CN116143779A - 一种造血祖细胞激酶1抑制剂的化合物及其制备方法和应用 - Google Patents
一种造血祖细胞激酶1抑制剂的化合物及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种造血祖细胞激酶1(HPK1)抑制剂的化合物及其制备方法和应用。具体的,本发明提供了一种如式I所示的化合物,其中,各基团的定义如说明书中所述。所述的化合物具有优异的HPK1抑制活性,因此可以用于治疗癌症及其他HPK活性相关疾病的药物组合物。
Description
技术领域
本发明涉及一种激酶抑制剂及其制备方法和应用,尤其涉及一种用作造血祖细胞激酶1(HPK1)抑制剂的化合物及其制备方法和应用。
背景技术
手术切除、放疗、化疗、小分子靶向药物是用于治疗癌症的主要方式,遗憾的是,对于很多形式的癌症或肿瘤,手术切除往往不是可行的选择,而放疗和化疗在杀死肿瘤细胞的同时,也会损害健康的细胞。此外,肿瘤细胞基因组的不稳定性促进了肿瘤细胞的突变,进一步导致癌症基因组的快速变化,使其对特异靶向肿瘤的药物产生耐药性,这让癌症的治疗困难重重。近几年来通过癌症患者自身的免疫系统来杀死肿瘤细胞,并且提高机体抗肿瘤免疫力是一种癌症治疗的新型策略。其中一种方法是抑制维持外周耐受功能的免疫应答的负调节因子,使肿瘤被识别为非己抗原,进而克服肿瘤细胞的免疫逃逸。造血祖细胞激酶(HPK1)是丝裂酶原激活蛋白激酶(MAP4K)家族成员之一,该家族成员还包括GCK/MAP4K2、GLK/MAP4K3、HGK/MAP4K4、KHS/MAP4K5、MINK/MAP4K6。HPK1是B细胞、T细胞、树突状细胞活化反应的负调节因子,抑制其表达可以针对性的提高机体抗肿瘤免疫力,其主要表达在造血细胞中,如T细胞、B细胞、树突状细胞、巨噬细胞、肥大细胞、嗜中性粒细胞。在T细胞中,HPK1通过TCR信号通路调控T细胞激活方面的作用。TCR活化之后,HPK1与T细胞受体蛋白相互作用,被酪氨酸激酶Zap70和Lck磷酸化,同时会磷酸化SLP-76受体蛋白,负调节TCR信号,从而抑制T细胞激活和增殖。研究发现HPK1可以参与许多信号级联反应,包括MAKP信号通路、Fas诱导的细胞凋亡通路及NF-κB信号通路。而且,HPK1还能抑制AP-1,AP-1在肿瘤形成和发展中促进细胞的增殖、抑制分化、促进肿瘤细胞侵袭与转移等方面发挥作用。HPK1激酶在主要器官中不表达,这暗示着HPK1激酶抑制剂可能并不会引起任何严重的并发症。
目前针对造血祖细胞激酶(HPK1)靶点尚未有上市药物。
发明内容
发明目的:本发明旨在提供一种具有选择性和高活性的用作造血祖细胞激酶1抑制剂的化合物;本发明的另一目的是提供一种用作造血祖细胞激酶1抑制剂的化合物的制备方法;本发明的另一目的是提供用作造血祖细胞激酶1抑制剂的化合物在制备用于预防或治疗在受试者中对HPK1活性的抑制有反应的疾病中药物组合物中的应用。
技术方案:本发明的一种如下式I所示的化合物,或其药学上可接受的盐、异构体或水合物:
其中:
X为C或N;且当所述的X为C时,可被R取代,即所述的R位于X上(为CR);
R为H或卤素;
R1和R2各自独立的选自下组:H、氘、卤素、OH、CN、NO2、C1-6氘代烷基、C1-6烷基、C3-8环烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C6-10芳基、P(O)RaRb、S(O)2Ra、S(O)2NRaRb、NRaRb、C(O)NRaRb、C(O)NRaS(O)2Rb、NRaS(O)2Rb、C(O)Ra、NRaC(O)Rb、具有1-3个选自下组N、S、O的杂原子的5-12元杂芳基、具有1-3个选自下组N、S、O的杂原子的3-12元杂环基,其中由R1和R2代表的基团中的烷基、烯基、炔基、烷氧基、苯基、杂芳基、环烷基或杂环基可被1-3个分别独立选自下组中的取代基取代:卤素、OH、CN、NO2、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、NRaRb、C(=O)NRaRb、C(=O)NRaS(=O)2Rb、P(=O)RaRb、S(=O)2Ra、S(=O)2NRaRb、NRaS(=O)2Rb;当R1或R2各自所在的芳环被多个R1或R2所取代时,处于邻位的两个R1或R2可形成C3-8环烷基、具有1-3个选自下组N、S、O的杂原子的5-12元杂芳基、具有1-3个选自下组N、S、O的杂原子的3-12元杂环基。
Ra、Rb各自独立为H或C1-6烷基、C1-6氘代烷基、C3-8环烷基、具有1-3个选自下组N、S和O的杂原子的C3-12杂环基,其中由R6或R7代表的烷基、环烷基、杂环基可被1-3个分别独立选自下组中的取代基取代:卤素、OH、CN、NO2、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C3-8环烷基,C3-12杂环基。Ra及Rb与其所连接的同一个氮原子或磷原子可共同形成C3-12杂环基,可被1-3个分别独立选自下组中的取代基取代:卤素、OH、CN、NO2、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷基、C1-6卤代烷氧基、C3-8环烷基、C3-12杂环基;
p、q各自独立的为0、1、2、3、4或5;
进一步地,所述的式I化合物具有如下式所示的任一结构:
其中:
X为C或N;且当所述的X为C时,可被R取代,即所述的R位于X上(为CR);
R为H或卤素;
R1和R2各自独立的选自下组:H、氘、卤素、OH、CN、NO2、C1-6氘代烷基、C1-6烷基、C3-8环烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C6-10芳基、P(O)RaRb、S(O)2Ra、S(O)2NRaRb、NRaRb、C(O)NRaRb、C(O)NRaS(O)2Rb、NRaS(O)2Rb、C(O)Ra、NRaC(O)Rb、具有1-3个选自下组N、S、O的杂原子的5-12元杂芳基、具有1-3个选自下组N、S、O的杂原子的3-12元杂环基,其中由R1和R2代表的基团中的烷基、烯基、炔基、烷氧基、苯基、杂芳基、环烷基或杂环基可被1-3个分别独立选自下组中的取代基取代:卤素、OH、CN、NO2、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、NRaRb、C(=O)NRaRb、C(=O)NRaS(=O)2Rb、P(=O)RaRb、S(=O)2Ra、S(=O)2NRaRb、NRaS(=O)2Rb;当R1或R2各自所在的芳环被多个R1或R2所取代时,处于邻位的两个R1或R2可形成C3-8环烷基、具有1-3个选自下组N、S、O的杂原子的5-12元杂芳基、具有1-3个选自下组N、S、O的杂原子的3-12元杂环基。
Ra、Rb各自独立为H或C1-6烷基、C1-6氘代烷基、C3-8环烷基、具有1-3个选自下组N、S和O的杂原子的C3-12杂环基,其中由R6或R7代表的烷基、环烷基、杂环基可被1-3个分别独立选自下组中的取代基取代:卤素、OH、CN、NO2、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C3-8环烷基,C3-12杂环基。Ra及Rb与其所连接的同一个氮原子或磷原子可共同形成C3-12杂环基,可被1-3个分别独立选自下组中的取代基取代:卤素、OH、CN、NO2、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷基、C1-6卤代烷氧基、C3-8环烷基、C3-12杂环基;
p、q各自独立的为0、1、2、3、4或5;
进一步地,所述的式I化合物具有如下式所示的任一结构:
合成方案为:
步骤IV:化合物A-3在强碱NaOH作用下,脱去Ts保护基团,得到A-4(即式I化合物)。
另一方面,本发明提供一种药物组合物,其包含治疗有效量的一种或多种上述的化合物、其药学上可接受的盐、异构体或水合物,以及药学上可接受的赋形剂。
另一方面,本发明提供一种上述的化合物,或其药学上可接受的盐、异构体或水合物在制备预防或治疗在受试者中对HPK1活性的抑制有反应的疾病的药物组合物中的应用。
上述化合物,或其药学上可接受的盐、异构体或水合物与其他肿瘤免疫治疗剂的联合使用方案,所述的其他肿瘤免疫抑制剂选自下组:小分子化合物及抗体(包括但不限于PD-1、PD-L1、CTLA-4、STING激动剂、LAG3拮抗剂等)、肿瘤靶向药、肿瘤疫苗、放疗方案。
上述化合物及其药学上可接受的盐、立体异构体、前药、溶剂化物、酯和氘代化合物与CAR-T免疫治疗相结合在癌症免疫治疗中的应用。
进一步地,所述疾病为癌症。
另一方面,本发明提供一种上述的化合物,或其药学上可接受的盐、异构体或水合物在HPK1激酶抑制剂中的应用。
由于本发明化合物具有非常好的HPK1激酶的抑制活性,所以本发明化合物及其各种晶型,药学上可接受的有机或无机盐,溶剂合物或水合物,以及含本发明化合物为主要活性成分的药物组合物可用于预防和/或治疗与HPK1激酶活性或表达量相关的疾病等(例如,癌症)。
本发明的药物组合物包括安全有效量范围内的本发明化合物及药学上可以接受的载体或赋形剂。其中“安全有效量”是指:化合物的量足以明显改善病情,而不至于产生严重的副作用。通常,药物组合物含有1-2000mg本发明化合物/剂,更好地,含有10-200mg本发明化合物/剂。较佳地,所述的“一剂”为一个胶囊或药片。
“药学上可接受的载体”是指:一种或多种相容性液体或固体填料或凝胶物质,它们适合于人使用,且必须有足够的纯度和足够低的毒性。“相容性”在此处指的是组合物中各组份能和本发明化合物以及它们之间相互掺和,且不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如乙基纤维素钠、羧甲基纤维素钠、纤维素乙酸酯等)、明胶、滑石、硫酸钙、固体润滑剂(如硬脂酸﹑硬脂酸镁)﹑植物油(如豆油、芝麻油、花生油、橄榄油等)﹑着色剂、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)﹑乳化剂(如吐温R、润湿剂(如十二烷基硫酸钠)﹑调味剂、防腐剂、稳定剂、抗氧化剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、肠胃外(静脉内、肌肉内或皮下)。
用于口服给药的固体剂型包括胶囊剂、丸剂、片剂、散剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如磷酸二钙或柠檬酸钠,或与下述成分混合:(a)填料或增容剂,例如:乳糖、蔗糖、淀粉、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如:羟甲基纤维素、明胶、藻酸盐、聚乙烯基吡咯烷酮、阿拉伯胶和蔗糖;(c)保湿剂,例如:甘油;(d)崩解剂,例如:碳酸钙、琼脂、马铃薯淀粉或木薯淀粉﹑藻酸、某些复合硅酸盐、和碳酸钠;(e)缓溶剂,例如石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如:高岭土;(i)润滑剂,例如,滑石、固体聚乙二醇、硬脂酸钙、硬脂酸镁、十二烷基硫酸钠或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
固体剂型如片剂、胶囊剂、糖丸、丸剂和颗粒剂可采用壳材和包衣制备,如肠衣和其它本领域公知的材料。它们可以包含不透明剂,并且,这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、悬浮液、溶液、糖浆或酊剂。除了活性化合物以外,液体剂型可以包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知:乙醇、异丙醇、丙二醇、乙酸乙酯、碳酸乙酯、1,3-丁二醇、二甲基甲酰胺以及油,特别是花生油、棉籽油、玉米胚油、橄榄油﹑芝麻油和蓖麻油或这些物质的混合物等。
除了这些惰性稀释剂外,组合物也可包含助剂,如乳化剂、润湿剂和悬浮剂、矫味剂、甜味剂和香料。
除了活性化合物以外,悬浮液可包含悬浮剂,例如:聚氧乙烯山梨醇和脱水山梨醇酯、乙氧基化异十八烷醇、微晶纤维素、琼脂和甲醇铝或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或分散液、无水溶液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和稀释剂、非水载体、溶剂或赋形剂包括水、多元醇、乙醇及其适宜的混合物。
本发明化合物可单独给药,或与其他药学上可接受的化合物联合给药。
联合给药时,所述药物组合物还包含与一种或多种其他药学上可接受的化合物。其他药学上可接受的化合物中的一种或多种可以与本发明的化合物同时、分开或顺序地给药。
使用药物组合物时,是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人),其中施用时剂量为药学上认为的有效给药量,对于60kg体重的人来说,日给药剂量通常是1~2000mg,优选20~500mg。当然,具体剂量还应考虑病人健康状况、给药途径等因素,这些都是熟练医师技能范围之内的。
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。
有益效果:与现有技术相比,本发明具有如下显著优点:具有优异的HPK1抑制活性,可以用于制备治疗癌症及其他HPK活性相关疾病的药物组合物。
具体实施方式
本发明提供了一种如下式I所示的化合物:
其中:
X为C或N;且当所述的X为C时,可被R取代,即所述的R位于X上(为CR);
R为H或卤素;
R1和R2各自独立的选自下组:H、氘、卤素、OH、CN、NO2、C1-6氘代烷基、C1-6烷基、C3-8环烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C6-10芳基、P(O)RaRb、S(O)2Ra、S(O)2NRaRb、NRaRb、C(O)NRaRb、C(O)NRaS(O)2Rb、NRaS(O)2Rb、C(O)Ra、NRaC(O)Rb、具有1-3个选自下组N、S、O的杂原子的5-12元杂芳基、具有1-3个选自下组N、S、O的杂原子的3-12元杂环基,其中由R1和R2代表的基团中的烷基、烯基、炔基、烷氧基、苯基、杂芳基、环烷基或杂环基可被1-3个分别独立选自下组中的取代基取代:卤素、OH、CN、NO2、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、NRaRb、C(=O)NRaRb、C(=O)NRaS(=O)2Rb、P(=O)RaRb、S(=O)2Ra、S(=O)2NRaRb、NRaS(=O)2Rb;当R1或R2各自所在的芳环被多个R1或R2所取代时,处于邻位的两个R1或R2可形成C3-8环烷基、具有1-3个选自下组N、S、O的杂原子的5-12元杂芳基、具有1-3个选自下组N、S、O的杂原子的3-12元杂环基。
Ra、Rb各自独立为H或C1-6烷基、C1-6氘代烷基、C3-8环烷基、具有1-3个选自下组N、S和O的杂原子的C3-12杂环基,其中由R6或R7代表的烷基、环烷基、杂环基可被1-3个分别独立选自下组中的取代基取代:卤素、OH、CN、NO2、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C3-8环烷基,C3-12杂环基。Ra及Rb与其所连接的同一个氮原子或磷原子可共同形成C3-12杂环基,可被1-3个分别独立选自下组中的取代基取代:卤素、OH、CN、NO2、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷基、C1-6卤代烷氧基、C3-8环烷基、C3-12杂环基;
p、q各自独立的为0、1、2、3、4或5;
所述的式I化合物中,各个手性中心为R构型或S构型。
优选地,所述的X、M1、M2、M3、M4、M5、R、R1、R2、Ra、Rb、p、q,各自独立地为各个实施例中具体化合物中的对应基团。
本发明的化合物可以作为HPK1激酶抑制剂,在优选的实施例中,为HPK1激酶选择性抑制剂。
式I化合物的制备
本发明式I的化合物可以通过以下示例性的方法制备:
步骤IV:化合物A-3在强碱NaOH作用下,脱去Ts保护基团,得到A-4(即式I化合物)。
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。
关键中间体1.5-溴-3-碘-1-(对甲苯基磺酰基)吡咯并[2,3-b]吡啶的制备
在25℃,向5-溴-3-碘-1H-吡咯并[2,3-b]吡啶(7.3g,22.61mmol)的四氢呋喃(140mL)溶液中加入NaH(1.36g,33.91mmol)。将混合物在25℃搅拌0.5小时。然后,加入对甲苯磺酰氯(4.74g,24.87mmol),并在25℃搅拌过夜。反应结束后用饱和NaHCO3(100mL)稀释,并用乙酸乙酯(3×250mL)萃取。合并的萃取物用盐水(3×100mL)洗涤,用Na2SO4干燥,过滤并减压浓缩,得5-溴-3-碘-1-(对甲苯基磺酰基)吡咯并[2,3-b]吡啶(10.3g,19.37mmol,86%),为黄色固体。MS(ESI):M/Z=478[M+H]+。
关键中间体2.5-溴-4-氯-3-碘-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶的制备
步骤同关键中间体1的操作过程,制备得到5-溴-4-氯-3-碘-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶。MS(ESI):M/Z=512[M+H]+。
关键中间体3.2-溴-7-碘-5-甲苯磺酰基-5H-吡咯并[2,3-b]吡嗪的制备
步骤同关键中间体1的操作过程,制备得到2-溴-7-碘-5-甲苯磺酰基-5H-吡咯并[2,3-b]吡嗪。MS(ESI):M/Z=479[M+H]+。
关键中间体4.6-氨基-2-氟-N,N-二甲基-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯甲酰胺的制备
步骤一:向6-氨基-3-溴-2-氟苯甲酸(1.17g,5mmol)的无水二氯甲烷(20mL)悬浮液中依次加入三乙胺(557mg,5.5mmol),HATU(1.7g,5.5mmol),并将混合物搅拌5分钟,然后在0℃中加入二甲胺(2M,在四氢呋喃中,5.0mL)。将混合物在室温搅拌3小时,然后用1M氢氧化钠和盐水洗涤。将水相用二氯甲烷再萃取两次。将合并的有机相,无水硫酸钠干燥。抽滤后减压旋干,得6-氨基-3-溴-2-氟-N,N-二甲基苯甲酰胺,无需进一步提纯。MS(ESI):M/Z=183[M+H]+。
步骤二:将6-氨基-3-溴-2-氟-N,N-二甲基苯甲酰胺(2.95g,11.3mmol),联硼酸频那醇酯(5.74g,22.6mmol),Pd(dppf)Cl2(922.8mg,1.13mmol),AcOK(3.33g,33.9mmol)添加至含有二氧六环(25ml)的反应瓶中,氮气保护下于85℃反应3h。将冷却的混合物通过硅藻土(Celite)过滤,用乙酸乙酯彻底洗涤,并将滤液蒸发至小体积。将残余物溶于乙酸乙酯和水中,再次通过硅藻土,并分离各相。用乙酸乙酯萃取水相3次。有机相减压浓缩。残余物在二氧化硅上进行色谱分离,用50-100%乙酸乙酯/石油醚洗脱,得到6-氨基-2-氟-N,N-二甲基-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯甲酰胺1.81g。MS(ESI):M/Z=309[M+H]+。关键中间体5.2-氨基-N,N-二甲基-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯甲酰胺的制备
步骤一、二:同关键中间体4的操作过程,制备得到2-氨基-N,N-二甲基-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯甲酰胺。MS(ESI):M/Z=291[M+H]+。
关键中间体6:N,N-二甲基-2-(4-甲基哌嗪-1-基)-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯甲酰胺的制备
步骤一:同关键中间体4步骤一的操作过程,制备得到5-溴-2-碘-N,N-二甲基苯甲酰胺。MS(ESI):M/Z=354[M+H]+。
步骤二:将上一步所得的5-溴-2-碘-N,N-二甲基苯甲酰胺(353mg,1mmol)溶于二氧六环(4ml)中,添加N-甲基哌嗪(101mmol,1mmol)、Pd2(dba)3(91.6mg,0.1mmol)、Xantphos(115.7mg,0.2mmol)、碳酸铯(977mg,3mmol),氮气保护下于110℃回流反应24h,冷却至室温,硅藻土抽滤,滤液减压旋干,柱层析纯化得5-溴-N,N-二甲基-2-(4-甲基哌嗪-1-基)苯甲酰胺(130mg)。MS(ESI):M/Z=327[M+H]+。
步骤三:同关键中间体4步骤二的操作过程,制备得到N,N-二甲基-2-(4-甲基哌嗪-1-基)-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯甲酰胺。MS(ESI):M/Z=374[M+H]+。关键中间体7.2-甲基-7-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1,2,3,4-四氢异喹啉的制备
同关键中间体4步骤二的操作过程,最终制备得到2-甲基-7-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1,2,3,4-四氢异喹啉。MS(ESI):M/Z=274[M+H]+。
关键中间体8.5-甲氧基-2-甲基-7-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1,2,3,4-四氢异喹啉的制备
同关键中间体4步骤二的操作过程,制备得到5-甲氧基-2-甲基-7-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1,2,3,4-四氢异喹啉。MS(ESI):M/Z=304[M+H]+。
关键中间体9.4-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)吗啉的制备
同关键中间体4步骤二的操作过程,制备得到4-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)吗啉。MS(ESI):M/Z=290[M+H]+。
关键中间体10.1-甲基-4-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)哌嗪的制备
同关键中间体4步骤二的操作过程,制备得到得到1-甲基-4-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)哌嗪。MS(ESI):M/Z=303[M+H]+。
关键中间体11.2,6-二氟-N,N-二甲基-3-硝基苯甲酰胺的制备
步骤一:同关键中间体4步骤一的操作过程,制备得到2,6-二氟-N,N-二甲基-3-硝基苯甲酰胺。MS(ESI):M/Z=231[M+H]+。
步骤二:将上一步得到的2,6-二氟-N,N-二甲基-3-硝基苯甲酰胺(2.31g,10mmol)、N-甲基哌嗪(900mg,9mmol)、TEA(2.7g,27mmol)添加至DMSO(20mL)中并于100℃下搅拌2小时,并冷却至室温。将反应用水(50mL)稀释,并用乙酸乙酯(3x50mL)萃取。合并的有机层用盐水(2x50mL)洗涤,经无水硫酸钠干燥,并真空浓缩。残余物通过硅胶柱纯化得目标化合物2-氟-N,N-二甲基-6-(4-甲基哌嗪-1-基)-3-硝基苯甲酰胺(2.2g,78.8%)。MS(ESI):M/Z=311[M+H]+。
步骤三:向40-mL圆底烧瓶中放入将上一步得到的2-氟-N,N-二甲基-6-(4-甲基哌嗪-1-基)-3-硝基苯甲酰胺(2.2g,7.1mmol)、Fe(2g,35.5mmol)、10滴浓盐酸和EtOH(20mL)/H2O(4mL)。将所得溶液在60℃下搅拌4小时,并冷却至室温。用硅藻土抽滤,用饱和碳酸氢钠(50mL)稀释,并用乙酸乙酯(3x60mL)萃取。将合并的有机层干燥并真空浓缩。残余物通过硅胶柱纯化得目标化合物3-氨基-2-氟-N,N-二甲基-6-(4-甲基哌嗪-1-基)苯甲酰胺(1.8g,90.4%)。MS(ESI):M/Z=281[M+H]+。
步骤四:向40-mL圆底烧瓶中放入CuBr2(1.31g,5.85mmol)、亚硝酸正丁酯(482mg,4.68mmol)和ACN(20mL)。将所得溶液在0℃下搅拌5分钟,并在0℃下用3-氨基-2-氟-N,N-二甲基-6-(4-甲基哌嗪-1-基)苯甲酰胺(655mg,2.34mmol)的ACN(5mL)溶液逐滴处理。将所得溶液在50℃下搅拌1小时。将反应混合物冷却至室温,并用水(50mL)稀释。用乙酸乙酯(3x50mL)萃取所得溶液。将合并的有机层干燥并真空浓缩。残余物通过硅胶柱纯化得目标化合物(201mg,35.2%)。MS(ESI):M/Z=345[M+H]+。
步骤五:同关键中间体4步骤二的操作过程,制备得到2-氟-N,N-二甲基-6-(4-甲基哌嗪-1-基)-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯甲酰胺。MS(ESI):M/Z=392[M+H]+。实施例1.6-氨基-2-氟-N,N-二甲基-3-(3-(吡啶-3-基)-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-5-基)苯甲酰胺的制备
步骤一:在室温下,将关键中间体1(954mg,2mmol),吡啶-3-硼酸(135.2mg,1.1mmol),Pd(dppf)Cl2(146.2mg,0.2mmol),碳酸钠(318mg,3mmol)加入到1,4-二氧六环(7mL)和水(1mL)中,然后N2保护条件下,80℃反应3h,停止反应。将反应液用硅藻土过滤,向反应液中加入20mL H2O和20mL EA,然后再用EA萃取三次,合并有机相,饱和氯化钠洗涤,柱层析分离得到白色固体状目标化合物5-溴-3-(吡啶-3-基)-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶(390mg,45.5%)。MS(ESI):M/Z=429[M+H]+。
步骤二:在室温下,将上一步所得化合物5-溴-3-(吡啶-3-基)-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶(214mg,0.5mmol),关键中间体4(169mg,0.55mmol),Pd(dppf)Cl2(73mg,0.1mmol),碳酸钠(159mg,1.5mmol)加入到1,4-二氧六环(7mL)和水(1mL)中,然后N2保护条件下,80℃反应3h,停止反应。将反应液用硅藻土过滤,向反应液中加入20mL H2O和20mL DCM,然后再用DCM萃取三次,合并有机相,饱和氯化钠洗涤,柱层析分离得到白色固体状目标化合物6-氨基-2-氟-N,N-二甲基-3-(3-(吡啶-3-基)-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-5-基)苯甲酰胺(120mg,45.5%)。MS(ESI):M/Z=530[M+H]+。
步骤三:将上一步所得的6-氨基-2-氟-N,N-二甲基-3-(3-(吡啶-3-基)-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-5-基)苯甲酰胺(100mg,0.189mmol)溶于丙酮(4ml)、甲醇(4ml)的混合溶液中,添加氢氧化钠的水溶液(2M,3ml),于60℃反应5h,冷却至室温,向反应液中加入20mL H2O和20mL DCM,然后再用DCM萃取三次,合并有机相,饱和氯化钠洗涤,柱层析分离得到白色固体状目标化合物6-氨基-2-氟-N,N-二甲基-3-(3-(吡啶-3-基)-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-5-基)苯甲酰胺(36mg,50.8%)。MS(ESI):M/Z=376[M+H]+。1HNMR(400MHz,DMSO-d6)δ8.87(t,J=1.9Hz,1H),8.73(dd,J=1.5,2.0Hz,1H),8.63(dt,J=1.8,4.7Hz,1H),8.21(dd,J=1.5,2.1Hz,1H),7.96(dt,J=1.9,8.3Hz,1H),7.57(dd,J=5.0,8.3Hz,1H),7.44(dd,J=4.8,8.3Hz,1H),7.14(d,J=2.6Hz,1H),6.75(d,J=8.4Hz,1H),6.05(s,2H),3.01(s,6H).
对比例
采用专利CN201980038718.0中记载的化合物作为对比例,挑选的化合物如下:
制备酶活测试缓冲液包含40mM Tris,pH7.5;20mM MgC12;0.1mg/ml BSA;50uMDTT。化合物用纯DMSO溶解,母液浓度为10mM。化合物DMSO溶液从100uM起,连续做三倍梯度稀释,共计11个浓度,稀释的化合物用酶活测试缓冲液以1:20稀释好,取1ul加入工作孔,每个浓度两复孔。阴性对照孔和阳性对照孔都加入1ul以1:20稀释的DMSO溶液。制备2.5×底物/ATP工作液为包含45uM ATP的酶活测试缓冲液和0.25ug/ul MBP蛋白,每个工作孔中加入2.5×底物/ATP工作液2ul。制备2.5×酶反应工作液为包含0.5ng/ul HPK1重组蛋白(Signalchem,货号M23-11G-10)的酶活测试缓冲液,每个工作孔中加入2.5×酶反应工作液2ul,阴性对照孔仅加入酶活测试缓冲液2ul。贴好封板膜并离心,将其置于室温反应30分钟,反应结束后每孔加入ADP-Glo试剂(Promega,货号V1901)5ul于室温继续反应40分钟,加入激酶检测试剂(Promega,货号V1901)10ul于室温反应20分钟后测定最终发光信号。
分别计算阳性孔和阴性孔平均值,作为阳性对照值(Signalpos)和阴性对照值(Signalneg)。将工作孔信号值(Signaltest)按照公式Inhibition rate=(Signalpos-Signaltest)/(Signalpos-Signalneg)×100%计算其抑制率。计算出的抑制率在GraphPadPrism软件中按非线性拟合绘制浓度-抑制率曲线,并计算IC50值。
生物活性测试例2GLK ADP-Glo酶学活性测试
制备酶活测试缓冲液包含40mM Tris,pH7.5;20mM MgC12;0.1mg/ml BSA;50uMDTT。化合物用纯DMSO溶解,母液浓度为10mM。化合物DMSO溶液从100uM起,连续做三倍梯度稀释,共计11个浓度,稀释的化合物用酶活测试缓冲液以1:20稀释好,取1ul加入工作孔,每个浓度两复孔。阴性对照孔和阳性对照孔都加入1ul以1:20稀释的DMSO溶液。制备2.5×底物/ATP工作液为包含105uM ATP的酶活测试缓冲液和0.5ug/ul PKA底物多肽,每个工作孔中加入2.5×底物/ATP工作液2ul。制备2.5×酶反应工作液包含2.5ng/ul GLK重组蛋白(Signalchem,货号M25-11G-10)的酶活测试缓冲液,每个工作孔中加入2.5×酶反应工作液2ul,阴性对照孔只加入酶活测试缓冲液2ul。贴好封板膜并离心,将其置于室温反应1小时,反应结束后每孔加入ADP-Glo试剂(Promega,货号V1901)5ul于室温反应40分钟,随后加入激酶检测试剂(Promega,货号V1901)10ul于室温反应20分钟,测定最终发光信号。
分别计算阳性孔和阴性孔平均值,作为阳性对照值(Signalpos)和阴性对照值(Signalneg)。将工作孔信号值(Signaltest)按照公式Inhibition rate=(Signalpos-Signaltest)/(Signalpos-Signalneg)×100%计算其抑制率。计算出的抑制率在GraphPadPrism软件中按非线性拟合绘制浓度-抑制率曲线,并计算IC50值。实验结果见下表:
表1 HPK1、GLK酶活测试实验结果
其中,A表示IC50值≤50nM;B表示50nM≤IC50值≤500nM;C表示500nM≤IC50值≤10uM。
Claims (10)
1.一种如下式I所示的化合物,或其药学上可接受的盐、异构体或水合物;
其中:
X为C或N;且当所述的X为C时,可被R取代,即所述的R位于X上(为CR);
R为H或卤素;
R1和R2各自独立的选自下组:H、氘、卤素、OH、CN、NO2、C1-6氘代烷基、C1-6烷基、C3-8环烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C6-10芳基、P(O)RaRb、S(O)2Ra、S(O)2NRaRb、NRaRb、C(O)NRaRb、C(O)NRaS(O)2Rb、NRaS(O)2Rb、C(O)Ra、NRaC(O)Rb、具有1-3个选自下组N、S、O的杂原子的5-12元杂芳基、具有1-3个选自下组N、S、O的杂原子的3-12元杂环基,其中由R1和R2代表的基团中的烷基、烯基、炔基、烷氧基、苯基、杂芳基、环烷基或杂环基可被1-3个分别独立选自下组中的取代基取代:卤素、OH、CN、NO2、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、NRaRb、C(=O)NRaRb、C(=O)NRaS(=O)2Rb、P(=O)RaRb、S(=O)2Ra、S(=O)2NRaRb、NRaS(=O)2Rb;当R1或R2各自所在的芳环被多个R1或R2所取代时,处于邻位的两个R1或R2可形成C3-8环烷基、具有1-3个选自下组N、S、O的杂原子的5-12元杂芳基、具有1-3个选自下组N、S、O的杂原子的3-12元杂环基;
Ra、Rb各自独立为H或C1-6烷基、C1-6氘代烷基、C3-8环烷基、具有1-3个选自下组N、S和O的杂原子的C3-12杂环基,其中由R6或R7代表的烷基、环烷基、杂环基可被1-3个分别独立选自下组中的取代基取代:卤素、OH、CN、NO2、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C3-8环烷基,C3-12杂环基;Ra及Rb与其所连接的同一个氮原子或磷原子可共同形成C3-12杂环基,可被1-3个分别独立选自下组中的取代基取代:卤素、OH、CN、NO2、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷基、C1-6卤代烷氧基、C3-8环烷基、C3-12杂环基;
p、q各自独立的为0、1、2、3、4或5。
2.根据权利要求1所述的化合物,或其药学上可接受的盐、异构体或水合物,所述的式I化合物具有如下式所示的任一结构:
其中:
X为C或N;且当所述的X为C时,可被R取代,即所述的R位于X上(为CR);
R为H或卤素;
R1和R2各自独立的选自下组:H、氘、卤素、OH、CN、NO2、C1-6氘代烷基、C1-6烷基、C3-8环烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C6-10芳基、P(O)RaRb、S(O)2Ra、S(O)2NRaRb、NRaRb、C(O)NRaRb、C(O)NRaS(O)2Rb、NRaS(O)2Rb、C(O)Ra、NRaC(O)Rb、具有1-3个选自下组N、S、O的杂原子的5-12元杂芳基、具有1-3个选自下组N、S、O的杂原子的3-12元杂环基,其中由R1和R2代表的基团中的烷基、烯基、炔基、烷氧基、苯基、杂芳基、环烷基或杂环基可被1-3个分别独立选自下组中的取代基取代:卤素、OH、CN、NO2、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、NRaRb、C(=O)NRaRb、C(=O)NRaS(=O)2Rb、P(=O)RaRb、S(=O)2Ra、S(=O)2NRaRb、NRaS(=O)2Rb;当R1或R2各自所在的芳环被多个R1或R2所取代时,处于邻位的两个R1或R2可形成C3-8环烷基、具有1-3个选自下组N、S、O的杂原子的5-12元杂芳基、具有1-3个选自下组N、S、O的杂原子的3-12元杂环基;
Ra、Rb各自独立为H或C1-6烷基、C1-6氘代烷基、C3-8环烷基、具有1-3个选自下组N、S和O的杂原子的C3-12杂环基,其中由R6或R7代表的烷基、环烷基、杂环基可被1-3个分别独立选自下组中的取代基取代:卤素、OH、CN、NO2、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C3-8环烷基,C3-12杂环基;Ra及Rb与其所连接的同一个氮原子或磷原子可共同形成C3-12杂环基,可被1-3个分别独立选自下组中的取代基取代:卤素、OH、CN、NO2、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷基、C1-6卤代烷氧基、C3-8环烷基、C3-12杂环基;
p、q各自独立的为0、1、2、3、4或5。
5.一种药物组合物,其包含治疗有效量的一种或多种权利要求1至3中任一项的化合物、其立体异构体或其药学上可接受的盐,以及药学上可接受的赋形剂。
6.一种根据权利要求1至3任一项所述的化合物及其药学上可接受的盐、立体异构体、前药、溶剂化物在制备预防或治疗在受试者中对HPK1活性的抑制有反应的疾病中的应用。
7.根据权利要求6所述的应用,其特征在于,所述疾病为癌症。
8.一种根据权利要求1至3任一项所述的化合物及其药学上可接受的盐、立体异构体、前药、溶剂化物、酯和氘代化合物与其他肿瘤免疫治疗剂的联合使用方案,其特征在于,所述的其他肿瘤免疫抑制剂选自下组:小分子化合物及抗体、肿瘤靶向药、肿瘤疫苗、放疗方案。
9.根据权利要求8所示的联合使用方案,其特征在于,所示抗体选自PD-1、PD-L1、CTLA-4或STING激动剂。
10.一种根据权利要求1至3任一项所述的化合物及其药学上可接受的盐、立体异构体、前药、溶剂化物、酯和氘代化合物与CAR-T免疫治疗相结合在癌症免疫治疗中的应用。
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