CN116655597A - P300/cbp溴结构域抑制剂及其制药用途 - Google Patents

P300/cbp溴结构域抑制剂及其制药用途 Download PDF

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CN116655597A
CN116655597A CN202210156248.1A CN202210156248A CN116655597A CN 116655597 A CN116655597 A CN 116655597A CN 202210156248 A CN202210156248 A CN 202210156248A CN 116655597 A CN116655597 A CN 116655597A
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cancer
ddd
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李英霞
耿美玉
刘瑞齐
黄荀
陈宗龙
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Shanghai Institute of Materia Medica of CAS
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Abstract

本发明属药物合成化学技术领域，涉及一种具有式(I)结构类型的化合物或者其药学上可接受的盐；具体涉及一种p300/CBP新型溴结构域抑制剂的设计合成及其生物评价。本发明的化合物能抑制组蛋白乙酰转移酶p300/CBP的活性，对多种p300/CBP抑制敏感的肿瘤细胞如前列腺癌细胞、恶性血液肿瘤细胞、乳腺癌细胞等具有显著的增殖抑制活性，且抑制效果优于该靶点临床在研药物CCS1477。本发明的化合物具有良好的代谢稳定性和安全性，类药性强，具有巨大的抗肿瘤药物开发潜力。

Description

P300/CBP溴结构域抑制剂及其制药用途
技术领域：
本发明属于药物合成化学技术领域，涉及一种具有式(Ⅰ)结构类型的化合物或者其药学上可接受的盐，具体涉及一种p300/CBP新型溴结构域抑制剂及其制备方法及其生物评价和用途。本发明涉及的化合物能够抑制组蛋白乙酰转移酶p300/CBP的活性，对多种p300/CBP抑制敏感的肿瘤细胞如前列腺癌细胞、恶性血液肿瘤细胞、乳腺癌细胞等具有显著的增殖抑制活性，且抑制效果优于该靶点临床在研药物CCS1477。
背景技术：
现有技术公开了组蛋白的乙酰化修饰作为一种可逆的翻译后修饰(post-translational modification,PTM)在真核细胞的基因表达调控中起关键作用，是一种重要的表观遗传调控方式。组蛋白乙酰转移酶(histone acetyltransferase,HAT)和组蛋白去乙酰化酶(histone deacetylase,HDAC)在细胞中负责调节细胞中的组蛋白乙酰化水平，是基因表达和细胞周期的关键调控步骤，这些酶的功能性缺陷可能导致包括肿瘤在内多种疾病的发生。
据研究报道，由高度同源的腺病毒E1A相关的300kDa蛋白(adenoviral E1Abinding protein of 300kDa,p300)和环磷酸腺苷反应元件结合蛋白的结合蛋白(CREBbinding protein,CBP)组成的p300/CBP家族是HAT家族的主要成员之一。因其结构的同源性和功能的相似性常被合称为p300/CBP。它在人类细胞中扮演转录辅助激活因子的角色，能调节许多转录因子，通过与特定的转录激活因子相互作用，而被招募到启动子部位，从而介导转录的激活。p300和CBP均具有一个保守的溴化结构域(BRD)和赖氨酸乙酰转移酶(KAT)结构域，这些结构域参与组蛋白和非组蛋白的翻译后修饰和相关转录因子以及一些激酶的募集，影响不同基因的表达。
p300/CBP溴结构域是目前仅次于BET家族溴结构域的第二大溴结构域靶标家族，其可以特异性结合乙酰化的赖氨酸残基，有助于p300/CBP以依赖于乙酰化的方式与组蛋白N端结合，并参与染色质结构的重排，是组蛋白乙酰化和染色质转录激活所必需的。研究表明，p300/CBP溴结构域的活性的异常与多种肿瘤的发生发展密切相关。因此，高效选择性p300/CBP溴结构域抑制剂的研究是目前转录调节剂的主要研究方向之一，对p300/CBP生物学功能研究以及表观遗传药物的开发均具有重要的意义。
有研究通过X-射线晶体学结合酶学的方法获得并解析了p300/CBP溴结构域晶体结构，与人体内其它溴结构域相同，p300/CBP溴结构域在空间结构上也呈现出特征性的“一束四螺旋”(αA，αB，αC，αZ)以及两个loop结构(较短的BC loop和较长的ZA loop)。KAc结合位点位于溴结构域“螺旋束”结构末端的结合口袋中。在溴结构域识别KAc的过程中，KAc的羰基氧原子可以直接与溴结构域C末端的天冬酰胺残基形成氢键相互作用以及通过水分子氢键网络与ZA环中更高保守的酪氨酸残基之间形成氢键来发挥作用。目前已报道的p300/CBP溴结构域抑制剂主要包括苯并咪唑衍生物、哌啶衍生物、苯并杂卓衍生物和吲哚衍生物等。这些抑制剂通过与KAc竞争性结合溴结构域中的KAc识别位点抑制溴结构域的功能。研究发现，p300/CBP溴结构域抑制剂可以抑制急性髓系白血病，结肠癌、肺癌、前列腺癌等多种肿瘤细胞的增殖作用，证明了设计靶向抑制p300/CBP溴结构域抑制剂用于治疗肿瘤的方法的可行性，为一些癌症的治疗提供了一个新的有希望的途径。
虽然对p300/CBP溴结构域抑制剂设计的探索研究不断前进，但是已报道的分子并不能够满足临床的要求，因此，获得更多抑制高活性、高选择性的p300/CBP溴结构域抑制剂对潜在肿瘤治疗药物的开发具有重要的意义。基于现有技术的现状，本申请的发明人拟提供一种p300/CBP新型溴结构域抑制剂及其制备方法及其生物评价和用途。
发明内容：
本发明的目的在于基于现有技术的现状及存在的缺陷，提供一种p300/CBP新型溴结构域抑制剂及其制备方法及其生物评价和用途。
本发明设计合成了新型组蛋白乙酰转移酶p300/CBP抑制剂，并对其进行生物评价。具体的，提供了具有通式(Ⅰ)结构的化合物或其药学上可接受的盐作为p300/CBP小分子抑制剂。这些化合物可以显著降低细胞内组蛋白乙酰化水平、抑制相关肿瘤细胞的生长且具有较好的类药性。本发明在制得的化合物中确定对p300/CBP溴结构域有抑制活性的化合物，并且该化合物在分子、细胞和动物水平上均具有较好的抑制活性，较高的选择性和较好的生物利用度，具有抗肿瘤药物的开发潜力。
更具体的，
本发明提供了一种式Ⅰ所示的化合物，
其中，R1选自酰基、磺酰基、取代或非取代的五元芳香杂环；
R2选自4-6元取代或非取代的脂肪环或脂肪杂环；
R3选自取代或非取代的芳香环或芳香并环；
R4选自氢、氘、氘代或非氘代的含1-3个碳原子的烃类基团；
X1,X2,X3分别独立地选自N或CH；
Y选择-CH2-,-CH2CH2-,-CH2CH2CH2-；
虚线为单键/>或双键/>当虚线/>为双键/>时，该双键/>相邻的两个虚线/>均为单键/>
进一步地，所述化合物的结构如式Ⅱ-1所示：
Z独立地选自C(R5R6),N(R7)，其中R5，R6独立地选自氢、羟基、卤素、烷基、烷氧基；R7选自酰基、磺酰基；n1，n2为0或1；
R1,R3,R4,X1,X2,X3和Y如上所示；
进一步地，R1选自 和/或，选自/>和/或，选自/>其中R3选自
进一步地，所述化合物为以下化合物之一：
本发明还提供了上述化合物、或其氘代物、或其盐、或其异构体、或其晶型、或其溶剂合物作为p300/CBP溴结构域抑制剂的用途。
进一步地，所述p300/CBP溴结构域抑制剂为预防和/或治疗肿瘤、髓系造血干细胞恶性疾病，调控调节性T细胞的药物；
优选的，所述癌症选自血液恶性肿瘤、胃癌、肠癌、宫颈癌、膀胱癌、喉癌、肝癌、肺癌、乳腺癌、卵巢癌、前列腺癌、淋巴瘤或多发性骨髓瘤。
本发明还提供了一种用于治疗疾病的药物，其特征在于：所述药物是以权利要求任意一项所述化合物、或其氘代物、或其盐、或其异构体、或其晶型、或其溶剂合物为活性成分，加上药学上可接受的辅料制得的制剂。
关于本发明的使用术语的定义：除非另有说明，本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语；对于本文没有具体定义的术语，应该根据公开内容和上下文，给出本领域技术人员能够给予它们的含义。
“脂肪环”是指饱和或非饱和的环状烃类片段或基团，“脂肪杂环”是指含杂原子(包括但不限于氮、氧、硫)的饱和或非饱和的环状片段或基团。
“药学上可接受的”是指某载体、运载物、稀释剂、辅料，和/或所形成的盐通常在化学上或物理上与构成某药物剂型的其它成分相兼容，并在生理上与受体相兼容。
“盐”是将化合物或其立体异构体，与无机和/或有机酸和/或碱形成的酸式和/或碱式盐，也包括两性离子盐(内盐)，还包括季铵盐，例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。也可以是通过将化合物，或其异构体，与一定数量的酸或碱适当(例如等当量)进行混合而得到。这些盐可能在溶液中形成沉淀而以过滤方法收集，或在溶剂蒸发后回收而得到，或在水介质中反应后冷冻干燥制得。
本发明中所述盐可以是化合物的盐酸盐、硫酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、洒石酸盐或三氟乙酸盐。
“其溶剂合物”指本发明化合物与溶剂形成溶剂合物，其中，所述溶剂包括(但并不限于)：水、乙醇、甲醇、异丙醇、丙二醇、四氢呋喃、二氯甲烷。
“其氘代物”指本发明化合物中的1个或多个氢原子被氘替换后所得的化合物。
本发明经生物实验结果表明，提供了一类结构新颖的p300/CBP溴结构域抑制剂，该抑制剂能够有效抑制p300/CBP的活性，且所述化合物对包括前列腺癌细胞、白血病细胞、乳腺癌细胞、多发性骨髓瘤细胞在内的多种肿瘤细胞均具有优异的抑制作用。本发明的抑制剂在制备p300/CBP抑制剂，以及预防和/或治疗肿瘤、髓系造血干细胞疾病，调控调节性T细胞的药物中具有广阔的应用前景。
本发明所述的化合物具有良好的代谢稳定性和安全性，类药性强，具有巨大的抗肿瘤药物开发潜力。
具体实施方式
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
实施例1：化合物1：(S)-1-(3,4-二氟苯基)-5-(5-(3,5-二甲基异恶唑-4-基)-1-(反式-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)-5-甲基吡咯烷-2-酮的合成
步骤1：4-(4-氟-3-硝基苯基)-3,5-二甲基异恶唑的合成：
将4溴-1-氟-2-硝基苯(10g，45.46mmol)、3,5-二甲基异恶唑频那醇酯(11.15g,50.00mmol)，1,1'-双二苯基膦二茂铁二氯化钯(351mg,0.45mmol)、碳酸钾(9.42g,68.18mmol)溶于50mL的N,N-二甲基甲酰胺中，向溶液中滴加少量水，氮气置换三次，100℃条件下反应过夜。反应完毕，冷却，加入200mL水，乙酸乙酯萃取(3*200mL)，合并有机相，饱和氯化钠溶液洗涤(2*100mL)，收集有机相，无水硫酸钠干燥，浓缩，柱层析(石油醚：乙酸乙酯＝5:1)得产物8.1g，收率75.4％。1H NMR(400MHz,CDCl3)δ7.96(dd,J＝7.0,2.5Hz,1H),7.54(ddd,J＝8.5,4.0,2.5Hz,1H),7.41(dd,J＝10.5,8.5Hz,1H),2.44(s,3H),2.29(s,3H).
步骤2：中间体1-2：4-(3,5-二甲基异恶唑基-4-基)-N-(反式-4-甲氧基环己基)-2-硝基苯胺的合成：
将上步所得中间体(300mg，1.27mmol)、反式-4-甲氧基环己基-1-胺(180.51mg,1.40mmol)、碳酸钾(438.83mg,3.18mmol)溶于5mL的N,N-二甲基甲酰胺中，70℃条件下反应过夜。反应完毕，冷却，加入50mL水，乙酸乙酯萃取(3*50mL)，合并有机相，饱和氯化钠溶液洗涤(2*25mL)，收集有机相，无水硫酸钠干燥，浓缩，柱层析(石油醚：乙酸乙酯＝3:1)得产物310mg，产率70.66％。1H NMR(400MHz,CDCl3)δ8.41(brs,1H),8.08(d,J＝2.0Hz,1H),7.33(dd,J＝9.0,2.0Hz,1H),6.96(d,J＝9.0Hz,1H),4.36(br.s.,1H),3.61(m,1H),3.42(m,1H),3.30(s,3H),2.40(s,3H)2.26(s,3H),1.99(m,4H),1.41-1.31(m,2H),1.17(m,2H).
步骤3：中间体1-3：4-(3,5-二甲基异恶唑基-4-基)-N1-(反式-4-甲氧基环己基)苯基-1,2-二胺的合成：
将上步所得中间体(200mg，0.58mmol)溶于10mL 1:1的四氢呋喃和水溶液中，向溶液中滴加氨水，分批加入连二亚硫酸钠(1.01g,5.79mmol)，室温反应2小时。反应完毕，加入50mL水，乙酸乙酯萃取(1*50mL)，合并有机相，饱和氯化钠溶液洗涤(2*25mL)，收集有机相，无水硫酸钠干燥，浓缩，不经纯化直接进行下一步。
步骤4：中间体1-4：(S)-5-(5-(3,5-二甲基异恶唑基-4-基)-1-(反式-4-甲氧基环己基)-1H-苯并[d]咪唑基-2-基)-5-甲基吡咯烷-2-酮的合成：
将上步所得中间体(110mg,0.35mmol)，羧酸(49.92mg,0.35mmol)、HATU(133mg,0.52mmol)，N,N-二异丙基乙胺(90.15mg,0.70mmol)溶于5mL的N,N-二甲基甲酰胺中，室温反应3小时。反应完毕，加入50mL水，乙酸乙酯萃取(2*50mL)，合并有机相，饱和氯化钠溶液洗涤(2*25mL)，收集有机相，无水硫酸钠干燥，浓缩，将所得物质(100mg,0.23mmol)溶于5mL的乙酸中，70℃反应过夜。反应完毕，冷却，加入50mL水，乙酸乙酯萃取(1*50mL)，合并有机相，饱和氯化钠溶液洗涤(2*25mL)，收集有机相，无水硫酸钠干燥，浓缩，柱层析(二氯甲烷：甲醇＝30:1)得产物60mg，产率62.74％。1H NMR(400MHz,CDCl3)δ7.78(d,J＝8.5Hz,1H),7.69(d,J＝1.6Hz,1H),7.14(dd,J＝8.5,1.7Hz,1H),5.77(t,J＝4.6Hz,1H),4.45–4.29(m,1H),3.45–3.34(m,1H),3.28(s,3H),2.63–2.52(m,2H),2.40(s,3H),2.38(s,3H),2.37–2.28(m,2H),2.23(s,3H),2.21–2.11(m,2H),2.07(s,3H),1.87–1.71(m,2H),1.26–1.10(m,1H).
步骤6:(S)-1-(3,4-二氟苯基)-5-(5-(3,5-二甲基异恶唑-4-基)-1-(反式-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)-5-甲基吡咯烷-2-酮的合成：
将上步所得中间体(60mg,0.14mmol)，3,4-二氟苯硼酸(44.85mg,0.28mmol)，一水醋酸铜(34.02mg,0.17mmol)、吡啶(112.33mg,1.42mmol)溶于5mL的二氯甲烷中，室温反应5小时。反应完毕，旋干反应液，加入50mL水，乙酸乙酯萃取(1*50mL)，合并有机相，饱和氯化钠溶液洗涤(2*25mL)，收集有机相，无水硫酸钠干燥，浓缩，柱层析(二氯甲烷：甲醇＝50:1)得产物。1H NMR(600MHz,MeOD)δ7.75(d,J＝8.5Hz,1H),7.55(d,J＝1.3Hz,1H),7.29(ddd,J＝12.5,7.3,2.5Hz,1H),7.17(dd,J＝8.5,1.6Hz,1H),7.05(dd,J＝19.2,9.1Hz,1H),6.74(d,J＝8.7Hz,1H),4.30(ddd,J＝12.3,8.5,3.8Hz,1H),3.36(ddd,J＝15.1,10.9,4.1Hz,1H),3.32–3.27(m,3H),2.86(ddd,J＝17.7,10.2,7.3Hz,1H),2.73–2.65(m,1H),2.53–2.36(m,4H),2.36–2.28(m,3H),2.23(dd,J＝12.5,3.5Hz,1H),2.17(d,J＝5.6Hz,3H),2.11(dd,J＝9.5,3.2Hz,1H),2.02–1.96(m,1H),1.86(s,3H),1.41(d,J＝13.1Hz,1H),1.32(ddd,J＝24.2,13.1,3.8Hz,1H),1.17(dd,J＝13.3,9.9Hz,1H).13C NMR(150MHz,MeOD)δ174.97,164.72,158.13,154.67,141.39,133.32,123.71,119.50,116.41,116.26,116.18,115.96,112.97,76.98,65.20,56.18,54.28,32.01,30.50,30.21,29.11,27.43,27.27,24.42,9.36,8.68.。
实施例2：化合物(S)-5-(3-(环己基胺)-7-(3,5-二甲基异恶唑基-4-基)咪唑[1,2-a]吡啶-2-基)-1-(3,4-二氟苯基)吡咯烷-2-酮的合成
步骤1：(S)-5-氧代吡咯烷-2-甲醛的合成：
将L-焦谷氨醇(1g,8.69mmol)溶于30mL的二氯甲烷中，氮气置换三次，冰浴条件下加入戴斯马汀氧化剂(4.42g,10.42mmol)，室温反应2小时。反应完毕，旋干反应液，加入100mL水，乙酸乙酯萃取(1*100mL)，合并有机相，饱和氯化钠溶液洗涤(2*50mL)，收集有机相，无水硫酸钠干燥，浓缩，柱层析(二氯甲烷：甲醇＝20:1)得产物780mg，产率79.39％。
步骤2:(S)-5-(7-溴-3-(环己基胺)咪唑[1,2-a]吡啶-2-基)吡咯烷-2-酮的合成：
将4-溴吡啶-2-胺(400mg,2.31mmol)，(S)-5-氧代吡咯烷2-甲醛(313.82mg,2.77mmol)，环己基异腈(252.40mg,2.31mmol)，三氟甲磺酸钪(91.03mg,0.18mmol)溶于4mL的3:1的二氯甲烷和甲醇中，100℃反应4小时。反应完毕，冷却，旋干反应液，加入50mL水，乙酸乙酯萃取(1*50mL)，合并有机相，饱和氯化钠溶液洗涤(2*25mL)，收集有机相，无水硫酸钠干燥，浓缩，柱层析(二氯甲烷：甲醇＝30:1)得产物610mg，产率69.9％。1H NMR(400MHz,CDCl3)δ7.88(d,J＝7.1Hz,1H),7.65(s,1H),6.88(d,J＝7.2Hz,1H),6.33(s,1H),5.25–4.44(m,1H),2.83(s,1H),2.66–2.38(m,4H),1.79(m,6H),1.39–1.07(m,4H).
步骤3：(S)-5-(7-溴-3-(环己基胺)咪唑[1,2-a]吡啶-2-基)-1-(3,4-二氟苯基)吡咯烷-2-酮的合成：
将上步所得中间体(50mg,0.13mmol)，3,4-二氟苯硼酸(31.39mg,0.20mmol)，一水醋酸铜(26.46mg,0.13mmol)、吡啶(106.75μL)溶于5mL的二氯甲烷中，室温反应5小时。反应完毕，旋干反应液，加入50mL水，乙酸乙酯萃取(1*50mL)，合并有机相，饱和氯化钠溶液洗涤(2*25mL)，收集有机相，无水硫酸钠干燥，浓缩，柱层析(二氯甲烷：甲醇＝50:1)得产物20mg，产率30.84％。1H NMR(400MHz,CDCl3)δ7.82(d,J＝6.9Hz,1H),7.67(d,J＝37.4Hz,1H),7.17(d,J＝21.0Hz,1H),7.10–6.94(m,2H),6.87(d,J＝6.5Hz,1H),5.32(s,1H),2.98(s,1H),2.82–2.28(m,6H),1.62-1.41(m,2H),1.36-1.10(m,6H).
步骤4：(S)-5-(3-(环己基胺)-7-(3,5-二甲基异恶唑基-4-基)咪唑[1,2-a]吡啶-2-基)-1-(3,4-二氟苯基)吡咯烷-2-酮的合成：
将上步所得中间体、3,5-二甲基异恶唑频那醇酯(20mg,40.87μmol)，1,1'-双二苯基膦二茂铁二氯化钯(3.12mg,4μmol)、碳酸钾(11.30mg,81.74μmol)溶于4mL的N,N-二甲基甲酰胺中，向溶液中滴加少量水，氮气置换三次，100℃条件下反应过夜。反应完毕，冷却，加入25mL水，乙酸乙酯萃取(3*25mL)，合并有机相，饱和氯化钠溶液洗涤(2*20mL)，收集有机相，无水硫酸钠干燥，浓缩，柱层析(二氯甲烷：甲醇＝50:1)得产物11mg，收率53.24％。1HNMR(600MHz,CDCl3)δ8.05(d,J＝7.0Hz,1H),7.42(s,1H),7.39–7.34(m,1H),7.16(d,J＝9.0Hz,1H),7.05(dd,J＝18.5,9.1Hz,1H),6.75(d,J＝6.5Hz,1H),5.50–5.39(m,1H),3.04(ddd,J＝16.0,9.8,6.0Hz,1H),2.82(s,1H),2.75–2.57(m,3H),2.52–2.41(m,4H),2.35(s,3H),1.79(d,J＝18.1Hz,4H),1.31–1.15(m,6H).。
实施例3：(S)-1-(3,4-二氟苯基)-6-(1-(((1r，4S)-4-甲氧基环己基)-5-(1-甲基-3-(三氟甲基)-1H-吡唑-5-基)-1H-苯并[d]咪唑-2-基)哌啶-2-酮
合成方法如实施例1，白色固体。1H NMR(600MHz,MeOD)δ7.84(d,J＝1.4Hz,1H),7.82(d,J＝8.5Hz,1H),7.40(dd,J＝8.5,1.7Hz,1H),7.28(ddd,J＝11.3,7.3,2.4Hz,1H),7.19(dd,J＝19.1,8.9Hz,1H),7.10–7.05(m,1H),6.73(s,1H),5.74(t,J＝5.3Hz,1H),4.40(ddd,J＝12.3,8.4,4.1Hz,1H),3.96(s,3H),3.48–3.43(m,1H),3.43(d,J＝3.3Hz,3H),2.80(dt,J＝17.5,5.6Hz,1H),2.66(ddd,J＝17.9,8.2,6.5Hz,1H),2.54–2.47(m,1H),2.41(d,J＝10.3Hz,1H),2.28(dt,J＝16.1,11.0Hz,2H),2.25–2.19(m,2H),2.02–1.96(m,1H),1.92(d,J＝12.1Hz,1H),1.55–1.48(m,1H),1.43(ddd,J＝24.0,12.9,3.6Hz,1H),1.27(s,1H).13C NMR(150MHz,MeOD)δ171.53,153.60,145.04,141.78,132.85,123.86,122.76,118.89,116.84,116.72,116.45,116.33,112.67,103.28,77.13,56.43,54.61,54.30,36.38,31.19,29.88,29.72,28.27,27.90,27.84,16.87.。
实施例4：(R)-1-(3,4-二氟苯基)-5-(5-(3,5-二甲基异恶唑-4-基)-1-((1r，4R)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)-5-甲基吡咯烷-2-酮
合成方法如实施例1，白色固体。1H NMR(600MHz,MeOD)δ7.75(d,J＝8.5Hz,1H),7.55(d,J＝1.3Hz,1H),7.29(ddd,J＝12.5,7.3,2.5Hz,1H),7.17(dd,J＝8.5,1.6Hz,1H),7.05(dd,J＝19.2,9.1Hz,1H),6.74(d,J＝8.7Hz,1H),4.30(ddd,J＝12.3,8.5,3.8Hz,1H),3.36(ddd,J＝15.1,10.9,4.1Hz,1H),3.32–3.27(m,3H),2.86(ddd,J＝17.7,10.2,7.3Hz,1H),2.73–2.65(m,1H),2.53–2.36(m,4H),2.36–2.28(m,3H),2.23(dd,J＝12.5,3.5Hz,1H),2.17(d,J＝5.6Hz,3H),2.11(dd,J＝9.5,3.2Hz,1H),2.02–1.96(m,1H),1.86(s,3H),1.41(d,J＝13.1Hz,1H),1.32(ddd,J＝24.2,13.1,3.8Hz,1H),1.17(dd,J＝13.3,9.9Hz,1H).13C NMR(150MHz,MeOD)δ174.97,164.72,158.13,154.67,141.39,133.32,123.71,119.50,116.41,116.26,116.18,115.96,112.97,76.98,65.20,56.18,54.28,32.01,30.50,30.21,29.11,27.43,27.27,24.42,9.36,8.68.。
实施例5：(R)-5-(1-(4,4-二氟环己基)-5-(3,5-二甲基异恶唑-4-基)-1H-苯并[d]咪唑-2-基)-1-(3,4)–二氟苯基)-5-甲基吡咯烷酮-2-酮
合成方法如实施例1，白色固体。1H NMR(600MHz,MeOD)δ7.73(d,J＝8.5Hz,1H),7.69(s,1H),7.47(ddd,J＝12.4,7.3,2.5Hz,1H),7.32(dd,J＝8.5,1.4Hz,1H),7.19(dd,J＝19.1,9.2Hz,1H),6.95(d,J＝9.0Hz,1H),4.61(d,J＝12.1Hz,1H),3.10-2.79(m,6H),2.66–2.52(m,3H),2.45(s,3H),2.31(s,1H),2.29(s,3H),2.24–2.13(m,3H),1.98(s,3H),1.60(d,J＝13.2Hz,1H),0.92–0.88(m,1H).13C NMR(150MHz,MeOD)δ175.12,164.95,158.21,154.56,141.39,133.16,123.88,119.69,116.29,114.32,112.59,65.33,54.12,32.37,31.63,29.08,25.46,25.26,24.13,9.35,8.66.。
实施例6：(R)-1-(1,2-二氢苊-5-基)-5-(5-(3,5-二甲基异恶唑-4-基)-1-((1r,4R)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)-5-甲基吡咯烷酮-2-酮
合成方法如实施例1，白色固体。1H NMR(600MHz,MeOD)δ7.84(d,J＝8.4Hz,1H),7.52(s,1H),7.48–7.43(m,1H),7.37(d,J＝8.3Hz,1H),7.26(d,J＝6.6Hz,1H),7.22(d,J＝8.3Hz,1H),6.89(d,J＝6.8Hz,1H),6.52–6.44(m,1H),4.39(s,1H),3.41(s,1H),3.28(d,J＝31.3Hz,3H),3.17–3.11(m,1H),2.85-2.53(m,7H),2.34(s,3H),2.24(d,J＝9.7Hz,1H),2.19(s,3H),2.12(d,J＝11.5Hz,1H),1.98(s,1H),1.64(s,3H),1.27(dd,J＝25.2,12.0Hz,3H),0.80(d,J＝6.7Hz,2H).13C NMR(150MHz,MeOD)δ175.19,164.89,158.08,155.50,146.77,145.99,141.29,139.47,128.62,127.82,125.49,123.68,119.42,118.97,118.32,117.57,116.00,113.12,77.02,65.81,56.14,54.25,30.66,30.28,29.39,29.19,28.79,27.58,27.07,9.39,8.71.。
实施例7：(S)-1-(3,4-二氟苯基)-6-(5-(3,5-二甲基吡唑-4-基)-1-((1r，4S)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)哌啶-2-酮
合成方法如实施例1，白色固体。1H NMR(600MHz,MeOD)δ7.74(d,J＝8.5Hz,1H),7.64–7.59(m,1H),7.27(ddd,J＝11.4,7.2,2.4Hz,1H),7.21–7.19(m,1H),7.17(dd,J＝10.3,8.8Hz,1H),7.08–7.00(m,1H),5.71(t,J＝5.4Hz,1H),4.43–4.28(m,2H),3.46–3.41(m,1H),3.41(s,2H),2.79(dt,J＝17.7,5.8Hz,1H),2.64(ddd,J＝17.9,8.2,6.5Hz,1H),2.53–2.44(m,1H),2.42(s,2H),2.41–2.35(m,1H),2.31–2.28(m,1H),2.26(s,2H),2.26–2.23(m,1H),2.24–2.15(m,3H),2.03–1.95(m,1H),1.90(d,J＝12.6Hz,1H),1.49(ddd,J＝24.3,13.0,3.8Hz,1H),1.45–1.36(m,1H),1.30–1.19(m,2H).13C NMR(150MHz,MeOD)δ171.65,164.94,158.51,152.76,142.33,131.55,123.83,123.70,123.24,118.82,116.84,116.72,116.45,116.28,116.02,112.53,77.17,56.39,54.52,54.29,31.66,31.22,29.89,29.74,28.35,27.86,16.93,9.35,8.67.。
实施例8：(S)-6-(5-乙酰基-1-(((1r，4S)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)-1-(3,4-二氟苯基)哌啶-2–酮
合成方法如实施例1，白色固体。1H NMR(600MHz,MeOD)δ8.38(d,J＝1.4Hz,1H),7.94(dd,J＝8.7,1.6Hz,1H),7.76(d,J＝8.7Hz,1H),7.28(ddd,J＝11.3,7.3,2.4Hz,1H),7.18(dd,J＝19.1,8.9Hz,1H),7.09–7.03(m,1H),5.73(t,J＝5.3Hz,1H),4.38(ddd,J＝16.4,8.2,4.0Hz,1H),3.48–3.43(m,1H),3.42(d,J＝6.3Hz,3H),2.81(dt,J＝18.0,5.9Hz,1H),2.69(s,3H),2.68–2.62(m,1H),2.54–2.47(m,1H),2.38(d,J＝11.8Hz,1H),2.29–2.16(m,5H),2.02–1.96(m,1H),1.90(d,J＝12.5Hz,1H),1.50(ddd,J＝24.2,13.0,3.8Hz,1H),1.42(ddd,J＝24.3,12.9,3.8Hz,1H),1.27(s,1H).13C NMR(150MHz,MeOD)δ198.05,171.54,154.25,141.34,137.62,137.60,135.95,131.21,123.87,121.97,119.71,116.87,116.74,116.44,116.31,112.04,77.08,56.48,54.67,54.29,31.17,29.86,29.70,28.18,27.87,27.79,24.70,16.84.。
实施例9：(S)-1-(3,4-二氟苯基)-6-(1-(((1r，4S)-4-甲氧基环己基)-5-(1-甲基-1H-吡唑-5-基)-1H-苯并[d]咪唑-2-基)哌啶-2-酮
合成方法如实施例1，白色固体。1H NMR(600MHz,MeOD)δ7.67(dd,J＝5.0,3.1Hz,2H),7.41(dd,J＝5.9,1.9Hz,1H),7.25(dd,J＝8.6,1.6Hz,1H),7.17(ddd,J＝11.4,7.3,2.4Hz,1H),7.07(dd,J＝19.1,8.8Hz,1H),6.98–6.92(m,1H),6.29(d,J＝1.9Hz,1H),5.62(t,J＝5.4Hz,1H),4.27(ddd,J＝12.4,8.3,4.1Hz,1H),3.79(d,J＝3.7Hz,3H),3.33(dd,J＝10.4,5.0Hz,1H),3.30(d,J＝4.8Hz,3H),2.69(dt,J＝17.7,5.8Hz,1H),2.59–2.51(m,2H),2.43–2.35(m,1H),2.29(d,J＝13.1Hz,1H),2.18–2.06(m,5H),1.90–1.85(m,1H),1.80(d,J＝12.4Hz,1H),1.40(ddd,J＝23.6,12.7,3.5Hz,1H),1.34–1.28(m,1H),1.13(s,1H).13C NMR(150MHz,MeOD)δ171.47,153.17,143.48,141.73,137.22,132.43,124.00,123.82,122.73,118.48,116.95,116.61,116.51,116.23,112.52,104.96,77.14,56.41,54.57,54.29,35.50,31.21,29.88,29.73,28.31,27.85,16.92.。
实施例10：(R)-1-(3,4-二氟苯基)-5-(5-(1,4-二甲基-1H-吡唑-5-基)-1-((1r，4R)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)-5-甲基吡咯烷酮-2--酮
合成方法如实施例1，白色固体。1H NMR(600MHz,MeOD)δ7.68(d,J＝8.5Hz,1H),7.52(t,J＝4.0Hz,1H),7.27(ddd,J＝11.4,7.3,2.4Hz,1H),7.17(dd,J＝19.1,8.9Hz,1H),7.14(dd,J＝8.5,1.6Hz,1H),7.04(d,J＝8.9Hz,1H),5.70(t,J＝5.5Hz,1H),4.37–4.32(m,1H),3.81–3.72(m,3H),3.42(t,J＝5.0Hz,1H),3.42–3.38(m,3H),2.80(dt,J＝17.2,5.6Hz,1H),2.66–2.61(m,1H),2.49–2.44(m,1H),2.41–2.36(m,1H),2.27(d,J＝5.9Hz,1H),2.26(s,3H),2.22(dd,J＝11.0,5.5Hz,1H),2.19(s,3H),2.17(d,J＝3.0Hz,1H),2.00–1.95(m,1H),1.89(d,J＝11.1Hz,1H),1.54–1.35(m,4H),1.21(s,1H).13C NMR(150MHz,MeOD)δ167.75,147.62,133.95,133.46,130.48,126.74,125.66,116.87,116.39,113.06,109.29,109.16,106.66,105.93,69.85,58.13,49.12,47.16,28.18,24.98,23.37,23.09,21.99,20.31,20.16,17.27.。
实施例11：(R)-1-(3,4-二氟苯基)-5-(5-(1,4-二甲基-1H-1,2,3-三唑-5-基)-1-((1r，4R)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)-5-甲基吡咯烷-2-酮
合成方法如实施例1，白色固体，收率77.8％。1H NMR(600MHz,MeOD)δ7.96(d,J＝8.5Hz,1H),7.79(d,J＝1.3Hz,1H),7.44(ddd,J＝12.5,7.3,2.5Hz,1H),7.36(dd,J＝8.5,1.6Hz,1H),7.18(dd,J＝19.2,9.1Hz,1H),6.91(d,J＝8.4Hz,1H),4.48–4.43(m,1H),4.01(s,3H),3.51–3.47(m,1H),3.47–3.41(m,3H),2.98–2.94(m,1H),2.80(dd,J＝9.7,5.9Hz,1H),2.65–2.61(m,1H),2.54(ddd,J＝22.9,12.6,7.3Hz,2H),2.35(d,J＝12.6Hz,1H),2.33(d,J＝12.1Hz,3H),2.24(d,J＝12.5Hz,1H),2.12(d,J＝13.3Hz,1H),1.98(s,3H),1.56(d,J＝12.7Hz,1H),1.46(dd,J＝16.9,7.5Hz,1H),1.38–1.30(m,2H).13C NMR(150MHz,MeOD)δ166.49,146.82,132.94,131.57,126.10,125.79,114.93,111.59,107.85,107.62,104.94,68.43,56.77,47.77,45.77,25.47,23.63,21.94,21.68,20.58,18.91,18.75,15.82.。
实施例12：(R)-5-(5-(3,5-二甲基异恶唑-4-基)-1-((1r，4R)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)-1-(4-甲氧基苯基)-5-甲基吡咯烷酮-2-酮
合成方法如实施例1，白色固体。1H NMR(600MHz,MeOD)δ7.77(d,J＝8.5Hz,1H),7.52(d,J＝1.3Hz,1H),7.18(dd,J＝8.5,1.6Hz,1H),6.83(d,J＝9.0Hz,2H),6.73–6.69(m,2H),4.32(ddd,J＝12.3,8.5,3.9Hz,1H),3.63–3.59(m,3H),3.37(td,J＝10.9,5.5Hz,1H),3.33–3.29(m,3H),2.93–2.88(m,1H),2.76–2.71(m,1H),2.57–2.53(m,1H),2.49–2.39(m,3H),2.33(d,J＝6.4Hz,3H),2.26–2.23(m,1H),2.18(d,J＝11.2Hz,3H),2.12(dd,J＝9.6,3.3Hz,1H),1.99(d,J＝13.2Hz,1H),1.81(s,3H),1.62(d,J＝13.1Hz,1H),1.34–1.27(m,1H),1.22–1.15(m,1H).13C NMR(150MHz,MeOD)δ174.90,164.91,158.20,157.89,155.02,141.21,133.03,128.34,125.89,123.69,123.64,119.32,115.97,113.18,77.01,64.97,56.12,54.26,53.81,31.23,30.68,30.32,29.19,27.51,27.13,25.20,9.37,8.70.。
实施例13：(S)-1-(3,4-二氟苯基)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((1r，4S)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)氮杂环丁烷-2-酮
合成方法如实施例1，白色固体。1H NMR(600MHz,MeOD)δ7.88(d,J＝8.5Hz,1H),7.54(d,J＝1.3Hz,1H),7.44(ddd,J＝11.7,7.0,2.5Hz,1H),7.27(dd,J＝8.5,1.5Hz,1H),7.23(dd,J＝19.0,8.9Hz,1H),6.99(d,J＝9.0Hz,1H),5.78(dd,J＝5.8,2.6Hz,1H),4.59(ddd,J＝12.3,8.3,4.0Hz,1H),3.80(dd,J＝15.0,5.8Hz,1H),3.55–3.50(m,1H),3.45(d,J＝10.5Hz,3H),3.22(dd,J＝15.0,2.6Hz,1H),2.55–2.45(m,2H),2.45–2.38(m,3H),2.35(ddd,J＝19.5,12.8,3.3Hz,2H),2.29–2.22(m,3H),2.22(dd,J＝13.0,3.2Hz,1H),1.98(d,J＝12.9Hz,1H),1.61–1.52(m,2H).13C NMR(150MHz,MeOD)δ164.87,163.28,158.18,150.76,142.00,132.86,123.84,123.54,118.99,116.63,115.98,112.25,111.95,106.02,105.88,77.23,55.17,54.31,43.57,30.07,28.24,9.29,8.61.。
实施例14：(S)-1-(3,4-二氟苯基)-6-(5-(1,5-二甲基-1H-吡唑-4-基)-1-((1r，4S)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)哌啶-2-酮
合成方法如实施例1，白色固体。1H NMR(600MHz,MeOD)δ7.75(d,J＝8.6Hz,1H),7.69(d,J＝1.3Hz,1H),7.60(s,1H),7.36(dd,J＝8.6,1.5Hz,1H),7.30(ddd,J＝11.2,7.2,2.4Hz,1H),7.20(dd,J＝19.0,8.9Hz,1H),7.08–7.04(m,1H),5.79(t,J＝5.6Hz,1H),4.41(ddd,J＝12.3,8.4,4.1Hz,1H),3.88(s,3H),3.48–3.44(m,1H),3.42(d,J＝3.6Hz,3H),2.82(dt,J＝17.9,6.2Hz,1H),2.67(dt,J＝13.8,6.4Hz,1H),2.55–2.48(m,1H),2.45(s,3H),2.41(d,J＝12.6Hz,1H),2.28(dt,J＝10.5,5.4Hz,2H),2.20(dd,J＝9.6,3.2Hz,2H),2.08–2.00(m,1H),1.93(d,J＝12.4Hz,1H),1.51(ddd,J＝24.3,13.1,3.8Hz,1H),1.42(ddd,J＝24.3,13.0,3.8Hz,1H),1.24(d,J＝3.4Hz,1H).13C NMR(150MHz,MeOD)δ171.40,151.88,150.73,139.98,137.32,135.93,135.33,130.37,128.56,123.82,123.03,116.78,116.66,116.59,116.47,115.87,112.67,77.07,56.23,54.91,54.30,34.48,31.28,29.83,29.69,28.38,27.84,27.81,17.15,8.23.。
实施例15：(R)-5-(5-(3,5-二甲基异恶唑-4-基)-1-((1r，4R)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)-5-甲基-1-(3-(三氟甲氧基)苯基)吡咯烷-2-酮
合成方法如实施例1，白色固体。1H NMR(600MHz,MeOD)δ7.83(d,J＝8.5Hz,1H),7.83(d,J＝8.5Hz,1H),7.64(d,J＝1.4Hz,1H),7.64(d,J＝1.4Hz,1H),7.34(t,J＝8.3Hz,1H),7.34(t,J＝8.3Hz,1H),7.27(dd,J＝8.5,1.6Hz,1H),7.27(dd,J＝8.5,1.6Hz,1H),7.25–7.19(m,2H),7.25–7.20(m,2H),7.07(d,J＝8.2Hz,2H),7.07(d,J＝8.2Hz,1H),4.39(d,J＝12.4Hz,1H),3.46–3.42(m,1H),3.39(s,3H),3.02(dd,J＝18.0,8.8Hz,1H),2.89–2.83(m,1H),2.63–2.58(m,1H),2.55–2.49(m,2H),2.42(s,3H),2.39–2.29(m,2H),2.27(s,3H),2.11(dd,J＝33.0,13.1Hz,2H),2.03(s,3H),1.43–1.37(m,1H),1.28(d,J＝11.2Hz,1H),1.22(d,J＝14.5Hz,1H).13C NMR(150MHz,MeOD)δ174.63,164.91,158.08,154.14,148.51,141.13,137.76,133.08,129.24,123.82,123.80,121.25,119.31,117.55,115.93,115.60,113.07,76.94,65.16,56.27,54.26,31.96,30.52,30.24,29.22,27.43,27.14,24.38,9.29,8.61.。
实施例16：(S)-1-(3,4-二氟苯基)-6-(1-(((1r，4S)-4-甲氧基环己基)-5-(2-甲基-2H-1,2,3-三唑-4-基)-1H-苯并[d]咪唑-2-基)哌啶-2-酮
合成方法如实施例1，白色固体。1H NMR(600MHz,MeOD)δ8.11(d,J＝1.0Hz,1H),8.11(d,J＝1.0Hz,1H),8.01(s,1H),8.01(s,1H),7.72(dd,J＝8.6,1.5Hz,1H),7.69(d,J＝8.6Hz,1H),7.26(ddd,J＝11.3,7.3,2.4Hz,1H),7.26(ddd,J＝11.3,7.3,2.4Hz,1H),7.15(dd,J＝19.1,8.9Hz,1H),7.15(dd,J＝19.1,8.9Hz,1H),7.03(dd,J＝5.7,3.2Hz,1H),7.03(dd,J＝5.7,3.2Hz,1H),5.68(t,J＝5.5Hz,1H),5.68(t,J＝5.5Hz,2H),4.33(tt,J＝12.3,4.0Hz,1H),4.22(s,3H),3.42(dd,J＝11.0,4.2Hz,1H),3.40(s,3H),2.80(dt,J＝17.9,6.1Hz,1H),2.66–2.60(m,1H),2.49–2.44(m,1H),2.37(d,J＝12.4Hz,1H),2.27–2.15(m,5H),2.00–1.96(m,1H),1.88(d,J＝12.2Hz,1H),1.52–1.46(m,1H),1.41–1.36(m,1H),1.18(s,1H).13C NMR(150MHz,MeOD)δ171.54,152.72,147.43,141.98,137.42,132.29,129.86,124.38,123.86,120.25,120.11,116.88,116.76,116.43,116.31,115.24,112.51,77.16,56.38,54.50,54.29,39.80,31.27,29.89,29.74,28.38,27.86,17.03.。
实施例17：(S)-1-(3,4-二氟苯基)-6-(1-(((1r，4S)-4-甲氧基环己基)-5-(1,3,5-三甲基-1H-吡唑-4-基)-1H-苯并[d]咪唑-2-基)哌啶-2-酮
合成方法如实施例1，白色固体。1H NMR(600MHz,MeOD)δ7.68(d,J＝8.5Hz,1H),7.52(t,J＝4.0Hz,1H),7.27(ddd,J＝11.4,7.3,2.4Hz,1H),7.17(dd,J＝19.1,8.9Hz,1H),7.14(dd,J＝8.5,1.6Hz,1H),7.04(d,J＝8.9Hz,1H),5.70(t,J＝5.5Hz,1H),4.37–4.32(m,1H),3.81–3.72(m,3H),3.42(t,J＝5.0Hz,1H),3.42–3.38(m,3H),2.80(dt,J＝17.2,5.6Hz,1H),2.66–2.61(m,1H),2.49–2.44(m,1H),2.41–2.36(m,1H),2.27(d,J＝5.9Hz,1H),2.26(s,3H),2.22(dd,J＝11.0,5.5Hz,1H),2.19(s,3H),2.17(d,J＝3.0Hz,1H),2.00–1.95(m,1H),1.89(d,J＝11.1Hz,1H),1.54–1.35(m,4H),1.21(s,1H).13C NMR(150MHz,MeOD)δ171.60,152.20,143.88,141.73,136.27,127.55,124.07,123.90,118.82,118.33,116.92,116.75,116.50,116.28,111.90,77.21,56.35,54.45,54.28,33.92,31.24,29.90,29.77,28.42,27.88,16.99,10.25,8.05.。
实施例18：(R)-1-(4-氯-3-(三氟甲基)苯基)-5-(5-(3,5-二甲基异恶唑-4-基)-1-((1r，4R)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)-5-甲基吡咯烷酮-2-酮
合成方法如实施例1，白色固体。1H NMR(600MHz,MeOD)δ7.75(d,J＝8.5Hz,1H),7.55(d,J＝1.3Hz,1H),7.29(ddd,J＝12.5,7.3,2.5Hz,1H),7.17(dd,J＝8.5,1.6Hz,1H),7.05(dd,J＝19.2,9.1Hz,1H),6.74(d,J＝8.7Hz,1H),4.30(ddd,J＝12.3,8.5,3.8Hz,1H),3.36(ddd,J＝15.1,10.9,4.1Hz,1H),3.32–3.27(m,3H),2.86(ddd,J＝17.7,10.2,7.3Hz,1H),2.73–2.65(m,1H),2.53–2.36(m,4H),2.36–2.28(m,3H),2.23(dd,J＝12.5,3.5Hz,1H),2.17(d,J＝5.6Hz,3H),2.11(dd,J＝9.5,3.2Hz,1H),2.02–1.96(m,1H),1.86(s,3H),1.41(d,J＝13.1Hz,1H),1.32(ddd,J＝24.2,13.1,3.8Hz,1H),1.17(dd,J＝13.3,9.9Hz,1H).13C NMR(150MHz,CD3CN)δ174.30,164.69,158.31,154.51,141.87,136.09,133.48,131.24,128.85,123.49,123.26,119.69,115.93,113.09,76.79,65.25,55.96,54.52,32.76,30.28,30.17,29.29,27.51,27.38,24.47,10.12,9.35.。
实施例19：(S)-1-(3,4-二氟苯基)-6-(5-(1,3-二甲基-1H-吡唑-5-基)-1-((1r，4S)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)哌啶-2-酮
合成方法如实施例1，白色固体。1H NMR(600MHz,MeOD)δ7.75(d,J＝8.5Hz,1H),7.55(d,J＝1.3Hz,1H),7.29(ddd,J＝12.5,7.3,2.5Hz,1H),7.17(dd,J＝8.5,1.6Hz,1H),7.05(dd,J＝19.2,9.1Hz,1H),6.74(d,J＝8.7Hz,1H),6.20(s,1H),4.30(ddd,J＝12.3,8.5,3.8Hz,1H),3.36(ddd,J＝15.1,10.9,4.1Hz,1H),3.32–3.27(m,3H),2.86(ddd,J＝17.7,10.2,7.3Hz,1H),2.73–2.65(m,1H),2.53–2.36(m,4H),2.36–2.28(m,3H),2.23(dd,J＝12.5,3.5Hz,1H),2.17(d,J＝5.6Hz,3H),2.11(dd,J＝9.5,3.2Hz,1H),2.02–1.96(m,1H),1.86(s,3H),1.41(d,J＝13.1Hz,1H),1.32(ddd,J＝24.2,13.1,3.8Hz,1H),1.17(dd,J＝13.3,9.9Hz,1H).13C NMR(150MHz,MeOD)δ171.47,153.27,146.72,144.28,141.69,132.39,124.23,123.85,122.72,118.42,116.86,116.76,116.49,116.33,112.36,104.63,77.14,56.40,54.56,54.29,35.10,31.21,29.88,29.73,28.31,27.85,16.92,11.15.。
实施例20：(R)-1-(3,4-二氟苯基)-5-(1-((1r,4R)-4-甲氧基环己基)-5-(3-甲基异噻唑-4-基)-1H-苯并[d]咪唑-2-基)-5-甲基吡咯烷-2-酮
合成方法如实施例1，白色固体。1H NMR(600MHz,MeOD)1H NMR(600MHz,MeOD)δ7.75(d,J＝8.5Hz,1H),7.54(d,J＝1.4Hz,1H),7.29(ddd,J＝12.5,7.3,2.5Hz,1H),7.17(dd,J＝8.5,1.7Hz,1H),7.05(dd,J＝19.2,9.1Hz,1H),6.74(d,J＝8.5Hz,1H),4.30(tt,J＝12.3,3.7Hz,1H),3.35(ddd,J＝11.2,7.8,4.4Hz,1H),3.30(s,3H),2.86(ddd,J＝17.7,10.2,7.2Hz,1H),2.72–2.65(m,1H),2.56–2.37(m,4H),2.36–2.29(m,3H),2.27–2.21(m,1H),2.17(s,3H),2.14–2.08(m,1H),2.02–1.96(m,1H),1.86(s,3H),1.41(d,J＝12.8Hz,1H),1.35–1.28(m,1H),1.21–1.13(m,1H).13C NMR(150MHz,MeOD)δ174.80,164.85,158.09,154.48,141.35,133.18,123.71,119.43,116.34,116.21,115.96,113.08,76.98,65.20,56.18,54.28,32.01,30.50,30.21,29.11,27.43,27.27,24.42,9.36,8.68.。
实施例21：(R)-1-(3,4-二氯苯基)-5-(5-(3,5-二甲基异恶唑-4-基)-1-((1r，4R)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)-5-甲基吡咯烷-2-酮
合成方法如实施例1，白色固体。1H NMR(600MHz,CD3CN)δ7.75(d,J＝8.5Hz,1H),7.73(d,J＝2.5Hz,1H),7.64(d,J＝1.4Hz,1H),7.38(d,J＝8.9Hz,1H),7.24–7.20(m,2H),4.40–4.38(m,1H),3.41–3.38(m,1H),3.35(s,3H),2.78–2.74(m,1H),2.68–2.65(m,1H),2.55–2.52(m,1H),2.45(d,J＝4.5Hz,1H),2.42(s,3H),2.38–2.35(m,1H),2.27(s,3H),2.13(s,3H),2.08–2.07(m,1H),2.05(s,1H),1.76(d,J＝5.6Hz,1H),1.56(s,1H),1.43–1.40(m,1H),1.37–1.34(m,2H).13C NMR(150MHz,CD3CN)δ174.28,165.23,158.51,154.52,141.66,136.55,133.55,129.52,127.86,125.44,123.48,119.75,76.80,55.95,54.52,32.90,30.39,30.25,29.94,29.29,27.51,24.47,22.02,21.60,12.72,10.17,9.40,5.46.。
实施例22：4-((R)-2-(5-(3,5-二甲基异恶唑-4-基)-1-((1r，4R)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)-2-甲基-5-氧吡咯烷-1-基)苄腈
合成方法如实施例1，白色固体。1H NMR(600MHz,MeOD)1H NMR(600MHz,MeOD)δ7.75(d,J＝8.5Hz,1H),7.54(d,J＝1.4Hz,1H),7.29(ddd,J＝12.5,7.3,2.5Hz,1H),7.17(dd,J＝8.5,1.7Hz,1H),7.05(dd,J＝19.2,9.1Hz,1H),6.74(d,J＝8.5Hz,1H),4.30(tt,J＝12.3,3.7Hz,1H),3.35(ddd,J＝11.2,7.8,4.4Hz,1H),3.30(s,3H),2.86(ddd,J＝17.7,10.2,7.2Hz,1H),2.72–2.65(m,1H),2.56–2.37(m,4H),2.36–2.29(m,3H),2.27–2.21(m,1H),2.17(s,3H),2.14–2.08(m,1H),2.02–1.96(m,1H),1.86(s,3H),1.41(d,J＝12.8Hz,1H),1.35–1.28(m,1H),1.21–1.13(m,1H).13C NMR(150MHz,MeOD)δ174.69,164.86,158.13,154.09,141.43,140.61,133.17,131.95,123.74,122.86,119.45,117.11,115.95,113.08,108.05,76.96,65.26,56.28,54.27,32.47,30.48,30.20,29.26,27.39,27.35,24.19,9.36,8.68.。
实施例23：(R)-1-(3,4-二氟苯基)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((1r，4S)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)氮杂环丁烷-2-酮
合成方法如实施例1，白色固体。1H NMR(600MHz,MeOD)δ7.87(d,J＝8.5Hz,1H),7.54(d,J＝1.3Hz,1H),7.44(ddd,J＝11.7,7.0,2.5Hz,1H),7.28(dd,J＝8.5,1.5Hz,1H),7.23(dd,J＝19.0,8.9Hz,1H),6.99(d,J＝9.0Hz,1H),5.78(dd,J＝5.8,2.6Hz,1H),4.59(ddd,J＝12.3,8.3,4.0Hz,1H),3.80(dd,J＝15.0,5.8Hz,1H),3.55–3.50(m,1H),3.44(d,J＝10.5Hz,3H),3.21(dd,J＝15.0,2.6Hz,1H),2.55–2.45(m,2H),2.43–2.37(m,3H),2.35(ddd,J＝19.5,12.8,3.3Hz,2H),2.29–2.22(m,3H),2.22(dd,J＝13.0,3.2Hz,1H),1.98(d,J＝12.9Hz,1H),1.61–1.52(m,2H).13C NMR(150MHz,MeOD)δ164.87,163.28,158.22,150.76,142.00,132.86,123.84,123.54,118.99,116.60,115.98,112.25,111.95,106.02,105.86,77.23,55.23,54.31,43.57,30.07,28.24,9.31,8.61.。
实施例24：(R)-5-(5-(3,5-二甲基异恶唑-4-基)-1-((1r，4R)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)-1-(4-甲氧基-3-甲基苯基)-5-甲基吡咯烷-2-酮
合成方法如实施例1，白色固体。1H NMR(600MHz,MeOD)δ7.88(d,J＝8.5Hz,1H),7.88(d,J＝8.5Hz,2H),7.64(d,J＝1.4Hz,1H),7.64(d,J＝1.4Hz,2H),7.29(dd,J＝8.5,1.5Hz,1H),7.29(dd,J＝8.5,1.5Hz,2H),6.93(d,J＝2.3Hz,2H),6.93(d,J＝2.3Hz,1H),6.74(d,J＝8.8Hz,1H),6.74(d,J＝8.8Hz,2H),6.64(d,J＝6.9Hz,1H),6.64(d,J＝6.9Hz,2H),4.42(ddd,J＝12.3,8.5,3.9Hz,1H),3.75(s,3H),3.53–3.46(m,1H),3.43(d,J＝15.1Hz,3H),3.06–3.00(m,1H),2.86(ddd,J＝17.0,9.8,4.0Hz,1H),2.68–2.56(m,2H),2.51(ddd,J＝14.4,9.4,3.9Hz,2H),2.46(d,J＝10.3Hz,3H),2.35(d,J＝13.0Hz,1H),2.30(s,3H),2.23(d,J＝12.8Hz,1H),2.09(d,J＝13.3Hz,1H),2.05(d,J＝10.4Hz,3H),1.93(s,3H),1.70(d,J＝13.0Hz,1H),1.41(dt,J＝13.1,9.5Hz,1H),1.29(dt,J＝12.8,9.3Hz,1H).13C NMR(150MHz,MeOD)δ174.79,164.87,158.18,155.96,154.95,141.28,133.08,127.84,127.33,126.25,123.68,123.62,122.63,119.27,116.05,113.06,108.96,77.01,65.02,56.10,54.26,53.87,31.26,30.67,30.32,29.21,27.51,27.12,25.28,14.27,9.37,8.68.。
实施例25：(R)-1-(3,4-二氟苯基)-5-(5-(3,5-二甲基异恶唑-4-基)-1-(1-(甲基磺酰基)哌啶-4-基)-1H-苯并[d]咪唑-2-基)-5-甲基吡咯烷-2-酮
合成方法如实施例1，白色固体。1H NMR(600MHz,MeOD)δ7.75(d,J＝8.5Hz,1H),7.55(d,J＝1.3Hz,1H),7.29(ddd,J＝12.5,7.3,2.5Hz,1H),7.17(dd,J＝8.5,1.6Hz,1H),7.05(dd,J＝19.2,9.1Hz,1H),6.74(d,J＝8.7Hz,1H),4.30(ddd,J＝12.3,8.5,3.8Hz,1H),3.36(ddd,J＝15.1,10.9,4.1Hz,1H),3.32–3.27(m,3H),2.86(ddd,J＝17.7,10.2,7.3Hz,1H),2.73–2.65(m,1H),2.53–2.36(m,4H),2.36–2.28(m,3H),2.23(dd,J＝12.5,3.5Hz,1H),2.17(d,J＝5.6Hz,3H),2.11(dd,J＝9.5,3.2Hz,1H),2.02–1.96(m,1H),1.86(s,3H),1.41(d,J＝13.1Hz,1H),1.32(ddd,J＝24.2,13.1,3.8Hz,1H),1.17(dd,J＝13.3,9.9Hz,1H).13C NMR(150MHz,MeOD)δ174.97,164.72,158.13,154.67,141.39,133.32,123.71,119.50,116.41,116.26,116.18,115.96,112.97,76.98,65.20,56.18,54.28,32.01,30.50,30.21,29.11,27.43,27.27,24.42,9.36,8.68.。
实施例26：(S)-1-(3,4-二氟苯基)-6-(1-(((1r，4S)-4-甲氧基环己基)-5-(甲基磺酰基)-1H-苯并[d]咪唑-2-基)哌啶-2-酮
合成方法如实施例1，白色固体，收率69.2％。1H NMR(600MHz,MeOD)δ8.30(d,J＝1.6Hz,1H),7.93(d,J＝8.8Hz,1H),7.83(dd,J＝8.7,1.8Hz,1H),7.29(dd,J＝13.0,5.6Hz,1H),7.18(dd,J＝19.1,8.9Hz,1H),7.18(dd,J＝19.1,8.9Hz,1H),7.07(d,J＝8.8Hz,1H),5.78–5.75(m,1H),4.42(s,1H),3.45(dd,J＝9.2,4.9Hz,1H),3.42(s,3H),3.42(s,3H),3.17(s,3H),3.17(s,3H),2.83–2.77(m,2H),2.70–2.63(m,2H),2.52(s,2H),2.40–2.36(m,1H),2.28(d,J＝12.3Hz,1H),2.20(d,J＝12.7Hz,3H),1.99–1.96(m,1H),1.93(s,1H),1.47(dd,J＝18.5,12.8Hz,2H).13C NMR(150MHz,MeOD)δ171.56,155.26,141.34,134.22,123.93,118.51,116.65,113.12,77.01,56.54,54.85,54.30,42.85,31.12,29.83,29.68,28.08,27.86,27.73,16.73.。
实施例27：(S)-1-(3,4-二氟苯基)-6-(5-(1,3-二甲基-1H-吡唑-4-基)-1-((1r，4S)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)哌啶-2-酮
合成方法如实施例1，白色固体。1H NMR(600MHz,CD3CN)δ7.69(d,J＝1.4Hz,1H),7.63(s,1H),7.59(d,J＝8.5Hz,1H),7.28(dd,J＝8.5,1.7Hz,1H),7.22–7.17(m,1H),7.16(dd,J＝17.2,6.7Hz,1H),7.05–7.01(m,1H),5.46–5.41(m,1H),4.19(dd,J＝10.1,6.2Hz,1H),3.84(s,3H),3.36(dd,J＝9.4,5.0Hz,1H),3.35(s,2H),2.67–2.53(m,3H),2.48–2.41(m,2H),2.37(s,3H),2.31(d,J＝12.1Hz,1H),2.20(dd,J＝12.5,3.4Hz,2H),2.13(d,J＝0.9Hz,3H),2.08(dd,J＝5.0,2.5Hz,1H),1.90–1.83(m,2H),1.45–1.39(m,1H),1.38–1.29(m,3H).13C NMR(150MHz,CD3CN)δ169.81,152.68,144.14,142.98,131.36,128.62,127.19,126.68,123.98,121.45,120.17,112.04,76.87,56.63,54.48,54.18,37.33,31.46,30.12,29.95,28.11,28.02,27.93,16.94,11.87.。
实施例28：(S)-1-(3,4-二氟苯基)-6-(5-(1,4-二甲基-1H-吡唑-5-基)-1-((1r，4S)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)哌啶-2-酮
合成方法如实施例1，白色固体。1H NMR(600MHz,MeOD)δ7.68(d,J＝8.5Hz,1H),7.52(t,J＝4.0Hz,1H),7.27(ddd,J＝11.4,7.3,2.4Hz,1H),7.17(dd,J＝19.1,8.9Hz,1H),7.14(dd,J＝8.5,1.6Hz,1H),7.04(d,J＝8.9Hz,1H),5.70(t,J＝5.5Hz,1H),4.37–4.32(m,1H),3.81–3.72(m,3H),3.42(t,J＝5.0Hz,1H),3.42–3.38(m,3H),2.80(dt,J＝17.2,5.6Hz,1H),2.66–2.61(m,1H),2.49–2.44(m,1H),2.41–2.36(m,1H),2.27(d,J＝5.9Hz,1H),2.26(s,3H),2.22(dd,J＝11.0,5.5Hz,1H),2.19(s,3H),2.17(d,J＝3.0Hz,1H),2.00–1.95(m,1H),1.89(d,J＝11.1Hz,1H),1.54–1.35(m,4H),1.21(s,1H).13C NMR(150MHz,CD3CN)δ170.40,153.43,142.30,140.20,138.58,137.72,132.87,124.10,123.34,123.19,120.02,116.36,113.56,112.37,76.85,56.62,54.50,54.36,36.15,31.36,30.03,29.86,28.08,28.00,27.87,16.86,7.75.。
实施例29：化合物对组蛋白乙酰转移酶p300/CBP抑制活性测试
检测化合物对p300/CBP蛋白溴结构域的抑制率采用TR-FRET技术。FRET技术利用了能量供体Donor和能量受体Acceptor荧光基团的能量转移，前者的发射光谱与后者的激发光谱重叠。当Donor被外来能源激发并且它与Acceptor在足够近的距离之内(1-10nm)，可以将能量共振转移到Acceptor上。Acceptor受到激发，会发出特定波长的发射光。检测体系中用5μL 1X TR-FRET Assay Buffer稀释化合物或阴性对照，使化合物浓度为4X最终工作浓度。加入10μLCBP溴结构域Europium Chelate，避光孵育15分钟。加入5μL CBPbromodomain Ligand/APC Acceptor混合物，避光孵育1小时。利用酶标仪读取激发光340nm/发射光620nm/670nm检测荧光信号，计算IC50值。实验结果见表1。
表1：化合物对p300/CBP抑制活性
++++：代表IC50<10nM
+++：代表10nM≤IC50＜100nM
++：代表100nM≤IC50＜1μM
+：代表IC50≥1μM
从以上实验可以看出，本发明的化合物对组蛋白乙酰转移酶p300/CBP具有良好的抑制活性，且部分化合物抑制活性强于该靶点唯一临床在研药物CCS1477。
实施例30：CCK8法检测敏感细胞增殖抑制实验
检测本发明的化合物对肿瘤细胞的增殖抑制作用，用本发明的化合物对前期工作中得到的p300/CBP抑制敏感细胞株进行细胞生长抑制活性测试。将处于对数生长期的细胞按合适密度接种至96孔板，24小时后加入梯度稀释的化合物，作用6天后，每孔加入10μLCCK-8，37℃孵育2小时后酶标仪测定450nm波长处的OD值。
表2：化合物敏感肿瘤增殖抑制实验结果
“—”表示未测
从以上实验可以看出，本发明的化合物对包括前列腺癌在内的多种肿瘤细胞表现出了良好的抑制活性，有进一步开发为治疗肿瘤的表观遗传药物的前景。
实施例31：药代动力学评价
25.1动物信息
种属/品种：ICR(CD-1)mice
性别/数量：雄性(n＝15)
体重(g)：雄性(25-30g)
饲养方式：标准锯齿类动物饮食，对饮水不做限制，给药前12h开始禁食并在给药后保持空腹2h。
饲养环境：控制动物室环境(目标条件：温度18到29℃，相对湿度30到70％。每天监测温度和相对湿度。电子时间控制照明系统用于提供12小时光照/12小时黑暗周期。
25.2给药信息
25.3样品处理和分析
8000rpm离心5min，转移上层血浆15μL至96孔板中。在15μL血浆中加入150μL甲醇：乙腊(v/v＝l:l)(含20ng/mL甲苯磺丁脲)，振荡3min,4500rpm，离心5min，取100μL上清至2mL深孔板。加入100μL稀释剂(纯水)，振荡3min,4500rpm离心5min。转移上清180μL至进样板中，用LC-MS/MS分析上清样品中化合物的含量，并使用WinNonlin软件计算各项药代动力学参数。受试化合物的药代动力学参数见表3。
表3：部分发明化合物小鼠体内PK性质
实验结果表明，本发明的化合物具有良好的口服吸收暴露量。

Claims (7)

1.式Ⅰ结构所示的化合物、或其氘代物、或其盐、或其异构体、或其晶型、或其溶剂合物，
其中，R1选自酰基、磺酰基、取代或非取代的五元芳香杂环；
R2选自4-6元取代或非取代的脂肪环或脂肪杂环；
R3选自取代或非取代的芳香环或芳香并环；
R4选自氢、氘、氘代或非氘代的含1-3个碳原子的烃类基团；
X,X1,X2分别独立地选自N或CH；
Y选择-CH2-,-CH2CH2-,-CH2CH2CH2-；
虚线为单键/>或双键/>当虚线/>为双键/>时，该双键/>相邻的两个虚线/>均为单键/>
2.根据权利要求1所述的化合物、或其氘代物、或其盐、或其异构体、或其晶型、或其溶剂合物，其特征在于，所述化合物其结构如式Ⅱ-1所示：
其中，Z独立地选自C(R5R6),N(R7)，其中R5，R6独立地选自氢、羟基、卤素、烷基、烷氧基；R7选自酰基、磺酰基；n1，n2分别独立地选自0或1；
R1,R3,R4,X,X1,X2和Y如权利要求1所述。
3.根据权利要求2所述的化合物、或其氘代物、或其盐、或其异构体、或其晶型、或其溶剂合物，其特征在于，R1选自 和/或，选自/>和/或，/>选自/>其中R3选自
4.根据权利要求1～3所述的化合物、或其氘代物、或其盐、或其异构体、或其晶型、或其溶剂合物，其特征在于：所述化合物为下述化合物之一：
5.权利要求1所述的化合物、或其氘代物、或其盐、或其异构体、或其晶型、或其溶剂合物在制备作为p300/CBP溴结构域抑制剂中的用途。
6.根据权利要求5所述的用途，其特征在于：所述p300/CBP溴结构域抑制剂为预防和/或治疗肿瘤、髓系造血干细胞恶性疾病，调控调节性T细胞的药物。
7.根据权利要求6所述的用途，其特征在于：所述的肿瘤、髓系造血干细胞恶性疾病选自血液恶性肿瘤、胃癌、肠癌、宫颈癌、膀胱癌、喉癌、肝癌、肺癌、乳腺癌、卵巢癌、前列腺癌、淋巴瘤或多发性骨髓瘤。
CN202210156248.1A 2022-02-21 2022-02-21 P300/cbp溴结构域抑制剂及其制药用途 Pending CN116655597A (zh)

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