CN110872277B - N-取代芳环-2-氨基嘧啶类化合物及用途 - Google Patents
N-取代芳环-2-氨基嘧啶类化合物及用途 Download PDFInfo
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- CN110872277B CN110872277B CN201911111234.2A CN201911111234A CN110872277B CN 110872277 B CN110872277 B CN 110872277B CN 201911111234 A CN201911111234 A CN 201911111234A CN 110872277 B CN110872277 B CN 110872277B
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Abstract
本发明提供一种N‑取代芳环‑2‑氨基嘧啶类化合物及用途,所述化合物包括光学异构体或其药学上可接受的盐。实验证明,本发明的具有全新骨架的N‑取代芳环‑2‑氨基嘧啶类化合物具有很好的CHK1蛋白抑制活性,化合物对MV4‑11,Z138等血液瘤细胞株有明显的体外增殖抑制作用。同时该类化合物还具有良好的口服效果。进一步的体内药效试验证明该类化合物对人急性髓系白血病MV‑4‑11Ba1b/c小鼠移植瘤具有较好的治疗作用,对肿瘤具有良好的治疗效果。本发明化合物的合成路线设计合理,所需原料易得,反应条件温和,各步产率高,操作简便,适合工业化生产。本发明N‑取代芳环‑2‑氨基嘧啶类化合物具有如下结构通式:
Description
技术领域
本发明涉及药物领域,尤其涉及一种N-取代芳环-2-氨基嘧啶类化合物以及作为细胞周期检查点激酶1(CHK1)抑制剂在制备抗肿瘤药物中的应用。
背景技术
DNA损伤是抗肿瘤治疗的主要机制之一。放射治疗和细胞毒药物通过损伤DNA,进而杀伤肿瘤。但是,近年来越来越多的研究显示,当DNA受到损伤时,细胞周期检查点被激活,造成细胞周期阻滞,从而利于细胞进行DNA损伤修复以保持基因组的完整和稳定,最终降低治疗的敏感性。
当DNA因受到放疗、细胞毒药物等外界刺激而引起一定程度损伤时,可引起G1期,S期或G2/M期细胞周期阻滞,进而修复受损的DNA。其中p53主要负责G1期检查点的调控,细胞周期检查点激酶1(Chk1)主要负责S和G2/M期检查点的调控。在肿瘤细胞中,P53基因缺陷导致其G1检查点缺失,因此大多数肿瘤细胞主要依赖于S和G2/M期查点。当DNA损伤时,抑制Chk1蛋白,清除仅存的S和G2/M期检查点,迫使受到损伤的DNA无法修复,可以直接诱导肿瘤细胞凋亡。由于正常细胞可以依靠p53进行自我修复和保护,因而对Chk1抑制剂相对不敏感,这使得Chk1抑制剂在肿瘤治疗中有很好的靶向肿瘤细胞的选择性。目前已有12个Chk1小分子抑制剂进入临床研究,处于临床II期研究的有LY2606368和CCT-245737,临床I期研究的为GDC-0575、XCCS605B和LY-2880070。
发明内容
本发明的目的是提供一种N-取代芳环-2-氨基嘧啶类化合物,及其光学异构体或其药学上可接受的盐。
可口服的N-取代芳环-2-氨基嘧啶化合物其具有Chk1抑制活性,对肿瘤具有良好的治疗效果。
为实现上述目的,本发明提供的N-取代芳环-2-氨基嘧啶类化合物具有通式I的结构:
及其光学异构体或其药学上可接受的盐,其中;
X选自NH、O;
W选自C、N;
R1选自三氟甲基、三氟甲基吡唑;
n选自0、1、2、3或4;
R2选自无取代或取代的C3-8环烷基、无取代或取代的C5-8杂环烷基,其中杂原子是氮、氧、硫中的至少一种、无取代或取代的C6-10氮杂双环、-L1-NRaRb;
所述的C3-8环烷基,C5-8杂环烷基,C6-10氮杂双环可任选地被一个或多个选自H、氘、卤素原子、氨基、氧代、羟基、C1-4烷基、卤代C1-4烷基、C1-4烷氧基、C3-6环烷基或卤代C3-6环烷基取代;
所述的C2-4烷基可任选地被一个或多个选自H、氘、卤素原子、羟基、氧代、C1-4烷基、卤代C1-4烷基、C1-4烷氧基、C3-6环烷基或卤代C3-6环烷基取代;
m和o分别独立地选自0、1、2或3,k选自1,2,3或4;
Ra和Rb分别独立地选自H、C1-4烷基、卤代C1-4烷基、C3-8环烷基、卤代C3-8环烷基、-L2-Rc;
L2为无取代或取代C2-4烷基,C2-4烷基可任选地被一个或多个选自H、卤素原子,羟基,氨基或C1-4烷基取代;
Rc选自羟基、C1-4烷氧基、吗啉基、哌嗪基、哌啶基、四氢吡咯基、C1-4烷基磺酰基或-C(O)NH2。
在第一方面,本发明提供具有通式II的结构:
及其光学异构体或其药学上可接受的盐,其中;
X选自NH、O;
W选自C、N;
R1选自三氟甲基、三氟甲基吡唑;
n选自0、1、2、3或4;
R2选自无取代或取代的C3-8环烷基、无取代或取代的C5-8杂环烷基,其中杂原子是氮、氧、硫中的至少一种、无取代或取代的C6-10氮杂双环、-L1-NRaRb;
所述的C3-8环烷基,C5-8杂环烷基,C6-10氮杂双环可任选地被一个或多个选自H、氘、卤素原子、氨基、氧代、羟基、C1-4烷基、卤代C1-4烷基、C1-4烷氧基、C3-6环烷基或卤代C3-6环烷基取代;
所述的C2-4烷基可任选地被一个或多个选自H、氘、卤素原子、羟基、氧代、C1-4烷基、卤代C1-4烷基、C1-4烷氧基、C3-6环烷基或卤代C3-6环烷基取代;
m和o分别独立地选自0、1、2或3,k选自1,2,3或4;
Ra和Rb分别独立地选自H、C1-4烷基、卤代C1-4烷基、C3-8环烷基、卤代C3-8环烷基、-L2-Rc;
L2为无取代或取代C2-4烷基,C2-4烷基可任选地被一个或多个选自H、卤素原子,羟基,氨基或C1-4烷基取代;
Rc选自羟基、C1-4烷氧基、吗啉基、哌嗪基、哌啶基、四氢吡咯基、C1-4烷基磺酰基或-C(O)NH2。
更具体地,本发明通式II结构的优选化合物选自:
5-((4-((3-氨基丙基)氨基)-5-(1-(三氟甲基)-1H-吡唑-4-基)嘧啶-2-基)氨基)-2-氰基吡啶,
(R)-5-((4-((吗啉-2-基甲基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶,
5-((4-(((1-甲基哌啶-4-基)甲基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶,
5-((4-((吡咯烷-3-基甲基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶,
5-((4-(吡咯烷-3-基氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶,
5-((4-(3-氨基哌啶-1-基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶,
5-((4-(奎宁环-3-基氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶,
5-((4-((哌啶-2-基甲基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶,
5-((4-((哌啶-3-基甲基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶,
5-((4-((8-氮杂双环[3.2.1]辛-3-基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶,
5-((4-((4-氨基环己基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶,
5-((4-((2-氨基乙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶,
5-((4-((2-(二甲基氨基)乙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶,
5-((4-((3-氨基丙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶,
5-((4-((4-氨基丁基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶,
5-((4-((3-(甲基氨基)丙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶,
5-((4-((3-(二甲基氨基)丙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶,
5-((4-((3-((2-(甲基磺酰基)乙基)氨基)丙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶,
N-(3-((2-((6-氰基吡啶-3-基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)丙基)甲酰胺,
5-((4-((3-((2-羟乙基)氨基)丙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶,
3-((3-((2-((6-氰基吡啶-3-基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)丙基)氨基)丙酰胺,
5-((4-((3-((2-吗啉代乙基)氨基)丙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶,
5-((4-((3-((2-甲氧基乙基)氨基)丙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶,
5-((4-((3-((2,3-二羟基丙基)氨基)丙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶,
5-((4-((3-(环己基氨基)丙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶,
5-((4-((3-(环戊基氨基)丙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶,
5-((4-((3-(环丁基氨基)丙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶,
5-((4-((3-(环丙基氨基)丙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶,
5-((4-((3-(异丙基氨基)丙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶,
5-((4-((3-氨基-3-甲基丁基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶,
5-((4-((3-氨基-2,2-二甲基丙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶,
5-((4-((3-氨基丁基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶,
5-((4-((3-(甲基氨基)丁基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶,
4-((4-((3-氨基丙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯腈,
4-((4-((3-(甲基氨基)丙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯腈,
4-((4-((哌啶-3-基甲基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯腈,
5-((4-(3-氨基丙氧基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶,
(S)-5-((4-(哌啶-3-基氧基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶。
在第二方面,本发明提供具有通式III的结构:
及其光学异构体或其药学上可接受的盐,其中;
X选自NH、O;
W选自C、N;
R1选自三氟甲基;
n选自0、1、2、3或4;
R2选自无取代或取代的C3-8环烷基、无取代或取代的C5-8杂环烷基,其中杂原子是氮、氧、硫中的至少一种、无取代或取代的C6-10氮杂双环、-L1-NRaRb;
所述的C3-8环烷基,C5-8杂环烷基,C6-10氮杂双环可任选地被一个或多个选自H、氘、卤素原子、氨基、氧代、羟基、C1-4烷基、卤代C1-4烷基、C1-4烷氧基、C3-6环烷基或卤代C3-6环烷基取代;
所述的C2-4烷基可任选地被一个或多个选自H、氘、卤素原子、羟基、氧代、C1-4烷基、卤代C1-4烷基、C1-4烷氧基、C3-6环烷基或卤代C3-6环烷基取代;
m和o分别独立地选自0、1、2或3,k选自1,2,3或4;
Ra和Rb分别独立地选自H、C1-4烷基、卤代C1-4烷基、C3-8环烷基、卤代C3-8环烷基、-L2-Rc;
L2为无取代或取代C2-4烷基,C2-4烷基可任选地被一个或多个选自H、卤素原子,羟基,氨基或C1-4烷基取代;
Rc选自羟基、C1-4烷氧基、吗啉基、哌嗪基、哌啶基、四氢吡咯基、C1-4烷基磺酰基或-C(O)NH2。
具体地,本发明通式III结构的优选化合物选自:
5-((4-((3-氨基丙基)氨基)-6-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶,
5-((4-((4-氨基环己基)氨基)-6-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶,
5-((4-(吡咯烷-3-基氨基)-6-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶,
5-((4-((吡咯烷-3-基甲基)氨基)-6-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶,
4-((4-(3-氨基丙氧基)-6-(三氟甲基)嘧啶-2-基)氨基)苯腈,
4-((4-((3-氨基丙基)氨基)-6-(三氟甲基)嘧啶-2-基)氨基)苯腈。
在第三方面,本发明提供的化合物可接受的盐可与无机酸和有机酸形成,例如盐酸盐、氢溴酸盐、硫酸盐、磷酸盐、硝酸盐、乙酸盐、甲酸盐、柠檬酸盐、酒石酸盐、马来酸盐、富马酸盐、扁桃酸盐、草酸盐、琥珀酸盐、苹果酸盐、葡糖酸盐、葡糖醛酸盐、丙二酸盐、甲磺酸盐、丙酸盐、硬脂酸盐和三氟乙酸盐。
在第四方面,本发明提供在第一方面、第二方面和第三方面任一所述的N-取代芳环-2-氨基嘧啶类化合物及其光学异构体或其药学上可接受的盐在制备抗肿瘤药物中的应用,其特征在于,所述肿瘤为白血病、淋巴癌、乳腺癌、肺癌、前列腺癌、结肠癌、直肠癌、肾癌、胰腺癌、成神经细胞瘤、神经胶质瘤、头颈癌、甲状腺癌、卵巢癌、骨髓瘤、胃肠道间质瘤、肝癌、膀胱癌、黑色素癌、子宫颈癌、皮肤癌。所述药物由N-取代芳环-2-氨基嘧啶类化合物及其光学异构体或其药学上可接受的盐与药学上允许的辅料制成。所述药物作为细胞周期检查点激酶1(CHK1)抑制剂,在肿瘤治疗中有很好的靶向肿瘤细胞的选择性。
所述药物可以经口服给药。所述药物单用和/或与其他化疗药物、放射治疗、免疫治疗药物等组合联用。
在第五方面,本发明提供的第一方面、第二方面和第三方面所述化合物的制备方法,通过以下步骤实现:
方法一:
以5-三氟甲基-2,4-二氯嘧啶为起始原料,依次经氨化和脂肪胺取代得5-三氟甲基-嘧啶-2,4-二胺中间体,进而与5-溴-2-氰基吡啶反应,脱保护基得到目标化合物(通式II):
方法二:
以5-溴-2,4-二氯嘧啶为起始原料,依次经脂肪胺取代和氨化,再经Suzuki偶联得5-(1-三氟甲基-1H-吡唑-4-基)-嘧啶-2,4-二胺中间体,进而与5-溴-2-氰基吡啶反应,脱保护基得到目标化合物(通式II):
方法三:
以5-三氟甲基-2,4-二氯嘧啶为起始原料,依次经氨化和脂肪醇取代得5-三氟甲基-嘧啶-2,4-二胺中间体,进而与5-溴-2-氰基吡啶反应,脱保护基得到目标化合物(通式II):
方法四:
以5-三氟甲基-2,4-二氯嘧啶为起始原料,依次经氨化和脂肪胺取代得5-三氟甲基-嘧啶-2,4-二胺中间体,进而与4-溴-苯腈反应,脱保护基得到目标化合物(通式II):
方法五:
以2-氨基-4-氯-6-三氟甲基嘧啶为起始原料,经与脂肪胺取代得6-三氟甲基-嘧啶-2,4-二胺中间体,进而与5-溴-2-氰基吡啶反应,脱保护基得到目标化合物(通式III):
方法六:
以2-氨基-4-氯-6-三氟甲基嘧啶为起始原料,经与脂肪胺取代得6-三氟甲基-嘧啶-2,4-二胺中间体,进而与4-溴-苯腈反应,脱保护基得到目标化合物(通式III):
方法七:
将1.2当量的无机酸或有机酸溶于乙醇溶液中,缓慢滴加到化合物的乙醇溶液中,加入适量的乙醚溶液,抽滤得到成盐化合物,用乙醚洗涤,干燥即得。
实验证明,本发明的具有全新骨架的N-取代芳环-2-氨基嘧啶类化合物具有很好的CHK1蛋白抑制活性,化合物对MV4-11,Z138等血液瘤细胞株有明显的体外增殖抑制作用。同时该类化合物还具有良好的口服效果。进一步的体内药效试验证明该类化合物对人急性髓系白血病MV-4-11Ba1b/c小鼠移植瘤具有较好的治疗作用。本发明化合物的合成路线设计合理,所需原料易得,反应条件温和,各步产率高,操作简便,适合工业化生产。
附图说明
图1是化合物的药代动力学结果。
图2是化合物对人急性髓系白血病MV-4-11Ba1b/c小鼠移植瘤的治疗作用。
具体实施方式
本发明结合附图和实施例作进一步的说明。
制备实施例1 5-((4-((哌啶-2-基甲基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物1)合成
步骤1. 5-三氟甲基-4氯-2-氨基嘧啶(中间体1-2)合成
将2,4-二氯-5-三氟甲基嘧啶(5.2g,24.07mmol)溶于氨气饱和的乙醇(25ml)中,室温搅拌2h,减压回收溶剂得残余物,用硅胶柱层析纯化,以PE:EA(5:1)为洗脱剂,得白色固体1-2(2.3g,11.67mmol),收率:48.5%。1H NMR(500MHz,CDCl3)δ8.57(s,1H),7.98(s,2H)。ESI-MS:m/z=198[M+H]+。
步骤2.N4-(N-叔丁氧羰基哌啶-2-基甲基)-5-(三氟甲基)嘧啶-2,4-二胺(中间体1-3)合成
冰浴条件下,取中间体1-2(197.0mg,1.0mmol),1-Boc-2-氨甲基哌啶(256.8mg,1.2mmol),溶于甲醇(8.0ml),回流搅拌过夜。减压回收溶剂得残余物,用硅胶柱层析纯化,以PE:EA(5:1)-(2:1)为洗脱剂,得白色固体1-3(252.7mg,0.7mmol),收率:70%。1H NMR(500MHz,CDCl3)δ8.05(s,1H),5.82(s,1H),5.18(s,2H),4.65–4.42(m,1H),4.05-3.96(m,1H),3.92-3.74(m,1H),3.39(t,J=12.5Hz,1H),2.86(t,J=12.5Hz,1H),1.77–1.61(m,4H),1.62-1.52(m,1H),1.50-1.46(m,1H),1.44(s,9H).ESI-MS:m/z=376[M+H]+。
步骤3.5-((4-((哌啶-2-基甲基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物1)合成
氮气保护下,向中间体1-3(262.5mg,0.7mmol),5-溴-2-氰基吡啶(153.0mg,0.84mmol),四三苯基膦钯(40mg,0.035mmol),4,5-双二苯基膦-9,9-二甲基氧杂蒽(40mg,0.07mmol),碳酸铯(342.1mg,1.05mmol)的混合物加入无水二氧六环(8ml),回流搅拌5h,抽滤,减压回收溶剂得残余物,用硅胶柱层析纯化,以PE:EA(4:1)为洗脱剂,得白色固体。用盐酸饱和的乙酸乙酯脱保护基得白色固体化合物1。收率:64%。1H NMR(500MHz,DMSO)δ10.35(s,1H),9.02(s,1H),8.45(d,J=7.0Hz,1H),8.29(s,1H),7.93(d,J=8.0Hz,1H),7.20(s,1H),3.46-3.36(m,2H),3.01-2.92(m,1H),2.80-2.73(m,1H),2.50-2.44(m,1H),1.70-1.68(m,1H),1.62-1.56(m,1H),1.50-1.45(m,1H),1.30-1.25(m,2H),1.10-1.07(m,1H).ESI-MS:m/z=378[M+H]+。
制备实施例2 5-((4-((哌啶-3-基甲基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物2)
步骤1.N4-(N-叔丁氧羰基哌啶-3-基甲基)-5-(三氟甲基)嘧啶-2,4-二胺(中间体1-4)合成
合成步骤参考实施例1步骤2。用1-Boc-3-氨甲基哌啶替换1-Boc-2-氨甲基哌啶合成中间体1-4。收率:70%。1H NMR(500MHz,CDCl3)δ8.08(s,1H),5.44(s,1H),5.10(s,2H),3.85(m,2H),3.40(m,2H),3.01(m,1H),2.88–2.73(m,1H),1.91–1.81(m,2H),1.77(m,2H),1.68
(m,1H),1.47(s,9H).ESI-MS:m/z=376[M+H]+。
步骤2. 5-((4-((哌啶-3-基甲基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物2)合成
合成步骤参考实施例1步骤3合成化合物2。收率:65%。1H NMR(500MHz,DMSO)δ10.30(s,1H),9.07(d,J=2.5Hz,1H),8.42(dd,J=9.0,2.5Hz,1H),8.29(s,1H),7.94(d,J=
9.0Hz,1H),7.51(s,1H),3.33(d,J=5.0Hz,2H),2.88(d,J=9.0Hz,1H),2.78(d,J=9.0Hz,1H),2.47–2.37(m,1H),2.28-2.21(m,1H),1.89–1.71(m,2H),1.62-1.54(m,1H),1.31–1.22(m,1H),1.15–1.05(m,1H).ESI-MS:m/z=378[M+H]+。
制备实施例3(R)-5-((4-((吗啉-2-基甲基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物3)
步骤1.(R)-N4-(N-叔丁氧羰基吗啉-2-基甲基)-5-(三氟甲基)嘧啶-2,4-二胺(中间体1-5)合成
合成步骤参考实施例1步骤2。用(S)-4-N-Boc-2-氨甲基吗啉替换1-Boc-2-氨甲基哌啶合成中间体1-5。收率:65%。1H NMR(500MHz,CDCl3)δ8.09(s,1H),5.50(s,1H),5.10(s,2H),4.13–3.67(m,4H),3.66–3.49(m,2H),3.47–3.37(m,1H),2.96(s,1H),2.69(s,1H),1.49(s,9H).ESI-MS:m/z=378[M+H]+。
步骤2.(R)-5-((4-((吗啉-2-基甲基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物3)合成
合成步骤参考实施例1步骤3合成化合物3。收率:70%。1H NMR(500MHz,DMSO)δ10.35(s,1H),9.04(d,J=2.0Hz,1H),8.50–8.42(m,1H),8.31(s,1H),7.92(d,J=9.0Hz,1H),7.32(t,J=5.0Hz,1H),3.75(d,J=11Hz,1H),3.68–3.60(m,1H),3.56-3.49(m,1H),3.46–
3.36(m,2H),2.80(dd,J=12.0,2.0Hz,1H),2.69–2.57(m,2H),2.40(dd,J=12.0,10.0Hz,1H).ESI-MS:m/z=380[M+H]+。
制备实施例4 5-((4-(((1-甲基哌啶-4-基)甲基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物4)
步骤1.N4-((1-甲基哌啶-4-基)甲基)-5-(三氟甲基)嘧啶-2,4-二胺(中间体1-4)(中间体1-6)合成
合成步骤参考实施例1步骤2。用4-(氨甲基)-1-甲基哌啶替换1-Boc-2-氨甲基哌啶合成中间体1-6。收率:65%。1H NMR(500MHz,CDCl3)δ8.04(s,1H),5.32(s,2H),5.21(s,1H),3.41(t,J=12.0Hz,2H),3.16(t,J=12.0Hz,2H),2.50(s,3H),2.35–2.24(m,2H),1.81(d,J=13.0Hz,2H),1.77–1.69(m,1H),1.66-1.58(m,2H).ESI-MS:m/z=290[M+H]+。
步骤2. 5-((4-(((1-甲基哌啶-4-基)甲基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物4)合成
合成步骤参考实施例1步骤3合成化合物4。收率:80%。1H NMR(500MHz,DMSO)δ10.32(s,1H),9.04(d,J=27.0Hz,1H),8.38(d,J=8.0Hz,1H),8.28(s,1H),7.94(d,J=8.5Hz,1H),7.48(s,1H),2.78-2.68(m,2H),2.56-2.50(m,2H),2.10(s,3H),1.82-1.71(m,2H),1.70-1.66(m,1H),1.65-1.56(m,2H),1.28-1.15(m,2H).ESI-MS:m/z=392[M+H]+。
制备实施例5 5-((4-(吡咯烷-3-基氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物5)
步骤1.N4-(N-叔丁氧羰基吡咯烷-3-基)-5-(三氟甲基)嘧啶-2,4-二胺(中间体1-7)合成
合成步骤参考实施例1步骤2。用N-Boc-3-氨基吡咯烷替换1-Boc-2-氨甲基哌啶合成中间体1-7。收率:70%。1H NMR(500MHz,CDCl3)δ8.08(s,1H),5.33(s,2H),5.04(s,1H),4.66(dd,J=39.0,5.5Hz,1H),3.86–3.68(m,1H),3.54-3.48(m,1H),3.46-3.38(m,1H),3.32–3.09(m,1H),2.28-2.20(m,1H),1.97–1.80(m,1H),1.48(s,9H).ESI-MS:m/z=348[M+H]+。
步骤2. 5-((4-(吡咯烷-3-基氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物5)合成
合成步骤参考实施例1步骤3合成化合物5。收率:40%。1H NMR(500MHz,DMSO)δ10.23(s,1H),9.05(d,J=2.0Hz,1H),8.40(dd,J=8.5,2.5Hz,1H),8.31(s,1H),7.95(d,J=8.5Hz,2H),6.88(s,1H),4.66-4.58(m,1H),3.10-2.95(m,2H),2.87-2.73(m,2H),2.18–2.06(m,1H),1.82-1.72(m,1H).ESI-MS:m/z=350[M+H]+。
制备实施例6 5-((4-((吡咯烷-3-基甲基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物6)
步骤1.N4-(N-叔丁氧羰基吡咯烷-3-基甲基)-5-(三氟甲基)嘧啶-2,4-二胺(中间体1-8)合成
合成步骤参考实施例1步骤2。用1-Boc-3-氨甲基吡咯烷替换1-Boc-2-氨甲基哌啶合成中间体1-8。收率:95%。1H NMR(500MHz,CDCl3)δ8.08(s,1H),5.22(s,3H),3.56–3.50(m,2H),3.47(m,1H),3.41–3.28(m,1H),3.20–3.00(m,1H),2.58-2.48(m,1H),2.26(s,1H),2.10-2.00(m,1H),1.73–1.61(m,1H),1.48(s,9H).ESI-MS:m/z=362[M+H]+。
步骤2. 5-((4-((吡咯烷-3-基甲基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物6)合成
合成步骤参考实施例1步骤3合成化合物6。收率:50%。1H NMR(500MHz,DMSO)δ10.08(s,1H),9.06(d,J=2.0Hz,1H),8.42(dd,J=8.5,2.5Hz,1H),8.29(s,1H),7.95(d,J=8.5Hz,1H),7.63(s,1H),3.38–3.31(m,2H),2.88–2.81(m,1H),2.78(dd,J=10.5,7.0Hz,1H),2.74–2.66(m,1H),2.63–2.55(m,1H),2.50-2.42(m,1H),1.83–1.70(m,1H),1.46-1.38(m,1H).ESI-MS:m/z=364[M+H]+。
制备实施例7 5-((4-(3-氨基哌啶-1-基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物7)
步骤1.4-(3-N-叔丁氧羰基氨基哌啶-1-基)-5-(三氟甲基)嘧啶-2-胺(中间体1-9)合成
合成步骤参考实施例1步骤2。用3-Boc-氨基哌啶替换1-Boc-2-氨甲基哌啶合成中间体1-9。收率:80%。1H NMR(500MHz,CDCl3)δ8.23(s,1H),5.61(s,2H),4.96(s,1H),3.86(d,J=11.5Hz,1H),3.78(d,J=11.5Hz,1H),3.66-3.58(m,1H),3.46-3.38(m,2H),1.86–1.75(m,2H),1.67(s,2H),1.47(s,9H).ESI-MS:m/z=362[M+H]+。
步骤2. 5-((4-(3-氨基哌啶-1-基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物7)合成
合成步骤参考实施例1步骤3合成化合物7。收率:58%。1H NMR(500MHz,DMSO)δ10.66(s,1H),9.03(d,J=2.5Hz,1H),8.55(s,1H),8.43(d,J=8.5Hz,1H),8.00(d,J=8.5Hz,1H),4.02(d,J=13.5Hz,1H),3.78(d,J=13.5Hz,1H),3.22-3.12(m,1H),2.10-1.94(m,1H),1.88-1.76(m,1H),1.63-1.52(m,2H),1.30-1.18(m,2H).ESI-MS:m/z=364[M+H]+。
制备实施例8 5-((4-(奎宁环-3-基氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物8)
步骤1.N4-(奎宁环-3-基)-5-(三氟甲基)嘧啶-2,4-二胺(中间体1-10)合成
合成步骤参考实施例1步骤2。用奎宁-3-氨基替换1-Boc-2-氨甲基哌啶合成中间体1-10。收率:60%。1H NMR(500MHz,DMSO)δ8.01(s,1H),6.78(s,2H),5.92(d,J=6.5Hz,1H),4.18-4.10(m,1H),3.18-3.10m,1H),2.92–2.80(m,1H),2.75-2.68(m,2H),2.68-2.63(m,2H),2.01-1.92(m,1H),1.69–1.61(m,1H),1.68-1.54(m,2H),1.38-1.32(m,1H).ESI-MS:m/z=288[M+H]+。
步骤2.5-((4-(奎宁环-3-基氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物8)合成
合成步骤参考实施例1步骤3合成化合物8。收率:78%。1H NMR(500MHz,MeOD)δ9.00(d,J=2.0Hz,1H),8.39(dd,J=8.5,2.5Hz,1H),8.24(d,J=0.5Hz,1H),7.75(dd,J=8.5,0.5Hz,1H),4.35–4.28(m,1H),3.42–3.35(m,2H),2.99–2.79(m,4H),2.16(dd,J=6.0,3.0Hz,1H),1.86–1.82(m,2H),1.81–1.76(m,1H),1.63–1.51(m,1H).ESI-MS:m/z=390[M+H]+。
制备实施例9 5-((4-(((1R,4R)-4-氨基环己基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物9)
步骤1.N4-((1R,4R)4-N-叔丁氧羰基氨基环己基)-5-(三氟甲基)嘧啶-2,4-二胺(中间体1-11)合成
合成步骤参考实施例1步骤2。收率:60%。1H NMR(500MHz,CDCl3)δ8.04(s,1H),5.03(s,2H),4.82(s,1H),4.39(s,1H),4.04-3.90(m,1H),3.52-3.34(m,1H),2.17–2.01(m,4H),1.45(s,9H),1.36–1.18(m,4H).ESI-MS:m/z=376[M+H]+。
步骤2. 5-((4-(((1R,4R)-4-氨基环己基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物9)合成
合成步骤参考实施例1步骤3合成化合物9。收率:78%。1H NMR(500MHz,DMSO)δ9.05(d,J=2.0Hz,1H),8.39(dd,J=8.5,2.5Hz,1H),8.29(s,1H),7.95(d,J=8.5Hz,1H),6.67(d,J=7.5Hz,1H),4.08–3.98(m,1H),2.59-2.50(m,1H),1.88-1.76(m,4H),1.59–1.47(m,2H),1.22–1.11(m,2H).ESI-MS:m/z=378[M+H]+。ESI-MS:m/z=390[M+H]+。
制备实施例10 5-((4-(((1S,4S)-4-氨基环己基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物10)
步骤1.N4-((1S,4S)4-N-叔丁氧羰基氨基环己基)-5-(三氟甲基)嘧啶-2,4-二胺(中间体1-12)合成
合成步骤参考实施例1步骤2。收率:76%。1H NMR(500MHz,CDCl3)δ8.04(s,1H),5.03(s,2H),4.82(s,1H),4.39(s,1H),4.00-3.92(m,1H),3.48-3.38(m,1H),2.17–2.01(m,4H),1.45(s,9H),1.36–1.18(m,4H).ESI-MS:m/z=376[M+H]+。
步骤2. 5-((4-(((1S,4S)-4-氨基环己基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶合成
合成步骤参考实施例1步骤3合成化合物10。收率:66%。ESI-MS:m/z=378[M+H]+。
制备实施例11 5-((4-((2-氨基乙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物11)
步骤1.N4-(2-N-叔丁氧羰基氨基乙基)-5-(三氟甲基)嘧啶-2,4-二胺(中间体1-13)合成
合成步骤参考实施例1步骤2。收率:73%。1H NMR(500MHz,CDCl3)δ8.05(s,1H),5.77(s,1H),5.10(s,2H),4.96(s,1H),3.55(dd,J=11.0,5.5Hz,2H),3.44–3.28(m,2H),1.44(s,9H).ESI-MS:m/z=322[M+H]+。
步骤2. 5-((4-((2-氨基乙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物11)合成
合成步骤参考实施例1步骤3合成化合物11。收率:54%。1H NMR(500MHz,DMSO)δ9.04(d,J=2.0Hz,1H),8.45(dd,J=9.0,2.5Hz,1H),8.31(s,1H),7.96(dd,J=13.5,9.0Hz,1H),3.46(t,J=6.5Hz,2H),2.78(t,J=6.5Hz,2H).ESI-MS:m/z=324[M+H]+。
制备实施例12 5-((4-((2-(二甲基氨基)乙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物12)
步骤1.N4-(2-(二甲基氨基)乙基)-5-(三氟甲基)嘧啶-2,4-二胺(中间体1-14)合成
合成步骤参考实施例1步骤2。收率:64%。1H NMR(500MHz,CDCl3)δ8.06(s,1H),5.93(s,1H),5.18(s,2H),3.61–3.37(m,2H),2.54(t,J=6.1Hz,2H),2.30(s,6H).ESI-MS:m/z=250[M+H]+。
步骤2. 5-((4-((2-(二甲基氨基)乙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物12)合成
合成步骤参考实施例1步骤3合成化合物12。收率:70%。1H NMR(500MHz,DMSO)δ10.34(s,1H),9.06(d,J=2.0Hz,1H),8.43(dd,J=8.5,2.5Hz,1H),8.31(s,1H),7.92(d,J=8.5Hz,1H),7.14(t,J=5.0Hz,1H),3.56(dd,J=12.5,6.5Hz,2H),2.48(t,J=7.0Hz,2H),2.20(s,6H).ESI-MS:m/z=352[M+H]+。
制备实施例13 5-((4-((3-氨基丙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物13)
步骤1.N4-(3-N-叔丁氧羰基氨基丙基)-5-(三氟甲基)嘧啶-2,4-二胺(中间体1-15)合成
合成步骤参考实施例1步骤2。收率:59%。1H NMR(500MHz,CDCl3)δ8.01(s,1H),5.61(s,1H),5.28(s,1H),5.09(s,2H),3.50(t,J=6.5Hz,2H),3.15(t,J=6.5Hz,2H),1.71–1.68(m,2H),1.41(s,9H).ESI-MS:m/z=336[M+H]+。
步骤2. 5-((4-((3-氨基丙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物13)合成
合成步骤参考实施例1步骤3合成化合物13。收率:68%。1H NMR(500MHz,DMSO)δ9.06(d,J=2.0Hz,1H),8.44(dd,J=9.0,2.5Hz,1H),8.27(s,1H),7.93(dd,J=9.0,0.5Hz,1H),3.54(t,J=6.5Hz,2H),2.65(t,J=6.5Hz,2H),1.67(p,J=6.5Hz,2H).ESI-MS:m/z=338[M+H]+。
制备实施例14 5-((4-((4-氨基丁基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物14)
步骤1.N4-(4-N-叔丁氧羰基氨基丁基)-5-(三氟甲基)嘧啶-2,4-二胺(中间体1-16)合成
合成步骤参考实施例1步骤2。收率:60%。1H NMR(500MHz,CDCl3)δ8.02(s,1H),5.57(s,2H),5.18(s,1H),5.07(s,1H),3.47(dd,J=12.0,5.5Hz,2H),3.19(dd,J=12.5,6.0Hz,2H),1.70–1.59(m,2H),1.58-1.46(m,2H),1.44(s,9H).ESI-MS:m/z=350[M+H]+。
步骤2. 5-((4-((4-氨基丁基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物14)合成
合成步骤参考实施例1步骤3合成化合物14。收率:64%。1H NMR(500MHz,DMSO)δ9.03(s,1H),8.42(dd,J=9.0,2.0Hz,1H),8.28(s,1H),7.95(d,J=9.0Hz,1H),3.46(t,J=7.0Hz,2H),2.58-2.48(m,2H),1.68-1.56(m,2H),1.47–1.36(m,2H).ESI-MS:m/z=352[M+H]+。
制备实施例15 5-((4-((3-(甲基氨基)丙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物15)
步骤1.N4-(3-(N-叔丁氧羰基甲基氨基)丙基)-5-(三氟甲基)嘧啶-2,4-二胺(中间体1-17)合成
合成步骤参考实施例1步骤2。收率:63%。1H NMR(500MHz,CDCl3)δ8.05(s,1H),6.39(s,1H),5.19(s,2H),3.50(t,J=7.0Hz,2H),3.38-2.29(m,2H),2.87(s,3H),1.80-1.72(m,2H),1.48(s,9H).ESI-MS:m/z=350[M+H]+。
步骤2. 5-((4-((3-(甲基氨基)丙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物15)合成
合成步骤参考实施例1步骤3合成化合物15。收率:65%。1H NMR(400MHz,DMSO)δ9.08(s,1H),8.45(d,J=8.0Hz,1H),8.30(s,1H),7.95(d,J=8.0Hz,1H),3.55(t,J=15.0Hz,2H),2.59(t,J=15.0Hz,2H),2.28(s,3H),1.84-1.66(m,2H).ESI-MS:m/z=352[M+H]+。
制备实施例16 5-((4-((3-(二甲基氨基)丙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物16)
步骤1.N4-(3-(二甲基氨基)丙基)-5-(三氟甲基)嘧啶-2,4-二胺(中间体1-18)合成
合成步骤参考实施例1步骤2。收率:53%。1H NMR(500MHz,CDCl3)δ8.04(s,1H),7.52(s,1H),5.12(s,2H),3.62-3.48(m,2H),2.60–2.53(m,2H),2.34(s,6H),1.84–1.77(m,2H).ESI-MS:m/z=264[M+H]+。
步骤2. 5-((4-((3-(二甲基氨基)丙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物16)合成
合成步骤参考实施例1步骤3合成化合物16。收率:50%。1H NMR(500MHz,DMSO)δ10.34(s,1H),9.07(d,J=2.5Hz,1H),8.42(dd,J=9.0,2.5Hz,1H),8.29(s,1H),8.20(s,1H),7.95(d,J=9.0Hz,1H),3.53(t,J=6.5Hz,2H),2.38(t,J=6.5Hz,2H),2.16(s,6H),1.78-1.70(m,2H).ESI-MS:m/z=366[M+H]+。
制备实施例17 5-((4-((3-((2-(甲基磺酰基)乙基)氨基)丙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物17)
步骤1.5-((4-((3-((2-(甲基磺酰基)乙基)氨基)丙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物17)合成
将化合物13(250.0mg,0.67mmol),1-氯-2-(甲基磺酰基)乙烷(142.0mg,1.0mmol),碳酸钾(138mg,1.0mmol),溶于N,N-二甲基甲酰胺溶液1mL,室温下反应36h,加入水(10mL),二氯甲烷(10mL×3)萃取,合并有机相,用饱和氯化钠(10mL)洗涤,无水硫酸钠干燥,过滤,减压回收溶剂得残余物。用硅胶柱层析纯化,以CH2Cl2:NH3/EtOH(30:1)为洗脱剂,得白色化合物17。收率:50%。1H NMR(500MHz,DMSO)δ10.32(s,1H),9.07(d,J=2.5Hz,1H),8.40(dd,J=8.5,2.5Hz,1H),8.30(s,1H),7.95(d,J=8.5Hz,1H),7.56(s,1H),3.54(t,J=6.5Hz,2H),3.36(t,J=7.0Hz,2H),3.11(t,J=6.5Hz,2H),3.04(s,3H),2.78(t,J=6.5Hz,2H),1.90-1.82(m,2H).ESI-MS:m/z=444[M+H]+。
制备实施例18N-(3-((2-((6-氰基吡啶-3-基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)丙基)甲酰胺(化合物18)
步骤1.N-(3-((2-((6-氰基吡啶-3-基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)丙基)甲酰胺(化合物18)合成
在冰浴情况下,将化合物13(150.0mg,0.45mmol),甲酸(65.0mg,1.42mmol),乙酸酐(118mg,1.16mmol),溶于无水四氢呋喃(20mL),60℃反应2h,冷却至室温,加入1N NaOH溶液,室温下搅拌1小时,加入二氯甲烷(10mL×3)萃取,合并有机相,用饱和氯化钠(10mL)洗涤,无水硫酸钠干燥,过滤,减压回收溶剂得残余物。用硅胶柱层析纯化,以CH2Cl2:NH3/EtOH(40:1)为洗脱剂,得白色化合物18。收率:80%。1H NMR(500MHz,DMSO)δ10.30(s,1H),9.02(d,J=2.5Hz,1H),8.42(dd,J=5.0,3.5Hz,1H),8.29(s,1H),8.04(s,1H),8.02(s,1H),7.95(d,J=8.5Hz,1H),7.38(t,J=5.5Hz,1H),3.56-3.48(m,2H),3.20–3.11(m,2H),1.78–1.68(m,2H).ESI-MS:m/z=366[M+H]+。
制备实施例19 5-((4-((3-((2-羟乙基)氨基)丙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物19)
步骤1. 5-((4-((3-((2-羟乙基)氨基)丙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物19)合成
将化合物13(200.0mg,0.59mmol),(2-溴乙氧基)-叔丁基二甲基硅烷(169.0mg,0.71mmol),碳酸钾(161.0mg,1.18mmol),溶于N,N-二甲基甲酰胺溶液(3mL),室温下反应24h,加入水(20mL),二氯甲烷(20mL×3)萃取,合并有机相,用饱和氯化钠(10mL)洗涤,无水硫酸钠干燥,过滤,减压回收溶剂得残余物。将得到的粗产品,溶于THF溶液(3mL),滴加四丁基氟化铵(1mL),室温下搅拌1小时,加入水(10mL)二氯甲烷(10mL×3)萃取,合并有机相,用饱和氯化钠(10mL)洗涤,无水硫酸钠干燥,过滤,减压回收溶剂得残余物。用硅胶柱层析纯化,以CH2Cl2:NH3/EtOH(20:1)为洗脱剂,得白色化合物19。收率:40%。1H NMR(500MHz,DMSO)δ9.05(d,J=2.5Hz,1H),8.43(dd,J=8.5,2.5Hz,1H),8.27(s,1H),7.92(d,J=8.5Hz,1H),3.53(t,J=6.5Hz,2H),3.46(t,J=6.0Hz,2H),2.64(t,J=6.0Hz,2H),2.57(t,J=6.0Hz,2H),1.79–1.67(m,2H).ESI-MS:m/z=382[M+H]+。
制备实施例20 3-((3-((2-((6-氰基吡啶-3-基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)丙基)氨基)丙酰胺(化合物20)
步骤1.3-((3-((2-((6-氰基吡啶-3-基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)丙基)氨基)丙酰胺(化合物20)合成
将化合物13(150.0mg,0.45mmol),丙烯酰胺(35.0mg,0.49mmol),三乙胺(90.0mg,0.89mmol),溶于甲苯溶液(5mL),室温下反应72h,减压回收溶剂得残余物,用硅胶柱层析纯化,以CH2Cl2:NH3/EtOH(20:1)为洗脱剂,得白色化合物20。收率:80%。1H NMR(500MHz,DMSO)δ10.29(s,1H),9.05(d,J=2.5Hz,1H),8.43(dd,J=9.0,2.5Hz,1H),8.28(s,1H),7.94(d,J=9.0Hz,1H),7.36(s,1H),6.77(s,1H),3.52(t,J=6.5Hz,2H),2.68(t,J=7.0Hz,2H),2.60(t,J=6.0Hz,2H),2.21(t,J=7.0Hz,2H),1.78–1.68(m,2H).ESI-MS:m/z=409[M+H]+。
制备实施例21 5-((4-((3-((2-吗啉代乙基)氨基)丙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物21)
步骤1. 5-((4-((3-((2-吗啉代乙基)氨基)丙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物21)合成
将化合物13(220.0mg,0.65mmol),4-(2-氯乙基)吗啉(241.8mg,1.3mmol),碳酸钾(285.0mg,2.08mmol),溶于N,N-二甲基甲酰胺(2mL),室温下反应36h,加入水(20mL)二氯甲烷(20mL×3)萃取,合并有机相,用饱和氯化钠(10mL)洗涤,无水硫酸钠干燥,过滤,减压回收溶剂得残余物。用硅胶柱层析纯化,以CH2Cl2:NH3/EtOH(20:1)为洗脱剂,得白色化合物21。收率:40%。1H NMR(500MHz,DMSO)δ10.31(s,1H),9.05(d,J=2.0Hz,1H),8.40(dd,J=8.5,2.5Hz,1H),8.30(s,1H),7.95(d,J=8.5Hz,1H),7.52(s,1H),3.80-3.60(m,4H),3.51(t,J=6.5Hz,2H),2.90-2.74(m,4H),2.70–2.50(m,6H),1.94-1.84(m,2H).ESI-MS:m/z=451[M+H]+。
制备实施例22 5-((4-((3-((2-甲氧基乙基)氨基)丙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物22)
步骤1. 5-((4-((3-((2-甲氧基乙基)氨基)丙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物22)合成
将化合物13(200.0mg,0.53mmol),2-氯乙基甲基醚(60mg,0.64mmol),碳酸钾(88.0mg,0.64mmol),溶于N,N-二甲基甲酰胺(3mL),室温下反应36h,加入水(20mL)二氯甲烷(20mL×3)萃取,合并有机相,用饱和氯化钠(10mL)洗涤,无水硫酸钠干燥,过滤,减压回收溶剂得残余物。用硅胶柱层析纯化,以CH2Cl2:NH3/EtOH(20:1)为洗脱剂,得白色化合物22。收率:45%。1H NMR(500MHz,DMSO)δ10.28(s,1H),9.05(d,J=2.5Hz,1H),8.42(dd,J=8.5,2.5Hz,1H),8.28(s,1H),7.93(d,J=8.5Hz,1H),7.84(s,1H),3.53(t,J=6.5Hz,2H),3.38(t,J=5.5Hz,2H),3.23(s,3H),2.69–2.60(m,4H),1.73(p,J=6.5Hz,2H).ESI-MS:m/z=396[M+H]+。
制备实施例23 5-((4-((3-((2,3-二羟基丙基)氨基)丙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物23)
步骤1. 5-((4-((3-((2,3-二羟基丙基)氨基)丙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物23)合成
将化合物13(100mg,0.27mmol),环氧丙醇(20mg,0.27mmol),溶于异丙醇,油浴60℃反应24h,减压回收溶剂得残余物,用硅胶柱层析纯化,以CH2Cl2:NH3/EtOH(20:1)为洗脱剂,得白色化合物23。收率:60%。1H NMR(500MHz,DMSO)δ10.32(s,1H),9.03(d,J=2.5Hz,1H),8.42(dd,J=8.5,2.5Hz,1H),8.28(s,1H),7.94(dd,J=8.5,2.5Hz,1H),7.82(s,1H),4.57(s,1H),4.49(s,1H),3.58-3.50(m,1H),3.51(t,J=6.5Hz,2H),3.31–3.28(m,2H),2.68–2.62(m,2H),2.48–2.37(m,2H),1.80-1.68(m,2H).ESI-MS:m/z=412[M+H]+。
制备实施例24 5-((4-((3-(环己基氨基)丙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物24)
步骤1.苄基(3-((2-氨基-5-(三氟甲基)嘧啶-4-基)氨基)丙基)(环己基)氨基甲酸酯(中间体1-19)合成
在冰浴条件下,取中间体1-2(197.0mg,1.0mmol),苄基(3-氨基丙基(环己基)氨基甲酸酯(348.0mg,1.2mmol),溶于甲醇(8.0mL),回流搅拌过夜。减压回收溶剂得残余物,用硅胶柱层析纯化,以CH2Cl2:EA(5:1)为洗脱剂,得白色固体1-19(270.0mg,0.6mmol),收率:60%。1H NMR(400MHz,CDCl3)δ8.01(s,1H),7.39–7.27(m,5H),5.39(s,2H),5.15(s,2H),3.90-3.76(m,1H),3.44(t,J=4.0Hz,2H),3.35-3.25(m,2H),1.78-1.68(m,6H),1.51–0.97(m,6H).ESI-MS:m/z=452[M+H]+。
步骤2. 5-((4-((3-(环己基氨基)丙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物24)合成
氮气保护下,向中间体1-19(270.0mg,0.6mmol),5-溴-2-氰基吡啶(131.0mg,0.72mmol),四三苯基膦钯(35.0mg,0.03mmol),4,5-双二苯基膦-9,9-二甲基氧杂蒽(35.0mg,0.03mmol),碳酸铯(293.2mg,0.9mmol)的混合物加入无水二氧六环(8mL),回流搅拌5h,抽滤,减压回收溶剂得残余物,用硅胶柱层析纯化,以PE:EA(4:1)为洗脱剂,得白色固体。用三氟乙酸(0.13mL),浓硫酸(0.91mL)脱保护基得白色固体化合物24。收率:40%1HNMR(500MHz,DMSO)δ10.36(s,1H),9.08(d,J=2.5Hz,1H),8.39(dd,J=8.5,2.5Hz,1H),8.29(s,1H),7.94(d,J=8.5Hz,2H),7.46–7.20(m,1H),4.40(s,1H),3.53(t,J=6.5Hz,2H),2.67(t,J=6.5Hz,2H),2.40-2.28(m,1H),1.90-1.76(m,2H),1.78–1.71(m,2H),1.70-1.58(m,2H),1.60–1.53(m,2H),1.50-1.44(m,2H),1.46–1.40(m,2H).ESI-MS:m/z=420[M+H]+。
制备实施例25 5-((4-((3-(环戊基氨基)丙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物25)
步骤1.苄基(3-((2-氨基-5-(三氟甲基)嘧啶-4-基)氨基)丙基)(环戊基)氨基甲酸酯(中间体1-20)合成
合成步骤参考实施例24步骤1。收率:60%。1H NMR(400MHz,CDCl3)δ8.04(s,1H),7.45–7.32(m,5H),5.34(s,2H),5.21(s,2H),4.28-4.20(m,1H),3.56-3.48(m,2H),3.38-3.28(m,2H),1.94-1.82(m,2H),1.86(s,2H),1.76-1.65(m,2H),1.62-1.56(m,4H).ESI-MS:m/z=438[M+H]+。
步骤2. 5-((4-((3-(环戊基氨基)丙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物25)合成
合成步骤参考实施例24步骤2合成化合物25。收率:53%。1H NMR(500MHz,DMSO)δ10.46(s,1H),9.10(s,1H),8.37(s,1H),8.33(s,1H),8.00(s,1H),7.63(s,1H),4.40(s,1H),3.58-3.46(m,2H),2.94-2.84(m,2H),2.06-1.95(m,1H),1.94-.86(m,2H),1.76–1.32(m,8H).ESI-MS:m/z=406[M+H]+。
制备实施例26 5-((4-((3-(环丁基氨基)丙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物26)
步骤1.苄基(3-((2-氨基-5-(三氟甲基)嘧啶-4-基)氨基)丙基)(环丁基)氨基甲酸酯(中间体1-21)合成
合成步骤参考实施例24步骤1。收率:58%。1H NMR(500MHz,CDCl3)δ8.02(s,1H),7.40–7.28(m,5H),5.31(s,2H),5.14(s,2H),4.30(s,1H),3.44(m,2H),3.37(s,2H),2.19–2.10(m,2H),2.10–2.03(m,2H),1.78–1.70(m,2H),1.68-1.58(m,2H).ESI-MS:m/z=424[M+H]+。
步骤2. 5-((4-((3-(环丁基氨基)丙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物26)合成
合成步骤参考实施例24步骤2合成化合物26。收率:50%。1H NMR(500MHz,DMSO)δ10.37(s,1H),9.08(d,J=2.0Hz,1H),8.40(dd,J=8.5,2.0Hz,1H),8.29(s,1H),8.01(s,1H),7.95(d,J=8.5Hz,1H),3.52(t,J=6.5Hz,2H),3.30-3.20(m 1H),2.57(t,J=6.5Hz,2H),2.10-2.02(m,2H),1.80–1.67(m,4H),1.64-1.57(m,2H).ESI-MS:m/z=392[M+H]+。
制备实施例27 5-((4-((3-(环丙基氨基)丙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物27)
步骤1.苄基(3-((2-氨基-5-(三氟甲基)嘧啶-4-基)氨基)丙基)(环丙基)氨基甲酸酯(中间体1-22)合成
合成步骤参考实施例24步骤1。收率:56%。1H NMR(500MHz,CDCl3)δ8.02(s,1H),7.38–7.32(m,5H),5.91(s,1H),5.26(s,2H),5.16(s,2H),3.44(q,J=6.4Hz,2H),3.37(t,J=6.5Hz,2H),2.60(s,1H),1.87-1.76(m,2H),0.78(m,2H),0.67–0.64(m,2H).ESI-MS:m/z=410[M+H]+。
步骤2. 5-((4-((3-(环丙基氨基)丙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物27)合成
合成步骤参考实施例24步骤2合成化合物27。收率:45%。1H NMR(500MHz,DMSO)δ10.34(s,1H),9.06(d,J=2.5Hz,1H),8.40(dd,J=8.5,2.5Hz,1H),8.28(s,1H),7.93(d,J=8.5Hz,1H),7.74(s,1H),7.36–7.23(m,1H),3.50(t,J=6.5Hz,2H),2.68(t,J=6.5Hz,2H),2.08–2.01(m,1H),1.73(p,J=6.5Hz,2H),0.38–0.32(m,2H),0.24–0.18(m,2H).ESI-MS:m/z=378[M+H]+。
制备实施例28 5-((4-((3-(异丙基氨基)丙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物28)
步骤1.苄基(3-((2-氨基-5-(三氟甲基)嘧啶-4-基)氨基)丙基)(异丙基)氨基甲酸酯(中间体1-23)合成
合成步骤参考实施例24步骤1。收率:55%。1H NMR(500MHz,CDCl3)δ7.99(s,1H),7.42–7.28(m,5H),5.44–5.19(m,2H),5.19(s,2H),4.40-4.20(m,1H),3.56-3.42(m,2H),3.28-3.20(m,2H),1.93-1.76(m,2H),1.14(d,J=12.0Hz,6H).ESI-MS:m/z=412[M+H]+。
步骤2. 5-((4-((3-(异丙基氨基)丙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物28)合成
合成步骤参考实施例24步骤2合成化合物28。收率:47%1H NMR(500MHz,DMSO)δ10.33(s,1H),9.06(d,J=2.5Hz,1H),8.39(dd,J=8.5,2.5Hz,1H),8.27(s,1H),8.01(s,1H),7.92(d,J=8.5Hz,1H),3.53(t,J=6.5Hz,2H),2.70-2.56(m,1H),2.62(t,J=6.5Hz,2H),1.79-1.65(m,2H),0.94(d,J=14.5Hz,6H).ESI-MS:m/z=380[M+H]+。
制备实施例29 5-((4-((3-氨基丙基)氨基)-5-(1-(三氟甲基)-1H-吡唑-4-基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物29)
步骤1.(3-((5-溴-2-氯嘧啶-4-基)氨基)丙基)氨基甲酸叔丁酯(中间体1-25)合成
将5-溴-2,4-二氯嘧啶(1g,4.4mmol)溶于乙腈(25mL),滴加N-叔丁氧羰基-1,3-丙二胺(847mg,4.86mmol)乙腈溶液(20mL),加入三乙胺(1mL),室温下搅拌30分钟,减压回收溶剂,用硅胶柱层析纯化,以PE:EA(2:1)为洗脱剂,得白色固体660mg。收率:41%。ESI-MS:m/z=365[M+H]+。
步骤2.N4-(3-N-叔丁氧羰基氨基丙基)-5-溴嘧啶-2,4-二胺(中间体1-26)合成
将化合物1-25(660mg,1.81mmol)置于封管中,加入氨气饱和的乙醇溶液(30mL),100℃下搅拌24小时。冷却至室温,减压回收溶剂得残余物。用硅胶柱层析纯化,以PE:EtOAc(2:1)为洗脱剂,得白色固体1-26。ESI-MS:m/z=346[M+H]+。
步骤3.N4-(3-N-叔丁氧羰基氨基丙基)-5-(1-(三氟甲基)-1H-吡唑-4-基)嘧啶-2,4-二胺(中间体1-27)合成
氮气保护下,向化合物1-26(316mg,0.92mmol),4-硼酸频哪醇酯基-1-(三氟甲基)-1H-吡唑(300mg,1.15mmol),Pd(dppf)Cl2(34mg,0.046mmol),碳酸钾(252mg,1.84mmol)的混合物中加入甲苯(12mL)异丙醇(3mL),回流搅拌过夜。减压回收溶剂得残余物。用硅胶柱层析纯化,以CH2Cl2:EA(1:1)为洗脱剂,得白色固体1-27。收率:55%。1H NMR(500MHz,CDCl3)δ8.09(s,1H),7.85(s,1H),7.77(s,1H),5.90(s,1H),5.23(s,1H),5.05(s,2H),3.56–3.47(m,2H),3.25-3.16(m,2H),1.78–1.64(m,2H),1.45(s,9H).ESI-MS:m/z=402[M+H]+。
步骤4.5-((4-((3-氨基丙基)氨基)-5-(1-(三氟甲基)-1H-吡唑-4-基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物29)合成
合成步骤参考实施例1步骤3合成化合物29。收率:50%。1H NMR(500MHz,MeOD)δ9.04(d,J=2.5Hz,1H),8.47(dd,J=8.5,2.5Hz,1H),8.39(s,1H),7.99(s,1H),7.93(d,J=3.0Hz,1H),7.78(d,J=8.5Hz,1H),3.62–3.54(m,2H),2.80–2.73(m,2H),1.85(p,J=7.0Hz,2H).ESI-MS:m/z=404[M+H]+。
制备实施例30 5-((4-(3-氨基丙氧基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物30)
步骤1.4-(3-N-叔丁氧羰基氨基丙氧基)-5-(三氟甲基)嘧啶-2-胺(中间体1-28)合成
冰浴条件下,将N-(3-羟丙基)氨基甲酸叔丁酯(320mg,1.82mmol)溶于无水的四氢呋喃溶液(6mL),加入氢化钠(47mg,1.98mmol),室温下反应0.5小时。在氮气条件下,将化合物1-2(300mg,1.52mmol)溶于无水的四氢呋喃溶液(3mL)中,加入上述反应液,室温搅拌过夜。加入饱和的氯化铵溶液淬灭反应,减压回收溶剂得残余物。用硅胶柱层析纯化,以PE:EA(6:1)为洗脱剂,得白色固体1-28。收率:95%。1H NMR(500MHz,CDCl3)δ8.28(s,1H),5.41(s,1H),4.91(s,1H),4.46(t,J=6.0Hz,2H),3.34–3.27(m,2H),2.03–1.96(m,2H),1.46(s,9H).ESI-MS:m/z=337[M+H]+。
步骤2. 5-((4-(3-氨基丙氧基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物30)合成
合成步骤参考实施例1步骤3合成化合物30收率:40%。1H NMR(500MHz,DMSO)δ10.84(s,1H),9.04(d,J=2.5Hz,1H),8.67(s,1H),8.43(d,J=8.5Hz,1H),8.01(d,J=8.5Hz,1H),4.50(t,J=6.0Hz,2H),3.14-3.02(m,2H),1.98-1.86(m,2H).ESI-MS:m/z=339[M+H]+。
制备实施例31(R)-5-((4-(哌啶-3-基甲氧基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物31)
步骤1.(R)-4-(N-叔丁氧羰基哌啶-3-基甲氧基)-5-(三氟甲基)嘧啶-2-胺(中间体1-29)合成
合成步骤参考实施例33步骤1。收率:85%。1H NMR(500MHz,CDCl3)δ8.27(s,1H),5.46(s,2H),4.28-4.17(m,2H),4.07(d,J=12.5Hz,1H),3.93(d,J=12.5Hz,1H),2.87(t,J=11.0Hz,1H),2.76(t,J=11.0Hz,1H),2.18-2.05(m,1H),2.05–1.60(m,4H),1.46(s,9H).ESI-MS:m/z=377[M+H]+。
步骤2.(R)-5-((4-(哌啶-3-基甲氧基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物31)合成
合成步骤参考实施例1步骤3合成化合物31。收率:42%。1H NMR(500MHz,DMSO)δ10.84(s,1H),9.07(d,J=2.5Hz,1H),8.69(s,1H),8.43(d,J=8.5,1H),8.02(d,J=8.5Hz,1H),4.49-4.42(m,1H),4.38(m,1H),3.18(d,J=12.5Hz,2H),2.74–2.66(m,2H),2.39-2.27(m,1H),1.88-1.78(m,2H),1.78-1.68(m,1H),1.40–1.30(m,1H).ESI-MS:m/z=379[M+H]+。
制备实施例32(S)-5-((4-(哌啶-3-基氧基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物32)
步骤1.(S)-4-(N-叔丁氧羰基哌啶-3-基氧基)-5-(三氟甲基)嘧啶-2-胺(中间体1-30)合成
合成步骤参考实施例30步骤1。收率:80%。ESI-MS:m/z=363[M+H]+。
步骤2.(S)-5-((4-(哌啶-3-基氧基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物32)合成
合成步骤参考实施例1步骤3合成化合物32。收率:35%。1H NMR(500MHz,DMSO)δ10.90(s,1H),9.03(d,J=8.5,1H),8.67(s,1H),8.44(d,J=8.5,1H),8.06(d,J=8.5Hz,1H),5.32–5.24(m,1H),3.27(m,2H),2.94–2.88(m,1H),2.88–2.84(m,1H),2.78-2.64(m,1H),2.13(m,1H),1.81–1.72(m,1H),1.70-1.62(m,1H).ESI-MS:m/z=365[M+H]+。
制备实施例33 4-((4-((3-氨基丙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯腈(化合物33)
步骤1.4-((4-((3-氨基丙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯腈(化合物33)合成
合成步骤参考实施例1步骤3。用4-溴苯腈替代5-溴-2-氰基吡啶合成化合物33。收率:60%。1H NMR(500MHz,DMSO)δ10.08(s,1H),8.24(s,1H),7.97(d,J=9.0Hz,2H),7.73(d,J=9.0Hz,2H),3.54(t,J=6.5Hz,1H),2.66(t,J=6.5Hz,1H),1.76–1.63(m,2H).ESI-MS:m/z=337[M+H]+。
制备实施例34 4-((4-((3-(甲基氨基)丙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯腈(化合物34)
步骤1.4-((4-((3-(甲基氨基)丙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯腈(化合物34)合成
合成步骤参考实施例1步骤3。用4-溴苯腈替代5-溴-2-氰基吡啶合成化合物34。收率:52%。1H NMR(500MHz,DMSO)δ10.13(s,1H),8.25(s,1H),7.98(d,J=9.0Hz,2H),7.73(d,J=9.0Hz,2H),3.53(t,J=6.5Hz,2H),2.59(t,J=6.5Hz,2H),2.30-2.20(s,3H),1.79-1.68(m,2H).ESI-MS:m/z=351[M+H]+。
制备实施例35 4-((4-((哌啶-3-基甲基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯腈(化合物35)
步骤1.4-((4-((哌啶-3-基甲基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯腈(化合物35)合成
合成步骤参考实施例1步骤3。用4-溴苯腈替代5-溴-2-氰基吡啶合成化合物35。收率:40%。1H NMR(500MHz,DMSO)δ10.08(s,1H),8.24(s,1H),7.97(d,J=9.0Hz,2H),7.71(d,J=9.0Hz,2H),7.37(t,J=5.5Hz,1H),3.38-3.27(m,2H),2.89(d,J=11.0Hz,1H),2.79(d,J=11.0Hz,1H),2.43(t,J=10.5Hz,1H),2.25(t,J=10.5Hz,1H),1.95-182(m,1H),1.86-1.72(m,1H),1.62-1.56(m,1H),1.30-1.18(m,1H),1.13-1.08(m,1H).ESI-MS:m/z=377[M+H]+。
制备实施例36 5-((4-((3-氨基-3-甲基丁基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物36)
步骤1.N4-(3-N-叔丁氧羰基氨基-3-甲基丁基)-5-(三氟甲基)嘧啶-2,4-二胺(中间体1-31)合成
合成步骤参考实施例1步骤2。收率:70%。1H NMR(500MHz,CDCl3)δ8.04(s,1H),6.30(s,1H),5.48(s,2H),3.47(t,J=7.0Hz,2H),1.76(t,J=7.0Hz,2H),1.47(s,9H),1.32(s,6H).ESI-MS:m/z=364[M+H]+。
步骤2. 5-((4-((3-氨基-3-甲基丁基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物36)合成
合成步骤参考实施例1步骤3合成化合物36。收率:72%。1H NMR(500MHz,DMSO)δ9.07(d,J=2.5Hz,1H),8.44(dd,J=8.5,2.5Hz,1H),8.26(s,1H),7.92(d,J=8.5Hz,1H),3.57(t,J=7.0Hz,2H),1.62(t,J=7.0Hz,2H),1.10(s,6H).ESI-MS:m/z=366[M+H]+。
制备实施例37 5-((4-((3-氨基-2,2-二甲基丙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物37)
步骤1.N4-(3-N-叔丁氧羰基氨基-2,2-二甲基丙基)-5-(三氟甲基)嘧啶-2,4-二胺(中间体1-32)合成
合成步骤参考实施例1步骤2。收率:64%。1H NMR(500MHz,DMSO)δ7.97(s,1H),7.16(t,J=6.5Hz,1H),6.75(t,J=6.0Hz,1H),6.69(s,2H),3.24(d,J=6.0Hz,2H),2.74(d,J=6.5Hz,2H),1.39(s,9H),0.76(s,6H).ESI-MS:m/z=364[M+H]+。
步骤2. 5-((4-((3-氨基-2,2-二甲基丙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物37)合成
合成步骤参考实施例1步骤3合成化合物37。收率:64%。1H NMR(500MHz,DMSO)δ9.05(d,J=2.5Hz,1H),8.42(dd,J=8.5,2.5Hz,1H),8.26(s,1H),7.93(d,J=8.5Hz,1H),3.41(s,2H),2.53(s,2H),0.88(s,6H).ESI-MS:m/z=366[M+H]+。
制备实施例38 5-((4-((3-氨基丁基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物38)
步骤1.N4-(3-N-叔丁氧羰基氨基丁基)-5-(三氟甲基)嘧啶-2,4-二胺(中间体1-33)合成
合成步骤参考实施例1步骤2。收率:70%。1H NMR(500MHz,CDCl3)δ8.02(s,1H),6.00(s,1H),5.32(s,2H),4.92(d,J=6.5Hz,1H),3.80-3.70(m,2H),3.28-3.18(m,1H),2.28-2.20(m,1H),1.90-1.70(m,1H),1.44(s,9H),1.15(d,J=6.5Hz,3H).ESI-MS:m/z=350[M+H]+。
步骤2. 5-((4-((3-氨基丁基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物38)合成
合成步骤参考实施例1步骤3合成化合物38。收率:64%。1H NMR(500MHz,DMSO)δ9.04(d,J=2.5Hz,1H),8.43(dd,J=8.5,2.5Hz,1H),8.25(s,1H),7.90(d,J=8.5Hz,1H),3.57–3.48(m,2H),2.93-2.82(m,1H),1.70-1.58(m,1H),1.52-1.42(m,1H),1.02(d,J=6.0Hz,3H).ESI-MS:m/z=352[M+H]+。
制备实施例39 5-((4-((3-(甲基氨基)丁基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物39)
步骤1.N4-(3-(N-叔丁氧羰基甲基氨基)丁基)-5-(三氟甲基)嘧啶-2,4-二胺(中间体1-34)合成
合成步骤参考实施例1步骤2。收率:60%。1H NMR(500MHz,CDCl3)δ8.04(s,1H),5.87(s,1H),5.09(s,2H),4.35(m,1H),3.87(m,1H),2.92(m,1H),2.68(s,3H),1.69–1.52(m,2H),1.46(s,9H),1.13(d,J=6.5Hz,3H).ESI-MS:m/z=364[M+H]+。
步骤2. 5-((4-((3-(甲基氨基)丁基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物39)合成
合成步骤参考实施例1步骤3合成化合物39。收率:64%。1H NMR(500MHz,DMSO)δ9.07(d,J=2.5Hz,1H),8.41(dd,J=8.5,2.5Hz,1H),8.26(s,1H),7.91(d,J=8.5Hz,1H),3.62-3.54(m,1H),3.53-3.46(m,1H),2.67–2.57(m,1H),2.26(s,3H),1.72–1.56(m,2H),1.05(d,J=6.5Hz,3H).ESI-MS:m/z=366[M+H]+。
制备实施例40 5-((4-((3-氨基丙基)氨基)-6-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物40)
步骤1.N4-(3-N-叔丁氧羰基氨基丙基)-6-(三氟甲基)嘧啶-2,4-二胺合成
冰浴条件下,将2-氨基-4-氯-6-三氟甲基嘧啶(197.0mg,1.0mmol),N-叔丁氧羰基-1,3-丙二胺(208.8mg,1.2mmol),溶于甲醇(8.0ml),回流搅拌过夜。减压回收溶剂得残余物,用硅胶柱层析纯化,先以PE:EA(5:1-2:1)为洗脱剂,得白色固体1-36,收率:72%。1HNMR(500MHz,CDCl3)δ6.10(s,1H),5.75(s,1H),5.16(s,1H),5.16(s,2H),3.48(t,J=7.0Hz,2H),3.21(t,J=7.0Hz,2H),1.77-1.65(m,2H),1.46(s,9H).ESI-MS:m/z=336[M+H]+。
步骤2. 5-((4-((3-氨基丙基)氨基)-6-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物40)合成
合成步骤参考实施例1步骤3合成化合物40。收率:50%。1H NMR(500MHz,DMSO)δ10.25(s,1H),9.06(d,J=2.0Hz,1H),8.41(dd,J=9.0,2.5Hz,1H),8.38(s,1H),7.96(d,J=8.5Hz,1H),6.53(s,1H),3.47(t,J=7.0Hz,2H),2.83(t,J=7.0Hz,2H),1.89–1.80(m,2H).ESI-MS:m/z=338[M+H]+。
制备实施例41 5-((4-((4-氨基环己基)氨基)-6-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物41)
步骤1.N4-(4-N-叔丁氧羰基氨基环己基)-6-(三氟甲基)嘧啶-2,4-二胺(中间体1-37)合成
合成步骤参考实施例40步骤1。收率:75%。1H NMR(500MHz,CDCl3)δ6.04(s,1H),5.11(s,2H),4.95(s,1H),4.48-4.38(m,1H),3.52-3.30(m,1H),2.14–2.05(m,4H),1.52–1.39(m,9H).1.30–1.25(m,4H).ESI-MS:m/z=376[M+H]+。
步骤2. 5-((4-((4-氨基环己基)氨基)-6-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物41)合成
合成步骤参考实施例1步骤3合成化合物41。收率:66%。1H NMR(500MHz,DMSO)δ9.08(d,J=2.5Hz,1H),8.37(dd,J=8.5,2.5Hz,1H),7.99(d,J=7.5Hz,1H),7.94(d,J=8.5Hz,1H),6.42(s,1H),3.83–3.72(m,1H),2.61–2.54(m,1H),2.02-1.92(m,2H),1.90-1.80(m,2H),1.31–1.15(m,4H).ESI-MS:m/z=378[M+H]+。
制备实施例42 5-((4-(吡咯烷-3-基氨基)-6-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物42)
步骤1.N4-(N-叔丁氧羰基吡咯烷-3-基)-6-(三氟甲基)嘧啶-2,4-二胺(中间体1-38)合成
合成步骤参考实施例40步骤1。收率:68%。1H NMR(500MHz,CDCl3)δ6.10(s,1H),5.14(s,2H),4.49(s,1H),3.72-3.58(m,1H),3.52-3.45(m,1H),3.50-3.40(m,1H),3.35–3.13(m,1H),2.25-2.18(m,1H),2.01–1.79(m,2H),1.53–1.40(m,9H).ESI-MS:m/z=348[M+H]+。
步骤2. 5-((4-(吡咯烷-3-基氨基)-6-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物42)合成
合成步骤参考实施例1步骤3合成化合物42。收率:50%。1H NMR(500MHz,CDCl3)δ10.44(s,1H),9.00(s,1H),8.76(d,J=5.5Hz,1H),8.41(d,J=6.5Hz,1H),8.00(d,J=8.5Hz,1H),6.53(s,1H),4.62-4.53(m,1H),3.52-3.44(m,1H),3.40-3.28(m,1H),3.28–3.24(m,1H),3.20-3.15(m,1H),2.34-2.27(m,1H),2.05-1.99(m,1H).ESI-MS:m/z=350[M+H]+。
制备实施例43 5-((4-((吡咯烷-3-基甲基)氨基)-6-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物43)
步骤1.N4-(N-叔丁氧羰基吡咯烷-3-基甲基)-6-(三氟甲基)嘧啶-2,4-二胺(中间体1-39)合成
合成步骤参考实施例40步骤1。收率:65%。1H NMR(500MHz,CDCl3)δ6.08(s,1H),5.37(s,1H),5.20(s,2H),3.58–3.46(m,2H),3.48-3.36(m,1H),3.39–3.27(m,2H),3.17–3.01(m,1H),2.56-3.43(m,1H),2.08-1.97(m,1H),1.68-1.57(m,1H),1.50-1.38(m,9H).ESI-MS:m/z=362[M+H]+。
步骤2. 5-((4-((吡咯烷-3-基甲基)氨基)-6-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶(化合物43)合成
合成步骤参考实施例1步骤3合成化合物43。收率:45%。1H NMR(500MHz,DMSO)δ10.17(s,1H),9.05(d,J=2.5Hz,1H),8.40(dd,J=8.5,2.5Hz,1H),8.17(d,J=2.5Hz,1H),7.94(d,J=8.5Hz,1H),6.48(s,1H),3.42-3.28(m,2H),2.92-2.84(m,1H),2.84–2.79(m,1H),2.76–2.67(m,1H),2.58-2.53(m,1H),2.38-2.32(m,1H),1.87–1.78(m,1H),1.41–1.34(m,1H).ESI-MS:m/z=364[M+H]+。
制备实施例44 4-((4-((3-氨基丙基)氨基)-6-(三氟甲基)嘧啶-2-基)氨基)苯腈(化合物44)
步骤1. 4-((4-((3-氨基丙基)氨基)-6-(三氟甲基)嘧啶-2-基)氨基)苯腈(化合物44)合成
合成步骤参考实施例1步骤3合成化合物44。收率:50%。ESI-MS:m/z=337[M+H]+。
生物活性测试部分
1.本发明提供的化合物对Chk1激酶的抑制活性测试。
采用KinEASETMSTK S1试剂盒对化合物进行Chk1激酶抑制活性测试。采用特异性的生物素标记的多肽S1作为底物,Chk1在ATP的参与下,能够催化多肽底物S1的磷酸化修饰。Eu标记的S1特异性磷酸化抗体就能够与底物通过抗原抗体反应而结合在一起,同时链霉亲和素标记的受体通过链霉亲和素与生物素的特异性相互作用而结合在一起。在荧光共振能量转移中,由于生物分子相互作用导致两个荧光基团接近时,在激发时被穴状化合物捕获的部分能量将被释放,发射波长为620nm;另一部分能量转移到受体上,发射波长665nm。665nm的发射光仅由供体引起的FRET产生。所以,当生物分子相互作用时,有两个激发光620nm和665nm;当不存在相互作用时,只有620nm一个激发光。通过检测665nm和620nm两个发射波长的荧光信号比值能反应Chk1磷酸化活性。样品用DMSO溶解,Chk1和底物用HTRF激酶缓冲溶液(1X Kinase buffer,5mM MgCl2,1mM DTT)稀释。将4μL酶、4μL底物和2μL不同浓度的待测化合物分别加入384反应板中。室温孵育1个小时后,加入抗体进行检测。每个样品每个浓度设3个复孔。利用Graphpad Prism 5软件处理数据,计算IC50值。
表1代表性化合物对Chk1激酶的IC50(nM)
从上面表1结果可知:本发明提供的化合物表现出较高的Chk1激酶抑制活性,说明该类化合物具有较好的抗肿瘤前景。
2.本发明提供的化合物对细胞增殖及生长抑制。
细胞株:MV-4-11(人急性髓性单核细胞白血病),Z-138(人套细胞株淋巴瘤细胞),Mino(人套细胞淋巴瘤),SUM149(人乳腺癌细胞),T47D(人乳腺导管癌细胞),SW620(人结肠癌细胞),Kasumi-1(人急性原粒细胞白血病细胞)THP1(人单核细胞白细胞),Maver-1(人淋巴细胞瘤)。
运用MTS法检测细胞存活率。将生长在对数生长期的细胞,吸取培养基,轻轻吹打,计数。以相应的细胞密度接种在96孔板中90uL,加10μL化合物,每一化合物设浓度梯度,每一浓度设三复孔,每一浓度分别加入到对应孔中,DMSO的终浓度是0.2%,于含有4.5%CO2的37℃培养箱内培养3天,加入20μL的MTS。37℃孵育3小时后,使用SpectraMAX 340测490nm(L1)光吸收值,参考波长690nm(L2),将(L1-L2)值对抑制剂不同浓度作图,百分比活性(%)=化合物OD值-BLANK OD值/DMSO OD值-BLANK OD*100%用graphpad,经公式拟合得IC50。
表2代表性化合物对MV-4-11、Z138细胞株的增殖及生长抑制作用
表3代表性化合物对Mino细胞株的增殖及生长抑制作用
表4代表性化合物对T47D细胞株的增殖及生长抑制作用
表5代表性化合物对SUM149细胞株的增殖及生长抑制作用
表6代表性化合物对THP1、Maver-1、SW620、Kasumi-1细胞株的增殖及生长抑制作用
从上表可以看出化合物对多株细胞株有生长抑制作用,其中对MV-4-11和Z138血液瘤细胞株有明显的生长抑制作用。
3.本发明提供的化合物的体内药代动力学研究。
通过单剂量灌胃于Bal b/c小鼠,测定小鼠血浆中受试物的浓度,评价受试物在小鼠体内药代特征。
小鼠灌胃(20mg/kg或10mg/kg)给药化合物9,13,15,17,36后,分别在0,3min,15min,30min,1h,2h,4h,6h,24h,经眼眶取血,测定给药后的药代动力学参数。结果如图1所示。
本研究的对照化合物选自专利CN106588885A具体实施例中化合物15,药代结果显示,未在血浆中检测到该化合物,表明该化合物不具有口服疗效。
从图1结果可知:本发明提供的化合物具有较好的口服利用度,表明该类化合物具有一定的口服疗效。
4.本发明提供的化合物的药效学研究。
为了验证化合物的体内抗肿瘤活性,选取化合物13,15,17对人急性髓系白血病MV-4-11Ba1b/c小鼠皮下移植瘤进行了生长抑制作用测试。
药物配制方法:精确称量化合物,倒入研钵中,先加入少量0.5%CMC-Na水溶液研磨均匀,分多次加入,配制成所需浓度3.0mg/mL,给药容积10mL/kg。
将人急性髓系白血病MV-4-11细胞株接种于小鼠右侧腋窝皮下,细胞接种量为1×107/只,形成移植瘤后即可开始实验。用游标卡尺测量移植瘤直径,待肿瘤长至100-200mm3,将动物随机分成0.5%CMC-Na溶媒对照组,阿糖胞苷(AraC)对照组和给药组。给药组每日灌胃给药化合物30mg/kg,溶媒对照组每日灌胃0.5%CMC-Na水溶液,对照组每日皮下注射阿糖胞苷(40mg/kg),持续3周。实验结果如图2所示。
从图2结果可知:本发明提供的化合物13和化合物15对人急性髓性白血病MV-4-11有显著抑制肿瘤生长作用。
Claims (4)
1.一种N-取代芳环-2-氨基嘧啶类化合物,其特征在于,所述的化合物选自:
5-((4-((3-氨基丙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶,
5-((4-((3-(甲基氨基)丙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶,
5-((4-((3-((2-(甲基磺酰基)乙基)氨基)丙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶,
5-((4-((3-氨基-3-甲基丁基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氰基吡啶。
2.根据权利要求1所述N-取代芳环-2-氨基嘧啶类化合物,其特征在于,所述化合物的药学上可接受的盐,是与无机酸和有机酸形成,选用盐酸盐、氢溴酸盐、硫酸盐、磷酸盐、硝酸盐、乙酸盐、甲酸盐、柠檬酸盐、酒石酸盐、马来酸盐、富马酸盐、扁桃酸盐、草酸盐、琥珀酸盐、苹果酸盐、葡糖酸盐、葡糖醛酸盐、丙二酸盐、甲磺酸盐、丙酸盐、硬脂酸盐和三氟乙酸盐。
3.权利要求1~2任一所述的N-取代芳环-2-氨基嘧啶类化合物或其药学上可接受的盐在制备抗肿瘤药物中的应用。
4.根据权利要求3所述的应用,其特征在于,所述肿瘤为白血病、淋巴癌、乳腺癌、结肠癌。
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