CN110343089A - 苯并咪唑类衍生物及其药学用途 - Google Patents
苯并咪唑类衍生物及其药学用途 Download PDFInfo
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- CN110343089A CN110343089A CN201810281504.3A CN201810281504A CN110343089A CN 110343089 A CN110343089 A CN 110343089A CN 201810281504 A CN201810281504 A CN 201810281504A CN 110343089 A CN110343089 A CN 110343089A
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- 150000003839 salts Chemical class 0.000 claims description 23
- 125000001072 heteroaryl group Chemical group 0.000 claims description 19
- 239000003146 anticoagulant agent Substances 0.000 claims description 16
- 125000005843 halogen group Chemical group 0.000 claims description 14
- 125000000623 heterocyclic group Chemical group 0.000 claims description 13
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 10
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- 125000005842 heteroatom Chemical group 0.000 claims description 5
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- GOLORTLGFDVFDW-UHFFFAOYSA-N 3-(1h-benzimidazol-2-yl)-7-(diethylamino)chromen-2-one Chemical compound C1=CC=C2NC(C3=CC4=CC=C(C=C4OC3=O)N(CC)CC)=NC2=C1 GOLORTLGFDVFDW-UHFFFAOYSA-N 0.000 claims description 2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Abstract
本发明公开了一种苯并咪唑类衍生物及其药学用途,特别是公开了一种如式I所示的苯并咪唑类衍生物及其在制备治疗和/或预防血栓形成或血栓栓塞病症的药物中的用途。
Description
技术领域
本发明涉及一种新型的含酰胺和苯并咪唑结构的化合物,尤其是涉及如式I所示的苯并咪唑类衍生物及其在制备治疗和/或预防血栓形成或血栓栓塞病症的药物中的用途。
背景技术
凝血能力的恶化是不稳定型心绞痛、脑栓塞、心肌梗塞、肺栓塞、血栓闭塞性脉管炎、深静脉血栓形成、弥散性血管内凝血综合征、更换瓣膜后的血栓形成、再血管化后的再闭塞或体外循环时血栓形成的重要因素。在动脉系统中,异常血栓形成主要与冠状动脉、脑血管和外周血管有关,与这些血管的血栓形成闭合有关的疾病主要包括急性心肌梗塞(AMI)、非稳定性心绞痛、血栓栓塞、与溶栓治疗和经皮刺冠状动脉腔内成形术(PTCA)有关的急性血管闭合、瞬时局部缺血发作、中风和冠状动脉旁路移植术(CABG)或外周动脉旁路移植术。对于静脉血管来说,病理性血栓形成常发生在腹部、膝关节和髋部手术后的下肢静脉(深静脉血栓形成DVT),DVT还使患者处于易患肺血栓栓塞的高度危险之中。因此,需要研制优良的抗凝血药物,这种抗凝血药物应当具有优良的剂量响应性、持续时间长、出血危险性小,几乎没有副作用,并且即使口服也能很快达到充分效果。
根据对现有的各种抗凝血药物的作用机理研究,凝血因子Xa抑制剂(FXa抑制剂)被认为是很好的抗凝血剂。凝血因子Xa是凝血链中倒数第二种酶。凝血因子Xa的抑制作用通过该抑制剂与酶之间直接形成复合体而获得,因此该酶与血浆辅助因子抗凝血酶III无关。有效的凝血因子Xa抑制作用通过口服给药、连续静脉输注、快速灌注静脉给药或任何其他非胃肠道途径施用该化合物来实现,由此可获得阻止凝血因子Xa诱发凝血酶原形成凝血酶的所需作用。FXa抑制剂的另一个优点是在血栓形成模型中的有效剂量与实验性出血模型中延长时间的剂量有很大的差别。由该试验结果可以认为FXa抑制剂是出血危险性较小的抗凝血剂。已报道了多种用作FXa抑制剂的化合物,并有许多在临床上批准,如利伐沙班、阿哌沙班、依度沙班等。
目前,为了预防经历了择期髋关节置换术或全膝关节置换手术的患者的静脉血栓栓塞(VTE),利伐沙班的标准剂量是10毫克,每天一次。然而,利伐沙班的较高疗效伴随着较高的出血倾向,重大或致命性出血的风险也不容小觑,尤其是在病人长期服药的情况下。此外,利伐沙班水溶性差,因而难以开发静脉注射制剂。因此,凝血因子Xa抑制剂的广泛应用有赖于针对上述问题的改进研究。
在这方面,从临床观点来看,开发对凝血因子Xa具有高特异性和强效抑制作用并且具有较高水溶性、口服给药更有效、更适合静脉给药、具有更大的治疗窗口和较少的出血倾向的药物已经成为新的研究趋势。
发明内容
本发明所要解决的技术问题是提供一类结构新颖的含酰胺和苯并咪唑结构的化合物,这些化合物可用于治疗和预防血栓异常疾病的抗凝药物。
具体地,一方面,本发明提供一种如式I所示的化合物或其药学上可接受的盐,以满足针对凝血Xa的选择性和强力抑制剂的现实需求。
其中
R1为为H或C1-C6烷基;
R2为为H,C1-C6烷基,C1-C6烷基羧基,C1-C6烷基-COO-C1-C6烷基;
R3a、R3b与它们所连接的C一起形成C3-C10环烷基;
A为取代或未取代的杂芳基、杂环基,或者与其所连接的氮原子一起形成具有1~3个选自N、O或S的环杂原子的杂环基或苯并杂环基;
X、Y各自独立地为-(CH2)w-或-Z(O)r-,且X、Y不相同;
Z为C或S,r为1或2的整数;
w、n、m相同或不同,各自分别独立地为0或1的整数;
B芳基或杂芳基;但当m=0时,B仅为芳基;
R4、R5相同或不同,各自分别独立地为氢、卤素、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、氰基、氨基、杂芳基或杂环基;进一步地,所述R4、R5可任选地被卤素或C1-C6烷基所取代。
进一步地,本发明所述的式I化合物是如下式IA所示的化合物或其药学上可接受的盐:
各基团如上文所定义。
进一步地,本发明所述的式I化合物是如下式IB所示的化合物或其药学上可接受的盐:
其中Y为-Z(O)r-,Z为C或S,r为1或2的整数;
其他各基团如上文所定义;但当m=0时,B仅为芳基。
进一步地,本发明所述的式I化合物是如下式IC所示的化合物或其药学上可接受的盐:
各基团如上文所定义。
在本发明的一个实施方案中,其中R1优选为甲基或乙基。
在本发明的一个实施方案中,其中R2优选为甲基、乙基,C1-C4烷基羧基,C1-C4烷基-COO-C1-C4烷基。
在本发明的一个实施方案中,其中优选R3a、R3b与它们所连接的C一起形成环丙基、环丁基或环辛基。
在本发明的一个实施方案中,其中A为取代或未取代的吡啶基、吡咯烷基,或者与其所连接的氮原子一起形成苯并吡咯烷基、苯并哌啶基、苯并哌嗪基、苯并吗啉基或苯并高哌嗪基。
在本发明的一个实施方案中,其中B为苯基、噻吩基、吡啶基、吡咯基、四唑基、恶二唑基、三唑基、吡唑基。
在本发明的一个实施方案中,其中R4、R5相同或不同,各自分别独立地为氢、卤素、C1-C4烷基、卤代C1-C4烷基、C1-C4烷氧基、卤代C1-C4烷氧基、氰基、氨基、杂芳基或杂环基;其中所述杂芳基选自噻吩基、吡啶基、吡咯基、四唑基、恶二唑基、三唑基、吡唑基;所述杂环基选自氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、吗啉基。进一步地,所述R4、R5可任选地被卤素或C1-C6烷基所取代。
在本发明的一个实施方案中,所述化合物是选自下述的化合物或其药学上可接受的盐:
在本发明的一个实施方案中,所述药学上可接受的盐选自:盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、乙酸盐、马来酸盐、琥珀酸盐、扁桃酸盐、富马酸盐、丙二酸盐、苹果酸盐、2-羟基丙酸盐、草酸盐、羟乙酸盐、水杨酸盐、葡萄糖醛酸盐、半乳糖醛酸盐、枸橼酸盐、酒石酸盐、门冬氨酸盐、谷氨酸盐、苯甲酸盐、肉桂酸盐、对甲苯磺酸盐、苯磺酸盐、甲磺酸盐、乙磺酸盐、三氟甲磺酸盐、三氟乙酸盐、阿魏酸盐,或它们的组合。
第二方面,本发明提供一种药物组合物,其包含前述任一项所述的式I(和/或式IA、IB、IC)化合物或其药学上可接受的盐,以及药学上可接受的载体和/或赋形剂。
第三方面,本发明提供如上文所述的式I(和/或式IA、IB、IC)化合物或其药学上可接受的盐,和包含所述化合物的组合物在制备治疗和/或预防血栓形成或血栓栓塞病症的药物中的用途。
所述血栓形成或血栓栓塞病症包括但不限于,例如动脉心血管血栓栓塞性病症、静脉心血管血栓栓塞性病症、心脏腔室或外周循环中的血栓栓塞性病症,和不稳定型心绞痛、急性冠状动脉综合征、心房纤维性颤动、心肌梗塞、短暂性缺血发作、中风、动脉粥样硬化、外周闭塞性动脉病、静脉血栓形成、深静脉血栓形成、血栓性静脉炎、动脉栓塞、冠状动脉血栓形成、脑动脉血栓形成、脑栓塞、肾栓塞、肺栓塞,以及由于其中血液暴露于促进血栓形成的人造表面的医疗植入物、装置或过程而引起的血栓形成。
第四方面,本发明提供上文所述的式I(和/或式IA、IB、IC)化合物或其药学上可接受的盐,和包含所述化合物的组合物在制备凝血酶抑制剂药物中的用途。
在本发明的一个实施方案中,所述药物为片剂、丸剂、颗粒剂、胶囊剂、注射剂、混悬剂、滴剂、浸膏剂、软膏剂、贴剂、乳剂、膜剂、栓剂、糊剂、凝胶剂,或喷雾剂。
第五方面,本发明提供一种联合制剂,其是将上文所述的式I(和/或式IA、IB、IC)化合物或所述组合物与抗凝血药物、抗血栓药物或抗静脉栓塞药物合用;所述抗凝血药物、抗血栓药物或抗静脉栓塞药物包括但不限于:肝素、低分子量肝素LMWH、依诺肝素、华法林、利伐沙班、阿哌沙班、依度沙班、贝曲沙班、奥米沙班、阿司匹林、噻氯匹啶、氯吡格雷、替罗非班、香豆素、尿激酶、血小板蛋白IIb/IIIa受体拮抗剂。
术语定义和说明
除非另有说明,在说明书和权利要求书中使用的术语其含义定义如下。
术语“烷基”是指直链和/或支链的饱和脂肪族烃基,例如该脂肪族烃基可包括1-6个碳原子、1-4个碳原子、1-3个碳原子,1或2个碳原子等。烷基的实例包括但不限于:甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、新戊基、正己基等。
术语“烷氧基”是指烷基-氧基,例如C1-6烷基氧基、C1-4烷基氧基,烷基定义如上。代表性的烷氧基的实例包括但不限于:甲氧基、乙氧基、丙氧基、丁氧基等。所述烷氧基可任选的被选自以下的一个或多个取代基取代:卤素、氰基、氨基、羧基等。
术语“环烷基”是指饱和或部分不饱和的3-10元全碳单环、稠合双环(例如4元/6元、5元/5元或3元/7元稠合双环)或多稠合环基团(“稠合”是指环系统中的一个环与另一个环共享一对相邻碳原子),其中一个或多个环可以包含一个或多个双键,但没有一个环具有完全共轭Pi-电子系统。环烷基的实例包括但不限于:环丙基、环丁基、环戊基、环戊烯基、环己基、环己二烯基、金刚烷基、环庚基等。
术语“杂环基”是指具有独立选自氮、氧或硫的1-3个环杂原子的3-10元的单环或稠合双环(例如4元/6元、5元/5元或3元/7元稠合双环)或多稠合环基团(“稠合”是指环系统中的一个环与另一个环共享一对相邻碳原子),其中一个或多个环可以包含一个或多个双键,但没有一个环具有完全共轭Pi-电子系统。杂环基的实例包括但不限于:环氧乙烷基、环硫乙烷基、吖丙啶基、氧杂环丙烷基、氮杂环丙烷基、硫杂环丙烷基、氧杂环丁烷基、硫杂环丁烷基、氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等。
术语“苯并杂环基”是指具有6~20个环原子的二环系统,其中一个环为苯环,另一个为杂环基(定义如上文所述),二者共享一对相邻环原子。苯并杂环基的实例包括但不限于:苯并吡咯烷基、苯并哌啶基、苯并哌嗪基、苯并吗啉基、苯并高哌嗪基等。
术语“杂芳基”是指其分子结构中具有5-20个环原子且包含至少一个杂芳环且所述杂芳环具有独立地选自氮、氧或硫的1-3个环杂原子,优选所述杂芳基为含有1-3个环杂原子的5元杂芳环、6元杂芳环,或6元/5元、6元/6元的稠合杂芳环。杂芳基的实例包括但不限于:呋喃基、噻吩基、吡啶基、吡咯基、四唑基、恶二唑基、三唑基、吡唑基、嘧啶基、吡嗪基、咪唑基、酞嗪基、哌啶基、哌嗪基、吗啉基、喹啉基、喋啶基等。所述杂芳基可任选的被选自以下的一个或多个取代基取代:卤素、氰基、氨基、C1-4烷基、卤代C1-4烷基、C1-4烷氧基、卤代C1-4烷氧基。
术语“芳基”是指其分子结构中具有6-20个碳原子且包含至少一个芳环的基团,即有一个共轭pi-电子系统。在本发明中,所述芳基的实例包括但不限于苯基、萘基。所述芳基可任选的被选自以下的一个或多个取代基取代:卤素、氰基、氨基、C1-4烷基、卤代C1-4烷基、C1-4烷氧基、卤代C1-4烷氧基。
术语“卤素”是指氟、氯、溴、碘,优选氟或氯。
术语“卤代烷基”是指烷基的一个或多个氢原子被相同/不同的卤原子取代而形成的基团,代表性的实例包括但不限于:氯甲基、三氟甲基、1-氯乙基、3-溴丙基等。
术语“卤代烷氧基”是指烷氧基的一个或多个氢原子被相同/不同的卤原子取代而形成的基团,代表性的实例包括但不限于:氯甲氧基、三氟甲氧基、三氟乙氧基、1-氯乙氧基、3-溴丙氧基等。
术语“氨基”是指-NH2基团。
术语“氰基”是指-C≡N基团。
术语“药学上可接受的盐”是指保持游离态的化合物与无毒的无机碱或有机碱、或者无毒的无机酸或有机酸反应获得的那些盐,包括但不限于:碱金属盐,如钠盐、钾盐、锂盐等;碱土金属盐,如钙盐、镁盐等;其他金属盐,如铁盐、铜盐、钴盐等;有机碱盐,如铵盐、三乙胺盐、吡啶盐、甲基吡啶盐、2,6-二甲基吡啶盐、乙醇胺盐、二乙醇胺盐、三乙醇胺盐、环己胺盐、乙二胺盐、胍盐、异丙基胺盐、三甲基胺盐、三丙基胺盐、三乙醇胺盐、二乙醇胺盐、乙醇胺盐、二甲基乙醇胺盐、二环己基胺盐、咖啡碱盐、普鲁卡因盐、胆碱盐、甜菜碱盐、苯明青霉素盐、葡萄糖胺盐、N-甲基葡糖胺盐、可可碱盐、氨丁三醇盐、嘌呤盐、哌嗪盐、吗啉盐、哌啶盐、N-乙基哌啶盐、四甲基胺盐、二苄基胺盐和苯基甘氨酸烷基酯盐;氢卤酸盐,如氢氟酸盐、盐酸盐、氢碘酸盐、氢溴酸盐;无机酸盐,如硝酸盐、硫酸盐、高氯酸盐、磷酸盐;低级烷磺酸盐,如甲磺酸盐、三氟甲磺酸盐、乙磺酸盐;芳基磺酸盐,如苯磺酸盐、对甲苯磺酸盐;有机酸盐,如蚁酸盐、富马酸盐、甲酸盐、三氟乙酸盐、糠酸盐、葡萄糖酸盐、谷氨酸盐、乙醇酸盐、羟乙磺酸盐、乳酸盐、马来酸盐、苹果酸盐、扁桃酸盐、粘液酸盐、双羟萘酸盐、泛酸盐、硬脂酸盐、琥珀酸盐、磺胺酸盐、酒石酸盐、丙二酸盐、2-羟基丙酸盐、柠檬酸盐、水杨酸盐、草酸盐、羟乙酸盐、葡萄糖醛酸盐、半乳糖醛酸盐、枸橼酸盐、赖氨酸盐、精氨酸盐、门冬氨酸盐或肉桂酸盐。
术语“药物组合物”是指包含一种或多种如本发明式I(和/或式IA、IB、IC)所示的化合物或其药学上可接受的盐的混合物。该药物组合物的目的是使本发明化合物给药更加方便。
术语“联合制剂”是指包含至少两种制剂(活性成分)的药物制剂,其中的一种制剂或另一种制剂可以在另外的组分给药之前、之后和/或同时给药(任选可重复)。在本文中,“同时给药”包括在彼此相隔48小时内如24小时内给药。
术语“药学上可接受的载体或赋形剂”是指在药物制剂领域熟知的任何类型的溶剂、分散介质、包衣材料、表面活性剂、抗氧化剂、防腐剂(例如抗真菌剂、抗菌剂)、等渗剂、吸收延迟剂、药物稳定剂、粘合剂、赋形剂、崩解剂、润滑剂、甜味剂、矫味剂、染料等或它们的组合。除了与活性成分不相容的载体之外,在本发明的药物组合物中可考虑使用任何常规载体或赋形剂。
需要说明的是,本发明提供的化合物、组合物以及联合制剂可根据给药途径配制成各种合适的剂型。使用一种或多种药学上可接受的载体或赋形剂,有利于将活性成分加工成可以在药学上使用的制剂。适当的制剂形式取决于所选择的给药途径,可以按照本领域熟知的常识进行制备。
还应理解,本发明提供的化合物、组合物以及联合制剂的给药途径可以是口服、非肠道(例如注射给药)或局部给药。可以口服的药物制剂包括胶囊剂和片剂等。病人吞咽有困难时,也可以采用舌下片或者其他非吞咽方式给药。本发明提供的化合物、组合物以及联合制剂也可以配制成用于肠胃外给药或者透皮给药或者经黏膜给药,或者采用栓剂或埋植剂的方式给药。本领域技术人员可以理解,本发明化合物可以采用合适的药物释放系统以得到更有利的效果。
另外需要说明的是,本发明提供的化合物、组合物以及联合制剂的使用剂量和使用方法取决于诸多因素,包括患者的年龄、体重、性别、自然健康状况、营养状况、化合物的活性强度、服用时间、代谢速率、病症的严重程度以及诊治医生的主观判断。
根据本发明,发明人出乎意料地发现,与已知抗凝药物利伐沙班相比,本发明所提供的如式I(和/或式IA、IB、IC)所示的化合物或其药学上可接受的盐表现出很强的抗凝血活性和针对其他酶(如凝血酶IIa和胰蛋白酶)的高选择性,并且试验表明没有显著的出血倾向;此外,本发明的化合物还具有优异的水溶解度(在pH6.5)。
具体实施方式
下面将结合具体实施例来详细说明本发明,应理解,示例性实施例和说明书仅用来解释本发明的基本原理、主要特征和本发明的优点,但并不作为对本发明的限定。本领域技术人员应理解,下述实施例和说明书中描述的只是本发明的基本原理,在不脱离本发明精神和范围的前提下,本发明还会有各种变化和改进,这些变化和改进都落入要求保护的本发明范围内。本发明要求保护的范围由所附的权利要求书及其等效物界定。
实施例
所有化合物的结构均经核磁共振(1H NMR)和/或质谱(MS)鉴定。
核磁共振化学位移(δ)以ppm(10-6)记录。
化合物简写:
CDI:N,N-羰基-二咪唑;THF:四氢呋喃;TBME:叔丁基甲基醚;DCM:二氯甲烷;HATU:2-(7-氧化苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯;DMF:N,N-二甲基甲酰胺;STAB:三乙酰氧基硼氢化钠;DIPEA:N,N-二异丙基乙胺。
中间体1的制备
按照以下反应式和方法制备中间体1。
步骤1):冰浴下,将CDI(7.80g,48.0mmol)缓慢加入到化合物1(8.0g,45.7mmol)的THF(150mL)溶液中,室温搅拌3小时。冷却至0℃,将化合物2(14.0g,41.1mmol)加到反应体系中,室温搅拌12小时。之后,加入TBME(50mL),搅拌10分钟,过滤、真空干燥得到白色固体。将此固体溶到醋酸(100mL)中,加热至90℃,搅拌30min。减压浓缩,加入DCM(100mL),使用饱和碳酸氢钠水溶液(20mL×3)进行清洗,有机相减压浓缩,残留物用硅胶色谱柱纯化,石油醚/乙酸乙酯=100∶1至30∶1梯度洗脱浓缩得到白色固体产品化合物3(12.7g)。
1H NMR(300MHz,CDCl3):δ8.42-8.40(m,1H),7.67(s,1H),7.34-7.28(m,2H),7.11(d,J=8.1Hz,1H),6.99-6.95(m,1H),6.67(d,J=8.1Hz,1H),5.58-5.55(m,1H),4.55(d,J=5.7Hz,2H),4.42(t,J=7.2Hz,2H),4.06(q,J=6.9Hz,2H),3.71(s,3H),2.80(d,J=6.9Hz,2H)。
步骤2):室温下,将化合物3(500mg,1.04mmol)加入到盐酸乙醇溶液(5mL,4M)中,室温搅拌16小时,浓缩、干燥得到黄色油状物中间体1(550mg)。
中间体2的制备
按照以下反应式和方法制备中间体2。
步骤1):室温下,将DMF(0.6mL)加入到化合物4(5.8g,30mmol)和二氯亚砜(30mL)的混合溶液中,加热至70℃,搅拌12小时,减压浓缩得到化合物5直接用于下一步合成。
步骤2):将步骤1得到的化合物5溶于DCM(8mL)中,冰水浴下,将混合液滴加到化合物6(3.2g,30mmol)的DCM(50mL)溶液中,加入三乙胺(8.3mL,60mmol),室温搅拌搅拌12小时后,减压浓缩,残留物经过硅胶柱纯化(石油醚∶乙酸乙酯=3∶∶1)得到黄色固体化合物7(4.8g)。
步骤3):室温下,将化合物7(4.8g,16.78mmol)和钯碳(2g,10%,w/w=50%)溶于乙醇/甲醇(40mL/10mL)溶液中,在氢气保护下搅拌16小时,过滤、浓缩得到黄色油状液体化合物8(3.6g)。
1H NMR(400MHz,CDCl3):d8.45(dd,J=4.0,0.8Hz,1H),7.41(t,J=8.0Hz,1H),7.02-6.99(m,1H),6.87(s,1H),6.78(d,J=8.4Hz,2H),6.36(d,J=8.4Hz,1H),3.56(s,3H),2.82(s,3H)。
步骤4):室温下,将CDI(3.8g,23.4mmol)加入化合物9(3.4g,19.5mmol)的THF(50mL)溶液中,搅拌5小时,得到的反应液(含有化合物10)直接用于下一步合成。
步骤5):室温下,将化合物8(3.0g,11.7mmol)加入到步骤4的反应液(含有化合物10)中,搅拌16小时,浓缩除去溶剂,加入醋酸(40mL),90℃下搅拌1小时,用饱和碳酸氢钠溶液调节混合液pH=9,使用DCM萃取,有机相浓缩蒸干,经硅胶柱纯化得到白色固体化合物11(3.7g)。
1H NMR(400MHz,DMSO_d6):d 8.37(dd,J=4.8,1.2Hz,1H),7.57(t,J=8.0Hz,1H),7.44-7.39(m,3H),7.19(d,J=8.0Hz,1H),7.12-7.09(m,1H),6.99(t,J=8.0Hz,1H),4.40(d,J=5.6Hz,2H),3.72(s,3H),3.46(s,3H),1.38(s,9H)。
步骤6):室温下,将化合物11(3.7g,9.36mmol)溶于盐酸乙酸乙酯(30mL,2M)中,搅拌2.5小时,浓缩干燥得到的白色固体中间体2(2.7g)。
1H NMR(400MHz,DMSO_d6):d9.16(br s,3H),8.38(dd,J=4.8,0.8Hz,1H),7.74-7.70(m,2H),7.65(s,1H),7.40(d,J=8.4,1.6Hz,1H),7.22-7.18(m,2H),4.51(s,2H),3.93(s,3H),3.48(s,3H)。
中间体3的制备
按照以下反应式和方法制备中间体3。
冰水浴下,将化合物13(867mg,8.18mmol)缓慢加入到含有化合物12(500mg,2.92mmol)和叠氮化钠(537mg,8.18mmol)的醋酸(10mL)溶液中,搅拌1小时后升至室温,搅拌16小时,减压浓缩,加入盐酸水溶液(20mL,3N),乙酸乙酯萃取(10mL×3),有机相用无水硫酸钠干燥,过滤,减压浓缩得到白色固体中间体3(400mg)。
1H NMR(300MHz,DMSO-d6):d 13.73(br s,1H),9.82(s,1H),8.06-8.03(m,1H),7.93-7.89(m,1H),7.80-7.74(m,1H)。
中间体4的制备
按照以下反应式和方法制备中间体4。
步骤1):室温下将化合物14(5.0g,21.2mmol)溶于乙醇(80mL)中,冰水浴下加入氯化亚砜(8mL),加热至60℃,搅拌12小时,减压浓缩,加入乙酸乙酯(30mL),依次使用饱和碳酸氢钠溶液(10mL×2)、水(8mL)、饱和氯化钠溶液(8mL)洗,有机相用无水硫酸钠干燥,过滤,减压浓缩得到黄色油状液体化合物15(5.0g)。
1H NMR(300MHz,CDCl3):δ7.77-7.73(m,1H),7.68-7.67(m,1H),7.36-7.32(m,1H),4.43-4.35(m,2H),1.42-1.25(m,3H)。
步骤2):室温下,将化合物15(5.0g,19mmol)溶于乙醇(100mL)溶液中,加入水合肼(9.5g,190mmol,85%),加热至100度,搅拌12小时,减压浓缩,残留物通过硅胶柱色谱纯化(PE/EA=5/1至1/1)得到产品白色固体化合物16(1.5g)。
1H NMR(300MHz,DMSO-d6):δ9.57(s,1H),7.79-7.78(m,1H),7.51-7.47(m,1H),8.36-7.33(m,1H),4.49(s,2H)。
步骤3):室温下,将化合物16(1.5g,6.0mmol)溶于化合物17(15mL)溶液中,加热到100℃,搅拌12小时,加水(20mL)淬灭,使用乙酸乙酯(15mL X 3)萃取,有机相减压浓缩,残留物通过硅胶柱色谱纯化(PE/EA=10/1 to3/1)得到产品白色固体化合物18(1.2g)。
1H NMR(300MHz,CDCl3):δ7.85(d,J=6.0Hz,1H),7.77(d,J=1.5Hz,1H),7.44(dd,J=6.0,1.2Hz,1H),2.65(s,3H)。
步骤4):室温下,将化合物18(1.1g,4.0mmol)溶于乙醇(30mL)溶液中,加入三乙胺(1.2g,12mmol)和Pd(dppf)Cl2(292mg,0.4mmol)。在一氧化碳氛围保护下,加热至80度,搅拌12小时,减压浓缩,残留物通过硅胶柱色谱纯化(PE/EA=10/1 to 3/1)得到产品黄色油状物化合物19(480mg)。
1H NMR(300MHz,CDCl3):δ7.88(dd,J=2.4,0.3Hz,1H),7.77-7.74(m,1H),7.61-7.58(m,1H),4.31(q,J=7.2Hz,2H),2.59(s,3H),1.28(t,J=7.2Hz,3H)。
步骤5):室温下,将LiOH(40mg,0.939mmol)加到化合物19(100mg,0.375mmol)的THF(9mL)和水(3mL)的混合溶液中,搅拌3小时,反应液用盐酸水溶液(1N)调到pH=4,使用乙酸乙酯萃取(10mL×3),有机相用无水硫酸钠干燥,过滤、减压浓缩得到产品白色固体中间体4(85mg)。
1H NMR(300MHz,DMSO-d6):δ13.56(s,1H),7.89-7.79(m,3H),2.53-2.47(m,3H)。
实施例1 化合物I-001的制备
室温下,将HATU(336mg,0.88mmol)和三乙胺(357mg,3.54mmol)加到中间体1(250mg,0.66mmol)和中间体3(134mg,0.59mmol)的DMF(6mL)溶液中,搅拌12小时,加入水(8mL)淬灭,用乙酸乙酯(8mL×3)萃取,减压浓缩,经制备色谱纯化,得到白色固体化合物1-001(150mg)。
1H NMR(400MHz,CDCl3):d 9.13(s,1H),8.41-8.40(m,1H),8.05(s,1H),7.75(d,J=2.0Hz,1H),7.63-7.60(m,2H),7.50(d,J=8.8Hz,1H),7.39-7.32(m,1H),7.14(d,J=8.0Hz,1H),7.05(d,J=8.0Hz,1H),6.99-6.97(m,1H),6.65(d,J=8.0Hz,1H),4.70(d,J=4.8Hz,2H),4.39(t,J=7.2Hz,2H),4.06(q,J=7.2Hz,2H),3.68(s,3H),2.77(t,J=7.2Hz,2H),1.21(t,J=7.2Hz,3H)。
LCMS:[M+H]+=588.2。
实施例2 化合物I-002的制备
室温下,将LiOH(27mg,0.638mmol)加到实施例1(150mg,0.26mmol)的THF(9mL)和水(3mL)溶液中,搅拌16小时,使用盐酸水溶液(1N)调到pH=6,浓缩,经制备色谱纯化,得到白色固体化合物I-002(100mg)。
1H NMR(400MHz,DMSO-d6):d 8.54(s,1H),8.34-8.32(m,1H),8.07(d,J=2.4Hz,1H),7.92-7.89(m,1H),7.76(d,J=8.8Hz,1H),7.55-7.51(m,1H),7.44-7.40(m,2H),7.14(dd,J1=8.4Hz,J2=1.6Hz,1H),7.09-7.06(m,1H),6.92(J=8.0Hz,1H),5.49(s,2H),4.12(t,J=7.6Hz,2H),3.87(s,3H),2.52(t,J=8.0Hz,2H)。
LCMS:[M+H]+=560。
实施例3 化合物I-003的制备
室温下,将HATU(287mg,0.75mmol)和三乙胺(153mg,1.52mmol)加到中间体2(168mg,0.50mmol)和中间体4(120mg,0.50mmol)的DMF(10mL)溶液中,搅拌12小时,加水(10mL)淬灭,使用乙酸乙酯(8mL×4)萃取,有机相减压浓缩,经制备色谱纯化,得到白色固体化合物I-003(40mg)。
1H NMR(400MHz,CDCl3):d 9.27-9.24(m,1H),8.37(d,J=3.2Hz,1H),7.89(t,J=4.0Hz,1H),7.74-7.72(m,2H),7.60-7.55(m,1H),7.46-7.44(m,2H),7.23-7.20(m,1H),7.13-7.10(m,1H),6.99(d,J=8.4Hz,1H),4.70(d,J=5.2Hz,2H),3.79(s,3H),3.46(s,3H),2.37(s,3H)。
LCMS:[M+H]+=515.9。
中间体5的制备
按照以下反应式和方法制备中间体5。
步骤1):冰水浴下,将BH3-THF(26.7mL,26.7mmo,1M)缓慢滴加到中间体3(2.0g,8.92mmol)的THF溶液(50mL)中,升至室温,搅拌12小时。冰水浴下,用MeOH(20mL)淬灭反应,减压浓缩,残留物通过硅胶柱色谱纯化(石油醚/乙酸乙酯=5/1 to 2/1)得到白色固体化合物20(900mg)。
1H NMR(300MHz,CDCl3):d 9.05(d,J=5.4Hz,1H),7.70(s,1H),7.54-7.50(m,1H),7.43-7.40(m,1H),7.54-7.50(m,2H),2.71-2.67(m,1H)。
步骤2):冰水浴下,将MsCl(814mg,0.71mmol)缓慢滴加到化合物20(100mg,0.47mmol)和三乙胺(144mg,1.43mmol)的DCM(10mL)溶液中,室温搅拌3小时,加入水(8mL)进行淬灭,并用二氯甲烷(8mL×3)萃取,有机相用无水硫酸钠干燥,过滤,减压浓缩得到黄色油状液体化合物21(137mg)。
步骤3):室温下,将KCN(557mg,8.5mmol)加到化合物21(2.0g,7.14mmol)的DMF(20mL)溶液中,搅拌12小时后,加入10mL水,并用乙酸乙酯萃取(10mL×4),有机相用无水硫酸钠干燥,过滤,减压浓缩,残留物通过硅胶柱色谱纯化(石油醚/乙酸乙酯=5/1 to 2/1)得到产品白色固体化合物22(800mg)。
1H NMR(300MHz,DMSO-d6):d 9.86(s,1H),7.79-7.72(m,3H),4.03(s,2H)。
步骤4):室温下,将化合物22(400mg,1.82mmol)溶于浓H2SO4/H2O(10mL,v/v=1/1)溶液中,加热到80℃,搅拌3小时,冷却到室温,将反应液慢慢倒入30mL冰水中,并用乙酸乙酯萃取(10mL×4),有机相用无水硫酸钠干燥,过滤,减压浓缩,残留物通过硅胶柱色谱纯化(石油醚/乙酸乙酯=5/1 to二氯甲烷/甲醇=20/1)得到产品白色固体中间体5(200mg)。
1H NMR(300MHz,DMSO-d6):d 12.43(br s,1H),9.77(s,1H),7.71-7.61(m,3H),3.62(d,J=2.4Hz,2H)。
中间体6的制备
按照以下反应式和方法制备中间体6。
步骤1):室温下,将化合物23(500mg,2.64mmol)、化合物24(704mg,3.96mmol)、叔丁基过氧化氢(0.72mL,3.96mmol)、醋酸钯(29.6mg,0.132mmol)和无水四氢呋喃(10mL)依次加入到封管中,混合体系加热到110℃并搅拌96小时。减压浓缩,残留物用硅胶色谱柱纯化,用石油醚/乙酸乙酯=5∶1洗脱,浓缩得到黄色油状物化合物25(220mg)。
步骤2):室温下,将一水合氢氧化锂(110mg,2.60mmol)加入到化合物25(170mg,0.65mmol)的四氢呋喃/水(6mL/2mL)混合溶液中,搅拌16小时。混合液用稀盐酸(1N)酸化到pH<4,减压浓缩,残留物用制备硅胶板(二氯甲烷/甲醇=10∶1)纯化得到黄色油状物中间体6(35mg)。
中间体7的制备
按照以下反应式和方法制备中间体7。
步骤1):将化合物26(400mg,2.14mmol)溶于DMF(10mL)中,室温下加入碳酸钾(887mg,6.43mmol)和化合物27(1.35g,6.43mmol)。反应液在密闭体系中,100℃下搅拌过夜。加水淬灭,乙酸乙酯萃取,干燥浓缩,过柱(PE/EA=20/1)得到白色固体化合物28(300mg)。
1H NMR(400MHz,CDCl3):δ7.83(d,J=2.4Hz,1H),7.45(dd,J=8.8,2.8Hz,1H),6.97(d,J=8.8Hz,1H),4.40(q,J=8.0Hz,2H),3.91(s,3H)。
步骤2):将化合物28(35mg,0.13mmol)溶于四氢呋喃(4mL)和水(1mL)混合溶液中,加入LiOH(11mg,0.26mmol),混合体系室温搅拌16小时。用稀盐酸(1N)调至弱酸,经乙酸乙酯萃取,无水硫酸钠干燥,旋干得到白色固体中间体7(25mg)。
中间体8的制备
按照以下反应式和方法制备中间体8。
步骤1):室温下,将化合物30(250mg,1mmol)、化合物29(190mg,0.9mmol)、Pd(PPh3)4(104mg,0.09mmol)和碳酸钾(248mg,1.8mmol)依此加入到二氧六环(20mL)和水(4mL)的混合溶液中,在氮气保护下,加热至90℃搅拌16小时,混合液经过乙酸乙酯萃取,有机相经过水、饱和食盐水洗涤后,干燥浓缩,残留物经过硅胶柱(PE/EA=3/1)纯化得到无色油状产品化合物31(150mg)。
步骤2):室温下,将化合物31(50mg,0.2mmol)溶于THF(5mL)和水(1mL)的混合溶液中,加入氢氧化锂(25mg,0.6mmol)。搅拌16小时,用盐酸(1N)调节混合液pH=2,混合液经过乙酸乙酯萃取,有机相经过水、饱和食盐水洗涤后,干燥浓缩,得到白色固体中间体8(44mg)。
中间体9的制备
按照以下反应式和方法制备中间体9。
室温下,将化合物32(2g,10.5mmol)、化合物33(1.82g,20.9mmol)、铜粉(67mg,1.05mmol)和碳酸钾(722mg,5.32mmol)依此加入到DMF(20mL)中,加热至回流搅拌5小时。盐酸(1N)调节混合液pH=2,混合液经过二氯甲烷萃取,有机相经过水、饱和食盐水洗涤后,干燥浓缩,残留物经过硅胶柱纯化得到黄色油状中间体9(2.3g)。
中间体10的制备
按照以下反应式和方法制备中间体10。
步骤1):零度下,向化合物32(500mg,2.7mmol)的乙腈(30mL)溶液中加入亚硝酸异戊酯(474mg,4.05mmol),随后滴加叠氮三甲基硅烷(465mg,4.05mmol)。滴加完毕零度搅拌10分钟,升温到室温搅拌1小时,加入三甲基乙炔基硅烷(793mg,8.10mmol)和氧化亚铜(39mg,0.27mmol),室温搅拌16小时。向反应体系中加入乙酸乙酯和饱和氯化铵,分液,有机相用盐水洗涤,干燥,减压浓缩用硅胶柱纯化(石油醚/乙酸乙酯=5∶1),浓缩得到白色固体化合物33(170mg)。
1H NMR(300MHz,DMSO-d6):δ8.59(s,1H),7.93-7.92(m,1H),7.88-7.84(m,1H),7.73(d,J=9.0Hz,1H),3.58(s,3H),0.28(s,9H)。
步骤2):将化合物33(50mg,0.162mmol)、NCS(75mg,0.57mmol)和硅胶(240mg)的乙腈(5mL)混合溶液加热到80度搅拌1.5小时。抽滤,用乙腈洗涤,滤液减压浓缩,残留物用制备硅胶板纯化(石油醚/乙酸乙酯=10∶1)得到白色固体化合物34(35mg)。
1H NMR(400MHz,CDCl3):δ8.02(d,J=2.4Hz,1H),7.79(s,1H),7.66(dd,J=8.0,2.4Hz,1H),7.26(s,1H),3.77(s,3H)。
步骤3):室温下,向化合物34(35mg,0.129mmol)的四氢呋喃/水(3mL/1mL)溶液加入氢氧化锂一水合物(16mg,0.386mmol),搅拌16小时。用稀盐酸调节pH<4,浓缩干燥得到白色固体中间体10(40mg)。
中间体11的制备
按照以下反应式和方法制备中间体11。
步骤1):将化合物35(500mg,2.91mmol)、化合物36(594mg,8.73mmol)、碳酸铯(2.80g,8.73mmol)和四丁基碘化铵(214mg,0.58mmol)的DMF(6mL)溶液加热到90℃,搅拌16小时,反应液冷却到室温,抽滤除去固体,滤液减压浓缩,残留物用水洗涤,收集固体并减压干燥得到化合物37(550mg)。
步骤2):将化合物37(100mg,0.49mmol)的浓盐酸(5mL)溶液加热至回流,搅拌72小时,减压浓缩得到灰白色固体中间体11(115mg)。
中间体12的制备
按照以下反应式和方法制备中间体12。
室温下,将一水合氢氧化锂(86.0mg,2.05mmol)加入到化合物38(100mg,0.513mmol)的四氢呋喃/水(2mL/2mL)混合溶液中,搅拌16小时。混合液用稀盐酸酸化到pH<6,减压浓缩得到白色固体中间体12(110mg)。
实施例4化合物I-004的制备
使用中间体1与化合物2-(2,5-二氯苯基)乙酸,按照实施例1的方法制备获得化合物I-004。
1H NMR(400MHz,DMSO-d6):d 8.79(t,J=5.6Hz,1H),8.40(d,J=4.8Hz,1H),7.56-7.52(m,2H),7.46-7.40(m,3H),7.36-7.33(m,1H),7.20(d,J=8.8Hz,1H),7.18-7.10(m,1H),6.88(d,J=8.0Hz,1H),4.56(d,J=5.6Hz,2H),4.23(d,J=6.8Hz,2H),4.00-3.95(m,2H),3.70(s,3H),3.67(s,2H),2.68(t,J=6.8Hz,2H),1.12(t,J=7.2Hz,3H)。
[M+H]+=568
实施例5化合物I-005的制备
使用中间体1与中间体4,按照实施例1的方法制备获得化合物I-005。
1H NMR(400MHz,DMSO-d6):d 9.87(s,1H),9.40(d,J=5.6Hz,1H),8.37(d,J=3.2Hz,1H),7.88-7.79(m,3H),7.58(t,J=6.8Hz,1H),7.49(s,1H),7.44(d,J=8.4Hz,1H),7.21(d,J=8.4Hz,1H),7.11(t,J=6.06Hz,1H),7.00(d,J=8.0Hz,1H),4.62(d,J=5.6Hz,2H),3.70(s,3H),3.47(s,3H)。
[M+H]+=602.1
实施例6 化合物I-006的制备
使用中间体1与中间体6,按照实施例1的方法制备获得化合物I-006。
1H NMR(400MHz,DMSO-d6):d 9.04(t,J=4.8Hz,1H),8.39(t,J=4.8Hz,2H),7.69(d,J=4.4Hz,1H),7.62-7.52(m,5H),7.44-7.4(m,2H),7.22-7.10(m,3H),6.92(d,J=8.0Hz,1H),4.58(d,J=5.6Hz,2H),4.23(d,J=7.2Hz,2H),3.96(q,J=7.2Hz,2H),3.68(s,3H),2.69(t,J=7.2Hz,2H),1.12(t,J=7.2Hz,3H)。
[M+H]+=597
实施例7 化合物I-007的制备
使用中间体1与中间体7,按照实施例1的方法制备获得化合物I-007。
1H NMR(400MHz,DMSO-d6):d 8.81(t,J=5.2Hz,1H),8.38(dd,J=4.8,1.2Hz,1H),7.61(d,J=2.8Hz,1H),7.58-7.50(m,2H),7.43-7.41(m,2H),7.27(d,J=7.2Hz,1H),7.19(d,J=8.4Hz,1H),7.10(t,J=4.8Hz,1H),6.87(d,J=8.0Hz,1H),4.83(q,J=8.4Hz,2H),4.73(d,J=5.2Hz,2H),4.23(t,J=6.8Hz,2H),3.97(q,J=7.6Hz,2H),3.74(s,3H),2.68(t,J=6.8Hz,2H),1.12(t,J=7.2Hz,3H)。
[M+H]+=618
实施例8 化合物I-008的制备
使用中间体1与中间体8,按照实施例1的方法制备获得化合物I-008。
1H NMR(400MHz,DMSO-d6):d 9.11(t,J=6.0Hz,1H),8.39(dd,J=4.8,1.2Hz,1H),7.89(s,1H),7.62(s,1H),7.57-7.52(m,2H),7.49-7.46(m,2H),7.43-7.40(m,2H),7.18(d,J=4.4Hz,1H),7.11(t,J=4.8Hz,1H),6.89(d,J=8.4Hz,1H),4.67(d,J=6.0Hz,2H),4.23(t,J=7.2Hz,2H),3.97(q,J=7.2Hz,2H),3.71(s,3H),3.67(s,3H),2.68(t,J=6.8Hz,2H),1.12(t,J=7.2Hz,3H)。
[M+H]+=600
实施例9 化合物I-009的制备
使用中间体1与中间体9,按照实施例1的方法制备获得化合物I-009。
1H NMR(400MHz,CDCl3):d10.69(s,1H),8.44(d,J=3.6Hz,1H),8.17(d,J=2.4Hz,1H),7.70(s,1H),7.43(dd,J=8.4,2.0Hz,1H),7.33(t,J=8.0Hz,2H),7.23-7.16(m,2H),7.00-6.97(m,1H),6.71(d,J=8.4Hz,1H),4.88(d,J=4.4Hz,2H),4.43(t,J=7.2Hz,2H),4.10-4.05(m,2H),3.86(t,J=4.4Hz,4H),3.78(s,3H),2.97-2.93(m,4H),2.81(t,J=6.8Hz,2H),1.21(t,J=7.2Hz,3H)。
[M+H]+=605
实施例10 化合物I-010的制备
使用中间体1与化合物2,5-二氯苯甲酸,按照实施例1的方法制备获得化合物I-010。
1H NMR(400MHz,DMSO-d6):9.18(t,J=5.2Hz,1H),8.38(dd,J=4.8,1.2Hz,1H),7.57-7.53(m,4H),7.45-7.41(m,2H),7.20(d,J=8.4Hz,1H),7.13-7.10(m,1H),6.89(d,J=8.0Hz,1H),4.70(d,J=6.4Hz,2H),4.23(t,J=6.8Hz,2H),3.97(q,J=7.2Hz,2H),3.78(s,3H),2.68(t,J=7.2Hz,2H),1.12(t,J=7.2Hz,3H)。
[M+H]+=554
实施例11 化合物I-011的制备
使用中间体1与中间体5,按照实施例1的方法制备获得化合物I-011。
1H NMR(400MHz,DMSO-d6):d 9.81(s,1H),8.64(t,J=5.2Hz,1H),8.39-8.38(m,1H),7.76(s,1H),7.61(d,J=1.6Hz,2H),7.56-7.52(m,1H),7.44-7.40(m,2H),7.18(dd,J=4.4,1.6Hz,1H),7.12-7.09(m,1H),6.87(d,J=7.6Hz,1H),4.43(d,J=5.2Hz,2H),4.22(t,J=7.2Hz,2H),3.97(q,J=7.2Hz,2H),3.64(s,3H),3.51(s,2H),2.68(t,J=7.2Hz,2H),1.12(t,J=5.2Hz,3H)。
[M+H]+=602.0
实施例12 化合物I-012的制备
使用中间体1与中间体11,按照实施例1的方法制备获得化合物I-012。
1H NMR(400MHz,DMSO-d6):d 9.44(t,J=4.8Hz,1H),8.93(s,1H),8.38(d,J=4.8Hz,1H),7.81-7.75(m,3H),7.69(t,J=8.4Hz,2H),7.63-7.60(t,2H),7.34(d,J=8.4Hz,1H),7.14(t,J=1.6Hz,1H),7.02(d,J=8.0Hz,1H),4.73(d,J=5.6Hz,2H),4.24(t,J=6.8Hz,2H),3.98(q,J=7.2Hz,2H),3.85(s,3H),2.71(t,J=7.2Hz,2H),1.12(t,J=6.8Hz,3H)。
[M+H]+=587
实施例13 化合物I-013的制备
使用中间体1与中间体12,按照实施例1的方法制备获得化合物I-012。
1H NMR(400MHz,DMSO-d6):d10.29(s,1H),8.35(dd,J=4.8,1.2Hz,1H),8.22(d,J=8.0Hz,1H),7.95-7.91(m,2H),7.53-7.50(m,1H),7.41-7.36(m,2H),7.11-7.07(m,2H),6.84(d,J=8.0Hz,1H),5.16(s,2H),4.19(t,J=7.2Hz,2H),3.94(q,J=7.2Hz,2H),3.84(s,3H),2.65(t,J=7.2Hz,2H),1.10(t,J=7.2Hz,3H)。
[M+H]+=545.1
实施例14 化合物I-014的制备
使用化合物I-007,按照实施例2的方法制备获得化合物I-014。
1H NMR(400MHz,DMSO-d6):d 8.82(t,J=5.2Hz,1H),8.37(d,J=4.8Hz,1H),7.61(d,J=2.8Hz,1H),7.58-7.52(m,2H),7.43-7.41(m,2H),7.27(d,J=8.8Hz,1H),7.19(d,J=7.2Hz,1H),7.10(t,J=4.8Hz,1H),6.93(d,J=8.0Hz,1H),4.84(q,J=8.8Hz,2H),4.73(d,J=5.2Hz,2H),4.17(t,J=7.6Hz,2H),3.74(s,3H),2.57(t,J=7.6Hz,2H)。
[M+H]+=590
实施例15 化合物I-015的制备
使用化合物I-011,按照实施例2的方法制备获得化合物I-014。
1H NMR(400MHz,DMSO-d6):d 9.82(s,1H),8.65(t,J=5.6Hz,1H),8.38-8.36(m,1H),7.76(s,1H),7.61(d,J=2.0Hz,2H),7.57-7.52(m,1H),7.44(s,1H),7.40(d,J=8.4Hz,1H),7.18(dd,J=4.4,1.6Hz,1H),7.12-7.09(m,1H),6.93(d,J=8.0Hz,1H),4.43(d,J=4.8Hz,2H),4.16(t,J=7.6Hz,2H),3.64(s,3H),3.51(s,2H),2.56(t,J=7.6Hz,2H)。
[M+H]+=574.2
实施例16 化合物I-016的制备
使用中间体2和中间体9,按照实施例3的方法制备获得化合物I-016。
1H NMR(400MHz,CDCl3):d 10.70(s,1H),8.44(d,J=3.6Hz,1H),8.17(d,J=2.8Hz,1H),7.73(s,1H),7.45(dd,J=8.4,2.0Hz,1H),7.39-7.34(m,2H),7.22-7.19(m,2H),7.01-6.98(m,1H),6.77(d,J=8.0Hz,1H),4.89(d,J=4.4Hz,2H),3.86(t,J=4.4Hz,4H),3.79(s,3H),3.63(s,3H),2.95(t,J=4.4Hz,4H)。
[M+H]+=519
实施例17 化合物I-017的制备
使用中间体2和中间体3,按照实施例3的方法制备获得化合物I-017。
1H NMR(400MHz,DMSO-d6):d9.87(s,1H),9.40(t,J=5.6Hz,1H),8.37(d,J=2.4Hz,1H),7.88-7.79(m,3H),7.58(t,J=6.8Hz,1H),7.49(s,1H),7.44(d,J=8.4Hz,1H),7.21(d,J=8.4Hz,1H),7.13-7.09(m,1H),7.00(d,J=8.0Hz,1H),4.61(d,J=5.6Hz,2H),3.70(s,3H),3.47(s,3H)。
[M+H]+=502.1
实施例18 化合物1-018的制备
使用中间体2和中间体10,按照实施例3的方法制备获得化合物I-018。
1H NMR(400MHz,CDCl3):d 8.46(d,J=4.8Hz,1H),7.96(s,1H),7.75-7.68(m,3H),7.62-7.59(m,1H),7.48(d,J=8.4Hz,1H),7.40-7.39(m,1H),7.29(d,J=8.8Hz,1H),7.16(d,J=8.4Hz,1H),7.03-7.02(m,1H),6.77(d,J=8.0Hz,1H),4.75(d,J=4.8Hz,2H),3.76(s,3H),3.63(s,3H)。
[M+H]+=536.9
中间体13的制备
按照以下反应式和方法制备中间体13。
室温下,将化合物8(6.4g,25mmol)溶于醋酸(20mL)中,加入化合物6(5.25g,30mmol)。搅拌6小时,减压浓缩,将残留物溶解于乙酸乙酯中(15mL),用饱和碳酸氢钠(10mL×3)洗涤,再用饱和氯化钠(10mL×3)洗涤,无水硫酸钠干燥,旋干后用硅胶柱纯化(石油醚/乙酸乙酯=4/1)得到黄色固体中间体13(7.2g)。
1H NMR(400MHz,CDCl3):δ8.43-8.42(m,1H),7.88-7.87(m,1H),7.49(d,J=1.6Hz,1H),7.42-7.38(m,1H),7.28-7.26(m,1H),7.02-6.99(m,1H),6.81(d,J=4.0Hz,1H),4.07(s,3H),3.62(s,3H)。
实施例19 化合物I-019的制备
按照以下反应式和方法制备化合物I-019。
室温下,将碳酸氢钠(158mg,1.88mmol)加入到中间体13(120mg,0.313mmol)和化合物40(58mg,0.313mmol)的乙腈/水(6mL/6mL)混合溶液中,加热至60℃并搅拌16小时。减压浓缩,残留物用制备高效液相色谱纯化(碳酸氢铵缓冲溶液)得到白色固体化合物I-019(65mg)。
1H NMR(400MHz,DMSO-d6):δ9.64(t,J=7.2Hz,1H),8.35(dd,J=4.8,1.2Hz,1H),7.62-7.57(m,2H),7.53(s,1H),7.37(dd,J=4.8,1.6Hz,1H),7.14-7.04(m,1H),7.05(d,J=8.0Hz,1H),6.95(d,J=4.0Hz,1H),6.88(d,J=4.0Hz,1H),4.50(d,J=6.0Hz,2H),4.08(s,3H),3.46(s,3H)。
LCMS:[M+H]+=440
中间体14的制备
按照以下反应式和方法制备中间体14。
冰水浴下,将化合物39(307mg,1.75mmol)慢慢滴加到化合物41(500mg,1.46mmol)的醋酸(50mL)溶液中,室温搅拌3小时后,减压浓缩,残留物经饱和碳酸氢钠溶液洗,乙酸乙酯萃取后,过硅胶柱(PE/EA=5/1至1/1)纯化得到白色固体中间体14(600mg)。
1H NMR(300MHz,DMSO-d6):δ8.42-8.40(m,1H),7.84(s,1H),7.48(d,J=8.7Hz,1H),7.40-7.36(m,1H),7.27-7.23(m,1H),7.00(t,J=6.0Hz,1H),6.77(d,J=8.4Hz,1H),4.42(t,J=6.9Hz,2H),4.15-4.06(m,5H),2.80(t,J=7.2Hz,2H),1.28-1.19(m,3H)。
中间体15的制备
按照以下反应式和方法制备中间体15。
室温下,将化合物21(270mg,0.94mmol)溶于的NH3/MeOH(20mL,4M)溶液中,搅拌12小时,减压浓缩后,加入乙酸乙酯(15mL),搅拌30min,过滤得到产品白色固体中间体15(150mg)。
1H NMR(300MHz,DMSO-d6):δ9.94(s,1H),7.99(s,1H),7.76-7.74(m,2H),3.96(s,2H),2.32(s,2H)。
实施例20 化合物I-020的制备
按照以下反应式和方法制备化合物I-020。
室温下,将中间体15(150mg,0.71mmol)溶于乙腈(8mL)和水(8mL)的混合溶液中,依次加入碳酸氢钠(301mg,3.58mmol)和中间体14(335mg,0.72mmol),60℃搅拌16小时,加入水,使用乙酸乙酯萃取,减压浓缩,残留物经制备色谱纯化得到白色固体化合物I-020(150mg)。
1H NMR(400MHz,CDCl3):δ9.02(s,1H),8.43-8.42(m,1H),8.23(d,J=6.4Hz,1H),7.75(s,1H),7.68(d,J=2.4Hz,1H),7.48-7.46(m,1H),7.40-7.36(m,2H),7.34-7.31(m,1H),7.29-7.23(m,1H),7.02-6.99(m,1H),6.72(d,J=8.4Hz,1H),4.44-4.40(m,4H),4.12(s,3H),4.07(q,J=7.2Hz,2H),2.81(t,J=7.2Hz,2H),1.12(t,J=7.2Hz,3H)。
LCMS:[M+H]+=588.2。
实施例21 化合物I-021的制备
按照以下反应式和方法制备化合物I-021。
室温下,将LiOH(21mg,0.51mmol)加到化合物I-020(150mg,0.25mmol)的THF(9mL)和水(3mL)的混合溶液中,搅拌3小时后,反应液用HCl(1N)调到pH=6,浓缩,残留物经制备色谱纯化得到白色固体化合物I-021(60mg)。
1H NMR(400MHz,DMSO-d6):δ9.90(s,1H),9.56-9.54(m,1H),8.38-8.36(m,1H),7.71(d,J=6.4Hz,1H),7.63-7.54(m,5H),7.35(d,J=8.8Hz,1H),7.15-7.12(m,1H),7.02(d,J=8.0Hz,1H),4.31(d,J=6.0Hz,2H),4.18(t,J=7.6Hz,2H),4.01(s,3H),2.59(t,J=7.2Hz,2H)。
LCMS:[M+H]+=559.9。
实施例22 化合物I-022的制备
按照以下反应式和方法制备化合物I-022。
步骤1):室温下,将化合物8(380mg,1.48mmol)和化合物39(520mg,2.96mmol)加入到醋酸(20mL)中,加完后混合体系搅拌16小时。减压浓缩,残留物经饱和碳酸氢钠水溶液洗涤,乙酸乙酯萃取后,经硅胶柱(DCM/CH3OH=30/1)纯化得到化合物42(340mg)。
步骤2):室温下,将化合物42(150mg,0.39mmol)和化合物40(79mg,0.43mmol)溶于乙腈(10mL)和水(10mL)中,再加入碳酸氢钠(49mg,0.59mmol)。混合体系60℃搅拌16小时,反应液经乙酸乙酯萃取后,减压浓缩,残留物经制备色谱纯化得到化合物I-022(39mg)。
1H NMR(400MHz,DMSO-d6):δ9.64(t,J=8.0Hz,1H),8.53(d,J=4.8Hz,2H),7.61(d,J=8.8Hz,1H),7.53(s,1H),7.37(d,J=8.8Hz,1H),7.14(t,J=4.8Hz,1H),6.95(d,J=4.0Hz,1H),6.88(d,J=4.0Hz,1H),4.50(d,J=6.4Hz,2H),4.09(s,3H),3.56(s,3H)。
LCMS:[M+H]+=441。
中间体16的制备
按照以下反应式和方法制备中间体16。
步骤1):室温下,将CuCN(343mg,3.86mmol)加到化合物14(350mg,1.28mmol)的NMP(15mL)溶液中,加热至140度,搅拌12小时,加水(10mL)淬灭,乙酸乙酯(10mL×4)萃取,有机相减压浓缩,残留物通过硅胶柱色谱纯化(PE/EA=10/1至3/1)得到产品白色固体化合物43(150mg)。
1H NMR(400MHz,DMSO-d6):δ8.15-8.12(m,1H),7.78-7.77(m,1H),7.70-7.66(m,1H),2.63-2.62(m,3H)。
步骤2):室温下,将Raney Ni(30mg)加到化合物43(150mg,0.68mmol)的NH3/MeOH(5mL,4M)溶液中,反应液在氢气氛围下搅拌12小时,过滤,减压浓缩,残留物经制备色谱纯化得到白色固体中间体16(40mg)。
LCMS:[M+H]+=224.0。
中间体17的制备
按照以下反应式和方法制备中间体17。
步骤1):室温下,将化合物44(2.0g,12.8mmol),化合物33(4.46g,51.3mmol)和三乙胺(5.36mL,38.5mmol)溶于DMSO(40mL)中,加热至90℃搅拌16小时。反应完毕后向反应液中加入水,用二氯甲烷萃取,有机相经过水洗,饱和食盐水洗涤后干燥浓缩蒸干残留物通过硅胶柱纯化得到黄色固体化合物45(2.6g)。
1H NMR(300MHz,DMSO-d6):δ7.83(d,J=2.4Hz,1H),7.64(dd,J=8.7,2.1Hz,1H),7.15(d,J=5.7Hz,1H),3.72(t,J=4.5Hz,4H),3.10(t,J=4.8Hz,4H)。
步骤2):室温下,将化合物45(260mg,1.17mmol)和RaneyNi溶于甲醇(8mL)中,在氢气保护中搅拌4小时后,过滤浓缩,残留物经过硅胶制备板纯化(PE∶EA=1∶1)得到白色固体中间体16(96mg)。
1H NMR(400MHz,CDCl3):δ7.40-7.25(m,2H),7.17-7.09(m,1H),4.02(s,2H),3.87-3.82(m,4H),2.94-2.87(m,4H)。
中间体18的制备
按照以下反应式和方法制备中间体18。
冰水浴下,将BH3-THF(2.8mL,2.8mmol,1M)慢慢滴加到化合物19(250mg,1.14mmol)的THF(20mL)溶液中,加热至60℃搅拌1.5小时,冰水浴下用MeOH(10mL)淬灭,减压浓缩、残留物经制备色谱纯化得到白色固体中间体18(80mg)。
1H NMR(300MHz,DMSO-d6):δ9.81(s,1H),7.64-7.54(m,3H),3.18-3.08(m,2H),2.62-2.58(m,2H),2.48-2.38(m,2H)。
实施例23 化合物I-023的制备
使用中间体13与16,按照实施例19的方法制备获得化合物I-023。
1H NMR(400MHz,CDCl3):d8.88-8.87(m,1H),8.44(dd,J=4.8,1.2Hz,1H),7.87(d,J=7.6Hz,1H),7.78(d,J=0.8Hz,1H),7.71(d,J=2.0Hz,1H),7.43-7.34(m,3H),7.23(s,1H),7.02-6.99(m,1H),6.77(d,J=8.0Hz,1H),4.95(d,J=7.2Hz,2H),4.15(s,3H),3.62(s,3H),2.67(s,3H)。
[M+H]+=516.1
实施例24 化合物I-024的制备
使用中间体13与17,按照实施例19的方法制备获得化合物I-024。
1H NMR(400MHz,CDCl3):d8.67(t,J=6.4Hz,1H),8.45(d,J=2.0Hz,1H),7.77(s,1H),7.41-7.35(m,2H),7.32(d,J=2.4Hz,1H),7.28-7.24(m,2H),7.13(d,J=8.8Hz,1H),7.02-6.99(m,1H),6.78(d,J=8.0Hz,1H),4.68(d,J=6.0Hz,2H),4.19(s,3H),3.92(t,J=4.4Hz,4H),3.62(s,3H),2.93(t,J=4.8Hz,4H)。
[M+H]+=519
实施例25 化合物I-025的制备
使用中间体14与18,按照实施例20的方法制备获得化合物I-025。
1H NMR(400MHz,DMSO-d6):d 9.76(s,1H),9.02(t,J=7.0Hz,1H),8.39-8.38(m,1H),7.67(s,1H),7.59-7.54(m,4H),7.48(s,1H),7.33(dd,J=4.4,1.2Hz,1H),7.14-7.11(m,1H),6.93(d,J=8.0Hz,,1H),4.23(t,J=7.2Hz,2H),4.00(s,2H),3.97(q,J=7.2Hz,,2H),3.41-3.36(m,2H),2.72-2.67(m,4H),1.12(t,J=7.2Hz,3H)。
[M+H]+=602.2
实施例26 化合物I-026的制备
使用中间体2与化合物(5-氯噻吩-2-基)甲胺,按照实施例20的方法制备获得化合物I-026。
1H NMR(400MHz,DMSO-d6):d8.42-8.41(m,1H),8.13(t,J=6.0Hz,1H),7.72(s,1H),7.40-7.32(m,2H),7.27-7.24(m,1H),7.01-6.98(m,1H),6.79-6.69(m,3H),4.64(d,J=6.0Hz,2H),4.42(t,J=7.2Hz,2H),4.17(s,3H),4.07(q,J=7.2Hz,2H),2.80(t,J=7.2Hz,2H),1.21(t,J=7.2Hz,3H)。
[M+H]+=526.1
实施例27 化合物I-027的制备
使用中间体2与化合物2-(2,5-二氯苯基)乙胺,按照实施例20的方法制备获得化合物I-027。
1H NMR(400MHz,DMSO-d6):d 9.10(t,J=6.0Hz,1H),8.40-8.38(m,1H),7.59-7.55(m,2H),7.51(s,1H),7.46-7.43(m,2H),7.36-7.15(m,2H),7.14(t,J=5.2Hz,1H),6.94(d,J=7.6Hz,1H),4.24(t,J=7.6Hz,2H),4.03(s,3H),3.98(q,J=7.2Hz,2H),3.53(q,J=6.4Hz,2H),2.98(t,J=7.2Hz,2H),2.69(t,J=7.2Hz,2H),1.12(t,J=7.2Hz,3H)。
[M+H]+=568.2
实施例28 化合物I-028的制备
使用中间体2与化合物(2,5-二氯苯基)甲胺,按照实施例20的方法制备获得化合物I-028。
1H NMR(400MHz,DMSO-d6):d 9.59(t,J=4.8Hz,1H),8.39(d,J=4.8Hz,1H),7.61-7.56(m,3H),7.50(d,J=8.4Hz,1H),7.41-7.35(m,3H),7.15(t,J=5.2Hz,1H),6.96(d,J=8.0Hz,1H),4.50(d,J=6.4Hz,2H),4.24(t,J=6.8Hz,2H),4.07(s,3H),3.98(q,J=7.2Hz,2H),2.70(t,J=7.2Hz,2H),1.13(t,J=7.2Hz,3H)。
[M+H]+=554
实施例29 化合物I-029的制备
使用化合物I-025,按照实施例21的方法制备获得化合物I-029。
1H NMR(400MHz,DMSO-d6):d 9.76(s,1H),9.03(t,J=7.0Hz,1H),8.37-8.36(m,1H),7.68(s,1H),7.60-7.55(m,4H),7.49(s,1H),7.34(dd,J=4.4,1.2Hz,1H),7.14-7.11(m,1H),7.01(d,J=8.4Hz,1H),4.16(t,J=7.6Hz,2H),4.00(s,3H),3.38(q,J=6.8Hz,2H),2.70(t,J=6.8Hz,2H),2.54(t,J=8.0Hz,2H)。
[M+H]+=574.2
实施例30 化合物I-030的制备
使用中间体1与化合物2,5-二氯苯甲醛,按照以下反应式和方法制备获得化合物I-030。
将中间体1(800mg,1.92mmol)、化合物2,5-二氯苯甲醛(336mg,1.92mmol)溶解到15mL二氯甲烷中,向混合液中加入STAB(1.62g,7.68mmol),室温下搅拌4小时。加入饱和碳酸氢钠溶液调节pH=7-8,用二氯甲烷萃取,有机相经过干燥浓缩后,取1/4粗品通过制备高效液相色谱纯化得到白色固体化合物I-30(33mg)。
1H NMR(400MHz,DMSO-d6):δ8.39(d,J=4.8Hz,1H),7.56(d,J=8.4Hz,1H),7.54(t,J=7.2Hz,1H),7.44-7.37(m,3H),7.33(d,J=6.8Hz,1H),7.17(d,J=7.2Hz,1H),7.13-7.10(m,1H),6.89(d,J=8.0Hz,1H),4.22(t,J=6.8Hz,2H),4.00-3.94(m,4H),3.75(s,2H),3.43(s,3H),2.68(t,J=6.8Hz,2H),1.12(t,J=7.2Hz,3H)。
LCMS:Rt=3.893min,[M+H]+=540。
实施例31 化合物I-031的制备
按照以下反应式和方法制备获得化合物I-031。
步骤1):室温下将化合物46(2.1g,17.6mmol),Pd/C(250mg,10%,w/w=50%)和三乙胺(16.3mL)加入到乙醇(35mL)中。在室温氢气保护下(50psi)搅拌过夜,反应液经过硅藻土过滤后浓缩蒸干得到1.82g白色固体粗品直接用于下步合成。
步骤2):室温下将中间体14(200mg,0.213mmol)、化合物47(80mg,0.64mmol)溶于乙腈/水(2mL/2mL)中,将碳酸氢钠(180mg,2.13mmol)加入到混合液中,60℃搅拌过夜,LCMS监测反应结束后,反应液经过乙酸乙酯萃取,有机相经过多次水洗后,用无水硫酸钠干燥后减压浓缩,残留物经制备色谱纯化得到白色固体50mg,经过硅胶制备板再次纯化得到白色固体化合物I-031(20mg)。
1H NMR(400MHz,DMSO-d6):δ9.50(t,J=6.0Hz,1H),8.39(d,J=4.4Hz,1H),7.80(d,J=5.6Hz,1H),7.61-7.53(m,3H),7.36(d,J=8.8Hz,1H),7.15-7.12(m,1H),6.96(d,J=7.6Hz,1H),6.44(d,J=5.6Hz,1H),6.35(s,1H),5.89(s,2H),4.29(d,J=6.0Hz,2H),4.23(t,J=6.8Hz,2H),4.07(s,3H),4.00-3.94(m,2H),2.69(t,J=6.8Hz,2H),1.12(t,J=7.6Hz,3H)。
LCMS:Rt=2.491min,[M+H]+=502。
实施例32 化合物I-032的制备
使用中间体1,按照以下反应式和方法制备获得化合物I-032。
室温下将化合物中间体1(100mg,0.24mmol)溶于4mL二氯甲烷和4mL水中,依次加入碳酸钠(76mg,0.72mmol)和化合物48(124mg,0.48mmol)室温搅拌过夜,水洗,二氯甲烷萃取后减压浓缩,残留物经制备色谱纯化得到白色固体化合物1-032(106mg)。
1H NMR(400MHz,DMSO-d6):δ8.37(d,J=4.8Hz,1H),8.14(t,J=5.6Hz,1H),7.51(d,J=6.0Hz,3H),7.45-7.42(m,3H),7.20(d,J=8.4Hz,1H),7.08(t,J=6.8Hz,1H),6.88(d,J=8.0Hz,1H),4.57(s,2H),4.50(d,J=6.0Hz,2H),4.22(t,J=6.8Hz,2H),3.97(q,J=7.2Hz,2H),3.74(s,3H),2.68(t,J=7.2Hz,2H),1.12(t,J=7.2Hz,3H)。
LCMS:Rt=3.338min,[M+H]+=604。
实施例33 化合物I-033的制备
使用中间体1,按照以下反应式和方法制备获得化合物I-033。
室温下将吡啶(156mg,1.77mmol)和DMAP(24mg,0.19mmol)加入到中间体1(150mg,0.394mmol)和化合物49(115mg,0.473mmol)的四氢呋喃/水(5mL/1mL)混合溶液中。加完后混合体系室温搅拌16小时后,将DIPEA(152mg,1.18mmol)加入到混合体系中并加热到40℃并搅拌16小时,减压浓缩,残留物用高效制备液相色谱纯化得到50mg白色固体I-033。
1H NMR(400MHz,DMSO-d6):δ8.80(br s,1H),8.40(d,J=4.8Hz,1H),7.83(s,1H),7.57-7.55(m,1H),7.48-7.47(m,2H),7.34-7.31(m,2H),7.16-7.13(m,2H),6.88(d,J=8.0Hz,1H),4.43(s,2H),4.22(t,J=7.2Hz,2H),3.98(q,J=7.2Hz,2H),3.67(s,3H),2.67(t,J=7.2Hz,2H),1.12(t,J=7.2Hz,3H)。
LCMS:Rt=2.915min,[M+H]+=590。
实施例34 化合物I-034的制备
使用中间体14,按照以下反应式和方法制备获得化合物I-034。
室温下将中间体14(150mg,0.32mmol)、化合物50(68mg,0.48mmol)和碳酸氢钠(134.6mg,1.6mmol)加入到乙腈/水(2mL/2mL)中。60℃下搅拌过夜,LCMS监测反应结束后,反应液经过乙酸乙酯萃取,有机相经过多次水洗后,用无水硫酸钠干燥后减压浓缩,残留物经制备色谱纯化得到105mg的白色固体化合物I-034。
1H NMR(400MHz,CDCl3):δ8.42(d,J=4.8Hz,1H),8.03(t,J=5.6Hz,1H),7.73(s,1H),7.40-7.24(m,6H),7.01-6.98(m,1H),6.72(d,J=8.0Hz,1H),4.58(d,J=6.4Hz,2H),4.42(t,J=7.2Hz,2H),4.17(s,3H),4.10-4.04(m,2H),2.80(t,J=7.2Hz,2H),1.12(t,J=6.8Hz,3H)。
LCMS:Rt=4.329min,[M+H]+=520。
实施例35 化合物I-035的制备
按照以下反应式和方法制备获得化合物I-035。
步骤1):-30℃下将化合物51(7.0g,35.7mmol)分批加到50mL的发烟硝酸中,加完后-30℃搅拌15min,反应液慢慢倾倒入100mL的冰水中,过滤,干燥得到产品黄色固体8.0g(化合物52)。
1H NMR(300MHz,DMSO-d6):δ12.55(br s,1H),7.93-7.69(m,1H),7.65-7.59(m,2H),1.49-1.46(m,2H),1.25-1.15(m,2H)。
步骤2):室温下将化合物52(8.4g,34.8mmol)溶到50mL的30%甲胺溶液中,反应加热到80℃搅拌12小时后,冷却用醋酸调到反应液pH=6,过滤,干燥得到产品红色固体4.5g(化合物53)。
1H NMR(300MHz,DMSO-d6):δ12.35(s,1H),8.13(d,J=4.8Hz,1H),7.89(s,1H),7.52-7.48(m,1H),6.91(d,J=9.0Hz,1H),2.92(d,J=5.1Hz,3H),1.42-1.38(m,2H)1.10-1.07(m,2H)。
步骤3):室温下将HATU(6.0g,15.8mmol)和DIPEA(4.1g,31.8mmol)加到化合物53(2.5g,10.6mmol)和化合54(1.1g,15.8mmol)的50mL的DMF溶液中,反应室温搅拌12小时后,20mL水加到反应液中,乙酸乙酯萃取10mL×4,有机相减压浓缩,残留物通过硅胶柱色谱纯化(PE/EA=10/1to3/1)得到黄色油状物2.4g(化合物55)。
1H NMR(300MHz,DMSO-d6):δ7.92(s,1H),7.34(d,J=2.1Hz,1H),6.94(d,J=9.0Hz,1H),3.15-3.10(m,4H),2.92-2.89(m,3H),1.72-1.68(m,4H),1.24-1.20(m,2H),1.04-1.00(m,2H)。
步骤4):室温下将500mg(10%,w/w=50%)Pd/C加到化合物55(2.3g,7.9mmol)的甲醇溶液中,反应液在氢气球下室温搅拌12小时后,过滤,减压浓缩,残留物通过硅胶柱色谱纯化(PE/EA=3/1 to DCM/MeOH=3/1)得到黄色油状物1.3g(化合物56)。
1H NMR(300MHz,DMSO-d6):δ6.40(d,J=1.8Hz,1H),6.34-6.24(m,2H),4.47(brs,3H),3.26-3.12(m,4H),2.64(s,3H),1.65(s,4H),1.08-1.06(m,2H),0.86-0.83(m,2H)。
步骤5):室温下将HATU(2.6g,6.94mmol)和三乙胺(1.4g,13.8mmol)加到化合物56(1.2g,4.63mmol)和化合57(891mg,5.09mmol)的20mL的DMF溶液中,反应室温搅拌12小时后,10mL水加到反应液中,乙酸乙酯萃取10mL×4,有机相减压浓缩,残留物通过硅胶柱色谱纯化(DCM/MeOH=100/1 to20/1)得到黄色固体1.1g(化合物58)。
LCMS:Rt=1.48min,[M+H]+=417.2。
步骤6):室温下将化合物58(1.1g,2.64mmol)溶于20mL醋酸溶液中,90℃搅拌3小时后,减压浓缩,粗品中加入10mL饱和碳酸氢钠溶液,乙酸乙酯萃取8mL×4,有机相用水洗8mL×4和饱和食盐水洗8mL×1,用无水硫酸钠干燥,过滤,减压浓缩,得到黄色固体680mg(化合物59)。
1H NMR(300MHz,DMSO-d6):δ7.40-7.33(m,3H),7.05-7.02(m,1H),4.35(d,J=5.7Hz,2H),3.69(s,3H),3.28-3.25(m,2H),3.06-3.02(m,2H),1.61(s,4H),1.38(s,9H),1.29-1.21(m,2H),1.08-1.04(m,2H)。
步骤7):室温下将化合物59(680mg,1.70mmol)溶于20mL的4M HCl/EA水溶液中,室温搅拌3小时,反应液直接减压浓缩得到黄色固体500mg(化合物60)。
1H NMR(300MHz,DMSO-d6):δ9.37(br s,3H),7.91(d,J=8.7Hz,1H),7.58(s,1H),7.42(d,J=8.7Hz,1H),4.60(s,2H),4.07(s,3H),3.28(br s,2H),3.04(br s,2H),1.63(s,4H),1.32(br s,2H),1.20(br s,2H)。
步骤8):室温下将HATU(169mg,0.44mmol)和三乙胺(150mg,1.48mmol)加到化合物60(120mg,0.37mmol)和化合物中间体3(83mg,0.37mmol)的10mL的DMF溶液中,反应室温搅拌12小时后,10mL水加到反应液中,乙酸乙酯萃取10mL×4,有机相减压浓缩,经制备色谱纯化得到白色固体35mg(化合物I-035)。
1H NMR(400MHz,DMSO-d6):δ9.92(s,1H),9.42(s,1H),7.89-7.80(m,3H),7.48-7.42(m,2H),7.11-7.09(m,1H),4.64(s,2H),3.78(s,3H),3.19-3.06(m,4H),1.67(br s,4H),1.28-1.22(m,4H)。
LCMS:Rt=3.738min,[M+H]+=505.2。
实施例36 化合物I-036的制备
使用中间体11,按照以下反应式和方法制备获得化合物I-036。
室温下将DIPEA(217mg,1.68mmol)加入到化合物55(100mg,0.336mmol)、中间体11(82.5mg,0.370mmol)和HATU(141mg,0.370mmol)的DMF(5mL)混合溶液中并室温搅拌16小时。减压浓缩,残留物用高效液相制备色谱纯化(碳酸氢钠缓冲液)得到白色固体18mg(化合物I-036)。
1H NMR(400MHz,DMSO-d6):δ9.24(t,J=1.2Hz,1H),9.02(s,1H),8.05(s,1H),7.75-7.69(m,3H),7.46(d,J=8.0Hz,1H),7.40(s,1H),7.10(dd,J=8.4,1.2Hz,1H),4.64(d,J=5.6Hz,2H),3.74(s,3H),3.34-3.33(m,2H),3.10(s,2H),1.66(s,4H),1.29-1.27(m,2H),1.13-1.10(m,2H)。
LCMS:Rt=2.711min,[M+H]+=504。
实施例37 化合物I-037的制备
按照以下反应式和方法制备获得化合物I-037。
步骤1):室温下将化合物5和化合物61(1.37g,10.2mmol),溶于40mL的二氯甲烷,冰水浴下滴加三乙胺(7.1mL)室温搅拌过24小时,经过TLC监测反应原料没有剩余,减压浓缩,残留物经过硅胶柱纯化(石油醚∶乙酸乙酯=2∶1)得到黄色固体粗品600mg(化合物62)。
步骤2):室温下将化合物62(600mg,1.92mmol)和300mg钯碳(10%,w/w=50%)溶于8mL/2mL的乙醇/甲醇溶液中,在氢气保护下室温搅拌过夜,反应完毕后混合液通过硅胶过滤,减压浓缩得到粗品白色固体500mg(化合物63)。
步骤3):冰水浴下将化合物63(450mg,1.6mmol)和化合物39(307mg,1.75mmol),加入到10mL醋酸中,室温下搅拌过夜,LCMS监测反应结束后减压浓缩蒸干,加入水和乙酸乙酯,萃取后有机相经过饱和碳酸氢钠洗涤后浓缩,残留物经过硅胶柱纯化(石油醚∶乙酸乙酯=3∶1)得到400mg黄色固体(化合物64)。
1H NMR(400MHz,DMSO-d6):δ7.99(s,1H),7.80(d,J=8.4Hz,1H),7.62(dd,J=1.6Hz,J=8.8Hz,1H),7.16(br s,1H),7.00-6.96(m,1H),6.92(dd,J=8.0,1.6Hz,1H),6.69(t,J=7.2Hz,1H),4.34(t,J=4.4Hz,2H),4.14(s,3H),3.91(t,J=4.4Hz,2H)。
步骤4):室温下将化合物64(100mg,0.24mmol),化合物40(44mg,0.24mmol),和碳酸氢钠(100mg,1.2mmol)依此加入到乙腈/水(3mL/3mL)中,加热到60℃搅拌过夜,反应结束后用二氯甲烷萃取,有机相浓缩蒸干,经制备色谱柱纯化得到白色固体65mg(化合物I-037)。
1H NMR(400MHz,DMSO-d6):δ9.70(d,J=6.0Hz,1H),7.88(s,1H),7.77(d,J=8.8Hz,1H),7.58(dd,J=1.2Hz,8.4Hz,1H),7.14(br s,1H),6.99-6.95(m,2H),6.91-6.89(m,2H),6.66(t,J=7.6Hz,1H),4.54(t,J=6.0Hz,2H),4.34(t,J=4.0Hz,2H),4.15(s,3H),3.91(t,J=4.4Hz,2H)。
LCMS:Rt=3.883min,[M+H]+=467。
实施例38 化合物I-038的制备
使用化合物I-012,按照类似于实施例2的方法制备获得化合物I-038。
1H NMR(400MHz,CD3OD):δ8.79(s,1H),8.38(d,J=4.4Hz,1H),7.82(s,2H),7.67-7.54(m,4H),7.40(d,J=8.4Hz,1H),7.32(d,J=8.4Hz,1H),7.13(t,J=5.6Hz,1H),7.01(d,J=8.4Hz,1H),4.71(s,2H),4.34(t,J=7.6Hz,2H),3.81(s,3H),2.70(t,J=7.6Hz,2H)。
LCMS:Rt=3.602min,[M+H]+=559。
药理学评价
1.示例化合物体外对人FXa(hFXa)的抑制试验
向待测示例化合物的5%DMSO溶液(10μL)中分别加入Tris缓冲液(100mM Tris、200mM氯化钾、0.2%BSA,pH7.4)(40μL)和0.0625U/mL hFXa(Enzyme ResearchLaboratories,Inc.),用Tris缓冲液溶解并稀释(10μL),放入96孔微型板的孔中,加入S2222(Chromogenix Co.)的750μM水溶液(40μL),测定10分钟室温下在405nM的吸光度,获得吸光度增加(ΔOD/min),计算受试化合物的IC50值。
阴性对照:Tris缓冲液。
结果参看表1。
2.示例化合物体外对人FIIa(hFIIa)的抑制试验
采用缓冲液(10mM的HEPES缓冲液,pH 7.4,2mM CaCl2)测定人凝血酶(hFIIa)活性抑制作用。选择Greiner 384微量滴定板中合适的孔测定IC50。
向不同浓度的待测示例化合物的DMSO溶液中分别加入含有50μL hFIIa(Sigma公司;T8885)的缓冲液(终浓度0.05NIH单位/mL),和含2μL 2%(V/V)DMSO的缓冲液,并用2%(V/V)DMSO的缓冲液稀释,再分别加入含有48μL底物S-2238(Chromogenix Co.)的缓冲液,终浓度为30μM。该试验中将受试化合物与酶预培养10分钟,然后加入底物得到100μL终体积以开始试验。
结果参看表1。
3.示例化合物在猴血浆中的体外活化部分凝血活酶时间的测定
受试对象:雄性食蟹猴(3~5kg)禁食静脉全血,3.2%的枸橼酸钠抗凝管中(食蟹猴血∶枸橼酸钠=9∶1,V/V)。3000RPM(~1560g)离心8min,制备血浆。
制备受试样品:用DMSO溶解受试化合物(或阳性对照),梯度稀释得到3000、600、120、24、4.8μM的储备液,各浓度分别按1∶49(V/V)与所制备的猴血浆混合。
阴性对照:将没有受试化合物的DMSO溶剂,梯度稀释得到3000、600、120、24、4.8μM的储备液,各浓度分别按1∶49(V/V)与所制备的猴血浆混合。
测试:所用测试样品均37℃预温。实验时,30μL血浆37℃预温2min,再加入30μLAPTT试剂,37℃孵育5min,加30μL CaCl2,立即开始计时,进行APTT测定。
浓度:各受试化合物分别测定60μM,12μM,2.4μM,0.48μM,0.096μM工作浓度的APTT。
按照以下公式计算:APTT比=APTT(受试化合物)/APTT(阴性对照)。
用指数方程拟合Lg(浓度)与APTT比(Origin Pro 8.5.1SR2),计算2×APTT比时的药物工作浓度,即EC200。
仪器:德高MC-2000半自动血凝仪。
结果见表1。
表1
“-”表示未测试。
如上表所示,结果表明,本发明的示例化合物通过特定的抗凝血因子Xa抑制试验表现出很强的抗凝血活性并表现出对其他酶(凝血酶IIa)的高选择性。
4.动力学溶解度的测定
将受试化合物溶解在DMSO中,以制备10mmol/L的原液。用移液管(Eppendorf公司)将980μL溶出介质加入到2mL的螺旋盖的玻璃管形瓶中。将20μL各受试化合物的原液添加到相当于pH 6.5的动力学检测溶液的缓冲溶液中(PBS体系)。受试化合物和DMSO溶液的终浓度分别是200μM和2%。药瓶压盖(最大浓度的理论值为200μM)。室温下以每分钟880转的速度旋转摇动该混合物24小时。将小瓶离心30分钟,每分钟13000转。用数字移液管将200μL上清液加入到96孔板中。用高效液相色谱测定受试化合物的溶解度。结果见表2。
表2
化合物 | 溶解度(μM)pH6.5 |
I-001 | 43.22 |
I-019 | 21.47 |
I-035 | 31.67 |
如上表所示,本发明的示例化合物表现出优异的水溶解度(在pH 6.5),更适合用于制备口服或注射的药剂。
Claims (18)
1.式I所示的化合物或其药学上可接受的盐:
其中
R1为H或C1-C6烷基;
R2为H,C1-C6烷基,C1-C6烷基羧基,C1-C6烷基-COO-C1-C6烷基;
R3a、R3b与它们所连接的C一起形成C3-C10环烷基;
A为取代或未取代的杂芳基、杂环基,或者与其所连接的氮原子一起形成具有1~3个选自N、O或S的环杂原子的杂环基或苯并杂环基;
X、Y各自独立地为-(CH2)w-或-Z(O)r-,且X、Y不相同;
Z为C或S,r为1或2的整数;
w、n、m相同或不同,各自分别独立地为0或1的整数;
B为芳基或杂芳基;但当m=0时,B仅为芳基;
R4、R5相同或不同,各自分别独立地为氢、卤素、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、氰基、氨基、杂芳基或杂环基;进一步地,所述R4、R5可任选地被卤素或C1-C6烷基所取代。
2.根据权利要求1的化合物,其是如下式IA所示的化合物或其药学上可接受的盐:
各基团如权利要求1所定义。
3.根据权利要求1的化合物,其是如下式IB所示的化合物或其药学上可接受的盐:
其中Y为-Z(O)r-,Z为C或S,r为1或2的整数;
其他各基团如权利要求1所定义;但当m=0时,B为芳基。
4.根据权利要求1的化合物,其是如下式IC所示的化合物或其药学上可接受的盐:
各基团如权利要求1所定义。
5.根据前述任一项的化合物,其中R1优选为甲基或乙基。
6.根据前述任一项的化合物,其中R2优选为甲基、乙基,C1-C4烷基羧基,C1-C4烷基-COO-C1-C4烷基。
7.根据前述任一项的化合物,其中优选R3a、R3b与它们所连接的C一起形成环丙基、环丁基或环辛基。
8.根据前述任一项的化合物,其中A为取代或未取代的吡啶基、吡咯烷基,或者与其所连接的氮原子一起形成苯并吡咯烷基、苯并哌啶基、苯并哌嗪基、苯并吗啉基或苯并高哌嗪基。
9.根据前述任一项的化合物,其中B选自苯基、噻吩基、吡啶基、吡咯基、四唑基、恶二唑基、三唑基、吡唑基。
10.根据前述任一项的化合物,其中R4、R5相同或不同,各自分别独立地为氢、卤素、C1-C4烷基、卤代C1-C4烷基、C1-C4烷氧基、卤代C1-C4烷氧基、氰基、氨基、杂芳基或杂环基;进一步地,所述R4、R5可任选地被卤素或C1-C6烷基所取代。
11.根据权利要求10的化合物,其中所述杂芳基选自噻吩基、吡啶基、吡咯基、四唑基、恶二唑基、三唑基、吡唑基;所述杂环基选自氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、吗啉基。
12.根据前述任一项的化合物,其选自下述化合物或其药学上可接受的盐:
13.根据前述任一项的化合物,其中所述药学上可接受的盐选自:盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、乙酸盐、马来酸盐、琥珀酸盐、扁桃酸盐、富马酸盐、丙二酸盐、苹果酸盐、2-羟基丙酸盐、草酸盐、羟乙酸盐、水杨酸盐、葡萄糖醛酸盐、半乳糖醛酸盐、枸橼酸盐、酒石酸盐、门冬氨酸盐、谷氨酸盐、苯甲酸盐、肉桂酸盐、对甲苯磺酸盐、苯磺酸盐、甲磺酸盐、乙磺酸盐、三氟甲磺酸盐、三氟乙酸盐、阿魏酸盐,或它们的组合。
14.一种药物组合物,其包含前述任一项所述的化合物或其药学上可接受的盐,以及药学上可接受的载体和/或赋形剂。
15.权利要求1-13任一项所述的化合物或其药学上可接受的盐,和权利要求14包含所述化合物的组合物在制备治疗和/或预防血栓形成或血栓栓塞病症的药物中的用途。
16.权利要求1-13任一项所述的化合物或其药学上可接受的盐,和权利要求15包含所述化合物的组合物在制备凝血酶抑制剂药物中的用途。
17.根据权利要求15或16所述的用途,其中所述药物为片剂、丸剂、颗粒剂、胶囊剂、注射剂、混悬剂、滴剂、浸膏剂、软膏剂、贴剂、乳剂、膜剂、栓剂、糊剂、凝胶剂,或喷雾剂。
18.一种联合制剂,其是将权利要求1-13任一项所述的化合物或权利要求14所述的组合物与抗凝血药物、抗血栓药物或抗静脉栓塞药物合用;所述抗凝血药物、抗血栓药物或抗静脉栓塞药物包括但不限于:肝素、低分子量肝素LMWH、依诺肝素、华法林、利伐沙班、阿哌沙班、依度沙班、贝曲沙班、奥米沙班、阿司匹林、噻氯匹啶、氯吡格雷、替罗非班、香豆素、尿激酶、血小板蛋白IIb/IIIa受体拮抗剂。
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CN106536504A (zh) * | 2014-08-06 | 2017-03-22 | 四川海思科制药有限公司 | 一种氟代达比加群酯衍生物及其制备方法和在药学上的用途 |
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