CN115838368B - 氧肟酸类化合物及其衍生物、制备方法、药物组合物和应用 - Google Patents
氧肟酸类化合物及其衍生物、制备方法、药物组合物和应用 Download PDFInfo
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- CN115838368B CN115838368B CN202111097980.8A CN202111097980A CN115838368B CN 115838368 B CN115838368 B CN 115838368B CN 202111097980 A CN202111097980 A CN 202111097980A CN 115838368 B CN115838368 B CN 115838368B
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- imidazol
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Abstract
本发明公开了一种氧肟酸类化合物及其衍生物、制备方法、药物组合物和应用。该化合物结构如式I，该氧肟酸类化合物衍生物涉及所述化合物药学上可接受的盐。该氧肟酸类化合物及其衍生物对FLT3、HDAC具有高效的抑制作用，可用于制备与FLT3、HDAC相关疾病的药物。所制备药物在分子水平和细胞水平均可以发挥药效，解决了现有药物单一用药疗效不佳、易耐药，不同药物联用的不良反应及病人顺应性等问题。此外，该类化合物合成方法适用性广，操作简便。
Description
技术领域
本发明涉及一种氧肟酸类化合物及其衍生物、制备方法、药物组合物和应用，尤其涉及一种可制备为对FLT3、HDAC靶点具有高效抑制作用的药物的氧肟酸类化合物及其衍生物、制备方法、药物组合物和应用。
背景技术
白血病是一种造血干细胞恶性克隆的疾病，因细胞增殖失控、分化障碍、凋亡受阻使肿瘤细胞在骨髓、淋巴等造血器官和血液中大量累积，并浸润至其他组织器官，引起人体正常造血功能紊乱，同时导致相应器官的功能性障碍。按照疾病进展速度，可分为急性和慢性白血病，前者白血病细胞分化阻滞于早期，以早幼干细胞为主，发病迅速；后者以成熟细胞为主，发展缓慢。根据受累细胞不同，又可分为髓系的粒细胞、巨核细胞、红细胞和淋巴系的T细胞、B细胞白血病等。
急性髓性白血病(Acute myeloid leukemia,AML)占新诊断成人急性白血病的60％-70％，并且呈现出逐年上升的趋势。其主要表现为骨髓造血系统功能紊乱，造血干细胞过度生长增殖，同时分化和凋亡过程受阻，其恶性程度高，病人死亡率也较高。AML在成人急性白血病中最常见，在儿童白血病的发病率中居第二位。相应地，儿科白血病死亡病例中有超过一半是由于AML，而无法耐受化疗的高龄患者在诊断后一般也只能生存5-10个月。对于初诊的AML，临床上多采用“7+3”疗法(标准剂量的阿糖胞苷联合蒽环类抗生素)，在治疗效果较好的情况下再给予高剂量的阿糖胞苷以巩固疗效；治疗效果较差时，则在患者病情首次缓解后进行造血干细胞移植(allogeneic hematopoietic stem cell transplant,alloHSCT)。但即使如此，低龄AML患者的5年总生存率(overall survival,OS)只有40％–50％，60岁以上患者的5年总生存率仅为10％–20％。WHO、National Comprehensive CancerNetwork(NCCN)和European LeukemiaNet(ELN)均已建立AML的分类及风险级别评估的标准。因此，开发新型抗AML药物在恶性血液肿瘤治疗方面具有重大意义。
Fms-like tyrosine kinase 3(FLT3)属于III型受体酪氨酸激酶(Receptortyrosine kinase,RTK)，是一种跨膜型激酶，在造血祖细胞(Hematopoietic progenitorcells,HPCs)的生长和分化过程中有着重要作用。FLT3的胞外区与其配体结合后发生同源二聚体，继而自身磷酸化活化，激活一系列下游信号传导途径，包括RAS/MEK、PI3K/AKT/mTOR和JAK/STAT等经典通路，从而调控细胞周期进程、抑制细胞凋亡及诱导细胞分化等。但是，FLT3基因突变常见于新发病的AML患者中，比例约为30％。FLT3基因突变会导致FLT3不依赖于配体而高度活化，且与患者的不良预后密切相关。FLT3突变包括通常发生于受体近膜区域(juxtamembrane domain)的内部串联重复(internal tandem duplication,ITD)，或者是受体激酶域(tyrosine kinase domain,TKD)的氨基酸点突变，发生率分别为25％和7％左右。具有FLT3-ITD突变的患者即使在接受化疗或者alloHSCT治疗后也非常容易复发，因此，NCCN和ELN均将FLT3-ITD列为AML中的高风险突变，建议在诊断时进行筛查。单独的FLT3-TKD点突变虽然也能上调FLT3的激酶活性，但其与AML发病和预后的关系仍然不是特别明确。鉴于FLT3突变与AML发生和不良预后的密切关系，FLT3抑制剂已经成为抗AML药物研究的重点领域。但是单一FLT3抑制剂往往疗效不佳，持续响应期短，易产生耐药性。
组蛋白去乙酰化酶(Histone deacetylases，HDACs)在维持组蛋白乙酰化和去乙酰化水平的平衡起着重要作用。HDACs将乙酰基从组蛋白尾端去除后，可促进其与沉默子之间的相互作用，共同发挥转录抑制作用。组蛋白乙酰化水平的过度下降可以使得多种抑癌基因沉默，对细胞周期、血管发生、免疫调节和细胞凋亡等均有调节作用，其中一些调节细胞周期和凋亡的基因对组蛋白乙酰化水平的变化高度敏感，HDACs已经成为癌症治疗的重要靶点。迄今为止，HDAC抑制剂(HDACi)已在肿瘤治疗方面取得巨大进展。此外，HDAC抑制剂在AML细胞中的增值抑制及凋亡诱导能力也有报道，但其单一用药往往临床疗效不佳，而与其其他药物联用改善了临床治疗效果。
虽然，激酶抑制剂与HDAC抑制剂的结合疗法已经在多项研究中证明，其比单一用药可以取得更好的治疗效果。然而，复杂的药代动力学特征，带来了药物-药物相互作用以及不良的患者依从性问题。
发明内容
发明目的：为解决现有药物疗效不佳、易耐药、药物之间不良反应等问题，本发明旨在提供一种可制备为对FLT3、HDAC靶点具有高效抑制作用的药物的氧肟酸类化合物及其衍生物、制备方法、药物组合物和应用。
技术方案：作为本发明涉及的第一方面，本发明的氧肟酸类化合物及其衍生物具有式I的结构，所述衍生物为所述氧肟酸类化合物的药学上可接受的盐：
其中：
R为苯基、呋喃基、噻吩基、噁唑基、异噁唑基、噻唑基、异噻唑基、1,2,4-噁二唑基、1,3,4-噁二唑基、1,2,4-噻二唑基、1,3,4-噻二唑基、吡啶基、嘧啶基、吡嗪基、3-8个碳原子的单环饱和烃基、3-8个碳原子的含单个双键的单环不饱和烃基、3-8个碳原子的含两个双键的单环不饱和烃基或6-12个碳原子的双环饱和烃基；其中，所述3-8个碳原子的单环饱和烃基、3-8个碳原子的含单个双键的单环不饱和烃基、3-8个碳原子的含两个双键的单环不饱和烃基或6-12个碳原子的双环饱和烃基环上的碳原子被0～4个O、S、N或NH替代；
R被一个或多个R1取代，R1为氢、烷基、氰基、卤素、卤代烷基、羟基、氨基、巯基、烷氧基、烷氨基、三氟甲基、三氟甲氧基、芳基、芳烷基、Het、NH2SO2-、烷基磺酰氨基、芳基磺酰氨基、Het磺酰氨基、烷基磺酰基、芳基磺酰基、Het磺酰基、HC(O)NH-、-C(O)H或NH2C(O)-；其中，羟基、巯基、氨基、烷基、烷氧基、烷氨基、芳基、芳烷基、Het、NH2SO2-、烷基磺酰氨基、芳基磺酰氨基、Het磺酰氨基、烷基磺酰基、芳基磺酰基、Het磺酰基、HC(O)NH-、-C(O)H或NH2C(O)-被一个或多个R2取代，R2为氢、烷基、卤素、卤代烷基、氰基、羟基、氨基、烷氧基、烷氨基、NH2SO2-、烷基磺酰氨基、芳基磺酰氨基、Het磺酰氨基、烷基磺酰基、芳基磺酰基、Het磺酰基、芳基或Het；
X为苯基、苯基烷基、萘基、吡咯基、吡唑基、咪唑基、呋喃基、噻吩基、噁唑基、异噁唑基、噻唑基、异噻唑基、三氮唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、1-10个碳原子的直链或支链饱和烷基或者1-10个碳原子的直链或支链不饱和烷基；
X被一个或多个R3取代，R3为氢、烷基、氰基、卤素、卤代烷基、羟基、氨基、巯基、烷氧基、烷氨基、芳基、芳烷基、Het、NH2SO2-、烷基磺酰氨基、芳基磺酰氨基、Het磺酰氨基、烷基磺酰基、芳基磺酰基、Het磺酰基、HC(O)NH-、-C(O)H或NH2C(O)-；其中，羟基、巯基、氨基、烷基、烷氧基、烷氨基、芳基、芳烷基、Het、NH2SO2-、烷基磺酰氨基、芳基磺酰氨基、Het磺酰氨基、烷基磺酰基、芳基磺酰基、Het磺酰基、HC(O)NH-、-C(O)H或NH2C(O)-被一个或多个R4取代，R4为氢、烷基、卤素、卤代烷基、氰基、羟基、氨基、烷氧基、烷氨基、NH2SO2-、烷基磺酰氨基、芳基磺酰氨基、Het磺酰氨基、烷基磺酰基、芳基磺酰基、Het磺酰基、芳基或Het；
所述芳基为被1～3个氢、烷基、氰基、卤素、卤代烷基、羟基、巯基、烷氧基、烷硫基、烷氧基烷基、芳烷基、二芳基烷基、芳基或Het取代的苯基、吡啶基、吡咯基、吡唑基、咪唑基、呋喃基、噻吩基、噁唑基、异噁唑基、噻唑基、异噻唑基、三氮唑基、1,2,4-噁二唑基、1,3,4-噁二唑基、1,2,4-噻二唑基、1,3,4-噻二唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、萘基、苊基或四氢萘基；
所述Het为吡咯基、吡唑基、咪唑基、呋喃基、噻吩基、噁唑基、异噁唑基、噻唑基、异噻唑基、三氮唑基、1,2,4-噁二唑基、1,3,4-噁二唑基、1,2,4-噻二唑基、1,3,4-噻二唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噻唑基、苯并异噻唑基、吡啶并噻吩基、嘧啶并噻吩基、3-8个碳原子的单环饱和烃基、3-8个碳原子的含单个双键的单环不饱和烃基、3-8个碳原子的含两个双键的单环不饱和烃基或6-12个碳原子的双环饱和烃基；其中，所述3-8个碳原子的单环饱和烃基、3-8个碳原子的含单个双键的单环不饱和烃基、3-8个碳原子的含两个双键的单环不饱和烃基或6-12个碳原子的双环饱和烃基环上的碳原子被0～4个O、S、N或NH替代；所述任一Het被1～3个氢、卤素、卤代烷基、羟基、烷基或烷氧基取代，卤素为氟、氯、溴或碘；
所述烷基为1-10个碳原子的直链或支链饱和或不饱和烷基、3-8个碳原子的环状饱和或不饱和的烷基或者1-10个碳原子的直链或支链饱和烷基取代的3-8个碳原子的环状饱和烷基；
所述烷氧基为1-10个碳原子的直链或支链饱和或不饱和烷氧基、3-8个碳原子的环状饱和或不饱和烷氧基或者1-10个碳原子的直链或支链饱和烷基取代的3-8个碳原子的环状饱和烷氧基；
所述烷氨基为1-10个碳原子的直链或支链饱和或不饱和烷氨基；或者为3-8个碳原子的环状饱和或不饱和烷氨基；或者为1-10个碳原子的直链或支链饱和烷基取代的3-8个碳原子的环状饱和烷氨基；
n等于0或1。
优选地，所述氧肟酸类化合物及其衍生物结构中：
R为苯基、噻吩基、吡啶基环丙基、环丁基、环戊基、环己基、环庚基或环辛基；其中，所述环丙基、环丁基、环戊基、环己基、环庚基或环辛基环上的碳原子可被0～4个O、S、N或NH替代；
R被一个或多个R1取代，R1为氢、甲基、乙基、丙基、丁基、异丙基、叔丁基、氰基、卤素、卤代烷基、羟基、氨基、巯基、甲氧基、乙氧基、异丙氧基、甲氨基、乙氨基、二甲氨基、二乙氨基、苯基、吡啶基、吡咯基、吡唑基、咪唑基、呋喃基、噻吩基、噁唑基、异噁唑基、噻唑基、异噻唑基、三氮唑基、1,2,4-噁二唑基、1,3,4-噁二唑基、1,2,4-噻二唑基、1,3,4-噻二唑基、吡啶基、嘧啶基、吡嗪基或哒嗪基、芳烷基、NH2SO2-、烷基磺酰氨基、芳基磺酰氨基、Het磺酰氨基、烷基磺酰基、芳基磺酰基、Het磺酰基、HC(O)NH-、-C(O)H或NH2C(O)-；其中，羟基、巯基、氨基、甲基、乙基、丙基、丁基、异丙基、叔丁基、甲氧基、乙氧基、异丙氧基、甲胺基、乙胺基、二甲胺基、二乙胺基、苯基、吡啶基、吡咯基、吡唑基、咪唑基、呋喃基、噻吩基、噁唑基、异噁唑基、噻唑基、异噻唑基、三氮唑基、1,2,4-噁二唑基、1,3,4-噁二唑基、1,2,4-噻二唑基、1,3,4-噻二唑基、吡啶基、嘧啶基、吡嗪基或哒嗪基、芳烷基、NH2SO2-、烷基磺酰氨基、芳基磺酰氨基、Het磺酰氨基、烷基磺酰基、芳基磺酰基、Het磺酰基、HC(O)NH-、-C(O)H或NH2C(O)-被一个或多个R2取代，R2为氢、烷基、卤素、卤代烷基、氰基、羟基、氨基、烷氧基、烷氨基、NH2SO2-、烷基磺酰氨基、芳基磺酰氨基、Het磺酰氨基、烷基磺酰基、芳基磺酰基、Het磺酰基、芳基或Het；
X为苯基、苯基烷基、吡啶基、1-8个碳原子的直链或支链饱和烷基或者1-8个碳原子的直链或支链不饱和烷基；
X被一个或多个R3取代，R3为氢、甲基、乙基、丙基、丁基、异丙基、叔丁基、氰基、卤素、卤代烷基、羟基、氨基、巯基、甲氧基、乙氧基、甲氨基、乙氨基、苯基、吡啶基、芳烷基、Het、NH2SO2-、烷基磺酰氨基、芳基磺酰氨基、Het磺酰氨基、烷基磺酰基、芳基磺酰基、Het磺酰基、HC(O)NH-、-C(O)H或NH2C(O)-；其中，羟基、巯基、氨基、烷基、烷氧基、烷氨基、芳基、芳烷基、Het、NH2SO2-、烷基磺酰氨基、芳基磺酰氨基、Het磺酰氨基、烷基磺酰基、芳基磺酰基、Het磺酰基、HC(O)NH-、-C(O)H或NH2C(O)-被一个或多个R4取代，R4为氢、烷基、卤素、卤代烷基、氰基、羟基、氨基、烷氧基、烷氨基、NH2SO2-、烷基磺酰氨基、芳基磺酰氨基、Het磺酰氨基、烷基磺酰基、芳基磺酰基、Het磺酰基、芳基或Het；
n等于0或1。
更优选地，所述氧肟酸类化合物及其衍生物结构中：
R为苯基、噻吩基、吡啶基或环戊基；
R被一个或多个R1取代，R1为氢、甲基、氰基、氟、氯、溴、羟基、氨基、巯基、甲氧基、甲氨基、三氟甲基、三氟甲氧基、NH2SO2-、烷基磺酰氨基、烷基磺酰基、HC(O)NH-、-C(O)H或NH2C(O)-；
X为苯基、苯基-丙-1-烯-3-基、苯基-丁-1-烯-4-基、苯基-戊-1-烯-5-基、苯基-己-1-烯-6-基、苯基-庚-1-烯-7-基、苯丙基、苯丁基、苯戊基、苯己基、苯庚基；或1-7个碳原子的直链或支链饱和烷基；
X被一个或多个R3取代，R3为氢、甲基、乙基、丙基、丁基、异丙基、叔丁基、氰基、氟、氯、溴、羟基、氨基、巯基、甲氧基、乙氧基、甲氨基、乙氨基、NH2SO2-、烷基磺酰氨基、烷基磺酰基、HC(O)NH-、-C(O)H或NH2C(O)-；
n等于0或1。
最优选地，所述氧肟酸类化合物及其衍生物结构中：
R为苯基；
R选被一个或两个R1取代，R1为氢、甲基、氟、氯或甲氧基；
X为苯基-丙-1-烯-3-基、苯基-丁-1-烯-4-基、苯基-戊-1-烯-5-基、苯基-己-1-烯-6-基、苯基-庚-1-烯-7-基、苯丙基、苯丁基、苯戊基、苯己基、苯庚基或2-7个碳原子的直链饱和烷基；
n等于1。
具体地，所述氧肟酸类化合物为以下任一化合物：
N1-(5-(1-苄基-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N4-羟基对苯二甲酰胺(I-1)，
N1-(5-(1-苄基-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N4-羟基琥珀酰胺(I-2)，
N1-(5-(1-苄基-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N5-羟基戊二酰胺(I-3)，
N1-(5-(1-苄基-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N6-羟基己二胺(I-4)，
N1-(5-(1-苄基-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N7-羟基庚二酰胺(I-5)，
N1-(5-(1-苄基-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N8-羟基辛二酰胺(I-6)，
N1-(5-(1-苄基-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N9-羟基壬二酰胺(I-7)，
N1-羟基-N7-(5-(1-(吡啶-4-甲基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-庚二酰胺(I-8)，
N1-(5-(1-环戊基-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N7-羟基庚二酰胺(I-9)，
N1-羟基-N7-(5-(1-(噻吩-2-甲基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-庚二酰胺(I-10)，
N1-(5-(1-(2-氟苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N7-羟基庚二酰胺(I-11)，
N1-(5-(1-(3-氟苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N7-羟基庚二酰胺(I-12)，
N1-(5-(1-(4-氟苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N7-羟基庚二酰胺(I-13)，
N1-(5-(1-(2-氯苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N7-羟基庚二酰胺(I-14)，
N1-(5-(1-(3-氯苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N7-羟基庚二酰胺(I-15)，
N1-(5-(1-(4-氯苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N7-羟基庚二酰胺(I-16)，
N1-羟基-N7-(5-(1-(2-甲基苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-庚二酰胺(I-17)，
N1-羟基-N7-(5-(1-(2-甲氧基苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-庚二酰胺(I-18)，
N1-(5-(1-(3,5-二氟苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N7-羟基庚二酰胺(I-19)，
N1-(5-(1-(2,6-二氟苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N7-羟基庚二酰胺(I-20)，
N1-(5-(1-(2-氯-6-氟苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N7-羟基庚二酰胺(I-21)，
N1-(5-(1-(2-氯-3-氟苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N7-羟基庚二酰胺(I-22)，
N1-(5-(1-(2-氯-5-氟苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N7-羟基庚二酰胺(I-23)，
N1-(5-(1-(2,6-二氯苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N7-羟基庚二酰胺(I-24)，
N1-(5-(1-(2-氯-6-甲基苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N7-羟基庚二酰胺(I-25)，
N1-(5-(1-(2,6-二甲基苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N7-羟基庚二酰胺(I-26)，
N1-(5-(1-(2-氯-3-氟苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N8-羟基辛二酰胺(I-27)，
N1-(5-(1-(2,6-二氯苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N8-羟基辛二酰胺(I-28)，
N1-(5-(1-(2-氯-6-甲基苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N8-羟基辛二酰胺(I-29)，
(E)-N-(5-(1-(2,6-二氯苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-4-(4-(羟基氨基)-4-氧代丁-1-烯-1-基)苯甲酰胺(I-30)，
(E)-N-(5-(1-(2,6-二氯苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-4-(5-(羟基氨基)-5-氧代戊-1-烯-1-基)苯甲酰胺(I-31)，
(E)-N-(5-(1-(2,6-二氯苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-4-(6-(羟基氨基)-6-氧代己-1-烯-1-基)苯甲酰胺(I-32)，
(E)-N-(5-(1-(2,6-二氯苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-4-(7-(羟基氨基)-7-氧代庚-1-烯-1-基)苯甲酰胺(I-33)，
(E)-N-(5-(1-(2,6-二氯苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-4-(8-(羟基氨基)-8-氧代辛-1-烯-1-基)苯甲酰胺(I-34)，
N-(5-(1-(2,6-二氯苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-4-(4-(羟基氨基)-4-氧丁基))苯甲酰胺(I-35)，
N-(5-(1-(2,6-二氯苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-4-(5-(羟基氨基)-5-氧代戊基))苯甲酰胺(I-36)，
N-(5-(1-(2,6-二氯苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-4-(6-(羟基氨基)-6-氧己基))苯甲酰胺(I-37)，
N-(5-(1-(2,6-二氯苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-4-(7-(羟基氨基)-7-氧代庚基))苯甲酰胺(I-38)，
N-(5-(1-(2,6-二氯苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-4-(8-(羟基氨基)-8-氧辛基))苯甲酰胺(I-39)。
在上述氧肟酸类化合物的基础上，所述药学上可接受的盐为上述氧肟酸类化合物与酸或碱形成的盐，所述酸为有机酸或无机酸；其中有机酸为甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、柠檬酸、苹果酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸、琥珀酸、富马酸、水杨酸、苯基乙酸或杏仁酸，无机酸为盐酸、氢溴酸、硫酸或磷酸；所述碱为含有碱性金属阳离子、碱土金属阳离子或铵阳离子盐的碱。
作为本发明涉及的第二方面，本发明的氧肟酸类化合物及其衍生物的制备方法为：
化合物1经氨基化反应得到化合物I；
其中，R、X、n的定义如前所述；
将相应的酸或碱与以上方法制备所得的化合物I成盐，即得所述氧肟酸类化合物的药学上可接受的盐。
作为本发明涉及的第三方面，本发明的药物组合物包含所述氧肟酸类化合物和/或其衍生物以及药学上可接受的载体。
所述氧肟酸类化合物及其衍生物可以添加药学上可接受的载体制成常见的药用制剂，如片剂、胶囊、糖浆、悬浮剂或注射剂，制剂可以加入香料、甜味剂、液体/固体填料、稀释剂等常用药用辅料。
作为本发明涉及的第四方面，本发明的氧肟酸类化合物及其衍生物在制备治疗和/或预防与FLT3或HDAC相关疾病药物中的应用，具体应用于急性髓性白血病、急性早幼粒细胞白血病、急性淋巴性白血病、骨髓增生异常综合症、炎症性结肠炎或类风湿性关节炎。
有益效果：与现有技术相比，本发明具有如下显著优点：
(1)该类氧肟酸类化合物及其衍生物和药物组合物可有效抑制FLT3、HDAC活性，IC50值均达到纳摩尔浓度级别，最优低于1nM；同时对肿瘤细胞也具有抑制作用，抑制率均达到80％以上，最优达到95％以上；
(2)该类氧肟酸类化合物及其衍生物和药物组合物应用广泛，可制备为治疗和/或预防与FLT3、HDAC相关疾病药物；所述药物在分子水平和细胞水平均可以发挥药效，并且治疗效果更优异，酶抑制活性可达到纳摩尔浓度级别，细胞抑制活性达到80％以上；
(3)化合物制备方法适用性广，操作简便。
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。
熔点测定采用RY-1G数字显示显微熔点测定仪(天津市新天光仪器公司)，温度计未经校正；1H-NMR用BRUKER AVANCE 300或400型核磁共振仪(瑞士布鲁克公司)，TMS为内标测定；MS用Agilent 1100LC/MSD质谱仪(美国安捷伦公司)和Q-totmicro MS(micromass公司)。
实施例1：N1-(5-(1-苄基-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N4-羟基对苯二甲酰胺(I-1)
(1)3-(苄氨基)-4-硝基苯甲酸甲酯
向溶有3-氟-4-硝基苯甲酸甲酯(5.00g,25.11mmol)的DMF(15mL)溶液中，依次加入苯甲胺(4.04g,37.66mmol)，三乙胺(7.62g,75.32mmol)，50℃反应6h。反应液以水(200mL)稀释，乙酸乙酯(50mL×3)萃取，合并有机相，再依次用1mol/L的稀盐酸水溶液(30ml×3)、饱和食盐水(30ml×3)洗涤，无水硫酸钠干燥。过滤除去无水硫酸钠后，滤液减压蒸馏除去溶剂得黄色固体6.82g，收率95％。MS(m/z):[M+H]+287.3。
(2)4-氨基-3-(苄基氨基)苯甲酸甲酯
50mL甲醇溶解3-(苄氨基)-4-硝基苯甲酸甲酯(6.60g,23.05mmol)，冰浴下依次加入冰醋酸(32.27mL)、锌粉(10.55g,161.38mmol)，室温下反应5h。反应液减压浓缩，再用饱和碳酸氢钠水溶液调节pH约为9，乙酸乙酯(50mL×3)萃取，合并有机相，再用饱和食盐水(30ml×3)洗涤，无水硫酸钠干燥。过滤除去无水硫酸钠后，滤液减压蒸馏除去溶剂得黑色固体5.10g，收率86％。MS(m/z):[M+H]+257.2。
(3)1-苄基-1H-苯并[d]咪唑-6-羧酸甲酯
将4-氨基-3-(苄基氨基)苯甲酸甲酯(4.9g,19.12mmol)溶解在30mL甲酸中，50℃反应7h。反应液减压浓缩，再用饱和碳酸氢钠水溶液调节pH约为9，乙酸乙酯(50mL×3)萃取，合并有机相，再用饱和食盐水(30ml×3)洗涤，无水硫酸钠干燥。过滤除去无水硫酸钠后，滤液减压浓缩柱层析(50％EA/PE)得棕色固体2.71g，收率53％。MS(m/z):[M+H]+267.3。
(4)3-(1-苄基-1H-苯并[d]咪唑-6-基)-3-氧代丙腈
冰浴条件下向250mL茄形瓶中依次加入四氢呋喃(20mL)、氢化钠(0.90g,37.55mmol)、乙腈(0.77g,18.78mmol)，随后加入1-苄基-1H-苯并[d]咪唑-6-羧酸甲酯(2.5g,9.39mmol)，65℃反应7h。反应液减压浓缩，冰浴下加水淬灭，再用1mol/L的稀盐酸水溶液调节pH约为4，大量固体析出，抽滤，干燥得棕色固体2.01g。收率78％。MS(m/z):[M-H]-274.2。
(5)5-(1-苄基-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-胺
将3-(1-苄基-1H-苯并[d]咪唑-6-基)-3-氧代丙腈(1.80g,6.54mmol)溶解在20mL乙醇中，随后加入水合肼(1.64g,32.69mmol)，氮气保护下回流反应8h。反应液减压浓缩柱层析(EA)得淡黄色固体1.03g，收率54％。MS(m/z):[M+H]+290.2。
(6)4-((5-(1-苄基-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)氨基甲酰基)苯甲酸甲酯
将5-(1-苄基-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-胺(0.50g,1.02mmol)溶解在10mL甲苯中，随后加入对苯二甲酸二甲酯(1.34g,6.91mol)，氮气保护下加入2mol/L三甲基铝的甲苯溶液(3.5mL)，氮气保护下回流反应5h。反应液减压浓缩柱层析(5％MeOH/DCM)得白色固体0.52g，收率67％。MS(m/z):[M+H]+452.5。
(7)N1-(5-(1-苄基-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N4-羟基对苯二甲酰胺(化合物I-1)
冰浴下，向溶有盐酸羟胺(1.85g,26.58mmol)的20mL甲醇溶液中加入氢氧化钾(1.49g,26.58mmol)，室温下搅拌30分钟。随后减压抽滤，滤液加入上步产物(0.40g,0.89mmol)的甲醇溶液中，最后加入甲醇钠(1.44g,26.58mmol)，室温下反应5h。稀盐酸调节pH至3-4，减压浓缩柱层析(9％MeOH/DCM)得白色固体0.16g，收率32％。mp:233–235℃；1HNMR(400MHz,DMSO-d6)δ12.95(s,1H),11.38(s,1H),11.00(s,1H),9.17(s,1H),8.47(s,1H),8.08(d,J＝8.0Hz,2H),8.01(d,J＝1.5Hz,1H),7.86(d,J＝8.0Hz,2H),7.73(d,J＝8.3Hz,1H),7.63(dd,J＝8.3,1.5Hz,1H),7.41–7.27(m,5H),7.10(s,1H),5.56(s,2H).HRMS-ESI m/z[M+H]+calcd for C25H21N6O3:453.1675,found:453.1676。
实施例2：N1-(5-(1-苄基-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N4-羟基琥珀酰胺(I-2)
制备方法类似于I-1。得白色固体51mg，收率25％。mp:159–161℃；1H NMR(300MHz,DMSO-d6)δ12.67(s,1H),10.57–10.32(m,2H),8.72(s,1H),8.47(s,1H),7.94(d,J＝1.6Hz,1H),7.70(d,J＝8.5Hz,1H),7.57(dd,J＝8.5,1.6Hz,1H),7.37–7.29(m,5H),6.86(s,1H),5.54(s,2H),2.56(t,J＝7.3Hz,2H),2.27(t,J＝7.3Hz,2H).13C NMR(75MHz,DMSO-d6)δ169.83,168.85,145.64,143.84,137.45,134.60,129.20,128.24,127.86,120.34,119.60,107.68,48.02,31.18,27.93.HRMS-ESI m/z[M+H]+calcd for C21H21N6O3:405.1675,found:405.1674。
实施例3：N1-(5-(1-苄基-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N5-羟基戊二酰胺(I-3)
制备方法类似于I-1。得白色固体64mg，收率32％。mp:166–168℃；1H NMR(300MHz,DMSO-d6)δ12.71(s,1H),10.50–10.33(m,2H),8.72(s,1H),8.46(s,1H),7.95(d,J＝1.6Hz,1H),7.70(d,J＝8.4Hz,1H),7.58(dd,J＝8.4,1.6Hz,1H),7.37–7.28(m,5H),6.89(s,1H),5.54(s,2H),2.31(t,J＝7.5Hz,2H),2.00(t,J＝7.5Hz,2H),1.85–1.75(m,2H).13C NMR(75MHz,DMSO-d6)δ170.40,169.21,145.65,143.81,137.46,134.60,129.20,128.24,127.84,120.33,119.62,107.71,93.81,48.00,35.28,32.16,21.71.HRMS-ESI m/z[M+H]+calcd for C22H23N6O3:419.1832,found:419.1836。
实施例4：N1-(5-(1-苄基-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N6-羟基己二胺(I-4)
制备方法类似于I-1。得白色固体89mg，收率30％。mp:179–181℃；1H NMR(400MHz,DMSO-d6)δ12.76(s,1H),10.46–10.26(m,2H),8.69(s,1H),8.51(s,1H),7.96(d,J＝1.6Hz,1H),7.71(d,J＝8.4Hz,1H),7.59(dd,J＝8.4,1.6Hz,1H),7.39–7.27(m,5H),6.90(s,1H),5.55(s,2H),2.30(t,J＝5.7Hz,2H),1.97(t,J＝6.8Hz,2H),1.58–1.49(m,4H).13C NMR(75MHz,DMSO-d6)δ170.75,169.46,145.48,142.95,137.28,134.41,129.22,128.30,127.90,125.96,120.05,119.92,107.87,48.13,35.77,32.65,25.34.HRMS-ESI m/z[M+H]+calcd for C23H25N6O3:433.1988,found:433.1983。
实施例5：N1-(5-(1-苄基-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N7-羟基庚二酰胺(I-5)
制备方法类似于I-1。得白色固体77mg，收率26％。mp:156–158℃；1H NMR(300MHz,DMSO-d6)δ12.75(s,1H),10.49–10.20(m,2H),8.68(s,1H),8.45(s,1H),7.95(d,J＝1.6Hz,1H),7.70(d,J＝8.5Hz,1H),7.57(dd,J＝8.5,1.6Hz,1H),7.38–7.25(m,5H),6.92(s,1H),5.54(s,2H),2.29(t,J＝7.3Hz,2H),1.95(t,J＝7.3Hz,2H),1.62–1.45(m,4H),1.32–1.21(m,2H).13C NMR(100MHz,DMSO-d6)δ170.86,169.58,145.65,143.81,137.44,134.60,129.20,128.24,127.84,120.34,119.63,107.71,93.88,48.01,35.83,32.67,28.71,25.44,25.36.HRMS-ESI m/z[M+H]+calcd for C24H27N6O3:447.2145,found:447.2146。
实施例6：N1-(5-(1-苄基-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N8-羟基辛二酰胺(I-6)
制备方法类似于I-1。得白色固体93mg，收率31％。mp:166–168℃；1H NMR(300MHz,DMSO-d6)δ12.75(s,1H),10.50–10.23(m,2H),8.67(s,1H),8.45(s,1H),7.95(d,J＝1.5Hz,1H),7.70(d,J＝8.4Hz,1H),7.57(dd,J＝8.4,1.5Hz,1H),7.37–7.27(m,5H),6.92(s,1H),5.54(s,2H),2.29(t,J＝7.3Hz,2H),1.94(t,J＝7.3Hz,2H),1.59–1.44(m,4H),1.30–1.23(m,4H).13C NMR(75MHz,DMSO-d6)δ170.89,169.55,145.65,143.81,137.48,134.60,129.20,128.24,127.85,120.33,119.59,107.71,47.99,35.92,32.70,28.88,25.52.HRMS-ESI m/z[M+H]+calcd for C25H29N6O3:461.2301,found:461.2298。
实施例7：N1-(5-(1-苄基-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N9-羟基壬二酰胺(I-7)
制备方法类似于I-1。得白色固体79mg，收率26％。mp:169–170℃；1H NMR(300MHz,DMSO-d6)δ12.76(s,1H),10.48–10.24(m,2H),8.68(s,1H),8.46(s,1H),7.95(d,J＝1.5Hz,1H),7.70(d,J＝8.5Hz,1H),7.57(dd,J＝8.5,1.5Hz,1H),7.41–7.24(m,5H),6.93(s,1H),5.54(s,2H),2.29(t,J＝7.2Hz,2H),1.94(t,J＝7.2Hz,2H),1.58–1.46(m,3H),1.30–1.21(m,7H).13C NMR(75MHz,DMSO-d6)δ170.91,169.54,145.64,143.82,137.48,134.60,129.20,128.23,127.85,120.32,119.58,107.71,47.99,35.94,32.71,29.02,25.59.HRMS-ESI m/z[M+H]+calcd for C26H31N6O3:475.2458,found:475.2462。
实施例8：N1-羟基-N7-(5-(1-(吡啶-4-甲基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-庚二酰胺(I-8)
制备方法类似于I-1。得白色固体73mg，收率24％。mp:160–162℃；1H NMR(300MHz,DMSO-d6)δ12.72(s,1H),10.45–10.31(m,2H),8.69(s,1H),8.55–8.51(m,1H),8.42(s,1H),7.91(d,J＝1.5Hz,1H),7.80(td,J＝7.7,1.8Hz,1H),7.71(d,J＝8.4Hz,1H),7.58(dd,J＝8.4,1.5Hz,1H),7.35–7.28(m,2H),6.90(s,1H),5.65(s,2H),2.29(t,J＝7.3Hz,2H),1.95(t,J＝7.3Hz,2H),1.62–1.46(m,4H),1.31–1.21(m,2H).13C NMR(75MHz,DMSO-d6)δ170.83,169.55,156.36,149.92,146.12,143.71,137.74,134.84,123.45,122.09,120.26,119.55,107.80,93.78,49.69,35.83,32.66,28.70,25.44,25.36.HRMS-ESI m/z[M+H]+calcd forC23H26N7O3:448.2097,found:448.2101。
实施例9：N1-(5-(1-环戊基-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N7-羟基庚二酰胺(I-9)
制备方法类似于I-1。得白色固体67mg，收率22％。mp:130–132℃；1H NMR(300MHz,DMSO-d6)δ12.77(s,1H),10.45–10.31(m,2H),8.70(s,1H),8.37(s,1H),7.99(d,J＝1.5Hz,1H),7.70(d,J＝8.4Hz,1H),7.58(dd,J＝8.4,1.5Hz,1H),6.96(s,1H),4.90(q,J＝7.3Hz,1H),2.34–2.20(m,4H),2.03–1.73(m,8H),1.64–1.47(m,4H),1.34–1.22(m,2H).13C NMR(75MHz,DMSO-d6)δ170.87,169.60,143.98,143.37,134.62,120.30,119.67,107.93,93.97,56.79,35.87,32.68,32.17,28.72,25.45,23.83.HRMS-ESI m/z[M+H]+calcd forC22H29N6O3:425.2301,found:425.2304。
实施例10：N1-羟基-N7-(5-(1-(噻吩-2-甲基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-庚二酰胺(I-10)
制备方法类似于I-1。得白色固体82mg，收率27％。mp:141–143℃；1H NMR(300MHz,DMSO-d6)δ12.78(s,1H),10.46–10.31(m,2H),8.69(d,J＝1.7Hz,1H),8.42(s,1H),8.05(d,J＝1.5Hz,1H),7.70(d,J＝8.5Hz,1H),7.59(dd,J＝8.5,1.5Hz,1H),7.46(dd,J＝5.1,1.3Hz,1H),7.28(d,J＝3.4Hz,1H),7.08–6.91(m,2H),5.76(s,2H),2.31(t,J＝7.3Hz,2H),1.96(t,J＝7.3Hz,2H),1.62–1.46(m,4H),1.33–1.22(m,2H).13C NMR(75MHz,DMSO-d6)δ170.85,169.55,145.22,143.77,139.81,134.30,127.70,127.60,126.87,120.33,119.60,107.85,93.83,42.78,35.83,32.66,28.71,25.45,25.37.HRMS-ESI m/z[M+H]+calcd forC22H25N6O3S:453.1709,found:453.1705。
实施例11：N1-(5-(1-(2-氟苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N7-羟基庚二酰胺(I-11)
制备方法类似于I-1。得白色固体90mg，收率30％。mp:132–134℃；1H NMR(300MHz,DMSO-d6)δ12.76(s,1H),10.47–10.27(m,2H),8.69(s,1H),8.46(s,1H),7.97(d,J＝1.5Hz,1H),7.71(d,J＝8.4Hz,1H),7.58(dd,J＝8.4,1.5Hz,1H),7.49–7.39(m,2H),7.24–7.15(m,2H),6.96(s,1H),5.54(s,2H),2.30(t,J＝7.3Hz,2H),1.95(t,J＝7.3Hz,2H),1.62–1.47(m,4H),1.32–1.22(m,2H).13C NMR(75MHz,DMSO-d6)δ170.88,169.59,163.72,160.49,145.56,143.80,134.47,133.70,133.66,130.14,130.03,120.36,119.69,116.17,115.88,107.68,93.97,47.26,35.84,32.66,28.71,25.45,25.37.HRMS-ESI m/z[M+H]+calcd forC24H26FN6O3:465.2050,found:465.2052。
实施例12：N1-(5-(1-(3-氟苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N7-羟基庚二酰胺(I-12)
制备方法类似于I-1。得白色固体79mg，收率26％。mp:184–186℃；1H NMR(300MHz,DMSO-d6)δ12.77(s,1H),10.49–10.27(m,2H),8.69(s,1H),8.48(s,1H),7.97(d,J＝1.5Hz,1H),7.71(d,J＝8.4Hz,1H),7.59(dd,J＝8.4,1.5Hz,1H),7.45–7.36(m,1H),7.28–7.09(m,3H),6.96(s,1H),5.57(s,2H),2.30(t,J＝7.3Hz,2H),1.95(t,J＝7.3Hz,2H),1.63–1.46(m,4H),1.31–1.22(m,2H).13C NMR(75MHz,DMSO-d6)δ170.85,169.57,164.30,161.07,145.68,143.78,140.32,140.22,134.53,131.33,131.22,123.91,123.88,120.40,119.71,115.25,114.96,114.65,107.63,93.90,47.43,35.84,32.67,28.71,25.45,25.37.HRMS-ESI m/z[M+H]+calcd for C24H26FN6O3:465.2050,found:465.2050。
实施例13：N1-(5-(1-(4-氟苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N7-羟基庚二酰胺(I-13)
制备方法类似于I-1。得白色固体81mg，收率27％。mp:195-197℃；1H NMR(300MHz,DMSO-d6)δ12.73(s,1H),10.46–10.31(m,2H),8.69(s,1H),8.46(s,1H),7.97(d,J＝1.5Hz,1H),7.70(d,J＝8.4Hz,1H),7.58(dd,J＝8.4,1.5Hz,1H),7.48–7.41(m,2H),7.23–7.16(m,2H),6.92(s,1H),5.53(s,2H),2.30(t,J＝7.3Hz,2H),1.95(t,J＝7.3Hz,2H),1.62–1.47(m,4H),1.33–1.22(m,2H).13C NMR(75MHz,DMSO-d6)δ170.83,169.52,163.72,160.49,145.56,143.82,134.48,133.74,130.15,130.04,120.36,119.64,116.17,115.89,107.67,47.23,35.82,32.65,28.71,25.44,25.36.HRMS-ESI m/z[M+H]+calcd for C24H26FN6O3:465.2050,found:465.2051。
实施例14：N1-(5-(1-(2-氯苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N7-羟基庚二酰胺(I-14)
制备方法类似于I-1。得白色固体62mg，收率21％。mp:186–188℃；1H NMR(300MHz,DMSO-d6)δ12.73(s,1H),10.50–10.26(m,2H),8.69(s,1H),8.38(s,1H),7.92(d,J＝1.5Hz,1H),7.74(d,J＝8.4Hz,1H),7.63–7.53(m,2H),7.40–7.27(m,2H),7.03–6.79(m,2H),5.66(s,2H),2.29(t,J＝7.2Hz,2H),1.95(t,J＝7.2Hz,2H),1.62–1.45(m,4H),1.31–1.20(m,2H).13C NMR(75MHz,DMSO-d6)δ170.81,169.54,145.99,143.68,134.76,134.62,132.54,130.15,130.11,129.16,128.14,120.45,119.76,107.68,93.83,46.08,35.83,32.66,28.71,25.44,25.36.HRMS-ESI m/z[M+H]+calcd for C24H26ClN6O3:481.1755,found:481.1758。
实施例15：N1-(5-(1-(3-氯苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N7-羟基庚二酰胺(I-15)
制备方法类似于I-1。得白色固体96mg，收率32％。mp:188–190℃；1H NMR(300MHz,DMSO-d6)δ12.79(s,1H),10.56–10.23(m,2H),8.71(s,1H),8.48(s,1H),7.98(d,J＝1.5Hz,1H),7.71(d,J＝8.4Hz,1H),7.59(dd,J＝8.4,1.5Hz,1H),7.49–7.28(m,4H),6.95(s,1H),5.56(s,2H),2.30(t,J＝7.3Hz,2H),1.95(t,J＝7.3Hz,2H),1.62–1.45(m,4H),1.29–1.22(m,2H).13C NMR(75MHz,DMSO-d6)δ170.84,169.55,145.66,143.76,139.96,134.50,133.80,131.13,128.25,127.72,126.51,120.40,119.73,107.60,93.90,47.31,35.84,32.67,28.71,25.45,25.37.HRMS-ESI m/z[M+H]+calcd for C24H26ClN6O3:481.1755,found:481.1758。
实施例16：N1-(5-(1-(4-氯苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N7-羟基庚二酰胺(I-16)
制备方法类似于I-1。得白色固体81mg，收率27％。mp:138–140℃；1H NMR(300MHz,DMSO-d6)δ12.76(s,1H),10.49–10.25(m,2H),8.69(s,1H),8.46(s,1H),7.95(d,J＝1.5Hz,1H),7.71(d,J＝8.5Hz,1H),7.58(dd,J＝8.5,1.5Hz,1H),7.45–7.36(m,4H),6.95(s,1H),5.55(s,2H),2.30(t,J＝7.3Hz,2H),1.95(t,J＝7.3Hz,2H),1.63–1.46(m,4H),1.32–1.20(m,2H).13C NMR(75MHz,DMSO-d6)δ170.86,169.58,145.62,143.80,136.47,134.50,132.90,129.74,129.19,120.39,119.71,107.65,94.02,47.26,35.84,32.67,28.71,25.45,25.37.HRMS-ESI m/z[M+H]+calcd for C24H26ClN6O3:481.1755,found:481.1754。
实施例17：N1-羟基-N7-(5-(1-(2-甲基苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-庚二酰胺(I-17)
制备方法类似于I-1。得白色固体66mg，收率22％。mp:169–171℃；1H NMR(300MHz,DMSO-d6)δ12.72(s,1H),10.45–10.30(m,2H),8.68(s,1H),8.31(s,1H),7.86(d,J＝1.5Hz,1H),7.75(d,J＝8.4Hz,1H),7.61(dd,J＝8.4,1.5Hz,1H),7.28–7.18(m,2H),7.11(td,J＝7.4,1.7Hz,1H),6.87(s,1H),6.69(d,J＝7.5Hz,1H),5.57(s,2H),2.38(s,3H),2.29(t,J＝7.3Hz,2H),1.95(t,J＝7.3Hz,2H),1.62–1.45(m,4H),1.31–1.20(m,2H).13C NMR(75MHz,DMSO-d6)δ170.83,169.56,145.89,143.71,136.04,135.41,134.98,130.85,128.07,126.72,126.63,120.39,119.64,107.80,93.87,46.25,35.83,32.66,28.70,25.44,25.36,19.21.HRMS-ESI m/z[M+H]+calcd for C25H29N6O3:461.2301,found:461.2304。
实施例18：N1-羟基-N7-(5-(1-(2-甲氧基苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-庚二酰胺(I-18)
制备方法类似于I-1。得白色固体75mg，收率25％。mp:132–134℃；1H NMR(300MHz,DMSO-d6)δ12.75(s,1H),10.45–10.31(m,2H),8.70(s,1H),8.33(s,1H),7.96(d,J＝1.5Hz,1H),7.69(d,J＝8.4Hz,1H),7.57(dd,J＝8.4,1.5Hz,1H),7.33–7.27(m,1H),7.16(dd,J＝7.5,1.7Hz,1H),7.06(dd,J＝8.4,1.0Hz,1H),7.01–6.82(m,2H),5.47(s,2H),3.89(s,3H),2.30(t,J＝7.2Hz,2H),1.96(t,J＝7.2Hz,2H),1.63–1.47(m,4H),1.33–1.21(m,2H).13CNMR(100MHz,DMSO-d6)δ170.87,169.58,157.32,145.99,143.63,134.75,130.00,129.35,124.83,120.90,120.25,119.46,111.51,107.74,93.84,55.88,43.68,35.86,32.66,28.71,25.44,25.38.HRMS-ESI m/z[M+H]+calcd for C25H29N6O4:477.2250,found:477.2253。
实施例19：N1-(5-(1-(3,5-二氟苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N7-羟基庚二酰胺(I-19)
制备方法类似于I-1。得白色固体91mg，收率30％。mp:243–245℃；1H NMR(300MHz,DMSO-d6)δ12.81(s,1H),10.55–10.27(m,2H),8.69(s,1H),8.50(s,1H),8.01(d,J＝1.5Hz,1H),7.76–7.57(m,2H),7.29–6.93(m,4H),5.57(s,2H),2.30(t,J＝7.3Hz,2H),1.94(t,J＝7.3Hz,2H),1.64–1.47(m,4H),1.34–1.19(m,2H).13C NMR(75MHz,DMSO-d6)δ170.85,169.55,164.64,164.46,161.37,161.19,145.62,143.63,141.87,134.41,120.37,119.86,111.49,111.16,107.60,104.17,103.84,103.50,47.12,35.83,32.66,28.71,25.45,25.37.HRMS-ESI m/z[M+Na]+calcd for C24H24F2N6O3Na:505.1776,found:505.1769。
实施例20：N1-(5-(1-(2,6-二氟苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N7-羟基庚二酰胺(I-20)
制备方法类似于I-1。得白色固体87mg，收率29％。mp:148–150℃；1H NMR(300MHz,DMSO-d6)δ12.80(s,1H),10.48–10.33(m,2H),8.71(s,1H),8.32(s,1H),7.88(d,J＝1.5Hz,1H),7.71(d,J＝8.4Hz,1H),7.60(dd,J＝8.4,1.5Hz,1H),7.53–7.42(m,1H),7.23–7.15(m,2H),6.91(s,1H),5.62(s,2H),2.32(t,J＝7.3Hz,2H),1.96(t,J＝7.3Hz,2H),1.64–1.48(m,4H),1.33–1.21(m,2H).13C NMR(75MHz,DMSO-d6)δ170.96,169.64,162.93,162.83,159.64,159.53,145.60,143.43,134.25,131.97,131.83,125.53,120.38,119.81,112.68,112.47,112.37,107.28,93.54,36.30,35.87,32.68,28.72,25.45,25.35.HRMS-ESI m/z[M+Na]+calcd for C24H24F2N6O3Na:505.1776,found:505.1760。
实施例21：N1-(5-(1-(2-氯-6-氟苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N7-羟基庚二酰胺(I-21)
制备方法类似于I-1。得白色固体63mg，收率21％。mp:134–136℃；1H NMR(300MHz,DMSO-d6)δ12.77(s,1H),10.54–10.25(m,2H),8.69(d,J＝1.8Hz,1H),8.27(s,1H),7.92(d,J＝1.5Hz,1H),7.71(d,J＝8.4Hz,1H),7.59(dd,J＝8.4,1.5Hz,1H),7.52–7.32(m,3H),6.89(s,1H),5.66(s,2H),2.31(t,J＝7.3Hz,2H),1.96(t,J＝7.3Hz,2H),1.64–1.47(m,4H),1.33–1.21(m,2H).13C NMR(75MHz,DMSO-d6)δ170.89,169.57,163.45,160.14,145.63,143.50,135.14,134.46,132.18,132.04,126.67,121.77,120.42,119.68,115.78,115.49,107.53,93.70,35.86,32.66,28.73,25.44,25.35.HRMS-ESI m/z[M+H]+calcd forC24H25ClFN6O3:499.1661,found:499.1673。
实施例22：N1-(5-(1-(2-氯-3-氟苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N7-羟基庚二酰胺(I-22)
制备方法类似于I-1。得白色固体59mg，收率20％。mp:215–217℃；1H NMR(300MHz,DMSO-d6)δ12.75(s,1H),10.42–10.34(m,2H),8.70(d,J＝1.7Hz,1H),8.41(s,1H),7.95(d,J＝1.4Hz,1H),7.77(d,J＝8.4Hz,1H),7.64(dd,J＝8.4,1.4Hz,1H),7.44–7.34(m,2H),6.95(s,1H),6.74(d,J＝7.5Hz,1H),5.73(s,2H),2.31(t,J＝7.3Hz,2H),1.97(t,J＝7.3Hz,2H),1.63–1.48(m,4H),1.33–1.22(m,2H).13C NMR(75MHz,DMSO-d6)δ170.82,169.55,159.75,156.48,146.01,143.64,137.34,134.73,129.32,129.21,124.32,120.48,119.83,119.32,119.08,116.68,116.40,107.68,93.93,45.79,35.83,32.66,28.70,25.43,25.36.HRMS-ESI m/z[M+H]+calcd for C24H25ClFN6O3:499.1661,found:499.1662。
实施例23：N1-(5-(1-(2-氯-5-氟苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N7-羟基庚二酰胺(I-23)
制备方法类似于I-1。得白色固体71mg，收率24％。mp:207–209℃；1H NMR(300MHz,DMSO-d6)δ12.76(s,1H),10.51–10.28(m,2H),8.69(s,1H),8.39(s,1H),7.95(d,J＝1.5Hz,1H),7.75(d,J＝8.4Hz,1H),7.66–7.58(m,2H),7.26(td,J＝8.5,3.1Hz,1H),7.08–6.72(m,2H),5.64(s,2H),2.29(t,J＝7.3Hz,2H),1.95(t,J＝7.3Hz,2H),1.62–1.45(m,4H),1.32–1.19(m,2H).13C NMR(75MHz,DMSO-d6)δ170.84,169.55,163.01,159.76,145.97,143.62,137.05,136.96,134.62,132.06,131.95,127.91,127.87,120.51,119.88,117.25,116.94,116.43,116.11,107.63,93.90,46.01,35.84,32.66,28.71,25.44,25.36.HRMS-ESI m/z[M+H]+calcd for C24H25ClFN6O3:499.1661,found:499.1661。
实施例24：N1-(5-(1-(2,6-二氯苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N7-羟基庚二酰胺(I-24)
制备方法类似于I-1。得白色固体85mg，收率28％。mp:215–217℃；1H NMR(300MHz,DMSO-d6)δ12.78(s,1H),10.48–10.31(m,2H),8.70(s,1H),8.06(s,1H),7.97(d,J＝1.5Hz,1H),7.71(d,J＝8.4Hz,1H),7.65–7.59(m,3H),7.50(dd,J＝9.0,7.1Hz,1H),6.93(s,1H),5.71(s,2H),2.31(t,J＝7.3Hz,2H),1.96(t,J＝7.3Hz,2H),1.64–1.47(m,4H),1.33–1.21(m,2H).13C NMR(75MHz,DMSO-d6)δ170.85,169.54,144.94,143.51,136.31,134.70,132.10,130.92,129.77,120.39,119.65,107.78,93.61,44.47,35.88,32.67,28.73,25.44,25.36.HRMS-ESI m/z[M+H]+calcd for C24H25Cl2N6O3:515.1365,found:515.1374。
实施例25：N1-(5-(1-(2-氯-6-甲基苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N7-羟基庚二酰胺(I-25)
制备方法类似于I-1。得白色固体99mg，收率33％。mp:201–203℃；1H NMR(300MHz,DMSO-d6)δ12.77(s,1H),10.50–10.25(m,2H),8.69(d,J＝1.6Hz,1H),7.97(s,1H),7.86(d,J＝1.5Hz,1H),7.71(d,J＝8.4Hz,1H),7.61(dd,J＝8.4,1.5Hz,1H),7.47–7.29(m,3H),6.93(s,1H),5.61(s,2H),2.37–2.27(m,5H),1.95(t,J＝7.3Hz,2H),1.65–1.47(m,4H),1.34–1.21(m,2H).13C NMR(100MHz,DMSO-d6)δ170.90,169.59,144.24,143.51,141.00,135.19,134.89,131.21,130.68,130.41,128.07,120.35,119.63,107.82,93.79,43.75,35.88,32.66,28.72,25.44,25.37,20.11.HRMS-ESI m/z[M+H]+calcd for C25H28ClN6O3:495.1911,found:495.1908。
实施例26：N1-(5-(1-(2,6-二甲基苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N7-羟基庚二酰胺(I-26)
制备方法类似于I-1。得白色固体104mg，收率35％。mp:137–139℃；1H NMR(300MHz,DMSO-d6)δ12.78(s,1H),10.47–10.33(m,2H),8.69(d,J＝1.7Hz,1H),7.98(s,1H),7.73–7.60(m,3H),7.26–7.13(m,3H),6.97(s,1H),5.47(s,2H),2.35–2.25(m,8H),1.96(t,J＝7.3Hz,2H),1.65–1.46(m,4H),1.34–1.22(m,2H).13C NMR(75MHz,DMSO-d6)δ170.87,169.57,143.84,143.60,138.23,135.11,131.87,129.06,129.00,120.30,119.56,107.86,94.01,43.27,35.88,32.68,28.73,25.45,25.40,19.88.HRMS-ESI m/z[M+H]+calcd for C26H31N6O3:475.2458,found:475.2463。
实施例27：N1-(5-(1-(2-氯-3-氟苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N8-羟基辛二酰胺(I-27)
制备方法类似于I-1。得白色固体51mg，收率17％。mp:123–125℃；1H NMR(400MHz,DMSO-d6)δ12.74(s,1H),10.49–10.29(m,2H),8.71(s,1H),8.39(s,1H),7.92(d,J＝1.5Hz,1H),7.75(d,J＝8.5Hz,1H),7.62(dd,J＝8.5,1.5Hz,1H),7.44–7.29(m,2H),6.91(s,1H),6.73(d,J＝7.6Hz,1H),5.70(s,2H),2.29(t,J＝7.4Hz,2H),1.94(t,J＝7.4Hz,2H),1.60–1.43(m,4H),1.32–1.20(m,4H).13C NMR(75MHz,DMSO-d6)δ170.92,169.63,159.75,156.49,146.01,143.64,137.33,134.73,129.32,129.20,124.33,120.49,119.86,119.34,119.10,116.68,116.41,107.68,93.91,45.80,35.94,32.73,28.89,25.53.HRMS-ESI m/z[M+H]+calcd for C25H27ClFN6O3:513.1817,found:513.1822。
实施例28：N1-(5-(1-(2,6-二氯苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N8-羟基辛二酰胺(I-28)
制备方法类似于I-1。得白色固体67mg，收率22％。mp:194–196℃；1H NMR(300MHz,DMSO-d6)δ12.79(s,1H),10.50–10.31(m,2H),8.68(s,1H),8.06(s,1H),7.97(d,J＝1.5Hz,1H),7.74–7.48(m,5H),6.93(s,1H),5.71(s,2H),2.31(t,J＝7.3Hz,2H),1.95(t,J＝7.3Hz,2H),1.63–1.46(m,4H),1.33–1.21(m,4H).13C NMR(75MHz,DMSO-d6)δ170.94,169.59,144.93,143.50,136.32,134.69,132.10,130.92,129.78,120.39,119.66,107.78,44.47,35.98,32.74,28.89,25.53.HRMS-ESI m/z[M+H]+calcd for C25H27Cl2N6O3:529.1522,found:529.1526。
实施例29：N1-(5-(1-(2-氯-6-甲基苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N8-羟基辛二酰胺(I-29)
制备方法类似于I-1。得白色固体82mg，收率27％。mp:140–142℃；1H NMR(300MHz,DMSO-d6)δ12.78(s,1H),10.49–10.36(m,2H),8.74(s,1H),7.96(s,1H),7.86(d,J＝1.5Hz,1H),7.74–7.60(m,2H),7.45–7.27(m,3H),6.91(s,1H),5.61(s,2H),2.37–2.27(m,5H),1.96(t,J＝7.3Hz,2H),1.62–1.45(m,4H),1.34–1.22(m,4H).13C NMR(100MHz,DMSO-d6)δ170.99,169.66,144.24,143.48,141.00,135.18,134.88,131.19,130.69,130.42,128.07,120.34,119.63,107.82,93.86,49.07,43.75,35.97,32.72,28.88,25.53,20.11.HRMS-ESIm/z[M+H]+calcd for C26H30ClN6O3:509.2068,found:509.2066。
实施例30：(E)-N-(5-(1-(2,6-二氯苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-4-(4-(羟基氨基)-4-氧代丁-1-烯-1-基)苯甲酰胺(I-30)
制备方法类似于I-1。得白色固体53mg，收率18％。1H NMR(500MHz,Chloroform-d)δ8.78(s,1H),8.01(s,1H),7.88–7.82(m,3H),7.77(s,1H),7.68–7.61(m,3H),7.57(d,J＝3.8Hz,2H),7.40–7.30(m,4H),6.79(s,1H),6.51(t,J＝1.0Hz,1H),6.31(s,1H),5.39(s,2H),3.10(s,2H)。
实施例31：(E)-N-(5-(1-(2,6-二氯苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-4-(5-(羟基氨基)-5-氧代戊-1-烯-1-基)苯甲酰胺(I-31)
制备方法类似于I-1。得白色固体102mg，收率34％。1H NMR(500MHz,Chloroform-d)δ8.78(s,1H),8.01(s,1H),7.92–7.86(m,3H),7.77(s,1H),7.60–7.54(m,5H),7.40–7.30(m,4H),6.79(s,1H),6.60(t,J＝1.0Hz,1H),6.11(s,1H),5.37(s,2H),2.41(s,2H),2.34(d,J＝12.5Hz,1H),2.17(d,J＝12.5Hz,1H)。
实施例32：(E)-N-(5-(1-(2,6-二氯苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-4-(6-(羟基氨基)-6-氧代己-1-烯-1-基)苯甲酰胺(I-32)
制备方法类似于I-1。得白色固体93mg，收率31％。1H NMR(500MHz,Chloroform-d)δ8.78(s,1H),8.01(s,1H),7.88–7.81(m,3H),7.77(s,1H),7.62–7.51(m,5H),7.40–7.29(m,4H),6.86(t,J＝1.0Hz,1H),6.79(s,1H),6.13(s,1H),5.37(s,2H),2.51(s,2H),2.39(s,2H),1.74(s,2H)。
实施例33：(E)-N-(5-(1-(2,6-二氯苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-4-(7-(羟基氨基)-7-氧代庚-1-烯-1-基)苯甲酰胺(I-33)
制备方法类似于I-1。得白色固体89mg，收率30％。1H NMR(500MHz,Chloroform-d)δ8.78(s,1H),8.01(s,1H),7.91–7.85(m,3H),7.77(s,1H),7.63(s,1H),7.60–7.51(m,4H),7.40–7.29(m,4H),6.79(s,1H),6.65(t,J＝1.0Hz,1H),6.14(s,1H),5.37(s,2H),2.35(d,J＝12.3Hz,1H),2.30(d,J＝12.5Hz,1H),2.16(d,J＝12.5Hz,1H),2.11(d,J＝12.5Hz,1H),1.66(s,2H),1.40(s,2H)。
实施例34：(E)-N-(5-(1-(2,6-二氯苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-4-(8-(羟基氨基)-8-氧代辛-1-烯-1-基)苯甲酰胺(I-34)
制备方法类似于I-1。得白色固体95mg，收率32％。1H NMR(500MHz,Chloroform-d)δ8.78(s,1H),8.01(s,1H),7.91–7.85(m,3H),7.77(s,1H),7.63(s,1H),7.60–7.51(m,4H),7.40–7.28(m,4H),6.79(s,1H),6.59(t,J＝1.0Hz,1H),6.14(s,1H),5.39(s,2H),2.36(d,J＝12.4Hz,1H),2.31(d,J＝12.3Hz,1H),2.13(s,2H),1.59(s,2H),1.36(d,J＝14.1Hz,4H)。
实施例35：N-(5-(1-(2,6-二氯苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-4-(4-(羟基氨基)-4-氧丁基))苯甲酰胺(I-35)
制备方法类似于I-1。得白色固体103mg，收率34％。1H NMR(500MHz,Chloroform-d)δ8.78(s,1H),8.06–7.99(m,4H),7.77(s,1H),7.57(d,J＝3.8Hz,2H),7.40–7.26(m,7H),6.74(s,1H),5.39(s,2H),2.64(t,J＝1.0Hz,2H),2.31(d,J＝12.3Hz,1H),2.25(d,J＝12.5Hz,1H),1.78(s,2H)。
实施例36：N-(5-(1-(2,6-二氯苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-4-(5-(羟基氨基)-5-氧代戊基))苯甲酰胺(I-36)
制备方法类似于I-1。得白色固体125mg，收率41％。1H NMR(500MHz,Chloroform-d)δ8.79(s,1H),8.03–7.97(m,4H),7.77(s,1H),7.57(d,J＝3.8Hz,2H),7.40–7.26(m,7H),6.74(s,1H),5.37(s,2H),2.68(t,J＝1.0Hz,2H),2.36(s,2H),1.60(d,J＝18.1Hz,4H)。
实施例37：N-(5-(1-(2,6-二氯苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-4-(6-(羟基氨基)-6-氧己基))苯甲酰胺(I-37)
制备方法类似于I-1。得白色固体96mg，收率32％。1H NMR(500MHz,Chloroform-d)δ8.78(s,1H),8.01(s,1H),7.97–7.91(m,3H),7.77(s,1H),7.59(d,J＝10.1Hz,3H),7.40–7.28(m,5H),7.31–7.25(m,2H),6.74(s,1H),5.37(s,2H),2.68(t,J＝0.9Hz,3H),2.38(d,J＝12.3Hz,1H),2.31(d,J＝12.5Hz,1H),1.65(s,2H),1.59(s,2H),1.37(s,2H)。
实施例38：N-(5-(1-(2,6-二氯苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-4-(7-(羟基氨基)-7-氧代庚基))苯甲酰胺(I-38)
制备方法类似于I-1。得白色固体93mg，收率31％。1H NMR(500MHz,Chloroform-d)δ8.78(s,1H),8.06–7.99(m,4H),7.77(s,1H),7.63(s,1H),7.58(s,1H),7.40–7.26(m,6H),6.74(s,1H),5.37(s,2H),2.67(t,J＝1.0Hz,2H),2.35(d,J＝12.3Hz,1H),2.30(d,J＝12.5Hz,1H),1.65(s,2H),1.60(s,2H),1.31(d,J＝2.5Hz,5H)。
实施例39：N-(5-(1-(2,6-二氯苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-4-(8-(羟基氨基)-8-氧辛基))苯甲酰胺(I-39)
制备方法类似于I-1。得白色固体87mg，收率29％。1H NMR(500MHz,Chloroform-d)δ8.78(s,1H),8.06–7.99(m,4H),7.77(s,1H),7.63(s,1H),7.58(s,1H),7.40–7.26(m,6H),6.74(s,1H),5.39(s,2H),2.66(t,J＝1.0Hz,2H),2.37(s,2H),1.65(s,2H),1.59(s,2H),1.33–1.26(m,7H)。
实施例40：酶抑制活性测试
1、FLT3-ITD激酶抑制活性测试
(1)实验材料
基本反应缓冲液：20mM Hepes(pH 7.5),10mM MgCl2,1mM EGTA,0.02％Brij35,0.02mg/ml BSA,0.1mM Na3VO4,2mM DTT,1％DMSO。
(2)实验方法
在新制的反应缓冲液中准备好底物，再把辅助因子和激酶依次加入配制好的上述底物溶液中并轻轻混合。随后用Acoustic技术(Echo550；纳升范围)把溶解在DMSO中的不同浓度的化合物加入激酶反应混合物中，室温下反应20min。再加入33P-ATP(放射强度率10mCi/ml)以引发反应，室温下反应120min。用滤波器的方法检测激酶活性，激酶活性数据用百分比表示：测试样本里的激酶活性与空白(DMSO)反应液之比，用Prism计算IC50值。
2、HDAC抑制活性测试
(1)实验材料
基本反应缓冲液：50mM Tris-HCl,pH8.0,137mM NaCl,2.7mM KCl,and 1mMMgCl2，并加入新制备的1mg/ml BSA,1％DMSO。
(2)实验方法
将2X的HDAC加入反应缓冲液中，空白对照组只加入缓冲液。随后用Acoustic技术(Echo550；纳升范围)把溶解在DMSO中的不同浓度的化合物加入到酶混合物中，混匀并室温下反应10min。将相应的2X底物混合物加入所有的缓冲液中以引发反应，30℃下反应60min。接着加入含有Trichostatin A的显影剂以停止反应并产生荧光颜色。使用Envision进行20分钟的动力学测量，间隔为5分钟(Ex/Em＝360/460nm)。达到平台期后取终点读数进行分析。
3、实验结果
表1化合物对FLT3-ITD和HDAC1的抑制活性
如表1所示，所有测试化合物对FLT3、HDAC均有抑制作用，对FLT3、HDAC的IC50值均达到纳摩尔级别，综合活性均优于现有单靶点抑制剂的生物活性。其中，化合物I-14、I-20～I-22、I-24～I-26、I-28～I-39对FLT3、HDAC的抑制活性较为突出，IC50值在十纳摩尔浓度级别；化合物I-28的抑制活性最优，IC50值低于1nM。说明本发明的化合物在分子水平生物活性优异，具有开发为FLT3、HDAC抑制剂的潜质。
实施例41：体外抗肿瘤活性测试(对MV4-11细胞株的抑制活性)
1、实验材料
RPMI 1640培养基，96孔细胞培养板，胎牛血清，EnoGeneCellTM Counting Kit-8(CCK-8)细胞活力检测试剂盒，ChemBase CBS-CJ-1FD超净工作台，二氧化碳培养箱，Vi-Cell XR细胞计数仪，Envision2104读板仪。
2、实验方法
收集处于指数生长期的细胞并用Vi-Cell XR细胞计数仪进行活细胞计数。用各细胞相应培养基调整细胞悬液浓度。每孔加90μL细胞悬液于96孔细胞培养板，最终细胞浓度为7000细胞/孔。以DMSO溶解各供试化合物为10mM储存液。然后分别用培养基稀释至10倍溶液，各2复孔。每株细胞每孔分别加入10μL相应的10倍溶液，最终药物浓度为1μM，DMSO终浓度分别为0.01％。置于37℃/5％CO2孵箱中培养72h。药物处理72h后，按照Celltiter-GloATP荧光活性检测方法(CTG法)操作说明，每孔加入50μL(1/2培养体积)预先融化并平衡到室温的CTG溶液，用微孔板震荡器混匀2min，于室温放置10min后用Envision 2104读板仪测定荧光信号值，计算IC50。
3、实验结果
表2化合物对MV4-11细胞株的抑制率(5μmol/L)
如表2所示，所有测试化合物在体外对MV4-11细胞株均有抑制作用，其中化合物I-1、I-6、I-10～I-12、I-14～I-18、I-24～I-39对MV4-11细胞株的抑制率均达到80％以上。说明本发明的化合物在细胞水平生物活性优异，综合上述分子水平活性，这些化合物具有开发为与FLT3、HDAC相关疾病药物的潜质。
Claims (7)
1.一种氧肟酸类化合物及其衍生物，其特征在于，具有式I的结构，所述衍生物为所述氧肟酸类化合物的药学上可接受的盐：
其中：
R为苯基；
R选被一个或两个R1取代，R1为氢、甲基、氟、氯或甲氧基；
X为苯基-丙-1-烯-3-基、苯基-丁-1-烯-4-基、苯基-戊-1-烯-5-基、苯基-己-1-烯-6-基、苯基-庚-1-烯-7-基、苯丙基、苯丁基、苯戊基、苯己基、苯庚基或2-7个碳原子的直链饱和烷基；
n等于1。
2.一种氧肟酸类化合物及其衍生物，其特征在于，为以下任一化合物：
N1-(5-(1-苄基-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N4-羟基对苯二甲酰胺(I-1)，
N1-(5-(1-苄基-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N4-羟基琥珀酰胺(I-2)，
N1-(5-(1-苄基-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N5-羟基戊二酰胺(I-3)，
N1-(5-(1-苄基-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N6-羟基己二胺(I-4)，
N1-(5-(1-苄基-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N7-羟基庚二酰胺(I-5)，
N1-(5-(1-苄基-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N8-羟基辛二酰胺(I-6)，
N1-(5-(1-苄基-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N9-羟基壬二酰胺(I-7)，
N1-羟基-N7-(5-(1-(吡啶-4-甲基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-庚二酰胺(I-8)，
N1-(5-(1-环戊基-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N7-羟基庚二酰胺(I-9)，
N1-羟基-N7-(5-(1-(噻吩-2-甲基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-庚二酰胺(I-10)，
N1-(5-(1-(2-氟苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N7-羟基庚二酰胺(I-11)，
N1-(5-(1-(3-氟苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N7-羟基庚二酰胺(I-12)，
N1-(5-(1-(4-氟苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N7-羟基庚二酰胺(I-13)，
N1-(5-(1-(2-氯苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N7-羟基庚二酰胺(I-14)，
N1-(5-(1-(3-氯苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N7-羟基庚二酰胺(I-15)，
N1-(5-(1-(4-氯苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N7-羟基庚二酰胺(I-16)，
N1-羟基-N7-(5-(1-(2-甲基苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-庚二酰胺(I-17)，
N1-羟基-N7-(5-(1-(2-甲氧基苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-庚二酰胺(I-18)，
N1-(5-(1-(3,5-二氟苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N7-羟基庚二酰胺(I-19)，
N1-(5-(1-(2,6-二氟苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N7-羟基庚二酰胺(I-20)，
N1-(5-(1-(2-氯-6-氟苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N7-羟基庚二酰胺(I-21)，
N1-(5-(1-(2-氯-3-氟苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N7-羟基庚二酰胺(I-22)，
N1-(5-(1-(2-氯-5-氟苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N7-羟基庚二酰胺(I-23)，
N1-(5-(1-(2,6-二氯苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N7-羟基庚二酰胺(I-24)，
N1-(5-(1-(2-氯-6-甲基苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N7-羟基庚二酰胺(I-25)，
N1-(5-(1-(2,6-二甲基苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N7-羟基庚二酰胺(I-26)，
N1-(5-(1-(2-氯-3-氟苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N8-羟基辛二酰胺(I-27)，
N1-(5-(1-(2,6-二氯苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N8-羟基辛二酰胺(I-28)，
N1-(5-(1-(2-氯-6-甲基苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-N8-羟基辛二酰胺(I-29)，
(E)-N-(5-(1-(2,6-二氯苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-4-(4-(羟基氨基)-4-氧代丁-1-烯-1-基)苯甲酰胺(I-30)，
(E)-N-(5-(1-(2,6-二氯苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-4-(5-(羟基氨基)-5-氧代戊-1-烯-1-基)苯甲酰胺(I-31)，
(E)-N-(5-(1-(2,6-二氯苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-4-(6-(羟基氨基)-6-氧代己-1-烯-1-基)苯甲酰胺(I-32)，
(E)-N-(5-(1-(2,6-二氯苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-4-(7-(羟基氨基)-7-氧代庚-1-烯-1-基)苯甲酰胺(I-33)，
(E)-N-(5-(1-(2,6-二氯苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-4-(8-(羟基氨基)-8-氧代辛-1-烯-1-基)苯甲酰胺(I-34)，
N-(5-(1-(2,6-二氯苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-4-(4-(羟基氨基)-4-氧丁基))苯甲酰胺(I-35)，
N-(5-(1-(2,6-二氯苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-4-(5-(羟基氨基)-5-氧代戊基))苯甲酰胺(I-36)，
N-(5-(1-(2,6-二氯苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-4-(6-(羟基氨基)-6-氧己基))苯甲酰胺(I-37)，
N-(5-(1-(2,6-二氯苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-4-(7-(羟基氨基)-7-氧代庚基))苯甲酰胺(I-38)，
N-(5-(1-(2,6-二氯苄基)-1H-苯并[d]咪唑-6-基)-1H-吡唑-3-基)-4-(8-(羟基氨基)-8-氧辛基))苯甲酰胺(I-39)。
3.根据权利要求1～2任一所述的氧肟酸类化合物及其衍生物，其特征在于，所述药学上可接受的盐为所述氧肟酸类化合物与酸形成的盐，所述酸为有机酸或无机酸；其中有机酸为甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、柠檬酸、苹果酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸、琥珀酸、富马酸、水杨酸、苯基乙酸或杏仁酸，无机酸为盐酸、氢溴酸、硫酸或磷酸。
4.一种权利要求1～3任一所述的氧肟酸类化合物及其衍生物的制备方法，其特征在于，所述制备方法为：
化合物1经氨基化反应得到化合物I；
其中，R、X、n的定义如权利要求1所述；
将相应的酸与以上方法制备所得的化合物I成盐，即得所述氧肟酸类化合物的药学上可接受的盐。
5.一种药物组合物，其特征在于，包含权利要求1～3任一所述的氧肟酸类化合物和/或其衍生物以及药学上可接受的载体。
6.一种权利要求1～3任一所述的氧肟酸类化合物及其衍生物在制备治疗和/或预防与FLT3或HDAC相关疾病药物中的应用。
7.根据权利要6所述的应用，其特征在于，所述FLT3或HDAC相关疾病为急性髓性白血病、急性早幼粒细胞白血病、急性淋巴性白血病、骨髓增生异常综合症、炎症性结肠炎或类风湿性关节炎。
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