(DMEM)上进行培养，该培养基包含10％小牛血清(FBS)，100U/mL的青霉素以及100g/mL的链霉素。当细胞增殖至80～90％时使其合并随后进行不超过20代的传代培养，然后在下一步处置前使它们适应环境达到24h。将这些细胞置于96孔板上(8×104/mL)，然后在含有5％CO2的湿润环境中培养过夜并控温在37℃。24h过后加入20μM/50μM的发明代表性化合物。再经过24h的培养,向其中加入MTT(5mg/mL)并继续培养4h。移除培养基质，将晶体溶解于DMSO中，利用酶标仪(TECAN SPECTRA,Wetzlar,德国)在490nm波长下测量吸光度。抑制作用通过抑制率和IC50值来表示。
按照上述方法测定本发明代表性化合物，结果示于表2。
表2
实施例21：对卵巢癌细胞SKOV3增殖的作用
对数生长期细胞用胰酶消化后，以6×103个/孔细胞数加人96孔培养板，置37℃、5％CO2培养箱中培养，第2天待大部分细胞贴壁后置人4℃恒温箱1h，以促成细胞同步化生长。吸去上清液，加人含10％新生小牛血清(FCS)RPMI 1640培养液，200μL/孔，按实验设计分组。把无菌生理盐水配制的化合物注射液加入96孔中，每孔中加入200μL，使每孔的药物浓度分别为1mg/mL、2mg/mL和5mg/mI，以0mg/mL为阴性对照组。继续培养24、48、72h后，各孔分别加人20μL MTT溶液(浓度为5mg/mL)，轻轻震荡培养板，放回培养箱内再孵育4h，然后吸尽上清液，于各孔中加二甲亚砜200μL，置震荡器上震荡5-10min，用酶标光度计测出每孔中波长为580nm的吸光值(A＝580)，A＝580值与活细胞数量成正比。
按照上述方法测定本发明代表性化合物，结果示于表3。
表3
实施例22：对骨肉瘤细胞U2OS-EGFP-4A12G增殖的作用
对数生长期细胞用胰酶消化后，台盼蓝计数，配制成细胞密度为1×l04个/mL的细胞悬液，接种于96孔板中，每孔200μL，每孔约2×103个细胞，预培养24h，把无菌生理盐水配制的化合物注射液加入96孔中，每孔中加入200μL，使每孔的药物浓度分别为1mg/mL、2mg/mL和5mg/mI，以0mg/mL为阴性对照组。在分别培养0h、12h、24h和48h后每孔加入MTT溶液(5mg/mL)20μL，继续孵育4h，终止培养。小心吸弃培养孔中的上清液，每孔加入150μL的二甲基亚砜(DMSO)，震荡10min，使甲腊充分溶解，选择490nm波长，在酶联免疫检测仪上测定各孔光吸收值(A值)，重复检测5次。
按照上述方法测定本发明代表性化合物，结果示于表4。
表4
制剂实施例
下列制剂实施例仅举例说明本发明的保护范围，但不以任何方式构成限定。
实施例23：明胶胶囊
硬明胶胶囊的制备采用：
可以根据所提供的合理变化来改进上述制剂。
实施例77：片剂
片剂的制备采用
将上述组分混合并压制成片剂。
实施例24：片剂
每片中含有2.5-1000mg活性组分的片剂制备如下：
使活性成分、淀粉和纤维素通过45号目筛并彻底混合。将聚乙烯吡咯烷酮溶液与所得粉末混合，随后经14号目筛。将生成的颗粒在50-60℃下干燥并经18号目筛。将预先经过60号目筛的羧甲基纤维素钠、硬脂酸镁和滑石粉加入到上述颗粒中，随后混合，在压片机上压制得到片剂。
实施例25：混悬液
每5ml含有0.1-1000mg药物的混悬液制备如下：
令药物经45号目筛并与羧甲基纤维素钠和糖浆混合形成平滑的糊剂。将苯甲酸溶液、矫味剂和着色剂用一些水稀释并在搅拌下加入上述糊剂。随后加入足量的水以达到所需的体积。
实施例26：组合片剂
使活性成分、淀粉和纤维素通过45号目筛并彻底混合。将聚乙烯吡咯烷酮溶液与所得粉末混合，随后经14号目筛。将生成的颗粒在50-60℃下干燥并经18号目筛。将预先经过60号目筛的羧甲基纤维素钠、硬脂酸镁和滑石粉加入到上述颗粒中，随后混合，在压片机上压制得到片剂。
对于上述说明，本领域技术人员可容易地理解本发明的必要特征，不背离本发明的精神和范围，本发明可进行各种改变和改进以适应不同的应用和条件。
Claims (9)
1.一种式Ⅰ的化合物或其药学上可接受的盐：
其中
R1、R2分别独立地选自氢、C1-C4烷基、卤素取代或未取代的苯基、或R1、R2与它们相连的氮原子一起组成吡咯烷基，哌啶基，吗啉基。
2.如权利要求1所述的化合物或其药学上可接受的盐，其中：
R1、R2分别独立地选自氢、乙基、苯基、4-氟苯基、4-氯苯基、4-溴苯基，或R1、R2与它们相连的氮原子一起组成吡咯烷基，哌啶基，吗啉基。
3.如权利要求1或2所述的式Ⅰ的化合物或其药学上可接受的盐，选自：
4-[2-(4-吗啉基)甲酰基甲氧基苯硫基]-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶；
4-[2-(1-哌啶基)甲酰基甲氧基苯硫基]-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶；
4-(2-二乙胺基甲酰基甲氧基苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶；
4-[2-(1-吡咯烷基)甲酰基甲氧基苯硫基]-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶；
4-(2-苯胺基甲酰基甲氧基苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶；
4-[2-(4-氟苯胺基)甲酰基甲氧基苯硫基]-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶；
4-[3-(4-吗啉基)甲酰基甲氧基苯硫基]-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶；
4-[3-(1-吡咯烷基)甲酰基甲氧基苯硫基]-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶；
4-(3-苯胺基甲酰基甲氧基苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶；
4-[3-(4-氟苯胺基)甲酰基甲氧基苯硫基]-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶；
4-[4-(4-吗啉基)甲酰基甲氧基苯硫基]-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶；
4-[4-(1-哌啶基)甲酰基甲氧基苯硫基]-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶；
4-(4-二乙胺基甲酰基甲氧基苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶；
4-[4-(1-吡咯烷基)甲酰基甲氧基苯硫基]-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶；
4-(4-苯胺基甲酰基甲氧基苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶；
4-[4-(4-氟苯胺基)甲酰基甲氧基苯硫基]-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶；
4-[4-(4-氯苯胺基)甲酰基甲氧基苯硫基]-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶；
4-[4-(4-溴苯胺基)甲酰基甲氧基苯硫基]-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶。
4.一种药物组合物，包含权利要求1-3任何一项所述的式Ⅰ的化合物或其药学上可接受的盐作为活性成分和药物可接受的载体。
5.权利要求1-3任何一项所述的式Ⅰ化合物或权利要求4所述的药物组合物在制备抗肿瘤药物中的应用。
6.权利要求1-3任何一项所述的式Ⅰ化合物或权利要求4所述的药物组合物在制备治疗非小细胞肺癌药物中的应用。
7.权利要求1-3任何一项所述的式Ⅰ化合物或权利要求4所述的药物组合物在制备预防和治疗与表皮生长因子受体信号转导失调相关的疾病药物中的应用。
8.根据权利要求7所述的应用，其特征在于：所述表皮生长因子受体为HER-1、HER-2、HER-3或HER-4。
9.根据权利要求7所述的应用，其特征在于：其中所述的表皮生长因子受体信号转导失调的相关疾病为鳞癌，腺癌，大细胞癌，结肠直肠癌、乳腺癌，卵巢癌，肾细胞癌或支气管哮喘。
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