CN113999221B - 6-位取代的吲哚酮衍生物及其医药用途 - Google Patents
6-位取代的吲哚酮衍生物及其医药用途 Download PDFInfo
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- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
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- C07D401/14—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 three or more hetero rings
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- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Abstract
本发明公开了一种6‑位取代的吲哚酮衍生物及其医药用途。属于药物化学领域;本发明所述的6‑位取代的吲哚酮衍生物是一类全新结构类型的CSF‑1R抑制剂,具有较强的CSF‑1R的抑制活性,能够通过特异性抑制巨噬细胞向肿瘤的趋化、诱导M2型TAMs向M1表型再极化实现对多种实体瘤的免疫治疗,尤其是用于结直肠癌治疗的起效剂量更低,同等剂量下的抑瘤率明显优于PLX3397,并且与PD‑L1单抗联用有很好的协同增效作用。
Description
技术领域
本发明涉及药物化学领域,具体涉及一种6-位取代的吲哚酮衍生物或其药学上可接受的盐,以及含有这些化合物的药物组合物,在制备抗肿瘤药物方面的用途。
背景技术
恶性肿瘤治疗一直是世界性医学难题,手术、放疗、化疗、靶向治疗等方法都把目标集中在肿瘤细胞上,然而肿瘤细胞是体内细胞变异产生的,不是外部入侵的病菌,所以在治疗过程中,肿瘤细胞无法清除干净,转移和复发的情况比比皆是。近年来,随着分子生物学、肿瘤免疫学的迅速发展,以选择性增强患者免疫应答为重点的免疫治疗如免疫检查点抑制剂、CAR-T细胞治疗等已成为一种新的肿瘤治疗手段。免疫治疗将治疗目标从肿瘤细胞转移到免疫细胞上面,通过增强患者自身的免疫力来治疗肿瘤,与传统治疗相比具有杀伤精准、副作用小、疗效持久、个性化程度高等优势。此外,机体免疫系统具有免疫记忆的特性,可以帮助患者形成记忆型免疫,在防止肿瘤复发和转移上具有显著优势。目前,无论是久热不止的PD-1和PD-L1单抗,还是LAG3、OX40等仍在路上的靶点,无一例外都是围绕如何恢复T淋巴细胞功能或如何提高获得性免疫系统的功能进行的。然而,固有免疫系统在肿瘤免疫治疗中的作用,却长期没有得到发挥。事实上在整个肿瘤浸润区域,肿瘤相关巨噬细胞(tumor-associated macrophages,TAMs)约占肿瘤间质免疫细胞总数的50%以上,是肿瘤微环境中最为丰富的免疫细胞,与肿瘤的发生发展及不良预后密切相关。因此,除了围绕T细胞的过继转移细胞疗法和检查点抑制剂疗法,基于TAMs的免疫疗法也越来越受到关注。
集落刺激因子1(colony-stimulating factor 1,CSF-1)的过表达会导致其受体CSF-1R的异常激活,促进大量的巨噬细胞向肿瘤细胞趋化,浸润肿瘤组织,并诱导巨噬细胞向M2型TAMs分化,与多种恶性肿瘤的发生发展及不良预后密切相关。阻断CSF-1/CSF-1R信号传导可显著降低巨噬细胞在肿瘤部位的浸润,抑制M2型TAMs的分化,并减缓原发性肿瘤生长、减少肿瘤转移。CSF-1R小分子抑制剂通过竞争性地占据CSF-1R的ATP结合位点,抑制CSF-1R的激活,可以阻断CSF-1/CSF-1R信号传导,抑制TAMs的存活和分化,改善肿瘤微环境,实现对肿瘤的免疫治疗。因此,以CSF-1R为靶标的小分子抑制剂为肿瘤等疾病的免疫治疗开辟了新途径。近年来,随着肿瘤免疫治疗的不断发展以及对CSF-1R抑制剂研究的不断深入,多个活性良好的CSF-1R抑制剂陆续进入临床研究。
虽然CSF-1R抑制剂的研究取得了较大的进展,然而大多数正在开发中的CSF-1R抑制剂由于调节TAMs的方式单一,作为单一药物对结直肠癌等实体瘤的疗效有限,缓解率较低。因此,如何获得高活性的新型CSF-1R小分子抑制剂实现对结直肠癌等实体瘤高效、精准的治疗是目前CSF-1R抑制剂研究开发面临的主要问题和挑战。本发明通过对CSF-1R蛋白结合口袋的分析研究,基于老药Sunitinib的吲哚酮骨架进行合理的药物设计和系统的活性筛选,发现了对结直肠癌等实体瘤治疗效果显著的6-位取代的吲哚酮类新型CSF-1R抑制剂候选化合物。
发明内容
发明目的:针对上述问题,本发明提供了一种通式I所示的6-位取代的吲哚酮类衍生物或其药学上可接受的盐。
本发明的技术方案是:一种6-位取代的吲哚酮类衍生物或其药学上可接受的盐,所述衍生物如下所示:
表1.化合物的编号、名称及结构
本发明的另一目的在于提供一种药物组合物,包括所述的6-位取代的吲哚酮类衍生物、其药学上可接受的盐,以及至少一种药学上可接受的载体、添加剂、助剂或赋形剂。
本发明的另一目的在于提供所述6-位取代的吲哚酮衍生物或药学上可接受的盐、及其药物组合物在制备CSF-1R等酪氨酸激酶抑制剂中的用途。本发明的化合物或其药学上可接受的盐,及其药物组合物对CSF-1R、VEGFR-1、VEGFR-2、PDGFRα、PDGFR-β、FLT3、c-KIT等受体酪氨酸激酶具有显著的抑制活性,尤其对CSF-1R具有很强的抑制活性,因此可以用于制备治疗酪氨酸激酶表达异常引起的相关肿瘤疾病的药物。
本发明的另一目的在于提供所述6-位取代的吲哚酮衍生物或药学上可接受的盐、及其药物组合物在调节肿瘤相关巨噬细胞功能中的用途。本发明的化合物或其药学上可接受的盐,及其药物组合物可以特异性抑制巨噬细胞向肿瘤的趋化、诱导M2型TAMs向M1表型再极化,因此可以作为肿瘤相关巨噬细胞的调节剂用于恶性肿瘤、炎症性疾病、骨疾病和神经性疾病的免疫治疗。
本发明的另一目的在于提供所述6-位取代的吲哚酮衍生物或药学上可接受的盐、及其药物组合物在制备抗肿瘤药物中的用途。体内外抗肿瘤试验表明,本发明化合物刺激的M2型巨噬细胞条件培养基能够显著抑制肝癌、肺癌、胰腺癌、结直肠癌等恶性肿瘤的生长。因此,本发明的化合物或其药学上可接受的盐,及其药物组合物可作为单一治疗剂,或者与其它抗肿瘤药物(包括靶向药物和免疫治疗药物)联合使用,用于多种恶性肿瘤的治疗。
本发明的另一目的在于提供所述6-位取代的吲哚酮衍生物或药学上可接受的盐、及其药物组合物在制备治疗结直肠癌药物中的用途。体外抗肿瘤活性实验表明,本发明的化合物刺激的M2型巨噬细胞条件培养基能够显著抑制结直肠癌细胞的增殖。整体动物试验表明,本发明化合物对结直肠癌具有很好的疗效,抑瘤效果显著优于PLX3397,并且与免疫检查点抑制剂PD-L1单抗联用具有协同增效作用。因此,本发明的化合物或其药学上可接受的盐,及其药物组合物可作为单一治疗剂,或者与免疫检查点抑制剂联合使用,用于结直肠癌的治疗。
本发明的有益效果是:本发明所述的6-位取代的吲哚酮衍生物是一种全新结构类型的CSF-1R抑制剂,相比目前上市CSF-1R抑制剂PLX3397,具有更强的CSF-1R抑制活性,更强的体外抗肿瘤活性和更强的体内抗肿瘤活性,尤其是用于结直肠癌治疗的起效剂量更低,同等剂量下的抑瘤率明显优于PLX3397,并且与PD-L1单抗联用有很好的协同增效作用,因此,本发明的CSF-1R抑制剂具有良好的产业化前景。
具体实施方式
为了更清楚地说明本发明的技术方案,下面对本发明的技术方案做进一步的详细说明:
实施例1
(S,Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)吡咯烷-2-甲酰胺盐酸盐(I-1)的合成:
中间体III-1的合成:将化合物II-1(0.70g,7.13mmol)溶解于无水四氢呋喃(20mL),然后加入K2CO3(1.22g,8.83mmol),氯甲酸苯酯(0.94mL,7.49mmol),室温反应4h。LC-MS监测反应完毕后,抽滤,滤饼用少量四氢呋喃洗涤,真空干燥,得到白色固体1.17g,收率75%。
中间体V-1的合成:将化合物III-1(0.31g,1.44mmol),IV-1(0.20g,1.20mmol),DMAP(0.0090g,0.07mmol)溶解于DCM(10mL),于搅拌下加入TEA(0.025mL,0.18mmol),加热至50℃反应20h。LC-MS监测反应完毕后,停止加热,冷却至室温,减压浓缩,乙酸乙酯打浆纯化,抽滤,滤饼用少量乙酸乙酯洗涤,真空干燥,得到灰色固体0.27g,收率75%。1H NMR(500MHz,DMSO-d6)δ(ppm):10.37(1H,s),9.45(1H,s),8.84(1H,s),7.23(1H,s),7.09(1H,d,J=7.9Hz),6.80(1H,d,J=8.0Hz),6.49(1H,s),3.40(2H,s),1.30(9H,s).13C NMR(125MHz,DMSO-d6)δ(ppm):180.6,177.3,158.8,151.7,144.6,138.8,125.0,119.9,111.4,100.6,92.9,35.8,32.9,28.8(3C)。
中间体XI-1的合成:将化合物V-1(0.80g,2.55mmol)和VI-1(0.43g,2.55mmol)溶解于乙醇(10mL),然后加入吡咯烷(0.27mL,3.31mmol),加热至50℃反应2h。LC-MS监测反应完毕后,停止加热,冷却至室温,抽滤,滤饼用少量乙醇洗涤,真空干燥,得到橙黄色固体1.00g,收率85%。1H NMR(500MHz,DMSO-d6)δ(ppm):14.22(1H,s),11.12(1H,s),9.57(1H,s),9.10(1H,s),7.78(1H,d,J=8.3Hz),7.59(1H,s),7.32(1H,s),6.94(1H,d,J=8.3Hz),6.51(1H,s),2.63(3H,s),2.55(3H,s),1.31(9H,s).13C NMR(125MHz,DMSO)δ(ppm):180.7,170.5,158.8,151.6,144.6,140.4,139.5,136.5,133.9,125.4,123.9,121.4,120.8,119.5,112.0,100.8,92.9,33.0,28.8(3C),15.3,11.5。
中间体XII-1的合成:将化合物XI-1(0.20g,0.43mmol)溶于四氢呋喃和甲醇(10mL/5mL,v/v)的混合溶剂,加入氯化铵(0.23g,4.31mmol)的饱和溶液(1mL),加热至50℃,分批加入锌粉(0.14g,2.15mmol),继续反应0.5h。LC-MS监测反应完毕后,停止加热,冷却至室温,减压浓缩,残留物用乙酸乙酯(100mL)和饱和碳酸钠溶液(100mL)溶解,分出有机层,依次用水和饱和氯化钠溶液洗涤,无水硫酸钠干燥。抽滤,减压浓缩,甲醇打浆纯化,抽滤,滤饼用少量甲醇洗涤,真空干燥,得到黄色固体0.10g,收率54%。1H NMR(500MHz,DMSO-d6)δ(ppm):13.22(1H,s),10.66(1H,s),9.45(1H,s),8.81(1H,s),7.55(1H,d,J=8.3Hz),7.31(1H,s),7.25(1H,d,J=1.6Hz),6.85(1H,dd,J1=8.3Hz,J2=1.8Hz),6.51(1H,s),3.92(2H,s),2.24(3H,s),2.13(3H,s),1.30(9H,s).13C NMR(125MHz,DMSO)δ(ppm):180.6,169.9,158.9,151.6,138.4,136.6,132.9,125.0,123.8,122.0,121.6,118.1,116.6,111.5,110.8,100.6,92.9,32.9,28.8(3C),11.6,8.9。
中间体XIII-1的合成:将化合物XII-1(0.40g,0.92mmol)和Boc-L-脯氨酸(0.22g,1.01mmol)溶于DMF(50mL),加入缩合剂PyBOP(0.57g,1.10mmol)和DIPEA(1.07mL,6.44mmol),于室温反应12h。TLC监测反应完毕后,将反应液加入水(50mL)中,乙酸乙酯(30mL×2)萃取,合并有机层,一次用水和氯化钠溶液洗涤,无水硫酸钠干燥。抽滤,浓缩滤液,柱层析纯化(二氯甲烷:甲醇=50:1~20:1)得到黄色固体0.45g,收率77%。
化合物I-1的合成:将化合物XIII-1(0.10g,0.16mmol)溶于乙醇(5mL),加入饱和HCl的乙醇溶液(5mL),于室温搅拌反应。TLC监测反应完毕后,减压浓缩,残留物加入乙酸乙酯(5mL)打浆纯化,抽滤,真空干燥得到黄色固体0.072g,收率75%。mp:>300℃.1H NMR(500MHz,DMSO-d6)δ(ppm):13.40(1H,s),10.87(1H,s),10.06(1H,brs),9.98(1H,s),9.81(1H,s),9.72(1H,s),8.65(1H,brs),7.63(1H,d,J=8.3Hz),7.47(1H,s),7.30(1H,d,J=1.7Hz),6.95(1H,dd,J1=8.3Hz,J2=1.7Hz),6.53(1H,s),4.39-4.43(1H,m),3.24-3.29(2H,m),2.21(3H,s),2.21(3H,s),1.94-2.02(4H,m),1.30(9H,s).13C NMR(125MHz,DMSO)δ(ppm):180.4,170.3,168.0,158.7,151.9,139.4,138.4,130.1,125.4,124.9,122.3,120.4,120.3,119.3,115.0,111.4,100.4,93.0,59.5,46.0,32.9,30.7,28.8(3C),24.1,12.1,9.6.HRMS(ESI):m/z[M+H]+calcd for C28H34N7O4 +,532.2672;found,532.2665.
实施例2
(R,Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)吡咯烷-2-甲酰胺盐酸盐(I-2)的合成:
中间体XII-2的合成:将化合物XIII-1(0.40g,0.92mmol)和Boc-L-脯氨酸(0.22g,1.01mmol)溶于DMF(50mL),加入缩合剂PyBOP(0.57g,1.10mmol)和DIPEA(1.07mL,6.44mmol),于室温反应12h。TLC监测反应完毕后,将反应液加入水(50mL)中,乙酸乙酯(30mL×2)萃取,合并有机层,一次用水和氯化钠溶液洗涤,无水硫酸钠干燥。抽滤,减压浓缩,柱层析纯化(二氯甲烷:甲醇=50:1~20:1)得到黄色固体0.44g,收率75%。
化合物I-2的合成:将化合物XIII-2(0.10g,0.16mmol)溶于乙醇(5mL),加入饱和HCl的乙醇溶液(5mL),于室温搅拌反应。TLC监测反应完毕后,减压浓缩滤液,残留物加入乙酸乙酯(5mL)打浆纯化,抽滤,真空干燥得到黄色固体0.064g,收率70%。mp:>300℃.1H NMR(500MHz,DMSO-d6)δ(ppm):13.40(1H,s),10.88(1H,s),9.90(1H,s),9.77(1H,brs),9.71(1H,s),9.44(1H,s),8.66(1H,brs),7.64(1H,d,J=8.3Hz),7.48(1H,s),7.30(1H,d,J=1.7Hz),6.94(1H,dd,J1=8.1Hz,J2=1.7Hz),6.53(1H,s),4.39-4.42(1H,m),3.24-3.29(2H,m),2.44-2.48(1H,m),2.21(3H,s),2.21(3H,s),1.95-2.02(3H,m),1.30(9H,s).13CNMR(125MHz,DMSO-d6)δ(ppm):180.5,170.3,168.0,158.8,151.8,139.4,138.2,130.2,125.4,124.9,122.4,120.5,120.2,119.3,115.0,111.6,100.5,92.9,59.6,46.1,32.9,30.6,28.8(3C),24.1,12.0,9.5.HRMS(ESI):m/z[M+H]+calcd for C28H34N7O4 +,532.2672;found,532.2668。
实施例3
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)哌啶-4-甲酰胺盐酸盐(I-3)的合成:
中间体XIII-3的合成:将化合物XII-1(0.40g,0.92mmol)和Boc-4-哌啶甲酸(0.23g,1.01mmol)溶于DMF(50mL),加入缩合剂PyBOP(0.57g,1.10mmol)和DIPEA(1.07mL,6.44mmol),于室温反应12h。TLC监测反应完毕后,将反应液加入水(50mL)中,乙酸乙酯(30mL×2)萃取,合并有机层,一次用水和氯化钠溶液洗涤,无水硫酸钠干燥。抽滤,减压浓缩,柱层析纯化(二氯甲烷:甲醇=50:1~20:1)得到黄色固体0.44g,收率80%。
化合物I-3的合成:将化合物XIII-3(0.10g,0.15mmol)溶于乙醇(5mL),加入饱和HCl的乙醇溶液(5mL),于室温搅拌反应。TLC监测反应完毕后,减压浓缩,残留物加入乙酸乙酯(5mL)打浆纯化,抽滤,真空干燥得到黄色固体0.055g,收率65%。mp:>300℃.1H NMR(500MHz,DMSO-d6)δ(ppm):13.35(1H,s),10.84(1H,s),9.68(1H,s),9.38(1H,s),9.23(1H,s),8.98(1H,brs),8.61(1H,brs),7.62(1H,d,J=8.3Hz),7.45(1H,s),7.29(1H,d,J=1.7Hz),6.92(1H,dd,J1=8.2Hz,J2=1.0Hz),6.52(1H,s),3.27-3.31(1H,m),2.91-2.98(2H,m),2.62-2.70(2H,m),2.21(3H,s),2.12(3H,s),1.97-2.02(2H,m),1.80-1.88(2H,m),1.30(9H,s).13C NMR(125MHz,DMSO-d6)δ(ppm):180.5,173.0,170.3,158.8,151.8,139.3,138.1,130.6,125.9,124.8,122.5,121.5,120.6,119.1,114.3,111.5,100.4,93.0,42.8(2C),32.9(2C),28.8(3C),25.8(2C),12.1,9.5.HRMS(ESI):m/z[M+H]+calcd forC29H36N7O4 +,546.2829;found,546.2819。
实施例4
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)哌啶-2-甲酰胺盐酸盐(I-4)的合成:
中间体XIII-4的合成:将化合物XII-1(0.40g,0.92mmol)和Boc-2-哌啶甲酸(0.23g,1.01mmol)溶于DMF(50mL),加入缩合剂PyBOP(0.57g,1.10mmol)和DIPEA(1.07mL,6.44mmol),于室温反应12h。TLC监测反应完毕后,将反应液加入水(50mL)中,乙酸乙酯(30mL×2)萃取,合并有机层,一次用水和氯化钠溶液洗涤,无水硫酸钠干燥。抽滤,减压浓缩,柱层析纯化(二氯甲烷:甲醇=50:1~20:1)得到黄色固体0.49g,收率83%。
化合物I-4的合成:将化合物XIII-4(0.10g,0.15mmol)溶于乙醇(5mL),加入饱和HCl的乙醇溶液(5mL),于室温搅拌反应。TLC监测反应完毕后,减压浓缩,残留物加入乙酸乙酯(5mL)打浆纯化,抽滤,真空干燥得到黄色固体0.060g,收率71%。mp:>300℃.1H NMR(500MHz,DMSO-d6)δ(ppm):13.39(1H,s),10.86(1H,s),9.82(1H,s),9.72(1H,s),9.49(1H,s),9.28(1H,brs),8.77(1H,brs),7.63(1H,d,J=8.3Hz),7.47(1H,s),7.29(1H,d,J=1.5Hz),6.94(1H,dd,J1=8.2Hz,J2=1.5Hz),6.52(1H,s),3.25-3.29(1H,m),2.96-2.99(1H,m),2.26-2.33(2H,m),2.20(3H,s),2.16(3H,s),1.84-1.86(1H,m),1.73-1.76(1H,m),1.54-1.60(1H,m),1.30(9H,s).13C NMR(125MHz,DMSO-d6)δ(ppm):180.5,170.3,168.5,158.8,151.8,139.4,138.2,130.2,125.5,124.9,122.4,120.4,120.2,119.3,115.0,111.5,100.5,92.9,57.5,43.7,32.9,28.8(3C),27.9,22.1,21.7,12.0,9.5.HRMS(ESI):m/z[M+H]+calcd for C29H36N7O4 +,546.2829;found,546.2814。
实施例5
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)哌啶-3-甲酰胺盐酸盐(I-5)的合成:
中间体XIII-5的合成:将化合物XII-1(0.40g,0.92mmol)和Boc-2-哌啶甲酸(0.23g,1.01mmol)溶于DMF(50mL),加入缩合剂PyBOP(0.57g,1.10mmol)和DIPEA(1.07mL,6.44mmol),于室温反应12h。TLC监测反应完毕后,将反应液加入水(50mL)中,乙酸乙酯(30mL×2)萃取,合并有机层,一次用水和氯化钠溶液洗涤,无水硫酸钠干燥。抽滤,减压浓缩,柱层析纯化(二氯甲烷:甲醇=50:1~20:1)得到黄色固体0.46g,收率78%。
化合物I-5的合成:将将化合物XIII-5(0.10g,0.15mmol)溶于乙醇(5mL),加入饱和HCl的乙醇溶液(5mL),于室温搅拌反应。TLC监测反应完毕后,减压浓缩,残留物加入乙酸乙酯(5mL)打浆纯化,抽滤,真空干燥得到黄色固体0.064g,收率73%。mp:>300℃.1H NMR(500MHz,DMSO-d6)δ(ppm):13.36(1H,s),10.84(1H,s),9.62(1H,s),9.39(1H,s),9.23(1H,s),8.85(1H,brs),8.70(1H,brs),7.63(1H,d,J=8.3Hz),7.46(1H,s),7.28(1H,d,J=1.4Hz),6.92(1H,dd,J1=8.2Hz,J2=1.6Hz),6.52(1H,s),3.29-3.32(1H,m),3.14-3.22(1H,m),3.02-3.09(1H,m),2.87-2.95(2H,m),2.18(3H,s),2.14(3H,s),2.04-2.09(1H,m),1.81-1.88(1H,m),1.70-1.76(2H,m),1.30(9H,s).13C NMR(125MHz,DMSO-d6)δ(ppm):180.6,171.7,170.3,158.8,151.7,139.3,138.0,130.5,125.8,124.8,122.5,121.1,120.6,119.2,114.5,111.6,100.6,92.9,44.8,43.5,39.0,32.9,28.8(3C),27.0,21.6,12.1,9.5.HRMS(ESI):m/z[M+H]+calcd for C29H36N7O4 +,546.2829;found,546.2812。
实施例6
(S,Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)吡咯烷-3-甲酰胺盐酸盐(I-6)的合成:
中间体XIII-6的合成:将化合物XII-1(0.40g,0.92mmol)和(R)-1-Boc-3-吡咯烷甲酸(0.22g,1.01mmol)溶于DMF(50mL),加入缩合剂PyBOP(0.57g,1.10mmol)和DIPEA(1.07mL,6.44mmol),于室温反应12h。TLC监测反应完毕后,将反应液加入水(50mL)中,乙酸乙酯(30mL×2)萃取,合并有机层,一次用水和氯化钠溶液洗涤,无水硫酸钠干燥。抽滤,减压浓缩,柱层析纯化(二氯甲烷:甲醇=50:1~20:1)得到黄色固体0.44g,收率75%。
化合物I-6的合成:将化合物XIII-6(0.10g,0.16mmol)溶于乙醇(5mL),加入饱和HCl的乙醇溶液(5mL),于室温搅拌反应。TLC监测反应完毕后,减压浓缩,残留物加入乙酸乙酯(5mL)打浆纯化,抽滤,真空干燥得到黄色固体0.068g,收率75%。mp:>300℃.1H NMR(500MHz,DMSO-d6)δ(ppm):13.36(1H,s),10.84(1H,s),9.74(1H,s),9.55(1H,s),9.51(1H,s),9.41(1H,brs),9.15(1H,brs),7.62(1H,d,J=8.2Hz),7.45(1H,s),7.29(1H,s),6.94(1H,d,J=8.1Hz),6.53(1H,s),3.39-3.45(1H,m),3.27-3.33(2H,m),3.20-3.24(2H,m),2.25-2.31(1H,m),2.18(3H,s),2.16(3H,s),2.03-2.10(1H,m),1.30(9H,s).13C NMR(125MHz,DMSO-d6)δ(ppm):180.5,171.2,170.3,158.8,151.8,139.3,138.1,130.4,125.7,124.8,122.5,121.3,120.5,119.2,114.5,111.5,100.5,92.9,47.3,45.2,42.5,32.9,29.7,28.8(3C),12.1,9.6.HRMS(ESI):m/z[M+H]+calcd for C28H34N7O4 +,532.2672;found,532.2653。
实施例7
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-3-(吡咯烷-1-基)丙酰胺(I-7)的合成:
中间体XIII-7的合成:化合物XII-1(0.50g,1.15mmol)溶于THF(20mL),加入DIPEA(0.50mL,3.45mmol),降温至0℃,滴加3-氯丙酰氯(0.10mL,5.75mmol),加毕,室温反应0.5h。TLC监测反应完毕后,减压浓缩,残留物加入乙酸乙酯(10mL)打浆。抽滤,滤饼用乙酸乙酯(1mL)洗涤,真空干燥得到黄色固体0.48g,收率80%。1H NMR(500MHz,DMSO-d6)δ(ppm):13.36(1H,s),10.82(1H,s),9.50(1H,s),9.26(1H,s),8.94(1H,s),7.63(1H,d,J=8.3Hz),7.46(1H,s),7.29(1H,d,J=1.7Hz),6.90(1H,dd,J1=8.3Hz,J2=1.8Hz),6.52(1H,s),3.88(2H,t,J=6.2Hz),2.78(2H,t,J=6.1Hz),2.19(3H,s),2.15(3H,s),1.31(9H,s).13C NMR(125MHz,DMSO)δ(ppm):180.6,170.3,168.7,158.8,151.7,139.3,137.8,130.8,126.0,124.8,122.6,121.7,120.7,119.2,114.3,111.6,100.6,92.9,41.8,38.7,32.9,28.8(3C),12.1,9.6。
化合物I-7的合成:将化合物XIII-7(0.17mg,0.30mmol)溶于DMF(5mL),加入吡咯烷(0.12mL,1.50mmol),于50℃反应12h。TLC监测反应完毕后,将反应液倒入水中,乙酸乙酯溶液(30mL×2)萃取,合并有机层,依次用水和饱和的氯化钠溶液洗涤,无水硫酸钠干燥。抽滤,减压浓缩,残留物加入乙酸乙酯(5mL)打浆纯化,抽滤,真空干燥得到黄色固体0.13g,收率79%。mp:>300℃.1H NMR(500MHz,DMSO-d6)δ(ppm):13.33(1H,s),10.82(1H,s),9.60(1H,s),9.23(1H,s),9.19(1H,s),7.62(1H,d,J=8.3Hz),7.45(1H,s),7.28(1H,d,J=1.4Hz),6.91(1H,dd,J1=8.2Hz,J2=1.5Hz),6.52(1H,s),2.74(2H,t,J=6.0Hz),2.51-2.60(4H,m),2.46(2H,t,J=7.0Hz),2.18(3H,s),2.13(3H,s),1.66-1.76(4H,m),1.30(9H,s).13CNMR(125MHz,DMSO-d6)δ(ppm):180.6,170.9,170.3,158.8,151.7,139.2,137.9,130.7,125.9,124.8,122.6,122.0,120.7,119.1,114.1,111.6,100.6,92.9,53.8(2C),52.3,35.5,32.9,28.8(3C),23.6(2C),12.1,9.5.HRMS(ESI):m/z[M+H]+calcd for C30H38N7O4 +,560.2985;found,560.2964。
实施例8
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-3-(哌啶-1-基)丙酰胺(I-8)的合成:
化合物I-8的合成:将化合物XIII-7(0.17g,0.30mmol)溶于DMF(5mL),加入哌啶(0.15mL,1.50mmol),于50℃反应12h。TLC监测反应完毕后,将反应液倒入水中,乙酸乙酯溶液(30mL×2)萃取,合并有机层,依次用水和饱和的氯化钠溶液洗涤,无水硫酸钠干燥。抽滤,减压浓缩,残留物加入乙酸乙酯(5mL)打浆纯化,抽滤,真空干燥得到黄色固体0.13g,收率76%。mp:>300℃.1H NMR(500MHz,DMSO-d6)δ(ppm):13.33(1H,s),10.81(1H,s),9.48(1H,s),9.20(1H,s),8.90(1H,s),7.62(1H,d,J=8.3Hz),7.45(1H,s),7.29(1H,s),6.90(1H,d,J=7.5Hz),6.51(1H,s),2.59(2H,t,J=6.6Hz),2.33-2.43(6H,m),2.19(3H,s),2.15(3H,s),1.46-1.52(4H,m),1.36-1.43(2H,m),1.30(9H,s).13C NMR(125MHz,DMSO-d6)δ(ppm):180.6,171.0,170.3,1588,151.7,139.2,137.7,130.8,126.0,124.8,122.6,122.0,120.8,119.1,114.0,111.7,100.6,92.9,55.4,54.2(2C),33.8,32.9,28.8(3C),26.1(2C),24.5,12.2,9.6.HRMS(ESI):m/z[M+H]+calcd for C31H40N7O4 +,574.3142;found,574.3123。
实施例9
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-3-(4-甲基哌嗪-1-基)丙酰胺(I-9)的合成:
化合物I-9的合成:将化合物XIII-7(0.17g,0.30mmol)溶于DMF(5mL),加入N-甲基哌嗪(0.17mL,1.50mmol),于50℃反应12h。TLC监测反应完毕后,将反应液倒入水中,乙酸乙酯溶液(30mL×2)萃取,合并有机层,依次用水和饱和的氯化钠溶液洗涤,无水硫酸钠干燥。抽滤,减压浓缩,残留物加入乙酸乙酯(5mL)打浆纯化,抽滤,真空干燥得到黄色固体0.13g,收率75%。mp:>300℃.1H NMR(500MHz,DMSO-d6)δ(ppm):13.33(1H,s),10.81(1H,s),9.54(1H,s),9.16(1H,s),9.04(1H,s),7.62(1H,d,J=8.3Hz),7.45(1H,s),7.29(1H,s),6.90(1H,d,J=8.1Hz),6.52(1H,s),2.62(2H,t,J=6.7Hz),2.42(4H,t,J=6.7Hz),2.25-2.39(6H,m),2.19(3H,s),2.18(3H,s),2.15(3H,s)1.31(9H,s).13C NMR(125MHz,DMSO-d6)δ(ppm):180.6,170.9,170.3,158.8,151.7,139.2,137.8,130.8,126.0,124.8,122.6,122.0,120.8,119.1,114.1,111.6,100.6,92.9,55.2(2C),54.6,52.8(2C),46.1,33.8,32.9,28.8(3C),12.2,9.6.HRMS(ESI):m/z[M+H]+calcd for C31H41N8O4 +,589.3251;found,589.3227。
实施例10
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-3-(二乙氨基)丙酰胺(I-10)的合成:
化合物I-10的合成:将化合物XIII-7(0.17g,0.30mmol)溶于DMF(5mL),加入二乙胺(0.16mL,1.50mmol),于50℃反应12h。TLC监测反应完毕后,将反应液倒入水中,乙酸乙酯溶液(30mL×2)萃取,合并有机层,依次用水和饱和的氯化钠溶液洗涤,无水硫酸钠干燥。抽滤,减压浓缩,残留物加入乙酸乙酯(5mL)打浆纯化,抽滤,真空干燥得到黄色固体0.12g,收率68%。mp:>300℃.1H NMR(500MHz,DMSO-d6)δ(ppm):13.34(1H,s),10.82(1H,s),9.60(1H,s),9.33(1H,s),9.19(1H,s),7.62(1H,d,J=8.3Hz),7.45(1H,s),7.29(1H,s),6.92(1H,d,J=8.3Hz),6.52(1H,s),2.64-2.94(7H,m),2.18(3H,s),2.15(3H,s),1.96-2.04(1H,m),1.30(9H,s),1.06-1.12(6H,m).13C NMR(125MHz,DMSO-d6)δ(ppm):180.6,170.4,170.3,158.8,151.8,139.2,137.9,130.6,125.9,124.8,122.5,121.7,120.7,119.1,114.3,111.6,100.6,92.9,48.5,46.7(2C),32.9(2C),28.8(3C),12.2(2C),9.6(2C).HRMS(ESI):m/z[M+H]+calcd for C30H40N7O4 +,562.3142;found,562.3123。
实施例11
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-3-(二甲氨基)丙酰胺(I-11)的合成:
化合物I-11的合成:将化合物XIII-7(0.17g,0.30mmol)溶于DMF(5mL),加入二甲胺(0.076mL,1.50mmol),于50℃反应12h。TLC监测反应完毕后,将反应液倒入水中,乙酸乙酯溶液(30mL×2)萃取,合并有机层,依次用水和饱和的氯化钠溶液洗涤,无水硫酸钠干燥。抽滤,减压浓缩,残留物加入乙酸乙酯(5mL)打浆纯化,抽滤,真空干燥得到黄色固体0.12g,收率72%。mp:>300℃.1H NMR(500MHz,DMSO-d6)δ(ppm):13.34(1H,s),10.81(1H,s),9.54(1H,s),9.20(1H,s),9.04(1H,s),7.62(1H,d,J=8.3Hz),7.45(1H,s),7.28(1H,d,J=1.2Hz),6.90(1H,dd,J1=8.2Hz,J2=1.3Hz),6.52(1H,s),2.60(2H,t,J=7.1Hz),2.43(2H,t,J=7.1Hz),2.22(6H,s),2.18(3H,s),2.14(3H,s),1.31(9H,s).13C NMR(125MHz,DMSO-d6)δ(ppm):180.6,170.8,170.3,158.8,151.7,139.2,137.8,130.7,125.9,124.8,122.6,122.0,120.8,119.1,114.1,111.6,100.6,92.9,55.9,45.3(2C),34.1,32.9,28.8(3C),12.1,9.5.HRMS(ESI):m/z[M+H]+calcd for C28H36N7O4 +,534.2829;found,534.2806。
实施例12
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-3-(乙氨基)丙酰胺(I-12)的合成:
化合物I-12的合成:将化合物XIII-7(0.17g,0.30mmol)溶于DMF(5mL),加入乙胺(0.083mL,1.50mmol),于50℃反应12h。TLC监测反应完毕后,将反应液倒入水中,乙酸乙酯溶液(30mL×2)萃取,合并有机层,依次用水和饱和的氯化钠溶液洗涤,无水硫酸钠干燥。抽滤,浓缩滤液,残留物加入乙酸乙酯(5mL)打浆纯化,抽滤,真空干燥得到黄色固体0.11g,收率70%。mp:>300℃.1H NMR(500MHz,DMSO-d6)δ(ppm):13.34(1H,s),10.81(1H,s),9.60(1H,s),9.30(1H,s),9.16-9.20(1H,m),7.62(1H,d,J=8.2Hz),7.45(1H,s),7.28(1H,s),6.91(1H,d,J=8.2Hz),6.52(1H,s),2.90(2H,t,J=6.7Hz),2.69(2H,q,J=7.0Hz),2.56(1H,t,J=6.9Hz),2.42(1H,t,J=7.0Hz),2.20(1H,s),2.18(3H,s),2.14(3H,s),1.30(9H,s),1.08(3H,t,J=7.1Hz).13C NMR(125MHz,DMSO-d6)δ(ppm):180.6,170.6,170.3,158.8,151.7,139.2,137.9,130.6,125.9,124.7,122.5,121.8,120.7,119.1,114.2,111.6,100.5,92.9,55.9,45.4,43.4,32.9,28.8(3C),14.5,12.2,9.6.HRMS(ESI):m/z[M+H]+calcd for C28H36N7O4 +,534.2829;found,534.2811。
实施例13
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-3-(丙氨基)丙酰胺(I-13)的合成:
化合物I-13的合成:将化合物XIII-7(0.17g,0.30mmol)溶于DMF(5mL),加入正丙胺(0.12mL,1.50mmol),于50℃反应12h。TLC监测反应完毕后,将反应液倒入水中,乙酸乙酯溶液(30mL×2)萃取,合并有机层,依次用水和饱和的氯化钠溶液洗涤,无水硫酸钠干燥。抽滤,浓缩滤液,残留物加入乙酸乙酯(5mL)打浆纯化,抽滤,真空干燥得到黄色固体0.12g,收率75%。mp:>300℃.1H NMR(500MHz,DMSO-d6)δ(ppm):13.33(1H,s),10.81(1H,s),9.58(1H,s),9.29(1H,s),9.13(1H,s),7.62(1H,d,J=8.2Hz),7.45(1H,s),7.28(1H,s),6.91(1H,d,J=8.2Hz),6.52(1H,s),2.85(2H,t,J=6.7Hz),2.56(2H,t,J=7.0Hz),2.46(2H,t,J=6.6Hz),2.20(1H,s),2.18(3H,s),2.14(3H,s),1.46(2H,q,J=7.0Hz),1.30(9H,s),0.88(3H,t,J=7.4Hz).13C NMR(125MHz,DMSO-d6)δ(ppm):180.6,171.0,170.3,158.8,151.7,139.2,137.9,130.7,125.9,124.8,122.6,121.9,120.7,119.1,114.1,111.6,100.6,92.9,56.0,51.1,46.0,45.4,32.9,28.8(3C),22.7,12.2,9.6.HRMS(ESI):m/z[M+H]+calcd forC29H38N7O4 +,548.2985;found,548.2966。
实施例14
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-3-(叔丁氨基)丙酰胺(I-14)的合成:
化合物I-14的合成:将化合物XIII-7(0.17g,0.30mmol)溶于DMF(5mL),加入叔丁胺(0.16mL,1.50mmol),于50℃反应12h。TLC监测反应完毕后,将反应液倒入水中,乙酸乙酯溶液(30mL×2)萃取,合并有机层,依次用水和饱和的氯化钠溶液洗涤,无水硫酸钠干燥。抽滤,减压浓缩,残留物加入乙酸乙酯(5mL)打浆纯化,抽滤,真空干燥得到黄色固体0.12g,收率72%。mp:>300℃.1H NMR(500MHz,DMSO-d6)δ(ppm):13.35(1H,s),10.83(1H,s),9.70(1H,s),9.43(2H,s),7.62(1H,d,J=8.3Hz),7.45(1H,s),7.29(1H,s),6.93(1H,d,J=8.1Hz),6.52(1H,s),3.11(2H,t,J=6.8Hz),2.78(2H,t,J=7.0Hz),2.20(3H,s),2.16(3H,s),1.30(18H,s).13C NMR(125MHz,DMSO-d6)δ(ppm):180.5,170.3,158.8,151.8,139.6,139.3,138.0,130.5,125.8,124.8,122.5,121.5,120.6,119.1,114.4,111.5,100.5,92.9,37.7,32.9,29.5,28.8(6C),26.0,12.3,9.7.HRMS(ESI):m/z[M+H]+calcd for C30H40N7O4 +,562.3142;found,562.3124。
实施例15
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-3-(环戊氨基)丙酰胺(I-15)的合成:
化合物I-15的合成:将化合物XIII-7(0.17g,0.30mmol)溶于DMF(5mL),加入环戊胺(0.15mL,1.50mmol),于50℃反应12h。TLC监测反应完毕后,将反应液倒入水中,乙酸乙酯溶液(30mL×2)萃取,合并有机层,依次用水和饱和的氯化钠溶液洗涤,无水硫酸钠干燥。抽滤,减压浓缩,残留物加入乙酸乙酯(5mL)打浆纯化,抽滤,真空干燥得到黄色固体0.13g,收率78%。mp:>300℃.1H NMR(500MHz,DMSO-d6)δ(ppm):13.33(1H,s),10.81(1H,s),9.49(1H,s),9.28(1H,s),8.89(1H,s),7.62(1H,d,J=8.3Hz),7.45(1H,s),7.28(1H,s),6.90(1H,d,J=8.2Hz),6.51(1H,s),3.03-3.07(1H,m),2.79(2H,t,J=6.6Hz),2.41(2H,t,J=6.5Hz),2.19(1H,s),2.18(3H,s),2.14(3H,s),1.70-1.75(2H,m),1.57-1.64(2H,m),1.44-1.51(2H,m),1.31-1.36(2H,m),1.30(18H,s).13C NMR(125MHz,DMSO-d6)δ(ppm):180.6,171.3,170.3,158.9,151.7,139.2,137.7,130.7,126.0,124.8,122.6,122.0,120.8,119.1,114.1,111.7,100.7,92.9,59.4(2C),44.9,36.5,32.9(2C),28.8(3C),24.0(2C),12.2,9.6.HRMS(ESI):m/z[M+H]+calcd for C31H41N7O4 +,574.3142;found,574.3119。
实施例16
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-3-吗啉基丙酰胺(I-16)的合成:
化合物I-16的合成:将化合物XIII-7(0.17g,0.30mmol)溶于DMF(5mL),加入吗啉(0.13mL,1.50mmol),于50℃反应12h。TLC监测反应完毕后,将反应液倒入水中,乙酸乙酯溶液(30mL×2)萃取,合并有机层,依次用水和饱和的氯化钠溶液洗涤,无水硫酸钠干燥。抽滤,减压浓缩,残留物加入乙酸乙酯(5mL)打浆纯化,抽滤,真空干燥得到黄色固体0.13g,收率74%。mp:>300℃.1H NMR(500MHz,DMSO-d6)δ(ppm):13.33(1H,s),10.81(1H,s),9.46(1H,s),9.13(1H,s),8.86(1H,s),7.62(1H,d,J=8.2Hz),7.46(1H,s),7.28(1H,s),6.89(1H,d,J=8.2Hz),6.51(1H,s),3.55-3.63(4H,m),2.62(2H,t,J=7.0Hz),2.42-2.45(6H,m),2.19(3H,s),2.15(3H,s),2.14(3H,s),1.31(9H,m).13C NMR(125MHz,DMSO-d6)δ(ppm):180.6,170.8,170.3,158.8,151.6,139.2,137.5,130.8,126.1,124.9,122.5,122.0,120.8,119.1,114.1,111.7,100.7,92.9,66.7(2C),55.1,53.5(2C),33.5,32.9,28.8(3C),12.2,9.6.HRMS(ESI):m/z[M+H]+calcd for C30H38N7O5 +,576.2934;found,576.2914。
实施例17
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-3-(吡咯烷-1-基)丙酰胺(I-17)的合成:
中间体XIII-8的合成:化合物XII-1(0.50g,1.15mmol)溶于THF(20mL),加入DIPEA(0.57mL,3.45mmol),降温至0℃,滴加氯乙酰氯(0.46mL,5.75mmol),加毕,室温反应0.5h。TLC监测反应完毕后,减压浓缩,残留物加入乙酸乙酯(10mL)打浆。抽滤,滤饼用乙酸乙酯(1mL)洗涤,真空干燥得到黄色固体0.46g,收率78%。1H NMR(500MHz,DMSO-d6)δ(ppm):13.37(1H,s),10.84(1H,s),9.59(1H,s),9.52(1H,s),9.18(1H,s),7.63(1H,d,J=8.3Hz),7.47(1H,s),7.29(1H,d,J=1.7Hz),6.92(1H,dd,J1=8.3Hz,J2=1.8Hz),6.52(1H,s),4.26(2H,s),2.19(3H,s),2.15(3H,s),1.31(9H,s).13C NMR(125MHz,DMSO)δ(ppm):180.6,170.3,165.8,158.8,151.7,139.3,137.9,130.5,125.8,124.8,122.6,120.9,120.7,119.3,114.6,111.7,100.6,92.9,43.2,32.9,28.8(3C),12.1,9.5。
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化合物I-17的合成:将化合物XIII-8(0.15g,0.30mmol)溶于DMF(5mL),加入吡咯烷(0.12mL,1.50mmol),于50℃反应12h。TLC监测反应完毕后,将反应液倒入水中,乙酸乙酯溶液(30mL×2)萃取,合并有机层,依次用水和饱和的氯化钠溶液洗涤,无水硫酸钠干燥。抽滤,减压浓缩,残留物加入乙酸乙酯(5mL)打浆纯化,抽滤,真空干燥得到黄色固体0.13g,收率79%。mp:>300℃.1H NMR(500MHz,DMSO-d6)δ(ppm):13.36(1H,s),10.82(1H,s),9.55(1H,s),9.05(1H,s),8.99(1H,s),7.63(1H,d,J=8.3Hz),7.46(1H,s),7.29(1H,d,J=1.4Hz),6.90(1H,dd,J1=8.2Hz,J2=1.5Hz),6.52(1H,s),3.25(2H,s),2.59-2.68(4H,m),2.18(3H,s),2.14(3H,s),1.72-1.81(4H,m),1.31(9H,s).13C NMR(125MHz,DMSO-d6)δ(ppm):180.6,170.3,169.5,159.1,151.7,139.2,137.8,130.9,126.3,124.8,122.6,121.6,120.8,119.2,114.2,111.6,100.6,92.9,59.4,54.2(2C),32.9,28.8(3C),23.9(2C),12.2,9.6.HRMS(ESI):m/z[M+H]+calcd for C30H38N7O4 +,546.2829;found,546.2820。
实施例18
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-2-(哌啶-1-基)乙酰胺(I-18)的合成:
化合物I-18的合成:将化合物XIII-8(0.15g,0.30mmol)溶于DMF(5mL),加入哌啶(0.15mL,1.50mmol),于50℃反应12h。TLC监测反应完毕后,将反应液倒入水中,乙酸乙酯溶液(30mL×2)萃取,合并有机层,依次用水和饱和的氯化钠溶液洗涤,无水硫酸钠干燥。抽滤,减压浓缩,残留物加入乙酸乙酯(5mL)打浆纯化,抽滤,真空干燥得到黄色固体0.12g,收率73%。mp:>300℃.1H NMR(500MHz,DMSO-d6)δ(ppm):13.36(1H,s),10.82(1H,s),9.48(1H,s),8.95(1H,s),8.89(1H,s),7.63(1H,d,J=8.3Hz),7.47(1H,s),7.28(1H,d,J=1.5Hz),6.90(1H,dd,J1=8.1Hz,J2=1.6Hz),6.52(1H,s),3.06(2H,s),2.37-2.50(4H,m),2.19(3H,s),2.14(3H,s),1.54-1.64(4H,m),1.36-1.46(2H,m),1.31(9H,s).13C NMR(125MHz,DMSO-d6)δ(ppm):180.6,170.3,169.3,158.8,151.6,139.2,137.8,130.8,126.1,124.8,122.6,121.5,120.8,119.2,114.2,111.7,100.6,92.9,62.7,54.7(2C),32.9(2C),28.8(3C),25.9,24.0,12.2,9.6.HRMS(ESI):m/z[M+H]+calcd for C30H38N7O4 +,560.2985;found,560.2978。
实施例19
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-2-(4-甲基哌嗪-1-基)乙酰胺(I-19)的合成:
化合物I-19的合成:将化合物XIII-8(0.15g,0.30mmol)溶于DMF(5mL),加入N-甲基哌嗪(0.17mL,1.50mmol),于50℃反应12h。TLC监测反应完毕后,将反应液倒入水中,乙酸乙酯溶液(30mL×2)萃取,合并有机层,依次用水和饱和的氯化钠溶液洗涤,无水硫酸钠干燥。抽滤,减压浓缩,残留物加入乙酸乙酯(5mL)打浆纯化,抽滤,真空干燥得到黄色固体0.13g,收率77%。mp:>300℃.1H NMR(500MHz,DMSO-d6)δ(ppm):13.37(1H,s),10.83(1H,s),9.73(1H,s),9.52(1H,s),8.98(1H,s),7.63(1H,d,J=8.3Hz),7.46(1H,s),7.29(1H,d,J=1.0Hz),6.93(1H,dd,J1=8.3Hz,J2=0.7Hz),6.52(1H,s),3.11(2H,s),2.57-2.64(4H,m),2.36-2.50(4H,m),2.24(3H,s),2.18(3H,s),2.14(3H,s),1.30(9H,s).13C NMR(125MHz,DMSO-d6)δ(ppm):180.5,170.3,169.0,158.8,151.9,139.3,138.1,130.7,126.0,124.8,122.5,121.4,120.5,119.1,114.3,111.4,100.4,93.0,61.6,54.8(2C),52.9,45.9,32.9(2C),28.9(3C),12.2,9.6.HRMS(ESI):m/z[M+H]+calcd for C30H39N8O4 +,575.3094;found,575.3088。
实施例20
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-2-(二乙氨基)乙酰胺(I-20)的合成:
化合物I-20的合成:将化合物XIII-8(0.15g,0.30mmol)溶于DMF(5mL),加入二乙胺(0.16mL,1.50mmol),于50℃反应12h。TLC监测反应完毕后,将反应液倒入水中,乙酸乙酯溶液(30mL×2)萃取,合并有机层,依次用水和饱和的氯化钠溶液洗涤,无水硫酸钠干燥。抽滤,减压浓缩,残留物加入乙酸乙酯(5mL)打浆纯化,抽滤,真空干燥得到黄色固体0.12g,收率73%。mp:>300℃.1H NMR(500MHz,DMSO-d6)δ(ppm):13.37(1H,s),10.82(1H,s),9.49(1H,s),8.97(1H,s),8.93(1H,s),7.63(1H,d,J=8.3Hz),7.46(1H,s),7.28(1H,d,J=1.6Hz),6.90(1H,dd,J1=8.3Hz,J2=1.7Hz),6.51(1H,s),3.14(2H,s),2.62(4H,q,J=6.8Hz),2.18(3H,s),2.14(3H,s),1.30(9H,s),1.07(6H,t,J=7.1Hz).13C NMR(125MHz,DMSO-d6)δ(ppm):180.6,170.6,170.3,158.8,151.7,139.2,137.8,130.8,126.2,124.8,122.6,121.6,120.8,119.2,114.2,111.6,100.6,92.9,57.3,48.5(2C),32.9(2C),28.8(3C),12.5,12.2,9.5.HRMS(ESI):m/z[M+H]+calcd for C29H38N7O4 +,548.2985;found,548.2982。
实施例21
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-2-吗啉基乙酰胺(I-21)的合成:
化合物I-21的合成:将化合物XIII-8(0.15g,0.30mmol)溶于DMF(5mL),加入吗啉(0.13mL,1.50mmol),于50℃反应12h。TLC监测反应完毕后,将反应液倒入水中,乙酸乙酯溶液(30mL×2)萃取,合并有机层,依次用水和饱和的氯化钠溶液洗涤,无水硫酸钠干燥。抽滤,减压浓缩,残留物加入乙酸乙酯(5mL)打浆纯化,抽滤,真空干燥得到黄色固体0.12g,收率72%。mp:>300℃.1H NMR(500MHz,DMSO-d6)δ(ppm):13.37(1H,s),10.82(1H,s),9.47(1H,s),9.04(1H,s),8.87(1H,s),7.64(1H,d,J=8.3Hz),7.46(1H,s),7.28(1H,d,J=1.6Hz),6.90(1H,dd,J1=8.3Hz,J2=1.6Hz),6.51(1H,s),3.62-3.72(4H,m),3.13(2H,s),2.50-2.62(4H,m),2.18(3H,s),2.14(3H,s),1.31(9H,s).13C NMR(125MHz,DMSO-d6)δ(ppm):180.7,170.3,168.8,158.8,151.6,139.2,137.8,130.9,126.2,124.8,122.6,121.5,120.8,119.2,114.2,111.7,100.7,92.9,66.5(2C),62.0,53.8(2C),32.9,28.8(3C),12.2,9.6.HRMS(ESI):m/z[M+H]+calcd for C29H36N7O5 +,562.2778;found,562.2771。
实施例22
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-2-(环戊氨基)乙酰胺(I-22)的合成:
化合物I-22的合成:将化合物XIII-8(0.15g,0.30mmol)溶于DMF(5mL),加入环戊胺(0.15mL,1.50mmol),于50℃反应12h。TLC监测反应完毕后,将反应液倒入水中,乙酸乙酯溶液(30mL×2)萃取,合并有机层,依次用水和饱和的氯化钠溶液洗涤,无水硫酸钠干燥。抽滤,减压浓缩,残留物加入乙酸乙酯(5mL)打浆纯化,抽滤,真空干燥得到黄色固体0.12g,收率74%。mp:>300℃.1H NMR(500MHz,DMSO-d6)δ(ppm):13.36(1H,s),10.82(1H,s),9.51(1H,s),9.13(1H,s),8.94(1H,s),7.63(1H,d,J=8.3Hz),7.46(1H,s),7.28(1H,d,J=1.6Hz),6.90(1H,dd,J1=8.0Hz,J2=0.9Hz),6.51(1H,s),3.10-3.13(1H,m),2.19(3H,s),2.14(3H,s),1.74-1.77(2H,m),1.63-1.69(2H,m),1.47-1.52(2H,m),1.38-1.42(2H,m),1.31(9H,s),1.24-1.26(2H,m).13C NMR(125MHz,DMSO-d6)δ(ppm):180.6,170.3,158.8,151.7,139.3,137.8,130.7,126.0,124.8,122.6,122.6,121.4,120.8,119.2,114.3,111.7,100.6,92.9,59.6,51.1,32.9,32.5(2C),28.8(3C),24.0(2C),12.2,9.6.HRMS(ESI):m/z[M+H]+calcd for C30H38N7O4 +,560.2985;found,560.2983。
实施例23
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-5-氟-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-2-(4-甲基哌嗪-1-基)乙酰胺(I-23)的合成:
中间体V-2的合成:将化合物III-1(0.31g,1.44mmol),IV-2(0.20g,1.20mmol),DMAP(0.0090g,0.07mmol)溶解于DCM(10mL),于搅拌下加入TEA(0.025mL,0.18mmol),加热至50℃反应20h。LC-MS监测反应完毕后,停止加热,冷却至室温,减压浓缩,乙酸乙酯打浆纯化,抽滤,滤饼用少量乙酸乙酯洗涤,真空干燥,得到灰色固体0.27g,收率75%。1H NMR(500MHz,DMSO-d6)δ(ppm):10.37(1H,s),9.45(1H,s),8.84(1H,s),7.23(1H,s),7.09(1H,d,J=7.9Hz),6.80(1H,d,J=8.0Hz),6.49(1H,s),3.40(2H,s),1.30(9H,s).13C NMR(125MHz,DMSO-d6)δ(ppm):180.6,177.3,158.8,151.7,144.6,138.8,125.0,119.9,111.4,100.6,92.9,35.8,32.9,28.8(3C)。
中间体XI-2的合成:将化合物V-2(0.80g,2.55mmol)和VI-1(0.43g,2.55mmol)溶解于乙醇(10mL),然后加入吡咯烷(0.27mL,3.31mmol),加热至50℃反应2h。LC-MS监测反应完毕后,停止加热,冷却至室温,抽滤,滤饼用少量乙醇洗涤,真空干燥,得到橙黄色固体1.00g,收率85%。1H NMR(500MHz,DMSO-d6)δ(ppm):14.22(1H,s),11.12(1H,s),9.57(1H,s),9.10(1H,s),7.78(1H,d,J=8.3Hz),7.59(1H,s),7.32(1H,s),6.94(1H,d,J=8.3Hz),6.51(1H,s),2.63(3H,s),2.55(3H,s),1.31(9H,s).13C NMR(125MHz,DMSO-d6)δ(ppm):180.7,170.5,158.8,151.6,144.6,140.4,139.5,136.5,133.9,125.4,123.9,121.4,120.8,119.5,112.0,100.8,92.9,33.0,28.8(3C),15.3,11.5。
中间体XII-2的合成:将化合物XI-2(0.20g,0.43mmol)溶于四氢呋喃和甲醇(10mL/5mL,v/v)的混合溶剂,加入氯化铵(0.23g,4.31mmol)的饱和溶液(1mL),加热至50℃,分批加入锌粉(0.14g,2.15mmol),继续反应0.5h。LC-MS监测反应完毕后,停止加热,冷却至室温,减压浓缩,残留物用乙酸乙酯(100mL)和饱和碳酸钠溶液(100mL)溶解,分出有机层,依次用水和饱和氯化钠溶液洗涤,无水硫酸钠干燥。抽滤,减压浓缩,甲醇打浆纯化,抽滤,滤饼用少量甲醇洗涤,真空干燥,得到黄色固体0.10g,收率54%。1H NMR(500MHz,DMSO-d6)δ(ppm):13.22(1H,s),10.66(1H,s),9.45(1H,s),8.81(1H,s),7.55(1H,d,J=8.3Hz),7.31(1H,s),7.25(1H,d,J=1.6Hz),6.85(1H,dd,J1=8.3Hz,J2=1.8Hz),6.51(1H,s),3.92(2H,s),2.24(3H,s),2.13(3H,s),1.30(9H,s).13C NMR(125MHz,DMSO-d6)δ(ppm):180.6,169.9,158.9,151.6,138.4,136.6,132.9,125.0,123.8,122.0,121.6,118.1,116.6,111.5,110.8,100.6,92.9,32.9,28.8(3C),11.6,8.9。
中间体XIII-9的合成:化合物XII-2(0.50g,1.15mmol)溶于THF(20mL),加入DIPEA(0.50mL,3.45mmol),降温至0℃,滴加3-氯丙酰氯(0.10mL,5.75mmol),加毕,室温反应0.5h。TLC监测反应完毕后,减压浓缩,残留物加入乙酸乙酯(10mL)打浆。抽滤,滤饼用乙酸乙酯(1mL)洗涤,真空干燥得到黄色固体0.48g,收率80%。
化合物I-23的合成:将化合物XIII-9(0.070g,0.14mmol)溶于DMF(5mL),加入N-甲基哌嗪(0.15mL,1.37mmol),于50℃反应12h。TLC监测反应完毕后,将反应液倒入水中,乙酸乙酯溶液(30mL×2)萃取,合并有机层,依次用水和饱和的氯化钠溶液洗涤,无水硫酸钠干燥。抽滤,减压浓缩,残留物加入乙酸乙酯(5mL)打浆纯化,抽滤,真空干燥得到黄色固体0.050g,收率59%。1H NMR(500MHz,DMSO-d6)δ(ppm):13.37(1H,s),10.83(1H,s),9.73(1H,s),9.52(1H,s),8.98(1H,s),7.63(1H,d,J=8.3Hz),6.93(1H,dd,J1=8.3Hz,J2=0.7Hz),6.52(1H,s),3.11(2H,s),2.57-2.64(4H,m),2.36-2.50(4H,m),2.24(3H,s),2.18(3H,s),2.14(3H,s),1.30(9H,s).13C NMR(125MHz,DMSO-d6)δ(ppm):180.8,170.2,169.0,158.7,151.5,149.6,147.7,134.8,131.8,127.2,124.9,124.1,121.8,120.7,113.6,105.9,102.0,92.8,61.8,55.0(2C),53.2(2C),46.2,33.0,28.8(3C),12.3,9.6。
实施例24
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-5-氟-2-氧化吲哚-3-亚基)甲基)-N-(2-(二乙氨基)乙基)-2,4-二甲基-1H-吡咯-3-甲酰胺(I-24)的合成:
化合物I-24的合成:将化合物V-1(0.35g,1.05mmol)和VI-2(0.42g,1.58mmol)溶解于乙醇(10mL),然后加入吡咯烷(0.13mL,1.58mmol),加热至50℃反应2h。LC-MS监测反应完毕后,停止加热,冷却至室温,抽滤,滤饼用少量乙醇洗涤,真空干燥,得到橙黄色固体0.30g,收率49%。1H NMR(500MHz,DMSO-d6)δ(ppm):δ13.55(1H,s),10.91(1H,s),9.90(1H,s),8.87(1H,s),7.84(1H,d,J=11.5Hz),7.78(1H,d,J=6.7Hz),7.61(1H,s),7.43(1H,t,J=4.3Hz),6.48(1H,s),3.28(2H,dd,J1=13.0Hz,J2=6.3Hz),2.52-2.56(6H,m),2.44(3H,s),2.41(3H,s),1.31(9H,s),1.00(6H,t,J=7.0Hz).13C NMR(125MHz,DMSO-d6)δ(ppm):180.8,170.3,165.0,158.7,151.4,136.3,135.1,129.7,126.3,125.5,125.4,123.8,120.9,120.3(2C),115.4,102.0,92.8,52.1,47.0(2C),37.4,33.0,28.8(3C),13.8,12.4(2C),11.1。
实施例25
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-5-氟-2-氧化吲哚-3-亚基)甲基)-N-(2-(二乙氨基)乙基)-2,4-二甲基-1H-吡咯-3-甲酰胺(I-25)的合成:
化合物I-25的合成:将化合物V-2(0.35g,1.05mmol)和VI-2(0.42g,1.58mmol)溶解于乙醇(10mL),然后加入吡咯烷(0.13mL,1.58mmol),加热至50℃反应2h。LC-MS监测反应完毕后,停止加热,冷却至室温,抽滤,滤饼用少量乙醇洗涤,真空干燥,得到橙黄色固体0.30g,收率49%。1H NMR(500MHz,DMSO-d6)δ(ppm):3.55(1H,s),10.91(1H,s),9.90(1H,s),8.87(1H,s),7.84(1H,d,J=11.5Hz),7.78(1H,d,J=6.7Hz),7.61(1H,s),7.43(1H,t,J=4.3Hz),6.48(1H,s),3.28(2H,dd,J1=13.0Hz,J2=6.3Hz),2.52-2.56(6H,m),2.44(3H,s),2.41(3H,s),1.31(9H,s),1.00(6H,t,J=7.0Hz).13C NMR(125MHz,DMSO-d6)δ(ppm):180.8,170.3,165.0,158.7,151.4,136.3,135.1,129.7,126.3,125.5,125.4,123.8,120.9,120.3(2C),115.4,102.0,92.8,52.1,47.0(2C),37.4,33.0,28.8(3C),13.8,12.4(2C),11.1。
实施例26
(Z)-N-(2-(二乙氨基)乙基)-2,4-二甲基-5-((6-(3-(5-甲基异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-1H-吡咯-3-甲酰胺(I-26)的合成:
中间体III-2的合成:将化合物II-2(0.70g,7.13mmol)溶解于无水四氢呋喃(20mL),然后加入K2CO3(1.22g,8.83mmol),氯甲酸苯酯(0.94mL,7.49mmol),室温反应4h。LC-MS监测反应完毕后,抽滤,滤饼用少量四氢呋喃洗涤,真空干燥,得到白色固体1.17g,收率75%。
中间体V-3的合成:将化合物III-2(0.31g,1.44mmol),IV-1(0.20g,1.20mmol),DMAP(0.0090g,0.07mmol)溶解于DCM(10mL),于搅拌下加入TEA(0.025mL,0.18mmol),加热至50℃反应20h。LC-MS监测反应完毕后,停止加热,冷却至室温,减压浓缩,乙酸乙酯打浆纯化,抽滤,滤饼用少量乙酸乙酯洗涤,真空干燥,得到灰色固体0.27g,收率69%。1H NMR(500MHz,DMSO-d6)δ(ppm):10.35(1H,s),9.39(1H,s),8.83(1H,s),7.23(1H,d,J=1.9Hz),7.10(1H,d,J=8.0Hz),6.80(1H,dd,J1=8.0Hz,J2=2.0Hz),6.53(1H,s),3.40(2H,s),2.37(3H,s).13C NMR(125MHz,DMSO-d6)δ(ppm):177.2,169.6,159.1,151.7,144.6,138.9,125.0,119.9,111.4,100.7,96.0,35.8,12.6。
化合物I-26的合成:将化合物V-3(0.29g,1.05mmol)和VI-2(0.42g,1.58mmol)溶解于乙醇(10mL),然后加入吡咯烷(0.13mL,1.58mmol),加热至50℃反应2h。LC-MS监测反应完毕后,停止加热,冷却至室温,抽滤,滤饼用少量乙醇洗涤,真空干燥,得到橙黄色固体0.38g,收率70%。1H NMR(500MHz,DMSO-d6)δ(ppm):13.49(1H,s),10.87(1H,s),9.43(1H,s),8.90(1H,s),7.68(1H,d,J=8.3Hz),7.51(1H,s),7.37(1H,t,J=5.5Hz),7.31(1H,d,J=1.7Hz),6.89(1H,dd,J1=8.3Hz,J2=1.8Hz),6.55(1H,s),3.28(2H,dd,J1=13.0Hz,J2=6.3Hz),2.52-2.56(6H,m),2.44(3H,s),2.40(3H,s),2.37(3H,s),0.99(6H,t,J=7.1Hz).13C NMR(125MHz,DMSO-d6)δ(ppm):170.4,169.7,165.1,159.1,151.6,139.6,138.2,135.5,128.6,126.2,122.3,120.6,120.5,119.6,115.9,111.8,100.7,96.0,52.15,47.0(2C),37.5,13.76,12.59,12.4(2C),11.0。
实施例27
(Z)-N-(2-(二乙氨基)乙基)-2,4-二甲基-5-((2-氧化-6-(3-(3-(三氟甲基)异恶唑-5-基)脲基)吲哚-3-亚基)甲基)-1H-吡咯-3-甲酰胺(I-27)的合成:
中间体III-3的合成:将化合物II-3(1.00g,7.13mmol)溶解于无水四氢呋喃(15mL),然后加入K2CO3(1.22g,8.83mmol),氯甲酸苯酯(0.94mL,7.49mmol),室温反应4h。LC-MS监测反应完毕后,抽滤,滤饼用少量四氢呋喃洗涤,真空干燥,得到白色固体1.40g,收率75%。
中间体V-4的合成:将化合物III-3(0.17g,0.61mmol),IV-1(0.080g,0.51mmol),DMAP(0.0040g,0.030mmol)溶解于DCM(10mL),于搅拌下加入TEA(0.21mL,1.53mmol),加热至50℃反应20h。LC-MS监测反应完毕后,停止加热,冷却至室温,减压浓缩,柱层析纯化(二氯甲烷:甲醇)得灰色固体0.12g,收率70%。1H NMR(500MHz,MeOD)δ(ppm):7.31(1H,d,J=1.9Hz),7.19(1H,d,J=8.1Hz),6.96(1H,dd,J1=8.0Hz,J2=2.0Hz),6.45(1H,s),3.50(2H,s).13C NMR(125MHz,DMSO-d6)δ(ppm):177.2,174.9,165.6,149.7,147.6,144.7,138.2,125.0,120.6,111.9,101.0,83.5,35.8。
化合物I-27的合成:将化合物V-4(0.10g,0.30mmol)和VI-2(0.12g,0.45mmol)溶解于乙醇(10mL),然后加入吡咯烷(0.030mL,0.30mmol),加热至50℃反应2h。LC-MS监测反应完毕后,停止加热,冷却至室温,抽滤,滤饼用少量乙醇洗涤,真空干燥,得到橙黄色固体0.37g,收率65%。1H NMR(500MHz,DMSO-d6)δ(ppm):13.51(1H,s),10.90(1H,s),10.44(1H,s),9.04(1H,s),7.67(1H,d,J=8.3Hz),7.51(1H,s),7.44(1H,t,J=5.3Hz),7.34(1H,d,J=1.4Hz),6.99(1H,dd,J1=8.3Hz,J2=1.5Hz),6.43(1H,s),3.33(2H,d,J=6.05Hz),2.63(6H,t,J=7.5Hz),2.44(3H,s),2.40(3H,s),1.02(6H,t,J=7.1Hz).13C NMR(125MHz,DMSO-d6)δ(ppm):170.4,167.8,165.3,155.7,155.4,151.3,139.5,138.4,135.6,128.5,126.2,122.1,121.5,120.4,119.5,116.0,112.0,100.8,82.8,51.9,47.0(2C),37.2,13.8,11.9(2C),11.0。
实施例28
(Z)-5-((6-(3-(3-(叔丁基)-1-甲基-1H-吡唑-5-基)脲基)-2-氧化吲哚-3-亚基)甲基)-N-(2-(二乙氨基)乙基-2,4-二甲基-1H-吡咯-3-甲酰胺(I-28)的合成:
中间体III-4的合成:将化合物II-4(0.20g,1.31mmol)溶解于无水四氢呋喃(10mL),然后加入K2CO3(0.22g,1.62mmol),氯甲酸苯酯(0.17mL,1.37mmol),室温反应4h。LC-MS监测反应完毕后,抽滤,滤饼用少量四氢呋喃洗涤,真空干燥,得到黄色油状液体0.23g,收率64%。
中间体V-5的合成:将化合物III-4(0.23g,0.84mmol),IV-1(0.11g,0.70mmol),DMAP(0.0050g,0.040mmol)溶解于DCM(10mL),于搅拌下加入TEA(0.030mL,0.20mmol),加热至50℃反应20h。LC-MS监测反应完毕后,停止加热,冷却至室温,减压浓缩,柱层析纯化(二氯甲烷:甲醇)得灰色固体0.19g,收率58%。1H NMR(500MHz,CDCl3)δ(ppm):6.88(1H,s),6.71(1H,d,J=8.1Hz),6.52(1H,s),6.12(1H,s),3.77(3H,s),3.49(2H,s),1.33(9H,s)。
化合物I-28的合成:将化合物V-5(0.19g,0.58mmol)和VI-2(0.23g,0.87mmol)溶解于乙醇(10mL),然后加入吡咯烷(0.050mL,0.58mmol),加热至50℃反应2h。LC-MS监测反应完毕后,停止加热,冷却至室温,抽滤,滤饼用少量乙醇洗涤,真空干燥,得到橙黄色固体0.37g,收率65%。1H NMR(500MHz,DMSO-d6)δ(ppm):13.48(1H,s),10.88(1H,s),9.88(1H,s),9.42(1H,s),7.65(1H,d,J=8.3Hz),7.48(1H,s),7.39(1H,t,J=5.5Hz),7.31(1H,d,J=1.7Hz),6.95(1H,dd,J1=8.3Hz,J2=1.7Hz),6.07(1H,s),3.65(1H,s),3.28(2H,q,J=6.4Hz),2.52-2.56(6H,m),2.44(3H,s),2.39(3H,s),1.22(9H,s),0.98(6H,t,J=7.1Hz).13C NMR(125MHz,DMSO-d6)δ(ppm):170.4,165.2,159.1,152.1,139.6,139.3,138.0,135.3,128.2,126.2,121.8,120.5,119.7,119.6,116.2,111.1,100.0,92.7,52.1,47.0(2C),37.4,35.7,32.3,30.9(3C),13.8,12.4(2C),11.1。
实施例29
(Z)-5-((6-(3-(4-氯-3-(三氟甲基)苯基)脲基)-2-氧化吲哚-3-亚基)甲基)-N-(2-(二乙氨基)乙基)-2,4-二甲基-1H-吡咯-3-甲酰胺(I-29)的合成:
中间体III-5的合成:将化合物II-5(0.40g,2.05mmol)溶解于无水四氢呋喃(15mL),然后加入K2CO3(0.35g,2.54mmol),氯甲酸苯酯(0.27mL,2.15mmol),室温反应4h。LC-MS监测反应完毕后,抽滤,滤饼用少量四氢呋喃洗涤,真空干燥,得到白色固体0.50g,收率77%。
中间体V-6的合成:将化合物III-5(0.50g,1.58mmol),IV-1(0.21g,1.32mmol),DMAP(0.010g,0.08mmol)溶解于DCM(15mL),于搅拌下加入TEA(0.055mL,0.33mmol),加热至50℃反应20h。LC-MS监测反应完毕后,停止加热,冷却至室温,减压浓缩,乙酸乙酯打浆纯化,抽滤,滤饼用少量乙酸乙酯洗涤,真空干燥,得白色固体0.30g,收率60%。
化合物I-29的合成:将化合物V-6(0.21g,0.58mmol)和VI-2(0.23g,0.87mmol)溶解于乙醇(10mL),然后加入吡咯烷(0.050mL,0.58mmol),加热至50℃反应2h。LC-MS监测反应完毕后,停止加热,冷却至室温,抽滤,滤饼用少量乙醇洗涤,真空干燥,得到橙黄色固体0.21g,收率60%。1H NMR(500MHz,DMSO-d6)δ(ppm):13.49(1H,s),10.87(1H,s),9.16(1H,s),8.97(1H,s),8.14(1H,s),7.67(1H,d,J=8.3Hz),7.63(1H,s),7.62(1H,s),7.50(1H,s),7.39(1H,t,J=4.8Hz),7.32(1H,s),6.94(1H,d,J=8.2Hz),3.28(2H,q,J=6.4Hz),2.52-2.56(6H,m),2.44(3H,s),2.40(3H,s),0.98(6H,t,J=7.0Hz).13C NMR(125MHz,DMSO-d6)δ(ppm):170.4,165.2,152.7,139.9,139.5,138.6,135.5,132.4,128.4,127.3,127.0,126.2,123.5,122.7,122.01,120.5,120.2,119.5,117.2,116.0,111.9,100.8,52.1,47.0(2C),31.4,14.4,13.8(2C),11.1。
实施例30
(Z)-N-(2-(二乙氨基)乙基)-2,4-二甲基-5-((2-氧化-6-(3-(三氟甲基)吡啶-3-基)脲基)吲哚-3-亚基)甲基)-1H-吡咯-3-甲酰胺(I-30)的合成:
中间体III-6的合成:将化合物II-6(0.30g,1.85mmol)溶解于无水四氢呋喃(15mL),然后加入K2CO3(0.32g,2.30mmol),氯甲酸苯酯(0.30mL,1.94mmol),室温反应4h。LC-MS监测反应完毕后,抽滤,滤饼用少量四氢呋喃洗涤,真空干燥,得到白色固体0.40g,收率76%。
中间体V-7的合成:将化合物III-6(0.40g,1.42mmol),IV-1(0.19g,1.18mmol),DMAP(0.0090g,0.070mmol)溶解于DCM(15mL),于搅拌下加入TEA(0.049mL,0.33mmol),加热至50℃反应20h。LC-MS监测反应完毕后,停止加热,冷却至室温,减压浓缩,乙酸乙酯打浆纯化,抽滤,滤饼用少量乙酸乙酯洗涤,真空干燥,得白色固体0.24g,收率60%。1H NMR(500MHz,DMSO-d6)δ(ppm):10.36(1H,s),9.32(1H,s),9.04(1H,s),8.19(1H,dd,J1=8.6Hz,J2=2.1Hz),7.82(1H,d,J=8.7Hz),7.26(1H,d,J=1.5Hz),7.11(1H,d,J=8.0Hz),6.86(1H,dd,J1=8.0Hz,J2=1.8Hz),6.80(1H,d,J=8.4Hz),3.41(2H,s)。
化合物I-30的合成:将化合物V-7(0.050g,0.15mmol)和VI-2(0.060g,0.22mmol)溶解于乙醇(5mL),然后加入吡咯烷(0.012mL,0.15mmol),加热至50℃反应2h。LC-MS监测反应完毕后,停止加热,冷却至室温,抽滤,滤饼用少量乙醇洗涤,真空干燥,得到橙黄色固体0.53g,收率60%。1H NMR(500MHz,DMSO-d6)δ(ppm):13.49(1H,s),10.88(1H,s),9.29(1H,s),9.08(1H,s),8.77(1H,d,J=2.1Hz),8.21(1H,dd,J1=8.5Hz,J2=1.9Hz),7.83(1H,d,J=8.7Hz),7.69(1H,d,J=8.3Hz),7.51(1H,s),7.38(1H,t,J=5.1Hz),7.33(1H,d,J=1.4Hz),6.96(1H,dd,J1=8.3Hz,J2=1.5Hz),3.28(2H,q,J=6.4Hz),2.52-2.56(6H,m),2.44(3H,s),2.40(3H,s),0.98(6H,t,J=7.1Hz).13C NMR(125MHz,DMSO-d6)δ(ppm):170.4,165.2,152.6,140.3,140.0,139.5,139.3,138.4,135.5,128.5,126.2,125.7,123.5,122.2,121.7,120.6,120.4,119.6,115.9,111.9,100.8,52.1,47.0(2C),37.4,13.8,12.4(2C),11.1。
实施例31
(Z)-5-((6-(3-(4-(叔丁基)-3-氯苯基)脲基)-2-氧化吲哚-3-亚基)甲基)-N-(2-(二乙氨基)乙基)-2,4-二甲基-1H-吡咯-3-甲酰胺(I-31)的合成:
中间体III-7的合成:将化合物II-7(0.20g,1.09mmol)溶解于无水四氢呋喃(15mL),然后加入K2CO3(0.19g,2.03mmol),氯甲酸苯酯(0.14mL,1.14mmol),室温反应4h。LC-MS监测反应完毕后,抽滤,滤饼用少量四氢呋喃洗涤,真空干燥,得到白色固体0.24g,收率72%。
中间体V-8的合成:将化合物III-7(0.24g,0.782mmol),IV-1(0.11g,0.65mmol),DMAP(0.0050g,0.040mmol)溶解于DCM(10mL),于搅拌下加入TEA(0.042mL,0.20mmol),加热至50℃反应20h。LC-MS监测反应完毕后,停止加热,冷却至室温,减压浓缩,乙酸乙酯打浆纯化,抽滤,滤饼用少量乙酸乙酯洗涤,真空干燥,得灰色固体0.13g,收率54%。1H NMR(500MHz,DMSO-d6)δ(ppm):10.34(1H,s),8.72(2H,d,J=10.5Hz),7.64(1H,d,J=2.1Hz),7.35(1H,d,J=8.7Hz),7.24(1H,s),7.22(1H,dd,J1=8.8Hz,J2=2.2Hz),7.08(1H,d,J=8.0Hz),6.82-6.81(1H,m),3.39(2H,s),1.42(9H,s)。
化合物I-31的合成:将化合物V-8(0.13g,0.35mmol)和VI-2(0.14g,0.52mmol)溶解于乙醇(10mL),然后加入吡咯烷(0.029mL,0.35mmol),加热至50℃反应2h。LC-MS监测反应完毕后,停止加热,冷却至室温,抽滤,滤饼用少量乙醇洗涤,真空干燥,得到橙黄色固体0.13g,收率60%。1H NMR(500MHz,DMSO-d6)δ(ppm):13.48(1H,s),10.86(1H,s),8.80(1H,s),8.76(1H,s),7.67(1H,s),7.65(1H,s),7.49(1H,s),7.37(1H,s),7.35(1H,s),7.31(1H,d,J=1.5Hz),7.24(1H,dd,J1=8.7Hz,J2=2.2Hz),6.91(1H,dd,J1=8.3Hz,J2=1.5Hz),3.29(2H,q,J=6.4Hz),2.52-2.56(6H,m),2.44(3H,s),2.40(3H,s),1.43(9H,s),0.97(6H,t,J=7.1Hz).13C NMR(125MHz,DMSO-d6)δ(ppm):170.4,165.5,152.8,139.5,139.4,139.1,138.8,135.5,132.9,128.5(2C),126.2,122.0,121.3,120.4,120.0,119.5,117.2,116.0,111.9,100.7,52.0,46.9(2C),37.3,35.6,30.0(3C),13.7,12.2(2C),11.0。
实施例32
(Z)-5-((6-(3-(4-(叔丁基)苯基)脲基)-2-氧化吲哚-3-亚基)甲基)-N-(2-(二乙氨基)乙基)-2,4-二甲基-1H-吡咯-3-甲酰胺(I-32)的合成:
中间体III-8的合成:将化合物II-8(0.20g,1.34mmol)溶解于无水四氢呋喃(15mL),然后加入K2CO3(0.23g,1.66mmol),氯甲酸苯酯(0.18mL,1.41mmol),室温反应4h。LC-MS监测反应完毕后,抽滤,滤饼用少量四氢呋喃洗涤,真空干燥,得到白色固体0.38g,收率75%。
中间体V-9的合成:将化合物III-8(0.20g,0.74mmol),IV-1(0.10g,0.62mmol),DMAP(0.0050g,0.040mmol)溶解于DCM(10mL),于搅拌下加入TEA(0.026mL,0.62mmol),加热至50℃反应20h。LC-MS监测反应完毕后,停止加热,冷却至室温,减压浓缩,乙酸乙酯打浆纯化,抽滤,滤饼用少量乙酸乙酯洗涤,真空干燥,得灰色固体0.11g,收率54%。
化合物I-32的合成:将化合物V-9(0.11g,0.33mmol)和VI-2(0.132g,0.50mmol)溶解于乙醇(10mL),然后加入吡咯烷(0.027mL,0.33mmol),加热至50℃反应2h。LC-MS监测反应完毕后,停止加热,冷却至室温,抽滤,滤饼用少量乙醇洗涤,真空干燥,得到橙黄色固体0.11g,收率61%。1H NMR(500MHz,DMSO-d6)δ(ppm):13.48(1H,s),10.85(1H,s),8.72(1H,s),8.55(1H,s),7.65(1H,d,J=8.2Hz),7.48(1H,s),7.38(1H,s),7.37(2H,s),7.34(1H,s),7.31(1H,s),7.29(1H,s),6.89(1H,d,J=8.2Hz),3.29(2H,q,J=6.2Hz),2.52-2.56(6H,m),2.44(3H,s),2.40(3H,s),1.27(9H,s),0.98(6H,t,J=7.0Hz).13C NMR(125MHz,DMSO-d6)δ(ppm):170.4,165.2,152.9,144.6,139.6,139.3,137.5,135.3,128.2,126.2,125.8(2C),121.8,120.5,119.7,119.6,118.5(2C),116.2,111.4,100.4,52.2,47.0(2C),37.4,34.4,31.7(3C),13.8,12.4(2C),11.1。
实施例33
(Z)-5-((6-(3-(3-氯-4-(三氟甲基)苯基)脲基)-2-氧化吲哚-3-亚基)甲基)-N-(2-(二乙氨基)乙基)-2,4-二甲基-1H-吡咯-3-甲酰胺(I-33)的合成:
中间体III-9的合成:将化合物II-9(0.40g,2.05mmol)溶解于无水四氢呋喃(15mL),然后加入K2CO3(0.35g,2.54mmol),氯甲酸苯酯(0.270mL,2.15mmol),室温反应4h。LC-MS监测反应完毕后,抽滤,滤饼用少量四氢呋喃洗涤,真空干燥,得到白色固体0.49g,收率75%。
中间体V-10的合成:将化合物III-9(0.22g,0.69mmol),IV-1(0.090g,0.58mmol),DMAP(0.0040g,0.030mmol)溶解于DCM(10mL),于搅拌下加入TEA(0.024mL,0.17mmol),加热至50℃反应20h。LC-MS监测反应完毕后,停止加热,冷却至室温,减压浓缩,乙酸乙酯打浆纯化,抽滤,滤饼用少量乙酸乙酯洗涤,真空干燥,得白色固体0.11g,收率59%。1H NMR(500MHz,DMSO-d6)δ(ppm):10.36(1H,s),9.25(1H,s),8.94(1H,s),7.92(1H,d,J=1.8Hz),7.74(1H,d,J=8.7Hz),7.47(1H,dd,J1=8.6Hz,J2=1.4Hz),7.23(1H,d,J=1.8Hz),7.10(1H,d,J=8.0Hz),6.85(1H,dd,J1=8.0Hz,J2=1.9Hz),3.41(2H,s)。
化合物I-33的合成:将化合物V-10(0.11g,0.30mmol)和VI-2(0.12g,0.44mmol)溶解于乙醇(6mL),然后加入吡咯烷(0.020mL,0.23mmol),加热至50℃反应2h。LC-MS监测反应完毕后,停止加热,冷却至室温,抽滤,滤饼用少量乙醇洗涤,真空干燥,得到橙黄色固体0.21g,收率60%。1H NMR(500MHz,DMSO-d6)δ(ppm):13.49(1H,s),10.88(1H,s),9.26(1H,s),9.01(1H,s),7.93(1H,d,J=1.6Hz),7.75(1H,d,J=8.8Hz),7.68(1H,d,J=8.3Hz),7.51(1H,s),7.49(1H,dd,J1=8.6Hz,J2=1.4Hz),7.38(1H,t,J=5.4Hz),7.30(1H,d,J=1.7Hz),6.96(1H,dd,J1=8.3Hz,J2=1.7Hz),3.29(2H,q,J=6.4Hz),2.52-2.56(6H,m),2.44(3H,s),2.40(3H,s),0.98(6H,t,J=7.1Hz).13C NMR(125MHz,DMSO-d6)δ(ppm):170.4,165.4,152.4,145.0,139.4,138.3,135.7,131.7,128.9,128.6,126.2,124.7,122.5,122.2,120.4,120.4,119.9,119.5,116.6,115.9,112.1,101.0,52.0,46.9(2C),37.3,13.7,12.1(2C),11.0。
实施例34
(Z)-5-((6-(3-(2-氯-4-(三氟甲基)苯基)脲基)-2-氧化吲哚-3-亚基)甲基)-N-(2-(二乙氨基)乙基)-2,4-二甲基-1H-吡咯-3-甲酰胺(I-34)的合成:
中间体III-10的合成:将化合物II-10(0.40g,2.05mmol)溶解于无水四氢呋喃(15mL),然后加入K2CO3(0.35g,2.54mmol),氯甲酸苯酯(0.27mL,2.15mmol),室温反应4h。LC-MS监测反应完毕后,抽滤,滤饼用少量四氢呋喃洗涤,真空干燥,得到白色固体0.50g,收率77%。
中间体V-11的合成:将化合物III-10(0.50g,1.58mmol),IV-1(0.21g,1.32mmol),DMAP(0.010g,0.080mmol)溶解于DCM(15mL),于搅拌下加入TEA(0.055mL,0.33mmol),加热至50℃反应20h。LC-MS监测反应完毕后,停止加热,冷却至室温,减压浓缩,乙酸乙酯打浆纯化,抽滤,滤饼用少量乙酸乙酯洗涤,真空干燥,得白色固体0.30g,收率60%。1H NMR(500MHz,DMSO)δ(ppm):10.39(1H,s),9.63(1H,s),9.55(1H,s),7.92(1H,d,J=1.8Hz),7.88(1H,d,J=1.7Hz),7.68(1H,dd,J1=8.9Hz,J2=1.7Hz),7.27(1H,d,J=1.7Hz),7.12(1H,d,J=8.0Hz),6.84(1H,dd,J1=8.0Hz,J2=1.9Hz),3.42(2H,s)。
化合物I-34的合成:将化合物V-11(0.070g,0.19mmol)和VI-2(0.080g,0.288mmol)溶解于乙醇(6mL),然后加入吡咯烷(0.020mL,0.23mmol),加热至50℃反应2h。LC-MS监测反应完毕后,停止加热,冷却至室温,抽滤,滤饼用少量乙醇洗涤,真空干燥,得到橙黄色固体0.08g,收率65%。1H NMR(500MHz,DMSO-d6)δ(ppm):13.49(1H,s),10.91(1H,s),9.71(1H,s),8.60(1H,s),8.49(1H,d,J=8.6Hz),7.89(1H,d,J=1.5Hz),7.71(1H,d,J=8.2Hz),7.68(1H,s),7.52(1H,s),7.39(1H,t,J=5.4Hz),7.33(1H,d,J=1.7Hz),6.94(1H,dd,J1=8.3Hz,J2=1.7Hz),3.28(2H,q,J=6.4Hz),2.52-2.56(6H,m),2.44(3H,s),2.40(3H,s),0.98(6H,t,J=7.1Hz).13C NMR(125MHz,DMSO-d6)δ(ppm):170.4,165.1,152.0,140.3,139.6,138.3,135.6,128.6,126.8,126.2,125.3,123.4,123.2,122.3,121.9,120.7,120.6,120.5,119.7,115.9,111.6,100.6,52.1,47.0(2C),37.4,13.8,12.4(2C),11.0。
实施例35
(Z)-N-(2-(二乙氨基)乙基)-5-((6-(3-(3-甲氧基-4-(三氟甲基)苯基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-甲酰胺(I-35)的合成:
中间体III-11的合成:将化合物II-11(0.30g,1.57mmol)溶解于无水四氢呋喃(10mL),然后加入K2CO3(0.27g,1.95mmol),氯甲酸苯酯(0.21mL,1.65mmol),室温反应4h。LC-MS监测反应完毕后,抽滤,滤饼用少量四氢呋喃洗涤,真空干燥,得到白色固体0.48g,收率98%。
中间体V-12的合成:将化合物III-11(0.48g,1.56mmol),IV-1(0.17g,1.05mmol),DMAP(0.0080g,0.060mmol)溶解于DCM(15mL),于搅拌下加入TEA(0.055mL,0.32mmol),加热至50℃反应20h。LC-MS监测反应完毕后,停止加热,冷却至室温,减压浓缩,乙酸乙酯打浆纯化,抽滤,滤饼用少量乙酸乙酯洗涤,真空干燥,得白色固体0.22g,收率57%。1H NMR(500MHz,DMSO)δ(ppm):10.33(1H,s),8.71(2H,d,J=3.0Hz),7.85(1H,d,J=2.1Hz),7.56(1H,dd,J1=8.8Hz,J2=1.7Hz),7.26(1H,s),7.21(1H,d,J=9.0Hz),7.08(1H,d,J=8.0Hz),6.81(1H,dd,J1=7.8Hz,J2=1.1Hz),3.85(3H,s),3.39(2H,s)。
化合物I-35的合成:将化合物V-12(0.22g,0.60mmol)和VI-2(0.24g,0.90mmol)溶解于乙醇(7mL),然后加入吡咯烷(0.050mL,0.60mmol),加热至50℃反应2h。LC-MS监测反应完毕后,停止加热,冷却至室温,抽滤,滤饼用少量乙醇洗涤,真空干燥,得到橙黄色固体0.25g,收率67%。1H NMR(500MHz,DMSO-d6)δ(ppm):13.48(1H,s),10.85(1H,s),8.80(1H,s),8.74(1H,s),7.87(1H,d,J=2.5Hz),7.65(1H,d,J=8.3Hz),7.58(1H,dd,J1=8.9Hz,J2=2.3Hz),7.48(1H,s),7.37(1H,t,J=5.5Hz),7.32(1H,d,J=1.6Hz),7.21(1H,d,J=9.1Hz),6.92(1H,dd,J1=8.3Hz,J2=1.6Hz),3.86(3H,s),3.28(2H,q,J=6.4Hz),2.52-2.56(6H,m),2.44(3H,s),2.40(3H,s),0.98(6H,t,J=7.1Hz).13C NMR(125MHz,DMSO-d6)δ(ppm):170.4,165.2,153.1,152.4,139.6,139.1,135.4,133.1,128.3,126.2,125.2,124.4,123.0,121.9,120.5,119.9,119.5,117.1,116.1,114.0,111.6,100.6,56.7,52.1,47.0(2C),37.4,13.8,12.4(2C),11.1。
实施例36
(Z)-N-(2-(二乙氨基)乙基)-2,4-二甲基-5-((2-氧化-6-(3-(3,4,5-三甲氧基苯基)脲基)吲哚-3-亚基)甲基)-1H-吡咯-3-甲酰胺(I-36)的合成:
中间体III-12的合成:将化合物II-12(0.30g,1.64mmol)溶解于无水四氢呋喃(10mL),然后加入K2CO3(0.28g,2.00mmol),氯甲酸苯酯(0.22mL,1.72mmol),室温反应4h。LC-MS监测反应完毕后,抽滤,滤饼用少量四氢呋喃洗涤,真空干燥,得到白色固体0.38g,收率75%。
中间体V-13的合成:将化合物III-12(0.38g,1.24mmol),IV-1(0.17g,1.05mmol),DMAP(0.0080g,0.060mmol)溶解于DCM(15mL),于搅拌下加入TEA(0.055mL,0.32mmol),加热至50℃反应20h。LC-MS监测反应完毕后,停止加热,冷却至室温,减压浓缩,乙酸乙酯打浆纯化,抽滤,滤饼用少量乙酸乙酯洗涤,真空干燥,得白色固体0.21g,收率55%。1H NMR(500MHz,MeOD)δ(ppm):7.28(1H,d,J=1.9Hz),7.16(1H,d,J=8.0Hz),6.90(1H,dd,J1=8.0Hz,J2=2.0Hz),6.81(2H,s),3.85(6H,s),3.75(3H,s),3.49(2H,s)。
化合物I-36的合成:将化合物V-13(0.21g,0.59mmol)和VI-2(0.23g,0.88mmol)溶解于乙醇(7mL),然后加入吡咯烷(0.050mL,0.59mmol),加热至50℃反应2h。LC-MS监测反应完毕后,停止加热,冷却至室温,抽滤,滤饼用少量乙醇洗涤,真空干燥,得到橙黄色固体0.24g,收率66%。1H NMR(500MHz,DMSO-d6)δ(ppm):13.48(1H,s),10.83(1H,s),8.73(1H,s),8.62(1H,d,J=9.7Hz),7.65(1H,d,J=8.3Hz),7.48(1H,s),7.36(1H,s),6.88(1H,d,J=8.2Hz),6.81(2H,s),6.80(1H,s),3.76(6H,s),3.75(3H,s),3.28(2H,q,J=6.3Hz),2.52-2.56(6H,m),2.44(3H,s),2.40(3H,s),0.98(6H,t,J=7.1Hz).13C NMR(125MHz,DMSO-d6)δ(ppm):170.4,165.2,153.3(2C),144.6,139.6,139.1,136.3,135.3,132.9,128.3,126.2,124.9,121.9,120.5,119.7,119.1,116.1,100.5,96.4(2C),60.6,56.1,56.2,52.2,47.0(2C),37.4,13.8,12.4(2C),11.1。
实施例37
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)乙酰胺(I-37)的合成:
化合物I-37的合成:化合物XII-1(0.17g,0.39mmol)溶于THF(10mL),加入DIPEA(0.19mL,1.17mmol),降温至0℃,滴加乙酰氯(0.040mL,0.58mmol),加毕,室温反应0.5h。TLC监测反应完毕后,减压浓缩,残留物加入乙酸乙酯(10mL)打浆。抽滤,滤饼用乙酸乙酯(1mL)洗涤,真空干燥得到黄色固体0.14g,收率78%。1H NMR(500MHz,DMSO-d6)δ(ppm):13.33(1H,s),10.80(1H,s),9.46(1H,s),9.08(1H,s),8.86(1H,s),7.63(1H,d,J=8.3Hz),7.45(1H,s),7.28(1H,d,J=1.7Hz),6.89(1H,dd,J1=8.3Hz,J2=1.8Hz),6.51(1H,s),2.18(3H,s),2.14(3H,s),2.10(3H,s),1.31(9H,s).13C NMR(125MHz,DMSO-d6)δ(ppm):180.6,170.3,168.9,158.9,151.7,139.2,137.7,130.8,126.0,124.7,122.6,122.1,120.8,119.1,114.1,111.7,100.6,92.9,32.9,28.8(3C),23.1,12.2,9.6。
实施例38
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-4-甲基-1H-吡咯-3-基)乙酰胺(I-38)的合成:
中间体XI-3的合成:将化合物V-1(0.63g,2.02mmol)和VI-3(0.40g,2.60mmol)溶解于乙醇(10mL),然后加入吡咯烷(0.17mL,2.02mmol),加热至50℃反应2h。LC-MS监测反应完毕后,停止加热,冷却至室温,抽滤,滤饼用少量乙醇洗涤,真空干燥,得到橙黄色固体0.86g,收率95%。1H NMR(500MHz,DMSO-d6)δ(ppm):14.13(1H,s),11.15(1H,s),9.53(1H,s),8.97(1H,s),8.25(1H,d,J=3.4Hz),7.81(1H,d,J=8.3Hz),7.62(1H,s),7.34(1H,d,J=1.8Hz),6.93(1H,dd,J1=8.3Hz,J2=1.9Hz),6.52(1H,s),2.58(3H,s),1.31(9H,s)。
中间体XII-3的合成:将化合物XI-3(0.86g,1.90mmol)溶于四氢呋喃和甲醇(10mL/5mL,v/v)的混合溶剂,加入氯化铵(0.31g,5.72mmol)的饱和溶液(1mL),加热至50℃,分批加入锌粉(0.63g,9.60mmol),继续反应0.5h。LC-MS监测反应完毕后,停止加热,冷却至室温,减压浓缩,残留物用乙酸乙酯(100mL)和饱和碳酸钠溶液(100mL)溶解,分出有机层,依次用水和饱和氯化钠溶液洗涤,无水硫酸钠干燥。抽滤,减压浓缩,甲醇打浆纯化,抽滤,滤饼用少量甲醇洗涤,真空干燥,得到黄色固体0.32g,收率54%。
化合物I-38的合成:化合物XII-3(0.22g,0.53mmol)溶于THF(10mL),加入DIPEA(0.19mL,1.17mmol),降温至0℃,滴加乙酰氯(0.060mL,0.80mmol),加毕,室温反应0.5h。TLC监测反应完毕后,减压浓缩,残留物加入乙酸乙酯(10mL)打浆。抽滤,滤饼用乙酸乙酯(1mL)洗涤,真空干燥得到黄色固体0.14g,收率41%。1H NMR(500MHz,DMSO-d6)δ(ppm):13.21(1H,d,J=2.4Hz),10.86(1H,s),9.48(1H,s),9.30(1H,s),8.87(1H,s),7.66(1H,d,J=8.3Hz),7.56(1H,d,J=8.3Hz),7.50(1H,s),7.29(1H,d,J=1.7Hz),6.90(1H,dd,J1=8.3Hz,J2=1.7Hz),6.52(1H,s),2.26(3H,s),2.04(3H,s),1.31(9H,s).13C NMR(125MHz,DMSO-d6)δ(ppm):180.7,170.2,167.9,158.8,151.6,139.7,138.2,125.5,124.8,122.7,120.5,119.5,119.2,118.0,116.2,111.7,100.6,92.9,33.0,28.8(3C),23.4,9.3。
实施例39
(Z)-5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-N,2,4-三甲基-1H-吡咯-3-甲酰胺(I-39)的合成:
中间体VI-5的合成:将化合物VI-4(0.15g,0.90mmol)溶解于乙腈(10mL),然后加入HOBT(0.015g,0.14mmol),1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(0.22g,1.17mmol),甲酰胺(0.079ml,1.62mmol),TEA(0.25ml,1.80mmol),室温反应12h,LC-MS监测反应完毕后,抽滤,减压浓缩,柱层析纯化(二氯甲烷:甲醇)得白色固体0.060g,收率37%。1H NMR(500MHz,MeOD)δ(ppm):9.54(1H,s),2.90(3H,s),2.44(3H,s),2.39(3H,s)。
化合物I-39的合成:将化合物V-1(0.087g,0.28mmol)和VI-5(0.060g,0.33mmol)溶解于乙醇(5mL),然后加入吡咯烷(0.023mL,0.28mmol),加热至50℃反应2h。LC-MS监测反应完毕后,停止加热,冷却至室温,抽滤,滤饼用少量乙醇洗涤,真空干燥,得到橙黄色固体0.11g,收率80%。1H NMR(500MHz,DMSO-d6)δ(ppm):13.48(1H,s),10.89(1H,s),9.48(1H,s),8.88(1H,s),7.69(1H,d,J=8.3Hz),7.51(1H,s),7.49(1H,d,J=4.7Hz),7.30(1H,d,J=1.8Hz),6.90(1H,dd,J1=8.3Hz,J2=1.8Hz),6.51(1H,s),2.75(3H,d,J=4.6Hz),2.42(3H,s),2.39(3H,s),1.31(9H,s).13C NMR(125MHz,DMSO-d6)δ(ppm):180.7,170.4,165.9,158.8,151.6,139.5,138.2,135.4,128.7,126.2,122.3,120.7,120.5,119.6,115.8,111.8,100.7,92.9,33.0,28.8(3C),26.4,13.7,11.0。
实施例40
(Z)-5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-甲酰胺(I-40)的合成:
中间体VI-6的合成:将化合物VI-4(0.10g,0.60mmol)溶解于无水四氢呋喃(7mL),0℃下滴加SOCl2,室温反应1h后滴加25%的NH4OH,室温下继续反应1h。LC-MS监测反应完毕后,将反应液加入水(15mL)中,乙酸乙酯(30mL×2)萃取,合并有机层,一次用水和氯化钠溶液洗涤,无水硫酸钠干燥。抽滤,减压浓缩,柱层析纯化(二氯甲烷:甲醇)得到白色固体0.030g,收率30%。
化合物I-40的合成:将化合物V-1(0.050g,0.15mmol)和VI-6(0.030g,0.18mmol)溶解于乙醇(5mL),然后加入吡咯烷(0.013mL,0.15mmol),加热至50℃反应2h。LC-MS监测反应完毕后,停止加热,冷却至室温,抽滤,滤饼用少量乙醇洗涤,真空干燥,得到橙黄色固体0.060g,收率81%。1H NMR(500MHz,DMSO-d6)δ(ppm):13.49(1H,s),10.88(1H,s),9.47(1H,s),8.88(1H,s),7.69(1H,d,J=8.3Hz),7.51(1H,s),7.30(1H,d,J=1.5Hz),7.07(1H,s),7.01(1H,s),6.90(1H,dd,J1=8.3Hz,J2=1.6Hz),6.51(1H,s),2.46(3H,s),2.41(3H,s),1.31(9H,s).13C NMR(125MHz,DMSO-d6)δ(ppm):180.7,170.4,167.3,158.8,151.6,139.5,138.2,136.0,129.1,126.2,122.4,120.5,120.3,119.6,115.8,111.8,100.7,92.9,33.0,28.8(3C),14.0,11.2。
实施例41
(Z)-5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-甲酸甲酯(I-41)的合成:
中间体VI-7的合成:将化合物VI-7(0.20g,1.20mmol)溶于丙酮(10mL),加入K2CO3(0.18g,1.32mmol),硫酸二甲酯(0.12ml,1.26mmol),室温下反应12h。LC-MS监测反应完毕后,抽滤,滤饼用乙酸乙酯洗涤,减压浓缩,柱层析纯化(二氯甲烷:甲醇)得到白色固体0.14g,收率65%。1H NMR(500MHz,CDCl3)δ(ppm):9.85(1H,s),9.64(1H,s),3.86(3H,s),2.59(3H,s),2.57(3H,s)。
化合物I-41的合成:将化合物V-1(0.050g,0.15mmol)和VI-7(0.044g,0.24mmol)溶解于乙醇(5mL),然后加入吡咯烷(0.013mL,0.15mmol),加热至50℃反应2h。LC-MS监测反应完毕后,停止加热,冷却至室温,抽滤,滤饼用少量乙醇洗涤,真空干燥,得到橙黄色固体0.060g,收率83%。1H NMR(500MHz,DMSO-d6)δ(ppm):13.75(1H,s),10.96(1H,s),9.48(1H,s),8.90(1H,s),7.71(1H,d,J=8.3Hz),7.55(1H,s),7.30(1H,d,J=1.6Hz),6.91(1H,dd,J1=8.3Hz,J2=1.7Hz),6.51(1H,s),3.76(3H,s),2.54(3H,s),2.48(3H,s),1.31(9H,s).13C NMR(125MHz,DMSO-d6)δ(ppm):180.7,170.4,165.4,158.8,151.6,140.1,139.9,138.67,131.2,126.6,122.0,120.2,120.0,117.4,113.4,111.9,100.7,92.9,51.1,33.0,28.8(3C),14.9,11.9。
实施例42
(Z)-5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-羧酸(I-42)的合成:
化合物I-42的合成:将化合物V-1(0.41g,1.30mmol)和化合物VI-4(0.26g,1.57mmol)溶解于乙醇(10mL),然后加入吡咯烷(0.14mL,1.70mmol),加热至50℃反应2h。LC-MS监测反应完毕后,停止加热,冷却至室温,抽滤,滤饼用少量乙醇洗涤,真空干燥,得到橙黄色固体0.51g,收率85%。1H NMR(500MHz,DMSO-d6)δ(ppm):13.69(1H,s),12.09(1H,s),10.95(1H,s),9.56(1H,s),8.97(1H,s),7.71(1H,d,J=8.3Hz),7.55(1H,s),7.31(1H,d,J=1.2Hz),6.91(1H,dd,J1=8.2Hz,J2=1.2Hz),6.52(1H,s),2.53(3H,s),2.48(3H,s),1.30(9H,s).13C NMR(125MHz,DMSO-d6)δ(ppm):180.7,170.4,170.1,158.8,151.6,140.2,139.8,138.4,131.7,126.5,124.1,124.0,122.2,120.3,119.9,111.9,100.7,92.9,33.0,28.8(3C),14.9,11.9。
实施例43
(Z)-1-(5-(叔丁基)异恶唑-3-基)-3-(3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-氧化吲哚-6-基)脲(I-43)的合成:
化合物I-43的合成:将化合物V-1(0.10g,0.32mmol)和VI-8(0.059g,0.48mmol)溶解于乙醇(6mL),然后加入吡咯烷(0.031mL,0.38mmol),加热至50℃反应2h。LC-MS监测反应完毕后,停止加热,冷却至室温,抽滤,滤饼用少量乙醇洗涤,真空干燥,得到橙黄色固体0.11g,收率85%。1H NMR(500MHz,DMSO-d6)δ(ppm):13.21(1H,s),10.79(1H,s),9.47(1H,s),8.85(1H,s),7.62(1H,d,J=8.3Hz),7.45(1H,s),7.28(1H,d,J=1.4Hz),6.89(1H,dd,J1=8.3Hz,J2=1.5Hz),6.51(1H,s),5.98(1H,s),2.31(3H,s),2.29(3H,s),1.30(9H,s).13C NMR(125MHz,DMSO-d6)δ(ppm):180.6,170.3,158.9,151.6,139.2,137.6,135.3,131.1,127.0,122.4,120.9,119.0,113.5,112.7,111.6,100.6,92.9,33.0,28.8(3C),14.0,11.8。
实施例44
(Z)-1-(3-((1H-吡咯-2-基)亚甲基)-2-氧化吲哚-6-基)-3-(5-(叔丁基)异恶唑-3-基)脲(I-44)的合成:
化合物I-44的合成:将化合物V-1(0.10g,0.32mmol)和VI-9(0.045g,0.38mmol)溶解于乙醇(6mL),然后加入吡咯烷(0.031mL,0.38mmol),加热至50℃反应2h。LC-MS监测反应完毕后,停止加热,冷却至室温,抽滤,滤饼用少量乙醇洗涤,真空干燥,得到橙黄色固体0.11g,收率86%。1H NMR(500MHz,DMSO-d6)δ(ppm):13.22(1H,s),10.91(1H,s),9.51(1H,s),8.90(1H,s),7.61(1H,s),7.54(1H,d,J=8.2Hz),7.33(1H,s),7.32(1H,s),6.88(1H,d,J=8.1Hz),6.78(1H,s),6.52(1H,s),6.34(1H,s),1.30(9H,s).13C NMR(125MHz,DMSO-d6)δ(ppm):180.7,170.1,158.8,151.6,140.1,138.6,130.1,125.5,125.2,120.0(2C),119.5,117.5,111.9,111.7,100.7,92.9,33.0,28.8(3C)。
实施例45
(Z)-N1-(3-((1H-咪唑-5-基)亚甲基)-2-氧化吲哚-6-基)-N3-(5-(叔丁基)异恶唑-3-基)丙二酰胺(I-45)的合成:
中间体VIII-1的合成:将化合物II-1(1.00g,7.13mmol)溶于乙腈(20mL),然后化合物VII-1(0.84g,7.13mmol),TCFH(2.40g,8.65mmol),NMI(2.00ml,25.00mmol),室温反应4h。LC-MS监测反应完毕后,将反应液加入水(15mL)中,乙酸乙酯(30mL×2)萃取,合并有机层,一次用水和氯化钠溶液洗涤,无水硫酸钠干燥。抽滤,减压浓缩,得到白色固体0.85g,收率50%。
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中间体IX-1的合成:将化合物VIII-1(0.85g,3.54mmol)溶解于CH3OH/H2O(20mL),然后加入LiOH.H2O(0.30g,7.08mmol),室温反应2h。LC-MS监测反应完毕后,用1N的HCl将反应液调至PH=1,待固体析出,抽滤,滤饼用少量乙酸乙酯洗涤,真空干燥,得到橙黄色固体0.57g,收率71%。1H NMR(500MHz,DMSO-d6)δ(ppm):12.72(1H,s),11.11(1H,s),6.57(1H,s),3.39(2H,s),1.30(9H,s)。
中间体X-1的合成:将化合物IV-1(0.45g,3.03mmol)溶解于DMF(15mL),于搅拌下加入IX-1(0.57g,2.52mmol),TCFH(0.85g,3.03mmol),DIPEA(1.25mL,7.56mmol),室温反应2h。LC-MS监测反应完毕后,向反应液中加入水(10ml),待固体析出后,抽滤,滤饼用少量乙酸乙酯洗涤,真空干燥,得黄色固体0.58g,收率65%。
化合物I-45的合成:将化合物X-1(0.080g,0.23mmol)和VI-10(0.026g,0.27mmol)溶解于乙醇(6mL),然后加入吡咯烷(0.020mL,0.22mmol),加热至50℃反应2h。LC-MS监测反应完毕后,停止加热,冷却至室温,抽滤,滤饼用少量乙醇洗涤,真空干燥,得到黄色固体0.090g,收率86%。1H NMR(500MHz,DMSO-d6)δ(ppm):13.61(1H,s),11.15(1H,s),10.95(1H,s),10.25(1H,s),7.98(1H,s),7.69(1H,s),7.59(1H,d,J=8.3Hz),7.54(1H,s),7.45(1H,d,J=1.6Hz),7.09(1H,dd,J1=8.3Hz,J2=1.6Hz),6.61(1H,s),3.52(2H,s),1.30(9H,s).13C NMR(125MHz,DMSO-d6)δ(ppm):181.0(2C),169.7,166.2,165.4,158.2,140.8,139.4,120.8,120.2(2C),112.5,101.4,93.6(2C),56.5,45.8,33.0,28.8(3C),19.0。
实施例46
(Z)-1-(3-((1H-咪唑-5-基)亚甲基)-2-氧化吲哚-6-基)-3-(3-甲氧基-4-(三氟甲基)苯基)脲(I-46)的合成:
化合物I-46的合成:将化合物V-12(0.22g,0.60mmol)和VI-10(0.026g,0.27mmol)溶解于乙醇(7mL),然后加入吡咯烷(0.050mL,0.60mmol),加热至50℃反应2h。LC-MS监测反应完毕后,停止加热,冷却至室温,抽滤,滤饼用少量乙醇洗涤,真空干燥,得到橙黄色固体0.25g,收率67%。1H NMR(500MHz,DMSO-d6)δ(ppm):13.48(1H,s),10.85(1H,s),8.80(1H,s),8.74(1H,s),7.87(1H,d,J=2.5Hz),7.65(1H,d,J=8.3Hz),7.58(1H,dd,J1=8.9Hz,J2=2.3Hz),7.48(1H,s),7.37(1H,t,J=5.5Hz),7.32(1H,d,J=1.6Hz),7.21(1H,d,J=9.1Hz),6.92(1H,dd,J1=8.3Hz,J2=1.6Hz),3.86(3H,s),3.28(2H,q,J=6.4Hz),2.52-2.56(6H,m),2.44(3H,s),2.40(3H,s),0.98(6H,t,J=7.1Hz).13C NMR(125MHz,DMSO-d6)δ(ppm):170.4,165.2,153.1,152.4,139.6,139.1,135.4,133.1,128.3,126.2,125.2,124.4,123.0,121.9,120.5,119.9,119.5,117.1,116.1,114.0,111.6,100.6,56.7,52.1,47.0(2C),37.4,13.8,12.4(2C),11.1。
实施例47
(Z)-1-(3-((1H-咪唑-5-基)亚甲基)-2-氧化吲哚-6-基)-3-(4-(叔丁基)苯基)脲(I-47)的合成:
化合物I-47的合成:将化合物V-9(0.11g,0.33mmol)和VI-10(0.132g,0.50mmol)溶解于乙醇(10mL),然后加入吡咯烷(0.027mL,0.33mmol),加热至50℃反应2h。LC-MS监测反应完毕后,停止加热,冷却至室温,抽滤,滤饼用少量乙醇洗涤,真空干燥,得到橙黄色固体0.11g,收率61%。1H NMR(500MHz,DMSO-d6)δ(ppm):13.48(1H,s),10.85(1H,s),8.72(1H,s),8.55(1H,s),7.65(1H,d,J=8.2Hz),7.48(1H,s),7.38(1H,s),7.37(2H,s),7.34(1H,s),7.31(1H,s),7.29(1H,s),6.89(1H,d,J=8.2Hz),3.29(2H,q,J=6.2Hz),2.52-2.56(6H,m),2.44(3H,s),2.40(3H,s),1.27(9H,s),0.98(6H,t,J=7.0Hz).13C NMR(125MHz,DMSO-d6)δ(ppm):170.4,165.2,152.9,144.6,139.6,139.3,137.5,135.3,128.2,126.2,125.8(2C),121.8,120.5,119.7,119.6,118.5(2C),116.2,111.4,100.4,52.2,47.0(2C),37.4,34.4,31.7(3C),13.8,12.4(2C),11.1。
实施例48
(Z)-1-(3-((1H-咪唑-5-基)亚甲基)-2-氧化吲哚-6-基)-3-(3-(叔丁基)-1-甲基-1H-吡唑-5-基)脲(I-48)的合成:
化合物I-48的合成:将化合物V-5(0.19g,0.58mmol)和VI-10(0.23g,0.87mmol)溶解于乙醇(10mL),然后加入吡咯烷(0.050mL,0.58mmol),加热至50℃反应2h。LC-MS监测反应完毕后,停止加热,冷却至室温,抽滤,滤饼用少量乙醇洗涤,真空干燥,得到橙黄色固体0.37g,收率65%。1H NMR(500MHz,DMSO-d6)δ(ppm):13.48(1H,s),10.88(1H,s),9.88(1H,s),9.42(1H,s),7.65(1H,d,J=8.3Hz),7.48(1H,s),7.39(1H,t,J=5.5Hz),7.31(1H,d,J=1.7Hz),6.95(1H,dd,J1=8.3Hz,J2=1.7Hz),6.07(1H,s),3.65(1H,s),3.28(2H,q,J=6.4Hz),2.52-2.56(6H,m),2.44(3H,s),2.39(3H,s),1.22(9H,s),0.98(6H,t,J=7.1Hz).13C NMR(125MHz,DMSO-d6)δ(ppm):170.4,165.2,159.1,152.1,139.6,139.3,138.0,135.3,128.2,126.2,121.8,120.5,119.7,119.6,116.2,111.1,100.0,92.7,52.1,47.0(2C),37.4,35.7,32.3,30.9(3C),13.8,12.4(2C),11.1。
实施例49
(Z)-1-(3-((1H-咪唑-5-基)亚甲基)-2-氧化吲哚-6-基)-3-(3-(叔丁基)异恶唑-5-基)脲(I-49)的合成:
中间体III-13的合成:将化合物II-13(1.00g,7.13mmol)溶解于无水四氢呋喃(20mL),然后加入K2CO3(1.22g,8.83mmol),氯甲酸苯酯(0.94mL,7.49mmol),室温反应4h。LC-MS监测反应完毕后,抽滤,滤饼用少量四氢呋喃洗涤,真空干燥,得到白色固体1.17g,收率75%。
中间体V-14的合成:将化合物III-13(0.31g,1.44mmol),IV-1(0.20g,1.20mmol),DMAP(0.0090g,0.070mmol)溶解于DCM(10mL),于搅拌下加入TEA(0.025mL,0.18mmol),加热至50℃反应20h。LC-MS监测反应完毕后,停止加热,冷却至室温,减压浓缩,乙酸乙酯打浆纯化,抽滤,滤饼用少量乙酸乙酯洗涤,真空干燥,得到灰色固体0.27g,收率75%。1H NMR(500MHz,MeOD)δ(ppm):7.30(1H,d,J=1.8Hz),7.19(1H,d,J=8.0Hz),6.93(1H,dd,J1=8.0Hz,J2=2.0Hz),6.13(1H,s),5.51(1H,s),1.34(9H,s)。
化合物I-49的合成:将化合物V-14(0.20g,0.64mmol)和VI-10(0.09g,0.96mmol)溶解于乙醇(7mL),然后加入吡咯烷(0.053mL,0.64mmol),加热至50℃反应2h。LC-MS监测反应完毕后,停止加热,冷却至室温,抽滤,滤饼用少量乙醇洗涤,真空干燥,得到橙黄色固体0.16g,收率65%。1H NMR(500MHz,DMSO-d6)δ(ppm):13.62(1H,s),11.03(1H,s),10.10(1H,s),8.97(1H,s),8.00(1H,s),7.71(1H,s),7.59(1H,s),7.57(1H,s),7.35(1H,d,J=1.4Hz),6.93(1H,dd,J1=8.3Hz,J2=1.6Hz),6.08(1H,s),1.27(9H,s).13C NMR(125MHz,DMSO-d6)δ(ppm):173.0,169.9,162.1,150.0,141.0,139.7,139.4,138.1,128.7,121.5,120.6,120.4,119.4,112.1,100.8,84.2,32.4,29.5(3C)。
实施例50
(Z)-1-(3-((1H-咪唑-5-基)亚甲基)-2-氧化吲哚-6-基)-3-(3-氯-4-(三氟甲基)苯基)脲(I-50)的合成:
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化合物I-50的合成:将化合物V-10(0.15g,0.41mmol)和VI-10(0.047g,0.49mmol)溶解于乙醇(5mL),然后加入吡咯烷(0.030mL,0.41mmol),加热至50℃反应2h。LC-MS监测反应完毕后,停止加热,冷却至室温,抽滤,滤饼用少量乙醇洗涤,真空干燥,得到橙黄色固体0.11g,收率60%。1H NMR(500MHz,DMSO-d6)δ(ppm):13.63(1H,s),11.00(1H,s),9.30(1H,s),9.09(1H,s),7.99(1H,s),7.93(1H,d,J=1.8Hz),7.75(1H,d,J=1.8Hz),7.70(1H,s),7.59(1H,s),7.57(1H,s),7.49(1H,dd,J1=8.5Hz,J2=1.2Hz),7.35(1H,d,J=1.6Hz),6.95(1H,dd,J1=8.3Hz,J2=1.7Hz).13C NMR(125MHz,DMSO-d6)δ(ppm):169.7,152.4,145.0,141.0,139.7,139.1,131.7,129.0,128.9,124.7,122.6,120.9,120.3,120.0,119.7,119.5,119.2,116.7,112.1,100.8。
实施例51
(Z)-1-(3-((1H-咪唑-5-基)亚甲基)-2-氧化吲哚-6-基)-3-(4-(哌啶-4-基)苯基)脲盐酸盐(I-51)的合成:
中间体III-14的合成:将化合物II-14(0.20g,0.72mmol)溶解于无水四氢呋喃(10mL),然后加入K2CO3(0.12g,0.90mmol),氯甲酸苯酯(0.10mL,0.80mmol),室温反应4h。LC-MS监测反应完毕后,抽滤,滤饼用少量四氢呋喃洗涤,真空干燥,得到白色固体0.24g,收率85%。
中间体V-15的合成:将化合物III-14(0.20g,0.51mmol),IV-1(0.055g,0.34mmol),DMAP(0.0030g,0.020mmol)溶解于DCM(15mL),于搅拌下加入TEA(0.014mL,0.10mmol),加热至50℃反应20h。LC-MS监测反应完毕后,停止加热,冷却至室温,减压浓缩,乙酸乙酯打浆纯化,抽滤,滤饼用少量乙酸乙酯洗涤,真空干燥,得白色固体0.11g,收率72%。
化合物XI-4的合成:将化合物V-15(0.11g,0.30mmol)和VI-10(0.12g,0.45mmol)溶解于乙醇(5mL),然后加入吡咯烷(0.025mL,0.30mmol),加热至50℃反应2h。LC-MS监测反应完毕后,停止加热,冷却至室温,抽滤,滤饼用少量乙醇洗涤,真空干燥,得到橙黄色固体0.10g,收率67%。
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化合物I-51的合成:将化合物XI-4(0.10g,0.19mmol)用少量乙酸乙酯溶解,后加入盐酸乙酸乙酯溶液,于室温下搅拌反应。TLC检测反应完全后,抽滤,滤饼用乙酸乙酯洗涤,真空干燥,得到橙黄色固体0.070g,收率80%。1H NMR(500MHz,DMSO-d6)δ(ppm):14.97(1H,s),11.23(1H,s),9.75(1H,s),9.42(1H,s),9.07(1H,s),8.94(1H,d,J=10.2Hz),8.76(1H,d,J=11.1Hz),8.22(1H,s),7.65(1H,s),7.57(1H,d,J=8.6Hz),7.43(2H,d,J=11.1Hz),7.41(1H,d,J=1.8Hz),7.15(2H,d,J=8.5Hz),6.99(1H,dd,J1=8.4Hz,J2=1.7Hz),3.35(2H,d,J=12.4Hz),2.97(2H,q,J=12.0Hz),2.81-2.76(1H,m),1.91(2H,d,J=12.8Hz),1.85-1.78(2H,m).13C NMR(125MHz,DMSO-d6)δ(ppm):169.6,153.0,142.6,142.3,138.6,138.5,136.0,129.0,127.6,127.3(2C),124.1,121.7,118.7(2C),117.1,116.8,111.7,100.3,44.0(2C),38.8,30.0(2C)。
实施例52
(Z)-1-(3-((1H-咪唑-5-基)亚甲基)-2-氧化吲哚-6-基)-3-(4-((4,4-二甲基哌啶-1-基)甲基)苯基脲(I-52)的合成:
中间体II-15的合成:将4,4-二甲基哌啶(0.10g,0.88mmol),4-氨基苯甲醛(0.13g,1.06mmol)溶于无水二氯甲烷(10mL),搅拌10min后加入NaBH(OAc)3(0.080g,3.54mmol),TEA(0.24mL,1.77mmol),室温反应12h。LC-MS监测反应完毕后,将反应液加入NaHCO3中,二氯甲烷:甲醇(10:1)萃取,合并有机层,一次用水和氯化钠溶液洗涤,无水硫酸钠干燥。柱层析纯化(二氯甲烷:甲醇)得到白色固体0.092g,收率48%。
中间体III-15的合成:将化合物II-15(0.092g,0.42mmol)溶解于无水四氢呋喃(10mL),然后加入K2CO3(0.72g,0.52mmol),氯甲酸苯酯(0.053mL,0.42mmol),室温反应4h。LC-MS监测反应完毕后,抽滤,滤饼用少量四氢呋喃洗涤,真空干燥,得到白色固体0.14g,收率85%。
中间体V-16的合成:将化合物III-15(0.14g,0.43mmol),IV-1(0.055g,0.34mmol),DMAP(0.0030g,0.020mmol)溶解于DCM(15mL),于搅拌下加入TEA(0.014mL,0.10mmol),加热至50℃反应20h。LC-MS监测反应完毕后,停止加热,冷却至室温,减压浓缩,乙酸乙酯打浆纯化,抽滤,滤饼用少量乙酸乙酯洗涤,真空干燥,得白色固体0.10g,收率72%。
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化合物I-52的合成:将化合物V-16(0.10g,0.25mmol)和VI-10(0.020g,0.25mmol)溶解于乙醇(5mL),然后加入吡咯烷(0.0021mL,0.25mmol),加热至50℃反应2h。LC-MS监测反应完毕后,停止加热,冷却至室温,抽滤,滤饼用少量乙醇洗涤,真空干燥,得到橙黄色固体0.080g,收率67%。1H NMR(500MHz,DMSO-d6)δ(ppm):13.63(1H,s),10.96(1H,s),8.85(1H,s),8.67(1H,s),7.98(1H,s),7.66(1H,s),7.57(1H,s),7.54(1H,d,J=8.2Hz),7.41(1H,s),7.39(2H,s),7.19(2H,d,J=8.2Hz),6.89(1H,dd,J1=8.2Hz,J2=1.2Hz),3.40(4H,s),2.32(4H,s),1.32(4H,t,J=4.9Hz),0.89(6H,s).13C NMR(125MHz,DMSO-d6)δ(ppm):170.0,152.8,141.0,140.6,139.5,138.8,138.6,137.7,131.5,129.7,128.7,128.2,120.9,120.4,118.7,118.5,118.4,112.4,111.7,100.5,62.4,55.7,49.7,38.8,28.7。
实施例53
(Z)-1-(3-((1H-咪唑-5-基)亚甲基)-5-氟-2-氧化吲哚-6-基)-3-(3-(叔丁基)异恶唑-5-基)脲(I-53)的合成:
中间体V-17的合成:将化合物III-13(0.27g,1.05mmol),IV-2(0.12g,0.70mmol),DMAP(0.0050g,0.06mmol)溶解于DCM(10mL),于搅拌下加入TEA(0.029mL,0.21mmol),加热至50℃反应20h。LC-MS监测反应完毕后,停止加热,冷却至室温,减压浓缩,乙酸乙酯打浆纯化,抽滤,滤饼用少量乙酸乙酯洗涤,真空干燥,得到灰色固体0.27g,收率75%。1H NMR(500MHz,DMSO-d6)δ(ppm):10.42(1H,s),10.34(1H,s),8.70(1H,d,J=2.5Hz),7.67(1H,d,J=6.8Hz),7.18(1H,d,J=10.6Hz),6.07(1H,s),3.45(2H,s),1.26(9H,s)。
化合物I-53的合成:将化合物V-17(0.20g,0.64mmol)和VI-10(0.090g,0.96mmol)溶解于乙醇(7mL),然后加入吡咯烷(0.053mL,0.64mmol),加热至50℃反应2h。LC-MS监测反应完毕后,停止加热,冷却至室温,抽滤,滤饼用少量乙醇洗涤,真空干燥,得到橙黄色固体0.16g,收率65%。1H NMR(500MHz,DMSO-d6)δ(ppm):13.65(1H,s),11.05(1H,s),10.41(1H,s),8.82(1H,s),8.01(1H,s),7.78(2H,s),7.69(1H,d,J=10.8Hz),7.60(1H,s),6.10(1H,s),1.27(9H,s).13C NMR(125MHz,DMSO-d6)δ(ppm):173.1,169.6,161.7,149.7,149.4,147.5,136.7,126.8,126.7,120.5,119.2,119.1,107.3,107.1,101.9,84.2,32.4,29.5(3C)。
实例54
实施例54
(Z)-1-(3-(叔丁基)异恶唑-5-基)-3-(5-氟-3-((4-甲基-1H-咪唑-5-基)亚甲基)-2-氧化吲哚-6-基)脲(I-54)的合成:
化合物I-54的合成:将化合物V-17(0.060g,0.17mmol)和VI-11(0.020g,0.21mmol)溶解于乙醇(4mL),然后加入吡咯烷(0.0010mL,0.17mmol),加热至50℃反应2h。LC-MS监测反应完毕后,停止加热,冷却至室温,柱层析纯化(二氯甲烷:甲醇)得到橙黄色固体0.030g,收率48%。1H NMR(500MHz,DMSO-d6)δ(ppm):13.81(1H,s),11.04(1H,s),10.43(1H,s),8.82(1H,d,J=2.7Hz),8.00(1H,s),7.89(1H,d,J=11.3Hz),7.78(1H,d,J=6.7Hz),7.74(1H,s),6.93(1H,dd,J1=8.3Hz,J2=1.6Hz),6.10(1H,s),2.46(3H,s),1.27(9H,s).13C NMR(125MHz,DMSO-d6)δ(ppm):173.0,170.3,162.1,150.0,147.0,140.5,139.0,138.2,127.9,125.0,121.2,120.5,119.9,112.0,100.8,84.1,32.4,29.5(3C),13.5。
实施例55
(Z)-1-(3-(叔丁基)异恶唑-5-基)-3-(3-((4-甲基-1H-咪唑-5-基)亚甲基)-2-氧化吲哚-6-基)脲(I-55)的合成:
化合物I-55的合成:将化合物V-14(0.090g,0.28mmol)和VI-11(0.030g,0.25mmol)溶解于乙醇(4mL),然后加入吡咯烷(0.0020mL,0.28mmol),加热至50℃反应2h。LC-MS监测反应完毕后,停止加热,冷却至室温,柱层析纯化(二氯甲烷:甲醇)得到橙黄色固体0.060g,收率57%。1H NMR(500MHz,DMSO-d6)δ(ppm):13.71(1H,s),11.00(1H,s),10.11(1H,s),8.97(1H,s),7.90(1H,s),7.74(1H,d,J=8.3Hz),7.64(1H,s),7.31(1H,d,J=1.8Hz),6.95(1H,dd,J1=8.3Hz,J2=1.9Hz),6.08(1H,s),2.43(3H,s),1.27(9H,s).13CNMR(125MHz,DMSO-d6)δ(ppm):173.0,170.3,162.1,150.0,147.0,140.5,139.0,138.2,127.9,125.0,121.2,120.5,119.9,118.6,112.0,100.8,84.1,32.4,29.5(3C),13.5。
实施例56
(Z)-N1-(5-(叔丁基)异恶唑-3-基)-N3-(3-((3,5-二甲基-4-(2-(4-甲基哌嗪-1-基)乙酰氨基)-1H-吡咯-2-基)亚甲基)-2-氧化吲哚-6-基)丙二酰胺(I-56)的合成:
化合物XI-1的合成:将化合物X-1(1.10g,3.00mmol)和VI-1(0.26g,3.24mmol)溶解于乙醇(10mL),然后加入吡咯烷(0.20mL,2.20mmol),加热至50℃反应2h。LC-MS监测反应完毕后,停止加热,冷却至室温,抽滤,滤饼用少量乙醇洗涤,真空干燥,得到黄色固体1.31g,收率86%。
中间体XII-1的合成:将化合物XI-1(1.31g,2.58mmol)溶于四氢呋喃和甲醇(20mL/10mL,v/v)的混合溶剂,加入氯化铵(1.38g,25.86mmol)的饱和溶液,加热至50℃,分批加入锌粉(0.84g,12.90mmol),继续反应0.5h。LC-MS监测反应完毕后,停止加热,冷却至室温,减压浓缩,残留物用乙酸乙酯(100mL)和饱和碳酸钠溶液(100mL)溶解,分出有机层,依次用水和饱和氯化钠溶液洗涤,无水硫酸钠干燥。抽滤,减压浓缩,甲醇打浆纯化,抽滤,滤饼用少量甲醇洗涤,真空干燥,得到黄色固体0.66g,收率54%。
中间体XIII-1的合成:将化合物XII-1(0.58g,1.15mmol)溶于THF(20mL),加入DIPEA(0.50mL,3.45mmol),降温至0℃,滴加氯乙酰氯(0.46mL,5.75mmol),加毕,室温反应0.5h。TLC监测反应完毕后,减压浓缩,残留物加入乙酸乙酯(10mL)打浆。抽滤,滤饼用乙酸乙酯(1mL)洗涤,真空干燥得到黄色固体0.50g,收率80%。
化合物I-56的合成:将化合物XIII-1(0.10g,0.18mmol)溶于DMF(5mL),加入N-甲基哌嗪(0.17mL,1.50mmol),于50℃反应12h。TLC监测反应完毕后,将反应液倒入水中,乙酸乙酯溶液(30mL×2)萃取,合并有机层,依次用水和饱和的氯化钠溶液洗涤,无水硫酸钠干燥。抽滤,减压浓缩,残留物加入乙酸乙酯(5mL)打浆纯化,抽滤,真空干燥得到黄色固体0.070g,收率65%。1H NMR(500MHz,DMSO-d6)δ(ppm):13.39(1H,s),11.14(1H,s),10.84(1H,s),10.16(1H,s),8.95(1H,s),7.65(1H,d,J=8.3Hz),7.48(1H,s),7.42(1H,d,J=1.9Hz),7.08(1H,dd,J=8.3,1.9Hz),6.61(1H,s),3.51(2H,s),3.10(2H,s),2.63-2.57(4H,m),2.4-2.34(4H,m),2.18(6H,s),2.14(3H,s),1.30(9H,s).13C NMR(125MHz,DMSO-d6)δ(ppm):181.0,170.2,169.0,166.3,165.1,158.2,139.0,137.7,131.0,126.3,124.8,122.9,121.6,121.6,119.0,114.0,112.3,101.3,93.6,61.8,55.0(2C),53.3(2C),46.2,45.7,33.0,28.8(3C),12.2,9.6。
实施例57
(Z)-N1-(5-(叔丁基)异恶唑-3-基)-N3-(3-((4-((2-(二乙氨基)乙基)氨基甲酰基)-3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-氧化吲哚-6-基)丙二酰胺(I-57)的合成:
化合物I-57的合成:将化合物X-1(1.10g,3.00mmol)和VI-2(0.23g,0.88mmol)溶解于乙醇(7mL),然后加入吡咯烷(0.050mL,0.59mmol),加热至50℃反应2h。LC-MS监测反应完毕后,停止加热,冷却至室温,抽滤,滤饼用少量乙醇洗涤,真空干燥,得到橙黄色固体0.24g,收率66%。1H NMR(500MHz,DMSO-d6)δ(ppm):13.51(1H,s),11.15(1H,s),10.91(1H,s),10.19(1H,s),7.70(1H,d,J=8.3Hz),7.53(1H,s),7.43(1H,d,J=1.8Hz),7.39(1H,t,J=5.6Hz),7.09(1H,dd,J=8.3,1.9Hz),6.61(1H,s),3.52(2H,s),3.31-3.24(2H,m),2.57-2.51(6H,m),2.44(3H,s),2.40(3H,s),1.30(9H,s),0.98(6H,t,J=7.1Hz).13C NMR(125MHz,DMSO-d6)δ(ppm):181.02,170.29,166.22,165.16,165.11,158.17,139.31,138.13,135.72,128.81,126.21,122.61,121.32,120.70,119.43,115.74,112.35,101.34,93.56,52.14,46.97(2C),37.44,32.99,28.81(3C),22.54,13.77,12.37(2C),11.03。
实施例58
(Z)-N-(5-(叔丁基)异恶唑-3-基)-N-(3-((4-((2-(二乙氨基)乙基)氨基甲酰基)-3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-氧化吲哚-6-基)环丙烷-1,1-二甲酰胺(I-58)的合成:
中间体VIII-2的合成:将化合物II-1(1.00g,7.13mmol)溶解于乙腈(20mL),然后加入化合物VII-2(1.03g,7.13mmol),TCFH(2.40g,8.65mmol),NMI(2.00ml,25.00mmol),室温反应4h。LC-MS监测反应完毕后,将反应液加入水(15mL)中,乙酸乙酯(30mL×2)萃取,合并有机层,一次用水和氯化钠溶液洗涤,无水硫酸钠干燥。抽滤,减压浓缩,得到白色固体1.04g,收率55%。
中间体IX-2的合成:将化合物VIII-2(0.94g,3.54mmol)溶解于CH3OH/H2O(20mL),然后加入LiOH·H2O(0.30g,7.08mmol),室温反应2h。LC-MS监测反应完毕后,用1N的HCl将反应液调至PH=1,待固体析出,抽滤,滤饼用少量乙酸乙酯洗涤,真空干燥,得到橙黄色固体0.62g,收率69%。
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中间体X-2的合成:将化合物IX-2(0.76g,3.03mmol)溶解于DMF(15mL),于搅拌下加入IV-1(0.38g,2.52mmol),TCFH(0.85g,3.03mmol),DIPEA(1.25mL,7.56mmol),室温反应2h。LC-MS监测反应完毕后,向反应液中加入水(10mL),待固体析出后,抽滤,滤饼用少量乙酸乙酯洗涤,真空干燥,得黄色固体0.78g,收率67%。
化合物I-58的合成:将化合物X-2(0.40g,1.05mmol)和VI-2(0.42g,1.58mmol)溶解于乙醇(10mL),然后加入吡咯烷(0.13mL,1.58mmol),加热至50℃反应2h。LC-MS监测反应完毕后,停止加热,冷却至室温,抽滤,滤饼用少量乙醇洗涤,真空干燥,得到橙黄色固体0.48g,收率72%。1H NMR(500MHz,DMSO-d6)δ(ppm):13.51(1H,s),11.12(1H,s),10.93(1H,s),9.95(1H,s),7.70(1H,d,J=8.3Hz),7.54(1H,s),7.43(1H,d,J=1.9Hz),7.40(1H,t,J=5.6Hz),7.16(1H,dd,J=8.3,1.9Hz),6.62(1H,s),3.28(2H,q,J=6.5Hz),2.53(6H,d,J=8.2Hz),2.44(3H,s),2.40(3H,s),1.52-1.46(4H,m),1.30(9H,s),0.98(6H,t,J=7.1Hz).13C NMR(125MHz,DMSO-d6)δ(ppm):180.6,170.3,169.1,168.1,165.1,139.1,138.1,135.7,128.8,126.2,122.7,121.4,120.7,119.1,115.8,113.7,102.7,94.3,52.1,47.0(2C),37.4,33.0,31.9,28.8(4C),16.4(2C),13.8,12.4(2C),11.0。
实施例59
(Z)-N-(5-(叔丁基)异恶唑-3-基)-N-(3-((3,5-二甲基-4-(2-(4-甲基哌啶-1-基)乙酰氨基)-1H-吡咯-2-基)亚甲基)-2-氧化吲哚-6-基)环丙烷-1,1-二甲酰胺(I-59)的合成:
化合物XI-2的合成:将化合物X-2(1.15g,3.00mmol)和VI-1(0.26g,3.24mmol)溶解于乙醇(10mL),然后加入吡咯烷(0.20mL,2.20mmol),加热至50℃反应2h。LC-MS监测反应完毕后,停止加热,冷却至室温,抽滤,滤饼用少量乙醇洗涤,真空干燥,得到黄色固体1.30g,收率86%。
中间体XII-2的合成:将化合物XI-2(1.37g,2.58mmol)溶于四氢呋喃和甲醇(20mL/10mL,v/v)的混合溶剂,加入氯化铵(1.38g,25.86mmol)的饱和溶液,加热至50℃,分批加入锌粉(0.84g,12.90mmol),继续反应0.5h。LC-MS监测反应完毕后,停止加热,冷却至室温,减压浓缩,残留物用乙酸乙酯(100mL)和饱和碳酸钠溶液(100mL)溶解,分出有机层,依次用水和饱和氯化钠溶液洗涤,无水硫酸钠干燥。抽滤,浓缩滤液,甲醇打浆纯化,抽滤,滤饼用少量甲醇洗涤,真空干燥,得到黄色固体0.71g,收率55%。
中间体XIII-2的合成:化合物XII-2(0.58g,1.15mmol)溶于THF(20mL),加入DIPEA(0.50mL,3.45mmol),降温至0℃,滴加氯乙酰氯(0.46mL,5.75mmol),加毕,室温反应0.5h。TLC监测反应完毕后,减压浓缩,残留物加入乙酸乙酯(10mL)打浆。抽滤,滤饼用乙酸乙酯(1mL)洗涤,真空干燥得到黄色固体0.47g,收率79%。
化合物I-59的合成:将化合物XIII-2(0.10g,0.18mmol)溶于DMF(5mL),加入N-甲基哌嗪(0.17mL,1.5mmol),于50℃反应12h。TLC监测反应完毕后,将反应液倒入水中,乙酸乙酯溶液(30mL×2)萃取,合并有机层,依次用水和饱和的氯化钠溶液洗涤,无水硫酸钠干燥。抽滤,减压浓缩,残留物加入乙酸乙酯(5mL)打浆纯化,抽滤,真空干燥得到黄色固体0.07g,收率65%。1H NMR(500MHz,DMSO-d6)δ(ppm):13.40(1H,s),11.13(1H,s),10.85(1H,s),9.90(1H,s),8.95(1H,s),7.65(1H,d,J=8.3Hz),7.49(1H,s),7.42(1H,d,J=1.9Hz),7.15(1H,dd,J=8.3,1.9Hz),6.62(1H,s),3.10(2H,s),2.62-2.52(4H,m),2.4-2.35(4H,m),2.19(6H,d,J=2.4Hz),2.14(3H,s),1.53-1.43(4H,m),1.30(9H,s).13C NMR(125MHz,DMSO-d6)δ(ppm):180.6,170.2,169.1,169.0,168.1,158.5,138.8,137.6,131.0,126.4,124.8,123.0,121.8,121.6,118.6,114.1,113.6,102.7,94.3,61.8,55.0(2C),53.2(2C),46.2,33.0,31.8,28.8(4C),16.4,12.2,9.6。
实施例60
(Z)-N1-(5-(叔丁基)异恶唑-3-基)-N3-(3-((3,5-二甲基-4-(2-(4-甲基哌嗪-1-基)乙酰氨基)-1H-吡咯-2-基)亚甲基)-2-氧化吲哚-6-基)-2,2-二甲基丙二酰胺(I-60)的合成:
中间体VIII-3的合成:将化合物II-1(1.00g,7.13mmol)溶解于乙腈(20mL),然后加入化合物VII-3(1.04g,7.13mmol),TCFH(2.40g,8.65mmol),NMI(2.00mL,25.00mmol),室温反应4h。LC-MS监测反应完毕后,将反应液加入水(15mL)中,乙酸乙酯(30mL×2)萃取,合并有机层,一次用水和氯化钠溶液洗涤,无水硫酸钠干燥。抽滤,减压浓缩,得到白色固体1.05g,收率55%。
中间体IX-3的合成:将化合物VIII-3(0.95g,3.54mmol)溶解于CH3OH/H2O(20mL),然后加入LiOH·H2O(0.30g,7.08mmol),室温反应2h。LC-MS监测反应完毕后,用1N的HCl将反应液调至PH=1,待固体析出,抽滤,滤饼用少量乙酸乙酯洗涤,真空干燥,得到橙黄色固体0.63g,收率70%。
中间体X-3的合成:将化合物IX-3(0.77g,3.03mmol)溶解于DMF(15mL),于搅拌下加入IV-1(0.38g,2.52mmol),TCFH(0.85g,3.03mmol),DIPEA(1.25mL,7.56mmol),室温反应2h。LC-MS监测反应完毕后,向反应液中加入水(10mL),待固体析出后,抽滤,滤饼用少量乙酸乙酯洗涤,真空干燥,得黄色固体0.79g,收率67%。
化合物XI-3的合成:将化合物X-3(1.16g,3.00mmol)和VI-1(0.26g,3.24mmol)溶解于乙醇(10mL),然后加入吡咯烷(0.20mL,2.20mmol),加热至50℃反应2h。LC-MS监测反应完毕后,停止加热,冷却至室温,抽滤,滤饼用少量乙醇洗涤,真空干燥,得到黄色固体1.38g,收率86%。
中间体XII-3的合成:将化合物XI-3(1.38g,2.58mmol)溶于四氢呋喃和甲醇(20mL/10mL,v/v)的混合溶剂,加入氯化铵(1.38g,25.86mmol)的饱和溶液,加热至50℃,分批加入锌粉(0.84g,12.90mmol),继续反应0.5h。LC-MS监测反应完毕后,停止加热,冷却至室温,减压浓缩,残留物用乙酸乙酯(100mL)和饱和碳酸钠溶液(100mL)溶解,分出有机层,依次用水和饱和氯化钠溶液洗涤,无水硫酸钠干燥。抽滤,减压浓缩,甲醇打浆纯化,抽滤,滤饼用少量甲醇洗涤,真空干燥,得到黄色固体0.72g,收率55%。
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中间体XIII-3的合成:化合物XII-3(0.58g,1.15mmol)溶于THF(20mL),加入DIPEA(0.5mL,3.45mmol),降温至0℃,滴加3-氯丙酰氯(0.1mL,5.75mmol),加毕,室温反应0.5h。TLC监测反应完毕后,减压浓缩,残留物加入乙酸乙酯(10mL)打浆。抽滤,滤饼用乙酸乙酯(1mL)洗涤,真空干燥得到黄色固体0.47g,收率79%。
化合物I-60的合成:将化合物XIII-3(0.10g,0.18mmol)溶于DMF(5mL),加入N-甲基哌嗪(0.17mL,1.5mmol),于50℃反应12h。TLC监测反应完毕后,将反应液倒入水中,乙酸乙酯溶液(30mL×2)萃取,合并有机层,依次用水和饱和的氯化钠溶液洗涤,无水硫酸钠干燥。抽滤,减压浓缩,残留物加入乙酸乙酯(5mL)打浆纯化,抽滤,真空干燥得到黄色固体0.070g,收率65%。1H NMR(500MHz,DMSO-d6)δ(ppm):13.39(1H,s),10.87(1H,s),10.69(1H,s),9.39(1H,s),8.95(1H,s),7.65(1H,d,J=8.3Hz),7.49(1H,s),7.44(1H,d,J=1.9Hz),7.21(1H,dd,J=8.4,1.9Hz),6.63(1H,s),3.10(2H,s),2.63-2.57(4H,m),2.47-2.34(4H,m),2.18(6H,s),2.14(3H,s),1.53(6H,s),1.30(9H,s).13C NMR(125MHz,DMSO-d6)δ(ppm):180.6,172.7,171.8,170.3,169.0,158.8,138.8,137.9,131.0,126.3,124.8,122.9,121.6,121.56,118.6,114.2,113.5,102.5,94.2,61.8,55.0(2C),53.3(2C),46.2,32.9,28.8(4C),23.5,21.2,12.2,9.6。
实施例61
(Z)-N1-(5-(叔丁基)异恶唑-3-基)-N3-(3-((4-((2-(二乙氨基)乙基)氨基甲酰基)-3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-氧化吲哚-6-基)-2,2-二甲基丙二酰胺(I-61)的合成:
化合物I-61的合成:将化合物X-3(0.40g,1.05mmol)和VI-2(0.42g,1.58mmol)溶解于乙醇(10mL),然后加入吡咯烷(0.13mL,1.58mmol),加热至50℃反应2h。LC-MS监测反应完毕后,停止加热,冷却至室温,抽滤,滤饼用少量乙醇洗涤,真空干燥,得到橙黄色固体0.48g,收率72%。1H NMR(500MHz,DMSO-d6)δ(ppm):13.50(1H,s),10.93(1H,s),10.68(1H,s),9.41(1H,s),7.70(1H,d,J=8.4Hz),7.53(1H,s),7.45(1H,d,J=1.8Hz),7.38(1H,t,J=5.6Hz),7.22(1H,dd,J=8.4,1.9Hz),6.63(1H,s),3.31-3.25(2H,m),2.57-2.51(6H,m),2.44(3H,s),2.40(3H,s),1.54(6H,s),1.30(9H,s),0.98(6H,t,J=7.1Hz).13C NMR(125MHz,DMSO-d6)δ(ppm):180.6,172.7,171.8,170.4,165.1,158.8,139.1,138.4,135.7,128.8,126.2,122.6,121.3,120.7,119.1,115.9,113.6,102.5,94.2,52.7,52.2,47.0(2C),37.4,32.9,28.8(4C),23.5(2C),13.8,12.4(2C),11.0。
实施例62
(Z)-5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-甲酸乙酯(I-62)的合成:
化合物I-62的合成:将化合物V-1(0.80g,2.55mmol)和VI-12(0.50g,2.55mmol)溶解于乙醇(10mL),然后加入吡咯烷(0.27mL,3.31mmol),加热至50℃反应2h。LC-MS监测反应完毕后,停止加热,冷却至室温,抽滤,滤饼用少量乙醇洗涤,真空干燥,得到橙黄色固体1.10g,收率85%。1H NMR(500MHz,DMSO-d6)δ(ppm):13.75(1H,s),10.97(1H,s),9.50(1H,s),8.91(1H,s),7.71(1H,d,J=8.2Hz),7.55(1H,s),7.30(1H,d,J=1.8Hz),6.91(1H,dd,J=8.2,2.0Hz),6.51(1H,s),4.22(2H,q,J=7.1Hz),2.54(3H,s),2.48(3H,s),1.33-1.28(12H,m).13C NMR(125MHz,DMSO-d6)δ(ppm):180.7,170.4,164.9,158.8,151.6,140.0,139.8,138.6,131.3,126.6,122.0,120.2,120.0,117.3,113.6,111.9,100.7,92.9,59.5,33.0,28.8(3C),15.0,14.8,11.8。
实施例63
(Z)-1-(3-((1H-咪唑-5-基)亚甲基)-2-氧化吲哚-6-基)-3-(5-(叔丁基)异恶唑-3-基)脲(I-63)的合成:
化合物I-63的合成:将化合物V-1(0.20g,0.64mmol)和VI-10(0.090g,0.96mmol)溶解于乙醇(7mL),然后加入吡咯烷(0.053mL,0.64mmol),加热至50℃反应2h。LC-MS监测反应完毕后,停止加热,冷却至室温,抽滤,滤饼用少量乙醇洗涤,真空干燥,得到橙黄色固体0.16g,收率65%。1H NMR(500MHz,DMSO-d6)δ(ppm):13.62(1H,s),11.00(1H,s),9.51(1H,s),8.95(1H,s),7.99(1H,s),7.69(1H,s),7.58(1H,s),7.57-7.55(1H,m),7.35(1H,d,J=1.9Hz),6.90(1H,dd,J=8.2,1.9Hz),6.52(1H,s),1.30(9H,s).13C NMR(125MHz,DMSO-d6)δ(ppm):180.7,169.9,158.8,151.6,141.0,139.7,139.6,138.0,128.7,121.4,120.6,120.4,119.2,112.0,100.8,92.9,33.0,28.8(3C)。
实施例64
(Z)-1-(5-(叔丁基)异恶唑-3-基)-3-(3-((4-甲基-1H-咪唑-5-基)亚甲基)-2-氧化吲哚-6-基)脲(I-64)的合成:
化合物I-64的合成:将化合物V-1(0.090g,0.28mmol)和VI-11(0.030g,0.25mmol)溶解于乙醇(4mL),然后加入吡咯烷(0.0020mL,0.28mmol),加热至50℃反应2h。LC-MS监测反应完毕后,停止加热,冷却至室温,柱层析纯化(二氯甲烷:甲醇)得到橙黄色固体0.050g,收率45%。1H NMR(500MHz,DMSO-d6)δ(ppm):13.71(1H,s),10.97(1H,s),9.51(1H,s),8.92(1H,s),7.90(1H,s),7.73(1H,d,J=8.2Hz),7.62(1H,s),7.32(1H,d,J=2.0Hz),6.92(1H,dd,J=8.2,2.0Hz),6.52(1H,s),2.43(3H,s),1.30(9H,s).13C NMR(125MHz,DMSO-d6)δ(ppm):180.7,170.3,158.8,151.6,147.0,140.5,139.2,138.2,125.0,121.1,120.5,119.7,118.6,111.9,100.7,92.9,33.0,28.8(3C),13.5。
实施例65
(Z)-1-(3-((1H-咪唑-2-基)亚甲基)-2-氧化吲哚-6-基)-3-(5-(叔丁基)异恶唑-3-基)脲(I-65)的合成:
化合物I-65的合成:将化合物V-1(0.090g,0.28mmol)和VI-13(0.023g,0.25mmol)溶解于乙醇(4mL),然后加入吡咯烷(0.0020mL,0.28mmol),加热至50℃反应2h。LC-MS监测反应完毕后,停止加热,冷却至室温,柱层析纯化(二氯甲烷:甲醇)得到橙黄色固体0.050g,收率45%。1H NMR(500MHz,DMSO-d6)δ(ppm):13.95(1H,s),11.14(1H,s),9.52(1H,s),9.00(1H,s),7.73(1H,d,J=8.3Hz),7.65(1H,s),7.52(1H,d,J=2.1Hz),7.39(1H,d,J=1.9Hz),7.31(1H,t,J=1.2Hz),6.89(1H,dd,J=8.3,1.9Hz),6.52(1H,s),1.30(9H,s).13CNMR(125MHz,DMSO-d6)δ(ppm):180.7,169.9,158.7,151.6,144.3,141.3,140.4,132.7,124.1,122.9,121.3,120.7,118.7,112.1,100.8,92.9,33.0,28.8(3C)。
实施例66
(Z)-N1-(3-((1H-吡咯-2-基)亚甲基)-2-氧化吲哚-6-基)-N3-(5-(叔丁基)异恶唑-3-基)丙二酰胺(I-66)的合成:
化合物I-66的合成:将化合物X-1(0.080g,0.23mmol)和VI-9(0.026g,0.27mmol)溶解于乙醇(6mL),然后加入吡咯烷(0.020mL,0.22mmol),加热至50℃反应2h。LC-MS监测反应完毕后,停止加热,冷却至室温,抽滤,滤饼用少量乙醇洗涤,真空干燥,得到黄色固体0.090g,收率86%。1H NMR(500MHz,DMSO-d6)δ(ppm):13.24(1H,s),11.15(1H,s),10.91(1H,s),10.21(1H,s),7.62(1H,s),7.56(1H,d,J=8.3Hz),7.44(1H,d,J=1.8Hz),7.33(1H,td,J=2.7,1.4Hz),7.08(dd,J=8.3,1.9Hz,1H),6.79(1H,dt,J=3.7,1.8Hz),6.61(1H,s),6.34(1H,dt,J=3.7,2.3Hz),3.52(2H,s),1.30(9H,s).13C NMR(125MHz,DMSO-d6)δ(ppm):181.0,170.0,166.2,165.2,158.2,139.9,138.5,130.1,125.7,125.5,120.9,120.2,119.4,117.4,112.5,111.7,101.4,93.6,45.8,33.0,28.8(3C)。
实施例67
(Z)-5-((6-(3-(3-(叔丁基)异恶唑-5-基)脲基)-2-氧化吲哚-3-亚基)甲基)-N-(2-(二乙氨基)乙基-2,4-二甲基-1H-吡咯-3-甲酰胺(I-67)的合成:
化合物I-67的合成:将化合物V-14(0.20g,0.64mmol)和VI-2(0.42g,1.58mmol)溶解于乙醇(7mL),然后加入吡咯烷(0.053mL,0.64mmol),加热至50℃反应2h。LC-MS监测反应完毕后,停止加热,冷却至室温,抽滤,滤饼用少量乙醇洗涤,真空干燥,得到橙黄色固体0.16g,收率65%。1H NMR(500MHz,DMSO-d6)δ(ppm):13.49(1H,s),10.91(1H,s),10.06(1H,s),8.91(1H,s),7.69(1H,d,J=8.3Hz),7.52(1H,s),7.39(1H,t,J=5.3Hz),7.28(1H,d,J=1.6Hz),6.94(1H,dd,J1=8.2Hz,J2=1.7Hz),6.07(1H,s),3.28(2H,q,J=6.4Hz),2.52-2.56(6H,m),2.44(3H,s),2.40(3H,s),1.27(9H,s),0.99(6H,t,J=7.1Hz).13C NMR(125MHz,DMSO-d6)δ(ppm):180.7,170.4,165.2,158.8,151.6,139.6,138.3,135.6,128.6,126.2,122.3,120.5(2C),119.6,115.9,111.8,100.7,92.9,52.0,47.0(2C),37.4,33.0,28.8(3C),13.8,12.1(2C),11.1。
实施例68
化合物对CSF-1R的抑制活性:
实验方法:采用Mobility Shift Assay的方法测定化合物对CSF-1R激酶的体外抑制活性:将化合物从1μM起始浓度,3倍稀释成10个浓度,然后用Echo550转移250nL至384孔板中,阴性对照孔和阳性对照孔中分别加入250nL的100%DMSO。在化合物孔和阳性对照孔中分别加入10μL的2.5倍终浓度的激酶溶液;在阴性对照孔中加入10μL的激酶buffer。1000rpm离心30秒,振荡混匀后室温孵育10分钟,加入15μL的25/15倍终浓度的ATP和激酶底物的混合溶液。将384孔板于1000rpm离心30秒,振荡混匀后室温孵育30分钟,加入30μL终止检测液,停止激酶反应,1000rpm离心30秒,振荡混匀,用Caliper EZ ReaderⅡ读取转化率。采用Graphpad Prism 5软件分析处理数据,求得IC50值。结果显示:大部分化合物对CSF-1R具有较好的抑制活性,优于PLX3397(表2)。
表2.实施例化合物对CSF-1R的抑制活性
实施例69
化合物I-17和I-19对结直肠癌细胞的体外促凋亡活性:
实验方法:MC-38为小鼠结肠癌细胞系。采用流式细胞术测定化合物对实体瘤细胞的体外促凋亡活性:体外诱导形成M2型巨噬细胞,加或不加I-17(10,30,100nM)和I-19(10,30,100nM)处理M2型巨噬细胞,随后用新鲜培养基替换培养基。48h后,收集上清液作为条件培养基。为了定量评估不同条件培养基的促凋亡效应,使用胰酶消化处于对数生长期的MC-38细胞,计数后取适量细胞悬液接种于6孔板中,过夜培养后,每孔加入上述不同的条件培养基,于37℃、5%CO2孵箱培养24h后。采用AnnexinV-PI试剂盒检测细胞凋亡情况。采用Graphpad Prism 5软件分析处理数据。
表3.化合物I-17和I-19对结直肠癌细胞的体外促凋亡活性
结果显示:用化合物I-17和I-19刺激M2巨噬细胞的条件培养基处理显著增加了MC-38细胞的凋亡(表3),并且在同等浓度下其促凋亡的活性都优于PLX3397。
实施例70
化合物I-17和I-19对结直肠癌细胞的体外抗增殖活性:
实验方法:MC-38为小鼠结肠癌细胞系。采用CCK-8法测定化合物对实体瘤细胞的体外抗增殖活性:体外诱导形成M2型巨噬细胞,加或不加I-17(10,30,100nM)和I-19(10,30,100nM)处理M2型巨噬细胞,随后用新鲜培养基替换培养基。48h后,收集上清液作为条件培养基。为了定量评估不同条件培养基的抗增殖效应,使用胰酶消化处于对数生长期的MC-38细胞,计数后取适量细胞悬液接种于96孔板中,过夜培养后,每孔加入上述不同的条件培养基,于37℃、5%CO2孵箱培养20h后,加入CCK-8(10μL)继续培养4h。采用全波长酶标仪检测波长为490nm处的吸光度值。采用Graphpad Prism 5软件分析处理数据,并计算抑制率。
表4.化合物I-17和I-19对结直肠癌细胞的体外抗增殖活性
结果显示:用化合物I-17和I-19刺激巨噬细胞的条件培养基处理显著抑制了MC-38细胞的增殖(表4),并且在同等浓度下其抗增殖增殖的活性都优于PLX3397。
实施例71
化合物I-19对部分酪氨酸激酶的体外抑制活性:
实验方法:采用Mobility Shift Assay的方法测定化合物I-19对部分酪氨酸激酶的体外抑制活性:将化合物从1μM起始浓度,3倍稀释成10个浓度,然后用Echo550转移250nL至384孔板中,阴性对照孔和阳性对照孔中分别加入250nL的100%DMSO。在化合物孔和阳性对照孔中分别加入10μL的2.5倍终浓度的激酶溶液;在阴性对照孔中加入10μL的激酶buffer。1000rpm离心30秒,振荡混匀后室温孵育10分钟,加入15μL的25/15倍终浓度的ATP和激酶底物的混合溶液。将384孔板于1000rpm离心30秒,振荡混匀后室温孵育30分钟,加入30μL终止检测液,停止激酶反应,1000rpm离心30秒,振荡混匀,用Caliper EZ ReaderⅡ读取转化率。采用Graphpad Prism 5软件分析处理数据,求得IC50值。结果显示:化合物I-19对PDGFRα、PDGFRβ、c-KIT、FLT3等多种酪氨酸激酶都显示出一定的抑制活性,尤其是对PDGFRα、PDGFRβ和c-KIT显示出较强的抑制活性(表5)。
表5.化合物I-19对部分酪氨酸激酶的体外抑制活性
实施例72
化合物I-17和I-19抑制MC-38结直肠癌小鼠移植瘤生长的作用:
实验方法:将MC-38细胞进行体外培养扩增,取适量处于对数生长期的细胞重悬于无血清DMEM培养基中,无菌条件下制备成1×106/100μL细胞悬液,用注射器将100μL细胞悬液接种于雌性C57BL/6小鼠前左肢腋窝皮下。待肿瘤体积生长至100mm3左右时,选取肿瘤大小适中的动物随机分组,每组6只。分别给予空白媒介(CMC-Na)、PLX3397(20mg/kg/d)、I-17低剂量(5mg/kg/d)、I-17中剂量(10mg/kg/d)、I-17高剂量(20mg/kg/d)、I-19低剂量(5mg/kg/d)、I-19中剂量(10mg/kg/d)、I-19高剂量(20mg/kg/d),每天灌胃一次,给药2周。给药期间,每天测量小鼠体重和瘤径。实验结束后颈椎脱臼处死,取瘤称重。
肿瘤体积(tumor volume,TV)的计算公式为:TV=1/2×a×b2,a表示肿瘤长径;b表示肿瘤短径。
表6.化合物I-17及I-19在MC-38结直肠癌小鼠模型上的抑瘤效果
*,p<0.05;**,p<0.01(与溶剂对照比较)。
结果显示:在MC-38小鼠移植瘤模型上,连续灌胃给药2周,化合物I-17(10,20mg/kg)和I-19(5,10,20mg/kg)能够剂量依赖性地抑制肿瘤的生长,并且对小鼠体重没有影响。其中I-17和I-19在20mg/kg/d剂量下的抑瘤率分别达到53.30%和66.81%,明显优于PLX3397在20mg/kg/d剂量下的抑瘤率(39.23%)(表6)。
实施例73
化合物I-19与免疫检查点抑制剂PD-L1单抗的协同抗肿瘤作用:
实验方法:将MC-38细胞体进行外培养扩增,取适量处于对数生长期的细胞重悬于无血清DMEM培养基中,无菌条件下制备成1×106/100μL细胞悬液,用注射器将100μL细胞悬液接种于雌性C57BL/6小鼠前左肢腋窝皮下。待肿瘤体积生长至100mm3左右时,选取肿瘤大小适中的动物随机分组,每组6只。分别给予空白媒介(CMC-Na)、I-19(20mg/kg/d)、anti-PD-L1(100μg/mouse)、I-19(20mg/kg/d)+anti-PD-L1(100μg/mouse),I-19每天灌胃一次,anti-PD-L1每3天腹腔注射一次,给药2周。给药期间,每天测量小鼠体重和瘤径。实验结束后颈椎脱臼处死,取瘤称重。
肿瘤体积(tumor volume,TV)的计算公式为:TV=1/2×a×b2,a表示肿瘤长径;b表示肿瘤短径。
表7.化合物I-19增强免疫检查点抑制剂的抗肿瘤作用
/>
*,p<0.05;**,p<0.01(与溶剂对照比较)。
结果显示:在MC-38小鼠移植瘤模型上,连续给药2周,化合物I-19(20mg/kg)和anti-PD-L1均明显抑制肿瘤的生长,且I-19可以增强anti-PD-L1的抗肿瘤作用,抑瘤率可达83.69%(表7)。
Claims (8)
1.6-位取代的吲哚酮衍生物或其药学上可接受的盐,结构如下所示:
2.一种药物组合物,包括如权利要求1中所述的6-位取代的吲哚酮衍生物或其药学上可接受的盐。
3.如权利要求1中所述的6-位取代的吲哚酮衍生物或其药学上可接受的盐在制备CSF-1R抑制剂中的用途。
4.如权利要求1中所述的6-位取代的吲哚酮衍生物或其药学上可接受的盐在制备肿瘤相关巨噬细胞免疫调节剂中的用途。
5.如权利要求1中所述的6-位取代的吲哚酮衍生物或其药学上可接受的盐在制备用于治疗恶性肿瘤、炎症性疾病、骨疾病和神经性疾病的药物的用途。
6.如权利要求1中所述的6-位取代的吲哚酮衍生物或其药学上可接受的盐,或根据权利要求2所述的药物组合物在制备用于治疗或预防恶性肿瘤的药物的用途。
7.如权利要求1中所述的6-位取代的吲哚酮衍生物或其药学上可接受的盐,或根据权利要求2所述的药物组合物与其他靶向抗肿瘤药物、T细胞免疫检查点抑制剂免疫治疗药物联合使用在制备用于治疗多种恶性肿瘤的药物的用途。
8.如权利要求1中所述的6-位取代的吲哚酮衍生物或其药学上可接受的盐,或根据权利要求2所述的药物组合物,与T细胞免疫检查点抑制剂联合使用在制备用于治疗结直肠癌的药物的用途。
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