CN117903136A - 一种no供体型pde5抑制剂及其应用 - Google Patents
一种no供体型pde5抑制剂及其应用 Download PDFInfo
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- CN117903136A CN117903136A CN202410054484.1A CN202410054484A CN117903136A CN 117903136 A CN117903136 A CN 117903136A CN 202410054484 A CN202410054484 A CN 202410054484A CN 117903136 A CN117903136 A CN 117903136A
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- Prior art keywords
- dioxol
- pyrido
- benzo
- hexahydropyrazino
- indol
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Abstract
本发明属于医药制药领域，涉及一种NO供体型PDE5抑制剂及其应用。PDE5抑制剂化学结构如式I所示：其中，X为长度为2～15个原子数的连接臂，R为或n为0或1，C‑y位为S构型或R构型。本发明通过在tadalafil的结构中引入NO释放基团能够同时靶向NO‑sGC‑cGMP通路上的2个靶点，通过提高cGMP的合成和抑制cGMP的降解双重手段维持高浓度cGMP，进而引起平滑肌的松弛及血管的舒张，并维持血液循环的低阻力状态。研究表明，该类化合物对于血管类疾病如PAH等将具有良好的治疗效果，可以作为先导化合物来发展新型PAH治疗药物。
Description
技术领域
本发明属于医药制药领域，涉及一种NO供体型PDE5抑制剂及其应用。
背景技术
公开该背景技术部分的信息仅仅旨在增加对本发明的总体背景的理解，而不必然被视为承认或以任何形式暗示该信息构成已经成为本领域一般技术人员所公知的现有技术。
5型磷酸二酯酶(PDE5)能够特异性水解细胞内重要的第二信使cGMP，并参与调节体内多种重要的生命活动。PDE5主要分布在人体肺部、阴茎海绵体平滑肌内，以及血管、内脏及气道平滑肌、骨骼肌、血小板等组织。其最为重要功能之一是通过一氧化氮(NO)-可溶性鸟苷环化酶(sGC)-环磷酸鸟苷(cGMP)通路来降低cGMP的浓度，进而调控血管的收缩和升高血压。PDE5抑制剂则能维持细胞高水平的cGMP浓度，促进血管的舒张和血压的降低，是治疗多种血管类疾病如高血压、肺动脉高压(Pulmonary Hypertension,PAH)的理想药物靶点。特别地，基于对脑部血管的扩张活性及增加血流量的作用，多种PDE5抑制剂如西地那非(Sildenafil)、伐地那非(Vardenafil)在长期的临床应用过程中表现出了对于阿尔兹海默症患者的认知功能显著的改善作用。
然而，发明人研究发现，目前PDE5抑制剂的靶点较为单一，需要对其结构进行改善从而提高其对于相关的血管类疾病的治疗效果。
发明内容
为了解决现有技术的不足，本发明的目的是提供一种NO供体型PDE5抑制剂及其应用，本发明通过在他达拉非(tadalafil)的结构中引入NO释放基团能够同时靶向NO-sGC-cGMP通路上的2个靶点蛋白，通过提高cGMP的合成和抑制cGMP的降解双重手段维持高浓度cGMP，进而引起平滑肌的松弛及血管的舒张，并维持血液循环的低阻力状态。研究表明，该类化合物对于血管类疾病如PAH等将具有良好的治疗效果，可以作为先导化合物来发展新型PAH治疗药物。
为了实现上述目的，本发明的技术方案为：
一方面，一种PDE5抑制剂，其化学结构如式I所示：
其中，X为长度为2～15个原子数的连接臂，R为H、n为0或1，C-y位为S构型或R构型。
本发明中C-y位中的y与n有关，当n为1时，D环为哌嗪二酮类结构，此时C-y位为C-12a位；当n为0时，D环为乙内酰脲结构，此时C-y位为C-11a位。在一些实施例中，n为1时，C-y位为R构型；n为0时，C-y位为S构型。
本发明所述的连接臂可以为纯碳原子的烷基链、聚乙二醇(PEG)长链、以及含有多种官能团的连接臂(如具有酯键、酰胺键、烯基、炔基，苯环及杂环的链)。
在一些实施例中，选自以下化合物：
甲基2-((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)乙酸酯(1)；
2-((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)乙酸(2)；
2-((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)-N-(6-羟己基氧基)乙酰胺(3)；
6-羟己基氧基2-((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)乙酸酯(4)；
4-((6-(2-((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)乙酰氨基)己基)氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(5)；
(Z)-5-((((6-(2-((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)乙酰氨基)己基)氧基)羰基)亚胺基)-3-苯基-5-氢-1,2,3-噁二唑-3-鎓-2-亚基(6)；
4-((6-(2-((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)乙酰氧基)己基)氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(7)；
(Z)-5-((((6-(2-((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)乙酰氧基)己基)氧基)羰基)亚胺基)-3-苯基-5-氢-1,2,3-噁二唑-3-鎓-2-亚基(8)；
(6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-(丙-2-炔-1-基)-2,3,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-1,4-二酮(9)；
(6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-((1-(2-(2-(2-(2-羟乙氧基)乙氧基)乙氧基)乙基)-1H-1,2,3-三氮唑-4-基)甲基)-2,3,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-1,4-二酮(10)；
4-(2-(2-(4-(((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)甲基)-1H-1,2,3-三氮唑-1-基)乙氧基)乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(11)；
(6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-((1-(2-(2-(2-羟乙氧基)乙氧基)乙基)-1H-1,2,3-三氮唑-4-基)甲基)-2,3,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-1,4-二酮(12)；
4-(2-(2-(2-(4-(((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)甲基)-1H-1,2,3-三氮唑-1-基)乙氧基)乙氧基)乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(13)；
(Z)-5-(((2-(2-(2-(4-(((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)甲基)-1H-1,2,3-三氮唑-1-基)乙氧基)乙氧基)乙氧基)羰基)亚胺基)-3-苯基-5-氢-1,2,3-噁二唑-3-鎓-2-亚基(14)；
(6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-((1-(2-(2-羟乙氧基)乙基)-1H-1,2,3-三氮唑-4-基)甲基)-2,3,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-1,4-二酮(15)；
4-(2-(2-(2-(2-(4-(((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)甲基)-1H-1,2,3-三氮唑-1-基)乙氧基)乙氧基)乙氧基)乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(16)；
(6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-((1-(3-羟丙基)-1H-1,2,3-三氮唑-4-基)甲基)-2,3,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-1,4-二酮(17)；
4-(3-(4-(((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)甲基)-1H-1,2,3-三氮唑-1-基)丙氧基)--3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(18)；
(6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-((1-(5-羟戊基)-1H-1,2,3-三氮唑-4-基)甲基)-2,3,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-1,4-二酮(19)；
4-((5-(4-(((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)甲基)-1H-1,2,3-三氮唑-1-基)戊基)氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(20)；
(Z)-5-((((5-(4-(((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)甲基)-1H-1,2,3-三氮唑-1-基)戊基)氧基)羰基)亚胺基)-3-苯基-5-氢-1,2,3-噁二唑-3-鎓-2-亚基(21)；
(6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-((1-(6-羟己基氧基)-1H-1,2,3-三氮唑-4-基)甲基)-2,3,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-1,4-二酮(22)；
4-((6-(4-(((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)甲基)-1H-1,2,3-三氮唑-1-基)己基)氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(23)；
(5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-(丙-2-炔-1-基)-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-1,3(2H)-二酮(24)；
(6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-((1-(8-羟辛基)-1H-1,2,3-三氮唑-4-基)甲基)-2,3,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-1,4-二酮(25)；
(6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-((1-(2-(4-(2-羟乙基)哌嗪-1-基)-2-氧代乙基-1H-1,2,3-三氮唑-4-基)甲基)-2,3,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-1,4-二酮(26)；
4-(2-(4-(2-(4-(((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)甲基)-1H-1,2,3-三氮唑-1-基)乙酰基)哌嗪-1-基)乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(27)；
2-(2-羟乙氧基)ethyl 2-(4-(((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)甲基)-1H-1,2,3-三氮唑-1-基)乙酸酯(28)；
4-(2-(2-(2-(4-(((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)甲基)-1H-1,2,3-三氮唑-1-基)乙酰氧基)乙氧基)乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(29)；
2-(4-(((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)甲基)-1H-1,2,3-三氮唑-1-基)-N-(6-羟己基氧基)乙酰胺(30)；
4-((6-(2-(4-(((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)甲基)-1H-1,2,3-三氮唑-1-基)乙酰氨基)己基)氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(31)；
2-(4-(((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)甲基)-1H-1,2,3-三氮唑-1-基)-N-(2-羟乙基)乙酰胺(32)；
4-(2-(2-(4-(((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)甲基)-1H-1,2,3-三氮唑-1-基)乙酰氨基)乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(33)；
(6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-((1-((Z)-4-羟基丁-2-烯-1-基)-1H-1,2,3-三氮唑-4-基)甲基)-2,3,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-1,4-二酮(34)；
4-(((Z)-4-(4-(((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)甲基)-1H-1,2,3-三氮唑-1-基)丁-2-烯-1-基)氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(35)；
(6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-((1-((E)-4-羟基丁-2-烯-1-基)-1H-1,2,3-三氮唑-4-基)甲基)-2,3,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-1,4-二酮(36)；
4-(((E)-4-(4-(((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)甲基)-1H-1,2,3-三氮唑-1-基)丁-2-烯-1-基)氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(37)；
(6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-((1-(4-(2-羟乙基)苯乙基)-1H-1,2,3-三氮唑-4-基)甲基)-2,3,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-1,4-二酮(38)；
4-(4-(2-(4-(((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)甲基)-1H-1,2,3-三氮唑-1-基)乙基)苯乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(39)；
(6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-(2-(2-(2-(2-羟乙氧基)乙氧基)乙氧基)乙基)-2,3,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-1,4-二酮(40)；
4-(2-(2-(2-(2-((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)乙氧基)乙氧基)乙氧基)乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(41)；
(6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-(2-(2-(2-羟乙氧基)乙氧基)乙基)-2,3,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-1,4-二酮(42)；
4-(2-(2-(2-((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)乙氧基)乙氧基)乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(43)；
(6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-(2-(2-羟乙氧基)乙基)-2,3,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-1,4-二酮(44)；
4-(2-(2-((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)乙氧基)乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(45)；
(6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-(2-羟乙基)-2,3,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-1,4-二酮(46)；
4-(2-((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(47)；
(Z)-5-(((2-((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)乙氧基)羰基)亚胺基)-3-苯基-5-氢-1,2,3-噁二唑-3-鎓-2-亚基(48)；
(6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-(5-羟戊基)-2,3,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-1,4-二酮(49)；
4-((5-((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)戊基)氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(50)；
(6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-(6-羟己基氧基)-2,3,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-1,4-二酮(51)；
4-((6-((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)己基)氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(52)；
(Z)-5-((((6-((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)己基)氧基)羰基)亚胺基)-3-苯基-5-氢-1,2,3-噁二唑-3-鎓-2-亚基(53)；
(6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-(8-羟辛基)-2,3,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-1,4-二酮(54)；
4-((8-(4-(((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)甲基)-1H-1,2,3-三氮唑-1-基)辛基)氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(55)；
(5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-(丙-2-炔-1-基)-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-1,3(2H)-二酮(56)；
(5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-((1-(2-(2-(2-(2-羟乙氧基)乙氧基)乙氧基)乙基)-1H-1,2,3-三氮唑-4-基)甲基)-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-1,3(2H)-二酮(57)；
4-(2-(2-(2-(2-(4-(((5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,3-二氧代-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-2(3H)-基)甲基)-1H-1,2,3-三氮唑-1-基)乙氧基)乙氧基)乙氧基)乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(58)；
(Z)-5-((13-(4-(((5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,3-二氧代-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-2(3H)-基)甲基)-1H-1,2,3-三氮唑-1-基)-2,5,8,11-四氧代十三酰)亚胺基)-3-苯基-5-氢-1,2,3-噁二唑-3-鎓-2-亚基(59)；
(5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-((1-(2-(2-(2-羟乙氧基)乙氧基)乙基)-1H-1,2,3-三氮唑-4-基)甲基)-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-1,3(2H)-二酮(60)；
4-(2-(2-(2-(4-(((5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,3-二氧代-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-2(3H)-基)甲基)-1H-1,2,3-三氮唑-1-基)乙氧基)乙氧基)乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(61)；
(5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-((1-(2-(2-羟乙氧基)乙基)-1H-1,2,3-三氮唑-4-基)甲基)-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-1,3(2H)-二酮(62)；
4-(2-(2-(4-(((5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,3-二氧代-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-2(3H)-基)甲基)-1H-1,2,3-三氮唑-1-基)乙氧基)乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(63)；
(5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-((1-(3-羟丙基)-1H-1,2,3-三氮唑-4-基)甲基)-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-1,3(2H)-二酮(64)；
4-(3-(4-(((5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,3-二氧代-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-2(3H)-基)甲基)-1H-1,2,3-三氮唑-1-基)丙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(65)；
(5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-((1-(5-羟戊基)-1H-1,2,3-三氮唑-4-基)甲基)-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-1,3(2H)-二酮(66)；
4-((5-(4-(((5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,3-二氧代-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-2(3H)-基)甲基)-1H-1,2,3-三氮唑-1-基)戊基)氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(67)；
(5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-((1-(6-羟己基氧基)-1H-1,2,3-三氮唑-4-基)甲基)-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-1,3(2H)-二酮(68)；
4-((6-(4-(((5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,3-二氧代-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-2(3H)-基)甲基)-1H-1,2,3-三氮唑-1-基)己基)氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(69)；
(5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-((1-(8-羟辛基)-1H-1,2,3-三氮唑-4-基)甲基)-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-1,3(2H)-二酮(70)；
4-((8-(4-(((5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,3-二氧代-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-2(3H)-基)甲基)-1H-1,2,3-三氮唑-1-基)辛基)氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(71)；
(5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-(2-(2-(2-(2-羟乙氧基)乙氧基)乙氧基)乙基)-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-1,3(2H)-二酮(72)；
4-(2-(2-(2-(2-((5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,3-二氧代-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-2(3H)-基)乙氧基)乙氧基)乙氧基)乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(73)；
(5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-(2-(2-(2-羟乙氧基)乙氧基)乙基)-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-1,3(2H)-二酮(74)；
4-(2-(2-(2-((5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,3-二氧代-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-2(3H)-基)乙氧基)乙氧基)乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(75)；
(5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-(2-(2-羟乙氧基)乙基)-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-1,3(2H)-二酮(76)；
4-(2-(2-((5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,3-二氧代-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-2(3H)-基)乙氧基)乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(77)；
(5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-(2-羟乙基)-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-1,3(2H)-二酮(78)；
4-(2-((5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,3-二氧代-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-2(3H)-基)乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(79)；
(5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-(5-羟戊基)-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-1,3(2H)-二酮(80)；
4-((5-((5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,3-二氧代-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-2(3H)-基)戊基)氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(81)；
(5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-(6-羟己基氧基)-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-1,3(2H)-二酮(82)；
4-((6-((5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,3-二氧代-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-2(3H)-基)己基)氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(83)；
(5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-(8-羟辛基)-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-1,3(2H)-二酮(84)；
4-((8-((5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,3-二氧代-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-2(3H)-基)辛基)氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(85)；
(Z)-5-((((8-((5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,3-二氧代-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-2(3H)-基)辛基)氧基)羰基)亚胺基)-3-苯基-5-氢-1,2,3-噁二唑-3-鎓-2-亚基(86)。
其中，化合物10、11、12、15、16、17、18、20、22、24、26、28、29、32、33、34、36、37、38、40、41、43、45、47、48、49、51、52、54、62、68、72、73、74、78、80、81、84。研究表明，该化合物在10nM浓度下PDE5抑制率大于80％，具有更强效的PDE5抑制活性。研究表明化合物29、41、45的IC50在5～10μM之间，具有微弱的细胞毒性；而化合物81的IC50大于20μM，无细胞毒性。
另一方面，一种NO供体型PDE5抑制剂，其为上述PDE5抑制剂，R代表的的NO释放基团的结构为
第三方面，一种上述NO供体型PDE5抑制剂的制备方法，其合成路线如下所示：
具体地，首先制备关键中间体α-氯带酰胺化合物，并与相应的胺类化合物进行反应，经过亲核进攻和酯交换反应得到一类哌嗪二酮类结构。其中，a)酯类化合物水解后成酯或形成酰胺键引入末端为羟基的侧链；b)炔基化合物经过高效的Huisgen 1,3-偶极环加成反应1,3-加成反应引入末端羟基侧链；c)在构建六元环的哌嗪二酮结构的过程中直接引入羟基侧链。另一方面，在三光气、三乙胺及胺类化合物存在的条件下，可以构建五元环的乙内酰脲结构，并经由三乙胺的甲醇溶液转变为相应的C11a-S构型。
具有末端羟基的中间体化合物与相应的NO供体，可以与furoxan(呋咱氮氧化物)在碱性条件下(如DBU或NaOH)发生反应，或与sydnonimine(斯德酮亚胺)在乙腈溶液中回流反应，最终生成相应的含有NO供体结构的PDE5抑制剂类化合物。
第四方面，一种药物组合物，包含上述PDE5抑制剂或其药学上可接受的盐、前药化合物、相应的活性代谢产物、对映异构体、溶剂化物。
在一些实施例中，还包括药用辅料。具体地，所述药用辅料包括药用载体和/或赋形剂。所述药用载体例如氧化铝、聚乳酸、海藻酸钠、壳聚糖、脂质体等。所述赋形剂例如粘合剂、填充剂、崩解剂、增溶剂等。
第五方面，一种药物制剂，活性成分为上述PDE5抑制剂或药物组合物，剂型为片剂、胶囊剂、锭剂、糖衣丸剂、丸剂、颗粒剂、粉末剂、溶液剂、乳剂、混悬剂、分散体、糖浆剂、凝胶剂、气溶胶剂及其他特殊剂型。
第六方面，一种上述PDE5抑制剂、药物组合物或药物制剂在制备治疗、缓解或预防的哺乳动物疾病的药物中的应用，所述疾病包括以下一种或多种：
a.与PDE5相关的疾病或疾病状态；
b.与NO缺乏相关的疾病或疾病状态。
在一些实施例中，所述哺乳动物包括人或非人哺乳动物。所述非人哺乳动物例如大鼠、小鼠、兔、狗、猪、牛、羊、猴、猩猩等。
在一些实施例中，所述疾病包括但不限于高血压、肺动脉高压(HP)、外周血管疾病、减少血管全开的疾病、充血性心力衰竭、动脉硬化、稳定型、不稳定型和变异型(普林兹默托尔氏)心绞痛、阿尔兹海默症(老年痴呆症，AD)、恶性肿瘤、男性勃起功能障碍(MED)、男性睾丸缺血、女性性功能障碍(FSD)、早产、痛经、良性前列腺增生(BPH)、膀胱出口阻塞、失禁、中风、慢性哮喘、支气管炎、变应性哮喘、过敏性鼻炎、青光眼或其特征为肠动力紊乱的疾病。优选为肺动脉高压(PAH)。
在一些实施例中，所述药物的给药方式为口服给药、局部给药、肌内给药、皮内给药、腹膜内给药、皮下给药、静脉内给药或吸入给药，优选吸入给药。
本发明的有益效果为：
本发明提供的小分子既能够有效并选择性的抑制PDE5的活性，也能够较好的释放出的NO分子，协同作用于NO-sGC-cGMP通路，有效地的舒张血管。该类化合物适用于治疗或预防由于血管压力升高引起的相关疾病，特别优选用于肺动脉高压(PAH)等疾病的治疗。
附图说明
构成本发明的一部分的说明书附图用来提供对本发明的进一步理解，本发明的示意性实施例及其说明用于解释本发明，并不构成对本发明的不当限定。
图1为本发明实施例中化合物81在BEAS-2B中NO释放的荧光成像照片，A为空白(DMSO)，B为浓度1.25μM，C为浓度2.5μM，D为浓度5μM；
图2为本发明实施例中化合物81在BEAS-2B中NO释放的荧光成像定量分析，A为曲线图，B为柱状图。
具体实施方式
为了使得本领域技术人员能够更加清楚地了解本发明的技术方案，以下将结合具体的实施例详细说明本发明的技术方案。
实施例1酯键/酰胺键连接的NO供体型tadalafil衍生物的合成。
中间体2的合成。以tadalafil中间体s1-1的盐酸盐形式为起始原料进行合成。s1-1(10g,28mmol,1eq)溶于THF/H2O(40/10mL)的混合溶液中，冷却至10℃后，依此加入Et3N(9.7mL,70mmol,2.5eq)与7mL的氯乙酰氯(3.2mL,43mmol,1.5eq)的THF溶液。反应在10℃下搅拌2h后，蒸除～70％的溶剂后再加入50mL异丙醇/水(4:1)的溶液，并再次旋蒸除去20％的溶剂。这时有大量白色的固体析出，该悬浊液搅拌1h后过滤，烘干后得到化合物s1-2(10.4g,87％)。ESI-MS m/z 427[M+H]+.化合物s1-2(426mg,1mmol,1eq)溶于25mL的MeOH中，加入甘氨酸甲酯(178mg,2mmol,2eq)后升温至90℃反应12h至大部分原料消失后，直接蒸干溶剂并用flash快速分离系统进行2次柱层析(0％-5％ MeOH/CH2Cl2)，可除去一部分反应剩余的原料。这时加入20mL的CH2Cl2后有大量白色固体析出，悬浊液搅拌15min后直接过滤、烘干后得产物1(255mg,57％)。
化合物1(550mg,1.23mmol,1eq)溶于4.4mL得MeOH中并滴加8.8mL NaOH的水溶液(1M)，该反应升温至40℃搅拌2h后用1N的盐酸进行中和。随着溶液的酸化，大量白色沉淀逐渐析出。将白色固体过滤并用水洗后，即得到中间体2(530mg,qunatative)。
化合物5的合成。化合物2(128mg,0.3mmol,1eq)、6-羟基己胺(48mg,0.41mmol,1.36eq)溶于2mL的无水DMF中，依此加入DIEA(107μL,0.6mmol,2eq)和HATU(126mg,0.45mmol,1.5eq)后室温搅拌约10分钟后加水终止反应。用CH2Cl2(3×20mL)进行萃取后，干燥、蒸干，并用flash快速分离系统进行柱层析(0％-5％ MeOH/CH2Cl2)得到化合物3(140mg,87％)。
化合物3(38mg,0.071mmol,1eq)与furoxan(40mg,0.107mmol,1.5eq)溶于2mL的CH2Cl2溶液中，并滴加DBU(63μL,0.42mmol,6eq)。室温反应2h后加水终止反应，萃取、干燥并蒸干后，用flash快速分离系统进行柱层析(0％-5％ MeOH/CH2Cl2)得到化合物5(12mg,22％)。
化合物6的合成。将末端为羟基的中间体化合物3(38mg,0.071mmol,1eq)溶于5mL乙腈中，加入(Z)-5-(((4-nitrophenoxy)carbonyl)imino)-3-phenyl-5H-1,2,3-oxadiazol-3-ium-2-ide(35mg,0.11mmol,1.5eq,按照Organic and BiomolecularChemistry,2013,11,4657-4671所述方法进行合成，以下称为N-((4-Nitrophenoxy)carbonyl)-3-phenylsydnonimine)后升温并回流18h至原料完全反应。蒸干溶剂后用flash快速分离系统进行柱层析(0％-5％ MeOH/CH2Cl2)得到化合物6(10mg,20％)。
化合物7的合成。化合物2(150mg,0.37mmol,1eq)、6-溴己醇(60μL,0.7mmol,2eq)以及K2CO3(151mg,1.1mmol,3eq)溶于1.5mL的超干DMF中，升温至50℃后反应2h。待原料转化完全后，蒸干溶剂，粗产品用flash快速分离系统进行纯化(0％-5％ MeOH/CH2Cl2)并得到相应的产物4(120mg,61％)。
将化合物4(38mg,0.071mmol,1eq)与furoxan(39mg,0.107mmol,1.5eq)溶于CH2Cl2(2mL)中，并逐步滴加DBU(63μL,0.42mmol,6eq)。在室温反应2h后向该混合物中加水终止反应，进行萃取、干燥、蒸除溶剂等操作后，油状产品用flash快速分离系统进行柱层析(0％-5％ MeOH/CH2Cl2)得到化合物5(10mg,20％)。
化合物8的合成。化合物4(38mg,0.071mmol,1eq)，N-((4-Nitrophenoxy)carbonyl)-3-phenylsydnonimine(35mg,0.11mmol,1.5eq)溶于5mL乙腈后，升温至回流状态反应18h至原料完全反应。除去溶剂后用flash快速分离系统进行柱层析(0％-5％ MeOH/CH2Cl2)得到化合物6(32mg,63％)。
实施例2三氮唑类连接臂的NO供体型tadalafil衍生物的合成。
炔丙基tadalafil衍生物9的合成。中间体s1-2(4.26g,10mmol,1eq)及炔丙胺(3.2mL,50mmol,5eq)溶于10mL的MeOH溶液中，并升温至回流状态搅拌12h。反应结束后冷却至室温，将生成的白色固体过滤出来，并用MeOH洗涤2次，干燥得化合物9(4.0g,97％)。
化合物13的合成。将化合物9(85mg,0.2mmol,1eq),S-12(39mg,0.25mmol,1.25eq)溶于DMF/H2O/tBuOH(1:1:1mL)的混合液中，依此加入少量TBTA，400μL Ascorbate Na(1M)溶液及150μLCuSO4(0.5M)溶液。升温至90℃后反应1h。加水并用CH2Cl2(3×20mL)进行萃取，将溶剂完全蒸干后用flash快速分离系统进行纯化(0％-5％ MeOH/CH2Cl2)并得到相应的产物12(117mg,99％)。
化合物12与furoxan(38mg,0.105mmol,1.5eq)溶于CH2Cl2(2mL)中，并逐步滴加DBU(60μL,0.40mmol,6eq)。在室温反应2h后向该混合物中加水终止反应，进行萃取、干燥、蒸除溶剂等操作后，油状产品用flash快速分离系统进行柱层析(0％-5％ MeOH/CH2Cl2)得到化合物13(30mg,53％)。Colorless crystal,mp.87-89℃.
化合物14的合成。N-((4-Nitrophenoxy)carbonyl)-3-phenylsydnonimine(32mg,0.105mmol,1.5eq)，化合物12(42mg,0.071mmol,1eq)溶于5mL乙腈后，升温至回流状态反应18h至原料完全反应。除去溶剂后用flash快速分离系统进行柱层析(0％-5％ MeOH/CH2Cl2)得到化合物14(44mg,80％)。
化合物21的合成。参考化合物12的合成方法，以化合物9(85mg,0.2mmol,1eq)和S-20(36mg,0.3mmol,1.5eq)为起始原料进行反应并处理，经flash快速分离系统(0％-5％MeOH/CH2Cl2)纯化后得中间体20(110mg,100％)。
按照合成化合物13的方法，化合物20(42mg,0.07mmol,1eq)与furoxan(38mg,0.105mmol,1.5eq)在DBU(60μL,0.40mmol,6eq)存在的条件下反应，并通过flash快速分离系统(0％-5％ MeOH/CH2Cl2)纯化得到化合物21(28mg,52％)。
化合物22的合成。参考化合物14的合成方法，N-((4-Nitrophenoxy)carbonyl)-3-phenylsydnonimine(32mg,0.105mmol,1.5eq)，化合物20(42mg,0.071mmol,1eq)在乙腈中回流18h并经过制备TLC(10％MeOH/CH2Cl2)纯化后得化合物22(34mg,67％)。Yellowcrystal,mp.145-147℃.
化合物26的合成。以化合物9(83mg,0.2mmol,1eq)，S-25(82mg,0.48mmol,2.4eq)为原料，参考化合物12的操作，并用flash快速分离系统(0％-5％ MeOH/CH2Cl2)进行纯化后得到产物25(96mg,82％)。
化合物25(40mg,0.068mmol,1eq)与furoxan(37mg,0.1mmol,1.5eq)溶于3mL的THF中，并加入50％的NaOH水溶液。反应2h后加入CH2Cl2(3×20mL)萃取、干燥并蒸干。粗品经flash快速分离系统(0％-5％MeOH/CH2Cl2)分离后得产物26(20mg,36％)。
化合物29的合成。化合物9(83mg,0.2mmol,1eq)，S-28(90mg,0.48mmol,2.4eq)为原料，参考化合物12的操作，并用flash快速分离系统(0％-5％ MeOH/CH2Cl2)进行纯化后得到产物28(96mg,82％)。
将化合物28(41mg,0.068mmol,1eq)与furoxan(37mg,0.1mmol,1.5eq)溶于CH2Cl2(2mL)中，并逐步滴加DBU(60μL,0.40mmol,6eq)，室温搅拌2h后加水终止反应，并用CH2Cl2(3×20mL)萃取、干燥和蒸干。粗品经flash快速分离系统(0％-5％ MeOH/CH2Cl2)分离后得产物29(10mg,18％)。
实施例3以直链为连接臂的tadalafil衍生物的合成。
化合物47的合成。中间体s1-2(426mg,1mmol,1eq)和S-46(122mg,2mmol,2eq)在20mL无水MeOH中回流反应12h，冷却后直接过滤得白色固体得产物47(378mg,90％)。
按照合成化合物13的方法，化合物46(42mg,0.1mmol,1eq)与furoxan(50mg,0.15mmol,1.5eq)在DBU(90μL,0.60mmol,6eq)存在的条件下反应，并通过flash快速分离系统(0％-5％ MeOH/CH2Cl2)纯化得到化合物47(29mg,45％)。
化合物48的合成。按照化合物14的合成方法，以N-((4-Nitrophenoxy)carbonyl)-3-phenylsydnonimine(50mg,0.15mmol,1.5eq)和46(42mg,0.1mmol,1eq)为原料，并用flash快速分离系统(0％-5％ MeOH/CH2Cl2)制备得产品48(34mg,56％)。
化合物52的合成。以s1-2(426mg,1mmol,1eq)和S-51(122mg,2mmol,2eq)为原料，在20mL无水MeOH中回流反应12h，蒸除溶剂后用flash快速分离系统(0％–5％MeOH/CH2Cl2)纯化后得到产物51(323mg,68％)。
化合物51(47mg,0.1mmol,1eq)与furoxan(50mg,0.15mmol,1.5eq)溶于2mL的CH2Cl2中，按照合成化合物13的方法，在DBU(90μL,0.60mmol,6eq)存在的条件下反应，并通过flash快速分离系统(0％–5％MeOH/CH2Cl2)纯化得到化合物52(22mg,31％)。
化合物53的合成。按照化合物14的合成方法，以N-((4-Nitrophenoxy)carbonyl)-3-phenylsydnonimine(50mg,0.15mmol,1.5eq)和51(47mg,0.1mmol,1eq)为原料，并用flash快速分离系统(0％–5％MeOH/CH2Cl2)制备得产品53(36mg,54％)。
化合物40的合成。以s1-2(426mg,1mmol,1eq)和S-41(386mg,2mmol,2eq)为原料，在20mL无水MeOH中回流反应12h，蒸除溶剂后用flash快速分离系统(0％–5％MeOH/CH2Cl2)纯化后得到产物40(418mg,76％)。
化合物51(55mg,0.1mmol,1eq)与furoxan(50mg,0.15mmol,1.5eq)溶于2mL的CH2Cl2中，溶于3mL的THF中，并加入50％的NaOH水溶液。反应2h后加水终止反应，并用CH2Cl2(3×20mL)萃取、干燥和蒸干。粗品经flash快速分离系统(0％–5％MeOH/CH2Cl2)分离后得产物41(43mg,54％).
实施例4乙内酰脲类β-咔啉PDE5抑制剂与NO供体偶联化合物的制备。
化合物55的合成。将化合物s1-1(1.05g,3mmol,1eq)与Et3N(2.07mL,15mmol,5eq)溶于20mL重蒸的CH2Cl2中并冷却至0℃，向其中缓慢滴加2mL三光气(439mg,1.5mmol,0.5eq)的CH2Cl2溶液。搅拌15min后，滴加炔丙胺(1.91mL,30mmol,10eq)并再搅拌15min。这时撤去冰浴条件并升温，保持回流状态反应3h后直接蒸除溶剂，TLC检测原料转化并生成55及其差向异构体。将粗产品再溶于20mL甲醇并加入Et3N(1.24mL,9mmol,3eq)，回流反应3h后即能够翻转C11a的构型，得到相对较纯的单一构型产物55。最后加入3×40mL的CH2Cl2和20mL HCl(2M)，分离有机相并蒸干，将白色固体悬浮于EtOAc并过滤，用EtOAc洗涤2次后得化合物55(520mg,43％)。
化合物69的合成。将化合物55(60mg,0.15mmol,1eq),S-12(48mg,0.3mmol,2eq)溶于DMF/H2O/tBuOH(1:1:1mL)的混合液中并搅拌均匀后，依此加入少量TBTA，400μL抗坏血酸盐钠(1M)溶液及150μL CuSO4(0.5M)溶液。将该反应液升温至90℃后反应1h后加水处理，并用CH2Cl2(3×20mL)进行萃取，将溶剂完全蒸干后用flash快速分离系统进行纯化(0％-5％MeOH/CH2Cl2)并得到相应的产物68(70mg,86％)。
参考化合物13的合成方法，将化合物68(30mg,0.06mmol,1eq)与furoxan(36mg,0.1mmol,1.5eq)溶于2mL的CH2Cl2中，在DBU(54μL,0.36mmol,6eq)存在的条件下反应，并通过flash快速分离系统(0％-5％ MeOH/CH2Cl2)纯化得到化合物69(22mg,48％)。
化合物73的合成。20mL重蒸的CH2Cl2置于圆底烧瓶中并冷却至0℃，依此加入化合物s1-1(500mg,1.5mmol,1eq)，Et3N(1.04mL,7.5mmol,5eq)，以及1mL三光气(218mg,0.75mmol,0.5eq)的CH2Cl2溶液。搅拌15min后，滴加S-72(2mL,15mmol,10eq)并再搅拌15min。随后撤去冰浴条件并升温，保持回流状态反应3h后直接蒸除溶剂。将混合物的粗产品再溶于10mL甲醇并加入Et3N(0.62mL,4.5mmol,3eq)，回流反应3h至TLC检测只有一个构型的产品时，加入20mL HCl(2M)处理反应并用CH2Cl2(3×20mL)萃取。有机相蒸干后用flash快速分离系统(0％-80％ EtOAc/Hexane)纯化得到化合物72(592mg,71％)。
参考化合物26的合成方法，化合物72(30mg,0.06mmol,1eq)与furoxan(40mg,0.1mmol,1.5eq)溶于2mL的THF中，加入50％ NaOH(60μL)存在的条件下反应，并通过flash快速分离系统(0％-5％
MeOH/CH2Cl2)纯化得到化合物73(28mg,60％)。
化合物81的合成。参考化合物73的合成操作，以s1-1(300mg,1.05mmol,1eq)，Et3N(0.6mL,5mmol,5eq)，1mL三光气(155mg,0.53mmol,0.5eq)的CH2Cl2溶液以及S-81(2mL,15mmol,10eq)为起始原料，并在8mL的Et3N(0.36mL,3mmol,3eq)的MeOH溶液回流完成构型的翻转。最后用flash快速分离系统(0％-70％ EtOAc/Hexane)进行分离得化合物80(197mg,44％)。
参考化合物13的合成方法，将化合物84(27mg,0.06mmol,1eq)与furoxan(36mg,0.1mmol,1.5eq)溶于2mL的CH2Cl2中，在DBU(54μL,0.36mmol,6eq)存在的条件下反应，并通过flash快速分离系统(0％-60％ EtOAc/Hexane)纯化得到化合物85(16mg,39％)。
化合物85的合成。参考化合物73的合成操作，以s1-1(300mg,1.05mmol,1eq)，Et3N(0.6mL,5mmol,5eq)，1mL三光气(155mg,0.53mmol,0.5eq)的CH2Cl2溶液以及S-84(2mL,15mmol,10eq)为起始原料，并在8mL的Et3N(0.36mL,3mmol,3eq)的MeOH溶液回流完成构型的翻转。最后用flash快速分离系统(0％-70％ EtOAc/Hexane)进行分离得化合物84(502mg,98％)。
参考化合物13的合成方法，将化合物84(30mg,0.06mmol,1eq)与furoxan(36mg,0.1mmol,1.5eq)溶于2mL的CH2Cl2中，在DBU(54μL,0.36mmol,6eq)存在的条件下反应，并通过flash快速分离系统(0％-60％ EtOAc/Hexane)纯化得到化合物85(24mg,56％)。
所有化合物的化学结构式及部分醇羟基化合物、NO供体衍生物的波谱数据。
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(6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-((1-(2-(2-(2-(2-羟乙氧基)乙氧基)乙氧基)乙基)-1H-1,2,3-三氮唑-4-基)甲基)-2,3,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-1,4-二酮(10).96％yield.Pale Yellow crystal,mp.83-85℃.1H NMR(400MHz,Chloroform-d)δ8.38(s,1H),7.80(s,1H),7.57(d,J＝7.3Hz,1H),7.26(d,J＝7.7Hz,1H),7.14(p,J＝7.0Hz,2H),6.82(d,J＝8.1Hz,1H),6.71(s,1H),6.66(d,J＝8.1Hz,1H),6.14(s,1H),5.84(d,J＝8.3Hz,2H),4.99(d,J＝14.9Hz,1H),4.51(t,J＝5.1Hz,2H),4.44(d,J＝14.9Hz,1H),4.25(dd,J＝11.6,4.7Hz,1H),4.21-4.04(m,2H),3.85(t,J＝5.2Hz,2H),3.78-3.68(m,3H),3.68-3.64(m,2H),3.60(d,J＝5.0Hz,8H),3.48(s,7H),3.20(dd,J＝16.0,11.5Hz,1H),3.06(s,1H).13C NMR(101MHz,CDCl3)δ167.0,166.6,147.8,147.0,142.0,136.6,135.4,133.0,126.1,124.3,122.4,120.7,120.0,118.5,111.3,108.2,107.4,106.2,101.1,72.5,70.5,70.5,70.4,70.2,69.3,61.6,56.5,56.3,50.8,50.4,50.3,41.2,23.7.ESI-MS m/z 633[M+H]+,HR-EI-MS:m/z 633.2680[M+H]+,(calcd for C32H37N6O8 +,633.2667).
4-(2-(2-(4-(((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)甲基)-1H-1,2,3-三氮唑-1-基)乙氧基)乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(11).45％yieldvia DBU condition.Light yellow crystal,mp.80-81℃.1H NMR(400MHz,Chloroform-d)δ8.04(d,J＝8.2Hz,2H),8.00(s,1H),7.84-7.70(m,2H),7.59(t,J＝7.9Hz,3H),7.27(d,J＝4.4Hz,1H),7.15(p,J＝7.2Hz,2H),6.84(d,J＝8.1Hz,1H),6.71(s,1H),6.67(d,J＝7.9Hz,1H),6.15(s,1H),5.85(d,J＝8.9Hz,2H),5.00(d,J＝14.9Hz,1H),4.60-4.48(m,4H),4.44(d,J＝15.0Hz,1H),4.28(dd,J＝11.5,4.8Hz,1H),4.24-4.06(m,2H),3.95-3.81(m,4H),3.81-3.69(m,3H),3.69-3.58(m,6H),3.21(dd,J＝16.1,11.4Hz,1H).13C NMR(101MHz,CDCl3)δ167.0,166.4,158.9,147.8,147.1,142.1,138.0,136.5,135.6,135.4,133.0,129.7,128.6,126.2,124.1,122.5,120.8,120.1,118.5,111.3,110.6,108.2,107.4,106.4,101.2,71.0,70.7,70.6,70.6,69.3,68.4,56.6,56.3,50.4,50.3,41.3,23.8.ESI-MS m/z 857[M+H]+,HR-EI-MS:m/z 857.2583[M+H]+,(calcd for C40H41N8O12S+,857.2559).
(6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-((1-(2-(2-(2-羟乙氧基)乙氧基)乙基)-1H-1,2,3-三氮唑-4-基)甲基)-2,3,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-1,4-二酮(12).99％yield.Colorless crystal,mp.105-107℃.1HNMR(400MHz,Methanol-d4)δ8.00(s,1H),7.51(d,J＝7.7Hz,1H),7.25(d,J＝7.9Hz,1H),7.13-6.95(m,2H),6.87-6.72(m,2H),6.66(d,J＝7.9Hz,1H),6.16(s,1H),5.83(d,J＝3.1Hz,2H),4.82(s,1H),4.64(d,J＝15.1Hz,1H),4.54(t,J＝5.0Hz,2H),4.38(dd,J＝11.8,4.7Hz,1H),4.18(dd,J＝17.2,1.7Hz,1H),4.03(d,J＝17.4Hz,1H),3.85(t,J＝5.0Hz,2H),3.70-3.60(m,3H),3.57(t,J＝3.6Hz,4H),3.49(t,J＝4.8Hz,2H),3.14(dd,J＝16.1,11.4Hz,1H).13C NMR(101MHz,MeOD)δ167.6,167.4,147.7,146.8,142.0,136.9,136.2,133.3,126.0,124.5,121.3,119.8,118.9,117.5,110.8,107.5,106.9,104.7,100.9,72.2,70.0,68.9,60.8,56.4,56.1,53.4,50.0,49.6,40.3,23.1.ESI-MS m/z 589[M+H]+,HR-EI-MS:m/z 589.2407[M+H]+,(calcd for C30H32N6O7 +,589.2405).
(6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-((1-(2-(2-羟乙氧基)乙基)-1H-1,2,3-三氮唑-4-基)甲基)-2,3,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-1,4-二酮(15).99％yield.Pale yellow crystal,mp.124-126℃.1H NMR(400MHz,Chloroform-d)δ8.84(s,1H),7.77(s,1H),7.51(d,J＝7.7Hz,1H),7.22(d,J＝7.8Hz,1H),7.15-7.01(m,2H),6.83-6.65(m,2H),6.60(d,J＝7.9Hz,1H),6.08(s,1H),5.78(d,J＝7.5Hz,2H),4.90(d,J＝15.0Hz,1H),4.55-4.33(m,3H),4.18-3.99(m,3H),3.81(t,J＝5.4Hz,2H),3.71-3.60(m,3H),3.54-3.43(m,5H),3.25-2.99(m,2H).13C NMR(101MHz,CDCl3)δ167.0,166.8,147.7,146.9,142.1,136.5,135.5,133.1,126.1,124.4,122.3,120.5,119.9,118.4,111.4,108.2,107.4,105.9,101.1,72.6,69.0,61.4,56.4,56.2,50.7,50.4,50.3,41.4,23.6.ESI-MS m/z 545[M+H]+,HR-EI-MS:m/z 545.2146[M+H]+,(calcd for C28H29N6O6 +,545.2143).
4-(2-(2-(2-(2-(4-(((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)甲基)-1H-1,2,3-三氮唑-1-基)乙氧基)乙氧基)乙氧基)乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(16).37％yield via DBU condition.Yellow crystal,mp.105-107℃.1H NMR(400MHz,Chloroform-d)δ8.01(d,J＝8.2Hz,3H),7.86-7.77(m,1H),7.74(t,J＝7.6Hz,1H),7.64-7.54(m,3H),7.25(d,J＝5.9Hz,1H),7.20-7.07(m,2H),6.83(d,J＝7.8Hz,1H),6.71(s,1H),6.66(d,J＝7.9Hz,1H),6.13(s,1H),5.84(d,J＝8.9Hz,2H),5.01(d,J＝15.2Hz,1H),4.65-4.37(m,5H),4.33-4.23(m,1H),4.14(q,J＝18.2,17.8Hz,2H),3.99(t,J＝5.1Hz,2H),3.85(t,J＝4.5Hz,2H),3.72(dd,J＝
16.3,4.9Hz,1H),3.19(dd,J＝16.1,11.6Hz,1H).13C NMR(101MHz,CDCl3)δ167.0,166.5,158.8,147.8,147.1,137.7,136.5,135.7,135.4,132.9,129.7,128.6,126.2,122.5,120.7,120.0,118.6,111.2,110.6,108.2,107.4,106.4,101.1,70.4,69.7,68.4,56.6,56.3,50.4,41.3,23.7.ESI-MS m/z 769[M+H]+,HR-EI-MS:m/z
769.2048[M+H]+,(calcd for C36H33N8O10S+,769.2035).
(6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-((1-(3-羟丙基)-1H-1,2,3-三氮唑-4-基)甲基)-2,3,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-1,4-二酮(17).96％yield.Colorless crystal,mp.151-152℃.1H NMR(400MHz,Chloroform-d)δ8.57(s,1H),7.59(s,1H),7.53(d,J＝7.7Hz,1H),7.31-
7.18(m,1H),7.18-6.98(m,2H),6.75(d,J＝8.1Hz,1H),6.67(s,1H),6.60(d,J＝8.1Hz,1H),6.10(s,1H),5.77(d,J＝5.9Hz,2H),4.88(d,J＝14.9Hz,1H),4.57-4.35(m,3H),4.27-3.98(m,3H),3.79-3.50(m,3H),3.17(dd,J＝15.9,11.5Hz,1H),2.72(t,J＝5.1Hz,1H),2.11-2.03(m,2H).13C NMR(101MHz,CDCl3)δ167.0,166.7,147.7,147.0,142.2,136.5,135.4,133.0,126.1,123.5,122.4,120.5,120.0,118.5,111.3,108.2,107.3,106.1,101.2,58.6,56.4,56.2,50.4,47.1,41.2,32.4,23.6.ESI-MS m/z 515[M+H]+,HR-EI-MS:m/z
515.2039[M+H]+,(calcd for C27H27N6O5 +,515.2037).
4-(3-(4-(((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)甲基)-1H-1,2,3-三氮唑-1-基)丙氧基)--3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(18).47％yield via DBUcondition.Yellow crystal,mp.123-125℃.1H NMR(400MHz,Chloroform-d)δ8.13(s,1H),8.07(d,J＝8.1Hz,2H),7.76(t,J＝7.4Hz,1H),7.70(s,1H),7.63(t,J＝7.6Hz,2H),7.57(d,J＝7.8Hz,1H),7.26(d,J＝6.1Hz,1H),7.21-7.11(m,2H),6.83(d,J＝8.1Hz,1H),6.71(s,1H),6.66(d,J＝8.1Hz,1H),6.14(s,1H),5.83(d,J＝8.6Hz,2H),4.97(d,J＝15.0Hz,1H),4.58(t,J＝6.7Hz,2H),4.49-4.35(m,3H),4.32-4.10(m,3H),3.73(dd,J＝16.0,4.6Hz,1H),3.20(dd,J＝16.0,11.4Hz,1H),2.49(t,J＝6.2Hz,2H).13C NMR(101MHz,CDCl3)δ166.9,166.6,158.6,147.8,147.1,137.7,136.5,135.8,135.4,132.9,129.8,128.6,126.1,122.5,120.7,120.1,118.5,111.3,110.5,108.2,107.4,106.3,101.2,67.5,56.6,56.3,50.6,46.4,41.5,28.9,23.7.ESI-MS m/z 739[M+H]+,HR-EI-MS:m/z 739.1933[M+H]+,(calcd for C35H31N8O9S+,739.1929).
4-((5-(4-(((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)甲基)-1H-1,2,3-三氮唑-1-基)戊基)氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(20).52％yield viaDBU condition.Colorless crystal,mp.112-113℃.1H NMR(400MHz,Chloroform-d)δ8.17(s,1H),7.98(d,J＝7.7Hz,2H),7.72(t,J＝7.5Hz,1H),7.68-7.54(m,4H),7.25(s,1H),7.22-7.09(m,2H),6.84(dd,J＝7.9,1.7Hz,1H),6.77-6.61(m,2H),6.16(s,1H),5.85(d,J＝7.8Hz,2H),5.00(d,J＝14.9Hz,1H),4.50-4.33(m,5H),4.27(dd,J＝11.6,4.7Hz,1H),4.15(q,J＝17.8Hz,2H),3.72(dd,J＝16.0,4.6Hz,1H),3.19(dd,J＝15.9,11.4Hz,1H),2.09-1.95(m,2H),1.95-1.83(m,2H),1.56-1.46(m,2H).13C NMR(101MHz,CDCl3)δ166.9,166.6,158.9,147.8,147.1,142.4,137.9,136.5,136.4,135.7,135.4,133.0,132.9,129.7,128.4,126.1,126.1,123.0,122.4,120.7,120.0,118.5,111.3,111.2,110.5,108.2,107.4,106.2,106.2,101.2,71.0,56.5,56.3,50.5,50.1,41.4,29.7,27.8,23.7,22.9.ESI-MS m/z 767[M+H]+,HR-EI-MS:m/z 767.2248[M+H]+,(calcd for C37H35N8O9S+,767.2242).
(6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-((1-(6-羟己基氧基)-1H-1,2,3-三氮唑-4-基)甲基)-2,3,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-1,4-二酮(22).100％yield.Pale yellow crystal,mp.113-115℃.1H NMR(400MHz,Chloroform-d)δ8.73(s,1H),7.66-7.48(m,2H),7.27-7.20(m,1H),7.14-7.03(m,2H),6.76(d,J＝8.2Hz,1H),6.68(s,1H),6.60(d,J＝8.1Hz,1H),6.11(s,1H),5.78(d,J＝7.5Hz,2H),4.90(d,J＝14.9Hz,1H),4.43(d,J＝15.0Hz,1H),4.27(t,J＝7.2Hz,2H),4.23-3.99(m,3H),3.68(dd,J＝15.9,4.6Hz,1H),3.59(d,J＝7.0Hz,2H),3.17(dd,J＝16.0,11.4Hz,1H),2.21(s,1H),1.92-
1.77(m,2H),1.60-1.45(m,2H),1.42-1.23(m,4H).13C NMR(101MHz,CDCl3)δ167.0,166.7,147.7,147.0,142.2,136.5,135.4,133.1,126.1,123.0,122.3,120.5,119.9,118.4,111.4,108.2,107.4,106.0,101.1,62.3,56.4,56.2,50.4,50.3,41.3,32.2,30.0,26.1,25.0,23.6.ESI-MS m/z 557[M+H]+,HR-EI-MS:m/z
557.2507[M+H]+,(calcd for C30H33N6O5 +,557.2507).
(5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-(丙-2-炔-1-基)-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-1,3(2H)-二酮(24).82％yield.Colorless crystal,mp.112-113℃.1H NMR(400MHz,Acetone-d6)δ10.22(s,1H),7.90(s,1H),7.60(d,J＝7.5Hz,1H),7.33(d,J＝7.9Hz,1H),7.17-6.98(m,2H),6.93-6.77(m,2H),6.68(d,J＝8.4Hz,1H),6.27(s,1H),5.89(d,J＝6.2Hz,2H),4.87(d,J＝15.0Hz,1H),4.64(d,J＝15.0Hz,1H),4.43(dd,J＝11.6,4.8Hz,1H),4.36(t,J＝7.2Hz,2H),4.22(d,J＝17.1Hz,1H),4.08(d,J＝17.1Hz,1H),3.67(dd,J＝15.9,4.8Hz,1H),3.59-3.43(m,3H),3.17(dd,J＝16.1,11.4Hz,1H),1.94-1.77(m,2H),1.59-1.42(m,2H),1.40-1.23(m,8H).13C NMR(101MHz,Acetone)δ167.0,166.6,147.6,146.7,142.4,137.0,136.9,134.1,126.3,123.0,121.6,120.1,119.2,118.1,111.3,107.7,107.3,105.6,101.1,61.6,56.0,55.9,50.0,49.8,40.5,32.8,30.1,29.1,26.2,25.7,23.3.ESI-MS m/z 585[M+H]+,HR-EI-MS:m/z 585.2819[M+H]+,(calcd for C32H37N6O5 +,585.2820).
(6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-((1-(2-(4-(2-羟乙基)哌嗪-1-基)-2-氧代乙基-1H-1,2,3-三氮唑-4-基)甲基)-2,3,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-1,4-二酮(26).86％yield.Colorless crystal,mp.174-176℃.1H NMR(400MHz,Methanol-d4)δ7.91(s,1H),7.52(d,J＝7.7Hz,1H),7.27(d,J＝8.1Hz,1H),7.05(dt,J＝23.7,7.2Hz,2H),6.90-6.76(m,2H),6.67(d,J＝7.9Hz,1H),6.16(s,1H),5.84(d,J＝3.5Hz,2H),5.50-5.33(m,2H),5.02-4.94(m,1H),4.59(d,J＝15.0Hz,1H),4.33(dd,J＝11.5,4.8Hz,1H),4.26-3.98(m,2H),3.75-3.55(m,7H),3.13(dd,J＝15.9,11.5Hz,1H),2.69-2.46(m,6H).13C NMR(101MHz,MeOD)δ167.5,167.3,164.6,147.6,146.7,142.1,136.9,136.2,133.3,126.0,125.5,121.4,119.8,118.9,117.6,110.9,107.5,106.9,104.8,100.9,59.6,58.4,56.4,56.2,52.9,52.5,50.6,49.7,44.4,41.7,40.4,23.1.ESI-MS m/z 627[M+H]+,HR-EI-MS:m/z 627.2671[M+H]+,(calcd for C32H35N8O6 +,627.2674).
2-(2-羟乙氧基)ethyl 2-(4-(((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)甲基)-1H-1,2,3-三氮唑-1-基)乙酸酯(28).97％yield.Colorless crystal,mp.120-122℃.1H NMR(400MHz,Chloroform-d)δ8.78(s,1H),7.70(s,1H),7.50(d,J＝7.6Hz,1H),7.21(d,J＝7.8Hz,1H),7.16-6.98(m,2H),6.74(d,J＝8.2Hz,1H),6.68(s,1H),6.58(d,J＝8.1Hz,1H),6.08(s,1H),5.75(d,J＝7.2Hz,2H),5.07(s,2H),4.92(s,1H),4.43-4.19(m,3H),4.19-3.98(m,3H),3.75-3.46(m,7H),3.13(dd,J＝16.0,11.3Hz,1H),2.93(t,J＝5.8Hz,1H).13C NMR(101MHz,CDCl3)δ167.0,166.8,166.3,147.7,146.9,142.6,136.5,135.5,133.2,126.1,124.8,122.3,120.4,119.9,118.4,111.4,108.2,107.3,105.9,101.1,72.5,68.5,65.1,61.5,56.3,56.2,50.8,50.4,41.2,23.6.ESI-MS m/z 603[M+H]+,HR-EI-MS:m/z 603.2193[M+H]+,(calcd for C30H31N6O8 +,603.2198).
4-(2-(2-(2-(4-(((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)甲基)-1H-1,2,3-三氮唑-1-基)乙酰氧基)乙氧基)乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(29).18％yieldvia DBU condition.Pale yellow crystal,mp.96-98℃.1H NMR(400MHz,Acetone-d6)δ10.18(s,1H),8.15-8.07(m,2H),8.02(s,1H),7.87(t,J＝7.5Hz,1H),7.74(t,J＝7.2Hz,2H),7.59(d,J＝7.3Hz,1H),7.32(d,J＝8.2Hz,1H),7.14-7.01(m,2H),6.92-6.81(m,2H),6.68(dd,J＝8.5,1.4Hz,1H),6.26(s,1H),5.90(d,J＝7.0Hz,2H),5.38(d,J＝1.2Hz,2H),4.89(d,J＝14.5Hz,1H),4.67(d,J＝14.5Hz,1H),4.64-4.56(m,2H),4.46(dd,J＝12.0,4.9Hz,1H),4.37(dt,J＝6.1,2.8Hz,2H),4.23(d,J＝17.1Hz,1H),4.08(d,J＝17.0Hz,1H),3.96-3.89(m,2H),3.88-3.80(m,2H),3.65(dd,J＝15.8,5.0Hz,1H),3.14(dd,J＝16.1,11.6Hz,1H).13C NMR(101MHz,Acetone)δ166.9,166.7,159.3,147.5,146.6,142.7,138.2,137.0,136.9,135.8,134.0,129.8,128.5,126.3,124.7,121.5,120.1,119.2,118.1,111.2,110.7,107.7,107.3,105.6,101.1,70.9,68.6,68.2,64.9,56.0,55.8,50.4,50.0,40.5,23.3.ESI-MS m/z827[M+H]+,HR-EI-MS:m/z 827.2099[M+H]+,(calcd for C38H35N8O12S+,827.2090).
2-(4-(((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)甲基)-1H-1,2,3-三氮唑-1-基)-N-(2-羟乙基)乙酰胺(32).68％yield Colorless crystal,mp.169-171℃.1HNMR(400MHz,Methanol-d4)δ7.95(s,1H),7.50(d,J＝7.7Hz,1H),7.26(d,J＝8.1Hz,1H),7.12-6.95(m,2H),6.84-6.74(m,2H),6.64(d,J＝8.1Hz,1H),6.13(s,1H),5.85-5.73(m,2H),5.20-5.08(m,2H),4.93-4.90(m,1H),4.56(d,J＝15.2Hz,1H),4.26(dd,J＝11.7,4.8Hz,1H),4.18-3.97(m,2H),3.72-3.58(m,3H),3.40-3.34(m,2H),3.12(dd,J＝15.8,11.6Hz,1H).13C NMR(101MHz,MeOD)δ167.5,167.3,166.6,147.6,146.7,142.2,136.8,136.2,133.3,125.9,125.3,121.4,119.8,118.9,117.6,110.9,107.5,106.8,104.8,100.9,59.9,56.5,56.1,51.7,49.7,41.8,40.4,23.1.ESI-MS m/z 558[M+H]+,HR-EI-MS:m/z 558.2096[M+H]+,(calcd for C28H28N7O6 +,558.2096).
4-(2-(2-(4-(((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)甲基)-1H-1,2,3-三氮唑-1-基)乙酰氨基)乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(33).33％yield via NaOH condition.Pale yellow crystal,mp.158-160℃.1H NMR(400MHz,Chloroform-d)δ8.00(d,J＝8.7Hz,2H),7.81(s,1H),7.72(t,J＝7.8Hz,1H),7.65-7.49(m,3H),7.35-7.19(m,3H),7.13(p,J＝7.0Hz,2H),6.78(t,J＝7.5Hz,1H),6.71-6.60(m,2H),6.12(s,1H),5.80(d,J＝8.7Hz,2H),5.16-4.92(m,3H),4.54-4.38(m,3H),4.26-4.04(m,3H),3.83-3.60(m,3H),3.16(dd,J＝15.8,11.6Hz,1H).13C NMR(101MHz,CDCl3)δ167.0,166.7,165.6,158.6,147.7,147.0,142.8,137.4,136.3,135.8,135.4,132.9,129.8,128.5,126.1,124.8,122.4,120.5,120.0,118.5,111.2,110.5,108.2,107.3,106.2,101.1,69.6,56.5,56.2,52.7,50.5,41.2,38.2,23.5.ESI-MS m/z 782[M+H]+,HR-EI-MS:m/z 782.1993[M+H]+,(calcd for C36H32N9O10S+,782.1987)
(6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-((1-((Z)-4-羟基丁-2-烯-1-基)-1H-1,2,3-三氮唑-4-基)甲基)-2,3,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-1,4-二酮(34).66％yield.Colorless crystal,mp.143-145℃.1H NMR(400MHz,Chloroform-d)δ8.27(s,1H),7.65-7.51(m,2H),7.24(s,1H),7.19-
7.08(m,2H),6.80(d,J＝8.1Hz,1H),6.69(d,J＝1.6Hz,1H),6.64(d,J＝7.9Hz,1H),6.11(s,1H),5.90(d,J＝3.9Hz,2H),5.82(d,J＝8.5Hz,2H),5.04-4.82(m,3H),4.44(d,J＝14.9Hz,1H),4.26-4.03(m,5H),3.71(dd,J＝16.0,4.8Hz,1H),3.19(dd,J＝16.0,11.4Hz,1H).13C NMR(101MHz,CDCl3)δ167.0,166.6,147.8,147.1,142.5,136.5,135.7,135.3,132.9,126.1,123.2,122.9,122.5,120.7,120.1,118.5,111.3,108.2,107.4,106.2,101.2,62.1,56.5,56.2,51.8,50.4,41.3,23.7.ESI-MS m/z 527[M+H]+,HR-EI-MS:m/z
527.2036[M+H]+,(calcd for C28H27N6O5 +527.2037).
(6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-((1-((E)-4-羟基丁-2-烯-1-基)-1H-1,2,3-三氮唑-4-基)甲基)-2,3,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-1,4-二酮(36).19％yield.Colorless crystal,mp.143-145℃.1H NMR(400MHz,Methanol-d4)δ8.02(s,1H),7.53(d,J＝7.7Hz,1H),7.28(d,J＝7.9Hz,1H),7.15-6.97(m,2H),6.82(d,J＝9.7Hz,2H),6.68(d,J＝7.8Hz,1H),6.26-6.07(m,2H),5.85(d,J＝4.3Hz,2H),5.50(d,J＝1.2Hz,2H),5.35(dd,J＝10.1,3.1Hz,1H),5.30-5.15(m,2H),4.94(d,J＝3.3Hz,1H),4.64(dd,J＝15.0,3.5Hz,1H),4.39(dd,J＝11.8,4.8Hz,1H),4.21(d,J＝17.2Hz,1H),4.11-3.93(m,3H),3.67(dd,J＝15.8,4.8Hz,1H),3.16(dd,J＝15.8,11.6Hz,1H).13C NMR(101MHz,MeOD)δ167.6,167.4,147.7,146.8,142.0,136.9,136.1,133.3,132.9,126.0,121.3,119.8,118.9,118.7,117.5,110.8,107.5,106.9,104.7,100.9,65.7,63.3,56.4,56.2,53.4,49.7,40.4,23.1.ESI-MS m/z 527[M+H]+,HR-EI-MS:m/z
527.2039[M+H]+,(calcd for C28H27N6O5 +527.2037).
4-(((E)-4-(4-(((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)甲基)-1H-1,2,3-三氮唑-1-基)丁-2-烯-1-基)氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(37).53％yield via NaOH condition.Yellow crystal,mp.114-116℃.1H NMR(400MHz,Chloroform-d)δ7.94-7.78(m,4H),7.70-7.63(m,1H),7.60-7.42(m,3H),7.17(s,1H),7.14-7.01(m,2H),6.76(d,J＝7.9Hz,1H),6.69-6.56(m,2H),6.24-5.92(m,2H),5.78(d,J＝8.7Hz,2H),5.62-5.29(m,3H),5.09(dd,J＝15.2,6.5Hz,1H),4.87-4.69(m,2H),4.33(dd,J＝15.2,8.3Hz,1H),4.23(dd,J＝11.5,4.8Hz,1H),4.14(dd,J＝17.8,4.5Hz,1H),4.04(d,J＝17.4Hz,1H),3.64(dt,J＝16.0,4.2Hz,1H),3.14(dd,J＝16.0,11.3Hz,1H).13CNMR(101MHz,CDCl3)δ166.9,166.7,158.1,147.8,147.1,142.6,137.5,136.5,135.8,135.4,132.9,132.9,130.3,130.3,129.8,128.5,128.5,126.2,123.4,123.0,122.5,122.2,122.2,120.7,120.0,118.5,111.2,110.2,108.2,107.4,106.4,101.1,70.9,70.8,61.8,61.6,56.7,56.3,50.6,41.5,23.7.ESI-MS m/z751[M+H]+,HR-EI-MS:m/z 751.1933[M+H]+,(calcd for C36H31N8O9S+,751.1929)
(6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-((1-(4-(2-羟乙基)苯乙基)-1H-1,2,3-三氮唑-4-基)甲基)-2,3,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-1,4-二酮(38).99％yield.Colorless crystal,mp.135-137℃.1H NMR(400MHz,Chloroform-d)δ8.83(s,1H),7.53(d,J＝7.8Hz,1H),7.27-7.18(m,2H),7.16-7.04(m,4H),6.95(d,J＝7.7Hz,2H),6.74(d,J＝8.1Hz,1H),6.68(s,1H),6.57(d,J＝8.1Hz,1H),6.10(s,1H),5.73(d,J＝6.2Hz,2H),4.83(d,J＝15.0Hz,1H),4.47(t,J＝7.2Hz,2H),4.33(d,J＝15.0Hz,1H),4.10(dd,J＝11.5,4.8Hz,1H),3.97(d,J＝3.5Hz,2H),3.78(q,J＝6.1Hz,2H),3.67(dd,J＝16.0,4.8Hz,1H),3.23-3.03(m,3H),2.76(t,J＝6.5Hz,2H),2.43(t,J＝5.7Hz,1H).13C NMR(101MHz,CDCl3)δ166.9,166.6,147.7,147.0,141.9,137.8,136.5,135.5,134.8,133.1,129.5,128.8,126.1,123.4,122.3,120.5,119.9,118.4,111.4,108.2,107.4,106.0,101.2,63.3,56.4,56.2,51.7,50.3,41.2,38.7,36.1,23.6.ESI-MSm/z605[M+H]+,HR-EI-MS:m/z 605.2512[M+H]+,(calcd for C34H33N6O5 +,605.2507).
(6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-(2-(2-(2-(2-羟乙氧基)乙氧基)乙氧基)乙基)-2,3,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-1,4-二酮(40).76％yield.Yellow crystal,mp.68-70℃.1H NMR(400MHz,Chloroform-d)δ8.33(s,1H),7.61(d,J＝7.7Hz,1H),7.30(d,J＝6.8Hz,1H),7.24-7.10(m,2H),6.85(d,J＝7.9Hz,1H),6.76(s,1H),6.68(d,J＝7.9Hz,1H),6.23(s,1H),5.87(d,J＝8.4Hz,2H),4.40-4.27(m,2H),4.13(d,J＝17.6Hz,1H),3.95(dt,J＝14.2,4.6Hz,1H),3.89-3.45(m,16H),3.45-3.37(m,1H),3.23(dd,J＝16.0,11.5Hz,1H).13C NMR(101MHz,CDCl3)δ167.9,166.7,147.8,147.0,136.5,135.4,133.0,126.2,122.4,120.6,120.0,118.6,111.3,108.2,107.5,106.4,101.1,72.5,70.6,70.5,70.4,70.3,69.3,61.6,56.3,56.2,52.3,46.7,23.4.ESI-MS m/z 552[M+H]+,HR-EI-MS:m/z 552.2344[M+H]+,(calcd for C29H34N3O8 +,552.2340).
4-(2-(2-(2-(2-((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)乙氧基)乙氧基)乙氧基)乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(41).54％yield via NaOHcondition.Yellow crystal,mp.84-86℃.1H NMR(400MHz,Acetone-d6)δ10.18(s,1H),8.07(d,J＝8.3Hz,2H),7.89-7.79(m,1H),7.69(t,J＝7.8Hz,2H),7.58(d,J＝7.6Hz,1H),7.32(d,J＝7.9Hz,1H),7.13-7.01(m,2H),6.85(d,J＝7.8Hz,2H),6.67(d,J＝7.7Hz,1H),6.29(s,1H),5.87(d,J＝6.1Hz,2H),4.64-4.48(m,2H),4.40(dd,J＝11.6,4.8Hz,1H),4.32(d,J＝17.2Hz,1H),4.07(d,J＝17.1Hz,1H),3.90-3.80(m,2H),3.79-3.72(m,1H),3.70-3.48(m,12H),3.14(dd,J＝16.0,11.6Hz,1H).13C NMR(101MHz,Acetone)δ167.5,166.8,159.3,147.6,146.7,138.3,137.0,136.8,135.8,134.0,129.8,128.5,126.4,121.6,120.1,119.2,118.2,111.3,111.3,110.6,107.8,107.4,105.6,101.1,70.9,70.5,70.5,70.3,70.2,68.8,68.2,55.8,55.6,51.6,45.8,23.1.ESI-MS m/z 776[M+H]+,HR-EI-MS:m/z798.2046[M+Na]+,(calcd for C37H37N5O12SNa+,798.2052).
4-(2-(2-(2-((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)乙氧基)乙氧基)乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(43).72％yield via NaOHcondition.Yellow crystal,mp.103-105℃.1H NMR(400MHz,Acetone-d6)δ10.19(s,1H),8.05(d,J＝8.3Hz,2H),7.87-7.78(m,1H),7.77-7.63(m,2H),7.57(d,J＝7.5Hz,1H),7.32(d,J＝7.7Hz,1H),7.15-7.00(m,2H),6.84(d,J＝7.7Hz,2H),6.67(d,J＝7.5Hz,1H),5.87(d,J＝7.2Hz,2H),4.61-4.47(m,2H),4.40(dd,J＝11.6,4.8Hz,1H),4.32(d,J＝17.5Hz,1H),4.06(d,J＝17.1Hz,1H),3.83(t,J＝4.5Hz,2H),3.78-3.52(m,9H),3.13(dd,J＝16.0,11.6Hz,1H).13C NMR(101MHz,Acetone)δ167.5,166.9,159.3,147.6,146.7,138.2,137.0,136.8,135.8,134.1,129.8,128.5,126.4,121.6,120.1,119.2,118.1,111.3,110.7,107.8,107.4,105.6,101.1,70.9,70.5,70.3,68.8,68.3,55.8,55.6,51.6,45.7,23.0.ESI-MS m/z754[M+H]+,HR-EI-MS:m/z 754.1792[M+Na]+,(calcd for C35H33N5O11SNa+,754.1789).
(6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-(2-(2-羟乙氧基)乙基)-2,3,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-1,4-二酮(44).99％yield.Pale yellow crystal,mp.121-123℃.1H NMR(400MHz,Chloroform-d)δ9.13(s,1H),7.55(d,J＝7.5Hz,1H),7.28(d,J＝7.5Hz,1H),7.23-7.05(m,2H),6.72(d,J＝10.4Hz,2H),6.59(d,J＝7.9Hz,1H),6.17(s,1H),5.75(s,2H),4.24-4.10(m,2H),4.04(d,J＝17.1Hz,1H),3.82-3.59(m,6H),3.59-3.43(m,3H),3.32(s,1H),3.17(dd,J＝16.0,11.4Hz,1H).13C NMR(101MHz,CDCl3)δ168.0,167.2,147.7,146.9,136.4,135.3,133.2,126.1,122.2,120.1,119.8,118.5,111.4,108.2,107.3,105.9,101.2,72.6,69.0,61.6,56.1,55.7,52.1,46.4,22.9.ESI-MS m/z 486[M+H]+,HR-EI-MS:m/z 464.1812[M+H]+,(calcdfor C25H26N3O6 +,464.1816).
4-(2-(2-((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并
[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)乙氧基)乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(45).61％yield via NaOH condition.Pale yellow crystal,mp.135-137℃.1H NMR(400MHz,Acetone-d6)δ10.17(s,1H),8.05(d,J＝7.8Hz,2H),7.89-7.76(m,1H),7.69(t,J＝7.2Hz,2H),7.58(d,J＝7.5Hz,1H),7.31(d,J＝7.7Hz,1H),7.18-7.00(m,2H),6.84(d,J＝7.6Hz,2H),6.67(d,J＝7.5Hz,1H),6.28(s,1H),5.87(d,J＝5.5Hz,2H),4.62-4.51(m,2H),4.44(dd,J＝11.6,5.0Hz,1H),4.37(d,J＝17.1Hz,1H),4.05(d,J＝17.1Hz,1H),3.95-3.73(m,5H),3.62(dd,J＝16.0,5.3Hz,1H),3.57-3.46(m,1H),3.14(dd,J＝16.1,11.6Hz,1H).13C NMR(101MHz,Acetone)δ167.4,167.0,159.3,147.6,146.7,138.1,137.0,136.8,135.8,134.0,129.8,128.6,126.4,121.5,120.1,119.2,118.1,111.2,110.7,107.8,107.3,105.6,101.1,70.8,68.8,68.1,55.8,55.6,51.6,45.8,23.0.ESI-MS m/z 688[M+H]+,HR-EI-MS:m/z 688.1712[M+H]+,(calcd for C33H30N5O10S+,688.1708).
4-(2-((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(47).45％yield via NaOH condition..Yellow crystal,mp.182-184℃.1H NMR(400MHz,DMSO-d6)δ11.08(s,1H),8.03(d,J＝7.8Hz,2H),7.85(t,J＝7.5Hz,1H),7.68(t,J＝7.9Hz,2H),7.54(d,J＝7.7Hz,1H),7.31(d,J＝7.9Hz,1H),7.13-6.95(m,2H),6.90-6.67(m,3H),6.20(s,1H),5.88(d,J＝12.7Hz,2H),4.64(t,J＝5.0Hz,2H),4.47(dd,J＝11.7,5.0Hz,1H),4.39(d,J＝17.0Hz,1H),4.17(d,J＝17.1Hz,1H),4.10-3.94(m,1H),3.90-3.70(m,1H),3.50(dd,J＝16.3,4.9Hz,1H),2.98(dd,J＝15.5,11.5Hz,1H).13CNMR(101MHz,DMSO)δ167.8,167.6,159.3,147.5,146.5,137.5,137.2,136.6,136.5,134.4,130.4,128.8,126.2,121.7,119.7,119.4,118.5,111.8,111.2,108.4,107.2,105.0,101.3,69.4,55.9,55.5,51.3,44.6,23.2.ESI-MS m/z 644[M+H]+,HR-EI-MS:m/z644.1446[M+H]+,(calcd for C31H26N5O9S+,644.1446).
(Z)-5-(((2-((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)乙氧基)羰基)亚胺基)-3-苯基-5-氢-1,2,3-噁二唑-3-鎓-2-亚基(48).56％yield.Yellow crystal,mp.179-181℃.1H NMR(400MHz,Chloroform-d)δ9.11(s,1H),8.08(s,1H),7.77-7.58(m,5H),7.46(d,J＝7.8Hz,1H),7.30(d,J＝8.1Hz,1H),7.10(dt,J＝29.2,7.3Hz,2H),6.81(d,J＝8.2Hz,1H),6.74(s,1H),6.59(d,J＝8.1Hz,1H),6.21(s,1H),5.75(d,J＝7.2Hz,2H),4.50-4.28(m,2H),4.28-4.09(m,2H),4.04-3.84(m,2H),3.49(dd,J＝16.0,4.8Hz,1H),3.40-3.20(m,1H),3.09(dd,J＝
16.0,11.4Hz,1H).13C NMR(101MHz,CDCl3)δ175.2,167.3,167.0,161.0,147.6,146.9,136.5,135.5,133.7,133.2,133.1,130.5,126.1,122.2,121.6,120.6,119.8,118.5,111.5,108.1,107.5,106.2,103.2,101.0,63.0,56.1,55.9,52.0,46.5,23.0.ESI-MS m/z 607[M+H]+,HR-EI-MS:m/z 6017.1941[M+H]+,(calcd for C32H27N6O7 +607.1936).
(6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-(5-羟戊基)-2,3,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-1,4-二酮(49).72％yield.Pale yellowcrystal,mp.131-133℃.1H NMR(400MHz,Acetone-d6)δ10.23(s,1H),7.60(d,J＝7.5Hz,1H),7.34(d,J＝7.9Hz,1H),7.08(dt,J＝16.6,7.3Hz,2H),6.96-6.80(m,2H),6.70(d,J＝8.1Hz,1H),6.30(s,1H),5.90(d,J＝5.4Hz,2H),4.42(dd,J＝11.6,5.0Hz,1H),4.23(d,J＝17.1Hz,1H),3.94(d,J＝17.1Hz,1H),3.73-3.51(m,5H),3.48-3.33(m,1H),3.16(dd,J＝16.1,11.5Hz,1H),1.70-1.50(m,4H),1.50-1.33(m,2H).13C NMR(101MHz,Acetone)δ167.3,166.7,147.6,146.7,137.0,136.8,134.0,126.4,121.6,120.0,119.2,118.2,111.3,107.8,107.3,105.6,101.1,61.4,55.9,55.7,50.0,45.6,32.5,26.7,23.1,22.9.ESI-MSm/z 462[M+H]+,HR-EI-MS:m/z 462.2025[M+H]+,(calcd for C26H28N3O5 +,462.2023).
(6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-(6-羟己基氧基)-2,3,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-1,4-二酮(51).68％yield.Graycrystal,mp.123-124℃.1H NMR(400MHz,Chloroform-d)δ8.15(s,1H),7.59(d,J＝7.1Hz,1H),7.33-7.26(m,1H),7.23-7.10(m,2H),6.82(dd,J＝8.1,1.8Hz,1H),6.76-6.61(m,2H),6.16(s,1H),5.84(d,J＝7.5Hz,2H),4.27(dd,J＝11.6,4.8Hz,1H),4.07(d,J＝17.4Hz,1H),3.90(d,J＝17.5Hz,1H),3.73(dd,J＝16.1,4.7Hz,1H),3.68-3.52(m,3H),3.45-3.31(m,1H),3.21(dd,J＝16.1,11.4Hz,1H),1.66-1.61(m,1H),1.62-1.50(m,4H),1.46-1.36(m,2H),1.36-1.28(m,2H).13C NMR(101MHz,CDCl3)δ167.3,166.4,147.9,147.1,136.5,135.3,132.8,126.2,122.5,120.6,120.1,118.6,111.2,108.2,107.4,106.4,101.2,62.5,56.4,56.2,50.3,46.1,32.4,26.8,26.2,25.2,23.5.ESI-MS m/z 476[M+H]+,HR-EI-MS:m/z 476.2176[M+H]+,(calcd for C27H30N3O5 +,476.2180).
4-((6-((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)己基)氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(52).31％yield via DBU condition.Pale yellow crystal,mp.99-101℃.1H NMR(400MHz,Chloroform-d)δ8.04(d,J＝8.8Hz,3H),7.74(t,J＝7.5Hz,1H),7.60(t,J＝7.8Hz,3H),7.28(s,1H),7.22-7.10(m,2H),6.84(dd,J＝8.0,1.8Hz,1H),6.72(d,J＝1.7Hz,1H),6.67(d,J＝8.1Hz,1H),6.18(s,1H),5.84(d,J＝8.1Hz,2H),4.40(t,J＝6.4Hz,2H),4.31(dd,J＝11.6,4.8Hz,1H),4.11(d,J＝16.8Hz,1H),3.93(d,J＝17.5Hz,1H),3.74(dd,J＝16.0,4.8Hz,1H),3.59(dd,J＝14.1,7.0Hz,1H),3.43-3.33(m,1H),3.21(dd,J＝16.0,11.3Hz,1H),1.93-1.80(m,2H),1.66-1.56(m,2H),1.57-1.44(m,2H),1.46-1.35(m,2H).13C NMR(101MHz,CDCl3)δ167.2,166.4,159.0,147.9,147.1,138.1,136.5,135.6,135.3,132.8,129.6,128.5,126.2,122.5,120.7,120.1,118.6,111.2,110.5,108.2,107.4,106.5,101.2,71.4,56.5,56.2,50.3,46.1,28.3,26.8,26.2,25.3,23.5.ESI-MS m/z700[M+H]+,HR-EI-MS:m/z 700.2078[M+H]+,(calcd for C35H34N5O9S+,700.2072).
(6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-(8-羟辛基)-2,3,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-1,4-二酮(54).70％yield.Colorlesscrystal,mp.102-104℃.1H NMR(400MHz,Acetone-d6)δ10.23(s,1H),7.61(d,J＝7.6Hz,1H),7.34(d,J＝7.8Hz,1H),7.20-7.00(m,2H),6.86(d,J＝10.1Hz,2H),6.70(d,J＝7.8Hz,1H),6.30(s,1H),5.90(d,J＝6.5Hz,2H),4.43(dd,J＝11.6,4.9Hz,1H),4.23(d,J＝17.0Hz,1H),3.94(d,J＝17.0Hz,1H),3.79-3.36(m,6H),3.16(dd,J＝16.1,11.4Hz,1H),1.69-1.47(m,4H),1.47-1.26(m,8H).13C NMR(101MHz,Acetone)δ167.3,166.7,147.6,146.7,137.0,136.8,134.0,126.4,121.6,120.0,119.2,118.2,111.2,107.8,107.3,105.6,101.1,61.6,55.9,55.7,50.0,45.5,32.9,29.3,26.8,26.5,25.7,23.1.ESI-MS m/z504[M+H]+,HR-EI-MS:m/z 504.2492[M+H]+,(calcd for C29H34N5O9S+,504.2493).
(5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-((1-(2-(2-羟乙氧基)乙基)-1H-1,2,3-三氮唑-4-基)甲基)-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-1,3(2H)-二酮(62).83％yield.Pale yellow crystal,mp.121-123℃.1H NMR(400MHz,Acetone-d6)δ10.10(s,1H),7.95(s,1H),7.55(d,J＝7.7Hz,1H),7.32(d,J＝7.9Hz,1H),7.10(dt,J＝21.4,7.2Hz,2H),6.99-6.83(m,2H),6.79(d,J＝7.3Hz,1H),6.26(s,1H),5.96(d,J＝4.6Hz,2H),4.87-4.66(m,2H),4.61-4.44(m,3H),3.92-3.78(m,2H),3.77-3.67(m,1H),3.65-3.55(m,2H),3.50(dd,J＝5.9,4.5Hz,2H),3.38(dd,J＝15.1,5.7Hz,1H),2.73(ddd,J＝15.2,10.9,1.7Hz,1H).13C NMR(101MHz,Acetone)δ172.1,154.2,148.0,147.6,142.4,137.2,134.1,131.2,126.3,123.8,122.0,121.8,119.2,118.2,111.3,108.4,108.1,107.0,101.3,72.5,69.1,61.0,53.2,51.8,49.8,33.6,22.8.ESI-MSm/z 531[M+H]+,HR-EI-MS:m/z 531.1983[M+H]+,(calcd for C27H27N6O6 +,531.1987).
(5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-((1-(6-羟己基氧基)-1H-1,2,3-三氮唑-4-基)甲基)-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-1,3(2H)-二酮(68).86％yield.Colorless crystal,mp.123-125℃.1H NMR(400MHz,Acetone-d6)δ10.09(s,1H),7.88(s,1H),7.57(d,J＝7.7Hz,1H),7.35(d,J＝8.1Hz,1H),7.11(dt,J＝23.2,7.4Hz,2H),6.95-6.74(m,3H),6.26(s,1H),5.97(d,J＝4.3Hz,2H),4.85-4.69(m,2H),4.56(dd,J＝11.1,5.6Hz,1H),4.34(t,J＝6.7Hz,2H),3.59-3.47(m,2H),3.47-3.32(m,2H),2.87-2.72(m,1H),1.93-1.79(m,2H),1.54-1.44(m,2H),1.43-1.27(m,4H).13C NMR(101MHz,Acetone)δ172.1,154.2,148.0,147.6,142.6,137.2,134.1,131.3,126.3,122.7,122.0,121.8,119.2,118.2,111.3,108.4,108.0,107.1,101.3,61.4,53.2,51.8,49.7,33.7,32.6,30.1,29.7,26.1,25.1,22.9.ESI-MS m/z 543[M+H]+,HR-EI-MS:m/z 543.2352[M+H]+,(calcd for C39H31N6O5 +,543.2350).
(5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-(2-(2-(2-(2-羟乙氧基)乙氧基)乙氧基)乙基)-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-1,3(2H)-二酮(72).71％yield.Colorless crystal,mp.67-68℃.1H NMR(400MHz,Acetone-d6)δ10.01(s,1H),7.55(d,J＝7.8Hz,1H),7.34(d,J＝7.9Hz,1H),7.09(dt,J＝23.8,7.3Hz,2H),6.99-6.71(m,3H),6.23(s,1H),5.94(d,J＝3.7Hz,2H),4.47(dd,J＝10.9,5.6Hz,1H),3.69-3.35(m,17H),2.77(dd,J＝15.3,10.8Hz,1H).13C NMR(101MHz,Acetone)δ
172.6,154.6,148.0,147.7,137.2,134.2,131.3,126.3,122.1,121.8,119.2,118.2,111.3,108.4,108.1,107.1,101.4,72.6,70.3,70.2,70.2,69.9,67.0,61.1,53.1,51.7,37.8,22.9.ESI-MS m/z 538[M+H]+,HR-EI-MS:m/z 560.1990[M+Na]+,(calcd forC28H31N3O8Na+,560.2003).
4-(2-(2-(2-(2-((5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,3-二氧代-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-2(3H)-基)乙氧基)乙氧基)乙氧基)乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(73).60％yield via DBUcondition.Pale yellow crystal,mp.77-78℃.1H NMR(400MHz,Acetone-d6)δ10.02(s,1H),8.07(d,J＝8.1Hz,2H),7.85(t,J＝7.5Hz,1H),7.72(t,J＝7.6Hz,2H),7.57(d,J＝7.7Hz,1H),7.35(d,J＝7.9Hz,1H),7.10(dt,J＝24.6,7.3Hz,2H),6.86(d,J＝8.4Hz,2H),6.80(d,J＝7.8Hz,1H),6.23(s,1H),5.97(d,J＝3.4Hz,2H),4.61-4.44(m,3H),3.81(t,J＝4.7Hz,2H),3.70-3.63(m,4H),3.61-3.50(m,8H),3.42(dd,J＝15.1,5.6Hz,1H),2.89-2.84(m,1H).13C NMR(101MHz,Acetone)δ172.5,159.3,154.5,148.0,147.7,138.3,137.2,135.8,134.2,131.3,129.8,128.5,126.4,122.1,121.8,119.2,118.2,111.3,108.4,108.1,107.2,101.3,70.9,70.5,70.5,70.3,70.0,68.2,66.9,53.0,51.7,37.8,23.0.ESI-MS m/z762[M+H]+,HR-EI-MS:m/z 779.2363[M+NH4]+,(calcd for C36H39N6O12S+,779.2341).
(5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-(2-(2-(2-羟乙氧基)乙氧基)乙基)-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-1,3(2H)-二酮(74).80％yield.Colorless crystal,mp.82-84℃.1H NMR(400MHz,Acetone-d6)δ10.01(s,1H),7.55(d,J＝7.7Hz,1H),7.34(d,J＝8.1Hz,1H),7.09(dt,J＝23.8,7.3Hz,2H),6.81(dd,J＝28.2,10.3Hz,3H),6.23(s,1H),5.93(d,J＝3.9Hz,2H),4.47(dd,J＝10.9,5.6Hz,1H),3.79-3.28(m,15H),2.76(dd,J＝15.3,10.7Hz,1H).13C NMR(101MHz,Acetone)δ172.7,154.6,148.0,147.7,137.2,134.2,131.3,126.3,122.1,121.8,119.2,118.2,111.3,108.4,108.1,107.1,101.4,72.6,70.2,69.9,67.0,61.1,53.1,51.7,37.8,22.9.ESI-MSm/z 494[M+H]+,HR-EI-MS:m/z 494.1924[M+H]+,(calcd for C26H28N3O7 +,494.1922).
(5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-(2-羟乙基)-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-1,3(2H)-二酮(78).54％yield.Colorless crystal,mp.233-234℃.1H NMR(400MHz,Methanol-d4)δ7.53(d,J＝7.8Hz,1H),7.30(d,J＝7.9Hz,1H),7.10(dt,J＝26.0,7.3Hz,2H),6.81(dd,J＝15.7,10.0Hz,3H),6.24(s,1H),5.93(d,J＝3.8Hz,2H),4.47(dd,J＝11.1,5.6Hz,1H),3.82-3.63(m,4H),3.44(dd,J＝15.2,5.7Hz,1H),2.87(dd,J＝15.1,10.9Hz,1H).13C NMR(101MHz,MeOD)δ173.8,155.1,148.1,147.8,137.2,133.7,130.6,126.0,121.8,121.6,118.9,117.6,110.8,108.2,107.8,106.6,101.2,58.4,53.2,51.9,40.8,22.6.ESI-MS m/z 406[M+H]+,HR-EI-MS:m/z 406.1399[M+H]+,(calcd for C22H20N3O5 +,406.1397).
(5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-(5-羟戊基)-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-1,3(2H)-二酮(80).44％yield.Colorless crystal,mp.185-186℃.1H NMR(400MHz,Chloroform-d)δ7.90(s,1H),7.58(d,J＝7.6Hz,1H),7.33(d,J＝7.9Hz,1H),7.23(dt,J＝21.2,7.1Hz,2H),6.86(d,J＝8.1Hz,1H),6.82-6.75(m,2H),6.24(s,1H),5.96(s,2H),4.32(dd,J＝11.1,5.5Hz,1H),3.65(t,J＝6.4Hz,2H),3.61-3.46(m,3H),2.89(dd,J＝15.3,11.0Hz,1H),1.75-1.66(m,2H),1.66-1.60(m,2H),1.48-1.35(m,2H).13C NMR(101MHz,CDCl3)δ172.8,154.9,148.3,148.1,136.6,133.0,130.5,126.1,
123.0,121.9,120.2,118.5,111.2,108.6,108.4,108.2,101.4,62.6,53.2,51.8,38.6,32.1,27.9,23.5,22.9.ESI-MS m/z 448[M+H]+,HR-EI-MS:m/z 448.1867[M+H]+,(calcd for C25H26N3O5 +,448.1867).
4-((5-((5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,3-二氧代-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-2(3H)-基)戊基)氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(81).39％yield via DBU condition.Pale yellow crystal,mp.108-110℃.1H NMR(400MHz,Acetone-d6)δ10.04(s,1H),8.07(d,J＝
8.1Hz,2H),7.92-7.85(m,1H),7.76(t,J＝7.1Hz,2H),7.58(d,J＝7.8Hz,1H),7.36(d,J＝8.3Hz,1H),7.11(dt,J＝25.3,7.3Hz,2H),6.88(t,J＝3.9Hz,2H),6.85-6.79(m,1H),6.26(s,1H),5.99(s,2H),4.55(dd,J＝10.9,4.8Hz,1H),4.46(t,J＝6.6Hz,2H),3.62-3.51(m,2H),3.45(dd,J＝15.1,5.6Hz,1H),2.96-2.86(m,1H),1.97-1.84(m,2H),1.77-1.66(m,2H),1.57-1.45(m,2H).13C NMR(101MHz,Acetone)δ172.6,159.3,154.7,148.0,147.6,138.3,137.2,135.7,134.3,131.4,129.8,128.5,126.4,122.0,121.8,119.2,118.2,
111.3,108.4,108.0,107.2,101.3,71.3,53.1,51.7,37.9,27.8,27.5,23.1,22.7.ESI-MS m/z 672[M+H]+,HR-EI-MS:m/z 689.2034[M+NH4]+,(calcd for C33H33N6O9S+,689.2024).
(5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-(8-羟辛基)-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-1,3(2H)-二酮(84).98％yield.lorlesscrystal,mp.96-97℃.1H NMR(400MHz,Acetone-d6)δ10.04(s,1H),7.57(d,J＝7.7Hz,1H),7.35(d,J＝7.9Hz,1H),7.10(dt,J＝23.4,7.3Hz,2H),6.81(dd,J＝
25.7,8.2Hz,3H),6.22(s,1H),6.04-5.89(m,2H),4.48(dd,J＝10.9,5.6Hz,1H),3.57-3.36(m,6H),2.81(dd,J＝15.3,10.9Hz,1H),1.68-1.54(m,2H),1.54-1.41(m,2H),1.29(s,8H).13C NMR(101MHz,Acetone)δ172.6,154.7,148.0,147.6,137.2,134.2,131.4,126.4,122.0,121.8,119.2,118.2,111.3,108.4,
108.1,107.1,101.3,61.6,53.0,51.7,38.2,32.8,27.9,26.5,25.7,23.0.ESI-MSm/z 490[M+H]+,HR-EI-MS:m/z 490.2338[M+H]+,(calcd for C28H32N3O5 +,490.2336).
实施例5活性化合物对PDE抑制活性的测定。
配制含有100nM FAM-cGMP和15ng/ml PDE5的酶促反应体系，其组分浓度包括40mMMOPS，pH7.5,0.5mM EDTA，15mM MgCl2，0.15mg/ml BSA，1mM DTT，0.05％ Proclin 200，加入待测化合物后在5℃条件下反应1h。最后加入100μL稀释IMAP溶液并并在25℃条件下低速振动1h，读取样品的在360nm和480nm激发光下的荧光数值，重复实验3次并计算PDE5的酶活和化合物对PDE5的抑制率。将底物更换为FAM-cAMP并将酶促反应的蛋白更换为PDE11可用于测定化合物对PDE11亚型的抑制率和选择型。实验结果如表1所示。
表1各化合物对PDE抑制活性
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由表1表明，化合物10、11、12、15、16、17、18、20、22、24、26、28、29、32、33、34、36、37、38、40、41、43、45、47、48、49、51、52、54、62、68、72、73、74、78、80、81、84，在10nM浓度下PDE5抑制率大于80％，与对照药物他达拉非相比(79％)，具有更强效的PDE5抑制活性。其中，化合物29、41、45、81对PDE5的抑制活性更高，其IC50值均在1.0nM以下。参照文献J.Biomol.Screen.,2002,7,215-222的中PDE11抑制剂的筛选方法，对优选的化合物29、41、45、81，测定了其对PDE11的抑制作用的IC50，并计算了这些化合物对PDE5的选择性。相关结果如表2所示。
表2化合物29、41、45、81对PDE5的选择性
表2表明，优选的化合物29、41、45和81表现出对PDE5的显著选择性。与PDE11相比，化合物29、41、45和81对PDE5的选择性分别为8.3至20倍。相较于对照药物他达拉非，对PDE11亚型的选择性有所提高。
进一步研究了化合物29、41、45、81，对人支气管上皮细胞BEAS-2B细胞的毒性。MTT实验结果表明，化合物29、41、45的IC50在5～10μM之间，仅表现出微弱的细胞毒性；而化合物81的IC50大于20μM，无细胞毒性。
实施例6细胞内NO释放的测定。
参考文献In Mast Cells,Springer:2015；pp 339-345中的方法，取适量BEAS-2B细胞接种在玻璃底细胞培养皿，原位装载DAF-FMDA(5μM)探针后，加入待测化合物(化合物81，1.25-5μM)37℃条件下培养6h。使用激光共聚焦显微镜进行直接观察并计算495nm激发波长下的荧光强度，扣除空白对照后即可得到这些化合物在活细胞内NO的实时释放情况。荧光成像结果如图1～2所示。
结果表明，利用NO探针检测到化合物81在人支气管上皮细胞BEAS-2B中能够有效的释放NO分子。进一步的荧光定量分析表明，化合物81在细胞内NO的释放量与的浓度具有显著的相关性。
实施例7动物水平的PH治疗作用研究。
对PAH大鼠模型肺部的研究：Wastar大鼠随机进行分组(n＝6)，并注射60mg/kg的野百合碱建立重度PAH的大鼠模型。14天后造模成功，形成正常对照组、肺动脉高压疾病模型组及3组肺动脉高压药物实验组(包括候选化合物81的低剂量组0.5mg/kg/d、高剂量组1mg/kg/d，以及他达拉非组1mg/kg/d作为阳性对照)。为了最大程度的避免全身性的血压降低及肝脏代谢导致的药物失活，将待测的NO供体型PDE5抑制剂类化合物通过口-鼻暴露式雾化吸入装置直接给药至气管和肺部，每日雾化给药一次，每次给药时间持续15分钟。雾化吸入过程中密切关注动物反应。雾化给药治疗连续14天后结束，并按照文献J.Med.Chem.2018,61,1474-1482中报道的方法进行PAH相关的血流动力学指标的测定。采用右心导管法测定大鼠平均动脉压(mPAP)、右心室收缩压(RVSP)等指标，计算血流动力学变化。处死后采集心肺组织并测定肺指数(LI)、右心肥厚指数(RVHI)。实验结果表明，与模型组相比，化合物81能够显著改善野百合碱诱导的肺动脉高压模型大鼠的病理情况：(1)改善了异常的血流动力学指标、心肌细胞肥大及纤维化；(2)有效抑制了肺血管小动脉的重构；(3)抑制肺小血管周围肺巨噬细胞浸润。同时，其治疗效果优于阳性药Tadalafil。
以上所述仅为本发明的优选实施例而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (10)
1.一种PDE5抑制剂，其特征是，其化学结构如式I所示
其中，X为长度为2～15个原子数的连接臂，R为H、n为0或1，C-y位为S构型或R构型。
2.如权利要求1所述的PDE5抑制剂，其特征是，n为1时，C-y位为R构型；n为0时，C-y位为S构型。
3.如权利要求1所述的PDE5抑制剂，其特征是，选自以下化合物：
甲基2-((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)乙酸酯；
2-((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)乙酸；
2-((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)-N-(6-羟己基氧基)乙酰胺；
6-羟己基氧基2-((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)乙酸酯；
4-((6-(2-((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)乙酰氨基)己基)氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物；
(Z)-5-((((6-(2-((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并
[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)乙酰氨基)己基)氧基)羰基)亚胺基)-3-苯基-5-氢-1,2,3-噁二唑-3-鎓-2-亚基；
4-((6-(2-((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)乙酰氧基)己基)氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物；
(Z)-5-((((6-(2-((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并
[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)乙酰氧基)己基)氧基)羰基)亚胺基)-3-苯基-5-氢-1,2,3-噁二唑-3-鎓-2-亚基；
(6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-(丙-2-炔-1-基)-2,3,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-1,4-二酮；
(6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-((1-(2-(2-(2-(2-羟乙氧基)乙氧基)乙氧基)乙基)-1H-1,2,3-三氮唑-4-基)甲基)-2,3,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-1,4-二酮；
4-(2-(2-(4-(((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并
[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)甲基)-1H-1,2,3-三氮唑-1-基)乙氧基)乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物；
(6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-((1-(2-(2-(2-羟乙氧基)乙氧基)乙基)-1H-1,2,3-三氮唑-4-基)甲基)-2,3,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-1,4-二酮；
4-(2-(2-(2-(4-(((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并
[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)甲基)-1H-1,2,3-三氮唑-1-基)乙氧基)乙氧基)乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物；
(Z)-5-(((2-(2-(2-(4-(((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)甲基)-1H-1,2,3-三氮唑-1-基)乙氧基)乙氧基)乙氧基)羰基)亚胺基)-3-苯基-5-氢-1,2,3-噁二唑-3-鎓-2-亚基；
(6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-((1-(2-(2-羟乙氧基)乙基)-1H-1,2,3-三氮唑-4-基)甲基)-2,3,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-1,4-二酮；
4-(2-(2-(2-(2-(4-(((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)甲基)-1H-1,2,3-三氮唑-1-基)乙氧基)乙氧基)乙氧基)乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物；
(6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-((1-(3-羟丙基)-1H-1,2,3-三氮唑-4-基)甲基)-2,3,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-1,4-二酮；
4-(3-(4-(((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)甲基)-1H-1,2,3-三氮唑-1-基)丙氧基)--3-(苯磺酰基)-1,2,5-噁二唑2-氧化物；
(6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-((1-(5-羟戊基)-1H-1,2,3-三氮唑-4-基)甲基)-2,3,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-1,4-二酮；
4-((5-(4-(((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并
[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)甲基)-1H-1,2,3-三氮唑-1-基)戊基)氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物；
(Z)-5-((((5-(4-(((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)甲基)-1H-1,2,3-三氮唑-1-基)戊基)氧基)羰基)亚胺基)-3-苯基-5-氢-1,2,3-噁二唑-3-鎓-2-亚基；
(6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-((1-(6-羟己基氧基)-1H-1,2,3-三氮唑-4-基)甲基)-2,3,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-1,4-二酮；
4-((6-(4-(((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并
[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)甲基)-1H-1,2,3-三氮唑-1-基)己基)氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物；
(5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-(丙-2-炔-1-基)-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-1,3(2H)-二酮；
(6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-((1-(8-羟辛基)-1H-1,2,3-三氮唑-4-基)甲基)-2,3,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-1,4-二酮；
(6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-((1-(2-(4-(2-羟乙基)哌嗪-1-基)-2-氧代乙基-1H-1,2,3-三氮唑-4-基)甲基)-2,3,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-1,4-二酮；
4-(2-(4-(2-(4-(((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并
[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)甲基)-1H-1,2,3-三氮唑-1-基)乙酰基)哌嗪-1-基)乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物；
2-(2-羟乙氧基)ethyl 2-(4-(((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)甲基)-1H-1,2,3-三氮唑-1-基)乙酸酯；
4-(2-(2-(2-(4-(((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并
[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)甲基)-1H-1,2,3-三氮唑-1-基)乙酰氧基)乙氧基)乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物；
2-(4-(((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)甲基)-1H-1,2,3-三氮唑-1-基)-N-(6-羟己基氧基)乙酰胺；
4-((6-(2-(4-(((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并
[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)甲基)-1H-1,2,3-三氮唑-1-基)乙酰氨基)己基)氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物；
2-(4-(((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)甲基)-1H-1,2,3-三氮唑-1-基)-N-(2-羟乙基)乙酰胺；
4-(2-(2-(4-(((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)甲基)-1H-1,2,3-三氮唑-1-基)乙酰氨基)乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物；
(6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-((1-((Z)-4-羟基丁-2-烯-1-基)-1H-1,2,3-三氮唑-4-基)甲基)-2,3,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-1,4-二酮；
4-(((Z)-4-(4-(((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并
[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)甲基)-1H-1,2,3-三氮唑-1-基)丁-2-烯-1-基)氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物；
(6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-((1-((E)-4-羟基丁-2-烯-1-基)-1H-1,2,3-三氮唑-4-基)甲基)-2,3,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-1,4-二酮；
4-(((E)-4-(4-(((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并
[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)甲基)-1H-1,2,3-三氮唑-1-基)丁-2-烯-1-基)氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物；
(6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-((1-(4-(2-羟乙基)苯乙基)-1H-1,2,3-三氮唑-4-基)甲基)-2,3,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-1,4-二酮；
4-(4-(2-(4-(((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并
[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)甲基)-1H-1,2,3-三氮唑-1-基)乙基)苯乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物；
(6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-(2-(2-(2-(2-羟乙氧基)乙氧基)乙氧基)乙基)-2,3,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-1,4-二酮；
4-(2-(2-(2-(2-((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)乙氧基)乙氧基)乙氧基)乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物；
(6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-(2-(2-(2-羟乙氧基)乙氧基)乙基)-2,3,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-1,4-二酮；
4-(2-(2-(2-((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并
[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)乙氧基)乙氧基)乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物；
(6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-(2-(2-羟乙氧基)乙基)-2,3,6,7,12,12a-六氢吡嗪并
[1',2':1,6]吡啶并[3,4-b]吲哚-1,4-二酮；
4-(2-(2-((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)乙氧基)乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物；
(6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-(2-羟乙基)-2,3,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-1,4-二酮；
4-(2-((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物；
(Z)-5-(((2-((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并
[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)乙氧基)羰基)亚胺基)-3-苯基-5-氢-1,2,3-噁二唑-3-鎓-2-亚基；
(6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-(5-羟戊基)-2,3,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-1,4-二酮；
4-((5-((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)戊基)氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物；
(6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-(6-羟己基氧基)-2,3,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-1,4-二酮；
4-((6-((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)己基)氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物；
(Z)-5-((((6-((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并
[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)己基)氧基)羰基)亚胺基)-3-苯基-5-氢-1,2,3-噁二唑-3-鎓-2-亚基；
(6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-(8-羟辛基)-2,3,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-1,4-二酮；
4-((8-(4-(((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,4-二氧代-3,4,6,7,12,12a-六氢吡嗪并
[1',2':1,6]吡啶并[3,4-b]吲哚-2(1H)-基)甲基)-1H-1,2,3-三氮唑-1-基)辛基)氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物；
(5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-(丙-2-炔-1-基)-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-1,3(2H)-二酮；
(5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-((1-(2-(2-(2-(2-羟乙氧基)乙氧基)乙氧基)乙基)-1H-1,2,3-三氮唑-4-基)甲基)-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-1,3(2H)-二酮(57)；
4-(2-(2-(2-(2-(4-(((5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,3-二氧代-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-2(3H)-基)甲基)-1H-1,2,3-三氮唑-1-基)乙氧基)乙氧基)乙氧基)乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物；
(Z)-5-((13-(4-(((5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,3-二氧代-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-2(3H)-基)甲基)-1H-1,2,3-三氮唑-1-基)-2,5,8,11-四氧代十三酰)亚胺基)-3-苯基-5-氢-1,2,3-噁二唑-3-鎓-2-亚基；
(5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-((1-(2-(2-(2-羟乙氧基)乙氧基)乙基)-1H-1,2,3-三氮唑-4-基)甲基)-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-1,3(2H)-二酮；
4-(2-(2-(2-(4-(((5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,3-二氧代-5,6,11,11a-四氢-1H-咪唑并
[1',5':1,6]吡啶并[3,4-b]吲哚-2(3H)-基)甲基)-1H-1,2,3-三氮唑-1-基)乙氧基)乙氧基)乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物；
(5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-((1-(2-(2-羟乙氧基)乙基)-1H-1,2,3-三氮唑-4-基)甲基)-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-1,3(2H)-二酮；
4-(2-(2-(4-(((5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,3-二氧代-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-2(3H)-基)甲基)-1H-1,2,3-三氮唑-1-基)乙氧基)乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物；
(5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-((1-(3-羟丙基)-1H-1,2,3-三氮唑-4-基)甲
基)-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-1,3(2H)-二酮；
4-(3-(4-(((5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,3-二氧代-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-2(3H)-基)甲基)-1H-1,2,3-三氮唑-1-基)丙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物；
(5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-((1-(5-羟戊基)-1H-1,2,3-三氮唑-4-基)甲
基)-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-1,3(2H)-二酮；
4-((5-(4-(((5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,3-二氧代-5,6,11,11a-四氢-1H-咪唑并
[1',5':1,6]吡啶并[3,4-b]吲哚-2(3H)-基)甲基)-1H-1,2,3-三氮唑-1-基)戊基)氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物；
(5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-((1-(6-羟己基氧基)-1H-1,2,3-三氮唑-4-基)甲基)-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-1,3(2H)-二酮；
4-((6-(4-(((5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,3-二氧代-5,6,11,11a-四氢-1H-咪唑并
[1',5':1,6]吡啶并[3,4-b]吲哚-2(3H)-基)甲基)-1H-1,2,3-三氮唑-1-基)己基)氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物；
(5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-((1-(8-羟辛基)-1H-1,2,3-三氮唑-4-基)甲
基)-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-1,3(2H)-二酮；
4-((8-(4-(((5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,3-二氧代-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-2(3H)-基)甲基)-1H-1,2,3-三氮唑-1-基)辛基)氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物；
(5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-(2-(2-(2-(2-羟乙氧基)乙氧基)乙氧基)乙
基)-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-1,3(2H)-二酮；
4-(2-(2-(2-(2-((5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,3-二氧代-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-2(3H)-基)乙氧基)乙氧基)乙氧基)乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物；
(5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-(2-(2-(2-羟乙氧基)乙氧基)乙基)-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-1,3(2H)-二酮；
4-(2-(2-(2-((5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,3-二氧代-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-2(3H)-基)乙氧基)乙氧基)乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物；
(5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-(2-(2-羟乙氧基)乙基)-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-1,3(2H)-二酮；
4-(2-(2-((5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,3-二氧代-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-2(3H)-基)乙氧基)乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(77)；
(5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-(2-羟乙基)-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-1,3(2H)-二酮；
4-(2-((5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,3-二氧代-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-2(3H)-基)乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物；
(5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-(5-羟戊基)-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-1,3(2H)-二酮；
4-((5-((5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,3-二氧代-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-2(3H)-基)戊基)氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物；
(5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-(6-羟己基氧基)-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-1,3(2H)-二酮；
4-((6-((5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,3-二氧代-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-2(3H)-基)己基)氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物；
(5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-(8-羟辛基)-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-1,3(2H)-二酮；
4-((8-((5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,3-二氧代-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-2(3H)-基)辛基)氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物；
(Z)-5-((((8-((5R,11aS)-5-(苯并[d][1,3]二氧杂环戊烯-5-基)-1,3-二氧代-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-2(3H)-基)辛基)氧基)羰基)亚胺基)-3-苯基-5-氢-1,2,3-噁二唑-3-鎓-2-亚基。
4.一种NO供体型PDE5抑制剂，其特征是，其为权利要求1～3任一所述的PDE5抑制剂，R为
5.一种药物组合物，其特征是，包含权利要求1～3任一所述的PDE5抑制剂或其药学上可接受的盐、前药化合物、相应的活性代谢产物、对映异构体、溶剂化物。
6.如权利要求5所述的药物组合物，其特征是，还包括药用辅料。
7.一种药物制剂，其特征是，活性成分为上述PDE5抑制剂或药物组合物，剂型为片剂、胶囊剂、锭剂、糖衣丸剂、丸剂、颗粒剂、粉末剂、溶液剂、乳剂、混悬剂、分散体、糖浆剂、凝胶剂、气溶胶剂及其他特殊剂型。
8.一种权利要求1～3任一所述的PDE5抑制剂、权利要求5或6所述的药物组合物或权利要求7所述的药物制剂在制备治疗、缓解或预防的哺乳动物疾病的药物中的应用，所述疾病包括以下一种或多种：
a.与PDE5相关的疾病或疾病状态；
b.与NO缺乏相关的疾病或疾病状态。
9.如权利要求8所述的应用，其特征是，所述哺乳动物包括人或非人哺乳动物。
10.如权利要求8所述的应用，其特征是，所述疾病包括但不限于高血压、肺动脉高压、外周血管疾病、减少血管全开的疾病、充血性心力衰竭、动脉硬化、稳定型、不稳定型和变异型心绞痛、阿尔兹海默症、恶性肿瘤、男性勃起功能障碍、男性睾丸缺血、女性性功能障碍、早产、痛经、良性前列腺增生、膀胱出口阻塞、失禁、中风、慢性哮喘、支气管炎、变应性哮喘、过敏性鼻炎、青光眼或肠动力紊乱的疾病；
或，所述药物的给药方式为口服给药、局部给药、肌内给药、皮内给药、腹膜内给药、皮下给药、静脉内给药或吸入给药，优选吸入给药。
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