CN116947763A - 2-巯基-5-氰基-6-芳基嘧啶杂环类化合物、制备方法和应用 - Google Patents
2-巯基-5-氰基-6-芳基嘧啶杂环类化合物、制备方法和应用 Download PDFInfo
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Abstract
本发明属于药物合成技术领域,具体涉及一种2‑巯基‑5‑氰基‑6‑芳基嘧啶杂环类化合物、制备方法和应用。本发明的2‑巯基‑5‑氰基‑6‑芳基嘧啶杂环类化合物,结构式如式Ⅰ所示:
Description
技术领域
本发明属于药物合成技术领域,具体涉及一种2-巯基-5-氰基-6-芳基嘧啶杂环类化合物、制备方法和应用。
背景技术
癌症,尤其是胃癌对人类健康造成重大威胁,目前我国胃癌的总体发病率呈上升趋势,大多数患者常被诊断为晚期,生存期缩短,预后性差。在这种情况下,手术切除原发性肿瘤治疗有限,并且发病率高;不能手术切除胃癌需要进行放化疗,但有严重的副作用。因此除了完善胃癌早期预防诊断技术之外,开发新型高效、高选择的抗癌药物是治疗癌症的最基本手段。
组蛋白赖氨酸去乙酰化酶6(Histone deacetylase 6,HDAC6)作为一种IIb类HDAC亚型,在乳腺癌、胃癌、卵巢癌、结直肠癌、肺癌等多种癌细胞中高表达。现有研究证实,HDAC6的异常表达与胃癌的发生发展密切相关,其过表达可诱导正常细胞向胃癌细胞转化,引发癌症,为此可通过抑制HDAC6活性阻止胃癌的发生发展。但是,目前报道HDAC6抑制剂用于治疗胃癌很少。因此,开发药效强、选择性高的小分子HDAC6抑制剂对胃癌的治疗及其预后有重要的意义。
发明内容
本发明的目的之一在于提供一种2-巯基-5-氰基-6-芳基嘧啶杂环类化合物,该类化合物不仅对HDAC6有较优的选择性抑制作用,而且能够以浓度依赖性的方式抑制胃癌MGC-803细胞增殖。本发明的目的之二在于提供一种2-巯基-5-氰基-6-芳基嘧啶杂环类化合物的制备方法。本发明的目的之三在于提供一种2-巯基-5-氰基-6-芳基嘧啶杂环类化合物的应用。
本发明的2-巯基-5-氰基-6-芳基嘧啶杂环类化合物,结构式如式I所示:
其中,R1为取代胺基、取代酰肼基中的一种;取代胺基、取代酰肼基中的取代基各自独立地选自氢、C1-C4饱和烷基、甲氧基、卤素、三氟甲基、硝基中的一种或多种;R2为取代芳香基或芳杂环基;所述取代芳香基的取代基为氢、甲基、甲氧基、卤素、三氟甲基中的一种;所述芳杂环基为呋喃基、噻吩基中的一种;R3为
进一步优选地,所述R1为
中的一种。
优选地,所述R2为 中的一种。
基于改善化合物对于HDAC6的抑制作用,以及对胃癌细胞MGC-803增殖的抑制效果的考虑,可选自如下典型结构的化合物,依次记为化合物I-1~I-50:
本发明的2-巯基-5-氰基-6-芳基嘧啶杂环类化合物的制备方法,包括以下步骤:
(1)将原料A、原料B、原料C、碱溶于溶剂a中,加热回流进行成环反应,得到中间体化合物D;
(2)将中间体化合物D溶于溶剂b中,然后在碱性物质作用下与4-溴甲基苯甲酸甲酯进行取代反应,得到中间体化合物E;
(3)将中间体化合物E加入到溶剂c中进行氯代反应,反应结束后淬灭、抽滤,得到中间体化合物F;
(4)将中间体化合物F、胺类物质、碱性物质在溶剂a中进行回流反应,反应结束后抽滤,得到中间体化合物G;所述胺类物质为不同取代的苯胺、苄胺、苯肼或脂肪族胺;
(5)将中间体化合物G溶于溶剂d中,搅拌状态下加入碱进行水解反应,得到中间体化合物H;
(6)将中间体化合物H溶于溶剂e中,在缩合剂的作用下与邻(4-氢-2H-吡喃-2-基)羟基胺或N-BOC-1,2苯二胺进行缩合反应,得到中间体化合物J;
(7)将中间体化合物J溶于溶剂e或溶剂f中,与浓盐酸进行反应,得到具有结构通式I的2-巯基-5-氰基-6-芳基嘧啶杂环类化合物;
其中,中间体化合物J中,R4为2-甲氧基四氢-2H-吡喃基或乙酸叔丁酯基。
基于提高产物得率和反应选择性的目的,优选地,步骤(1)中,原料A、原料B、原料C与碱的添加摩尔比为1:1:1.2:1.5;步骤(2)中,中间体化合物D与4-溴甲基苯甲酸甲酯、碱性物质的添加摩尔比为1:1:2;步骤(3)中,中间体化合物E与溶剂c的添加摩尔比为1:10;步骤(4)中,中间体化合物F、胺类物质、碱性物质添加摩尔比为1:2:1.5;步骤(5)中,中间体化合物G与溶剂d的添加摩尔比为1:10;步骤(6)中,中间体化合物H与邻(4-氢-2H-吡喃-2-基)羟基胺的添加摩尔比为1:1.5;中间体化合物H与N-BOC-1,2苯二胺的添加摩尔比为1:1.1;步骤(7)中,中间体化合物J与浓盐酸的添加摩尔比为1:(2~100)。
为提高反应效率和产物得率,进一步地,步骤(1)中,成环反应的温度为80℃,成环反应在搅拌中进行,搅拌的速率为600~700rpm,成环反应的时间为6h;步骤(2)中,取代反应在搅拌条件下进行,搅拌的速率为600~700rpm,取代反应的温度为60℃,时间为3h;步骤(3)中,氯代反应在搅拌条件下进行,搅拌的速率为600~700rpm,氯代反应的温度为80℃,时间为2h;步骤(4)中,回流反应在搅拌条件下进行,搅拌的速率为600~700rpm,回流反应温度为80℃,时间为2h;步骤(5)中,水解反应在搅拌条件下进行,搅拌的速率为600~700rpm,水解反应的温度为60℃,时间为12h;步骤(6)中,缩合反应在搅拌条件下进行,搅拌的速率为600~700rpm,缩合反应的温度为室温,时间为3h;步骤(7)中,与浓盐酸的反应在常温搅拌中进行,搅拌的速率为600~700rpm。
作为进一步优选的方案,步骤(1)中,所述碱为氢氧化钾或碳酸钾;步骤(2)、步骤(4)中,所述碱性物质为三乙胺;所述溶剂a为乙醇,溶剂b为甲醇,溶剂c为三氯氧磷,溶剂d为四氢呋喃,溶剂e为二氯甲烷,溶剂f为1,4-二氧六环;步骤(6)中,所述缩合剂为1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐和1-羟基苯并三唑。
本发明的如上所述的2-巯基-5-氰基-6-芳基嘧啶杂环类化合物的应用,具体是在制备基于HDAC6靶点的抑制剂中的应用,或者在制备抑制胃癌细胞增殖活性的药物中的应用。
进一步地,所述胃癌细胞为MGC-803。
所述抑制胃癌细胞增殖活性的药物包括所述2-巯基-5-氰基-6-芳基嘧啶杂环类化合物中的至少一种以及药学上可接受的辅料;2-巯基-5-氰基-6-芳基嘧啶杂环类化合物的质量含量优选为93%;对于辅料没有特殊的限定,采用本领域技术人员熟知的药学上可接受的辅料即可。
相比现有技术,本发明的有益效果在于:
本发明提供的2-巯基-5-氰基-6-芳基嘧啶杂环类化合物,结构新颖,且对HDAC6具有良好的抑制作用,能够作为HDAC6的抑制剂应用。并且该类型化合物通过与胃癌细胞内金属离子鳌合形成稳定的配合物,能够抑制胃癌细胞MGC-803的增殖活性。本发明提供的上述化合物的制备方法,合成条件温和,易于实现,并且该方法得到的化合物具有产率高、纯度高的特点。试验结果表明,与阳性对照SAHA、ACY-1215相比,本发明提供的2-巯基-5-氰基-6-芳基嘧啶杂环类化合物,不仅对HDAC6蛋白具有较优的选择性抑制作用,而且能够以浓度依赖性的方式抑制胃癌MGC-803细胞增殖,因此本发明的化合物在制备基于HDAC6靶点的抑制剂以及抑制胃癌细胞增殖活性的药物中具有良好的应用前景,对基于HDAC6靶点的抑制剂和抗肿瘤药物的研发以及相关疾病的研究治疗均具有重要意义。
具体实施方式
以下结合具体实施方式,对本发明作进一步描述。需要说明的是,在不相冲突的前提下,以下描述的各实施例之间或各技术特征之间可以任意组合形成新的实施例。
实施例1
2-巯基-5-氰基-6-芳基嘧啶杂环类化合物物I-1制备过程如下:
(1)将1.5mmol氢氧化钾、1mmol硫脲置于250mL圆底烧瓶中,加入乙醇溶解,室温下边搅拌边依次加入1mmol对氯苯甲醛、1.2mmol氰乙酸乙酯,然后转至80℃条件下回流6h,薄层色谱监测(二氯甲烷:甲醇=15:1)完全后大量固体析出,静置至室温。采用杯状抽滤斗进行抽滤,在0.1MPa压力下使用杯状抽滤漏斗进行抽滤,时间15min,得到4-(4-氯苯基)-5-氰基-6-羟基嘧啶-2-硫代酸钾,产率为95%,纯度为97%。
(2)将1mmol步骤(1)得到的4-(4-氯苯基)-5-氰基-6-羟基嘧啶-2-硫代酸钾溶于甲醇制成溶液,室温650rpm搅拌状态下加入2mmol三乙胺和1mmol 4-溴甲基苯甲酸甲酯,转至60℃条件下回流3h,反应过程中,有大量白色絮状固体析出,薄层色谱监测(二氯甲烷:甲醇=15:1)待完全反应后,静置至室温进行抽滤,滤饼用甲醇淋洗,干燥得4-((4-氯苯基)-5-氰基-6-羟基嘧啶-2-基)硫代)甲基)苯甲酸甲酯,产率为75%,纯度为98%。
(3)在650rpm的搅拌下,将1mmol步骤(2)得到的4-((4-氯苯基)-5-氰基-6-羟基嘧啶-2-基)硫代)甲基)苯甲酸甲酯置于50mL圆底烧瓶中,加入三氯氧磷作为溶剂,由于三氯氧磷后处理较为麻烦,所以三氯氧磷的量以能够溶解原料且尽可能的少为宜。80℃条件下回流2h,薄层色谱监测(石油醚:乙酸乙酯=5:1)待完全反应后,静置至室温,准备好装有冰水的烧杯,将反应液逐滴加入烧杯中,边滴加边搅拌,待完全淬灭后,烧杯中有大量固体析出,直接抽滤,干燥可得4-((4-氯-6-(4-氯苯基)-5-氰基嘧啶-2-基)硫代)甲基)苯甲酸甲酯,产率为93%,纯度为98%。
(4)在650rpm的搅拌速度下,室温下将1mmol步骤(3)得到的4-((4-氯-6-(4-氯苯基)-5-氰基嘧啶-2-基)硫代)甲基)苯甲酸甲酯置于50mL圆底烧瓶中,加入乙醇溶解原料,室温搅拌状态下加入1.5mmol三乙胺以及2mmol苯胺,转至80℃条件下回流2h,随着反应的进行,有大量白色絮状固体析出,薄层色谱监测(石油醚:乙酸乙酯=5:1)待完全反应后,静置至室温进行抽滤,滤饼用乙醇淋洗,干燥得4-((4-氯苯基)-5-氰基-6-(苯基氨基)嘧啶-2-基)硫代)甲基)苯甲酸甲酯,产率为85%,纯度为95%。
(5)在650rpm的搅拌下,将1mmol步骤(4)得到的4-((4-氯苯基)-5-氰基-6-(苯基氨基)嘧啶-2-基)硫代)甲基)苯甲酸甲酯加入到以四氢呋喃:水=1:1(20mL)的溶剂中,搅拌均匀后加入10mmol氢氧化钠,于60℃下回流12h。随着反应的进行,反应液逐渐变得澄清,薄层色谱监测(石油醚:乙酸乙酯=5:1)待完全反应后,用旋转蒸发仪除去四氢呋喃,加入水,搅拌状态下,用浓盐酸调节PH至中性,有大量白色固体析出,采用杯状抽滤漏斗抽滤,在0.1MPa压力下抽滤20min,得到4-((4-氯苯基)-5-氰基-6-(苯基氨基)嘧啶-2-基)硫代)甲基)苯甲酸,产率为95%,纯度为95%。
(6)在650rpm的搅拌速度下,室温下将1mmol步骤(5)得到的4-((4-氯苯基)-5-氰基-6-(苯基氨基)嘧啶-2-基)硫代)甲基)苯甲酸溶于二氯甲烷溶剂中,搅拌状态下加入1mmol的EDCI(1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐)和1mmol的HOBT(1-羟基苯并三唑),待反应半小时后,加入1.5mmol邻(4-氢-2H-吡喃-2-基)羟基胺发生缩合反应,常温反应3h,薄层色谱监测(二氯甲烷:甲醇=15:1)待完全反应后,用二氯甲烷(15mL)萃取三次,将有机相合并,再用饱和食盐水(30mL)洗涤两次,用旋转蒸发仪除去有机相,将粗产品与100-200目的硅胶混合炒样,柱层析法(二氯甲烷:甲醇=80:1)快速分离得4-((4-氯苯基)-5-氰基-6-(苯基氨基)嘧啶-2-基)硫代)甲基)-N-(四氢-2H-吡喃-2-氧基)苯甲酰胺,产率为83%,纯度为95%。
(7)在650rpm的搅拌速度下,室温下将1mmol步骤(4)得到的4-((4-氯苯基)-5-氰基-6-(苯基氨基)嘧啶-2-基)硫代)甲基)-N-(四氢-2H-吡喃-2-氧基)苯甲酰胺溶于二氯甲烷中,于25mmol浓盐酸进行反应,随着反应的进行,有固体析出,待反应半小时后,薄层色谱监测(石油醚:乙酸乙酯=2:1)待完全反应后,将反应溶剂蒸干,加水、用盐酸将溶液调至弱酸性,产物不断析出,静置20min后,采用杯状抽滤漏斗抽滤,在0.1MPa压力下抽滤10min,即可得到如I-1所示化合物,产率为86%。
具有式I-1所示结构的化合物为白色固体,熔点为208.2-209.1℃,总产率为40%,纯度为97%。结构表征结果为:1H NMR(400MHz,DMSO-d6,ppm)δ11.16(s,1H),9.97(s,1H),9.00(s,1H),7.87(d,J=8.5Hz,2H),7.65(d,J=8.5Hz,2H),7.58(d,J=8.2Hz,2H),7.53(d,J=7.6Hz,2H),7.41(t,J=8.2Hz,2H),7.23(t,J=7.4Hz,1H),7.17(d,J=8.2Hz,2H),4.29(s,2H).13C NMR(100MHz,DMSO-d6,ppm)δ172.77,167.02,163.89,160.32,141.01,137.49,136.07,134.55,131.39,130.53,128.74,128.65,128.50,126.80,125.46,124.61,115.74,84.83,33.77.HR-MS(ESI):calcd.C25H18ClN5O2S,[M+H]+m/z:488.0943,found:488.0946.
实施例2
2-巯基-5-氰基-6-芳基嘧啶杂环类化合物I-2,结构式为:制备过程与实施例1的区别在于:将步骤(4)中的苯胺调整为对甲基苯胺,其余与实施例1相同。所得到的化合物式I-2所示结构的化合物为白色固体,熔点为205.4-206.1℃,总产率为48%,纯度为96%。结构表征结果为:1H NMR(400MHz,DMSO-d6,ppm)δ11.25(s,1H),9.91(s,1H),9.05(s,1H),7.86(d,J=8.5Hz,2H),7.65(d,J=8.5Hz,2H),7.61(d,J=8.1Hz,2H),7.40(d,J=8.3Hz,2H),7.21(d,J=8.2Hz,2H),7.17(d,J=8.0Hz,2H),4.29(s,2H),2.31(s,3H).13CNMR(100MHz,DMSO-d6,ppm)δ172.74,166.95,160.29,141.00,136.01,134.87,134.71,134.59,130.52,128.92,128.74,128.63,126.81,124.60,115.77,84.63,33.79,20.57.HR-MS(ESI):calcd.C26H20ClN5O2S,[M+H]+m/z:502.1099,found:502.1098.
实施例3
2-巯基-5-氰基-6-芳基嘧啶杂环类化合物I-3,结构式为:制备过程与实施例1的区别在于:将步骤(4)中的苯胺调整为对乙基苯胺,其余与实施例1相同。所得到的具有式I-3所示结构的化合物为白色固体,熔点为203.1-205.2℃,总产率为42%,纯度为94%。结构表征结果为:1H NMR(400MHz,DMSO-d6,ppm)δ11.19(s,1H),10.31(s,1H),9.91(s,1H),7.86(d,J=8.5Hz,2H),7.65(d,J=8.5Hz,2H),7.58(d,J=8.2Hz,2H),7.42(d,J=8.3Hz,2H),7.25(d,J=8.3Hz,2H),7.14(d,J=8.2Hz,2H),4.28(s,2H),2.64-2.58(m,2H),1.16(t,J=7.6Hz,3H).13C NMR(100MHz,DMSO-d6,ppm)δ172.74,166.95,163.83,160.33,141.18,141.09,136.02,135.04,134.57,131.32,130.51,128.74,128.63,127.76,126.76,124.75,115.77,84.60,33.77,27.71,15.70.HR-MS(ESI):calcd.C27H22ClN5O2S,[M+H]+m/z:516.1256,found:516.1259.
实施例4
2-巯基-5-氰基-6-芳基嘧啶杂环类化合物I-4,结构式为:制备过程与实施例1的区别在于:将步骤(4)中的苯胺调整为对异丙基苯胺,其余与实施例1相同。所得到的具有式I-4所示结构的化合物为白色固体,熔点为200.9-202.5℃,总产率为44%,纯度为97%。结构表征结果为:1H NMR(400MHz,DMSO-d6,ppm)δ11.08(s,1H),9.90(s,1H),9.00(s,1H),7.85(d,J=8.4Hz,2H),7.65(d,J=8.4Hz,2H),7.56(d,J=8.1Hz,2H),7.43(d,J=8.2Hz,2H),7.29(d,J=8.3Hz,2H),7.10(d,J=8.0Hz,2H),4.27(s,2H),2.94-2.87(m,1H),1.20(d,J=6.9Hz,6H).13C NMR(100MHz,DMSO-d6,ppm)δ172.75,166.95,163.90,160.35,145.83,141.15,136.03,135.11,134.57,131.29,130.50,128.73,128.63,126.72,126.26,124.80,115.78,84.56,33.77,33.03,23.89.HR-MS(ESI):calcd.C28H24ClN5O2S,[M+H]+m/z:530.1412,found:530.1416.
实施例5
2-巯基-5-氰基-6-芳基嘧啶杂环类化合物I-5,结构式为:制备过程与实施例1的区别在于:将步骤(4)中的苯胺调整为对叔丁基苯胺,其余与实施例1相同。所得到的具有式I-5所示结构的化合物为白色固体,熔点为196.9-197.5℃,总产率为40%,纯度为95%。结构表征结果为:1H NMR(400MHz,DMSO-d6,ppm)δ11.17(s,1H),9.91(s,1H),9.01(s,1H),7.86(d,J=8.5Hz,2H),7.65(d,J=8.5Hz,2H),7.56(d,J=8.2Hz,2H),7.43(s,4H),7.09(d,J=8.1Hz,2H),4.27(s,2H),1.28(s,9H).13C NMR(100MHz,DMSO-d6,ppm)δ173.26,167.46,164.40,160.85,148.53,141.67,136.53,135.33,135.10,131.81,131.02,129.19,129.14,127.23,125.67,124.91,116.28,85.13,34.70,34.28,31.64,30.31.HR-MS(ESI):calcd.C29H26ClN5O2S,[M+H]+m/z:544.1569,found:544.1567.
实施例6
2-巯基-5-氰基-6-芳基嘧啶杂环类化合物I-6,结构式为制备过程与实施例1的区别在于:将步骤(4)中的苯胺调整为邻甲氧基苯胺,其余与实施例1相同。所得到的具有式I-6所示结构的化合物为白色固体,熔点为213.5-214.1℃,总产率为35%,纯度为95%。结构表征结果为:1H NMR(400MHz,DMSO-d6,ppm)δ11.17(s,1H),9.47(s,1H),9.01(s,1H),7.86(d,J=8.0Hz,2H),7.65(d,J=8.4Hz,2H),7.57(d,J=8.1Hz,2H),7.52(d,J=7.0Hz,1H),7.31(t,J=7.2Hz,1H),7.19(d,J=8.3Hz,1H),7.08(t,J=8.0Hz,3H),4.20(s,2H),3.84(s,3H).13C NMR(100MHz,DMSO-d6,ppm)δ172.76,166.50,163.84,160.44,153.37,141.21,136.07,134.48,131.31,130.63,130.48,128.74,128.66,127.59,126.78,125.88,120.34,115.72,111.83,84.29,55.72,33.70.HR-MS(ESI):calcd.C26H20ClN5O3S,[M+H]+m/z:518.1048,found:518.1048.
实施例7
2-巯基-5-氰基-6-芳基嘧啶杂环类化合物I-7,结构式为:制备过程与实施例1的区别在于:将步骤(4)中的苯胺调整为间甲氧基苯胺,其余与实施例1相同。具有式I-7所示结构的化合物为白色固体,熔点为217.1-218.3℃,总产率为66.0%,纯度为93%。1H NMR(400MHz,DMSO-d6,ppm)δ11.15(s,1H),9.92(s,1H),9.00(s,1H),7.86(d,J=8.5Hz,2H),7.66(d,J=8.5Hz,2H),7.59(d,J=8.2Hz,2H),7.30(t,J=8.1Hz,1H),7.23(d,J=8.2Hz,2H),7.20-7.19(m,1H),7.16(d,J=7.9Hz,1H),6.81(dd,J=8.2,2.2Hz,1H),4.33(s,2H),3.76(s,3H).13C NMR(100MHz,DMSO-d6,ppm)δ172.79,167.03,163.92,160.23,159.39,140.97,138.69,136.09,134.54,131.46,130.54,129.21,128.79,128.66,126.84,116.55,115.70,111.07,109.98,85.01,55.17,33.84.HR-MS(ESI):calcd.C26H20ClN5O3S,[M+H]+m/z:518.1048,found:518.1048.
实施例8
2-巯基-5-氰基-6-芳基嘧啶杂环类化合物I-8,结构式为:制备过程与实施例1的区别在于:将步骤(4)中的苯胺调整为对甲氧基苯胺,其余与实施例1相同。具有式I-8所示结构的化合物为白色固体,熔点为212.5-213.3℃,总产率为52.0%,纯度为96%。1H NMR(400MHz,DMSO-d6,ppm)δ11.07(s,1H),9.97(s,1H),9.03(s,1H),7.85(d,J=8.5Hz,2H),7.64(d,J=8.5Hz,2H),7.60(d,J=8.1Hz,2H),7.41(d,J=8.8Hz,2H),7.16(d,J=8.1Hz,2H),6.97(d,J=8.9Hz,2H),4.26(s,2H),3.76(s,3H).13C NMR(100MHz,DMSO-d6,ppm)δ172.72,166.86,160.44,157.07,141.10,135.98,134.62,130.49,130.22,128.75,128.62,126.77,126.39,115.80,113.70,84.34,55.27,33.76.HR-MS(ESI):calcd.C26H20ClN5O3S,[M+H]+m/z:518.1048,found:518.1048.
实施例9
2-巯基-5-氰基-6-芳基嘧啶杂环类化合物I-9,结构式为:制备过程与实施例1的区别在于:将步骤(4)中的苯胺调整为对氟苯胺,其余与实施例1相同。具有式I-9所示结构的化合物为白色固体,熔点为215.2-215.9℃,总产率为46.0%,纯度为94%。1H NMR(400MHz,DMSO-d6,ppm)δ11.17(s,1H),10.23(s,1H),9.99(s,1H),7.86(d,J=8.5Hz,2H),7.65(d,J=8.5Hz,2H),7.60(d,J=8.1Hz,2H),7.54(dd,J=8.9,5.0Hz,2H),7.25(t,J=8.8Hz,2H),7.18(d,J=8.2Hz,2H),4.28(s,2H).13C NMR(100MHz,DMSO-d6,ppm)δ172.80,166.95,160.83,160.46,158.43,141.00,136.08,134.51,133.77,133.74,131.42,130.52,128.71,128.66,126.89,126.81,115.71,115.31,115.08,84.71,33.79.HR-MS(ESI):calcd.C25H17ClFN5O2S,[M+H]+m/z:506.0849,found:506.0851.
实施例10
2-巯基-5-氰基-6-芳基嘧啶杂环类化合物I-10,结构式为:制备过程与实施例1的区别在于:将步骤(4)中的苯胺调整为对氯苯胺,其余与实施例1相同。具有式I-10所示结构的化合物为白色固体,熔点为213.7-214.2℃,总产率为48.0%,纯度为97%。1H NMR(400MHz,DMSO-d6,ppm)δ11.17(s,1H),10.04(s,1H),9.02(s,1H),7.87(d,J=8.6Hz,2H),7.66(d,J=8.6Hz,2H),7.61(d,J=8.2Hz,2H),7.57(d,J=8.8Hz,2H),7.45(d,J=8.8Hz,2H),7.23(d,J=8.2Hz,2H),4.32(s,2H).13C NMR(100MHz,DMSO-d6,ppm)δ172.83,167.01,163.88,160.23,140.89,136.52,136.14,134.46,131.44,130.55,129.26,128.72,128.67,128.38,126.83,126.09,115.66,85.10,33.86.HR-MS(ESI):calcd.C25H17Cl2N5O2S,[M+H]+m/z:522.0553,found:522.0555.
实施例11
2-巯基-5-氰基-6-芳基嘧啶杂环类化合物I-11:制备过程与实施例1的区别在于:将步骤(4)中的苯胺调整为4-三氟甲基苯胺,其余与实施例1相同。具有式I-11所示结构的化合物为白色固体,熔点为210.5-211.4℃,总产率为43.0%,纯度为95%。1HNMR(400MHz,DMSO-d6,ppm)δ11.19(s,1H),10.30(s,1H),10.26(s,1H),7.89(d,J=8.6Hz,2H),7.80(d,J=8.6Hz,2H),7.75(d,J=8.8Hz,2H),7.67(d,J=8.5Hz,2H),7.61(d,J=8.2Hz,2H),7.26(s,2H),4.36(s,2H).13C NMR(100MHz,DMSO-d6,ppm)δ173.45,167.69,164.37,160.69,141.94,141.23,136.75,134.88,131.95,131.09,129.21,129.17,127.33,126.12,126.09,124.49,116.06,86.27,34.45.HR-MS(ESI):calcd.C26H17ClF3N5O2S,[M+H]+m/z:556.0817,found:556.0815.
实施例12
2-巯基-5-氰基-6-芳基嘧啶杂环类化合物I-12,结构式为:制备过程与实施例1的区别在于:将步骤(4)中的苯胺调整为3-三氟甲基苯胺,其余与实施例1相同。具有式I-12所示结构的化合物为白色固体,熔点为214.6-215.7℃,总产率为35.0%,纯度为96%。1H NMR(400MHz,DMSO-d6,ppm)δ11.17(s,1H),10.28(s,1H),10.23(s,1H),8.05(s,1H),7.87(t,J=8.5Hz,2H),7.67(d,J=8.5Hz,3H),7.60(s,2H),7.58-7.55(m,2H),7.22(d,J=8.1Hz,2H),4.33(s,2H).13C NMR(100MHz,DMSO-d6,ppm)δ172.89,167.10,163.89,160.15,140.61,138.47,136.20,134.41,131.55,130.56,129.66,129.35,129.04,128.71,127.81,126.88,125.37,122.66,121.47,120.67,120.64,115.56,85.43,33.88.HR-MS(ESI):calcd.C26H17ClF3N5O2S,[M+H]+m/z:556.0817,found:556.0815.
实施例13
2-巯基-5-氰基-6-芳基嘧啶杂环类化合物I-13,结构式为:制备过程与实施例1的区别在于:将步骤(4)中的苯胺调整为3-硝基苯胺,其余与实施例1相同。具有式I-13所示结构的化合物为白色固体,熔点为210.3-210.9℃,总产率为32.2%,纯度为95%。1H NMR(400MHz,DMSO-d6,ppm)δ11.19(s,1H),10.36(s,1H),10.11(s,1H),8.62(s,1H),8.03(t,J=6.2Hz,2H),7.89(d,J=8.5Hz,2H),7.68(d,J=8.7Hz,3H),7.61(d,J=8.1Hz,2H),7.28(d,J=8.1Hz,2H),4.39(s,2H).13C NMR(100MHz,DMSO-d6,ppm)δ172.96,167.15,163.84,160.15,147.70,140.44,138.96,136.26,134.36,130.60,129.85,129.78,128.73,126.92,119.36,118.12,115.50,85.77,34.05.HR-MS(ESI):calcd.C25H17ClN6O4S,[M+H]+m/z:533.0794,found:533.0795.
实施例14
2-巯基-5-氰基-6-芳基嘧啶杂环类化合物I-14,结构式为:制备过程与实施例1的区别在于:将步骤(4)中的苯胺调整为4-甲基苯甲胺,其余与实施例1相同。具有式I-14所示结构的化合物为白色固体,熔点为216.5-217.9℃,总产率为41.0%,纯度为96%。1H NMR(400MHz,DMSO-d6,ppm)δ11.17(s,1H),9.02(s,1H),8.75(s,1H),7.85(d,J=8.4Hz,2H),7.63(d,J=2.2Hz,2H),7.61(d,J=1.7Hz,2H),7.33(d,J=8.0Hz,2H),7.20(d,J=7.8Hz,2H),7.11(d,J=7.8Hz,2H),4.62(d,J=5.5Hz,2H),4.37(s,2H),2.27(s,3H).13CNMR(100MHz,DMSO-d6,ppm)δ172.85,165.98,163.95,161.06,141.10,135.99,135.95,135.56,134.56,131.45,130.42,128.87,128.60,127.05,126.98,115.93,83.69,43.87,33.83,20.64.HR-MS(ESI):calcd.C27H22ClN5O2S,[M+H]+m/z:516.1256,found:516.1259.
实施例15
2-巯基-5-氰基-6-芳基嘧啶杂环类化合物I-15,结构式为:制备过程与实施例1的区别在于:将步骤(4)中的苯胺调整为4-氟苯甲胺,其余与实施例1相同。具有式I-15所示结构的化合物为白色固体,熔点为217.3-218.7℃,总产率为43.0%,纯度为95%。1H NMR(400MHz,DMSO-d6,ppm)δ11.17(s,1H),9.03(s,1H),8.77(t,J=5.9Hz,1H),7.86(d,J=8.5Hz,2H),7.65(d,J=4.1Hz,2H),7.63(d,J=4.6Hz,2H),7.37(m,J=8.0Hz,4H),7.14(t,J=8.8Hz,2H),4.64(d,J=5.7Hz,2H),4.38(s,2H).13C NMR(100MHz,DMSO-d6,ppm)δ172.89,165.98,163.93,162.42,161.07,160.01,141.00,135.98,134.81,134.78,134.54,131.52,130.43,129.21,129.13,128.60,126.99,115.90,115.14,114.93,83.82,43.43,33.88.HR-MS(ESI):calcd.C26H19ClFN5O2S,[M+H]+m/z:520.1005,found:520.1003.
实施例16
2-巯基-5-氰基-6-芳基嘧啶杂环类化合物I-16,结构式为:制备过程与实施例1的区别在于:将步骤(4)中的苯胺调整为苯肼,其余与实施例1相同。具有式I-16所示结构的化合物为白色固体,熔点为215.2-215.9℃,总产率为47.0%,纯度为95%。1H NMR(400MHz,DMSO-d6,ppm)δ11.16(s,1H),9.00(s,1H),8.08(d,J=7.9Hz,2H),7.89(d,J=8.3Hz,2H),7.69(d,J=4.8Hz,2H),7.67(d,J=5.1Hz,2H),7.56(d,J=8.2Hz,2H),7.51(d,J=8.1Hz,2H),7.29(t,J=7.4Hz,1H),5.57(s,2H),4.57(s,2H).13C NMR(100MHz,DMSO-d6,ppm)δ168.28,163.90,160.69,153.11,148.85,141.11,138.35,135.77,134.66,131.46,131.07,129.07,128.91,128.64,126.93,125.17,119.86,102.38,62.76,34.24.HR-MS(ESI):calcd.C25H19ClN6O2S,[M+H]+m/z:503.1052,found:503.1055.
实施例17
2-巯基-5-氰基-6-芳基嘧啶杂环类化合物I-17,结构式为:制备过程与实施例1的区别在于:将步骤(4)中的苯胺调整为4-甲基苯肼,其余与实施例1相同。具有式I-17所示结构的化合物为白色固体,熔点为210.8-211.3℃,总产率为45.0%,纯度为97%。1H NMR(400MHz,DMSO-d6,ppm)δ11.17(s,1H),9.00(s,1H),7.94(d,J=8.4Hz,2H),7.88(d,J=8.5Hz,2H),7.69(d,J=8.2Hz,2H),7.66(d,J=8.6Hz,2H),7.55(d,J=8.2Hz,2H),7.32(d,J=8.4Hz,2H),5.54(s,2H),4.55(s,2H),2.35(s,3H).13C NMR(100MHz,DMSO-d6,ppm)δ168.13,163.90,160.61,152.79,148.67,141.15,135.99,135.74,134.69,134.47,131.46,131.05,129.45,128.89,128.65,126.93,119.92,102.16,34.20,20.50.HR-MS(ESI):calcd.C26H21ClN6O2S,[M+H]+m/z:517.1208,found:517.1212.
实施例18
2-巯基-5-氰基-6-芳基嘧啶杂环类化合物I-18,结构式为:制备过程与实施例1的区别在于:将步骤(4)中的苯胺调整为4-氟苯肼,其余与实施例1相同。具有式I-18所示结构的化合物为白色固体,熔点为220.3-221.5℃,总产率为28.0%,纯度为93%。1H NMR(400MHz,DMSO-d6,ppm)δ11.17(s,1H),9.01(s,1H),8.08-8.05(m,2H),7.88(d,J=8.3Hz,2H),7.68(t,J=8.3Hz,4H),7.55(d,J=8.1Hz,2H),7.37(t,J=8.1Hz,2H),5.58(s,2H),4.56(s,2H).13C NMR(100MHz,DMSO-d6,ppm)δ168.36,163.90,160.71,158.08,152.96,148.89,141.06,135.80,134.78,134.76,134.61,131.44,131.05,128.92,128.64,126.93,121.78,121.70,115.94,115.71,102.22,34.25.HR-MS(ESI):calcd.C25H18ClFN6O2S,[M+H]+m/z:521.0958,found:521.0959.
实施例19
2-巯基-5-氰基-6-芳基嘧啶杂环类化合物I-19,结构式为:制备过程与实施例1的区别在于:将步骤(4)中的苯胺调整为环己胺,其余与实施例1相同。具有式I-19所示结构的化合物为白色固体,熔点为174.5-175.0℃,总产率为50.0%,纯度为95%。1H NMR(400MHz,DMSO-d6,ppm)δ11.10(s,1H),9.03(s,1H),7.82(d,J=8.3Hz,2H),7.70(d,J=8.0Hz,2H),7.62(d,J=8.4Hz,2H),7.49(d,J=8.0Hz,2H),4.45(s,2H),4.06-4.03(m,1H),1.74(t,J=13.4Hz,4H),1.61(d,J=11.9Hz,1H),1.49-1.41(m,2H),1.31-1.22(m,2H),1.14-1.05(m,1H).13C NMR(100MHz,DMSO-d6,ppm)δ172.76,166.30,163.88,160.04,141.27,135.84,134.70,131.41,130.40,128.55,128.50,126.91,115.95,83.44,50.16,33.94,31.50,24.93.HR-MS(ESI):calcd.C25H24ClN5O2S,[M+H]+m/z:494.1412,found:494.1415.
实施例20
2-巯基-5-氰基-6-芳基嘧啶杂环类化合物I-20,结构式为:制备过程与实施例1的区别在于:将步骤(4)中的苯胺调整为乙胺,其余与实施例1相同。具有式I-20所示结构的化合物为白色固体,熔点为216.0-217.7℃,总产率为42.0%,纯度为96%。1H NMR(400MHz,DMSO-d6,ppm)δ11.20(s,1H),9.05(s,1H),8.18(t,J=5.6Hz,1H),7.84(d,J=8.5Hz,2H),7.70(d,J=8.2Hz,2H),7.62(d,J=8.5Hz,2H),7.49(d,J=8.2Hz,2H),4.46(s,2H),3.50-3.45(m,2H),1.12(t,J=7.1Hz,3H).13C NMR(100MHz,DMSO-d6,ppm)δ173.38,166.35,164.44,161.33,141.71,136.38,135.17,132.00,130.88,129.13,129.09,127.50,116.49,84.01,36.36,34.51,14.79.HR-MS(ESI):calcd.C21H18ClN5O2S,[M+H]+m/z:440.0943,found:440.0945.
实施例21
2-巯基-5-氰基-6-芳基嘧啶杂环类化合物I-21,结构式为:制备过程与实施例1的区别在于:将步骤(4)中的苯胺调整为丙胺,其余与实施例1相同。具有式I-21所示结构的化合物为白色固体,熔点为206.2-207.8℃,总产率为39.0%,纯度为94%。1H NMR(400MHz,DMSO-d6,ppm)δ11.21(s,1H),9.03(s,1H),8.19(t,J=5.6Hz,1H),7.84(d,J=8.5Hz,2H),7.71(d,J=8.2Hz,2H),7.63(d,J=8.5Hz,2H),7.49(d,J=8.2Hz,2H),4.46(s,2H),3.40(d,J=7.2Hz,2H),1.58-1.52(m,2H),0.85(t,J=7.4Hz,3H).13C NMR(100MHz,DMSO-d6,ppm)δ173.33,166.40,164.41,161.53,141.67,136.38,135.17,132.00,130.89,129.08,127.49,120.33,116.49,83.97,43.07,34.48,22.30,11.70.HR-MS(ESI):calcd.C22H20ClN5O2S,[M+H]+m/z:454.1099,found:454.1098.
实施例22
2-巯基-5-氰基-6-芳基嘧啶杂环类化合物I-22,结构式为:制备过程与实施例1的区别在于:将步骤(4)中的苯胺调整为丁胺,其余与实施例1相同。具有式I-22所示结构的化合物为白色固体,熔点为214.8-215.3℃,总产率为37.0%,纯度为96%。1H NMR(400MHz,DMSO-d6,ppm)δ11.20(s,1H),9.02(s,1H),8.18(t,J=5.5Hz,1H),7.84(d,J=8.5Hz,2H),7.71(d,J=8.2Hz,2H),7.62(d,J=8.5Hz,2H),7.48(d,J=8.2Hz,2H),4.46(s,2H),3.46-3.41(m,2H),1.54-1.50(m,2H),1.31-1.25(m,2H),0.87(t,J=7.3Hz,3H).13C NMR(100MHz,DMSO-d6,ppm)δ173.33,166.41,164.38,161.48,141.65,136.37,135.17,132.01,130.89,129.08,127.50,116.49,83.97,34.45,31.12,19.98,14.15.HR-MS(ESI):calcd.C23H22ClN5O2S,[M+H]+m/z:468.1256,found:468.1254.
实施例23
2-巯基-5-氰基-6-芳基嘧啶杂环类化合物I-23,结构式为:制备过程与实施例1的区别在于:将步骤(4)中的苯胺调整为3-甲氧基丙胺,其余与实施例1相同。具有式I-23所示结构的化合物为白色固体,熔点为159.5-160.6℃,总产率为32.0%,纯度为97%。1H NMR(400MHz,DMSO-d6,ppm)δ11.18(s,1H),9.02(s,1H),8.15(t,J=5.3Hz,1H),7.84(d,J=8.5Hz,2H),7.70(d,J=8.1Hz,2H),7.63(d,J=8.5Hz,2H),7.50(d,J=8.1Hz,2H),4.47(s,2H),3.53-3.48(m,2H),3.23(s,3H),1.82-1.76(m,2H).13C NMR(100MHz,DMSO-d6,ppm)δ172.86,165.81,163.93,161.02,141.21,135.90,134.62,131.49,130.37,128.64,128.60,126.99,124.50,115.95,83.57,69.79,57.90,33.95,28.52.HR-MS(ESI):calcd.C23H22ClN5O3S,[M+H]+m/z:484.1205,found:484.1208.
实施例24
2-巯基-5-氰基-6-芳基嘧啶杂环类化合物I-24,结构式为:制备过程与实施例1的区别在于:将步骤(4)中的苯胺调整为2-甲氧基乙胺,其余与实施例1相同。具有式I-24所示结构的化合物为白色固体,熔点为141.8-142.6℃,总产率为32.0%,纯度为97%。1H NMR(400MHz,DMSO-d6,ppm)δ11.19(s,1H),9.02(s,1H),8.11(t,J=5.5Hz,1H),7.85(d,J=8.5Hz,2H),7.70(d,J=8.2Hz,2H),7.63(d,J=8.5Hz,2H),7.49(d,J=8.2Hz,2H),4.46(s,2H),3.64-3.60(m,2H),3.46(t,J=5.8Hz,2H),3.25(s,3H).13C NMR(100MHz,DMSO-d6,ppm)δ172.87,165.91,163.92,161.17,141.16,135.94,134.58,131.52,130.39,128.61,127.01,115.90,83.63,69.68,57.91,33.98.HR-MS(ESI):calcd.C22H20ClN5O3S,[M+H]+m/z:470.1048,found:470.1046.
实施例25
2-巯基-5-氰基-6-芳基嘧啶杂环类化合物I-25,结构式为:制备过程与实施例1的区别在于:将步骤(4)中的苯胺调整为3-羟基丙胺,其余与实施例1相同。具有式I-25所示结构的化合物为白色固体,熔点为182.3-183.9℃,总产率为17.0%,纯度为97%。1H NMR(400MHz,DMSO-d6,ppm)δ11.18(s,1H),9.02(s,1H),8.13(t,J=5.2Hz,1H),7.84(d,J=8.4Hz,2H),7.70(d,J=8.1Hz,2H),7.63(d,J=8.4Hz,2H),7.50(d,J=8.1Hz,2H),4.61(t,J=5.0Hz,1H),4.47(s,2H),3.55-3.52(m,2H),3.50-3.46(m,2H),1.75-1.70(m,2H).13CNMR(100MHz,DMSO-d6,ppm)δ172.85,165.78,163.96,160.97,141.22,135.89,134.63,131.50,130.37,128.69,128.59,126.99,115.97,83.55,58.70,33.98,31.49.HR-MS(ESI):calcd.C22H20ClN5O3S,[M+H]+m/z:470.1048,found:470.1047.
实施例26
2-巯基-5-氰基-6-芳基嘧啶杂环类化合物I-26,结构式为:制备过程与实施例1的区别在于:将步骤(4)中的苯胺调整为哌嗪,其余与实施例1相同。具有式I-26所示结构的化合物为白色固体,熔点为210.2-211.8℃,总产率为19.0%,纯度为93%。1H NMR(400MHz,DMSO-d6,ppm)δ11.23(s,1H),9.54(s,1H),9.04(s,1H),7.87(d,J=8.5Hz,2H),7.71(d,J=8.2Hz,2H),7.65(d,J=8.5Hz,2H),7.50(d,J=8.2Hz,2H),4.49(s,2H),4.14-4.10(m,4H),3.25-3.23(m,2H),2.52-2.49(m,2H).13C NMR(100MHz,DMSO-d6,ppm)δ172.58,169.19,164.45,162.49,141.42,136.86,135.07,132.08,131.56,129.15,127.56,117.92,85.44,44.11,42.70,34.67.HR-MS(ESI):calcd.C23H21ClN6O2S,[M+H]+m/z:481.1208,found:481.1211.
实施例27
2-巯基-5-氰基-6-芳基嘧啶杂环类化合物I-27,结构式为:制备过程与实施例1的区别在于:将步骤(4)中的苯胺调整为吗啉,其余与实施例1相同。具有式I-27所示结构的化合物为白色固体,熔点为230.0-230.9℃,总产率为18.0%,纯度为95%。1HNMR(400MHz,DMSO-d6,ppm)δ11.19(s,1H),9.03(s,1H),7.85(d,J=8.5Hz,2H),7.70(d,J=8.2Hz,2H),7.63(d,J=8.5Hz,2H),7.49(d,J=8.2Hz,2H),4.46(s,2H),3.93-3.90(m,4H),3.71-3.68(m,4H).13C NMR(100MHz,DMSO-d6,ppm)δ172.34,169.39,164.42,161.88,141.52,136.66,135.29,132.05,131.57,129.13,129.05,127.51,118.15,84.55,66.32,47.54,34.62.HR-MS(ESI):calcd.C23H20ClN5O3S,[M+H]+m/z:482.1048,found:482.1052.
实施例28
2-巯基-5-氰基-6-芳基嘧啶杂环类化合物I-28,结构式为:制备过程与实施例1的区别在于:将步骤(4)中的苯胺调整为N-甲基哌嗪,其余与实施例1相同。具有式I-28所示结构的化合物为白色固体,熔点为239.1-240.7℃,总产率为20.0%,纯度为96%。1H NMR(400MHz,DMSO-d6,ppm)δ11.24(s,1H),9.06(s,1H),7.89(d,J=8.5Hz,2H),7.72(d,J=8.2Hz,2H),7.66(d,J=8.6Hz,2H),7.51(d,J=8.2Hz,2H),4.75-4.62(m,2H),4.50(s,2H),3.66(s,2H),3.59(s,2H),3.17(s,2H),2.80(s,3H).13C NMR(100MHz,DMSO-d6,ppm)δ171.80,168.90,167.09,161.33,142.88,141.01,136.14,134.82,131.53,131.09,129.43,128.75,128.62,128.52,126.99,117.71,84.02,62.76,54.21,46.60,45.38,34.11.HR-MS(ESI):calcd.C24H23ClN6O2S,[M+H]+m/z:495.1365,found:495.1364.
实施例29
2-巯基-5-氰基-6-芳基嘧啶杂环类化合物I-29,结构式为:制备过程与实施例1的区别在于:将步骤(4)中的苯胺调整为N-乙基哌嗪,其余与实施例1相同。具有式I-29所示结构的化合物为白色固体,熔点为223.0-224.8℃,总产率为18.0%,纯度为94%。1H NMR(400MHz,DMSO-d6,ppm)δ11.23(s,1H),9.04(s,1H),7.89(d,J=8.6Hz,2H),7.72(d,J=8.2Hz,2H),7.66(d,J=8.5Hz,2H),7.51(d,J=8.2Hz,2H),4.70(d,J=14.0Hz,2H),4.50(s,2H),3.70(t,J=12.8Hz,2H),3.60(d,J=11.6Hz,2H),3.14-3.10(m,2H),3.07-3.05(m,2H),1.28(t,J=7.2Hz,3H).13C NMR(100MHz,DMSO-d6,ppm)δ172.67,169.12,164.37,162.52,141.36,136.92,135.02,132.11,131.58,129.17,129.14,127.57,117.87,85.65,51.13,50.08,44.14,34.69,9.25.HR-MS(ESI):calcd.C25H25ClN6O2S,[M+H]+m/z:509.1521,found:509.1525.
实施例30
2-巯基-5-氰基-6-芳基嘧啶杂环类化合物I-30,结构式为:制备过程与实施例1的区别在于:将步骤(4)中的苯胺调整为N-异丙基哌嗪,其余与实施例1相同,其余与实施例1相同。具有式I-30所示结构的化合物为白色固体,熔点为211.2-212.0℃,总产率为20.0%,纯度为96%。1H NMR(400MHz,DMSO-d6,ppm)δ11.22(s,1H),9.03(s,1H),7.87(d,J=8.6Hz,2H),7.72(d,J=8.2Hz,2H),7.66(d,J=8.6Hz,2H),7.51(d,J=8.2Hz,2H),4.78-4.70(m,2H),4.49(s,2H),3.80-3.72(m,2H),3.55-3.45(m,4H),3.08(s,1H),1.28(d,J=6.5Hz,6H).13C NMR(100MHz,DMSO-d6,ppm)δ172.57,169.17,164.36,162.30,141.42,136.85,135.08,132.08,131.56,129.17,129.10,127.57,117.94,85.38,57.60,47.19,44.02,34.67,16.80.HR-MS(ESI):calcd.C26H27ClN6O2S,[M+H]+m/z:523.1678,found:523.1681.
实施例31
2-巯基-5-氰基-6-芳基嘧啶杂环类化合物I-31,结构式为:制备过程与实施例1的区别在于:将步骤(4)中的苯胺调整为N-乙酰哌嗪,其余与实施例1相同。具有式I-31所示结构的化合物为白色固体,熔点为234.6-235.2℃,总产率为15.0%,纯度为96%。1H NMR(400MHz,DMSO-d6,ppm)δ7.86(d,J=8.3Hz,2H),7.75-7.72(m,2H),7.63(d,J=8.1Hz,2H),7.47-7.45(m,2H),4.46(s,2H),3.96(s,2H),3.90(s,2H),3.62-3.59(m,4H),2.05(s,3H).13C NMR(100MHz,DMSO-d6,ppm)δ171.81,168.78,168.70,164.19,161.50,136.16,134.78,131.08,128.60,128.56,126.96,117.66,84.14,46.60,46.17,44.75,34.14,21.24.HR-MS(ESI):calcd.C25H23ClN6O3S,[M+H]+m/z:523.1314,found:523.1313.
实施例32
2-巯基-5-氰基-6-芳基嘧啶杂环类化合物I-32,结构式为:制备过程如下:
步骤(1)~(2)与实施例1相同。
(3):在50rpm的搅拌速度下,将1mmol步骤(2)得到的4-((4-氯苯基)-5-氰基-6-羟基嘧啶-2-基)硫代)甲基)苯甲酸甲酯加入到以四氢呋喃:水=1:1(20mL)的溶剂中,搅拌均匀后加入10mmol氢氧化钠,于60℃下回流12h。随着反应的进行,反应液逐渐变得澄清,薄层色谱监测(石油醚:乙酸乙酯=5:1)待完全反应后,用旋转蒸发仪除去四氢呋喃,加入水,搅拌状态下,用浓盐酸调节PH至中性,有大量白色固体析出,采用杯状抽滤漏斗抽滤,在0.1MPa压力下抽滤20min,得到4-((4-氯苯基)-5-氰基-6-羟基嘧啶-2-基)硫代)甲基)苯甲酸,产率为95%,纯度为95%。
(4)在650rpm的搅拌下,将1mmol步骤(3)得到的4-((4-氯苯基)-5-氰基-6-羟基嘧啶-2-基)硫代)甲基)苯甲酸置于50mL圆底烧瓶中,加入三氯氧磷作为溶剂,三氯氧磷的量以能够溶解原料且尽可能的少为宜。80℃条件下回流2h,薄层色谱监测(石油醚:乙酸乙酯=5:1)待完全反应后,静置至室温,准备好装有冰水的烧杯,将反应液逐滴加入烧杯中,边滴加边搅拌,待完全淬灭后,烧杯中有大量固体析出,直接抽滤,干燥可得4-((4-氯-6-(4-氯苯基)-5-氰基嘧啶-2-基)硫代甲基)苯甲酸,产率为93%,纯度为98%。
(5)在650rpm的搅拌速度下,室温下将1mmol步骤(4)得到的4-((4-氯-6-(4-氯苯基)-5-氰基嘧啶-2-基)硫代甲基)苯甲酸置于50mL圆底烧瓶中,加入乙醇溶解原料,室温搅拌状态下加入1.5mmol三乙胺以及2mmol巯基四氮唑,转至80℃条件下回流2h,随着反应的进行,有大量白色絮状固体析出,薄层色谱监测(石油醚:乙酸乙酯=5:1)待完全反应后,静置至室温进行抽滤,滤饼用乙醇淋洗,干燥得4-((4-氯苯基)-5-氰基-6-(1-甲基-1H-四氮唑-5-基)硫代)嘧啶-2-基)硫代)甲基)苯甲酸,产率为85%,纯度为95%。
步骤(6)~(7)与实施例1相同。
所得到的具有式I-32所示结构的化合物为白色固体,熔点为212.3-213.6℃,总产率为41.0%,纯度为95%。1H NMR(400MHz,DMSO-d6,ppm)δ11.19(s,1H),10.26(s,1H),9.94(s,1H),7.84(d,J=7.9Hz,2H),7.58(d,J=7.5Hz,3H),7.54(d,J=7.9Hz,3H),7.41(t,J=7.9Hz,2H),7.23(t,J=7.5Hz,2H),7.17(d,J=8.2Hz,2H),4.29(s,2H).13C NMR(100MHz,DMSO-d6,ppm)δ172.70,168.24,166.99,163.85,160.41,141.07,137.54,135.76,131.35,131.16,128.75,128.64,128.51,126.80,125.41,124.59,115.90,84.78,33.75.HR-MS(ESI):calcd.C25H19N5O2S,[M+H]+m/z:454.1332,found:454.1335.
实施例33
2-巯基-5-氰基-6-芳基嘧啶杂环类化合物I-33,结构式为:制备过程与实施例32的区别在于:将步骤(1)中的对氯苯甲醛调整为间甲氧基苯甲醛其余与实施例32相同。所得到的具有式I-33所示结构的化合物为白色固体,熔点为210.0-211.4℃,总产率为45.0%,纯度为95%。1H NMR(400MHz,DMSO-d6,ppm)δ11.16(s,1H),9.85(s,1H),7.87(d,J=7.8Hz,2H),7.58(d,J=8.2Hz,2H),7.53(d,J=7.8Hz,2H),7.40(d,J=8.1Hz,2H),7.38(d,J=5.3Hz,1H),7.18(t,J=8.2Hz,2H),7.13(d,J=8.1Hz,2H),4.30(s,2H),3.86(s,3H).13CNMR(100MHz,DMSO-d6,ppm)δ172.87,164.42,161.19,159.72,157.51,141.77,140.23,133.75,131.91,131.27,130.75,129.50,129.19,127.33,126.83,116.82,114.15,80.71,55.76,34.16.HR-MS(ESI):calcd.C26H21N5O3S,[M+H]+m/z:484.1438,found:484.1441.
实施例34
2-巯基-5-氰基-6-芳基嘧啶杂环类化合物I-34,结构式为:制备过程与实施例32的区别在于:将步骤(1)中的对氯苯甲醛调整为对氟苯甲醛,其余与实施例32相同。具有式I-34所示结构的化合物为白色固体,熔点为202.4-203.3℃,总产率为41.0%,纯度为94%。1H NMR(400MHz,DMSO-d6,ppm)δ11.16(s,1H),9.89(s,1H),9.00(s,1H),7.76(d,J=7.9Hz,2H),7.58(d,J=8.0Hz,2H),7.53(d,J=7.9Hz,2H),7.42(d,J=7.6Hz,2H),7.38(d,J=7.8Hz,2H),7.23(d,J=7.2Hz,1H),7.18(d,J=8.0Hz,2H),4.29(s,2H),2.41(s,3H).13CNMR(100MHz,DMSO-d6,ppm)δ172.61,168.01,163.93,160.48,141.35,141.13,137.59,132.92,131.35,129.08,128.74,128.64,128.48,126.80,125.34,124.53,116.04,84.41,33.75,21.01.HR-MS(ESI):calcd.C26H21N5O2S,[M+H]+m/z:468.1489,found:468.1487.
实施例35
2-巯基-5-氰基-6-芳基嘧啶杂环类化合物I-35,结构式为:制备过程与实施例32的区别在于:将步骤(1)中的对氯苯甲醛调整为2-噻吩甲醛,其余与实施例32相同。具有式I-35所示结构的化合物为白色固体,熔点为208.2-208.8℃,总产率为34.0%,纯度为97%。1H NMR(400MHz,DMSO-d6,ppm)δ11.16(s,1H),9.91(s,1H),9.02(s,1H),7.64(d,J=8.2Hz,1H),7.60(t,J=6.8Hz,2H),7.53(d,J=7.7Hz,2H),7.43(m,5H),7.23(t,J=6.8Hz,1H),7.18(d,J=8.2Hz,2H),4.29(s,2H),2.40(s,3H).13C NMR(100MHz,DMSO-d6,ppm)δ173.17,168.85,164.41,160.91,141.62,138.39,138.05,136.25,132.27,129.52,129.23,129.00,128.88,127.29,126.30,125.90,125.08,116.39,85.25,34.26,21.44.HR-MS(ESI):calcd.C26H21N5O2S,[M+H]+m/z:468.1489,found:468.1487.
实施例36
2-巯基-5-氰基-6-芳基嘧啶杂环类化合物I-36,结构式为:制备过程与实施例32的区别在于:将步骤(1)中的对氯苯甲醛调整为2-呋喃甲醛,其余与实施例32相同。具有式I-36所示结构的化合物为白色固体,熔点为210.3-211.2℃,总产率为28.0%,纯度为94%。1H NMR(400MHz,DMSO-d6,ppm)δ11.16(s,1H),9.97(s,1H),9.01(s,1H),7.57(d,J=4.6Hz,2H),7.55(d,J=4.0Hz,2H),7.43(m,2H),7.36(dd,J=10.7,5.4Hz,4H),7.23(t,J=7.8Hz,1H),7.15(d,J=8.2Hz,2H),4.26(s,2H),2.25(s,3H).13C NMR(100MHz,DMSO-d6,ppm)δ172.55,170.65,163.91,159.71,140.95,137.44,136.12,135.28,131.38,130.48,129.82,128.78,128.58,128.52,126.81,125.76,125.45,124.60,115.13,87.06,33.68,19.05.HR-MS(ESI):calcd.C26H21N5O2S,[M+H]+m/z:468.1489,found:468.1487.
实施例37
2-巯基-5-氰基-6-芳基嘧啶杂环类化合物I-37,结构式为:制备过程与实施例1的区别在于:将步骤(1)中的对氯苯甲醛调整为苯甲醛,其余与实施例1相同。具有式I-37所示结构的化合物为白色固体,熔点为218.2-219.1℃,总产率为37.0%,纯度为96%。1H NMR(400MHz,DMSO-d6,ppm)δ10.33(s,1H),10.07(s,1H),8.03(d,J=8.2Hz,2H),7.96(d,J=8.4Hz,2H),7.59(d,J=8.2Hz,2H),7.54(d,J=7.7Hz,2H),7.43(t,J=7.8Hz,2H),7.25(t,J=7.3Hz,1H),7.16(d,J=8.2Hz,2H),4.29(s,2H).13C NMR(100MHz,DMSO-d6,ppm)δ172.92,167.05,163.82,160.19,140.96,139.68,137.41,131.38,131.06,130.74,129.58,129.20,128.92,128.75,128.53,126.81,125.50,125.46,125.23,124.69,122.52,115.51,85.36,33.77.HR-MS(ESI):calcd.C26H18F3N5O2S,[M+H]+m/z:522.1206,found:522.1210.
实施例38
2-巯基-5-氰基-6-芳基嘧啶杂环类化合物I-38,结构式为:制备过程与实施例1的区别在于:将步骤(1)中的对氯苯甲醛调整为4-甲氧基苯甲醛,其余与实施例1相同。具有式I-38所示结构的化合物为白色固体,熔点212.0-212.8℃,总产率为35.0%,纯度为96%。1H NMR(400MHz,DMSO-d6,ppm)δ11.18(s,1H),10.31(s,1H),9.97(s,1H),7.93(d,J=5.5Hz,2H),7.91(d,J=5.5Hz,2H),7.60(d,J=7.4Hz,2H),7.53(d,J=2.4Hz,2H),7.44(d,J=3.8Hz,1H),7.42(d,J=2.4Hz,2H),7.24(t,J=7.4Hz,2H),7.17(d,J=7.8Hz,2H),4.29(s,2H).13C NMR(100MHz,DMSO-d6,ppm)δ173.21,167.59,165.48,164.39,163.00,160.87,141.56,138.00,132.71,132.69,131.83,131.74,129.25,129.02,127.31,125.95,125.09,116.36,116.22,116.00,85.19,34.27.HR-MS(ESI):calcd.C25H18FN5O2S,[M+H]+m/z:472.1238,found:472.1237.
实施例39
2-巯基-5-氰基-6-芳基嘧啶杂环类化合物I-39,结构式为:制备过程与实施例1的区别在于:将步骤(1)中的对氯苯甲醛调整为4-甲基苯甲醛,其余与实施例1相同。具有式I-39所示结构的化合物为白色固体,熔点为210.7-211.5℃,总产率为28.0%,纯度为95%。1H NMR(400MHz,DMSO-d6,ppm)δ11.18(s,1H),10.09(s,1H),9.02(s,1H),7.68-7.62(m,2H),7.59(d,J=8.2Hz,2H),7.54(d,J=7.7Hz,2H),7.42(t,J=7.4Hz,2H),7.39(d,J=7.7Hz,2H),7.24(t,J=7.4Hz,1H),7.15(d,J=8.2Hz,2H),4.27(s,2H).13C NMR(100MHz,DMSO-d6,ppm)δ173.07,164.97,163.95,160.12,159.50,157.64,140.97,137.32,133.01,132.92,131.37,130.92,128.79,128.56,126.81,125.60,124.86,124.82,124.65,124.20,124.06,116.20,115.99,114.84,87.44,33.73.HR-MS(ESI):calcd.C25H18FN5O2S,[M+H]+m/z:472.1238,found:472.1237.
实施例40
2-巯基-5-氰基-6-芳基嘧啶杂环类化合物I-40,结构式为:制备过程与实施例1的区别在于:将步骤(1)中的对氯苯甲醛调整为3-甲基苯甲醛,其余与实施例1相同。具有式I-40所示结构的化合物为白色固体,熔点为215.0-216.2℃,总产率为30.0%,纯度为96%。1H NMR(400MHz,DMSO-d6,ppm)δ11.16(s,1H),9.90(s,1H),8.26(d,J=3.3Hz,1H),7.98(d,J=4.5Hz,1H),7.59(d,J=8.2Hz,2H),7.52(d,J=7.8Hz,2H),7.41(t,J=7.6Hz,2H),7.33(t,J=7.8Hz,1H),7.23(d,J=8.3Hz,3H),4.31(s,2H).13C NMR(100MHz,DMSO-d6,ppm)δ172.92,161.07,159.87,141.63,140.17,138.06,133.89,131.92,131.39,129.55,129.17,128.95,127.35,125.84,125.00,116.77,81.21,34.18.HR-MS(ESI):calcd.C23H17N5O2S2,[M+H]+m/z:460.0897,found:460.0899.
实施例41
2-巯基-5-氰基-6-芳基嘧啶杂环类化合物I-41,结构式为:制备过程与实施例1的区别在于:将步骤(1)中的对氯苯甲醛调整为2-甲基苯甲醛,其余与实施例1相同。具有式I-41所示结构的化合物为白色固体,熔点为212.1-213.8℃,总产率为18.0%,纯度为95%。1H NMR(400MHz,DMSO-d6,ppm)δ11.16(s,1H),9.82(s,1H),9.01(s,1H),8.11(s,1H),7.59(d,J=8.2Hz,2H),7.54-7.51(m,3H),7.39(t,J=7.8Hz,2H),7.23-7.19(m,3H),6.82(dd,J=3.5,1.6Hz,1H),4.30(s,2H).13C NMR(100MHz,DMSO-d6,ppm)δ173.05,164.42,161.00,156.08,149.74,147.78,141.69,138.06,131.88,129.21,128.93,127.33,125.79,124.98,117.24,115.78,113.51,80.88,34.22.HR-MS(ESI):calcd.C23H17N5O3S,[M+H]+m/z:444.1125,found:444.1128.
实施例42
2-巯基-5-氰基-6-芳基嘧啶杂环类化合物I-42,结构式为:制备过程与实施例1的区别在于:将步骤(1)中的对氯苯甲醛调整为4-三氟甲基苯甲醛,其余与实施例1相同。具有式I-42所示结构的化合物为白色固体,熔点为243.8-244.5℃,总产率为17.0%,纯度为95%。1H NMR(400MHz,DMSO-d6,ppm)δ7.97(d,J=8.6Hz,2H),7.73(d,J=8.6Hz,2H),7.68(d,J=8.2Hz,2H),7.28(d,J=8.2Hz,2H),4.13(s,2H),4.08(s,3H).13CNMR(100MHz,DMSO-d6,ppm)δ173.17,169.36,165.50,163.67,145.66,139.60,137.26,133.02,131.82,130.83,129.07,128.60,127.05,114.63,98.64,34.65,33.93.HR-MS(ESI):calcd.C21H15ClN8O2S2,[M+H]+m/z:511.0521,found:511.0520./>
实施例43
2-巯基-5-氰基-6-芳基嘧啶杂环类化合物I-43,结构式为:制备过程与实施例1的区别在于:将步骤(1)中的对氯苯甲醛调整为4-氟苯甲醛,其余与实施例1相同。具有式I-43所示结构的化合物为白色固体,熔点为265.3-266.0℃,总产率为20.0%,纯度为96%。1H NMR(400MHz,DMSO-d6,ppm)δ8.01(d,J=8.7Hz,2H),7.68(d,J=8.0Hz,2H),7.29(d,J=8.0Hz,2H),7.18(d,J=8.8Hz,2H),4.13(s,2H),4.07(s,3H),3.88(s,3H).13CNMR(100MHz,DMSO-d6,ppm)δ172.79,169.30,165.61,163.71,162.70,145.77,139.75,131.77,131.06,128.59,127.04,126.21,115.16,114.42,97.32,55.63,34.65,33.88.HR-MS(ESI):calcd.C22H18N8O3S2,[M+H]+m/z:507.1016,found:507.1019.
实施例44
2-巯基-5-氰基-6-芳基嘧啶杂环类化合物I-44,结构式为:制备过程与实施例1的区别在于:将步骤(1)中的对氯苯甲醛调整为2-氟苯甲醛,其余与实施例1相同。具有式I-44所示结构的化合物为白色固体,熔点为269.2-270.9℃,总产率为12.0%,纯度为95%。1H NMR(400MHz,DMSO-d6,ppm)δ11.24(s,1H),8.04(d,J=3.3Hz,2H),7.68(d,J=8.1Hz,3H),7.49(t,J=8.8Hz,3H),7.28(d,J=8.1Hz,2H),4.13(s,2H),4.08(s,3H).13CNMR(100MHz,DMSO-d6,ppm)δ173.08,169.32,165.63,165.52,163.67,163.13,145.69,139.62,131.82,131.73,130.74,130.71,128.61,127.04,116.22,116.00,114.75,98.49,34.64,33.92.HR-MS(ESI):calcd.C21H15FN8O2S2,[M+H]+m/z:495.0816,found:495.0816.
实施例45
2-巯基-5-氰基-6-芳基嘧啶杂环类化合物I-45,结构式为:制备过程与实施例1的区别在于:将步骤(1)中的对氯苯甲醛调整为2-噻吩甲醛,其余与实施例1相同。具有式I-45所示结构的化合物为白色固体,熔点为274.2-275.1℃,总产率为24.0%,纯度为97%。1H NMR(400MHz,DMSO-d6,ppm)δ11.20(s,1H),8.33(d,J=3.8Hz,1H),8.13(d,J=4.9Hz,1H),7.68(d,J=8.1Hz,2H),7.39(t,J=4.9Hz,1H),7.33(d,J=8.1Hz,2H),4.14(s,2H),4.06(s,3H).13C NMR(100MHz,DMSO-d6,ppm)δ172.73,169.53,163.72,162.66,158.30,139.77,138.22,135.67,132.55,131.81,129.76,128.55,127.06,115.07,94.22,34.64,33.79.HR-MS(ESI):calcd.C19H14N8O2S3,[M+H]+m/z:483.0475,found:483.0473.
实施例46
2-巯基-5-氰基-6-芳基嘧啶杂环类化合物I-46,结构式为:制备过程与实施例1的区别在于:将步骤(1)中的对氯苯甲醛调整为2-呋喃甲醛,其余与实施例1相同。具有式I-45所示结构的化合物为白色固体,熔点为269.0-269.5℃,总产率为10.0%,纯度为97%。1H NMR(400MHz,DMSO-d6,ppm)δ11.20(s,1H),10.21(s,1H),8.24(s,1H),7.86(d,J=8.1Hz,1H),7.71(d,J=3.4Hz,1H),7.67(d,J=3.4Hz,1H),7.32(d,J=8.0Hz,2H),6.91-6.89(m,1H),4.12(s,2H),4.05(s,3H).13C NMR(100MHz,DMSO-d6,ppm)δ172.78,169.58,154.14,148.99,148.34,145.65,141.74,139.83,129.43,128.77,128.61,127.03,119.03,114.21,113.82,93.56,34.60,33.83.HR-MS(ESI):calcd.C19H14N8O3S2,[M+H]+m/z:467.0703,found:467.0706.
实施例47
2-巯基-5-氰基-6-芳基嘧啶杂环类化合物I-47:制备过程如下:
步骤(1)~(5)与实施例1相同。步骤(6):在650rpm的搅拌速度下,室温下将1mmol步骤(5)得到的4-((4-氯苯基)-5-氰基-6-(苯基氨基)嘧啶-2-基)硫代)甲基)苯甲酸溶于二氯甲烷溶剂中,搅拌状态下加入1mmol的EDCI(1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐)和1mmol HOBT(1-羟基苯并三唑),待反应0.5h后,加入1.1mmol N-BOC苯二胺发生缩合反应,常温反应3h,薄层色谱监测(二氯甲烷:甲醇=15:1)待完全反应后,用二氯甲烷(15mL)萃取三次,将有机相合并,再用饱和食盐水(30mL)洗涤两次,用旋转蒸发仪除去有机相,将粗产品与100-200目的硅胶混合炒样,柱层析法(二氯甲烷:甲醇=80:1)快速分离得4-((5-氰基-4-(4-氟苯基)-6-(苯基氨基)嘧啶-2-基)硫代)甲基)苯甲酰胺基)苯基)氨基甲酸叔丁酯,产率为83%,纯度为94%。
(7)在650rpm的搅拌速度下,室温下将1mmol步骤(6)得到的4-((5-氰基-4-(4-氟苯基)-6-(苯基氨基)嘧啶-2-基)硫代)甲基)苯甲酰胺基)苯基)氨基甲酸叔丁酯溶于二氯甲烷中,于25mmol浓盐酸进行反应,随着反应的进行,有固体析出,待反应半小时后,薄层色谱监测(石油醚:乙酸乙酯=2:1)待完全反应后,将反应溶剂蒸干,加水、用盐酸将溶液调至弱酸性,产物不断析出,静置20min后,采用杯状抽滤漏斗抽滤,在0.1MPa压力下抽滤10min,即可得到如I-47所示化合物,产率为88%,纯度为96%。
具有式I-47所示结构的化合物为白色固体,熔点为301.7-302.5℃,总产率为25.0%,纯度为96%。1H NMR(400MHz,DMSO-d6,ppm)δ9.99(s,1H),9.91(s,1H),7.94(t,J=7.2Hz,2H),7.87(d,J=7.8Hz,2H),7.56(d,J=7.8Hz,2H),7.43(m,5H),7.26(m,5H),7.09(d,J=7.2Hz,1H),6.99(d,J=7.5Hz,1H),6.83(t,J=7.4Hz,1H),4.34(s,2H).13C NMR(100MHz,DMSO-d6,ppm)δ172.69,167.09,165.06,164.99,162.51,160.37,141.53,137.54,132.93,132.24,132.21,131.35,131.26,128.69,128.53,127.85,126.85,126.43,125.44,124.61,119.54,118.37,115.88,115.73,115.51,84.70,33.82.HR-MS(ESI):calcd.C31H23FN6OS,[M+H]+m/z:547.1711,found:547.1715.
实施例48
2-巯基-5-氰基-6-芳基嘧啶杂环类化合物I-48,结构式为:制备过程与实施例47的区别在于:将步骤(1)中的对氟苯甲醛调整为对甲基苯甲醛,其余与实施例47相同。具有式I-48所示结构的化合物为白色固体,熔点为311.2-311.8℃,总产率为30.0%,纯度为95%。1H NMR(400MHz,DMSO-d6,ppm)δ9.91(s,1H),9.61(s,1H),7.82-7.77(m,4H),7.56(d,J=7.9Hz,2H),7.42(d,J=7.6Hz,2H),7.38(d,J=8.0Hz,2H),7.24(d,J=7.8Hz,3H),7.14(d,J=7.6Hz,1H),6.97(t,J=7.4Hz,1H),6.78(d,J=7.8Hz,1H),6.59(t,J=7.5Hz,1H),4.88(s,2H),4.34(s,2H),2.41(s,3H).13C NMR(100MHz,DMSO-d6,ppm)δ172.61,168.02,164.94,160.48,143.12,141.40,141.36,137.63,133.23,132.94,129.09,128.66,128.49,127.72,126.66,126.44,125.34,124.52,123.25,116.19,116.07,84.42,33.81,21.01.HR-MS(ESI):calcd.C32H26N6OS,[M+H]+m/z:543.1962,found:543.1960.
实施例49
2-巯基-5-氰基-6-芳基嘧啶杂环类化合物I-49,结构式为:制备过程与实施例47的区别在于:将步骤(4)中的苯胺调整为4-甲氧基苯胺,步骤(1)中的对氟苯甲醛调整为对氯苯甲醛,其余与实施例47相同。具有式I-49所示结构的化合物为白色固体,熔点为311.2-311.6℃,总产率为37.0%,纯度为97%。1H NMR(400MHz,DMSO-d6,ppm)δ10.42(s,1H),9.88(s,1H),7.94(d,J=8.1Hz,2H),7.87(d,J=8.5Hz,2H),7.66(d,J=8.5Hz,2H),7.52(d,J=7.8Hz,1H),7.43(d,J=8.9Hz,3H),7.35-7.31(m,2H),7.26(d,J=8.2Hz,2H),7.01(d,J=8.9Hz,2H),4.32(s,2H),3.77(s,3H).13C NMR(100MHz,DMSO-d6,ppm)δ173.19,167.41,165.87,160.99,157.62,142.65,136.51,135.12,132.75,131.02,130.69,129.30,129.15,128.49,127.66,127.10,126.97,123.45,116.29,114.27,84.87,66.83,55.82,34.32.HR-MS(ESI):calcd.C32H25ClN6O2S,[M+H]+m/z:593.1521,found:593.1526.
实施例50
2-巯基-5-氰基-6-芳基嘧啶杂环类化合物I-50,结构式为:制备过程与实施例47的区别在于:将步骤(4)中的苯胺调整为4-氟苯胺,步骤(1)中对氟苯甲醛调整为对氯苯甲醛,其余与实施例47相同。具有式I-50所示结构的化合物为白色固体,熔点为308.0-309.6℃,总产率为32.0%,纯度为96%。1H NMR(400MHz,DMSO-d6,ppm)δ10.01(s,1H),9.63(s,1H),7.88(d,J=8.5Hz,2H),7.83(d,J=8.0Hz,2H),7.66(d,J=8.5Hz,2H),7.58-7.54(m,2H),7.28(d,J=8.9Hz,2H),7.25(d,J=6.1Hz,2H),7.15(d,J=7.7Hz,1H),6.96(t,J=7.3Hz,1H),6.78(d,J=7.4Hz,1H),6.59(t,J=7.6Hz,1H),4.89(s,2H),4.33(s,2H).13C NMR(100MHz,DMSO-d6,ppm)δ172.79,166.96,164.94,160.44,158.43,148.33,146.15,143.13,141.29,136.09,134.53,133.83,133.28,130.54,128.67,127.74,126.88,126.68,126.45,123.24,116.19,115.72,115.33,115.10,84.72,33.85.HR-MS(ESI):calcd.C31H22ClFN6OS,[M+H]+m/z:581.1321,found:581.1325.
试验例1
对具有式□-1~□-50所示结构的化合物进行体外酶活性测定,具体如下:利用HDAC6具有去乙酰化特性,首先将HDAC6重组蛋白与带有乙酰化的赖氨酸及AMC荧光基团的多肽37℃孵育20min,以暴露AMC荧光基团;加入胰酶水解多肽,释放荧光基团,使用酶标仪,在激发波长355nm,发射波长460nm处测定荧光强度变化值。评价候选化合物的抑制率。根据设定的浓度梯度,测定不同浓度下化合物作用后的荧光强度,计算抑制率,HDAC1的测试同上。用GraphPad Prism8.0软件计算拟合,求出化合物的IC50。抑制率(100%)=(阳性对照荧光强度-化合物荧光强度)/(阳性对照荧光强度-空白组荧光强度)×100%。抑制率试验结果如表1所示。
进一步以SAHA为阳性对照,选取对HDAC6抑制率在60%以上的化合物,测定其对HDAC6的IC50值,试验结果如表2所示。
表1本发明化合物对于HDAC6的选择性抑制活性
表2本发明部分化合物对HDAC6的IC50值
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由以上表1和表2的试验结果可知,相对于阳性对照SAHA、ACY-1215,本发明提供的2-巯基-5-氰基-6-芳基嘧啶杂环类化合物对HDAC6具有良好的选择性抑制作用。
试验例2
选取对HDAC6有高效、高选择性抑制的化合物I-28,采用MTT方法测试对胃癌细胞MGC-803的增殖抑制作用,具体如下:在含有10%的胎牛血清的高糖培养基(DMEM)中培养MGC-803细胞,将MGC-803细胞以3×103个细胞/孔铺在96孔板上,边缘孔用无菌5%CO2,37℃过夜孵育,加终浓度为0.15625、0.3125、0.625、1.25、2.5、5、10、20μM的化合物I-28,每个药物浓度设3个复孔,72h后每孔加20μL MTT溶液(终质量浓度为0.5g/L),37℃孵育4h后终止培养小心吸弃培养上清液,每孔加200μL二甲基亚砜,置摇床上低速振荡15min,使结晶物充分溶解后,使用酶标仪测定570nm处的吸光度(A),同时设置调零孔即空白组、阴性对照孔。计算抑制率,用GraphPad Prism8.0软件计算、拟合,求出IC50。抑制率(100%)=(对照组-加药组)/(对照组-空白组)×100%。试验结果如表3所示。
表3本发明的化合物I-28与SAHA的增殖抑制对比
化合物 | MGC-803 IC50(μM) |
I-28 | 2.68±0.76 |
SAHA | 8.67±0.93 |
表3结果表明,本发明的2-巯基-5-氰基-6-芳基嘧啶杂环类化合物I-28对MGC-803细胞有良好的增殖抑制效果,其对MGC-803细胞的增殖抑制作用显著优于阳性对照SAHA。
综上可知,本发明提供的2-巯基-5-氰基-6-芳基嘧啶杂环类化合物,通过与胃癌细胞内金属离子鳌合形成稳定的配合物,从而抑制了胃癌细胞MGC-803的增殖活性。试验结果表明,与阳性对照SAHA、ACY-1215相比,本发明提供的2-巯基-5-氰基-6-芳基嘧啶杂环类化合物不仅对HDAC6有较优的选择性抑制作用,而且能够以浓度依赖性的方式抑制胃癌MGC-803细胞增殖,在制备基于HDAC6靶点的抑制剂以及抑制胃癌细胞增殖活性的药物中具有良好的应用前景。
Claims (10)
1.一种2-巯基-5-氰基-6-芳基嘧啶杂环类化合物,其特征在于,结构式如式Ⅰ所示:
其中,R1为取代胺基、取代酰肼基中的一种;取代胺基、取代酰肼基中的取代基各自独立地选自氢、C1-C4饱和烷基、甲氧基、卤素、三氟甲基、硝基中的一种或多种;
R2为取代芳香基或芳杂环基;所述取代芳香基的取代基为氢、甲基、甲氧基、卤素、三氟甲基中的一种;所述芳杂环基为呋喃基、噻吩基中的一种;
R3为
2.根据权利要求1所述的2-巯基-5-氰基-6-芳基嘧啶杂环类化合物,其特征在于,所述R1为
中的一种。
3.根据权利要求1所述的2-巯基-5-氰基-6-芳基嘧啶杂环类化合物,其特征在于,所述R2为 中的一种。
4.根据权利要求1所述的2-巯基-5-氰基-6-芳基嘧啶杂环类化合物,其特征在于,选自如下具体结构的化合物,依次记为化合物I-1~I-50:
5.如权利要求1~4任一项所述的2-巯基-5-氰基-6-芳基嘧啶杂环类化合物的制备方法,其特征在于,包括以下步骤:
(1)将原料A、原料B、原料C、碱溶于溶剂a中,加热回流进行成环反应,得到中间体化合物D;
(2)将中间体化合物D溶于溶剂b中,然后在碱性物质作用下与4-溴甲基苯甲酸甲酯进行取代反应,得到中间体化合物E;
(3)将中间体化合物E加入到溶剂c中进行氯代反应,反应结束后淬灭、抽滤,得到中间体化合物F;
(4)将中间体化合物F、胺类物质、碱性物质在溶剂a中进行回流反应,反应结束后抽滤,得到中间体化合物G;所述胺类物质为不同取代的苯胺、苄胺、苯肼或脂肪族胺;
(5)将中间体化合物G溶于溶剂d中,搅拌状态下加入碱进行水解反应,得到中间体化合物H;
(6)将中间体化合物H溶于溶剂e中,在缩合剂的作用下与邻(4-氢-2H-吡喃-2-基)羟基胺或N-BOC-1,2苯二胺进行缩合反应,得到中间体化合物J;
(7)将中间体化合物J溶于溶剂e或溶剂f中,与浓盐酸进行反应,得到具有结构通式Ⅰ的2-巯基-5-氰基-6-芳基嘧啶杂环类化合物;
其中,中间体化合物J中,R4为2-甲氧基四氢-2H-吡喃基或乙酸叔丁酯基。
6.根据权利要求5所述的2-巯基-5-氰基-6-芳基嘧啶杂环类化合物的制备方法,其特征在于,步骤(1)中,原料A、原料B、原料C与碱的添加摩尔比为1:1:1.2:1.5;步骤(2)中,中间体化合物D与4-溴甲基苯甲酸甲酯、碱性物质的添加摩尔比为1:1:2;步骤(3)中,中间体化合物E与溶剂c的添加摩尔比为1:10;步骤(4)中,中间体化合物F、胺类物质、碱性物质添加摩尔比为1:2:1.5;步骤(5)中,中间体化合物G与溶剂d的添加摩尔比为1:10;步骤(6)中,中间体化合物H与邻(4-氢-2H-吡喃-2-基)羟基胺的添加摩尔比为1:1.5;中间体化合物H与N-BOC-1,2苯二胺的添加摩尔比为1:1.1;步骤(7)中,中间体化合物J与浓盐酸的添加摩尔比为1:(2~100)。
7.如权利要求5所述的2-巯基-5-氰基-6-芳基嘧啶杂环类化合物的制备方法,其特征在于,步骤(1)中,成环反应的温度为80℃,成环反应在搅拌中进行,搅拌的速率为600~700rpm,成环反应的时间为6h;步骤(2)中,取代反应在搅拌条件下进行,搅拌的速率为600~700rpm,取代反应的温度为60℃,时间为3h;步骤(3)中,氯代反应在搅拌条件下进行,搅拌的速率为600~700rpm,氯代反应的温度为80℃,时间为2h;步骤(4)中,回流反应在搅拌条件下进行,搅拌的速率为600~700rpm,回流反应温度为80℃,时间为2h;步骤(5)中,水解反应在搅拌条件下进行,搅拌的速率为600~700rpm,水解反应的温度为60℃,时间为12h;步骤(6)中,缩合反应在搅拌条件下进行,搅拌的速率为600~700rpm,缩合反应的温度为室温,时间为3h;步骤(7)中,与浓盐酸的反应在常温搅拌中进行,搅拌的速率为600~700rpm。
8.如权利要求5所述的2-巯基-5-氰基-6-芳基嘧啶杂环类化合物的制备方法,其特征在于,步骤(1)中,所述碱为氢氧化钾或碳酸钾;步骤(2)、步骤(4)中,所述碱性物质为三乙胺;所述溶剂a为乙醇,溶剂b为甲醇,溶剂c为三氯氧磷,溶剂d为四氢呋喃,溶剂e为二氯甲烷,溶剂f为1,4-二氧六环;步骤(6)中,所述缩合剂为1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐和1-羟基苯并三唑。
9.如权利要求1~4任一项所述的2-巯基-5-氰基-6-芳基嘧啶杂环类化合物的应用,其特征在于,在制备基于HDAC6靶点的抑制剂中的应用,或者在制备抑制胃癌细胞增殖活性的药物中的应用。
10.如权利要求9所述的2-巯基-5-氰基-6-芳基嘧啶杂环类化合物的应用,其特征在于,所述胃癌细胞为MGC-803。
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