CN117466761A - 谷氨酰胺转运抑制剂、药物组合物和应用 - Google Patents
谷氨酰胺转运抑制剂、药物组合物和应用 Download PDFInfo
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- CN117466761A CN117466761A CN202210859330.0A CN202210859330A CN117466761A CN 117466761 A CN117466761 A CN 117466761A CN 202210859330 A CN202210859330 A CN 202210859330A CN 117466761 A CN117466761 A CN 117466761A
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- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 125000000440 benzylamino group Chemical group [H]N(*)C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
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- WYKFWIYGJGNLRD-UHFFFAOYSA-N methyl 2-prop-2-ynoxybenzoate Chemical compound COC(=O)C1=CC=CC=C1OCC#C WYKFWIYGJGNLRD-UHFFFAOYSA-N 0.000 description 1
- 229960001047 methyl salicylate Drugs 0.000 description 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical compound [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
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Abstract
本发明公开了一种谷氨酰胺转运抑制剂及其药物组合物和应用。该类抑制剂结构如式I，还包含其异构体、药学上可接受的盐或它们的混合物。该类抑制剂及其药物组合物具有ASCT2抑制活性，能够有效抑制肿瘤细胞谷氨酰胺摄取，实现对肿瘤细胞的抑制作用。应用广泛，可制备为治疗与ASCT2相关的疾病药物，所述药物在分子水平和细胞水平均可以发挥药效。此外，化合物制备方法简便、易操作。
Description
技术领域
本发明涉及一种谷氨酰胺转运抑制剂、药物组合物和应用，尤其涉及一种可制备为治疗与Na+依赖性谷氨酰胺载体2相关疾病药物的谷氨酰胺转运抑制剂、药物组合物和应用。
背景技术
肿瘤细胞往往程序性依赖谷氨酰胺进行代谢。谷氨酰胺通过谷氨酰胺转运体进入细胞中，经谷氨酰胺酶水解生成谷氨酸，谷氨酸进一步转化为α酮戊二酸进入三羧酸循环为癌细胞提供能量以及大分子生物合成材料。
Na+依赖性谷氨酰胺载体2(Alanine-Serine-Cysteine Transporter 2，ASCT2)属于SLC1A膜蛋白家族，是细胞膜上特异性转运谷氨酰胺的载体之一。ASCT2往往在肿瘤中高表达，并且与肿瘤的谷氨酰胺能量代谢途径密切相关。
目前尚无针对ASCT2的抑制剂药物上市，PNA是第一个ASCT2抑制剂，其抑制活性较低(IC50＝～1mM)；后续的V9302在动物异种肿瘤模型中展现出良好的抗肿瘤活性，然而其较差的选择性限制了其临床的进展。
发明内容
发明目的：针对现有化合物疗效有效、靶点选择性不佳等不足，本发明旨在提供一种具有优异的抑制肿瘤细胞增殖作用的谷氨酰胺转运抑制剂、药物组合物和应用。
技术方案：作为本发明涉及的第一方面，本发明的谷氨酰胺转运抑制剂具有式I的结构，所述化合物还包含其异构体、药学上可接受的盐或它们的混合物：
其中：
X、Q为
Ra为氢或甲基，或者多个Ra与所连接的碳原子成环；
R1为氢、卤素、氰基、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基或C1-C4卤代烷氧基；
R2为1-4个氢被R2a取代的6-10元芳基或5-10元杂芳基；
R2a为氢、卤素、氰基、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基或C1-C4卤代烷氧基；
R3为卤素、氰基、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基、C1-C4卤代烷氧基、1-4个氢被R3b取代的6-10元芳基或5-10元杂芳基，或者R3a-L1-；
R3a-L1-为R3a-[C(RbRc)]0-5-、R3a-[C(RbRc)]0-2-O-[C(RbRc)]0-2-、R3a-C≡C-[C(RbRc)]1-2-O-、R3a-C＝C-[C(RbRc)]1-2-O-、R3a-[C(RbRc)]0-2-C(O)-[C(RbRc)]0-2-、R3a-[C(RbRc)]0-2-C(O)NH-[C(RbRc)]0-2-、R3a-[C(RbRc)]0-2-NHC(O)-[C(RbRc)]0-2-、R3a-[C(RbRc)]0-2-S(O)2-[C(RbRc)]0-2-、R3a-[C(RbRc)]0-2-NHS(O)2-[C(RbRc)]0-2-或R3a-[C(RbRc)]0-2-S(O)2NH-[C(RbRc)]0-2-；
R3a为1-4个氢被R3c取代的6-10元芳基或5-10元杂芳基；
R3b、R3c为氢、卤素、氰基、羟基、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基或C1-C4卤代烷氧基；
Rb、Rc为氢、卤素、C1-C3烷基或C3-C6环烷基，或者Rb、Rc与所连接的碳原子形成环丙基；
m为0、1、2、3或4；
n为0、1、2、3或4；
z为0、1或2；
所述5-10元杂芳基中的杂原子为N、O或S，杂原子的个数为1、2、3或4个。
优选，上述结构中：
X、Q为
Ra为氢或甲基，或者两个Ra与所连接的碳原子形成
R1为氢、溴、碘、甲基、异丙基、叔丁基、三氟甲基或甲氧基；
R2为1-4个氢被R2a取代的苯基、萘基或吡啶基；
R2a为氢、氟、氰基、甲基、异丙基、叔丁基、三氟甲基、甲氧基、乙氧基或异丙氧基；
R3为氯、溴、碘、甲基、异丙基、叔丁基、C1-C4氟代烷基、甲氧基、R3a-CH2O-、R3a-C≡C-CH2O-、R3a-C(O)NH-或R3a-S(O)2NH-，或者1-4个氢被氢、氟、氯、溴、C1-C4氟代烷基、甲氧基取代的萘基、苯并噁唑基或苯并噻唑基；
R3a为1-4个氢被R3c取代的苯基、萘基、吡啶基、苯并噁唑基或苯并噻唑基；
R3c为氢、氟、氯、氰基、羟基、甲基、乙基、异丙基、三氟甲基、甲氧基、乙氧基或异丙氧基；
z为0、1或2。
优选，上述结构中：
X为-C(O)-；
Q为Ra为氢或甲基；
R1为溴、碘、甲基、异丙基、叔丁基、C1-C4氟代烷基或甲氧基；
R2为1-4个氢被R2a取代的苯基或萘基；
R2a为氢、氟、甲基、异丙基、叔丁基、C1-C4氟代烷基、甲氧基、乙氧基或异丙氧基；
R3为溴、碘、甲基、异丙基、叔丁基、C1-C4氟代烷基、甲氧基、R3a-CH2O-或R3a-C≡C-OCH2-，或者1-4个氢被氢、氟、溴、C1-C4氟代烷基、甲氧基取代的苯基或萘基；
R3a为1-4个氢被R3c取代的苯基或萘基；
R3c为氢、氟、氯、氰基、羟基、甲基、乙基、异丙基、C1-C4氟代烷基、甲氧基、乙氧基或异丙氧基；
z为0、1或2。
优选，上述结构中：
X、Q为
Ra为氢或甲基；
R1为溴、碘、甲基、异丙基、叔丁基、C1-C4氟代烷基、甲氧基；
R2为1-4个氢被R2a取代的苯基或萘基；
R2a为氢、氟、甲基、异丙基、叔丁基、C1-C4氟代烷基、甲氧基、乙氧基或异丙氧基；
R3为溴、碘、甲基、异丙基、三氟甲基、甲氧基或R3a-C≡C-CH2O-，或者1-4个氢被氢、氟、溴、C1-C4氟代烷基、甲氧基取代的萘基；
R3a为1-4个氢被R3c取代的苯基、萘基、吡啶基、苯并噁唑基或苯并噻唑基；
R3c为氢、氟、氯、氰基、甲基、乙基、异丙基、C1-C4氟代烷基、甲氧基、乙氧基或异丙氧基；
z为0或1。
优选，上述抑制剂具有以下任一通式结构：
其中，k、y为0、1、2、3或4；R1、R2a、R3、R3a、m、n的定义如前所述。
更优选地，上述抑制剂选自以下任一化合物：
上述抑制剂的药学上可接受的盐为上述化合物与酸或碱形成的盐，所述酸为盐酸、氢溴酸、硫酸、磷酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸、琥珀酸、富马酸、水杨酸、苯基乙酸或杏仁酸，所述碱为含有碱性金属阳离子、碱土金属阳离子或铵阳离子盐的无机碱。
上述抑制剂以及药学上可接受的载体形成药物组合物，制成常见的药用制剂，如片剂、胶囊、糖浆、悬浮剂或注射剂，制剂可以加入香料、甜味剂、液体/固体填料、稀释剂等常用药用辅料。
上述抑制剂及其药物组合物可制备为治疗与Na+依赖性谷氨酰胺载体2相关疾病的药物，具体用于治疗癌症或病毒性感染。
有益效果：与现有技术相比，本发明具有如下显著优点：
(1)该类谷氨酰胺转运抑制剂及其药物组合物具有ASCT2抑制活性，可有效肿瘤细胞谷氨酰胺摄取，实现对肿瘤细胞的抑制作用，抑制IC50值最优小于10μM；
(2)该类抑制剂及其药物组合物应用广泛，可制备为治疗与ASCT2相关的疾病药物；所述药物在分子水平和细胞水平均可以发挥药效，达到为摩尔浓度水平；
(3)化合物制备方法简便、易操作。
具体实施方式
下面结合实施例对本发明的技术方案作进一步说明。
实施例1：化合物L-1
步骤1：将水杨醛(2.00g，16.38mmol)溶于30mL丙酮中，加入3-溴丙炔(1.95g，16.38mmol)和碳酸钾(4.53g，32.76mmol)，升温至60℃反应1.5小时，待反应完全后，冷却至室温，抽滤除去碳酸钾，减压除去丙酮，然后用异丙醚低温打浆得到白色固体2.42g，收率92％。1H NMR(300MHz,CDCl3):δ10.49(s,1H),7.87(dd,J＝7.5Hz,1H),7.58(td,1H),7.07-7.14(m,2H),4.84(d,J＝2.4Hz,2H),2.58(t,J＝2.4Hz,1H)ppm。
步骤2：将2-((丙基-2-炔-1-氧基)苯甲醛(2.00g，12.50mmol)溶于30mL四氢呋喃中，加入碘苯(2.55g，12.50mmol)，三乙胺(6.4g，62.48mmol)，碘化亚铜(0.24g，1.25mmol)，Pd(PPh3)4(0.58g，0.50mmol)，反应氮气保护，升至60℃反应3小时，冷却至室温，将反应液倒入40mL水中，乙酸乙酯萃取，使用无水硫酸钠干燥，减压除去溶液，通过柱层析(石油醚：乙酸乙酯＝50：1)分离得到白色固体(2.07g，70％)。1H NMR(300MHz,DMSO-d6)δ10.41(s,1H),7.80–7.66(m,2H),7.51–7.33(m,6H),7.16(t,J＝7.5Hz,1H),5.26(s,2H)ppm。
步骤3：将(S)-2，4-二氨基丁酸(0.2g,0.92mmol)溶于5mL甲醇中，加入2-((3-苯基丙-2-炔-1-基)氧基)苯甲醛(0.54g,2.29mmol)，室温搅拌半小时，然后加入氰基硼氢化钠(0.2g,3.21mmol)，在室温条件下搅拌12小时，减压除去溶剂，通过柱层析分离(二氯甲烷：甲醇＝30：1)得到白色固体(0.31g，51.35％)。HRMS(ESI):m/z[M+H]+.C41H43N2O6计算值659.3116；实测值659.3127。
步骤4：将(S)-4-(双(2-(((3-苯基丙-2-炔-1-基)氧基)苄基)氨基)-2-((叔丁氧基羰基)氨基)丁酸(0.24g，0.47mmol)溶于10mL 1,4-二氧六环中，然后加入4mol/L盐酸8mL，升温至45℃反应3小时，减压除去溶剂，通过柱层析纯化(二氯甲烷：甲醇＝10：1)得到白色固体(0.12g，60％)。1H NMR(300MHz,DMSO-d6):δ7.45(t,J＝7.6Hz,4H),7.35-7.29(m,10H),7.23(d,J＝8.5Hz,2H),7.02(t,J＝7.3Hz,2H),5.02(s,4H),4.30(m,4H),3.70(s,1H),3.26(s,2H),2.39–2.15(m,2H)ppm.HRMS(ESI):m/z[M+H]+.C36H38N2O4计算值559.2591；实测值559.2564。
实施例2-实施例14所述化合物的制备，可参考实施例1中所描述的方法和路线制备得到。
实施例2：化合物L-2
1H NMR(300MHz,DMSO-d6):δ7.49–7.37(m,4H),7.24(dd,J＝15.3,7.0Hz,6H),7.19–7.07(m,4H),7.01(t,J＝7.3Hz,2H),5.08(s,4H),4.15(m,4H),3.23(s,1H),3.14(s,2H),2.17(s,6H),1.98(s,1H)ppm.HRMS(ESI):m/z[M+H]+.C38H38N2O4计算值587.2904；实测值587.2912。
实施例3：化合物L-3
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1H NMR(300MHz,DMSO-d6):δ7.36–7.31(m,4H),7.29–7.23(m,2H),7.19(td,J＝7.7,1.5Hz,2H),7.15-7.10(m,4H),6.97–6.89(m,4H),4.85(s,4H),3.77–3.69(m,4H),3.66(s,1H),3.42-3.38(m,2H),2.21(s,6H),2.01-1.96(m,2H)ppm.HRMS(ESI):m/z[M+H]+.C38H38N2O4计算值587.2904；实测值587.2923。
实施例4：化合物L-4
1H NMR(300MHz,DMSO-d6):δ7.49–7.39(m,2H),7.35–7.26(m,10H),7.05–6.97(m,4H),5.01(s,4H),4.23(m,4H),3.60(s,1H),3.56-3.45(m,2H),2.38(s,6H),1.93–1.81(m,2H)ppm.HRMS(ESI):m/z[M+H]+.C38H38N2O4计算值587.2904；实测值587.2902。
实施例5：化合物L-5
1H NMR(300MHz,DMSO-d6):δ7.31(t,J＝6.9Hz,2H),7.28–7.20(m,4H),7.18(dd,J＝7.8,1.6Hz,2H),7.14(d,J＝4.1Hz,2H),6.99–6.89(m,6H),4.85(s,4H),3.82(s,6H),3.76–3.69(m,4H),3.66(s,2H),3.55(s,1H)1.93–1.81(m,2H)ppm.HRMS(ESI):m/z[M+H]+.C38H38N2O6计算值619.2803；实测值619.2822。
实施例6：化合物L-6
1H NMR(300MHz,DMSO-d6):δ7.53–7.38(m,4H),7.24(t,J＝8.1Hz,4H),7.02(t,J＝7.4Hz,2H),6.98–6.85(m,6H),5.05(s,4H),4.33–4.11(m,4H),3.69(s,6H),3.19(s,2H),3.15(s,1H),2.32–2.10(m,2H)ppm.HRMS(ESI):m/z[M+H]+.C38H38N2O6计算值619.2803；实测值619.2809。
实施例7：化合物L-7
1H NMR(300MHz,DMSO-d6):δ7.40(d,J＝6.7,2H),7.24(m,4H),7.24–7.12(m,6H),6.97–6.89(m,4H),5.02(s,4H),4.01(s,4H),3.23(s,1H),3.15(s,2H),1.93–1.81(m,2H)ppm.HRMS(ESI):m/z[M+H]+.C36H33F2N2O4计算值595.2403；实测值595.2408。
实施例8：化合物L-8
1H NMR(300MHz,DMSO-d6):δ7.43–7.35(m,4H),7.01(d,J＝2.1Hz,4H),6.97–6.89(m,6H),5.00(s,4H),4.12–4.08(m,4H),3.66(d,J＝5.0Hz,1H),2.85-2.76(m,2H),2.22(s,12H)1.93–1.81(m,2H)ppm.HRMS(ESI):m/z[M+H]+.C40H43N2O4计算值615.3217；实测值615.3225。
实施例9：化合物L-9
1H NMR(300MHz,DMSO-d6):δ7.44–7.33(m,8H),7.29–7.23(m,2H),7.19(td,J＝7.7,1.5Hz,2H),6.97–6.89(m,4H),4.95(s,4H),3.87–3.80(m,4H),3.70(s,1H),3.21(s,2H)1.93–1.81(m,2H),1.03(s,18H)ppm.HRMS(ESI):m/z[M+H]+.C44H51N2O4计算值671.3843；实测值671.3859。
实施例10：化合物L-10
1H NMR(300MHz,DMSO-d6):δ7.70–7.64(m,4H),7.63–7.57(m,4H),7.29–7.23(m,2H),7.19(td,J＝7.7,1.5Hz,2H),6.97–6.89(m,4H),4.89(s,4H),3.79(s,4H),3.80(s,1H)3.67-3.60(m,2H),2.01-1.95(m,2H)ppm.HRMS(ESI):m/z[M+H]+.C38H33F6N2O4计算值695.2339；实测值695.2358。
实施例11：化合物L-11
1H NMR(300MHz,DMSO-d6):δ7.90-7.67(m,6H),7.49(t,J＝5.7Hz,2H),7.29–7.19(m,4H),6.97–6.89(m,4H),5.01(s,4H),3.79(s,1H),3.69-3.58(m,2H),2.05–1.93(m,2H)ppm.HRMS(ESI):m/z[M+H]+.C28H33N4O4计算值609.2496；实测值609.2458。
实施例12：化合物L-12
1H NMR(300MHz,DMSO-d6):δ8.62(d,J＝4.5Hz,4H),7.91(s,2H),7.58(s,2H),7.47(dd,J＝12.4,5.0Hz,4H),7.28(d,J＝8.3Hz,2H),7.05(t,J＝7.4Hz,2H),5.13(s,4H),4.46–4.29(m,4H),4.02(s,1H),3.30(d,J＝8.0Hz,2H),3.15(s,2H)ppm.HRMS(ESI):m/z[M+H]+.C34H33N4O4计算值561.2496；实测值561.2485。
实施例13：化合物L-13
1H NMR(300MHz,DMSO-d6):δ8.40(d,J＝4.8Hz,2H),7.78(s,2H),7.33–7.23(m,4H),7.19–6.89(m,6H),5.10(s,4H),3.99(s,6H),3.77–3.70(m,4H),3.68(s,1H),3.50(s,2H),2.30–2.14(m,2H)ppm.HRMS(ESI):m/z[M+H]+.C36H37N4O6计算值621.2708；实测值621.2755。
实施例14：化合物L-14
步骤1：将(S)-4-氨基-2-((叔丁氧羰基)氨基)丁酸(0.15g，0.68mmol)溶于5mL甲醇中，加入2-((3-苯基丙-2-炔-1-基)氧基)苯甲醛(0.20g，0.83mmol)，室温搅拌半小时，然后加入氰基硼氢化钠(65mg，1.03mmol)，继续室温搅拌1.5小时，减压除去溶剂。通过柱层析分离(二氯甲烷：甲醇＝15:1)得到白色固体(0.24g，79.63％)。HRMS(ESI):m/z[M+H]+.C25H30N2O5计算值438.2155；实测值438.2159。
步骤2：将(S)-2-((叔丁氧基羰基)氨基)-4-((2-((3-苯基丙-2-炔-1-基)氧基)苄基)氨基)丁酸(0.29g，0.66mmol)溶于8mL甲醇中，加入2-((3-(吡啶-4-基)丙-2-炔-1-基)氧基)苯甲醛(0.18g，0.79mmol)，室温搅拌半小时，然后加入氰基硼氢化钠(87mg，1.37mmol)，在室温条件下搅拌12小时，减压除去溶剂，通过柱层析分离(二氯甲烷：甲醇＝30：1)得到白色固体(0.23g，52.71％)。HRMS(ESI):m/z[M+H]+.C41H43N2O6计算值660.3068；实测值660.3054。
步骤3：将(S)-2-((叔丁氧羰基)氨基)-4-((2-((3-苯基丙-2-炔-1-基)氧基)苄基)(2-((3-(吡啶-4-基)丙-2-烯-1-基)氧基)苄基)氨基)丁酸(0.22g,0.33mmol)溶于3mL1,4-二氧六环中，然后加入4mol/L盐酸5mL，室温反应4小时，减压除去溶剂，通过柱层析纯化(二氯甲烷：甲醇＝10：1)得到白色固体(0.12g，60％)。1HNMR(300MHz,DMSO-d6):δ8.61–8.56(m,2H),7.43–7.31(m,7H),7.26-7.10(m,4H),6.97–6.89(m,4H),5.07(s,4H),3.89–3.75(m,5H),3.56(s,2H),2.05-1.98(m,2H)ppm.HRMS(ESI):m/z[M+H]+.C35H34N3O4计算值560.2544；实测值560.2564。
实施例15和实施例16所述化合物的制备，可参考实施例14中所描述的方法和路线制备得到。
实施例15：化合物L-15
1H NMR(300MHz,DMSO-d6):δ7.51–7.47(m,5H),7.32–7.27(m,2H),7.19(td,J＝7.8,1.6Hz,2H),7.03(d,J＝2.1Hz,2H),6.97–6.89(m,5H),5.03(s,4H),4.03-3.86(m,4H),3.70(s,1H),3.66(s,2H),2.23(s,6H),2.02–1.95(m,2H)ppm.HRMS(ESI):m/z[M+H]+.C38H39N2O4计算值587.2904；实测值587.2948。
实施例16：化合物L-16
1H NMR(300MHz,DMSO-d6):δ7.90(s,1H),7.73-7.68(m,1H),7.61–7.37(m,7H),7.26(d,J＝8.1,2H),7.19(td,J＝7.8,1.6Hz,2H),6.97–6.89(m,4H),5.01(s,4H),4.20-4.13(m,4H),3.75(s,1H),3.56(s,2H),1.94–1.81(m,2H)ppm.HRMS(ESI):m/z[M+H]+.C37H34N3O4计算值584.2544；实测值584.2547。
实施例17：化合物L-17
步骤1：将2-羟基苯乙酮(2.00g，14.69mmol)溶于30mL丙酮中，加入3-溴丙炔(2.62g，22.03mmol)和碳酸钾(5.08g，36.72mmol)，升温至60℃反应3小时，待反应完全后，冷却至室温，抽滤除去碳酸钾，减压除去丙酮，柱层析(石油醚：乙酸乙酯＝20:1)得到白色固体(2.03g,79.33％)1H NMR(300MHz,Chloroform-d)δ7.76(s,1H),7.41(td,J＝7.8,1.5Hz,1H),7.15(dd,J＝8.0,1.2Hz,1H),7.00(s,1H),4.84(d,J＝3.0Hz,2H),2.59(s,3H),2.55(t,J＝3.0Hz,1H)ppm。
步骤2：将2-((丙基-2-炔-1-氧基)苯乙酮(2.00g，11.48mmol)溶于30mL四氢呋喃中，加入碘苯(2.13g，10.44mmol)，三乙胺(5.28g，52.19mmol)，碘化亚铜(0.20g，1.04mmol)，Pd(PPh3)4(0.60g，0.52mmol)，反应氮气保护，升至60℃反应3小时，冷却至室温，将反应液倒入40mL水中，乙酸乙酯萃取(50mL×3)，使用无水硫酸钠干燥，减压除去溶液，通过柱层析(石油醚：乙酸乙酯＝50：1)分离得到白色固体(1.70g，65.07％)1H NMR(300MHz,Chloroform-d)δ7.76(dd,J＝7.9,1.6Hz,1H),7.47–7.33(m,6H),7.15(dd,J＝8.0,1.2Hz,1H),7.00(td,J＝7.8,1.2Hz,1H),4.87(s,2H),2.59(s,3H)ppm。
步骤3：将(S)-4-氨基-2-((叔丁氧羰基)氨基)丁酸(0.2g，0.92mmol)溶于5mL甲醇中，加入2-((3-苯基丙-2-炔-1-基)氧基)苯乙酮(0.57g，2.29mmol)，室温搅拌一小时，然后加入氰基硼氢化钠(0.2g,3.21mmol)，继续室温搅拌8小时，减压除去溶剂。通过柱层析分离(二氯甲烷：甲醇＝20:1)得到白色固体(0.31g，49.18％)。HRMS(ESI):m/z[M+H]+.C43H47N2O6计算值687.3429；实测值687.3450。
步骤4：将(S)-4-(双(2-(((3-苯基丙-2-炔-1-基)氧基)苄基)氨基)-2-((叔丁氧基羰基)氨基)丁酸(0.20g，0.30mmol)溶于1,4-二氧六环(5mL)中，然后加入4mol/L盐酸5mL，室温搅拌6小时，减压除去溶剂，通过柱层析纯化(二氯甲烷：甲醇＝10：1)得到白色固体(0.12g，70.24％)。1H NMR(300MHz,DMSO-d6):δ7.43–7.34(m,10H),7.27–7.19(m,4H),7.04–6.94(m,4H),5.16(s,4H),3.77-3.66(m,3H),2.87-2.76(m,2H),2.00-1.92(m,2H),1.28(d,J＝6.6Hz,6H)ppm.HRMS(ESI):m/z[M+H]+.C38H39N2O4计算值587.2904；实测值587.2952。
实施例18：化合物L-18
步骤1：将(S)-4-氨基-2-((叔丁氧羰基)氨基)丁酸(0.15g，0.69mmol)溶于5mL甲醇中，加入2-((3-苯基丙-2-炔-1-基)氧基)苯乙酮(0.20g，0.82mmol)，室温搅拌一小时，然后加入氰基硼氢化钠(64mg,1.03mmol)，继续室温搅拌8小时，减压除去溶剂。通过柱层析分离(二氯甲烷：甲醇＝15:1)得到白色固体(0.24g，79.63％)。HRMS(ESI):m/z[M+H]+.C26H33N2O5计算值453.2384；实测值453.2376。
步骤2：(S)-2-((叔丁氧羰基)氨基)-4-((1-(2-((3-苯基丙-2-炔-1-基)氧)苯基)乙氨基)丁酸(0.20g，0.44mmol)溶于8mL甲醇中，加入2-((3-苯基丙-2-炔-1-基)氧基)苯乙酮(0.125g，0.53mmol)，室温搅拌半小时，然后加入氰基硼氢化钠(42mg，0.66mmol)，在室温条件下搅拌过夜，减压除去溶剂，通过柱层析分离(二氯甲烷：甲醇＝30：1)得到白色固体(0.21g，70.62％)。HRMS(ESI):m/z[M+H]+.C42H45N2O6计算值673.3272；实测值673.3258。
步骤3：将(2S)-4-(双(1-(2-((3-苯基丙-2-炔-1-基)氧)苯基)乙基)氨基)-2-((叔丁氧羰基)氨基)丁酸(0.20g，0.29mmol)溶于5mL 1,4-二氧六环中，然后加入4mol/L盐酸5mL，室温反应6小时，减压除去溶剂，通过柱层析纯化(二氯甲烷：甲醇＝10：1)得到白色固体(0.12g，70.24％)。1H NMR(300MHz,DMSO-d6):δ7.43–7.34(m,10H),7.27–7.16(m,4H),7.04–6.89(m,4H),5.13(s,4H),3.89–3.75(m,3H),3.70(s,1H),2.81(s,2H),2.15-1.97(m,2H),1.41(d,J＝6.8Hz,3H)ppm.HRMS(ESI):m/z[M+H]+.C38H39N2O4计算值587.2904；实测值587.2911。
实施例19：化合物L-19
步骤1：将CuI(15mg,81μmol)，三乙胺(3mL)，2-氯苯并[d]恶唑(250mg,1.63mmol)，Pd(PPh3)2Cl2(57mg,81μmol)，三苯基磷(98mg,293μmol)和2-((丙基-2-炔-1-氧基)苯甲醛(250mg,1.92mmol)加入5mL N,N-二甲基甲酰胺中，升温至120摄氏度反应1小时。TLC确认反应完全，冷却至室温，加水利用乙酸乙酯萃取，有机层饱和食盐水洗涤，无水硫酸钠干燥，有机层旋干，粗残余通过硅胶柱层析(环己烷:乙酸乙酯＝60:1)提纯，得到橙色油(163mg,40％)1H NMR(300MHz,Chloroform-d)δ7.88–7.79(m,1H),7.76–7.53(m,2H),7.48–7.31(m,3H),7.17(dd,J＝8.1,1.2Hz,1H),7.09(td,J＝7.7,1.2Hz,1H),4.88(s,2H)ppm。
步骤2：将(S)-4-氨基-2-((叔丁氧羰基)氨基)丁酸(0.2g，0.92mmol)溶于5mL甲醇中，加入2-((3-(苯并[d]恶唑-2-基)丙-2-炔-1-基)氧基)苯甲醛(0.635g，2.29mmol)，室温搅拌一小时，然后加入氰基硼氢化钠(0.2g,3.21mmol)，继续室温搅拌8小时，减压除去溶剂。通过柱层析分离(二氯甲烷：甲醇＝20:1)得到黄色固体(0.25g，36.83％)。HRMS(ESI):m/z[M+H]+.C43H41N4O8计算值741.2919实测值741.2978。
步骤3：将(S)-4-(双(2-((3-(苯并[d]恶唑-2-基)丙-2-炔-1-基)氧)苄氨基)-2-((叔丁氧羰基)氨基)丁酸(0.2g,0.27mmol)溶于5mL二氧六环，加入4mol/L盐酸5mL，室温反应6小时，减压除去溶剂，通过柱层析纯化(二氯甲烷：甲醇＝10：1)得到黄色固体(0.11g，63.59％)。
1H NMR(300MHz,DMSO-d6):δ7.72–7.61(m,4H),7.44–7.34(m,4H),7.29–7.23(m,2H),7.19(td,J＝7.7,1.5Hz,2H),6.97–6.89(m,4H),4.99(s,4H),4.01-3.95(m,4H),3.77(s,1H),3.69–3.63(m,2H),1.93–1.81(m,2H)ppm.HRMS(ESI):m/z[M+H]+.C38H33N4O6计算值641.2395；实测值641.2376。
实施例20：化合物L-20
步骤1：将(S)-4-氨基-2-((叔丁氧羰基)氨基)丁酸(0.2g，0.92mmol)溶于5mL甲醇中，加入2-((3-(苯并[d]恶唑-2-基)丙-2-炔-1-基)氧基)苯甲醛(0.304g，1.10mmol)，室温搅拌一小时，然后加入氰基硼氢化钠(86mg,1.37mmol)，继续室温搅拌8小时，减压除去溶剂。通过柱层析分离(二氯甲烷：甲醇＝10:1)得到黄色固体(0.38g，86.48％)。HRMS(ESI):m/z[M+H]+.C26H30N3O6计算值480.2129；实测值480.2146。
步骤2：(S)-4-((2-((3-(苯并[d]恶唑-2-基)丙-2-炔-1-基)氧基)苄基)氨基)-2-((叔丁氧羰基)氨基)丁酸(0.20g，0.54mmol)溶于5mL甲醇中，加入2-((3-苯基丙-2-炔-1-基)氧基)苯甲醛(0.13g，0.53mmol)，室温搅拌半小时，然后加入氰基硼氢化钠(52mg，0.83mmol)，在室温条件下搅拌过夜，减压除去溶剂，通过柱层析分离(二氯甲烷：甲醇＝30：1)得到白色固体(0.12g，41.06％)。HRMS(ESI):m/z[M+H]+.C42H42N3O7计算值700.3017；实测值700.3023。
步骤3：将(S)-4-((2-((3-(苯并[d]恶唑-2-基)丙-2-炔-1-基)氧基)苄基)(2-((3-苯基丙-2-炔-1-基)氧基)苄基)氨基)-2-((叔丁氧羰基)氨基)丁酸(0.1g，0.14mmol)溶于5mL 1,4-二氧六环中，然后加入4mol/L盐酸5mL，室温搅拌6小时，减压除去溶剂，通过柱层析纯化(二氯甲烷：甲醇＝10：1)得到黄色固体(50mg，58.35％)。1H NMR(300MHz,DMSO-d6):δ7.72–7.39(m,9H),7.29–7.19(m,4H),6.97–6.89(m,4H),5.16(s,4H),3.95-3.89(m,4H),3.70(s,1H),3.66(s,2H),2.03-1.90(m,2H)ppm.HRMS(ESI):m/z[M+H]+.C42H42N3O7计算值600.2493；实测值600.2487。
实施例21-实施例23所述化合物的制备，可参考实施例14中所描述的方法和路线制备得到。
实施例21：化合物L-21
1H NMR(300MHz,DMSO-d6):δ7.82–7.42(m,9H),7.24–7.13(m,4H),6.97–6.89(m,4H),5.11(s,4H),4.02-3.95(m,4H),3.79(s,1H),3.66(s,2H),2.00-1.79(m,2H),1.35(s,3H)ppm.HRMS(ESI):m/z[M+H]+.C28H36N3O5计算值614.2649；实测值614.2623。
实施例22：化合物L-22
1H NMR(300MHz,DMSO-d6):δ7.72–7.56(m,2H),7.44–7.34(m,7H),7.29–7.16(m,3H),7.02(s,1H),6.97–6.85(m,3H),5.05(s,4H),4.32–4.13(m,4H),3.81(s,1H),3.63–3.58(m,2H),2.27(s,3H),1.94–1.73(m,2H)ppm.HRMS(ESI):m/z[M+H]+.C28H36N3O5计算值614.2649；实测值614.2627。
实施例23：化合物L-23
1H NMR(300MHz,DMSO-d6):δ7.86–7.79(m,2H),7.44–7.23(m,9H),7.23–6.92(m,4H),6.81(d,J＝7.6Hz,1H),5.08(s,4H),3.89–3.72(m,5H),3.54(s,4H),2.11-1.84(m,2H),1.31(s,9H)ppm.HRMS(ESI):m/z[M+H]+.C41H42N3O5计算值656.3119；实测值656.3137。
实施例24：化合物L-24
步骤1：将5-甲基水杨醛(2.0g,14.64mmol)溶解于30mL丙酮，依次加入碳酸钾(4.06g,29.38mmol)，溴丙炔(2.62g,22.03mmol)，搅拌，加热至回流，反应2h。TLC确认反应完全，冷却至室温，抽滤，滤饼用丙酮洗涤，滤液旋干。旋干后固体用适量异丙醚打浆，得淡黄色固体(2.12g，82.85％)1H NMR(300MHz,Chloroform-d)δ10.07(s,1H),7.77–7.70(m,1H),7.24–7.08(m,2H),5.06(s,2H),2.55(s,1H),2.39(s,3H)ppm。
步骤2：将碘苯(1.7g，8.61mmol)，三乙胺(4.36g，43.05mmol)，碘化亚铜(164mg，0.86mmol)，Pd(PPh3)4(498mg，0.43mmol)溶于15mL四氢呋喃中，氮气保护，升至60℃。将5-甲基-2-((丙基-2-炔-1-氧基)苯甲醛(1.5g,8.61mmol)溶于5mL四氢呋喃中，逐滴加入反应液，滴加完全后反应3小时，TLC确认反应完全，冷却至室温，将反应液倒入水中，乙酸乙酯萃取，使用饱和食盐水洗涤，无水硫酸钠干燥，减压除去溶液，通过硅胶柱层析(石油醚：乙酸乙酯＝50：1)分离得到淡黄色固体(1.73g，80.27％)1H NMR(300MHz,Chloroform-d)δ10.10(s,1H),7.74(d,J＝2.5Hz,1H),7.46–7.33(m,5H),7.24–7.08(m,2H),5.09(s,2H),2.45(s,3H)ppm。
步骤3：将(S)-4-氨基-2-((叔丁氧基羰基)氨基)丁酸(0.2g,0.92mmol)溶解于5mL甲醇中，加入5-甲基-2-((3-苯基丙-2-炔-1-基)氧基)苯甲醛(0.57g,2.29mmol)，室温搅拌30分钟。缓慢加入NaBH3CN(0.17g,2.75mmol)，室温搅拌12小时。TLC确认反应完全，溶剂旋干，加水，乙酸乙酯萃取，饱和食盐水溶液洗涤，无水硫酸钠干燥，有机层旋干，通过硅胶柱层析(二氯甲烷：甲醇＝20:1)纯化，得白色固体(0.2g,33.68％)。HRMS(ESI):m/z[M+H]+.C43H47N2O4计算值687.3429；实测值587.3456。
步骤4：将(S)-4-(双(5-甲基-2-((3-苯基丙-2-炔-1-基)氧)苄氨基)-2-((叔丁氧羰基)氨基)丁酸(0.2g，0.29mmol)溶于5mL 1,4-二氧六环中，然后加入4mol/L盐酸5mL，室温反应3小时，减压除去溶剂，通过柱层析纯化(二氯甲烷：甲醇＝10：1)得到白色固体(0.12g，70.24％)。1H NMR(300MHz,DMSO-d6)δ7.36(s,10H),7.29–7.20(m,4H),7.14(d,J＝8.2Hz,2H),5.05(s,4H),4.17(q,J＝13.5Hz,4H),3.21(s,1H),2.23(s,8H)ppm.HRMS(ESI):m/z[M+H]+.C38H39N2O4计算值587.2904；实测值587.2917。
实施例25-实施例31所述化合物的制备，可参考实施例14中所描述的方法和路线制备得到。
实施例25：化合物L-25
1H NMR(300MHz,DMSO-d6)δ7.34(s,10H),7.20(d,J＝9.0Hz,2H),7.07(d,J＝16.6Hz,4H),4.97(s,4H),3.64(s,4H),2.64(s,2H),2.11–1.77(m,2H)ppm.HRMS(ESI):m/z[M+H]+.C36H33Br2N2O4计算值715.0802；实测值715.0815。
实施例26：化合物L-26
1H NMR(300MHz,DMSO-d6)δ7.62(s,2H),7.55(dd,J＝8.8,2.5Hz,2H),7.34(s,10H),7.17(d,J＝8.9Hz,2H),5.06(s,4H),4.13(s,4H),3.88(s,1H),3.14(s,2H),2.28(s,2H)ppm.HRMS(ESI):m/z[M+H]+.C36H33F2N2O4计算值595.2403；实测值595.2426。
实施例27：化合物L-27
1H NMR(300MHz,DMSO-d6)δ7.43–7.34(m,10H),7.26(s,2H),7.15(dd,J＝7.6,1.9Hz,2H),6.81(d,J＝7.6Hz,2H),5.04(s,4H),3.79–3.67(m,5H),3.16-3.02(m,2H),1.93–1.81(m,2H),1.31(s,18H)ppm.HRMS(ESI):m/z[M+H]+.C44H51N2O4计算值671.3843；实测值671.3841。
实施例28：化合物L-28
1H NMR(300MHz,DMSO-d6)δ7.45–7.37(m,10H),6.86(d,J＝9.0Hz,2H),6.81–6.73(m,4H),5.01(s,4H),3.83–3.65(m,11H),3.13-3.03(s,2H),2.13–1.87(m,2H)ppm.HRMS(ESI):m/z[M+H]+.C38H39N2O6计算值619.2803；实测值619.2827。
实施例29：化合物L-29
1H NMR(300MHz,DMSO-d6)δ7.57–7.41(m,10H),7.32–7.16(m,2H),7.07(d,J＝1.8,2H),6.88(d,J＝7.9Hz,2H),4.98(s,4H),3.91-3.72(m,5H),3.55-3.43(m,2H),2.93–2.83(m,2H),2.13–1.82(m,2H),1.29(d,J＝6.6Hz,6H),1.24(d,J＝6.6Hz,6H)ppm.HRMS(ESI):m/z[M+H]+.C42H47N2O4计算值643.3530；实测值643.3503。
实施例30：化合物L-30
1H NMR(300MHz,DMSO-d6)δ7.72–7.59(m,4H),7.43–7.34(m,10H),7.00(d,J＝7.3Hz,2H),5.09(s,4H),4.03–3.87(m,5H),3.41-3.37(m,2H),2.10–1.84(m,2H)ppm.HRMS(ESI):m/z[M+H]+.C38H33F6N2O4计算值695.2339；实测值695.2348。
实施例31：化合物L-31
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1H NMR(300MHz,DMSO-d6)δ7.40-7.37(m,14H),7.12(d,J＝8.0Hz,2H),5.10(s,4H),3.80(s,4H),3.62(s,1H),2.87(s,2H),2.05–1.90(m,2H)ppm.HRMS(ESI):m/z[M+H]+.C36H33Br2N2O4计算值715.0802；实测值715.0817。
实施例32：化合物L-32
步骤1：将(S)-4-氨基-2-((叔丁氧羰基)氨基)丁酸(0.15g，0.68mmol)溶于5mL甲醇中，加入5-甲基-2-((3-苯基丙-2-炔-1-基)氧基)苯甲醛(0.21g，0.83mmol)，室温搅拌半小时，然后加入氰基硼氢化钠(65mg，1.03mmol)，继续室温搅拌6小时，减压除去溶剂。通过柱层析分离(二氯甲烷：甲醇＝20:1)得到白色固体(0.24g，77.02％)。HRMS(ESI):m/z[M+H]+.C26H33N2O5计算值453.2384；实测值453.2372。
步骤2：将(S)-2-((叔丁氧羰基)氨基)-4-((5-甲基-2-((3-苯基丙-2-炔-1-基)氧)苄氨基)丁酸(0.20g，0.44mmol)溶于8mL甲醇中，加入3-(3-(2-甲酰苯氧基)丙-1-炔-1-基)苯腈(0.14g，0.53mmol)，室温搅拌半小时，然后加入氰基硼氢化钠(42mg，0.66mmol)，在室温条件下搅拌12小时，减压除去溶剂，通过柱层析分离(二氯甲烷：甲醇＝30：1)得到白色固体(0.15g，48.64％)。HRMS(ESI):m/z[M+H]+.C43H44N3O6计算值698.3325；实测值698.3346。
步骤3：将(S)-2-((叔丁氧羰基)氨基)-4-((2-((3-(3-氰基苯基)丙-2-炔-1-基)氧基)苄基)(5-甲基-2-((3-苯基丙-2-炔-1)氧基)苄基)氨基)丁酸(0.12g,0.17mmol)溶于3mL 1,4-二氧六环中，然后加入4mol/L盐酸5mL，室温反应4h，减压除去溶剂，通过柱层析纯化(二氯甲烷：甲醇＝10：1)得到白色固体(65mg，63.24％)。1H NMR(300MHz,DMSO-d6)δ7.90–7.73(m,2H),7.61-7.56(m,1H),7.49(t,J＝5.7Hz,1H),7.43–7.34(m,5H),7.26(s,1H),7.23–6.89(m,5H),6.75(d,J＝8.8Hz,1H),5.01(s,4H),3.86–3.73(m,5H),3.16–3.07(m,2H),2.27(s,3H),2.12-1.93(m,2H)ppm.HRMS(ESI):m/z[M+H]+.C38H36N3O4计算值598.2700；实测值598.2734。
实施例33所述化合物的制备，可参考实施例12中所描述的方法和路线制备得到。
实施例33：化合物L-33
1H NMR(300MHz,DMSO-d6)δ7.43–7.28(m,8H),7.23–7.16(m,2H),7.02(s,1H),6.97–6.89(m,2H),6.85(d,J＝8.8Hz,1H),6.81–6.75(m,2H),4.98(s,4H),3.89(s,4H),3.76–3.63(m,1H),3.13-3.07(m,2H),2.29–1.83(m,5H)ppm.HRMS(ESI):m/z[M+H]+.C37H37N2O5计算值589.2697；实测值589.2697。
实施例34：化合物L-34
步骤1：将[1,1'-联苯]-3-甲醛(0.19g,1.03mmol)，(S)-2-((叔丁氧基羰基)氨基)-4-((2-((3-苯基丙-2-炔-1-基)氧基)苄基)氨基)丁酸(0.3g,0.68mmol)溶于5mL甲醇，室温搅拌1小时，加入氰基硼氢化钠(0.11g,1.71mmol)，室温搅拌8小时，TLC确认反应完全，减压除去溶剂。通过柱层析分离(二氯甲烷：甲醇＝20:1)得到白色固体(0.21g，50.76％)。HRMS(ESI):m/z[M+H]+.C38H41N2O5计算值605.3010；实测值605.3015。
步骤2：(S)-4-(([1,1'-联苯]-3-基甲基)(2-((3-苯基丙-2-炔-1-基)氧基)苄基)氨基)-2-((叔丁氧羰基)氨基)丁酸(0.2g,0.33mmol)溶于5mL二氧六环中，加入5mL4N HCl溶液，室温搅拌3小时，TLC确认反应完全，减压除去溶剂，通过柱层析纯化(二氯甲烷：甲醇＝10：1)得到白色固体(130mg，77.90％)。1H NMR(300MHz,DMSO-d6)δ7.61–7.55(m,3H),7.50(s,1H),7.47–7.41(m,3H),7.41–7.35(m,6H),7.32–7.26(m,2H),7.19(td,J＝7.7,1.5Hz,1H),6.97–6.89(m,2H),4.97(s,2H),4.10–4.03(m,4H),3.51(s,1H),2.79-2.69(m,2H),2.01-1.87(m,2H)ppm.HRMS(ESI):m/z[M+H]+.C33H33N2O3计算值505.2486；实测值505.2465。
实施例35：化合物L-35
步骤1：将2-氯苯并[d]恶唑(1g,6.51mmol)，碳酸钾(1.8g,13.02mmol)，3-甲酰基苯硼酸(1.17g,7.81mmol)，Pd(PPh3)2Cl2(200mg,0.65mmol)，加入5mL二氧六环与0.5mL水中，升温至100℃反应3小时。TLC确认反应完全，冷却至室温，抽滤，滤液旋干后加水，利用乙酸乙酯萃取，有机层饱和食盐水洗涤，无水硫酸钠干燥，有机层旋干，粗残余通过硅胶柱层析(环己烷:乙酸乙酯＝50:1)提纯，得到白色固体(163mg,40％)。
步骤2：将3-(苯并[d]恶唑-2-基)苯甲醛(0.23g,1.03mmol)，(S)-2-((叔丁氧基羰基)氨基)-4-((2-((3-苯基丙-2-炔-1-基)氧基)苄基)氨基)丁酸(0.3g,0.68mmol)溶于5mL甲醇，室温搅拌1小时，加入氰基硼氢化钠(0.11g,1.71mmol)，室温搅拌8小时，TLC确认反应完全，减压除去溶剂。通过柱层析分离(二氯甲烷：甲醇＝20:1)得到白色固体(0.21g，47.54％)。HRMS(ESI):m/z[M+H]+.C39H40N3O6计算值646.2912；实测值646.2937。
步骤3：(S)-4-((3-(苯并[d]恶唑-2-基)苄基)(2-((3-苯基丙-2-炔-1-基)氧基)苄基)氨基)-2-((叔丁氧羰基)氨基)丁酸(0.2g,0.31mmol)溶于5mL二氧六环中，加入5mL4N HCl溶液，室温搅拌3小时，TLC确认反应完全，减压除去溶剂，通过柱层析纯化(二氯甲烷：甲醇＝10：1)得到白色固体(130mg，76.93％)。1H NMR(300MHz,DMSO-d6)δ8.45(s,1H),8.28(d,J＝7.8Hz,1H),7.89-7.69(m,4H),7.51(q,J＝6.7,5.3Hz,4H),7.33–7.18(m,6H),5.04(s,2H),4.67–4.49(m,2H),4.46–4.31(m,2H),3.98(s,1H),3.40(s,2H),2.45(s,2H)ppm.HRMS(ESI):m/z[M+H]+.C34H32N3O4计算值546.2387；实测值546.2381。
实施例36所述化合物的制备，可参考实施例14中所描述的方法和路线制备得到。
实施例36：化合物L-36
1H NMR(300MHz,DMSO-d6)δ8.57(s,1H),8.23(d,J＝7.7Hz,1H),7.91-7.69(m,4H),7.64-7.51(m,4H),7.33–7.18(m,6H),5.07(s,2H),4.63–4.44(m,2H),4.46–4.31(m,2H),3.89(s,1H),3.40(s,2H),2.43-2.24(m,5H)ppm.HRMS(ESI):m/z[M+H]+.C35H34N3O4计算值560.2544；实测值560.2529。
实施例37：化合物L-37
步骤1：将水杨酸甲酯(1g,6.57mmol)溶于30mL四氢呋喃中，加入碳酸钾(1.82g,13.15mmol)与溴丙炔(0.94g,7.89mmol)，升温至60℃搅拌8小时。TLC确认反应完全，冷却至室温，抽滤后滤液旋干，残余物通过硅胶柱层析(石油醚：乙酸乙酯＝50：1)分离得到无色油(1g,80％)。HRMS(ESI):m/z[M+Na]+.C11H10NaO3计算值213.0522；实测值213.0546。
步骤2：将2-(丙-2-炔-1-氧基)苯甲酸甲酯(1g,5.26mmol)，碘苯(0.98g，4.78mmol)，三乙胺(2.42g，23.90mmol)，碘化亚铜(91mg，0.48mmol)，Pd(PPh3)4(276mg，0.24mmol)溶于15mL四氢呋喃中，氮气保护，升至60℃，反应3小时，TLC确认反应完全，冷却至室温，将反应液倒入水中，乙酸乙酯萃取，使用饱和食盐水洗涤，无水硫酸钠干燥，减压除去溶液，通过硅胶柱层析(石油醚：乙酸乙酯＝50：1)分离得到淡黄色固体(0.81g，63.64％)。
步骤3：将2-((3-苯基丙-2-炔-1-基)氧基)苯甲酸甲酯(0.8g,3.00mmol)溶于四氢呋喃，滴加1N氢氧化锂溶液，室温反应8小时，TLC确认反应完全，真空浓缩反应液，向残余物中加水，利用1N HCl溶液调节pH＝5，抽滤得白色固体(0.7g,92.37％)。
步骤4：将2-((3-苯基丙-2-炔-1-基)氧基)苯甲酸(0.17g,0.68mmol)溶于8mLDMF中，加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(0.39g,1.03mmol)，二异丙基乙胺(0.27g,2.05mmol)，室温搅拌半小时。然后加入(S)-2-((叔丁氧基羰基)氨基)-4-((2-((3-苯基丙-2-炔-1-基)氧基)苄基)氨基)丁酸(0.3g,0.68mmol)，在室温条件下搅拌12小时，加水，EA萃取，饱和食盐水洗涤，无水硫酸钠干燥，通过柱层析分离(二氯甲烷：甲醇＝30：1)得到白色固体(0.31g，67.37％)。HRMS(ESI):m/z[M+H]+.C41H40N2O7计算值673.2908；实测值673.2947。
步骤5：将(S)-2-((叔丁氧羰基)氨基)-4-(2-((3-苯基丙-2-炔-1-基)氧)-N-(2-((3-苯基丙-2-炔-1-基)氧)苯甲酰胺)丁酸(0.3g,0.45mmol)溶于5mL二氧六环，加入5mL4N HCl溶液，室温搅拌6小时，TLC确认反应完全，减压除去溶剂，通过柱层析分离(二氯甲烷：甲醇＝10：1)得白色固体(0.2g,78.32％)。1H NMR(300MHz,DMSO-d6)δ7.75(s,1H),7.48–7.41(m,1H),7.41–7.34(m,10H),7.30-7.19(m,2H),7.14–6.97(m,4H),5.23(s,4H),4.61-4.55(m,2H),3.73(t,J＝6.6,1H),3.48–3.38(m,2H),2.33(s,2H)ppm.HRMS(ESI):m/z[M+H]+.C41H40N2O7计算值573.2384；实测值573.2326。
实施例38-实施例40所述化合物的制备，可参考实施例14中所描述的方法和路线制备得到。
实施例38：化合物L-38
1H NMR(300MHz,DMSO-d6)δ8.01(t,J＝2.0Hz,1H),7.91(s,1H),7.88(d,J＝7.1Hz,1H),7.87–7.24(m,12H),7.14–7.07(m,2H),7.07–6.94(m,2H),5.15(s,4H),4.56-4.48(m,2H),3.89(s,1H),3.58–3.48(m,2H),2.10–1.85(m,5H)ppm.HRMS(ESI):m/z[M+H]+.C24H27N2O4计算值407.1965；实测值407.1954。
实施例39：化合物L-39
1H NMR(300MHz,DMSO-d6)δ8.10(d,J＝7.9Hz,1H),7.83-7.73(m,3H),7.55–7.39(m,9H),7.21(s,1H),7.19–7.15(m,1H),7.08–7.01(m,2H),6.87(d,J＝8.9Hz,1H),5.22(s,2H),4.85(s,2H),3.73(s,1H),3.48–3.38(m,2H),2.45–2.24(m,5H),2.17(s,3H)ppm.HRMS(ESI):m/z[M+H]+.C31H29N2O4计算值493.2122；实测值493.2153。
实施例40：化合物L-40
1H NMR(300MHz,DMSO-d6)δ7.59–7.44(m,12H),7.34–7.27(m,2H),7.17(td,J＝7.7,1.1Hz,2H),7.04–6.94(m,2H),4.96(s,1H),5.03(s,4H),3.77(s,1H),3.50–3.41(m,2H),2.42–2.31(m,2H),1.48(d,J＝6.5Hz,3H)ppm.HRMS(ESI):m/z[M+H]+.C37H35N2O5计算值587.2540；实测值587.2529。
实施例41：化合物L-41
步骤1：将2-氨基苯甲醛(1.0g,8.25mmol)溶于四氢呋喃中，加入三乙胺(1.67g,16.51mmol)，降温至0℃，滴加苯甲酰氯(1.16g,8.25mmol)，滴加完成后移至室温反应3小时，TLC确认反应完全，抽滤后滤液旋干，残余物利用正己烷洗涤，抽滤得白色固体(1.3g,69.91％)。HRMS(ESI):m/z[M+H]+.C14H12NO2计算值226.0863；实测值226.0837。
步骤2：将N-(2-甲酰基苯基)苯甲酰胺(0.31g,1.37mmol)，(S)-2-((叔丁氧羰基)氨基)-4-((2-((3-苯基丙-2-炔-1-基)氧)苄氨基)丁酸(0.3g,0.68mmol)溶于甲醇，室温搅拌1小时，加入氰基硼氢化钠(0.13g,2.05mmol)，TLC确认反应完全，减压除去溶剂，通过柱层析分离(二氯甲烷：甲醇＝20：1)得白色固体(0.2g,45.13％)。HRMS(ESI):m/z[M+H]+.C39H42N3O6计算值648.3068；实测值648.3042。
步骤3：将(S)-4-((2-苯甲酰胺基)(2-((3-苯基丙-2-炔-1-基)氧)苄基)氨基)-2-((叔丁氧羰基)氨基)丁酸(0.15g,0.23mmol)溶于3mL二氧六环，加入3mL 4N HCl溶液，室温搅拌3小时，TLC确认反应完全，减压除去溶剂，通过柱层析分离(二氯甲烷：甲醇＝10：1)得白色固体(0.2g,78.32％)。1H NMR(300MHz,DMSO-d6)δ9.40(s,1H),7.95(dt,J＝8.0,1.2Hz,2H),7.67–7.60(m,2H),7.50–7.43(m,2H),7.43–7.18(m,9H),7.11-6.98(m,3H),5.10(s,2H),4.35-4.29(m,4H),3.71–3.68(m,1H),3.54(s,2H),2.21-2.04(m,2H)ppm.HRMS(ESI):m/z[M+H]+.C34H34N3O4计算值548.2544；实测值548.2561。
实施例42-实施例48所述化合物的制备，可参考实施例14中所描述的方法和路线制备得到。
实施例42：化合物L-42
1H NMR(300MHz,DMSO-d6)δ9.45(s,1H),8.24–8.16(m,2H),7.73–7.65(m,2H),7.55(d,J＝8.3,1H),7.43–7.34(m,5H),7.29–7.16(m,4H),7.11-6.95(m,3H),5.10(s,2H),4.35-4.28(m,4H),3.75(s,1H),3.56(s,2H),2.20-2.08(m,2H)ppm.HRMS(ESI):m/z[M+H]+.C35H33F3N3O4计算值616.2418；实测值616.2435。
实施例43：化合物L-43
1H NMR(300MHz,DMSO-d6)δ9.37(s,1H),7.98–7.92(m,2H),7.55(s,1H),7.43–7.34(m,5H),7.29–7.16(m,4H),7.11(dd,J＝8.3,7.3,1H),7.01–6.97(m,2H),6.97–6.89(m,2H),5.09(s,2H),4.01-3.96(m,4H),3.83(s,4H),3.49(s,2H),2.19-2.03(m,2H)ppm.HRMS(ESI):m/z[M+H]+.C35H36N3O5计算值578.2649；实测值578.2638。
实施例44：化合物L-44
1H NMR(300MHz,DMSO-d6)δ9.46(s,1H),8.35(t,J＝1.3Hz,1H),8.05–7.96(m,2H),7.94–7.86(m,2H),7.61–7.51(m,3H),7.43–7.34(m,5H),7.29–7.16(m,4H),7.05–6.89(m,2H),5.09(s,3H),4.38-4.29(m,4H),3.87(s,1H),3.68–3.57(m,2H),2.13-2.01(m,2H)ppm.HRMS(ESI):m/z[M+H]+.C38H36N3O4计算值598.2700；实测值598.2741。
实施例45：化合物L-45
1H NMR(300MHz,DMSO-d6)δ9.40(s,1H),7.95(dt,J＝8.0,1.2Hz,2H),7.67–7.46(m,4H),7.29–7.16(m,4H),7.11(s,1H),7.01(d,J＝2.1Hz,2H),6.97–6.89(m,3H),5.19(s,2H),4.10-3.98(m,4H),3.87(s,1H),3.56(s,2H),2.38–2.12(m,8H)ppm.HRMS(ESI):m/z[M+H]+.C36H38N3O4计算值576.2857；实测值576.2841。
实施例46：化合物L-46
1H NMR(300MHz,DMSO-d6)δ9.39(s,1H),7.95(dt,J＝8.0,1.2Hz,2H),7.57–7.31(m,9H),7.27–7.21(m,2H),7.18(dt,J＝1.9,1.0Hz,1H),7.11(s,1H),7.05–6.99(m,2H),5.09(s,2H),3.79–3.65(m,5H),3.15–3.07(m,2H),2.29–1.97(m,5H)ppm.HRMS(ESI):m/z[M+H]+.C35H36N3O4计算值562.2700；实测值562.2754。
实施例47：化合物L-47
1H NMR(300MHz,DMSO-d6)δ9.45(s,1H),7.95(dt,J＝8.0,1.2Hz,2H),7.57–7.47(m,4H),7.43–7.34(m,5H),7.28–7.14(m,4H),7.07(s,1H),6.81(d,J＝7.6Hz,1H),5.17(s,2H),4.32-4.12(m,4H),3.84(s,1H),3.19(s,1H),2.27–2.14(m,2H),1.31(s,9H)ppm.HRMS(ESI):m/z[M+H]+.C38H42N3O4计算值604.3170；实测值604.3175。
实施例48：实施例L-48
1H NMR(300MHz,DMSO-d6)δ9.35(s,1H),7.88–7.82(m,2H),7.45–7.38(m,2H),7.30(s,3H),7.18(dt,J＝2.0,0.9Hz,1H),7.10–6.99(m,3H),6.92–6.87(m,2H),6.85(d,J＝8.8Hz,1H),5.13(s,2H),4.10-4.03(m,4H),3.83(s,3H),3.76(s,1H),3.45–3.41(m,2H),2.32–1.89(m,8H)ppm.HRMS(ESI):m/z[M+H]+.C38H42N3O5计算值620.3119；实测值620.3146。
实施例49：实施例L-49
步骤1：将2-氨基苯甲醛(1.0g,8.25mmol)溶于四氢呋喃中，加入三乙胺(1.67g,16.51mmol)，降温至0℃，滴加苯磺酰氯(1.46g,8.25mmol)，滴加完成后移至室温反应3小时，TLC确认反应完全，抽滤后滤液旋干，残余物利用正己烷洗涤，抽滤得白色固体(1.5g,69.54％)。HRMS(ESI):m/z[M+H]+.C13H12NO3S计算值262.0532；实测值262.0516。
步骤2：将N-(2-甲酰基苯基)苯甲酰胺(0.36g,1.37mmol)，(S)-2-((叔丁氧羰基)氨基)-4-((2-((3-苯基丙-2-炔-1-基)氧)苄氨基)丁酸(0.3g,0.68mmol)溶于甲醇，室温搅拌1小时，加入氰基硼氢化钠(0.13g,2.05mmol)，TLC确认反应完全，减压除去溶剂，通过柱层析分离(二氯甲烷：甲醇＝20：1)得白色固体(0.2g,42.75％)。HRMS(ESI):m/z[M+H]+.C38H42N3O7S计算值684.2738；实测值684.2761。
步骤3：(S)-2-((叔丁氧羰基)氨基)-4-((2-((3-苯基丙-2-炔-1-基)氧)苄基)(2-(苯磺酰胺)苄基)氨基)丁酸(0.13g,0.19mmol)溶于3mL二氧六环，加入3mL 4N HCl溶液，室温搅拌3小时，TLC确认反应完全，减压除去溶剂，通过柱层析分离(二氯甲烷：甲醇＝10：1)得白色固体(60mg,46.15％)。1H NMR(300MHz,DMSO-d6)δ8.90(s,1H),7.81–7.73(m,3H),7.48–7.34(m,7H),7.32(d,J＝7.9,1H),7.29–7.14(m,4H),7.00(s,1H),6.97–6.89(m,2H),5.12(s,2H),4.01-3.96(m,4H),3.78–3.73(m,1H),3.68(s,2H),2.31-2.07(m,2H)ppm.HRMS(ESI):m/z[M+H]+.C33H34N3O5S计算值584.2214；实测值584.2231。
实施例50-实施例52所述化合物的制备，可参考实施例14中所描述的方法和路线制备得到。
实施例50：实施例L-50
1H NMR(300MHz,DMSO-d6)δ8.76(s,1H),7.90–7.81(m,3H),7.58–7.41(m,7H),7.19–7.04(m,4H),6.98(d,J＝7.6Hz,1H),6.85(s,1H),5.09(s,2H),4.01-3.96(s,2H),3.76–3.71(m,1H),3.54–3.47(m,2H),2.32–2.11(m,8H)ppm.HRMS(ESI):m/z[M+H]+.C35H38N3O5S计算值612.2527；实测值612.2546。
实施例51：实施例L-51
1H NMR(300MHz,DMSO-d6)δ9.50(s,1H),7.49(dd,J＝8.2,1.9Hz,2H),7.43–7.34(m,5H),7.18(dd,J＝2.0,0.9Hz,1H),7.10–6.95(m,5H),6.85(d,J＝8.8Hz,1H),5.16(s,2H),3.89–3.77(m,4H),3.71(s,1H),3.23–3.19(m,2H),2.27-1.96(m,8H)ppm.HRMS(ESI):m/z[M+H]+.C35H36F2N3O5S计算值648.2338；实测值618.2353。
实施例52：实施例L-52
1H NMR(300MHz,DMSO-d6)δ9.14(s,1H),8.43(t,J＝1.9Hz,1H),8.09(d,J＝8.9Hz,1H),8.01(dt,J＝8.3,1.8Hz,1H),7.96–7.85(m,2H),7.57–7.48(m,2H),7.43–7.34(m,5H),7.18(d,J＝1.9Hz,1H),7.06–7.00(m,3H),6.98(d,J＝7.6Hz,1H),6.85(d,J＝8.8Hz,1H),5.09(s,2H),3.98–3.68(m,5H),3.23–3.12(s,2H),2.32–2.02(m,8H)ppm.HRMS(ESI):m/z[M+H]+.C39H40N3O5S计算值662.2683；实测值662.2647。
实施例53：化合物体外活性实验
1、抗肿瘤细胞增殖实验
A549细胞(3000/well)接种于96孔板中，37℃，5％CO2培养12h后，细胞给予不同浓度的化合物，继续培养72h。每孔加入20μL MTT，37℃，5％CO2孵育4h，弃去培养基，加入150μL溶解甲瓒结晶，490nm波长检测吸光度。/2、谷氨酰胺转运实验
(1)细胞培养
(2)铺板：24孔板50000/well，37℃，5％CO2培养24h；
(3)洗细胞板：待细胞长满后，从培养箱中取出24孔板，弃尽板中的培养基，用37℃预热的Assay buffer清洗3遍；
(4)加入250μL不同浓度的抑制剂溶液(10mM化合物母液用Assay buffer稀释成100μM、50μM、20μM、10μM、5μM、2μM、1μM)，37℃预温孵15分钟，弃掉化合物溶液，再次加入250μL(用含5μM 13C5-Glutamine的Assay buffer稀释)，37℃水浴15分钟。孵育结束后，吸出液体，用Assay buffer洗涤细胞三次。加入250μL超纯水。于-80℃反复冻融三次，将细胞刮出至1.5mL EP管中，超声15min。超声破碎后的细胞样品，取30μL加入1.5mL EP管中，加入30μL稀释液，60μL内标溶液，涡旋振荡3min；4℃，12000rpm，离心10min。取60μL上清液到进样小瓶中，LC-MS检测13C5-Glutamine浓度。
3、数据分析
(1)抗肿瘤细胞增殖实验计算公式
％Inhibition＝[1-(OD_sample-OD_min)]/(OD_max-OD_min)
其中：OD_sample表示给药孔吸光度，OD_min表示空白孔吸光度，OD_max表示阴性孔吸光度。
(2)谷氨酰胺转运实验计算公式
％Inhibition＝[1-(A_sample/A_max)]
其中:A_sample表示样品中13C5-Glutamine含量，A_max表示空中13C5-Glutamine含量。
(3)拟合量效曲线以浓度的log值作为X轴，百分比抑制率为Y轴，采用分析软件GraphPad Prism5的log(inhibitor)vs.response-Variable slope拟合量效曲线，从而得出各个化合物对酶活性的IC50值。
计算公式：
Y＝Bottom+(Top-Bottom)/(1+10^((Log IC50-X)×Hill Slope))。
IC50数据具体见表1。
表1.化合物体外活性(IC50)
注：A：1-10μM，B：10-50μM，C：＞50μM。
如表1所示，所有测试化合物对A549肿瘤细胞增殖及谷氨酰胺转运酶均有抑制作用，其中化合物L-1、L-3、L-6、L-17～L-18、L-25的转运酶的IC50值均小于10μM，化合物L-25～L-26、L-30的抗肿瘤活性IC50值均小于10μM，其余化合物的IC50值也在微摩尔浓度水平。
Claims (10)
1.一种谷氨酰胺转运抑制剂，其特征在于，具有式I的结构，所述化合物还包含其异构体、药学上可接受的盐或它们的混合物：
其中：
X、Q为
Ra为氢或甲基，或者多个Ra与所连接的碳原子成环；
R1为氢、卤素、氰基、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基或C1-C4卤代烷氧基；
R2为1-4个氢被R2a取代的6-10元芳基或5-10元杂芳基；
R2a为氢、卤素、氰基、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基或C1-C4卤代烷氧基；
R3为卤素、氰基、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基、C1-C4卤代烷氧基、1-4个氢被R3b取代的6-10元芳基或5-10元杂芳基，或者R3a-L1-；
R3a-L1-为R3a-[C(RbRc)]0-5-、R3a-[C(RbRc)]0-2-O-[C(RbRc)]0-2-、R3a-C≡C-[C(RbRc)]1-2-O-、R3a-C＝C-[C(RbRc)]1-2-O-、R3a-[C(RbRc)]0-2-C(O)-[C(RbRc)]0-2-、R3a-[C(RbRc)]0-2-C(O)NH-[C(RbRc)]0-2-、R3a-[C(RbRc)]0-2-NHC(O)-[C(RbRc)]0-2-、R3a-[C(RbRc)]0-2-S(O)2-[C(RbRc)]0-2-、R3a-[C(RbRc)]0-2-NHS(O)2-[C(RbRc)]0-2-或R3a-[C(RbRc)]0-2-S(O)2NH-[C(RbRc)]0-2-；
R3a为1-4个氢被R3c取代的6-10元芳基或5-10元杂芳基；
R3b、R3c为氢、卤素、氰基、羟基、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基或C1-C4卤代烷氧基；
Rb、Rc为氢、卤素、C1-C3烷基或C3-C6环烷基，或者Rb、Rc与所连接的碳原子形成环丙基；
m为0、1、2、3或4；
n为0、1、2、3或4；
z为0、1或2；
所述5-10元杂芳基中的杂原子为N、O或S，杂原子的个数为1、2、3或4个。
2.根据权利要求1所述的抑制剂，其特征在于，所述结构中：
X、Q为
Ra为氢或甲基，或者两个Ra与所连接的碳原子形成
R1为氢、氟、溴、碘、甲基、异丙基、叔丁基、三氟甲基或甲氧基；
R2为1-4个氢被R2a取代的苯基、萘基或吡啶基；
R2a为氢、氟、氰基、甲基、异丙基、叔丁基、三氟甲基、甲氧基、乙氧基或异丙氧基；
R3为氯、溴、碘、甲基、异丙基、叔丁基、C1-C4氟代烷基、甲氧基、R3a-CH2O-、R3a-C≡C-CH2O-、R3a-C(O)NH-或R3a-S(O)2NH-，或者1-4个氢被氢、氟、氯、溴、C1-C4氟代烷基、甲氧基取代的苯基、萘基、苯并噁唑基或苯并噻唑基；
R3a为1-4个氢被R3c取代的苯基、萘基、吡啶基、苯并噁唑基或苯并噻唑基；
R3c为氢、氟、氯、氰基、羟基、甲基、乙基、异丙基、三氟甲基、甲氧基、乙氧基或异丙氧基；
z为0、1或2。
3.根据权利要求1所述的抑制剂，其特征在于，所述结构中：
X为-C(O)-；
Q为Ra为氢或甲基；
R1为溴、碘、甲基、异丙基、叔丁基、C1-C4氟代烷基或甲氧基；
R2为1-4个氢被R2a取代的苯基或萘基；
R2a为氢、氟、甲基、异丙基、叔丁基、C1-C4氟代烷基、甲氧基、乙氧基或异丙氧基；
R3为溴、碘、甲基、异丙基、叔丁基、C1-C4氟代烷基、甲氧基、R3a-CH2O-或R3a-C≡C-OCH2-，或者1-4个氢被氢、氟、溴、C1-C4氟代烷基、甲氧基取代的苯基或萘基；
R3a为1-4个氢被R3c取代的苯基或萘基；
R3c为氢、氟、氯、氰基、羟基、甲基、乙基、异丙基、C1-C4氟代烷基、甲氧基、乙氧基或异丙氧基；
z为0、1或2。
4.根据权利要求1所述的抑制剂，其特征在于，所述结构中：
X、Q为
Ra为氢或甲基；
R1为溴、碘、甲基、异丙基、叔丁基、C1-C4氟代烷基或甲氧基；
R2为1-4个氢被R2a取代的苯基或萘基；
R2a为氢、氟、甲基、异丙基、叔丁基、C1-C4氟代烷基、甲氧基、乙氧基或异丙氧基；
R3为溴、碘、甲基、异丙基、三氟甲基、甲氧基或R3a-C≡C-CH2O-，或者1-4个氢被氢、氟、溴、C1-C4氟代烷基或甲氧基取代的萘基；
R3a为1-4个氢被R3c取代的苯基、萘基、吡啶基、苯并噁唑基或苯并噻唑基；
R3c为氢、氟、氯、氰基、甲基、乙基、异丙基、C1-C4氟代烷基、甲氧基、乙氧基或异丙氧基；
z为0或1。
5.根据权利要求1所述的抑制剂，其特征在于，具有以下任一通式结构：
其中，k、y为0、1、2、3或4；R1、R2a、R3、R3a、m、n的定义如权利要求1-4任一所述。
6.根据权利要求1所述的抑制剂，其特征在于，选自以下任一化合物：
7.根据权利要求1-6任一所述的抑制剂，其特征在于，所述药学上可接受的盐为所述化合物与酸或碱形成的盐，所述酸为盐酸、氢溴酸、硫酸、磷酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸、琥珀酸、富马酸、水杨酸、苯基乙酸或杏仁酸，所述碱为含有碱性金属阳离子、碱土金属阳离子或铵阳离子盐的无机碱。
8.一种药物组合物，其特征在于，所述药物组合物包含权利要求1-7任一所述抑制剂以及药学上可接受的载体。
9.一种权利要求1-7任一所述的抑制剂或者权利要求8所述的药物组合物在制备治疗与Na+依赖性谷氨酰胺载体2相关疾病的药物中的应用。
10.根据权利要9所述的应用，其特征在于，所述与Na+依赖性谷氨酰胺载体2相关疾病为癌症或病毒性感染。
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