CN114276349B - 2-氨基喋啶酮类衍生物或其盐及其制备方法和用途 - Google Patents
2-氨基喋啶酮类衍生物或其盐及其制备方法和用途 Download PDFInfo
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- CN114276349B CN114276349B CN202111514246.7A CN202111514246A CN114276349B CN 114276349 B CN114276349 B CN 114276349B CN 202111514246 A CN202111514246 A CN 202111514246A CN 114276349 B CN114276349 B CN 114276349B
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- ethyl
- methylfuran
- pteridin
- piperazin
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明属于化学医药领域,涉及一种2‑氨基喋啶酮类衍生物或其盐及其制备方法和用途。这些化合物具有式(I)的结构,具有腺苷A2A受体(adenosine A2A receptor,A2AR)抑制活性,可用于制备治疗或预防与A2AR有关的疾病的药物。
Description
技术领域
本发明涉及化学医药领域,涉及一种2-氨基喋啶酮类衍生物或其盐及其制备方法和用途。
背景技术
腺苷作为内源性嘌呤核苷参与诸多的生理和病理过程:它是合成腺苷三磷酸(ATP)的必须前体、储存细胞能量的主要分子、合成核苷酸的重要代谢中间体。自1983年,四类亚型的腺苷受体(A1、A2A、A2B和A3)被克隆出来,胞外的腺苷正是通过调控这四类受体而发挥作用。腺苷受体属于一类G蛋白偶联受体(GPCR),在体内分布广泛且发挥着不同作用,包括:血管舒张和缺血再灌注、血管生成、心律和循环、睡眠和唤醒、神经退行性疾病、炎症。靶向腺苷受体以期获得临床疗效由来已久也显而易见。腺苷本身作为一种仿制药(商品名Adenocard or Adenoscan)就在临床上用于治疗室上性心动过速,咖啡因在某些临床情况下也用于早产儿的呼吸暂停,很多临床药物(双嘧达莫、甲氨蝶呤)也很有可能是通过腺苷受体而发挥相应的作用。瑞加德松(商品名Lexiscan)被美国FDA批准为心肌血流灌注显影剂用以诊断冠状动脉疾病,伊曲茶碱(商品名Nouriast)在日本上市用于治疗早期帕金森综合征症状,这些更加证实了A2AR作为药物研发靶点的可能性。
在中枢神经系统(CNS)中,腺苷是一种有效的内源性神经调节剂,它控制许多神经递质的释放,因此涉及影响运动功能、睡眠、焦虑、疼痛和精神运动活动。大脑中主要的腺苷受体亚型是A1和A2A。腺苷A1受体高密度地分布于整个大脑。A1受体拮抗剂可降低癫痫发作阈值,并有潜在的促惊厥作用(e.g.,Cotter G,et al.,2008,J.Card.Fail.14:631-640)。A2A受体分布较为局限,在基底神经节纹状体(尾壳核、伏隔核、嗅结核)上高密度分布,与多巴胺D2受体一起位于纹状体输出神经元上。A2A受体在纹状体上地的离散分布及其对多巴胺D2受体的抑制作用,使A2A受体抑制剂展现出改善由神经退行性疾病,如帕金森氏症、阿尔茨海默症、亨廷顿氏舞蹈症和精神病引起的运动障碍等(e.g.,Rodrigo C,et al.,2008,Curr.Pharm.Des.14:1512-1524;Tuite P,et al.,2003,Expert Opin.Investig.Drugs12:1335-52;Popoli P.et al.,2002,J.Neurosci.22:1967-75)。
这些运动障碍通常可能是脑部病变的结果。涉及基底神经节导致运动障碍的疾病包括帕金森氏症、亨廷顿舞蹈症和威尔逊氏病。帕金森氏症的特征是黑质纹状体多巴胺能通路的逐步退化。纹状体多巴胺水平降低是导致运动障碍症状的原因。震颤,僵硬,运动障碍和体位变化是帕金森氏症的四个典型症状,但该疾病还与睡眠障碍,抑郁,焦虑,精神病,痴呆和整体认知能力下降有关(e.g.,Jankovic J,et al.,2008,J.Neural.Neurosurg.Psychiatry 79:368-376)。尽管可以使用药物减轻症状和/或减慢疾病的进程,帕金森氏症仍是一种进行性且目前无法治愈的疾病,并且没有明确的预防性治疗方法。当前的疗法是基于突触前末梢的多巴胺替代疗法,例如,通过使用L-DOPA(多巴胺前体),直接刺激突触后D2受体或使用B型单胺氧化酶(MAO-B)或儿茶酚邻甲基转移酶(COMT)抑制代谢。尽管L-DOPA是治疗帕金森氏病的主要手段,但由于耐受性问题和诸多的不良反应,包括不自主运动和呕吐,且随着持续治疗,这种不良反应会变得越来越严重,对新疗法的需求仍然很高。为此,高度选择性的A2A受体拮抗剂已显示出其减轻与神经退行性疾病(如帕金森氏症)相关的运动症状的功效(e.g.,Shook and Jackson,2011,ACSChem.Neurosci.2:555-567)。
A2A受体拮抗剂也可能是成瘾治疗的潜在有用疗法。主要导致成瘾的药物(鸦片,可卡因,乙醇等)直接或间接调节神经元中的多巴胺信号传导,尤其是在伏隔核中。而伏隔核中含有高水平的A2A受体,腺苷信号通路激活显示出药物依赖性的增强,A2A受体拮抗剂可减少对成瘾性物质的渴望(e.g.,Stephen H,Macdonald C,2003,Crit.Rev.Neurobiol.15:235-274)。
近年来,癌症免疫治疗赢得学术界、工业界的青睐和各大商业资本的投入,毒性T淋巴细胞相关抗原4(CTLA-4)和程序性细胞死亡蛋白1(PD-1)的免疫药物也接连上市,免疫疗法必将成为继放化疗、靶向治疗之后的又一次革命,并开创肿瘤治疗的新局面。尽管免疫治疗在各类型癌症中取得一定成功,但肿瘤微环境(tumor microenvironment,TME)存在多种代偿性免疫抑制机制,导致免疫疗法的响应率偏低。腺苷信号通路在TME的免疫炎症调控中扮演重要角色,成为下调抗肿瘤免疫的关键负反馈回路。高浓度腺苷是TME的重要标志,激活表达在T淋巴细胞、NK细胞、单核细胞和树突状细胞等免疫细胞上的A2AR,从而抑制免疫细胞的先天性免疫功能和适应性免疫功能。A2AR拮抗剂可以阻断腺苷和A2AR结合从而逆转腺苷的免疫抑制作用,作为一种小分子免疫微环境调节剂(当前癌症免疫疗法几乎全是多肽、抗体和细胞药物),A2AR拮抗剂可以激活抗肿瘤免疫,其作为癌症免疫治疗药物开发的潜力和市场价值巨大。
发明内容
1.一种通式(I)所示的化合物或其药学上可接受的盐或溶剂化物或其立体异构体。
其中
X选自O、S或者NH;
L选自C1-6亚烷基,-C1-6亚烷基-O-或者-C1-6亚烷基-N(R4)-;
A选自共价键,或者/>
B选自C1-6烷基,C3-8环烷基,含3-8个环原子的杂环烷基,芳基或杂芳基;
C选自芳基或杂芳基;
R1选自氢,卤素,羟基,氰基,三氟甲基,三氟甲氧基,二氟甲氧基,C1-8烷基,-O-C1-8烷基,-G1-O-C1-8烷基,-O-G1-O-C1-8烷基,-G1-O-G1-O-C1-8烷基,-C(O)R8,-C(O)OR8,-NR8R9,-C(O)NR8R9,-S(O2)R8,-S(O2)NR8R9,C3-8环烷基,-O-C3-8环烷基,含3-8个环原子的杂环烷基,-G1-O-含3-8个环原子的杂环烷基,芳基,杂芳基,-O-芳基或者-O-杂芳基中的一种或数种;
R2选自氢,卤素,羟基,氰基,C1-8烷基,-O-C1-8烷基,C3-8环烷基,含3-8个环原子的杂环烷基,芳基或杂芳基中的一种或几种;
R3选自氢,C1-8烷基,或者卤素取代的C1-8烷基;
R4选自氢,C1-8烷基,C3-8环烷基,含3-8个环原子的杂环烷基;
R5、R6各自独立地选自氢,C1-8烷基,C3-8环烷基,或者R5和R6桥接并与他们各自所连接的原子一起组成含有3-8个环原子的环烷基或杂环烷基;
R7选自氢,C1-8烷基,C3-8环烷基,含3-8个环原子的杂环烷基;
R8、R9各自独立地选自氢,C1-8烷基,C3-8环烷基,含3-8个环原子的杂环烷基;
G1选自C1-4亚烷基;
n1、n2选自0,1,2,3;
n3、n4选自1,2,3。
在一些优选的实施方案中,X为O。
在一些优选的实施方案中,R3为氢、CH3或CF3。
在一些优选的实施方案中,L为C1-6亚烷基;更为优选地,L为C1-4亚烷基。
在一些优选的实施方案中,A选自共价键,
在一些优选的实施方案中,B选自甲基,环丙基,环戊基,环己基,苯基,吡啶基,呋喃基,嘧啶基。
在一些优选的实施方案中,R1选自氢,卤素,氰基,三氟甲基,三氟甲氧基,二氟甲氧基,-O-C1-8烷基,-O-C1-4亚烷基-O-C1-8烷基,-C1-4亚烷基-O-C3-8环烷基,含3-8个环原子的杂环烷基,-C1-4亚烷基-O-含3-8个环原子的杂环烷基,-O-芳基中的一种或数种。
在一些优选的实施方案中,C选自呋喃基,苯基,吡唑基。
在一些优选的实施方案中,R2选自氢,卤素,氰基,CH3或CF3中的一种或几种;更为优选地,R2选自氢,氰基或-CH3中的一种或数种。
最优选地,本发明提供的2-氨基喋啶酮类化合物包括但不限于以下具体化合物实例:
1. 2-氨基-8-(4-甲氧基苯基)-4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮
2. 2-氨基-8-(3-甲氧基苯基)-4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮
3. 2-氨基-8-(2-甲氧基苯基)-4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮
4. 2-氨基-8-(3-氟苯基)-4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮
5. 2-氨基-4-(5-甲基呋喃-2-基)-8-(3-(三氟甲基)苄基)喋啶-7(8H)-酮
6. 3-((2-氨基-4-(5-甲基呋喃-2-基)-7-氧代喋啶-8(7H)-基)亚甲基)苯腈
7.(S)-2-氨基-4-(5-甲基呋喃-2-基)-8-((6-(((四氢呋喃-3-基)氧基)甲基)吡啶-2-基)亚甲基)喋啶-7(8H)-酮
8. 2-氨基-4-(5-甲基呋喃-2-基)-8-(吡啶-2-基亚甲基)喋啶-7(8H)-酮
9. 2-氨基-8-(呋喃-2-基亚甲基)-4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮
10. 2-氨基-8-(环己基亚甲基)-4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮
11. 2-氨基-8-(环丙亚甲基)-4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮
12. 2-氨基-8-苄基-4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮
13. 2-氨基-4-(5-甲基呋喃-2-基)-8-苯乙基喋啶-7(8H)-酮
14. 2-氨基-4-(5-甲基呋喃-2-基)-8-(3-苯基正丙基)喋啶-7(8H)-酮
15. 2-氨基-4-(5-甲基呋喃-2-基)-8-(4-苯基正丁基)喋啶-7(8H)-酮
16. 2-氨基-4-(5-甲基呋喃-2-基)-8-(2-(4-甲基哌嗪-1-基)乙基)喋啶-7(8H)-酮
17. 2-氨基-8-(2-(4-环戊基哌嗪-1-基)乙基)-4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮
18. 2-氨基-4-(5-甲基呋喃-2-基)-8-(2-(4-苯基哌嗪-1-基)乙基)喋啶-7(8H)-酮
19. 2-氨基-8-(2-(4-(2-甲氧基苯基)哌嗪-1-基)乙基)-4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮
20. 2-氨基-8-(2-(4-(3-甲氧基苯基)哌嗪-1-基)乙基)-4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮
21. 2-氨基-8-(2-(4-(4-甲氧基苯基)哌嗪-1-基)乙基)-4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮
22. 2-氨基-8-(2-(4-(2-氟苯基)哌嗪-1-基)乙基)-4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮
23. 2-氨基-8-(2-(4-(3-氟苯基)哌嗪-1-基)乙基)-4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮
24. 2-氨基-8-(2-(4-(4-氟苯基)哌嗪-1-基)乙基)-4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮
25. 2-氨基-4-(5-甲基呋喃-2-基)-8-(2-(4-(2-(三氟甲基)苯基)哌嗪-1-基)乙基)喋啶-7(8H)-酮
26. 2-氨基-4-(5-甲基呋喃-2-基)-8-(2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙基)喋啶-7(8H)-酮
27. 2-氨基-4-(5-甲基呋喃-2-基)-8-(2-(4-(4-(三氟甲基)苯基)哌嗪-1-基)乙基)喋啶-7(8H)-酮
28. 2-氨基-4-(5-甲基呋喃-2-基)-8-(2-(4-(2-(三氟甲氧基)苯基)哌嗪-1-基)乙基)喋啶-7(8H)-酮
29. 2-氨基-4-(5-甲基呋喃-2-基)-8-(2-(4-(3-(三氟甲氧基)苯基)哌嗪-1-基)乙基)喋啶-7(8H)-酮
30. 2-氨基-4-(5-甲基呋喃-2-基)-8-(2-(4-(4-(三氟甲氧基)苯基)哌嗪-1-基)乙基)喋啶-7(8H)-酮
31.(S)-2-氨基-8-(2-(4-(4-甲氧基苯基)-2-甲基哌嗪-1-基)乙基)-4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮
32.(R)-2-氨基-8-(2-(4-(4-甲氧基苯基)-2-甲基哌嗪-1-基)乙基)-4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮
33.(S)-2-氨基-8-(2-(4-(4-甲氧基苯基)-3-甲基哌嗪-1-基)乙基)-4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮
34.(R)-2-氨基-8-(2-(4-(4-甲氧基苯基)-3-甲基哌嗪-1-基)乙基)-4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮
35. 2-氨基-8-(2-((2S,5R)-4-(4-甲氧基苯基)-2,5-二甲基哌嗪-1-基)乙基)-4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮
36. 2-氨基-8-(2-((1S,4S)-5-(4-甲氧基苯基)-2,5-二氮杂二环[2.2.1]庚烷-2-基)乙基)-4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮
37. 2-氨基-8-(2-(3-(4-甲氧基苯基)-3,8-二氮杂二环[3.2.1]辛烷-8-基)乙基)-4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮
38. 2-氨基-8-(2-(4-(4-甲氧基苯基)-1,4-二氮杂环庚烷-1-基)乙基)-4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮
39. 2-氨基-4-(5-甲基呋喃-2-基)-8-((1-苯基哌啶-4-基)亚甲基)喋啶-7(8H)-酮
40. 2-氨基-4-(5-甲基呋喃-2-基)-8-(2-(1-苯基哌啶-4-基)乙基)喋啶-7(8H)-酮
41. 2-氨基-4-(5-甲基呋喃-2-基)-8-(2-(4-苯基哌啶-1-基)乙基)喋啶-7(8H)-酮
42. 2-氨基-8-(2-(3-((4-甲氧基苯基)(甲基)氨基)吡咯-1-基)乙基)-4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮
43. 2-氨基-8-(2-((1-(4-甲氧基苯基)吡咯-3-基)(甲基)氨基)乙基)-4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮
44. 2-氨基-8-(2-(3-((4-甲氧基苯基)(甲基)氨基)氮杂环丁烷-1-基)乙基)-4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮
45. 2-氨基-8-(2-(4-(2-氟-4-甲氧基苯基)哌嗪-1-基)乙基)-4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮
46. 2-氨基-8-(2-(4-(2,4-二氟苯基)哌嗪-1-基)乙基)-4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮
47. 2-氨基-8-(2-(4-(2-氟-4-甲氧基苯基)哌嗪-1-基)乙基)-6-甲基-4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮
48. 2-氨基-8-(2-(4-(2-氟苯基)哌嗪-1-基)乙基)-6-甲基-4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮
49. 2-氨基-8-(2-(4-(2-氟苯基)哌嗪-1-基)乙基)-6-三氟甲基-4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮
50. 2-(2-氨基-8-(2-(4-(2-氟苯基)哌嗪-1-基)乙基)-7-氧代-7,8-二氢喋啶-4-基)-6-甲基苯甲腈
51. 2-氨基-8-(2-(4-(2-氟苯基)哌嗪-1-基)乙基)-4-(1H-吡唑-4-基)喋啶-7(8H)-酮52. 2-氨基-8-(2-(4-(2-氟-4-(2-甲氧基乙氧基)苯基)哌嗪-1-基)乙基)-4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮
53. 2-氨基-8-(2-(4-(2,3-二氟-4-(2-甲氧基乙氧基)苯基)哌嗪-1-基)乙基)-4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮
54.(S)-2-氨基-8-(2-(4-(2-氟-4-甲氧基苯基)-2-甲基哌嗪-1-基)乙基)-4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮
55. 2-氨基-8-(2-(4-(6-甲氧基吡啶-3-基)哌嗪-1-基)乙基)-6-甲基-4-(5-甲基呋喃-2-基)蝶呤-7(8H)-酮
56. 2-氨基-8-(2-(4-(6-甲氧基吡啶-3-基)哌嗪-1-基)乙基)-4-(5-甲基呋喃-2-基)蝶呤-7(8H)-酮
57. 2-氨基-8-(2-(4-(5-甲氧基吡啶-2-基)哌嗪-1-基)乙基)-4-(5-甲基呋喃-2-基)蝶呤-7(8H)-酮
58. 2-氨基-8-(2-(4-(6-异丙氧基吡啶-3-基)哌嗪-1-基)乙基)-4-(5-甲基呋喃-2-基)吡啶-7(8H)-酮
59. 2-氨基-8-(2-(4-(4-(二氟甲氧基)苯基)哌嗪-1-基)乙基)-4-(5-甲基呋喃-2-基)蝶呤-7(8H)-酮
60. 2-氨基-4-(5-甲基呋喃-2-基)-8-(2-(4-(嘧啶-5-基)哌嗪-1-基)乙基)蝶呤-7(8H)-酮
61. 2-氨基-8-(2-(4-(3-氟-5-甲氧基吡啶-2-基)哌嗪-1-基)乙基)-4-(5-甲基呋喃-2-基)蝶呤-7(8H)-酮
62. 2-氨基-8-(2-(4-(5-(二氟甲氧基)-3-氟吡啶-2-基)哌嗪-1-基)乙基)-4-(5-甲基呋喃-2-基)蝶呤-7(8H)-酮
63. 2-氨基-8-(2-(4-(5-(二氟甲氧基)-3-氟吡啶-2-基)哌嗪-1-基)乙基)-6-甲基-4-(5-甲基呋喃-2-基)蝶呤-7(8H)-酮
64. 2-氨基-8-(2-(4-(2-氟-4-(三氟甲氧基)苯基)哌嗪-1-基)乙基)-4-(5-甲基呋喃-2-基)蝶呤-7(8H)-酮
65. 2-氨基-8-(2-(4-(2-氟-4-(三氟甲基)苯基)哌嗪-1-基)乙基)-4-(5-甲基呋喃-2-基)蝶呤-7(8H)-酮
66. 2-氨基-8-(2-(4-(2-甲氧基嘧啶-5-基)哌嗪-1-基)乙基)-4-(5-甲基呋喃-2-基)蝶呤-7(8H)-酮
67. 2-氨基-8-(2-(4-(5-(二氟甲氧基)-3-氟吡啶-2-基)哌嗪-1-基)乙基)-4-(5-甲基呋喃-2-基)-6-(三氟甲基)蝶呤-7(8H)-酮
68. 2-氨基-4-(5-甲基呋喃-2-基)-8-(2-(4-(4-苯氧基苯基)哌嗪-1-基)乙基)蝶呤-7(8H)-酮
本发明还提供了一种制备上述2-氨基喋啶酮类化合物的方法,包括以下合成方案:
反应条件:a)Et3N,Sec-BuOH,105℃,24h;b)HOAc,EtOH,80℃,4~6h;c)Pd(PPh3)4,Na2CO3,dioxane/H2O,95℃,12h。
Scheme 1代表了具有化学通式(I)的部分化合物的通用合成路线,起始原料1.1与取代亚甲基胺试剂通过亲核反应取代得到6-氯-N4-取代基嘧啶-2,4,5三胺中间体1.2,然后与乙醛酸乙酯通过关环得到中间体1.3,最后与相应的芳基硼酸或硼酸酯试剂通过Suzuki-Miyaura反应得到终产物1.4。
反应条件:a)Pd2(dba)3,2-二环己基膦-2',6'-二异丙氧基-1,1'-联苯,toluene,105℃,24h;b)①2M HCl in EA,MeOH/EA,25℃,16h;②DIPEA,CH3CN,75℃,24h;c)①2M HClin EA,MeOH/EA,25℃,10h;②Et3N,Sec-BuOH,105℃,24h;d)HOAc,EtOH,80℃,4~6h;e)Pd(PPh3)4,Na2CO3,dioxane/H2O,95℃,12h。
Scheme 2代表了具有化学通式(I)的部分化合物的通用合成路线,起始原料2.1与相应的Boc保护的二胺试剂通过钯催化的碳氮偶联反应得到中间体2.2,然后酸性条件脱去Boc保护基并与相应的卤代物通过亲核取代反应得到中间体2.3,再经酸性条件脱去Boc保护基并与2,5-二氨基-4,6-二氯嘧啶通过亲核取代反应得到中间体2.4,然后与乙醛酸乙酯通过关环得到中间体2.5,最后与相应的芳基硼酸或硼酸酯试剂通过Suzuki-Miyaura反应得到终产物2.6。
除非另有说明,上述合成方案中所述基团、术语的含义与通式I化合物中的含义相同。
上述合成方案只是列举了本发明中部分化合物的制备方法,按照本领域的公知技术,技术人员在上述合成方案的基础上,采用类似的方法也可合成本发明的化合物。
本发明所述的“化合物”,包括所有立体异构体、几何异构体、互变异构体和同位素。
本发明所述的“化合物”,可以是不对称的,例如,具有一个或多个立体异构体。除非另有说明,所有立体异构体都包括,如对映异构体和非对映异构体。本发明中含有不对称碳原子的化合物,可以光学活性纯的形式或外消旋形式被分离出来。光学活性纯的形式可以从外消旋混合物拆分,或通过使用手性原料或手性试剂合成。
本发明所述的“化合物”,还包括互变异构体形式。互变异构体形式来源于一个单键与相邻的双键交换并一起伴随一个质子的迁移。
本发明还包括所有同位素的原子,无论是在中间体或最后的化合物。同位素的原子包括具有相同的原子数、但不同质量数的。例如,氢的同位素包括氘和氚。
本发明中,除特殊说明外,所用的术语具有如下含义:
术语“卤素”是指氟、氯、溴或碘,优选氟或氯。
术语“氰基”,指-CN。
术语“羟基”,指-OH。
术语“烷基”,指由碳原子和氢原子组成的直链或支链的饱和烃基团,如C1-C20烷基,优选为C1-C6烷基,例如甲基、乙基、丙基(包括正丙基和异丙基)、丁基(包括正丁基、异丁基、仲丁基或叔丁基)、戊基(包括正戊基、异戊基、新戊基)、正己基、2-甲基己基等。所述烷基可以是非取代的、或是被一个或多个取代基所取代,取代基包括但不限于烷基、烷氧基、氰基、羟基、羰基、羧基、芳基、杂芳基、氨基、卤素、磺酰基、亚磺酰基、磷酰基。
术语“亚烷基”,指烷基失去一个氢原子所得到的二价基团,其中烷基如上定义。,优选为C1-C4亚烷基,例如亚甲基、亚乙基、亚丙基、亚丁基。取代基包括但不限于烷基、烷氧基、氰基、羟基、羰基、羧基、芳基、杂芳基、氨基、卤素、磺酰基、亚磺酰基、磷酰基。
术语“环烷基”,指全部为碳的单环、稠合、螺环或桥环的环,如环丙基、环丁基、环戊基、环戊烯基、环己基、螺[3.4]辛烷基、二环[3.1.1]己烷基。
术语“杂环烷基”,指含1个或多个N、O或S的杂原子的单环或稠合的环。典型地为含1个或多个N、O或S的杂原子的5-6元杂环基,例如四氢呋喃基、哌嗪基、吗啉基、哌啶基、吡咯烷基及其衍生物。
术语“芳基”,指具有完全共轭的π电子体系的全碳单环或稠合环,通常具有6-14个碳原子,优选具有6-12个碳原子,最优选具有6个碳原子。芳基可以是非取代的、或被一个或多个取代基所取代,取代基包括但不限于烷基、烷氧基、氰基、羟基、羰基、羧基、芳基、芳烷基、氨基、卤素、磺酰基、亚磺酰基、磷酰基。非取代的芳基的实例包括但不限于苯基、萘基和蒽基。
术语“杂芳基”是指5-12个环原子的单环或稠合环,其中含有1-4个选自N、O、S的环原子,其余环原子为C,且具有完全共轭的π-电子体系,包括但不限于吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、异噁唑基、吡唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、喹啉基、异喹啉基、三唑基、四氢吡咯基。杂芳基可以是非取代的或取代的,所述的取代基包括但不限于烷基、烷氧基、芳基、芳烷基、氨基、卤素、羟基、氰基、硝基、羰基和杂脂环基。
术语“共价键”,指原子间通过共用电子对所形成的相互作用。“治疗”意味着对哺乳动物体内疾病的任何治疗,包括:(1)防止疾病,即造成临床疾病的症状不发展;(2)抑制疾病,即阻止临床症状的发展;(3)减轻疾病,即造成临床症状的消退。
本发明还提供了一种药物组合物,包含如前所述的化合物或其药学上可接受的盐或溶剂化物作为活性成份,以及一种或多种药学上可接受的载体。
本发明所述的“药物组合物”,指一种或多种本发明的化合物或其盐或溶剂化物与在本领域中通常接受的用于将生物活性化合物输送至有机体(例如人)的载体的制剂。药物组合物的目的是有利于对有机体给药输送。
术语“药学上可接受的载体”,指与活性成份共同给药的、且有利于活性成份给药的物质,包括但不限于国家食品药品监督管理局许可的可接受的用于人或动物(例如家畜)的任何助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味增强剂、表面活性剂、润湿剂、分散剂、崩解剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。例如包括但不限于碳酸钙、磷酸钙、各种糖和各类淀粉、纤维素衍生物、明胶、植物油和聚乙二醇。
本发明所述的药物组合物,可配制成固态、半固态、液态或气态制剂,如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、溶液剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等等。
本发明所述的药物组合物,可以采用本领域熟知的方法制造,如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。
本发明所述的化合物或其药学上可接受的盐或其药物组合物的给药途径,包括但不限于口服、直肠、透黏膜、经肠给药,或者局部、经皮、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。优选的给药途径是口服给药。
对于口服给药,可以通过将活性化合物与本领域熟知的药学上可接受的载体混合,来配制该药物组合物。这些载体能使本发明的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂、悬浮剂等,以用于对患者的口服给药。例如,用于口服给药的药物组合物,可采用如下方式获得片剂:将活性成分与一种或多种固体载体合并,如果需要将所得混合物制粒,并且如果需要加入少量的赋形剂加工成混合物或颗粒,以形成片剂或片芯。片芯可与任选适合肠溶的包衣材料结合,加工成更有利于有机体(例如人)吸收的包衣制剂形式。
本发明还提供了一种如前所述的化合物或其药学上可接受的盐或溶剂化物,或前述药物组合物在制备腺苷A2AR抑制剂方面的应用。
本发明同时还提供了一种如前所述的化合物或其药学上可接受的盐或或溶剂化物或它们的药物组合物作为腺苷A2AR抑制剂在制备用于治疗或预防与A2AR有关的疾病的药物中的用途。
本发明化合物的药学上可接受的盐包括通过碱性和无机酸或有机酸反应形成的常规无毒盐。即采用化合物的游离碱,与无机或有机酸成盐反应进行。无机或有机酸可选自盐酸、硫酸、硝酸、氢氟酸、氢溴酸、甲酸、乙酸、苦味酸、柠檬酸、马来酸、甲烷磺酸、三氟甲烷磺酸、乙烷磺酸、对甲苯磺酸等。
如果发明化合物为酸性的,则适当的“药学上可接受的盐”指通过药学上可接受的无毒碱包括无机碱及有有机碱制备的盐。可选自铝盐、铵盐、锂盐、镁盐、钠盐等。特别优选铵盐、钙盐、镁盐、钾盐和钠盐。得自药学上可接受的有机无毒碱的盐,所述碱包括伯胺、仲胺和叔胺的盐,取代的胺包括天然存在的取代胺、环状胺及碱性离子交换树脂例如精氨酸、甜菜碱和咖啡因等。
优选的,前述与A2AR有关的疾病选自癌症(cancer)、帕金森病(Parkinson’sdisease)、肌萎缩性侧束硬化症(amyotrophic lateral sclerosis;ALS)、冠状动脉疾病(coronary artery disease)、轻度认知障碍(mild cognitive impairment)、多发性硬化(mμLtiple sclerosis)、心包性假性肝硬变(Pick’s disease)、类风湿性关节炎(rheumatoid arthritis)、双相型障碍(bipolar disorder)、实验性内毒素血症(experimental endotoxemia)、及精神分裂症(schizophrenia)或前述疾病组合。
本发明提供了一类具有通式(I)结构的2-氨基喋啶-7(8H)-酮类衍生物。经研究发现,该类化合物可有效抑制腺苷A2A受体,从而调节免疫微环境中胞内环磷酸腺苷(cAMP)的水平,调控机体的免疫生理反应,可作为治疗或预防与A2AR有关疾病的药物。
除在文献中已知的或在实验程序中例证的标准方法外,可采用如下列方案中显示的反应制备本发明化合物。因此,下列说明性方案是为说明的目的而不是局限于所列化合物或任何特定的取代基。方案中显示的取代基数目并不必需要符合权利要求中所用的数目,且为清楚起见,显示单取代基连接到本专利结构式的定义允许有多取代基的化合物。
具体实施方式
以下是本发明的具体实施例,对本发明的技术方案做进一步的描述,但是本发明的保护范围并不限于这些实施例。凡是不背离本发明构思的改变或等同替代均包括在本发明的保护范围之内。
本发明提供的目标化合物制备方法中,柱层析色谱采用乳山太阳干燥剂有限公司生产的硅胶(300-400目);薄层色谱采用GF254(0.25毫米);核磁共振色谱(NMR)使用Varian-400核磁共振仪测定;液质连用(LC/MS)使用Agilent Technologies 6120液质联用仪。
此外,凡涉及易氧化或易水解的原料的所有操作都在氮气保护下进行。除非另有说明,本发明使用的原料都是市售原料、无需进一步纯化可以直接使用。
PE:石油醚
EA:乙酸乙酯
DCM:二氯甲烷
CH3CN:乙腈
Sec-BuOH:仲丁醇
MeOH:甲醇
EtOH:乙醇
DMF:N,N’-二甲基甲酰胺
Et3N:三乙胺
DIPEA:N,N’-二异丙基乙胺
HOAc:乙酸
2M HCl in EA:2mol/L盐酸乙酸乙酯溶液
Na2CO3:碳酸钠
Cs2CO3:碳酸铯
Pd2(dba)3:三(二亚苄基丙酮)二钯
Pd(PPh3)4:四(三苯基膦)钯
RuPhos:2-二环己基磷-2’,6’-二异丙氧基-1,1’-联苯
TLC:薄层硅胶板(G254)分析
P-TLC:制备薄层硅胶板
实施例一2-氨基-8-(4-甲氧基苄基)-4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮
(2-Amino-8-(4-methoxybenzyl)-4-(5-methylfuran-2-yl)pteridin-7(8H)-one)
步骤1:6-氯-N4-(4-甲氧基苄基)吡啶-2,4,5-三胺的合成
2,5-二氨基-4,6-二氯嘧啶(1.79g,10.0mmol,1.0equiv.),4-甲氧基苄胺(2.06g,15.0mmol,1.5equiv.),Et3N(2.02g,20.0mmol,2.0equiv.)溶于适量Sec-BuOH,氮气保护下,105℃搅拌12小时。TLC实时监测反应。反应毕,于2~8℃静置至析出固体,过滤,先后用冷乙醇、石油醚洗涤,干燥,即得到粉红色固体(2.0g,收率:71.5%)。
ESI(m/z):[M+1]+279.9;1H NMR(400MHz,DMSO-d6)δ7.25(d,J=8.4Hz,2H),6.94(s,1H),6.87(d,J=8.5Hz,2H),5.67(s,2H),4.47(s,2H),3.93(s,2H),3.71(s,3H).
步骤2:2-氨基-4-氯-8-(4-甲氧基苄基)喋啶-7(8H)-酮的合成
6-氯-N4-(4-甲氧基苄基)吡啶-2,4,5-三胺(1.0g,3.6mmol,1.0equiv.)溶于乙醇(15mL),随后滴加乙醛酸乙酯的50wt.%甲苯溶液(795.5mg)、冰醋酸(1090.2μL),密封,80℃搅拌4~6小时。TLC实时监测反应。反应毕,于2~8℃静置至析出固体,过滤,先后用冷乙醇、石油醚洗涤,干燥,即得到黄色固体(802.2mg,收率:70.6%)。
ESI(m/z):[M+1]+317.8;1H NMR(400MHz,DMSO-d6)δ7.89(s,1H),7.87(s,2H),7.35(d,J=7.6Hz,2H),6.84(d,J=7.5Hz,2H),5.24(s,2H),3.70(s,3H).
步骤3:2-氨基-8-(4-甲氧基苄基)-4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮的合成
2-氨基-4-氯-8-(4-甲氧基苄基)喋啶-7(8H)-酮(158.9mg,0.5mmol,1.0equiv.),5-甲基呋喃硼酸(125.9mg,1.0mmol,2.0equiv.),Pd(PPh3)4(115.6mg,20%),Na2CO3(105.9mg,1.0mmol,2.0equiv.)溶于dioxane/H2O(6mL/0.6mL),氮气置换2min,密闭,95℃搅拌12小时。TLC实时监测反应。反应毕,冷至室温,用DCM/MeOH(10:1)稀释,依次用水、饱和食盐水洗涤,有机相浓缩后经硅胶柱层析(DCM/MeOH=200/1)分离得到黄色固体(120.1mg,收率:66.1%)。
ESI(m/z):[M+1]+363.8;1H NMR(400MHz,DMSO-d6)δ7.88(s,1H),7.75(d,J=3.0Hz,1H),7.51(brs,2H),7.38(d,J=6.4Hz,2H),6.84(d,J=6.5Hz,2H),6.38(d,J=3.6Hz,1H),5.28(s,2H),3.69(s,3H),2.39(s,3H).
实施例二2-氨基-8-(3-甲氧基苄基)-4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮
(2-Amino-8-(3-methoxybenzyl)-4-(5-methylfuran-2-yl)pteridin-7(8H)-one)
路线参照实施例1。
ESI(m/z):[M+1]+363.8;1H NMR(400MHz,DMSO-d6)δ7.90(s,1H),7.77(d,J=3.5Hz,1H),7.52(brs,2H),7.21(t,J=7.9Hz,1H),6.97(s,1H),6.92(d,J=7.5Hz,1H),6.82(d,J=8.1Hz,1H),6.39(d,J=3.6Hz,1H),5.34(s,2H),3.72(s,3H),2.41(s,3H).
实施例三2-氨基-8-(2-甲氧基苄基)-4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮
(2-Amino-8-(2-methoxybenzyl)-4-(5-methylfuran-2-yl)pteridin-7(8H)-one)
路线参照实施例1。
ESI(m/z):[M+1]+363.8;1H NMR(400MHz,DMSO-d6)δ7.93(s,1H),7.81(d,J=3.4Hz,1H),7.56(brs,2H),7.21(d,J=8.0Hz,1H),7.02(d,J=8.2Hz,1H),6.78(t,J=7.3Hz,1H),6.58(d,J=7.6Hz,1H),6.41(s,1H),5.31(s,2H),3.87(s,3H),2.41(s,3H).
实施例四2-氨基-8-(3-氟苄基)-4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮
(2-Amino-8-(3-fluorobenzyl)-4-(5-methylfuran-2-yl)pteridin-7(8H)-one)
路线参照实施例1。
ESI(m/z):[M+1]+351.8;1H NMR(400MHz,DMSO-d6)δ7.90(s,1H),7.77(d,J=3.3Hz,1H),7.54(brs,2H),7.35(dd,J=14.3,7.9Hz,1H),7.22(t,J=8.5Hz,2H),7.09(t,J=8.5Hz,1H),6.39(d,J=3.3Hz,1H),5.36(s,2H),2.40(s,3H).
实施例五2-氨基-4-(5-甲基呋喃-2-基)-8-(3-(三氟甲基)苄基)喋啶-7(8H)-酮
(2-Amino-4-(5-methylfuran-2-yl)-8-(3-(trifluoromethyl)benzyl)pteridin-7(8H)-one)
路线参照实施例1。
ESI(m/z):[M+1]+401.8;1H NMR(400MHz,DMSO-d6)δ7.91(s,1H),7.79–7.76(m,2H),7.67–7.61(m,2H),7.54–7.48(m,3H),6.40(d,J=2.6Hz,1H),5.44(s,2H),2.40(s,3H).
实施例六3-((2-氨基-4-(5-甲基呋喃-2-基)-7-氧代喋啶-8(7H)-基)亚甲基)苯 腈
(3-((2-Amino-4-(5-methylfuran-2-yl)-7-oxopteridin-8(7H)-yl)methyl)benzonit rile)
路线参照实施例1。
ESI(m/z):[M+1]+358.8;1H NMR(400MHz,DMSO-d6)δ7.91(s,1H),7.87(s,1H),7.77(d,J=3.3Hz,1H),7.75–7.70(m,2H),7.64–7.41(m,3H),6.39(dd,J=3.4,0.9Hz,1H),5.38(s,2H),2.40(s,3H).
实施例七(S)-2-氨基-4-(5-甲基呋喃-2-基)-8-((6-(((四氢呋喃-3-基)氧基)甲 基)吡啶-2-基)亚甲基)喋啶-7(8H)-酮
((S)-2-Amino-4-(5-methylfuran-2-yl)-8-((6-(((tetrahydrofuran-3-yl)oxy)methyl)pyridin-2-yl)methyl)pteridin-7(8H)-one)
步骤1:(S)-2-氰基-6-(((四氢呋喃-3-基)氧)甲基)吡啶的合成
(S)-3-羟基四氢呋喃(440.6mg,5.0mmol,1.0equiv.)溶于适量无水DMF,0℃条件下缓缓加入NaH(60wt.%,240mg,6.0mmol,1.2equiv.),氮气保护下搅拌10分钟后,缓慢滴加2-氰基-6-溴甲基吡啶(1083.7mg,5.5mmol,1.1equiv.)的无水DMF溶液,然后移至室温搅拌4~6小时。TLC实时监测反应。反应毕,冷至室温,用EA稀释,依次用清水、饱和食盐水洗涤,有机相浓缩后经硅胶柱层析(DCM/MeOH=200/1)分离得到黄色油状液体(802.3mg,收率:78.6%)。
步骤2:(S)-2-胺甲基-6-((四氢呋喃-3-基)氧)甲基吡啶的合成
(S)-2-氰基-6-(((四氢呋喃-3-基)氧)甲基)吡啶(802.3mg,3.9mmol,1.0equiv.)溶于MeOH/EA(3mL/3mL),氮气保护下加入10wt.%的钯碳(80.2mg),氢气置换,室温搅拌8小时。TLC实时监测反应。反应毕,硅藻土过滤,有机相旋干得到黄色油状液体(781.7mg,直接用于下一步)。
步骤3:(S)-6-氯-N4-((6-(((四氢呋喃-3-基)氧)甲基)吡啶-2-基)甲基)嘧啶-2,4,5-三胺的合成
2,5-二氨基-4,6-二氯嘧啶(671.8mg,3.7mmol,1.0equiv.),(S)-2-胺甲基-6-((四氢呋喃-3-基)氧)甲基吡啶(781.7mg,3.7mmol,1.0equiv.),Et3N(5.6g,55.5mmol,15.0equiv.)溶于适量Sec-BuOH,氮气保护下,105℃搅拌24小时。反应液冷至室温,用EA稀释,依次用清水、饱和食盐水洗涤,有机相浓缩后经硅胶柱层析(DCM/MeOH/NH4OH=200/3/0.5~200/5/0.5)分离得到黄色固体(736.7mg,收率:56.8%)。
步骤4:(S)-2-氨基-4-氯-8-((6-(((四氢呋喃-3-基)氧)甲基)吡啶-2-基)甲基)喋啶-7(8H)-酮的合成
(S)-6-氯-N4-((6-(((四氢呋喃-3-基)氧)甲基)吡啶-2-基)甲基)嘧啶-2,4,5-三胺(526.2mg,1.5mmol,1.0equiv.)溶于乙醇(8mL),随后滴加乙醛酸乙酯的50wt.%甲苯溶液(333.3mg)、冰醋酸(456.8μL),密封,80℃搅拌4~6小时。TLC实时监测反应。反应毕,于2~8℃静置至析出固体,过滤,先后用冷乙醇、石油醚洗涤,干燥,即得到黄色固体(120.7mg,收率:34.4%)。
步骤5:3-((2-氨基-4-(5-甲基呋喃-2-基)-7-氧代喋啶-8(7H)-基)亚甲基)苯腈的合成
(S)-2-氨基-4-氯-8-((6-(((四氢呋喃-3-基)氧)甲基)吡啶-2-基)甲基)喋啶-7(8H)-酮(97.2mg,0.25mmol,1.0equiv.),5-甲基呋喃硼酸(62.9mg,0.5mmol,2.0equiv.),Pd(PPh3)4(57.8mg,20%),Na2CO3(53.0mg,0.5mmol,2.0equiv.)溶于dioxane/H2O(6mL/0.6mL),氮气置换2min,密闭,95℃搅拌12小时。TLC实时监测反应。反应毕,冷至室温,用DCM/MeOH(10:1)稀释,依次用水、饱和食盐水洗涤,有机相浓缩后经硅胶柱层析(DCM/MeOH/NH4OH=200/3/0.5~200/5/0.5)分离得到黄色固体(35.4mg,收率:32.6%)。
ESI(m/z):[M+1]+434.9;1H NMR(400MHz,DMSO-d6)δ7.94(s,1H),7.81(d,J=3.4Hz,1H),7.71(t,J=7.8Hz,1H),7.60(brs,2H),7.28(d,J=7.7Hz,1H),7.08(d,J=7.8Hz,1H),6.42(d,J=3.4Hz,1H),5.46(s,2H),4.44(s,2H),3.76–3.59(m,5H),2.41(s,3H),1.91(t,J=6.4Hz,2H).
实施例八2-氨基-4-(5-甲基呋喃-2-基)-8-(吡啶-2-基亚甲基)喋啶-7(8H)-酮
(2-Amino-4-(5-methylfuran-2-yl)-8-(pyridin-2-ylmethyl)pteridin-7(8H)-one)
路线参照实施例1。
ESI(m/z):[M+1]+334.8;1H NMR(400MHz,DMSO-d6)δ8.71(s,1H),8.46(s,1H),7.91–7.90(m,1H),7.82–7.80(m,1H),7.76–7.75(m,1H),7.60(brs,2H),7.33(d,J=4.4Hz,1H),6.39(d,J=3.3Hz,1H),5.36(s,2H),2.40(s,3H).
实施例九2-氨基-8-(呋喃-2-基亚甲基)-4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮
(2-Amino-8-(furan-2-ylmethyl)-4-(5-methylfuran-2-yl)pteridin-7(8H)-one)
路线参照实施例1。
ESI(m/z):[M+1]+323.8;1H NMR(400MHz,DMSO-d6)δ7.88(s,1H),7.75(d,J=3.4Hz,1H),7.55(brs,2H),6.42(d,J=3.2Hz,1H),6.40–6.36(m,2H),5.75(s,1H),5.35(s,2H),2.40(s,3H).
实施例十2-氨基-8-(环己基亚甲基)-4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮
(2-Amino-8-(cyclohexylmethyl)-4-(5-methylfuran-2-yl)pteridin-7(8H)-one)
路线参照实施例1。
ESI(m/z):[M+1]+339.8;1H NMR(400MHz,DMSO-d6)δ7.84(s,1H),7.75(s,1H),7.40(brs,2H),6.38(d,J=3.6Hz,1H),4.04(d,J=7.2Hz,2H),2.39(s,3H),1.92–1.82(m,1H),1.66–1.64(m,2H),1.66–1.55(m,4H),1.07–1.02(m,4H).
实施例十一2-氨基-8-(环丙基亚甲基)-4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮
(2-Amino-8-(cyclopropylmethyl)-4-(5-methylfuran-2-yl)pteridin-7(8H)-one)
路线参照实施例1。
ESI(m/z):[M+1]+297.8;1H NMR(400MHz,DMSO-d6)δ7.87(s,1H),7.75(d,J=2.7Hz,2H),7.52(brs,2H),6.39(d,J=4.0Hz,2H),4.05(d,J=7.0Hz,2H),2.40(s,3H),1.36–1.21(m,1H),0.44(dd,J=5.4,2.5Hz,4H).
实施例十二2-氨基-8-苄基-4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮
(2-Amino-8-benzyl-4-(5-methylfuran-2-yl)pteridin-7(8H)-one)
路线参照实施例1。
ESI(m/z):[M+1]+333.8;1H NMR(400MHz,DMSO-d6)δ7.90(s,1H),7.78–7.74(m,1H),7.66(s,2H),7.44–7.20(m,5H),6.39–6.37(m,1H),5.36(s,2H),2.39(s,3H).
实施例十三2-氨基-4-(5-甲基呋喃-2-基)-8-苯乙基喋啶-7(8H)-酮
(2-Amino-4-(5-methylfuran-2-yl)-8-phenethylpteridin-7(8H)-one)
路线参照实施例1。
ESI(m/z):[M+1]+347.8;1H NMR(400MHz,DMSO-d6)δ7.85(s,1H),7.75(d,J=3.3Hz,1H),7.52(brs,2H),7.31(dd,J=4.4,1.5Hz,4H),7.23(q,J=4.2Hz,1H),6.39(d,J=3.7Hz,1H),4.42–4.25(m,2H),2.94–2.90(m,2H),2.40(s,3H).
实施例十四2-氨基-4-(5-甲基呋喃-2-基)-8-(3-苯正丙基)喋啶-7(8H)-酮
(2-Amino-4-(5-methylfuran-2-yl)-8-(3-phenylpropyl)pteridin-7(8H)-one)
路线参照实施例1。
ESI(m/z):[M+1]+361.8;1H NMR(400MHz,DMSO-d6)δ7.83(s,1H),7.74(d,J=3.4Hz,1H),7.45(s,2H),7.28–7.19(m,4H),7.17–7.11(m,1H),6.38(dd,J=3.4,0.9Hz,1H),4.24–4.18(m,2H),2.72–2.59(m,2H),2.39(s,3H),1.97(dt,J=15.2,7.7Hz,2H).
实施例十五2-氨基-4-(5-甲基呋喃-2-基)-8-(4-苯正丁基)喋啶-7(8H)-酮
(2-Amino-4-(5-methylfuran-2-yl)-8-(4-phenylbutyl)pteridin-7(8H)-one)
路线参照实施例1。
ESI(m/z):[M+1]+375.9;1H NMR(400MHz,DMSO-d6)δ7.83(s,1H),7.74(d,J=3.3Hz,1H),7.45(brs,2H),7.28–7.22(m,2H),7.21–7.12(m,3H),6.38(dd,J=3.4,0.9Hz,1H),4.19(t,J=7.0Hz,2H),2.62(t,J=7.5Hz,2H),2.39(s,3H),1.75–1.49(m,4H).
实施例十六2-氨基-4-(5-甲基呋喃-2-基)-8-(2-(4-甲基哌嗪-1-基)乙基)喋啶- 7(8H)-酮
(2-Amino-4-(5-methylfuran-2-yl)-8-(2-(4-methylpiperazin-1-yl)ethyl)pteridin-7(8H)-one)
路线参照实施例1。
ESI(m/z):[M+1]+369.8;1H NMR(400MHz,DMSO-d6)δ7.84(s,1H),7.75(d,J=3.3Hz,1H),7.46(brs,2H),6.38(d,J=3.4Hz,1H),4.27(t,J=6.9Hz,2H),2.55(t,J=6.9Hz,2H),2.50(s,3H),2.39–2.23(m,8H),2.11(s,3H).
实施例十七2-氨基-8-(2-(4-环戊基哌嗪-1-基)乙基)-4-(5-甲基呋喃-2-基)喋 啶-7(8H)-酮
(2-Amino-8-(2-(4-cyclopentylpiperazin-1-yl)ethyl)-4-(5-methylfuran-2-yl)pteridin-7(8H)-one)
路线参照实施例1。
ESI(m/z):[M+1]+423.9;1H NMR(400MHz,DMSO-d6)δ7.84(s,1H),7.75(d,J=3.3Hz,1H),7.45(brs,2H),6.38(d,J=3.4Hz,1H),4.28(t,J=6.9Hz,2H),2.55–2.25(m,9H),2.01–1.97(m,2H),1.76–1.72(m,1H),1.59–1.57(m,2H),1.49–1.46(m,4H),1.45–1.43(m,4H).
实施例十八2-氨基-4-(5-甲基呋喃-2-基)-8-(2-(4-苯基哌嗪-1-基)乙基)喋啶- 7(8H)-酮
(2-Amino-4-(5-methylfuran-2-yl)-8-(2-(4-phenylpiperazin-1-yl)ethyl)pteridin-7(8H)-one)
步骤1:叔丁基(2-(4-苯基哌嗪-1-基)乙基)氨基甲酸酯的合成
苯基哌嗪(486.7mg,3.0mmol,1.0equiv.)和Boc-溴乙胺(806.8mg,3.6mmol,1.2equiv.)溶于适量乙腈(9mL),随后滴加DIPEA(465.3mg,3.6mmol,1.2equiv.),75℃搅拌4小时。TLC实时监测反应。反应毕,用DCM/MeOH(20/1)稀释,依次用水、饱和食盐水洗涤,有机相浓缩后得到粗品,直接用于下一步。
步骤2:6-氯-N4-(2-(4-苯基哌嗪-1-基)乙基)嘧啶-2,4,5-三胺的合成
上一步的叔丁基(2-(4-苯基哌嗪-1-基)乙基)氨基甲酸酯(1.33g,3.6mmol,2.4equiv.)溶于甲醇(5mL),随后滴加4M的盐酸二氧六环溶液(4mL),室温搅拌4小时。TLC实时监测反应。反应毕,冷却至室温,析出大量固体,过滤干燥得到白色固体,溶于适量异丙醇,边搅拌边缓慢滴加Et3N(1.5mL),再加入2,5-二氨基-4,6-二氯嘧啶(268.0mg,1.5mmol,1.0equiv.),氮气保护下,105℃搅拌16小时。TLC实时监测反应。反应毕,用DCM/MeOH(20/1)稀释,依次用水、饱和食盐水洗涤,有机相浓缩后经硅胶柱层析(DCM/MeOH/NH3·H2O=200/5.0/0.5~200/8.0/0.5)分离得到类白色固体(381.2mg,收率:73.2%)。
步骤3:2-氨基-4-氯-8-(2-(4-苯基哌嗪-1-基)乙基)喋啶-7(8H)-酮的合成
6-氯-N4-(2-(4-苯基哌嗪-1-基)乙基)嘧啶-2,4,5-三胺(381.2mg,1.1mmol,1.0equiv.)溶于乙醇(4mL),随后滴加乙醛酸乙酯的50wt.%甲苯溶液(244.4mg)、冰醋酸(336.3μL),密封,80℃搅拌4~6小时。TLC实时监测反应。反应毕,用DCM/MeOH(20/1)稀释,依次用水、饱和食盐水洗涤,有机相浓缩后经硅胶柱层析(PE/EA=3/1~2/3)分离得到黄色固体(61.3mg,收率:14.5%)。
步骤4:2-氨基-4-氯-8-(2-(4-环戊基哌嗪-1-基)乙基)喋啶-7(8H)-酮的合成
6-氯-N4-(2-(4-环戊基哌嗪-1-基)乙基)嘧啶-2,4,5-三胺(110.0mg,0.3mmol,1.0equiv.),溶于乙醇(4mL),随后滴加乙醛酸乙酯的50wt.%甲苯溶液(71.8mg)、冰醋酸(98.8μL),密封,80℃搅拌4~6小时。TLC实时监测反应。反应毕,用DCM/MeOH(20/1)稀释,依次用水、饱和食盐水洗涤,有机相浓缩后经硅胶柱层析(DCM/MeOH/NH3·H2O=200/2.5/0.5~200/7.5/0.5)分离得到白色固体(91.2mg,收率:74.5%)。
步骤5:2-氨基-4-(5-甲基呋喃-2-基)-8-(2-(4-苯基哌嗪-1-基)乙基)喋啶-7(8H)-酮的合成
2-氨基-4-氯-8-(2-(4-环戊基哌嗪-1-基)乙基)喋啶-7(8H)-酮(60.0mg,0.15mmol,1.0equiv.),5-甲基呋喃硼酸(37.8mg,0.3mmol,2.0equiv.),Pd(PPh3)4(26.0mg,15%),Na2CO3(31.8mg,0.3mmol,2.0equiv.)溶于dioxane/H2O(4mL/0.5mL),氮气置换2min,密闭,95℃搅拌12小时。TLC实时监测反应。反应毕,用DCM/MeOH(20/1)稀释,依次用水、饱和食盐水洗涤,有机相浓缩后经硅胶柱层析(DCM/MeOH=50/1~30/1)分离得到黄色固体(26.3mg,收率:39.2%)。
ESI(m/z):[M+1]+431.8;1H NMR(400MHz,DMSO-d6)δ7.86(s,1H),7.75(d,J=3.3Hz,1H),7.44(brs,2H),7.19(t,J=7.9Hz,2H),6.89(d,J=8.1Hz,2H),6.76(t,J=7.1Hz,1H),6.38(d,J=2.5Hz,1H),4.34(t,J=6.6Hz,2H),3.12–2.98(m,4H),2.72–2.54(m,6H),2.39(s,3H).
实施例十九2-氨基-8-(2-(4-(2-甲氧基苯基)哌嗪-1-基)乙基)-4-(5-甲基呋喃- 2-基)喋啶-7(8H)-酮
(2-Amino-8-(2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl)-4-(5-methylfuran-2-yl)pteridin-7(8H)-one)
步骤1:叔丁基4-(2-甲氧基苯基)哌嗪-1-氨基甲酸酯的合成
氮气保护下,2-甲氧基碘苯(1.17g,5.0mmol,1.0equiv.),Boc-哌嗪(931.3mg,5.0mmol,1.0equiv.),Cs2CO3(2.11g,6.5mmol,1.3equiv.),Pd2(dba)3(45.7mg,1%),RuPhos(69.9mg,3%)溶于适量甲苯,密封,105℃搅拌24小时。TLC实时监测反应。反应毕,用EA稀释,依次用水、饱和食盐水洗涤,有机相浓缩后经硅胶柱层析(PE/EA=20/1~5/1)分离得到黄色粘稠油状物(1.07g,收率:73.2%)。
步骤2:叔丁基(2-(4-(2-甲氧基苯基)哌嗪-1-基)乙基)氨基甲酸酯的合成
上一步的叔丁基4-(2-甲氧基苯基)哌嗪-1-氨基甲酸酯(1.07g,3.66mmol,1.0equiv.)溶于甲醇(5mL),随后滴加4M的盐酸二氧六环溶液(4mL),室温搅拌4小时。TLC实时监测反应。反应毕,冷却至室温,析出大量固体,过滤干燥得到白色固体,直接用于下一步。溶于适量乙腈(7mL),边搅拌边缓慢滴加Et3N(5mL),再每12小时加入Boc-溴乙胺(820.2mg,3.66mmol,1.0equiv.)*2次,氮气保护下,75℃搅拌24小时。TLC实时监测反应。反应毕,用EA稀释,依次用水、饱和食盐水洗涤,有机相浓缩后经硅胶柱层析(DCM/MeOH=200/3~200/6)分离得到黄色粘稠油状物(1.23g,收率:100.0%)。
步骤3:6-氯-N4-(2-(4-(2-甲氧基苯基)哌嗪-1-基)乙基)嘧啶-2,4,5-三胺的合成上一步的叔丁基(2-(4-(2-甲氧基苯基)哌嗪-1-基)乙基)氨基甲酸酯(1.23g,3.66mmol,1.0equiv.)溶于甲醇(5mL),随后滴加4M的盐酸二氧六环溶液(4mL),室温搅拌4小时。TLC实时监测反应。反应毕,冷却至室温,析出大量固体,过滤干燥得到白色固体,直接用于下一步。溶于适量Sec-BuOH,边搅拌边缓慢滴加Et3N(7mL),再加入2,5-二氨基-4,6-二氯嘧啶(655.1mg,3.66mmol,1.0equiv.),氮气保护下,105℃搅拌24小时。TLC实时监测反应。反应毕,用EA稀释,依次用水、饱和食盐水洗涤,有机相浓缩后经硅胶柱层析(DCM/MeOH/NH3·H2O=200/3.0/0.5~200/6.0/0.5)分离得到淡黄色固体(604.4mg,收率:43.7%)。
步骤4:2-氨基-4-氯-8-(2-(4-(2-甲氧基苯基)哌嗪-1-基)乙基)喋啶-7(8H)-酮的合成
6-氯-N4-(2-(4-(2-甲氧基苯基)哌嗪-1-基)乙基)嘧啶-2,4,5-三胺(566.8mg,1.5mmol,1.0equiv.)溶于乙醇(4mL),随后滴加乙醛酸乙酯的50wt.%甲苯溶液(333.3mg)、冰醋酸(456.8μL),密封,80℃搅拌4~6小时。TLC实时监测反应。反应毕,冷却至室温,过滤分离得到黄色固体(510.3mg,收率:81.8%)。
步骤5:2-氨基-8-(2-(4-(2-甲氧基苯基)哌嗪-1-基)乙基)-4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮的合成
2-氨基-4-氯-8-(2-(4-(2-甲氧基苯基)哌嗪-1-基)乙基)喋啶-7(8H)-酮(103.9mg,0.25mmol,1.0equiv.),5-甲基呋喃硼酸(62.9mg,0.5mmol,2.0equiv.),Pd(PPh3)4(43.4mg,15%),Na2CO3(53.0mg,0.5mmol,2.0equiv.)溶于dioxane/H2O(5mL/0.5mL),氮气置换2min,密闭,95℃搅拌12小时。TLC实时监测反应。反应毕,用DCM/MeOH(20/1)稀释,依次用水、饱和食盐水洗涤,有机相浓缩后经硅胶柱层析(DCM/MeOH/NH3·H2O=200/3.0/0.5~200/5.0/0.5)分离得到淡黄色固体(93.9mg,收率:81.4%)。
ESI(m/z):[M+1]+461.8;1H NMR(400MHz,DMSO-d6)δδ7.86(s,1H),7.75(d,J=3.4Hz,1H),7.44(brs,2H),6.93–6.90(m,2H),6.85–6.83(m,2H),6.41–6.30(m,1H),4.33(t,J=6.7Hz,2H),3.76(s,3H),2.90(s,4H),2.63(s,6H),2.40(s,3H).
实施例二十2-氨基-8-(2-(4-(3-甲氧基苯基)哌嗪-1-基)乙基)-4-(5-甲基呋喃- 2-基)喋啶-7(8H)-酮
(2-Amino-8-(2-(4-(3-methoxyphenyl)piperazin-1-yl)ethyl)-4-(5-methylfuran-2-yl)pteridin-7(8H)-one)
路线参照实施例19。
ESI(m/z):[M+1]+461.8;1H NMR(400MHz,DMSO-d6)δ7.85(s,1H),7.74(d,J=3.3Hz,1H),7.45(brs,2H),7.08(t,J=8.2Hz,1H),6.48(dd,J=8.2,1.9Hz,1H),6.42–6.30(m,3H),4.33(t,J=6.7Hz,2H),3.70(s,3H),3.09–3.00(m,4H),2.65–2.50(m,6H),2.39(s,3H).
实施例二十一2-氨基-8-(2-(4-(4-甲氧基苯基)哌嗪-1-基)乙基)-4-(5-甲基呋 喃-2-基)喋啶-7(8H)-酮
(2-Amino-8-(2-(4-(4-methoxyphenyl)piperazin-1-yl)ethyl)-4-(5-methylfuran-2-yl)pteridin-7(8H)-one)
路线参照实施例19。
ESI(m/z):[M+1]+461.9;1H NMR(400MHz,DMSO-d6)δ7.85(s,1H),7.75(d,J=3.3Hz,1H),7.43(brs,2H),6.83–6.78(m,4H),6.38(dd,J=3.4,0.9Hz,1H),4.33(t,J=6.7Hz,2H),3.67(s,3H),2.94(s,4H),2.63(s,6H),2.39(s,3H).
实施例二十二2-氨基-8-(2-(4-(2-氟苯基)哌嗪-1-基)乙基)-4-(5-甲基呋喃-2- 基)喋啶-7(8H)-酮
(2-Amino-8-(2-(4-(2-fluorophenyl)piperazin-1-yl)ethyl)-4-(5-methylfuran-2-yl)pteridin-7(8H)-one)
路线参照实施例19。
ESI(m/z):[M+1]+449.9;1H NMR(400MHz,DMSO-d6)δ7.86(s,1H),7.75(d,J=3.3Hz,1H),7.43(brs,2H),7.14–7.03(m,2H),7.02–6.90(m,2H),6.38(dd,J=3.4,0.9Hz,1H),4.33(t,J=6.7Hz,2H),2.94(s,4H),2.65(s,6H),2.39(s,3H).
实施例二十三2-氨基-8-(2-(4-(3-氟苯基)哌嗪-1-基)乙基)-4-(5-甲基呋喃-2- 基)喋啶-7(8H)-酮
(2-Amino-8-(2-(4-(3-fluorophenyl)piperazin-1-yl)ethyl)-4-(5-methylfuran-2-yl)pteridin-7(8H)-one)
路线参照实施例19。
ESI(m/z):[M+1]+449.9;1H NMR(400MHz,DMSO-d6)δ7.86(s,1H),7.75(d,J=3.3Hz,1H),7.4Z5(brs,2H),7.19(dd,J=15.7,8.0Hz,1H),6.70(t,J=12.0Hz,2H),6.52(t,J=8.3Hz,1H),6.38(dd,J=3.4,0.9Hz,1H),4.33(t,J=6.6Hz,2H),3.18–3.03(m,4H),2.73–2.55(m,6H),2.39(s,3H).
实施例二十四2-氨基-8-(2-(4-(4-氟苯基)哌嗪-1-基)乙基)-4-(5-甲基呋喃-2- 基)喋啶-7(8H)-酮
(2-Amino-8-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-4-(5-methylfuran-2-yl)pteridin-7(8H)-one)
路线参照实施例19。
ESI(m/z):[M+1]+449.9;1H NMR(400MHz,DMSO-d6)δ7.86(s,1H),7.75(d,J=3.3Hz,1H),7.45(s,1H),7.02(t,J=8.9Hz,2H),6.94–6.86(m,2H),6.38(dd,J=3.4,0.9Hz,1H),4.33(t,J=6.7Hz,2H),3.00(s,4H),2.73–2.57(m,6H),2.39(s,3H).
实施例二十五2-氨基-4-(5-甲基呋喃-2-基)-8-(2-(4-(2-(三氟甲基)苯基)哌 嗪-1-基)乙基)喋啶-7(8H)-酮
(2-Amino-4-(5-methylfuran-2-yl)-8-(2-(4-(2-(trifluoromethyl)phenyl)piperazin-1-yl)ethyl)pteridin-7(8H)-one)
路线参照实施例19。
ESI(m/z):[M+1]+499.9;1H NMR(400MHz,DMSO-d6)δ7.86(s,1H),7.75(d,J=3.4Hz,1H),7.62(dd,J=13.6,7.7Hz,2H),7.49(d,J=8.0Hz,1H),7.43(brs,2H),7.30(t,J=7.6Hz,1H),6.38(dd,J=3.3,0.8Hz,1H),4.32(t,J=6.7Hz,2H),2.81(t,J=4.4Hz,4H),2.68–2.60(m,4H),2.51–2.49(m,2H),2.40(s,3H).
实施例二十六2-氨基-4-(5-甲基呋喃-2-基)-8-(2-(4-(3-(三氟甲基)苯基)哌 嗪-1-基)乙基)喋啶-7(8H)-酮
(2-Amino-4-(5-methylfuran-2-yl)-8-(2-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)ethyl)pteridin-7(8H)-one)
路线参照实施例19。
ESI(m/z):[M+1]+499.9;1H NMR(400MHz,DMSO-d6)δ7.85(s,1H),7.74(d,J=3.3Hz,1H),7.48(brs,2H),7.40(t,J=8.0Hz,1H),7.18(d,J=8.4Hz,1H),7.11(s,1H),7.04(d,J=7.6Hz,1H),6.37(dd,J=3.4,0.9Hz,1H),4.33(t,J=6.6Hz,2H),3.15(s,4H),2.72–2.56(m,6H),2.39(s,3H).
实施例二十七2-氨基-4-(5-甲基呋喃-2-基)-8-(2-(4-(4-(三氟甲基)苯基)哌 嗪-1-基)乙基)喋啶-7(8H)-酮
(2-Amino-4-(5-methylfuran-2-yl)-8-(2-(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)ethyl)pteridin-7(8H)-one)
路线参照实施例19。
ESI(m/z):[M+1]+499.9;1H NMR(400MHz,DMSO-d6)δ7.86(s,1H),7.75(d,J=3.1Hz,1H),7.59(brs,1H),7.49(d,J=8.4Hz,2H),7.02(d,J=8.9Hz,2H),6.38(s,1H),4.34(t,J=6.6Hz,2H),3.25–3.15(m,4H),2.70–2.55(m,6H),2.39(s,3H).
实施例二十八2-氨基-4-(5-甲基呋喃-2-基)-8-(2-(4-(2-(三氟甲氧基)苯基)哌 嗪-1-基)乙基)喋啶-7(8H)-酮
(2-Amino-4-(5-methylfuran-2-yl)-8-(2-(4-(2-(trifluoromethoxy)phenyl)piperazin-1-yl)ethyl)pteridin-7(8H)-one)
路线参照实施例19。
ESI(m/z):[M+1]+515.8;1H NMR(400MHz,DMSO-d6)δ7.86(s,1H),7.75(d,J=3.3Hz,1H),7.47(brs,2H),7.32–7.21(m,2H),7.11–6.98(m,2H),6.38(dd,J=3.4,0.9Hz,1H),4.33(t,J=6.4Hz,2H),2.93(s,4H),2.64(s,6H),2.39(s,3H).
实施例二十九2-氨基-4-(5-甲基呋喃-2-基)-8-(2-(4-(3-(三氟甲氧基)苯基)哌 嗪-1-基)乙基)喋啶-7(8H)-酮
(2-Amino-4-(5-methylfuran-2-yl)-8-(2-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)ethyl)pteridin-7(8H)-one)
路线参照实施例19。
ESI(m/z):[M+1]+515.8;1H NMR(400MHz,DMSO-d6)δ7.85(s,1H),7.74(d,J=3.3Hz,1H),7.46(brs,2H),7.28(t,J=8.3Hz,1H),6.91(dd,J=8.5,2.1Hz,1H),6.78(s,1H),6.68(d,J=8.1Hz,1H),6.38(dd,J=3.4,0.9Hz,1H),4.33(t,J=6.7Hz,2H),3.15–3.07(m,4H),2.66–2.62(m,6H),2.39(s,3H).
实施例三十2-氨基-4-(5-甲基呋喃-2-基)-8-(2-(4-(4-(三氟甲氧基)苯基)哌 嗪-1-基)乙基)喋啶-7(8H)-酮
(2-Amino-4-(5-methylfuran-2-yl)-8-(2-(4-(4-(trifluoromethoxy)phenyl)piperazin-1-yl)ethyl)pteridin-7(8H)-one)
路线参照实施例19。
ESI(m/z):[M+1]+515.8;1H NMR(400MHz,DMSO-d6)δ7.86(s,1H),7.75(d,J=3.3Hz,1H),7.52(brs,2H),7.17(d,J=8.7Hz,2H),6.96(d,J=9.2Hz,2H),6.40–6.34(m,1H),4.33(t,J=6.6Hz,2H),3.15–3.00(m,4H),2.75–2.55(m,6H),2.39(s,3H).
实施例三十一(S)-2-氨基-8-(2-(4-(4-甲氧基苯基)-2-甲基哌嗪-1-基)乙基)- 4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮
((S)-2-Amino-8-(2-(4-(4-methoxyphenyl)-2-methylpiperazin-1-yl)ethyl)-4-(5-methylfuran-2-yl)pteridin-7(8H)-one)
路线参照实施例19。
ESI(m/z):[M+1]+475.9;1H NMR(400MHz,DMSO-d6)δ7.85(s,1H),7.75(d,J=3.3Hz,1H),7.38(brs,2H),6.82(dd,J=21.7,9.2Hz,4H),6.40–6.35(m,1H),4.46–4.34(m,1H),4.28–4.16(m,1H),3.67(s,3H),3.29–3.17(m,2H),3.13–2.97(m,2H),2.66–2.52(m,4H),2.39(s,3H),2.31–2.20(m,1H),0.99(d,J=6.0Hz,3H).
实施例三十二(R)-2-氨基-8-(2-(4-(4-甲氧基苯基)-2-甲基哌嗪-1-基)乙基)- 4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮
((R)-2-Amino-8-(2-(4-(4-methoxyphenyl)-2-methylpiperazin-1-yl)ethyl)-4-(5-methylfuran-2-yl)pteridin-7(8H)-one)
路线参照实施例19。
ESI(m/z):[M+1]+475.9;1H NMR(400MHz,DMSO-d6)δ7.85(s,1H),7.75(d,J=3.3Hz,1H),7.46(brs,2H),6.82(dd,J=21.8,9.2Hz,4H),6.38(dd,J=3.4,0.9Hz,1H),4.46–4.32(m,1H),4.29–4.13(m,1H),3.67(s,3H),3.28–3.17(m,2H),3.14–2.96(m,2H),2.67–2.51(m,4H),2.39(s,3H),2.31–2.18(m,1H),0.99(d,J=6.1Hz,3H).
实施例三十三(S)-2-氨基-8-(2-(4-(4-甲氧基苯基)-3-甲基哌嗪-1-基)乙基)- 4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮
((S)-2-Amino-8-(2-(4-(4-methoxyphenyl)-3-methylpiperazin-1-yl)ethyl)-4-(5-methylfuran-2-yl)pteridin-7(8H)-one)
路线参照实施例19。
ESI(m/z):[M+1]+475.9;1H NMR(400MHz,DMSO-d6)δ7.85(s,1H),7.74(d,J=3.3Hz,1H),7.46(brs,2H),6.81(q,J=9.3Hz,4H),6.38(dd,J=3.4,0.9Hz,1H),4.39–4.28(m,2H),3.67(s,3H),3.60–3.49(m,1H),2.96–2.88(m,1H),2.85–2.74(m,2H),2.69(dt,J=12.8,6.5Hz,1H),2.60–2.52(m,2H),2.39(s,3H),0.73(d,J=6.3Hz,3H).
实施例三十四(R)-2-氨基-8-(2-(4-(4-甲氧基苯基)-3-甲基哌嗪-1-基)乙基)- 4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮
((R)-2-Amino-8-(2-(4-(4-methoxyphenyl)-3-methylpiperazin-1-yl)ethyl)-4-(5-methylfuran-2-yl)pteridin-7(8H)-one)
路线参照实施例19。
ESI(m/z):[M+1]+475.9;1H NMR(400MHz,DMSO-d6)δ7.85(s,1H),7.74(d,J=3.3Hz,1H),7.45(brs,2H),6.88–6.74(m,4H),6.38(dd,J=3.4,0.9Hz,1H),4.40–4.26(m,2H),3.67(s,3H),3.60–3.50(m,1H),2.95–2.88(m,1H),2.85–2.75(m,2H),2.73–2.63(m,1H),2.61–2.52(m,4H),2.39(s,3H),0.73(d,J=6.3Hz,3H).
实施例三十五2-氨基-8-(2-((2S,5R)-4-(4-甲氧基苯基)-2,5-二甲基哌嗪-1- 基)乙基)-4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮
(2-Amino-8-(2-((2S,5R)-4-(4-methoxyphenyl)-2,5-dimethylpiperazin-1-yl)ethyl)-4-(5-methylfuran-2-yl)pteridin-7(8H)-one)
路线参照实施例19。
ESI(m/z):[M+1]+489.9;1H NMR(400MHz,DMSO-d6)δ7.86(s,1H),7.76(d,J=3.4Hz,1H),7.38(brs,2H),6.95(d,J=8.9Hz,2H),6.82(d,J=9.0Hz,2H),6.42–6.36(m,1H),4.47–4.34(m,1H),4.29–4.18(m,1H),3.69(s,3H),3.13–2.90(m,4H),2.85–2.77(m,1H),2.69–2.61(m,1H),2.57–2.51(m,1H),2.26(dd,J=10.8,8.0Hz,1H),0.91(d,J=6.2Hz,3H),0.78(d,J=6.1Hz,3H).
实施例三十六2-氨基-8-(2-((1S,4S)-5-(4-甲氧基苯基)-2,5-二氮杂双环 [2.2.1]庚烷-2-基)一乙基)-4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮
(2-Amino-8-(2-((1S,4S)-5-(4-methoxyphenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)ethyl)-4-(5-methylfuran-2-yl)pteridin-7(8H)-one)
路线参照实施例19。
ESI(m/z):[M+1]+473.9;1H NMR(400MHz,DMSO-d6)δ7.80(s,1H),7.72(d,J=3.2Hz,1H),7.48(brs,2H),6.75(d,J=9.0Hz,2H),6.48(d,J=9.0Hz,2H),6.37(dd,J=3.4,0.9Hz,1H),4.27–4.07(m,3H),3.64(s,3H),3.57(s,1H),3.29(s,1H),2.97(d,J=9.0Hz,1H),2.89(d,J=8.1Hz,1H),2.71–2.56(m,3H),2.39(s,3H),1.74(s,2H).
实施例三十七2-氨基-8-(2-(3-(4-甲氧基苯基)-3,8-二氮杂双环[3.2.1]辛烷- 8-基)乙基)-4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮
(2-Amino-8-(2-(3-(4-methoxyphenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)ethyl)-4-(5-methylfuran-2-yl)pteridin-7(8H)-one)
路线参照实施例19。
ESI(m/z):[M+1]+487.8;1H NMR(400MHz,DMSO-d6)δ7.84(s,1H),7.73(d,J=3.3Hz,1H),7.43(brs,2H),6.76(d,J=9.2Hz,2H),6.70(d,J=9.2Hz,2H),6.37(dd,J=3.4,0.9Hz,1H),4.30(t,J=6.7Hz,2H),3.65(s,3H),3.41(s,2H),3.21(d,J=9.9Hz,2H),2.62–2.50(m,4H),2.39(s,3H),1.84(d,J=7.0Hz,2H),1.64(d,J=7.0Hz,2H).
实施例三十八2-氨基-8-(2-(4-(4-甲氧基苯基)-1,4-二氮杂环庚烷-1-基)乙 基)-4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮
(2-Amino-8-(2-(4-(4-methoxyphenyl)-1,4-diazepan-1-yl)ethyl)-4-(5-methylfuran-2-yl)pteridin-7(8H)-one)
路线参照实施例19。
ESI(m/z):[M+1]+475.8;1H NMR(400MHz,DMSO-d6)δ7.83(s,1H),7.75(d,J=3.3Hz,1H),7.36(brs,2H),6.74(d,J=9.0Hz,2H),6.61(d,J=9.0Hz,2H),6.41–6.36(m,1H),4.26(t,J=6.6Hz,2H),3.63(s,3H),3.41–3.36(m,2H),3.36–3.34(m,2H),2.86–2.77(m,2H),2.76–2.68(m,2H),2.65–2.56(m,2H),2.40(s,3H),1.85–1.70(m,2H).
实施例三十九2-氨基-4-(5-甲基呋喃-2-基)-8-((1-苯基哌啶-4-基)亚甲基)喋 啶-7(8H)-酮
(2-Amino-4-(5-methylfuran-2-yl)-8-((1-phenylpiperidin-4-yl)methyl)pteridin-7(8H)-one)
路线参照实施例19。
ESI(m/z):[M+1]+416.8;1H NMR(400MHz,DMSO-d6)δ7.86(s,1H),7.76(d,J=3.3Hz,1H),7.42(brs,2H),7.17(dd,J=8.6,7.3Hz,2H),6.90(d,J=8.0Hz,2H),6.72(t,J=7.2Hz,1H),6.38(dd,J=3.4,0.9Hz,1H),4.13(d,J=7.2Hz,2H),3.67(d,J=12.5Hz,2H),2.58(t,J=11.2Hz,2H),2.40(s,3H),2.06(ddd,J=11.3,7.5,3.8Hz,1H),1.64(d,J=11.1Hz,2H),1.40(qd,J=12.5,3.7Hz,2H).
实施例四十2-氨基-4-(5-甲基呋喃-2-基)-8-(2-(1-苯基哌啶-4-基)乙基)喋啶- 7(8H)-酮
(2-Amino-4-(5-methylfuran-2-yl)-8-(2-(1-phenylpiperidin-4-yl)ethyl)pteridin-7(8H)-one)
路线参照实施例19。
ESI(m/z):[M+1]+430.8;1H NMR(400MHz,DMSO-d6)δ7.84(s,1H),7.75(d,J=3.3Hz,1H),7.37(brs,2H),7.18(dd,J=8.6,7.3Hz,2H),6.91(d,J=8.0Hz,2H),6.72(t,J=7.2Hz,1H),6.38(dd,J=3.4,0.9Hz,1H),4.26–4.16(m,2H),3.66(d,J=12.4Hz,2H),2.62(dd,J=11.9,10.3Hz,2H),2.39(s,3H),1.86(d,J=11.1Hz,2H),1.60(dd,J=14.5,6.9Hz,2H),1.48–1.38(m,1H),1.29(ddd,J=15.3,12.3,3.7Hz,2H).
实施例四十一2-氨基-4-(5-甲基呋喃-2-基)-8-(2-(4-苯基哌啶-1-基)乙基)喋 啶-7(8H)-酮
(2-Amino-4-(5-methylfuran-2-yl)-8-(2-(4-phenylpiperidin-1-yl)ethyl)pteridin-7(8H)-one)
路线参照实施例19。
ESI(m/z):[M+1]+430.8;1H NMR(400MHz,DMSO-d6)δ7.86(s,1H),7.76(s,1H),7.40(brs,2H),7.32–7.11(m,5H),6.39(s,1H),5.78–5.71(m,1H),4.32(s,2H),3.09(d,J=9.4Hz,2H),2.61(s,2H),2.40(s,3H),2.10(t,J=10.9Hz,2H),1.72(d,J=11.0Hz,2H),1.57–1.54(m,2H).
实施例四十二2-氨基-8-(2-(3-((4-甲氧基苯基)(甲基)氨基)吡咯-1-基)乙基)-4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮
(2-Amino-8-(2-(3-((4-methoxyphenyl)(methyl)Amino)pyrrolidin-1-yl)ethyl)-4-(5-methylfuran-2-yl)pteridin-7(8H)-one)
步骤1:叔丁基3-((4-甲氧基苯基)(甲基)氨基)吡咯啉-1-氨基甲酸酯的合成氮气保护下,4-甲氧基碘苯(1.64g,7.0mmol,1.0equiv.),叔丁基3-(甲胺基)吡咯啉-1-胺基甲酸酯(1.40g,7.0mmol,1.0equiv.),Cs2CO3(2.73g,8.4mmol,1.2equiv.),Pd2(dba)3(64.1mg,1%),RuPhos(97.8mg,3%)溶于适量甲苯,密封,105℃搅拌24小时。TLC实时监测反应。反应毕,用EA稀释,依次用水、饱和食盐水洗涤,有机相浓缩后经硅胶柱层析(PE/EA=20/1~5/1)分离得到黄棕色粘稠油状物(1860.0mg,收率:85.3%)。
步骤2:叔丁基(2-(3-((4-甲氧基苯基)(甲基)胺基)吡咯啉-1-基)乙基)胺基甲酸酯的合成
上一步的叔丁基3-((4-甲氧基苯基)(甲基)氨基)吡咯啉-1-氨基甲酸酯(1860.0mg,6.07mmol,1.0equiv.)溶于甲醇(8mL),随后滴加4M的盐酸二氧六环溶液(6mL),室温搅拌4小时。TLC实时监测反应。反应毕,冷却至室温,析出大量固体,过滤干燥得到白色固体,直接用于下一步。溶于适量乙腈(15mL),边搅拌边缓慢滴加Et3N(8mL),再每12小时加入Boc-溴乙胺(1086.6mg,6.07mmol,1.0equiv.)*2次,氮气保护下,75℃搅拌24小时。TLC实时监测反应。反应毕,用DCM/MeOH(20/1)稀释,依次用水、饱和食盐水洗涤,有机相浓缩后经硅胶柱层析(DCM/MeOH/NH3·H2O=200/3.0/0.5~200/4.5/0.5)分离得到棕色油状物(855.0mg,收率:41.7%)。
步骤3:6-氯-N4-(2-(3-((4-甲氧基苯基)(甲基)胺基)吡咯啉-1-基)乙基)嘧啶-2,4,5-三胺的合成
上一步的叔丁基(2-(3-((4-甲氧基苯基)(甲基)胺基)吡咯啉-1-基)乙基)胺基甲酸酯(885.0mg,2.53mmol,1.0equiv.)溶于甲醇(6mL),随后滴加4M的盐酸二氧六环溶液(4mL),室温搅拌4小时。TLC实时监测反应。反应毕,冷却至室温,析出大量固体,过滤干燥得到白色固体,直接用于下一步。溶于适量Sec-BuOH,边搅拌边缓慢滴加Et3N(7mL),再加入2,5-二氨基-4,6-二氯嘧啶(453.3mg,2.53mmol,1.0equiv.),氮气保护下,105℃搅拌24小时。TLC实时监测反应。反应毕,用DCM/MeOH(20/1)稀释,依次用水、饱和食盐水洗涤,有机相浓缩后经硅胶柱层析(DCM/MeOH/NH3·H2O=200/3.0/0.5~200/6.0/0.5)分离得到黄色固体(602.0mg,收率:60.6%)。
步骤4:2-胺基-4-氯-8-(2-(3-((4-甲氧基苯基)(甲基)胺基)吡咯啉-1-基)乙基)喋啶-7(8H)-酮的合成
6-氯-N4-(2-(3-((4-甲氧基苯基)(甲基)胺基)吡咯啉-1-基)乙基)嘧啶-2,4,5-三胺(587.8mg,1.5mmol,1.0equiv.)溶于乙醇(8mL),随后滴加乙醛酸乙酯的50wt.%甲苯溶液(333.3mg)、冰醋酸(456.8μL),密封,80℃搅拌4~6小时。TLC实时监测反应。反应毕,冷却至室温,过滤分离得到黄色固体(130.0mg,收率:20.1%)。
步骤5:2-氨基-8-(2-(3-((4-甲氧基苯基)(甲基)氨基)吡咯啉-1-基)乙基)-4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮的合成
2-胺基-4-氯-8-(2-(3-((4-甲氧基苯基)(甲基)胺基)吡咯啉-1-基)乙基)喋啶-7(8H)-酮(107.5mg,0.25mmol,1.0equiv.),5-甲基呋喃硼酸(62.9mg,0.5mmol,2.0equiv.),Pd(PPh3)4(43.4mg,15%),Na2CO3(53.0mg,0.5mmol,2.0equiv.)溶于dioxane/H2O(5mL/0.5mL),氮气置换2min,密闭,95℃搅拌12小时。TLC实时监测反应。反应毕,用DCM/MeOH(20/1)稀释,依次用水、饱和食盐水洗涤,有机相浓缩后经硅胶柱层析(DCM/MeOH/NH3·H2O=200/3.0/0.5~200/5.0/0.5)分离得到黄色固体(61.0mg,收率:51.3%)。
ESI(m/z):[M+1]+475.8;1H NMR(400MHz,DMSO-d6)δ7.85(s,1H),7.75(d,J=3.3Hz,1H),7.43(brs,2H),6.75(s,4H),6.38(dd,J=3.4,0.9Hz,1H),4.39–4.16(m,3H),3.65(s,3H),2.84–2.74(m,3H),2.63–2.53(m,5H),2.40(s,3H),2.39–2.30(m,1H),1.96(ddd,J=16.7,12.9,4.1Hz,1H),1.58(td,J=13.6,7.9Hz,1H).
实施例四十三2-氨基-8-(2-((1-(4-甲氧基苯基)吡咯-3-基)(甲基)氨基)乙基)-4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮
(2-Amino-8-(2-((1-(4-methoxyphenyl)pyrrolidin-3-yl)(methyl)Amino)ethyl)-4-(5-methylfuran-2-yl)pteridin-7(8H)-one)
路线参照实施例42。
ESI(m/z):[M+1]+475.8;1H NMR(400MHz,DMSO-d6)δ7.84(s,1H),7.74(d,J=3.3Hz,1H),7.45(brs,2H),6.75(d,J=9.0Hz,2H),6.42(d,J=9.0Hz,2H),6.38(dd,J=3.4,0.8Hz,1H),4.37–4.24(m,2H),3.63(s,3H),3.29–3.16(m,3H),3.10(dd,J=16.1,9.0Hz,1H),2.84(t,J=7.7Hz,1H),2.74–2.73(m,2H),2.40(s,3H),2.35(s,3H),2.15–2.03(m,1H),1.69(dq,J=17.8,8.9Hz,1H).
实施例四十四2-氨基-8-(2-(3-((4-甲氧基苯基)(甲基)氨基)氮杂环丁烷-1-基) 乙基)-4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮
(2-Amino-8-(2-(3-((4-methoxyphenyl)(methyl)Amino)azetidin-1-yl)ethyl)-4-(5-methylfuran-2-yl)pteridin-7(8H)-one)
路线参照实施例42。
ESI(m/z):[M+1]+461.8;1H NMR(400MHz,DMSO-d6)δ7.85(s,1H),7.75(d,J=3.3Hz,1H),7.46(brs,2H),6.79(d,J=9.1Hz,2H),6.70(d,J=9.1Hz,2H),6.38(dd,J=3.4,0.9Hz,1H),4.16(t,J=6.2Hz,2H),3.80(s,1H),3.66(s,5H),2.95(s,2H),2.73(s,2H),2.65(s,3H),2.40(s,3H).
实施例四十五2-氨基-8-(2-(4-(2-氟-4-甲氧基苯基)哌嗪-1-基)乙基)-4-(5-甲 基呋喃-2-基)喋啶-7(8H)-酮
(2-Amino-8-(2-(3-((4-methoxyphenyl)(methyl)amino)azetidin-1-yl)ethyl)-4-(5-methylfuran-2-yl)pteridin-7(8H)-one)
路线参照实施例19。
ESI(m/z):[M+1]+480.2;1H NMR(400MHz,DMSO-d6)δ7.85(s,1H),7.75(d,J=3.4Hz,1H),7.42(s,2H),6.97–6.89(m,1H),6.77(dd,J=14.1,2.8Hz,1H),6.67(dd,J=8.8,2.3Hz,1H),6.38(dd,J=3.3,1.1Hz,1H),4.33(t,J=6.7Hz,2H),3.70(s,3H),2.85(s,4H),2.64(d,J=6.5Hz,6H),2.40(s,3H).
实施例四十六2-氨基-8-(2-(4-(2,4-二氟苯基)哌嗪-1-基)乙基)-4-(5-甲基呋 喃-2-基)喋啶-7(8H)-酮
(2-Amino-8-(2-(3-((4-methoxyphenyl)(methyl)amino)azetidin-1-yl)ethyl)-4-(5-methylfuran-2-yl)pteridin-7(8H)-one)
路线参照实施例19。
ESI(m/z):[M+1]+462.2;1H NMR(400MHz,DMSO-d6)δ7.86(s,1H),7.75(d,J=3.4Hz,1H),7.41(s,2H),7.15(ddd,J=12.2,9.0,2.8Hz,1H),7.05–6.92(m,2H),6.38(dd,J=3.4,1.1Hz,1H),4.33(t,J=6.7Hz,2H),2.90(s,4H),2.65(s,6H),2.40(s,3H).
实施例四十七2-氨基-8-(2-(4-(2-氟-4-甲氧基苯基)哌嗪-1-基)乙基)-6-甲基- 4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮
(2-Amino-8-(2-(4-(2-fluoro-4-methoxyphenyl)piperazin-1-yl)ethyl)-6-methyl-4-(5-methylfuran-2-yl)pteridin-7(8H)-one)
步骤1:2-氨基-4-氯-8-(2-(4-(2-氟-4-甲氧基苯基)哌嗪-1-基)乙基)-6-甲基喋啶-7(8H)-酮的合成
6-氯-N4-(2-(4-(2-氟-4-甲氧基苯基)哌嗪-1-基)乙基)嘧啶-2,4,5-三胺(170.2mg,0.43mmol,1.0equiv.)溶于乙醇(4mL),随后滴加丙酮酸乙酯(54.9mg)、冰醋酸(130.9μL),密封,80℃搅拌4~6小时。TLC实时监测反应。反应毕,冷却至室温,过滤分离得到棕褐色固体(139.2mg,收率:72.3%)。
步骤2:2-氨基-8-(2-(4-(2-氟-4-甲氧基苯基)哌嗪-1-基)乙基)-6-甲基-4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮的合成
2-氨基-4-氯-8-(2-(4-(2-氟-4-甲氧基苯基)哌嗪-1-基)乙基)-6-甲基喋啶-7(8H)-酮(111.9mg,0.25mmol,1.0equiv.),5-甲基呋喃硼酸(62.9mg,0.5mmol,2.0equiv.),Pd(PPh3)4(43.4mg,15%),Na2CO3(53.0mg,0.5mmol,2.0equiv.)溶于dioxane/H2O(5mL/0.5mL),氮气置换2min,密闭,95℃搅拌12小时。TLC实时监测反应。反应毕,用DCM/MeOH(20/1)稀释,依次用水、饱和食盐水洗涤,有机相浓缩后经硅胶柱层析(DCM/MeOH/NH3·H2O=200/3.0/0.5~200/5.0/0.5)分离得到黄色固体(75.8mg,收率:63.2%)。
ESI(m/z):[M+1]+493.9;1H NMR(400MHz,DMSO-d6)δ7.87(d,J=3.2Hz,1H),7.24(brs,2H),6.98–6.89(m,1H),6.78(dd,J=14.1,2.8Hz,1H),6.67(dd,J=8.8,2.3Hz,1H),6.38(dd,J=3.3,0.9Hz,1H),4.34(t,J=6.8Hz,2H),3.70(s,3H),2.92–2.79(m,4H),2.74–2.54(m,6H),2.40(s,3H),2.39(s,3H).
实施例四十八2-氨基-8-(2-(4-(2-氟苯基)哌嗪-1-基)乙基)-6-甲基-4-(5-甲基 呋喃-2-基)喋啶-7(8H)-酮
(2-Amino-8-(2-(4-(2-fluorophenyl)piperazin-1-yl)ethyl)-6-methyl-4-(5-methylfuran-2-yl)pteridin-7(8H)-one)
路线参照实施例47。
ESI(m/z):[M+1]+463.9;1H NMR(400MHz,DMSO-d6)δ7.86(d,J=3.3Hz,1H),7.24(brs,2H),7.14–7.04(m,2H),7.00–6.92(m,2H),6.38(dd,J=3.3,0.9Hz,1H),4.34(t,J=6.7Hz,2H),2.95(s,4H),2.70–2.59(m,6H),2.40(s,3H),2.39(s,3H).
实施例四十九2-氨基-8-(2-(4-(2-氟苯基)哌嗪-1-基)乙基)-6-三氟甲基-4-(5- 甲基呋喃-2-基)喋啶-7(8H)-酮
(2-Amino-8-(2-(4-(2-fluorophenyl)piperazin-1-yl)ethyl)-4-(5-methylfuran-2-yl)-6-(trifluoromethyl)pteridin-7(8H)-one)
步骤1:2-氨基-4-氯-8-(2-(4-(2-氟苯基)哌嗪-1-基)乙基)-6-三氟甲基喋啶-7(8H)-酮的合成
6-氯-N4-(2-(4-(2-氟苯基)哌嗪-1-基)乙基)嘧啶-2,4,5-三胺(157.3mg,0.43mmol,1.0equiv.)溶于乙醇(4mL),随后滴加三氟丙酮酸乙酯(80.5mg)、冰醋酸(130.9μL),密封,80℃搅拌4~6小时。TLC实时监测反应。反应毕,冷却至室温,过滤分离得到棕褐色固体(110.8mg,收率:54.6%)。
步骤5:2-氨基-8-(2-(4-(2-氟苯基)哌嗪-1-基)乙基)-6-三氟甲基-4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮的合成
2-氨基-4-氯-8-(2-(4-(2-氟苯基)哌嗪-1-基)乙基)-6-三氟甲基喋啶-7(8H)-酮(110.8mg,0.23mmol,1.0equiv.),5-甲基呋喃硼酸(62.9mg,0.5mmol,2.0equiv.),Pd(PPh3)4(43.4mg,15%),Na2CO3(53.0mg,0.5mmol,2.0equiv.)溶于dioxane/H2O(5mL/0.5mL),氮气置换2min,密闭,95℃搅拌12小时。TLC实时监测反应。反应毕,用DCM/MeOH(20/1)稀释,依次用水、饱和食盐水洗涤,有机相浓缩后经硅胶柱层析(DCM/MeOH/NH3·H2O=200/3.0/0.5~200/5.0/0.5)分离得到黄色固体(55.8mg,收率:46.9%)。
ESI(m/z):[M+1]+517.9;1H NMR(400MHz,DMSO-d6)δ8.07(brs,NH,1H),7.78(brs,NH,1H),7.78(d,J=3.4Hz,1H),7.14–7.04(m,2H),7.00–6.91(m,2H),6.45(dd,J=3.4,0.9Hz,1H),4.35(t,J=6.8Hz,2H),2.95(s,4H),2.66(s,6H),2.41(s,3H).
实施例五十2-(2-氨基-8-(2-(4-(2-氟苯基)哌嗪-1-基)乙基)-7-氧代-7,8-二氢 喋啶-4-基)-6-甲基苯甲腈
(2-(2-Amino-8-(2-(4-(2-fluorophenyl)piperazin-1-yl)ethyl)-7-oxo-7,8-dihydropteridin-4-yl)-6-methylbenzonitrile)
路线参照实施例19。
ESI(m/z):[M+1]+484.9;1H NMR(400MHz,DMSO-d6)δ7.90(dd,J=7.7,1.2Hz,1H),7.77(s,1H),7.63(dd,J=7.7,1.1Hz,1H),7.58(brs,2H),7.49(t,J=7.7Hz,1H),7.15–7.06(m,2H),7.03–6.92(m,2H),4.35(t,J=6.8Hz,2H),2.97(s,4H),2.68(s,6H),2.29(s,3H).
实施例五十一2-氨基-8-(2-(4-(2-氟苯基)哌嗪-1-基)乙基)-4-(1H-吡唑-4-基) 喋啶-7(8H)-酮
(2-Amino-8-(2-(4-(2-fluorophenyl)piperazin-1-yl)ethyl)-4-(1H-pyrazol-4-yl)pteridin-7(8H)-one)
路线参照实施例19。
ESI(m/z):[M+1]+435.9;1H NMR(400MHz,DMSO-d6)δ13.31(s,1H),8.47(brs,2H),7.87(s,1H),7.26(s,2H),7.09(ddd,J=15.7,7.8,1.4Hz,2H),7.01–6.91(m,2H),4.34(t,J=6.6Hz,2H),2.94(s,4H),2.66(d,J=5.1Hz,6H),1.99(s,3H).
实施例五十二2-氨基-8-(2-(4-(2-氟-4-(2-甲氧基乙氧基)苯基)哌嗪-1-基)乙 基)-4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮
(2-Amino-8-(2-(4-(2-fluoro-4-(2-methoxyethoxy)phenyl)piperazin-1-yl)ethyl)-4-(5-methylfuran-2-yl)pteridin-7(8H)-one)
路线参照实施例19。
ESI(m/z):[M+1]+523.8;1H NMR(400MHz,DMSO-d6)δ7.86(s,1H),7.75(d,J=3.4Hz,1H),7.41(s,2H),6.92(t,J=9.5Hz,1H),6.79(dd,J=14.1,2.8Hz,1H),6.68(dd,J=9.0,2.9Hz,1H),6.38(d,J=2.8Hz,1H),4.33(t,J=6.8Hz,2H),4.05–4.01(m,2H),3.64–3.60(m,2H),2.85(s,4H),2.65(s,6H),2.40(s,3H).
实施例五十三2-氨基-8-(2-(4-(2,3-二氟-4-(2-甲氧基乙氧基)苯基)哌嗪-1- 基)乙基)-4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮
(2-Amino-8-(2-(4-(2,3-difluoro-4-(2-methoxyethoxy)phenyl)piperazin-1-yl)ethyl)-4-(5-methylfuran-2-yl)pteridin-7(8H)-one)
路线参照实施例19。
ESI(m/z):[M+1]+541.8;1H NMR(400MHz,DMSO-d6)δ7.85(s,1H),7.75(d,J=3.4Hz,1H),7.43(s,2H),6.88(td,J=9.0,2.1Hz,1H),6.72(td,J=9.2,2.3Hz,1H),6.38(dd,J=3.4,1.1Hz,1H),4.32(t,J=6.7Hz,2H),4.15–4.09(m,2H),3.68–3.61(m,2H),2.89(s,4H),2.65(s,6H),2.40(s,3H).
实施例五十四(S)-2-氨基-8-(2-(4-(2-氟-4-甲氧基苯基)-2-甲基哌嗪-1-基)乙 基)-4-(5-甲基呋喃-2-基)喋啶-7(8H)-酮
((S)-2-Amino-8-(2-(4-(2-fluoro-4-methoxyphenyl)-2-methylpiperazin-1-yl)ethyl)-4-(5-methylfuran-2-yl)pteridin-7(8H)-one)
路线参照实施例19。
ESI(m/z):[M+1]+493.8;1H NMR(400MHz,DMSO-d6)δ7.85(s,1H),7.75(d,J=3.3Hz,1H),7.40(s,2H),6.91(t,J=9.5Hz,1H),6.77(dd,J=14.1,2.8Hz,1H),6.66(dd,J=8.8,2.6Hz,1H),6.38(dd,J=3.3,1.1Hz,1H),4.40(dt,J=12.2,7.6Hz,1H),4.22(ddd,J=12.4,8.3,4.4Hz,1H),3.70(s,3H),3.12–2.91(m,4H),2.71–2.52(m,4H),2.40(s,3H),2.35(dd,J=11.0,8.5Hz,1H),0.98(d,J=6.1Hz,3H).
实施例五十五2-氨基-8-(2-(4-(6-甲氧基吡啶-3-基)哌嗪-1-基)乙基)-6-甲基- 4-(5-甲基呋喃-2-基)蝶呤-7(8H)-酮
(2-Amino-8-(2-(4-(6-methoxypyridin-3-yl)piperazin-1-yl)ethyl)-6-methyl-4-(5-methylfuran-2-yl)pteridin-7(8H)-one)
路线参照实施例47。
ESI(m/z):[M+1]+476.8;1H NMR(400MHz,DMSO-d6)δ7.85(d,J=3.4Hz,1H),7.74(d,J=3.0Hz,1H),7.40(dd,J=9.0,3.1Hz,1H),7.24(s,2H),6.69(d,J=9.0Hz,1H),6.38(dd,J=3.3,1.1Hz,1H),4.34(t,J=6.8Hz,2H),3.77(s,3H),3.11–2.92(m,4H),2.64(s,6H),2.39(s,6H).
实施例五十六2-氨基-8-(2-(4-(6-甲氧基吡啶-3-基)哌嗪-1-基)乙基)-4-(5-甲 基呋喃-2-基)蝶呤-7(8H)-酮
(2-Amino-8-(2-(4-(6-methoxypyridin-3-yl)piperazin-1-yl)ethyl)-4-(5-methylfuran-2-yl)pteridin-7(8H)-one)
路线参照实施例19。
ESI(m/z):[M+1]+462.8;1H NMR(400MHz,DMSO-d6)δ7.85(s,1H),7.74(t,J=3.5Hz,2H),7.55–7.29(m,3H),6.69(d,J=9.0Hz,1H),6.38(dd,J=3.4,1.1Hz,1H),4.33(t,J=6.7Hz,2H),3.77(s,3H),2.98(s,4H),2.65(s,6H),2.40(s,3H).
实施例五十七2-氨基-8-(2-(4-(5-甲氧基吡啶-2-基)哌嗪-1-基)乙基)-4-(5-甲 基呋喃-2-基)蝶呤-7(8H)-酮
(2-Amino-8-(2-(4-(5-methoxypyridin-2-yl)piperazin-1-yl)ethyl)-4-(5-methylfuran-2-yl)pteridin-7(8H)-one)
路线参照实施例19。
ESI(m/z):[M+1]+462.8;1H NMR(400MHz,DMSO-d6)δ7.87(d,J=3.1Hz,1H),7.85(s,1H),7.74(d,J=3.3Hz,1H),7.43(s,2H),7.24(dd,J=9.1,3.1Hz,1H),6.76(d,J=9.1Hz,1H),6.37(dd,J=3.4,1.1Hz,1H),4.34(t,J=6.7Hz,2H),3.72(s,3H),3.28(t,J=5.1Hz,4H),2.63(t,J=6.8Hz,2H),2.59(t,J=5.0Hz,4H),2.40(s,3H).
实施例五十八2-氨基-8-(2-(4-(6-异丙氧基吡啶-3-基)哌嗪-1-基)乙基)-4-(5- 甲基呋喃-2-基)吡啶-7(8H)-酮
(2-Amino-8-(2-(4-(6-isopropoxypyridin-3-yl)piperazin-1-yl)ethyl)-4-(5-methylfuran-2-yl)pteridin-7(8H)-one)
路线参照实施例19。
ESI(m/z):[M+1]+490.8;1H NMR(400MHz,DMSO-d6)δ7.86(s,1H),7.73(dd,J=11.4,3.2Hz,2H),7.37(dd,J=9.0,3.1Hz,3H),6.61(d,J=8.9Hz,1H),6.38(dd,J=3.3,1.1Hz,1H),5.10(p,J=6.1Hz,1H),4.33(t,J=6.8Hz,2H),2.97(t,J=4.8Hz,4H),2.64(s,6H),2.40(s,3H),1.24(d,J=6.1Hz,6H).
实施例五十九2-氨基-8-(2-(4-(4-(二氟甲氧基)苯基)哌嗪-1-基)乙基)-4-(5- 甲基呋喃-2-基)蝶呤-7(8H)-酮
(2-Amino-8-(2-(4-(4-(difluoromethoxy)phenyl)piperazin-1-yl)ethyl)-4-(5-methylfuran-2-yl)pteridin-7(8H)-one)
路线参照实施例19。
ESI(m/z):[M+1]+497.8;1H NMR(400MHz,DMSO-d6)δ7.85(s,1H),7.75(d,J=3.3Hz,1H),7.43(s,2H),7.22–6.83(m,5H),6.38(dd,J=3.3,1.1Hz,1H),4.34(t,J=6.8Hz,2H),3.04(s,4H),2.64(s,6H),2.39(s,3H).
实施例六十2-氨基-4-(5-甲基呋喃-2-基)-8-(2-(4-(嘧啶-5-基)哌嗪-1-基)乙 基)蝶呤-7(8H)-酮
(2-Amino-4-(5-methylfuran-2-yl)-8-(2-(4-(pyrimidin-5-yl)piperazin-1-yl)ethyl)pteridin-7(8H)-one)
路线参照实施例19。
ESI(m/z):[M+1]+433.8;1H NMR(400MHz,DMSO-d6)δ8.57(s,1H),8.44(s,2H),7.85(s,1H),7.74(d,J=3.4Hz,1H),7.42(s,2H),6.38(dd,J=3.3,1.1Hz,1H),4.34(t,J=6.8Hz,2H),3.20(s,4H),2.65(s,6H),2.40(s,3H).
实施例六十一2-氨基-8-(2-(4-(3-氟-5-甲氧基吡啶-2-基)哌嗪-1-基)乙基)-4- (5-甲基呋喃-2-基)蝶呤-7(8H)-酮
(2-Amino-8-(2-(4-(3-fluoro-5-methoxypyridin-2-yl)piperazin-1-yl)ethyl)-4-(5-methylfuran-2-yl)pteridin-7(8H)-one)
路线参照实施例19。
ESI(m/z):[M+1]+480.8;1H NMR(400MHz,DMSO-d6)δ7.85(s,1H),7.79(d,J=2.1Hz,1H),7.75(d,J=3.3Hz,1H),7.33(dd,J=14.0,2.6Hz,3H),6.38(dd,J=3.4,1.1Hz,1H),4.33(t,J=6.7Hz,2H),3.77(s,3H),3.14(s,4H),2.64(s,6H),2.40(s,3H).
实施例六十二2-氨基-8-(2-(4-(5-(二氟甲氧基)-3-氟吡啶-2-基)哌嗪-1-基)乙 基)-4-(5-甲基呋喃-2-基)蝶呤-7(8H)-酮
(2-Amino-8-(2-(4-(5-(difluoromethoxy)-3-fluoropyridin-2-yl)piperazin-1-yl)ethyl)-4-(5-methylfuran-2-yl)pteridin-7(8H)-one)
路线参照实施例19。
ESI(m/z):[M+1]+516.8;1H NMR(400MHz,DMSO-d6)δ7.98(d,J=2.3Hz,
1H),7.85(s,1H),7.75(d,J=3.4Hz,1H),7.61(dd,J=13.3,2.4Hz,1H),7.54-6.95(m,3H),6.41–6.36(m,1H),4.33(t,J=6.7Hz,2H),3.29(s,4H),2.64(s,6H),2.40(s,3H).
实施例六十三2-氨基-8-(2-(4-(5-(二氟甲氧基)-3-氟吡啶-2-基)哌嗪-1-基)乙 基)-6-甲基-4-(5-甲基呋喃-2-基)蝶呤-7(8H)-酮
(2-Amino-8-(2-(4-(5-(difluoromethoxy)-3-fluoropyridin-2-yl)piperazin-1-yl)ethyl)-6-methyl-4-(5-methylfuran-2-yl)pteridin-7(8H)-one)
路线参照实施例47。
ESI(m/z):[M+1]+530.8;1H NMR(400MHz,DMSO-d6)δ7.97(d,J=2.4Hz,1H),7.86(d,J=3.3Hz,1H),7.60(dd,J=13.3,2.4Hz,1H),7.34–6.94(m,3H),6.38(dd,J=3.3,1.1Hz,1H),4.35(t,J=6.8Hz,2H),3.30(s,4H),2.63(s,6H),2.40(s,6H).
实施例六十四2-氨基-8-(2-(4-(2-氟-4-(三氟甲氧基)苯基)哌嗪-1-基)乙基)- 4-(5-甲基呋喃-2-基)蝶呤-7(8H)-酮
(2-Amino-8-(2-(4-(2-fluoro-4-(trifluoromethoxy)phenyl)piperazin-1-yl)ethyl)-4-(5-methylfuran-2-yl)pteridin-7(8H)-one)
路线参照实施例19。
ESI(m/z):[M+1]+533.8;1H NMR(400MHz,DMSO-d6)δ7.86(s,1H),7.75(d,J=3.3Hz,1H),7.41(s,2H),7.28(dd,J=12.6,2.6Hz,1H),7.15–7.02(m,2H),6.38(dd,J=3.4,1.1Hz,1H),4.33(t,J=6.7Hz,2H),2.97(t,J=4.6Hz,4H),2.66(s,6H),2.40(s,3H).
实施例六十五2-氨基-8-(2-(4-(2-氟-4-(三氟甲基)苯基)哌嗪-1-基)乙基)-4- (5-甲基呋喃-2-基)蝶呤-7(8H)-酮
(2-Amino-8-(2-(4-(2-fluoro-4-(trifluoromethyl)phenyl)piperazin-1-yl)ethyl)-4-(5-methylfuran-2-yl)pteridin-7(8H)-one)
路线参照实施例19。
ESI(m/z):[M+1]+533.8;1H NMR(400MHz,DMSO-d6)δ7.86(s,1H),7.75(d,J=3.4Hz,1H),7.56–7.24(m,4H),7.13(t,J=8.6Hz,1H),6.38(dd,J=3.4,1.1Hz,1H),4.33(t,J=6.7Hz,2H),3.07(s,4H),2.66(s,6H),2.40(s,3H).
实施例六十六2-氨基-8-(2-(4-(2-甲氧基嘧啶-5-基)哌嗪-1-基)乙基)-4-(5-甲 基呋喃-2-基)蝶呤-7(8H)-酮
(2-Amino-8-(2-(4-(2-methoxypyrimidin-5-yl)piperazin-1-yl)ethyl)-4-(5-methylfuran-2-yl)pteridin-7(8H)-one)
路线参照实施例19。
ESI(m/z):[M+1]+463.8;1H NMR(400MHz,DMSO-d6)δ8.18(s,2H),7.85(s,1H),7.74(d,J=3.3Hz,1H),7.42(s,2H),6.38(dd,J=3.4,1.1Hz,1H),4.34(t,J=6.7Hz,2H),3.76(s,3H),3.60–3.49(m,4H),2.63(t,J=6.7Hz,2H),2.55(t,J=4.9Hz,4H),2.40(s,3H).
实施例六十七2-氨基-8-(2-(4-(5-(二氟甲氧基)-3-氟吡啶-2-基)哌嗪-1-基)乙 基)-4-(5-甲基呋喃-2-基)-6-(三氟甲基)蝶呤-7(8H)-酮
(2-Amino-8-(2-(4-(5-(difluoromethoxy)-3-fluoropyridin-2-yl)piperazin-1-yl)ethyl)-4-(5-methylfuran-2-yl)-6-(trifluoromethyl)pteridin-7(8H)-one)
路线参照实施例47。
ESI(m/z):[M+1]+584.8;1H NMR(400MHz,DMSO-d6)δ8.04(s,1H),7.97(d,J=2.4Hz,1H),7.78(d,J=3.4Hz,2H),7.60(dd,J=13.3,2.4Hz,1H),7.14(t,J=73.7Hz,1H),6.45(dd,J=3.5,1.1Hz,1H),4.36(t,J=6.8Hz,2H),3.30(s,4H),2.64(s,6H),2.41(s,3H).
实施例六十八2-氨基-4-(5-甲基呋喃-2-基)-8-(2-(4-(4-苯氧基苯基)哌嗪-1- 基)乙基)蝶呤-7(8H)-酮
(2-amino-4-(5-methylfuran-2-yl)-8-(2-(4-(4-phenoxyphenyl)piperazin-1-yl)ethyl)pteridin-7(8H)-one)
路线参照实施例47。
ESI(m/z):[M+1]+524.2;1H NMR(400MHz,DMSO-d6)δ7.86(s,1H),7.75(d,J=3.3Hz,1H),7.44(brs,2H),7.34–7.30(m,2H),7.04(t,J=7.4Hz,1H),6.98–6.83(m,6H),6.38(dd,J=3.4,0.9Hz,1H),4.34(t,J=6.7Hz,2H),3.03(s,4H),2.65(s,6H),2.39(s,3H).
实施例六十九化合物对A2AR-cAMP信号通路的抑制活性测试
在诱导表达人腺苷2A受体(A2AR)的HEK-293细胞上进行拮抗剂cAMP抑制功能的活性测定(上海睿智化学研究有限公司,ChemPartner)。将细胞以每孔1000至2500个细胞的密度接种到白色的384孔板中,然后与各种浓度的化合物(范围从1μM到0.46nM,三倍稀释)在37℃孵育60分钟。
a)通过Echo技术将化合物转移至测定板(化合物总体积为100nL);
b)用刺激缓冲液收集细胞:从烧瓶中取出培养基,然后用5mL PBS洗涤细胞;吸出PBS,加入1.5mL versene,并在37℃孵育2-5分钟;加入4mL培养基并离心,然后使用刺激缓冲液将细胞悬液调节至适当的密度;使用50μL的细胞悬液进行细胞计数;
c)反应:将NECA(购于Sigma Aldrich)以1:2稀释到细胞刺激混合物中,以600rpm的转速离心3分钟,然后在室温下孵育60分钟。孵育60分钟后,加入5μLΜLight-anti-cAMP(由Perkin Elmer提供)和5μL Eu-cAMP示踪剂(由Perkin Elmer提供)。以600rpm的转速离心3分钟,然后在室温下孵育60分钟;
d)读取数值:使用装有615nm激发滤光片和655nm发射滤光片的Envision多标签读板器(由Perkin Elmer提供)检测FRET信号。
使用GraphPad Prism(7.02版)进行数据分析以确定被测化合物的IC50值。
测定结果见表二。
表二、实施例化合物的A2AR cAMP抑制活性(IC50,nM)
表二中:++++表示小于10nM;+++表示IC50大于等于10nM且小于100nM;++表示IC50大于等于100nM且小于1000nM;+表示IC50大于等于1000nM;在40nMNECA浓度下测定。
实验结果表明,本发明的化合物对A2AR-cAMP信号通路有较好的抑制活性。
实施例七十化合物在不同NECA浓度下对A2AR-cAMP的抑制活性测试
在诱导表达人腺苷2A受体(A2AR)的HEK-293细胞上进行模拟肿瘤微环境下化合物对cAMP功能的抑制活性测定(上海睿智化学研究有限公司,ChemPartner)。将细胞以每孔1000至2500个细胞的密度接种到白色的384孔板中,然后与各种浓度的化合物(范围从1μM到0.46nM,三倍稀释)在37℃孵育60分钟。
a)通过Echo技术将化合物转移至测定板(化合物总体积为100nL);b)用刺激缓冲液收集细胞:从烧瓶中取出培养基,然后用5mL PBS洗涤细胞;吸出PBS,加入1.5mLversene,并在37℃孵育2-5分钟;加入4mL培养基并离心,然后使用刺激缓冲液将细胞悬液调节至适当的密度;使用50μL的细胞悬液进行细胞计数。c)反应:将不同浓度(40nM~5000nM)的NECA(购于Sigma Aldrich)以1:2稀释到细胞刺激混合物中,以600rpm的转速离心3分钟,然后在室温下孵育60分钟。孵育60分钟后,加入5μLΜLight-anti-cAMP(由PerkinElmer提供)和5μL Eu-cAMP示踪剂(由Perkin Elmer提供)。以600rpm的转速离心3分钟,然后在室温下孵育60分钟。d)读取数值:使用装有615nm激发滤光片和655nm发射滤光片的Envision多标签读板器(由Perkin Elmer提供)检测FRET信号。
使用GraphPad Prism(7.02版)进行数据分析以确定被测化合物的IC50值。
测定结果见表三、表四。
表三、实施例47在不同NECA浓度下的A2AR cAMP抑制活性
表四、实施例54在不同NECA浓度下的A2AR cAMP抑制活性
实验结果表明,本发明的实施例47和54化合物在模拟肿瘤微环境的高NECA浓度的条件下对A2AR-cAMP信号通路具有较好的抑制活性,预示着在癌症免疫治疗中更有价值的应用。
以上所述实施例仅表达了本发明的几种实施方式,其描述较为具体和详细,但并不能因此而理解为对本发明专利范围的限制,应当指出的是,对于本领域的技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改造,这些都属于本发明的保护范围,因此,本发明专利的保护范围以所附权利要求为准。
Claims (7)
1.一种通式(I)所示的化合物或其药学上可接受的盐或其立体异构体,
其中
X选自O;
L选自C1-4亚烷基;
A选自共价键,或者/>
B选自甲基,C3-C6环烷基,苯基,吡啶基,呋喃基,嘧啶基;
C选自苯基,呋喃基,吡唑基;
R1选自氢,卤素,氰基,三氟甲基,三氟甲氧基,二氟甲氧基,C1-8烷基,-O-C1-8烷基,-O-G1-O-C1-8烷基,-G1-O-四氢呋喃基,或者-O-苯基中的一种或数种;
R2选自氢,氰基或甲基中的一种或数种;
R3选自氢,甲基或三氟甲基;
R5、R6各自独立地选自氢,甲基,乙基,或者R5与R6桥接为亚甲基或亚乙基;
R7选自氢或甲基;
G1选自C1-4亚烷基;
n1、n2选自0,1,2,3;
n3、n4选自1,2,3。
2.根据权利要求1所述通式(I)所示的化合物或其药学上可接受的盐或其立体异构体,其特征在于,A选自共价键,
3.根据权利要求1所述的化合物或其药学上可接受的盐或其立体异构体,包括:
4.一种药物组合物,其特征在于,包含根据权利要求1至3中任一项所述的化合物或其药学上可接受的盐或其立体异构体,以及药学上可接受的载体。
5.权利要求1至3中任一项所述的化合物或其药学上可接受的盐或其立体异构体,或权利要求4中所述的药物组合物,在制备腺苷A2A受体抑制剂中的应用。
6.权利要求1至3中任一项所述的化合物或其药学上可接受的盐或其立体异构体,或权利要求4中所述的药物组合物,在制备用于治疗或预防与A2AR有关的疾病的药物中的用途。
7.如权利要求6所述的用途,其特征在于,所述疾病为癌症、帕金森病、肌萎缩性侧束硬化症、冠状动脉疾病、轻度认知障碍、多发性硬化、心包性假性肝硬变、类风湿性关节炎、双相型障碍、实验性内毒素血症、及精神分裂症或前述疾病组合。
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