CN117143093A - 一种蛋白降解剂及其制备方法和用途 - Google Patents
一种蛋白降解剂及其制备方法和用途 Download PDFInfo
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- CN117143093A CN117143093A CN202210572229.7A CN202210572229A CN117143093A CN 117143093 A CN117143093 A CN 117143093A CN 202210572229 A CN202210572229 A CN 202210572229A CN 117143093 A CN117143093 A CN 117143093A
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Abstract
本发明提供了一种蛋白降解剂及其制备方法和用途。本发明的蛋白降解剂包括:至少一个可以与LC3结合的部分;以及,至少一个可以与CDK结合的部分;用于将所述可以与LC3结合的部分各自独立地与所述可以与CDK结合的部分共价连接的连接部分。本发明的蛋白降解剂体现了优异的抗肿瘤活性,可以下调细胞内多种CDK的量,为CDK在其中起作用的疾病或病症的治疗、预防或改善提供了新的范例。
Description
技术领域
本发明涉及医药技术领域,尤其是涉及一类香豆素与CDK抑制剂连接类蛋白降解剂及其制备方法,以及在与CDK相关疾病的预防或治疗药物制备中的用途。
背景技术
靶向蛋白降解是一种十分有潜力的生物机制研究工具和治疗手段。通过直接降解靶蛋白,可以克服靶标蛋白突变产生的耐药问题。在过去的二十多年里,PROTAC技术取得了长足的发展,已有数个PROTAC候选药物进入了临床研究。但PROTAC技术依然面临泛素化连接酶配体的成药性不足以及依赖于泛素蛋白酶体系统但细胞内仍有许多物质并不是蛋白酶体清除的底物等问题。
因此,仍然需要开发用于降解靶蛋白的新型蛋白降解剂。
发明内容
本申请的发明人以在胞质中有分布的CDK9作为一个实例,在4-苯基香豆素的5,7位通过不同的连接方式与CDK9的配体相连接,同时对香豆素的4位的取代基也进行了考察,得到了一系列对CDK9具有降解作用的化合物,明确其可以通过招募LC3B实现CDK9的自噬降解,并体现出优异的抗肿瘤作用。本发明首次提供了香豆素类结构与CDK9抑制剂连接化合物可以自噬降解CDK9,体现抗肿瘤活性,可以推测与该类香豆素结构连接的胞质内蛋白结合化合物,均可以通过招募LC3B实现蛋白的降解,产生生物学效应,进行胞质内蛋白相关疾病的治疗和预防。由此,完成了本发明。
本发明的目的之一在于提供一种蛋白降解剂。
本发明的目的之二在于提供一种蛋白降解剂的制备方法。
本发明的目的之三在于提供一种包含蛋白降解剂的药物组合物。
本发明的目的之四在于提供一种蛋白降解剂在制备用于治疗、预防或改善与CDK相关疾病的药物中的应用。
为了实现本发明的上述目的,特采用以下技术方案:
本发明第一方面提供了一种蛋白降解剂或其药学上可接受的盐,其包括:
至少一个可以与LC3结合的部分;以及,
至少一个可以与CDK结合的部分;
用于将所述可以与LC3结合的部分各自独立地与所述可以与CDK结合的部分共价连接的连接部分linker。
LC3指的是微管相关蛋白1A/1B-轻链3(light chain 3),其是一种可溶性蛋白,分子量约为17kDa。LC3普遍存在于哺乳动物组织和培养细胞,是自噬(真核细胞的回收系统)的关键组分。其在自噬体生物合成过程中掺入自噬体的内外膜。因此,LC3是自噬(尤其是自噬体形成)的特异性标志物。
CDK指的是丝氨酸/苏氨酸激酶家族的细胞周期蛋白依赖激酶。
本发明的蛋白降解剂的结构可以表示为:
LCBM-Linker-POIL;
其中:LCBM表示可以与LC3结合的部分(LC3 Binding Moiety,简称LCBM部分);Linker表示共价连接部分;POIL表示可以与CDK结合的部分(Protein Of InterestLigand,简称POIL部分)。
LCBM部分和POIL部分可以各自独立地选自小分子化合物。
在一些实施方案中,LCBM部分和POIL部分的分子量各自独立地为约100-约2000,优选为约100-约l000,例如约100-约900、约100-约800、约100-约700、约100-约600、约100-约500。
LCBM部分可以连接一个或多个POIL部分,反之亦然。在存在多于一个POIL部分的情况下,POIL部分可以各自独立地选择,各个POIL部分之间可以相同,也可以不同。在一些实施方案中,存在多个针对相同靶标的POIL部分。即使针对相同靶标,也可以根据需要在一个分子中使用多个相同或各自不同的POIL部分。当使用多于一个POIL部分的情况下,所用的linker也可以各自独立地选择。
LCBM部分
该部分表示可以与LC3结合的部分,是指对于LC3蛋白具有亲和力的部分。
在一些实施方案中,LCBM部分为香豆素类化合物,优选为式⑴化合物,或其药学上可接受的盐、立体异构体、溶剂化物、多晶型、互变异构体、同位素化合物、代谢产物或前药,
其中:
Y为O或S;
R1和R2各自独立地选自H和Ra;
Ra在每次出现时各自独立地选自氢、C1-6烷基、卤代C1-6烷基、C3-6环烷基,3-7元杂环基、C6-10芳基、3-7元杂芳基、C1-6烷氧基、卤代C1-6烷氧基、氨基;杂环基或芳基任选地被一个或多个选自卤素、-NO2、-CN、C1-6烷基、-OH、-O(C1-6烷基)、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-COOH、-C(=O)O(C1-6烷基)、-C(=O)NH(C1-6烷基)、-C(=O)N(C1-6烷基)2、-OC(=O)(C1-6烷基)、-NHC(=O)(C1-6烷基)、-C(=O)(C1-6烷基)的取代基取代;
R3、R4、R5和R6各自独立地选自H和Rb;
Rb在每次出现时各自独立地选自卤素、-NO2、-CN、C1-6烷基、C2-6烯基、C2-6炔基、-OR7、-SR7、-NR7R8、-C(=O)OR7、-C(=O)NR7R8、-OC(=O)R7、-NC(=O)R7R8、-C(=O)R7、-S(=O)2OR7、-S(=O)2R7、-S(=O)2NR7R8、-OS(=O)2R7、-NS(=O)2R7R8、-S(=O)R7,其中所述烷基、烯基或炔基任选地被一个或多个选自卤素、-NO2、-CN、-OH、-O(C1-6烷基)、-O(C3-6环烷基)、-O(C1-4亚烷基-C3-6环烷基)、-O(3-7元杂环基)、-O(C1-4亚烷基)-(3-7元杂环基)、-SH、-S(C1-6烷基)、-S(C3-6环烷基)、-S(C1-4亚烷基-C3-6环烷基)、-S(3-7元杂环基)、-S(C1-4亚烷基)-(3-7元杂环基)、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-NH(C3-6环烷基)、-N(C3-6环烷基)2、-NH(C1-4亚烷基-C3-6环烷基)、-N(C1-4亚烷基-C3-6环烷基)2、NH(3-7元杂环基)、-N(3-7元杂环基)2、-NH(C1-4亚烷基-3-7元杂环基)、-N(C1-4亚烷基-3-7元杂环基)2、=O、-COOH和C1-6烷基的取代基取代;
R7和R8在每次出现时各自独立地选自H、C1-6烷基、C2-6烯基、C2-6炔基、C3-6环烷基、C3-6环烷基-C1-4烷基、3-7元杂环基、3-7元杂环基-C1-4烷基、C6-10芳基-C1-4烷基,其中所述烷基、烯基、炔基、环烷基、杂环基或芳基任选地被一个或多个选自卤素、-NO2、-CN、C1-6烷基、-OH、-O(C1-6烷基)、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-COOH、-C(=O)O(C1-6烷基)、-C(=O)NH(C1-6烷基)、-C(=O)N(C1-6烷基)2、-OC(=O)(C1-6烷基)、-NHC(=O)(C1-6烷基)、-C(=O)(C1-6烷基)的取代基取代;
所述杂环基或杂芳基含有1-4个选自N、O和S中的杂原子。
在一些实施方案中,式(1)化合物选自如下式II化合物:
其中,R3和R5各自独立地选自H和OH;
R2选自氢、C1-6烷基、卤代C1-6烷基、C6-10芳基、卤代C6-10芳基、氧代C6-10芳基、3-7元杂芳基;优选选自氢、C1-3烷基、卤代C1-3烷基、苯基、卤代苯基、氧代苯基、吡啶基。
在一些实施方案中,式(1)化合物选自如下化合物:
POIL部分
该部分表示可以与CDK结合的部分,是指能够与CDK发生相互作用的部分,即POIL部分针对的靶标为CDK。
所述CDK包括CDK1,CDK2,CDK3,CDK4,CDK5,CDK6,CDK7,CDK8,CDK9,CDK10,CDK11,CDK12,CDK13,CDK14,CDK15,CDK16,CDK17,CDK18,CDK19,CDK20,CDK21及其所述CDK的所有亚型。
在一些实施方案中,POIL部分与CDK9结合。
POIL部分可以为已上市或文献已报道的CDK探针、CDK抑制剂,包括但不限于下列化合物:
Linker
Linker为用于连接LCBM部分和POIL部分的连接部分,其可以是化学键或基团。
Linker可以是刚性的,也可以是柔性的。在一些优选的实施方案中,Linker是柔性的。
在一些实施方案中,Linker为化学键。
在另一些实施方案中,Linker为包含1-30个,优选2-16个(例如,2、3、4、5、6、7、8、9、10、11、12、13、14、15或16)碳原子的直链或支链或环状结构,其中的每个碳原子可以任选地被一个或多个(例如2、3、4、5、6个),特别是一个杂原子代替;其中杂原子选自氧、硫、氮、磷,优选为氧、硫或氮,更优选为氧或氮,特别是氧。每个碳原子也可以任选地被-C(=O)-、-C(=S)-、-S(=O)-、-SO2-及具有0到4个杂原子的3到6元环代替,杂原子选自氧、硫、氮、磷。
在一些实施方案中,Linker包括如下结构:
共价连接的位点可以是任何合适的位点。
在一些实施方案中,LCBM部分的碳原子与Linker共价连接;在另一些实施方案中,LCBM部分的杂原子与Linker共价连接。同理,POIL部分也可以通过碳原子或者杂原子与linker共价连接。所述杂原子选自氧、硫、氮、磷。本领域技术人员可以根据这三部分的结构选择合适的反应用于连接。
在一些实施方案中,蛋白降解剂选自如下I-1~I-6中的任一结构:
其中,n为1、2、3、4、5或6;m为1、2或3;
R2、R3和R5的定义同式II。
在一些实施例中,蛋白降解剂选自如下结构:
本发明中的术语定义如下:
所述“卤素”可以为氟、氯、溴或碘。
所述“C1-6烷基”是指具有1-6个碳原子的链状烷基;其具体实例可以包括甲基、乙基、丙基、正丙基、异丙基、丁基、正丁基、异丁基、叔丁基、1-甲基-丁基、1-乙基-丁基、戊基、正戊基、异戊基、新戊基、叔戊基、己基、正己基、1-甲基戊基、2-甲基戊基、4-甲基-2-戊基、3,3-二甲基丁基、2-乙基丁基以及类似基团,但不限于此。
所述“卤代C1-6烷基”是指如上所定义的C1-C6烷基的一个或多个氢被卤素取代。
所述“C2-6烯基”是指直链或支链的含有2-6个碳原子,至少有一个碳碳双键的基团;其具体实例可以包括乙烯基、丙烯基、2-丙烯基、(E)-2-丁烯基、(Z)-2-丁烯基、(E)-2-甲基-2-丁烯基、(Z)-2-甲基-2-丁烯基、2,3-二甲基-2-丁烯基、(Z)-2-戊烯基、(E)-1-戊烯基、(E)-2-戊烯基、(Z)-2-己烯基、(E)-1-己烯基、(Z)-1-己烯基、(E)-2-己烯基、(Z)-3-己烯基、(E)-3-己烯基、(E)-1,3-己二烯基、4-甲基-3-戊烯基或降冰片烯。
所述“C1-6烷氧基”是指RO-基团,其中R为如上所述的C1-C6烷基。烷氧基的具体实例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、仲丁氧基、正戊氧基、异戊氧基、新戊氧基、正己氧基、异己氧基、3-甲基戊氧基、3,3-二甲基丁氧基、2-乙基丁氧基等。
所述“卤代C1-6烷氧基”是指如上所述的烷氧基的至少一个氢被卤素取代得到的基团;其具体实例包括三氟甲氧基等。
所述“C3-6环烷基”是指包含3-6个碳原子的完全饱和的环状烃类化合物基团,其具体实例包括环丙基、环丁基、环戊基、环己基。
所述“3-7元杂环基”是指环上含有1至4个选自氮、氧、硫中的杂原子的3-7元环烷基团,其具体实例包括环氧乙烷、四氢咪唑、四氢呋喃等。
所述“C6-10芳基”是指具有6至10个碳原子的单环或多环芳基;其具体实例包括苯基、萘基。
所述“3-7元杂芳基”是指环上含有1至4个选自氮、氧、硫中的杂原子的3-7元芳香基团,其具体实例包括吡啶、哒嗪、嘧啶等。
“药学上可接受的盐”包括式(I)化合物的阴离子盐和阳离子盐,例如式(1)化合物与酸或碱形成的盐;例如式(1)化合物的无机酸或有机酸盐;优选地,所述无机酸包括盐酸、氢溴酸、氢碘酸、硫酸、硝酸、磷酸、碳酸、高氯酸;优选地,所述有机酸包括甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、柠檬酸、枸橼酸、酒石酸、苦味酸、甲磺酸、乙磺酸、对甲苯磺酸、谷氨酸、双羟萘酸;或者式(1)化合物的的无机碱或有机碱盐;例如式(I)化合物的碱金属的盐、碱土金属的盐、铵盐;优选地,所述碱金属包括钠、钾、锂、铯,所述碱土金属包括镁、钙、锶,例如所述有机碱包括三烷基胺、吡啶、喹啉、哌啶、咪唑、甲基吡啶、二甲氨基吡啶、二甲基苯胺、N-烷基吗啉、1,5-二氮杂双环[4.3.0]壬烯-5、1,8-二氮杂双环[5.4.0]十一碳烯-7、1,4-二氮杂双环[2.2.2]辛烷;优选地,所述三烷基胺包括三甲胺、三乙胺、N,N-二异丙基乙胺;优选地,所述N-烷基吗啉包括N-甲基吗啉。
本发明第二方面提供了一种蛋白降解剂的制备方法,所述方法包括通过共价连接将可以与LC3结合的部分与可以与CDK结合的部分连接起来的步骤。
实现连接的反应类型包括亲核取代反应、mitsunobu反应、缩合反应等,但不限于此,可以采用任何合适的能够通过共价连接将可以与LC3结合的部分与可以与CDK结合的部分连接起来的反应。
在一些实施方案中,蛋白降解剂的药学上可接受的盐,可以通过将蛋白降解剂溶于相应的酸饱和的醇溶液或乙酸乙酯溶液或二氧六环溶液中进行反应而制备,例如:将蛋白降解剂溶于氯化氢饱和的甲醇溶液,室温搅拌30分钟,将溶剂蒸干,即可制得相应的蛋白降解剂的盐酸盐。但本发明不限于此,本领域技术人员可以根据蛋白降解剂的性质采用任何适合的成盐方式。
本发明第三方面提供了一种药物组合物,其包含选自治疗有效量的上述蛋白降解剂或其药学上可接受的盐中的一种或多种以及任选存在的药学上可接受的载体。
药学上可接受的载体是指药学领域常规的药物载体,例如:稀释剂,如水等;填充剂,如淀粉、蔗糖等;粘合剂,如纤维素衍生物、藻酸盐、明胶、聚乙烯吡咯烷酮;湿润剂,如甘油;崩解剂,如琼脂、碳酸钙和碳酸氢钠;吸收促进剂,如季铵化合物;表面活性剂,如十六烷醇;吸附载体,如高岭土和皂粘土;润滑剂,如滑石粉、硬脂酸钙和硬脂酸镁和聚乙二醇等。另外,还可以在上述药物组合物中加入其它辅剂,如香味剂和甜味剂等。
本发明的蛋白降解剂或其组合物可以以常规制剂形式口服或肠胃外给药至患者,所述常规制剂形式为,比如,胶囊、微囊、片剂、颗粒剂、散剂、锭剂、丸剂、栓剂、注射剂、混悬剂、糖浆、贴剂、乳膏剂、洗剂、软膏剂、凝胶、喷雾剂、溶液和乳剂。适合的制剂可以使用常规的有机或无机添加剂,通过通常采用的方法制备,所述有机或无机添加剂为,比如,赋形剂(例如,蔗糖、淀粉、甘露醇、山梨醇、乳糖、葡萄糖、纤维素、滑石、磷酸钙或碳酸钙)、粘合剂(例如,纤维素、甲基纤维素、羟甲基纤维素、聚丙基吡咯烷酮、聚乙烯吡咯烷酮、明胶、阿拉伯胶、聚乙二醇、蔗糖或淀粉)、崩解剂(例如,淀粉、羧甲基纤维素、羟丙基淀粉、低取代的羟丙基纤维素、碳酸氢钠、磷酸钙或柠檬酸钙)、润滑剂(例如,硬脂酸镁、轻质无水硅酸、滑石或月桂基硫酸钠)、矫味剂(例如,柠檬酸、薄荷醇、甘氨酸或橘子粉)、防腐剂(例如,苯甲酸钠、亚硫酸氢钠、尼泊金甲酯或尼泊金丙酯)、稳定剂(例如,柠檬酸、柠檬酸钠或乙酸)、助悬剂(例如,甲基纤维素、聚乙烯吡咯烷酮或硬脂酸铝)、分散剂(例如,羟丙基甲基纤维素)、稀释剂(例如,水)和底蜡(例如,可可脂、白凡士林或聚乙二醇)。
可调整给药方案以提供最佳所需响应。例如,以注射剂形式用药时,可给药单次推注、团注和/或连续输注,等等。例如,可随时间给药数个分剂量,或可如治疗情况的急需所表明而按比例减少或增加剂量。例如,可随时间给药数个分剂量,或可依据治疗情况而按比例减少或增加剂量。要注意,剂量值可随要减轻的病况的类型及严重性而变化,且可包括单次或多次剂量。一般地,治疗的剂量是变化的,这取决于所考虑的事项,例如:待治疗患者的年龄、性别和一般健康状况;治疗的频率和想要的效果的性质;组织损伤的程度;症状的持续时间;以及可由各个医师调整的其它变量。要进一步理解,对于任何特定个体,具体的给药方案应根据个体需要及给药组合物或监督组合物的给药的人员的专业判断来随时间调整。可以通过临床领域的普通技术人员容易地确定所述药物组合物的施用量和施用方案。例如,本发明的蛋白降解剂或其组合物可以以分剂量每天4次至每7天给药1次,给药量可以是例如0.01~1000mg/次。可以一次或多次施用需要的剂量,以获得需要达到的结果。也可以以单位剂量形式提供根据本发明的药物组合物。
丝氨酸/苏氨酸激酶家族的细胞周期蛋白依赖激酶(CDKs)是细胞周期调节机制的主要驱动力,它们可以通过磷酸化关键底物来促进细胞DNA的合成和有丝分裂(Siemeister等,Mol.Cancer Ther.2012;11(10):2265-2273.)。CDK9在与肿瘤细胞的增殖和存活相关的凋亡调节因子Mcl-1和原癌基因MYC的转录调控中发挥重要作用(Rahaman等,Endocrine-Related Cancer.2016;23(12):T211-T226.)。在多种血液系统恶性肿瘤和实体瘤发现CDK9信号转导过度活跃。抑制CDK9可以引起癌细胞生长抑制和诱导细胞凋亡,这使得CDK9成为一个潜在的、有吸引力的癌症治疗靶点(Lee等,Expert Opinion on InvestigationalDrugs.2019;28(11):989-1001.),此外CDK9被证明在病毒复制、炎症反应和心血管疾病的病理过程中也发挥着重要作用。
因此,本发明的蛋白降解剂可以用于治疗、预防或改善CDK相关疾病或病症。
因此,本发明第四方面提供了上述的蛋白降解剂在制备用于治疗、预防或改善CDK相关疾病或病症的药物中的应用。
所述CDK相关疾病或病症包含但不限于炎症,关节炎,类风湿性关节炎,脊椎关节病,痛风性关节炎,骨关节炎,青少年关节炎和其他关节炎病症,系统性红斑狼疮(SLE),皮肤相关病症,牛皮癣,湿疹,烧伤,皮炎,神经炎症,过敏,疼痛,神经性疼痛,发热,肺部疾病,肺部炎症,成人呼吸窘迫综合征,肺部肉瘤病,哮喘,矽肺病,慢性肺部炎症疾病,和慢性阻塞性肺病(COPD),心血管疾病,动脉硬化,心肌梗塞(包括心肌梗塞后适应症),血栓形成,充血性心力衰竭,心脏再灌注损伤,以及与高血压和/或心力衰竭相关的并发症,如血管器官损伤,再狭窄,心肌病,中风,包括缺血性和出血性中风,再灌注损伤,肾脏再灌注损伤,局部缺血,包括中风和脑局部缺血,以及由心脏/冠状动脉旁路,神经变性疾病,肝病和肾炎引起的局部缺血,胃肠道病症,炎症性肠病,克罗恩病,胃炎,肠易激综合征,溃疡性结肠炎,溃疡性疾病,胃溃疡,病毒和细菌感染,败血症,败血性休克,革兰氏阴性败血症,疟疾,脑膜炎,HIV感染,机会性感染,继发于感染或恶性肿瘤的恶病质,继发于获得性免疫缺陷综合症(AIDS)的恶病质,AIDS,ARC(AIDS相关综合征),肺炎,疱疹病毒,感染引起的肌痛,流行性感冒,自身免疫性疾病,移植物抗宿主反应和同种异体移植排斥反应,治疗骨吸收疾病,骨质疏松症,多发性硬化症,癌症,白血病,淋巴瘤,结肠直肠癌,脑癌,骨癌,上皮细胞来源的肿瘤(上皮癌),基底细胞癌,腺癌,胃肠癌,唇癌,口腔癌,食道癌,小肠癌,胃癌,结肠癌,肝癌,膀胱癌,胰腺癌,卵巢癌,宫颈癌,肺癌,乳腺癌,皮肤癌,鳞状细胞和/或基底细胞癌,前列腺癌,肾细胞癌和其他已知影响全身上皮细胞的癌症,慢性髓性白血病(CML),急性髓性白血病(AML)和急性早幼粒细胞白血病(APL),血管生成,包括瘤形成,转移,中枢神经系统疾病,具有炎性或凋亡组分的中枢神经系统疾病,阿尔茨海默病,帕金森病,亨廷顿病,肌萎缩侧索硬化,脊髓损伤和周围神经病,或B细胞淋巴瘤。此外,通过借助本申请的蛋白降解剂(例如本文所述的那些)的LC3介导的自噬降解调节细胞内CDK的量,也为治疗、预防或改善CDK在其中起作用的疾病或病症提供了新的范例。
本发明提供的蛋白降解剂,或本发明的药物组合物还可以与用于治疗或预防肿瘤的其他治疗剂联用。
本发明具有以下有益效果:
本发明提供了一系列对LC3具有招募作用的香豆素类小分子,得到了一系列对于CDK9具有降解作用的蛋白降解剂,这些降解剂体现了优异的抗肿瘤活性;此外,借助于本文中提供的降解剂也可以下调细胞内其他CDK的量,为CDK在其中起作用的疾病或病症的治疗、预防或改善提供了新的范例。
在上文中已经详细地描述了本发明,但是上述实施方式本质上仅是例示性,且并不欲限制本发明。此外,本文并不受前述现有技术或发明内容或以下实施例中所描述的任何理论的限制。
附图说明
图1示出了代表性化合物诱导CDK9降解并下调Mcl-1蛋白,其中A为化合物2、3、4、5、6、7处理U-2932细胞,B为化合物3、9、10处理U-2932细胞,C为化合物14、15、16、17、18、19处理U-2932细胞,D为化合物20、16、21、22处理U-2932细胞。
图2示出了代表性化合物诱导CDK9和LC3B的结合,其中A为化合物10和16处理U-2932细胞,B为化合物10和16处理293T细胞。
图3示出了代表性化合物对于其它CDK的降解作用,其中A为化合物10对于其它CDK的降解作用,B为化合物16对于其它CDK的降解作用。
具体实施方式
下面结合实施例对本发明作进一步的说明,需要说明的是,提供以下实施例仅出于说明目的并不构成对本发明要求保护范围的限制。
除特殊说明外,在实施例中所采用的原料、试剂、方法等均为本领域常规的原料、试剂、方法。
在以下实施例中,核磁共振氢谱用BrukerAMX-400型核磁共振仪记录,化学位移δ的单位为ppm。如无特别说明,所有反应溶剂均按照常规方法进行纯化。柱层析用硅胶(200-300目)为青岛海洋化工分厂生产。薄层层析使用GF254高效板,为烟台化工研究所生产。制备型薄层层析板由中国科学院上海药物研究所制备,固定相采用GF254(HG/T2354-92)硅胶和羧甲基纤维素钠(800-1200)制备,分别为青岛海洋化工有限公司和中国医药(集团)上海化学试剂公司生产。如无特别标注,所有溶剂均为分析纯试剂,所用试剂均购自国药集团化学试剂有限公司。采用碘、紫外荧光等方法显色。减压蒸除有机溶剂在旋转蒸发仪中进行。
实施例1蛋白降解剂1的合成
第一步
将1-1(150.0mg,0.59mmol),1-2(82.0mg,0.59mmol),三苯基膦(309.5mg,1.18mmol)溶于3ml无水四氢呋喃中,N2保护,0℃下滴加DIAD(0.23ml,1.18mmol),滴加完毕后,40℃加热8h,旋干四氢呋喃,加入二氯甲烷,无水硫酸钠干燥后,硅胶柱层析分离(PE/EA=4/1),得到1-3(白色固体,114.7mg,收率52%)。1H NMR(400MHz,Methanol-d4)δ7.47-7.42(m,3H),7.37-7.31(m,2H),6.45(d,J=2.2Hz,1H),6.32(d,J=2.2Hz,1H),5.86(s,1H),3.85(t,J=5.5Hz,2H),2.79(t,J=6.7Hz,2H),1.73-1.66(m,2H).
第二步
将1-3(114.7mg,0.31mmol),SNS-032(104.7mg,0.28mmol)溶于2ml DMF中,加入DIPEA(152μL,0.92mmol),60℃加热过夜,加入10ml乙酸乙酯,用水洗4遍,饱和氯化钠溶液洗一遍,无水硫酸钠干燥,硅胶柱层析(DCM/MeOH=94/6),得到蛋白降解剂1(白色固体,54.9mg,收率29%)。1H NMR(400MHz,Methanol-d4)δ7.46-7.42(m,3H),7.38–7.29(m,3H),6.69(s,1H),6.43(d,J=2.2Hz,1H),6.31(d,J=2.2Hz,1H),5.85(s,1H),4.00(s,2H),3.79(t,J=6.0Hz,2H),2.88-2.82(m,2H),2.53-2.43(m,1H),2.07–1.91(m,4H),1.89–1.72(m,4H),1.44-1.36(m,2H),1.26(s,9H).
实施例2蛋白降解剂2的合成
第一步
0℃下将苯胺(2.16g,23.19mmol)加入到11.5ml HBF4的50%水溶液中,将亚硝酸钠(1.76g,25.51mmol)溶于3.6ml水中,缓慢滴加到反应体系中,0℃下搅拌1h。抽滤,用HBF4的50%水溶液洗一次,乙醇洗一次,乙醚洗三次,得到2-1(粗品,3.14g,71%)。1H NMR(400MHz,Deuterium Oxide)δ8.52–8.38(m,2H),8.25–8.09(m,1H),7.92–7.73(m,2H).
第二步
将2-2(300.0mg,1.54mmol)溶于9ml甲醇中,加入碳酸钙(154.6mg,1.54mmol),醋酸钯(34.7mg,0.15mmol),2-1(593.0mg,3.09mmol),60℃加热,敞口搅拌,过夜。TLC监测反应完全后,旋干甲醇,加乙酸乙酯,水洗两次,盐洗,硅胶柱层析(PE/EA=70/30),得到2-3(白色固体,132.5mg,36.2%)。1H NMR(400MHz,Chloroform-d)δ7.60–7.54(m,3H),7.51–7.38(m,3H),7.03–6.96(m,1H),6.74–6.67(m,1H),6.18–6.13(m,1H),5.41–5.37(m,1H).
第三步
将2-3(132.5mg,0.56mmol),2-4(154.6mg,1.11mmol),三苯基膦(291.8mg,1.11mmol)溶于3ml无水四氢呋喃中,N2保护,0℃下滴加DIAD(0.22ml,1.11mmol),滴加完毕后,室温搅拌过夜,旋干四氢呋喃,加入二氯甲烷,无水硫酸钠干燥后,硅胶柱层析分离(PE/EA=4/1),得到2-5(黄白色固体,92.3mg,46.2%)。1H NMR(400MHz,Chloroform-d)δ7.52–7.46(m,1H),7.44–7.40(m,3H),7.34–7.29(m,2H),7.06(dd,J=8.4,1.0Hz,1H),6.70(dd,J=8.4,1.0Hz,1H),6.17(s,1H),3.88(t,J=5.5Hz,2H),2.79(t,J=6.4Hz,2H),1.73–1.64(m,2H).
第四步
将2-5(92.3mg,0.26mmol),SNS-032(88.0mg,0.23mmol)溶于2ml DMF中,加入DIPEA(127μL,0.77mmol),60℃加热过夜,加入10ml乙酸乙酯,用水洗4遍,饱和氯化钠溶液洗一遍,无水硫酸钠干燥,硅胶柱层析(DCM/MeOH=94/6),得到蛋白降解剂2(白色固体,14.9mg,收率9%)。1H NMR(400MHz,Methanol-d4)δ7.61–7.56(m,1H),7.49–7.43(m,3H),7.40–7.35(m,2H),7.33(s,1H),7.07–7.02(m,1H),6.92–6.87(m,1H),6.69(s,1H),6.13(s,1H),4.00(s,2H),3.86(t,J=6.1Hz,2H),2.89–2.78(m,2H),2.51–2.41(m,1H),2.00–1.91(m,4H),1.88-1.74(m,4H),1.45–1.34(m,2H),1.26(s,9H).
实施例3蛋白降解剂3的合成
第一步
将3-1(400.0mg,2.08mmol)溶于5ml DMF中,加入1,3-二溴丙烷(634μL,6.24mmol),碳酸钾(345.2mg,2.50mmol),室温搅拌6h,加乙酸乙酯,用水洗4次,饱和食盐水洗一次,无水硫酸钠干燥,硅胶柱层析分离纯化,得到3-2(白色固体,65.7mg,收率10%)。1HNMR(400MHz,Methanol-d4)δ6.40(d,J=2.3Hz,1H),6.35(d,J=2.3Hz,1H),5.94–5.92(m,1H),4.21(t,J=5.9Hz,2H),3.68(t,J=6.5Hz,2H),2.61–2.56(m,3H),2.46–2.36(m,2H).
第二步
合成方法同实施例2第四步,将2-5换成3-2,得到蛋白降解剂3(白色固体,收率20%)。1H NMR(400MHz,DMSO-d6)δ12.26(s,1H),10.71(s,1H),7.38(s,1H),6.72(s,1H),6.39–6.26(m,2H),5.92(s,1H),4.07–4.00(m,4H),2.99–2.86(m,2H),2.50–2.38(m,6H),1.98–1.88(m,4H),1.82–1.73(m,2H),1.69–1.54(m,2H),1.18(s,9H).
实施例4蛋白降解剂4的合成
第一步
将间苯三酚4-1(2.0g,15.86mmol)溶于30ml三氟乙酸中,0℃下滴加10ml 4-2(3.4g,16.33mmol)的三氟乙酸溶液,滴加完毕后升到室温搅拌过夜。减压蒸馏除去三氟乙酸,加入40ml二氯甲烷,抽滤,得到4-3(米白色固体,367.6mg,8%)。1H NMR(400MHz,DMSO-d6)δ10.39(s,1H),10.12(s,1H),7.32–7.26(m,2H),6.96–6.90(m,2H),6.26(d,J=2.3Hz,1H),6.18(d,J=2.4Hz,1H),5.74(s,1H),3.80(s,3H).
第二步
除4-3代替2-3外,以与合成化合物2-5相同的方法合成化合物4-4(白色固体,收率45%)。1H NMR(400MHz,Chloroform-d)δ7.27–7.22(m,2H),6.96–6.92(m,3H),6.73(d,J=2.3Hz,1H),6.28(d,J=2.4Hz,1H),5.99(s,1H),3.89(s,3H),3.86(t,J=5.6Hz,2H),2.81(t,J=6.6Hz,2H),1.83–1.75(m,2H).
第三步
除4-4代替2-5外,以与合成蛋白降解剂2相同的方法合成蛋白降解剂4(白色固体,收率30%)。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.63(s,1H),7.39(s,1H),7.29–7.23(m,2H),6.99–6.93(m,2H),6.73(s,1H),6.40(d,J=2.2Hz,1H),6.29(d,J=2.3Hz,1H),5.78(s,1H),4.06(s,2H),3.81(s,3H),3.73(t,J=5.9Hz,2H),2.72–2.64(m,2H),2.47–2.36(m,1H),1.82–1.67(m,6H),1.62–1.48(m,2H),1.32(s,2H),1.18(s,9H).
实施例5蛋白降解剂5的合成
合成方法参照实施例4,把4-2换成4-氟苯甲酰乙酸乙酯,得到蛋白降解剂5(白色固体,收率30%)。1H NMR(400MHz,Methanol-d4)δ7.41–7.36(m,2H),7.34(s,1H),7.22–7.16(m,2H),6.70(s,1H),6.43(d,J=2.2Hz,1H),6.33(d,J=2.2Hz,1H),5.87(s,1H),4.00(s,2H),3.82(t,J=6.0Hz,2H),2.91–2.83(m,2H),2.54–2.44(m,1H),2.05–1.96(m,4H),1.90–1.73(m,4H),1.52–1.43(m,2H),1.26(s,9H).
实施例6蛋白降解剂6的合成
合成方法参照实施例4,把4-2换成异烟酰乙酸乙酯,得到蛋白降解剂6(白色固体,收率19%)。1H NMR(400MHz,DMSO-d6)δ12.23(s,1H),10.82(s,1H),8.62–8.59(m,2H),7.38(s,1H),7.37–7.35(m,2H),6.72(s,1H),6.43(d,J=2.2Hz,1H),6.30(d,J=2.3Hz,1H),5.87(s,1H),4.05(s,2H),3.73(t,J=6.1Hz,2H),2.74–2.66(m,2H),2.47–2.37(m,1H),1.85–1.68(m,6H),1.61–1.48(m,2H),1.18(s,9H).
实施例7蛋白降解剂7的合成
合成方法参照实施例3,把3-1换成5,7-二羟基香豆素,得到蛋白降解剂7(白色固体,收率25%)。1H NMR(400MHz,Methanol-d4)δ8.13–8.08(m,1H),7.34(s,1H),6.70(s,1H),6.38–6.30(m,2H),6.13–6.09(m,1H),4.15(t,J=6.1Hz,2H),4.00(s,2H),3.15–3.07(m,2H),2.69–2.62(m,2H),2.59–2.48(m,1H),2.23–2.06(m,4H),1.95–1.81(m,4H),1.26(s,9H).
实施例8蛋白降解剂8的合成
合成方法参照实施例3,把1,3–二溴丙烷换成1,2–二溴乙烷,得到蛋白降解剂8(白色固体,收率17%)。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.54(s,1H),7.39(s,1H),6.72(s,1H),6.37(d,J=2.2Hz,1H),6.31(d,J=2.1Hz,1H),5.93(d,J=1.3Hz,1H),4.13–4.08(m,2H),4.05(s,2H),3.00–2.93(m,2H),2.77–2.72(m,2H),2.55–2.53(m,3H),2.48–2.44(m,1H),2.10–2.01(m,2H),1.82–1.73(m,2H),1.67–1.54(m,2H),1.17(s,9H).
实施例9蛋白降解剂9的合成
合成方法参照实施例3,把1,3–二溴丙烷换成1,4–二溴丁烷,得到蛋白降解剂9(白色固体,收率32%)。1H NMR(400MHz,DMSO-d6)δ12.22(s,1H),10.53(s,1H),7.38(s,1H),6.72(s,1H),6.34(d,J=2.3Hz,1H),6.30(d,J=2.1Hz,1H),5.95–5.91(m,1H),4.05(s,2H),4.03(t,J=6.7Hz,2H),2.94–2.85(m,2H),2.48–2.41(m,1H),2.36–2.30(m,2H),1.94–1.84(m,2H),1.83–1.72(m,4H),1.67–1.54(m,4H),1.18(s,9H).
实施例10蛋白降解剂10的合成
合成方法参照实施例3,把1,3–二溴丙烷换成1,5–二溴戊烷,得到蛋白降解剂10(白色固体,收率20%)。1H NMR(400MHz,DMSO-d6)δ12.22(s,1H),10.52(s,1H),7.38(s,1H),6.72(s,1H),6.34(d,J=2.3Hz,1H),6.30(d,J=2.2Hz,1H),5.94–5.90(m,1H),4.05(s,2H),4.01(t,J=6.2Hz,2H),2.94–2.85(m,2H),2.48–2.40(m,1H),2.34–2.25(m,2H),1.92–1.72(m,6H),1.66–1.56(m,2H),1.54–1.42(m,4H),1.18(s,9H).
实施例11蛋白降解剂11的合成
合成方法参照实施例3,把1,3–二溴丙烷换成2,2'-二溴二乙醚,得到蛋白降解剂11(白色固体,收率31%)。1H NMR(400MHz,DMSO-d6)δ12.22(s,1H),10.56(s,1H),7.38(s,1H),6.72(s,1H),6.35(d,J=2.3Hz,1H),6.32(d,J=2.1Hz,1H),5.96–5.89(m,1H),4.16–4.11(m,2H),4.05(s,2H),3.81–3.76(m,2H),3.59(t,J=5.7Hz,2H),2.98–2.87(m,2H),2.48–2.34(m,1H),2.04–1.88(m,2H),1.78–1.68(m,2H),1.66–1.52(m,2H),1.17(s,9H).
实施例12蛋白降解剂12的合成
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合成方法参照实施例3,把3-1换成5,7-二羟基香豆素,把1,3–二溴丙烷换成1,5–二溴戊烷,得到蛋白降解剂12(白色固体,收率17%)。1H NMR(400MHz,DMSO-d6)δ12.23(s,1H),7.97(d,J=9.7Hz,1H),7.38(s,1H),6.72(s,1H),6.36–6.34(m,1H),6.32–6.30(m,1H),6.12(d,J=9.7Hz,1H),4.09–4.02(m,4H),2.96–2.86(m,2H),2.48–2.39(m,1H),2.35–2.23(m,2H),1.94–1.83(m,2H),1.82–1.72(m,4H),1.66–1.56(m,2H),1.55–1.40(m,4H),1.17(s,9H).
实施例13蛋白降解剂13的合成
第一步
将2,4-二羟基苯甲醛(2.0g,14.48mmol)溶于36ml二氯甲烷中,加入甲氧甲酰基亚甲基三苯基膦(5.8g,17.38mmol),室温搅拌过夜,减压浓缩,硅胶柱层析分离纯化,得到13-1(白色固体,1.4g,收率50%)。1H NMR(400MHz,Methanol-d4)δ7.90(d,J=16.0Hz,1H),7.38–7.33(m,1H),6.43(d,J=16.0Hz,1H),6.35–6.31(m,2H),3.76(s,3H).
第二步
合成方法参照实施例2第二步,将2-2换成13-1,得到化合物13-2(黑绿色固体,收率7%)
第三步
合成方法参照实施例2第三步,将2-3换成13-2,得到化合物13-3(黄色固体,收率49%)。1H NMR(400MHz,Chloroform-d)δ7.57–7.51(m,3H),7.49–7.44(m,2H),7.41(d,J=8.9Hz,1H),6.92(d,J=2.5Hz,1H),6.82(dd,J=8.9,2.5Hz,1H),6.24(s,1H),4.21(t,J=5.8Hz,2H),3.63(t,J=6.4Hz,2H),2.38(p,J=6.1Hz,2H).
第四步
合成方法参照实施例2第四步,将2-5换成13-3,得到蛋白降解剂13(白色固体,收率21%)。1H NMR(400MHz,Methanol-d4)δ7.61–7.56(m,3H),7.55–7.50(m,2H),7.45(d,J=8.9Hz,1H),7.33(s,1H),7.03(d,J=2.5Hz,1H),6.94(dd,J=8.9,2.5Hz,1H),6.69(s,1H),6.23(s,1H),4.18(t,J=6.1Hz,2H),4.00(s,2H),3.12–3.05(m,2H),2.65–2.59(m,2H),2.57–2.48(m,1H),2.20–2.04(m,4H),1.95–1.79(m,4H),1.26(s,9H).
实施例14蛋白降解剂14的合成
第一步
将1-1(1.0g,3.93mmol)溶于10ml二氯甲烷中,加入乙酸酐(2.2ml,23.60mmol),DMAP(48.1mg,0.39mmol),室温搅拌4h,加水洗两次,饱和食盐水洗一次,无水硫酸钠干燥,硅胶柱层析分离。得到14-1(白色固体,1.3g,收率98%)。1H NMR(400MHz,Chloroform-d)δ7.52–7.45(m,3H),7.37–7.32(m,2H),7.18(d,J=2.3Hz,1H),6.79(d,J=2.3Hz,1H),6.22(s,1H),2.35(s,3H),1.36(s,3H).
第二步
将14-1(600.0mg,1.77mmol)溶于2ml二氯甲烷中,加入1ml甲醇,1ml水,室温搅拌4小时,减压蒸馏除去溶剂,加入10ml乙酸乙酯,水洗一次,饱和食盐水洗一次,无水硫酸钠干燥,硅胶柱层析分离。等到化合物14-2(白色固体,217.3mg,收率41%)。1H NMR(400MHz,DMSO-d6)δ10.96(s,1H),7.53–7.46(m,3H),7.35–7.31(m,2H),6.77(d,J=2.4Hz,1H),6.49(d,J=2.4Hz,1H),5.98(s,1H),1.27(s,3H).
第三步
将14-2(217.3mg,0.73mmol)溶于3ml无水DMF中,加入1,3-二溴丙烷(0.37ml,3.67mmol),无水碳酸钾(152.1mg,1.10mmol),室温搅拌6h,加10ml乙酸乙酯,用水洗4次,饱和食盐水洗一次,无水硫酸钠干燥,硅胶柱层析分离纯化,得到化合物14-3(无色油状,200.1mg,65%)。1H NMR(400MHz,Chloroform-d)δ7.51–7.45(m,3H),7.36–7.31(m,2H),6.88–6.86(m,1H),6.52–6.49(m,1H),6.10–6.08(m,1H),4.20(t,J=5.7Hz,2H),3.61(t,J=6.2Hz,2H),2.40–2.34(m,2H),1.35(s,3H).
第四步
将化合物14-3(200.1mg,0.48mmol)溶于2ml DMF中,加2ml水,加入碳酸钾(198.8mg,1.44mmol),室温搅拌2h,加10ml乙酸乙酯,用水洗4次,饱和食盐水洗一次,无水硫酸钠干燥,硅胶柱层析分离纯化,得到化合物14-4(白色固体,44.2mg,收率25%)。1H NMR(400MHz,Methanol-d4)δ7.41–7.33(m,5H),6.54(d,J=2.5Hz,1H),6.28(d,J=2.4Hz,1H),5.90(s,1H),4.19(t,J=5.9Hz,2H),3.65(t,J=6.5Hz,2H),2.34(p,J=6.2Hz,2H).
第五步
合成方法参照实施例2第四步,将2-5换成14-4,得到蛋白降解剂14(白色固体,收率29%)。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.31(s,1H),7.44–7.32(m,6H),6.72(s,1H),6.52(d,J=2.4Hz,1H),6.22(d,J=2.4Hz,1H),5.84(s,1H),4.10–4.01(m,4H),2.98–2.84(m,2H),2.48–2.37(m,3H),1.97–1.84(m,4H),1.81–1.71(m,2H),1.70–1.54(m,2H),1.18(s,9H).
实施例15蛋白降解剂15的合成
合成方法参照实施例14,将1-1换成5,7-二羟基香豆素,得到蛋白降解剂15(白色固体,收率23%)。1H NMR(500MHz,DMSO-d6)δ12.19(s,1H),10.79(s,1H),7.98(d,J=9.6Hz,1H),7.36(s,1H),6.70(s,1H),6.41(d,J=2.2Hz,1H),6.30(d,J=2.3Hz,1H),6.10(d,J=9.6Hz,1H),4.05–3.99(m,4H),2.94–2.85(m,2H),2.46–2.37(m,3H),1.95–1.82(m,4H),1.78–1.71(m,2H),1.66–1.55(m,2H),1.16(s,9H).
实施例16蛋白降解剂16的合成
合成方法参照实施例14,将1-1换成5,7-二羟基-4-甲基香豆素,得到蛋白降解剂16(白色固体,收率21%)。1H NMR(400MHz,DMSO-d6)δ12.23(s,1H),10.69(s,1H),7.38(s,1H),6.72(s,1H),6.41(d,J=2.4Hz,1H),6.32(d,J=2.4Hz,1H),5.96–5.93(m,1H),4.08–3.99(m,4H),2.97–2.86(m,2H),2.48–2.37(m,3H),1.96–1.84(m,4H),1.80–1.72(m,2H),1.69–1.54(m,2H),1.18(s,9H).
实施例17蛋白降解剂17的合成
合成方法参照实施例14,将1-1换成5,7-二羟基-4-(4-吡啶基)香豆素,得到蛋白降解剂17(白色固体,收率14%)。1H NMR(600MHz,DMSO-d6)δ12.19(s,1H),10.43(s,1H),8.58–8.54(m,2H),7.36–7.33(m,3H),6.68(s,1H),6.50(d,J=2.4Hz,1H),6.18(d,J=2.5Hz,1H),5.88(s,1H),4.05–3.99(m,4H),2.94–2.82(m,2H),2.46–2.34(m,3H),1.94–1.81(m,4H),1.76–1.69(m,2H),1.62–1.54(m,2H),1.14(s,9H).
实施例18蛋白降解剂18的合成
合成方法参照实施例14,将1-1换成4-(4-氟苯基)-5,7-二羟基-2H-1-苯并吡喃-2-酮,得到蛋白降解剂18(白色固体,收率27%)。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.35(s,1H),7.44–7.36(m,3H),7.25–7.17(m,2H),6.72(s,1H),6.52(d,J=2.4Hz,1H),6.23(d,J=2.4Hz,1H),5.87(s,1H),4.09–4.01(m,4H),2.99–2.86(m,2H),2.49–2.37(m,3H),1.97–1.83(m,4H),1.83–1.72(m,2H),1.69–1.54(m,2H),1.18(s,9H).
实施例19蛋白降解剂19的合成
合成方法参照实施例14,将1-1换成4-(4-甲氧基苯基)-5,7-二羟基-2H-1-苯并吡喃-2-酮,得到蛋白降解剂19(白色固体,收率36%)。1H NMR(500MHz,DMSO-d6)δ12.19(s,1H),10.27(s,1H),7.36(s,1H),7.31–7.26(m,2H),6.94–6.89(m,2H),6.69(s,1H),6.47(d,J=2.4Hz,1H),6.22(d,J=2.4Hz,1H),5.80(s,1H),4.05–4.00(m,4H),3.78(s,3H),2.94–2.83(m,2H),2.46–2.37(m,3H),1.95–1.82(m,4H),1.78–1.71(m,2H),1.66–1.55(m,2H),1.16(s,9H).
实施例20蛋白降解剂20的合成
合成方法参照实施例14,将1-1换成5,7-二羟基-4-甲基香豆素,1,3-二溴丙烷换成1,2-二溴乙烷,得到蛋白降解剂20(白色固体,收率42%)。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.70(s,1H),7.38(s,1H),6.72(s,1H),6.45(d,J=2.4Hz,1H),6.32(d,J=2.5Hz,1H),5.95–5.93(m,1H),4.11(t,J=5.7Hz,2H),4.05(s,2H),3.02–2.93(m,2H),2.69(t,J=5.7Hz,2H),2.52(s,3H),2.48–2.42(m,1H),2.11–2.01(m,2H),1.81–1.71(m,2H),1.68–1.55(m,2H),1.17(s,9H).
实施例21蛋白降解剂21的合成
合成方法参照实施例14,将1-1换成5,7-二羟基-4-甲基香豆素,1,3-二溴丙烷换成1,4-二溴丁烷,得到蛋白降解剂21(白色固体,收率37%)。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.71(s,1H),7.38(s,1H),6.72(s,1H),6.42(d,J=2.4Hz,1H),6.31(d,J=2.5Hz,1H),5.95–5.92(m,1H),4.05(s,2H),4.01(t,J=6.4Hz,2H),2.94–2.86(m,2H),2.49–2.40(m,1H),2.36–2.27(m,2H),1.94–1.83(m,2H),1.80–1.67(m,4H),1.66–1.51(m,4H),1.17(s,9H).
实施例22蛋白降解剂22的合成
合成方法参照实施例14,将1-1换成5,7-二羟基-4-甲基香豆素,1,3-二溴丙烷换成1,5-二溴戊烷,得到蛋白降解剂22(白色固体,收率39%)。1H NMR(400MHz,DMSO-d6)δ12.23(s,1H),10.70(s,1H),7.38(s,1H),6.72(s,1H),6.42(d,J=2.4Hz,1H),6.31(d,J=2.5Hz,1H),5.96–5.92(m,1H),4.05(s,2H),3.99(t,J=6.5Hz,2H),2.94–2.86(m,2H),2.48–2.40(m,1H),2.32–2.24(m,2H),1.93–1.82(m,2H),1.81–1.68(m,4H),1.66–1.54(m,2H),1.52–1.35(m,4H),1.18(s,9H).
实施例23蛋白降解剂23的合成
合成方法参照实施例14,将1-1换成5,7-二羟基-4-甲基香豆素,1,3-二溴丙烷换成2,2'-二溴二乙醚,得到蛋白降解剂23(白色固体,收率30%)。1H NMR(400MHz,DMSO-d6)δ12.23(s,1H),10.73(s,1H),7.38(s,1H),6.72(s,1H),6.45(d,J=2.5Hz,1H),6.32(d,J=2.5Hz,1H),5.96–5.93(m,1H),4.15–4.09(m,2H),4.05(s,2H),3.73(t,J=4.5Hz,2H),3.57(t,J=5.9Hz,2H),2.97–2.87(m,2H),2.47–2.38(m,1H),1.97(t,J=11.4Hz,2H),1.77–1.67(m,2H),1.65–1.52(m,2H),1.17(s,9H).
实施例24蛋白降解剂24的合成
第一步
将24-1(1.0g,2.23mmol),K2HPO4(1.2g,6.70mmol),X-Phos(212.9mg,0.45mmol),Pd2(dba)3(204.5mg,0.22mmol)置于三口瓶中,氮气保护,加入20ml 1,4-二氧六环,4ml水,然后加入24-2(702.6mg,2.68mmol),85℃搅拌过夜,TLC监测反应完全后,冷却至室温,加入40ml二氯甲烷,40ml水萃取,二氯甲烷层用饱和食盐水洗,无水硫酸钠干燥,硅胶柱层析,得到化合物24-3(306.0mg,白色固体,收率27%)。1H NMR(400MHz,DMSO-d6)δ9.08(s,1H),8.23(s,1H),7.97(s,1H),7.67(s,1H),7.46–7.39(m,1H),6.76(d,J=7.9Hz,1H),3.94(s,2H),3.48–3.38(m,1H),3.28–3.19(m,1H),2.88(s,2H),1.92–1.85(m,2H),1.82–1.76(m,2H),1.38(s,9H),1.27(s,6H),1.25–1.23(m,2H),1.23–1.21(m,2H).
第二步
将24-3(50mg,0.10mmol)溶于1ml二氯甲烷中,加入0.25ml 4M的盐酸二氧六环溶液,室温搅拌1h,旋干溶剂,得到24-4(46.3mg,白色固体,收率98%)。1H NMR(400MHz,DMSO-d6)δ9.19(s,1H),8.22(s,1H),8.01–7.94(m,4H),7.68(s,1H),7.56–7.51(m,1H),3.95(s,2H),3.52–3.42(m,1H),3.07–2.95(m,1H),2.88(s,2H),2.00–1.91(m,4H),1.49–1.37(m,2H),1.32–1.21(m,8H).
第三步
将3-1(1.0g,5.20mmol)溶于17ml DMF中,加入24-5(2.0g,10.41mmol),碳酸钾(1.4g,10.41mmol)室温搅拌6h,得到24-6(325.0mg,白色固体,收率20%)。1H NMR(400MHz,DMSO-d6)δ10.54(s,1H),6.34(d,J=2.3Hz,1H),6.26(d,J=2.4Hz,1H),5.86–5.85(m,1H),4.01(t,J=5.9Hz,2H),3.60(s,3H),2.49(d,J=1.2Hz,3H),2.41(t,J=7.1Hz,2H),1.84–1.76(m,2H),1.75–1.68(m,2H).
第四步
将24-6(325.0mg,1.06mmol)溶于2ml四氢呋喃,2ml水中,加入一水合氢氧化锂(68.4mg,1.63mmol),室温搅拌3h,旋干溶剂,加入4ml水,用冰醋酸调pH至4~5,大量白色固体析出,抽滤,得到24-7(132.2mg,白色固体,收率61%)。1H NMR(400MHz,DMSO-d6)δ6.34(d,J=2.3Hz,1H),6.31(d,J=2.2Hz,1H),5.94–5.92(m,1H),4.01(t,J=6.1Hz,2H),2.50(d,J=1.2Hz,3H),2.31(t,J=7.2Hz,2H),1.85–1.76(m,2H),1.73–1.63(m,2H).
第五步
将24-4(46.3mg,0.10mmol),24-7(28.4mg,0.10mmol),DIPEA(85μL,0.49mmol)溶于1ml二氯甲烷中,加入HATU(55.5mg,0.15mmol)室温搅拌1h,硅胶柱层析,得到蛋白降解剂24(12.9mg,白色固体,收率20%)。1H NMR(400MHz,DMSO-d6)δ10.55(s,1H),9.08(s,1H),8.23(s,1H),7.97(s,1H),7.75(d,J=7.7Hz,1H),7.68(s,1H),7.47–7.42(m,1H),6.34(d,J=2.2Hz,1H),6.31(d,J=2.1Hz,1H),5.95–5.93(m,1H),4.01(t,J=6.0Hz,2H),3.94(s,2H),3.58–3.51(m,1H),3.49–3.43(m,1H),2.88(s,2H),2.12(t,J=7.0Hz,2H),1.94–1.87(m,2H),1.82–1.73(m,4H),1.72–1.65(m,2H),1.29–1.22(m,10H).
实施例25蛋白降解剂25的合成
第一步
将25-1(2.0g,24.07mmol),25-2(4.0g,25.27mmol)溶于60ml冰醋酸中,回流3h冷却至室温,旋去溶剂,加入乙酸乙酯,抽滤,得到25-3(3.6g,白色固体,收率84%)。1H NMR(400MHz,DMSO-d6)δ12.23(s,1H),7.83(d,J=2.0Hz,1H),6.11(d,J=2.0Hz,1H),5.59(s,1H),2.57–2.49(m,2H),1.74–1.61(m,2H),0.92(t,J=7.3Hz,3H).
第二步
将25-3(3.6g,20.29mmol)溶于50ml乙腈中,滴加三氯氧磷(7.6ml,81.15mmol),随后加入吡啶(2.0ml,24.35mmol),DMAP(123.9mg,1.01mmol),回流3h,旋去溶剂,加入冰水,用乙酸乙酯萃取,无水硫酸钠干燥,硅胶柱层析,得到25-4(2.2g,无色油状,收率55%)。1HNMR(400MHz,Chloroform-d)δ8.17(d,J=2.2Hz,1H),6.86(s,1H),6.69(d,J=2.2Hz,1H),2.81(t,J=7.6,1.3Hz,2H),1.90–1.76(m,2H),1.05–0.98(m,3H).
第三步
将25-4(235mg,1.20mmol),25-5(250.0mg,1.25mmol)溶于4ml乙腈中,加入碳酸钾(332.0mg,2.40mmol),60℃搅拌3h,冷却,旋去乙腈,硅胶柱层析,得到25-6(342.9mg,白色固体,收率79%)。1H NMR(400MHz,Chloroform-d)δ7.95(d,J=2.2Hz,1H),6.41(d,J=2.3Hz,1H),6.22(d,J=6.8Hz,1H),5.80(s,1H),4.64–4.57(m,1H),4.23–4.10(m,2H),2.74–2.68(m,2H),2.43–2.21(m,2H),2.18–2.02(m,2H),1.86–1.67(m,3H),1.65–1.52(m,1H),1.47(s,9H),1.02(t,J=7.3Hz,3H).
第四步
将25-6(342.9mg,0.95mmol)溶于3ml二氯甲烷中,加入2.4ml 4M盐酸二氧六环溶液,TLC监测反应完全后,抽滤,得到25-7(227.8mg,白色固体,收率92%)。1H NMR(400MHz,DMSO-d6)δ9.96(d,J=8.3Hz,1H),8.51–8.38(m,3H),8.32(d,J=2.2Hz,1H),6.82(s,1H),6.57(d,J=2.2Hz,1H),4.90–4.77(m,1H),3.79–3.69(m,1H),2.83(t,J=7.6Hz,2H),2.29–2.13(m,4H),1.89–1.77(m,3H),1.76–1.64(m,1H),0.96(t,J=7.3Hz,3H).
第五步
将25-7(20mg,0.07mmol),24-7(19.8mg,0.07mmol),DIPEA(35μL,0.20mmol)溶于1ml二氯甲烷中,加入HATU(38.6mg,0.10mmol),室温搅拌1h,硅胶柱层析,得到蛋白降解剂25(13.1mg,白色固体,收率36%)。1H NMR(400MHz,Chloroform-d)δ7.93(d,J=2.3Hz,1H),6.97(d,J=7.1Hz,1H),6.42(d,J=2.1Hz,1H),6.39–6.35(m,2H),6.31(d,J=2.2Hz,1H),5.85(s,1H),5.81–5.79(m,1H),4.53–4.41(m,1H),4.28–4.17(m,1H),3.94–3.86(m,2H),3.74–3.59(m,2H),3.12(q,J=7.4Hz,2H),2.72–2.63(m,2H),2.48–2.44(m,3H),2.35–2.30(m,2H),2.17–2.12(m,2H),1.79–1.64(m,6H),0.96(t,J=7.3Hz,3H).
实施例26蛋白降解剂26的合成
合成方法参照实施例1,将3-溴-1-丙醇换成2-溴乙醇,得到蛋白降解剂26(白色固体,收率45%)。1H NMR(400MHz,Methanol-d4)δ7.48–7.42(m,3H),7.37–7.31(m,3H),6.69(s,1H),6.45(d,J=2.2Hz,1H),6.34(d,J=2.3Hz,1H),5.87(s,1H),4.00(s,2H),3.88(t,J=5.7Hz,2H),2.73–2.64(m,2H),2.45–2.35(m,1H),2.14(t,J=5.7Hz,2H),1.96–1.86(m,2H),1.81–1.66(m,4H),1.26(s,9H).
实施例27蛋白降解剂27的合成
合成方法参照实施例1,将3-溴-1-丙醇换成4-溴-1-丁醇,得到蛋白降解剂27(白色固体,收率22%)。1H NMR(400MHz,Chloroform-d)δ7.38–7.29(m,4H),7.25–7.20(m,2H),6.59(s,1H),6.23(d,J=2.0Hz,1H),6.16(d,J=2.2Hz,1H),5.86(s,1H),3.98(s,2H),3.67–3.58(m,2H),2.98–2.90(m,2H),2.53–2.42(m,1H),2.22–2.13(m,2H),2.12–1.97(m,2H),1.95–1.82(m,4H),1.24(s,9H),1.14–1.03(m,4H).
实施例28蛋白降解剂28的合成
合成方法参照实施例1,将3-溴-1-丙醇换成5-溴-1-戊醇,得到蛋白降解剂28(白色固体,收率15%)。1H NMR(400MHz,Methanol-d4)δ7.48–7.42(m,3H),7.37–7.32(m,3H),6.69(s,1H),6.43(d,J=2.2Hz,1H),6.29(d,J=2.3Hz,1H),5.85(s,1H),4.01(s,2H),3.74(t,J=5.8Hz,2H),3.28–3.21(m,2H),2.68–2.58(m,1H),2.57–2.41(m,4H),2.04–1.84(m,4H),1.46–1.35(m,2H),1.27(s,9H),1.24–1.17(m,2H),0.91–0.80(m,2H).
实施例29蛋白降解剂29的合成
合成方法参照实施例1,将3-溴-1-丙醇换成2-(2-溴乙氧基)乙醇,得到蛋白降解剂29(白色固体,收率33%)。1H NMR(400MHz,Methanol-d4)δ7.49–7.39(m,3H),7.37–7.30(m,3H),6.69(s,1H),6.43(d,J=2.2Hz,1H),6.31(d,J=2.3Hz,1H),5.86(s,1H),4.00(s,2H),3.85(t,J=4.6Hz,2H),3.10(t,J=4.5Hz,2H),3.06–2.99(m,2H),2.54(t,J=5.6Hz,2H),2.51–2.45(m,1H),2.23–2.12(m,2H),1.91–1.78(m,4H),1.26(s,9H).
实施例30蛋白降解剂30的合成
合成方法参照实施例14,将1,3-二溴丙烷换成1,2-二溴乙烷,得到蛋白降解剂30(白色固体,收率25%)。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.30(s,1H),7.44–7.31(m,6H),6.72(s,1H),6.56(d,J=2.4Hz,1H),6.21(d,J=2.5Hz,1H),5.85(s,1H),4.13(t,J=5.8Hz,2H),4.05(s,2H),3.02–2.93(m,2H),2.70(t,J=5.7Hz,2H),2.48–2.41(m,1H),2.06(t,J=11.4Hz,2H),1.82–1.72(m,2H),1.69–1.55(m,2H),1.18(s,9H).
实施例31蛋白降解剂31的合成
合成方法参照实施例14,将1,3-二溴丙烷换成1,4-二溴丁烷,得到蛋白降解剂31(白色固体,收率28%)。1H NMR(400MHz,DMSO-d6)δ12.23(s,1H),10.30(s,1H),7.42–7.31(m,6H),6.72(s,1H),6.53(d,J=2.4Hz,1H),6.20(d,J=2.5Hz,1H),5.84(s,1H),4.09–4.00(m,4H),2.97–2.85(m,2H),2.49–2.40(m,1H),2.36–2.27(m,2H),1.95–1.83(m,2H),1.79–1.67(m,4H),1.66–1.52(m,4H),1.17(s,9H).
实施例32蛋白降解剂32的合成
合成方法参照实施例14,将1,3-二溴丙烷换成1,5-二溴戊烷,得到蛋白降解剂32(白色固体,收率31%)。1H NMR(400MHz,DMSO-d6)δ12.23(s,1H),10.29(s,1H),7.43–7.31(m,6H),6.72(s,1H),6.53(d,J=2.4Hz,1H),6.20(d,J=2.4Hz,1H),5.84(s,1H),4.05(s,2H),4.02(t,J=6.5Hz,2H),2.99–2.82(m,2H),2.48–2.40(m,1H),2.35–2.22(m,2H),1.95–1.82(m,2H),1.80–1.66(m,4H),1.67–1.54(m,2H),1.54–1.34(m,4H),1.18(s,9H).
实施例33蛋白降解剂33的合成
合成方法参照实施例14,将1,3-二溴丙烷换成2,2'-二溴二乙醚,得到蛋白降解剂33(白色固体,收率39%)。1H NMR(400MHz,DMSO-d6)δ12.23(s,1H),10.31(s,1H),7.44–7.30(m,6H),6.72(s,1H),6.55(d,J=2.4Hz,1H),6.21(d,J=2.4Hz,1H),5.85(s,1H),4.18–4.12(m,2H),4.05(s,2H),3.76–3.69(m,2H),3.58(t,J=5.9Hz,2H),2.98–2.86(m,2H),2.48–2.38(m,1H),2.03–1.91(m,2H),1.78–1.69(m,2H),1.65–1.50(m,2H),1.17(s,9H).
实施例34蛋白降解剂34的合成
合成方法参照实施例4,将4-2换成三氟乙酰乙酸乙酯,3-溴-1-丙醇换成5-溴-1-戊醇,得到蛋白降解剂34(白色固体,收率20%)。1H NMR(400MHz,DMSO-d6)δ12.25(s,1H),7.38(s,1H),6.72(s,1H),6.60(s,1H),6.45–6.39(m,2H),4.13–3.99(m,4H),2.95–2.86(m,2H),2.50–2.39(m,1H),2.33–2.24(m,2H),1.89(t,J=11.4Hz,2H),1.81–1.70(m,4H),1.65–1.55(m,2H),1.52–1.38(m,4H),1.17(s,9H).
生物实验实施例
细胞IC50测定
在96孔板的每个孔中,用100μl新鲜培养基接种10000个细胞。与化合物孵育72小时后,每孔加入10μL Cell Counting Kit-8(CCK8)。37℃孵育2h后,用SpectraMAX190(Molecular Devices)在450nm处测量各孔的吸光度,用SoftMax Pro计算IC50值。
阳性对照化合物采用SNS-032和THAL-SNS-032,结构如下。
结果见表1。
表1对相关细胞株的抑制活性
注:带*化合物细胞IC50测定使用的是人淋巴瘤细胞WSU-DLCL2,其余化合物使用的是人淋巴瘤细胞U-2932。
Western Blot实验
适量人淋巴瘤细胞U-2932种板于6孔板,加药处理后离心收集细胞以备后续试验,根据细胞的量加入相应量的1X上样缓冲液,裂解后100℃煮样20min。吸取相同体积的样品,进行SDS-PAGE,电泳结束后,利用金斯瑞快转仪将凝胶上的蛋白质转移到硝酸纤维素膜上,根据蛋白的大小剪下相应的条带,用含有5%脱脂奶粉的TBST封闭1h,4℃孵育一抗过夜。用TBST洗脱多余一抗,每次十分钟共三次,在室温下孵育二抗1h,再用TBST洗脱多余二抗,每次十分钟共三次。最后利用Bio-Rad发色仪对条带进行发色和拍照。结果见图1和图3。图1中用不同化合物处理U-2932细胞24h后分析其中的CDK9和Mcl-1蛋白水平。图3中用100nM浓度的化合物10(A)和16(B)处理U-2932细胞24小时后WesternBlot检测,化合物可以降解其他CDK,比如CDK1,CDK4,CDK6。
Co-IP
加药处理的细胞离心收集后用适量含磷酸酶和蛋白酶抑制剂的NP-40裂解液在冰上裂解60min,12000g、4℃离心10min后取上清进行BCA定量,调齐后的样品分为IgG、IP两组孵相应的抗体4℃过夜,次日加入protein A/G magnetic beads孵育4h后用NP-40和PBS各洗三次后煮样进行Western Blot。如图2中在500nMBafA1存在的条件下,500nM浓度的化合物10和16处理U-2932细胞(A)和293T细胞(B)12小时,Co-IP实验证明化合物诱导CDK9和LC3B结合。
以上各实施例仅用以举例说明本发明的技术方案,而非对其限制。尽管参照前述各实施例对本发明进行了详细的说明,本领域的普通技术人员应当理解:在没有脱离本发明权利要求所限定的精神和实质的范围内,可以对前述各实施例所记载的技术方案进行修改,或者对其中部分或者全部技术特征进行等同替换;而这些修改或者替换仍然在本发明权利要求所限定的范围内。
Claims (10)
1.一种蛋白降解剂或其药学上可接受的盐,其包括:
至少一个可以与LC3结合的部分;以及,
至少一个可以与CDK结合的部分;
用于将所述可以与LC3结合的部分各自独立地与所述可以与CDK结合的部分共价连接的连接部分。
2.根据权利要求1所述的蛋白降解剂或其药学上可接受的盐,其中,所述可以与LC3结合的部分和所述可以与CDK结合的部分的分子量各自独立地为100-2000,优选为100-l000;
和/或
所述CDK包括CDK1,CDK2,CDK3,CDK4,CDK5,CDK6,CDK7,CDK8,CDK9,CDK10,CDK11,CDK12,CDK13,CDK14,CDK15,CDK16,CDK17,CDK18,CDK19,CDK20,CDK21及其所述CDK的所有亚型;
特别地,所述CDK为CDK9。
3.根据权利要求1所述的蛋白降解剂或其药学上可接受的盐,其中,所述可以与LC3结合的部分选自如下式⑴化合物,或其药学上可接受的盐、立体异构体、溶剂化物、多晶型、互变异构体、同位素化合物、代谢产物或前药,
其中:
Y为O或S;
R1和R2各自独立地选自H和Ra;
Ra在每次出现时各自独立地选自氢、C1-6烷基、卤代C1-6烷基、C3-6环烷基,3-7元杂环基、C6-10芳基、3-7元杂芳基、C1-6烷氧基、卤代C1-6烷氧基、氨基;杂环基或芳基任选地被一个或多个选自卤素、-NO2、-CN、C1-6烷基、-OH、-O(C1-6烷基)、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-COOH、-C(=O)O(C1-6烷基)、-C(=O)NH(C1-6烷基)、-C(=O)N(C1-6烷基)2、-OC(=O)(C1-6烷基)、-NHC(=O)(C1-6烷基)、-C(=O)(C1-6烷基)的取代基取代;
R3、R4、R5和R6各自独立地选自H和Rb;
Rb在每次出现时各自独立地选自卤素、-NO2、-CN、C1-6烷基、C2-6烯基、C2-6炔基、-OR7、-SR7、-NR7R8、-C(=O)OR7、-C(=O)NR7R8、-OC(=O)R7、-NC(=O)R7R8、-C(=O)R7、-S(=O)2OR7、-S(=O)2R7、-S(=O)2NR7R8、-OS(=O)2R7、-NS(=O)2R7R8、-S(=O)R7,其中所述烷基、烯基或炔基任选地被一个或多个选自卤素、-NO2、-CN、-OH、-O(C1-6烷基)、-O(C3-6环烷基)、-O(C1-4亚烷基-C3-6环烷基)、-O(3-7元杂环基)、-O(C1-4亚烷基)-(3-7元杂环基)、-SH、-S(C1-6烷基)、-S(C3-6环烷基)、-S(C1-4亚烷基-C3-6环烷基)、-S(3-7元杂环基)、-S(C1-4亚烷基)-(3-7元杂环基)、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-NH(C3-6环烷基)、-N(C3-6环烷基)2、-NH(C1-4亚烷基-C3-6环烷基)、-N(C1-4亚烷基-C3-6环烷基)2、NH(3-7元杂环基)、-N(3-7元杂环基)2、-NH(C1-4亚烷基-3-7元杂环基)、-N(C1-4亚烷基-3-7元杂环基)2、=O、-COOH和C1-6烷基的取代基取代;
R7和R8在每次出现时各自独立地选自H、C1-6烷基、C2-6烯基、C2-6炔基、C3-6环烷基、C3-6环烷基-C1-4烷基、3-7元杂环基、3-7元杂环基-C1-4烷基、C6-10芳基-C1-4烷基,其中所述烷基、烯基、炔基、环烷基、杂环基或芳基任选地被一个或多个选自卤素、-NO2、-CN、C1-6烷基、-OH、-O(C1-6烷基)、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-COOH、-C(=O)O(C1-6烷基)、-C(=O)NH(C1-6烷基)、-C(=O)N(C1-6烷基)2、-OC(=O)(C1-6烷基)、-NHC(=O)(C1-6烷基)、-C(=O)(C1-6烷基)的取代基取代;
其中,所述杂环基或杂芳基含有1-4个选自N、O和S中的杂原子;
和/或
所述可以与CDK结合的部分选自如下化合物:
和/或
所述连接部分是化学键或基团。
4.根据权利要求3所述的蛋白降解剂或其药学上可接受的盐,其中,式(1)化合物选自如下式II化合物:
其中,R3和R5各自独立地选自H和OH;
R2选自氢、C1-6烷基、卤代C1-6烷基、C6-10芳基、卤代C6-10芳基、氧代C6-10芳基、3-7元杂芳基;优选选自氢、C1-3烷基、卤代C1-3烷基、苯基、卤代苯基、氧代苯基、吡啶基;
优选地,式(1)化合物选自如下化合物:
和/或
所述连接部分选自包含1-30个碳原子的直链或支链或环状结构,其中的每个碳原子可以任选地被一个或多个杂原子、-C(=O)-、-C(=S)-、-S(=O)-、-SO2-及具有0到4个杂原子的3到6元环代替;其中杂原子选自氧、硫、氮、磷。
5.根据权利要求1-4任一项所述的蛋白降解剂或其药学上可接受的盐,其中
连接部分选自如下结构:
6.根据权利要求4所述的蛋白降解剂或其药学上可接受的盐,其中,蛋白降解剂选自如下I-1~I-6中的任一结构:
其中,n为1、2、3、4、5或6;m为1、2或3;
R2、R3和R5的定义同式II。
7.一种蛋白降解剂或其药学上可接受的盐,其中,所述蛋白降解剂选自如下结构:
8.如权利要求1-7中任一项所述的蛋白降解剂的制备方法,所述方法包括:通过共价连接将可以与LC3结合的部分与可以与CDK结合的部分连接起来的步骤。
9.一种药物组合物,其包含:选自权利要求1-7中任一项所述的蛋白降解剂或其药学上可接受的盐中的一种或多种,以及任选存在的药学上可接受的载体。
10.如权利要求1-7中任一项所述的蛋白降解剂或其药学上可接受的盐在制备用于治疗、预防或改善CDK相关疾病或病症的药物中的应用。
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