CN117534631B - 一种苯基噻唑胺类PI4KIIIβ抑制剂、制法及其药物组合物和应用 - Google Patents
一种苯基噻唑胺类PI4KIIIβ抑制剂、制法及其药物组合物和应用 Download PDFInfo
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- CN117534631B CN117534631B CN202410028674.6A CN202410028674A CN117534631B CN 117534631 B CN117534631 B CN 117534631B CN 202410028674 A CN202410028674 A CN 202410028674A CN 117534631 B CN117534631 B CN 117534631B
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- methylthiazol
- butyl ester
- acid tert
- methoxyphenyl
- dmso
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- 230000008685 targeting Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- KLKBCNDBOVRQIJ-UHFFFAOYSA-N tert-butyl 4-(aminomethyl)piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(CN)CC1 KLKBCNDBOVRQIJ-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- WUOQXNWMYLFAHT-MRVPVSSYSA-N tert-butyl n-[(3r)-piperidin-3-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@@H]1CCCNC1 WUOQXNWMYLFAHT-MRVPVSSYSA-N 0.000 description 1
- DQQJBEAXSOOCPG-ZETCQYMHSA-N tert-butyl n-[(3s)-pyrrolidin-3-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H]1CCNC1 DQQJBEAXSOOCPG-ZETCQYMHSA-N 0.000 description 1
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- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/44—Acylated amino or imino radicals
- C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
本发明公开了一种苯基噻唑胺类PI4KIIIβ抑制剂,所述抑制剂为通式V所示的取代苯基噻唑胺类化合物,或其立体异构体、水合物或药学上可接受的盐;所述抑制剂具有有效抑制PI4KIIIβ的PI3K/Akt/mTOR信号通路的特点,具有高效优异的PI4KIIIβ酶抑制活性,且成本低、疗效佳、毒性小,在合成过程中的中间产物收率高,降低了资源浪费,进而有利于降低成本;应用于抗肿瘤药物中使用剂量小,活性显著。
Description
技术领域
本发明涉及一种苯基噻唑胺类PI4KIIIβ抑制剂,还涉及上述抑制剂的制法、药物组合物和应用,属于医药技术领域。
背景技术
传统的恶性肿瘤治疗方法主要包括手术治疗、化学治疗、放射治疗。手术治疗虽然是一种较好的方法,但如果不继续进行其他的辅助治疗,对于延长患者生命的效果并不理想;化学治疗可能会有耐药性的产生,产生药物的副作用,常见的有对骨髓的抑制,对肠道功能的抑制等;放射治疗是一种局部治疗,放疗可以抑制肿瘤的生长,但另一方面也会对周围组织产生影响以及造成损伤。分子靶向治疗因特异性强和毒性低等特点成为治疗癌症的新方法。
脂质磷脂酰肌醇是无数细胞过程的重要调节因子,包括信号传导、膜运输和胞质***。磷脂酰肌醇通过磷脂酰肌醇的肌醇环磷酸化产生。磷脂酰肌醇可以通过一组不同的酶进行磷酸化和去磷酸化,这导致总共七种不同的单磷酸化和多磷酸化磷脂酰肌醇。脂质种类磷脂酰肌醇4-磷酸(PI4P)是由磷脂酰肌醇4激酶(PI4Ks)的作用产生的。PI4P是多重磷酸化信号脂质磷脂酰肌醇4,5-二磷酸(PIP2)和磷脂酰肌醇3,4,5-三磷酸(PIP3)的主要生物合成途径。在哺乳动物中,有四种不同的PI4K酶:两种II型酶(PI4KIIα和PI4KIIβ)和两种III型酶(PI4KIIIα和PI4KIIIβ)。
PI4KIIIβ是一种外周膜蛋白,主要定位于高尔基体和反式高尔基体网络(TGN)。在与 Rab GTP酶一起介导脂质转运胞质***、维持溶酶体身份和调节膜运输中起关键作用。PI4KIIIβ的失调也与癌症有关。PI4KIIIβ在肿瘤中经常被扩增和致癌激活,其表达可以抑制癌细胞凋亡。PI4KIIIβ亚型的缺失诱导癌细胞凋亡。尽管 PI4KIIIβ已被证实为一种新的癌症驱动因素,但参与癌症治疗的特异性 PI4KIIIβ抑制剂的研究几乎没有报道。到目前为止,在临床前研究中,几种PI4KIIIβ小分子抑制剂已被披露为有效的抗病毒候选药物。许多研究证实了PI4KIIIβ抑制剂的药用潜力,但对探索 PI4KIIIβ抑制剂作为癌症治疗化疗的关注要少得多。因此,开发一类新型PI4KIIIβ抑制剂并探索其在癌症治疗中的应用是一项有意义和有价值的工作。
发明内容
发明目的:本发明的目的是提供一种高活性的苯基噻唑胺类PI4KIIIβ抑制剂,还提供上述抑制剂的制法、药物组合物和应用。
本发明所述的苯基噻唑胺类PI4KIIIβ抑制剂,为通式V所示的取代苯基噻唑胺类化合物,或其立体异构体或药学上可接受的盐:其中,A为或/>;
R1为苯环上取代基选自氢、氟、氯、溴、碘、羟基、氨基、氰基、C1-C6烷基、卤代C1-C6烷基、羟基C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、羟基C1-C6烷氧基或C1-C6烷氧基C1-C6烷基;R2为;R3或R4为C1-C6烷基、含一个或多个取代基的C1-C6烷基、C1-C6烷氧基、含一个或多个取代基的C1-C6烷氧基、C1-C6烷基酰基、C1-C6烷基磺酰基、C3-C6杂环基、含一个或多个取代基的C3-C6杂环基;
X为砜基或羰基。
优选的,所述抑制剂为通式Ⅰ或Ⅱ所示的化合物:其中,R1、R2、R4和X的定义同上述;R3为。优选的,所述通式V的抑制剂中,与碳相连的氢替换为氢的同位素氘。
进一步优选为,烷基由氘代烷基替代,烷氧基由氘代环氧基替代,苯环由氘代苯环替代,芳环由氘代芳环替代。
优选的,药学上可接受的盐是指把母体化合物中的碱性基团转换成盐的形式;其中,药学上可接受的盐为碱性基团,进一步优选为胺基或氨基的无机或有机酸盐类;由母体化合物中的碱性基团与1~4当量的酸在一个溶剂***中反应。
优选的,本发明中化合物碱性基团可与酸成盐,所述酸成盐具体为,与无机酸,尤其氢卤酸(如氢氯酸、氢溴酸、氢碘酸)、硝酸、硫酸、磷酸、碳酸等形成的盐;低级烷基磺酸,如甲磺酸,三氟甲磺酸形成的盐;与芳基磺酸,如苯磺酸或对甲苯磺酸形成的盐;与有机酸,如乙酸、富马酸、酒石酸、草酸、柠檬酸、马来酸、苹果酸或琥珀酸形成的盐;与氨基酸,如天冬氨酸或谷氨酸形成的盐。
优选的,本发明的化合物和药学上可接受的盐还包括溶剂化物或水合物的形式。
优选的,本发明的苯基噻唑胺类PI4KIIIβ抑制剂中化合物的结构式包括同分异构形式,如对映异构、非对映异构、几何异构或构象异构,具体为含有不对称中心的R、S构型,双键的(Z)、(E)异构体,(Z)、(E)的构象异构体。
优选的,所述抑制剂为以下其中之一:
(1)(2-(5-(2-乙酰氨基-4-甲基噻唑-5-基)-2-氯苯基磺酰胺基)乙基)氨基甲酸叔丁酯;
(2)N-(5-(4-氯-3-(N-(2-羟基-2-甲基丙基)氨基磺酰基)苯基)-4-甲基噻唑-2-基)乙酰胺;
(3)N-(2-(2-乙酰氨基-4-甲基噻唑-5-基)-2-氯苯基磺酰胺基)乙基丙酰胺;
(4)(2-(2-乙酰氨基-4-甲基噻唑-5-基)-2-氯苯基磺酰胺基)乙基氨基甲酸甲酯;
(5)(2-((5-(2-乙酰氨基-4-甲基噻唑-5-基)-2-甲氧基苯基)磺酰胺基)乙基)氨基甲酸叔丁酯;
(6)N-(5-(4-氯-3-(N-(3-羟基-4-甲基苯基)氨基磺酰基)苯基)-4-甲基噻唑-2-基)乙酰胺;
(7)N-(5-(3-(N-(2 ,4-二氟苯基)氨基磺酰基)-4-甲氧基苯基)-4-甲基噻唑-2-基)乙酰胺;
(8)(5-(2-丙酰胺基-4-甲基噻唑-5-基)-2-甲氧基苯基磺酰胺基)乙基氨基甲酸叔丁酯;
(9)(5-(2-丁酰胺基-4-甲基噻唑-5-基)-2-甲氧基苯基磺酰胺基)乙基氨基甲酸叔丁酯;
(10)(5-(2-戊酰胺基-4-甲基噻唑-5-基)-2-甲氧基苯基磺酰胺基)乙基氨基甲酸叔丁酯;
(11)(5-(2-己酰胺基-4-甲基噻唑-5-基)-2-甲氧基苯基磺酰胺基)乙基氨基甲酸叔丁酯;
(12)(5-(2-庚酰胺基-4-甲基噻唑-5-基)-2-甲氧基苯基磺酰胺基)乙基氨基甲酸叔丁酯;
(13)(2-(2-甲氧基-5-(4-甲基-2-(3-丙基脲基)噻唑-5-基)苯基)磺酰胺基)乙基氨基甲酸叔丁酯;
(14)(2-(5-(2-(3-丁基脲基)-4-甲基噻唑-5-基)-2-甲氧基苯基磺酰胺基)乙基)氨基甲酸叔丁酯;
(15)(2-(2-甲氧基-5-(4-甲基-2-(3-甲基丁酰胺)噻唑-5-基)苯基)磺酰胺基)乙基氨基甲酸叔丁酯;
(16)(5-(2-异丁酰胺基-4-甲基噻唑-5-基)-2-甲氧基苯基磺酰胺基)乙基氨基甲酸叔丁酯;
(17)(2-(2-甲氧基-5-(4-甲基-2-特戊酰胺噻唑-5-基)苯基)磺酰胺基)乙基氨基甲酸叔丁酯;
(18)(5-(2-(3,3-二甲基丁酰胺)-4-甲基噻唑-5-基)-2-甲氧基苯基磺酰胺基)乙基氨基甲酸叔丁酯;
(19)(2-(2-甲氧基-5-(4-甲基-2-(4-甲基戊酰胺)噻唑-5-基)苯基)磺酰胺基)乙基氨基甲酸叔丁酯;
(20)(2-(2-甲氧基-5-(4-甲基-2-(5-甲基己酰胺基)噻唑-5-基)苯基)磺酰胺基)乙基氨基甲酸叔丁酯
(21)(2-(5-(2-(环己烷甲酰胺基)-4-甲基噻唑-5-基)-2-甲氧基苯基)磺酰胺基)乙基氨基甲酸叔丁酯;
(22)(2-(2-氯-5-(4-甲基-2-(3-甲基丁酰胺基)噻唑-5-基)苯基)磺酰胺基)乙基氨基甲酸叔丁酯;
(23)(2-氯-5-(2-(3,3-二甲基丁酰胺)-4-甲基噻唑-5-基)苯基磺酰胺基)乙基氨基甲酸叔丁酯;
(24)(2-氯-5-(4-甲基-2-戊酰胺基-5-基)苯基磺酰胺基)乙基氨基甲酸叔丁酯;
(25)(2-氯-5-(2-己酰胺基-4-甲基噻唑-5-基)苯基磺酰胺基)乙基氨基甲酸叔丁酯;
(26)(2-(5-(2-(3-乙酰氨基丙酰胺基)-4-甲基噻唑-5-基)-2-甲氧基苯基)磺酰胺基)乙基氨基甲酸叔丁酯;
(27)(2-(2-甲氧基-5-(4-甲基-2-(6-氧代庚酰胺基)噻唑-5-基)苯基)磺酰胺基)乙基氨基甲酸叔丁酯;
(28)(2-(2-甲氧基-5-(4-甲基-2-(6-氧代已酰胺基)噻唑-5-基)苯基)磺酰胺基)乙基氨基甲酸叔丁酯;
(29)(R)-(1-((5-(2-己酰胺基-4-甲基噻唑-5-基)-2-甲氧基苯基)磺酰基)哌啶-3-基)氨基甲酸叔丁酯;
(30)(S)-(1-((5-(2-己酰胺基-4-甲基噻唑-5-基)-2-甲氧基苯基)磺酰基)吡咯烷-3-基)氨基甲酸叔丁酯;
(31)4-((2-己酰胺基-4-甲基噻唑-5-基)-2-甲氧基苯基磺酰胺基)哌啶-1-羧酸叔丁酯;
(32)N-(5-(3-(2-(3,3-二甲基丁酰胺)乙基氨基磺酰基)-4-甲氧基苯基)-4-甲基噻唑-2-基)己酰胺;
(33)N-(5-(3-(2-羟基-2-甲基丙基)氨基磺酰基)-4-甲氧基苯基)-4-甲基噻唑-2-基己酰胺;
(34)N-(5-(3-(N-(2-啉乙基)氨基磺酰基))-4-甲氧基苯基)-4-甲基噻唑-2-基己酰胺;
(35)N-(5-(3-(((4-氟苯基)-l2-氮酰基)磺酰基)-4-甲氧基苯基)-4-甲基噻唑-2-基)己酰胺;
(36)N-(5-(3-(((4-氯苯基)-l2-亚氮基)磺酰基)-4-甲氧基苯基)-4-甲基噻唑-2-基)己酰胺;
(37)N-(5-(3-(((4-氟苄基)-l2-亚氮基)磺酰基)-4-甲氧基苯基)-4-甲基噻唑-2-基)己酰胺;
(38)N-(5-(3-(((3-氟苄基)-l2-亚氮基)磺酰基)-4-甲氧基苯基)-4-甲基噻唑-2-基)己酰胺;
(39)N-(5-(3-(((2-氟苄基)-l2-亚氮基)磺酰基)-4-甲氧基苯基)-4-甲基噻唑-2-基)己酰胺;
(40)N-(4-(3-(((2 ,4-二氟苄基)-l2-亚氮基)磺酰基)-4-甲氧基苯基)-5-甲基噻唑-2-基)己酰胺;
(41)N-(5-(3-(((3 ,4-二氟苄基)-l2-亚氮基)磺酰基)-4-甲氧基苯基)-4-甲基噻唑-2-基)己酰胺;
(42)N-(5-(3-(((3-氯-4-氟苄基)-l2-亚氮基)磺酰基)-4-甲氧基苯基)-4-甲基噻唑-2-基)己酰胺;
(43)N-(5-(3-(((4-氟-3-(三氟甲基)苄基)-l2-亚氮基)磺酰基)-4-甲氧基苯基)-4-甲基噻唑-2-基)己酰胺;
(44)N-(5-(4-甲氧基-3-(((3 ,4 ,5-三氟苄基)-l2-亚氮基)磺酰基)苯基)-4-甲基噻唑-2-基)己酰胺;
(45)N-(5-(3-(((4-氟苯乙基)-l2-亚氮基)磺酰基)-4-甲氧基苯基)-4-甲基噻唑-2-基)己酰胺;
(46)(2-(2-己酰胺基-4-甲基噻唑-5-基)-2-甲氧基苯甲酰胺基)乙基氨基甲酸叔丁酯;
(47)N-(4-(3-(((2 ,4-二氟苄基)-l2-亚氮基)磺酰基)-4-甲氧基苯基)-5-甲基噻唑-2-基)己酰胺。
上述抑制剂的制法为,以1-(4-氯苯基)-2-丙酮或1-(4-甲氧基苯基)-2-丙酮为原料(1a, 1b),原料(1a, 1b)与氯磺酸在苯环3号位发生取代反应得到中间体(2a, 2b);在中间体(2a, 2b)的基础上通过Hinsberg反应,引入R2
基团得到中间体(3a-3g);中间体(3a-3g)与苯基三甲基三溴化铵发生α-溴代反应得到中间体(4a-4g);中间体(4a-4g)与N-乙酰硫脲缩合反应得到目标化合物(5a-5g),合成路线如下:
。
上述抑制剂的制法还包括,根据目标化合物(5a-5g)的制备方法,以上述中间体(4d, 4e)为原料,同时将硫脲与各种酰氯发生取代反应引入R3基团得到N-取代硫脲为另一类原料;二者缩合反应得到目标化合物(7a-7r);或只以中间体(4e)为原料,与硫脲发生缩合反应得到中间体(8);中间体(8)分别与3-乙酰氨基丙酰氯、6-羰基庚酰氯和5-羰基己酰氯发生取代反应得到目标化合物(9a-9c),合成路线如下:
或根据目标化合物(5a-5g)的制法,得到化合物(4h-4x)为原料,与N-己酰硫脲发生缩合反应得到目标化合物(10a-10q),合成路线如下:
。
上述抑制剂的制法还包括,以化合物(11)为原料,经过两步反应得到中间体(12);中间体(12)在乙酸中加热回流与铁粉发生还原反应得到中间体(13);中间体(13)在酸性条件下发生水解反应得到中间体(14);中间体(14)与(2-氨基乙基)氨基甲酸叔丁酯反应得到中间体(15),经过两步反应得到目标化合物(17),合成路线如下:
。
或以4´-甲氧基苯丙酮(18)为原料,经过四步反应得到目标化合物(22),合成路线如下:。
本发明还公开了一种药物组合物,包含至少一种药学上可接受的辅料、辅助剂或载体,以及上述的苯基噻唑胺类PI4KIIIβ抑制剂。
上述苯基噻唑胺类PI4KIIIβ抑制剂或药物组合物在制备用于预防、治疗或辅助治疗PI4KIIIβ激酶过度活化引起的增殖性疾病、代谢性疾病、神经***性疾病或结节性硬化症的药物中的应用。
优选的,所述增殖性疾病包括结直肠癌、胃癌、乳腺癌、肺癌、肝癌、***癌、胰腺癌、甲状腺癌、膀胱癌、肾癌、脑癌、***、CNS的癌症、恶性胶质瘤、骨髓增生病、血液癌或淋巴癌。
上述苯基噻唑胺类PI4KIIIβ抑制剂或药物组合物在制备用于抑制癌症细胞生长的药物中的应用。
发明原理:由于PIK4KIIIβ的抑制活性不强,抗肿瘤作用不足,PIK-93被选为进一步结构修饰的先导化合物。确定以苯基噻唑胺为基本骨架结构,通过筛选取代基团,从而带来高效抑制效果。
有益效果:与现有技术相比,本发明具有如下显著优点:(1)具有有效抑制PI4KIIIβ的PI3K/Akt/mTOR信号通路的特点,具有高效优异的PI4KIIIβ酶抑制活性;(2)成本低、疗效佳、毒性小,且在合成过程中的中间产物收率高,降低了资源浪费,进而有利于降低成本;(3)抗肿瘤活性显著,使用剂量小。
附图说明
图1为实施例11和27的体内抗肿瘤疗效和毒性研究的结果,图A为小鼠肿瘤体积变化曲线,图B为体重的生长曲线,图C为小鼠肿瘤组织的代表性图像;
图2为实施例40的体内抗肿瘤疗效和毒性研究的结果,图A为小鼠肿瘤体积变化曲线,图B为体重的生长曲线,图C为小鼠肿瘤组织的代表性图像;
图3为肿瘤小鼠的组织病理切片染色图像。
具体实施方式
下面结合实施例和附图对本发明的技术方案作进一步说明。
试剂购买于商品供应商如安徽泽升科技有限公司、百灵威科技有限公司、阿拉丁试剂有限公司、北京偶合科技有限公司等,使用时都没有经过进一步纯化,除非其他方面表明。一般的试剂从西陇化工股份有限公司、南京化学试剂股份有限公司、国药集团化学试剂有限公司和青岛海洋化工有限公司等购买得到。实施例中除非其他方面表明所有的温度定为摄氏度。
下面所描述的实施例中色谱柱使用硅胶柱,硅胶(200-300目)购于青岛海洋化工有限公司。核磁共振光谱以Chloroform-d或DMSO-d 6为溶剂(以ppm为单位)),用TMS(0 ppm)作为参照标准。当出现多重峰的时候,将使用下面的缩写:s(singlet,单峰),d(doublet,双峰),t(triplet ,三重峰),m(multiplet,多重峰),br(broadened ,宽峰),dd(doublet ofdoublets,双双重峰),dt(doublet of triplets,双三重峰)。偶合常数,用赫兹(Hz)表示。
下面所描述的实施例中低分辨率质谱(MS)数据通过配备G1311B四元泵和G1316A柱温箱的Agilent 6120系列LC-MS的G1329B自动采样器和 G4212B检测器应用于分析,ESI源应用于LC-MS光谱仪。
下面描述的实施例为了便于表述,部分原料会以其简称进行描述,这些简称与其全称对照说明如下:DCM为CH2Cl2,即二氯甲烷;Chloroform-d与CDC13为氘代氯仿;PE为石油醚;EtOAc与EA均为乙酸乙酯;MeOH与CH3OH均为甲醇;ClSO3H为氯磺酸;TEA与Et3N为三乙胺;DMSO-d 6为六氘代二甲亚砜;THF为四氢呋喃;NaCl为氯化钠;Na2SO4为硫酸钠;CDI为N,N-羰基二咪唑。
实施例1
(2-(5-(2-乙酰氨基-4-甲基噻唑-5-基)-2-氯苯基磺酰胺基)乙基)氨基甲酸叔丁酯的合成,合成步骤如下:
步骤1:2-氯-5-(2-氧代丙基)苯磺酰氯的合成:
量取10 mL的ClSO3H (132 mmol,11.0 eq.)加到25 mL的茄形反应瓶中在冰浴下预冷30 min,将2.02 g(12.0 mmol)4-氯苯基丙酮缓慢的滴加到ClSO3H中,室温反应大约6h,通过TLC点板至原料1a全部消耗完。将反应液缓慢滴加到冰块上淬灭未反应的ClSO3H,再用乙酸乙酯溶液(3x100 mL)萃取上述水溶液,收集有机相,用饱和氯化钠水溶液(50 mL)洗涤有机相,经无水硫酸钠干燥,减压浓缩得到粗品,经硅胶柱层析(PE:EA=4:1-2:1)纯化。白色固体,收率:60 %。1H NMR (300 MHz, Chloroform-d)δ7.95 (d,J= 2.1 Hz, 1H), 7.63(d,J= 8.2 Hz, 1H), 7.50 (dd,J= 8.2, 2.1 Hz, 1H), 3.86 (s, 2H), 2.30 (s, 3H).
步骤2:(2-(2-氯-5-(2-氧代丙基)苯基磺酰胺基)乙基)氨基甲酸叔丁酯的合成:称取5 mmol的2-氯-5-(2-氧代丙基)苯磺酰氯溶于20mL二氯甲烷中,将7.5 mmol的(2-氨基乙基)氨基甲酸叔丁酯(1.5 eq.)和1.01 g三乙胺(2.0 eq.)加至反应液中室温搅拌12 h至2-氯-5-(2-氧代丙基)苯磺酰氯全部消耗完。反应结束经浓缩柱层析(PE:EA=1:1)纯化。白色固体,收率:78 %。1H NMR (400 MHz, DMSO-d 6)δ7.85 (t,J= 5.9 Hz, 1H), 7.78 (d,J= 2.1 Hz, 1H), 7.60 (d,J= 8.1 Hz, 1H), 7.43(dd,J= 8.2, 2.2 Hz, 1H), 6.78 (t,J= 5.8 Hz, 1H), 3.95 (s, 2H), 3.02–2.93 (m,2H), 2.84 (dt,J= 8.2, 6.0 Hz, 2H), 2.18 (s, 3H), 1.35 (s, 9H);13C NMR (101MHz, DMSO-d 6)δ205.63, 155.97, 137.78, 135.79, 135.40, 132.09, 131.92, 129.09,78.30, 48.54, 42.60, 30.21, 28.64.
步骤3:(5-(1-溴-2-氧代丙基)-2-氯苯基磺酰胺基)乙基)氨基甲酸叔丁酯的合成:称取1 mmol(2-(2-氯-5-(2-氧代丙基)苯基磺酰胺基)乙基)氨基甲酸叔丁酯溶于5 mL四氢呋喃溶液中并置于茄形瓶中,在冰浴状态下,缓慢滴加含有1.1 mmol的苯基三甲基三溴化铵的10 mL的四氢呋喃溶液至上述反应液中,滴加结束撤去冰浴于室温反应0.5 h至反应物全部消耗完,经纯化(PE:EA=1:1)得到溴代产物。淡黄色油状物,收率:60 %。1H NMR (300 MHz, Chloroform-d)δ8.11 (d,J= 2.3 Hz, 1H),7.66 (dd,J= 8.3, 2.3 Hz, 1H), 7.57 (d,J= 8.3 Hz, 1H), 5.72 (s, 1H), 5.42 (s,1H), 4.87 (s, 1H), 3.28 (q,J= 5.7 Hz, 2H), 3.08 (q,J= 5.8 Hz, 2H), 2.44 (s,3H), 1.46 (s, 9H).
步骤4:(2-(5-(2-乙酰氨基-4-甲基噻唑-5-基)-2-氯苯基磺酰胺基)乙基)氨基甲酸叔丁酯的合成,结构式如下:首先制备N-乙酰硫脲,称10 mmol的硫脲溶于30 mL的无水甲苯溶液中并置于100 mL的茄形瓶中,称取15 mmol的乙酰氯溶于2 mL无水甲苯中并缓慢滴加至反应器中,将反应升温至110 ℃回流反应5 h,反应结束将反应液冷却至室温浓缩反应液,经柱层析(PE:EA=8:1)得到白色固体N-乙酰硫脲,收率:71 %(1H NMR (400 MHz, Chloroform-d)δ9.88 (s, 1H), 8.99 (s, 1H), 7.14 (s,1H), 2.19 (s, 3H).)。称取1 mmol中间体4d于25 mL的茄形瓶中,加入10 mL丙酮溶液,再将1 mmol N-乙酰硫脲(1.0 eq.)加入反应液中,升温至 60℃回流反应1 h,TLC监测直到中间体4a全部消耗完(DCM:MeOH=25:1),真空浓缩,柱层析纯化。白色固体,收率:60 %。1H NMR(400 MHz, DMSO-d 6 )δ12.25 (s, 1H), 8.04 (t,J= 5.7 Hz, 1H), 7.93 (t,J= 1.3 Hz,1H), 7.72 (d,J= 1.3 Hz, 2H), 6.77 (t,J= 5.6 Hz, 1H), 2.97 (q,J= 6.4 Hz, 2H),2.93 – 2.80 (m, 2H), 2.37 (s, 3H), 2.15 (s, 3H), 1.33 (s, 9H);13C NMR (101MHz, DMSO-d 6 )δ175.44, 156.03, 155.52, 143.80, 138.28, 133.23, 132.53, 131.84,129.39, 128.96, 121.44, 77.86, 42.22, 42.21, 28.19, 19.09, 16.13.ESI-HRMScalcdforC19H25ClN4O5S2 m/z[M + H]+489.1028, found [M + H]+489.1032.
实施例2
N-(5-(4-氯-3-(N-(2-羟基-2-甲基丙基)氨基磺酰基)苯基)-4-甲基噻唑-2-基)乙酰胺,结构式如下:将实施例1中步骤2中的片段(2-氨基乙基)氨基甲酸叔丁酯改为1-氨基-2-甲基-2-丙醇,其他步骤及操作同实施例1;白色固体,收率:25 %。1H NMR (400 MHz, DMSO-d 6 )δ12.24 (s, 1H), 7.94 (s, 1H), 7.77 (t,J= 6.3Hz, 1H), 7.72–7.68 (m, 2H), 4.45 (s, 1H), 2.83 (d,J= 6.2 Hz, 2H), 2.37 (s,3H), 2.16 (s, 3H), 1.05 (s, 6H);13C NMR (101 MHz, DMSO-d 6 )δ166.42, 145.50,138.51, 132.58, 132.11, 132.03, 128.42, 127.28, 114.92, 68.87, 53.89, 27.03,16.48.ESI-HRMScalcdforC16H20ClN3O4S2 m/z[M + H]+418.0657, found [M + H]+418.0663.
实施例3
N-(2-(2-乙酰氨基-4-甲基噻唑-5-基)-2-氯苯基磺酰胺基)乙基丙酰胺,结构式如下:将实施例1中步骤2中的片段(2-氨基乙基)氨基甲酸叔丁酯改为N-(2-氨基乙基)丙酰胺,其他步骤及操作同实施例1;白色固体,收率:30%。1HNMR (400 MHz, DMSO-d 6 )δ7.93 (s, 1H), 7.76 (t,J= 5.7 Hz, 1H), 7.71 –7.69 (m,2H), 3.09 (q,J= 6.4 Hz, 2H), 2.92 (t,J= 6.7 Hz, 2H), 2.37 (s, 3H), 2.15 (s,3H), 2.00 (q,J= 7.5 Hz, 2H), 0.93 (td,J= 7.6, 3H);13C NMR (101 MHz, DMSO-d 6 )δ173.13, 168.66, 155.88, 143.79, 138.26, 133.20, 132.48, 131.80, 129.34,128.92, 121.34, 42.07, 38.62, 28.39, 22.48, 16.16, 9.74. ESI-HRMScalcdforC17H21ClN4O4S2 m/z[M + H]+445.0766, found [M + H]+445.0762.
实施例4
(2-(2-乙酰氨基-4-甲基噻唑-5-基)-2-氯苯基磺酰胺基)乙基氨基甲酸甲酯,结构式如下:将实施例1中步骤2中的片段(2-氨基乙基)氨基甲酸叔丁酯改为(2-氨基乙基)氨基甲酸甲酯,其他步骤及操作同实施例1;白色固体,收率:29 %。1H NMR (400 MHz, DMSO-d 6 )δ12.24 (s, 1H), 8.06 (t,J= 5.8 Hz, 1H), 7.93 (s,1H), 7.71 (d,J= 1.3 Hz, 2H), 7.07 (t,J= 5.7 Hz, 1H), 3.46 (s, 3H), 3.03 (q,J=6.4 Hz, 2H), 2.93 (q,J= 6.4 Hz, 2H), 2.37 (s, 3H), 2.15 (s, 3H);13C NMR (101MHz, DMSO-d 6 )δ168.66, 156.65, 155.90, 143.79, 138.28, 133.17, 132.47, 131.80,129.33, 128.94, 121.38, 51.35, 42.12, 40.33, 22.48, 16.16.ESI-HRMScalcdforC16H19ClN4O5S2 m/z[M + H]+447.0558, found [M + H]+447.0556.
实施例5
(2-((5-(2-乙酰氨基-4-甲基噻唑-5-基)-2-甲氧基苯基)磺酰胺基)乙基)氨基甲酸叔丁酯,结构式如下: 将实施例1中步骤1中的原料改为1-(4-氯苯基)-2-丙酮改为1-(4-甲氧基苯基)-2-丙酮,其他步骤及操作同实施例1;白色固体,收率:28%。1H NMR (400 MHz, DMSO-d 6 )δ12.14 (s, 1H), 7.71 (d,J= 2.4 Hz, 1H),7.68 (dd,J= 8.6, 2.4 Hz, 1H), 7.38 (t,J= 5.9 Hz, 1H), 7.31 (d,J= 8.6 Hz, 1H),6.74 (t,J= 5.8 Hz, 1H), 3.94 (s, 3H), 2.95 (q,J= 6.5 Hz, 2H), 2.82 (q,J= 6.5Hz, 2H), 2.32 (s, 3H), 2.14 (s, 3H), 1.34 (s, 9H);13C NMR (101 MHz, DMSO-d 6 )δ168.41, 155.46, 155.30, 155.01, 142.06, 134.26, 128.89, 128.17, 124.02,122.27, 113.62, 77.80, 56.37, 42.38, 42.36, 28.19, 22.46, 15.85; ESI-HRMScalcd for C20H28N4O6S2 m/z[M + H]+485.1523, found [M + H]+485.1519.
实施例6
N-(5-(4-氯-3-(N-(3-羟基-4-甲基苯基)氨基磺酰基)苯基)-4-甲基噻唑-2-基)乙酰胺,结构式如下:将实施例1中步骤2中的片段(2-氨基乙基)氨基甲酸叔丁酯改为5-氨基-2-甲基苯酚,其他步骤及操作同实施例1;白色固体,收率:25%。1H NMR (400 MHz, DMSO-d 6 ) δ12.20 (s, 1H), 9.89 (s, 1H), 9.72 (s, 1H), 7.84(dd,J= 10.3, 2.1 Hz, 1H), 7.73 – 7.61 (m, 2H), 7.25 (s, 1H), 6.72 (s, 1H),5.75 (d,J= 1.6 Hz, 1H), 2.22 (d,J= 4.8 Hz, 3H), 2.18 – 2.09 (m, 6H);13C NMR(101 MHz, DMSO-d 6 ) δ168.58, 155.90, 150.55, 143.61, 138.06, 135.64, 133.50,132.38, 131.30, 129.72, 129.51, 128.46, 122.67, 121.26, 117.71, 111.63,22.44,21.99, 15.78; ESI-HRMScalcdforC19H18ClN3O4S2 m/z[M + H]+452.0500, found [M + H]+452.0511.
实施例7
N-(5-(3-(N-(2,4-二氟苯基)氨基磺酰基)-4-甲氧基苯基)-4-甲基噻唑-2-基)乙酰胺,结构式如下:将实施例1中步骤1中的原料改为1-(4-氯苯基)-2-丙酮改为1-(4-甲氧基苯基)-2-丙酮以及步骤2中的片段(2-氨基乙基)氨基甲酸叔丁酯改为2,4-二氟苯胺,其他步骤及操作同实施例1;白色固体,收率:39%。1H NMR (400MHz, DMSO-d 6)δ12.12 (d,J= 5.6 Hz, 1H), 9.89 (s, 1H), 7.81–7.53 (m, 2H), 7.37–7.16 (m, 3H), 7.11–6.87 (m, 1H), 3.90 (d,J= 22.1 Hz, 4H), 2.25–2.10 (m, 6H);13C NMR (101 MHz, DMSO)δ168.40, 155.64, 155.01, 142.09, 134.86, 129.78,129.08, 128.91, 128.86, 128.80, 128.77, 127.48, 123.76, 122.01, 113.61,111.63, 111.58, 104.70, 104.41, 104.17, 56.26, 22.43, 14.22; ESI-HRMScalcdforC19H17F2N3O4S2 m/z[M + H]+454.0701, found [M + H]+454.0709.
实施例8
(5-(2-丙酰胺基-4-甲基噻唑-5-基)-2-甲氧基苯基磺酰胺基)乙基氨基甲酸叔丁酯,结构式如下:将实施例1中步骤1中的原料改为1-(4-氯苯基)-2-丙酮改为1-(4-甲氧基苯基)-2-丙酮,以及步骤4中的乙酰氯改为丙酰氯,其他步骤及操作同实施例1;白色固体,收率:32%。1H NMR (400 MHz, DMSO-d 6 ) δ12.09 (s,1H), 7.72 (d,J= 2.4 Hz, 1H), 7.67 (dd,J= 8.5, 2.4 Hz, 1H), 7.38 (t,J= 5.9 Hz,1H), 7.31 (d,J= 8.7 Hz, 1H), 6.75 (t,J= 5.7 Hz, 1H), 3.94 (s, 3H), 2.96 (q,J=6.5 Hz, 2H), 2.83 (q,J= 6.6 Hz, 2H), 2.43 (q,J= 7.5 Hz, 2H), 2.32 (s, 3H),1.34 (s, 9H), 1.09 (t,J= 7.6 Hz, 3H);13C NMR (101 MHz, DMSO-d 6 )δ172.07,155.46, 155.30, 155.06, 142.07, 134.25, 128.90, 128.20, 124.06, 122.22,113.63, 77.80, 56.37, 42.39, 28.23, 28.19, 15.84, 9.18; ESI-HRMS calcd forC21H30N4O6S2 m/z[M + H]+499.1680, found [M + H]+499.1671.
实施例9
(5-(2-丁酰胺基-4-甲基噻唑-5-基)-2-甲氧基苯基磺酰胺基)乙基氨基甲酸叔丁酯,结构式如下:将实施例1中步骤1中的原料改为1-(4-氯苯基)-2-丙酮改为1-(4-甲氧基苯基)-2-丙酮,以及步骤4中的乙酰氯改为丁酰氯,其他步骤及操作同实施例1;白色固体,收率:34%。1H NMR (400 MHz, DMSO-d 6 ) δ12.11 (s,1H), 7.72 (d,J= 2.4 Hz, 1H), 7.67 (dd,J= 8.6, 2.4 Hz, 1H), 7.37 (t,J= 6.9,6.4 Hz, 1H), 7.31 (d,J= 8.6 Hz, 1H), 6.74 (t,J= 5.6 Hz, 1H), 3.94 (s, 3H),2.96 (q,J= 6.5 Hz, 2H), 2.88–2.76 (m, 2H), 2.40 (t,J= 7.3 Hz, 2H), 2.32 (s,3H), 1.66–1.57 (m, 2H), 1.34 (s, 9H), 0.89 (t,J= 7.4 Hz, 3H);13C NMR (101 MHz,DMSO-d 6 ) δ171.24, 155.47, 155.31, 154.99, 142.07, 134.26, 128.93, 128.20,124.06, 122.26, 113.62, 77.80, 56.37, 42.39, 36.78, 28.18, 18.23, 15.82,13.50; ESI-HRMS calcd for C22H32N4O6S2 m/z[M + H]+513.1836, found [M + H]+513.1841.
实施例10
(5-(2-戊酰胺基-4-甲基噻唑-5-基)-2-甲氧基苯基磺酰胺基)乙基氨基甲酸叔丁酯,结构式如下:将实施例1中步骤1中的原料改为1-(4-氯苯基)-2-丙酮改为1-(4-甲氧基苯基)-2-丙酮,以及步骤4中的乙酰氯改为戊酰氯,其他步骤及操作同实施例1;白色固体,收率:35 %.1H NMR (300 MHz, DMSO-d 6 ) δ12.12 (s,1H), 7.72 (d,J= 2.4 Hz, 1H), 7.68 (dd,J= 8.5, 2.4 Hz, 1H), 7.46 (t,J= 5.9 Hz,2H), 7.31 (d,J= 8.7 Hz, 1H), 3.94 (s, 3H), 3.15 – 3.03 (m, 2H), 2.83 (q,J=6.6 Hz, 2H), 2.42 (t,J= 7.4 Hz, 2H), 2.32 (s, 3H), 1.63–1.53 (m, 2H), 1.36–1.24 (m, 2H), 1.04 (s, 9H), 0.88 (t,J= 7.3 Hz, 3H);13C NMR (101 MHz, DMSO) δ171.42, 155.50, 155.33, 155.02, 142.10, 134.29, 128.94, 128.23, 124.08,122.29, 113.66, 77.83, 56.40, 42.41, 40.17, 39.96, 39.75, 39.54, 39.33,39.12, 38.92, 34.88, 28.20, 24.45, 21.85, 15.83, 13.85; ESI-HRMS calcd forC23H34N4O6S2 m/z[M + H]+527.1993, found [M + H]+527.1995.
实施例11
(5-(2-己酰胺基-4-甲基噻唑-5-基)-2-甲氧基苯基磺酰胺基)乙基氨基甲酸叔丁酯,结构式如下:将实施例1中步骤1中的原料改为1-(4-氯苯基)-2-丙酮改为1-(4-甲氧基苯基)-2-丙酮,以及步骤4中的乙酰氯改为己酰氯,其他步骤及操作同实施例1;白色固体,收率:34%。1H NMR (300 MHz, DMSO-d 6 )δ12.11 (s,1H), 7.72 (d,J= 2.4 Hz, 1H), 7.67 (dd,J= 8.5, 2.4 Hz, 1H), 7.38 (t,J= 5.8 Hz,1H), 7.31 (d,J= 8.7 Hz, 1H), 6.74 (t,J= 5.5 Hz, 1H), 3.94 (s, 3H), 3.03–2.90(m, 2H), 2.90–2.76 (m, 2H), 2.41 (t,J= 7.3 Hz, 2H), 2.31 (s, 3H), 1.64–1.54(m, 2H), 1.34 (s, 9H), 1.29–1.22 (m, 4H), 0.88–0.84 (m, 3H);13C NMR (101 MHz,DMSO-d 6 )δ171.40, 155.48, 155.31, 155.00, 142.08, 134.27, 128.92, 128.21,124.06, 122.27, 113.64, 77.81, 56.38, 42.39, 34.86, 30.72, 28.18, 24.43,21.83, 15.81, 13.83; ESI-HRMS calcd for C24H36N4O6S2 m/z[M + H]+541.2149, found[M + H]+541.2147.
实施例12
(5-(2-庚酰胺基-4-甲基噻唑-5-基)-2-甲氧基苯基磺酰胺基)乙基氨基甲酸叔丁酯,结构式如下:将实施例1中步骤1中的原料改为1-(4-氯苯基)-2-丙酮改为1-(4-甲氧基苯基)-2-丙酮,以及步骤4中的乙酰氯改为庚酰氯,其他步骤及操作同实施例1;白色固体,收率:35%。1H NMR (400 MHz, DMSO-d 6 ) δ12.11 (s,1H), 7.72 (d,J= 2.4 Hz, 1H), 7.67 (dd,J= 8.6, 2.4 Hz, 1H), 7.38 (t,J= 5.8 Hz,1H), 7.31 (d,J= 8.6 Hz, 1H), 6.74 (t,J= 5.7 Hz, 1H), 3.94 (s, 3H), 2.95 (q,J=6.5 Hz, 2H), 2.86–2.77 (m, 2H), 2.41 (t,J= 7.4 Hz, 2H), 2.32 (s, 3H), 1.62–1.55 (m, 2H), 1.34 (s, 9H), 1.30–1.26 (m, 6H), 0.87–0.84 (m, 3H);13C NMR (101MHz, DMSO-d 6 )δ171.36, 155.45, 155.29, 154.98, 142.06, 134.24, 128.91, 128.20,124.04, 122.25, 113.62, 77.78, 56.35, 42.37, 34.88, 30.93, 28.17, 24.68,21.95, 15.80, 13.91.; ESI-HRMS calcd for C25H38N4O6S2 m/z[M + H]+555.2306, found[M + H]+555.2310.
实施例13
(2-(2-甲氧基-5-(4-甲基-2-(3-丙基脲基)噻唑-5-基)苯基)磺酰胺基)乙基氨基甲酸叔丁酯,结构式如下:将实施例1中步骤1中的原料改为1-(4-氯苯基)-2-丙酮改为1-(4-甲氧基苯基)-2-丙酮,以及步骤4中的乙酰氯改为丙基氨基甲酰氯,其他步骤及操作同实施例1;白色固体,收率:36%。1H NMR (400 MHz,DMSO-d 6 )δ10.36 (s, 1H), 7.68 (d,J= 2.4 Hz, 1H), 7.63 (dd,J= 8.6, 2.4 Hz, 1H),7.39 (t,J= 5.9 Hz, 1H), 7.29 (d,J= 8.7 Hz, 1H), 6.76 (t,J= 5.7 Hz, 1H), 6.57(t,J= 5.9 Hz, 1H), 3.93 (s, 3H), 3.08 (q,J= 6.6 Hz, 2H), 2.95 (q,J= 6.5 Hz,2H), 2.81 (q,J= 6.6 Hz, 2H), 2.26 (s, 3H), 1.49–1.40 (m, 2H), 1.33 (s, 9H),0.86 (t,J= 7.4 Hz, 3H);13C NMR (101 MHz, DMSO-d 6 )δ156.83, 155.50, 155.05,152.76, 141.76, 134.00, 128.72, 128.09, 124.51, 120.77, 113.60, 77.85, 65.01,56.37, 50.02, 42.41, 28.81, 28.22, 15.96, 15.24; ESI-HRMS calcd forC22H33N5O6S2 m/z[M + H]+528.1945, found [M + H]+528.1940.
实施例14
(2-(5-(2-(3-丁基脲基)-4-甲基噻唑-5-基)-2-甲氧基苯基磺酰胺基)乙基)氨基甲酸叔丁酯,结构式如下:将实施例1中步骤1中的原料改为1-(4-氯苯基)-2-丙酮改为1-(4-甲氧基苯基)-2-丙酮,以及步骤4中的乙酰氯改为丁基氨基甲酰氯,其他步骤及操作同实施例1;白色固体,收率:42 %。1H NMR (400 MHz,DMSO-d 6 )δ10.33 (s, 1H), 7.69 (d,J= 2.4 Hz, 1H), 7.63 (dd,J= 8.6, 2.4 Hz, 1H),7.36 (t,J= 5.8 Hz, 1H), 7.29 (d,J= 8.7 Hz, 1H), 6.74 (t,J= 5.7 Hz, 1H), 6.56–6.53 (m, 1H), 3.93 (s, 3H), 3.12 (q,J= 6.5 Hz, 2H), 2.95 (q,J= 6.5 Hz, 2H),2.82 (q,J= 6.5 Hz, 2H), 2.26 (s, 3H), 1.46–1.39 (m, 2H), 1.34 (s, 9H), 1.29(t,J= 7.5 Hz, 2H), 0.89 (t,J= 7.3 Hz, 3H);13C NMR (101 MHz, DMSO-d 6 )δ164.06,155.50, 155.08, 153.83, 141.81, 134.05, 128.73, 128.10, 124.45, 113.60,77.85, 65.01, 56.37, 42.41, 41.05, 28.22, 22.82, 15.93, 15.24, 11.30; ESI-HRMS calcd for C23H35N5O6S2 m/z[M + H]+542.2102, found [M + H]+542.2105.
实施例15
(2-(2-甲氧基-5-(4-甲基-2-(3-甲基丁酰胺)噻唑-5-基)苯基)磺酰胺基)乙基氨基甲酸叔丁酯,结构式如下:将实施例1中步骤1中的原料改为1-(4-氯苯基)-2-丙酮改为1-(4-甲氧基苯基)-2-丙酮,以及步骤4中的乙酰氯改为3-甲基丁酰氯,其他步骤及操作同实施例1;白色固体,收率:40%。1H NMR (400 MHz,DMSO-d 6 ) δ12.10 (s, 1H), 7.72 (d,J= 2.4 Hz, 1H), 7.68 (dd,J= 8.6, 2.4 Hz,1H), 7.37 (t,J= 5.8 Hz, 1H), 7.31 (d,J= 8.7 Hz, 1H), 6.73 (t,J= 5.7 Hz, 1H),3.94 (s, 3H), 2.96 (q,J= 6.5 Hz, 2H), 2.83 (q,J= 6.3 Hz, 2H), 2.31 (d,J= 7.7Hz, 5H), 2.11–2.03 (m, 1H), 1.34 (s, 9H), 0.92 (d,J= 6.7 Hz, 6H);13C NMR (75MHz, DMSO-d 6 ) δ170.76, 155.49, 155.34, 154.95, 142.11, 134.31, 128.98,128.19, 124.07, 122.31, 113.64, 77.83, 59.81, 56.39, 43.94, 42.41, 28.20,25.59, 22.19, 15.83; ESI-HRMS calcd for C23H34N4O6S2 m/z[M + H]+527.1993, found[M + H]+527.2001.
实施例16
(5-(2-异丁酰胺基-4-甲基噻唑-5-基)-2-甲氧基苯基磺酰胺基)乙基氨基甲酸叔丁酯,结构式如下:将实施例1中步骤1中的原料改为1-(4-氯苯基)-2-丙酮改为1-(4-甲氧基苯基)-2-丙酮,以及步骤4中的乙酰氯改为2-甲基丙酰氯,其他步骤及操作同实施例1;白色固体,收率:26%。1H NMR (400 MHz, DMSO-d 6 )δ12.11(s, 1H), 7.72 (d,J= 2.4 Hz, 1H), 7.67 (dd,J= 8.6, 2.4 Hz, 1H), 7.39 (t,J= 5.9Hz, 1H), 7.31 (d,J= 8.7 Hz, 1H), 6.75 (t,J= 5.7 Hz, 1H), 3.94 (s, 3H), 2.95(q,J= 6.6 Hz, 2H), 2.82 (q,J= 6.5 Hz, 2H), 2.75–2.69 (m, 1H), 2.32 (s, 3H),1.34 (s, 9H), 1.11 (d,J= 6.9 Hz, 6H);13C NMR (101 MHz, DMSO-d 6 )δ175.22,155.47, 155.32, 155.15, 142.09, 134.29, 128.93, 128.23, 124.06, 122.35,113.64, 77.80, 56.38, 42.40, 39.82, 33.82, 28.19, 19.11, 15.80; ESI-HRMScalcdfor C22H32N4O6S2 m/z[M + H]+513.1836, found [M + H]+513.1839.
实施例17
(2-(2-甲氧基-5-(4-甲基-2-特戊酰胺噻唑-5-基)苯基)磺酰胺基)乙基氨基甲酸叔丁酯,结构式如下:将实施例1中步骤1中的原料改为1-(4-氯苯基)-2-丙酮改为1-(4-甲氧基苯基)-2-丙酮,以及步骤4中的乙酰氯改为2,2-二甲基丙酰氯,其他步骤及操作同实施例1;白色固体,收率:30%。1H NMR (300 MHz, DMSO-d 6 ) δ11.85 (s, 1H), 7.72 (d,J= 2.4 Hz, 1H), 7.67 (dd,J= 8.5, 2.4 Hz, 1H),7.40 (t,J= 5.9 Hz, 1H), 7.32 (d,J= 8.6 Hz, 1H), 6.76 (t,J= 5.6 Hz, 1H), 3.94(s, 3H), 3.05–2.90 (m, 2H), 2.83 (q,J= 6.8 Hz, 2H), 2.33 (s, 3H), 1.34 (s,9H), 1.24 (s, 9H);13C NMR (101 MHz, DMSO) δ176.70, 155.79, 155.48, 155.32,141.99, 134.28, 128.95, 128.26, 124.11, 122.42, 113.64, 77.81, 56.37, 42.43,38.77, 28.18, 26.60, 15.71; ESI-HRMS calcd for C23H34N4O6S2 m/z[M + H]+527.1993,found [M + H]+527.2000.
实施例18
(5-(2-(3,3-二甲基丁酰胺)-4-甲基噻唑-5-基)-2-甲氧基苯基磺酰胺基)乙基氨基甲酸叔丁酯,结构式如下:将实施例1中步骤1中的原料改为1-(4-氯苯基)-2-丙酮改为1-(4-甲氧基苯基)-2-丙酮,以及步骤4中的乙酰氯改为3,3-二甲基丁酰氯,其他步骤及操作同实施例1;白色固体,收率:40 %。1H NMR (400MHz, DMSO-d 6 ) δ12.05 (s, 1H), 7.73 (d,J= 2.4 Hz, 1H), 7.68 (dd,J= 8.6, 2.4Hz, 1H), 7.36 (t,J= 5.8 Hz, 1H), 7.31 (d,J= 8.6 Hz, 1H), 6.73 (t,J= 5.7 Hz,1H), 3.94 (s, 3H), 2.95 (q,J= 6.5 Hz, 2H), 2.89–2.77 (m, 2H), 2.32 (d,J= 2.6Hz, 5H), 1.34 (s, 9H), 1.00 (s, 9H);13C NMR (101 MHz, DMSO-d 6 ) δ174.22,155.45, 155.29, 155.10, 142.05, 134.25, 128.90, 128.22, 124.07, 122.27,113.62, 77.78, 56.35, 43.33, 42.38, 28.76, 28.17, 25.03, 15.78; ESI-HRMScalcd for C24H36N4O6S2 m/z[M + H]+541.2149, found [M + H]+541.2152.
实施例19
(2-(2-甲氧基-5-(4-甲基-2-(4-甲基戊酰胺)噻唑-5-基)苯基)磺酰胺基)乙基氨基甲酸叔丁酯,结构式如下:将实施例1中步骤1中的原料改为1-(4-氯苯基)-2-丙酮改为1-(4-甲氧基苯基)-2-丙酮,以及步骤4中的乙酰氯改为4-甲基戊酰氯,其他步骤及操作同实施例1;白色固体,收率:34%。1H NMR (400 MHz,DMSO-d 6 ) δ12.14 (s, 1H), 7.71 (d,J= 2.4 Hz, 1H), 7.67 (dd,J= 8.6, 2.4 Hz,1H), 7.40 (t,J= 5.9 Hz, 1H), 7.31 (d,J= 8.6 Hz, 1H), 6.76 (t,J= 5.7 Hz, 1H),3.94 (s, 3H), 2.95 (q,J= 6.5 Hz, 2H), 2.86–2.75 (m, 2H), 2.43 (t,J= 7.3 Hz,2H), 2.31 (s, 3H), 1.53–1.47 (m, 3H), 1.33 (s, 9H), 0.87 (d,J= 6.2 Hz, 6H);13CNMR (101 MHz, DMSO) δ 169.96, 155.44, 155.29, 154.81, 142.05, 134.24, 128.93,128.18, 124.05, 122.26, 113.60, 77.77, 56.35, 47.91, 42.37, 30.98, 29.44,28.16, 15.79; ESI-HRMS calcd for C24H36N4O6S2 m/z[M + H]+541.2149, found [M + H]+541.2143.
实施例20
(2-(2-甲氧基-5-(4-甲基-2-(5-甲基己酰胺基)噻唑-5-基)苯基)磺酰胺基)乙基氨基甲酸叔丁酯,结构式如下:将实施例1中步骤1中的原料改为1-(4-氯苯基)-2-丙酮改为1-(4-甲氧基苯基)-2-丙酮,以及步骤4中的乙酰氯改为5-甲基己酰氯,其他步骤及操作同实施例1;白色固体,收率:34 %。1H NMR (400MHz, DMSO-d 6 ) δ12.09 (s, 1H), 7.73 (t,J= 1.9 Hz, 1H), 7.67 (dt,J= 8.7, 2.1Hz, 1H), 7.37 (t,J= 5.8 Hz, 1H), 7.31 (dd,J= 8.7, 1.8 Hz, 1H), 6.73 (t,J= 5.8Hz, 1H), 3.94 (s, 3H), 2.96 (q,J= 6.6 Hz, 2H), 2.83 (q,J= 6.6 Hz, 2H), 2.45–2.36 (m, 2H), 2.32 (d,J= 1.7 Hz, 3H), 1.67–1.46 (m, 3H), 1.34 (s, 9H), 1.21–1.11 (m, 2H), 0.86 (dd,J= 6.7, 1.9 Hz, 6H);13C NMR (101 MHz, DMSO-d 6 ) δ171.37,155.47, 155.31, 155.00, 142.07, 134.26, 128.93, 128.20, 124.06, 122.27,113.62, 77.80, 56.37, 42.39 , 37.81, 35.11, 28.18, 27.25, 22.66, 22.42,15.82; ESI-HRMS calcd for C25H38N4O6S2 m/z[M + H]+555.2306, found [M + H]+555.2307.
实施例21
(2-(5-(2-(环己烷甲酰胺基)-4-甲基噻唑-5-基)-2-甲氧基苯基)磺酰胺基)乙基氨基甲酸叔丁酯,结构式如下:将实施例1中步骤1中的原料改为1-(4-氯苯基)-2-丙酮改为1-(4-甲氧基苯基)-2-丙酮,以及步骤4中的乙酰氯改为环己烷甲酰氯,其他步骤及操作同实施例1;白色固体,收率:45 %。1H NMR (400 MHz,DMSO-d 6 ) δ12.06 (s, 1H), 7.71 (d,J= 2.4 Hz, 1H), 7.66 (dd,J= 8.6, 2.4 Hz,1H), 7.38 (t,J= 5.9 Hz, 1H), 7.31 (d,J= 8.7 Hz, 1H), 6.74 (t,J= 5.8 Hz, 1H),3.94 (s, 3H), 2.95 (q,J= 6.5 Hz, 2H), 2.82 (q,J= 6.5 Hz, 2H), 2.45 (dt,J=11.4, 3.5 Hz, 1H), 2.31 (s, 3H), 1.82–1.72 (m, 4H), 1.45 – 1.38 (m, 2H), 1.34(s, 9H), 1.29 – 1.15 (m, 4H);13C NMR (101 MHz, DMSO-d 6 ) δ174.26, 155.48,155.32, 155.12, 142.08, 134.29, 128.92, 128.21, 124.08, 122.29, 113.65,77.82, 56.39, 43.36, 42.40, 39.82, 28.79, 28.20, 25.29, 25.06, 15.82; ESI-HRMS calcd for C25H36N4O6S2 m/z[M + H]+553.2149, found [M + H]+553.2153.
实施例22
(2-(2-氯-5-(4-甲基-2-(3-甲基丁酰胺基)噻唑-5-基)苯基)磺酰胺基)乙基氨基甲酸叔丁酯,结构式如下:将实施例1中步骤4中的乙酰氯改为3-甲基丁酰氯,其他步骤及操作同实施例1;白色固体,收率:35 %。1H NMR (300MHz, DMSO-d 6 ) δ 12.23 (s, 1H), 8.05 (t,J= 5.6 Hz, 1H), 7.97 – 7.91 (m, 1H),7.72 (t,J= 1.4 Hz, 2H), 6.79 (t,J= 5.5 Hz, 1H), 2.97 (dd,J= 12.2, 6.6 Hz,2H), 2.91 (d,J= 6.7 Hz, 2H), 2.38 (s, 3H), 1.34 (s, 8H), 1.16 (dd,J = 18.6,7.0 Hz, 8H);13C NMR (101 MHz, DMSO-d 6 ) δ 175.85, 156.46, 155.94, 144.22,138.72, 133.64, 132.94, 132.27, 129.82, 129.38, 121.86, 78.28, 60.22, 42.65,34.28, 28.62, 21.23, 19.52, 16.55, 14.55; ESI-HRMS calcd for C22H31N4O5S2m/z [M+ H]+531.1497, found [M + H]+531.1495.
实施例23
(2-氯-5-(2-(3,3-二甲基丁酰胺)-4-甲基噻唑-5-基)苯基磺酰胺基)乙基氨基甲酸叔丁酯,结构式如下:将实施例1中步骤4中的乙酰氯改为3,3-二甲基丁酰氯,其他步骤及操作同实施例1;白色固体,收率:35%。1H NMR (300MHz, DMSO-d 6 ) δ12.19 (s, 1H), 8.04 (t,J= 5.7 Hz, 1H), 7.94 (t,J= 1.3 Hz, 1H),7.72 (d,J= 1.3 Hz, 2H), 6.78 (t,J= 5.6 Hz, 1H), 2.98–2.88 (m, 4H), 2.37 (s,3H), 2.33 (s, 2H), 1.33 (s, 9H), 1.00 (s, 9H);13C NMR (101 MHz, DMSO-d 6 ) δ170.17, 155.67, 155.48, 143.75, 138.21, 133.18, 132.45, 131.82, 129.40,128.90, 121.34, 77.81, 47.90, 42.17, 40.15, 39.94, 39.73, 39.52, 39.31,39.10, 38.89, 31.01, 29.43, 28.16, 16.09; ESI-HRMS calcd for C23H33ClN4O6S2 m/z[M + H]+545.1654, found [M + H]+ 545.1660.
实施例24
(2-氯-5-(4-甲基-2-戊酰胺基-5-基)苯基磺酰胺基)乙基氨基甲酸叔丁酯,结构式如下:将实施例1中步骤4中的乙酰氯改为戊酰氯,其他步骤及操作同实施例1;白色固体,收率:35 %。1H NMR (400 MHz, DMSO-d 6 )δ12.22(s, 1H), 8.03 (t,J= 5.6 Hz, 1H), 7.93 (s, 1H), 7.73 – 7.69 (m, 2H), 6.77 (t,J= 5.6 Hz, 1H), 2.98 (q,J= 6.5 Hz, 2H), 2.90 (q,J= 6.8, 6.2 Hz, 2H), 2.43 (t,J= 7.4 Hz, 2H), 2.37 (s, 3H), 1.62–1.54 (m, 2H), 1.33 (s, 9H), 1.31–1.25 (m,2H), 0.88 (t,J= 7.4 Hz, 3H);13C NMR (101 MHz, DMSO-d 6 )δ171.59, 155.87, 155.50,143.77, 138.25, 133.19, 132.48, 131.82, 129.39, 128.92, 121.34, 77.84, 42.20,34.61, 28.17, 26.81, 21.67, 16.11, 13.65; ESI-HRMS calcd for C22H31ClN4O5S2 m/z[M + H]+531.1497, found [M + H]+531.1498.
实施例25
(2-氯-5-(2-己酰胺基-4-甲基噻唑-5-基)苯基磺酰胺基)乙基氨基甲酸叔丁酯,结构式如下:将实施例1中步骤4中的乙酰氯改为己酰氯,其他步骤及操作同实施例1;白色固体,收率:36%。1H NMR (400 MHz, DMSO-d 6 )δ12.20 (s, 1H), 8.02 (s, 1H), 7.93 (s, 1H), 7.71 (d,J= 1.8 Hz, 2H), 6.85–6.65(m, 1H), 2.98 (q,J= 6.5 Hz, 2H), 2.91 (q,J= 6.6 Hz, 2H), 2.43 (t,J= 7.4 Hz,2H), 2.37 (s, 3H), 1.64–1.56 (m, 2H), 1.33 (s, 9H), 1.30–1.24 (m, 4H), 0.86(t,J= 6.8 Hz, 3H);13C NMR (101 MHz, DMSO-d 6 )δ171.56, 155.84, 155.47, 143.74,138.24, 133.16, 132.46, 131.81, 129.37, 128.90, 121.32, 77.81, 42.18, 39.87,34.84, 30.69, 28.15, 24.37, 21.80, 16.10, 13.81; ESI-HRMS calcd forC23H33ClN4O5S2 m/z[M + H]+545.1654, found [M + H]+545.1645.
实施例26
(2-(5-(2-(3-乙酰氨基丙酰胺基)-4-甲基噻唑-5-基)-2-甲氧基苯基)磺酰胺基)乙基氨基甲酸叔丁酯,结构式如下:
将实施例1中步骤1中的原料改为1-(4-氯苯基)-2-丙酮改为1-(4-甲氧基苯基)-2-丙酮,以及步骤4中的乙酰氯改为3-乙酰氨基丙酰氯,其他步骤及操作同实施例1;白色固体,收率:30%。1H NMR (300 MHz, DMSO-d 6 )δ12.17 (s, 1H), 7.99 (t,J= 5.7 Hz, 1H),7.72 (d,J= 2.4 Hz, 1H), 7.68 (dd,J= 8.5, 2.4 Hz, 1H), 7.39 (t,J= 5.8 Hz, 1H),7.31 (d,J= 8.7 Hz, 1H), 6.83–6.67 (m, 1H), 3.94 (s, 3H), 3.31 (t,J= 6.2 Hz,2H), 2.95 (q,J= 6.5 Hz, 2H), 2.82 (q,J= 6.4 Hz, 2H), 2.59 (t,J= 6.7 Hz, 2H),2.32 (s, 3H), 1.78 (s, 3H), 1.34 (s, 9H);13C NMR (101 MHz, DMSO-d 6 )δ169.72,169.36, 155.50, 155.36, 154.91, 142.14, 134.33, 128.97, 128.20, 124.02,122.36, 113.68, 77.86, 56.42, 42.40, 39.83, 35.16, 34.66, 28.22, 22.60,15.88; ESI-HRMS calcd for C23H33N5O7S2 m/z[M + H]+556.1894, found [M + H]+556.1896.
实施例27
(2-(2-甲氧基-5-(4-甲基-2-(6-氧代庚酰胺基)噻唑-5-基)苯基)磺酰胺基)乙基氨基甲酸叔丁酯,结构式如下:将实施例1中步骤1中的原料改为1-(4-氯苯基)-2-丙酮改为1-(4-甲氧基苯基)-2-丙酮,以及步骤4中的乙酰氯改为6-羰基庚酰氯,其他步骤及操作同实施例1;白色固体,收率:35%。1H NMR (400 MHz,DMSO-d 6 )δ12.10 (s, 1H), 7.72 (d,J= 2.4 Hz, 1H), 7.67 (dd,J= 8.5, 2.4 Hz, 1H),7.36 (t,J= 5.8 Hz, 1H), 7.31 (d,J= 8.6 Hz, 1H), 6.73 (t,J= 5.7 Hz, 1H), 3.94(s, 3H), 2.96 (q,J= 6.5 Hz, 2H), 2.89–2.77 (m, 2H), 2.43 (dt,J= 13.9, 7.3 Hz,4H), 2.32 (s, 3H), 2.07 (s, 3H), 1.63–1.41 (m, 4H), 1.34 (s, 9H);13C NMR (101MHz, DMSO-d 6 )δ208.42, 171.28, 155.53, 155.36, 155.00, 142.13, 134.32, 128.96,128.22, 124.07, 122.33, 113.67, 77.88, 56.41, 42.43, 42.36, 39.84, 34.77,29.76, 28.21, 24.29, 22.71, 15.84; ESI-HRMS calcd for C25H36N4O7S2 m/z[M + H]+569.2098, found [M + H]+569.2103.
实施例28
(2-(2-甲氧基-5-(4-甲基-2-(6-氧代已酰胺基)噻唑-5-基)苯基)磺酰胺基)乙基氨基甲酸叔丁酯,结构式如下:将实施例1中步骤1中的原料改为1-(4-氯苯基)-2-丙酮改为1-(4-甲氧基苯基)-2-丙酮,以及步骤4中的乙酰氯改为5-羰基已酰氯,其他步骤及操作同实施例1;白色固体,收率:35 %。1H NMR (400MHz, DMSO-d 6 )δ12.11 (s, 1H), 7.72 (d,J= 2.4 Hz, 1H), 7.67 (dd,J= 8.6, 2.4 Hz,1H), 7.36 (t,J= 5.9 Hz, 1H), 7.31 (d,J= 8.7 Hz, 1H), 6.73 (t,J= 5.7 Hz, 1H),3.94 (s, 3H), 2.96 (q,J= 6.5 Hz, 2H), 2.83 (q,J= 6.6 Hz, 2H), 2.46 (t,J= 3.6Hz, 2H), 2.42 (t,J= 7.3 Hz, 2H), 2.32 (s, 3H), 2.08 (s, 3H), 1.77 (p,J= 7.4Hz, 2H), 1.34 (s, 9H);13C NMR (101 MHz, DMSO-d 6 )δ208.03, 171.04, 155.50,155.34, 154.98, 142.10, 134.28, 128.96, 128.23, 124.07, 122.32, 113.65,77.84, 56.39, 41.86, 41.81, 34.01, 29.75, 28.20, 18.80, 15.83; ESI-HRMS calcdfor C24H34N4O7S2 m/z[M + H]+555.1942, found [M + H]+555.1946.
实施例29
(R)-(1-((5-(2-己酰胺基-4-甲基噻唑-5-基)-2-甲氧基苯基)磺酰基)哌啶-3-基)氨基甲酸叔丁酯,结构式如下:将实施例1中步骤1中的原料改为1-(4-氯苯基)-2-丙酮改为1-(4-甲氧基苯基)-2-丙酮,步骤2中的片段(2-氨基乙基)氨基甲酸叔丁酯改为(R)-哌啶-3-基氨基甲酸叔丁酯,以及步骤4中的乙酰氯改为己酰氯,其他步骤及操作同实施例1;白色固体,收率:18%。1H NMR (400 MHz, DMSO-d 6 )δ12.09 (s, 1H), 7.73 (d,J= 2.3 Hz, 1H), 7.69 (dd,J= 8.6, 2.5 Hz, 1H), 7.33(d,J= 8.6 Hz, 1H), 6.83 (d,J= 7.7 Hz, 1H), 3.93 (s, 3H), 3.55 (dd,J= 63.9,12.2 Hz, 2H), 2.59 (t,J= 11.5 Hz, 1H), 2.41 (t,J= 7.4 Hz, 2H), 2.31 (s, 3H),1.76 – 1.68 (m, 2H), 1.63 – 1.56 (m, 2H), 1.37 (s, 9H), 1.29 – 1.17 (m, 8H),0.86 (t,J= 6.8 Hz, 3H);13C NMR (101 MHz, DMSO-d 6 )δ171.43, 155.65, 155.06,154.87, 142.17, 134.71, 130.23, 126.27, 124.24, 122.14, 113.99, 77.96, 56.34,50.00, 46.74, 45.50, 34.87, 30.74, 29.42, 28.23, 24.45, 23.70, 21.86, 15.83,13.86; ESI-HRMS calcd for C27H40N4O6S2 m/z[M + H]+581.2462, found [M + H]+ 581.2471.
实施例30
(S)-(1-((5-(2-己酰胺基-4-甲基噻唑-5-基)-2-甲氧基苯基)磺酰基)吡咯烷-3-基)氨基甲酸叔丁酯,结构式如下:将实施例1中步骤1中的原料改为1-(4-氯苯基)-2-丙酮改为1-(4-甲氧基苯基)-2-丙酮,步骤2中的片段(2-氨基乙基)氨基甲酸叔丁酯改为(S)-吡咯烷-3-基氨基甲酸叔丁酯,以及步骤4中的乙酰氯改为己酰氯,其他步骤及操作同实施例1;白色固体,收率:20%。1H NMR (300 MHz, DMSO-d 6 )δ12.11 (s, 1H), 7.76 (d,J= 2.4 Hz, 1H), 7.69 (dd,J= 8.6, 2.4 Hz, 1H), 7.34(d,J= 8.7 Hz, 1H), 7.11 (d,J= 6.5 Hz, 1H), 3.95 (s, 3H), 3.55 – 3.38 (m, 2H),3.25 (q,J= 7.9 Hz, 1H), 2.41 (t,J= 7.4 Hz, 2H), 2.32 (s, 3H), 2.06 – 1.66 (m,2H), 1.65 – 1.53 (m, 2H), 1.35 (s, 9H), 1.34 – 1.20 (m, 6H), 0.89 – 0.82 (m,3H);13C NMR (101 MHz, DMSO-d 6 )δ171.39, 155.59, 155.21, 155.02, 142.11, 134.55,130.65, 126.31, 124.17, 122.18, 113.83, 78.02, 56.36, 52.49, 49.98, 45.99,34.85, 30.73, 30.56, 28.17, 24.43, 21.85, 15.82, 13.84; ESI-HRMScalcdforC26H38N4O6S2 m/z[M + H]+567.2306, found [M + H]+567.2313.
实施例31
4-((2-己酰胺基-4-甲基噻唑-5-基)-2-甲氧基苯基磺酰胺基)哌啶-1-羧酸叔丁酯,结构式如下:将实施例1中步骤1中的原料改为1-(4-氯苯基)-2-丙酮改为1-(4-甲氧基苯基)-2-丙酮,步骤2中的片段(2-氨基乙基)氨基甲酸叔丁酯改为4-氨甲基哌啶-1-羧酸叔丁酯,以及步骤4中的乙酰氯改为己酰氯,其他步骤及操作同实施例1;白色固体,收率:40%。1H NMR (300 MHz, DMSO-d 6 )δ12.11 (s, 1H),7.72 (d,J= 2.4 Hz, 1H), 7.67 (dd,J= 8.5, 2.4 Hz, 1H), 7.47 (t,J= 6.0 Hz, 1H),7.30 (d,J= 8.6 Hz, 1H), 3.92 (s, 3H), 3.87 (t,J= 13.1 Hz, 2H), 2.69 (t,J= 6.3Hz, 2H), 2.41 (t,J= 7.3 Hz, 2H), 2.31 (s, 3H), 1.64 – 1.49 (m, 5H), 1.36 (s,9H), 1.28 – 1.14 (m, 6H), 0.96 – 0.83 (m, 5H);13C NMR (101 MHz, DMSO-d 6 )δ171.46, 155.37, 155.02, 153.88, 142.07, 134.17, 129.00, 128.61, 124.03,122.34, 113.61, 78.52, 59.82, 56.35, 47.98, 35.82, 34.89, 30.75, 28.12,24.46, 21.86, 15.83, 13.86; ESI-HRMS calcd for C28H42N4O6S2m/z [M + H]+595.2619,found [M + H]+595.2624.
实施例32
N-(5-(3-(2-(3,3-二甲基丁酰胺)乙基氨基磺酰基)-4-甲氧基苯基)-4-甲基噻唑-2-基)己酰胺,结构式如下:将实施例1中步骤1中的原料改为1-(4-氯苯基)-2-丙酮改为1-(4-甲氧基苯基)-2-丙酮,步骤2中的片段(2-氨基乙基)氨基甲酸叔丁酯改为N-(2-氨基乙基)-3,3-二甲基丁酰胺,以及步骤4中的乙酰氯改为己酰氯,其他步骤及操作同实施例1;白色固体,收率:30%。1H NMR (300 MHz, DMSO-d 6 )δ12.11 (s, 1H), 7.84 – 7.59 (m, 3H), 7.42 (t,J= 5.9 Hz, 1H), 7.31 (d,J= 8.7Hz, 1H), 3.93 (s, 3H), 3.37 (s, 3H), 3.07 (t,J= 6.6 Hz, 2H), 2.84 (q,J= 6.7Hz, 2H), 2.41 (t,J= 7.4 Hz, 2H), 2.31 (s, 3H), 1.88 (s, 2H), 1.59 (t,J= 7.2Hz, 2H), 1.32 – 1.21 (m, 4H), 0.97 – 0.83 (m, 9H);13C NMR (101 MHz, DMSO-d 6 )δ171.39, 171.06, 155.33, 155.02, 142.07, 134.25, 128.94, 128.23, 124.09,122.26, 113.64, 56.38, 48.83, 42.40, 38.46, 34.87, 30.73, 30.29, 29.64,24.44, 21.84, 15.81, 13.82; ESI-HRMScalcdforC25H38N4O5S2m/z [M + H]+539.2356,found [M + H]+539.2358.
实施例33
N-(5-(3-(2-羟基-2-甲基丙基)氨基磺酰基)-4-甲氧基苯基)-4-甲基噻唑-2-基己酰胺,结构式如下:将实施例1中步骤1中的原料改为1-(4-氯苯基)-2-丙酮改为1-(4-甲氧基苯基)-2-丙酮,步骤2中的片段(2-氨基乙基)氨基甲酸叔丁酯改为1-氨基-2-甲基-2-丙醇,以及步骤4中的乙酰氯改为己酰氯,其他步骤及操作同实施例1;白色固体,收率:31%。1H NMR (400 MHz, DMSO-d 6 ) δ12.12 (s, 1H), 7.72(d,J= 2.4 Hz, 1H), 7.68 (dd,J= 8.6, 2.4 Hz, 1H), 7.32 (d,J= 8.7 Hz, 1H), 6.96(t,J= 6.4 Hz, 1H), 3.94 (s, 3H), 2.70 (d,J= 6.4 Hz, 2H), 2.41 (t,J= 7.4 Hz,2H), 2.32 (s, 3H), 1.59 (p,J= 7.4 Hz, 2H), 1.32 – 1.23 (m, 4H), 1.06 (s, 6H),0.92 – 0.81 (m, 3H);13C NMR (101 MHz, DMSO-d 6 ) δ171.37, 155.23, 154.97,142.04, 134.12, 128.94, 128.23, 124.05, 122.25, 113.60, 68.74, 56.39, 53.89,34.84, 30.71, 27.06, 24.40, 21.81, 15.81, 13.81; ESI-HRMS calcd forC21H30N3O5S2 m/z[M + H]+470.1778, found [M + H]+470.1785.
实施例34
N-(5-(3-(N-(2-啉乙基)氨基磺酰基))-4-甲氧基苯基)-4-甲基噻唑-2-基己酰胺,结构式如下:将实施例1中步骤1中的原料改为1-(4-氯苯基)-2-丙酮改为1-(4-甲氧基苯基)-2-丙酮,步骤2中的片段(2-氨基乙基)氨基甲酸叔丁酯改为N-(2-氨基乙基)吗啉,以及步骤4中的乙酰氯改为己酰氯,其他步骤及操作同实施例1;白色固体,收率:20%。1H NMR (400 MHz, DMSO-d 6 )δ12.12 (s, 1H), 7.73 (d,J=2.3 Hz, 1H), 7.68 (dd,J= 8.6, 2.4 Hz, 1H), 7.32 (d,J= 8.7 Hz, 1H), 7.16 –7.04 (m, 1H), 3.96 (s, 3H), 3.45 (t,J= 4.7 Hz, 4H), 2.96 (q,J= 6.3 Hz, 2H),2.42 (t,J= 7.4 Hz, 2H), 2.32 (s, 3H), 2.28 – 2.19 (m, 6H), 1.79 – 1.73 (m,2H), 1.37 – 1.17 (m, 4H), 0.90 – 0.85 (m, 3H);13C NMR (101 MHz, DMSO) δ155.35, 154.96, 136.08, 134.65, 130.56, 129.14, 126.96, 126.53, 113.86,112.90, 63.17, 56.35, 55.51, 51.35, 47.92, 36.94, 30.70, 24.40, 21.80, 15.85,13.82.ESI-HRMS calcd for C23H34N4O5S2 m/z[M + H]+511.2043, found [M + H]+511.2044.
实施例35
N-(5-(3-(((4-氟苯基)-l2-氮酰基)磺酰基)-4-甲氧基苯基)-4-甲基噻唑-2-基)己酰胺,结构式如下:将实施例1中步骤1中的原料改为1-(4-氯苯基)-2-丙酮改为1-(4-甲氧基苯基)-2-丙酮,步骤2中的片段(2-氨基乙基)氨基甲酸叔丁酯改为4-氟苯胺,以及步骤4中的乙酰氯改为己酰氯,其他步骤及操作同实施例1;白色固体,收率:55 %。1H NMR (300 MHz, DMSO-d 6 )δ12.10 (s, 1H), 10.10 (s, 1H),7.71–7.67 (m, 1H), 7.65–7.59 (m, 1H), 7.24 (dd,J= 9.1, 3.3 Hz, 1H), 7.15–7.01(m, 4H), 3.91 (d,J= 2.0 Hz, 3H), 2.46–2.35 (m, 2H), 2.22 (q,J= 2.7, 1.9 Hz,3H), 1.57 (d,J= 7.4 Hz, 2H), 1.30–1.19 (m, 4H), 0.88–0.82 (m, 3H);13C NMR (101MHz, DMSO-d 6 )δ171.47, 160.10 (d,J= 241.4 Hz), 155.43, 155.05, 142.21, 134.97,134.01, 129.75, 126.46, 124.04, 122.19(d,J= 8.1 Hz), 122.00, 115.91(d,J= 23.2Hz), 113.70, 56.42, 34.87, 30.75, 24.46, 21.87, 15.72, 13.87; ESI-HRMS calcdfor C23H25FN3O4S2 m/z[M + H]+492.1422, found [M + H]+492.1420.
实施例36
N-(5-(3-(((4-氯苯基)-l2-亚氮基)磺酰基)-4-甲氧基苯基)-4-甲基噻唑-2-基)己酰胺,结构式如下:将实施例1中步骤1中的原料改为1-(4-氯苯基)-2-丙酮改为1-(4-甲氧基苯基)-2-丙酮,步骤2中的片段(2-氨基乙基)氨基甲酸叔丁酯改为4-氯苯胺,以及步骤4中的乙酰氯改为己酰氯,其他步骤及操作同实施例1;白色固体,收率:49 %。1H NMR (300 MHz, DMSO-d 6 ) δ12.11 (s, 1H), 10.32 (s, 1H),7.74 (d,J= 2.4 Hz, 1H), 7.63 (dd,J= 8.6, 2.4 Hz, 1H), 7.29–7.22 (m, 3H),7.15–7.10 (m, 2H), 3.89 (s, 3H), 2.40 (t,J= 7.4 Hz, 2H), 2.24 (s, 3H), 1.58(p,J= 7.3 Hz, 2H), 1.37–1.12 (m, 4H), 0.84 (t,J= 6.8 Hz, 3H);13C NMR (101 MHz,DMSO-d 6 ) δ171.45, 155.43, 155.09, 142.25, 136.83, 135.06, 129.79,129.03,127.86, 126.45, 124.12, 121.98, 121.06, 113.77, 56.44, 34.88, 30.75, 24.45,21.86, 15.72, 13.85; ESI-HRMS calcd for C23H25ClN3O4S2 m/z[M + H]+508.1126, found[M + H]+508.1133.
实施例37
N-(5-(3-(((4-氟苄基)-l2-亚氮基)磺酰基)-4-甲氧基苯基)-4-甲基噻唑-2-基)己酰胺,结构式如下:将实施例1中步骤1中的原料改为1-(4-氯苯基)-2-丙酮改为1-(4-甲氧基苯基)-2-丙酮,步骤2中的片段(2-氨基乙基)氨基甲酸叔丁酯改为4-氟苄胺,以及步骤4中的乙酰氯改为己酰氯,其他步骤及操作同实施例1;白色固体,收率:54 %。1H NMR (300 MHz, DMSO-d 6 )δ12.11 (s, 1H), 7.96 (t,J= 6.4Hz, 1H), 7.64–7.52 (m, 2H), 7.23–7.09 (m, 3H), 6.96 (dd,J= 10.1, 7.7 Hz, 2H),4.08 (d,J= 6.4 Hz, 2H), 3.85 (s, 3H), 2.41 (t,J= 7.4 Hz, 2H), 2.29 (s, 3H),1.65–1.54 (m, 2H), 1.26 (dd,J= 6.4, 2.9 Hz, 4H), 0.86 (t,J= 6.7 Hz, 3H);13CNMR (101 MHz, DMSO-d 6 )δ171.41, 162.40 (d,J= 244.4 Hz), 155.11, 155.00,141.96, 134.01, 133.71, 133.68, 129.71(d,J= 8.1 Hz), 128.84, 123.78, 122.38,114.68(d,J= 21.2 Hz), 113.18, 56.15, 45.63, 34.88, 30.74, 24.45, 21.85,15.72, 13.85; ESI-HRMS calcd for C24H28FN3O4S2 m/z[M + H]+506.1578, found [M + H]+506.1581.
实施例38
N-(5-(3-(((3-氟苄基)-l2-亚氮基)磺酰基)-4-甲氧基苯基)-4-甲基噻唑-2-基)己酰胺,结构式如下:将实施例1中步骤1中的原料改为1-(4-氯苯基)-2-丙酮改为1-(4-甲氧基苯基)-2-丙酮,步骤2中的片段(2-氨基乙基)氨基甲酸叔丁酯改为3-氟苄胺,以及步骤4中的乙酰氯改为己酰氯,其他步骤及操作同实施例1;白色固体,收率:48 %。1H NMR (400 MHz, DMSO-d 6 )δ12.10 (s, 1H), 8.03 (t,J= 6.5Hz, 1H), 7.62 (d,J= 2.4 Hz, 1H), 7.54 (dd,J= 8.6, 2.4 Hz, 1H), 7.21–7.16 (m,1H), 7.11 (d,J= 8.8 Hz, 1H), 7.00–6.91 (m, 3H), 4.12 (d,J= 6.5 Hz, 2H), 3.85(s, 3H), 2.41 (t,J= 7.4 Hz, 2H), 2.28 (s, 3H), 1.62–1.56 (m, 2H), 1.38–1.16(m, 4H), 0.85 (d,J= 7.1 Hz, 3H);13C NMR (101 MHz, DMSO-d 6 )δ171.43, 163.11(d,J=244.4 Hz), 155.15, 155.02, 142.00, 140.54(d,J= 7.1 Hz), 134.17, 129.89(d,J=9.1 Hz), 128.86(d,J= 10.1 Hz), 123.81, 123.66(d,J= 3.0 Hz), 122.38, 114.34,114.12, 113.82(d,J= 21.2 Hz), 113.15, 56.15, 45.77, 34.89, 30.77, 24.48,21.89, 15.74, 14.02, 13.89; ESI-HRMS calcd for C24H28FN3O4S2 m/z[M + H]+506.1578,found [M + H]+506.1584.
实施例39
N-(5-(3-(((2-氟苄基)-l2-亚氮基)磺酰基)-4-甲氧基苯基)-4-甲基噻唑-2-基)己酰胺,结构式如下:将实施例1中步骤1中的原料改为1-(4-氯苯基)-2-丙酮改为1-(4-甲氧基苯基)-2-丙酮,步骤2中的片段(2-氨基乙基)氨基甲酸叔丁酯改为2-氟苄胺,以及步骤4中的乙酰氯改为己酰氯,其他步骤及操作同实施例1;白色固体,收率:42 %。1H NMR (400 MHz, DMSO-d 6 ) δ12.10 (s, 1H), 7.93 (t,J= 6.4Hz, 1H), 7.63 (d,J= 2.4 Hz, 1H), 7.56–7.49 (m, 1H), 7.32 (td,J= 7.6, 1.8 Hz,1H), 7.22–7.13 (m, 1H), 7.09–6.97 (m, 2H), 6.93–6.89 (m, 1H), 4.12 (dd,J=28.1, 6.3 Hz, 2H), 3.82 (s, 3H), 2.41 (t,J= 7.4 Hz, 2H), 2.29 (s, 3H), 1.60(p,J= 7.4 Hz, 2H), 1.36–1.21 (m, 4H), 0.90–0.81 (m, 3H);13C NMR (101 MHz,DMSO-d 6 ) δ171.41, 160.78 (d,J= 245.4 Hz), 155.09, 155.02, 141.94, 134.14,130.37(d,J= 3.0 Hz), 129.69(d,J= 132.3 Hz), 129.33(d,J= 8.1 Hz), 128.88,124.29(d,J= 15.2 Hz), 123.97(d,J= 3.0 Hz), 123.72, 122.40, 114.79(d,J= 21.2Hz), 113.04, 56.06, 55.90(d,J= 788.8 Hz), 34.88, 30.76, 24.47, 21.88, 15.71,13.87; ESI-HRMS calcd for C24H28FN3O4S2 m/z[M + H]+506.1578, found [M + H]+506.1575.
实施例40
N-(4-(3-(((2,4-二氟苄基)-l2-亚氮基)磺酰基)-4-甲氧基苯基)-5-甲基噻唑-2-基)己酰胺,结构式如下:将实施例1中步骤1中的原料改为1-(4-氯苯基)-2-丙酮改为1-(4-甲氧基苯基)-2-丙酮,步骤2中的片段(2-氨基乙基)氨基甲酸叔丁酯改为2,4-二氟苄胺,以及步骤4中的乙酰氯改为己酰氯,其他步骤及操作同实施例1;白色固体,收率:52 %。1H NMR (400 MHz, DMSO-d 6 )δ12.09 (s, 1H), 7.92(t,J= 6.4 Hz, 1H), 7.60 (d,J= 2.4 Hz, 1H), 7.54 (dd,J= 8.6, 2.4 Hz, 1H), 7.35(td,J= 8.7, 8.3, 6.6 Hz, 1H), 7.07 (d,J= 8.7 Hz, 1H), 6.96–6.84 (m, 2H), 4.13(d,J= 6.4 Hz, 2H), 3.83 (s, 3H), 2.42 (t,J= 7.4 Hz, 2H), 2.30 (s, 3H), 1.60(p,J= 7.4 Hz, 2H), 1.32–1.25 (m, 4H), 0.87 (t,J= 6.9 Hz, 3H);13C NMR (101 MHz,DMSO)δ171.35, 162.73(dd,J= 189.9, 12.1 Hz), 160.28(dd,J= 192.9, 11.1 Hz),154.98, 141.93, 134.04, 131.70(dd,J= 15.2, 5.1 Hz), 128.79, 128.35, 123.73,122.32, 120.67(d,J= 4.0 Hz), 120.54(m), 112.97, 111.09(dd,J= 18.2, 2.0 Hz),103.03(t,J= 51.5 Hz), 56.04, 34.84, 30.72, 24.42, 21.82, 15.65, 13.82.; ESI-HRMS calcd for C24H27F2N3O4S2 m/z[M + H]+524.1484, found [M + H]+524.1489.
实施例41
N-(5-(3-(((3,4-二氟苄基)-l2-亚氮基)磺酰基)-4-甲氧基苯基)-4-甲基噻唑-2-基)己酰胺,结构式如下:将实施例1中步骤1中的原料改为1-(4-氯苯基)-2-丙酮改为1-(4-甲氧基苯基)-2-丙酮,步骤2中的片段(2-氨基乙基)氨基甲酸叔丁酯改为3,4-二氟苄胺,以及步骤4中的乙酰氯改为己酰氯,其他步骤及操作同实施例1;白色固体,收率:54 %。1H NMR (400 MHz, DMSO-d 6 )δ12.09 (s, 1H), 8.00(t,J= 6.5 Hz, 1H), 7.60 (d,J= 2.4 Hz, 1H), 7.55 (dd,J= 8.6, 2.4 Hz, 1H),7.20–7.09 (m, 3H), 7.04–6.96 (m, 1H), 4.10 (d,J= 6.5 Hz, 2H), 3.86 (s, 3H),2.41 (t,J= 7.4 Hz, 2H), 2.29 (s, 2H), 1.63–1.56 (m, 2H), 1.27 (dt,J= 10.3,4.9, 4H), 0.87 (t,J= 6.9 Hz, 3H);13C NMR (101 MHz, DMSO-d 6 )δ171.36, 155.02,154.99, 141.96, 135.32 (dd,J= 4.0,3.0Hz), 134.05, 129.65, 128.82, 128.74,124.50 (dd,J= 3.0, 3.0 Hz), 123.80, 122.29, 116.86(d,J= 17.2 Hz), 116.62(d,J=17.2 Hz), 113.03, 56.12, 45.27, 34.85, 30.72, 24.42, 21.83, 15.65, 13.82;ESI-HRMS calcd for C24H27F2N3O4S2 m/z[M + H]+524.1484, found [M + H]+524.1480.
实施例42
N-(5-(3-(((3-氯-4-氟苄基)-l2-亚氮基)磺酰基)-4-甲氧基苯基)-4-甲基噻唑-2-基)己酰胺,结构式如下:将实施例1中步骤1中的原料改为1-(4-氯苯基)-2-丙酮改为1-(4-甲氧基苯基)-2-丙酮,步骤2中的片段(2-氨基乙基)氨基甲酸叔丁酯改为3-氯-4-氟苄胺,以及步骤4中的乙酰氯改为己酰氯,其他步骤及操作同实施例1;白色固体,收率:50 %。1H NMR (400 MHz, DMSO-d 6 )δ12.08 (s, 1H), 8.00(t,J= 6.6 Hz, 1H), 7.61–7.50 (m, 2H), 7.31 (d,J= 7.3 Hz, 1H), 7.15 (d,J= 7.3Hz, 2H), 7.10 (d,J= 8.6 Hz, 1H), 4.11 (d,J= 6.5 Hz, 2H), 3.86 (s, 3H), 2.41(t,J= 7.3 Hz, 2H), 2.29 (s, 3H), 1.63–1.56 (m, 2H), 1.32–1.25 (m, 4H), 0.86(t,J= 6.8 Hz, 3H);13C NMR (101 MHz, DMSO-d 6 )δ171.35, 157.31(d,J= 247.4 Hz),154.97, 154.94, 141.94, 135.29(d,J= 3.0 Hz), 134.03, 129.66, 128.76, 128.70,128.41(d,J= 7.1 Hz), 123.84, 122.29, 118.86(d,J= 17.2 Hz), 116.23(d,J= 20.2Hz), 112.96, 56.11, 45.14, 34.85, 30.72, 24.42, 21.82, 15.71, 13.82; ESI-HRMScalcd for C24H27ClFN3O4S2 m/z[M + H]+540.1188, found [M + H]+540.1182.
实施例43
N-(5-(3-(((4-氟-3-(三氟甲基)苄基)-l2-亚氮基)磺酰基)-4-甲氧基苯基)-4-甲基噻唑-2-基)己酰胺,结构式如下:将实施例1中步骤1中的原料改为1-(4-氯苯基)-2-丙酮改为1-(4-甲氧基苯基)-2-丙酮,步骤2中的片段(2-氨基乙基)氨基甲酸叔丁酯改为3-氟-4-(三氟甲基)苄胺,以及步骤4中的乙酰氯改为己酰氯,其他步骤及操作同实施例1;白色固体,收率:44 %。1H NMR (400 MHz, DMSO-d 6 )δ12.08 (s, 1H), 8.05 (t,J= 6.5 Hz, 1H), 7.58 (d,J= 2.4 Hz, 1H), 7.56–7.50 (m,3H), 7.32–7.24 (m, 1H), 7.08 (d,J= 8.7 Hz, 1H), 4.19 (d,J= 6.5 Hz, 2H), 3.83(s, 3H), 2.41 (t,J= 7.4 Hz, 2H), 2.28 (s, 3H), 1.60 (p,J= 7.4 Hz, 2H), 1.36–1.18 (m, 4H), 0.87 (t,J= 6.9 Hz, 3H);13C NMR (101 MHz, DMSO-d 6 )δ171.44, 156.56(d,J= 194.9 Hz), 155.03, 154.90, 142.00, 134.65(d,J= 54.5 Hz), 134.61 (d,J=5.0 Hz), 130.20(d,J= 49.5 Hz), 128.74, 128.67, 127.92, 126.60, 126.27 (m),123.90, 122.29, 116.68(d,J= 20.2 Hz), 113.00, 56.06, 45.15, 34.90, 30.79,24.50, 21.91, 15.75, 13.90; ESI-HRMS calcd for C25H27F4N3O4S2 m/z[M + H]+574.1452, found [M + H]+574.1444.
实施例44
N-(5-(4-甲氧基-3-(((3,4,5-三氟苄基)-l2-亚氮基)磺酰基)苯基)-4-甲基噻唑-2-基)己酰胺,结构式如下:将实施例1中步骤1中的原料改为1-(4-氯苯基)-2-丙酮改为1-(4-甲氧基苯基)-2-丙酮,步骤2中的片段(2-氨基乙基)氨基甲酸叔丁酯改为3,4,5-三氟苄胺,以及步骤4中的乙酰氯改为己酰氯,其他步骤及操作同实施例1;白色固体,收率:31 %。1H NMR (400 MHz, DMSO-d 6 )δ12.09 (s, 1H),8.06 (t,J= 6.6 Hz, 1H), 7.60 (d,J= 2.3 Hz, 1H), 7.57 (dd,J= 8.5, 2.4 Hz, 1H),7.14 (d,J= 8.7 Hz, 1H), 7.09 (dd,J= 8.9, 6.7 Hz, 2H), 4.12 (d,J= 6.6 Hz, 2H),3.87 (s, 3H), 2.41 (t,J= 7.4 Hz, 2H), 2.28 (s, 3H), 1.60 (p,J= 7.2 Hz, 2H),1.33–1.23 (m, 4H), 0.87 (t,J= 6.8 Hz, 3H);13C NMR (101 MHz, DMSO-d 6 )δ171.37,155.04, 154.99, 154.72, 141.98, 135.49, 134.15, 130.23, 128.87, 128.66,127.85, 126.62, 123.87, 122.22, 112.96(d,J= 72.7 Hz), 112.03 (m), 56.14(d,J=22.2 Hz), 47.94, 45.10, 45.00, 34.85, 30.72, 24.43, 21.83, 15.59, 13.82; ESI-HRMS calcd for C24H26F3N3O4S2 m/z[M + H]+542.1390, found [M + H]+542.1395.
实施例45
N-(5-(3-(((4-氟苯乙基)-l2-亚氮基)磺酰基)-4-甲氧基苯基)-4-甲基噻唑-2-基)己酰胺,结构式如下:将实施例1中步骤1中的原料改为1-(4-氯苯基)-2-丙酮改为1-(4-甲氧基苯基)-2-丙酮,步骤2中的片段(2-氨基乙基)氨基甲酸叔丁酯改为4-氟苯乙胺,以及步骤4中的乙酰氯改为己酰氯,其他步骤及操作同实施例1;白色固体,收率:32 %。1H NMR (400 MHz, DMSO-d 6 )δ12.12 (s, 1H), 7.70 (d,J= 2.4 Hz, 1H), 7.65 (dd,J= 8.6, 2.4 Hz, 1H), 7.43 (t,J= 5.8 Hz, 1H), 7.26(d,J= 8.7 Hz, 1H), 7.17–7.13 (m, 2H), 7.06–7.01 (m, 2H), 3.89 (s, 3H), 3.06(q,J= 6.8 Hz, 2H), 2.68 (t,J= 7.1 Hz, 2H), 2.41 (t,J= 7.4 Hz, 2H), 2.31 (s,3H), 1.59 (p,J= 7.2 Hz, 2H), 1.27 (td,J= 8.5, 7.4, 5.0 Hz, 4H), 0.86 (t,J=6.8 Hz, 3H);13C NMR (101 MHz, DMSO-d 6 )δ171.54, 162.12(d,J= 242.4 Hz), 155.38,155.07, 142.11, 135.00(d,J= 3.0 Hz),134.22, 130.55, 130.47, 128.93(d,J= 53.5Hz),, 124.05, 122.40, 115.10(d,J= 20.2 Hz), 113.65, 56.36, 44.20, 34.94,34.49, 30.81, 24.53, 21.93, 15.87, 13.92; ESI-HRMS calcd for C25H30FN3O4S2 m/z[M+ H]+520.1735, found [M + H]+520.1735.
实施例46
(2-(2-己酰胺基-4-甲基噻唑-5-基)-2-甲氧基苯甲酰胺基)乙基氨基甲酸叔丁酯:
步骤1:2-甲氧基-5-(2-氧代丙基)苯甲酸的合成:将原料10mmol 5-甲酰基-2-甲氧基苯甲酸甲酯和丁胺(2.0 eg.)溶解于甲苯中回流反应3 h,经减压蒸馏至干燥后溶解于10 mL的乙酸中,向反应液缓慢加入1.14 mL硝基乙烷(1.5 eq.),将混合物加热至100 ℃反应3 h。反应结束后,将反应液冷却至室温并将其缓慢倒入40 mL冰水溶液中(全程剧烈搅拌),用乙酸乙酯溶液(2x40 mL)萃取混合物,收集有机相,依次用水(2x40 mL),10%碳酸氢钠溶液(2x30 mL)和盐水洗涤有机相,经无水硫酸镁干燥,柱层析纯化(PE:EA=2:1)得到(Z)-2-甲氧基-5-(2-硝基丙烯-1-基)苯甲酸甲酯,收率:80 %;将100mmol 的铁粉加入到22 mL 乙酸的反应瓶中,在氮气保护下,将溶有(Z)-2-甲氧基-5-(2-硝基丙烯-1-基)苯甲酸甲酯(8 mmol)的12 mL乙酸溶液缓慢滴加到上述反应器中,回流反应2h 后,冷却反应液至室温,过滤铁粉,向滤液加入30 mL 水,用乙酸乙酯溶液(3x40 mL)萃取混合物,收集有机相,依次用水(2x30 mL),10%碳酸氢钠溶液(2x30 mL)和盐水(30 mL)洗涤有机相,经无水硫酸镁干燥,柱层析纯化(PE:EA=1:1)得到2-甲氧基-5-(2-氧代丙基)苯甲酸甲酯,收率:90 %。称取2 mmol 2-甲氧基-5-(2-氧代丙基)苯甲酸甲酯经酸解得到白色固体2-甲氧基-5-(2-氧代丙基)苯甲酸,收率:95%(以1.0 mL 盐酸溶液(1 mol/L和4 mL 乙酸的混合溶液)作为酸解液)。1H NMR (400 MHz, DMSO-d 6 ) δ 12.58 (s, 1H), 7.46 (d,J=2.3 Hz, 1H), 7.30 (dd,J= 8.5, 2.4 Hz, 1H), 7.07 (d,J= 8.6 Hz, 1H), 3.80 (s,3H), 3.75 (s, 2H), 2.13 (s, 3H).
步骤2:(2-(2-己酰胺基-4-甲基噻唑-5-基)-2-甲氧基苯甲酰胺基)乙基氨基甲酸叔丁酯的合成,结构式如下:将2-甲氧基-5-(2-氧代丙基)苯甲酸(1 mmol)与CDI(1 mmol)溶于10 mL DCM溶液中预反应1 h,之后将1.5 mmol(2-氨基乙基)氨基甲酸叔丁酯加入反应液中室温反应。反应结束纯化得到(2-(2-甲氧基-5-(2-氧代丙基)苯甲酰胺基)乙基)氨基甲酸叔丁酯;后根据实例1中的步骤3和步骤4得到白色固体(2-(2-己酰胺基-4-甲基噻唑-5-基)-2-甲氧基苯甲酰胺基)乙基氨基甲酸叔丁酯,收率:40%。1H NMR (400 MHz, DMSO-d 6 )δ12.12 (s, 1H), 7.73 (d,J= 2.3 Hz, 1H),7.68 (dd,J= 8.6, 2.4 Hz, 1H), 7.32 (d,J= 8.7 Hz, 1H), 7.16 – 7.04 (m, 1H),3.96 (s, 3H), 3.45 (t,J= 4.7 Hz, 4H), 2.96 (q,J= 6.3 Hz, 2H), 2.42 (t,J= 7.4Hz, 2H), 2.32 (s, 3H), 2.28 – 2.19 (m, 6H), 1.79 – 1.73 (m, 2H), 1.37 – 1.17(m, 4H), 0.90 – 0.85 (m, 3H);13C NMR (101 MHz, DMSO) δ 155.35, 154.96, 136.08,134.65, 130.56, 129.14, 126.96, 126.53, 113.86, 112.90, 63.17, 56.35, 55.51,51.35, 47.92, 36.94, 30.70, 24.40, 21.80, 15.85, 13.82.ESI-HRMS calcd forC23H34N4O5S2 m/z[M + H]+511.2043, found [M + H]+511.2044.
实施例47
N-(4-(3-(((2,4-二氟苄基)-l2-亚氮基)磺酰基)-4-甲氧基苯基)-5-甲基噻唑-2-基)己酰胺,结构式如下:与实施例1的制备方法类似,将实施例1中步骤1中的原料改为1-(4-氯苯基)-2-丙酮改为4´-甲氧基苯丙酮,步骤2中的片段(2-氨基乙基)氨基甲酸叔丁酯改为2,4-二氟苄胺,以及步骤4中的乙酰氯改为己酰氯,其他步骤及操作同实施例1。白色固体,收率:51 %。1H NMR (300 MHz, DMSO-d 6 )δ12.08(s, 1H), 8.01 (d,J= 2.3 Hz, 1H), 7.84 (d,J= 6.4 Hz, 1H), 7.75 (dd,J= 8.7, 2.3Hz, 1H), 7.39–7.31 (m, 1H), 7.09 (d,J= 8.7 Hz, 1H), 6.97–6.89 (m, 2H), 4.09(d,J= 6.3 Hz, 2H), 3.84 (s, 3H), 2.45 (s, 3H), 2.40 (t,J= 7.4 Hz, 2H), 1.64–1.56 (m, 2H), 1.26 (td,J= 6.4, 6.0, 3.0 Hz, 4H), 0.89–0.84 (m, 3H);13C NMR(101 MHz, DMSO)δ171.33, 162.77 (d,J= 204.0 Hz), 160.17 (d,J= 177.8 Hz),154.88, 154.01, 142.26, 132.99, 131.58 (d,J= 6.1 Hz), 128.78, 127.96, 126.88,120.88 (dd,J= 15.2, 3.0 Hz), 120.26, 112.27, 111.08 (dd,J= 18.2, 3.0 Hz),103.12 (t,J= 52.5 Hz), 55.98, 34.81, 30.74, 24.43, 21.82, 13.82, 11.77.; ESI-HRMS calcd for C24H27F2N3O4S2 m/z[M + H]+524.1484, found [M + H]+524.1491.
针对本发明抑制剂进行PI4KIIIβ激酶抑制实验:使用ADP-Glo LuminescentKinase Assay法测试,激酶反应用到的试剂如下:HEPES (50 mM) pH 7.5 with NaCl (100mM), EGTA (1.0 mM), MgCl2(3.0 mM), DTT (2.0 mM) 及CHAPS (0.03 %)。反应过程中,每10 mL含不同浓度的受试化合物 (0.05 nM-1.0 μM)中加入50 μM PIP2及25 μM ATP。反应体系在室温下孵育1h,然后加入10 μL试剂ADP-Glo终止酶反应。数据收集使用Envision软件,并使用Graphpad Prism 5分析及拟合化合物的IC50值。
表1 实施例化合物的PI4KIIIβ酶抑制活性(IC50,nM)
如表1所示,本发明化合物对PI4KIIIβ激酶具有纳摩尔水平抑制活性,且部分化合物显著优于阳性对照PIK-93,尤其是实施例10、11、12、14、20、21、24、27和实施例33对PI4KIIIβ激酶的抑制活性明显优于阳性对照PIK-93。由此说明,本发明实施例化合物为高效的PI4KIIIβ抑制剂。
针对本发明抑制剂进行肿瘤细胞株抗增殖活性实验:
采用CCK-8法评价化合物对细胞的增殖抑制活性,通过单浓度活性初筛和多浓度测定半数抑制浓度IC50值。检测原理如下:细胞毒性(CCK-8法)检测原理:CCK-8试剂中含有WST–8,它在电子载体1-甲氧基-5-甲基吩嗪硫酸二甲酯(1-Methoxy PMS)的作用下被细胞线粒体中的脱氢酶还原为具有高度水溶性的黄色甲臜产物(Formazan)。生成的甲臜物的数量与活细胞的数量成正比。
实验方法如下:
(1)接种细胞:用含10 %胎牛血清的培养液将细胞配成单个细胞悬液,96孔板每孔接种90 μL 5×104/mL的贴壁细胞和9×104/mL的悬浮细胞,在5 % CO2,37 ℃的条件下预培养24 h。
(2)加入待测样品溶液:每孔加入10 μL样品溶液,活性初筛每个样品设置1个浓度,设3个复孔;IC50测定8个浓度(含0浓度),每种浓度均设3个复孔;置于培养箱培养48 h。实验设置空白组(Blank)、对照组(Control)和药物组(Drug)。
(3)显色:贴壁细胞吸出旧培养基和药物溶液(悬浮细胞直接加入10 μL CCK-8溶液原液),每孔加入稀释十倍的100 μL CCK-8溶液,在37 ℃,5 % CO2继续培养1-4 h(操作,实时观察)。
(4)检测:用酶标仪测定450 nm处吸光度,记录原始数据结果。
(5)应用Excel软件进行原始数据标准化处理,初筛通过每孔OD值计算细胞增殖抑制率(公式=(ODControl-ODDrug)/(ODControl-ODBlank)×100 %),统计抑制率。IC50通过GraphPadPrism 8计算。
表2 实施例化合物的肿瘤细胞株增值抑制活性(IC50,μM)
实施例 | MCF-7 | MDA-MB-231 | A549 | H446 | DU145 | PC3 | HT29 | HCT116 |
实施例1 | 2.36 | 2.05 | 2.91 | 0.44 | 1.97 | 1.24 | 2.04 | 1.54 |
实施例2 | 2.83 | 2.87 | 3.3 | 0.79 | 3.53 | 2.98 | 2.64 | 2.31 |
实施例3 | >4 | >4 | >4 | 2.09 | >4 | >4 | >4 | >4 |
实施例4 | >4 | >4 | >4 | 0.80 | >4 | >4 | >4 | >4 |
实施例5 | 2.11 | 3.94 | 3.87 | 0.70 | >4 | 2.4 | 2.98 | 2.38 |
实施例6 | >4 | >4 | >4 | 3.32 | >4 | >4 | >4 | 3.89 |
实施例7 | >4 | >4 | >4 | >4 | >4 | >4 | >4 | >4 |
实施例8 | 1.16 | 1.04 | 1.87 | 0.21 | 1.51 | 0.84 | 0.80 | 0.38 |
实施例9 | 0.42 | 0.62 | 0.54 | 0.094 | 0.56 | 0.42 | 0.16 | 0.29 |
实施例10 | 0.31 | 0.49 | 0.48 | 0.067 | 0.43 | 0.28 | 0.12 | 0.25 |
实施例11 | 0.097 | 0.15 | 0.16 | 0.038 | 0.082 | 0.074 | 0.049 | 0.074 |
实施例12 | 0.14 | 0.18 | 0.24 | 0.05 | 0.12 | 0.13 | 0.078 | 0.14 |
实施例13 | 0.68 | 0.54 | 0.95 | 0.14 | 0.87 | 0.63 | 0.45 | 0.60 |
实施例14 | 0.50 | 0.47 | 0.63 | 0.095 | 0.58 | 0.45 | 0.28 | 0.35 |
实施例15 | 0.34 | 0.44 | 0.74 | 0.062 | 0.31 | 0.24 | 0.05 | 0.29 |
实施例16 | >2 | >2 | >2 | 0.71 | >2 | >2 | 1.45 | >2 |
实施例17 | >2 | >2 | >2 | 1.10 | >2 | >2 | >2 | >2 |
实施例18 | 0.36 | 0.46 | 0.81 | 0.058 | 0.32 | 0.24 | 0.064 | 0.38 |
实施例19 | 0.75 | 0.93 | 1.56 | 0.17 | 0.74 | 0.43 | 0.062 | 0.64 |
实施例20 | 0.55 | 0.68 | 1.59 | 0.11 | 0.53 | 0.38 | 0.10 | 0.42 |
实施例21 | 0.77 | 1.15 | 1.98 | 0.16 | 1.35 | 0.70 | 0.24 | 0.99 |
实施例22 | 0.86 | 0.77 | 0.92 | 0.071 | 0.48 | 0.37 | 0.094 | 0.53 |
实施例23 | 1.10 | 0.91 | 0.86 | 0.042 | 0.40 | 0.31 | 0.076 | 0.18 |
实施例24 | 1.17 | 1.92 | 1.38 | 0.07 | 0.94 | 0.64 | 0.096 | 0.36 |
实施例25 | 1.04 | 1.07 | 1.21 | 0.062 | 0.64 | 0.45 | 0.078 | 0.28 |
实施例26 | >2 | >2 | >2 | >2 | >2 | >2 | >2 | >2 |
实施例27 | 0.28 | 0.39 | 0.42 | 0.086 | 0.29 | 0.31 | 0.096 | 0.23 |
实施例28 | >2 | >2 | >2 | >2 | >2 | >2 | >2 | >2 |
实施例29 | >4 | >4 | >4 | 0.45 | >4 | 0.92 | 0.70 | >4 |
实施例30 | 0.89 | 1.47 | 1.86 | 0.32 | 1.28 | 0.67 | 0.52 | 0.80 |
实施例31 | >4 | >4 | >4 | >4 | >4 | >4 | >4 | >4 |
实施例32 | >4 | >4 | >4 | >4 | >4 | >4 | >4 | >4 |
实施例33 | >4 | >4 | >4 | >4 | >4 | >4 | >4 | >4 |
实施例34 | 0.82 | 1.57 | >2 | 0.34 | 1.73 | 0.76 | 0.52 | 1.46 |
实施例35 | 0.46 | 0.87 | 2.76 | 0.20 | 0.32 | 0.21 | 0.14 | 0.52 |
实施例36 | 1.05 | 2.41 | >4 | 0.43 | 0.57 | 0.84 | 0.38 | 0.94 |
实施例37 | 0.20 | 0.34 | 0.59 | 0.12 | 0.37 | 0.19 | 0.18 | 0.20 |
实施例38 | 0.21 | 0.74 | 1.24 | 0.35 | 0.68 | 0.43 | 0.42 | 0.38 |
实施例39 | 0.20 | 0.68 | 1.07 | 0.24 | 0.53 | 0.22 | 0.31 | 0.27 |
实施例40 | 0.13 | 0.18 | 0.24 | 0.098 | 0.19 | 0.16 | 0.14 | 0.15 |
实施例41 | 0.20 | 0.28 | 0.34 | 0.22 | 0.30 | 0.21 | 0.25 | 0.19 |
实施例42 | 0.19 | 0.26 | 0.30 | 0.18 | 0.24 | 0.19 | 0.21 | 0.24 |
实施例43 | 0.32 | 0.53 | 0.79 | 0.30 | 0.60 | 0.24 | 0.40 | 0.29 |
实施例44 | 0.21 | 0.35 | 0.40 | 0.38 | 0.42 | 0.18 | 0.17 | 0.19 |
实施例45 | 0.42 | 1.02 | 1.84 | 0.16 | 0.87 | 0.48 | 0.46 | 0.75 |
实施例46 | >2 | >2 | >2 | >2 | >2 | >2 | >2 | >2 |
实施例47 | >4 | >4 | >4 | >4 | >4 | >4 | >4 | >4 |
PIK-93 | 3.30 | 3.12 | >4 | 0.68 | >4 | 3.53 | 1.94 | 3.73 |
从表2可以看出,本发明化合物对不同肿瘤株都具有微摩尔水平的增殖抑制活性,特别大部分实施例化合物对人小细胞肺癌细胞株H446及人结肠癌细胞株HT29具有较高的敏感性。其中,实施例9等12个化合物对表2中多种细胞株均表现出纳摩尔水平抑制活性,显著优于阳性对照PIK-93;其中,实施例11对表2中8种细胞株其中的6种,具有纳摩尔水平抑制活性,对细胞株H446及HT29的抑制活性分别为38 nM、49 nM,显著优于阳性对照PIK-93。由此可见,本发明实施例化合物可潜在用于上述肿瘤的临床治疗。
针对本发明抑制剂进行PI4KIIIβ药代动力学实验:
称取供试品置千无菌小瓶中,加入250 µL DMSO,再加入10 μL甲磺酸,溶解后,加入4.78 mL 5 %葡萄糖注射液,超声、振荡混匀,配制成2 mg/mL的供试品溶液,以此溶液作为灌胃给药制剂。另外,取 0.5ml 2 mg/mL的供试品溶液,加入4.5 mL的5 %葡萄糖注射液,振荡混匀,配制成0.2 mg/mL的供试品溶液,作为静脉注射给药制剂。
将20只SD大鼠分为四组,由于实施例11和27结构在酸性条件下的不稳定性,所以实施例11、27只进行尾静脉注射(5 mg/kg),而分别尾静脉注射(5 mg/kg)和灌胃(50 mg/kg)给予实施例40,静脉注射组于给药后2 min、5 min、15 min、30 min、1 h、2 h、4 h、6 h、8h、12 h;灌胃组于给药后5 min、15 min、30 min、1 h、2 h、4 h、6 h、8 h、12 h、24 h自眼眶后静脉丛采集血样约0.25 mL。采用LC-MS/MS法测定SD大鼠血浆样本中实施例11、27和40的浓度,用WinNolin软件计算药代动力学参数,结果如表3。
结果如表3所示,本发明实施例11、27和40在大鼠体内代谢较好,有较好的吸收和暴露量,实施例40的生物利用度较高。
表3 药代动力学参数记录
表3中,Cmax表示血药浓度;CL表示总清除率;Vss表示稳态分布容积;Vz表示分布体积;T1/2表示消除半衰期;MRTINF表示药物从血液循环中运输到组织和器官的平均时间;AUC0-t表示从0时到最终可定量时间点的血药浓度-时间曲线下面积;AUC0-∞表示从0到无穷大时间的血药浓度-时间曲线下面积;F表示生物利用度。
针对本发明抑制剂进行PI4KIIIβ抗肿瘤疗效和毒性研究实验:
药物为实施例11、27和40。细胞株为人小细胞肺癌细胞株H446含10 %胎牛血清的RPMI-1640培养基中培养。受试动物为SPF级BALB/c裸小鼠;雄性;每组5只。药物剂量设置如表4。
表4 药物剂量配置
组别 | 受试药 | 剂量(mg/kg) | 给药体积(mL/20 体重) | 给药途径 | 观察周期(days) |
模型组1 | 生理盐水 | - | 0.2 | 注射给药 | 25 |
实施例11低剂量组 | 实施例11 | 20 | 0.2 | 注射给药 | 25 |
实施例11高剂量组 | 实施例11 | 30 | 0.2 | 注射给药 | 25 |
实施例27 | 实施例27 | 30 | 0.2 | 注射给药 | 25 |
模型组2 | 生理盐水 | - | 0.2 | 灌胃给药 | 25 |
实施例40低剂量组 | 实施例40 | 75 | 0.2 | 灌胃给药 | 25 |
实施例40高剂量组 | 实施例40 | 150 | 0.2 | 灌胃给药 | 25 |
药物配制方法:
实施例11 (20 mg/kg):称取4 mg待测试化合物粉末溶于2 mL生理盐水,配成浓度为2 mg/mL药物,口服注射给药,给药体积为0.2 mL/20 g。
实施例11 (30 mg/kg):称取6 mg待测试化合物粉末溶于2 mL生理盐水,配成浓度为3 mg/mL药物,口服注射给药,给药体积为0.2 mL/20 g。
实施例27 (30 mg/kg):称取6 mg待测试化合物粉末溶于2 mL生理盐水,配成浓度为3 mg/mL药物,口服注射给药,给药体积为0.2 mL/20 g。
实施例40 (75 mg/kg):称取15 mg待测试化合物粉末溶于2 mL生理盐水,配成浓度为7.5 mg/mL药物,口服灌胃给药,给药体积为0.2 mL/20 g。
实施例40 (150 mg/kg):称取30 mg待测试化合物粉末溶于2 mL生理盐水,配成浓度为15 mg/mL药物,口服灌胃给药,给药体积为0.2 mL/20 g。
实验方法:人肺癌裸鼠移植瘤模型,由人小细胞肺癌细胞株H446接种千裸鼠腋窝皮下而建立。取对数生长期的H446细胞,在无菌条件下,接种于50只裸小鼠右侧腋窝皮下,细胞接种量为5×106个/只。用游标卡尺测量移植瘤直径,待肿瘤生长至80 mm3左右时挑选生长状态良好且肿瘤大小均一的荷瘤裸鼠42只,随机分成7组,每组6只,即模型组1、实施例11(20 mg/kg)低剂量组、实施例11(30 mg/kg)高剂量组、实施例27(30 mg/kg)组、模型组2、实施40(75 mg/kg)低剂量组、实施例40(150 mg/kg)高剂量组。受试药实施例11低剂量和高剂量组、实施例27为注射给药,实施例40低剂量和高剂量组为灌胃给药,2天给药一次,模型组1和2给予等容量的溶媒对照。使用测量瘤径的方法,动态观察受试物抗肿瘤的效应。肿瘤直径的测量次数为隔天一次,测量肿瘤直径的同时称量裸鼠体重。第27天时处死小鼠,手术剥取瘤块分别使用10 %甲醛固定、液氮保存备用。
实验结果显示:受试药实施例11在20 mg/kg时表现出有效的抗肿瘤活性,肿瘤生长抑制率TGI值为25.7 %,与模型组对比相对肿瘤增殖率T/C值为72.3 %。当剂量增加到30mg/kg时,肿瘤生长抑制效果更好(TGI = 37.1 %,T/C = 60.2 %),远高于实施例27(TGI =30.2 %和T/C = 66.8 %)。此外,实施例40在口服剂量为150 mg/kg时表现出更显着的抗肿瘤功效。TGI值为42.2 %,T/C值为52.1 %。(图1-3分别是PI4KIIIβ抑制剂的体内抗肿瘤疗效和毒性研究的结果。图1和2包含小鼠肿瘤体积、体重的生长曲线和小鼠肿瘤组织的代表性图像,图3从携带肺肿瘤的小鼠身上获得主要组织的病理切片;用苏木精和伊红(H&E)对器官进行染色,并捕获代表性图像),结合上述附图可以看出,实施例11以及40制得的受试药对人肺癌H446裸鼠异种移植瘤生长有明显的抑制作用。
本发明的苯基噻唑胺类PI4KIIIβ抑制剂,通过对PI4KIIIβ的高效抑制多种实体瘤与血液瘤细胞的增殖,对小细胞肺癌和结肠癌具有较高的敏感性,以及其对抗肿瘤的疗效,可潜在用于其临床治疗。
Claims (9)
1.一种苯基噻唑胺类PI4KIIIβ抑制剂,其特征在于,所述抑制剂为通式V所示的取代苯基噻唑胺类化合物,或其立体异构体或药学上可接受的盐:其中,A为或/>;
R1为苯环上取代基选自氢、氟、氯、溴、碘、羟基、氨基、氰基、C1-C6烷基、卤代C1-C6烷基、羟基C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、羟基C1-C6烷氧基或C1-C6烷氧基C1-C6烷基;
R2为;
R3或R4为C1-C6烷基、含一个或多个取代基的C1-C6烷基、C1-C6烷氧基、含一个或多个取代基的C1-C6烷氧基、C1-C6烷基酰基、C1-C6烷基磺酰基、C3-C6杂环基、含一个或多个取代基的C3-C6杂环基;
X为砜基或羰基。
2.根据权利要求1所述的抑制剂,其特征在于,所述抑制剂为通式Ⅰ或Ⅱ所示的化合物:
其中,R1、R2、R4和X的定义同权利要求1所述;
R3为。
3.一种抑制剂,其特征在于,所述抑制剂为以下其中之一:
(2-(5-(2-乙酰氨基-4-甲基噻唑-5-基)-2-氯苯基磺酰胺基)乙基)氨基甲酸叔丁酯;
N-(2-(2-乙酰氨基-4-甲基噻唑-5-基)-2-氯苯基磺酰胺基)乙基丙酰胺;
(2-(2-乙酰氨基-4-甲基噻唑-5-基)-2-氯苯基磺酰胺基)乙基氨基甲酸甲酯;
(2-((5-(2-乙酰氨基-4-甲基噻唑-5-基)-2-甲氧基苯基)磺酰胺基)乙基)氨基甲酸叔丁酯;
(5-(2-丙酰胺基-4-甲基噻唑-5-基)-2-甲氧基苯基磺酰胺基)乙基氨基甲酸叔丁酯;
(5-(2-丁酰胺基-4-甲基噻唑-5-基)-2-甲氧基苯基磺酰胺基)乙基氨基甲酸叔丁酯;
(5-(2-戊酰胺基-4-甲基噻唑-5-基)-2-甲氧基苯基磺酰胺基)乙基氨基甲酸叔丁酯;
(5-(2-己酰胺基-4-甲基噻唑-5-基)-2-甲氧基苯基磺酰胺基)乙基氨基甲酸叔丁酯;
(5-(2-庚酰胺基-4-甲基噻唑-5-基)-2-甲氧基苯基磺酰胺基)乙基氨基甲酸叔丁酯;
(2-(2-甲氧基-5-(4-甲基-2-(3-丙基脲基)噻唑-5-基)苯基)磺酰胺基)乙基氨基甲酸叔丁酯;
(2-(5-(2-(3-丁基脲基)-4-甲基噻唑-5-基)-2-甲氧基苯基磺酰胺基)乙基)氨基甲酸叔丁酯;
(2-(2-甲氧基-5-(4-甲基-2-(3-甲基丁酰胺)噻唑-5-基)苯基)磺酰胺基)乙基氨基甲酸叔丁酯;
(5-(2-异丁酰胺基-4-甲基噻唑-5-基)-2-甲氧基苯基磺酰胺基)乙基氨基甲酸叔丁酯;
(2-(2-甲氧基-5-(4-甲基-2-特戊酰胺噻唑-5-基)苯基)磺酰胺基)乙基氨基甲酸叔丁酯;
(5-(2-(3,3-二甲基丁酰胺)-4-甲基噻唑-5-基)-2-甲氧基苯基磺酰胺基)乙基氨基甲酸叔丁酯;
(2-(2-甲氧基-5-(4-甲基-2-(4-甲基戊酰胺)噻唑-5-基)苯基)磺酰胺基)乙基氨基甲酸叔丁酯;
(2-(2-甲氧基-5-(4-甲基-2-(5-甲基己酰胺基)噻唑-5-基)苯基)磺酰胺基)乙基氨基甲酸叔丁酯
(2-(5-(2-(环己烷甲酰胺基)-4-甲基噻唑-5-基)-2-甲氧基苯基)磺酰胺基)乙基氨基甲酸叔丁酯;
(2-(2-氯-5-(4-甲基-2-(3-甲基丁酰胺基)噻唑-5-基)苯基)磺酰胺基)乙基氨基甲酸叔丁酯;
(2-氯-5-(2-(3,3-二甲基丁酰胺)-4-甲基噻唑-5-基)苯基磺酰胺基)乙基氨基甲酸叔丁酯;
(2-氯-5-(4-甲基-2-戊酰胺基-5-基)苯基磺酰胺基)乙基氨基甲酸叔丁酯;
(2-氯-5-(2-己酰胺基-4-甲基噻唑-5-基)苯基磺酰胺基)乙基氨基甲酸叔丁酯;
(2-(5-(2-(3-乙酰氨基丙酰胺基)-4-甲基噻唑-5-基)-2-甲氧基苯基)磺酰胺基)乙基氨基甲酸叔丁酯;
(2-(2-甲氧基-5-(4-甲基-2-(6-氧代庚酰胺基)噻唑-5-基)苯基)磺酰胺基)乙基氨基甲酸叔丁酯;
(2-(2-甲氧基-5-(4-甲基-2-(6-氧代已酰胺基)噻唑-5-基)苯基)磺酰胺基)乙基氨基甲酸叔丁酯;
(R)-(1-((5-(2-己酰胺基-4-甲基噻唑-5-基)-2-甲氧基苯基)磺酰基)哌啶-3-基)氨基甲酸叔丁酯;
(S)-(1-((5-(2-己酰胺基-4-甲基噻唑-5-基)-2-甲氧基苯基)磺酰基)吡咯烷-3-基)氨基甲酸叔丁酯;
4-((2-己酰胺基-4-甲基噻唑-5-基)-2-甲氧基苯基磺酰胺基)哌啶-1-羧酸叔丁酯;
N-(5-(3-(2-(3,3-二甲基丁酰胺)乙基氨基磺酰基)-4-甲氧基苯基)-4-甲基噻唑-2-基)己酰胺;
N-(5-(3-(2-羟基-2-甲基丙基)氨基磺酰基)-4-甲氧基苯基)-4-甲基噻唑-2-基己酰胺;
N-(5-(3-(N-(2-啉乙基)氨基磺酰基))-4-甲氧基苯基)-4-甲基噻唑-2-基己酰胺;
N-(4-(3-(((2 ,4-二氟苄基)-l2-亚氮基)磺酰基)-4-甲氧基苯基)-5-甲基噻唑-2-基)己酰胺;
(2-(2-己酰胺基-4-甲基噻唑-5-基)-2-甲氧基苯甲酰胺基)乙基氨基甲酸叔丁酯。
4.一种权利要求1所述抑制剂的制法,其特征在于,以1-(4-氯苯基)-2-丙酮或1-(4-甲氧基苯基)-2-丙酮为原料1a、1b,原料1a、1b与氯磺酸在苯环3号位发生取代反应得到中间体2a、 2b;在中间体2a、2b的基础上通过Hinsberg反应,引入R2基团得到中间体3a-3g;中间体3a-3g与苯基三甲基三溴化铵发生α-溴代反应得到中间体4a-4g;中间体4a-4g与N-乙酰硫脲缩合反应得到目标化合物5a-5g,合成路线如下:
。
5.根据权利要求4所述的制法,其特征在于,根据目标化合物5a-5g的制备方法,以权利要求4中的中间体4d、 4e为原料,同时将硫脲与各种酰氯发生取代反应引入R3基团得到中间体N-取代硫脲为另一类原料;二者缩合反应得到目标化合物7a-7r;或以中间体4e为原料,与硫脲发生缩合反应得到中间体8;中间体8分别与3-乙酰氨基丙酰氯、6-羰基庚酰氯和5-羰基己酰氯发生取代反应得到目标化合物9a-9c,合成路线如下:
;
或根据目标化合物5a-5g的制法,得到化合物4h-4x为原料,与N-己酰硫脲发生缩合反应得到目标化合物10a-10q,合成路线如下:
。
6.根据权利要求5所述的制法,其特征在于,以化合物(11)为原料,经过两步反应得到中间体12;中间体12在乙酸中加热回流与铁粉发生还原反应得到中间体13;中间体13在酸性条件下发生水解反应得到中间体14;中间体14与(2-氨基乙基)氨基甲酸叔丁酯反应得到中间体15,经过两步反应得到目标化合物17,合成路线如下:
;
或以4´-甲氧基苯丙酮18为原料,经过四步反应得到目标化合物22,合成路线如下:
。
7.一种药物组合物,其特征在于,所述组合物包含至少一种药学上可接受的辅料、辅助剂或载体,以及权利要求1~3任一项所述的苯基噻唑胺类PI4KIIIβ抑制剂。
8.一种权利要求1所述苯基噻唑胺类PI4KIIIβ抑制剂或权利要求7所述药物组合物在制备用于预防、治疗或辅助治疗PI4KIIIβ激酶过度活化引起的增殖性疾病、代谢性疾病、神经***性疾病或结节性硬化症的药物中的应用。
9.一种权利要求1所述苯基噻唑胺类PI4KIIIβ抑制剂或权利要求7所述药物组合物在制备用于抑制癌症细胞生长的药物中的应用。
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