CN116925080A - 作为Akt蛋白激酶抑制剂的化合物及其制备方法和用途 - Google Patents
作为Akt蛋白激酶抑制剂的化合物及其制备方法和用途 Download PDFInfo
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Abstract
本发明提供了一种式(I)所示的化合物,可用于预防和/或治疗肿瘤疾病,以及制备抗肿瘤药物。该化合物对蛋白激酶Akt具有很好的抑制活性,且具有优良的药代和药效活性。
Description
技术领域
本发明属于医药领域,具体涉及一种作为Akt激酶抑制剂的化合物、药物组合物及其制备方法和用途。
背景技术
丝/苏氨酸蛋白激酶Akt,又名蛋白激酶B(PKB),是PI3K/Akt/mTOR信号转导通路的重要成员。Akt位于该信号通路的核心位置,其通过影响下游众多效应器进而在调控细胞生长、增殖、迁移、分化、代谢和凋亡等多种生理活动中发挥重要功能,Akt在超过50%的肿瘤中过度活化,尤以乳腺癌、前列腺癌、胰腺癌、膀胱癌和卵巢癌为主,Akt过度活化可导致肿瘤发生、转移以及耐药性的产生。抑制Akt活性既可避免抑制上游PI3K造成的严重副作用,也可避免抑制下游mTOR引起的负反馈机制影响药效。因此,Akt作为PI3K信号通路中的重要节点成为肿瘤靶向药物开发的热门靶点。然而,Akt发现至今已近30年,虽然有十几个Akt小分子抑制剂先后进入临床研究,但尚无小分子抑制剂成功上市。近期Akt抑制剂Ipatasertib和Capivasertib的成功研发,以及其对三阴性乳腺癌和转移性去势抵抗性前列腺癌Ⅱ期临床研究取得的良好疗效,确证了Akt抑制剂对PIK3CA/AKT1/PTEN基因突变或缺失患者的治疗优势,也指明了激酶选择性更好的ATP竞争性抑制剂是Akt抑制剂未来的发展方向。因此,Akt已成为一个极具开发前景的抗肿瘤靶点,寻找高效、新颖和选择性好的Akt抑制剂是当前肿瘤靶向药物研发的重要策略。
目前全球范围内尚无靶向Akt的药物上市,Capivasertib目前已进入临床三期,展现出了良好的发展前景。本发明尝试开发体外活性以及体内药代药效学更优的Akt抑制剂。
发明内容
为改善上述技术问题,本发明提供了一种式(I)所示的化合物、其消旋体、立体异构体、互变异构体、氮氧化物或它们药学上可接受的盐:
其中,R1、R2、R3相同或不同,彼此独立地选自H、卤素、羟基、-CN、硝基、未取代或任选被一个、两个或更多个Re取代的C1-10烷基、、C1-10烷氧基、C3-10环烷基、C6-20芳基、-NH2,每个Re相同或不同,彼此独立地选自氧代、OH、CN、卤素、C1-10烷基、或C1-10烷氧基;
R4、R5相同或不同,彼此独立地选自H、被一个、两个或更多个Ra取代的C3-10环烷基、无取代或被一个、两个或更多个Ra取代的3-10元杂环基;每个Ra相同或不同,彼此独立地选自氧代(=O)、卤素、-OH、硝基、无取代或任选被一个、两个或更多个Ra1取代的如下基团:C1-10烷基、C1-10烷氧基、-NH2;每个Ra1相同或不同,彼此独立的选自OH、卤素、CN、C1-10烷基、C1-10烷氧基;或者
R4和R5与其所连接的原子可以形成无取代或任选被一个、两个或更多个Rb取代的下列基团:C3-10环烷基、3-12元杂环基;每个Rb相同或不同,彼此独立地选自氧代(=O)、OH、卤素、硝基,无取代或任选被一个、两个或更多个Rc取代的下列基团:C1-10烷基、C1-10烷氧基、Rb1-C(O)-或Rb2-S(O)2-、Rb2-S(O)-、Rb1-C(O)-NH-、-NH2;Rb1、Rb2相同或不同,彼此独立地选自未取代或任选被一个、两个或更多个Rd取代的下列基团:C1-10烷基、C3-10环烷基、C1-10烷基-NH-、C3-10环烷基-NH-、C3-10环烷基C1-10烷基-NH-、C1-10烷基-O-、C3-10环烷基-O-、C3-10环烷基C1-10烷基-O-;每个Rc、Rd相同或不同,彼此独立地选自氧代、OH、CN、卤素、C1-10烷基、C1-10烷氧基;
R6可以选自H、卤素、CN、硝基、C1-10烷基、C1-10烷氧基、C3-10环烷基。
根据本发明的实施方案,R1、R2、R3相同或不同,彼此独立地选自H、卤素或卤代C1-6烷基;在一种实施方式中,R1可以选自卤素或卤代C1-3烷基,R2可以选自H、卤素或卤代C1-3烷基;R3可以选自H或卤素。
根据本发明的实施方案,R6可以选自H、卤素、CN、C1-6烷基。在一个实施方案中,R6可以选自H、卤素、CN、C1-3烷基。
根据本发明的实施方案,R4、R5相同或不同,彼此独立地选自H、被一个、两个或更多个Ra取代的C3-6环烷基,被一个、两个或更多个Ra取代的3-8元杂环基。在一个实施方式中,R4为羟基C1-6烷基取代的C3-6环烷基、R5为H;在一个实施方式中,R4为羟基C1-6烷基取代的环丙基、羟基C1-6烷基取代的环丁基、羟基C1-6烷基取代的环戊基;根据本发明的实施方案,R4和R5与其所连接的原子可以形成无取代或任选被一个、两个或更多个Rb取代的下列基团:C3-8环烷基、3-8元杂环基;在一个实施方式中,R4和R5与其所连接的原子可以形成无取代或任选被一个、两个或更多个Rb取代的下列基团:C3-6环烷基、3-6元杂环基;所述C3-8环烷基例如为环丙基、环丁基、环戊基、环己基,所述3-8元杂环基例如为含氧杂环基、含硫杂环、含氮杂环基,具体的可为氧杂环丙基、氧杂环丁基、氧杂环戊基、氧杂环己基、氮杂环丙基、氮杂环丁基、氮杂环戊基、氮杂环己基。
根据本发明的实施方案,每个Rb相同或不同,彼此独立地选自OH、氧代(=O),无取代或任选被一个、两个或更多个Rc取代的下列基团:C1-6烷基、C1-6烷氧基、Rb1-C(O)-或Rb2-S(O)2-、Rb2-S(O)-、Rb1-C(O)-NH-、-NH2;
根据本发明的实施方案,Rb1、Rb2相同或不同,彼此独立地选自C1-6烷基、C3-8环烷基、C1-6烷基-NH-、C3-8环烷基-NH-、C3-8环烷基C1-6烷基-NH-、C1-6烷基-O-、C3-8环烷基-O-、C3-8环烷基C1-6烷基-O-;
根据本发明的实施方案,Rc相同或不同,彼此独立地选自OH、CN或卤素;
根据本发明的实施方案,每个Rb相同或不同,彼此独立地选自OH、氧代(=O)、C1-6烷基、C1-6烷氧基、-NH2、-NH-C1-6烷基、C1-6烷基-C(O)-、卤代C1-6烷基-C(O)-、羟基C1-6烷基-C(O)-、氰基C1-6烷基-C(O)-、C3-8环烷基-C(O)-、卤代C3-8环烷基-C(O)-、C1-6烷基-NH-C(O)-、C1-6烷基-O-C(O)-、C1-6烷基-S(O)2-、C3-8环烷基-S(O)2-。
根据本发明的实施方案,每个Rb相同或不同,彼此独立地选自甲基、氧代(=O)、OH、CH3C(O)-、CN-CH2C(O)-、HO-CH2C(O)-、CH3S(O)2-、CH3CH2C(O)-、(CH3)2CHC(O)-、
根据本发明的实施方案,R1可以选自F、Cl或三氟甲基;
R2可以选自H、F、Cl或三氟甲基;
R3可以选自H或F;
R4和R5与其所连接的原子可以形成如下所示的结构:
R6可以选自H、F、Cl、CN、甲基。
根据本发明的实施方案,式(I)所示化合物可以选自以下结构:
本发明还提供式(I)所示化合物的制备方法,包括以下步骤:化合物I-1脱保护得到式(I)所示化合物;
其中,R1、R2、R3、R4、R5、R6彼此独立地具有上文所述的定义;PG为氨基保护基,例如苄氧羰基、苄基、叔丁氧羰基。
根据本发明的实施方案,化合物I-1的制备方法包括以下步骤:化合物I-2和化合物I-3反应得到化合物I-1;
其中,R1、R2、R3、R4、R5、R6、PG彼此独立地具有上文所述的定义。
本发明还提供一种药物组合物,其包含治疗有效量的式(I)所示的化合物、其消旋体、立体异构体、互变异构体、氮氧化物或它们药学上可接受的盐中的至少一种。
根据本发明的实施方案,所述药物组合物还包括至少一种药学上可接受的辅料。
可按药剂领域中熟知的方式制备这些药物组合物,可通过多种途径给予它们,这取决于是否需要局部或全身治疗和所治疗的区域。可局部(例如,透皮、皮肤、眼和粘膜包括鼻内、阴道和直肠递药)、肺(例如,通过吸入或吹入粉末或气雾剂,包括通过喷雾器;气管内、鼻内)、口服或肠胃外给药。肠胃外给药包括静脉内、动脉内、皮下、腹膜内或肌内注射或输注;或颅内例如鞘内或脑室内给药。可按单次大剂量形式肠胃外给药,或可通过例如连续灌注泵给药。局部给予的药用组合物和制剂可包括透皮贴剂、软膏、洗剂、霜剂、凝胶剂、滴剂、栓剂、喷雾剂、液体剂、粉末制剂和散剂。常规药物载体、水、粉末或油性基质、增稠剂等可能是必须的或需要的。
在制备本发明的药物组合物时,通常将活性成分与辅料混合,通过辅料稀释或装入例如胶囊、小药囊、纸或其它容器形式的这种载体内。当辅料用作稀释剂时,它可以是固体、半固体或液体物质,用作溶媒、载体或活性成分的介质。因此,所述药物组合物可以是以下形式:片剂、丸剂、散剂、锭剂、小药囊、扁囊剂、酏剂、混悬剂、乳剂、溶液剂、糖浆剂、气雾剂(固体或溶于液体溶媒);含例如高达10%重量活性化合物的软膏剂、软和硬明胶胶囊、栓剂、无菌注射溶液和无菌包装粉末。
适宜的辅料的某些实例包括乳糖、葡萄糖、蔗糖、山梨醇、甘露醇、淀粉、阿拉伯胶、磷酸钙、藻酸盐、黄蓍胶、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆和甲基纤维素。所述辅料还可选自:润滑剂例如滑石粉、硬脂酸钠、硬脂酸镁、油酸钠、苯甲酸钠、乙酸钠、氯化钠和矿物油;湿润剂;乳化剂和悬浮剂;防腐剂例如苯甲酸甲酯和苯甲酸羟基丙酯;甜味剂和矫味剂。可通过使用本领域中已知的方法配制本发明组合物,以便在给予患者后提供速释、缓释或延迟释放活性成分的作用。
可按单位剂型配制组合物,每一剂量含约5~1000mg,更通常约100~500mg活性成分。术语“单位剂型”是指物理上分离的适宜作为用于人患者和其它哺乳动物的单一剂量单位,各单位含有与适宜的药物赋形剂混合的经计算可产生所需疗效的预定量的活性物质。
活性化合物的有效剂量的范围可很大,通常按药用有效量给药。但是,可以理解实际给予的化合物的量通常由医师根据相关情况决定,它们包括所治疗的病症、所选择的给药途径、所给予的实际化合物;患者个体的年龄、重量和反应;患者症状的严重程度等。
对于制备固体组合物例如片剂,将主要的活性成分与药物赋形剂混合,形成含本发明化合物的均匀混合物的固体预制剂组合物。当称这些预制剂组合物为均匀时,是指活性成分通常均匀地分布在整个组合物中,致使该组合物可容易地划分为同等有效的单位剂型例如片剂、丸剂和胶囊剂。然后将该固体预制剂划分为上述类型的含例如约0.1~1000mg本发明活性成分的单位剂型。
可将本发明的片剂或丸剂包衣或复合,得到提供长效作用优点的剂型。例如,片剂或丸剂含内剂量和外剂量组分,后者是前者的被膜形式。可通过肠溶层将两种组分隔离,肠溶层用于在胃中阻止崩解,以使内组分完整通过十二指肠或延迟释放。多种物质可用于此类肠溶层或包衣剂,此类物质包括多种高分子酸和高分子酸与此类物质如虫胶、鲸蜡醇和醋酸纤维素的混合物。
其中可掺入本发明化合物和药物组合物,用于口服或注射给药的液体形式包括水溶液、适当矫味的糖浆剂、水或油混悬液;和用食用油例如棉子油、芝麻油、椰子油或花生油矫味的乳剂;以及酏剂和类似的药用溶媒。
用于吸入或吹入的药物组合物包括溶于药学上可接受的水或有机溶剂或其混合物的溶液剂和混悬液、散剂。液体或固体组合物可含有如上所述适宜的药学上可接受的赋形剂。在某些实施方案中,通过口服或鼻呼吸途径给予所述药物组合物,实现局部或全身作用。可通过使用呈惰性的气体,使组合物成雾化。可直接由雾化装置吸入雾化溶液,或雾化装置可与面罩帷或间歇正压呼吸机连接。可通过口服或由按适当方式递送制剂的装置通过鼻给予溶液、混悬液或粉末形式的药物组合物。
给予患者的化合物或药物组合物的量不固定,取决于给予的药物、给药的目的例如预防或治疗;患者的状态、给药的方式等。在治疗应用时,可给予已患疾病的患者足够治愈或至少部分抑制疾病及其并发症症状的量的组合物。有效剂量应取决于所治疗的疾病状态和主治临床医师的判断,该判断取决于例如疾病的严重程度、患者的年龄、体重和一般状况等因素。
给予患者的药物组合物可以是上述药用组合物形式。可通过常规灭菌技术或可过滤灭菌,将这些组合物灭菌。可将水溶液包装原样使用,或冻干,给药前,将冻干制剂与无菌水性载体混合。化合物制剂的pH通常为3~11,更优选5~9,最优选7~8。可以理解,使用某些前述赋形剂、载体或稳定剂会导致形成药物盐。
本发明化合物的治疗剂量可根据例如以下而定:治疗的具体用途、给予化合物的方式、患者的健康和状态,以及签处方医师的判断。本发明化合物在药用组合物中的比例或浓度可不固定,取决于多种因素,它们包括剂量、化学特性(例如疏水性)和给药途径。例如可通过含约0.1~10%(w/v)该化合物的生理缓冲水溶液提供本发明化合物,用于肠胃外给药。某些典型剂量范围为约1μg/kg~约1g/kg体重/日。在某些实施方案中,剂量范围为约1mg/kg~约2000mg/kg体重/日,优选约50mg/kg~约500mg/kg体重/日。剂量很可能取决于此类变量,如疾病或病症的种类和发展程度、具体患者的一般健康状态、所选择的化合物的相对生物学效力、赋形剂制剂及其给药途径。可通过由体外或动物模型试验系统导出的剂量-反应曲线外推,得到有效剂量。
本发明还提供式I所示的化合物、其消旋体、立体异构体、互变异构体、氮氧化物或它们药学上可接受的盐在制备药物中的用途。
根据本发明的实施方案,所述药物用于预防和/或治疗癌症。
根据本发明的实施方案,所述药物为Akt抑制剂。
根据本发明的实施方案,所述癌症可以选自乳腺癌、前列腺癌、胰腺癌、膀胱癌或卵巢癌。
本发明还提供式I所示的化合物、其消旋体、立体异构体、互变异构体、氮氧化物或它们药学上可接受的盐,在治疗和/或预防癌症中的用途。
本发明还提供治疗和/或预防癌症的方法,包括给予患者治疗或预防有效量的式I所示的化合物、其消旋体、立体异构体、互变异构体、氮氧化物或它们药学上可接受的盐中的至少一种。
有益效果
本发明化合物可用于预防和/或治疗肿瘤疾病,以及制备抗肿瘤药物。该化合物对蛋白激酶Akt具有很好的抑制活性,且具有优良的药代和药效活性。
术语定义与说明
除非另有说明,本申请说明书和权利要求书中记载的基团和术语定义,包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等,可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构,应当被理解为本申请说明书和/或权利要求书记载的范围内。
除非另有说明,本说明书和权利要求书记载的数值范围相当于至少记载了其中每一个具体的整数数值。例如,数值范围“1-10”相当于记载了数值范围“1-20”中的每一个整数数值即1、2、3、4、5、6、7、8、9或10。
术语“卤素”表示氟、氯、溴和碘。
术语“C1-10烷基”应理解为表示具有1~10个碳原子的直链或支链饱和一价烃基。例如,表示具有1、2、3、4、5、6、7、8、9或10个碳原子的直链和支链烷基。“C1-6烷基”表示具有1、2、3、4、5或6个碳原子的直链和支链烷基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基等或它们的异构体。
术语“C3-10环烷基”应理解为表示饱和的一价单环、双环(如桥环、螺环)烃环或三环烷烃,其具有3、4、5、6、7、8、9或10个碳原子。所述C3-10环烷基可以是单环烃基,如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基或环癸基,或者是双环烃基如龙脑基、吲哚基、六氢吲哚基、四氢萘基、十氢萘基、二环[2.1.1]己基、二环[2.2.1]庚基、二环[2.2.1]庚烯基、6,6-二甲基二环[3.1.1]庚基、2,6,6-三甲基二环[3.1.1]庚基、二环[2.2.2]辛基、2,7-二氮杂螺[3,5]壬烷基、2,6-二氮杂螺[3,4]辛烷基,或者是三环烃基如金刚烷基。
术语“3-12元杂环基”是指饱和的或不饱和的非芳族的环或环系,例如,其是4-、5-、6-或7-元的单环、7-、8-、9-、10-、11-或12-元的二环(如稠环、桥环、螺环)或者10-、11-、12-的三环环系,并且含有至少一个,例如1、2、3、4、5个或更多个选自O、S和N的杂原子,其中N和S还可以任选被氧化成各种氧化状态,以形成氮氧化物、-S(O)-或-S(O)2-的状态。优选地,所述杂环基可以选自“3-10元杂环基”。术语“3-10元杂环基”意指饱和的或不饱和的非芳族的环或环系,并且含有至少一个选自O、S和N的杂原子。所述杂环基可以通过所述碳原子中的任一个或氮原子(如果存在的话)与分子的其余部分连接。所述杂环基可以包括稠合的或桥连的环以及螺环的环。特别地,所述杂环基可以包括但不限于:4元环,如氮杂环丁烷基、氧杂环丁烷基;5元环,如四氢呋喃基、二氧杂环戊烯基、吡咯烷基、咪唑烷基、吡唑烷基、吡咯啉基;或6元环,如四氢吡喃基、哌啶基、吗啉基、二噻烷基、硫代吗啉基、哌嗪基或三噻烷基;或7元环,如二氮杂环庚烷基。任选地,所述杂环基可以是苯并稠合的。所述杂环基可以是双环的,例如但不限于5,5元环,如六氢环戊并[c]吡咯-2(1H)-基环,或者5,6元双环,如六氢吡咯并[1,2-a]吡嗪-2(1H)-基环。杂环基可以是部分不饱和的,即它可以包含一个或多个双键,例如但不限于二氢呋喃基、二氢吡喃基、2,5-二氢-1H-吡咯基、4H-[1,3,4]噻二嗪基、1,2,3,5-四氢噁唑基或4H-[1,4]噻嗪基,或者,它可以是苯并稠合的,例如但不限于二氢异喹啉基。所述3-12元杂环基与其它基团相连构成本发明的化合物时,可以为3-12元杂环基上的碳原子与其它基团相连,也可以为3-12元杂环基环上杂环原子与其它基团相连。例如当3-12元杂环基选自哌啶基时,可以为哌啶基环上的氮原子和其对位上的碳原子与其它基团相连。
术语“螺环”是指两个环共用1个成环原子的环系。
术语“稠环”是指两个环共用2个成环原子的环系。
术语“桥环”是指两个环共用3个以上成环原子的环系。
本发明的化合物可以溶剂合物(如水合物)的形式存在,其中本发明的化合物包含作为所述化合物晶格的结构要素的极性溶剂,特别是例如水、甲醇或乙醇。极性溶剂特别是水的量可以化学计量比或非化学计量比存在。
根据其分子结构,本发明的化合物可以是手性的,因此可能存在各种对映异构体形式。因而这些化合物可以以消旋体形式或光学活性形式存在。本发明的化合物涵盖了各手性碳为R或S构型的异构体或其混合物、消旋体。本发明的化合物或其中间体可以通过本领域技术人员公知的化学或物理方法分离为对映异构体化合物,或者以此形式用于合成。在外消旋的胺的情况中,通过与光学活性的拆分试剂反应,从混合物制得非对映异构体。适当的拆分试剂的示例是光学活性的酸,例如R和S形式的酒石酸、二乙酰酒石酸、二苯甲酰酒石酸、扁桃酸、苹果酸、乳酸、适当的N-保护的氨基酸(例如N-苯甲酰脯氨酸或N-苯磺酰基脯氨酸)或各种光学活性的樟脑磺酸。借助光学活性的拆分试剂(例如固定在硅胶上的二硝基苯甲酰基苯基甘氨酸、三乙酸纤维素或其它碳水化合物的衍生物或手性衍生化的异丁烯酸酯聚合物),也可有利地进行色谱对映体拆分。用于此目的的适当的洗脱剂是含水或含醇的溶剂混合物,例如,己烷/异丙醇/乙腈。可以根据已知的方法,例如通过萃取、过滤或柱层析来分离相应的稳定异构体。
术语“患者”是指包括哺乳动物在内的任何动物,优选小鼠、大鼠、其它啮齿类动物、兔、狗、猫、猪、牛、羊、马或灵长类动物,最优选人。
术语“治疗有效量”是指研究人员、兽医、医师或其它临床医师正在组织、系统、动物、个体或人中寻找的引起生物学或医学反应的活性化合物或药物的量,它包括以下一项或多项:(1)预防疾病:例如在易感染疾病、紊乱或病症但尚未经历或出现疾病病理或症状的个体中预防疾病、紊乱或病症。(2)抑制疾病:例如在正经历或出现疾病、紊乱或病症的病理或症状的个体中抑制疾病、紊乱或病症(即阻止病理和/或症状的进一步发展)。(3)缓解疾病:例如在正经历或出现疾病、紊乱或病症的病理或症状的个体中缓解疾病、紊乱或病症(即逆转病理和/或症状)。治疗有效量最初可以由细胞培养测定来进行估计,也可以从体内数据估计初始剂量。使用这些初步指导,本领域普通技术人员可以确定人类的有效剂量。此外,也可以通过细胞培养物或实验动物中的标准药物程序来确定本文所述化合物的毒性和治疗功效,例如通过测定LD50和ED50。
具体实施方式
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解,下列实施例仅为示例性地说明和解释本发明,而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明,以下实施例中使用的原料和试剂均为市售商品,或者可以通过已知方法制备。
实施例1
第一步:
将A1(800mg,2.11mmol)置于单口瓶中,加入DMF(8mL)及K2CO3(350mg,2.54mmol),随后缓慢加入CH3I(360mg,2.54mmol),加毕,室温下搅拌反应3.5h,反应完成后,将反应液减压浓缩,直接进行下一步。
第二步:
将A2置于单口瓶中,加入DCM(20mL)及TFA(5mL),室温下搅拌反应2.5h。反应结束后,将反应液减压浓缩脱溶,抽干后得到无色油状物(536mg,100%)。MS:m/z[M+1]+=293.4。
第三步:
将A3(268mg,0.66mmol)置于单口瓶中,加入DMF(5mL)及DIPEA(512mg,3.96mmol),室温搅拌0.5min,加入A4,加毕,85℃条件下搅拌反应过夜。TLC监控,原料完全反应,停止反应。反应结束后,将反应液降温至室温,加入水(60mL),析出黄色固体,室温下搅拌0.5h,过滤,滤饼用水洗涤,抽干后,用PE(20mL)洗涤。将滤饼用DCM溶解(20mL),滤液用无水硫酸钠干燥,过滤,滤饼用DCM(20mL)洗涤,滤液减压浓缩,抽干后得到黄色固体A5(235mg,80%)
第四步:
将A5(235mg,0.53mmol)置于单口瓶中,加入THF(1.5mL)及EtOH(1.5mL),搅拌溶解,加入NaOH的水溶液(106mg,2.65mmol,1.5mL),升温至60℃,搅拌反应,2h,原料完全反应,停止反应。反应结束后,将反应液降温至室温,用稀盐酸调pH至酸性,加入DCM(20mL),析出固体,过滤抽干得到淡黄色固体A6(87mg,76%)。MS:m/z[M+1]+=410.5。
第五步:
将A8(2g,13.19mmol)置于单口瓶中,加入DMF(20mL),降温至0℃,分批加入NaH(分3批加入,每批间隔5min),加毕,在此温度下搅拌反应0.5h,随后加入A7(1.7g,11.87mmol),转至室温,搅拌反应过夜。TLC监控,原料完全反应,停止反应。反应结束后,往反应液中加入水(150mL),用EA萃取(100mL×3),合并有机相,减压浓缩脱溶后进行柱层析纯化(PE:EA=15:1)得到淡黄色油状物A9(2291mg,87%)。
NMR:1H NMR(500MHz,CDCl3)δ7.44–7.38(m,4H),4.11–4.05(m,2H),3.89(td,J=12.2,2.3Hz,2H),2.13–2.01(m,4H)。
第六步:
将A9(800mg,3.62mmol)置于单口瓶中,加入i-PrOH(10mL)及NaOH(434mg),升温至90℃,搅拌反应4h(析出白色固体),TLC监控原料完全反应,停止反应。反应结束后,将反应液降温至室温,加入水(70mL),析出白色固体,过滤,滤饼用水洗涤,抽干后用PE(20mL)洗涤,抽干得到白色固体A10(300mg)。
第七步:
将A10(300mg,1.25mmol)置于单口瓶中,加入t-BuOH(1.2mL),降温至0℃,依次加入NaClO的水溶液(3.5mmol,1.5mL)、NaOH的水溶液(3.5mmol,1.5mL),加毕,转至室温,搅拌反应过夜,停止反应。反应结束后,往反应液中加入水(20mL),用EA萃取(60mL×3),合并有机相,用无水硫酸钠干燥,过滤,滤饼用EA(20mL)洗涤,所得的滤液减压浓缩得到无色油状物A11(234mg,89%)。MS:m/z[M+1]+=212.4。
第八步
将A6(87mg,0.21mmol)与A11(54mg,0.25mmol)置于单口瓶中,加入DMF(3mL),搅拌溶解,加入DIPEA(81mg,0.63mmol),最后加入HATU(97mg,0.25mmol),加毕,升温至50℃,搅拌反应1.5h,原料完全反应,停止反应,将反应液降温至室温。往反应液中加入水(30mL),析出固体,常温下搅拌0.5h。过滤,滤饼依次用水(20mL)、石油醚(20mL)洗涤,抽干得到黄色固体,将固体溶解于DCM(20mL)中,用无水硫酸钠干燥,过滤,滤液减压浓缩脱溶得到黄色固体A12(108mg,86%)。
第九步
将A12(108mg,0.18mmol)置于单口瓶中,加入MeOH(6mL)及10%Pd/C(60mg),H2抽换气3次,室温搅拌反应过夜。TLC监控,原料完全反应,停止反应,将反应液减压浓缩后进行柱层析纯化(PE:EA-DCM:MeOH=1:1-20:1)得到白色固体实施例1化合物(45mg,58%)。MS:m/z[M+1]+=468.4。
参照上述方法制备得到实施例2-15化合物,实施例1-15化合物信息如下表所示:
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实施例16
第一步:
将化合物A3(1.6g,5.47mmol)溶于异丙醇(30mL)中,加入DIPEA(2.7mL,16.4mmol)搅拌10min,然后加入化合物B1(924mg,6.02mmol),升温至80℃反应24h。反应结束后减压旋干溶剂,水洗,过滤,然后加入石油醚洗涤,烘干后化合物B2(1.6g,71%)
第二步:
将化合物B2(1.6g,3.91mmol)溶于EtOH(30mL)中,加入氢氧化钠水溶液(468mg,11.7mmol,15mL),升温至60℃反应4h。反应结束后将反应液滴入100mL醋酸水溶液中(5mL醋酸)。析出固体后过滤,自来水洗涤(10mL),旋干后得到化合物B3(1.16g,75%)
第三步:
将化合物B4(1.38g,9.08mmol)溶于DMF(20mL)中,冷却至0℃,氮气保护下分批加入钠氢,加料完毕后在此温度下继续搅拌30min,然后加入化合物B5(2.0g,8.26mmol),转移至室温反应16h。TLC点板检测有新点出现,加水淬灭(10mL)反应,乙酸乙酯萃取(20mL×3),饱和食盐水洗涤(30mL),无水硫酸钠干燥后减压旋干拌硅胶过柱(PE:EA=10:1)得到化合物B6(2.1g,79%)
第四步:
将化合物B6(1.3g,4.06mmol)溶于异丙醇中,加入氢氧化钠(487mg,12.2mmol),升温至90℃反应3h。反应结束后,将反应液冷却至室温后倒入水中搅拌30min后过滤,减压旋干后得到化合物B7(1.04g,76%)。
第五步:
将化合物B7(500mg,1.48mmol)溶于MeCN(10mL)和H2O(5mL)的混合液中,加入[双(三氟乙酰氧基)碘]苯(640mg,1.48mmol)搅拌15h。反应结束后,加水(10mL)稀释,乙酸乙酯(15mL×3)萃取,饱和食盐水(30mL)洗涤,无水硫酸钠干燥后减压旋干柱层析(DCM:MeOH=30:1)得到化合物B8(380mg,83%)
第六步:
将化合物B8(147mg,0.47mmol)和化合物B3(210mg,0.52mmol)溶于DMF(10mL)中,加入DIPEA(0.2mL,1.41mmol),然后加入HATU(300mg,0.78mmol),升温至50℃反应4h。反应结束后,冷却至室温,加20mL水搅拌30min后过滤,石油醚(10mL)洗涤,旋干后柱层析(DCM:MeOH=30:1)得到化合物B9(196mg,61%)
第七步:
将化合物B9溶于DCM(5mL)中,加入HCl\1,4-二氧六环(5mL),室温反应3h。反应结束后,减压旋干后的产物(化合物B10)直接进行下一步。
第八步:
将化合物B10(100mg,0.17mmol)溶于甲醇(3mL)中,加入碳酸氢钠(50mg)和甲醛(0.1mL)升温至50℃搅拌0.5h,冷却至室温。加入氰基硼氢化钠(30mg,0.48mmol),室温反应3h。反应结束后,加水(10mL)洗涤,二氯甲烷萃取(15mL×3)减压旋干拌硅胶过柱(DCM:MeOH=8:1)得到化合物B11(50mg,49%)。
第九步:
将化合物B11溶于氢溴酸乙酸溶液(33%,10mL)中,室温反应1h。反应结束后,加入50mL饱和碳酸氢钠淬灭反应,二氯甲烷萃取(20mL*3),无水硫酸钠干燥,减压旋干后柱层析(DCM:MeOH=30:1)得到实施例16化合物(24mg,42%)。
参照上述方法制备得到实施例17-38化合物,实施例16-38化合物的结构信息如下所示:
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实施例39,40
第一步:
将化合物B4溶于DMF(30mL)中,降温至0℃,然后分3批次(每次间隔5min加料)加入氢化钠(0.77g,19.22mmol),加料完毕后继续反应30min,然后加入化合物C1(2.0g,7.69mmol),升温至50℃反应6h。反应完成后,加水(10mL)淬灭反应。乙酸乙酯(20mL×3)萃取,水(20mL×3)洗涤,饱和食盐水(20mL)洗涤一次,无水硫酸钠干燥后减压旋干柱层析(PE:EA=15:1)得到化合物C2(1.2g,62%)。
第二步:
将化合物C2溶于异丙醇(30mL)中,加入氢氧化钠(0.7g,17.4mmol),升温至90℃反应4h。反应完成后,冷却至室温,析出红褐色固体,加入稀盐酸调pH至中性。减压旋干溶剂,二氯甲烷(30mL)溶解后过滤,收集滤液,减压旋干后柱层析(DCM:MeOH=30:1)得到化合物C3(690mg,44%)。
第三步:
将化合物C3溶于MeCN(10mL)和H2O(5mL)的混合液中,冷却至0℃,加入[双(三氟乙酰氧基)碘]苯(800mg,1.85mmol)搅拌20h。反应完成后,加水(10mL)稀释,乙酸乙酯(20mL×3)萃取,饱和食盐水(20mL)洗涤,无水硫酸钠干燥后减压旋干,柱层析(DCM:MeOH=30:1)得到化合物C4.(290mg,65%)
第四步:
将化合物C4(100mg,0.41mmol)和化合物A1(185mg,0.49mmol)溶于DMF(15mL)中,加入DIPEA(0.2mL),然后加入HATU(185mg,0.49mmol),升温至50℃反应4h。反应完成后,冷却至室温,加20mL水搅拌30min后过滤,石油醚(15mL)洗涤,柱层析(DCM:MeOH=30:1)得到化合物C5(150mg,61%)
第五步:
将化合物C5(150mg,0.25mmol)溶于DCM(5mL)中,加入HCl\1,4-二氧六环(5mL),室温反应3h。反应完成后,减压旋干后得到化合物C6,无需处理直接用于下一步。
第六步:
将化合物C6溶于异丙醇(15mL)中,加入DIPEA(0.3mL)搅拌10min,然后再加入化合物B1(58mg,0.38mmol),升温至80℃反应15h。反应完成后,将反应液旋干后饱和碳酸氢钠(15mL)洗涤,二氯甲烷(15mL×3)萃取,旋干后柱层析(DCM:MeOH=20:1)得到化合物C7(100mg,68%)。
第七步:
将化合物C7溶于氢溴酸乙酸溶液(33%,10mL)中,室温反应1h。反应完成后,加入50mL饱和碳酸氢钠淬灭反应,二氯甲烷(20mL×3)萃取,无水硫酸钠干燥,减压旋干后柱层析(DCM:MeOH=30:1)得到实施例39化合物(36mg,48%)。
第八步:
将实施例39化合物(26mg,0.06mmol)溶于甲醇(1mL)和四氢呋喃(15mL)混合液中,加入硼氢化钠(5mg,0.12mmol)室温反应0.5h。反应完成后,减压旋干溶剂,水(10mL)洗,二氯甲烷(20mL×3)萃取,无水硫酸钠干燥后柱层析(DCM:MeOH=10:1)得到实施例40化合物(21mg,81%)。
参考上述方法制备得到实施例41化合物,实施例39-41化合物信息如下表所示:
实施例42
第一步:
将化合物D1(1.0g,10.2mmol)、化合物D2(1.36g,11.2mmol)溶于THF(30mL)中,加入钛酸四乙酯(4.6g,20.4mmol),氮气保护下室温反应过夜。反应完成后,加入100mL水剧烈搅拌。过滤,收集滤液,乙酸乙酯(40mL×3)萃取,减压旋干后柱层析(PE:EA=3:1)得到化合物D3(708mg,35%)。第二步:
将化合物D3(708mg,1.18mmol)溶于无水THF(10mL)中,冷却至0℃,然后滴加化合物D4(4.5mL,5.28mmol),转移至室温反应2h。加水(10mL)淬灭反应,乙酸乙酯(20mL×3)萃取后无水硫酸钠干燥,减压旋干柱层析(PE:EA=1:1)得到化合物D5(550mg,23%)
第三步:
将化合物D5溶于DCM(7mL)中,加入HCl\1,4-二氧六环(7mL),室温反应1h。反应完成后,减压旋干后得到化合物D6,无需处理投下一步。
第四步
将化合物D6(200mg,0.76mmol)和化合物B3(150mg,0.38mmol)溶于DMF(10mL)中,加入DIPEA(0.2mL),然后加入HATU(216mg,0.57mmol),升温至50℃反应4h。反应完成后,冷却至室温,加20mL水搅拌30min后过滤,石油醚(10mL)洗涤,旋干后柱层析(DCM:MeOH=30:1)得到化合物D7(103mg,46%)
第五步
将化合物D7(72mg,0.12mmol)和钯碳(20mg)溶于甲醇(5mL)中,在氢气氛围下室温反应20h。TLC检测发现剩余部分原料没有反应完全,将反应液过滤,减压旋干后柱层析(DCM:MeOH=20:1)得到实施例42化合物(21mg,39%)
参考上述方法制备实施例43-46化合物,实施例42-46化合物的结构信息如下所示:
实施例47
第一步
氮气保护下将THF(5mL)加入单口瓶中,降温至-78℃,加入LDA(4.22mL,8.44mmol),随后逐滴加入E1的THF(3mL,7.04mmol)溶液,加毕,搅拌反应2h,随后逐滴加入E2的THF(1mL,7.04mmol)溶液,升温至室温,搅拌反应6h。反应结束后,往反应液中加入NH4Cl溶液(180mL),用DCM萃取(150mL×3),合并有机相,减压旋干后柱层析(DCM:MeOH=20:1)得到E3(1.16g,48%)。
第二步
将E3(1.16g,4.11mmol)和E4(0.91g,6.16mmol)置于单口瓶中,加入干燥THF(20mL)及PPh3(1.62g,6.16mmol),逐滴加入DIAD的THF(10mL)溶液,室温下搅拌反应2h,TLC监控,原料完全反应,停止反应。反应结束后,将反应液减压浓缩脱溶后进行柱层析纯化(PE:EA=10:1)得到淡黄色油状物E5(473mg,28%)。
第三步
将E5(473mg,1.15mmol)置于单口瓶中,加入EtOH及水合肼(461mg,9.20mmol),升温至85℃,搅拌反应2h,原料完全反应,停止反应。反应结束后,过滤除去白色不溶物,滤饼用DCM(10mL×3)洗涤,所得的滤液减压浓缩脱溶后进行柱层析纯化(PE:EA-DCM:MeOH=1:1-20:1)得到无色油状物E6(241mg,75%)。
第四步
将E6(241mg,0.86mmol)置于单口瓶中,加入DCM(6mL)及TFA(6mL),室温下搅拌反应过夜。TLC监控,原料完全反应,停止反应。反应结束后,将反应液减压浓缩脱溶后进行柱层析纯化得到淡黄色油状物E7(207mg,100%)。
第五步
将E7(207mg,0.61mmol)置于单口瓶中,加入THF(3mL),降温至0℃,氮气保护下逐滴加入BH3-THF(3.1mL,0.61mmol),加毕,升温至25℃,搅拌反应2h。反应结束后,减压浓缩除去THF,加入饱和的NaHCO3溶液至pH为碱性,再加入水(10mL),用DCM萃取(60mL×3),合并有机相,减压浓缩脱溶后进行柱层析纯化(PE:EA=0:1-20:1-15:1)得到白色固体E8(70mg,54%)。
第六步
将E8(70mg,0.33mmol)和E9(79mg,0.22mmol)置于单口瓶中,加入DMF(3mL),搅拌溶解,加入DIPEA(85mg,0.66mmol)及HATU(125mg,0.33mmol),升温至50℃,搅拌反应1h。反应结束后,将反应液降温至室温,往反应液中加入水(30mL),析出白色固体,室温下搅拌1h。过滤,滤饼用水洗涤,抽干后用石油醚(20mL)洗涤,抽干得到白色固体E10(119mg,96%)。MS:m/z[M+1]+=555.2
第七步
将E10(119mg,0.21mmol)置于单口瓶中,加入DCM(3mL)及CF3COOH(1.5mL),室温下搅拌反应1h,停止反应。反应结束后,向反应液中加入饱和NaHCO3溶液至pH为碱性,用DCM萃取(50mL×3),合并有机相,减压浓缩脱溶后进行柱层析纯化(PE:EA-DCM:MeOH=0:1-20:1-15:1)得到白色固体为实施例47化合物(55mg,58%)
实施例1-47中制备的目标化合物的核磁数据:
实施例1
1H NMR(500MHz,MeOD)δ8.13(s,1H),7.42(d,J=8.7Hz,2H),7.43(d,J=8.6Hz,2H),7.11(d,J=3.6Hz,1H),6.63(d,J=3.6Hz,1H),4.51(d,J=13.7Hz,2H),3.89(d,J=9.6Hz,2H),3.76(t,J=11.7Hz,2H),3.61(t,J=11.4Hz,2H),2.87(s,3H),2.34(d,J=13.3Hz,2H),2.18–2.08(m,4H),1.60(d,J=13.3Hz,2H).
实施例2
1H NMR(500MHz,MeOD)δ8.13(s,1H),7.41(d,J=8.7Hz,2H),7.33(d,J=8.6Hz,2H),7.13(d,J=3.6Hz,1H),6.63(d,J=3.6Hz,1H),4.52(d,J=13.7Hz,2H),3.88(d,J=9.6Hz,2H),3.78(t,J=11.7Hz,2H),3.62(t,J=11.4Hz,2H),2.37(d,J=13.3Hz,2H),2.18–2.08(m,4H),1.60(d,J=13.3Hz,2H).
实施例3
1H NMR(500MHz,MeOD)δ8.13(s,1H),7.41(d,J=8.6Hz,2H),7.33(d,J=8.6Hz,2H),7.00(d,J=2.1Hz,1H),4.40(d,J=13.7Hz,2H),3.90–3.86(m,2H),3.78(t,J=11.4Hz,2H),3.57(dd,J=18.6,7.0Hz,2H),2.37(d,J=13.0Hz,2H),2.19–2.08(m,4H),1.60(d,J=13.7Hz,2H).
实施例4
1H NMR(500MHz,MeOD)δ8.23(s,1H),7.43(d,J=8.7Hz,2H),7.34(d,J=8.6Hz,2H),7.26(s,1H),4.15(d,J=13.5Hz,2H),3.89(dd,J=11.9,2.4Hz,2H),3.79(t,J=11.4Hz,2H),3.49–3.43(m,2H),2.38(d,J=13.2Hz,2H),2.30(td,J=13.2,4.2Hz,2H),2.12(td,J=13.5,4.6Hz,2H),1.61(d,J=13.4Hz,2H).
实施例5
1H NMR(500MHz,MeOD)δ8.31(s,1H),8.02(s,1H),7.42(d,J=8.6Hz,2H),7.33(d,J=8.7Hz,2H),4.33(d,J=13.7Hz,2H),3.88(d,J=12.1Hz,2H),3.79(t,J=11.4Hz,2H),3.60(t,J=11.4Hz,2H),2.38(d,J=12.9Hz,2H),2.32–2.25(m,2H),2.15–2.09(m,2H),1.65(d,J=13.6Hz,2H).
实施例6
1H NMR(500MHz,MeOD)δ8.18(s,1H),7.45–7.33(m,1H),7.23(d,J=3.6Hz,1H),6.91–6.88(m,2H),6.62(d,J=3.7Hz,1H),4.53(dt,J=13.7,3.5Hz,2H),3.93–3.87(m,2H),3.82(t,J=11.3Hz,2H),3.65–3.57(m,2H),2.51(d,J=13.1Hz,2H),2.19–2.10(m,4H),1.53(d,J=13.5Hz,2H).
实施例7
1H NMR(500MHz,MeOD)δ8.13(s,1H),7.48–7.43(m,1H),7.13(d,J=3.6Hz,1H),6.96–6.90(m,2H),6.62(d,J=3.7Hz,1H),4.50(dt,J=13.7,3.5Hz,2H),3.90–3.85(m,2H),3.82(t,J=11.3Hz,2H),3.65–3.58(m,2H),2.53(d,J=13.1Hz,2H),2.21–2.10(m,4H),1.57(d,J=13.5Hz,2H).
实施例8
1H NMR(500MHz,MeOD)δ8.14(s,1H),7.57(d,J=2.1Hz,1H),7.48(d,J=8.5Hz,1H),7.37(dd,J=8.5,2.2Hz,1H),7.14(d,J=3.6Hz,1H),6.64(d,J=3.7Hz,1H),4.54(dt,J=7.5,3.2Hz,2H),3.89(dd,J=11.9,2.6Hz,2H),3.78(t,J=12.1Hz,2H),3.65–3.59(m,2H),2.35(d,J=12.7Hz,2H),2.18–2.08(m,4H),1.61(d,J=13.5Hz,2H).
实施例9
1H NMR(500MHz,MeOD)δ8.14(s,1H),7.43(t,J=8.1Hz,1H),7.31(dd,J=11.1,2.0Hz,1H),7.25(dd,J=8.5,2.0Hz,1H),7.14(d,J=3.6Hz,1H),6.64(d,J=3.6Hz,1H),4.53(d,J=13.6Hz,2H),3.89(dd,J=11.1,2.8Hz,2H),3.78(t,J=11.7Hz,2H),3.65–3.59(m,2H),2.35(d,J=13.3Hz,2H),2.18–2.07(m,4H),1.61(d,J=13.3Hz,2H).
实施例10
1H NMR(500MHz,MeOD)δ8.12(s,1H),7.41(t,J=8.6Hz,1H),7.19–7.11(m,3H),6.61(d,J=3.6Hz,1H),4.51(d,J=13.8Hz,2H),3.79(t,J=11.3Hz,2H),3.62–3.54(m,2H),2.51(d,J=13.8Hz,2H),2.16(t,J=10.8Hz,4H),1.59(d,J=13.4Hz,2H),1.30(t,J=4.3Hz,2H).
实施例11
1H NMR(500MHz,MeOD)δ8.13(s,1H),7.42(d,J=8.7Hz,2H),7.43(d,J=8.6Hz,2H),7.11(d,J=3.6Hz,1H),6.63(d,J=3.6Hz,1H),4.51(d,J=13.7Hz,2H),3.89(d,J=9.6Hz,2H),3.76(t,J=11.7Hz,2H),3.61(t,J=11.4Hz,2H),2.81(s,3H),2.31(d,J=13.3Hz,2H),2.12–2.01(m,4H),1.60(d,J=13.3Hz,2H).
实施例12
1H NMR(500MHz,MeOD)δ8.13(s,1H),7.42(d,J=8.7Hz,2H),7.43(d,J=8.6Hz,2H),7.11(d,J=3.6Hz,1H),6.63(d,J=3.6Hz,1H),4.51(d,J=13.7Hz,2H),3.89(d,J=9.6Hz,2H),3.76(t,J=11.7Hz,2H),3.61(t,J=11.4Hz,2H),2.84(s,6H),2.34(d,J=13.3Hz,2H),2.10–2.05(m,4H),1.39(d,J=13.3Hz,2H).
实施例13
1H NMR(500MHz,MeOD)δ8.13(s,1H),7.65–7.61(m,4H),7.13(d,J=3.6Hz,1H),6.63(d,J=3.6Hz,1H),4.52(d,J=13.7Hz,2H),3.91(dd,J=11.9,2.8Hz,2H),3.81(t,J=11.6Hz,2H),3.66–3.59(m,2H),2.38(d,J=13.4Hz,2H),2.15(td,J=13.5,4.2Hz,4H),1.62(d,J=13.5Hz,2H).
实施例14
1H NMR(500MHz,MeOD)δ7.81(d,J=1.7Hz,2H),7.69(dd,J=8.5,2.0Hz,2H),7.63(d,J=8.5Hz,2H),3.88(dt,J=11.7,3.6Hz,4H),3.72–3.66(m,4H),2.50(d,J=13.3Hz,4H),2.03–1.97(m,4H).
实施例15
1H NMR(500MHz,MeOD)δ8.14(s,1H),7.40(d,J=8.6Hz,2H),7.33(d,J=8.5Hz,2H),7.14(d,J=3.6Hz,1H),6.64(d,J=3.6Hz,1H),4.46(d,J=13.8Hz,2H),4.14(q,J=9.3Hz,2H),4.08–3.99(m,2H),3.68(t,J=11.4Hz,2H),2.69–2.62(m,1H),2.41(dt,J=12.7,8.2Hz,1H),2.20–2.10(m,2H),1.61(d,J=13.4Hz,2H).
实施例16
1H NMR(500MHz,MeOD)δ8.13(s,1H),7.40(d,J=8.6Hz,2H),7.32(d,J=8.6Hz,2H),7.13(d,J=3.6Hz,1H),6.63(d,J=3.6Hz,1H),4.53(d,J=13.7Hz,2H),3.62(t,J=11.5Hz,2H),2.84(d,J=11.1Hz,2H),2.49–2.39(m,4H),2.37(s,3H),2.14(ddd,J=33.8,17.0,7.8Hz,4H),1.60(d,J=13.5Hz,2H).
实施例17
1H NMR(500MHz,MeOD)δ8.13(s,1H),7.41(d,J=8.6Hz,2H),7.32(d,J=8.6Hz,2H),7.13(d,J=3.6Hz,1H),6.63(d,J=3.6Hz,1H),4.53(d,J=13.7Hz,2H),3.62(t,J=11.5Hz,2H),2.84(d,J=11.1Hz,2H),2.49–2.39(m,4H),2.13(m,4H),1.50(d,J=13.5Hz,2H).
实施例18
1H NMR(500MHz,MeOD)δ8.14(s,1H),7.42(t,J=8.1Hz,1H),7.30(dd,J=11.1,1.8Hz,1H),7.23(d,J=8.5Hz,1H),7.13(d,J=3.6Hz,1H),6.62(d,J=3.6Hz,1H),4.52(d,J=13.7Hz,2H),3.61(t,J=11.6Hz,2H),3.06(d,J=11.7Hz,2H),2.57(dd,J=14.8,6.8Hz,3H),2.51(d,J=16.6Hz,2H),2.19–2.09(m,4H),1.68–1.57(m,4H).
实施例19
1H NMR(500MHz,MeOD)δ8.16(s,1H),7.40(d,J=8.7Hz,2H),7.33(d,J=8.6Hz,2H),7.16(d,J=3.6Hz,1H),6.66(d,J=3.6Hz,1H),4.61(d,J=13.8Hz,3H),4.41(d,J=13.8Hz,1H),3.60(t,J=11.7Hz,2H),3.44(t,J=12.2Hz,1H),3.23(q,J=7.4Hz,2H),3.07(t,J=12.0Hz,1H),2.55(dd,J=43.4,12.8Hz,2H),2.33–2.23(m,2H),2.10(td,J=13.3,4.2Hz,1H),1.99–1.90(m,1H),1.73(d,J=13.8Hz,2H).
实施例20
1H NMR(500MHz,MeOD)δ8.14(s,1H),7.40(d,J=8.3Hz,2H),7.33(d,J=8.1Hz,2H),7.14(s,1H),6.64(s,1H),4.53(d,J=13.7Hz,2H),4.44(d,J=13.4Hz,1H),4.29(dd,J=41.6,15.1Hz,2H),3.71(s,1H),3.63(t,J=12.5Hz,2H),3.07(t,J=12.9Hz,1H),2.51(dd,J=47.0,13.0Hz,2H),2.24–1.88(m,6H),1.61(d,J=13.5Hz,2H).
实施例21
1H NMR(500MHz,MeOD)δ8.14(s,1H),7.42(d,J=8.6Hz,2H),7.33(d,J=8.6Hz,2H),7.14(d,J=3.6Hz,1H),6.63(d,J=3.6Hz,1H),4.53(d,J=13.6Hz,2H),3.69(d,J=12.3Hz,2H),3.62(t,J=11.6Hz,2H),3.07(t,J=11.7Hz,2H),2.92(s,3H),2.57(d,J=13.3Hz,2H),2.19–2.09(m,4H),1.61(d,J=13.6Hz,2H).
实施例22
1H NMR(500MHz,MeOD)δ8.14(s,1H),7.40(d,J=8.3Hz,2H),7.32(d,J=8.2Hz,2H),7.13(d,J=3.0Hz,1H),6.63(d,J=2.9Hz,1H),4.54(d,J=13.5Hz,2H),4.47(d,J=13.3Hz,1H),3.92(d,J=13.3Hz,1H),3.61(t,J=12.1Hz,2H),3.39(t,J=13.0Hz,1H),3.00(t,J=12.8Hz,1H),2.57(d,J=13.5Hz,1H),2.50–2.39(m,3H),2.18(t,J=12.4Hz,2H),2.03(t,J=11.2Hz,1H),1.89(t,J=11.3Hz,1H),1.62(d,J=13.3Hz,2H),1.15(t,J=7.3Hz,3H).
实施例23
1H NMR(500MHz,MeOD)δ8.14(s,1H),7.40(d,J=8.4Hz,2H),7.33(d,J=8.3Hz,2H),7.13(d,J=3.3Hz,1H),6.63(d,J=3.2Hz,1H),4.53(d,J=13.0Hz,2H),4.48(d,J=14.4Hz,1H),4.02(d,J=13.3Hz,1H),3.62(t,J=12.0Hz,2H),3.43(t,J=12.9Hz,1H),3.05–2.96(m,2H),2.59(d,J=13.5Hz,1H),2.44(d,J=13.6Hz,1H),2.17(t,J=12.5Hz,2H),2.05–1.98(m,1H),1.89(t,J=11.3Hz,1H),1.62(d,J=13.4Hz,2H),1.15–1.10(m,6H).
实施例24
1H NMR(500MHz,DMSO)δ11.70(s,1H),8.50(s,1H),8.13(d,J=5.2Hz,1H),7.39(d,J=8.7Hz,2H),7.34(d,J=8.7Hz,2H),7.18(d,J=2.2Hz,1H),4.39(d,J=13.4Hz,2H),4.26(dd,J=57.3,12.6Hz,2H),4.15–4.06(m,1H),3.60(t,J=11.7Hz,2H),2.86(t,J=12.4Hz,1H),2.38(d,J=11.9Hz,1H),2.12–2.00(m,3H),1.88–1.67(m,2H),1.61(d,J=12.8Hz,2H),1.26(d,J=4.2Hz,1H),0.72(t,J=17.9Hz,4H).
实施例25
1H NMR(500MHz,MeOD)δ8.14(s,1H),7.43(t,J=8.1Hz,1H),7.32(dd,J=11.1,2.1Hz,1H),7.24(dd,J=8.5,1.7Hz,1H),7.14(d,J=3.6Hz,1H),6.64(d,J=3.7Hz,1H),4.55(d,J=13.5Hz,2H),4.47(d,J=13.4Hz,1H),4.32(d,J=13.3Hz,1H),3.62(t,J=11.5Hz,2H),3.49(t,J=13.3Hz,1H),3.03(t,J=12.3Hz,1H),2.61(d,J=12.9Hz,1H),2.42(d,J=13.7Hz,1H),2.17(t,J=10.8Hz,2H),2.05(dd,J=8.5,5.3Hz,2H),1.90(t,J=11.2Hz,1H),1.63(d,J=13.4Hz,2H),0.91(d,J=12.1Hz,2H),0.85(dd,J=8.0,3.1Hz,2H).
实施例26
1H NMR(500MHz,MeOD)δ8.13(s,1H),7.39(d,J=8.5Hz,2H),7.32(d,J=8.5Hz,2H),7.13(d,J=3.5Hz,1H),6.63(d,J=3.5Hz,1H),4.53(d,J=13.7Hz,2H),4.44(d,J=13.7Hz,1H),3.78(d,J=13.6Hz,1H),3.62(t,J=11.8Hz,2H),3.51–3.44(m,1H),3.01(t,J=12.2Hz,1H),2.54(d,J=13.4Hz,1H),2.43(d,J=13.8Hz,1H),2.35–2.26(m,2H),2.24–2.14(m,4H),2.08–2.00(m,1H),1.90–1.81(m,2H),1.61(d,J=13.4Hz,2H),1.31(d,J=5.1Hz,2H).
实施例27
1H NMR(500MHz,MeOD)δ8.14(s,1H),7.44–7.39(m,2H),7.33(d,J=7.9Hz,2H),7.14(d,J=3.6Hz,1H),6.64(d,J=3.4Hz,1H),4.78–4.61(m,1H),4.54(d,J=13.4Hz,2H),4.34(dd,J=75.7,13.3Hz,2H),3.62(t,J=11.7Hz,2H),3.57–3.46(m,1H),3.05(t,J=10.9Hz,1H),2.67–2.51(m,2H),2.44(d,J=13.3Hz,1H),2.18(t,J=12.8Hz,2H),2.08(dd,J=17.8,9.1Hz,1H),1.63(d,J=13.3Hz,2H),1.45(dd,J=20.0,9.0Hz,1H),1.32(d,J=9.4Hz,2H).
实施例28
1H NMR(500MHz,MeOD)δ8.14(s,1H),7.40(dd,J=14.7,8.6Hz,2H),7.33(d,J=8.6Hz,2H),7.14(d,J=2.9Hz,1H),6.63(d,J=3.6Hz,1H),4.53(d,J=13.6Hz,2H),4.44(d,J=21.4Hz,1H),4.11(dd,J=23.9,13.9Hz,1H),3.62(dd,J=22.4,10.9Hz,2H),3.15–2.94(m,2H),2.63(dd,J=45.3,12.0Hz,1H),2.48(d,J=13.8Hz,1H),2.19–2.13(m,2H),2.06–1.76(m,4H).
实施例29
1H NMR(500MHz,MeOD)δ8.41(s,1H),7.44(t,J=6.5Hz,3H),7.33(d,J=8.6Hz,2H),7.04(d,J=3.7Hz,1H),4.32(d,J=13.6Hz,1H),3.89(t,J=13.0Hz,3H),3.60(t,J=12.4Hz,1H),3.26(d,J=12.9Hz,2H),2.84(t,J=10.6Hz,2H),2.77(t,J=11.5Hz,2H),2.13(d,J=14.7Hz,2H),2.06–2.01(m,2H),1.34–1.28(m,1H).
实施例30
1H NMR(500MHz,MeOD)δ8.14(s,1H),7.40(d,J=8.1Hz,2H),7.33(d,J=8.0Hz,2H),7.14(s,1H),6.63(s,1H),4.53(d,J=14.5Hz,2H),4.47(s,1H),3.89(d,J=13.6Hz,1H),3.59(dt,J=20.6,11.0Hz,4H),3.44(t,J=12.8Hz,1H),3.05(t,J=12.5Hz,1H),2.53(dd,J=62.4,13.6Hz,2H),2.17(t,J=11.9Hz,2H),2.07(t,J=11.3Hz,1H),1.92(t,J=11.3Hz,1H),1.62(d,J=13.0Hz,2H).
实施例31
1H NMR(500MHz,MeOD)δ8.13(s,1H),7.63(d,J=3.1Hz,4H),7.14(d,J=3.6Hz,1H),6.64(d,J=3.6Hz,1H),4.51(t,J=15.6Hz,3H),4.35(d,J=13.4Hz,1H),3.67–3.61(m,2H),3.52(t,J=12.8Hz,1H),3.06(t,J=12.7Hz,1H),2.64(d,J=14.4Hz,1H),2.45(d,J=14.2Hz,1H),2.16(dd,J=24.3,12.4Hz,3H),2.07–2.03(m,1H),1.98–1.91(m,1H),1.64(d,J=13.4Hz,2H),0.91(d,J=7.3Hz,2H),0.85(dd,J=8.0,2.8Hz,2H).
实施例32
1H NMR(500MHz,MeOD)δ8.14(s,1H),7.64(t,J=7.0Hz,4H),7.14(d,J=3.6Hz,1H),6.64(d,J=3.5Hz,1H),4.54(d,J=13.5Hz,2H),4.46(d,J=13.4Hz,1H),4.30(d,J=14.1Hz,1H),3.64(t,J=11.5Hz,2H),3.54(dd,J=24.8,12.2Hz,1H),3.06(td,J=12.8,5.8Hz,1H),2.65(d,J=14.0Hz,1H),2.61–2.54(m,1H),2.46(d,J=13.9Hz,1H),2.17(ddd,J=15.9,9.1,4.4Hz,3H),1.95(ddd,J=17.6,13.5,4.5Hz,1H),1.64(d,J=13.6Hz,2H),1.51–1.42(m,1H),1.33–1.30(m,2H).
实施例33
1H NMR(500MHz,MeOD)δ8.13(s,1H),7.39(d,J=8.6Hz,2H),7.32(d,J=8.5Hz,2H),7.13(d,J=3.5Hz,1H),6.63(d,J=3.5Hz,1H),4.52(d,J=13.6Hz,2H),3.94(d,J=13.5Hz,2H),3.61(t,J=11.7Hz,2H),3.12(t,J=12.6Hz,2H),2.75(s,3H),2.44(d,J=13.2Hz,2H),2.16(td,J=13.4,4.1Hz,2H),1.94(td,J=13.3,4.0Hz,2H),1.60(d,J=13.4Hz,2H).
实施例34
1H NMR(500MHz,MeOD)δ8.13(s,1H),7.39(d,J=8.0Hz,2H),7.32(d,J=8.0Hz,2H),7.13(s,1H),6.62(s,1H),4.52(d,J=13.3Hz,2H),4.06(d,J=9.8Hz,2H),3.72(s,3H),3.61(t,J=12.2Hz,2H),2.81(d,J=6.7Hz,2H),2.44(d,J=13.2Hz,2H),2.15(t,J=10.6Hz,2H),1.95(t,J=13.5Hz,2H),1.60(d,J=12.9Hz,2H).
实施例35
1H NMR(500MHz,MeOD)δ8.14(s,1H),7.42(t,J=8.1Hz,1H),7.30(dd,J=11.1,2.0Hz,1H),7.23(dd,J=8.6,1.8Hz,1H),7.14(d,J=3.6Hz,1H),6.63(d,J=3.6Hz,1H),4.54(d,J=13.7Hz,2H),4.08(d,J=13.5Hz,2H),3.72(s,3H),3.64–3.58(m,2H),3.21–3.13(m,2H),2.44(d,J=13.2Hz,2H),2.15(td,J=13.3,4.3Hz,2H),1.95(td,J=13.3,4.5Hz,2H),1.61(d,J=13.5Hz,2H).
实施例36
1H NMR(500MHz,MeOD)δ8.14(s,1H),7.42(d,J=8.5Hz,2H),7.34(d,J=8.5Hz,2H),7.14(d,J=3.5Hz,1H),6.63(d,J=3.5Hz,1H),4.52(d,J=13.8Hz,2H),3.71(d,J=12.3Hz,2H),3.64(t,J=11.7Hz,2H),3.20(t,J=12.1Hz,2H),2.56(d,J=10.9Hz,3H),2.22–2.07(m,4H),1.62(d,J=13.4Hz,2H).
实施例37
1H NMR(500MHz,MeOD)δ8.14(s,1H),7.41(d,J=8.6Hz,2H),7.33(d,J=8.6Hz,2H),7.13(d,J=3.6Hz,1H),6.63(d,J=3.6Hz,1H),4.53(d,J=13.7Hz,2H),4.42(d,J=13.7Hz,1H),4.24(d,J=14.1Hz,1H),3.67–3.58(m,2H),3.51(t,J=12.7Hz,1H),3.16(t,J=12.7Hz,1H),2.56(t,J=13.2Hz,2H),2.22–2.13(m,2H),2.08–1.95(m,2H),1.85(t,J=19.8Hz,3H),1.62(d,J=13.5Hz,2H).
实施例38
1H NMR(500MHz,MeOD)δ8.14(s,1H),7.43(t,J=8.1Hz,1H),7.31(dd,J=11.1,1.9Hz,1H),7.24(dd,J=8.4,1.7Hz,1H),7.14(d,J=3.6Hz,1H),6.64(d,J=3.6Hz,1H),4.55(d,J=13.7Hz,2H),4.43(d,J=13.6Hz,1H),4.25(d,J=14.1Hz,1H),3.61(t,J=11.5Hz,2H),3.50(t,J=12.7Hz,1H),3.15(t,J=12.9Hz,1H),2.55(t,J=12.0Hz,2H),2.18(td,J=13.2,3.9Hz,2H),2.01(dtd,J=17.1,13.2,3.9Hz,2H),1.85(t,J=19.8Hz,3H),1.64(d,J=13.5Hz,2H).
实施例39
1H NMR(500MHz,MeOD)δ8.14(s,1H),7.45(dd,J=37.9,7.2Hz,2H),7.39–7.29(m,2H),7.14(d,J=3.6Hz,1H),6.64(d,J=3.6Hz,1H),4.46(d,J=13.8Hz,2H),3.72–3.64(m,4H),3.37(s,1H),2.88–2.67(m,1H),2.16(dt,J=13.3,9.5Hz,2H),1.61(d,J=13.7Hz,2H).
实施例40
1H NMR(500MHz,MeOD)δ8.13(s,1H),7.41(dd,J=43.8,8.4Hz,2H),7.31(dd,J=16.5,5.9Hz,2H),7.13(d,J=3.5Hz,1H),6.62(d,J=3.2Hz,1H),4.41(dd,J=12.9,8.8Hz,2H),3.68(t,J=12.3Hz,2H),3.07–2.89(m,2H),2.46–2.33(m,2H),2.19–2.09(m,2H),1.58(d,J=13.5Hz,2H).
实施例41
1H NMR(500MHz,MeOD)δ8.15(s,1H),7.41(d,J=6.3Hz,2H),7.36(t,J=7.1Hz,2H),7.15(d,J=3.5Hz,1H),6.64(d,J=3.5Hz,1H),5.33(m,1H),4.47(d,J=13.5Hz,2H),3.59(d,J=7.2Hz,2H),2.26–2.14(m,4H),2.12–2.04(m,4H),1.68(d,J=5.6Hz,2H),1.60(d,J=5.5Hz,2H),1.37(d,J=9.2Hz,2H).
实施例42
1H NMR(500MHz,MeOD)δ8.15(s,1H),7.41(d,J=6.3Hz,2H),7.36(t,J=7.1Hz,2H),7.15(d,J=3.5Hz,1H),6.64(d,J=3.5Hz,1H),4.47(d,J=13.5Hz,2H),3.59(d,J=7.2Hz,2H),2.26–2.14(m,4H),2.12–2.04(m,4H),1.68(d,J=5.6Hz,2H),1.60(d,J=5.5Hz,2H),1.37(d,J=9.2Hz,2H).
实施例43
1H NMR(500MHz,MeOD)δ8.14(s,1H),7.37(d,J=8.7Hz,2H),7.32(d,J=8.7Hz,2H),7.14(d,J=3.6Hz,1H),6.64(d,J=3.6Hz,1H),4.57(d,J=13.7Hz,2H),3.61(t,J=11.7Hz,2H),3.02(t,J=12.8Hz,2H),2.69(d,J=14.0Hz,2H),2.53(d,J=14.3Hz,2H),2.23–2.09(m,4H),1.63(d,J=13.5Hz,2H).
实施例44
1H NMR(500MHz,MeOD)δ8.14(s,1H),7.37(d,J=8.7Hz,2H),7.32(d,J=8.7Hz,2H),7.14(d,J=3.6Hz,1H),6.64(d,J=3.6Hz,1H),4.57(d,J=13.6Hz,2H),3.61(t,J=11.7Hz,2H),3.02(t,J=12.8Hz,2H),2.69(d,J=14.1Hz,2H),2.53(d,J=14.3Hz,2H),2.22–2.08(m,4H),1.63(d,J=13.4Hz,2H).
实施例45
1H NMR(500MHz,MeOD)δ8.13(s,1H),7.45(d,J=8.0Hz,2H),7.32(d,J=8.0Hz,2H),7.13(d,J=2.4Hz,1H),6.62(d,J=2.3Hz,1H),4.41(d,J=13.4Hz,2H),3.69(t,J=11.7Hz,2H),2.56(dd,J=16.3,8.6Hz,4H),2.18–2.11(m,2H),2.11–2.03(m,1H),1.92(dd,J=17.9,7.7Hz,1H),1.57(d,J=13.5Hz,2H).
实施例46
1H NMR(500MHz,MeOD)δ8.14(s,1H),7.27(d,J=8.6Hz,2H),7.20(d,J=8.6Hz,2H),7.14(d,J=3.6Hz,1H),6.64(d,J=3.6Hz,1H),4.44(dt,J=13.5,4.0Hz,2H),3.78–3.66(m,2H),2.23–2.15(m,2H),1.62(d,J=13.7Hz,2H),1.26(d,J=6.6Hz,4H).
实施例47
1H NMR(500MHz,MeOD)δ11.63(1H,s),8.43(1H,d),8.12(1H,s),7.32-7.38(4H,m),7.16(1H,t),6.58(1H,t),4.88(1H,d),4.53(1H,t),4.35-4.38(2H,m),3.51-3.58(2H,m),3.38(2H,q),2.18-2.56(5H,m),1.90-1.93(1H,m),1.86(1H,d),1.45(2H,d).
生物学测试评价
测试例1本发明实施例化合物对Akt1激酶抑制活性测定实验
实验方法:
1.用于激酶活性测试的激酶反应缓冲液和终止反应缓冲液的配制
1)1×激酶反应缓冲液:50mM HEPES,pH 7.5,0.0015%Brij-35;
2)终止反应缓冲液:100mM HEPES,pH 7.5,0.015%Brij-35,0.2%被膜剂,50mMEDTA。
2.化合物准备
1)用100%DMSO将化合物稀释至最高使用浓度的50倍。然后将100μL转移至96孔板的A1孔中;
2)然后将30μL化合物转移到含有60μL 100%DMSO的第二个孔中,连续稀释到第十个孔,向最后两个孔中加入100μL 100%DMSO。此96孔板作为母板;
3)从母板各孔中转移10μL到一块新的96孔板(中间板)中,每孔中再加入90μL 1×激酶反应缓冲液,将此板在振荡器上摇10分钟。
3.准备激酶反应384孔板
1)将中间板各孔中取5μL转移到384孔板中,每孔平行转移两次,比如,96孔板中的A1转移到384孔板中的A1和A2,96孔板中的A2转移到384孔板中的A3和A4,以此类推。
4.激酶反应
1)配制2.5×酶溶液,加入1×激酶反应缓冲液;
2)配制2.5×多肽溶液,加入溶解在1×激酶反应缓冲液中的FAM标记的多肽和ATP;
3)激酶反应板中已含有5μL溶解在10%DMSO中的待测化合物;
4)在384孔测试板中加入10μL 2.5×酶溶液;
5)在室温下孵育10分钟;
6)在384孔测试板中加入10μL 2.5×多肽溶液;
7)在28℃条件下孵育一段时间;
8)加入终止反应缓冲液。
4.Caliper读数
5.实验数据处理:
1)将数据用Caliper软件进行转换;
2)通过转换后的数据计算抑制率;
3)抑制百分比=(DMSO对照-转化数据)/(DMSO对照-低对照);
4)通过XLFit excel add-in版本5.4.0.8获得IC50值。
测试例2本发明实施例化合物对乳腺癌细胞的增殖抑制作用的测定
实验目的:
测试本发明实施例化合物对BT474、MDA-MB-453和T47D三株乳腺癌细胞的增殖抑制活性。
实验仪器:
离心机和移液器购自Eppendorf公司,二氧化碳培养箱购自Thermo公司,酶标仪购自美国BioTekInstruments,Inc.公司,型号为Cytation 5多功能酶标仪。
实验方法:
采用CCK-8方法检测了本发明实施例化合物对BT474、MDA-MB-453和T47D三株乳腺癌细胞的增殖抑制作用,具体实验方法如下:
待测细胞系按照5000-10000个/孔接种到96孔培养板中,放入37℃,5%CO2培养箱培养过夜。根据实验需要,加入配制好的不同浓度的化合物溶液,,同时设置溶剂对照(DMSO)和阴性对照孔,每组设3个复孔,放入37℃,5%CO2的培养箱中继续培养72h。培养结束后,按照说明书用CCK-8试剂盒进行检测。每孔加入10ul CCK8试剂,孵育一定时间后用酶标仪进行检测。
实验数据处理:
扣除阴性对照的背景值后,计算相对细胞活力(%)=(测试孔OD值/溶剂对照孔的OD值)×100%。使用Graphpad Prism软件进行曲线拟合,计算IC50。
通过以上方案得出本发明实施例化合物对Akt1激酶的抑制活性及BT474、MDA-MB-453和T47D三株乳腺癌细胞的增殖抑制活性试验结果见表1。
表1:本发明实施例化合物的Akt1激酶活性及对BT474、MDA-MB-453和T47D细胞的生长抑制活性
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注:“-”代表未检测。
如表1所示,本发明中的大部分化合物对Akt1激酶均具有很好的抑制作用,同时对BT474、MDA-MB-453和T47D三株乳腺癌细胞也展现出了优良的抑制活性。其中实施例2,实施例8,实施例13,实施例14,实施例20,实施例22,实施例23,实施例24,实施例25,实施例27,实施例28,实施例29,实施例30,实施例34,和实施例43对T47D癌细胞的抑制活性明显优于阳性对照Capivasertib。
以上对本发明技术方案的实施方式进行了示例性的说明。应当理解,本发明的保护范围不拘囿于上述实施方式。凡在本发明的精神和原则之内,本领域技术人员所做的任何修改、等同替换、改进等,均应包含在本申请权利要求书的保护范围之内。
Claims (10)
1.一种式(I)所示的化合物、其消旋体、立体异构体、互变异构体、氮氧化物或它们药学上可接受的盐:
其中,R1、R2、R3相同或不同,彼此独立地选自H、卤素、羟基、-CN、硝基、未取代或任选被一个、两个或更多个Re取代的C1-10烷基、、C1-10烷氧基、C3-10环烷基、C6-20芳基、-NH2,每个Re相同或不同,彼此独立地选自氧代、OH、CN、卤素、C1-10烷基、或C1-10烷氧基;
R4、R5相同或不同,彼此独立地选自H、被一个、两个或更多个Ra取代的C3-10环烷基、无取代或被一个、两个或更多个Ra取代的3-10元杂环基;每个Ra相同或不同,彼此独立地选自氧代(=O)、卤素、-OH、硝基、无取代或任选被一个、两个或更多个Ra1取代的如下基团:C1-10烷基、C1-10烷氧基、-NH2;每个Ra1相同或不同,彼此独立的选自OH、卤素、CN、C1-10烷基、C1-10烷氧基;或者
R4和R5与其所连接的原子可以形成无取代或任选被一个、两个或更多个Rb取代的下列基团:C3-10环烷基、3-12元杂环基;每个Rb相同或不同,彼此独立地选自氧代(=O)、OH、卤素、硝基,无取代或任选被一个、两个或更多个Rc取代的下列基团:C1-10烷基、C1-10烷氧基、Rb1-C(O)-或Rb2-S(O)2-、Rb2-S(O)-、Rb1-C(O)-NH-、-NH2;Rb1、Rb2相同或不同,彼此独立地选自未取代或任选被一个、两个或更多个Rd取代的下列基团:C1-10烷基、C3-10环烷基、C1-10烷基-NH-、C3-10环烷基-NH-、C3-10环烷基C1-10烷基-NH-、C1-10烷基-O-、C3-10环烷基-O-、C3-10环烷基C1-10烷基-O-;每个Rc、Rd相同或不同,彼此独立地选自氧代、OH、CN、卤素、C1-10烷基、C1-10烷氧基;
R6可以选自H、卤素、CN、硝基、C1-10烷基、C1-10烷氧基、C3-10环烷基。
2.根据权利要求1所述的化合物,其特征在于,R1、R2、R3相同或不同,彼此独立地选自H、卤素或卤代C1-6烷基;
优选地,R4、R5可以相同或不同,彼此独立地选自H、被一个、两个或更多个Ra取代的C3-6环烷基,被一个、两个或更多个Ra取代的3-8元杂环基;例如,R4为羟基C1-6烷基取代的C3-6环烷基、R5为H;还例如,R4为羟基C1-6烷基取代的环丙基、羟基C1-6烷基取代的环丁基、羟基C1-6烷基取代的环戊基;或者,
R4和R5与其所连接的原子可以形成无取代或任选被一个、两个或更多个Rb取代的下列基团:C3-8环烷基、3-8元杂环基;所述C3-8环烷基例如为环丙基、环丁基、环戊基、环己基,所述3-8元杂环基例如为含氧杂环基、含硫杂环、含氮杂环基,具体的可为氧杂环丙基、氧杂环丁基、氧杂环戊基、氧杂环己基、氮杂环丙基、氮杂环丁基、氮杂环戊基、氮杂环己基;每个Rb相同或不同,彼此独立地选自OH、氧代(=O),无取代或任选被一个、两个或更多个Rc取代的下列基团:C1-6烷基、C1-6烷氧基、Rb1-C(O)-或Rb2-S(O)2-、Rb2-S(O)-、Rb1-C(O)-NH-、-NH2;Rb1、Rb2相同或不同,彼此独立地选自C1-6烷基、C3-8环烷基、C1-6烷基-NH-、C3-8环烷基-NH-、C3-8环烷基C1-6烷基-NH-、C1-6烷基-O-、C3-8环烷基-O-、C3-8环烷基C1-6烷基-O-;每个Rc相同或不同,彼此独立地选自OH、CN或卤素;
优选地,R6可以选自H、卤素、CN、C1-6烷基;
优选地,每个Rb相同或不同,彼此独立地选自OH、氧代(=O)、C1-6烷基、C1-6烷氧基、-NH2、-NH-C1-6烷基、C1-6烷基-C(O)-、卤代C1-6烷基-C(O)-、羟基C1-6烷基-C(O)-、氰基C1-6烷基-C(O)-、C3-8环烷基-C(O)-、卤代C3-8环烷基-C(O)-、C1-6烷基-NH-C(O)-、C1-6烷基-O-C(O)-、C1-6烷基-S(O)2-、C3-8环烷基-S(O)2-。
3.根据权利要求1或2所述的化合物,其特征在于,R1可以选自卤素或卤代C1-3烷基;
R2可以选自H、卤素或卤代C1-3烷基;
R3可以选自H或卤素;
R4、R5可以相同或不同,彼此独立地选自H、羟甲基取代的环丙基;或者,
R4和R5与其所连接的原子可以形成无取代或任选被一个、两个或更多个Rb取代的下列基团:C3-6环烷基、3-6元杂环基;每个Rb相同或不同,彼此独立地选自甲基、氧代(=O)、OH、CH3C(O)-、CN-CH2C(O)-、HO-CH2C(O)-、CH3S(O)2-、CH3CH2C(O)-、(CH3)2CHC(O)-、
R6可以选自H、卤素、CN、C1-3烷基。
4.根据权利要求1-3任一项所述的化合物,其特征在于,R1可以选自F、Cl或三氟甲基;
R2可以选自H、F、Cl或三氟甲基;
R3可以选自H或F;
R4和R5可以与其所连接的原子可以形成如下所示的结构:
R6可以选自H、F、Cl、CN、甲基。
5.根据权利要求1-4任一项所述的化合物,其特征在于,式(I)所示化合物选自以下结构:
6.权利要求1-5任一项所述式(I)所示化合物的制备方法,其特征在于,包括以下步骤:化合物I-1脱保护得到式(I)所示化合物;
其中,R1、R2、R3、R4、R5、R6彼此独立地具有权利要求1-5任一项所述的定义;PG为氨基保护基,例如苄氧羰基、苄基、叔丁氧羰基。
7.根据权利要求6所述的制备方法,其特征在于,所述化合物I-1的制备方法包括以下步骤:化合物I-2和化合物I-3反应得到化合物I-1;
其中,R1、R2、R3、R4、R5、R6、PG彼此独立地具有权利要求6所述的定义。
8.一种药物组合物,其包含治疗有效量的权利要求1-5任一项所述式(I)所示的化合物、其消旋体、立体异构体、互变异构体、氮氧化物或它们药学上可接受的盐中的至少一种。
9.权利要求1-5任一项所述式(I)所示的化合物、其消旋体、立体异构体、互变异构体、氮氧化物或它们药学上可接受的盐在制备药物中的用途。
10.根据权利要求9所述的用途,其特征在于,所述药物用于预防和/或治疗癌症;
优选地,所述药物为Akt抑制剂。
优选地,所述癌症选自乳腺癌、前列腺癌、胰腺癌、膀胱癌或卵巢癌。
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