CN115710251B - 一种髓样分化因子88抑制剂及其制备方法和应用 - Google Patents
一种髓样分化因子88抑制剂及其制备方法和应用 Download PDFInfo
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- CN115710251B CN115710251B CN202211458016.8A CN202211458016A CN115710251B CN 115710251 B CN115710251 B CN 115710251B CN 202211458016 A CN202211458016 A CN 202211458016A CN 115710251 B CN115710251 B CN 115710251B
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- piperazin
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- 239000003112 inhibitor Substances 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 230000004069 differentiation Effects 0.000 title abstract description 3
- 102000010168 Myeloid Differentiation Factor 88 Human genes 0.000 claims abstract description 31
- 108010077432 Myeloid Differentiation Factor 88 Proteins 0.000 claims abstract description 31
- 206010061218 Inflammation Diseases 0.000 claims abstract description 19
- 230000004054 inflammatory process Effects 0.000 claims abstract description 19
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 8
- -1 2-methoxypyridin-5-yl Chemical group 0.000 claims description 132
- 150000001875 compounds Chemical class 0.000 claims description 83
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 30
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 23
- 206010040047 Sepsis Diseases 0.000 claims description 12
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 12
- 206010069351 acute lung injury Diseases 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 6
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 5
- 208000035475 disorder Diseases 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 3
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 3
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 3
- 125000006514 pyridin-2-ylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 3
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 claims description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 claims description 2
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Abstract
本发明属于有机合成技术领域，提供了一种新的髓样分化因子88抑制剂及其制备方法和应用。所述新的髓样分化因子88抑制剂可以抑制炎症细胞因子超出正常量表达和释放，并以此为药理机制治疗过度炎症相关的疾病。实验表明，本发明提供的MyD88抑制剂具有有效的炎症因子的抑制作用以及更优的体内抗炎活性。
Description
技术领域
本发明涉及有机物合成技术领域，尤其涉及一种髓样分化因子88抑制剂及其制备方法和应用。
背景技术
固有免疫是人体应对外源性或内源性异质物刺激的生理过程。通常情况下，固有免疫能通过炎症反应清除产生刺激的异质物，保护人体健康。但当某些疾病发生时，免疫调节出现异常，使病变部位产生过量的炎症反应，即炎症风暴，进一步损害人体健康。
固有免疫系统依赖于种系编码受体，即模式识别受体(pattern recognitionreceptors,PRRs)，这些受体可以识别一种或多种病原相关模式分子(pathogen-associated molecular pattern,PAMPs)，以及损伤相关分子模式(damage-associatedmolecular pattern,DAMPs)，是启动固有免疫应答的免疫受体的代表。常见的模式识别受体包括Toll样受体(Toll-like receptors)，RIG-I样受体(RIG-I like receptors)，NOD样受体(NOD like receptors)，AIM2样受体(AIM2 like receptors)和C型凝集素受体，以及cGas和其他细胞内DNA传感器。Toll样受体是研究最多的PRR之一，哺乳动物中目前共发现有10种Toll样受体，其识别DAMPs或PAMPs后通过下游的衔接蛋白进行信号转导。目前发现5种衔接蛋白，分别为MyD88，TRIF，TRAM，MAI和SARM，其中MyD88和TRIF作为主要的衔接蛋白将信号转导至下游。TRIF参与TLR3和TLR4的信号转导，介导IFNβ的产生，主要作为MyD88非依赖途径参与炎性信号转导，而MyD88则参与除TLR3外的所有TLRs家族的信号转导，其是TLRs/IL-1R信号转导的中心分子，也是炎症相关信号通路调节的关键蛋白。
MyD88的激活，一方面导致下游MAPKs/p38/JNK通路激活，从而使AP-1活化，另一方面激活TAK1/TAB复合物，激活NF-κB，使其入核，进而产生促炎因子如TNF-α和IL-6，使得大量炎症相关因子和化学因子转录和表达。有多项研究表明，基因敲除MyD88的小鼠对脂多糖以及葡萄球菌肠毒素诱导的死亡有所耐受。MyD88作为TLRs/IL-R信号通路的一个关键蛋白靶点，有作为治疗炎症相关疾病的潜在能力，已逐渐受到越来越多的研究者关注。但是，目前现有技术中MyD88抑制剂却有限，亟需研发一些新的MyD88抑制剂。
发明内容
本发明的目的在于提供一种髓样分化因子88抑制剂及其制备方法和应用，以弥补现有技术的不足。
本发明提供了一种髓样分化因子88抑制剂，为结构如式(Ⅰ)所示的化合物或其药学上可接受的盐、水合物、溶剂化物或前药；
其中:X和Y独立的包含CH2，NH，C(O)，S(O)2中的一种；R1包含H，可以被1至3个相同或不同的取代基任选取代的芳基、可以被1至3个相同或不同的取代基任选取代的杂环基或可以被1至3个相同或不同的取代基任选取代的杂芳基，所述取代基选自烷基、卤素、烷氧基、取代芳基和取代杂芳基；R2包含氢或硝基；R3和R4独立地包含氢、烷基和芳基，或者R3和R4独立地成环从而使得-C(R3)R4形成取代杂环基或取代杂芳基，或者R3和X、Y独立地成环使得-XYCR3形成取代杂环基或取代芳杂基。
优选的，当X为C(O)或S(O)2时，Y为NH或CH2，R3和R4独立地成环从而使得-C(R3)R4形成取代芳基或取代杂芳基，R2为硝基，R1为
优选的，R3和X、Y独立地成环使得-XYCR3形成取代杂环基或取代芳杂基，R2为H，R1为 R4为/>或与-XYCR3形成并环取代芳基，R5为H，CH3O或Br。
优选的，为以下化合物及其药学上可接受的盐、溶剂化物或前药：
化合物1：N-(2-甲氧基吡啶-5-基)-3-硝基-4-[4-(嘧啶-2-基)哌嗪-1-基]苯磺酰胺
化合物2：4-(4-苄基哌嗪-1-基)-N-(2-甲氧基吡啶-5-基)-3-硝基苯磺酰胺
化合物3：N-(2-甲氧基吡啶-5-基)-3-硝基-4-{4-[(3-硝基苯基)甲基]哌嗪-1-基}苯磺酰胺
化合物4：N-(2-甲氧基吡啶-5-基)-3-硝基-4-{4-[(4-硝基苯基)甲基]哌嗪-1-基}苯磺酰胺
化合物5：4-{4-[(4-甲氧基苯基)甲基]哌嗪-1-基}-N-(2-甲氧基吡啶-5-基)-3-硝基苯磺酰胺
化合物6：N-(5-{[4-(4-{[(6-甲氧基吡啶-3-基)氨基]二氧亚基-λ6-硫基}-2-硝基苯基)哌嗪-1-基]甲基}-1,3-噻唑-2-基)乙酰胺
化合物7：N-(萘-1-基)-3-硝基-4-{4-[(3-硝基苯基)甲基]哌嗪-1-基}苯甲酰胺
化合物8：3-硝基-4-{4-[(3-硝基苯基)甲基]哌嗪-1-基}-N-(吡啶-2-基甲基)苯磺酰胺
化合物9：3-硝基-4-{4-[(4-硝基苯基)甲基]哌嗪-1-基}-N-(吡啶-2-基甲基)苯磺酰胺
化合物10：4-(4-苄基哌嗪-1-基)-3-硝基-N-(吡啶-2-基甲基)苯甲酰胺
化合物11：3-硝基-4-{4-[(4-硝基苯基)甲基]哌嗪-1-基}-N-(吡啶-2-基甲基)苯甲酰胺
化合物12：3-硝基-4-{4-[(3-硝基苯基)甲基]哌嗪-1-基}-N-(吡啶-2-基甲基)苯甲酰胺
化合物13：3-硝基-4-{4-[(3-硝基苯基)甲基]哌嗪-1-基}-N-苯基苯甲酰胺
化合物14：3-硝基-4-{4-[(4-硝基苯基)甲基]哌嗪-1-基}-N-苯基苯甲酰胺
化合物15：3-硝基-4-[4-(4-硝基苯基)哌嗪-1-基]-N-苯基苯甲酰胺
化合物16：2-(4-{2-硝基-4-[(苯基氨基)甲基]苯基}哌嗪-1-基)乙-1-醇
化合物17：4-[4-(2-甲氧基乙基)哌嗪-1-基]-3-硝基-N-苯基苯甲酰胺
化合物18：4-[4-(2-羟基乙基)哌嗪-1-基]-N-(6-甲氧基吡啶-3-基)-3-硝基苯磺酰胺
化合物19：4-[4-(2-甲氧基乙基)哌嗪-1-基]-N-(6-甲氧基吡啶-3-基)-3-硝基苯磺酰胺
化合物20：4-[4-(2-甲氧基乙基)哌嗪-1-基]-3-硝基-N-(吡啶-2-基甲基)苯磺酰胺
化合物21：4-[4-(2-羟基乙基)哌嗪-1-基]-3-硝基-N-(吡啶-2-基甲基)苯磺酰胺
化合物22：4-[4-(2-甲氧基乙基)哌嗪-1-基]-3-硝基-N-苯基苯磺酰胺
化合物23：4-[4-(2-羟基乙基)哌嗪-1-基]-3-硝基-N-苯基苯磺酰胺
化合物24：3-硝基-4-{4-[(3-硝基苯基)甲基]哌嗪-1-基}-N-苯基苯磺酰胺
化合物25：3-硝基-4-{4-[(4-硝基苯基)甲基]哌嗪-1-基}-N-苯基苯磺酰胺
化合物26：3-硝基-4-[4-(4-硝基苯基)哌嗪-1-基]-N-苯基苯磺酰胺
化合物27：4-(4-苄基哌嗪-1-基)-3-硝基-N-(吡啶-2-基甲基)苯磺酰胺
化合物28：3-硝基-4-{4-[(3-硝基苯基)甲基]哌嗪-1-基}-N-(吡啶-2-基甲基)苯磺酰胺
化合物29：3-硝基-4-{4-[(4-硝基苯基)甲基]哌嗪-1-基}-N-(吡啶-2-基甲基)苯磺酰胺
化合物30：3-硝基-4-[4-(4-硝基苯基)哌嗪-1-基]-N-(吡啶-2-基甲基)苯磺酰胺
化合物31：4-{4-[(4-甲氧基苯基)甲基]哌嗪-1-基}-3-硝基-N-(吡啶-2-基甲基)苯磺酰胺
化合物32：3-硝基-N-(吡啶-2-基甲基)-4-[4-(嘧啶-2-基)哌嗪-1-基]苯磺酰胺
化合物33：N-(5-{[4-(4-{二氧亚基[(吡啶-2-基甲基)氨基]-λ6-硫基}-2-硝基苯基)哌嗪-1-基]甲基}-1,3-噻唑-2-基)乙酰胺
化合物34：1-[4-(苄基磺酰基)-2-硝基苯基]-3-甲基哌啶
化合物35：1-[4-(苄基磺酰基)-2-硝基苯基]-4-甲基哌嗪
化合物36：1-[4-(苄基磺酰基)-2-硝基苯基]-4-乙基哌嗪
化合物37：1-{4-[4-(苄基磺酰基)-2-硝基苯基]哌嗪-1-基}乙-1-酮
化合物38：1-[4-(苄基磺酰基)-2-硝基苯基]-4-(4-硝基苯基)哌嗪
化合物39：2-{4-[4-(苄基磺酰基)-2-硝基苯基]哌嗪-1-基}乙-1-醇
化合物40：1-[4-(苄基磺酰基)-2-硝基苯基]-4-(2-甲氧基乙基)哌嗪
化合物41：1-[4-(苄基磺酰基)-2-硝基苯基]-4-(3-硝基苄基)哌嗪
化合物42：4-[(3-氟苄基)磺酰基]-N，N-二甲基-2-硝基苯胺
化合物43：1-乙基-4-{4-[(3-氟苄基)磺酰基]-2-硝基苯基}哌嗪
化合物44：1-(4-{4-[(3-氟苄基)磺酰基]-2-硝基苯基}哌嗪-1-基)乙-1-酮
化合物45：1-{4-[(3-氟苄基)磺酰基]-2-硝基苯基}-4-(4-硝基苯基)哌嗪
化合物46：2-(4-{4-[(3-氟苄基)磺酰基]-2-硝基苯基}哌嗪-1-基)乙-1-醇
化合物47：1-{4-[(3-氟苄基)磺酰基]-2-硝基苯基}-4-(2-甲氧基乙基)哌嗪
化合物48：1-{4-[(3-氟苄基)磺酰基]-2-硝基苯基}-4-(3-硝基苄基)哌嗪
化合物49：4-[(4-氟苄基)磺酰基]-N，N-二甲基-2-硝基苯胺
化合物50：1-乙基-4-[4-(4-氟苄基)磺酰基]-2-硝基苯基哌嗪
化合物51：1-(4-{4-[(4-氟苄基)磺酰基]-2-硝基苯基}哌嗪-1-基)乙-1-酮
化合物52：1-{4-[(4-氟苄基)磺酰基]-2-硝基苯基}-4-(4-硝基苯基)哌嗪
化合物53：2-(4-{4-[(4-氟苄基)磺酰基]-2-硝基苯基}哌嗪-1-基)乙-1-醇
化合物54：1-{4-[(4-氟苄基)磺酰基]-2-硝基苯基}-4-(2-甲氧基乙基)哌嗪
化合物55：1-{4-[(4-氟苄基)磺酰基]-2-硝基苯基}-4-(3-硝基苄基)哌嗪
化合物56：1-{4-[(4-氟苄基)磺酰基]-2-硝基苯基}-4-(4-硝基苄基)哌嗪
化合物57：1-乙基-4-[4-(4-甲基苄基)磺酰基]-2-硝基苯基)哌嗪
化合物58：1-(4-{4-[(4-甲基苄基)磺酰基]-2-硝基苯基}哌嗪-1-基)乙-1-酮
化合物59：1-{4-[(4-甲基苄基)磺酰基]-2-硝基苯基}-4-(4-硝基苯基)哌嗪
化合物60：2-(4-{4-[(4-甲基苄基)磺酰基]-2-硝基苯基}哌嗪-1-基)乙-1-醇
化合物61：1-(2-甲氧基乙基)-4-[4-(4-甲基苄基)磺酰基]2-硝基苯基)哌嗪
化合物62：4-[(4-甲氧基苄基)磺酰基]-N，N-二甲基-2-硝基苯胺
化合物63：1-{4-[(3-甲氧基苄基)磺酰基]-2-硝基苯基}哌嗪
化合物64：1-乙基-4-{4-[(3-甲氧基苄基)磺酰基]-2-硝基苯基}哌嗪
化合物65：1-(4-{4-[(3-甲氧基苄基)磺酰基]-2-硝基苯基}哌嗪-1-基)乙-1-酮
化合物66：1-{4-[(3-甲氧基苄基)磺酰基]-2-硝基苯基}-4-(4-硝基苯基)哌嗪
化合物67：2-(4-{4-[(3-甲氧基苄基)磺酰基]-2-硝基苯基}哌嗪-1-基)乙-1-醇
化合物68：1-{4-[(3-甲氧基苄基)磺酰基]-2-硝基苯基}-4-(2-甲氧基乙基)哌嗪
化合物69：1-{4-[(3-甲氧基苄基)磺酰基]-2-硝基苯基}-4-(3-硝基苄基)哌嗪
化合物70：4-(4-{[4-(2-羟基乙基)哌嗪-1-基]甲基}苯基)-6-苯基-1,2-二氢嘧啶-2-酮
化合物71：4-(4-{[4-(2-甲氧基乙基)哌嗪-1-基]甲基}苯基)-6-(4-甲氧基苯基)-1,2-二氢嘧啶-2-酮
化合物72：4-{4-[(4-{2-[(2-羟基乙基)氧基]乙基}哌嗪-1-基)甲基]苯基}-6-苯基-1,2-二氢嘧啶-2-酮
化合物73：4-{4-[(苯并[d][1,3]噻唑-2-基氨基)甲基]苯基}-6-苯基-1,2-二氢嘧啶-2-酮
化合物74：4-(4-{[4-(2-羟基乙基)哌嗪-1-基]甲基}苯基)-6-(4-甲氧基苯基)-1,2-二氢嘧啶-2-酮
化合物75：4-{4-[(4-{2-[(2-羟基乙基)氧基]乙基}哌嗪-1-基)甲基]苯基}-6-(4-甲氧基苯基)-1,2-二氢嘧啶-2-酮
化合物76：4-{4-[(戊基氨基)甲基]苯基}-6-苯基-1,2-二氢嘧啶-2-酮
化合物77：6-(4-甲氧基苯基)-4-{4-[(戊基氨基)甲基]苯基}-1,2-二氢嘧啶-2-酮
化合物78：4-(4-{[4-(2-甲氧基乙基)哌嗪-1-基]甲基}苯基)-6-苯基-1,2-二氢嘧啶-2-酮
化合物79：6-(4-溴苯基)-4-(4-{[4-(2-羟基乙基)哌嗪-1-基]甲基}苯基)-1,2-二氢嘧啶-2-酮
化合物80：4-(4-{[4-(4-硝基苯基)哌嗪-1-基]甲基}苯基)-6-苯基-1,2-二氢嘧啶-2-酮
化合物81：6-(4-溴苯基)-4-{4-[(4-{2-[(2-羟基乙基)氧基]乙基}哌嗪-1-基)甲基]苯基}-1,2-二氢嘧啶-2-酮
化合物82：6-(4-甲氧基苯基)-4-(4-{[4-(4-硝基苯基)哌嗪-1-基]甲基}苯基)-1,2-二氢嘧啶-2-酮
化合物83：6-(4-溴苯基)-4-(4-{[4-(2-甲氧基乙基)哌嗪-1-基]甲基}苯基)-1,2-二氢嘧啶-2-酮
化合物84：4-{4-[(4-乙酰基哌嗪-1-基)甲基]苯基}-6-(4-溴苯基)-1,2-二氢嘧啶-2-酮
化合物85：2-(4-{[4-(2-甲氧基乙基)哌嗪-1-基]甲基}苯基)-3,4-二氢喹唑啉-4-酮
化合物86：2-(4-{[4-(2-羟基乙基)哌嗪-1-基]甲基}苯基)-3,4-二氢喹唑啉-4-酮
化合物87：2-(4-{[4-(4-硝基苯基)哌嗪-1-基]甲基}苯基)-3,4-二氢喹唑啉-4-酮
化合物88：2-{4-[(4-乙酰基哌嗪-1-基)甲基]苯基}-3,4-二氢喹唑啉-4-酮
化合物89：7-{[4-(2-甲氧基乙基)哌嗪-1-基]甲基}-2-苯基-3,4-二氢喹唑啉-4-酮
化合物90：7-{[4-(2-羟基乙基)哌嗪-1-基]甲基}-2-苯基-3,4-二氢喹唑啉-4-酮
化合物91：7-{[4-(4-硝基苯基)哌嗪-1-基]甲基}-2-苯基-3,4-二氢喹唑啉-4-酮
化合物92：7-[(4-乙酰基哌嗪-1-基)甲基]-2-苯基-3,4-二氢喹唑啉-4-酮
化合物93：7-[(4-{2-[(2-羟基乙基)氧基]乙基}哌嗪-1-基)甲基]-2-苯基-3,4-二氢喹唑啉-4-酮。
本发明还提供了所述髓样分化因子88抑制剂的制备方法，化合物1～33的制备方法包含如下步骤：
(1)将H2N-R3和二氯甲烷混合后进行反应，生成所述/>H2N-R3和二氯甲烷的用量比为1.4～2mmol：1.4～2mmol：2～8mL；所述反应的温度为-5～5℃，时间为5～15h；
(2)将含R1化合物、碳酸钾、碘化钠和无水四氢呋喃混合后进行反应，生成化合物1～33中的一种；所述/>含R1化合物、碳酸钾、碘化钠和无水四氢呋喃的用量比为0.1～0.2mmol：0.1～0.3mmol：0.2～0.4mmol：0.2～0.4mmol：4～8mL；所述反应的温度为60～80℃，时间为1～10h。
本发明还提供了所述髓样分化因子88抑制剂的制备方法，化合物34～69的制备方法包含如下步骤：
(1)将碳酸氢钠、亚硫酸钠、4-氯-3-硝基苯磺酰氯和水混后合后进行反应，生成4-氯-3-硝基苯亚磺酸；所述碳酸氢钠、亚硫酸钠、4-氯-3-硝基苯磺酰氯和水的用量比为7～9mmol:7～9mmol:3～5mmol:20～40mL；所述反应的温度为室温，时间为1～5h；
(2)将4-氯-3-硝基苯亚磺酸、溴苄类物质和N,N-二甲基甲酰胺混合后进行反应，生成所述4-氯-3-硝基苯亚磺酸、溴苄类物质和N,N-二甲基甲酰胺的用量比为0.4～0.5mmol:0.6～0.8mmol:2～8mL；所述反应的温度为70～90℃，时间为1～5h；
(3)将碘化钾、三甲基哌啶、碳酸钾和乙腈混合后进行反应，生成化合物34～69中的一种；所述/>碘化钾、三甲基哌啶、碳酸钾和乙腈的用量比为0.09～0.11mmol:0.05～0.2mmol:0.05～0.2mmol:0.05～0.2mmol:2～8ml；所述反应的温度为80～90℃，时间为1～5h。
本发明还提供了所述髓样分化因子88抑制剂的制备方法，化合物70～84的制备方法包含如下步骤：
(1)将苯乙酮、氢氧化钠、和乙醇混合后进行反应，生成所述苯乙酮、氢氧化钠、/>和乙醇的用量比为15～18mmol:23～28mmol:15～18mmol:5～15mL；所述反应的温度为室温，时间为5～15h；
(2)在保护气氛下，将N-溴代琥珀酰亚胺、偶氮二异丁腈和四氯化碳混合后进行反应，生成/>所述/>N-溴代琥珀酰亚胺、偶氮二异丁腈和四氯化碳的用量比为2～2.5mmol:2～3mmol:0.2～0.8mmol:15～25mL；所述反应的温度为80～90℃，时间为1～5h；
(3)将含R1化合物、三乙胺和乙腈混合后进行反应，生成所述/>含R1化合物、三乙胺和乙腈的用量比为0.5～0.8mmol:0.8～1.2mmol:0.8～1.2mmol:5～15mL；所述反应的温度为80～90℃，时间为1～5h；
(4)在保护气氛下，将脲、叔丁醇钠和四氢呋喃混合后进行反应，生成化合物70～84中的一种；所述/>脲、叔丁醇钠和四氢呋喃的用量比为0.2～0.4mmol:0.3～0.5mmol:0.3～0.4mmol:1～10mL；所述反应的温度为80～90℃，时间为1～5h。
本发明还提供了所述髓样分化因子88抑制剂的制备方法，化合物85～93的制备方法包含如下步骤：
(1)将碘、/>和乙醇混合后进行反应，生成
所述碘、/>和乙醇的用量比为7～8mmol:7～9mmol:8～10mmol:5～15mL；
所述反应的温度为80～90℃，时间为1～5h；
所述为2-氨基-苯甲酰胺或2-氨基-4-甲基苯甲酰胺；
所述为对甲基苯甲醛或苯甲醛；
所述R5和R1有一个为H；
(2)在保护气氛下，将N-溴代琥珀酰亚胺、偶氮二异丁腈和四氯化碳混合后进行反应，生成中间产物；
所述N-溴代琥珀酰亚胺、偶氮二异丁腈和四氯化碳的用量比为7～8mmol:7～9mmol:1～2mmol:25～35mL；
所述反应的温度为80～90℃，时间为1～5h；
(3)在保护气氛下，将中间产物、2-甲氧基乙基哌嗪、三乙胺和乙腈混合后进行反应，生成化合物85～93中的一种；
所述中间产物、2-甲氧基乙基哌嗪、三乙胺和乙腈的用量比为0.1～0.5mmol:0.1～0.5mmol:45～55μL:5～15mL；
所述反应的温度为80～90℃，时间为1～5h。
本发明还提供了所述髓样分化因子88抑制剂在制备治疗炎症相关疾病的药物制剂中的应用。
优选的，所述炎症相关疾病包含急性肺损伤和/或脓毒血症。
本发明提供了一种新的髓样分化因子88抑制剂及其制备方法和应用。所述新的髓样分化因子88抑制剂可以抑制炎症细胞因子超出正常量表达和释放，并以此为药理机制治疗过度炎症相关的疾病。实验表明，本发明提供的MyD88抑制剂具有有效的炎症因子的抑制作用以及更优的体内抗炎活性。
本发明通式I的MyD88抑制剂可以与酸生成它的药学上可接受的盐。酸可以包括无机酸或有机酸，与下列酸形成的盐是特别优选的：盐酸、氢溴酸、硫酸、磷酸、甲磺酸、乙磺酸、甲苯磺酸、苯磺酸、萘二磺酸、乙酸、丙酸、乳酸、三氟乙酸、马来酸、柠檬酸、富马酸、酒石酸、苯磺酸、苯甲酸或对甲苯磺酸等。
本发明还包括通式IMyD88抑制剂的前药。依据本发明，前药是通式I化合物的衍生物，它们自身可能具有较弱的活性或甚至没有活性，但是在给药后，在生理条件下(例如通过代谢、溶剂分解或另外的方式)被转化成相应的生物活性形式。
本发明可以含有上述通式I含有MyD88抑制剂，及其药学上可接受的盐、水合物或溶剂化物作为活性成份，与药学上可接受的载体或赋型剂混合制备成组合物，并制备成临床上可接受的剂型，上述药学上可接受的赋型剂是指任何可用于药学领域的稀释剂、辅助剂和/或载体。本发明的衍生物可以与其他活性成份组合使用，只要它们不产生其他不利的作用，例如过敏反应。
发明的药用组合物可配制成若干种剂型，其中含有药物领域中一些常用的赋形剂。如上所述的若干种剂型可以采用注射剂、片剂、胶囊剂、气雾剂、栓剂、膜剂、滴丸剂、外用搽剂、软膏剂等剂型药物。
用于本发明药物组合物的载体是药物领域中可得到的常见类型，包括：粘合剂、润滑剂、崩解剂、助溶剂、稀释剂、稳定剂、悬浮剂、无色素、矫味剂、防腐剂、加溶剂和基质等。药物制剂可以经口服或胃肠外方式(例如静脉内、皮下、腹膜内或局部)给药，如果某些药物在胃部条件下不稳定的，可将其配制成肠衣片剂。
附图说明
图1为实施例3化合物与MyD88蛋白的结合亲和力与浓度的关系。
图2为部分实施例化合物抑制LPS刺激J774A.1细胞释放IL-6的量效关系。
图3为部分实施例化合物抑制LPS刺激J774A.1细胞释放TNF-α的量效关系。
图4为以急性肺损伤为例，实施例3化合物缓解炎症引起的小鼠生理学变化效果。A湿重/干重比(W/D)；B肺泡灌洗液中白细胞蛋白浓度；C肺泡灌洗液中IL-6表达量；D肺泡灌洗液中TNF-α表达量；E血清中IL-6表达量；F血清TNF-α表达量。
图5为以急性肺损伤中肺组织为例，实施例3化合物缓解炎症引起的病理学变化。
图6为以脓毒血症为例，实施例3化合物缓解炎症引起小鼠死亡的变化。
图7为以脓毒血症为例，实施例3化合物缓解炎症引起小鼠脾脏的病理学变化。
具体实施方式
按照本发明的通式Ⅰ化合物，R1,R2,R3,R4,R5,X,Y如前述内容部分所定义，均可按以下路线的方法制备而成。
抑或：
抑或：
抑或：
化合物1～33的制备方法中：
所述H2N-R3和二氯甲烷的用量比为1.4～2mmol：1.4～2mmol：2～8mL，优选为1.6～1.8mmol：1.6～1.8mmol：4～6mL；
步骤(1)所述反应的温度为-5～5℃，优选为-2～2℃，进一步优选为0℃；时间为5～15h，优选为8～12h，进一步优选为10h；
所述含R1化合物、碳酸钾、碘化钠和无水四氢呋喃的用量比为0.1～0.2mmol：0.1～0.3mmol：0.2～0.4mmol：0.2～0.4mmol：4～8mL，优选为0.12～0.18mmol：0.15～0.28mmol：0.25～0.35mmol：0.25～0.35mmol：5～7mL，进一步优选为0.14～0.16mmol：0.2～0.25mmol：0.3～0.32mmol：0.3～0.33mmol：5～6mL；
步骤(2)所述反应的温度为60～80℃，优选为65～75℃，进一步优选为70～72℃；时间为1～10h，优选为2～8h，进一步优选为4～6h。
化合物34～69的制备方法中：
所述碳酸氢钠、亚硫酸钠、4-氯-3-硝基苯磺酰氯和水的用量比为7～9mmol:7～9mmol:3～5mmol:20～40mL，优选为8mmol:8mmol:4mmol:25～30mL；
步骤(1)所述反应的温度为室温，时间为1～5h，优选为2～4h；
所述4-氯-3-硝基苯亚磺酸、溴苄类物质和N,N-二甲基甲酰胺的用量比为0.4～0.5mmol:0.6～0.8mmol:2～8mL，优选为0.42～0.45mmol:0.65～0.7mmol:4～6mL；
步骤(2)所述反应的温度为70～90℃，优选为75～85℃，进一步优选为80℃；时间为1～5h，优选为2～4h，进一步优选为3h；
所述碘化钾、三甲基哌啶、碳酸钾和乙腈的用量比为0.09～0.11mmol:0.05～0.2mmol:0.05～0.2mmol:0.05～0.2mmol:2～8ml，优选为0.095～0.10mmol:0.1～0.12mmol:0.1～0.12mmol:0.1～0.12mmol:4～6ml；
步骤(3)所述反应的温度为80～90℃，优选为85～87℃；时间为1～5h，优选为2～4h。
化合物70～84的制备方法中：
所述苯乙酮、氢氧化钠、和乙醇的用量比为15～18mmol:23～28mmol:15～18mmol:5～15mL，优选为16～17mmol:25～26mmol:16～17mmol:8～10mL；
步骤(1)中所述反应的温度为室温，时间为5～15h，优选为8～12h；
步骤(2)所述保护气氛优选为氮气或者氩气；
所述N-溴代琥珀酰亚胺、偶氮二异丁腈和四氯化碳的用量比为2～2.5mmol:2～3mmol:0.2～0.8mmol:15～25mL，优选为2.2～2.3mmol:2.4～2.7mmol:0.4～0.6mmol:19～22mL；
步骤(2)所述反应的温度为80～90℃，优选为85～87℃；时间为1～5h，优选为2～3h；
所述含R1化合物、三乙胺和乙腈的用量比为0.5～0.8mmol:0.8～1.2mmol:0.8～1.2mmol:5～15mL，优选为0.6～0.7mmol:0.9～1.1mmol:0.9～1.1mmol:9～12mL；
步骤(3)所述反应的温度为80～90℃，优选为85～87℃；时间为1～5h，优选为2～3h；
步骤(4)所述保护气氛优选为氮气或者氩气；
所述脲、叔丁醇钠和四氢呋喃的用量比为0.2～0.4mmol:0.3～0.5mmol:0.3～0.4mmol:1～10mL，优选为0.3～0.35mmol:0.35～0.4mmol:0.33～0.37mmol:4～7mL；
步骤(4)所述反应的温度为80～90℃，优选为85～87℃；时间为1～5h，优选为2～3h。
化合物85～93的制备方法中：
步骤(1)中所述碘、/>和乙醇的用量比为7～8mmol:7～9mmol:8～10mmol:5～15mL，优选为7.4～7.8mmol:7.5～8.5mmol:9～9.5mmol:10～12mL；
所述反应的温度为80～90℃，优选为85～87℃；时间为1～5h，优选为2～3h；
步骤(2)中所述N-溴代琥珀酰亚胺、偶氮二异丁腈和四氯化碳的用量比为7～8mmol:7～9mmol:1～2mmol:25～35mL，优选为7.3～7.8mmol:7.9～8.5mmol:1.2～1.7mmol:28～32mL；
所述反应的温度为80～90℃，优选为85～87℃；时间为1～5h，优选为2～3h；
步骤(3)中所述中间产物、2-甲氧基乙基哌嗪、三乙胺和乙腈的用量比为0.1～0.5mmol:0.1～0.5mmol:45～55μL:5～15mL，优选为0.2～0.3mmol:0.3～0.4mmol:48～53μL:8～12mL；
所述反应的温度为80～90℃，优选为85～87℃；时间为1～5h，优选为2～3h；
步骤(2)和步骤(3)中所述保护气氛独立的包含氮气或氩气。
本发明按照制备通式I的方法，分别制得实施例1～93的化合物，结构式如下表1所示。
表1实施例1～93的结构式
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实施例1、N-(2-甲氧基吡啶-5-基)-3-硝基-4-[4-(嘧啶-2-基)哌嗪-1-基]苯磺酰胺
步骤一：4-氯-N-(6-甲氧基吡啶-3-基)-3-硝基苯磺酰胺
在25mL圆底烧瓶中加入二氯甲烷(5mL)溶解5-氨基-2-甲氧基吡啶(200mg,1.61mmol)，而后在0℃下分批加入4-氯-3-硝基苯磺酰氯(413mg,1.61mmol)，室温反应过夜。减压蒸干二氯甲烷，加入水中溶解产物，并用EtOAc萃取水层。将合并的有机提取物用无水硫酸钠干燥。减压蒸干乙酸乙酯，柱层析分离(PE:EA＝4:1)得，即为4-氯-N-(6-甲氧基吡啶-3-基)-3-硝基苯磺酰胺，收率为70％。
步骤二：N-(6-甲氧基吡啶-3-基)-3-硝基-4-(4-嘧啶-2-基)哌嗪-1-基)苯磺酰胺
在25mL圆底烧瓶中依次将步骤一中合成的4-氯-N-(6-甲氧基吡啶-3-基)-3-硝基苯磺酰胺(50mg,0.15mmol)，2-(哌嗪-1-基)嘧啶(35mg,0.22mmol)，碳酸钾(40mg,0.29mmol)，碘化钠(44mg,0.29mmol)加入6mL无水四氢呋喃中，70℃下回流4h。反应结束后减压蒸干四氢呋喃，用EA萃取，有机层用饱和氯化钠溶液洗涤三次，无水硫酸镁干燥。减压蒸干EA，柱层析分离(DCM:Methanol＝20:1)得，即为N-(6-甲氧基吡啶-3-基)-3-硝基-4-(4-嘧啶-2-基)哌嗪-1-基)苯磺酰胺，收率为90％。
1H NMR(400MHz,Chloroform-d)δ8.34(d,J＝4.8Hz,2H),8.20(d,J＝2.3Hz,1H),7.79(d,J＝2.7Hz,1H),7.67(dd,J＝8.9,2.3Hz,1H),7.50(dd,J＝8.8,2.8Hz,1H),7.09(d,J＝8.9Hz,1H),6.93–6.75(brs,1H),6.72(d,J＝8.8Hz,1H),6.57(t,J＝4.8Hz,1H),4.04–3.97(m,4H),3.89(s,3H),3.34–3.27(m,4H),2.18(s,1H).13C NMR(100MHz,Chloroform-d)δ158.89,156.09,149.23,137.04,130.48,129.62,122.83,122.16,113.70,62.30,55.32,52.99,52.73,52.65,49.01,47.73ppm.MS(ESI,m/z):472.2[M+H]+.
按照实施例1的方法，分别制得实施例2～33化合物
实施例2、4-(4-苄基哌嗪-1-基)-N-(2-甲氧基吡啶-5-基)-3-硝基苯磺酰胺
1H NMR(400MHz,Chloroform-d)δ8.14(d,J＝2.3Hz,1H),7.79(d,J＝2.7Hz,1H),7.63(dd,J＝8.9,2.3Hz,1H),7.48(dd,J＝8.8,2.8Hz,1H),7.38–7.22(m,5H),7.03(d,J＝9.0Hz,1H),6.69(d,J＝8.8Hz,1H),3.87(s,3H),3.56(s,2H),3.19(t,J＝4.9Hz,4H),2.62–2.55(m,4H).13C NMR(100MHz,Chloroform-d)δ162.74,148.43,142.70,139.18,137.49,136.04,131.93,129.26,128.59,128.45,127.44,126.86,126.37,120.14,111.36,62.84,53.85,52.45,50.62ppm.MS(ESI,m/z):484.2[M+H]+.
实施例3、N-(2-甲氧基吡啶-5-基)-3-硝基-4-{4-[(3-硝基苯基)甲基]哌嗪-1-基}苯磺酰胺
1H NMR(400MHz,Chloroform-d)δ8.24(d,J＝2.0Hz,1H),8.18–8.10(m,2H),7.79(d,J＝2.7Hz,1H),7.72–7.61(m,2H),7.56–7.45(m,2H),7.05(d,J＝8.9Hz,1H),6.70(d,J＝8.8Hz,1H),3.88(s,3H),3.67(s,2H),3.22(t,J＝4.8Hz,4H),2.66–2.58(m,4H),1.27(d,J＝7.1Hz,0H).13C NMR(100MHz,Chloroform-d)δ162.76,148.47,148.38,142.71,140.14,139.35,136.05,135.12,132.02,129.43,128.93,126.80,126.33,123.77,122.55,120.24,111.35,61.77,53.85,52.46,50.60ppm.MS(ESI,m/z):529.2[M+H]+.
实施例4、N-(2-甲氧基吡啶-5-基)-3-硝基-4-{4-[(4-硝基苯基)甲基]哌嗪-1-基}苯磺酰胺
1H NMR(400MHz,Chloroform-d)δ8.23–8.15(m,3H),8.10(s,1H),7.79(d,J＝2.8Hz,1H),7.65(dd,J＝8.9,2.3Hz,1H),7.55–7.45(m,3H),7.05(d,J＝8.9Hz,1H),6.70(d,J＝8.8Hz,1H),3.88(s,3H),3.67(s,2H),3.26–3.16(m,4H),2.66–2.56(m,4H).13C NMR(100MHz,Chloroform-d)δ162.82,148.37,147.39,145.73–145.43(m),142.75,139.42,136.13,132.03,129.64,129.03,126.80,126.24,123.74,120.23,111.43,61.89,53.85,52.55,50.60ppm.MS(ESI,m/z):529.2[M+H]+.
实施例5、4-{4-[(4-甲氧基苯基)甲基]哌嗪-1-基}-N-(2-甲氧基吡啶-5-基)-3-硝基苯磺酰胺
1H NMR(500MHz,Chloroform-d)δ8.13(d,J＝2.3Hz,1H),7.76(d,J＝2.8Hz,1H),7.62(dd,J＝8.9,2.3Hz,1H),7.49(dd,J＝8.8,2.8Hz,1H),7.24(d,J＝8.5Hz,2H),7.03(d,J＝8.9Hz,1H),6.87(d,J＝8.6Hz,2H),6.72(d,J＝8.8Hz,1H),6.39(s,1H),3.90(s,3H),3.81(s,3H),3.51(s,2H),3.20(t,J＝4.9Hz,4H),2.60–2.55(m,4H),2.05(s,1H),1.27(t,J＝7.2Hz,2H).13C NMR(100MHz,Chloroform-d)δ162.74,158.97,148.42,142.73,139.11,136.06,131.92,130.50,129.38,128.50,126.86,126.34,120.15,113.81,111.35,62.20,55.37,55.34,53.88,53.85,52.32,50.58ppm.MS(ESI,m/z):514.2[M+H]+.
实施例6、N-(5-{[4-(4-{[(6-甲氧基吡啶-3-基)氨基]二氧亚基-λ6-硫基}-2-硝基苯基)哌嗪-1-基]甲基}-1,3-噻唑-2-基)乙酰胺
1H NMR(400MHz,DMSO-d6)δ11.98(s,1H),8.05(d,J＝3.1Hz,1H),7.81(d,J＝3.0Hz,1H),7.70–7.65(m,1H),7.40(dd,J＝8.8,2.8Hz,1H),7.35(d,J＝9.0Hz,1H),7.28(s,1H),6.74(d,J＝8.8Hz,1H),3.77(s,3H),3.69(s,2H),3.14(t,J＝4.8Hz,4H),2.48(s,4H),2.11(s,3H).13C NMR(100MHz,Chloroform-d)δ168.16,162.60,148.27,142.50,139.49,135.89,134.69,132.07,129.37,126.73,126.62,120.15,111.39,54.14,53.76,52.10,50.63,23.23ppm.MS(ESI,m/z):548.2[M+H]+.
实施例7、N-(萘-1-基)-3-硝基-4-{4-[(3-硝基苯基)甲基]哌嗪-1-基}苯甲酰胺
1H NMR(400MHz,Chloroform-d)δ8.44–8.34(m,2H),8.26(t,J＝2.0Hz,1H),8.14(ddd,J＝8.2,2.4,1.1Hz,1H),8.04(dd,J＝8.6,2.3Hz,1H),7.91–7.81(m,3H),7.75–7.66(m,2H),7.55–7.43(m,4H),7.11(d,J＝8.7Hz,1H),3.67(s,2H),3.25–3.17(m,4H),2.68–2.59(m,4H).13C NMR(100MHz,Chloroform-d)δ164.10,148.48,148.01,140.60,140.28,134.98,134.16,132.60,132.15,129.30,128.74,127.88,126.57,126.47,126.13,125.80,125.65,123.71,122.43,122.04,121.06,120.13,61.82,52.63,50.88ppm.HRMS(ESI,m/z):512.3[M+H]+.
实施例8、3-硝基-4-{4-[(3-硝基苯基)甲基]哌嗪-1-基}-N-(吡啶-2-基甲基)苯磺酰胺
1H NMR(400MHz,Chloroform-d)δ8.44(s,1H),8.22(d,J＝20.7Hz,2H),8.14(d,J＝8.3Hz,1H),7.84(d,J＝8.8Hz,1H),7.67(d,J＝7.7Hz,1H),7.65–7.57(m,1H),7.51(s,1H),7.16(d,J＝7.9Hz,2H),7.04(d,J＝8.8Hz,1H),6.12(s,1H),4.29(s,2H),3.66(s,2H),3.18(s,4H),2.62(s,4H).13C NMR(100MHz,Chloroform-d)δ154.40,149.07,148.48,148.03,140.18,139.71,136.89,134.95,131.84,130.66,129.33,126.45,123.69,122.76,122.46,122.10,120.12,61.77,52.49,50.67,47.38ppm.HRMS(ESI,m/z):513.2671[M+H]+.
实施例9、3-硝基-4-{4-[(4-硝基苯基)甲基]哌嗪-1-基}-N-(吡啶-2-基甲基)苯磺酰胺
1H NMR(400MHz,Chloroform-d)δ8.43(d,J＝4.9Hz,1H),8.23–8.15(m,3H),7.83(dd,J＝8.9,2.3Hz,1H),7.61(t,J＝7.6Hz,1H),7.53(d,J＝8.4Hz,2H),7.16(dd,J＝14.1,8.0Hz,2H),7.04(d,J＝8.8Hz,1H),6.29(d,J＝6.2Hz,1H),4.28(d,J＝2.8Hz,2H),3.67(s,2H),3.21–3.14(m,4H),2.64–2.57(m,4H).13C NMR(100MHz,Chloroform-d)δ154.56,149.06,147.99,147.27,145.71,139.59,136.94,131.82,130.66,129.51,126.40,123.61,122.76,122.22,120.18,61.85,52.55,50.66,47.46ppm.HRMS(ESI,m/z):513.2305[M+H]+.
实施例10、4-(4-苄基哌嗪-1-基)-3-硝基-N-(吡啶-2-基甲基)苯甲酰胺
1H NMR(400MHz,DMSO-d6)δ9.21(t,J＝5.9Hz,1H),8.51(ddd,J＝4.7,1.8,0.9Hz,1H),8.38(d,J＝2.2Hz,1H),8.07(dd,J＝8.8,2.2Hz,1H),7.75(td,J＝7.7,1.8Hz,1H),7.39–7.22(m,8H),4.55(d,J＝5.8Hz,2H),3.54(s,2H),3.11(t,J＝4.8Hz,4H),2.48(s,4H).13C NMR(100MHz,Chloroform-d)δ165.13,156.20,149.01,147.86,140.75,137.54,137.06,132.31,129.32,128.42,127.40,125.93,125.76,122.63,122.40,119.96,62.92,52.68,50.90,44.81ppm.MS(ESI,m/z):432.2[M+H]+.
实施例11、3-硝基-4-{4-[(4-硝基苯基)甲基]哌嗪-1-基}-N-(吡啶-2-基甲基)苯甲酰胺
1H NMR(400MHz,DMSO-d6)δ9.23(t,J＝5.9Hz,1H),8.51(ddd,J＝4.8,1.8,0.9Hz,1H),8.39(d,J＝2.2Hz,1H),8.26–8.18(m,2H),8.09(dd,J＝8.7,2.2Hz,1H),7.75(td,J＝7.7,1.8Hz,1H),7.68–7.60(m,2H),7.39–7.23(m,3H),4.56(d,J＝6.0Hz,2H),3.69(s,2H),3.14(t,J＝4.7Hz,4H),2.53(t,J＝4.9Hz,4H).13C NMR(100MHz,Chloroform-d)δ165.05,156.15,149.00,147.77,147.31,145.90,140.91,137.08,132.31,129.61,126.23,125.76,123.67,122.65,122.40,120.04,61.98,52.80,50.95,44.80ppm.MS(ESI,m/z):477.3[M+H]+.
实施例12、3-硝基-4-{4-[(3-硝基苯基)甲基]哌嗪-1-基}-N-(吡啶-2-基甲基)苯甲酰胺
1H NMR(400MHz,DMSO-d6)δ9.23(t,J＝5.9Hz,1H),8.51(ddd,J＝4.9,1.8,0.9Hz,1H),8.38(d,J＝2.2Hz,1H),8.23–8.04(m,3H),7.85–7.71(m,2H),7.70–7.60(m,1H),7.39–7.23(m,3H),4.56(d,J＝5.9Hz,2H),3.17–3.10(m,4H),2.55(q,J＝5.6,4.9Hz,4H).13C NMR(100MHz,Chloroform-d)δ165.03,156.01,149.03,148.51,147.82,140.97,140.39,137.05,135.07,132.33,129.35,126.29,125.70,123.78,122.65,122.46,122.38,120.07,67.13,61.89,52.72,50.97,44.77ppm.MS(ESI,m/z):477.2[M+H]+.
实施例13、3-硝基-4-{4-[(3-硝基苯基)甲基]哌嗪-1-基}-N-苯基苯甲酰胺
1H NMR(400MHz,Chloroform-d)δ8.33(d,J＝2.3Hz,1H),8.29(t,J＝2.0Hz,1H),8.20–8.15(m,1H),8.03(dd,J＝8.7,2.3Hz,1H),7.91(s,1H),7.72(d,J＝7.7Hz,1H),7.68–7.64(m,2H),7.55(t,J＝7.9Hz,1H),7.41(t,J＝7.9Hz,2H),7.23–7.15(m,2H),3.71(s,2H),3.28–3.21(m,4H),2.68(dd,J＝5.9,3.7Hz,4H).13C NMR(100MHz,Chloroform-d)δ163.28,148.09,140.39(d,J＝9.9Hz),137.62,135.03,132.59,129.36,129.21,126.34,125.51,124.89,123.77,122.50,120.32(d,J＝11.6Hz),61.87,52.66,50.92.HRMS(ESI,m/z):462.1767[M+H]+.
实施例14、3-硝基-4-{4-[(4-硝基苯基)甲基]哌嗪-1-基}-N-苯基苯甲酰胺
1H NMR(400MHz,DMSO-d6)δ10.29(s,1H),8.47(d,J＝2.2Hz,1H),8.24(d,J＝8.4Hz,2H),8.16(dd,J＝8.8,2.3Hz,1H),7.77(d,J＝8.0Hz,2H),7.65(d,J＝8.3Hz,2H),7.43–7.32(m,3H),7.12(t,J＝7.4Hz,1H),3.72(s,2H),3.18(t,J＝4.6Hz,4H),2.56(t,J＝4.8Hz,4H).13C NMR(100MHz,Chloroform-d)δ164.24,147.79,147.22,145.56,137.94,132.90,129.67,128.86,126.53,125.89,124.63,123.60,120.82,120.02,61.90,52.68,50.74.HRMS(ESI,m/z):462.1767[M+H]+.
实施例15、3-硝基-4-[4-(4-硝基苯基)哌嗪-1-基]-N-苯基苯甲酰胺
1H NMR(400MHz,DMSO-d6)δ10.18(s,1H),8.55(d,J＝2.1Hz,1H),8.18(dd,J＝8.8,2.2Hz,1H),8.11–8.03(m,3H),7.74(d,J＝8.0Hz,2H),7.30(t,J＝7.9Hz,3H),7.07(t,J＝7.4Hz,1H),6.95(d,J＝9.3Hz,2H),3.67(dd,J＝6.6,3.7Hz,4H),3.43–3.36(m,4H).13C NMR(100MHz,DMSO-d6)δ163.62,154.70,147.21,139.42(d,J＝13.4Hz),137.43,133.46,129.14,126.59,126.28,125.75,124.26,120.92,119.92,112.73,49.58,46.02.HRMS(ESI,m/z):448.1610[M+H]+.
实施例16、2-(4-{2-硝基-4-[(苯基氨基)甲基]苯基}哌嗪-1-基)乙-1-醇
1H NMR(400MHz,Chloroform-d)δ9.29(s,1H),8.51(d,J＝2.3Hz,1H),8.11(dd,J＝8.7,2.3Hz,1H),7.70(d,J＝8.0Hz,2H),7.33(t,J＝7.8Hz,2H),7.16–7.05(m,2H),3.66(t,J＝5.4Hz,2H),3.19(t,J＝4.8Hz,4H),2.68(t,J＝4.8Hz,4H),2.62(t,J＝5.4Hz,2H).13C NMR(100MHz,Methanol-d4)δ164.83,147.70,140.91,138.17,132.60,128.63,126.56,126.07,124.55,121.17,120.03,59.86,58.37,52.91,50.35.HRMS(ESI,m/z):371.1712[M+H]+.
实施例17、4-[4-(2-甲氧基乙基)哌嗪-1-基]-3-硝基-N-苯基苯甲酰胺
1H NMR(400MHz,Chloroform-d)δ8.47(s,1H),8.35–8.26(m,1H),8.02–7.93(m,1H),7.64(d,J＝7.9Hz,2H),7.33(t,J＝7.7Hz,2H),7.14(t,J＝7.4Hz,1H),7.04(d,J＝8.7Hz,1H),3.56(t,J＝5.3Hz,2H),3.39(s,3H),3.16(t,J＝4.7Hz,4H),2.64(q,J＝4.5,3.8Hz,6H).13C NMR(100MHz,Chloroform-d)δ163.43,148.10,140.23,137.70,132.64,129.17,126.04,125.56,124.83,120.45,120.09,69.93,59.04,57.87,53.08,50.73.HRMS(ESI,m/z):385.1861[M+H]+.
实施例18、4-[4-(2-羟基乙基)哌嗪-1-基]-N-(6-甲氧基吡啶-3-基)-3-硝基苯磺酰胺
1H NMR(400MHz,Chloroform-d)δ8.19(d,J＝2.3Hz,1H),7.82(dd,J＝2.8,0.6Hz,1H),7.69(dd,J＝8.9,2.3Hz,1H),7.53(dd,J＝8.8,2.8Hz,1H),7.08(d,J＝8.9Hz,1H),6.73(dd,J＝8.8,0.7Hz,1H),3.91(s,3H),3.70(t,J＝5.3Hz,2H),3.27–3.22(m,4H),2.73–2.69(m,4H),2.67(t,J＝5.3Hz,2H).13C NMR(100MHz,Chloroform-d)δ162.84,148.34,142.81,139.45,136.20,132.03,129.09,126.78,126.15,120.13,111.50,59.22,57.81,53.84,52.30,50.67.HRMS(ESI,m/z):438.1447[M+H]+.
实施例19、4-[4-(2-甲氧基乙基)哌嗪-1-基]-N-(6-甲氧基吡啶-3-基)-3-硝基苯磺酰胺
1H NMR(400MHz,Chloroform-d)δ8.15(d,J＝2.3Hz,1H),7.82(d,J＝2.7Hz,1H),7.66(dd,J＝8.9,2.3Hz,1H),7.51(dd,J＝8.8,2.8Hz,1H),7.05(d,J＝8.9Hz,1H),6.70(d,J＝8.8Hz,1H),3.88(s,3H),3.55(t,J＝5.4Hz,2H),3.36(s,3H),3.25–3.20(m,4H),2.69–2.63(m,6H).13C NMR(100MHz,Chloroform-d)δ162.62,148.33,142.52,139.19,135.92,131.96,128.79,126.77,126.46,120.07,111.32,69.76,58.96,57.68,53.84,52.82,50.37.HRMS(ESI,m/z):452.1595[M+H]+.
实施例20、4-[4-(2-甲氧基乙基)哌嗪-1-基]-3-硝基-N-(吡啶-2-基甲基)苯磺酰胺
1H NMR(400MHz,Chloroform-d)δ8.42(t,J＝4.7Hz,1H),8.13(dd,J＝4.0,2.3Hz,1H),7.79(ddt,J＝8.9,4.0,2.5Hz,1H),7.60(dtt,J＝7.7,4.0,1.9Hz,1H),7.19(dd,J＝7.9,3.4Hz,1H),7.13(dt,J＝7.8,4.1Hz,1H),7.03(dd,J＝8.8,3.6Hz,1H),6.80(s,1H),4.29(t,J＝3.5Hz,2H),3.53(dt,J＝8.9,4.0Hz,2H),3.36(d,J＝3.6Hz,3H),3.18(dd,J＝6.1,3.4Hz,4H),2.69–2.59(m,6H).13C NMR(100MHz,Chloroform-d)δ154.39,149.14,148.14,139.53,136.91,131.88,130.26,126.60,122.81,122.12,119.96,69.93,59.05,57.82,52.95,50.55,47.39.HRMS(ESI,m/z):436.1654[M+H]+.
实施例21、4-[4-(2-羟基乙基)哌嗪-1-基]-3-硝基-N-(吡啶-2-基甲基)苯磺酰胺
1H NMR(400MHz,Chloroform-d)δ8.47–8.42(m,1H),8.18(d,J＝2.2Hz,1H),7.85(dd,J＝8.8,2.3Hz,1H),7.63(td,J＝7.7,1.8Hz,1H),7.22(d,J＝7.8Hz,1H),7.16(dd,J＝7.5,4.9Hz,1H),7.07(d,J＝8.9Hz,1H),6.63(s,1H),4.30(s,2H),3.69(t,J＝5.3Hz,2H),3.19(t,J＝4.9Hz,4H),2.69(dd,J＝5.9,3.7Hz,4H),2.65(t,J＝5.3Hz,2H).13C NMR(100MHz,Chloroform-d)δ154.54,149.10,148.05,139.71,137.01,131.95,130.76,126.54,122.84,122.26,120.17,59.33,57.83,52.38,50.72,47.46.HRMS(ESI,m/z):422.1495[M+H]+.
实施例22、4-[4-(2-甲氧基乙基)哌嗪-1-基]-3-硝基-N-苯基苯磺酰胺
1H NMR(400MHz,Chloroform-d)δ8.21(d,J＝2.3Hz,1H),7.74(dd,J＝8.9,2.3Hz,1H),7.34–7.28(m,3H),7.21–7.15(m,1H),7.15–7.11(m,2H),7.05(d,J＝8.9Hz,1H),3.56(t,J＝5.4Hz,2H),3.39(s,3H),3.27–3.20(m,4H),2.67(td,J＝5.2,2.3Hz,6H).13C NMR(100MHz,Chloroform-d)δ148.36,139.23,136.12,131.88,129.58,129.11,126.82,125.73,121.63,119.93,69.87,59.01,57.76,52.88,50.44.HRMS(ESI,m/z):421.1544[M+H]+.
实施例23、4-[4-(2-羟基乙基)哌嗪-1-基]-3-硝基-N-苯基苯磺酰胺
1H NMR(400MHz,Chloroform-d)δ8.24(d,J＝2.3Hz,1H),7.76(dd,J＝8.8,2.3Hz,1H),7.29(dd,J＝8.8,6.9Hz,2H),7.15(tt,J＝8.3,1.2Hz,3H),7.05(d,J＝8.9Hz,1H),3.70(t,J＝5.3Hz,2H),3.23–3.17(m,4H),2.70–2.66(m,4H),2.65(d,J＝5.3Hz,2H).13CNMR(100MHz,Chloroform-d)δ139.56,135.95,131.96,129.63,126.73,125.92,121.79,120.00,59.24,57.78,52.31,50.68.HRMS(ESI,m/z):407.1409[M+H]+.
实施例24、3-硝基-4-{4-[(3-硝基苯基)甲基]哌嗪-1-基}-N-苯基苯磺酰胺
1H NMR(400MHz,Chloroform-d)δ8.24(dd,J＝9.5,2.1Hz,2H),8.18–8.11(m,1H),7.77(dt,J＝8.9,1.8Hz,1H),7.70(dt,J＝7.7,1.4Hz,1H),7.53(t,J＝8.0Hz,1H),7.33–7.24(m,2H),7.19–7.10(m,3H),7.06(d,J＝8.9Hz,1H),3.68(s,2H),3.25–3.17(m,4H),2.63(dd,J＝6.0,3.7Hz,4H).13C NMR(100MHz,Chloroform-d)δ148.44,148.35,140.18,139.30,136.21,135.13,131.96,129.56,129.42,129.35,126.79,125.67,123.76,122.53,121.60,120.16,61.77,52.46,50.60.HRMS(ESI,m/z):498.1435[M+H]+.
实施例25、3-硝基-4-{4-[(4-硝基苯基)甲基]哌嗪-1-基}-N-苯基苯磺酰胺
1H NMR(400MHz,Chloroform-d)δ8.22(dd,J＝9.3,2.2Hz,3H),7.76(dd,J＝8.9,2.3Hz,1H),7.55(d,J＝8.5Hz,2H),7.33–7.26(m,2H),7.20–7.09(m,4H),7.06(d,J＝8.9Hz,1H),3.69(s,2H),3.22(t,J＝4.8Hz,4H),2.63(t,J＝4.8Hz,4H).13C NMR(100MHz,Chloroform-d)δ148.34,147.35,145.64,139.39,136.07,131.95,129.58,129.42,126.79,125.78,123.72,121.64,120.12,61.90,52.55,50.62.HRMS(ESI,m/z):498.1438[M+H]+.
实施例26、3-硝基-4-[4-(4-硝基苯基)哌嗪-1-基]-N-苯基苯磺酰胺
1H NMR(400MHz,Methanol-d4)δ8.23(d,J＝2.2Hz,1H),8.16–8.12(m,2H),7.80(dd,J＝8.9,2.3Hz,1H),7.28–7.22(m,2H),7.19(d,J＝8.9Hz,1H),7.14–7.07(m,3H),6.91–6.87(m,2H),3.68–3.64(m,4H),3.44–3.39(m,4H).13C NMR(100MHz,DMSO-d6)δ154.50,147.61,137.96,137.50,137.30,131.81,129.83,128.79,126.37(d,J＝17.5Hz),124.82,120.61,120.42,112.46,49.07,45.58.HRMS(ESI,m/z):484.1277[M+H]+.
实施例27、4-(4-苄基哌嗪-1-基)-3-硝基-N-(吡啶-2-基甲基)苯磺酰胺
1H NMR(400MHz,Chloroform-d)δ8.43(s,1H),8.16(s,1H),7.80(d,J＝8.9Hz,1H),7.60(s,1H),7.32(s,4H),7.28(d,J＝7.0Hz,1H),7.19–7.10(m,2H),7.02(d,J＝8.8Hz,1H),6.34(s,1H),4.28(s,2H),3.56(s,2H),3.15(d,J＝5.3Hz,4H),2.58(s,4H).13CNMR(100MHz,Chloroform-d)δ154.52,149.07,148.07,139.47,137.55,136.85,131.75,130.23,129.15,128.35,127.32,126.51,122.72,122.10,119.97,62.83,52.46,50.68,47.41ppm.HRMS(ESI,m/z):468.3416[M+H]+
实施例28、3-硝基-4-{4-[(3-硝基苯基)甲基]哌嗪-1-基}-N-(吡啶-2-基甲基)苯磺酰胺
1H NMR(400MHz,Chloroform-d)δ8.44(s,1H),8.22(d,J＝20.7Hz,2H),8.14(d,J＝8.3Hz,1H),7.84(d,J＝8.8Hz,1H),7.67(d,J＝7.7Hz,1H),7.65–7.57(m,1H),7.51(s,1H),7.16(d,J＝7.9Hz,2H),7.04(d,J＝8.8Hz,1H),6.12(s,1H),4.29(s,2H),3.66(s,2H),3.18(s,4H),2.62(s,4H).13C NMR(100MHz,Chloroform-d)δ154.40,149.07,148.48,148.03,140.18,139.71,136.89,134.95,131.84,130.66,129.33,126.45,123.69,122.76,122.46,122.10,120.12,61.77,52.49,50.67,47.38ppm.HRMS(ESI,m/z):513.2671[M+H]+
实施例29、3-硝基-4-{4-[(4-硝基苯基)甲基]哌嗪-1-基}-N-(吡啶-2-基甲基)苯磺酰胺
1H NMR(400MHz,Chloroform-d)δ8.43(d,J＝4.9Hz,1H),8.23–8.15(m,3H),7.83(dd,J＝8.9,2.3Hz,1H),7.61(t,J＝7.6Hz,1H),7.53(d,J＝8.4Hz,2H),7.16(dd,J＝14.1,8.0Hz,2H),7.04(d,J＝8.8Hz,1H),6.29(d,J＝6.2Hz,1H),4.28(d,J＝2.8Hz,2H),3.67(s,2H),3.21–3.14(m,4H),2.64–2.57(m,4H).13C NMR(100MHz,Chloroform-d)δ154.56,149.06,147.99,147.27,145.71,139.59,136.94,131.82,130.66,129.51,126.40,123.61,122.76,122.22,120.18,61.85,52.55,50.66,47.46ppm.HRMS(ESI,m/z):513.2305[M+H]+
实施例30、3-硝基-4-[4-(4-硝基苯基)哌嗪-1-基]-N-(吡啶-2-基甲基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ8.39(d,J＝4.8Hz,1H),8.35(s,1H),8.10(dd,J＝5.9,3.4Hz,3H),7.82(dd,J＝8.9,2.3Hz,1H),7.34(dd,J＝21.0,8.4Hz,2H),7.20(dd,J＝7.5,4.9Hz,1H),7.00(d,J＝9.3Hz,2H),4.13(s,2H),3.68(dd,J＝6.9,3.7Hz,4H),3.40(dd,J＝6.7,3.8Hz,4H).13C NMR(100MHz,Chloroform-d)δ154.28,154.22,148.99,147.61,139.55,139.08,137.18,132.07,131.23,126.66,126.08,122.95,122.26,119.64,112.68,49.81,47.31,46.42ppm.HRMS(ESI,m/z):499.2028[M+H]+
实施例31、4-{4-[(4-甲氧基苯基)甲基]哌嗪-1-基}-3-硝基-N-(吡啶-2-基甲基)苯磺酰胺
1H NMR(400MHz,Chloroform-d)δ8.47–8.40(m,1H),8.18(d,J＝2.3Hz,1H),7.81(dd,J＝8.8,2.3Hz,1H),7.60(td,J＝7.7,1.8Hz,1H),7.23(d,J＝8.4Hz,4H),7.14(t,J＝7.0Hz,2H),7.02(d,J＝8.9Hz,1H),6.91–6.83(m,2H),5.99(t,J＝5.3Hz,1H),4.28(d,J＝5.1Hz,2H),3.81(s,3H),3.50(s,2H),3.19–3.11(m,4H),2.60–2.52(m,4H).13C NMR(100MHz,Chloroform-d)δ158.90,154.50,149.07,148.06,139.40,136.87,131.74,130.35,130.17,129.48,126.49,122.73,122.14,119.98,113.71,62.19,55.27,52.33,50.66,47.42ppm.MS(ESI,m/z):398.2[M+H]+
实施例32、3-硝基-N-(吡啶-2-基甲基)-4-[4-(嘧啶-2-基)哌嗪-1-基]苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ8.41(d,J＝4.7Hz,2H),8.38(dt,J＝5.8,3.0Hz,2H),8.09(d,J＝2.3Hz,1H),7.81(dd,J＝8.9,2.3Hz,1H),7.68(td,J＝7.7,1.8Hz,1H),7.38(d,J＝9.0Hz,1H),7.31(d,J＝7.8Hz,1H),7.20(dd,J＝7.6,4.8Hz,1H),6.69(t,J＝4.7Hz,1H),4.14(s,2H),3.91–3.84(m,4H),3.29–3.21(m,4H).13C NMR(100MHz,Chloroform-d)δ161.49,157.88,154.49,149.05,148.20,139.48,137.09,131.93,130.70,126.67,122.87,122.29,119.97,110.61,50.41,47.42,43.21ppm.MS(ESI,m/z):456.2[M+H]+
实施例33、N-(5-{[4-(4-{二氧亚基[(吡啶-2-基甲基)氨基]-λ6-硫基}-2-硝基苯基)哌嗪-1-基]甲基}-1,3-噻唑-2-基)乙酰胺
1H NMR(400MHz,DMSO-d6)δ11.99(s,1H),8.39–8.30(m,2H),8.03(d,J＝2.3Hz,1H),7.77(dd,J＝8.9,2.3Hz,1H),7.67(td,J＝7.7,1.8Hz,1H),7.34–7.27(m,3H),7.19(dd,J＝7.6,4.9Hz,1H),4.12(d,J＝5.8Hz,2H),3.71(s,2H),3.13(t,J＝4.7Hz,4H),2.52(s,4H),2.12(s,3H).13C NMR(100MHz,DMSO-d6)δ168.72,157.10,149.24,137.09,136.62,131.97,128.33,125.93,122.90,122.36,121.44,53.72,52.15,50.74,48.47,22.94ppm.MS(ESI,m/z):532.2[M+H]+
实施例34、1-[4-(苄基磺酰基)-2-硝基苯基]-3-甲基哌啶
步骤一：4-氯-3-硝基苯亚磺酸
在25mL圆底烧瓶中将碳酸氢钠(656.16mg,7.81mmol)，亚硫酸钠(984.46mg,7.81mmol)，4-氯-3-硝基苯磺酰氯(1.00g,3.91mmol)依次加入水(30mL)中，室温反应2小时。减压蒸干乙醇，用EA萃取，乙醇重结晶得，即为4-氯-3-硝基苯亚磺酸，收率为90％。
步骤二：4-苄基磺酰基-1-氯-2-硝基苯
在25mL圆底烧瓶中将步骤一制得的4-氯-3-硝基苯亚磺酸(100.00mg,0.45mmol)，溴苄(115.77mg,0.67mmol)，依次加入DMF(5mL)中，80℃反应2小时。加入冰水淬灭反应，用EA萃取，柱层析分离(DCM:MeOH＝20:1)得，即为4-苄基磺酰基-1-氯-2-硝基苯，收率为36％。
步骤三：1-[4-(苄基磺酰基)-2-硝基苯基]-3-甲基哌啶
在25mL圆底烧瓶中将步骤二制得的4-苄基磺酰基-1-氯-2-硝基苯(30mg,0.096mmol)，碘化钾(19.17mg,0.12mmol)，三甲基哌啶(11.45mg,0.12mmol)，碳酸钾(15.96mg,0.12mmol)依次加入乙腈(5mL)中，85℃反应2小时。加入冰水淬灭反应，用EA萃取，柱层析分离(DCM:MeOH＝20:1)得，即为1-(4-苄基磺酰基)-2-硝基苯基-3-甲基哌啶，收率为76％。
1H NMR(400MHz,Chloroform-d)δ7.98(d,J＝2.2Hz,1H),7.49(dd,J＝8.9,2.2Hz,1H),7.36(dd,J＝13.8,7.0Hz,3H),7.18(d,J＝7.4Hz,2H),7.02(d,J＝9.0Hz,1H),4.34(s,2H),3.31(dd,J＝24.7,12.7Hz,2H),2.98(td,J＝12.0,3.3Hz,1H),2.74–2.64(m,1H),1.98–1.69(m,4H),1.18(qd,J＝11.5,4.4Hz,1H),0.96(d,J＝6.5Hz,3H).13C NMR(100MHz,Chloroform-d)δ149.12,138.42,132.84,130.91,129.04,128.76,128.60,128.09,126.28,119.56,63.16,58.29,51.39,32.24,30.93,24.94,19.00.ESI-MS m/z:397.1[M+Na]+.
按照实施例34的方法，分别制得实施例35～69化合物
实施例35、1-[4-(苄基磺酰基)-2-硝基苯基]-4-甲基哌嗪
1H NMR(400MHz,Chloroform-d)δ7.98(d,J＝2.2Hz,1H),7.56(dd,J＝8.8,2.3Hz,1H),7.40–7.31(m,3H),7.19–7.15(m,2H),7.05(d,J＝8.9Hz,1H),4.35(s,2H),3.28(t,J＝4.9Hz,4H),2.65(t,J＝4.9Hz,4H),2.43(s,3H).13C NMR(100MHz,Chloroform-d)δ148.74,139.20,133.12,130.90,129.11,128.80,128.28,127.94,127.71,119.56,63.12,54.38,50.52,46.00.ESI-MS m/z:376.1[M+H]+.
实施例36、1-[4-(苄基磺酰基)-2-硝基苯基]-4-乙基哌嗪
1H NMR(400MHz,Chloroform-d)δ7.97(t,J＝2.8Hz,1H),7.55(dt,J＝8.9,2.8Hz,1H),7.41–7.31(m,3H),7.20–7.14(m,2H),7.04(dd,J＝8.8,3.0Hz,1H),4.34(d,J＝3.0Hz,2H),3.27(p,J＝3.3Hz,4H),2.74–2.61(m,4H),2.55(qd,J＝7.3,2.8Hz,2H),1.17(td,J＝7.3,2.9Hz,3H).13C NMR(100MHz,Chloroform-d)δ148.72,139.13,133.10,130.90,129.10,128.79,128.27,127.96,127.61,119.49,63.12,52.21,52.14,50.56,11.95.ESI-MS m/z:390.1[M+H]+.
实施例37、1-{4-[4-(苄基磺酰基)-2-硝基苯基]哌嗪-1-基}乙-1-酮
1H NMR(400MHz,Chloroform-d)δ7.98(d,J＝2.2Hz,1H),7.56(dd,J＝8.8,2.3Hz,1H),7.41–7.31(m,3H),7.19–7.15(m,2H),7.05(d,J＝8.8Hz,1H),4.35(s,2H),3.28(t,J＝4.9Hz,4H),2.65(t,J＝4.9Hz,4H),2.43(s,3H).13C NMR(100MHz,Chloroform-d)δ169.34,148.54,139.48,133.34,130.89,129.19,128.87,128.84,128.22,127.80,119.65,63.07,50.75,49.96,45.54,40.84,21.40.ESI-MS m/z:426.1[M+Na]+.
实施例38、1-[4-(苄基磺酰基)-2-硝基苯基]-4-(4-硝基苯基)哌嗪
1H NMR(400MHz,Chloroform-d)δ8.23–8.18(m,2H),8.03(d,J＝2.2Hz,1H),7.61(dd,J＝8.8,2.2Hz,1H),7.42–7.31(m,3H),7.21–7.16(m,2H),7.08(d,J＝8.8Hz,1H),6.89–6.82(m,2H),4.37(s,2H),3.72–3.64(m,4H),3.51–3.44(m,4H).13C NMR(100MHz,DMSO-d6)δ154.47,148.12,137.46,137.33,133.11,131.56,129.20,128.95,128.81,128.32,127.30,126.29,119.74,112.42,61.31,49.04,45.52.ESI-MS m/z:505.2[M+Na]+.
实施例39、2-{4-[4-(苄基磺酰基)-2-硝基苯基]哌嗪-1-基}乙-1-醇
1H NMR(400MHz,Chloroform-d)δ7.89(d,J＝2.2Hz,1H),7.48(dd,J＝8.8,2.2Hz,1H),7.27(ddd,J＝14.4,7.9,6.2Hz,3H),7.11–7.06(m,2H),6.96(d,J＝8.8Hz,1H),4.26(s,2H),3.62(t,J＝5.3Hz,2H),3.22–3.15(m,4H),2.62(dd,J＝10.4,5.6Hz,5H),2.58(d,J＝5.3Hz,2H).13C NMR(100MHz,Chloroform-d)δ148.69,139.25,133.17,130.90,129.12,128.80,128.24,127.92,119.62,63.09,59.31,57.89,52.31,50.63.ESI-MS m/z:406.1[M+H]+.
实施例40、1-[4-(苄基磺酰基)-2-硝基苯基]-4-(2-甲氧基乙基)哌嗪
1H NMR(400MHz,Chloroform-d)δ7.97(d,J＝2.2Hz,1H),7.55(dd,J＝8.9,2.3Hz,1H),7.41–7.30(m,3H),7.19–7.14(m,2H),7.03(d,J＝8.9Hz,1H),4.34(s,2H),3.59(t,J＝5.3Hz,2H),3.40(s,3H),3.29(t,J＝4.9Hz,4H),2.78–2.67(m,6H).13C NMR(100MHz,Chloroform-d)δ148.74,139.15,133.11,130.91,129.11,128.80,128.29,127.97,127.61,119.44,69.98,63.15,59.03,57.79,52.88,50.45.ESI-MS m/z:420.2[M+H]+.
实施例41、1-[4-(苄基磺酰基)-2-硝基苯基]-4-(3-硝基苄基)哌嗪
1H NMR(400MHz,Chloroform-d)δ8.28(d,J＝2.0Hz,1H),8.17(dd,J＝8.3,2.4Hz,1H),7.97(d,J＝2.3Hz,1H),7.71(d,J＝7.5Hz,1H),7.58–7.52(m,2H),7.40–7.30(m,3H),7.17(d,J＝6.8Hz,2H),7.04(d,J＝8.8Hz,1H),4.35(s,2H),3.70(s,2H),3.26(t,J＝4.8Hz,4H),2.66(t,J＝4.8Hz,4H).13C NMR(100MHz,Chloroform-d)δ148.73,148.52,140.16,139.30,135.00,133.18,130.90,129.41,129.13,128.81,128.23,127.95,127.92,123.72,122.54,119.60,63.11,61.78,52.43,50.58.ESI-MS m/z:519.1[M+Na]+.
实施例42、4-[(3-氟苄基)磺酰基]-N，N-二甲基-2-硝基苯胺
1H NMR(400MHz,Chloroform-d)δ8.03(d,J＝2.3Hz,1H),7.50(dd,J＝9.1,2.3Hz,1H),7.31(td,J＝8.1,5.8Hz,1H),7.09(td,J＝8.4,2.5Hz,1H),7.00–6.89(m,3H),4.32(s,2H),3.03(s,6H).13C NMR(100MHz,Chloroform-d)δ148.58,136.39,132.28,130.46,130.38,130.34,130.25,128.87,126.68,126.65,124.28,117.98,117.76,117.00,116.20,115.99,62.64,42.25.ESI-MS m/z:361.0[M+Na]+.
实施例43、1-乙基-4-{4-[(3-氟苄基)磺酰基]-2-硝基苯基}哌嗪
1H NMR(400MHz,Chloroform-d)δ8.03(d,J＝2.2Hz,1H),7.57(dd,J＝8.9,2.3Hz,1H),7.36–7.31(m,1H),7.13–7.03(m,2H),6.99–6.88(m,2H),4.32(s,2H),3.27(t,J＝4.9Hz,4H),2.63(t,J＝5.0Hz,4H),2.53(q,J＝7.2Hz,2H),1.15(t,J＝7.2Hz,3H).13C NMR(100MHz,Chloroform-d)δ148.85,139.10,133.04,130.42,130.34,128.29,127.32,126.69,126.66,119.62,118.02,117.79,116.33,116.12,62.58,52.22,52.13,50.56,29.76,11.94.ESI-MS m/z:408.1[M+H]+.
实施例44、1-(4-{4-[(3-氟苄基)磺酰基]-2-硝基苯基}哌嗪-1-基)乙-1-酮
1H NMR(400MHz,Chloroform-d)δ8.05(d,J＝2.2Hz,1H),7.59(dd,J＝8.8,2.2Hz,1H),7.33–7.24(m,1H),7.06(t,J＝9.2Hz,2H),6.97–6.86(m,2H),4.33(s,2H),3.80(t,J＝5.1Hz,2H),3.66(dd,J＝6.4,3.5Hz,2H),3.24(dq,J＝7.8,4.4,4.0Hz,4H),2.14(s,3H).13CNMR(100MHz,Chloroform-d)δ169.35,148.69,139.29,133.23,130.47,130.39,130.09,130.01,128.42,128.22,126.73,126.69,119.81,117.99,117.77,116.35,116.14,62.43,50.65,49.93,45.48,40.79,21.40.ESI-HRMS m/z:422.1172[M+H]+.
实施例45、1-{4-[(3-氟苄基)磺酰基]-2-硝基苯基}-4-(4-硝基苯基)哌嗪
1H NMR(400MHz,DMSO-d6)δ8.14–8.08(m,3H),7.72(dd,J＝9.0,2.3Hz,1H),7.44–7.35(m,2H),7.25–7.18(m,1H),7.11–7.03(m,2H),7.01–6.95(m,2H),4.78(s,2H),3.71(dd,J＝7.0,3.7Hz,4H),3.53–3.43(m,4H).13C NMR(100MHz,DMSO-d6)δ154.46,148.19,137.43,137.33,133.09,130.83,130.74,128.36,127.73,127.03,126.29,119.78,118.33,118.12,115.99,115.78,112.42,60.63,49.03,45.51.ESI-HMS m/z:501.1231[M+H]+.
实施例46、2-(4-{4-[(3-氟苄基)磺酰基]-2-硝基苯基}哌嗪-1-基)乙-1-醇
1H NMR(400MHz,Chloroform-d)δ8.05(d,J＝2.2Hz,1H),7.60(dd,J＝8.8,2.3Hz,1H),7.33(dd,J＝8.0,5.9Hz,1H),7.13–7.05(m,2H),6.98(dd,J＝7.6,1.6Hz,1H),6.92(dt,J＝9.2,2.1Hz,1H),4.33(s,2H),3.73(t,J＝5.3Hz,2H),3.30(t,J＝4.9Hz,4H),2.80–2.74(m,4H),2.71(t,J＝5.3Hz,2H).13C NMR(100MHz,Chloroform-d)δ148.82,139.22,133.08,130.42,128.25,127.63,126.68,126.65,119.71,117.99,117.77,116.33,116.12,62.55,59.28,57.87,52.27,50.64.ESI-MS m/z:424.2[M+H]+.
实施例47、1-{4-[(3-氟苄基)磺酰基]-2-硝基苯基}-4-(2-甲氧基乙基)哌嗪
1H NMR(400MHz,Chloroform-d)δ8.01(d,J＝2.2Hz,1H),7.55(dd,J＝8.9,2.3Hz,1H),7.32–7.25(m,1H),7.06(td,J＝8.7,3.1Hz,2H),6.98–6.88(m,2H),4.31(s,2H),3.55(t,J＝5.3Hz,2H),3.38(s,3H),3.26(t,J＝4.9Hz,4H),2.67(t,J＝4.6Hz,6H).13C NMR(100MHz,Chloroform-d)δ148.85,138.99,133.02,130.40,130.23,128.27,127.24,126.71,126.68,119.64,118.00,117.78,116.28,116.07,69.93,62.51,59.03,59.00,57.75,52.84,50.40.ESI-MS m/z:438.1[M+H]+.
实施例48、1-{4-[(3-氟苄基)磺酰基]-2-硝基苯基}-4-(3-硝基苄基)哌嗪
1H NMR(400MHz,Chloroform-d)δ8.28(t,J＝2.1Hz,1H),8.17(dd,J＝8.3,2.3Hz,1H),8.04(d,J＝2.2Hz,1H),7.71(d,J＝7.6Hz,1H),7.60–7.56(m,1H),7.54(d,J＝7.9Hz,1H),7.32(td,J＝8.0,5.8Hz,2H),7.10(dd,J＝8.2,2.5Hz,1H),7.06(d,J＝8.8Hz,1H),6.99–6.96(m,1H),6.92(dt,J＝9.2,2.2Hz,1H),4.33(s,2H),3.70(s,2H),3.30–3.25(m,4H),2.66(dd,J＝6.2,3.6Hz,4H).13C NMR(100MHz,Chloroform-d)δ148.85,148.52,140.14,139.23,135.00,133.08,130.42,129.41,128.23,127.61,126.68,123.72,122.55,119.71,117.99,117.77,116.33,116.12,62.55,61.77,52.41,50.58.ESI-MS m/z:537.1[M+Na]+.
实施例49、4-[(4-氟苄基)磺酰基]-N，N-二甲基-2-硝基苯胺
1H NMR(400MHz,Chloroform-d)δ8.06(d,J＝2.3Hz,1H),7.46(dd,J＝9.0,2.3Hz,1H),7.20–7.14(m,2H),7.04(t,J＝8.6Hz,2H),6.96(d,J＝9.1Hz,1H),4.31(s,2H),3.03(s,7H).13C NMR(100MHz,Chloroform-d)δ148.51,132.71,132.63,132.37,128.82,124.40,124.08,116.91,115.98,115.77,62.28,42.25.ESI-MS m/z:361.1[M+Na]+.
实施例50、1-乙基-4-[4-(4-氟苄基)磺酰基]-2-硝基苯基哌嗪
1H NMR(400MHz,Chloroform-d)δ8.03(d,J＝2.2Hz,1H),7.52(dd,J＝8.9,2.3Hz,1H),7.20–7.11(m,2H),7.03(q,J＝8.9Hz,3H),4.30(s,2H),3.29–3.22(m,4H),2.65–2.58(m,4H),2.51(q,J＝7.2Hz,2H),1.13(t,J＝7.2Hz,3H).13C NMR(100MHz,Chloroform-d)δ148.78,139.09,133.07,132.76,132.68,128.22,127.36,123.87,123.83,119.62,116.02,115.81,62.18,62.14,62.11,52.21,52.14,50.57,29.74,11.96.ESI-MS m/z:408.1[M+H]+.
实施例51、1-(4-{4-[(4-氟苄基)磺酰基]-2-硝基苯基}哌嗪-1-基)乙-1-酮
1H NMR(400MHz,DMSO-d6)δ8.06(d,J＝2.3Hz,1H),7.68(dd,J＝8.9,2.3Hz,1H),7.39(d,J＝9.0Hz,1H),7.28–7.22(m,2H),7.22–7.15(m,2H),4.73(s,2H),3.61(q,J＝5.4Hz,4H),3.31–3.21(m,4H),2.04(s,3H).13C NMR(100MHz,Chloroform-d)δ169.31,148.61,139.53,133.32,132.74,132.65,128.74,128.15,123.68,123.65,119.71,116.10,115.88,62.14,50.76,49.97,45.53,40.82,21.40.ESI-MS m/z:444.1[M+Na]+.
实施例52、1-{4-[(4-氟苄基)磺酰基]-2-硝基苯基}-4-(4-硝基苯基)哌嗪
1H NMR(400MHz,DMSO-d6)δ8.08–8.02(m,2H),8.01(d,J＝2.2Hz,1H),7.62(dd,J＝8.9,2.4Hz,1H),7.34(d,J＝9.0Hz,1H),7.23–7.16(m,2H),7.12(dd,J＝9.9,7.8Hz,2H),6.95–6.88(m,2H),4.67(s,2H),3.64(dd,J＝7.1,3.6Hz,4H),3.46–3.37(m,4H).13C NMR(100MHz,DMSO-d6)δ154.47,148.16,137.47,137.33,133.67,133.59,133.13,128.36,127.06,126.29,125.58,125.55,119.76,115.90,115.68,112.42,60.32,49.04,45.52.ESI-MS m/z:523.1[M+Na]+.
实施例53、2-(4-{4-[(4-氟苄基)磺酰基]-2-硝基苯基}哌嗪-1-基)乙-1-醇
1H NMR(400MHz,Chloroform-d)δ8.06(d,J＝2.3Hz,1H),7.56(dd,J＝8.8,2.3Hz,1H),7.18(dd,J＝8.5,5.0Hz,2H),7.08–7.01(m,3H),4.32(s,2H),3.71(t,J＝5.3Hz,2H),3.27(t,J＝4.9Hz,4H),2.72(t,J＝4.9Hz,4H),2.68(t,J＝5.3Hz,2H).13C NMR(100MHz,Chloroform-d)δ148.75,139.26,133.13,132.75,132.66,128.17,127.72,123.81,123.78,119.71,116.04,115.82,62.14,59.30,57.89,52.29,50.63.ESI-MS m/z:424.2[M+H]+.
实施例54、1-{4-[(4-氟苄基)磺酰基]-2-硝基苯基}-4-(2-甲氧基乙基)哌嗪
1H NMR(400MHz,Chloroform-d)δ8.01(d,J＝2.2Hz,1H),7.51(dd,J＝8.9,2.3Hz,1H),7.19–7.10(m,2H),7.02(q,J＝8.7Hz,3H),4.29(s,2H),3.54(t,J＝5.4Hz,2H),3.37(s,3H),3.29–3.22(m,4H),2.66(t,J＝4.7Hz,6H).13C NMR(100MHz,Chloroform-d)δ148.79,139.04,133.06,132.77,132.69,128.21,127.32,123.88,123.84,119.62,116.00,115.79,69.94,62.11,59.02,58.99,57.76,52.85,50.42.ESI-MS m/z:438.1[M+H]+.
实施例55、1-{4-[(4-氟苄基)磺酰基]-2-硝基苯基}-4-(3-硝基苄基)哌嗪
1H NMR(400MHz,Chloroform-d)δ8.27(t,J＝2.0Hz,1H),8.17(ddd,J＝8.2,2.4,1.1Hz,1H),8.05(d,J＝2.3Hz,1H),7.71(dt,J＝7.6,1.4Hz,1H),7.59–7.50(m,2H),7.21–7.12(m,2H),7.09–6.99(m,3H),4.32(s,2H),3.71(s,2H),3.30–3.23(m,4H),2.69–2.62(m,4H).13C NMR(100MHz,Chloroform-d)δ148.78,148.54,140.14,139.34,134.97,133.14,132.73,132.65,129.41,128.15,127.78,123.72,122.56,119.67,116.06,115.84,62.18,61.78,52.42,50.58.ESI-MS m/z:537.1[M+Na]+.
实施例56、1-{4-[(4-氟苄基)磺酰基]-2-硝基苯基}-4-(4-硝基苄基)哌嗪
1H NMR(400MHz,Chloroform-d)δ8.26–8.21(m,2H),8.06(d,J＝2.2Hz,1H),7.59–7.53(m,3H),7.20–7.15(m,2H),7.04(t,J＝8.7Hz,3H),4.32(s,2H),3.71(s,2H),3.29–3.24(m,4H),2.65(dd,J＝5.8,3.9Hz,4H).13C NMR(100MHz,DMSO-d6)δ148.61,147.17,146.75,138.52,133.66,133.58,133.29,130.35,128.10,127.74,123.92,120.99,115.89,115.68,61.18,60.27,52.53,50.55.ESI-MS m/z:537.1[M+Na]+.
实施例57、1-乙基-4-[4-(4-甲基苄基)磺酰基]-2-硝基苯基)哌嗪
1H NMR(400MHz,Chloroform-d)δ7.93(d,J＝2.2Hz,1H),7.56(dd,J＝8.9,2.3Hz,1H),7.17–7.00(m,5H),4.29(s,2H),3.31–3.19(m,4H),2.61(t,J＝4.8Hz,4H),2.51(q,J＝7.2Hz,2H),2.35(s,3H),1.14(t,J＝7.2Hz,4H).13C NMR(100MHz,Chloroform-d)δ148.70,139.17,139.14,133.13,130.78,129.50,128.28,127.77,124.82,119.52,62.83,52.23,52.17,50.59,29.75,21.28,11.98.ESI-MS m/z:404.2[M+H]+.
实施例58、1-(4-{4-[(4-甲基苄基)磺酰基]-2-硝基苯基}哌嗪-1-基)乙-1-酮
1H NMR(400MHz,Chloroform-d)δ8.00(d,J＝2.0Hz,1H),7.62(dd,J＝8.5,2.2Hz,1H),7.14(d,J＝7.7Hz,2H),7.09–7.02(m,3H),4.32(s,2H),3.76(d,J＝62.6Hz,4H),3.25(s,4H),2.37(s,3H),2.18(s,3H).13C NMR(100MHz,Chloroform-d)δ169.30,148.50,139.61,139.27,133.37,130.75,129.54,129.13,128.21,124.64,119.63,62.81,50.82,50.00,45.58,40.85,21.40,21.28.ESI-MS m/z:440.1[M+Na]+.
实施例59、1-{4-[(4-甲基苄基)磺酰基]-2-硝基苯基}-4-(4-硝基苯基)哌嗪
1H NMR(400MHz,Chloroform-d)δ8.25–8.18(m,2H),8.02(d,J＝2.1Hz,1H),7.65(dd,J＝8.8,2.2Hz,1H),7.15(d,J＝7.8Hz,2H),7.08(dd,J＝15.0,8.3Hz,3H),6.88(d,J＝9.3Hz,2H),4.33(s,2H),3.69(dd,J＝6.6,3.7Hz,4H),3.48(dd,J＝6.5,3.8Hz,4H),2.38(s,3H).13C NMR(100MHz,DMSO-d6)δ154.48,148.09,138.35,137.52,137.33,133.11,131.43,129.40,128.26,127.44,126.30,126.09,119.76,112.44,61.02,49.05,45.54,21.27.
实施例60、2-(4-{4-[(4-甲基苄基)磺酰基]-2-硝基苯基}哌嗪-1-基)乙-1-醇
1H NMR(400MHz,Chloroform-d)δ7.95(d,J＝2.2Hz,1H),7.57(dd,J＝8.8,2.3Hz,1H),7.12(d,J＝7.8Hz,2H),7.04(dd,J＝8.4,6.5Hz,3H),4.30(s,2H),3.69(t,J＝5.3Hz,2H),3.31–3.22(m,4H),2.70(t,J＝4.9Hz,4H),2.66(t,J＝5.3Hz,2H),2.56(s,1H),2.36(s,3H).13C NMR(100MHz,Chloroform-d)δ148.67,139.31,139.18,133.21,130.78,129.52,128.25,128.11,124.76,119.64,62.81,59.33,57.89,52.33,50.63,21.29.ESI-MS m/z:420.2[M+H]+.
实施例61、1-(2-甲氧基乙基)-4-[4-(4-甲基苄基)磺酰基]2-硝基苯基)哌嗪
1H NMR(400MHz,Chloroform-d)δ7.93(d,J＝2.2Hz,1H),7.55(dd,J＝8.8,2.3Hz,1H),7.12(d,J＝7.9Hz,2H),7.06–7.01(m,3H),4.29(s,2H),3.56(t,J＝5.3Hz,2H),3.39(s,3H),3.30–3.21(m,4H),2.67(t,J＝5.1Hz,7H),2.35(s,3H).13C NMR(100MHz,Chloroform-d)δ148.71,139.14,133.13,130.77,129.49,128.27,127.76,124.81,119.49,69.95,62.86,62.83,59.04,59.01,57.78,52.88,50.44,21.27.ESI-MS m/z:434.2[M+H]+.
实施例62、4-[(4-甲氧基苄基)磺酰基]-N，N-二甲基-2-硝基苯胺
1H NMR(400MHz,Chloroform-d)δ7.98(d,J＝2.3Hz,1H),7.50(dd,J＝9.0,2.3Hz,1H),7.24–7.18(m,1H),6.95(d,J＝9.1Hz,1H),6.92–6.87(m,1H),6.70(dd,J＝7.1,1.4Hz,2H),4.29(s,2H),3.78(s,3H),3.01(s,6H).13C NMR(100MHz,Chloroform-d)δ159.73,148.49,136.42,132.39,129.70,129.51,128.92,124.60,123.19,116.86,116.32,114.73,63.22,55.34,42.23,29.75.ESI-MS m/z:373.1[M+Na]+.
实施例63、1-{4-[(3-甲氧基苄基)磺酰基]-2-硝基苯基}哌嗪
1H NMR(400MHz,Chloroform-d)δ7.99(d,J＝2.2Hz,1H),7.58(dd,J＝8.9,2.3Hz,1H),7.26–7.19(m,1H),7.05(d,J＝8.9Hz,1H),6.91(ddd,J＝8.4,2.4,1.1Hz,1H),6.76–6.67(m,2H),4.31(s,2H),3.79(s,3H),3.25–3.18(m,4H),3.08–3.02(m,4H).13C NMR(100MHz,DMSO-d6)δ159.46,148.76,138.36,133.31,130.54,129.86,128.19,127.72,123.75,120.90,117.06,114.56,61.27,55.51,50.94,45.06.ESI-MS m/z:392.1[M+H]+.
实施例64、1-乙基-4-{4-[(3-甲氧基苄基)磺酰基]-2-硝基苯基}哌嗪
1H NMR(400MHz,Chloroform-d)δ7.97(d,J＝2.2Hz,1H),7.56(dd,J＝8.9,2.3Hz,1H),7.21(dd,J＝8.8,7.6Hz,1H),7.04(d,J＝8.9Hz,1H),6.93–6.87(m,1H),6.74–6.68(m,2H),4.30(s,2H),3.77(s,3H),3.29–3.20(m,4H),2.61(t,J＝4.9Hz,4H),2.51(q,J＝7.2Hz,2H),1.14(t,J＝7.2Hz,3H).13C NMR(100MHz,Chloroform-d)δ159.76,148.73,139.20,133.12,129.77,129.26,128.28,127.68,123.17,119.46,116.31,114.82,63.16,55.35,52.22,52.14,50.55,11.92.ESI-MS m/z:420.2[M+H]+.
实施例65、1-(4-{4-[(3-甲氧基苄基)磺酰基]-2-硝基苯基}哌嗪-1-基)乙-1-酮
1H NMR(400MHz,DMSO-d6)δ8.05(d,J＝2.3Hz,1H),7.71(dd,J＝8.9,2.3Hz,1H),7.40(d,J＝9.0Hz,1H),7.24(t,J＝7.9Hz,1H),6.95–6.89(m,1H),6.79(dt,J＝7.6,1.2Hz,1H),6.74(t,J＝2.0Hz,1H),4.69(s,2H),3.68(s,3H),3.61(q,J＝5.3Hz,4H),3.26(dd,J＝15.1,4.8Hz,4H),2.05(s,3H).13C NMR(100MHz,Chloroform-d)δ169.36,159.77,148.57,139.39,133.31,129.80,129.13,128.78,128.22,123.17,119.73,116.49,114.70,63.02,55.39,55.36,50.68,49.98,45.53,40.83,21.40.ESI-MS m/z:456.1(M+Na)+.
实施例66、1-{4-[(3-甲氧基苄基)磺酰基]-2-硝基苯基}-4-(4-硝基苯基)哌嗪
1H NMR(400MHz,DMSO-d6)δ8.15–8.08(m,2H),8.06(d,J＝2.2Hz,1H),7.73(dd,J＝8.9,2.3Hz,1H),7.41(d,J＝9.0Hz,1H),7.25(t,J＝7.9Hz,1H),7.02–6.96(m,2H),6.92(dd,J＝8.1,2.6Hz,1H),6.79(d,J＝7.6Hz,1H),6.76(t,J＝2.0Hz,1H),4.69(s,2H),3.70(d,J＝11.6Hz,7H),3.51–3.45(m,4H).13C NMR(100MHz,DMSO-d6)δ159.47,154.47,148.12,137.51,137.34,133.16,130.56,129.86,128.35,127.29,126.29,123.75,119.72,117.10,114.53,112.44,61.30,55.52,49.06,45.53.
实施例67、2-(4-{4-[(3-甲氧基苄基)磺酰基]-2-硝基苯基}哌嗪-1-基)乙-1-醇
1H NMR(400MHz,Chloroform-d)δ8.00(d,J＝2.2Hz,1H),7.59(dd,J＝8.8,2.3Hz,1H),7.23(t,J＝8.2Hz,1H),7.05(d,J＝8.8Hz,1H),6.94–6.89(m,1H),6.71(dd,J＝6.9,1.5Hz,2H),4.31(s,2H),3.79(s,3H),3.71(t,J＝5.3Hz,2H),3.30–3.23(m,4H),2.72(dd,J＝6.0,3.7Hz,4H),2.68(t,J＝5.3Hz,2H).13C NMR(100MHz,DMSO-d6)δ159.45,148.53,138.41,133.29,130.54,129.85,128.13,127.66,123.74,120.77,117.03,114.57,61.28,60.43,58.90,55.51,53.05,50.48.ESI-MS m/z:458.2[M+Na]+.
实施例68、1-{4-[(3-甲氧基苄基)磺酰基]-2-硝基苯基}-4-(2-甲氧基乙基)哌嗪
1H NMR(400MHz,Chloroform-d)δ7.97(d,J＝2.2Hz,1H),7.56(dd,J＝8.9,2.3Hz,1H),7.29(d,J＝3.9Hz,1H),7.21(t,J＝8.2Hz,1H),7.02(d,J＝8.9Hz,1H),6.98–6.93(m,1H),6.92–6.83(m,2H),6.70(dt,J＝6.6,1.6Hz,2H),4.69(s,1H),4.29(s,2H),3.83(s,2H),3.77(s,3H),3.56(t,J＝5.3Hz,2H),3.38(s,3H),3.25(t,J＝4.9Hz,4H),2.67(t,J＝4.6Hz,6H).13C NMR(100MHz,Chloroform-d)δ159.75,148.74,139.13,133.11,129.76,129.26,128.27,127.59,123.17,119.45,116.31,114.80,69.94,63.13,59.01,57.77,55.35,52.86,50.43.ESI-MS m/z:450.2[M+H]+.
实施例69、1-{4-[(3-甲氧基苄基)磺酰基]-2-硝基苯基}-4-(3-硝基苄基)哌嗪
1H NMR(400MHz,Chloroform-d)δ8.28(t,J＝1.9Hz,1H),8.18(ddd,J＝8.2,2.3,1.1Hz,1H),7.99(d,J＝2.2Hz,1H),7.71(dt,J＝7.6,1.4Hz,1H),7.59(dd,J＝8.9,2.3Hz,1H),7.55(t,J＝7.9Hz,1H),7.23(dd,J＝8.7,7.6Hz,1H),7.05(d,J＝8.9Hz,1H),6.94–6.89(m,1H),6.71(dd,J＝6.9,1.4Hz,2H),4.32(s,2H),3.79(s,3H),3.71(s,2H),3.29–3.23(m,4H),2.66(dd,J＝5.9,3.7Hz,4H).13C NMR(100MHz,DMSO-d6)δ159.44,148.57,148.36,140.86,138.52,136.12,133.32,130.47,130.30,129.87,128.08,127.83,123.75,122.64,120.93,117.02,114.59,61.28,60.96,55.50,52.39,50.54.ESI-MS m/z:549.1[M+Na]+.
实施例70、4-(4-{[4-(2-羟基乙基)哌嗪-1-基]甲基}苯基)-6-苯基-1,2-二氢嘧啶-2-酮
步骤一：(E)-1-苯基-3-(对甲苯基)丙-2-烯-1-酮
在25mL圆底烧瓶中将苯乙酮(2.00g,16.65mmol)，氢氧化钠(1.00g,25.00mmol)，对甲基苯甲醛(2.00g,16.65mmol)依次加入乙醇(10mL)中，室温反应过夜。抽滤得，即为(E)-1-苯基-3-(对甲苯基)丙-2-烯-1-酮，收率为90％。
步骤二：(E)-3-[4-(溴甲基)苯基]-1-苯基丙-2-烯-1-酮
在25mL圆底烧瓶中将步骤一制得的(E)-1-苯基-3-(对甲苯基)丙-2-烯-1-酮(500.00mg,2.25mmol)，N-溴代琥珀酰亚胺(440.38mg,2.47mmol)，偶氮二异丁腈(73.87mg,0.45mmol)依次加入四氯化碳(20mL)中，氮气保护下85℃反应2h。旋蒸蒸干四氯化碳，EA萃取。蒸干EA，柱层析(PE:EA＝10:1)得，即为(E)-3-[4-(溴甲基)苯基]-1-苯基丙-2-烯-1-酮，收率为60％。
步骤三：(E)-3-(4-{[4-(2-羟乙基)哌嗪-1-基]甲基}苯基)-1-苯基丙-2-烯-1-酮
在25mL圆底烧瓶中将步骤二制得的(E)-3-[4-(溴甲基)苯基]-1-苯基丙-2-烯-1-酮(200mg,0.66mmol)，2-羟乙基哌嗪(129.68mg,1.00mmol)，三乙胺(100.80mg,1.00mmol)依次加入乙腈(10mL)中，85℃反应2h。旋蒸蒸干乙腈，EA萃取。蒸干EA，柱层析(PE:EA＝1:1)得，即为(E)-3-(4-{[4-(2-羟乙基)哌嗪-1-基]甲基}苯基)-1-苯基丙-2-烯-1-酮，收率为60％。
步骤四：4-(4-{[4-(2-羟基乙基)哌嗪-1-基]甲基}苯基)-6-苯基-1,2-二氢嘧啶-2-酮
在25mL圆底烧瓶中将步骤三制得的E)-3-(4-{[4-(2-羟乙基)哌嗪-1-基]甲基}苯基)-1-苯基丙-2-烯-1-酮(100.00mg,0.29mmol)，脲(25.70mg,0.43mmol)，叔丁醇钠(32.91mg,0.34mmol)依次加入四氢呋喃(5mL)中，氮气保护下85℃反应2h。旋蒸蒸干四氢呋喃，EA萃取。蒸干EA，柱层析(PE:EA＝1:1)得，即为4-(4-{[4-(2-羟基乙基)哌嗪-1-基]甲基}苯基)-6-苯基-1,2-二氢嘧啶-2-酮，收率为40％。
1H NMR(400MHz,DMSO-d6)δ8.22–8.12(m,4H),7.56(dd,J＝18.4,8.1Hz,6H),3.84(s,2H),2.57(d,J＝7.2Hz,2H),1.49(t,J＝7.2Hz,2H),1.30(td,J＝9.3,8.4,4.7Hz,4H),0.88(h,J＝4.9Hz,2H).13C NMR(100MHz,Chloroform-d)δ160.39,142.20,134.08,133.10,131.95,129.57,129.47,129.18,127.82,127.74,127.69,99.88,52.84,49.09,29.76,28.62,22.53,14.07ppm.HRMS(ESI,m/z):calcd.for C22H26N3O[M+H]+,348.2076；found,348.2075.
按照实施例70的方法，分别制得实施例71～84化合物
实施例71、4-(4-{[4-(2-甲氧基乙基)哌嗪-1-基]甲基}苯基)-6-(4-甲氧基苯基)-1,2-二氢嘧啶-2-酮
1H NMR(400MHz,Chloroform-d)δ8.14–8.09(m,2H),8.04(d,J＝7.9Hz,2H),7.54(d,J＝7.9Hz,2H),7.10(d,J＝4.7Hz,2H),7.08(d,J＝1.5Hz,1H),3.93(d,J＝1.3Hz,3H),3.63(s,2H),3.57(t,J＝5.6Hz,2H),3.38(d,J＝1.3Hz,3H),2.74–2.51(m,10H).13C NMR(100MHz,Chloroform-d)δ162.87,160.43,142.47,129.86,129.55,127.62,114.61,99.10,69.92,62.52,58.96,57.81,55.58,53.49,52.75.ESI-MS m/z:435.2388[M+H]+.
实施例72、4-{4-[(4-{2-[(2-羟基乙基)氧基]乙基}哌嗪-1-基)甲基]苯基}-6-苯基-1,2-二氢嘧啶-2-酮
1H NMR(400MHz,Chloroform-d)δ8.13–8.07(m,2H),8.04(d,J＝8.0Hz,2H),7.59(dd,J＝5.3,1.9Hz,3H),7.54(d,J＝8.1Hz,2H),7.16(s,1H),3.75–3.70(m,2H),3.68(t,J＝5.1Hz,2H),3.63(d,J＝5.7Hz,4H),2.65(t,J＝5.3Hz,2H),2.60(s,8H).13C NMR(100MHz,Chloroform-d)δ160.38,142.67,134.24,132.88,131.92,129.81(d,J＝4.8Hz),129.15,128.87,127.68(d,J＝2.8Hz),126.63,125.20,99.85,72.50,67.35,62.44,61.92,57.88,53.18(d,J＝5.5Hz),52.64(d,J＝14.7Hz).ESI-MS m/z:435.2397[M+H]+.
实施例73、4-{4-[(苯并[d][1,3]噻唑-2-基氨基)甲基]苯基}-6-苯基-1,2-二氢嘧啶-2-酮
1H NMR(400MHz,DMSO-d6)δ12.09(s,1H),9.51(s,1H),8.24–8.06(m,4H),7.61–7.55(m,3H),7.41(d,J＝8.3Hz,2H),7.37(t,J＝7.6Hz,2H),7.17–7.11(m,1H),7.01(td,J＝7.6,1.3Hz,1H),4.19(s,2H).13C NMR(100MHz,Methanol-d4)δ142.01,140.38,137.06,132.01,130.67,129.58,129.08,128.38–126.81(m),127.63,123.37,115.07,100.35,39.86.ESI-MS m/z:411.1279[M+H]+.
实施例74、4-(4-{[4-(2-羟基乙基)哌嗪-1-基]甲基}苯基)-6-(4-甲氧基苯基)-1,2-二氢嘧啶-2-酮
1H NMR(400MHz,Chloroform-d)δ8.14–8.08(m,2H),8.04(d,J＝8.0Hz,2H),7.54(d,J＝8.1Hz,2H),7.12–7.06(m,3H),3.93(s,3H),3.69(q,J＝4.8Hz,2H),3.64(s,2H),2.73–2.51(m,10H).13C NMR(100MHz,Methanol-d4)δ162.25,141.79,129.84,129.38,127.45,126.17,114.20,113.66,99.29,61.93,59.81,58.27,54.72,52.81(d,J＝15.3Hz),52.11(d,J＝19.6Hz).ESI-MS m/z:421.2232[M+H]+.
实施例75、4-{4-[(4-{2-[(2-羟基乙基)氧基]乙基}哌嗪-1-基)甲基]苯基}-6-(4-甲氧基苯基)-1,2-二氢嘧啶-2-酮
1H NMR(400MHz,Methanol-d4)δ8.05(dd,J＝17.2,8.1Hz,4H),7.57(d,J＝7.9Hz,2H),7.32(s,1H),7.15–7.09(m,2H),3.92(s,3H),3.68(dd,J＝8.2,4.2Hz,6H),3.60–3.54(m,2H),2.78–2.67(m,6H),2.67–2.55(m,4H).13C NMR(100MHz,Chloroform-d)δ162.89,160.33,142.58,129.84,129.54,127.62,114.61,99.09,72.50,67.32,62.49,62.05,57.92,55.58,53.22,52.76.ESI-MS m/z:465.2489[M+H]+.
实施例76、4-{4-[(戊基氨基)甲基]苯基}-6-苯基-1,2-二氢嘧啶-2-酮
1H NMR(400MHz,DMSO-d6)δ8.22–8.12(m,4H),7.56(dd,J＝18.4,8.1Hz,6H),3.84(s,2H),2.57(d,J＝7.2Hz,2H),1.49(t,J＝7.2Hz,2H),1.30(td,J＝9.3,8.4,4.7Hz,4H),0.88(h,J＝4.9Hz,2H).13C NMR(100MHz,Chloroform-d)δ160.39,142.20,134.08,133.10,131.95,129.57,129.47,129.18,127.82,127.74,127.69,99.88,52.84,49.09,29.76,28.62,22.53,14.07.ESI-MS m/z:348.2075[M+H]+.
实施例77、6-(4-甲氧基苯基)-4-{4-[(戊基氨基)甲基]苯基}-1,2-二氢嘧啶-2-酮
1H NMR(400MHz,DMSO-d6)δ8.22–8.15(m,2H),8.14–8.09(m,2H),7.53(d,J＝8.1Hz,2H),7.49(s,1H),7.15–7.09(m,2H),3.88(s,3H),3.82(s,2H),2.56(s,2H),1.53–1.43(m,2H),1.30(h,J＝3.7Hz,4H),0.93–0.85(m,2H).13C NMR(100MHz,Chloroform-d)δ162.82,160.49,143.54,133.05,129.54,129.08,127.78,126.27,114.56,99.09,55.55,53.31,49.36,29.76,29.30,22.62,14.11.ESI-MS m/z:378.2128[M+H]+.
实施例78、4-(4-{[4-(2-甲氧基乙基)哌嗪-1-基]甲基}苯基)-6-苯基-1,2-二氢嘧啶-2-酮1H NMR(400MHz,Chloroform-d)δ8.07(dd,J＝6.8,2.9Hz,2H),8.03(d,J＝8.0Hz,2H),7.55(dd,J＝5.1,1.9Hz,3H),7.51(d,J＝8.0Hz,2H),7.14(s,1H),3.59(s,2H),3.53(t,J＝5.6Hz,2H),3.35(s,3H),2.62(q,J＝5.1,4.5Hz,2H),2.57(s,8H).13C NMR(100MHz,Chloroform-d)δ160.46,142.72,134.21,132.83,132.00,129.90,129.23,127.72,127.67,100.00,69.97,62.52,58.94,57.80,53.46,52.81.ESI-MS m/z:405.2295[M+H]+.
实施例79、6-(4-溴苯基)-4-(4-{[4-(2-羟基乙基)哌嗪-1-基]甲基}苯基)-1,2-二氢嘧啶-2-酮
1H NMR(400MHz,Methanol-d4)δ8.03(t,J＝8.8Hz,4H),7.77–7.73(m,2H),7.59(d,J＝8.2Hz,2H),7.40(s,1H),3.81(t,J＝5.6Hz,2H),3.73(s,2H),3.02(s,4H),2.94(t,J＝5.6Hz,2H),2.73(s,4H).13C NMR(100MHz,Chloroform-d)δ160.23,143.01,132.42,129.98,129.31,127.57,126.99,99.69,62.48,59.32,57.67,53.03,52.87.ESI-MS m/z:469.1238[M+H]+.
实施例80、4-(4-{[4-(4-硝基苯基)哌嗪-1-基]甲基}苯基)-6-苯基-1,2-二氢嘧啶-2-酮
1H NMR(400MHz,Chloroform-d)δ8.20–8.14(d,2H),8.09(d,J＝7.5Hz,4H),7.61(d,J＝7.2Hz,5H),7.18(s,1H),6.86(d,J＝9.4Hz,2H),3.72(s,2H),3.51(s,4H),2.70(s,4H).13C NMR(100MHz,DMSO-d6)δ155.23,137.36,132.00,129.76,129.35,128.07,126.23,113.14,61.84,52.67,46.84.ESI-MS m/z:468.2027[M+H]+.
实施例81、6-(4-溴苯基)-4-{4-[(4-{2-[(2-羟基乙基)氧基]乙基}哌嗪-1-基)甲基]苯基}-1,2-二氢嘧啶-2-酮
1H NMR(400MHz,Chloroform-d)δ8.00(dd,J＝8.4,3.6Hz,4H),7.73–7.68(m,2H),7.56–7.52(m,2H),7.12(s,1H),3.74–3.69(m,4H),3.64(d,J＝6.0Hz,4H),2.71(q,J＝5.6Hz,6H),2.63(s,4H).13C NMR(100MHz,Chloroform-d)δ160.33,142.80,133.65,132.41,132.09,131.38,131.25,129.99,129.32,127.63,126.96,99.75,72.55,67.07,62.30,61.92,57.70,53.11,52.40.ESI-MS m/z:513.1497[M+H]+.
实施例82、6-(4-甲氧基苯基)-4-(4-{[4-(4-硝基苯基)哌嗪-1-基]甲基}苯基)-1,2-二氢嘧啶-2-酮
1H NMR(400MHz,Chloroform-d)δ8.20–8.06(m,6H),7.60(d,J＝7.8Hz,2H),7.14(s,1H),7.10(d,J＝8.5Hz,2H),6.86(d,J＝9.1Hz,2H),3.94(s,3H),3.72(s,2H),3.51(s,4H),2.70(s,4H).13C NMR(100MHz,Chloroform-d)δ162.96,160.25,154.91,142.06,138.42,129.66(d,J＝22.5Hz),127.75,126.00,114.64,112.69,99.06,62.46,55.58,52.65,47.07.ESI-MS m/z:498.2139[M+H]+.
实施例83、6-(4-溴苯基)-4-(4-{[4-(2-甲氧基乙基)哌嗪-1-基]甲基}苯基)-1,2-二氢嘧啶-2-酮
1H NMR(400MHz,Methanol-d4)δ8.06–8.00(m,4H),7.78–7.73(m,2H),7.58(d,J＝8.1Hz,2H),7.39(d,J＝3.4Hz,1H),3.66(s,2H),3.58(t,J＝5.5Hz,2H),3.37(s,3H),2.69(t,J＝5.4Hz,6H),2.60(s,4H).13C NMR(100MHz,Chloroform-d)δ160.21,132.42,130.01,129.33,127.53,126.95,99.64,69.99,62.51,58.98,57.88,53.56,52.85.ESI-MS m/z:483.1391[M+H]+.
实施例84、4-{4-[(4-乙酰基哌嗪-1-基)甲基]苯基}-6-(4-溴苯基)-1,2-二氢嘧啶-2-酮
1H NMR(400MHz,Methanol-d4)δ7.97(t,J＝8.0Hz,4H),7.73–7.69(m,2H),7.56(d,J＝8.1Hz,2H),7.26(s,1H),3.66(s,2H),3.63(t,J＝5.2Hz,2H),3.57(t,J＝5.1Hz,2H),2.54(t,J＝5.1Hz,2H),2.49(t,J＝5.1Hz,2H),2.11(s,3H).13C NMR(100MHz,Methanol-d4)δ170.08,159.57,141.92,132.27,131.44,129.91,129.20,127.61,126.81,100.15,62.10,52.94,52.49,46.17,41.38,20.67.ESI-MS m/z:467.1081[M+H]+.
实施例85、2-(4-{[4-(2-甲氧基乙基)哌嗪-1-基]甲基}苯基)-3,4-二氢喹唑啉-4-酮
步骤一：2-(4-甲基苯基)-3,4-二氢喹唑啉-4-酮
在25mL圆底烧瓶中将2-氨基苯甲酰胺(1.00g,7.34mmol)，碘(2.05g,8.08mmol)，对甲基苯甲醛(1.06g,8.81mmol)依次加入乙醇(10mL)中，85℃反应2小时。5％亚硫酸钠溶液淬灭反应，抽滤得，即为2-(4-甲基苯基)-3,4-二氢喹唑啉-4-酮，收率为90％。
步骤二：2-[4-(溴甲基)苯基]-3,4-二氢喹唑啉-4-酮
在25mL圆底烧瓶中将步骤一制得的2-(4-甲基苯基)-3,4-二氢喹唑啉-4-酮(1.70g,7.20mmol)，N-溴代琥珀酰亚胺(1.41g,7.91mmol)，偶氮二异丁腈(236.30mg,1.44mmol)依次加入四氯化碳(30mL)中，氮气保护下85℃反应2h。旋蒸蒸干四氯化碳，EA萃取。蒸干EA，柱层析(PE:EA＝5:1)得，即为2-[4-(溴甲基)苯基]-3,4-二氢喹唑啉-4-酮，收率为60％。
步骤三：2-(4-{[4-(2-甲氧基乙基)哌嗪-1-基]甲基}苯基)-3,4-二氢喹唑啉-4-酮
在25mL圆底烧瓶中将步骤二制得的(E)-3-[4-(溴甲基)苯基]-1-苯基丙-2-烯-1-酮(100mg,0.32mmol)，2-甲氧基乙基哌嗪(50.33mg,0.35mmol)，三乙胺(48.51μL)依次加入乙腈(10mL)中，氮气保护下85℃反应2h。旋蒸蒸干乙腈，EA萃取。蒸干EA，柱层析(PE:EA＝1:1)得，即为(E)-3-(4-{[4-(2-羟乙基)哌嗪-1-基]甲基}苯基)-1-苯基丙-2-烯-1-酮，收率为60％。
1H NMR(400MHz,Methanol-d4)δ8.29–8.24(m,1H),8.07–8.01(m,2H),7.86–7.78(m,2H),7.57–7.49(m,3H),3.69(s,2H),3.63(t,J＝5.3Hz,2H),3.37(s,3H),2.95–2.79(m,6H),2.69(s,4H).13C NMR(100MHz,Methanol-d4)δ140.54,134.98,129.87,127.71,127.40,126.94,126.20,68.54,61.90,58.67,57.06,52.84,51.34.ESI-MS m/z:379.2132[M+H]+.
按照实施例85的方法，分别制得实施例86～93化合物
实施例86、2-(4-{[4-(2-羟基乙基)哌嗪-1-基]甲基}苯基)-3,4-二氢喹唑啉-4-酮
1H NMR(400MHz,DMSO-d6)δ8.17(dd,J＝8.3,3.0Hz,3H),7.85(t,J＝7.6Hz,1H),7.75(d,J＝8.1Hz,1H),7.53(t,J＝7.5Hz,1H),7.48(d,J＝7.9Hz,2H),3.55(s,2H),3.50(t,J＝6.3Hz,2H),2.41(q,J＝11.0,6.3Hz,10H).13C NMR(100MHz,Chloroform-d)δ163.88,151.69,149.56,142.28,134.99,131.73,129.79,128.01,127.39,126.82,126.43,120.85,62.58,59.33,57.74,53.09,52.86.ESI-MS m/z:365.1987[M+H]+.
实施例87、2-(4-{[4-(4-硝基苯基)哌嗪-1-基]甲基}苯基)-3,4-二氢喹唑啉-4-酮
1H NMR(400MHz,DMSO-d6)δ12.53(s,1H),8.22–8.15(m,3H),8.10–8.04(m,2H),7.86(ddd,J＝8.5,7.0,1.6Hz,1H),7.76(d,J＝8.1Hz,1H),7.54(dd,J＝7.6,6.1Hz,3H),7.07–7.00(m,2H),3.65(s,2H),3.50(t,J＝5.1Hz,4H),2.56(d,J＝5.2Hz,4H).13C NMR(100MHz,DMSO-d6)δ162.74,155.19,152.62,149.28,142.14,137.35,135.12,132.00,129.50,128.11,127.03,126.29,121.46,113.10,61.81,52.64,46.81.ESI-MS m/z:442.1871[M+H]+.
实施例88、2-{4-[(4-乙酰基哌嗪-1-基)甲基]苯基}-3,4-二氢喹唑啉-4-酮
1H NMR(400MHz,Chloroform-d)δ10.86(s,1H),8.37(d,J＝7.9Hz,1H),8.20(d,J＝7.8Hz,2H),7.86(dd,J＝5.9,1.7Hz,2H),7.62(s,2H),7.56(ddd,J＝8.2,6.0,2.2Hz,1H),3.71(s,4H),3.56(s,2H),2.54(s,4H),2.13(s,3H).13C NMR(100MHz,Chloroform-d)δ169.09,163.86,151.59,149.56,141.85,135.02,131.93,129.71,128.06,127.51,126.87,126.41,120.87,62.48,53.17,52.88,46.32,41.47,21.43.ESI-MS m/z:363.1826[M+H]+.
实施例89、7-{[4-(2-甲氧基乙基)哌嗪-1-基]甲基}-2-苯基-3,4-二氢喹唑啉-4-酮
1H NMR(400MHz,Methanol-d4)δ8.23(d,J＝8.2Hz,1H),8.07–8.02(m,2H),7.77(d,J＝1.5Hz,1H),7.61–7.51(m,5H),3.72(s,2H),3.56(t,J＝5.6Hz,2H),3.36(s,3H),2.74–2.54(m,10H).13C NMR(100MHz,Chloroform-d)δ163.76,151.95,149.60,146.41,132.93,131.68,129.09,127.92,127.80,127.44,126.34,119.74,70.13,62.75,58.96,57.97,53.65,53.06.ESI-MS m/z:379.2141[M+H]+.
实施例90、7-{[4-(2-羟基乙基)哌嗪-1-基]甲基}-2-苯基-3,4-二氢喹唑啉-4-酮
1H NMR(400MHz,DMSO-d6)δ12.45(s,1H),8.16–8.10(m,2H),8.06(d,J＝8.1Hz,1H),7.61(s,1H),7.58–7.44(m,4H),7.41(dd,J＝8.2,1.6Hz,1H),4.49(s,1H),3.60(s,2H),3.47(t,J＝6.3Hz,2H),2.62(s,7H),2.66–2.45(m,10H).13C NMR(100MHz,Chloroform-d)δ167.43,157.44,153.17,149.23,136.87,135.57,132.83,131.99,131.76,131.50,130.26,123.80,66.23,63.68,61.86,56.90,56.12.ESI-MS m/z:365.1968[M+H]+.
实施例91、7-{[4-(4-硝基苯基)哌嗪-1-基]甲基}-2-苯基-3,4-二氢喹唑啉-4-酮
1H NMR(400MHz,DMSO-d6)δ12.53(s,1H),8.23–8.18(m,2H),8.15(d,J＝8.1Hz,1H),8.10–8.03(m,2H),7.72(d,J＝1.6Hz,1H),7.65–7.51(m,5H),7.07–7.01(m,2H),3.73(s,2H),3.51(t,J＝5.0Hz,4H),2.58(dd,J＝6.6,3.6Hz,4H).13C NMR(100MHz,DMSO-d6)δ162.69,155.09,152.78,145.43,137.67,131.57,128.84,128.12,127.50(d,J＝23.7Hz),126.27,126.00,112.96,62.15,52.68,46.96.ESI-MS m/z:442.1874[M+H]+.
实施例92、7-[(4-乙酰基哌嗪-1-基)甲基]-2-苯基-3,4-二氢喹唑啉-4-酮
1H NMR(400MHz,Chloroform-d)δ11.26(s,1H),8.33(dd,J＝8.1,1.8Hz,1H),8.28–8.22(m,2H),7.84(s,1H),7.63(dd,J＝4.9,2.6Hz,3H),7.56(d,J＝8.1Hz,1H),3.74(s,2H),3.69(d,J＝6.0Hz,2H),3.53(t,J＝5.0Hz,2H),2.54(d,J＝6.5Hz,4H),2.13(d,J＝1.8Hz,3H).13C NMR(100MHz,Methanol-d4)δ170.16,145.42,131.48,128.74,127.63,127.60,127.26,126.16,62.06,52.91,52.52,47.91,47.69,47.48,46.20,41.42,20.34.ESI-MS m/z:363.1823[M+H]+.
实施例93、7-[(4-{2-[(2-羟基乙基)氧基]乙基}哌嗪-1-基)甲基]-2-苯基-3,4-二氢喹唑啉-4-酮
1H NMR(400MHz,DMSO-d6)δ12.51(s,1H),8.23–8.17(m,2H),8.12(d,J＝8.1Hz,1H),7.67(d,J＝1.5Hz,1H),7.65–7.53(m,3H),7.48(dd,J＝8.2,1.6Hz,1H),3.66(s,2H),3.54(t,J＝5.8Hz,2H),3.50(t,J＝5.1Hz,2H),3.43(d,J＝5.1Hz,4H),2.65–2.54(m,4H),2.50–2.41(m,4H).13C NMR(100MHz,DMSO-d6)δ162.57,152.90,149.28,146.07,133.21,131.90,129.12,128.23,127.60(d,J＝13.6Hz),126.32,120.30,72.69,68.15,61.93,60.69,57.50,53.46,52.75.ESI-MS m/z:409.2237[M+H]+.
本发明产物的药理研究
(1)实施例化合物与MyD88蛋白的结合亲和力与浓度的关系
本实施例测试了实施例3化合物与MyD88蛋白的结合亲和力与浓度的关系。具体方法如下：利用标准氨基化学偶联法固定rh MyD88蛋白于CM7传感芯片表面，先20μg/mL蛋白溶于醋酸缓冲液(pH 5.5、5.0、4.5、4.0)以静电吸附作用预富集在CM7传感芯片(流速10μL/min)，再以100μL的0.05M NHS和0.2M EDC混合溶液活化，反应10min催化蛋白的氨基和芯片上的活性羧基基团交联。最后用150μL的1M盐酸乙醇胺封闭未反应的活性羧基基团并洗去非共价吸附的物质(蛋白偶联量至少25000RFU)。PBSP缓冲液冲洗直至基线稳定。取出CM7芯片备用。动力学测定时，实施例3化合物用PBSP(含5％DMSO)稀释50μM，分别注射到已固定rhMyD88的CM7传感芯片上，每次注射50μl，测定3次。每次测定后，用含10mM Gly-Hcl(pH 2.5)溶液再生传感芯片，然后进行下一次测定。实验结果用评估软件BIAevaluation评估其结合力。实验结果如图1所示，所测试的实施例3化合物可直接结合MyD88，其结合亲和力的Kd值为5.3×10-5M。
(2)实施例化合物抑制LPS刺激巨噬细胞释放炎症因子的量效关系
本实施例测试了部分活性实施例化合物抑制LPS刺激J774A.1小鼠巨噬细胞释放IL-6和TNF-α的量效关系。具体方法如下：1.2×106个小鼠巨噬细胞用DMEM培养液培养于37℃，24小时后更新培养液，并加入受测化合物(终浓度为10μM)预处理2h，再用0.5μg/mL的LPS继续处理22小时，收集培养液用ELISA法检测IL-6和TNF-α含量；收集细胞检测总蛋白浓度，ELISA结果用相应的总蛋白浓度相除较准，以LPS对照组的IL-6和TNF-α含量定标为100，计算平均值和误差值。实验结果如图2、图3所示，由图2可知，所测试的实施例化合物1、3、4、5、6、7、8、9、10、11、12、16、17、20、21、22、23、24、25、26、70、71、72、73、75、77、81、83、85、88对于IL-6的释放具有明显的抑制作用。由图3可知，所测试的实施例化合物1、3、4、5、6、7、8、9、10、11、12、16、17、20、21、22、23、24、25、26、70、71、72、73、75、77、81、83、85、88对于TNF-α的释放具有明显的抑制作用。这些实施例化合物都具有新颖的化合物骨架结构，也融入了具有优秀抗炎活性的片段，这突出表明了本发明通式结构的创新性所在。
(3)实施例化合物缓解由炎症引起的小鼠生理学变化
以缓解急性肺损伤所引起的生理学变化为例。用0.5％羧甲基纤维素钠与实施例化合物制成混悬液用于腹腔给药。各组小鼠乙醚麻醉后暴露气管，除对照组外，其余各组气管内缓慢滴入50μL 5mg/kg LPS，造成小鼠急性肺损伤，对照组以相同的方式滴入等量生理盐水，缝合伤口，建立急性肺损伤模型。动物造模24h后，按照5mL/kg的剂量腹腔注射10％的水合氯醛麻醉老鼠，开胸结扎左肺，右肺用1mL生理盐水进行支气管肺泡灌洗，收集灌洗液，相同操作重复3次。
肺泡灌洗液收集后，4℃1000rpm离心5分钟，取上清液，测肺泡灌洗液的蛋白浓度。肺泡灌洗液离心后，用50μL生理盐水重悬沉淀，混匀后取20μL用细胞计数仪Standard计数肺泡灌洗液中的总细胞数。此外，取右肺上叶，滤纸吸去组织上的水分后称取湿重，放入60℃烘烤48h以上，直到其重量不再发生变化为止，称取干重，计算肺组织湿重/干重比(W/D)，判断肺水肿程度。以实施例3化合物为例，实验数据见图4，其中3代表实施例3化合物，结果表明实施例化合物在生理学上可有效缓解小鼠急性肺损伤。
(4)实施例化合物缓解炎症引起的小鼠病理学变化试验
以缓解由急性肺损伤引起的小鼠肺组织病理学变化为例。实验数据见图5，正常对照组小鼠肺泡腔清晰，结构完整，壁光滑；气管滴注LPS造成急性肺损伤模型后，肺泡壁明显水肿、增厚，炎症细胞浸润增加；给予实施例3化合物治疗后细胞水肿、增厚显著减弱，且炎症细胞浸润明显减少，与正常组差别不大，说明实施例3化合物可有效缓解急性肺损伤中肺组织损伤。
(5)实施例化合物缓解炎症引起的小鼠生存率变化试验
以缓解脓毒血症所引起的小鼠生存率变化为例。用0.5％羧甲基纤维素钠与实施例3化合物制成混悬液用于腹腔给药。各组小鼠乙醚麻醉后暴露气管，除对照组外，其余各组腹腔注射20μL 20mg/kg LPS，造成小鼠脓毒血症，对照组以相同的方式注射等量生理盐水，建立脓毒血症模型。动物造模7天内，每日记录小鼠存活情况。实验数据见图6，结果表明实施例化合物可以有效降低脓毒血症引起的小鼠的死亡率。
(6)实施例化合物缓解炎症引起的小鼠脾脏病理学变化试验
以缓解由脓毒血症引起的小鼠脾脏组织病理学变化为例。实验数据见图7，正常对照组小鼠脾脏清晰，结构完整，白髓红髓分明；腹腔注射LPS造成脓毒血症模型后，小鼠脾脏肿大，白髓扩散；给予实施例3化合物治疗后脾脏肿大减少，白髓与正常组差别不大，说明实施例3化合物可有效缓解脓毒血症引起的脾脏损伤。
从上述试验结果可以清楚地看出，本发明所要保护的通式Ⅰ的化合物，具有良好的抗炎活性。
Claims (3)
1.一种髓样分化因子88抑制剂，其特征在于，为以下化合物及其药学上可接受的盐：
化合物1：N-(2-甲氧基吡啶-5-基)-3-硝基-4-[4-(嘧啶-2-基)哌嗪-1-基]苯磺酰胺
化合物2：4-(4-苄基哌嗪-1-基)-N-(2-甲氧基吡啶-5-基)-3-硝基苯磺酰胺
化合物3：N-(2-甲氧基吡啶-5-基)-3-硝基-4-{4-[(3-硝基苯基)甲基]哌嗪-1-基}苯磺酰胺
化合物4：N-(2-甲氧基吡啶-5-基)-3-硝基-4-{4-[(4-硝基苯基)甲基]哌嗪-1-基}苯磺酰胺
化合物5：4-{4-[(4-甲氧基苯基)甲基]哌嗪-1-基}-N-(2-甲氧基吡啶-5-基)-3-硝基苯磺酰胺
化合物6：N-(5-{[4-(4-{[(6-甲氧基吡啶-3-基)氨基]二氧亚基-λ6-硫基}-2-硝基苯基)哌嗪-1-基]甲基}-1,3-噻唑-2-基)乙酰胺
化合物7：N-(萘-1-基)-3-硝基-4-{4-[(3-硝基苯基)甲基]哌嗪-1-基}苯甲酰胺
化合物8：3-硝基-4-{4-[(3-硝基苯基)甲基]哌嗪-1-基}-N-(吡啶-2-基甲基)苯磺酰胺
化合物9：3-硝基-4-{4-[(4-硝基苯基)甲基]哌嗪-1-基}-N-(吡啶-2-基甲基)苯磺酰胺
化合物10：4-(4-苄基哌嗪-1-基)-3-硝基-N-(吡啶-2-基甲基)苯甲酰胺
化合物11：3-硝基-4-{4-[(4-硝基苯基)甲基]哌嗪-1-基}-N-(吡啶-2-基甲基)苯甲酰胺
化合物12：3-硝基-4-{4-[(3-硝基苯基)甲基]哌嗪-1-基}-N-(吡啶-2-基甲基)苯甲酰胺
化合物13：3-硝基-4-{4-[(3-硝基苯基)甲基]哌嗪-1-基}-N-苯基苯甲酰胺
化合物14：3-硝基-4-{4-[(4-硝基苯基)甲基]哌嗪-1-基}-N-苯基苯甲酰胺
化合物15：3-硝基-4-[4-(4-硝基苯基)哌嗪-1-基]-N-苯基苯甲酰胺
化合物16：2-(4-{2-硝基-4-[(苯基氨基)甲基]苯基}哌嗪-1-基)乙-1-醇
化合物17：4-[4-(2-甲氧基乙基)哌嗪-1-基]-3-硝基-N-苯基苯甲酰胺
化合物18：4-[4-(2-羟基乙基)哌嗪-1-基]-N-(6-甲氧基吡啶-3-基)-3-硝基苯磺酰胺
化合物19：4-[4-(2-甲氧基乙基)哌嗪-1-基]-N-(6-甲氧基吡啶-3-基)-3-硝基苯磺酰胺
化合物20：4-[4-(2-甲氧基乙基)哌嗪-1-基]-3-硝基-N-(吡啶-2-基甲基)苯磺酰胺
化合物21：4-[4-(2-羟基乙基)哌嗪-1-基]-3-硝基-N-(吡啶-2-基甲基)苯磺酰胺化合物24：3-硝基-4-{4-[(3-硝基苯基)甲基]哌嗪-1-基}-N-苯基苯磺酰胺
化合物25：3-硝基-4-{4-[(4-硝基苯基)甲基]哌嗪-1-基}-N-苯基苯磺酰胺
化合物26：3-硝基-4-[4-(4-硝基苯基)哌嗪-1-基]-N-苯基苯磺酰胺
化合物27：4-(4-苄基哌嗪-1-基)-3-硝基-N-(吡啶-2-基甲基)苯磺酰胺
化合物28：3-硝基-4-{4-[(3-硝基苯基)甲基]哌嗪-1-基}-N-(吡啶-2-基甲基)苯磺酰胺
化合物29：3-硝基-4-{4-[(4-硝基苯基)甲基]哌嗪-1-基}-N-(吡啶-2-基甲基)苯磺酰胺
化合物30：3-硝基-4-[4-(4-硝基苯基)哌嗪-1-基]-N-(吡啶-2-基甲基)苯磺酰胺
化合物31：4-{4-[(4-甲氧基苯基)甲基]哌嗪-1-基}-3-硝基-N-(吡啶-2-基甲基)苯磺酰胺
化合物32：3-硝基-N-(吡啶-2-基甲基)-4-[4-(嘧啶-2-基)哌嗪-1-基]苯磺酰胺
化合物33：N-(5-{[4-(4-{二氧亚基[(吡啶-2-基甲基)氨基]-λ6-硫基}-2-硝基苯基)哌嗪-1-基]甲基}-1,3-噻唑-2-基)乙酰胺。
2.权利要求1所述髓样分化因子88抑制剂在制备治疗炎症相关疾病的药物制剂中的应用。
3.根据权利要求2所述的应用，其特征在于，所述炎症相关疾病包含急性肺损伤和/或脓毒血症。
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| CN102166214A (zh) * | 2011-03-02 | 2011-08-31 | 华中科技大学同济医学院附属同济医院 | 氨基噻唑类MyD88特异性抑制剂在医学上的用途 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102166214A (zh) * | 2011-03-02 | 2011-08-31 | 华中科技大学同济医学院附属同济医院 | 氨基噻唑类MyD88特异性抑制剂在医学上的用途 |
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