CN109956912B - 含二苯基噁二唑的羧酸类化合物、其制备方法及医药用途 - Google Patents
含二苯基噁二唑的羧酸类化合物、其制备方法及医药用途 Download PDFInfo
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- CN109956912B CN109956912B CN201711434127.4A CN201711434127A CN109956912B CN 109956912 B CN109956912 B CN 109956912B CN 201711434127 A CN201711434127 A CN 201711434127A CN 109956912 B CN109956912 B CN 109956912B
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- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
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- Plural Heterocyclic Compounds (AREA)
Abstract
本发明涉及药物化学领域，具体涉及一类含二苯基噁二唑骨架的羧酸类化合物(I)，其制备方法，药物制剂，及其作为药物，尤其作为免疫调节药物的用途。药理试验证明，本发明的羧酸类化合物对鞘胺醇‑1‑磷酸受体1(S1P1)具有较强的激动活性，该类化合物可用于制备一系列治疗自身免疫性疾病，如多发硬化症、类风湿关节炎、系统性红斑狼疮、牛皮癖、银屑病等，并可用于减轻器官移植排异反应。
Description
技术领域
本发明涉及药物化学领域，具体涉及一类含二苯基噁二唑的羧酸类化合物、其制备方法、包含其的药物制剂及其医药用途。
背景技术
自身免疫性疾病(autoimmune disease，AID)是由于机体自身免疫系统功能紊乱，对自身抗原发生免疫反应而导致自身组织损害所引起的疾病，主要包括多发硬化症、类风湿关节炎、系统性红斑狼疮、银屑病等。近年来，自身免疫及其引起的疾病越来越受到人们的关注，该病病程长，可致残甚至致死，全球约有几亿人正遭受着该病带来的痛苦，严重威胁人民的生活健康和生活质量。
人体内源性物质鞘氨醇-1-磷酸(sphingosine-1-phosphate，S1P)是一种两性离子形式的溶血磷脂，可作用于相应的鞘胺醇-1-磷酸受体(S1PR 1-5)，其中S1P1受体与免疫调节有关，而S1P3 受体与心血管功能有关。深入研究发现：S1P可通过作用于S1P受体激活复杂的下游信号，调节多种生理过程，如：淋巴细胞迁移、血管再生、内皮细胞成熟与完整、心率调节、炎症诱导以及肿瘤发生等。
传统的免疫抑制剂如环孢素A、环磷酰胺、皮质类固醇等药物，可用于抑制淋巴细胞生长，治疗自身免疫性疾病，但是长期服用这类药物会破坏机体淋巴细胞的功能，导致患者免疫系统紊乱，容易诱发感染、心血管疾病等继发性病症。一些免疫抑制活性好且毒副作用小的高选择性S1P1受体激动剂已进入临床或临床前研究，2010年上市药物FTY720(Fingolimod)，其磷酸化代谢产物FTY720-P可激动S1P受体，诱导外周循环系统中的淋巴细胞发生“归巢”，降低外周血液循环中的淋巴细胞数量，从而发挥免疫抑制作用，现用于多发性硬化症的治疗。然而，FTY720属于非选择性S1P受体激动剂，其对S1P3受体的激动作用，已被证明与该药物临床上产生心动过缓，血压降低等心血管不良反应密切相关。此外，FTY720药物代谢缓慢，在人体内的半衰期可达89-157h。
因此，随着近年来自身免疫性疾病的患病人数逐年上升，亟需发现高活性和选择性的新型S1P1受体激动剂，在保证较好疾病治疗效果的同时，改善药物代谢性质，以进一步提高临床应用上的安全性和有效性。
发明内容
本发明解决的技术问题是提供一类含二苯基噁二唑的羧酸类化合物及其药学上可接受盐、其制备方法、药物组合物以及其在制备治疗与S1P1受体功能相关的疾病的药物中的应用。
为解决本发明的技术问题，本发明提供如下技术方案：
本发明技术方案的第一方面是提供如通式(I)所示的化合物或其药学上可接受的盐：
其中，
R1选自取代的烷基，烷氧基，苯基，苯氧基，所述的取代选自烷基，烷氧基或卤素；
R2和R3分别选自氢，烷基，烷氧基，卤素，氰基，三氟甲基，三氟甲氧基；
R4选自具有如下结构的取代基：
其中，R’，R”，R”’可以相同或不同，选自氢，烷基；m，n可以相同或不同，选自0，1 或2；Ra选自羧基、羟基或酯基，所述酯基为甲酯基、乙酯基或磷酸酯基。
进一步地，所述烷基选自C1-8直链或支链烷基或C3-8环烷基；所述烷氧基选自C1-8直链或支链烷基氧基或C3-8环烷基氧基；
进一步地，所述烷基选自甲基、乙基、正丙基、异丙基、环丙基、正丁基、异丁基、叔丁基、环丁基、正戊基、异戊基、环戊基；所述烷氧基选自甲氧基、乙氧基、正丙基氧基、异丙基氧基、环丙基氧基、正丁基氧基、异丁基氧基、叔丁基氧基、环丁基氧基、正戊基氧基、异戊基氧基、环戊基氧基；
所述卤素选自氟、氯、溴；
所述药学上可接受的盐选自盐酸盐、硫酸盐、磷酸盐、醋酸盐、柠檬酸盐、苹果酸盐、富马酸盐、酒石酸盐、甲磺酸盐。
作为本发明的优选方案，通式(I)的化合物具体是如下的化合物：
本发明技术方案的另一方面是提供如通式(I)所示的化合物或其药学上可接受的盐的合成方法，其合成路线如下：
试剂与条件：(a)氮甲酰基哌啶，异丙基氯化镁，四氢呋喃，0℃,2h；(b)乙二醇，对甲苯磺酸，甲苯，回流；(c)盐酸羟胺，碳酸氢钠，甲醇，回流；(d)取代苯甲酸，1-羟基苯并三唑，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐，碳酸钾，N,N-二甲基甲酰胺，110℃；(e)2mol/L盐酸，丙酮，55℃；(f)氨基酸酯盐酸盐或氨基醇，二异丙基乙基胺，醋酸，氰基硼氢化钠，二氯甲烷，甲醇；(g)0.5mol/L氢氧化锂,甲醇，酸化。
本发明技术方案的另一方面是提供药物组合物，所述药物组合物中除包含通式(I)所示的化合物或其药学上可接受的盐以及药学上可接受的载体。
本发明技术方案的另一方面是提供如通式(I)所示的化合物在制备治疗自身免疫性疾病的药物中的应用，所述的自身免疫性疾病包括但不限于多发硬化症、类风湿关节炎、系统性红斑狼疮、牛皮癖、银屑病等。
本发明技术方案的另一方面是提供如通式(I)所示的化合物在制备减轻器官移植排异反应的药物中的应用。
附图说明
图1(A)化合物SYL2425(实施例24)口服给药的血药浓度-时间曲线；(B)化合物SYL2426(实施例25)口服给药的血药浓度-时间曲线；(C)化合物SYL2439(实施例38)口服给药的血药浓度-时间曲线；(D)化合物SYL2443(实施例42)口服给药的血药浓度-时间曲线；(E)化合物 SYL2449(实施例48)口服给药的血药浓度-时间曲线；(F)阳性对照组RPC106口服给药的血药浓度-时间曲线
图2(A)化合物SYL2439(实施例38)静脉注射的血药浓度-时间曲线；(B)化合物SYL2443(实施例42)静脉注射的血药浓度-时间曲线
具体实施方式
实施例1
(3-氯-4-(5-(4-苯氧基苯基)-1,2,4-噁二唑-3-基)苄基)甘氨酸盐酸盐
(1)3-氯-4-氰基苯甲醛的制备
将2-氯-4-溴苯甲腈(5.0g,23.10mmol)溶于120mL无水四氢呋喃中，冰浴0℃条件下滴加 2N异丙基氯化镁的四氢呋喃溶液(15.0ml,30.03mmol)，反应混合液在0℃氩气保护下反应2小时，此后在0℃下加入N-甲酰基哌啶(3.33ml,30.03mmol)继续在0℃下反应2小时。饱和氯化铵溶液淬灭反应，用乙酸乙酯萃取3次(3×50mL)，合并有机层，蒸馏水洗2次，饱和氯化钠溶液洗1次，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为石油醚：乙酸乙酯＝3:1，得白色固体2.52g，收率65.9％。
1H NMR(400MHz,DMSO-d6)δ10.07(s,1H),8.23-8.22(m,2H),8.02(d,J＝7.6Hz,1H).
(2)2-(3-氯-4-氰基苯基)-1,3-二氧戊环的制备
将3-氯-4-氰基苯甲醛(2.5g,15.10mmol)，乙二醇(3.07ml,60.39mmol)，对甲苯磺酸(206.81mg, 1.2mmol)溶于120ml甲苯中，分水器持续分水，加热回流18h。将反应冷却至室温，蒸除溶剂，残留物以150ml乙酸乙酯溶解，用饱和碳酸氢钠溶液洗2次，蒸馏水洗2次，饱和氯化钠溶液洗1次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为石油醚：二氯甲烷：丙酮＝24:3:1，得白色固体2.35g，收率74.2％，
1H NMR(400MHz,DMSO-d6)δ8.02(d,J＝8.0Hz,1H),7.76(s,1H),7.60(d,J＝8.0Hz,1H), 5.86(s,1H),4.09–3.94(m,4H).
(3)2-(3-氯-4-(N'-羟基甲脒基)苯基)-1,3-二氧戊环的制备
将2-(3-氯-4-氰基苯基)-1,3-二氧戊环(2.30g,10.97mmol)溶于120ml无水甲醇中，搅拌状态下依次加入盐酸羟胺(2.67g,38.40mmol)，碳酸氢钠(3.69g,43.89mmol)，加热回流5h。将反应冷却至室温，减压抽滤，滤饼用无水甲醇洗2次，合并滤液。加入蒸馏水，乙酸乙酯萃取3次(3 ×50mL)，饱和氯化钠溶液洗2次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为二氯甲烷：甲醇＝20:1，得白色固体2.10g，收率79.1％，
1H NMR(400MHz,DMSO-d6)δ9.50(s,1H),7.50(s,1H),7.45-7.39(m,2H),5.84(s,2H),5.77 (s,1H),4.09–3.92(m,4H).
(4)3-(2-氯-4-(1,3-二氧戊环-2-基)苯基)-5-(4-苯氧基苯基)-1,2,4-噁二唑的制备
将4-苯氧基苯甲酸(1.84g,8.61mmol)，1-羟基苯并三唑(1.06g,7.83mmol)，1-(3-二甲氨基丙基)-3- 乙基碳二亚胺盐酸盐(1.50g,7.83mmol)，碳酸钾(1.62g,11.74mmol)溶于120ml N,N-二甲基甲酰胺中，室温搅拌30分钟后加入2-(3-氯-4-(N'-羟基甲脒基)苯基)-1,3-二氧戊环(1.90g,7.83mmol)，氩气保护下加热至110℃反应4h。将反应冷却至室温，减压抽滤，滤饼用乙酸乙酯洗2次，合并滤液，加入蒸馏水，乙酸乙酯萃取3次(3×50mL)，蒸馏水洗2次，饱和氯化钠溶液洗1 次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为石油醚：乙酸乙酯＝3:1，得白色固体2.23g，收率64.7％
1H NMR(500MHz,DMSO-d6)δ8.20(d,J＝6.8Hz,2H),8.04(d,J＝6.0Hz,1H),7.72(s,1H), 7.62(d,J＝6.0Hz,1H),7.50(t,J＝6.2Hz,2H),7.29(t,J＝6.0Hz,1H),7.21-7.18(m,4H),5.87(s, 1H),4.12–3.97(m,4H).
(5)3-氯-4-(5-(4-苯氧基苯基)-1,2,4-噁二唑-3-基)苯甲醛的制备
将3-(2-氯-4-(1,3-二氧戊环-2-基)苯基)-5-(4-苯氧基苯基)-1,2,4-噁二唑(2.00g,4.75mmol)溶于 30ml丙酮中，搅拌状态下加入2N盐酸溶液(19.00.ml,38.00mmol)，45℃下加热3h。将反应冷却至室温，减压抽滤，干燥得白色固体1.69g，收率94.4％
1H NMR(400MHz,DMSO-d6)δ10.10(s,1H),8.25–8.20(m,4H),8.06(d,J＝8.0Hz,1H),7.50 (t,J＝7.6Hz,2H),7.29(t,J＝7.4Hz,1H),7.22-7.19(m,4H).
(6)(3-氯-4-(5-(4-苯氧基苯基)-1,2,4-噁二唑-3-基)苄基)甘氨酸甲酯的制备
将3-氯-4-(5-(4-苯氧基苯基)-1,2,4-噁二唑-3-基)苯甲醛(200mg,0.53mmol)溶于35ml二氯甲烷中，向其中依次加入甘氨酸甲酯盐酸盐(100mg,0.80mmol)、冰醋酸(0.12ml,2.12mmol)、N,N-二异丙基乙胺(0.14ml,0.80mmol)、5ml甲醇，室温反应3h后加入氰基硼氢化钠(33mg,0.53mmol)，氩气保护下反应5h。加入饱和碳酸氢钠溶液，二氯甲烷萃取3次(3×30mL)，蒸馏水洗1次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为二氯甲烷：甲醇＝20:1，得白色固体192mg，收率80.5％，熔点62-65℃
1H NMR(400MHz,Chloroform-d)δ8.17(d,J＝8.4Hz,2H),7.98(d,J＝7.6Hz,1H),7.57(s,1H), 7.41(q,J＝8.5Hz,3H),7.22(t,J＝7.4Hz,1H),7.11(d,J＝8.0Hz,4H),3.88(s,2H),3.75(s,3H), 3.44(s,2H),1.92(s,1H).
(7)标题化合物的制备
将甲基(3-氯-4-(5-(4-苯氧基苯基)-1,2,4-噁二唑-3-基)苄基)甘氨酸甲酯(192mg,0.43mmol)溶于 20ml甲醇中，加入0.5N氢氧化锂溶液(6.83ml,3.41mmol)，加热至45℃，反应3h。将反应冷却至室温，滴加2N盐酸溶液至PH2-3，蒸除溶剂，加入蒸馏水，减压抽滤，滤饼用乙醚洗，干燥得白色固体153mg，收率75.3％，熔点220-223℃
1H NMR(400MHz,DMSO-d6)δ10.77(s,2H),8.19(d,J＝8.4Hz,2H),8.05(d,J＝8.0Hz,1H), 7.89(s,1H),7.68(d,J＝8.0Hz,1H),7.50(t,J＝7.6Hz,2H),7.29(t,J＝7.4Hz,1H),7.20(t,J＝ 7.4Hz,4H),4.24(s,2H),3.82(s,2H).
HRMS calcd.For C23H19ClN3O4(M+H)+436.1059,found 436.1057.
实施例2
(3-氯-4-(5-(4-苯氧基苯基)-1,2,4-噁二唑-3-基)苄基)丙氨酸盐酸盐
(1)(3-氯-4-(5-(4-苯氧基苯基)-1,2,4-噁二唑-3-基)苄基)丙氨酸甲酯的制备
将3-氯-4-(5-(4-苯氧基苯基)-1,2,4-噁二唑-3-基)苯甲醛(200mg,0.53mmol)溶于35ml二氯甲烷中，向其中依次加入丙氨酸甲酯盐酸盐(111mg,0.80mmol)、冰醋酸(0.12ml,2.12mmol)、N,N-二异丙基乙胺(0.14ml,0.80mmol)、5ml甲醇，室温反应3h后加入氰基硼氢化钠(33mg,0.53mmol)，氩气保护下反应5h。加入饱和碳酸氢钠溶液，二氯甲烷萃取3次(3×30mL)，蒸馏水洗1次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为二氯甲烷：甲醇＝20:1，得白色固体184mg，收率74.1％，熔点77-79℃
1H NMR(400MHz,Chloroform-d)δ8.17(d,J＝8.8Hz,2H),7.97(d,J＝8.0Hz,1H),7.57(s,1H), 7.41(q,J＝8.0Hz,3H),7.22(t,J＝7.4Hz,1H),7.10(d,J＝8.4Hz,4H),3.90(d,J＝13.6Hz,1H), 3.75(m,3H),3.71(s,1H),3.40(q,J＝6.9Hz,1H),2.22(s,1H),1.36(d,J＝7.2Hz,3H).
(7)标题化合物的制备
按实施例1中步骤(7)方法制备，得白色固体133mg，收率69.5％，熔点232-235℃
1H NMR(400MHz,DMSO-d6)δ9.78(s,2H),8.20(d,J＝8.4Hz,2H),8.07(d,J＝8.0Hz,1H), 7.93(s,1H),7.72(d,J＝8.0Hz,1H),7.50(t,J＝7.6Hz,2H),7.29(t,J＝7.4Hz,1H),7.20(t,J＝ 7.8Hz,4H),4.29(q,J＝13.5Hz,2H),4.06(q,J＝7.1Hz,1H),1.54(d,J＝7.2Hz,3H).
HRMS calcd.For C24H21ClN3O4(M+H)+450.1215,found 450.1206.
实施例3
3-((3-氯-4-(5-(4-苯氧基苯基)-1,2,4-噁二唑-3-基)苄基)氨基)丙酸盐酸盐
(1)3-((3-氯-4-(5-(4-苯氧基苯基)-1,2,4-噁二唑-3-基)苄基)氨基)丙酸甲酯的制备
将3-氯-4-(5-(4-苯氧基苯基)-1,2,4-噁二唑-3-基)苯甲醛(200mg,0.53mmol)溶于35ml二氯甲烷中，向其中依次加入3-氨基丙酸甲酯盐酸盐(111mg,0.80mmol)、冰醋酸(0.12ml,2.12mmol)、N,N- 二异丙基乙胺(0.14ml,0.80mmol)、5ml甲醇，室温反应3h后加入氰基硼氢化钠(33mg, 0.53mmol)，氩气保护下反应5h。加入饱和碳酸氢钠溶液，二氯甲烷萃取3次(3×30mL)，蒸馏水洗1次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为二氯甲烷：甲醇＝20:1，得白色固体196mg，收率79.6％，熔点60-63℃
1H NMR(400MHz,Chloroform-d)δ8.17(d,J＝8.4Hz,2H),7.97(d,J＝8.0Hz,1H),7.55(s,1H), 7.44-7.36(m,3H),7.22(t,J＝7.4Hz,1H),7.11(d,J＝8.0Hz,4H),3.87(s,2H),3.71(s,3H),2.91 (t,J＝6.4Hz,2H),2.56(t,J＝6.4Hz,2H).
(7)标题化合物的制备
按实施例1中步骤(7)方法制备，得白色固体140mg，收率68.4％，熔点218-219℃
1H NMR(400MHz,DMSO-d6)δ12.64(s,1H),9.32(s,2H),8.20(d,J＝8.4Hz,2H),8.07(d,J＝ 8.0Hz,1H),7.94(s,1H),7.72(d,J＝8.0Hz,1H),7.50(t,J＝7.8Hz,2H),7.29(t,J＝7.4Hz,1H), 7.20(t,J＝7.6Hz,4H),4.29(s,2H),3.16(t,J＝7.2Hz,2H),2.74(t,J＝7.2Hz,2H).
HRMS calcd.For C24H21ClN3O4(M+H)+450.1215,found 450.1206.
实施例4
1-(3-氯-4-(5-(4-苯氧基苯基)-1,2,4-噁二唑-3-基)苄基)吡咯烷-3-甲酸盐酸盐
(1)1-(3-氯-4-(5-(4-苯氧基苯基)-1,2,4-噁二唑-3-基)苄基)吡咯烷-3-甲酸甲酯的制备
将3-氯-4-(5-(4-苯氧基苯基)-1,2,4-噁二唑-3-基)苯甲醛(200mg,0.53mmol)溶于35ml二氯甲烷中，向其中依次加入吡咯烷3-羧酸甲酯盐酸盐(132mg,0.80mmol)、冰醋酸(0.12ml,2.12mmol)、N,N- 二异丙基乙胺(0.14ml,0.80mmol)、5ml甲醇，室温反应3h后加入氰基硼氢化钠(33mg, 0.53mmol)，氩气保护下反应5h。加入饱和碳酸氢钠溶液，二氯甲烷萃取3次(3×30mL)，蒸馏水洗1次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为二氯甲烷：甲醇＝20:1，得白色固体184mg，收率70.8％，熔点78-79℃
1H NMR(400MHz,Chloroform-d)δ8.17(d,J＝8.4Hz,2H),7.94(d,J＝8.0Hz,1H),7.54(s,1H), 7.44-7.36(m,3H),7.22(t,J＝7.6Hz,1H),7.10(d,J＝8.0Hz,4H),3.70(s,3H),3.68-3.63(m,2H), 3.10-3.02(m,1H),2.88(t,J＝8.6Hz,1H),2.72-2.68(m,2H),2.58(q,J＝8.0Hz,1H),2.16-2.10 (m,2H).
(7)标题化合物的制备
按实施例1中步骤(7)方法制备，得白色固体115mg，收率59.7％，熔点228-231℃
1H NMR(400MHz,DMSO-d6)δ12.87(s,1H),11.71(s,1H),8.20(d,J＝8.4Hz,2H),8.07–8.03 (m,2H),7.80(d,J＝8.0Hz,1H),7.50(t,J＝7.8Hz,2H),7.28(t,J＝7.4Hz,1H),7.20(t,J＝7.2 Hz,4H),4.47(s,2H),3.34(m,5H),2.33-2.08(m,2H).
HRMS calcd.For C26H23ClN3O4(M+H)+476.1372,found 476.1363.
实施例5
(3-氯-4-(5-(4-苯氧基苯基)-1,2,4-噁二唑-3-基)苄基)脯氨酸盐酸盐
(1)(3-氯-4-(5-(4-苯氧基苯基)-1,2,4-噁二唑-3-基)苄基)脯氨酸甲酯的制备
将3-氯-4-(5-(4-苯氧基苯基)-1,2,4-噁二唑-3-基)苯甲醛(200mg,0.53mmol)溶于35ml二氯甲烷中，向其中依次加入脯氨酸甲酯盐酸盐(132mg,0.80mmol)、冰醋酸(0.12ml,2.12mmol)、N,N-二异丙基乙胺(0.14ml,0.80mmol)、5ml甲醇，室温反应3h后加入氰基硼氢化钠(33mg,0.53mmol)，氩气保护下反应5h。加入饱和碳酸氢钠溶液，二氯甲烷萃取3次(3×30mL)，蒸馏水洗1次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为二氯甲烷：甲醇＝20:1，得白色固体190mg，收率73.2％，熔点52-54℃
1H NMR(400MHz,Chloroform-d)δ8.17(d,J＝8.4Hz,2H),7.95(d,J＝8.0Hz,1H),7.56(s,1H), 7.41(q,J＝8.0Hz,3H),7.22(t,J＝7.4Hz,1H),7.11(d,J＝8.0Hz,4H),3.99(d,J＝13.2Hz,1H), 3.70(s,3H),3.59(d,J＝13.4Hz,1H),3.33(t,J＝7.4Hz,1H),3.08-3.03(m,1H),2.43(q,J＝8.3 Hz,1H),2.22-2.12(m,1H),2.04–1.89(m,2H),1.86–1.82(m,1H).
(7)标题化合物的制备
按实施例1中步骤(7)方法制备，得白色固体104mg，收率54.1％，熔点200-202℃
1H NMR(400MHz,DMSO-d6)δ12.05(s,1H),8.19(d,J＝8.8Hz,2H),8.03(d,J＝7.6Hz,1H), 7.82(s,1H),7.65(d,J＝8.0Hz,1H),7.50(t,J＝7.8Hz,2H),7.29(t,J＝7.4Hz,1H),7.21-7.18(m, 4H),4.35(d,J＝13.2Hz,1H),4.14(d,J＝13.6Hz,1H),3.94(s,1H),3.30(s,1H),2.95(s,1H), 2.35-2.30(m,1H),2.01-1.92(m,2H),1.85-1.82(m,1H).
HRMS calcd.For C26H23ClN3O4(M+H)+476.1372,found 476.1368.
实施例6
N-甲基-N-(3-氯-4-(5-(4-苯氧基苯基)-1,2,4-噁二唑-3-基)苄基)甘氨酸盐酸盐
(1)N-甲基-N-(3-氯-4-(5-(4-苯氧基苯基)-1,2,4-噁二唑-3-基)苄基)甘氨酸乙酯的制备
将3-氯-4-(5-(4-苯氧基苯基)-1,2,4-噁二唑-3-基)苯甲醛(200mg,0.53mmol)溶于35ml二氯甲烷中，向其中依次加入肌氨酸乙酯盐酸盐(123mg,0.80mmol)、冰醋酸(0.12ml,2.12mmol)、N,N-二异丙基乙胺(0.14ml,0.80mmol)、5ml甲醇，室温反应3h后加入氰基硼氢化钠(33mg,0.53mmol)，氩气保护下反应5h。加入饱和碳酸氢钠溶液，二氯甲烷萃取3次(3×30mL)，蒸馏水洗1次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为二氯甲烷：甲醇＝20:1，得白色固体141mg，收率57.5％
1H NMR(400MHz,Chloroform-d)δ8.17(d,J＝8.4Hz,2H),7.96(d,J＝8.0Hz,1H),7.58(s,1H), 7.42(t,J＝7.6Hz,3H),7.22(t,J＝7.4Hz,1H),7.11(d,J＝8.4Hz,4H),4.20(q,J＝7.1Hz,2H), 3.77(s,2H),3.32(s,2H),2.43(s,3H),1.30(t,J＝7.0Hz,3H).
(7)标题化合物的制备
按实施例1中步骤(7)方法制备，得白色固体113mg，收率76.3％，熔点189-191℃
1H NMR(400MHz,DMSO-d6)δ12.28(s,1H),8.20(d,J＝8.4Hz,2H),8.02(d,J＝8.0Hz,1H), 7.79(s,1H),7.62(d,J＝8.0Hz,1H),7.50(t,J＝7.6Hz,2H),7.29(t,J＝7.4Hz,1H),7.22-7.18(m, 4H),4.09(s,2H),3.67(s,2H),2.54(s,3H).
HRMS calcd.For C24H21ClN3O4(M+H)+450.1215,found 450.1206.
实施例7
1-(3-氯-4-(5-(4-苯氧基苯基)-1,2,4-噁二唑-3-基)苄基)氮杂环丁烷-3-羧酸盐酸盐
(1)1-(3-氯-4-(5-(4-苯氧基苯基)-1,2,4-噁二唑-3-基)苄基)氮杂环丁烷-3-羧酸甲酯的制备
将3-氯-4-(5-(4-苯氧基苯基)-1,2,4-噁二唑-3-基)苯甲醛(200mg,0.53mmol)溶于35ml二氯甲烷中，向其中依次加入氮杂环丁烷-3-甲酸甲酯盐酸盐(121mg,0.80mmol)、冰醋酸(0.12ml,2.12mmol)、 N,N-二异丙基乙胺(0.14ml,0.80mmol)、5ml甲醇，室温反应3h后加入氰基硼氢化钠(33mg, 0.53mmol)，氩气保护下反应5h。加入饱和碳酸氢钠溶液，二氯甲烷萃取3次(3×30mL)，蒸馏水洗1次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为二氯甲烷：甲醇＝20:1，得白色固体185mg，收率73.5％
1H NMR(400MHz,Chloroform-d)δ8.17(d,J＝8.4Hz,2H),7.95(d,J＝8.0Hz,1H),7.50(s,1H), 7.42(t,J＝7.8Hz,2H),7.32(d,J＝8.0Hz,1H),7.22(t,J＝7.6Hz,1H),7.10(d,J＝8.4Hz,4H), 3.72(s,3H),3.66(s,2H),3.58-3.54(m,2H),3.36(m,3H).
(7)标题化合物的制备
按实施例1中步骤(7)方法制备，得白色固体119mg，收率63.4％，熔点183-185℃
1H NMR(400MHz,DMSO-d6)δ13.13(s,1H),11.49(s,1H),8.19(d,J＝8.4Hz,2H),8.05(d,J＝ 8.0Hz,1H),7.92(s,1H),7.71(d,J＝8.0Hz,1H),7.50(t,J＝7.8Hz,2H),7.29(t,J＝7.4Hz,1H), 7.20(t,J＝7.2Hz,4H),4.49(s,2H),4.20(d,J＝8.4Hz,4H),3.68-3.62(m,1H).
HRMS calcd.For C25H21ClN3O4(M+H)+462.1215,found 462.1206.
实施例8
3-(3-氯-4-(5-(4-苯氧基苯基)-1,2,4-噁二唑-3-基)苯基)丙酸
(1)3-(3-氯-4-(5-(4-苯氧基苯基)-1,2,4-噁二唑-3-基)苯基)丙烯酸甲酯的制备
将3-氯-4-(5-(4-苯氧基苯基)-1,2,4-噁二唑-3-基)苯甲醛(200mg,0.53mmol)溶于20mlN,N-二甲基甲酰胺中，向其中加入甲氧甲酰基亚甲基三苯基膦(212.96mg,0.64mmol)，氩气保护下室温反应3h。加入蒸馏水，乙酸乙酯萃取3次(3×30mL)，合并有机相，蒸馏水洗2次，饱和氯化钠溶液洗1次，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为石油醚：乙酸乙酯＝3:1，得白色固体160mg，收率69.7％
1H NMR(400MHz,DMSO-d6)δ8.20(d,J＝8.4Hz,2H),8.12(s,1H),8.05(d,J＝8.0Hz,1H), 7.93(d,J＝8.0Hz,1H),7.73(d,J＝16.0Hz,1H),7.50(t,J＝7.6Hz,2H),7.29(t,J＝7.6Hz,1H), 7.21-7.18(m,4H),6.89(d,J＝16.0Hz,1H),3.76(s,3H).
(2)3-(3-氯-4-(5-(4-苯氧基苯基)-1,2,4-噁二唑-3-基)苯基)丙酸甲酯的制备
将3-(3-氯-4-(5-(4-苯氧基苯基)-1,2,4-噁二唑-3-基)苯基)丙烯酸甲酯(150mg,0.35mmol)溶于 20ml乙酸乙酯中，搅拌状态下加入干粉钯碳(15mg)，通入氢气，室温下反应4h。用硅藻土滤除钯碳，浓缩，柱层析分离，洗脱剂为石油醚：乙酸乙酯＝3:1，得白色固体119mg，收率52.1％，熔点88-90℃
1H NMR(400MHz,Chloroform-d)δ8.17(d,J＝8.4Hz,2H),7.94(d,J＝8.0Hz,1H),7.44–7.41 (m,3H),7.24–7.20(m,2H),7.10(d,J＝8.4Hz,4H),3.69(s,3H),3.01(t,J＝7.6Hz,2H),2.68(t, J＝7.6Hz,2H).
(3)标题化合物的制备
按实施例1中步骤(7)方法制备，得白色固体73mg，收率63.5％，熔点137-139℃
1H NMR(400MHz,DMSO-d6)δ12.22(s,1H),8.18(d,J＝8.4Hz,2H),7.90(d,J＝8.0Hz,1H), 7.59(s,1H),7.49(t,J＝7.8Hz,2H),7.43(d,J＝8.0Hz,1H),7.28(t,J＝7.4Hz,1H),7.20-7.18(m, 4H),2.92(t,J＝7.6Hz,2H),2.63(t,J＝7.4Hz,2H).
HRMS calcd.For C23H18ClN2O4(M+H)+421.0950,found 421.0942.
实施例9
2-甲基-2-((3-氯-4-(5-(4-苯氧基苯基)-1,2,4-噁二唑-3-基)苄基)氨基)丙酸盐酸盐
(1)2-甲基-2-((3-氯-4-(5-(4-苯氧基苯基)-1,2,4-噁二唑-3-基)苄基)氨基)丙酸甲酯的制备
将3-氯-4-(5-(4-苯氧基苯基)-1,2,4-噁二唑-3-基)苯甲醛(200mg,0.53mmol)溶于35ml二氯甲烷中，向其中依次加入2-氨基-2-甲基丙酸甲酯盐酸盐(122mg,0.80mmol)、冰醋酸(0.12ml,2.12mmol)、 N,N-二异丙基乙胺(0.14ml,0.80mmol)、5ml甲醇，室温反应3h后加入氰基硼氢化钠(33mg, 0.53mmol)，氩气保护下反应5h。加入饱和碳酸氢钠溶液，二氯甲烷萃取3次(3×30mL)，蒸馏水洗1次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为二氯甲烷：甲醇＝20:1，得白色固体181mg，收率71.6％，熔点96-98℃
1H NMR(400MHz,DMSO-d6)δ8.19(d,J＝8.8Hz,2H),7.92(d,J＝8.0Hz,1H),7.66(s,1H), 7.50(t,J＝7.4Hz,3H),7.28(t,J＝7.4Hz,1H),7.21-7.18(m,4H),3.70(d,J＝6.8Hz,2H),3.64(s, 3H),2.78(t,J＝7.4Hz,1H),1.28(s,6H).
(7)标题化合物的制备
按实施例1中步骤(7)方法制备，得白色固体112mg，收率59.4％，熔点230-233℃
1H NMR(400MHz,DMSO-d6)δ9.74(s,2H),8.20(d,J＝8.4Hz,2H),8.09(d,J＝8.0Hz,1H), 7.93(s,1H),7.72(d,J＝8.4Hz,1H),7.50(t,J＝7.8Hz,2H),7.29(t,J＝7.4Hz,1H),7.20(t,J＝ 7.8Hz,4H),4.25(s,2H),1.61(s,6H).
HRMS calcd.For C25H23ClN3O4(M+H)+464.1372,found 464.1364.
实施例10
1-(3-氯-4-(5-(4-苯氧基苯基)-1,2,4-噁二唑-3-基)苄基)哌啶-4-甲酸盐酸盐
(1)1-(3-氯-4-(5-(4-苯氧基苯基)-1,2,4-恶二唑-3-基)苄基)哌啶-4-羧酸乙酯的制备
将3-氯-4-(5-(4-苯氧基苯基)-1,2,4-噁二唑-3-基)苯甲醛(200mg,0.53mmol)溶于35ml二氯甲烷中，向其中依次加入4-哌啶甲酸乙酯(250mg,1.59mmol)、冰醋酸(0.09ml,1.59mmol)、5ml甲醇，室温反应3h后加入三乙酰氧基硼氢化钠(337mg,1.59mmol)，氩气保护下反应5h。加入饱和碳酸氢钠溶液，二氯甲烷萃取3次(3×30mL)，蒸馏水洗1次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为二氯甲烷：甲醇＝20:1，得白色固体190mg，收率68.9％，熔点93-95℃1H NMR(400MHz,DMSO-d6)δ8.21(d,J＝8.4Hz,2H),7.96(d,J＝8.0Hz,1H),7.62(s,1H), 7.51(t,J＝7.8Hz,3H),7.30(t,J＝7.4Hz,1H),7.23-7.20(m,3H),5.77(s,1H),4.08(q,J＝7.1Hz, 2H),3.57(s,2H),2.78(d,J＝11.2Hz,2H),2.36-2.30(m,1H),2.08(t,J＝11.2Hz,2H),1.83(d,J ＝12.8Hz,2H),1.66–1.56(m,2H),1.19(t,J＝7.0Hz,3H).
(7)标题化合物的制备
按实施例1中步骤(7)方法制备，得白色固体96mg，收率48.3％，熔点233-235℃
1H NMR(400MHz,DMSO-d6)δ12.14(s,1H),8.19(d,J＝8.0Hz,2H),7.95(d,J＝8.0Hz,1H), 7.60(s,1H),7.50(t,J＝7.6Hz,3H),7.28(t,J＝7.4Hz,1H),7.21-7.18(m,4H),3.55(s,2H),2.76 (d,J＝11.2Hz,2H),2.22(m,1H),2.05(t,J＝11.4Hz,2H),1.80(d,J＝12.8Hz,2H),1.59(t,J＝ 11.8Hz,2H).
HRMS calcd.For C27H25ClN3O4(M+H)+490.1528,found 490.1524.
实施例11
(3-氯-4-(5-(4-苯氧基苯基)-1,2,4-噁二唑-3-基)苄基)天冬氨酸盐酸盐
(1)(3-氯-4-(5-(4-苯氧基苯基)-1,2,4-噁二唑-3-基)苄基)天冬氨酸二甲酯的制备
将3-氯-4-(5-(4-苯氧基苯基)-1,2,4-噁二唑-3-基)苯甲醛(200mg,0.53mmol)溶于35ml二氯甲烷中，向其中依次加入天冬氨酸二甲酯盐酸盐(158mg,0.80mmol)、冰醋酸(0.12ml,2.12mmol)、N,N- 二异丙基乙胺(0.14ml,0.80mmol)、5ml甲醇，室温反应3h后加入氰基硼氢化钠(33mg, 0.53mmol)，氩气保护下反应5h。加入饱和碳酸氢钠溶液，二氯甲烷萃取3次(3×30mL)，蒸馏水洗1次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为二氯甲烷：甲醇＝20:1，得白色固体207mg，收率74.9％，熔点62-63℃
1H NMR(400MHz,DMSO-d6)δ8.19(d,J＝8.4Hz,2H),7.93(d,J＝8.0Hz,1H),7.63(s,1H), 7.49(q,J＝8.0Hz,3H),7.28(t,J＝7.4Hz,1H),7.21-7.18(m,4H),3.90(dd,J＝15.0,6.0Hz,1H), 3.73(dd,J＝15.0,6.0Hz,1H),3.64(s,3H),3.61(s,3H),3.58-3.54(m,1H),3.02-2.96(m,1H), 2.73(dd,J＝16.0,6.4Hz,1H),2.64(dd,J＝16.0,7.2Hz,1H).
(7)标题化合物的制备
按实施例1中步骤(7)方法制备，得白色固体133mg，收率63.1％，熔点212-214℃
1H NMR(400MHz,DMSO-d6)δ11.20(s,2H),8.19(d,J＝8.4Hz,2H),8.01(d,J＝7.6Hz,1H), 7.89(s,1H),7.68(d,J＝8.0Hz,1H),7.49(t,J＝7.8Hz,2H),7.28(t,J＝7.4Hz,1H),7.19(dd,J＝ 8.4,4.8Hz,4H),4.22(q,J＝12.9Hz,2H),3.98(t,J＝6.0Hz,1H),3.38(q,J＝7.1Hz,1H), 2.97-2.85(m,2H).
HRMS calcd.For C25H21ClN3O6(M+H)+494.1113,found 494.1104.
实施例13
1-(3-氯-4-(5-(4-苯氧基苯基)-1,2,4-噁二唑-3-基)苄基)哌啶-4-乙酸盐酸盐
(1)1-(3-氯-4-(5-(4-苯氧基苯基)-1,2,4-噁二唑-3-基)苄基)哌啶-4-乙酸甲酯的制备
将3-氯-4-(5-(4-苯氧基苯基)-1,2,4-噁二唑-3-基)苯甲醛(200mg,0.53mmol)溶于35ml二氯甲烷中，向其中依次加入4-哌啶基乙酸甲酯盐酸盐(126mg,0.80mmol)、冰醋酸(0.12ml,2.12mmol)、N,N- 二异丙基乙胺(0.14ml,0.80mmol)、5ml甲醇，室温反应3h后加入氰基硼氢化钠(33mg, 0.53mmol)，氩气保护下反应5h。加入饱和碳酸氢钠溶液，二氯甲烷萃取3次(3×30mL)，蒸馏水洗1次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为二氯甲烷：甲醇＝20:1，得白色固体190mg，收率69.3％，熔点109-112℃
1H NMR(400MHz,DMSO-d6)δ8.18(d,J＝8.4Hz,2H),7.94(d,J＝7.6Hz,1H),7.59(s,1H), 7.51–7.46(m,3H),7.28(t,J＝7.4Hz,1H),7.20-7.18(m,4H),3.58(s,3H),3.54(s,2H),2.78(d,J ＝11.2Hz,2H),2.24(d,J＝6.4Hz,2H),1.98(t,J＝11.4Hz,2H),1.70-1.60(m,3H),1.27–1.18(m, 2H).
(7)标题化合物的制备
按实施例1中步骤(7)方法制备，得白色固体122mg，收率61.4％，熔点234-236℃
1H NMR(400MHz,DMSO-d6)δ12.25(s,1H),10.84(s,1H),8.20–8.04(m,4H),7.79(m,2H), 7.49(m,2H),7.40–6.97(m,5H),4.47-4.36(m,2H),3.14(s,1H),2.97-2.95(m,3H),2.41(s,1H), 2.19(m,2H),2.05–1.39(m,5H).
HRMS calcd.For C28H27ClN3O4(M+H)+504.1685,found 504.1686.
实施例14
(3-氯-4-(5-([1,1'-联苯]-4-基)-1,2,4-噁二唑-3-基)苄基)甘氨酸甲酯
(1)5-([1,1'-联苯]-4-基)-3-(2-氯-4-(1,3-二氧戊环-2-基)苯基)-1,2,4-噁二唑的制备
将4-苯基苯甲酸(180mg,0.91mmol)，1-羟基苯并三唑(111mg,0.82mmol)，1-(3-二甲氨基丙基)-3- 乙基碳二亚胺盐酸盐(158mg,0.82mmol)，碳酸钾(171mg,1.24mmol)溶于30ml N,N-二甲基甲酰胺中，室温搅拌30分钟后加入2-氯-4-(1,3-二氧戊环-2-基)-N'-羟基苯甲脒(200mg,0.82mmol)，氩气保护下加热至110℃反应4h。将反应冷却至室温，减压抽滤，滤饼用乙酸乙酯洗2次，合并滤液，加入蒸馏水，乙酸乙酯萃取3次(3×50mL)，蒸馏水洗2次，饱和氯化钠溶液洗1 次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为石油醚：乙酸乙酯＝3:1，得白色固体205mg，收率61.8％
1H NMR(500MHz,DMSO-d6)δ8.30(d,J＝8.0Hz,2H),8.11(d,J＝8.0Hz,1H),8.01(d,J＝8.5 Hz,2H),7.83(d,J＝7.5Hz,2H),7.76(s,1H),7.67(d,J＝8.0Hz,1H),7.57(t,J＝7.5Hz,2H), 7.49(t,J＝7.5Hz,1H),5.91(s,1H),4.12–4.03(m,4H).
(5)3-氯-4-(5-([1,1'-联苯]-4-基)-1,2,4-噁二唑-3-基)苯甲醛的制备
将5-([1,1'-联苯]-4-基)-3-(2-氯-4-(1,3-二氧戊环-2-基)苯基)-1,2,4-噁二唑(200mg,0.49mmol)溶于 20ml丙酮中，搅拌状态下加入2N盐酸溶液(1.98ml,3.95mmol)，45℃下加热3h。将反应冷却至室温，减压抽滤，干燥得白色固体168mg，收率94.8％，熔点193-195℃
1H NMR(500MHz,DMSO-d6)δ10.11(s,1H),8.30-8.27(m,3H),8.22(s,1H),8.08(d,J＝8.0Hz, 1H),8.00(d,J＝8.0Hz,2H),7.81(d,J＝8.0Hz,2H),7.54(t,J＝7.5Hz,2H),7.47(t,J＝7.5Hz, 1H).
(6)(3-氯-4-(5-([1,1'-联苯]-4-基)-1,2,4-噁二唑-3-基)苄基)甘氨酸甲酯的制备
将3-氯-4-(5-([1,1'-联苯]-4-基)-1,2,4-噁二唑-3-基)苯甲醛(160mg,0.44mmol)溶于35ml二氯甲烷中，向其中依次加入甘氨酸甲酯盐酸盐(84mg,0.66mmol)、冰醋酸(0.10ml,1.77mmol)、N,N-二异丙基乙胺(0.11ml,0.66mmol)、5ml甲醇，室温反应3h后加入氰基硼氢化钠(28mg,0.44mmol)，氩气保护下反应5h。加入饱和碳酸氢钠溶液，二氯甲烷萃取3次(3×30mL)，蒸馏水洗1次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为二氯甲烷：甲醇＝20:1，得白色固体138mg，收率72.5％，熔点88-90℃
1H NMR(500MHz,DMSO-d6)δ8.27(d,J＝8.5Hz,2H),7.98(dd,J＝8.0,2.0Hz,3H),7.80(d,J ＝7.5Hz,2H),7.67(s,1H),7.56–7.50(m,3H),7.46(t,J＝7.2Hz,1H),3.84(s,2H),3.64(s,3H), 3.37(s,2H),2.77(s,1H).
(7)标题化合物的制备
按实施例1中步骤(7)方法制备，得白色固体94mg，收率64.7％，熔点248-250℃
1H NMR(500MHz,DMSO-d6)δ9.81(s,1H),8.28(d,J＝8.5Hz,2H),8.10(d,J＝8.0Hz,1H), 8.00(d,J＝8.0Hz,2H),7.93(s,1H),7.81(d,J＝7.5Hz,2H),7.72(d,J＝8.0Hz,1H),7.55(t,J＝ 7.5Hz,2H),7.48-7.46(m,1H),4.29(s,2H),3.91(s,2H).
HRMS calcd.For C23H19ClN3O3(M+H)+420.1109,found 420.1107.
实施例15
(3-氯-4-(5-(4-(叔丁基)苯基)-1,2,4-噁二唑-3-基)苄基)甘氨酸盐酸盐
(1)5-(4-叔丁基苯基)-3-(2-氯-4-(1,3-二氧戊环-2-基)苯基)-1,2,4-噁二唑的制备
将对叔丁基苯甲酸(242mg,1.36mmol)，1-羟基苯并三唑(168mg,1.24mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(238mg,1.24mmol)，碳酸钾(256mg,1.85mmol)溶于30ml N,N-二甲基甲酰胺中，室温搅拌30分钟后加入2-氯-4-(1,3-二氧戊环-2-基)-N'-羟基苯甲脒(300mg, 1.24mmol)，氩气保护下加热至110℃反应4h。将反应冷却至室温，减压抽滤，滤饼用乙酸乙酯洗2次，合并滤液，加入蒸馏水，乙酸乙酯萃取3次(3×50mL)，蒸馏水洗2次，饱和氯化钠溶液洗1次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为石油醚：乙酸乙酯＝3:1，得白色固体297mg，收率62.2％，熔点77-79℃
1H NMR(400MHz,DMSO-d6)δ8.11(d,J＝8.4Hz,2H),8.05(d,J＝8.0Hz,1H),7.72–7.67(m, 3H),7.62(d,J＝8.0Hz,1H),5.87(s,1H),4.12–3.96(m,4H),1.33(s,9H).
(5)3-氯-4-(5-(4-叔丁基苯基)-1,2,4-噁二唑-3-基)苯甲醛的制备
将5-(4-叔丁基苯基)-3-(2-氯-4-(1,3-二氧戊环-2-基)苯基)-1,2,4-噁二唑(297mg,0.77mmol)溶于 20ml丙酮中，搅拌状态下加入2N盐酸溶液(3.09ml,6.17mmol)，45℃下加热3h。将反应冷却至室温，减压抽滤，干燥得白色固体231mg，收率88.0％，熔点132-135℃
1H NMR(500MHz,DMSO-d6)δ10.10(s,1H),8.25(d,J＝8.0Hz,1H),8.21(s,1H),8.13(d,J＝ 8.5Hz,2H),8.07(d,J＝8.0Hz,1H),7.70(d,J＝8.5Hz,2H),1.34(s,9H).
(6)(3-氯-4-(5-(4-叔丁基苯基)-1,2,4-噁二唑-3-基)苄基)甘氨酸甲酯的制备
将3-氯-4-(5-(4-叔丁基苯基)-1,2,4-噁二唑-3-基)苯甲醛(230mg,0.67mmol)溶于35ml二氯甲烷中，向其中依次加入甘氨酸甲酯盐酸盐(127mg,1.01mmol)、冰醋酸(0.15ml,1.77mmol)、N,N-二异丙基乙胺(0.17ml,1.01mmol)、5ml甲醇，室温反应3h后加入氰基硼氢化钠(42mg,0.67mmol)，氩气保护下反应5h。加入饱和碳酸氢钠溶液，二氯甲烷萃取3次(3×30mL)，蒸馏水洗1次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为二氯甲烷：甲醇＝20:1，得白色固体160mg，收率57.7％，熔点79-82℃
1H NMR(500MHz,DMSO-d6)δ8.11(d,J＝8.0Hz,2H),7.95(d,J＝8.0Hz,1H),7.69(d,J＝8.0 Hz,2H),7.65(s,1H),7.50(d,J＝8.0Hz,1H),3.82(s,2H),3.63(s,3H),3.37(s,2H),2.76(s,1H), 1.34(s,9H).
(7)标题化合物的制备
按实施例1中步骤(7)方法制备，得白色固体120mg，收率71.4％，熔点212-215℃
1H NMR(500MHz,DMSO-d6)δ8.12(d,J＝8.0Hz,2H),8.02(d,J＝8.0Hz,1H),7.78(s,1H), 7.70(d,J＝8.0Hz,2H),7.60(d,J＝8.0Hz,1H),4.06(s,2H),3.47(s,2H),1.35(s,9H).
HRMS calcd.For C21H23ClN3O3(M+H)+400.1422,found 400.1427.
实施例16
(3-氯-4-(5-(4-异丙基苯基)-1,2,4-噁二唑-3-基)苄基)甘氨酸盐酸盐
(1)5-(4-异丙基苯基)-3-(2-氯-4-(1,3-二氧戊环-2-基)苯基)-1,2,4-噁二唑的制备
将4-异丙基苯甲酸(223mg,1.36mmol)，1-羟基苯并三唑(168mg,1.24mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(238mg,1.24mmol)，碳酸钾(256mg,1.85mmol)溶于30ml N,N-二甲基甲酰胺中，室温搅拌30分钟后加入2-氯-4-(1,3-二氧戊环-2-基)-N'-羟基苯甲脒(300mg, 1.24mmol)，氩气保护下加热至110℃反应4h。将反应冷却至室温，减压抽滤，滤饼用乙酸乙酯洗2次，合并滤液，加入蒸馏水，乙酸乙酯萃取3次(3×50mL)，蒸馏水洗2次，饱和氯化钠溶液洗1次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为石油醚：乙酸乙酯＝3:1，得白色固体218mg，收率47.5％，熔点53-55℃
1H NMR(500MHz,DMSO-d6)δ8.11(d,J＝8.0Hz,2H),8.05(d,J＝8.0Hz,1H),7.72(s,1H), 7.62(d,J＝8.0Hz,1H),7.54(d,J＝8.0Hz,2H),5.87(s,1H),4.10–3.98(m,4H),3.02(hept,J＝ 7.0Hz,1H),1.25(d,J＝7.0Hz,6H).
(5)3-氯-4-(5-(4-异丙基苯基)-1,2,4-噁二唑-3-基)苯甲醛的制备
将5-(4-异丙基苯基)-3-(2-氯-4-(1,3-二氧戊环-2-基)苯基)-1,2,4-噁二唑(200mg,0.54mmol)溶于 20ml丙酮中，搅拌状态下加入2N盐酸溶液(2.16ml,4.31mmol)，45℃下加热3h。将反应冷却至室温，减压抽滤，干燥得白色固体157mg，收率89.0％，熔点119-121℃
1H NMR(400MHz,DMSO-d6)δ10.11(s,1H),8.26(d,J＝8.0Hz,1H),8.22(d,J＝1.6Hz,1H), 8.14(dt,J＝8.4,1.9Hz,2H),8.07(dd,J＝7.8,1.4Hz,1H),7.58–7.55(m,2H),3.04(hept,J＝6.9 Hz,1H),1.27(d,J＝6.8Hz,6H).
(6)(3-氯-4-(5-(4-异丙基苯基)-1,2,4-噁二唑-3-基)苄基)甘氨酸甲酯的制备
将3-氯-4-(5-(4-异丙基苯基)-1,2,4-噁二唑-3-基)苯甲醛(150mg,0.46mmol)溶于35ml二氯甲烷中，向其中依次加入甘氨酸甲酯盐酸盐(86mg,0.69mmol)、冰醋酸(0.10ml,1.84mmol)、N,N-二异丙基乙胺(0.11ml,0.69mmol)、5ml甲醇，室温反应3h后加入氰基硼氢化钠(29mg,0.46mmol)，氩气保护下反应5h。加入饱和碳酸氢钠溶液，二氯甲烷萃取3次(3×30mL)，蒸馏水洗1次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为二氯甲烷：甲醇＝20:1，得白色固体130mg，收率70.7％，熔点68-70℃
1H NMR(400MHz,DMSO-d6)δ8.12-8.10(m,2H),7.95(d,J＝8.0Hz,1H),7.66(d,J＝1.2Hz, 1H),7.56-7.54(m,2H),7.50(dd,J＝8.0,1.2Hz,1H),3.83(s,2H),3.63(s,3H),3.37(s,2H),3.03 (hept,J＝6.9Hz,1H),2.78(s,1H),1.26(d,J＝6.8Hz,6H).
(7)标题化合物的制备
按实施例1中步骤(7)方法制备，得白色固体88mg，收率64.2％，熔点117-119℃
1H NMR(400MHz,DMSO-d6)δ11.14(s,1H),8.11(d,J＝8.4Hz,2H),8.06(d,J＝8.0Hz,1H), 7.93(d,J＝1.2Hz,1H),7.72(dd,J＝8.2,1.4Hz,1H),7.55(d,J＝8.4Hz,2H),4.27(s,2H),3.87(s, 2H),3.03(hept,J＝6.8Hz,1H),1.26(d,J＝6.8Hz,6H).
HRMS calcd.For C20H21ClN3O3(M+H)+386.1266,found 386.1269.
实施例17
(3-氯-4-(5-(4-异丙氧基苯基)-1,2,4-噁二唑-3-基)苄基)甘氨酸盐酸盐
(1)3-(2-氯-4-(1,3-二氧戊环-2-基)苯基)-5-(4-异丙氧基苯基)-1,2,4-噁二唑的制备
将4-异丙氧基苯甲酸(245mg,1.36mmol)，1-羟基苯并三唑(168mg,1.24mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(238mg,1.24mmol)，碳酸钾(256mg,1.85mmol)溶于30ml N,N-二甲基甲酰胺中，室温搅拌30分钟后加入2-氯-4-(1,3-二氧戊环-2-基)-N'-羟基苯甲脒(300mg, 1.24mmol)，氩气保护下加热至110℃反应4h。将反应冷却至室温，减压抽滤，滤饼用乙酸乙酯洗2次，合并滤液，加入蒸馏水，乙酸乙酯萃取3次(3×50mL)，蒸馏水洗2次，饱和氯化钠溶液洗1次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为石油醚：乙酸乙酯＝3:1，得白色固体203mg，收率42.3％，熔点88-90℃
1H NMR(400MHz,DMSO-d6)δ8.12–8.09(m,2H),8.03(d,J＝8.0Hz,1H),7.72(d,J＝1.2Hz, 1H),7.62(dd,J＝7.8,1.4Hz,1H),7.19–7.15(m,2H),5.87(s,1H),4.79(hept,J＝6.0Hz,1H), 4.11–3.98(m,4H),1.32(d,J＝6.4Hz,6H).
(5)3-氯-4-(5-(4-异丙氧基苯基)-1,2,4-噁二唑-3-基)苯甲醛的制备
将3-(2-氯-4-(1,3-二氧戊环-2-基)苯基)-5-(4-异丙基苯基)-1,2,4-噁二唑(190mg,0.49mmol)溶于 20ml丙酮中，搅拌状态下加入2N盐酸溶液(1.96ml,3.93mmol)，45℃下加热3h。将反应冷却至室温，减压抽滤，干燥得白色固体123mg，收率73.2％，熔点107-109℃
1H NMR(400MHz,DMSO-d6)δ10.10(s,1H),8.23(d,J＝8.0Hz,1H),8.20(d,J＝1.2Hz,1H), 8.14–8.10(m,2H),8.06(dd,J＝7.8,1.4Hz,1H),7.20–7.16(m,2H),4.80(hept,J＝6.1Hz,1H), 1.32(d,J＝6.0Hz,6H).
(6)(3-氯-4-(5-(4-异丙氧基苯基)-1,2,4-噁二唑-3-基)苄基)甘氨酸甲酯的制备
将3-氯-4-(5-(4-异丙氧基苯基)-1,2,4-噁二唑-3-基)苯甲醛(120mg,0.35mmol)溶于35ml二氯甲烷中，向其中依次加入甘氨酸甲酯盐酸盐(65mg,0.52mmol)、冰醋酸(0.08ml,1.40mmol)、N,N-二异丙基乙胺(0.09ml,0.52mmol)、5ml甲醇，室温反应3h后加入氰基硼氢化钠(22mg,0.35mmol)，氩气保护下反应5h。加入饱和碳酸氢钠溶液，二氯甲烷萃取3次(3×30mL)，蒸馏水洗1次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为二氯甲烷：甲醇＝20:1，得白色固体126mg，收率86.6％，熔点59-60℃
1H NMR(400MHz,DMSO-d6)δ8.11(d,J＝8.8Hz,2H),7.93(d,J＝8.0Hz,1H),7.65(s,1H), 7.49(d,J＝8.0Hz,1H),7.18-7.16(m,2H),4.80(hept,J＝6.1Hz,1H),3.82(s,2H),3.63(s,3H), 3.36(s,2H),2.76(s,1H),1.32(d,J＝6.0Hz,6H).
(7)标题化合物的制备
按实施例1中步骤(7)方法制备，得白色固体87mg，收率65.6％，熔点204-207℃
1H NMR(400MHz,DMSO-d6)δ10.13(s,1H),8.10(d,J＝8.8Hz,2H),8.02(d,J＝8.0Hz,1H), 7.83(s,1H),7.63(d,J＝8.0Hz,1H),7.18(d,J＝8.8Hz,2H),4.80(hept,J＝6.1Hz,1H),4.15(s, 2H),3.64(s,2H),1.32(d,J＝6.0Hz,6H).
HRMS calcd.For C20H21ClN3O4(M+H)+402.1215,found 402.1216.
实施例18
(3-氯-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苄基)甘氨酸盐酸盐
(1)3-(2-氯-4-(1,3-二氧戊环-2-基)苯基)-5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑的制备
将4-异丙氧基-3-氰基苯甲酸(186mg,0.91mmol)，1-羟基苯并三唑(111mg,0.82mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(158mg,0.82mmol)，碳酸钾(256mg,1.24mmol)溶于30ml N,N-二甲基甲酰胺中，室温搅拌30分钟后加入2-氯-4-(1,3-二氧戊环-2-基)-N'-羟基苯甲脒(200mg,0.82mmol)，氩气保护下加热至110℃反应4h。将反应冷却至室温，减压抽滤，滤饼用乙酸乙酯洗2次，合并滤液，加入蒸馏水，乙酸乙酯萃取3次(3×50mL)，蒸馏水洗2次，饱和氯化钠溶液洗1次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为石油醚：乙酸乙酯＝3:1，得白色固体294mg，收率87.0％，熔点153-155℃
1H NMR(400MHz,DMSO-d6)δ8.51(d,J＝2.4Hz,1H),8.40(dd,J＝9.0,2.2Hz,1H),8.05(d,J ＝8.0Hz,1H),7.72(d,J＝1.2Hz,1H),7.62(dd,J＝8.0,1.2Hz,1H),7.55(d,J＝9.2Hz,1H),5.87 (s,1H),4.98(hept,J＝6.0Hz,1H),4.13–3.96(m,4H),1.38(d,J＝6.0Hz,6H).
(5)3-氯-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苯甲醛的制备
将3-(2-氯-4-(1,3-二氧戊环-2-基)苯基)-5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑(290mg, 0.70mmol)溶于20ml丙酮中，搅拌状态下加入2N盐酸溶液(2.82ml,5.63mmol)，45℃下加热 3h。将反应冷却至室温，减压抽滤，干燥得白色固体198mg，收率76.9％，熔点177-179℃
1H NMR(400MHz,DMSO-d6)δ10.10(s,1H),8.53(d,J＝2.4Hz,1H),8.41(dd,J＝9.0,2.2Hz, 1H),8.25(d,J＝8.0Hz,1H),8.21(d,J＝1.2Hz,1H),8.08–8.05(m,1H),7.56(d,J＝9.2Hz,1H), 4.98(hept,J＝5.9Hz,1H),1.39(d,J＝6.0Hz,6H).
(6)(3-氯-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苄基)甘氨酸甲酯的制备
将3-氯-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苯甲醛(174mg,0.47mmol)溶于35ml 二氯甲烷中，向其中依次加入甘氨酸甲酯盐酸盐(89mg,0.71mmol)、冰醋酸(0.11ml,1.89mmol)、 N,N-二异丙基乙胺(0.12ml,0.71mmol)、5ml甲醇，室温反应3h后加入氰基硼氢化钠(30mg, 0.47mmol)，氩气保护下反应5h。加入饱和碳酸氢钠溶液，二氯甲烷萃取3次(3×30mL)，蒸馏水洗1次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为二氯甲烷：甲醇＝20:1，得白色固体183mg，收率88.3％，熔点107-110℃
1H NMR(400MHz,DMSO-d6)δ8.50(d,J＝2.4Hz,1H),8.39(dd,J＝9.2,2.4Hz,1H),7.95(d,J ＝8.0Hz,1H),7.65(d,J＝1.2Hz,1H),7.55(d,J＝9.2Hz,1H),7.50(dd,J＝8.0,1.6Hz,1H),4.98 (hept,J＝6.1Hz,1H),3.82(s,2H),3.63(s,3H),3.37(s,2H),2.77(s,1H),1.38(d,J＝6.0Hz,6H).
(7)标题化合物的制备
按实施例1中步骤(7)方法制备，得白色固体109mg，收率62.3％，熔点198-200℃
1H NMR(400MHz,DMSO-d6)δ10.06(s,1H),8.50(m,1H),8.40(m,1H),8.04(m,1H),7.83(s, 1H),7.65-7.57(m,2H),4.98(s,1H),4.13(s,2H),3.61(s,2H),1.39(m,6H).
HRMS calcd.For C21H20ClN4O4(M+H)+427.1168,found 427.1166.
实施例19
(3-氯-4-(5-(4-异丙氧基-3-三氟甲基苯基)-1,2,4-噁二唑-3-基)苄基)甘氨酸盐酸盐
(1)4-异丙氧基-3-三氟甲基苯甲酸异丙酯的制备
将3-三氟甲基-4-羟基苯甲酸(400mg,1.94mmol)和碳酸铯(1.90g,5.82mmol)溶于30mlN,N-二甲基甲酰胺中，之后向其中滴加异丙基溴(596mg,4.85mmol)，反应混合液加热至80℃反应4h。将反应冷却至室温，加入饱和氯化铵溶液，乙酸乙酯萃取3次(3×30mL)，合并有机相，蒸馏水洗2次，饱和氯化钠溶液洗1次，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为石油醚：乙酸乙酯＝8:1，得无色油状物522mg，收率92.7％
1H NMR(400MHz,DMSO-d6)δ8.14(dd,J＝8.8,2.4Hz,1H),8.06(d,J＝2.4Hz,1H),7.41(d,J ＝8.8Hz,1H),5.12(hept,J＝6.3Hz,1H),4.90(hept,J＝6.1Hz,1H),1.31(d,J＝6.4Hz,12H).
(2)4-异丙氧基-3-三氟甲基苯甲酸的制备
将4-异丙氧基-3-三氟甲基苯甲酸异丙酯(480mg,1.65mmol)溶于20ml甲醇中，加入1N氢氧化钠溶液(4.96ml,4.96mmol)，加热至60℃，反应3h。将反应冷却至室温，滴加2N盐酸溶液至 PH2-3，二氯甲烷萃取3次(3×30mL)，合并有机相，蒸馏水洗2次，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为二氯甲烷：甲醇＝20:1，得白色固体320mg，收率78.1％，熔点148-150℃1H NMR(400MHz,DMSO-d6)δ13.08(s,1H),8.15(dd,J＝8.6,1.8Hz,1H),8.08(m,1H),7.40(d, J＝8.8Hz,1H),4.90(hept,J＝6.0,1H),1.32(d,J＝6.0,6H).
(3)3-(2-氯-4-(1,3-二氧戊环-2-基)苯基)-5-(4-异丙氧基-3-三氟甲基苯基)-1,2,4-噁二唑的制备
将4-异丙氧基-3-三氟甲基苯甲酸(318mg,1.28mmol)，1-羟基苯并三唑(157mg,1.16mmol)，1-(3- 二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(222mg,1.16mmol)，碳酸钾(241mg,1.75mmol)溶于30ml N,N-二甲基甲酰胺中，室温搅拌30分钟后加入2-氯-4-(1,3-二氧戊环-2-基)-N'-羟基苯甲脒 (281mg,1.16mmol)，氩气保护下加热至110℃反应4h。将反应冷却至室温，减压抽滤，滤饼用乙酸乙酯洗2次，合并滤液，加入蒸馏水，乙酸乙酯萃取3次(3×50mL)，蒸馏水洗2次，饱和氯化钠溶液洗1次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为石油醚：乙酸乙酯＝3:1，得白色固体421mg，收率72.3％，熔点131-134℃
1H NMR(400MHz,DMSO-d6)δ8.39(dd,J＝8.8,2.4Hz,1H),8.29(d,J＝2.0Hz,1H),8.06(d,J ＝8.0Hz,1H),7.72(d,J＝1.6Hz,1H),7.62(dd,J＝8.4,1.6Hz,1H),7.58(d,J＝8.8Hz,1H),5.87 (s,1H),4.97(hept,J＝6.0Hz,1H),4.12–3.96(m,4H),1.35(d,J＝6.0Hz,6H).
(5)3-氯-4-(5-(4-异丙氧基-3-三氟甲基苯基)-1,2,4-噁二唑-3-基)苯甲醛的制备
将3-(2-氯-4-(1,3-二氧戊环-2-基)苯基)-5-(4-异丙氧基-3-三氟甲基苯基)-1,2,4-噁二唑(410mg, 0.90mmol)溶于20ml丙酮中，搅拌状态下加入2N盐酸溶液(3.60ml,7.21mmol)，45℃下加热3h。将反应冷却至室温，加入饱和碳酸氢钠溶液，乙酸乙酯萃取3次(3×50mL)，合并有机相，蒸馏水洗2次，饱和氯化钠溶液洗1次，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为石油醚：乙酸乙酯＝3:1，得白色固体262mg，收率70.9％，熔点121-124℃
1H NMR(400MHz,DMSO-d6)δ10.10(d,J＝2.0Hz,1H),8.41(d,J＝8.8Hz,1H),8.31(m,1H), 8.26(dd,J＝7.8,1.4Hz,1H),8.20(m,1H),8.07-8.05(m,1H),7.59(d,J＝8.8Hz,1H),4.98(hept, J＝6.0Hz,1H),1.36(dd,J＝6.0,1.6Hz,6H).
(6)(3-氯-4-(5-(4-异丙氧基-3-三氟甲基苯基)-1,2,4-噁二唑-3-基)苄基)甘氨酸甲酯的制备
将3-氯-4-(5-(4-异丙氧基-3-三氟甲基苯基)-1,2,4-噁二唑-3-基)苯甲醛(260mg,0.63mmol)溶于 35ml二氯甲烷中，向其中依次加入甘氨酸甲酯盐酸盐(119mg,0.95mmol)、冰醋酸(0.14ml, 2.53mmol)、N,N-二异丙基乙胺(0.16ml,0.95mmol)、5ml甲醇，室温反应3h后加入氰基硼氢化钠(40mg,0.63mmol)，氩气保护下反应5h。加入饱和碳酸氢钠溶液，二氯甲烷萃取3次(3×30mL)，蒸馏水洗1次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为二氯甲烷：甲醇＝20:1，得白色固体224mg，收率73.5％，熔点88-90℃
1H NMR(400MHz,DMSO-d6)δ8.39(dd,J＝8.8,2.0Hz,1H),8.30(d,J＝2.0Hz,1H),7.96(d,J ＝7.6Hz,1H),7.66(d,J＝1.6Hz,1H),7.58(d,J＝8.8Hz,1H),7.50(dd,J＝8.0,1.6Hz,1H),4.98 (hept,J＝6.0Hz,1H),3.83(s,2H),3.63(s,3H),3.37(s,2H),2.77(s,1H),1.35(d,J＝6.0Hz,6H). (7)标题化合物的制备
按实施例1中步骤(7)方法制备，得白色固体160mg，收率68.3％，熔点202-205℃
1H NMR(400MHz,DMSO-d6)δ8.39(d,J＝8.4Hz,1H),8.30(s,1H),8.00(d,J＝7.6Hz,1H), 7.72(s,1H),7.60-7.54(m,2H),5.01-4.95(m,1H),3.94(s,2H),3.23(s,2H),1.35(d,J＝5.6Hz, 6H).
HRMS calcd.For C21H20ClF3N3O4(M+H)+470.1089,found 470.1091.
实施例20
(3-氯-4-(5-(3-氯-4-异丙氧基苯基)-1,2,4-噁二唑-3-基)苄基)甘氨酸盐酸盐
(1)3-氯-4-异丙氧基苯甲酸甲酯的制备
将3-氯-4-羟基苯甲酸甲酯(400mg,2.14mmol)和碳酸钾(889mg,6.43mmol)溶于30mlN,N-二甲基甲酰胺中，之后向其中滴加异丙基溴(527mg,4.29mmol)，反应混合液加热至80℃反应4h。将反应冷却至室温，加入饱和氯化铵溶液，乙酸乙酯萃取3次(3×30mL)，合并有机相，蒸馏水洗2次，饱和氯化钠溶液洗1次，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为石油醚：乙酸乙酯＝8:1，得无色油状物474mg，收率96.9％
1H NMR(400MHz,DMSO-d6)δ7.91(d,J＝2.4Hz,1H),7.87(dd,J＝8.6,2.2Hz,1H),7.28(d,J ＝8.8Hz,1H),4.81(hept,J＝6.1Hz,1H),3.82(s,3H),1.32(d,J＝6.0Hz,6H).
(2)3-氯-4-异丙氧基苯甲酸的制备
将3-氯-4-异丙氧基苯甲酸甲酯(470mg,2.06mmol)溶于20ml甲醇中，加入1N氢氧化钠溶液 (6.17ml,6.17mmol)，加热至60℃，反应3h。将反应冷却至室温，滴加2N盐酸溶液至PH2-3，二氯甲烷萃取3次(3×30mL)，合并有机相，蒸馏水洗2次，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为二氯甲烷：甲醇＝20:1，得白色固体380mg，收率85.9％，熔点118-121℃
1H NMR(400MHz,DMSO-d6)δ12.93(s,1H),7.89(d,J＝2.0Hz,1H),7.85(dd,J＝8.6,2.2Hz, 1H),7.26(d,J＝8.8Hz,1H),4.80(hept,J＝6.1Hz,1H),1.32(d,J＝6.0Hz,6H).
(3)3-(2-氯-4-(1,3-二氧戊环-2-基)苯基)-5-(3-氯-4-异丙氧基苯基)-1,2,4-噁二唑的制备
将3-氯-4-异丙氧基苯甲酸(370mg,1.72mmol)，1-羟基苯并三唑(212mg,1.57mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(300mg,1.57mmol)，碳酸钾(357mg,2.58mmol)溶于30ml N,N-二甲基甲酰胺中，室温搅拌30分钟后加入2-氯-4-(1,3-二氧戊环-2-基)-N'-羟基苯甲脒 (380mg,1.57mmol)，氩气保护下加热至110℃反应4h。将反应冷却至室温，减压抽滤，滤饼用乙酸乙酯洗2次，合并滤液，加入蒸馏水，乙酸乙酯萃取3次(3×50mL)，蒸馏水洗2次，饱和氯化钠溶液洗1次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为石油醚：乙酸乙酯＝3:1，得白色固体474mg，收率71.7％，熔点130-133℃
1H NMR(400MHz,DMSO-d6)δ8.18(dd,J＝2.4,0.8Hz,1H),8.11(ddd,J＝8.7,2.2,0.7Hz,1H), 8.05(d,J＝8.0Hz,1H),7.72(m,1H),7.63-7.61(m,1H),7.44(d,J＝8.4Hz,1H),5.87(s,1H), 4.88(hept,J＝6.1Hz,1H),4.13–3.98(m,4H),1.36(d,J＝6.0Hz,6H).
(5)3-氯-4-(5-(3-氯-4-异丙氧基苯基)-1,2,4-噁二唑-3-基)苯甲醛的制备
将3-(2-氯-4-(1,3-二氧戊环-2-基)苯基)-5-(3-氯-4-异丙氧基苯基)-1,2,4-噁二唑(470mg,1.12mmol) 溶于20ml丙酮中，搅拌状态下加入2N盐酸溶液(4.46ml,8.92mmol)，45℃下加热3h。将反应冷却至室温，加入饱和碳酸氢钠溶液，乙酸乙酯萃取3次(3×50mL)，合并有机相，蒸馏水洗2次，饱和氯化钠溶液洗1次，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为石油醚：乙酸乙酯＝3:1，得白色固体367mg，收率86.8％，熔点136-138℃
1H NMR(400MHz,DMSO-d6)δ10.10(s,1H),8.25(d,J＝8.0Hz,1H),8.21-8.19(m,2H),8.12 (dd,J＝8.8,2.4Hz,1H),8.06(dd,J＝8.0,1.6Hz,1H),7.46(d,J＝9.2Hz,1H),4.89(hept,J＝5.9 Hz,1H),1.36(d,J＝6.0Hz,6H).
(6)(3-氯-4-(5-(4-异丙氧基-3-(三氟甲基)苯基)-1,2,4-噁二唑-3-基)苄基)甘氨酸甲酯的制备
将3-氯-4-(5-(3-氯-4-异丙氧基苯基)-1,2,4-噁二唑-3-基)苯甲醛(360mg,0.95mmol)溶于35ml二氯甲烷中，向其中依次加入甘氨酸甲酯盐酸盐(180mg,1.43mmol)、冰醋酸(0.22ml,3.82mmol)、 N,N-二异丙基乙胺(0.24ml,1.43mmol)、5ml甲醇，室温反应3h后加入氰基硼氢化钠(60mg, 0.63mmol)，氩气保护下反应5h。加入饱和碳酸氢钠溶液，二氯甲烷萃取3次(3×30mL)，蒸馏水洗1次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为二氯甲烷：甲醇＝20:1，得白色固体353mg，收率82.5％，熔点83-86℃
1H NMR(400MHz,DMSO-d6)δ8.16(d,J＝2.0Hz,1H),8.09(dd,J＝8.6,2.2Hz,1H),7.94(d,J ＝7.6Hz,1H),7.64(d,J＝1.2Hz,1H),7.48(dd,J＝8.0,1.6Hz,1H),7.43(d,J＝9.2Hz,1H),4.87 (hept,J＝6.1Hz,1H),3.82(s,2H),3.63(s,3H),3.36(s,2H),2.76(s,1H),1.36(d,J＝6.0Hz,6H).
(7)标题化合物的制备
按实施例1中步骤(7)方法制备，得白色固体239mg，收率64.5％，熔点217-220℃
1H NMR(400MHz,DMSO-d6)δ8.16(d,J＝2.4Hz,1H),8.09(dd,J＝8.6,2.2Hz,1H),8.02(d,J ＝8.0Hz,1H),7.80(d,J＝1.6Hz,1H),7.61(dd,J＝8.0,1.6Hz,1H),7.44(d,J＝9.2Hz,1H),4.88 (hept,J＝5.9Hz,1H),4.09(s,2H),3.49(s,2H),1.36(d,J＝6.4Hz,6H).
HRMS calcd.For C20H20Cl2N3O4(M+H)+436.0825,found 436.0827.
实施例21
(3-氯-4-(5-(3-甲基-4-异丙氧基苯基)-1,2,4-噁二唑-3-基)苄基)甘氨酸盐酸盐
(1)3-甲基-4-异丙氧基苯甲酸甲酯的制备
将3-甲基-4-羟基苯甲酸甲酯(400mg,2.41mmol)和碳酸钾(998mg,7.22mmol)溶于30mlN,N-二甲基甲酰胺中，之后向其中滴加异丙基溴(592mg,4.81mmol)，反应混合液加热至80℃反应4h。将反应冷却至室温，加入饱和氯化铵溶液，乙酸乙酯萃取3次(3×30mL)，合并有机相，蒸馏水洗2次，饱和氯化钠溶液洗1次，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为石油醚：乙酸乙酯＝8:1，得无色油状物409mg，收率81.5％
1H NMR(400MHz,DMSO-d6)δ7.78(ddd,J＝8.5,2.4,0.5Hz,1H),7.74(dd,J＝2.0,0.8Hz,1H), 7.04(d,J＝8.8Hz,1H),4.70(hept,J＝6.0Hz,1H),3.79(s,3H),2.15(s,3H),1.30(d,J＝6.0Hz, 6H).
(2)3-甲基-4-异丙氧基苯甲酸的制备
将3-甲基-4-异丙氧基苯甲酸甲酯(400mg,1.92mmol)溶于20ml甲醇中，加入1N氢氧化钠溶液 (5.76ml,5.76mmol)，加热至60℃，反应3h。将反应冷却至室温，滴加2N盐酸溶液至PH2-3，二氯甲烷萃取3次(3×30mL)，合并有机相，蒸馏水洗2次，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为二氯甲烷：甲醇＝20:1，得白色固体305mg，收率81.8％，熔点140-143℃
1H NMR(500MHz,DMSO-d6)δ12.47(s,1H),7.75(dd,J＝8.5,2.0Hz,1H),7.72(s,1H),7.01(d, J＝8.5Hz,1H),4.70(hept,J＝6.0Hz,1H),2.14(s,3H),1.30(d,J＝6.0Hz,6H).
(3)3-(2-氯-4-(1,3-二氧戊环-2-基)苯基)-5-(3-甲基-4-异丙氧基苯基)-1,2,4-噁二唑的制备
将3-甲基-4-异丙氧基苯甲酸(300mg,1.54mmol)，1-羟基苯并三唑(190mg,1.40mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(269mg,1.40mmol)，碳酸钾(291mg,2.11mmol)溶于30ml N,N-二甲基甲酰胺中，室温搅拌30分钟后加入2-氯-4-(1,3-二氧戊环-2-基)-N'-羟基苯甲脒 (341mg,1.40mmol)，氩气保护下加热至110℃反应4h。将反应冷却至室温，减压抽滤，滤饼用乙酸乙酯洗2次，合并滤液，加入蒸馏水，乙酸乙酯萃取3次(3×50mL)，蒸馏水洗2次，饱和氯化钠溶液洗1次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为石油醚：乙酸乙酯＝3:1，得白色固体364mg，收率64.9％，熔点71-74℃
1H NMR(400MHz,DMSO-d6)δ8.03(d,J＝8.0Hz,1H),8.00–7.97(m,2H),7.71(d,J＝1.6Hz, 1H),7.61(dd,J＝8.0,1.6Hz,1H),7.20(d,J＝8.4Hz,1H),5.87(s,1H),4.78(hept,J＝6.1Hz,1H), 4.12–3.96(m,4H),2.23(s,3H),1.33(d,J＝6.0Hz,6H).
(5)3-氯-4-(5-(3-甲基-4-异丙氧基苯基)-1,2,4-噁二唑-3-基)苯甲醛的制备
将3-(2-氯-4-(1,3-二氧戊环-2-基)苯基)-5-(3-甲基-4-异丙氧基苯基)-1,2,4-噁二唑(360mg, 0.90mmol)溶于20ml丙酮中，搅拌状态下加入2N盐酸溶液(3.59ml,7.18mmol)，45℃下加热 3h。将反应冷却至室温，加入饱和碳酸氢钠溶液，乙酸乙酯萃取3次(3×50mL)，合并有机相，蒸馏水洗2次，饱和氯化钠溶液洗1次，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为石油醚：乙酸乙酯＝3:1，得白色固体267mg，收率83.1％
1H NMR(400MHz,DMSO-d6)δ10.09(s,1H),8.23(d,J＝8.0Hz,1H),8.19(d,J＝1.6Hz,1H), 8.05(dd,J＝8.0,1.6Hz,1H),8.02-7.98(m,2H),7.22(d,J＝8.4Hz,1H),4.78(hept,J＝6.1Hz, 1H),2.23(s,3H),1.34(d,J＝6.0Hz,6H).
(6)(3-氯-4-(5-(3-甲基-4-异丙氧基苯基)-1,2,4-噁二唑-3-基)苄基)甘氨酸甲酯的制备
将3-氯-4-(5-(3-甲基-4-异丙氧基苯基)-1,2,4-噁二唑-3-基)苯甲醛(260mg,0.76mmol)溶于35ml 二氯甲烷中，向其中依次加入甘氨酸甲酯盐酸盐(143mg,1.14mmol)、冰醋酸(0.17ml,3.03mmol)、 N,N-二异丙基乙胺(0.19ml,1.14mmol)、5ml甲醇，室温反应3h后加入氰基硼氢化钠(48mg, 0.76mmol)，氩气保护下反应5h。加入饱和碳酸氢钠溶液，二氯甲烷萃取3次(3×30mL)，蒸馏水洗1次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为二氯甲烷：甲醇＝20:1，得白色固体254mg，收率77.7％，熔点83-85℃
1H NMR(400MHz,DMSO-d6)δ7.99-7.96(m,2H),7.93(d,J＝8.0Hz,1H),7.64(d,J＝1.6Hz, 1H),7.48(dd,J＝8.0,1.6Hz,1H),7.19(d,J＝8.8Hz,1H),4.77(hept,J＝6.1Hz,1H),3.82(s,2H), 3.63(s,3H),3.36(s,2H),2.76(s,1H),2.22(s,3H),1.33(d,J＝6.4Hz,6H).
(7)标题化合物的制备
按实施例1中步骤(7)方法制备，得白色固体164mg，收率61.2％，熔点212-214℃
1H NMR(400MHz,DMSO-d6)δ8.00-7.97(m,3H),7.77(s,1H),7.59(d,J＝8.0Hz,1H),7.21(d, J＝8.4Hz,1H),4.78(hept,J＝5.9Hz,1H),4.05(s,2H),3.41(s,2H),2.23(s,3H),1.33(d,J＝6.0 Hz,6H).
HRMS calcd.For C21H23ClN3O4(M+H)+416.1372,found 416.1369.
实施例22
N-甲基-N-(3-氯-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苄基)甘氨酸盐酸盐
(1)N-甲基-N-(3-氯-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苄基)甘氨酸乙酯的制备
将3-氯-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苯甲醛(200mg,0.54mmol)溶于35ml 二氯甲烷中，向其中依次加入肌氨酸甲酯盐酸盐(126mg,0.82mmol)、冰醋酸(0.12ml,2.18mmol)、 N,N-二异丙基乙胺(0.13ml,0.82mmol)、5ml甲醇，室温反应3h后加入氰基硼氢化钠(34mg, 0.47mmol)，氩气保护下反应5h。加入饱和碳酸氢钠溶液，二氯甲烷萃取3次(3×30mL)，蒸馏水洗1次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为二氯甲烷：甲醇＝20:1，得白色固体159mg，收率62.5％
1H NMR(400MHz,DMSO-d6)δ8.50(d,J＝2.4Hz,1H),8.39(dd,J＝9.0,2.2Hz,1H),7.97(d,J ＝8.0Hz,1H),7.64(m,1H),7.55(d,J＝9.2Hz,1H),7.51-7.49(m,1H),4.98(hept,J＝6.1Hz,1H), 4.11(q,J＝7.1Hz,2H),3.75(s,2H),3.36(s,2H),2.30(s,3H),1.38(d,J＝6.0Hz,6H),1.21(t,J＝ 7.0Hz,3H).
(2)标题化合物的制备
按实施例1中步骤(7)方法制备，得白色固体107mg，收率64.1％，熔点152-155℃
1H NMR(400MHz,DMSO-d6)δ8.51(d,J＝2.4Hz,1H),8.40(dd,J＝9.0,2.2Hz,1H),8.08(d,J ＝8.0Hz,1H),7.90(d,J＝1.2Hz,1H),7.70(dd,J＝8.2,1.4Hz,1H),7.57(d,J＝9.2Hz,1H),4.98 (hept,J＝6.1Hz,1H),4.34(s,2H),3.97(s,2H),2.73(s,3H),1.38(d,J＝6.0Hz,6H).
实施例23
1-(3-氯-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苄基)氮杂环丁烷-3-羧酸盐酸盐
(1)1-(3-氯-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苄基)氮杂环丁烷-3-羧酸甲酯的制备
将3-氯-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苯甲醛(200mg,0.54mmol)溶于35ml 二氯甲烷中，向其中依次加入吖啶酸甲酯盐酸盐(124mg,0.82mmol)、冰醋酸(0.12ml,2.18mmol)、 N,N-二异丙基乙胺(0.13ml,0.82mmol)、5ml甲醇，室温反应3h后加入氰基硼氢化钠(34mg, 0.47mmol)，氩气保护下反应5h。加入饱和碳酸氢钠溶液，二氯甲烷萃取3次(3×30mL)，蒸馏水洗1次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为二氯甲烷：甲醇＝20:1，得白色固体185mg，收率72.8％
1H NMR(400MHz,DMSO-d6)δ8.49(d,J＝2.0Hz,1H),8.39(dd,J＝9.2,2.0Hz,1H),7.95(d,J ＝8.0Hz,1H),7.57–7.54(m,2H),7.45(d,J＝7.6Hz,1H),4.98(hept,J＝6.0Hz,1H),3.66(s, 2H),3.64(s,3H),3.47(t,J＝7.0Hz,2H),3.39–3.34(m,1H),3.27(t,J＝6.6Hz,2H),1.38(d,J＝ 6.0Hz,6H).
(2)标题化合物的制备
按实施例1中步骤(7)方法制备，得白色固体134mg，收率69.3％，熔点145-147℃
1H NMR(400MHz,DMSO-d6)δ8.52(d,J＝2.4Hz,1H),8.40(dd,J＝9.0,2.2Hz,1H),8.06(d,J ＝8.0Hz,1H),7.88(s,1H),7.68(dd,J＝7.8,2.0Hz,1H),7.57(d,J＝9.2Hz,1H),4.98(hept,J＝ 6.2Hz,1H),4.38(s,2H),4.11-4.09(m,4H),3.59(quint,J＝8.2Hz,1H),1.38(d,J＝6.0Hz,6H).
实施例24
(3-氯-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苄基)天冬氨酸盐酸盐
(1)(3-氯-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苄基)天冬氨酸的制备
将3-氯-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苯甲醛(200mg,0.54mmol)溶于35ml 二氯甲烷中，向其中依次加入天冬氨酸二甲酯盐酸盐(161mg,0.82mmol)、冰醋酸(0.12ml, 2.18mmol)、N,N-二异丙基乙胺(0.13ml,0.82mmol)、5ml甲醇，室温反应3h后加入氰基硼氢化钠(34mg,0.47mmol)，氩气保护下反应5h。加入饱和碳酸氢钠溶液，二氯甲烷萃取3次(3×30mL)，蒸馏水洗1次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为二氯甲烷：甲醇＝20:1，得白色固体218mg，收率78.1％
1H NMR(400MHz,DMSO-d6)δ8.50(d,J＝2.4Hz,1H),8.39(dd,J＝8.8,2.4Hz,1H),7.94(d,J ＝8.0Hz,1H),7.63(d,J＝0.8Hz,1H),7.55(d,J＝9.2Hz,1H),7.47(dd,J＝8.0,1.2Hz,1H),4.98 (hept,J＝6.1Hz,1H),3.93-3.72(m,2H),3.64(s,3H),3.61(s,3H),3.57(s,1H),3.00(s,1H), 2.76-2.61(m,2H),1.38(d,J＝6.0Hz,6H).
(2)标题化合物的制备
按实施例1中步骤(7)方法制备，得白色固体157mg，收率67.2％，熔点165-167℃
1H NMR(400MHz,DMSO-d6)δ10.14(s,1H),8.50(d,J＝2.0Hz,1H),8.39(dd,J＝9.0,2.2Hz, 1H),7.99(d,J＝8.0Hz,1H),7.75(d,J＝1.2Hz,1H),7.58–7.54(m,2H),4.97(hept,J＝6.0Hz, 1H),4.09-3.93(m,2H),3.62(t,J＝6.6Hz,1H),2.74–2.59(m,2H),1.38(d,J＝6.0Hz,6H).
实施例25
1-(3-氯-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苄基)吡咯烷-3-甲酸盐酸盐
(1)1-(3-氯-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苄基)吡咯烷-3-甲酸甲酯的制备
将3-氯-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苯甲醛(200mg,0.54mmol)溶于35ml 二氯甲烷中，向其中依次加入吡咯烷-3-甲酸甲酯盐酸盐(135mg,0.82mmol)、冰醋酸(0.12ml, 2.18mmol)、N,N-二异丙基乙胺(0.13ml,0.82mmol)、5ml甲醇，室温反应3h后加入氰基硼氢化钠(34mg,0.47mmol)，氩气保护下反应5h。加入饱和碳酸氢钠溶液，二氯甲烷萃取3次(3×30mL)，蒸馏水洗1次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为二氯甲烷：甲醇＝20:1，得白色固体181mg，收率69.1％。
1H NMR(400MHz,DMSO-d6)δ8.49(d,J＝2.4Hz,1H),8.39(dd,J＝9.0,2.2Hz,1H),7.96(d,J ＝7.6Hz,1H),7.62(d,J＝1.6Hz,1H),7.55(d,J＝9.2Hz,1H),7.49(dd,J＝8.0,1.6Hz,1H),4.98 (h,J＝6.1Hz,1H),3.73–3.64(m,2H),3.61(s,3H),3.11-3.03(m,1H),2.76–2.67(m,2H),2.56(t, J＝6.8Hz,2H),2.05–1.95(m,2H),1.38(d,J＝6.0Hz,6H).
(2)标题化合物的制备
按实施例1中步骤(7)方法制备，得白色固体110mg，收率58.3％，熔点212-214℃
1H NMR(400MHz,DMSO-d6)δ12.90(s,1H),11.76-11.40(m,1H),8.50(d,J＝2.0Hz,1H),8.39 (dd,J＝9.0,2.2Hz,1H),8.08–8.01(m,2H),7.82(d,J＝7.6Hz,1H),7.56(d,J＝9.2Hz,1H), 4.98(hept,J＝5.9Hz,1H),4.50(s,2H),3.44-3.36(m,5H),2.22(s,2H),1.38(d,J＝6.0Hz,6H).
实施例26
1-(3-氯-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苄基)哌啶-4-乙酸盐酸盐
(1)1-(3-氯-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苄基)哌啶-4-乙酸甲酯的制备
将3-氯-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苯甲醛(200mg,0.54mmol)溶于35ml 二氯甲烷中，向其中依次加入哌啶乙酸甲酯盐酸盐(129mg,0.82mmol)、冰醋酸(0.12ml, 2.18mmol)、N,N-二异丙基乙胺(0.13ml,0.82mmol)、5ml甲醇，室温反应3h后加入氰基硼氢化钠(34mg,0.47mmol)，氩气保护下反应5h。加入饱和碳酸氢钠溶液，二氯甲烷萃取3次(3×30mL)，蒸馏水洗1次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为二氯甲烷：甲醇＝20:1，得白色固体181mg，收率69.1％。
1H NMR(400MHz,DMSO-d6)δ8.49(d,J＝2.0Hz,1H),8.39(dd,J＝8.8,2.4Hz,1H),7.95(d,J ＝8.0Hz,1H),7.59(s,1H),7.55(d,J＝9.2Hz,1H),7.48(d,J＝8.0Hz,1H),4.98(hept,J＝6.1Hz, 1H),3.58(s,3H),3.54(s,2H),2.78(d,J＝11.2Hz,2H),2.25(d,J＝6.8Hz,2H),1.98(t,J＝11.0 Hz,2H),1.72-1.61(m,3H),1.38(d,J＝6.0Hz,6H),1.28-1.18(m,2H).
(2)标题化合物的制备
按实施例1中步骤(7)方法制备，得白色固体110mg，收率58.3％，熔点205-207℃
1H NMR(400MHz,DMSO-d6)δ12.25(s,1H),10.43(s,1H),8.52(d,J＝2.0Hz,1H),8.40(dd,J ＝9.0,2.2Hz,1H),8.11-8.08(m,1H),8.00(s,1H),7.77–7.75(m,1H),7.57(d,J＝9.2Hz,1H), 4.99(hept,J＝6.1Hz,1H),4.37-4.36(m,2H),3.41(m,2H),3.02–2.93(m,2H),2.20(d,J＝6.8 Hz,2H),1.87-1.84(m,3H),1.58-1.48(m,2H),1.38(d,J＝6.0Hz,6H).
实施例27
1-(3-氯-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苄基)-2-氧代吡咯烷盐酸盐
(1)4-((3-氯-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苄基)氨基)丁酸甲酯的制备
将3-氯-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苯甲醛(200mg,0.54mmol)溶于35ml 二氯甲烷中，向其中依次加入4-氨基丁酸甲酯盐酸盐(125mg,0.82mmol)、冰醋酸(0.12ml, 2.18mmol)、N,N-二异丙基乙胺(0.13ml,0.82mmol)、5ml甲醇，室温反应3h后加入氰基硼氢化钠(34mg,0.47mmol)，氩气保护下反应5h。加入饱和碳酸氢钠溶液，二氯甲烷萃取3次(3×30mL)，蒸馏水洗1次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为二氯甲烷：甲醇＝20:1，得白色固体148mg，收率58.2％。
1H NMR(400MHz,DMSO-d6)δ8.62(d,J＝2.0Hz,1H),8.51(dd,J＝9.2,2.0Hz,1H),8.07(d,J ＝8.0Hz,1H),7.77(s,1H),7.68(d,J＝9.2Hz,1H),7.62(d,J＝8.0Hz,1H),5.10(hept,J＝5.9Hz, 1H),3.89(s,2H),3.71(s,3H),3.45(s,1H),2.63–2.61(m,4H),1.82(quint,J＝7.0Hz,2H),1.51 (d,J＝6.0Hz,6H).
(2)标题化合物的制备
按实施例1中步骤(7)方法制备，得白色固体90mg，收率60.5％，熔点107-109℃
1H NMR(400MHz,DMSO-d6)δ8.50(d,J＝2.0Hz,1H),8.39(dd,J＝9.0,2.2Hz,1H),7.98(d,J ＝8.0Hz,1H),7.57-7.55(m,2H),7.41(d,J＝8.4Hz,1H),4.98(hept,J＝6.1Hz,1H),4.48(s,2H), 3.32-3.28(m,2H),2.33(t,J＝8.2Hz,2H),1.97(quint,J＝7.5Hz,2H),1.38(d,J＝6.0Hz,6H).
实施例28
N-甲基-N-(3-氯-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苄基)丙酸盐酸盐
(1)N-甲基-N-(3-氯-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苄基)丙酸甲酯的制备
将3-氯-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苯甲醛(200mg,0.54mmol)溶于35ml 二氯甲烷中，向其中依次加入3-(甲基氨基)丙酸甲酯(96mg,0.82mmol)、冰醋酸(0.12ml, 2.18mmol)、N,N-二异丙基乙胺(0.13ml,0.82mmol)、5ml甲醇，室温反应3h后加入氰基硼氢化钠(34mg,0.47mmol)，氩气保护下反应5h。加入饱和碳酸氢钠溶液，二氯甲烷萃取3次(3×30mL)，蒸馏水洗1次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为二氯甲烷：甲醇＝20:1，得白色固体134mg，收率54.0％。
1H NMR(400MHz,DMSO-d6)δ8.48(d,J＝2.4Hz,1H),8.38(dd,J＝8.8,2.4Hz,1H),7.95(d,J ＝8.0Hz,1H),7.58(d,J＝1.2Hz,1H),7.54(d,J＝9.2Hz,1H),7.45(dd,J＝8.0,1.2Hz,1H),4.97 (hept,J＝6.1Hz,1H),3.60(s,3H),3.57(s,2H),2.66(t,J＝6.8Hz,2H),2.53(t,J＝6.6Hz,2H), 2.17(s,3H),1.38(d,J＝6.0Hz,6H).
(2)标题化合物的制备
按实施例1中步骤(7)方法制备，得白色固体88mg，收率62.8％，熔点194-196℃
1H NMR(400MHz,DMSO-d6)δ8.52(d,J＝2.4Hz,1H),8.40(dd,J＝9.2,2.0Hz,1H),8.09(d,J ＝8.0Hz,1H),8.02(s,1H),7.79(d,J＝8.0Hz,1H),7.57(d,J＝9.2Hz,1H),4.98(hept,J＝6.0Hz, 1H),4.41(s,2H),3.30–3.28(m,2H),2.87(t,J＝7.6Hz,2H),2.67(s,3H),1.38(d,J＝6.0Hz, 6H).
实施例29
1-(3-氯-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苄基)哌啶-3-甲酸盐酸盐
(1)1-(3-氯-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苄基)哌啶-3-甲酸甲酯的制备
将3-氯-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苯甲醛(200mg,0.54mmol)溶于35ml 二氯甲烷中，向其中依次加入甲基哌啶-3-甲酸甲酯盐酸盐(146mg,0.82mmol)、冰醋酸(0.12ml, 2.18mmol)、N,N-二异丙基乙胺(0.13ml,0.82mmol)、5ml甲醇，室温反应3h后加入氰基硼氢化钠(34mg,0.47mmol)，氩气保护下反应5h。加入饱和碳酸氢钠溶液，二氯甲烷萃取3次(3×30mL)，蒸馏水洗1次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为二氯甲烷：甲醇＝20:1，得白色固体131mg，收率54.0％。
1H NMR(400MHz,DMSO-d6)δ8.51(d,J＝2.4Hz,1H),8.40(dd,J＝9.2,2.4Hz,1H),7.97(d,J ＝8.0Hz,1H),7.61(d,J＝1.2Hz,1H),7.56(d,J＝9.2Hz,1H),7.48(dd,J＝8.0,1.6Hz,1H),4.98 (hept,J＝6.0Hz,1H),3.63–3.53(m,5H),2.77-2.74(m,1H),2.67–2.56(m,2H),2.34–2.15(m, 2H),1.80–1.66(m,2H),1.53–1.48(m,2H),1.38(d,J＝6.0Hz,6H).
(2)标题化合物的制备
按实施例1中步骤(7)方法制备，得白色固体75mg，收率55.1％，熔点212-215℃
1H NMR(400MHz,DMSO-d6)δ12.92(s,1H),11.00(s,1H),8.52(d,J＝2.4Hz,1H),8.40(dd,J ＝9.0,2.2Hz,1H),8.09(d,J＝7.6Hz,1H),8.00(s,1H),7.77(m,1H),7.57(d,J＝9.2Hz,1H), 4.98(hept,J＝5.9Hz,1H),4.40(s,2H),3.47(s 2H),2.92(s,3H),2.01(s,1H),1.84(s,2H),1.47(s, 1H),1.38(d,J＝6.0Hz,6H).
实施例30
4-((3-氯-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苄基)氨基)环己烷-1-羧酸盐酸盐
(1)4-((3-氯-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苄基)氨基)环己烷-1-羧酸甲酯的制备
将3-氯-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苯甲醛(200mg,0.54mmol)溶于35ml 二氯甲烷中，向其中依次加入4-氨基环己烷-1-羧酸甲酯盐酸盐(169mg,0.82mmol)、冰醋酸 (0.12ml,2.18mmol)、N,N-二异丙基乙胺(0.13ml,0.82mmol)、5ml甲醇，室温反应3h后加入氰基硼氢化钠(34mg,0.47mmol)，氩气保护下反应5h。加入饱和碳酸氢钠溶液，二氯甲烷萃取3 次(3×30mL)，蒸馏水洗1次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为二氯甲烷：甲醇＝20:1，得白色固体191mg，收率69.0％。
1H NMR(400MHz,DMSO-d6)δ8.50(d,J＝2.0Hz,1H),8.39(dd,J＝9.0,2.2Hz,1H),7.94(d,J ＝8.0Hz,1H),7.65(d,J＝1.2Hz,1H),7.55(d,J＝9.2Hz,1H),7.50(d,J＝8.0,1.2Hz,1H),4.98 (hept,J＝6.0Hz,1H),3.76(s,2H),3.58(m,3H),2.32(d,J＝6.8Hz,2H),2.23(tt,J＝12.2,3.4Hz, 1H),1.91–1.82(m,4H),1.38(d,J＝6.0Hz,6H),1.36–1.26(m,2H),0.96-0.86(m,2H).
(2)标题化合物的制备
按实施例1中步骤(7)方法制备，得白色固体142mg，收率71.3％，熔点149-151℃
1H NMR(400MHz,DMSO-d6)δ12.06(s,1H),9.28(s,2H),8.51(d,J＝2.0Hz,1H),8.40(dd,J＝9.0,2.2Hz,1H),8.07(d,J＝8.0Hz,1H),7.99(d,J＝1.6Hz,1H),7.76(dd,J＝8.0,1.6Hz,1H), 7.57(d,J＝9.2Hz,1H),4.98(hept,J＝6.1Hz,1H),4.24(s,2H),2.79(d,J＝6.4Hz,2H),2.15(tt, J＝12.2,3.3Hz,1H),1.94–1.85(m,4H),1.38(d,J＝6.0Hz,6H),1.35–1.24(m,3H),1.04–0.94 (m,2H).
实施例31
(3-氯-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苄基)丝氨酸盐酸盐
(1)(3-氯-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苄基)丝氨酸甲酯的制备
将3-氯-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苯甲醛(200mg,0.54mmol)溶于35ml 二氯甲烷中，向其中依次加入甲基丝氨酸盐酸盐(127mg,0.82mmol)、冰醋酸(0.12ml,2.18mmol)、 N,N-二异丙基乙胺(0.13ml,0.82mmol)、5ml甲醇，室温反应3h后加入氰基硼氢化钠(34mg, 0.47mmol)，氩气保护下反应5h。加入饱和碳酸氢钠溶液，二氯甲烷萃取3次(3×30mL)，蒸馏水洗1次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为二氯甲烷：甲醇＝20:1，得白色固体164mg，收率64.2％。
1H NMR(400MHz,DMSO-d6)δ8.49(d,J＝2.4Hz,1H),8.39(dd,J＝9.0,2.2Hz,1H),7.95(d,J ＝8.0Hz,1H),7.66(d,J＝0.8Hz,1H),7.55(d,J＝9.2Hz,1H),7.50(dd,J＝8.0,1.2Hz,1H),4.97 (hept,J＝6.1Hz,1H),4.88(t,J＝5.8Hz,1H),3.92–3.71(m,2H),3.63-3.60(m,5H),3.30(t,J＝ 5.2Hz,1H),1.38(d,J＝6.0Hz,6H).
(2)标题化合物的制备
按实施例1中步骤(7)方法制备，得白色固体106mg，收率61.9％，熔点219-222℃
1H NMR(400MHz,DMSO-d6)δ8.50(s,1H),8.39(d,J＝9.6Hz,1H),8.01(d,J＝8.8Hz,1H), 7.83(s,1H),7.64-7.54(m,2H),4.98(m,1H),4.17–4.07(m,2H),3.84-3.75(m,2H),3.58(s,1H), 1.39-1.38(m,6H).
实施例32
(3-氯-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苄基)高丝氨酸盐酸盐
(1)3-((3-氯-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苄基)氨基)-2-氧代四氢呋喃的制备
将3-氯-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苯甲醛(200mg,0.54mmol)溶于35ml 二氯甲烷中，向其中依次加入DL-高丝氨酸内酯盐酸盐(112mg,0.82mmol)、冰醋酸(0.12ml, 2.18mmol)、N,N-二异丙基乙胺(0.13ml,0.82mmol)、5ml甲醇，室温反应3h后加入氰基硼氢化钠(34mg,0.47mmol)，氩气保护下反应5h。加入饱和碳酸氢钠溶液，二氯甲烷萃取3次(3×30mL)，蒸馏水洗1次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为二氯甲烷：甲醇＝20:1，得白色固体154mg，收率62.5％。
1H NMR(400MHz,DMSO-d6)δ8.49(d,J＝2.4Hz,1H),8.39(dd,J＝9.0,2.2Hz,1H),7.96(d,J ＝7.6Hz,1H),7.69(d,J＝1.2Hz,1H),7.56–7.52(m,2H),4.97(hept,J＝5.9Hz,1H),4.32(td,J ＝8.5,2.7Hz,1H),4.18–4.12(m,1H),4.00-3.89(m,2H),3.58-3.53(m,1H),3.03–3.01(m,1H), 2.44-2.37(m,1H),2.03–1.95(m,1H),1.38(d,J＝6.0Hz,6H).
(2)标题化合物的制备
按实施例1中步骤(7)方法制备，得白色固体102mg，收率59.0％，熔点189-192℃
1H NMR(400MHz,DMSO-d6)δ8.51(s,1H),8.40(d,J＝8.8Hz,1H),7.97(d,J＝8.0Hz,1H), 7.71(s,1H),7.55(t,J＝7.2Hz,2H),4.98(hept,J＝6.0Hz,1H),3.99-3.77(m,2H),3.60-3.49(m, 2H),3.59–3.50(m,2H),3.24(t,J＝6.4Hz,1H),1.83-1.68(m,2H),1.38(d,J＝6.0Hz,6H).
实施例33
(3-氯-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苄基)谷氨酸盐酸盐
(1)(3-氯-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苄基)谷氨酸二甲酯的制备
将3-氯-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苯甲醛(200mg,0.54mmol)溶于35ml 二氯甲烷中，向其中依次加入谷氨酸二甲酯盐酸盐(173mg,0.82mmol)、冰醋酸(0.12ml, 2.18mmol)、N,N-二异丙基乙胺(0.13ml,0.82mmol)、5ml甲醇，室温反应3h后加入氰基硼氢化钠(34mg,0.47mmol)，氩气保护下反应5h。加入饱和碳酸氢钠溶液，二氯甲烷萃取3次(3×30mL)，蒸馏水洗1次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为二氯甲烷：甲醇＝20:1，得白色固体193mg，收率67.3％。
1H NMR(400MHz,DMSO-d6)δ8.50(d,J＝2.0Hz,1H),8.39(dd,J＝9.0,2.2Hz,1H),7.94(d,J ＝8.0Hz,1H),7.63(d,J＝1.6Hz,1H),7.55(d,J＝9.2Hz,1H),7.47(dd,J＝8.0,1.6Hz,1H),4.98 (hept,J＝6.0Hz,1H),3.88-3.84(m,1H),3.66-3.61(m,4H),3.57(s,3H),3.25–3.19(m,1H), 2.81-2.75(m,1H),2.47-2.42(m,2H),1.92–1.74(m,2H),1.38(d,J＝6.0Hz,6H).
(2)标题化合物的制备
按实施例1中步骤(7)方法制备，得白色固体113mg，收率57.6％，熔点147-149℃
1H NMR(400MHz,DMSO-d6)δ8.50(d,J＝2.0Hz,1H),8.40(dd,J＝9.0,2.2Hz,1H),7.97(d,J ＝8.0Hz,1H),7.70(s,1H),7.57–7.53(m,2H),4.98(hept,J＝6.0Hz,1H),3.99-3.78(m,2H), 3.22(t,J＝6.6Hz,1H),2.43-2.33(m,2H),1.92-1.79(m,2H),1.38(d,J＝6.0Hz,6H).
实施例34
2-((3-氯-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苄基)氨基)丙烷-1,3-二醇盐酸盐
(1)标题化合物的制备
将3-氯-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苯甲醛(200mg,0.54mmol)溶于35ml 二氯甲烷中，向其中依次加入氨基丙二醇(74mg,0.82mmol)、冰醋酸(0.12ml,2.18mmol)、N,N- 二异丙基乙胺(0.13ml,0.82mmol)、5ml甲醇，室温反应3h后加入氰基硼氢化钠(34mg, 0.47mmol)，氩气保护下反应5h。加入饱和碳酸氢钠溶液，二氯甲烷萃取3次(3×30mL)，蒸馏水洗1次，合并有机相，无水硫酸钠干燥。减压抽滤，滤液用1.25mol/LHCl的乙醚溶液调节PH到2-3。浓缩，柱层析分离，洗脱剂为二氯甲烷：甲醇＝8:1，得白色固体166mg，收率 63.5％，熔点134-136℃
1H NMR(400MHz,DMSO-d6)δ8.49(d,J＝2.4Hz,1H),8.38(dd,J＝9.0,2.2Hz,1H),7.94(d,J ＝8.0Hz,1H),7.70(s,1H),7.53(t,J＝8.0Hz,2H),4.97(hept,J＝6.0Hz,1H),4.47(s,2H),3.88(s, 2H),3.42(s,2H),3.38(s,2H),2.54(q,J＝5.6Hz,1H),1.38(d,J＝6.0Hz,6H).
实施例35
2-((3-氯-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苄基)氨基)乙烷-1-醇盐酸盐
(1)标题化合物的制备
将3-氯-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苯甲醛(200mg,0.54mmol)溶于35ml 二氯甲烷中，向其中依次加入乙醇胺(50mg,0.82mmol)、冰醋酸(0.12ml,2.18mmol)、N,N-二异丙基乙胺(0.13ml,0.82mmol)、5ml甲醇，室温反应3h后加入氰基硼氢化钠(34mg,0.47mmol)，氩气保护下反应5h。加入饱和碳酸氢钠溶液，二氯甲烷萃取3次(3×30mL)，蒸馏水洗1次，合并有机相，无水硫酸钠干燥。减压抽滤，滤液用1.25mol/LHCl的乙醚溶液调节PH到2-3。浓缩，柱层析分离，洗脱剂为二氯甲烷：甲醇＝8:1，得白色固体172mg，收率70.2％，熔点 132-135℃
1H NMR(400MHz,DMSO-d6)δ8.52(d,J＝2.4Hz,1H),8.40(dd,J＝9.0,2.2Hz,1H),8.01(d,J ＝8.0Hz,1H),7.79(s,1H),7.62-7.59(m,1H),7.56(d,J＝9.2Hz,1H),5.76(s,1H),4.98(hept,J＝ 6.0Hz,1H),4.86(s,1H),4.02(s,2H),3.57(s,2H),2.77(t,J＝5.6Hz,2H),1.38(d,J＝6.0Hz, 6H).
实施例36
1-((3-氯-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苄基)氨基)丙烷-2-醇盐酸盐
(1)标题化合物的制备
将3-氯-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苯甲醛(200mg,0.54mmol)溶于35ml 二氯甲烷中，向其中依次加入1-氨基-2-丙醇(61mg,0.82mmol)、冰醋酸(0.12ml,2.18mmol)、 N,N-二异丙基乙胺(0.13ml,0.82mmol)、5ml甲醇，室温反应3h后加入氰基硼氢化钠(34mg, 0.47mmol)，氩气保护下反应5h。加入饱和碳酸氢钠溶液，二氯甲烷萃取3次(3×30mL)，蒸馏水洗1次，合并有机相，无水硫酸钠干燥。减压抽滤，滤液用1.25mol/L HCl的乙醚溶液调节PH到2-3。浓缩，柱层析分离，洗脱剂为二氯甲烷：甲醇＝8:1，得白色固体147mg，收率 58.4％，熔点172-175℃
1H NMR(400MHz,DMSO-d6)δ8.51(d,J＝2.0Hz,1H),8.40(dd,J＝9.0,2.2Hz,1H),8.01(d,J ＝8.0Hz,1H),7.82(s,1H),7.63(d,J＝7.2Hz,1H),7.56(d,J＝9.2Hz,1H),4.98(hept,J＝6.1Hz, 2H),4.05-4.00(m,2H),3.47-3.44(m,2H),2.90(s,1H),1.38(d,J＝6.0Hz,6H),1.10(d,J＝6.4Hz, 3H).
实施例37
(4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苄基)甘氨酸盐酸盐
(1)2-(4-氰基苯基)-1,3-二氧戊环的制备
将4-氰基苯甲醛(3.0g,22.88mmol)，乙二醇(4.66ml,91.51mmol)，对甲苯磺酸(313mg,1.83mmol) 溶于120ml甲苯中，分水器持续分水，加热回流18h。将反应冷却至室温，蒸除溶剂，残留物以150ml乙酸乙酯溶解，用饱和碳酸氢钠溶液洗2次，蒸馏水洗2次，饱和氯化钠溶液洗1 次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为石油醚：二氯甲烷：丙酮＝24:3:1，得白色固体2.90g，收率72.5％。
1H NMR(400MHz,DMSO-d6)δ7.87(d,J＝8.4Hz,2H),7.62(d,J＝8.4Hz,2H),5.83(s,1H), 4.08–3.94(m,4H).
(2)2-(4-(N'-羟基甲脒基)苯基)-1,3-二氧戊环的制备
将2-(4-氰基苯基)-1,3-二氧戊环(2.80g,15.98mmol)溶于120ml无水甲醇中，搅拌状态下依次加入盐酸羟胺(3.89g,55.94mmol)，碳酸氢钠(5.37g,63.93mmol)，加热回流5h。将反应冷却至室温，减压抽滤，滤饼用无水甲醇洗2次，合并滤液。加入蒸馏水，乙酸乙酯萃取3次(3×50mL)，饱和氯化钠溶液洗2次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为二氯甲烷：甲醇＝20:1，得白色固体2.70g，收率81.2％。
1H NMR(400MHz,DMSO-d6)δ9.66(s,1H),7.69–7.67(m,2H),7.43–7.41(m,2H),5.82(s, 2H),5.74(s,1H),4.07–3.93(m,4H).
(3)3-(4-(1,3-二氧戊环-2-基)苯基)-5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑的制备
将4-异丙氧基-3-氰基苯甲酸(2.42g,11.79mmol)，1-羟基苯并三唑(1.45g,10.71mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(2.05g,10.71mmol)，碳酸钾(2.22g,16.07mmol)溶于120ml N,N-二甲基甲酰胺中，室温搅拌30分钟后加入2-(4-(N'-羟基甲脒基)苯基)-1,3-二氧戊环(2.60g, 10.71mmol)，氩气保护下加热至110℃反应4h。将反应冷却至室温，减压抽滤，滤饼用乙酸乙酯洗2次，合并滤液，加入蒸馏水，乙酸乙酯萃取3次(3×50mL)，蒸馏水洗2次，饱和氯化钠溶液洗1次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为石油醚：乙酸乙酯＝3:1，得白色固体2.41g，收率59.7％。
1H NMR(400MHz,DMSO-d6)δ8.46(s,1H),8.37(d,J＝8.8Hz,1H),8.09(d,J＝8.0Hz,2H), 7.64(d,J＝8.0Hz,2H),7.52(d,J＝9.2Hz,1H),5.82(s,1H),4.96(hept,J＝6.0Hz,1H),4.10– 3.95(m,4H),1.38(d,J＝6.0Hz,6H).
(4)4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苯甲醛的制备
将3-(4-(1,3-二氧戊环-2-基)苯基)-5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑(2.30g,6.09mmol)溶于30ml丙酮中，搅拌状态下加入2N盐酸溶液(24.38ml,48.75mmol)，45℃下加热3h。将反应冷却至室温，减压抽滤，干燥得白色固体1.68g，收率82.6％。
1H NMR(400MHz,DMSO-d6)δ10.11(s,1H),8.48(d,J＝2.4Hz,1H),8.39(dd,J＝9.0,2.2Hz, 1H),8.28(d,J＝8.4Hz,2H),8.10(d,J＝8.0Hz,2H),7.54(d,J＝9.2Hz,1H),4.97(hept,J＝6.0 Hz,1H),1.38(d,J＝6.0Hz,6H).
(5)(4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苄基)甘氨酸甲酯的制备
将4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苯甲醛(200mg,0.60mmol)溶于35ml二氯甲烷中，向其中依次加入甘氨酸甲酯盐酸盐(111mg,0.90mmol)、冰醋酸(0.14ml,2.40mmol)、N,N- 二异丙基乙胺(0.15ml,0.90mmol)、5ml甲醇，室温反应3h后加入氰基硼氢化钠(38mg, 0.60mmol)，氩气保护下反应5h。加入饱和碳酸氢钠溶液，二氯甲烷萃取3次(3×30mL)，蒸馏水洗1次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为二氯甲烷：甲醇＝20:1，得白色固体192mg，收率78.7％。
1H NMR(400MHz,DMSO-d6)δ8.49(m,1H),8.39(dt,J＝9.2,1.7Hz,1H),8.03(d,J＝8.0 Hz,2H),7.56-7.53(m,3H),4.97(hept,J＝5.9Hz,1H),3.81(s,2H),3.63(s,3H),3.36(s,2H),2.73 (s,1H),1.38(d,J＝6.0Hz,6H).
(6)标题化合物的制备
按实施例1中步骤(7)方法制备，得白色固体143mg，收率70.6％，熔点212-215℃
1H NMR(400MHz,DMSO-d6)δ8.49(d,J＝2.0Hz,1H),8.39(dd,J＝8.8,2.4Hz,1H),8.11(d,J ＝8.4Hz,2H),7.70(d,J＝8.4Hz,2H),7.56(d,J＝9.2Hz,1H),4.98(hept,J＝5.9Hz,1H),4.18(s, 2H),3.66(s,2H),1.38(d,J＝6.0Hz,6H).
实施例38
N-甲基-N-(4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苄基)甘氨酸盐酸盐
(1)N-甲基-N-(4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苄基)甘氨酸乙酯的制备
将4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苯甲醛(200mg,0.60mmol)溶于35ml二氯甲烷中，向其中依次加入肌氨酸乙酯盐酸盐(126mg,0.90mmol)、冰醋酸(0.14ml,2.40mmol)、N,N- 二异丙基乙胺(0.15ml,0.90mmol)、5ml甲醇，室温反应3h后加入氰基硼氢化钠(38mg, 0.60mmol)，氩气保护下反应5h。加入饱和碳酸氢钠溶液，二氯甲烷萃取3次(3×30mL)，蒸馏水洗1次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为二氯甲烷：甲醇＝20:1，得白色固体179mg，收率68.8％。
1H NMR(400MHz,DMSO-d6)δ8.47(d,J＝2.0Hz,1H),8.38(dd,J＝9.0,1.8Hz,1H),8.03(d,J ＝8.0Hz,2H),7.53(t,J＝7.8Hz,3H),4.97(hept,J＝5.8Hz,1H),4.10(q,J＝7.1Hz,2H),3.73(s, 2H),3.33(s,2H),2.28(s,3H),1.38(d,J＝6.0Hz,6H),1.20(t,J＝7.0Hz,3H).
(2)标题化合物的制备
按实施例1中步骤(7)方法制备，得白色固体138mg，收率75.5％，熔点199-210℃
1H NMR(400MHz,DMSO-d6)δ8.50(d,J＝2.4Hz,1H),8.40(dd,J＝9.0,2.2Hz,1H),8.16(d,J ＝8.4Hz,2H),7.79(d,J＝8.4Hz,2H),7.56(d,J＝9.2Hz,1H),4.98(hept,J＝6.1Hz,1H),4.45(s, 2H),4.07(s,2H),2.79(s,3H),1.38(d,J＝6.0Hz,6H).
实施例39
1-(4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苄基)吡咯烷-3-甲酸盐酸盐
(1)1-(4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苄基)吡咯烷-3-甲酸甲酯的制备
将4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苯甲醛(200mg,0.60mmol)溶于35ml二氯甲烷中，向其中依次加入吡咯烷-3-甲酸甲酯盐酸盐(149mg,0.90mmol)、冰醋酸(0.14ml,2.40mmol)、 N,N-二异丙基乙胺(0.15ml,0.90mmol)、5ml甲醇，室温反应3h后加入氰基硼氢化钠(38mg, 0.60mmol)，氩气保护下反应5h。加入饱和碳酸氢钠溶液，二氯甲烷萃取3次(3×30mL)，蒸馏水洗1次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为二氯甲烷：甲醇＝20:1，得白色固体179mg，收率68.8％。
1H NMR(400MHz,DMSO-d6)δ8.48(d,J＝2.0Hz,1H),8.39(dd,J＝8.8,2.4Hz,1H),8.04–8.02 (m,2H),7.56-7.51(m,3H),4.97(hept,J＝6.0Hz,1H),3.70–3.63(m,2H),3.61(s,3H),3.10– 3.02(m,1H),2.75(t,J＝8.6Hz,1H),2.68–2.64(m,1H),2.56–2.53(m,2H),2.07–1.94(m,2H), 1.38(d,J＝6.0Hz,6H).
(2)标题化合物的制备
按实施例1中步骤(7)方法制备，得白色固体138mg，收率75.5％，熔点187-189℃
1H NMR(400MHz,DMSO-d6)δ12.04(s,0H),8.50(d,J＝2.4Hz,1H),8.40(dd,J＝9.0,2.2Hz, 1H),8.13(d,J＝8.4Hz,2H),7.78(d,J＝8.0Hz,2H),7.56(d,J＝9.2Hz,1H),4.98(hept,J＝6.0 Hz,1H),4.34(s,2H),3.26–3.16(m,5H),2.29–2.10(m,2H),1.38(d,J＝6.0Hz,6H).
实施例40
(4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苄基)天冬氨酸盐酸盐
(1)(4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苄基)天冬氨酸二甲酯的制备
将4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苯甲醛(200mg,0.60mmol)溶于35ml二氯甲烷中，向其中依次加入天冬氨酸二甲酯盐酸盐(178mg,0.90mmol)、冰醋酸(0.14ml,2.40mmol)、N,N-二异丙基乙胺(0.15ml,0.90mmol)、5ml甲醇，室温反应3h后加入氰基硼氢化钠(38mg, 0.60mmol)，氩气保护下反应5h。加入饱和碳酸氢钠溶液，二氯甲烷萃取3次(3×30mL)，蒸馏水洗1次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为二氯甲烷：甲醇＝20:1，得白色固体205mg，收率71.3％。
1H NMR(400MHz,DMSO-d6)δ8.49(d,J＝2.0Hz,1H),8.39(dd,J＝9.0,2.2Hz,1H),
8.03-8.01(m,2H),7.56-7.50(m,3H),4.97(hept,J＝6.1Hz,1H),3.91–3.71(m,2H),3.64(s,3H), 3.60(s,3H),3.57(m,1H),2.87(s,1H),2.76–2.61(m,2H),1.38(d,J＝6.0Hz,6H).
(2)标题化合物的制备
按实施例1中步骤(7)方法制备，得白色固体140mg，收率67.5％，熔点216-219℃
1H NMR(400MHz,DMSO-d6)δ10.51(s,2H),8.48(d,J＝2.4Hz,1H),8.38(dd,J＝9.0,2.2Hz, 1H),8.07(d,J＝8.4Hz,2H),7.64(d,J＝8.0Hz,2H),7.54(d,J＝9.2Hz,1H),4.97(hept,J＝6.0 Hz,1H),4.15–4.01(m,2H),3.69(dd,J＝7.6,5.2Hz,1H),2.77–2.62(m,2H),1.38(d,J＝6.0Hz, 6H).
实施例41
1-(4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苄基)哌啶-4-乙酸盐酸盐
(1)1-(4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苄基)哌啶-4-乙酸乙酯的制备
将4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苯甲醛(200mg,0.60mmol)溶于35ml二氯甲烷中，向其中依次加入哌啶乙酸甲酯盐酸盐(141mg,0.90mmol)、冰醋酸(0.14ml,2.40mmol)、 N,N-二异丙基乙胺(0.15ml,0.90mmol)、5ml甲醇，室温反应3h后加入氰基硼氢化钠(38mg, 0.60mmol)，氩气保护下反应5h。加入饱和碳酸氢钠溶液，二氯甲烷萃取3次(3×30mL)，蒸馏水洗1次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为二氯甲烷：甲醇＝20:1，得白色固体213mg，收率74.8％。
1H NMR(400MHz,DMSO-d6)δ8.49(d,J＝2.4Hz,1H),8.39(dd,J＝9.0,2.2Hz,1H),8.04-8.02(m,2H),7.55(d,J＝9.2Hz,1H),7.50(d,J＝8.0Hz,1H),4.97(hept,J＝6.1Hz,1H), 3.58(s,3H),3.52(s,2H),2.78(d,J＝11.6Hz,2H),2.24(d,J＝6.8Hz,2H),1.99–1.93(m,2H), 1.63-1.60(m,3H),1.38(d,J＝6.0Hz,6H),1.27–1.17(m,2H).
(2)标题化合物的制备
按实施例1中步骤(7)方法制备，得白色固体154mg，收率69.2％，熔点252-256℃
1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.78(s,1H),8.50(d,J＝2.3Hz,1H),8.40(dd,J ＝9.0,2.3Hz,1H),8.14(d,J＝8.3Hz,2H),7.83(d,J＝8.2Hz,2H),7.57(d,J＝9.3Hz,1H),4.98 (p,J＝6.1Hz,1H),4.35(d,J＝4.1Hz,2H),3.31(s,2H),3.04–2.89(m,2H),2.18(d,J＝6.6Hz, 2H),1.86(t,J＝15.1Hz,3H),1.58(q,J＝13.0,12.2Hz,2H),1.38(d,J＝6.0Hz,6H).
实施例42
(4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)-3-氟苄基)甘氨酸盐酸盐
(1)3-氟-4-氰基苯甲醛的制备
将2-氟-4-溴苯甲腈(8.00g,40.00mmol)溶于120mL无水四氢呋喃中，冰浴0℃条件下滴加2N 异丙基氯化镁的四氢呋喃溶液(26.00ml,52.00mmol)，反应混合液在0℃氩气保护下反应2小时，此后在0℃下加入N-甲酰基哌啶(5.77ml,52.00mmol)继续在0℃下反应2小时。饱和氯化铵溶液淬灭反应，用乙酸乙酯萃取3次(3×50mL)，合并有机层，蒸馏水洗2次，饱和氯化钠溶液洗1次，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为石油醚：乙酸乙酯＝3:1，得白色固体3.17g，收率53.1％。
1H NMR(400MHz,DMSO-d6)δ10.07(s,1H),8.20(dd,J＝8.0,6.4Hz,1H),7.99(dd,J＝9.2,1.2 Hz,1H),7.94(dd,J＝7.8,1.2Hz,1H).
(2)2-(3-氟-4-氰基苯基)-1,3-二氧戊环的制备
将3-氟-4-氰基苯甲醛(3.10g,20.79mmol)，乙二醇(4.23ml,83.15mmol)，对甲苯磺酸(284.75mg, 1.66mmol)溶于120ml甲苯中，分水器持续分水，加热回流18h。将反应冷却至室温，蒸除溶剂，残留物以150ml乙酸乙酯溶解，用饱和碳酸氢钠溶液洗2次，蒸馏水洗2次，饱和氯化钠溶液洗1次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为石油醚：二氯甲烷：丙酮＝24:3:1，得白色固体3.15g，收率78.4％。
1H NMR(400MHz,DMSO-d6)δ7.96(dd,J＝8.0,6.4Hz,1H),7.54(dd,J＝10.0,1.2Hz,1H), 7.48–7.46(m,1H),5.86(s,1H),4.08–3.94(m,4H).
(3)2-(3-氟-4-(N'-羟基甲脒基)苯基)-1,3-二氧戊环的制备
将2-(3-氟-4-氰基苯基)-1,3-二氧戊环(3.10g,16.05mmol)溶于120ml无水甲醇中，搅拌状态下依次加入盐酸羟胺(3.90g,56.16mmol)，碳酸氢钠(5.39g,64.19mmol)，加热回流5h。将反应冷却至室温，减压抽滤，滤饼用无水甲醇洗2次，合并滤液。加入蒸馏水，乙酸乙酯萃取3次(3 ×50mL)，饱和氯化钠溶液洗2次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为二氯甲烷：甲醇＝20:1，得白色固体2.25g，收率76.9％。
1H NMR(400MHz,DMSO-d6)δ9.66(s,1H),7.54–7.50(m,1H),7.28–7.24(m,2H),5.83(s, 2H),5.77(s,1H),4.08–3.92(m,4H).
(4)3-(2-氟-4-(1,3-二氧戊环-2-基)苯基)-5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑的制备
将4-异丙氧基-3-氰基苯甲酸(2.24g,10.93mmol)，1-羟基苯并三唑(1.31g,9.94mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(1.86g,9.94mmol)，碳酸钾(2.02g,14.59mmol)溶于120ml N,N- 二甲基甲酰胺中，室温搅拌30分钟后加入2-(3-氟-4-(N'-羟基甲脒基)苯基)-1,3-二氧戊环(2.20g, 9.94mmol)，氩气保护下加热至110℃反应4h。将反应冷却至室温，减压抽滤，滤饼用乙酸乙酯洗2次，合并滤液，加入蒸馏水，乙酸乙酯萃取3次(3×50mL)，蒸馏水洗2次，饱和氯化钠溶液洗1次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为石油醚：乙酸乙酯＝3:1，得白色固体3.14g，收率81.7％。
1H NMR(400MHz,DMSO-d6)δ8.51(d,J＝2.4Hz,1H),8.41(dd,J＝9.2,2.4Hz,1H),8.18-8.14 (m,1H),7.56(d,J＝9.2Hz,1H),7.53–7.49(m,2H),5.87(s,1H),4.98(hept,J＝5.9Hz,1H),4.12 –3.96(m,4H),1.38(d,J＝6.0Hz,6H).
(5)3-氟-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苯甲醛的制备
将3-(2-氟-4-(1,3-二氧戊环-2-基)苯基)-5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑(3.10g, 7.84mmol)溶于30ml丙酮中，搅拌状态下加入2N盐酸溶液(31.36ml,62.72mmol)，45℃下加热3h。将反应冷却至室温，减压抽滤，干燥得白色固体1.74g，收率63.2％。
1H NMR(400MHz,DMSO-d6)δ10.09(d,J＝1.2Hz,1H),8.51(d,J＝2.4Hz,1H),8.40(dd,J＝ 8.8,2.4Hz,1H),8.36-8.32(m,1H),7.99–7.94(m,2H),7.56(d,J＝9.2Hz,1H),4.98(hept,J＝ 6.1Hz,1H),1.38(d,J＝6.0Hz,6H).
(6)(3-氟-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苄基)甘氨酸甲酯的制备
将3-氟-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苯甲醛(200mg,0.57mmol)溶于35ml 二氯甲烷中，向其中依次加入甘氨酸甲酯盐酸盐(107mg,0.85mmol)、冰醋酸(0.13ml,2.28mmol)、 N,N-二异丙基乙胺(0.14ml,0.85mmol)、5ml甲醇，室温反应3h后加入氰基硼氢化钠(36mg, 0.57mmol)，氩气保护下反应5h。加入饱和碳酸氢钠溶液，二氯甲烷萃取3次(3×30mL)，蒸馏水洗1次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为二氯甲烷：甲醇＝20:1，得白色固体239mg，收率92.1％。
1H NMR(400MHz,DMSO-d6)δ8.50(d,J＝2.2Hz,1H),8.39(dd,J＝8.8,2.4Hz,1H),8.05(t,J ＝7.6Hz,1H),7.55(d,J＝9.2Hz,1H),7.43–7.38(m,2H),4.98(hept,J＝6.1Hz,1H),3.84(s, 2H),3.63(s,3H),3.37(s,2H),1.38(d,J＝6.0Hz,6H).
(7)标题化合物的制备
按实施例1中步骤(7)方法制备，得白色固体182mg，收率72.5％，熔点212-214℃
1H NMR(400MHz,DMSO-d6)δ8.51(d,J＝2.4Hz,1H),8.39(dd,J＝8.8,2.0Hz,1H),8.15(t,J ＝7.8Hz,1H),7.62(d,J＝11.2Hz,1H),7.55(t,J＝9.4Hz,2H),4.98(hept,J＝6.1Hz,1H),4.18(s, 2H),3.67(s,2H),1.38(d,J＝6.0Hz,6H).
实施例43
N-甲基-N-(3-氟-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苄基)甘氨酸盐酸盐
(1)N-甲基-N-(3-氟-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苄基)甘氨酸乙酯的制备
将3-氟-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苯甲醛(200mg,0.57mmol)溶于35ml 二氯甲烷中，向其中依次加入肌氨酸乙酯盐酸盐(131mg,0.85mmol)、冰醋酸(0.13ml,2.28mmol)、 N,N-二异丙基乙胺(0.14ml,0.85mmol)、5ml甲醇，室温反应3h后加入氰基硼氢化钠(36mg, 0.57mmol)，氩气保护下反应5h。加入饱和碳酸氢钠溶液，二氯甲烷萃取3次(3×30mL)，蒸馏水洗1次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为二氯甲烷：甲醇＝20:1，得白色固体152mg，收率58.9％。
1H NMR(400MHz,DMSO-d6)δ8.48(d,J＝2.4Hz,1H),8.38(dd,J＝8.8,2.4Hz,1H),8.06(t,J ＝7.8Hz,1H),7.54(d,J＝9.2Hz,1H),7.40–7.37(m,2H),4.97(hept,J＝6.1Hz,1H),4.11(q,J＝ 7.1Hz,2H),3.75(s,2H),3.36(s,2H),2.30(s,3H),1.38(d,J＝6.0Hz,6H),1.21(t,J＝7.0Hz, 3H).
(2)标题化合物的制备
按实施例1中步骤(7)方法制备，得白色固体95mg，收率61.4％，熔点208-211℃
1H NMR(400MHz,DMSO-d6)δ8.49(d,J＝2.0Hz,1H),8.39(dd,J＝9.0,2.2Hz,1H),8.08(t,J ＝7.8Hz,1H),7.55(d,J＝9.2Hz,1H),7.42(t,J＝9.4Hz,2H),4.97(hept,J＝5.9Hz,1H),3.84(s, 2H),3.36(s,2H),2.35(s,3H),1.38(d,J＝6.0Hz,6H).
实施例44
1-(3-氟-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苄基)吡咯烷-3-甲酸盐酸盐
(1)1-(3-氟-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苄基)吡咯烷-3-甲酸甲酯的制备
将3-氟-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苯甲醛(200mg,0.57mmol)溶于35ml 二氯甲烷中，向其中依次加入吡咯烷-3-甲酸甲酯盐酸盐(141mg,0.85mmol)、冰醋酸(0.13ml, 2.28mmol)、N,N-二异丙基乙胺(0.14ml,0.85mmol)、5ml甲醇，室温反应3h后加入氰基硼氢化钠(36mg,0.57mmol)，氩气保护下反应5h。加入饱和碳酸氢钠溶液，二氯甲烷萃取3次(3×30mL)，蒸馏水洗1次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为二氯甲烷：甲醇＝20:1，得白色固体171mg，收率66.7％。
1H NMR(400MHz,DMSO-d6)δ8.49(d,J＝2.0Hz,1H),8.39(dd,J＝9.0,2.2Hz,1H),8.06(t,J ＝7.6Hz,1H),7.55(d,J＝9.2Hz,1H),7.39(m,1H),7.37(m,1H),4.98(p,J＝6.1Hz,1H),3.73– 3.65(m,2H),3.61(s,3H),3.11–3.03(m,1H),2.77–2.66(m,2H),2.56(t,J＝7.0Hz,2H), 2.08-1.95(m,2H),1.38(d,J＝6.0Hz,6H).
(2)标题化合物的制备
按实施例1中步骤(7)方法制备，得白色固体137mg，收率74.3％，熔点222-224℃
1H NMR(400MHz,DMSO-d6)δ12.87(s,1H),11.35-11.09(m,1H),8.48(d,J＝2.0Hz,1H),8.37 (dd,J＝9.0,2.2Hz,1H),8.16(t,J＝7.8Hz,1H),7.76(d,J＝11.2Hz,1H),7.62(d,J＝8.0Hz,1H), 7.54(d,J＝9.2Hz,1H),4.95(hept,J＝6.1Hz,1H),4.46(s,2H),3.58(m,1H),3.40(m,1H),3.12 (s,3H),2.29–2.03(m,2H),1.34(d,J＝6.0Hz,6H).
实施例45
(3-氟-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苄基)天冬氨酸盐酸盐
(1)(3-氟-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苄基)天冬氨酸二甲酯的制备
将3-氟-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苯甲醛(200mg,0.57mmol)溶于35ml 二氯甲烷中，向其中依次加入天冬氨酸二甲酯盐酸盐(169mg,0.85mmol)、冰醋酸(0.13ml, 2.28mmol)、N,N-二异丙基乙胺(0.14ml,0.85mmol)、5ml甲醇，室温反应3h后加入氰基硼氢化钠(36mg,0.57mmol)，氩气保护下反应5h。加入饱和碳酸氢钠溶液，二氯甲烷萃取3次(3×30mL)，蒸馏水洗1次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为二氯甲烷：甲醇＝20:1，得白色固体208mg，收率73.7％。
1H NMR(400MHz,DMSO-d6)δ8.49(s,1H),8.39(d,J＝8.0Hz,1H),8.04(t,J＝7.6Hz,1H), 7.55(d,J＝8.8Hz,1H),7.37(t,J＝11.2Hz,2H),5.00-4.94(m,1H),3.92(dd,J＝15,2.2Hz,1H), 3.75(dd,J＝15.8,3.4Hz,1H),3.64-3.56(m,7H),2.99(s,1H),2.76-2.61(m,2H),1.38(d,J＝5.9 Hz,6H).
(2)标题化合物的制备
按实施例1中步骤(7)方法制备，得白色固体146mg，收率68.8％，熔点223-225℃
1H NMR(400MHz,DMSO-d6)δ10.48(s,1H),8.48(d,J＝2.4Hz,1H),8.37(dd,J＝9.0,2.2Hz, 1H),8.08(t,J＝7.8Hz,1H),7.56-7.52(m,2H),7.46(d,J＝8.0Hz,1H),4.97(hept,J＝5.9Hz,1H), 4.14–3.98(m,2H),3.68(t,J＝6.4Hz,1H),2.77-2.63(m,2H),1.38(d,J＝6.0Hz,6H).
实施例46
1-(3-氟-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苄基)哌啶-4-乙酸盐酸盐
(1)1-(3-氟-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苄基)哌啶-4-乙酸甲酯的制备
将3-氟-4-(5-(4-异丙氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苯甲醛(200mg,0.57mmol)溶于35ml 二氯甲烷中，向其中依次加入哌啶乙酸甲酯盐酸盐(134mg,0.85mmol)、冰醋酸(0.13ml, 2.28mmol)、N,N-二异丙基乙胺(0.14ml,0.85mmol)、5ml甲醇，室温反应3h后加入氰基硼氢化钠(36mg,0.57mmol)，氩气保护下反应5h。加入饱和碳酸氢钠溶液，二氯甲烷萃取3次(3×30mL)，蒸馏水洗1次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为二氯甲烷：甲醇＝20:1，得白色固体150mg，收率53.4％。
1H NMR(400MHz,DMSO-d6)δ8.49(s,1H),8.39(d,J＝8.8Hz,1H),8.05(t,J＝7.8Hz,1H), 7.55(d,J＝9.2Hz,1H),7.36(d,J＝9.6Hz,2H),5.00-4.94(m,1H),3.58(s,3H),3.54(s,2H),2.78 (d,J＝10.0Hz,2H),2.25(d,J＝6.4Hz,2H),1.98(t,J＝11.2Hz,2H),1.64-1.61(m,3H),1.38(d,J ＝6.0Hz,6H),1.28-1.19(m,2H).
(2)标题化合物的制备
按实施例1中步骤(7)方法制备，得白色固体103mg，收率65.9％，熔点199-201℃
1H NMR(400MHz,DMSO-d6)δ12.22(s,1H),11.06-10.91(m,1H),8.50(d,J＝2.4Hz,1H),8.40 (dd,J＝9.0,2.2Hz,1H),8.18(t,J＝7.6Hz,1H),7.85(d,J＝11.2Hz,1H),7.66(d,J＝8.0Hz,1H), 7.57(d,J＝9.2Hz,1H),4.98(hep,t J＝6.1Hz,1H),4.37-4.36(m,2H),3.36(s,2H),2.96(q,J＝ 11.3Hz,2H),2.19(d,J＝6.4Hz,2H),1.90–1.83(m,3H),1.64-1.55(m,2H),1.38(d,J＝6.0Hz, 6H).
实施例47
(4-(5-(4-环戊氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苄基)甘氨酸盐酸盐
(1)4-环戊氧基-3-氰基苯甲酸甲酯的制备
将4-羟基-3-氰基苯甲酸甲酯(3.00g,16.93mmol)和碳酸钾(7.02g,50.80mmol)溶于120mlN,N-二甲基甲酰胺中，之后向其中滴加异丙基溴(3.63ml,33.87mmol)，反应混合液加热至80℃反应 4h。将反应冷却至室温，加入饱和氯化铵溶液，乙酸乙酯萃取3次(3×50mL)，合并有机相，蒸馏水洗2次，饱和氯化钠溶液洗1次，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为石油醚：乙酸乙酯＝8:1，得白色固体3.82g，收率92.0％。
1H NMR(400MHz,DMSO-d6)δ8.20(d,J＝2.0Hz,1H),8.17(dd,J＝9.0,2.2Hz,1H),7.37(d,J ＝8.9Hz,1H),5.12–5.08(m,1H),3.84(s,3H),2.03-1.94(m,2H),1.79–1.58(m,6H).
(2)4-环戊氧基-3-氰基苯甲酸的制备
将4-环戊氧基-3-氰基苯甲酸甲酯(3.80g,15.49mmol)溶于30ml甲醇中，加入2N氢氧化钠溶液(11.62ml,23.24mmol)，加热至60℃，反应3h。将反应冷却至室温，滴加2N盐酸溶液至PH2-3，二氯甲烷萃取3次(3×30mL)，合并有机相，蒸馏水洗2次，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为二氯甲烷：甲醇＝20:1，得白色固体2.94g，收率82.1％。
1H NMR(400MHz,DMSO-d6)δ13.12(s,1H),8.17–8.14(m,2H),7.36-7.34(m,1H),5.10–5.07 (m,1H),2.02-1.94(m,2H),1.80–1.58(m,6H).
(3)3-(4-(1,3-二氧戊环-2-基)苯基)-5-(4-环戊氧基-3-氰基苯基)-1,2,4-噁二唑的制备
将4-环戊氧基-3-氰基苯甲酸(2.90g,12.54mmol)，1-羟基苯并三唑(1.54g,11.40mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(2.18g,11.40mmol)，碳酸钾(2.36g,17.10mmol)溶于120ml N,N-二甲基甲酰胺中，室温搅拌30分钟后加入4-(1,3-二氧戊环-2-基)-N'-羟基苯甲脒(2.37g, 11.40mmol)，氩气保护下加热至110℃反应4h。将反应冷却至室温，减压抽滤，滤饼用乙酸乙酯洗2次，合并滤液，加入蒸馏水，乙酸乙酯萃取3次(3×50mL)，蒸馏水洗2次，饱和氯化钠溶液洗1次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为石油醚：乙酸乙酯＝3:1，得白色固体3.35g，收率72.9％。
1H NMR(400MHz,DMSO-d6)δ8.50(d,J＝2.4Hz,1H),8.41(dd,J＝9.0,2.2Hz,1H),8.12– 8.10(m,2H),7.67-7.65(m,2H),7.52(d,J＝8.8Hz,1H),5.84(s,1H),5.18-5.14(m,1H),4.12– 3.96(m,4H),2.06–1.99(m,2H),1.82–1.63(m,6H).
(4)4-(5-(4-环戊氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苯甲醛的制备
将3-(4-(1,3-二氧戊环-2-基)苯基)-5-(4-环戊氧基-3-氰基苯基)-1,2,4-噁二唑(3.30g,8.18mmol)溶于30ml丙酮中，搅拌状态下加入2N盐酸溶液(12.27ml,24.54mmol)，45℃下加热3h。将反应冷却至室温，减压抽滤，干燥得白色固体1.89g，收率64.4％。
1H NMR(400MHz,DMSO-d6)δ10.12(s,1H),8.52(d,J＝2.4Hz,1H),8.42(dd,J＝8.8,2.4Hz, 1H),8.32–8.29(m,2H),8.14–8.10(m,2H),7.53(d,J＝9.2Hz,1H),5.19-5.15(m,1H), 2.07-1.98(m,2H),1.83–1.63(m,6H).
(5)(4-(5-(4-环戊氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苄基)甘氨酸甲酯的制备
将4-(5-(4-环戊氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苯甲醛(200mg,0.56mmol)溶于35ml二氯甲烷中，向其中依次加入甘氨酸甲酯盐酸盐(105mg,0.83mmol)、冰醋酸(0.13ml,2.22mmol)、N,N- 二异丙基乙胺(0.14ml,0.83mmol)、5ml甲醇，室温反应3h后加入氰基硼氢化钠(35mg, 0.56mmol)，氩气保护下反应5h。加入饱和碳酸氢钠溶液，二氯甲烷萃取3次(3×30mL)，蒸馏水洗1次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为二氯甲烷：甲醇＝20:1，得白色固体150mg，收率62.2％。
1H NMR(400MHz,DMSO-d6)δ8.47(d,J＝2.4Hz,1H),8.37(dd,J＝9.0,2.2Hz,1H),8.02– 8.00(m,2H),7.54-7.48(m,3H),5.16-5.12(m,1H),3.80(s,2H),3.63(s,3H),3.36(s,2H),2.66(s, 1H),2.05-1.96(m,2H),1.81–1.62(m,6H).
(6)标题化合物的制备
按实施例1中步骤(7)方法制备，得白色固体112mg，收率71.3％，熔点209-211℃
1H NMR(400MHz,DMSO-d6)δ10.37(s,1H),8.48(s,1H),8.39(dd,J＝9.2,2.0Hz,1H),8.11(d, J＝8.0Hz,2H),7.70(d,J＝8.0Hz,2H),7.52(d,J＝9.2Hz,1H),5.17-5.14(m,1H),4.19(s,2H), 3.69(s,2H),2.06-1.97(m,2H),1.80–1.64(m,6H).
实施例48
N-甲基-N-(4-(5-(4-环戊氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苄基)甘氨酸盐酸盐
(1)N-甲基-N-(4-(5-(4-环戊氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苄基)甘氨酸乙酯的制备
将4-(5-(4-环戊氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苯甲醛(200mg,0.56mmol)溶于35ml二氯甲烷中，向其中依次加入肌氨酸乙酯盐酸盐(128mg,0.83mmol)、冰醋酸(0.13ml,2.22mmol)、N,N- 二异丙基乙胺(0.14ml,0.83mmol)、5ml甲醇，室温反应3h后加入氰基硼氢化钠(35mg, 0.56mmol)，氩气保护下反应5h。加入饱和碳酸氢钠溶液，二氯甲烷萃取3次(3×30mL)，蒸馏水洗1次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为二氯甲烷：甲醇＝20:1，得白色固体186mg，收率72.6％。
1H NMR(400MHz,DMSO-d6)δ8.46(d,J＝2.4Hz,1H),8.38(dd,J＝9.0,2.2Hz,1H),8.04-8.02 (m,2H),7.53–7.48(m,3H),5.16-5.12(m,1H),4.10(q,J＝7.2Hz,2H),3.72(s,2H),3.32(s,2H), 2.28(s,3H),2.06-1.96(m,2H),1.82–1.62(m,6H),1.20(t,J＝7.2Hz,3H).
(2)标题化合物的制备
按实施例1中步骤(7)方法制备，得白色固体134mg，收率70.9％
1H NMR(400MHz,DMSO-d6)δ8.45(s,1H),8.37(d,J＝8.0Hz,1H),8.05(d,J＝6.8Hz,2H), 7.58(d,J＝6.4Hz,2H),7.50(d,J＝8.4Hz,1H),5.14(s,1H),3.91(s,2H),3.42(s,2H),2.41(s, 3H),2.00(m,2H),1.80–1.65(m,6H).
实施例49
1-(4-(5-(4-环戊氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苄基)吡咯烷-3-甲酸盐酸盐
(1)1-(4-(5-(4-环戊氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苄基)吡咯烷-3-甲酸甲酯的制备
将4-(5-(4-环戊氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苯甲醛(200mg,0.56mmol)溶于35ml二氯甲烷中，向其中依次加入吡咯烷-3-甲酸甲酯盐酸盐(138mg,0.83mmol)、冰醋酸(0.13ml,2.22mmol)、 N,N-二异丙基乙胺(0.14ml,0.83mmol)、5ml甲醇，室温反应3h后加入氰基硼氢化钠(35mg, 0.56mmol)，氩气保护下反应5h。加入饱和碳酸氢钠溶液，二氯甲烷萃取3次(3×30mL)，蒸馏水洗1次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为二氯甲烷：甲醇＝20:1，得白色固体184mg，收率69.8％。
1H NMR(400MHz,DMSO-d6)δ8.48(d,J＝2.0Hz,1H),8.39(dd,J＝9.0,2.2Hz,1H),8.03(d,J ＝8.1Hz,2H),7.51(d,J＝8.0Hz,3H),5.17–5.14(m,1H),3.66(m,2H),3.60(s,3H),3.10–3.02 (m,1H),2.74(t,J＝8.8Hz,1H),2.67–2.63(m,1H),2.57-2.52(m,2H),2.06-1.94(m,4H), 1.81-1.60(m,6H).
(2)标题化合物的制备
按实施例1中步骤(7)方法制备，得白色固体123mg，收率64.1％，熔点229-232℃
1H NMR(400MHz,DMSO-d6)δ12.94-11.36(m,1H),8.51(d,J＝2.0Hz,1H),8.41(dd,J＝9.0, 2.2Hz,1H),8.15(d,J＝8.4Hz,2H),7.82(d,J＝8.0Hz,2H),7.54(d,J＝9.2Hz,1H),5.18–5.15 (m,1H),4.46(s,2H),3.35(s,5H),2.33–2.16(m,2H),2.06-1.97(m,2H),1.82–1.61(m,6H).
实施例50
(4-(5-(4-环戊氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苄基)天冬氨酸盐酸盐
(1)(4-(5-(4-环戊氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苄基)天冬氨酸盐酸盐二甲酯的制备
将4-(5-(4-环戊氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苯甲醛(200mg,0.56mmol)溶于35ml二氯甲烷中，向其中依次加入天冬氨酸二甲酯盐酸盐(165mg,0.83mmol)、冰醋酸(0.13ml,2.22mmol)、 N,N-二异丙基乙胺(0.14ml,0.83mmol)、5ml甲醇，室温反应3h后加入氰基硼氢化钠(35mg, 0.56mmol)，氩气保护下反应5h。加入饱和碳酸氢钠溶液，二氯甲烷萃取3次(3×30mL)，蒸馏水洗1次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为二氯甲烷：甲醇＝20:1，得白色固体281mg，收率74.4％。
1H NMR(400MHz,DMSO-d6)δ8.49(d,J＝2.4Hz,1H),8.40(dd,J＝9.0,2.2Hz,1H),8.04-8.01 (m,2H),7.53-7.51(m,3H),5.19-5.14(m,1H),3.91-3.70(m,2H),3.64(s,3H),3.60(s,3H),3.58– 3.54(m,1H),2.88-2.84(m,1H),2.76–2.61(m,2H),2.06-1.98(m,2H),1.83–1.63(m,6H).
(2)标题化合物的制备
按实施例1中步骤(7)方法制备，得白色固体193mg，收率64.1％，熔点204-207℃
1H NMR(400MHz,DMSO-d6)δ10.56(s,2H),8.48(d,J＝2.4Hz,1H),8.38(dd,J＝9.0,2.2Hz, 1H),8.08(d,J＝8.0Hz,2H),7.64(d,J＝8.0Hz,2H),7.51(d,J＝9.2Hz,1H),5.17–5.14(m,1H), 4.15–4.01(m,2H),3.73–3.69(m,1H),2.78–2.63(m,2H),2.06-1.97(m,2H),1.81–1.63(m,6H).
实施例51
1-(4-(5-(4-环戊氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苄基)哌啶-4-乙酸盐酸盐
(1)1-(4-(5-(4-环戊氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苄基)哌啶-4-乙酸乙酯的制备
将4-(5-(4-环戊氧基-3-氰基苯基)-1,2,4-噁二唑-3-基)苯甲醛(200mg,0.56mmol)溶于35ml二氯甲烷中，向其中依次加入哌啶乙酸甲酯盐酸盐(131mg,0.83mmol)、冰醋酸(0.13ml,2.22mmol)、 N,N-二异丙基乙胺(0.14ml,0.83mmol)、5ml甲醇，室温反应3h后加入氰基硼氢化钠(35mg, 0.56mmol)，氩气保护下反应5h。加入饱和碳酸氢钠溶液，二氯甲烷萃取3次(3×30mL)，蒸馏水洗1次，合并有机相，无水硫酸钠干燥。浓缩，柱层析分离，洗脱剂为二氯甲烷：甲醇＝20:1，得白色固体212mg，收率76.3％
1H NMR(400MHz,DMSO-d6)δ8.48(d,J＝2.0Hz,1H),8.39(dd,J＝9.0,2.2Hz,1H),8.02(d,J ＝8.4Hz,2H),7.52-7.49(m,3H),5.17–5.13(m,1H),3.57(s,3H),3.51(s,2H),2.78(d,J＝11.2 Hz,2H),2.24(d,J＝6.8Hz,2H),2.06–1.92(m,4H),1.82-1.60(m,9H),1.25–1.17(m,2H).
(2)标题化合物的制备
按实施例1中步骤(7)方法制备，得白色固体144mg，收率65.0％，熔点244-246℃
1H NMR(400MHz,DMSO-d6)δ12.17(s,1H),10.58-10.43(m,1H),8.47(d,J＝2.4Hz,1H),8.37 (dd,J＝9.0,2.2Hz,1H),8.12(d,J＝8.0Hz,2H),7.77(d,J＝8.0Hz,2H),7.50(d,J＝9.2Hz,1H), 5.15-5.11(m,1H),4.32–4.31(m,2H),3.32(s,2H),2.98-2.88(m,2H),2.15(d,J＝6.8Hz,2H), 2.03-1.94(m,2H),1.83–1.45(m,11H).
实验例
本发明化合物的部分药理学试验及结果如下：
实验1本发明化合物对S1P1和S1P3受体的激动活性
实验方法：通过IP-One Tb检测试剂盒(Cisbio公司)，对本发明化合物进行体外S1P1和S1P3受体的激动活性研究。
在384孔板上接种细胞(S1P1 CHO-K1 Gαqi5 stable cell line，S1P3CHO-K1Gαqi5stable cell line)， 37℃培养过夜。加入不同浓度的待测化合物，37℃孵育30min后加入Anti-IP1-Tb和IP1-d2，室温孵育1小时，检测665nm和620nm的吸光度值，计算得到化合物的EC50。(参考文献： Ballatore,C.；Soper,J.H.；Piscitelli,F.；James,M.；Huang,L.；Atasoylu,O.；Huryn,D.M.； Trojanowski,J.Q.；Lee,V.M.；Brunden,K.R.；Smith,A.B.,Cyclopentane-1,3-dione:a novel isostere for the carboxylic acid functionalgroup.Application to the design of potent thromboxane (A2)receptorantagonists.Journal of Medicinal Chemistry 2011,54(19),6969-83.)
表1本发明化合物对S1P1和S1P3受体的激动活性
由表1可见，本发明化合物具有较强的S1P1受体激动活性以及S1P1/S1P3受体选择性，部分化合物与阳性对照药水平相当或更高。
实验2本发明化合物体内淋巴细胞降低活性
实验方法：选用雄性SD大鼠，体重200～220g。设定空白对照组、阳性对照组(RPC1063) 以及试验药物组，用双蒸水将药物溶解至浓度为2.5mg/mL。大鼠尾部取血10μL，测定给药前大鼠淋巴细胞数量。所有动物称重后，阳性药组和试验药物组大鼠灌胃给药，药物剂量为 10mg/kg；正常对照组大鼠灌胃相应体积的双蒸水。尾部取血10μL，使用血液淋巴计数器 (MEK-7222K Hematology Analyzer)测定大鼠给药后淋巴细胞数量，测定时间点为给药后1小时、给药后2小时、给药后4小时、给药后8小时、给药后12小时、给药后24小时和给药后48小时，计算各时间点大鼠淋巴细胞数量的变化。
表2本发明化合物体内淋巴细胞降低活性
上述实验结果显示，本发明所述化合物具有较高的体内免疫抑制活性，与其具有高S1P1受体激动活性的体外结果相一致。该类化合物及其药用制剂可以用于治疗器官移植排异反应和自身免疫性疾病如银屑病、多发硬化症、类风湿关节炎、系统性红斑狼疮等。
实验3本发明化合物口服药代动力学特性
选用雄性SD大鼠，体重200～220g。设定阳性对照组(RPC1063)以及试验药物组，0.5％CMC 超声配成混悬液用于口服给药，浓度为3mg/kg/10ml。所有动物称重后，阳性药组和试验药物组大鼠灌胃给药，药物剂量为3mg/kg，于给药后的5min，10min，15min，30min，1h，2h， 4h，6h，8h，12h，24h各时间点分别于眼眶静脉丛取血，制备血浆，利用UPLC/MS测定血浆药物浓度,绘制药时曲线，如图1所示，经Phonix软件分析和非房室模型拟合，得到药代动力学参数，见下表3。
表3本发明化合物口服给药的药代动力学参数a
a药代参数为5次实验结果的平均值.
上述实验结果显示，本发明所述化合物口服给药具有较好的体内药代性质，Cmax和AUC(0-t) 均高于阳性药RPC1063。
实验4本发明化合物静脉注射药代动力学特性
选用雄性SD大鼠，体重200～220g。设定试验药物组，DMSO溶解配置成1mg/ml的溶液，再用生理盐水稀释成0.06mg/ml溶液或混悬液用于静脉注射给药。所有动物称重后，试验药物组大鼠静脉注射给药，药物剂量为0.3mg/kg/5ml，于给药后的5min，10min，15min，30min， 1h，2h，4h，6h，8h，12h，24h各时间点分别于眼眶静脉丛取血，制备血浆，利用UPLC/MS 测定血浆药物浓度，绘制药时曲线，如图2所示，经Phonix软件分析和非房室模型拟合，得到药代动力学参数，见下表4。
表4本发明化合物静脉注射的药代动力学参数a
a药代参数为5次实验结果的平均值.
上述实验结果显示，本发明所述化合物静脉注射给药后体内清除较快，结合大鼠口服药代动力学数据，SYL2439(实施例38)和SYL2443(实施例42)口服生物利用度分别为50.31％和12.48％。
说明书附图中conc(ng/ml)表示浓度(ng/ml),time(h)表示时间(h)。
Claims (5)
1.具有如下结构的化合物：
2.一种药物组合物，其特征在于，所述药物组合物含有权利要求1所述的化合物以及药学上可接受的载体。
3.权利要求1所述的化合物或权利要求2所述的药物组合物在制备预防或治疗自身免疫性疾病的药物中的应用。
4.根据权利要求3的应用，其特征在于，所述的自身免疫性疾病选自多发硬化症、类风湿关节炎、系统性红斑狼疮、牛皮癖、银屑病。
5.权利要求1所述的化合物或权利要求2所述的药物组合物在制备减轻器官移植排异反应的药物中的应用。
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