CN116496283B - 五氮杂苊类化合物、制备方法、药物组合物和应用 - Google Patents
五氮杂苊类化合物、制备方法、药物组合物和应用 Download PDFInfo
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- CN116496283B CN116496283B CN202210055799.9A CN202210055799A CN116496283B CN 116496283 B CN116496283 B CN 116496283B CN 202210055799 A CN202210055799 A CN 202210055799A CN 116496283 B CN116496283 B CN 116496283B
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- Prior art keywords
- amino
- piperidin
- prop
- phenoxyphenyl
- pentazaacenaphthylen
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- 125000006727 (C1-C6) alkenyl group Chemical group 0.000 claims description 6
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
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Abstract
本发明公开了一类五氮杂苊类化合物、制备方法、药物组合物和应用。该化合物结构如式(I),该类化合物包含其异构体、非对映异构体、对映异构体、互变异构体、溶剂化物、溶剂化物的盐、药学上可接受的盐或它们的混合物。该类化合物对Bruton酪氨酸激酶具有高效的抑制作用,可制备为治疗和/或预防B细胞过度增殖性肿瘤、炎症、自身免疫性疾病,所制备药物疗效显著,应用广泛,并且该类化合物合成方法简便、易操作。
Description
技术领域
本发明涉及一类五氮杂苊类化合物、制备方法、药物组合物和应用,尤其涉及一类可有效抑制Bruton酪氨酸激酶并制备为治疗和/或预防肿瘤和炎症等疾病药物的五氮杂苊类化合物、制备方法、药物组合物和应用。
背景技术
Bruton酪氨酸激酶(BTK)是Tec酪氨酸激酶家族中的重要一员,存在于浆细胞,包括B细胞、肥大细胞和巨噬细胞中,在B细胞受体(BCR)介导的信号通路中起了决定性的作用。当BTK被上游的Src家族激酶激活后,可以磷酸化下游的磷脂酶C(PLC),从而激活PI3和DAG信号通路。这一信号可以促进细胞的增殖、粘附和存活,在B细胞淋巴瘤的发展过程中起重要的作用。
BTK抑制剂通过抑制BTK的活性,可以抑制B细胞淋巴瘤细胞的增殖,破坏肿瘤细胞的粘附,促进癌细胞的凋亡,使BTK在与B细胞有关的癌症中成为令人瞩目的药物靶点,尤其对B细胞淋巴瘤和白血病,比如非霍奇金淋巴瘤(non-Hodgkin’s lymphoma,NHL)、慢性淋巴细胞白血病(chrpnic lymphocytic leukemia,CLL)和抗复发性或者难治性套细胞淋巴瘤(mantle cell lymphoma,MCL)等。目前市场上有五款BTK不可逆抑制剂,分别为Abbvie的第一款BTK抑制剂Ibrutinib,Astra Zeneca公司的第二款BTK抑制剂Acalabrutinib,Beigene公司的Zanubrutinib,OnoPharmaceutical公司的Tirabrutinib,以及诺诚健华于2020年底上市的Orelabrutinib。这五款抑制剂均为不可逆的BTK小分子抑制剂,适应症也分布在B细胞相关肿瘤。
BTK抑制剂除了可以抗B细胞淋巴瘤和白血病,还可以抑制B细胞自身抗体和细胞因子的产生。BTK的突变会导致一种罕见的遗传疾病X-联无丙种球蛋白血症(XLA),因为在这种疾病中,BTK的功能被抑制,从而导致B细胞的产生或者成熟受阻,循环抗体很少,容易出现严重甚至致命的感染。临床前的动物模型研究显示短少BTK基因的小鼠可以抵抗胶原诱导的关节炎,而且临床结果也发现Rituxan,一种清楚B细胞的抗体药物,对于治疗免疫性疾病有很好的效果。因此,BTK抑制剂也可以用于治疗自身免疫性相关疾病,比如类风湿性关节炎(rheumatoid arthritis,RA)、系统系红斑狼疮(systemic lupus erythematosus,SLE)、过敏性疾病(例如食道炎、eosoniphilic esophagitis)、干燥症(Primary drynesssyndrome,PDS)、多发性硬化症(multiple sclerosis,MS)等。目前市场上还没有用于免疫性疾病的BTK特异性抑制剂上市,但有多个处于临床阶段,Celgene公司的CC-292、Hanmi的HM-71224、Principia的PRN-1008和Pharmacyclics的化合物,目前来看临床实验数据优异的也有很多。
但目前阶段BTK抑制剂仍然有许多缺点,其一是化合物分子的脱靶效应导致许多副作用,例如腹泻,心房颤动,皮疹等。这些原因使得其作为治疗炎症和自身免疫药物存在很大的潜在风险,这也是导致目前很多抑制剂临床失败的原因。虽然在B细胞淋巴瘤方向已有五款抑制剂上市,但这些抑制剂同样也存在毒副作用较大等问题。其二是目前有许多抑制剂在体外存在清除率较高,代谢较快等问题,导致这些BTK抑制剂在体内的半衰期较短,不能发挥最大的药效。因此,开发具有较高蛋白选择性,低毒性,长效的BTK抑制剂十分必要。
发明内容
发明目的:针对现有化合物存在疗效有限、毒性大、代谢不稳定等不足,本发明旨在提供一类活性优异的五氮杂苊类化合物、制备方法、药物组合物和应用。
技术方案:作为本发明涉及的方面,本发明的五氮杂苊类化合物具有式(I)的结构,所述化合物包含其异构体、非对映异构体、对映异构体、互变异构体、溶剂化物、溶剂化物的盐、药学上可接受的盐或它们的混合物:
其中:
X选自O、S、NH或CH2;
Y选自N或CH;
L选自NH、O或S;
R1选自氢、卤素、硝基、氨基、羟基、羧基、C1-C6烷基、C1-C6烷氨基、C1-C6烷氧基或C3-C6环烷基,其中C1-C6烷基、C1-C6烷氨基、C1-C6烷氧基或C3-C6环烷基被一个或多个卤素、羟基、氨基、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氨基或C1-C6烷氧基取代;
R2选自C3-C7环烷基,含1-3个N、O或S的4-9元杂环基,或者在任意位置被一个或多个R4取代的胺丙基、环烷基、杂环烷基或苯基;
R3选自C6-C10芳基,含1-3个N、O或S的4-9元芳杂环,或者在任意位置被一个或多个R5取代的芳环或杂芳环;
R4选自在任意位置被一个或多个C1-C6烷基取代的C1-C4烷氧基或苯基,在任意位置被一个或多个C1-C6烯基取代的C1-C4酰基,-COCH=CH(CH2)nR6,-CO(CH2)nR6,在任意位置被一个或多个C1-C2卤代烷取代的酰基,在任意位置被一个或多个C1-C3炔基取代的酰基,在任意位置被一个或多个C1-C6烯基取代的磺酰基,-COCR7=CH2,或者-N-R8;
n选自0或1;
R6选自氢、二甲氨基或C4-C6杂环基;
R7选自氢、卤素、氰基或C1-C3烷基;
R8选自在任意位置被一个或多个C1-C6烯基取代的C1-C4酰基,-COCH=CH(CH2)nR6,-CO(CH2)nR6,在任意位置被一个或多个C1-C2卤代烷取代的酰基,或者在任意位置被一个或多个C1-C3炔基取代的酰基;
R5选自C1-C4烷基,C1-C4卤代烷基,在任意位置被一个或多个C1-C4烷基取代的烷氧基,卤素,在任意位置被一个或多个C1-C4烷基取代的芳环,芳杂环,或者-L1-R9;
L1选自-C0-2烷基-、-CR10R11-、-C1-2烷基(R10)(OH)-、-C(O)-、-CR10R11O-、-OCR10R11-、-SCR10R11-、-NR10-、-NR10C(O)-、-C(O)NR10-、-NR10CONR11-、-CF2-、-O-、-S-、-S(O)m-、-NR10S(O)2-或-S(O)2NR10-;
R10、R11各自独立地选自氢、氘、C0-8烷基、C3-8环基、3-8元杂环基、芳基或杂芳基,其中所述C0-8烷基、C3-8环基、3-8元杂环基、芳基或杂芳基任选被一个或多个G所取代;
R9选自氢、C3-8环基、3-8元杂环基、芳基或杂芳基,其中所述C3-8环基、3-8元杂环基、芳基或杂芳基任选被一个或多个G所取代;
G选自氢、氘、卤素、氰基、烷基、烯基、炔基、环基、杂环基、芳基、杂芳基、-OR12、-OC(O)NR12R13、-C(O)OR13、-C(O)NR12R13、-C(O)R12、-NR12R13、-NR12C(O)R13、-NR12C(O)NR13R14、-S(O)mR13或-NR12S(O)mR13,其中所述烷基、烯基、炔基、环基、杂环基、芳基或杂芳基任选被一个或多个氘、卤素、氰基、C1-8烷基、C3-8环烷基、3-8元杂环基、-OR15、-OC(O)NR15R16、-C(O)OR15、-C(O)NR15R16、-C(O)R15、-NR15R16、-NR15C(O)R16、-NR15C(O)NR16R17、-S(O)mR15、-NR15S(O)mR16的取代基所取代;
R12、R13、R14、R15、R16或R17各自独立地选自氢、C1-6烷基、C1-6杂烷基、C1-8环烷基、3-8元单环杂环基、单环杂芳基或单环芳基;
m选自1或2。
优选,上述结构中:
X选自NH;Y选自N;L选自NH;R1选自氢。
进一步优选,上述结构中:
R2选自在任意位置被一个或多个R4取代的胺丙基、环烷基、杂环烷基或苯基。
进一步优选,上述结构中:
R2选自
进一步优选,上述结构中:
R3选自:
R4选自:
更具体地,上述五氮杂苊类化合物选自以下任一化合物:
1-(4-(3-((4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-1),
1-(3-(3-((4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)吡咯-1-基)丙-2-烯-1-酮(I-2),
1-(3-(3-((4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-3),
N-(4-(3-((4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)环己基)丙烯酰胺(I-4),
N-(3-(3-((4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)环己基)丙烯酰胺(I-5),
1-(4-(3-((4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)甲基)哌啶-1-基)丙-2-烯-1-酮(I-6),
1-(4-(3-((4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)氮杂环庚烷-1-基)丙-2-烯-1-酮(I-7),
1-(3-(3-((4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)氮杂环丁烷-1-基)丙-2-烯-1-酮(I-8),
1-(3-(3-((4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)氮杂环丁烷-1-基)丙-2-烯-1-酮(I-9),
N-(4-((3-((4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)甲基)苯基)丙烯酰胺(I-10),
1-(4-(3-((3-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-11),
1-(4-(3-((2-氯-4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-12),
1-(4-(3-((4-(吡啶-2-氧)苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-13),
1-(4-(3-((4-(吡啶-3-氧)苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-14),
1-(4-(3-((4-(吡啶-4-氧)苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-15),
1-(4-(3-((6-苯氧基吡啶-3-基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-16),
4-((5-(1-丙烯酰哌啶-4-基)-1,5-二氢-1,4,5,6,8-五氮杂苊-3-基)氨基)-N-(吡啶-2-基)苯甲酰胺(I-17),
1-(4-(3-((4-(4-(叔丁基)苯氧基)苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-18),
1-(4-(3-((2-甲基-4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-19),
1-(4-(3-((4-(环戊基甲氧基)苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-20),
1-(4-(3-((4-(环戊基氧基)苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-21),
1-(4-(3-((4-甲氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-22),
1-(4-(3-((4-(2-甲氧基乙氧基)苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-23),
1-(4-(3-(苯胺基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-24),
1-(4-(3-((4-吗啉基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-25),
1-(4-(3-((5-苯氧基吡啶-2-基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-26),
1-(4-(3-((2-氟-4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-27),
1-(4-(3-((3-氟-4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-28),
1-(4-(3-((4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙烷-1-酮(I-29),
1-(4-(3-((4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丁-2-炔-1-酮(I-30),
2-氯-1-(4-(3-((4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)乙烷-1-酮(I-31),
2-氟-1-(4-(3-((4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-32),
(E)-3-环丙基-2-(4-(3-((4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)哌啶-1-羰基)丙烯腈(I-33),
1-(4-(3-((4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-炔-1-酮(I-34),
N-(4-苯氧基苯基)-5-(1-(乙烯砜基)哌啶-4-基)-1,5-双氢-1,4,5,6,8-五氮杂苊-3-胺(I-35),
(E)-4-(二甲氨基)-1-(4-(3-((4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丁-2-烯-1-酮(I-36),
(E)-4-吗啉-1-(4-(3-((4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丁-2-烯-1-酮(I-37),
5-苄基-N-(4-苯氧基苯基)-1,5-二氢-1,4,5,6,8-五氮杂苊-3-胺(I-38),
N-(4-苯氧基苯基)-5-(四氢-2H-吡喃-4-基)-1,5-二氢-1,4,5,6,8-五氮杂苊-3-胺(I-39),
(4-(3-((4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)环己基)甲醇(I-40),
N-(4-苯氧基苯基)-5-(四氢-2H-吡喃-3-基)-1,5-二氢-1,4,5,6,8-五氮杂苊-3-胺(I-41),
2-(4-甲基哌嗪-1-基)-1-(4-(3-((4-苯氧基苯基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)乙烷-1-酮(I-42),
2-(4-甲基哌嗪-1-基)-N-(4-(3-((4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)环己基)乙酰胺(I-43),
1-(4-(3-(4-苯氧基苯基)-1,4,5,6,8-无氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-44),
1-(4-(3-((4-((1-甲基-1H-吡唑-4-基)氧基)苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-45),
N-(4-((5-(1-丙烯酰哌啶-4-基)-1,5-二氢-1,4,5,6,8-五氮杂苊-3-基)氨基)苯基)苯甲酰胺(I-46),
4-((5-(1-丙烯酰哌啶-4-基)-1,5-二氢-1,4,5,6,8-五氮杂苊-3-基)氨基)-N-苯甲酰胺(I-47),
1-(4-(3-((4-(吗啉-4-羧基)苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-48),
4-((5-(1-丙烯酰哌啶-4-基)-1,5-二氢-1,4,5,6,8-五氮杂苊-3-基)氨基)-N-环己基苯甲酰胺(I-49),
4-((5-(1-丙烯酰哌啶-4-基)-1,5-二氢-1,4,5,6,8-五氮杂苊-3-基)氨基)-N-环丙基苯甲酰胺(I-50),
4-((5-(1-丙烯酰哌啶-4-基)-1,5-二氢-1,4,5,6,8-五氮杂苊-3-基)氨基)-N-(1-甲基-1H-吡唑-4-基)苯甲酰胺(I-51),
1-(4-(3-((4-(嘧啶-2-氧)苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-52),
1-(4-(3-((4-((3-甲基吡啶-2-基)氧)苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-53),
1-(4-(3-((4-((3-三氟甲基吡啶-2-基)氧)苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-54),
1-(4-(3-((4-((4-甲基吡啶-2-基)氧)苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-55),
1-(4-(3-((4-((5-三氟甲基吡啶-2-基)氧)苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-56),
1-(4-(3-((4-((5-甲基吡啶-2-基)氧)苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-57),
1-(4-(3-((4-(苯胺基)苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-58),
1-(4-(3-((4-(苯砜基)苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-59),
1-(4-(3-((4-(吡啶-2-氧基)苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)吡咯烷-2-基)丙-2-烯-1-酮(I-60),
4-((5-(1-丙烯酰吡咯烷-3-基)-1,5-二氢-1,4,5,6,8-五氮杂苊-3-基)氨基)-N-(吡啶-2-基)苯甲酰胺(I-61),
1-(4-(3-((4-(吡啶-2-氧基)苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-炔-1-酮(I-62),
N-(3-(3-((4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)环丁基)丙烯酰胺(I-63),1-(2-(3-((4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)吡咯烷-1-基)丙-2-烯-1-酮(I-64),
1-(2-(3-((4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-65)。
上述五氮杂苊类化合物的药学上可接受的盐为所述五氮杂苊类化合物与酸或碱形成的盐,所述酸为盐酸、氢溴酸、硫酸、磷酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、柠檬酸、苹果酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸、琥珀酸、富马酸、水杨酸、苯基乙酸或杏仁酸,所述碱为含有碱性金属阳离子、碱土金属阳离子或铵阳离子盐的无机碱。
作为本发明涉及的第二方面,上述五氮杂苊类化合物的制备方法为:
当X为NH,Y为N,L为NH时,化合物1与化合物2,经亲核取代、环合、偶联、脱保护基、缩合、脱保护基反应得到化合物(I);
其中,R2、R3的定义如前所述;
将相应的酸或碱与以上方法制备的化合物(I)成盐,即得所述五氮杂苊类化合物的药学上可接受的盐。
作为本发明涉及的第三方面,本发明的药物组合物包含上述五氮杂苊类化合物以及药学上可接受的载体。
上述五氮杂苊类化合物可以添加药学上可接受的载体制成常见的药用制剂,如片剂、胶囊、糖浆、悬浮剂或注射剂,制剂可以加入香料、甜味剂、液体/固体填料、稀释剂等常用药用辅料。
作为本发明涉及的第四方面,本发明的上述五氮杂苊类化合物及其药物组合物可制备为Bruton酪氨酸激酶抑制剂药物,用于治疗和/或预防肿瘤或者炎症免疫性。
有益效果:与现有技术相比,本发明具有如下显著优点:
(1)该五氮杂苊类化合物及其药物组合物可有效抑制BTK激酶活性,BTK激酶抑制IC50值最优小于0.1μM,达到纳摩尔浓度水平;
(2)该五氮杂苊类化合物及其药物组合物应用广泛,可制备为治疗和/或预防肿瘤与炎症等疾病;所述药物在分子水平发挥优异的药效,IC50值最优可达到纳摩尔浓度水平;
(3)化合物制备方法简便、易操作。
具体实施方式
下面结合实施例对本发明的技术方案作进一步说明。
试剂与材料:
化合物制备所使用的化学试剂来源于上海毕得医药科技有限公司、上海皓鸿生物医药科技有限公司、萨恩化学技术有限公司;
BTK来源于美国Reaction Biology Corp.(Malvern PA)公司。
仪器:
1H-NMR采用BRUKER AVANCE-300型核磁共振仪(瑞士Brucker公司)测定,以TMS为内标,位移值(δ)单位为ppm;低分辨质谱采用expression紧凑型型傅里叶变换质谱仪测定。
实施例1:1-(4-(3-((4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(化合物I-1)的合成
(1)4-氯-7-((2-(三甲基硅烷基)乙氧基)甲基)-7H-吡咯[2,3-d]嘧啶-5-甲腈(化合物1)的合成
在250mL双颈瓶中加入4-氯-7H-吡咯[2,3-d]嘧啶-5-甲腈(5g,28mmol),碳酸钾(7.73g,56mmol),加入50mL无水DMF溶解后,逐滴加入2-(三甲基硅烷基)乙氧甲基氯(5.95mL,33.6mmol),氮气保护下,于室温下反应3h,反应结束后,加50mL水和500mL的乙酸乙酯,收集有机层,浓缩后柱层析分离纯化的类白色固体7.5g,收率87%。ESI-MS m/z:309[M+H]+。
(2)N-苄氧羰基-4-肼烯基哌啶(化合物2a)的合成
在100mL单颈瓶中加入1-Cbz-4-哌啶酮(10g,42.9mmol),水合肼(2.8ml,85mmol),加入50mL THF溶解后,于80℃下反应5h,反应结束后,旋蒸去溶剂,加20mL水和200mL的乙酸乙酯萃取,合并有机相,加入无水Na2SO4干燥,浓缩后柱层析分离纯化得到油状半固体8g,收率75%。ESI-MS m/z:248.1[M+H]+。
(3)N-苄氧羰基-4-肼基哌啶(化合物2b)的合成
在250mL双颈瓶中加入化合物2a(8g,32.5mmol),加入无水100mL THF溶解后,氮气保护,冰浴下逐滴加入1mol/L BH3-THF(65mL,65mmol),于室温下反应12h,反应结束后,逐滴加入甲醇,待不再放出气泡后旋蒸去溶剂,得到半固体8g粗品,粗品不纯化投下一步。
(4)1-Cbz-4-(1-(5-氰基-7-((2-(三甲基硅烷基)乙氧基)甲基)-7H-吡咯[2,3-d]嘧啶-4-基)肼基)哌啶(化合物2c)的合成
在100mL单颈瓶中加入化合物2b(3.24g,13mmol),化合物1(2g,6.5mmol),加入50mL二氧六环溶解后,加入3mL饱和K2CO3水溶液,于110℃下反应8h,反应结束后,旋蒸去溶剂,加30mL水和250mL的乙酸乙酯萃取,合并有机相,加入无水Na2SO4干燥,浓缩后柱层析分离纯化得到油状半固体1.4g,收率42%。ESI-MS m/z:523[M+H]+。
(5)1-Cbz-4-(3-氨基-1-((2-(三甲基硅烷基)乙氧基)甲基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶(化合物2d)的合成
在100mL单口茄型瓶中加入2c(1g,1.9mmol),加入30mL甲醇溶解后,加入甲醇钠(516.3mg,9.5mmol),于70℃下反应3h,反应结束后,旋蒸除去溶剂,加20mL水和300mL的乙酸乙酯萃取,合并有机相,加入无水Na2SO4干燥,浓缩后柱层析分离纯化得到油状淡黄色半固体892.6mg,收率90%。ESI-MS m/z:522[M+H]+。
(6)1-Cbz-4-(3-((4-苯氧基苯基)氨基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶(化合物2e)的合成
在100mL单口茄型瓶中加入化合物2d(500mg,0.96mmol),1-溴-4-联苯醚(241mg,0.97mmol),加入30mL二氧六环溶解后,加入K2CO3(414mg,3mmol),X-Phos(4.8mg,0.01mmol),Pd2(DBA)3(9mg,0.01mmol)于110℃下反应3h,反应结束后,旋蒸除去溶剂,加20mL水和300mL的乙酸乙酯萃取,合并有机相,加入无水Na2SO4干燥,浓缩后柱层析分离纯化得到油状黄色半固体464mg,收率70%。ESI-MS m/z:590.8[M+H]+。
(7)N-(4-苯氧基苯基)-5-(哌啶-4-基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1,5-二氢-1,4,5,6,8-五氮杂苊-3-胺(化合物2f)的合成
在100mL单口茄型瓶中加入化合物2e(464mg,0.79mmol),加入20mL甲醇溶解后,加入10%的Pd-C 100mg,H2氛围下,于室温下反应8h,反应结束后,过滤掉过量的催化剂,浓缩后未纯化得到油状淡黄色半固体435mg,收率99%。ESI-MS m/z:556[M+H]+。
(8)1-(4-(3-((4-苯氧基苯基)氨基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(化合物2g)的合成
在100mL单口茄型瓶中加入化合物2f(435mg,0.78mmol),加入20mL DCM溶解后,加入HATU(892mg,2.35mmol),丙烯酸(107μL,1.56mmol),0.5mL的DIEA,于室温下反应3h,反应结束后,加20mL水和300mL的乙酸乙酯萃取,合并有机相,加入无水Na2SO4干燥,浓缩后柱层析分离纯化得到黄色固体285mg,收率60%。ESI-MS m/z:611[M+H]+。
(9)1-(4-(3-((4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(化合物I-1)的合成
在100mL单口茄型瓶中加入2g(285mg,0.42mmol),加入20ml DCM溶解后,加入4ml三氟乙酸,于室温下反应3h,反应结束后,旋干后加入饱和Na2CO3调节PH至碱性,加20mL水和300mL的乙酸乙酯萃取,合并有机相,加入无水Na2SO4干燥,浓缩后柱层析分离纯化得到类白色固体101mg,收率50%。1H NMR(300MHz,Methanol-d4)δ8.10(s,1H),7.67(d,J=9.0Hz,2H),7.35(dd,J=8.6,7.3Hz,2H),7.14–
7.05(m,2H),7.02–6.89(m,4H),6.83(dd,J=16.8,10.6Hz,1H),6.19(dd,J=16.8,2.0Hz,1H),5.72(dd,J=10.6,2.0Hz,1H),4.35–4.21(m,1H),3.29–3.19(m,1H),2.92(t,J=12.8Hz,1H),2.26–1.91(m,2H),1.68(p,J=8.3,7.7Hz,2H),1.44(h,J=7.3Hz,2H).ESI-MS m/z:480.5[M+H]+。
采用与实施例I-1相似的操作,制得下列化合物:
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实施例2:N-(4-((3-((4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)甲基)苯基)丙烯酰胺(化合物I-10)的合成
(1)4-硝基苄肼(化合物3a)的合成
在100mL单颈瓶中加入4-硝基苄氯(5g,29.1mmol),加入50mL DCM溶解后,加入水合肼(2.8mL,87.3mmol),于室温下反应3h,反应结束后,旋蒸去溶剂,加20mL水和300mL的乙酸乙酯萃取,合并有机相,加入无水Na2SO4干燥,浓缩后柱层析分离纯化得到油状液体3.9g,收率80%。ESI-MS m/z:168[M+H]+。
(2)4-(1-(4-硝基苯基)肼基)-7-((2-(三甲基硅烷基)乙氧基)甲基)-7H-吡咯[2,3-d]嘧啶-5-甲腈(化合物3b)
化合物3b的合成方法与化合物2c一致。得到淡黄色半固体化合物。ESI-MS m/z:440[M+H]+。
(3)5-(4-硝基苯基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1,5-二氢-1,4,5,6,8-五氮杂苊-3-胺(化合物3c)
化合物3c的合成方法与化合物2d一致。得到淡黄色半固体化合物。ESI-MS m/z:441[M+H]+。
(4)5-(4-硝基苯基)-N-(4-苯氧基苯基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1,5-二氢-1,4,5,6,8-五氮杂苊-3-胺(化合物3d)
化合物3d的合成方法与化合物2e一致。得到淡黄色半固体化合物。ESI-MS m/z:609[M+H]+。
(5)5-(4-氨基苯基)-N-(4-苯氧基苯基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1,5-二氢-1,4,5,6,8-五氮杂苊-3-胺(化合物3e)
在100mL单口茄型瓶中加入化合物3d(547mg,0.9mmol),加入20mL甲醇溶解后,加入10%的Pd-C 200mg,H2氛围下,于室温下反应12h,反应结束后,过滤掉过量的催化剂,浓缩后未纯化得到油状淡黄色半固体511mg,收率98%。ESI-MS m/z:579[M+H]+。
(6)N-(4-((3-((4-苯氧基苯基)氨基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1,4,5,6,8-五氮杂苊-5(1H)-基)甲基)苯基)丙烯酰胺(化合物3f)
化合物3f的合成方法与化合物2g一致。得到淡黄色粉末状固体化合物。ESI-MS m/z:633[M+H]+。
(7)N-(4-((3-((4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)甲基)苯基)丙烯酰胺(化合物I-10)
化合物I-10的合成方法与I-1一致。得到类白色粉末状固体。1H NMR(300MHz,Methanol-d4)δ8.10(s,1H),7.72–7.54(m,4H),7.43(d,J=8.6Hz,2H),7.38–7.25(m,2H),7.17–7.01(m,2H),7.01–6.84(m,4H),6.53–6.24(m,2H),5.76(dd,J=9.3,2.7Hz,1H),5.11(s,2H).ESI-MS m/z:502.5[M+H]+。
实施例3:1-(4-(3-((2-氯-4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(化合物I-12)的合成
(1)1-溴-2-氯-4-二苯醚(化合物4)的合成
在100mL单颈瓶中加入4-溴-3-氯酚(5g,24.1mmol),苯硼酸(2.939g,24.1mmol),加入50mL DCM溶解后,加入醋酸铜(0.998g,5mmol),0.5mL三乙胺,于室温下反应5h,反应结束后,抽滤掉过量的醋酸铜,旋蒸去溶剂,加20mL水和300mL的乙酸乙酯萃取,合并有机相,加入无水Na2SO4干燥,浓缩后柱层析分析纯化得到油状液体5.8g,收率85%。ESI-MS m/z:284.5[M+H]+。
(2)1-Cbz-4-(3-((2-氯-4-苯氧基苯基)氨基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶(化合物5a)
化合物5a的合成方法与2e一致。得到淡黄色粉末状固体化合物。ESI-MS m/z:724.33[M+H]+。
(3)N-(2-氯-4-苯氧基苯基)-5-(哌啶-4-基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1,5-二氢-1,4,5,6,8-五氮杂苊-3-胺(化合物5b)
化合物5b的合成方法与化合物2f一致。得到淡黄色粉末状固体化合物。ESI-MS m/z:591[M+H]+。
(4)1-(4-(3-((2-氯-4-苯氧基苯基)氨基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(化合物5c)
化合物5c的合成方法与化合物2g一致。得到淡黄色粉末状固体化合物。ESI-MS m/z:645[M+H]+。
(5)1-(4-(3-((2-氯-4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(化合物I-12)
化合物I-12的合成方法与I-1一致。得到淡黄色粉末状固体化合物。1H NMR(300MHz,Methanol-d4)δ8.09(s,1H),7.72(d,J=8.9Hz,1H),7.54–7.33(m,2H),7.24–7.13(m,1H),7.10–6.98(m,3H),6.97–6.87(m,2H),6.79(dd,J=16.8,10.7Hz,1H),6.19(dd,J=16.8,2.0Hz,1H),5.73(dd,J=10.6,2.0Hz,1H),4.62(d,J=13.4Hz,1H),4.35–3.91(m,1H),3.05–2.78(m,1H),2.14–1.81(m,4H).ESI-MS m/z:514.9[M+H]+。
采用与实施例I-12相似的操作,制得下列化合物:
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实施例4:1-(4-(3-((4-(吡啶-2-氧)苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(化合物I-13)的合成
(1)2-(4-溴苯氧基)-吡啶(化合物6)的合成
在100mL单颈瓶中加入4-溴苯酚(5g,28.9mmol),2-氟吡啶(5.6g,57.8mmol),加入50mL DMF溶解后,加入K2CO3(13.8g,100mmol),120℃下反应3h,反应结束后,加20mL水和300mL的乙酸乙酯萃取,合并有机相,加入无水Na2SO4干燥,浓缩后柱层析分离纯化得到油状液体6.5g,收率90%。ESI-MS m/z:250.51[M+H]+。
(2)1-Cbz-4-(3-((4-(吡啶-2-氧)苯基)氨基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶(化合物7a)
化合物7a的合成方法与化合物2e一致。得到淡黄色粉末状固体化合物。ESI-MS m/z:690.80[M+H]+。
(3)5-(哌啶-4-基)-N-(4-(吡啶-2-氧基)苯基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1,5-二氢-1,4,5,6,8-五氮杂苊-3-胺的合成(化合物7b)
化合物7b的合成方法与化合物2f一致。得到黄色粉末状固体化合物。ESI-MS m/z:556.8[M+H]+。
(4)5-(哌啶-4-基)-N-(4-(吡啶-2-氧基)苯基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(化合物7c)
化合物7c的合成方法与2g一致。得到淡黄色粉末状固体化合物。ESI-MS m/z:610.8[M+H]+。
(5)1-(4-(3-((4-(吡啶-2-氧)苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(化合物I-13)
化合物I-13的合成方法与I-1一致。得到淡黄色粉末状固体化合物。1H NMR(300MHz,DMSO-d6)δ12.05(s,1H),9.08(d,J=4.6Hz,1H),8.25–8.08(m,2H),7.87(t,J=7.8Hz,1H),7.74(d,J=8.7Hz,2H),7.16(d,J=5.7Hz,2H),7.02(dd,J=8.9,2.8Hz,3H),6.89(dd,J=16.7,10.5Hz,1H),6.09(dd,J=16.6,2.5Hz,1H),5.65(dd,J=10.3,2.5Hz,1H),4.91–4.75(m,1H),4.58(d,J=12.9Hz,1H),4.22(d,J=13.9Hz,1H),3.20(s,1H),2.98–2.75(m,1H),2.10–1.78(m,4H).ESI-MS m/z:481.5[M+H]+。
采用与实施例I-13相似的操作,制得下列化合物:
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实施例5:1-(4-(3-((4-(吡啶-2-基氨甲基)苯基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(化合物I-17)的合成
(1)4-溴-N-(吡啶-2-基)苯甲酰胺(化合物8)的合成
在250mL单颈瓶中加入4-溴苯甲酸(6g,29.8mmol),2-氨基吡啶(2.8g,29.8mmol),加入100mL DCM溶解后,加入HATU(16.9g,45mmol),DIPEA(10.4mL,60mmol),室温下反应3h,反应结束后,旋蒸去除溶剂,加50mL水和300mL的乙酸乙酯萃取,合并有机相,加入无水Na2SO4干燥,浓缩后柱层析分离纯化得到油状液体5.37g,收率65%。ESI-MS m/z:277.5[M+H]+。
(2)1-Cbz-4-(3-((4-(吡啶-2-基氨甲基)苯基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶(化合物9a)
化合物9a的合成方法与化合物2e一致。得到淡黄色粉末状固体化合物。ESI-MS m/z:703.89[M+H]+。
(3)5-(哌啶-4-基)-N-(4-(吡啶-2-基氨甲基)苯基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1,5-二氢-1,4,5,6,8-五氮杂苊-3-胺的合成(化合物9b)
化合物9b的合成方法与化合物2f一致。得到黄色粉末状固体化合物。ESI-MS m/z:569.7[M+H]+。
(4)5-(哌啶-4-基)-N-(4-(吡啶-2-基氨甲基)苯基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(化合物9c)
化合物9c的合成方法与2g一致。得到淡黄色粉末状固体化合物。ESI-MS m/z:623.8[M+H]+。
(5)1-(4-(3-((4-(吡啶-2-基氨甲基)苯基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(化合物I-17)
化合物I-17的合成方法与I-1一致。得到淡黄色粉末状固体化合物。1H NMR(300MHz,DMSO-d6)δ12.05(s,1H),10.49(s,1H),9.42(s,1H),8.22(d,J=5.0Hz,1H),8.11(s,1H),8.05(d,J=1.4Hz,1H),8.01–7.93(m,3H),7.80(d,J=8.9Hz,2H),7.20(d,J=5.7Hz,1H),7.02–6.95(m,1H),6.94–6.86(m,1H),6.17(ddd,J=16.6,13.9,2.5Hz,1H),5.80–5.67(m,1H),4.83(tt,J=11.0,4.7Hz,1H),4.62(d,J=13.1Hz,1H),4.24(d,J=13.5Hz,1H),3.25(q,J=15.6,14.4Hz,1H),2.85(d,J=11.4Hz,1H),2.10–1.74(m,4H).ESI-MS m/z:508.5[M+H]+。
采用与实施例I-17相似的操作,制得下列化合物:
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实施例6:1-(4-(3-((4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙烷-1-酮(化合物I-29)的合成
(1)1-(4-(3-((4-氧基苯基)氨基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙烷-1-酮(化合物10)
在50mL单颈瓶中加入化合物2f(200mg,0.36mmol),丙酸(53.3mg,0.72mmol),加入10mL DCM溶解后,加入HATU(380mg,1mmol),DIPEA(0.52mL,3mmol),室温下反应3h,反应结束后,旋蒸去除溶剂,加10mL水和100mL的乙酸乙酯萃取,合并有机相,加入无水Na2SO4干燥,浓缩后柱层析分离纯化得到油状液体154.2mg,收率70%。ESI-MS m/z:612[M+H]+。
(2)1-(4-(3-((4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙烷-1-酮(化合物I-29)
化合物I-29的合成方法与I-1一致。得到淡黄色粉末状固体化合物。1H NMR(300MHz,DMSO-d6)δ12.06–11.86(m,1H),8.95(s,1H),8.10(s,1H),7.85–7.61(m,2H),7.56–7.33(m,2H),7.18–7.06(m,2H),7.06–6.90(m,4H),4.79(dq,J=10.9,5.4,4.6Hz,1H),4.54(d,J=13.0Hz,1H),4.03(dd,J=14.3,10.3Hz,1H),3.20(s,1H),2.82–2.57(m,1H),2.36(t,J=7.5Hz,1H),1.82(d,J=14.3Hz,4H),0.98(t,J=7.4Hz,3H).ESI-MS m/z:482.5[M+H]+。
采用与实施例I-29相似的操作,制得下列化合物:
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实施例7:2-氯-1-(4-(3-((4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)乙烷-1-酮(化合物I-31)的合成
(1)2-氯-1-(4-(3-((4-苯氧基苯基)氨基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)乙烷-1-酮(化合物11)
在50mL单颈瓶中加入2f(200mg,0.36mmol),氯乙酰氯(41.8mg,0.37mmol),加入10mL DCM溶解后,冰浴下反应3h,反应结束后,旋蒸去除溶剂,加10mL水和100mL的乙酸乙酯萃取,合并有机相,加入无水Na2SO4干燥,浓缩后柱层析分离纯化得到油状液体222.2mg,收率90%。ESI-MS m/z:633[M+H]+。
(2)2-氯-1-(4-(3-((4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)乙烷-1-酮(化合物I-31)
化合物I-31的合成方法与I-1一致。得到淡黄色粉末状固体化合物。1H NMR(300MHz,DMSO-d6)δ11.95(s,1H),8.96(s,1H),8.08(s,1H),7.84–7.64(m,2H),7.45–7.30(m,2H),7.19–7.04(m,2H),7.04–6.90(m,4H),4.81(dt,J=11.2,6.7Hz,1H),4.57–4.21(m,3H),3.99(d,J=13.6Hz,1H),2.94–2.70(m,1H),2.30–2.03(m,1H),1.83(d,J=12.7Hz,4H).ESI-MS m/z:503[M+H]+。
实施例8:(E)-3-环丙基-2-(4-(3-((4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)哌啶-1-羰基)丙烯腈(化合物I-33)的合成
(1)2-氰基-1-(4-(3-((4-苯氧基苯基)氨基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)乙烷-1-酮(化合物12)
化合物12的合成方法与化合物10一致。ESI-MS m/z:624[M+H]+。
(2)(E)-3-环丙基-2-(4-(3-((4-苯氧基苯基)氨基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-羰基)丙烯腈(化合物13)
在50mL单颈瓶中加入化合物12(100mg,0.15mmol),环丙甲醛(21mg,0.30mmol),哌啶40μL,加入10mL乙醇溶解后,室温反应6h,反应结束后,旋蒸去除溶剂,加10mL水和100mL的乙酸乙酯萃取,合并有机相,加入无水Na2SO4干燥,浓缩后柱层析分离纯化得到油状液体90.1mg,收率89%。ESI-MS m/z:675[M+H]+。
(3)(E)-3-环丙基-2-(4-(3-((4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)哌啶-1-羰基)丙烯腈(化合物I-33)
化合物I-33的合成方法与化合物I-1一致。得到淡黄色粉末状固体化合物。1H NMR(300MHz,DMSO-d6)δ11.98(s,1H),8.98(s,1H),8.11(s,1H),7.83–7.68(m,2H),7.49–7.31(m,2H),7.22–7.07(m,2H),7.07–6.93(m,4H),6.63(d,J=11.1Hz,1H),4.86(s,1H),2.21–1.72(m,2H),1.29–1.05(m,3H),0.91(td,J=7.4,3.6Hz,2H).ESI-MS m/z:545.6[M+H]+。
实施例9:N-(4-苯氧基苯基)-5-(1-(乙烯砜基)哌啶-4-基)-1,5-双氢-1,4,5,6,8-五氮杂苊-3-胺(化合物I-35)的合成
(1)N-(4-苯氧基苯基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-5-(1-(乙烯砜基)哌啶-4-基)-1,5-二氢-1,4,5,6,8-五氮杂苊-3-胺(化合物14)
在50mL单颈瓶中加入化合物2f(200mg,0.36mmol),2-氯乙烷磺酰氯(65.2mg,0.40mmol),三乙胺100μL,加入10mL DCM溶解后,室温下反应3h,反应结束后,旋蒸去除溶剂,加10mL水和100mL的乙酸乙酯萃取,合并有机相,加入无水Na2SO4干燥,浓缩后柱层析分析纯化得到油状液体197.2mg,收率85%。ESI-MS m/z:646[M+H]+。
(2)N-(4-苯氧基苯基)-5-(1-(乙烯砜基)哌啶-4-基)-1,5-双氢-1,4,5,6,8-五氮杂苊-3-胺(化合物I-35)
化合物I-35的合成方法与I-1一致。得到淡黄色粉末状固体化合物。1H NMR(300MHz,DMSO-d6)δ11.96(s,1H),8.98(s,1H),8.07(s,1H),7.87–7.60(m,1H),7.45–7.30(m,2H),7.19(s,0H),7.15–7.06(m,2H),7.06–6.93(m,4H),6.86(dd,J=16.5,10.0Hz,1H),6.26–5.92(m,2H),4.62(d,J=11.5Hz,0H),3.71(d,J=12.7Hz,2H),3.03–2.79(m,2H),1.83(d,J=12.6Hz,2H),1.40–1.26(m,4H).ESI-MS m/z:516.6[M+H]+。
实施例10:化合物对BTK激酶活性的抑制作用
所合成的化合物由美国Reaction Biology Corp.(Malvern PA)公司通过HotSpotSM激酶法/荧光共振能量转移(FRET)法测试对BTK的抑制活性。
具体操作方法:BTK用激酶稀释液稀释至合适浓度后待用。激酶反应混合物中含Peptide substrate、HEPES(pH7.5)、BRIJ-35、MgCl2和EDTA。将BTK激酶加入底物溶剂中,轻轻混合,通过声学技术加入DMSO溶解的化合物。室温下孵育20min后,向开始的反应体系中加入33P-ATP。室温下孵育2h,通过P81膜过滤法检测激酶活力。按公式计算受试化合物抑制率(n=2),IC50由百分抑制率和对数浓度值作图求得,分析结果见表1。
表1化合物对BTK激酶活性的抑制作用
Cpd. | IC50(μM) | Cpd. | IC50(μM) | Cpd. | IC50(μM) | Cpd. | IC50(μM) | Cpd. | IC50(μM) |
I-1 | A | I-14 | A | I-27 | C | I-40 | C | I-53 | B |
I-2 | A | I-15 | A | I-28 | A | I-41 | C | I-54 | A |
I-3 | B | I-16 | A | I-29 | C | I-42 | C | I-55 | A |
I-4 | C | I-17 | A | I-30 | C | I-43 | C | I-56 | A |
I-5 | C | I-18 | C | I-31 | A | I-44 | C | I-57 | A |
I-6 | C | I-19 | C | I-32 | C | I-45 | A | I-58 | B |
I-7 | C | I-20 | A | I-33 | C | I-46 | A | I-59 | B |
I-8 | A | I-21 | A | I-34 | A | I-47 | B | I-60 | A |
I-9 | C | I-22 | A | I-35 | A | I-48 | A | I-61 | B |
I-10 | C | I-23 | A | I-36 | B | I-49 | A | I-62 | A |
I-11 | B | I-24 | A | I-37 | C | I-50 | A | I-63 | A |
I-12 | C | I-25 | A | I-38 | C | I-51 | A | I-64 | B |
I-13 | A | I-26 | B | I-39 | C | I-52 | A | I-65 | B |
注:“A”代表IC50值小于0.1μM,“B”代表IC50值在0.1μM到0.5μM之间,“C”代表IC50值大于0.5μM。
如表1所示,所有测试化合物对BTK激酶活性均有抑制作用,其中化合物I-1~I-2、I-8、I-13~I-17、I-20~I-25、I-28、I-31、I-34~I-35、I-45~I-46、I-48~I-52、I-54~I-57、I-60、I-62~I-63抑制BTK激酶的IC50值均小于0.1μM,可达到纳摩尔浓度水平;其余化合物抑制BTK激酶的IC50值均大于0.1μM,达到微摩尔浓度水平。
结论:该系列化合物对BTK活性有明显抑制。
Claims (10)
1.一种五氮杂苊类化合物,其特征在于,具有式(I)的结构,所述化合物包含其药学上可接受的盐:
其中:
X选自NH;
Y选自N;
L选自NH;
R1选自氢;
R2选自C3-C7环烷基,含1-3个N、O或S的4-9元杂环基,或者在任意位置被一个或多个R4取代的胺丙基或苯基;
R3选自:
R4选自在任意位置被一个或多个C1-C6烯基取代的C1-C4酰基,-COCH=CH(CH2)nR6,-CO(CH2)nR6,在任意位置被一个或多个C1-C2卤代烷取代的酰基,在任意位置被一个或多个C1-C3炔基取代的酰基,在任意位置被一个或多个C1-C6烯基取代的磺酰基,-COCR7=CH2,或者-N-R8;
n选自0或1;
R6选自氢、二甲氨基;
R7选自氢、卤素、氰基或C1-C3烷基;
R8选自在任意位置被一个或多个C1-C6烯基取代的C1-C4酰基,-COCH=CH(CH2)nR6,-CO(CH2)nR6,在任意位置被一个或多个C1-C2卤代烷取代的酰基,或者在任意位置被一个或多个C1-C3炔基取代的酰基。
2.根据权利要求1所述的五氮杂苊类化合物,其特征在于,所述结构中:
R2选自
3.根据权利要求1所述的五氮杂苊类化合物,其特征在于,所述结构中:
R4选自:
4.一种五氮杂苊类化合物,其特征在于,选自以下任一化合物:
1-(4-(3-((4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-1),1-(3-(3-((4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)吡咯-1-基)丙-2-烯-1-酮(I-2),1-(3-(3-((4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-3),
N-(4-(3-((4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)环己基)丙烯酰胺(I-4),
N-(3-(3-((4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)环己基)丙烯酰胺(I-5),
1-(4-(3-((4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)甲基)哌啶-1-基)丙-2-烯-1-酮(I-6),
1-(4-(3-((4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)氮杂环庚烷-1-基)丙-2-烯-1-酮(I-7),
1-(3-(3-((4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)氮杂环丁烷-1-基)丙-2-烯-1-酮(I-8),
1-(3-(3-((4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)氮杂环丁烷-1-基)丙-2-烯-1-酮(I-9),
N-(4-((3-((4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)甲基)苯基)丙烯酰胺(I-10),1-(4-(3-((3-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-11),1-(4-(3-((2-氯-4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-12),
1-(4-(3-((4-(吡啶-2-氧)苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-13),
1-(4-(3-((4-(吡啶-3-氧)苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-14),
1-(4-(3-((4-(吡啶-4-氧)苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-15),
1-(4-(3-((6-苯氧基吡啶-3-基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-16),
4-((5-(1-丙烯酰哌啶-4-基)-1,5-二氢-1,4,5,6,8-五氮杂苊-3-基)氨基)-N-(吡啶-2-基)苯甲酰胺(I-17),
1-(4-(3-((4-(4-(叔丁基)苯氧基)苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-18),
1-(4-(3-((2-甲基-4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-19),
1-(4-(3-((4-(环戊基甲氧基)苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-20),
1-(4-(3-((4-(环戊基氧基)苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-21),
1-(4-(3-((4-甲氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-22),1-(4-(3-((4-(2-甲氧基乙氧基)苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-23),
1-(4-(3-(苯胺基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-24),
1-(4-(3-((4-吗啉基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-25),1-(4-(3-((5-苯氧基吡啶-2-基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-26),
1-(4-(3-((2-氟-4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-27),
1-(4-(3-((3-氟-4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-28),
1-(4-(3-((4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙烷-1-酮(I-29),
1-(4-(3-((4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丁-2-炔-1-酮(I-30),2-氯-1-(4-(3-((4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)乙烷-1-酮(I-31),
2-氟-1-(4-(3-((4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-32),
(E)-3-环丙基-2-(4-(3-((4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)哌啶-1-羰基)丙烯腈(I-33),
1-(4-(3-((4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-炔-1-酮(I-34),
N-(4-苯氧基苯基)-5-(1-(乙烯砜基)哌啶-4-基)-1,5-双氢-1,4,5,6,8-五氮杂苊-3-胺(I-35),
(E)-4-(二甲氨基)-1-(4-(3-((4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丁-2-烯-1-酮(I-36),
(E)-4-吗啉-1-(4-(3-((4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丁-2-烯-1-酮(I-37),
5-苄基-N-(4-苯氧基苯基)-1,5-二氢-1,4,5,6,8-五氮杂苊-3-胺(I-38),
N-(4-苯氧基苯基)-5-(四氢-2H-吡喃-4-基)-1,5-二氢-1,4,5,6,8-五氮杂苊-3-胺(I-39),
(4-(3-((4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)环己基)甲醇(I-40),
N-(4-苯氧基苯基)-5-(四氢-2H-吡喃-3-基)-1,5-二氢-1,4,5,6,8-五氮杂苊-3-胺(I-41),
2-(4-甲基哌嗪-1-基)-1-(4-(3-((4-苯氧基苯基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)乙烷-1-酮(I-42),
2-(4-甲基哌嗪-1-基)-N-(4-(3-((4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)环己基)乙酰胺(I-43),
1-(4-(3-(4-苯氧基苯基)-1,4,5,6,8-无氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-44),
1-(4-(3-((4-((1-甲基-1H-吡唑-4-基)氧基)苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-45),
N-(4-((5-(1-丙烯酰哌啶-4-基)-1,5-二氢-1,4,5,6,8-五氮杂苊-3-基)氨基)苯基)苯甲酰胺(I-46),
4-((5-(1-丙烯酰哌啶-4-基)-1,5-二氢-1,4,5,6,8-五氮杂苊-3-基)氨基)-N-苯甲酰胺(I-47),
1-(4-(3-((4-(吗啉-4-羧基)苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-48),
4-((5-(1-丙烯酰哌啶-4-基)-1,5-二氢-1,4,5,6,8-五氮杂苊-3-基)氨基)-N-环己基苯甲酰胺(I-49),
4-((5-(1-丙烯酰哌啶-4-基)-1,5-二氢-1,4,5,6,8-五氮杂苊-3-基)氨基)-N-环丙基苯甲酰胺(I-50),
4-((5-(1-丙烯酰哌啶-4-基)-1,5-二氢-1,4,5,6,8-五氮杂苊-3-基)氨基)-N-(1-甲基-1H-吡唑-4-基)苯甲酰胺(I-51),
1-(4-(3-((4-(嘧啶-2-氧)苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-52),
1-(4-(3-((4-((3-甲基吡啶-2-基)氧)苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-53),
1-(4-(3-((4-((3-三氟甲基吡啶-2-基)氧)苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-54),
1-(4-(3-((4-((4-甲基吡啶-2-基)氧)苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-55),
1-(4-(3-((4-((5-三氟甲基吡啶-2-基)氧)苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-56),
1-(4-(3-((4-((5-甲基吡啶-2-基)氧)苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-57),
1-(4-(3-((4-(苯胺基)苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-58),1-(4-(3-((4-(苯砜基)苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-59),1-(4-(3-((4-(吡啶-2-氧基)苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)吡咯烷-2-基)丙-2-烯-1-酮(I-60),
4-((5-(1-丙烯酰吡咯烷-3-基)-1,5-二氢-1,4,5,6,8-五氮杂苊-3-基)氨基)-N-(吡啶-2-基)苯甲酰胺(I-61),
1-(4-(3-((4-(吡啶-2-氧基)苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-炔-1-酮(I-62),
N-(3-(3-((4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)环丁基)丙烯酰胺(I-63),
1-(2-(3-((4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)吡咯烷-1-基)丙-2-烯-1-酮(I-64),
1-(2-(3-((4-苯氧基苯基)氨基)-1,4,5,6,8-五氮杂苊-5(1H)-基)哌啶-1-基)丙-2-烯-1-酮(I-65)。
5.根据权利要求1~4任一所述的五氮杂苊类化合物,其特征在于,所述药学上可接受的盐为所述五氮杂苊类化合物与酸或碱形成的盐,所述酸为盐酸、氢溴酸、硫酸、磷酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、柠檬酸、苹果酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸、琥珀酸、富马酸、水杨酸、苯基乙酸或杏仁酸,所述碱为含有碱性金属阳离子、碱土金属阳离子或铵阳离子盐的无机碱。
6.一种权利要求1~5任一所述的五氮杂苊类化合物的制备方法,其特征在于,所述制备方法为:
当X为NH,Y为N,L为NH时,化合物1与化合物2,经亲核取代、环合、偶联、脱保护基、缩合、脱保护基反应得到化合物(I);
其中,R2、R3的定义如权利要求1~2任一所述;
将相应的酸或碱与以上方法制备的化合物(I)成盐,即得所述五氮杂苊类化合物的药学上可接受的盐。
7.一种药物组合物,其特征在于,所述药物组合物包含权利要求1~5任一所述五氮杂苊类化合物以及药学上可接受的载体。
8.根据权利要求7所述的药物组合物,其特征在于,所述五氮杂苊类化合物添加药学上可接受的载体制成片剂、胶囊、糖浆、悬浮剂或注射剂,所述药学上可接受的载体为香料、甜味剂、液体/固体填料、稀释剂。
9.一种权利要求1~5任一所述的五氮杂苊类化合物或者权利要求7所述的药物组合物在制备Bruton酪氨酸激酶抑制剂药物中的应用。
10.根据权利要求9所述的应用,其特征在于,所述药物用于治疗和/或预防肿瘤或者炎症免疫性疾病。
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