CN118005638A - 含吡唑并[3,4-d]嘧啶结构的化合物及其制备方法与用途 - Google Patents
含吡唑并[3,4-d]嘧啶结构的化合物及其制备方法与用途 Download PDFInfo
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Abstract
本发明涉及药物化学领域，公开了一类具有BTK/JAK3抑制活性的吡唑并[3,4‑d]嘧啶衍生物及其制备方法和用途。本发明还公开了含有所述具有BTK/JAK3抑制活性的吡唑并[3,4‑d]嘧啶衍生物或其药学上可接受的盐及药学上可接受的载体的组合物、及其在制备BTK/JAK3抑制剂中的应用。本发明的化合物可用于治疗炎症和肿瘤，包括类风湿性关节炎和B细胞淋巴瘤。
Description
技术领域
本发明属于药物化学领域，具体涉及一类含有吡唑并[3,4-d]嘧啶结构的BTK和JAK3激酶抑制剂，它们的制备方法，以及含有这些化合物的药物组合物及其在制备治疗类风湿性关节炎或B细胞淋巴瘤等自身免疫性疾病或B细胞恶性肿瘤等药物方面的用途。
技术背景
类风湿性关节炎(RA)是一种病因未明的慢性、以炎性滑膜炎为主的自身免疫性疾病，其主要病理表现为滑膜组织炎性细胞浸润、血管翳形成以及进行性关节软骨和骨破坏，最终导致关节畸形甚至功能丧失。
JAK(Janus Kinase)属于非受体酪氨酸激酶，包含四个亚型JAK1、JAK2、JAK3、TYK2。目前已有多种JAK抑制剂上市，如托法替尼(Tofacitinib)、鲁索替尼(Ruxolitinib)、巴瑞克替尼(Baricitinib)、阿布昔替尼(Abrocitinib)、迪高替尼(Delgocitinib)、非洛替尼(Filgotinib)等。目前，由辉瑞公司研发的选择性JAK3抑制剂Ritlecitinib(PF-06651600)正在日本，美国和欧盟进行监管审查，用以治疗斑秃。托法替尼于2012年上市用于治疗中度至重度类风湿性关节炎，2017年又被批准用于治疗银屑病性关节炎。但托法替尼具有较严重的感染和贫血等副作用，究其原因，主要是由于托法替尼属于泛JAK抑制剂，在抑制JAK1和JAK3产生治疗效果的同时，由于抑制了JAK2活性而产生贫血的副作用。所以在治疗类风湿性关节炎时，应开发选择性JAK1或JAK3抑制剂。由于JAK1除了可与JAK3形成二聚体外，还可与JAK2或TYK2形成二聚体或多聚体，从而引起副作用。因此选择性抑制JAK3引起的副作用可能要小于抑制JAK1产生的副作用。
BTK(Bruton’s tyrosine kinase)是TEC家族的一员，属于非受体酪氨酸激酶，主要在B细胞、髓细胞、肥大细胞、血小板中表达，在T细胞和NK细胞中不表达。BTK在BCR信号通路中起到了至关重要的作用，除此之外，BTK还参与很多其他信号通路的传导。B细胞的异常活化会导致B细胞淋巴瘤和自身免疫性疾病。目前已有五个BTK抑制剂上市，包括依鲁替尼(Ibrutinib)、阿卡替尼(Acalabrutinib)、泽布替尼(Zanubrutinib)、奥布替尼(Orelabrutinib)和替拉鲁替尼(Tirabrutinib)。
有文献报道联合使用BTK抑制剂LFM-A13和JAK3抑制剂JANEX-1治疗移植物抗宿主反应(GVHD)的效果要远优于单独使用LFM-A13、JANEX-1或甲氨蝶呤的治疗效果。另外JAK3选择性抑制剂Ritlecitinib(PF-06651600)在临床上显示出较好的抗RA效果，究其原因，不仅与抑制JAK3有关，也与抑制BTK等TEC家族激酶密切相关。因此，本发明人认为同时抑制BTK和JAK3对治疗RA等自身免疫性疾病具有协同增效作用。然而，对此本领域技术人员会将现有的BTK抑制剂和JAK3抑制剂来组合使用，而同时具有优良的BTK和JAK3抑制活性的化合物却无法根据现有技术显而易见地获得。
发明内容
本发明提供了一类含有吡唑并[3,4-d]嘧啶结构的化合物，能同时抑制BTK和JAK3。另外，本发明还提供了该类化合物的具体制备方法以及作为BTK和JAK3激酶抑制剂的制药应用等。
具体而言，本发明提供了一类如通式(I)所示的含有吡唑并[3,4-d]嘧啶结构的化合物以及其药学上可接受的盐：
其中：X1、X2各自独立地代表O或CH2；
R1代表：其中R2代表H、F、Cl、Br、I、C1-C6烷基、CF3、OH、C1-C6烷氧基、OCF3、CN、NO2、-NH2、C1-C6的烷胺基、-NHCH3、-N(CH3)2、-N(C2H5)2、-CH(CH3CN)、-NHCOCH3、、/> R2可以是单取代、双取代或三取代；Y1、Y2、代表N或C-R3，R3代表H、F、Cl、Br、I、CH3、CF3、OH、OCH3、OCF3或CN；Z代表O、S或N-R4，R4代表H、CH3、C2H5或环丙基；
优选在通式(I)中，X1代表CH2或O；X2代表O；
优选在通式(Ⅰ)中，R1代表 其中R5代表H、F、Cl、CH3、t-Bu、CF3、CN、OH、OCH3、OCF3、-NH2、-NHCH3、-N(CH3)2、-N(C2H5)2、/>NHCOCH3、、R5可以是单取代、双取代或三取代。
进一步的，R5优选代表H、F、Cl、CF3、OCH3、CN、-NHCH3、-N(CH3)2、R5可以是单取代、双取代或三取代。
更优选地，本发明的含有吡唑并[3,4-d]嘧啶结构的化合物为I-1、I-2、I-3、I-4、I-5、I-6、I-7、I-8、I-9、I-10、I-11、I-12、I-13、I-14、I-15、I-16、I-17、I-18、I-19、I-20、I-21、I-22和I-23。
进一步优选地，本发明的含有吡唑并[3,4-d]嘧啶结构的化合物选自以下化合物：
本发明的化合物的药学上可接受的盐为通式(I)化合物的酸加成盐，其中用于成盐的酸为：氯化氢、溴化氢、硫酸、碳酸、草酸、柠檬酸、琥珀酸、酒石酸、磷酸、乳酸、丙酮酸、乙酸、马来酸、甲磺酸、苯磺酸、对甲苯磺酸或阿魏酸。
当X2代表O时，本发明通式(I)的化合物可用下列方法制备：
其中，R1、X1的定义同权利要求1。
由化合物(III)与化合物(IV)通过Suzuki偶联反应制备化合物(V)，所用溶剂选自甲苯、N,N-二甲基甲酰胺(DMF)、乙二醇二甲醚、1,4-二氧六环、四氢呋喃、甲醇、乙醇、乙腈、丙酮、水或任意两种溶剂组成的混合溶剂，优选乙二醇二甲醚；所用碱选自乙醇钠、乙酸钠、乙酸钾、磷酸钾、氢氧化钠、氢氧化钾、碳酸钾、碳酸钠或三乙胺，优选碳酸钠或碳酸钾；所用催化剂选自四(三苯基膦)钯(Pd(PPh3)4)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(Pd(dppf)Cl2)、双(三苯基磷)二氯化钯(Pd(PPh3)2Cl2)、醋酸钯(Pd(OAc)2)或(1,1'-双(二苯基膦)二茂铁)二氯化镍(NiCl2(dppf))，优选Pd(dppf)Cl2；反应温度选自室温至120℃，优选70～100℃。
由化合物(V)通过脱除叔丁氧羰基(Boc)保护基制备化合物(VI)，所用试剂选自三氟乙酸、浓盐酸、氯化氢/乙酸乙酯溶液或氯化氢/甲醇溶液,优选三氟乙酸或氯化氢/乙酸乙酯溶液；反应溶剂选自丙酮、二氯甲烷、乙酸乙酯、1,4-二氧六环或乙腈,优选乙酸乙酯或二氯甲烷。
由化合物(VI)与丙烯酰氯反应制备化合物(I)，所用缚酸剂选自三乙胺、吡啶、N,N-二异丙基乙胺、4-二甲氨基吡啶、碳酸钾或碳酸钠，优选三乙胺；所用溶剂选自二氯甲烷、四氢呋喃、1,4-二氧六环、乙酸乙酯、丙酮、甲苯或DMF，优选二氯甲烷。
化合物(I)也可由化合物(VI)与丙烯酸在缩合剂存在下反应制备得到，所述缩合剂选自N,N'-羰基二咪唑(CDI)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)/1-羟基苯并***(HOBt)或二环己基碳二亚胺(DCC)/4-二甲氨基吡啶(DMAP)，优选EDCI/HOBt。
当X1为O，X2为CH2时，目标化合物的制备方法与上述相同。
中间体(IV)可用下列方法制备：
其中R1、X1的定义同权利要求1。
化合物IX溶于DMF，加入N-溴代丁二酰亚胺(NBS)进行溴代即得7-溴-2,3-二氢苯并呋喃-4-胺(X)。
化合物X和联硼酸频那醇酯溶于1,4-二氧六环中，在催化剂Pd(dppf)Cl2和乙酸钾存在下反应即得7-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-2,3-二氢苯并呋喃-4-胺(XI)。
由化合物XI与相应的酰氯反应制备中间体(IV)，所用缚酸剂选自三乙胺、吡啶、N,N-二异丙基乙胺、4-二甲氨基吡啶、碳酸钾或碳酸钠，优选N,N-二异丙基乙胺或三乙胺；所用溶剂选自二氯甲烷、四氢呋喃、1,4-二氧六环、乙酸乙酯、丙酮、甲苯或DMF，优选二氯甲烷。
本发明还公开了一种药物组合物，其含有上述通式(I)化合物或其药学上可接受的盐及药学上可接受的载体。所述的化合物可以添加药学上可接受的载体制成常见的药用制剂，如片剂、胶囊、糖浆、悬浮剂、注射剂，可以加入香料、甜味剂、液体或固体填料或稀释剂等常用药用辅料。
本发明的药物组合物可通过所属领域技术人员所熟知的给药方式来进行给药，例如口服、直肠、舌下、肺部、透皮、离子透入、***及鼻内给药。本发明的药物组合物优选胃肠道外给药，如皮下、肌内或静脉内注射。给药剂量根据制剂形式和期望的作用时间以及治疗对象的情况而有所变化，实际治疗所需的治疗有效量可以由医师根据实际情况(如：病人的病情、体重等)而确定。对于一般的成人，本发明的药物组合物的剂量，以式通式(I)化合物计，可以是每kg成人体重1ng-10g，如每kg体重100ng-10mg。
本发明的通式(I)化合物或其立体异构体、水合物、溶剂合物、结晶或药学上可接受的盐在制备BTK和/或JAK3抑制剂药物中的用途也在本发明的保护范围内。相应地，本发明还提供了一种治疗方法，其包括向需要抑制BTK和/或JAK3活性的受治疗者给予治疗有效量的本发明的通式(I)化合物或其立体异构体、水合物、溶剂合物、结晶或药学上可接受的盐。
优选地，本发明提供了本发明的通式(I)化合物或其立体异构体、水合物、溶剂合物、结晶或药学上可接受的盐在制备BTK和JAK3双靶点抑制剂药物中的用途。
进一步地，其中的BTK和JAK3抑制剂用于治疗自身免疫性疾病和B细胞恶性肿瘤，优选地，所述的自身免疫性疾病包括类风湿性关节炎、银屑病和斑秃等，所述的B细胞恶性肿瘤包括B细胞淋巴瘤等。相应地，本发明还提供了一种用于治疗自身免疫性疾病或B细胞恶性肿瘤的方法，其包括向患有自身免疫性疾病或B细胞恶性肿瘤的受治疗者给予治疗有效量的本发明的通式(I)化合物或其立体异构体、水合物、溶剂合物、结晶或药学上可接受的盐。
本发明的有益效果在于提供了新的通式(I)所示吡唑并[3,4-d]嘧啶衍生物的制备方法。药理实验结果显示，本发明的化合物(I)可以对BTK和JAK3激酶均产生良好的抑制作用，可用于制备治疗BTK、JAK3通路过度活化所致的类风湿性关节炎的药物。
具体实施方式
下面结合具体实施例对本申请作出详细说明。
实施例1
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)-2,3-二氢苯并呋喃-4-基)-6-甲氧基烟酰胺(Ⅰ-1)的合成
7-溴-2,3-二氢苯并呋喃-4-胺(X-1)的合成
将2,3-二氢苯并呋喃-4-胺IX-1(5.00g,0.037mol)置于150mL三颈瓶中，加入60mLDMF溶解，于-40℃下分批加入NBS(6.59g,0.037mol)，反应约2h。加入饱和亚硫酸氢钠水溶液(20mL)淬灭反应，加入80mL水，乙酸乙酯(100mL×2)萃取，合并有机相，分别用水(50mL×2)和饱和氯化钠水溶液(50mL×2)洗涤。无水硫酸钠干燥，抽滤，滤液减压蒸除溶剂，得到6.67g褐色油状物，产率84.2％。1H NMR(400MHz,DMSO-d6)δ(ppm):6.91(dd,J＝8.5,2.4Hz,1H,ArH),6.09(dd,J＝8.6,2.4Hz,1H,ArH),4.54(t,J＝8.7Hz,2H,CH2CH2 O),3.03(t,J＝8.8Hz,2H,CH2 CH2O).
7-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-2,3-二氢苯并呋喃-4-胺(XI-1)的合成
将化合物X-1(5.60g,0.026mol)，联硼酸频那醇酯(8.25g,0.032mol)，醋酸钾(7.74g,0.079mol)，Pd(dppf)Cl2(950mg,0.0013mol)加入250mL三颈瓶中，加入1,4-二氧六环80mL，氮气保护下，70℃搅拌反应8h。硅藻土抽滤，滤液加入150mL乙酸乙酯，分别用水(50mL×2)和饱和氯化钠水溶液(50mL×2)洗涤。无水硫酸钠干燥，抽滤，滤液减压蒸除溶剂。柱层析纯化(洗脱剂:石油醚:乙酸乙酯＝10:1-2:1)，得到4.21g淡黄色固体，产率:62.0％。1H NMR(300MHz,CDCl3)δ(ppm):7.38(d,J＝8.0Hz,1H,ArH),6.21(d,J＝8.0Hz,1H,ArH),4.65(t,J＝8.7Hz,2H,CH2CH2 O),2.94(t,J＝8.7Hz,2H,CH2 CH2O),1.32(s,12H,4CH3).
6-甲氧基-N-(7-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-2,3-二氢苯并呋喃-4-基)烟酰胺(Ⅳ-1)的合成
将6-甲氧基烟酸(345mg,2.3mmol)和10mL无水二氯甲烷加入50mL茄形瓶中，滴加两滴DMF，再在冰浴下缓慢滴加草酰氯(197μL,4.6mmol)，加毕，转至室温反应30分钟。减压蒸除溶剂，残留物用无水二氯甲烷溶解后备用(酰氯溶液A)。
将化合物XI-1(500mg,0.0019mol)和三乙胺(530μL,0.0038mol)加入50mL茄形瓶中，冰浴下缓慢滴加上述酰氯溶液A，加毕，室温下反应约3h。加饱和碳酸钠水溶液淬灭反应，二氯甲烷萃取，合并有机相后分别用水(20mL×2)和饱和氯化钠水溶液(20mL×2)洗涤。无水硫酸钠干燥，抽滤，滤液减压蒸除溶剂，石油醚:乙酸乙酯＝6:1打浆。抽滤，得到615mg类白色固体，产率81.7％。1H NMR(400MHz,DMSO-d6)δ(ppm):10.07(s,1H,CONH),8.77(s,1H,ArH),8.20(d,J＝8.6Hz,1H,ArH),7.35(d,J＝8.1Hz,1H,ArH),7.02(d,J＝8.5Hz,1H,ArH),6.94(d,J＝8.6Hz,1H,ArH),4.63-4.41(m,2H,OCH2 CH2),3.93(s,3H,OCH3),3.22-3.06(m,2H,CH2 CH2O),1.26(s,12H,4CH3).
(R)-3-(4-氨基-3-(4-(6-甲氧基烟酰氨基)-2,3-二氢苯并呋喃-7-基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(Ⅴ-1)的合成
将化合物Ⅳ-1(520mg,1.30mmol)、Ⅲ(560mg,1.30mmol)和Pd(dppf)Cl2(48mg,0.065mmol)加入100mL三颈瓶中，1,4-二氧六环溶解，加入2mol/L的碳酸钠水溶液(1.3mL,2.60mmol)，氮气保护下70℃反应约4h。冷却至室温，硅藻土抽滤，加入50mL乙酸乙酯溶解，分别用水和饱和氯化钠水溶液洗涤。无水硫酸钠干燥，抽滤，滤液减压蒸除溶剂。柱层析纯化(洗脱剂:二氯甲烷:甲醇＝200:1-50:1)，得到440mg白色固体，产率57.7％。1H NMR(400MHz,DMSO-d6)δ(ppm):10.17(s,1H,NHCO),8.82(s,1H,ArH),8.28-8.22(m,2H,ArH),7.32(d,J＝8.3Hz,1H,ArH),7.23(d,J＝8.4Hz,1H,ArH),6.97(d,J＝8.7Hz,1H,ArH),4.66(m,3H,CH2CH2 O,NCH 2CH),4.19-4.00(m,1H,NCH2CH),3.95(s,3H,OCH3),3.88-3.73(m,1H,NCH 2CH),3.69-3.61(m,1H,NCH 2CH2),3.31(t,J＝8.7Hz,2H,CH 2CH2O),3.14-2.87(m,1H,NCH 2CH2),2.31-2.14(m,1H,NCH2CHCH 2),2.13-2.05(m,1H,NCH2CHCH 2),1.96-1.80(m,1H,NCH2CH 2),1.65-1.52(m,1H,NCH2CH 2),1.34(s,9H).
(R)-N-(7-(4-氨基-1-(哌啶-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基)-2,3-二氢苯并呋喃-4-基)-6-甲氧基烟酰胺(Ⅵ-1)的合成
将化合物Ⅴ-1(400mg,0.68mmol)和10mL二氯甲烷加入茄形瓶中，溶解，冰浴下加入氯化氢饱和的乙酸乙酯溶液1mL，室温反应1h。抽滤，得到306mg淡黄色固体，产率92.5％，未经纯化直接投下一步。
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)-2,3-二氢苯并呋喃-4-基)-6-甲氧基烟酰胺(Ⅰ-1)的合成
将化合物Ⅵ-1(300mg,0.62mmol)和8mL二氯甲烷加入50mL茄形瓶中，溶解，加入三乙胺(160μL,1.20mmol)，搅拌反应30分钟。冰浴下加入稀释的丙烯酰氯(44μL,0.55mmol)的二氯甲烷溶液，继续反应约1h。加入5mL饱和碳酸钠水溶液淬灭，二氯甲烷(15mL×2)萃取，合并有机相，分别用水(5mL×2)和饱和氯化钠水溶液(5mL×2)洗涤。无水硫酸钠干燥，抽滤，滤液减压蒸除溶剂。柱层析纯化(洗脱剂:二氯甲烷:甲醇＝200:1-30:1)，得到151mg白色固体，产率45.1％。HPLC纯度:98.00％。1H NMR(400MHz,DMSO-d6)δ(ppm):10.16(s,1H,NH),8.81(s,1H,ArH),8.29-8.20(m,2H,ArH),7.31(d,J＝8.3Hz,1H,ArH),7.22(d,J＝8.3Hz,1H,ArH),6.98(d,J＝8.7Hz,1H,ArH),6.92-6.70(m,1H,CH＝CH2),6.22-6.01(m,1H,CH＝CH 2),5.76-5.55(m,1H,CH＝CH 2),4.75-4.51(m,3.5H,OCH2 CH2,NCH 2CH,NCH2CH),4.31-4.17(m,1H,NCH 2CH),4.13-4.02(m,0.5H,NCH2CH),3.96(s,3H,OCH3),3.81-3.62(m,0.5H,NCH 2CH2)3.30(t,J＝8.5Hz,2H,CH2 CH2O),3.27-3.16(m,1H,NCH 2CH2),3.04-2.91(m,0.5H,NCH 2CH2),2.31-2.20(m,1H,NCH2CHCH2),2.18-2.08(m,1H,NCH2CHCH 2),2.01-1.89(m,1H,NCH2CH 2),1.61(m,1H,NCH2CH 2)
实施例2
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)-2,3-二氢苯并呋喃-4-基)-4-(二甲基氨基)苯甲酰胺(Ⅰ-2)的合成4-(二甲基氨基)-N-(7-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-2,3-二氢苯并呋喃-4-基)苯甲酰胺(Ⅳ-2)的合成
以4-二甲氨基苯甲酸(402mg,2.40mmol)和化合物XI-1(530mg,2.00mol)为原料，操作同化合物Ⅳ-1，得到400mg黄色固体(IV-2)，产率49.0％。
(R)-N-3-(4-氨基-3-(4-(4-(二甲基氨基)苯甲酰氨基)-2,3-二氢苯并呋喃-7-基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(Ⅴ-2)的合成
以化合物Ⅳ-2(0.40g,0.98mmol)和Ⅲ(415mg,0.94mmol)为原料，操作过程同化合物Ⅴ-1，得淡黄色固体128mg，产率21.82％。1H NMR(300MHz,DMSO-d6)δ(ppm):9.79(s,1H,CONH),8.22(s,1H,ArH),7.88(d,J＝8.9Hz,2H,ArH),7.28(d,J＝8.3Hz,1H,ArH),7.19(d,J＝8.4Hz,1H,ArH),6.78(d,J＝9.1Hz,2H,ArH),4.78-4.59(m,3H,CH2CH2 O,NCH 2CH),4.12-4.00(m,1H,NCH2CH),3.98-3.73(m,2H,NCH 2CH,NCH 2CH2),3.28(t,J＝8.6Hz,2H,CH2 CH2O),3.01(s,6H,N(CH3)2),2.28-2.16(m,1H,NCH 2CH2),2.11-2.03(m,1H,NCH2CHCH 2),1.96-1.80(m,1H,NCH2CHCH 2),1.70-1.52(m,2H,NCH2CH2 ),1.36(s,9H,NBoc).
(R)-N-(7-(4-氨基-1-(哌啶-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基]-2,3-二氢苯并呋喃-4-基)-4-(二甲基氨基)苯甲酰胺(Ⅵ-2)的合成
以化合物Ⅴ-2(100mg,0.17mmol)为原料，操作同化合物ⅤI-1，得到淡黄色固体57mg，产率67.2％。
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基]-2,3-二氢苯并呋喃-4-基)-4-(二甲基氨基)苯甲酰胺(Ⅰ-2)的合成
以化合物Ⅵ-2(57mg,0.011mmol)为原料，操作同化合物Ⅰ-1，得到11mg白色固体，产率18.1％。HPLC纯度:97.83％。1H NMR(300MHz,DMSO-d6)δ(ppm):9.84(s,1H,NHCO),8.21(s,1H,ArH),7.88(d,J＝8.5Hz,2H,ArH),7.27(d,J＝8.3Hz,1H,ArH),7.18(d,J＝8.4Hz,1H,ArH),6.95-6.70(m,3H,ArH,CH＝CH2),6.20-6.03(m,1H,CH＝CH2),5.81-.56(m,1H,CH＝CH 2),4.74-4.49(m,3H,CH2CH2 O,NCH 2CH),4.31-4.15(m,1H,NCH2CH),4.13-3.95(m,1H,NCH 2CH),3.32-3.12(m,4H,CH2 CH2O,NCH2 CH2),3.00(s,6H,N(CH3)2),2.30-2.22(m,1H,NCH2CHCH 2),2.16-2.04(m,1H,NCH2CHCH 2),1.95-1.85(m,1H,NCH2CH 2),1.67-1.52(m,1H,NCH2CH 2).
实施例3
(R)-N-(7-1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烷-4-基)-4-氟苯甲酰胺(Ⅰ-3)的合成
7-溴苯并[d][1,3]二氧杂环戊烷-4-胺(X-2)的合成
将苯并[d][1,3]二氧杂环戊烷-4-胺(Ⅸ-2)(1.24g,9.04mmol)和DMF(30mL)混合，搅拌溶解，降温至-30℃，分批加入NBS(1.69g,9.50mmol)，加毕，保温反应1小时。加入水(60mL)，用乙酸乙酯(15mL×3)萃取，有机相依次用水(10mL×3)和饱和氯化钠溶液(10mL×3)洗涤，无水硫酸钠干燥。抽滤，滤液减压蒸干，残留物柱层析(洗脱剂:石油醚:乙酸乙酯＝30:1-10:1)分离，得白色固体1.01g，产率51.7％，m.p.99-100℃.1H-NMR(300MHz,CDCl3)δ(ppm):6.80(d,J＝8.67Hz,1H,ArH),6.23(d,J＝8.67Hz,1H,ArH),6.02(s,2H,OCH2O),3.58(s,2H,NH2).
7-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯并[d][1,3]二氧杂环戊烷-4-胺(Ⅺ-2)的合成
将化合物X-2(3.14g,14.54mmol)、联硼酸频那醇酯(7.39g,29.07mmol)、Pd(dppf)Cl2(0.53g,0.73mmol)、乙酸钾(4.28g,43.62mmol)和1,4-二氧六环(25mL)混合，N2保护，升温至95℃反应12h。经硅藻土抽滤，滤液减压蒸除溶剂，加入乙酸乙酯(20mL)溶解，依次用水(10mL×3)和饱和氯化钠溶液(10mL×3)洗涤，无水硫酸钠干燥，抽滤，滤液减压蒸干，残留物柱层析(洗脱剂:石油醚:二氯甲烷＝10:1-5:1)得白色固体2.7g，产率70.6％。m.p.84-86℃。1H-NMR(300MHz,CDCl3)δ(ppm):7.09(d,J＝8.16Hz,1H,ArH),6.31(d,J＝8.19Hz,1H,ArH),5.99(s,2H,OCH2O),3.71(br,2H,NH2),1.34(s,12H,4CH3)。
4-氟-N-(7-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯并[d][1,3]二氧杂环戊烷-4-基)苯甲酰胺(Ⅳ-3)的合成
将4-氟苯甲酸(0.64g,4.60mmol)和12mL无水二氯甲烷加入50mL茄形瓶中，加入3滴DMF，冰浴下滴加草酰氯(645μL,7.60mmol)的无水二氯甲烷溶液，滴毕，室温搅拌。随着反应的进行，反应液由白色浑浊变为无色澄清。反应约30分钟，TLC(石油醚:乙酸乙酯＝3:1)监测反应完全。减压蒸除溶剂，产物用无水二氯甲烷15mL溶解待用(酰氯溶液C)。
向50mL茄形瓶中加入化合物Ⅺ-2(1.00g,3.80mmol)、无水二氯甲烷15mL、三乙胺(1.50mL,11.40mmol)，搅拌溶解。于冰浴下，滴加上述酰氯溶液C，滴毕，室温反应3.5h，TLC(石油醚:乙酸乙酯＝3:1)监测原料反应完全。有机相分别用水(10mL×3)、饱和氯化钠水溶液(10mL×3)洗涤，无水硫酸钠干燥。抽滤，滤液减压浓缩，得淡黄色固体。石油醚:乙酸乙酯＝8:1打浆(1g/6mL)，得类白色固体1.38g，产率94.3％。1H NMR(300MHz,DMSO-d6)δ(ppm):10.22(s,1H,NHCO),8.06(d,J＝5.5Hz,1H,ArH),8.03(d,J＝5.5Hz,1H,ArH),7.42-7.34(m,2H,ArH),7.07(d,J＝8.3Hz,1H,ArH),7.02(d,J＝8.3Hz,1H,ArH),6.07(s,2H,OCH2O),1.29(s,12H,4CH3).
(R)-3-(4-氨基-3-(7-(4-氟苯甲酰氨基)苯并[d][1,3]二氧杂环戊烷-4-基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(V-3)的合成
向50mL三颈瓶中加入化合物Ⅳ-3(1.27g,3.30mmol)、化合物Ⅲ(1.46g,3.67mmol)、1,4-二氧六环15mL、2mol/L Na2CO3(3mL)和Pd(dppf)Cl2(0.12g,0.17mmol)，氮气保护，70℃反应2h，反应液由黄色浑浊变为黑色。TLC(二氯甲烷:甲醇＝30:1)监测反应完全。硅藻土抽滤，滤液减压蒸除溶剂，用二氯甲烷(25mL)溶解，再分别用水(10mL×3)、饱和氯化钠水溶液(10mL×3)洗涤，无水硫酸钠干燥。抽滤，滤液减压浓缩，柱层析纯化(洗脱剂：二氯甲烷:甲醇＝200:1-100:1-50:1-40:1)得黄褐色固体1.52g，产率80.0％。m.p.176-178℃。1H NMR(300MHz,DMSO-d6)δ(ppm):10.29(s,1H,NHCO),8.23(s,1H,ArH),8.13-8.00(m,2H,ArH),7.42-7.33(m,2H,ArH),7.18(d,J＝8.6Hz,1H,ArH),7.03(d,J＝8.5Hz,1H,ArH),6.15(s,2H,OCH2O),5.77(s,1H,NH),4.81-4.63(m,1H,NCH 2CH),4.35-4.10(m,1H,NCH2CH),4.09-3.90(m,1H,NCH 2CH),3.44-3.27(m,1H,NCH 2CH2),3.17(s,1H,NH),2.81-2.63(m,1H,NCH 2CH2),2.24-2.07(m,2H,NCH2CHCH2 ),1.85-1.67(m,1H,NCH2CH2 ),1.65-1.48(m,1H,NCH2CH2 ),1.32(s,9H,NBoc).
(R)-N-(7-(4-氨基-1-(哌啶-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烷-4-基)-4-氟苯甲酰胺(Ⅵ-3)的合成
将化合物V-3(1.40g,2.43mmol)溶于5mL无水二氯甲烷中，冰浴下加入约2.5mL氯化氢饱和的乙酸乙酯溶液，立即有大量固体析出，加毕，撤去冰浴。室温搅拌反应约2h，TLC(二氯甲烷:甲醇＝20:1)监测反应完全，抽滤，滤饼用乙酸乙酯洗涤，真空干燥，得类白色固体1.13g，产率97.8％。
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烷-4-基)-4-氟苯甲酰胺(Ⅰ-3)的合成
将化合物Ⅵ-3(1.10g,2.31mmol)加入二氯甲烷5mL中，加Et3N(498μL,5.56mmol)，化合物逐渐溶解，反应液为黄褐色澄清。室温搅拌0.5h后，冰浴条件下缓慢滴加丙烯酰氯(127μL,2.08mmol)的二氯甲烷(1mL)溶液，滴毕，室温搅拌2h。TLC(二氯甲烷:异丙醇＝15:1)监测反应完全。二氯甲烷稀释，水(10mL×3)洗涤，饱和氯化钠水溶液(10mL×3)洗涤，减压浓缩得粗品。柱层析纯化(洗脱剂:二氯甲烷:甲醇＝100:1-75:1-50:1-40:1-35:1)得白色固体450mg，产率40.9％。HPLC纯度:99.13％。m.p.157-159℃。1H NMR(400MHz,DMSO-d6)δ(ppm):10.27(s,1H,NHCO),8.24(s,1H,ArH),8.10-8.05(m,2H,ArH),7.41-7.35(m,2H,ArH),7.20(d,J＝8.6Hz,1H,ArH),7.05(d,J＝8.5Hz,1H,ArH),6.81-6.76(m,1H,CH＝CH2),6.16(s,2H,OCH2O),6.09-5.96(m,1H,CH＝CH 2),5.91(s,2H,NH2),5.87-5.63(m,1H,CH＝CH 2),4.77-4.65(m,1H,NCH 2CH),4.59-4.52(m,0.5H,NCH2CH),4.30-4.17(m,1H,NCH 2CH),4.12-4.05(m,0.5H,NCH2CH),3.73-3.66(m,0.5H,NCH 2CH2),3.26-3.15(m,1H,NCH 2CH2),3.02-2.92(m,0.5H,NCH 2CH2),2.31-2.22(m,1H,NCH2CHCH 2),2.16-2.08(m,1H,NCH2CHCH 2),1.97-1.89(m,1H,NCH2CH 2),1.67-1.54(m,1H,NCH2CH 2).13C NMR(101MHz,DMSO-d6)δ(ppm):165.19(d,J＝250.3Hz),165.05,163.44,158.54,156.18,154.16,146.36,141.49,138.84,131.06(d,J＝9.2Hz,2C),130.91(d,J＝2.9Hz),128.78,127.93,122.56,121.76,119.46,115.96(d,J＝21.9Hz,2C),112.12,102.16,99.09,53.39(0.5C),52.63(0.5C),49.72(0.5C),46.17(0.5C),45.62(0.5C),42.05(0.5C),30.09(0.5C),29.98(0.5C),25.39(0.5C),23.86(0.5C).HRMS(ESI):m/z[M+Na]+.Calcd for C27H24FN7NaO4:552.1772；Found:552.1762.
实施例4
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烷-4-基)-4-氰基苯甲酰胺(Ⅰ-4)的合成4-氰基-N-(7-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯并[d][1,3]二氧杂环戊烷-4-基)苯甲酰胺(Ⅳ-4)的合成
以4-氰基苯甲酸(0.67g,4.56mmo)和化合物Ⅺ-2(1.00g,3.80mmol)为原料，操作同化合物Ⅳ-3，得淡黄色固体1.47g，产率99.1％。1H NMR(300MHz,CDCl3)δ(ppm):8.24(s,1H,NHCO),7.98(d,J＝8.1Hz,2H,ArH),7.85-7.74(m,4H,ArH),6.08(s,2H,OCH2O),1.37(s,12H,4CH3).
(R)-3-(4-氨基-3-(7-(4-氰基苯甲酰氨基)苯并[d][1,3]二氧杂环戊烷-4-基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(Ⅴ-4)的合成
以化合物Ⅳ-4(1.45g,3.72mmol)和化合物Ⅲ(1.65g,3.72mmol)为原料，操作同化合物Ⅴ-3的合成，得到黄色固体1.49g，产率68.1％。m.p.159-161℃。1H NMR(300MHz,DMSO-d6)δ(ppm):10.54(s,1H,NHCO),8.23(s,1H,ArH),8.13(d,J＝8.2Hz,2H,ArH),8.04(d,J＝8.3Hz,2H,ArH),7.20(d,J＝8.6Hz,1H,ArH),7.04(d,J＝8.6Hz,1H,ArH),6.15(s,2H,OCH2O),5.77(s,2H,NH2),4.74-4.60(m,1H,NCH 2CH),4.10-3.95(m,1H,NCH2CH),3.91-3.75(m,1H,NCH 2CH),3.19-3.14(m,1H,NCH 2CH2),3.09-2.88(m,1H,NCH 2CH2),2.24-2.15(m,1H,NCH2CHCH 2),2.12-2.02(m,1H,NCH2CHCH 2),2.00-1.82(m,1H,NCH2CH 2),1.60-1.51(m,1H,NCH2CH 2),1.32(s,9H,NBoc).
(R)-N-(7-(4-氨基-1-(哌啶-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烷-4-基)-4-氰基苯甲酰胺(Ⅵ-4)的合成
以化合物Ⅴ-4(1.44g,0.0025mol)为原料，操作同化合物Ⅵ-3，得到淡黄色固体1.18g，产率99.15％。
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烷-4-基)-4-氰基苯甲酰胺(Ⅰ-4)的合成
以化合物Ⅵ-4(1.18g,2.44mmol)为原料，操作同化合物Ⅰ-3的合成，得到白色固体470mg，产率35.9％。HPLC纯度:99.13％。m.p.180-182℃。1H NMR(400MHz,DMSO-d6)δ(ppm):10.53(s,1H,NHCO),8.24(s,1H,ArH),8.14(d,J＝8.4Hz,2H,ArH),8.04(d,J＝8.4Hz,2H,ArH),7.22(d,J＝8.6Hz,1H,ArH),7.06(d,J＝8.6Hz,1H,ArH),6.89-6.79(m,1H,CH＝CH2),6.17(s,2H,OCH2O),6.14-6.05(m,1H,CH＝CH 2),5.75-5.57(m,1H,CH＝CH 2),4.75-4.67(m,1H,NCH 2CH),4.58-4.55(m,0.5H,NCH2CH),4.38-4.24(m,1H,NCH 2CH),4.13-4.01(m,0.5H,NCH2CH),3.76-3.64(m,0.5H,NCH 2CH2),3.26-3.15(m,1H,NCH 2CH2),3.03-2.94(m,0.5H,NCH 2CH2),2.31-2.20(m,1H,NCH2CHCH 2),2.17-2.08(m,1H,NCH2CHCH 2),1.99-1.89(m,1H,NCH2CH 2),1.68-1.53(m,1H,NCH2CH 2).13C NMR(101MHz,DMSO)δ(ppm):165.04,164.27,158.53,156.18,154.17,146.44,141.49,138.79,138.46,132.98,129.16,128.80,127.88,122.62,121.32,119.30,118.77,114.55,112.36,102.25,99.09,53.39(0.5C),52.63(0.5C),49.71(0.5C),46.17(0.5C),45.62(0.5C),42.05(0.5C),30.09(0.5C),29.87(0.5C),25.39(0.5C),23.85(0.5C).HRMS(ESI):m/z[M+Na]+.Calcd for C28H24N8NaO4:559.1818；Found:559.1801.
实施例5
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烷-4-基)-3-(二甲基氨基)苯甲酰胺(Ⅰ-5)的合成3-二甲基氨基-N-(7-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯并[d][1,3]二氧杂环戊烷-4-基)苯甲酰胺(Ⅳ-5)的合成
以化合物3-二甲基氨基苯甲酸(0.60g,3.64mmol)和化合物Ⅺ-2(0.80g,3.00mmol)为原料，操作同化合物Ⅳ-3，得淡黄色固体0.92g，产率74.8％。1HNMR(300MHz,DMSO-d6)δ(ppm):9.60(s,1H,NHCO),7.71(d,J＝8.3Hz,2H,ArH),7.03(d,J＝8.6Hz,2H,ArH),6.85(d,J＝8.5Hz,1H,ArH),6.42(d,J＝8.4Hz,1H,ArH),5.97(s,2H,OCH2O),3.13(s,6H,N(CH3)2).1.32(s,12H,4CH3).
(R)-3-(4-氨基-3-(7-(3-(二甲基氨基)苯甲酰氨基)苯并[d][1,3]二氧杂环戊烷-4-基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(Ⅴ-5)的合成
以化合物Ⅳ-5(0.71g,1.73mmol)和化合物Ⅲ(0.73g,1.64mmol)为原料，操作同化合物Ⅴ-3的合成，得到黄色固体0.82g，产率83.2％。1H NMR(300MHz,DMSO-d6)δ(ppm):9.76(s,1H,NHCO),8.23(s,1H,ArH),7.87(d,J＝8.4Hz,2H,ArH),7.19(d,J＝8.6Hz,1H,ArH),7.01(d,J＝8.6Hz,1H,ArH),6.58(d,J＝8.5Hz,2H,ArH),6.13(s,2H,OCH2O),5.68(s,2H,NH2),4.73-4.61(m,1H,NCH 2CH),4.23-3.89(m,1H,NCH2CH),3.90-3.67(m,1H,NCH 2CH),3.13(s,6H,N(CH3)2),3.09-2.86(m,2H,NCH 2CH2),2.27-2.13(m,1H,NCH2CHCH 2),2.12-2.04(m,1H,NCH2CHCH 2),1.62-1.49(m,2H,NCH2CH 2),1.30(s,9H,NBoc).
(R)-N-(7-(4-氨基-1-(哌啶-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烷-4-基)-3-(二甲基氨基)苯甲酰胺(Ⅵ-5)的合成
以化合物Ⅴ-5(0.60g,1.00mmol)为原料，操作同化合物Ⅵ-3，得到淡黄色固体0.42g，产率84.0％。
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烷-4-基)-3-(二甲基氨基)苯甲酰胺(Ⅰ-5)的合成
以化合物Ⅵ-5(0.37g,0.74mmol)为原料，操作同化合物Ⅰ-3的合成，得到白色固体45mg，产率11.0％。HPLC纯度:99.15％。m.p.168-170℃.1H NMR(300MHz,DMSO-d6)δ(ppm):10.12(s,1H,NHCO),8.24(s,1H,ArH),7.36-7.24(m,3H,ArH),7.17(d,J＝8.6Hz,1H,ArH),7.04(d,J＝8.6Hz,1H,ArH),6.94(d,J＝9.3Hz,1H,ArH),6.90-6.70(m,1H,CH＝CH2),6.15(s,2H,OCH2O),6.13-6.04(m,1H,CH＝CH 2),5.76-5.58(m,1H,CH＝CH 2),4.78-4.65(m,1H,NCH 2CH),4.63-4.51(m,0.5H,NCH2CH),4.34-4.16(m,1H,NCH 2CH),4.17-4.01(m,0.5H,NCH2CH),3.80-3.56(m,0.5H,NCH 2CH2),3.27-3.11(m,1H,NCH 2CH2),2.99(s,6H,N(CH3)2),2.98-2.91(m,0.5H,CH 2CH2),2.36-2.18(m,1H,NCH2CHCH 2),2.20-2.04(m,1H,NCH2CHCH 2),2.01-1.88(m,1H,NCH2CH 2),1.72-1.52(m,1H,NCH2CH 2).13CNMR(75MHz,DMSO-d6)δ166.11,165.06,158.58,156.22,154.19,150.81,146.35,141.55,135.15,138.99,129.44,128.85,128.05,127.87,122.54,122.07,119.66,115.94,112.01,111.84,102.15,99.15,60.28(0.5C),53.45(0.5C),52.70(0.5C),49.75(0.5C),46.21(0.5C),45.74(0.5C),40.65,30.07(0.5C),29.93(0.5C),25.46(0.5C),23.92(0.5C).
实施例6
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烷-4-基)-2-(二甲基氨基)苯甲酰胺(Ⅰ-6)的合成2-二甲基氨基-N-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯并[d][1,3]二氧杂环戊烷-4-基)苯甲酰胺(Ⅳ-6)的合成
以化合物2-二甲基氨基苯甲酸(0.53g,3.19mmol)和化合物XI-2(0.70g,2.66mmol)为原料，操作同化合物Ⅳ-3，得淡黄色固体0.86g，产率78.8％。1H NMR(300MHz,DMSO-d6)δ(ppm):10.18(s,1H,NHCO),8.07(d,J＝7.8Hz,1H,ArH),7.96(d,J＝8.7Hz,1H,ArH),7.58(d,J＝8.7Hz,1H,ArH),7.52(d,J＝6.8Hz,1H,ArH),7.32(d,J＝7.4Hz,1H,ArH),7.04(d,J＝8.7Hz,1H,ArH),6.21(s,2H,OCH2O),1.35(s,12H,4CH3).
(R)-3-(4-氨基-3-(7-(2-(二甲基氨基)苯甲酰氨基)苯并[d][1,3]二氧杂环戊烷-4-基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(Ⅴ-6)的合成
以化合物Ⅳ-6(0.85g,2.10mmol)和化合物Ⅲ(0.84g,1.88mmol)为原料，操作同化合物Ⅴ-3的合成，得到黄色固体444mg，产率39.3％。1H NMR(300MHz,DMSO-d6)δ(ppm):10.10(s,1H,NHCO),8.24(s,1H,ArH),8.11(d,J＝7.8Hz,1H,ArH),8.01(d,J＝8.7Hz,1H,ArH),7.59(d,J＝6.9Hz,1H,ArH),7.52(d,J＝6.8Hz,1H,ArH),7.42(d,J＝8.1Hz,1H,ArH),6.98(d,J＝8.7Hz,1H,ArH),6.21(s,2H,OCH2O),4.78-4.56(m,1H,NCH 2CH),4.35-4.22(m,2H,NCH 2CH),3.57-3.31(m,1H,NCH 2CH2),3.39(s,6H,N(CH3)2)3.17-2.99(m,1H,NCH 2CH2),2.29-2.09(m,1H,NCH2CHCH 2),2.16-2.02(m,1H,NCH2CHCH 2),1.98-1.85(m,1H,NCH2CH 2),1.66-1.43(m,1H,NCH2CH 2),1.33(s,9H,NBoc).
(R)-N-(7-(4-氨基-1-(哌啶-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烷-4-基)-2-(二甲基氨基)苯甲酰胺(Ⅵ-6)的合成
以化合物Ⅴ-6(0.41g,0.68mmol)为原料，操作同化合物Ⅵ-3，得到淡黄色固体300mg，产率88.2％。
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烷-4-基)-2-(二甲基氨基)苯甲酰胺(Ⅰ-6)的合成
以化合物Ⅵ-6(0.30g,0.60mmol)为原料，操作同化合物Ⅰ-3的合成，得到白色固体63mg，产率19.0％。HPLC纯度:95.38％。1H NMR(400MHz,DMSO-d6)δ(ppm):13.09(s,1H,NHCO),8.23(s,1H,ArH),8.08(dd,J＝7.8,1.7Hz,1H,ArH),7.97(d,J＝8.7Hz,1H,ArH),7.60(t,J＝6.8Hz,1H,ArH),7.53(d,J＝8.1Hz,1H,ArH),7.33(t,J＝7.4Hz,1H,ArH),7.05(d,J＝8.7Hz,1H,ArH),6.91-6.82(m,1H,CH＝CH2),6.22(s,2H,OCH2O),6.12(m,1H,CH＝CH 2),5.76-5.57(m,1H,CH＝CH 2),4.75-4.67(m,1H,NCH 2CH),4.64-4.55(m,0.5H,NCH2CH),4.30-4.20m,1H,NCH 2CH),4.14-4.03(m,0.5H,NCH2CH),3.75-3.57(m,0.5H,NCH 2CH2),3.26-3.16(m,1H,NCH 2CH2),3.02-2.91(m,0.5H,NCH 2CH2),2.80(s,6H,N(CH3)2),2.32-2.22(m,1H,NCH2CHCH 2),2.17-2.08(m,1H,NCH2CHCH 2),1.97-1.87(m,1H,NCH2CH 2),1.66-1.51(m,1H,NCH2CH 2).13C NMR(101MHz,DMSO-d6)δ(ppm):165.03,163.97,158.53,156.16,154.14,152.87,145.73,138.98,138.03,133.37,130.96,128.85,127.88,127.25,125.24,123.36,123.09,122.14,115.06,110.69,102.62,99.05,53.38(0.5C),52.61(0.5C),49.72(0.5C),46.18(0.5C),45.60(0.5C),45.42,42.03(0.5C),30.00(0.5C),29.90(0.5C),25.41(0.5C),23.88(0.5C).
实施例7
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烷-4-基)-4-吗啉苯甲酰胺(Ⅰ-7)的合成4-吗啉基-N-(7-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯并[d][1,3]-二氧杂环戊烷-4-基)苯甲酰胺(Ⅳ-7)的合成
以4-吗啉基苯甲酸(0.75g,3.64mmol)化合物XI-2(0.80g,3.04mmol)为原料，操作同化合物Ⅳ-3，得淡黄色固体1.37g，产率99.7％。1H NMR(400MHz,CDCl3)δ(ppm):7.84(m,4H,ArH),6.91(d,J＝8.4Hz,2H,ArH),6.06(s,2H,OCH2O),3.92-3.82(m,4H,N(CH2 CH2)2O),3.34-3.23(m,4H,N(CH2CH2 O)2),1.35(s,12H,4CH3).
(R)-3-(4-氨基-3-(7-(4-吗啉苯甲酰氨基)苯并[d][1,3]二氧杂环戊烷-4-基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(Ⅴ-7)的合成
以化合物Ⅳ-7(1.27g,2.81mmol)和化合物Ⅲ(1.00g,2.26mmol)为原料，操作同化合物Ⅴ-3的合成，得到黄色固体374mg，产率25.8％。1H NMR(300MHz,DMSO-d6)δ(ppm):9.91(s,1H,NHCO),8.23(s,1H,ArH),7.90(d,J＝8.7Hz,2H,ArH),7.18(d,J＝8.6Hz,1H,ArH),7.01(m,3H,ArH),6.13(s,2H,OCH2O),5.75(s,2H,NH2),4.71-4.61(m,1H,NCH 2CH),4.19-4.01(m,1H,NCH2CH),3.98-3.87(m,1H,NCH 2CH),3.76-3.72(m,4H,N(CH2 CH2)2O),3.38-3.37(m,1H,NCH 2CH2),3.27-3.23(m,4H,N(CH2CH2 ) 2 O),3.05-2.92(m,1H,NCH 2CH2),2.24-2.16(m,1H,NCH2CHCH 2),2.11-2.04(m,1H,NCH2CHCH 2),1.97-1.87(m,1H,NCH2CH 2),1.59-1.51(m,1H,NCH2CH 2),1.28(s,9H,NBoc).
(R)-N-(7-(4-氨基-1-(哌啶-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烷-4-基)-4-吗啉苯甲酰胺(Ⅵ-7)的合成
以化合物Ⅴ-7(0.37g,0.58mmol)为原料，操作过程同化合物Ⅵ-3的合成过程，得到白色固体0.26g，产率82.7％。
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烷-4-基)-4-吗啉苯甲酰胺(Ⅰ-7)的合成
以化合物Ⅵ-7(250mg,0.46mmol)为原料，操作同化合物Ⅰ-3的合成，得到白色固体80mg，产率29.1％。HPLC纯度:97.79％。1H NMR(400MHz,DMSO-d6)δ(ppm):9.90(s,1H,NHCO),8.23(s,1H,ArH),7.92(s 1H,ArH),7.91(d,J＝6.8Hz,1H,ArH),7.20(d,J＝8.6Hz,1H,ArH),7.06-7.01(m,3H,ArH),6.85-6.73(m,1H,CH＝CH2),6.14(s,2H,OCH2O),6.11-6.06(m,1H,CH＝CH 2),5.90(s,2H,NH2),5.74-5.57(m,1H,CH＝CH 2),4.75-4.64(m,1H,NCH 2CH),4.59-4.53(m,0.5H,NCH2CH),4.29-4.18(m,1H,NCH 2CH),4.11-4.04(m,0.5H,NCH2CH),3.80-3.74(m,4H,N(CH2 CH2)2O),3.72-3.65(m,0.5H,NCH 2CH2),3.32-3.21(m,4H,N(CH2CH 2)2O),3.22-3.15(m,1H,NCH 2CH2),3.01-2.90(m,0.5H,NCH 2CH2),2.32-2.20(m,1H,NCH2CHCH 2),2.14-2.08(m,1H,NCH2CHCH 2),1.96-1.88(m,1H,NCH2CH 2),1.65-1.52(m,1H,NCH2CH 2).
实施例8
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烷-4-基)-4-(吡咯烷-1-基)苯甲酰胺(Ⅰ-8)的合成
4-吡咯烷-1-基-N-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯并[d][1,3]二氧杂环戊烷-4-基)苯甲酰胺(Ⅳ-8)的合成
以4-(吡咯烷-1-基)苯甲酸(0.61g,3.19mmol)化合物XI-2(0.70g,2.66mmol)为原料，操作同化合物Ⅳ-3，得淡黄色固体1.13g，产率97.4％。1H NMR(300MHz,DMSO-d6)δ(ppm):9.68(s,1H,NHCO),7.83(d,J＝8.5Hz,2H,ArH),7.02(s,2H,ArH),6.56(d,J＝8.9Hz,2H,ArH),6.03(s,2H,OCH2O),3.31-3.26(m,4H,N(CH2 CH2)2),1.98-1.94(m,4H,N(CH2CH2 )2),1.27(s,12H,4CH3).
(R)-3-(4-氨基-3-(7-(4-(吡咯烷-1-基)苯甲酰氨基)苯并[d][1,3]二氧杂环戊烷-4-基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(Ⅴ-8)的合成
以化合物Ⅳ-8(1.12g,2.54mmol)和化合物Ⅲ(1.03g,2.32mmol)为原料，操作同化合物Ⅴ-3的合成，得到黄色固体0.42g，产率28.9％。1H NMR(400MHz,DMSO-d6)δ(ppm):9.73(s,1H,NHCO),8.24(s,1H,ArH),7.87(d,J＝8.78Hz,2H,ArH),7.19(d,J＝8.6Hz,1H,ArH),7.01(d,J＝8.6Hz,1H,ArH),6.59(d,J＝8.9Hz,2H,ArH),6.12(s,2H,OCH2O),5.64(s,2H,NH2),4.70-4.65(m,1H,NCH 2CH),4.17-4.02(m,1H,N CH2CH),3.87-3.78(m,1H,NCH 2CH),3.57-3.56(m,0.5H,NCH 2CH2),3.35-3.29(m,4H,N(CH2 CH2)2),3.06-3.01(m,0.5H,NCH 2CH2),3.00-2.92(m,1H,NCH 2CH2),2.65-2.39(m,1H,NCH2CHCH 2),2.23-2.15(m,1H,NCH2CHCH 2),2.12-2.07(m,1H,NCH2CH 2),2.00-1.95(m,4H,N(CH2CH2 )2),1.60-1.54(m,1H,NCH2CH 2),1.34(s,9H,NBoc).
(R)-N-(7-(4-氨基-1-(哌啶-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烷-4-基)-4-(吡咯烷-1-基)苯甲酰胺(Ⅵ-8)的合成
以化合物Ⅴ-8(0.378g,0.61mmol)为原料，操作过程同化合物Ⅵ-3的合成过程，得白色固体0.27g，产率84.1％。
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烷-4-基)-4-(吡咯烷-1-基)苯甲酰胺(Ⅰ-8)的合成
以化合物Ⅵ-8(254mg,0.48mmol)为原料，操作同化合物Ⅰ-3的合成，得到白色固体60mg，产率21.5％。HPLC纯度:97.98％。1H NMR(300MHz,DMSO-d6)δ(ppm):9.74(s,1H,NHCO),8.23(s,1H,ArH),7.87(d,J＝8.4Hz,2H,ArH),7.20(d,J＝8.5Hz,1H,ArH),7.01(d,J＝8.5Hz,1H,ArH),6.94-6.68(m,1H,CH＝CH2),6.59(d,J＝8.5Hz,2H,ArH),6.20-6.03(m,3H,OCH2O,CH＝CH 2),5.77-5.56(m,1H,CH＝CH 2),4.79-4.62(m,1H,NCH 2CH),4.62-4.69(m,0.5H,NCH2CH),4.34-4.15(m,1H,NCH 2CH),4.14-4.00(m,0.5H,NCH2CH),3.75-3.65(m,0.5H,NCH 2CH2),3.27-3.13(m,1H,NCH 2CH2),3.41-3.28(m,4H,N(CH2 CH2)2),3.04-2.88(m,0.5H,NCH 2CH2),2.35-2.19(m,1H,NCH2CHCH 2),2.16-2.07(m,1H,NCH2CHCH 2),2.03-1.87(m,4H,N(CH2CH2 )2),1.71-1.50(m,1H,NCH2CH 2),1.31-1.19(m,1H,NCH2CH 2).
实施例9
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烷-4-基)-4-(1-氰基)乙基苯甲酰胺(Ⅰ-9)的合成4-((1-氰基)乙基)-N-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯并[d][1,3]-二氧杂环戊烷-4-基)苯甲酰胺(Ⅳ-9)的合成
以4-(1-氰基)乙基苯甲酸(0.44g,2.53mmol)和化合物XI-2(0.60g,2.28mmol)为原料，操作同化合物Ⅳ-3，得淡黄色固体0.71g，产率74.1％。1H NMR(400MHz,CDCl3)δ(ppm):10.50(s,1H,NHCO),7.90-7.86(m,2H,ArH),7.81(d,J＝7.6Hz,2H,ArH),7.59(d,J＝7.8Hz,1H,ArH),7.53(d,J＝7.7Hz,1H,ArH),6.07(s,2H,OCH2O),4.92(q,J＝7.3Hz,1H,CH3CHCN),1.71(d,J＝6.0Hz,3H,CH3),1.31(s,12H,4CH3).
(R)-3-(4-氨基-3-(7-(4-((1-氰基)乙基)苯甲酰氨基)苯并[d][1,3]二氧杂环戊烷-4-基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(Ⅴ-9)的合成
以化合物Ⅳ-9(0.7g,1.67mmol)和化合物Ⅲ(0.74g,1.67mmol)为原料，操作同化合物Ⅴ-3的合成，得到黄色固体374mg，产率36.7％。
(R)-N-(7-(4-氨基-1-哌啶-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烷-4-基)-4-((1-氰基)乙基)苯甲酰胺(Ⅵ-9)的合成
以化合物Ⅴ-9(0.37g,0.61mmol)为原料，操作过程同化合物Ⅵ-3的合成过程，得白色固体0.31g，产率99.7％。
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烷-4-基)-4-((1-氰基)乙基)苯甲酰胺(Ⅰ-9)的合成
以化合物Ⅵ-9(300mg,0.59mmol)为原料，操作同化合物Ⅰ-3的合成，得到白色固体137mg，产率41.3％。HPLC纯度:98.28％。1H NMR(400MHz,DMSO-d6)δ(ppm):10.34(s,1H,CONH),8.24(s,1H,ArH),8.03(s,1H,ArH),7.97(d,J＝7.7Hz,1H,ArH),7.66(d,J＝7.8Hz,1H,ArH),7.59(t,J＝7.7Hz,1H,ArH),7.22(d,J＝8.6Hz,1H,ArH),7.06(d,J＝8.5Hz,1H,ArH),6.91-6.72(m,1H,CH＝CH2),6.17(s,2H),6.14-6.03(m,1H,CH＝CH 2),5.73-5.60(m,1H,CH＝CH 2),4.79-4.65(m,1H,NCH 2CH),4.60-4.46(m,0.5H,NCH2CH),4.44(q,J＝7.2Hz,1H,CHCN),4.52-4.18(m,1H,NCH 2CH),4.13-4.04(m,0.5H,NCH2CH),3.75-3.64(m,0.5H,NCH 2CH2),3.27-3.17(m,1H,NCH 2CH2),3.02-2.92(m,0.5H,NCH 2CH2),2.34-2.21(m,1H,NCH2CHCH 2),2.17-2.09(m,1H,NCH2CHCH 2),1.96-1.88(m,1H,NCH2CH 2),1.63-1.53(m,4H,CH3 ,NCH2CH 2).13C NMR(101MHz,DMSO-d6)δ(ppm):165.07,165.04,158.54,156.18,154.17,146.38,141.46,138.89,138.46,135.19,130.76,129.70,128.79,127.97,127.88,126.88,122.56,121.71,119.42,112.15,102.18,99.09,53.40(0.5C),52.63(0.5C),49.72(0.5C),46.18(0.5C),45.62(0.5C),30.30,30.09(0.5C),29.86(0.5C),25.40(0.5C),23.86(0.5C),21.04.
实施例10
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烷-4-基)-4-氟-2-(三氟甲基)苯甲酰胺(Ⅰ-10)的合成
4-氟-N-(7-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯并[d][1,3]二氧杂环戊烷-4-基)-2-(三氟甲基)苯甲酰胺(Ⅳ-10)的合成
以4-氟-2-(三氟甲基)苯甲酸(0.96g,4.60mmol)和化合物XI-2(1.00g,3.80mmol)为原料，操作同化合物Ⅳ-3，得淡黄色固体0.98g，产率60.0％。1H NMR(400MHz,DMSO-d6)δ(ppm):10.48(s,1H,NHCO),7.81-7.69(m,2H,ArH),7.64(td,J＝8.5,2.6Hz,1H,ArH),7.30(d,J＝8.4Hz,1H,ArH),7.07(d,J＝8.4Hz,1H,ArH),6.07(s,2H,OCH2O),1.29(s,12H,4CH3).
(R)-3-(4-氨基-3-(4-(4-氟-2-(三氟甲基)苯甲酰氨基)苯并[d][1,3]二氧杂环戊烷-4-基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(Ⅴ-10)的合成
以化合物Ⅳ-10(0.80g,1.77mmol)和化合物Ⅲ(0.75g,1.77mmol)为原料，操作同化合物Ⅴ-3的合成，得到黄色固体1.06g，产率93.1％。1H NMR(300MHz,DMSO-d6)δ(ppm):10.16(s,1H,NHCO),8.77(d,J＝2.8Hz,1H,ArH),8.27(dd,J＝8.7,4.6Hz,1H,ArH),8.22(s,1H,ArH),8.02(td,J＝8.7,2.8Hz,1H,ArH),7.71(d,J＝8.6Hz,1H,ArH),7.06(d,J＝8.6Hz,1H,ArH),6.20(s,2H,OCH2O),5.75(s,2H,NH2),4.73-4.60(m,1H,NCH 2CH),4.20-3.95(m,1H,NCH2CH),3.90-3.70(m,1H,NCH 2CH),3.09-2.82(m,2H,NCH2 CH2),2.29-2.12(m,1H,NCH2CHCH 2),2.11-2.01(m,1H,NCH2CHCH 2),1.99-1.84(m,1H,NCH2CH 2),1.60-1.50(m,1H,NCH2CH 2),1.34(s,9H,NBoc).
(R)-N-(7-(4-氨基-1-(哌啶-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烷-4-基)-4-氟-2-(三氟甲基)苯甲酰胺(Ⅵ-10)的合成
以化合物Ⅴ-10(0.82g,1.27mmol)为原料，操作过程同化合物Ⅵ-3的合成过程，得淡黄色固体0.64g，产率92.8％。
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烷-4-基)-4-氟-2-(三氟甲基)苯甲酰胺(Ⅰ-10)的合成
以化合物Ⅵ-10(0.60g,1.10mmol)为原料，操作同化合物Ⅰ-3的合成，得到白色固体160mg，产率24.3％。HPLC纯度:98.30％。1H NMR(400MHz,DMSO-d6)δ(ppm):10.55(s,1H,ArH),8.23(s,1H,ArH),7.81-7.79(m,1H,ArH),7.77(dd,J＝6.2,3.8Hz,1H,ArH),7.67(td,J＝8.4,2.6Hz,1H,ArH),7.43(d,J＝8.7Hz,1H,ArH),7.05(d,J＝8.6Hz,1H,ArH),6.92-6.70(m,1H,CH＝CH2),6.17(s,2H,OCH2O),6.13-6.02(m,1H,CH＝CH 2),5.76-5.59(m,1H,CH＝CH 2),4.78-4.64(m,1H,NCH 2CH),4.62-4.52(m,0.5H,NCH2CH),4.31-4.18(m,1H,NCH 2CH),4.15-4.07(m,0.5H,NCH2CH),3.78-3.60(m,0.5H,NCH 2CH2),3.26-3.16(m,1H,NCH 2CH2),3.02-2.92(m,0.5H,NCH 2CH2),2.34-2.20(m,1H,NCH2CHCH 2),2.18-2.06(m,1H,NCH2CHCH 2),2.00-1.88(m,1H,NCH2CH 2),1.68-1.51(m,1H,NCH2CH 2).
实施例11
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烷-4-基)-3-氯-4-(三氟甲基)苯甲酰胺(Ⅰ-11)的合成3-氯-N-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯并[d][1,3]二氧杂环戊烷-4-基)-4-三氟甲基苯甲酰胺(Ⅳ-11)的合成
以3-氯-(4-三氟甲基)苯甲酸(0.82g,3.64mmol)和化合物XI-2(0.8g,3.00mmol)为原料，操作同化合物Ⅳ-3，得淡黄色固体1.32g，产率93.8％。
(R)-3-(4-氨基-3-(7-(3-氯-4-(三氟甲基)苯甲酰氨基)苯并[1,3]二氧杂环戊烷-4-基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(Ⅴ-11)的合成
以化合物Ⅳ-11(1.10g,2.34mmol)和化合物Ⅲ(0.99g,2.23mmol)为原料，操作同化合物Ⅴ-3的合成，得到黄色固体1.16g，产率78.9％。1H NMR(300MHz,DMSO-d6)δ(ppm):10.62(s,1H,NHCO),8.42(s,1H,ArH),8.27(dd,J＝8.4,2.2Hz,1H,ArH),8.22(s,1H,ArH),7.93(d,J＝8.4Hz,1H,ArH),7.21(d,J＝8.5Hz,1H,ArH),7.05(d,J＝8.6Hz,1H,ArH),6.16(s,2H,OCH2O),5.68(s,2H,NH2),4.73-4.62(m,1H,NCH 2CH),4.05-3.97(m,1H,NCH2CH),3.93-3.75(m,1H,NCH 2CH),3.57-3.56(m,1H,NCH 2CH2),3.06-2.91(m,1H,NCH 2CH2),2.24-2.15(m,1H,NCH2CHCH 2),2.12-2.02(m,1H,NCH2CHCH 2),1.96-1.85(m,1H,NCH2CH 2),1.62-1.50(m,1H,NCH2CH 2),1.34(s,9H,NBoc).
(R)-N-(7-(4-氨基-1-(哌啶-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烷-4-基)-3-氯-(4-三氟甲基)苯甲酰胺(Ⅵ-11)的合成
以化合物Ⅴ-11(1.11g,1.68mmol)为原料，操作过程同化合物Ⅵ-3的合成过程，得褐色固体0.86g，产率91.5％。
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烷-4-基)-3-氯-4-(三氟甲基)苯甲酰胺(Ⅰ-11)的合成
以化合物Ⅵ-11(860mg,1.54mmol)为原料，操作同化合物Ⅰ-3的合成，得到白色固体422mg，产率44.6％。HPLC纯度:98.83％。1H NMR(400MHz,DMSO-d6)δ(ppm):10.62(s,1H,CONH),8.43(d,J＝2.1Hz,1H,ArH),8.28(dd,J＝8.4,2.2Hz,1H,ArH),8.24(s,1H,ArH),7.94(d,J＝8.4Hz,1H,ArH),7.23(d,J＝8.6Hz,1H,ArH),7.07(d,J＝8.5Hz,1H,ArH),6.96-6.69(m,1H,CH＝CH2),6.17(s,2H,OCH2O),6.15-6.04(m,1H,CH＝CH 2,5.75-5.57(m,1H,CH＝CH 2),4.79-4.61(m,1H,NCH 2CH),4.61-4.50(m,0.5H,NCH2CH),4.32-4.17(m,1H,NCH 2CH),4.13-4.05(m,0.5H,NCH2CH),3.79-3.59(m,0.5H,NCH 2CH2),3.30-3.11(m,1H,NCH 2CH2),3.08-2.91(m,0.5H,NCH 2CH2),2.36-2.22(m,1H,NCH2CHCH 2),2.20-2.09(m,1H,NCH2CHCH 2),2.02-1.89(m,1H,NCH2CH 2),1.64-1.57(m,1H,NCH2CH 2).
实施例12
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烷-4-基)-2,4-双(三氟甲基)苯甲酰胺(Ⅰ-12)的合成
N-(7-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯并[d][1,3]二氧杂环戊烷-4-基)-2,4-双(三氟甲基)苯甲酰胺(Ⅳ-12)的合成
以2,4-双(三氟甲基)苯甲酸(0.94g,3.64mmol)和化合物XI-2(0.80g,3.00mmol)为原料，操作同化合物Ⅳ-3，得淡黄色固体1.26g，产率83.4％。1H NMR(300MHz,DMSO-d6)δ(ppm):10.65(s,1H,NHCO),8.18(d,J＝7.2Hz,2H,ArH),7.92(d,J＝8.0Hz,1H,ArH),7.36(d,J＝8.4Hz,1H,ArH),7.09(d,J＝8.4Hz,1H,ArH),6.09(s,2H,OCH2O),1.28(s,12H,4CH3).
(R)-3-(4-氨基-3-(7-(2,4-双(三氟甲基)苯甲酰氨基)苯并[1,3]二氧杂环戊烷-4-基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(Ⅴ-12)的合成
以化合物Ⅳ-12(1.17g,2.33mmol)和化合物Ⅲ(0.98g,2.21mmol)为原料，操作同化合物Ⅴ-3的合成，得到黄色固体1.24g，产率80.9％。
(R)-N-(7-(4-氨基-1-(哌啶-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烷-4-基)-2,4-双(三氟甲基)苯甲酰胺(Ⅵ-12)的合成
以化合物Ⅴ-12(1.10g,1.59mmol)为原料，操作过程同化合物Ⅵ-3的合成过程，得淡黄色固体0.93g，产率98.6％。
(R)-N-(7-1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烷-4-基)-2,4-双(三氟甲基)苯甲酰胺(Ⅰ-12)的合成
以化合物Ⅵ-12(0.93g,1.57mmol)为原料，操作同化合物Ⅰ-3的合成，得到白色固体410mg，产率40.3％。HPLC纯度:97.38％。1H NMR(400MHz,DMSO-d6)δ(ppm):10.71(s,1H,NHCO),10.09(s,1H,ArH),8.22(s,1H,ArH),8.19(s,1H,ArH),7.94(d,J＝7.9Hz,1H,ArH),7.48(d,J＝8.6Hz,1H,ArH),7.05(d,J＝8.6Hz,1H,ArH),6.91-6.79(m,,1H,CH＝CH2),6.17(s,2H,OCH2O),6.12-6.05(m,1H,CH＝CH 2),5.89(s,2H,NH2),5.74-5.58(m,1H,CH＝CH 2),4.75-4.65(m,1H,NCH 2CH),4.59-4.53(m,0.5H,NCH2CH),4.29-4.17(m,1H,NCH 2CH),4.12-4.04(m,0.5H,NCH2CH),3.74-3.65(m,0.5H,NCH 2CH),3.24-3.14(m,1H,NCH 2CH2),2.99-2.93(m,0.5H,NCH 2CH2),2.32-2.21(m,1H,NCH2CHCH 2),2.16-2.08(m,1H,NCH2CHCH 2),1.98-1.89(m,1H,NCH2CH 2),1.65-1.53(m,1H,NCH2CH 2).
实施例13
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烷-4-基)-5-氟吡啶甲酰胺(Ⅰ-13)的合成5-氟-N-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯并[d][1,3]二氧杂环戊烷-4-基)吡啶甲酰胺(Ⅳ-13)的合成
以5-氟-2-吡啶甲酸(0.65g,4.60mmol)和化合物XI-2(1.00g,3.80mmol)为原料，操作同化合物Ⅳ-3，得淡黄色固体1.04g，产率70.9％。
(R)-3-(4-氨基-3-(7-(5-氟吡啶酰氨基)苯并[1,3]二氧杂环戊烷-4-基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(Ⅴ-13)的合成
以化合物Ⅳ-13(0.8g,2.07mmol)和化合物Ⅲ(0.87g,1.97mmol)为原料，操作同化合物Ⅴ-3的合成，得到黄色固体1.06g，产率93.4％。1H NMR(300MHz,DMSO-d6)δ(ppm):10.16(s,1H,NHCO),8.77(d,J＝2.8Hz,1H,ArH),8.27(dd,J＝8.7,4.6Hz,1H,ArH),8.22(s,1H,ArH),8.02(td,J＝8.7,2.8Hz,1H,ArH),7.71(d,J＝8.6Hz,1H,ArH),7.06(d,J＝8.6Hz,1H,ArH),6.20(s,2H,OCH2O),5.75(s,2H,NH2),4.73-4.60(m,1H,NCH 2CH),4.20-3.95(m,1H,NCH2CH),3.90-3.70(m,1H,NCH 2CH),3.09-2.82(m,2H,NCH 2CH2),2.29-2.12(m,1H,NCH2CHCH 2),2.11-2.01(m,1H,NCH2CHCH 2),1.99-1.84(m,1H,NCH2CH 2),1.60-1.50(m,1H,NCH2CH 2),1.34(s,9H,NBoc).
(R)-N-(7-(4-氨基-1-(哌啶-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烷-4-基)-5-氟吡啶甲酰胺(Ⅵ-13)的合成
以化合物Ⅴ-13(1.00g,1.73mmol)为原料，操作过程同化合物Ⅵ-3的合成过程，得淡黄色固体0.79g，产率96.1％。
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烷-4-基)-5-氟吡啶甲酰胺(Ⅰ-13)的合成
以化合物Ⅵ-13(0.78g,1.64mmol)为原料，操作同化合物Ⅰ-3的合成，得到白色固体450mg，产率51.7％。HPLC纯度:98.36％。1H NMR(400MHz,DMSO-d6)δ(ppm):10.52(s,1H,NHCO),8.23(s,1H,ArH),8.13(d,J＝8.26Hz,2H,ArH),8.03(d,J＝8.4Hz,2H,ArH),7.21(d,J＝8.6Hz,1H,ArH),7.05(d,J＝8.6Hz,1H,ArH),6.89-6.74(m,1H,CH＝CH2),6.16(s,2H,OCH2O),6.13-6.03(m,1H,CH＝CH 2),5.91(s,2H,NH2),5.75-5.57(m,1H,CH＝CH2),4.77-4.63(m,1H,NCH 2CH),4.60-4.52(m,0.5H,NCH2CH),4.28-4.17(m,1H,NCH 2CH),4.11-4.05(m,0.5H,NCH2CH),3.72-3.64(m,0.5H,NCH 2CH2),3.26-3.15(m,1H,NCH 2CH2),3.00-2.92(m,0.5H,NCH 2CH2),2.32-2.20(m,1H,NCH2CHCH 2),2.16-2.07(m,1H,NCH2CHCH 2),1.96-1.89(m,1H,NCH2CH 2),1.66-1.53(m,1H,NCH2CH 2).
实施例14
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烷-4-基)-6-甲氧基烟酰胺(Ⅰ-14)的合成6-甲氧基-N-(7-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯并[d][1,3]二氧杂环戊烷-4-基)烟酰胺(Ⅳ-14)的合成
以6-甲氧基烟酸(0.52g,3.60mmol)和化合物XI-2(0.80g,3.00mmol)为原料，操作同化合物Ⅳ-3，得淡黄色固体0.78g，收率65.3％。1H NMR(300MHz,DMSO-d6)δ(ppm):10.62(s,1H,NHCO),8.15(d,J＝7.2Hz,2H,ArH),7.89(d,J＝8.0Hz,1H,ArH),7.33(d,J＝8.4Hz,1H,ArH),7.06(d,J＝8.4Hz,1H,ArH),6.06(s,2H,OCH2O),1.25(s,12H,4CH3).
(R)-3-(4-氨基-3-(7-(6-甲氧基烟酰胺基)苯并[1,3]二氧杂环戊烷-4-基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(Ⅴ-14)的合成
以化合物Ⅳ-14(0.70g,1.76mmol)和化合物Ⅲ(0.74g,1.67mmol)为原料，操作同化合物Ⅴ-3的合成，得到黄色固体0.95g，产率96.7％。1H NMR(300MHz,DMSO-d6)δ(ppm):10.28(s,1H,NHCO),8.81(d,J＝2.5Hz,1H,ArH),8.26(d,J＝3.0Hz,1H,ArH),8.23(s,1H,ArH),7.19(d,J＝8.6Hz,1H,ArH),7.03(d,J＝8.5Hz,1H,ArH),6.96(d,J＝8.7Hz,1H,ArH),6.15(s,2H,OCH2O),5.68(s,2H,NH2),4.72-4.61(m,1H,NCH 2CH),4.22-4.08(m,0.5H,NCH2CH),3.94(s,3H,OCH3),3.92-3.90(m,0.5H,NCH2CH),3.84-3.72(m,1H,NCH 2CH),3.59-3.45(m,0.5H,NCH 2CH2),3.18-3.15(m,0.5H,NCH 2CH2),3.07-2.90(m,1H,NCH 2CH2),2.28-2.16(m,1H,NCH2CHCH 2),2.12-2.02(m,1H,NCH2CHCH 2),1.99-1.87(m,1H,NCH2CH 2),1.60-1.50(m,1H,NCH2CH 2),1.34(s,9H,NBoc).
(R)-N-(7-(4-氨基-1-(哌啶-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烷-4-基)-6-甲氧基烟酰胺(Ⅵ-14)的合成
以化合物Ⅴ-14(0.94g,1.60mmol)为原料，操作过程同化合物Ⅵ-3的合成过程，得褐色固体0.66g，产率84.4％。
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烷-4-基)-6-甲氧基烟酰胺(Ⅰ-14)的合成
以化合物Ⅵ-14(0.60g,1.23mmol)为原料，操作同化合物Ⅰ-3的合成，得到白色固体122mg，产率18.3％。HPLC纯度:96.38％。1H NMR(400MHz,DMSO-d6)δ(ppm):10.28(s,1H,NHCO),8.82(s,1H,ArH),8.30-8.22(m,2H,ArH),7.21(d,J＝8.6Hz,1H,ArH),7.05(d,J＝8.6Hz,1H,ArH),6.97(d,J＝8.7Hz,1H,ArH),6.93-6.69(m,1H,CH＝CH2),6.16(s,2H,OCH2O),6.14-6.05(m,1H,CH＝CH 2),5.79-5.55(m,1H,CH＝CH 2),4.78-4.65(m,1H,NCH 2CH),4.64-4.51(m,0.5H,NCH2CH),4.34-4.16(m,1H,NCH 2CH),4.17-3.99(m,0.5H,NCH2CH),3.95(s,3H,OCH3),3.77-3.64(m,0.5H,NCH2CH2 ),3.26-3.12(m,1H,NCH 2CH2),3.08-2.93(m,0.5H,NCH2CH2 ),2.31-2.23(m,1H,NCH2CHCH 2),2.17-2.07(s,1H,NCH2CHCH2 ),1.97-1.88(m,1H,NCH2CH2 ),1.69-1.51(m,1H,NCH2CH2 ).
实施例15
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烷-4-基)-呋喃-2-甲酰胺(Ⅰ-15)的合成
N-(7-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯并[d][1,3]二氧杂环戊烷-4-基)呋喃-2-甲酰胺(Ⅳ-15)的合成
以呋喃-2-甲酸(0.51g,4.56mmol)和化合物XI-2(1.00g,3.80mmol)为原料，操作同化合物Ⅳ-3，得淡黄色固体1.24g，产率91.4％。1H NMR(300MHz,DMSO-d6)δ(ppm):9.98(s,1H,NHCO),7.96-7.92(m,1H,ArH),7.35(dd,J＝3.5,0.8Hz,1H,ArH),7.06(s,2H,ArH),6.70(dd,J＝3.5,1.7Hz,1H,ArH),6.07(s,2H,OCH2O),1.29(s,12H,4CH3).
(R)-3-(4-氨基-3-(7-(呋喃-2-甲酰氨基)苯并[d][1,3]二氧杂环戊烷-4-基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(Ⅴ-15)的合成
以化合物Ⅳ-15(1.14g,3.19mmol)和化合物Ⅲ(1.35g,3.04mmol)为原料，操作同化合物Ⅴ-3的合成，得到黄色固体1.43g，收率86.0％。
(R)-N-(7-(4-氨基-1-(哌啶-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烷-4-基)-呋喃-2-甲酰胺(Ⅵ-15)的合成
以化合物Ⅴ-15(1.43g,2.61mmol)为原料，操作过程同化合物Ⅵ-3的合成过程，得淡黄色固体1.13g，产率96.8％。
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烷4-基)-呋喃-2-甲酰胺(Ⅰ-15)的合成
以化合物Ⅵ-15(1.13g,2.25mmol)为原料，操作同化合物Ⅰ-3的合成，得到白色固体238mg，产率22.2％。m.p.158-160℃。HPLC纯度:97.79％。1H NMR(400MHz,DMSO-d6)δ(ppm):10.05(s,1H,ArH),8.24(s,1H,ArH),7.96(d,J＝1.8Hz,1H,ArH),7.38(d,J＝7.5Hz,1H,ArH),7.21(d,J＝8.6Hz,1H,ArH),7.04(d,J＝8.6Hz,1H,ArH),6.92-6.76(m,1H,CH＝CH2),6.72(dd,J＝3.5,1.8Hz,1H,ArH),6.16(s,2H,OCH2O),6.14 -6.04(m,1H,CH＝CH 2),5.75-5.58(m,1H,CH＝CH 2),4.77-4.65(m,1H,NCH 2CH),4.61-4.50(m,0.5H,NCH2CH),4.30-4.18(m,1H,NCH 2CH),4.10-4.03(m,0.5H,NCH2CH),3.74-3.60(m,0.5H,NCH 2CH2),3.25-3.16(m,1H,NCH 2CH2),3.00-2.94(m,0.5H,NCH 2CH2),2.33-2.21(m,1H,NCH2CHCH 2),2.17-2.06(m,1H,NCH2CHCH 2),1.97-1.88(m,1H,NCH2CH 2),1.66-1.54(m,1H,NCH2CH 2).13C NMR(101MHz,DMSO-d6)δ(ppm):165.04,158.53,156.36,156.17,154.20,147.62,146.40,146.36,141.26,138.86,128.78,127.88,122.60,121.05,119.14,115.47,112.62,112.11,102.22,99.07,52.61(0.5C),52.61(0.5C),49.72(0.5C),46.17(0.5C),45.62(0.5C),42.05(0.5C),30.08(0.5C),29.98(0.5C),25.39(0.5C),23.85(0.5C).
实施例16
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烷-4-基)喹啉-2-甲酰胺(Ⅰ-16)的合成
N-(7-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯并[d][1,3]二氧杂环戊烷-4-基)喹啉-2-甲酰胺(Ⅳ-16)的合成
以喹啉-2-甲酸(0.55g,3.19mmol)和化合物XI-2(0.70g,2.66mmol)为原料，操作同化合物Ⅳ-3，得淡黄色固体0.92g，产率71.9％。1H NMR(300MHz,DMSO-d6)δ(ppm):10.37(s,1H,NHCO),8.67(d,J＝8.5Hz,1H,ArH),8.27(dd,J＝8.5,1.3Hz,1H,ArH),8.19(d,J＝8.5Hz,1H,ArH),8.14(dd,J＝8.3,1.4Hz,1H,ArH),7.93(td,J＝4.1,3.2,1.6Hz,2H,ArH),7.81-7.76(m,1H,ArH),7.72(d,J＝8.4Hz,1H,ArH),6.18(s,2H,OCH2O),1.30(s,12H,4CH3).
(R)-3-(4-氨基-3-(7-(喹啉-2-甲酰氨基)苯并[d][1,3]二氧杂环戊烷-4-基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(Ⅴ-16)的合成
以化合物Ⅳ-16(0.83g,1.72mmol)和化合物Ⅲ(0.89g,2.00mmol)为原料，操作同化合物Ⅴ-3的合成，得到黄色固体384mg，产率31.6％。
(R)-N-(7-(4-氨基-1-(哌啶-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烷-4-基)-喹啉-2-甲酰胺(Ⅵ-16)的合成
以化合物Ⅴ-16(0.38g,0.62mmol)为原料，操作过程同化合物Ⅵ-3的合成过程，得淡黄色固体0.31g，产率98.4％。
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烷-4-基)喹啉-2-甲酰胺(Ⅰ-16)的合成
以化合物Ⅵ-16(0.28g,0.55mmol)为原料，操作同化合物Ⅰ-3的合成，得到白色固体137mg，产率49.0％。HPLC纯度:97.92％。1H NMR(400MHz,DMSO-d6)δ(ppm):10.42(s,1H,NHCO),8.69(d,J＝8.5Hz,1H,ArH),8.31(d,J＝8.5Hz,1H,ArH),8.25(s,1H,ArH),8.22(d,J＝8.3Hz,1H,ArH),8.16(d,J＝8.2Hz,1H,ArH),7.94(t,J＝7.7Hz,1H,ArH),7.85(d,J＝8.7Hz,1H,ArH),7.79(t,J＝7.0Hz,1H,ArH),7.11(d,J＝8.6Hz,1H,ArH),6.91-6.72(m,1H,CH＝CH2),6.27(s,2H,OCH2O),6.20-6.05(m,1H,CH＝CH 2),5.77-5.58(m,1H,CH＝CH 2),4.78-4.65(m,1H,NCH 2CH),4.62-4.54(m,0.5H,NCH2CH),4.31-4.19(m,1H,NCH 2CH),4.13-4.00(m,0.5H,NCH2CH 2),3.34-3.16(m,1H,NCH 2CH2),3.02-2.92(m,1H,NCH 2CH2),2.36-2.21(m,1H,NCH2CHCH 2),2.17-2.08(m,1H,NCH2CHCH 2),2.02-1.90(m,1H,NCH2CH 2),1.66-1.53(m,1H,NCH2CH 2).
实施例17
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烷-4-基)-双环[2.2.1]庚烷-1-甲酰胺(Ⅰ-17)的合成N-(7-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯并[d][1,3]二氧杂环戊烷-4-基)双环[2.2.1]庚烷-1-甲酰胺(Ⅳ-17)的合成
以双环[2.2.1]庚烷-1-甲酸(0.65g,4.61mmol)和化合物XI-2(1.00g,3.80mmol)为原料，操作同化合物Ⅳ-3，得淡黄色固体1.39g，产率95.0％。1H NMR(300MHz,DMSO-d6)δ(ppm):9.59(s,1H,ArH),7.28(d,J＝8.4Hz,1H,ArH),7.00(d,J＝8.4Hz,1H,ArH),6.05(s,2H,OCH2O),2.96-2.87(m,1H,(CH2)3CH),2.60-2.54(m,1H,C(CH 2CH2)2),2.25-2.16(m,1H,C(CH 2CH2)2),1.67-1.58(m,2H,C(CH 2CH2)2),1.57-1.45(m,2H,C(CH2CH 2)2),1.44-1.36(m,2H,C(CH2CH 2)2),1.35-1.29(m,2H,CHCH2 C),1.27(s,12H,4CH3).
(R)-3-(4-氨基-3-(7-(双环[2.2.1]庚烷-1-甲酰氨基)苯并[d][1,3]二氧杂环戊烷-4-基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(Ⅴ-17)的合成
以化合物Ⅳ-17(1.09g,2.80mmol)和化合物Ⅲ(1.38g,3.10mmol)为原料，操作同化合物Ⅴ-3的合成，得到黄色固体1.48g，产率91.9％。1H NMR(300MHz,DMSO-d6)δ(ppm):9.66(s,1H,NHCO),8.21(s,1H,ArH),7.42(d,J＝8.7Hz,1H,ArH),6.95(d,J＝8.7Hz,1H,ArH),6.12(s,2H,OCH2O),4.74-4.59(m,1H,NCH 2CH),4.18-3.72(m,1.5H,NCH 2CH,NCH2CH),3.04-2.89(m,1.5H,NCH2CH,(CH2)3CH),2.64-2.55(m,1H,NCH 2CH2),2.26-2.11(m,2H,C(CH2 CH2)2),2.10-2.01(m,1H,NCH 2CH2),1.96-1.81(m,1H,NCH2CHCH 2),1.70-1.61(m,1H,NCH2CHCH 2),1.60-1.56(m,1H,NCH2CH 2),1.55-1.47(m,2H,C(CH2 CH2)2),1.45-1.37(m,5H,C(CH2CH2 )2,NCH2CH 2),1.33(s,9H,NBoc),1.21-1.05(m,2H,CHCH2 C).
(R)-N-(7-(4-氨基-1-(哌啶-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烷-4-基)双环[2.2.1]庚烷-1-甲酰胺(Ⅵ-17)的合成
化合物Ⅴ-17(1.41g,2.46mmol)为原料，操作同化合物Ⅵ-3，得淡黄色固体1.08g，产率92.4％。
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烷-4-基)双环[2.2.1]庚烷-1-甲酰胺(Ⅰ-17)的合成
以化合物Ⅵ-17(1.00g,2.10mmol)为原料，操作同化合物Ⅰ-3的合成，得到白色固体557mg，产率55.8％。HPLC纯度:97.52％。m.p.180-182℃。1H NMR(400MHz,DMSO-d6)δ(ppm):9.63(s,1H,NHCO),8.22(s,1H,ArH),7.43(d,J＝8.7Hz,1H,ArH),6.97(d,J＝8.6Hz,1H,ArH),6.78-6.71(m,1H,CH＝CH2),6.18-6.01(m,3H,CH＝CH 2,OCH2O),5.73-5.59(m,1H,CH＝CH 2),4.70-4.54(m,1H,NCH 2CH),4.59-4.50(m,0.5H,NCH2CH),4.30-4.16(m,1H,NCH 2CH),4.15-4.01(m,0.5H,NCH2CH),3.72-3.63(m.0.5H,NCH 2CH2),3.25-3.12(m,1H,NCH 2CH2),3.01-2.91(m,1H,NCH2CHCH 2),2.63-2.54(m,1H,(CH2)3CH),2.29-2.19(m,2H,C(CH2 CH2)2),2.15-2.06(m,1H,NCH2CHCH 2),1.97-1.82(m,1.5H,NCH 2CH2,NCH2CH 2),1.68-1.61(m,1H,NCH2CH 2,),1.59-1.14(m,8H,C(CH2 CH2 )2,CHCH2 C).13C NMR(101MHz,DMSO-d6)δ172.81,165.03,158.52,156.14,154.10,146.01,139.34,138.64,128.78,127.88,122.85,122.56,117.31,110.85,101.97,99.05,53.36(0.5C),52.58(0.5C),49.71(0.5C),47.06(0.5C),46.84,46.17(0.5C),45.61(0.5C),42.42(0.5C),41.35,40.74,37.14,30.08(0.5C),29.88(0.5C),29.29,28.80,25.40(0.5C),23.87(0.5C).
实施例18
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烷-4-基)金刚烷-1-甲酰胺(Ⅰ-18)的合成
N-(7-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯并[d][1,3]二氧杂环戊烷-4-基)金刚烷-1-甲酰胺(Ⅳ-18)的合成
以1-金刚烷甲酸(0.61g,3.38mmol)和化合物XI-2(0.74g,2.80mmol)为原料，操作同化合物Ⅳ-3，得淡黄色固体1.12g，产率94.1％。1H NMR(300MHz,DMSO-d6)δ(ppm):8.96(s,1H,ArH),7.06-6.86(m,2H,ArH),6.03(s,2H,OCH2O),2.04-1.97(m,3H,3CH(CH2)3),1.96-1.80(m,6H,CH(CH2 )3CH),1.70(m,6H,C(CH2 ) 3 CH),1.28(s,12H,4CH3).
(R)-3-(3-(7-(金刚烷-1-甲酰氨基)苯并[d][1,3]二氧杂环戊烷-4-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(Ⅴ-18)的合成
以化合物Ⅳ-18(0.97g,2.28mmol)和化合物Ⅲ(0.93g,2.09mmol)为原料，操作同化合物Ⅴ-3的合成，得到黄色固体1.10g，产率85.5％。1H NMR(300MHz,DMSO-d6)δ(ppm):.8.96(s,1H,NHCO),8.30(s,1H,ArH),7.56(d,J＝8.4Hz,1H,ArH),7.50(d,J＝8.7Hz,1H,ArH),6.08(s,2H,OCH2O),4.12-3.96(m,1H,NCH 2CH),3.89-3.75(m,1H,NCH2CH),3.73-3.56(m,2H,NCH 2CH,NCH 2CH2),3.50-3.43(m,2H,NCH 2CH2,NCH2CHCH 2),2.36-2.19(m,2H,NCH2CHCH 2,NCH2CH 2),2.14-2.05(m,1H,NCH2CH 2),2.01-1.89(m,1H,CH(CH2)3CH),1.80-1.68(m,6H,CH(CH2 )3CH),1.66-1.49(m,4H,C(CH2 )3CH),1.46-1.37(m,2H,2CH(CH2)3CH),1.34(s,9H,NBoc),1.33-1.28(m,2H,C(CH2 )3CH).
(R)-N-(7-(4-氨基-1-(哌啶-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烷-4-基)-金刚烷-1-甲酰胺(Ⅵ-18)的合成
以化合物Ⅴ-18(1.03g,1.67mmol)为原料，操作同化合物Ⅵ-3，得白色固体0.85g，产率98.8％。
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烷-4-基)金刚烷-1-甲酰胺(Ⅰ-18)的合成
以化合物Ⅵ-18(0.85g,1.65mmol)为原料，操作同化合物Ⅰ-3的合成，得到白色固体448mg，产率47.7％。HPLC纯度:98.25％。m.p.187-190℃。1H NMR(400MHz,DMSO-d6)δ(ppm):9.01(s,1H,NHCO),8.23(s,1H,ArH),7.13(d,J＝8.6Hz,ArH),6.98(d,J＝8.5Hz,ArH),6.90-6.71(m,1H,CH＝CH2),6.16-6.02(m,3H,OCH2O,CH＝CH 2),5.73-5.59(m,1H,CH＝CH 2),4.77-4.62(m,1H,NCH 2CH),4.60-4.52(m,0.5H,NCH2CH),4.31-4.18(m,1H,NCH 2CH),4.12-4.03(m,0.5H,NCH2CH),3.73-3.62(m,0.5H,NCH 2CH2),3.20(m,1H,NCH 2CH2),3.00-2.91(m,0.5H,NCH 2CH2),2.33-2.19(m,1H,NCH2CHCH 2),2.15-2.08(m,1H,NCH2CHCH 2),2.06-1.98(m,3H,3CH(CH2)3CH),1.97-1.87(m,7H,CH(CH2 )3CH,NCH2CH 2),1.75-1.68(m,6H,C(CH2 )3CH),1.64-1.52(m,1H,NCH2CH 2).13C NMR(101MHz,DMSO-d6)δ(ppm):176.10,165.03,158.50,156.13,154.11,146.05,140.91,138.95,128.78,127.88,122.35,122.28,119.31,111.55,102.02,99.08,53.40(0.5C),52.62(0.5C),49.70(0.5C),46.16(0.5C),45.61(0.5C),42.02(0.5C),41.15(3C),38.89(3C),36.48,30.08(0.5C),29.88(0.5C),28.14(3C),25.40(0.5C),23.88(0.5C).
实施例19
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烷-4-基)-4-(甲氨基)苯甲酰胺(Ⅰ-19)的合成4-(((苄氧基)羰基)(甲基)氨基)-N-(7-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯并[d][1,3]二氧杂环戊烷-4-基)苯甲酰胺(Ⅳ-19)的合成
以4-(((苄氧基)羰基)(甲基)氨基)苯甲酸(1.31g,0.0046mol)和化合物XI-2(1g,0.0038mol)为原料，操作同化合物Ⅳ-3，得到1.09g淡黄色固体，产率54.1％。
(R)-3-(4-氨基-3-(7-(4-(((苄氧基)羰基)(甲基)氨基)-苯甲酰氨基)苯并[d][1,3]二氧杂环戊烷-4-基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(Ⅴ-19)的合成
以化合物Ⅳ-19(1.00g,1.90mmol)和化合物Ⅲ(762mg,1.71mmol)为原料，操作同化合物V-3，得到918mg淡黄色固体，产率74.5％。1H NMR(300MHz,DMSO-d6)δ(ppm):10.30(s,1H,NHCO),8.24(s,1H,ArH),8.01(d,J＝8.7Hz,2H,ArH),7.51(d,J＝8.5Hz,2H,ArH),7.46-7.27(m,5H,ArH),7.19(d,J＝8.6Hz,1H,ArH),7.03(d,J＝8.5Hz,1H,ArH),6.15(s,2H,OCH2O),5.15(d,J＝4.6Hz,2H,CH2),4.73-4.65(m,1H,NCH 2CH),4.19-3.64(m,3H,NCH 2CH,NCH2CH,NCH 2CH2),3.33(s,3H,NCH3),3.12-2.86(m,1H,NCH 2CH2),2.31-1.86(m,3H,NCH2CHCH2 ,NCH2CH 2),1.69-1.53(m,1H,NCH2CH 2),1.34(s,9H,NBoc).
(R)-3-(4-氨基-3-(7-(4-(甲氨基)苯甲酰氨基)苯并[d][1,3]二氧杂环戊烷-4-基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-羧酸叔丁酯(Ⅵ-19-1)的合成
化合物Ⅴ-19(0.90g,1.25mmol)用15mL无水乙醇溶解，加入5％的钯碳(90mg)，氢气保护下室温反应约24h。硅藻土抽滤，滤液减压蒸除溶剂，加入50mL乙酸乙酯溶解，分别用水(10mL×2)和饱和氯化钠水溶液(10mL×2)洗涤。无水硫酸钠干燥，抽滤，滤液减压蒸除溶剂，得到646mg黑褐色固体，未经纯化直接投下一步。产率88.1％。1H NMR(300MHz,DMSO-d6)δ(ppm):9.81(s,1H,NHCO),8.23(s,1H,ArH),8.09(s,1H,NHCH3),7.88(d,J＝8.6Hz,2H,ArH),7.18(d,J＝8.6Hz,1H,ArH),7.01(d,J＝8.5Hz,1H,ArH),6.76(d,J＝8.8Hz,2H,ArH),6.13(s,2H,OCH2O),4.78-4.58(m,1H,NCH 2CH),4.29-4.18(m,1H,NCH2CH),3.97-3.68(m,1H,NCH 2CH),3.04-2.95(m,4H,NHCH3 ,NCH 2CH2),2.29-2.16(m,1H,NCH 2CH2),2.13-2.06(m,1H,NCH2CHCH 2),1.94-1.80(m,1H,NCH2CHCH 2),1.60-1.50(m,1H,NCH2CH 2),1.48-1.43(m,1H,NCH2CH 2),1.29(s,9H,NBoc).
(R)-N-(7-(4-氨基-1-(哌啶-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烷-4-基)-4-(甲氨基)苯甲酰胺(Ⅵ-19)的合成
以化合物Ⅴ-19-1(635mg,1.08mol)为原料，操作同化合物Ⅵ-3的合成，得到521mg淡黄色固体，产率99.1％。
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烷-4-基)-4-(甲氨基)苯甲酰胺(Ⅰ-19)的合成
以化合物Ⅵ-19(510mg,1.05mmol)为原料，操作同化合物Ⅰ-3的合成，得到82mg白色固体，产率14.4％。HPLC纯度:96.86％。1H NMR(300MHz,DMSO-d6)δ(ppm):9.87(s,1H,NHCO),8.22(d,J＝5.1Hz,1H,ArH),7.84(d,J＝7.6Hz,2H,ArH),7.35(d,J＝5.7Hz,1H,ArH),7.14(d,J＝8.4Hz,1H,ArH),7.00(s,1H,NHCH3),6.92-6.63(m,3H,ArH,CH＝CH2),6.21-6.01(m,4H,OCH2O,NH2,CH＝CH 2),5.77-5.55(m,1H,CH＝CH 2),4.77-4.62(m,1H,NCH 2CH),4.57-4.52(m,1H,NCH2CH),4.29-4.12(m,1H,NCH 2CH),4.10-3.94(m,1H,NCH 2CH2),3.27-3.09(m,1H,NCH 2CH2),2.98(s,3H,NHCH3 ),2.33-2.21(m,1H,NCH2CHCH 2),2.15-2.04(m,1H,NCH2CHCH 2),1.98-1.85(m,1H,NCH2CH 2),1.69-1.48(m,1H,NCH2CH 2).
实施例20
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基]-苯并[d][1,3]二氧杂环戊烷-4-基)-4-(吡咯烷-1-基甲基)苯甲酰胺(Ⅰ-20)的合成4-(吡咯烷-1-基甲基)-N-(7-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯并[d][1,3]二氧杂环戊烷-4-基)苯甲酰胺(Ⅳ-20)的合成
以4-(吡咯烷-1-基甲基)苯甲酸(754mg,3.67mmol)和化合物XI-2(800mg,3.04mmol)为原料，操作同化合物Ⅳ-3的操作，得到830mg白色固体，产率60.6％。1H NMR(300MHz,DMSO-d6)δ(ppm):10.16(s,1H,NHCO),8.00(d,J＝7.9Hz,2H,ArH),7.95(d,J＝7.8Hz,1H,ArH),7.61(d,J＝7.7Hz,2H,ArH),7.38(d,J＝8.1Hz,1H,ArH),6.05(s,2H,OCH2O),3.98(s,2H,CH2),2.94-2.81(m,4H,N(CH2 CH2)2),2.12-1.99(m,4H,N(CH2CH2 )2),1.30(s,12H,4CH3).
(R)-3-(4-氨基-3-(7-(4-(吡咯烷-1-基甲基)苯甲酰氨基)-苯并[d][1,3]二氧杂环戊烷-4-基)-1H吡唑并[3,4-d]嘧啶-1-基)哌啶-1-羧酸叔丁酯(Ⅴ-20)的合成
以化合物Ⅳ-20(800mg,1.78mmol)和化合物Ⅲ(800mg,1.80mmol)为原料，操作同化合物Ⅴ-3，得到841mg淡黄色固体，产率73.7％。
(R)-N-(7-(4-氨基-1-(哌啶-3-基)-1H吡唑并[3,4-d]嘧啶-3-基]-苯并[d][1,3]二氧杂环戊烷-4-基)-4-(吡咯烷-1-基甲基)苯甲酰胺(Ⅵ-20)的合成
以化合物Ⅴ-20(841mg,1.31mmol)为原料，操作同化合物Ⅵ-3,得到678mg淡黄色固体，产率95.7％。1H NMR(300MHz,DMSO-d6)δ10.22(s,1H,NHCO),8.24(s,1H,ArH),7.96(d,J＝8.0Hz,2H,ArH),7.48(d,J＝8.0Hz,2H,ArH),7.19(d,J＝8.6Hz,1H,ArH),7.04(d,J＝8.5Hz,1H,ArH),6.15(s,2H,OCH2 O),4.76-4.61(s,1H,NCH 2CH),4.22-4.01(m,1H,NCH2CH),3.99-3.85(m,1H,NCH 2CH),3.72(s,2H,CH2),3.52-3.25(m,4H,N(CH2 CH2)2),3.09-2.91(m,1H,NCH 2CH2),2.31-2.14(m,1H,NCH 2CH2),2.14-2.03(m,1H,NCH2CHCH 2),2.02-1.83(m,1H,NCH2CHCH 2),1.81-1.69(m,4H,N(CH2CH2 )2),1.66-1.51(m,2H,NCH2CH 2),1.29(s,9H,NBoc).
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基]-苯并[d][1,3]二氧杂环戊烷-4-基)-4-(吡咯烷-1-基甲基)苯甲酰胺(Ⅰ-20)的合成
以化合物Ⅵ-20(640mg,1.18mmol)为原料，操作同化合物Ⅰ-3的合成，得到189mg白色固体，产率27.0％。1H NMR(400MHz,DMSO-d6)δ(ppm):10.24(s,1H，NHCO),8.24(s,1H,ArH),7.97(d,J＝8.0Hz,2H,ArH),7.49(d,J＝7.9Hz,2H,ArH),7.20(d,J＝8.6Hz,1H,ArH),7.04(d,J＝8.5Hz,1H,ArH),6.87(dd,J＝15.2,9.1Hz,1H,ArH),6.84-6.69(m,1H,CH＝CH2),6.18-6.02(m,4H,OCH2O,CH＝CH 2,NH2),5.75-5.58(m,1H,CH＝CH 2),4.82-4.65(m,1H,NCH 2CH),4.62-4.49(m,0.5H,NCH2CH),4.30-4.17(m,1H,NCH 2CH),4.13-3.99(m,0.5H,NCH2CH),3.72(s,2H,CH2),3.45-3.29(m,4H,N(CH2 CH2)2),3.26-3.14(m,1H,NCH 2CH2),3.03-2.91(m,1H,NCH 2CH2),2.36-2.20(m,1H,NCH2CHCH 2),2.19-2.00(m,1H,NCH2CHCH 2),1.97-1.87(m,1H,NCH2CH 2),1.74(m,4H,N(CH2CH2 )2),1.61(m,1H,NCH2CH 2).
实施例21
(R)-N-(7-(1-(1-丙烯酰哌啶基-3-基)-4-氨基-1H-吡唑[3,4-d]嘧啶-3-基)-2,3-苯并二氢呋喃-4-基)-4-(甲氨基)苯甲酰胺(Ⅰ-21)的合成
4-(((苄氧基)羰基)(甲基)氨基)-N-(7-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)2,3-二氢苯并呋喃-4-基)苯甲酰胺(Ⅳ-21)的合成
以化合物4-(((苄氧基)羰基)(甲基)氨基)苯甲酸(961mg,3.37mmol)和化合物XI-1(792mg,3.03mmol)为原料，操作同化合物Ⅳ-1的合成，得到1.4g淡黄色固体，产率87.4％。
(R)-3-(4-氨基-3-(4-(4-(((苄氧基)羰基)(甲基)氨基)苯甲酰氨基)-2,3-苯并二氢呋喃-7-基)-1H-吡唑[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(Ⅴ-21)的合成
以化合物Ⅳ-21(1.35g,2.56mmol)和化合物Ⅲ(1.14g,2.56mmol)为原料，操作同化合物Ⅴ-1的合成，得到630mg，产率34.2％。1H NMR(300MHz,DMSO-d6)δ10.16(s,1H,NHCO),8.22(s,1H,ArH),7.97(d,J＝8.3Hz,2H,ArH),7.52(d,J＝8.3Hz,2H,ArH),7.37(s,1H,NHCH3),7.30(d,J＝9.1Hz,1H),7.20(d,J＝8.4Hz,1H),5.16(s,2H,CH2),4.76-4.49(m,3H,OCH2 CH2,NCH2 CH,),4.12-3.09(m,1H,NCH2CH),3.96-3.71(m,1H,NCH 2CH),3.33(s,3H,CH3),3.27(d,J＝9.0Hz,2H,OCH2CH2 ),3.09-2.86(m,1H,NCH 2CH2),2.30-2.14(m,1H,NCH 2CH2),2.13-2.06(m,1H,NCH2CHCH 2),1.94-1.78(m,1H,NCH2CHCH 2),1.64-1.49(m,1H,NCH2CH 2),1.46-1.30(m,1H,NCH2CH 2),1.33(s,9H,NBoc).
(R)-3-(4-氨基-3-(4-(4-(甲氨基)苯甲酰氨基)-2,3-苯并二氢呋喃-7-基)-1H-吡唑[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(Ⅵ-21-1)的合成
以化合物Ⅴ-21(570mg,0.79mmol)为原料，操作同化合物Ⅵ-19-1的合成，得到431mg褐色固体，产率93.31％。
(R)-N-(7-(4-氨基-1-(哌啶-3-基)-1-1H-吡唑[3,4-d]嘧啶-3-基)-2,3-苯并二氢呋喃-4-基)-4-(甲胺基)苯甲酰胺(Ⅵ-21)的合成
以化合物Ⅵ-21-1(420mg，0.72mmol)为原料，操作同化合物Ⅵ-1的合成，得到310mg淡黄色固体，产率88.8％。
(R)-N-(7-(1-(1-丙烯酰哌啶基-3-基)-4-氨基-1H-吡唑[3,4-d]嘧啶-3-基)-2,3-苯并二氢呋喃-4-基)-4-(甲氨基)苯甲酰胺(Ⅰ-21)的合成
以化合物Ⅵ-21(300mg,0.62mmol)为原料，操作同化合物Ⅰ-1的合成，得到，产率。1H NMR(300MHz,DMSO-d6)δ9.84(s,1H,NHCO),8.21(s,1H,ArH),7.89(d,J＝8.0Hz,2H,ArH),7.39-7.14(m,2H,ArH),6.77(d,J＝8.2Hz,3H,ArH,CH＝CH2),6.22-5.99(m,1H,CH＝CH 2),5.84-5.65(m,1H,CH＝CH 2),4.77-4.52(m,4H,CH2CH2 O,NCH 2CH,NH),4.35-3.98(m,2H,NCH2CH),3.77-3.60(m,1H,NCH 2CH2),3.24(m,2H,CH2 CH2O),2.99(s,3H,CH3),2.35-2.21(m,2H,NCH 2CH2,NCH2CHCH 2),2.16-2.06(m,1H,NCH2CHCH 2),1.97-1.85(s,1H,NCH2CH 2),1.68-1.51(s,1H,NCH2CH 2).
实施例22
(R)-N-(7-(1-(1-丙烯酰哌啶基-3-基)-4-氨基-1H-吡唑[3,4-d]嘧啶-3-基)-2,3-苯并二氢呋喃-4-基)-4-(吡咯-1-基)苯甲酰胺(Ⅰ-22)的合成
4-(吡咯-1-基)-N-(7-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)2,3-二氢苯并呋喃-4-基)苯甲酰胺(Ⅳ-22)的合成
以化合物4-(吡咯-1-基)苯甲酸(806mg,4.22mmol)和化合物XI-1(1g,3.8mmol)为原料，操作同化合物Ⅳ-1的合成，得到1.34g淡黄色固体，产率81.2％。
(R)-3-(4-氨基-3-(4-(4-(吡咯-1-基)苯甲酰氨基)-2,3-苯并二氢呋喃-7-基)-1H-吡唑[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(Ⅴ-22)的合成
以化合物Ⅳ-22(1.0g,2.30mmol)和化合物Ⅲ(1.0g,2.30mmol)为原料，操作同化合物Ⅴ-1的合成，得到335mg淡黄色固体，产率23.3％。1H NMR(300MHz,DMSO-d6)δ9.79(s,1H,NHCO),8.21(s,1H,ArH),7.88(d,J＝8.4Hz,2H,ArH),7.29-7.13(m,2H,ArH),6.59(d,J＝8.5Hz,2H,ArH),4.70-4.49(m,3H,CH2CH2 O,NCH 2CH),4.13-3.69(m,2H,NCH 2CH),3.41-3.23(m,4H,N(CH2 CH2)2),3.11-2.72(m,1H,NCH 2CH2),2.37-2.22(m,1H,NCH 2CH2),2.20-2.08(m,1H,NCH2CHCH 2),2.07-2.03(m,1H,NCH2CHCH 2),1.97(q,J＝7.2,6.6Hz,4H,N(CH2 CH2)2),1.81-1.72(m,1H,NCH2CH 2),1.64-1.47(m,1H,NCH2CH 2).
(R)-N-(7-(4-氨基-1-(哌啶-3-基)-1H-吡唑[3,4-d]嘧啶-3-基)-2,3-苯并二氢呋喃-4-基)-4-(吡咯-1-基)苯甲酰胺(Ⅵ-22)的合成
以化合物Ⅵ-22(300mg，0.48mmol)为原料，操作同化合物Ⅵ-1的合成，得到241mg淡黄色固体，产率95.8％。
(R)-N-(7-(1-(1-丙烯酰哌啶基-3-基)-4-氨基-1H-吡唑[3,4-d]嘧啶-3-基)-2,3-苯并二氢呋喃-4-基)-4-(吡咯-1-基)苯甲酰胺(Ⅰ-22)的合成
以化合物Ⅵ-22(221mg,0.42mmol)为原料，操作同化合物Ⅰ-1的合成，得到32mg，产率11.53％。1H NMR(300MHz,DMSO-d6)δ9.80(s,1H,NHCO),8.22(s,1H,ArH),7.88(d,J＝8.4Hz,2H,ArH),7.34-7.15(m,2H,ArH),6.6.93-6.66(m,1H,CH＝CH2),6.59(d,J＝8.3Hz,2H,ArH),6.25-6.01(m,1H,CH＝CH 2),5.86-5.55(m,1H,CH＝CH 2),4.77-4.44(m,4H,CH2CH2 O,NCH2 CH),4.41-3.94(m,2H,NCH2CH,NCH 2CH2),3.82-3.59(m,0.5H,NCH 2CH2),3.33-3.27(m,4H,N(CH2 CH2)2),3.21-3.09(m,2H,CH2 CH2O),3.03-2.89(m,0.5H,NCH 2CH2),2.34-2.19(m,1H,NCH2CHCH 2),2.16-2.06(m,1H,NCH2CHCH 2),2.02-1.86(m,4H,N(CH2CH2 )2),1.66-1.48(m,1H,NCH2CH 2),1.29-1.09(m,1H,NCH2CH 2).
实施例23
(R)-N-(7-(1-(1-丙烯酰哌啶基-3-基)-4-氨基-1H-吡唑[3,4-d]嘧啶-3-基)-2,3-苯并二氢呋喃-4-基)-4-(吡咯-1-基甲基)苯甲酰胺(Ⅰ-22)的合成
4-(吡咯-1-基甲基)-N-(7-(4,4,5,5,-四甲基-1,3,2，-二氧硼杂环戊烷-2-基)-2,3-苯并二氢呋喃-4-基)苯甲酰胺(Ⅳ-23)的合成
以化合物4-(吡咯-1-甲基)苯甲酸(754mg,3.68mmol)和化合物XI-1(800mg,3.06mmol)为原料，操作同化合物Ⅳ-1的合成，得到817mg淡黄色固体，产率59.5％。
(R)-3-(4-氨基-3-(4-(4-(吡咯-1-基甲基)苯甲酰氨基)-2,3-苯并二氢呋喃-7-基)-1H-吡唑[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(Ⅴ-23)的合成
以化合物Ⅳ-23(800mg,1.78mmol)和化合物Ⅲ(791mg,1.78mmol)为原料，操作同化合物Ⅴ-1的合成，得到826mg淡黄色固体，产率72.7％。1H NMR(300MHz,DMSO-d6)δ10.19(s,1H,NHCO),8.22(s,1H,ArH),7.95(d,J＝7.8Hz,2H,ArH),7.50(d,J＝7.9Hz,2H,ArH),7.29(d,J＝8.2Hz,1H,ArH),7.19(d,J＝8.4Hz,1H,ArH),4.75-4.55(m,3H,OCH2 CH2,NCH 2CH),4.03-3.82(m,1H,NCH2CH),3.73(s,2H,CH2),3.56-3.32(m,2H,OCH2CH2 ),3.29(t,J＝8.8Hz,4H,N(CH2 CH2)2),3.12-2.85(m,1H,NCH 2CH),2.30-2.13(m,1H,NCH2 CH2),2.13-2.01(m,1H,NCH2 CH2),1.99-1.80(m,1H,NCH2CHCH 2),1.74(t,J＝6.6Hz,4H,N(CH2CH2 )2),1.64-1.53(m,1H,NCH2CHCH 2),1.50-1.42(s,2H,NCH2CH2 ),1.27(s,9H,NBoc).
(R)-N-(7-(4-氨基-1-(哌啶-3-基)-1H-吡唑[3,4-d]嘧啶-3-基)-2,3-苯并二氢呋喃-4-基)-4-(吡咯-1-基甲基)苯甲酰胺(Ⅵ-23)的合成
以化合物Ⅵ-23(815mg，1.28mmol)为原料，操作同化合物Ⅵ-1的合成，得到678mg淡黄色固体，产率98.5％。
(R)-N-(7-(1-(1-丙烯酰哌啶基-3-基)-4-氨基-1H-吡唑[3,4-d]嘧啶-3-基)-2,3-苯并二氢呋喃-4-基)-4-(吡咯-1-基甲基)苯甲酰胺(Ⅰ-22)的合成
以化合物Ⅵ-23(650mg,1.20mmol)为原料，操作同化合物Ⅰ-1的合成，得到146mg白色固体，产率20.4％。1H NMR(400MHz,DMSO-d6)δ10.16(s,1H,NHCO),8.23(s,1H,ArH),7.96(d,J＝8.1Hz,2H,ArH),7.52(d,J＝7.8Hz,2H,ArH),7.31(d,J＝8.3Hz,1H,ArH),7.22(d,J＝8.4Hz,1H,ArH),6.94-6.68(m,1H,CH＝CH2),6.20-6.05(m,1H,CH＝CH 2),5.75-5.58(m,1H,CH＝CH 2),4.77-4.51(m,3.5H,NCH 2CH,OCH2 CH2),4.32-4.17(m,1H,NCH 2CH),4.11-4.05(m,0.5H,NCH2CH),3.82-3.65(m,3H,CH2,NCH 2CH2),3.33-3.27(m,4H,N(CH2 CH2)2),3.23-3.14(m,2H,OCH2CH2 ),3.03-2.88(m,1H,NCH 2CH2),2.29-2.22(m,1H,NCH2CHCH 2),2.17-2.06(m,1H,NCH2CHCH 2),1.99-1.92(m,1H,NCH2CH 2),1.79-1.72(m,4H,N(CH2CH2 )2),1.55(d,1H,NCH2CH 2).
实施例24
上述制备所得部分化合物的药理学实验及结果如下：
1.BTK、JAK3激酶抑制活性实验(100nM浓度下的抑制率)
实验方法：384孔反应板分为化合物孔(100nM)、阳性对照孔和阴性对照孔，化合物孔和阳性对照孔加入激酶溶液，阴性对照孔加入
1×kinase buffer，离心30秒后室温孵育10min。加入15μL的ATP和底物的混合溶液，离心后震荡混匀室温孵育(JAK3孵育30分钟，BTK孵育20分钟)。加入终止检测液停止反应，用Caliper EZ reader读取转化率。
数据分析：计算公式其中：Conversion％_sample是样品的转化率读数；Conversion％_min是阴性对照孔均值，代表没加酶孔的转化率读数；Conversion％_max是阳性对照比值孔均值，代表没加化合物孔的转化率读数。
拟合量效曲线：以浓度的log值作为X轴，百分比抑制率为Y轴，采用分析软件GraphPad Prism 5的log(inhibitor)vs.response-Variable slope拟合量效曲线，从而得出各个化合物对酶活性的IC50值。
实验结果：对本发明部分化合物进行体外BTK、JAK3激酶抑制活性的筛选，结果见表1。
注：A:抑制率≧75％；B:75％>抑制率≧50％；C:抑制率<50％
表1.部分化合物对BTK、JAK3激酶的抑制活性
表1结果显示，本发明化合物对BTK、JAK3激酶均有较好的抑制活性，其中化合物I-2、I-8、I-16、I-19对BTK和JAK3呈现出良好的抑制活性。
选择活性较好的目标化合物，我们测定了它们对BTK和JAK3的IC50，结果见表2。
表2.部分化合物对BTK、JAK3激酶的IC50注：A:IC50≤10nM；B:10nM<IC50≤30nM；C:IC50>30nM
实施例25
目标化合物的液相色谱条件：色谱柱为BDS Hypersil C18(4.6×250mm，5μm)；检测波长为254nm；柱温为30℃；流速为1.0mL/min；进样量为10μL；流动相为缓冲液(3.56gNa2HPO3+1.56g NaH2PO3+1000mL H2O)-乙腈，梯度洗脱：0-1min(乙腈25％)，1-5min(乙腈25％-75％)，5-18min(乙腈75％)，18-22min(乙腈75％-25％)，22-23min(乙腈25％)。
Claims (10)
1.通式(I)的化合物或其药学上可接受的盐：
其中：X1、X2各自独立地代表O或CH2；
R1代表：其中R2代表H、F、Cl、Br、I、C1-C6烷基、CF3、OH、C1-C6烷氧基、OCF3、CN、NO2、NH2、C1-C6的烷胺基、-NHCH3、-N(CH3)2、-N(C2H5)2、-CH(CH3CN)、-NHCOCH3、/> R2可以是单取代、双取代或三取代；Y1、Y2各自代表N或C-R3，R3代表H、F、Cl、Br、I、CH3、CF3、OH、OCH3、OCF3或CN；Z代表O、S或N-R4，R4代表H、CH3、C2H5或环丙基。
2.权利要求1的化合物或其药学上可接受的盐，其特征在于，X1代表O或CH2，X2代表O。
3.权利要求1的化合物或其药学上可接受的盐，其特征在于，R1代表 其中R5代表H、F、Cl、CH3、t-Bu、CF3、CN、OH、OCH3、OCF3、-NH2、-NHCH3、-N(CH3)2、-N(C2H5)2、/>-NHCOCH3、 R5可以是单取代、双取代或三取代。
4.权利要求3的化合物或其药学上可接受的盐，其中R5代表H、F、Cl、CF3、OCH3、CN、-NHCH3、-N(CH3)2、R5可以是单取代、双取代或三取代。
5.权利要求1～4的化合物或其药学上可接受的盐，其特征在于，所述化合物为：
，
优选是I-2、I-8、I-19、I-21或I-22。
6.权利要求1～5的化合物或其药学上可接受的盐，其中，药学上可接受的盐为权利要求1的通式(I)化合物与下列酸形成的酸加成盐：氯化氢、溴化氢、硫酸、碳酸、草酸、柠檬酸、琥珀酸、酒石酸、磷酸、乳酸、丙酮酸、乙酸、马来酸、甲磺酸、苯磺酸、对甲苯磺酸或阿魏酸。
7.一种药物组合物，其特征在于，其包含权利要求1～6中任一项的化合物或其药学上可接受的盐，以及药学上可接受的载体。
8.权利要求1的化合物的制备方法，其化学反应路线如下：
其中，R1、X1的定义同权利要求1。
9.权利要求1～6中任一项的化合物或其药学上可接受的盐在制备BTK和/或JAK3抑制剂药物中的用途。
10.权利要求9的用途，其中，所述的BTK和JAK3双靶点抑制剂药物是治疗类风湿性关节炎或B细胞淋巴瘤的药物。
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