CN103626787B - 噻吩并硫杂类化合物及其应用 - Google Patents
噻吩并硫杂类化合物及其应用 Download PDFInfo
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- CN103626787B CN103626787B CN201310666934.4A CN201310666934A CN103626787B CN 103626787 B CN103626787 B CN 103626787B CN 201310666934 A CN201310666934 A CN 201310666934A CN 103626787 B CN103626787 B CN 103626787B
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- pyrazoles
- carbonyl
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- piperazine
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- C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D495/14—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- 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，涉及噻吩并噻喃类化合物及其应用。噻吩并噻喃类化合物包括噻吩并噻喃类化合物的衍生物和药学上适用的盐，其结构通式如下所示：噻吩并噻喃类化合物以及该类化合物药学上适用的酸加成的盐可以与现有药物合并或单独使用作为表皮上生长因子酪氨酸激酶抑制剂，用于治疗表皮生长因子受体信号转到失调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。
Description
技术领域
本发明属于医药技术领域，涉及噻吩并硫杂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。
已知表皮生长因子受体（epidermalgrowthfactorreceptor,EGFR）作为受体型酪氨酸激酶家族的一员，是一种跨膜糖蛋白，其由细胞外的表皮生长因子结合区（包含621个氨基酸残基）、疏水跨膜结构域（23个氨基酸残基）、细胞内的激酶区（542个氨基酸残基）和羧基末端四部分所组成。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转导通路，刺激细胞生长增殖。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和II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
n为1、2；
R1可以为H或卤素；
R2可以为氢或卤素；
R3为由1个、2个或3个独立地选自H、卤素、C1-C4烷基、C1-C4烷氧基、-CF3、-OCF3取代的苯环，二苯甲基，4-氯二苯甲基，苄基；
R4、R5分别独立地选自氢、C1-C4烷基、N,N-二乙基、苯基、呋喃甲基、苄基，优选氢、甲基、乙基、叔丁基、异丙基、N,N-二乙基、苯基、呋喃甲基，或R2、R3与它们相连的氮原子一起组成吡咯烷基，哌啶基，N-甲基哌啶基，吗啉基，六亚甲基亚胺基环。
“药物可接受的盐”指保留了式I、II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、赋性剂、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、II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、II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。
本发明中应用的术语“卤素”包括氯、溴或氟。
“取代的”，除非另外说明，指取代基可以在一个或多个位置存在，取代基独立地选自具体地选项。
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，应当明白，本发明不限于具体叙述的下述实例。
实施例1：1-(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-甲基苯基)哌嗪(化合物编号01)的制备
步骤A：5,6-二氢-4H-噻吩并[2,3-b]噻喃-4-酮的制备
100mL圆底烧瓶中加入4.64g(0.04mol)2-巯基噻吩、80mL四氢呋喃，搅拌下滴加11mL三乙胺，再加入3.3mL丙烯酸，加热回流12h。反应完毕，蒸去四氢呋喃。冷却后，加入40mL乙酸乙酯和20mL水，用18%盐酸调pH至2，收集有机层。水层用乙酸乙酯萃取，合并有机层，用无水硫酸镁干燥。抽滤，滤液蒸去溶剂，冷却后析出棕色固体。石油醚重结晶得白色针状固体，产量6.02g，收率80.0%，熔点43-45℃。
100mL圆底烧瓶中加入3.76g(0.02mol)3-(噻吩-2-硫基)丙酸、20mL二氯甲烷和2滴DMF，氮气保护下，边搅拌边滴加含有草酰氯的二氯甲烷溶液(草酰氯2.2mL，二氯甲烷16mL)，室温搅拌1h。将反应液用冰盐浴冷却至-10℃,边搅拌边滴加含有四氯化锡的二氯甲烷溶液(四氯化锡1.15mL，二氯甲烷10mL)。滴毕，0℃下搅拌0.5h。向烧瓶中加入20mL水，提取有机相，水相用二氯甲烷萃取，合并有机相。有机相依次用碳酸钠饱和溶液、水和氯化钠饱和溶液洗涤，用无水硫酸镁。抽滤，滤液蒸去溶剂，冷却后得粗品，收率100%。石油醚重结晶得白色针状固体，产量2.59g，收率76.2%，熔点59-60℃。
步骤B：4,5,6,7-四氢噻吩并[2,3-b]硫杂-4-酮的制备
向500mL的圆底烧瓶中加入小钠块（6.6g，0.29mol），在干燥室温下加入无水乙醇（120mL）。待钠完全消失后冷却，加入2-巯基噻吩，室温条件下搅拌30min左右，反应液变暗红色。加入-丁内酯（15.6mL，0.3mol），加热回流条件下反应约19h反应液变粘稠。将产物减压蒸馏，除去乙醇。用约100mL石油醚、乙酸乙酯（V:V=3:1）洗涤剩余固体。将洗涤后的固体加入冷却的1N盐酸中，底层析出暗红色油状物，用乙酸乙酯萃取后用饱和NaCl水溶液洗涤有机层，用无水MgSO4干燥。滤去干燥剂、浓缩。浓缩液中加入石油醚约250mL，加热回流约1h后停止搅拌和加热，静置。待反应液澄清后倒入锥形瓶中，溶液成浑浊，静置澄清后转移至另一个锥形瓶中。冷冻过夜析出白色晶体。收率41.26%。
向250ml三颈瓶中加入4-(噻吩-2-硫基)丁酸（4.04g,0.02mol）和25ml的二氯甲烷。在氮气保护条件下滴加草酰氯(5.4mL,0.06mol)的二氯甲烷溶液(25mL)，反应液变淡黄绿色，滴加完搅拌2h。在氮气保护和冰浴条件下，缓慢滴加四氯化锡（2.3mL,0.02mol）的二氯甲烷溶液（20ml），反应液变墨绿色。室温条件下搅拌24h。向反应液中加入50ml盐酸（V:V=1:1），搅拌至不在有气体放出为止。水洗有机层，至pH近中性有机层变为橙黄色。用饱和的NaCl溶液洗涤有机层，分离用MgSO4干燥。用石油醚重结晶得白色晶体。收率27%。
步骤C：7-溴-1,4-二氢噻吩并[3’,2’:5,6]噻喃并[4,3-c]吡唑-3-甲酸的制备
100mL圆底烧瓶中加入0.46g金属钠和20mL无水甲醇，加热回流至钠固体消失，蒸去甲醇。向反应瓶中加入2.36g（0.02mol）草酸二甲酯、20mL甲苯、1.70g(0.01mol)5,6-二氢-4H-噻吩并[2,3-b]噻喃-4-酮。室温搅拌24h，将反应液倾入100mL冰水中，提取水相。有机相用20mL10%氢氧化钠溶液萃取。合并水相，用无水乙醚洗涤后，用18%稀盐酸调pH至2，得黄色固体，抽滤得粗品。石油醚重结晶得黄色针状晶体1.5g，收率43.86%，熔点：93-95℃。
100mL圆底烧瓶中加入2-氧代-2-(4-氧代-5,6-二氢-4H-噻吩并[2,3-b]噻喃-5-基)乙酸甲酯0.51g(2mmol)和10mL冰醋酸，搅拌下加入水合肼2mL（3.2mmol），加热回流12h。将反应液倒入200mL冰水中搅拌，出现白色固体，抽滤得粗品。石油醚重结晶得白色固体0.32g，收率63.2%，熔点：94-96℃。
在100mL圆底烧瓶中加入1,4-二氢噻吩并[3’,2’:5,6]噻喃并[4,3-c]吡唑-3-羧酸甲酯2.52g（0.01mol），50mL冰醋酸，5mL水，冰浴冷却搅拌下滴加溴素2.08g（0.013mol），滴加结束后室温反应24h。将反应液倒入200mL冰水中，析出白色固体，抽滤，得到产品。ESI-MS:m/z330.9[M]+。
100mL圆底烧瓶中加入0.62g（2mmol）7-溴-1,4-二氢噻吩并[3’,2’:5,6]噻喃并[4,3-c]吡唑-3-羧酸甲酯、20mL水和0.4g氢氧化钠，加热回流2h。反应液用18%的盐酸调pH至2，出现白色固体，抽滤得粗品。石油醚重结晶得白色固体0.57g，收率90.0%。
步骤D：4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羧酸的制备
将钠(0.23g,0.01mol)切成钠屑，加入10ml无水甲醇中，搅拌至钠固体消失，旋蒸蒸去甲醇，得白色固体。向反应瓶中加入(COOMe)2(1.18g,0.01mol)，4,5,6,7-四氢噻吩并[2,3-b]硫杂-5-酮(1g,0.005mol)和7ml的甲苯，室温搅拌40h。倒入约100ml的冰水中，取水层，水层为暗红色。用10%的NaOH水溶液萃取有机层，合并水层。水层用乙醚洗涤。1N的盐酸酸化，酸化过程中液体变混浊，调至pH=2时得到黄色混浊液体放入冰箱中静置。析出固体很粘稠，用CH2Cl2萃取浓缩后得到粘稠固体。用无水乙醚洗涤得到红色粉末，收率40.29%。
将(4-氧代-4,5,6,7-四氢噻吩并[2,3-b]硫杂-5-基)乙酮酸甲酯（0.5g,2mmol）和水合肼（0.1g,2mmol）加入圆底烧瓶中，加入5mL冰乙酸，加热回流3h。将反应液倒入冰水中，析出黄色固体，过滤，干燥。收率79%。
100mL圆底烧瓶中加入0.51g(2mmol)4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羧酸甲酯、20mL水和0.4g氢氧化钠，加热回流2h。反应液用18%的盐酸调pH至2，出现白色固体，抽滤得粗品。石油醚重结晶得白色固体0.31g，收率65.1%。1H-NMR(300MHz,DMSO):δ2.74(t,2H),3.26(m,2H),7.27(d,1H,J=5.4Hz),7.63(d,1H,J=5.3Hz)。13.13(s,1H)
步骤E：7,8-二溴-1,4-二氢噻吩并[3’,2’:5,6]噻喃并[4,3-c]吡唑-3-羧酸的制备
3.31g（0.01mol）7-溴-1,4-二氢噻吩并[3’,2’:5,6]噻喃并[4,3-c]吡唑-3-羧酸甲酯加入乙酸（50mL）-水（5mL）混合溶液中，室温条件下滴加液溴（8g,0.05mol），室温搅拌48h。将反应液倒入冰水混合液中（100g），析出浅黄色固体。抽滤，柱层析色谱分离纯化（石油醚：乙酸乙酯=10:1），得到白色固体，收率8%。ESI-MS:m/z410.7[M+H]+
将7,8-二溴-1,4-二氢噻吩并[3’,2’:5,6]噻喃并[4,3-c]吡唑-3-羧酸甲酯（0.82g,2mmol）加入到30mL水中，加入氢氧化钠（0.1g,2.5mmol），加热回流直至固体消失。将反应液冷却到室温，18%盐酸调节pH值，至不再有固体析出，抽滤，得到白色固体，收率90%。
步骤F：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-甲基苯基)哌嗪(化合物编号01)的制备
将7-溴-1,4-二氢噻吩并[3’,2’:5,6]噻喃并[4,3-c]吡唑-3-甲酸（1.27g，4mmol），4-甲基苯基哌嗪（0.74g,4.2mmol），1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐（1g,5mmol），1-羟基苯并三唑（0.1g,0.74mmol），三乙胺（2mL）加入20mL二氯甲烷中，室温搅拌48h，过滤，滤液分别用18%盐酸、饱和碳酸钠和水洗涤。提取有机相，无水硫酸镁干燥。过滤，滤液蒸去溶剂，经硅胶柱层析色谱分离（石油醚:乙酸乙酯=5:1），得白色固体。收率30%。m.p.:185-186℃；IR(KBr,cm-1):3441,2920,2852,1610,1513,1445,1384,1156,1023,813,619;1H-NMR(600MHz,CDCl3):δ7.24(1H,s),6.91(2H,dd,J=7.2Hz,2.4Hz),6.85(2H,dd,J=7.2Hz,2.4Hz),4.28(2H,s),3.99(7H,m),3.13(4H,m)；ESI-MS(m/z):345.1[M+H]+。
实施例2：1-(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-(二苯基甲基)哌嗪(化合物编号02)的制备
按照实例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-(二苯基甲基)哌嗪0.77g，收率35%。m.p.:175-176℃；IR(KBr,cm-1):3420,2921,2851,1607,1451,1384,1262,1154,1027,997,877,831,705;1H-NMR(600MHz,CDCl3):δ2.44(4H,m),3.79(4H,m),4.16(2H,s),4.25(1H,s),7.19(2H,d,J=8.4Hz),7.28(4H,dd,J=7.2Hz,8.4Hz),7.41(4H,d,J=7.2Hz)；ESI-MS(m/z):551.2[M+H]+。
实施例3：N,N-二乙基-7-溴-1,4-二氢噻吩并[3’,2’:5,6]噻喃并[4,3-c]吡唑-3-酰胺(化合物编号03)的制备
按照实例1的方法，制得N,N-二乙基-7-溴-1,4-二氢噻吩并[3’,2’:5,6]噻喃并[4,3-c]吡唑-3-酰胺(化合物编号03)0.75g，收率50%。m.p.:147-148℃；IR(KBr,cm-1):3212,2958,2917,2849,1735,1583,1535,1508,1485,1461,1375,1215,1159,967,849;1H-NMR(600MHz,CDCl3):δ1.25(6H,m),3.54(4H,m),4.12(2H,s),7.72(1H,s)；ESI-MS(m/z):372.0,374.0[M+H]+。
实施例4：1-(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-(3-氯-4-氟苯基)哌嗪的制备
按照实例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-(3-氯-4-氟苯基)哌嗪(化合物编号04)0.72g，收率36%。m.p.:120℃；IR(KBr,cm-1):3233,2924,2853,1745,1609,1586,1502,1464,1382,1223,1154,998;1H-NMR(600MHz,CDCl3):δ3.16(4H,t,J=6.0Hz),3.95(4H,t,J=6.0Hz),4.26(2H,s),6.79(1H,m),6.95(1H,dd,J=6.3Hz,J=2.4Hz),7.05(1H,dd,J=8.7Hz,J=9Hz),7.25(1H,s)；ESI-MS(m/z):512.8,514.9,517.0[M+H]+。
实施例5：1-(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-氯苯基)哌嗪的制备
按照实例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-氯苯基)哌嗪(化合物编号05)0.50g，收率25%。m.p.:235℃；IR(KBr,cm-1):3159.9,2918.2,2849.7,1740.4,1590.8,1496.6,1480.7,1441.4,1387.7,1234.2,120.6,1151.0,998.1,810.2;1H-NMR(600MHz,DMSO-d6):δ3.10(4H,m),3.51(4H,m),4.26(2H,s),7.21(1H,s),7.56(2H,d,J=5.4Hz),7.58(2H,d,J=5.4Hz),13.29(1H,s)；ESI-MS(m/z):497.3,495.4,499.2[M+H]+。
实施例6：1-(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-(4-三氟甲氧基苯基)哌嗪的制备
按照实例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-(4-三氟甲氧基苯基)哌嗪(化合物编号06)0.92g，收率42%。m.p.:228-230℃；IR(KBr,cm-1):3240,2919,2850,1730,1605,1532,1510,1475,1386,1368,1327,1272,1153,1028,1004;1H-NMR(600MHz,DMSO-d6):δ3.33(8H,m),4.27(2H,s),7.03(2H,d,J=8.6Hz),7,20(2H,d,J=8.6Hz),7.56(1H,s),13.84(1H,s)；ESI-MS(m/z):547.0,545.1[M+H]+。
实施例7：1-(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-(2-氟苯基)哌嗪的制备
按照实例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-(2-氟苯基)哌嗪(化合物编号07)0.75g，收率39%。m.p.:78-80℃；IR(KBr,cm-1):3221,2921,2851,1720,1641,1500,1446,1394,1385,1287,1240,1151,999;1H-NMR(600MHz,CDCl3):δ3.11(4H,t,J=10.2Hz),4.02(4H,t,J=10.2Hz),4.24(2H,s),7.02(3H,m),7.23(1H,s),7.38(1H,d,J=7.8Hz)；ESI-MS(m/z):479.1,481.0[M+H]+。
实施例8：1-(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-(4-三甲氧基苯基)哌嗪的制备
按照实例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-(4-三甲氧基苯基)哌嗪(化合物编号08)0.87g，收率44%。m.p.:90℃；IR(KBr,cm-1):2922,1730,1618,1511,1446,1379,1255,1224,1186,1137,1096,1034,992,816;1H-NMR(600MHz,CDCl3):δ3.13(4H,m),3.99(7H,m),4.28(2H,s),6.85(2H,dd,J=7.2Hz,2.4Hz),6.91(2H,dd,J=7.2Hz,2.4Hz),7.24(1H,s)；ESI-MS(m/z):491.1,493.2[M+H]+。
实施例9：1-(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-苯基哌嗪的制备
按照实例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-苯基哌嗪(化合物编号09)0.85g，收率43%。m.p.:112℃；IR(KBr,cm-1):2923,2853,1619,1517,1499,1468,1377,1276,1154,992,832;1H-NMR(600MHz,CDCl3):δ3.26(4H,t),4.01(4H,t),4.27(2H,s),6.91(1H,d,J=7.8Hz),6.96(2H,d,J=7.8Hz),7,28(2H,dd,J=7.8Hz,7.8Hz),7.25(1H,s)；ESI-MS(m/z):461.1,463.1[M+H]+。
实施例10：1-(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-氟苯基)哌嗪的制备
按照实例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-氟苯基)哌嗪(化合物编号10)0.67g，收率35%。m.p.:185-186℃；IR(KBr,cm-1):3443,2922,2852,1605,1507,1443,1384,1225,1116;1H-NMR(600MHz,CDCl3):δ3.19(4H,t),4.04(4H,t),4.24(2H,s),7.00(4H,m),7.24(1H,s)；ESI-MS(m/z):479.1,481.0[M+H]+。
实施例11：1-(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-甲基哌嗪的制备
按照实例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-甲基哌嗪(化合物编号11)0.95g，收率60%。m.p.:220-222℃；IR(KBr,cm-1):3424.0,2917.8,849.5,1704.1,1465.5,1433.1,1383.9,1296.8,1204.9,940.2;1H-NMR(600MHz,CDCl3):δ2.36(3H,s),2.51(4H,t),3.86(4H,t),4.19(2H,s),7.28(1H,s)；ESI-MS(m/z):399.2,401.2[M+H]+。
实施例12：1-(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-苄基哌嗪的制备
按照实例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-苄基哌嗪(化合物编号12)0.89g，收率47%。m.p.:180℃；IR(KBr,cm-1):3422,3206,2918,2850,1730,1601,1509,1446,1384,1266,1126,1029,999;1H-NMR(600MHz,CDCl3):δ2.50(4H,t),3.54(2H,s),3.77(4H,t),4.28(2H,s),7.24(1H,s),7.31(5H,m)；ESI-MS(m/z):474.9,477.1[M+H]+。
实施例13：1-(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-氯苯基)(苯基)甲基]哌嗪的制备
按照实例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-氯苯基)(苯基)甲基]哌嗪(化合物编号13)0.89g，收率38%。m.p.:212-214℃；IR(KBr,cm-1):3442,2920,2851,1602,1452,1384,1126,998;1H-NMR(600MHz,CDCl3):δ2.44(4H,m),3.79(4H,m),4.16(2H,s),4.25(1H,s),7.22(2H,m),7,25(1H,s),7.27(1H,m),7.29(2H,dd,J=7.8Hz,7.8Hz),7.37(4H,m)；ESI-MS(m/z):584.9,586.8[M+H]+。
实施例14：N-叔丁基-7-溴-1,4-二氢噻吩并[3’,2’:5,6]噻喃并[4,3-c]吡唑-3-酰胺的制备
按照实例1的方法，制得N-叔丁基-7-溴-1,4-二氢噻吩并[3’,2’:5,6]噻喃并[4,3-c]吡唑-3-酰胺(化合物编号14)1.12g，收率75%。m.p.:205-207℃；IR(KBr,cm-1):3364,3201,2919,1638,1553,1526,1492,1450,1385,1296,1220,1167,969,863;1H-NMR(600MHz,CDCl3):δ1.49(9H,s),4.49(2H,s),7,21(1H,s),7.40(1H,s)；ESI-MS(m/z):372.0,374.2[M+H]+。
实施例15：1-(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-(3-溴苯基)哌嗪的制备
按照实例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-(3-溴苯基)哌嗪(化合物编号15)0.82g，收率38%。m.p.:150-151℃；IR(KBr,cm-1):3418.7,3217.5,2920.0,2850.7,1590.4,1480.6,1442.9,1384.6,1224.6,1157.9,999.9,938.2,764.3;1H-NMR(600MHz,CDCl3):δ3.25(4H,m),4.00(4H,m),4.26(2H,s),6.85(1H,m),7.01(1H,m),7.06(1H,m),7.13(1H,m),7.23(1H,s)；ESI-MS(m/z):538.9,540.8,542.9[M+H]+。
实施例16：1-(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)哌嗪的制备
按照实例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)0.89g，收率44%。m.p.:178-180℃；IR(KBr,cm-1):3443.4,2918.4,2850.2,1618.7,1511.5,1446.0,1384.5,1273.2,1254.0,1224.2,1137.0,1021.6,993.6,834.2,816.7;1H-NMR(600MHz,CDCl3):δ1.40(3H,t),3.13(4H,t),3.99(6H,m),4.28(2H,s),6.85(2H,dd,J=7.2Hz,2.4Hz),6.91(2H,dd,J=7.2Hz,2.4Hz),7.24(1H,s)；ESI-MS(m/z):505.3,507.3[M+H]+。
实施例17：4-(7-溴-1,4-二氢噻吩并[3’,2’:5,6]噻喃并[4,3-c]吡唑-3-羰基)吗啉的制备
按照实例1的方法，制得4-(7-溴-1,4-二氢噻吩并[3’,2’:5,6]噻喃并[4,3-c]吡唑-3-羰基)吗啉(化合物编号17)0.76g，收率49%。m.p.:150℃；IR(KBr,cm-1):3444.9,3169.7,2918.2,2850.3,1729.9,1592.2,1441.1,1266.5,1148.2,1113.9,1000.1,969.6,844.0;1H-NMR(600MHz,DMSO-d6):δ3.61(4H,t),3.96(4H,t),4.28(2H,s),7.42(1H,s),13.59(1H,s)；ESI-MS(m/z):388.2[M+H]+。
实施例18：1-(7-溴-1,4-二氢噻吩并[3’,2’:5,6]噻喃并[4,3-c]吡唑-3-羰基)吡咯烷的制备
按照实例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)吡咯烷(化合物编号18)0.77g，收率52%。m.p.:220℃；IR(KBr,cm-1):3442.7,2920.1,2851.2,1606.7,1575.4,1508.2,1454.8,1384.3,1156.9,969.2,844.5;1H-NMR(600MHz,DMSO-d6):δ1.81(2H,t),1.87(2H,t),3.46(2H,t),3.84(2H,t),4.37(2H,s),7.42(1H,s),14.57(1H,s)；ESI-MS(m/z):370.1,372.3[M+H]+。
实施例19：N-异丙基-7-溴-1,4-二氢噻吩并[3’,2’:5,6]噻喃并[4,3-c]吡唑-3-酰胺的制备
按照实例1的方法，制得N-异丙基-7-溴-1,4-二氢噻吩并[3’,2’:5,6]噻喃并[4,3-c]吡唑-3-酰胺(化合物编号19)0.99g，收率69%。m.p.:189-190℃；IR(KBr,cm-1):3400.5,3207.5,2974.5,2921.3,1637.4,1556.3,1528.3,1452.1,1384.6,1175.4,967.5,836.5;1H-NMR(600MHz,DMSO-d6):δ4.50(1H,m),4.39(2H,s),7.50(1H,s),8.08(1H,s)；ESI-MS(m/z):357.1,359.1[M+H]+。
实施例20：N-(2-二乙胺基)乙基-7-溴-1,4-二氢噻吩并[3’,2’:5,6]噻喃并[4,3-c]吡唑-3-酰胺的制备
按照实例1的方法，制得N-(2-二乙胺基)乙基-7-溴-1,4-二氢噻吩并[3’,2’:5,6]噻喃并[4,3-c]吡唑-3-酰胺(化合物编号20)1.06g，收率64%。m.p.:165-167℃；IR(KBr,cm-1):3420.4,2968.1,2921.8,1635.0,1556.8,1528.9,1456.6,1384.3,1124.4,968.5,831.9;1H-NMR(600MHz,CDCl3):δ1.07(6H,t),2.68(4H,m),2.77(2H,t),3.55(2H,t),4.43(2H,s),7.21(1H,s),8.05(1H,s)；ESI-MS(m/z):415.3[M+H]+。
实施例21：N,N-二甲基-7-溴-1,4-二氢噻吩并[3’,2’:5,6]噻喃并[4,3-c]吡唑-3-酰胺的制备
按照实例1的方法，制得N,N-二甲基-7-溴-1,4-二氢噻吩并[3’,2’:5,6]噻喃并[4,3-c]吡唑-3-酰胺(化合物编号21)0.94g，收率68%。m.p.:220℃；IR(KBr,cm-1):3443.5,3205.2,2920.4,1612.5,1536.4,1485.5,1420.6,1384.3,1259.4,1160.8,1101.3,966.7,822.5;1H-NMR(600MHz,DMSO-d6):δ2.97(6H,s),4.26(2H,s),7.43(1H,s),13.54(1H,s)；ESI-MS(m/z):344.2,346.3[M+H]+。
实施例22：N-苯基-7-溴-1,4-二氢噻吩并[3’,2’:5,6]噻喃并[4,3-c]吡唑-3-酰胺的制备
按照实例1的方法，制得N-苯基-7-溴-1,4-二氢噻吩并[3’,2’:5,6]噻喃并[4,3-c]吡唑-3-酰胺(化合物编号22)0.47g，收率30%。m.p.:190-191℃；IR(KBr,cm-1):3443.8,2919.8,2850.5,1730.5,1612.4,1555.1,1441.0,1384.2,1296.2,1114.0,1038.4,778.5;1H-NMR(600MHz,DMSO-d6):δ4.42(2H,s),7.40(5H,m),7.42(1H,s),8.82(1H,s),13.64(1H,s)；ESI-MS(m/z):415.3,417.3[M+Na]+。
实施例23：1-(7-溴-1,4-二氢噻吩并[3’,2’:5,6]噻喃并[4,3-c]吡唑-3-羰基)哌啶的制备
按照实例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)哌啶(化合物编号23)0.95g，收率62%。m.p.:196-198℃；IR(KBr,cm-1):3442.6,2931.0,2852.9,1603.1,1570.1,1538.8,1445.3,1384.3,274.9,1112.4,966.6,851.8;1H-NMR(600MHz,CDCl3):δ1.66(6H,m),3.72(4H,t),4.14(2H,s),7.30(1H,s)；ESI-MS(m/z):384.2,386.3[M+H]+,406.2,408.4[M+Na]+。
实施例24：N–苄基-7-溴-1,4-二氢噻吩并[3’,2’:5,6]噻喃并[4,3-c]吡唑-3-酰胺的制备
按照实例1的方法，制得N–苄基-7-溴-1,4-二氢噻吩并[3’,2’:5,6]噻喃并[4,3-c]吡唑-3-酰胺(化合物编号24)0.91g，收率56%。m.p.:98-100℃；IR(KBr,cm-1):3421.9,2920.9,2851.7,1629.7,1446.5,1384.2,1274.3,1114.1,850.9;1H-NMR(600MHz,DMSO-d6):δ4.40(2H,d),4.42(2H,s),7.40(5H,m),7.42(1H,s),8.82(1H,s),13.64(1H,s)；ESI-MS(m/z):408.3[M+H]+,430.1[M+Na]+。
实施例25：N–(呋喃-2-基亚甲基)-7-溴-1,4-二氢噻吩并[3’,2’:5,6]噻喃并[4,3-c]吡唑-3-酰胺的制备
按照实例1的方法，制得N–(呋喃-2-基亚甲基)-7-溴-1,4-二氢噻吩并[3’,2’:5,6]噻喃并[4,3-c]吡唑-3-酰胺(化合物编号25)0.62g，收率39%。m.p.:89-90℃；IR(KBr,cm-1):3444.2,2921.3,2851.3,16307,1440.4,1384.0,1236.2,1112.3,1089.9,975.6,737.9;1H-NMR(600MHz,CDCl3):δ4.22(2H,s),4.60(2H,d),6.29(1H,d,J=6Hz),6.33(1H,d,J=6Hz),7.20(1H,dd,J=6Hz,6Hz),7.25(1H,s)；ESI-MS(m/z):395.3,397.2[M+H]+,418.3,420.1[M+Na]+。
实施例26：N–(吡啶-2-基)-7-溴-1,4-二氢噻吩并[3’,2’:5,6]噻喃并[4,3-c]吡唑-3-酰胺的制备
按照实例1的方法，制得N–(吡啶-2-基)-7-溴-1,4-二氢噻吩并[3’,2’:5,6]噻喃并[4,3-c]吡唑-3-酰胺(化合物编号26)0.49g，收率31%。m.p.:83-84℃；IR(KBr,cm-1):3421.0,2921.4,2851.5,1630.3,1445.7,1384.2,1274.8,1126.2;1H-NMR(600MHz,CDCl3):δ4.31(2H,s),.6.50(1H,d,J=8.2Hz),6.65(1H,m),7.42(2H,m),8.07(1H,d,J=4.8Hz)；ESI-MS(m/z):395.2[M+H]+。
实施例27：1-(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-(3,5-二三氟甲基苯基)哌嗪的制备
按照实例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-(3,5-二三氟甲基苯基)哌嗪(化合物编号27)1.08g，收率45%。m.p.:220-221℃；IR(KBr,cm-1):3421.2,2918.2,1610.2,1581.2,1485.5,1400.4,1275.0,1175.,1131.4,995.3,963.6,862.4;1H-NMR(600MHz,DMSO-d6):δ3.45(4H,t),3.77(2H,t),4.14(2H,t),4.31(2H,s),7.33(1H,s),7.45(1H,s),7.50(2H,s),13.64(1H,s)；ESI-MS(m/z):596.9,599.1[M+H]+,619.1,621.0[M+Na]+。
实施例28：1-(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-(3,4-二氟苯基)哌嗪的制备
按照实例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-(3,4-二氟苯基)哌嗪(化合物编号28)0.88g，收率44%。m.p.:190-192℃；IR(KBr,cm-1):3444.2,2919.8,1656.7,1560.4,1417.7,1384.3,1276.6,1116.2;1H-NMR(600MHz,DMSO-d6):δ3.15(4H,t),3.72(4H,t),4.27(2H,s),6.75(1H,m),7.03(1H,m),7.25(1H,d,J=9.6Hz),7.45(1H,s)；ESI-MS(m/z):518.9,521.0[M+Na]+。
实施例29：1-(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-(2-甲基苯基)哌嗪的制备
按照实例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-(2-甲基苯基)哌嗪(化合物编号29)0.91g，收率48%。m.p.:167-170℃；IR(KBr,cm-1):3442.6,2920.4,2851.6,1621.6,1491.9,1443.3,1384.0,1327.3,1274.9,1224.2,1126.5,1021.8,1000.2,762.3;1H-NMR(600MHz,CDCl3):δ2.35(3H,s),2.98(4H,t),3.97(4H,t),4.23(2H,s),7.01(2H,m),7.20(2H,m),7.25(1H,s)；ESI-MS(m/z):475.1,476.4[M+H]+。
实施例30：1-(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-(2-氯苯基)哌嗪的制备
按照实例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-(2-氯苯基)哌嗪(化合物编号30)0.73g，收率37%。m.p.:185-186℃；IR(KBr,cm-1):3444.2,2920.3,2851.4,1610.1,1478.0,1384.4,1265.9,1227.6,1124.4,1022.3;1H-NMR(600MHz,CDCl3):δ3.11(4H,t),4.02(4H,t),4.24(2H,s),7.02(3H,m),7.23(1H,s),7.38(1H,d,J=7.8Hz)；ESI-MS(m/z):495.1,497.1[M+H]+。
实施例31：1-(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-(2,5-二甲基苯基)哌嗪的制备
按照实例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-(2,5-二甲基苯基)哌嗪(化合物编号31)0.92g，收率47%。m.p.:150-152℃；IR(KBr,cm-1):3443.5,2919.6,2850.9,1606.7,1457.4,1384.1,1125.3;1H-NMR(600MHz,CDCl3):δ2.29(3H,s),2.30(3H,s),2.95(4H,t),3.96(4H,t),4.27(2H,s),6.82(1H,s),6.84(1H,d,J=7.2Hz),7.08(1H,d,J=7.2Hz),7.25(1H,s)；ESI-MS(m/z):489.1,491.1[M+H]+。
实施例32：1-(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-(3-三氟甲基苯基)哌嗪的制备
按照实例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-(3-三氟甲基苯基)哌嗪(化合物编号32)0.95g，收率45%。m.p.:185-186℃；IR(KBr,cm-1):3444.9,3219.1,2918.2,2849.8,1591.1,1444.4,1384.4,1349.9,1319.6,1269.0,1222.1,1163.5,1112.2,1075.2,999.6,946.4,864.1,785.5;1H-NMR(600MHz,DMSO-d6):δ3.31(8H,t),4.27(2H,s),7.09(d,J=7.7Hz,1H),7.24(d,J=8.4Hz,1H),7.43(t,J=8.0Hz,1H),7.50(1H,s)；MS(m/z):427.2,429.0[M-H]+。
实施例33：1-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)-4-(二苯甲基苯基)哌嗪的制备
按照实例1的方法，制得1-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)-4-(二苯甲基苯基)哌嗪(化合物编号33)0.74g，收率38%。m.p.:138-139℃；IR(KBr,cm-1):3422.1,3207.1,2919.3,2851.1,1617.2,1491.3,1448.8,1384.3,1285.9,1242.7,1142.9,995.3,859.8,747.1,706.2;1H-NMR(600MHz,CDCl3):δ2.44(4H,t),3.08(2H,t),3.47(2H,t),3.76(4H,t),5.25(1H,s),7.19(2H,d,J=7.2Hz),7.22(1H,d,J=5.4Hz),7.26(1H,d,J=5.4Hz),7.28(4H,t,J=7.2Hz),7.41(4H,d,J=7.2Hz)；MS(m/z):487.2[M+H]+。
实施例34：1-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)-4-(4-氯苯基)哌嗪的制备
按照实例1的方法，制得1-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)-4-(4-氯苯基)哌嗪(化合物编号34)0.60g，收率35%。m.p.:140-141℃；IR(KBr,cm-1):3381.8,2920.9,2850.4,1613.8,1493.2,1440.8,1383.9,1342.3,1270.7,1230.9,1155.5,1021.5,998.6,883.5,860.0,825.0;1H-NMR(600MHz,CDCl3):δ3.10(2H,t),3.21(4H,t),3.47(2H,t),3.94(4H,t),6.90(2H,d,J=9.0Hz),7.12(2H,d,J=9.0Hz),7.23(1H,d,J=5.4Hz),7.26(1H,d,J=5.4Hz)；MS(m/z):431.1[M+H]+。
实施例35：1-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)-4-[(4-氯苯基)(苯基)甲基]哌嗪的制备
按照实例1的方法，制得1-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)-4-[(4-氯苯基)(苯基)甲基]哌嗪(化合物编号35)0.87g，收率42%。m.p.:142-143℃；IR(KBr,cm-1):3432.2,2919.3,2851.4,1618.6,1488.1,1445.5,1384.4,1286.8,1241.9,1142.8,995.7,860.1,757.4,719.2;1H-NMR(600MHz,CDCl3):δ2.32(4H,t),3.02(2H,t),3.38(2H,t),3.68(4H,t),4.16(1H,s),7.12(d,J=5.4Hz,1H),7.19(d,J=5.4Hz,1H),7.24(3H,m),7.28(2H,d,J=5.4Hz),7.33(4H,m)；MS(m/z):521.2[M+H]+。
实施例36：N-叔丁基-4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-酰胺的制备
按照实例1的方法，制得N-叔丁基-4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-酰胺(化合物编号36)0.64g，收率52%。m.p.:170-171℃；IR(KBr,cm-1):3393.2,3253.5,2962.0,2921.2,2851.0,1644.8,1521.4,1484.0,1384.6,1363.0,1258.8,1217.8,1124.6,1053.3,877.9,865.2;1H-NMR(600MHz,CDCl3):δ1.47(9H,s),3.10(2H,t),3.69(2H,t),7.21(1H,d,J=5.4Hz),7.24(1H,d,J=5.4Hz)；MS(m/z):308.2[M+H]+。
实施例37：1-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)-4-甲基哌嗪的制备
按照实例1的方法，制得1-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)-4-甲基哌嗪(化合物编号37)0.60g，收率45%。m.p.:107-108℃；IR(KBr,cm-1):3429.0,3228.4,2915.6,2792.8,1608.8,1504.8,1439.5,1352.5,1290.1,1253.7,1225.3,1142.0,997.9,861.7,766.6;1H-NMR(600MHz,CDCl3):δ2.33(3H,s),2.46(4H,t),3.10(2H,t),3.46(2H,t),3.91(4H,t),7.23(1H,d,J=5.4Hz,),7.26(1H,d,J=5.4Hz)；MS(m/z):335.2[M+H]+。
实施例38：N,N-二乙基-4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-酰胺的制备
按照实例1的方法，制得N,N-二乙基-4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-酰胺(化合物编号38)0.69g，收率56%。m.p.:183-185℃；IR(KBr,cm-1):3443.6,3200.5,2929.8,1601.5,1509.2,1479.3,1374.1,1284.1,1262.2,1195.5,1127.7,1092.8,1073.0,1015.8,881.7,859.0;1H-NMR(600MHz,CDCl3):δ1.24(6H,t),3.10(2H,t),3.42(2H,t),3.54(4H,m),7.22(1H,d,J=5.4Hz),7.25(1H,d,J=5.4Hz)；MS(m/z):308.2[M+H]+。
实施例39：1-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)-4-(4-甲基苯基)哌嗪的制备
按照实例1的方法，制得1-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)-4-(4-甲基苯基)哌嗪(化合物编号39)0.71g，收率43%。m.p.:186-187℃；IR(KBr,cm-1):3124.2,2916.4,1631.5,1579.3,1513.5,1443.3,1384.4,1340.9,1264.6,1236.5,1203.3,1154.1,1016.6,999.2,876.2,811.3;1H-NMR(600MHz,CDCl3):δ2.28(3H,s),3.10(2H,t),3.18(4H,t),3.47(2H,t),3.93(4H,t),6.85(2H,d,J=8.4Hz),7.10(2H,d,J=8.4Hz),7.23(1H,d,J=5.4Hz),7.27(1H,d,J=5.4Hz)；MS(m/z):411.2[M+H]+。
实施例40：1-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)-4-苯基哌嗪的制备
按照实例1的方法，制得1-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)-4-苯基哌嗪(化合物编号40)0.75g，收率47%。m.p.:74-75℃；IR(KBr,cm-1):3441.7,3209.2,2920.5,2851.6,1599.6,1495.6,1444.2,1384.1,1260.4,1230.6,1153.3,1016.0,998.3,875.4,759.5;1H-NMR(600MHz,CDCl3):δ3.10(2H,t),3.20(1H,t),3.27(4H,t),3.47(1H,t),4.02(4H,t),6.90(1H,m),6.95(2H,m),7.23(1H,d,J=5.4Hz),7.28(1H,d,J=5.4Hz),7.29(2H,m)；MS(m/z):397.2[M+H]+。
实施例41：1-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)-4-(4-三氟甲氧基苯基)哌嗪的制备
按照实例1的方法，制得1-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)-4-(4-三氟甲氧基苯基)哌嗪(化合物编号41)0.85g，收率44%。m.p.:85-86℃；IR(KBr,cm-1):3441.7,3209.2,2920.5,2851.6,1599.6,1495.6,1444.2,1384.1,1260.4,1230.6,1153.3,1016.0,998.3,875.4,759.5;1H-NMR(600MHz,CDCl3):δ3.10(2H,t),3.21(4H,t),3.47(2H,t),3.94(4H,t),6.90(2H,d,J=9.0Hz),7.12(2H,d,J=9.0Hz),7.23(1H,d,J=5.4Hz),7.26(1H,d,J=5.4Hz)；MS(m/z):481.1[M+H]+。
实施例42：1-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)-4-(4-三氟甲氧基苯基)哌嗪的制备
按照实例1的方法，制得1-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)-4-(4-三氟甲氧基苯基)哌嗪(化合物编号42)0.75g，收率45%。m.p.:195-197℃；IR(KBr,cm-1):3441.9,2919.7,2851.3,1603.7,1509.0,1444.9,1384.5,1341.8,1263.2,1229.1,1157.7,1017.4,999.5,877.7,817.2;1H-NMR(600MHz,CDCl3):δ3.11(2H,t),3.30(4H,t),3.50(2H,t),3.98(4H,t),6.91(2H,dd,J=9.1Hz,4.2Hz),6.99(2H,dd,J=9.1Hz,4.2Hz),7.24(1H,d,J=5.4Hz),7.25(1H,d,J=5.4Hz)；MS(m/z):415.1[M+H]+。
实施例43：1-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)-4-苄基哌嗪的制备
按照实例1的方法，制得1-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)-4-苄基哌嗪(化合物编号43)0.80g，收率49%。m.p.:72-73℃；IR(KBr,cm-1):3427.6,3210.5,2918.4,2851.1,2809.1,1613.9,1446.0,1384.2,1347.7,1287.2,1229.1,1143.5,997.1,860.2,740.7,699.1;1H-NMR(600MHz,CDCl3):δ2.50(4H,t),3.10(2H,t),3.44(2H,t),3.54(2H,s),3.77(4H,t),7.24(d,J=4.8Hz,1H),7.26(d,J=4.8Hz,1H),7.31(5H,m)；MS(m/z):411.2[M+H]+,433.1[M+Na]+。
实施例44：1-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)-4-(4-甲氧基苯基)哌嗪的制备
按照实例1的方法，制得1-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)-4-(4-甲氧基苯基)哌嗪(化合物编号44)0.84g，收率49%。m.p.:156-158℃；IR(KBr,cm-1):3443.8,3196.6,2920.6,2851.1,1611.7,1510.5,1445.2,1384.2,1279.1,1246.5,1225.8,1154.6,1034.6,995.2,859.4;1H-NMR(600MHz,CDCl3):δ3.11(10H,m),3.47(2H,t),3.78(3H,s),6.85(2H,J=9Hz),6.92(2H,d,J=9Hz),7.24(d,J=4.8Hz,1H),7.32(d,J=4.8Hz,1H)；MS(m/z):427.2[M+H]+,449.2[M+Na]+。
实施例45：1-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)-4-(3-三氟甲基苯基)哌嗪的制备
按照实例1的方法，制得1-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)-4-(3-三氟甲基苯基)哌嗪(化合物编号45)0.80g，收率43%。m.p.:85-87℃；IR(KBr,cm-1):3444.3,3212.2,2919.3,2851.0,1610.1,1495.4,1445.9,1384.5,1348.8,1232.6,1162.9,1120.8,995.3,860.3;1H-NMR(600MHz,CDCl3):δ3.11(2H,t),3.30(4H,t),3.50(2H,t),3.98(4H,t),7.08(1H,d,J=8.4Hz),7.13(2H,m),7.25(2H),7.38(1H,dd,J=8.4Hz,8.4Hz),10.26(1H,s)；MS(m/z):465.1[M+H]+。
实施例46：1-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)-4-(3-溴苯基)哌嗪的制备
按照实例1的方法，制得1-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)-4-(3-溴苯基)哌嗪(化合物编号46)0.76g，收率40%。m.p.:195-197℃；IR(KBr,cm-1):3443.9,2920.9,2851.1,1589.7,1444.0,1384.1,1236.2,1124.2,994.4,860.0;1H-NMR(600MHz,CDCl3):δ3.06(2H,t),3.24(8H,t),3.78(2H,t),6.94(2H,m),7.10(1H,d),7.15(1H,t),7.54(d,J=5.4Hz,1H),7.56(d,J=5.4Hz,1H),13.15(1H,s)；MS(m/z):474.4,476.3[M+H]+。
实施例47：1-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)-4-(3,4-二氟苯基)哌嗪的制备
按照实例1的方法，制得1-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)-4-(3,4-二氟苯基)哌嗪(化合物编号47)0.80g，收率46%。m.p.:230-232℃；IR(KBr,cm-1):3369.6,3258.9,2920.5,2850.8,1662.4,1629.5,1555.5,1515.3,1434.9,1384.1,1280.9,1222.0,1189.0,1116.2,1004.4,870.1,805.1;1H-NMR(600MHz,CDCl3):δ2.95(4H,t),3.15(2H,t),3.74(2H,t),3.91(4H,t),7.13(1H),7.22(1H,d,J=5.4Hz),7.24(1H,m),7.28(1H,d,J=5.4Hz),7.80(1H,m)；MS(m/z):433.2[M+H]+。
实施例48：N,N-二甲基-4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-酰胺的制备
按照实例1的方法，制得N,N-二甲基-4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-酰胺(化合物编号48)0.59g，收率53%。m.p.:232-233℃；IR(KBr,cm-1):3199.3,3153.2,3055.3,2924.6,1616.9,1524.1,1425.8,1385.1,1144.7,1088.7,1007.5,914.6,861.8,769.0,696.6;1H-NMR(600MHz,CDCl3):δ3.10(2H,t),3.16(6H,m),3.45(2H,t),7.24(1H,d,J=5.5Hz,),7.27(1H,d,J=5.5Hz,)；MS(m/z):280.0[M+H]+。
实施例49：1-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)吡咯烷的制备
按照实例1的方法，制得1-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)吡咯烷(化合物编号49)0.60g，收率49%。m.p.:170℃；IR(KBr,cm-1):3263.2,2920.4,2875.7,1595.8,1526.9,1492.2,1470.4,1432.4,1382.8,1339.4,1224.1,1007.6,898.7,861.2,760.5,688.5;1H-NMR(600MHz,CDCl3):δ1.82(2H,m),1.93(2H,m),3.11(2H,t),3.37(4H,t),3.59(2H,t),7.23(1H,d,J=5.5Hz),7.25(1H,d,J=5.5Hz)；MS(m/z):306.2[M+H]+,328.1[M+Na]+。
实施例50：N-异丙基-4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-酰胺的制备
按照实例1的方法，制得N-异丙基-4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-酰胺(化合物编号50)0.66g，收率56%。m.p.:214-215℃；IR(KBr,cm-1):3408.8,3256.4,2922.4,1644.1,1543.5,1523.7,1485.7,1446.4,1384.0,1125.5,1007.9,859.5,760.8,692.2;1H-NMR(600MHz,CDCl3):δ1.26(6H,d),3.12(2H,t),3.71(2H,t),4.25(1H,m),7.20(1H,d,J=5.5Hz),7.24(1H,d,J=5.5Hz)；MS(m/z):294.1[M+H]+。
实施例51：N-苄基-4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-酰胺的制备
按照实例1的方法，制得N-苄基-4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-酰胺(化合物编号51)0.63g，收率46%。m.p.:136-138℃；IR(KBr,cm-1):33401.9,3217.8,2921.8,2851.3,1648.5,1546.9,1452.8,1384.2,1241.6,1128.0,861.8,752.2,698.0,615.7;1H-NMR(600MHz,CDCl3):δ3.12(2H,t),3.73(2H,t),4.62(2H,d),7.20(1H,m),7.23(1H,d,J=5.5Hz),7.28(1H,d,J=5.5Hz),7.34(4H,m)；MS(m/z):342.1[M+H]+。
实施例52：N-苯基-4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-酰胺的制备
按照实例1的方法，制得N-苯基-4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-酰胺(化合物编号52)0.50g，收率38%。m.p.:240℃；IR(KBr,cm-1):3422.8,2921.0,2850.9,1663.2,1596.1,1542.8,1440.4,1384.1,1121.3,861.5,753.4,694.0,618.0;1H-NMR(600MHz,CDCl3):δ3.15(2H,t),3.76(2H,t),7.13(1H,m),7.22(1H,d,J=5.5Hz,),7.28(1H,d,J=5.5Hz),7.37(2H,dd,J=7.9Hz,7.9Hz),7.68(2H,d,J=7.9Hz)；MS(m/z):328.1[M+H]+。
实施例53：4-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)吗啉的制备
按照实例1的方法，制得4-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)吗啉(化合物编号53)0.67g，收率52%。m.p.:176-178℃；IR(KBr,cm-1):3439.5,2920.5,2851.6,1611.7,1434.2,1271.5,1242.1,1194.6,1115.5,1024.6,995.5,861.4,619.7;1H-NMR(600MHz,CDCl3):δ3.11(2H,t),3.48(2H,t),3.75(4H,t),3.81(4H,t),7.22(1H,d,J=5.4Hz),7.25(1H,d,J=5.4Hz)；MS(m/z):322.0[M+H]+。
实施例54：1-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)哌啶的制备
按照实例1的方法，制得1-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)哌啶(化合物编号54)0.55g，收率43%。m.p.:76-78℃；IR(KBr,cm-1):3435.9,3229.1,2920.1,2851.2,1607.8,1514.6,1445.3,1384.1,1254.9,1138.8,1027.8,989.4,859.0,774.5,617.9;1H-NMR(600MHz,CDCl3):δ1.27(2H,m),1.64(4H,m),3.11(2H,t),3.42(2H,t),3.66(4H,t),7.23(1H,d,J=5.4Hz),7.24(1H,d,J=5.4Hz)；MS(m/z):320.1[M+H]+。
实施例55：N-(呋喃-2-基亚甲基)-4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-酰胺的制备
按照实例1的方法,制得N-(呋喃-2-基亚甲基)-4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-酰胺(化合物编号55)0.46g，收率35%。m.p.:155-156℃；IR(KBr,cm-1):3408.3,3227.4,2921.6,2850.7,1650.4,1542.9,1523.7,1484.0,1417.8,1384.2,1190.0,1147.0,1003.1,964.7,861.9,747.9,693.0;1H-NMR(600MHz,CDCl3):δ3.12(2H,t),3.71(2H,t),4.60(2H,d),6.29(1H,m),6.33(1H,m),7.20(1H,d,J=5.4Hz),7.25(1H,d,J=5.4Hz),7.37(1H,m)；MS(m/z):331.6[M+H]+。
实施例56：1-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)-4-(3-氯-4-氟苯基)哌嗪的制备
按照实例1的方法，制得1-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)-4-(3-氯-4-氟苯基)哌嗪(化合物编号56)0.88g，收率49%。m.p.:205-206℃；IR(KBr,cm-1):33434.2,3288.2,2919.2,2850.7,1603.4,1503.1,1462.9,1444.8,1384.2,1223.5,1156.2,994.4,945.2,865.3,733.5,688.5;1H-NMR(600MHz,CDCl3):δ3.12(2H,t),3.16(4H,t),3.49(2H,t),3.95(4H,t),6.79(1H,m),6.95(1H,dd,J=6.3Hz,2.4Hz),7.05(1H,dd,J=9.0Hz,8.7Hz),7.23(1H,d,J=5.4Hz),7.25(1H,d,J=5.4Hz)；MS(m/z):449.0,450.8[M+H]+。
实施例57：1-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)-4-(2-甲基苯基)哌嗪的制备
按照实例1的方法，制得1-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)-4-(2-甲基苯基)哌嗪(化合物编号57)0.72g，收率44%。m.p.:192-194℃；IR(KBr,cm-1):3442.6,3264.4,2919.3,2851.2,1601.8,1492.0,1474.7,1442.8,1383.7,1223.1,1152.0,1026.2,995.5,861.7,761.1,691.0;1H-NMR(600MHz,CDCl3):δ2.33(3H,s),2.95(4H,t),3.12(2H,t),3.48(2H,t),3.91(4H,t),7.02(2H,m),7.18(2H,m),7.23(1H,d,J=5.5Hz),7.27(1H,d,J=5.5Hz)；MS(m/z):409.0[M-H]+。
实施例58：1-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)-4-(3,5-二三氟甲基苯基)哌嗪的制备
按照实例1的方法，制得1-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)-4-(3,5-二三氟甲基苯基)哌嗪(化合物编号58)0.92g，收率43%。m.p.:89-91℃；IR(KBr,cm-1):3444.6,2920.4,1618.5,1476.8,1384.9,1277.4,1240.0,1177.9,1130.4,995.0,963.9,861.1,720.5,682.3;1H-NMR(600MHz,CDCl3):δ3.12(2H,t),3.38(4H,t),3.51(2H,t),4.01(4H,t),7.23(2H,m),7.27(1H,s),7.24(1H,s),7.34(1H,s)；MS(m/z):533.4[M+H]+。
实施例59：1-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)-4-(2-氟苯基)哌嗪的制备
按照实例1的方法，制得1-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)-4-(2-氟苯基)哌嗪(化合物编号59)0.66g，收率40%。m.p.:79-81℃；IR(KBr,cm-1):3439.4,2918.7,1611.8,1500.0,1440.3,1384.7,1342.1,1286.6,1236.6,1201.2,1147.9,998.6,884.5,860.5,747.8;1H-NMR(600MHz,CDCl3):δ2.23(2H,t),3.12(4H,t),3.48(4H,t),3.66(2H,t),7.01(1H,m),7.03(1H,m),7.25(2H,m),7.38(1H,m),7.39(1H,m)；MS(m/z):415.3[M+H]+,437.1[M+Na]+。
实施例60：1-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)-4-(2-氯苯基)哌嗪的制备
按照实例1的方法，制得1-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)-4-(2-氯苯基)哌嗪(化合物编号60)0.66g，收率38%。m.p.:203-205℃；IR(KBr,cm-1):3441.5,3214.1,2920.0,2851.1,1601.9,1500.3,1477.4,1443.6,1384.1,1336.5,1286.9,1237.1,1202.8,1146.5,1025.4,997.1,861.8,759.2,689.2;1H-NMR(600MHz,CDCl3):δ2.23(2H,t),3.12(4H,t),3.48(4H,t),3.66(2H,t),7.02(2H,m),7.25(2H,m),7.38(2H,m)；MS(m/z):431.0,432.9[M+H]+。
实施例61：N–叔丁基-7,8-二溴-1,4-二氢噻吩并[3',2':5,6]噻喃并[4,3-c]吡唑-3-酰胺的制备
按照实例1的方法，制得N–叔丁基-7,8-二溴-1,4-二氢噻吩并[3',2':5,6]噻喃并[4,3-c]吡唑-3-酰胺(化合物编号61)0.58g，收率32%。m.p.:224-226℃；IR(KBr,cm-1):3391.7,3075.6,2935.1,1653.5,1544.7,1520.1,1439.2,1366.5,1265.9,1217.1,1018.8,987.3,966.9,858.4,822.7;1H-NMR(600MHz,CDCl3):δ1.49(9H,s),4.49(2H,s),7.40(1H,s)；ESI-MS(m/z):450.2,452.2,454.2[M+H]+。
实施例62：N,N–二甲基-7,8-二溴-1,4-二氢噻吩并[3',2':5,6]噻喃并[4,3-c]吡唑-3-酰胺的制备
按照实例1的方法，制得N,N–二甲基-7,8-二溴-1,4-二氢噻吩并[3',2':5,6]噻喃并[4,3-c]吡唑-3-酰胺(化合物编号62)0.76g，收率42%。m.p.:159-160℃；IR(KBr,cm-1):3422.3,2977.2,2933.9,2603.8,1602.2,1476.5,1397.8,1383.3,1271.0,1172.0,1036.7,850.8,807.0;1H-NMR(600MHz,CDCl3):δ1.25(6H,m),3.54(4H,m),4.12(2H,s)；ESI-MS(m/z):450.2,452.2,454.2[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63：
雌激素受体α快速板测定
本测定检测放射性标记雌激素与雌激素受体的结合。该测定是在BioMek2000(Beckman)上进行的。板在闪烁计数器(PackardTopcount)上读数，计数减少说明化合物与所述受体结合。所述测定按照Allan等，Anal.Biochem(1999),275(2),243-247介绍的方法进行。
第一天，向与山羊抗小鼠抗体(NENLifeSciences)交联的96孔FlashPlatePlus板的各孔中加入100μL含有5mM二硫苏糖醇(DTT,Panvera)，0.5μg小鼠抗刺激素受体单克隆抗体(SRA-1010,Stressgen)和50ng纯化人雌激素受体α(Panvera)的雌激素筛选缓冲液(ESB,Panvera)。密封该板并于4℃保温过夜。
第二天，各孔用200μLPBSpH7.2在室温下洗涤三次，然后向各孔中加入98μL放射性标记雌激素(0.5nM,对于每批120Ci/mmol相当于6nCi,Amersham)，用ESB和5mM二硫苏糖醇(DTT)稀释。然后向各孔中加入2.5μL用30%(v/v)二甲亚砜/50mMHEPESpH7.5稀释的试验化合物。通过吸打将各孔混合三次，密封该板并在室温下保温1小时。然后在Topcount闪烁计数器(Packard)中，对各孔计数1分钟。
实施例64：
雌激素受体β荧光偏振测定
本测定检测雌激素荧光类似物(FluormoneES2,Panvera)与雌激素受体的结合。板在可以设定为偏振模式的荧光计数器(PackardTopCount)上读数。相对于溶媒对照，荧光减少说明化合物与所述受体结合。
至关重要的是，在整个过程中，避免将气泡引入96孔板各孔中的反应中。(反应表面的气泡破坏光通量，从而影响偏振读数)。然而，在将反应组分加入到各孔后充分混合也是至关重要的。
在冰上制备测定缓冲液(Panvera)、10nMDTT和40nMES2的2Ｘ标准混合物。在冰上也制备测定缓冲液(Panvera)和20nMhER-β(Panvera)和40nMES2的2X反应混合物。
用30%(v/v)二甲亚砜/50mMHEPESpH7.5制备试验化合物的稀释液。此时，所述稀释液为40X所需终浓度。
然后向各孔中加入50μL标准混合物。向所有孔中加入48μL反应混合物。向适当孔中加入2.5μL所述化合物稀释液。用手工吸移管混合所述反应混合物，将一卷铝箔粘性面覆盖在该板上，然后将该板在室温下保温1小时。
然后在LjLAnalyst上，读出激发波长265nm和发射波长538nm下该板各孔的读数。
按照上述方法，测试本发明代表性化合物与雌激素受体α和雌激素受体β的结合，结果示于表1。
表1
实施例65：
MCF-7细胞增殖测定
按照Welshons等(BreastCancetRes.Treat.,1987,10(2),169-75)介绍的方法，进行本项测定。
将MCF-7细胞维持在RPMI1640无酚红培养基(Gibco)中，所述培养基含有10%FBS(Hyclone)、补充牛胰岛素和非必需氨基酸(Sigma)。所述细胞首先用4-羟基他莫西芬(10-8Ｍ)处理，然后让其于37℃静置24小时。在与他莫西芬进行该保温后，所述细胞用不同浓度的化合物进行处理。
向所述培养基中加入不同浓度的激动剂模式的待测化合物。同样制备拮抗剂模式的待处理化合物，也向所述培养基中加入10nM17β-雌二醇。将所述细胞于37℃保温24小时。保温后，向所述培养基中加入0.1μCi14C-胸苷(56mCi/mmol,Amersham)，将所述细胞再于37℃保温24小时。所述细胞然后用Hank氏缓冲盐溶液(HBSS)(Gibco)洗涤两次，然后用闪烁计数器进行计数。相对于溶媒对照细胞，用所述化合物处理的细胞14C-胸苷增加报告为细胞增殖增加百分率。
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
NA表示在试验浓度下没有检测到活性。
实施例66
人子宫内膜Ishikawa细胞的碱性磷酸酶测定
按照Albert等，CancerRes，(9910)，50(11)，330-6-10介绍的方法进行本项测定。
将Ishikawa细胞维持在补充10%小牛血清(Hyclone)的DMEM/F12(1：1)无酚红培养基(Gibco)中。测试前24小时，将培养基更换为含2%小牛血清的无酚红DMEM/F12(1：1)。
向所述培养基中加入不同浓度的激动剂模式的待测化合物。同样制备拮抗剂模式的待处理化合物，也向所述培养基中加入10nM17β-雌二醇。将所述细胞于37℃保温3天。在第三天，去除培养基，向各孔中先加入1倍体积的1X稀释缓冲液(Clontech)，加入1倍体积的测定缓冲液(Clontech)。然后将所述细胞在室温下保温5分钟。加入1倍体积的新鲜制备的化学发光缓冲液(1倍体积的化学发光底物(CSPD)，19倍体积的化学发光增强剂，CSPD的终浓度为1.25mM；SigmaChemicalCo.)将所述细胞在室温下保温10分钟，然后在发光计上进行定量。相对于溶媒对照，用化学发光增加计算碱性磷酸酶活性的增强。
按照上述方法，测试本发明代表性化合物，结果示于表3。
表3
实施例67:对HOB细胞中IL-6和GM-CSF生产的作用
将人体破骨细胞HOB铺板在96孔皿内使其在常规HOB培养基(Ham氏F12，补充有28mMHEPES，pH7.4，10%FCS，1.1mMCaCl2，2mM谷酰胺和1%抗生素-抗真菌剂)中的密度为7×103个细胞/孔。次日，细胞用化合物或载体处理(0.2%DMSO)处理30分钟，随后加入IL-1β(1ng/mL)和TNF-α(10ng/mL)。培养持续18至24小时。利用市售ELISA试剂盒测定培养基中IL-6和GM-CSF水平。本发明化合物显示出对IL-6和GM-CSF的抑制作用。
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
实施例68：对HOB细胞中IL-6和GM-CSF生产的作用
将人体破骨细胞HOB铺板在96孔皿内使其在常规HOB培养基(Ham氏F12，补充有28mMHEPES，pH7.4，10%FCS，1.1mMCaCl2，2mM谷酰胺和1%抗生素-抗真菌剂)中的密度为7×103个细胞/孔。次日，细胞用化合物或载体处理(0.2%DMSO)处理30分钟，随后加入IL-1β(1ng/mL)和TNF-α(10ng/mL)。培养持续18至24小时。利用市售ELISA试剂盒测定培养基中IL-6和GM-CSF水平。本发明化合物显示出对IL-6和GM-CSF的抑制作用
按照上述方法测定本发明代表性化合物，结果示于表5。
表5
实施例69：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)RPMI1640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20μLMTT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6。
表6
实施例70：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7。
表7
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71：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72：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73：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、淀粉和纤维素通过美国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，随后经美国14号目筛。将生成的颗粒在50-60℃下干燥并经美国18号目筛。将预先经过美国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74：混悬液
每5ml含有0.1-1000mg药物的混悬液制备如下：
令药物经美国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75：组合片剂
使活性成分、淀粉和纤维素通过美国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，随后经美国14号目筛。将生成的颗粒在50-60℃下干燥并经美国18号目筛。将预先经过美国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 (7)
1.下列1,4-二氢噻吩并[3’,2’:5,6]噻喃并[4,3-c]吡唑类化合物及其药学上可接受的盐，选自：
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-甲基苯基)哌嗪；
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-(二苯基甲基)哌嗪；
N,N-二乙基-7-溴-1,4-二氢噻吩并[3’,2’:5,6]噻喃并[4,3-c]吡唑-3-酰胺；
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-(3-氯-4-氟苯基)哌嗪；
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-氯苯基)哌嗪；
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-(4-三氟甲氧基苯基)哌嗪；
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-(2-氟苯基)哌嗪；
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-(4-三甲氧基苯基)哌嗪；
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-苯基哌嗪；
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-氟苯基)哌嗪；
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-甲基哌嗪；
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-苄基哌嗪；
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-氯苯基)(苯基)甲基]哌嗪；
N-叔丁基-7-溴-1,4-二氢噻吩并[3’,2’:5,6]噻喃并[4,3-c]吡唑-3-酰胺；
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-(3-溴苯基)哌嗪；
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；
4-(7-溴-1,4-二氢噻吩并[3’,2’:5,6]噻喃并[4,3-c]吡唑-3-羰基)吗啉；
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)吡咯烷；
N-异丙基-7-溴-1,4-二氢噻吩并[3’,2’:5,6]噻喃并[4,3-c]吡唑-3-酰胺；
N-(2-二乙胺基)乙基-7-溴-1,4-二氢噻吩并[3’,2’:5,6]噻喃并[4,3-c]吡唑-3-酰胺；
N,N-二甲基-7-溴-1,4-二氢噻吩并[3’,2’:5,6]噻喃并[4,3-c]吡唑-3-酰胺；
N-苯基-7-溴-1,4-二氢噻吩并[3’,2’:5,6]噻喃并[4,3-c]吡唑-3-酰胺；
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)哌啶；
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)哌啶；
N–(呋喃-2-基亚甲基)-7-溴-1,4-二氢噻吩并[3’,2’:5,6]噻喃并[4,3-c]吡唑-3-酰胺；
N–(吡啶-2-基)-7-溴-1,4-二氢噻吩并[3’,2’:5,6]噻喃并[4,3-c]吡唑-3-酰胺；
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-(3,5-二三氟甲基苯基)哌嗪；
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-(3,4-二氟苯基)哌嗪；
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-(2-甲基苯基)哌嗪；
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-(2-氯苯基)哌嗪；
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-(2,5-二甲基苯基)哌嗪；
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-(3-三氟甲基苯基)哌嗪；
N–叔丁基-7,8-二溴-1,4-二氢噻吩并[3',2':5,6]噻喃并[4,3-c]吡唑-3-酰胺。
2.下列3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑类化合物及其药学上可接受的盐，选自：
1-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)-4-(二苯甲基苯基)哌嗪；
1-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)-4-(4-氯苯基)哌嗪；
1-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)-4-[(4-氯苯基)(苯基)甲基]哌嗪；
N-叔丁基-4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-酰胺；
1-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)-4-甲基哌嗪；
N,N-二乙基-4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-酰胺；
1-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)-4-(4-甲基苯基)哌嗪；
1-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)-4-苯基哌嗪；
1-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)-4-(4-三氟甲氧基苯基)哌嗪；
1-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)-4-(4-三氟甲氧基苯基)哌嗪；
1-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)-4-苄基哌嗪；
1-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)-4-(4-甲氧基苯基)哌嗪；
1-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)-4-(3-三氟甲基苯基)哌嗪；
1-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)-4-(3-溴苯基)哌嗪；
1-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)-4-(3,4-二氟苯基)哌嗪；
N,N-二甲基-4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-酰胺；
1-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)吡咯烷；
N-异丙基-4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-酰胺；
N-苄基-4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-酰胺；
N-苯基-4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-酰胺；
4-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)吗啉；
1-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)哌啶；
N-(呋喃-2-基亚甲基)-4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-酰胺；
1-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)-4-(3-氯-4-氟苯基)哌嗪；
1-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)-4-(2-甲基苯基)哌嗪；
1-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)-4-(3,5-二三氟甲基苯基)哌嗪；
1-(4,5-二氢-3aH-噻吩并[2',3':2,3]硫杂并[4,5-c]吡唑-3-羰基)-4-(2-氯苯基)哌嗪。
3.一种药物组合物，包含作为活性成分的权利要求1-2任一项所述化合物及其药学上可接受的盐和药物可接受的载体。
4.权利要求1或2所述的化合物或权利要求3所述的药物组合物在制备治疗非小细胞肺癌、小细胞肺癌药物中的应用。
5.权利要求1或2所述的化合物或权利要求3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。
6.根据权利要求5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。
7.根据权利要求5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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