CN115093398A - 一种化合物及其制备方法和药物组合物及应用 - Google Patents
一种化合物及其制备方法和药物组合物及应用 Download PDFInfo
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- CN115093398A CN115093398A CN202210829763.1A CN202210829763A CN115093398A CN 115093398 A CN115093398 A CN 115093398A CN 202210829763 A CN202210829763 A CN 202210829763A CN 115093398 A CN115093398 A CN 115093398A
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- C—CHEMISTRY; METALLURGY
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
本发明提供了一种化合物及其制备方法和药物组合物及应用,属于药物技术领域。本发明提供的化合物能够通过抑制STAT3活性达到预防和/或治疗肿瘤目的,同时本发明提供的化合物能够提高机体对肿瘤的免疫能力而增强抗肿瘤活性,可以通过向需要肿瘤预防和/或治疗的患者给予有效量的化合物来达到预防和/或治疗肿瘤的目的。实施例的结果显示,本发明提供的化合物具有抗肿瘤药理活性。
Description
技术领域
本发明涉及药物技术领域,具体涉及一种化合物及其制备方法和药物组合物及应用。
背景技术
信号转导和转录激活因子(STAT)家族为一类具有信号传导功能和转录活化功能的胞浆蛋白,可与不同的细胞因子受体结合,并将胞外信号传递至细胞核内,从而引发相应靶基因的转录。作为STAT家族成员之一的STAT3因具有多种重要作用(例如调节细胞生长、分化和程序性死亡以及血管形成等)而备受研究人员关注。近来研究表明,在正常生理状态下,STAT3蛋白的激活受到严格控制;而在多种肿瘤(如乳腺癌、卵巢癌、头颈部鳞状细胞癌、多发性骨髓瘤、淋巴瘤、脑瘤以及非小细胞肺癌等)的细胞中均可见该蛋白过度激活。事实上,在STAT家族中,STATl和STAT6的异常激活亦可导致肿瘤的发生及发展,但STAT3更适合作为肿瘤治疗的靶点,原因是STAT3被激活后可产生免疫抑制作用,抑制STAT3的过度表达不仅能阻断肿瘤细胞的过度增殖,还可增强机体对肿瘤的免疫能力。
最近研究表明,抑制STAT3信号可以克服包括肺癌、白血病等多种肿瘤的耐药性,STAT3已成为一个热门的抗肿瘤靶标。因此,发现新的STAT3抑制剂对于肿瘤的防治具有重要意义。
发明内容
本发明的目的在于提供一种化合物及其制备方法和药物组合物及应用,本发明提供的化合物能够抑制STAT3活性,且能够提高机体对肿瘤的免疫能力,因而可以用于预防和/或治疗肿瘤。
为了实现上述发明目的,本发明提供以下技术方案:
本发明提供了一种具有式I所示结构的化合物、其药学上可接受的盐、立体异构体、水合物、溶剂合物或同位素化合物,所述式I如下所示:
式I中,R1选自甲基磺酰基或环丙基磺酰基;R2选自取代或未取代的苯基、取代或未取代的芳杂基。
优选地,所述芳杂基中杂原子为氮,所述芳杂基为单环芳杂基或稠环芳杂基。
优选地,所述芳杂基选自吡唑基、吡咯基、咪唑基或吡啶基。
优选地,所述取代的苯基和取代的芳杂基中一个或多个取代基独立地选自卤素、烷基、烷氧基、氰基或氨基甲酰基。
优选地,所述具有式I所示结构的化合物为以下化合物中的至少一种:
本发明提供了上述技术方案所述具有式I所示结构的化合物的制备方法,包括以下步骤:
将化合物II、化合物III、第一碱试剂与第一溶剂混合,进行取代反应,得到化合物IV;
将所述化合物IV、第二碱试剂与第二溶剂混合,进行水解反应,得到化合物V;
将所述化合物V、化合物VI、缩合剂、第三碱试剂与第三溶剂混合,进行缩合反应,得到化合物VII;
将所述化合物VII、化合物VIII、催化剂、第四碱试剂与第四溶剂混合,进行偶联反应,得到具有式I所示结构的化合物;
所述化合物II、化合物III、化合物IV、化合物V、化合物VI、化合物VII和化合物VIII的结构式依次如下所示:
本发明提供了一种药物组合物,包括活性成分和药学上可接受的辅料,所述活性成分为上述技术方案所述具有式I所示结构的化合物、其药学上可接受的盐、立体异构体、水合物、溶剂合物或同位素化合物。
本发明提供了上述技术方案所述具有式I所示结构的化合物、其药学上可接受的盐、立体异构体、水合物、溶剂合物或同位素化合物或上述技术方案所述药物组合物在制备STAT3抑制剂中的应用。
本发明提供了上述技术方案所述具有式I所示结构的化合物、其药学上可接受的盐、立体异构体、水合物、溶剂合物或同位素化合物或上述技术方案所述药物组合物在制备预防和/或治疗肿瘤药物中的应用。
优选地,所述肿瘤选自皮肤癌、膀胱癌、卵巢癌、乳腺癌、胃癌、前列腺癌、结肠癌、肺癌、骨癌、脑癌、直肠癌、食管癌、舌癌、胃癌、肾癌、肾实质癌、宫颈癌、子宫体癌、子宫内膜癌、睾丸癌、泌尿癌、黑素癌、星型细胞癌、脑膜瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、急性淋巴性白血病、慢性淋巴性白血病、急性骨髓性白血病,慢性粒细胞白血病、成人T细胞白血病淋巴瘤、肝细胞癌、支气管癌、小细胞肺癌、非小细胞肺癌、多发性骨髓瘤、基底细胞瘤、精原细胞瘤、横纹肌肉瘤、软骨肉瘤、肌肉瘤或纤维肉瘤。
本发明提供了一种化合物,本发明提供的化合物能够通过抑制STAT3活性达到预防和/或治疗肿瘤目的,同时本发明提供的化合物能够提高机体对肿瘤的免疫能力而增强抗肿瘤活性,可以通过向需要肿瘤预防和/或治疗的患者给予有效量的化合物来达到预防和/或治疗肿瘤的目的。实施例的结果显示,本发明提供的化合物具有抗肿瘤药理活性。
具体实施方式
本发明提供了一种具有式I所示结构的化合物、其药学上可接受的盐、立体异构体、水合物、溶剂合物或同位素化合物,所述式I如下所示:
式I中,R1选自甲基磺酰基或环丙基磺酰基;R2选自取代或未取代的苯基、取代或未取代的芳杂基。
在本发明中,所述芳杂基中杂原子优选为氮,所述芳杂基优选为单环芳杂基或稠环芳杂基。在本发明中,所述芳杂基优选为吡唑基、吡咯基、咪唑基或吡啶基。
在本发明中,所述取代的苯基和取代的芳杂基中一个或多个取代基优选独立地选自卤素、烷基、烷氧基、氰基或氨基甲酰基。在本发明中,所述烷基和烷氧基中碳原子个数优选独立地为1~5,更优选为1~3。在本发明中,所述烷基优选为直链烷基或环烷基,所述直链烷基优选为甲基或异丙基,所述环烷基优选为环丙基;所述烷氧基优选为甲氧基。在本发明中,所述卤素优选为-F或-Cl。
在本发明中,所述具有式I所示结构的化合物(记为化合物I)优选为表1中所示化合物中的至少一种。
表1化合物I的可选种类
本发明提供的化合物可以为化合物I,也可以为化合物I的药学上可接受的盐、立体异构体、水合物、溶剂合物或同位素化合物。下面分别进行详细说明。
在本发明中,所述药学上可接受的盐是指那些保留母体化合物的生物有效性及特性的盐,具体包括:酸加成盐,其是通过母体化合物的游离碱与无机酸或与有机酸的反应而获得的;所述无机酸诸如盐酸、氢溴酸、氢碘酸、硝酸、磷酸、硫酸或高氯酸,所述有机酸诸如乙酸、草酸、(D)-苹果酸或(L)-苹果酸、马来酸、甲烷磺酸、乙烷磺酸、对甲苯磺酸、水杨酸、酒石酸、苯磺酸(苯磺酸盐)、苯甲酸、樟脑磺酸、柠檬酸、富马酸、葡萄糖酸、谷氨酸、羟乙磺酸、乳酸、马来酸、苹果酸、扁桃酸、黏液酸、双羟萘酸、泛酸、琥珀酸、酒石酸或丙二酸;优选为盐酸或(L)-苹果酸;或者当母体化合物中存在的酸质子被置换为金属离子或与有机碱配位时形成盐,所述金属离子诸如碱金属离子、碱土离子或铝离子;所述有机碱诸如乙醇胺、二乙醇胺、三乙醇胺、缓血酸胺、N-甲基葡糖胺或类似物。
本发明的化合物I可能具有一个或多个不对称中心,因此该化合物I可以个别(R)-立体异构体或(S)-立体异构体形式制备或以其混合物形式制备。除非另有说明,否则本说明书及权利要求中的特定化合物的描述或名称意欲包括个别对映异构体与其外消旋混合物或其它混合物。用于测定立体化学构型及分离立体异构体的方法在本领域中是熟知的(参见“Advanced Organic Chemistry”的第4章中的论述,第4版,J.March,John Wiley及Sons,New York,1992)。因此,本发明亦涵盖具有抑制STAT3活性的基于化合物I的任何立体异构形式、其相应对映异构体(D-异构体及L-异构体,或者(+)异构体及(-)异构体)、非对映异构体或其混合物,且不限于任一种立体异构形式。
本发明对所述化合物I的水合物、溶剂合物以及同位素化合物没有特殊限定。
本发明提供了上述技术方案所述化合物I的制备方法,包括以下步骤:
将化合物II、化合物III、第一碱试剂与第一溶剂混合,进行取代反应,得到化合物IV;
将所述化合物IV、第二碱试剂与第二溶剂混合,进行水解反应,得到化合物V;
将所述化合物V、化合物VI、缩合剂、第三碱试剂与第三溶剂混合,进行缩合反应,得到化合物VII;
将所述化合物VII、化合物VIII、催化剂、第四碱试剂与第四溶剂混合,进行偶联反应,得到化合物I;
所述化合物II、化合物III、化合物IV、化合物V、化合物VI、化合物VII和化合物VIII的结构式依次如下所示:
在本发明中,制备化合物I的反应路线如下所示:
下面结合上述反应路线,对所述化合物I的制备方法进行详细说明。
本发明将化合物II、化合物III、第一碱试剂与第一溶剂混合,进行取代反应,得到化合物IV。在本发明中,所述化合物II与化合物III的摩尔比优选为1:(0.8~1.2),更优选为1:1。在本发明中,所述第一碱试剂优选为三乙胺、二异丙基乙胺、吡啶、碳酸钾或碳酸铯,更优选为三乙胺;所述第一碱试剂与化合物II的摩尔比优选为(1.3~1.7):1,更优选为1.5:1。在本发明中,所述第一溶剂优选为二氯甲烷、四氢呋喃、乙腈或甲苯,更优选为二氯甲烷;本发明对所述第一溶剂的用量没有特殊限定,能够保证取代反应顺利进行即可。本发明优选将化合物II与第一碱试剂溶于第一溶剂中,降温至-2~2℃,向所得混合液中滴加化合物III,滴加完毕后调整至取代反应所需温度,进行取代反应。在本发明中,所述取代反应的温度优选为0~80℃,更优选为20~50℃,具体可以在室温(25℃)条件下进行所述取代反应;时间优选为5~7h,更优选为6h,本发明优选通过TLC监测反应进程。
所述取代反应后,本发明优选将所得产物体系与水混合淬灭反应,将所得有机层依次进行干燥、浓缩以及柱层析分离,得到的黄色固体即为化合物IV。
得到化合物IV后,本发明将所述化合物IV、第二碱试剂与第二溶剂混合,进行水解反应,得到化合物V。在本发明中,所述第二碱试剂优选为碱金属氢氧化物,更优选为氢氧化锂、氢氧化钠或氢氧化钾;所述第二碱试剂与化合物IV的摩尔比优选为(1.8~2.2):1,更优选为2:1。在本发明中,所述第二溶剂优选为甲醇、乙醇、四氢呋喃水溶液、二氧六环水溶液或甲醇水溶液,更优选为四氢呋喃水溶液,所述四氢呋喃水溶液中四氢呋喃与水的体积比优选为(1.5~2.5:):1,更优选为2:1;本发明对所述第二溶剂的用量没有特殊限定,保证水解反应顺利进行即可。在本发明中,所述水解反应的温度优选为20~80℃,更优选为20~40℃,具体可以在室温条件下进行所述水解反应;时间优选为7~9h,更优选为8h,本发明优选通过TLC监测反应进程。
所述水解反应后,本发明优选将所得产物体系与盐酸混合淬灭反应,然后用乙酸乙酯萃取,将所得有机层浓缩后经柱层析分离,得到的类白色固体即为化合物V。在本发明中,所述盐酸的浓度优选为1~3mol/L,更优选为2mol/L。
得到化合物V后,本发明将所述化合物V、化合物VI、缩合剂、第三碱试剂与第三溶剂混合,进行缩合反应,得到化合物VII。在本发明中,所述化合物V与化合物VI的摩尔比优选为1:(0.8~1.2),更优选为1:1。在本发明中,所述缩合剂可以为2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯或二环己基碳二亚胺,也可以为1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐与1-羟基苯并三氮唑,优选为2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯;所述缩合剂与化合物V的摩尔比优选为(1.3~1.7):1,更优选为1.5:1。在本发明中,所述第三碱试剂优选为三乙胺、二异丙基乙胺或4-二甲基氨基吡啶,更优选为二异丙基乙胺;所述第三碱试剂与化合物V的摩尔比优选为(1.3~1.7):1,更优选为1.5:1。在本发明中,所述第三溶剂优选为二氯甲烷或N,N-二甲基甲酰胺,更优选为N,N-二甲基甲酰胺;本发明对所述第三溶剂的用量没有特殊限定,保证缩合反应顺利进行即可。在本发明中,所述缩合反应的温度优选为20~80℃,更优选为20~40℃,具体可以在室温条件下进行所述水解反应;时间优选为3~5h,更优选为4h,本发明优选通过TLC监测反应进程。
所述缩合反应后,本发明优选将所得产物体系与水混合淬灭反应,然后用乙酸乙酯萃取,将所得有机层浓缩后经柱层析分离,得到的类白色固体即为化合物VII。
得到化合物VII后,本发明将所述化合物VII、化合物VIII、催化剂、第四碱试剂与第四溶剂混合,进行偶联反应,得到化合物I。在本发明中,所述化合物VII与化合物VIII的摩尔比优选为1:(0.8~1.2),更优选为1:1。在本发明中,所述催化剂优选为四三苯基膦钯、醋酸钯、三二亚苄基丙酮二钯或1,1'-双(二苯膦基)二茂铁二氯化钯,所述催化剂与化合物VII的摩尔比优选为(0.08~0.12):1,更优选为0.1:1。在本发明中,所述第四碱试剂优选为碳酸铯、叔丁醇钠、叔丁醇钾或碳酸钾,所述第四碱试剂与化合物VII的摩尔比优选为(1.8~2.2):1,更优选为2:1。在本发明中,所述第四溶剂优选为四氢呋喃水溶液、二氧六环、N,N-二甲基甲酰胺或甲苯,更优选为四氢呋喃水溶液,本发明对所述第四溶剂的用量没有特殊限定,保证偶联反应顺利进行即可。在本发明中,所述偶联反应的温度优选为80~120℃,更优选为80~120℃;时间优选为8~12h,更优选为10h,本发明优选通过TLC监测反应进程。
所述偶联反应后,本发明优选将所得产物体系用乙酸乙酯萃取,将所得有机层依次进行干燥、浓缩以及柱层析分离,得到的类白色固体即为化合物I。
本发明对制备所述化合物I过程中涉及的柱层析分离所用洗脱剂没有特殊限定。
本发明对所述化合物I的药学上可接受的盐、立体异构体、水合物、溶剂合物或同位素化合物的制备方法没有特殊限定,采用本领域技术人员熟知的方法制备得到即可。
本发明提供了一种药物组合物,包括活性成分和药学上可接受的辅料,所述活性成分为上述技术方案所述化合物I、其药学上可接受的盐、立体异构体、水合物、溶剂合物或同位素化合物。在本发明中,所述药学上可接受的辅料优选包括药用载体、赋形剂和稀释剂中的一种或几种;本发明所述药学上可接受的辅料是指对生物不产生明显刺激且不会消除所给予的化合物的生物活性及特性的物质。在本发明中,所述药物组合物中活性成分的含量优选≥10wt%,更优选为10~50wt%。
本发明提供了上述技术方案所述化合物I、其药学上可接受的盐、立体异构体、水合物、溶剂合物或同位素化合物或上述技术方案所述药物组合物在制备STAT3抑制剂中的应用。
本发明提供了上述技术方案所述化合物I、其药学上可接受的盐、立体异构体、水合物、溶剂合物或同位素化合物或上述技术方案所述药物组合物在制备预防和/或治疗肿瘤药物中的应用。在本发明中,所述肿瘤优选为皮肤癌、膀胱癌、卵巢癌、乳腺癌、胃癌、前列腺癌、结肠癌、肺癌、骨癌、脑癌、直肠癌、食管癌、舌癌、胃癌、肾癌、肾实质癌、宫颈癌、子宫体癌、子宫内膜癌、睾丸癌、泌尿癌、黑素癌、星型细胞癌、脑膜瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、急性淋巴性白血病、慢性淋巴性白血病、急性骨髓性白血病,慢性粒细胞白血病、成人T细胞白血病淋巴瘤、肝细胞癌、支气管癌、小细胞肺癌、非小细胞肺癌、多发性骨髓瘤、基底细胞瘤、精原细胞瘤、横纹肌肉瘤、软骨肉瘤、肌肉瘤或纤维肉瘤。在本发明中,所述预防和/或治疗肿瘤药物的剂型优选包括片剂、胶囊或针剂。
下面将结合本发明中的实施例,对本发明中的技术方案进行清楚、完整地描述。显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
实施例1
制备N-(3-(1-环丙基-1H吡唑-4-基)吡啶-4-基)-7-(甲基磺酰氨基)喹唑啉-2-甲酰胺(化合物1)的反应路线如下:
(1)将化合物1a(20.3g,100.0mmol)与三乙胺(1.5g,150.0mmol)溶于二氯甲烷(300mL)中,降温至0℃,滴加甲基磺酰氯(11.4g,100.0mmol),滴加完毕后升至室温(25℃),保温反应6h,TLC监测反应,反应完毕后加水(100mL)淬灭反应,将所得有机层依次进行干燥、浓缩以及柱层析分离,得到的黄色固体即为化合物1b,产量20.3g,收率72.2%。
(2)将所述化合物1b(20.0g,71.1mmol)溶于四氢呋喃(200mL)和水(100mL)中,室温条件下加入氢氧化锂(3.4g,142.2mmol),搅拌反应8h,TLC监测反应,反应完毕后加入浓度为2mol/L的盐酸淬灭反应,然后用乙酸乙酯(500mL×2)萃取,将所得有机层浓缩后经柱层析分离,得到的类白色固体即为化合物1c,产量15.5g,收率81.6%。
(3)将所述化合物1c(15.0g,56.2mmol)、化合物1d(9.6g,56.2mmol)、二异丙基乙胺(DIEA,10.9mg,84.3mmol)溶于N,N-二甲基甲酰胺(DMF,100mL)中,室温条件下加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU,32.0g,84.3mmol),搅拌反应4h,TLC监测反应,反应完毕后加水(100mL)淬灭反应,然后用乙酸乙酯(500mL×2)萃取,将所得有机层浓缩后经柱层析分离,得到的类白色固体即为化合物1e,产量17.7g,收率75.0%。
(4)将所述化合物1e(420mg,1.0mmol)、化合物1f(152mg,1.0mmol)、四三苯基膦钯(115mg,0.1mmol)与碳酸钾(276mg,2.0mmol)溶于四氢呋喃(10mL)和水(5mL)中,油浴加热升温至80℃,搅拌反应10h,TLC监测反应,反应完毕后用乙酸乙酯(50mL×2)萃取,将所得有机层依次进行干燥、浓缩以及柱层析分离,得到的类白色固体即为化合物1,产量318mg,收率70.8%,表征数据如下:
ESI(+)m/z=450.1,1H-NMR(500MHz,d6-DMSO)δ9.80(d,J=1.7Hz,1H),8.74(d,J=1.6Hz,1H),8.46(dd,J=5.7,1.6Hz,1H),8.31(d,J=5.7Hz,1H),8.05–7.98(m,1H),7.82(d,J=1.4Hz,1H),7.68(dq,J=4.8,2.2Hz,2H),7.18(d,J=1.4Hz,1H),3.71(p,J=5.7Hz,1H),2.99(s,3H),0.92(dddd,J=10.2,8.4,5.7,1.8Hz,2H),0.82(dddd,J=10.6,9.0,5.7,1.8Hz,2H),0.71(s,1H)。
实施例2
制备N-(3-(2-异丙基-1H-吡唑-4-基)吡啶-4-基)-7-(甲基磺酰氨基)喹唑啉-2-甲酰胺(化合物2)的反应路线如下:
将化合物1e(420mg,1.0mmol)、化合物2a(154mg,1.0mmol)、四三苯基膦钯(115mg,0.1mmol)与碳酸钾(276mg,2.0mmol)溶于四氢呋喃(10mL)和水(5mL)中,油浴加热升温至80℃,搅拌反应10h,TLC监测反应,反应完毕后用乙酸乙酯(50mL×2)萃取,将所得有机层依次进行干燥、浓缩以及柱层析分离,得到的类白色固体即为化合物2,产量278mg,收率61.6%,表征数据如下:
ESI(+)m/z=452.1,1H-NMR(500MHz,d6-DMSO)δ9.80(d,J=2.1Hz,1H),8.74(d,J=1.6Hz,1H),8.46(dd,J=5.6,1.5Hz,1H),8.31(d,J=5.6Hz,1H),8.04–7.98(m,1H),7.82(d,J=1.4Hz,1H),7.68(dq,J=4.9,2.2Hz,2H),7.09(d,J=1.4Hz,1H),4.55(hept,J=6.3Hz,1H),2.99(s,3H),1.33(d,J=6.4Hz,6H),0.70(s,1H)。
实施例3
制备N-(3-(1-甲基-1H-吡唑-4-基)吡啶-4-基)-7-(甲基磺酰氨基)喹唑啉-2-甲酰胺(化合物3)的反应路线如下:
将化合物1e(420mg,1.0mmol)、化合物3a(126mg,1.0mmol)、四三苯基膦钯(115mg,0.1mmol)与碳酸钾(276mg,2.0mmol)溶于四氢呋喃(10mL)和水(5mL)中,油浴加热升温至80℃,搅拌反应10h,TLC监测反应,反应完毕后用乙酸乙酯(50mL×2)萃取,将所得有机层依次进行干燥、浓缩以及柱层析分离,得到的类白色固体即为化合物3,产量285mg,收率67.4%,表征数据如下:
ESI(+)m/z=424.1,1H-NMR(500MHz,d6-DMSO)δ9.80(d,J=2.2Hz,1H),8.73(d,J=1.6Hz,1H),8.47(dd,J=5.7,1.6Hz,1H),8.28(d,J=5.7Hz,1H),8.00(dd,J=8.4,1.7Hz,1H),7.79(d,J=1.4Hz,1H),7.74–7.66(m,2H),7.09(d,J=1.4Hz,1H),3.97(s,3H),2.99(s,3H),1.09(s,1H)。
实施例4
制备N-(3-(1-甲基-1H-吡咯-3-基)吡啶-4-基)-7-(甲基磺酰氨基)喹唑啉-2-甲酰胺(化合物4)的反应路线如下:
将化合物1e(420mg,1.0mmol)、化合物4a(125mg,1.0mmol)、四三苯基膦钯(115mg,0.1mmol)与碳酸钾(276mg,2.0mmol)溶于四氢呋喃(10mL)和水(5mL)中,油浴加热升温至80℃,搅拌反应10h,TLC监测反应,反应完毕后用乙酸乙酯(50mL×2)萃取,将所得有机层依次进行干燥、浓缩以及柱层析分离,得到的类白色固体即为化合物4,产量294mg,收率69.7%,表征数据如下:
ESI(+)m/z=423.1,1H-NMR(500MHz,d6-DMSO)δ9.80(d,J=1.8Hz,1H),8.67(d,J=1.6Hz,1H),8.46(dd,J=5.7,1.6Hz,1H),8.19(d,J=5.6Hz,1H),8.01(dd,J=8.4,1.7Hz,1H),7.74–7.66(m,2H),7.02(d,J=4.3Hz,1H),6.80(d,J=1.4Hz,1H),6.03(dd,J=4.2,1.5Hz,1H),3.68(s,3H),2.99(s,3H),1.07(s,1H)。
实施例5
制备N-(3-(1-甲基-1H-咪唑-4-基)吡啶-4-基)-7-(甲基磺酰氨基)喹唑啉-2-甲酰胺(化合物5)的反应路线如下:
将化合物1e(420mg,1.0mmol)、化合物5a(126mg,1.0mmol)、四三苯基膦钯(115mg,0.1mmol)与碳酸钾(276mg,2.0mmol)溶于四氢呋喃(10mL)和水(5mL)中,油浴加热升温至80℃,搅拌反应10h,TLC监测反应,反应完毕后用乙酸乙酯(50mL×2)萃取,将所得有机层依次进行干燥、浓缩以及柱层析分离,得到的类白色固体即为化合物5,产量247mg,收率58.4%,表征数据如下:
ESI(+)m/z=424.1,1H-NMR(500MHz,d6-DMSO)δ10.00(s,1H),9.80(d,J=2.1Hz,1H),8.82(d,J=1.6Hz,1H),8.46(dd,J=5.6,1.5Hz,1H),8.01(dd,J=8.4,1.8Hz,1H),7.86(d,J=5.6Hz,1H),7.78(s,1H),7.74–7.66(m,2H),7.15(s,1H),3.71(s,3H),2.99(s,3H),1.07(s,1H)。
实施例6
制备N-(3-(4-氟苯基)吡啶-4-基)-7-(甲基磺酰氨基)喹唑啉-2-甲酰胺(化合物6)的反应路线如下:
将化合物1e(420mg,1.0mmol)、化合物6a(140mg,1.0mmol)、四三苯基膦钯(115mg,0.1mmol)与碳酸钾(276mg,2.0mmol)溶于四氢呋喃(10mL)和水(5mL)中,油浴加热升温至80℃,搅拌反应10h,TLC监测反应,反应完毕后用乙酸乙酯(50mL×2)萃取,将所得有机层依次进行干燥、浓缩以及柱层析分离,得到的类白色固体即为化合物6,产量258mg,收率59.0%,表征数据如下:
ESI(+)m/z=438.1,1H-NMR(500MHz,d6-DMSO)δ9.81(s,1H),9.73(d,J=2.2Hz,1H),8.73(d,J=1.6Hz,1H),8.46(dd,J=5.7,1.6Hz,1H),8.25(d,J=5.7Hz,1H),8.02–7.95(m,1H),7.68(dq,J=4.5,2.2Hz,2H),7.56–7.49(m,2H),7.21–7.13(m,2H),2.99(s,3H),0.78(s,1H)。
实施例7
制备N-(3-(4-氯苯基)吡啶-4-基)-7-(甲基磺酰氨基)喹唑啉-2-甲酰胺(化合物7)的反应路线如下:
将化合物1e(420mg,1.0mmol)、化合物7a(156mg,1.0mmol)、四三苯基膦钯(115mg,0.1mmol)与碳酸钾(276mg,2.0mmol)溶于四氢呋喃(10mL)和水(5mL)中,油浴加热升温至80℃,搅拌反应10h,TLC监测反应,反应完毕后用乙酸乙酯(50mL×2)萃取,将所得有机层依次进行干燥、浓缩以及柱层析分离,得到的类白色固体即为化合物7,产量272mg,收率为60.0%,表征数据如下:
ESI(+)m/z=454.1,1H-NMR(500MHz,d6-DMSO)δ9.86(s,1H),9.73(d,J=2.2Hz,1H),8.77(d,J=1.5Hz,1H),8.46(dd,J=5.6,1.5Hz,1H),8.25(d,J=5.7Hz,1H),8.01–7.95(m,1H),7.68(dq,J=4.5,2.2Hz,2H),7.53–7.47(m,2H),7.36–7.30(m,2H),2.99(s,3H),0.78(s,1H)。
实施例8
制备N-(3-(4-甲氧基苯基)吡啶-4-基)-7-(甲基磺酰氨基)喹唑啉-2-甲酰胺(化合物8)的反应路线如下:
将化合物1e(420mg,1.0mmol)、化合物8a(152mg,1.0mmol)、四三苯基膦钯(115mg,0.1mmol)与碳酸钾(276mg,2.0mmol)溶于四氢呋喃(10mL)和水(5mL)中,油浴加热升温至80℃,搅拌反应10h,TLC监测反应,反应完毕后用乙酸乙酯(50mL×2)萃取,将所得有机层依次进行干燥、浓缩以及柱层析分离,得到的类白色固体即为化合物8,产量234mg,收率为52.1%,表征数据如下:
ESI(+)m/z=450.1,1H-NMR(500MHz,d6-DMSO)δ9.86(s,1H),9.73(d,J=2.2Hz,1H),8.74(d,J=1.6Hz,1H),8.45(dd,J=5.7,1.6Hz,1H),8.23(d,J=5.7Hz,1H),8.00–7.94(m,1H),7.68(dq,J=4.9,2.2Hz,2H),7.26–7.20(m,2H),6.95–6.89(m,2H),3.80(s,3H),2.99(s,3H),0.61(s,1H)。
实施例9
制备N-(3-(4-氰基苯基)吡啶-4-基)-7-(甲基磺酰氨基)喹唑啉-2-甲酰胺(化合物9)的反应路线如下:
将化合物1e(420mg,1.0mmol)、化合物9a(147mg,1.0mmol)、四三苯基膦钯(115mg,0.1mmol)与碳酸钾(276mg,2.0mmol)溶于四氢呋喃(10mL)和水(5mL)中,油浴加热升温至80℃,搅拌反应10h,TLC监测反应,反应完毕后用乙酸乙酯(50mL×2)萃取,将所得有机层依次进行干燥、浓缩以及柱层析分离,得到的类白色固体即为化合物9,产量293mg,收率66.0%,表征数据如下:
ESI(+)m/z=445.1,1H-NMR(500MHz,d6-DMSO)δ9.81(s,1H),9.73(d,J=1.7Hz,1H),8.81(d,J=1.6Hz,1H),8.46(dd,J=5.7,1.6Hz,1H),8.28(d,J=5.6Hz,1H),8.02–7.96(m,1H),7.93–7.87(m,2H),7.78–7.72(m,2H),7.68(dq,J=4.9,2.2Hz,2H),2.99(s,3H),0.76(s,1H)。
实施例10
制备N-(3-(4-氨基羰基苯基)吡啶-4-基)-7-(甲基磺酰氨基)喹唑啉-2-甲酰胺(化合物10)的反应路线如下:
将化合物1e(420mg,1.0mmol)、化合物10a(165mg,1.0mmol)、四三苯基膦钯(115mg,0.1mmol)与碳酸钾(276mg,2.0mmol)溶于四氢呋喃(10mL)和水(5mL)中,油浴加热升温至80℃,搅拌反应10h,TLC监测反应,反应完毕后用乙酸乙酯(50mL×2)萃取,将所得有机层依次进行干燥、浓缩以及柱层析分离,得到的类白色固体即为化合物10,产量301mg,收率65.2%,表征数据如下:
ESI(+)m/z=463.1,1H-NMR(500MHz,d6-DMSO)δ9.87(s,1H),9.74(d,J=1.7Hz,1H),8.84(d,J=1.6Hz,1H),8.46(dd,J=5.6,1.5Hz,1H),8.27(d,J=5.7Hz,1H),8.03–7.96(m,3H),7.68(dq,J=4.1,2.2Hz,2H),7.64–7.58(m,2H),7.10(s,2H),2.99(s,3H),0.76(s,1H)。
实施例11
制备N-(3'-氟-[3,4'-联吡啶]-4-基)-7-(甲基磺酰氨基)喹唑啉-2-甲酰胺(化合物11)的反应路线如下:
将化合物1e(420mg,1.0mmol)、化合物11a(141mg,1.0mmol)、四三苯基膦钯(115mg,0.1mmol)与碳酸钾(276mg,2.0mmol)溶于四氢呋喃(10mL)和水(5mL)中,油浴加热升温至80℃,搅拌反应10h,TLC监测反应,反应完毕后用乙酸乙酯(50mL×2)萃取,将所得有机层依次进行干燥、浓缩以及柱层析分离,得到的类白色固体即为化合物11,产量310mg,收率70.8%,表征数据如下:
ESI(+)m/z=439.1,1H-NMR(500MHz,d6-DMSO)δ9.97(s,1H),9.76(d,J=1.8Hz,1H),8.79(t,J=1.8Hz,1H),8.72(dd,J=5.7,1.7Hz,1H),8.57(dd,J=8.1,1.6Hz,1H),8.45(dd,J=5.6,1.5Hz,1H),8.26(d,J=5.7Hz,1H),8.03–7.97(m,1H),7.71–7.61(m,3H),2.99(s,3H),0.71(s,1H)。
实施例12
制备N-(2',6'-二氯-[3,4'-联吡啶]-4-基)-7-(甲基磺酰氨基)喹唑啉-2-甲酰胺(化合物12)的反应路线如下:
将化合物1e(420mg,1.0mmol)、化合物12a(191mg,1.0mmol)、四三苯基膦钯(115mg,0.1mmol)与碳酸钾(276mg,2.0mmol)溶于四氢呋喃(10mL)和水(5mL)中,油浴加热升温至80℃,搅拌反应10h,TLC监测反应,反应完毕后用乙酸乙酯(50mL×2)萃取,将所得有机层依次进行干燥、浓缩以及柱层析分离,得到的类白色固体即为化合物12,产量393mg,收率80.5%,表征数据如下:
ESI(+)m/z=489.1,1H-NMR(500MHz,d6-DMSO)δ9.78–9.73(m,2H),8.82(d,J=1.6Hz,1H),8.44(dd,J=5.7,1.6Hz,1H),8.31(d,J=5.6Hz,1H),8.02–7.95(m,1H),7.81(s,2H),7.68(dq,J=4.8,2.2Hz,2H),2.99(s,3H),0.54(s,1H)。
实施例13
制备N-(3-(2-氟-4-甲氧基苯基)吡啶-4-基)-7-(甲基磺酰氨基)喹唑啉-2-甲酰胺(化合物13)的反应路线如下:
将化合物1e(420mg,1.0mmol)、化合物13a(170mg,1.0mmol)、四三苯基膦钯(115mg,0.1mmol)与碳酸钾(276mg,2.0mmol)溶于四氢呋喃(10mL)和水(5mL)中,油浴加热升温至80℃,搅拌反应10h,TLC监测反应,反应完毕后用乙酸乙酯(50mL×2)萃取,将所得有机层依次进行干燥、浓缩以及柱层析分离,得到的类白色固体即为化合物13,产量367mg,收率为78.6%,表征数据如下:
ESI(+)m/z=468.1,1H-NMR(500MHz,d6-DMSO)δ9.96(s,1H),9.73(d,J=1.8Hz,1H),8.72(t,J=1.8Hz,1H),8.45(dd,J=5.7,1.6Hz,1H),8.24(d,J=5.7Hz,1H),8.02–7.96(m,1H),7.68(dq,J=4.1,2.2Hz,2H),7.55(dd,J=8.4,5.0Hz,1H),6.98(dd,J=8.4,2.0Hz,1H),6.47(dd,J=7.9,1.9Hz,1H),3.82(s,3H),2.99(s,3H),0.71(s,1H)。
实施例14
制备N-(2'-甲氧基-[3,4'-联吡啶]-4-基)-7-(甲基磺酰氨基)喹唑啉-2-甲酰胺(化合物14)的反应路线如下:
将化合物1e(420mg,1.0mmol)、化合物14a(153mg,1.0mmol)、四三苯基膦钯(115mg,0.1mmol)与碳酸钾(276mg,2.0mmol)溶于四氢呋喃(10mL)和水(5mL)中,油浴加热升温至80℃,搅拌反应10h,TLC监测反应,反应完毕后用乙酸乙酯(50mL×2)萃取,将所得有机层依次进行干燥、浓缩以及柱层析分离,得到的类白色固体即为化合物14,产量344mg,收率76.4%,表征数据如下:
ESI(+)m/z=451.1,1H-NMR(500MHz,d6-DMSO)δ9.78–9.72(m,2H),8.80(d,J=1.6Hz,1H),8.47–8.41(m,2H),8.24(d,J=5.7Hz,1H),8.02–7.96(m,1H),7.68(h,J=2.2Hz,2H),7.36(d,J=2.0Hz,1H),7.19(dd,J=5.7,1.8Hz,1H),3.97(s,3H),2.99(s,3H),0.71(s,1H)。
实施例15
制备N-(3-(3-氨基羰基苯基)吡啶-4-基)-7-(甲基磺酰氨基)喹唑啉-2-甲酰胺(化合物15)的反应路线如下:
将化合物1e(420mg,1.0mmol)、化合物15a(165mg,1.0mmol)、四三苯基膦钯(115mg,0.1mmol)与碳酸钾(276mg,2.0mmol)溶于四氢呋喃(10mL)和水(5mL)中,油浴加热升温至80℃,搅拌反应10h,TLC监测反应,反应完毕后用乙酸乙酯(50mL×2)萃取,将所得有机层依次进行干燥、浓缩以及柱层析分离,得到的类白色固体即为化合物15,产量329mg,收率71.2%,表征数据如下:
ESI(+)m/z=463.1,1H-NMR(500MHz,d6-DMSO)δ9.89(s,1H),9.74(d,J=2.3Hz,1H),8.75(d,J=1.6Hz,1H),8.47(dd,J=5.6,1.5Hz,1H),8.28(d,J=5.6Hz,1H),8.06–7.96(m,2H),7.92–7.86(m,1H),7.78(ddd,J=7.7,1.8,1.1Hz,1H),7.71–7.60(m,3H),7.51(d,J=7.9Hz,1H),7.45(d,J=7.9Hz,1H),2.99(s,3H),0.79(s,1H)。
实施例16
制备N-(5'-氯-[3,3'-联吡啶]-4-基)-7-(甲基磺酰氨基)喹唑啉-2-甲酰胺(化合物16)的反应路线如下:
将化合物1e(420mg,1.0mmol)、化合物16a(157mg,1.0mmol)、四三苯基膦钯(115mg,0.1mmol)与碳酸钾(276mg,2.0mmol)溶于四氢呋喃(10mL)和水(5mL)中,油浴加热升温至80℃,搅拌反应10h,TLC监测反应,反应完毕后用乙酸乙酯(50mL×2)萃取,将所得有机层依次进行干燥、浓缩以及柱层析分离,得到的类白色固体即为化合物16,产量366mg,收率80.6%,表征数据如下:
ESI(+)m/z=455.1,1H-NMR(500MHz,d6-DMSO)δ9.93(s,1H),9.74(d,J=2.2Hz,1H),8.80(dd,J=10.8,1.6Hz,2H),8.62(d,J=1.4Hz,1H),8.48(dd,J=5.7,1.6Hz,1H),8.33(d,J=5.5Hz,1H),8.02–7.95(m,2H),7.68(dq,J=4.4,2.2Hz,2H),2.99(s,3H),0.81(s,1H)。
实施例17
制备7-(甲基磺酰基氨基)-N-(3-(嘧啶-4-基)吡啶-4-基)喹唑啉-2-甲酰胺(化合物17)的反应路线如下:
将化合物1e(420mg,1.0mmol)、化合物17a(124mg,1.0mmol)、四三苯基膦钯(115mg,0.1mmol)与碳酸钾(276mg,2.0mmol)溶于四氢呋喃(10mL)和水(5mL)中,油浴加热升温至80℃,搅拌反应10h,TLC监测反应,反应完毕后用乙酸乙酯(50mL×2)萃取,将所得有机层依次进行干燥、浓缩以及柱层析分离,得到的类白色固体即为化合物17,产量348mg,收率82.7%,表征数据如下:
ESI(+)m/z=422.1,1H-NMR(500MHz,d6-DMSO)δ9.92(s,1H),9.80(d,J=1.8Hz,1H),9.48(d,J=1.4Hz,1H),9.16(d,J=5.5Hz,1H),9.01(d,J=1.5Hz,1H),8.49(dd,J=5.7,1.6Hz,1H),8.35(d,J=5.7Hz,1H),8.04–7.98(m,2H),7.74–7.66(m,2H),2.99(s,3H),1.24(s,1H)。
实施例18
制备N-(2'-氨基羰基-[3,4'-联吡啶]-4-基)-7-(甲基磺酰氨基)喹唑啉-2-甲酰胺(化合物18)的反应路线如下:
将化合物1e(420mg,1.0mmol)、化合物18a(166mg,1.0mmol)、四三苯基膦钯(115mg,0.1mmol)与碳酸钾(276mg,2.0mmol)溶于四氢呋喃(10mL)和水(5mL)中,油浴加热升温至80℃,搅拌反应10h,TLC监测反应,反应完毕后用乙酸乙酯(50mL×2)萃取,将所得有机层依次进行干燥、浓缩以及柱层析分离,得到的类白色固体即为化合物18,产量360mg,收率77.8%,表征数据如下:
ESI(+)m/z=464.1,1H-NMR(500MHz,d6-DMSO)δ9.87(s,1H),9.81(d,J=2.1Hz,1H),9.06(d,J=5.6Hz,1H),8.81(d,J=1.6Hz,1H),8.47(dd,J=5.7,1.6Hz,1H),8.34(d,J=5.7Hz,1H),8.23(d,J=1.9Hz,1H),8.04–7.98(m,1H),7.83(dd,J=5.6,1.9Hz,1H),7.75–7.65(m,3H),7.57(d,J=7.9Hz,1H),2.99(s,3H),0.68(s,1H)。
实施例19
制备7-(环丙基磺酰基氨基)-N-(3-(1-环丙基-1H-吡唑-4-基)吡啶-4-基)喹唑啉-2-甲酰胺(化合物19)的反应路线如下:
(1)将化合物1a(20.3g,100.0mmol)与三乙胺(1.5g,150.0mmol)溶于二氯甲烷(300mL)中,降温至0℃,滴加环丙基磺酰氯(14.0g,100.0mmol),滴加完毕后升至室温,保温反应6h,TLC监测反应,反应完毕后加水(100mL)淬灭反应,将所得有机层依次进行干燥、浓缩以及柱层析分离,得到的黄色固体即为化合物19a,产量20.7g,收率67.4%。
(2)将所述化合物19a(20.0g,65.1mmol)溶于四氢呋喃(200mL)和水(100mL)中,室温条件下加入氢氧化锂((3.1g,130.2mmol)),搅拌反应8h,TLC监测反应,反应完毕后加入浓度为2mol/L的盐酸淬灭反应,然后用乙酸乙酯(500mL×2)萃取,将所得有机层浓缩后经柱层析分离,得到的类白色固体即为化合物19b,产量15.1g,收率79.1%。
(3)将所述化合物19b(15.0g,51.2mmol)、化合物1d(9.6g,51.2mmol)、DIEA(9.9mg,76.8mmol)溶于DMF(100mL)中,室温条件下加入HATU(29.2g,76.8mmol),搅拌反应4h,TLC监测反应,反应完毕后加水(100mL)淬灭反应,用乙酸乙酯(500mL×2)萃取,将所得有机层浓缩后经柱层析分离,得到的类白色固体即为化合19c,产量18.2g,收率79.5%。
(4)将所述化合物19c(447mg,1.0mmol)、化合物1f(152mg,1.0mmol)、四三苯基膦钯(115mg,0.1mmol)与碳酸钾(276mg,2.0mmol)溶于四氢呋喃(10mL)和水(5mL)中,油浴加热升温至80℃,搅拌反应10h,TLC监测反应,反应完毕后用乙酸乙酯(50mL×2)萃取,将所得有机层依次进行干燥、浓缩以及柱层析分离,得到的类白色固体即为化合物19,产量299mg,收率62.9%,表征数据如下:
ESI(+)m/z=476.1,1H-NMR(500MHz,d6-DMSO)δ9.79(d,J=1.7Hz,1H),9.28(s,1H),8.74(d,J=1.6Hz,1H),8.46(dd,J=5.7,1.5Hz,1H),8.31(d,J=5.7Hz,1H),8.00(dd,J=8.4,1.9Hz,1H),7.82(d,J=1.5Hz,1H),7.75–7.67(m,2H),7.19(d,J=1.5Hz,1H),3.71(p,J=5.7Hz,1H),1.84(p,J=5.5Hz,1H),1.11(dddd,J=10.1,8.6,5.5,1.3Hz,2H),1.02–0.87(m,4H),0.87–0.78(m,2H)。
实施例20
制备7-(环丙基磺酰基氨基)-N-(3-(1-异丙基-1H-吡唑-4-基)吡啶-4-基)喹唑啉-2-甲酰胺(化合物20)的反应路线如下所示:
将化合物19c(447mg,1.0mmol)、化合物2a(154mg,1.0mmol)、四三苯基膦钯(115mg,0.1mmol)与碳酸钾(276mg,2.0mmol)溶于四氢呋喃(10mL)和水(5mL)中,油浴加热升温至80℃,搅拌反应10h,TLC监测反应,反应完毕后用乙酸乙酯(50mL×2)萃取,将所得有机层依次进行干燥、浓缩以及柱层析分离,得到的类白色固体即为化合物20,产量319mg,收率66.9%,表征数据如下:
ESI(+)m/z=478.1,1H-NMR(500MHz,d6-DMSO)δ9.81(d,J=1.8Hz,1H),9.28(s,1H),8.74(d,J=1.5Hz,1H),8.47(dd,J=5.6,1.5Hz,1H),8.31(d,J=5.7Hz,1H),8.05–7.99(m,1H),7.81(d,J=1.4Hz,1H),7.74–7.67(m,2H),7.10(d,J=1.4Hz,1H),4.55(hept,J=6.4Hz,1H),1.84(p,J=5.6Hz,1H),1.33(d,J=6.4Hz,6H),1.10(dddd,J=9.9,8.4,5.6,1.7Hz,2H),1.00(dddd,J=10.6,8.8,5.5,1.8Hz,2H)。
实施例21
制备7-(环丙基磺酰基氨基)-N-(3-(1-甲基-1H-吡唑-4-基)吡啶-4-基)喹唑啉-2-甲酰胺(化合物21)的反应路线如下所示:
将化合物19c(447mg,1.0mmol)、化合物3a(126mg,1.0mmol)、四三苯基膦钯(115mg,0.1mmol)与碳酸钾(276mg,2.0mmol)溶于四氢呋喃(10mL)和水(5mL)中,油浴加热升温至80℃,搅拌反应10h,TLC监测反应,反应完毕后用乙酸乙酯(50mL×2)萃取,将所得有机层依次进行干燥、浓缩以及柱层析分离,得到的类白色固体即为化合物21,产量281mg,收率62.6%,表征数据如下:
ESI(+)m/z=450.1,1H-NMR(500MHz,d6-DMSO)δ9.80(d,J=1.7Hz,1H),9.19(s,1H),8.73(d,J=1.6Hz,1H),8.46(dd,J=5.7,1.5Hz,1H),8.28(d,J=5.6Hz,1H),8.03–7.96(m,1H),7.79(d,J=1.5Hz,1H),7.72–7.66(m,2H),7.10(d,J=1.5Hz,1H),3.98(s,3H),1.84(p,J=5.5Hz,1H),1.12(dddd,J=10.1,8.4,5.5,1.6Hz,2H),1.01(dddd,J=10.4,9.0,5.5,1.6Hz,2H)。
实施例22
制备7-(环丙基磺酰基氨基)-N-(3-(1-甲基-1H-吡咯-3-基)吡啶-4-基)喹唑啉-2-甲酰胺(化合物22)的反应路线如下所示:
将化合物19c(447mg,1.0mmol)、化合物4a(125mg,1.0mmol)、四三苯基膦钯(115mg,0.1mmol)与碳酸钾(276mg,2.0mmol)溶于四氢呋喃(10mL)和水(5mL)中,油浴加热升温至80℃,搅拌反应10h,TLC监测反应,反应完毕后用乙酸乙酯(50mL×2)萃取,将所得有机层依次进行干燥、浓缩以及柱层析分离,得到的类白色固体即为化合物22,产量268mg,收率59.8%,表征数据如下:
ESI(+)m/z=449.1,1H-NMR(500MHz,d6-DMSO)δ9.79(d,J=2.0Hz,1H),9.19(s,1H),8.67(d,J=1.6Hz,1H),8.45(dd,J=5.6,1.6Hz,1H),8.19(d,J=5.6Hz,1H),8.05–7.98(m,1H),7.72–7.66(m,2H),7.02(d,J=4.3Hz,1H),6.79(d,J=1.6Hz,1H),6.03(dd,J=4.2,1.5Hz,1H),3.69(s,3H),1.84(p,J=5.5Hz,1H),1.09(dddd,J=10.1,8.5,5.5,1.7Hz,2H),0.99(dddd,J=10.5,8.8,5.6,1.7Hz,2H)。
实施例23
制备7-(环丙基磺酰基氨基)-N-(3-(1-甲基1H-咪唑-4-基)吡啶-4-基)喹唑啉-2-甲酰胺(化合物23)的反应路线如下所示:
将化合物19c(447mg,1.0mmol)、化合物5a(126mg,1.0mmol)、四三苯基膦钯(115mg,0.1mmol)与碳酸钾(276mg,2.0mmol)溶于四氢呋喃(10mL)和水(5mL)中,油浴加热升温至80℃,搅拌反应10h,TLC监测反应,反应完毕后用乙酸乙酯(50mL×2)萃取,将所得有机层依次进行干燥、浓缩以及柱层析分离,得到的类白色固体即为化合物23,产量245mg,收率为54.6%,表征数据如下:
ESI(+)m/z=450.1,1H-NMR(500MHz,d6-DMSO)δ9.98(s,1H),9.79(d,J=1.7Hz,1H),9.19(s,1H),8.80(d,J=1.6Hz,1H),8.46(dd,J=5.7,1.6Hz,1H),8.03–7.96(m,1H),7.86(d,J=5.7Hz,1H),7.74(s,1H),7.72–7.66(m,2H),7.23(s,1H),3.71(s,3H),1.84(p,J=5.5Hz,1H),1.12(dddd,J=10.1,8.4,5.5,1.6Hz,2H),1.01(dddd,J=10.4,9.0,5.5,1.6Hz,2H)。
实施例24
制备7-(环丙基磺酰基氨基)-N-(3-(4-氟苯基)吡啶-4-基)喹唑啉-2-甲酰胺(化合物24)的反应路线如下所示:
将化合物19c(447mg,1.0mmol)、化合物6a(140mg,1.0mmol)、四三苯基膦钯(115mg,0.1mmol)与碳酸钾(276mg,2.0mmol)溶于四氢呋喃(10mL)和水(5mL)中,油浴加热升温至80℃,搅拌反应10h,TLC监测反应,反应完毕后用乙酸乙酯(50mL×2)萃取,将所得有机层依次进行干燥、浓缩以及柱层析分离,得到的类白色固体即为化合物24,产量297mg,收率64.1%,表征数据如下:
ESI(+)m/z=464.1,1H-NMR(500MHz,d6-DMSO)δ9.83–9.75(m,2H),9.28(s,1H),8.74(d,J=1.6Hz,1H),8.47(dd,J=5.6,1.6Hz,1H),8.24(d,J=5.7Hz,1H),8.04–7.98(m,1H),7.72–7.66(m,2H),7.57–7.49(m,2H),7.21–7.13(m,2H),1.84(p,J=5.5Hz,1H),1.14(dddd,J=10.1,8.6,5.5,1.2Hz,2H),1.04–0.95(m,2H)。
实施例25
制备N-(3-(4-氯苯基)吡啶-4-基)-7-(环丙基磺酰基氨基)喹唑啉-2-甲酰(化合物25)的反应路线如下所示:
将化合物19c(447mg,1.0mmol)、化合物7a(156mg,1.0mmol)、四三苯基膦钯(115mg,0.1mmol)与碳酸钾(276mg,2.0mmol)溶于四氢呋喃(10mL)和水(5mL)中,油浴加热升温至80℃,搅拌反应10h,TLC监测反应,反应完毕后用乙酸乙酯(50mL×2)萃取,将所得有机层依次进行干燥、浓缩以及柱层析分离,得到的类白色固体即为化合物25,产量297mg,收率为64.1%,表征数据如下:
ESI(+)m/z=480.1,1H-NMR(500MHz,d6-DMSO)δ9.85(s,1H),9.73(d,J=2.0Hz,1H),9.28(s,1H),8.77(d,J=1.5Hz,1H),8.46(dd,J=5.7,1.6Hz,1H),8.25(d,J=5.7Hz,1H),8.00–7.94(m,1H),7.72–7.66(m,2H),7.54–7.48(m,2H),7.36–7.31(m,2H),1.84(p,J=5.5Hz,1H),1.25–1.07(m,4H)。
实施例26
制备7-(环丙基磺酰基氨基)-N-(3-(4-甲氧基苯基)吡啶-4-基)喹唑啉-2-甲酰胺(化合物26)的反应路线如下所示:
将化合物19c(447mg,1.0mmol)、化合物8a(152mg,1.0mmol)、四三苯基膦钯(115mg,0.1mmol)与碳酸钾(276mg,2.0mmol)溶于四氢呋喃(10mL)和水(5mL)中,油浴加热升温至80℃,搅拌反应10h,TLC监测反应,反应完毕后用乙酸乙酯(50mL×2)萃取,将所得有机层依次进行干燥、浓缩以及柱层析分离,得到的类白色固体即为化合物26,产量297mg,收率为63.4%,表征数据如下:
ESI(+)m/z=476.1,1H-NMR(500MHz,d6-DMSO)δ9.86(s,1H),9.73(d,J=1.7Hz,1H),9.28(s,1H),8.74(d,J=1.5Hz,1H),8.45(dd,J=5.7,1.6Hz,1H),8.23(d,J=5.7Hz,1H),7.98(dd,J=8.4,1.9Hz,1H),7.84(d,J=2.2Hz,1H),7.71(dd,J=8.4,2.2Hz,1H),7.24–7.18(m,2H),6.95–6.89(m,2H),3.79(s,3H),1.84(p,J=5.6Hz,1H),1.13–0.94(m,4H)。
实施例27
制备N-(3-(4-氰基苯基)吡啶-4-基)-7-(环丙基磺酰基氨基)喹唑啉-2-甲酰胺(化合物27)的反应路线如下所示:
将化合物19c(447mg,1.0mmol)、化合物9a(147mg,1.0mmol)、四三苯基膦钯(115mg,0.1mmol)与碳酸钾(276mg,2.0mmol)溶于四氢呋喃(10mL)和水(5mL)中,油浴加热升温至80℃,搅拌反应10h,TLC监测反应,反应完毕后用乙酸乙酯(50mL×2)萃取,将所得有机层依次进行干燥、浓缩以及柱层析分离,得到的类白色固体即为化合物27,产量277mg,收率为58.9%,表征数据如下:
ESI(+)m/z=471.1,1H-NMR(500MHz,d6-DMSO)δ9.75–9.69(m,2H),9.28(s,1H),8.80(d,J=1.5Hz,1H),8.47(dd,J=5.7,1.6Hz,1H),8.28(d,J=5.6Hz,1H),8.00(dd,J=8.4,1.9Hz,1H),7.93–7.87(m,2H),7.78–7.67(m,4H),1.84(p,J=5.6Hz,1H),1.11(dddd,J=9.9,8.4,5.5,1.8Hz,2H),1.01(dddd,J=10.6,8.8,5.5,1.8Hz,2H)。
实施例28
制备N-(3-(4-氨基羰基苯基)吡啶-4-基)-7-(环丙基磺酰基氨基)喹唑啉-2-甲酰胺(化合物28)的反应路线如下所示:
将化合物19c(447mg,1.0mmol)、化合物10a(165mg,1.0mmol)、四三苯基膦钯(115mg,0.1mmol)与碳酸钾(276mg,2.0mmol)溶于四氢呋喃(10mL)和水(5mL)中,油浴加热升温至80℃,搅拌反应10h,TLC监测反应,反应完毕后用乙酸乙酯(50mL×2)萃取,将所得有机层依次进行干燥、浓缩以及柱层析分离,得到的类白色固体即为化合物28,产量289mg,收率为59.2%,表征数据如下:
ESI(+)m/z=489.1,1H-NMR(500MHz,d6-DMSO)δ9.88(s,1H),9.73(d,J=1.6Hz,1H),9.28(s,1H),8.83(d,J=1.6Hz,1H),8.46(dd,J=5.6,1.5Hz,1H),8.28(d,J=5.7Hz,1H),8.02–7.95(m,3H),7.74–7.67(m,2H),7.64–7.58(m,2H),7.13(s,2H),1.84(p,J=5.6Hz,1H),1.11(dddd,J=10.1,8.4,5.5,1.6Hz,2H),1.01(dddd,J=10.6,9.0,5.6,1.8Hz,2H)。
实施例29
制备7-(环丙基磺酰基氨基)-N-(3'-氟-[3,4'-联吡啶]-4-基)喹唑啉-2-甲酰胺(化合物29)的反应路线如下所示:
将化合物19c(447mg,1.0mmol)、化合物11a(141mg,1.0mmol)、四三苯基膦钯(115mg,0.1mmol)与碳酸钾(276mg,2.0mmol)溶于四氢呋喃(10mL)和水(5mL)中,油浴加热升温至80℃,搅拌反应10h,TLC监测反应,反应完毕后用乙酸乙酯(50mL×2)萃取,将所得有机层依次进行干燥、浓缩以及柱层析分离,得到的类白色固体即为化合物29,产量311mg,收率为67.0%,表征数据如下:
ESI(+)m/z=465.1,1H-NMR(500MHz,d6-DMSO)δ9.92(s,1H),9.78(d,J=1.7Hz,1H),9.28(s,1H),8.80(t,J=1.8Hz,1H),8.72(dd,J=5.6,1.6Hz,1H),8.58(dd,J=8.0,1.6Hz,1H),8.45(dd,J=5.6,1.6Hz,1H),8.28(d,J=5.7Hz,1H),8.04–7.98(m,1H),7.72–7.62(m,3H),1.84(p,J=5.5Hz,1H),1.18–1.00(m,4H)。
实施例30
制备7-(环丙基磺酰基氨基)-N-(2',6'-二氯-[3,4'-联吡啶]-4-基)喹唑啉-2-甲酰胺(化合物30)的反应路线如下所示:
将化合物19c(447mg,1.0mmol)、化合物12a(191mg,1.0mmol)、四三苯基膦钯(115mg,0.1mmol)与碳酸钾(276mg,2.0mmol)溶于四氢呋喃(10mL)和水(5mL)中,油浴加热升温至80℃,搅拌反应10h,TLC监测反应,反应完毕后用乙酸乙酯(50mL×2)萃取,将所得有机层依次进行干燥、浓缩以及柱层析分离,得到的类白色固体即为化合物30,产量315mg,收率为61.3%,表征数据如下:
ESI(+)m/z=515.1,1H-NMR(500MHz,d6-DMSO)δ9.79–9.74(m,2H),9.28(s,1H),8.82(d,J=1.6Hz,1H),8.45(dd,J=5.6,1.5Hz,1H),8.25(d,J=5.6Hz,1H),8.01–7.95(m,1H),7.82(s,2H),7.71–7.66(m,2H),1.84(p,J=5.5Hz,1H),1.24–1.08(m,4H).
实施例31
制备7-(环丙基磺酰基氨基)-N-(3-(2-氟-4-甲氧基苯基)吡啶-4-基)喹唑啉-2-甲酰胺(化合物31)的反应路线如下所示:
将化合物19c(447mg,1.0mmol)、化合物13a(170mg,1.0mmol)、四三苯基膦钯(115mg,0.1mmol)与碳酸钾(276mg,2.0mmol)溶于四氢呋喃(10mL)和水(5mL)中,油浴加热升温至80℃,搅拌反应10h,TLC监测反应,反应完毕后用乙酸乙酯(50mL×2)萃取,将所得有机层依次进行干燥、浓缩以及柱层析分离,得到的类白色固体即为化合物31,产量302mg,收率为61.3%,表征数据如下:
ESI(+)m/z=494.1,1H-NMR(500MHz,d6-DMSO)δ9.89(s,1H),9.73(d,J=1.7Hz,1H),9.28(s,1H),8.72(t,J=1.8Hz,1H),8.45(dd,J=5.6,1.5Hz,1H),8.24(d,J=5.7Hz,1H),7.98(dd,J=8.3,1.9Hz,1H),7.74–7.67(m,2H),7.53(dd,J=8.4,4.9Hz,1H),7.01(dd,J=8.5,1.9Hz,1H),6.42(dd,J=7.9,1.9Hz,1H),3.81(s,3H),1.84(p,J=5.6Hz,1H),1.12(dddd,J=10.1,8.6,5.5,1.5Hz,2H),1.01(dddd,J=10.4,9.0,5.5,1.6Hz,2H)。
实施例32
制备7-(环丙基磺酰基氨基)-N-(2'-甲氧基-[3,4'-联吡啶]-4-基)喹唑啉-2-甲酰胺(化合物32)的反应路线如下所示:
将化合物19c(447mg,1.0mmol)、化合物14a(153mg,1.0mmol)、四三苯基膦钯(115mg,0.1mmol)与碳酸钾(276mg,2.0mmol)溶于四氢呋喃(10mL)和水(5mL)中,油浴加热升温至80℃,搅拌反应10h,TLC监测反应,反应完毕后用乙酸乙酯(50mL×2)萃取,将所得有机层依次进行干燥、浓缩以及柱层析分离,得到的类白色固体即为化合物32,产量321mg,收率为67.4%,表征数据如下:
ESI(+)m/z=477.1,1H-NMR(500MHz,d6-DMSO)δ9.76(d,J=1.7Hz,1H),9.68(s,1H),9.28(s,1H),8.80(d,J=1.6Hz,1H),8.47–8.41(m,2H),8.24(d,J=5.6Hz,1H),8.00(dd,J=8.4,1.9Hz,1H),7.84(d,J=2.2Hz,1H),7.71(dd,J=8.4,2.2Hz,1H),7.36(d,J=1.9Hz,1H),7.21(dd,J=5.6,1.9Hz,1H),3.97(s,3H),1.84(p,J=5.6Hz,1H),1.15–0.97(m,4H)。
实施例33
制备N-(3-(3-氨基羰基苯基)吡啶-4-基)-7-(环丙基磺酰基氨基)喹唑啉-2-甲酰胺(化合物33)的反应路线如下所示:
将化合物19c(447mg,1.0mmol)、化合物15a(165mg,1.0mmol)、四三苯基膦钯(115mg,0.1mmol)与碳酸钾(276mg,2.0mmol)溶于四氢呋喃(10mL)和水(5mL)中,油浴加热升温至80℃,搅拌反应10h,TLC监测反应,反应完毕后用乙酸乙酯(50mL×2)萃取,将所得有机层依次进行干燥、浓缩以及柱层析分离,得到的类白色固体即为化合物33,产量321mg,收率为67.4%,表征数据如下:
ESI(+)m/z=489.1,1H-NMR(500MHz,d6-DMSO)δ9.88(s,1H),9.74(d,J=2.2Hz,1H),9.28(s,1H),8.75(d,J=1.6Hz,1H),8.47(dd,J=5.7,1.6Hz,1H),8.28(d,J=5.7Hz,1H),8.04(t,J=1.9Hz,1H),8.01–7.95(m,1H),7.90(ddd,J=7.7,1.8,1.1Hz,1H),7.77(ddd,J=7.8,1.9,1.2Hz,1H),7.74–7.67(m,2H),7.63(t,J=7.8Hz,1H),7.51(d,J=7.9Hz,1H),7.45(d,J=7.9Hz,1H),1.84(p,J=5.6Hz,1H),1.12(dddd,J=10.1,8.5,5.5,1.5Hz,2H),1.01(dddd,J=10.4,9.0,5.5,1.6Hz,2H).
测试例1
实施例1~33制备的化合物1~33作为待测化合物进行生物学评价,具体步骤如下:
将待测化合物用二甲基亚砜(DMSO)稀释,然后3倍稀释至9个浓度梯度,备用;将含有稳定操作的STAT3启动子的人前列腺癌细胞系在含有10%胎牛血清(FBS)和150μg/Ml G-418溶液的RPMI1640培养基中培养,使用LNCaP稳定细胞接种在2个96孔板中,每个孔板中具有30000个细胞/50μL;将细胞在37℃,5%CO2条件下培养24h,然后加入待测化合物并将IL-6加入到每个孔中,最终浓度为10ng/mL,细胞在37℃、5%CO2条件下培养24h。其中一个孔板除去96孔板中的液体培养基,然后向每个孔中加入20μL被动细胞裂解缓冲液,摇动板30min后,使用荧光素酶测定系统,在PHERAstar酶标仪中测量各孔的荧光素酶活性。另外一个孔板置于室温下30min,加入20μL/孔的CellTiter-Glo溶液,摇动10min以测定各实施例中制备的化合物导致的细胞毒性,使用PHERAstar酶标仪中测量,不经过0.1%DMSO和刺激的孔被用作阴性对照,经受0.1%DMSO和刺激的孔作为阳性对照。通过计算得到待测化合物的IC50,具体结果见表2。由表2可知,化合物1~33在酶水平表现出较好的活性,都强于阳性化合物Stattic。
表2待测化合物的活性测试结果
化合物 | IC<sub>50</sub>(STAT3)nM | 化合物 | IC<sub>50</sub>(STAT3)nM |
1 | 10.5 | 18 | 55.1 |
2 | 15.6 | 19 | 12.2 |
3 | 18.9 | 20 | 10.4 |
4 | 33.9 | 21 | 8.9 |
5 | 43.7 | 22 | 4.5 |
6 | 10.3 | 23 | 32.5 |
7 | 33.6 | 24 | 120.5 |
8 | 67.7 | 25 | 226.4 |
9 | 150.8 | 26 | 175.3 |
10 | 7.7 | 27 | 33.6 |
11 | 10.5 | 28 | 94.5 |
12 | 33.6 | 29 | 77.8 |
13 | 45.2 | 30 | 32.1 |
14 | 67.1 | 31 | 10.6 |
15 | 77.6 | 32 | 11.8 |
16 | 22.6 | 33 | 20.3 |
17 | 44.4 | Stattic | 7.2μM |
细胞生长抑制实验,具体步骤如下:
将胃癌细胞系(NCI-N87)在参考的方案下培养,在96孔板中,NCI-N87为5000细胞/孔;这些细胞用不同浓度的待测化合物处理后,在37℃、5%CO2条件下培养96h,然后在显微镜和药物沉淀下观察平板并对各个发现进行调查和记录;将96孔板先放置在室温30min,加入20μL/孔的CellTiter-Glo溶液,摇动10min,然后使用PHERAstar酶标仪测量,含有0.1%DMSO代替待测化合物的培养液的孔作为阳性对照,通过计算得到待测化合物对细胞生长抑制的结果,具体结果见表3。由表3可知,化合物1~33在细胞水平(胃癌)表现出较高的活性,IC50都达到纳摩尔级。
表3待测化合物对细胞生长抑制的结果
化合物 | IC<sub>50</sub>(NCI-N87)nM | 化合物 | IC<sub>50</sub>(NCI-N87)nM |
1 | 35.6 | 18 | 98.4 |
2 | 65.4 | 19 | 22.5 |
3 | 35.8 | 20 | 43.6 |
4 | 231.2 | 21 | 55.3 |
5 | 145.2 | 22 | 88.3 |
6 | 231.4 | 23 | 164.5 |
7 | 46.7 | 24 | 342.1 |
8 | 55.6 | 25 | 88.4 |
9 | 64.7 | 26 | 22.5 |
10 | 80.5 | 27 | 45.3 |
11 | 135.5 | 28 | 55.2 |
12 | 159.4 | 29 | 66.1 |
13 | 188.3 | 30 | 43.2 |
14 | 67.3 | 31 | 18.4 |
15 | 26.3 | 32 | 27.3 |
16 | 44.5 | 33 | 43.4 |
17 | 48.2 | / | / |
以上所述仅是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
Claims (10)
2.根据权利要求1所述的具有式I所示结构的化合物、其药学上可接受的盐、立体异构体、水合物、溶剂合物或同位素化合物,其特征在于,所述芳杂基中杂原子为氮,所述芳杂基为单环芳杂基或稠环芳杂基。
3.根据权利要求2所述的具有式I所示结构的化合物、其药学上可接受的盐、立体异构体、水合物、溶剂合物或同位素化合物,其特征在于,所述芳杂基选自吡唑基、吡咯基、咪唑基或吡啶基。
4.根据权利要求1所述的具有式I所示结构的化合物、其药学上可接受的盐、立体异构体、水合物、溶剂合物或同位素化合物,其特征在于,所述取代的苯基和取代的芳杂基中一个或多个取代基独立地选自卤素、烷基、烷氧基、氰基或氨基甲酰基。
7.一种药物组合物,包括活性成分和药学上可接受的辅料,所述活性成分为权利要求1~5任一项所述具有式I所示结构的化合物、其药学上可接受的盐、立体异构体、水合物、溶剂合物或同位素化合物。
8.权利要求1~5任一项所述具有式I所示结构的化合物、其药学上可接受的盐、立体异构体、水合物、溶剂合物或同位素化合物或权利要求7所述药物组合物在制备STAT3抑制剂中的应用。
9.权利要求1~5任一项所述具有式I所示结构的化合物、其药学上可接受的盐、立体异构体、水合物、溶剂合物或同位素化合物或权利要求7所述药物组合物在制备预防和/或治疗肿瘤药物中的应用。
10.根据权利要求9所述的应用,其特征在于,所述肿瘤选自皮肤癌、膀胱癌、卵巢癌、乳腺癌、胃癌、前列腺癌、结肠癌、肺癌、骨癌、脑癌、直肠癌、食管癌、舌癌、胃癌、肾癌、肾实质癌、宫颈癌、子宫体癌、子宫内膜癌、睾丸癌、泌尿癌、黑素癌、星型细胞癌、脑膜瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、急性淋巴性白血病、慢性淋巴性白血病、急性骨髓性白血病,慢性粒细胞白血病、成人T细胞白血病淋巴瘤、肝细胞癌、支气管癌、小细胞肺癌、非小细胞肺癌、多发性骨髓瘤、基底细胞瘤、精原细胞瘤、横纹肌肉瘤、软骨肉瘤、肌肉瘤或纤维肉瘤。
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