CN118221610A - 一种苯基噻唑胺类PI4KIIIβ/HDAC双靶抑制剂、制备方法及其药物组合物和应用 - Google Patents
一种苯基噻唑胺类PI4KIIIβ/HDAC双靶抑制剂、制备方法及其药物组合物和应用 Download PDFInfo
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- CN118221610A CN118221610A CN202410660509.2A CN202410660509A CN118221610A CN 118221610 A CN118221610 A CN 118221610A CN 202410660509 A CN202410660509 A CN 202410660509A CN 118221610 A CN118221610 A CN 118221610A
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- methyl
- phenyl
- methoxy
- hydroxy
- sulfamide
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- -1 Phenylthiazole amine Chemical class 0.000 title claims abstract description 127
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- 238000006243 chemical reaction Methods 0.000 claims description 38
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 36
- 150000001875 compounds Chemical class 0.000 claims description 33
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 27
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Abstract
本发明涉及一种苯基噻唑胺类PI4KIIIβ/HDAC双靶抑制剂、制备方法及其药物组合物和应用,属于医药技术领域。本发明提供一种苯基噻唑胺类PI4KIIIβ/HDAC双靶抑制剂,为通式I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。本发明有益效果:(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/HDAC双酶抑制活性;(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)有较高抗丙型肝炎病毒的活性,使用剂量小。
Description
技术领域
本发明涉及一种苯基噻唑胺类PI4KIIIβ/HDAC双靶抑制剂、制备方法及其药物组合物和应用,属于医药技术领域。
背景技术
磷脂酰肌醇4-激酶(PI4Ks)的高表达与多种疾病密切相关,包括病毒感染、癌症、疟疾以及神经退行性疾病等。磷脂酰肌醇(PI)经过PI4Ks磷酸化产生磷脂酰肌醇4-磷酸(PI4P),它在高尔基功能、蛋白质分选以及膜运输等方面也发挥着关键性的作用,其中对外源病原体(如病毒)在宿主内的复制与扩增也起重要作用。因此,有关PI4Ks的抑制剂广谱抗病毒的研究成为当前药物化学研究的热点之一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、膜运输和胞质分裂。磷脂酰肌醇通过磷脂酰肌醇的肌醇环磷酸化产生。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是一种分布在高尔基体以及质膜上的外周膜蛋白,在介导脂质转运和细胞分裂中起关键作用。PI4KIIIβ蛋白由801个氨基酸残基组成,包括一个螺旋结构域和一个脂质激酶结构域以及介导与调节蛋白结合的3个无序区域。PI4KIIIβ的N端主要负责与高尔基体的蛋白(如酰基辅酶A结合结构域蛋白3,ACBD3)发生作用进而募集;其C端包含一个两亲性的脂质堆积传感器基序负责病毒信号传感与转运。多种病毒(包括常见的脊髓灰质炎病毒、柯萨奇病毒以及丙型肝炎病毒等)在宿主细胞复制都需要依赖于病毒复制位点PI4KIIIβ及其催化产物PI4P,因此,PI4KIIIβ也是许多病毒复制的关键因子。一般表现为病毒劫持PI4KIIIβ形成含有PI4P的复制细胞器(ROs),从而诱导病毒蛋白在生物膜上形成复制结构。PI4K IIIβ在人类遗传疾病中也发挥着关键性作用,PI4KIIIβ通过调节骨形态发生蛋白膜II型受体(BMPR2)和信号传导蛋白1/5/9(Smad1/5/9),进而影响靶基因HES相关家族bHLH转录因子与YRPW基序1(hey1)的转录激活,最终影响斑马鱼前庭器官发育。STING是先天免疫反应的关键信号转导因子,cGAS-STING通路的激活,触发外源性DNA,从而调节自发性抗肿瘤、抗DNA病毒等免疫反应。ARMH3是STING激活的关键因子,ARMH3通过募集PI4KIIIβ,从而激活STING的目的。
组蛋白脱乙酰酶(HDACs)是一类表观遗传酶,催化从组蛋白和其他蛋白质的赖氨酸残基中去除乙酰基,从而调节染色质结构和转录活性。HDAC的经典异羟肟酸抑制剂——伏立诺他(SAHA,Vorinostat),其结构包含形成药效团的三个主要元素的序列:帽、连接体和锌结合基(ZBG)。一方面,连接体与ZBG结合,并促进其渗透到HDAC活性位点的疏水性“隧道”中,在其底部发生催化锌离子的螯合作用。另一方面,连接体与帽状结构相关,最常见的是芳基或杂芳基自由基,其额外地与蛋白质底物结合腔相互作用,影响抑制的强度和选择性。最近的蛋白质组学研究揭示了小鼠和人类肝细胞中广泛的乙酰化。HCV感染引起的HDAC活性的上调也有报道。此外,三种HDAC酶(HDAC2、3和5)的多态性已被证明与慢性HCV的持续病毒学反应独立相关。许多观察结果表明,HDAC抑制剂在阻断HCV复制方面具有前景,且近期苯甲异羟肟酸和泛HDAC抑制剂伏立诺他(SAHA)已被报道为潜在的抗HCV药物。
根据已有的文献资料表明,同时抑制PI4KIIIβ与HDAC可高效阻断HCV复制,并通过提高疗效从而限制耐药性,PI4KIIIβ与HDAC的选择性抑制剂可能具有更低的毒性,目前还尚未有文献报道关于PI4KIIIβ/HDAC双靶抑制剂 。
发明内容
本发明的目的是针对现有技术存在的缺陷,提出一种苯基噻唑胺类PI4KIIIβ/HDAC双靶抑制剂、其制备方法,含抑制剂的药物组合物及应用,提高抑制活性。
本发明首先提供:一种苯基噻唑胺类PI4KIIIβ/HDAC双靶抑制剂,为通式I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:其中,R1-R4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;
R5和R6选自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选自砜基或羰基;
Y选自C1-C6亚烷基、含一个或多个取代基的C1-C6亚烷基、4-取代苯基、4-取代的苄基或4-取代的苯氧乙基等;Z选自如下结构:。优选的,所述通式I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系统中反应。
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)N-羟基-3-((2-甲氧基-5-(4-甲基-2-特戊酰胺基噻唑-5-基)苯基)磺酰胺基)丙酰胺;
(2)N-羟基-4-((2-甲氧基-5-(4-甲基-2-特戊酰胺基噻唑-5-基)苯基)磺酰胺基)丁酰胺;
(3)N-羟基-5-((2-甲氧基-5-(4-甲基-2-特戊酰胺基噻唑-5-基)苯基)磺酰胺基)戊酰胺;
(4)N-羟基-6-((2-甲氧基-5-(4-甲基-2-特戊酰胺基噻唑-5-基)苯基)磺酰胺基)己酰胺;
(5)N-羟基-7-((2-甲氧基-5-(4-甲基-2-特戊酰胺基噻唑-5-基)苯基)磺酰胺基)庚酰胺;
(6)N-羟基-4-(((2-甲氧基-5-(4-甲基-2-特戊酰胺基噻唑-5-基)苯基)磺酰胺基)甲基)苯甲酰胺;
(7)N-羟基-4-(2-((2-甲氧基-5-(4-甲基-2-戊酰胺基噻唑-5-基)苯基)磺酰氨基)乙氧基)苯甲酰胺;
(8)N-羟基-4-((2-甲氧基-5-(4-甲基-2-丙酰胺基噻唑-5-基)苯基)磺酰胺基)丁酰胺;
(9)N-羟基-4-((2-甲氧基-5-(4-甲基-2-丁酰胺基噻唑-5-基)苯基)磺酰胺基)丁酰胺;
(10)N-羟基-4-((2-甲氧基-5-(4-甲基-2-异丁酰胺基噻唑-5-基)苯基)磺酰胺基)丁酰胺;
(11)N-羟基-4-((2-甲氧基-5-(4-甲基-2-戊酰胺基噻唑-5-基)苯基)磺酰胺基)丁酰胺;
(12)N-羟基-4-((2-甲氧基-5-(4-甲基-2-异戊酰胺基噻唑-5-基)苯基)磺酰胺基)丁酰胺;
(13)N-羟基-4-((2-甲氧基-5-(4-甲基-2-己酰胺基噻唑-5-基)苯基)磺酰胺基)丁酰胺;
(14)N-羟基-3-((2-甲氧基-5-(4-甲基-2-戊酰胺基噻唑-5-基)苯基)磺酰胺基)丙酰胺;
(15)N-羟基-5-((2-甲氧基-5-(4-甲基-2-戊酰胺基噻唑-5-基)苯基)磺酰胺基)戊酰胺;
(16)N-羟基-6-((2-甲氧基-5-(4-甲基-2-戊酰胺基噻唑-5-基)苯基)磺酰胺基)己酰胺;
(17)N-羟基-4-(((2-甲氧基-5-(4-甲基-2-戊酰胺基噻唑-5-基)苯基)磺酰胺基)甲基)苯甲酰胺;
(18)N-羟基-7-((2-甲氧基-5-(4-甲基-2-乙酰胺基噻唑-5-基)苯基)磺酰胺基)庚酰胺;
(19)N-羟基-5-((2-甲氧基-5-(4-甲基-2-丙酰胺基噻唑-5-基)苯基)磺酰胺基)戊酰胺;
(20)N-羟基-5-((2-甲氧基-5-(4-甲基-2-丁酰胺基噻唑-5-基)苯基)磺酰胺基)戊酰胺;
(21)N-羟基-4-(((2-甲氧基-5-(4-甲基-2-丁酰胺基噻唑-5-基)苯基)磺酰胺基)甲基)苯甲酰胺;
(22)N-羟基-5-((2-甲氧基-5-(4-甲基-2-异丁酰胺基噻唑-5-基)苯基)磺酰胺基)戊酰胺;
(23)N-羟基-7-((2-甲氧基-5-(4-甲基-2-异戊酰胺基噻唑-5-基)苯基)磺酰胺基)庚酰胺;
(24)N-羟基-4-(((2-甲氧基-5-(4-甲基-2-异戊酰胺基噻唑-5-基)苯基)磺酰胺基)甲基)苯甲酰胺;
(25)N-羟基-3-((2-甲氧基-5-(4-甲基-2-己酰胺基噻唑-5-基)苯基)磺酰胺基)丙酰胺;
(26)N-羟基-6-((2-甲氧基-5-(4-甲基-2-己酰胺基噻唑-5-基)苯基)磺酰胺基)己酰胺;
(27)N-羟基-7-((2-甲氧基-5-(4-甲基-2-己酰胺基噻唑-5-基)苯基)磺酰胺基)庚酰胺;
(28)N-羟基-4-(((2-甲氧基-5-(4-甲基-2-己酰胺基噻唑-5-基)苯基)磺酰胺基)甲基)苯甲酰胺;
(29)N-(2-氨基-4-氟苯基)-4-(((2-甲氧基-5-(4-甲基-2-特戊酰胺基噻唑-5-基)苯基)磺酰胺)甲基)苯甲酰胺;
(30)N-(7-(羟基氨基)-4-氧代丁基)-5-(2-己酰胺基-4-甲基噻唑-5-基)-2-甲氧基苯甲酰胺;
(31)N-(7-(羟基氨基)-7-氧代庚基) -5-(2-异丁酰胺基-4-甲基噻唑-5-基)-2-甲氧基苯甲酰胺;
(32)N-(7-(羟基氨基)-7-氧代庚基)-5-(2-己酰胺基-4-甲基噻唑-5-基)-2-甲氧基苯甲酰胺;
(33)N-(4-(羟基氨基甲酰基)苄基)-5-(2-己酰胺基-4-甲基噻唑-5-基)-2-甲氧基苯甲酰胺。
上述抑制剂的制法为,根据目标化合物的制备方法之一,以4-甲氧基苯丙酮为原料(1),原料(1)与氯磺酸在苯环3号位发生取代反应得到中间体(2);在中间体(2)的基础上通过Hinsberg 反应,引入氨基羧酸甲酯得到中间体(3);中间体(3)与苯基三甲基三溴化铵发生α-溴代反应得到中间体(4);硫脲(5)与多种酰氯反应得到N-取代硫脲(6),与中间体(4)缩合反应得到中间体(7);中间体(7)与羟胺发生酰胺缩合得到目标化合物(8)。制备路线如下:。
上述抑制剂的制法还包括,根据目标化合物的制备方法,以4-甲氧基苯丙酮为原料(1),原料(1)与氯磺酸在苯环3号位发生取代反应得到中间体(2);在中间体(2)的基础上通过Hinsberg反应,引入氨基羧酸甲酯得到中间体(3);中间体(3)与苯基三甲基三溴化铵发生α-溴代反应得到中间体(4);硫脲(5)与多种酰氯反应得到N-取代硫脲(6),与中间体(4)缩合反应得到中间体(7);中间体(7)与4-氟-1,2-苯二胺发生酰胺缩合得到目标化合物(9)。制备路线如下:。
上述抑制剂的制法还包括,以5-甲酰基-2-甲氧基苯甲酸甲酯为原料(10),经过两步反应得到中间体(11);中间体(11)在乙酸中加热回流与铁粉发生还原反应得到中间体(12);中间体(12)在酸性条件下发生水解反应得到中间体(13);中间体(13)被二氯亚砜氯化生成中间体(14);中间体(14)与氨基羧酸甲酯反应得到中间体(15);中间体(15)与苯基三甲基三溴化铵发生α-溴代反应得到中间体(16);中间体(16)与N-取代硫脲缩合反应得到中间体(17);中间体(17)与羟胺发生酰胺缩合得到目标化合物(18)。制备路线如下:。
本发明进一步提供一种药物组合物,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/HDAC双靶抑制剂。
本发明再进一步提供苯基噻唑胺类PI4KIIIβ/HDAC双靶抑制剂或药物组合物在制备用于抑制丙型肝炎病毒生长的药物中的应用,同时用于预防、治疗或辅助治疗由HCV病毒引起的丙型肝炎。
由于PI4KIIIβ靶点的抑制活性不强,抗丙型肝炎病毒作用不足且无文献报道PI4KIIIβ/HDAC双靶抑制剂,PIK-93被选为进一步结构修饰的先导化合物。本发明确定以苯基噻唑胺为基本骨架结构,通过筛选取代基团,实现对PI4KIIIβ和HDAC的高效抑制,进而抑制HCV病毒的生长,同时对细胞毒性较小,从而可潜在地用于临床治疗药物。其有益效果:(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/HDAC双酶抑制活性;(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)有较高抗丙型肝炎病毒的活性,使用剂量小。
具体实施方式
下面结合实施例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
N-羟基-3-((2-甲氧基-5-(4-甲基-2-特戊酰胺基噻唑-5-基)苯基)磺酰胺基)丙酰胺的合成,合成步骤如下:
步骤1:2-甲氧基-5-(2-氧代丙基)苯磺酰氯的合成,结构式:,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30min,将2.02 g(12.0 mmol)4-甲氧基苯基丙酮缓慢的滴加到ClSO3H中,室温反应大约6 h,通过TLC点板至原料全部消耗完。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。黄色固体,收率:60 %。1H NMR (300 MHz, Chloroform-d) δ 7.77 (s, 1H), 7.54 (d, J = 2.3Hz, 1H), 7.52 (d, J = 2.3 Hz, 1H), 3.77 (s, 4H), 2.26 (s, 5H).
步骤2:3-((2-甲氧基-5-(2-氧代丙基)苯基)磺酰胺基)丙酸甲酯的合成,结构式:,称取5 mmol的2-甲氧基-5-(2-氧代丙基)苯磺酰氯溶于20mL二氯甲烷中,将7.5 mmol的3-氨基丙酸甲酯盐酸盐(1.5 eq.)和1.52 g三乙胺(3.0 eq.)加至反应液中室温搅拌12 h至2-甲氧基-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:75 %。1H NMR (400 MHz, Chloroform-d)δ 7.52 (dt, J = 2.1, 1.0 Hz, 1H), 7.25 (ddt, J = 8.4, 2.2, 1.1 Hz, 1H), 7.01– 6.93 (m, 2H), 3.82 (s, 3H), 3.78 (t, J = 1.0 Hz, 2H), 3.64 (s, 3H), 3.15(q, J = 6.3 Hz, 2H), 2.75 (t, J = 6.2 Hz, 2H).
步骤3:3-((2-甲氧基-5-(4-甲基-2-戊酰胺基噻唑-5-基)苯基)磺酰胺基)丙酸甲酯的合成,结构式:,称取1 mmol 3-((2-甲氧基-5-(2-氧代丙基)苯基)磺酰胺基)丙酸甲酯溶于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(3-((5-(1-溴乙基)-2-甲氧基苯基)磺酰胺基)丙酸甲酯)。淡黄色油状物,收率:60 %。(1H NMR (300 MHz, Chloroform-d) δ 7.95 – 7.91 (m, 1H), 7.45 – 7.39(m, 1H), 7.14 (d, J = 8.4 Hz, 1H), 7.06 (t, J = 6.7 Hz, 1H), 5.90 (d, J = 0.9Hz, 1H), 3.89 (s, 2H), 3.64 (s, 2H), 3.19 (q, J = 6.3 Hz, 2H), 2.66 (t, J =6.2 Hz, 2H))。之后,先制备N-特戊酰硫脲,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的特戊酰氯溶于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-特戊酰硫脲,收率:71 %(1H NMR (400 MHz,Chloroform-d) δ 9.84 (s, 1H), 8.87 (s, 2H), 1.34 (s, 9H))。称取1 mmol中间体于25 mL的茄形瓶中,加入10 mL丙酮溶液,再将N-特戊酰硫脲(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, Chloroform-d) δ 8.24 (d, J = 2.2 Hz,1H), 7.56 (dd, J = 7.9, 2.2 Hz, 1H), 7.02 (d, J = 7.9 Hz, 1H), 7.00 (t, J =6.7 Hz, 1H), 3.70 (s, 2H), 3.44 (s, 2H), 3.02 (q, J = 6.3 Hz, 2H), 2.62 (t, J= 6.2 Hz, 2H), 1.14 (s, 7H).
步骤4:N-羟基-3-((2-甲氧基-5-(4-甲基-2-特戊酰胺基噻唑-5-基)苯基)磺酰胺基)丙酰胺的合成,结构式如下:,首先制备3-((2-甲氧基-5-(4-甲基-2-戊酰胺基噻唑-5-基)苯基)磺酰胺基)丙酸,称5 mmol的3-((2-甲氧基-5-(4-甲基-2-戊酰胺基噻唑-5-基)苯基)磺酰胺基)丙酸甲酯溶于10 mL的甲醇四氢呋喃水的混合溶液(MeOH:THF:H2O=2:2:1)中并置于50 mL的茄形瓶中,称取10 mmol的氢氧化锂(2 eq.)缓慢滴加至反应瓶中,室温过夜,反应结束将反应液趁热加入冰盐水中析出大量白色固体,干燥后得3-((2-甲氧基-5-(4-甲基-2-戊酰胺基噻唑-5-基)苯基)磺酰胺基)丙酸粗品。称取1 mmol 3-((2-甲氧基-5-(4-甲基-2-戊酰胺基噻唑-5-基)苯基)磺酰胺基)丙酸粗品和1.5 mmol的PyBOP缩合剂(1.5 eq.)于25 mL的反应瓶中,加入6 mL DMF溶液,量取590 µL DIPEA(3.5 eq.)加入反应液中,室温搅拌几分钟后加入0.14 g盐酸羟胺(2.0eq.),室温反应6 h后,TLC监测直到中间体全部消耗完(DCM:MeOH=25:1),真空浓缩,柱层析纯化。白色固体,收率:66 %。1H NMR (300 MHz, DMSO-d 6) δ 11.23 (s, 2H), 10.49 (s,1H), 8.77 (s, 1H), 7.74 (d, J = 2.3 Hz, 1H), 7.69 (dd, J = 8.5, 2.4 Hz, 1H),7.33 (d, J = 8.7 Hz, 1H), 3.95 (s, 3H), 3.01 (t, J = 7.4 Hz, 2H), 2.34 (s,3H), 2.15 (t, J = 7.3 Hz, 2H), 1.24 (s, 9H). 13C NMR (101 MHz, DMSO-d 6) δ177.18, 167.27, 156.24, 155.77, 142.43, 134.76, 129.40, 128.44, 124.57,122.82, 114.14, 56.87, 40.58, 40.37, 40.16, 39.96, 39.75, 39.54, 39.33,39.22, 33.04, 27.05, 16.19.
实施例2
N-羟基-4-((2-甲氧基-5-(4-甲基-2-特戊酰胺基噻唑-5-基)苯基)磺酰胺基)丁酰胺,结构式如下:,将实施例1中步骤2中的片段3-氨基丙酸甲酯盐酸盐改为4-氨基丁酸甲酯盐酸盐,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) δ 11.85 (s, 1H), 10.34 (s, 1H), 8.70(s, 1H), 7.73 (d, J = 2.4 Hz, 1H), 7.67 (dd, J = 8.6, 2.4 Hz, 1H), 7.43 (t, J= 5.9 Hz, 1H), 7.32 (d, J = 8.7 Hz, 1H), 3.94 (s, 3H), 2.80 (q, J = 6.7 Hz,2H), 2.34 (s, 3H), 1.95 (t, J = 7.5 Hz, 2H), 1.60 (p, J = 7.4 Hz, 2H), 1.24(s, 9H). 13C NMR (101 MHz, DMSO-d 6) δ 177.18, 169.08, 156.21, 155.79, 142.43,134.63, 129.38, 128.87, 124.51, 122.87, 114.09, 56.79, 42.82, 40.59, 40.38,40.17, 39.97, 39.76, 39.55, 39.34, 39.22, 30.02, 27.05, 25.92, 16.20.
实施例3
N-羟基-5-((2-甲氧基-5-(4-甲基-2-特戊酰胺基噻唑-5-基)苯基)磺酰胺基)戊酰胺,结构式如下:,将实施例1中步骤2中的片段3-氨基丙酸甲酯盐酸盐改为5-氨基戊酸甲酯盐酸盐,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) δ 11.85 (s, 1H), 10.32 (s, 1H), 8.68 (s,1H), 7.73 (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 = 8.8 Hz, 1H), 3.94 (s, 3H), 2.81 (q, J = 6.5 Hz,2H), 2.34 (s, 3H), 1.88 (t, J = 7.2 Hz, 2H), 1.52 – 1.31 (m, 4H), 1.24 (s,9H). 13C NMR (101 MHz, DMSO-d 6) δ 177.14, 169.32, 156.17, 155.80, 142.40,134.56, 129.37, 129.02, 124.46, 122.91, 114.06, 56.76, 42.83, 40.59, 40.38,40.17, 39.96, 39.75, 39.54, 39.33, 39.22, 32.25, 29.32, 27.05, 22.73, 16.18.
实施例4
N-羟基-6-((2-甲氧基-5-(4-甲基-2-特戊酰胺基噻唑-5-基)苯基)磺酰胺基)己酰胺,结构式如下:,将实施例1中步骤2中的片段3-氨基丙酸甲酯盐酸盐改为6-氨基己酸甲酯盐酸盐,其他步骤及操作同实施例1;白色固体,收率:39 %。1H NMR (300 MHz, DMSO-d 6) δ 11.84 (s, 1H), 10.33 (s, 1H), 8.67(s, 1H), 7.73 (d, J = 2.3 Hz, 1H), 7.67 (dd, J = 8.6, 2.4 Hz, 1H), 7.41 –7.27 (m, 2H), 3.94 (s, 3H), 2.80 (q, J = 6.5 Hz, 2H), 2.34 (s, 3H), 1.88 (t,J = 7.3 Hz, 2H), 1.38 (dp, J = 16.2, 7.4 Hz, 5H), 1.24 (s, 9H), 1.22 – 1.13(m, 1H). 13C NMR (101 MHz, DMSO-d 6) δ 177.15, 169.44, 156.17, 155.81, 142.41,134.58, 129.38, 129.03, 124.47, 122.91, 114.04, 56.77, 43.01, 40.59, 40.38,40.17, 39.96, 39.75, 39.54, 39.34, 39.22, 32.63, 29.37, 27.04, 26.11, 25.20,16.16.
实施例5
N-羟基-7-((2-甲氧基-5-(4-甲基-2-特戊酰胺基噻唑-5-基)苯基)磺酰胺基)庚酰胺,结构式如下:,将实施例1中步骤2中的片段3-氨基丙酸甲酯盐酸盐改为7-氨基庚酸甲酯盐酸盐,其他步骤及操作同实施例1;白色固体,收率:38 %。1H NMR (300 MHz, DMSO-d 6) δ 11.83 (s, 1H), 10.32 (s, 1H),8.66 (s, 1H), 7.76 – 7.62 (m, 2H), 7.41 – 7.27 (m, 2H), 3.94 (s, 3H), 2.81(q, J = 6.5 Hz, 2H), 2.34 (s, 3H), 1.89 (t, J = 7.3 Hz, 2H), 1.38 (dt, J =20.6, 6.9 Hz, 3H), 1.24 (s, 9H), 1.22 – 1.09 (m, 5H). 13C NMR (101 MHz, DMSO-d 6) δ 177.17, 169.51, 156.20, 155.81, 142.37, 134.56, 129.37, 129.11, 124.46,122.90, 114.03, 56.76, 43.09, 40.59, 40.38, 40.17, 39.96, 39.75, 39.54,39.33, 39.22, 32.63, 29.48, 28.64, 27.04, 26.20, 25.50, 16.15.
实施例6
N-羟基-4-(((2-甲氧基-5-(4-甲基-2-特戊酰胺基噻唑-5-基)苯基)磺酰胺基)甲基)苯甲酰胺,结构式如下:,将实施例1中步骤2中的片段3-氨基丙酸甲酯盐酸盐改为4-氨甲基苯甲酸甲酯盐酸盐,其他步骤及操作同实施例1;白色固体,收率:45 %。1H NMR (300 MHz, DMSO-d 6) δ 11.85 (s, 1H), 11.15(s, 1H), 9.00 (s, 1H), 8.04 (t, J = 6.4 Hz, 1H), 7.69 (d, J = 2.4 Hz, 1H),7.58 (t, J = 7.8 Hz, 3H), 7.26 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 8.7 Hz, 1H),4.14 (d, J = 6.2 Hz, 2H), 3.86 (s, 3H), 2.32 (s, 3H), 1.25 (s, 9H). 13C NMR(101 MHz, DMSO-d 6) δ 178.88, 165.27, 161.15, 157.55, 149.05, 142.53, 131.81,131.55, 130.58, 128.42 - 127.92 (m), 125.94, 114.21, 55.80, 47.71, 39.54,27.57, 19.26.
实施例7
N-羟基-4-(2-((2-甲氧基-5-(4-甲基-2-戊酰胺基噻唑-5-基)苯基)磺酰氨基)乙氧基)苯甲酰胺,结构式如下:,将实施例1中步骤2中的片段3-氨基丙酸甲酯盐酸盐改为4-(2-氨基乙氧基)苯甲酸甲酯盐酸盐,其他步骤及操作同实施例1;白色固体,收率:49 %。 1H NMR (400 MHz, DMSO-d 6) δ 11.83 (s,1H), 11.05 (s, 1H), 8.92 - 8.87 (m, 1H), 7.76 (d, J = 2.4 Hz, 1H), 7.71 -7.60 (m, 4H), 7.26 (d, J = 8.7 Hz, 1H), 6.87 - 6.80 (m, 2H), 4.00 (t, J = 5.3Hz, 2H), 3.90 (s, 3H), 3.27 (t, J = 5.7 Hz, 2H), 2.33 (s, 3H), 1.25 (s, 9H).13C NMR (101 MHz, DMSO-d 6) δ 178.88, 164.94, 162.74, 161.15, 157.55, 149.05,131.81, 130.58, 129.30, 128.14, 127.23, 126.16, 125.94, 115.25, 114.21,66.73, 55.80, 43.44, 39.54, 27.57, 19.26.
实施例8
N-羟基-4-((2-甲氧基-5-(4-甲基-2-丙酰胺基噻唑-5-基)苯基)磺酰胺基)丁酰胺,结构式如下:,将实施例1中步骤2中的片段3-氨基丙酸甲酯盐酸盐改为4-氨基丁酸甲酯盐酸盐以及步骤3中的特戊酰氯改为丙酰氯,其他步骤及操作同实施例1;白色固体,收率:42 %。1H NMR (300 MHz, DMSO-d 6) δ 11.03(d, J = 56.8 Hz, 2H), 9.82 (s, 1H), 8.85 (s, 1H), 7.72 (d, J = 2.3 Hz, 1H),7.66 (dd, J = 8.6, 2.4 Hz, 1H), 7.30 (d, J = 8.7 Hz, 1H), 3.93 (s, 3H), 2.80(t, J = 7.1 Hz, 2H), 2.42 (q, J = 7.5 Hz, 2H), 2.31 (s, 3H), 1.94 (t, J = 7.5Hz, 2H), 1.59 (t, J = 7.3 Hz, 2H), 1.09 (td, J = 7.3, 2.6 Hz, 3H). 13C NMR(101 MHz, DMSO-d 6) δ 173.58, 172.12, 161.10, 157.54, 149.05, 131.81, 130.58,128.01, 127.66, 125.82, 114.21, 55.80, 42.78, 31.54, 28.65, 24.85, 19.26,9.52.
实施例9
N-羟基-4-((2-甲氧基-5-(4-甲基-2-丁酰胺基噻唑-5-基)苯基)磺酰胺基)丁酰胺,结构式如下:,将实施例1中步骤2中的片段3-氨基丙酸甲酯盐酸盐改为4-氨基丁酸甲酯盐酸盐以及步骤3中的特戊酰氯改为丁酰氯,其他步骤及操作同实施例1;白色固体,收率:44 %。1H NMR (300 MHz, DMSO-d 6) δ 12.09(s, 1H), 10.34 (s, 1H), 8.70 (s, 1H), 7.76 – 7.63 (m, 2H), 7.43 (t, J = 5.7Hz, 1H), 7.31 (d, J = 8.7 Hz, 1H), 3.94 (s, 3H), 2.80 (q, J = 6.7 Hz, 2H),2.41 (t, J = 7.3 Hz, 2H), 2.33 (s, 3H), 1.95 (t, J = 7.4 Hz, 2H), 1.62 (qd, J= 7.3, 3.2 Hz, 4H), 0.90 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, DMSO-d 6) δ171.70, 169.09, 155.80, 155.41, 142.50, 134.60, 129.38, 128.86, 124.48,122.73, 114.07, 56.79, 42.81, 40.60, 40.40, 40.19, 39.98, 39.77, 39.56,39.35, 37.24, 30.02, 25.92, 18.68, 16.29, 13.95.
实施例10
N-羟基-4-((2-甲氧基-5-(4-甲基-2-异丁酰胺基噻唑-5-基)苯基)磺酰胺基)丁酰胺,结构式如下:,将实施例1中步骤2中的片段3-氨基丙酸甲酯盐酸盐改为4-氨基丁酸甲酯盐酸盐以及步骤3中的特戊酰氯改为异丁酰氯,其他步骤及操作同实施例1;白色固体,收率:45 %。1H NMR (300 MHz, DMSO-d 6) δ 10.96(s, 1H), 10.27 (s, 1H), 9.77 (s, 1H), 8.87 (s, 1H), 7.76 – 7.60 (m, 2H), 7.31(d, J = 8.7 Hz, 1H), 3.94 (s, 3H), 2.76 (dt, J = 25.4, 7.0 Hz, 3H), 2.32 (s,3H), 1.95 (t, J = 7.4 Hz, 2H), 1.59 (q, J = 7.2 Hz, 2H), 1.11 (dd, J = 7.0,3.0 Hz, 6H). 13C NMR (101 MHz, DMSO-d 6) δ 178.34, 172.12, 161.34, 157.54,149.05, 131.81, 130.58, 128.01, 127.66, 125.94, 114.21, 55.80, 42.78, 35.73,31.54, 24.85, 19.24, 19.21.
实施例11
N-羟基-4-((2-甲氧基-5-(4-甲基-2-戊酰胺基噻唑-5-基)苯基)磺酰胺基)丁酰胺,结构式如下:,将实施例1中步骤2中的片段3-氨基丙酸甲酯盐酸盐改为4-氨基丁酸甲酯盐酸盐以及步骤3中的特戊酰氯改为戊酰氯,其他步骤及操作同实施例1;白色固体,收率:43 %。1H NMR (300 MHz, DMSO-d 6) δ12.12 (s, 1H), 10.34 (s, 1H), 8.70 (s, 1H), 7.73 (d, J = 2.4 Hz, 1H), 7.68(dd, J = 8.5, 2.4 Hz, 1H), 7.42 (t, J = 5.9 Hz, 1H), 7.31 (d, J = 8.7 Hz,1H), 3.94 (s, 3H), 2.80 (q, J = 6.7 Hz, 2H), 2.43 (t, J = 7.4 Hz, 2H), 2.33(s, 3H), 1.95 (t, J = 7.4 Hz, 2H), 1.68 – 1.51 (m, 4H), 1.37 – 1.26 (m, 2H),0.89 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, DMSO-d 6) δ 171.70, 169.09, 155.80,155.41, 142.50, 134.60, 129.38, 128.86, 124.48, 122.73, 114.07, 56.79, 42.81,40.60, 40.40, 40.19, 39.98, 39.77, 39.56, 39.35, 37.24, 30.02, 25.92, 18.68,16.29, 13.95.
实施例12
N-羟基-4-((2-甲氧基-5-(4-甲基-2-异戊酰胺基噻唑-5-基)苯基)磺酰胺基)丁酰胺,结构式如下:,将实施例1中步骤2中的片段3-氨基丙酸甲酯盐酸盐改为4-氨基丁酸甲酯盐酸盐以及步骤3中的特戊酰氯改为异戊酰氯,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) δ 12.11 (s, 1H), 10.34 (s, 1H), 8.70 (s, 1H), 7.73 (d, J = 2.4 Hz, 1H), 7.68(dd, J = 8.5, 2.4 Hz, 1H), 7.42 (t, J = 6.0 Hz, 1H), 7.31 (d, J = 8.7 Hz,1H), 3.94 (s, 3H), 2.80 (q, J = 6.8 Hz, 2H), 2.32 (d, J = 8.4 Hz, 5H), 2.08(m, J = 6.9 Hz, 1H), 1.95 (t, J = 7.4 Hz, 2H), 1.60 (m, J = 7.2 Hz, 2H), 0.92(d, J = 6.6 Hz, 6H). 13C NMR (101 MHz, DMSO-d 6) δ 173.97, 172.12, 161.50,157.54, 149.05, 131.81, 130.58, 128.01, 127.66, 125.82, 114.21, 55.80, 46.39,42.78, 31.54, 25.22, 24.85, 22.53, 19.26
实施例13
N-羟基-4-((2-甲氧基-5-(4-甲基-2-己酰胺基噻唑-5-基)苯基)磺酰胺基)丁酰胺,结构式如下:,将实施例1中步骤2中的片段3-氨基丙酸甲酯盐酸盐改为4-氨基丁酸甲酯盐酸盐以及步骤3中的特戊酰氯改为己酰氯,其他步骤及操作同实施例1;白色固体,收率:46 %。1H NMR (300 MHz, DMSO-d 6) δ12.10 (s, 1H), 10.32 (s, 1H), 8.68 (s, 1H), 7.73 (d, J = 2.4 Hz, 1H), 7.68(dd, J = 8.6, 2.4 Hz, 1H), 7.40 (t, J = 5.9 Hz, 1H), 7.31 (d, J = 8.6 Hz,1H), 3.94 (s, 3H), 2.80 (q, J = 6.7 Hz, 2H), 2.42 (t, J = 7.4 Hz, 2H), 2.33(s, 3H), 1.97 (d, J = 11.7 Hz, 2H), 1.60 (p, J = 7.2 Hz, 4H), 1.37 – 1.22 (m,J = 5.5 Hz, 4H), 0.87 (t, J = 6.7 Hz, 3H).13C NMR (101 MHz, DMSO-d 6) δ 171.84,169.08, 155.78, 155.42, 142.49, 134.60, 129.38, 128.83, 124.48, 122.72,114.05, 56.77, 42.80, 35.30, 31.18, 30.01, 25.91, 24.88, 22.29, 16.29, 14.29.
实施例14
N-羟基-3-((2-甲氧基-5-(4-甲基-2-戊酰胺基噻唑-5-基)苯基)磺酰胺基)丙酰胺,结构式如下:,
将实施例1中步骤3中的特戊酰氯改为戊酰氯,其他步骤及操作同实施例1;白色固体,收率:42 %。1H NMR (300 MHz, DMSO-d 6) δ 12.14 (s, 1H), 10.46 (s, 1H), 8.77(s, 1H), 7.76 – 7.65 (m, 2H), 7.45 – 7.28 (m, 2H), 3.94 (s, 3H), 3.00 (q, J =6.8 Hz, 2H), 2.43 (t, J = 7.4 Hz, 2H), 2.33 (s, 3H), 2.14 (t, J = 7.4 Hz,2H), 1.58 (p, J = 7.4 Hz, 2H), 1.30 (m, J = 8.6, 7.9 Hz, 2H), 0.89 (t, J =7.3 Hz, 3H). 13C NMR (101 MHz, DMSO-d 6) δ 173.67, 169.83, 161.18, 157.55,149.05, 131.81, 130.58, 128.10, 127.60, 125.82, 114.21, 55.80, 39.99, 36.01,33.99, 26.86, 21.77, 19.26, 13.82.
实施例15
N-羟基-5-((2-甲氧基-5-(4-甲基-2-戊酰胺基噻唑-5-基)苯基)磺酰胺基)戊酰胺,结构式如下:,将实施例1中步骤2中的片段3-氨基丙酸甲酯盐酸盐改为5-氨基戊酸甲酯盐酸盐以及步骤3中的特戊酰氯改为戊酰氯,其他步骤及操作同实施例1;白色固体,收率:40 %。1H NMR (400 MHz, DMSO-d 6) δ12.10 (s, 1H), 10.31 (s, 1H), 8.66 (s, 1H), 7.73 (d, J = 2.4 Hz, 1H), 7.67(dd, J = 8.6, 2.4 Hz, 1H), 7.37 (t, J = 5.9 Hz, 1H), 7.30 (d, J = 8.7 Hz,1H), 3.94 (s, 3H), 2.80 (q, J = 6.5 Hz, 2H), 2.43 (t, J = 7.4 Hz, 2H), 2.32(s, 3H), 1.91 (dt, J = 25.8, 7.3 Hz, 2H), 1.59 (p, J = 7.5 Hz, 2H), 1.52 –1.36 (m, 2H), 1.39 – 1.20 (m, 4H), 0.87 (dt, J = 12.6, 7.3 Hz, 3H). 13C NMR(101 MHz, DMSO) δ 171.85, 169.32, 155.79, 155.42, 142.47, 134.54, 129.37,128.98, 124.43, 122.75, 114.03, 56.76, 42.81, 40.58, 40.37, 40.21, 40.16,39.95, 39.75, 39.54, 39.33, 35.05, 32.42, 32.24, 29.31, 27.72, 27.30, 22.73,22.14, 16.28, 14.12.
实施例16
N-羟基-6-((2-甲氧基-5-(4-甲基-2-戊酰胺基噻唑-5-基)苯基)磺酰胺基)己酰胺,结构式如下:,将实施例1中步骤2中的片段3-氨基丙酸甲酯盐酸盐改为6-氨基己酸甲酯盐酸盐以及步骤3中的特戊酰氯改为戊酰氯,其他步骤及操作同实施例1;白色固体,收率:36 %。1H NMR (400 MHz, DMSO-d 6) δ12.12 (s, 1H), 10.32 (s, 1H), 8.66 (s, 1H), 7.73 (d, J = 2.4 Hz, 1H), 7.67(dd, J = 8.6, 2.4 Hz, 1H), 7.39 – 7.27 (m, 2H), 3.94 (s, 3H), 2.79 (q, J =6.6 Hz, 2H), 2.43 (t, J = 7.4 Hz, 2H), 2.32 (s, 3H), 1.88 (t, J = 7.4 Hz,2H), 1.58 (p, J = 7.5 Hz, 2H), 1.43 – 1.32 (m, 4H), 1.31 – 1.14 (m, 4H), 0.89(t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, DMSO-d 6) δ 174.80, 173.67, 161.18,157.54, 149.05, 131.81, 130.58, 128.01, 127.75, 125.82, 114.21, 55.80, 43.53,36.01, 32.22, 29.51, 26.86, 26.07, 24.39, 21.77, 19.26, 13.82.
实施例17
N-羟基-4-(((2-甲氧基-5-(4-甲基-2-戊酰胺基噻唑-5-基)苯基)磺酰胺基)甲基)苯甲酰胺,结构式如下:,将实施例1中步骤2中的片段3-氨基丙酸甲酯盐酸盐改为4-氨甲基苯甲酸甲酯盐酸盐以及步骤3中的特戊酰氯改为戊酰氯,其他步骤及操作同实施例1;白色固体,收率:30%。1H NMR (400 MHz, DMSO-d 6)δ 11.98 (s, 1H), 11.14 (s, 1H), 8.95 (s, 1H), 8.02 (s, 1H), 7.69 (d, J = 2.3Hz, 1H), 7.58 (td, J = 8.3, 2.1 Hz, 3H), 7.26 (d, J = 8.1 Hz, 2H), 7.14 (d, J= 8.7 Hz, 1H), 4.14 (s, 2H), 3.86 (s, 3H), 2.43 (t, J = 7.4 Hz, 2H), 2.30 (s,3H), 1.59 (p, J = 7.4 Hz, 2H), 1.38 – 1.24 (m, 2H), 0.89 (t, J = 7.3 Hz, 3H).13C NMR (101 MHz, DMSO-d 6) δ 171.85, 164.26, 155.62, 155.43, 142.46, 141.48,134.57, 131.78, 129.32, 129.09, 127.84, 126.97, 124.28, 122.77, 113.74,56.61, 46.36, 35.05, 27.30, 22.13, 16.20, 14.12.
实施例18
N-羟基-7-((2-甲氧基-5-(4-甲基-2-乙酰胺基噻唑-5-基)苯基)磺酰胺基)庚酰胺,结构式如下:,将实施例1中步骤2中的片段3-氨基丙酸甲酯盐酸盐改为7-氨基庚酸甲酯盐酸盐以及步骤3中的特戊酰氯改为乙酰氯,其他步骤及操作同实施例1;白色固体,收率:50 %。1H NMR (400 MHz, Chloroform-d)δ 8.79 (d, J = 2.4 Hz, 1H), 8.17 (dd, J = 8.8, 2.4 Hz, 1H), 7.58 (t, J = 5.5Hz, 1H), 7.28 (s, 0H), 7.12 – 6.97 (m, 1H), 4.07 (s, 3H), 3.68 (s, 3H), 3.47(td, J = 7.1, 5.6 Hz, 2H), 2.53 (s, 3H), 2.33 (t, J = 7.5 Hz, 2H), 1.72 –1.58 (m, 5H), 1.41 (m, J = 3.7 Hz, 4H). 13C NMR (101 MHz, DMSO-d 6) δ 171.75,169.57, 164.96, 156.43, 155.21, 141.95, 132.26, 130.55, 124.76, 124.53,123.51, 113.15, 56.55, 35.32, 31.19, 29.43, 26.65, 24.89, 22.28, 16.29,14.28.
实施例19
N-羟基-5-((2-甲氧基-5-(4-甲基-2-丙酰胺基噻唑-5-基)苯基)磺酰胺基)戊酰胺,结构式如下:,将实施例1中步骤2中的片段3-氨基丙酸甲酯盐酸盐改为5-氨基戊酸甲酯盐酸盐以及步骤3中的特戊酰氯改为丙酰氯,其他步骤及操作同实施例1;白色固体,收率:44 %。1H NMR (400 MHz, DMSO-d 6) δ 11.95(s, 1H), 10.31 (s, 0H), 8.66 (s, 1H), 7.73 (d, J = 2.4 Hz, 1H), 7.67 (dd, J =8.6, 2.4 Hz, 1H), 7.37 (t, J = 6.0 Hz, 1H), 7.30 (dd, J = 8.7, 1.0 Hz, 1H),3.94 (d, J = 1.4 Hz, 3H), 2.81 (p, J = 6.3 Hz, 2H), 2.41 (t, J = 7.3 Hz, 2H),2.32 (s, 3H), 2.12 (t, J = 7.2 Hz, 1H), 1.94 – 1.83 (m, 1H), 1.62 (h, J = 7.4Hz, 2H), 1.48 (dt, J = 15.2, 7.7 Hz, 1H), 1.44 (s, 1H), 1.43 – 1.29 (m, 2H),0.90 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, DMSO-d 6) δ 172.54, 169.33, 155.79,155.48, 142.46, 134.53, 129.35, 128.99, 124.44, 122.72, 114.03, 56.76, 42.81,40.58, 40.37, 40.16, 39.95, 39.75, 39.54, 39.33, 32.24, 29.31, 28.68, 22.73,16.30, 9.63.
实施例20
N-羟基-5-((2-甲氧基-5-(4-甲基-2-丁酰胺基噻唑-5-基)苯基)磺酰胺基)戊酰胺,结构式如下:,将实施例1中步骤2中的片段3-氨基丙酸甲酯盐酸盐改为5-氨基戊酸甲酯盐酸盐以及步骤3中的特戊酰氯改为丁酰氯,其他步骤及操作同实施例1;白色固体,收率:43 %。1H NMR (400 MHz, DMSO-d 6) δ 11.95(s, 1H), 10.31 (s, 0H), 8.66 (s, 1H), 7.73 (d, J = 2.4 Hz, 1H), 7.67 (dd, J =8.6, 2.4 Hz, 1H), 7.37 (t, J = 6.0 Hz, 1H), 7.30 (dd, J = 8.7, 1.0 Hz, 1H),3.94 (d, J = 1.4 Hz, 3H), 2.81 (p, J = 6.3 Hz, 2H), 2.41 (t, J = 7.3 Hz, 2H),2.32 (s, 3H), 2.12 (t, J = 7.2 Hz, 1H), 1.94 – 1.83 (m, 1H), 1.62 (h, J = 7.4Hz, 2H), 1.48 (dt, J = 15.2, 7.7 Hz, 1H), 1.44 (s, 1H), 1.43 – 1.29 (m, 2H),0.90 (t, J = 7.4 Hz, 3H).13C NMR (101 MHz, DMSO-d 6) δ 174.82, 171.70, 155.79,155.40, 142.47, 134.55, 129.37, 129.02, 128.98, 124.43, 122.75, 114.02,56.76, 42.76, 39.75, 39.54, 39.33, 37.23, 33.67, 29.09, 22.04, 18.68, 16.27,14.02, 13.95.
实施例21
N-羟基-4-(((2-甲氧基-5-(4-甲基-2-丁酰胺基噻唑-5-基)苯基)磺酰胺基)甲基)苯甲酰胺,结构式如下:,将实施例1中步骤2中的片段3-氨基丙酸甲酯盐酸盐改为4-氨甲基苯甲酸甲酯盐酸盐以及步骤3中的特戊酰氯改为丁酰氯,其他步骤及操作同实施例1;白色固体,收率:45 %。1H NMR (400 MHz,DMSO-d 6) δ 12.09 (s, 1H), 11.14 (s, 1H), 8.98 (s, 1H), 8.02 (t, J = 6.4 Hz,1H), 7.69 (d, J = 2.4 Hz, 1H), 7.59 (ddd, J = 9.9, 7.7, 2.0 Hz, 3H), 7.29 –7.23 (m, 2H), 7.14 (d, J = 8.7 Hz, 1H), 4.14 (d, J = 6.2 Hz, 2H), 3.86 (s,3H), 2.41 (t, J = 7.3 Hz, 2H), 2.31 (s, 3H), 1.63 (h, J = 7.3 Hz, 2H), 0.91(t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, DMSO-d 6) δ 171.69, 155.64, 155.42,142.46, 141.50, 134.57, 131.79, 129.33, 129.13, 127.83, 126.99, 124.30,122.78, 113.76, 56.62, 46.36, 37.24, 18.68, 16.21, 13.95.
实施例22
N-羟基-5-((2-甲氧基-5-(4-甲基-2-异丁酰胺基噻唑-5-基)苯基)磺酰胺基)戊酰胺,结构式如下:,将实施例1中步骤2中的片段3-氨基丙酸甲酯盐酸盐改为5-氨基戊酸甲酯盐酸盐以及步骤3中的特戊酰氯改为异丁酰氯,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) δ12.08 (s, 1H), 10.31 (s, 1H), 8.66 (s, 1H), 7.73 (d, J = 2.4 Hz, 1H), 7.67(dd, J = 8.6, 2.4 Hz, 1H), 7.37 (t, J = 5.8 Hz, 1H), 7.31 (d, J = 8.7 Hz,1H), 3.94 (s, 3H), 2.81 (q, J = 6.4 Hz, 2H), 2.73 (p, J = 6.8 Hz, 1H), 2.33(s, 3H), 1.88 (t, J = 7.3 Hz, 2H), 1.52 – 1.40 (m, 2H), 1.36 (q, J = 7.2 Hz,2H), 1.12 (d, J = 6.8 Hz, 6H). 13C NMR (101 MHz, DMSO-d 6) δ 175.68, 169.32,155.81, 155.55, 142.48, 134.56, 129.36, 129.01, 124.43, 122.84, 114.05,56.76, 42.82, 40.58, 40.38, 40.17, 39.96, 39.75, 39.54, 39.33, 34.26, 32.24,29.31, 22.73, 19.55, 16.26.
实施例23
N-羟基-7-((2-甲氧基-5-(4-甲基-2-异戊酰胺基噻唑-5-基)苯基)磺酰胺基)庚酰胺,结构式如下:,将实施例1中步骤2中的片段3-氨基丙酸甲酯盐酸盐改为7-氨基庚酸甲酯盐酸盐以及步骤3中的特戊酰氯改为异戊酰氯,其他步骤及操作同实施例1;白色固体,收率:45 %。1H NMR (300 MHz, DMSO-d 6)δ 12.11 (s, 1H), 10.33 (s, 1H), 8.67 (s, 1H), 7.73 (d, J = 2.4 Hz, 1H), 7.67(dd, J = 8.6, 2.4 Hz, 1H), 7.42 – 7.26 (m, 2H), 3.94 (s, 3H), 2.80 (q, J =6.3 Hz, 2H), 2.75 – 2.65 (m, 1H), 2.32 (s, 3H), 1.99 (s, 1H), 1.89 (t, J =7.3 Hz, 2H), 1.39 (dq, J = 21.2, 7.1 Hz, 3H), 1.26 – 1.14 (m, 5H), 1.12 (d, J= 6.9 Hz, 6H). 13C NMR (101 MHz, DMSO-d 6) δ 175.68, 169.51, 155.82, 155.56,142.47, 134.55, 129.36, 129.10, 124.43, 122.83, 114.02, 60.23, 56.75, 43.08,34.26, 32.63, 29.47, 28.63, 26.20, 25.50, 19.55, 16.23.
实施例24
N-羟基-4-(((2-甲氧基-5-(4-甲基-2-异戊酰胺基噻唑-5-基)苯基)磺酰胺基)甲基)苯甲酰胺,结构式如下:,将实施例1中步骤2中的片段3-氨基丙酸甲酯盐酸盐改为4-氨甲基苯甲酸甲酯盐酸盐以及步骤3中的特戊酰氯改为异戊酰氯,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) δ 12.08 (s, 1H), 11.14 (s, 1H), 8.98 (s, 1H), 8.03 (t, J = 6.4 Hz,1H), 7.69 (d, J = 2.4 Hz, 1H), 7.61 (d, J = 1.7 Hz, 1H), 7.62 – 7.53 (m, 2H),7.26 (d, J = 8.3 Hz, 2H), 7.14 (d, J = 8.7 Hz, 1H), 4.14 (d, J = 5.7 Hz, 2H),3.86 (s, 3H), 2.73 (p, J = 6.8 Hz, 1H), 2.31 (s, 3H), 1.12 (d, J = 6.8 Hz,6H). 13C NMR (101 MHz, DMSO-d 6) δ 175.67, 155.65, 155.57, 142.47, 141.48,134.58, 131.79, 129.33, 129.15, 127.83, 126.98, 124.29, 122.86, 113.77,56.62, 46.38, 34.26, 19.56, 16.18.
实施例25
N-羟基-3-((2-甲氧基-5-(4-甲基-2-己酰胺基噻唑-5-基)苯基)磺酰胺基)丙酰胺,结构式如下:,将实施例1中步骤3中的特戊酰氯改为己酰氯,其他步骤及操作同实施例1;白色固体,收率:46 %。1H NMR (400 MHz,DMSO-d 6) δ 12.08 (s, 1H), 11.14 (s, 1H), 8.98 (s, 1H), 8.03 (t, J = 6.4 Hz,1H), 7.69 (d, J = 2.4 Hz, 1H), 7.61 (d, J = 1.7 Hz, 1H), 7.62 – 7.53 (m, 2H),7.26 (d, J = 8.3 Hz, 2H), 7.14 (d, J = 8.7 Hz, 1H), 4.14 (d, J = 5.7 Hz, 2H),3.86 (s, 3H), 2.73 (p, J = 6.8 Hz, 1H), 2.31 (s, 3H), 1.12 (d, J = 6.8 Hz,6H). 13C NMR (101 MHz, DMSO-d 6) δ 175.67, 155.65, 155.57, 142.47, 141.48,134.58, 131.79, 129.33, 129.15, 127.83, 126.98, 124.29, 122.86, 113.77,56.62, 46.38, 34.26, 19.56, 16.18.
实施例26
N-羟基-6-((2-甲氧基-5-(4-甲基-2-己酰胺基噻唑-5-基)苯基)磺酰胺基)己酰胺,结构式如下:,将实施例1中步骤2中的片段3-氨基丙酸甲酯盐酸盐改为6-氨基己酸甲酯盐酸盐以及步骤3中的特戊酰氯改为己酰氯,其他步骤及操作同实施例1;白色固体,收率:40 %。1H NMR (400 MHz, DMSO-d 6) δ12.05 (s, 1H), 10.31 (s, 1H), 8.65 (s, 1H), 7.73 (d, J = 2.4 Hz, 1H), 7.67(dd, J = 8.6, 2.4 Hz, 1H), 7.38 – 7.27 (m, 2H), 3.94 (s, 3H), 2.80 (p, J =6.2 Hz, 2H), 2.42 (t, J = 7.4 Hz, 2H), 2.32 (s, 3H), 1.89 (t, J = 7.4 Hz,2H), 1.67 – 1.54 (m, 2H), 1.43 – 1.05 (m, 10H), 0.87 (t, J = 6.9 Hz, 3H). 13CNMR (75 MHz, DMSO-d 6) δ 171.85, 169.44, 155.80, 155.42, 142.46, 134.55,129.38, 128.98, 124.44, 122.75, 114.00, 56.75, 42.99, 35.30, 32.63, 31.18,29.35, 26.11, 25.19, 24.88, 22.29, 16.26, 14.29.
实施例27
N-羟基-7-((2-甲氧基-5-(4-甲基-2-己酰胺基噻唑-5-基)苯基)磺酰胺基)庚酰胺,结构式如下:,将实施例1中步骤2中的片段3-氨基丙酸甲酯盐酸盐改为7-氨基庚酸甲酯盐酸盐以及步骤3中的特戊酰氯改为己酰氯,其他步骤及操作同实施例1;白色固体,收率:45 %。1H NMR (400 MHz, DMSO-d 6) δ 12.21 (s, 1H), 10.30 (s, 1H), 8.64 (s, 1H), 7.98 (s, 1H), 7.94 (d, J =1.8 Hz, 1H), 7.71 (d, J = 2.2 Hz, 2H), 2.89 (t, J = 7.0 Hz, 2H), 2.44 (t, J =7.4 Hz, 2H), 2.37 (s, 3H), 1.89 (t, J = 7.4 Hz, 2H), 1.61 (p, J = 7.3 Hz,2H), 1.45 – 1.32 (m, 4H), 1.32 – 1.08 (m, 6H), 0.87 (t, J = 6.8 Hz, 3H). 13CNMR (101 MHz, DMSO-d 6) δ 172.07, 169.50, 156.29, 144.17, 139.11, 133.51,132.89, 132.22, 129.78, 129.44, 121.80, 42.98, 35.31, 32.62, 31.17, 29.53,28.58, 26.12, 25.47, 24.84, 22.28, 16.54, 14.29.
实施例28
N-羟基-4-(((2-甲氧基-5-(4-甲基-2-己酰胺基噻唑-5-基)苯基)磺酰胺基)甲基)苯甲酰胺,结构式如下:,将实施例1中步骤2中的片段3-氨基丙酸甲酯盐酸盐改为4-氨甲基苯甲酸甲酯盐酸盐以及步骤3中的特戊酰氯改为已酰氯,其他步骤及操作同实施例1;白色固体,收率:45 %。1H NMR (300 MHz,DMSO-d 6) δ 12.08 (s, 1H), 11.19 (s, 1H), 9.02 (s, 1H), 8.86 (t, J = 6.1 Hz,1H), 7.79 – 7.68 (m, 3H), 7.56 (dd, J = 8.6, 2.5 Hz, 1H), 7.40 (d, J = 8.2Hz, 2H), 7.25 (d, J = 8.7 Hz, 1H), 4.55 (d, J = 6.0 Hz, 2H), 3.94 (s, 3H),2.41 (t, J = 7.4 Hz, 2H), 2.32 (s, 3H), 1.60 (p, J = 7.4 Hz, 2H), 1.36 – 1.18(m, 4H), 0.92 – 0.82 (m, 3H).13C NMR (101 MHz, DMSO-d 6) δ 171.75, 165.32,156.59, 155.23, 143.41, 142.01, 132.59, 131.66, 130.66, 127.38, 127.36,124.81, 124.02, 123.44, 113.21, 56.58, 42.90, 35.31, 31.19, 24.89, 22.29,16.30, 14.30.
实施例29
N-(2-氨基-4-氟苯基)-4-(((2-甲氧基-5-(4-甲基-2-特戊酰胺基噻唑-5-基)苯基)磺酰胺)甲基)苯甲酰胺,结构式如下:,将实施例1中步骤2中的片段3-氨基丙酸甲酯盐酸盐改为4-氨甲基苯甲酸甲酯盐酸盐,以及步骤4中的盐酸羟胺改为4-氟-1,2,-苯二胺,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) δ 9.45 (s, 1H), 8.14 (d, J = 2.2 Hz, 1H), 7.98– 7.92 (m, 2H), 7.77 (dd, J = 7.9, 2.2 Hz, 1H), 7.67 (dd, J = 8.2, 5.0 Hz,1H), 7.47 – 7.40 (m, 3H), 7.17 (d, J = 7.9 Hz, 1H), 6.86 – 6.75 (m, 2H), 4.84(s, 2H), 4.24 (dt, J = 7.2, 1.0 Hz, 2H), 3.90 (s, 3H), 1.14 (s, 9H). 13C NMR(101 MHz, DMSO-d 6) δ 178.88, 173.88, 161.15, 159.89, 157.87, 157.55, 149.05,142.29, 142.01, 141.95, 132.73, 131.81, 130.58, 128.87, 128.27, 128.20,128.14, 126.22, 126.20, 125.94, 122.86, 122.80, 114.21, 106.69, 106.53,102.71, 102.55, 55.80, 47.71, 39.54, 27.57, 19.26.
实施例30
N-(7-(羟基氨基)-4-氧代丁基)-5-(2-己酰胺基-4-甲基噻唑-5-基)-2-甲氧基苯甲酰胺:
步骤1:2-甲氧基-5-(2-氧代丙基)苯甲酸的合成,结构式如下:,将原料10 mmol 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3h,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(1.5eq.),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100 mmol 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2 h 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(3x40mL)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(30mL)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4mL 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2:4-(5-(2-己酰胺基-4-甲基噻唑-5-基)-2-甲氧基苯甲酰胺基)丁酸甲酯的合成,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 mmol4-氨基丁酸甲酯加入反应液中室温反应。反应结束纯化得到4-(2-甲氧基-5-(2-氧丙基)苯甲酰胺基)丁酸甲酯;后根据实例1中的步骤3,将步骤3中的特戊酰氯改己酰氯,即可得到白色固体4-(5-(2-己酰胺基-4-甲基噻唑-5-基)-2-甲氧基苯甲酰胺基)丁酸甲酯,收率:60%。1H NMR (400 MHz, DMSO-d 6) δ 8.42 (d, J = 2.2 Hz, 1H), 7.80 (t, J = 5.0 Hz,1H), 7.69 (dd, J = 8.0, 2.3 Hz, 1H), 7.07 (d, J = 7.9 Hz, 1H), 3.93 (s, 2H),3.64 (s, 2H), 3.39 – 3.32 (m, 2H), 2.47 (s, 2H), 2.42 (t, J = 8.0 Hz, 2H),2.31 (t, J = 8.4 Hz, 2H), 1.88 (tt, J = 8.4, 5.8 Hz, 2H), 1.67 – 1.57 (m,2H), 1.39 – 1.25 (m, 4H), 0.92 – 0.86 (m, 3H).
步骤3:N-(7-(羟基氨基)-4-氧代丁基)-5-(2-己酰胺基-4-甲基噻唑-5-基)-2-甲氧基苯甲酰胺的合成,结构式如下:,根据实例1中的步骤4,首先制备4-(5-(2-己酰胺基-4-甲基噻唑-5-基)-2-甲氧基苯甲酰胺基)丁酸,称5 mmol的4-(5-(2-己酰胺基-4-甲基噻唑-5-基)-2-甲氧基苯甲酰胺基)丁酸甲酯溶于10 mL的甲醇、四氢呋喃、水的混合溶液(MeOH:THF:H2O=2:2:1)中并置于50 mL的茄形瓶中,称取10 mmol的氢氧化锂(2 eq.)缓慢滴加至反应瓶中,室温过夜,反应结束将反应液趁热加入冰盐水中析出大量白色固体,干燥后得4-(5-(2-己酰胺基-4-甲基噻唑-5-基)-2-甲氧基苯甲酰胺基)丁酸粗品。称取1 mmol的粗品和1.5 mmol的PyBOP缩合剂(1.5 eq.)于25 mL的反应瓶中,加入6 mL DMF溶液,量取590 µL DIPEA(3.5 eq.)加入反应液中,室温搅拌几分钟后加入0.14 g盐酸羟胺(2.0 eq.),室温反应4 h后,TLC监测直到中间体全部消耗完(DCM:MeOH=30:1),真空浓缩,柱层析纯化。白色固体,收率:70 %。1H NMR (300 MHz,DMSO-d 6) δ 12.06 (s, 1H), 10.41 (s, 1H), 8.72 (s, 1H), 8.28 (t, J = 5.7 Hz,1H), 7.72 (d, J = 2.5 Hz, 1H), 7.53 (dd, J = 8.6, 2.5 Hz, 1H), 7.21 (d, J =8.7 Hz, 1H), 3.92 (s, 3H), 3.27 (q, J = 6.6 Hz, 2H), 2.41 (t, J = 7.4 Hz,2H), 2.32 (s, 3H), 2.02 (t, J = 7.5 Hz, 2H), 1.74 (p, J = 7.3 Hz, 2H), 1.60(p, J = 7.5 Hz, 2H), 1.27 (td, J = 6.4, 3.3 Hz, 4H), 0.92 – 0.82 (m, 3H). 13CNMR (101 MHz, DMSO-d 6) δ 171.75, 169.32, 165.10, 156.46, 155.19, 141.96,132.34, 130.58, 124.71, 124.38, 123.49, 113.11, 56.53, 35.30, 31.19, 30.43,25.78, 24.89, 22.29, 16.29, 14.30.
实施例31
N-(7-(羟基氨基)-7-氧代庚基) -5-(2-异丁酰胺基-4-甲基噻唑-5-基)-2-甲氧基苯甲酰胺,结构式如下:,将实施例30中步骤2中的片段3-氨基丙酸甲酯盐酸盐改为7-氨基庚酸甲酯盐酸盐以及步骤3中的己酰氯改为异戊酰氯,其他步骤及操作同实施例30。白色固体,收率:46 %。1H NMR (400 MHz,DMSO-d 6) δ 11.80 (s, 1H), 10.34 (s, 1H), 8.66 (s, 1H), 8.21 (t, J = 5.7 Hz,1H), 7.71 (d, J = 2.5 Hz, 1H), 7.52 (dd, J = 8.6, 2.5 Hz, 1H), 7.21 (d, J =8.7 Hz, 1H), 3.91 (s, 3H), 3.27 (dt, J = 13.2, 6.8 Hz, 2H), 2.73 (p, J = 6.9Hz, 1H), 2.32 (s, 3H), 2.04 – 1.91 (m, 2H), 1.50 (ddt, J = 9.8, 7.3, 4.6 Hz,4H), 1.29 (dt, J = 9.5, 6.2 Hz, 4H), 1.12 (d, J = 6.9 Hz, 6H). 13C NMR (101MHz, DMSO-d 6) δ 175.58, 169.57, 164.96, 156.43, 155.33, 141.96, 132.28,130.54, 124.74, 124.52, 123.58, 113.15, 56.54, 34.26, 32.71, 29.43, 28.79,26.65, 25.61, 19.91, 19.57, 16.27./>
实施例32
N-(7-(羟基氨基)-7-氧代庚基)-5-(2-己酰胺基-4-甲基噻唑-5-基)-2-甲氧基苯甲酰胺,结构式如下:,将实施例30中步骤2中的片段3-氨基丙酸甲酯盐酸盐改为7-氨基庚酸甲酯盐酸盐,其他步骤及操作同实施例30。白色固体,收率:40 %。1H NMR (300 MHz, DMSO-d 6) δ 12.06 (s, 1H), 10.36(s, 1H), 8.69 (s, 1H), 8.22 (t, J = 5.7 Hz, 1H), 7.70 (d, J = 2.5 Hz, 1H),7.53 (dd, J = 8.6, 2.5 Hz, 1H), 7.21 (d, J = 8.7 Hz, 1H), 3.91 (s, 3H), 3.33– 3.19 (m, 2H), 2.41 (t, J = 7.4 Hz, 2H), 2.32 (s, 3H), 1.95 (t, J = 7.3 Hz,2H), 1.49 (d, J = 7.2 Hz, 4H), 1.31 – 1.21 (m, 10H), 0.92 – 0.80 (m, 3H).13CNMR (101 MHz, DMSO-d 6) δ 171.85, 169.51, 155.80, 155.41, 142.46, 134.53,129.36, 129.06, 124.43, 122.75, 114.00, 56.75, 43.07, 35.30, 32.63, 31.18,29.47, 28.64, 26.20, 25.50, 24.88, 22.29, 16.26, 14.30.
实施例33
N-(4-(羟基氨基甲酰基)苄基)-5-(2-己酰胺基-4-甲基噻唑-5-基)-2-甲氧基苯甲酰胺,结构式如下:,将实施例30中步骤2中的片段3-氨基丙酸甲酯盐酸盐改为4-氨甲基苯甲酸甲酯盐酸盐,其他步骤及操作同实施例30。白色固体,收率:51 %。1H NMR (300 MHz, DMSO-d 6) δ 12.08 (s, 1H), 11.19(s, 1H), 9.02 (s, 1H), 8.86 (t, J = 6.1 Hz, 1H), 7.79 – 7.68 (m, 3H), 7.56(dd, J = 8.6, 2.5 Hz, 1H), 7.40 (d, J = 8.2 Hz, 2H), 7.25 (d, J = 8.7 Hz,1H), 4.55 (d, J = 6.0 Hz, 2H), 3.94 (s, 3H), 2.41 (t, J = 7.4 Hz, 2H), 2.32(s, 3H), 1.60 (p, J = 7.4 Hz, 2H), 1.36 – 1.18 (m, 4H), 0.92 – 0.82 (m, 3H).13C NMR (101 MHz, DMSO-d 6) δ 171.75, 165.32, 156.59, 155.23, 143.41, 142.01,132.59, 131.66, 130.66, 127.38, 127.36, 124.81, 124.02, 123.44, 113.21,56.58, 42.90, 35.31, 31.19, 24.89, 22.29, 16.30, 14.30.
通过以下实验来说明本发明通式(I)代表的化合物所具有的有益效果和应用。
针对本发明抑制剂进行PI4KIIIβ激酶抑制实验:
使用ADP-Glo Luminescent Kinase Assay法测试,激酶反应用到的试剂如下:HEPES (50 mM) pH 7.5 with NaCl (100 mM), 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)
实施例 | PI4KIIIβ | 实施例 | PI4KIIIβ | 实施例 | PI4KIIIβ |
实施例1 | 42 | 实施例13 | 3.2 | 实施例26 | 29 |
实施例2 | 25 | 实施例15 | 6.1 | 实施例27 | 7.6 |
实施例3 | 47 | 实施例17 | 13 | 实施例28 | 24 |
实施例4 | 56 | 实施例18 | 75 | 实施例29 | 245 |
实施例5 | 64 | 实施例19 | 75 | 实施例30 | 17 |
实施例6 | 173 | 实施例20 | 18 | 实施例31 | 39 |
实施例7 | 154 | 实施例21 | 42 | 实施例32 | 14 |
实施例8 | 57 | 实施例22 | 44 | 实施例33 | 22 |
实施例9 | 14 | 实施例23 | 204 | PIK93 | 17 |
实施例10 | 7.3 | 实施例24 | 81 | PIK93-10 | 6.8 |
实施例11 | 2.3 | 实施例25 | 3.7 |
,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11、13、25对PI4KIIIβ激酶的抑制活性优于阳性对照PIK-93。由此说明,本发明部分实施例化合物为高效的PI4KIIIβ抑制剂。
针对本发明抑制剂进行HDAC1激酶抑制实验:
使用BPS公司的HDAC1荧光检测试剂盒(Cat#50051),采用荧光标记法(Fluorescence assay),对实施例化合物进行了HDAC1抑制活性测试。实验步骤如下:(1)制备1x分析缓冲液(改良的Tris缓冲液);(2)化合物的稀释:通过Echo在100 %DMSO中将化合物转移至分析板。DMSO的最终分数为1%;(3)酶溶液的制备:在1x检测缓冲液中制备酶溶液;(4)底物溶液的制备:在1x检测缓冲液中加入胰蛋白酶和Ac-肽底物,制成底物溶液;(5)将15μL酶溶液转移至检测板,或对于低对照转移15μL 1x检测缓冲液。在室温下孵育15 min。向每个孔中加入10 μL底物溶液,开始反应;(6)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2 实施例化合物的HDAC1酶抑制活性(IC50, nM)
实施例 | HDAC1 | 实施例 | HDAC1 | 实施例 | HDAC1 |
实施例1 | 809 | 实施例13 | 16 | 实施例26 | 5.4 |
实施例2 | 25 | 实施例15 | 114 | 实施例27 | 77 |
实施例3 | 119 | 实施例17 | >1000 | 实施例28 | 478 |
实施例4 | 70 | 实施例18 | 58 | 实施例29 | >2000 |
实施例5 | 53 | 实施例19 | 131 | 实施例30 | 26 |
实施例6 | 902 | 实施例20 | 240 | 实施例31 | 53 |
实施例7 | 640 | 实施例21 | 627 | 实施例32 | 218 |
实施例8 | 24 | 实施例22 | 136 | 实施例33 | 48 |
实施例9 | 20 | 实施例23 | 4.1 | Vorinostat | 17 |
实施例10 | 12 | 实施例24 | 462 | Tucidinostat | 122 |
实施例11 | 11 | 实施例25 | 463 |
,如表2所示,本发明部分化合物对HDAC1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Vorinostat,尤其是实施例10、11、13、23、26对HDAC1激酶的抑制活性优于阳性对照Vorinostat。由此说明,本发明部分实施例化合物为高效的HDAC抑制剂。
结合表1和表2的实验数据,分析对比可得实施例11对PI4KIIIβ和HDAC1均具有最好的激酶抑制活性,分别为2.3 nM和1 nM,对此针对实施例11进行激酶选择性实验,实验方法上述相同,实施例激酶亚型抑制活性结果如表3、4所示。
表3 实施例11的PI3Ks酶抑制活性(IC50, nM)
实施例 | PI4KIIIβ | PI3Kα | PI3Kδ | PI3Kγ | hVPS34 |
实施例11 | 2.3 | 542 | 47.8 | 1091 | >5000 |
,
表4 实施例11的HDACS酶抑制活性(IC50, nM)
实施例 | HDAC1 | HDAC2 | HDAC3 | HDAC4 | HDAC5 | HDAC6 |
实施例11 | 11 | 17 | 20 | >5000 | >5000 | 23 |
实施例 | HDAC7 | HDAC8 | HDAC9 | HDAC10 | HDAC11 | |
实施例11 | >5000 | >1000 | >5000 | 75 | >5000 |
,结合表3和表4的实验数据,分析可知实施例11对PI4KIIIβ的抑制活性最好IC50值达到2.3 nM,也可抑制PI3Kδ的活性,IC50值为47.8 nM。同时实施例11也是一种广谱的HDAC抑制剂,对HDAC1、2、3、6和10均有较好的抑制活性,IC50值分别为11,17,20,23,75 nM。
针对本发明抑制剂进行抗HCV病毒活性测试实验,实验方法如下:
(1)样品处理:将要测活性的样品,用DMSO溶解后,用0.22 μm
滤膜过滤除菌,原药浓度为20 mg/mL。
(2)细胞培养:取出液氮中冷冻的人肝癌细胞株Huh-7.5.1细胞,浸入37 ℃水浴中,振荡使之尽快融化(1 min内在离心管中吸入细胞悬液,加入培养液5 mL,在1000 rpm强度下离心5 min,弃除上层清液。再加入约3-4 mL培养液,混匀后,接种于25 cm2培养瓶中,放入CO2培养箱中培养,次日换培养液。每三天进行细胞传代,在实验前一天对细胞进行换液并观察细胞,让细胞处在良好状态的指数生长期。
(3)病毒培养:在有指数生长期的Huh-7.5.1细胞培养瓶中加入J6/JFH1病毒液,孵育5-8 h弃除上层清液,换入新鲜培养基,每隔两天对细胞进行换液,6天后弃出培养基,然后加入约15 mL培养基培养至第7天,用3000 rpm/min强度离心10 min,收集澄清培养液,分装保存于-80 ℃。
(4)检测方法:MTT法。取对数生长期的Huh-7.5.1细胞,用0.25 %胰酶消化,然后用1000 rpm/min 强度离心3 min,血球计数板计数,调整细胞浓度为9×104 cells/mL后,铺于96孔板(100 μL/well),在37 ℃ 5 % CO2培养箱中培养。贴壁5 h,加入用DMSO梯度稀释的药物,共8个稀释度,且每个梯度设三个重复孔,同时设置空白对照(只含培养基)、DMSO对照、细胞对照、阳性药物对照、药物颜色对照,使培养基终体积为200 μL/well,将培养板置于37 ℃ 5 % CO2培养箱进行培养。第三天在实验孔加5 mg/mL MTT溶液20 μL,在37 ℃ 5% CO2条件下孵育4小时,弃上层清液,加入100 μL/well的DMSO,振荡溶解10 min后,于酶标仪上测定OD490的值。并以软件GraphPad Prism 5.0计算药物IC50(IC50:半数细胞生长抑制浓度,将细胞生长抑制50 %所需的浓度)的值。(HCV复制抑制率公式=(OD Control-ODDrug)/(OD Control-OD Blank)×100 %)
表5 部分实施例化合物的抗HCV病毒活性
实施例 | 实施例1 | 实施例2 | 实施例3 | 实施例4 | 实施例5 | 实施例6 | 实施例7 |
CC50 (μM) | 61.74 | 8.38 | 64.33 | 120.1 | 49.31 | 77.04 | 38.44 |
IC50 (nM) | - | 18.41 | - | 59.96 | - | 1267 | 6027 |
SI | - | 455.13 | - | 2003 | - | 60.81 | 6.38 |
实施例 | 实施例8 | 实施例9 | 实施例10 | 实施例11 | 实施例12 | 实施例13 | 实施例14 |
CC50 (μM) | 106.1 | 90.56 | 110.23 | 89.41 | 70.12 | 35.63 | 74.46 |
IC50 (nM) | 614.4 | - | 31634 | 537 | 3594 | 419.9 | 24530 |
SI | 172.69 | - | 3.48 | 166.5 | 19.51 | 84.85 | 3.04 |
实施例 | 实施例15 | 实施例16 | 实施例30 | 实施例31 | 实施例32 | 实施例33 | PIK93-10 |
CC50 (μM) | 123.5 | 31.94 | 5.32 | 112.9 | 1.74 | 0.37 | 42.63 |
IC50 (nM) | - | - | - | 46.41 | - | 188.9 | 529.3 |
SI | - | - | - | 2432.67 | - | 1.96 | 80.54 |
,其中CC50表示细胞半数中毒浓度,它表示导致细胞发生50 %形态改变的药物浓度。IC50表示半数有效浓度,它表示使病毒感染率下降50 %的药物浓度。SI表示选择性,它等于CC50与IC50的比值,用于评估药物的治疗潜力。SI值越高,说明药物在抗HCV病毒的效力越强。“-”表示10 μM初筛对HCV无抑制效果,或无法拟合IC50值。
从表5可以看出,本发明部分实施例对HCV病毒具有较高水平的增殖抑制活性且细胞毒性较低,其中实施例2对HCV病毒达到18.41 nM。特别地实施例4和31的SI值大于2000,且CC50值大于100 μM,IC50值在60 nM以下,显著优于阳性对照PIK93-10。由此可见,本发明部分实施例化合物可潜在用于抗HCV的临床治疗。
除上述实施外,本发明还可以有其他实施方式。凡采用等同替换或等效变换形成的技术方案,均落在本发明要求的保护范围。
Claims (8)
1.一种苯基噻唑胺类PI4KIIIβ/HDAC双靶抑制剂,其特征在于:所述抑制剂为通式I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,,其中R1-R4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;
R5和R6选自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选自砜基或羰基;
Y选自C1-C6亚烷基、含一个或多个取代基的C1-C6亚烷基、4-取代苯基、4-取代的苄基或4-取代的苯氧乙基;
Z选自以下结构,。
2.根据权利要求1所述苯基噻唑胺类PI4KIIIβ/HDAC双靶抑制剂,其特征在于:所述通式I中与碳相连的氢替换为氢的同位素氘。
3.根据权利要求1或2所述苯基噻唑胺类PI4KIIIβ/HDAC双靶抑制剂,其特征在于:所述抑制剂为以下其中之一,
N-羟基-3-((2-甲氧基-5-(4-甲基-2-特戊酰胺基噻唑-5-基)苯基)磺酰胺基)丙酰胺;
N-羟基-4-((2-甲氧基-5-(4-甲基-2-特戊酰胺基噻唑-5-基)苯基)磺酰胺基)丁酰胺;
N-羟基-5-((2-甲氧基-5-(4-甲基-2-特戊酰胺基噻唑-5-基)苯基)磺酰胺基)戊酰胺;
N-羟基-6-((2-甲氧基-5-(4-甲基-2-特戊酰胺基噻唑-5-基)苯基)磺酰胺基)己酰胺;
N-羟基-7-((2-甲氧基-5-(4-甲基-2-特戊酰胺基噻唑-5-基)苯基)磺酰胺基)庚酰胺;
N-羟基-4-(((2-甲氧基-5-(4-甲基-2-特戊酰胺基噻唑-5-基)苯基)磺酰胺基)甲基)苯甲酰胺;
N-羟基-4-(2-((2-甲氧基-5-(4-甲基-2-戊酰胺基噻唑-5-基)苯基)磺酰氨基)乙氧基)苯甲酰胺;
N-羟基-4-((2-甲氧基-5-(4-甲基-2-丙酰胺基噻唑-5-基)苯基)磺酰胺基)丁酰胺;
N-羟基-4-((2-甲氧基-5-(4-甲基-2-丁酰胺基噻唑-5-基)苯基)磺酰胺基)丁酰胺;
N-羟基-4-((2-甲氧基-5-(4-甲基-2-异丁酰胺基噻唑-5-基)苯基)磺酰胺基)丁酰胺;
N-羟基-4-((2-甲氧基-5-(4-甲基-2-戊酰胺基噻唑-5-基)苯基)磺酰胺基)丁酰胺;
N-羟基-4-((2-甲氧基-5-(4-甲基-2-异戊酰胺基噻唑-5-基)苯基)磺酰胺基)丁酰胺;
N-羟基-4-((2-甲氧基-5-(4-甲基-2-己酰胺基噻唑-5-基)苯基)磺酰胺基)丁酰胺;
N-羟基-3-((2-甲氧基-5-(4-甲基-2-戊酰胺基噻唑-5-基)苯基)磺酰胺基)丙酰胺;
N-羟基-5-((2-甲氧基-5-(4-甲基-2-戊酰胺基噻唑-5-基)苯基)磺酰胺基)戊酰胺;
N-羟基-6-((2-甲氧基-5-(4-甲基-2-戊酰胺基噻唑-5-基)苯基)磺酰胺基)己酰胺;
N-羟基-4-(((2-甲氧基-5-(4-甲基-2-戊酰胺基噻唑-5-基)苯基)磺酰胺基)甲基)苯甲酰胺;
N-羟基-7-((2-甲氧基-5-(4-甲基-2-乙酰胺基噻唑-5-基)苯基)磺酰胺基)庚酰胺;
N-羟基-5-((2-甲氧基-5-(4-甲基-2-丙酰胺基噻唑-5-基)苯基)磺酰胺基)戊酰胺;
N-羟基-5-((2-甲氧基-5-(4-甲基-2-丁酰胺基噻唑-5-基)苯基)磺酰胺基)戊酰胺;
N-羟基-4-(((2-甲氧基-5-(4-甲基-2-丁酰胺基噻唑-5-基)苯基)磺酰胺基)甲基)苯甲酰胺;
N-羟基-5-((2-甲氧基-5-(4-甲基-2-异丁酰胺基噻唑-5-基)苯基)磺酰胺基)戊酰胺;
N-羟基-7-((2-甲氧基-5-(4-甲基-2-异戊酰胺基噻唑-5-基)苯基)磺酰胺基)庚酰胺;
N-羟基-4-(((2-甲氧基-5-(4-甲基-2-异戊酰胺基噻唑-5-基)苯基)磺酰胺基)甲基)苯甲酰胺;
N-羟基-3-((2-甲氧基-5-(4-甲基-2-己酰胺基噻唑-5-基)苯基)磺酰胺基)丙酰胺;
N-羟基-6-((2-甲氧基-5-(4-甲基-2-己酰胺基噻唑-5-基)苯基)磺酰胺基)己酰胺;
N-羟基-7-((2-甲氧基-5-(4-甲基-2-己酰胺基噻唑-5-基)苯基)磺酰胺基)庚酰胺;
N-羟基-4-(((2-甲氧基-5-(4-甲基-2-己酰胺基噻唑-5-基)苯基)磺酰胺基)甲基)苯甲酰胺;
N-(2-氨基-4-氟苯基)-4-(((2-甲氧基-5-(4-甲基-2-特戊酰胺基噻唑-5-基)苯基)磺酰胺)甲基)苯甲酰胺;
N-(7-(羟基氨基)-4-氧代丁基)-5-(2-己酰胺基-4-甲基噻唑-5-基)-2-甲氧基苯甲酰胺;
N-(7-(羟基氨基)-7-氧代庚基) -5-(2-异丁酰胺基-4-甲基噻唑-5-基)-2-甲氧基苯甲酰胺;
N-(7-(羟基氨基)-7-氧代庚基)-5-(2-己酰胺基-4-甲基噻唑-5-基)-2-甲氧基苯甲酰胺;
N-(4-(羟基氨基甲酰基)苄基)-5-(2-己酰胺基-4-甲基噻唑-5-基)-2-甲氧基苯甲酰胺。
4.根据权利要求3所述苯基噻唑胺类PI4KIIIβ/HDAC双靶抑制剂的制备方法,其特征在于:按照以下步骤制备目标化合物(8),以4-甲氧基苯丙酮为原料(1),原料(1)与氯磺酸在苯环3号位发生取代反应得到中间体(2);在中间体(2)的基础上通过Hinsberg 反应,引入氨基羧酸甲酯得到中间体(3);中间体(3)与苯基三甲基三溴化铵发生α-溴代反应得到中间体(4);硫脲(5)与酰氯反应得到N-取代硫脲(6),与中间体(4)缩合反应得到中间体(7);中间体(7)与羟胺发生酰胺缩合得到目标化合物(8),制备路线如下,。
5.根据权利要求3所述苯基噻唑胺类PI4KIIIβ/HDAC双靶抑制剂的制备方法,其特征在于:按照以下步骤制备目标化合物(9),以4-甲氧基苯丙酮为原料(1),原料(1)与氯磺酸在苯环3号位发生取代反应得到中间体(2);在中间体(2)的基础上通过Hinsberg 反应,引入氨基羧酸甲酯得到中间体(3);中间体(3)与苯基三甲基三溴化铵发生α-溴代反应得到中间体(4);硫脲(5)与酰氯反应得到N-取代硫脲(6),与中间体(4)缩合反应得到中间体(7);中间体(7) 与4-氟-1,2-苯二胺发生酰胺缩合得到目标化合物(9),制备路线如下,。
6.根据权利要求3所述苯基噻唑胺类PI4KIIIβ/HDAC双靶抑制剂的制备方法,其特征在于:按照以下步骤制备目标化合物(18),以5-甲酰基-2-甲氧基苯甲酸甲酯为原料(10),经过两步反应得到中间体(11);中间体(11)在乙酸中加热回流与铁粉发生还原反应得到中间体(12);中间体(12)在酸性条件下发生水解反应得到中间体(13);中间体(13)被二氯亚砜氯化生成中间体(14);中间体(14)与氨基羧酸甲酯反应得到中间体(15);中间体(15)与苯基三甲基三溴化铵发生α-溴代反应得到中间体(16);中间体(16)与N-取代硫脲缩合反应得到中间体(17);中间体(17)与羟胺发生酰胺缩合得到目标化合物(18)制备路线如下,。
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任一项所述苯基噻唑胺类PI4KIIIβ/HDAC双靶抑制剂。
8.一种如权利要求1-3任一项所述苯基噻唑胺类PI4KIIIβ/HDAC双靶抑制剂或如权利要求7所述药物组合物在制备用于抑制丙型肝炎病毒生长的药物中的应用。
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WO2013052845A1 (en) * | 2011-10-05 | 2013-04-11 | The Board Of Trustees Of The Leland Stanford Junior University | Pi-kinase inhibitors with broad spectrum anti-infective activity |
US20190062323A1 (en) * | 2016-02-26 | 2019-02-28 | The Board Of Trustees Of The Leland Stanford Junior University | PI-Kinase Inhibitors with Anti-Infective Activity |
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