CN113321640A - 一种吲哚类化合物及其应用 - Google Patents
一种吲哚类化合物及其应用 Download PDFInfo
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- CN113321640A CN113321640A CN202110124967.0A CN202110124967A CN113321640A CN 113321640 A CN113321640 A CN 113321640A CN 202110124967 A CN202110124967 A CN 202110124967A CN 113321640 A CN113321640 A CN 113321640A
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- acetyl
- indole
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- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 title claims abstract description 15
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 title claims abstract description 15
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
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Abstract
本发明提供一种吲哚化合物及其应用,所述化合物可有效抑制CBP/EP300Bromodomain受体,可作为癌症、炎症疾病及自身免疫疾病、败血症、病毒感染的药物。
Description
本发明为申请号为201710480445.8、申请日为2017年6月22日、名称为一种吲哚类化合物及其应用的分案申请。
技术领域
本发明涉及化学医药技术领域,具体涉及一种吲哚类化合物及其应用。
背景技术
Bromodomain是一类进化保守,可以介导蛋白-蛋白相互作用的模块。Bromodomain是组蛋白乙酰化的读者,可特异性识别组蛋白乙酰化赖氨酸残基,从而影响靶基因的转录和翻译,该蛋白复合的功能异常与多种疾病的发生相关,这使得Bromodomain蛋白成为一类新颖的靶点。Bromodomain蛋白的抑制剂具有重要的生物学意义,例如已有大量化合物被报道其在癌症、炎症疾病及自身免疫疾病、败血症、病毒感染等疾病具有疗效。
Bromodomain蛋白因首先在果蝇基因中发现而得名,自此溴结构域蛋白在很多核蛋白中发现,如组蛋白乙酰转移酶(HATs),ATP依赖的染色质重塑复合物,甲基转移酶和转录共激活因子等。人类蛋白质组编码的61种溴结构域,目前存在于46个不同的核蛋白和胞质蛋白中。Bromodomain蛋白家族根据其功能可划分为8个亚家族。其中组蛋白乙酰化转移酶是其中一类,它包括:CBP、EP300、P/CAF和GCN5等。 CBP与EP300为同源蛋白。
CBP/EP300是cAMP反应元件结合蛋白CREB的多功能转录辅激活因子,它参与多种生理过程:细胞周期调控、细胞分化和细胞凋亡等。CBP/EP300蛋白通过自身的HAT发挥转录因子与靶DNA之间的桥梁作用;可以抑制细胞复制,使细胞停留在G1期;CBP/EP300蛋白本身具有抑癌因子的功能,同时还参与多条抑癌信息传导通路。CBP/EP300除与复发性急性淋巴细胞白血病、RTS和神经退行性疾病有关以外,同时还与***癌、炎症治疗(肺炎症和哮喘)相关等各种疾病相关。靶向CBP/EP300蛋白有助于为癌症、神经退行性疾病和炎症等疾病提供新的治疗策略。
周明明和其团队在研究中发现CBP Bromodomain与p53蛋白中肿瘤抑制基因KAc382相互作用。为了抑制CBP-p53的相互作用,周明明和同事利用核磁共振技术发现了CBP/EP300 Bromodomain小分子抑制剂MS2126和MS7972。随后,通过表观遗传学筛选和靶向生物化学等手段的应用,已有一些的小分子化合物被发现,但目前无进入临床研究的化合物。
发明内容
针对现有技术中存在的技术问题,本发明提供一种吲哚化合物及其应用,所述化合物可有效抑制 CBP/EP300 Bromodomain受体,可作为癌症、炎症疾病及自身免疫疾病、败血症、病毒感染的药物。
为达到上述目的,本发明采用以下技术方案:
本发明目的之一在于提供一种吲哚类化合物,所述化合物就有下述化学式I和化学式II的结构:
式I中,R1为C1~C4烷基,R2为H、C1~C7烷基、-R-X1或-X2,R3为H、C1~C5烷基、C3~C5环烷基、-OX3、-NHX3或-N(X3)2;
其中,R为C1~C4亚烷基,X1为-OX3、-COOX4、-CONHX4、环烷基、杂环基、-COX5或-S(O)mX5, X2为C3~C7环烷基、苯基、萘基、杂环基、-COX5或-S(O)mX5;
其中,m为0或2,X4和X5独立地为H、C1~C4烷基、C3~C7环烷基、苯基、萘基或杂环基;
式II中,R4为C1~C4烷基,R5为C1~C7烷基、-R′-Y1、Y1′-(C1-C4次烷基)-Y1或Y2,R6为H、C1~C5烷基、C3~C5环烷基、-OY3、-NHY3或-N(Y3)2;
其中,R′为C1~C4亚烷基,Y1为-NHCOOtBu、C3~C7环烷基、苯基、萘基、-OY4、-COY4、-COOY4、 -NHCOY4或-S(O)mY4,Y1′为-NHCOOtBu、C3~C7环烷基、苯基、萘基、-OY4、-COY4、-COOY4、-NHCOY4或-S(O)mY4,Y2为C3~C7环烷基、苯基、萘基或杂环基;
其中,m为0或2,Y4为H、C1~C4烷基、C3~C7环烷基、苯基、萘基或杂环基。
其中,式I中,R1可以是C1、C2、C3或C4烷基,R2可以是C1、C2、C3、C4、C5、C6或C7烷基,R3可以是C1、C2、C3、C4或C5烷基,R3可以是C3、C4或C5环烷基,R可以是C1、C2、C3或C4亚烷基, X2可以是C3、C4、C5、C6或C7环烷基,X4和X5独立地可以是C1、C2、C3或C4烷基,X4和X5独立地可以是C3、C4、C5、C6或C7环烷基。
其中,式II中,R4可以是C1、C2、C3或C4烷基,R5可以是C1、C2、C3、C4、C5、C6或C7烷基,Y1′-(C1-C4次烷基)-Y1中次烷基可以是C1次烷基、C2次烷基、C3次烷基或C4次烷基,R6可以是C1、 C2、C3、C4或C5烷基,R6可以是C3、C4或C5环烷基,R′可以是C1、C2、C3或C4亚烷基,Y1可以是C3、 C4、C5、C6或C7环烷基,Y1′可以是C3、C4、C5、C6或C7环烷基,Y2可以是C3、C4、C5、C6或C7环烷基,Y4可以是C1、C2、C3或C4烷基,Y4可以是C3、C4、C5、C6或C7环烷基。
作为本发明优选的技术方案,所述式I中R1包括甲基、乙基、正丙基、异丙基或叔丁基。
优选地,所述式I中R2包括-R-X1或-X2,其中R为C1~C2亚烷基,X1为-COOX4、-CONHX4、环烷基或杂环基,X2为-COX5或-S(O)2X5,其中X5为C1~C3烷基、C3~C7环烷基、苯基、萘基或杂环基。
优选地,所述式I中R3包括H、甲基、乙基、正丙基、异丙基、正丁基、正戊基、环丙基、环丁基、环戊基、酚羟基、甲氧基、乙氧基、丙氧基、丁氧基、氮甲基、氮乙基、氮丙基或氮丁基。
优选地,所述式II中R4包括甲基、乙基、正丙基、异丙基或叔丁基。
优选地,所述式II中R5包括-R′-Y1或Y2,其中R′为C1~C4亚烷基,Y1为C3~C7环烷基、苯基、萘基、-OY4、-COY4、-COOY4、-NHCOY4或-S(O)2Y4,Y2为C3~C7环烷基、苯基、萘基或杂环基,其中 Y4为H、C1~C4烷基、C3~C7环烷基、苯基、萘基或杂环基。
优选地,所述式II中R6包括H、甲基、乙基、正丙基、异丙基、正丁基、正戊基、环丙基、环丁基、环戊基、酚羟基、甲氧基、乙氧基、丙氧基、丁氧基、氮甲基、氮乙基、氮丙基或氮丁基。
作为本发明优选的技术方案,式I中所述C3~C7环烷基、苯基以及萘基含有0~3个取代基,取代基个数可以是0、1、2或3个。
优选地,所述取代基为卤素、C1~C4烷基、三氟甲基、氰基、硝基、氨基、酰胺、-COOX6、-COX6、 -OX6、-NHCOX6、-C6H5X7、吗啉基、哌啶基、呋喃基、四氢呋喃基或吡啶基其中X6为H、C1~C4烷基、苯基,X7为C1~C4烷基、卤素、三氟甲基、氰基、硝基、氨基、酰胺、乙酰基、甲氧基或乙氧基。
其中,取代基可以是C1、C2、C3或C4烷基,X6可以是C1、C2、C3或C4烷基,X7可以是C1、C2、C3或C4烷基。
作为本发明优选的技术方案,式I中所述杂环基为氮杂环丁基、氧杂环丁基、氮杂环戊基、氧杂环戊基、氮杂环己基、氧杂环己基、氮杂环己基、咪唑-2-酮基、咪唑基、呋喃基、噻吩基、噁唑基、异噁唑基、嘧啶基、吡咯基、哌嗪基、四氢吡咯基、哌啶基、吗啉基、1,3-二氧戊环基或苯并[d]噻唑基。
优选地,式I中所述杂环基含有0~3个取代基,取代基个数可以是0、1、2或3个。
优选地,所述取代基为卤素、C1~C4烷基、三氟甲基、氰基、硝基、氨基、酰胺、-COOX6、-COX6、 -OX6、-NHCOX6、-C6H5X7、吗啉基、哌啶基、呋喃基、四氢呋喃基或吡啶基其中X6为H、C1~C4烷基、苯基,X7为C1~C4烷基、卤素、三氟甲基、氰基、硝基、氨基、酰胺、乙酰基、甲氧基或乙氧基。
其中,取代基可以是C1、C2、C3或C4烷基,X6可以是C1、C2、C3或C4烷基,X7可以是C1、C2、C3或C4烷基。
作为本发明优选的技术方案,式II中所述C3~C7环烷基、苯基以及萘基含有0~3个取代基,取代基个数可以是0、1、2或3个。
优选地,所述取代基为卤素、C1~C4烷基、三氟甲基、氰基、硝基、氨基、1,3-二氧戊环基、-COOY5、 -COY5、-OY5、-NHCOY5、-C6H5Y6、-(CH2)nNHY7、-NHCOOtBu、-CH2OCOOtBu、1-甲基哌嗪、吗啉基、异噁唑基、3,5-二甲基异恶唑基、喹啉基、异喹啉基、哌啶基、噻吩基、呋喃基、四氢呋喃基、吡啶基、嘧啶基、2-吗啉基吡啶基、吲哚基、1,4-苯并二氧杂环基、苯并呋喃基、苯并噻吩基、1-甲基-1H-吲唑基、吡咯基、1H-吡唑基、1-甲基-1H-吡唑基或四氢吡喃基,其中n为0~2,Y5为自氢、C1~C4烷基或苯基, Y6为氢、C1~C4烷基、卤素、甲酰基、乙酰基、甲氧基、乙氧基、三氟甲基、氰基或甲砜基,Y7为C1~ C5烷基、C0~C2亚烷基-苯基、C0~C2亚烷基-萘基或C0~C2亚烷基-杂环基,其中Y7中所述苯基、萘基或杂环基被0~3个卤素、C1~C4烷基、三氟甲基、氰基、硝基或氨基取代。
其中,取代基可以是C1、C2、C3或C4烷基,Y6可以是C1、C2、C3或C4烷基,Y7可以是C1、C2、C3、C4或C5烷基,Y7可以是苯基、C1亚烷基-苯基或C2亚烷基-苯基,Y7可以是萘基、C1亚烷基-萘基或 C2亚烷基-萘基,Y7可以是杂环基、C1亚烷基-杂环基或C2亚烷基-杂环基,Y7中所述苯基、萘基或杂环基被0、1、2或3个取代基取代,Y7中的取代基可以是C1、C2、C3或C4烷基。
作为本发明优选的技术方案,式II中所述杂环基为氮杂环丁基、氧杂环丁基、氮杂环戊基、氧杂环戊基、氮杂环己基、氧杂环己基、氮杂环己基、呋喃基、噻吩基、噁唑基、异噁唑基、嘧啶基、吡咯基、四氢吡咯基、吗啉基、1,3-二氧戊环基、苯并[d]噻唑基、吡啶基、1,4-苯并二氧杂环基、吲唑基、N-甲基苯并咪唑基、吲哚基、二氢吲哚基或2-咪唑烷酮基;
优选地,式II中所述杂环基含有0~3个取代基,取代基个数可以是0、1、2或3个。
优选地,所述取代基为卤素、C1~C4烷基、三氟甲基、氰基、羧基、硝基、氨基、1,3-二氧戊环基、 -COOY5、-COY5、-OY5、-NHCOY5、-NHCOOtBu或-C6H5Y6,其中Y5为氢、C1~C4烷基或苯基,Y6为 C1~C4烷基、卤素、乙酰基、甲氧基或乙氧基。
其中,取代基可以是C1、C2、C3或C4烷基,Y5可以是C1、C2、C3或C4烷基,Y6可以是C1、C2、C3或C4烷基。
当结构类型为式I时,化合物可以通过下述反应制备得到:
当式I中R2为-R-COX5时,化合物可以通过下述反应制备得到:
当式I中R2为-S(O)mX5(m=2)时,化合物可以通过下述反应制备得到:
当结构类型为式II时,可以通过下述2步反应制备得到:
上诉制备方法是以说明为的目,而非用来局限于所列化合物或任何特定的取代基。方案中显示的取代基数目并不必需符合权利要求中所用的数目,且为清楚起见,显示单取代基连接到在上文中式I和式II的定义下允许有多取代基的化合物上。
本发明目的之二在于提供一种上述吲哚类化合物的应用,述吲哚类化合物用于制备CBP/EP300 Bromodomain受体抑制剂。
作为本发明优选的技术方案,所述CBP/EP300 Bromodomain受体抑制剂用于制备治疗癌症、细胞增殖性紊乱疾病、炎症疾病及自身免疫疾病、败血症、病毒感染、神经性衰退性疾病的药物。
本发明目的之三在于提供一种药物组合物,所述药物组合物含有上述所述吲哚类化合物。
作为本发明优选的技术方案,所述药物组合物用于治疗、预防或改善癌症、细胞增殖性紊乱、炎症、自身免疫性疾病、败血症、病毒感染或神经性衰退性疾病。
CBP/EP300 Bromodomain受体抑制剂制备的药物,以及所述药物组合物可治疗的癌症包括肾上腺肿瘤、听神经瘤、肢端黑色素瘤、肢端汗腺瘤、急性嗜酸性白血病、急性红色的白血病,急性淋巴母细胞性白血病、急性巨核细胞白血病、急性单核细胞的白血病、急性早幼粒细胞性白血病、腺癌、腺样囊性癌、脂肪组织肿瘤、肾上腺皮质癌、成人T细胞白血病/淋巴瘤、艾滋病相关淋巴瘤、肺泡横纹肌肉瘤、肺泡软肉瘤、成釉细胞的纤维瘤、间变性大细胞淋巴瘤、未分化甲状腺癌、血管肌脂肪瘤、血管肉瘤、星形细胞瘤、非典型畸形杆状的肿瘤、B细胞慢性淋巴细胞白血病、B细胞前淋巴细胞白血病、B细胞淋巴瘤、基底细胞癌、胆道癌、膀胱癌、胚细胞瘤、骨肿瘤、棕色肿瘤、伯基特淋巴瘤、乳腺癌、脑癌、原位癌、软骨瘤、牙骨质瘤、髓系肉瘤、软骨瘤、脊索瘤、绒毛膜癌、脉络丛***状瘤、肾透明细胞肉瘤、颅咽管瘤、皮肤 t细胞淋巴瘤、***、结肠癌、小圆细胞肿瘤、细胞弥漫型B细胞淋巴瘤、神经上皮的肿瘤、无性细胞瘤、胚胎性癌内分泌腺肿瘤、内胚层窦肿瘤、食道癌、纤维瘤、纤维肉瘤、滤泡淋巴瘤、滤泡星形胶质细胞瘤、甲状腺癌胃肠道癌症、生殖细胞肿瘤、妊娠期绒毛膜癌、巨细胞成纤维细胞瘤、骨巨细胞瘤、神经胶质细胞瘤、多形性胶质母细胞瘤、神经胶质瘤、颗粒细胞瘤、男性细胞瘤、胆囊癌症、胃癌、成血管细胞瘤、头部和颈部癌症、血管外皮细胞瘤恶性肿瘤、肝母细胞癌、细胞淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、浸润性小叶癌、肠道癌症、肾癌、喉癌、致命的中线癌、白血病、***细胞瘤、脂肪肉瘤、肺癌、***瘤、淋巴上皮瘤、淋巴瘤、急性***肉瘤,淋巴细胞性白血病、慢性淋巴细胞白血病、肝癌,小细胞肺癌、非小细胞肺癌、麦芽淋巴瘤、恶性纤维组织细胞瘤、恶性周围神经鞘瘤、边缘区b细胞淋巴瘤、肥大细胞白血病、纵隔生殖细胞肿瘤、乳腺髓样癌、髓样甲状腺癌、成神经管细胞瘤、黑色素瘤、脑膜瘤、默克尔细胞癌症、间皮瘤、转移性细胞癌、混合缪氏肿瘤、粘液性肿瘤、多发性骨髓瘤、肌肉组织肿瘤、蕈样黏液样脂肪肉瘤、粘液瘤、粘液肉瘤、鼻咽癌、神经母细胞瘤、神经纤维瘤、神经瘤、眼部癌症、嗜酸性、视神经鞘脑膜瘤、肿瘤、口腔癌、骨肉瘤、卵巢癌、***状甲状腺癌、肿瘤副神经节瘤、成松果体细胞瘤、垂体细胞瘤、前体T-淋巴母细胞性淋巴瘤、原发性中枢神经***淋巴瘤,腹膜癌、***癌、胰腺癌、咽癌、肾细胞癌、肾髓样癌、成视网膜细胞瘤、横纹肌瘤、横纹肌肉瘤、直肠癌、肉瘤、***瘤、滋养细胞肿瘤、皮肤癌、小圆细胞肿瘤、小细胞癌、软组织肉瘤、生长抑素瘤、脊髓肿瘤、脾边缘带淋巴瘤、鳞状细胞癌、滑膜肉瘤、小肠癌症、鳞状细胞癌、胃癌、T细胞淋巴瘤、睾丸癌、甲状腺癌症、移行细胞癌、喉癌、脐尿管癌、泌尿生殖癌症、子宫癌症、疣状癌、视觉途径神经胶质瘤、外阴癌或***癌等。
CBP/EP300 Bromodomain受体抑制剂制备的药物,以及所述药物组合物可治疗的细胞增殖性紊乱疾病包括良性软组织肿瘤、脑和脊髓肿瘤、眼睑和轨道肿瘤、肉芽肿、脂肪瘤、脑膜瘤、多发性内分泌瘤、鼻息肉、垂体肿瘤、泌乳素瘤、脂溢性角质的、胃息肉、甲状腺结节、肝血管瘤、声带结节、息肉、囊肿、藏毛病、皮肤纤维瘤、皮拉尔囊肿或化脓性肉芽肿等。
CBP/EP300 Bromodomain受体抑制剂制备的药物,以及所述药物组合物可治疗的炎症疾病包括炎症盆腔疾病、尿道炎、皮肤晒伤、鼻窦炎、肺炎、脑炎、脑膜炎、心肌炎、肾炎、骨髓炎、肌炎、肝炎、胃炎、肠炎、皮炎、牙龈炎、胰腺炎、牛皮癣、过敏、克罗恩氏病、肠道综合症、溃疡性结肠炎、组织移植排斥、器官移植排斥、哮喘、过敏性鼻炎、慢性阻塞性肺疾病、自身免疫性疾病、自身免疫性脱发、贫血、肾小球肾炎、皮肌炎、多发性硬化症、硬皮病、血管炎、自身免疫性溶血性和血小板减少、肺出血肾炎综合征、动脉粥样硬化、阿狄森氏病、帕金森氏症、阿尔茨海默氏症、糖尿病、感染性休克、***性红斑狼疮、类风湿性关节炎、银屑病关节炎、骨关节炎、慢性特发性血小板减少性紫癜、重症肌无力、桥本甲状腺炎、过敏性皮肤炎、退化性关节疾病、格林-巴利综合征、蕈样真菌病或急性炎症反应等。
CBP/EP300 Bromodomain受体抑制剂制备的药物,以及所述药物组合物可治疗的病毒感染包括人类***瘤病毒、疱疹病毒、巴尔病毒、人类免疫缺陷病毒、乙型肝炎病毒或丙型肝炎病毒感染等。
CBP/EP300 Bromodomain受体抑制剂制备的药物,以及所述药物组合物可治疗的神经性衰退性疾病包括阿兹海默病、肌肉萎缩性侧索硬化症、共济失调毛细血管扩张症、牛海绵状脑病、克雅二氏病、亨廷顿氏病、小脑萎缩症、多发性硬化症、帕金森氏病、原发性侧索硬化或脊髓性肌萎缩症等。
CBP/EP300 Bromodomain受体抑制剂制备的药物,以及所述药物组合物可适用于各种给药途径,所述给药途径典型但非限制性实例有:口服、颊、吸入、舌下、直肠、***、脑池内的或鞘内、通过腰椎穿刺、经尿道、经皮肤或肠外(包括静脉注射、肌肉注射、皮下、行皮内注射、腹腔内、鞘内、手术植入)等。
本发明所述的药物组合物可以是液体、半液体或固体形式,按照适合于所用的给药途径的方式配制。本发明所述的组合物可以按照下列给药方式给药:口服、肠胃外、腹膜内、静脉内、透皮、舌下、肌内、直肠、口腔、鼻内、脂质体等方式。
口服的药物组合物可以是固体、凝胶或液体。固体制剂的实例包括但不限于片剂、胶囊剂、颗粒剂和散装粉剂。这些制剂可以选择地含有粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂和矫味剂等。粘合剂的实例包括但不限于微晶纤维素、葡萄糖溶液、***胶浆、明胶溶液、蔗糖和淀粉糊;润滑剂的实例包括但不限于滑石、淀粉、硬脂酸镁、硬脂酸钙、硬脂酸;稀释剂的实例包括但不限于乳糖、蔗糖、淀粉、甘露糖醇、磷酸二钙;助流剂的实例包括但不限于二氧化硅;崩解剂的实例包括但不限于交联羧甲基纤维素钠、淀粉羟乙酸钠、藻酸、玉米淀粉、马铃薯淀粉、甲基纤维素、琼脂和羧甲基纤维素。
以肠胃外给予本发明所述药物组合物,一般以注射为主,包括皮下、肌内或静脉内注射。注射剂可以被制成任何常规形式,如液体溶液或悬液、适合于在注射之前溶解或悬浮在液体中的固体形式或者乳剂。可用于本发明注射剂的药学上可接收的载体的实例包括但不限于水性载体、非水性载体、抗微生物剂、等渗剂、缓冲剂、抗氧剂、悬浮与分散剂、乳化剂、螯合剂和其它药学上可接受的物质。水性载体的实例包括氯化钠注射液、林格式注射液、等渗葡萄糖注射液、无菌水注射液、葡萄糖与乳酸化林格氏注射液;非水性载体的实例包括植物来源的固定油、棉籽油、玉米油、芝麻油和花生油;抗微生物剂的实例包括间甲酚、苄醇、氯丁醇、苯扎氯铵等;等渗剂的实例包括氯化钠和葡萄糖;缓冲剂包括磷酸盐和柠檬酸盐。
发明所述药物组合物还可以制备成无菌的冻干粉针剂,将化合物溶于磷酸钠缓冲溶液,其中含有葡萄糖或其他适合的赋形剂,随后在本领域技术人员已知的标准条件下将溶液无菌过滤,继之以冷冻干燥,得到所需的制剂。
本发明所述化合物中,当任何变量(例如R1、R2等)在任何组分中出现超过一次,则其每次出现的定义独立于其它每次出现的定义。同样,允许取代基及变量的组合,只要这种组合使化合物稳定。自取代基划入环***的线表示所指的键可连接到任何能取代的环原子上。如果环***为多环,其意味着这种键仅连接到邻近环的任何适当的碳原子上。要理解本领域普通技术人员可选择本发明化合物的取代基及取代型式而提供化学上稳定的并可通过本领域技术和自可容易获得的原料容易的合成的化合物。如果取代基自身被超过一个基团取代,应理解这些基团可在相同碳原子上或不同碳原子上,只要使结构稳定。短语“任选被一个或多个取代基取代”被认为与短语“任选被至少一个取代基取代”相当且在此情况下优选的实施方案将具有0-3个取代基。
本文所用术语“烷基”和“亚烷基”意指包括具有特定碳原子数目的支链的和直链的饱和脂肪烃基。例如,“C1~C4”烷基中“C1~C4”的定义包括以直链或支链排列的具有1、2、3、4、碳原子的基团。例如,“C1~C4”烷基“具体包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基。术语“环烷基”指具有特定碳原子数目的单环饱和脂肪烃基。例如“环烷基”包括环丙基、环丁基、环戊基、环己基、环庚基、苯基、萘基、甲基-环丙基、2,2-二甲基-环丁基、2-乙基-环戊基等。
除非另有定义,烷基、苯环、萘环、环烷基和杂环基取代基可为未被取代的或取代的。例如,C1~C4 烷基可被一个、两个或三个选自卤素、烷氧基、甲基、乙基、丙基、异丙基、叔丁基、三氟甲基、氰基、羧基、硝基、氨基、甲砜基、苯基二氮烯基或杂环基取代,例如吗啉基、哌啶基、喹啉基、呋喃基、四氢呋喃基、吡啶基等取代基取代。
本发明包括式I和式II化合物的游离形式,也包括其药学上可接受的盐及立体异构体。本文中一些特定的示例性化合物为胺类化合物的质子化了的盐。术语“游离形式”指以非盐形式的胺类化合物。包括在内的药学上可接受盐不仅包括本文所述特定化合物的示例性盐,也包括所有式I和式II化合物游离形式的典型的药学上可接受的盐。可使用本领域已知技术分离所述化合物特定盐的游离形式。例如,可通过用适当的碱稀水溶液例如NaOH稀水溶液、碳酸钾稀水溶液、稀氨水及碳酸氢钠稀水溶液处理该盐使游离形式再生。游离形式在某些物理性质例如在极性溶剂中溶解度上与其各自盐形式多少有些区别,但是为发明的目的这种酸盐及碱盐在其它药学方面与其各自游离形式相当。
可通过常规化学方法自含有碱性部分或酸性部分的本发明化合物合成本发明的药学上可接受的盐。通常,通过离子交换色谱或通过游离碱和化学计算量或过量的所需盐形式的无机或有机酸在适当溶剂或多种溶剂的组合中反应制备碱性化合物的盐。类似的,通过和适当的无机或有机碱反应形成酸性化合物的盐。
因此,本发明化合物的药学上可接受的盐包括通过碱性本发明化合物和无机或有机酸反应形成的本发明化合物的常规无毒盐。例如,常规的无毒盐包括得自无机酸例如盐酸、氢溴酸、硫酸、氨基磺酸、磷酸、硝酸等的盐,也包括自有机酸例如乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、扑酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、对氨基苯磺酸、2-乙酰氧基-苯甲酸、富马酸、甲苯磺酸、甲磺酸、乙烷二磺酸、草酸、羟乙基磺酸、三氟乙酸等制备的盐。
如果本发明化合物为酸性的,则适当的“药学上可接受的盐”指通过药学上可接受的无毒碱包括无机碱及有机碱制备的盐.得自无机碱的盐包括铝盐、铵盐、钙盐、铜盐、铁盐、亚铁盐、锂盐、镁盐、锰盐、亚锰盐、钾盐、钠盐、锌盐等。特别优选铵盐、钙盐、镁盐、钾盐和钠盐。得自药学上可接受的有机无毒碱的盐,所述碱包括伯胺、仲胺和叔胺的盐,取代的胺包括天然存在的取代胺、环状胺及碱性离子交换树脂例如精氨酸、甜菜碱、咖啡因、胆碱、N,N'-二苄基乙二胺、二乙胺、2-二乙基氨基乙醇、2-二甲基氨基乙醇、氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡萄糖胺、氨基葡萄糖、组氨酸、羟钴胺、异丙基胺、赖氨酸、甲基葡萄糖胺、吗啉、哌嗪,哌啶、呱咤、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨基丁三醇等。
由于在生理条件下化合物中脱质子化的酸性部分例如羧基可为阴离子的,而这种带有的电荷然后可被内部带有阳离子的质子化了的或烷基化的碱性部分例如四价氮原子平衡抵消,所以应注意本发明化合物是潜在的内盐或两性离子。
与现有技术方案相比,本发明至少具有以下有益效果:
本发明提供了一种吲哚类化合物,所述吲哚类化合物可有效抑制CBP/EP300Bromodomain受体,可作为治疗癌症、细胞增殖性紊乱、炎症疾病、自身免疫疾病、败血症、病毒感染或神经性衰退性疾病的治疗药物。
具体实施方式
为更好地说明本发明,便于理解本发明的技术方案,本发明的典型但非限制性的实施例如下:
实施例1
1-(2-(3-乙酰基-1H-吲哚-1-基)乙酰基)哌啶-4-羧酸甲酯的合成:
(1)1-(2-氯乙酰基)哌啶-4-甲酸甲酯的合成
将甲基哌啶-4-羧酸乙酯(2g,14mmol)溶于20mL DCM溶液中,然后加入2-氯乙酰氯(1.16mL,15.4mmol)和K2CO3(5.8g,42mmol)。反应体系在室温下搅拌5h。TLC监测,反应结束后加入30mL 水,用DCM萃取(3×20mL),有机相用饱和食盐水洗涤一次,无水硫酸钠干燥。真空旋干有机相,得到黄色油状物2.072g(产率67.4%)。1H NMR(400MHz,CDCl3)δ4.32(m,1H),4.10(m,1H),4.02–3.76(s, 3H),3.70(s,2H),3.30–3.14(m,1H),2.94(td,J=13.4,2.9Hz,1H),2.70–2.50(m,1H),2.08–1.90(m,2H), 1.90–1.61(m,2H).
(2)QP19 1-(2-(3-乙酰基-1H-吲哚-1-基)乙酰基)哌啶-4-羧酸甲酯的合成
将中间体1-(2-氯乙酰基)哌啶-4-甲酸甲酯(437.48mg,2mmol)溶于50mL丙酮中,再加入1-乙酰基吲哚(264mg,1.66mmol),K2CO3(688mg,4.98mmol,KI(42mg,0.252mmol)。反应体系在56℃搅拌5h。反应结束后,冷却至室温,加入20mL水,用EA萃取(3×30mL),有机相用饱和食盐水洗涤一次,无水硫酸钠干燥。真空旋干有机相,粗产物经硅胶柱分离(MeOH:DCM=1:10),白色固体 397mg(产率70%)。1H NMR(400MHz,DMSO-d6)δ8.24(s,1H),8.18(d,J=6.9Hz,1H),7.44(d,J=7.2Hz, 1H),7.20(s,2H),5.29(m,2H),4.17(d,J=12.5Hz,1H),3.94(d,J=12.9Hz,1H),3.64(s,3H),3.24(t,J=12.1 Hz,1H),2.80(t,J=11.7Hz,1H),2.69(t,J=10.7Hz,1H),2.42(s,3H),1.94(d,J=11.6Hz,1H),1.86(d,J= 12.6Hz,1H),1.71(d,J=10.5Hz,1H),1.44(d,J=9.9Hz,1H).
实施例2
乙基2-(3-乙酰基-1H-吲哚-1-基)乙酸酯的合成,合成方法如实施例1。1H NMR(400MHz,CDCl3)δ 8.39(dd,J=6.4,2.6Hz,1H),7.76(s,1H),7.31(dt,J=6.9,3.5Hz,2H),7.26(s,1H),4.88(s,2H),4.25(q,J= 7.1Hz,2H),1.60(s,3H),1.28(d,J=7.1Hz,3H).
实施例3
2-(3-乙酰基-1H-吲哚-1-基)乙酸的合成,合成方法如实施例8。1H NMR(400MHz,DMSO)δ8.32(s, 1H),8.22–8.16(m,1H),7.49(d,J=7.4Hz,1H),7.28–7.18(m,2H),5.12(s,2H),2.44(s,3H).
实施例4
(3-乙酰基-1H-吲哚-1-基)-N-异丁基乙酰胺的合成,合成方法如实施例1。1H NMR(400MHz,CDCl3) δ8.47–8.34(m,1H),7.74(s,1H),7.42–7.29(m,3H),5.46(s,1H),4.85(s,2H),3.03(t,J=6.5Hz,2H),2.51 (s,3H),0.74(d,J=6.7Hz,6H).
实施例5
(3-乙酰基-1H-吲哚-1-基)乙酰胺的合成,合成方法如实施例1。1H NMR(400MHz,CDCl3)δ8.29(s, 1H),8.18(d,J=7.9Hz,1H),7.71(s,1H),7.41(d,J=7.6Hz,1H),7.34(s,1H),7.31–7.15(m,2H),4.89(s, 2H),2.44(s,3H).
实施例6
乙基3-(3-乙酰基-1H-吲哚-1-基)丙酸酯的合成,合成方法如实施例1。1H NMR(400MHz,CDCl3)δ 8.46–8.32(m,1H),7.83(s,1H),7.35(dd,J=10.0,5.2Hz,1H),7.33–7.27(m,2H),4.50(t,J=6.5Hz,2H), 4.13(q,J=7.1Hz,2H),2.87(t,J=6.5Hz,2H),2.52(s,3H),1.21(t,J=7.1Hz,3H).
实施例7
(3-乙酰基-1H-吲哚-1-基)-1-(哌啶-1-基)乙酮的合成,合成方法如实施例1。1HNMR(400MHz, DMSO)δ8.24(s,1H),8.19–8.15(m,1H),7.42(dd,J=6.7,1.7Hz,1H),7.25–7.16(m,2H),5.26(s,2H),3.53 (s,2H),3.48–3.39(m,2H),2.43(s,3H),1.63(s,4H),1.47(s,2H).
实施例8
1-(2-(3-乙酰基-1H-吲哚-1-基)乙酰基)哌啶-4-羧酸合成,1-(2-(3-乙酰基-1H-吲哚-1-基)乙酰基) 哌啶-4-羧酸甲酯合成如实施例1。
将化合物1-(2-(3-乙酰基-1H-吲哚-1-基)乙酰基)哌啶-4-羧酸甲酯(284mg,0.83mmol)溶于8mL MeOH中,向反应体系中加入1M NaOH(4mL,4.15mmol)。反应体系在室温下搅拌2h,TLC跟踪监测。反应结束后,真空旋去大部分溶剂,剩余溶液用1M盐酸溶液调节pH至弱酸性,有大量白色固体析出,减压抽滤,用20mL水洗涤滤饼,真空干燥得白色固体156mg(产率57.2%)。合成方法如实施例1。1H NMR (400MHz,DMSO)δ12.32(s,1H),8.23(s,1H),8.20–8.09(m,1H),7.44(d,J=7.2Hz,1H),7.27–7.14(m, 2H),5.28(d,J=3.9Hz,2H),4.16(d,J=13.0Hz,1H),3.94(d,J=13.4Hz,1H),3.27–3.19(m,1H),2.81(t,J= 11.1Hz,1H),2.61–2.55(m,1H),2.43(s,3H),1.98–1.89(m,1H),1.85(d,J=11.2Hz,1H),1.69(d,J=10.6 Hz,1H),1.43(d,J=9.9Hz,1H),1.24(s,1H).
实施例9
1-(2-(3-乙酰基-1H-吲哚-1-基)乙酰基)哌啶-3-羧酸甲酯的合成,合成方法如实施例1。1H NMR(400 MHz,DMSO)δ8.21(d,J=6.4Hz,1H),8.18(d,J=6.8Hz,1H),7.42(t,J=7.6Hz,1H),7.21(m,2H),5.33(d, J=7.8Hz,1H),5.27(s,1H),3.86(t,J=11.7Hz,1H),3.76(s,1H),3.64(s,3H),3.57–3.48(m,1H),3.16(dt,J =19.7,10.4Hz,1H),2.77(s,1H),2.43(s,3H),1.99(s,1H),1.79(d,J=9.9Hz,1H),1.72–1.52(m,1H),1.43 (d,J=9.2Hz,1H).
实施例10
1-(2-(3-乙酰基-1H-吲哚-1-基)乙酰基)哌啶-3-羧酸的合成,合成方法如实施例8。1H NMR(400MHz, DMSO)δ8.21(d,J=12.3Hz,1H),8.17(d,J=8.4Hz,1H),7.44(d,J=5.7Hz,1H),7.25–7.16(m,2H),5.44– 5.24(m,2H),3.83(dd,J=12,11.9Hz,1H),3.66–3.55(m,1H),2.89–2.78(m,1H),2.66(s,1H),2.43(s,3H), 2.34(s,1H),2.00(d,J=8.3Hz,1H),1.78(s,1H),1.69–1.49(m,1H),1.44(s,1H).
实施例11
1-(1-(噻吩-2-羰基)-1H-吲哚-3-基)乙酮的合成,将1-(1H-吲哚-3-基)乙-1-酮(100mg,0.628mmol) 溶于30mL四氢呋喃中,再加入叔丁醇甲(281.87mg,2.512mmol),在常温下搅拌15min,向反应体系中加入噻吩-2-羰基氯(184.1mg,1.256mmol),常温搅拌。TLC监测,反应结束后加入水,用DCM萃取 (3×20mL),有机相用饱和食盐水洗涤一次,无水硫酸钠干燥。真空旋干有机相,粗产物用硅胶柱分离 (PE:EA=10:1,4:1)得到产物152mg(产率90%)。1H NMR(400MHz,DMSO)δ8.71(s,1H),8.28(dd,J =6.3,2.4Hz,1H),8.23(dd,J=5.0,1.0Hz,1H),8.19(dd,J=6.7,2.1Hz,1H),8.03(dd,J=3.8,1.0Hz,1H), 7.45–7.41(m,2H),7.39(dd,J=4.9,3.9Hz,1H),2.57(s,3H).
实施例12
1-(1-(丙基磺酰基)-1H-吲哚-3-基)乙酮的合成,将1-(1H-吲哚-3-基)乙-1-酮(100mg,0.628mmol) 溶于30mL四氢呋喃中,把反应体系置于0℃,向其中加入NaH(75.2mg,1.88mmol),在常温下搅拌1h,向体系中加入丙烷-1-磺酰氯(98.325mg,0.7mmol)。TLC监测,反应结束后加入水,用EA萃取(3×20 mL),有机相用饱和食盐水洗涤一次,无水硫酸钠干燥。真空旋干有机相,粗产物用硅胶柱分离(PE:EA= 4:1)得到产物117mg(产率70.27%)。1H NMR(400MHz,CDCl3)δ8.46–8.34(m,1H),8.06(s,1H),7.87(dt, J=4.8,3.0Hz,1H),7.48–7.36(m,2H),3.42–3.26(m,2H),2.57(s,3H),1.83–1.68(m,2H),0.99(t,J=7.4 Hz,3H).
实施例13
1-(1-(苯基磺酰基)-1H-吲哚-3-基)乙酮的合成,合成方法如实施例12。1H NMR(400MHz,CDCl3) δ8.38–8.29(m,1H),8.21(s,1H),7.95(t,J=7.8Hz,3H),7.60(t,J=7.5Hz,1H),7.50(t,J=7.8Hz,2H),7.44 –7.30(m,2H),2.58(s,3H).
实施例14
1-(1-(噻吩-2-基磺酰基)-1H-吲哚-3-基)乙酮的合成,合成方法如实施例12。1HNMR(400MHz,DMSO) δ8.75(s,1H),8.21(d,J=7.7Hz,1H),8.14(s,1H),8.13(q,J=1.4Hz,1H),7.97(d,J=8.3Hz,1H),7.50–7.43 (m,1H),7.43–7.36(m,1H),7.24(dd,J=4.7,4.2Hz,1H),2.59(s,3H).
实施例15
1-(2-(3-乙酰基-6-甲氧基-1H-吲哚-1-基)乙酰基)哌啶-4-羧酸甲酯的合成,合成方法如实施例1。 1H NMR(400MHz,DMSO)δ8.10(s,1H),8.02(d,J=8.7Hz,1H),6.99(d,J=2.0Hz,1H),6.83(dd,J=8.7, 2.2Hz,1H),5.23(d,J=3.0Hz,2H),4.18(d,J=13.4Hz,1H),3.94(d,J=13.6Hz,1H),3.78(s,3H),3.64(s, 3H),2.81(t,J=11.5Hz,1H),2.69(dd,J=12.9,9.1Hz,1H),2.39(s,3H),2.03–1.82(m,2H),1.71(d,J=9.4 Hz,1H),1.52–1.37(m,1H),1.20(d,J=23.7Hz,1H).
实施例16
1-(2-(3-乙酰基-6-甲氧基-1H-吲哚-1-基)乙酰基)哌啶-4-羧酸的合成,合成方法如实施例8。1H NMR (400MHz,DMSO)δ8.10(s,1H),8.02(d,J=8.7Hz,1H),6.99(d,J=1.9Hz,1H),6.83(dd,J=8.7,2.1Hz, 1H),5.29–5.14(m,2H),4.17(d,J=13.1Hz,1H),3.93(d,J=13.6Hz,1H),3.78(s,3H),2.81(t,J=11.2Hz, 1H),2.56(m,1H),2.39(s,3H),1.89(m,2H),1.69(m,1H),1.50–1.34(m,1H).
实施例17
1-(2-(3-乙酰基-6-羟基-1H-吲哚-1-基)乙酰基)哌啶-4-羧酸甲酯的合成:
1-(2-(3-乙酰基-6-甲氧基-1H-吲哚-1-基)乙酰基)哌啶-4-羧酸甲酯合成方法如实施例1。
将1-(2-(3-乙酰基-6-甲氧基-1H-吲哚-1-基)乙酰基)哌啶-4-羧酸甲酯(100mg,0.27mmol)溶于15mL 二氯甲烷,取BBr3(167mg,0.68mmol)溶于10mL DCM,冰浴条件下滴入到反应体系,后转至室温反应, TLC监测。反应结束,缓慢滴加甲醇和NH4Cl水溶液淬灭,加水,EA萃取(3×30mL),饱和食盐水洗涤,无水硫酸钠干燥,旋干,重结晶,得白色固体76.86mg(产率57.2%)。1H NMR(400MHz,DMSO)δ9.34 (s,1H),8.04(s,1H),7.90(d,J=8.7Hz,1H),6.72(d,J=8.1Hz,2H),5.23–5.06(m,2H),4.15(d,J=13.4Hz, 1H),3.93(d,J=12.7Hz,1H),3.63(s,1H),3.21(s,2H),2.80(t,J=11.9Hz,1H),2.36(s,3H),2.02–1.76(m, 2H),1.64(d,J=9.9Hz,1H),1.42(s,1H),1.22(s,2H).
实施例18
1-(2-(3-乙酰基-6-羟基-1H-吲哚-1-基)乙酰基)哌啶-4-羧酸的合成,合成方法如实施例8。1H NMR (400MHz,DMSO)δ9.22(s,1H),8.02(s,1H),7.98–7.85(m,1H),6.70(s,2H),5.25–5.04(m,2H),4.16(d,J =12.9Hz,1H),3.93(d,J=12.9Hz,1H),2.80(t,J=11.8Hz,1H),2.37(s,3H),1.89(dd,J=29.8,11.7Hz,2H), 1.65(d,J=10.9Hz,1H),1.41(d,J=10.8Hz,1H),1.23(s,1H).
实施例19
1-(6-甲氧基-1-(苯基磺酰基)-1H-吲哚-3-基)乙酮的合成,合成方法如实施例12。1H NMR(400MHz, CDCl3)δ8.19(d,J=8.8Hz,1H),8.09(s,1H),7.98–7.85(m,2H),7.62(t,J=7.5Hz,1H),7.51(t,J=7.8Hz, 2H),7.44(d,J=2.2Hz,1H),6.96(dd,J=8.8,2.3Hz,1H),3.87(s,3H),2.55(s,3H).
结构类型为II时:
实施例20
3-(1-乙酰基-1H-吲哚-3-甲酰氨基)吡咯烷-1-羧酸叔丁酯的合成:
(1)1-乙酰基-1H-吲哚-3-羧酸的合成
将3-吲哚甲酸(1.5g,9.3mmol)加入12mL DCE中,再加入Et3N(4mL,27.9mmol),DMAP(0.114 g,0.93mmol),乙酸酐(2.8mL,27.9mmol)。反应体系在60℃下反应3h,TLC跟踪监测反应。反应结束,真空旋去大部分溶剂,用EA重新溶解,用饱和的NaHCO3洗,弃除有机相,水层用1M HCl溶液酸化,产生大量白色沉淀,真空抽滤,滤饼用水洗三遍,真空干燥得白色固体1.20g(产率63%)。1H NMR (400MHz,DMSO)δ8.42(s,1H),8.35(dd,J=6.9,1.8Hz,1H),8.08(dd,J=6.5,2.1Hz,1H),7.44–7.28(m, 2H),2.73(s,3H).
(2)3-(1-乙酰基-1H-吲哚-3-甲酰氨基)吡咯烷-1-羧酸叔丁酯的合成
将30mL DCM加入到中间体1-乙酰基-1H-吲哚-3-羧酸中(100mg,0.49mmol)中,再加入HATU(218 mg,0.74mmol),DIPEA(191mg,1.48mmol)。室温搅拌30min以后,加入3-氨基吡咯烷-1-羧酸叔丁酯 (111.9mg,0.74mmol)。反应体系在室温下搅拌过夜。反应结束后加入20mL水,用EA萃取(3×30mL),再用饱和食盐水洗涤一遍,最后用无水硫酸钠干燥。真空旋干有机相,粗产物用硅胶柱分离(PE:EA=2:1)。得到白色固体130mg(产率71.5%)。1H NMR(400MHz,DMSO)δ8.56(s,1H),8.32(d,J=7.4Hz,2H),8.23 –8.15(m,1H),7.35(tt,J=7.3,6.0Hz,2H),4.46(s,1H),3.60(s,1H),3.44(dt,J=14.1,5.8Hz,2H),3.21(d,J= 7.8Hz,1H),2.70(s,3H),2.14(dt,J=13.4,6.6Hz,1H),1.91(s,1H),1.41(s,9H).
实施例21
N-(2-乙酰氨基乙基)-1-乙酰基-1H-吲哚-3-甲酰胺的合成,合成方法如实施例20。1H NMR(400MHz, CDCl3)δ8.51–8.43(m,1H),8.12–8.05(m,1H),8.02(s,1H),7.46–7.37(m,2H),7.17(s,1H),6.34(s,1H), 3.64(dd,J=10.7,5.0Hz,2H),3.55(dd,J=10.9,5.5Hz,2H),2.70(s,3H),2.03(s,3H).
实施例22
4-(1-乙酰基-1H-吲哚-3-甲酰胺基)丁基)氨基甲酸叔丁酯的合成,合成方法如实施例20。1H NMR(400 MHz,DMSO)δ8.50(s,1H),8.32(d,J=7.8Hz,1H),8.30–8.14(m,2H),7.34(dq,J=7.3,6.2Hz,2H),6.80(s, 1H),3.29–3.15(m,2H),2.95(dd,J=12.6,6.4Hz,2H),2.69(s,3H),1.62–1.41(m,4H),1.38(d,J=11.5Hz, 9H),1.23(s,1H).
实施例23
1-乙酰基-N-(2-(2-氧代咪唑烷-1-基)乙基)-1H-吲哚-3-甲酰胺的合成,合成方法如实施例20。1H NMR (400MHz,DMSO)δ8.48(s,1H),8.33(d,J=8.2Hz,2H),8.19(d,J=7.4Hz,1H),7.43–7.25(m,2H),6.29(s, 1H),3.51–3.37(m,4H),3.23(dd,J=13.8,6.9Hz,4H),2.69(s,3H).
实施例24
1-乙酰基-N-(2-(吡啶-2-基)乙基)-1H-吲哚-3-甲酰胺的合成,合成方法如实施例20。1H NMR(400 MHz,DMSO)δ8.53(d,J=3.9Hz,1H),8.48(s,1H),8.38(t,J=5.5Hz,1H),8.32(d,J=7.4Hz,1H),8.21– 8.15(m,1H),7.72(td,J=7.6,1.8Hz,1H),7.40–7.29(m,3H),7.23(dd,J=7.0,5.3Hz,1H),3.72–3.61(m, 2H),3.03(t,J=7.4Hz,2H),2.68(s,3H).
实施例25
1-乙酰基-N-(2-氯苯乙基)-1H-吲哚-3-甲酰胺的合成,合成方法如实施例20。1HNMR(400MHz, DMSO)δ8.48(s,1H),8.41(t,J=5.6Hz,1H),8.32(d,J=7.9Hz,1H),8.18(d,J=7.0Hz,1H),7.44(dd,J= 7.4,1.7Hz,1H),7.42–7.20(m,5H),3.53(dd,J=14.1,6.3Hz,2H),3.00(t,J=7.4Hz,2H),2.68(s,3H).
实施例26
3-(1-乙酰基-1H-吲哚-3-甲酰氨基)氮杂环丁烷-1-羧酸叔丁酯的合成,合成方法如实施例20。1H NMR (400MHz,DMSO)δ8.80(d,J=7.3Hz,1H),8.56(s,1H),8.33(d,J=7.8Hz,1H),8.18(d,J=7.2Hz,1H),7.35 (m,2H),4.81–4.59(m,1H),4.18(t,J=8.1Hz,2H),3.95–3.74(m,2H),2.71(s,3H),1.40(s,9H).
实施例27
1-乙酰基-N-(3-氯苄基)-1H-吲哚-3-甲酰胺的合成,合成方法如实施例20。1HNMR(400MHz,CDCl3) δ8.45(d,J=7.8Hz,1H),8.00(s,1H),7.90(d,J=7.3Hz,1H),7.40(dd,J=19.7,7.6Hz,3H),7.27(s,4H),6.44 (s,1H),4.66(d,J=5.6Hz,2H),2.66(s,3H).
实施例28
1-乙酰基-N-((6-氯吡啶-3-基)甲基)-1H-吲哚-3-甲酰胺的合成,合成方法如实施例20。1H NMR(400 MHz,CDCl3)δ8.46(d,J=8.1Hz,1H),8.41(d,J=2.2Hz,1H),8.02(s,1H),7.88(d,J=7.4Hz,1H),7.74(dd, J=8.2,2.5Hz,1H),7.48–7.30(m,3H),6.47(s,1H),4.69(d,J=6.0Hz,2H),2.69(s,3H).
实施例29
1-乙酰基-N-(3,5-双(三氟甲基)苄基)-1H-吲哚-3-甲酰胺的合成,合成方法如实施例20。1H NMR(400 MHz,DMSO)δ9.00(t,J=5.9Hz,1H),8.58(s,1H),8.34(d,J=7.8Hz,1H),8.19(d,J=7.3Hz,1H),8.06(s, 2H),8.01(s,1H),7.36(ddd,J=13.6,10.5,6.1Hz,2H),4.69(d,J=5.9Hz,2H),2.70(s,3H).
实施例30
1-乙酰基-N-(4-甲氧基苄基)-1H-吲哚-3-甲酰胺的合成,合成方法如实施例20。1H NMR(400MHz, DMSO)δ8.70(t,J=5.8Hz,1H),8.58(s,1H),8.33(d,J=7.6Hz,1H),8.27–8.19(m,1H),7.40–7.32(m,2H), 7.30(s,1H),7.28(s,1H),6.92(s,1H),6.90(s,1H),4.44(d,J=5.8Hz,2H),3.73(s,3H),2.68(s,3H).
实施例31
1-乙酰基-N-(3,4,5-三氟苄基)-1H-吲哚-3-甲酰胺的合成,合成方法如实施例20。1H NMR(400MHz, DMSO)δ8.88(t,J=5.9Hz,1H),8.59(s,1H),8.34(d,J=7.7Hz,1H),8.22–8.15(m,1H),7.42–7.35(m,1H), 7.35–7.24(m,3H),4.49(d,J=5.9Hz,2H),2.70(s,3H).
实施例32
1-乙酰基-N-(吡啶-4-基甲基)-1H-吲哚-3-甲酰胺的合成,合成方法如实施例20。1H NMR(400MHz, DMSO)δ8.91(s,1H),8.62(s,1H),8.53(d,J=4.6Hz,3H),8.35(d,J=7.8Hz,1H),8.21(d,J=7.5Hz,1H), 8.17–8.03(m,1H),7.51–7.21(m,5H),7.13(dd,J=14.3,7.5Hz,1H),4.52(dd,J=16.4,5.6Hz,3H),2.71(s, 3H).
实施例33
1-乙酰基-N-(2-氯-4-氟苄基)-1H-吲哚-3-甲酰胺的合成,合成方法如实施例20。1H NMR(400MHz, DMSO)δ8.56(s,1H),8.48(t,J=4.5Hz,1H),8.32(d,J=7.5Hz,1H),8.23(d,J=7.1Hz,1H),7.47–7.24(m, 5H),4.63(d,J=3.6Hz,2H),2.66(s,3H).
实施例34
1-乙酰基-N-((5-甲基-1H-吲唑-3-基)甲基)-1H-吲哚-3-甲酰胺的合成,合成方法如实施例20。1H NMR (400MHz,DMSO)δ12.75(s,1H),8.76(t,J=5.5Hz,1H),8.57(s,1H),8.37–8.23(m,2H),7.60(s,1H),7.44– 7.30(m,3H),7.17(d,J=8.4Hz,1H),4.82(d,J=5.7Hz,2H),2.64(s,3H),2.36(s,3H).
实施例35
1-乙酰基-N-((4-甲基-6-(三氟甲基)嘧啶-2-基)甲基)-1H-吲哚-3-甲酰胺的合成,合成方法如实施例20。1H NMR(400MHz,CDCl3)δ8.57–8.44(m,1H),8.23–8.08(m,2H),7.54(s,1H),7.49–7.37(m,3H), 5.01(d,J=4.6Hz,2H),2.70(s,6H).
实施例36
1-乙酰基-N-(4-氟-3-(三氟甲基)苄基)-1H-吲哚-3-甲酰胺的合成,合成方法如实施例20。1H NMR (400MHz,DMSO)δ8.90(t,J=5.6Hz,1H),8.57(s,1H),8.34(d,J=7.9Hz,1H),8.20(d,J=7.2Hz,1H),7.77 (d,J=6.9Hz,2H),7.57–7.45(m,1H),7.45–7.28(m,2H),4.57(d,J=5.8Hz,2H),2.69(s,3H).
实施例37
1-乙酰基-N-((1-甲基-5-(三氟甲基)-1H-苯并[d]咪唑-2-基)甲基)-1H-吲哚-3-甲酰胺的合成,合成方法如实施例20。1H NMR(400MHz,DMSO)δ8.98(t,J=5.4Hz,1H),8.66(s,1H),8.34(d,J=7.7Hz,1H), 8.24(d,J=7.2Hz,1H),7.96(s,1H),7.79(d,J=8.5Hz,1H),7.58(d,J=8.5Hz,1H),7.43–7.28(m,2H),4.86 (d,J=5.5Hz,2H),3.92(s,3H),2.68(s,3H).
实施例38
1-乙酰基-N-((5-氟-1H-吲哚-2-基)甲基)-1H-吲哚-3-甲酰胺的合成,合成方法如实施例20。1H NMR (400MHz,DMSO)δ11.11(s,1H),8.78(t,J=5.5Hz,1H),8.62(s,1H),8.34(d,J=7.2Hz,1H),8.29–8.19(m, 1H),7.35(ddt,J=11.0,8.9,5.3Hz,3H),7.22(dd,J=10.0,2.5Hz,1H),6.87(td,J=9.4,2.6Hz,1H),6.36(s, 1H),4.64(d,J=5.5Hz,2H),2.68(s,3H).
实施例39
1-乙酰基-N-((5-甲氧基-1H-吲哚-2-基)甲基)-1H-吲哚-3-甲酰胺的合成,合成方法如实施例20。1H NMR(400MHz,DMSO)δ10.82(s,1H),8.73(t,J=5.4Hz,1H),8.62(s,1H),8.42–8.30(m,1H),8.30–8.21 (m,1H),7.36(dq,J=7.3,5.8Hz,2H),7.23(d,J=8.7Hz,1H),6.97(d,J=2.3Hz,1H),6.68(dd,J=8.7,2.4Hz, 1H),6.28(s,1H),4.62(d,J=5.5Hz,2H),3.72(s,3H),2.68(d,J=4.9Hz,4H).
实施例40
3-(1-乙酰基-1H-吲哚-3-甲酰氨基)-3-(3,5-二甲基苯基)丙酸甲酯的合成,合成方法如实施例20。 1H NMR(400MHz,CDCl3)δ8.46(dd,J=5.9,3.1Hz,1H),8.00(t,J=4.3Hz,2H),7.45–7.36(m,2H),7.26– 7.18(m,2H),6.99(d,J=9.9Hz,2H),5.81(dd,J=13.9,6.2Hz,1H),3.65(s,3H),2.96(dd,J=6.2,2.4Hz,2H), 2.64(s,3H),2.45(s,3H),2.28(s,3H).
实施例41
2-((1-乙酰基-1H-吲哚-3-甲酰氨基)甲基)苯甲酸甲酯的合成,合成方法如实施例20。1H NMR(400 MHz,DMSO)δ8.71(s,1H),8.38(d,J=8.0Hz,1H),7.92(d,J=7.4Hz,1H),7.85(d,J=7.6Hz,1H),7.79(t,J =7.3Hz,1H),7.74(d,J=7.5Hz,1H),7.59(t,J=7.2Hz,1H),7.39(dt,J=20.9,6.9Hz,2H),5.10(s,2H),3.83 (s,3H),2.71(s,3H).
实施例42
2-(1-乙酰基-1H-吲哚-3-甲酰氨基)-3-(呋喃-2-基)丙酸甲酯的合成,合成方法如实施例20。1H NMR (400MHz,DMSO)δ8.70(d,J=7.8Hz,1H),8.62(s,1H),8.33(d,J=8.1Hz,1H),8.15(d,J=7.4Hz,1H),7.55 (d,J=0.8Hz,1H),7.35(dt,J=14.3,6.9Hz,2H),6.39–6.30(m,1H),6.23(d,J=2.9Hz,1H),4.81(dd,J= 14.1,8.4Hz,1H),3.67(s,3H),3.20(m,2H),2.71(s,3H).
实施例43
乙基3-(1-乙酰基-1H-吲哚-3-甲酰氨基)-4-(5-甲基呋喃-2-基)丁酸乙酯的合成,合成方法如实施例 20。1H NMR(400MHz,DMSO)δ8.62(d,J=8.4Hz,1H),8.58(s,1H),8.33(d,J=7.6Hz,1H),8.22(d,J=7.0 Hz,1H),7.42–7.28(m,2H),6.21(d,J=3.0Hz,1H),6.01(d,J=2.2Hz,1H),5.58(q,J=7.8Hz,1H),4.12– 4.00(m,2H),2.98–2.84(m,2H),2.69(s,3H),2.24(s,3H),1.23(s,2H),1.13(t,J=7.1Hz,3H).
实施例44
4-((1-乙酰基-1H-吲哚-3-甲酰胺基)甲基)噻吩-2-羧酸甲酯的合成,合成方法如实施例20。1H NMR (400MHz,DMSO)δ9.04(t,J=5.9Hz,1H),8.58(s,1H),8.34(d,J=7.6Hz,1H),8.22(d,J=7.2Hz,1H),7.68 (d,J=3.8Hz,1H),7.46–7.28(m,2H),7.15(d,J=3.8Hz,1H),4.70(d,J=5.8Hz,2H),3.79(s,3H),2.69(s, 3H).
实施例45
4-((1-乙酰基-1H-吲哚-3-甲酰胺基)甲基)噻吩-2-羧酸的合成,合成方法如实施例8。1H NMR(400 MHz,DMSO)δ9.03(t,J=5.8Hz,1H),8.59(s,1H),8.40–8.30(m,1H),8.22(dd,J=6.9,1.7Hz,1H),7.59(d, J=3.7Hz,1H),7.36(pd,J=7.2,1.4Hz,2H),7.12(d,J=3.7Hz,1H),4.68(d,J=5.8Hz,2H),2.69(s,3H).
实施例46
3-(1-乙酰基-1H-吲哚-3-甲酰氨基)-3-(3,5-二甲基苯基)丙酸的合成,合成方法如实施例8。1H NMR (400MHz,DMSO)δ12.25(s,1H),8.61(s,1H),8.59(s,1H),8.32(d,J=8.0Hz,1H),8.17(d,J=7.1Hz,1H), 7.36(d,J=7.4Hz,1H),7.32(d,J=4.0Hz,1H),7.29(d,J=7.3Hz,1H),7.00(d,J=8.1Hz,1H),6.97(s,1H), 5.70–5.56(m,1H),2.86–2.73(m,2H),2.71(s,3H),2.40(s,3H),2.23(s,3H).
实施例47
1-乙酰基-N-(3-乙酰基苯基)-1H-吲哚-3-甲酰胺的合成
结构类型为II时:
1-乙酰基-1H-吲哚-3-羧酸的合成与上述方法相同。将1-(3-氨基苯基)乙-1-酮(110mg,0.82mmol) 溶解在30mL甲苯中,再加入中间体1-乙酰基-1H-吲哚-3-羧酸(200mg,0.98mmol),2-氯-1-甲基吡啶碘化物(502mg,1.96mmol)和n-Bu3N(729mg,3.93mmol)。反应体系在氮气保护下,90℃下搅拌过夜。反应结束后,冷却至室温,加入30mL水,用EA萃取(3×30mL),有机相用饱和食盐水洗涤一遍,无水硫酸钠干燥。真空旋干有机相,粗产物用硅胶柱分离(PE:EA=4:1)。得到白色固体105mg(产率33.4%)。 1H NMR(400MHz,DMSO)δ10.27(s,1H),8.81(s,1H),8.36(d,J=7.4Hz,1H),8.29(s,1H),8.26(d,J=7.1 Hz,1H),8.10(d,J=8.1Hz,1H),7.73(d,J=7.7Hz,1H),7.54(t,J=7.9Hz,1H),7.48–7.30(m,2H),2.76(s,3H),2.50(s,3H).
实施例48
3-(1-乙酰基-1H-吲哚-3-甲酰氨基)苯甲酸甲酯的合成,合成方法如实施例47。1HNMR(400MHz, CDCl3)δ8.45(d,J=7.6Hz,1H),8.15(s,1H),8.10(s,1H),8.08–8.04(m,1H),8.03(s,1H),8.02(s,1H),7.81 (d,J=7.8Hz,1H),7.48–7.44(m,1H),7.42(d,J=1.7Hz,1H),7.42–7.38(m,1H),3.91(s,3H),2.68(s,3H).
实施例49
1-乙酰基-N-(3,5-二硝基苯基)-1H-吲哚-3-甲酰胺的合成,合成方法如实施例47。1H NMR(400MHz, DMSO)δ10.88(s,1H),9.17–9.02(m,2H),8.87(s,1H),8.51(d,J=26.7Hz,1H),8.37(d,J=7.5Hz,1H), 8.28(d,J=7.4Hz,1H),7.58–7.33(m,2H),2.79(s,3H).
实施例50
1-乙酰基-N-(4-溴-2-硝基苯基)-1H-吲哚-3-甲酰胺的合成,合成方法如实施例47。1H NMR(400MHz, CDCl3)δ11.07(s,1H),8.93(d,J=9.1Hz,1H),8.55–8.35(m,2H),8.20(dd,J=5.8,3.0Hz,1H),8.12(s,1H), 7.81(dd,J=9.1,2.2Hz,1H),7.54–7.40(m,2H),2.76(s,3H).
实施例51
1-乙酰基-N-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-1H-吲哚-3-甲酰胺的合成,合成方法如实施例47。1H NMR(400MHz,DMSO)δ9.91(s,1H),8.72(s,1H),8.36(d,J=7.8Hz,1H),8.23(d,J=7.2Hz,1H), 7.45–7.29(m,3H),7.16(dd,J=8.7,2.3Hz,1H),6.85(d,J=8.7Hz,1H),4.24(dd,J=9.8,5.1Hz,4H),2.72 (d,J=21.3Hz,3H).
实施例52
(1-乙酰基-1H-吲哚-3-甲酰氨基)间苯二甲酸二甲酯的合成,合成方法如实施例47。1H NMR(400 MHz,CDCl3)δ8.52(s,2H),8.45(d,J=8.8Hz,2H),8.15(s,1H),8.11(s,1H),8.05(d,J=7.1Hz,1H),7.44(m, 2H),3.95(s,6H),2.72(s,3H).
实施例53
N-(3-(1,3-二氧戊环-2-基)苯基)-1-乙酰基-1H-吲哚-3-甲酰胺的合成,合成方法如实施例47。1H NMR (400MHz,DMSO)δ10.12(s,1H),8.81(s,1H),8.37(d,J=7.7Hz,1H),8.26(d,J=7.0Hz,1H),7.94–7.77 (m,2H),7.47–7.29(m,3H),7.17(d,J=7.6Hz,1H),5.75(s,1H),4.07(dd,J=8.9,4.8Hz,2H),4.04–4.01(m, 1H),3.98(dd,J=9.0,4.8Hz,2H),2.76(s,3H),2.50(s,2H),2.05–1.90(m,1H),1.17(t,J=7.1Hz,1H).
实施例54
1-乙酰基-N-(1-乙酰基二氢吲哚-5-基)-1H-吲哚-3-甲酰胺的合成
合成方法如实施例47。1H NMR(400MHz,DMSO)δ9.99(s,1H),8.75(s,1H),8.36(d,J=8.0Hz,1H), 8.24(d,J=7.3Hz,1H),8.02(d,J=8.7Hz,1H),7.74(s,1H),7.52–7.29(m,3H),4.11(t,J=8.5Hz,2H),3.17 (t,J=8.4Hz,2H),2.75(s,3H),2.15(s,3H).
实施例55
(1-乙酰基-1H-吲哚-3-甲酰氨基)苯甲酸的合成,合成方法如实施例8。1H NMR(400MHz,DMSO)δ 12.99(s,1H),10.24(s,1H),8.84(s,1H),8.38(d,J=1.1Hz,1H),8.36(d,J=1.9Hz,1H),8.27(dd,J=6.5,1.3 Hz,1H),8.11(dd,J=8.1,1.1Hz,1H),7.68(d,J=7.8Hz,1H),7.51(t,J=7.9Hz,1H),7.40(pd,J=7.2,1.4Hz, 2H),2.76(s,3H).
实施例56
3-(1-乙酰基-1H-吲哚-3-甲酰氨基)-5-溴苯甲酸甲酯的合成,合成方法如实施例47。1H NMR(400MHz, DMSO)δ10.39(s,1H),8.83(s,1H),8.44(s,1H),8.37(s,1H),8.35(s,1H),8.26(d,J=7.1Hz,1H),7.77(s, 1H),7.56–7.31(m,2H),3.90(s,3H),2.76(s,3H).
实施例57
(1-乙酰基-1H-吲哚-3-甲酰氨基)-5-溴苯甲酸的合成,合成方法如实施例8。1HNMR(400MHz, DMSO)δ10.38(s,1H),8.84(s,1H),8.41(t,J=1.9Hz,1H),8.36(d,J=7.3Hz,1H),8.34–8.31(m,1H),8.28 –8.23(m,1H),7.78–7.74(m,1H),7.45–7.35(m,2H),2.76(s,3H).
实施例58
3-(1-乙酰基-1H-吲哚-3-甲酰氨基)-5-(呋喃-2-基)苯甲酸甲酯的合成,合成方法如实施例47。1H NMR (400MHz,DMSO)δ10.35(s,1H),8.87(s,1H),8.47(s,1H),8.37(d,J=7.7Hz,1H),8.34(s,1H),8.30(d,J= 7.0Hz,1H),7.98(s,1H),7.84(s,1H),7.54–7.28(m,2H),7.07(d,J=3.0Hz,1H),6.66(s,1H),3.92(s,3H), 2.77(s,3H).
实施例59
3-(1-乙酰基-1H-吲哚-3-甲酰氨基)-5-(((四氢-2H-吡喃-2-基)氧基)甲基)苯甲酸甲酯的合成,合成方法如实施例47。1H NMR(400MHz,DMSO)δ10.29(s,1H),8.84(s,1H),8.38(s,2H),8.27(d,J=7.2Hz, 1H),8.09(s,1H),7.67(s,1H),7.46–7.28(m,2H),4.77(s,1H),4.73(d,J=6.7Hz,1H),4.55(d,J=12.4Hz, 1H),3.89(s,3H),3.86–3.77(m,1H),3.55–3.47(m,1H),2.76(s,3H),1.84–1.64(m,2H),1.62–1.42(m, 4H).
实施例60
3-(1-乙酰基-1H-吲哚-3-甲酰氨基)-5-(4-甲基哌嗪-1-基)苯甲酸甲酯的合成,合成方法如实施例47。1H NMR(400MHz,DMSO)δ10.34(s,1H),8.97(s,1H),8.37(d,J=7.9Hz,1H),8.27(d,J=7.6Hz,1H),7.93 (s,2H),7.46–7.33(m,2H),7.31(s,1H),3.87(s,4H),3.50(s,3H),3.18(s,4H),2.85(s,3H),2.77(s,3H).
实施例61
(1-乙酰基-1H-吲哚-3-甲酰氨基)-5-(((四氢-2H-吡喃-2-基)氧基)甲基)苯甲酸的合成,合成方法如实施例7。1H NMR(400MHz,DMSO)δ13.04(s,1H),10.27(s,1H),8.85(s,1H),8.37(d,J=7.8Hz,1H), 8.34(s,1H),8.27(d,J=7.1Hz,1H),8.07(s,1H),7.65(s,1H),7.46–7.32(m,2H),4.74(t,J=7.9Hz,2H),4.54 (d,J=12.4Hz,1H),3.82(m,1H),3.53–3.48(m,1H),2.76(s,3H),1.74(m,2H),1.53(m,4H).
实施例62
3-(1-乙酰基-1H-吲哚-3-甲酰氨基)-5-(羟甲基)苯甲酸甲酯的合成,合成方法如实施例47。1H NMR (400MHz,DMSO)δ10.25(s,1H),8.83(s,1H),8.36(dd,J=7.1,1.3Hz,1H),8.31(s,1H),8.29–8.24(m,1H), 8.08(s,1H),7.66(s,1H),7.39(pd,J=7.2Hz,1.4Hz,2H),5.45(t,J=5.7Hz,1H),4.59(d,J=5.5Hz,2H),3.88 (s,3H),2.75(s,3H).
实施例63
(1-乙酰基-1H-吲哚-3-甲酰氨基)-5-(呋喃-2-基)苯甲酸的合成,合成方法如实施例8。1H NMR(400 MHz,DMSO)δ10.34(s,1H),8.88(s,1H),8.45(s,1H),8.37(d,J=7.4Hz,1H),8.31(s,1H),8.28(d,J=1.5 Hz,1H),7.98(s,1H),7.83(s,1H),7.47–7.34(m,2H),7.05(d,J=3.4Hz,1H),6.65(m,1H),2.77(s,3H).
实施例64
(1-乙酰基-1H-吲哚-3-甲酰氨基)-4-((3-氟苯基)氨基)苯甲酸甲酯的合成,合成方法如实施例47。1H NMR(400MHz,DMSO)δ9.74(s,1H),8.73(s,1H),8.37(d,J=7.4Hz,1H),8.28(s,1H),8.23–8.17(m, 1H),8.11(d,J=2.0Hz,1H),7.77(dd,J=8.6,2.0Hz,1H),7.43(d,J=3.6Hz,1H),7.41(s,1H),7.39(t,J=1.7 Hz,1H),7.30(dd,J=15.2,8.1Hz,1H),6.97(dd,J=8.1,1.4Hz,1H),6.90(dt,J=11.5,2.2Hz,1H),6.73(td,J =8.4,2.2Hz,1H),3.84(s,3H),2.71(s,3H).
实施例65
3-(1-乙酰基-1H-吲哚-3-甲酰胺基)-4-(苄基氨基)苯甲酸甲酯的合成,合成方法如实施例47。1H NMR (400MHz,DMSO)δ9.67(s,1H),8.80(s,1H),8.37(d,J=7.5Hz,1H),8.28–8.19(m,1H),7.77(d,J=2.0Hz, 1H),7.63(dd,J=8.6,2.0Hz,1H),7.45–7.40(m,2H),7.40–7.36(m,2H),7.33(t,J=7.5Hz,2H),7.23(t,J= 7.2Hz,1H),6.68(t,J=6.1Hz,1H),6.59(d,J=8.7Hz,1H),4.47(d,J=6.0Hz,2H),3.76(s,3H),2.75(s,3H).
实施例66
3-(1-乙酰基-1H-吲哚-3-甲酰氨基)-4-(环戊基氨基)苯甲酸甲酯的合成,合成方法如实施例47。1H NMR(400MHz,DMSO)δ9.59(s,1H),8.78(s,1H),8.37(d,J=7.6Hz,1H),8.25–8.09(m,1H),7.80(d,J= 2.0Hz,1H),7.73(dd,J=8.6,2.0Hz,1H),7.47–7.32(m,2H),6.81(d,J=8.8Hz,1H),5.60(d,J=6.4Hz,1H), 3.88(dd,J=12.2,6.5Hz,1H),3.78(s,3H),2.74(s,3H),2.10–1.95(m,2H),1.67(d,J=6.4Hz,2H),1.57(dd, J=9.8,5.4Hz,2H),1.54–1.46(m,2H).
实施例67
3-(1-乙酰基-1H-吲哚-3-甲酰氨基)-4-(环丙基氨基)苯甲酸甲酯的合成,合成方法如实施例47。1H NMR(400MHz,DMSO)δ9.46(s,1H),8.77(s,1H),8.37(d,J=7.6Hz,1H),8.23–8.11(m,1H),7.83(d,J= 2.0Hz,1H),7.77(dd,J=8.6,2.0Hz,1H),7.48–7.28(m,2H),7.11(d,J=8.6Hz,1H),6.35(s,1H),3.79(s, 3H),2.74(s,3H),1.65–1.51(m,1H),0.84–0.75(m,2H),0.54–0.45(m,2H).
实施例68
(1-乙酰基-1H-吲哚-3-甲酰氨基)-4-(环戊基氨基)苯甲酸的合成,合成方法如实施例7。1H NMR(400 MHz,DMSO)δ12.17(s,1H),9.62(s,1H),8.79(s,1H),8.37(d,J=7.7Hz,1H),8.18(d,J=7.0Hz,1H),7.77 (d,J=1.9Hz,1H),7.71(dd,J=8.6,1.9Hz,1H),7.46–7.32(m,2H),6.79(d,J=8.7Hz,1H),5.51(d,J=6.3 Hz,1H),3.87(dd,J=12.5,6.3Hz,1H),2.74(s,3H),2.10–1.95(m,2H),1.67(d,J=6.6Hz,2H),1.62–1.54 (m,2H),1.50(dd,J=12.1,6.7Hz,2H).
实施例69
3-(1-乙酰基-1H-吲哚-3-甲酰氨基)-4-(异丙基氨基)苯甲酸甲酯的合成,合成方法如实施例47。1H NMR(400MHz,DMSO)δ9.55(s,1H),8.78(s,1H),8.37(d,J=7.9Hz,1H),8.18(d,J=7.6Hz,1H),7.78(s, 1H),7.73(d,J=8.6Hz,1H),7.51–7.27(m,2H),6.79(d,J=8.8Hz,1H),5.46(d,J=7.5Hz,1H),3.77(s,3H), 2.74(s,3H),1.20(d,J=6.3Hz,6H).
实施例70
3-(1-乙酰基-1H-吲哚-3-甲酰氨基)-4-(丁基氨基)苯甲酸叔丁酯的合成,合成方法如实施例47。1H NMR(400MHz,DMSO)δ9.79(s,1H),8.40(s,1H),8.35(d,J=8.2Hz,1H),8.23(d,J=8.3Hz,1H),8.02(d,J =7.8Hz,1H),7.91(s,1H),7.79(dd,J=12.6,8.9Hz,2H),7.47(d,J=8.3Hz,1H),7.40(t,J=7.6Hz,1H),7.31 (t,J=7.6Hz,2H),7.19(t,J=7.6Hz,1H),2.63(s,3H),2.32(s,3H),1.54(s,9H),0.86(dd,J=14.6,7.7Hz, 6H).
实施例71
(1-乙酰基-1H-吲哚-3-甲酰胺基)-4-(丁基氨基)苯甲酸的合成,3-(1-乙酰基-1H-吲哚-3-甲酰氨基) -4-(丁基氨基)苯甲酸叔丁酯合成方法如实施例45。
将3-(1-乙酰基-1H-吲哚-3-甲酰氨基)-4-(丁基氨基)苯甲酸叔丁酯(50mg,0.112mmol)溶于二氯甲烷(20mL)中,加入三氟乙酸(0.5mL)。室温反应5h,水洗,DCM萃取(3×20mL),合并有机层,饱和氯化钠溶液洗一遍,无水硫酸钠干燥,旋干,用乙酸乙酯和石油醚重结晶,得到产物28.9mg(57.5%)。 1H NMR(400MHz,DMSO)δ9.77(s,1H),8.39(s,1H),8.34(d,J=8.3Hz,1H),8.23(d,J=8.3Hz,1H),8.05 –7.94(m,2H),7.85(d,J=8.2Hz,1H),7.78(d,J=7.8Hz,1H),7.48(d,J=8.2Hz,1H),7.39(t,J=7.7Hz, 1H),7.30(t,J=8.6Hz,2H),7.18(t,J=7.5Hz,1H),2.63(s,3H),2.30(s,3H),0.87(m,6H).
实施例72
(1-乙酰基-1H-吲哚-3-甲酰胺基)-4-(丙基氨基)苯甲酸的合成,合成方法如实施例71。1H NMR(400 MHz,DMSO)δ12.24(s,1H),9.56(s,1H),8.77(s,1H),8.37(d,J=7.9Hz,1H),8.19(d,J=7.4Hz,1H),7.74 (s,1H),7.71(d,J=8.6Hz,1H),7.51–7.27(m,2H),6.74(d,J=8.6Hz,1H),5.80(s,1H),3.14(t,J=6.9Hz, 3H),2.74(s,3H),1.59(dd,J=14.4,7.2Hz,2H),0.93(t,J=7.3Hz,3H).
实施例73
(1-乙酰基-1H-吲哚-3-甲酰胺基)-4-氟苯甲酸的合成,合成方法如实施例71。1HNMR(400MHz, DMSO)δ10.11(s,1H),8.84(s,1H),8.37(d,J=7.2Hz,2H),8.21(d,J=7.3Hz,1H),7.83(s,1H),7.50–7.33 (m,3H),2.75(s,3H).
实施例74
3-(1-乙酰基-1H-吲哚-3-甲酰氨基)-4-(苄基氨基)苯甲酸叔丁酯的合成,合成方法如实施例47。1H NMR(400MHz,DMSO)δ9.69(s,1H),8.80(s,1H),8.37(d,J=7.5Hz,1H),8.27–8.19(m,1H),7.67(d,J= 1.9Hz,1H),7.57(dd,J=8.6,1.9Hz,1H),7.39(dd,J=7.1,5.2Hz,4H),7.32(t,J=7.5Hz,3H),7.23(d,J=7.2 Hz,1H),6.56(d,J=8.8Hz,2H),4.46(d,J=6.0Hz,2H),2.75(s,3H),1.50(s,9H).
实施例75
(1-乙酰基-1H-吲哚-3-甲酰胺基)-4-(苄基氨基)苯甲酸的合成,合成方法如实施例71。1H NMR(400 MHz,DMSO)δ12.46(s,1H),9.66(s,1H),8.80(s,1H),8.38(d,J=7.4Hz,1H),8.23(d,J=7.5Hz,1H),7.75 (s,1H),7.61(d,J=8.1Hz,1H),7.40(d,J=7.3Hz,4H),7.34(d,J=7.5Hz,2H),7.24(d,J=7.0Hz,1H),6.57 (d,J=8.4Hz,1H),4.47(s,2H),2.75(s,3H).
实施例76
3-(1-乙酰基-1H-吲哚-3-甲酰氨基)-4-(环丙基氨基)苯甲酸叔丁酯的合成,合成方法如实施例47。 1H NMR(400MHz,DMSO)δ9.48(s,1H),8.76(s,1H),8.37(d,J=7.8Hz,1H),8.19(d,J=7.1Hz,1H),7.77 –7.66(m,2H),7.44–7.30(m,2H),7.08(d,J=9.1Hz,1H),6.24(s,1H),2.73(s,3H),1.52(s,9H),1.17(t,J= 7.1Hz,1H),0.85(dd,J=7.2,5.0Hz,2H),0.78(d,J=4.7Hz,2H).
实施例77
3-(1-乙酰基-1H-吲哚-3-甲酰氨基)-4-((环己基甲基)氨基)苯甲酸叔丁酯的合成,合成方法如实施例47。1H NMR(400MHz,DMSO)δ9.59(s,1H),8.76(s,1H),8.37(d,J=7.9Hz,1H),8.18(d,J=7.8Hz,1H), 7.68(s,1H),7.65(d,J=4.2Hz,1H),7.44–7.33(m,2H),6.72(d,J=8.7Hz,1H),5.80(t,J=5.7Hz,1H),3.02 (t,J=6.2Hz,2H),2.74(s,3H),1.78(d,J=12.5Hz,2H),1.66(s,2H),1.59(s,1H),1.51(s,9H),1.14(d,J=8.2 Hz,2H),0.97–0.91(m,2H),0.87–0.80(m,2H).
实施例78
(1-乙酰基-1H-吲哚-3-甲酰氨基)-4-((环己基甲基)氨基)苯甲酸的合成,合成方法如实施例71。 1H NMR(400MHz,DMSO)δ12.25(s,1H),9.58(s,1H),8.77(s,1H),8.37(d,J=7.9Hz,1H),8.18(d,J=7.4 Hz,1H),7.72(s,1H),7.69(s,1H),7.43–7.32(m,2H),6.72(d,J=8.5Hz,1H),3.03(d,J=6.6Hz,2H),2.74(s, 3H),1.79(d,J=12.5Hz,2H),1.67(d,J=10.8Hz,2H),1.61(d,J=4.0Hz,2H),1.23(s,1H),1.16(s,2H),0.94 (dd,J=22.5,11.0Hz,2H).
实施例79
3-(1-乙酰基-1H-吲哚-3-甲酰氨基)-4-((3-氟苯基)氨基)苯甲酸叔丁酯的合成,合成方法如实施例 47。1H NMR(400MHz,DMSO)δ10.37(s,1H),8.84(s,1H),8.40(s,1H),8.38(d,J=7.6Hz,1H),8.33(s,1H), 8.28(d,J=7.3Hz,1H),7.88(s,1H),7.56(m,3H),7.46–7.36(m,2H),7.28(t,J=8.3Hz,1H),2.78(s,3H), 1.60(s,9H).
实施例80
3-(1-乙酰基-1H-吲哚-3-甲酰氨基)-4-(苯基氨基)苯甲酸甲酯的合成,合成方法如实施例47。1H NMR (400MHz,DMSO)δ9.73(s,1H),8.75(s,1H),8.37(d,J=7.4Hz,1H),8.26–8.17(m,1H),8.08(s,1H),8.06 (d,J=2.0Hz,1H),7.73(dd,J=8.6,2.0Hz,1H),7.44–7.36(m,2H),7.36–7.33(m,1H),7.32(d,J=2.5Hz, 1H),7.30(d,J=1.3Hz,1H),7.18(s,1H),7.16(s,1H),6.99(t,J=7.3Hz,1H),3.82(s,3H),2.72(s,3H).
实施例81
3-(1-乙酰基-1H-吲哚-3-甲酰氨基)-4-(丙基氨基)苯甲酸叔丁酯的合成,合成方法如实施例47。1H NMR(400MHz,DMSO)δ9.58(s,1H),8.77(s,1H),8.37(d,J=8.0Hz,1H),8.19(d,J=7.4Hz,1H),7.68(s, 1H),7.66(s,1H),7.46–7.32(m,2H),6.73(d,J=9.2Hz,1H),5.79(t,J=5.4Hz,1H),3.13(dd,J=13.3,6.5 Hz,2H),2.74(s,3H),1.58(d,J=7.6Hz,2H),1.51(s,9H),0.93(t,J=7.3Hz,3H).
实施例82
3-(1-乙酰基-1H-吲哚-3-甲酰氨基)-4-(环庚基氨基)苯甲酸叔丁酯的合成,合成方法如实施例47。 1H NMR(400MHz,DMSO)δ9.62(s,1H),8.77(s,1H),8.37(d,J=7.7Hz,1H),8.18(d,J=6.9Hz,1H),7.68 (dd,J=4.4,2.5Hz,2H),7.48–7.33(m,2H),6.69(d,J=9.3Hz,1H),5.34(d,J=7.5Hz,1H),3.55(m,1H), 2.74(s,3H),1.91(m,2H),1.64(m,3H),1.56(m,3H),1.51(s,9H).
实施例83
3-(1-乙酰基-1H-吲哚-3-甲酰氨基)-4-((环丙基甲基)氨基)苯甲酸叔丁酯的合成,合成方法如实施例47。1H NMR(400MHz,DMSO)δ9.64(s,1H),8.79(s,1H),8.37(d,J=7.6Hz,1H),8.23–8.17(m,1H), 7.68(s,1H),7.67(d,J=2.0Hz,1H),7.45–7.33(m,2H),6.77(d,J=9.3Hz,1H),5.81(t,J=5.5Hz,1H),3.07 (t,J=6.1Hz,2H),2.74(s,3H),1.52(s,9H),1.13–1.04(m,1H),0.51–0.42(m,2H),0.30–0.21(m,2H).
实施例84
3-(1-乙酰基-1H-吲哚-3-甲酰氨基)-4-(异丁基氨基)苯甲酸叔丁酯的合成,合成方法如实施例47。 1H NMR(400MHz,DMSO)δ9.63(s,1H),8.78(s,1H),8.37(d,J=7.9Hz,1H),8.19(d,J=7.2Hz,1H),7.68 (s,1H),7.65(d,J=2.7Hz,1H),7.46–7.31(m,2H),6.73(d,J=8.6Hz,1H),5.79(t,J=5.7Hz,1H),2.99(t,J= 6.3Hz,2H),2.74(s,3H),1.88(dt,J=13.3,6.7Hz,1H),1.52(s,9H),0.92(d,J=6.6Hz,6H).
实施例85
(1-乙酰基-1H-吲哚-3-甲酰氨基)-4-(环庚基氨基)苯甲酸的合成,合成方法如实施例71。1H NMR (400MHz,DMSO)δ12.18(s,1H),9.62(s,1H),8.78(s,1H),8.37(d,J=7.9Hz,1H),8.18(d,J=7.5Hz,1H), 7.75(s,1H),7.71(d,J=8.6Hz,1H),7.46–7.31(m,2H),6.69(d,J=8.7Hz,1H),5.37(d,J=7.1Hz,1H),3.58 (m,1H),2.74(s,3H),1.97–1.85(m,2H),1.71–1.46(m,10H).
实施例86
(1-乙酰基-1H-吲哚-3-甲酰氨基)-4-((环丙基甲基)氨基)苯甲酸的合成,合成方法如实施例71。 1H NMR(400MHz,DMSO)δ12.22(s,1H),9.63(s,1H),8.79(s,1H),8.37(d,J=7.9Hz,1H),8.20(d,J=7.4 Hz,1H),7.75(s,1H),7.71(d,J=8.5Hz,1H),7.48–7.30(m,2H),6.77(d,J=8.6Hz,1H),5.82(s,1H),3.07(d, J=4.9Hz,2H),2.74(s,3H),1.10(m,1H),0.47(m,2H),0.26(m,2H).
实施例87
(1-乙酰基-1H-吲哚-3-甲酰氨基)-4-(异丁基氨基)苯甲酸的合成,合成方法如实施例71。1H NMR (400MHz,DMSO)δ12.34(s,1H),8.78(s,1H),8.37(d,J=7.9Hz,1H),8.19(d,J=7.7Hz,1H),7.72(d,J= 2.2Hz,1H),7.70(d,J=1.7Hz,1H),7.45–7.32(m,2H),6.74(d,J=8.6Hz,1H),3.00(d,J=6.8Hz,2H),2.74 (s,3H),1.89(dt,J=13.3,6.6Hz,1H),0.93(d,J=6.6Hz,6H).
实施例88
3-(1-乙酰基-1H-吲哚-3-甲酰氨基)-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯甲酸叔丁酯的合成,合成方法如实施例47。1H NMR(400MHz,DMSO)δ9.59(s,1H),8.76(s,1H),8.37(d,J=7.7Hz,1H),8.24– 8.13(m,1H),7.67(dd,J=8.6,1.9Hz,1H),7.64(d,J=1.9Hz,1H),7.43–7.31(m,2H),6.76(d,J=8.7Hz, 1H),5.87(t,J=5.8Hz,1H),3.84(dd,J=11.1,2.9Hz,2H),3.24(t,J=10.9Hz,2H),3.08(t,J=6.3Hz,2H), 2.74(s,3H),2.32(t,J=6.9Hz,1H),1.90–1.77(m,1H),1.65(d,J=12.3Hz,2H),1.51(s,9H),0.88–0.83(m,2H).
实施例89
3-(1-乙酰基-1H-吲哚-3-甲酰氨基)-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯甲酸的合成,合成方法如实施例71。1H NMR(400MHz,DMSO)δ12.21(s,1H),9.57(s,1H),8.76(s,1H),8.37(d,J=7.9Hz,1H), 8.18(d,J=7.3Hz,1H),7.72(s,1H),7.70(d,J=1.9Hz,1H),7.45–7.30(m,2H),6.77(d,J=8.4Hz,1H),5.88 (s,1H),3.84(dd,J=11.0,2.9Hz,2H),3.27(d,J=10.7Hz,2H),3.09(d,J=6.6Hz,2H),2.74(s,3H),1.92– 1.78(m,1H),1.67(d,J=12.6Hz,2H),1.24(m,2H).
实施例90
(1-乙酰基-1H-吲哚-3-甲酰氨基)-4-((四氢-2H-吡喃-4-基)氨基)苯甲酸的合成,合成方法如实施例71。1H NMR(400MHz,DMSO)δ12.26(s,1H),9.58(s,1H),8.78(s,1H),8.37(d,J=7.8Hz,1H),8.19(d,J =7.4Hz,1H),7.78(s,1H),7.70(d,J=8.3Hz,1H),7.46–7.32(m,2H),6.87(d,J=8.7Hz,1H),5.49(s,1H), 3.87(d,J=11.2Hz,2H),3.67(m,1H),3.46(d,J=11.2Hz,2H),2.74(s,3H),1.92(d,J=12.2Hz,2H),1.49(m, 2H).
实施例91
(1-乙酰基-1H-吲哚-3-甲酰氨基)-5-(((叔丁氧羰基)氧基)甲基)苯甲酸甲酯的合成,合成方法如实施例47。1H NMR(500MHz,DMSO)δ10.32(s,1H),8.84(s,1H),8.41–8.34(m,2H),8.27(d,J=7.8Hz, 1H),8.13(s,1H),7.68(s,1H),7.48–7.33(m,2H),5.17(s,2H),3.90(s,3H),2.76(s,3H),1.45(s,9H).
实施例92
(1-乙酰基-1H-吲哚-3-甲酰氨基)-5-环丙基苯甲酸的合成,合成方法如实施例71。1H NMR(400MHz, DMSO)δ12.97(s,1H),10.18(s,1H),8.83(d,J=4.0Hz,1H),8.37(d,J=7.7Hz,1H),8.27(d,J=5.4Hz,1H), 8.20(s,1H),7.94(s,1H),7.52(s,1H),7.45–7.34(m,2H),2.76(d,J=4.0Hz,3H),2.66(d,J=7.4Hz,2H), 1.65(d,J=7.4Hz,1H),0.93(m,2H).
实施例93
甲基3-(1-乙酰基-1H-吲哚-3-甲酰氨基)-5-(((2-氟苯基)氨基)甲基)苯甲酸甲酯的合成,合成方法如实施例47。1H NMR(500MHz,DMSO)δ10.27(s,1H),8.82(s,1H),8.36(d,J=7.9Hz,1H),8.31(s,1H), 8.26(d,J=7.8Hz,1H),8.10(s,1H),7.72(s,1H),7.38(dq,J=13.7,7.0Hz,2H),7.03(dd,J=11.8,8.0Hz,1H), 6.87(t,J=7.6Hz,1H),6.53(t,J=6.9Hz,2H),6.35(s,1H),4.42(d,J=5.8Hz,2H),3.87(s,3H),2.75(s,3H).
实施例94
甲基3-(1-乙酰基-1H-吲哚-3-甲酰氨基)-5-(((环丙基甲基)氨基)甲基)苯甲酸甲酯的合成,合成方法如实施例47。1H NMR(400MHz,DMSO)δ10.31(s,1H),8.82(s,1H),8.36(dd,J=10.9,4.0Hz,2H), 8.28(d,J=7.0Hz,1H),8.22(s,1H),8.09(s,1H),7.76(d,J=7.6Hz,1H),7.46–7.30(m,4H),4.94(s,2H), 3.89(s,3H),2.76(s,3H),2.51–2.49(m,2H),0.83(dd,J=11.7,5.9Hz,1H),0.43(s,2H),0.13(s,2H).
实施例95
5-(1-乙酰基-1H-吲哚-3-甲酰氨基)-[1,1'-联苯]-3-羧酸的合成,合成方法如实施例71。1H NMR(400 MHz,DMSO)δ13.07(s,1H),10.33(s,1H),8.86(s,1H),8.42(s,1H),8.39(s,1H),8.37(s,1H),8.29(d,J=7.2 Hz,1H),7.92(s,1H),7.72(s,1H),7.70(s,1H),7.54(t,J=7.6Hz,2H),7.48–7.35(m,3H),2.78(s,3H).
实施例96
5-(1-乙酰基-1H-吲哚-3-甲酰氨基)-3'-氟-[1,1'-联苯]-3-羧酸的合成,合成方法如实施例71。1H NMR (400MHz,DMSO)δ13.15(s,1H),10.34(s,1H),8.85(s,1H),8.41(d,J=0.9Hz,2H),8.38(d,J=7.8Hz,1H), 8.29(d,J=7.1Hz,1H),7.93(s,1H),7.61–7.50(m,3H),7.46–7.35(m,2H),7.28(t,J=7.8Hz,1H),2.77(s, 3H).
实施例97
甲基3-(1-乙酰基-1H-吲哚-3-甲酰氨基)-5-(((3-氟苯基)氨基)甲基)苯甲酸甲酯的合成,合成方法如实施例47。1H NMR(400MHz,DMSO)δ10.27(s,1H),8.83(s,1H),8.37(d,J=7.8Hz,1H),8.30(s,1H), 8.26(d,J=7.3Hz,1H),8.12(s,1H),7.71(s,1H),7.38(m,2H),7.06(m,1H),6.74(s,1H),6.42(d,J=7.8Hz, 1H),6.30(m,2H),4.37(d,J=5.5Hz,2H),3.87(s,3H),2.75(s,3H).
实施例98
甲基3-(1-乙酰基-1H-吲哚-3-甲酰胺基)-5-((环戊基氨基)甲基)苯甲酸甲酯的合成,合成方法如实施例47。1H NMR(400MHz,DMSO)δ10.31(s,1H),8.84(s,1H),8.37(t,J=8.1Hz,2H),8.30(d,J=6.7 Hz,1H),8.14(s,1H),8.04(s,1H),7.46–7.36(m,3H),4.78(s,2H),3.90(s,3H),2.77(s,3H),1.79(s,2H),1.63 (s,4H),1.42(s,2H),1.23(s,1H).
实施例99
(1-乙酰基-1H-吲哚-3-甲酰氨基)-5-异丁基苯甲酸的合成,合成方法如实施例71。1H NMR(400MHz, DMSO)δ12.87(s,1H),10.17(s,1H),8.83(s,1H),8.37(d,J=7.8Hz,1H),8.27(d,J=7.4Hz,1H),8.22(s, 1H),7.91(s,1H),7.49(s,1H),7.45–7.34(m,2H),2.76(s,3H),2.54(d,J=7.0Hz,2H),1.87(m,1H),0.91(d,J =6.5Hz,6H).
实施例100
(1-乙酰基-1H-吲哚-3-甲酰氨基)-5-环戊基苯甲酸的合成,合成方法如实施例71。1H NMR(400MHz, DMSO)δ10.17(s,1H),8.83(s,1H),8.37(d,J=7.9Hz,1H),8.27(d,J=7.1Hz,1H),8.22(s,1H),7.98(s,1H), 7.57(s,1H),7.46–7.33(m,2H),3.10–3.04(m,1H),2.76(s,3H),2.07(m,2H),1.81(m,2H),1.70(m,2H), 1.64–1.51(m,2H).
实施例101
(1-乙酰基-1H-吲哚-3-甲酰氨基)-5-环己基苯甲酸的合成,合成方法如实施例71。1H NMR(400MHz, DMSO)δ12.97(s,1H),10.16(s,1H),8.82(s,1H),8.37(d,J=7.7Hz,1H),8.27(d,J=7.1Hz,1H),8.20(s, 1H),7.97(s,1H),7.55(s,1H),7.45–7.35(m,2H),2.76(s,3H),2.60(s,1H),1.84(m,4H),1.73(m,1H),1.51– 1.34(m,5H).
实施例102
(1-乙酰基-1H-吲哚-3-甲酰氨基)-5-(2-甲基吡啶-4-基)苯甲酸的合成,合成方法如实施例71。1H NMR (500MHz,DMSO)δ10.43(s,1H),8.92(s,1H),8.88(s,1H),8.65(s,1H),8.51(s,1H),8.44(s,1H),8.38(d,J= 7.9Hz,1H),8.34(s,1H),8.29(d,J=7.7Hz,1H),8.02(s,1H),7.41(m,2H),2.78(s,3H),2.51(s,3H).
实施例103
(1-乙酰基-1H-吲哚-3-甲酰氨基)-5-(苯并呋喃-3-基)苯甲酸的合成,合成方法如实施例71。1H NMR (400MHz,DMSO)δ10.39(s,1H),8.85(s,1H),8.27(d,J=7.5Hz,1H),8.12(d,J=7.7Hz,1H),7.99(s,1H), 7.97(s,1H),7.89(s,1H),7.56–7.45(m,2H),7.45–7.34(m,2H),2.77(s,3H).
实施例104
3-(1-乙酰基-1H-吲哚-3-甲酰氨基)-5-乙基苯甲酸的合成,合成方法如实施例71。1H NMR(500MHz, DMSO)δ12.95(s,1H),10.17(s,1H),8.83(s,1H),8.37(d,J=8.0Hz,1H),8.27(d,J=7.2Hz,1H),8.21(s, 1H),7.96(s,1H),7.54(s,1H),7.39(m,2H),2.76(s,3H),2.70(q,J=7.5Hz,2H),1.24(t,J=7.6Hz,3H).
实施例105
(1-乙酰基-1H-吲哚-3-甲酰氨基)-5-苯乙基苯甲酸的合成,合成方法如实施例71。1H NMR(500MHz, DMSO)δ12.97(s,1H),10.18(d,J=5.1Hz,1H),8.82(d,J=14.8Hz,1H),8.37(d,J=7.6Hz,1H),8.30–8.24 (m,1H),8.22(s,1H),7.98(d,J=12.1Hz,1H),7.57(s,1H),7.39(dd,J=15.2,7.9Hz,2H),7.35–7.26(m,4H), 7.19(d,J=6.4Hz,1H),2.95(d,J=6.6Hz,3H),2.76(d,J=6.3Hz,3H),1.63(d,J=7.1Hz,1H).
实施例106
5-(1-乙酰基-1H-吲哚-3-甲酰氨基)-3'-(三氟甲基)-[1,1'-联苯]-3-羧酸的合成,合成方法如实施例71。 1H NMR(500MHz,DMSO)δ10.37(s,1H),8.85(s,1H),8.48(s,1H),8.41(s,1H),8.37(d,J=8.1Hz,1H), 8.29(d,J=7.6Hz,1H),8.03(d,J=7.4Hz,1H),7.99(s,1H),7.96(s,1H),7.79(m,2H),7.47–7.33(m,2H), 2.77(s,3H).
实施例107
5-(1-乙酰基-1H-吲哚-3-甲酰氨基)-3'-甲氧基-[1,1'-联苯]-3-羧酸的合成,合成方法如实施例71。1H NMR (500MHz,DMSO)δ10.33(s,1H),8.85(s,1H),8.41(s,1H),8.38(d,J=7.9Hz,2H),8.29(d,J=7.7Hz,1H), 7.91(s,1H),7.50–7.36(m,3H),7.26(d,J=7.6Hz,1H),7.20(s,1H),7.02(d,J=8.2,2.0Hz,1H),3.85(s,3H), 2.77(s,3H).
实施例108
5-(1-乙酰基-1H-吲哚-3-甲酰氨基)-3'-氯-[1,1'-联苯]-3-羧酸的合成,合成方法如实施例71。1H NMR (500MHz,DMSO)δ13.13(s,1H),10.35(s,1H),8.86(s,1H),8.41(s,1H),8.39(s,1H),8.37(s,1H),8.29(d,J =6.8Hz,1H),7.92(s,1H),7.71(s,1H),7.70(s,1H),7.54(t,J=7.6Hz,2H),7.48–7.35(m,3H),2.77(s,3H).
实施例109
3-(1-乙酰基-1H-吲哚-3-甲酰氨基)-5-(1-甲基-1H-吲唑-5-基)苯甲酸的合成,合成方法如实施例71。 1H NMR(500MHz,DMSO)δ10.34(s,1H),8.87(s,1H),8.46(s,1H),8.39(s,1H),8.37(s,1H),8.30(d,J=7.6 Hz,1H),8.16(s,1H),8.09(s,1H),7.97(s,1H),7.77(dd,J=18.6,8.8Hz,2H),7.47–7.36(m,2H),4.10(s,3H), 2.78(s,3H).
实施例110
3-(1-乙酰基-5-甲氧基-1H-吲哚-3-甲酰氨基)-5-(呋喃-2-基)苯甲酸的合成,合成方法如实施例71。 1H NMR(400MHz,DMSO)δ13.19(s,1H),8.84(s,1H),8.44(s,1H),8.32(s,1H),8.25(d,J=9.0Hz,1H), 7.98(s,1H),7.83(d,J=1.2Hz,1H),7.80(d,J=2.5Hz,1H),7.06(d,J=3.3Hz,1H),7.01(m,1H),6.65(m, 1H),3.84(s,3H),2.74(s,3H).
实施例111
3-(1-乙酰基-5-羟基-1H-吲哚-3-甲酰氨基)-5-(呋喃-2-基)苯甲酸的合成,合成方法如实施例17。 1H NMR(500MHz,DMSO)δ13.15(s,1H),10.25(s,1H),9.40(s,1H),8.78(s,1H),8.45(s,1H),8.29(s,1H), 8.15(s,1H),7.97(s,1H),7.83(s,1H),7.67(s,1H),7.04(s,1H),6.86(s,1H),6.65(s,1H),2.72(s,3H).
实施例112
(1-乙酰基-5-乙氧基-1H-吲哚-3-甲酰氨基)-5-(呋喃-2-基)苯甲酸的合成,3-(1-乙酰基-5-羟基-1H- 吲哚-3-甲酰氨基)-5-(呋喃-2-基)苯甲酸合成方法如实例17。
3-(1-乙酰基-5-羟基-1H-吲哚-3-甲酰氨基)-5-(呋喃-2-基)苯甲酸(120mg,0.26mmol)溶于20mL丙酮中,随后加入K2CO3(107.6g,0.78mmol),碘乙烷(0.037ml,0.39mmol),70℃搅拌过夜。反应结束后,丙酮真空旋干,加水,乙酸乙酯萃取(3×50mL),有机层用饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩,硅胶柱层析分离,得到白色固体(56mg,48.27%)。1H NMR(500MHz,DMSO)δ11.89(s,1H),10.06(s,1H), 8.50(s,1H),8.42(d,J=2.3Hz,1H),8.31(s,1H),7.92(s,2H),7.83(s,1H),7.49(d,J=8.7Hz,1H),7.02(d,J= 3.0Hz,1H),6.96(d,J=8.6Hz,1H),6.65(s,1H),4.29(t,J=6.6Hz,2H),2.29(s,3H),1.77(dd,J=14.1,7.0 Hz,2H),1.01(t,J=7.4Hz,3H).
实施例113
3-(1-乙酰基-5-丙氧基-1H-吲哚-3-甲酰氨基)-5-(呋喃-2-基)苯甲酸的合成,合成方法如实例112。 1H NMR(500MHz,DMSO)δ11.89(s,1H),10.06(s,1H),8.50(s,1H),8.42(d,J=2.3Hz,1H),8.31(s,1H), 7.92(s,2H),7.83(s,1H),7.49(d,J=8.7Hz,1H),7.02(d,J=3.0Hz,1H),6.96(d,J=8.6Hz,1H),6.65(s,1H), 4.29(t,J=6.6Hz,2H),2.29(s,3H),1.77(dd,J=14.1,7.0Hz,2H),1.01(t,J=7.4Hz,3H).
实施例114
3-(1-乙酰基-5-甲氧基-1H-吲哚-3-甲酰胺基)-5-(1-甲基-1H-吡唑-4-基)苯甲酸的合成,合成方法如实例71。1H NMR(500MHz,DMSO)δ13.07(s,1H),10.22(s,1H),8.83(s,1H),8.25(t,J=6.5Hz,3H),8.19 (s,1H),7.87(s,1H),7.83(s,1H),7.79(d,J=2.3Hz,1H),7.01(dd,J=9.0,2.5Hz,1H),3.90(s,3H),3.84(s, 3H),2.74(s,3H).
实施例115
3-(1-乙酰基-5-甲氧基-1H-吲哚-3-甲酰胺基)-5-(呋喃-2-基)苯甲酸甲酯的合成,合成方法如实例 47。1H NMR(400MHz,DMSO)δ10.31(s,1H),8.84(s,1H),8.47(t,J=1.7Hz,1H),8.38–8.30(m,1H),8.25 (d,J=9.1Hz,1H),7.98(s,1H),7.84(d,J=1.3Hz,1H),7.79(d,J=2.6Hz,1H),7.08(d,J=3.3Hz,1H),7.01 (m,1H),6.66(dd,J=3.4,1.8Hz,1H),3.92(s,3H),3.84(s,3H),2.74(s,3H).
实施例116
3-(1-乙酰基-5-甲氧基-1H-吲哚-3-甲酰氨基)-5-(1-甲基-1H-吡唑-4-基)苯甲酸叔丁酯的合成,合成方法如实例47。1H NMR(400MHz,DMSO)δ10.24(s,1H),8.81(s,1H),8.29–8.23(m,2H),8.22(s,1H), 8.07(s,1H),7.86(s,1H),7.78(d,J=2.0Hz,2H),7.02(m,1H),3.90(s,3H),3.83(s,3H),2.74(s,3H),1.59(s, 9H).
实施例117
3-(1-乙酰基-5-甲氧基-1H-吲哚-3-甲酰胺基)-5-(1-甲基-1H-吡唑-4-基)苯甲酸甲酯的合成,合成方法如实例47。1H NMR(400MHz,DMSO)δ10.31(s,1H),8.89(s,1H),8.26(dd,J=12.2,7.9Hz,4H),7.88(s, 1H),7.84(s,1H),7.79(d,J=2.3Hz,1H),7.01(dd,J=9.0,2.2Hz,1H),3.90(s,3H),3.83(s,3H),2.74(s,3H).
实施例118
3-(1-乙酰基-5-甲氧基-1H-吲哚-3-甲酰氨基)-5-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)苯甲酸叔丁酯的合成,合成方法如实例47。1H NMR(400MHz,DMSO)δ10.28(s,1H),8.81(s,1H),8.33(s,1H),8.28 –8.20(m,2H),7.78(s,2H),7.19–7.13(m,2H),7.02(d,J=4.0Hz,1H),7.00(d,J=3.9Hz,1H),4.30(s,4H), 3.83(s,3H),2.74(s,3H),1.59(s,9H).
实施例119
3-(1-乙酰基-5-甲氧基-1H-吲哚-3-甲酰胺基)-5-(1-甲基-1H-吲唑-5-基)苯甲酸叔丁酯的合成,合成方法如实例47。1H NMR(400MHz,DMSO)δ10.33(s,1H),8.83(s,1H),8.45(s,1H),8.27(s,1H),8.24(s, 1H),8.16(s,1H),8.07(s,1H),7.91(s,1H),7.79(d,J=8.8Hz,2H),7.74(d,J=8.8Hz,1H),7.02(dd,J=9.0, 2.5Hz,1H),4.10(s,3H),3.83(s,3H),2.75(s,3H),1.61(s,9H).
实施例120
3-(1-乙酰基-5-甲氧基-1H-吲哚-3-甲酰氨基)-5-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)苯甲酸的合成,合成方法如实例71。1H NMR(400MHz,DMSO)δ13.05(s,1H),8.82(s,1H),8.34(s,1H),8.31(s,1H), 8.25(d,J=9.0Hz,1H),7.83(s,1H),7.79(s,1H),7.17(d,J=6.1Hz,2H),7.00(d,J=7.7Hz,2H),4.30(s,4H), 3.83(s,3H),2.74(s,3H).
实施例121
(1-乙酰基-5-甲氧基-1H-吲哚-3-甲酰胺基)-5-(1-甲基-1H-吲唑-5-基)苯甲酸的合成,合成方法如实例71。1H NMR(400MHz,DMSO)δ13.19(s,1H),10.30(s,1H),8.85(s,1H),8.44(s,1H),8.39(s,1H),8.25 (d,J=8.2Hz,1H),8.16(s,1H),8.09(s,1H),7.97(s,1H),7.79(m,3H),7.02(s,1H),4.10(s,3H),3.83(s,3H), 2.75(s,3H).
实施例122
N-([1,1'-联苯]-3-基)-1-乙酰基-5-甲氧基-1H-吲哚-3-甲酰胺的合成,合成方法如实例47。1H NMR(500 MHz,DMSO)δ10.15(s,1H),8.79(s,1H),8.25(d,J=9.1Hz,1H),8.08(s,1H),7.80(s,1H),7.77(d,J=2.7 Hz,1H),7.68(s,1H),7.67(s,1H),7.49(m,3H),7.41(s,1H),7.40(s,1H),7.01(m,1H),3.82(s,3H),2.74(s, 3H).
实施例123
1-乙酰基-5-甲氧基-N-(3-(1-甲基-1H-吲唑-5-基)苯基)-1H-吲哚-3-甲酰胺的合成,合成方法如实例 47。1H NMR(500MHz,DMSO)δ10.14(s,1H),8.80(s,1H),8.25(d,J=9.0Hz,1H),8.13(s,1H),8.11(s,1H), 8.03(s,1H),7.80–7.76(m,2H),7.75(s,1H),7.74(d,J=1.4Hz,1H),7.51–7.41(m,2H),7.01(m,1H),4.09 (s,3H),3.83(s,3H),2.74(s,3H).
实施例124
N-([1,1'-联苯]-3-基)-1-乙酰基-5-羟基-1H-吲哚-3-甲酰胺的合成,合成方法如实例17。1H NMR(500 MHz,DMSO)δ10.10(s,1H),9.40(s,1H),8.72(s,1H),8.15(d,J=8.7Hz,1H),8.07(s,1H),7.79(d,J=7.7 Hz,1H),7.67(d,J=7.8Hz,3H),7.57–7.43(m,3H),7.40(m,2H),6.84(d,J=8.4Hz,1H),2.72(s,3H).
实施例125
1-乙酰基-5-羟基-N-(3-(1-甲基-1H-吲唑-5-基)苯基)-1H-吲哚-3-甲酰胺的合成,合成方法如实例 17。1H NMR(500MHz,DMSO)δ10.09(s,1H),9.40(s,1H),8.73(s,1H),8.14(m,3H),8.03(s,1H),7.76(m, 3H),7.67(s,1H),7.46(m,2H),6.84(d,J=7.1Hz,1H),4.09(s,3H),2.72(s,3H).
实施例126
1-乙酰基-5-甲氧基-N-(3-(1-甲基-1H-吡唑-4-基)苯基)-1H-吲哚-3-甲酰胺的合成,合成方法如实例 47。1H NMR(500MHz,DMSO)δ10.06(s,1H),8.78(s,1H),8.25(d,J=9.0Hz,1H),8.11(s,1H),7.92(s,1H), 7.81(s,1H),7.77(s,1H),7.59(d,J=7.8Hz,1H),7.36(t,J=7.8Hz,1H),7.30(d,J=7.6Hz,1H),7.00(d,J= 9.0Hz,1H),3.88(s,3H),3.82(s,3H),2.73(s,3H).
实施例127
1-乙酰基-5-羟基-N-(3-(1-甲基-1H-吡唑-4-基)苯基)-1H-吲哚-3-甲酰胺的合成,合成方法如实例 17。1H NMR(500MHz,DMSO)δ10.09(s,1H),9.40(s,1H),8.80(s,1H),8.15(d,J=8.9Hz,1H),8.10(s,1H), 7.94(s,1H),7.80(s,1H),7.65(s,1H),7.61(d,J=8.0Hz,1H),7.35(t,J=7.8Hz,1H),7.29(d,J=7.4Hz,1H), 6.89–6.79(m,1H),3.89(s,3H),2.72(s,3H).
实施例128
(呋喃-2-基)-5-(1H-吲哚-3-甲酰氨基)苯甲酸的合成,(1-乙酰基-1H-吲哚-3-甲酰氨基)-5-(呋喃 -2-基)苯甲酸合成方法如实施例7。
将(1-乙酰基-1H-吲哚-3-甲酰氨基)-5-(呋喃-2-基)苯甲酸(100mg,0.25mmol)溶于8mL MeOH 中,向反应体系中加入1M NaOH(1.25mL,1.25mmol)。反应体系在室温下搅拌,TLC跟踪监测。反应结束后,真空旋去大部分溶剂,剩余溶液用1M盐酸溶液调节pH至弱酸性,有大量白色固体析出,减压抽滤,用20mL水洗涤滤饼,真空干燥得白色固体49.52mg(产率57.20%)。1H NMR(400MHz,DMSO)δ 11.85(s,1H),9.97(s,1H),8.44(s,1H),8.40(d,J=2.8Hz,1H),8.27(s,1H),8.24(d,J=7.4Hz,1H),7.92(s, 1H),7.81(s,1H),7.48(d,J=7.6Hz,1H),7.25–7.10(m,2H),6.96(d,J=3.2Hz,1H),6.63(m,1H).
实施例129
3-(呋喃-2-基)-5-(1-丙酰基-1H-吲哚-3-甲酰氨基)苯甲酸叔丁酯的合成,合成方法如实例47。1H NMR (400MHz,DMSO)δ10.32(s,1H),8.90(s,1H),8.47–8.43(m,1H),8.40(d,J=7.5Hz,1H),8.33–8.26(m, 1H),8.22(d,J=1.5Hz,1H),7.92(s,1H),7.84(d,J=1.2Hz,1H),7.40(tt,J=7.2,3.8Hz,2H),7.04(d,J=3.3 Hz,1H),6.66(dd,J=3.4,1.8Hz,1H),3.18(q,J=7.2Hz,2H),1.60(s,9H),1.24(d,J=7.2Hz,3H).
实施例130
(呋喃-2-基)-5-(1-丙酰基-1H-吲哚-3-甲酰氨基)苯甲酸的合成,合成方法如实例71。1H NMR(400 MHz,DMSO)δ10.30(s,1H),8.92(s,1H),8.45(s,1H),8.41(d,J=7.6Hz,1H),8.31(s,1H),8.29(s,1H),7.98 (s,1H),7.83(d,J=1.2Hz,1H),7.46-7.35(m,2H),7.05(d,J=3.3Hz,1H),6.65(dd,J=3.3,1.8Hz,1H),3.21 -3.16(m,2H),1.25(d,J=7.3Hz,3H).
实施例131
3-(1-乙酰基-5-甲氧基-1H-吲哚-3-甲酰氨基)-4-氟-5-(1-甲基-1H-吡唑-4-基)苯甲酸的合成,合成方法如实施例71。1H NMR(500MHz,DMSO)δ13.16(s,1H),10.10(s,1H),8.85(s,1H),8.29(s,1H),8.26(d,J =9.1Hz,1H),8.19(d,J=5.4Hz,1H),8.07(d,J=4.9Hz,1H),7.96(s,1H),7.74(s,1H),7.01(d,J=8.9Hz, 1H),3.92(s,3H),3.81(s,3H),2.73(s,3H).
实施例132
3-(1-乙酰基-5-甲氧基-1H-吲哚-3-甲酰氨基)-4-氟-5-(1-甲基-1H-吡唑-4-基)苯甲酸叔丁酯的合成,合成方法如实施例71。1H NMR(400MHz,DMSO)δ10.13(s,1H),8.83(s,1H),8.31-8.24(m,2H),8.06(d,J =6.8Hz,1H),8.03(d,J=6.4Hz,1H),7.96(s,1H),7.72(d,J=2.1Hz,1H),7.01(dd,J=9.0,2.1Hz,1H),3.92 (s,3H),3.81(s,3H),2.73(s,3H),1.58(s,9H).
实施例133
3-(1-乙酰基-5-甲氧基-1H-吲哚-3-甲酰胺基)-4-氟-5-(1-甲基-1H-吲唑-6-基)苯甲酸叔丁酯的合成,合成方法如实施例47。1H NMR(500MHz,DMSO)δ10.17(s,1H),8.84(s,1H),8.26(d,J=9.1Hz,2H),8.16 (s,1H),7.99(s,1H),7.88(d,J=6.6Hz,1H),7.79(d,J=8.7Hz,1H),7.73(s,1H),7.61(d,J=8.8Hz,1H),7.02 (d,J=9.,1Hz,1H),4.10(s,3H),3.82(s,3H),2.73(s,3H),1.99(d,J=1.6Hz,2H),1.58(s,9H).
实施例134
3-(1-乙酰基-5-甲氧基-1H-吲哚-3-甲酰氨基)-4-氟-5-(1-甲基-1H-吲唑-6-基)苯甲酸的合成,合成方法如实施例71。1H NMR(400MHz,DMSO)δ10.15(s,1H),8.86(s,1H),8.38(dd,J=6.8,1.9Hz,1H),8.26(d, J=9.1Hz,1H),8.15(s,1H),8.01(s,1H),7.93(dd,J=6.8,2.0Hz,1H),7.79(d,J=8.8Hz,1H),7.75(d,J=2.6 Hz,1H),7.63(d,J=8.6Hz,1H),7.02(dd,J=9.1,2.6Hz,1H),4.10(s,3H),3.82(s,3H),2.73(s,3H).
实施例135
3-(1-乙酰基-5-甲氧基-1H-吲哚-3-甲酰氨基)-5-(苯并呋喃-6-基)-4-氟苯甲酸叔丁酯的合成,合成方法如实施例47。1H NMR(500MHz,DMSO)δ10.18(s,1H),8.84(s,1H),8.26(d,J=9.3Hz,2H),8.09(s,1H), 7.92-7.85(m,2H),7.79-7.70(m,2H),7.52(d,J=8.2Hz,1H),7.07(s,1H),7.02(d,J=9.0Hz,1H),3.81(s, 3H),2.73(s,3H),1.58(s,9H).
实施例136
3-(1-乙酰基-5-甲氧基-1H-吲哚-3-甲酰氨基)-5-(苯并呋喃-6-基)-4-氟苯甲酸的合成,合成方法如实施例71。1H NMR(400MHz,DMSO)δ13.03(s,1H),10.15(s,1H),8.86(s,1H),8.39(d,J=5.0Hz,1H),8.26 (d,J=9.1Hz,1H),8.09(d,J=2.0Hz,1H),7.92(s,1H),7.90(s,1H),7.76(d,J=6.4Hz,1H),7.74(s,1H),7.06 (d,J=1.2Hz,1H),7.01(dd,J=9.1,2.5Hz,1H),3.82(s,3H),2.73(s,3H).
实施例137
3-(1-乙酰基-5-甲氧基-1H-吲哚-3-甲酰氨基)-5-(2,3-二氢苯并[b][1,4]二恶英-6-基)-4-氟苯甲酸叔丁酯的合成,合成方法如实施例47。1H NMR(400MHz,DMSO)δ10.13(s,1H),8.83(s,1H),8.24(dd,J=11.7, 7.7Hz,2H),7.77(dd,J=6.7,2.1Hz,1H),7.72(d,J=2.6Hz,1H),7.08(s,2H),7.01(d,J=7.9Hz,2H),4.31(s, 4H),3.81(s,3H),2.72(s,3H),1.57(s,9H).
实施例138
3-(1-乙酰基-5-甲氧基-1H-吲哚-3-甲酰氨基)-5-(2,3-二氢苯并[b][1,4]二恶英-6-基)-4-氟苯甲酸的合成,合成方法如实施例71。1H NMR(400MHz,DMSO)δ13.07(s,1H),10.12(s,1H),8.85(s,1H),8.34(d,J= 5.1Hz,1H),8.25(d,J=9.1Hz,1H),7.82(d,J=5.1Hz,1H),7.73(d,J=2.3Hz,1H),7.08(d,J=13.1Hz,2H), 7.05-6.93(m,2H),4.31(s,4H),3.81(s,3H),2.73(s,3H).
实施例139
甲基3-(1-乙酰基-5-甲氧基-1H-吲哚-3-甲酰氨基)-5-(2,3-二氢苯并[b][1,4]二恶英-6-基)-4-氟苯甲酸酯的合成,合成方法如实施例47。1HNMR(400MHz,DMSO)δ1O.14(s,1H),8.85(s,1H),8.38(dd,J=6.7, 2.1Hz,1H),8.26(d,J=9.1Hz,1H),7.83(dd,J=6.8,2.2Hz,1H),7.73(d,J=2.6Hz,1H),7.13-7.05(m,2H), 7.01(dd,J=8.7,2.9Hz,2H),4.31(s,4H),3.90(s,3H),3.82(s,3H),2.73(s,3H).
实施例140
甲基3-(1-乙酰基-5-甲氧基-1H-吲哚-3-甲酰氨基)-5-(苯并呋喃-6-基)-4-氟苯甲酸甲酯的合成,合成方法如实施例47。1H NMR(400MHz,DMSO)δ10.17(s,1H),8.86(s,1H),8.43(dd,J=6.7,2.1Hz,1H), 8.26(d,J=9.1Hz,1H),8.09(d,J=2.1Hz,1H),7.93(dd,J=8.4,3.7Hz,2H),7.75(t,J=6.3Hz,2H),7.56(dd, J=12.8,5.5Hz,1H),7.07(d,J=2.1Hz,1H),7.02(dd,J=9.1,2.6Hz,1H).
实施例141
甲基3-(1-乙酰基-5-甲氧基-1H-吲哚-3-甲酰氨基)-4-氟-5-(1-甲基-1H-吲唑-6-基)苯甲酸甲酯的合成,合成方法如实施例47。1H NMR(400MHz,DMSO)δ10.16(s,1H),8.86(s,1H),8.42(dd,J=6.7,2.0Hz,1H), 8.26(d,J=9.1Hz,1H),8.16(s,1H),8.01(s,1H),7.94(dd,J=6.8,2.1Hz,1H),7.79(d,J=8.8Hz,1H),7.74(d, J=2.6Hz,1H),7.63(d,J=8.7Hz,1H),7.02(dd,J=9.0,2.6Hz,1H),4.10(s,3H),3.91(s,3H),3.82(s,3H), 2.73(s,3H).
实施例142
3-(1-乙酰基-5-甲氧基-1H-吲哚-3-甲酰氨基)-5-(呋喃-2-基)苯甲酸叔丁酯的合成,合成方法如实施例47。1H NMR(400MHz,DMSO)δ10.31(s,1H),8.82(s,1H),8.45(s,1H),8.25(d,J=9.0Hz,1H),8.19(s, 1H),7.92(s,1H),7.84(d,J=1.2Hz,1H),7.78(d,J=2.6Hz,1H),7.01(m,2H),6.66(dd,J=3.3,1.8Hz,1H), 3.84(s,3H),2.74(s,3H),1.60(s,9H).
对比例1
对SGC-CBP30体外活性实验,采用AlphaScreen检测技术验证本发明化合物的对CBP/EP300蛋白抑制能力。
实施例1-142以及对比例1的化合物结构如表1所示。
对实施例1-142制备得到的吲哚类化合物进行体外活性实验:本发明采用AlphaScreen检测技术验证本发明化合物的对CBP/EP300蛋白抑制能力。
所述体外活性实验材料包括:目的蛋白CBP;实验缓冲液(10×)MOPS(500mm),CHAPS(0.5mm), NaF(500mm),BSA(1mg/mL),PH7.4;试剂盒中供体微珠50μg/mL,受体微珠50μg/mL;CBP配体,短肽H4KAc4-botin(SGRG{Lys-Ac}GG{Lys-Ac}GLG{Lys-Ac}GGA{Lys-Ac}RHR{Lys(biotin)})50nM; 150μL反应体系中:CBP:15μL,实验缓冲液:15μL,去离子水:15μL,小分子化合物:15μL,供体微珠:15μL,受体微珠:15μL;阳性抑制剂:SGC-CBP30。
所述体外活性实验方法为将蛋白、短肽加入反应溶液中,在20℃下孵育1.5h,加入供体和受体微珠,避光孵育1h。转移至384孔板,每孔转移40μL液体,通过PE Envison2104多功能检测酶标仪,激发波长:680nM,发射波长520-620nM检测读数。
对比例1采用AlphaScreen检测技术验证结果,验证结果见表1:
表1
注:以上活性数据针对Bromodomain家族的CBP/EP300蛋白。
表中的部分化合物表现出与阳性对照SGC-CBP30相当的活性,虽然较SGC-CBP30略低,但也显示出较强的活性。其中实施例44,46,51,63,73,109,110,111,114,120,121和131已达到纳摩尔水平,特别是实施例110,111,114和131所介绍的化合物与阳性化合物相当,且对比阳性化合物具有结构稳定和容易制备的优点。且大部分实施例对CBP/EP300有很好的选择性。表1分子水平活性数据表明,这些化合物可以有效结合具有Bromodomain结构域的蛋白。
吲哚类化合物细胞活性测定:用RPMI1640培养***癌细胞(LNCaP和22Rv1),并加上10%FBS。让细胞在37℃在5%CO2培养箱中生长。为了测试细胞的存活能力,将细胞以总体积为20μL的培养基以1000个细胞/孔(最佳生长密度)接种在具有透明底部的384个不透壁板中。12小时后,向每个孔中加入总体积为10μL培养基(三次稀释)的化合物,最终浓度为5nM至100μM。对于LNCaP细胞,培养基是含有10%FBS的RPMI1640。对于22Rv1细胞,培养基是含有10%cds-FBS的RPMI1640。接种后96 小时进行测定,加入25μLCell-Titer GLO试剂(Promega),根据制造商的说明书,在GLOMAX微孔板光度计(Promega)上测量发光。使用GraphPad Prism 6软件计算估计的体外最大半抑制浓度(IC50)值。其中实施例115,132和142细胞活性为5μM以内的水平。
对于集落形成,将1000个22Rv1细胞和2000个C4-2B细胞分别接种在6孔板的孔中,并用载体或指示浓度的化合物与3mL培养基一起培养14天。当细胞克隆生长可见时,除去培养基,并将板用2mL PBS 洗涤一次。细胞集落用2.5%结晶紫(在MeOH中)染色2小时。用水清洗3次后,计数菌落数。实施例 115在细胞克隆形成实验中,表现出5μM以内的水平。因此充分表明这类化合物具有成为癌症、炎症疾病及自身免疫疾病、败血症、病毒感染等疾病的潜力。
申请人声明,本发明通过上述实施例来说明本发明的详细结构特征,但本发明并不局限于上述详细结构特征,即不意味着本发明必须依赖上述详细结构特征才能实施。所属技术领域的技术人员应该明了,对本发明的任何改进,对本发明所选用部件的等效替换以及辅助部件的增加、具体方式的选择等,均落在本发明的保护范围和公开范围之内。
以上详细描述了本发明的优选实施方式,但是,本发明并不限于上述实施方式中的具体细节,在本发明的技术构思范围内,可以对本发明的技术方案进行多种简单变型,这些简单变型均属于本发明的保护范围。另外需要说明的是,在上述具体实施方式中所描述的各个具体技术特征,在不矛盾的情况下,可以通过任何合适的方式进行组合,为了避免不必要的重复,本发明对各种可能的组合方式不再另行说明。此外,本发明的各种不同的实施方式之间也可以进行任意组合,只要其不违背本发明的思想,其同样应当视为本发明所公开的内容。
Claims (8)
1.一种用于抑制CBP/EP300 Bromodomain受体的吲哚类化合物,其特征在于,所述化合物就有下述化学式I的结构:
式I中,R1为C1~C4烷基,R2为-R-X1或-X2,R3为H、C1~C5烷基、C3~C5环烷基、-OX3、-NHX3或-N(X3)2;
其中,R为C1~C2亚烷基,X1为-COOX4、-CONHX4、环烷基或杂环基,X2为-COX5或-S(O)mX5,其中X5为C1~C3烷基、C3~C7环烷基、苯基、萘基或杂环基;
其中,m为0或2,X4为H、C1~C4烷基、C3~C7环烷基、苯基、萘基或杂环基;
式I中所述C3~C7环烷基、苯基以及萘基含有2~3个取代基,所述取代基为氰基、硝基、氨基、酰胺、-COOX6、-COX6、-OX6、-NHCOX6、吗啉基、哌啶基、呋喃基、四氢呋喃基或吡啶基其中X6为H、C1~C4烷基、苯基;
所述杂环基为氮杂环丁基、氧杂环丁基、氮杂环戊基、氧杂环戊基、氮杂环己基、氧杂环己基、氮杂环己基、咪唑-2-酮基、咪唑基、呋喃基、噻吩基、噁唑基、异噁唑基、嘧啶基、吡咯基、哌嗪基、四氢吡咯基、哌啶基、吗啉基、1,3-二氧戊环基或苯并[d]噻唑基。
2.根据权利要求1所述的化合物,其特征在于,所述式I中R1包括甲基、乙基、正丙基、异丙基或叔丁基。
3.根据权利要求1所述的化合物,其特征在于,所述式I中R3包括H、甲基、乙基、正丙基、异丙基、正丁基、正戊基、环丙基、环丁基、环戊基、酚羟基、甲氧基、乙氧基、丙氧基、丁氧基、氮甲基、氮乙基、氮丙基或氮丁基。
4.根据权利要求1所述的化合物,其特征在于,式I中所述杂环基含有0~3个取代基。
5.根据权利要求4所述的化合物,其特征在于,所述取代基为卤素、C1~C4烷基、三氟甲基、氰基、硝基、氨基、酰胺、-COOX6、-COX6、-OX6、-NHCOX6、-C6H5X7、吗啉基、哌啶基、呋喃基、四氢呋喃基或吡啶基其中X6为H、C1~C4烷基、苯基,X7为C1~C4烷基、卤素、三氟甲基、氰基、硝基、氨基、酰胺、乙酰基、甲氧基或乙氧基。
6.一种权利要求1-5任一项所述吲哚类化合物的应用,其特征在于,所述吲哚类化合物用于制备CBP/EP300 Bromodomain受体抑制剂。
7.根据权利要求8所述的应用,其特征在于,所述CBP/EP300 Bromodomain受体抑制剂用于制备治疗癌症、细胞增殖性紊乱疾病、炎症疾病及自身免疫疾病、败血症、病毒感染、神经性衰退性疾病的药物。
8.一种药物组合物,其特征在于,所述药物组合物含有权利要求1-5任一项所述吲哚类化合物。
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