CN111836803A - 化合物及其在治疗癌症中的用途 - Google Patents
化合物及其在治疗癌症中的用途 Download PDFInfo
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- CN111836803A CN111836803A CN201880082111.8A CN201880082111A CN111836803A CN 111836803 A CN111836803 A CN 111836803A CN 201880082111 A CN201880082111 A CN 201880082111A CN 111836803 A CN111836803 A CN 111836803A
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- dmso
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Abstract
本公开涉及式(I)的双胍衍生物及其重排产物。本公开还涉及这些化合物在用于治疗癌症,特别是黑色素瘤的方法中的用途。
Description
技术领域
本公开涉及双胍衍生物及其重排产物。本公开还涉及这些化合物在治疗癌症(特别是黑色素瘤)的方法中的用途。
背景技术
在法国,癌症是最重要的死亡原因之一。在癌症中,黑色素瘤是在法国很普遍的皮肤癌,每年诊断出约8000例新病例,并有1000例以上死亡。因此,该癌症是主要的公共卫生问题。黑色素瘤是由负责合成作为光保护性色素的黑色素的黑色素细胞发展而来的恶性肿瘤。黑色素瘤是极具侵略性的肿瘤,对淋巴结、肝、肺、中枢神经系统和皮肤具有高的转移可能。一旦出现转移,由于目前所有治疗方法的效率低下,生命预后(vital prognosis)变得不利。
最近,BRAF抑制剂(威罗菲尼(PLX 4032)和达拉非尼)获得了令人鼓舞的结果,它们仅靶向B-Raf突变型黑色素瘤(约转移性黑色素瘤的50%)。不幸的是,在短暂的缓解后,几乎所有病例中,黑色素瘤都对这些药物产生了耐药性,并且转移再次发展,使患者的预期寿命延长了约2个月。最近还开发了免疫疗法。它们基于可重新激活免疫应答的抗CTLA4和抗PD1抗体。但是,免疫疗法仅在15%-30%的患者中产生客观应答。
也有报道称二甲双胍(通常用于治疗糖尿病的药物)能够抑制黑色素瘤细胞生长(Tomic et al.,Cell Death and Disease,1;2:e199,2011)和转移发展(Cerezo et al,Molecular Cancer Therapeutics,12(8):1605-15,2013)。但是,可能需要高剂量的二甲双胍诱导细胞死亡(IC50=10mM,十毫摩尔)。
因此,需要具有抗增殖性能的化合物和组合物,其可以特别用于治疗患有黑色素瘤的患者,例如,具有耐BRAF抑制剂的黑色素瘤的患者。
发明内容
发明人惊奇地发现,包含杂芳基部分的双胍衍生物及其重排产物对癌症系(诸如黑色素瘤细胞系),包括对BRAF抑制剂具有耐药性的黑色素瘤细胞系具有高生物活性。
因此,在第一方面,本公开涉及式(I)的化合物
其中,
R1和R2独立地选自H、卤素、C1-C6烷基、C3-C6环烷基、C1-C6卤代烷基、C2-C6烯基、C2-C6炔基、具有5-10个环原子的杂环基、具有6-10个环原子的芳基、具有5-10个环原子的杂芳基和C7-C16芳烷基,所述烷基、环烷基、卤代烷基、烯基、炔基、杂环基、芳基、杂芳基和芳烷基任选地被一个或多个独立地选自氧、卤素、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、-OH、-NR”R”’、-NO2、-CN和-(CO)-R的取代基取代;
或R1和R2与它们之间的碳-碳双键一起形成6-10元的芳基或杂芳基环,所述芳基和杂芳基任选地被一个或多个独立地选自氧、卤素、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、-OH、-NR”R”’、-NO2、-CN和-(CO)-R的取代基取代;
Y是-O-或-S-;
R3选自C1-C6烷基、C3-C6环烷基、C1-C6卤代烷基、C2-C6烯基、C2-C6炔基、具有5-10个环原子的杂环基、具有6-10个环原子的芳基、具有5-10个环原子的杂芳基和C7-C16芳烷基,所述烷基、环烷基、卤代烷基、烯基、炔基、杂环基、芳基、杂芳基和芳烷基任选地被一个或多个独立地选自氧、卤素、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、-OH、-NR”R”’、-NO2、-CN和-(CO)-R的取代基取代;
每个R独立地选自H、C1-C6烷基、C1-C6烷氧基和-NR”R”’;
每个R”和R”’独立地选自H和C1-C6烷基。
在第二方面,本公开涉及式(II)或(III)的化合物
其中
Y’是-SR4或-OR5,
R4选自H、C1-C6烷基和保护基;
R5选自H和保护基;
每个R’独立地选自卤素、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、-OH、-NR”R”’、-NO2、-CN和-(CO)-R;
n为0-4;
R3选自C1-C6烷基、C3-C6环烷基、C1-C6卤代烷基、C2-C6烯基、C2-C6炔基、具有5-10个环原子的杂环基、具有6-10个环原子的芳基、具有5-10个环原子的杂芳基和C7-C16芳烷基,所述烷基、环烷基、卤代烷基、烯基、炔基、杂环基、芳基、杂芳基和芳烷基任选地被一个或多个独立地选自氧、卤素、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、-OH、-NR”R”’、-NO2、-CN和-(CO)-R的取代基取代;
每个R独立地选自H、C1-C6烷基、C1-C6烷氧基和-NR”R”’;
每个R”和R”’独立地选自H和C1-C6烷基。
在第三方面,本公开涉及包含式(I)、(II)或(III)的化合物以及药学上可接受的载体的药物组合物。
在第四方面,本公开涉及式(I)、(II)或(III)的化合物用于治疗癌症的方法的用途。
在第五方面,本公开涉及用于治疗癌症的方法,所述方法包括向受试者施用治疗有效量的
(i)式(I)的化合物,
(ii)式(II)或(III)的化合物,或
(iii)如本文所述的药物组合物。
在第六方面,本公开涉及式(I)、(II)或(III)的化合物在制备用于治疗癌症的药物中的用途。
在第七方面,本公开涉及式(I)、(II)或(III)的化合物用作药物的用途。
发明详述
定义
如本文所用,术语“C1-C6烷基”本身或作为另一取代基的一部分,是指具有1-6个碳原子的直链或支链烷基官能团。合适的烷基包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基和叔丁基、戊基及其异构体(例如正戊基、异戊基)以及己基和其异构体(例如正己基、异己基)。
如本文所用,术语“C3-C6环烷基”是指具有3-6个碳原子的饱和或不饱和环状基团。合适的环烷基包括环丙基、环丁基、环戊基和环己基。
如本文所用,术语“卤素”是指氟(-F)、氯(-Cl)、溴(-Br)或碘(-I)基团。
如本文所用,术语“C1-C6卤代烷基”是指被一个或多个如本文所定义的卤素基团取代的如本文所定义的C1-C6烷基。合适的C1-C6卤代烷基包括三氟甲基和二氯甲基。
如本文所用,术语“C2-C6烯基”是指具有至少一个碳-碳双键的直链或支链烃部分。例如,烯基包括乙烯基、丙烯基、丁烯基、1-甲基-2-丁烯-1-基、戊烯基、己烯基、辛烯基和丁二烯基。
如本文所用,术语“C2-C6炔基”是指具有至少一个碳-碳三键的直链或支链烃部分。“炔基”的实例包括乙炔基、2-丙炔基(炔丙基)、1-丙炔基、戊炔基、己炔基和炔丙基(allenyl groups)等。
如本文所用,术语“C1-C6烷氧基”是指-O-烷基,其中所述烷基是如本文所定义的C1-C6烷基。合适的C1-C6烷氧基包括甲氧基、乙氧基、丙氧基。
如本文所用,术语“具有6-10个环原子的芳基”是指含有6-10个环原子的单环或稠合在一起的多个芳环的多不饱和芳族烃基,其中至少一个环是芳族的。芳环可任选地包括与其稠合的1-2个另外的环(如本文所定义的环烷基、杂环基或杂芳基)。合适的芳基包括与杂环基稠合的苯基、萘基和苯环,例如苯并吡喃基、苯并二噁唑基、苯并二噁烷基等。
如本文所用,术语“具有5-10个环原子的杂芳基”是指含有5-10个原子的单环或稠合在一起或共价连接的多个芳环的多不饱和芳族环系统,其中至少一个环是芳族的并且至少一个环原子是选自N、O和S的杂原子。氮和硫杂原子可任选被氧化并且氮杂原子可任选被季铵化。这种环可以与芳环、环烷基环或杂环基环稠合。非限制性的这类杂芳基的实例包括:呋喃基、苯硫基、吡咯基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、三唑基、噁二唑基、噻二唑基、四唑基、氧杂三唑基、噻三唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、噁嗪基、二噁基、噻嗪基、三嗪基、吲哚基、异吲哚基、苯并呋喃基、异苯并呋喃基、苯并噻吩基、异苯并噻吩基、吲唑基、苯并咪唑基、苯并噁唑基、嘌呤基、苯并噻二唑基、喹啉基、异喹啉基、噌啉基、喹唑啉基和喹喔啉基。
如本文所用,术语“具有5-10个环原子的杂环基”是指具有5-10个环原子的饱和或不饱和环状基团,其中至少一个环原子是选自N、O和S的杂原子。氮和硫杂原子可任选被氧化并且氮杂原子可任选被季铵化。杂环的示例包括但不限于四氢吡啶基、哌啶基、吗啉基、四氢呋喃基、四氢噻吩基、哌嗪基、杂氮环庚基、咪唑啉基、1,4-二噁基等。
如本文所用,术语“C7-C16芳烷基”是指被一个或多个如本文定义的芳基取代的如本文定义的烷基。例如,芳烷基包括苄基。
本文描述了本公开的各种实施方案。将认识到,在每种实施方案中限定的特征可以与其他限定的特征组合以提供其他实施方案。
本公开内容涵盖式(I)、(II)、(III)的化合物,其互变异构体、对映异构体、非对映异构体、外消旋体或其混合物,及其水合物、溶剂化物或药学上可接受的盐。
术语“药学上可接受的盐”是指保留本公开化合物的生物学效力和性能并且典型地在生物学上或其他方面不是不良的盐。
本文给出的任何化学式也旨在表示化合物的未标记以及同位素形式,例如氘标记的化合物或14C标记的化合物。
式(I)的化合物
本公开涉及式(I)的化合物
其中,
R1和R2独立地选自H、卤素、C1-C6烷基、C3-C6环烷基、C1-C6卤代烷基、C2-C6烯基、C2-C6炔基、具有5-10个环原子的杂环基、具有6-10个环原子的芳基、具有5-10个环原子的杂芳基和C7-C16芳烷基,所述烷基、环烷基、卤代烷基、烯基、炔基、杂环基、芳基、杂芳基和芳烷基任选地被一个或多个独立地选自氧、卤素、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、-OH、-NR”R”’、-NO2、-CN和-(CO)-R的取代基取代;
或R1和R2与它们之间的碳-碳双键一起形成6-10元的芳基或杂芳基环,所述芳基和杂芳基任选地被一个或多个独立地选自氧、卤素、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、-OH、-NR”R”’、-NO2、-CN和-(CO)-R的取代基取代;
Y是-O-或-S-;
R3选自C1-C6烷基、C3-C6环烷基、C1-C6卤代烷基、C2-C6烯基、C2-C6炔基、具有5-10个环原子的杂环基、具有6-10个环原子的芳基、具有5-10个环原子的杂芳基和C7-C16芳烷基,所述烷基、环烷基、卤代烷基、烯基、炔基、杂环基、芳基、杂芳基和芳烷基任选地被一个或多个独立地选自氧、卤素、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、-OH、-NR”R”’、-NO2、-CN和-(CO)-R的取代基取代;
每个R独立地选自H、C1-C6烷基、C1-C6烷氧基和-NR”R”’;
每个R”和R”’独立地选自H和C1-C6烷基。
在一种实施方案中,本公开涉及式(I)的化合物,其中
R1和R2独立地选自H、卤素、C1-C6烷基、C3-C6环烷基、C1-C6卤代烷基、具有5-10个环原子的杂环基、具有6-10个环原子的芳基、具有5-10个环原子的杂芳基和C7-C16芳烷基,所述烷基、环烷基、杂环基、芳基、杂芳基和芳烷基任选地被一个或多个独立地选自卤素、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、-NO2、-CN和-(CO)-R的取代基取代;
或R1和R2与它们之间的碳-碳双键一起形成6元芳基或杂芳基环,所述芳基和杂芳基任选地被一个或多个独立地选自卤素、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、-NO2、-CN和-(CO)-R的取代基取代;
Y是-O-或-S-;
R3选自C1-C6烷基、C3-C6环烷基、C1-C6卤代烷基、具有5-10个环原子的杂环基、具有6-10个环原子的芳基、具有5-10个环原子的杂芳基和C7-C16芳烷基,所述烷基、环烷基、杂环基、芳基、杂芳基和芳烷基任选地被一个或多个独立地选自卤素、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、-NO2、-CN和-(CO)-R的取代基取代;
每个R独立地选自H、C1-C6烷基和C1-C6烷氧基。
在一种实施方案中,R1选自H、C1-C6烷基和具有6-10个环原子的芳基,所述烷基和芳基任选地被一个或多个独立地选自卤素、C1-C6烷基、C1-C6烷氧基和-NO2的取代基取代。
在另一种实施方案中,R2选自H和C1-C6烷基,所述烷基任选地被一个或多个独立地选自卤素的取代基取代。
在另一种实施方案中,R1和R2独立地选自H、C1-C6烷基和具有6-10个环原子的芳基,所述芳基任选地被一个或多个-NO2取代。
在另一种实施方案中,R1和R2与它们之间的碳-碳双键一起形成6元芳基环,其任选地被一个或多个独立地选自卤素、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、-NO2、-CN和-(CO)-R的取代基取代;每个R独立地选自H、C1-C6烷基和C1-C6烷氧基。
在另一种实施方案中,R3选自C1-C6卤代烷基、具有5-10个环原子的杂环基、具有6-10个环原子的芳基和具有5-10个环原子的杂芳基,所述杂环基、芳基和杂芳基任选地被一个或多个独立地选自卤素、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、-NO2、-CN和-(CO)-R的取代基取代;每个R独立地选自C1-C6烷基。
在另一种实施方案中,Y是-S-。
在另一种实施方案中,本公开提供式(I)的化合物,其中
R1和R2与它们之间的碳-碳双键一起形成6元芳基环;
Y是-O-;
R3选自具有6-10个环原子的芳基,所述芳基任选地被一个或多个独立地选自卤素的取代基取代。
在另一种实施方案中,本公开提供式(I)的化合物,其中
R1和R2独立地选自H、C1-C6烷基和具有6-10个环原子的芳基,所述芳基任选地被一个或多个-NO2取代;
或R1和R2与它们之间的碳-碳双键一起形成6元芳基环,其任选地被一个或多个独立地选自卤素、C1-C6烷基和C1-C6烷氧基的取代基取代,
Y是-S-;
R3选自C1-C6卤代烷基、具有5-10个环原子的杂环基、具有6-10个环原子的芳基、具有5-10个环原子的杂芳基、和C7-C16芳烷基,所述杂环基、芳基、杂芳基和芳烷基任选地被一个或多个独立地选自卤素、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、-NO2、-CN和-(CO)-R的取代基取代;
每个R独立地选自C1-C6烷基。
在另一种实施方案中,本公开提供式(I)的化合物,其中
R1和R2以及它们之间的碳-碳双键形成6元芳基环,
Y是-S-;
R3选自具有6-10个环原子的芳基和具有5-10个环原子的杂芳基,所述芳基和杂芳基任选地被一个或多个独立地选自卤素、C1-C6卤代烷基、C1-C6烷氧基、-CN和-(CO)-R的取代基取代;每个R独立地选自C1-C6烷基。
在另一种实施方案中,式(I)的化合物选自
根据一种实施方案,式(I)的化合物选自
在优选的实施方案中,式(I)的化合物选自
在一些实施方案中,如本文所述的式(I)的化合物具有针对黑色素瘤细胞系的抗增殖活性。因此,它们可以有利地用于治疗癌症(特别是黑色素瘤)的方法中。
不受该理论的束缚,发明人推定,在一些实施方案中,式(I)的化合物诱导参与调节凋亡的AMPK(AMP激活的蛋白激酶)的活化,从而诱导癌细胞死亡。
式(II)或(III)的化合物
式(I)的化合物(其中R1和R2以及它们之间的碳-碳双键一起形成任选被取代的6-元芳基环)可以自发地或在特定条件下(取决于双胍结构)通过打开苯并噻唑或苯并噁唑部分并形成三嗪环而重排形成式(II)的化合物。例如,在某些情况下,当将其中Y是-S-的式(I)的化合物在氧化条件下经处理时,会发生重排为式(II)的化合物。当Y’为-SH时,式(II)的化合物可通过形成S-S键而二聚形成式(III)的化合物。
因此,本发明还涉及式(II)或(III)的化合物
其中
Y’是-SR4或-OR5,
R4选自H、C1-C6烷基和保护基;
R5选自H和保护基;
每个R’独立地选自卤素、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、-OH、-NR”R”’、-NO2、-CN和-(CO)-R;
n为0-4;
R3选自C1-C6烷基、C3-C6环烷基、C1-C6卤代烷基、C2-C6烯基、C2-C6炔基、具有5-10个环原子的杂环基、具有6-10个环原子的芳基、具有5-10个环原子的杂芳基和C7-C16芳烷基,所述烷基、环烷基、卤代烷基、烯基、炔基、杂环基、芳基、杂芳基和芳烷基任选地被一个或多个独立地选自氧、卤素、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、-OH、-NR”R”’、-NO2、-CN和-(CO)-R的取代基取代;
每个R独立地选自H、C1-C6烷基、C1-C6烷氧基和-NR”R”’;
每个R”和R”’独立选自H和C1-C6烷基。
在一种实施方案中,本公开涉及式(II)或(III)的化合物,其中
Y’是-SR4或-OR5,
R4选自H、C1-C6烷基和保护基;
R5选自H和保护基;
每个R’独立地选自卤素、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、-NO2、-CN和-(CO)-R;
n为0-4;
R3选自C1-C6烷基、C1-C6卤代烷基、具有5-10个环原子的杂环基、具有6-10个环原子的芳基、具有5-10个环原子的杂芳基和C7-C16芳烷基、所述烷基、杂环基、芳基、杂芳基和芳烷基任选地被一个或多个独立地选自卤素、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、-NO2、-CN和-(CO)-R的取代基取代;
每个R独立地选自H、C1-C6烷基和C1-C6烷氧基。
在一种实施方案中,n为1且R’选自卤素和C1-C6烷氧基。在另一实施方案中,n为1且R’选自卤素、C1-C6烷基、C1-C6烷氧基和-NO2。
在另一实施方案中,n为0。
在另一实施方案中,Y'是-SR4且R4选自C1-C6烷基和保护基。优选地,该保护基选自由二硫官能团连接的任何基团、硫酯、烷基、烯基和炔基硫醚、苄基硫醚、烷基芳基甲基硫醚和三芳基甲基硫醚。
在另一实施方案中,Y’是-OR5且R5选自H和保护基。优选地,该保护基选自酯、烯基和炔基醚、甲硅烷基化醚、烷氧基甲基醚、苄基醚、四氢吡喃基醚、戊糖和己糖。
在一种实施方案中,Y’是-OH,n为1,并且R’选自卤素和-NO2。
在另一实施方案中,R3选自C1-C6卤代烷基,具有6-10个环原子的芳基、具有5-10个环原子的杂芳基和C7-C16芳烷基,所述芳基、杂芳基和芳烷基任选地被一个或多个独立地选自卤素、C1-C6烷氧基、C1-C6卤代烷基和-CN的取代基取代。
在另一实施方案中,本公开提供式(II)或(III)的化合物,其中
Y’是-SR4,R4选自C1-C6烷基;
每个R’独立地选自卤素和C1-C6烷氧基;
n为0-1;
R3选自C1-C6卤代烷基、具有6-10个环原子的芳基、具有5-10个环原子的杂芳基和C7-C16芳烷基,所述芳基、杂芳基和芳烷基任选地被一个或多个独立地选自卤素、C1-C6烷氧基和-CN的取代基取代。
在另一实施方案中,本公开提供式(II)的化合物,其中
Y’是-SR4,R4选自C1-C6烷基;
每个R’独立地选自卤素和C1-C6烷氧基;
n为0-1;
R3选自C1-C6卤代烷基、具有6-10个环原子的芳基、具有5-10个环原子的杂芳基和C7-C16芳烷基,所述芳基、杂芳基和芳烷基任选地被一个或多个独立地选自卤素、C1-C6烷氧基和-CN的取代基取代。
在另一实施方案中,本公开提供式(II)的化合物,其中
Y’是-OR5,且R5是H;
每个R’独立地选自卤素、C1-C6烷基和-NO2;
n为0-1;
R3选自C1-C6卤代烷基、具有6-10个环原子的芳基和具有5-10个环原子的杂芳基,所述芳基和杂芳基任选地被一个或多个独立地选自卤素、C1-C6烷氧基和-CN的取代基取代。
在另一实施方案中,本公开提供式(II)的化合物,其中
每个R’独立地选自卤素和C1-C6烷氧基;
n为0-1;
R3选自C1-C6卤代烷基、具有6-10个环原子的芳基、具有5-10个环原子的杂芳基和C7-C16芳烷基,所述芳基、杂芳基和芳烷基任选地被一个或多个独立地选自卤素、C1-C6烷氧基和-CN的取代基取代。
在另一实施方案中,本公开提供选自以下的式(II)的化合物
在另一实施方案中,本公开提供选自以下的式(II)的化合物
在另一实施方案中,本公开提供式(III)的化合物,其中
每个R’独立地选自卤素和C1-C6烷氧基;
n为0-1;
R3选自C1-C6卤代烷基、具有6-10个环原子的芳基、具有5-10个环原子的杂环基、具有5-10个环原子的杂芳基和C7-C16芳烷基,所述芳基、杂芳基、杂环和芳烷基任选地被一个或多个独立地选自卤素、C1-C6烷氧基、C1-C6烷基、-NR”R”’、-NO2、-CN和-(CO)-R的取代基取代;
每个R独立地选自C1-C6烷基;
R”和R”’是H。
在另一实施方案中,本公开提供选自以下的式(III)的化合物
在另一实施方案中,本公开提供选自以下的式(III)的化合物
在优选实施方案中,本公开提供选自以下的(III)的化合物
在式(II)的化合物中,可以用保护基保护羟基或硫醇官能团。如本文所用,保护基是指在生物介质中可裂解的任何基团,特别是通过水解或经由血浆酶或生物有机亲核试剂(诸如谷胱甘肽)的去除。合适的羟基保护基包括但不限于酯、烷基、烯基和炔基醚、甲硅烷基化醚、烷氧基甲基醚、苄基醚、四氢吡喃基醚、戊糖、己糖。硫醇基的合适保护基包括但不限于通过二硫官能团连接的任何基团、硫酯、烷基、烯基和炔基硫醚、苄基硫醚、烷基芳基甲基硫醚、三芳基甲基硫醚。
本文所述的式(II)或(III)的化合物对黑色素瘤(包括对BRAF抑制剂有耐药性的黑色素瘤)具有高的生物学活性。因此,它们可以用于治疗癌症,特别是黑色素瘤的方法中。
不受限于该理论,发明人推定式(II)和(III)的化合物是式(I)的化合物的前药。向受试者施用后,通过体内生理作用将式(II)和(III)的化合物修饰成式(I)的化合物。
药物组合物
本公开还涉及包含式(I)、(II)或(III)的化合物和药学上可接受的载体的药物组合物。
“药学上”或“药学上可接受的”是指当适当地施用于哺乳动物(特别是人)时,不产生不利、过敏或其他不良反应的分子实体和组合物。药学上可接受的载体或赋形剂是指任何类型的无毒固体、半固体或液体填充剂、稀释剂、包封材料或制剂助剂。
药物组合物的形式、施用途径、剂量和方案自然取决于待治疗的病症、疾病的严重程度、患者的年龄、体重和性别等。
可以将本公开的药物组合物配制成用于局部、口服、鼻内、眼内、静脉内、肌内或皮下施用等。
药物组合物可以采取片剂、丸剂、胶囊剂、半固体、粉末、缓释制剂、溶液剂、混悬剂、乳剂、糖浆剂、酏剂、气雾剂或任何其他合适的组合物的形式;且包含至少一种根据本公开的化合物。
由于易于施用,片剂和胶囊剂是最有利的口服剂量单位形式,在这种情况下,显然会使用固体药物载体。如果需要,可以通过标准技术将片剂包糖衣或肠溶衣。可以将片剂或丸剂包衣以提供具有延长作用的优点的剂型。例如,片剂或丸剂可包含内部剂量和外部剂量组分,后者为前者上的包封形式。这两种成分可以由肠溶层分开,该肠溶层用于抵抗胃中的崩解并允许内部成分完整地进入十二指肠或延迟释放。多种材料可以用于这种肠溶层或包衣,这种材料包括许多聚合酸,以及诸如虫胶、鲸蜡醇和乙酸纤维素的材料。
本公开的化合物和其他试剂也可以脂质体递送系统的形式施用,诸如小的单层囊泡、大的单层囊泡和多层囊泡。脂质体可由多种磷脂形成,诸如胆固醇、硬脂胺或磷脂酰胆碱。
优选地,药物组合物含有对于能够被注射的制剂而言是药学上可接受的载体。特别地,这些可以是等渗的无菌盐溶液(磷酸一钠或磷酸二钠、氯化钠、氯化钾、氯化钙或氯化镁等,或此类盐的混合物)、或在通过添加无菌水或生理盐水可被配制成可注射液的情况下,干燥的(尤其是冻干的)组合物。
适用于注射用途的药物形式包括无菌水溶液或分散体;制剂包括麻油、花生油或丙二醇水溶液;以及用于临时制备无菌可注射液或分散体的无菌粉剂。在所有情况下,该形式必须是无菌的并且必须具有一定的流动性,以达到易于注射的目的。它必须在生产和储存条件下稳定,并且必须保存以防微生物(诸如细菌和真菌)的污染。活性化合物的游离碱或药理学上可接受的盐的溶液可以在水中适当地与表面活性剂(诸如羟丙基纤维素)混合而制备。分散体也可以在甘油、液态聚乙二醇、其混合物和油中制备。在常规的储存和使用条件下,这些制剂含有防腐剂以防止微生物的生长。
载体也可以是溶剂或分散介质,其包含例如水、乙醇、多元醇(例如甘油、丙二醇和液体聚乙二醇等)、其合适的混合物和植物油。例如,可以通过使用包衣(诸如卵磷脂),在分散体的情况下通过维持所需的粒度以及通过使用表面活性剂来维持适当的流动性。可以通过各种抗菌剂和抗真菌剂来防止微生物的作用,例如对羟基苯甲酸酯、氯丁醇、苯酚、山梨酸、硫柳汞等。在许多情况下,优选包括等渗剂,例如糖或氯化钠。通过在组合物中使用延迟吸收的试剂(例如单硬脂酸铝和明胶),可以使可注射组合物的吸收延长。
通过将所需量的活性化合物与所需的上述各种其他成分掺入适当的溶剂中,然后过滤灭菌,从而制备无菌可注射溶液。通常,通过将各种灭菌的活性成分掺入无菌载体中来制备分散体,所述无菌载体含有基本分散体介质和来自上文列举的那些的所需的其他成分。就用于制备无菌可注射溶液的无菌粉而言,优选的制备方法是真空干燥和冷冻干燥技术,其从其先前的无菌过滤溶液中产生活性成分和任何其他所需成分的粉末。通过配制,将以与剂型相容的方式和治疗有效量施用溶液。该制剂易于以多种剂型施用,诸如上述可注射溶液的类型,但是也可以使用药物释放胶囊等。
例如,对于在水溶液中的肠胃外施用,可以适当地缓冲溶液,并且首先用足够的盐水或葡萄糖使液体稀释剂等渗。这些具体水溶液特别适合于静脉内、肌内、皮下和腹膜内施用。就此而言,根据本公开,本领域技术人员将知道可以采用的无菌水性介质。例如,一种剂量可以溶解在1ml等渗NaCl溶液中,或者添加到1000ml皮下注射液中,或者在建议的输注位点注射(例如,参见“Remington's Pharmaceutical Sciences"第15版,1035-1038页和1570-1580页)。取决于治疗对象的病症,必然会发生剂量的一些变化。在任何情况下,负责施用的人员将确定适用于个体受试者的适当剂量。
对于气雾剂施用,优选与表面活性剂和推进剂一起细分地提供本公开的化合物和其他试剂。当然,表面活性剂必须是无毒的,并且优选可溶于推进剂中。这类试剂的代表是含有6-22个碳原子的脂肪酸的酯或偏酯,诸如己酸、辛酸、月桂酸、棕榈酸、硬脂酸、亚油酸、亚麻酸、油酸和含脂族多元醇的油酸或其环状酸酐的酯或偏酯。可以采用混合酯,诸如混合或天然甘油酯。如果需要,还可以包括载体,例如,用于鼻内递送的卵磷脂。一个实例包括每毫升包括7.5mg NaCl、1.7mg一水柠檬酸、3mg磷酸二钠二水合物和0.2mg苯扎氯铵溶液(50%)的溶液(Gozes et al.,J Mol Neurosci.19(1-2):167-70(2002))。
用于局部施用的合适的组合物包括水溶液、悬浮液、软膏、乳膏、凝胶或可喷雾制剂,例如气雾剂施用。
用于施用的剂量可以根据各种参数,特别是根据所用的施用方式、相关病理学或所需的治疗持续时间进行调节。应当理解,化合物的适当剂量以及包含该化合物的组合物可以因患者而异。确定最佳剂量通常将涉及治疗益处水平与本文所述治疗的任何风险或有害副作用之间的平衡。选择的剂量水平将取决于多种因素,包括但不限于具体化合物的活性、施用途径、施用时间、化合物的排泄速率、治疗持续时间、其他组合使用的药物、化合物和/或材料、以及患者的年龄、性别、体重、病症、一般健康状况和既往病史。化合物的量和施用途径最终将由医师决定,尽管通常剂量将是在作用位点达到局部浓度,该浓度可达到所需的作用而不会引起实质的有害或有害副作用。
根据一种实施方案,药物组合物包含非离子型乳化剂,优选Kolliphor EL。这种非离子型乳化剂的存在使组合物中DMSO的最终浓度降低。式(I)、(II)或(III)的化合物可以溶解在非离子型乳化剂中,例如Kolliphor EL。
使用方法
如实施例中提供的体外和体内测试所示,式(I)、(II)或(III)的化合物表现出有价值的药物性能,因此被指明用于治疗。
本公开还涉及式(I)、(II)或(III)的化合物用作药物的用途。
本公开还涉及式(I)、(II)或(III)的化合物用于治疗癌症的方法的用途。
如本文所用,术语“癌症”在本领域中具有其一般含义,并且包括以快速增殖的细胞生长为特征的异常状态或病症。该术语旨在包括所有类型的癌性生长或致癌过程;转移组织或恶性转化的细胞、组织或器官,而与组织病理学类型或侵入性阶段无关。术语癌症包括各种器官系统的恶性肿瘤,诸如影响皮肤、肺、乳腺、甲状腺、淋巴、胃肠道和生殖泌尿道的腺癌,以及包括恶性肿瘤的腺癌,诸如大多数结肠癌、肾细胞癌、前列腺癌和/或睾丸肿瘤、肺非小细胞癌、小肠癌和食道癌。
癌症的示例包括但不限于血液系统恶性肿瘤,诸如B细胞淋巴瘤、T细胞淋巴瘤、非霍奇金淋巴瘤(NHL)、B-NHL、T-NHL、慢性淋巴细胞性白血病(CLL)、小淋巴细胞淋巴瘤(SLL)、套细胞淋巴瘤(MCL)、NK细胞淋巴样肿瘤和髓样细胞谱系肿瘤。非血液学癌症的示例包括但不限于皮肤癌、结肠癌、乳腺癌、肺癌、脑癌、前列腺癌、头颈癌、胰腺癌、膀胱癌、结肠直肠癌、骨癌、宫颈癌癌症、肝癌、口腔癌、食道癌、甲状腺癌、肾癌、胃癌和睾丸癌。
在特定实施方案中,本公开涉及式(I)、(II)或(III)的化合物用于治疗黑色素瘤的方法的用途。在一种具体实施方案中,本公开还涉及式(I)、(II)或(III)的化合物用于治疗耐BRAF抑制剂的黑色素瘤的方法的用途。
在一种特定实施方案中,式(I)、(II)或(III)的化合物诱导AMPK的活化。二甲双胍,一种通常用于治疗II型糖尿病的药物,也能诱导AMPK的活化,并且已显示二甲双胍也抑制黑色素瘤细胞的生长。因此,类似于二甲双胍,在一种具体实施方案中,本发明还涉及式(I)、(II)或(III)的化合物用于治疗II型糖尿病的方法的用途。
本公开涉及用于治疗癌症的方法,所述方法包括向受试者施用治疗有效量的
(i)式(I)的化合物,
(ii)式(II)或(III)的化合物,或
(iii)本文所述的药物组合物。
化合物的术语“治疗有效量”是指将引起受试者的生物学或医学反应,例如改善症状、缓解病症、减慢或延迟疾病进展或预防疾病的化合物的量。
本公开内容还涉及式(I)、(II)或(III)的化合物在制备用于治疗癌症的药物中的用途。在一种实施方案中,癌症是黑色素瘤。在一种实施方案中,癌症是耐BRAF抑制剂的黑色素瘤。
附图说明
在所有图中,条形表示平均值±SEM:*p<0.05;**p<0.01;***p<0.001。
图1A表示在图上所示时间用5μM CRO15或PLX4032处理的A375S细胞的细胞活力。
图1B表示用不同浓度的CRO15或用5μM PLX4032处理48小时的A375S细胞的细胞活力。
图1C表示用5μM CRO15处理48小时后具有各种突变的不同黑色素瘤细胞的活力。在黑色素瘤细胞系名称旁边指定了突变。突变的蛋白质以“*”表示。
图1D表示用5μM CRO15处理48小时的患者黑色素瘤细胞的活力。突变的蛋白质以“*”表示。
图1E表示用5μM CRO15处理48小时的正常细胞的活力。
图2表示蛋白质印迹分析的结果。
图3A表示皮下接种A375敏感性黑色素瘤细胞并用CRO15或PLX4032处理的异种移植小鼠的肿瘤体积的演变。
图3B表示小鼠安乐死后皮下接种A375敏感的黑色素瘤细胞并用CRO15或PLX4032处理的异种移植小鼠的肿瘤重量。
图4A表示用CRO15或PLX4032处理的敏感和抗性A375黑色素瘤细胞的活力。
图4B表示皮下接种A375耐药性黑色素瘤细胞并用CRO15或PLX4032处理的异种移植小鼠的肿瘤体积的演变。
图4C表示小鼠安乐死后皮下接种A375耐药性黑色素瘤细胞并用CRO15或PLX4032处理的异种移植小鼠的肿瘤重量。
图5表示用不同浓度的CRO15或1μM威罗菲尼和0.5μM考比替尼处理24小时的DR6细胞的细胞活力。
图6A表示皮下接种A375耐药性黑色素瘤细胞并用MTF319或PLX4032处理的异种移植小鼠的肿瘤体积的演变。
图6B表示小鼠安乐死后皮下接种A375耐药性黑色素瘤细胞并用MTF319或PLX4032处理的异种移植小鼠的肿瘤重量。
图7A表示皮下接种小鼠黑色素瘤细胞并用CRO15处理的同种异体移植小鼠的肿瘤体积的演变。
图7B表示用PLX4032、CRO15或MTF255处理8周并用10μM的每种药物刺激48小时后,WM9细胞的细胞活力。
具体实施方式
实验程序
化学合成与表征
甲醇、乙酸乙酯、乙醚和二氯甲烷购自Carlo Erba,并按原样使用。无水DMF(98.8%,隔离保存)购自Sigma Aldrich,并按原样使用。所有化学品均购自Aldrich、Fisher或Alfa Aesar,无需进一步纯化即可使用。薄层色谱(TLC)在预涂的Merck 60GF254硅胶板上进行,首先通过在紫外光(254nm和360nm)下可视化显示,并在Bruker Advance200MHz光谱仪或Bruker Advance 400MHz或Bruker Advance 500MHz光谱仪上记录1H和13CNMR光谱。在Bruker(Daltonics Esquire 3000+)上记录质谱(ESI-MS)。HRMS光谱在ThermoFisher Q Exactive(ESI-MS)上以140 000的分辨率在m/z 200下进行记录。化合物的纯度进一步通过在带有Supelco分析柱Ascentis Express C18,100mm×46mm 5μM的JASCO PU-2089装置上的HPLC分析进行测定。洗脱液A:含1‰甲酸的水。洗脱液B:含1‰甲酸的CH3CN。方法1:30%B持续1分钟,5分钟内30%B-100%B,100%B持续2.5分钟,然后30秒内100%B-30%B,30%B持续7分钟(总计16分钟)。方法2:30%B持续1分钟,5分钟内30%B-100%B,100%B持续20分钟,然后在1分钟内100%B-30%B,30%B持续4分钟(总计31分钟)。方法3:30%B持续1分钟,5分钟内30%B-100%B,100%B持续2.5分钟,然后30秒内100%B-30%B(总计9分钟)。方法4:10%B持续10分钟,8分钟内10%B-95%B,95%B持续2分钟,然后4分钟内95%B-10%B,10%B持续1分钟(总计25分钟)。
合成程序和表征:
形成式I的双胍的一般程序(A)。向相应的胍(1当量)的N,N-二甲基甲酰胺溶液中(25mL/g的胍)添加氢化钠(60%的在矿物油中的分散体,1.5当量),并将混合物在室温搅拌30分钟。向该溶液中一次性添加相应的腈(1当量)。将反应在室温搅拌过夜,并通过TLC监测。反应完成后,将混合物倒入水中(200mL/g的胍),收集沉淀并用水、甲醇和乙醚洗涤。
形成式II和III(B)的N2,N2'-(二硫代二基双(2,1-亚苯基))双(6-芳基/杂芳基-1,3,5-三嗪-2,4-二胺)的一般程序(B)。在回流温度下搅拌相应双胍(1当量)的工业级乙醇溶液(约25mL/100mg的双胍),并通过LCMS监测。完全转化后(约6-7小时),将形成的沉淀物过滤并用工业级乙醇洗涤。
形成式II和III的N2,N2'-(二硫代二基双(4-烷基/hal-2,1-亚苯基))双(6-(三氯甲基)-1,3,5-三嗪-2,4-二胺)的一般程序(C)。向相应的胍(1当量)的工业级乙醇溶液中(约10mL/g的胍)添加三氯乙腈(2当量),并将反应混合物在回流温度下搅拌并通过LCMS监测。完全转化后(约6-7小时),将形成的沉淀物过滤并用工业级乙醇和乙醚洗涤。
用于形成2-((6-亚氨基-4-(三氯甲基)-1,6-二氢-1,3,5-三嗪-2-基)氨基)酚的一般程序(D)。向相应的胍(1当量)的工业级乙醇溶液中(25mL/g的胍)添加三氯乙腈(10当量),并将反应混合物在密封管中在氩气气氛下于60℃搅拌。完全转化后(约18小时),将混合物浓缩至干。将残余物通过硅胶快速色谱纯化。
形成2-((4-氨基-6-苯基-1,3,5-三嗪-2-基)氨基)酚的一般程序(E)。向相应的胍(1当量)的N,N-二甲基甲酰胺溶液中(25mL/g的胍)添加氢化钠(60%的在矿物油中的分散体,1.1当量),并将反应混合物在氩气气氛下在密封管中搅拌。当停止向该溶液中放出气体时,添加相应的腈(1当量)并将管密封。然后,将所得溶液在80℃下搅拌。完全转化后(约18小时),将混合物浓缩至干。将残余物通过硅胶快速色谱纯化。
N2,N2'-(二硫代二基双(2,1-亚苯基))双(6-(三氯甲基)-1,3,5-三嗪-2,4-二胺)(CRO15)。将1-(苯并[d]噻唑-2-基)胍(10.0g,52mmol)和三氯乙腈(10.0mL,1.92mmol)的工业级乙醇(100mL)溶液在75℃下搅拌。1小时后,黄色溶液中出现大量白色沉淀。反应完成后(TLC监测,约3小时),将悬浮液冷至室温并过滤。沉淀物用少量冷乙醇洗涤并在空气中干燥。用丙酮/二乙醚重结晶,得到白色固体状所需化合物(10.03g,57.5%)。TLC:Rf(Et2O/PE,1/1,v/v)=0.23。1H NMR(200MHz,丙酮-d6):δ8.54(s,1H),7.96(d,J=8.0Hz,1H),7.58(dd,J=7.8,1.6Hz,1H),7.35(td,J=7.8,1.6Hz,1H),7.22–6.93(m,3H)。13C NMR(101MHz,丙酮-d6):δ174.00,168.98,166.37,139.05,133.76,130.58,129.92,126.33,125.34,97.43。HRMS-ESI(m/z):[M+H]+对于C20H15Cl6N10S2 +,计算值,668.90482;实测值:668.90497。HPLC(λ280):纯度97.4%;tR:7.958分钟(方法2)。
N2,N2'-(二硫代二基双(4-甲氧基-2,1-亚苯基))双(6-(三氯甲基)-1,3,5-三嗪-2,4-二胺)(MTF-232)。按照一般程序C,使用1-(6-甲氧基苯并[d]噻唑-2-基)胍(300mg,1.35mmol)合成,得到绿色粉末状标题化合物(418mg,85%)。1H NMR(400MHz,DMSO-d6):δ9.64(s,1H),7.59(s,1H),7.45(s,1H),7.20(d,J=8.7Hz,1H),7.10(s,1H),6.84(dd,J=8.7,2.8Hz,1H),3.70(s,3H)。13C NMR(50MHz,DMSO-d6):δ172.28,167.38,166.07,158.26,135.44,129.22,128.28,113.08,112.20,96.77,55.48。HPLC(λ280):纯度100.0%;tR:7.433min(方法3)。
N2,N2'-(二硫代二基双(4-氯-2,1-亚苯基))双(6-(三氯甲基)-1,3,5-三嗪-2,4-二胺)(MTF-233)。按照一般程序C,使用1-(6-氯苯并[d]噻唑-2-基)胍(300mg,1.32mmol)合成,得到白色粉末状标题化合物(454mg,93%)。1H NMR(400MHz,DMSO-d6):δ9.66(s,1H),7.71(s,1H),7.58(s,2H),7.40(d,J=8.5Hz,1H),7.35(dd,J=8.5,2.3Hz,1H)。13C NMR(50MHz,DMSO-d6):δ172.39,167.34,165.59,135.71,134.89,131.29,129.12,127.91,127.52,96.63.HPLC(λ280):纯度95.1%;tR:13.767min(方法1)。
N2,N2'-(二硫代二基双(4-氟-2,1-亚苯基))双(6-(三氯甲基)-1,3,5-三嗪-2,4-二胺)(MTF-234)。按照一般程序C,使用1-(6-氟苯并[d]噻唑-2-基)胍(300mg,1.42mmol)合成,得到白色粉末状标题化合物(457mg,91%)。1H NMR(200MHz,DMSO-d6):δ9.06(br.s.,2H),7.69(br.s.,1H),7.57(br.s.,1H),7.45-7.30(m,2H),7.14(t,1H,J=8.6Hz,H1).13CNMR(50MHz,DMSO-d6):δ172.42,167.38,165.94,160.87(d),136.40,131.93,130.04,114.76(d),113.61(d),96.69.HPLC(λ280):纯度98.7%;tR:6.858min(方法3)。
N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基)-3-溴苯甲酰胺(MTF-242)。按照一般程序A,使用1-(苯并[d]噻唑-2-基)胍(1.00g,5.20mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,312mg,7.81mmol)和3-溴苄腈(0.95g,5.20mmol)合成,得到白色-淡黄色粉末状标题化合物(708mg,36%)。1H NMR(500MHz,DMSO-d6):δ10.29(br.s,1H),9.36(br.s,1H),8.94(br.s,1H),8.26(s,1H),8.11(s,1H),8.03(d,J=7.9Hz,1H),7.80(d,J=7.7Hz,1H),7.76(dd,J=7.9,1.1Hz,1H),7.66(d,J=8.0Hz,1H),7.47(t,J=7.9Hz,1H),7.39–7.30(m,1H),7.24–7.15(m,1H).13C NMR(50MHz,DMSO-d6):δ172.23,161.94,160.52,151.47,137.42,134.08,131.23,130.43,126.51,125.66,122.86,121.70,121.15,119.78.HRMS-ESI(m/z):[M+H]+对于C15H12BrN5S+,计算值374.00696;实测值:374.00797.HPLC(λ280):纯度99.3%;tR:6.775min(方法1)。
N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基)-3-氯苯甲酰胺(MTF-243)。按照一般程序A,使用1-(苯并[d]噻唑-2-基)胍(1.00g,5.20mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,312mg,7.81mmol)和3-氯苄腈(715mg,5.20mmol)合成,得到黄色粉末状标题化合物(206mg,12%)。1H NMR(500MHz,DMSO-d6):δ10.30(br.s,1H),9.37(br.s,1H),8.90(br.s,1H),8.12(t,br.s,J=1.8Hz,2H),7.99(d,J=7.9Hz,1H),7.80(d,J=7.7Hz,1H),7.66(d,J=7.9Hz,1H),7.65–7.60(m,1H),7.54(t,J=7.9Hz,1H),7.38–7.30(m,1H),7.22–7.17(m,1H).13C NMR(50MHz,DMSO-d6):δ172.22,161.95,160.57,151.47,137.26,133.22,131.23,131.20,130.20,127.53,126.14,125.67,122.87,121.16,119.79.HRMS-ESI(m/z):[M+H]+对于C15H12ClN5S+,计算值330,05747;实测值:330,05774.HPLC(λ280):纯度99.2%;tR:6.792min(方法1)。
N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基)-2-氯苯甲酰胺(MTF-244)。按照一般程序A,使用1-(苯并[d]噻唑-2-基)胍(1.00g,5.20mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,312mg,7.81mmol)和2-氯苄腈(715mg,5.20mmol)合成,得到白色粉末状标题化合物(326mg,19%)。1H NMR(500MHz,DMSO-d6):δ10.14(br.s,1H),9.30(br.s,1H),8.81(br.s,1H),8.09(br.s,1H),7.80(d,J=7.5Hz,1H),7.65(d,J=7.7Hz,1H),7.53(br.s,2H),7.50–7.40(m,2H),7.34(t,J=7.1Hz,1H),7.20(t,J=7.1Hz,1H).13C NMR(50MHz,DMSO-d6):δ172.40,162.90,162.00,151.45,136.67,131.23,130.66,130.29,129.56,129.46,126.97,125.63,122.82,121.16,119.74.HRMS-ESI(m/z):[M+H]+对于C15H12ClN5S+,计算值330.05747;实测值:330.05783.HPLC(λ280):纯度96.6%;tR:6.500min(方法1)。
N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基)-4-氯苯甲酰胺(MTF-245)。按照一般程序A,使用1-(苯并[d]噻唑-2-基)胍(1.00g,5.20mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,312mg,7.81mmol)和4-氯苄腈(715mg,5.20mmol)合成,得到白色-淡黄色粉末状标题化合物(721mg,42%)。1H NMR(500MHz,DMSO-d6):δ10.27(br.s,1H),9.36(br.s,1H),8.85(br.s,1H),8.06(d,br.s,J=8.6Hz,3H),7.79(d,J=7.4Hz,1H),7.66(d,J=7.9Hz,1H),7.59(d,J=8.6Hz,2H),7.34(t,J=7.7Hz,1H),7.19(t,J=7.6Hz,1H).13C NMR(50MHz,DMSO-d6):δ172.22,162.00,160.95,151.47,136.28,134.00,131.21,129.44,128.36,125.65,122.83,121.15,119.74.HRMS-ESI(m/z):[M+H]+,对于C15H12ClN5S+,计算值330.05747;实测值:330.05743.HPLC(λ280):纯度98.8%;tR:6.800min(方法1)。
N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基)-4-甲基苯甲酰胺(MTF-246)。按照一般程序A,使用1-(苯并[d]噻唑-2-基)胍(1.00g,5.20mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,312mg,7.81mmol)和对甲苯二酚(609mg,5.20mmol)合成,得到米色粉末状标题化合物(145mg,9%)。1H NMR(500MHz,DMSO-d6):δ10.28(br.s,1H),9.34(br.s,1H),8.74(br.s,1H),7.96(d,br.s,J=7.9Hz,3H),7.79(d,J=7.7Hz,1H),7.65(d,J=7.9Hz,1H),7.33(dd,J=18.6,7.7Hz,3H),7.19(t,J=7.5Hz,1H),2.37(s,3H).13C NMR(50MHz,DMSO-d6):δ172.21,161.99,161.33,151.46,137.15,134.68,131.21,129.49,125.64,122.82,121.13,119.74,99.13.HRMS-ESI(m/z):[M+H]+对于C16H15N5S+,计算值310.11209;实测值:310.11218.HPLC(λ280):纯度97.9%;tR:6.592min(方法1)。
N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基)-4-碘代苯并咪唑胺(MTF-247)。按照一般程序A,使用1-(苯并[d]噻唑-2-基)胍(1.00g,5.20mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,312mg,7.81mmol)和4-碘苄腈(1.19g,5.20mmol)合成,得到米色粉末状标题化合物(832mg,38%)。1H NMR(500MHz,DMSO-d6):δ10.24(br.s,1H),9.34(br.s,1H),8.82(br.s,1H),8.03(br.s,1H),7.90(d,J=8.5Hz,2H),7.82(d,J=8.5Hz,2H),7.79(d,J=7.8Hz,1H),7.65(d,J=7.9Hz,1H),7.34(t,J=7.6Hz,1H),7.19(t,J=8.0Hz,1H).13CNMR(126MHz,DMSO-d6):δ172.20,161.97,161.31,151.45,137.13(2C),134.68,131.20,129.47(2C),125.62,122.79,121.11,119.72,99.09.HRMS-ESI(m/z):[M+H]+对于C15H12IN5S+,计算值421.99309;实测值:421.99316.HPLC(λ280):纯度98.8%;tR:6.900min(方法1)。
N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基)苯甲酰胺(MTF-248)。按照一般程序A,使用1-(苯并[d]噻唑-2-基)胍(1.00g,5.20)、氢化钠(60%的在矿物油中的分散体,1.5当量,312mg,7.81mmol)和苄腈(0.54mL,5.20mmol)合成,得到米色粉末状标题化合物(430mg,28%)。1H NMR(500MHz,DMSO-d6):δ10.28(br.s,1H),9.35(br.s,1H),8.80(br.s,1H),8.03(d,br.s,J=7.3Hz,3H),7.79(d,J=7.6Hz,1H),7.66(d,J=7.9Hz,1H),7.60–7.54(m,1H),7.51(t,J=7.2Hz,2H),7.34(t,J=7.4Hz,1H),7.19(t,J=7.4Hz,1H).13C NMR(50MHz,DMSO-d6):δ172.37,162.29,162.21,151.57,135.28,131.44,131.26,128.28,127.60,125.67,122.82,121.15,119.75.HRMS-ESI(m/z):[M+H]+对于C15H13N5S+,计算值296.09644;实测值:296.09659。HPLC(λ280):纯度97.9%;tR:6.358min(方法1)。
N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基)-2-氟苯甲酰胺(MTF-249)。按照一般程序A,使用1-(苯并[d]噻唑-2-基)胍(1.00g,5.20mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,312mg,7.81mmol)和2-氟苄腈(0.56mL,5.20mmol)合成,得到红色粉末状标题化合物(179mg,11%)。1H NMR(400MHz,DMSO-d6):δ10.16(s,1H),9.31(s,1H),8.69(s,1H),8.05(s,1H),7.80(d,J=7.7Hz,1H),7.72(td,J=7.6,1.4Hz,1H),7.65(d,J=7.9Hz,1H),7.55(ddd,J=9.4,7.3,1.6Hz,1H),7.37–7.28(m,3H),7.20(t,J=7.5Hz,1H).13C NMR(101MHz,DMSO-d6):δ172.30(s),161.95(s),159.34(d,J=250.6Hz),160.01(s),151.43(s),132.26(d,J=8.6Hz),131.21(s),130.39(d,J=2.6Hz),125.62(s),124.59(d,J=13.0Hz),124.28(d,J=3.4Hz),122.82(s),121.14(s),119.73(s),116.09(d,J=21.9Hz).19F NMR(377MHz,DMSO-d6):δ-114.77.HPLC(λ280):纯度97.4%;tR:6.792min(方法1)。
N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基)-2-溴苯甲酰胺(MTF-250)。按照一般程序A,使用1-(苯并[d]噻唑-2-基)胍(1.00g,5.20mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,312mg,7.81mmol)和2-溴苄腈(946mg,5.20mmol)合成,得到米色粉末状标题化合物(136mg,7%)。1HNMR(400MHz,DMSO-d6):δ9.26(s,1H),7.67(d,J=7.9Hz,1H),7.54(d,br.s,J=7.0Hz,2H),7.44(t,J=7.3Hz,2H),7.35(t,J=7.1Hz,1H),7.28–7.04(m,4H).13CNMR(101MHz,DMSO-d6):δ173.15,166.81,165.00,139.47,136.49,133.16,132.85,130.48,130.28,128.84,127.32,127.03,126.48,126.12,120.08.HRMS-ESI(m/z):[M+H]+对于C15H12BrN5S+,计算值374.00696;实测值:374.00702.HPLC(λ280):纯度97.8%;tR:4.158min(方法1)。
N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基)吡啶甲酰胺(MTF-251)。按照一般程序A,使用1-(苯并[d]噻唑-2-基)胍(1.00g,5.20)、氢化钠(60%的在矿物油中的分散体,1.5当量,312mg,7.81mmol)和2-吡啶甲腈(541mg,5.20mmol)合成,得到白色-淡黄色粉末状标题化合物(955mg,62%)。1H NMR(200MHz,DMSO-d6):δ10.10(br.s,1H),9.40(br.s,1H),8.92(br.s,1H),8.72(ddd,J=4.7,1.6,0.9Hz,1H),8.37(dt,J=7.9,1.0Hz,1H),8.03(br.s,td,J=7.7,1.7Hz,2H),7.81(dd,J=7.8,0.8Hz,1H),7.73–7.58(m,2H),7.35(td,J=7.7,1.4Hz,1H),7.20(td,J=7.6,1.2Hz,1H).13CNMR(101MHz,DMSO-d6):δ170.26,167.51,165.72,154.24,149.29,136.70,133.47,128.60,127.35,126.57,126.22,125.45,123.31.HRMS-ESI(m/z):[M+H]+计算值for C14H12N6S+,291.09169;实测值:291.09174.HPLC(λ280):纯度98.6%;tR:6.075min(方法1)。
N-(N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基]烟碱甲酰胺(MTF-252)。按照一般程序A,使用1-(苯并[d]噻唑-2-基)胍(1.00g,5.20)、氢化钠(60%的在矿物油中的分散体,1.5当量,312mg,7.81mmol)、3-吡啶甲腈(541mg,5.20mmol)合成,得到白色-淡黄色粉末状标题化合物(1.49g,97%)。1H NMR(200MHz,DMSO-d6):δ10.20(br.s,1H),9.34(br.s,1H),9.17(dd,J=2.2,0.6Hz,1H),8.95(br.s,1H),8.74(dd,J=4.8,1.6Hz,1H),8.37–8.28(m,1H),8.11(br.s,1H),7.66(dd,J=8.0,0.6Hz,1H),7.55(ddd,J=8.0,4.8,0.8Hz,1H),7.35(td,J=7.7,1.4Hz,1H),7.20(td,J=7.6,1.2Hz,1H).13C NMR(101MHz,DMSO-d6):δ172.18,161.92,160.34,151.88,151.43,148.75,135.10,131.24,130.86,125.61,123.24,122.82,121.11,19.75.HRMS-ESI(m/z):[M+H]+对于C14H12N6S+,计算值297.09169;实测值:297.09174.HPLC(λ280):纯度100.0%;tR:5.592min(方法1)。
N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基)异烟碱甲酰胺(MTF-253)。按照一般程序A,使用1-(苯并[d]噻唑-2-基)胍(1.00g,5.20)、氢化钠(60%的在矿物油中的分散体,1.5当量,312mg,7.81mmol)和4-吡啶甲腈(541mg,5.20mmol)合成,得到白色-淡黄色粉末状标题化合物(1.12g,73%)。1H NMR(200MHz,DMSO-d6):δ10.15(br.s,1H),9.35(br.s,1H),8.96(br.s,1H),8.76(dd,J=4.6,1.5Hz,2H),8.15(br.s,1H),7.91(dd,J=4.6,1.5Hz,2H),7.81(dd,J=7.7,0.7Hz,1H),7.67(d,J=8.0Hz,1H),7.42–7.30(m,1H),7.27–7.14(m,1H).13C NMR(101MHz,DMSO-d6):δ172.12,161.90,160.07,151.38,150.07,142.53,131.28,125.64,122.88,121.43,121.13,119.81.HRMS-ESI(m/z):[M+H]+对于C14H12N6S+,计算值297.09169;实测值:297.09177.HPLC(λ280):纯度95.9%;tR:5.308min(方法1)。
N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基)-4-甲氧基苯甲酰胺(MTF-254)。按照一般程序A,使用1-(苯并[d]噻唑-2-基)胍(1.00g,5.20mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,312mg,7.81mmol)和4-甲氧基苄腈(692mg,5.20mmol)合成,得到米色粉末状标题化合物(135mg,8%)。1H NMR(500MHz,DMSO-d6):δ10.27(br.s,1H),9.30(br.s,1H),8.69(br.s,1H),8.03(d,J=5.9Hz,2H),7.92(br.s,1H),7.78(d,J=5.4Hz,1H),7.64(d,J=5.8Hz,1H),7.33(s,1H),7.18(s,1H),7.05(d,J=5.6Hz,2H),3.83(s,3H).13C NMR(50MHz,DMSO-d6):δ172.33,162.14,161.96,161.71,151.58,131.16,129.40,127.19,125.62,122.72,121.10,119.64,113.56,55.41.HRMS-ESI(m/z):[M+H]+对于C16H15N5OS+,计算值326.10701;实测值:326.10718.HPLC(λ280):纯度95.3%;tR:6.592min(方法1)。
3-乙酰基-N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基)苯甲酰胺(MTF-255)。按照一般程序A,使用1-(苯并[d]噻唑-2-基)胍(1.00g,5.20mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,312mg,7.81mmol)和3-乙酰基苄腈(755mg,5.20mmol)合成,得到红色粉末状标题化合物(228mg,13%)。1H NMR(200MHz,DMSO-d6):δ10.25(br.s,1H),9.33(br.s,1H),8.98(br.s,1H),8.58(t,J=1.6Hz,1H),8.30–8.22(m,1H),8.20–7.97(m,2H),7.81(dd,J=7.8,0.8Hz,1H),7.68(t,J=7.7Hz,2H),7.35(td,J=7.7,1.4Hz,1H),7.20(td,J=7.6,1.2Hz,1H),2.66(s,3H).13C NMR(50MHz,DMSO-d6):δ197.59,172.28,162.07,161.35,151.50,136.86,135.70,132.04,131.24,131.07,128.79,127.31,125.67,122.85,121.16,119.77,26.89.HRMS-ESI(m/z):[M+H]+对于C17H15N5OS+,计算值338.10701;实测值:338.10701.HPLC(λ280):纯度95.2%;tR:6.283min(方法1)。
3-溴-N-(N-(4-苯基噻唑-2-基)氨基甲酰氨基)苯甲酰胺(MTF-256)。按照一般程序A,使用1-(4-苯基噻唑-2-基)胍(1.00g,4.58mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,275mg,6.87mmol)和3-溴苄腈(833mg,4.58mmol)合成,得到黄色粉末状标题化合物(715mg,39%)。1H NMR(500MHz,DMSO-d6):δ10.36(br.s,1H),9.15(br.s,1H),8.79(br.s,1H),8.25(s,1H),8.02(d,J=7.8Hz,1H),7.88(d,br.s,J=7.3Hz,3H),7.76(dd,J=7.9,1.0Hz,1H),7.47(dd,J=9.1,6.6Hz,2H),7.43(t,J=7.7Hz,2H),7.31(t,J=7.3Hz,1H).13C NMR(50MHz,DMSO-d6):δ173.11,160.69,160.04,149.88,137.62,134.52,133.94,130.38,128.71,127.61,126.46,125.61,121.73,106.53.HRMS-ESI(m/z):[M+H]+对于C17H14BrN5S+,计算值400.02261;实测值:400.02213.HPLC(λ280):纯度98.7%;tR:7.033min(方法1)。
3-溴-N-(N-(4-(3-硝基苯基)噻唑-2-基)氨基甲酰氨基)苯甲酰胺(MTF-257)。按照一般程序A,使用1-(4-(3-硝基苯基)噻唑-2-基)胍(1.00g,3.80mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,228mg,5.70mmol)和3-溴苄腈(692mg,3.80mmol)合成,得到黄色粉末状标题化合物(711mg,42%)。1H NMR(500MHz,DMSO-d6):δ10.21(s,1H),8.78(s,2H),8.62(s,1H),8.34(d,J=7.5Hz,1H),8.23(s,1H),8.19(br.s,1H),8.15(d,J=7.8Hz,1H),8.01(d,J=7.5Hz,1H),7.80(s,1H),7.76(d,J=7.7Hz,1H),7.72(t,J=7.9Hz,1H),7.48(t,J=7.8Hz,1H).13C NMR(50MHz,DMSO-d6):δ173.32,160.75,159.98,148.31,147.48,137.51,136.01,133.95,131.81,130.37,130.20,126.47,121.99,121.66,119.77,109.28.HRMS-ESI(m/z):[M+H]+对于C17H13BrN6O2S+,计算值445.00768;实测值:445.00806.HPLC(λ280):纯度99.1%;tR:7.100min(方法1)。
N-(N-(4-(3-硝基苯基)噻唑-2-基)氨基甲酰氨基)吡啶甲酰胺(MTF-259)。按照一般程序A,使用1-(4-(3-硝基苯基)噻唑-2-基)胍(1.00g,3.80mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,228mg,5.70mmol)和2-吡啶甲腈(366mL,3.80mmol)合成,得到黄色粉末状标题化合物(796mg,57%)。1H NMR(500MHz,DMSO-d6):δ10.03(br.s,1H),9.08(br.s,1H),8.78(br.s,1H),8.71(d,J=4.2Hz,1H),8.66–8.61(m,1H),8.38(d,J=7.9Hz,1H),8.35(d,J=7.9Hz,1H),8.16(dd,J=8.1,1.5Hz,1H),8.02(td,J=7.8,1.6Hz,1H),7.91(br.s,1H),7.82(s,1H),7.73(t,J=8.0Hz,1H),7.63(ddd,J=7.4,4.8,1.0Hz,1H).13CNMR(50MHz,DMSO-d6):δ173.49,161.02,158.37,150.67,148.58,148.29,147.51,137.39,135.99,131.78,130.16,126.39,122.10,121.99,119.78,109.31.HRMS-ESI(m/z):[M+H]+对于C16H13N7O2S+,计算值368.09242;实测值:368.09274.HPLC(λ280):纯度99.2%;tR:6.850min(方法1)。
N-(N-(4-(3-硝基苯基)噻唑-2-基)氨基甲酰氨基)烟碱甲酰胺(MTF-260)。按照一般程序A,使用1-(4-(3-硝基苯基)噻唑-2-基)胍(1.00g,3.80mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,228mg,5.70mmol)和3-吡啶甲腈(395mg,3.80mmol)合成,得到黄色粉末状标题化合物(656mg,47%)。1H NMR(500MHz,DMSO-d6):δ10.14(br s,1H),8.84(br.s,2H),8.75(d,J=5.8Hz,2H),8.63(s,1H),8.34(d,J=7.8Hz,1H),8.15(dd,J=8.0,1.4Hz,1H),7.91(d,J=5.8Hz,2H),7.86(br.s,1H),7.82(s,1H),7.72(t,J=8.0Hz,1H).13CNMR(50MHz,DMSO-d6):δ173.23,160.74,159.55,150.07,148.33,147.49,142.64,136.00,131.80,130.20,122.01,121.49,119.79,109.48.HRMS-ESI(m/z):[M+H]+对于C16H13N7O2S+,计算值368.09242;实测值:368.09283.HPLC(λ280):纯度95.1%;tR:6.350min(方法1)。
N-(N-(4-(3-硝基苯基)噻唑-2-基)氨基甲酰氨基)异烟碱甲酰胺(MTF-261)。按照一般程序A,使用1-(4-(3-硝基苯基)噻唑-2-基)胍(1.00g,3.80mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,228mg,5.70mmol)和4-吡啶甲腈(395mg,3.80mmol)合成,得到黄色粉末状标题化合物(544mg,39%)。1H NMR(500MHz,DMSO-d6):δ10.14(br.s,1H),9.17(d,J=1.6Hz,1H),8.81(br.s,2H),8.73(dd,J=4.7,1.4Hz,1H),8.63(s,1H),8.33(t,J=8.4Hz,2H),8.15(dd,J=8.1,1.5Hz,1H),7.81(s,1H),7.76(br.s,1H),7.72(t,J=8.0Hz,1H),7.54(dd,J=7.8,4.8Hz,1H).13CNMR(50MHz,DMSO-d6):δ173.30,160.78,159.84,151.81,148.78,148.32,147.48,136.02,135.13,131.79,130.97,130.19,123.25,121.99,119.79,109.31.HRMS-ESI(m/z):[M+H]+对于C16H13N7O2S+,计算值368.09242;实测值:368.09283.HPLC(λ280):纯度96.8%;tR:6.367min(方法1)。
4-甲氧基-N-(N-(4-苯基噻唑-2-基)氨基甲酰氨基)苯甲酰胺(MTF-262)。按照一般程序A,使用1-(4-苯基噻唑-2-基)胍(1.00g,4.58mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,275mg,6.87mmol)和4-甲氧基苄腈(610mg,4.58mmol)合成,得到米色粉末状标题化合物(32mg,2%)。1H NMR(400MHz,DMSO-d6):δ10.30(br.s,1H),9.05(br.s,1H),8.55(s,1H),8.01(d,J=8.9Hz,2H),7.87(d,J=7.3Hz,2H),7.68(br.s,1H),7.46(s,1H),7.43(t,J=7.7Hz,1H),7.31(t,J=7.3Hz,1H),7.04(d,J=8.9Hz,2H),3.83(s,3H).13C NMR(101MHz,DMSO-d6):δ173.16,161.77,161.07,160.84,149.72,134.54,129.21,128.64,127.50,127.36,125.51,113.46,106.11,55.37,38.89.HRMS-ESI(m/z):[M+H]+对于C18H17N5OS+,计算值352.12266;实测值:352.12268.HPLC(λ280):纯度95.1%;tR:6.842min(方法1)。
N-(N-(4-苯基噻唑-2-基)氨基甲酰氨基)吡啶甲酰胺(MTF-263)。按照一般程序A,使用1-(4-苯基噻唑-2-基)胍(1.00g,4.58mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,275mg,6.87mmol)和2-吡啶甲腈(441mL,4.58mmol)合成,得到黄色粉末状标题化合物(369mg,25%)。1HNMR(500MHz,DMSO-d6):δ10.16(br.s,1H),9.19(br.s,1H),8.79(br.s,1H),8.70(d,J=3.6Hz,1H),8.38(d,J=7.7Hz,1H),8.01(t,J=7.4Hz,1H),8.19–7.70(m,4H),7.88(d,br.s,J=7.4Hz,4H),7.66–7.57(m,1H),7.50(s,1H),7.43(t,J=7.3Hz,2H),7.32(t,J=7.0Hz,1H).13C NMR(50MHz,DMSO-d6):δ173.20,160.91,158.35,150.73,149.86,148.61,137.40,134.50,128.70,127.61,126.38,125.59,122.04,106.61.HRMS-ESI(m/z):[M+H]+对于C16H14N6S+,计算值323.10734;实测值:323.10770.HPLC(λ280):纯度98.0%;tR:6.692min(方法1)。
3-溴-N-(N-(N-(6-甲氧基苯并[d]噻唑-2-基)氨基甲酰氨基)苯甲酰胺(MTF-264)。按照一般程序A,使用1-(6-甲氧基苯并[d]噻唑-2-基)胍(1.00g,4.50mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,270mg,6.75mmol)和3-溴苄腈(819mg,4.50mmol)合成,得到深灰色粉末状标题化合物(146mg,8%)。1H NMR(500MHz,DMSO-d6):δ10.29(br.s,1H),9.24(br.s,1H),8.84(br.s,1H),8.23(s,1H),8.01(d,br.s,J=7.5Hz,2H),7.77(d,J=7.2Hz,1H),7.56(d,J=8.6Hz,1H),7.48(t,J=7.8Hz,1H),7.42(s,1H),6.95(d,J=8.5Hz,1H),3.79(s,3H).13C NMR(50MHz,DMSO-d6):δ170.29,161.45,160.30,155.69,145.55,137.47,134.03,132.39,130.45,130.36,126.46,121.68,120.37,113.92,104.89,55.55.HRMS-ESI(m/z):[M+H]+对于C16H14BrN5OS+,计算值404.01752;实测值:404.01733.HPLC(λ280):纯度95.2%;tR:6.825min(方法1)。
3-溴-N-(N-(6-甲基苯并[d]噻唑-2-基)氨基甲酰氨基)苯甲酰胺(MTF-265)。按照一般程序A,使用1-(6-甲基苯并[d]噻唑-2-基)胍(1.00g,4.85mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,291mg,7.28mmol)和3-溴苄腈(883mg,4.85mmol)合成,得到米色粉末状标题化合物(207mg,11%)。1H NMR(500MHz,DMSO-d6):δ10.30(br.s,1H),9.32(br.s,1H),8.87(br.s,1H),8.24(s,1H),8.01(d,br.s,J=7.6Hz,2H),7.77(d,J=7.7Hz,1H),7.60(s,1H),7.54(d,J=8.1Hz,1H),7.48(t,J=7.8Hz,1H),7.16(d,J=8.0Hz,1H),2.37(s,3H).13C NMR(50MHz,DMSO-d6):δ171.42,161.76,160.43,149.40,137.44,134.05,132.22,131.30,130.41,126.86,126.47,121.69,120.95,119.45,20.93.HRMS-ESI(m/z):[M+H]+对于C16H14BrN5S+,计算值388.02261;实测值:388.02313.HPLC(λ280):纯度98.3%;tR:6.992min(方法1)。
3-氯-N-(N-(4-苯基噻唑-2-基)氨基甲酰氨基)苯并咪酰胺(MTF-267)。按照一般程序A,使用1-(4-苯基噻唑-2-基)胍(1.00g,4.58mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,275mg,6.87mmol)和3-氯苄腈(630mg,4.58mmol)得到白色-淡黄色粉末状标题化合物(749mg,46%)。1H NMR(500MHz,DMSO-d6):δ10.36(br.s,1H),9.15(br.s,1H),8.78(br.s,1H),8.10(t,J=1.7Hz,1H),7.98(d,J=7.9Hz,1H),7.88(d,br.s,J=7.2Hz,3H),7.63(dd,J=8.0,1.2Hz,1H),7.54(t,J=7.9Hz,1H),7.48(s,1H),7.43(t,J=7.7Hz,2H),7.31(t,J=7.3Hz,1H).13C NMR(50MHz,DMSO-d6):δ173.05,160.66,160.04,149.85,137.43,134.51,133.20,131.03,130.14,128.69,127.59,127.46,126.08,125.58,106.53.HRMS-ESI(m/z):[M+H]+对于C17H14ClN5S+,计算值356.07312;实测值:356.07321.HPLC(λ280):纯度98.0%;tR:7.008min(方法1)。
4-氯-N-(N-(5-苯基噻唑-2-基)氨基甲酰氨基)苯甲酰胺(MTF-268)。按照一般程序A,使用1-(4-苯基噻唑-2-基)胍(1.00g,4.58mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,275mg,6.87mmol)和4-氯苄腈(630mg,4.58mmol)合成,得到黄色粉末状标题化合物(717mg,44%)。1H NMR(500MHz,DMSO-d6):δ10.35(br.s,1H),9.14(br.s,1H),8.73(br.s,1H),8.05(d,J=8.6Hz,2H),7.87(d,J=7.2Hz,2H),7.73(br.s,1H),7.58(d,J=8.6Hz,2H),7.47(s,1H),7.43(t,J=7.7Hz,2H),7.31(t,J=7.3Hz,1H).13C NMR(50MHz,DMSO-d6):δ173.07,160.72,160.43,149.82,136.13,134.52,134.17,129.37,128.69,128.31,127.58,125.57,106.47.HRMS-ESI(m/z):[M+H]+对于C17H14ClN5S+,计算值356.07312;实测值:356.07318.HPLC(λ280):纯度99.1%;tR:6.925min(方法1)。
N-(N-(4-苯基噻唑-2-基)氨基甲酰氨基)苯甲酰胺(MTF-272)。按照一般程序A,使用1-(4-苯基噻唑-2-基)胍(1.00g,4.58mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,275mg,6.87mmol)和苄腈(0.471mL,4.58mmol)合成,得到米色粉末状标题化合物(486mg,33%)。1H NMR(500MHz,DMSO-d6):δ10.33(br.s,1H),9.13(br.s,1H),8.67(br.s,1H),8.02(d,J=7.2Hz,2H),7.88(d,J=7.3Hz,2H),7.72(br.s,1H)7.56(t,J=7.2Hz,1H),7.49(dd,J=14.9,7.7Hz,3H),7.43(t,J=7.7Hz,2H),7.31(t,J=7.3Hz,1H).13C NMR(50MHz,DMSO-d6):δ173.16,161.66,160.90,149.80,135.41,134.54,131.26,128.71(2C),128.22(2C),127.57,127.50(2C),125.57(2C),106.37.HPLC(λ280):纯度82.0%;tR:6.850min(方法1)。
N-(N-(4-苯基噻唑-2-基)氨基甲酰氨基)烟碱甲酰胺(MTF-273)。按照一般程序A,使用1-(4-苯基噻唑-2-基)胍(1.00g,4.58mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,275mg,6.87mmol)和3-氰基吡啶(477mg,4.58mmol)合成,得到淡黄色粉末状标题化合物(694mg,47%)。1H NMR(500MHz,DMSO-d6):δ10.30(br.s,1H),9.17(d,br.s,J=1.6Hz,2H),8.82(br.s,1H),8.73(dd,J=4.7,1.4Hz,1H),8.33(d,J=8.0Hz,1H),7.88(d,br.s,J=7.3Hz,3H),7.54(dd,J=7.8,4.8Hz,1H),7.49(s,1H),7.43(t,J=7.6Hz,2H),7.32(t,J=7.3Hz,1H).13C NMR(50MHz,DMSO-d6):δ173.07,160.68,159.88,151.80,149.86,148.77,135.10,134.52,131.05,128.71,127.60,125.59,123.25,106.58.HRMS-ESI(m/z):[M+H]+对于C16H14N6S+,计算值323.10734;实测值:323.10764.HPLC(λ280):纯度96.9%;tR:6.075min(方法1)。
N-(N-(4-苯基噻唑-2-基)氨基甲酰氨基)异烟碱甲酰胺(MTF-274)。按照一般程序A,使用1-(4-苯基噻唑-2-基)胍(1.00g,4.58mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,275mg,6.87mmol)和4-吡啶甲腈(477mg,4.58mmol)合成,得到淡黄色粉末状标题化合物(871mg,59%)。1H NMR(500MHz,DMSO-d6):δ10.30(br.s,1H),9.20(br.s,1H),8.86(br.s,1H),8.75(dd,J=4.5,1.6Hz,2H),7.92(dd,J=4.5,1.6Hz,2H),7.88(d,br.s,J=7.2Hz,3H),7.50(s,1H),7.43(t,J=7.7Hz,2H),7.32(t,J=7.3Hz,1H).13C NMR(50MHz,DMSO-d6):δ173.00,160.64,159.63,150.09,149.90,142.74,134.50,128.72,127.63,125.61,121.49,106.75.HRMS-ESI(m/z):[M+H]+对于C16H14N6S+,计算值323.10734;实测值:323.10757.HPLC(λ280):纯度95.2%;tR:6.058min(方法1)。
2-氯-N-(N-(N-(4-(3-硝基苯基)噻唑-2-基)氨基甲酰氨基)苯甲酰胺(MTF-276)。按照一般程序A,使用1-(4-(3-硝基苯基)噻唑-2-基)胍(1.00g,3.80mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,228mg,5.70mmol)和2-氯苄腈(523mg,3.80mmol)合成,得到棕色粉末状标题化合物(30mg,2%)。1H NMR(400MHz,DMSO-d6):δ10.08(br.s,1H),8.83(br.s,1H),8.70(br.s,1H),8.62(s,1H),8.34(d,J=7.7Hz,1H),8.15(d,J=7.4Hz,1H),8.03-7.64(br.s,1H),7.81(s,1H),7.72(t,J=7.7Hz,1H),7.52(t,J=7.8Hz,2H),7.49–7.37(m,2H).13C NMR(101MHz,DMSO-d6):δ173.55,162.25,160.72,148.36,147.36,136.69,136.00,131.76,130.52,130.25(2C),129.51,129.39,126.87,121.95,119.70,109.25.HRMS-ESI(m/z):[M+H]+对于C17H13ClN6O2S+,计算值401.05820;实测值:401.05820.HPLC(λ280):纯度95.2%;tR:6.858min(方法1)。
3-氯-N-(N-(4-(3-硝基苯基)噻唑-2-基)氨基甲酰氨基)苯甲酰胺(MTF-277)。按照一般程序A,使用1-(4-(3-硝基苯基)噻唑-2-基)胍(1.00g,3.80mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,228mg,5.70mmol)和3-氯苄腈(523mg,3.80mmol)合成,得到棕色粉末状标题化合物(457mg,30%)。1H NMR(500MHz,DMSO-d6):δ10.22(br.s,1H),8.77(br.s,1H),8.62(s,1H),8.34(d,J=7.7Hz,1H),8.23-7.91(br.s,1H),8.15(d,J=8.0Hz,1H),8.09(s,1H),7.97(d,J=7.7Hz,1H),7.80(s,1H),7.72(t,J=8.0Hz,1H),7.63(d,J=7.9Hz,1H),7.54(t,J=7.9Hz,1H).13CNMR(50MHz,DMSO-d6):δ173.31,160.75,160.02,148.34,147.48,137.34,136.02,133.17,131.83,131.05,130.24,130.17,127.45,126.11,122.02,119.78,109.32.HRMS-ESI(m/z):[M+H]+对于C17H13ClN6O2S+,计算值401.05820;实测值:401.05835.HPLC(λ280):纯度95.5%;tR:7.025min(方法1)。
4-氯-N-(N-(4-(3-硝基苯基)噻唑-2-基)氨基甲酰氨基)苯甲酰胺(MTF-281)。按照一般程序A,使用1-(4-(3-硝基苯基)噻唑-2-基)胍(1.00g,3.80mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,228mg,5.70mmol)和4-氯苄腈(523mg,3.80mmol)合成,得到黄色粉末状标题化合物(640mg,42%)。1H NMR(200MHz,DMSO-d6):δ10.15(br.s,1H),8.74(br.s,2H),8.68–8.60(m,1H),8.55-7.90(br.s,1H),8.39–8.30(m,1H),8.16(ddd,J=8.2,2.3,0.8Hz,1H),8.10–7.97(m,2H),7.82(s,1H),7.72(t,J=8.0Hz,1H),7.66–7.48(m,2H).13C NMR(50MHz,DMSO-d6):δ173.37,160.84,160.46,148.30,147.47,136.17,136.04,134.10,131.77,130.16,129.40(2C),128.29(2C),121.96,119.77,109.19.HRMS-ESI(m/z):[M+H]+对于C17H13ClN6O2S+,计算值401.05820;实测值:401.05820.HPLC(λ280):纯度96.7%;tR:7.033min(方法1)。
N-(N-(4-甲基噻唑-2-基)氨基甲酰氨基)苯甲酰胺(MTF-283)。按照一般程序A,使用1-(4-甲基噻唑-2-基)胍(1.00g,6.41mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,384mg,9.61mmol)和苄腈(0.66mL,6.41mmol)合成,得到棕色粉末状标题化合物(382mg,23%)。1H NMR(500MHz,DMSO-d6):δ10.42(br.s,1H),9.11(br.s,1H),8.61(br.s,1H),8.02–7.96(m,2H),7.57–7.52(m,1H),7.85–7.39(br.s,4H),7.51–7.46(m,2H),6.57(d,J=1.0Hz,1H),2.24(d,J=0.9Hz,3H).13C NMR(50MHz,DMSO-d6):δ172.99,161.63,160.69,147.64,135.50,131.20,128.21,127.45,105.64,17.56.HRMS-ESI(m/z):[M+H]+f对于C12H13N5S+,计算值260.09644;实测值:260.09653.HPLC(λ280):纯度95.7%;tR:5.167min(方法1)。
2-氯-N-(N-(N-(4-甲基噻唑-2-基)氨基甲酰氨基)苯甲酰胺(MTF-284)。按照一般程序A,使用1-(4-甲基噻唑-2-基)胍(1.00g,6.41mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,384mg,9.61mmol)和2-氯苄腈(881mg,6.41mmol)合成,得到白色粉末状标题化合物(132mg,7%)。1H NMR(400MHz,DMSO-d6):δ10.27(br.s,1H),9.06(br.s,1H),8.63(br.s,1H),7.63(br.s,1H),7.46(m,4H),6.57(s,1H),2.24(s,3H).13C NMR(101MHz,DMSO-d6):δ172.87,162.18,160.47,147.49,136.79,130.49,130.27,129.55,129.40,126.88,105.69,17.46.HRMS-ESI(m/z):[M+H]+对于C12H12ClN5S+,计算值294.05747;实测值:294.05747.HPLC(λ280):纯度95.0%;tR:5.500min(方法1)。
3-氯-N-(N-(4-甲基噻唑-2-基)氨基甲酰氨基)苯甲酰胺(MTF-285)。按照一般程序A,使用1-(4-甲基噻唑-2-基)胍(1.00g,6.41)、氢化钠(60%的在矿物油中的分散体,1.5当量,384mg,9.61mmol)和3-氯苄腈(881mg,6.41mmol)合成,得到白色-淡黄色状标题化合物(1.24g,66%)。1HNMR(500MHz,DMSO-d6):δ10.43(br.s,1H),9.13(br.s,1H),8.71(br.s,1H),8.11–8.05(m,1H),7.95(d,J=7.9Hz,1H),7.64–7.59(m,1H),7.58(br.s,1H),7.53(t,J=7.9Hz,1H),6.59(d,J=0.9Hz,1H),2.25(d,J=0.5Hz,3H).13C NMR(50MHz,DMSO-d6):δ172.82,160.44,159.91,147.64,137.47,133.18,130.97,130.15,127.39,126.00,105.82,17.53.HRMS-ESI(m/z):[M+H]+对于C12H12ClN5S+,计算值294.05747;实测值:294.05768.HPLC(λ280):纯度95.0%;tR:5.933min(方法1)。
4-氯-N-(N-(4-甲基噻唑-2-基)氨基甲酰氨基)苯甲酰胺(MTF-286)。按照一般程序A,使用1-(4-甲基噻唑-2-基)胍(1.00g,6.41mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,384mg,9.61mmol)和4-氯苄腈(881mg,6.41mmol)合成,得到白色-淡黄色状标题化合物(923mg,49%)。1H NMR(500MHz,DMSO-d6):δ10.42(br.s,1H),9.13(br.s,1H),8.67(br.s,1H),8.01(d,J=8.6Hz,2H),7.57(d,br.s J=8.6Hz,3H),6.57(d,J=1.0Hz,1H),2.24(d,J=0.7Hz,3H).13C NMR(50MHz,DMSO-d6):δ172.87,160.50,160.37,147.63,136.08,134.23,129.30,128.29,105.74,17.53.HRMS-ESI(m/z):[M+H]+对于C12H12ClN5S+,计算值294.05747;实测值:294.05762.HPLC(λ280):纯度95.3%;tR:5.958min(方法1)。
2-溴-N-(N-(4-甲基噻唑-2-基)氨基甲酰氨基)苯甲酰胺(MTF-287)。按照一般程序A,使用1-(4-甲基噻唑-2-基)胍(1.00g,6.41mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,384mg,9.61mmol)和2-溴苄腈(1.17g,6.41mmol)合成,得到白色-淡黄色状标题化合物(499mg,23%)。1H NMR(400MHz,DMSO-d6):δ10.27(br.s,1H),9.07(br.s,1H),8.63(br.s,1H),7.67(d,br.s,J=7.9Hz,2H),7.46–7.43(m,2H),7.36(ddd,J=8.1,6.0,3.2Hz,1H),6.57(s,1H),2.24(s,3H).13C NMR(101MHz,DMSO-d6):δ172.89,163.29,160.49,147.50,138.85,132.49,130.57,129.44,127.37,119.62,105.68,17.46.HRMS-ESI(m/z):[M+H]+对于C12H12BrN5S+,计算值338.00696;实测值:338.00705.HPLC(λ280):纯度95.8%;tR:5.192min(方法1)。
3-溴-N-(N-(N-(4-甲基噻唑-2-基)氨基甲酰氨基)苯甲酰胺(MTF-288)。按照一般程序A,使用1-(4-甲基噻唑-2-基)胍(1.00g,6.41mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,384mg,9.61mmol)和3-溴苄腈(1.17g,6.41mmol)合成,得到白色-淡黄色状标题化合物(1.11g,51%)。1H NMR(500MHz,DMSO-d6):δ10.42(s,1H),9.12(s,1H),8.72(s,1H),8.21(t,J=1.7Hz,1H),7.98(d,J=8.0Hz,1H),7.75(dd,br.s,J=8.0,1.1Hz,2H),7.46(t,J=7.9Hz,1H),6.59(d,J=0.9Hz,1H),2.24(d,J=0.8Hz,3H).13C NMR(50MHz,DMSO-d6):δ172.80,160.42,159.83,147.63,137.63,133.86,130.38,130.27,126.35,121.66,105.81,17.53.HRMS-ESI(m/z):[M+H]+对于C12H12BrN5S+,计算值338.00696;实测值:338.00760.HPLC(λ280):纯度95.1%;tR:6.042min(方法1)。
N-(N-(4-甲基噻唑-2-基)氨基甲酰氨基)吡啶甲酰胺(MTF-289)。按照一般程序A,使用1-(4-甲基噻唑-2-基)胍(1.00g,6.41mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,384mg,9.61mmol)和2-吡啶甲腈(0.617mL,6.41mmol)合成,得到黄色粉末状标题化合物(1.05g,63%)。1H NMR(200MHz,DMSO-d6):δ10.20(s,1H),9.15(s,1H),8.77(s,1H),8.73–8.65(m,1H),8.34(d,J=8.5Hz,1H),8.00(td,J=7.8,1.7Hz,1H),7.61(ddd,J=7.4,4.8,1.1Hz,2H),6.60(d,J=1.0Hz,1H),2.25(s,3H).13C NMR(101MHz,DMSO-d6):δ172.90,160.61,158.17,150.75,148.52,147.60,137.32,126.26,121.87,105.82,17.46.HRMS-ESI(m/z):[M+H]+对于C11H12N6S+,计算值261.09169;实测值:261.09174.HPLC(λ280):纯度95.7%;tR:5.708min(方法1)。
N-(N-(4-甲基噻唑-2-基)氨基甲酰氨基)烟碱甲酰胺(MTF-290)。按照一般程序A,使用1-(4-甲基噻唑-2-基)胍(1.00g,6.41mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,384mg,9.61mmol)和3-吡啶甲腈(0.667mg,6.41mmol)合成,得到黄色粉末状标题化合物(751mg,45%)。1H NMR(500MHz,DMSO-d6):δ10.39(br.s,1H),9.15(d,br.s,J=1.7Hz,2H),8.77(br.s,1H),8.71(dd,J=4.7,1.5Hz,1H),8.36–8.23(m,1H),7.65(br.s,1H),7.52(dd,J=7.5,4.8Hz,1H),6.59(d,J=0.7Hz,1H),2.25(s,3H).13C NMR(50MHz,DMSO-d6):δ172.84,160.46,159.79,151.75,148.72,147.67,135.03,131.09,123.24,105.89,17.54.HRMS-ESI(m/z):[M+H]+对于C11H12N6S+,计算值261.09169;实测值:261.09171.HPLC(λ280):纯度97.1%;tR:5.508min(方法1)。
N-(N-(4-甲基噻唑-2-基)氨基甲酰氨基)异烟碱甲酰胺(MTF-291)。按照一般程序A,使用1-(4-甲基噻唑-2-基)胍(1.00g,6.41mmol)、氢化钠(60%的在矿物油中的分散体,384mg,9.61mmol)和4-吡啶甲腈(0.667mg,6.41mmol)合成,得到黄色粉末状标题化合物(985mg,59%)。1H NMR(500MHz,DMSO-d6):δ10.37(br.s,1H),9.15(br.s,1H),8.80(br.s,1H),8.74(dd,J=4.5,1.6Hz,2H),7.89(dd,J=4.5,1.6Hz,2H),7.68(br.s,1H),6.60(d,J=0.9Hz,1H),2.25(d,J=0.8Hz,3H).13C NMR(50MHz,DMSO-d6):δ172.77,160.43,159.58,150.08,147.74,142.81,121.45,106.08,17.54.HRMS-ESI(m/z):[M+H]+对于C11H12N6S+,计算值261.09169;实测值:261.09174.HPLC(λ280):纯度99.5%;tR:4.525min(方法1)。
4-甲氧基-N-(N-(4-甲基噻唑-2-基)氨基甲酰氨基)苯甲酰胺(MTF-292)。按照一般程序A,使用1-(4-甲基噻唑-2-基)胍(1.00g,6.41mmol)、氢化钠(60%在矿物油中的分散体,1.5当量,384mg,9.61mmol)和4-甲氧基苄腈(0.853mg,6.41mmol)合成,得到米色粉末状标题化合物(167mg,9%)。1H NMR(500MHz,DMSO-d6):δ10.40(br.s,1H),9.06(br.s,1H),8.50(br.s,1H),7.98(d,J=8.9Hz,2H),7.49(br.s,1H),7.02(d,J=8.9Hz,2H),6.55(d,J=0.8Hz,1H),3.83(s,3H),2.24(s,3H).13CNMR(101MHz,DMSO-d6):δ172.97,161.71,160.99,160.62,147.51,129.13,127.43,113.43,105.33,55.34,17.48.HRMS-ESI(m/z):[M+H]+对于C13H15N5OS+,计算值290.10701;实测值:290.10709.HPLC(λ280):纯度100.0%;tR:5.308min(方法1)。
2-溴-N-(N-(4,5-二甲基噻唑-2-基)氨基甲酰氨基)苯甲酰胺(MTF-295)。按照一般程序A,使用1-(4,5-二甲基噻唑-2-基)胍(1.00g,5.88mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,353mg,8.82mmol)和2-溴苄腈(1.07g,5.88mmol)合成,得到棕色粉末状标题化合物(746mg,36%)。1H NMR(500MHz,DMSO-d6):δ10.28(br.s,1H),9.01(br.s,1H),8.58(br.s,1H),7.70-7.30(br.s,1H),7.67(d,J=7.9Hz,1H),7.44(dd,J=8.1,5.2Hz,2H),7.40–7.33(m,1H),2.21(s,3H),2.14(s,3H).13C NMR(101MHz,DMSO-d6):δ169.26,163.14,160.22,142.62,138.85,132.48,130.54,129.44,127.36,119.64,116.98,14.58,10.71.HRMS-ESI(m/z):[M+H]+对于C13H14BrN5S+,计算值352.02261;实测值:352.02289.HPLC(λ280):纯度97.8%;tR:5.717min(方法1)。
2-溴-N-(N-(4,5-二甲基噻唑-2-基)氨基甲酰氨基)苯甲酰胺(MTF-296)。按照一般程序A,使用1-(4,5-二甲基噻唑-2-基)胍(1.00g,5.88mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,353mg,8.82mmol)和3-溴苄腈(1.07g,5.88mmol)合成,得到棕色粉末状标题化合物(746mg,36%)。1H NMR(200MHz,DMSO-d6):δ10.45(br.s,1H),9.01(br.s,1H),8.70(br.s,1H),8.20(t,J=1.7Hz,1H),8.06-7.28(br.s,1H),7.97(d,J=8.0Hz,1H),7.74(ddd,J=7.9,1.9,0.8Hz,1H),7.46(t,J=7.9Hz,1H),2.21(s,3H),2.15(s,3H).13C NMR(50MHz,DMSO-d6):δ169.14,160.12,159.63,142.74,137.65,133.81,130.41,130.18,126.29,121.61,117.13,14.63,10.76.HRMS-ESI(m/z):[M+H]+对于C13H15BrN5S+,计算值352.02261;实测值:352.02377.HPLC(λ280):纯度97.3%;tR:5.767min(方法1)。
N-(N-(4,5-二甲基噻唑-2-基)氨基甲酰氨基)吡啶甲酰胺(MTF-297)。按照一般程序A,使用1-(4,5-二甲基噻唑-2-基)胍(1.00g,5.88mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,353mg,8.82mmol)和2-吡啶甲腈(0.566mL,5.88mmol)合成,得到黄色粉末状标题化合物(726mg,45%)。1H NMR(500MHz,DMSO-d6):δ10.19(br.s,1H),9.09(br.s,1H),8.68(d,br.s.J=4.1Hz,2H),8.33(d,J=7.9Hz,1H),7.99(td,J=7.7,1.3Hz,1H),7.60(dd,br.s,J=6.5,5.0Hz,2H),2.21(s,3H),2.15(s,3H).13C NMR(101MHz,DMSO-d6):δ169.29,160.32,158.01,150.80,148.50,142.71,137.28,126.19,121.80,117.16,14.56,10.69.HRMS-ESI(m/z):[M+H]+对于C12H14N6S+,计算值275.10734;实测值:275.10742.HPLC(λ280):纯度100.0%;tR:5.475min(方法1)。
N-(N-(4,5-二甲基噻唑-2-基)氨基甲酰氨基)烟碱甲酰胺(MTF-298)。按照一般程序A,使用1-(4,5-二甲基噻唑-2-基)胍(1.00g,5.88mmol)、氢化钠(60%的在矿物油中的分散体,353mg,8.82mmol)和3-吡啶甲腈(612mg,5.88mmol)合成,得到黄色粉末状标题化合物(742mg,46%)。1H NMR(500MHz,DMSO-d6):δ10.43(br.s,1H),9.04(br.s,1H),8.67(br.s,1H),8.20(t,J=1.6Hz,1H),7.97(d,J=8.0Hz,1H),7.80–7.70(m,1H),7.88–7.29(br.s,1H),7.46(t,J=7.9Hz,1H),2.21(s,3H),2.15(s,3H).13C NMR(101MHz,DMSO-d6):δ169.13,160.11,159.55,151.63,148.60,142.72,134.89,131.06,123.17,117.16,14.57,10.69.HRMS-ESI(m/z):[M+H]+对于C12H14N6S+,计算值275.10734;实测值:275.10736.HPLC(λ280):纯度97.0%;tR:5.458min(方法1)。
N-(N-(4,5-二甲基噻唑-2-基)氨基甲酰氨基)异烟碱甲酰胺(MTF-299)。按照一般程序A,使用1-(4,5-二甲基噻唑-2-基)胍(1.00g,5.88mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,353mg,8.82mmol)和4-吡啶甲腈(612mg,5.88mmol)合成,得到黄色粉末状标题化合物(548mg,34%)。1H NMR(500MHz,DMSO-d6):δ10.40(br.s,1H),9.09(br.s,1H),8.73(d,br.s.,J=5.7Hz,3H),7.88(d,J=5.5Hz,2H),7.61(br.s,1H),2.21(s,3H),2.15(s,3H).13C NMR(101MHz,DMSO-d6):δ169.05,160.06,159.33,149.98,142.78,121.31,117.38,14.55,10.68.HRMS-ESI(m/z):[M+H]+对于C12H14N6S+,计算值275.10734;实测值:275.10739.HPLC(λ280):纯度99.5%;tR:5.108min(方法1)。
2-氯-N-(N-(4,5-二甲基噻唑-2-基)氨基甲酰氨基)苯甲酰胺(MTF-300)。按照一般程序A,使用1-(4,5-二甲基噻唑-2-基)胍(1.00g,5.88mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,353mg,8.82mmol)和2-氯苄腈(809mg,5.88mmol)合成,得到黄色粉末状标题化合物(109mg,6%)。1H NMR(500MHz,DMSO-d6):δ10.30(br.s,1H),9.01(br.s,1H),8.59(br.s,1H),7.46(m,5H),2.21(s,3H),2.14(s,3H).13C NMR(101MHz,DMSO-d6):δ169.26,162.01,160.22,142.63,136.82,130.47,130.28,129.56,129.39,126.88,117.00,14.58,10.71.HRMS-ESI(m/z):[M+H]+对于C13H14ClN5S+,计算值308.07312;实测值:308.07318.HPLC(λ280):纯度95.4%;tR:5.425min(方法1)。
3-氯-N-(N-(4,5-二甲基噻唑-2-基)氨基甲酰氨基)苯甲酰胺(MTF-301)。按照一般程序A,使用1-(4,5-二甲基噻唑-2-基)胍(1.00g,5.88mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,353mg,8.82mmol)和3-氯苄腈(809mg,5.88mmol)合成,得到黄色粉末状标题化合物(416mg,23%)。1H NMR(500MHz,DMSO-d6):δ10.44(br.s,1H),9.04(br.s,1H),8.68(br.s,1H),8.08–8.03(m,1H),7.93(d,J=7.9Hz,1H),7.61(ddd,J=8.0,2.1,0.9Hz,1H),7.78–7.39(br.s,1H),7.52(t,J=7.9Hz,1H),2.21(s,3H),2.15(s,3H).13C NMR(50MHz,DMSO-d6):δ169.15,160.14,159.71,142.73,137.49,133.13,130.91,130.15,127.31,125.93,117.14,14.62,10.75.HRMS-ESI(m/z):[M+H]+对于C13H14ClN5S+,计算值308.07312;实测值:308.07321.HPLC(λ280):纯度95.2%;tR:6.075min(方法1)。
4-氯-N-(N-(4,5-二甲基噻唑-2-基)氨基甲酰氨基)苯甲酰胺(MTF-302)。按照一般程序A,使用1-(4,5-二甲基噻唑-2-基)胍(1.00g,5.88mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,353mg,8.82mmol)、4-氯苄腈(809mg,5.88mmol)合成,得到黄色粉末状标题化合物(90mg,5%)。1H NMR(500MHz,DMSO-d6):δ10.44(br.s,1H),9.04(br.s,1H),8.64(br.s,1H),8.01(d,J=8.6Hz,2H),7.57(d,br.s,J=8.6Hz,3H),2.22(s,3H),2.15(s,3H).13C NMR(101MHz,DMSO-d6):δ169.15,160.16,160.11,142.66,135.93,134.23,129.19(2C),128.22(2C),117.02,14.57,10.70.HRMS-ESI(m/z):[M+H]+对于C13H14ClN5S+,计算值308.07312;实测值:308.07315.HPLC(λ280):纯度98.0%;tR:6.267min(方法1)。
N-(N-(4,5-二甲基噻唑-2-基)氨基甲酰氨基)苯甲酰胺(MTF-303)。按照一般程序A,使用1-(4,5-二甲基噻唑-2-基)胍(1.00g,5.88mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,353mg,8.82mmol)和苄腈(0.605mL,5.88mmol)合成,得到黄色粉末状标题化合物(113mg,7%)。1H NMR(200MHz,DMSO-d6):δ10.45(s,1H),8.94(s,1H),8.61(s,1H),7.98(dd,J=7.9,1.7Hz,2H),7.84–7.31(m,4H),2.21(d,J=0.6Hz,3H),2.15(s,3H).13C NMR(101MHz,DMSO-d6):δ169.26,161.31,160.33,142.65,135.47,131.06,128.12,127.30,116.88,14.58,10.70.HRMS-ESI(m/z):[M+H]+对于C13H15N5S+,计算值274.11209;实测值:274.11212.HPLC(λ280):纯度97.5%;tR:5.408min(方法1)。
N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基)-2,2,2-三氯乙酰胺(MTF-305)。将1-(苯并[d]噻唑-2-基)胍(500mg,2.6mmol)和三氯乙腈(260μL,2.6mmol)的工业级乙醇(5mL)溶液在室温下、氩气气氛下搅拌22小时。将形成的沉淀物过滤,用少量冷乙醇洗涤,然后用很少量二乙醚洗涤,在空气中迅速干燥(该化合物在空气中随时间氧化)并在氩气中储存。黄色固体(100mg,11%)。TLC:Rf(CHCl3/MeOH,95/5,v/v)=0.90.1HNMR(400MHz,丙酮-d6):δ10.71(s,1H),9.84(s,1H),8.39(s,1H),7.80(dd,J=7.9,1.3Hz,1H),7.72(d,J=8.0Hz,1H),7.66(s,1H),7.38(td,J=8.2,7.8,1.3Hz,1H),7.25(td,J=7.6,1.2Hz,1H).13C NMR(101MHz,丙酮-d6):δ206.12,126.63,124.28,121.93,121.33.HRMS-ESI(m/z):[M+H]+对于C10H9Cl3N5S+,计算值335.96388;实测值:335.96420.HPLC(λ254):纯度99.7%;tR:7.983min(方法1)。
N2-(2-(甲硫基)苯基)-6-(三氯甲基)-1,3,5-三嗪-2,4-二胺(MTF-316)。向N2,N2'-(二硫代二基双(2,1-亚苯基))双(6-(三氯甲基)-1,3,5-三嗪-2,4-二胺)CRO15(150mg,0.225mmol)在甲醇中的悬浮液中添加10mL巯基乙醇(350μL,4.5mmol),并将混合物在室温搅拌。搅拌10分钟后,达到总溶解度。TLC和LCMS显示完全转化为还原的硫酚。在室温搅拌20h后,添加K2CO3(62.1mg,0.45mmol),并将混合物超声处理直至完全溶解。然后,添加MeI(28μL,0.45mmol),并将溶液在室温搅拌5h(反应时间未优化)。TLC和LCMS显示完全转化为两种新化合物(比率2/1)。将混合物用EtOAc萃取两次,并将合并的有机层用Na2SO4干燥并且在减压下蒸发。通过硅胶快速色谱法(环己烷/EtOAc,10/0-7/3,v/v)纯化,得到白色晶体状所需的化合物(2步内,27.0mg,34%)。1H NMR(200MHz,丙酮-d6):δ8.04(s,1H),7.73(d,J=7.9Hz,1H),7.11(dd,J=7.7,1.7Hz,1H),7.01–6.57(m,4H),2.05(s,3H).13C NMR(50MHz,丙酮-d6):δ174.04,168.91,166.25,138.04,131.38,130.32,128.05,125.84,124.21,97.43.HRMS-ESI(m/z):[M+H]+对于C11H11Cl3N5S+,计算值349.97953;实测值:349.97983.HPLC(λ254):纯度97.6%;tR:10.483min(方法2)。
6-(二氯甲基)-N2-(2-(甲硫基)苯基)-1,3,5-三嗪-2,4-二胺(MTF-317)。向N2,N2'-(二硫代二基双(2,1-亚苯基))双(6-(三氯甲基)-1,3,5-三嗪-2,4-二胺)CRO15(150mg,0.225mmol)在甲醇(10mL)中的悬浮液中添加巯基乙醇(350μL,4.5mmol),并将混合物在室温搅拌。搅拌10分钟后,达到总溶解度。TLC和LCMS显示完全转化为还原的硫酚。在室温搅拌20h后,添加K2CO3(62.1mg,0.45mmol),并将混合物超声处理直至完全溶解。然后,添加MeI(28μL,0.45mmol),并将溶液在室温搅拌5h(反应时间未优化)。TLC和LCMS显示完全转化为两种新化合物(比率2/1)。将混合物用EtOAc萃取两次,并将合并的有机层用Na2SO4干燥并且在减压下蒸发。通过硅胶快速色谱法(环己烷/EtOAc,10/0-7/3,v/v)纯化,得到白色晶体状标题化合物(2步内,12.7mg,18%)。1H NMR(200MHz,丙酮-d6):δ8.27(s,1H),8.19–8.07(m,1H),7.49(dd,J=7.6,1.7Hz,1H),7.32–7.23(m,1H),7.16(td,J=7.5,1.5Hz,1H),6.90(s,2H),6.54(s,1H),2.43(s,3H).13C NMR(50MHz,丙酮-d6):δ173.85,168.61,166.05,138.23,131.54,130.28,128.11,125.67,124.06,71.59,17.73.HRMS-ESI(m/z):[M+H]+对于C11H12Cl2N5S+,计算值316.01850;实测值:316.01892.HPLC(λ254):纯度97.3%;tR:10.658min(方法2)。
N2,N2'-(二硫代二基双(2,1-亚苯基))双(6-(3-甲氧基苯基)-1,3,5-三嗪-2,4-二胺(MTF-318)。根据一般程序B,使用N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基)-3-甲氧基苯甲酰胺(325mg,1mmol)合成,得到白色粉末状标题化合物(272mg,84%)。1H NMR(200MHz,DMSO-d6):δ9.25(s,2H),7.82(dd,J=8.1,5.1Hz,4H),7.61(dd,J=7.7,1.4Hz,2H),7.44–7.33(m,4H),7.27(td,J=7.5,1.4Hz,2H),7.22–6.97(m,8H),3.78(s,6H).13C NMR(50MHz,DMSO-d6):δ169.95,167.28,165.48,159.19,138.15,136.69,133.74,129.31,128.36,127.63,126.62,126.32,120.25,117.26,112.78,55.10.HRMS-ESI(m/z):[M+H]+对于C15H12BrN5S+,计算值374.00696;实测值:374.00797.HPLC(λ280):纯度100.0%;tR:11.458min(方法2)。
N2,N2'-(二硫代二基双(2,1-亚苯基))双(6-(3-乙氧基苯基)-1,3,5-三嗪-2,4-二胺)(MTF-319)。按照一般程序B,使用N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基)-3-乙氧基苯甲酰胺(339mg,1mmol)合成,得到白色粉末状标题化合物(291mg,86%)。1H NMR(200MHz,DMSO-d6):δ9.24(s,2H),7.83(d,J=8.8Hz,4H),7.62(dd,J=7.6,1.1Hz,2H),7.37(t,J=7.8Hz,4H),7.32–7.23(m,2H),7.22–7.15(m,2H),7.14–6.98(m,6H),4.04(q,J=6.9Hz,4H),1.33(t,J=6.9Hz,6H).13C NMR(50MHz,DMSO-d6):δ169.98,167.28,165.48,158.46,138.12,136.73,133.68,129.30,128.39,127.64,126.61,126.29,120.13,117.81,113.27,63.06,14.68.HRMS-ESI(m/z):[M+H]+对于C34H33N10O2S2 +,计算值677.22239;实测值:677.22253.HPLC(λ280):纯度100.0%;tR:13.058min(方法2)。
N2,N2'-(二硫代二基双(2,1-亚苯基))双(6-(3-氟苯基)-1,3,5-三嗪-2,4-二胺(MTF-320)。按照一般程序B,使用N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基)-3-氟苯甲酰胺(313mg,1mmol)合成,得到白色粉末状标题化合物(237mg,76%)。1H NMR(200MHz,DMSO-d6):δ9.32(s,2H),8.08(d,J=7.6Hz,2H),7.93(d,J=9.7Hz,2H),7.62(d,J=7.7Hz,2H),7.57–7.45(m,2H),7.45–7.06(m,12H).19F NMR(188MHz,DMSO-d6):δ-113.29.13C NMR(50MHz,DMSO-d6):δ168.98,167.26,165.51,164.58,159.75,139.31(d,J=7.7Hz),136.52,133.76,130.39(d,J=7.8Hz),128.22,127.66,126.62(d,J=16.1Hz),123.79,118.23(d,J=20.5Hz),114.11(d,J=22.6Hz).HRMS-ESI(m/z):[M+H]+对于C30H23F2N10S2 +,计算值625.15112;实测值:625.15125.HPLC(λ280):纯度97.5%;tR:12.817min(方法2)。
N2,N2'-(二硫代二基双(2,1-亚苯基))双(6-(吡啶-2-基)-1,3,5-三嗪-2,4-二胺)(MTF-321)。按照一般程序B,使用N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基)吡啶甲酰胺(296mg,1mmol)合成,得到白色粉末状标题化合物(266mg,90%)。1H NMR(200MHz,DMSO-d6):δ9.39(s,1H),8.74–8.64(m,1H),8.20(d,J=7.8Hz,1H),7.93(td,J=7.7,1.8Hz,1H),7.61(dd,J=7.6,1.5Hz,1H),7.51(ddd,J=7.5,4.7,1.2Hz,1H),7.39(dd,J=7.7,1.4Hz,1H),7.35–7.08(m,4H).13C NMR(50MHz,DMSO-d6):δ170.30,167.53,165.79,154.32,149.29,136.74,136.57,133.61,128.25,127.64,126.88,126.47,125.48,123.33.HRMS-ESI(m/z):[M+H]+对于C28H23N12S2 +,计算值591.16048;实测值:591.16048.HPLC(λ280):纯度95.3%;tR:6.483min(方法2)。
N2,N2'-(二硫代二基双(2,1-亚苯基))双(6-(3-氯苯基)-1,3,5-三嗪-2,4-二胺)(MTF-322)。按照一般程序B,使用N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基)-3-氯苯甲酰胺(329mg,1mmol)合成,得到白色粉末状标题化合物(260mg,79%)。1H NMR(200MHz,DMSO-d6):δ9.33(s,2H),8.24(s,2H),8.16(d,J=7.6Hz,2H),7.58(ddd,J=20.7,9.4,4.5Hz,6H),7.44–7.08(m,10H).13C NMR(50MHz,DMSO-d6):δ168.82,167.23,165.50,138.80,136.49,133.81,133.18,131.14,130.31,128.22,127.66,127.45,126.79,126.51,126.27.HRMS-ESI(m/z):[M+H]+对于C30H23Cl2N10S2 +,计算值657.09201;实测值:657.09222.HPLC(λ280):纯度96.9%;tR:12.867min(方法2)。
N2,N2'-(二硫代二基双(2,1-亚苯基))双(6-(3-溴苯基)-1,3,5-三嗪-2,4-二胺)(MTF-323)。按照一般程序B,使用N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基)-3-溴苯甲酰胺(374mg,1mmol)合成,得到白色粉末状标题化合物(339mg,91%)。1H NMR(200MHz,DMSO-d6):δ9.34(s,2H),8.40(s,2H),8.20(d,J=7.8Hz,2H),7.74(ddd,J=8.0,2.0,1.0Hz,2H),7.62(dd,J=7.5,1.6Hz,2H),7.46(t,J=7.9Hz,2H),7.40–7.13(m,10H).13C NMR(50MHz,DMSO-d6):δ168.73,167.22,165.49,138.97,136.48,134.02,133.83,130.60,130.43,128.22,127.66,126.81,126.63,126.55,121.69.HRMS-ESI(m/z):[M+H]+对于C30H23Br2N10S2 +,计算值744.99098;实测值:744.99098.HPLC(λ280):纯度100.0%;tR:17.600min(方法2)。
N2,N2'-(二硫代二基双(2,1-亚苯基))双(6-(4-甲氧基苯基)-1,3,5-三嗪-2,4-二胺)(MTF-324)。按照一般程序B,用N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基)-4-甲氧基苯甲酰胺(325mg,1mmol)合成,得到白色粉末状标题化合物(263mg,81%)。1H NMR(200MHz,DMSO-d6):δ9.13(s,2H),8.20(d,J=8.8Hz,4H),7.62(dd,J=7.8,1.2Hz,2H),7.40(d,J=7.2Hz,2H),7.32–7.22(m,2H),7.22–7.12(m,2H),7.01(d,J=8.8Hz,8H),3.82(s,6H).13CNMR(50MHz,DMSO-d6):δ169.77,167.19,165.36,161.99,136.91,133.33,129.62(2C),128.90,128.61,127.72,126.36,126.10,113.57(2C),55.30.HRMS-ESI(m/z):[M+H]+对于C32H29N10O2S2 +,计算值649.19109;实测值:649.19116.HPLC(λ280):纯度100.0%;tR:10.800min(方法2)。
3,3'-(((二硫醚二基双(2,1-亚苯基))双(氮杂二基))双(6-氨基-1,3,5-三嗪-4,2-二基))二苄腈(MTF-325)。按照一般程序B,使用N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基)-3-氰基苯甲酰胺(320mg,1mmol)合成,得到白色粉末状标题化合物(291mg,91%)。1HNMR(200MHz,DMSO-d6):δ9.37(s,2H),8.49(d,J=10.9Hz,4H),8.02(d,J=7.7Hz,2H),7.72(t,J=7.8Hz,2H),7.63(dd,J=7.6,1.4Hz,2H),7.42–7.15(m,10H).13C NMR(50MHz,DMSO-d6):δ168.32,167.24,165.49,137.79,136.48,134.74,133.71,132.16,131.22,129.88,128.38,127.79,126.80,126.59,118.56,111.54.HRMS-ESI(m/z):[M+H]+对于C32H23N12S2 +,计算值639.16046;实测值:639.16064.HPLC(λ280):纯度96.1%;tR:11.858min(方法2)。
N2,N2'-(二硫代二基双(2,1-亚苯基))双(6-苯基-1,3,5-三嗪-2,4-二胺)(MTF-326)。根据一般程序B,使用N-(N-(苯并[d]噻唑-2-基)氨基酰胺基)苯甲酰胺(295mg,1mmol)合成,得到白色粉末状标题化合物(218mg,74%)。1H NMR(200MHz,DMSO-d6):δ9.23(s,2H),8.24(d,J=6.5Hz,4H),7.62(d,J=7.3Hz,2H),7.57–7.34(m,8H),7.33–7.01(m,8H).13C NMR(50MHz,DMSO-d6):δ170.16,167.29,165.51,136.71,136.61,133.59,131.41,128.37,128.24(2C),127.82(2C),127.66,126.61,126.31.HRMS-ESI(m/z):[M+H]+对于C30H25N10S2 +,计算值589.16996;实测值:589.16992.HPLC(λ280):纯度100.0%;tR:11.792min(方法2)。
N2,N2'-(二硫代二基双(2,1-亚苯基))双(6-(4-氯苯基)-1,3,5-三嗪-2,4-二胺)(MTF-327)。按照一般程序B,使用N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基)-4-氯苯甲酰胺(329mg,1mmol)合成,得到白色粉末状标题化合物(283mg,86%)。1H NMR(200MHz,DMSO-d6):δ9.27(s,2H),8.22(d,J=8.5Hz,4H),7.66–7.50(m,6H),7.38(dd,J=7.6,1.0Hz,2H),7.33–7.05(m,8H).13C NMR(50MHz,DMSO-d6):δ169.18,167.22,165.46,136.62,136.20,135.47,133.52,129.53(2C),128.42(3C),127.73,126.65,126.37.HRMS-ESI(m/z):[M+H]+对于C30H23Cl2N10S2 +,计算值657.09201;实测值:657.09210.HPLC(λ280):纯度100.0%;tR:15.633min(方法2)。
N2,N2'-(二硫代二基双(2,1-亚苯基))双(6-(4-碘苯基)-1,3,5-三嗪-2,4-二胺)(MTF-328)。按照一般程序B,使用N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基)-4-碘代苯甲酰胺(421mg,1mmol)合成,得到白色粉末状标题化合物(387mg,92%)。1H NMR(200MHz,DMSO-d6):δ9.26(s,2H),8.00(d,J=8.4Hz,4H),7.87(d,J=8.4Hz,4H),7.61(d,J=7.6Hz,2H),7.39(d,J=7.4Hz,2H),7.33–6.99(m,8H).13C NMR(50MHz,DMSO-d6):δ169.58,167.21,165.45,137.24(2C),136.63,136.19,133.49,129.70(2C),128.47,127.73,126.61,126.34,99.15.HRMS-ESI(m/z):[M+H]+对于C30H23I2N10S2 +,计算值840.96324;实测值:840.96289.HPLC(λ280):纯度100.0%;tR:17.833min(方法2)。
N2,N2'-(二硫代二基双(2,1-亚苯基))双(6-(吡啶-4-基)-1,3,5-三嗪-2,4-二胺)(MTF-329)。按照一般程序B,使用N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基)异烟碱甲酰胺(296mg,1mmol)合成,得到白色粉末状标题化合物(266mg,90%)。1H NMR(200MHz,DMSO-d6):δ9.41(s,2H),8.73(dd,J=4.5,1.5Hz,4H),8.05(d,J=5.8Hz,4H),7.62(dd,J=7.4,1.2Hz,2H),7.43–7.08(m,10H).13C NMR(50MHz,DMSO-d6):δ168.77,167.33,165.59,150.23(2C),144.04,136.41,133.74,128.33,127.75,126.86,126.61,121.55(2C).HRMS-ESI(m/z):[M+H]+对于C28H23N12S2 +,计算值591.16046;实测值:591.16089.HPLC(λ280):纯度99.2%;tR:7.742min(方法2)。
N2,N2'-(二硫代二基双(2,1-亚苯基))双(6-(吡啶-3-基)-1,3,5-三嗪-2,4-二胺)(MTF-330)。按照一般程序B,使用N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基)烟碱甲酰胺(296mg,1mmol)合成,得到白色粉末状标题化合物(266mg,90%)。(277mg,94%)。1H NMR(200MHz,DMSO-d6):δ9.35(s,4H),8.71(dd,J=4.8,1.7Hz,2H),8.47(d,J=8.1Hz,2H),7.62(dd,J=7.6,1.2Hz,2H),7.52(dd,J=7.8,4.6Hz,2H),7.38(dd,J=7.7,1.4Hz,2H),7.33–7.06(m,8H13C NMR(50MHz,DMSO-d6):δ168.81,167.12,165.37,151.99,149.09,136.50,135.09,133.66,132.00,128.31,127.69,126.77,126.49,123.51HRMS-ESI(m/z):[M+H]+对于C28H23N12S2 +,计算值591.16046;实测值:591.16052.HPLC(λ280):纯度100.0%;tR:7.700min(方法2)。
2-((4-氨基-6-(3-溴苯基)-1,3,5-三嗪-2-基)氨基)苯酚(MTF-331)。按照一般程序A,使用1-(苯并[d]噁唑-2-基)胍(1.00g,5.68mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,341mg,8.52mmol)和3-溴苄腈(1.034g,5.68mmol)合成,得到棕色粉末状标题化合物(1.46g,72%)。1H NMR(400MHz,DMSO-d6):δ9.97(s,1H),8.44(s,1H),8.36(s,1H),8.26(d,J=7.5Hz,1H),7.90(d,J=7.7Hz,1H),7.76(d,J=7.7Hz,1H),7.48(t,J=7.8Hz,1H),7.29(s,2H),6.99–6.92(m,1H),6.89(d,J=7.4Hz,1H),6.82(t,J=7.1Hz,1H).13C NMR(50MHz,DMSO-d6):δ168.84,167.06,164.48,148.30,138.75,133.26,131.22,130.38,127.46,126.84,126.29,124.12,122.65,118.99,115.77.HRMS-ESI(m/z):[M+H]+对于C15H13BrN5O+,计算值358.02980实测值:358.03094.HPLC(λ280):纯度97.1%;tR:9.808min(方法1)。
2-((4-氨基-6-(3-氯苯基)-1,3,5-三嗪-2-基)氨基)苯酚(MTF-332)。按照一般程序A,使用1-(苯并[d]噁唑-2-基)胍(1.00g,5.68mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,341mg,8.52mmol)和3-氯苄腈(781mg,5.68mmol)合成,得到棕色粉末状标题化合物(1.45g,82%)。1H NMR(400MHz,DMSO-d6):δ10.03(s,1H),8.36(s,1H),8.29(s,1H),8.23(d,J=7.4Hz,1H),7.92(d,J=7.5Hz,1H),7.62(d,J=7.5Hz,1H),7.55(t,J=7.8Hz,1H),7.29(s,2H),6.99–6.92(m,1H),6.89(d,J=7.3Hz,1H),6.82(t,J=7.1Hz,1H).13C NMR(50MHz,DMSO-d6):δ168.74,167.02,164.48,148.21,138.90,134.11,130.67,130.40,126.66(2C),124.17,122.79,121.73,119.10,115.78.HRMS-ESI(m/z):[M+H]+对于C15H13ClN5O+,计算值314.08031;实测值:314.08066.HPLC(λ280):纯度97.3%;tR:9.625min(方法1)。
N2,N2'-(二硫代二基双(2,1-亚苯基))双(6-苄基-1,3,5-三嗪-2,4-二胺(MTF-333)。在微波管中,在氩气气氛下将1-(苯并[d]噻唑-2-基)胍(100mg,0.52mmol)溶于NMP(2mL)中,然后将试管冷却至0℃,然后添加NaH(60%的在油中的悬浮液,23mg,0.57mmol)。在停止放出气体后,将管密封,并将混合物在微波辐射下加热至110℃,持续15分钟。将所得浆液溶于Et2O中并过滤。然后通过硅胶快速色谱法纯化沉淀物(二氯甲烷/MeOH,10/0-9/1)得到白色粉末状所需产物(50mg,31%)。TLC:Rf(二氯甲烷/MeOH,9/1,v/v)=0.83。1H NMR(400MHz,DMSO-d6):δ9.05(s,1H),7.54(dd,J=7.8,0.9Hz,1H),7.35–7.17(m,7H),7.14(t,J=7.7Hz,1H),6.95(d,J=16.0Hz,2H),3.71(s,2H).13C NMR(101MHz,DMSO-d6):δ176.6,166.9,165.3,151.5,139.2,137.9,136.6,129.1,128.2,128.0,127.6,126.3,124.9,30.4.HRMS-ESI(m/z):[M+H]+对于C32H29N10S2 +,计算值617.20126,实测值617.20154.HPLC(λ254):纯度96.2%;tR:10.742min(方法2)。
N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基)-3-甲氧基苯甲酰胺(MTF-342)。按照一般程序A,使用1-(苯并[d]噻唑-2-基)胍(1.00g,5.20mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,312mg,7.81mmol)和3-甲氧基苄腈(0.635mL,5.20mmol)合成,得到白色粉末状标题化合物(914mg,54%)。1H NMR(200MHz,DMSO-d6):δ10.26(s,1H),9.33(s,1H),8.82(s,1H),8.05(s,1H),7.80(d,J=7.6Hz,1H),7.73–7.52(m,3H),7.48–7.29(m,2H),7.17(dd,J=14.6,7.6Hz,2H),3.83(s,3H).13C NMR spectrum could not be properlyrecorded as this compound rearranges and dimerizes into compound MTF-318during the time of the analysis.HRMS-ESI(m/z):[M+H]+对于C16H16N5OS+,计算值326.10701;实测值:326.10706.HPLC(λ280):纯度100.0%;tR:6.558min(方法1)。
N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基)-3-(三氟甲基)苯甲酰胺(MTF-343)。按照一般程序A,使用1-(苯并[d]噻唑-2-基)胍(1.00g,5.20mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,312mg,7.81mmol)和3-(三氟甲基)苄腈(890mg,5.20mmol)合成,得到白色粉末状标题化合物(435mg,23%)。1H NMR(200MHz,DMSO-d6):δ10.33(br.s,1H),9.36(br.s,1H),8.93(br.s,1H),8.39(s,1H),8.31(d,J=7.9Hz,1H),8.16(br.s,1H),7.95(d,J=7.9Hz,1H),7.86–7.72(m,2H),7.67(d,J=8.0Hz,1H),7.35(t,J=7.6Hz,1H),7.20(t,J=7.5Hz,1H).19F NMR(376MHz,DMSO-d6):δ-61.04.由于该化合物在分析期间发生了重排和二聚,因此无法正确记录13C NMR光谱。HRMS-ESI(m/z):[M+H]+对于C16H13F3N5S+,计算值364.08383;实测值:364.08408.HPLC(λ280):纯度97.9%;tR:6.533min(方法1)。
N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基)-3-乙氧基苯甲酰胺(MTF-344)。按照一般程序A,使用1-(苯并[d]噻唑-2-基)胍(1.00g,5.20mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,312mg,7.81mmol)和3-乙氧基苄腈(765mg,5.20mmol)合成,得到白色粉末状标题化合物(830mg,47%)。1H NMR(200MHz,DMSO-d6):δ10.23(br.s,1H),9.30(br.s,1H),8.78(br.s,1H),8.03(br.s,1H),7.80(dd,J=7.8,0.8Hz,1H),7.65(dd,J=8.0,0.6Hz,1H),7.62–7.53(m,2H),7.46–7.29(m,2H),7.24–7.07(m,2H),4.09(q,J=6.9Hz,2H),1.36(t,J=6.9Hz,3H).13C NMR(50MHz,DMSO-d6):δ172.24,162.07,161.82,158.40,151.49,136.56,131.16,129.36,125.63,122.78,121.13,119.68,119.65,117.34,113.64,63.24,14.63.HRMS-ESI(m/z):[M+H]+对于C17H18N5OS+,计算值340.12266;实测值:340.12296.HPLC(λ280):纯度100.0%;tR:6.733min(方法1)。
N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基)吡嗪-2-羧甲酰胺(MTF-345)。按照一般程序A,使用1-(苯并[d]噻唑-2-基)胍(1.00g,5.20mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,312mg,7.81mmol)和吡嗪腈(0.465mL,5.20mmol)合成,得到黄色粉末状标题化合物(959mg,62%)。1H NMR(200MHz,DMSO-d6):δ10.13(br.s,1H),9.50(s,1H),9.44(br.s,1H),8.99(br.s,1H),8.88(d,J=2.5Hz,1H),8.79(dd,J=2.5,1.4Hz,1H),8.26(br.s,1H),7.83(d,J=7.7Hz,1H),7.69(d,J=7.9Hz,1H),7.44–7.30(m,1H),7.29–7.15(m,1H).13C NMR(50MHz,DMSO-d6):δ172.18,161.92,157.68,151.39,147.21,145.85,143.84,143.44,131.22,125.73,123.01,121.22,119.90.HRMS-ESI(m/z):[M+H]+对于C13H12N7S+,计算值298.08694;实测值:298.08707.HPLC(λ280):纯度95.7%;tR:5.508min(方法1)。
N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基)-3-氟苯甲酰胺(MTF-346)。按照一般程序A,使用1-(苯并[d]噻唑-2-基)胍(1.00g,5.20mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,312mg,7.81mmol)和3-氟苄腈(0.56mL,5.20mmol)合成,得到白色粉末状标题化合物(895mg,55%)。1H NMR(200MHz,DMSO-d6):δ10.26(s,1H),9.34(s,1H),8.89(s,1H),8.09(s,1H),7.95–7.76(m,3H),7.70–7.51(m,2H),7.50–7.28(m,2H),7.19(td,J=7.6,1.2Hz,1H).19F NMR(376MHz,DMSO-d6):δ-112.99.由于在分析期间该化合物重排并二聚为化合物MTF-320,因此无法正确记录13C NMR谱。HRMS-ESI(m/z):[M+H]+对于C15H13FN5S+,计算值314.08702;实测值:314.08722.HPLC(λ280):纯度98.7%;tR:6.442min(方法1)。
N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基)-3-氰基苯甲酰胺(MTF-347)。按照一般程序A,使用1-(苯并[d]噻唑-2-基)胍(1.00g,5.20mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,312mg,7.81mmol)和1,3-二氰基苯(667mg,5.20mmol)合成,得到白色-淡黄色粉末状标题化合物(1.23g,74%)。1H NMR(200MHz,DMSO-d6):δ10.27(br.s,1H),9.37(br.s,1H),8.97(br.s,1H),8.45(s,1H),8.33(dd,J=8.0,1.0Hz,1H),8.15(br.s,1H),8.06(dd,J=7.7,1.0Hz,1H),7.89–7.62(m,3H),7.35(t,J=7.6Hz,1H),7.20(t,J=7.5Hz,1H).13C NMR(50MHz,DMSO-d6):δ172.17,161.83,159.93,151.42,136.30,134.69,132.15,131.40,131.24,129.67,125.67,122.89,121.17,119.81,118.39,111.50.HRMS-ESI(m/z):[M+H]+对于C16H13N6S+,计算值321.09169;实测值:321.09167.HPLC(λ280):纯度96.4%;tR:6.342min(方法1)。
N2,N2'-(二硫代二基双(2,1-亚苯基))双(6-(吡嗪-2-基)-1,3,5-三嗪-2,4-二胺)(MTF-348)。按照一般程序B,使用N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基)吡嗪-2-羧甲酰胺(297mg,1mmol)合成,得到淡黄色粉末状标题化合物(279mg,94%)。1H NMR(400MHz,DMSO-d6):δ9.48(br.s,1H),9.33(br.s,1H),8.77(m,2H),7.61(d,J=7.7Hz,1H),7.38(d,J=6.7Hz,2H),7.23(m,3H).13C NMR(50MHz,DMSO-d6):δ168.83,167.37,165.65,149.51,146.27,144.58,144.38,136.35,133.76,128.18,127.66,127.06,126.68.HRMS-ESI(m/z):[M+H]+对于C28H23N12S2 +,计算值591.16046;实测值:591.16052.HPLC(λ280):纯度99.2%;tR:8.875min(方法2)。
N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基)-6-氯烟碱甲酰胺(MTF-379)。按照一般程序A,使用1-(苯并[d]噻唑-2-基)胍(1.00g,5.20mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,312mg,7.81mmol)和6-氯-3-吡啶甲腈(720mg,5.20mmol)合成,得到米色粉末状标题化合物(1.48g,86%)。1H NMR(400MHz,DMSO-d6):δ10.21(s,1H),9.37(s,1H),9.01(d and br.s,J=2.1Hz,2H),8.38(dd,J=8.4,2.3Hz,1H),8.12(s,1H),7.80(d,J=7.8Hz,1H),7.69(d,J=8.4Hz,1H),7.66(d,J=8.1Hz,1H),7.34(t,J=7.6Hz,1H),7.19(t,J=7.5Hz,1H).13C NMR(101MHz,DMSO-d6):δ172.16,161.79,159.12,152.70,151.42,149.28,138.70,131.29,130.36,125.68,123.98,122.91,121.17,119.83.HPLC(λ280):纯度97.2%;tR:7.033min(方法1)。
N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基)-2-氯异烟碱甲酰胺(MTF-380)。按照一般程序A,使用1-(苯并[d]噻唑-2-基)胍(1.00g,5.20mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,312mg,7.81mmol)和2-氯-4-吡啶甲腈(720mg,5.20mmol)合成,得到米色粉末状标题化合物(327mg,19%)。1H NMR(400MHz,DMSO-d6):δ10.22(br.s,1H),9.39(br.s,1H),9.04(br.s,1H),8.60(d,J=5.1Hz,1H),8.21(br.s,1H),8.05(s,1H),7.94(dd,J=5.2,1.3Hz,1H),7.81(d,J=7.3Hz,1H),7.67(d,J=7.9Hz,1H),7.38–7.31(m,1H),7.24–7.17(m,1H).13C NMR(101MHz,DMSO-d6):δ172.08,161.68,158.50,151.36,150.84,150.52,146.10,131.31,125.70,122.99,122.27,121.20,120.99,119.90.HPLC(λ280):纯度97.8%;tR:7.108min(方法1)。
N-(N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基]噻吩-2-羧甲酰胺(MTF-381)。按照一般程序,使用1-(苯并[d]噻唑-2-基)胍(1.00克,5.20mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,312mg,7.81mmol)和2-噻吩甲腈(0.48mL,5.20mmol)合成,得到淡黄色粉末状标题化合物(815mg,52%)。1H NMR(400MHz,DMSO-d6):δ10.22(br.s,1H),9.34(br.s,1H),8.88(br.s,1H),7.94(dd,J=3.7,0.9Hz,2H),7.79(d,J=6.2Hz,2H),7.65(d,J=7.9Hz,1H),7.39–7.28(m,1H),7.24–7.14(m,2H).13C NMR(101MHz,DMSO-d6):δ172.22,161.71,157.31,151.46,140.40,131.89,131.13,128.97,128.11,125.65,122.79,121.12,119.68.HPLC(λ280):纯度99.2%;tR:6.975min(方法1)。
N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基)-3,4,5-三甲氧基苯甲酰胺(MTF-382)。按照一般程序A,使用1-(苯并[d]噻唑-2-基)胍(1.00g,5.20mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,312mg,7.81mmol)和3,4,5-三甲氧基苄腈(1g,5.20mmol)合成,得到米色粉末状标题化合物(441mg,22%)。1H NMR(200MHz,DMSO-d6):δ10.22(br.s,1H),9.29(br.s,1H),8.77(br.s,1H),8.01(br.s,1H),7.80(d,J=7.0Hz,1H),7.65(d,J=7.5Hz,1H),7.39(s,2H),7.38–7.27(m,1H),7.19(td,J=7.7,1.1Hz,1H),3.87(s,6H),3.74(s,3H).13C NMR(50MHz,DMSO-d6):δ172.28,161.97,161.53,152.51(2C),151.54,140.27,131.19,130.33,125.63,122.75,121.12,119.66,105.29(2C),60.14,56.06(2C).HPLC(λ280):纯度96.1%;tR:7.175min(方法1)。
N-(N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基]苯并[d][1,3]二噁唑-5-羧甲酰胺(MTF-383)。根据一般程序A,使用1-(苯并[d]噻唑-2-基)胍(1.00g,5.20mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,312mg,7.81mmol)和胡椒基腈(765mg,5.20mmol)得到米色粉末状标题化合物(600mg,34%)。1H NMR(400MHz,DMSO-d6):δ10.27(s,1H),9.29(s,1H),8.68(s,1H),7.95(s,1H),7.79(d,J=7.7Hz,1H),7.68–7.62(m,2H),7.60(d,J=1.6Hz,1H),7.37–7.29(m,1H),7.22–7.15(m,1H),7.04(d,J=8.2Hz,1H),6.13(s,2H).13CNMR(50MHz,DMSO-d6):δ172.25,161.95,161.27,151.52,150.06,147.38,131.13,128.99,125.62,122.74,122.56,121.11,119.65,107.85,107.61,101.80.HPLC(λ280):纯度96.0%;tR:7.133min(方法1)。
N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基)-2-萘甲酰胺(MTF-384)。按照一般程序A,使用1-(苯并[d]噻唑-2-基)胍(1.00g,5.20mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,312mg,7.81mmol)和萘-2-甲腈(796mg,5.20mmol)合成,得到米色粉末状标题化合物(1.04g,58%)。1H NMR(400MHz,DMSO-d6):δ10.38(br.s,1H),9.42(br.s,1H),8.99(br.s,1H),8.64(s,1H),8.16(br.s and dd,J=8.6,1.4Hz,2H),8.08–7.96(m,3H),7.81(d,J=7.7Hz,1H),7.67(d,J=7.9Hz,1H),7.66–7.57(m,2H),7.40–7.31(m,1H),7.25–7.15(m,1H).13C NMR(50MHz,DMSO-d6):δ172.34,162.16(2C),151.53,134.30,132.66,132.15,131.22,128.83,127.84,127.75(2C),127.66,126.80,125.65,124.55,122.81,121.14,119.73.HPLC(λ280):纯度95.7%;tR:7.392min(方法1)。
N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基)-4-(三氟甲基)苯甲酰胺(MTF-385)。按照一般程序A,使用1-(苯并[d]噻唑-2-基)胍(1.00g,5.20mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,312mg,7.81mmol)和4-(三氟甲基)苄腈(889mg,5.20mmol)合成,得到米色粉末状标题化合物(1.38g,73%)。1H NMR(400MHz,DMSO-d6):δ10.28(br.s,1H),9.38(br.s,1H),8.97(br.s,1H),8.22(d,J=8.2Hz,2H),8.11(br.s,1H),7.90(d,J=8.3Hz,2H),7.80(d,J=7.3Hz,1H),7.67(d,J=7.7Hz,1H),7.39–7.30(m,1H),7.24–7.16(m,1H).19F NMR(377MHz,DMSO-d6):δ-61.28.13C NMR(50MHz,DMSO-d6):δ172.11,161.89,160.69,151.37,139.09,131.19,131.40(q,J=31.8Hz),128.36(2C),125.57,125.16(q,J=3.8Hz,2C),123.91(q,J=67.7Hz),122.79,121.07,119.72.HPLC(λ280):纯度96.4%;tR:7.442min(方法1)。
N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基)-2-溴异烟碱甲酰胺(MTF-386)。按照一般程序A,使用1-(苯并[d]噻唑-2-基)胍(1.00g,5.20mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,312mg,7.81mmol)和2-溴-4-氰基吡啶(952mg,5.20mmol)合成,得到黄色粉末状标题化合物(859mg,44%)。1H NMR(400MHz,DMSO-d6):δ10.19(br.s,1H),9.38(br.s,1H),9.04(br.s,1H),8.58(d,J=5.1Hz,1H),8.18(s and br.s,2H),7.96(dd,J=5.1,1.3Hz,1H),7.81(d,J=7.4Hz,1H),7.67(d,J=7.9Hz,1H),7.39–7.32(m,1H),7.24–7.17(m,1H).13C NMR(50MHz,DMSO-d6):δ172.08,161.67,158.42,151.36,151.00,145.67,141.81,131.32,125.94,125.71,123.00,121.25,121.21,119.91.HPLC(λ280):纯度97.0%;tR:7.192min(方法1)。
N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基)-4-溴噻吩-3-羧甲酰胺(MTF-387)。使用1-(苯并[d]噻唑-2-基)胍(1.00g,5.20mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,312mg,7.81mmol)和4-溴噻吩-3-甲腈(978mg,5.20mmol)合成,得到棕色粉末状标题化合物(969mg,49%)。1H NMR(400MHz,DMSO-d6):δ10.03(br.s,1H),9.30(br.s,1H),8.60(br.s,1H),7.98(br.s and d,J=3.4Hz,2H),7.80(d,J=7.7Hz,1H),7.77(d,J=3.4Hz,1H),7.64(d,J=8.0Hz,1H),7.38–7.30(m,1H),7.20(d,J=7.3Hz,1H).13C NMR(50MHz,DMSO-d6):δ172.41,161.84,159.08,151.48,137.36,131.24,129.06,125.66,125.44,122.85,121.16,119.75,108.70.HPLC(λ280):纯度96.6%;tR:6.967min(方法1)。
N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基]-2,2-二甲基-2H-色烯-6-羧甲亚胺(MTF-388)。按照一般程序A,使用1-(苯并[d]]噻唑-2-基)胍(1.00g,5.20mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,312mg,7.81mmol)和2,2-二甲基-2H-1-苯并吡喃-6-甲腈(963mg,5.20mmol)合成,得到米色粉末状标题化合物(118mg,6%)。1H NMR(400MHz,DMSO-d6):δ10.25(br.s,1H),9.29(br.s,1H),8.66(br.s,1H),7.91(br.s,1H),7.84–7.75(m,3H),7.64(d,J=7.8Hz,1H),7.37–7.30(m,1H),7.22–7.15(m,1H),6.85(d,J=8.5Hz,1H),6.45(d,J=9.9Hz,1H),5.84(d,J=9.8Hz,1H),1.41(s,6H).13C NMR(101MHz,DMSO-d6):δ169.68,167.16,165.32,155.42,136.88,133.37,131.25,129.27,129.18,128.53,127.69,126.40,126.16,126.10,121.61,120.27,115.66,76.97,27.93(2C).HPLC(λ280):纯度98.4%;tR:7.492min(方法1)。
N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基)-3,5-二氯吡啶甲酰胺(MTF-389)。按照一般程序A,使用1-(苯并[d]噻唑-2-基)胍(1.00g,5.20mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,312mg,7.81mmol)和3,5-二氯吡啶-2-甲腈(900mg,5.20mmol)合成,得到棕色粉末状标题化合物(779mg,41%)。1H NMR(400MHz,DMSO-d6):δ9.73(br.s,1H),9.29(br.s,1H),8.73(br.s,1H),8.67(d,J=1.5Hz,1H),8.37(s,1H),8.12(br.s,1H),7.77(d,J=7.7Hz,1H),7.62(d,J=7.9Hz,1H),7.32(t,J=7.5Hz,1H),7.18(t,J=7.5Hz,1H).13CNMR(50MHz,DMSO-d6):δ172.48,161.60,160.60,151.43,150.95,145.79,137.15,131.46,131.19,129.02,125.59,122.77,121.12,119.67.HPLC(λ280):纯度95.3%;tR:7.192min(方法1)。
N2,N2'-(二硫代二基双(2,1-亚苯基))双(6-(4-(三氟甲基)苯基)-1,3,5-三嗪-2,4-二胺)(MTF-394)。按照一般程序B,使用N-(N-(苯并[d]噻唑-2-基)氨基酰胺基)-4-(三氟甲基)苯甲酰胺(363mg,1mmol),得到白色粉末状标题化合物(239mg,66%)。1H NMR(400MHz,DMSO-d6):δ9.34(s,1H),8.42(d,J=7.8Hz,2H),7.86(d,J=8.4Hz,2H),7.64(d,J=7.7Hz,1H),7.41(d,J=7.4Hz,1H),7.25(ddd,J=34.2,11.4,4.1Hz,4H).19F NMR(377MHz,DMSO-d6):δ-61.24.13C NMR(101MHz,DMSO-d6):δ168.98,167.28,165.53,140.54,136.56,133.57,131.18,128.46(2C),127.76,126.75,126.48,125.50,125.30(2C),122.80.HPLC(λ254):纯度97.0%;tR:16.125min(方法2)。
N2,N2'-(二硫代二基双(2,1-亚苯基))双(6-(噻吩-2-基)-1,3,5-三嗪-2,4-二胺)(MTF-396)。按照一般程序B,使用N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基)噻吩-2-羧甲酰胺(301mg,1mmol)合成,得到白色粉末状标题化合物(250mg,83%)。1H NMR(400MHz,DMSO-d6):δ9.21(s,1H),7.84(d,J=2.9Hz,1H),7.75(dd,J=5.0,1.1Hz,1H),7.61(dd,J=7.9,1.1Hz,1H),7.37(d,J=7.4Hz,1H),7.26(td,J=7.7,1.2Hz,1H),7.21–7.16(m,2H),7.09(d,J=15.2Hz,2H).13C NMR(101MHz,DMSO-d6):δ166.91,166.58,165.13,142.40,136.55,133.67,131.03,129.34,128.37,128.08,127.60,126.68,126.35.HPLC(λ280):纯度97.1%;tR:11.817min(方法2)。
N2,N2'-(二硫代二基双(2,1-亚苯基))双(6-(4-溴噻吩-3-基)-1,3,5-三嗪-2,4-二胺)(MTF-397)。按照一般程序B,使用N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基)-4-溴噻吩-3-羧甲酰胺(380mg,1mmol)合成,得到白色粉末状标题化合物(167mg,44%)。1H NMR(400MHz,DMSO-d6):δ9.14(s,1H),8.11(d,J=3.6Hz,1H),7.73(d,J=3.6Hz,1H),7.57(d,J=7.3Hz,1H),7.42(d,J=7.7Hz,1H),7.28–7.22(m,1H),7.12(t,J=7.4Hz,1H),7.07(s,2H).13C NMR(101MHz,DMSO-d6):δ167.68,166.88,165.20,137.92,136.60,133.26,130.88,128.44,127.69,126.98,126.29,126.03,109.03.HPLC(λ254):纯度97.1%;tR:12.483min(方法2)。
N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基)-4-硝基苯甲酰胺(MTF-398)。按照一般程序A,使用1-(苯并[d]噻唑-2-基)胍(1.00g,5.20mmol)、氢化钠(60%的在矿物油中的分散体,1.5当量,312mg,7.81mmol)和4-硝基苄腈(770mg,5.20mmol)得到黄色粉末状标题化合物(212mg,12%)。1H NMR(500MHz,DMSO-d6):δ10.30(br.s,1H),9.37(br.s,1H),8.90(br.s,1H),8.12(t,br.s,J=1.8Hz,2H),7.99(d,J=7.9Hz,1H),7.80(d,J=7.7Hz,1H),7.66(d,J=7.9Hz,1H),7.65–7.60(m,1H),7.54(t,J=7.9Hz,1H),7.38–7.30(m,1H),7.22–7.17(m,1H).13C NMR(50MHz,DMSO-d6):δ172.22,161.95,160.57,151.47,137.26,133.22,131.23,131.20,130.20,127.53,126.14,125.67,122.87,121.16,119.79.HPLC(λ280):纯度99.2%;tR:6.792min(方法1)。
2-((4-氨基-6-(三氯甲基)-1,3,5-三嗪-2-基)氨基)苯酚(MTF373)。按照一般程序D,使用1-(苯并[d]噁唑-2-酰基)胍(100mg,0.6mmol)和三氯乙腈(600μL,6mmol)合成,得到米色粉末状标题化合物(61mg,32%)。1H NMR(400MHz,丙酮-d6):δ9.10(s,1H),8.38(br.s,1H),7.99(br.s,1H),7.28(br.s,1H),7.15(br.s,1H),7.05–6.92(m,2H),6.87(td,J=7.8,1.7Hz,1H).13C NMR(101MHz,丙酮-d6):δ174.0,168.9,165.8,148.6,127.6,125.6,123.2,120.8,117.2,97.4.HRMS-ESI(m/z):[M+H]+对于C10H9ON5Cl3 +,计算值319.98672;实测值319.98709.HPLC(λ254):97.9%;tR:9.108min(方法4)。
2-((4-氨基-6-(三氯甲基)-1,3,5-三嗪-2-基)氨基)-4-氯苯酚(MTF374)。按照一般程序D,使用2-(5-氯苯并[d]噁唑-2-基)胍(100mg,0.48mmol)和三氯乙腈(450μL,4.8mmol)合成,得到淡粉红色粉末状标题化合物(55mg,32%)。1H NMR(400MHz,丙酮-d6):δ9.48(s,1H),8.30(s,1H),8.18(s,1H),7.43(s,1H),7.20(s,1H),7.01–6.92(m,2H).13C NMR(101MHz,丙酮-d6):δ174.0,168.9,165.6,146.6,128.8,124.9,124.3,121.9,117.3,97.3.HRMS-ESI(m/z):[M+H]+对于C10H8ON5Cl4 +,计算值353.94775;实测值353.94830.HPLC(λ254):97.1%;tR:10.504min(方法4)。
2-((4-氨基-6-(三氯甲基)-1,3,5-三嗪-2-基)氨基)-5-氯苯酚(MTF375)。按照一般程序D,使用2-(6-氯苯并[d]噁唑-2-基)胍(100mg,0.48mmol)和三氯乙腈(480μL,4.8mmol)合成,得到淡绿色粉末状标题化合物(59mg,35%)。1H NMR(400MHz,丙酮-d6):δ9.66(br.s,1H),8.32(br.s,1H),8.04(br.s,1H),7.29(br.s,1H),7.18(br.s,1H),6.99(d,J=2.2Hz,1H),6.90(dd,J=8.7,2.1Hz,1H).13C NMR(101MHz,丙酮-d6):δ174.0,168.9,165.7,149.5,129.5,126.7,124.1,120.4,116.8,97.3.HRMS-ESI(m/z):[M+H]+对于C10H8ON5Cl4 +,计算值353.94775;实测值353.94837.HPLC(λ254):95.3%;tR:10.615min(方法4)。
2-((4-氨基-6-(三氯甲基)-1,3,5-三嗪-2-基)氨基)-5-硝基苯酚(MTF376)。按照一般程序D,使用2-(6-硝基苯并[d]噁唑-2-基)胍(100mg,0.45mmol)和三氯乙腈(450μL,4.5mmol)合成,得到淡黄色粉末状标题化合物(50mg,30%)。1H NMR(400MHz,MeOD):δ8.72(d,J=9.1Hz,1H),7.78(dd,J=9.1,2.5Hz,1H),7.70(d,J=2.5Hz,1H).13C NMR(101MHz,丙酮-d6):δ174.3,169.1,165.7,147.1,143.7,134.5,120.3,116.6,110.4,97.1.HRMS-ESI(m/z):[M+H]+对于C10H8O3N6Cl3 +,计算值364.97180;实测值364.97208.HPLC(λ254):95.1%;tR:10.623min(方法4)。
2-((4-氨基-6-(三氯甲基)-1,3,5-三嗪-2-基)氨基)-4-硝基苯酚(MTF377)。按照一般程序D,使用2-(5-硝基苯并[d]噁唑-2-基)胍(100mg,0.45mmol)和三氯乙腈(450μL,4.5mmol)合成,得到淡橙色粉末状标题化合物(117mg,71%)。1H NMR(400MHz,丙酮-d6):δ9.29(br.s,1H),8.32(br.s,1H),7.91(dd,J=8.9,2.6Hz,1H),7.54(br.s,1H),7.23(br.s,1H),7.11(d,J=8.9Hz,1H),6.61(br.s,1H).13C NMR(101MHz,丙酮-d6):δ174.3,168.9,165.6,146.9,143.6,134.3,120.3,116.7,110.3,97.1.HRMS-ESI(m/z):[M+H]+对于C10H8O3N6Cl3 +,计算值364.97180;实测值364.97229.HPLC(λ254):97.7%;tR:9.434min(方法4)。
2-((4-氨基-6-苯基-1,3,5-三嗪-2-基)氨基)-4-氯苯酚(MTF409)。按照一般程序E,使用1-(5-氯苯并[d]噁唑-2-基)胍(500mg,2.4mmol)、氢化钠(60%的油悬浮液,104mg,2.6mmol)和苄腈(0.25mL,2.4mmol)合成,得到米色粉末状标题化合物(210mg,28%)。1HNMR(400MHz,丙酮-d6):δ9.88(br.s,1H),8.41–8.37(m,2H),8.16(s,2H),7.56(t,J=7.2Hz,1H),7.50(t,J=7.3Hz,2H),7.01–6.92(m,2H),6.81(br.s,2H).13C NMR(101MHz,丙酮-d6):δ172.1,168.6,165.7,147.0,137.3,132.6,129.9,129.1(2C),129.0(2C),124.8,124.1,121.9,118.4.HRMS-ESI(m/z):[M+H]+对于C15H13OClN5 +,计算值314.08031;实测值314.08044.HPLC(λ254):98.1%;tR:9.916min(方法4)。
2-((6-亚氨基-4-(三氯甲基)-1,6-二氢-1,3,5-三嗪-2-基)氨基)-5-甲基苯酚(MTF410)。按照一般程序D,使用1-(6-甲基苯并[d]噁唑-2-基)胍(500mg,2.6mmol)和三氯乙腈(2.6mL,26mmol)合成,得到淡灰色粉末状标题化合物(480mg,55%)。1H NMR(400MHz,丙酮-d6):δ9.01(br.s,1H),8.31(br.d,J=75.1Hz,1H),7.79(br.d,J=51.9Hz,1H),7.25(br.s,1H),7.14(br.s,1H),6.79(d,J=0.9Hz,1H),6.69(dd,J=8.1,1.0Hz,1H),2.25(s,3H).13C NMR(101MHz,丙酮-d6):δ173.8,168.7,165.6,149.0,135.8,124.7,123.6,121.3,118.0,97.3,20.9.HRMS-ESI(m/z):[M+H]+对于C11H11OCl3N5 +,计算值334.00237;实测值334.00250.HPLC(λ254):100%;tR:9.948min(方法4)。
2-((4-氨基-6-苯基-1,3,5-三嗪-2-基)氨基)-5-甲基苯酚(MTF411)。按照一般程序E,使用1-(6-甲基苯并[d]噁唑-2-基)胍(500mg,2.6mmol)、氢化钠(60%的油悬浮液,114mg,2.9mmol)和苄腈(0.27mL,2.6mmol)合成,得到米色粉末状标题化合物(410mg,54%)。1H NMR(400MHz,丙酮-d6):δ9.75(br.s,1H),8.37(d,J=7.4Hz,2H),8.30(br.s,1H),7.59-7.53(m,2H),7.48(t,J=7.3Hz,2H),6.80(s,1H),6.74(br.s,2H),6.69(d,J=8.0Hz,1H),2.26(s,3H).13C NMR(101MHz,丙酮-d6):δ171.9,168.4,165.6,149.1,137.4,135.4,132.5,129.1,129.0(2C),125.9,123.3,121.3(2C),119.2,20.9.HRMS-ESI(m/z):[M+H]+对于C16H16ON5 +,计算值294.13494;实测值294.13495.HPLC(λ254):99.7%;tR:8.456min(方法4)。
2-((4-氨基-6-苯基-1,3,5-三嗪-2-基)氨基)苯酚(MTF412)。按照一般程序E,使用1-(苯并[d]噁唑-2-基)胍(500mg,2.8mmol)、氢化钠(60%的在油中的悬浮液,123mg,3.1mmol)和苄腈(0.29mL,2.8mmol)合成,得到淡棕色粉末状标题化合物(53mg,7%)。1HNMR(400MHz,丙酮-d6):δ9.82(br.s,1H),8.39(d,J=7.1Hz,2H),8.31(br.s,1H),7.83(d,J=7.7Hz,1H),7.58–7.52(m,1H),7.52–7.46(m,2H),7.03–6.94(m,2H),6.90–6.84(m,1H),6.77(br.s,2H).13C NMR(101MHz,丙酮-d6):δ172.0,168.5,165.7,148.9,137.4,132.6,129.1(2C),129.0(2C),128.5,125.3,123.1,120.7,118.3.HRMS-ESI(m/z):[M+H]+对于C15H14ON5 +,计算值280.11929;实测值280.11929.HPLC(λ254):98.9%;tR:8.100min(方法4)。
2-((6-亚氨基-4-苯基-1,6-二氢-1,3,5-三嗪-2-基)氨基)-4-硝基苯酚(MTF413)。按照一般程序E,使用1-(6-硝基苯并[d]噁唑-2-基)胍(500mg,2.3mmol)、氢化钠(60%的油悬浮液,100mg,2.5mmol)和苄腈(0.24mL,2.3mmol)合成,得到淡黄色粉末状标题化合物(62mg,8%)。1H NMR(400MHz,DMSO-d6):δ11.39(br.s,1H),8.63(d,J=9.0Hz,1H),8.36–8.30(m,2H),8.26(s,1H),7.80(dd,J=9.0,2.6Hz,1H),7.70(d,J=2.6Hz,1H),7.61–7.56(m,1H),7.52(dd,J=11.4,4.4Hz,2H),7.45(br.s,2H).13C NMR(101MHz,DMSO-d6):δ170.7,167.2,164.2,146.4,141.5,136.1,134.5,131.9,128.5(2C),128.0(2C),118.9,115.4,108.9.HRMS-ESI(m/z):[M+H]+对于C15H13O3N6 +,计算值325.10436;实测值325.10446.HPLC(λ254):99.1%;tR:10.242min(方法4)。
2-((6-亚氨基-4-(吡嗪-2-基)-1,6-二氢-1,3,5-三嗪-2-基)氨基)苯酚(MTF439)。按照一般程序E,使用1-(苯并[d]噁唑-2-基)胍(500mg,2.8mmol)、氢化钠(60%的油悬浮液,123mg,3.08mmol)和吡嗪腈(250μL,2.8)合成,得到亮黄色粉末状标题化合物(510mg,65%)。然后,将双胍溶于DMSO中,并在室温下搅拌8小时,得到亮黄色粉末状所需产物。1H NMR(400MHz,DMSO-d6):δ10.07(br.s,1H),9.41(s,1H),8.79(s,2H),8.57(s,1H),7.88(dd,J=8.0,0.6Hz,1H),7.53(br.s,1H),7.41(br.s,1H),6.99–6.93(m,1H),6.90(dd,J=8.0,1.4Hz,1H),6.85–6.79(m,1H).13C NMR(101MHz,DMSO-d6):δ168.7,167.2,164.6,149.4,148.4,146.4,144.6,144.5,126.8,124.4,123.0,119.2,116.1.HRMS-ESI(m/z):[M+H]+对于C13H12ON7 +,计算值282.10978;实测值282.10977.HPLC(λ254):98.8%;tR:4.209min(方法4)。
N-(N-(苯并[d]噁唑-2-基)氨基甲酰氨基)吡嗪-2-羧甲酰胺(MTF440)。按照一般程序E,使用1-(苯并[d]噁唑-2-基)胍(500mg,2.8mmol)氢化钠(60%的油悬浮液,123mg,3.08mmol)和3-吡啶甲腈(292mg,2.8mmol)合成,得到亮黄色粉末状标题化合物(510mg,65%)。1H NMR(400MHz,DMSO-d6):δ9.98(s,1H),9.40(d,J=1.4Hz,1H),8.73(dd,J=4.8,1.7Hz,1H),8.54(d,J=8.0Hz,1H),8.34(s,1H),7.93(dd,J=7.9,1.4Hz,1H),7.54(ddd,J=8.0,4.8,0.5Hz,1H),7.32(s,2H),6.98–6.93(m,1H),6.91–6.88(m,1H),6.86–6.80(m,1H).13C NMR(101MHz,DMSO-d6):δ168.8,167.0,164.4,152.1,149.1,148.1,135.2,132.0,126.8,124.1,123.6,122.7,119.1,115.7.HRMS-ESI(m/z):[M+H]+对于C14H13ON6 +,计算值281.11454;实测值281.11450.HPLC(λ254):99.7%;tR:4.165min(方法4)。
N2,N2'-(二硫代二基双(2,1-亚苯基))双(6-(萘-2-基)-1,3,5-三嗪-2,4-二胺)(MTF443)。按照一般程序B,使用N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基)-2-萘啶亚酰胺(345mg,1mmol)合成,得到白色粉末状标题化合物(299mg,87%)。1H NMR(400MHz,DMSO-d6):δ9.30(s,1H),8.87(s,1H),8.36(d,J=8.5Hz,1H),7.99(dd,J=19.5,10.4Hz,3H),7.68(d,J=7.8Hz,1H),7.63–7.53(m,2H),7.48(d,J=7.7Hz,1H),7.29(t,J=7.2Hz,1H),7.25–7.11(m,3H).13C NMR(101MHz,DMSO-d6):δ170.19,167.33,165.53,136.81,134.58,134.17,133.57,132.40,128.98,128.66,128.16,127.74,127.65(2C),127.51,126.55(2C),126.26,124.75.HPLC(λ280):纯度97.3%;tR:15.642min(方法2)。
N2,N2'-(二硫代二基双(2,1-亚苯基))双(6-(2,2-二甲基-2H-铬6-基)-1,3,5-三嗪-2,4-二胺)(MTF444)。按照一般程序B,使用N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基)-2,2-二甲基-2H-色烯-6-羧甲酰胺(377mg,1mmol)合成,得到白色粉末状标题化合物(241mg,64%)。1H NMR(400MHz,DMSO-d6):δ9.10(s,1H),8.00(d,J=8.5Hz,1H),7.95(s,1H),7.61(d,J=9.0Hz,1H),7.41(d,J=7.1Hz,1H),7.27(t,J=7.0Hz,1H),7.16(t,J=7.5Hz,1H),6.99(s,2H),6.81(d,J=8.5Hz,1H),6.45(d,J=9.9Hz,1H),5.80(d,J=9.8Hz,1H),1.40(s,6H).13C NMR(101MHz,DMSO-d6):δ169.67,167.15,165.33,155.42,136.86,133.39,131.25,129.26,129.18,128.51,127.69,126.41,126.16(2C),121.61,120.26,115.65,76.97,27.93(2C).HPLC(λ280):纯度95.2%;tR:15.767min(方法2)。
N2,N2'-(二硫代二基双(2,1-亚苯基))双(6-(3-硝基苯基)-1,3,5-三嗪-2,4-二胺)(MTF445)。按照一般程序B,使用N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基)-3-硝基苯甲酰胺(340mg,1mmol)合成,得到白色粉末状标题化合物(265mg,78%)。1H NMR(400MHz,DMSO-d6):δ9.41(s,1H),9.04(s,1H),8.60(d,J=6.8Hz,1H),8.39(dd,J=8.2,1.4Hz,1H),7.79(t,J=8.0Hz,1H),7.64(dd,J=7.9,0.9Hz,1H),7.39(dd,J=7.8,0.9Hz,1H),7.36–7.17(m,4H).13C NMR(101MHz,DMSO-d6):δ168.16,167.23,165.49,147.97,138.33,136.42,133.75(2C),130.10,128.35,127.72,126.82,126.57,125.93,122.27.HPLC(λ280):纯度95.3%;tR:13.550min(方法2)。
N2,N2'-(二硫代二基双(2,1-亚苯基))双(6-(3,4,5-三甲氧基苯基)-1,3,5-三嗪-2,4-二胺)(MTF446)。按照一般程序B,使用N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基)-3,4,5-三甲氧基苯甲酰胺(385mg,1mmol)合成,得到白色粉末状标题化合物(358mg,93%)。1H NMR(400MHz,DMSO-d6):δ9.24(s,1H),7.59(s,3H),7.40(d,J=7.7Hz,1H),7.27(t,J=7.5Hz,1H),7.12(dd,J=23.2,15.8Hz,3H),3.79(s,6H),3.73(s,3H).13C NMR(101MHz,DMSO-d6):δ169.55,167.26,165.29,152.58(2C),140.36,136.92,133.81,131.90,128.71,127.66,126.37,126.11,105.08(2C),60.11,55.74(2C).HPLC(λ280):纯度96.6%;tR:10.367min(方法2)。
N2,N2'-(二硫代二基双(2,1-亚苯基))双(6-(苯并[d][1,3]二氧杂-5-基)-1,3,5-三嗪-2,4-二胺)(MTF449)。按照一般程序B,使用N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基)苯并[d][1,3]二噁唑-5-羧甲亚胺(340mg,1mmol)合成,得到白色粉末状标题化合物(247mg,73%)。1H NMR(400MHz,DMSO-d6):δ9.14(s,1H),7.87(d,J=8.1Hz,1H),7.68(s,1H),7.61(d,J=7.8Hz,1H),7.39(d,J=7.7Hz,1H),7.27(t,J=7.4Hz,1H),7.17(t,J=7.5Hz,1H),7.08–6.97(m,3H),6.10(s,2H).13C NMR(101MHz,DMSO-d6):δ169.41,167.15,165.34,150.10,147.37,136.77,133.53,130.76,128.41,127.66,126.47,126.21,122.88,107.97,107.44,101.60.HPLC(λ280):纯度95.1%;tR:10.767min(方法2)。
N2,N2'-(二硫代二基双(2,1-亚苯基))双(6-(2-氯苯基)-1,3,5-三嗪-2,4-二胺)(MTF450)。按照一般步骤B使用N-(N-(苯并[d]噻唑-2-基)氨基酰胺基)-2-氯苯甲酰胺(329mg,1mmol)合成,得到白色粉末状标题化合物(273mg,83%)。1H NMR(400MHz,DMSO-d6):δ9.30(s,1H),7.58(dt,J=9.4,4.8Hz,2H),7.51(dd,J=7.8,1.0Hz,1H),7.45(td,J=7.7,2.0Hz,1H),7.41(dd,J=7.4,1.3Hz,1H),7.38(d,J=6.8Hz,1H),7.28–7.22(m,1H),7.22–7.09(m,3H).13C NMR(101MHz,DMSO-d6):δ172.24,166.83,165.19,137.48,136.34,133.55,130.93,130.50,130.47,129.82,128.16,127.59,127.08,126.87,126.52.HPLC(λ280):纯度95.1%;tR:10.517min(方法2)。
N2,N2'-(二硫代二基双(2,1-亚苯基))双(6-(对甲苯基)-1,3,5-三嗪-2,4-二胺)(MTF451)。按照一般程序B,使用N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基)-4-甲基苯甲酰胺(309mg,1mmol)合成,得到白色粉末状标题化合物(179mg,58%)。1H NMR(400MHz,DMSO-d6):δ9.15(s,1H),8.14(d,J=8.0Hz,2H),7.61(d,J=7.9Hz,1H),7.41(d,J=7.1Hz,1H),7.26(dd,J=8.8,4.7Hz,3H),7.17(t,J=7.5Hz,1H),7.04(s,2H),2.36(s,3H).13C NMR(101MHz,DMSO-d6):δ170.14,167.25,165.46,141.31,136.80,133.90,133.44,128.86(2C),128.52,127.86(2C),127.71,126.51,126.21,21.09.HPLC(λ280):纯度96.7%;tR:12.958min(方法2)。
N2,N2'-(二硫代二基双(2,1-亚苯基))双(6-(2-氟苯基)-1,3,5-三嗪-2,4-二胺)(MTF452)。按照一般程序B,使用N-(N-(苯并[d]噻唑-2-基)氨基酰胺基)-2-氟苯甲酰胺(313mg,1mmol)合成,得到白色粉末状标题化合物(191mg,61%)。1H NMR(400MHz,DMSO-d6):δ9.26(s,1H),7.87(td,J=7.7,1.6Hz,1H),7.59(dd,J=7.9,1.0Hz,1H),7.56–7.49(m,1H),7.39(d,J=7.6Hz,1H),7.30–7.23(m,3H),7.20–7.10(m,3H).13C NMR(101MHz,DMSO-d6):δ169.77(d),166.97,165.31,160.33(d),136.49,133.54,132.19(d),131.13(d),128.26,127.65,126.92,126.46,125.89(d),124.09(d),116.50(d).HPLC(λ280):纯度95.4%;tR:10.333min(方法2)。
N2,N2'-(二硫代二基双(2,1-亚苯基))双(6-(2,6-二氯苯基)-1,3,5-三嗪-2,4-二胺)(MTF455)。按照一般程序B,用N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基)-2,6-二氯苯甲酰胺(364mg,1mmol)合成,得到白色粉末状标题化合物(320mg,88%)。1H NMR(400MHz,DMSO-d6):δ9.44(s,1H),7.55(dd,J=13.4,7.9Hz,3H),7.45(dd,J=9.0,7.1Hz,1H),7.33(d,J=7.7Hz,1H),7.30–7.22(m,3H),7.18(t,J=7.1Hz,1H).13C NMR(101MHz,DMSO-d6):δ170.75,166.93,165.40,136.69,135.98,133.90,132.08(2C),130.63,128.12(2C),127.88,127.50,127.25,126.83.HPLC(λ280):纯度95.8%;tR:10.150min(方法2)。
N2,N2'-(二硫代二基双(2,1-亚苯基))双(6-(3,5-二溴吡啶-4-基)-1,3,5-三嗪-2,4-二胺)(MTF456)。按照一般程序B,使用N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基)-3,5-二溴异烟碱甲酰胺(454mg,1mmol)合成,得到白色粉末状标题化合物(412mg,91%)。1H NMR(400MHz,DMSO-d6):δ9.56(s,1H),8.84(s,2H),7.57(d,J=7.7Hz,1H),7.39(d,J=14.8Hz,2H),7.31(d,J=7.6Hz,1H),7.25(t,J=7.2Hz,1H),7.20(d,J=5.4Hz,1H).13C NMR(101MHz,DMSO-d6):δ170.93,166.78,165.27,150.32(2C),146.43,135.71,133.98,127.70,127.49,127.35,127.02,119.05(2C).HPLC(λ280):纯度95.1%;tR:9.700min(方法2)。
N2,N2'-(二硫代二基双(2,1-亚苯基))双(6-(6-溴苯并[d][1,3]二氧-5-基)-1,3,5-三嗪-2,4-(MTF458)。按照一般程序B,使用N-(N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基)-6-溴苯并[d][1,3]二噁唑-5-羧甲酰胺)(418mg,1mmol)合成,得到白色粉末状标题化合物(300mg,72%)。1H NMR(400MHz,DMSO-d6):δ9.31(s,1H),7.57(d,J=7.6Hz,1H),7.38(d,J=7.3Hz,1H),7.28–7.23(m,2H),7.22–7.11(m,4H),6.12(s,2H).13C NMR(101MHz,DMSO-d6):δ172.43,166.50,165.08,148.68,146.86,136.29,133.50,132.49,128.17,127.63,127.08,126.58,112.81,111.49,109.98,102.31.HPLC(λ280):纯度96.1%;tR:10.475min(方法12)。
N2,N2'-(二硫代二基双(2,1-亚苯基))双(6-(3-氨基苯基)-1,3,5-三嗪-2,4-二胺)(MTF460)。按照一般程序B,使用3-氨基-N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基)苯甲酰胺(310mg,1mmol)合成,得到黄色粉末状标题化合物(241mg,78%)。1H NMR(400MHz,DMSO-d6):δ9.06(s,1H),7.61(dd,J=7.9,1.2Hz,1H),7.49(s,1H),7.43(d,J=7.8Hz,2H),7.27(td,J=7.7,1.3Hz,1H),7.17(t,J=7.6Hz,1H),7.09(t,J=7.8Hz,1H),6.98(s,2H),6.71(dd,J=7.9,1.4Hz,1H),5.18(s,2H).13C NMR(101MHz,DMSO-d6):δ170.95,167.23,165.44,148.52,137.33,136.87,133.20,128.59,128.55,127.72,126.43,126.12,116.94,115.86,113.34.HPLC(λ280):纯度97.8%;tR:7.167min(方法2)。
1,1'-((((二硫代二基双(2,1-亚苯基))双(氮杂二基))双(6-氨基-1,3,5-三嗪-4,2-二基))双(3,1-亚苯基))双(乙烷-1-酮)(MTF462)。按照一般程序B,使用3-乙酰基-N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基)苯甲酰胺(337mg,1mmol)合成,得到白色粉末状标题化合物(225mg,67%)。1H NMR(400MHz,DMSO-d6):δ9.32(s,1H),8.83(s,1H),8.46(d,J=7.4Hz,1H),8.13(d,J=7.8Hz,1H),7.64(t,J=7.1Hz,2H),7.40(d,J=7.1Hz,1H),7.23(dt,J=15.3,8.0Hz,4H),2.61(s,3H).13C NMR(101MHz,DMSO-d6):δ197.57,169.41,167.28,165.49,137.06,136.86,136.62,133.74,132.14,131.24,128.80,128.46,127.69,127.32,126.67,126.40,26.77.HPLC(λ280):纯度96.9%;tR:10.908min(方法2)。
N2,N2'-(二硫代二基双(2,1-亚苯基))双(6-(2-硝基苯基)-1,3,5-三嗪-2,4-二胺)(MTF463)。按照一般程序B,使用N-(N-(苯并[d]噻唑-2-基)氨基甲酰氨基)-2-硝基苯甲酰胺(340mg,1mmol)合成,得到白色粉末状标题化合物(278mg,82%)。1H NMR(400MHz,DMSO-d6):δ9.29(s,1H),7.92(d,J=7.6Hz,1H),7.86(d,J=7.3Hz,1H),7.77(t,J=7.3Hz,1H),7.70(t,J=7.6Hz,1H),7.57(d,J=7.8Hz,1H),7.32(d,J=7.6Hz,1H),7.28–7.07(m,4H).13C NMR(101MHz,DMSO-d6):δ170.32,166.77,165.14,149.12,136.11,133.49,132.58,132.34,130.89,130.51,128.06,127.58,127.11,126.63,123.88.HPLC(λ280):纯度98.9%;tR:10.350min(方法2)。
细胞培养
在Nice CHU医院从诊断为转移性黑色素瘤的患者的手术废料中获得新鲜的无菌组织。表皮细胞悬液从白种人儿童的包皮中获得,方法是:在4℃下于含有0.5%分散酶II级的磷酸盐缓冲盐水中消化过夜,然后在37℃下,在磷酸盐缓冲盐水中用0.05%胰蛋白酶-0.02%EDTA消化20分钟(V/V)。在补充2%FCS、0.4μg/ml氢化可的松、5μg/ml胰岛素、16nMphorbol-12肉豆蔻酸酯13-乙酸酯、1ng/ml碱性成纤维细胞生长因子、10μg/ml牛垂体提取物和青霉素/链霉素(100U/ml/50μg/ml)的MCDB 153培养基中生长人原代黑素细胞。在添加了0.1ng/ml表皮生长因子、15μg/ml牛垂体提取物和青霉素/链霉素(100U/ml/50μg/ml)的KSFM培养基中培养人原代角质形成细胞。在DMEM 7%胎牛血清(FCS)和青霉素/链霉素(100U/ml/50μg/ml)中生长源自相应真皮的人原代成纤维细胞和黑色素瘤细胞。从该研究中包括的每位患者获得书面知情同意书,并且该研究获得医院伦理委员会的批准(NiceHospital Center and University of Nice Sophia Antipolis,no.210-2998)。
从美国组织培养物保藏中心购买了不同的黑色素瘤细胞系:A375和WM9细胞在B-Raf、CDKN2A和PTEN蛋白上突变;SKmel28细胞在B-Raf和P53蛋白上突变;1205Lu细胞在B-Raf和PTEN蛋白上突变;G-361细胞在B-Raf和CDKN2A蛋白上突变;C8161细胞在B-Raf和K-Ras蛋白上突变;WM3912细胞在B-Raf和CDKN2A蛋白上突变;MeWo细胞在P53和CDKN2A蛋白上突变;WM3918在特征蛋白上没有突变。
耐药性黑色素瘤细胞系A375和SKMel28来自P.Marchetti教授的赠送,并在Corazao-Rozas等人(2013)的文章中进行了描述。将细胞在37℃和5%CO2下补充有10%胎牛血清(FCS)和青霉素/链霉素(100U/ml/50mg/ml)的RPMI 1640或DMEM中生长。
台盼蓝排除测定
对于台盼蓝染色,将200mL细胞(黑色素瘤和正常人细胞)无菌转移至1.5mL透明Eppendorf管中,并在室温下用等体积的0.4%台盼蓝溶液温育3分钟。计数活细胞,结果表示为对照细胞值的百分比。所有实验一式三份进行3次。
活力测试
A375敏感细胞用不同浓度的合成分子(5.0μM或10μM)处理不同的时间(24小时或48小时)或用DMSO(对照)处理12或48小时。在刺激结束时,使用台盼蓝染色排除法计数活细胞。将结果标准化为与对照相比的百分比。结果显示在表1中。它们表明式(I)、(II)和(III)的化合物诱导黑色素瘤细胞的活力降低。
CRO15的动力学
A375敏感细胞用5μM CRO15处理不同的时间(2小时、4小时、6小时、8小时、12小时、24小时或48小时)或用5μM PLX4032(B-Raf抑制剂)处理48小时或用DMSO(对照)处理48小时。在刺激结束时,使用台盼蓝染色排除法计数活细胞。将结果标准化为相对于对照的百分数和以三次重复进行的三个独立实验的数据均值±SEM(*SEM);**p<0.01;***p<0.001。结果示于图1A。它们表明,CRO15诱导黑色素瘤细胞活力降低,并且48小时后用CRO15处理的活力降低比用PLX4032处理更明显。
CRO15的IC50
A375敏感性细胞用不同浓度的CRO15(0.5μM、2.5μM、5.0μM、7.5μM、50μM)处理48小时或用5μMPLX4032(B-Raf抑制剂)处理48小时或用DMSO(对照)处理48小时。在刺激结束时,使用台盼蓝染色排除法计数活细胞。将结果标准化为相对于对照的百分数和以三次重复进行的三个独立实验的数据均值±SEM(*SEM);**p<0.01;***p<0.001。CRO15的IC50在48小时测定为3.75μM。结果如图1B所示。它们表明,CRO15对黑色素瘤细胞活力具有剂量反应关系。
使用CRO15进行活力测试
具有各种突变的不同黑色素瘤细胞系、具有各种突变的患者细胞和正常人细胞用5μMCRO15处理48小时或用DMSO(对照)处理。在刺激结束时,使用台盼蓝染色排除法计数活细胞。将结果标准化为相对于对照的百分数和以三次重复进行的三个独立实验的数据均值±SEM(*SEM);**p<0.01;***p<0.001。结果显示在图1C(具有各种突变的黑色素瘤细胞系)和1D(具有各种突变的患者细胞)和1E(正常人类细胞)中。它们表明,CRO15诱导具有各种突变的不同黑色素瘤细胞系和具有各种突变的不同患者细胞的活力降低,而CRO15对正常细胞无毒。
CRO15对耐药性黑色素瘤细胞的活性测试
A375敏感性和耐药性黑色素瘤细胞用5μM CRO15或45μM PLX4032或DMSO(对照)处理48小时。在48小时时,使用台盼蓝染色排除法计数活细胞。将结果标准化为相对于对照的百分数和以三次重复进行的三个独立实验的数据均值±SEM(*SEM);**p<0.01;***p<0.001。结果显示在图4A中。它们表明,CRO15在敏感和耐药性的黑色素瘤细胞中均诱导细胞活力的降低,并且与PLX4032相比,用CRO15处理的活力降低更明显。
CRO15对BRAF和MEK抑制剂双重耐药性细胞的活力测试
对B-Raf抑制剂(威罗非尼=PLX4032)和对MEK抑制剂(Cobimetinib)耐药的黑色素瘤细胞系DR6细胞用DMSO(对照)、用5μM或10μM CRO15或用1μM威罗非尼和0,5μM的Cobimetinib的组合处理。刺激24小时后,使用台盼蓝染色排除法计数活细胞。将结果标准化为与对照相比的百分比。误差条表示一式三份的±SEM。
结果如图5所示。它们表明CRO15诱导了对B-Raf抑制剂(PLX4032)和MEK抑制剂(Cobimetinib)耐药的黑色素瘤细胞系的细胞活力下降。
蛋白质印迹分析
如所述的进行蛋白质印迹分析(Lehraiki et al.,2014)。在含有50mmol/l Tris-HCl(pH 7.5)、15mmol/l、NaCl、1%Triton X-100和1X蛋白酶和磷酸酶抑制剂的缓冲液中提取蛋白质。简言之,通过SDS-PAGE分离细胞裂解物(30mg),转移至聚偏二氟乙烯膜(Millipore)上,然后暴露于适当的抗体。用Amersham的ECL系统可视化蛋白质。所示的蛋白质印迹分析表示至少三个独立的实验。
蛋白质印迹分析:A375敏感细胞用5μM CRO15处理不同的时间(6小时、12小时或24小时)或用DMSO(对照)24小时。
结果显示在图2中。它们显示CRO15诱导AMPK的激活。
体内鼠癌模型
动物实验是根据赫尔辛基宣言进行的,并得到了当地伦理委员会CIEPAL(ComitéInstitutionnel d‘Ethique Pour l’Animal de Laboratoire-Azur)的批准。雌性免疫缺陷的BALB/c nu/nu(裸)小鼠在5周龄时从Envigo实验室((Gannat,France)获得。将裸小鼠皮下接种A375敏感的或耐药性的黑色素瘤细胞(1,0x106个细胞/小鼠)。肿瘤消失后(±5天),将动物腹膜内注射Labrafil(对照)、溶解于Labrafil的PLX4032(0.7mg/小鼠/天)或CRO15(0.7mg/小鼠/天)。通过使用等式V=(L*W2)/2(V=肿瘤体积,W=肿瘤宽度,L=肿瘤长度)测量肿瘤体积来确定生长肿瘤曲线。实验结束时,通过颈脱位法对小鼠实施安乐死,并对肿瘤进行Western印迹和免疫荧光实验(LC3,Cleaved Caspase 3)。使用原位细胞死亡检测试剂盒(Roche,Meylan,法国)进行TUNEL测定。结果显示在图3A和3B(A375敏感黑色素瘤细胞)和4B和4C(A375耐药性黑色素瘤细胞)中。它们表明,CRO15减少接种了敏感和耐药性黑色素瘤细胞的小鼠的肿瘤体积和重量。
异种移植物–A375耐药性细胞(Riv)
体内鼠癌模型动物实验是根据赫尔辛基宣言进行的,并得到当地伦理委员会CIEPAL(Comite Institutionnel d‘Ethique Pour l’Animal de Laboratoire-Azur)的批准。雌性免疫缺陷的BALB/c nu/nu(裸)小鼠在5周龄时从Envigo实验室(Gannat,France)获得。裸小鼠皮下接种A375耐药性黑色素瘤细胞(1,0x106个细胞/小鼠)。肿瘤消失后(±5天),动物接受腹膜内注射Labrafil(对照)、溶解在Labrafil中的PLX4032(0.7毫克/小鼠/天)或MTF319(0.7毫克/小鼠/天)。通过使用等式V=(L*W2)/2测量肿瘤体积来确定生长肿瘤曲线(V=肿瘤体积,W=肿瘤宽度,L=肿瘤长度)。实验结束时,通过颈脱位法对小鼠实施安乐死。
结果显示在图6A和6B中。当给小鼠注射MTF319时,它们显示肿瘤体积的减少。肿瘤重量也表明MTF319对肿瘤生长有影响。
CRO15抑制同种异体移植到C57BL6小鼠的鼠黑色素瘤BP细胞的肿瘤生长
体内鼠癌模型动物实验是根据赫尔辛基宣言进行的,并得到当地伦理委员会CIEPAL(Comite Institutionnel d‘Ethique Pour l’Animal de Laboratoire-Azur)的批准。在5周龄时从Envigo实验室(Gannat,France)获得雌性C57BL6/J小鼠。用BP黑色素瘤细胞(1x106个细胞/小鼠)皮下接种小鼠。肿瘤消失后(±5天),动物接受腹膜内注射Labrafil(载体)或CRO15(0.7mg/小鼠/天)。通过使用等式V=(L*W2)/2测量肿瘤体积来确定生长肿瘤曲线,(V=肿瘤体积,W=肿瘤宽度,L=肿瘤长度)。在实验结束时,通过颈椎错位使小鼠安乐死。
结果显示在图7A中。条形表示平均值±SEM。*p<0.05;**p<0.01。它们显示,与用载体处理的小鼠相比,每天用CRO15处理时,皮下注射小鼠黑色素瘤细胞(BP细胞)的免疫活性小鼠(C57BL/6)没有肿瘤生长。
为了研究黑色素瘤细胞WM9是否会对CRO15产生耐药性,将这些细胞在增加浓度的DMSO(对照)、PLX4032、CRO15或MTF255的存在下培养8周。起始浓度为0.2μM。如图中所观察到的,每2次传代,药物浓度就会略微增加(+0.2μM),直到如图7B所示的当以10μM的强度挑战时,达到对PLX4032的耐药性。
然后,将未经处理的WM9S(未处理的细胞)与经药物处理的WM9S分别用10μM的每种药物刺激48小时。使用台盼蓝染色排除法计数活细胞。将结果标准化为与对照(DMSO)相比的百分比。误差条表示一式三份的±SEM。
结果显示在图7B中。它们表明,PLX处理的WM9对PLX4032产生耐药性,而CRO15仍然能够在CRO15处理的WM9中诱导细胞死亡。
表1
Claims (13)
1.式(I)的化合物
其中,
R1和R2独立地选自H、卤素、C1-C6烷基、C3-C6环烷基、C1-C6卤代烷基、C2-C6烯基、C2-C6炔基、具有5-10个环原子的杂环基、具有6-10个环原子的芳基、具有5-10个环原子的杂芳基和C7-C16芳烷基,所述烷基、环烷基、卤代烷基、烯基、炔基、杂环基、芳基、杂芳基和芳烷基任选地被一个或多个独立地选自氧、卤素、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、-OH、-NR”R”’、-NO2、-CN和-(CO)-R的取代基取代;
或R1和R2与它们之间的碳-碳双键一起形成6-10元的芳基或杂芳基环,所述芳基和杂芳基任选地被一个或多个独立地选自氧、卤素、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、-OH、-NR”R”’、-NO2、-CN和-(CO)-R的取代基取代;
Y是-O-或-S-;
R3选自C1-C6烷基、C3-C6环烷基、C1-C6卤代烷基、C2-C6烯基、C2-C6炔基、具有5-10个环原子的杂环基、具有6-10个环原子的芳基、具有5-10个环原子的杂芳基和C7-C16芳烷基,所述烷基、环烷基、卤代烷基、烯基、炔基、杂环基、芳基、杂芳基和芳烷基任选地被一个或多个独立地选自氧、卤素、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、-OH、-NR”R”’、-NO2、-CN和-(CO)-R的取代基取代;
每个R独立地选自H、C1-C6烷基、C1-C6烷氧基和-NR”R”’;
每个R”和R”’独立地选自H和C1-C6烷基。
2.根据权利要求1所述的式(I)的化合物,其中
R1和R2独立地选自H、C1-C6烷基和具有6-10个环原子的芳基,所述芳基任选地被一个或多个-NO2取代;
或R1和R2与它们之间的碳-碳双键一起形成6元芳基环,其任选地被一个或多个独立地选自卤素、C1-C6烷基和C1-C6烷氧基的取代基取代,
Y是-S-;
R3选自C1-C6卤代烷基、具有5-10个环原子的杂环基、具有6-10个环原子的芳基、具有5-10个环原子的杂芳基、和C7-C16芳烷基,所述杂环基、芳基、杂芳基和芳烷基任选地被一个或多个独立地选自卤素、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、-NO2、-CN和-(CO)-R的取代基取代;
每个R独立地选自C1-C6烷基。
5.式(II)或(III)的化合物
其中
Y’是-SR4或-OR5,
R4选自C1-C6烷基和保护基,所述保护基选自由二硫官能团连接的任何基团、硫酯、烷基、烯基和炔基硫醚、苄基硫醚、烷基芳基甲基硫醚和三芳基甲基硫醚;
R5选自H和保护基,所述保护基选自酯、烯基和炔基醚、甲硅烷基化醚、烷氧基甲基醚、苄基醚、四氢吡喃基醚、戊糖和己糖;
每个R’独立地选自卤素、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、-OH、-NR”R”’、-NO2、-CN和-(CO)-R;
n为0-4;
R3选自C1-C6烷基、C3-C6环烷基、C1-C6卤代烷基、C2-C6烯基、C2-C6炔基、具有5-10个环原子的杂环基、具有6-10个环原子的芳基、具有5-10个环原子的杂芳基和C7-C16芳烷基,所述烷基、环烷基、卤代烷基、烯基、炔基、杂环基、芳基、杂芳基和芳烷基任选地被一个或多个独立地选自氧、卤素、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、-OH、-NR”R”’、-NO2、-CN和-(CO)-R的取代基取代;
每个R独立地选自H、C1-C6烷基、C1-C6烷氧基和-NR”R”’;
每个R”和R”’独立地选自H和C1-C6烷基。
6.根据权利要求5所述的式(II)或(III)的化合物,其中
Y’是-SR4,R4选自C1-C6烷基;
每个R’独立地选自卤素和C1-C6烷氧基;
n为0-1;
R3选自C1-C6卤代烷基、具有6-10个环原子的芳基、具有5-10个环原子的杂芳基和C7-C16芳烷基,所述芳基、杂芳基和芳烷基任选地被一个或多个独立地选自卤素、C1-C6烷氧基和-CN的取代基取代。
9.药物组合物,其包含根据权利要求1-4中任一项所述的式(I)的化合物或根据权利要求5-8中任一项所述的式(II)或(III)的化合物,以及药学上可接受的载体。
10.根据权利要求1-4中任一项所述的式(I)的化合物,或根据权利要求5-8中任一项所述的式(II)或(III)的化合物用作药物的用途。
11.根据权利要求10所述的化合物的用途,其用于治疗癌症的方法。
12.根据权利要求10或11所述的化合物的用途,其用于治疗黑色素瘤的方法。
13.根据权利要求10或11所述的化合物的用途,其用于治疗耐BRAF抑制剂的黑色素瘤的方法。
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