CN1184208C - 取代的苯并咪唑及其制备和用途 - Google Patents
取代的苯并咪唑及其制备和用途 Download PDFInfo
- Publication number
- CN1184208C CN1184208C CNB998151130A CN99815113A CN1184208C CN 1184208 C CN1184208 C CN 1184208C CN B998151130 A CNB998151130 A CN B998151130A CN 99815113 A CN99815113 A CN 99815113A CN 1184208 C CN1184208 C CN 1184208C
- Authority
- CN
- China
- Prior art keywords
- benzimidazole
- carboxamide
- alkyl
- phenyl
- piperazine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Abstract
式Ia或Ib的化合物和它们的互变异构型、可能的对映异构与非对映异构型、它们的前体药物和可能的生理学上耐受的盐。式中各基团定义详见说明书。
Description
技术领域
本发明涉及新的苯并咪唑,它们的制备方法,及其作为酶聚(腺苷二磷酸-核糖)聚合酶即PARP(EC 2.4.2.30)的抑制剂用于制备药物的用途。
背景技术
人们已都知道聚(腺苷二磷酸-核糖)聚合酶(PARP)或聚(腺苷二磷酸-核糖)合成酶(PARS)是细胞核中的调节酶(K.Ikal et al.,J.Histochem.Cytochem.31(1983),1261-1264)。推断PARP扮演了修复DNA损伤的角色(M.S Satoh et al.,Nature 356(1992),356-358)。如果它被激活,DNA破损激活了催化腺苷二磷酸-核糖从NAD转移的酶PARP(S.Shaw,Adv.Radiat.Biol.11(1984),1-69)。从NAD中释放出烟酰胺。用其它酶消耗能量载体ATP将烟酰胺转换回NAD中。PARP过度激活会相应地导致ATP非生理机能上的高耗量,并导致极端情况下的细胞损伤和细胞死亡。
人们已知诸如过氧化阴离子、NO和过氧化氢的自由基能够导致细胞中的DNA损伤并因此激活PARP。许多病理生理学症状注意到了自由基的大量形成,且推断此种自由基的积聚导致或有助于观测到的细胞或器官的损伤。这些例如包括:象中风、心肌梗塞等器官局部出血的情况(C.Thiemermann et al.,Proc.Natl.Acad.Sci.USA 94(1997),679-683)或肾局部出血,也发生再灌注损伤,例如:心肌梗塞的后遗症(见上文:C.Thiemermann et al.)。酶PARP的抑制作用可相应地具有预防意义或至少部分减少此种损伤。PARP抑制剂因此可构成一种治疗许多病症的新的治疗原理。
因为已注意到具有更高的对抗肿瘤组织作用的潜能,酶PARP可影响DNA损伤的修复,并能治疗癌症(G.Chen et al.Cancer Chemo.Pharmacol.22(1988),303)。
癌症的无限制例子是白血病、恶性胶质瘤、淋巴瘤、黑瘤、乳癌和宫颈癌。
也发现了PARP抑制剂能具有免疫抑制效果(D.Weltin et al.Int.J.Immunopharmacol.17(1995),265-271)。
还发现了PARP涉及免疫学疾病和病症,在免疫系统中扮演着重要的角色,例如:类风湿性关节炎和脓毒性中风,且PARP抑制剂在疾病过程具有有益的效果(H.Kroger et al.Inflammation 20(1996),203-215;W.Ehrlich et al.Rheumatol.Int.15(1995),171-172;C.Szabo et al.,Proc.Natl.Acad.Sci.USA 95(1998),3867-3872;S.Cuzzocrea et al.Eur.J.Pharmacol.342(1998),67-76)。
出于本发明的目的,PARP也被理解为意味着上述PARP酶的同功酶。
此外,PARP抑制剂3-氨基苯甲酰胺展示了对循环性休克的预防效果(S.Cuzzocrea et al.,Br.J.Pharmacol.121(1997),1065-1074)。
PARP也涉及糖尿病(V.Burkhart et al.,Nature Medicine(1999),5314-19)。
苯并咪唑已广泛描述。
在酰胺基上携带取代的烷基链的2-苯基苯并咪唑-4-基酰胺的合成,且据说具有细胞毒素效果,被提及于J.Med.Chem.33(1990),814-819。WO 97/04771提到4-苯并咪唑酰胺抑制PARS。特别是,2-位携带苯基的衍生物,在那里苯基环可另外被象硝基、甲氧基或CF3等简单基团取代,这些被作为有效成分进行描述。虽然这些物质展示了酶PARP良好的抑制作用,但其描述的衍生物具有很少或没有在水溶液中的可溶性的缺点且因此不能作为水溶液来应用。
在2-位携带哌啶环的苯并咪唑也已被描述。所以在J.Het.Chem.24(1987),31中,衍生物被制备作为抗组胺药。在J.Het.Chem.32(1995),707和J.Het.Chem.26(1989),541中,描述了具有相同用途的类似化合物。2-哌啶苯并咪唑在EP818454中作为抗组胺药被提及,且在WO9736554中作为抗肝炎剂被提及。衍生物同样在CA80,146143,Fr.2103639和Khim.Geterotsikl.Soedin1(1974),104中被提及。
然而,苯并咪唑片段中的苯芳基上的取代基的重要性还未被研究。而且,那些在2-位携带4-到8-元杂环、特别是哌啶环的苯并咪唑迄今为止还未被描述作为PARP抑制剂。
本申请描述了令人惊讶的发现,将羧酰胺基团引至苯并咪唑芳基得到作为新奇、高效PARP抑制剂的苯并咪唑,前提条件是在2-位上用饱和杂环取代。
在许多治疗中,如中风的治疗,活性的化合物作为静脉内注射的注射溶液来应用。基本上必要的是在此PARP抑制剂中,其在生理pH值(即ph 5-8)下具有充足的水溶解性,因此可制备为注射溶液。然而,许多描述的PARP抑制剂,特别是更有效的PARP抑制剂,在该pH值下具有很少或非水溶解性的缺点,并因此不适合于静脉内应用。此活性化合物能只与想要给予水溶解性的赋形剂结合应用(参见WO 97/04771)。例如聚乙二醇和二甲亚砜的这些赋形剂经常引起副作用或甚至不能容许。迄今为止,具有充足的水溶解性的高效的PARP抑制剂尚无描述。
令人惊讶的发现,咪唑环上携带哌啶环的苯并咪唑是高效的抑制剂,并且因为结合有脂肪胺基,可与酸结合成盐,使得水溶解性大大改善,因此可制备注射溶液。
发明内容
本发明描述了新的式I的苯并咪唑衍生物,其优点超过前述化合物且构成有效的PARP抑制剂并同时具有充分的水溶性。当引用式I化合物时,它们被理解为式Ia和Ib的化合物。
本发明涉及式I的取代的苯并咪唑:
其中
R1是氢或者是支链或直链的C1-C6-烷基,其中烷基的一个碳原子可以进一步携带OR5(其中R5是氢或C1-C4-烷基),或者链中的一个碳原子也可以携带=O基团或基团NR8R9,其中彼此独立的R8和R9各自是氢或C1-C4-烷基,NR8R9一起可以是具有4至8个环原子的环胺,其中R8和R9中的碳链或由NR8R9形成的环可以进一步携带基团R6,R6可以具有与R2相同的含义而独立于R2,
R4是氢、支链或直链的C1-C6-烷基、氯、溴、氟、硝基、氰基、NR8R9、NH-CO-R10或OR8,其中彼此独立的R8和R9各自是氢或C1-C4-烷基,NR8R9一起可以是具有4至8个环原子的环胺,其中该环可以进一步携带基团(支链或直链的C1-C6-烷基、C3-C7-环烷基-C1-C4-烷基、CO-R41、COOR41或苯基),R10可以是氢、C1-C4-烷基或苯基,R41可以具有与R21相同的含义,
A是饱和的或单不饱和的4-到8-元杂环,其中含有一或两个氮原子,另外还结合氧或硫原子也是可能的,该氧或硫原子被R2和R3取代,其中
R2是氢、支链或直链的C1-C8-烷基,它可以进一步被R23取代,该链的碳原子可以携带=O基团、C3-C7-环烷基-C1-C4-烷基、-CO-(NH)0、1-R21、COOR21或苯基,其中R21是氢、支链或直链的C1-C6-烷基、C3-C7-环烷基-C1-C4-烷基、苯基-C1-C4-烷基、C3-C7-环烷基或苯基,每个基团可以进一步携带(CH2)0-2-R23,各苯基环又可以进一步被1、2或3个下列基团取代:氯、氟、溴、碘、支链和直链的C1-C4-烷基、硝基、CF3、氰基、-(CH2)0-2-NR24R25、NH-CO-R10、OR10、COOR10、SO2-C1-C4-烷基、SO2Ph、SO2NH、NHSO2-C1-C4-烷基、NHSO2Ph和CF3,其中彼此独立的R24和R25各自是氢或C1-C4-烷基,NR24R25一起可以是具有4至8个环原子的环胺,其中该环可以进一步携带支链或直链的C1-C6-烷基、C3-C7-环烷基-C1-C4-烷基、CO-R22、COOR22(其中R22是氢、支链或直链的C1-C6-烷基、C3-C7-环烷基-C1-C4-烷基、苯基-C1-C4-烷基、C3-C7-环烷基或苯基)或苯基,R10是氢、C1-C4-烷基或苯基,
R23是NR26R27,其中R26和R27各自是氢、C1-C6烷基、C0-C4-烷基苯基,其中苯基环可以进一步被至多3个基团Cl、F、Br、I、C1-C4-烷基、CF3、CN、SO2-C1-C4-烷基、SO2-苯基、NO2、NH2、NHCO-C1-C4-烷基、NHCO-苯基、OH、O-C1-C4-烷基、O-C1-C4-烷基苯基取代,NR26R27也可以是具有3至8个环原子的环胺,另外还可以存在其它杂原子,例如O、N和S,该环可以进一步被基团R28取代,其中R28可以是C1-C4-烷基和C1-C4-烷基苯基,
R3是氢、支链或直链的C1-C6-烷基、C3-C7-环烷基-C1-C4-烷基,它是未取代的或者被C4-C6-烷基或C3-C7-环烷基取代,后者是未取代的或者被C1-C6-烷基取代,其中该基团的一个碳原子可以进一步携带苯基环,该苯基环又可以被1、2或3个下列基团取代:氯、氟、溴、碘、支链或直链的C1-C4-烷基、硝基、CF3、氰基、-(CH2)0-2-NR32R33、NH-CO-R10、OR10、COOR10、SO2-C1-C4-烷基、SO2Ph、CH3、SO2NH、NHSO2-C1-C4-烷基、NHSO2Ph和CF3,其中彼此独立的R32和R33各自是氢或C1-C4-烷基,NR32R33一起可以是具有4至8个环原子的环胺,其中该环可以进一步携带支链或直链的C1-C6-烷基、C3-C7-环烷基-C1-C4-烷基、CO-R31、COOR31或苯基,R10是氢、C1-C4-烷基或苯基,R31可以具有与R21相同的含义,
和它们的互变异构型、可能的对映异构与非对映异构型、它们的前体药物和可能的生理学上耐受的盐。
优选的式I化合物中,R1是氢。
优选的式I化合物中,R2是氢。
优选的式I化合物中,R4是氢。
优选的式I化合物中,R3与A的氮键合。
优选的式I化合物中,R3是氢、C1-C6-烷基、苄基或苯乙基。
特别优选的式I化合物中,R1、R2和R4各自是氢,A是键合在苯并咪唑4-位上的哌啶,R3是氢、C1-C6-烷基、苄基或苯乙基,并且键合在哌啶环的1-位上。
R5到R10的各自含义彼此独立地同R1到R4。
NR8R9、NR24R25和NR32R33作为环胺的优选含义是哌啶、吡咯烷、哌嗪和高哌嗪。在哌嗪和高哌嗪的情况下,该环可以优选地进一步携带支链或直链的C1-C6-烷基、C3-C7-环烷基-C1-C4-烷基、CO-R7(其中对于NR8R9,R7=R41或R21,对于NR24R25,R7=R22对于NR32R33,R7=R31)或苯基。
A的优选含义是哌啶、吡咯烷、哌嗪、吗啉或高哌嗪。
特别优选的式I化合物中,A是哌嗪或哌啶。
式I化合物可以使用外消旋物、对映异构纯的化合物或非对映异构体的形态。如果要求对映异构纯的化合物,例如可以通过用式I化合物或它们的用在合适的旋光活性碱或酸中的中间体进行外消旋物的经典拆分而获得这些。
饱和或单不饱和的环状结构A可以是顺式异构体、反式异构体或其混合物。
本发明也涉及这样的化合物,它们是式I化合物的内消旋体或互变异构体。
本发明进一步涉及化合物I的生理学上耐受的盐,它可以通过化合物I与合适的酸或碱的反应而得到。合适的酸和碱例如列在Fortschritte der Arzneimittelforschung,1966,BirkhauserVerlag,Vol.10,pages 224-285上。这些例如包括盐酸、柠檬酸、酒石酸、乳酸、磷酸、甲磺酸、乙酸、甲酸、马来酸、富马酸等,和氢氧化钠、氢氧化锂、氢氧化钾和Tris。
前体药物被理解为意味着那些体内代谢得到式I化合物的化合物。典型的前体药物是磷酸酯、氨基酸的氨基甲酸酯、酯及其它。
新颖的苯并咪唑I的制备可以通过各种途径进行,它们显示在合成流程1中。
合成流程1
通过醛V和苯二胺VI的缩合作用获得苯并咪唑I或VII,该步骤优选的是在如乙醇或二甲基甲酰胺的极性溶剂中,添加酸例如乙酸,在升温的条件下通常为80-120℃下进行。加入例如作为水溶液添加的铜(II)盐的弱氧化剂对反应是有益的。
合成流程2
如果在苯二胺VI中R是NH2,新的化合物I是在缩合作用中直接形成。否则,如果R是O-烷基,这些酯能与氨水反应,如果需要在升温和超大气压下,得到酰胺I。此外,酯VII在优选为80-130℃的升温条件下,在例如丁醇、乙醇或二甲基甲酰胺的极性溶剂中与肼反应,得到酰肼VII(R=NHNH2),它随后能在回流下在醇中用例如阮内镍的还原条件下被还原,得到酰胺I。
式I中的苯并咪唑基团(R1=H)上的基团R1在常规烷基化条件下引入。苯并咪唑I用R1-L烷基化,其中L是离去基团,用碱在25-150℃温度下,但主要是在例如60-130℃的升温下,获得其中R1≠氢的新产物I。在例如二甲基甲酰胺、二甲基亚砜、醇(例如乙醇)、酮(例如甲基乙基酮或丙酮)、脂肪醚(例如四氢呋喃)和碳氢化合物(例如甲苯)及其混合物的溶剂中,进行该步骤。适用的碱例如是:如乙醇钠和叔丁醇钾的醇化物、如碳酸钾的碳酸盐、如氢化钠的氢化物、和如氢氧化钠和氢氧化钾的氢氧化物。
也可加人催化量的如18-冠-6的各种冠醚。也可使用相转移条件(R.C.Larock,Comprehensive Organic Transformations,1989,page 445et seq.的方法)。使用的离去基团L可以为如溴、氯或碘的卤素,或为甲苯磺酰基或甲磺酰基。
合成流程3
此外,合成流程1中的醛V也可使用如IX(参见合成流程2)的酸或如XIII(参见合成流程3)的腈来代替醛。这些衍生物的制备与取代的醛V的制备相类似。从IX开始,进行得到VII的缩合分为两个阶段。首先,酸IX与苯胺反应,通过肽键状偶联得到酰胺XI。这里使用的是已知的常规条件,例如,在Houben-Weyl,Methoden der OrganischenChemie,4th Edition,E5,Chapter V,或C.R.Larock,Comprehensive Organic Transformations,VCH Publisher,1989,page 972et seq中。随后在例如60-180℃的升温下环化为苯并咪唑,如二甲基甲酰胺的溶剂可有可无,须加入如乙酸这样的酸或直接在乙酸中进行反应。
苯二胺VI与腈XIII的反应同样在常规条件下进行。该反应可能使用如二甲基甲酰胺的溶剂,并在如60-200℃的升温下添加酸。也可能用象描述在J.Amer.Chem.Soc.(1957),427和J.Org.Chem.(1987),1017中的常规方法从腈制备酰胺。
本发明包括的取代的苯并咪唑I是酶聚(ADP-核糖)聚合酶或PARP的抑制剂(EC2.4.2.30)。
取代的苯并咪唑I的抑制效果是由在文献中已知的酶试验决定的,Ki值表示活性的范围。用此方法测量苯并咪唑I作为酶聚(ADP-核糖)聚合酶或PARP的抑制剂(EC2.4.2.30)的效果。
式I的取代的苯并咪唑是酶聚(ADP-核糖)聚合酶或PARP的抑制剂,或当其也提及时,也是酶聚(ADP-核糖)合成酶或PARS的抑制剂,并能因此用于病症的治疗和预防,其与增加这些酶的活性是相关联的。
人们期望式I化合物能用于制备下列局部出血伤害的治疗药物,和各种器官局部出血的预防药物。
现有的式I苯并咪唑然后能用于发生于局部出血、创伤(颅脑创伤)、大出血、蛛网膜下出血和中风后的神经变性症的治疗和预防,和用于如多种梗塞性痴呆、早老性痴呆、杭廷顿氏舞蹈病的神经变性症的治疗和预防,和用于癫痫症、例如小病和强直阵挛性发作的特别广义癫痫发作、如颞叶部分癫痫发作、和络合物部分发作的治疗和预防,且此外用于下列心肌局部出血的心脏损害和下列肾脏局部出血的肾损害的治疗和预防,例如,严重肾功能不全、严重肾衰竭、药物治疗引起的损害如环孢菌素治疗期间或肾移植期间或术后产生的损害。此外,式I化合物能用于急性心梗和对其药物治疗(例如:TPA、reteplase或链激酶或者用激光或Rotablator的物理疗法)期间和见效后损害的治疗和预防,并能用于小梗塞如更换心脏瓣膜、切除动脉瘤和心脏移植期间或术后损害的治疗和预防。现有的苯并咪唑I也能用于冠状动脉狭窄的血管再形成的治疗,例如在PCTA和旁路手术中;也能用于外周动脉狭窄的血管再形成的治疗,例如腿动脉。此外,苯并咪唑I可用于肿瘤及其转移的化疗和治疗炎症和风湿症,例如类风湿性关节炎。另外,式I化合物能用于治疗糖尿病或用于治疗败血病和多器官衰竭,如脓毒性休克和成人呼吸窘迫综合征(ARDS,肺休克)。
除了常规药物赋形剂之外,该新药制剂包括了治疗有效量的化合物I。
局部表面应用,例如以粉剂、膏剂和喷雾的形式,该活性化合物以常规浓度存在。通常,该活性化合物的存在量按重量为0.001%至1%,优选为从0.001%至0.1%。
在内用的情况下,该制剂可以单剂量给药。按体重从0.1至100mg/kg是给药的单剂量。根据病症的类型和程度,制剂能够每天一次或多次量给药。
按应用所要求的方法,该新药制剂包括加入活性化合物中的常规载体和稀释液。药物的赋形剂如乙醇、异丙醇、乙氧基化蓖麻油、乙氧基氢化蓖麻油、聚丙烯酸、聚乙二醇、聚乙二醇硬脂酸酯、乙氧基化脂肪醇、液体石蜡、凡士林和羊毛脂,可用于局部表面应用。如乳糖、丙二醇、乙醇、淀粉、滑石和聚烯吡酮等适合于内用。
还可使用抗氧化剂如生育酚和叔丁对甲氧酚,和2,6-二叔丁基对甲酚、味道改善添加剂、稳定剂、乳化剂和润滑剂。
除了活性化合物之外,制剂中包含的物质和用于药物制剂的物质在毒理学上是安全的,并与各自的活性化合物是相容的。该药物制剂的制备是以常规方式进行的,例如将活性化合物与其它常规载体和稀释剂混合。
该药物制剂的给药可以多种方法进行,例如:口服,非肠道如静脉输注、皮下、腹膜内和局部。因此可以是配制成片剂、乳剂、输液和注射液、糊剂、软膏、凝胶、霜剂、洗剂、粉剂和喷雾剂。
除了在实施例中所述的物质外,下列化合物是特别优选且能够根据已述的制备方法合成:
1. 2-(N-(O-叔-丁氧羰基)哌啶-4-基)苯并咪唑-4-甲酰胺
2. 2-(N-甲基哌啶-4-基)苯并咪唑-4-甲酰胺
3. 2-(N-异丙基哌啶-4-基)苯并咪唑-4-甲酰胺
4. 2-(N-环己基哌啶-4-基)苯并咪唑-4-甲酰胺
5. 2-(N-(反式-4-丙基环己-1-基)哌啶-4-基)苯并咪唑-4-甲酰胺
6. 2-(N-苄基哌啶-4-基)苯并咪唑-4-甲酰胺
7. 2-(N-(2-苯基)乙-1-基)哌啶-4-基)苯并咪唑-4-甲酰胺
8. 2-(N-(2(4-氟苯基)乙-1-基)哌啶-4-基)苯并咪唑-4-甲酰胺
9. 2-(N-(2(4-氯苯基)乙-1-基)哌啶-4-基)苯并咪唑-4-甲酰胺
10. 2-(N-(2(4-溴苯基)乙-1-基)哌啶-4-基)苯并咪唑-4-甲酰胺
11. 2-(N-(2(4-碘苯基)乙-1-基)哌啶-4-基)苯并咪唑-4-甲酰胺
12. 2-(N-(2(4-硝基苯基)乙-1-基)哌啶-4-基)苯并咪唑-4-甲酰胺
13. 2-(N-(2(4-氰基苯基)乙-1-基)哌啶-4-基)苯并咪唑-4-甲酰胺
14. 2-(N-(2(4-(三氟甲基)苯基)乙-1-基)哌啶-4-基)苯并咪唑-4-甲酰胺
15. 2-(N-(2(4-甲基苯基)乙-1-基)哌啶-4-基)苯并咪唑-4-甲酰胺
16. 2-(N-(2(4-羟基苯基)乙-1-基)哌啶-4-基)苯并咪唑-4-甲酰胺
17. 2-(N-(2(4-甲氧基苯基)乙-1-基)哌啶-4-基)苯并咪唑-4-甲酰胺
18. 2-(N-(2(4-(N’,N’-二甲氨基)苯基)乙-1-基)哌啶-4-基)苯并咪唑-4-甲酰胺
19. 2-(N-(2(4-(N’-乙酰氨基)苯基)乙-1-基)哌啶-4-基)苯并咪唑-4-甲酰胺
20. 2-(N-(2(4-(N’-苯磺酰氨基)苯基)乙-1-基)哌啶-4-基)苯并咪唑-4-甲酰胺
21. 2-(N-(2(4-(苯磺酰基)苯基)乙-1-基)哌啶-4-基)苯并咪唑-4-甲酰胺
22. 2-(N-(2(4-(甲氧羰基)苯基)乙-1-基)哌啶-4-基)苯并咪唑-4-甲酰胺
23. 2-(N-乙酰哌啶-3-基)苯并咪唑-4-甲酰胺
24. 2-(N-丙基哌啶-3-基)苯并咪唑-4-甲酰胺
25. 2-(N-异丙基哌啶-3-基)苯并咪唑-4-甲酰胺
26. 2-(N-环己基哌啶-3-基)苯并咪唑-4-甲酰胺
27. 2-(N-(反式-4-丙基环己-1-基)哌啶-3-基)苯并咪唑-4-甲酰胺
28. 2-(N-(2-苯基)乙-1-基)哌啶-3-基)苯并咪唑-4-甲酰胺
29. 2-(N-(2(4-氯苯基)乙-1-基)哌啶-3-基)苯并咪唑-4-甲酰胺
30. 2-吡咯烷-3-基苯并咪唑-4-甲酰胺
31. 2-(N-乙酰吡咯烷-3-基)苯并咪唑-4-甲酰胺
32. 2-(N-(O-叔-丁氧羰基)吡咯烷-3-基)苯并咪唑-4-甲酰胺
33. 2-(N-丙基吡咯烷-3-基)苯并咪唑-4-甲酰胺
34. 2-(N-异丙基吡咯烷-3-基)苯并咪唑-4-甲酰胺
35. 2-(N-环己基吡咯烷-3-基)苯并咪唑-4-甲酰胺
36. 2-(N-(反式-4-丙基环己基-1-基)吡咯烷-3-基)苯并咪唑-4-甲酰胺
37. 2-(N-苄基吡咯烷-3-基)苯并咪唑-4-甲酰胺
38. 2-(N-(2-苯基)乙-1-基)吡咯烷-3-基)苯并咪唑-4-甲酰胺
39. 2-(N-(2(4-氯苯基)乙-1-基)吡咯烷-3-基)苯并咪唑-4-甲酰胺
40. 2-(N-(2(4-硝基苯基)乙-1-基)吡咯烷-3-基)苯并咪唑-4-甲酰胺
41. 2-(N-(2(4-氰基苯基)乙-1-基)吡咯烷-3-基)苯并咪唑-4-甲酰胺
42. 2-(N-(2(4-(三氟甲基)苯基)乙-1-基)吡咯烷-3-基)苯并咪唑-4-甲酰胺
43. 2-(N-(2(4-甲基苯基)乙-1-基)吡咯烷-3-基)苯并咪唑-4-甲酰胺
44. 2-(N-(2(4-羟基苯基)乙-1-基)吡咯烷-3-基)苯并咪唑-4-甲酰胺
45. 2-(N-(2(4-甲氧基苯基)乙-1-基)吡咯烷-3-基)苯并咪唑-4-甲酰胺
46. 2-(N-(2(4-(N’,N’-二甲氨基)苯基)乙-1-基)吡咯烷-3-基)苯并咪唑-4-甲酰胺
47. 2-(N-(2(4-(N’-乙酰氨基)苯基)乙-1-基)吡咯烷-3-基)苯并咪唑-4-甲酰胺
48. 2-(N-(2(4-(N’-苯磺酰氨基)苯基)乙-1-基)吡咯烷-3-基)苯并咪唑-4-甲酰胺
49. 2-(N-(2(4-(苯磺酰)苯基)乙-1-基)吡咯烷-3-基)苯并咪唑-4-甲酰胺
50. 2-(N-(2(4-(甲氧羰基)苯基)乙-1-基)吡咯烷-3-基)苯并咪唑-4-甲酰胺
51. 2-吡咯烷-2-基苯并咪唑-4-甲酰胺
52. 2-(N-乙酰哌嗪-4-基)苯并咪唑-4-甲酰胺
53. 2-(N-(O-叔-丁氧羰基)哌嗪-4-基)苯并咪唑-4-甲酰胺
54. 2-(N-甲基哌嗪-4-基)苯并咪唑-4-甲酰胺
55. 2-(N-丙基哌嗪-4-基)苯并咪唑-4-甲酰胺
56. 2-(N-异丙基哌嗪-4-基)苯并咪唑-4-甲酰胺
57. 2-(N-环己基哌嗪-4-基)苯并咪唑-4-甲酰胺
58. 2-(N-(反式-4-丙基环己基-1-基)哌嗪-4-基)苯并咪唑-4-甲酰胺
59. 2-(N-苄基哌嗪-4-基)苯并咪唑-4-甲酰胺
60. 2-(N-(2-苯基)乙-1-基)哌嗪-4-基)苯并咪唑-4-甲酰胺
61. 2-(N-(2(4-氟苯基)乙-1-基)哌嗪-4-基)苯并咪唑-4-甲酰胺
62. 2-(N-(2(4-氯苯基)乙-1-基)哌嗪-4-基)苯并咪唑-4-甲酰胺
63. 2-(N-(2(4-溴苯基)乙-1-基)哌嗪-4-基)苯并咪唑-4-甲酰胺
64. 2-(N-(2(4-碘苯基)乙-1-基)哌嗪-4-基)苯并咪唑-4-甲酰胺
65. 2-(N-(2(4-硝基苯基)乙-1-基)哌嗪-4-基)苯并咪唑-4-甲酰胺
66. 2-(N-(2(4-氰基苯基)乙-1-基)哌嗪-4-基)苯并咪唑-4-甲酰胺
67. 2-(N-(2(4-(三氟甲基)苯基)乙-1-基)哌嗪-4-基)苯并咪唑-4-甲酰胺
68. 2-(N-(2(4-甲基苯基)乙-1-基)哌嗪-4-基)苯并咪唑-4-甲酰胺
69. 2-(N-(2(4-羟基苯基)乙-1-基)哌嗪-4-基)苯并咪唑-4-甲酰胺
70. 2-(N-(2(4-甲氧基苯基)乙-1-基)哌嗪-4-基)苯并咪唑-4-甲酰胺
71. 2-(N-(2(4-(N’,N’-二甲氨基)苯基)乙-1-基)哌嗪-4-基)苯并咪唑-4-甲酰胺
72. 2-(N-(2(4-(N’-乙酰氨基)苯基)乙-1-基)哌嗪-4-基)苯并咪唑-4-甲酰胺
73. 2-(N-(2(4-(N’-苯磺酰氨基)苯基)乙-1-基)哌嗪-4-基)苯并咪唑-4-甲酰胺
74. 2-(N-(2(4-(苯磺酰)苯基)乙-1-基)哌嗪-4-基)苯并咪唑-4-甲酰胺
75. 2-(N-(2(4-(甲氧羰基)苯基)乙-1-基)哌嗪-4-基)苯并咪唑-4-甲酰胺
76. 2-高哌嗪-4-基苯并咪唑-4-甲酰胺
77. 2-(N-乙酰高哌嗪-4-基)苯并咪唑-4-甲酰胺
78. 2-(N-(O-叔-丁氧羰基)高哌嗪-4-基)苯并咪唑-4-甲酰胺
79. 2-(N-甲基高哌嗪-4-基)苯并咪唑-4-甲酰胺
80. 2-(N-丙基高哌嗪-4-基)苯并咪唑-4-甲酰胺
81. 2-(N-异丙基高哌嗪-4-基)苯并咪唑-4-甲酰胺
82. 2-(N-环己基高哌嗪-4-基)苯并咪唑-4-甲酰胺
83. 2-(N-(反式-4-丙基环己基-1-基)高哌嗪-4-基)苯并咪唑-4-甲酰胺
84. 2-(N-苄基高哌嗪-4-基)苯并咪唑-4-甲酰胺
85. 2-(N-(2-苯基)乙-1-基)高哌嗪-4-基)苯并咪唑-4-甲酰胺
86. 2-(N-(2(4-氟苯基)乙-1-基)高哌嗪-4-基)苯并咪唑-4-甲酰胺
87. 2-(N-(2(4-氯苯基)乙-1-基)高哌嗪-4-基)苯并咪唑-4-甲酰胺
88. 2-(N-(2(4-溴苯基)乙-1-基)高哌嗪-4-基)苯并咪唑-4-甲酰胺
89. 2-(N-(2(4-碘苯基)乙-1-基)高哌嗪-4-基)苯并咪唑-4-甲酰胺
90. 2-(N-(2(4-硝基苯基)乙-1-基)高哌嗪-4-基)苯并咪唑-4-甲酰胺
91. 2-(N-(2(4-氰基苯基)乙-1-基)高哌嗪-4-基)苯并咪唑-4-甲酰胺
92. 2-(N-(2(4-(三氟甲基)苯基)乙-1-基)高哌嗪-4-基)苯并咪唑-4-甲酰胺
93. 2-(N-(2(4-甲基苯基)乙-1-基)高哌嗪-4-基)苯并咪唑-4-甲酰胺
94. 2-(N-(2(4-羟基苯基)乙-1-基)高哌嗪-4-基)苯并咪唑-4-甲酰胺
95. 2-(N-(2(4-甲氧基苯基)乙-1-基)高哌嗪-4-基)苯并咪唑-4-甲酰胺
96. 2-(N-(2(4-(N’,N’-二甲氨基)苯基)乙-1-基)高哌嗪-4-基)苯并咪唑-4-甲酰胺
97. 2-(N-(2(4-(N’-乙酰氨基)苯基)乙-1-基)高哌嗪-4-基)苯并咪唑-4-甲酰胺
98. 2-(N-(2(4-(N’-苯磺酰氨基)苯基)乙-1-基)高哌嗪-4-基)苯并咪唑-4-甲酰胺
99. 2-(N-(2(4-(苯磺酰)苯基)乙-1-基)高哌嗪-4-基)苯并咪唑-4-甲酰胺
100. 2-(N-(2(4-(甲氧羰基)苯基)乙-1-基)高哌嗪-4-基)苯并咪唑-4-甲酰胺
101. 1-甲基-2-(哌啶-4-基)苯并咪唑-4-甲酰胺
102. 2-(N-(O-叔-丁氧羰基)哌啶-4-基)-1-甲基苯并咪唑-4-甲酰胺
103. 1-甲基-2-(N-甲基哌啶-4-基)苯并咪唑-4-甲酰胺
104. 1-甲基-2-(N-异丙基哌啶-4-基)苯并咪唑-4-甲酰胺
105. 2-(N-苄基哌啶-4-基)-1-甲基苯并咪唑-4-甲酰胺
106. 1-甲基-2-(N-(2-苯基)乙-1-基)哌啶-4-基)苯并咪唑-4-甲酰胺
107. 2-(N-(2(4-氯苯基)乙-1-基)哌啶-4-基)-1-甲基苯并咪唑-4-甲酰胺
108. 2-(N-乙酰哌啶-3-基)-1-甲基苯并咪唑-4-甲酰胺
109. 1-甲基-2-(吡咯烷-3-基)苯并咪唑-4-甲酰胺
110. 2-(N-乙酰吡咯烷-3-基)-1-甲基苯并咪唑-4-甲酰胺
111. 2-(N-(O-叔-丁氧羰基)吡咯烷-3-基)-1-甲基苯并咪唑-4-甲酰胺
112. 1-甲基-2-(N-甲基吡咯烷-3-基)苯并咪唑-4-甲酰胺
113. 1-甲基-2-(N-丙基吡咯烷-3-基)苯并咪唑-4-甲酰胺
114. 1-甲基-2-(N-异丙基吡咯烷-3-基)苯并咪唑-4-甲酰胺
115. 2-(N-苄基吡咯烷-3-基)-1-甲基苯并咪唑-4-甲酰胺
116. 1-甲基-2-(N-(2-苯基)乙-1-基)吡咯烷-3-基)苯并咪唑-4-甲酰胺
117. 2-(N-(2(4-氯苯基)乙-1-基)吡咯烷-3-基)-1-甲基苯并咪唑-4-甲酰胺
118. 1-甲基-2-(吡咯烷-2-基)苯并咪唑-4-甲酰胺
119. 2-(N-乙酰吡咯烷-2-基)-1-甲基苯并咪唑-4-甲酰胺
120. 1-甲基-2-哌嗪-4-基苯并咪唑-4-甲酰胺
121. 2-(N-乙酰哌嗪-4-基)-1-甲基苯并咪唑-4-甲酰胺
122. 2-(N-(O-叔-丁氧羰基)哌嗪-4-基)-1-甲基苯并咪唑-4-甲酰胺
123. 1-甲基-2-(N-甲基哌嗪-4-基)苯并咪唑-4-甲酰胺
124. 1-甲基-2-(N-丙基哌嗪-4-基)苯并咪唑-4-甲酰胺
125. 1-甲基-2-(N-异丙基哌嗪-4-基)苯并咪唑-4-甲酰胺
126. 2-(N-苄基哌嗪-4-基)-1-甲基苯并咪唑-4-甲酰胺
127. 1-甲基-2-(N-(2-苯基)乙-1-基)哌嗪-4-基)苯并咪唑-4-甲酰胺
128. 2-(N-(2(4-氯苯基)乙-1-基)哌嗪-4-基)-1-甲基苯并咪唑-4-甲酰胺
129. 2-(N-高哌嗪-3-基)-1-甲基苯并咪唑-4-甲酰胺
130. 2-(N-乙酰高哌嗪-4-基)-1-甲基苯并咪唑-4-甲酰胺
131. 2-(N-(O-叔-丁氧羰基)高哌嗪-4-基)-1-甲基苯并咪唑-4-甲酰胺
132. 1-甲基-2-(N-甲基高哌嗪-4-基)苯并咪唑-4-甲酰胺
133. 1-甲基-2-(N-丙基高哌嗪-4-基)苯并咪唑-4-甲酰胺
134. 1-甲基-2-(N-异丙基高哌嗪-4-基)苯并咪唑-4-甲酰胺
135. 2-(N-苄基高哌嗪-4-基)-1-甲基苯并咪唑-4-甲酰胺
136. 1-甲基-2-(N-(2-苯基)乙-1-基)高哌嗪-4-基)苯并咪唑-4-甲酰胺
137. 2-(N-(2(4-氯苯基)乙-1-基)高哌嗪-4-基)-1-甲基苯并咪唑-4-甲酰胺
138. 1-乙基-2-(哌啶-4-基)苯并咪唑-4-甲酰胺
139. 2-(哌啶-4-基)-1-异丙基苯并咪唑-4-甲酰胺
140. 1-(2-(羟基)乙-1-基)-2-(哌啶-4-基)苯并咪唑-4-甲酰胺
141. 1-(2-(甲氧基)乙-1-基)-2-(哌啶-4-基)苯并咪唑-4-甲酰胺
142. 1-(2-(氨基)乙-1-基)-2-(哌啶-4-基)苯并咪唑-4-甲酰胺
143. 1-(2-(N,N-二甲氨基)乙-1-基)-2-(哌啶-4-基)苯并咪唑-4-甲酰胺
144. 1-(2-(哌啶-1-基)乙-1-基)-2-(哌啶-4-基)苯并咪唑-4-甲酰胺
145. 2-(哌啶-4-基)-1-(2-(哌啶-1-基)乙-1-基)苯并咪唑-4-甲酰胺
146. 1-(2-(2-乙基哌啶-1-基)乙-1-基)-2-(哌啶-4-基)苯并咪唑-4-甲酰胺
147. 1-乙基-2-(哌啶-3-基)苯并咪唑-4-甲酰胺
148. 2-(哌啶-3-基)-1-异丙基苯并咪唑-4-甲酰胺
149. 1-(2-(羟基)乙-1-基)-2-(哌啶-3-基)苯并咪唑-4-甲酰胺
150. 1-(2-(甲氧基)乙-1-基)-2-(哌啶-3-基)苯并咪唑-4-甲酰胺
151. 1-(2-(氨基)乙-1-基)-2-(哌啶-3-基)苯并咪唑-4-甲酰胺
152. 1-(2-(N,N-二甲氨基)乙-1-基)-2-(哌啶-3-基)苯并咪唑-4-甲酰胺
153. 1-(2-(哌啶-1-基)乙-1-基)-2-(哌啶-3-基)苯并咪唑-4-甲酰胺
154. 2-(哌啶-3-基)-1-(2-(哌啶-1-基)乙-1-基)苯并咪唑-4-甲酰胺
155. 1-(2-(2-乙基哌啶-1-基)乙-1-基)-2-(哌啶-3-基)苯并咪唑-4-甲酰胺
156. 1-乙基-2-(吡咯烷-3-基)苯并咪唑-4-甲酰胺
157. 1-异丙基-2-(吡咯烷-3-基)苯并咪唑-4-甲酰胺
158. 1-(2-(羟基)乙-1-基)-2-(吡咯烷-3-基)苯并咪唑-4-甲酰胺
159. 1-(2-(甲氧基)乙-1-基)-2-(吡咯烷-3-基)苯并咪唑-4-甲酰胺
160. 1-(2-(氨基)乙-1-基)-2-(吡咯烷-3-基)苯并咪唑-4-甲酰胺
161. 1-(2-(N,N-二甲氨基)乙-1-基)-2-(吡咯烷-3-基)苯并咪唑-4-甲酰胺
162. 1-(2-(哌啶-1-基)乙-1-基)-2-(吡咯烷-3-基)苯并咪唑-4-甲酰胺
163. 2-(吡咯烷-3-基)-1-(2-(吡咯烷-1-基)乙-1-基)苯并咪唑-4-甲酰胺
164. 1-(2-(2-乙基哌啶-1-基)乙-1-基)-2-(吡咯烷-3-基)苯并咪唑-4-甲酰胺
165. 1-乙基-2-(吡咯烷-2-基)苯并咪唑-4-甲酰胺
166. 1-异丙基-2-(吡咯烷-2-基)苯并咪唑-4-甲酰胺
167. 1-(2-(羟基)乙-1-基)-2-(吡咯烷-2-基)苯并咪唑-4-甲酰胺
168. 1-(2-(甲氧基)乙-1-基)-2-(吡咯烷-2-基)苯并咪唑-4-甲酰胺
169. 1-(2-(氨基)乙-1-基)-2-(吡咯烷-2-基)苯并咪唑-4-甲酰胺
170. 1-(2-(N,N-二甲氨基)乙-1-基)-2-(吡咯烷-2-基)苯并咪唑-4-甲酰胺
171. 1-(2-(哌啶-1-基)乙-1-基)-2-(吡咯烷-2-基)苯并咪唑-4-甲酰胺
172. 2-(吡咯烷-2-基)-1-(2-(吡咯烷-1-基)乙-1-基)苯并咪唑-4-甲酰胺
173. 1-(2-(2-乙基哌啶-1-基)乙-1-基)-2-(吡咯烷-2-基)苯并咪唑-4-甲酰胺
174. 1-乙基-2-(哌嗪-4-基)苯并咪唑-4-甲酰胺
175. 1-异丙基-2-(哌嗪-4-基)苯并咪唑-4-甲酰胺
176. 1-(2-(羟基)乙-1-基)-2-(哌嗪-4-基)苯并咪唑-4-甲酰胺
177. 1-(2-(甲氧基)乙-1-基)-2-(哌嗪-4-基)苯并咪唑-4-甲酰胺
178. 1-(2-(氨基)乙-1-基)-2-(哌嗪-4-基)苯并咪唑-4-甲酰胺
179. 1-(2-(N,N-二甲氨基)乙-1-基)-2-(哌嗪-4-基)苯并咪唑-4-甲酰胺
180. 2-(哌嗪-4-基)-1-(2-(哌啶-1-基)乙-1-基)苯并咪唑-4-甲酰胺
181. 2-(哌嗪-4-基)-1-(2-(吡咯烷-1-基)乙-1-基)苯并咪唑-4-甲酰胺
182. 1-(2-(2-乙基-哌啶-1-基)乙-1-基)-2-(哌嗪-4-基)苯并咪唑-4-甲酰胺
183. 1-乙基-2-(高哌嗪-4-基)苯并咪唑-4-甲酰胺
184. 1-异丙基-2-(高哌嗪-4-基)苯并咪唑-4-甲酰胺
185. 1-(2-(羟基)乙-1-基)-2-(高哌嗪-4-基)苯并咪唑-4-甲酰胺
186. 1-(2-(甲氧基)乙-1-基)-2-(高哌嗪-4-基)苯并咪唑-4-甲酰胺
187. 1-(2-(氨基)乙-1-基)-2-(高哌嗪-4-基)苯并咪唑-4-甲酰胺
188. 1-(2-(N,N-二甲氨基)乙-1-基)-2-(高哌嗪-4-基)苯并咪唑-4-甲酰胺
189. 2-(高哌嗪-4-基)-1-(2-(哌啶-1-基)乙-1-基)苯并咪唑-4-甲酰胺
190. 2-(高哌嗪-4-基)-1-(2-(吡咯烷-1-基)乙-1-基)苯并咪唑-4-甲酰胺
191. 1-(2-(2-乙基-哌啶-1-基)乙-1-基)-2-(高哌嗪-4-基)苯并咪唑-4-甲酰胺
192. 1-乙基-2-(N-丙基哌啶-4-基)苯并咪唑-4-甲酰胺
193. 1-异丙基-2-(N-丙基哌啶-4-基)苯并咪唑-4-甲酰胺
194. 1-(2-(羟基)乙-1-基)-2-(N-丙基哌啶-4-基)苯并咪唑-4-甲酰胺
195. 1-(2-(甲氧基)乙-1-基)-2-(N-丙基哌啶-4-基)苯并咪唑-4-甲酰胺
196. 1-(2-(氨基)乙-1-基)-2-(N-丙基哌啶-4-基)苯并咪唑-4-甲酰胺
197. 1-(2-(N,N-二甲氨基)乙-1-基)-2-(N-丙基哌啶-4-基)苯并咪唑-4-甲酰胺
198. 1-(2-(哌啶-1-基)乙-1-基)-2-(N-丙基哌啶-4-基)苯并咪唑-4-甲酰胺
199. 2-(N-丙基哌啶-4-基)-1-(2-(吡咯烷-1-基)乙-1-基)苯并咪唑-4-甲酰胺
200. 1-(2-(2-乙基-哌啶-1-基)乙-1-基)-2-(N-丙基哌啶-4-基)苯并咪唑-4-甲酰胺
201. 1-乙基-2-(N-丙基哌啶-3-基)苯并咪唑-4-甲酰胺
202. 1-异丙基-2-(N-丙基哌啶-3-基)苯并咪唑-4-甲酰胺
203. 1-(2-(羟基)乙-1-基)-2-(N-丙基哌啶-3-基)苯并咪唑-4-甲酰胺
204. 1-(2-(甲氧基)乙-1-基)-2-(N-丙基哌啶-3-基)苯并咪唑-4-甲酰胺
205. 1-(2-(氨基)乙-1-基)-2-(N-丙基哌啶-3-基)苯并咪唑-4-甲酰胺
206. 1-(2-(N,N-二甲氨基)乙-1-基)-2-(N-丙基哌啶-3-基)苯并咪唑-4-甲酰胺
207. 1-(2-(哌啶-1-基)乙-1-基)-2-(N-丙基哌啶-3-基)苯并咪唑-4-甲酰胺
208. 2-(N-丙基哌啶-3-基)-1-(2-(1-乙基-2-(N-丙基哌啶-3-基)苯并咪唑-4-甲酰胺
209. 1-(2-(2-乙基-哌啶-1-基)乙-1-基)-2-(N-丙基哌啶-3-基)苯并咪唑-4-甲酰胺
210. 1-乙基-2-(N-丙基吡咯烷-3-基)苯并咪唑-4-甲酰胺
211. 1-异丙基-2-(N-丙基吡咯烷-3-基)苯并咪唑-4-甲酰胺
212. 1-(2-(羟基)乙-1-基)-2-(N-丙基吡咯烷-3-基)苯并咪唑-4-甲酰胺
213. 1-(2-(甲氧基)乙-1-基)-2-(N-丙基吡咯烷-3-基)苯并咪唑-4-甲酰胺
214. 1-(2-(氨基)乙-1-基)-2-(N-丙基吡咯烷-3-基)苯并咪唑-4-甲酰胺
215. 1-(2-(N,N-二甲氨基)乙-1-基)-2-(N-丙基吡咯烷-3-基)苯并咪唑-4-甲酰胺
216. 1-(2-(哌啶-1-基)乙-1-基)-2-(N-丙基吡咯烷-3-基)苯并咪唑-4-甲酰胺
217. 2-(N-丙基吡咯烷-3-基)-1-(2-(吡咯烷-1-基)乙-1-基)苯并咪唑-4-甲酰胺
218. 1-(2-(2-乙基-哌啶-1-基)乙-1-基)-2-(N-丙基吡咯烷-3-基)苯并咪唑-4-甲酰胺
219. 1-乙基-2-(N-丙基吡咯烷-2-基)苯并咪唑-4-甲酰胺
220. 1-异丙基-2-(N-丙基吡咯烷-2-基)苯并咪唑-4-甲酰胺
221. 1-(2-(羟基)乙-1-基)-2-(N-丙基吡咯烷-2-基)苯并咪唑-4-甲酰胺
222. 1-(2-(甲氧基)乙-1-基)-2-(N-丙基吡咯烷-2-基)苯并咪唑-4-甲酰胺
223. 1-(2-(氨基)乙-1-基)-2-(N-丙基吡咯烷-2-基)苯并咪唑-4-甲酰胺
224. 1-(2-(N,N-二甲氨基)乙-1-基)-2-(N-丙基吡咯烷-2-基)苯并咪唑-4-甲酰胺
225. 1-(2-(哌啶-1-基)乙-1-基)-2-(N-丙基吡咯烷-2-基)苯并咪唑-4-甲酰胺
226. 2-(N-丙基吡咯烷-2-基)-1-(2-(吡咯烷-1-基)乙-1-基)苯并咪唑-4-甲酰胺
227. 1-(2-(2-乙基-哌啶-1-基)乙-1-基)-2-(N-丙基吡咯烷-2-基)苯并咪唑-4-甲酰胺
228. 1-乙基-2-(N-丙基哌嗪-4-基)苯并咪唑-4-甲酰胺
229. 1-异丙基-2-(N-丙基哌嗪-4-基)苯并咪唑-4-甲酰胺
230. 1-(2-(羟基)乙-1-基)-2-(N-丙基哌嗪-4-基)苯并咪唑-4-甲酰胺
231. 1-(2-(甲氧基)乙-1-基)-2-(N-丙基哌嗪-4-基)苯并咪唑-4-甲酰胺
232. 1-(2-(氨基)乙-1-基)-2-(N-丙基哌嗪-4-基)苯并咪唑-4-甲酰胺
233. 1-(2-(N,N-二甲氨基)乙-1-基)-2-(N-丙基哌嗪-4-基)苯并咪唑-4-甲酰胺
234. 1-(2-(哌啶-1-基)乙-1-基)-2-(N-丙基哌嗪-4-基)苯并咪唑-4-甲酰胺
235. 2-(N-丙基哌嗪-4-基)-1-(2-(吡咯烷-1-基)乙-1-基)苯并咪唑-4-甲酰胺
236. 1-(2-(2-乙基-哌啶-1-基)乙-1-基)-2-(N-丙基哌嗪-4-基)苯并咪唑-4-甲酰胺
237. 1-乙基-2-(N-丙基高哌嗪-4-基)苯并咪唑-4-甲酰胺
238. 1-异丙基-2-(N-丙基高哌嗪-4-基)苯并咪唑-4-甲酰胺
239. 1-(2-(羟基)乙-1-基)-2-(N-丙基高哌嗪-4-基)苯并咪唑-4-甲酰胺
240. 1-(2-(甲氧基)乙-1-基)-2-(N-丙基高哌嗪-4-基)苯并咪唑-4-甲酰胺
241. 1-(2-(氨基)乙-1-基)-2-(N-丙基高哌嗪-4-基)苯并咪唑-4-甲酰胺
242. 1-(2-(N,N-二甲氨基)乙-1-基)-2-(N-丙基高哌嗪-4-基)苯并咪唑-4-甲酰胺
243. 1-(2-(哌啶-1-基)乙-1-基)-2-(N-丙基高哌嗪-4-基)苯并咪唑-4-甲酰胺
244. 2-(N-丙基高哌嗪-4-基)-1-(2-(吡咯烷-1-基)乙-1-基)苯并咪唑-4-甲酰胺
245. 1-(2-(2-乙基-哌啶-1-基)乙-1-基)-2-(N-丙基高哌嗪-4-基)苯并咪唑-4-甲酰胺
246. 6-氯-2-(哌啶-4-基)苯并咪唑-4-甲酰胺
247. 6-氯-2-(哌啶-3-基)苯并咪唑-4-甲酰胺
248. 6-氯-2-(吡咯烷-3-基)苯并咪唑-4-甲酰胺
249. 6-氯-2-(哌嗪-4-基)苯并咪唑-4-甲酰胺
250. 6-氯-2-(高哌嗪-4-基)苯并咪唑-4-甲酰胺
251. 6-乙基-2-(哌啶-4-基)苯并咪唑-4-甲酰胺
252. 6-乙基-2-(哌啶-3-基)苯并咪唑-4-甲酰胺
253. 6-乙基-2-(吡咯烷-3-基)苯并咪唑-4-甲酰胺
254. 6-乙基-2-(哌嗪-4-基)苯并咪唑-4-甲酰胺
255. 6-乙基-2-(高哌嗪-4-基)苯并咪唑-4-甲酰胺
256. 6-氨基-2-(哌啶-4-基)苯并咪唑-4-甲酰胺
257. 6-氨基-2-(哌啶-3-基)苯并咪唑-4-甲酰胺
258. 6-氨基-2-(吡咯烷-3-基)苯并咪唑-4-甲酰胺
259. 6-氨基-2-(哌嗪-4-基)苯并咪唑-4-甲酰胺
260. 6-氨基-2-(高哌嗪-4-基)苯并咪唑-4-甲酰胺
261. 2-(哌啶-4-基)-6-(吡咯烷-1-基)苯并咪唑-4-甲酰胺
262. 2-(哌啶-3-基)-6-(吡咯烷-1-基)苯并咪唑-4-甲酰胺
263. 2-(吡咯烷-3-基)-6-(吡咯烷-1-基)苯并咪唑-4-甲酰胺
264. 2-(哌嗪-4-基)-6-(吡咯烷-1-基)苯并咪唑-4-甲酰胺
265. 2-(高哌嗪-4-基)-6-(吡咯烷-1-基)苯并咪唑-4-甲酰胺
266. 2-(3-甲基哌啶-4-基)苯并咪唑-4-甲酰胺
267. 2-(3-环己基哌啶-4-基)苯并咪唑-4-甲酰胺
268. 2-(2-环己基哌啶-4-基)苯并咪唑-4-甲酰胺
269. 2-(3-苯基哌啶-4-基)苯并咪唑-4-甲酰胺
270. 2-(4-苯基哌啶-4-基)苯并咪唑-4-甲酰胺
271. 2-(2-(羟基羰基)哌啶-4-基)苯并咪唑-4-甲酰胺
272. 2-(2-(乙氧羰基)哌啶-4-基)苯并咪唑-4-甲酰胺
273. 2-(2-(环己氧羰基)哌啶-4-基)苯并咪唑-4-甲酰胺
274. 2-(2-(苄氧羰基)哌啶-4-基)苯并咪唑-4-甲酰胺
275. 2-(2-(苯氧羰基)哌啶-4-基)苯并咪唑-4-甲酰胺
具体实施方式
实施例1
2-(哌啶-4-基)苯并咪唑-4-甲酰胺·2HC1
a)N-(2-氨基-3-乙氧羰基)-1-(叔-丁氧羰基)-哌啶-4-甲酰苯胺将5.5g(24mmol)1-(叔-丁氧羰基)哌啶-4-羧酸和4.3g(24mmol)2,3-二氨基苯甲酸乙酯与6.0g(60mmol)三乙胺和3.2g(24mmol)1-羟基苯并三唑溶于100ml无水四氢呋喃。然后在0℃下,加入4.6g(24mmol)N’-(3-二甲氨基丙基)-N-乙基碳二亚胺,全部搅拌1小时。然后在室温下继续搅拌24小时。在减压下蒸发反应混合物,所得残余物在乙酸乙酯与碳酸氢钠水溶液之间分配。用5%浓度的柠檬酸水溶液洗涤乙酸乙酯相,在减压下干燥和蒸发。获得8.4g产物。
b)2-(1-(叔-丁氧羰基)哌啶-4-基)苯并咪唑-4-羧酸乙酯
将8.1g中间体1a在100ml浓乙酸中回流30分钟。然后全部在减压下蒸发,残余物在乙酸乙酯与水之间分配。用碳酸氢钠水溶液和水洗涤乙酸乙酯相,在减压下干燥和蒸发。获得4.6g产物。
c)2-哌啶-4-基苯并咪唑-4-羧酸酯x 2HCl
将3.7g(9.9mmol)中间体1b加入到50ml 4M氯化氢的二恶烷溶液中,并在室温下搅拌1小时。其后,该批以大量乙醚稀释并用吸滤法滤出所得沉淀。获得3.2g产物。
d)2-哌啶-4-基苯并咪唑-4-羧酰肼
将2.7g(7.8mmol)中间体1c和2.7g(54mmol)肼的30ml正丁醇溶液回流15小时,其后,全部在减压下蒸发,所得残余物在乙酸乙酯和碳酸氢钠水溶液之间分配。在减压下将有机相分离、干燥和蒸发。获得0.9g产物。
e)2-哌啶-4-基苯并咪唑-4-甲酰胺x 2 HCl
将约2.4g阮内镍的20ml水溶液加入到0.8g(3.1mmol)中间体1d的20ml二甲基甲酰胺溶液中,且全部加热至100℃达8小时。然后过滤反应混合物。将残余物溶于乙醇,加入乙醚以沉淀出粗产物。将沉淀溶于异丙醇,加入氯化氢的异丙醇溶液。用吸滤法滤出所得沉淀,获得0.52g产物。
1H-NMR(D6-DMSO).δ=1.8-2.3(4H),2.8-3.5(5H),7.2(1H),7.7(1H),7.8(1H),8.5(宽峰)和9.2(宽峰)ppm.
实施例2
2-哌啶-4-基苯并咪唑-4-甲酰胺
该实施例的制备与实施例1相似。
1H-NMR(D6-DMSO).δ=1.7(1H),1.9-2.2(4H),2.75(1H),3.8(1H),7.2(1H),7.6(1H),7.8(1H)和9.3(宽峰)ppm.
实施例3
2-(N-乙酰哌啶-4-基)苯并咪唑-4-甲酰胺
a)2-(N-乙酰哌啶-4-基)苯并咪唑-4-羧酸甲酯
将3.3g(19.9mmol)2,3-二氨基苯甲酸甲酯溶于100ml甲醇,并在室温下滴加4.0g(25.8mmol)N-乙酰哌啶-4-甲醛的100ml甲醇溶液。全部在室温下搅拌约10分钟。其后,滴加5.2g(25.8mmol)乙酸铜(II)的100ml水溶液,全部回流30分钟。冷却后,小心加入25ml浓盐酸,全部再次回流。然后滴加7.15g(29.8mmol)硫化钠九水合物的100ml水溶液,全部再煮沸10分钟。冷却后,在减压下蒸发反应溶液,所得残余物分散在水中,过滤。滤液用碳酸氢钠水溶液赋予碱性,用乙酸乙酯萃取数次。合并后的有机相用水洗涤,在减压下干燥和蒸发。获得4.5g产物。
b)2-(N-乙酰哌啶-4-基)苯并咪唑-4-羧酰肼
将4.3g(14.9mmol)中间体3a与3.7g(74.3mmol)水合肼在100ml乙醇中回流2.5小时。全部然后在减压下蒸发,所得粗产物直接用于下一反应步骤。
c)2-(N-乙酰哌啶-4-基)苯并咪唑-4-甲酰胺
将5g阮内镍加入到100ml二甲基甲酰胺与50ml水的混合物中。然后在室温下小心滴加反应步骤3b残余物的水溶液,以便所观察到的气体放出能够控制。全部然后加热至100℃达2小时。冷却后,进行过滤,在减压下蒸发滤液。将所得残余物溶于少许二氯甲烷,小心加入乙醚以沉淀出产物。获得3.2g产物。
1H-NMR(D6-DMSO).δ=1.8-2.3(4H),2.8-3.5(5H),7.2(1H),7.7(1H),7.8(1H),8.5(宽峰)和9.2(宽峰)ppm.
实施例4
2-(N-丙基哌啶-4-基)苯并咪唑-4-甲酰胺
将0.25g(1mmol)实施例2产物、59mg(1mmol)正丙醛和125μl(2mmol)乙酸溶于25ml乙醇。其后,在室温下加入64mg(1mmol)氰基硼氢化钠,全部搅拌16小时。反应溶液在减压下蒸发,残余物在二氯甲烷和碳酸氢钠水溶液之间分配。有机相以水洗涤、分离、干燥并在减压下蒸发。所得残余物经过色谱纯化,所用移动相为4/1乙酸乙酯/甲醇,获得0.07g产物。
1H-NMR(D6-DMSO).δ=0.9(3H),1.5(2H),1.9(2H),2.3(2H),2.9(2H),3.3(1H),7.25(1H),7.6(1H),7.8(1H),9,3(1H)和12.8(1H)ppm.
实施例5
2-哌啶-3-基苯并咪唑-4-甲酰胺x 2 HCl
将1.3g(3.8mmol)实施例6产物溶于20ml异丙醇,加入50ml盐酸的异丙醇溶液。全部在室温下搅拌1小时。用吸滤法滤出所得沉淀,获得1.1g产物。
1H-NMR(D6-DMSO).δ=1.95-2.3(3H),2.45(1H),3.2(1H),3.5(1H),3.9(1H),7.6(1H)和7.95(2H)ppm.
实施例6
2-(N-(O-叔-丁氧羰基)哌啶-3-基)苯并咪唑-4-甲酰胺
a)2-氨基-3-(N-(O-叔-丁氧羰基)哌啶-3-基)酰氨基-苯甲酸乙酯
将4g(17.4mmol)N-(O-叔-丁氧羰基)哌啶-3-羧酸和4.8ml(34.9mmol)三乙胺溶于100ml无水四氢呋喃。然后在-10℃下滴加1.7ml(17.4mmol)氯甲酸乙酯的10ml无水四氢呋喃溶液。全部在0℃下搅拌1小时。其后,仍然在-10℃下加入2.9g(17.4mmol)2,3-二氨基苯甲酸甲酯,全部在室温下搅拌12小时。反应溶液在减压下蒸发,所得残余物在乙酸乙酯和水之间分配。有机相用碳酸氢钠水溶液和水洗涤、干燥并在减压下蒸发。获得5.5g产物。
b)2-(N-(O-叔-丁氧羰基)哌啶-3-基)苯并咪唑-4-羧酸甲酯
将5.4g(14.3mmol)6a产物在100ml乙酸中回流75分钟。冷却后,全部在减压下蒸发,所得残余物经过色谱纯化,所用移动相为1/1乙酸乙酯/庚烷。获得2.7g产物。
c)2-(N-(O-叔-丁氧羰基)哌啶-3-基)苯并咪唑-4-羧酰肼
将2.3g(6.4mmol)6b产物与1.6g(32mmol)水合肼在20ml乙醇中回流2.5小时。冷却后,全部在减压下蒸发。用水处理该残余物,用吸滤法滤出所得沉淀,干燥。获得1.6g产物。
d)2-(N-(O-叔-丁氧羰基)哌啶-3-基)苯并咪唑-4-甲酰胺
将1.6g 6c产物按类似于3c的方法进行反应。获得1.3g产物。
1H-NMR(D6-DMSO).δ=1.4(1H),1.5(1H),2.9(1H),3.1(1H),3.9(1H),4.2(1H),7.3(1H),7.7(1H),7.8(1H),9.1(宽峰)和13(宽峰)ppm.
下列实施例中提到的物质制备与实施例1-6相似:
实施例7
2-(N-苄基哌啶-3-基)-苯并咪唑-4-甲酰胺
1H-NMR(D6-DMSO);δ=1.6-1.8(3H),2.1(2H),2.3(1H),2.8(1H),3.1(1H),3.2(1H),3.5(2H),7.2-7.4(6H),7.6(2H),7.8(2H)和9.2(宽峰)ppm.
实施例8
2-(N-甲基哌啶-3-基)-苯并咪唑-4-甲酰胺x 2 HCl
1H-NMR(D2O):δ=2.1(2H),2.3(1H),2.5(1H),3.1(3H),3.2(1H),3.5(1H),3.7(1H),4.0(2H),7.7(1H)和8.0(2H)ppm.
实施例9
2-哌嗪-4-基-苯并咪唑-4-甲酰胺
1H-NMR(D6-DMSO):δ=2.5(4H),3.3(4H),7.2(1H),7.6-7.7(2H),7.8(1H)和9.3(1H)ppm.
实施例10
2-(N-丙基哌啶-3-基)-苯并咪唑-4-甲酰胺x 2 HCl
1H-NMR(D6-DMSO):δ=0.9(3H),1.5(2H),1.9(2H),2.0(4H),2.3(2H),2.9(3H),7.2(1H),7.6(2H),7.8(1H)和9.3(宽峰)ppm.
实施例11
2-(N-(3-苯基丙-1-基)-哌啶-3-基)-苯并咪唑-4-甲酰胺x 2HCl
1H-NMR(D6-DMSO):δ=2.0-2.5(6H),2.8(2H),3.1(1H),3.2-3.4(3H),3.7(1H),3.8-4.0(2H),7.3-7.5(5H),7.7(1H)和8.0(2H)ppm.
实施例12
2-(N-苯甲酰基哌啶-3-基)-苯并咪唑-4-甲酰胺
1H-NMR(CF3COOD):δ=1.9(1H),2.6(1H),3.8(1H),3.9-4.2(4H),4.3(1H),4.8(1H)和7.5-8.2(8H)ppm.
实施例13
2-(N-苄基哌啶-4-基)-苯并咪唑-4-甲酰胺x 2 HCl
1H-NMR(D2O):δ=2.3(2H),2.6(2H),3.3(2H),3.8(3H),4.5(2H)和7.5-8.0(8H)ppm.
实施例14
2-(1-(1-甲基哌啶-4-基)哌啶-4-基)-苯并咪唑-4-甲酰胺x 3HCl
1H-NMR(D6-DMSO):δ=1.4(2H),1.6-2.0(6H),2.0-2.4(7H),2.7-3.0(6H),7.2(1H),7.7(2H),7.8(1H)和9.4(宽峰)ppm.
实施例15
2-(N-正戊基哌啶-4-基)-苯并咪唑-4-甲酰胺
1H-NMR(D6-DMSO):δ=0.9(3H),1.2-1.5(6H),1.7-2.1(6H),2.3(2H),2.8-3.0(4H),7.3(1H),7.6-7.8(3H),9.4(1H)和12.8(宽峰)ppm.
实施例16
2-(N-异丁-1-基哌啶-4-基)-苯并咪唑-4-甲酰胺
1H-NMR(D6-DMSO):δ=0.9(6H),1.8-2.1(10H),2.9(2H),7.2(1H),7.6(2H),7.8(1H),9.2(1H)和12.5(宽峰)ppm.
实施例17
2-(N-正丁基哌啶-4-基)-苯并咪唑-4-甲酰胺x HCl
1H-NMR(D6-DMSO):δ=O.9(3H),1.3(2H),1.7(2H),2.2-2.4(4H),3.0-3.2(4H),3.4-3.6(3H),7.5(1H),7.8-8.0(2H),8.0(1H),8.7(宽峰)和10.9(宽峰)ppm.
实施例18
2-(N-(3-甲基-丁-1-基)哌啶-4-基)-苯并咪唑-4-甲酰胺x HCl
1H-NMR(D6-DMSO):δ=0.9(6H),1.7(3H),2.2-2.4(4H),3.1(4H),3.3(1H),3.7(2H),7.5(1H),7.8-8.0(3H),8.7(宽峰)和10.5(宽峰)ppm.
实施例19
2-(1,4-二甲基哌嗪-2-基)-苯并咪唑-4-甲酰胺x 2 HCl
1H-NMR(D6-DMSO):δ=2.5(3H),2.9(3H),3.3-3.8(5H),3.9(1H),5.0(1H),7.4(1H),7.7(1H),7.8(1H),7.9(1H)和8.6(宽峰)ppm.
实施例20
2-哌嗪-2-基-苯并咪唑-4-甲酰胺x 2 HCl
将1.83g(3.67mmol)实施例23产物与1g 10%钯/碳引入到250ml甲醇中,并用大约165ml氢进行氢化。用吸滤法滤出催化剂,浓缩滤液。将残余物溶于20ml异丙醇,加入50ml盐酸的异丙醇溶液。用吸滤法滤出所得沉淀,获得1.1g产物。
1H-NMR(D6-DMSO):δ=3.2-3.7(5H),4.0(1H),5.2(1H),7.4(1H),7.8(1H),7.9(1H)和10.2(宽峰)ppm.
实施例21
2-(N-异丙基哌啶-4-基)-苯并咪唑-4-甲酰胺x HCl
1H-NMR(D6-DMSO):δ=1.25(6H),2.3(4H),3.1(1H),3.4-3.6(4H),3.7(1H),7.5(1H),7.7-8.0(3H),8.7(1H)和10.7(宽峰)ppm.
实施例22
2-(4-(2-乙基-丙-1-基)哌啶-4-基)-苯并咪唑-4-甲酰胺
实施例23
2-(1,4-二苄基哌嗪-2-基)-苯并咪唑-4-甲酰胺x 2 HCl
1H-NMR(D6-DMSO):δ=2.95-3.7(7H),3.8-4.9(4H),7.1-7.55(8H),7.65(2H),7.85(2H),7.94(1H),8.7(宽峰)和12.2(宽峰)ppm.
实施例24
2-(N-苄基哌啶-4-基)-1-(1-苄基哌啶-4-基羰基)苯并咪唑-4-甲酰胺
1H-NMR(D6-DMSO):δ=1.7(2H),1.8-2.0(6H),2.1(4H),2.5-2.7(2H),2.8-3.0(4H),3.5(4H),7.2-7.5(11H),7.7(1H),8.6(1H),9.5(1H)和12.3(宽峰)ppm.
实施例A:酶聚(ADP-核糖)聚合酶或PARP的抑制作用(EC2.4.2.30)
用组蛋白(型号II-AS;SIGMA H7755)覆盖96-孔微量滴定盘(Falcon)。另外,组蛋白溶于碳酸盐缓冲剂(0.05M NaHCO3;ph9.4)中,浓度为50μg/ml。微量滴定盘的各孔培养整夜,每个用100μl组蛋白溶液。其后,除去该组蛋白溶液且用200μl 1%浓度的BSA(牛血清蛋白)溶液在碳酸盐缓冲剂中,在室温下培养各孔达2小时。然后用洗涤缓冲剂(0.05%吐温10在PBS中)洗涤三次。该酶反应,每孔需50μl酶反应溶液(5μl反应缓冲剂、(1M Tris-HCL ph8.0、100mM MgCl2、10mM DTT)、0.5μl PARP(c=0.22μg/μl)、4Rl活化DNA(SIGMA D-4522,1mg/ml水溶液)、40.5μl HCL)与10μl抑制剂溶液进行10分钟前期培养。添加40μl酶解物溶液(4μl反应缓冲剂(见上文)、8μl NAD溶液(100μm在HCL中)、28μlH2O)使该酶反应开始。在室温下反应时间是20分钟。用洗涤缓冲剂洗涤三次使反应结束(见上文)。用特异性抗-聚尿苷酸-(ADP-核糖)抗体在室温下培养1小时使此反应继续。所用抗体为单克隆抗-聚尿苷酸-(ADP-核糖)抗体”10H”(Biomol SA-276)。
该抗体用于稀度为1∶5000的抗体缓冲剂(1%BSA和PBS;0.05%吐温20)。用次生抗体在室温下培养1小时后用洗涤缓冲剂洗涤三次。这里,抗-鼠-IgG与过氧化物酶(Boehringer Mannheim)偶合用作单克隆抗体且抗-兔-IgG与过氧化物酶(SIGMA A-6154)偶合用作兔抗体,每个都用稀度为1∶10,000的抗体缓冲剂。用洗涤缓冲剂洗涤三次后,用100μl/well显色试剂(SIGMA,TMB ready-mix,T8540)在室温下进行约15分钟显色试验。用100μl 2M H2SO4使显色试验结束。随后立即进行测量(450对620nm;ELISA“Easy Reader”EAR340AT平板读数器,SLT-Lab instruments,Austria)。用各种酶解物浓度抑制作用曲线的常规方法测定Ki。
实施例B:水溶解度的测定
被测量的化合物直接溶于指定容积的水中且用乙酸钠溶液使其ph值达到5-6,因此活性化合物的浓度达到测试标准。如果测试物质现不是水溶性的盐,在ph值也在此调节后,其溶于非常少数量的二甲亚砜中且随后用水稀释(二甲亚砜最终浓度≤1%)。此时,根据本发明的实施例1得到>0.5%的溶解度。
Claims (9)
1.式Ia或Ib的化合物
其中
R1是氢或者支链或直链的C1-C6-烷基,链中的一个碳原子还携带=O基团或基团NR8R9,其中的NR8R9一起构成具有4至8个环原子的环胺,并且由NR8R9形成的环被苄基取代,
R4是氢,
A是饱和的6-元杂环,其中含有一或两个氮原子,所述的环可以被R2和R3取代,其中
R2是氢、支链或直链的C1-C8-烷基,它可以进一步被R23取代,该链的碳原子可以携带=O基团、-CO-R21、COOR21或苯基,其中R21是氢、支链或直链的C1-C6-烷基、苯基-C1-C4-烷基或苯基,
R23是C1-C6-烷基、C0-C4-烷基苯基,
R3是氢、支链或直链的C1-C6-烷基、其中该基团的一个碳原子可以进一步携带苯基环,
或其生理学上可耐受的盐。
2.如权利要求1的化合物,其中R1、R2和R4各自是氢,A是哌啶、哌嗪,R3与A的氮键合。
3.如权利要求1或2的化合物,其中A是通过其4-位与苯并咪唑键合的哌啶,R3可以是氢、C1-C4-烷基、苄基或苯乙基,并且位于哌啶环的1-位。
4.用于治疗发生PARP活性病理学增加的机能紊乱的药物,除了常规载体和赋形剂之外,还含有权利要求1的化合物。
5.权利要求1的式I化合物用于制备药物的用途,该药物用于治疗发生PARP活性病理学增加的机能紊乱。
6.权利要求1或2的化合物,其为2-(N-丙基哌啶-4-基)苯并咪唑-4-甲酰胺或其生理上可接受的盐。
7.权利要求1或2的化合物,其为2-(N-甲基哌啶-3-基)苯并咪唑-4-甲酰胺其生理上可接受的盐。
8.用于治疗发生PARP活性病理学增加的机理紊乱的药物组合物,其含有2-(N-丙基哌啶-4-基)苯并咪唑-4-甲酰胺或其生理上可接受的盐以及药学上可接受的载体或赋形剂。
9.用于治疗发生PARP活性病理学增加的机理紊乱的药物组合物,其含有2-(N-甲基哌啶-3-基)苯并咪唑-4-甲酰胺或其生理上可接受的盐以及药学上可接受的载体或赋形剂。
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CN110234640A (zh) * | 2016-09-20 | 2019-09-13 | 利昂贝拉尔中心 | 作为抗癌剂的苯并咪唑衍生物 |
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Publication number | Priority date | Publication date | Assignee | Title |
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CN110234640A (zh) * | 2016-09-20 | 2019-09-13 | 利昂贝拉尔中心 | 作为抗癌剂的苯并咪唑衍生物 |
CN109232540A (zh) * | 2018-06-15 | 2019-01-18 | 深圳市坤健创新药物研究院 | 一种取代苯并咪唑衍生物及应用 |
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