CN114616224A - 新型三环5-ht2拮抗剂 - Google Patents
新型三环5-ht2拮抗剂 Download PDFInfo
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- CN114616224A CN114616224A CN202080044100.8A CN202080044100A CN114616224A CN 114616224 A CN114616224 A CN 114616224A CN 202080044100 A CN202080044100 A CN 202080044100A CN 114616224 A CN114616224 A CN 114616224A
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- Prior art keywords
- methyl
- dihydro
- benzo
- indole
- carboximidamide
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- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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Abstract
Description
发明领域
本发明涉及新的5-HT2B受体拮抗剂。本发明具体涉及对血清素5-HT2B受体表现出拮抗活性的此类衍生物。本发明还涉及所述化合物作为药物和用于治疗纤维化、心血管疾病、疼痛、IBD、炎性疾病和癌症的用途,以及包含一种或多种所述化合物的药物组合物和治疗方法。
发明背景
血清素(5-羟色胺,5-HT)是一种特征明确的神经递质和血管活性胺,其与涉及中枢神经、胃肠道、心血管和肺系统的常见疾病有关。外周5-HT主要由肠道中的肠嗜铬细胞合成和释放。当到达血流时,它被隔离在血小板内。在正常情况下,血浆中游离5-HT的水平低,并且受到存在于例如血小板表面的特定5-HT转运蛋白以及5-HT降解酶的严格调节。血小板激活后会释放5-HT,并观察到5-HT浓度的局部增加。多年来,有证据表明5-HT在哺乳动物身体的功能中具有重要作用。例如,已显示其调节心血管功能、肠蠕动和膀胱控制等过程。5-HT和5-HT受体系统也与疼痛的调节有关,更具体地说,5-HT2受体已显示在炎症性疼痛过程中起重要作用。
通过对至少14种不同的人类受体进行表征,对5-HT功能有了更深入的了解,这些受体根据其结构和药理学差异分为亚家族。每个受体表现出独特的分布,并对不同的配体表现出不同的偏好。除了5-HT3受体是配体门控离子通道外,所有受体都是G蛋白偶联受体。5-HT2受体家族由3个亚型组成,5-HT2A、5-HT2B和5-HT2C。5-HT2受体在氨基酸水平上具有显著的序列同源性并与G蛋白的Gq家族偶联。
5-HT2B受体在炎症细胞中表达,该受体参与5-HT诱导的在小鼠心脏成纤维细胞中产生IL-1β、IL-6和TNF-α。在LPS诱导的炎症小鼠模型中,TNF-α在用选择性5-HT2B受体拮抗剂治疗后已显示出水平降低(WO2016/207231A1)。
5-HT2B受体以前与肺动脉高压(PAH)有关,5-HT2B受体敲除小鼠的表型显示其对心脏发育的重要性。它表明5-HT通过5-HT2B受体调节发育中心脏和成人心脏的分化和增殖。相反,5-HT2B在小鼠中的过度表达会导致心脏肥大。
与此一致的是,5-HT及其受体,特别是5-HT2A和5-HT2B,与多种纤维化疾病的病因有关,包括腹膜后纤维化、类癌性心脏病、硬皮病、肝和肺纤维化。纤维化实际上是许多不同类型的慢性呼吸系统疾病的一个特征,包括IPF、PAH、COPD和哮喘。纤维化和5-HT之间的机制联系在1960年代首次报道,用于称为类癌综合征的病症,该病症由分泌大量5-HT的神经内分泌类癌瘤引起。该综合征的特点是组织纤维化,其特别影响心脏瓣膜,但也会影响其他器官,包括肺和皮肤。随后,对5-HT2B受体的激动作用与用于治疗肥胖症和精神疾病的芬氟拉明引起的纤维化有关。纤维化的特征是成纤维细胞/肌成纤维细胞增殖和活化增强,其导致细胞外基质沉积改变,这最终导致器官衰竭。
纤维化过程的一个重要介质是转化生长因子β,TGF-β。这种细胞因子通过转录调节来调节多种生理过程。在人肺成纤维细胞中,众所周知,TGF-β诱导肌成纤维细胞分化,其中细胞内应力纤维中α-SMA的表达水平增加,以及基质沉积增加。许多证据支持5-HT在纤维化中的作用,尽管5-HT如何促进纤维化的确切机制尚未确定。5-HT已显示通过5-HT2B受体增加TGF-β的产生,并且在硬皮病人皮肤成纤维细胞模型中,TGF-βmRNA的剂量依赖性增加以响应5-HT,以及5-HT2B受体的表达增加。这导致胶原蛋白1a1、胶原蛋白1a2和纤连蛋白的表达增加。5-HT对基质合成的影响被5-HT2B受体拮抗剂或转染的5-HT2B siRNA阻断。同一研究表明,选择性5-HT2B受体拮抗剂在体内预防博莱霉素诱导的皮肤纤维化(Dees C.et al.,J.Exp.Med.(2011)208(5),961-72)。在肝纤维化等其他纤维化疾病中,用5-HT2B受体拮抗剂治疗导致慢性肝病体内模型中的纤维发生减弱(Ebrahimkhani,M.R.et al.,Nat Med.(2011)17(12),1668-73)。在患有IPF的患者中发现了对5-HT和纤维化的进一步支持,5-HT2A和5-HT2B受体在纤维化肺中的表达增加。另一项研究确定了5-HT2B受体在来自IPF患者的人肺样本的成纤维细胞灶中的强成纤维细胞表达。此外,用5-HT2A和5-HT2B受体拮抗剂Terguride治疗降低TGF-β1刺激的人肺成纤维细胞中I型胶原蛋白的表达。在博来霉素(BLM)诱导的小鼠肺纤维化模型中,抗纤维化作用在用5-HT2A和5-HT2B受体拮抗剂以及也用选择性5-HT2B拮抗剂治疗后可见(WO2016/207231A1)。
伤口愈合、慢性纤维化和肿瘤具有相似的特征,其中肌成纤维细胞的存在已成为一个共同的标志。在慢性组织纤维化过程中和肿瘤激活的基质(结缔组织增生)中发现了持久的肌成纤维细胞群,而它们在急性伤口愈合过程中短暂存在。肌成纤维细胞产生过量的细胞外基质(ECM),在癌症中这导致形成在癌症发展、进展和转移中起关键作用的肿瘤基质。肿瘤基质具有致密且改变的ECM,并且由于药物进入肿瘤的严重受损而对治疗提出了挑战。因此,通过抗纤维化药物治疗可以实现更有效的抗肿瘤药物递送。纤维化也已被证明是某些癌(例如胰腺癌和肝细胞癌)的易感性因素(Rybinski,B.et al.,Physiol Genomics(2014)46(7),223-44)。除了建议的参与肿瘤基质之外,5-HT最近已作为人类肿瘤细胞的生长因子出现。神经内分泌细胞产生和分泌5-HT已在几种实体瘤的进展中得到证实。最近的一项研究表明,与非肿瘤胰腺组织相比,人胰腺导管腺癌(PDAC)组织中5-HT的水平增加。5-HT增加PDAC细胞系的增殖并阻止细胞凋亡。5-HT2B受体在PDAC和5-HT2B受体激动剂中的表达增加,但其他5-HT受体没有,促进了PDAC细胞的增殖并阻止细胞凋亡,而5-HT2B受体抑制剂则减少了它们作为小鼠中异种移植物肿瘤的生长(Jiang,S.H.et al.,Gastroenterology(2017)153(1),277-91e19)。5-HT2B受体也存在于人肝细胞癌(HCC)中,5-HT通过激活5-HT2B受体促进细胞存活和肝细胞癌细胞的生长。此外,5-HT2B受体参与葡萄膜黑色素瘤(UM),其中高水平的HTR2B mRNA转录物是区分转移性和非转移性UM细胞系的区分标记。在UM细胞中使用5-HT2B受体拮抗剂的药理学抑制降低了活力并削弱了迁移潜力(Weidmann,C.et al.,Clin Exp Metastasis(2018)35(3),123-34)。
5-HT2B拮抗剂
文献中已经描述了许多不同结构类别的5-HT2B拮抗剂;有关评论,参阅Poissonnet,G.,et al.,Mini-Reviews in Medicinal Chemistry(2004),4(3),325-330以及Brea,J.et al.,Current Topics in Medicinal Chemistry(Sharjah,United ArabEmirates)(2010),10(5),493-503。这些包括二脲SB206553和SB215505、哌嗪衍生物EGIS-7625、2-氨基-4-萘基-嘧啶MT-500(RS127445)、噻吨结构、麦角衍生物特麦角、四氢-β-咔啉、噻吩并嘧啶PRX-08066和喹啉衍生物。5-HT2B拮抗剂的其他实例公开于US8252790B2、US2009062363A1、EP1728784A1和WO2016/207231A1。
仍然需要开发用于药物开发的新的有效和选择性的5-HT2B拮抗剂。
发明内容
本发明的一个目的是提供用于治疗诸如纤维化、心血管疾病、疼痛、IBD、炎性疾病和癌症等疾病的血清素5-HT2B受体的新拮抗剂。
本发明涉及通式I的化合物
已经发现,如所附权利要求中所述的1-脒基-4-甲基-[2,3-稠合]-2-吡咯啉衍生物是具有高的效力和/或选择性的5-HT2B受体拮抗剂。特别地,本发明化合物的酰胺化刚性甲基化稠合三环结构已被鉴定为5-HT2B受体拮抗剂的有用骨架。
具体实施方式
在本发明的一个方面,提供了通式I的化合物
其中
环A
表示含有0-3个独立地选自N、O和S的杂原子的5-6元芳族或杂芳族环;
R1、R2和R3独立地选自氢、甲基、乙基、正丙基、异丙基、环丙基、叔丁基、乙炔基、CF3、羟基、甲氧基、乙氧基、异丙氧基、OCF3、SCH3、S(O)2OH、S(O)CH3、S(O)2CH3、S(O)2NH2、S(O)2N(CH3)2、NH2、NHCH3、N(CH3)2、NHC(O)CH3、C(O)N(CH3)2、F、Cl、Br、I、CN和含有0-3个独立地选自N、O和S的杂原子的5-6元芳族或杂芳族环;
X-Y,其中X通过单键或双键连接到Y或不存在,选自CH=CH、C(CH3)=CH、C(F)=CH、C(Cl)=CH、C(OMe)=CH、CH2-CH2、N=CH、CH=N、N=N、O-CH2、O-C(O)、NH、NCH3、O或S;
Z选自氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、新丁基、叔丁基、烯丙基、2-丙炔基、环丙基、环丙基甲基、环戊基、环己基、CF3、CH2CF3、CH2CH2F、CH2CH2CF2CF3、CH2CH2OCH3、苯基、苄基、羟基和甲氧基,其中所述苯基和苄基任选地被独立地选自甲基、甲氧基、F、Cl和CF3的取代基单或二取代;和
其药学上可接受的盐、互变异构体和立体异构体。
X-Y,其中X通过单键或双键连接到Y或不存在,选自CH=CH、C(CH3)=CH、C(F)=CH、C(Cl)=CH、C(OMe)=CH、CH2-CH2、N=CH、CH=N、N=N、O-CH2、O-C(O)、NH、NCH3、O或S。换言之,当X通过单键连接到Y时,X-Y选自CH2-CH2、O-CH2或OC(O)。当X通过双键连接到Y时,X-Y选自CH=CH、C(CH3)=CH、C(F)=CH、C(Cl)=CH、C(OMe)=CH、N=CH、CH=N或N=N。当X不存在时,X-Y选自NH、NCH3、O或S。
在一些实施方案中
选自
其中
R1、R2和R3独立地选自氢、甲基、乙基、正丙基、异丙基、环丙基、叔丁基、乙炔基、CF3、羟基、甲氧基、乙氧基、异丙氧基、OCF3、SCH3、S(O)2OH、S(O)CH3、S(O)2CH3、S(O)2NH2、S(O)2N(CH3)2、NH2、NHCH3、N(CH3)2、NHC(O)CH3、C(O)N(CH3)2、F、Cl、Br、I、CN和含有0-3个独立地选自N、O和S的杂原子的5-6元芳族或杂芳族环。
在一些实施方案中
选自
其中
R1选自氢、甲基、乙基、异丙基、环丙基、叔丁基、乙炔基、CF3、甲氧基、OCF3、SCH3、S(O)2N(CH3)2、F、Cl、Br、I、CN、苯基、噻吩-2-基、噻吩-3-基、吡唑-3-基、吡唑-4-基、咪唑-2-基、咪唑-4-基、异噁唑-3-基、异噁唑-4-基;和
R2选自氢和F。
在一些实施方案中,Z选自氢、甲基、乙基、正丙基、异丙基、正丁基、环丙基、烯丙基、2-丙炔基、CH2CH2F、CH2CF3、CH2CH2CF2CF3、苯基和苄基,其中所述苯基和苄基任选地被独立地选自甲基、甲氧基、F、Cl和CF3的取代基单或二取代。
在一些实施方案中
选自
Z选自氢、甲基、正丁基、环丙基、烯丙基、2-丙炔基、CH2CH2F、CH2CF3、CH2CH2CF2CF3、苯基、苄基,其中所述苯基和苄基任选地被独立地选自甲基、甲氧基、F、Cl和CF3的取代基单或二取代。
在一些实施方案中,环A
R1、R2和R3是独立地选自氢、正丙基、环丙基、乙炔基、CF3、甲氧基、SCH3、S(O)CH3、S(O)2CH3、S(O)2N(CH3)2、N(CH3)2、NHC(O)CH3、F、Cl、Br、I和苯基;
X-Y选自CH=CH、C(F)=CH、C(OMe)=CH、N=CH、CH=N;和
Z选自氢、甲基、乙基、正丙基、异丙基、正丁基、烯丙基、2-丙炔基、环丙基、环己基、CH2CF3、CH2CH2F、CH2CH2OCH3、苯基和苄基,其中所述苯基和苄基任选地被选自甲基、甲氧基、F和Cl的取代基单取代。
在一些实施方案中,绝对构型是如式Ia中所示的(S)
在一些实施方案中,化合物选自:
1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N,1-二甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-丁基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-烯丙基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
1-甲基-N-(丙-2-炔-1-基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-(2-氟乙基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-苄基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-(4-氟苄基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-(3,4-二氟苄基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-(4-氯苄基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
1-甲基-N-(4-(三氟甲基)苄基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-(4-甲氧基苄基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
1-甲基-N-苯基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-(4-氟苯基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-(4-氯苯基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
1-甲基-N-(4-(三氟甲基)苯基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-(4-甲氧基苯基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-氟-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-氯-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-氯-N,1-二甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-丁基-6-氯-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-烯丙基-6-氯-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-氯-1-甲基-N-(丙-2-炔-1-基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-氯-N-(2-氟乙基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-苄基-6-氯-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-氯-1-甲基-N-苯基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-N,1-二甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-N-乙基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-1-甲基-N-丙基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-N-丁基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-N-异丙基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-烯丙基-6-溴-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-1-甲基-N-(丙-2-炔-1-基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-N-环丙基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-N-环己基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-N-(2-氟乙基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-1-甲基-N-(2,2,2-三氟乙基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-N-(2-甲氧基乙基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-苄基-6-溴-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-1-甲基-N-(4-甲基苄基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-N-(4-氟苄基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-N-(4-甲氧基苄基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-1-甲基-N-苯基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-1-甲基-N-(p-甲苯基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-N-(4-氟苯基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-N-(4-氯苯基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-N-(4-甲氧基苯基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-碘-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
1,6-二甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-乙炔基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
1-甲基-6-苯基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-环丙基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
1-甲基-6-丙基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
1-甲基-6-(三氟甲基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N,1-二甲基-6-(三氟甲基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-丁基-1-甲基-6-(三氟甲基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-烯丙基-1-甲基-6-(三氟甲基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
1-甲基-N-(丙-2-炔-1-基)-6-(三氟甲基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-(2-氟乙基)-1-甲基-6-(三氟甲基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-苄基-1-甲基-6-(三氟甲基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
1-甲基-N-苯基-6-(三氟甲基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-甲氧基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
1-甲基-6-(甲硫基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
1-甲基-6-(甲基亚硫酰基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
1-甲基-6-(甲基磺酰基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
5-甲氧基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-(3-脒基-1-甲基-2,3-二氢-1H-苯并[e]吲哚-6-基)乙酰胺;
6-(二甲基氨基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-(N,N-二甲基氨磺酰)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-氯-7-氟-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-氯-5-氟-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
5-氟-6-甲氧基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
5,6-二氟-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
7-氟-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
7-氟-N,1-二甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-丁基-7-氟-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-烯丙基-7-氟-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
7-氟-1-甲基-N-(丙-2-炔-1-基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
7-氟-N-(2-氟乙基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-苄基-7-氟-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
7-氟-1-甲基-N-苯基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
5,7-二氟-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
1-甲基-1,2-二氢-3H-吡咯并[2,3-c]异喹啉-3-甲酰亚胺酰胺;和
1-甲基-1,2-二氢-3H-吡咯并[2,3-c]喹啉-3-甲酰亚胺酰胺。
在一些实施方案中,化合物选自:
7-氟-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
1-甲基-1,2-二氢-3H-吡咯并[2,3-c]异喹啉-3-甲酰亚胺酰胺;
1-甲基-1,2-二氢-3H-吡咯并[2,3-c]喹啉-3-甲酰亚胺酰胺
N,1-二甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-丁基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-苄基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-(4-氯苄基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-(3,4-二氟苄基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-氯-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-N,1-二甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-N-乙基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-1-甲基-N-丙基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-N-丁基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-N-异丙基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-烯丙基-6-溴-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-1-甲基-N-(丙-2-炔-1-基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-N-环丙基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-N-环己基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-N-(2-氟乙基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-1-甲基-N-(2,2,2-三氟乙基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-N-(2-甲氧基乙基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-苄基-6-溴-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-1-甲基-N-(4-甲基苄基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-N-(4-氟苄基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-N-(4-甲氧基苄基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-1-甲基-N-苯基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-1-甲基-N-(p-甲苯基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-N-(4-氟苯基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-N-(4-氯苯基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-N-(4-甲氧基苯基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-氟-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-碘-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
1-甲基-6-(三氟甲基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-甲氧基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
1-甲基-6-(甲硫基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
1-甲基-6-(甲基亚硫酰基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
1-甲基-6-(甲基磺酰基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-乙炔基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
1-甲基-6-苯基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-环丙基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
1-甲基-6-丙基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
5-甲氧基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-氯-5-氟-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-(3-脒基-1-甲基-2,3-二氢-1H-苯并[e]吲哚-6-基)乙酰胺;
6-(二甲基氨基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;和
6-(N,N-二甲基氨磺酰)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺。
在本发明的另一方面,提供了用作药物的式I化合物。
在本发明的另一方面,提供了用于治疗纤维化、心血管疾病、疼痛、IBD、炎性疾病或癌症的式I化合物。通常,纤维化选自系统性硬化症、皮肤纤维化、肝纤维化、心脏纤维化、肾纤维化、肠纤维化、肺纤维化,包括特发性肺纤维化(IPF)和与肺动脉高压(PAH)相关的纤维化,以及与移植、手术、狭窄或瘢痕疙瘩相关的纤维化。通常,所述心血管疾病选自动脉粥样硬化和高血压。通常,所述疼痛选自偏头痛和与炎性疾病相关的疼痛。通常,所述IBD选自克罗恩病和溃疡性结肠炎。通常,所述癌症选自产生细胞外基质的癌症,例如乳腺癌、胰腺癌和肝癌。
在本发明的另一方面,提供了用于治疗炎性关节疾病包括类风湿性关节炎(RA)和骨关节炎(OA)的式I化合物。
在本发明的另一方面,提供了式I化合物在制备用于治疗纤维化、心血管疾病、疼痛、IBD炎性疾病或癌症的药物中的用途。通常,所述纤维化选自系统性硬化症、皮肤纤维化、肝纤维化、心脏纤维化、肾纤维化、肠纤维化、肺纤维化,包括特发性肺纤维化(IPF)和与肺动脉高压(PAH)相关的纤维化,以及与移植、手术、狭窄或瘢痕疙瘩相关的纤维化。通常,所述心血管疾病选自动脉粥样硬化和高血压。通常,所述疼痛选自偏头痛和与炎性疾病相关的疼痛。通常,所述IBD选自克罗恩病和溃疡性结肠炎。通常,所述癌症选自产生细胞外基质的癌症,例如乳腺癌、胰腺癌和肝癌。
在本发明的另一方面,提供了式I化合物在制备用于治疗炎性关节疾病包括类风湿性关节炎(RA)和骨关节炎(OA)的药物中的用途。
在本发明的另一方面,提供了一种治疗纤维化、心血管疾病、疼痛、IB、炎性疾病或癌症的方法,包括向有需要的患者施用治疗有效量的式I化合物。通常,所述纤维化选自系统性硬化症、皮肤纤维化、肝纤维化、心脏纤维化、肾纤维化、肠纤维化、肺纤维化,包括特发性肺纤维化(IPF)和与肺动脉高压(PAH)相关的纤维化,以及与移植、手术、狭窄或瘢痕疙瘩相关的纤维化。通常,所述心血管疾病选自动脉粥样硬化和高血压。通常,所述疼痛选自偏头痛和与炎性疾病相关的疼痛。通常,所述IBD选自克罗恩病和溃疡性结肠炎。通常,所述癌症选自产生细胞外基质的癌症,例如乳腺癌、胰腺癌和肝癌。
在本发明的另一方面,提供了治疗包括类风湿性关节炎(RA)和骨关节炎(OA)在内的炎性关节疾病的方法,包括向有需要的患者施用治疗有效量的式I化合物。
在本发明的另一方面,提供了一种药物组合物,其包含与一种或多种药学上可接受的赋形剂或载体混合的式I化合物。通常,所述赋形剂选自填充剂、润滑剂、调味剂、着色剂、甜味剂、缓冲剂、酸化剂、稀释剂和防腐剂。通常,将所述组合物配制成经口、经口吸入、肌肉内、静脉内、腹膜内或皮下、经由植入物、直肠、鼻内或经皮施用;优选地经口。
本发明的化合物可以因此用于预防和治疗,或优选以药物组合物的形式使用。虽然活性成分可能单独施用,但优选的是其存在于药物制剂或组合物中。因此,本发明提供了包含根据本发明的化合物和药学上可接受的稀释剂、赋形剂或载体(在本文中统称为“载体”材料)的药物制剂。本发明的药物组合物可以采用如下所述的药物制剂的形式。因此,本发明涉及包含至少一种式I化合物以及常规赋形剂的药物组合物。
用于口服施用的示例性组合物包括混悬剂(包括纳米混悬剂),其可以包含例如用于增加体积的微晶纤维素、作为悬浮剂的海藻酸或海藻酸钠、作为粘度增强剂的甲基纤维素、以及甜味剂或调味剂,例如本领域已知的那些;和速释片剂,其可含有例如微晶纤维素、磷酸二钙、淀粉、硬脂酸镁、硫酸钙、山梨糖醇、葡萄糖和/或乳糖和/或其他赋形剂、粘合剂、增量剂、崩解剂、稀释剂和润滑剂,例如如本领域已知的那些。合适的粘合剂包括淀粉、明胶、天然糖例如葡萄糖或β-乳糖、玉米甜味剂、天然和合成树胶例如阿拉伯胶、黄蓍胶或海藻酸钠、羧甲基纤维素、聚乙二醇、蜡等。崩解剂包括但不限于淀粉、甲基纤维素、琼脂、膨润土、黄原胶等。式I化合物还可以通过舌下和/或口腔含服施用通过口腔递送。模压片、压制片或冻干片是可以使用的示例性形式。示例性组合物包括将本发明化合物与速溶稀释剂例如甘露醇、乳糖、蔗糖和/或环糊精一起配制的那些。此类制剂中还可以包括高分子量赋形剂,例如纤维素(avicel)或聚乙二醇(PEG)。此类制剂还可包括有助于粘膜粘附的赋形剂,例如羟丙基纤维素(HPC)、羟丙基甲基纤维素(HPMC)、羧甲基纤维素钠(SCMC)、马来酸酐共聚物(例如,Gantrez)和控制释放的试剂例如聚丙烯酸共聚物(例如Carbopol 934)。还可以添加润滑剂、助流剂、调味剂、着色剂和稳定剂以易于制造和使用。这些剂型中使用的润滑剂包括油酸钠、硬脂酸钠、硬脂酸镁、苯甲酸钠、乙酸钠、氯化钠等。对于液体形式的口服施用,口服药物组分可以与任何口服的、无毒的、药学上可接受的惰性载体如乙醇、甘油、水等组合。
根据本发明的药物制剂包括适合于口服、肠胃外[包括皮下、皮内、肌内、静脉内(推注或输注)和关节内]、吸入(包括可以通过各种类型的计量剂量加压气雾剂产生的细颗粒粉尘或雾)、雾化器或吹入器、直肠、腹膜内和局部(包括皮肤、口腔、舌下和眼内)施用的那些,尽管最合适的途径可能取决于例如接受者的状况和病症。
适用于口服施用的本发明制剂可以作为离散单位,例如胶囊剂、扁囊剂、丸剂或片剂,每一种含有预定量的活性成分;作为粉末或颗粒呈递;作为在水性液体或非水性液体中的溶液或悬浮液,例如作为酏剂、酊、悬浮液(包括纳米悬浮液)或糖浆呈递;或作为水包油液体乳液或油包水液体乳液呈递。活性成分也可以作为丸剂、药糖剂或糊剂呈递。
片剂可通过压缩或模塑制成,任选地与一种或多种辅助成分一起。压制片剂可以通过在合适的机器中压制自由流动形式例如粉末或颗粒的活性成分来制备,任选地与粘合剂、润滑剂、惰性稀释剂、润滑剂、表面活性剂或分散剂混合。模制片可以通过在合适的机器中模制用惰性液体稀释剂润湿的粉状化合物的混合物来制备。片剂可以任选地被包衣或刻痕并且可以被配制以提供其中活性成分的缓慢或受控释放。例如,本化合物可以以适合立即释放或延长释放的形式施用。立即释放或延长释放可以通过使用包含本化合物的合适的药物组合物来实现,或者,特别是在延长释放的情况下,通过使用诸如皮下植入物或渗透泵之类的装置来实现。本化合物也可以脂质体施用。优选的单位剂量制剂是含有活性成分的有效剂量(如上文所述)或其适当部分的那些。
应该理解,除了上面特别提到的成分之外,本发明的制剂可以包括本领域中关于所讨论的制剂类型常规的其他试剂,例如那些适合口服施用的试剂可以包括调味剂。
制剂可以方便地以单位剂型存在并且可以通过药学领域众所周知的任何方法制备。所有方法都包括将活性成分与构成一种或多种辅助成分的载体结合的步骤。通常,通过将活性成分与液体载体或细碎的固体载体或两者均匀且紧密地结合,然后如果需要,将产品成型为期望制剂来制备制剂。
本发明的化合物还可以以脂质体递送系统的形式施用,例如小单层囊泡、大单层囊泡和多层囊泡。脂质体可由多种磷脂、1,2-二棕榈酰磷脂酰胆碱、磷脂酰乙醇胺(脑磷脂)、磷脂酰丝氨酸、磷脂酰肌醇、二磷脂酰甘油(心磷脂)或磷脂酰胆碱(卵磷脂)形成。
用于肠胃外施用的制剂包括水性和非水性无菌注射液,其可含有抗氧化剂、缓冲剂、抑菌剂和使制剂与预期接受者的血液等渗的溶质;以及水性和非水性无菌混悬液(包括纳米混悬液),其可包括助悬剂和增稠剂。制剂可以以单位剂量或多剂量容器呈递,例如密封的安瓿和小瓶,并且可以在冷冻干燥(冻干)条件下储存,其仅需在使用前立即添加无菌液体载体,例如盐水或注射用水。临时注射溶液和悬浮液可以由前述种类的无菌粉末、颗粒和片剂制备。用于肠胃外施用的示例性组合物包括可注射溶液或混悬液,其可包含例如合适的无毒、肠胃外可接受的稀释剂或溶剂,例如聚乙二醇、乙醇、1,3-丁二醇、水、林格氏溶液、等渗氯化钠溶液,或其他合适的分散剂或润湿剂和悬浮剂,包括合成的甘油单酯或甘油二酯,以及脂肪酸,包括油酸、聚山梨醇酯和Cremaphor。
用于鼻腔、气雾剂或吸入施用的示例性组合物包括盐水溶液,其可含有例如苯甲醇或其他合适的防腐剂、吸收促进剂以提高生物利用度,和/或其他增溶剂或分散剂,例如本领域已知的那些。
用于直肠施用的制剂可以作为栓剂与常用载体如可可脂、合成甘油酯或聚乙二醇一起呈递。这种载体在常温下通常是固体,但在直肠腔中液化和/或溶解以释放药物。
用于口腔局部施用的制剂,例如含服或舌下给药,包括包含在调味基质如蔗糖和阿拉伯胶或黄蓍胶中的活性成分的锭剂,以及包含在如明胶和甘油或蔗糖和阿拉伯胶的基质中的活性成分的含片。用于局部施用的示例性组合物包括局部载体,例如Plastibase(用聚乙烯凝胶化的矿物油)。
达到治疗效果所需的活性成分的量当然随着特定化合物,施用途径,接受治疗的对象,包括对象的类型、物种、年龄、体重、性别和医学状况,以及对象的肾和肝功能,以及正在治疗的特定病症或疾病,以及其严重程度而变化。普通熟练的医师、兽医或临床医生可以容易地确定和开出预防、对抗或阻止病症进展所需的药物的有效量。
本发明的口服剂量,当用于指定的效果时,对于成年人,范围在约0.01mg/kg体重/天(mg/kg/天)至约100mg/kg/天之间,优选0.01mg/kg体重/天(mg/kg/天)至10mg/kg/天,最优选0.1至5.0mg/kg/天。对于口服施用,组合物优选以包含0.01、0.05、0.1、0.5、1.0、2.5、5.0、10.0、15.0、25.0、50.0、100和500毫克活性成分的片剂形式或以离散单位提供的其他形式提供,以便对待治疗患者的剂量进行对症调整。药物通常含有约0.01mg至约500mg的活性成分。此外,本发明的优选化合物可以通过局部使用合适的鼻内载体以鼻内形式施用,或通过使用本领域普通技术人员公知的那些形式的经皮皮肤贴剂的经皮途径施用。为了以经皮递送系统的形式施用,剂量施用当然在整个给药方案中是连续的而不是间断的。
在一些实施方案中,组合物进一步包含另外的治疗剂。
通式(I)的化合物可以作为唯一的药剂或与一种或多种另外的治疗剂组合施用,其中该组合不会引起不可接受的副作用。这种药物组合包括施用含有通式(I)化合物和一种或多种另外的治疗剂的单一药物剂量制剂,以及施用通式(I)化合物和在其单独的药物剂量制剂中的每种另外的治疗剂。例如,通式(I)的化合物和治疗剂可以在单一口服剂量组合物例如片剂或胶囊中一起施用至患者,或者每种药剂可以以分开的剂量制剂施用。
当使用分开的剂量制剂时,通式(I)的化合物和一种或多种另外的治疗剂可以基本上同时(例如并行)或分开交错的时间(例如顺序)施用。
特别地,本发明的化合物可以与核受体、转录因子、G蛋白偶联受体、离子通道、整联蛋白、激酶或酶的效应物固定或单独组合使用。
特别地,本发明的化合物可以与以下物质固定或单独组合使用:糖皮质激素受体激动剂,例如曲安西龙、泼尼松、泼尼松龙或布地奈德;盐皮质激素受体拮抗剂,例如螺内酯、依普利酮或坎利酮;PPAR激动剂,例如罗格列酮、GFT 505、沙格列扎、吡格列酮或法格列扎;FXR激动剂,例如奥贝胆酸、Px 102或熊去氧胆酸;PXR激动剂,例如孕烯醇酮16α-腈;NR4A1激动剂,例如胞孢菌素B;Nrf2激活剂,例如甲基巴多索隆;WNT/β-连环蛋白抑制剂,例如ICG-001;趋化因子拮抗剂,例如bindarit;LPA拮抗剂,例如BMS 986020或SAR 100842;前列环素类似物,例如(+/–)贝前列素钠、伊洛前列素或曲前列素;AT1受体拮抗剂,例如氯沙坦;ETA受体拮抗剂,例如阿曲生坦、安立生坦、波生坦或马西替坦;CCR5拮抗剂,例如马拉韦罗;CCR2拮抗剂,例如RS-504393;CXCR4拮抗剂,例如AMD3100;PAR1抑制剂,例如SCH 79797;S1P配体,例如芬戈莫德(FTY720);PTGER激动剂,例如(R)-rutaprost(前药);PTGFR拮抗剂,例如AL-8810;LXA4激动剂,例如BML-111;RXFP1激动剂;5-HT2A或5-HT2B受体拮抗剂,例如沙格雷酯;P2X7拮抗剂,例如A-438079;KCa3.1/IKCa1阻滞剂,例如TRAM-34;T型Ca2+通道阻滞剂,例如依福地平;Na-K-Cl协同转运蛋白抑制剂,例如托拉塞米;αVβ6整联蛋白抑制剂,例如CWHM12;αVβ1整联蛋白抑制剂,例如c8;半乳糖凝集素3拮抗剂,例如TD139;TGF-β或p38抑制剂,例如吡非尼酮或F-351;酪氨酸激酶抑制剂,例如尼达尼布、伊马替尼或尼罗替尼;激酶抑制剂,例如索拉非尼、达沙替尼、巴瑞替尼或坦齐塞替布;PI3K–mTOR抑制剂,例如GSK2126458;MK2抑制剂,例如MMI 0100;IGFII拮抗剂,例如PXS 64或PXS 25;PKCδ抑制剂,例如rottlerin;p38 MAPK抑制剂,例如SB239063或FR-167653;RHO激酶抑制剂,例如Y-27632;FAK抑制剂,例如PF-562271;ALK5抑制剂,例如SB-431542;SMAD3抑制剂,例如SIS-3;抑制TGFβ1的肽,例如二硫特肽;PDE抑制剂,例如己酮可可碱或CTP 499;PDE5抑制剂,例如西地那非;NADPH氧化酶抑制剂,例如GKT 137831;TAFI抑制剂,例如UK 396,082;组织蛋白酶B抑制剂,例如VBY 376;半胱天冬酶抑制剂,例如emricasan;LOXL2抑制剂例如β-氨基丙腈;TGM2拮抗剂,例如NTU281;脯氨酰羟化酶抑制剂,例如HOE 077或吡啶-2,4-二羧酸盐;BMP1或BMP1样蛋白酶抑制剂,例如UK-421045;中性粒细胞弹性蛋白酶,例如ONO-5046;EPRS抑制剂,例如卤夫酮;TNKS1抑制剂,例如XAV939;ACE抑制剂,例如依那普利;ATX抑制剂,例如GWJ-A-23;AT1受体拮抗剂,例如氯沙坦;5LO抑制剂,例如齐留通;HMG-CoA还原酶抑制剂(他汀类药物),例如阿托伐他汀、氟伐他汀、洛伐他汀、匹伐他汀、普伐他汀、瑞舒伐他汀或辛伐他汀;PAI1拮抗剂,例如TM5275;FKBP12结合剂,例如西罗莫司;S100A9结合剂,例如帕喹莫德;甲基转移辅因子,例如腺苷蛋氨酸;免疫调节化合物,例如沙利度胺或泊马度胺;线粒体靶向抗氧化剂,例如线粒体醌;维生素衍生物,例如吡哆胺或α-生育酚;嘌呤拮抗剂,例如硫唑嘌呤;ROS清除剂或抗氧化剂,例如N-乙酰半胱氨酸、α-硫辛酸或α-生育酚;微管干扰物,如秋水仙碱;铜螯合剂,例如D-青霉胺;烷基化剂,例如环磷酰胺;HSP47表达抑制剂或BET抑制剂,例如(+)JQ-1;或干扰素γ-1b。
本发明的新化合物可以通过文献中描述的已知方法制备。制备本发明化合物的一般合成路线可包括以下步骤:
-双环芳香族前体的制备。
-添加取代基和结构部分以实现吡咯啉环化反应。
-环化形成稠合吡咯啉环,提供三环系统。
-吡咯啉氮的酰胺化以形成胍部分。
应当理解,可以使用保护基团(PG)并且取代基的添加、删除或转化可以是合成路线的一部分。在下面的方法描述中,为了清楚起见省略了具体的取代基和保护基化学。
吡咯啉氮的酰胺化(方案1)可以使用多种不同的方法和试剂进行,例如在高温下与MeSC(NH)NHZ或其盐在吡啶中或与脒基-吡唑反应,任选地有脒基的二-t-BOC或二-CBZ保护。受保护的脒基,例如二-t-BOC-脒基,可以通过烷基化试剂烷基化以引入Z-取代基,例如使用Mitsunobu反应。另一种酰胺化方法是使用氰胺试剂(NC-NHZ)。或者,可以使用多步反应,例如与溴化氰反应,然后是H2N-Z添加,或与异硫氰酸酯(ZN=C=S)或受保护的异硫氰酸酯(例如BzNCS,通过碱性水解脱保护)反应,然后进行S-甲基化并与胺(H2N-Z)反应得到胍产物。
环化形成三环衍生物的3-甲基-吡咯啉环(方案2)可以通过自由基诱导的2-烯丙基氨基-1-卤基-萘基衍生物环化来进行,通常X=Br或I,N-保护基团例如t-BOC(Tercel,M.et al.,J Med Chem(2003)46,2132-51)
对于3-甲基二氢吲哚所述的类似方法是通过碳锂化反应引发环化,这也允许手性配体的不对称诱导(Guyon,H.et al.,J Org Chem(2017)82,4949-57)。
用于β-四氢萘酮衍生物的一种替代的环化方法是将相应的四氢萘酮烯胺与2-溴丙酰胺烷基化(Ghosh,D.et al.,Eur J Med Chem(1995)30,943-48),然后还原内酰胺羰基。
对于吲哚-吡咯啉稠合衍生物,可以使用氧化环化方法,例如使用t-BuOCl作为氧化试剂(Kawano,M.et al.Angewandte Chemie Int Ed(2013),52(3),906-10)(方案4)。
如上所示,用于环化反应的前体化合物的结构和方法可以根据目标化合物而变化。然而,一个共同的主题是如方案5中的(d)所示例的邻位烯丙基氨基卤化物取代模式(卤化物以Br为例)。
从起始材料(a)制备氨基衍生物(b)可以通过许多不同的方法进行:例如通过还原硝基;通过Bucherer反应;通过Ullmann或Buchwald型反应;和通过Curtius型重排。或者,烯丙氨基或受保护的氨基衍生物(c)可直接从(a)制备,例如通过Bucherer反应、Ullmann或Buchwald型反应、或Curtius型重排。因此,起始材料(a)中的取代基A可以代表例如硝基、卤化物、羟基或羧酸。在起始材料(a)是烯醇/酮化合物的情况下,例如当Y是CH2并且A是OH时,可以通过烯胺形成将其转化为氨基衍生物,包括烯丙氨基衍生物。
烯丙基部分也可以通过胺衍生物(b)的烯丙基化引入,方法是在碱(例如三乙胺)或优选NaH(如果胺被酰胺或氨基甲酸酯保护基(PG)例如t-BOC或CBZ保护)存在下使胺与例如溴化烯丙酯或甲磺酸烯丙酯反应。
卤素,优选Br或I,如果不存在于起始材料中,可以通过使氨基或烯丙基氨基衍生物与卤化试剂如溴、正溴琥珀酰亚胺或碘反应而通过卤化反应引入。
在制备实施例中,NMR分析是在Varian Mercury或Bruker UltraShield机器上进行的(频率和溶剂如所示)。化合物的化学名称是使用ChemDraw 18.1(PerkinElmer)生成的。
现在将通过以下实施例更详细地描述本发明,包括这些实施例是为了公开本发明的某些实施方案,但不以任何方式限制本发明的范围。
实施例
实施例1
盐酸7-氟-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺
步骤1:(6-氟萘-2-基)氨基甲酸叔丁基酯
将二苯基磷酰基叠氮化物(7.38g,26.8mmol)加入到6-氟-2-萘甲酸(5.10g,26.8mmol)和三乙胺(2.71g,26.8mmol)在THF(85mL)中的溶液中。将反应混合物在室温搅拌48小时,然后减压浓缩。将残余物溶解在t-BuOH(95mL)中并在回流温度下搅拌7小时。冷却后,过滤除去沉淀的固体物质,减压浓缩滤液,将残余物分配在EtOAc(150mL)和水(50mL)中,用NaOH水溶液(1M,25mL)碱化。有机相用水(2×50mL)洗涤,干燥(Na2SO4),减压浓缩,得到标题化合物,为米色晶体(4.43g,63%)。
1H NMR((CD3)2SO,400MHz)δ:1.50(s,9H),7.34(dt,1H),7.54(dd,1H),7.58(dd,1H),7.79(d,1H),7.85(dd,1H),8.14(s,1H),9.58(s,1H)。
步骤2:6-氟萘-2-胺
将三氟乙酸(10mL)加入到(6-氟萘-2-基)氨基甲酸叔丁酯(4.35g,16.6mmol)在CH2Cl2(80mL)中的溶液中。将反应混合物在室温搅拌20小时,然后减压浓缩。将残余物分配在CH2Cl2(100mL)和水(75mL)中并用KHCO3水溶液(饱和)碱化。有机相用水(2×50mL)洗涤,干燥(Na2SO4),减压浓缩,得到标题化合物,为固体物质(2.65g,99%)。
1H NMR((CD3)2SO,400MHz)δ:5.35(s,2H),6.86(d,1H),6.99(dd,1H),7.18(dt,1H),7.41(dd,1H),7.56(dd,1H),7.58(d,1H)。
步骤3:1-溴-6-氟萘-2-胺
在2分钟内将N-溴代琥珀酰亚胺(2.87g,16.1mmol)分批加入6-氟萘-2-胺(2.60g,16.1mmol)在DMF(45mL)中的溶液中。在室温下搅拌反应混合物20小时后,缓慢加入水(100mL)并继续搅拌15分钟。过滤收集沉淀的晶体,用水(2×50mL)洗涤并干燥,得到标题化合物,为棕色晶体(3.60g,93%)。
1H NMR((CD3)2SO,400MHz)δ:5.73(s,2H),7.17(d,1H),7.38(dt,1H),7.56(dd,1H),7.65(d,1H),7.87(dd,1H)。
步骤4:(1-溴-6-氟萘-2-基)氨基甲酸叔丁基酯
将二碳酸二叔丁酯(9.76g,44.7mmol)加入1-溴-6-氟萘-2-胺3.58g,14.9mmol)、三乙胺(1.81g,17.9mmol)和4-二甲氨基吡啶(0.18g,1.5mmol)在CH2Cl2(75mL)中的溶液中。将反应混合物在密封容器中在55-60℃下搅拌48小时,冷却至室温并在减压下浓缩。将残余物溶解在MeOH(85mL)中,加入K2CO3(6.3g),并将反应混合物在回流温度下搅拌3小时。冷却后,加入水(125mL)并继续搅拌15分钟。过滤收集沉淀的晶体,用水(2×50mL)洗涤并干燥,得到标题化合物,为棕色晶体(4.80g,95%)。
1H NMR(CDCl3,400MHz)δ:1.58(s,9H),7.26(宽s,1H),7.34(m,1H),7.43(dd,1H),7.73(d,1H),8.15(dd,1H),8.37(d,1H)。
步骤5:(1-溴-6-氟萘-2-基)氨基甲酸叔丁基烯丙基酯
在10分钟内在氩气下在室温将NaH(668mg,油中60%,16.7mmol)分批加入(1-溴-6-氟萘-2-基)氨基甲酸叔丁酯(4.74g,13.9mmol)的干燥THF(180mL)的溶液中。将反应混合物搅拌15分钟,加入DMF(25mL),接着加入烯丙基溴(2.52g,20.8mmol),然后将反应混合物在室温搅拌24小时。加入MeOH(2mL)以淬灭残余的NaH,将反应混合物减压浓缩,并将残余物分配在Et2O(150mL)和水(100mL)中。有机相用水(2×75mL)洗涤,干燥(Na2SO4)并减压浓缩。通过硅胶柱色谱法(庚烷-EtOAc,15:1)纯化残余物,得到为油的标题化合物,其静置固化(4.10g,78%)。
1H NMR(CDCl3,400MHz)δ:1.33,1.56(2s,旋转异构体,9H),3.97(dd,1H),4.56(dd,1H),5.04-5.15(m,2H),5.96(m,1H),7.29(d,1H),7.37(m,1H),7.47(m,1H),7.71(d,1H),8.15(dd,1H),8.34(dd,1H)。
步骤6:7-氟-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-羧酸叔丁基酯
在氩气下将偶氮二异丁腈(136mg,0.83mmol)和三丁基氢化锡(3.73g,12.8mmol)加入到(1-溴-6-氟萘-2-基)氨基甲酸烯丙基叔丁酯(4.08g,10.7mmol)在苯(140mL,在氩气下脱气两次)中的溶液中。将反应混合物在回流温度下搅拌1.5小时,然后冷却并在减压下浓缩。残余物通过硅胶柱色谱法(庚烷-EtOAc,15:1)纯化,得到标题化合物,为淡黄色油,其静置固化(2.51g,78%)。
1H NMR(CDCl3,400MHz)δ:1.41(d,3H),1.61(宽s,9H),3.73-3.89(m,2H),4.18(dd,1H),7.26(dt,1H),7.44(dd,1H),7.66(d,1H),7.74(dd,1H),7.83,8.23(2宽s,旋转异构体,1H)。
步骤7:7-氟-1-甲基-2,3-二氢-1H-苯并[e]吲哚
将三氟乙酸(2.5mL)加入7-氟-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-羧酸叔丁酯(2.50g,8.29mmol)在CH2Cl2(25mL)中的溶液中。将反应混合物在室温搅拌20小时,然后减压浓缩。将残余物分配在CH2Cl2(50mL)和水(25mL)中并用KHCO3水溶液(饱和)碱化。有机相用水(2×20mL)洗涤,干燥(Na2SO4),减压浓缩,得到标题化合物,为褐色油(1.60g,96%)。
1H NMR(CDCl3,400MHz)δ:1.39(d,3H),3.37(d,1H),3.75-3.89(m,3H),7.04(d,1H),7.22(dt,1H),7.39(dd,1H),7.54(d,1H),7.67(dd,1H)。
步骤8:(((叔丁氧基羰基)亚氨基)(7-氟-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-
基)甲基)氨基甲酸叔丁酯
将N,N'-双-叔丁氧基羰基吡唑-1H-甲脒(632mg,2.04mmol)加入到7-氟-1-甲基-2,3-二氢-1H-苯并[e]吲哚(410(mg,2.04mmol)在THF(12mL)中的溶液,并将反应混合物在密封小瓶中在70℃下搅拌20小时。冷却后,将反应混合物减压浓缩,残余物通过硅胶柱色谱法(甲苯-EtOAc,50:1)纯化,得到标题化合物,为泡沫状物(90mg,10%)。
1H NMR(CDCl3,400MHz)δ:1.44(d,3H),1.48(宽s,18H),3.72(m,1H),4.01(d,1H),4.44(dd,1H),7.28(dt,1H),7.43(dd,1H),7.61(d,1H),7.69(宽s,1H),7.76(dd,1H),10.44(s,1H)。
步骤9:盐酸7-氟-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺
将三氟乙酸(0.4mL)加入到(((叔丁氧基羰基)亚氨基)(7-氟-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-基)甲基)氨基甲酸叔丁酯(90mg,0.203mmol)在CH2Cl2(2mL)中的溶液中。将反应混合物在室温搅拌20小时,然后减压浓缩。将残余物溶解在CH2Cl2(2mL)中,加入HCl/Et2O(1M,1mL),并将溶液减压蒸发至干。该过程重复两次以除去三氟乙酸。将固体残余物在Et2O(3mL)中搅拌,过滤收集,用Et2O洗涤并干燥,得到为浅绿色晶体的标题化合物(54mg,95%)。
1H NMR((CD3)2SO,400MHz)δ:1.35(d,3H),3.80(dd,3H),3.92(m,1H),4.35(dd,1H),7.50(dt,1H),7.68(d,1H),7.78(dd,1H),7.90(d,1H),7.98(dd,1H),8.12(s,4H)。
实施例2
盐酸6-溴-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺
通过实施例1中描述的方法由5-溴-2-萘甲酸制备。
1H NMR((CD3)2SO,400MHz)δ:1.35(d,3H),3.83(dd,1H),3.94(m,1H),4.38(dd,1H),7.48(t,1H),7.79(d,1H),7.82(d,1H),7.94(d,1H),8.11(d,1H),8.21(s,4H)。
实施例3
盐酸1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺
通过实施例1中描述的方法由(1-溴萘-2-基)氨基甲酸叔丁酯制备。
1H NMR((CD3)2SO,400MHz)δ:1.36(d,3H),3.81(dd,1H),3.91(m,1H),4.33(dd,1H),7.46(t,1H),7.57(t,1H),7.64(d,1H),7.89(d,1H),7.91(d,1H),7.96(d,1H),8.17(宽s,4H)。
实施例4
盐酸1-甲基-1,2-二氢-3H-吡咯并[2,3-c]异喹啉-3-甲酰亚胺酰胺
1-甲基-2,3-二氢-1H-吡咯并[2,3-c]异喹啉
通过实施例1中描述的方法从异喹啉-3-胺制备。
1H NMR(CDClC3,400MHz)δ:1.44(d,3H),3.35(dd,1H),3.80(m,1H),3.90(t,1H),7.20(ddd,1H),7.51(ddd,1H),7.60(dd,1H),7.80(d,1H),8.73(s,1H)。
步骤1:((((苄氧基)羰基)氨基)(1-甲基-1,2-二氢-3H-吡咯并[2,3-c]异喹啉-3-
基)亚甲基)氨基甲酸苄酯
将((((苄氧基)羰基)氨基)(1H-吡唑-1-基)亚甲基)氨基甲酸苄酯(945mg,2.50mmol)加入到1-甲基-2,3-二氢-1H-吡咯并[2,3-c]异喹啉(460mg,2.50mmol)的THF(15mL)溶液中。将反应混合物在室温下搅拌24小时,然后在65℃下搅拌48小时,冷却至室温,然后减压浓缩。残余物通过硅胶柱色谱法(庚烷-EtOAc,3:2)纯化,得到仍被吡唑试剂污染的材料(850mg)。将材料溶解在EtOAc(50mL)中,用水(2×25mL)洗涤,干燥有机相(Na2SO4)并减压浓缩。将残余物从庚烷-EtOAc(1:1)中重结晶,得到标题化合物,为灰色晶体(550mg,44%)。
1H NMR(CDCl3,400MHz)δ:1.45(d,3H),3.79(m,1H),4.08(dd,1H),4.36(dd,1H),5.20(s,2H),5.22(s,2H),7.28-7.50(m,11H),7.70(t,1H),7.76(d,1H),7.94(d,1H),8.84(s,1H),12.28(s,1H)。
步骤2:盐酸1-甲基-1,2-二氢-3H-吡咯并[2,3-c]异喹啉-3-甲酰亚胺酰胺
将((((苄氧基)羰基)氨基)(1-甲基-1,2-二氢-3H-吡咯并[2,3-c]异喹啉-3-基)亚甲基)氨基甲酸苄酯溶液(240mg,4.85mmol)的THF(30mL)溶液通过在室温1大气压H2(g)下用Pd/C(220mg,10%)作为催化剂搅拌48小时氢化。过滤反应混合物后,通过加入1M HCl/EtOAc酸化滤液,然后减压浓缩。将残余物通过硅胶柱色谱法(CH2Cl2-MeOH-AcOH,7:1:0.1)纯化,得到标题化合物,为灰色晶体(36mg,28%)。
1H NMR((CD3)2SO,400MHz)δ:1.43(d,3H),3.86(dd,1H),4.06(m,1H),4.35(t,1H),7.61(t,1H),7.84(t,1H),7.99(d,1H),8.21(d,1H),8.49(宽s,4H),9.12(s,1H)。
实施例5
盐酸1-甲基-1,2-二氢-3H-吡咯并[2,3-c]喹啉-3-甲酰亚胺酰胺
通过实施例4中描述的方法从喹啉-3-胺制备。
1H NMR((CD3)2SO,400MHz)δ:1.39(d,3H),3.84(d,1H),4.00(m,1H),4.37(t,1H),7.67(m,2H),8.01(m,2H),8.62(宽s,4H),9.07(s,1H)。
实施例6
盐酸N,1-二甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺
(((叔丁氧羰基)亚氨基)(1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-基)甲基)氨基甲
酸叔丁酯
通过实施例1中描述的方法由(1-溴萘-2-基)氨基甲酸叔丁酯制备。
1H NMR(CDCl3,400MHz)δ:1.41(s,9H),1.46(d,3H),1.56(s,9H),3.75(m,1H),4.03(d,1H),4.44(dd,1H),7.63-7.69(m,2H),7.39,(ddd,1H),7.49(ddd,1H),7.79(d,1H),7.82(d,1H),10.41(s,1H)。
(((叔丁氧羰基)亚氨基)(1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-基)甲基)(甲基)
氨基甲酸叔丁酯
将(((叔丁氧基羰基)亚氨基)(1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-基)甲基)氨基甲酸叔丁酯(80mg,0.19mmol)、PPh3(76mg,0.29mmol)、偶氮二羧酸二异丙酯(58mg,0.29mmol)和MeOH(9mg,29mmol)在THF(1mL)中的溶液在室温下搅拌过夜。然后在减压下浓缩反应混合物并且通过硅胶柱色谱法(庚烷-EtOAc,4:1)纯化残余物,得到呈油状的标题化合物(68mg,82%)。
1H NMR(CDCl3,400MHz)δ:1.33,1.36(2宽s,旋转异构体,9H),1.45(m,旋转异构体,3H),1.55(s,9H),3.13,3.16(2s,旋转异构体,3H),3.82(m,1H),3.91(d,1H),4.34(t,1H),7.30-7.60(宽,1H),7.40(m,1H),7.51(m,1H),7.72(宽d,1H),7.80(d,1H),7.83(d,1H)。
盐酸N,1-二甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺
通过实施例1(步骤9)中描述的方法制备为浅灰色晶体(43mg,98%)。
1H NMR((CD3)2SO,400MHz)δ:1.34(d,3H),2.94(s,3H),3.78(dd,1H),3.88(m,1H),4.37(dd,1H),7.44(t,1H),7.57(t,1H),7.58(d,1H),7.88(m,2H),7.95(d,1H),8.36(宽s,3H)。
实施例7
盐酸N-丁基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺
使用相应的醇通过实施例6中所述的方法制备。
1H NMR((CD3)2SO,400MHz)δ:0.94(t,3H),1.34(d,3H),1.40(m,2H),1.62(m,2H),3.29(m,1H),3.37(m,1H),3.78(d,1H),3.87(m,1H),4.42(t,1H),7.44(t,1H),7.52-7.59(m,2H),7.88(t,2H),7.94(d,1H),8.37(s,2H),8.53(t,1H)。
实施例8
盐酸N-苄基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺
使用相应的醇通过实施例6中所述的方法制备。
1H NMR((CD3)2SO,400MHz)δ:1.35(d,3H),3.84(dd,1H),3.89(m,1H),4.45(dd,1H),4.53(dd,1H),4.71(dd,1H),7.35(tt,1H),7.41-7.7.50(m,5H),7.55(d,1H),7.57(m,1H),7.88(d,2H),7.94(d,1H),8.52(s,2H),9.04(t,1H)。
实施例9
盐酸N-(4-氯苄基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺
使用相应的醇通过实施例6中所述的方法制备。
1H NMR((CD3)2SO,400MHz)δ:1.35(d,3H),3.84(dd,1H),3.89(m,1H),4.45(dd,1H),4.53(dd,1H),4.71(dd,1H),7.42-7.7.59(m,7H),7.88(d,2H),7.94(d,1H),8.54(s,2H),9.07(t,1H)。
实施例10
盐酸N-(3,4-二氟苄基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺
使用相应的醇通过实施例6中所述的方法制备。
1H NMR((CD3)2SO,400MHz)δ:1.35(d,3H),3.83-3.94(m,2H),4.44(dd,1H),4.54(dd,1H),4.69(dd,1H),7.34(m,1H),7.42-7.7.65(m,5H),7.88(d,2H),7.94(d,1H),8.54(s,2H),9.04(t,1H)。
实施例11
盐酸6-氯-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺
步骤1:(5-氯萘-2-基)氨基甲酸叔丁酯
由5-氯-2-萘甲酸通过实施例1中所述的方法制备(步骤1)。
1H NMR(CDCl3,400MHz)δ:1.57(s,9H),6.73(s,1H),7.34(t,1H),7.39(d,1H),7.44(d,1H),7.68(d,1H),8.09(s,1H),8.17(d,1H)。
步骤2:(1-溴-5-氯萘-2-基)氨基甲酸叔丁酯
在室温下在30分钟内将N-溴代琥珀酰亚胺(8.65g,48.6mmol)分批加入(5-氯萘-2-基)氨基甲酸叔丁酯(11.4g,41.0mmol)在MeCN(80mL)和THF(25mL)中的混合物中。搅拌1.5小时后,过滤收集固体,用冷MeCN洗涤并干燥,得到标题化合物(11.3g,77%)。
1H NMR((CD3)2SO,400MHz)δ:1.49(s,9H),6.65(dd,1H),7.75(dd,1H),7.90(d,1H),8.17(dt,1H),8.20(d,1H),8.95(s,1H)。
盐酸6-氯-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺
通过实施例1中描述的方法由(1-溴-5-氯萘-2-基)氨基甲酸叔丁酯制备。
1H NMR((CD3)2SO,400MHz)δ:1.35(d,3H),3.83(dd,1H),3.94(m,1H),4.39(dd,1H),7.55(t,1H),7.63(dd,1H),7.79(d,1H),7.90(d,1H),8.14(d,1H),8.27(s,4H)。
实施例12
6-溴-N,1-二甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺2,2,2-三氟乙酸
盐
6-溴-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-羧酸叔丁酯
通过实施例1中描述的方法由5-溴-2-萘甲酸制备。
1H NMR(CDCl3,400MHz)δ:1.40(d,3H),1.62(s,9H),3.78(m,1H),3.85(m,1H),4.20(dd,1H),7.28(dd,1H),7.63(dd,1H),7.72(d,1H),8.13(d,1H),8.26(2宽d,旋转异构体,1H)。
6-溴-1-甲基-2,3-二氢-1H-苯并[e]吲哚
由6-溴-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-羧酸叔丁酯通过实施例1中所述的方法制备(步骤7)。
1H NMR(CDCl3,400MHz)δ:1.38(d,3H),3.40(dd,1H),3.79(m,1H),3.89(dd,1H),7.08(d,1H),7.23,(dd,1H),7.51(dd,1H),7.64(dt,1H),8.03(d,1H)。
N-(6-溴-1-甲基-2,3-二氢-1H-苯并[e]吲哚-3-硫代碳酰)苯甲酰胺
将异硫氰酸苯甲酰酯(0.24g,1.46mmol)添加到6-溴-1-甲基-2,3-二氢-1H-苯并[e]吲哚(0.38g,1.46mmol)在MeCN(20mL)中的溶液中。将反应混合物在室温下搅拌过夜。过滤收集沉淀物并用乙腈洗涤。浓缩母液,将残留物从甲醇/水中重结晶。过滤收集沉淀物并与第一批收获物合并。产量0.60g(97%)。
1H NMR(SO(CD3)2,400MHz)δ:1.41(d,3H),3.85(m,1H),4.31(d,1H),4.56(dd,1H),7.46–7.56(m,3H),7.65(t,1H),7.67-8.05(宽,1H),7.82(d,1H),7.90(宽d,1H),7.95-8.01(m,3H),11.41(s,1H)。
6-溴-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-硫代碳酰胺
将N-(6-溴-1-甲基-2,3-二氢-1H-苯并[e]吲哚-3-硫代碳酰)苯甲酰胺(1.20g,2.82mmol)和吡咯烷(2.00g,2.82mmol)的THF(45mL)溶液在氩气下在60℃下搅拌20小时。冷却后,将反应混合物浓缩并通过硅胶柱色谱法(庚烷-EtOAc,1:1)纯化残余物,得到呈白色晶体的标题化合物(645mg,71%)。
1H NMR(SO(CD3)2,400MHz)δ:1.31(d,3H),3.86(m,1H),3.96(d,1H),4.34(t,1H),7.42(t,1H),7.75(d,1H),7.80-8.00(宽,2H),7.90(d,1H),7.99(d,1H),9.16(d,1H)。
6-溴-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-硫代碳酰亚胺甲酯氢碘酸盐
将MeI(265mg,1.87mmol)添加到6-溴-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-硫代碳酰胺(200mg,0.62mmol)在EtOH(10mL)中的溶液中。将反应混合物在密封小瓶中在30℃搅拌过夜,然后在减压下浓缩。将残余物在Et2O/MeOH中回流搅拌10分钟。冷却后,过滤收集固体并用Et2O洗涤,得到标题化合物(270mg,94%)。
1H NMR(SO(CD3)2,400MHz)δ:1.39(d,3H),2.80(s,3H),4.03(m,1H),4.10(dd,1H),4.55(dd,1H),7.54(t,1H),7.91(d,1H),8.03(d,1H),8.18(s,2H),9.66(s,2H)。
6-溴-N,1-二甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺2,2,2-三氟乙酸 盐将MeNH2水溶液(40%,0.150mmol)添加到6-溴-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-硫代碳酰亚胺甲酯氢碘酸盐(23mg,0.050mmol)在叔戊醇(0.5mL)中的溶液中。将反应混合物在密封小瓶中在80℃搅拌2天,然后用水和甲醇稀释,用TFA酸化,并通过HPLC(Gemini NX-C18,21*150mm,水(0.1%TFA)/乙腈纯化,得到呈白色固体的标题化合物(19mg,88%)。
1H NMR(SO(CD3)2,400MHz)δ:1.34(d,3H),2.94(d,3H),3.80(d,1H),3.91(m,1H),4.37(t,1H),7.47(t,1H),7.72(d,1H),7.80(d,1H),7.92(d,1H),8.10(d,1H),8.33(s,2H),8.46(m,1H)。
实施例13
6-溴-N-乙基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺2,2,2-三氟乙
酸盐
使用相应的胺通过实施例12中所述的方法制备。
1H NMR(SO(CD3)2,400MHz)δ:1.24(t,3H),1.34(d,3H),3.27-3.44(m,2H),3.81(dd,1H),3.91(m,1H),4.38(dd,1H),7.47(t,1H),7.71(d,1H),7.80(d,1H),7.93(d,1H),8.11(d,1H),8.31(s,2H),8.47(t,1H)。
实施例14
6-溴-1-甲基-N-丙基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺2,2,2-三氟乙
酸盐
使用相应的胺通过实施例12中所述的方法制备。
1H NMR(SO(CD3)2,400MHz)δ:0.97(t,3H),1.34(d,3H),1.65(m,2H),3.20-3.37(m,2H),3.81(d,1H),3.91(m,1H),4.40(dd,1H),7.48(t,1H),7.70(d,1H),7.81(d,1H),7.93(d,1H),8.12(d,1H),8.32(s,2H),8.48(t,1H)。
实施例15
6-溴-N-丁基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺2,2,2-三氟乙
酸盐
使用相应的胺通过实施例12中所述的方法制备。
1H NMR(SO(CD3)2,400MHz)δ:0.95(t,3H),1.34(d,3H),1.40(m,2H),1.62(m,2H),3.22-3.40(m,2H),3.80(d,1H),3.90(m,1H),4.39(t,1H),7.47(t,1H),7.69(d,1H),7.80(d,1H),7.93(d,1H),8.12(d,1H),8.32(s,2H),8.45(t,1H)。
实施例16
6-溴-N-异丙基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺2,2,2-三氟
乙酸盐
使用相应的胺通过实施例12中所述的方法制备。
1H NMR(SO(CD3)2,400MHz)δ:1.25(d,3H),1.31(d,3H),1.34(d,3H),3.80(d,1H),3,85-3.96(m,2H),4.39(t,1H),7.47(t,1H),7.68(d,1H),7.80(d,1H),7.92(d,1H),8.12(d,1H),8.30(s,2H),8.37(d,1H)。
实施例17
N-烯丙基-6-溴-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺2,2,2-三氟
乙酸盐
使用相应的胺通过实施例12中所述的方法制备。
1H NMR(SO(CD3)2,400MHz)δ:1.35(d,3H),3.83(dd,1H),3.87-4.09(m,3H),4.41(dd,1H),5.27(dd,1H),5.34(dd,1H),5.96(m,1H),7.48(t,1H),7.72(d,1H),7.81(d,1H),7.93(d,1H),8.11(d,1H),8.34(s,2H),8.69(t,1H)。
实施例18
6-溴-1-甲基-N-(丙-2-炔-1-基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺2,
2,2-三氟乙酸盐
使用相应的胺通过实施例12中所述的方法制备。
1H NMR(SO(CD3)2,400MHz)δ:1.34(d,3H),3.51(t,1H),3.81(d,1H),3.92(m,1H),4.18(m,1H),4.28(m,1H),4.40(t,1H),7.49(t,1H),7.72(d,1H),7.82(d,1H),7.94(d,1H),8.12(d,1H),8.54(s,2H),8.96(t,1H)。
实施例19
6-溴-N-环丙基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺2,2,2-三氟
乙酸盐
使用相应的胺通过实施例12中所述的方法制备。
1H NMR(SO(CD3)2,400MHz)δ:0.73-0.95(m,4H),1.33(d,3H),2.70(m,1H),3.80(d,1H),3.90(m,1H),4.35(t,1H),7.47(t,1H),7.65(t,1H),7.80(d,1H),7.92(d,1H),8.10(d,1H),8.47(s,2H),8.80(s,1H)。
实施例20
6-溴-N-环己基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺2,2,2-三氟
乙酸盐
使用相应的胺通过实施例12中所述的方法制备。
1H NMR(SO(CD3)2,400MHz)δ:1.6(m,1H),1.26-1.49(m,4H),1.34(d,3H),1.63(m,1H),1.76(m,2H),1.97(m,2H),3.56(m,1H,水峰下),3.79(dd,1H),3.90(m,1H),4.40(dd,1H),7.47(t,1H),7.67(t,1H),7.80(d,1H),7.92(d,1H),8.11(d,1H),8.31(s,2H),8.36(d,1H)。
实施例21
6-溴-N-(2-氟乙基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺2,2,2-
三氟乙酸盐
使用相应的胺通过实施例12中所述的方法制备。
1H NMR(SO(CD3)2,400MHz)δ:1.35(d,3H),3.76(m,1H),3.82(m,2H),3.91(m,1H),4.41(dd,1H),4.67(dt,2H),7.48(t,1H),7.72(d,1H),7.82(d,1H),7.94(d,1H),8.11(d,1H),8.44(s,2H),8.71(t,1H)。
实施例22
6-溴-1-甲基-N-(2,2,2-三氟乙基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺
2,2,2-三氟乙酸盐
使用相应的胺通过实施例12中所述的方法制备。
1H NMR(SO(CD3)2,400MHz)δ:1.35(d,3H),3.83(dd,1H),3.94(m,1H),4.15-4.50(2m,2H),4.45(dd,1H),7.50(t,1H),7.68(d,1H),7.84(d,1H),7.96(d,1H),8.14(d,1H),8.76(s,2H),9.15(s,1H)。
实施例23
6-溴-N-(2-甲氧基乙基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺2,
2,2-三氟乙酸盐
使用相应的胺通过实施例12中所述的方法制备。
1H NMR(SO(CD3)2,400MHz)δ:1.34(d,3H),3.40-3.64(m,4H,部分在水峰下),3.80(dd,1H),3.91(m,1H),4.40(dd,1H),7.48(t,1H),7.73(d,1H),7.81(d,1H),7.93(d,1H),8.10(d,1H),8.34(s,2H),8.56(t,1H)。
实施例24
N-苄基-6-溴-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺2,2,2-三氟乙
酸盐
使用相应的胺通过实施例12中所述的方法制备。
1H NMR(SO(CD3)2,400MHz)δ:1.35(d,3H),3.87(d,1H),3.92(m,1H),4.44(t,1H),4.52(dd,1H),4.65(dd,1H),7.33-7.40(m,1H),7.42-7.51(m,5H),7.71(d,1H),7.81(d,1H),7.93(d,1H),8.10(d,1H),8.46(s,2H),8.97(t,1H)。
实施例25
6-溴-1-甲基-N-(4-甲基苄基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺2,2,
2-三氟乙酸盐
使用相应的胺通过实施例12中所述的方法制备。
1H NMR(SO(CD3)2,400MHz)δ:1.34(d,3H),2.32(s,3H),3.85(dd,1H),3.91(m,1H),4.39-4.50(m,2H),4.58(dd,1H),7.25(d,2H),7.35(d,2H),7.48(t,1H),7.69(d,1H),7.81(d,1H),7.93(d,1H),8.09(d,1H),8.44(s,2H),8.94(t,1H)。
实施例26
6-溴-N-(4-氟苄基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺2,2,2-
三氟乙酸盐
使用相应的胺通过实施例12中所述的方法制备。
1H NMR(SO(CD3)2,400MHz)δ:1.34(d,3H),3.86(dd,1H),3.92(m,1H),4.43(dd,1H),4.50(dd,1H),4.62(dd,1H),7.28(t,2H),7.45-7.55(m,3H),7.70(d,1H),7.81(d,1H),7.93(d,1H),8.10(d,1H),8.47(s,2H),8.95(t,1H)。
实施例27
6-溴-N-(4-甲氧基苄基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺2,
2,2-三氟乙酸盐
使用相应的胺通过实施例12中所述的方法制备。
1H NMR(SO(CD3)2,400MHz)δ:1.34(d,3H),3.77(s,3H),3.84(d,1H),3.91(m,1H),4.39-4.47(m,2H),4.56(dd,1H),7.00(d,2H),7.40(d,2H),7.47(t,1H),7.68(d,1H),7.81(d,1H),7.93(d,1H),8.09(d,1H),8.43(s,2H),8.91(t,1H)。
实施例28
6-溴-1-甲基-N-苯基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺2,2,2-三氟乙
酸盐
使用相应的胺通过实施例12中所述的方法制备。
1H NMR(SO(CD3)2,400MHz)δ:1.40(d,3H),3.92-4.01(m,2H),4.45(t,1H),7.26(t,1H),7.35(d,2H),7.46(t,2H),7.50(t,1H),7.70(d,1H),7.83(d,1H),7.96(d,1H),8.08(d,1H),8.70(s,2H),10.44(s,1H)。
实施例29
6-溴-1-甲基-N-(p-甲苯基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺2,2,2-
三氟乙酸盐
使用相应的胺通过实施例12中所述的方法制备。
1H NMR(SO(CD3)2,400MHz)δ:1.39(d,3H),2.32(s,3H),3.93(d,1H),3.96(m,1H),4.43(t,1H),7.24(d,2H),7.28(d,2H),7.49(t,1H),7.70(d,1H),7.82(d,1H),7.96(d,1H),8.08(d,1H),8.60(s,2H),10.35(s,1H)。
实施例30
6-溴-N-(4-氟苯基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺2,2,2-
三氟乙酸盐
使用相应的胺通过实施例12中所述的方法制备。
1H NMR(SO(CD3)2,400MHz)δ:1.40(d,3H),3.91-4.02(m,2H),4.45(t,1H),7.32(t,2H),7.41(m,2H),7.50(t,1H),7.74(d,1H),7.83(d,1H),7.96(d,1H),8.10(d,1H),8.62(s,2H),10.40(s,1H)。
实施例31
6-溴-N-(4-氯苯基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺2,2,2-
三氟乙酸盐
使用相应的胺通过实施例12中所述的方法制备。
1H NMR(SO(CD3)2,400MHz)δ:1.40(d,3H),3.92-4.02(m,2H),4.45(t,1H),7.47-7.56(m,3H),7.72(d,1H),7.84(d,1H),7.97(d,1H),8.09(d,1H),8.72(s,2H),10.47(s,1H)。
实施例32
6-溴-N-(4-甲氧基苯基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺2,
2,2-三氟乙酸盐
使用相应的胺通过实施例12中所述的方法制备。
1H NMR(SO(CD3)2,400MHz)δ:1.39(d,3H),3.78(s,3H),3.90-4.00(m,2H),4.43(t,1H),7.04(d,2H),7.31(d,2H),7.49(t,1H),7.74(d,1H),7.82(d,1H),7.96(d,1H),8.10(d,1H),8.46(s,2H),10.25(s,1H)。
实施例33
6-氟-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺2,2,2-三氟乙酸盐
6-氟-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-羧酸叔丁酯
在-75℃下在Ar(g)下将n-BuLi(0.35mL,2.5M己烷溶液,0.875mmol)滴加(5分钟)到6-溴-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-羧酸叔丁酯(316mg,0.872mmol)在THF(3mL)中的溶液中。将反应混合物在-75℃下搅拌1小时,然后分批加入N-氟苯磺酰亚胺(275mg,0.872mmol)并将反应混合物在-75℃下搅拌1小时,然后在室温下搅拌过夜。加入水(1mL),然后将反应混合物分配在EtOAc(10mL)和水(5mL)中。有机相用水洗涤并减压浓缩。将残余物通过硅胶柱色谱法(庚烷-EtOAc,25:1)纯化,得到油状标题化合物(185mg,70%,被脱卤副产物污染)。1H NMR(CDCl3,400MHz)δ:1.41(d,3H),1.62(s,9H),3.73-3.87(m,2H),4.19(dd,1H),6.99(ddd,1H),7.38(dt,1H),7.52(d,1H),8.00(d,1H),8.24(宽,1H)。
6-氟-1-甲基-2,3-二氢-1H-苯并[e]吲哚
由6-氟-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-羧酸叔丁酯通过实施例1中所述的方法制备(步骤7)。通过二氧化硅柱色谱法(CH2Cl2)纯化粗产物以得到呈油状的标题化合物(61mg,49%)。1H NMR(CDCl3,400MHz)δ:1.39(d,3H),3.40(dd,1H),3.80(m,1H),3.89(t,1H),6.87(ddd,1H),7.06(d,1H),7.33(ddd,1H),7.45(dt,1H),7.89(d,1H)。
6-氟-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺2,2,2-三氟乙酸盐
由6-氟-1-甲基-2,3-二氢-1H-苯并[e]吲哚通过实施例4中描述的方法制备,然后进行HPLC纯化。
1H NMR(SO(CD3)2,400MHz)δ:1.36(d,3H),3.81(dd,1H),3.92(m,1H),4.36(dd,1H),7.28(dd,1H),7.57(td,1H),7.71-7.77(m,2H),8.00-8.08(m,5H)。
实施例34
6-碘-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺2,2,2-三氟乙酸盐
6-碘-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-羧酸叔丁酯
在-78℃下在氩下将n-BuLi(2M己烷溶液,0.304mL,0.607mol)加入6-溴-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-羧酸叔丁酯(200mg,0.552mmol)在THF(1.5mL)中的溶液中。在搅拌5分钟后,逐滴加入I2(210mg,0.828mmol)在THF(0.5mL)中的溶液,然后在3小时内使反应混合物缓慢升温至室温。加入盐水(10mL)并用EtOAc(3x10mL)萃取混合物。有机相用分相器干燥并减压浓缩。将残余物通过硅胶柱色谱法(庚烷-EtOAc,100:1-10)纯化,得到标题化合物(138mg,61%)。
1H NMR((CD3)2SO,400MHz)δ:1.30(d,3H),1.54(s,9H),3.76(d,1H),3.84(m,1H),4.17(t,1H),7.24(t,1H),7.86-7.91(m,2H),7.98(d,1H),7.95-8.30(宽,1H)。
6-碘-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺2,2,2-三氟乙酸盐在最后一步由6-碘-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-羧酸叔丁酯通过实施例12中所述的方法使用NH3水溶液(28%)制备。
1H NMR((CD3)2SO,400MHz)δ:1.34(d,3H),3.83(dd,1H),3.93(m,1H),4.37(dd,1H),7.32(t,1H),7.74(d,2H),7.95(d,1H),7.99(d,1H),8.00(s,4H),8.09(d,1H)。
实施例35
1-甲基-6-(三氟甲基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺2,2,2-三氟
乙酸盐
1-甲基-6-(三氟甲基)-1,2-二氢-3H-苯并[e]吲哚-3-羧酸叔丁酯
将6-碘-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-羧酸叔丁酯(100mg,0.244mmol)、2,2-二氟-2-(氟磺酰)乙酸甲酯(0.174mL,1.38mmol)和CuI(246mg,1.29mmol)在DMF(2mL)中的溶液在70℃下搅拌过夜。冷却后,反应混合物用水(20mL)稀释并用庚烷-EtOAc(3×10mL)萃取。有机相用盐水(3x10mL)洗涤,通过硅藻土过滤并在减压下浓缩,得到呈红色油的标题化合物(133mg,定量,带有残留溶剂)。
1H NMR((CD3)2SO,400MHz)δ:1.32(d,3H),1.55(s,9H),3.76(dd,1H),3.91(m,1H),4.17(t,1H),7.63(t,1H),7.83(d,1H),7.98(d,1H),8.05-8.30(宽,1H),8.16(d,1H)。
1-甲基-6-(三氟甲基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺2,2,2-三氟 乙酸盐在最后一步由1-甲基-6-(三氟甲基)-1,2-二氢-3H-苯并[e]吲哚-3-羧酸叔丁酯通过实施例12中所述的方法使用NH3(28%)水溶液制备。
1H NMR((CD3)2SO,400MHz)δ:1.36(d,3H),3.83(d,1H),3.99(m,1H),4.37(t,1H),7.72(t,1H),7.85(d,1H),7.94(d,1H),8.01(s,4H),8.06(d,1H),8.24(d,1H)。
实施例36
6-甲氧基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺2,2,2-三氟乙酸
盐
1-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1,2-二氢-3H-苯并
[e]吲哚-3-羧酸叔丁值
将6-溴-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-羧酸叔丁酯(300mg,0.828mmol)、双(频哪醇)二硼烷(231mg,0.911mmol)、AcOK(244mg,2.48mmol)和PdCl2(dppf)(30mg,0.04mmol)在二噁烷(5mL)中的混合物在氮气下在密封小瓶中在80℃下搅拌3小时。冷却后,反应混合物用水稀释并用庚烷萃取。有机相用水、NaHCO3水溶液和盐水洗涤,干燥(Na2SO4)并减压浓缩。通过硅胶柱色谱法(庚烷-EtOAc,100:0-10)纯化残余物,得到呈白色固体的标题化合物(230mg,68%)。
1H NMR((CD3)2SO,400MHz)δ:1.29(d,3H),1.30(s,12H),1.55(s,9H),3.73(dd,1H),3.83(m,1H),4.13(t,1H),7.49(t,1H),7.82(d,1H),7.96(d,1H),7.83-8.15(宽,1H),8.50(d,1H)。
6-羟基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-羧酸叔丁酯
将1-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1,2-二氢-3H-苯并[e]吲哚-3-羧酸叔丁酯(230mg,0.562mmol)和30%H2O2水溶液(0.574mL,5.62mmol)在MeCN(30mL)中的混合物在40℃下搅拌12小时。冷却后,将反应混合物浓缩以除去大部分溶剂,然后用EtOAc稀释。有机相用0.1M HCl、NaHCO3水溶液和盐水洗涤,干燥(Na2SO4),过滤并在减压下浓缩,得到呈黄色油状的粗标题化合物(180mg,定量),将其直接用于下一步。
6-甲氧基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-羧酸叔丁酯
将粗6-羟基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-羧酸叔丁酯(90mg,0.30mmol)、K2CO3(124mg,0.90mmol)和MeI(0.056mL,0.90mmol)在MeCN(5mL)中的混合物在室温下搅拌5天。然后将反应混合物浓缩,用庚烷-EtOAc稀释并用水、NaHCO3水溶液和盐水洗涤,干燥(Na2SO4)并减压浓缩。通过硅胶柱色谱法(庚烷-EtOAc,100:0-10)纯化残余物,得到呈白色固体的标题化合物(70mg,74%)。
1H NMR((CD3)2SO,400MHz)δ:1.29(d,3H),1.53(s,9H),3.71(dd,1H),3.78(m,1H),3.94(s,3H),4.13(t,1H),6.82(d,1H),7.34-7.44(m,2H),7.80-8.10(宽,1H),8.04(d,1H)。
6-甲氧基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺2,2,2-三氟乙酸 盐在最后一步由6-甲氧基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-羧酸叔丁酯通过实施例 12中所述的方法使用NH3水溶液(28%)制备。
1H NMR((CD3)2SO,500MHz)δ:1.34(d,3H),3.78(dd,1H),3.87(m,1H),3.97(s,3H),4.33(dd,1H),6.93(d,1H),7.43(d,1H),7.50(t,1H),7.60(d,1H),7.94(宽,4H),8.12(d,1H)。
实施例37
1-甲基-6-(甲硫基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺2,2,2-三氟乙
酸盐
1-甲基-6-((三异丙基甲硅烷基)硫基)-1,2-二氢-3H-苯并[e]吲哚-3-羧酸叔丁
酯
将NaH(油中60%,48mg,1.20mmol)加入到6-溴-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-羧酸叔丁酯(362mg,1.00mmol)、三异丙基硅烷硫醇(229mg,1.10mmol)和PdCl2(dppf)(37mg,0.05mmol)在甲苯(5mL)中的混合物中。将反应混合物在氮气下于100℃搅拌1小时。冷却后,将反应混合物减压浓缩,将残余物通过硅胶柱色谱法(庚烷-EtOAc,100:0-5)纯化,得到油状标题化合物,静置固化(370mg,78%)。
1H NMR(CDCl3,400MHz)δ:1.03,1.05(2d,18H),1.28(m,3H),1.40(d,3H),1.61(s,9H),3.72-3.90(m,2H),4.18(t,1H),7.29(t,1H),7.59(d,1H),7.65(d,1H),8.24(宽,1H),8.64(d,1H)。
1-甲基-6-(甲硫基)-1,2-二氢-3H-苯并[e]吲哚-3-羧酸叔丁酯
将四正丁基氟化铵(在THF中1M,0.941mL,0.941mmol)加入到1-甲基-6-((三异丙基甲硅烷基)硫基)-1,2-二氢-3H-苯并[e]吲哚-3-羧酸叔丁酯(370mg,0.784mmol)和MeI(223mg,1.57mmol)在THF(20mL)中的溶液中。将反应混合物在室温搅拌1小时。在减压下浓缩反应混合物并且通过硅胶柱色谱法(庚烷-EtOAc,100:0-10)纯化残余物,得到呈白色固体的标题化合物(230mg,89%)。
1H NMR((CD3)2SO,400MHz)δ:1.30(d,3H),1.54(s,9H),2.57(s,3H),3.73(dd,1H),3.82(m,1H),4.14(t,1H),7.26(d,1H),7.47(t,1H),7.64(d,1H),7.80-8.15(宽,1H),8.01(d,1H)。
1-甲基-6-(甲硫基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺2,2,2-三氟乙
酸盐
在最后一步由1-甲基-6-(甲硫基)-1,2-二氢-3H-苯并[e]吲哚-3-羧酸叔丁酯通过实施例12中所述的方法使用NH3水溶液(28%)制备。
1H NMR((CD3)2SO,500MHz)δ:1.34(d,3H),2.59(s,3H),3.80(dd,1H),3.91(m,1H),4.34(dd,1H),7.36(d,1H),7.55(t,1H),7.69(d,1H),7.70(d,1H),7.92(s,4H),8.10(d,1H)。
实施例38
1-甲基-6-(甲基亚硫酰基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺2,2,2-
三氟乙酸盐
将1-甲基-6-(甲硫基)-1,2-二氢-3H-苯并[e]吲哚-3-羧酸叔丁酯(70mg,0.21mmol)和间氯过氧苯甲酸(70%,52mg,0.21mmol)在CH2Cl2(2mL)中的混合物在室温下搅拌过夜。将反应混合物用庚烷-EtOAc稀释,然后用水、0.1M NaOH、饱和NaHCO3和盐水洗涤,干燥(Na2SO4)并减压浓缩。在最后一步将粗产物1-甲基-6-(甲基亚硫酰基)-1,2-二氢-3H-苯并[e]吲哚-3-羧酸叔丁酯通过实施例12中所述的方法使用NH3水溶液(28%)进一步转化。
1H NMR((CD3)2SO,500MHz)δ:1.37,1.37(2d,3H),2.81,2.82(2s,3H),3.82(m,1H),3.97(m,1H),4.34,4.37(2t,1H),7.75,7.76(2d,1H),7.81(t,1H),7.96-8.07(m,6H),8.10(d,1H)。
实施例39
1-甲基-6-(甲基磺酰基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺2,2,2-三
氟乙酸盐
在第一步由1-甲基-6-(甲硫基)-1,2-二氢-3H-苯并[e]吲哚-3-羧酸叔丁酯通过实施例38中所述的方法使用3当量间氯过氧苯甲酸制备。
1H NMR((CD3)2SO,500MHz)δ:1.36(d,3H),3.30(s,3H),3.84(dd,1H),4.00(m,1H),4.37(dd,1H),7.79(t,1H),7.87(d,1H),8.02(s,4H),8.17(d,1H),8.30(d,1H),8.62(d,1H)。
实施例40
6-乙炔基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺2,2,2-三氟乙酸
盐
1-甲基-6-((三甲基甲硅烷基)乙炔基)-1,2-二氢-3H-苯并[e]吲哚-3-羧酸叔丁
酯
在氮气下将PdCl2(PPh3)2(39mg,0.055mmol)和CuI(11mg,0.058mmol)添加到6-溴-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-羧酸叔丁酯(200mg,0.552mmol)、Et3N(0.500mL,3.59mmol)和三甲基甲硅烷基乙炔(0.229mL,1.66mmol)在THF(1.5mL)中的脱气溶液中。将反应混合物在60℃搅拌过夜。LC-MS表明反应不完全,加入额外批次的三甲基甲硅烷基乙炔(0.300mL)、Pd和CuI催化剂(各约10mg)并继续搅拌24小时。冷却后,将反应混合物用EtOAc稀释,通过硅藻土过滤,并在减压下浓缩洗脱液。将残余物通过硅胶柱色谱法(庚烷-EtOAc,100:0-10)纯化,得到标题化合物(210mg,100%)。
1H NMR((CD3)2SO,400MHz)δ:0.31(s,9H),1.31(d,3H),1.54(s,9H),3.74(dd,1H),3.84(m,1H),4.16(t,1H),7.48(t,1H),7.57(d,1H),7.89(d,1H),8.10(d,1H)。1H不可见(在类似衍生物中宽或很宽)。
6-乙炔基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺2,2,2-三氟乙酸
盐
在最后一步由1-甲基-6-((三甲基甲硅烷基)乙炔基)-1,2-二氢-3H-苯并[e]吲哚-3-羧酸叔丁酯通过实施例12中所述的方法使用NH3水溶液(28%)制备。脱甲硅烷基化(TMS基团丢失)发生在第二步(异硫氰酸苯甲酰反应)。
1H NMR((CD3)2SO,500MHz)δ:1.35(d,3H),3.81(d,1H),4.93(m,1H),4.36(dd,1H),4.68(s,1H),7.58(t,1H),7.70(d,1H),7.76(d,1H),7.86-8.01(m,5H),8.20(d,1H)。
实施例41
盐酸1-甲基-6-苯基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺
1-甲基-6-苯基-1,2-二氢-3H-苯并[e]吲哚-3-羧酸叔丁酯
在氩气下将PdCl2(dppf)添加到6-溴-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-羧酸叔丁酯(300mg,0.828mmol)在脱气二噁烷(7.2mL)的溶液中。将反应混合物在室温搅拌30分钟。添加苯基硼酸(151mg,1.24mmol)和K2CO3(343mg,2.48mmol)在脱气水(1.3mL)中的溶液并在90℃下继续搅拌20小时。冷却后,将反应混合物在EtOAc和水中分配,有机相用水洗涤并减压浓缩。残余物通过硅胶柱色谱法(庚烷-EtOAc,30:1)纯化,得到油状标题化合物(230mg,77%)。1H NMR(CDCl3,400MHz)δ:1.46(d,3H),1.60(s,9H),3.80-3.93(m,2H),4.21(dd,1H),7.29(dd,1H),7.42-7.54(m,5H),7.65-7.90(m,3H),8.13(宽,1H)。
盐酸1-甲基-6-苯基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺
通过实施例4中描述的方法由1-甲基-6-苯基-1,2-二氢-3H-苯并[e]吲哚-3-羧酸叔丁酯制备。
1H NMR((CD3)2SO,400MHz)δ:1.38(d,3H),3.82(d,1H),3.94(m,1H),4.34(t,1H),7.35(d,1H),7.43-7.57(m,5H),7.62(dd,1H),7.69(s,2H),7.85-7.95(m,5H)。
实施例42
盐酸6-环丙基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺
由6-溴-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-羧酸叔丁酯和环丙基硼酸通过实 施例41中所述的方法制备,然后进行HPLC纯化。
1H NMR((CD3)2SO,400MHz)δ:0.71(m,1H),1.06(m,2H),1.34(d,3H),2.40(m,1H),3.80(dd,1H),3.90(m,1H),4.34(dd,1H),7.21(d,1H),7.47(t,1H),7.69(d,1H),7.74(d,1H),7.98(s,4H,8.37(d,1H)。
实施例43
盐酸1-甲基-6-丙基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺
由在实施例42的制备中作为最终cbz脱保护(氢化)步骤中的副产物的((((苄氧基)羰基)亚氨基)(6-环丙基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-基)甲基)氨基甲酸苄酯制备。
1H NMR((CD3)2SO,400MHz)δ:0.96(t,3H),1.35(d,3H),1.69(m,2H),3.01(m,2H),3.79(dd,1H),3.90(m,1H),4.33(dd,1H),7.31(d,1H),7.49(t,1H),7.65(d,1H),7.75(d,1H),7.95(s,4H),8.06(d,1H)。
实施例44
盐酸5-甲氧基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺
5-(苄氧基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-羧酸叔丁酯
通过实施例1中描述的方法(步骤5和6)从(4-(苄氧基)-1-碘萘-2-基)氨基甲酸叔丁酯制备,为淡黄色胶状物(685mg,89%)。
1H NMR(CD3OD,400MHz)δ:1.41(d,3H),1.62(s,9H),3.69-3.86(m,2H),4.19(dd,1H),5.28(s,2H),7.33(t,1H),7.38(t,1H),7.45(t,2H),7.49(t,1H),7.57(d,2H),7.71(d,1H),7.89(宽s,1H),8.30(d,1H)。
5-羟基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-羧酸叔丁酯
在氩气下将甲酸铵(325mg,5.16mmol)在水(1.6mL)中的溶液,然后Pd/C(10%,140mg)加入到5-(苄氧基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-羧酸叔丁酯(232mg,0.645mmol)在THF(8mL)中的溶液中。将反应混合物在35℃下搅拌1.5小时,冷却并过滤。滤液在EtOAc(30mL)和水(15mL)中分配,然后有机相用水(2×15mL)洗涤并减压浓缩。通过硅胶柱色谱法(庚烷-EtOAc,5:1)纯化残余物,得到呈固体物质的标题化合物(187mg,97%)。
1H NMR(CDCl3,400MHz)δ:1.39(d,3H),1.61(s,9H),3.68-3.83(m,2H),4.18(t,1H),6.40(宽s,1H),7.32(t,1H),7.47(t,1H),7.69(d,1H),7.78(宽s,1H),8.18(d,1H)。
5-甲氧基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-羧酸叔丁酯
将5-羟基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-羧酸叔丁酯(187mg,0.624mmol)、K2CO3(173mg,1.25mmol)和MeI(133mg,0.936mol)在DMF(5mL)中的混合物在氩气下在室温下搅拌20小时。然后将混合物分配在Et2O(30mL)和水(20mL)中,有机相用水(2×15mL)洗涤,干燥(Na2SO4)并减压浓缩。通过硅胶柱色谱法(庚烷-EtOAc,10:1)纯化残余物,得到呈油状的标题化合物(144mg,74%)。
盐酸5-甲氧基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺
在最后一步由5-甲氧基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-羧酸叔丁酯通过实施例12中描述的方法使用NH3的EtOH溶液(5M,20当量)制备,接着进行盐交换(通过在HCl/EtOAc中重复蒸发,将碘化物交换为氯化物)并通过硅胶柱色谱法(EtOAc-MeOH-AcOH,100:40:3)进行纯化。
1H NMR(CD3OD,400MHz)δ:1.43(d,3H),3.79-3.89(m,2H),4.05(s,3H),4.39(dd,1H),7.10(s,1H),7.42(t,1H),7.57(t,1H),7.82(d,1H),7.21(d,1H)。
实施例45
盐酸6-氯-5-氟-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺
(5-氯-4-氟萘-2-基)氨基甲酸叔丁酯
将5-氯-4-氟萘-2-胺(2.34g,10.1mmol)、二碳酸二叔丁酯(5.99g,2.74mmol)、三乙胺(2.15g,2.12mmol)和4-二甲氨基吡啶(0.12g,1.0mmol)在CH2Cl2(55mL)中的溶液在60℃下在密封烧瓶中搅拌20小时。冷却后,加入另外的二碳酸二叔丁酯(5.99g,2.74mmol)并在60℃下继续搅拌3天。冷却后,反应混合物用水(40mL)洗涤,过滤,将洗脱液减压浓缩。残余物通过硅胶柱色谱法(庚烷-EtOAc,10:1)纯化,得到标题化合物,为米色晶体(1.40g,47%)。
1H NMR((CD3)2SO,400MHz)δ:1.51(s,9H),7.41-7.50(m,3H),7.81(dt,1H),7.97(d,1H),9.85(s,1H)。
(1-溴-5-氯-4-氟萘-2-基)氨基甲酸叔丁酯
由(5-氯-4-氟萘-2-基)氨基甲酸叔丁酯按实施例11所述方法制备(步骤2),得到标题化合物,为米色晶体(1.65g,94%)。
1H NMR(CDCl3,400MHz)δ:1.58(s,9H),7.40(s,1H),7.41-7.51(m,2H),8.12(d,1H),8.34(d,1H)。
盐酸6-氯-5-氟-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺
通过实施例1(步骤5-7)和实施例12中描述的方法,使用NH3的EtOH溶液(5M,20eq.)并且EtOH作为最后一步中的溶剂,然后进行盐交换(通过添加HCl/EtOAc进行碱性处理和HCl盐沉淀,从(1-溴-5-氯-4-氟萘-2-基)氨基甲酸叔丁酯制备。
1H NMR(CD3OD,400MHz)δ:1.43(d,3H),3.84-3.95(m,2H),4.41(dd,1H),7.47-7.58(m,3H),7.85(dt,1H)。
实施例46
盐酸N-(3-脒基-1-甲基-2,3-二氢-1H-苯并[e]吲哚-6-基)乙酰胺
(1-溴-5-硝基萘-2-基)氨基甲酸叔丁基烯丙酯
通过实施例11和实施例1中描述的方法从5-硝基-2-萘甲酸制备(步骤5)。
1H NMR(CDCl3,400MHz)δ:1.34(s,9H),4.01(dd,1H),4.56(dd,1H),5.03-5.17(m,2H),5.96(m,1H),7.50(d,1H),7.69(t,1H),8.25(d,1H),8.46(d,1H),8.71(d,1H)。
(5-氨基-1-溴萘-2-基)氨基甲酸叔丁基烯丙酯
将SnCl2·H20(873mg,3.87mmol)加入到(1-溴-5-硝基萘-2-基)氨基甲酸叔丁基烯丙酯(450mg,1.1mmol)在EtOAc(20mL)中的溶液中并且将反应混合物在室温下搅拌20小时。加入EtOAc(20mL)和NaHCO3饱和水溶液(20mL)并继续搅拌5分钟。进行相分离,水相用EtOAc(15mL)萃取。合并有机相,用水(20mL)洗涤,干燥(Na2SO4)并减压浓缩。残余物通过硅胶柱色谱法(庚烷-EtOAc,3:1)纯化,得到标题化合物,为米色晶体(280mg,67%)。
1H NMR(CDCl3,400MHz)δ:1.33(s,9H),3.96(dd,1H),4.57(dd,1H),5.03-5.24(m,2H),5.97(m,1H),6.94(d,1H),7.25(d,1H),7.43(t,1H),7.79-7.86(m,2H)。
(5-乙酰氨基-1-溴萘-2-基)(烯丙基)氨基甲酸叔丁酯
将AcCl(64mg,0.82mmol)添加到(5-氨基-1-溴萘-2-基)氨基甲酸叔丁基烯丙酯(280mg,0.74mmol)和NEt3(83mg,0.82mmol)在CH2Cl2(10mL)中的溶液中,然后将反应混合物在室温下搅拌20小时,用水(5mL)洗涤并在减压下浓缩。残余物通过硅胶柱色谱法(庚烷-EtOAc,3:1)纯化,得到标题化合物,为米色晶体(260mg,84%)。
1H NMR(CDCl3,400MHz)δ:1.32,1.61(2s,9H),3.83,3.96(2dd,1H),4.43,4.55(2dd,1H),5.01-5.21(m,2H),5.94(m,1H),6.94(d,1H),7.08-8.42(m,6H)。由于旋转异构体混合物的比例约为5:3,光谱复杂。
盐酸N-(3-脒基-1-甲基-2,3-二氢-1H-苯并[e]吲哚-6-基)乙酰胺
通过实施例1(步骤6和7)和实施例4中描述的方法从(5-乙酰氨基-1-溴萘-2-基)(烯丙基)氨基甲酸叔丁酯制备。
1H NMR(CD3OD,400MHz)δ:1.35(d,3H),2.19(s,3H),3.81(dd,1H),3.91(m,1H),4.35(dd,1H),7.36(t,1H),7.61(d,1H),7.64(d,1H),7.71(d,1H),8.05(d,1H),8.14(s,4H),10.03(s,1H)。
实施例47
二盐酸6-(二甲基氨基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺
6-(二甲氨基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-羧酸叔丁酯
在氩气下将6-溴-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-羧酸叔丁酯(290mg,0.800mmol)、HNMe2(2.20mL,THF中2M,4.40mmol)、t-BuONa(128mg,1.33mol)、(±)-BINAP(24mg,0.038mmol)和三(二亚苄基丙酮)二钯(0)(12mg,0.013mmol)在甲苯(20mL)中的混合物在110℃搅拌20小时。冷却后,过滤反应混合物,滤液用水(10mL)洗涤并减压浓缩。通过硅胶柱色谱法(庚烷-EtOAc,10:1)纯化残余物,得到呈棕色油状的标题化合物(260mg,99%)。
1H NMR(CDCl3,400MHz)δ:1.41(d,3H),1.61(s,9H),2.90(s,6H),3.74-3.90(m,2H),4.18(dd,1H),6.95(d,1H),7.19(m,1H),7.35-7.48(m,2H),8.15(d,1H)。
二盐酸6-(二甲基氨基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺
由6-(二甲氨基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-羧酸叔丁酯通过实施例1(步骤7)和实施例4中所述的方法制备。
1H NMR(CD3OD,400MHz)δ:1.47(d,3H),3.45(s,6H),3.95(d,1H),4.01(m,1H),4.44(t,1H),7.74(t,1H),7.88(d,1H),7.94(d,1H),7.97(s,1H),8.10(d,1H),8.34(d,1H)。
实施例48
盐酸6-(N,N-二甲基氨磺酰)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰
胺。
6-(1,3-二氧杂异二氢吲哚-2-基)-N,N-二甲基萘-1-磺酰胺
在5分钟内将二甲胺(21.5mL,THF中2M,43.0mmol)加入到6-(1,3-二氧杂异二氢吲哚-2-基)萘-1-磺酰氯(15.2g,40.9mmol)和NEt3(4.14g,40.9mmol)在THF(270mL)中的溶液中,然后将反应混合物在室温下搅拌过夜。在减压下浓缩至约100mL,加入水(400mL)并将混合物搅拌15分钟。过滤收集沉淀产物,用水洗涤,干燥,得到黄色晶体状标题化合物(15.2g,98%)。
1H NMR((CD3)2SO,400MHz)δ:2.79(s,6H),7.77(t,1H),7.84(dd,1H),7.95(m,2H),8.02(m,2H),8.18(d,1H),8.23(d,1H),8.36(d,1H),8.79(d,1H)。
6-氨基-N,N-二甲基萘-1-磺酰胺
将水合肼(1.97g,39.4mmol)添加到6-(1,3-二氧杂异二氢吲哚-2-基)-N,N-二甲基萘-1-磺酰胺(15.0g,39.4mmol)在MeOH(200mL)中的浆液中并将反应混合物在回流温度加热8小时。冷却后,过滤混合物,减压浓缩滤液。将残余物分配在EtOAc(250mL)和水(150mL)中。在减压下浓缩有机相并且通过硅胶柱色谱法(庚烷-EtOAc,1:1)纯化残余物以得到呈油状的标题化合物(5.90g,60%)。
1H NMR((CD3)2SO,400MHz)δ:2.70(s,6H),5.69(s,2H),6.93(d,1H),7.09(dd,1H),7.41(dd,1H),7.62(dd,1H),7.82(d,1H),8.36(d,1H),8.79(d,1H)。
(5-(N,N-二甲基氨磺酰)萘-2-基)氨基甲酸叔丁酯
将6-氨基-N,N-二甲基萘-1-磺酰胺(5.90g,2.36mmol)、二碳酸二叔丁酯(5.40g,2.48mmol)和4-二甲氨基吡啶(0.29g,2.4mmol)在THF(60mL)中的溶液在65℃下搅拌40小时。冷却后,将反应混合物减压浓缩,残余物通过硅胶柱色谱法(庚烷-EtOAc,3:1)纯化,得到标题化合物,为白色晶体(4.97g,60%)。
1H NMR(CDCl3,400MHz)δ:1.57(s,9H),2.80(s,6H),6.74(s,1H),7.39(dd,1H),7.51(dd,1H),7.99(d,1H),8.05(dd,1H),8.21(s,1H),8.71(d,1H)。
盐酸6-(N,N-二甲基氨磺酰)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰
胺。
通过实施例11(步骤2)和实施例1(步骤5-9)中描述的方法从(5-(N,N-二甲基氨磺酰)萘-2-基)氨基甲酸叔丁酯制备。
1H NMR(CD3OD,400MHz)δ:1.47(d,3H),2.81(s,6H),3.93(d,1H),4.00(m,1H),4.43(t,1H),7.71(t,1H),7.84(d,1H),8.10(d,1H),8.23(d,1H),8.78(d,1H)。
实施例49
在配体置换试验中确定与在CHO-K1细胞中表达的人受体蛋白结合的5-HT2B受体(在Eurofins Panlabs Taiwan,Ltd.进行),其使用3H-麦角酸二乙酰胺(LSD)作为放射性配体和酮丝氨酸作为标准参考化合物,或者替代地*,以3H-美舒麦角和SB 206553作为参考。数据表示为指定化合物浓度下放射性配体的%置换,参见表1。
表1.
实施例50
5-HT2B受体拮抗作用(在Eurofins Panlabs Taiwan,Ltd.进行)在表达人类受体蛋白的CHO-K1细胞中测定为抑制5-HT(5nM)刺激的IP-1积累,通过HTRF定量测量。SB 206553用作标准参考化合物。拮抗反应表示为对5-HT诱导作用的%抑制,见表2。
表2.
结果证明了与受体结合效力一致的有效拮抗作用。
实施例51
5-HT2B受体激动作用(在Eurofins Panlabs Taiwan,Ltd.进行)在与上述实施例50中所述相同的模型中测定,无需预先用5-HT刺激。激动反应表示为5-HT(1uM)刺激诱导的IP-1积累的%,见表3。
表3.
结果证明不存在激动作用。
实施例52
在博莱霉素诱导的小鼠皮肤纤维化中的抗纤维化作用。
通过每隔一天皮下注射博莱霉素(2.5mg/kg)三或六周,在雌性DBA/2小鼠中诱导皮肤纤维化。
对于预防性治疗,将小鼠用博来霉素攻击三周,同时建立口服管饲治疗。对于治疗性治疗,首先通过在没有治疗的情况下注射博莱霉素三周来诱导纤维化。此后,开始口服管饲治疗,同时继续注射博来霉素。分别在首次注射博来霉素进行预防性和治疗性处理后三或六周分析结果。注射了0.9%NaCl(博莱霉素的载体)的小鼠作为非纤维化对照,用ddH2O(测试化合物的载体)经口管饲治疗的小鼠作为阴性对照。
n=8只雌性DBA/2小鼠的第1-8组:
预防性给药共3周
1. 0.9%NaCl(注射)和ddH2O(口服)第1-3周。
2.博来霉素(注射)和ddH2O(口服)第1-3周。
3.博来霉素(注射)和测试化合物(10mg/kg,每天一次,口服)第1-3周。
治疗性给药共6周
4. 0.9%NaCl(注射)第1-6周和ddH2O(口服)第4-6周。
5.博来霉素(注射)第1-3周,0.9%NaCl(注射)第4-6周,ddH2O(口服)第4-6周。
6.博来霉素(注射)第1-6周和ddH2O(口服)第4-6周。
7.博来霉素(注射)第1-6周和测试化合物(1mg/kg,每天一次,口服)第4-6周。
8.博来霉素(注射)第1-6周和测试化合物(10mg/kg,每天一次,口服)第4-6周。
测试化合物:
盐酸1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺(实施例3)
每天制备测试化合物在ddH2O中的新鲜溶液。
读数:
真皮厚度
切除上背部皮肤的特定区域,随后在4%福尔马林中固定6小时,然后包埋在石蜡中。切下皮肤切片并用苏木精/伊红染色。真皮厚度(测量为任意单位的表皮-真皮边界到真皮-皮下边界之间的距离)在来自不同部位的4个不同切片中进行量化,每个切片进行2次测量。分析以盲法进行。
肌成纤维细胞计数
肌成纤维细胞的特征在于α-平滑肌肌动蛋白(αSMA)的表达。通过与单克隆抗αSMA抗体(克隆1A4,Sigma-Aldrich,德国Steinheim)一起温育,从上背部的石蜡包埋载玻片中检测到αSMA阳性的成纤维细胞。用辣根过氧化物酶标记的二抗和3,3-二氨基联苯胺四盐酸盐(DAB)(Sigma-Aldrich)可视化该表达。单克隆小鼠IgG抗体(Calbiochem,San Diego,CA,USA)用于对照。分析由不知情的审阅者进行,评估每个样品四个切片的肌成纤维细胞。
羟脯氨酸测定
皮肤样品中胶原蛋白的量(ug/mL)是通过羟脯氨酸测定法确定的。在6M HCl中在120℃下消化取自上背部的全皮肤厚度穿孔活检三小时后,用6M NaOH将样品的pH值调节至6。然后,将0.06M氯胺T添加到每个样品中,并在室温下温育20分钟。接下来,加入3.15M高氯酸和20%对二甲氨基苯甲醛,并将样品在60℃下再温育20分钟。使用SpectraMAX 190微孔板分光光度计,使用由纯化的I型胶原蛋白(Sigma-Aldrich)生成的标准曲线,在557nm处测定吸光度。
统计和结果
所有数据均表示为组平均值(±SEM),并且通过对非相关样品的Mann-Whitney U非参数检验来测试组间差异的统计显著性。P值小于0.05被认为是显著显著的。
***:与第2组相比,p<0,001。
+:0,01<p<0,05,++:0,001<p<0,01,和+++:p<0,001,这是与第5组相比。
##:0,001<p<0,01和###:p<0,001,这是与第6组相比。
结论
博莱霉素攻击的小鼠出现显著的皮肤纤维化,皮肤增厚、肌成纤维细胞分化和羟脯氨酸含量增加。
与媒介物处理的、博来霉素攻击的小鼠相比,用测试化合物的预防性和治疗性处理均显著降低了皮下增厚、肌成纤维细胞计数和羟脯氨酸含量。在治疗方案中,与1mg/kg/qd相比,10mg/kg/qd的剂量显示出更有效的抗纤维化作用。
Claims (35)
1.通式I的化合物
其中
环A
表示含有0-3个独立地选自N、O和S的杂原子的5-6元芳族或杂芳族环;
R1、R2和R3独立地选自氢、甲基、乙基、正丙基、异丙基、环丙基、叔丁基、乙炔基、CF3、羟基、甲氧基、乙氧基、异丙氧基、OCF3、S(O)2OH、SCH3、S(O)CH3、S(O)2CH3、S(O)2NH2、S(O)2N(CH3)2、NH2、NHCH3、N(CH3)2、NHC(O)CH3、C(O)N(CH3)2、F、Cl、Br、I、CN和含有0-3个独立地选自N、O和S的杂原子的5-6元芳族或杂芳族环;
X-Y,其中X通过单键或双键连接到Y或不存在,选自CH=CH、C(CH3)=CH、C(F)=CH、C(Cl)=CH、C(OMe)=CH、CH2-CH2、N=CH、CH=N、N=N、O-CH2、O-C(O)、NH、NCH3、O或S;
Z选自氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、新丁基、叔丁基、烯丙基、2-丙炔基、环丙基、环丙基甲基、环戊基、环己基、CF3、CH2CF3、CH2CH2F、CH2CH2CF2CF3、CH2CH2OCH3、苯基、苄基、羟基和甲氧基,其中所述苯基和苄基任选地被独立地选自甲基、甲氧基、F、Cl和CF3的取代基单或二取代;和
其药学上可接受的盐、互变异构体和立体异构体。
4.根据权利要求1至3中任一项所述的化合物,
其中
Z选自氢、甲基、乙基、正丙基、异丙基、正丁基、环丙基、烯丙基、2-丙炔基、CH2CH2F、CH2CF3、CH2CH2CF2CF3、苯基和苄基,其中所述苯基和苄基任选地被独立地选自甲基、甲氧基、F、Cl和CF3的取代基单或二取代。
8.根据权利要求1所述的化合物,所述化合物选自:
1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N,1-二甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-丁基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-烯丙基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
1-甲基-N-(丙-2-炔-1-基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-(2-氟乙基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-苄基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-(4-氟苄基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-(3,4-二氟苄基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-(4-氯苄基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
1-甲基-N-(4-(三氟甲基)苄基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-(4-甲氧基苄基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
1-甲基-N-苯基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-(4-氟苯基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-(4-氯苯基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
1-甲基-N-(4-(三氟甲基)苯基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-(4-甲氧基苯基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-氟-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-氯-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-氯-N,1-二甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-丁基-6-氯-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-烯丙基-6-氯-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-氯-1-甲基-N-(丙-2-炔-1-基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-氯-N-(2-氟乙基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-苄基-6-氯-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-氯-1-甲基-N-苯基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-N,1-二甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-N-乙基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-1-甲基-N-丙基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-N-丁基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-N-异丙基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-烯丙基-6-溴-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-1-甲基-N-(丙-2-炔-1-基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-N-环丙基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-N-环己基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-N-(2-氟乙基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-1-甲基-N-(2,2,2-三氟乙基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-N-(2-甲氧基乙基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-苄基-6-溴-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-1-甲基-N-(4-甲基苄基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-N-(4-氟苄基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-N-(4-甲氧基苄基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-1-甲基-N-苯基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-1-甲基-N-(p-甲苯基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-N-(4-氟苯基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-N-(4-氯苯基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-N-(4-甲氧基苯基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-碘-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
1,6-二甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-乙炔基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
1-甲基-6-苯基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-环丙基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
1-甲基-6-丙基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
1-甲基-6-(三氟甲基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N,1-二甲基-6-(三氟甲基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-丁基-1-甲基-6-(三氟甲基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-烯丙基-1-甲基-6-(三氟甲基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
1-甲基-N-(丙-2-炔-1-基)-6-(三氟甲基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-(2-氟乙基)-1-甲基-6-(三氟甲基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-苄基-1-甲基-6-(三氟甲基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
1-甲基-N-苯基-6-(三氟甲基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-甲氧基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
1-甲基-6-(甲硫基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
1-甲基-6-(甲基亚硫酰基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
1-甲基-6-(甲基磺酰基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
5-甲氧基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-(3-脒基-1-甲基-2,3-二氢-1H-苯并[e]吲哚-6-基)乙酰胺;
6-(二甲基氨基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-(N,N-二甲基氨磺酰)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-氯-7-氟-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-氯-5-氟-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
5-氟-6-甲氧基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
5,6-二氟-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
7-氟-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
7-氟-N,1-二甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-丁基-7-氟-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-烯丙基-7-氟-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
7-氟-1-甲基-N-(丙-2-炔-1-基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
7-氟-N-(2-氟乙基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-苄基-7-氟-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
7-氟-1-甲基-N-苯基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
5,7-二氟-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
1-甲基-1,2-二氢-3H-吡咯并[2,3-c]异喹啉-3-甲酰亚胺酰胺;和
1-甲基-1,2-二氢-3H-吡咯并[2,3-c]喹啉-3-甲酰亚胺酰胺。
9.根据权利要求1所述的化合物,所述化合物选自:
7-氟-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
1-甲基-1,2-二氢-3H-吡咯并[2,3-c]异喹啉-3-甲酰亚胺酰胺;
1-甲基-1,2-二氢-3H-吡咯并[2,3-c]喹啉-3-甲酰亚胺酰胺
N,1-二甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-丁基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-苄基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-(4-氯苄基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-(3,4-二氟苄基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-氯-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-N,1-二甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-N-乙基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-1-甲基-N-丙基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-N-丁基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-N-异丙基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-烯丙基-6-溴-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-1-甲基-N-(丙-2-炔-1-基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-N-环丙基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-N-环己基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-N-(2-氟乙基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-1-甲基-N-(2,2,2-三氟乙基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-N-(2-甲氧基乙基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-苄基-6-溴-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-1-甲基-N-(4-甲基苄基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-N-(4-氟苄基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-N-(4-甲氧基苄基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-1-甲基-N-苯基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-1-甲基-N-(p-甲苯基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-N-(4-氟苯基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-N-(4-氯苯基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-溴-N-(4-甲氧基苯基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-氟-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-碘-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
1-甲基-6-(三氟甲基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-甲氧基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
1-甲基-6-(甲硫基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
1-甲基-6-(甲基亚硫酰基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
1-甲基-6-(甲基磺酰基)-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-乙炔基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
1-甲基-6-苯基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-环丙基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
1-甲基-6-丙基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
5-甲氧基-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
6-氯-5-氟-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;
N-(3-脒基-1-甲基-2,3-二氢-1H-苯并[e]吲哚-6-基)乙酰胺;
6-(二甲基氨基)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺;和
6-(N,N-二甲基氨磺酰)-1-甲基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰亚胺酰胺。
10.根据权利要求1至9中任一项的化合物,其用作药物。
11.根据权利要求1至9中任一项的化合物,其用于治疗纤维化、心血管疾病、疼痛、IBD、炎性疾病或癌症。
12.根据权利要求1至9中任一项所述的化合物,其用于治疗纤维化,其中所述纤维化选自系统性硬化症、皮肤纤维化、肝纤维化、心脏纤维化、肾纤维化、肠纤维化、肺纤维化,包括特发性肺纤维化(IPF)和与肺动脉高压(PAH)相关的纤维化,以及与移植、手术、狭窄或瘢痕疙瘩相关的纤维化。
13.根据权利要求1至9中任一项所述的化合物,其用于治疗选自动脉粥样硬化和高血压的心血管疾病。
14.根据权利要求1至9中任一项所述的化合物,其用于治疗选自偏头痛和与炎性疾病相关的疼痛的疼痛。
15.根据权利要求1至9中任一项所述的化合物,其用于治疗选自克罗恩病和溃疡性结肠炎的IBD。
16.根据权利要求1至9中任一项所述的化合物,其用于治疗炎性关节疾病,包括类风湿性关节炎(RA)和骨关节炎(OA)。
17.根据权利要求1至9中任一项所述的化合物,其用于治疗癌症,包括产生细胞外基质的癌症,例如乳腺癌、胰腺癌和肝癌。
18.根据权利要求1至9中任一项所述的化合物在制备用于治疗纤维化、心血管疾病、疼痛、IBD、炎性疾病或癌症的药物中的用途。
19.根据权利要求1至9中任一项所述的化合物在制备用于治疗纤维化的药物中的用途,其中所述纤维化选自系统性硬化症、皮肤纤维化、肝纤维化、心脏纤维化、肾纤维化、肠纤维化、肺纤维化,包括特发性肺纤维化(IPF)和与肺动脉高压(PAH)相关的纤维化,以及与移植、手术、狭窄或瘢痕疙瘩相关的纤维化。
20.根据权利要求1至9中任一项所述的化合物在制备用于治疗心血管疾病的药物中的用途,所述心血管疾病选自动脉粥样硬化和高血压。
21.根据权利要求1至9中任一项所述的化合物在制备用于治疗疼痛的药物中的用途,所述疼痛选自偏头痛和与炎性疾病相关的疼痛。
22.根据权利要求1至9中任一项所述的化合物在制备用于治疗IBD的药物中的用途,所述IBD选自克罗恩病和溃疡性结肠炎。
23.根据权利要求1至9中任一项所述的化合物在制备用于治疗包括类风湿性关节炎(RA)和骨关节炎(OA)在内的炎性关节疾病的药物中的用途。
24.根据权利要求1至9中任一项所述的化合物在制备用于治疗癌症的药物中的用途,所述癌症包括产生细胞外基质的癌症,例如乳腺癌、胰腺癌和肝癌。
25.一种治疗纤维化、心血管疾病、疼痛、IBD、炎性疾病或癌症的方法,包括向有需要的患者施用治疗有效量的根据权利要求1至9中任一项所述的化合物。
26.一种治疗纤维化的方法,其中所述纤维化选自系统性硬化症、皮肤纤维化、肝纤维化、心脏纤维化、肾纤维化、肠纤维化、肺纤维化,包括特发性肺纤维化(IPF)和与肺动脉高压(PAH)相关的纤维化,以及与移植、手术、狭窄或瘢痕疙瘩相关的纤维化,所述方法包括向有需要的患者施用治疗有效量的权利要求1至9中任一项所述的化合物。
27.一种治疗选自动脉粥样硬化和高血压的心血管疾病的方法,包括向有需要的患者施用治疗有效量的权利要求1至9中任一项所述的化合物。
28.一种治疗选自偏头痛和与炎性疾病相关的疼痛的疼痛的方法,包括向有需要的患者施用治疗有效量的权利要求1至9中任一项所述的化合物。
29.一种治疗选自克罗恩病和溃疡性结肠炎的IBD的方法,包括向有需要的患者施用治疗有效量的权利要求1至9中任一项所述的化合物。
30.一种治疗包括类风湿性关节炎(RA)和骨关节炎(OA)在内的炎性关节疾病的方法,包括向有需要的患者施用治疗有效量的权利要求1至9中任一项所述的化合物。
31.一种治疗癌症的方法,所述癌症包括产生细胞外基质的癌症,例如乳腺癌、胰腺癌和肝癌,所述方法包括向有需要的患者施用治疗有效量的权利要求1至9中任一项所述的化合物。
32.一种药物组合物,其包含与一种或多种药学上可接受的赋形剂或载体混合的权利要求1至9中任一项所述的化合物。
33.根据权利要求32的组合物,其中所述赋形剂选自填充剂、润滑剂、调味剂、着色剂、甜味剂、缓冲剂、酸化剂、稀释剂和防腐剂。
34.根据权利要求32或权利要求33所述的组合物,其被配制成经口、经口吸入、肌肉内、静脉内、腹膜内或皮下、经由植入物、直肠、鼻内或经皮施用;优选地经口施用。
35.根据权利要求32至34中任一项所述的组合物,其进一步包含另外的治疗剂。
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IL288514A (en) | 2022-01-01 |
AU2020295685A1 (en) | 2021-12-23 |
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