CN108017659A - 苯并咪唑并噻唑甲酰胺类化合物及其应用 - Google Patents
苯并咪唑并噻唑甲酰胺类化合物及其应用 Download PDFInfo
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- CN108017659A CN108017659A CN201711258608.4A CN201711258608A CN108017659A CN 108017659 A CN108017659 A CN 108017659A CN 201711258608 A CN201711258608 A CN 201711258608A CN 108017659 A CN108017659 A CN 108017659A
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- Prior art keywords
- imidazo
- methylbenzo
- thiazole
- carboxamide
- piperazin
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- 208000000587 small cell lung carcinoma Diseases 0.000 claims abstract description 3
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- 238000002360 preparation method Methods 0.000 claims description 118
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 84
- MPJGUDCVLUNWPK-UHFFFAOYSA-N imidazo[2,1-b][1,3]thiazole-2-carboxamide Chemical compound S1C=2N(C=C1C(=O)N)C=CN=2 MPJGUDCVLUNWPK-UHFFFAOYSA-N 0.000 claims description 15
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Abstract
本发明属于医药技术领域，涉及苯并咪唑并噻唑甲酰胺类化合物及其应用。苯并咪唑并噻唑甲酰胺类化合物包括苯并咪唑并噻唑甲酰胺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：其中R1、R2如权利要求和说明书所述。苯并咪唑并噻唑甲酰胺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导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。
Description
技术领域
本发明属于医药技术领域，涉及苯并咪唑并噻唑甲酰胺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
长期以来，肿瘤治疗一直属于世界性难题，成为医药研究领域面临的一项重要挑战。近年来，随着肿瘤发病机制的进一步阐明和抗肿瘤作用靶点的不断发现，蛋白酪氨酸激酶(protein tyrosine kinase,PTK)已经成为效果显著且前景广阔的抗肿瘤药物靶点之一。
表皮生长因子受体(epidermal growth factor receptor,EGFR)，是一种同时具有膜外配体受体结合域及细胞内酪氨酸激酶活性域的跨膜蛋白。EGFR家族主要包括四类成员：EGFR/ErbB-1、HER-2/ErbB-2、HER-3/ErbB-3和HER-4/ErbB-4。EGFR广泛分布在哺乳类动物的上皮细胞膜，其基因定位于7号染色体P12-P14区段，是一种由1186个氨基酸所组成的相对分子量约为170kD的跨膜糖蛋白。它包括：由621个氨基酸残基组成的N端胞外区(ECD)，具有配体结合位点，细分为I、II、III、IV四个亚区；由23个氨基酸残基组成的具有α螺旋结构的跨膜区(TM)，其通过一个脯氨酸与胞外区相连；由542个氨基酸残基构成的C端胞内区，具有一个酪氨酸激酶结构域，包含近膜区(JM)、酪氨酸激酶区(TK)、C-末端等三个亚区。
EGFR信号通路包括配体诱导胞外区构象变化、跨膜信号转导、胞内区形成激酶活性与下游信号激活、信号灭活四部分。配体与EGFR结合后形成二聚体，同时结合1个ATP分子，促使胞内域相互作用形成激酶活性，并完成胞内域酪氨酸残基的磷酸化。EGFR二聚体化和磷酸化后，激活下游的信号转导系统并成为亲和位点，与多种参与有丝分裂的信号转导分子发生高亲和作用。这些系统将有丝分裂信号从细胞外传递到细胞内，进而有效调节细胞对外界刺激的反应及细胞增殖、存活、黏附、迁移和分化等。
目前大量的研究表明，人类许多实体肿瘤与EGFR和/或其一级配体中的任一个过度表达或行为失调密切相关。Sebastian等报道了EGFR信号转导与肿瘤的关系，研究结果表明，至少有33％-50％的人类表皮肿瘤与EGFR相关，它是表皮肿瘤治疗的重要靶点。EGFR在多种肿瘤细胞中均存在高表达现象，头颈癌中为90％-95％，子宫颈癌中为90％，乳腺癌中为82％-90％，肾癌中为76％-89％，食道癌中为43％-89％。而在卵巢癌、前列腺癌、胰腺癌、结肠癌、非小细胞肺癌、神经胶质瘤等肿瘤细胞中，EGFR同样呈现高水平表达现象。由于EGFR及其配体在多种肿瘤的发生发展中发挥着重要作用，针对EGFR的抗肿瘤治疗成为近年来肿瘤治疗研究的热点。
目前，表皮生长因子受体酪氨酸激酶抑制剂(epidermal growth factorreceptor-tyrosine kinase inhibitors,EGFR-TKI)主要分为两大类：(1)EGFR单克隆抗体，代表药物有西妥昔单抗、帕尼单抗等；(2)小分子EGFR-TKI，代表药物有吉非替尼、厄洛替尼等。
EGFR-TKI类药物，尤其是以吉非替尼和厄洛替尼等为代表的小分子EGFR-TKI靶向治疗药物，在人类肿瘤治疗领域应用已经取得了显著成果。然而，该类药物的研制与开发也面临着诸多挑战：由于肿瘤细胞基因突变而造成的耐药问题日益严重；多靶点抑制作用和高选择性抑制作用之间应该寻求平衡；在临床前实验中准确预测化合物毒性、药动学特征等。这些问题亟待科学家去解决，从而提高新药研发效率和避免浪费资源。因此，研制高效低毒、结构新颖的小分子EGFR-TKI具有重大理论意义和实际意义。
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，药效作用与现有药物相当或优于现有药物的特点，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，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可以独立地地选自H，C1-C8烷基，羟基取代的C2-C8烷基，卤素取代的C2-C8烷基，C3-C6环烷基，2-(2-甲氧基苯氧基)乙基，苄基，C1-C6烷基取代的苄基，C1-C6烷氧基取代的苄基，卤素取代的苄基，苯基，C1-C6烷基取代的苯基，C1-C6烷氧基取代的苯基，羟基取代的苯基，苄氧基苯基，卤素取代的苯基，硝基取代的苯基，4-联苯基，1-萘基，2-萘基，1-苯基乙基，2-苯基乙基，4-吗啉基，2-(4-吗啉基)乙基，3-(4-吗啉基)丙基，2-吡啶甲基，2-吡啶基，C1-C6烷基取代的2-吡啶基，2-呋喃甲基，苯并[d]噻唑-2-基，1H-1,2,4-三氮唑-3-基，或2-乙氧基羰甲基；或与它们相连的氮原子一起组成1-哌啶基，1-吡咯烷基，4-吗啉基，苯基哌嗪-1-基，C1-C6烷基取代的苯基哌嗪-1-基，C1-C6烷氧基取代的苯基哌嗪-1-基，卤素取代的苯基哌嗪-1-基，苄基哌嗪-1-基，C1-C6烷基取代的苄基哌嗪-1-基，C1-C6烷氧基取代的苄基哌嗪-1-基，卤素取代的苄基哌嗪-1-基。
进一步地，R1、R2可以独立地选自H，甲基，异丙基，正丁基，异丁基，正辛基，2-羟基乙基，2-羟基-1,1-二甲基乙基，2-氯乙基，2-溴乙基，2-羟基乙基，环戊基，环己基，2-(2-甲氧基苯氧基)乙基，苄基，4-氟苄基，4-氯苄基，3-氯-4-甲氧基苄基，苯基，2-甲基苯基，4-甲基苯基，2,4-二甲基苯基，2-乙基苯基，4-乙基苯基，4-三氟甲基苯基，2-甲氧基苯基，4-甲氧基苯基，2,5-二甲氧基苯基，4-烯丙氧基苯基，2-羟基苯基，4-羟基苯基，4-苄氧基苯基，4-氟苯基，4-氯苯基，4-溴苯基，3,5-二氟苯基，3-溴-4-氟苯基，4-溴-3-氟苯基，5-氟-2-甲氧基苯基，5-溴-2-甲氧基苯基，4-氯-3-三氟甲基苯基，3-硝基苯基，4-硝基苯基，4-联苯基，1-萘基，2-萘基，1-苯基乙基，2-苯基乙基，4-吗啉基，2-(4-吗啉基)乙基，3-(4-吗啉基)丙基，2-吡啶甲基，2-吡啶基，3-甲基-2-吡啶基，4-甲基-2-吡啶基，3-苄氧基-2-吡啶基，2-呋喃甲基，苯并[d]噻唑-2-基，1H-1,2,4-三氮唑-3-基，或2-乙氧基羰甲基；或与它们相连的氮原子一起组成1-哌啶基，1-吡咯烷基，4-吗啉基，4-苯基哌嗪-1-基，4-(2-甲基苯基)哌嗪-1-基，4-(4-甲基苯基)哌嗪-1-基，4-(2,4-二甲基苯基)哌嗪-1-基，4-(2-乙基苯基)哌嗪-1-基，4-(3-三氟甲基苯基)哌嗪-1-基，4-(4-甲氧基苯基)哌嗪-1-基，4-(4-氟苯基)哌嗪-1-基，4-(3-氯苯基)哌嗪-1-基，4-(3-溴苯基)哌嗪-1-基，4-(2,3-二氯苯基)哌嗪-1-基，4-(4-氯苯基)哌嗪-1-基，4-(4-氯-3-三氟甲氧基苯基)哌嗪-1-基，4-苄基哌嗪-1-基，4-(4-甲基苄基)哌嗪-1-基，4-(4-甲氧基苄基)哌嗪-1-基，4-二苯甲基哌嗪-1-基，4-[(4-氯苯基)(苯基)甲基]哌嗪-1-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”如药学上可接受的载体、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。
本发明中应用的术语“卤素”包括氟、氯或溴。
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。
如下流程概括了制备本发明化合物的制备步骤。
具体实施方式
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：N-(2-甲基苯基)-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺(化合物X01)的制备
步骤A：2-巯基苯并咪唑的制备
将邻苯二胺(21.61g,0.20mol)，二硫化碳(18.24g,0.24mol)，碳酸钠(14.84g,0.14mol)与水300mL置于500mL茄形瓶中，加热回流反应7h后，反应液凉至室温，抽滤，干燥，得白色固体29.4g，收率98.0％，m.p.290-292℃(lit.:303-305℃),ESI-MS(m/z):151.1([M+H]+)；IR(KBr):υ3441,3153,3114,2979,2877,1618,1513,1467,1215；1H-NMR(400MHz,DMSO):δ7.10～7.15(m,4H),12.51(s,2H)。
步骤B：2-((1H-苯并[d]咪唑-2-基)巯基)-3-氧基丁酸乙酯的制备
将2-巯基苯并咪唑(18.00g,0.12mol)，碳酸氢钠(30.24g,0.36mol)，2-氯乙酰乙酸乙酯(22.96g,0.14mol)和乙醇200mL置于1000mL茄形瓶中，常温搅拌5h后，反应液倒入700mL水中，有白色固体析出，搅拌15min，抽滤，干燥，得白色固体33.02g，收率99％，m.p.：141-143℃(lit.:149-150℃)；IR:(KBr,cm-1)3422.4(m),3042.3(m),2984.5(m),2872.8(m),1735.2(s),1640.1(s),1593.9(s),1418.2(s),1396.0(s),1260.9(s),1180.2(m),741.8(s)；1HNMR(400MHz,DMSO):δ1.07(t,3H,CH3,，J＝7.1Hz),1.19(dd,3H,CH3，J＝16.2,9.1Hz),5.48(s,3H,CH3),7.15(d,1H,Ar-H，J＝2.3Hz),7.16(d,1H,Ar-H,J＝2.5Hz),7.47-7.48(m,1H,Ar-H),7.57-7.60(m,1H,Ar-H),12.52(s,1H,NH)；ESI-MS(m/z):279.1([M+H]+)。未经纯化，直接用于下一步反应。
步骤C：3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酸钠的制备
将上步制得的2-((1H-苯并[d]咪唑-2-基)硫基)-3-氧基丁酸乙酯粗品(27.81g,0.10mol)，醋酸酐(30.60g,0.30mol)和三乙胺(60.60g,0.60mol)置于500mL茄形瓶中，搅拌下回流反应4h后，倒入400ml水中，有大量固体析出，抽滤，常温干燥，得24.44g，收率94％,m.p.：119-121℃(lit.[a]:122-123℃)[a]John J.,D’Amico,Robert H.,Campbell,EarlC.G,Derivatives of 3-Methylthiazolo[3,2-a]benzimidazole,Journal of OrganicCh.；IR:(KBr,cm-1)2980.7(m),2828.4(m),1691.8(s),1593.0(s),1488.6(s),1314.9(s),1246.3(s),1223.3(s),1079.1(s),738.2(s)；1HNMR(400MHz,DMSO):δ1.33(t,3H,CH3,，J＝7.1Hz),3.12(s,3H,CH3),4.35(q,2H,CH2,J＝7.1Hz),7.31-7.35(m,1H,Ar-H),7.40-7.44(m,1H,Ar-H),7.73(d,1H,Ar-H,J＝8.1Hz),8.07(d,1H,Ar-H,J＝8.1Hz)；ESI-MS(m/z):261.1([M+H]+)。步骤D：2-(苯并[4,5]咪唑并[2,1-b]噻唑-3-基)乙酸的制备
将上步制得的3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酸乙酯(1.56g,0.006mol)，氢氧化钠(0.72g,0.018mol)和50mL的含水50％的乙醇，置于100mL的茄形瓶中，搅拌回流30min后，有大量固体析出，抽滤，10ml乙醇洗涤两次，干燥，得白色固体1.45g，收率95.0％，m.p.：285-287℃；IR:(KBr,cm-1)3442.9(s),2919.3(m),2852.1(m),1683.6(s),1597.1(s),1458.0(s),1321.1(s),1231.5(s),741.6(s)；1HNMR(400MHz,DMSO):δ3.09(s,3H,CH3),7.29-7.33(m,1H,Ar-H),7.39-7.43(m,1H,Ar-H),7.71(d,1H,Ar-H,J＝8.0Hz),8.04(d,1H,Ar-H,J＝8.1Hz)；ESI-MS(m/z):230.8([M-H]-)。
步骤E：N-(2-甲基苯基)-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺(化合物X01)的制备
将3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酸钠(0.23g,0.001mol)，邻甲基苯胺(0.11g,0.001mol)，HOBt(0.16g,0.0012mol)，EDCI(0.23g,0.0012mol)和DMF20mL置于50mL茄形瓶中，常温搅拌12h后，反应液倒入50mL饱和碳酸钠溶液中，有大量固体析出，抽滤，干燥，含水50％的DMF重结晶，得白色固体0.14g，收率43％,m.p.：221-223℃；IR:(KBr,cm-1)3017(m),2925(s),1663(s),1614(m),1596(s),1527(s),1452(s),1384(s),1315(s),876(s),732(s)；1HNMR(400MHz,DMSO):δ2.26(s,3H,CH3),3.09(s,3H,CH3),7.18-7.26(m,2H,Ar-H),7.29-7.32(m,2H,Ar-H),7.34-7.38(m,1H,Ar-H),7.40-7.44(m,1H,Ar-H),7.74(d,1H,Ar-H,J＝8.0Hz),8.09(d,1H,Ar-H,J＝8.0Hz),9.89(s,1H,NH)；ESI-MS(m/z):322.0([M+H]+)。
实施例2：N,3-二甲基-N-苯基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺(化合物X02)的制备
参照实施例1的制备方法，得到白色固体0.16g，收率49％,m.p.：167-169℃；IR:(KBr,cm-1)3444(s),2924(s),2854(s),1638(s),1455(m),1383(s),741(s),700(s)；1HNMR(400MHz,DMSO):δ2.75(s,3H,CH3),3.40(s,3H,CH3),7.22-7.26(m,1H,Ar-H),7.28-7.31(m,1H,Ar-H),7.32-7.36(m,1H,Ar-H),7.38(d,4H,Ar-H,J＝4.3Hz),7.64(d,1H,Ar-H,J＝8.0Hz),7.93(d,1H,Ar-H,J＝8.0Hz)；ESI-MS(m/z):322.0([M+H]+)。
实施例3：3-甲基-N-(3-硝基苯基)苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺(化合物X03)的制备
参照实施例1的制备方法，得到白色固体0.07g，收率20％,m.p.：258-260℃；IR:(KBr,cm-1)3441(s),2924(s),2853(s),1637(s),1456(m),1384(s),736(s),620(s)；1HNMR(400MHz,DMSO):δ3.09(s,3H,CH3),7.32-7.36(m,1H,Ar-H),7.41-7.45(m,1H,Ar-H),7.69(t,1H,Ar-H,J＝8.2Hz),7.75(d,1H,Ar-H,J＝8.1Hz),8.01(dd,1H,Ar-H,J＝8.1,1.8Hz),8.11(dd,2H,Ar-H,J＝8.1,2.4Hz),8.68(t,1H,Ar-H,J＝2.1Hz),10.74(s,1H,NH)；ESI-MS(m/z):350.7([M-H]-)。
实施例4：3-甲基-N-(4-硝基苯基)苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺(化合物X04)的制备
参照实施例1的制备方法，得到白色固体0.11g，收率30％,m.p.：288-290℃；IR:(KBr,cm-1)3430(s),2925(s),1768(s),1690(s),1671(s),1426(m),1384(s),917(s),875(s)；1HNMR(400MHz,DMSO):δ3.07(s,3H,CH3),7.32-7.36(m,1H,Ar-H),7.41-7.45(m,1H,Ar-H),7.75(d,1H,Ar-H,J＝8.0Hz),7.97(d,2H,Ar-H,J＝9.2Hz)，8.12(d,1H,Ar-H,J＝8.0Hz),8.29(d,2H,Ar-H,J＝9.2Hz),10.86(s,1H,NH)；ESI-MS(m/z):350.7([M-H]-)。
实施例5：N-(3-溴-4-氟苯基)-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺(化合物X05)的制备的制备
参照实施例1的制备方法，得到白色固体0.17g，收率41％，m.p.：265-267℃；IR:(KBr,cm-1)3441(s),2924(s),2853(s),1734(s),1634(s),1455(m),1384(s),619(s)；1HNMR(400MHz,DMSO):δ3.06(s,3H,CH3),7.31-7.35(m,1H,Ar-H),7.39-7.44(m,2H,Ar-H),7.67-7.71(m,1H,Ar-H)，7.74(d,1H,Ar-H,J＝8.0Hz),8.07-8.11(m,2H,Ar-H)，10.45(s,1H,NH)；ESI-MS(m/z):403.9([M+H]+)。
实施例6：N-(4-溴-3-氟苯基)-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺(化合物X06)的制备
参照实施例1的制备方法，得到白色固体0.25g，收率61.0％，m.p.：289-291℃；IR:(KBr,cm-1)3437(s),2924(s),1673(s),1605(s),1573(s),1534(s),1479(m),1454(m),1418(m),1312(s),1246(s),1226(s),972(s),852(s),805(s),733(s),718(s),637(s)；1HNMR(400MHz,DMSO):δ3.05(s,3H,CH3),7.33(t,1H,Ar-H,J＝7.6Hz),7.42(t,1H,Ar-H,J＝7.6Hz),7.48(dd,1H,Ar-H,J＝8.7,1.4Hz)，7.70(d,1H,Ar-H,J＝8.0Hz),7.74(d,1H,Ar-H,J＝8.0Hz),7.80(dd,1H,Ar-H,J＝11.3,1.9Hz),8.10(d,1H,Ar-H,J＝8.0Hz),10.58(s,1H,NH)；ESI-MS(m/z):401.7([M-H]-)。
实施例7：3-甲基-N-(4-三氟甲氧基苯基)苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺(化合物X07)的制备
参照实施例1的制备方法，得到白色固体0.20g，收率52％，m.p.：202-204℃；IR:(KBr,cm-1)3438(s),2926(s),1666(s),1612(s),1572(s),1536(s),1510(s),1481(m),1455(m),1428(m),1409(m),1384(m),1315(s),1274(s),922(s),837(s),796(s),754(s),740(s),670(s)；1HNMR(400MHz,DMSO):δ3.05(s,3H,CH3),7.31-7.35(m,1H,Ar-H),7.39-7.44(m,3H,Ar-H),7.74(d,1H,Ar-H,J＝8.0Hz),7.78-7.79(m,1H,Ar-H),7.80-7.82(m,1H,Ar-H),8.10(d,1H,Ar-H,J＝8.0Hz),10.48(s,1H,NH)；ESI-MS(m/z):392.0([M+H]+)。
实施例8：N-(5-氟-2-甲氧基苯基)-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺(化合物X08)的制备
参照实施例1的制备方法，得到白色固体0.14g，收率39％，m.p.：215-217℃；IR:(KBr,cm-1)3428(s),2925(s),2854(s),1654(s),1640(s),1544(s),1489(m),1451(m),1383(m),1349(s),1254(s),966(s),861(s),801(s),735(s),714(s)；1HNMR(400MHz,DMSO):δ3.08(s,3H,CH3),3.88(s,3H,CH3),7.02-7.07(m,1H,Ar-H),7.12-7.16(m,1H,Ar-H),7.31-7.35(m,1H,Ar-H),7.40-7.44(m,1H,Ar-H),7.73-7.77(m,2H,Ar-H),8.09(d,1H,Ar-H,J＝8.0Hz),9.55(s,1H,NH)；ESI-MS(m/z):356.0([M+H]+)。
实施例9：N-(5-溴-2-甲氧基苯基)-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺(化合物X09)的制备
参照实施例1的制备方法，得到白色固体0.27g，收率64％，m.p.：223-225℃；IR:(KBr,cm-1)3374(s),2926(s),1677(s),1597(s),1571(s),1530(s),1492(m),1453(m),1417(m),1323(s),1223(s),1022(s),873(s),797(s),736(s)；1HNMR(400MHz,DMSO):δ3.06(s,3H,CH3),3.88(s,3H,CH3)，6.99-7.05(m,1H,Ar-H),7.31-7.35(m,1H,Ar-H),7.41-7.47(m,3H,Ar-H),7.74(d,1H,Ar-H,J＝8.0Hz),8.10(d,1H,Ar-H,J＝8.0Hz),10.63(s,1H,NH)；ESI-MS(m/z):416.0([M+H]+)。
实施例10：N-(2,5-二甲氧基苯基)-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺(化合物X10)的制备
参照实施例1的制备方法，得到白色固体0.21g，收率58％，m.p.：217-219℃；IR:(KBr,cm-1)3431(s),2924(s),2853(s),1651(s),1537(s),1487(m),1453(m),1452(m),1432(m),1383(m),1310(s),1222(s),1023(s),872(s),779(s),740(s),712(s)；1HNMR(400MHz,DMSO):δ3.08(s,3H,CH3),3.73(s,3H,CH3)，3.82(s,3H,CH3)，6.77(dd,1H,Ar-H,J＝8.7,2.4Hz),7.05(d,1H,Ar-H,J＝9.0Hz),7.30-7.34(m,1H,Ar-H),7.40-7.44(m,1H,Ar-H),7.48(d,1H,Ar-H,J＝2.4Hz),7.73(d,1H,Ar-H,J＝8.0Hz),8.08(d,1H,Ar-H,J＝8.0Hz),9.44(s,1H,NH)；ESI-MS(m/z):368.1([M+H]+)。
实施例11：N-(3,5-二氟苯基)-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺(化合物X11)的制备
参照实施例1的制备方法，得到白色固体0.07g，收率43％，m.p.：286-288℃；IR:(KBr,cm-1)3441(s),2926(s),1677(s),1614(s),1576(s),1553(s),1479(m),1433(m),1384(m),1314(s),1230(s),1117(s),994(s),875(s),849(s),732(s),668(s),652(s)；1HNMR(400MHz,DMSO):δ3.06(s,3H,CH3),6.99-7.05(m,1H,Ar-H),7.31-7.35(m,1H,Ar-H),7.41-7.47(m,3H,Ar-H),7.74(d,1H,Ar-H,J＝8.0Hz),8.11(d,1H,Ar-H,J＝8.0Hz),10.62(s,1H,NH)；ESI-MS(m/z):344.0([M+H]+)。
实施例12：N-(4-氯-3-三氟甲基苯基)-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺(化合物X12)的制备
参照实施例1的制备方法，得到白色固体0.22g，收率53％，m.p.：211-213℃；IR:(KBr,cm-1)3113(s),3049(s),2924(s),2854(s),1671(s),1617(s),1594(s),1536(s),1478(m),1414(m),1384(m),1326(s),1224(s),1145(s),1033(s),893(s),846(s),746(s),664(s)；1HNMR(400MHz,DMSO):δ3.07(s,3H,CH3),7.32-7.36(m,1H,Ar-H),7.41-7.45(m,1H,Ar-H),7.75(d,2H,Ar-H,J＝8.0Hz),8.02(dd,1H,Ar-H,J＝8.8,2.5Hz),8.11(d,1H,Ar-H,J＝8.0Hz),8.26(d,1H,Ar-H,J＝2.5Hz),10.69(s,1H,NH)；ESI-MS(m/z):408.1([M-H]-)。
实施例13：N-(4-烯丙氧基苯基)-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺(化合物X13)的制备
参照实施例1的制备方法，得到白色固体0.13g，收率37％，m.p.：201-203℃；IR:(KBr,cm-1)3297(s),3055(s),2923(s),2854(s),1645(s),1612(s),1600(s),1510(s),1481(m),1454(m),1384(m),1317(s),1226(s),999(s),927(s),828(s),739(s)；1HNMR(400MHz,DMSO):δ3.04(s,3H,CH3),4.57(d,2H,CH2,J＝5.2Hz),5.27(dd,1H,-C＝CH,J＝10.5,1.5Hz),5.40(dd,1H,-C＝CH,J＝17.3,1.7Hz),6.00-6.10(m,1H,-C＝CH),6.97(d,2H,Ar-H,J＝9.0Hz),7.30-7.34(m,1H,Ar-H),7.39-7.43(m,1H,Ar-H),7.57(d,2H,Ar-H,J＝9.0Hz),7.73(d,1H,Ar-H,J＝8.1Hz),8.09(d,1H,Ar-H,J＝8.1Hz),10.18(s,1H,NH)；ESI-MS(m/z):364.3([M+H]+)。
实施例14：N-(3-甲基-2-吡啶基)-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺(化合物X14)的制备
参照实施例1的制备方法，得到白色固体0.09g，收率28％，m.p.：204-206℃；IR:(KBr,cm-1)3424(s),2924(s),1658(s),1632(s),1598(s),1575(s),1475(m),1431(m),1380(m),1365(s),1232(s),995(s),875(s),810(s),786(s)，740(s),726(s)；1HNMR(400MHz,DMSO):δ2.04(s,3H,CH3),3.10(s,3H,CH3),6.50(dd,1H,Ar-H,J＝7.0,5.3Hz),7.30(dd,2H,Ar-H,J＝9.5,4.8Hz),7.40(d,1H,Ar-H,J＝7.5Hz),7.71(d,1H,Ar-H,J＝8.1Hz),7.77-7.78(m,1H,Ar-H),8.04(d,1H,Ar-H,J＝8.1Hz)；ESI-MS(m/z):323.2([M+H]+)。
实施例15：N-(苯并[d]噻唑-2-基)-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺(化合物X15)的制备
参照实施例1的制备方法，得到白色固体0.08g，收率23％，m.p.：234-236℃；IR:(KBr,cm-1)3053(s),2957(s),2923(s),2853(s),1670(s),1609(s),1588(s),1530(s),1487(m),1458(m),1383(m),1308(s),1222(s),944(s),896(s),880(s),834(s)，748(s),684(s)；1HNMR(400MHz,DMSO):δ3.27(s,3H,CH3),7.29-7.36(m,2H,Ar-H),7.38-7.42(m,1H,Ar-H),7.46-7.50(m,2H,Ar-H)，7.71(d,1H,Ar-H,J＝8.0Hz),7.91(d,1H,Ar-H,J＝8.0Hz)，8.08(d,1H,Ar-H,J＝8.0Hz),13.66(s,1H,NH)；ESI-MS(m/z):362.9([M-H]-)。
实施例16：N-[4-(4-吗啉基)苯基]-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺(化合物X16)的制备
参照实施例1的制备方法，得到白色固体0.16g，收率41％，m.p.：179-181℃；IR:(KBr,cm-1)3228(s)，3174(s)，3101(s),3036(s)，2954(s),2920(s),2849(s),1663(s),1601(s),1530(s),1517(s),1454(m),1458(m),1384(m),1322(s),1224(s),1123(s),926(s),879(s),829(s),754(s)；1HNMR(400MHz,DMSO):δ3.03(s,3H,CH3),3.07-3.10(m,4H,CH2),3.73-3.75(m,4H,CH2),6.96(d,2H,Ar-H,J＝9.0Hz),7.30-7.34(m,1H,Ar-H),7.39-7.43(m,1H,Ar-H)，7.53(d,2H,Ar-H,J＝9.0Hz),7.73(d,1H,Ar-H,J＝8.0Hz)，8.08(d,1H,Ar-H,J＝8.0Hz),10.12(s,1H,NH)；ESI-MS(m/z):393.1([M+H]+)。
实施例17：N-(1H-1,2,4-三氮唑-3-基)-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺(化合物X17)的制备
参照实施例1的制备方法，得到白色固体0.06g，收率21％，m.p.：213-215℃；IR:(KBr,cm-1)；1HNMR(400MHz,DMSO):δ3.28(s,3H,CH3),7.32-7.36(m,1H,Ar-H),7.43-7.47(m,1H,Ar-H),7.73(d,1H,Ar-H,J＝8.0Hz),7.77(s,1H,NH),7.80-7.81(m,1H,Ar-H),8.14(d,1H,Ar-H,J＝8.0Hz),9.04(s,1H,NH)；ESI-MS(m/z):299.1([M+H]+)。
实施例18：N-(1-萘基)-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺(化合物X18)的制备
参照实施例1的制备方法，得到白色固体0.18g，收率51％，m.p.：231-233℃；IR:(KBr,cm-1)3054(s),2923(s),1660(s),1663(s),1642(s),1592(s),1529(s),1479(m),1455(m),1397(m),1346(s),1227(s),872(s),794(s),768(s),734(s)；1HNMR(400MHz,DMSO):δ3.15(s,3H,CH3),7.32-7.36(m,1H,Ar-H),7.41-7.45(m,1H,Ar-H)，7.56-7.61(m,3H,Ar-H),7.62-7.65(m,1H,Ar-H),7.76(d,1H,Ar-H,J＝8.1Hz),7.91(d,1H,Ar-H,J＝8.1Hz),7.98-8.02(m,2H,Ar-H),8.12(d,1H,Ar-H,J＝8.1Hz),10.42(s,1H,NH)；ESI-MS(m/z):358.4([M+H]+)。
实施例19：N-(4-联苯基)-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺(化合物X19)的制备
参照实施例1的制备方法，得到白色固体0.16g，收率43％，m.p.：202-204℃；IR:(KBr,cm-1)3030(s),2923(s),2853(s),1637(s),1609(s),1594(s),1500(s),1481(m),1453(m),1385(m),1224(s),1002(s),817(s),739(s)；1HNMR(400MHz,DMSO):δ3.07(s,3H,CH3),6.63(d,2H,Ar-H,J＝8.4Hz),7.29-7.42(m,5H,Ar-H)，7.50(d,2H,Ar-H,J＝8.5Hz),7.65(d,2H,Ar-H,J＝8.5Hz),7.72(d,1H,Ar-H,J＝8.1Hz),8.08(d,1H,Ar-H,J＝8.1Hz),10.33(s,1H,NH)；ESI-MS(m/z):383.9([M+H]+)。
实施例20：N-(4-吗啉基)-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺(化合物X20)的制备
参照实施例1的制备方法，得到白色固体0.06g，收率19％，m.p.：205-207℃；IR:(KBr,cm-1)；1HNMR(400MHz,DMSO):δ2.78-2.97(m,4H,CH2),3.21(s,3H,CH3),3.70-3.86(m,4H,CH2),7.27(t,1H,Ar-H,J＝7.6Hz),7.36-7.40(m,1H,Ar-H)，7.70(d,1H,Ar-H,J＝8.1Hz),8.06(d,1H,Ar-H,J＝8.1Hz),9.29(s,1H,NH)；ESI-MS(m/z):317.2([M+H]+)。
实施例21：N-(3-苄氧基-2-吡啶基)-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺(化合物X21)的制备
参照实施例1的制备方法，得到白色固体0.15g，收率37％，m.p.：216-218℃；IR:(KBr,cm-1)3284(s),3143(s),2924(s),2854(s),1629(s),1565(s),1489(m),1453(m),1384(m),1214(s),998(s),919(s),777(s),741(s),698(s)；1HNMR(400MHz,DMSO):δ3.32(s,3H,CH3),5.11(s,2H,CH2),5.23(s,1H,NH)5.64(s,2H,Ar-H),6.47(dd,1H,Ar-H,J＝7.7,5.0Hz),7.08(dd,1H,Ar-H,J＝7.7,1.1Hz)，7.32(t,2H,Ar-H,J＝7.8Hz),7.39(dd,3H,Ar-H,J＝8.0,6.6Hz),7.50(dd,3H,Ar-H,J＝8.0,4.2Hz)；ESI-MS(m/z):415.3([M+H]+)。
实施例22：N-(4-氟苯基)-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺(化合物X22)的制备
参照实施例1的制备方法，得到白色固体0.11g，收率34％，m.p.：197-199℃；IR:(KBr,cm-1)3266(s),3140(s),3053(s),2924(s),2854(s),1676(s),1615(s),1543(s),1510(s),1478(m),1454(m),1373(m),1224(s),851(s),823(s),785(s),729(s)；1HNMR(400MHz,DMSO):δ3.05(s,3H,CH3),7.20-7.25(m,2H,Ar-H),7.31-7.35(m,1H,Ar-H)，7.40-7.44(m,1H,Ar-H),7.68-7.71(m,2H,Ar-H),7.74(d,1H,Ar-H,J＝8.0Hz),8.10(d,1H,Ar-H,J＝8.0Hz),10.35(s,1H,NH)；ESI-MS(m/z):323.9([M-H]-)。
实施例23：N-(4-氯苯基)-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺(化合物X23)的制备
参照实施例1的制备方法，得到白色固体0.12g，收率36％，m.p.：189-191℃；IR:(KBr,cm-1)3173(s),3097(s),3023(s),2923(s),1667(s),1596(s),1572(s),1526(s),1491(m),1478(m),1453(m),1395(m),1313(s),1227(s),819(s),754(s),741(s)；1HNMR(400MHz,DMSO):δ3.05(s,3H,CH3),7.31-7.35(m,1H,Ar-H),7.40-7.42(m,1H,Ar-H)，7.43-7.46(m,2H,Ar-H),7.70-7.75(m,3H,Ar-H),8.10(d,1H,Ar-H,J＝8.1Hz),10.43(s,1H,NH)；ESI-MS(m/z):342.1([M+H]+)。
实施例24：N-苄基-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺(化合物X24)的制备
参照实施例1的制备方法，得到白色固体0.14g，收率43％，m.p.：195-197℃；IR:(KBr,cm-1)3289(s),3027(s),2920(s),2853(s),1657(s),1593(s),1530(s),1526(s),1470(m),1453(m),1425(m),1386(m),1312(s),1285(s),1258(s),1231(s),832(s),797(s),742(s),697(s)；1HNMR(400MHz,DMSO):δ3.03(s,3H,CH3),4.47(d,2H,CH2,J＝5.9Hz),7.24-7.32(m,2H,Ar-H),7.34-7.36(m,4H,Ar-H)，7.37-7.41(m,1H,Ar-H),7.71(d,1H,Ar-H,J＝8.1Hz),8.05(d,1H,Ar-H,J＝8.1Hz),8.91(t,1H,NH,5.9Hz)；ESI-MS(m/z):322.1([M+H]+)。
实施例25：N-(4-氟苄基)-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺(化合物X25)的制备
参照实施例1的制备方法，得到白色固体0.12g，收率34％，m.p.：199-201℃；IR:(KBr,cm-1)3324(s),3264(s),3061(s),2931(s),2853(s),1655(s),1590(s),1510(s),1526(s),1480(m),1453(m),1453(m),1376(m),1314(s),1280(s),1260(s),1220(s),927(s),853(s),836(s),753(s),737(s)；1HNMR(400MHz,DMSO):δ3.03(s,3H,CH3),4.44(d,2H,CH2,J＝5.9Hz),7.15-7.21(m,2H,Ar-H),7.28-7.32(m,1H,Ar-H)，7.37-7.42(m,3H,Ar-H),7.71(d,1H,Ar-H,J＝8.0Hz),8.05(d,1H,Ar-H,J＝8.0Hz),8.91(t,1H,NH,5.9Hz)；ESI-MS(m/z):340.1([M+H]+)。
实施例26：N-(2-氯苄基)-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺(化合物X26)的制备
参照实施例1的制备方法，得到白色固体0.11g，收率32％，m.p.：221-223℃；IR:(KBr,cm-1)3334(s),3240(s),3055(s),2924(s),2852(s),1633(s),1595(s),1550(s),1526(s),1485(m),1455(m),1375(m),1323(s),1264(s),1232(s),945(s),837(s),752(s),678(s)；1HNMR(400MHz,DMSO):δ3.04(s,3H,CH3),4.54(s,2H,CH2),7.28-7.35(m,2H,Ar-H),7.36-7.42(m,3H,Ar-H)，7.48(dd,1H,Ar-H,J＝7.6,1.5Hz),7.72(d,1H,Ar-H,J＝8.0Hz),8.06(d,1H,Ar-H,J＝8.0Hz),8.93(s,1H,NH)；ESI-MS(m/z):356.3([M+H]+)。
实施例27：N-(4-甲氧基苄基)-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺(化合物X27)的制备
参照实施例1的制备方法，得到白色固体0.15g，收率43％，m.p.：223-225℃；IR:(KBr,cm-1)3263(s),2923(s),1644(s),1613(s),1590(s),1512(s),1479(m),1384(m),1316(s),1250(s),1233(s),1029(s),828(s),739(s)；1HNMR(400MHz,DMSO):δ3.02(s,3H,CH3),3.74(s,3H,OCH3),4.39(d,2H,CH2,J＝5.9Hz),6.90-6.93(m,2H,Ar-H),7.26-7.32(m,3H,Ar-H)，7.37-7.41(m,1H,Ar-H),7.71(d,1H,Ar-H,J＝8.0Hz),8.05(d,1H,Ar-H,J＝8.0Hz),8.86(t,1H,NH,5.9Hz)；ESI-MS(m/z):352.0([M+H]+)。
实施例28：N-(3-氯-4-甲氧基苄基)-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺(化合物X28)的制备
参照实施例1的制备方法，得到白色固体0.14g，收率37％，m.p.：236-238℃；IR:(KBr,cm-1)3235(s),3034(s),2928(s),2846(s),1652(s),1614(s),1590(s),1575(s),1534(s),1503(s),1483(m),1453(m),1380(m),1313(s),1282(s),1231(s),1024(s),875(s),833(s),753(s),740(s),687(s)；1HNMR(400MHz,DMSO):δ3.03(s,3H,CH3),3.84(s,3H,OCH3),4.38(d,2H,CH2,J＝5.8Hz),7.13(d,1H,Ar-H,J＝8.5Hz),7.28-7.32(m,2H,Ar-H),7.37-7.41(m,2H,Ar-H)，7.71(d,1H,Ar-H,J＝8.1Hz),8.05(d,1H,Ar-H,J＝8.1Hz),8.87(t,1H,NH,5.8Hz)；ESI-MS(m/z):386.1([M+H]+)。
实施例29：(R)-N-(1-苯基乙基)-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺(化合物X29)的制备
参照实施例1的制备方法，得到白色固体0.08g，收率25％，m.p.：215-217℃；IR:(KBr,cm-1)3221(s),3027(s),2970(s),2928(s),1653(s),1612(s),1590(s),1575(s),1529(s),1477(s),1453(m),1385(m),1313(s),1260(s),1232(s),926(s),833(s),756(s),739(s),700(s)；1HNMR(400MHz,DMSO):δ1.50(d,3H,CH3,J＝7.1Hz),2.99(s,3H,CH3),5.14(p,1H,CH,J＝7.1Hz),7.23-7.28(m,2H,Ar-H),7.34-7.38(m,2H,Ar-H),7.39-7.43(m,3H,Ar-H)，7.71(d,1H,Ar-H,J＝8.1Hz),8.05(d,1H,Ar-H,J＝8.1Hz),8.79(d,1H,NH,7.9Hz)；ESI-MS(m/z):336.4([M+H]+)。
实施例30：N-(2-吡啶甲基)-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺(化合物X30)的制备
参照实施例1的制备方法，得到白色固体0.07g，收率23％，m.p.：188-190℃；IR:(KBr,cm-1)3350(s),3053(s),2918(s),2855(s),1649(s),1613(s),1587(s),1571(s),1510(s),1477(s),1452(m),1393(m),1307(s),1253(s),1227(s),994(s),875(s),833(s),755(s),736(s)；1HNMR(400MHz,DMSO):δ3.06(s,3H,CH3),4.57(d,2H,CH2,J＝5.8Hz),7.27-7.33(m,2H,Ar-H)，7.36-7.42(m,2H,Ar-H),7.72(d,1H,Ar-H,J＝8.0Hz),7.79(td,1H,Ar-H,J＝7.7,1.8Hz),8.06(d,1H,Ar-H,J＝8.0Hz),8.53-8.55(m,1H,Ar-H),8.95(t,1H,NH,5.8Hz)；ESI-MS(m/z):323.2([M+H]+)。
实施例31：N-(2-呋喃甲基)-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺(化合物X31)的制备
参照实施例1的制备方法，得到白色固体0.17g，收率54％，m.p.：190-192℃；IR:(KBr,cm-1)3424.2(s),2922.9(m),1663.6(s),1596.3(s),1479.5(s),1452.8(s),1384.0(s),1253.3(s),742.1(s)；1HNMR(400MHz,DMSO):δ3.02(s,3H,CH3),4.46(d,2H,CH2,J＝5.6Hz),6.32(dd,1H,Ar-H,J＝3.2,0.6Hz),6.42(dd,1H,Ar-H,J＝3.2,1.9Hz),7.28-7.32(m,1H,Ar-H),7.37-7.41(m,1H,Ar-H),7.61(dd,1H,Ar-H,J＝1.7,0.8Hz),7.71(d,1H,Ar-H,J＝8.0Hz),8.05(d,1H,Ar-H,J＝8.0Hz),8.88(t,1H,NH,J＝5.6Hz)；ESI-MS(m/z):311.9([M+H]+)。
实施例32：(3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-基)[4-(4-甲基苯基)哌嗪-1-基]甲基酮(化合物X32)的制备
参照实施例1的制备方法，得到白色固体0.23g，收率59％，m.p.：217-219℃；IR:(KBr,cm-1)2999(s),2914(s),2855(s),2821(s),1649(s),1615(s),1519(s),1480(s),1450(m),1425(m),1384(s),1309(s),1244(s),1228(s),986(s),814(s),754(s),736(s),670(s)；1HNMR(400MHz,DMSO):δ2.20(s,3H,CH3),2.79(s,3H,CH3)，3.12-3.15(m,4H,CH2),3.74-3.77(m,4H,CH2),6.88(d,2H,Ar-H,J＝8.0Hz),7.05(d,2H,Ar-H,J＝8.0Hz)，7.28-7.32(m,1H,Ar-H),7.36-7.41(m,1H,Ar-H),7.72(d,1H,Ar-H,J＝8.0Hz),8.01(d,1H,Ar-H,J＝8.0Hz)；ESI-MS(m/z):391.2([M+H]+)。
实施例33：[4-(4-甲氧基苯基)哌嗪-1-基](3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-基)甲基酮(化合物X33)的制备
参照实施例1的制备方法，得到白色固体0.27g，收率67％，m.p.：213-215℃；IR:(KBr,cm-1)3000(s),2917(s),2830(s),2800(s),1620(s),1512(s),1452(s),1430(m),1382(m),1246(s),989(s),914(s),831(s),801(s),742(s),670(s)；1HNMR(400MHz,DMSO):δ2.79(s,3H,CH3),3.05-3.08(m,4H,CH2),3.69(s,3H,OCH3),3.74-3.77(m,4H,CH2),6.82-6.86(m,2H,Ar-H),6.92-6.96(m,2H,Ar-H),7.28-7.32(m,1H,Ar-H),7.36-7.41(m,1H,Ar-H),7.72(d,1H,Ar-H,J＝8.0Hz),8.00(d,1H,Ar-H,J＝8.0Hz)；ESI-MS(m/z):407.3([M+H]+)。
实施例34：(4-苄基哌嗪-1-基)(3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-基)甲基酮(化合物X34)的制备
参照实施例1的制备方法，得到白色固体0.24g，收率61％，m.p.：211-213℃；IR:(KBr,cm-1)3058(s),3026(s),2917(s),2809(s),2767(s),1629(s),1481(s),1436(m),1395(m),1227(s),998(s),875(s),802(s),740(s),700(s)；1HNMR(400MHz,DMSO):δ2.42(s,4H,CH2),2.75(s,3H,CH3)，3.52(s,2H,CH2),3.62(s,4H,CH2),7.26-7.30(m,2H,Ar-H),7.32-7.33(m,4H,Ar-H),7.35-7.39(m,1H,Ar-H),7.70(d,1H,Ar-H,J＝8.0Hz),7.98(d,1H,Ar-H,J＝8.0Hz)；ESI-MS(m/z):391.2([M+H]+)。
实施例35：[4-(2-甲氧基苯基)哌嗪-1-基](3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-基)甲基酮(化合物X35)的制备
参照实施例1的制备方法，得到白色固体0.28g，收率68％，m.p.：237-239℃；IR:(KBr,cm-1)3060(s),2960(s),2923(s),2830(s),1609(s),1500(s),1442(m),1384(m),1228(s),917(s),836(s),744(s),666(s)；1HNMR(400MHz,DMSO):δ2.81(s,3H,CH3)，3.00-3.02(m,4H,CH2),3.76-3.78(m,4H,CH2),3.79(s,3H,OCH3),6.87-7.01(m,4H,Ar-H),7.28-7.32(m,1H,Ar-H),7.36-7.40(m,1H,Ar-H),7.72(d,1H,Ar-H,J＝8.0Hz),8.01(d,1H,Ar-H,J＝8.0Hz)；ESI-MS(m/z):407.2([M+H]+)。
实施例36：{4-[(4-氯苯基)(苯基)甲基]哌嗪-1-基}(3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-基)甲基酮(化合物X36)的制备
参照实施例1的制备方法，得到白色固体0.36g，收率72％，m.p.：159-161℃；IR:(KBr,cm-1)2959(s),2924(s),2854(s),1631(s),1480(s),1439(m),1384(m),999(s),849(s),805(s),758(s),741(s),720(s)；1HNMR(400MHz,DMSO):δ2.36(m,4H,CH2),2.89(s,3H,CH3)，3.64(m,4H,CH2),4.43(s,1H,CH),7.19-7.23(m,2H,Ar-H),7.26-7.31(m,4H,Ar-H),7.43-7.48(m,4H,Ar-H),7.69(d,1H,Ar-H,J＝8.0Hz),7.95-7.98(m,2H,Ar-H)；ESI-MS(m/z):501.2([M+H]+)。
实施例37：[4-(3-三氟甲基苯基)哌嗪-1-基](3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-基)甲基酮(化合物X37)的制备
参照实施例1的制备方法，得到白色固体0.24g，收率54％，m.p.：219-221℃；IR:(KBr,cm-1)2923(s),2854(s),1924(s),1659(s),1622(s),1453(s),1382(m),995(s),834(s),705(s),657(s)；1HNMR(400MHz,DMSO):δ2.80(s,3H,CH3)，3.00-3.02(m,4H,CH2)，3.75-3.78(m,4H,CH2),7.11(d,1H,Ar-H,J＝7.7Hz),7.21(s,1H,Ar-H),7.25-7.32(m,2H,Ar-H),7.36-7.41(m,1H,Ar-H),7.45(t,1H,Ar-H,J＝8.0Hz),7.72(t,1H,Ar-H,J＝8.0Hz),8.01(d,1H,Ar-H,J＝8.0Hz)；ESI-MS(m/z):445.3([M+H]+)。
实施例38：[4-(4-氟苯基)哌嗪-1-基](3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-基)甲基酮(化合物X38)的制备
参照实施例1的制备方法，得到白色固体0.31g，收率78％，m.p.：215-217℃；IR:(KBr,cm-1)2923(s),2542(s),1924(s),1658(s),1620(s),1511(s),1452(s),1401(m),1382(m),996(s),834(s),704(s),658(s)；1HNMR(400MHz,DMSO):δ2.80(s,3H,CH3)，3.14-3.16(m,4H,CH2),3.75-3.78(m,4H,CH2),6.98-7.02(m,2H,Ar-H),7.08(t,2H,Ar-H,J＝8.9Hz),7.28-7.32(m,1H,Ar-H),7.37-7.41(m,1H,Ar-H),7.72(d,1H,Ar-H,J＝8.0Hz),8.01(d,1H,Ar-H,J＝8.0Hz)；ESI-MS(m/z):395.2([M+H]+)。
实施例39：[4-(3-氯苯基)哌嗪-1-基](3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-基)甲基酮(化合物X39)的制备
参照实施例1的制备方法，得到白色固体0.26g，收率64％，m.p.：207-209℃；IR:(KBr,cm-1)3061(s),2922(s),2546(s),1922(s),1665(s),1620(s),1553(s),1452(s),1401(m),1332(m),998(s),836(s),702(s),658(s)；1HNMR(400MHz,DMSO):δ2.80(s,3H,CH3)，3.26-3.28(m,4H,CH2),3.74-3.76(m,4H,CH2),6.83(dd,1H,Ar-H,J＝8.2,1.8Hz),6.94(dd,1H,Ar-H,J＝8.4,2.1Hz),6.99(t,1H,Ar-H,J＝2.2Hz),7.24(t,1H,Ar-H,J＝8.1Hz),7.28-7.32(m,1H,Ar-H),7.37-7.41(m,1H,Ar-H),7.72(d,1H,Ar-H,J＝8.0Hz),8.01(d,1H,Ar-H,J＝8.0Hz)；ESI-MS(m/z):411.2([M+H]+)。
实施例40：(4-二苯甲基哌嗪-1-基)(3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-基)甲基酮(化合物X40)的制备
参照实施例1的制备方法，得到白色固体0.22g，收率47％，m.p.：198-200℃；IR:(KBr,cm-1)2925(s),1633(s),1447(s),1384(m),997(s),848(s),743(s),706(s)；1HNMR(400MHz,DMSO):δ2.37(s,4H,CH2),2.75(s,3H,CH3)，3.63-3.65(m,4H,CH2),4.38(s,1H,CH),7.19(t,2H,Ar-H,J＝7.3Hz),7.26-7.28(m,2H,Ar-H),7.30-7.32(m,3H,Ar-H),7.34-7.39(m,1H,Ar-H),7.44-7.46(m,4H,Ar-H),7.69(d,1H,Ar-H,J＝8.0Hz),7.96(d,1H,Ar-H,J＝8.0Hz)；ESI-MS(m/z):467.2([M+H]+)。
实施例41：[4-(2,5-二甲基苯基)哌嗪-1-基](3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-基)甲基酮(化合物X41)的制备
参照实施例1的制备方法，得到白色固体0.19g，收率48％，m.p.：185-187℃；IR:(KBr,cm-1)3050.4(m),2960.4(s),2910.9(s),2806.6(s),1615.9(s),1507.1(s)，1482.7(s)，1454.7(s)，1429.4(s),1316.0(s)，1228.7(s)，1151.5(s),829.0(s)，809.7(s),737.6(s)；1HNMR(400MHz,DMSO):δ2.23(s,3H,CH3),2.24(s,3H,CH3),2.81(s,3H,CH3),2.86-2.89(m,4H,CH2),3.76-3.78(m,4H,CH2),6.79(d,1H,Ar-H,J＝7.6Hz),6.87(s,1H,Ar-H),7.05(d,1H,Ar-H,J＝7.6Hz),7.28-7.32(m,1H,Ar-H),7.32-7.40(m,1H,Ar-H),7.72(d,1H,Ar-H,J＝8.0Hz),8.01(d,1H,Ar-H,J＝8.0Hz)；ESI-MS(m/z):405.2([M+H]+)。
实施例42：[4-(4-氯-3-三氟甲基苯基)哌嗪-1-基](3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-基)甲基酮(化合物X42)的制备
参照实施例1的制备方法，得到白色固体0.20g，收率41％，m.p.：228-230℃；IR:(KBr,cm-1)2915.2(m),2835.2(s),1626.8(s),1573.8(s),1484.9(s),1424.7(s),1307.3(s),1227.4(s),1143.8(s),1021.5(s),814.1(s),756.7(s),744.1(s)；1HNMR(400MHz,DMSO):δ2.78(s,3H,CH3),3.31-3.34(m,4H,CH2),3.74-3.76(m,4H,CH2),7.22-7.25(m,1H,Ar-H),7.28-7.32(m,2H,Ar-H),7.37-7.41(m,1H,Ar-H),7.51(d,1H,Ar-H,J＝8.0Hz),7.71(d,1H,Ar-H,J＝8.0Hz),8.00(d,1H,Ar-H,J＝8.0Hz)；ESI-MS(m/z):479.2([M+H]+)。
实施例43：[4-(4-甲基苯基)哌嗪-1-基](3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-基)甲基酮(化合物X43)的制备
参照实施例1的制备方法，得到白色固体0.25g，收率65％，m.p.：300-302℃；IR:(KBr,cm-1)2918.6(s),1663.4(s),1452.1(s),1355.9(s),997..5(s),835.2.(s),706.0(s)；1HNMR(400MHz,DMSO):δ2.20(s,3H,CH3),2.79(s,3H,CH3),3.12-3.15(m,4H,CH2),3.74-3.77(m,4H,CH2),6.88(d,2H,Ar-H,J＝8.0Hz),7.05(d,2H,Ar-H,J＝8.0Hz),7.28-7.32(m,1H,Ar-H),7.37-7.41(m,1H,Ar-H),7.72(d,1H,Ar-H,J＝8.0Hz),8.01(d,1H,Ar-H,J＝8.0Hz)；ESI-MS(m/z):391.1([M+H]+)。
实施例44：[4-(2-乙基苯基)哌嗪-1-基](3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-基)甲基酮(化合物X44)的制备
参照实施例1的制备方法，得到白色固体0.29g，收率73％，m.p.：208-210℃；IR:(KBr,cm-1)2919.7(m),1621.7(s),1484.5(s),1426.7(s),1308.4(s),1227.2(s),1143.8(s),737.3(s)；1HNMR(400MHz,DMSO):δ1.20(t,3H,CH3,J＝7.5Hz),2.70(dd,2H,CH2,J＝15.0,7.5Hz),2.82(s,3H,CH3),2.86-2.88(m,4H,CH2),3.78(m,4H,CH2),7.04-7.08(m,1H,Ar-H),7.11-7.19(m,2H,Ar-H),7.24(dd,1H,Ar-H,J＝7.5,1.2Hz),7.28-7.32(m,1H,Ar-H),7.36-7.40(m,1H,Ar-H),7.72(d,1H,Ar-H,J＝8.0Hz),8.01(d,1H,Ar-H,J＝8.0Hz)；ESI-MS(m/z):427.3([M+Na]+)。
实施例45：[4-(2-氯苯基)哌嗪-1-基](3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-基)甲基酮(化合物X45)的制备
参照实施例1的制备方法，得到白色固体0.23g，收率55％，m.p.：300-302℃；IR:(KBr,cm-1)2922.7(s),1619.4(s),1452.9(s),1400.8(s),1331.6(s),1046.3(m),996.3(s),834.6(s),702.4(s)；1HNMR(400MHz,DMSO):δ2.81(s,3H,CH3),3.02-3.05(m,4H,CH2),3.78-3.80(m,4H,CH2),7.06-7.10(m,1H,Ar-H),7.20(dd,1H,Ar-H,J＝8.0,1.4Hz),7.28-7.34(m,2H,Ar-H),7.37-7.41(m,1H,Ar-H),7.43(dd,1H,Ar-H,J＝8.0,1.4Hz),7.71(d,1H,Ar-H,J＝8.0Hz),8.00(d,1H,Ar-H,J＝8.0Hz)；ESI-MS(m/z):411.0([M+H]+)。
实施例46：[4-(2,4-二甲基苯基)哌嗪-1-基](3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-基)甲基酮(化合物X46)的制备
参照实施例1的制备方法，得到白色固体0.23g，收率57％，m.p.：310-312℃；IR:(KBr,cm-1)2921.1(s),1618.7(s),1452.4(s),1401.0(s),1311.8(s),996.5(s),835.3(s),698.2(s)；1HNMR(400MHz,DMSO):δ2.21(s,3H,CH3),2.24(s,3H,CH3)，2.81(s,3H,CH3)，2.83-2.85(m,4H,CH2),3.75-3.77(m,4H,CH2),6.95(s,2H,Ar-H),6.99(s,1H,Ar-H),7.28-7.32(m,1H,Ar-H),7.36-7.40(m,1H,Ar-H),7.71(d,1H,Ar-H,J＝8.0Hz),8.01(d,1H,Ar-H,J＝8.0Hz)；ESI-MS(m/z):405.1([M+H]+)。
实施例47：[4-(3-溴苯基)哌嗪-1-基](3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-基)甲基酮(化合物X47)的制备
参照实施例1的制备方法，得到白色固体0.25g，收率56％，m.p.：181-183℃；IR:(KBr,cm-1)3059.8(m),2918.9(m),2822.5(m),1620.3(s),1589.7(s),1483.3(s),1435.1(s),1384.5(s),1227.4(s),1011.5(m),756.0(s),740.1(s)；1HNMR(400MHz,DMSO):δ2.80(s,3H,CH3),3.26-2.80(m,4H,CH2),3.73-3.76(m,4H,CH2),6.95-6.99(m,2H,Ar-H),7.12-7.13(m,1H,Ar-H),7.18(t,1H,Ar-H,J＝8.1Hz),7.28-7.32(m,1H,Ar-H),7.37-7.40(m,1H,Ar-H),7.72(d,1H,Ar-H,J＝8.1Hz),8.01(d,1H,Ar-H,J＝8.1Hz)；ESI-MS(m/z):455.1([M+H]+)。
实施例48：[4-(2,3-二氯苯基)哌嗪-1-基](3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-基)甲基酮(化合物X48)的制备
参照实施例1的制备方法，得到白色固体0.34g，收率77％，m.p.：175-177℃；IR:(KBr,cm-1)3054.1(m),2923.8(s),2827.7(s),1621.3(s),1576.5(s),1483.2(s),1451.8(s),1229.7(s),1037.6(m),782.0(s),739.9(s),713.7(m)；1HNMR(400MHz,DMSO):δ2.81(s,3H,CH3),3.04-3.06(m,4H,CH2),3.79-3.82(m,4H,CH2),7.19(s,1H,Ar-H，J＝5.9，3.7Hz),7.28-7.32(m,1H,Ar-H),7.33(d,1H,Ar-H,J＝2.2Hz),7.35(s,1H,Ar-H),7.36-7.41(m,1H,Ar-H),7.72(d,1H,Ar-H,J＝8.0Hz),8.01(d,1H,Ar-H,J＝8.0Hz)；ESI-MS(m/z):445.2([M+H]+)。
实施例49：N-苯乙基-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺(化合物X49)的制备
参照实施例1的制备方法，得到白色固体0.18g，收率53％，m.p.：168-170℃；IR:(KBr,cm-1)2927(s),1633(s),1534(s),1480(s),1454(s),1384(m),739(s),699(s)；1HNMR(400MHz,DMSO):δ2.86(t,2H,CH2)，2.95(s,3H,CH3),3.46-3.51(m,2H,CH2),7.22-7.28(m,3H,Ar-H),7.29-7.34(m,3H,Ar-H),7.37-7.41(m,1H,Ar-H),7.71(d,1H,Ar-H,J＝8.1Hz),8.04(d,1H,Ar-H,J＝8.1Hz),8.44(t,1H,NH,J＝8.1Hz)；ESI-MS(m/z):336.0([M+H]+)。
实施例50：N-异丙基-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺(化合物X50)的制备
参照实施例1的制备方法，得到白色固体0.10g，收率37％，m.p.：218-220℃；IR:(KBr,cm-1)3282(s),2974(s),2926(s),2545(s),1923(s),1665(s),1623(s),1534(s),1453(s),1402(s),1358(m),997(s),834(s),734(s),706(s)；1HNMR(400MHz,DMSO):δ1.19(d,6H,CH3,J＝6.6Hz),2.99(s,3H,CH3),4.07(dq,1H,CH,J＝13.5,6.7Hz),7.27-7.32(m,1H,Ar-H),7.37-7.41(m,1H,Ar-H),7.70(d,1H,Ar-H,J＝8.1Hz),8.04(d,1H,Ar-H,J＝8.1Hz),8.20(d,1H,NH,J＝7.2Hz)；ESI-MS(m/z):274.0([M+H]+)。
实施例51：N-异丁基-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺(化合物X51)的制备
参照实施例1的制备方法，得到白色固体0.13g，收率47％，m.p.：160-162℃；IR:(KBr,cm-1)2959(s),2926(s),2970(s),1633(s),1481(s),1455(s),1383(m),1230(s),835(s),739(s)；1HNMR(400MHz,DMSO):δ0.91(d,6H,CH3,J＝6.7Hz),1.86(dp,1H,CH,J＝13.5,6.8Hz),3.00(s,3H,CH3),3.08(dd,2H,CH2,J＝6.8,6.0Hz),7.28-7.32(m,1H,Ar-H),7.37-7.41(m,1H,Ar-H),7.71(d,1H,Ar-H,J＝8.0Hz),8.05(d,1H,Ar-H,J＝8.0Hz),8.38(t,1H,NH,J＝5.7Hz)；ESI-MS(m/z):288.0([M+H]+)。
实施例52：N-(2-羟基-1,1-二甲基乙基)-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺(化合物X52)的制备
参照实施例1的制备方法，得到白色固体0.06g，收率21％，m.p.：114-116℃；IR:(KBr,cm-1)3435(s),2926(s),1641(s),1482(s),1454(s),1383(m),1224(s),876(s),739(s)；1HNMR(400MHz,DMSO):δ1.48(s,6H,CH3),2.97(s,3H,CH3),4.56(s,2H,CH2),6.52(s,1H,OH),7.31-7.35(m,1H,Ar-H),7.41-7.45(m,1H,Ar-H),7.73(d,1H,Ar-H,J＝8.0Hz),8.08(d,1H,Ar-H,J＝8.0Hz),8.19(s,1H,NH)；ESI-MS(m/z):304.0([M+H]+)。
实施例53：(3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰基)甘氨酸乙酯(化合物X53)的制备
参照实施例1的制备方法，得到白色固体0.14g，收率43％，m.p.：156-158℃；IR:(KBr,cm-1)2985(s),2934(s),1750(s),1664(s),1595(s),1534(s),1484(s),1454(s),1374(m),1201(s),1026(s),980(s),866(s),737(s)；1HNMR(400MHz,DMSO):δ1.23(t,3H,CH3,J＝7.1Hz),3.04(s,3H,CH3),4.01(d,2H,CH2,J＝5.8Hz),4.15(d,2H,CH2,J＝7.1Hz),7.28-7.32(m,1H,Ar-H),7.38-7.42(m,1H,Ar-H),7.72(d,1H,Ar-H,J＝8.0Hz),8.05(d,1H,Ar-H,J＝8.0Hz),8.78(t,1H,NH,J＝5.7Hz)；ESI-MS(m/z):318.0([M+H]+)。
实施例54：N-正辛基-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺(化合物X54)的制备
参照实施例1的制备方法，得到白色固体0.09g，收率27％，m.p.：123-125℃；IR:(KBr,cm-1)3299(s),3056(s),2925(s),2854(s),1619(s),1533(s),1483(s),1455(s),1382(m),1258(s),1228(s),875(s),833(s),733(s)；1HNMR(400MHz,DMSO):δ0.86(t,3H,CH3,J＝6.7Hz),1.28(d,10H,CH2,J＝10.0Hz),1.49-1.54(m,2H,CH2),3.00(s,3H,CH3),3.24(dd,2H,CH2,J＝13.1,6.8Hz),7.27-7.31(m,1H,Ar-H),7.37-7.41(m,1H,Ar-H),7.71(d,1H,Ar-H,J＝8.1Hz),8.04(d,1H,Ar-H,J＝8.1Hz),8.34(t,1H,NH,J＝5.5Hz)；ESI-MS(m/z):344.1([M+H]+)。
实施例55：N-[2-(2-甲氧基苯氧基)乙基]-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺(化合物X55)的制备
参照实施例1的制备方法，得到白色固体0.21g，收率56％，m.p.：185-187℃；IR:(KBr,cm-1)3450(s),2946(s),2923(s),2880(s),2838(s),1649(s),1591(s),1509(s),1481(s),1455(s),1384(m),1254(s),1223(s),1123(s),921(s),832(s),740(s)；1HNMR(400MHz,DMSO):δ3.02(s,3H,CH3),3.62(q,2H,CH2,J＝5.8Hz),3.77(s,3H,OCH3),4.12(t,2H,CH2,J＝5.9Hz),6.86-6.94(m,2H,Ar-H),6.99(dd,1H,Ar-H,J＝7.7,1.9Hz),7.04(dd,1H,Ar-H,J＝7.5,1.9Hz),7.28-7.32(m,1H,Ar-H),7.37-7.41(m,1H,Ar-H),7.71(d,1H,Ar-H,J＝8.0Hz),8.06(d,1H,Ar-H,J＝8.0Hz),8.56(t,1H,NH,J＝5.4Hz)；ESI-MS(m/z):382.2([M+H]+)。
实施例56：N-环己基-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺(化合物X56)的制备
参照实施例1的制备方法，得到白色固体0.17g，收率55％，m.p.：229-231℃；IR:(KBr,cm-1)3434(s),3229(s),3048(s),2931(s),2855(s),1647(s),1594(s),1533(s),1473(s),1456(s),1382(m),1322(m),1263(s),1229(s),924(s),891(s),831(s),742(s),692(s)；1HNMR(400MHz,DMSO):δ1.12-1.39(m,5H,CH2),1.59-1.85(m,5H,CH2),2.97(s,3H,CH3),3.73(dd,1H,CH,J＝7.3,3.6Hz),7.27-7.31(m,1H,Ar-H),7.37-7.41(m,1H,Ar-H),7.70(d,1H,Ar-H,J＝8.0Hz),8.04(d,1H,Ar-H,J＝8.0Hz),8.21(d,1H,NH,J＝7.8Hz)；ESI-MS(m/z):314.1([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57：受试化合物对HeLa、SW480、HepG2、HL7702及HUVEC细胞增殖的抑制活性
(1)实验材料
细胞系：HeLa、SW480、HepG2、HL7702及HUVEC细胞，以8000/孔的密度铺于96孔板，每孔100ul，24h后使用。
编号X01至X56目标化合物：以DMSO溶解，用培养液稀释配制为50μM、20μM、10μM、5μM、2μM五个不同浓度保存于-20℃待用，DMSO在培养液中的终浓度低于0.1％。
阳性对照药：5-氟尿嘧啶(5-Fu)。
MTT：以PBS溶解为5mg/mL，保存于-20℃。
(2)实验方法
利用MTT方法，选取HeLa、SW480、HepG2、HL7702及HUVEC细胞来评价供试样品的抗肿瘤增值活性。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)。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过后加入不同浓度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,WetDar,德国)在490nm波长下测量吸光度。根据公式：细胞生长抑制率＝(1-药物组OD值/对照组OD值)×100％，计算相应浓度下的细胞生长抑制率，以受试化合物的不同浓度及对细胞的抑制率作对数曲线，计算受试化合物相对应的IC50值。按照上述方法测定本发明代表性化合物，结果示于表1：
表1
实施例58：受试化合物对EGFR激酶活性的体外抑制效果实验方法。
(1)实验材料
野生型及各种突变型(T790M,L858/T70M)EGFR，待测化合物均为细胞增殖抑制活性较好的化合物。
(2)实验方法
将一系列梯度浓度的受试化合物，在室温条件下与特定浓度的酶溶液共同孵育5min，之后加入适量的酶反应底物、ATP，启动酶反应过程，30min后，向酶反应体系中加入适量的反应终止液和检测液，孵育1h后，在Molecular Device公司的Flexstation III多功能酶标仪上，测定特定化合物浓度下的酶活力，并计算不同浓度的化合物对酶活力的抑制活性，之后根据四参数方程，对不同浓度化合物下酶活力的抑制活性进行拟合，计算出IC50值。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
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59：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60：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61：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62：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63：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 (10)
1.一种式(Ⅰ)的化合物，其前体药物和药物活性代谢物，及药学上可接受的盐：
其中
R1、R2可以独立地地选自H，C1-C8烷基，羟基取代的C2-C8烷基，卤素取代的C2-C8烷基，C3-C6环烷基，2-(2-甲氧基苯氧基)乙基，苄基，C1-C6烷基取代的苄基，C1-C6烷氧基取代的苄基，卤素取代的苄基，苯基，C1-C6烷基取代的苯基，C1-C6烷氧基取代的苯基，羟基取代的苯基，苄氧基苯基，卤素取代的苯基，硝基取代的苯基，4-联苯基，1-萘基，2-萘基，1-苯基乙基，2-苯基乙基，4-吗啉基，2-(4-吗啉基)乙基，3-(4-吗啉基)丙基，2-吡啶甲基，2-吡啶基，C1-C6烷基取代的2-吡啶基，2-呋喃甲基，苯并[d]噻唑-2-基，1H-1,2,4-三氮唑-3-基，或2-乙氧基羰甲基；或与它们相连的氮原子一起组成1-哌啶基，1-吡咯烷基，4-吗啉基，苯基哌嗪-1-基，C1-C6烷基取代的苯基哌嗪-1-基，C1-C6烷氧基取代的苯基哌嗪-1-基，卤素取代的苯基哌嗪-1-基，苄基哌嗪-1-基，C1-C6烷基取代的苄基哌嗪-1-基，C1-C6烷氧基取代的苄基哌嗪-1-基，卤素取代的苄基哌嗪-1-基。
2.权利要求1的化合物，其前体药物和药物活性代谢物，及药学上可接受的盐：
其中，
R1、R2可以独立地选自H，甲基，异丙基，正丁基，异丁基，正辛基，2-羟基乙基，2-羟基-1,1-二甲基乙基，2-氯乙基，2-溴乙基，2-羟基乙基，环戊基，环己基，2-(2-甲氧基苯氧基)乙基，苄基，4-氟苄基，4-氯苄基，3-氯-4-甲氧基苄基，苯基，2-甲基苯基，4-甲基苯基，2,4-二甲基苯基，2-乙基苯基，4-乙基苯基，4-三氟甲基苯基，2-甲氧基苯基，4-甲氧基苯基，2,5-二甲氧基苯基，4-烯丙氧基苯基，2-羟基苯基，4-羟基苯基，4-苄氧基苯基，4-氟苯基，4-氯苯基，4-溴苯基，3,5-二氟苯基，3-溴-4-氟苯基，4-溴-3-氟苯基，5-氟-2-甲氧基苯基，5-溴-2-甲氧基苯基，4-氯-3-三氟甲基苯基，3-硝基苯基，4-硝基苯基，4-联苯基，1-萘基，2-萘基，1-苯基乙基，2-苯基乙基，4-吗啉基，2-(4-吗啉基)乙基，3-(4-吗啉基)丙基，2-吡啶甲基，2-吡啶基，3-甲基-2-吡啶基，4-甲基-2-吡啶基，3-苄氧基-2-吡啶基，2-呋喃甲基，苯并[d]噻唑-2-基，1H-1,2,4-三氮唑-3-基，或2-乙氧基羰甲基；或与它们相连的氮原子一起组成1-哌啶基，1-吡咯烷基，4-吗啉基，4-苯基哌嗪-1-基，4-(2-甲基苯基)哌嗪-1-基，4-(4-甲基苯基)哌嗪-1-基，4-(2,4-二甲基苯基)哌嗪-1-基，4-(2-乙基苯基)哌嗪-1-基，4-(3-三氟甲基苯基)哌嗪-1-基，4-(4-甲氧基苯基)哌嗪-1-基，4-(4-氟苯基)哌嗪-1-基，4-(3-氯苯基)哌嗪-1-基，4-(3-溴苯基)哌嗪-1-基，4-(2,3-二氯苯基)哌嗪-1-基，4-(4-氯苯基)哌嗪-1-基，4-(4-氯-3-三氟甲氧基苯基)哌嗪-1-基，4-苄基哌嗪-1-基，4-(4-甲基苄基)哌嗪-1-基，4-(4-甲氧基苄基)哌嗪-1-基，4-二苯甲基哌嗪-1-基，4-[(4-氯苯基)(苯基)甲基]哌嗪-1-基。
3.权利要求1所述的化合物，其前体药物和药物活性代谢物，及药学上可接受的盐，选自：
N-(2-甲基苯基)-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺；
N,3-二甲基-N-苯基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺；
3-甲基-N-(3-硝基苯基)苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺；
3-甲基-N-(4-硝基苯基)苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺；
N-(3-溴-4-氟苯基)-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺；
N-(4-溴-3-氟苯基)-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺；
3-甲基-N-(4-三氟甲氧基苯基)苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺；
N-(5-氟-2-甲氧基苯基)-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺；
N-(5-溴-2-甲氧基苯基)-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺；
N-(2,5-二甲氧基苯基)-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺；
N-(3,5-二氟苯基)-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺；
N-(4-氯-3-三氟甲基苯基)-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺；
N-(4-烯丙氧基苯基)-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺；
N-(3-甲基-2-吡啶基)-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺；
N-(苯并[d]噻唑-2-基)-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺；
N-[4-(4-吗啉基)苯基]-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺；
N-(1H-1,2,4-三氮唑-3-基)-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺；
N-(1-萘基)-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺；
N-(4-联苯基)-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺；
N-(4-吗啉基)-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺；
N-(3-苄氧基-2-吡啶基)-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺；
N-(4-氟苯基)-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺；
N-(4-氯苯基)-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺；
N-苄基-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺；
N-(4-氟苄基)-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺；
N-(2-氯苄基)-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺；
N-(4-甲氧基苄基)-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺；
N-(3-氯-4-甲氧基苄基)-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺；
(R)-N-(1-苯基乙基)-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺；
N-(2-吡啶甲基)-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺；
N-(2-呋喃甲基)-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺；
(3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-基)[4-(4-甲基苯基)哌嗪-1-基]甲基酮；
[4-(4-甲氧基苯基)哌嗪-1-基](3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-基)甲基酮；
(4-苄基哌嗪-1-基)(3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-基)甲基酮；
[4-(2-甲氧基苯基)哌嗪-1-基](3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-基)甲基酮；
{4-[(4-氯苯基)(苯基)甲基]哌嗪-1-基}(3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-基)甲基酮；
[4-(3-三氟甲基苯基)哌嗪-1-基](3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-基)甲基酮；
[4-(4-氟苯基)哌嗪-1-基](3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-基)甲基酮；
[4-(3-氯苯基)哌嗪-1-基](3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-基)甲基酮；
(4-二苯甲基哌嗪-1-基)(3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-基)甲基酮；
[4-(2,5-二甲基苯基)哌嗪-1-基](3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-基)甲基酮；
[4-(4-氯-3-三氟甲基苯基)哌嗪-1-基](3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-基)甲基酮；
[4-(4-甲基苯基)哌嗪-1-基](3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-基)甲基酮；
[4-(2-乙基苯基)哌嗪-1-基](3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-基)甲基酮；
[4-(2-氯苯基)哌嗪-1-基](3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-基)甲基酮；
[4-(2,4-二甲基苯基)哌嗪-1-基](3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-基)甲基酮；
[4-(3-溴苯基)哌嗪-1-基](3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-基)甲基酮；
[4-(2,3-二氯苯基)哌嗪-1-基](3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-基)甲基酮；
N-苯乙基-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺；
N-异丙基-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺；
N-异丁基-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺；
N-(2-羟基-1,1-二甲基乙基)-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺；
(3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰基)甘氨酸乙酯；
N-正辛基-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺；
N-[2-(2-甲氧基苯氧基)乙基]-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺；
N-环己基-3-甲基苯并[4,5]咪唑并[2,1-b]噻唑-2-甲酰胺。
4.一种药物组合物，包括作为活性成分的权利要求1-3任何一项所述的化合物，其前体药物和药物活性代谢物，及药学上可接受的盐和药学上可接受的载体或稀释剂。
5.权利要求1-3任何一项所述的化合物、其前体药物和药物活性代谢物，及药学上可接受的盐在制备治疗肿瘤药物中的应用。
6.权利要求4所述的药物组合物在制备治疗肿瘤药物中的应用。
7.权利要求1-3任何一项所述的化合物、其前体药物和药物活性代谢物，及药学上可接受的盐在制备治疗表皮生长因子受体信号转导失调的相关疾病药物中的应用。
8.权利要求4所述的药物组合物在在制备治疗表皮生长因子受体信号转导失调的相关疾病药物中的应用。
9.根据权利要求7或8所述的应用，其特征在于：其中表皮生长因子受体为HER-1、HER-2、HER-3或HER-4。
10.根据权利要求5-9中任何一项所述的应用，其特征在于：其中所述的肿瘤或表皮生长因子受体信号转导失调的相关疾病为小细胞肺癌，鳞癌，腺癌，大细胞癌，结肠直肠癌、乳腺癌，卵巢癌，肾细胞癌。
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1167369A1 (en) * | 1999-04-06 | 2002-01-02 | Yamanouchi Pharmaceutical Co. Ltd. | Novel thiazolobenzimidazole derivatives |
-
2017
- 2017-12-04 CN CN201711258608.4A patent/CN108017659A/zh active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1167369A1 (en) * | 1999-04-06 | 2002-01-02 | Yamanouchi Pharmaceutical Co. Ltd. | Novel thiazolobenzimidazole derivatives |
Non-Patent Citations (3)
| Title |
|---|
| ABDEL-AZIZ, HATEM A.等: "Immunomodulatory and anticancer activities of some novel 2-substituted-6-bromo-3- methylthiazolo[3,2-a]benzimidazole derivatives", 《ARCHIV DER PHARMAZIE (WEINHEIM, GERMANY)》 * |
| D"AMICO, JOHN J.等: "Derivatives of 3-Methylthiazolo [3,2-a]benzimidazole", 《JOURNAL OF ORGANIC CHEMISTRY》 * |
| SUPPLIER: AMBINTER: "450383-46-7 REGISTRY", 《STN-REGISTRY》 * |
Cited By (1)
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|---|---|---|---|---|
| CN113773261A (zh) * | 2021-10-21 | 2021-12-10 | 鹤壁元昊化工有限公司 | 一种2-巯基苯并咪唑类化合物的制备方法 |
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