本发明属医药领域，涉及新型喹啉-2(1h)酮哌嗪类化合物的设计合成及其在抗微生物方面的应用。
背景技术：
：：喹诺酮化合物具有优良的抗菌活性以来，成千上万的喹诺酮衍生物已被合成。喹诺酮是喹啉生物碱家族的一部分，是一类重要的杂环化合物，代表着一类具有广谱生物活性的化合物，如在抗癌、抗细菌、抗真菌、抗疟药、抗病毒]等方面给人印像深刻。喹啉-2-(1h)酮的结构存在于许多合成化合物和天然产物中，具有广泛的药物活性。哌嗪及其取代衍生物是应用较为成功的药效片段之一，这已被目前临床使用的药物所证明，通常，化合物具有哌嗪部分都能显示出一定的药理活性，如抗菌剂、抗抑郁药、抗肿瘤、抗惊厥药、抗病毒、抗疟疾和潜在的抗精神病药物，这类化合物的研究文章可见：bioorg.med.chem.2006,14:2859-2868；arch.pharm.chem.life.sci.2009,342:405-411；bioorg.med.chem.lett.2013,23:3225-3229；j.med.chem.2010,53:7076-7094；j.nat.prod.2005,6:1397-1399；curr.med.chem.2001,8:371-384；med.chem.2011,19:7281-7298。这些文献均未覆盖或包括本发明所涉及的新型化合物的结构、合成方法和用途。本发明设计并合成了一类喹啉-2(1h)酮哌嗪类化合物，以多氧霉素b为对照，测定了该类化合物对几丁质合成酶的抑制作用，并测定了其在抗真菌、抗细菌方面的活性，拓展了喹诺酮的应用范围。到目前为止，本发明所涉及的新型化合物在抑制几丁质合成酶活性方面还未见报道，所以可将其作为几丁质合成酶的抑制剂，开发成新型的抗真菌制剂，为人类的健康做出贡献。技术实现要素：综上所述，本发明的目的在于设计合成一类新的喹啉-2(1h)酮哌嗪类化合物，从中筛选出几丁质合成酶抑制活性和抗真菌活性较好的化合物，并提供这些化合物简单易行的制备方法及其在抗微生物领域中的应用。本发明的具体内容如下：喹啉-2(1h)酮哌嗪类化合物，所述化合物的结构通式i所示：其中，r1,r2基团分别为：氢，1-5个碳原子的直链或支键烷基；3-8个碳原子组成的环烷基与杂环基；芳香基；或者与n原子组成5-8元杂环或芳杂环等，上述物质是分别对应一个结构式的具体化合物，这是本领域技术人员公知的。进一步说明，通式ⅰ所示的化合物中r1,r2为氢和下述基团中的任意一种：或者r1,r2与n组成下列基团：但并不限于所举例子。上述化合物的合成方法，按如下进行，如scheme1所示scheme1：化合物1的合成路线上述scheme1反应条件如下：a)5-氨基-3,4-二氢喹啉-2(1h)酮（化合物2）与二乙醇胺或者二-(2-溴乙基)胺氢溴酸盐在氢氧化钾中溶液于加热反应3小时得到化合物3;b)将化合物3与碘化钾，四叔丁基溴化胺，溶解在氢氧化钠水溶液，再加入环氧氯丙烷，反应4小时，待反应进行完全后，得膏状白色固体，用乙酸乙酯结晶，过滤，干燥，得白色粉末状固体，即化合物4;c)将化合物4、通式1中所述的各种氨基化合物，混合均匀后加热至呈熔融状，搅拌反应0.5小时。冷却，过柱得无色油状液体。油状物经浓盐酸酸化后，用甲醇-丙酮混合溶剂重结晶，得1a~1w。具体地在步骤a中，化合物2与二乙醇胺或者二-（2-溴乙基）胺盐的摩尔比为1:1-3，最适宜的比值为1:1-1.4，加热温度为50-100℃，优选75-85℃，氢氧化钾溶液浓度为10-15%，用量为化合物2的2-3倍。在步骤b中，反应温度为20-50℃，优选25-30℃。在步骤c中，反应温度为熔融状态，不用额外添加溶剂。本领域普通技术人员均可按上述公开的制备方法制得相应的化合物。上述化合物可作为几丁质合成酶抑制剂应用，也可作为抗病原微生物药物应用。所述微生物为病原细菌或病原真菌，如大肠杆菌、金黄色葡萄球菌、耐甲氧西林金黄色葡萄球菌、枯草杆菌、变形杆菌、铜绿色假单胞菌；白色念珠菌、新型隐球菌、黄曲霉菌、烟曲霉菌等。具体实施方式为了加深对本发明的理解，下面将结合实施例对本发明作进一步详述，该实施例仅用于解释本发明，并不构成对本发明保护范围的限定，本领域的技术人员根据本发明的上述内容作出的一些非本质的改进和调整均属于本发明的保护范围。所有使用的试剂都是商业购买的分析纯或化学纯，如未说明则未经过特殊处理。反应进度通过薄层色谱监控，在紫外灯254nm处显色，部分用碘和浓硫酸显色。熔点使用x-6熔点测定仪测定。核磁共振氢谱和碳谱使用brukerav300核磁共振仪测定，使用的氘代试剂有dmso-d6，cdcl3和d2o，内含内标物质tms。化学位移δ单位为ppm，偶合常数j单位为hz，s、d、t、q、m分别表示单峰、两重峰、三重峰、四重峰和多重峰。质谱使用shimadzulc-ms-2010a/ev测试。实施例一5-(派嗪-1-基)-3,4-二氢喹啉-2(1h)酮(2)依次向40ml水中加入5-氨基-3,4-二氢喹啉-2(1h)酮7(5.00g,30.83mmol)，二-(2-溴乙基)胺氢溴酸盐(50.57g,33.91mmol)，搅拌升温至80°c，半小时内分三批滴加氢氧化钾(1.90g,33.91mmol,10ml)的水溶液。加完毕后将反应升温至100°c，再保温反应3小时。待反应完毕后，冷却至室温，过滤，滤液用10%的氢氧化钾水溶液调ph为10，析出大量白色固体。抽滤，用适量水洗涤，干燥，得白色粉末状固体8（6.4g，收率61%，mp235-237°c）;1hnmr(300mhz,dmso-d6)δ:10.01(s,1h,quinolin,-conh-),7.07(t,j=7.9hz,1h,quinolin-h7),6.65(d,j=8.0hz,1h,quinolin-h8),6.58(d,j=7.8hz,1h,quinolin-h6),3.94(s,1h,nh),2.82-2.94(m,4h,quinolin-h4and-ch2-),2.67-2.84(m,6h,-ch2-),2.35(t,j=7.3hz,2h,quinolin-h3);13cnmr(75mhz,dmso-d6)δ:170.59,150.18,139.44,127.33,117.62,112.55,110.18,51.34,46.73,30.16,20.38;lc-ms(esi):m/z232[m+h]+.实施例二5-(4-(环氧乙烷-2-基-甲基)派嗪-1-基)-3,4-二氢喹啉-2(1h)酮(3)依次向氢氧化钠水溶液(1.4g,34.88mmol,26ml)中加入5-(派嗪-1-基)-3,4-二氢喹啉-2(1h)酮8(6.2g,29.07mmol)，碘化钾(0.12g,0.73mmol)，四叔丁基溴化胺(0.24g,0.73mmol)，室温搅拌至溶解完全，再加入环氧氯丙烷(5.38g,58.14mmol)，搅拌约10分钟后析出白色胶状固体。室温搅拌反应4小时，待反应进行完全后，得膏状白色固体沉于瓶低。除去上层水层，加入乙酸乙酯结晶，过滤，干燥，得白色粉末状固体9（5.3g，收率64%，mp184-186°c）;1hnmr(300mhz,dmso-d6)δ:10.02(s,1h,quinolin,-conh-),7.08(t,j=7.9hz,1h,quinolin-h7),6.69(d,j=7.9hz,1h,quinolin-h8),6.60(d,j=7.8hz,1h,quinolin-h6),3.05(m,1h,ch),2.76-2.87(m,6h,-ch2-),2.52-2.74(m,6h,-ch2-),2.47(m,1h,-ch2-),2.36(t,j=7.3hz,2hquinolin-h3),2.26(m,1h,-ch2-);13cnmr(75mhz,cdcl3)δ:172.74,150.86,138.28,127.67,117.86,113.95,111.31,61.03,53.91,51.61,50.23,44.88,30.51,20.59;lc-ms(esi):m/z288[m+h]+.实施例三5-(4-(2-羟基-3-((4-甲氧苯基)氨基)丙基)哌嗪-1-基)-2-氧代-1,2,3,4-四氢喹啉盐酸盐（1a）将5-(4-(环氧乙烷-2-基-甲基)派嗪-1-基)-3,4-二氢喹啉-2(1h)酮9(0.20g,0.7mmol)、对甲氧基苯胺(0.17g,1.4mmol)混合均匀后加热至90°c至反应呈熔融状，搅拌反应0.5小时。冷却，过柱得无色油状液体。油状物经浓盐酸酸化后，用甲醇-丙酮混合溶剂重结晶，得白色粉末状固体10a（收率75%，mp258-261°c）;1hnmr(300mhz,cdcl3)δ:7.99(s,1h,quinolin,-conh-),7.17(t,j=7.9hz,1h,quinolin-h7),6.80(m,3h,quinolin-h8andar-h2,h6),6.65(d,j=8.8hz,2h,ar-h3,h5),6.55(d,j=7.8hz,1h,quinolin-h6),4.05(m,1h,nh),3.77(s,3h,ch3o-),3.17-3.34(m,1h,ch),2.78-3.14(m,10h,-ch2-),2.36-2.76(m,6h,-ch2-);13cnmr(75mhz,dmso-d6)δ:170.53,150.66,143.28,139.15,127.28,117.33,114.59,113.19,112.79,111.01,110.66,66.42,62.69,55.30,53.89,51.53,49.18,30.26,20.32;lc-ms(esi):m/z411[m+h]+.按照实验例三相同的方法，可制备1b-1w各种化合物：1b;(收率69%,mp261-263°c);1hnmr(300mhz,dmso-d6)δ:10.09(s,1h,quinolin,-conh-),7.11(t,j=7.9hz,1h,quinolin-h7),6.92-7.05(m,2h,ar-h4,h5),6.82-6.93(m,2h,ar-h3,h6),6.69(d,j=8.2hz,1h,quinolin-h8),6.65(d,j=8.0hz,1h,quinolin-h6),4.38(m,1h,nh),3.82(s,3h,ch3o-),3.62-3.74(m,1h,ch),2.99-3.59(m,12h,-ch2-),2.82(t,j=7.3hz,2h,quinolin-h4),2.36(t,j=7.3hz,2h,quinolin-h3);13cnmr(75mhz,dmso-d6)δ:170.37,149.60,149.11,139.36,137.23,127.48,121.02,119.54,117.35,112.78,111.61,111.50,110.17,62.73,59.24,55.91,51.83,50.54,48.06,30.11,20.16;lc-ms(esi):m/z411[m+h]+.1c;(收率72%,mp223-225°c);1hnmr(300mhz,dmso-d6)δ:10.10(s,1h,quinolin,-conh-),7.22-7.43(m,4h,ar-h3,h4,h5andquinolin-h7),7.11(m,2h,ar-h2,h6),6.67(t,j=7.1hz,2h,quinolin-h6,h8),4.44(s,1h,nh),2.96-3.83(m,13h,-ch2-),2.82(t,j=7.1hz,2h,quinolin-h4),2.36(t,j=7.0hz,2h,quinolin-h3);13cnmr(75mhz,dmso-d6)δ:170.36,149.11,140.77,139.37,129.51,127.49,124.20,119.25,117.57,112.91,111.52,62.48,59.15,52.82,51.88,48.04,30.11,20.16;lc-ms(esi):m/z381[m+h]+.1d;(收率70%,mp241-243°c);1hnmr(300mhz,cdcl3)δ:9.51(s,1h,quinolin,-conh-),7.14(t,j=7.9hz,1h,quinolin-h7),7.01(d,j=7.4hz,2h,ar-h3,h5),6.84(t,j=7.4hz,1h,ar-h4),6.76(d,j=8.0hz,1h,quinolin-h8),6.64(d,j=7.8hz,1h,quinolin-h6),3.89-4.01(m,1h,nh),3.70(m,2h,chandoh),2.74-3.11(m,10h,-ch2-),2.40-2.70(m,6h,-ch2-),2.34(s,6h,-ch3);13cnmr(75mhz,cdcl3)δ:172.40,150.39,145.48,137.92,129.27,128.43,127.34,121.59,117.50,113.61,111.06,65.76,61.06,53.27,51.56,51.43,30.15,20.25,18.09;lc-ms(esi):m/z409[m+h]+.1e;(收率68%,mp261-264°c);1hnmr(300mhz,dmso-d6)δ:10.10(s,1h,quinolin,-conh-),7.34(d,j=7.6hz,2h,ar-h3,h5),7.24(d,j=7.9hz,2h,ar-h2,h6),7.10(t,j=7.8hz,1h,quinolin-h7),6.67(t,j=6.9hz,2h,quinolin-h6,h8),4.46(s,1h,nh),3.00-3.75(m,13h,-ch2-andch),2.82(t,j=6.9hz,2h,quinolin-h4),2.35(t,j=6.9hz,2h,quinolin-h3),2.28(s,3h,-ch3);13cnmr(75mhz,dmso-d6)δ:170.37,149.10,139.36,135.87,130.06,127.49,123.40,121.24,117.56,112.89,111.52,61.92,58.93,53.22,51.89,48.02,30.11,20.53,20.15;lc-ms(esi):m/z395[m+h]+.1f;(收率62%,mp259-262°c);1hnmr(300mhz,cdcl3)δ:9.15(s,1h,quinolin,-conh-),7.14(m,2h,ar-h3,andquinolin-h7),7.07(d,j=7.2hz,1h,ar-h6),6.77(d,j=8.0hz,1h,quinolin-h8),6.69(t,j=7.5hz,1h,ar-h4),6.63(m,2h,ar-h5,andquinolin-h6),3.99-4.19(m,1h,nh),3.62(s,2h,-ch2-),3.27-3.41(m,1h,ch),3.14(dd,j=12.4,6.4hz,1h,-ch2-),2.74-3.02(m,8h,-ch2-),2.45-2.72(m,6h,-ch2-),2.18(s,3h,-ch3);13cnmr(75mhz,cdcl3)δ:172.19,150.38,145.85,137.86,129.75,127.36,126.68,122.18,117.53,116.85,113.64,111.00,109.52,64.89,61.37,53.21,51.40,47.29,30.14,20.25,17.19;lc-ms(esi):m/z395[m+h]+.1g;(收率59%,mp191-194°c);1hnmr(300mhz,cdcl3)δ:8.98(s,1h,quinolin,-conh-),7.97-7.86(m,1h,naphthalen-h8),7.75-7.83(m,1h,naphthalen-h5),7.40-7.49(m,2h,naphthalen-h4,h7),7.35(t,j=7.8hz,1h,quinolin-h7),7.26(d,j=8.1hz,1h,naphthalen-h2),7.15(t,j=8.0hz,1h,naphthalen-h3),6.77(d,j=8.0hz,1h,quinolin-h8),6.56-6.65(m,2h,quinolin-h6andnaphthalen-h6),4.26(s,1h,nh),2.97-3.73(m,13h,-ch2-),2.85(t,j=7.1hz,2h,quinolin-h4),2.33(t,j=7.0hz,2h,quinolin-h3);13cnmr(75mhz,cdcl3)δ:172.19,150.26,143.19,137.75,133.89,128.18,127.40,126.12,125.39,124.34,123.37,119.83,117.55,117.30,113.74,111.06,104.14,64.79,61.51,53.23,51.15,47.51,30.08,20.19;lc-ms(esi):m/z431[m+h]+.1h;(收率65%,mp193-195°c);1hnmr(300mhz,cdcl3)δ:8.87(s,1h,quinolin,-conh-),7.24(d,j=8.6hz,2h,ar-h3,h5),7.14(t,j=7.9hz,1h,quinolin-h7),6.76(d,j=8.0hz,1h,quinolin-h8),6.59(d,j=7.8hz,1h,quinolin-h6),6.51(d,j=8.6hz,2h,ar-h2,h6),4.25(s,1h,nh),4.00(m,1h,ch),2.98-3.25(m,10h,-ch2-),2.39-2.68(m,6h,-ch2-);13cnmr(75mhz,cdcl3)δ:172.00,150.38,146.94,137.81,131.49,127.36,117.54,114.25,113.64,110.92,108.72,64.73,61.07,52.17,51.42,47.13,30.12,20.24;lc-ms(esi):m/z459[m+h]+.1i;(收率63%,mp221-223°c);1hnmr(300mhz,dmso-d6)δ:10.09(s,1h,quinolin,-conh-),7.23(d,j=8.5hz,2h,ar-h3,h5),7.10(t,j=7.9hz,1h,quinolin-h7),6.94(d,j=8.6hz,2h,ar-h2,h6),6.67(m,2h,quinolin-h6,h8),4.32(s,1h,nh),2.97-3.80(m,13h,-ch2-andch),2.81(t,j=6.9hz,2h,quinolin-h4),2.35(t,j=6.9hz,2h,quinolin-h3);13cnmr(75mhz,dmso-d6)δ:170.38,149.07,142.97,139.34,129.03,127.48,124.45,118.00,117.54,112.90,111.52,63.00,59.33,52.77,51.76,48.03,30.10,20.15;lc-ms(esi):m/z415[m+h]+.1j;(收率67%,mp175-177°c);1hnmr(300mhz,cdcl3)δ:9.03(s,1h,quinolin,-conh-),7.25(d,j=7.3hz,1h,ar-h3),7.14(t,j=7.7hz,2h,quinolin-h7andar-h5),6.76(d,j=8.0hz,1h,quinolin-h8),6.69(d,j=8.7hz,1h,quinolin-h6),6.51-6.65(m,2har-h4,h6),4.79(s,1h,nh),3.97-4.31(m,1h,oh),3.25-3.40(m,1h,-ch2-),3.09-3.23(m,1h,-ch2-),2.73-3.03(m,9h,-ch2-),2.43-2.72(m,6h,-ch2-);13cnmr(75mhz,cdcl3)δ:172.13,150.38,143.72,137.82,131.41,128.80,127.36,122.39,119.14,117.52,117.03,113.66,110.97,64.84,61.28,53.24,51.39,46.98,30.13,20.23;lc-ms(esi):m/z415[m+h]+.1k;（收率53%,mp177-180°c）;1hnmr(300mhz,dmso-d6)δ:10.12(s,1h,quinolin,-conh-),9.21(s,1h,imidazol-h2),7.74(d,j=36.9hz,2h,imidazol-h4,h5),7.08(t,j=7.5hz,1h,quinolin-h7),6.48-6.74(m,2h,quinolin-h6,h8),4.49(m,2h,-ch2-),4.27(m,1h,ch),2.94-3.74(m,11h,-ch2-),2.80(t,j=6.9hz,2h,quinolin-h4),2.33(t,j=6.9hz,2h,quinolin-h3);13cnmr(75mhz,dmso-d6)δ:170.38,149.04,139.33,135.79,127.46,122.75,119.39,117.56,112.91,111.56,64.01,58.36,52.51,51.90,48.02,30.09,20.14;lc-ms(esi):m/z356[m+h]+.1l（收率42%,mp192-195°c）;1hnmr(300mhz,dmso-d6)δ:10.01(s,1h,quinolin,-conh-),8.42(s,1h,triazol-h2),7.93(s,1h,triazol-h5),7.05(t,j=7.9hz,1h,quinolin-h7),6.66(d,j=8.0hz,1h,quinolin-h8),6.59(d,j=7.8hz,1h,quinolin-h6),4.24-4.37(m,1h,ch),4.05-4.18(m,1h,oh),3.91-4.04(m,2h,-ch2-),2.67-2.88(m,6h,-ch2-andquinolin-h4),2.49-2.66(m,4h,-ch2-),2.22-2.42(m,4h,quinolin-h3and-ch2-);13cnmr(75mhz,dmso-d6)δ:170.58,151.08,150.61,144.74,139.11,127.29,117.33,112.80,110.70,66.35,61.61,53.73,53.47,51.42,30.23,20.29;lc-ms(esi):m/z357[m+h]+.1m;（收率75%,mp240-243°c）;1hnmr(300mhz,d2o)δ:7.03(t,j=8.0hz,1h,quinolin-h7),6.71(d,j=8.0hz,1h,quinolin-h8),6.48(d,j=7.8hz,1h,quinolin-h6),4.33(t,j=9.1hz,1h,ch),3.58(m,2h,-ch2-),2.81-3.41(m,11h,-ch2-),2.62(t,j=7.3hz,2h,quinolin-h4),2.20(t,j=7.3hz,2h,quinolin-h3),1.24(s,9h,-ch3);13cnmr(75mhz,d2o)δ:174.12,147.98,136.95,127.61,117.84,114.23,112.10,61.24,58.27,57.43,53.57,47.78,43.91,28.72,24.26,19.16;lc-ms(esi):m/z361[m+h]+.1n;（收率72%,mp265-268°c）;1hnmr(300mhz,dmso-d6)δ:10.10(s,1h,quinolin,-conh-),7.11(t,j=7.9hz,1h,quinolin-h7),6.67(t,j=8.1hz,2h,quinolin-h6,h8),4.52(m,1h,ch),2.90-3.76(m,16h,-ch2-,nhandoh),2.73-2.85(m,2h,quinolin-h4),2.36(t,j=7.1hz,2h,quinolin-h3),1.63(m,2h,-ch2-),1.31(m,2h,-ch2-),0.87(t,j=7.3hz,3h,-ch3);13cnmr(75mhz,dmso-d6)δ:170.37,149.12,139.36,127.49,117.56,112.90,111.51,61.39,58.76,52.72,50.03,48.02,46.76,30.11,27.26,20.15,19.39,13.59;lc-ms(esi):m/z361[m+h]+.1o;(收率82%,mp228-230°c);1hnmr(300mhz,dmso-d6)δ:10.01(s,1h,quinolin,-conh-),7.05(t,j=7.8hz,1h,quinolin-h7),6.66(d,j=8.0hz,1h,quinolin-h8),6.58(d,j=7.8hz,1h,quinolin-h6),3.69(m,1h,ch),2.78(m,6h,-ch2-),2.10-2.66(m,14h,-ch2-),0.92(t,j=6.9hz,6h,-ch3);13cnmr(75mhz,dmso-d6)δ:170.50,150.68,139.15,127.25,117.31,112.73,110.65,66.13,62.81,57.72,53.85,51.54,47.13,30.26,20.31,11.87;lc-ms(esi):m/z361[m+h]+.1p;（收率82%,mp228-230°c）;1hnmr(300mhz,dmso-d6)δ:10.01(s,1h,quinolin,-conh-),7.05(t,j=7.8hz,1h,quinolin-h7),6.66(d,j=8.0hz,1h,quinolin-h8),6.58(d,j=7.8hz,1h,quinolin-h6),3.69(m,1h,ch),2.78(m,6h,-ch2-),2.10-2.66(m,14h,-ch2-),0.92(t,j=6.9hz,6h,-ch3);13cnmr(75mhz,dmso-d6)δ:170.50,150.68,139.15,127.25,117.31,112.73,110.65,66.13,62.81,57.72,53.85,51.54,47.13,30.26,20.31,11.87;lc-ms(esi):m/z361[m+h]+.1q;(收率66%,mp280-283°c);1hnmr(300mhz,dmso-d6)δ:10.11(s,1h,quinolin,-conh-),7.25(d,j=8.5hz,2h,ar-h3,h5,),7.12(t,j=7.9hz,1h,quinolin-h7),6.87(d,j=8.4hz,2h,ar-h2,h6),6.72(d,j=7.8hz,1h,quinolin-h8),6.59(d,j=7.8hz,1h,quinolin-h6),4.51(s,1h,oh),4.14(s,2h,ar-ch2-),3.34-3.77(m,7h,-ch2-andch),2.71-3.09(m,7h,-ch2-),2.87(t,j=7.2hz,2h,quinolin-h4),2.31(t,j=7.2hz,2h,quinolin-h3);13cnmr(75mhz,dmso-d6)δ:170.74,150.36,139.44,137.21,133.61,129.56,128.44,127.58,117.69,112.17,110.33,60.47,58.51,51.82,49.44,48.62,47.38,30.18,20.23;lc-ms(esi):m/z429[m+h]+.1r;(收率75%,mp258-261°c);1hnmr(300mhz,dmso-d6)δ:10.02(s,1h,quinolin,-conh-),7.08(t,j=7.9hz,1h,quinolin-h7),6.68(d,j=7.9hz,1h,quinolin-h8),6.60(d,j=7.8hz,1h,quinolin-h6),4.31(s,1h,oh),3.82(m,1h,ch),3.27-3.67(m,5h,-ch2-),2.80(m,6h,-ch2-),2.59(m,3h,-ch2-),2.11-2.47(m,10h,-ch2-);13cnmr(75mhz,dmso-d6)δ:170.51,150.66,139.14,127.27,117.32,112.77,110.65,66.27,65.15,63.37,62.86,54.02,53.77,51.48,30.25,20.31;lc-ms(esi):m/z375[m+h]+.1s;(收率71%,mp229-232°c);1hnmr(300mhz,dmso-d6)δ:10.09(s,1h,quinolin,-conh-),7.09(t,j=7.9hz,1h,quinolin-h7),6.70(d,j=8.0hz,1h,quinolin-h8),6.62(d,j=7.8hz,1h,quinolin-h6),3.81(m,1h,ch),3.39-3.76(m,8h,-ch2-andoh),2.75-2.90(m,6h,-ch2-),2.69(d,j=3.9hz,4h,-ch2-),2.27-2.48(m,8h,-ch2-andnh);13cnmr(75mhz,dmso-d6)δ:170.56,150.67,139.13,127.26,117.31,112.77,110.66,65.07,63.72,62.96,54.60,53.78,51.50,45.44,30.25,20.31;lc-ms(esi):m/z374[m+h]+.1t;(收率64%,mp221-223°c);1hnmr(300mhz,dmso-d6)δ:10.02(s,1h,quinolin,-conh-),7.08(t,j=7.9hz,1h,quinolin-h7),6.68(d,j=7.9hz,1h,quinolin-h8),6.60(d,j=7.8hz,1h,quinolin-h6),3.81(m,1h,ch),3.25-3.72(m,2h,-ch2-),2.70-2.90(m,6h,-ch2-),2.18-2.70(m,13h,-ch2-andoh),1.43-1.56(m,4h,piperidine-h3,h5),1.31-1.42(m,2h,piperidine-h4);13cnmr(75mhz,dmso-d6)δ:170.49,150.67,139.14,127.26,117.32,112.76,110.66,65.06,63.53,62.95,54.62,53.79,51.51,30.26,25.51,23.90,20.32;lc-ms(esi):m/z373[m+h]+.1u;(收率75%,mp255-258°c);1hnmr(300mhz,dmso-d6)δ:10.03(s,1h,quinolin,-conh-),7.08(t,j=7.8hz,1h,quinolin-h7),6.68(d,j=7.9hz,1h,quinolin-h8),6.61(d,j=7.7hz,1h,quinolin-h6),3.65-3.83(m,1h,ch),2.75-2.96(m,6h,-ch2-),2.65-2.75(m,4h,-ch2-),2.18-2.64(m,11h,-ch2-),1.46-1.67(m,8h,azepane-h3,h4,h5,h6);13cnmr(75mhz,dmso-d6)δ:170.48,150.66,139.14,127.25,117.30,112.74,110.66,65.81,62.76,62.13,55.37,53.84,51.51,30.26,27.56,26.61,20.32;lc-ms(esi):m/z387[m+h]+.1v;(收率54%,mp189-192°c);1hnmr(300mhz,dmso-d6)δ:10.01(s,1h,quinolin,-conh-),7.08(t,j=7.9hz,1h,quinolin-h7),6.69(d,j=7.9hz,1h,quinolin-h8),6.60(d,j=7.8hz,1h,quinolin-h6),4.42(s,3h,oh),3.63-3.77(m,1h,ch),3.29-3.54(m,5h,-ch2-),2.71-289(m,6h,-ch2-),2.51-2.70(m,8h,-ch2-),2.19-2.45(m,5h,-ch2-);13cnmr(75mhz,dmso-d6)δ:170.52,150.68,139.13,127.27,117.32,112.76,110.63,66.31,62.44,60.08,59.22,57.55,53.88,51.44,30.25,20.31;lc-ms(esi):m/z393[m+h]+.1w;(收率65%,mp233-236°c);1hnmr(300mhz,dmso-d6)δ:10.102(s,1h,quinolin,-conh-),7.13(t,j=7.9hz,1h,quinolin-h7),6.71(d,j=7.9hz,1h,quinolin-h8),6.63(d,j=7.8hz,1h,quinolin-h6),3.79(m,1h,ch),3.19-3.68(m,2h,-ch2-),2.72-2.85(m,6h,-ch2-),2.19-2.66(m,13h,-ch2-andoh),1.52-1.64(m,4h,piperidine-h3,h4),1.31-1.42(m,2h,piperidine-h4);13cnmr(75mhz,dmso-d6)δ:170.43,150.43,138.72,127.24,117.47,112.77,110.79,65.15,63.44,62.61,54.68,53.49,51.27,30.16,26.53,20.03;lc-ms(esi):m/z359[m+h]+.实施例四，几丁质合成酶活性抑制实验几丁质合成酶来源于啤酒酵母细胞膜，酶与底物在微孔板上一起孵化反应，产生的几丁质与板上包被的wga结合在一起而被固定，然后加入wga-hrp，wga-hrp可与固定在板上的几丁质结合，将多余的试剂用蒸馏水洗掉，然后使用tmb底物溶液检测hrp的活性，使用2m的硫酸终止反应后在450nm处检测其od，计算出化合物的ic50值。化合物1a-1w都进行了几丁质合成酶抑制活性初筛，初筛的最高药物浓度为300μg/ml，抑制率（ip,inhibitionpercentage）为该最高药物浓度对几丁质合成酶的抑制率，对几丁质合成酶抑制活性较好的化合物进一步测试其ic50值，初筛结果和ic50值如表1所示。表1所测化合物药物浓度为300μg/ml时的chs抑制率和部分化合物的ic50值table1thechsinhibitionpercentageandic50valuesofthetestcompounds实施例五，化合物抗真菌实验本发明的化合物用dmso溶解后，用高压灭菌的蒸馏水制成溶液备用，将96孔板，西林瓶，枪头等物品高压灭菌，用移液枪移取稀释好的菌液溶液100ul到96孔板中，用氧氟沙星，链霉素；氟康唑，多氧霉素b作为参比对照。目标化合物1a-1w都进行了体外抗真菌活性筛选，其数据见表2。表2.化合物1a-w的体外抗真菌活性数据table2invitroantifungalactivityofcompounds1a-1w实施例六，化合物抗细菌实验所有合成的目标化合物1a~1w都进行了体外抗细菌活性筛选，其数据见表3。表3化合物1a~1w的体外抗细菌活性数据table3invitroantibacterialactivityofcompounds1a-1w当前第1页12当前第1页12