CN111848641A - 4-苯氧基噻吩[3,2-d]嘧啶并α-酰胺基硫代酰胺类化合物及其制备方法和用途 - Google Patents
4-苯氧基噻吩[3,2-d]嘧啶并α-酰胺基硫代酰胺类化合物及其制备方法和用途 Download PDFInfo
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Abstract
本发明涉及4‑苯氧基噻吩[3,2‑d]嘧啶并α‑酰胺基硫代酰胺类化合物I，该4‑苯氧基噻吩[3,2‑d]嘧啶并α‑酰胺基硫代酰胺类化合物I作为酪氨酸激酶抑制剂，特别是c‑Met抑制剂。本发明还涉及该类化合物的制备方法；本发明更涉及含4‑苯氧基噻吩[3,2‑d]嘧啶并α‑酰胺基硫代酰胺类化合物I作为药物用以治疗与酪氨酸激酶c‑Met相关的疾病，特别是c‑Met相关的癌症的用途。
Description
技术领域
本发明涉及一种4-苯氧基噻吩[3,2-d]嘧啶并α-酰胺基硫代酰胺类化合物，其中间体、制备方法及其作为药物用以治疗与酪氨酸激酶c-Met相关的疾病，特别是c-Met相关的癌症的用途。
背景技术
蛋白激酶（PKs）指催化蛋白质磷酸化过程的酶。蛋白质的磷酸化过程是神经信息在细胞内传递的最后环节，可致离子通道蛋白及通道门控电压的状态变化，继而介导包括细胞生长、分化和增殖，器官的形成，新血管的生成，组织的修复与再生等多种生理过程。除在正常组织/器官发挥重要功能外，异常的蛋白激酶在包括恶性肿瘤在内的许多疾病发挥着更特殊的作用。蛋白激酶的亚群（致癌蛋白激酶）在失调时可导致肿瘤的形成和生长，且进一步引起肿瘤的恶化。
受体酪氨酸激酶c-Met是met原癌基因编码的一类多效性的细胞活素，为肝细胞生长因子（HGF）目前唯一已知的受体，属于Ron亚族，其四级结构为50 kDa的α亚基和145 kDa的β亚基通过二硫键相连而成的异二聚体，分为胞外域和胞内域。胞外域包含有3个功能不同的结构域：覆盖整个α链和部分β链的N-端配体结合域（SEMA区域）；4个保守二硫键的胱氨酸富集区域；免疫球蛋白样结构域，胞内域同样由3个调控区域组成：Tyr1003磷酸化位点的近膜结构域；Tyr1234和Tyr1235磷酸化位点的酪氨酸激酶催化结构域；Tyr1349和Tyr1356结合酪氨酸的C-端多功能结合区域。c-Met在正常细胞与肿瘤细胞中均有表达，生理条件下HGF/c-Met可促进胚胎和胎盘的发育，调节肺、肾和乳腺等器官的发育和结构的形成，还可促进神经系统和肌肉的发育。然而c-Met的异常活化则与多种人实体癌的发生发展密切有关，如甲状腺癌、肺癌、胃癌、结直肠癌、胰腺癌、肾癌等。大量临床证据表明c-Met的过表达和c-met的扩增与肿瘤的分期和预后不良密切相关。此外，不同于其它激酶，c-Met与细胞表面其他肿瘤因子也存在交联作用，例如整合素家族、其它受体酪氨酸激酶等，进而激活并放大肿瘤相关效应，极大的促进了肿瘤的形成及发展，其中c-Met起到了枢纽作用，抑制c-Met即可抑制多个肿瘤通路。另有研究表明：临床应用的EGFR受体酪氨酸激酶抑制剂获得性耐药正是由于MET基因扩增激活ERBB3信号传导通路而引起的。体外试验得出，阻断c-Met信号后，易瑞沙可以恢复疗效。因此，c-Met抑制剂与EGFR抑制剂的联合用药能够减缓EGFR-TKIs获得性耐药的产生，延长其临床周期，具有重要的临床意义。
综上，抑制c-Met信号通路已成为肿瘤治疗的重要策略，尤其是针对c-Met催化区域的小分子抑制剂目前已成为研究热点。目前已有基于c-Met为靶点的小分子药物上市，如：Cabozantinib、Crizotinib、Capmatinib及Tepotinib。此外，还有许多能够有效阻断c-Met信号传导途径的化合物正在进行相关的临床前或临床研究，如Exelixis公司的XL-184、XL-180，Pfizer公司的PF-4217903，MethylGene公司的MGCD-265，Johnson&Johnson的JNJ-38877605等。故在c-Met受体活化起到关键作用的原发型或继发型肿瘤中，靶向HGF/c-Met的物质尤其是c-Met靶向的小分子抑制剂被寄予了厚望。
本发明涉及作为酪氨酸激酶抑制剂的N-4-酰氧基苯基酰胺类化合物及一种（2H-四唑-5-基）丙基苯胺类化合物，尤其是c-Met抑制剂，未见诸报道。
发明内容
本发明所要解决的技术问题之一是提供一种4-苯氧基噻吩[3,2-d]嘧啶并α-酰胺基硫代酰胺类化合物。
本发明所要解决的技术问题之二是提供一种4-苯氧基噻吩[3,2-d]嘧啶并α-酰胺基硫代酰胺类化合物的制备方法。
本发明所要解决的技术问题之三是提供上述4-苯氧基噻吩[3,2-d]嘧啶并α-酰胺基硫代酰胺类化合物的应用。
作为本发明第一方面的4-苯氧基噻吩[3,2-d]嘧啶并α-酰胺基硫代酰胺类化合物，为具有如式I所示的化合物：
其中，R1选自氢、叔丁基、正丁基、环己基、苯基、3,4-二甲氧基苯基、4-氟苯基；R2选自苯基、4-氟苯基。
所述式I的4-苯氧基噻吩[3,2-d]嘧啶并α-酰胺基硫代酰胺为药学上可接受的衍生物。
本发明所述药学上可接受的盐为式I化合物的盐酸盐、硫酸盐、磷酸盐、三氟乙酸盐、甲磺酸盐、对甲苯磺酸盐、酒石酸盐、马来酸盐、琥珀酸盐。
作为本发明第二方面的关键中间体，为具有式II所示的化合物。其中，中间体II通过3-氨基-2- 噻吩甲酸甲酯依次经酰胺化、分子内关环、氯代，然后与3-氟-4-羟基苯胺偶联，进而与甲酸乙酯进 行酰胺化，最后在POCl3/TEA作用下脱水得到关键中间体II。
作为本发明第二方面的4-苯氧基噻吩[3,2-d]嘧啶并α-酰胺基硫代酰胺类化合物I的制备方法， 通过中间体II与醛、胺、硫代羧酸反应获得，具体反应式如下：
式中R1、R2的定义同权利要求1。
作为本发明第三方面的应用，其中是4-苯氧基噻吩[3,2-d]嘧啶并α-酰胺基硫代酰胺类化合物I在制备调节蛋白激酶催化活性制品中的应用。
作为本发明第三方面的应用，其中是4-苯氧基噻吩[3,2-d]嘧啶并α-酰胺基硫代酰胺类化合物I的药学可接受的衍生物在制备调节蛋白激酶催化活性制品中的应用。
作为本发明第三方面的应用，其中是4-苯氧基噻吩[3,2-d]嘧啶并α-酰胺基硫代酰胺类化合物I的可药用盐在制备调节蛋白激酶催化活性制品中的应用。
作为本发明第三方面的应用，其中是药物组合物在制备治疗与蛋白质激酶有关的疾病的药物中的应用。
所述蛋白激酶为c-Met受体酪氨酸激酶。
所述癌症选自肺癌、结肠癌、胃癌、乳腺癌。
本发明所涉及的4-苯氧基噻吩[3,2-d]嘧啶并α-酰胺基硫代酰胺类化合物I还可用于生物学或药理学现象、酪氨酸激酶参与的信号传导通路的研究，以及对于新型酪氨酸激酶抑制剂的评价。
本发明所涉及的4-苯氧基噻吩[3,2-d]嘧啶并α-酰胺基硫代酰胺类化合物I经体外抗肿瘤活性筛选结果表明，本发明所涉及的式I类化合物对人肺癌细胞、人结肠癌细胞、人胃癌细胞和人乳腺癌细胞均表现出较强的抑制活性。本发明所述的4-苯氧基噻吩[3,2-d]嘧啶并α-酰胺基硫代酰胺类化合物I结构新颖、合成工艺简单、产品纯度高，对肿瘤细胞表现出较强的抑制活性，具有优良的应用前景。
具体实施方式
应该指出，以下详细说明都是例示性的，旨在对本申请提供进一步的说明。除非另有指明，本文使用的所有技术和科学术语具有与本申请所属技术领域的普通技术人员通常理解的相同含义。
“药学上可接受的酸加成盐”指这样的盐，他们保留了游离碱的生物学效应和性质，不会在生物学或其他方面产生不良后果，可以为盐酸、硫酸、磷酸、三氟乙酸、甲磺酸、对甲苯磺酸、酒石酸、马来酸、琥珀酸，但不限于上述酸。
同时，尽管本发明的化合物的受保护的衍生物本身可能不具有药理学活性，但它们可以被给药至哺乳动物，然后在体内代谢而形成具有药理活性的化合物。此种衍生物被描述为“前药”。因此，本发明化合物的所有前药亦保括在本发明的范围内。
一、化合物的制备
实施例1：目标化合物Ia的合成
步骤1. 3-甲酰胺基噻吩-2-羧酸甲酯的合成，反应式如下：
将3-氨基-2-噻吩甲酸甲酯（2.04 g，13.0 mmol）在0 °C下缓慢加入到甲酸（8mL）和醋酸酐（12 mL）的混合溶液中，待添加完毕后，撤去冰浴升至室温，并在室温下反应12 h。随后将H2O（20 mL）加入到反应液中，有大量固体析出，过滤所得固体经硅胶柱层析纯化得目标产物（1.97 g, 82%）。M.p.: 125–127 °C. 1H NMR (400 MHz, DMSO-d 6) δ 10.36 (s, 1H), 8.44 (s, 1 H), 8.02 (d, J = 5.2 Hz, 1 H), 7.84 (d, J = 5.2 Hz, 1 H), 3.84(s, 3 H). 13C NMR (100 MHz, DMSO-d 6) δ 163.6, 160.5, 142.8, 133.4, 123.0,111.6, 52.3. ESI-MS: m/z 186.0 [M+H]+.
步骤2.3H-噻吩[3,2-d]嘧啶-4-酮的合成，反应式如下：
将甲酸铵（3.4 g，54.0 mmol）和甲酰胺（5 mL）的混合溶液加热至150 °C，然后在此温度下加入3-甲酰胺基噻吩-2-羧酸甲酯（1.85 g，10.0 mmol），待添加完毕后在此温度下继续反应8 h。TLC检测反应进度，原料反应完全后，将反应液冷却至室温，加入H2O后有大量固体产生，过滤所得固体，用水反复洗涤，在真空下干燥，最后将所得粗品用硅胶柱层析纯化收得纯品（1.09 g，72%）。M.p.: 207–209 °C. 1H NMR (400 MHz, DMSO-d 6) δ 12.49 (brs, 1 H), 8.16 (d, J = 5.2 Hz, 1 H), 8.15 (s, 1 H), 7.39 (d, J = 5.2 Hz, 1 H).13C NMR (100 MHz, DMSO-d 6) δ 157.7, 157.3, 146.5, 134.9, 125.2, 123.0. ESI-MS:m/z 153.1 [M+H]+.
步骤3.4-氯噻吩[3,2-d]嘧啶的合成，反应式如下：
在氮气保护下，将草酰氯（1.7 mL，20.0 mol）在0 °C下缓慢加入到DMF（1.0 mL）和CH2Cl2（8 mL）的混合溶液中，随后加入3H-噻吩[3,2-d]嘧啶-4-酮（0.92 g，6.0 mmol），添加完毕后撤去冰浴，继而升温至回流，并在此温度下反应3 h。TLC检测反应进度，待原料反应完全后，反应液冷却至室温，随后将反应液缓慢倾倒至饱和的碳酸氢钠水溶液中，用CH2Cl2萃取（3 × 20 mL），有机层用无水硫酸钠干燥，过滤、减压浓缩，最后得深棕色固体（0.82g，80%），未经纯化可直接用于下步反应。M.p.: 125–127 °C. 1H NMR (400 MHz, DMSO-d 6)δ 9.04 (s, 1 H), 8.60 (d, J = 5.6 Hz, 1 H), 7.76 (d, J = 5.2 Hz, 1 H). 13C NMR(100 MHz, DMSO-d 6) δ 161.7, 154.2, 153.7, 139.7, 129.9, 124.7. ESI-MS: m/z 171.0 [M+H]+.
步骤4.3-氟-4-(噻吩[3,2-d]嘧啶-4氧基)苯胺的合成，反应式如下：
将2-氟-4-羟基苯胺（2.13 g，16.8 mmol）溶于干燥的DMSO（20 mL）中，将混合液冷却至0 °C后加入NaH（0.72 g，30 mmol），室温下反应30 min。稍后加入4-氯噻吩[3,2-d]嘧啶（2.04 g, 12 mmol），然后升温到60 °C过夜。TLC检测反应，待原料反应完全后，将反应液冷却至室温，饱和氯化铵水溶液淬灭反应，CH2Cl2萃取（3×30 mL），有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤、减压浓缩，残渣用硅胶柱层析纯化得到黄色固体（2.12 g，68%）。M.p.: 159–161 °C. 1H NMR (400 MHz, DMSO-d 6) δ 8.70 (s, 1 H), 8.46 (d, J = 5.2Hz, 1 H), 7.66 (d, J = 5.6 Hz, 1 H), 7.08 (t, J = 9.2 Hz, 1 H), 6.50 (dd, J =2.0, 12.8 Hz, 1 H), 6.42 (dd, J = 1.6, 8.4 Hz, 1 H), 5.47 (br s, 2 H). 13C NMR(100 MHz, DMSO-d 6) δ163.5, 163.1, 154.3 (d, J = 241.4 Hz), 154.2, 148.7 (d, J= 10.3 Hz), 137.3, 127.9 (d, J = 13.1 Hz), 124.2, 116.2, 109.5 (d, J = 1.8Hz), 101.0 (d, J = 20.9 Hz). ESI-MS: m/z 262.1 [M+H]+.
步骤5.N-(3-氟-4-(噻吩[3,2-d]嘧啶-4氧基)苯基)甲酰胺的合成，反应式如下：
将3-氟-4-(噻吩[3,2-d]嘧啶-4氧基)苯胺（1.31 g，5.0 mmol）加入到甲酸乙酯（5.0mL）和三乙胺（0.75 mL）的混合溶液中，在回流温度下反应24 h。TLC检测原料反应完全后，将反应混合液冷却至室温，减压浓缩。残渣中加入水（25 mL），用乙酸乙酯萃取（3 × 50mL），合并的有机层用无水硫酸钠干燥，过滤、减压浓缩，粗产物经柱层析纯化得到白色固体1.18 g，收率为81.8%。M.p.: 171–173 °C.1H NMR (400 MHz, DMSO-d 6) δ10.52 (s, 1 H),8.70 (s, 1 H), 8.56 (d, J = 4.4 Hz, 1 H), 8.34 (s, 1 H), 8.12 (s, 1 H), 7.83(d, J = 12.4 Hz, 1 H), 7.42 (m, 1 H), 6.44 (d, J = 3.6 Hz, 1 H). 13C NMR (100MHz, DMSO-d 6) δ163.1, 160.1, 159.3, 153.5 (d, J = 244.8 Hz), 152.7, 149.5,135.9 (d, J = 12.2 Hz), 124.3, 116.0 (d, J = 2.6 Hz), 114.5, 108.1 (d, J =22.7 Hz), 107.9, 102.1. ESI-MS: m/z 290.1 [M+H]+.
步骤6.3-氟-4-(噻吩[3,2-d]嘧啶-4氧基)苯基异腈的合成，反应式如下：
将N-(3-氟-4-(噻吩[3,2-d]嘧啶-4氧基)苯基)甲酰胺（1.16 g，4.0 mmol）和三乙胺（1.68 mL，12.0 mmol）依次加入CH2Cl2中（12 mL），混合液随后冷却至0 °C，然后逐滴加入POCl3（0.44 mL，4.8 mmol），滴加完毕后，在0 °C反应30 min，继而体系升至室温反应8 h。TLC检测反应进度，待原料反应完全后，用饱和碳酸氢钠水溶液淬灭反应，混合液在室温下搅拌1 h，之后加入水和二氯甲烷，待分层后，水层用二氯甲烷多次萃取，合并有机层，无水硫酸钠干燥，过滤、减压浓缩，粗产物经硅胶柱层析纯化得到淡黄色固体1.01 g，收率为92.8%。M.p.: 128–130°C. 1H NMR (400 MHz, DMSO-d 6) δ8.49 (d, J = 4.8 Hz, 1 H),7.94 (d, J = 10.8 Hz, 1 H), 7.57–7.54 (m, 2 H), 7.47 (s, 1 H), 6.57 (d, J =5.2 Hz, 1 H). 13C NMR (100 MHz, DMSO-d 6) δ 165.3, 158.3, 153.4 (d, J = 249.0Hz), 152.8, 149.7, 148.8, 124.7, 124.5 (d, J = 3.5 Hz), 116.7, 116.4, 114.7,107.9, 103.1. ESI-MS: m/z 272.2 [M+H]+.
步骤7. 目标化合物4-苯氧基噻吩[3,2-d]嘧啶并α-酰胺基硫代酰胺类化合物Ia的合成
在室温下，将3-氟-4-(噻吩[3,2-d]嘧啶-4氧基)苯基异腈（109 mg，0.4 mmol）、特戊醛（65 µL，51.6 mg）、正丁胺（60 µL，43.8 mg）及苯基硫代羧酸（82.8 mg，0.6 mmol）依次加入THF（5 mL）。添加完毕后，混合液升温至45 °C反应12 h。TLC监测反应进度，待异腈化合物反应完全后，将反应混合液冷却到室温，减压浓缩，所得残渣用硅胶柱层析纯化（乙酸乙酯/石油醚）得到目标化合物，收得淡黄色固体154 mg，收率70.5%。1H NMR (400 MHz, DMSO-d 6) δ10.70 (s, 1 H), 8.50 (d, J = 4.8 Hz, 1 H), 7.87 (d, J = 12.8 Hz, 1 H), 7.51(m, 4 H), 7.44 (d, J = 9.2 Hz, 1 H), 7.40 (s, 1 H), 7.28 (t, J = 8.0 Hz, 2H), 6.45 (d, J = 4.8 Hz, 1 H), 5.27 (s, 1 H), 3.49 (m, 2 H), 1.26–0.95 (m, 13H), 0.51 (t, 3 H). ESI-MS: m/z 551.3 [M+H]+.
实施例2：目标化合物Ib的合成
实施步骤与实施例Ia相同，仅以叔丁胺代替正丁胺。淡黄色固体，收率64.5%。1H NMR(400 MHz, DMSO-d 6) δ 11.77 (s, 1 H), 8.50 (d, J = 4.8 Hz, 1 H), 7.83 (d, J =11.2 Hz, 1 H), 7.61 (m, 3 H), 7.47 (s, 1 H), 7.35 (d, J = 8.0 Hz, 1 H), 7.28–7.22 (m, 1 H), 7.14 (t, J = 7.2 Hz, 2 H), 6.46 (d, J = 4.4 Hz, 1 H), 3.98 (s,1 H), 1.31 (s, 9 H), 1.29 (s, 9 H). ESI-MS: m/z 573.3 [M+Na]+.
实施例3：目标化合物Ic的合成
实施步骤与实施例Ia相同，仅以环己胺代替正丁胺。淡黄色固体，收率66.3%。1H NMR(400 MHz, CDCl3) δ 11.31 (s, 1 H), 8.49 (d, J = 4.0 Hz, 1 H), 7.81 (d, J =11.6 Hz, 1 H), 7.60 (s, 1 H), 7.53 (m, 2 H), 7.45 (s, 1 H), 7.31–7.22 (m, 2H), 7.16 (t, J = 8.0 Hz, 2 H), 6.44 (d, J = 4.0 Hz, 1 H), 3.82 (s, 1 H),3.64–3.57 (m, 1 H), 1.96–1.65 (m, 6 H), 1.30 (s, 9 H), 1.25–1.07 (m, 4 H).ESI-MS: m/z 577.2 [M+H]+.
实施例4：目标化合物Id的合成
实施步骤与实施例Ia相同，仅以苯胺代替正丁胺。淡黄色固体，收率50.8%。1H NMR(400 MHz, CDCl3) δ 9.79 (s, 1 H), 8.52 (d, J = 4.0 Hz, 1 H), 7.87 (d, J =11.6 Hz, 1 H), 7.61 (s, 1 H), 7.48 (s, 1 H), 7.33–7.24 (m, 8 H), 6.87 (t, J =8.0 Hz, 3 H), 6.47 (d, J = 4.4 Hz, 1 H), 5.00 (s, 1 H), 1.22 (s, 9 H).ESI-MS:m/z 571.1 [M+H]+.
实施例5：目标化合物Ie的合成
实施步骤与实施例Ia相同，仅以3,4-二甲氧基苯胺代替正丁胺。淡黄色固体，收率41.6%。1H NMR (400 MHz, DMSO-d 6) δ 10.69 (s, 1 H), 8.47 (d, J = 5.2 Hz, 1 H),7.89 (d, J = 13.2 Hz, 1 H), 7.58 (d, J = 8.8 Hz, 1 H), 7.52 (s, 1 H), 7.44(d, J = 8.8 Hz, 1 H), 7.40 (s, 1 H), 7.32–7.29 (m, 3 H), 7.01 (t, J = 8.8 Hz,2 H), 6.70–6.66 (m, 2 H), 6.43 (d, J = 5.2 Hz, 1 H), 5.47 (s, 1 H), 3.64 (s,3 H), 3.55 (s, 3 H), 1.04 (s, 9 H). ESI-MS: m/z 631.2 [M+H]+.
实施例6：目标化合物If的合成
实施步骤与实施例Ia相同，仅以4-氟苯胺代替正丁胺。淡黄色固体，收率56.3%。1H NMR(400 MHz, CDCl3) δ 9.67 (s, 1 H), 8.52 (d, 1 H), 7.82 (d, J = 11.6 Hz, 1 H),7.60 (s, 1 H), 7.49 (s, 1 H), 7.30 (t, J = 8.0 Hz, 1 H), 7.21 (m, 5 H), 6.94–6.86 (m, 4 H), 6.44 (d, J = 3.6 Hz, 1 H), 5.16 (s, 1 H), 1.16 (s, 9 H).ESI-MS: m/z 589.2 [M+H]+.
实施例7：目标化合物Ig的合成
实施步骤与实施例Ia相同，仅以氨水代替正丁胺。淡黄色固体，收率38.5%。1H NMR(400 MHz, CDCl3) δ 11.23 (br s, 1 H), 8.41 (d, J = 4.0 Hz, 1 H), 8.09 (br s,1 H), 7.73 (d, J = 11.6 Hz, 1 H), 7.52 (s, 1 H), 7.45 (t, J = 6.0 Hz, 2 H),7.37 (s, 1 H),7.23–7.14 (m, 2 H), 7.10–7.06 (m, 2 H), 6.36 (d, J = 4.0 Hz, 1H), 3.74 (s, 1 H), 1.22 (s, 9 H). ESI-MS: m/z 495.1 [M+H]+.
实施例8：目标化合物Ih的合成
实施步骤与实施例Ia相同，仅以对氟苯基硫代羧酸代替苯基硫代羧酸。淡黄色固体，收率52.3%。1H NMR (400 MHz, DMSO-d 6) δ 10.70 (s, 1 H), 8.46 (d, J = 4.8 Hz, 1 H),7.84 (d, J = 12.8 Hz, 1 H), 7.51 (m, 3 H), 7.44 (d, J = 9.2 Hz, 1 H), 7.40(s, 1 H), 7.28 (t, J = 8.0 Hz, 2 H), 6.45 (d, J = 4.8 Hz, 1 H), 5.23 (s, 1H), 3.49 (m, 2 H), 1.26–0.92 (m, 13 H), 0.56 (t, 3 H). ESI-MS: m/z 569.2 [M+H]+.
实施例9：目标化合物Ii的合成
实施步骤与实施例Ia相同，仅以对氟苯基硫代羧酸代替苯基硫代羧酸，叔丁胺代替正丁胺。淡黄色固体，收率64.6%。1H NMR (400 MHz, DMSO-d 6) δ 10.70 (s, 1 H), 8.46 (d, J = 4.8 Hz, 1 H), 7.84 (d, J = 12.8 Hz, 1 H), 7.51 (m, 2 H), 7.44 (d, J = 9.2Hz, 1 H), 7.40 (s, 1 H), 7.28 (t, J = 8.0 Hz, 2 H), 6.45 (d, J = 4.8 Hz, 1H), 5.23 (s, 1 H), 3.49 (m, 2 H), 1.26–0.92 (m, 13 H), 0.56 (t, 3 H). ESI-MS:m/z 569.2 [M+H]+.
实施例10：目标化合物Ij的合成
实施步骤与实施例Ia相同，仅以对氟苯基硫代羧酸代替苯基硫代羧酸，环己胺代替正丁胺。淡黄色固体，收率66.3%。1H NMR (400 MHz, CDCl3) δ 11.31 (s, 1 H), 8.49 (d, J= 4.0 Hz, 1 H), 7.81 (d, J = 11.6 Hz, 1 H), 7.60 (s, 1 H), 7.53 (m, 2 H),7.45 (s, 1 H), 7.31–7.22 (m, 1 H), 7.16 (t, J = 8.0 Hz, 2 H), 6.44 (d, J =4.0 Hz, 1 H), 3.82 (s, 1 H), 3.64–3.57 (m, 1 H), 1.96–1.65 (m, 6 H), 1.30 (s,9 H), 1.25–1.07 (m, 4 H). ESI-MS: m/z 595.2 [M+H]+.
实施例11：目标化合物Ik的合成
实施步骤与实施例Ia相同，仅以对氟苯基硫代羧酸代替苯基硫代羧酸，苯胺代替正丁胺。淡黄色固体，收率50.8%。1H NMR (400 MHz, CDCl3) δ 9.79 (s, 1 H), 8.52 (d, J =4.0 Hz, 1 H), 7.87 (d, J = 11.6 Hz, 1 H), 7.61 (s, 1 H), 7.48 (s, 1 H), 7.33–7.24 (m, 7 H), 6.87 (t, J = 8.0 Hz, 3 H), 6.47 (d, J = 4.4 Hz, 1 H), 5.00 (s,1 H), 1.22 (s, 9 H). ESI-MS: m/z 589.1 [M+H]+.
实施例12：目标化合物Il的合成
实施步骤与实施例Ia相同，仅以对氟苯基硫代羧酸代替苯基硫代羧酸，3,4-二甲氧基苯胺代替正丁胺。淡黄色固体，收率41.6%。1H NMR (400 MHz, DMSO-d 6) δ 10.69 (s, 1H), 8.47 (d, J = 5.2 Hz, 1 H), 7.78 (d, J = 13.2 Hz, 1 H), 7.52 (d, J = 8.8Hz, 1 H), 7.36 (s, 1 H), 7.44 (d, J = 8.8 Hz, 1 H), 7.40 (s, 1 H), 7.32–7.29(m, 3 H), 7.01 (t, J = 8.8 Hz, 2 H), 6.70–6.66 (m, 2 H), 6.43 (d, J = 5.2 Hz,1 H), 5.47 (s, 1 H), 3.64 (s, 3 H), 3.55 (s, 3 H), 1.02 (s, 9 H). ESI-MS: m/z 649.2 [M+H]+.
实施例13：目标化合物Im的合成
实施步骤与实施例Ia相同，仅以对氟苯基硫代羧酸代替苯基硫代羧酸，4-氟苯胺代替正丁胺。淡黄色固体，收率56.3%。1H NMR (400 MHz, CDCl3) δ 9.58 (s, 1 H), 8.49 (d,1 H), 7.82 (d, J = 11.6 Hz, 1 H), 7.60 (s, 1 H), 7.49 (s, 1 H), 7.30 (t, J =8.0 Hz, 1 H), 7.21 (m, 4 H), 6.94–6.86 (m, 4 H), 6.44 (d, J = 3.6 Hz, 1 H),5.16 (s, 1 H), 1.16 (s, 9 H). ESI-MS: m/z 607.2 [M+H]+.
实施例14：目标化合物In的合成
实施步骤与实施例Ia相同，仅以对氟苯基硫代羧酸代替苯基硫代羧酸，氨水代替正丁胺。淡黄色固体，收率42.6%。1H NMR (400 MHz, CDCl3) δ 11.23 (br s, 1 H), 8.41 (d, J = 4.0 Hz, 1 H), 8.09 (br s, 1 H), 7.73 (d, J = 11.6 Hz, 1 H), 7.52 (s, 1H), 7.45 (t, J = 6.0 Hz, 2 H), 7.37 (s, 1 H),7.23–7.14 (m, 1 H), 7.10–7.06(m, 2 H), 6.36 (d, J = 4.0 Hz, 1 H), 3.74 (s, 1 H), 1.22 (s, 9 H). ESI-MS: m/z 512.1 [M+H]+.
二、化合物抗肿瘤活性的实验方法及结果
本发明的药理实验采用MTT染色法。肿瘤细胞培养选用含有10%胎牛血清（FBS）的RPMI-1640培养基，将肿瘤细胞接种于96孔板，接种量为3-5×103个/孔，培养12 h 待细胞贴壁后加入不同浓度的待测化合物溶液。培养72 h后，每孔加入MTT溶液使终浓度为5 μg/mL，培养4 h后，倒掉上清液，PBS缓冲液洗涤三次，每孔加入DMSO 200 μL，振摇溶解，测定492 nm处光吸收值。所有试验均设3个平行组或重复3次。
化合物Ia-In的细胞毒活性测试结果见表1
表1化合物Ia-In的细胞毒活性试验结果
体外实验表明，本发明所述的化合物Ia-In对人肺癌细胞、人结肠癌细胞、人胃癌细胞、人乳 腺癌细胞表现出较好的抑制活性，大部分化合物均表现出了中等到优异的抗增殖活性。尤其In对于 A549、HT-29及MDA-MB-231三种肿瘤细胞表现出最优的抗增殖活性，其IC50值在2.89～8.63μM。 此外，本类化合物相较于人胃癌细胞、人乳腺癌细胞、人结肠癌细胞，对于人肺癌细胞表现出更高 的选择性，因此本发明所制得的化合物可用于制备抗肿瘤药物。另外，由实施例可知，该类化合物 合成方法简单、原料廉价易得，终产物易处理，产品纯度高等优点。
以上所述仅为本申请的优选实施例，并不用于限制本申请，对于本领域的技术人员来说，本申请可以有各种更改和变化。凡在本申请的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本申请的保护范围之内。
Claims (9)
1.一种4-苯氧基噻吩[3,2-d]嘧啶并α-酰胺基硫代酰胺类化合物，为具有如式I所示的化合物：
其中，R1选自氢、叔丁基、正丁基、环己基、苯基、3,4-二甲氧基苯基、4-氟苯基；R2选自苯基、4-氟苯基。
2.根据权利要求1所述的4-苯氧基噻吩[3,2-d]嘧啶并α-酰胺基硫代酰胺类化合物，其中所述式I的化合物可以以药学上可接受的盐的形式存在。
3.根据权利要求2所述的4-苯氧基噻吩[3,2-d]嘧啶并α-酰胺基硫代酰胺类化合物，其中所述药学上可接受的盐为式I化合物的盐酸盐、硫酸盐、磷酸盐、三氟乙酸盐、甲磺酸盐、对甲苯磺酸盐、酒石酸盐、马来酸盐、琥珀酸盐。。
4.一种权利要求1所述的4-苯氧基噻吩[3,2-d]嘧啶并α-酰胺基硫代酰胺类化合物I的制备方法，通过中间体II与醛、胺、硫代羧酸反应获得，具体反应式如下：
5.一种权利要求4所述的中间体II的制备方法，中间体II通过3-氨基-2-噻吩甲酸甲酯依次经酰胺化、分子内关环、氯代，然后与3-氟-4-羟基苯胺偶联，进而与甲酸乙酯进行酰胺化，最后在POCl3/TEA作用下脱水得到关键中间体II。
6.一种权利要求1和2所述的4-苯氧基噻吩[3,2-d]嘧啶并α-酰胺基硫代酰胺类化合物I及其盐在调节蛋白激酶催化活性制品中的应用；所述蛋白激酶为酪氨酸激酶。
7.一种权利要求6在治疗与酪氨酸蛋白激酶有关的疾病中的应用，具体为c-Met受体酪氨酸激酶。
8.一种权利要求7和6在治疗c-Met受体酪氨酸激酶过表达中的应用，具体为癌症方面的应用。
9.根据权利要求8所述中的应用，其特征在于，其中所述癌症包括肺癌、结肠癌、胃癌、乳腺癌。
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