CN113444078A - 抗凋亡蛋白Bcl-2抑制剂及其制备方法和应用 - Google Patents
抗凋亡蛋白Bcl-2抑制剂及其制备方法和应用 Download PDFInfo
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- CN113444078A CN113444078A CN202010219779.1A CN202010219779A CN113444078A CN 113444078 A CN113444078 A CN 113444078A CN 202010219779 A CN202010219779 A CN 202010219779A CN 113444078 A CN113444078 A CN 113444078A
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Abstract
本发明提供了抗凋亡蛋白Bcl‑2抑制剂及其制备方法和应用，具体地，本发明提供了一种如下式(I)所示的化合物，或其光学异构体、互变异构体，或其药学上可接受的盐。所述的化合物具有优异的Bcl‑2抑制活性，因此可以用于治疗或预防因抗凋亡蛋白Bcl‑2表达异常导致的相关哺乳动物疾病或病症。
Description
技术领域
本发明属于药物化学和医药技术领域，涉及一类新型的能够抑制抗凋亡(anti-apoptotic)Bcl-2蛋白的活性化合物及其制备方法和应用。
背景技术
细胞凋亡(apoptosis)，又称程序性细胞死亡，是由内部或外部刺激引发的程序性自杀死亡过程。细胞凋亡是生物体内精确控制的细胞死亡机制，能够有序排除体内不 需要的或已受损的细胞，对胚胎发育及维持细胞稳态具有重要作用。细胞凋亡与许多 人类疾病的发生密切相关，抑制凋亡与肿瘤等疾病的产生有关。研究发现，具有逃脱 凋亡的能力是癌细胞的重要标志之一。
Bcl-2家族蛋白，是拮抗和逆转恶性肿瘤永生性的最重要的分子靶点。在一些恶性肿瘤中，Bcl-2蛋白家族的抗凋亡蛋白成员过度表达，导致一般的化疗手段无法使肿瘤 细胞发生凋亡，从而影响肿瘤的治疗效果，产生耐药性。因此，针对Bcl-2蛋白家族抗 凋亡成员的抑制剂研究，已经成为近年来抗肿瘤药物的研究热点，特异性拮抗Bcl-2家 族蛋白的药物，将通过专一诱导肿瘤细胞凋亡，最终实现高选择性、安全、高效、无 毒副作用的抗癌目标。为今后寻找新型的、克服细胞耐药的抗肿瘤药物提供了新的方 向。
已知Bcl-2蛋白涉及膀胱癌，脑癌，乳腺癌，骨髓癌，子宫颈癌，慢性淋巴细胞性 白血病，结肠直肠癌，食道癌，肝细胞癌，淋巴细胞性白血病，滤泡性淋巴瘤，T细 胞或B细胞源的淋巴恶性肿瘤，黑素瘤，粒细胞性白血病，骨髓瘤，口腔癌，卵巢癌， 非小细胞肺癌，前列腺癌，小细胞肺癌，脾癌等。目前上市的唯一一个Bcl-2蛋白抑制 剂为美国艾伯维公司的Venetoclax(ABT-199)(Nature Medicine(2013),19(2),202-210) 于2016年4月获得美国食品药物监督管理局(FDA)批准上市，用于治疗带有17p基因 缺失突变并且曾接受过至少一种治疗的慢性淋巴细胞白血病(CLL)患者。然而，临 床研究发现已有Bcl-2抑制剂尚存在很多不足，特别是选择性差及耐药性的产生，导致 该类药物的临床应用受到很大限制。因此，发展新型有效的Bcl-2抑制剂是抗肿瘤药物 研究中具有挑战性和研究价值的课题。
发明内容
本发明的目的是提供一种新型有效的Bcl-2抑制剂，以及相应的抗肿瘤药物。
本发明的第一方面，一种如下式(I)所示的化合物，或其光学异构体、互变异构体，或其药学上可接受的盐：
其中：
X选自下组：C(Ra)2、C＝O、N(Ra)、O或S；其中，所述的Ra选自下组：H、卤 素、C1-4烷基、C2-4酰基；
Y选自下组：O、S、NRa；
Z选自下组：O、S、或NRa；
所述A环选自下组：取代或未取代的C6-10芳基、取代或未取代的5-12元杂芳基；
B环选自下组：取代或未取代的苯基、取代或未取代的5-7元杂芳基；
R1和R2各自独立地选自下组：取代或未取代的C1-C4烷基、或所述的R1和R2共同 构成-(CH2)n-；其中，n选自下组：2、3或4；
R3选自下组：H、卤素、C1-4烷基、C2-10酰基、NO2；
C环选自下组：取代或未取代的C6-10芳基、取代或未取代的5-12元杂芳基、取代 或未取代的5-12元杂环基；
其中，所述的取代指基团被选自下组的一个或多个取代基所取代：卤素、C1-6烷基、C1-6烷氧基、C1-4烷氧基(C1-6烷基)、C1-4烷氧基(C1-6烷氧基)、C1-4卤代烷基、C1-6卤代烷 氧基、C2-4烯基、C2-4炔基、C3-8环烷基、3-至12-元杂环基(优选3-至8-元杂环基)、C6-10芳基、5-12元杂芳基、苄基、C6-10芳氧基、5-12元杂芳基氧基、苄氧基、CN、NO2、 OR1、SR1、NR1R2、C(O)R1、C(O)OR1、C(O)NR1R2、NR1C(O)R2、或S(O)2R1；其中，R1和R2各自独立为氢或C1-4烷基。
在另一优选例中，所述的A环为
其中，M为N或CR5；所述的R4和R5各 自独立地选自下组：H、卤素、C1-C4烷基、C2-C4酰基；或所述的R4和R5与相连的 碳原子共同构成5-6元饱和或不饱和杂环(其含有1、2或3个选自N、O或S的杂原 子)。
在另一优选例中，所述的C环为5元并6元环或6元并6元环。
在另一优选例中，所述的C环为取代或未取代的C6-C10芳基，或取代或未取代 的5-12元杂芳基。
在另一优选例中，C环为取代或未取代的选自下组的基团：
其中，所述的取代指基团上 的一个或多个氢原子被选自下组的取代基取代：C1-6烷基、C1-6卤代烷基、C1-4烷氧基 (C1-6烷基)、苄基。
在另一优选例中，所述的C环选自下组：
其中，
R4选自下组：H、Me、
Bn。
在另一优选例中，所述的C环不为：
在另一优选例中，所述的A环不为取代或未取代的苯基。
在另一优选例中，所述的B环不为苯环。
在另一优选例中，所述的Z选自下组：S、或NRa。
在另一优选例中，所述的A环不为4-氯苯基。
在另一优选例中，所述的B环选自下组：取代或未取代的苯基、取代或未取代的 5-7元氮杂芳基。
在另一优选例中，所述的B环选自下组：
在另一优选例中，所述的A环选自下组：
在另一优选例中，所述的R1和R2各自独立地为CH3，或R1与R2共同构成- (CH2)2-。
在另一优选例中，X为CH2或C＝O；
Y选自下组：O或S；
Z选自下组：O、S、或NH。
本发明的第二方面，提供了一种如本发明第一方面所述的化合物的用途，所述 的化合物用于制备预防或治疗因抗凋亡蛋白Bcl-2表达异常导致的相关哺乳动物疾病 或病症的药物组合物；
较佳地，所述的疾病或病症选自下组：小细胞肺癌或脾癌、膀胱癌、慢性淋巴 细胞性白血病、脑癌、乳腺癌、骨髓癌、宫颈癌、结肠直肠癌、食道癌、肝细胞 癌、原始淋巴细胞性白血病、滤泡性淋巴瘤、T细胞或B细胞源的淋巴恶性肿瘤、黑 色素瘤、粒细胞性白血病、骨髓瘤、口腔癌、卵巢癌、非小细胞肺癌、前列腺癌、 心肌梗塞、胎膜早破、神经退行性疾病、自身免疫性疾病。
本发明的第三方面，提供了一种药物组合物，所述的药物组合物包括：治疗有效量的本发明第一方面所述的式I化合物、或其药学上可接受的盐、其外消旋体、R-异构 体或S-异构体，以及药学上可接受的载体。
在另一优选例中，所述的药物组合物用于治疗或预防因抗凋亡蛋白Bcl-2表达异常导致的相关哺乳动物疾病或病症。
在另一优选例中，所述疾病或病症选自下组：小细胞肺癌或脾癌、膀胱癌、慢 性淋巴细胞性白血病、脑癌、乳腺癌、骨髓癌、宫颈癌、结肠直肠癌、食道癌、肝 细胞癌、原始淋巴细胞性白血病、滤泡性淋巴瘤、T细胞或B细胞源的淋巴恶性肿 瘤、黑色素瘤、粒细胞性白血病、骨髓瘤、口腔癌、卵巢癌、非小细胞肺癌、前列 腺癌、心肌梗塞、胎膜早破、神经退行性疾病、自身免疫性疾病。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇 幅，在此不再一一累述。
附图说明
图1显示了对荷瘤小鼠施用实施例10中各个化合物后，小鼠的体重变化；
图2显示了对荷瘤小鼠施用实施例10中各个化合物后，小鼠的肿瘤体积变化；
图3显示了实施例10中给药后小鼠的肿瘤体积变化照片。
具体实施方式
本发明人经过长期而深入的研究，意外地发现，形如本发明所述的式I化合物具有良好 的抗凋亡蛋白BCL-2抑制活性，且活性优于现有通用的抗凋亡蛋白BCL-2抑制活性药物。 所述的化合物可以时间依赖性及剂量依赖性地在体内或体外抑制肿瘤细胞或肿瘤组织的生 长，进而用于治疗肿瘤的用途。基于上述发现，发明人完成了本发明。
术语
如本文所用，术语“C1-C4烷基”或“C1-C6烷基”指具有1～4个或1-6个碳原子的直链或支链烷基，例如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基，或类似基 团。
术语“C3-C6环烷基”指具有3～6个碳原子的环烷基，例如环丙基、环丁基、甲基环丁基、环戊基，或类似基团。
如本文所用，术语“C2-C10酰基”指形如“具有1-9个碳原子的直链或支链烷基/环烷基 /芳基/杂芳基-羰基”结构的取代基，如乙酰基、丙酰基、丁酰基，或类似基团。
术语“C1-C4烷氧基”指具有1～4个碳原子的直链或支链烷基，例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基、叔丁氧基，或类似基团。
术语“卤素”指F、Cl、Br和I。
术语“C6-C10芳基”指具有6-10个碳原子的芳基，例如苯基、萘基等，所述的芳基可以 是取代或未取代的。
术语“5-12元杂芳基”指具有5-12个成环原子(其中包括一个或多个选自O、S和/或N 的杂原子)的杂芳基，优选5-7元杂芳基。所述的杂芳基可以是取代或未取代的。
本发明中，术语“含有”、“包含”或“包括”表示各种成分可一起应用于本发明的混合物或组合物中。因此，术语“主要由...组成”和“由...组成”包含在术语“含有”中。
本发明中，术语“药学上可接受的”成分是指适用于人和/或动物而无过度不良副反应 (如毒性、刺激和变态反应)，即有合理的效益/风险比的物质。
本发明中，术语“有效量”指治疗剂治疗、缓解或预防目标疾病或状况的量，或是表现出可检测的治疗或预防效果的量。对于某一对象的精确有效量取决于该对象的体型和健康状况、病症的性质和程度、以及选择给予的治疗剂和/或治疗剂的组合。因此，预先指定准确的有效量是没用的。然而，对于某给定的状况而言，可以用常规实验来确定该有效量，临床医师是能够判断出来的。
在本文中，除特别说明之处，术语“取代”指基团上的一个或多个氢原子被选自下组 的取代基取代：卤素、未取代或卤代的C1-C6烷基、未取代或卤代的C2-C6酰基、未取代或卤代的C1-C6烷基-羟基。
除非特别说明，本发明中，所有出现的化合物均意在包括所有可能的光学异构体，如 单一手性的化合物，或各种不同手性化合物的混合物(即外消旋体)。本发明的所有化合物之 中，各手性碳原子可以任选地为R构型或S构型，或R构型和S构型的混合物。
如本文所用，术语“本发明化合物”指式I所示的化合物。该术语还包括及式I化合物的 各种晶型形式、药学上可接受的盐、水合物或溶剂合物。
如本文所用，术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作 药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形 成的盐。适合形成盐的酸包括但并不限于：盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸，甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石 酸、柠檬酸、苦味酸、甲磺酸、苯甲磺酸，苯磺酸等有机酸；以及天冬氨酸、谷氨酸等酸性 氨基酸。
式I化合物
本发明提供了一种如下式I所示的化合物：
其中：
X选自下组：C(Ra)2、C＝O、N(Ra)、O或S；其中，所述的Ra选自下组：H、卤 素、C1-4烷基、C2-4酰基；
Y选自下组：O、S、NRa；
Z选自下组：O、S、或NRa；
所述A环选自下组：取代或未取代的C6-10芳基、取代或未取代的5-12元杂芳基；
B环选自下组：取代或未取代的苯基、取代或未取代的5-7元杂芳基；
R1和R2各自独立地选自下组：取代或未取代的C1-C4烷基、或所述的R1和R2共同 构成-(CH2)n-；其中，n选自下组：2、3或4；
R3选自下组：H、卤素、C1-4烷基、C2-10酰基、NO2；
C环选自下组：取代或未取代的C6-10芳基、取代或未取代的5-12元杂芳基、取代 或未取代的5-12元杂环基；
其中，所述的取代指基团被选自下组的一个或多个取代基所取代：卤素、C1-6烷基、C1-6烷氧基、C1-4烷氧基(C1-6烷基)、C1-4烷氧基(C1-6烷氧基)、C1-4卤代烷基、C1-6卤代烷 氧基、C2-4烯基、C2-4炔基、C3-8环烷基、3-至8-元杂环基、C6-10芳基、5-12元杂芳基、苄 基、C6-10芳氧基、5-12元杂芳基氧基、苄氧基、CN、NO2、OR1、SR1、NR1R2、C(O)R1、 C(O)OR1、C(O)NR1R2、NR1C(O)R2、或S(O)2R1；其中，R1和R2各自独立为氢或C1-4烷 基。
本发明优选的化合物包括选自下表的化合物：
应用
本发明的化合物具有优异的抗凋亡蛋白BCL-2抑制活性，可用于以本发明的化合物为活性成分的药物组合物，用于预防和/或治疗与抗凋亡蛋白BCL-2有关或由抗凋亡 蛋白BCL-2调节的疾病，例如小细胞肺癌或脾癌、膀胱癌、慢性淋巴细胞性白血病、 脑癌、乳腺癌、骨髓癌、宫颈癌、结肠直肠癌、食道癌、肝细胞癌、原始淋巴细胞性 白血病、滤泡性淋巴瘤、T细胞或B细胞源的淋巴恶性肿瘤、黑色素瘤、粒细胞性白血 病、骨髓瘤、口腔癌、卵巢癌、非小细胞肺癌、前列腺癌、心肌梗塞、胎膜早破、神 经退行性疾病、自身免疫性疾病。
在本申请中，术语“药物组合物”是指本发明化合物与本领域通常接受的用于将生物活性化合物输送至哺乳动物(例如人)的介质的制剂。该介质包括药学上可接受的载 体。药物组合物的目的是促进生物体的给药，利于活性成分的吸收进而发挥生物活性。
在本申请中，术语“药学上可接受的”是指不影响本发明化合物的生物活性或性质的物质(如载体或稀释剂)，并且相对无毒，即该物质可施用于个体而不造成不良的生 物反应或以不良方式与组合物中包含的任意组分相互作用。
在本申请中，术语“药学上可接受的赋形剂”包括但不限于任何被相关的政府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释 剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、 等渗剂、溶剂或乳化剂。
在本申请中，术语“预防的”、“预防”和“防止”包括使病患减少疾病或病症的发生或恶化的可能性。
在本申请中，术语“治疗”和其它类似的同义词包括以下含义：
(i)预防疾病或病症在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病或病 症，但尚未被诊断为已患有该疾病或病症时；
(ii)抑制疾病或病症，即遏制其发展；
(iii)缓解疾病或病症，即，使该疾病或病症的状态消退；或者
(iv)减轻该疾病或病症所造成的症状。
在本申请中，术语“有效量”、“治疗有效量”或“药学有效量”是指服用后足以在某种程度上缓解所治疗的疾病或病症的一个或多个症状的至少一种药剂或化合物的量。 其结果可以为迹象、症状或病因的消减和/或缓解，或生物系统的任何其它所需变化。 例如，用于治疗的“有效量”是在临床上提供显著的病症缓解效果所需的包含本文公开 化合物的组合物的量。可使用诸如剂量递增试验的技术测定适合于任意个体病例中的 有效量。
在本申请中，术语“服用”、“施用”、“给药”等是指能够将化合物或组合物递送到进行生物作用的所需位点的方法。这些方法包括但不限于口服途径、经十二指肠途径、 胃肠外注射(包括静脉内、皮下、腹膜内、肌内、动脉内注射或输注)、局部给药和经 直肠给药。本领域技术人员熟知可用于本文所述化合物和方法的施用技术，例如在 Goodman andGilman,The Pharmacological Basis of Therapeutics,current ed.；Pergamon； andRemington's,Pharmaceutical Sciences(current edition),Mack Publishing Co.,Easton, Pa中讨论的那些。在优选的实施方案中，本文讨论的化合物和组合物通过口服施用。
在本申请中，术语“药物组合”、“药物联用”、“联合用药”、“施用其它治疗”、“施 用其它治疗剂”等是指通过混合或组合不止一种活性成分而获得的药物治疗，其包括 活性成分的固定和不固定组合。术语“固定组合”是指以单个实体或单个剂型的形式向 患者同时施用至少一种本文所述的化合物和至少一种协同药剂。术语“不固定组合”是 指以单独实体的形式向患者同时施用、合用或以可变的间隔时间顺次施用至少一种本 文所述的化合物和至少一种协同制剂。这些也应用到鸡尾酒疗法中，例如施用三种或 更多种活性成分。
可通过以多种方式测定抑制抗凋亡蛋白BCL-2活性所需要的化合物的量，从而测定化合物的相对抑制效能，例如，在体外检验中使用重组人蛋白或使用重组非人酶、 在表达正常啮齿动物酶的细胞检验中、在已经使用人蛋白转染的细胞检验中、在啮齿 动物和其他哺乳动种类的体内试验中等。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照 常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量 计算。
本发明实施例所述的反应方案示例性的说明了制备式I所示化合物或其立体异构体或外消旋体或其药学上可接受的盐的方法，其中各基团均如在上所述。应理解在下 列反应方案中，所述通式中取代基和/或变量的组合只有在这类组合导致稳定的化合 物时才是可允许的。还应理解其他的通式可由有机化学领域的技术人员通过本文公开 的方法(通过应用适当取代的起始材料并利用本领域技术人员公知的方法根据需要修 改合成参数)或已知方法进行制备。
本领域技术人员还应当理解，在下文所述的方法中，中间体化合物官能团可能需要由适当的保护基保护。这样的官能团包括羟基、氨基、巯基及羧酸。合适的羟基保 护基包括三烷基甲硅烷基或二芳基烷基甲硅烷基(例如叔丁基二甲基甲硅烷基、叔丁 基二苯基甲硅烷基或三甲基甲硅烷基)、四氢吡喃基、苄基等。合适的氨基、脒基及胍 基的保护基包括叔丁氧羰基、苄氧羰基等。合适的巯基保护基包括-C(O)-R”(其中R”为 烷基、芳基或芳烷基)、对甲氧基苄基、三苯甲基等。合适的羧基保护基包括烷基、芳 基或芳烷基酯类。
保护基可根据本领域技术人员已知的，或本文所述的标准技术来引入和除去。
实施例1化合物Bcl-003的制备
在氩气保护下，向500mL反应瓶中加入原料苯并[d]噻唑-6-醇X-3(10g,66.14mmol)、2,4-二氟苯甲酸甲酯II-3(13.7g,79.37mmol)和磷酸钾(21.1g, 99.21mmol)，溶于70mL二乙二醇二甲醚，搅拌下加热到115℃,并于该温度下反应24 小时。自然冷却至室温后，用300mL乙酸乙酯稀释反应液，并分别用水(200mL×2), 饱和氯化钠水溶液(200mL×2)洗涤，无水硫酸钠干燥，旋转蒸发移除溶剂，快速柱层 析得到中间体III-3：6g，收率:30％。1H NMR(400MHz,CDCl3)δ8.93(s,1H),8.11(d,J ＝8.9Hz,1H),8.00(dd,J＝8.8,6.6Hz,1H),7.51(d,J＝2.4Hz,1H),7.23(dd,J＝8.9,2.4Hz, 1H),6.91(ddd,J＝8.8,7.6,2.5Hz,1H),6.67(dd,J＝9.8,2.5Hz,1H),3.82(s,3H)；ESI-MS m/z 304.0(M+H)+。
以上述所得的中间体III-3(6g,19.78mmol)为原料,与1-((4’-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪IV-3(8.8g,27.69mmol)和磷酸氢二钾(5.2g,29.87mmol)与氩气保护下共同混合于250mL的反应瓶中，加入无水二甲亚砜60mL。 将反应液置于提前预热至135℃的油浴中反应24小时，停止加热反应冷却至室温，用 200mL乙酸乙酯稀释反应液，并分别用水(150mL×2),饱和氯化钠水溶液(150mL×2) 洗涤，之后无水硫酸钠干燥，旋转蒸发移除溶剂，快速柱层析得到产品V-3：8.7g，收 率:73％。1H NMR(400MHz,CDCl3)δ8.86(s,1H),8.04(d,J＝8.9Hz,1H),7.91(d,J＝8.9 Hz,1H),7.33(d,J＝2.3Hz,1H),7.25(d,J＝8.0Hz,2H),7.19(dd,J＝8.9,2.4Hz,1H),6.95 (d,J＝8.2Hz,2H),6.67(dd,J＝8.9,2.0Hz,1H),6.42(d,J＝2.1Hz,1H),3.70(s,3H),3.24– 3.16(m,4H),2.80(s,2H),2.34–2.27(m,4H),2.21(t,J＝6.0Hz,2H),1.99(s,2H),1.44(t,J＝ 6.4Hz,2H),0.96(s,6H)；ESI-MS m/z 602.1(M+H)+。
以上述得到的化合物V-3为原料，将其溶于170mL二氧六环中，加入170mL 1M的 氢氧化钠溶液，搅拌下将反应液加热至50℃，并于该温度下反应24小时。自然冷却至 室温后，用2N的盐酸水溶液调节反应液PH值至3-4。用200mL乙酸乙酯稀释反应液， 并分别用水(150mL×2),饱和氯化钠水溶液(150mL×2)洗涤，之后无水硫酸钠干燥， 旋转蒸发移除溶剂得到中间体VI-3(7.4g,收率87％)。该羧酸中间体无需进一步纯 化，可直接用于后续反应。1H NMR(400MHz,CDCl3)δ8.98(s,1H),8.13(d,J＝8.9Hz, 1H),8.03(d,J＝9.0Hz,1H),7.59(d,J＝2.3Hz,1H),7.29(d,J＝2.4Hz,1H),7.26–7.21(m, 2H),6.93(d,J＝8.4Hz,2H),6.64(dd,J＝9.0,2.3Hz,1H),6.17(d,J＝2.3Hz,1H),3.20–3.08 (m,4H),2.80(s,2H),2.33–2.23(m,4H),2.22–2.15(s,2H),1.98(s,2H),1.42(t,J＝6.4Hz, 2H),0.94(s,6H)；ESI-MS m/z 588.1(M+H)+。
将化合物VI-3(7.4g,12.58mmol)，与试剂3-硝基-4-(((四氢-2H-吡喃-4基)甲基)氨 基)苯磺酰胺7(4.0g,12.58mmol)、EDAC(5.1g,26.42mmol)、DMAP(2.3g,18.87mmol) 混合于500mL反应瓶中，并在氩气保护下，加入80mL无水二氯甲烷溶剂，反应液在室 温下搅拌反应24小时，停止反应，减压旋转蒸发移除溶剂，快速柱层析得到最终产品 Bcl-003：7.8g，收率:70％，黄色固体。1H NMR(400MHz,CDCl3)δ9.94(brs,1H),9.02 (s,1H),8.83(d,J＝2.2Hz,1H),8.50(t,J＝5.3Hz,1H),8.18(d,J＝8.9Hz,1H),8.04(dd, J＝9.1,2.1Hz,1H),7.95(d,J＝9.1Hz,1H),7.62(d,J＝2.3Hz,1H),7.30(dd,J＝8.9, 2.4Hz,1H),7.23(d,J＝8.3Hz,2H),6.91(d,J＝8.3Hz,2H),6.82(d,J＝9.3Hz,1H), 6.60(dd,J＝9.2,2.1Hz,1H),6.08(d,J＝2.1Hz,1H),4.03(dd,J＝11.3,3.6Hz,2H), 3.42(t,J＝11.7Hz,2H),3.24(t,J＝6.0Hz,2H),3.15–3.05(m,4H),2.76(s,2H),2.27– 2.20(m,4H),2.20–2.13(m,2H),2.00–1.91(m,3H),1.77–1.69(m,2H),1.49–1.36(m,4H), 0.94(s,6H)；13C NMR(100MHz,CDCl3)δ171.11,161.82,157.68,155.59,154.28,152.51, 150.64,147.77,142.01,135.31,135.23,133.75,131.86,130.63,129.63,129.05,128.96, 128.15,125.01,124.89,119.16,113.59,112.48,109.64,109.46,102.05,77.20,67.35, 60.34,60.24,52.13,49.07,46.88,46.79,35.25,34.55,30.72,29.13,28.10,25.51,21.01, 14.14；ESI-MS m/z885.3(M+H)+。
采用实施例1的合成方法，换用不同的原料X、II和IV，可以得到如下表2中所示的目标化合物I。原料X、II和IV可通过商业化购买或参考已知文献方法制备获得，其中 IV-66、IV-67、IV-68、IV-69可以采用实施例6的方法制备。
表2
表2中各个最终产品I的波谱数据：
Bcl-002:1H NMR(400MHz,CDCl3)δ9.92(brs,1H),8.94(dd,J＝4.2,1.6Hz,1H),8.83 (d,J＝2.2Hz,1H),8.47(t,J＝5.4Hz,1H),8.19(d,J＝9.2Hz,1H),8.09(d,J＝8.5Hz,1H), 8.00–7.93(m,2H),7.51(dd,J＝9.2,2.7Hz,1H),7.46(dd,J＝8.3,4.2Hz,1H),7.39(d,J＝2.7 Hz,1H),7.22(d,J＝8.3Hz,2H),6.91(d,J＝8.3Hz,2H),6.74(d,J＝9.3Hz,1H),6.62(dd,J ＝9.2,2.3Hz,1H),6.13(d,J＝2.2Hz,1H),4.02(dd,J＝11.4,3.8Hz,2H),3.42(td,J＝12.0, 1.9Hz,2H),3.23–3.17(m,2H),3.15–3.07(m,4H),2.75(s,2H),2.26–2.19(m,4H),2.16(t,J＝ 5.4Hz,2H),1.99–1.88(m,3H),1.76–1.68(m,2H),1.47–1.37(m,4H),0.93(s,6H)；ESI-MS m/z 881.3(M-H)-.
Bcl-003:1H NMR(400MHz,CDCl3)δ9.94(brs,1H),9.02(s,1H),8.83(d,J＝2.2 Hz,1H),8.50(t,J＝5.3Hz,1H),8.18(d,J＝8.9Hz,1H),8.04(dd,J＝9.1,2.1Hz,1H), 7.95(d,J＝9.1Hz,1H),7.62(d,J＝2.3Hz,1H),7.30(dd,J＝8.9,2.4Hz,1H),7.23(d,J ＝8.3Hz,2H),6.91(d,J＝8.3Hz,2H),6.82(d,J＝9.3Hz,1H),6.60(dd,J＝9.2,2.1Hz, 1H),6.08(d,J＝2.1Hz,1H),4.03(dd,J＝11.3,3.6Hz,2H),3.42(t,J＝11.7Hz,2H), 3.24(t,J＝6.0Hz,2H),3.15–3.05(m,4H),2.76(s,2H),2.27–2.20(m,4H),2.20–2.13(m, 2H),2.00–1.91(m,3H),1.77–1.69(m,2H),1.49–1.36(m,4H),0.94(s,6H)；13C NMR(100 MHz,CDCl3)δ171.11,161.82,157.68,155.59,154.28,152.51,150.64,147.77,142.01, 135.31,135.23,133.75,131.86,130.63,129.63,129.05,128.96,128.15,125.01,124.89, 119.16,113.59,112.48,109.64,109.46,102.05,77.20,67.35,60.34,60.24,52.13,49.07,46.88,46.79,35.25,34.55,30.72,29.13,28.10,25.51,21.01,14.14；ESI-MS m/z 885.3(M+H)+.
Bcl-004:1H NMR(400MHz,CDCl3)δ9.21(s,1H),8.68(s,1H),8.47(d,J＝3.8Hz,1H), 8.39(d,J＝5.8Hz,1H),8.01(d,J＝24.2Hz,1H),7.92(d,J＝8.4Hz,1H),7.78(s,1H),7.45(s, 1H),7.39(d,J＝16.8Hz,1H),7.22(d,J＝8.3Hz,2H),7.13(s,1H),6.91(d,J＝8.3Hz,2H), 6.65(d,J＝22.8Hz,1H),6.56(s,1H),6.21(s,1H),4.01(dd,J＝11.4,3.6Hz,2H),3.40(t,J＝ 11.1Hz,2H),3.15(s,6H),2.76(s,2H),2.28–2.22(m,4H),2.17(t,J＝6.0Hz,2H),1.96(s,2H), 1.94–1.84(m,1H),1.75–1.65(m,2H),1.46–1.35(m,4H),0.93(s,6H)；ESI-MS m/z 879.3 (M+H)+.
Bcl-005:1H NMR(400MHz,CDCl3)δ10.15(s,1H),8.88(d,J＝2.2Hz,1H),8.52(t,J＝ 5.4Hz,1H),8.21(d,J＝2.5Hz,1H),8.18(dd,J＝9.2,2.2Hz,1H),7.94(d,J＝9.1Hz,1H), 7.66(d,J＝2.5Hz,1H),7.31(d,J＝3.4Hz,1H),7.23(d,J＝8.3Hz,2H),6.91(dd,J＝8.9,2.8 Hz,3H),6.52(dd,J＝9.2,2.2Hz,1H),6.48(d,J＝3.4Hz,1H),5.96(d,J＝2.2Hz,1H),4.03 (dd,J＝11.5,3.5Hz,2H),3.95(s,3H),3.42(td,J＝11.8,1.8Hz,2H),3.30–3.24(m,2H),3.08–3.01(m,4H),2.73(s,2H),2.22–2.16(m,4H),2.14(d,J＝6.4Hz,2H),2.00–1.93(m,3H),1.74 (d,J＝14.6Hz,2H),1.48–1.39(m,4H),0.93(s,6H)；ESI-MS m/z 882.2(M+H)+.
Bcl-009:1H NMR(400MHz,CDCl3)δ10.13(s,1H),9.39(s,1H),8.89(d,J＝2.2Hz,1H), 8.52(t,J＝5.3Hz,1H),8.21(d,J＝2.5Hz,1H),8.17(dd,J＝9.1,2.1Hz,1H),7.95(d,J＝9.1 Hz,1H),7.70(d,J＝2.5Hz,1H),7.46(t,J＝2.8Hz,1H),7.10(d,J＝8.0Hz,2H),6.99(d,J＝ 8.6Hz,2H),6.91(d,J＝9.3Hz,1H),6.57–6.50(m,2H),5.98(d,J＝2.2Hz,1H),4.03(dd,J＝ 11.4,3.7Hz,2H),3.42(td,J＝11.8,1.7Hz,2H),3.30–3.24(m,2H),3.10–3.02(m,4H),2.74(s, 2H),2.24–2.13(m,6H),2.02–1.93(m,3H),1.78–1.70(m,2H),1.50–1.37(m,4H),0.93(s,6H)； ESI-MS m/z 918.2(M+H)+.
Bcl-010:1H NMR(400MHz,CDCl3)δ9.07(d,J＝46.7Hz,1H),8.88(d,J＝2.2Hz,1H),8.51(t,J＝5.3Hz,1H),8.20(dd,J＝7.8,4.6Hz,1H),8.16(dd,J＝9.1,1.9Hz,1H),8.03(d,J ＝2.2Hz,1H),7.95(d,J＝9.1Hz,1H),7.68(d,J＝2.3Hz,1H),7.45(s,1H),7.29(dd,J＝8.2, 2.4Hz,1H),7.23(d,J＝8.1Hz,1H),6.90(d,J＝9.2Hz,1H),6.54(d,J＝11.1Hz,2H),6.49(d, J＝6.6Hz,1H),5.99(d,J＝1.9Hz,1H),4.03(dd,J＝11.0,3.6Hz,2H),3.42(td,J＝11.8,1.5 Hz,2H),3.29–3.23(m,2H),3.09–3.02(m,4H),2.74(s,2H),2.23–2.16(m,6H),2.01–1.92(m, 3H),1.77–1.70(m,2H),1.49–1.40(m,4H),0.94(s,6H)；ESI-MS m/z 869.1(M+H)+.
Bcl-012:1H NMR(500MHz,cdcl3)δ8.87(d,J＝2.1Hz,1H),8.76(s,1H),8.50(t,J＝5.4 Hz,1H),8.06(dd,J＝9.1,2.0Hz,1H),7.94(d,J＝9.1Hz,1H),7.42(d,J＝8.7Hz,1H),7.30 (dd,J＝5.4,2.4Hz,2H),7.18(t,J＝7.9Hz,1H),6.92(dd,J＝8.7,2.1Hz,1H),6.83(d,J＝9.3 Hz,1H),6.73(dd,J＝8.2,2.4Hz,1H),6.58(d,J＝7.5Hz,1H),6.53(d,J＝6.6Hz,3H),6.09 (d,J＝2.0Hz,1H),4.03(dd,J＝11.4,3.4Hz,2H),3.81(d,J＝5.4Hz,1H),3.77(s,3H),3.43 (td,J＝11.9,1.9Hz,2H),3.24(t,J＝7.5Hz,2H),3.11–3.03(m,4H),2.79(s,2H),2.26–2.21 (m,4H),2.16(t,J＝5.7Hz,2H),2.03–1.91(m,3H),1.74(d,J＝12.7Hz,2H),1.49–1.38(m, 4H),0.94(s,6H).
Bcl-013:1H NMR(500MHz,cdcl3)δ10.34(s,1H),8.87(d,J＝2.2Hz,1H),8.63(s,1H), 8.50(t,J＝5.4Hz,1H),8.08(dd,J＝9.2,2.1Hz,1H),7.94(d,J＝9.1Hz,1H),7.43(d,J＝8.7 Hz,1H),7.35–7.28(m,2H),6.94(dd,J＝8.7,2.2Hz,1H),6.84(d,J＝9.3Hz,1H),6.71(d,J ＝7.9Hz,1H),6.57–6.49(m,2H),6.47(d,J＝1.2Hz,1H),6.42(dd,J＝7.9,1.3Hz,1H),6.09 (d,J＝2.1Hz,1H),5.92(s,2H),4.03(dd,J＝11.4,3.6Hz,2H),3.43(dd,J＝11.7,10.5Hz,2H), 3.33–3.20(m,2H),3.09(s,3H),2.82(s,2H),2.20(d,J＝45.5Hz,5H),1.97(s,3H),1.74(d,J ＝12.8Hz,2H),1.50–1.35(m,4H),1.27(s,2H),0.94(d,J＝14.0Hz,6H).
Bcl-014:1H NMR(500MHz,cdcl3)δ10.38(s,1H),8.87(s,1H),8.71(s,1H),8.50(t,J＝ 5.1Hz,1H),8.07(d,J＝9.1Hz,1H),7.94(d,J＝9.2Hz,1H),7.43(d,J＝8.6Hz,1H),7.31(d, J＝5.7Hz,2H),7.27(d,J＝6.7Hz,1H),7.04(d,J＝8.2Hz,1H),6.93(d,J＝7.9Hz,2H),6.88 –6.81(m,2H),6.53(d,J＝7.4Hz,2H),6.10(s,1H),4.03(dd,J＝11.3,3.3Hz,2H),3.43(t,J ＝11.7Hz,2H),3.25(t,J＝6.0Hz,2H),3.06(s,4H),2.75(s,2H),2.24–2.15(m,6H),1.97(d, J＝20.7Hz,3H),1.74(d,J＝12.6Hz,2H),1.47–1.39(m,4H),0.95(s,6H).
Bcl-023:1H NMR(400MHz,CDCl3)δ8.70(s,1H),8.43(s,1H),8.03(d,J＝8.6Hz,1H),7.81(d,J＝8.8Hz,1H),7.21(t,J＝9.7Hz,3H),6.91(t,J＝11.1Hz,5H),6.55(d,J ＝8.6Hz,1H),6.12(s,1H),4.59(s,4H),3.98(dd,J＝11.1,3.1Hz,2H),3.38(t,J＝11.4 Hz,2H),3.24(t,J＝5.5Hz,2H),3.16(s,4H),2.83(s,2H),2.32(s,4H),2.20(s,2H),2.01 –1.87(m,3H),1.70(d,J＝12.2Hz,2H),1.47–1.34(m,4H),0.93(s,6H).
Bcl-024:1H NMR(400MHz,CDCl3)δ9.93(brs,1H),8.76(dd,J＝24.0,2.2Hz,1H),8.49 (dd,J＝9.8,5.0Hz,1H),8.18–8.09(m,1H),7.92(d,J＝9.1Hz,1H),7.35–7.28(m,1H),7.23 (d,J＝8.3Hz,2H),7.02(dt,J＝8.3,2.2Hz,1H),6.97(dd,J＝8.7,1.8Hz,1H),6.91(t,J＝9.1 Hz,3H),6.58(dt,J＝9.2,2.7Hz,1H),6.06(dd,J＝5.6,2.2Hz,1H),4.86–4.74(m,4H),4.02 (dd,J＝11.4,3.6Hz,2H),3.41(td,J＝11.8,1.6Hz,2H),3.25(t,J＝6.1Hz,2H),3.13(s,4H), 2.78(s,2H),2.26(s,4H),2.19(d,J＝3.7Hz,5H),2.02–1.92(m,3H),1.73(d,J＝14.5Hz, 2H),1.49–1.36(m,4H),0.94(s,6H).
Bcl-025:1H NMR(400MHz,CDCl3)δ10.28(s,1H),8.62(d,J＝2.1Hz,1H),8.46(t,J＝ 5.2Hz,1H),8.14(s,1H),7.94(d,J＝9.1Hz,1H),7.76(d,J＝9.0Hz,1H),7.33(d,J＝3.2Hz, 1H),7.24(d,J＝8.4Hz,2H),6.93(d,J＝8.4Hz,2H),6.76(d,J＝9.2Hz,1H),6.70(dd,J＝9.2, 2.2Hz,1H),6.51(d,J＝4.0Hz,1H),6.44(d,J＝3.2Hz,1H),6.34(d,J＝2.1Hz,1H),4.01(dd, J＝11.3,3.6Hz,2H),3.49–3.38(m,2H),3.25–3.13(m,6H),2.80(s,2H),2.28(s,4H),2.19 (t,J＝5.7Hz,2H),1.98(s,2H),1.96–1.87(m,1H),1.70(d,J＝13.0Hz,2H),1.46–1.34(m, 4H),0.94(s,6H).
Bcl-026:1H NMR(400MHz,CDCl3)δ9.27(s,1H),8.84(s,1H),8.47(t,J＝4.9Hz,1H), 8.35(s,1H),8.02(d,J＝8.7Hz,1H),7.88(d,J＝9.1Hz,1H),7.50(d,J＝22.6Hz,2H),7.21 (d,J＝8.3Hz,2H),6.91(d,J＝8.3Hz,2H),6.83(d,J＝9.3Hz,1H),6.78(s,1H),6.50(d,J＝ 8.8Hz,1H),5.98(s,1H),4.01(dd,J＝11.3,3.4Hz,2H),3.41(t,J＝11.2Hz,2H),3.23(t,J＝ 6.0Hz,2H),3.06(s,4H),2.76(s,2H),2.30–2.10(m,6H),2.02–1.89(m,3H),1.72(d,J＝ 12.2Hz,2H),1.48–1.36(m,4H),0.92(s,6H).
Bcl-028:ESI-MS m/z 865.0(M+H)+.
Bcl-029:ESI-MS m/z 879.0(M+H)+.
Bcl-030:ESI-MS m/z 918.9(M+H)+.
Bcl-031:1H NMR(400MHz,CDCl3)δ10.33(s,1H),8.86(d,J＝2.2Hz,1H),8.51(t,J＝ 4.3Hz,2H),8.10(dd,J＝9.2,2.2Hz,1H),8.03(d,J＝2.2Hz,1H),7.93(d,J＝9.1Hz,1H), 7.44(d,J＝8.7Hz,1H),7.34–7.28(m,3H),7.23(d,J＝8.1Hz,1H),6.95(dd,J＝8.7,2.3Hz, 1H),6.85(d,J＝9.3Hz,1H),6.56–6.54(m,1H),6.51(dd,J＝9.1,2.3Hz,1H),6.07(d,J＝2.2 Hz,1H),4.02(dd,J＝11.4,3.5Hz,2H),3.42(td,J＝11.8,1.7Hz,2H),3.28–3.22(m,2H),3.08– 3.00(m,4H),2.73(s,2H),2.23–2.19(d,J＝5.1Hz,6H),2.00–1.90(m,3H),1.77–1.69(m,2H), 1.49–1.36(m,4H),0.95(d,J＝5.7Hz,6H)；ESI-MS m/z 868.3(M+H)+.
Bcl-032:1H NMR(400MHz,CDCl3)δ10.25(s,1H),8.81(d,J＝2.2Hz,1H),8.49(t,J＝ 5.3Hz,1H),8.09–8.01(m,2H),7.93(d,J＝9.1Hz,1H),7.40(d,J＝8.8Hz,1H),7.32–7.27 (m,2H),7.22(dd,J＝11.5,5.6Hz,2H),7.03(dd,J＝8.8,2.3Hz,1H),6.84(d,J＝9.3Hz,1H), 6.54(dd,J＝11.3,2.6Hz,2H),6.23–5.91(m,2H),4.51(td,J＝14.3,3.7Hz,2H),4.02(dd,J ＝11.3,3.6Hz,2H),3.42(td,J＝11.8,1.7Hz,2H),3.28–3.21(m,2H),3.11–3.02(m,4H), 2.74(s,2H),2.25–2.15(m,6H),1.96(s,3H),1.73(d,J＝12.8Hz,2H),1.49–1.36(m,4H), 0.95(s,6H)；ESI-MS m/z 932.3(M+H)+.
Bcl-033:1H NMR(400MHz,CDCl3)δ10.08(brs,1H),8.86(d,J＝2.2Hz,1H),8.51(t,J ＝5.3Hz,1H),8.21(d,J＝2.5Hz,1H),8.14(dd,J＝9.2,2.2Hz,1H),7.95(d,J＝9.1Hz,1H), 7.65(d,J＝2.5Hz,1H),7.38(d,J＝3.5Hz,1H),7.22(d,J＝9.0Hz,2H),6.90(dd,J＝10.0, 4.9Hz,3H),6.55(dd,J＝9.7,2.9Hz,2H),6.17(tt,J＝55.6,4.1Hz,1H),6.00(d,J＝2.2Hz, 1H),4.69(td,J＝14.2,4.1Hz,2H),4.03(dd,J＝11.2,3.5Hz,2H),3.42(td,J＝11.9,1.8Hz, 2H),3.31–3.23(m,2H),3.13–3.03(m,4H),2.75(s,2H),2.25–2.19(m,4H),2.16(t,J＝6.1Hz, 2H),2.02-1.90(m,3H),1.78–1.70(m,2H),1.48–1.38(m,4H),0.93(s,6H)；ESI-MS m/z932.3 (M+H)+.
Bcl-034:1H NMR(400MHz,CDCl3)δ10.16(s,1H),8.89(d,J＝2.2Hz,1H),8.53(t,J＝ 5.4Hz,1H),8.19(d,J＝2.5Hz,1H),8.15(dd,J＝9.2,2.1Hz,1H),7.94(d,J＝9.1Hz,1H), 7.65(d,J＝2.5Hz,1H),7.46(d,J＝3.5Hz,1H),7.22(d,J＝8.4Hz,2H),6.91(dd,J＝8.9,3.0 Hz,3H),6.53(dd,J＝9.2,2.2Hz,1H),6.48(d,J＝3.5Hz,1H),5.99(d,J＝2.2Hz,1H),4.52 (t,J＝5.1Hz,2H),4.03(dd,J＝11.3,3.8Hz,2H),3.83–3.76(m,2H),3.42(td,J＝11.9,1.6 Hz,2H),3.38(s,3H),3.29–3.23(m,2H),3.11–3.02(m,4H),2.74(s,2H),2.24–2.12(m,6H), 1.96(s,3H),1.74(d,J＝12.9Hz,2H),1.50–1.36(m,4H),0.93(s,6H)；ESI-MSm/z926.1 (M+H)+.
Bcl-035:1H NMR(400MHz,CDCl3)δ10.07(s,1H),8.85(d,J＝2.3Hz,1H),8.52(t,J＝ 5.3Hz,1H),8.24(d,J＝2.5Hz,1H),8.13(dd,J＝9.2,2.2Hz,1H),7.94(d,J＝9.1Hz,1H), 7.65(d,J＝2.5Hz,1H),7.40(d,J＝3.6Hz,1H),7.23(d,J＝8.4Hz,2H),6.94–6.87(m,3H), 6.59(d,J＝3.6Hz,1H),6.55(dd,J＝9.2,2.3Hz,1H),5.99(d,J＝2.2Hz,1H),4.95(q,J＝8.7 Hz,2H),4.03(dd,J＝11.2,3.7Hz,2H),3.42(td,J＝11.9,1.8Hz,2H),3.29–3.23(m,2H), 3.12–3.04(m,4H),2.74(s,2H),2.24–2.18(m,4H),2.15(t,J＝6.2Hz,2H),1.96(s,3H),1.74 (d,J＝12.9Hz,2H),1.49–1.37(m,4H),0.93(s,6H)；ESI-MS m/z 950.2(M+H)+.
Bcl-036:1H NMR(400MHz,CDCl3)δ10.12(brs,1H),8.88(d,J＝2.2Hz,1H),8.52(t,J ＝5.3Hz,1H),8.19(d,J＝2.5Hz,1H),8.14(dd,J＝9.2,2.2Hz,1H),7.94(d,J＝9.1Hz,1H), 7.66(d,J＝2.5Hz,1H),7.44(d,J＝3.4Hz,1H),7.23(d,J＝8.4Hz,2H),6.90(dd,J＝8.8,7.0 Hz,3H),6.54(dd,J＝9.2,2.2Hz,1H),6.51(d,J＝3.5Hz,1H),5.99(d,J＝2.2Hz,1H),4.83 (dt,J＝47.1,4.7Hz,2H),4.65(dt,J＝27.6,4.6Hz,2H),4.03(dd,J＝11.3,3.5Hz,2H),3.42 (td,J＝11.9,1.7Hz,2H),3.30–3.22(m,2H),3.11–3.04(m,4H),2.74(s,2H),2.24–2.11(m, 6H),2.00–1.92(m,3H),1.78–1.69(m,2H),1.49–1.36(m,4H),0.93(s,6H)；ESI-MS m/z 914.2 (M+H)+.
Bcl-037:1H NMR(400MHz,CDCl3)δ9.94(s,1H),9.02(s,1H),8.83(d,J＝2.2Hz,1H), 8.50(t,J＝5.4Hz,1H),8.18(d,J＝8.9Hz,1H),8.07–8.02(m,2H),7.95(d,J＝9.1Hz,1H), 7.63(d,J＝2.4Hz,1H),7.30(dd,J＝9.4,2.1Hz,2H),7.24(d,J＝8.1Hz,1H),6.82(d,J＝9.3 Hz,1H),6.60(dd,J＝9.2,2.3Hz,1H),6.07(d,J＝2.2Hz,1H),4.03(dd,J＝11.3,3.6Hz,2H), 3.42(td,J＝11.9,1.8Hz,2H),3.27–3.21(m,2H),3.14–3.06(m,4H),2.75(s,2H),2.27–2.16(m,6H),2.01–1.90(m,3H),1.72(dt,J＝9.1,4.6Hz,2H),1.49–1.36(m,4H),0.95(s, 6H)；ESI-MS m/z 886.1(M+H)+.
Bcl-038:1H NMR(400MHz,CDCl3)δ10.22(s,1H),8.89(d,J＝2.2Hz,1H),8.51(t,J＝ 5.3Hz,1H),8.22(d,J＝2.5Hz,1H),8.16(dd,J＝9.1,2.2Hz,1H),7.95(d,J＝9.1Hz,1H), 7.71(d,J＝2.4Hz,1H),7.48(t,J＝3.3Hz,1H),6.90(d,J＝9.3Hz,1H),6.73(d,J＝8.2Hz, 1H),6.57–6.52(m,2H),6.48(d,J＝1.8Hz,1H),6.43(dd,J＝8.2,1.9Hz,1H),5.99(d,J＝2.1 Hz,1H),4.22(s,4H),4.02(dd,J＝11.3,3.4Hz,2H),3.42(t,J＝11.8Hz,2H),3.29–3.22(m, 2H),3.07(t,J＝4.6Hz,4H),2.81(s,2H),2.28–2.19(m,4H),2.17–2.08(m,2H),1.99–1.90(m, 3H),1.78–1.68(m,2H),1.48–1.36(m,4H),0.91(s,6H)；ESI-MS m/z892.3(M+H)+.
Bcl-043:ESI-MS m/z 896.6(M+H)+.
Bcl-044:ESI-MS m/z 895.5(M+H)+.
Bcl-045:1H NMR(500MHz,cdcl3)δ8.87(d,J＝5.5Hz,1H),8.82(s,1H),8.54–8.48(m, 1H),8.21–8.13(m,2H),8.08(dd,J＝13.3,8.5Hz,2H),8.00(d,J＝8.8Hz,1H),7.93(d,J＝ 8.9Hz,1H),7.68(s,1H),7.42(d,J＝15.6Hz,2H),7.37(d,J＝10.1Hz,2H),6.90(d,J＝9.6 Hz,1H),6.57–6.49(m,2H),5.96(s,1H),4.68(d,J＝4.2Hz,2H),4.03(dd,J＝13.2,3.1Hz, 2H),3.42(t,J＝11.4Hz,2H),3.29–3.23(m,2H),3.10–3.01(m,4H),2.80(s,2H),2.26–2.17 (m,5H),2.09(s,2H),1.73(d,J＝13.2Hz,2H),1.48–1.41(m,4H),0.99(s,6H).
Bcl-046:1H NMR(500MHz,cdcl3)δ10.11(s,1H),9.17(s,1H),8.88(d,J＝2.1Hz,1H), 8.52(t,J＝5.2Hz,1H),8.21(d,J＝2.4Hz,1H),8.15(dd,J＝9.2,1.8Hz,1H),8.02(d,J＝2.0 Hz,1H),7.93(d,J＝9.1Hz,1H),7.69(d,J＝2.3Hz,1H),7.46(s,1H),7.28(d,J＝2.3Hz,1H), 7.19(d,J＝8.1Hz,1H),6.90(d,J＝9.3Hz,1H),6.57(d,J＝3.3Hz,1H),6.42(dd,J＝9.2,2.0 Hz,1H),5.89(d,J＝1.9Hz,1H),4.03(dd,J＝11.4,3.7Hz,2H),3.42(t,J＝11.6Hz,2H),3.26 (t,J＝6.1Hz,2H),3.05(s,2H),2.75–2.62(m,6H),2.09(s,2H),2.00–1.95(m,1H),1.93(s, 2H),1.74(d,J＝11.7Hz,2H),1.58(s,4H),1.47–1.38(m,4H),0.93(s,6H).
Bcl-050:1H NMR(500MHz,cdcl3)δ10.11(s,1H),9.15(s,1H),8.88(s,1H),8.54–8.50 (m,1H),8.19(d,J＝2.2Hz,1H),8.16(d,J＝10.2Hz,1H),8.01(d,J＝2.0Hz,1H),7.92(d,J ＝9.1Hz,1H),7.69(s,1H),7.44(s,1H),7.35–7.19(m,1H),6.90(d,J＝9.1Hz,1H),6.55(s, 1H),6.49(d,J＝9.2Hz,1H),5.93(s,1H),5.34(t,J＝4.7Hz,1H),4.03(dd,J＝11.4,3.2Hz, 2H),3.42(t,J＝11.2Hz,2H),3.30–3.23(m,2H),3.02–2.97(m,2H),2.75(s,2H),2.25–2.20 (m,2H),2.20–2.13(m,4H),2.05–1.91(m,3H),1.73(d,J＝11.6Hz,2H),1.48–1.39(m,4H), 0.93(s,6H),0.83(s,6H).
Bcl-057:1H NMR(400MHz,CDCl3)δ9.76(s,1H),8.89(d,J＝2.2Hz,1H),8.61(s,1H), 8.55(t,J＝5.3Hz,1H),8.23–8.18(m,2H),7.75(d,J＝2.4Hz,1H),7.54–7.50(m,1H),7.23 (d,J＝8.4Hz,2H),6.95(d,J＝9.3Hz,1H),6.89(d,J＝8.4Hz,2H),6.60(dd,J＝3.5,1.9Hz, 1H),6.09(s,1H),4.03(dd,J＝11.3,3.5Hz,2H),3.43(td,J＝11.8,1.8Hz,2H),3.32–3.26(m, 2H),2.88(s,4H),2.75(s,2H),2.22(s,4H),2.11(s,2H),2.02–1.91(m,3H),1.75(d,J＝12.8 Hz,2H),1.50–1.42(m,2H),1.38(t,J＝6.3Hz,2H),0.91(s,6H).
Bcl-058:1H NMR(400MHz,CDCl3)δ10.04(s,1H),8.87(d,J＝2.1Hz,1H),8.52(t,J＝ 5.3Hz,1H),8.19(d,J＝2.4Hz,1H),8.14(dd,J＝9.2,2.0Hz,1H),7.68(t,J＝8.5Hz,2H),7.51 –7.46(m,1H),7.23(d,J＝8.3Hz,2H),6.94–6.87(m,3H),6.54(dd,J＝3.2,1.9Hz,1H),6.09 (d,J＝6.9Hz,1H),4.03(dd,J＝11.4,3.5Hz,2H),3.42(td,J＝11.8,1.6Hz,2H),3.26(t,J＝ 6.1Hz,2H),3.02–2.93(m,4H),2.75(s,2H),2.25(brs,4H),2.13(s,2H),2.01–1.91(m,3H), 1.74(d,J＝12.8Hz,2H),1.50–1.36(m,4H),0.92(s,6H).
Bcl-063:1H NMR(400MHz,CDCl3)δ9.93(brs,1H),9.02(s,1H),8.83(d,J＝2.3Hz,1H),8.49(t,J＝5.4Hz,1H),8.18(d,J＝8.9Hz,1H),8.03(dd,J＝9.1,2.1Hz,1H),7.95(d,J＝9.1Hz,1H),7.62(d,J＝2.4Hz,1H),7.30(dd,J＝8.9,2.5Hz,1H),6.82(d,J＝9.3Hz,1H),6.74(d,J＝8.2Hz,1H),6.61(dd,J＝9.2,2.4Hz,1H),6.49(d,J＝2.0Hz,1H),6.44(dd,J＝8.2,2.0Hz,1H),6.09(d,J＝2.3Hz,1H),4.23(s,4H),4.03(dd,J＝11.1,3.5Hz,2H),3.42(td, J＝11.9,1.9Hz,2H),3.24(t,J＝6.6Hz,2H),3.16–3.08(m,4H),2.81(s,2H),2.30–2.23(m, 4H),2.14(t,J＝6.1Hz,2H),2.02–1.90(m,3H),1.77–1.69(m,2H),1.49–1.36(m,4H),0.92(s, 6H)；ESI-MS m/z 909.3(M+H)+.
Bcl-065:1H NMR(400MHz,CDCl3)δ9.90(s,1H),9.02(s,1H),8.81(d,J＝2.3Hz,1H), 8.49(t,J＝5.4Hz,1H),8.17(d,J＝8.9Hz,1H),8.01(dd,J＝9.1,2.2Hz,1H),7.91(d,J＝9.1 Hz,1H),7.61(d,J＝2.4Hz,1H),7.30(d,J＝2.5Hz,1H),7.22(dd,J＝6.3,4.5Hz,2H),6.91 (d,J＝8.4Hz,2H),6.80(d,J＝9.3Hz,1H),6.56(dd,J＝9.2,2.4Hz,1H),6.04(d,J＝2.3Hz, 1H),4.02(dd,J＝11.3,3.3Hz,2H),3.42(td,J＝11.9,1.9Hz,2H),3.26–3.20(m,2H),3.09– 3.04(m,2H),2.91(s,2H),2.76(s,2H),2.25–2.19(m,2H),2.15(t,J＝6.1Hz,2H),2.01–1.89 (m,3H),1.73(dd,J＝12.9,1.8Hz,2H),1.49–1.36(m,4H),0.92(s,6H),0.85(s,6H)；ESI-MS m/z 913.1(M+H)+.
Bcl-066:1H NMR(500MHz,cdcl3)δ10.12(s,1H),9.36(s,1H),8.89(d,J＝1.7Hz,1H), 8.52(t,J＝5.2Hz,1H),8.18(dd,J＝14.5,5.6Hz,2H),7.96(d,J＝9.1Hz,1H),7.70(d,J＝1.8 Hz,1H),7.48(s,1H),7.16(dd,J＝17.9,8.5Hz,4H),6.91(d,J＝9.1Hz,1H),6.57(s,1H),6.45 (d,J＝9.1Hz,1H),5.88(s,1H),4.03(dd,J＝11.7,3.7Hz,2H),3.42(t,J＝11.0Hz,4H),3.26 (t,J＝6.1Hz,2H),3.08–3.93(m,2H),2.85–2.77(m,2H),2.61–2.55(m,1H),2.25–2.20 (m,2H),2.03–1.93(m,4H),1.73(d,J＝13.1Hz,2H),1.49–1.39(m,4H),0.99(s,6H).
Bcl-067:1H NMR(500MHz,cdcl3)δ10.12(s,1H),9.05(s,1H),8.90(s,1H),8.53(s,1H), 8.24–8.15(m,3H),7.97(d,J＝9.1Hz,1H),7.70(s,1H),7.52(d,J＝8.0Hz,1H),7.46(s,1H), 7.19(d,J＝7.9Hz,1H),6.92(d,J＝9.1Hz,1H),6.57(s,1H),6.48(d,J＝9.5Hz,1H),5.93(s, 1H),4.03(d,J＝13.1Hz,2H),3.42(t,J＝11.6Hz,2H),3.27(t,J＝5.8Hz,2H),3.00–2.83(m, 5H),2.63–2.47(m,3H),2.08–1.91(m,4H),1.74(d,J＝12.3Hz,2H),1.50–1.38(m,4H), 1.01(s,6H).
Bcl-068:ESI-MS m/z 909.3(M+H)+.
Bcl-069:1H NMR(500MHz,cdcl3)δ10.11(s,1H),9.09(s,1H),8.88(s,1H),8.52(s,1H), 8.21–8.13(m,2H),7.94(d,J＝9.0Hz,1H),7.68(s,1H),7.46(s,1H),7.17(d,J＝8.4Hz,2H), 7.04(d,J＝8.0Hz,2H),6.91(d,J＝9.2Hz,1H),6.56(s,1H),6.41(d,J＝13.9Hz,1H),5.85(s, 1H),4.03(dd,J＝11.0,3.5Hz,2H),3.42(t,J＝11.6Hz,2H),3.26(t,J＝5.8Hz,2H),3.15– 3.00(m,2H),2.89–2.72(m,2H),2.63–2.51(m,2H),2.25–2.19(m,1H),2.07–1.92(m,6H), 1.74(d,J＝12.5Hz,2H),1.49–1.39(m,4H),0.98(s,6H),0.91–0.85(m,2H).
Bcl-070:1H NMR(500MHz,cdcl3)δ10.13(s,1H),9.37(s,1H),8.89(d,J＝1.5Hz,1H),8.52(t,J＝5.2Hz,1H),8.30(d,J＝2.4Hz,1H),8.20(d,J＝2.2Hz,1H),8.17(dd,J ＝9.2,1.9Hz,1H),8.08(s,1H),7.95(d,J＝9.0Hz,1H),7.70(d,J＝2.3Hz,1H),7.47– 7.44(m,1H),7.07(d,J＝9.2Hz,1H),6.91(d,J＝9.2Hz,1H),6.54(dd,J＝9.5,1.9Hz, 2H),5.98(d,J＝1.6Hz,1H),4.03(dd,J＝11.5,3.6Hz,2H),3.42(t,J＝11.4Hz,2H), 3.26(t,J＝6.1Hz,2H),3.09–3.02(m,4H),2.75(s,2H),2.38–2.16(m,6H),2.06–1.92 (m,3H),1.74(d,J＝12.7Hz,2H),1.49–1.40(m,4H),0.95(s,6H).
Bcl-071:1H NMR(400MHz,cdcl3)δ10.12(s,1H),9.19(s,1H),8.89(s,1H),8.52(s,1H), 8.22–8.14(m,2H),7.94(d,J＝9.6Hz,1H),7.71(s,1H),7.44(s,1H),6.95–6.78(m,6H), 6.54(s,1H),5.97(s,1H),4.15–3.98(m,4H),3.72(d,J＝7.0Hz,4H),3.51–3.37(m,4H), 3.32–3.23(m,2H),3.06(s,2H),2.77(s,2H),2.28–2.11(m,6H),2.03–1.93(m,4H),1.74(d, J＝12.3Hz,2H),1.47–1.37(m,4H),1.26(s,6H).
Bcl-072:1H NMR(400MHz,CDCl3)δ8.83(d,J＝2.1Hz,1H),8.50(t,J＝5.4Hz,1H),8.12(d,J＝1.8Hz,1H),8.07(dd,J＝9.2,2.1Hz,1H),7.90(d,J＝9.1Hz,1H),7.78(s,1H),7.66(s,1H),7.22(d,J＝8.4Hz,2H),7.13(d,J＝9.2Hz,1H),6.92(d,J＝8.3Hz,2H),6.87(d, J＝9.3Hz,1H),6.57(dd,J＝9.2,2.1Hz,1H),6.02(d,J＝2.0Hz,1H),4.01(dd,J＝11.4,3.5 Hz,2H),3.41(td,J＝11.8,1.6Hz,2H),3.29–3.22(m,2H),3.12(d,J＝4.5Hz,4H),2.77(s, 2H),2.24(brs,4H),2.17(t,J＝5.7Hz,2H),2.01–1.90(m,3H),1.73(d,J＝14.3Hz,2H),1.48 –1.37(m,4H),0.93(s,6H).
表2中的化合物Bcl-023，利用表格中所示的原料，经过本实施例中的四步反应后，还需要增加一步脱保护反应，得到最终的产物Bcl-023。该步脱保护反应具体条件如下 所示。
将Bcl-023-A(98mg,0.101mmol)溶于10mL DCM溶剂中，室温条件下让该溶液中 缓慢滴加2mL三氟醋酸，搅拌下反应2小时。停止搅拌，减压旋转蒸发移除溶剂，利用 快速柱层析纯化得到最终产品Bcl-023：60mg,收率：68.3％。1H NMR(400MHz,CDCl3) δ8.70(s,1H),8.43(s,1H),8.03(d,J＝8.6Hz,1H),7.81(d,J＝8.8Hz,1H),7.21(t,J＝9.7Hz,3H),6.91(t,J＝11.1Hz,5H),6.55(d,J＝8.6Hz,1H),6.12(s,1H),4.59(s,4H), 3.98(dd,J＝11.1,3.1Hz,2H),3.38(t,J＝11.4Hz,2H),3.24(t,J＝5.5Hz,2H),3.16(s, 4H),2.83(s,2H),2.32(s,4H),2.20(s,2H),2.01–1.87(m,3H),1.70(d,J＝12.2Hz,2H), 1.47–1.34(m,4H),0.93(s,6H)。
实施例2化合物Bcl-006的制备
将化合物Bcl-003(30mg,0.034mmol)溶解于2mL无水1,4-二氧六环溶剂中，室温下加入Lawsson’s reagent(27mg,0.068mmol),在氩气保护下，反应温度升高至85℃, 搅拌下反应6小时，停止加热反应冷却至室温，用20mL乙酸乙酯稀释反应液，并分别 用水(15mL×2),饱和氯化钠水溶液(15mL×2)洗涤，之后无水硫酸钠干燥，旋转蒸 发移除溶剂，快速柱层析得到最终产品Bcl-006：12mg，收率:40％，黄色固体。1H NMR (400MHz,CDCl3)δ9.00(s,1H),8.75(d,J＝2.2Hz,1H),8.46(t,J＝5.3Hz,1H),8.29 (d,J＝9.3Hz,1H),8.16(d,J＝8.9Hz,1H),7.74(dd,J＝9.2,2.0Hz,1H),7.52(d,J＝2.3 Hz,1H),7.29(dd,J＝8.9,2.4Hz,1H),7.24(d,J＝8.3Hz,2H),6.92(d,J＝8.3Hz,2H), 6.60(dd,J＝13.8,5.7Hz,2H),6.12(d,J＝2.3Hz,1H),4.02(dd,J＝11.5,3.6Hz,2H), 3.42(t,J＝11.8Hz,2H),3.23–3.12(m,6H),2.79(s,2H),2.31–2.22(m,4H),2.16(s,2H), 1.98(s,2H),1.95–1.88(m,1H),1.72(d,J＝11.0Hz,2H),1.46–1.38(m,4H),0.94(s,6H)； ESI-MS m/z 901.1(M+H)+。
换用不同的底物，利用该实施例中提供的方法，还可以制备出化合物Bcl-007与Bcl-011。
Bcl-007:1H NMR(400MHz,CDCl3)δ8.81(d,J＝2.3Hz,1H),8.51(t,J＝5.3Hz,1H),8.34(d,J＝9.3Hz,1H),8.23(d,J＝2.5Hz,1H),8.03(dd,J＝9.1,2.2Hz,1H),7.63(d,J＝2.6Hz,1H),7.31(d,J＝3.4Hz,1H),7.23(d,J＝8.3Hz,2H),6.91(d,J＝8.4Hz,2H),6.80(d,J＝9.2Hz,1H),6.51(dd,J＝9.4,2.3Hz,1H),6.47(d,J＝3.4Hz,1H),5.96(d,J＝2.3Hz,1H),4.03(dd,J＝11.1,3.6Hz,2H),3.95(s,3H),3.42(td,J＝11.9,1.8Hz,2H),3.27–3.21(m, 2H),3.10(s,4H),2.76(s,2H),2.26–2.13(m,6H),2.00–1.93(m,3H),1.78–1.69(m,2H), 1.48–1.39(m,4H),0.93(s,6H)；ESI-MS m/z 898.2(M+H)+.
Bcl-011:1H NMR(400MHz,CDCl3)δ9.90(s,1H),8.80(d,J＝2.2Hz,1H),8.49(t,J＝4.6Hz,1H),8.29(d,J＝9.2Hz,1H),8.16(d,J＝2.4Hz,1H),7.96(dd,J＝9.2,2.0Hz,1H),7.64(d,J＝2.5Hz,1H),7.42(d,J＝3.5Hz,1H),7.09(d,J＝8.1Hz,2H),6.98(d,J＝8.6Hz,2H),6.75(d,J＝9.3Hz,1H),6.55–6.48(m,2H),5.96(d,J＝2.2Hz,1H),4.01(dd,J＝11.7,3.9Hz,2H),3.45–3.38(m,2H),3.25–3.19(m,2H),3.12–3.03(m,4H),2.74(s,2H),2.25–2.12 (m,6H),2.01–1.92(m,3H),1.76–1.68(m,2H),1.47–1.34(m,4H),0.92(s,6H).
实施例3化合物Bcl-051的制备
以II-51(5.0g,24.88mmol)和IV-3(8.3g,26.12mmol)为原料,与磷酸氢二钾(5.2g,29.87mmol)共同混合于250mL的反应瓶中，于氩气保护下加入无水二甲亚砜 60mL。将反应液置于提前预热至80℃的油浴中反应6小时，停止加热反应冷却至室温， 用200mL乙酸乙酯稀释反应液，并分别用水(150mL×2),饱和氯化钠水溶液(150mL×2) 洗涤，之后无水硫酸钠干燥，旋转蒸发移除溶剂，快速柱层析得到产品VII-51：11.8g， 收率:95％。ESI-MS m/z 501.0(M+H)+。
以上一步得到的VII-51(5.0g,10mmol)为原料，与X-51(2.78g,10.5mmol)、Cs2CO3(3.51g,10.76mmol)混合溶于40mL NMP溶剂中，于80℃条件下搅拌反应24小时， 停止加热反应冷却至室温，用200mL乙酸乙酯稀释反应液，并分别用水(150mL×2), 饱和氯化钠水溶液(150mL×2)洗涤，之后无水硫酸钠干燥，旋转蒸发移除溶剂，快 速柱层析得到产品V-51：6.69g，收率:98％。ESI-MS m/z 683.2(M+H)+。
将V-51(1.36g,2mmol)置于250mL的反应瓶中，加入50mL DCM溶剂，之后缓缓加 入TFA(20mL),反应混合液由室温加热至40℃，搅拌反应3小时，停止加热搅拌，减 压条件下除去溶剂，快速柱层析得到产品VIII-51：944mg，收率:81％。ESI-MS m/z 583.1 (M+H)+。
将上一步反应中得到的化合物VIII-51(333mg,0.57mmol)溶解在16mL THF和4.8mL H2O的混合溶剂中，加入0.75M的氢氧化钾水溶液，回流条件下反应7小时。停 止加热反应冷却至室温，用80mL乙酸乙酯稀释反应液，并分别用水(60mL×2),饱和 氯化钠水溶液(60mL×2)洗涤，之后无水硫酸钠干燥，旋转蒸发移除溶剂，快速柱层 析得到产品V-51-2：180mg，收率:57％。ESI-MS m/z 553.1(M+H)+。
将上一步反应中得到的化合物V-51-2(100mg,0.18mmol)溶解于0.7mL乙醇溶剂中，加入6N的氢氧化钠水溶液(0.3mL)中，于80℃温度下搅拌反应8小时，停止加热将 反应冷却至室温，用3N的盐酸溶液将反应液中和至PH值为4左右。减压除去溶剂，C18 反相色谱柱层析得到目标产物VI-51：92mg，收率:89％。ESI-MS m/z 572.1(M+H)+。
将上步反应中得到的产物VI-51(50mg,0.087mmol)、与化合物7(27.5mg,0.087mmol)和DMAP(21.3mg,0.175mmol)溶于4mL的无水DCM中，在氩气保护下，加 入固体EDAC(17.1mg,0.11mmol)。反应混合物在室温下搅拌24小时，停止反应，减压 旋转蒸发移除溶剂，快速柱层析得到最终产品Bcl-051：39mg，收率:51％，黄色固体。 1H NMR(400MHz,CDCl3)δ10.21(s,1H),8.89(d,J＝2.1Hz,1H),8.50(t,J＝4.8Hz, 1H),8.22(d,J＝9.1Hz,1H),8.07(s,1H),7.83(s,1H),7.59(d,J＝2.1Hz,1H),7.40(s, 1H),7.22(d,J＝8.3Hz,2H),6.90(dd,J＝9.0,2.8Hz,3H),6.46(s,1H),6.27(s,1H),4.00 (dd,J＝11.3,3.4Hz,2H),3.40(t,J＝11.3Hz,2H),3.24(t,J＝6.0Hz,2H),3.11(d,J＝ 4.6Hz,4H),2.75(s,2H),2.30–2.11(m,6H),2.00–1.92(m,3H),1.71(d,J＝12.0Hz, 2H),1.49–1.35(m,4H),0.92(s,6H)；ESI-MS m/z 869.3(M+H)+。
采用实施例3的合成方法，换用不同的原料X、II和IV，可以得到如下表3中所示的目标化合物I。原料X、II和IV可通过商业化购买或参考已知文献方法制备获得。
表3
表3中各个最终产品I的波谱数据：
Bcl-015:1H NMR(400MHz,CDCl3)δ10.11(s,1H),9.42(s,1H),8.95(d,J＝2.2Hz,1H), 8.54(t,J＝5.3Hz,1H),8.22(dd,J＝6.4,2.3Hz,2H),8.12(d,J＝8.9Hz,1H),7.45–7.40(m, 1H),7.22(d,J＝8.3Hz,2H),6.95(d,J＝9.3Hz,1H),6.89(d,J＝8.3Hz,2H),6.56(dd,J＝3.3, 2.0Hz,1H),6.26(d,J＝8.9Hz,1H),4.03(dd,J＝11.5,3.5Hz,2H),3.42(t,J＝11.6Hz,2H), 3.28(s,6H),2.70(s,2H),2.18–2.09(m,6H),2.04–1.96(m,3H),1.74(d,J＝12.6Hz,2H), 1.51–1.36(m,4H),0.93(s,6H).
Bcl-016:1H NMR(400MHz,CDCl3)δ9.14(s,1H),8.85(d,J＝2.2Hz,1H),8.53(t,J＝5.4Hz,1H),8.19–8.10(m,2H),7.78(s,1H),7.67(d,J＝2.4Hz,1H),7.32(d,J＝8.4Hz,2H),7.25–7.23(m,1H),7.02(d,J＝8.4Hz,2H),6.95(d,J＝9.3Hz,1H),6.62(d,J＝8.5Hz,1H),6.47(dd,J＝3.5,2.0Hz,1H),4.03(dd,J＝11.3,3.6Hz,2H),3.42(td,J＝11.9,1.8Hz,2H),3.31–3.25(m,2H),2.91(s,4H),2.79(s,2H),2.33(s,4H),2.14(t,J＝5.9Hz,2H),2.03–1.93 (m,3H),1.74(d,J＝14.7Hz,2H),1.51–1.39(m,4H),0.95(s,6H).
Bcl-019:ESI-MS m/z 870.2(M+H)+.
Bcl-020:ESI-MS m/z 870.2(M+H)+.
Bcl-051:1H NMR(400MHz,CDCl3)δ10.21(s,1H),8.89(d,J＝2.1Hz,1H),8.50(t,J＝ 4.8Hz,1H),8.22(d,J＝9.1Hz,1H),8.07(s,1H),7.83(s,1H),7.59(d,J＝2.1Hz,1H),7.40(s, 1H),7.22(d,J＝8.3Hz,2H),6.90(dd,J＝9.0,2.8Hz,3H),6.46(s,1H),6.27(s,1H),4.00(dd, J＝11.3,3.4Hz,2H),3.40(t,J＝11.3Hz,2H),3.24(t,J＝6.0Hz,2H),3.11(d,J＝4.6Hz,4H), 2.75(s,2H),2.30–2.11(m,6H),2.00–1.92(m,3H),1.71(d,J＝12.0Hz,2H),1.49–1.35(m, 4H),0.92(s,6H).ESI-MS m/z 869.3(M+H)+.
Bcl-052:ESI-MS m/z 869.3(M+H)+.
Bcl-053：ESI-MS m/z 870.1(M+H)+.
Bcl-054:1H NMR(400MHz,CDCl3)δ9.45(s,1H),8.88(s,1H),8.47(t,J＝5.1Hz,1H), 8.05(d,J＝9.5Hz,2H),7.69(d,J＝1.9Hz,1H),7.33(d,J＝7.3Hz,3H),6.97(d,J＝7.1Hz, 2H),6.90(d,J＝9.2Hz,1H),6.48(s,1H),6.42(s,1H),4.02(dd,J＝11.5,3.3Hz,2H),3.40(t, J＝11.7Hz,2H),3.24(dd,J＝12.5,6.4Hz,6H),2.69–2.45(m,4H),2.33–2.17(m,2H),2.09 –1.88(m,5H),1.72(d,J＝12.9Hz,2H),1.50–1.35(m,4H),0.96(s,6H).
Bcl-055:1H NMR(400MHz,CDCl3)δ10.11(s,1H),9.23(s,1H),8.95(d,J＝2.2Hz,1H), 8.54(t,J＝5.3Hz,1H),8.22(dd,J＝8.1,2.1Hz,2H),8.13(d,J＝8.9Hz,1H),8.02(d,J＝2.0 Hz,1H),7.74(d,J＝2.3Hz,1H),7.44–7.39(m,1H),7.29(dd,J＝8.1,2.3Hz,1H),7.23(d,J ＝8.1Hz,1H),6.95(d,J＝9.3Hz,1H),6.56(dd,J＝3.4,1.9Hz,1H),6.26(d,J＝8.9Hz,1H), 4.03(dd,J＝11.3,3.5Hz,2H),3.42(t,J＝11.7Hz,2H),3.28(t,J＝5.9Hz,6H),2.70(s,2H), 2.17(s,2H),2.09(s,4H),2.04–1.90(m,3H),1.75(d,J＝12.6Hz,2H),1.50–1.39(m,4H), 0.94(s,6H).
Bcl-056:1H NMR(400MHz,CDCl3)δ8.84(d,J＝1.9Hz,1H),8.54(t,J＝4.7Hz,1H),8.24(dd,J＝18.9,10.1Hz,2H),8.14(s,2H),7.78(s,1H),7.48–7.38(m,2H),7.31(d,J＝8.1 Hz,1H),6.99(d,J＝9.3Hz,1H),6.75(d,J＝7.8Hz,1H),6.54(s,1H),4.03(dd,J＝11.4,3.6 Hz,2H),3.42(t,J＝11.7Hz,2H),3.34–3.26(m,2H),3.06–2.85(m,4H),2.63–2.42(m,2H), 2.31–2.11(m,4H),2.07–1.92(m,5H),1.74(d,J＝14.6Hz,2H),1.49–1.39(m,4H),0.98(s, 6H).
Bcl-074:ESI-MS m/z 919.3(M+H)+.
Bcl-075:1H NMR(400MHz,CDCl3)δ10.32(s,1H),8.88(d,J＝2.1Hz,1H),8.49(t,J＝ 5.3Hz,1H),8.20(dd,J＝9.1,1.9Hz,1H),8.04(s,1H),7.83(d,J＝1.8Hz,1H),7.58(d,J＝ 2.0Hz,1H),7.39(s,1H),6.90(d,J＝9.3Hz,1H),6.70(d,J＝7.9Hz,1H),6.49–6.37(m,3H),6.27(d,J＝1.6Hz,1H),5.90(s,2H),4.00(dd,J＝10.9,3.8Hz,2H),3.40(t,J＝11.1Hz, 2H),3.26–3.10(m,6H),2.86(s,2H),2.31(s,4H),2.16(s,2H),2.04–1.88(m,3H),1.71(d,J ＝12.3Hz,2H),1.46–1.35(m,4H),0.91(s,6H).
Bcl-077:1H NMR(400MHz,CDCl3)δ10.09(s,1H),9.49(s,1H),8.94(d,J＝2.2Hz,1H), 8.54(t,J＝5.3Hz,1H),8.20(dd,J＝12.5,2.4Hz,2H),8.13(d,J＝8.8Hz,1H),7.84(d,J＝2.1 Hz,1H),7.75(d,J＝2.4Hz,1H),7.47–7.39(m,2H),6.95(d,J＝9.3Hz,1H),6.84(dd,J＝8.3, 2.8Hz,1H),6.56(dd,J＝3.3,1.9Hz,1H),6.26(d,J＝8.9Hz,1H),4.03(dd,J＝11.3,3.7Hz, 2H),3.42(t,J＝11.7Hz,2H),3.33–3.24(m,6H),2.71(s,2H),2.20–2.08(m,6H),2.03–1.94 (m,3H),1.74(d,J＝14.0Hz,2H),1.50–1.38(m,4H),0.94(s,6H).
Bcl-078:1H NMR(400MHz,CDCl3)δ9.63(s,1H),8.84(d,J＝2.3Hz,1H),8.53(t,J＝5.4Hz,1H),8.13(d,J＝8.6Hz,2H),7.91(d,J＝2.3Hz,1H),7.76(s,1H),7.68(d,J＝2.4Hz,1H),7.54(td,J＝8.1,2.4Hz,1H),7.34–7.30(m,1H),6.97(d,J＝9.3Hz,1H),6.93(dd,J＝8.3,2.7Hz,1H),6.62(d,J＝8.5Hz,1H),6.49(dd,J＝3.5,2.0Hz,1H),4.02(dd,J＝11.3,3.5 Hz,2H),3.42(td,J＝11.8,1.8Hz,2H),3.32–3.25(m,2H),2.90(s,4H),2.78(s,2H),2.30(s, 4H),2.18(s,2H),2.04–1.93(m,3H),1.74(d,J＝12.8Hz,2H),1.50–1.38(m,4H),0.96(s, 6H).
Bcl-079:1H NMR(400MHz,CDCl3)δ10.43(s,1H),9.54(s,1H),8.90(d,J＝2.2Hz,1H), 8.51(t,J＝5.4Hz,1H),8.24(dd,J＝9.1,2.1Hz,1H),8.07(s,1H),7.84(d,J＝2.2Hz,1H), 7.61(s,1H),7.39(s,1H),6.91(d,J＝9.3Hz,1H),6.75(d,J＝8.2Hz,1H),6.48(d,J＝1.9Hz, 2H),6.44(dd,J＝8.2,2.0Hz,1H),6.27(d,J＝1.9Hz,1H),4.23(s,4H),4.01(dd,J＝11.3,3.6 Hz,2H),3.41(td,J＝11.8,1.7Hz,2H),3.15–3.10(m,4H),2.84(t,J＝17.2Hz,2H),2.25(d, J＝24.1Hz,4H),2.15(t,J＝17.2Hz,2H),2.04–1.90(m,5H),1.73(d,J＝13.1Hz,2H),1.48 –1.36(m,4H),0.92(s,6H)；ESI-MS m/z 893.2(M+H)+.
Bcl-080:1H NMR(400MHz,CDCl3)δ9.94(s,1H),8.90(d,J＝2.2Hz,1H),8.51(t,J＝5.3Hz,1H),8.23(dd,J＝9.2,2.1Hz,1H),8.05(d,J＝2.0Hz,1H),7.83(d,J＝2.2Hz,1H),7.60(d,J＝2.3Hz,1H),7.42–7.37(m,1H),7.18(t,J＝7.9Hz,1H),6.90(d,J＝9.3Hz,1H),6.73(dd,J＝8.2,2.1Hz,1H),6.56(d,J＝7.6Hz,1H),6.52(s,1H),6.46(d,J＝1.7Hz,1H),6.27(d,J＝2.1Hz,1H),4.01(dd,J＝11.1,3.4Hz,2H),3.76(s,3H),3.41(td,J＝11.8,1.5Hz, 2H),3.24(s,2H),3.15(s,4H),2.84(s,2H),2.30(s,4H),2.17(s,2H),2.03–1.90(m,3H),1.72 (d,J＝12.8Hz,2H),1.48–1.38(m,4H),0.93(s,6H)；ESI-MS m/z 864.3(M+H)+.
Bcl-081:ESI-MS m/z 865.3(M+H)+.
Bcl-096(9-72-A):ESI-MS m/z 887.3(M+H)+.
Bcl-099(XSH-9-74-A):1H NMR(400MHz,CDCl3)δ9.17(s,1H),8.89(d,J＝2.1Hz,1H),8.47(t,J＝5.2Hz,1H),8.22(d,J＝9.1Hz,1H),8.09(d,J＝2.5Hz,1H),7.84(d,J＝2.3Hz,1H),7.58(d,J＝2.4Hz,1H),7.40–7.36(m,1H),7.07(d,J＝7.8Hz,2H),6.87(d,J＝7.9Hz,3H),6.48–6.44(m,1H),6.29(s,1H),4.01(dd,J＝11.3,3.8Hz,2H),3.40(td,J＝11.9,1.6Hz,2H),3.33(d,J＝16.8Hz,2H),3.23(t,J＝6.2Hz,2H),3.14–3.06(m,4H),2.80(s,2H),2.31(s,3H),2.28–2.22(m,4H),2.15(t,J＝6.2Hz,2H),2.02–1.91(m,3H),1.46–1.36(m,4H),0.93(s,6H)；ESI-MS m/z 847.2(M-H)-.
实施例4：化合物V-52的制备
以II-52(52mg,0.3mmol)和IV-3(96mg,0.3mmol)为原料,与磷酸氢二钾(157mg,0.9mmol)共同混合于25mL的圆底反应瓶中，于氩气保护下加入无水DMF 3mL。将反 应液置于提前预热至80℃的油浴中反应20小时，停止加热反应冷却至室温，用20mL 乙酸乙酯稀释反应液，并分别用水(15mL×2),饱和氯化钠水溶液(15mL×2)洗涤， 之后无水硫酸钠干燥，旋转蒸发移除溶剂，快速柱层析得到化合物VII-52-1：57mg， 收率:40％，ESI-MS m/z472.1(M+H)+；与化合物VII-52-2：64mg，收率:45％。
在氩气保护下，向25mL反应瓶中加入上一步得到的产物VII-52-1：(30mg,0.064mmol)、化合物X-9(21.3mg,0.073mmol)和磷酸钾(110mg,0.52mmol)，溶于 5mL二乙二醇二甲醚，搅拌下加热到115℃,并于该温度下反应5小时。自然冷却至室温 后，用10mL乙酸乙酯稀释反应液，并分别用水(15mL×2),饱和氯化钠水溶液(15mL×2) 洗涤，无水硫酸钠干燥，旋转蒸发移除溶剂，快速柱层析得到中间体V-52：27mg，收 率:72％。ESI-MS m/z586.2(M+H)+。
以V-52为原料，利用实施例1中最后两步反应相同的方法，可以得到最终产物Bcl-052。
Bcl-052:ESI-MS m/z 869.3(M+H)+.
实施例5：化合物Bcl-059的制备
于50mL茄型反应瓶中加入底物II-59(1.0g,4.29mmol)、A-59(794mg,5.15mmol)，以及试剂Cs2CO3(2.1g,6.44mmol)、Pd(dppf)2Cl2(196mg,0.21mmol)，用氩气置换空气 3次，在氩气保护下加入无水1,4-二氧六环溶剂10mL，并于120℃温度下反应12小时， 停止加热并将反应冷却至室温，用60mL乙酸乙酯稀释反应液，并分别用水(50mL×2), 饱和氯化钠水溶液(50mL×2)洗涤，之后无水硫酸钠干燥，旋转蒸发移除溶剂，快速 柱层析得到化合物II-59-1：1.30g，收率:99％，ESI-MS m/z 329.0(M+Na)+。
将上一步得到的II-59-1(1.30g,4.25mmol)于90℃下回流反应过夜。停止加热，减压除去过量的三氟醋酸，快速柱层析得到白色固体化合物II-59-2：759mg,收率96％。
将II-59-2(500mg,2.7mmol)、X-59(967mg,2.95mmol)、XantPhos(311mg,0.54mmol)、Pd2(dba)3(246mg,0.27mmol)混溶于10mL1,4-二氧六环溶剂中，于Ar保护 下加入0.9mL DIPEA,升温至100℃搅拌反应12小时。停止加热反应冷却至室温，用硅 藻土过滤，滤液加入50mL乙酸乙酯，之后分别用水(40mL×2),饱和氯化钠水溶液 (40mL×2)洗涤，无水硫酸钠干燥，旋转蒸发移除溶剂，快速柱层析得到乳白色固体 化合物III-59：642mg,收率55％，ESI-MS m/z 433.1(M+H)+。
以III-59(400mg,0.92mmol)和IV-3(324mg,1.02mmol)为原料,与磷酸氢二钾(242mg,1.39mmol)共同混合于15mL的反应管中，于氩气保护下加入无水二甲亚砜 5mL。将反应液置于提前预热至135℃的油浴中反应12小时，停止加热反应冷却至室 温，用25mL乙酸乙酯稀释反应液，并分别用水(20mL×2),饱和氯化钠水溶液(20mL×2) 洗涤，之后无水硫酸钠干燥，旋转蒸发移除溶剂，快速柱层析得到产品V-59：246mg， 收率:36％，ESI-MS m/z 731.1(M+H)+。
将上一步得到的化合物V-59(246mg,0.34mmol)置于50mL茄型反应瓶中，Ar保护下加入10mL无水THF溶剂，之后缓慢滴加3.4mL TBAF溶液(1.0M in THF),于80℃回流 条件下反应3小时。停止加热，反应冷却至室温，加入1mL水淬灭反应。之后用40mL 乙酸乙酯稀释反应液，并分别用水(30mL×2),饱和氯化钠水溶液(30mL×2)洗涤， 之后无水硫酸钠干燥，旋转蒸发移除溶剂，快速柱层析得到产品V-59-2：170.9mg,收 率85％，ESI-MS m/z 601.1(M+H)+。
之后利用与实施例1中最后两步相同的方法，可得到最终产品化合物Bcl-059:ESI- MS m/z 884.1(M+H)+。
采用该实施例中相同的方法，将第三步反应中的X-59分别替换为
(X-60)和
(X-61)时，可相应得到最终化合物Bcl-060与Bcl-061。
Bcl-060:ESI-MS m/z 884.2(M+H)+；
Bcl-061:ESI-MS m/z 885.0(M+H)+。
实施例6化合物IV-66的制备
将化合物1(0.2g，0.71mmol)置于反应瓶中，加入1,4-二氧六环(2ml)，1M NaOH 溶液(1ml)，将反应液加热至50℃过夜反应。反应完毕后，将反应液倒入到饱和 NaH2PO4溶液中，用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，抽 滤，减压浓缩得无色油状物2:170mg,收率90％，ESI-MS m/z 265.1(M+H)+,287.0(M +Na)+。
上一步中得到的化合物2(0.188g，0.71mmol)，Boc-哌嗪(0.145g，0.78mmol)，EDAC(271mg，1.42mmol)，HOBT(105mg，0.78mmol)，DIEA(143mg，1.42mmol)， DCM(2.5ml)混合后，于27℃条件下搅拌反应22h。反应完毕后，用DCM萃取，有机 相用饱和食盐水洗，无水硫酸钠干燥，过滤，减压浓缩，经快速柱层析纯化得0.3g白 色固体3：收率98％，ESI-MS m/z433.2(M+H)+，455.2(M+Na)+。
将上一步得到的化合物3(0.3g，0.69mmol)溶于DCM中，依次加入Et3SiH， CF3COOH，室温反应1h。反应完毕，将反应液减压蒸干，用DCM稀释，缓慢加入饱 和碳酸钠水溶液，调PH至碱性，DCM萃取，有机相用饱和食盐水洗涤，无水硫酸钠 干燥，减压浓缩得0.22g白色固体IV-66：收率95％，ESI-MS m/z 333.1(M+H)+。
替换相应的反应物，采用同样的合成方法，可以制备出化合物IV-67、IV-68、IV-69。
实施例7化合物Bcl-003-salt的制备
将底物Bcl-003(500mg,0.56mmol)溶于5mL二氯甲烷中，加入0.21μL的甲酸，室温下充分震荡搅拌至溶液澄清，减压除去溶剂，即得到甲酸盐产物Bcl-003-salt(526mg)。
实施例8化合物Bcl-085的制备
预先配制好0.01mol/L浓度的对甲苯磺酸的甲醇溶液(38mg TsOH·H2O溶解于20mL 的甲醇溶剂中)。将8.7mg的底物Bcl-051混溶在2mL的三氯甲烷中，加入1mL 0.01M的TsOH的甲醇溶液，室温下搅拌至溶液澄清，减压除去溶剂即得到成盐产物Bcl-085。
利用同样的方法，可得到以下盐化合物：Bcl-086、Bcl-088、Bcl-089、Bcl-092、Bcl-093、Bcl-095、Bcl-098、Bcl-100、Bcl-101。
实施例9
式I化合物对肿瘤细胞Jurkat、Jurkat Bcl-2、Jurkat bclxl、MV-4-11、细胞增殖的影响
实验方法：
悬浮细胞MTT检测方法：
体外培养人白血病细胞MV-4-11、Jurkat、Jurkat Bcl-2、Jurkat bclxl，细胞生长至对 数生长期后，收集细胞，1000rpm离心5min，弃上清，适量培养基悬浮，调整细胞浓度至1.5×105个/ml。将细胞悬液接种到96孔细胞培养板中，每孔90μl，用药组每孔加入 细胞培养基稀释的药物10μl,空白对照组加入等量的细胞培养基，每种药物设三个复 孔，同时设仅加药物(无细胞)的对照孔三个，阴性对照组为含0.5％DMSO培养基。 培养箱中培养48h后，每孔加入5mg/ml的MTT 10μl，37℃放置3h。每孔加入三联液 100μl，置37℃过夜。于酶标仪595nm检测吸光度(OD)。运用Prism Graphpad 5.0统 计软件计算IC50值。
表4中的化合物编号和结构同上文中表1，ABT-199为阳性对照物，结果如下表中所示：
表4.Bcl-2抑制剂对4种肿瘤细胞增殖的影响(IC50)
结果显示，本申请的化合物具有与阳性对照化合物相似或更佳的活性，一部分本申 请化合物表现出显著优于现有的Bcl-2抑制剂的抑制肿瘤细胞增殖的活性。
实施例10Bcl-2抑制剂系列化合物对BALB/c-Nude裸鼠人髓性单核细胞白血病细胞MV-4-11皮下移植瘤的体内药效
本实验目的在于检测Bcl-2抑制剂化合物在动物肿瘤模型上是否安全有效。
实验步骤:
体外培养MV-4-11，并扩增到合适的数量用于小鼠移植瘤接种。以1.0×107/100μl加等体积matrigel接种于小鼠右侧腋皮下，接种18天后动物随机分成9组：溶媒对照 组、阳性药ABT-199、Bcl-038、Bcl-051、Bcl-079、、Bcl-080、Bcl-099、Bcl-003-salt、 Bcl-003-sobmit(即Bcl-003)，给药剂量为100mg/kg，给药体积0.2ml/10g体重，每组7-8 只动物，连续灌胃给药14天。
实验结果如附图1、2和3中所示，动物实验结果表明，在给药剂量下，本申请的Bcl-2抑制剂化合物对小鼠体重没有显著影响，可认为在实验剂量下安全，并且一部分本申请的Bcl-2抑制剂化合物对BALB/c-Nude裸鼠人髓性单核细胞白血病细胞MV-4-11皮 下移植瘤有明显的抑制作用，说明本申请的Bcl-2抑制剂化合物具有显著的抗肿瘤药 效。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技 术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求 书所限定的范围。
Claims (12)
1.一种如下式(I)所示的化合物，或其光学异构体、互变异构体，或其药学上可接受的盐：
其中：
X选自下组：C(Ra)2、C＝O、N(Ra)、O或S；其中，所述的Ra选自下组：H、卤素、C1-4烷基、C2-4酰基；
Y选自下组：O、S、NRa；
Z选自下组：O、S、或NRa；
所述A环选自下组：取代或未取代的C6-10芳基、取代或未取代的5-12元杂芳基；
B环选自下组：取代或未取代的苯基、取代或未取代的5-7元杂芳基；
R1和R2各自独立地选自下组：取代或未取代的C1-C4烷基、或所述的R1和R2共同构成-(CH2)n-；其中，n选自下组：2、3或4；
R3选自下组：H、卤素、C1-4烷基、C2-10酰基、NO2；
C环选自下组：取代或未取代的C6-10芳基、取代或未取代的5-12元杂芳基、取代或未取代的5-12元杂环基；
其中，所述的取代指基团被选自下组的一个或多个取代基所取代：卤素、C1-6烷基、C1-6烷氧基、C1-4烷氧基(C1-6烷基)、C1-4烷氧基(C1-6烷氧基)、C1-4卤代烷基、C1-6卤代烷氧基、C2-4烯基、C2-4炔基、C3-8环烷基、3-至12-元杂环基(优选3-至8-元杂环基)、C6-10芳基、5-12元杂芳基、苄基、C6-10芳氧基、5-12元杂芳基氧基、苄氧基、CN、NO2、OR1、SR1、NR1R2、C(O)R1、C(O)OR1、C(O)NR1R2、NR1C(O)R2、或S(O)2R1；其中，R1和R2各自独立为氢或C1-4烷基。
2.如权利要求1所述的化合物，其特征在于，
C环为取代或未取代的选自下组的基团：
其中，所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代：C1-6烷基、C1-6卤代烷基、C1-4烷氧基(C1-6烷基)、苄基。
3.如权利要求1所述的化合物，其特征在于，所述的C环选自下组：
其中，
R4选自下组：H、Me、
Bn。
4.如权利要求1所述的化合物，其特征在于，所述的B环选自下组：取代或未取代的苯基、取代或未取代的5-7元氮杂芳基。
5.如权利要求1所述的化合物，其特征在于，所述的B环选自下组：
6.如权利要求1所述的化合物，其特征在于，所述的A环选自下组：
7.如权利要求1所述的化合物，其特征在于，所述的R1和R2各自独立地为CH3，或R1与R2共同构成-(CH2)2-。
8.如权利要求1所述的化合物，其特征在于，
X为CH2或C＝O；
Y选自下组：O或S；
Z选自下组：O、S、或NH。
9.如权利要求1所述的化合物，其特征在于，所述的化合物选自下组：
10.如权利要求1-9任一所述的化合物的用途，其特征在于，用于制备预防或治疗因抗凋亡蛋白Bcl-2表达异常导致的相关哺乳动物疾病或病症的药物组合物；
较佳地，所述的疾病或病症选自下组：小细胞肺癌或脾癌、膀胱癌、慢性淋巴细胞性白血病、脑癌、乳腺癌、骨髓癌、宫颈癌、结肠直肠癌、食道癌、肝细胞癌、原始淋巴细胞性白血病、滤泡性淋巴瘤、T细胞或B细胞源的淋巴恶性肿瘤、黑色素瘤、粒细胞性白血病、骨髓瘤、口腔癌、卵巢癌、非小细胞肺癌、前列腺癌、心肌梗塞、胎膜早破、神经退行性疾病、自身免疫性疾病。
11.一种药物组合物，其特征在于，所述的药物组合物包括：治疗有效量的如权利要求1-9任一所述的式I化合物、或其药学上可接受的盐、其外消旋体、R-异构体或S-异构体，以及药学上可接受的载体。
12.如权利要求11所述的药物组合物，其特征在于，所述的药物组合物用于治疗或预防因抗凋亡蛋白Bcl-2表达异常导致的相关哺乳动物疾病或病症。
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