选择性雌激素受体下调剂化合物、制备方法及用途

1.本发明涉及药物化学领域，具体的是，涉及一类选择性雌激素受体下调剂化合物、制备方法及用途。


背景技术：

2.雌激素在蛋白质合成、凝血、脂质平衡、液体平衡、黑色素、胃肠道功能、肺功能、认知、免疫反应和心脏疾病中发挥作用。雌激素受体(er)是配体激活的转录调节蛋白，其通过与内源雌激素(包括17β-雌二醇和雌酮类)的相互作用来介导多种生物学效应的诱导。er已发现具有erα和erβ两种亚型，且两种亚型都参与雌性生殖道的调控和发育。er和雌激素通过几种不同的途径调节生物过程。经典途径涉及配体激活的er与雌激素反应元件(ere)的特定dna序列基序的结合。药物开发的目标是通过作为拮抗剂或激动剂发挥作用或者作为部分拮抗剂或部分激动剂发挥作用来调节雌激素活性的新化合物。fulvestrant是没有激动剂活性的完全雌激素受体拮抗剂的实例，它是选择性雌激素受体下调剂(serd)，由imperial chemical industries(ici)在u.s.专利no.4,659,516中公开且由astra zeneca以商品名faslodex销售。它用于在抗雌激素治疗后具有疾病进展的绝经后妇女中治疗激素受体阳性转移性乳腺癌。fulvestrant具有有限的水溶性且只能肌肉(tm)注射，不能口服给药。患者依从性差，临床使用受到限制。另一类抗雌激素是选择性雌激素受体调节剂(serms)，其以基因特异性或组织特异性的方式作为拮抗剂或激动剂发挥作用。serm治疗的目标是提供有利的靶向抗雌激素活性且避免不利的脱靶效应或表现出附带的有利雌激素副作用(j med chem2020,63,15094-15114.)。serm的实例是它莫西芬，最初由astrazeneca以商品名nolvadex销售，也由ici在u.s.专利no.4,659,516中公开。(也参见u.s.专利no.6,774,122和7,456,160)。它莫西芬用于乳腺癌治疗后的进一步乳腺癌及在乳房切除术和放疗后治疗妇女的淋巴结阳性乳腺癌。它莫西芬可以影响骨健康，在绝经前妇女中可以引起骨质减少(bone thinning)，在绝经后妇女中可能对于骨健康是有利的。其严重的副作用包括增加绝经后妇女中患有子宫癌风险和患有扩散到骨的乳腺癌的妇女中的“肿瘤爆发(tumor flares)”。除了这些副作用外，获得性的抗药性也是一个问题，在一些情况中，er阳性乳腺癌不仅变成它莫西芬耐药性的，而且它莫西芬变成诱导肿瘤增殖的激动剂。乳腺癌的三线治疗包括甾体和非甾体芳香酶抑制剂(ais)，其阻断雌激素的产生且因此阻断er依赖性的生长。这些药物(其包括来曲唑、阿那曲唑和依西美坦)具有从更年期后妇女体内除去所有雌激素的风险，从而增加骨质减少、骨质疏松和骨折的风险(j med chem 2019,62,11301-11323.)
3.已经公开了多种serd、serm和ai。serm雷洛昔芬由elililly在1981年(u.s.专利no.4,418,068；5,478,847；5,393,763和5,457，117)公开用于预防乳腺癌和治疗骨质疏松。在2011年六月，aragon pharmaceuticals公开了苯并吡喃衍生物和阿考比芬类似物用于治疗它莫西芬耐药性乳腺癌(参见w02011/156518，us专利no.8，455，534和8，299，112)。genentech在us2016/0175289中公开了具有雌激素受体调节活性的一系列四氢吡啶并[3,
4-b]吲哚-1-基化合物且在us2015/0258080中公开了三种化合物(其中之一gdn-0810)用于雌激素受体调节的联合疗法。astrazeneca目前正在开发azd9496,一种用于雌激素受体阳性乳腺癌患者的新型的口服选择性雌激素受体下调剂(wo 2014/191726)。考虑到雌激素调控障碍(包括癌症、肿瘤和特别地乳腺癌)的通常灾难性的影响，仍然存在着对于产生具有显著的抗雌激素效力而没有不可接受的副作用的新药的强烈需求。


技术实现要素：

[0004]
针对上述问题，本发明提供了一种新型的选择性雌激素受体下调剂化合物(serd)。
[0005]
本发明的另一目的是提供了所述选择性雌激素受体下调剂化合物的制备方法及用途。
[0006]
本发明的技术方案是：本发明公开了选择性雌激素受体下调剂化合物，其特征在于，所述化合物的化学结构式如式(i)所示：
[0007][0008]
式中：
[0009]
m是0、1、2、3或4；n是0、1、2、3或4；
[0010]
x选自-o-、-ch
2-、-s-、-nr
17
、-chf-、-cf
2-和环烷基；y选自-c(o)-、-cf
2-、环烷基、-ch
2-和-chf-；
[0011]
环b选自苯基，二联苯基、萘基、喹啉基、5-或6-元单环杂芳基、环烷基或者7-、8-、9-或10-元双环杂环基；环a选自苯基、杂芳基、苯硫基、5-或6-元单环杂芳基、环烷基或者7-、8-、9-或10-元双环杂环基；
[0012]
r1选自-ch＝chcoor
17
、-nr
17
(co)coor
17
、-coor
17
、环烷基-coor
17
、-c
2-c6亚烯基-coor
17
、-c
2-c6亚炔基-coor
17
、-ch＝chc(o)r
16
、-cooh、-nh(co)cooh、-ch＝chcooh、-nr
17
(co)c(o)r
16
、-c(o)r
16
、-环烷基-c(o)r
16
、-c
2-c6亚烯基-c(o)r
16
和-c
2-c6亚炔基-c(o)r
16
；
[0013]
r2和r3选自-or
15
、-sr
15
、-n(r
15
)2、氢、芳基、杂芳基、卤素、-cn、-no2、卤代烷基、环烷基、硫醇基、亚硝基、c
1-c6烷基、羟基、-o(c
1-c6烷基)、-o(c
1-c6氟烷基)、-sf5、-b(oh)2、-b(or
15
)2、-c(o)or
15
、-c(o)r
16
、-c(s)r
16
、-oso2or
15
、-oso2r
16
、-nhso2or
15
、-nhso2r
16
、-n(烷基)so2or
15
、-n(烷基)so2r
16
、-op(o)(or
15
)2、-op(o)(r
16
)2、-p(o)(or
15
)3、-p(o)(r
16
)3、-p(o)or
15
、-p(o)r
16
、-so2r
16
、-so2or
15
、炔、烯、芳基烷基、芳氧基、杂芳基烷基和c
1-c6氟烷基；
[0014]
其中，r
15
在每次出现时独立地选自氢、烷基、烯基、炔基、环烷基、芳基、芳基烷基、杂芳基和杂芳基烷基；r
16
在每次出现时独立地选自-n(r
15
)2、-sr
15
、-or
15
；r
17
在每次出现时独立地选自氢、烷基、烯基、炔基、环烷基、芳基、-c(o)r
15
、-c(s)r
15
、-c(o)r
16
、-c(s)r
16
和杂芳基。
[0015]
进一步的，所述r1选自-cooh、-nh(co)cooh或-ch＝chcooh。
[0016]
进一步的，所述环a是苯基或、5-或6-元单环杂芳基。
[0017]
进一步的，所述环b是苯基、二联苯基、萘基或喹啉基。
[0018]
进一步的，所述的化合物为如下任一种：
[0019][0020]
进一步的，其具体合成路线如下：
[0021]
合成路线1：
[0022][0023]
合成线2：
[0024][0025]
进一步的，一种药物组合物，其含有治疗有效量为所述的选择性雌激素受体下调剂化合物及药学上可接受的载体。
[0026]
进一步的，所述的选择性雌激素受体下调剂化合物在制备治疗雌激素相关障碍疾病中的用途。
[0027]
进一步的，在所述的用途中，所述雌激素相关障碍疾病为乳腺癌、卵巢癌、子宫内膜癌、前列腺癌、肺癌、已经转移至骨的癌症或骨损失；所述乳腺癌为激素受体阳性转移性乳腺癌、它莫西芬耐药性乳腺癌或三阴性乳腺癌。
[0028]
本发明中的周期蛋白依赖性激酶(cdk)4/6抑制剂属于一类新的药物，通过抑制细胞周期的进展来中断恶性细胞的增殖。palbociclib、ribociclib和abemaciclib这三种抑制剂最近被批准用于各种环境和联合方案的乳腺癌治疗。基于其令人印象深刻的疗效，所有三种cdk4/6抑制剂现在在治疗hr+，her2-乳腺癌患者中发挥重要作用。
[0029]
在所述的与cdk4/6联合给药方案中，包括单不限于palbociclib、ribociclib和abemaciclib这三种抑制剂。
[0030]
本发明的有益效果是：本发明公开的化合物是可口服的雌激素受体下调剂，其活性实现了纳摩尔级别，对于乳腺癌等肿瘤的防止具有非常显著的效果。
附图说明
[0031]
图1是本发明实施例中蛋白质印迹分析图；
[0032]
图2是本发明实施例中免疫荧光分析图；
[0033]
图3本发明实施例中显示化合物10和21组与fulvestrant和tamoxifen组及对照组对mcf-7细胞中通过对ere荧光素酶转录活性影响的条形图，y-轴是相关ere荧光素酶转录活性，x-轴是化合物10和21组与fulvestrant和tamoxifen组及对照组；
[0034]
图4是本发明实施例中显示化合物10和21诱导mcf-7细胞周期g0/g1期阻滞的曲线图，y-轴是mcf-7细胞数目，和x-轴是细胞周期的区域范围，经10和21处理24h后，收集mcf-7细胞，用pi染色，流式细胞术分析，与对照组dmso比较，*p《0.05，**p《0.01；
[0035]
图5是本发明实施例中显示化合物10和21对er信号通路的影响的条形图，y-轴是mcf-7细胞中greb1、pgr、tff1基因的表达，x-轴是细胞个周期的区域范围不同浓度化合物处理，n＝3,ns》0.05，*p《0.05，**p《0.01，***p《0.001；
[0036]
图6是本发明实施例中显示化合物10进行了体内pk研究的曲线图，y-轴是小鼠血液中化合物10的浓度，x-轴是所对应的时间，对在体外试验中表现出最佳抗增殖特性的化合物10进行了完整的pk(包括静脉注射5mg/kg和口服给药20mg/kg)；
[0037]
图7是本发明实施例中显示化合物对照组、10组、21组、fulvestrant组、ribociclib组、fulvestrant+ribociclib组、10+ribociclib组、21+ribociclib组对小鼠移植瘤体积和小鼠体重的实物图和直方图，及口服对照组、化合物10组、21组、fulvestrant组、ribociclib组、fulvestrant+ribociclib组、10+ribociclib组、21+ribociclib组随时间变化小鼠肿瘤体积和荷瘤小鼠重量的曲线图；7a是30天给药后小鼠乳腺癌肿瘤实物图，7b图y-轴是小鼠体重，x-轴是时间；7c和7d图y-轴是小鼠移植肿瘤体积和肿瘤重量，x-轴是所对应对照组、化合物10组、21组、fulvestrant组、ribociclib组、fulvestrant+ribociclib组、10+ribociclib组、21+ribociclib组；7e图y-轴是小鼠移植肿瘤体积，x-轴是时间，用游标卡尺测量肿瘤长径(a)和短径(b)，肿瘤体积按以下公式计算:v＝1/2
×a×
b2，当平均肿瘤体积达到100mm3左右时，将小鼠随机分为8组(每组n＝8)，命名为:对照组、fulvestrant组、10组、21组、ribociclib组、fulvestrant+ribociclib组、10+ribociclib组、21+ribociclib组；fulvestrant组小鼠每周单次皮下注射fulvestrant 250mg/kg；10组小鼠每天口服10 60mg/kg；21组小鼠每天灌胃21 60mg/kg；小鼠每天口服ribociclib 60mg/kg。fulvestrant+ribociclib组小鼠每天口服ribociclib 60mg/kg，每周给予单次皮下注射fulvestrant 250mg/kg；10+ribociclib组小鼠每天口服10 60mg/kg和ribociclib 60mg/kg。21+ribociclib组小鼠每天口服21和ribociclib60mg/kg；在给药30天内，每5天记录小鼠体重和肿瘤体积；
[0038]
图8是本发明实施例中显示对小鼠心肝脾肺肾组织影响的he染色切片，选取心脏、肝脏、脾脏、肾脏和大鼠子宫进行组织学检查，解剖组织，石蜡包埋，切片(6μm厚)，切片用苏木精和伊红染色(h&e)；
[0039]
图9是本发明实施例中显示对照组、fulvestrant组、10组、21组、ribociclib组、fulvestrant+ribociclib组、10+ribociclib组、21+ribociclib组对小鼠肿瘤组织中ki67、er和pr的表达影响的曲线图，图9a，9b、9c中折线图图y-轴是小鼠肿瘤组织中ki67、er和pr的表达指数，x-轴是对照组、fulvestrant组、10组、21组、ribociclib组、fulvestrant+ribociclib组、10+ribociclib组、21+ribociclib组，*p《0.05，**p《0.01；
[0040]
图10是本发明实施例中显示化合物10和21组与雌激素组和fulvestrant组及对照组对雌性大鼠幼鼠子宫内膜影响的h&e染色图和立方图，10a是h&e染色图，10b图y-轴是雌
性大鼠幼鼠子宫湿重占体重的比例，x-轴是化合物10和21组与雌激素组和fulvestrant组及对照组。
具体实施方式
[0041]
为了更清楚地说明本发明的技术方案，下面对本发明的技术方案做进一步的详细说明：
[0042][0043]
下表为反应路线1合成的中间体种类：
[0044]
[0045][0046]
合成步骤1
[0047]
中间体1：7-(苄氧基)-4-羟基喹啉-3-甲酸乙酯
[0048]
中间体1的合成步骤：将三苄氧基苯胺(2g，10.00mmol)置于100ml圆底烧瓶中，再加入乙氧基甲叉丙二酸二乙酯(3.256g，15.00mmol)，油浴120℃，反应2h，用分水器除去生成的乙醇；再加入25ml的二苯醚，升温至250℃，反应5h，tlc监测反应终点；反应结束后待反应液冷却加入40ml正己烷，有固体析出，抽滤，滤饼用乙醇洗，干燥得褐色固体，产率51.4％。1h nmr(500mhz,dmso-d6)δ12.12(s,1h),8.47(d,j＝4.5hz,1h),8.06(d,j＝9.6hz,1h),7.49(d,j＝7.2hz,2h),7.42(t,j＝7.4hz,2h),7.36(t,j＝7.3hz,1h),7.10
–
7.06(m,2h),5.22(s,2h),4.19(q,j＝7.0hz,2h),1.27(t,j＝7.1hz,3h).
[0049][0050]
合成步骤2
[0051]
中间体2：7-(苄氧基)-4-氯喹啉-3-甲酸乙酯
[0052]
中间体2的合成步骤：将化合物1(1g，3.09mmol)加入100ml圆底烧瓶中，再加入6ml甲苯，以及socl2(11g，92.77mmol)，1ml dmf，升温至70℃，回流8h，tlc监测反应终点；反应结束后待反应液冷却，将反应液滴加到冰水混合物中除去多余的socl2，再用dcm萃取3次；收集有机相，用无水硫酸钠干燥后减压蒸干，硅胶柱层析分离得黄色固体，产率58.7％。1h nmr(500mhz,dmso-d6)δ9.10(s,1h),8.30(d,j＝9.2hz,1h),7.63(d,j＝2.6hz,1h),7.58
–
7.51(m,4h),7.43(t,j＝7.5hz,3h),7.37(t,j＝7.3hz,2h),5.36(s,2h),4.41(q,j＝7.1hz,3h),1.38(t,j＝7.1hz,4h).
13
c nmr(126mhz,cdcl3)δ164.49,161.86,151.31,150.96,143.87,135.72,128.79,128.46,127.84,126.97,121.99,121.53,120.84,108.73,77.32,77.07,76.81,70.79,61.99,14.35.
[0053][0054]
合成步骤3
[0055]
中间体3：(7-(苄氧基)-4-氯喹啉-3-基)甲醇
[0056]
中间体3的合成步骤：将化合物2(620mg，1.81mmol)加入100ml圆底烧瓶中，再加入6ml无水thf，搅拌均匀；在冰浴的条件下滴加1mol/l的二异丁基氢化铝(5.44ml，5.44mmol)；滴加完毕之后常温搅拌20分钟，tlc监测反应终点；反应完毕之后在冰浴的条件下往反应液中加入饱和酒石酸钾钠水溶液，搅拌过夜，分解铝盐；反应液用ea萃取3次，收集有机相，用无水硫酸钠干燥后减压蒸干，硅胶柱层析分离得黄色固体，产率86.4％。1h nmr(500mhz,dmso-d6)δ8.89(s,1h),8.12(d,j＝9.2hz,1h),7.56(d,j＝2.6hz,1h),7.52(d,j＝7.4hz,3h),7.47(dd,j＝9.3,2.5hz,1h),7.42(t,j＝7.5hz,2h),7.36(t,j＝7.3hz,1h),5.57(t,j＝5.7hz,1h),5.31(s,2h),4.77(d,j＝5.6hz,2h).
13
c nmr(126mhz,chloroform-d)δ160.43,150.69,150.17,141.03,136.17,128.94,128.84,128.44,127.88,125.42,121.48,121.38,108.54,70.48,61.07.
[0057][0058]
合成步骤4
[0059]
中间体4：7-(苄氧基)-4-氯喹啉-3-甲醛
[0060]
中间体4的合成步骤：将化合物3(450mg，1.50mmol)加入100ml圆底烧瓶中，再加入6ml无水dcm，搅拌均匀；冰浴条件下缓慢加入dess-martin氧化剂(1.27g，3.00mmol)，后常温反应20分钟；tlc监测反应终点，反应完毕之后在冰浴的条件下往反应液中加入饱和碳酸氢钠水溶液除去过量的氧化剂以及醋酸；反应液用dcm萃取3次，收集有机相，用无水硫酸钠干燥后减压蒸干，硅胶柱层析分离得黄色固体，产率87％。1h nmr(500mhz,dmso-d6)δ10.49(s,1h),9.08(s,1h),8.33(d,j＝9.3hz,1h),7.65(d,j＝2.5hz,1h),7.58(dd,j＝9.3,2.6hz,1h),7.53(d,j＝7.1hz,2h),7.43(t,j＝7.5hz,2h),7.37(t,j＝7.3hz,1h),5.38(s,2h).
13
c nmr(126mhz,chloroform-d)δ188.97,163.03,152.99,149.42,147.89,135.65,128.93,128.65,127.89,126.66,123.10,122.26,120.78,109.39,70.85.
[0061][0062]
合成步骤1-5
[0063]
中间体1-5-a-q的合成步骤：
[0064]
将环a的br代芳烃6.72mmol加入干燥后的50ml圆底烧瓶中，再依次加入6ml无水thf，mg粉(163.2mg，6.72mmol)，催化量的碘单质，在n2保护的条件下，升温至80℃，回流3h；
反应液冷却后，在冰浴条件下，将反应液缓慢滴加到化合物4(400mg，1.34mmol)的无水thf溶液中，滴加完之后常温反应10分钟；tlc监测反应终点，反应完毕之后在冰浴的条件下往反应液中加入1m稀盐酸除去过量的mg粉及mg盐；反应液用ea萃取3次，收集有机相，用无水硫酸钠干燥后减压蒸干，硅胶柱层析分离得黄色固体或油状物。
[0065]
中间体1-5-a：(7-(苄氧基)-4-氯喹啉-3-基)(苯基)甲醇
[0066]1h nmr(500mhz,dmso-d6)δ8.97(s,1h),8.12(d,j＝9.3hz,1h),7.55(d,j＝2.6hz,1h),7.51(d,j＝7.3hz,3h),7.47(dd,j＝9.2,2.6hz,1h),7.44
–
7.39(m,9h),7.37
–
7.29(m,3h),7.24(t,j＝7.3hz,1h),6.40(d,j＝4.2hz,1h),6.25(d,j＝4.1hz,1h),5.31(s,2h).
13
cnmr(126mhz,chloroform-d)δ160.48,149.93,149.79,142.06,140.17,136.19,131.72,128.86,128.84,128.43,128.20,127.86,126.76,125.66,121.45,121.24,108.64,71.94,70.51.
[0067]
以下中间体利用合适的起始原料通过步骤1-5类似的过程制备：
[0068]
中间体1-5-b：(7-(苄氧基)-4-氯喹啉-3-基)(3-氟苯基)甲醇
[0069]1h nmr(500mhz,dmso-d6)δ8.94(s,1h),8.13(d,j＝9.3hz,1h),7.56(d,j＝2.6hz,1h),7.51(d,j＝7.2hz,2h),7.48(dd,j＝9.2,2.6hz,1h),7.41(t,j＝7.4hz,2h),7.38
–
7.32(m,2h),7.28(d,j＝10.2hz,1h),7.21(d,j＝7.7hz,1h),7.09(td,j＝8.5,2.7hz,1h),6.53(d,j＝4.4hz,1h),6.27(d,j＝4.3hz,1h).
13
c nmr(126mhz,chloroform-d)δ163.10(d,j＝246.4hz),160.64,149.81,149.73,144.67(d,j＝6.1hz),140.31,136.12,131.42,130.36(d,j＝8.2hz),128.85,128.45,127.86,125.71,122.21(d,j＝2.7hz),121.62,121.16,114.99(d,j＝21.1hz),113.69(d,j＝22.4hz),108.52,71.11,70.54.
[0070]
中间体1-5-c：(7-(苄氧基)-4-氯喹啉-3-基)(4-氟苯基)甲醇
[0071]1h nmr(500mhz,chloroform-d)δ8.99(s,1h),8.10(d,j＝9.2hz,1h),7.51
–
7.46(m,3h),7.44
–
7.38(m,4h),7.37
–
7.33(m,2h),7.02(t,j＝8.7hz,2h),6.42(s,1h),5.19(s,2h).
13
c nmr(126mhz,chloroform-d)δ162.49(d,j＝247.0hz),160.62,149.66,149.60,140.25,137.84(d,j＝3.1hz),136.12,131.65,128.85,128.53(d,j＝8.2hz),128.46,127.87,125.65,121.63,121.20,115.72(d,j＝21.6hz),108.47,71.26,70.55.
[0072]
中间体1-5-d：(7-(苄氧基)-4-氯喹啉-3-基)(2-(三氟甲基)苯基)甲醇
[0073]1h nmr(500mhz,chloroform-d)δ8.85(s,1h),8.07(d,j＝9.2hz,1h),7.68(d,j＝7.8hz,1h),7.54
–
7.49(m,2h),7.47
–
7.43(m,3h),7.42
–
7.35(m,3h),7.35
–
7.29(m,2h),6.74(s,1h),5.16(s,2h).
13
c nmr(126mhz,chloroform-d)δ160.62,149.78,149.70,141.11,140.11,136.10,132.40,130.78,129.06,128.77,128.37,128.30,127.82,126.47,126.42,125.60,121.58,121.39,108.19,70.46,67.75.
[0074]
中间体1-5-e：(7-(苄氧基)-4-氯喹啉-3-基)(4-(三氟甲基)苯基)甲醇
[0075]1h nmr(500mhz,dmso-d6)δ8.94(s,1h),8.13(d,j＝9.3hz,1h),7.70(d,j＝8.3hz,2h),7.65(d,j＝8.2hz,2h),7.56(d,j＝2.6hz,1h),7.51(d,j＝7.3hz,2h),7.48(dd,j＝9.2,2.6hz,1h),7.41(t,j＝7.5hz,2h),7.35(t,j＝7.3hz,1h),6.62(d,j＝4.3hz,1h),6.34(d,j＝4.1hz,1h),5.31(s,2h).
13
c nmr(126mhz,dmso-d6)δ159.79,150.24,149.31,147.83,140.49,138.18,136.43,132.15,128.51,128.03,127.85,127.18,125.35,125.31,125.25,121.23,120.01,109.13,69.74,69.51.
[0076]
中间体1-5-f：(7-(苄氧基)-4-氯喹啉-3-基)(4-(三氟甲氧基)苯基)甲醇
[0077]1h nmr(500mhz,chloroform-d)δ8.93(s,1h),8.06(d,j＝9.3hz,1h),7.47(d,j＝7.9hz,5h),7.40(t,j＝7.4hz,2h),7.37
–
7.30(m,2h),7.17(d,j＝8.3hz,2h),6.43(s,1h),5.16(s,2h).
13
c nmr(126mhz,chloroform-d)δ160.65,149.67,149.60,148.86,140.77,140.26,136.09,131.60,128.84,128.46,128.14,127.86,125.65,121.65,121.21,121.12,108.37,70.93,70.53.
[0078]
中间体1-5-g：(7-(苄氧基)-4-氯喹啉-3-基)(4-甲氧基苯基)甲醇
[0079]1h nmr(500mhz,chloroform-d)δ9.06(s,1h),8.09(d,j＝9.2hz,1h),7.52
–
7.46(m,3h),7.40(t,j＝7.4hz,2h),7.37
–
7.31(m,4h),6.86(d,j＝8.8hz,2h),6.37(s,1h),5.18(s,2h),3.77(s,3h).
13
c nmr(126mhz,chloroform-d)δ160.42,159.45,149.75,149.67,140.04,136.21,134.31,131.97,128.83,128.42,128.19,127.88,125.58,121.41,121.28,114.20,108.51,71.63,70.50,55.42.
[0080]
中间体1-5-h：(7-(苄氧基)-4-氯喹啉-3-基)(噻吩-2-基)甲醇
[0081]1h nmr(500mhz,chloroform-d)δ9.08(s,1h),8.10(d,j＝9.2hz,1h),7.52
–
7.46(m,3h),7.41(t,j＝7.4hz,2h),7.37
–
7.32(m,2h),7.29
–
7.26(m,1h),6.95
–
6.92(m,2h),6.65(s,1h),5.19(s,2h).
13
c nmr(126mhz,chloroform-d)δ160.62,149.82,149.50,146.12,140.12,136.15,131.38,128.85,128.45,127.88,127.00,125.93,125.69,125.32,121.57,121.12,108.53,70.54,68.28.
[0082]
中间体1-5-i：苯并呋喃-5-基(7-(苄氧基)-4-氯喹啉-3-基)甲醇
[0083]1h nmr(500mhz,chloroform-d)δ9.11(s,1h),8.05(d,j＝9.3hz,1h),7.64(s,1h),7.58(s,1h),7.55(s,1h),7.45(d,j＝7.5hz,2h),7.43
–
7.30(m,7h),6.69(d,j＝2.2hz,1h),6.50(s,1h),5.15(s,2h).
13
c nmr(126mhz,chloroform-d)δ160.78,154.63,148.99,145.80,136.73,136.03,132.49,131.18,128.80,128.43,127.93,127.77,125.64,123.43,121.80,121.39,119.72,111.72,107.52,106.84,71.94,70.59.
[0084]
中间体1-5-j：(7-(苄氧基)-4-氯喹啉-3-基)(2-乙基苯基)甲醇
[0085]1h nmr(500mhz,chloroform-d)δ8.83(s,1h),8.09(d,j＝9.2hz,1h),7.50
–
7.45(m,3h),7.43
–
7.35(m,4h),7.33(dd,j＝9.2,2.5hz,1h),7.29
–
7.17(m,3h),6.59(s,1h),5.15(s,2h),2.79
–
2.58(m,2h),1.19(t,j＝7.5hz,3h).
13
c nmr(126mhz,chloroform-d)δ160.50,150.36,149.81,141.89,140.84,138.99,136.19,131.32,128.99,128.82,128.45,128.42,127.89,126.74,126.36,125.61,121.47,121.28,108.44,70.49,68.73,27.05,15.18.
[0086]
中间体1-5-k：(7-(苄氧基)-4-氯喹啉-3-基)(2-异丙基苯基)甲醇
[0087]1h nmr(500mhz,chloroform-d)δ8.82(s,1h),8.10(d,j＝9.2hz,1h),7.52
–
7.45(m,3h),7.41(t,j＝7.4hz,2h),7.38
–
7.28(m,5h),7.18(t,j＝7.9hz,1h),6.68(s,1h),5.16(s,2h),3.27(p,j＝6.8hz,1h),1.29(d,j＝6.7hz,3h),1.06(d,j＝6.8hz,3h).
13
c nmr(126mhz,chloroform-d)δ160.49,150.45,149.87,146.82,140.67,138.02,136.16,131.47,128.84,128.67,128.44,127.91,126.66,126.20,126.07,125.62,121.49,121.26,108.47,70.49,68.62,28.67,24.52,23.74.
[0088]
中间体1-5-l：(7-(苄氧基)-4-氯喹啉-3-基)(2，6-二甲基苯基)甲醇
[0089]1h nmr(500mhz,chloroform-d)δ9.01(s,1h),8.11(d,j＝9.3hz,1h),7.50
–
7.46(m,3h),7.43
–
7.39(m,2h),7.37
–
7.32(m,2h),7.14
–
7.10(m,1h),7.02(d,j＝7.6hz,2h),6.58(s,1h),5.18(s,2h),2.31(s,6h).
13
c nmr(126mhz,chloroform-d)δ160.30,150.50,149.64,140.41,137.10,136.83,136.11,130.73,129.65,128.71,128.30,128.26,127.77,125.22,121.36,121.27,108.34,70.38,69.69,21.24.
[0090]
中间体1-5-m：(7-(苄氧基)-4-氯喹啉-3-基)(3，5-二甲基苯基)甲醇
[0091]1h nmr(500mhz,chloroform-d)δ9.07(s,1h),8.03(d,j＝9.2hz,1h),7.57(d,j＝2.5hz,1h),7.49(d,j＝7.2hz,2h),7.41(t,j＝7.3hz,2h),7.38
–
7.35(m,1h),7.30(dd,j＝9.2,2.5hz,1h),7.05(s,2h),6.88(s,1h),6.33(s,1h),5.16(s,2h),2.27(s,6h).
13
c nmr(126mhz,chloroform-d)δ160.50,149.36,141.96,141.19,138.26,137.48,136.08,132.48,129.66,128.72,128.34,127.91,125.54,124.54,123.92,121.48,107.50,71.52,70.47,21.41.
[0092]
中间体1-5-n：(7-(苄氧基)-4-氯喹啉-3-基)(2，4-二甲基苯基)甲醇
[0093]1h nmr(500mhz,chloroform-d)δ8.93(s,1h),8.11(d,j＝9.2hz,1h),7.61(d,j＝2.5hz,1h),7.49(d,j＝7.2hz,2h),7.40(t,j＝7.3hz,2h),7.37
–
7.32(m,2h),7.19(d,j＝7.7hz,1h),7.01
–
6.96(m,2h),6.49(s,1h),5.21(s,2h),2.32(s,3h),2.29(s,3h).
13
c nmr(126mhz,chloroform-d)δ160.71,149.66,141.45,137.99,136.61,136.13,135.85,131.73,128.82,128.43,128.03,127.94,127.13,126.65,125.63,121.71,121.42,107.83,70.60,69.11,21.16,19.26.
[0094]
中间体1-5-o：(7-(苄氧基)-4-氯喹啉-3-基)(4氟-2-甲基苯基)甲醇
[0095]1h nmr(500mhz,chloroform-d)δ8.75(s,1h),8.02(d,j＝9.3hz,1h),7.49
–
7.45(m,2h),7.43
–
7.38(m,3h),7.38
–
7.34(m,1h),7.33
–
7.27(m,2h),6.87
–
6.81(m,2h),6.41(s,1h),5.11(s,2h),4.80(s,1h),2.24(s,3h).
13
c nmr(126mhz,chloroform-d)δ162.23(d,j＝246.3hz),160.57,149.87,149.39,141.08,138.36(d,j＝8.0hz),136.06,135.59(d,j＝2.8hz),131.02,128.79,128.42,128.34(d,j＝8.5hz),127.88,125.55,121.59,121.16,117.45(d,j＝21.2hz),112.92(d,j＝20.9hz),107.94,70.45,68.40,19.29.
[0096]
中间体1-5-p：(7-(苄氧基)-4-氯喹啉-3-基)(4-氯-2甲基苯基)甲醇
[0097]1h nmr(500mhz,chloroform-d)δ8.76(s,1h),8.09(d,j＝9.3hz,1h),7.52
–
7.46(m,3h),7.40(t,j＝7.4hz,2h),7.37
–
7.30(m,3h),7.18
–
7.14(m,2h),6.45(s,1h),5.18(s,2h),2.25(s,3h).
13
c nmr(126mhz,chloroform-d)δ160.74,149.78,149.57,141.44,141.29,138.14,137.78,136.07,133.77,130.70,130.55,128.84,128.47,128.03,126.49,125.66,121.77,121.25,108.14,70.56,68.69,19.18.
[0098]
中间体1-5-q：(7-(苄氧基)-4-氯喹啉-3-基)(4氟-2，6-二甲基苯基)甲醇
[0099]1h nmr(500mhz,chloroform-d)δ9.00(s,1h),8.12(d,j＝9.3hz,1h),7.51(d,j＝2.5hz,1h),7.49(d,j＝7.1hz,2h),7.41(t,j＝7.4hz,2h),7.38
–
7.33(m,2h),6.74(d,j＝9.3hz,2h),6.54(s,1h),5.20(s,2h),2.31(s,6h).
13
c nmr(126mhz,chloroform-d)δ161.99(d,j＝246.6hz),160.58,150.24,149.68,144.40,139.86(d,j＝8.2hz),136.16,132.84(d,j＝3.3hz),130.55,128.86,128.46,127.88,125.36,121.59,121.47,116.13(d,j＝20.5hz),108.41,70.57,69.28,21.51(d,j＝1.6hz).
[0100][0101]
合成步骤1-6
[0102]
中间体1-6-a-q的合成步骤：
[0103]
将1-5-a-q(1.02mmol)加到100ml圆底烧瓶中，加入6ml的无水dcm，搅拌均匀；冰浴条件下缓慢加入dess-martin氧化剂(2.04mmol)，后常温反应20分钟；tlc监测反应终点，反应完毕之后在冰浴的条件下往反应液中加入饱和碳酸氢钠水溶液除去过量的氧化剂以及醋酸；反应液用dcm萃取3次，收集有机相，用无水硫酸钠干燥后减压蒸干，硅胶柱层析分离得黄色固体或油状物。
[0104]
中间体1-6-a：(7-(苄氧基)-4-氯喹啉-3-基)(苯基)甲酮
[0105]1h nmr(500mhz,chloroform-d)δ8.77(s,1h),8.24(d,j＝9.2hz,1h),7.86(d,j＝7.7hz,2h),7.64(t,j＝7.4hz,1h),7.60(d,j＝2.5hz,1h),7.53
–
7.47(m,4h),7.47
–
7.41(m,3h),7.37(t,j＝7.4hz,1h),5.27(s,2h).
13
c nmr(126mhz,chloroform-d)δ193.69,161.39,151.17,149.15,140.36,136.77,135.89,134.06,130.12,129.28,128.86,128.81,128.44,127.76,126.09,122.11,120.97,109.01,70.56.
[0106]
中间体1-6-b：(7-(苄氧基)-4-氯喹啉-3-基)(3-氟苯基)甲酮
[0107]1h nmr(500mhz,chloroform-d)δ8.76(s,1h),8.22(d,j＝9.2hz,1h),7.60
–
7.56(m,3h),7.50(d,j＝7.1hz,2h),7.47
–
7.40(m,4h),7.39
–
7.30(m,2h),5.26(s,2h).
13
c nmr(126mhz,chloroform-d)δ192.58(d,j＝2.4hz),162.98(d,j＝248.9hz),161.64,151.37,149.03,140.61,138.96(d,j＝6.4hz),135.87,130.60(d,j＝7.7hz),128.87,128.75,128.52,127.82,126.18,126.10(d,j＝3.0hz),122.35,121.15(d,j＝21.5hz),120.95,116.47(d,j＝22.6hz),109.05,70.66.
[0108]
中间体1-6-c：(7-(苄氧基)-4-氯喹啉-3-基)(4-氟苯基)甲酮
[0109]1h nmr(500mhz,chloroform-d)δ8.75(s,1h),8.23(d,j＝9.2hz,1h),7.92
–
7.84(m,2h),7.57(d,j＝2.5hz,1h),7.51(d,j＝7.1hz,2h),7.48
–
7.41(m,3h),7.37(t,j＝7.3hz,1h),7.17(t,j＝8.6hz,2h),5.27(s,2h).
13
c nmr(126mhz,chloroform-d)δ192.24,166.46(d,j＝257.0hz),161.58,151.30,149.02,140.41,135.92,133.30(d,j＝3.0hz),132.92(d,j＝9.6hz),129.10,128.91,128.56,127.86,126.17,122.35,121.02,116.24(d,j＝22.1hz),109.06,70.69.
[0110]
中间体1-6-d：(7-(苄氧基)-4-氯喹啉-3-基)(2-(三氟甲基)苯基)甲酮
[0111]1h nmr(500mhz,chloroform-d)δ8.93(s,1h),8.24(d,j＝9.3hz,1h),7.84(d,j＝7.7hz,1h),7.69
–
7.59(m,2h),7.54(d,j＝2.5hz,1h),7.51
–
7.40(m,6h),7.37(t,j＝7.3hz,1h),5.26(s,2h).
13
c nmr(126mhz,chloroform-d)δ193.36,162.31,152.14,151.31,143.19,139.00,135.79,131.95,131.24,129.15,128.92,128.60,127.87,127.40,127.36,127.25,126.95,124.68,122.31,121.12,109.10,70.76.
[0112]
中间体1-6-e：(7-(苄氧基)-4-氯喹啉-3-基)(4-(三氟甲基)苯基)甲酮
[0113]1h nmr(500mhz,chloroform-d)δ8.79(s,1h),8.23(d,j＝9.2hz,1h),7.96(d,j＝
8.1hz,2h),7.76(d,j＝8.2hz,2h),7.61(d,j＝2.5hz,1h),7.51(d,j＝7.3hz,2h),7.47(dd,j＝9.3,2.5hz,1h),7.43(t,j＝7.4hz,2h),7.37(t,j＝7.3hz,1h),5.28(s,2h).
13
c nmr(126mhz,chloroform-d)δ192.90,151.44,149.09,140.95,139.71,135.84,130.35,128.92,128.59,128.47,127.87,126.26,126.03,126.00,122.56,120.96,108.99,70.75.
[0114]
中间体1-6-f：(7-(苄氧基)-4-氯喹啉-3-基)(4-(三氟甲氧基)苯基)甲酮
[0115]1h nmr(500mhz,chloroform-d)δ8.76(s,1h),8.23(d,j＝9.2hz,1h),7.91(d,j＝8.8hz,2h),7.58(d,j＝2.6hz,1h),7.51(d,j＝7.1hz,2h),7.48
–
7.40(m,3h),7.37(t,j＝7.3hz,1h),7.32(d,j＝8.3hz,2h),5.27(s,2h).
13
c nmr(126mhz,chloroform-d)δ192.30,161.68,153.41,151.45,149.06,140.51,135.92,135.07,132.21,128.92,128.82,128.57,127.85,126.19,122.41,121.44,120.99,120.61,109.15,70.72.
[0116]
中间体1-6-g：(7-(苄氧基)-4-氯喹啉-3-基)(4-甲氧基苯基)甲酮
[0117]1h nmr(500mhz,chloroform-d)δ8.74(s,1h),8.23(d,j＝9.2hz,1h),7.83(d,j＝8.8hz,2h),7.57(d,j＝2.6hz,1h),7.51(d,j＝7.1hz,2h),7.46
–
7.40(m,3h),7.37(t,j＝7.2hz,1h),6.96(d,j＝8.9hz,2h),5.26(s,2h),3.89(s,3h).
13
c nmr(126mhz,chloroform-d)δ192.18,164.54,161.32,151.06,149.09,140.08,136.01,132.73,129.86,129.77,128.89,128.52,127.85,126.11,122.13,121.13,114.24,109.04,70.64,55.74.
[0118]
中间体1-6-h：(7-(苄氧基)-4-氯喹啉-3-基)(噻吩-2-基)甲酮
[0119]1h nmr(500mhz,chloroform-d)δ8.82(s,1h),8.25(d,j＝9.3hz,1h),7.81(d,j＝4.9hz,1h),7.57(d,j＝2.5hz,1h),7.50(d,j＝7.0hz,2h),7.49
–
7.40(m,4h),7.38(d,j＝7.2hz,1h),7.17
–
7.14(m,1h),5.26(s,2h).
13
c nmr(126mhz,chloroform-d)δ185.40,161.51,151.23,148.64,143.99,140.34,136.27,136.22,135.94,129.42,128.91,128.66,128.55,127.86,126.30,122.30,121.21,109.02,70.67.
[0120]
中间体1-6-i：苯并呋喃-5-基(7-(苄氧基)-4-氯喹啉-3-基)甲酮
[0121]1h nmr(500mhz,chloroform-d)δ8.79(s,1h),8.23(d,j＝9.3hz,1h),8.09(d,j＝1.8hz,1h),7.91(dd,j＝8.7,1.8hz,1h),7.70(d,j＝2.2hz,1h),7.61
–
7.56(m,2h),7.51(d,j＝7.1hz,2h),7.46
–
7.40(m,3h),7.37(t,j＝7.3hz,1h),6.82(d,j＝2.2hz,1h),5.27(s,2h).
13
c nmr(126mhz,chloroform-d)δ193.27,161.35,158.11,151.13,149.11,146.86,140.22,135.94,132.31,129.81,128.86,128.49,127.89,127.81,126.64,126.12,125.00,122.15,121.07,112.06,109.03,107.45,70.60.
[0122]
中间体1-6-j：(7-(苄氧基)-4-氯喹啉-3-基)(2-乙基苯基)甲酮
[0123]1h nmr(500mhz,chloroform-d)δ8.82(s,1h),8.23(d,j＝9.3hz,1h),7.56(d,j＝2.5hz,1h),7.52
–
7.46(m,3h),7.45
–
7.31(m,6h),7.20(t,j＝7.5hz,1h),5.26(s,2h),2.97(q,j＝7.5hz,2h),1.30(t,j＝7.5hz,3h).
13
c nmr(126mhz,chloroform-d)δ195.92,161.67,151.49,150.37,145.59,141.31,137.23,135.94,132.44,131.05,130.64,130.01,128.90,128.54,127.84,126.51,125.83,122.14,121.16,109.07,70.67,27.05,15.95.
[0124]
中间体1-6-k：(7-(苄氧基)-4-氯喹啉-3-基)(2-异丙基苯基)甲酮
[0125]1h nmr(500mhz,chloroform-d)δ8.85(s,1h),8.24(d,j＝9.3hz,1h),7.57
–
7.48(m,5h),7.45
–
7.40(m,3h),7.37(t,j＝7.3hz,1h),7.28
–
7.24(m,2h),7.21
–
7.16(m,1h),5.26(s,2h),1.31(s,3h),1.29(s,3h).
13
c nmr(126mhz,chloroform-d)δ196.34,161.76,
151.60,150.74,149.52,141.69,137.75,135.88,132.15,129.80,129.72,128.89,128.54,127.84,126.97,126.63,125.57,122.14,121.17,109.01,70.66,29.61,24.21.
[0126]
中间体1-6-l：(7-(苄氧基)-4-氯喹啉-3-基)(2，6-二甲基苯基)甲酮
[0127]1h nmr(500mhz,chloroform-d)δ8.93(s,1h),8.31(d,j＝9.3hz,1h),7.54(d,j＝2.6hz,1h),7.49(d,j＝7.2hz,2h),7.44
–
7.39(m,3h),7.36(t,j＝7.3hz,1h),7.27(t,1h),7.09(d,j＝7.7hz,2h),5.25(s,2h),2.20(s,6h).
13
c nmr(126mhz,chloroform-d)δ197.69,162.06,151.91,151.47,142.86,140.05,135.70,134.63,129.64,128.74,128.40,128.18,127.68,127.11,122.01,121.37,108.89,70.56,19.81.
[0128]
中间体1-6-m：(7-(苄氧基)-4-氯喹啉-3-基)(3，5-二甲基苯基)甲酮
[0129]1h nmr(500mhz,chloroform-d)δ8.75(s,1h),8.20(d,j＝9.2hz,1h),7.57(d,j＝2.6hz,1h),7.49(d,j＝7.4hz,2h),7.47(s,2h),7.44
–
7.38(m,3h),7.34(t,j＝7.3hz,1h),7.25(s,1h),5.24(s,2h),2.33(s,6h).
13
c nmr(126mhz,chloroform-d)δ193.84,161.21,151.00,149.06,140.15,138.54,136.80,135.87,135.79,129.59,128.72,128.33,127.85,127.66,126.03,121.92,120.95,108.95,70.46,21.15.
[0130]
中间体1-6-n：(7-(苄氧基)-4-氯喹啉-3-基)(2，4-二甲基苯基)甲酮
[0131]1h nmr(500mhz,chloroform-d)δ8.77(s,1h),8.21(d,j＝9.2hz,1h),7.56(d,j＝2.6hz,1h),7.50(d,j＝7.2hz,2h),7.45
–
7.40(m,3h),7.36(t,j＝7.3hz,1h),7.26(d,j＝7.9hz,1h),7.16(s,1h),7.00(d,j＝7.8hz,1h),5.25(s,2h),2.61(s,3h),2.38(s,3h).
13
c nmr(126mhz,chloroform-d)δ195.35,161.45,151.22,149.83,143.45,140.63,140.17,135.97,134.24,133.14,132.17,130.66,128.88,128.51,127.83,126.56,126.30,122.06,121.13,109.02,70.63,21.68,21.51.
[0132]
中间体1-6-o：(7-(苄氧基)-4-氯喹啉-3-基)(4氟-2-甲基苯基)甲酮
[0133]1h nmr(500mhz,chloroform-d)δ8.78(s,1h),8.20(d,j＝9.3hz,1h),7.55(d,j＝2.5hz,1h),7.49(d,j＝7.2hz,2h),7.43
–
7.34(m,5h),7.04(dd,j＝9.7,2.6hz,1h),6.88(td,j＝8.3,2.6hz,1h),5.25(s,2h),2.62(s,3h).
13
c nmr(126mhz,chloroform-d)δ194.40,164.73(d,j＝254.8hz),161.61,151.40,149.76,143.50(d,j＝9.1hz),140.80,135.88,134.09(d,j＝9.6hz),133.46(d,j＝2.9hz),130.04,128.86,128.50,127.80,126.30,122.19,120.99,119.14(d,j＝21.5hz),112.91(d,j＝21.4hz),109.03,70.63,21.55.
[0134]
中间体1-6-p：(7-(苄氧基)-4-氯喹啉-3-基)(4-氯-2甲基苯基)甲酮
[0135]1h nmr(500mhz,chloroform-d)δ8.79(s,1h),8.21(d,j＝9.2hz,1h),7.56(d,j＝2.5hz,1h),7.50(d,j＝7.1hz,2h),7.46
–
7.40(m,3h),7.39
–
7.34(m,2h),7.29(d,j＝8.3hz,1h),7.19(dd,j＝8.3,2.1hz,1h),5.26(s,2h),2.58(s,3h).
13
c nmr(126mhz,chloroform-d)δ194.75,161.79,151.38,149.75,141.65,141.19,138.52,135.84,135.65,132.55,132.19,129.74,128.90,128.57,127.86,126.41,126.15,122.35,121.03,108.92,70.70,21.19.
[0136]
中间体1-6-q：(7-(苄氧基)-4-氯喹啉-3-基)(4氟-2，6-二甲基苯基)甲酮
[0137]1h nmr(500mhz,chloroform-d)δ8.91(s,1h),8.28(d,j＝9.3hz,1h),7.52(d,j＝2.5hz,1h),7.47(d,j＝7.1hz,2h),7.43
–
7.38(m,3h),7.34(t,j＝7.3hz,1h),6.78(d,j＝
9.3hz,2h),5.24(s,2h),2.16(s,6h).
13
c nmr(126mhz,chloroform-d)δ196.83,162.96(d,j＝248.9hz),162.18,152.04,151.32,142.85,137.84(d,j＝8.7hz),136.27(d,j＝3.1hz),135.71,128.80,128.47,127.73,127.60,127.12,122.15,121.30,115.06(d,j＝21.2hz),108.96,70.63,20.06(d,j＝1.7hz).
[0138][0139]
合成步骤1-7
[0140]
中间体1-7-a-q的合成步骤：
[0141]
将1-6-a-q(0.68mmol)加到100ml圆底烧瓶中，加入6ml的dmf，再加入碳酸铯(2.04mmol)以及反-对香豆酸甲酯(0.714mmol)，搅拌均匀，升温至70℃，回流1h；tlc监测反应终点，反应完毕之后旋去dmf，再加入适量的稀盐酸去除过量的碳酸铯；反应液用ea萃取3次，收集有机相，用无水硫酸钠干燥后减压蒸干，硅胶柱层析分离得黄色固体或油状物。
[0142]
中间体1-7-a：甲基(e)-3-(4-((3-苯甲酰基-7(苄氧基)喹啉-4-基)氧)苯基)丙烯酸
[0143]1h nmr(500mhz,dmso-d6)δ8.90(s,1h),7.93(d,j＝9.2hz,1h),7.70
–
7.62(m,4h),7.56
–
7.49(m,5h),7.48
–
7.40(m,5h),7.36(t,j＝7.3hz,1h),6.62(d,j＝8.8hz,2h),6.47(d,j＝16.0hz,1h),5.37(s,2h),3.69(s,3h).
13
c nmr(126mhz,chloroform-d)δ193.20,167.44,161.87,159.35,157.16,153.41,152.13,143.72,137.42,135.94,133.48,129.65,129.56,129.46,128.82,128.45,128.43,127.78,124.41,121.36,120.78,117.26,116.99,116.78,108.96,70.54,51.74.
[0144]
中间体1-7-b：甲基(e)-3-(4-((7-(苄氧基)-3-(3-氟苯甲酰基)喹啉-4-基)氧)苯基)丙烯酸
[0145]1h nmr(500mhz,chloroform-d)δ8.95(s,1h),8.01(d,j＝9.3hz,1h),7.60(d,j＝2.5hz,1h),7.54(d,j＝16.0hz,1h),7.51
–
7.46(m,2h),7.43
–
7.33(m,5h),7.31(dd,j＝9.2,2.4hz,1h),7.29
–
7.22(m,4h),6.52(d,j＝8.8hz,2h),6.26(d,j＝16.0hz,1h),5.25(s,2h),3.76(s,3h).
13
c nmr(126mhz,chloroform-d)δ192.00,167.38,162.63(d,j＝248.4hz),162.02,159.27,157.23,153.62,151.92,143.57,139.50(d,j＝6.4hz),135.88,130.08(d,j＝7.6hz),129.70,129.65(d,j＝9.9hz),128.82,128.45,127.76,125.38(d,j＝3.0hz),124.44,121.47,120.41(d,j＝21.6hz),120.29,117.16,117.13,116.69,115.93(d,j＝22.5hz),109.03,70.55,51.74.
[0146]
中间体1-7-c：甲基(e)-3-(4-((7-(苄氧基)-3-(4-氟苯甲酰基)喹啉-4-基)氧)苯基)丙烯酸
[0147]1h nmr(500mhz,chloroform-d)δ8.93(s,1h),8.01(d,j＝9.2hz,2h),7.65
–
7.58(m,3h),7.53(d,j＝16.0hz,1h),7.48(d,j＝7.5hz,2h),7.41
–
7.36(m,2h),7.35
–
7.28(m,2h),7.24(d,j＝2.2hz,1h),7.04(t,j＝7.5hz,2h),6.52(d,j＝6.6hz,2h),6.25(d,j＝16.0hz,1h),5.24(s,2h),3.75(s,3h).
13
c nmr(126mhz,chloroform-d)δ191.51,167.31,
165.93(d,j＝256.0hz),162.60,161.90,159.12,156.96,153.31,151.81,143.51,135.81,133.73(d,j＝2.7hz),132.13(d,j＝9.4hz),129.61,129.50,128.72,128.36,127.69,124.31,121.40,120.43,117.05,116.62,115.57(d,j＝22.0hz),108.80,70.45,51.65.
[0148]
中间体1-7-d：甲基(e)-3-(4-((7-(苄氧基)-3-(2-(三氟甲基)苯甲酰基)喹啉-4-基)氧)苯基)丙烯酸
[0149]1h nmr(500mhz,chloroform-d)δ9.28(s,1h),7.73(d,j＝9.3hz,1h),7.64(d,j＝7.9hz,1h),7.60(d,j＝2.4hz,1h),7.56(d,j＝16.0hz,1h),7.50
–
7.45(m,3h),7.44
–
7.34(m,4h),7.29
–
7.26(m,2h),7.24
–
7.19(m,2h),6.37(d,j＝8.8hz,2h),6.27(d,j＝16.0hz,1h),5.25(s,2h),3.78(s,3h).
13
c nmr(126mhz,chloroform-d)δ192.42,167.52,162.56,159.35,158.41,154.56,152.98,143.74,139.39,135.78,131.43,130.20,129.66,129.37,128.91,128.60,127.86,127.83,127.43,125.20,121.55,120.65,117.14,116.99,115.65,109.40,70.72,51.83.
[0150]
中间体1-7-e：甲基(e)-3-(4-((7-(苄氧基)-3-(4-(三氟甲基)苯甲酰基)喹啉-4-基)氧)苯基)丙烯酸
[0151]1h nmr(500mhz,chloroform-d)δ8.99(s,1h),8.00(d,j＝9.1hz,1h),7.66(d,j＝8.1hz,2h),7.63
–
7.58(m,3h),7.53(d,j＝16.0hz,1h),7.48(d,j＝7.2hz,2h),7.40(t,j＝7.3hz,2h),7.37
–
7.33(m,1h),7.31(dd,j＝9.2,2.5hz,1h),7.23(d,j＝8.7hz,2h),6.44(d,j＝8.8hz,2h),6.25(d,j＝16.0hz,1h),5.25(s,2h),3.76(s,3h).
13
c nmr(126mhz,chloroform-d)δ192.31,167.32,162.18,159.15,157.33,153.85,152.02,143.43,140.40,135.83,129.70,129.62,129.58,128.81,128.46,127.75,125.40,125.37,124.45,121.57,119.93,117.25,117.06,116.62,116.43,109.08,70.56,53.52.
[0152]
中间体1-7-f：甲基(e)-3-(4-((7-(苄氧基)-3-(4-(三氟甲氧基)苯甲酰基)喹啉-4-基)氧)苯基)丙烯酸
[0153]1h nmr(500mhz,chloroform-d)δ8.98(s,1h),8.04(d,j＝9.2hz,1h),7.66
–
7.60(m,3h),7.55(d,j＝16.0hz,1h),7.49(d,j＝7.1hz,2h),7.42(t,j＝7.0hz,2h),7.38
–
7.31(m,2h),7.24(s,2h),7.20(d,j＝8.3hz,2h),6.48(d,j＝8.8hz,2h),6.27(d,j＝16.0hz,1h),5.26(s,2h),3.79(s,3h).
13
c nmr(126mhz,chloroform-d)δ191.74,167.49,162.28,159.17,157.37,153.52,151.97,144.81,143.59,135.88,135.83,131.47,130.13,129.76,128.91,128.57,127.86,124.54,121.71,120.43,117.34,117.21,116.66,116.17,115.11,108.88,70.69,51.86.
[0154]
中间体1-7-g：甲基(e)-3-(4-((7-(苄氧基)-3-(4-甲氧基苯甲酰基)喹啉-4-基)氧)苯基)丙烯酸
[0155]1h nmr(500mhz,chloroform-d)δ8.92(s,1h),8.02(d,j＝9.1hz,1h),7.64
–
7.59(m,3h),7.55(d,j＝16.0hz,1h),7.50(d,j＝7.1hz,2h),7.42(t,j＝7.4hz,2h),7.37(t,j＝7.3hz,1h),7.32(dd,j＝9.2,2.5hz,1h),7.28
–
7.26(m,2h),6.86(d,j＝8.9hz,2h),6.57(d,j＝8.8hz,2h),6.26(d,j＝16.0hz,1h),5.27(s,2h),3.88(s,3h),3.78(s,3h).
13
c nmr(126mhz,chloroform-d)δ191.67,167.56,164.14,161.72,159.44,156.76,153.26,152.08,143.87,136.05,132.19,130.38,129.70,129.50,128.89,128.51,127.86,124.39,121.45,121.35,117.39,116.97,116.95,113.79,109.02,70.59,55.70,51.82.
[0156]
中间体1-7-h：甲基(e)-3-(4-((7-(苄氧基)-3-(噻吩-2-羰基)喹啉-4-基)氧)苯基)丙烯酸
[0157]1h nmr(500mhz,chloroform-d)δ8.95(s,1h),8.02(d,j＝9.2hz,1h),7.67(d,j＝4.9hz,1h),7.59(d,j＝2.5hz,1h),7.55(d,j＝16.0hz,1h),7.52(d,j＝3.8hz,1h),7.48(d,j＝7.1hz,2h),7.40(t,j＝7.4hz,2h),7.34(t,j＝7.3hz,1h),7.32
–
7.27(m,3h),7.11
–
7.08(m,1h),6.68(d,j＝8.8hz,2h),6.26(d,j＝16.0hz,1h),5.24(s,2h),3.76(s,3h).
13
c nmr(126mhz,chloroform-d)δ184.54,167.41,161.74,159.37,156.84,153.23,151.24,144.02,143.72,135.91,135.57,135.24,129.71,129.57,128.79,128.42,128.17,127.75,124.37,121.36,121.20,117.33,117.04,117.00,108.93,70.49,51.70.
[0158]
中间体1-7-i：甲基(e)-3-(4-((3-(苯并呋喃-5-羰基)-7-(苄氧基)喹啉-4-基)氧)苯基)丙烯酸
[0159]1h nmr(500mhz,chloroform-d)δ8.97(s,1h),8.02(d,j＝9.2hz,1h),7.88(s,1h),7.67(s,1h),7.64
–
7.58(m,2h),7.55
–
7.43(m,4h),7.40(t,j＝7.3hz,2h),7.37
–
7.29(m,2h),7.20(d,j＝8.3hz,2h),6.76(d,j＝2.1hz,1h),6.49(d,j＝8.3hz,2h),6.22(d,j＝16.0hz,1h),5.25(s,2h),3.75(s,3h).
13
c nmr(126mhz,chloroform-d)δ192.72,167.40,161.72,159.32,157.72,156.89,153.29,152.08,146.61,143.69,135.93,132.87,129.58,129.41,128.79,128.42,127.75,127.45,126.15,124.37,124.18,121.29,121.23,117.26,116.90,116.80,111.51,108.95,107.31,70.48,51.72.
[0160]
中间体1-7-j：甲基(e)-3-(4-((7-(苄氧基)-3-(2-乙基苯甲酰基)喹啉-4-基)氧)苯基)丙烯酸
[0161]1h nmr(500mhz,chloroform-d)δ9.10(s,1h),7.94(d,j＝9.2hz,1h),7.60(d,j＝2.5hz,1h),7.56(d,j＝16.0hz,1h),7.48(d,j＝7.4hz,2h),7.42
–
7.32(m,4h),7.30
–
7.23(m,4h),7.19
–
7.10(m,2h),6.39(d,j＝8.8hz,2h),6.27(d,j＝15.9hz,1h),5.24(s,2h),3.77(s,3h),2.33(q,j＝7.5hz,2h),1.03(t,j＝7.5hz,3h).
13
c nmr(126mhz,chloroform-d)δ194.69,167.49,162.12,159.56,157.35,153.70,152.97,144.78,143.73,137.72,135.88,131.79,130.12,129.67,129.64,129.37,128.46,127.78,125.36,124.66,121.78,121.39,117.38,116.89,116.15,108.96,70.56,51.76,26.28,15.57.
[0162]
中间体1-7-k：甲基(e)-3-(4-((7-(苄氧基)-3-(2-异丙基苯甲酰基)喹啉-4-基)氧)苯基)丙烯酸
[0163]1h nmr(500mhz,chloroform-d)δ9.14(s,1h),7.86(d,j＝9.2hz,1h),7.59(d,j＝2.5hz,1h),7.55(d,j＝16.0hz,1h),7.46(d,j＝7.3hz,2h),7.41
–
7.29(m,5h),7.27(d,j＝9.1hz,2h),7.24(dd,j＝9.2,2.5hz,1h),7.20(d,j＝7.5hz,1h),7.07(td,j＝7.5,1.2hz,1h),6.45(d,j＝8.7hz,2h),6.26(d,j＝16.0hz,1h),5.23(s,2h),3.75(s,3h),2.98(p,j＝6.8hz,1h),1.03(s,3h),1.02(s,3h).
13
c nmr(126mhz,chloroform-d)δ194.96,171.11,167.40,162.05,159.54,157.12,153.88,153.11,148.66,143.70,137.82,135.81,131.46,129.67,129.18,128.77,128.41,127.72,126.13,125.11,124.74,122.18,121.34,117.32,116.74,115.76,109.08,70.50,51.68,29.70,24.06.
[0164]
中间体1-7-l：甲基(e)-3-(4-((7-(苄氧基)-3-(2，6-二甲基苯甲酰基)喹啉-4-基)氧)苯基)丙烯酸
[0165]1h nmr(500mhz,chloroform-d)δ9.29(s,1h),7.75(d,j＝9.2hz,1h),7.59
–
7.55(m,2h),7.47(d,j＝7.2hz,2h),7.40(t,j＝7.4hz,2h),7.35(t,j＝7.3hz,1h),7.27(d,j＝9.3hz,2h),7.21(dd,j＝9.2,2.5hz,1h),7.05(t,j＝7.6hz,1h),6.86(d,j＝7.6hz,2h),6.42(d,j＝8.8hz,2h),6.27(d,j＝16.0hz,1h),5.24(s,2h),3.78(s,3h),1.99(s,6h).
13
c nmr(126mhz,chloroform-d)δ196.97,167.58,162.45,159.66,158.28,154.39,153.34,143.91,140.79,135.79,134.03,129.47,129.09,129.06,128.88,128.55,127.86,127.82,125.32,121.49,121.30,117.57,116.71,115.57,109.28,70.67,51.80,19.65.
[0166]
中间体1-7-m：甲基(e)-3-(4-((7-(苄氧基)-3-(3，5-二甲基苯甲酰基)喹啉-4-基)氧)苯基)丙烯酸
[0167]1h nmr(500mhz,chloroform-d)δ8.94(s,1h),8.03(d,j＝9.2hz,1h),7.62(d,j＝2.6hz,1h),7.56(d,j＝16.0hz,1h),7.49(d,j＝7.1hz,2h),7.42(t,j＝7.3hz,2h),7.36(t,j＝7.3hz,1h),7.32(dd,j＝9.2,2.5hz,1h),7.27(d,j＝8.8hz,2h),7.17(s,3h),6.57(d,j＝8.8hz,2h),6.27(d,j＝16.0hz,1h),5.26(s,2h),3.79(s,3h),2.27(s,6h).
13
c nmr(126mhz,chloroform-d)δ193.63,167.57,161.91,159.49,157.36,153.12,152.04,143.85,138.24,137.58,135.97,135.23,130.12,129.65,129.49,128.89,128.52,127.85,127.32,124.62,121.41,117.44,116.97,116.22,108.78,70.62,51.84,21.23.
[0168]
中间体1-7-n：甲基(e)-3-(4-((7-(苄氧基)-3-(2，4-二甲基苯甲酰基)喹啉-4-基)氧)苯基)丙烯酸
[0169]1h nmr(500mhz,chloroform-d)δ9.03(s,1h),8.01(d,j＝9.2hz,1h),7.60(d,j＝2.4hz,1h),7.57(d,j＝16.0hz,1h),7.48(d,j＝7.2hz,2h),7.40(t,j＝8.1hz,2h),7.35(t,j＝7.2hz,1h),7.31(dd,j＝9.2,2.5hz,1h),7.27(d,j＝8.8hz,2h),7.22(d,j＝7.8hz,1h),6.96(d,j＝8.0hz,1h),6.93(s,1h),6.44(d,j＝8.7hz,2h),6.28(d,j＝16.0hz,1h),5.24(s,2h),3.79(d,j＝1.2hz,3h),2.35(s,3h),2.01(s,3h).
13
c nmr(126mhz,chloroform-d)δ194.34,167.63,162.13,159.49,157.36,152.67,144.94,143.83,142.79,135.90,132.42,131.29,130.13,129.69,129.56,128.88,128.52,127.86,126.20,124.59,121.51,116.99,116.55,116.19,114.90,108.63,70.62,51.87,21.64,20.35.
[0170]
中间体1-7-o：甲基(e)-3-(4-((7-(苄氧基)-3-(4-氟-2-甲基苯甲酰基)喹啉-4-基)氧)苯基)丙烯酸
[0171]1h nmr(500mhz,chloroform-d)δ9.04(s,1h),7.98(d,j＝9.1hz,1h),7.59(d,j＝2.5hz,1h),7.55(d,j＝16.0hz,1h),7.46(d,j＝7.4hz,2h),7.38(t,j＝7.5hz,2h),7.35
–
7.30(m,2h),7.30
–
7.25(m,3h),6.86
–
6.77(m,2h),6.40(d,j＝8.7hz,2h),6.27(d,j＝16.0hz,1h),5.23(s,2h),3.76(s,3h),1.99(s,3h).
13
c nmr(126mhz,chloroform-d)δ193.17,167.35,164.33(d,j＝253.7hz),162.13,159.32,157.11,153.62,152.58,143.48,142.75(d,j＝8.9hz),135.81,134.01(d,j＝2.8hz),133.15(d,j＝9.5hz),129.66,129.57,128.76,128.40,127.72,124.44,121.43,121.27,118.22(d,j＝21.3hz),117.18,117.08,116.18,112.40(d,j＝21.6hz),108.86,70.50,51.71,20.25.
[0172]
中间体1-7-p：甲基(e)-3-(4-((7-(苄氧基)-3-(4-氯-2-甲基苯甲酰基)喹啉-4-基)氧)苯基)丙烯酸
[0173]1h nmr(500mhz,chloroform-d)δ9.07(s,1h),7.99(d,j＝9.2hz,1h),7.61(d,j＝
2.4hz,1h),7.57(d,j＝16.0hz,1h),7.48(d,j＝7.3hz,2h),7.44
–
7.39(m,2h),7.36(t,j＝7.3hz,1h),7.33
–
7.28(m,3h),7.24(d,j＝8.3hz,1h),7.15
–
7.09(m,2h),6.41(d,j＝8.8hz,2h),6.29(d,j＝16.0hz,1h),5.25(s,2h),3.79(d,j＝1.9hz,3h),1.99(s,3h).
13
c nmr(126mhz,chloroform-d)δ193.60,167.53,162.38,159.40,157.46,153.72,152.61,144.86,143.60,141.04,137.83,136.23,135.83,131.77,131.40,130.13,129.78,129.70,128.90,128.56,127.86,125.73,124.62,121.68,117.23,116.24,108.85,70.66,51.89,20.02.
[0174]
中间体1-7-q：甲基(e)-3-(4-((7-(苄氧基)-3-(4-氟-2，6-二甲基苯甲酰基)喹啉-4-基)氧)苯基)丙烯酸
[0175]1h nmr(500mhz,chloroform-d)δ9.31(s,1h),7.75(d,j＝9.2hz,1h),7.61
–
7.54(m,2h),7.46(d,j＝7.1hz,2h),7.39(t,j＝7.3hz,2h),7.33(t,j＝7.3hz,1h),7.29(d,j＝8.8hz,2h),7.21(dd,j＝9.2,2.5hz,1h),6.56(d,j＝9.4hz,2h),6.43(d,j＝8.7hz,2h),6.29(d,j＝16.0hz,1h),5.23(s,2h),3.76(s,3h),1.97(s,6h).
13
c nmr(126mhz,chloroform-d)δ195.86,167.39,162.47(d,j＝247.7hz),162.45,159.54,158.08,154.43,153.08,143.65,137.05(d,j＝8.5hz),136.96(d,j＝3.1hz),135.70,129.43,129.19,128.79,128.46,127.72,125.19,121.49,121.25,117.37,116.84,115.33,114.47(d,j＝21.2hz),109.29,70.58,51.69,19.72.
[0176][0177]
合成步骤1-8
[0178]
中间体1-8-a-q的合成步骤：
[0179]
将1-7-a-q(0.60mmol)加到100ml圆底烧瓶中，加入6ml的dcm，搅拌均匀，并用n2保护；在冰浴的条件下缓慢滴加1mol/l的三溴化硼(1.20mmol)，滴加完毕之后反应5分钟；tlc监测反应终点，反应完毕之后加入过量的无水甲醇猝灭未反应的三溴化硼以及分解形成的硼络合物；反应液减压蒸干，硅胶柱层析分离得黄色固体或油状物。
[0180]
中间体1-8-a：甲基(e)-3-(4-((3-苯甲酰基-7-羟基喹啉-4-基)氧)苯基)丙烯酸
[0181]1h nmr(500mhz,dmso-d6)δ10.74(s,1h),8.84(s,1h),7.89(d,j＝9.1hz,1h),7.67
–
7.59(m,3h),7.56
–
7.50(m,3h),7.46(t,j＝7.7hz,2h),7.40(d,j＝2.4hz,1h),7.24(dd,j＝9.1,2.4hz,1h),6.59(d,j＝8.5hz,2h),6.47(d,j＝16.0hz,1h),3.69(s,3h).
13
c nmr(126mhz,chloroform-d)δ192.98,167.62,161.89,159.32,158.25,152.16,151.45,143.82,137.42,133.62,129.77,129.66,128.57,126.69,125.00,121.29,120.07,117.14,116.98,116.56,109.52,51.88.
[0182]
中间体1-8-b：甲基(e)-3-(4((3-(3-氟苯甲酰基)-7-羟基喹啉-4-基)氧)苯基)丙烯酸
[0183]1h nmr(500mhz,chloroform-d)δ8.88(s,1h),7.99(d,j＝9.1hz,1h),7.59(d,j＝
2.3hz,1h),7.54(d,j＝16.0hz,1h),7.36(q,j＝6.6,5.4hz,2h),7.29
–
7.23(m,4h),7.19(dd,j＝9.1,2.3hz,1h),6.53(d,j＝8.8hz,2h),6.27(d,j＝16.0hz,1h),3.78(s,3h).
13
c nmr(126mhz,chloroform-d)δ191.86,167.61,162.66(d,j＝248.4hz),162.06,159.15,158.19,152.60,151.42,143.67,139.45(d,j＝6.3hz),130.17(d,j＝7.7hz),129.76,125.38(d,j＝2.9hz),125.08,121.48,120.53(d,j＝21.3hz),119.53,117.23,116.81,116.46,115.92(d,j＝22.6hz),109.85,51.86.
[0184]
中间体1-8-c：甲基(e)-3-(4((3-(4-氟苯甲酰基)-7-羟基喹啉-4-基)氧)苯基)丙烯酸
[0185]1h nmr(500mhz,chloroform-d)δ8.90(s,1h),7.98(d,j＝9.2hz,1h),7.67
–
7.62(m,2h),7.58
–
7.52(m,2h),7.29(d,j＝8.8hz,2h),7.12(dd,j＝9.1,2.3hz,1h),7.07(t,j＝8.6hz,2h),6.57(d,j＝8.8hz,2h),6.28(d,j＝16.0hz,1h),3.79(s,3h),3.50(s,1h).
13
c nmr(126mhz,chloroform-d)δ191.28,167.41,166.04(d,j＝256.6hz),161.46,159.02,157.88,152.20,151.35,143.51,133.70(d,j＝2.9hz),132.18(d,j＝9.2hz),129.73,129.68,125.01,121.16,119.88,117.23,116.78,116.55,115.69(d,j＝21.9hz),109.75,51.77.
[0186]
中间体1-8-d：甲基(e)-3-(4-((7-羟基-3-(2-(三氟甲基)苯甲酰基)喹啉-4-基)氧)苯基)丙烯酸
[0187]1h nmr(500mhz,dmso-d6)δ10.99(s,1h),9.10(s,1h),7.75(d,j＝7.9hz,1h),7.64(d,j＝9.1hz,1h),7.62
–
7.58(m,1h),7.57
–
7.50(m,5h),7.40(d,j＝2.4hz,1h),7.18(dd,j＝9.1,2.4hz,1h),6.47(d,j＝16.0hz,1h),6.44(d,j＝8.6hz,2h),3.69(s,3h).
13
c nmr(126mhz,dmso-d6)δ192.01,166.76,162.00,158.99,158.02,153.94,152.05,144.82,143.63,132.10,130.68,130.38,130.06,128.81,128.08,125.40,120.97,116.66,115.82,115.48,115.11,113.95,110.88,56.09,18.59.
[0188]
中间体1-8-e：甲基(e)-3-(4-((7-羟基-3-(4-(三氟甲基)苯甲酰基)喹啉-4-基)氧)苯基)丙烯酸
[0189]1h nmr(500mhz,chloroform-d)δ8.94(s,1h),7.95(d,j＝9.2hz,1h),7.71(d,j＝8.1hz,2h),7.65(d,j＝8.2hz,2h),7.55(d,j＝16.0hz,1h),7.45(s,1h),7.28(d,j＝8.8hz,2h),7.04(dd,j＝9.2,2.1hz,1h),6.52(d,j＝8.8hz,2h),6.29(d,j＝16.0hz,1h),3.79(s,3h).
13
cnmr(126mhz,chloroform-d)δ191.96,167.49,162.24,159.07,158.57,152.31,151.40,143.46,140.35,130.00,129.87,129.69,125.59,125.57,125.28,121.54,119.43,117.56,116.71,116.56,109.44,51.94.
[0190]
中间体1-8-f：甲基(e)-3-(4-((7-羟基-3-(4-(三氟甲氧基)苯甲酰基)喹啉-4-基)氧)苯基)丙烯酸
[0191]1h nmr(500mhz,chloroform-d)δ8.93(s,1h),7.99(d,j＝9.1hz,1h),7.64(d,j＝8.7hz,2h),7.58
–
7.51(m,2h),7.27(d,j＝7.7hz,2h),7.21(d,j＝8.4hz,2h),7.14(dd,j＝9.1,2.2hz,1h),6.52(d,j＝8.6hz,2h),6.28(d,j＝16.0hz,1h),3.79(s,3h).
13
c nmr(126mhz,chloroform-d)δ191.47,167.58,161.90,159.05,151.50,144.90,143.59,135.76,131.48,130.12,129.95,129.81,128.22,125.23,121.43,120.48,117.46,116.79,116.64,116.10,115.67,109.76,51.93.
[0192]
中间体1-8-g：甲基(e)-3-(4-((7-羟基-3-(4-甲氧基苯甲酰基)喹啉-4-基)氧)苯基)丙烯酸
[0193]1h nmr(500mhz,chloroform-d)δ8.83(s,1h),7.93(d,j＝9.1hz,1h),7.61(d,j＝8.9hz,2h),7.56
–
7.50(m,2h),7.28
–
7.26(m,2h),7.08(dd,j＝9.2,2.3hz,1h),6.85(d,j＝8.9hz,2h),6.61(d,j＝8.8hz,2h),6.25(d,j＝16.0hz,1h),5.28(s,6h),3.49(s,1h).
13
c nmr(126mhz,chloroform-d)δ191.16,167.58,164.20,162.00,159.14,158.10,151.47,150.88,143.78,132.16,130.11,129.68,124.90,121.44,120.45,117.11,117.04,116.56,113.83,109.10,55.67,51.81.
[0194]
中间体1-8-h：甲基(e)-3-(4-((7-羟基-3-(噻吩-2-羰基)喹啉-4-基)氧)苯基)丙烯酸
[0195]1h nmr(500mhz,dmso-d6)δ10.71(s,1h),8.89(s,1h),8.09(dd,j＝4.9,1.2hz,1h),7.90(d,j＝9.1hz,1h),7.70(dd,j＝3.8,1.2hz,1h),7.59
–
7.53(m,3h),7.40(d,j＝2.5hz,1h),7.29
–
7.21(m,2h),6.74(d,j＝8.8hz,2h),6.49(d,j＝16.1hz,1h),3.69(s,3h).
13
cnmr(126mhz,dmso-d6)δ184.30,166.74,160.87,159.27,155.84,152.85,150.75,143.61,143.35,136.77,136.49,130.24,129.02,128.96,124.45,120.78,120.70,116.82,116.60,115.51,110.64,51.46.
[0196]
中间体1-8-i：甲基(e)-3-(4-((3-(苯并呋喃-5-羰基)-7-羟基喹啉-4-基)氧)苯基)丙烯酸
[0197]1h nmr(500mhz,chloroform-d)δ8.91(s,1h),7.97(d,j＝9.1hz,1h),7.93(d,j＝1.8hz,1h),7.70(d,j＝2.2hz,1h),7.63(dd,j＝8.6,1.9hz,1h),7.52
–
7.45(m,2h),7.43
–
7.34(m,1h),7.23(d,j＝8.7hz,2h),7.10(dd,j＝9.1,2.3hz,1h),6.82
–
6.79(m,1h),6.57(d,j＝8.8hz,2h),6.24(d,j＝16.0hz,1h),3.78(s,3h).
13
c nmr(126mhz,chloroform-d)δ192.29,167.56,162.11,159.16,158.44,157.89,146.78,143.72,132.81,129.82,129.72,128.89,127.88,127.65,126.21,125.14,124.36,120.53,117.20,117.14,116.96,116.67,111.73,109.08,107.44,51.88.
[0198]
中间体1-8-j：甲基(e)-3-(4-((3-(2-乙基苯甲酰基)7-羟基喹啉-4-基)氧)苯基)丙烯酸
[0199]1h nmr(500mhz,chloroform-d)δ9.01(s,1h),7.89(d,j＝9.1hz,1h),7.61
–
7.52(m,2h),7.42
–
7.33(m,2h),7.28(d,j＝8.4hz,2h),7.21
–
7.14(m,2h),7.07(dd,j＝9.2,2.2hz,1h),6.46(d,j＝8.5hz,2h),6.28(d,j＝15.9hz,1h),3.79(s,3h),2.33(q,j＝7.5hz,2h),1.03(t,j＝7.5hz,3h).
13
c nmr(126mhz,chloroform-d)δ193.89,167.63,162.76,159.36,158.89,151.68,151.50,145.04,143.75,137.35,132.08,130.29,130.08,129.80,125.52,125.42,121.83,121.10,117.13,116.79,116.42,116.13,108.90,51.90,26.33,15.59.
[0200]
中间体1-8-k：甲基(e)-3-(4-((7-羟基-3-(2-异丙基苯甲酰基)喹啉-4-基)氧)苯基)丙烯酸
[0201]1h nmr(500mhz,chloroform-d)δ9.01(s,1h),7.76(d,j＝9.2hz,1h),7.57(d,j＝16.0hz,1h),7.41
–
7.35(m,2h),7.34
–
7.30(m,3h),7.27(d,j＝8.0hz,1h),7.11(t,j＝7.5hz,1h),6.93(dd,j＝9.1,2.2hz,1h),6.55(d,j＝8.4hz,2h),6.28(d,j＝16.0hz,1h),
3.78(s,3h),2.99(p,j＝6.8hz,1h),1.04(s,3h),1.03(s,3h).
13
c nmr(126mhz,chloroform-d)δ194.53,167.66,162.52,159.52,158.41,152.25,148.82,143.85,137.65,131.66,130.08,129.83,129.47,129.27,126.30,125.42,125.29,121.55,116.92,116.64,116.12,116.03,109.17,51.88,29.81,24.15.
[0202]
中间体1-8-l：甲基(e)-3-(4-((3-(2，6-二甲基苯甲酰基)-7-羟基喹啉-4-基)氧)苯基)丙烯酸
[0203]1h nmr(500mhz,chloroform-d)δ9.18(s,1h),7.68(d,j＝9.2hz,1h),7.59(d,j＝16.0hz,1h),7.40(d,j＝2.4hz,1h),7.31(d,j＝8.7hz,2h),7.05(t,j＝7.6hz,1h),6.93(dd,j＝9.2,2.3hz,1h),6.86(d,j＝7.7hz,2h),6.49(d,j＝8.6hz,2h),6.30(d,j＝16.0hz,1h),3.79(s,3h),2.01(s,6h).
13
c nmr(126mhz,chloroform-d)δ196.54,167.74,162.78,159.54,159.33,152.77,152.52,143.96,140.45,134.02,130.08,129.56,129.27,127.92,125.96,121.53,120.67,116.79,116.10,115.69,109.50,51.91,19.68.
[0204]
中间体1-8-m：甲基(e)-3-(4-((3-(3，5-二甲基苯甲酰基)-7-羟基喹啉-4-基)氧)苯基)丙烯酸
[0205]1h nmr(500mhz,chloroform-d)δ8.86(s,1h),7.92(d,j＝9.1hz,1h),7.57(d,j＝16.0hz,1h),7.45(d,j＝2.4hz,1h),7.29(d,j＝8.8hz,2h),7.20(s,2h),7.17(s,1h),7.04(dd,j＝9.2,2.3hz,1h),6.62(d,j＝8.8hz,2h),6.28(d,j＝16.0hz,1h),3.79(s,3h),2.27(s,6h).
13
cnmr(126mhz,chloroform-d)δ193.42,167.67,161.83,159.41,158.30,151.90,151.36,143.88,138.32,137.59,135.27,130.10,129.71,129.62,127.30,125.16,121.20,120.47,117.08,116.64,116.11,51.89,21.20.
[0206]
中间体1-8-n：甲基(e)-3-(4-((3-(2，4-二甲基苯甲酰基)-7-羟基喹啉-4-基)氧)苯基)丙烯酸
[0207]1h nmr(500mhz,chloroform-d)δ8.95(s,1h),7.95(d,j＝9.1hz,1h),7.60
–
7.53(m,2h),7.28(d,j＝8.7hz,2h),7.25(d,j＝8.2hz,1h),7.15(d,j＝9.1hz,1h),6.96(d,j＝7.9hz,1h),6.92(s,1h),6.44(d,j＝8.8hz,2h),6.28(d,j＝16.0hz,1h),3.78(s,3h),2.34(s,3h),1.99(s,3h).
13
c nmr(126mhz,chloroform-d)δ194.17,167.66,161.91,159.44,158.01,152.53,152.23,143.84,142.75,139.42,134.90,132.37,131.22,129.69,129.58,126.20,125.09,121.29,121.28,116.97,116.70,116.55,109.70,51.86,21.61,20.25.
[0208]
中间体1-8-o：甲基(e)-3-(4-((3-(4-氟-2-甲基苯甲酰基)-7-羟基喹啉-4-基)氧)苯基)丙烯酸
[0209]1h nmr(500mhz,chloroform-d)δ8.97(s,1h),7.88(d,j＝9.1hz,1h),7.57(d,j＝15.9hz,1h),7.46
–
7.38(m,2h),7.31(d,j＝8.7hz,2h),7.00(dd,j＝9.1,2.3hz,1h),6.88(td,j＝8.3,2.6hz,1h),6.47(d,j＝8.8hz,2h),6.29(d,j＝15.9hz,1h),5.29(s,1h),3.97(s,1h),3.79(s,3h),2.01(s,3h).
13
c nmr(126mhz,chloroform-d)δ192.96,167.61,164.49(d,j＝254.0hz),162.44,159.33,158.17,152.36,151.96,143.63,142.94(d,j＝9.0hz),133.99(d,j＝2.9hz),133.32(d,j＝9.5hz),130.08,129.83,129.81,125.12,121.49,120.71,118.38(d,j＝21.3hz),117.25,116.38,112.57(d,j＝21.4hz),109.35,51.91,20.32.
[0210]
中间体1-8-p：甲基(e)-3-(4-((3-(4-氯-2-甲基苯甲酰基)-7-羟基喹啉-4-基)
氧)苯基)丙烯酸
[0211]1h nmr(500mhz,chloroform-d)δ8.99(s,1h),7.96(d,j＝9.1hz,1h),7.65
–
7.54(m,2h),7.36
–
7.30(m,3h),7.17(dd,j＝8.3,2.1hz,1h),7.14
–
7.08(m,2h),6.48(d,j＝8.7hz,2h),6.31(d,j＝16.0hz,1h),3.80(s,3h),1.98(s,3h).
13
c nmr(126mhz,chloroform-d)δ192.74,167.52,162.81,159.15,158.93,151.46,151.33,143.49,141.27,138.12,135.87,131.91,131.52,130.10,129.87,125.86,125.42,121.94,120.61,117.51,116.79,116.49,108.87,51.94,20.04.
[0212]
中间体1-8-q：甲基(e)-3-(4-((3-(4-氟-2，6-二甲基苯甲酰基)-7-羟基喹啉-4-基)氧)苯基)丙烯酸
[0213]1h nmr(500mhz,chloroform-d)δ9.21(s,1h),7.70(d,j＝9.2hz,1h),7.59(d,j＝15.7hz,1h),7.44
–
7.43(m,1h),7.33(d,j＝8.8hz,2h),7.26
–
7.23(m,1h),6.58(d,j＝9.3hz,2h),6.49(d,j＝8.8hz,2h),6.31(d,j＝15.9hz,1h),4.04(s,1h),3.80(s,3h),2.00(s,6h).
13
c nmr(126mhz,chloroform-d)δ195.62,167.65,162.66(d,j＝248.1hz),162.37,159.56,158.20,153.09,152.61,143.77,137.18(d,j＝8.6hz),130.12,129.60,129.51,126.02,121.42,120.91,117.09,116.95,116.08,114.68(d,j＝21.2hz),110.01,51.93,19.87.
[0214][0215]
下表为反应路线2合成的中间体种类
[0216][0217]
合成步骤2-1
[0218]
中间体2-1-d的合成步骤：
[0219]
将邻乙基苯酚(1g，8.18mmol)加入100ml圆底烧瓶中，加入6ml thf溶解，在冰浴条件下加入nbs(1.45g，8.15mmol)，加入几滴稀硫酸催化；常温反应48h，tlc监测反应终点，反应完毕之后反应液用ea和h2o萃取3次，收集有机相，用无水硫酸钠干燥后减压蒸干，硅胶柱层析分离得透明油状物。
[0220]
中间体2-1-d 4-溴-2-乙基苯酚
[0221]1h nmr(500mhz,chloroform-d)δ7.25(d,j＝2.6hz,1h),7.17(dd,j＝8.5,2.5hz,1h),6.64(d,j＝8.5hz,1h),4.80(s,1h),2.60(q,j＝7.5hz,2h),1.23(t,j＝7.6hz,3h).
13
c nmr(126mhz,chloroform-d)δ152.61,132.47,132.11,129.77,116.94,113.03,22.95,13.81.
[0222][0223]
合成步骤2-2
[0224]
中间体2-2-a-g的合成步骤：
[0225]
将2-1-a-g(5.36mmol)加到100ml圆底烧瓶中，加入6ml的dmf，搅拌均匀，再加入丙烯酸甲酯(16.08mmol)，二(三苯基膦)二氯化钯(0.536mmol)，三乙胺(10.72mmol)，油浴135
℃，n2保护，反应4h。tlc监测反应终点，反应完毕之后反应液用ea和h2o萃取3次，收集有机相，用无水硫酸钠干燥后减压蒸干，硅胶柱层析分离得透明油状物。
[0226]
中间体2-2-a甲基(e)-3-(4-羟基-3-甲基苯基)丙烯酸
[0227]1h nmr(500mhz,dmso-d6)δ9.95(s,1h),7.52(d,j＝15.9hz,1h),7.46(s,1h),7.36(d,j＝8.3hz,1h),6.80(d,j＝8.3hz,1h),6.37(d,j＝15.9hz,1h),3.68(s,3h),2.12(s,3h).
13
c nmr(126mhz,dmso-d6)δ167.12,158.13,145.04,130.96,127.98,124.91,124.60,114.88,113.60,51.23,15.87.
[0228]
中间体2-2-b甲基(e)-3-(4-羟基-2-甲基苯基)丙烯酸
[0229]1h nmr(500mhz,dmso-d6)δ9.90(s,1h),7.78(d,j＝15.7hz,1h),7.60(d,j＝9.1hz,1h),6.66
–
6.61(m,2h),6.33(d,j＝15.8hz,1h),3.69(s,3h),2.31(s,3h).
13
c nmr(126mhz,dmso-d6)δ167.11,159.54,141.67,139.69,128.48,123.58,117.24,114.70,113.82,51.29,19.45.
[0230]
中间体2-2-c甲基(e)-3-(3-氟-4-羟基苯基)丙烯酸
[0231]1h nmr(500mhz,dmso-d6)δ10.47(s,1h),7.62(dd,j＝12.5,2.1hz,1h),7.55(d,j＝16.0hz,1h),7.36(dd,j＝8.2,2.1hz,1h),6.96(t,j＝8.7hz,1h),6.49(d,j＝16.0hz,1h),3.69(s,3h).
13
c nmr(126mhz,dmso-d6)δ166.87,151.07(d,j＝241.5hz),147.34(d,j＝12.4hz),143.78(d,j＝2.3hz),126.03(d,j＝2.7hz),125.91(d,j＝6.6hz),117.80(d,j＝3.3hz),115.66,115.63(d,j＝18.6hz),51.35.
[0232]
中间体2-2-d甲基(e)-3-(3-乙基-4-羟基苯基)丙烯酸
[0233]1h nmr(500mhz,chloroform-d)δ7.64(d,j＝16.0hz,1h),7.32(d,j＝2.2hz,1h),7.26
–
7.23(m,1h),6.80(d,j＝8.3hz,1h),6.30(d,j＝15.9hz,1h),3.81(s,3h),2.65(q,j＝7.6hz,2h),1.24(t,j＝7.6hz,3h).
13
c nmr(126mhz,chloroform-d)δ168.55,156.24,145.55,130.91,129.60,127.62,127.06,115.70,114.63,51.86,23.05,13.92.
[0234]
中间体2-2-e甲基(e)-3-(4-羟基-3-甲氧苯基)丙烯酸
[0235]1h nmr(500mhz,chloroform-d)δ7.61(d,j＝15.9hz,1h),7.05(dd,j＝8.2,1.9hz,1h),7.01(d,j＝1.9hz,1h),6.90(d,j＝8.1hz,1h),6.28(d,j＝15.9hz,1h),3.90(s,3h),3.78(s,3h).
13
c nmr(126mhz,chloroform-d)δ167.87,148.18,146.96,145.10,127.01,123.12,115.21,114.90,109.55,56.04,51.71.
[0236]
中间体2-2-f甲基(e)-3-(4-羟基-3，5-二甲氧苯基)丙烯酸
[0237]1h nmr(500mhz,chloroform-d)δ7.58(d,j＝16.0hz,1h),7.17(s,2h),6.28(d,j＝15.9hz,1h),5.13(s,1h),3.79(s,3h),2.26(s,6h).
13
c nmr(126mhz,chloroform-d)δ168.14,154.63,145.19,128.99,126.66,123.69,114.84,51.71,16.03.
[0238]
中间体2-2-g甲基(e)-3-(4-羟基-2，6-二甲氧苯基)丙烯酸
[0239]1h nmr(500mhz,dmso-d6)δ9.64(s,1h),7.74(d,j＝16.3hz,1h),6.52(s,2h),6.05(d,j＝16.3hz,1h),3.71(s,3h),2.26(s,6h).
13
c nmr(126mhz,dmso-d6)δ166.94,157.71,142.36,139.10,123.75,120.13,115.51,51.37,21.28.
[0240][0241]
合成步骤2-3
[0242]
中间体2-3-a-g的合成步骤：
[0243]
将1-6-j(0.99mmol)和2-2-a-g(1.04mmol)加到100ml圆底烧瓶中，加入6ml的dmf，搅拌均匀，再加入无水碳酸钾(1.48mmol)，升温至70℃，n2保护，反应2h；tlc监测反应终点，反应完毕之后反应液中加入稀盐酸除去碳酸钾，用ea和h2o萃取3次，收集有机相，用无水硫酸钠干燥后减压蒸干，硅胶柱层析分离得黄色固体或油状物。
[0244]
中间体2-3-a甲基(e)-3-(4-((7-(苄氧基)-3-(2-乙基苯甲酰)喹啉-4-基)氧)-3-甲基苯基)丙烯酸
[0245]1h nmr(500mhz,chloroform-d)δ9.11(s,1h),7.92(d,j＝9.2hz,1h),7.66(s,1h),7.56(d,j＝16.0hz,1h),7.51(d,j＝7.8hz,2h),7.45
–
7.34(m,4h),7.32
–
7.27(m,2h),7.22(d,j＝7.4hz,2h),7.14(t,j＝7.5hz,1h),7.09(d,j＝8.5hz,1h),6.32
–
6.23(m,2h),5.28(s,2h),3.79(s,3h),2.40
–
2.24(m,2h),1.79(s,3h),1.01(t,j＝7.5hz,3h).
13
c nmr(126mhz,chloroform-d)δ194.96,167.52,162.02,158.01,157.39,153.60,152.65,144.78,143.98,137.95,135.87,131.72,130.82,130.16,129.68,129.10,128.78,128.42,127.87,127.77,127.23,125.33,124.45,122.26,121.32,117.29,116.54,113.85,108.90,70.53,51.68,26.00,15.50,15.41.
[0246]
中间体2-3-b甲基(e)-3-(4-((7-(苄氧基)-3-(2-乙基苯甲酰)喹啉-4-基)氧)-2-甲基苯基)丙烯酸
[0247]1h nmr(500mhz,chloroform-d)δ9.10(s,1h),7.97(d,j＝9.2hz,1h),7.82(d,j＝15.9hz,1h),7.60(d,j＝2.4hz,1h),7.50(d,j＝7.3hz,2h),7.44
–
7.34(m,4h),7.31
–
7.27(m,3h),7.19
–
7.12(m,2h),6.27
–
6.15(m,3h),5.27(s,2h),3.79(s,3h),2.32(q,j＝7.5hz,2h),2.23(s,3h),1.03(t,j＝7.5hz,3h).
13
c nmr(126mhz,chloroform-d)δ194.77,167.63,162.13,159.26,157.51,153.83,153.15,144.94,141.46,139.94,137.72,135.99,131.75,130.28,129.58,128.90,128.53,128.37,128.09,127.85,125.40,124.76,121.63,121.33,117.91,117.83,117.54,113.83,109.06,70.62,51.82,26.36,19.90,15.62.
[0248]
中间体2-3-c甲基(e)-3-(4-((7-(苄氧基)-3-(2-乙基苯甲酰)喹啉-4-基)氧)-3-氟苯基)丙烯酸
[0249]1h nmr(500mhz,chloroform-d)δ9.04(s,1h),8.01(d,j＝9.2hz,1h),7.60(d,j＝2.5hz,1h),7.53
–
7.47(m,3h),7.45
–
7.34(m,4h),7.31(dd,j＝9.2,2.5hz,1h),7.30
–
7.27(m,1h),7.21(d,j＝7.7hz,1h),7.16
–
7.10(m,2h),7.01(d,j＝8.5hz,1h),6.46(t,j＝8.4hz,1h),6.27(d,j＝15.9hz,1h),5.27(s,2h),3.79(s,3h),2.40(q,j＝7.5hz,2h),1.07(t,j＝7.5hz,3h).
13
c nmr(126mhz,chloroform-d)δ194.64,167.18,162.19,157.21,
153.76,152.93,151.00,147.14(d,j＝11.4hz),144.72,142.76,137.36,135.93,132.06,130.57(d,j＝6.3hz),130.26,129.85,128.91,128.56,127.86,125.59,124.82(d,j＝3.2hz),124.46,121.59,121.39,118.31,117.23,116.99,115.72(d,j＝18.4hz),109.09,70.65,51.96,26.45,15.72.
[0250]
中间体2-3-d甲基(e)-3-(4-((7-(苄氧基)-3-(2-乙基苯甲酰)喹啉-4-基)氧)-3-乙基苯基)丙烯酸
[0251]1h nmr(500mhz,chloroform-d)δ9.08(s,1h),7.86(d,j＝9.1hz,1h),7.61(d,j＝2.4hz,1h),7.56(d,j＝16.0hz,1h),7.49(d,j＝7.3hz,2h),7.42(t,j＝7.4hz,2h),7.39
–
7.34(m,2h),7.29
–
7.26(m,2h),7.24(d,j＝2.2hz,1h),7.19(d,j＝7.7hz,1h),7.14
–
7.07(m,2h),6.30
–
6.23(m,2h),5.26(s,2h),3.79(s,3h),2.39
–
2.23(m,2h),2.21
–
2.05(m,2h),1.07(t,j＝7.5hz,3h),1.00(t,j＝7.5hz,3h).
13
c nmr(126mhz,chloroform-d)δ195.19,167.68,162.04,157.81,157.37,153.81,152.79,144.87,144.27,138.04,135.97,133.50,131.79,130.23,129.79,129.33,129.05,128.90,128.54,127.85,127.22,125.43,124.54,122.63,121.40,117.42,116.56,113.97,109.13,70.63,51.79,26.13,22.32,15.61,13.59.
[0252]
中间体2-3-e甲基(e)-3-(4-((7-(苄氧基)-3-(2-乙基苯甲酰)喹啉-4-基)氧)-3-甲氧基苯基)丙烯酸
[0253]1h nmr(500mhz,chloroform-d)δ9.00(s,1h),8.04(d,j＝9.3hz,1h),7.57(d,j＝2.5hz,1h),7.54(d,j＝16.0hz,1h),7.49(d,j＝7.0hz,2h),7.41(t,j＝7.3hz,2h),7.39
–
7.33(m,2h),7.31(d,j＝7.6hz,1h),7.28(dd,j＝9.3,2.5hz,1h),7.17
–
7.12(m,2h),6.85(d,j＝1.9hz,1h),6.82(dd,j＝8.3,2.0hz,1h),6.34(d,j＝8.3hz,1h),6.27(d,j＝16.0hz,1h),5.25(s,2h),3.79(s,3h),3.57(s,3h),2.31(q,j＝7.5hz,2h),1.04(t,j＝7.5hz,3h).
13
cnmr(126mhz,chloroform-d)δ194.79,167.47,162.03,157.96,153.58,152.90,149.12,148.94,145.08,144.13,137.40,136.02,131.65,130.71,130.28,129.52,128.86,128.48,127.85,125.46,124.81,121.57,121.28,121.15,117.23,117.08,116.27,110.81,108.87,70.57,55.78,51.84,26.38,15.65.
[0254]
中间体2-3-f甲基(e)-3-(4-((7-(苄氧基)-3-(2-乙基苯甲酰)喹啉-4-基)氧)-3，5-二甲氧基苯基)丙烯酸
[0255]1h nmr(500mhz,chloroform-d)δ8.63(s,1h),8.23(d,j＝9.2hz,1h),7.57(d,j＝2.5hz,1h),7.53
–
7.47(m,3h),7.42(t,j＝7.5hz,2h),7.39
–
7.31(m,3h),7.28
–
7.23(m,1h),7.16(d,j＝7.6hz,1h),7.09(t,j＝7.5hz,1h),6.93(s,2h),6.27(d,j＝16.0hz,1h),5.26(s,2h),3.80(s,3h),2.32(q,j＝7.4hz,2h),1.79(s,6h),1.07(t,j＝7.4hz,3h).
13
c nmr(126mhz,chloroform-d)δ194.58,167.51,161.28,157.51,154.00,152.36,151.87,146.53,143.99,136.39,136.18,132.50,131.38,130.49,130.32,129.19,128.83,128.40,127.79,125.36,124.24,120.52,119.15,117.37,115.87,108.82,70.45,51.80,27.14,16.87,15.64.
[0256]
中间体2-3-g甲基(e)-3-(4-((7-(苄氧基)-3-(2-乙基苯甲酰)喹啉-4-基)氧)-2，6-二甲氧基苯基)丙烯酸
[0257]1h nmr(500mhz,chloroform-d)δ9.09(s,1h),8.00(d,j＝9.2hz,1h),7.71(d,j＝
16.3hz,1h),7.60(d,j＝2.5hz,1h),7.50(d,j＝7.3hz,2h),7.45
–
7.34(m,4h),7.32
–
7.27(m,2h),7.16(t,j＝6.8hz,2h),6.05(s,2h),5.97(d,j＝16.3hz,1h),5.27(s,2h),3.80(s,3h),2.32(q,j＝7.5hz,2h),2.14(s,6h),1.05(t,j＝7.5hz,3h).
13
c nmr(126mhz,chloroform-d)δ194.74,167.37,162.12,157.75,157.65,153.79,153.22,145.07,142.57,139.06,137.63,136.06,131.67,130.43,129.49,128.90,128.81,128.52,127.85,125.39,124.85,123.09,121.46,121.21,117.72,115.62,109.04,70.62,51.84,26.41,21.32,15.63.
[0258][0259]
合成步骤2-4
[0260]
中间体2-4-a-g的合成步骤：
[0261]
将2-3-a-g(0.34mmol)加到100ml圆底烧瓶中，加入6ml的dcm，搅拌均匀，并用n2保护。在冰浴的条件下缓慢滴加1mol/l的三溴化硼(0.68mmol)，滴加完毕之后反应5分钟。tlc监测反应终点，反应完毕之后加入过量的无水甲醇猝灭未反应的三溴化硼以及分解形成的硼络合物。反应液减压蒸干，硅胶柱层析分离得黄色固体或油状物。
[0262]
中间体2-4-a甲基(e)-3-(4-((3-(2-乙基苯甲酰)-7-羟基喹啉-4-基)氧)-3-甲基苯基)丙烯酸
[0263]1h nmr(500mhz,chloroform-d)δ8.98(s,1h),7.80(d,j＝9.1hz,1h),7.58
–
7.50(m,2h),7.41
–
7.34(m,2h),7.24
–
7.19(m,2h),7.17(t,j＝7.5hz,1h),7.12(dd,j＝8.5,2.3hz,1h),7.01(dd,j＝9.1,2.3hz,1h),6.35(d,j＝8.5hz,1h),6.28(d,j＝15.9hz,1h),5.29(s,1h),3.79(d,j＝2.0hz,3h),2.35
–
2.25(m,2h),1.82(s,3h),1.00(t,j＝7.5hz,3h).
13
c nmr(126mhz,chloroform-d)δ194.35,167.74,162.58,158.88,157.92,151.62,151.49,145.03,144.07,137.72,131.98,131.02,130.34,129.83,129.50,128.13,127.38,125.51,125.12,121.67,121.63,116.79,116.70,114.23,108.94,51.87,26.09,15.56.
[0264]
中间体2-4-b甲基(e)-3-(4-((3-(2-乙基苯甲酰)-7-羟基喹啉-4-基)氧)-2-甲基苯基)丙烯酸
[0265]1h nmr(500mhz,chloroform-d)δ9.00(s,1h),7.87(d,j＝9.2hz,1h),7.83(d,j＝15.8hz,1h),7.44
–
7.37(m,3h),7.33(d,j＝8.7hz,1h),7.22
–
7.15(m,2h),6.97(dd,j＝9.2,2.3hz,1h),6.32(dd,j＝8.7,2.7hz,1h),6.27(d,j＝2.7hz,1h),6.23(d,j＝15.8hz,1h),3.80(s,3h),2.32(q,j＝7.5hz,2h),2.25(s,3h),1.04(t,j＝7.5hz,3h).
13
c nmr(126mhz,chloroform-d)δ194.09,167.69,162.43,159.12,158.75,152.06,151.90,145.10,141.45,140.06,137.46,131.91,130.41,129.65,128.66,128.19,125.51,125.40,121.46,120.98,118.07,118.02,116.83,114.04,109.06,51.88,26.38,19.90,15.61.
[0266]
中间体2-4-c甲基(e)-3-(4-((3-(2-乙基苯甲酰)-7-羟基喹啉-4-基)氧)-3-氟苯基)丙烯酸
[0267]1h nmr(500mhz,chloroform-d)δ8.91(s,1h),8.06(d,j＝9.2hz,1h),7.84(d,j＝
2.3hz,1h),7.50(d,j＝16.0hz,1h),7.45
–
7.38(m,1h),7.34
–
7.31(m,1h),7.26
–
7.15(m,4h),7.11(dd,j＝11.4,2.0hz,1h),7.08
–
7.04(m,1h),6.63(t,j＝8.3hz,1h),6.28(d,j＝16.0hz,1h),3.80(s,3h),2.41(q,j＝7.5hz,2h),1.07(t,j＝7.5hz,3h).
13
c nmr(126mhz,dmso-d6)δ193.02,166.85,166.50,162.62,150.93,150.23,143.88,142.54,136.59,132.16,130.81(d,j＝6.7hz),130.30,129.65,126.02,125.64,125.16,121.67,120.25,118.43,117.79(d,j＝3.6hz),117.42,115.93,115.65,115.53,108.15,51.53,25.61,15.46.
[0268]
中间体2-4-d甲基(e)-3-(3-乙基-4-((3-(2-乙基苯甲酰)-7-羟基喹啉-4-基)氧)苯基)丙烯酸
[0269]1h nmr(500mhz,chloroform-d)δ8.96(s,1h),7.96
–
7.88(m,2h),7.56(d,j＝15.9hz,1h),7.39(t,j＝7.5hz,1h),7.33(d,j＝7.5hz,1h),7.25
–
7.11(m,6h),6.40(d,j＝8.5hz,1h),6.29(d,j＝16.1hz,1h),3.79(s,3h),2.38
–
2.24(m,2h),2.22
–
2.07(m,2h),1.09(t,j＝7.5hz,3h),1.00(t,j＝7.5hz,3h).
13
c nmr(126mhz,chloroform-d)δ193.26,167.63,163.52,160.14,157.21,149.92,145.43,144.01,137.00,133.95,132.33,130.50,130.20,130.03,129.25,127.26,125.64,125.52,122.65,121.69,117.11,117.04,114.64,107.86,51.88,26.21,22.38,15.57,13.59.
[0270]
中间体2-4-e甲基(e)-3-(4-((3-(2-乙基苯甲酰)-7-羟基喹啉-4-基)氧)-3-甲氧基苯基)丙烯酸
[0271]1h nmr(500mhz,chloroform-d)δ8.90(s,1h),7.96(d,j＝9.2hz,1h),7.55(d,j＝16.0hz,1h),7.43(s,1h),7.37(d,j＝7.6hz,2h),7.17(t,j＝8.4hz,2h),7.03(dd,j＝9.1,2.2hz,1h),6.89
–
6.83(m,2h),6.46(d,j＝8.2hz,1h),6.28(d,j＝15.9hz,1h),3.80(s,3h),3.59(s,3h),2.32(q,j＝7.4hz,2h),1.04(t,j＝7.5hz,3h).
13
c nmr(126mhz,chloroform-d)δ194.34,167.55,162.04,159.05,152.10,152.00,149.21,148.72,145.18,144.18,137.24,131.75,130.87,130.52,129.58,125.55,125.39,121.64,121.13,120.51,117.17,116.75,116.44,110.95,109.41,55.81,51.90,26.43,15.66.
[0272]
中间体2-4-f甲基(e)-3-(4-((3-(2-乙基苯甲酰)-7-羟基喹啉-4-基)氧)-3，5-二甲氧基苯基)丙烯酸
[0273]1h nmr(500mhz,chloroform-d)δ8.57(s,1h),8.23(d,j＝9.2hz,1h),7.49(d,j＝16.0hz,1h),7.40(t,j＝7.5hz,1h),7.30(t,j＝8.0hz,3h),7.20
–
7.12(m,2h),6.94(s,2h),6.27(d,j＝16.0hz,1h),3.81(s,3h),2.36(q,j＝7.4hz,2h),1.87(s,6h),1.06(t,j＝7.4hz,3h).
13
c nmr(126mhz,chloroform-d)δ192.44,167.49,162.96,160.53,153.56,148.38,147.92,146.93,143.74,135.54,133.07,132.62,132.14,130.64,130.55,129.29,125.65,125.12,122.20,118.73,117.96,115.16,107.30,51.93,27.29,16.94,15.62.
[0274]
中间体2-4-g甲基(e)-3-(4-((3-(2-乙基苯甲酰)-7-羟基喹啉-4-基)氧)-2，6-二甲氧基苯基)丙烯酸
[0275]1h nmr(500mhz,chloroform-d)δ8.96(s,1h),8.00(d,j＝9.1hz,1h),7.67(d,j＝16.3hz,1h),7.53(d,j＝2.4hz,1h),7.39(t,j＝8.1hz,1h),7.29
–
7.26(m,1h),7.21(dd,j＝9.1,2.4hz,1h),7.17
–
7.11(m,2h),6.04(s,2h),5.94(d,j＝16.3hz,1h),3.78(s,3h),2.30
–
2.24(m,2h),2.11(s,6h),1.02(t,j＝7.5hz,3h).
13
c nmr(126mhz,chloroform-d)δ
193.89,167.42,162.61,159.17,157.26,151.66,145.22,142.50,139.44,139.09,137.08,131.89,130.44,129.55,129.10,125.44,123.14,121.62,120.56,116.91,115.71,115.60,108.85,51.86,26.37,21.20,15.52.
[0276]
代表性化合物的合成过程
[0277][0278]
合成步骤9
[0279]
化合物1～24的合成步骤：
[0280]
将1-8a-q或2-4-a-g(0.68mmol)加到100ml圆底烧瓶中，加入6ml的thf，搅拌均匀；将lioh(3.40mmol)溶于2ml水配置成naoh溶液；在冰浴的条件下往反应液中滴加naoh溶液，滴加完后常温反应15h；tlc监测反应终点，反应完毕之后在冰浴的条件下滴加稀盐酸调ph至1；反应液用ea萃取3次，收集有机相，用无水硫酸钠干燥后减压蒸干，硅胶柱层析分离得白色或青色固体。
[0281]
化合物1到化合物24利用合适的起始原料通过步骤9类似的过程制备；这些化合物的表征如下：化合物1到化合物17是由反应路线1合成
[0282]
化合物1：(e)-3-(4-((3-苯甲酰基-7-羟基喹啉-4-基)氧)苯基)丙烯酸：具体结构见化合物1～24的结构总结；
[0283]
该化合物由中间体1-8-a反应得。1h nmr(500mhz,dmso-d6)δ12.26(s,1h),10.78(s,1h),8.85(s,1h),7.90(d,j＝9.1hz,1h),7.66
–
7.61(m,3h),7.50
–
7.44(m,6h),7.41(d,j＝2.4hz,1h),7.26(dd,j＝9.1,2.4hz,1h),6.59(d,j＝8.8hz,2h),6.36(d,j＝16.0hz,1h).
13
cnmr(126mhz,dmso)δ192.88,167.91,161.10,158.95,156.37,153.03,151.49,142.68,137.07,133.68,129.94,129.36,129.28,128.65,124.53,120.83,120.27,118.68,116.36,115.46,110.67.esi-ms(-)[m/z]:410.58[m-h]-.
[0284]
化合物2：(e)-3-(4((3-(3-氟苯甲酰基)-7-羟基喹啉-4-基)氧)苯基)丙烯酸：具体结构见化合物1～24的结构总结；
[0285]
该化合物由中间体1-8-b反应得。1h nmr(500mhz,dmso-d6)δ8.85(s,1h),7.90(d,j＝9.1hz,1h),7.52
–
7.45(m,5h),7.43(d,j＝16.0hz,1h),7.40(d,j＝2.4hz,1h),7.36(d,j＝9.1hz,1h),7.25(dd,j＝9.1,2.4hz,1h),6.61(d,j＝8.8hz,2h),6.36(d,j＝16.0hz,1h).
13
c nmr(126mhz,dmso)δ192.18,192.16,168.51,163.37,161.79,161.41,159.21,157.04,153.64,151.91,142.63,142.61,142.60,139.85,139.80,131.26,131.20,130.27,129.87,126.08,126.05,125.01,121.25,120.91,120.74,120.00,119.72,116.71,115.82,115.64,111.10.esi-ms(-)[m/z]:428.77[m-h]-.
[0286]
化合物3：(e)-3-(4((3-(4-氟苯甲酰基)-7-羟基喹啉-4-基)氧)苯基)丙烯酸：具体结构见化合物1～24的结构总结；
[0287]
该化合物由中间体1-8-c反应得。1h nmr(500mhz,methanol-d4)δ8.80(s,1h),8.02(d,j＝9.1hz,1h),7.64(dd,j＝8.8,5.4hz,2h),7.51(d,j＝16.0hz,1h),7.40(d,j＝
2.4hz,1h),7.35(d,j＝8.8hz,2h),7.24(dd,j＝9.1,2.4hz,1h),7.13(t,j＝8.7hz,2h),6.54(d,j＝8.8hz,2h),6.30(d,j＝16.0hz,1h).
13
c nmr(126mhz,meod)δ193.12,170.33,168.47,166.45,163.25,160.41,158.97,154.20,152.73,144.96,135.31,135.29,133.47,133.39,131.18,131.07,130.88,125.83,122.01,121.15,118.80,117.93,117.51,116.69,116.52,110.79.esi-ms(-)[m/z]:428.82[m-h]-.
[0288]
化合物4：(e)-3-(4-((7-羟基-3-(2-(三氟甲基)苯甲酰基)喹啉-4-基)氧)苯基)丙烯酸：具体结构见化合物1～24的结构总结；
[0289]
该化合物由中间体1-8-d反应得。1h nmr(500mhz,dmso-d6)δ9.07(s,1h),7.75(d,j＝7.9hz,1h),7.63
–
7.56(m,2h),7.54
–
7.47(m,2h),7.41(d,j＝8.5hz,2h),7.38
–
7.33(m,2h),7.15(dd,j＝9.2,2.4hz,1h),6.40(d,j＝8.5hz,2h),6.33(d,j＝15.9hz,1h).
13
c nmr(126mhz,dmso)δ192.07,158.48,158.06,154.26,152.03,149.51,138.92,132.09,130.58,129.54,129.44,128.02,125.81,125.29,121.39,119.07,115.47,115.38,114.73,111.04.esi-ms(-)[m/z]:478.81[m-h]-.
[0290]
化合物5：(e)-3-(4-((7-羟基-3-(4-(三氟甲基)苯甲酰基)喹啉-4-基)氧)苯基)丙烯酸：具体结构见化合物1～24的结构总结；
[0291]
该化合物由中间体1-8-e反应得。1h nmr(500mhz,dmso-d6)δ10.91(s,1h),8.91(s,1h),7.92(d,j＝9.1hz,1h),7.79(s,4h),7.50
–
7.39(m,4h),7.29
–
7.22(m,1h),6.56(d,j＝8.3hz,2h),6.35(d,j＝16.0hz,1h).
13
c nmr(126mhz,dmso)δ192.14,167.62,161.52,158.79,157.02,152.97,151.45,142.89,140.52,130.01,129.86,129.36,125.55,125.54,124.87,124.76,120.96,119.45,118.35,116.24,115.42,110.42.esi-ms(-)[m/z]:478.55[m-h]-.
[0292]
化合物6：(e)-3-(4-((7-羟基-3-(4-(三氟甲氧基)苯甲酰基)喹啉-4-基)氧)苯基)丙烯酸：具体结构见化合物1～24的结构总结；
[0293]
该化合物由中间体1-8-f反应得。1h nmr(500mhz,dmso-d6)δ10.90(s,1h),8.92(s,1h),7.95(d,j＝9.1hz,1h),7.73(d,j＝8.8hz,2h),7.51
–
7.37(m,6h),7.28(dd,j＝9.1,2.4hz,1h),6.59(d,j＝8.8hz,2h),6.35(d,j＝16.0hz,1h).
13
c nmr(126mhz,dmso)δ191.19,167.47,161.50,158.60,156.99,152.20,151.67,151.02,142.75,135.86,131.58,129.85,129.37,124.67,120.92,120.59,119.47,118.84,118.32,116.29,115.41,109.85.esi-ms(-)[m/z]:494.76[m-h]-.
[0294]
化合物7：(e)-3-(4-((7-羟基-3-(4-甲氧基苯甲酰基)喹啉-4-基)氧)苯基)丙烯酸：具体结构见化合物1～24的结构总结；
[0295]
该化合物由中间体1-8-g反应得。1h nmr(500mhz,dmso-d6)δ8.80(s,1h),7.88(d,j＝9.1hz,1h),7.63(d,j＝8.8hz,2h),7.49(d,j＝8.6hz,2h),7.45(d,j＝16.0hz,1h),7.40(d,j＝2.4hz,1h),7.24(dd,j＝9.1,2.4hz,1h),6.99(d,j＝8.8hz,2h),6.62(d,j＝8.6hz,2h),6.35(d,j＝16.0hz,1h),3.84(s,3h).
13
c nmr(126mhz,dmso)δ191.01,167.72,163.64,160.73,158.93,155.76,152.73,151.22,142.78,131.90,129.89,129.73,129.17,124.31,120.83,120.67,116.37,115.46,113.94,110.60,55.66.esi-ms(-)[m/z]:440.80[m-h]-.
[0296]
化合物8：(e)-3-(4-((7-羟基-3-(噻吩-2-羰基)喹啉-4-基)氧)苯基)丙烯酸：具体结构见化合物1～24的结构总结；
[0297]
该化合物由中间体1-8-h反应得。1h nmr(500mhz,dmso-d6)δ8.88(s,1h),8.08(d,j＝4.9hz,1h),7.90(d,j＝9.1hz,1h),7.70(d,j＝3.8hz,1h),7.52(d,j＝8.7hz,2h),7.46(d,j＝16.0hz,1h),7.40(d,j＝2.4hz,1h),7.28
–
7.21(m,2h),6.73(d,j＝8.6hz,2h),6.37(d,j＝16.0hz,1h).
13
c nmr(126mhz,dmso)δ184.26,167.74,160.88,158.97,155.85,152.80,150.68,143.31,142.66,136.68,136.40,129.91,129.26,128.89,124.39,120.74,120.60,118.53,116.53,115.44,110.58.esi-ms(-)[m/z]:416.52[m-h]-.
[0298]
化合物9：(e)-3-(4-((3-(苯并呋喃-5-羰基)-7-羟基喹啉-4-基)氧)苯基)丙烯酸：具体结构见化合物1～24的结构总结；
[0299]
该化合物由中间体1-8-i反应得。1h nmr(500mhz,methanol-d4)δ8.72(s,1h),7.91(d,j＝9.0hz,1h),7.77(d,j＝1.8hz,1h),7.74(d,j＝2.3hz,1h),7.45(dd,j＝8.7,1.8hz,1h),7.38(d,j＝8.7hz,1h),7.34
–
7.28(m,2h),7.17
–
7.09(m,3h),6.77(d,j＝2.2hz,1h),6.37(d,j＝8.8hz,2h),6.17(d,j＝15.9hz,1h).
13
c nmr(126mhz,meod)δ194.33,171.80,163.04,160.07,159.14,158.95,153.97,152.74,148.29,143.43,134.13,131.45,130.44,128.94,127.02,125.79,125.26,121.87,121.60,120.71,117.96,117.54,112.34,110.75,108.30.esi-ms(-)[m/z]:450.81[m-h]-.
[0300]
化合物10：(e)-3-(4-((3-(2-乙基苯甲酰基)7-羟基喹啉-4-基)氧)苯基)丙烯酸：具体结构见化合物1～24的结构总结；
[0301]
该化合物由中间体1-8-j反应得。1h nmr(500mhz,dmso-d6)δ12.28(s,1h),10.80(s,1h),8.92(s,1h),7.82(d,j＝9.1hz,1h),7.60
–
7.36(m,5h),7.33(d,j＝7.7hz,1h),7.28
–
7.11(m,3h),6.44(d,j＝8.2hz,2h),6.36(d,j＝16.0hz,1h),2.31(q,j＝7.6hz,2h),0.95(t,j＝7.5hz,3h).
13
c nmr(126mhz,dmso)δ194.45,167.58,161.33,159.07,156.71,153.38,152.16,143.39,142.96,137.73,131.54,129.89,129.64,129.37,129.03,125.44,124.74,120.73,118.01,115.71,115.41,110.68,25.48,15.41.esi-ms(-)[m/z]:438.90[m-h]-.
[0302]
化合物11：(e)-3-(4-((7-羟基-3-(2-异丙基苯甲酰基)喹啉-4-基)氧)苯基)丙烯酸：具体结构见化合物1～24的结构总结；
[0303]
该化合物由中间体1-8-k反应得。1h nmr(500mhz,dmso-d6)δ12.20(s,1h),10.84(s,1h),8.96(s,1h),7.76(d,j＝9.1hz,1h),7.54
–
7.47(m,4h),7.47
–
7.41(m,2h),7.40
–
7.34(m,2h),7.28(d,j＝7.5hz,1h),7.20(dd,j＝9.1,2.4hz,1h),7.14(t,j＝7.4hz,1h),6.51(d,j＝8.8hz,2h),6.36(d,j＝16.0hz,1h),2.88(p,j＝6.8hz,1h),0.98(d,j＝6.8hz,6h).
13
cnmr(126mhz,dmso)δ194.73,167.62,161.44,159.10,156.66,153.56,152.32,147.47,144.19,143.01,137.93,131.29,130.11,129.98,128.97,128.73,126.00,125.23,121.07,120.80,117.96,115.75,115.46,110.77,29.29,23.77.esi-ms(-)[m/z]:452.24[m-h]-.
[0304]
化合物12：(e)-3-(4-((3-(2，6-二甲基苯甲酰基)-7-羟基喹啉-4-基)氧)苯基)丙烯酸：具体结构见化合物1～24的结构总结；
[0305]
该化合物由中间体1-8-l反应得。1h nmr(500mhz,dmso-d6)δ12.23(s,1h),10.94(s,1h),9.07(s,1h),7.66(d,j＝9.2hz,1h),7.57
–
7.44(m,3h),7.38(d,j＝2.4hz,1h),7.18(dd,j＝9.2,2.4hz,1h),7.10(t,j＝7.6hz,1h),6.93(d,j＝7.7hz,2h),6.48(d,j＝
8.4hz,2h),6.37(d,j＝16.0hz,1h),1.93(s,6h).
13
c nmr(126mhz,dmso)δ196.30,167.63,161.85,159.15,157.62,153.96,152.18,143.09,140.59,133.27,129.71,128.76,128.74,127.55,125.43,120.92,120.07,117.84,115.43,115.23,110.89,19.07.esi-ms(-)[m/z]:438.24[m-h]-.
[0306]
化合物13：(e)-3-(4-((3-(3，5-二甲基苯甲酰基)-7-羟基喹啉-4-基)氧)苯基)丙烯酸：具体结构见化合物1～24的结构总结；
[0307]
该化合物由中间体1-8-m反应得。1h nmr(500mhz,dmso-d6)δ11.06(s,1h),8.91(s,1h),7.95(d,j＝9.1hz,1h),7.52
–
7.44(m,4h),7.29(dd,j＝9.2,2.3hz,1h),7.25(s,1h),7.20(s,2h),6.69(d,j＝8.8hz,2h),6.38(d,j＝16.0hz,1h),2.24(s,6h).
13
c nmr(126mhz,dmso)δ192.37,167.58,161.74,158.66,150.35,142.90,137.90,137.04,135.01,130.11,129.86,129.48,126.88,126.72,125.00,121.15,120.45,118.33,116.81,115.70,101.94,20.60.esi-ms(-)[m/z]:438.78[m-h]-.
[0308]
化合物14：(e)-3-(4-((3-(2，4-二甲基苯甲酰基)-7-羟基喹啉-4-基)氧)苯基)丙烯酸：具体结构见化合物1～24的结构总结；
[0309]
该化合物由中间体1-8-n反应得。1h nmr(500mhz,dmso-d6)δ10.82(s,1h),8.86(s,1h),7.89(d,j＝9.1hz,1h),7.53
–
7.44(m,3h),7.40(s,1h),7.24(d,j＝6.3hz,2h),7.02(d,j＝7.2hz,2h),6.47(d,j＝8.3hz,2h),6.37(d,j＝16.0hz,1h),2.31(s,3h),1.96(s,3h).
13
cnmr(126mhz,dmso)δ193.96,167.63,161.27,159.03,156.62,152.93,151.88,143.00,142.03,138.02,134.92,131.93,130.79,129.91,129.20,126.18,124.61,121.07,120.80,118.12,116.04,115.58,110.44,21.05,19.65.esi-ms(-)[m/z]:438.79[m-h]-.
[0310]
化合物15：(e)-3-(4-((3-(4-氟-2-甲基苯甲酰基)-7-羟基喹啉-4-基)氧)苯基)丙烯酸：具体结构见化合物1～24的结构总结；
[0311]
该化合物由中间体1-8-o反应得。1h nmr(500mhz,dmso-d6)δ8.91(s,1h),7.88(d,j＝9.1hz,1h),7.51(d,j＝8.7hz,2h),7.47(d,j＝15.8hz,2h),7.45
–
7.42(m,1h),7.39(d,j＝2.4hz,1h),7.23(dd,j＝9.1,2.4hz,1h),7.08
–
7.00(m,2h),6.46(d,j＝8.7hz,2h),6.37(d,j＝16.0hz,1h),1.96(s,3h).
13
c nmr(126mhz,dmso)δ193.12,167.73,164.46,162.47,161.42,158.92,156.60,153.37,152.04,142.71,141.66,141.58,134.43,134.41,133.09,133.02,129.94,129.30,124.64,120.78,120.39,117.90,117.73,115.80,115.37,112.52,112.35,110.65,19.45.esi-ms(-)[m/z]:442.59[m-h]-.
[0312]
化合物16：(e)-3-(4-((3-(4-氯-2-甲基苯甲酰基)-7-羟基喹啉-4-基)氧)苯基)丙烯酸：具体结构见化合物1～24的结构总结；
[0313]
该化合物由中间体1-8-p反应得。1h nmr(500mhz,dmso-d6)δ12.27(s,1h),10.84(s,1h),8.93(s,1h),7.87(d,j＝9.0hz,1h),7.55
–
7.44(m,3h),7.43
–
7.34(m,2h),7.32
–
7.19(m,3h),6.46(d,j＝8.6hz,2h),6.39(d,j＝16.0hz,1h),1.94(s,3h).
13
c nmr(126mhz,dmso)δ193.39,167.61,161.51,158.94,156.82,153.36,151.98,142.92,140.03,136.64,136.06,131.72,130.70,129.98,129.26,125.56,124.72,120.82,120.27,118.21,115.76,115.38,110.60,19.09.esi-ms(-)[m/z]:458.19[m-h]-.
[0314]
化合物17：(e)-3-(4-((3-(4-氟-2，6-二甲基苯甲酰基)-7-羟基喹啉-4-基)氧)苯基)丙烯酸：具体结构见化合物1～24的结构总结；
[0315]
该化合物由中间体1-8-q反应得。1h nmr(500mhz,dmso-d6)δ12.16(s,1h),11.00(s,1h),9.11(s,1h),7.65(d,j＝9.1hz,1h),7.52
–
7.46(m,3h),7.38(d,j＝2.4hz,1h),7.18(dd,j＝9.1,2.4hz,1h),6.76(d,j＝9.9hz,2h),6.50(d,j＝8.5hz,2h),6.37(d,j＝16.0hz,1h),1.95(s,7h).
13
c nmr(126mhz,dmso)δ195.50,167.65,162.60,161.94,160.65,159.05,157.57,154.02,152.07,143.01,137.17,137.14,136.65,136.58,129.68,128.85,125.41,120.97,120.17,117.98,115.32,115.11,114.18,114.00,110.93,19.08.esi-ms(-)[m/z]:456.61[m-h]-.化合物18到化合物24是由反应路线2合成
[0316]
化合物18：(e)-3-(4-((3-(2-乙基苯甲酰)-7-羟基喹啉-4-基)氧)-3-甲基苯基)丙烯酸：具体结构见化合物1～24的结构总结；
[0317]
该化合物由中间体2-4-a反应得。1h nmr(500mhz,dmso-d6)δ12.16(s,1h),10.83(s,1h),8.94(s,1h),7.80(d,j＝9.1hz,1h),7.50
–
7.38(m,4h),7.32(d,j＝7.3hz,1h),7.26(d,j＝7.6hz,2h),7.23
–
7.16(m,2h),6.34(d,j＝16.0hz,1h),6.20(d,j＝8.5hz,1h),2.23(d,j＝7.7hz,2h),1.72(s,3h),0.90(t,j＝7.5hz,3h).
13
c nmr(126mhz,dmso)δ194.71,167.62,161.32,157.59,156.77,153.39,151.98,143.40,143.14,138.04,131.49,130.69,129.68,129.40,128.69,127.50,126.95,125.43,124.60,121.08,120.70,117.74,115.30,113.32,110.68,25.20,15.31,14.88.esi-ms(-)[m/z]:452.27[m-h]-.
[0318]
化合物19：(e)-3-(4-((3-(2-乙基苯甲酰)-7-羟基喹啉-4-基)氧)-2-甲基苯基)丙烯酸：具体结构见化合物1～24的结构总结；
[0319]
该化合物由中间体2-4-b反应得。1h nmr(500mhz,dmso-d6)δ12.24(s,1h),10.83(s,1h),8.91(s,1h),7.86(d,j＝9.1hz,1h),7.66(d,j＝15.8hz,1h),7.51(d,j＝8.3hz,1h),7.45(t,j＝7.5hz,1h),7.38(d,j＝2.4hz,1h),7.33(d,j＝7.6hz,1h),7.22(m,j＝12.7,8.8,6.1hz,3h),6.28(dd,j＝11.8,3.6hz,3h),2.28(q,j＝7.4hz,2h),2.19(s,3h),0.95(t,j＝7.5hz,3h).
13
c nmr(126mhz,dmso)δ194.35,167.62,161.35,158.73,156.86,153.34,152.25,143.60,140.14,139.47,137.56,131.58,129.80,128.23,127.71,125.47,124.77,120.71,120.50,118.97,117.33,115.54,113.46,110.64,25.53,19.17,15.46.esi-ms(-)[m/z]:452.26[m-h]-.
[0320]
化合物20：(e)-3-(4-((3-(2-乙基苯甲酰)-7-羟基喹啉-4-基)氧)-3-氟苯基)丙烯酸：具体结构见化合物1～24的结构总结；
[0321]
该化合物由中间体2-4-c反应得。1h nmr(500mhz,dmso-d6)δ12.36(s,1h),10.88(s,1h),8.88(s,1h),7.89(d,j＝9.1hz,1h),7.62(d,j＝12.1hz,1h),7.48
–
7.36(m,3h),7.32(d,j＝7.7hz,1h),7.29
–
7.21(m,3h),7.17(t,j＝7.5hz,1h),6.57(t,j＝8.6hz,1h),6.45(d,j＝16.0hz,1h),2.35(q,j＝7.5hz,2h),0.98(t,j＝7.5hz,3h).
13
c nmr(126mhz,dmso)δ194.29,167.44,161.45,156.54,153.29,152.14,150.13,146.39,146.30,143.32,141.98,137.40,131.66,129.68,129.49,125.54,125.35,125.33,124.49,120.93,120.20,119.63,116.84,115.87,115.02,110.67,25.53,15.50.esi-ms(-)[m/z]:456.21[m-h]-.
[0322]
化合物21：(e)-3-(3-乙基-4-((3-(2-乙基苯甲酰)-7-羟基喹啉-4-基)氧)苯基)丙烯酸：具体结构见化合物1～24的结构总结；
[0323]
该化合物由中间体2-4-d反应得。1h nmr(500mhz,dmso-d6)δ8.93(s,1h),7.74(d,j＝9.1hz,1h),7.50
–
7.38(m,5h),7.33(d,j＝7.8hz,1h),7.24(m,j＝19.5,9.5,4.8hz,4h),
6.36(d,j＝15.9hz,1h),6.23(d,j＝8.5hz,1h),2.26(s,2h),2.09(s,2h),1.02(t,j＝7.5hz,3h),0.90(t,j＝7.5hz,3h).
13
c nmr(126mhz,dmso)δ194.74,167.61,161.24,157.20,156.66,153.36,151.94,143.42,143.22,137.95,132.49,131.49,129.69,129.44,129.11,128.88,127.34,125.45,124.44,121.35,120.77,117.77,115.31,113.50,110.73,25.24,21.64,15.33,13.46.esi-ms(-)[m/z]:466.29[m-h]-.
[0324]
化合物22：(e)-3-(4-((3-(2-乙基苯甲酰)-7-羟基喹啉-4-基)氧)-3-甲氧基苯基)丙烯酸：具体结构见化合物1～24的结构总结；
[0325]
该化合物由中间体2-4-e反应得。1h nmr(500mhz,dmso-d6)δ8.81(s,1h),7.84(d,j＝9.2hz,1h),7.46
–
7.37(m,3h),7.27(d,j＝7.4hz,1h),7.25
–
7.20(m,3h),7.16(t,j＝7.5hz,1h),6.95(d,j＝8.3hz,1h),6.43(d,j＝15.9hz,1h),6.36(d,j＝8.3hz,1h),3.55(s,3h),2.29(q,j＝7.5hz,2h),0.98(t,j＝7.5hz,3h).
13
c nmr(126mhz,dmso)δ194.49,161.25,157.41,153.09,151.93,148.65,148.08,143.64,137.25,131.48,130.30,130.13,129.26,125.44,124.48,121.29,120.56,120.18,115.80,115.13,111.48,110.58,55.66,25.54,15.42.esi-ms(-)[m/z]:468.25[m-h]-.
[0326]
化合物23：(e)-3-(4-((3-(2-乙基苯甲酰)-7-羟基喹啉-4-基)氧)-3，5-二甲氧基苯基)丙烯酸：具体结构见化合物1～24的结构总结；
[0327]
该化合物由中间体2-4-f反应得。1h nmr(500mhz,dmso-d6)δ12.35(s,1h),10.60(s,1h),8.53(s,1h),8.12(d,j＝9.1hz,1h),7.45(td,j＝7.3,1.7hz,1h),7.39(d,j＝15.9hz,1h),7.34(d,j＝2.5hz,1h),7.26
–
7.14(m,6h),6.36(d,j＝16.0hz,1h),2.24(q,j＝7.4hz,2h),1.70(s,6h),0.98(t,j＝7.4hz,3h).
13
c nmr(126mhz,dmso)δ194.43,167.59,160.42,156.94,153.39,152.00,151.15,145.08,143.02,136.28,132.41,131.96,131.05,129.93,129.45,129.24,125.67,124.21,119.93,118.67,118.13,113.95,110.38,26.17,16.18,15.42.esi-ms(-)[m/z]:466.28[m-h]-.
[0328]
化合物24：(e)-3-(4-((3-(2-乙基苯甲酰)-7-羟基喹啉-4-基)氧)-2，6-二甲氧基苯基)丙烯酸：具体结构见化合物1～24的结构总结；
[0329]
该化合物由中间体2-4-g反应得。1h nmr(500mhz,dmso-d6)δ12.40(s,1h),10.77(s,1h),8.89(s,1h),7.89(d,j＝9.0hz,1h),7.56(d,j＝16.3hz,1h),7.45(t,j＝7.4hz,1h),7.38(d,j＝2.4hz,1h),7.33(d,j＝7.5hz,1h),7.23(dd,j＝8.9,2.4hz,3h),6.14(s,2h),5.95(d,j＝16.3hz,1h),2.31
–
2.23(m,3h),2.10(s,6h),0.97(t,j＝7.5hz,3h).
13
c nmr(126mhz,dmso)δ194.23,167.31,161.29,157.08,157.03,153.26,152.30,143.80,141.13,138.58,137.35,131.53,129.95,129.28,128.24,125.44,124.75,124.02,120.58,120.22,115.70,115.12,110.58,25.56,20.74,15.46.esi-ms(-)[m/z]:466.28[m-h]-.
[0330][0331]
化合物1～24的结构总结
[0332]
药理实验：
[0333]
(1)、mcf-7细胞或ishikawa细胞存活
[0334]
mtt法检测细胞活力：mcf-7在每次实验前将培养基换成无酚红的rpmi-1640并使用活性炭处理的fbs，去除雌激素2天；(96孔板中每孔接种1000-2000个mcf-7细胞)将每孔1000-2000个mcf-7细胞接种到96孔板中，过夜培养使细胞贴壁；所有化合物溶于dmso中，对照组用0.1％ dmso处理，处理后细胞孵育96～120h；细胞中加入5％mtt(5mg/ml，磷酸缓冲盐水(pbs))试剂，孵育约4h后，弃去培养液，加入200μldmso，(于摇床震荡约10分钟后在490nm处测定吸光度)摇匀约10分钟；最后在490nm处检测吸光度；mtt法计算化合物的生长抑制率为(ac-as)/(ac-ab)
×
100％，其中ac为对照孔吸光度；样品孔的吸光度为as；ab为空白井吸光度，mtt法检测ishikawa细胞活力，3000-4000个ishikawa细胞接种到96孔板中，过夜培养使细胞贴壁；所有化合物溶于dmso中，对照组用0.1％ dmso处理，20μm化合物处理72h，细胞中加入5％mtt(5mg/ml，磷酸缓冲盐水(pbs))试剂，孵育约4h后，弃去培养液，加入200μl dmso，(于摇床震荡约10分钟后在490nm处测定吸光度)摇匀约10分钟；最后在490nm处检测吸光度。mtt法计算化合物的生长抑制率为(ac-as)/(ac-ab)
×
100％，其中ac为对照
孔吸光度；样品孔的吸光度为as；ab为空白井吸光度，其结果见表1。
[0335]
表1mcf-7和ishikawa细胞中喹啉serd化合物的抗增殖活性
[0336][0337][0338]
(2)、蛋白质免疫印迹：
[0339]
mcf-7细胞在实验前用无酚红培养基和活性炭处理的fbs培养2天；当细胞在6孔板
中培养到80％的密度时，加入对照以及测试化合物处理24小时；之后使用预冷的pbs洗涤细胞，加入细胞裂解液裂解细胞从而提取细胞内蛋白(然后，在冷pbs中洗涤细胞，然后在细胞放射免疫沉淀试验(ripa)裂解缓冲液中再悬浮，制备细胞提取物)；根据计算得到的蛋白质浓度上样；电泳条件为20ma,120分钟。转膜条件为100v,90分钟，操作必须在冰浴环境中进行；用5％脱脂牛奶室温封闭2小时后，用pbst洗涤3次，每次10分钟；然后将一抗抗体使用一抗稀释液按照适当的比例进行稀释(用pbst制备5％牛血清白蛋白，将各种特异性抗体erα按1:1000稀释，5％牛血清白蛋白作为稀释剂)，4℃孵育过夜；回收一抗，二抗置于摇床上孵育2h后使用pbst洗涤3次(二抗室温孵育2h后置于摇床上，用pbst冲洗膜3次)；最后，将ecl发光液均匀地滴在膜表面(将其与ecl化学发光混合均匀地撒在膜表面)，用凝胶成像仪对条带进行成像分析。其结果显示于图1。
[0340]
(3)、免疫荧光检测
[0341]
mcf-7细胞在实验前48h换用去激素条件培养(无酚红1640和活性炭处理的fbs)；细胞在24孔(每孔4
×
104个细胞)培养板中培养过夜；贴壁后，用待测化合物处理细胞，培养24h；所有样品均先固定后封闭。与相应稀释后的抗体于4℃孵育过夜后，加入与荧光团偶联的二抗；然后，用pbs冲洗细胞三次；细胞核用dapi染色，之后用荧光显微镜(leica,dim8)检测免疫荧光。其结果显示于图2。
[0342]
mcf-7细胞雌激素反应元件(ere)荧光素酶测定：
[0343]
mcf-7细胞在实验前48h换用去激素条件培养(无酚红1640和活性炭处理的fbs)。细胞以1.5
×
104细胞/孔的密度被接种在96孔板中，并与100ng的ere-荧光素酶质粒共转染(3x ere tata luc was a gift from donald mcdonnell(addgene plasmid#11354；http://n2t.net/addgene:11354；rrid:addgene_11354))；根据说明书说明，使用lipofecta分钟e 8000转染试剂(beyotime)在rpim 1640培养基中转染24h；24h后用相应化合物处理细胞24h，24h后用荧光素酶测定系统(beyotime)测定荧光素酶活性；其结果显示于图3。
[0344]
(4)、细胞周期阻滞
[0345]
mcf-7细胞在实验前48h换用去激素条件培养(无酚红1640和活性炭处理的fbs)；细胞以5
×
105细胞/孔的密度接种于6孔板中，使用相应化合物处理24h后按照凯基细胞周期检测试剂盒说明书收集并处理细胞，之后使用流式细胞仪进行检测；其结果显示于图4。
[0346]
(5)、qpcr检测
[0347]
使用总rna提取试剂盒提取rna(converted to cdna using theiii 1st strand cdna synthesis supermix for qpcr(gdna digester plus)according to the manufacturer’srecommendations.)定量实时pcr在7500rt-pcr系统上进行，使用qpcr sybr green master mix进行qpcr；以β-actin为归一化对照，用δδct方法计算基因表达的相对差异。
[0348]
(6)、对目标化合物的药代动力学实验
[0349]
6只spf级雌性icr小鼠，6-8周龄，体重18-22g，动物许可证号：scxk(京)2021-0006；实验动物接收后进行一周的适应性饲养，随后进行药动学研究；动物房的温度为20～26℃；湿度为40-70％；12h光照黑暗交替；自由饮水和取食；动物实验开始前禁食12h；本发明采用单剂量单周期给药方案，选择6只健康适宜的动物，分为2组，记为1、2两组；给药方案
见表2；给药后，从颈静脉采血，具体采集时间点如下表3时间点所示；采样要求及处理：取血使用肝素钠抗凝管并置于湿冰环境下静置15分钟以上，6000r/分钟，离心3分钟，分离血浆，保存在-20℃中待测；使用lc-ms/ms法测定每只动物每个时间点样品的浓度；对于高浓度超过检测限的样品，需要用空白血浆进行稀释到定量范围浓度，然后进行测定；选用microsoft excel2010电子表格软件进行数据管理，用winnolin 8.2软件计算药代动力学参数；绝对生物利用度计算公式：
[0350]
f(％)＝(doseiv
×
auc
oral(0-∞)
)/(doseoral
×
auc
iv(0-∞)
)
×
100％。
[0351]
药代动力学参数计算：根据试验中测得的各受试动物的血药浓度-时间数据，求得受试物的主要药代动力学参数；包括t
max
(达峰时间)、c
max
(峰浓度)、t
1/2
(消除半衰期)、auc
[0352]
(血药浓度-时间曲线下面积)等参数值。
[0353]
表2给药方案
[0354][0355]
给药后，从颈静脉采血，具体采集时间点如下表3时间点所示。
[0356]
表3血液样本采集设计
[0357][0358]
其结果见表4和5和图7。
[0359]
表4化合物10的体内药代动力学数据
60mg/kg，每周给予单次皮下注射fulvestrant 250mg/kg；10+ribociclib组小鼠每天口服10 60mg/kg和ribociclib 60mg/kg；21+ribociclib组小鼠每天口服21和ribociclib 60mg/kg；在给药30天内，每5天记录小鼠体重和肿瘤体积；处死小鼠，取肿瘤、心脏、肝脏、脾脏、肾脏。见图7。
[0367]
(8)、he染色切片
[0368]
选取取大鼠心脏、肝脏、脾脏、肾脏和子宫进行组织学检查。组织解剖，石蜡包埋，切片(6μm厚)；切片用苏木精和伊红染色(h&e)。
[0369]
1)、将制备好的组织石蜡切片放入恒温电炉中，60℃烘烤3小时；
[0370]
2)、干燥的石蜡切片分别在二甲苯ⅰ和二甲苯ⅱ中脱蜡5分钟，然后在100％乙醇、95％乙醇、90％乙醇、80％乙醇和70％乙醇中分别浸泡1min，用蒸馏水洗涤2分钟；
[0371]
3)、苏木精染色5分钟，盐酸乙醇分化30s，清水冲洗；
[0372]
4)、用伊红染料溶液染色1分钟，洗去残留染料溶液；
[0373]
5)、70％乙醇30s；80％乙醇30s；90％乙醇两次，每次3分钟。无水乙醇两次，每次5分钟，二甲苯透明，中性胶封，显微镜下观察。其结果见图8。
[0374]
(9)、免疫组织化学
[0375]
将肿瘤组织用4％的福尔马林固定24小时，石蜡包埋后，切取6μm切片，贴于plus玻片上；切片在二甲苯中脱蜡，然后暴露于分级醇(100％，95％，70％，50％，水)中水化；将载玻片浸泡在抗原回收液中加热10分钟；冷却至室温后，将载玻片在tbst中渗透15分钟，用水冲洗，然后用3％过氧化氢孵育10分钟，以灭内源性过氧化物酶活性；为阻断非特异性结合，将载玻片用阻断液孵育30分钟；分别用ki67一抗(稀释比例为1:500)、er一抗(稀释比例为1:250)或pr一抗(稀释比例为1:100)孵育4℃过夜。阴性对照用阻断液替代一抗；用tbst清洗一抗后，加入过氧化物酶标记的山羊抗兔免疫球蛋白偶联聚合物30分钟；为进行信号检测，用elite abc-显色试剂孵育30分钟，二氨基联苯胺混合物孵育5分钟；用hematoxylin反染色，分级酒精脱水，显微镜下观察。其结果见图9。
[0376]
(10)、子宫湿重测定
[0377]
试验前自适应饲养15只3周龄、体重约100g的雌性未成熟sd大鼠7d；对照剂、10、21口服(60mg/kg)，每日1次，连续2d；fulvestrant皮下注射剂量为2mg/kg，每日1次，连续2天；各组大鼠子宫均于实验结束后第一天采集；去除外周脂肪组织，用pbs冲洗大鼠子宫2～3次，沥干，储存，称重。记录子宫湿重，计算子宫系数。
[0378]
子宫系数＝子宫湿重(g)/体重(g)
×
100。其结果见图10。
[0379]
以上仅是本发明的优选实施方式，本发明的保护范围并不仅局限于上述实施例，凡属于本发明思路下的技术方案均属于本发明的保护范围。应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理前提下的若干改进和润饰，应视为本发明的保护范围。

技术特征：
1.选择性雌激素受体下调剂化合物，其特征在于，所述化合物的化学结构式如式(i)所示：式中：m是0、1、2、3或4；n是0、1、2、3或4；x选自-o-、-ch
2-、-s-、-nr
17
、-chf-、-cf
2-和环烷基；y选自-c(o)-、-cf
2-、环烷基、-ch
2-和-chf-；环b选自苯基，二联苯基、萘基、喹啉基、5-或6-元单环杂芳基、环烷基或者7-、8-、9-或10-元双环杂环基；环a选自苯基、杂芳基、苯硫基、5-或6-元单环杂芳基、环烷基或者7-、8-、9-或10-元双环杂环基；r1选自-ch＝chcoor
17
、-nr
17
(co)coor
17
、-coor
17
、环烷基-coor
17
、-c
2-c6亚烯基-coor
17
、-c
2-c6亚炔基-coor
17
、-cooh、-nh(co)cooh、-ch＝chcooh、-ch＝chc(o)r
16
、-nr
17
(co)c(o)r
16
、-c(o)r
16
、-环烷基-c(o)r
16
、-c
2-c6亚烯基-c(o)r
16
和-c
2-c6亚炔基-c(o)r
16
；r2和r3选自-or
15
、-sr
15
、-n(r
15
)2、氢、芳基、杂芳基、卤素、-cn、-no2、卤代烷基、环烷基、硫醇基、亚硝基、c
1-c6烷基、羟基、-o(c
1-c6烷基)、-o(c
1-c6氟烷基)、-sf5、-b(oh)2、-b(or
15
)2、-c(o)or
15
、-c(o)r
16
、-c(s)r
16
、-oso2or
15
、-oso2r
16
、-nhso2or
15
、-nhso2r
16
、-n(烷基)so2or
15
、-n(烷基)so2r
16
、-op(o)(or
15
)2、-op(o)(r
16
)2、-p(o)(or 15
)3、-p(o)(r
16
)3、-p(o)or
15
、-p(o)r
16
、-so2r
16
、-so2or
15
、炔、烯、芳基烷基、芳氧基、杂芳基烷基和c
1-c6氟烷基；其中，r
15
在每次出现时独立地选自氢、烷基、烯基、炔基、环烷基、芳基、芳基烷基、杂芳基和杂芳基烷基；r
16
在每次出现时独立地选自-n(r
15
)2、-sr
15
、-or
15
；r
17
在每次出现时独立地选自氢、烷基、烯基、炔基、环烷基、芳基、-c(o)r
15
、-c(s)r
15
、-c(o)r
16
、-c(s)r
16
和杂芳基。2.根据权利要求1所述的选择性雌激素受体下调剂化合物，其特征在于，所述r1选自-cooh、-nh(co)cooh或-ch＝chcooh。3.根据权利要求1所述的选择性雌激素受体下调剂化合物，其特征在于，所述环a是苯基或、5-或6-元单环杂芳基。4.根据权利要求1所述的选择性雌激素受体下调剂化合物，其特征在于，所述环b是苯基、二联苯基、萘基或喹啉基。5.根据权利要求1所述的选择性雌激素受体下调剂化合物，其特征在于，所述的化合物为如下任一种：
6.如权利要求1-5任一项所述的选择性雌激素受体下调剂化合物的制备方法，其特征在于；其具体合成路线如下：合成路线1：
合成路线2：
7.一种药物组合物，其含有治疗有效量的一种或多种如权利要求1-5任一项所述的选择性雌激素受体下调剂化合物及药学上可接受的载体。8.如权利要求1-5中任一项所述的选择性雌激素受体下调剂化合物在制备治疗雌激素相关障碍疾病中的用途。9.根据权利要求8所述的用途，其特征在于，所述雌激素相关障碍疾病为乳腺癌、卵巢癌、子宫内膜癌、前列腺癌、肺癌、已经转移至骨的癌症或骨损失。10.根据权利要求9所述的用途，其特征在于，所述乳腺癌为激素受体阳性转移性乳腺癌、它莫西芬耐药性乳腺癌或三阴性乳腺癌。

技术总结
本发明公开了一种选择性雌激素受体下调剂化合物、制备方法及用途。涉及药物化学领域；本发明公开的化合物是可口服的雌激素受体下调剂，其活性实现了纳摩尔级别，对于乳腺癌等肿瘤的防止具有非常显著的效果；本发明所述的周期蛋白依赖性激酶(CDK)4/6抑制剂属于一类新的药物，其在治疗HR+，HER2-乳腺癌患者中发挥重要作用，可与雌激素受体下调剂联合使用等，发挥抗肿瘤效果。发挥抗肿瘤效果。发挥抗肿瘤效果。


技术研发人员：路云龙 刘武昆 梁震林 刘丽娟 杜前明 刘超 赵郅昊 郑天棚
受保护的技术使用者：南京中医药大学
技术研发日：2023.05.15
技术公布日：2023/8/14