CN113773310A - 一种具有心血管益处的glp-1小分子 - Google Patents
一种具有心血管益处的glp-1小分子 Download PDFInfo
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- CN113773310A CN113773310A CN202011478961.5A CN202011478961A CN113773310A CN 113773310 A CN113773310 A CN 113773310A CN 202011478961 A CN202011478961 A CN 202011478961A CN 113773310 A CN113773310 A CN 113773310A
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Abstract
本发明提供了一种具有心血管益处的GLP‑1小分子化合物,其不仅具有糖尿病的治疗用途,而且可单独或联合施用作为心血管保护剂,具有降低心血管不良事件,或者降低2型糖尿病中的心血管不良事件的制药用途。所述的降低心血管不良事件包括能够降低患者心肌梗死的发生率,以及因心力衰竭而住院的频率,能够降低患者发生心肌梗死和卒中的风险,能够降低射血分数降低的成人心力衰竭的心血管死亡风险和因心力衰竭住院的风险(NYHA II‑IV级)。
Description
背景技术
心血管疾病是2型糖尿病患者的主要发病和死亡原因。随着越来越多的糖尿病药物投放市场,人们开始担心这些药物对心血管风险的影响,尤其是与罗格列酮药物有关,这与心肌梗塞风险的显着增加有关。考虑到这些担忧,2008年FDA提出了一项建议,即新的糖尿病降糖药物应不会增加心血管疾病的风险。Jardiance(恩格列净,SGLT-2抑制剂)是第一个在临床中显示出心血管获益的降糖药,于2016/12/2被FDA扩大批准新适应症,用于降低2型糖尿病患者的心血管死亡风险。
在GLP-1治疗药物中,最初认为GLP-1主要影响胰岛素释放。然而,已经发现它在葡萄糖代谢中发挥了许多其他作用。进餐后数分钟内,GLP-1从回肠末端和结肠释放出来,尽管它确实增强了葡萄糖依赖性胰岛素的产生和分泌,但还显示它可以减少胰高血糖素的分泌,增加周围组织的葡萄糖摄取和糖原合成,延迟胃排空并增加饱腹感,使其成为糖尿病治疗的理想目标。尽管已经表明改善的血糖控制可以减少糖尿病的微血管并发症,但其对大血管并发症的作用尚不清楚,心血管疾病仍然是2型糖尿病(T2D)患者死亡的第一原因。尽管GLP-1可以改善传统的心血管事件高危因素,如体重、糖化血红蛋、血脂水平、血压等,然而可能除了这些传统高危因素外,还存在影响心血管事件的其他因素。
2017年8月25日,FDA批准Victoza(利拉鲁肽)的新适应症,用于降低伴有心血管疾病的2型糖尿病患者的主要不良心血管事件、心脏病、卒中和心血管死亡风险。FDA此项批准是基于具有里程碑意义的大型LEADER研究的结果。LEADER研究是一项国际多中心、随机、双盲、安慰剂对照试验,在来自32个国家的9340例伴有较高心血管风险的2型糖尿病患者中考察了利拉鲁肽相比安慰剂联合标准疗法的长期(3.5~5年)临床结局差异。结果显示,利拉鲁肽相比安慰剂可使患者发生心血管死亡、非致命性心肌梗死和非致命性卒中等主要心血管事件的风险降低13%,绝对风险降低1.9%。可使心血管死亡风险降低22%,使全因死亡风险降低15%。Victoza(GLP-1激动剂)此次获批的心血管获益范围更大,成为唯一一个能降低心血管死亡、心肌梗死、卒中等心血管事件风险的降糖药。
但是,并非所有的GLP-1均可显示出心血管的获益,Sheahan KH,et al.PostgradMed J2020;96:156-161报道Lixisenatide在6068名患者的临床试验中,只显示非劣效于安慰剂组,并未取得心血管的益处,Liraglutide在9340名患者的临床试验中,是第一个显示出心血管益处优于安慰剂的GLP-1激动剂,Semaglutide在3297名的临床试验中,在心源性猝死或者非致死性心肌梗死上与安慰剂没有显著性的差异,Albiglutide在9463名患者的临床试验中,Albiglutide组的主要复合心血管终点发生在7%的患者中,而安慰剂组的这一比例为9%,二者具有显著性差异,Dulaglutide在9901名患者的临床试验中,在非致死性的中风上具人显著的差异(2.7%vs 3.5%,p=0.017),口服Semaglutide在3183名患者的临床试验中,在心血管获益方面未显示出显著性的差异。
而且,上述的GLP-1均为大分子多肽药物,目前尚未有GLP-1小分子药物上市,处于临床研究阶段的小分子例如TTP-OAD2、TTP273、PF-06882961、OWL833(LY-3502970),TTP273正处于临床II期、OWL833正处于临床I期,目前尚未见到心血管获益的报道,而PF-06882961的临床I期数据显示,其每天3-240毫克对心脏有轻度至中度损害,对胸腺有中度至重度影响(有助于控制感染),在大鼠中给予最高剂量的中度至中度胃溃疡,另Molecular Cell80,1-16,November 5,2020报道,PF-06882961,而非CHU-128,能够模仿GLP-1蛋白的激动作用,与此形成鲜明对比的是,PF-06882961在各个分析方面都具有活性(效力比GLP-1低30至100倍浓度),显示出与GLP-1类似的最大内在化作用,但在pERK1/2、钙动员和β-arrestin募集方面仅显示部分激动,即PF-06882961显示出具有与GLP-1胰高血糖素样肽相似的信号传导作用和调节特性,而TTP-OAD2与OWL833则显示出相似的信号传导作用和调节特性,包括促进了β-arrestin的募集或内在化,但是对于pERK1/2和钙动员都非常差的激动作用,即便如所述报道,PF-06882961仍然存在如临床I期数据所述的心脏轻度至中度的损害作用。因此,在GLP-1小分子的药物开发上,获得如利拉鲁肽、恩格列净一样,具有潜在的心血管能够获益、或者更大心血管安全性的降糖药仍然是十分必要的。
发明内容
本发明提供一种小分子GLP-1受体调节剂,其不仅具有糖尿病的治疗用途,而且同时具有心血管保护作用,所述心血管保护不依赖是否具有糖尿病的基础病症,可单独或联合用于降低心血管不良事件,或者降低2型糖尿病中的心血管不良事件的制药用途。
具体来说,本发明提供了如下结构的小分子GLP-1受体调节剂,其药学上可接受的盐、酯、立体异构体、醚、前药或溶剂化物:
其中,
A为取代或未取代的芳环、芳杂环、C2-C8的烯基,所述的取代为一个或两个以上,取代基可以相同或不同;
L为连接链,选自-(CH2)m-,-CONR7-,-SO2NR7-,-NR7CO-,-NR7SO2-,-(CH2)mO-,-O(CH2)m-,-(CH2)mS-,-S(CH2)m-,-(CH2)mNR7-,-NR7(CH2)m-;所述R7选自氢,C1-8直链或支链烷基或C3-8环烷基,且所述烷基任选的进一步被一个或两个以上卤素,氰基,氨基或羟基取代;优选的,R7选自氢,C1.3直链烷基;更优选的,所述的L选自-CH2O-,-CONH-,-CH2NH-或者-CH2N(CH3)-。
B为两个或两个以上的饱和或不饱和的碳环的组合结构,所述碳环上任选的包含一个或两个以上杂原子;
m,n独立地选自1,2或3;
Z可以相同或不同,选自C-H,C-R9或N;所述的R9为卤素,选自F,Cl,Br,I;
R4选自C1-4烷基或C1-4烷氧基,所述的C1-4烷基或C1-4烷氧基任选的进一步被一个或多个卤素、氰基,羟基取代,或进一步被饱和或不饱和的碳环或含杂原子的碳环取代;所述的饱和或不饱和的碳环或含杂原子的碳环任选的进一步被一个或两个以上卤素,氰基,氨基或羟基取代;优选的,所述饱和或不饱和的碳环或含杂原子的碳环为四元环、五元环,或六元环;更优选的,所述饱和或不饱和的碳环或含杂原子的碳环为环氧丁烷取代基、环氧戊烷取代基或噁唑取代基;优选的,R4选自被环氧丁烷取代基、环氧戊烷取代基或噁唑取代基取代的甲基、乙基、丙基;更优选的,R4选自被环氧丁烷取代基、环氧戊烷取代基或噁唑取代基取代的甲基;
R5为一个或两个以上,选自氢,羟基,氨基,卤素,氰基,羧基,四氮唑基,酰胺基;且所述羟基,氨基,羧基,四氮唑基或酰胺基任选的进一步被一个或两个以上羟基,羟基烷基,羧基烷基,氨基烷基取代,所述烷基选自C1-4烷基;优选的,R5选自羧基、酰胺基、或者被一个羟基,羟基烷基,羧基烷基,氨基烷基取代的酰胺基;所述的被一个羟基,羟基烷基,羧基烷基,氨基烷基取代的酰胺基例如是被羟基、羟甲基、羟乙基、羧甲基、羧乙基取代的酰胺基;
或R5可形成环系结构,所述环系结构上可进一步含有一个或多个氮原子和/或一个或多个环内羰基,所述环系结构任选的被一个或两个以上R6取代,所述R6选自氢,羟基,氨基,卤素,氰基,羧基,四氮唑基,酰胺基;且所述羟基,氨基,羧基,四氮唑基或酰胺基任选的进一步被一个或两个以上羟基,羟基烷基,羧基烷基,氨基烷基取代,所述烷基选自C1-4烷基;优选的,R5与连接的形成环系结构或者所述环系结构任选的被一个或两个以上R6取代。
在某些实施方案中,L选自-(CH2)mO-,-SO2NR7-,-(CH2)mNR7-,m为1;更优选的,R7选自H或甲基;
在某些实施方案中,A为一个或两个以上R1取代的芳环或芳杂环或C2-C8的烯基,R1选自氢,羟基,氨基,卤素,氰基,C1-4烷基,C1-4烷氧基,由一个或多个卤素取代的C1-4烷基或C1-4烷氧基;优选的,A为一个或两个以上R1取代的苯基i选自1-5的整数,例如是1,2,3,4,5;优选的,i为1或2,优选的,R1选自氰基,F,Cl,Br,I,更优选的,A为所述的X为卤素,选自F,Cl,Br,I;优选的,A为优选的,R1选自F,Cl,Br,I;在某些实施方案中,B选自如下的示例性结构:
其中,Y可以相同也可以不同,选自C-H或N;Z的定义同前,R2,R3,R8可以为一个或两个以上,独立地选自氢,羟基,氨基,卤素,氰基,C1-4烷基,C1-4烷氧基,由一个或多个卤素取代的C1-4烷基或C1-4烷氧基。
进一步的,B选自如下的示例性结构:
进一步的,B选自如下的示例性结构:
R2,R3的定义同前;
作为一种具体的实施方式,本发明的化合物具有如下的结构:
其中,Y可以相同也可以不同,选自C-H或N;Z,R2,R3,R4,R5的定义同前,(R1)i代表苯基上可以为i个相同或不同的R1所取代,R1的定义同前,i选自1-5的整数,例如是1,2,3,4,5,优选的,i为1或2。
进一步的,本发明的化合物具有如下的结构:
进一步的,本发明的化合物具有如下的结构:
作为一种具体的实施方式,本发明的化合物具有如下的结构:
其中,R1,R2,R3,R4,R5,R7,i的定义同前,X选自-CH2-,-CO-或-SO2-,Y可以相同或不同,选自C-H或N,Z可以相同或不同,选自C-H,C-R9或N,所述的R9为卤素,选自F,Cl,Br,I。
作为一种具体的实施方式,本发明的化合物具有如下的结构:
其中,R1,R2,R3,R4,R5,R7,i的定义同前,X选自-CH2-,-CO-或-SO2-,Y可以相同或不同,选自C-H或N。
作为一种具体的实施方式,本发明的化合物具有如下的结构:
其中,R1,R2,R3,R4,R5,R7,i的定义同前,X选自-CH2-,-CO-或-SO2-,Y可以相同或不同,选自C-H或N。
作为一种具体的实施方式,本发明的化合物具有如下的结构:
其中,R1,R3,R4,R5,i定义同前,Z可以相同或不同,选自C-H,C-R9或N,所述的R9为卤素,选自F,Cl,Br,I。
作为一种具体的实施方式,本发明的化合物具有如下的结构:
其中,R1,R2,R3,R4,i定义同前,Y可以相同或不同,选自C-H或N,R6为一个或两个以上,选自氢,羟基,氨基,卤素,氰基,羧基,四氮唑基,酰胺基,且所述羟基,氨基,羧基,四氮唑基或酰胺基任选的进一步被一个或两个以上羟基烷基、羧基烷基取代,所述烷基选自C1-4烷基;
作为一种具体的实施方式,本发明的化合物具有如下的结构:
其中,R1,R2,R3,R4,R5,i定义同前,X选自-CH2-,-CO-或-SO2-,Y可以相同或不同,选自C-H或N,Z可以相同或不同,选自C-H,C-R9或N,所述的R9为卤素,选自F,Cl,Br,I。
作为一种具体的实施方式,本发明的化合物具有如下的结构:
其中,R1,R2,R3,R4,R5,R7,i定义同前,X选自-CH2-,-CO-或-SO2-,Y可以相同或不同,选自C-H或N,Z可以相同或不同,选自C-H,C-R9或N,所述的R9为卤素,选自F,Cl,Br,I。
作为一种具体的实施方式,本发明的化合物具有如下的结构:
其中,R1,R2,R3,R4,R5,i定义同前,Y可以相同或不同,选自C-H或N,Z可以相同或不同,选自C-H,C-R9或N,所述的R9为卤素,选自F,Cl,Br,I。
作为一种具体的实施方式,本发明的化合物具有如下的结构:
其中,R1,R2,R3,R4,R5,R7,R8,i定义同前,X选自*CH2-,*CO-或-SO2-,Y可以相同或不同,选自C-H或N,Z可以相同或不同,选自C-H,C-R9或N,所述的R9为卤素,选自F,Cl,Br,I。
作为一种具体的实施方式,本发明的化合物具有如下的结构:
其中,R1,R4,R5,R7,i定义同前,X选自-CH2-,-CO-或-SO2-,Y可以相同或不同,选自C-H或N,Z可以相同或不同,选自C-H,C-R9或N,所述的R9为卤素,选自F,Cl,Br,I;优选的,R1选自氢,卤素,氰基,C1-4烷基,C1-4烷氧基,由一个或多个卤素取代的C1-4烷基或C1-4烷氧基。
示例性的,本发明的化合物具有如下结构:
作为本发明的一种具体实施方式,本发明所述的小分子GLP-1受体调节剂,其药学上可接受的盐、酯、立体异构体、醚、前药或溶剂化物,其具有如下结构:
其中,
X为一个或两个以上的卤素取代,选自F,Cl,Br,I;
Q为氰基、或咪唑基、或吡啶基;
Y可以相同也可以不同,选自C-H或N;
作为上述的结构的小分子GLP-1受体调节剂,示例性地选自如下化合物:
上述化合物具有心血管保护作用,所述心血管保护不依赖是否具有糖尿病的基础病症,可单独或联合作为心血管保护剂,或者用于降低心血管不良事件,或者降低2型糖尿病中的心血管不良事件的制药用途。所述的降低心血管不良事件包括能够降低患者心肌梗死的发生率,或者因心力衰竭而住院的频率,或者能够降低患者发生心肌梗死和卒中的风险,或者能够降低射血分数降低的成人心力衰竭的心血管死亡风险和因心力衰竭住院的风险(NYHA II-IV级)。所述的降低心血管不良事件包括降低心血管死亡、降低非致死性心肌梗死、降低卒中发生率,降低心血管死亡风险,以及降低心衰风险的住院率。
为进一步地获得所述化合物的心血管益处,和/或在糖尿病患者中的治疗中增加心血管的益处,所述的化合物可以与SGTL1和/或SGLT2化物组合使用。所述的SGTL1和/或SGLT2化合物为恩格列净和达格列净。
本发明所述化合物的一般合成方法如下:
路线1:
路线2:
路线3:
路线4:
本发明还提供了如下结构的化合物,其在制备本发明化合物时作为中间体:
其中,R1,R2,R3,R7,Z,Y,i定义同前,Y’选自C-R10或N-R10,所述的R10选自H,C1-C8的烷基,C1-C4的烷基羧基,C1-C4的烷基羟基;优选的,所述的R10选自H,甲基、羧基、羧甲基、羧乙基。
在本发明的具体实施方式中,所述的中间体具有如下结构:
其中,R1,R2,R3,R7,Z,Y,i,Y’定义同前。
示例性的,本发明所述的中间体具有如下结构:
本发明提供的GLP-1受体调节剂具有激活、增强或激动GLP-1受体的功能。
本发明提供的化合物不仅具有糖尿病的治疗用途,而且同时具有心血管保护作用,或者降低心血管不良事件,或者降低2型糖尿病中的心血管不良事件的制药用途。
所述的降低心血管不良事件包括能够降低患者心肌梗死的发生率,以及因心力衰竭而住院的频率,能够降低患者发生心肌梗死和卒中的风险,能够降低射血分数降低的成人心力衰竭的心血管死亡风险和因心力衰竭住院的风险(NYHA II-IV级)。
所述的降低心血管不良事件还包括降低心血管死亡、降低非致死性心肌梗死、降低卒中发生率,降低心血管死亡风险,以及降低心衰风险的住院率。所述心血管获益在不同龄、性别、种族、地理区域间无差别。
本发明提供包含本发明化合物、其药物可接受的盐、可水解的酯、立体异构体、醚、前药或溶剂化物和至少一种药物可接受的载体的药物组合物。
本发明的GLP-1受体调节剂化合物、其药物可接受的盐、可水解的酯、立体异构体、醚、前药或溶剂化物可以与药物可接受的载体结合,以提供适用于哺乳动物(优选人类)的病症的药物组合物。在这些药物组合物中使用的具体载体可以根据需要的施用类型(例如,静脉内的、口服的、局部的、栓剂的或胃肠外的施用类型)而变化。
在口服液剂型的组合物的制备中,可以使用常规的药物介质例如水、二醇类、油类、醇类、调味剂、防腐剂、着色剂等进行调配。类似地,当制备口服固体剂型时,可以使用例如稀释剂、制粒剂、润滑剂、粘结剂、崩解剂等的载体。
本发明的实施方案还包括本发明化合物的前药,其在体内通过酶学和化学反应转化为具有药理活性的本发明的化合物。实际上,这类前药为本发明的化合物的功能性衍生物,选择和制备合适的前药衍生物的常规方法为本领域已知。
本发明化合物提供了治疗在医学上需要GLP-1受体的激活、增强或激动的对象的恶性病况的方法,其通过按照足以为患者提供有益作用的频率或持续时间向对象施用有效量的发明化合物来进行治疗。
在施用本发明的化合物时,可单独或联合施用作为心血管保护剂,所述心血管保护不依赖是否具有糖尿病的基础病症,具有降低心血管不良事件,或者降低2型糖尿病中的心血管不良事件。所述的降低心血管不良事件包括能够降低患者心肌梗死的发生率,以及因心力衰竭而住院的频率,能够降低患者发生心肌梗死和卒中的风险,能够降低射血分数降低的成人心力衰竭的心血管死亡风险和因心力衰竭住院的风险(NYHA II-IV级)。所述的降低心血管不良事件还包括降低心血管死亡、降低非致死性心肌梗死、降低卒中发生率,降低心血管死亡风险,以及降低心衰风险的住院率。所述心血管获益在不同龄、性别、种族、地理区域间无差别。
由本发明提供的治疗方法包括对患有医学上需要胰高血糖素样肽1受体的激活、增强或激动的恶性病况的对象或患者单独施用本发明的化合物,或结合另一药理学活性试剂或第二药物施用本发明的化合物,所述恶性病况例如I型糖尿病、II型糖尿病、妊娠期糖尿病、肥胖症、食欲过盛、饱腹感不足或代谢紊乱;或者保护心血管,或者降低心血管不良事件,或者降低2型糖尿病中的心血管不良事件。
本发明提供包含本发明化合物和第二药物的药物组合物。在某些这类实施方案中,第二药物为多肽类GLP-1激动剂或其他II型糖尿病治疗药物,例如DPP-IV抑制剂。
在某些实施方案中,第二药物为艾塞那肽、索马鲁肽、利拉鲁肽、他司鲁肽、阿必鲁肽、利西拉肽和/或其他胰岛素调节肽。
在某些实施方案中,第二药物为DPPIV抑制剂,例如西格列汀。
在多种组合中,第二药物为钠-葡萄糖共转运载体SGLT1和/或SGLT2抑制剂;或第二药物为双胍类降糖药物,例如二甲双胍;或第二药物为磺酰脲类降糖药物,例如格列本脲、格列吡嗪、格列齐特和/或格列美脲;或第二药物为噻唑烷二酮类降糖药,吡格列酮和/或罗格列酮;或第二药物为阿卡波糖、米格列醇、考来维仑和/或溴隐亭等糖尿病治疗或辅助治疗药物。
在某些实施方案中,本发明化合物及PF-06882961显示出与SGLT2抑制剂,如达格列净、恩格列净的组合在保护心血管,或者作为心血管保护剂,或者降低心血管不良事件,或者降低2型糖尿病中的心血管不良事件联合施用上良好的协同效果,有助于联合施用发挥心血管的保护作用,或者降低心血管不良事件,或者降低2型糖尿病中的心血管不良事件。所述的降低心血管不良事件包括能够降低患者心肌梗死的发生率,以及因心力衰竭而住院的频率,能够降低患者发生心肌梗死和卒中的风险,能够降低射血分数降低的成人心力衰竭的心血管死亡风险和因心力衰竭住院的风险(NYHA II-IV级)。所述的降低心血管不良事件还包括降低心血管死亡、降低非致死性心肌梗死、降低卒中发生率,降低心血管死亡风险,以及降低心衰风险的住院率。所述心血管获益在不同龄、性别、种族、地理区域间无差别。
具体实施方式
下面结合具体实施例对本发明作进一步的详细说明。以下实施例用于理解本发明的方法和核心思想,对于本领域的技术人员来说,在不脱离本发明构思的前提下,进行任何可能的变化或替换,均属于本发明的保护范围。除非特别说明,本发明中所用原料和试剂均为化学纯及以上纯度。
一、示例性化合物的制备
化合物A
(1)中间体制备
将二异丙胺(1.84mL,13.12mmol)溶于四氢呋喃(12mL)并降温至-26℃,n-BuLi(2.5M,5.2mL,13mmol)十五分钟之内滴加。降温至-30℃,将化合物1a(3.12g,12.82mmol)溶于四氢呋喃(10mL)后滴加加入,反应半小时以后,加入化合物1(1.88g,12.82mmol)。然后升温至25℃搅拌2.5小时。向反应液中滴HCl溶液(6M),pH调节到7-8。MTBE萃取,用饱和氯化钠溶液(50mLx2)洗涤,干燥。硅胶柱纯化(PE∶EA=5∶1)得到3.4g黄色油状物。收率:75.0%。LCMS[M+H]+=355.1。
将化合物2(3.4g,9.62mmol)在43℃下溶于甲醇(12mL),然后加入到NaOH溶液(4M,12mL)中,升温至50℃搅拌40min。通过滴加6M的HCl调节pH至2.0,有白色固体析出,过滤,得白色固体3.27g。收率:95.0%。LCMS[M+H]+=341.1。
将化合物3(3.27g,9.62mmol)溶于二氯乙烷(20mL)中,加热至82℃并搅拌过夜。旋干后得到淡黄色油状2.99g。LCMS[M+H]+=425.1。
将化合物4(1.2g,4.05mmol)溶于二氧六环(20mL)中,加入t-BuOK(0.91g,8.10mmol)和化合物4a(1.0g,6.08mmol),Pd2(dba)3(0.37g,0.405mmol),BINAP(0.50g,0.81mmol)。氮气保护下110℃搅拌12h。硅胶柱纯化(PE∶EA=5∶1),旋干,得到淡黄色油状1.12g。收率:65.0%。LCMS[M+H]+=425.1。
将化合物5(2.12g,2.64mmol)溶于二氯甲烷(15mL)中,加入5mL三氟乙酸。室温搅拌1h。旋干,重新溶于30mL的乙酸乙酯和30mL饱和碳酸氢钠溶液中,分液,水相用乙酸乙酯萃取三次(40mL x 3),干燥,浓缩得到蜡状固体1.5g,收率90%。LCMS[M+H]+=325.1。
将化合物7(480mg,2.0mmol)溶于乙腈(10mL)中,加入三乙胺(0.3g,3mmol)和化合物7a(210mg,2.4mmol)。氮气保护下室温搅拌12h。旋干,得到618mg,直接用于下一步。
将化合物8(618mg,2.0mmol)溶于乙醇(20mL)和水(4mL)中,加入铁粉(0.45g,8.10mmoL)和氯化铵(0.45g,8.1mmoL),80℃搅拌2h。加硅藻土过滤,浓缩,硅胶柱纯化,得到黄色油状560mg。收率95%。LCMS[M+H]+=279.2。
将化合物9(560mg,2mmol)溶于乙腈(20mL)中,加入9a(450mg,3mmol)和对甲基苯磺酸(10mg),70℃搅拌1h。旋干,硅胶柱纯化(PE∶EA=5∶1),得到淡黄色油状530mg。收率:85.0%。LCMS[M+H]+=337.2。
将化合物6(80mg,0.25mmol)和化合物10(108mg,0.32mmol)溶于乙腈(6mL)中,加入K2CO3(104.3mg,0.75mmol),KI(4.15mg,0.025mmol)。50℃搅拌2h。水洗,乙酸乙酯萃取,旋干,硅胶柱纯化(PE∶EA=1∶2)。得到淡黄色固体112.0mg。收率:72.0%。LCMS[M+H]+=625.2。
(2)目标化合物制备
将化合物11(112.0mg,0.18mmol)溶于二氯甲烷(3mL)中,加入三氟乙酸(3mL)。室温搅拌1h,旋干,反相C-18柱色谱分离(甲酸条件)得到白色固体23.2mg。收率:22.75%。
1H NMR(400MHz,DMSO)δ11.04(s,1H),8.27(s,1H),8.00(d,J=9.6Hz,2H),7.88-7.74(m,4H),7.64(d,J=8.4Hz,1H),7.09(d,J=7.5Hz,1H,5.09(dd,J=7.1,2.4Hz,1H),4.82(dd,J=15.2,7.2Hz,1H),4.68(dd,J=15.2,2.6Hz,1H),4.56-4.45(m,1H),4.43-4.31(m,1H),3.95(d,J=13.5Hz,1H),3.80(d,J=13.5Hz,1H),2.99(d,J=10.3Hz,1H),2.87(d,J=11.0Hz,1H),2.79-2.68(m,1H),2.65(d,J=19.6Hz,1H),2.47-2.34(m,1H),2.30-2.09(m,2H),1.96-1.61(m,4H)
HRMS(ESI)m/z[M+H]+calcd for C31H30FN6O4 569.61,found 569.23
化合物B
(1)中间体制备
将化合物7(480mg,2.0mmol)溶于乙腈(10mL)中,加入三乙胺(0.6g,6mmol)和化合物7b(220mg,2.4mmol)。氮气保护下室温搅拌12h。旋干,得到632mg,直接用于下一步。
将化合物12(632mg,2.0mmol)溶于乙醇(20mL)和水4mL中,加入铁粉(0.45g,8.10mmol)和氯化铵(0.45g,8.1mmol),80℃搅拌2h。加硅藻土过滤,浓缩,flash纯化,得到黄色油状物530mg,收率88%。LCMS[M+H]+=293.2。
将化合物13(530mg,1.9mmol)溶于乙腈(20mL)中,加入9a(450mg,3mmol)和对甲基苯磺酸(10mg),70℃搅拌1h。旋干,flash纯化(PE∶EA=5∶1),得到淡黄色油状物530mg。收率:90.0%。LCMS[M+H]+=337.2。
将化合物6(80mg,0.25mmol)和化合物14(113.75mg,0.33mmoL)溶于乙腈(6mL)中,加入K2CO3(104.3mg,0.75mmoL),KI(4.15mg,0.025mmoL)。50℃搅拌2h。水洗,乙酸乙酯萃取,旋干,flash纯化(PE∶EA=1∶3),得到淡黄色固体113.68mg。收率:65.0%。LCMS[M+H]+=639.2。
(2)目标化合物制备
将化合物15(113.68mg,0.18mmol)溶于二氯甲烷(3mL)中,加入三氟乙酸(3mL)。室温搅拌1h。旋干,反相C-18柱色谱分离(甲酸)得到白色固体28.6mg。收率:27.32%。LCMS[M+H]+=583.2。
1H NMR(400MHz,DMSO)δ11.02(s,1H),8.28(s,1H),8.02(d,J=9.5Hz,2H),7.83(t,J=7.8Hz,4H),7.71(s,1H),7.11(s,1H),4.61(d,J=13.8Hz,1H),4.55-4.36(m,1H),4.18(s,1H),3.72(dq,J=68.0,7.1Hz,3H),3.21-2.75(m,2H),2.29-1.69(m,8H),1.69-1.51(m,1H)
HRMS(ESI)m/z[M+H]+calcd for C32H32FN6O4583.64,found 583.24
化合物C
(1)中间体制备
将化合物7(723mg,3.0mmol)溶于乙腈(10mL)中,加入三乙胺(1.5g,15mmol)和化合物7c(510mg,3.0mmol)。氮气保护下室温搅拌12h。旋干,得到960mg,直接用于下一步。
将化合物16(960mg,3.13mmol)溶于EtOH(20mL),H2O(20mL)中,加入铁粉(0.70g,12.52mmol)和NH4Cl(0.67g,12.52mmol)。氮气保护下90℃搅拌4h。过滤,滤液旋干。flash纯化(PE∶EA=1∶1)得到淡黄色油状物0.544g。收率:60.0%。LCMS[M+H]+=290.1。
将化合物17(0.544g,1.88mmol)溶于乙腈(10mL)中,加入一水对甲苯磺酸(17.9mg,0.094mmol)和化合物9a(0.434g,2.82mmol)。氮气保护下60℃搅拌1h。flash纯化(PE∶EA=5∶1),得到淡黄色油状0.59g。收率:90.0%。LCMS[M+H]+=348.1。
将化合物6(80mg,0.25mmol)和化合物18(114.51mg,0.33mmol)溶于乙腈(6mL)中,加入K2CO3(104.3mg,0.75mmol),KI(4.15mg,0.025mmol)。50℃搅拌2h。旋干,flash纯化(PE∶EA=1∶3),得到淡黄色固体101.6mg。收率:64.0%。LCMS[M+H]+=636.2。
(2)目标化合物制备
将化合物19(101.6mg,0.16mmol)溶于二氯甲烷(3mL)中,加入三氟乙酸(3mL)。室温搅拌1h。旋干,反相C-18柱色谱分离(甲酸)得到白色固体21.6mg。收率:23.28%。
1H NMR(400MHz,DMSO)δ11.04(s,1H),8.32(s,1H),8.29(s,1H),8.01(d,J=9.5Hz,2H),7.86-7.74(m,3H),7.67(d,J=8.4Hz,1H),7.27(s,1H),7.07(d,J=7.5Hz,1H),5.88(s,2H),3.90(s,2H),2.94(s,2H),2.73-2.58(m,1H),2.20(s,2H),1.80-1.65(m,4H)
HRMS(ESI)m/z[M+H]+calcd for C31H27FN7O4 580.59,found 580.21
化合物D
(1)中间体制备
将化合物20(3.0g,12.37mmol)溶于四氢呋喃(50mL)中,N2保护下降温至零下78℃,缓慢滴加n-BuLi。零下78℃反应30min后,加入DMF,自然升温继续反应30min。向反应液中滴加饱和NH4Cl溶液淬灭反应,乙酸乙酯(30mLx3)萃取。用饱和氯化钠溶液(50mL)洗涤,干燥。flash纯化(PE∶EA=5∶1),得到白色固体1.24g。收率:52.31%。LCMS[M+H]+=192.1。
将化合物21(500mg,2.62mmol)溶于EtOH(10mL)中,依次加入CH3CH2NH2HCl(424mg,5.24mmol),AcOH(471.6mg,7.86mmol)和NaBH3CN(330.1mg,5.24mmol)。80℃搅拌1h后,LCMS显示化合物消失,主峰LCMS[M+H]+=221.1。继续将Na2CO3(1.39g,13.1mmol)和Boc2O(1.13g,5.24mmol)加入反应液,室温反应1h。抽滤,滤饼用甲醇洗涤,滤液旋干。flash纯化(PE∶EA=8∶1)得到淡黄色固体469.5mg。收率:56.0%。LCMS[M+H]+=321.1。
将化合物22a(1.11g,7.35mmol)溶于二氧六环(20mL)中,加入t-BuOK(1.13g,7.35mmol)和化合物22(469.5mg,1.47mmol)。110℃搅拌2h。旋干,flash纯化(PE∶EA=5∶1)得到淡黄色油状物276.2mg。收率:43.21%。LCMS[M+H]+=436.21。
将化合物23(470mg,0.63mmol)溶于二氯甲烷(5mL)中,加入三氟乙酸(2mL)。室温搅拌1h。旋干,得到白色固体(盐酸盐)395mg。收率:98.0%。LCMS[M+H]+=336.1。
将化合物24(60mg,0.18mmol)和化合物10(78.6mg,0.234mmol)溶于乙腈(6mL)中,加入K2CO3(75.1mg,0.54mmol),KI(3.00mg,0.018mmol)。50℃搅拌2h。旋干,flash纯化(PE∶EA=1∶3),得到淡黄色固体82.3mg。收率:72.0%。LCMS[M+H]+=636.2。
(2)目标化合物制备
将化合物25(82.3mg,0.130mmol)溶于二氯甲烷(3mL)中,加入三氟乙酸(3mL)。室温搅拌1h。旋干,反相C-18柱色谱分离(甲酸)得到白色固体25.4mg。收率:28.1%。
1H NMR(400MHz,DMSO)δ8.26(d,J=8.9Hz,1H),8.18(s,1H),7.94(d,J=9.8Hz,1H),7.88(d,J=8.2Hz,1H),7.82(t,J=7.6Hz,1H),7.80-7.71(m,3H),7.62(d,J=8.4Hz,1H),7.46(dd,J=8.2,1.3Hz,1H),7.08(d,J=8.8Hz,1H),5.64(s,2H),4.97-4.83(m,1H),4.66(dd,J=15.1,8.1Hz,1H),4.50(d,J=13.3Hz,1H),4.30(d,J=5.6Hz,1H),4.05(d,J=13.6Hz,1H),3.98(dd,J=5.8,3.2Hz,1H),3.86(t,J=13.0Hz,2H),3.72(d,J=13.5Hz,1H),2.71-2.57(m,1H),2.21-2.09(m,1H),1.08(t,J=7.0Hz,3H)
HRMS(ESI)m/z[M+H]+calcd for C33H31FN5O4 580.63,found 580.23
化合物E
将化合物24(60mg,0.18mmol)和化合物14(81.9mg,0.24mmol)溶于乙腈(6mL)中,加入K2CO3(75.06mg,0.54mmol),KI(3.00mg,0.018mmol)。50℃搅拌2h。水洗,乙酸乙酯萃取,旋干。flash纯化(PE∶EA=1∶3)。得到淡黄色固体79.4mg。收率:67.5%。LCMS[M+H]+=650.1。
将化合物26(79.4mg,0.122mmol)溶于二氯甲烷(3mL)中,加入三氟乙酸(3mL)。室温搅拌1h。旋干。得到白色固体86.3mg(三氟乙酸盐)。反相C-18柱色谱分离(甲酸)得到白色固体21.5mg。收率:29.66%。
1H NMR(400MHz,DMSO)δ8.27(d,J=8.8Hz,1H),8.13(d,J=1.0Hz,1H),7.94(dd,J=9.9,1.4Hz,1H),7.87(d,J=8.2Hz,1H),7.82(t,J=7.6Hz,1H),7.79-7.72(m,3H),7.63(d,J=8.4Hz,1H),7.45(dd,J=8.2,1.4Hz,1H),7.09(d,J=8.8Hz,1H),5.65(d,J=13.2Hz,2H),4.44(dd,J=14.8,2.7Hz,1H),4.27(dd,J=14.8,9.0Hz,1H),4.10-3.95(m,2H),3.90(d,J=13.4Hz,1H),3.78(d,J=13.5Hz,1H),3.66(d,J=13.4Hz,1H),3.41-3.35(m,2H),3.30-3.24(m,2H),2.69-2.56(m,1H),1.86(ddd,J=14.8,12.0,7.4Hz,1H),1.67-1.52(m,1H),1.52-1.38(m,1H),1.26(ddd,J=16.1,12.2,8.2Hz,1H),1.07(t,J=7.1Hz,3H)
HRMS(ESI)m/z[M+H]+calcd for C34H33FN5O4 594.66,found 594.25
化合物F
将化合物24(60mg,0.18mmol)和化合物18(81.2mg,0.234mmol)溶于乙腈(6mL)中,加入K2CO3(75.06mg,0.54mmol),KI(3.00mg,0.018mmol)。50℃搅拌2h。水洗,乙酸乙酯萃取,旋干。flash纯化(PE∶EA=1∶3)。得到淡黄色固体81.5mg。收率:70.0%。LCMS[M+H]+=647.2。
将化合物27(81.5mg,0.126mmol)溶于二氯甲烷(3mL)中,加入三氟乙酸(3mL)。室温搅拌1h。旋干,反相C-18柱色谱分离(甲酸)得到白色固体20.3mg。收率:27.32%。LCMS[M+H]+=591.2。
1H NMR(400MHz,DMSO)δ8.32-8.18(m,3H),7.94(dd,J=9.9,1.4Hz,1H),7.89(d,J=8.1Hz,1H),7.85(dd,J=7.1,5.9Hz,1H),7.81(d,J=7.4Hz,1H),7.74(dd,J=11.6,5.1Hz,2H),7.52(d,J=8.0Hz,1H),7.13(d,J=8.8Hz,2H),5.77(s,2H),5.64(s,2H),4.44-4.31(m,5H),3.01(s,2H),1.23(s,3H)
HRMS(ESI)m/z[M+H]+calcd for C33H28FN6O4 591.62,found 591.21
化合物G
(1)中间体制备
将化合物1(7.5g,50mmol)溶于NMP(50mL)中,加入K2CO3(7g,50mmol),化合物28(9.3g,50mmol),然后130℃反应10h后,加水稀释,乙酸乙酯萃取,柱色谱纯化(PE∶EA=5∶1),得到7.5g白色固体,收率:50.5%。
将化合物29(1.2g,4.05mmol)溶于二氧六环(20mL)中,加入t-BuONa(0.91g,8.10mmol)和化合物4a(1.0g,6.08mmol),Pd2(dba)3(0.37g,0.405mmol),BINAP(0.50g,0.81mmol)。氮气保护下110℃搅拌12h。旋干。flash纯化(PE∶EA=5∶1)得到淡黄色油状989mg。收率:55.0%。LCMS[M+H]+=426.1。
将化合物30(300mg,7.2mmol)溶于二氯甲烷(15mL)中,加入三氟乙酸(5mL)。室温搅拌1h。旋干,重新溶于30mL乙酸乙酯和30mL的饱和碳酸氢钠溶液中,分液,水相用乙酸乙酯萃取,干燥,浓缩得到蜡状固体220mg,收率90%。LCMS[M+H]+=326.1。
将化合物31(40mg,0.13mmol)和化合物10(50mg,0.16mmol)溶于乙腈(6mL)中,加入K2CO3(104.3mg,0.75mmol),KI(4.15mg,0.025mmol),50℃搅拌2h。旋干,flash纯化(PE∶EA=1∶3),得到淡黄色固体49mg。收率:58.0%。LCMS[M+H]+=626.2。
(2)目标化合物制备
将化合物32(49mg,0.15mmol)溶于二氯甲烷(3.0mL)中,加入三氟乙酸(3.0mL)。室温搅拌1h。反相C-18柱色谱分离(甲酸)得到白色固体26.5mg。收率:31.0%。
1H NMR(400MHz,DMSO)δ12.74(s,1H),10.67(s,1H),8.28(d,J=1.0Hz,1H),8.00(d,J=9.6Hz,1H),7.81(dd,J=8.3,1.5Hz,3H),7.66(d,J=8.4Hz,1H),7.58(t,J=8.0Hz,1H),7.44(s,1H),6.59(d,J=8.0Hz,1H),5.11(dd,J=7.2,2.5Hz,1H),4.78(d,J=7.2Hz,1H),4.72-4.62(m,1H),4.49(dd,J=7.7,2.0Hz,1H),4.38(dd,J=5.9,3.1Hz,1H),3.98(d,J=13.6Hz,1H),3.81(d,J=13.6Hz,1H),3.49(s,3H),2.79-2.64(m,1H),2.55(s,3H),2.43(ddd,J=8.9,4.0,1.7Hz,1H)
HRMS(ESI)m/z[M+H]+calcd for C30H29FN7O4 570.60,found 570.22
化合物H
将化合物31(80mg,0.25mmol)和化合物13(112mg,0.32mmol)溶于乙腈(6mL)中,加入K2CO3(104.3mg,0.75mmol),KI(4.15mg,0.025mmol)。50℃搅拌2h,水洗,乙酸乙酯萃取,旋干,flash纯化(PE∶EA=1∶3),得到淡黄色固体96.0mg。收率:60.0%。LCMS[M+H]+=640.2。
将化合物33(96.0mg,0.15mmol)溶于二氯甲烷(3.0mL)中,加入三氟乙酸(3.0mL),室温搅拌1h,旋干,得到白色固体99mg,反相C-18柱色谱分离(甲酸)得到白色固体20.1mg。收率:22.95%。
1H NMR(400MHz,DMSO)δ12.72(s,1H),10.67(s,1H),8.23(d,J=1.0Hz,1H),8.00(d,J=9.6Hz,1H),7.88-7.73(m,3H),7.65(d,J=8.5Hz,1H),7.58(t,J=8.0Hz,1H),7.45(s,1H),6.59(d,J=8.0Hz,1H),4.57(dd,J=14.8,2.8Hz,1H),4.46(dd,J=14.8,8.2Hz,1H),4.25(dd,J=7.7,2.7Hz,1H),4.01(d,J=13.7Hz,1H),3.79(dt,J=16.1,10.2Hz,2H),3.68-3.58(m,1H),3.48(s,3H),2.55(s,3H),2.06(dt,J=8.1,4.8Hz,1H),1.85(ddd,J=21.7,11.5,6.6Hz,2H),1.73-1.56(m,1H)
HRMS(ESI)m/z[M+H]+calcd for C31H31FN7O4 584.62,found 584.24
化合物I
将化合物31(80mg,0.25mmol)和化合物16(111mg,0.32mmol)溶于乙腈(6mL)中,加入K2CO3(104.3mg,0.75mmol),KI(4.15mg,0.025mmol)。50℃搅拌2h,水洗,乙酸乙酯萃取,旋干;flash纯化(PE∶EA=1∶3),得到淡黄色固体100.2mg。LCMS[M+H]+=637.2。
将化合物34(100.2mg,0.16mmoL)溶于二氯甲烷(3.0mL)中,加入三氟乙酸(3.0mL)。室温搅拌1h,旋干,得到白色固体110mg,反相C-18柱色谱分离(甲酸)得到白色固体24.13mg,收率:26.0%。
1H NMR(400MHz,DMSO)δ12.68(s,1H),10.66(s,1H),8.30(d,J=8.7Hz,2H),8.00(d,J=9.7Hz,1H),7.88-7.74(m,3H),7.69(d,J=8.4Hz,1H),7.58(t,J=8.0Hz,1H),7.44(s,1H),7.24(s,1H),6.58(d,J=7.9Hz,1H),5.87(s,2H),3.92(s,2H),3.43(s,3H),2.60-2.53(m,2H)
HRMS(ESI)m/z[M+H]+calcd for C30H26FN8O4 581.58,found 581.21
化合物J,K,L,M
(1)中间体制备
微波管中,将化合物4(0.89g,3.07mmol)溶于二氧六环(20mL)中,依次加入22a(0.7g,4.6mmol),xantphos(355mg,0.61mmol),Pd2(dba)3(290mg,0.32mmol)和Cs2CO3(2.5g,7.62mmol)。反应体系用N2吹扫置换,在微波反应仪中加热到130℃,反应2h。旋干,柱层析(PE∶EA=2∶1)后浓缩得到淡黄色油状物975mg。收率:63.1%。LCMS[M+H]+=412.5。
将化合物35(750mg,1.82mmol)溶于二氯甲烷(3mL)中,加入三氟乙酸(3mL)。室温搅拌1h。旋干,得到白色固体700mg,NaHCO3溶液中和,萃取,旋干,flash纯化(PE∶EA=I∶1),得到淡黄色固体500mg。收率:88.34%。LCMS[M+H]+=312.2。
将化合物36(500mg,1.61mmol)和化合物10(702mg,2.09mmol)溶于乙腈(6mL)中,加入K2CO3(671mg,4.83mmol),KI(26.73mg,0.161mmol)。50℃搅拌2h,水洗,乙酸乙酯萃取,旋干,flash纯化(PE∶EA=1∶1),得到淡黄色固体460mg。收率:46.74%。LCMS[M+H]+=612.2。
将化合物37(460mg,0.753mmol)溶于二氯甲烷(3mL)中,加入三氟乙酸(3mL)。室温搅拌1h,旋干,得到白色固体450mg,反相C-18柱色谱分离(甲酸)得到白色固体320mg,收率:76.56%。LCMS[M+H]+=556.2。
将化合物38(80mg,0.14mmol)溶于DMF(3.0mL)中,加入HATU(60.25mg,0.16mmol),DIPEA(54.2mg,0.42mmol)。室温搅拌10min,接着加入甘氨酸叔丁酯(36.7mg,0.28mmol),室温搅拌1h,水洗,乙酸乙酯萃取,干燥,flash纯化(PE∶EA=1∶2)得到淡黄色固体70.0mg。收率:74.85%。LCMS[M+H]+=669.2。
(2)目标化合物制备
将化合物38(80mg,0.14mmol)溶于DMF(3.0mL)中,加入HATU(58.5mg,0.154mmol),DIPEA(361.2mg,2.8mmol)。室温搅拌10min,接着加入羟胺盐酸盐(96.6mg,1.4mmol),室温搅拌1h。水洗,乙酸乙酯萃取,旋干,反相C-18柱色谱分离(甲酸)得到白色固体11.8mg。收率:13.98%。
1H NMR(400MHz,DMSO)δ11.25(s,1H),9.99(s,1H),9.07(s,1H),8.16(d,J=10.4Hz,1H),7.78(d,J=8.5Hz,1H),7.73-7.65(m,2H),7.56(dt,J=20.2,9.3Hz,3H),6.94(d,J=7.3Hz,1H),6.76(d,J=8.2Hz,1H),6.28(s,2H),5.44(s,2H),5.08(dd,J=7.1,2.4Hz,1H),4.88-4.69(m,3H),4.63(dd,J=15.3,2.3Hz,1H),4.51(d,J=6.2Hz,1H),4.37(dd,J=6.0,3.0Hz,1H),3.74(s,2H),2.96(s,1H),2.79-2.71(m,1H),2.69(s,3H),2.43-2.28(m,1H),2.07(d,J=28.6Hz,3H)
HRMS(ESI)m/z[M+H]+calcd for C31H35FN7O5 604.66,found 604.26。
将化合物38(80mg,0.14mmol)溶于DMF(3.0mL)中,加入HATU(58.5mg,0.154mmol),DIPEA(54.2mg,0.42mmol)。室温搅拌10min,接着加入乙醇胺(21.4mg,0.35mmoL),室温搅拌1h。水洗,乙酸乙酯萃取,旋干,反相C-18柱色谱分离(甲酸)得到白色固体25.6mg,收率:30.58%。
1H NMR(400MHz,DMSO)δ8.47(t,J=5.7Hz,1H),8.26(s,1H),7.91(d,J=9.5Hz,1H),7.86-7.68(m,4H),6.96(d,J=7.1Hz,1H),6.80(d,J=8.2Hz,1H),5.51(s,2H),5.08(d,J=6.9Hz,1H),4.78(dd,J=15.5,7.1Hz,3H),4.63(d,J=13.0Hz,1H),4.56-4.46(m,1H),4.38(d,J=2.7Hz,1H),4.33-4.22(m,1H),3.95-3.54(m,7H),2.93(s,1H),2.80-2.58(m,1H),2.43-2.26(m,1H),2.22-1.90(m,4H)
HRMS(ESI)m/z[M+H]+calcd for C33H36FN6O4 599.68,found 599.28。
将化合物38(80mg,0.14mmol)溶于DMF(3.0mL)中,加入HATU(58.5mg,0.154mmoL),DIPEA(54.2mg,0.42mmol)。室温搅拌10min,接着加入NH3/DMF(1M,0.42mL,0.42mmol),室温搅拌1h。水洗,乙酸乙酯萃取,旋干,反相C-18柱色谱分离(甲酸)得到白色固体36.1mg。收率:46.52%。
1H NMR(400MHz,DMSO)δ8.30(s,1H),8.01(s,1H),7.91(d,J=9.6Hz,1H),7.85(dd,J=8.5,1.5Hz,1H),7.80-7.68(m,4H),7.42(s,1H),6.96(d,J=7.3Hz,1H),6.80(d,J=8.2Hz,1H),5.51(s,2H),5.08(dd,J=7.1,2.4Hz,1H),4.94-4.72(m,3H),4.62(dd,J=15.4,2.5Hz,1H),4.58-4.46(m,1H),4.37(dt,J=8.9,6.0Hz,1H),3.95-3.75(m,4H),3.32(s,2H),2.95(s,1H),2.81-2.64(m,1H),2.44-2.30(m,1H),2.15-1.97(m,4H),1.80-1.61(m,1H)
HRMS(ESI)m/z[M+H]+calcd for C31H32FN6O3 555.63,found 555.25。
将化合物39(70mg,0.11mmol)溶于二氯甲烷(3mL)中,加入三氟乙酸(3mL)。室温搅拌1h,旋干,得到白色固体91.5mg。反相C-18柱色谱分离(甲酸)得到白色固体18.6mg。收率:27.64%。
1H NMR(400MHz,DMSO)δ12.59(s,1H),10.07(s,1H),8.88(dd,J=13.4,5.9Hz,1H),8.33(d,J=23.9Hz,1H),7.97-7.77(m,3H),7.77-7.66(m,3H),6.94(dd,J=20.0,7.3Hz,1H),6.80(dd,J=8.2,3.3Hz,1H),5.51(s,1H),5.48(d,J=5.4Hz,1H),5.44-5.25(m,1H),5.15-5.00(m,1H),4.98-4.73(m,2H),4.64(d,J=13.0Hz,1H),4.59-4.47(m,1H),4.47-4.34(m,1H),4.17(s,2H),3.99(d,J=4.2Hz,2H),3.76(s,1H),3.62(dd,J=11.0,4.9Hz,1H),3.10-2.83(m,2H),2.72(d,J=7.1Hz,1H),2.41-2.30(m,1H),2.18(d,J=10.0Hz,1H),2.02-1.90(m,1H),1.90-1.74(m,1H)
HRMS(ESI)m/z[M+H]+calcd for C33H34FN6O5 613.66,found 613.25。
化合物N
(1)中间体制备
将化合物21(700mg,3.66mmol)溶于EtOH(15mL)中,依次加入CH3NH2HCl(495mg,7.33mmol),AcOH(660mg,10.99mmol)和NaBH3CN(462mg,7.33mmol)。80℃搅拌1h后,LCMS显示化合物消失,主峰LCMS[M+H]+=207.1。继续将Na2CO3(1.94g,18.32mmol)和Boc2O(965mg,7.33mmol)加入反应液,室温反应1h。LCMS显示主峰是产物。抽滤,滤饼用甲醇洗涤,旋干,flash纯化(PE∶EA=8∶1),得到淡黄色固体620mg。
收率:55.32%。LCMS[M+H]+=307.2。
将化合物5(1.52g,10.10mmol)溶于二氧六环(20mL)中,加入t-BuOK(1.13g,10.10mmol)和化合物40(620mg,2.02mmol)。110℃搅拌2h。旋干,flash纯化(PE∶EA=5∶1),得到淡黄色油状物334mg。收率:39.21%。LCMS[M+H]+=422.3。
将化合物41(334mg,0.79mmoL)溶于二氯甲烷(5mL)中,加入HCl/二氧六环(1mL)。室温搅拌1h。旋干,得到白色固体228.0mg。收率:80.41%。LCMS[M+H]+=322.3。
将化合物42(100mg,0.28mmol)和化合物10(121mg,0.36mmol)溶于乙腈(6mL)中,加入K2CO3(116.8mg,0.84mmol),KI(4.65mg,0.028mmol)。50℃搅拌2h。水洗,乙酸乙酯萃取,旋干,flash纯化(PE∶EA=1∶3),得到淡黄色固体113.0mg。收率:65.0%。LCMS[M+H]+=622.2。
(2)目标化合物制备
将化合物43(113mg,0.182mmol)溶于二氯甲烷(3mL)中,加入三氟乙酸(3mL)。室温搅拌1h。旋干,得到白色固体125mg,反相C-18柱色谱分离(甲酸)得到白色固体32.1mg。收率:31.06%。LCMS[M+H]+=566.2。
1H NMR(400MHz,DMSO)δ8.36-8.27(m,2H),7.95(dd,J=13.5,4.7Hz,3H),7.88(dd,J=8.5,1.3Hz,1H),7.84-7.71(m,3H),7.59(d,J=8.8Hz,1H),7.18(d,J=8.8Hz,1H),5.65(s,2H),4.95(ddd,J=14.5,7.3,2.8Hz,1H),4.77-4.44(m,5H),4.36(dd,J=13.7,7.7Hz,1H),4.23-4.10(m,1H),2.77(s,3H),2.71-2.57(m,2H),2.29-2.15(m,1H)
HRMS(ESI)m/z[M+H]+calcd for C32H29FN5O4 566.61,found 566.22。
化合物O
(1)中间体制备
将化合物1e(0.6g,2.02mmol)溶于二氧六环(10ml)中,加入K2CO3(0.42g,3.04mmol)和化合物1f(1.0g,6.08mmol),Pd2(dba)3(0.18g,0.202mmol),xantphos(0.50g,0.81mmol)。氮气保护下130℃搅拌1h。旋干,flash纯化(PE∶EA=5∶1)得到淡黄色油状物239mg。收率:27.0%。LCMS[M+1]+=437.2。
将化合物2e(220mg,0.5mmol)溶于二氯甲烷(3ml)中,加入三氟乙酸(3mL)。室温搅拌1h。旋干,重新溶于30mL乙酸乙酯和30mL的饱和碳酸氢钠溶液中,分液,水相用乙酸乙酯萃取,干燥,浓缩得到蜡状固体160mg,收率98%。LCMS[M+1]+=327.2。
将化合物3e(110mg,0.3mmol)和化合物10(72mg,0.2mmol,0.7eq)溶于乙腈(6m1)中,加入K2CO3(104.3mg,0.75mmoL),KI(4.15mg,0.025mmol)。50℃搅拌2h。旋干,flash纯化(PE∶EA=1∶3),得到淡黄色固体49mg。收率:40.0%。LCMS[M+1]+=636.3。
将化合物4e(49mg,0.15mmol)溶于二氯甲烷(3.0ml)中,加入三氟乙酸(3.0mL)。室温搅拌1h。浓缩后用反相C-18柱色谱(甲酸)分离,冻干后得到白色固体12.5mg。收率:31.0%。
1H NMR(400MHz,DMSO)δ11.18(s,1H),8.37(s,1H),7.99(td,J=7.7,1.5Hz,1H),7.95-7.88(m,1H),7.78(d,J=8.5Hz,1H),7.66(dd,J=8.3,5.1Hz,1H),7.46(t,J=8.0Hz,1H),7.40(dd,J=10.0,8.6Hz,1H),7.37-7.29(m,1H),6.41(d,J=8.4Hz,1H),6.24(d,J=7.7Hz,1H),5.04(dd,J=7.1,2.2Hz,1H),4.80(dd,J=15.4,7.1Hz,1H),4.66(dd,J=15.3,2.5Hz,1H),4.50(dd,J=13.6,7.7Hz,2H),4.35(dt,J=9.0,5.9Hz,1H),3.04(s,6H),2.77-2.64(m,1H),2.41-2.27(m,1H)
HRMS(ESI)m/z[M+H]+calcd for C28H30FN6O5S 581.64,found 581.20。
化合物1T,2T
(1)中间体合成
将化合物1b(1.6g,5.4mmol)溶于二氧六环(20mL)中,依次加入1a(1.3g,10.8mmol),BINAP(670mg,1.08mmol),Pd2(dba)3(500mg,0.54mmol)和Cs2CO3(5.4g,16.5mmol)。加热到110℃,在氮气保护下搅拌12h。旋干,柱层析纯化(PE∶EA=5∶1)后浓缩得到淡黄色油状物1.31g。收率:63.7%。LCMS[M+H]+=382.3。
将化合物2b(1.3g,3.4mmoL)在43℃下溶于甲醇(12mL),然后加入到NaOH溶液中(4M,12mL),升温至50℃搅拌7h。乙酸乙酯萃取,干燥,浓缩,柱层析(PE∶EA=1∶1)后浓缩得白色固体0.85g。收率:90.0%。LCMS[M+H]+=279.2。
将化合物3b(0.85g,3.06mmol)溶于DMF(20mL)中,依次加入3a(840mg,3.95mmol,1.3eq)和DIEA(1.1g,8.5mmol,2.78eq),反应体系加热到65℃并搅拌5h。加水稀释,乙酸乙酯萃取,饱和食盐水洗涤,干燥,浓缩,柱层析(PE∶EA=1∶1)后浓缩得淡黄色油状0.83g。收率:72.0%。LCMS[M+H]+=412.2。
将化合物4b(0.83g,2.1mmol)溶于二氯甲烷(15mL)中,加入三氟乙酸(5mL)反应体系在室温下搅拌1h。浓缩,加乙酸乙酯和饱和碳酸氢钠水溶液,分液,水相用乙酸乙酯萃取,有机相用饱和食盐水洗涤,干燥,过滤,浓缩得到蜡状固体0.61g。收率:97.1%。LCMS[M+H]+=312.2。
将化合物5b(80mg,0.25mmol)和5a(108mg,0.32mmol)溶于乙腈(6mL)中,加入K2CO3(104mg,0.75mmol)和KI(4.15mg,0.025mmol)。反应体系在50℃下搅拌2h。加水稀释,用乙酸乙酯萃取,有机相浓缩,柱层析(PE∶EA=1∶2)后浓缩得淡黄色固体112mg。收率:71.3%。LCMS[M+H]+=611.2。
(2)目标化合物合成
将化合物6b(112mg,0.18mmol)溶于二氯甲烷(3mL)中,加入三氟乙酸(3mL)。室温下搅拌1h。浓缩之后得到白色固体123mg,反相C-18柱色谱分离(甲酸)得到白色固体35mg;。收率:34.5%。
1H NMR(400MHz,MeOD)δ8.30(t,J=7.0Hz,1H),7.94(dd,J=8.5,1.4Hz,1H),7.65(d,J=8.5Hz,1H),7.50(t,J=7.8Hz,1H),7.48-7.40(m,2H),7.19(t,J=4.0Hz,1H),5.89(dd,J=17.2,8.0Hz,1H),5.22(ddd,J=14.6,7.2,2.6Hz,1H),4.81(s,1H),4.68(dd,J=15.4,2.6Hz,1H),4.61(td,J=7.9,6.0Hz,1H),4.43(dt,J=9.1,5.9Hz,1H),4.00(d,J=13.8Hz,1H),3.88(d,J=13.8Hz,1H),3.34(t,J=4.8Hz,4H),2.83-2.68(m,1H),2.59-2.43(m,5H)
HRMS(ESI)m/z[M+H]+calcd for C30H31FN7O3 556.62,found 556.24。
将化合物1T(16mg,0.03mmol)溶于甲醇(2mL)中,依次加入HCHO水溶液(0.2mL)、氰基硼氢化钠(10mg)。室温下搅拌2h。浓缩,反相C-18柱色谱分离(甲酸)得到白色固体10mg。收率:60%。
1H NMR(400MHz,DMSO)δ8.39(s,1H),7.98-7.89(m,1H),7.87-7.78(m,2H),7.68-7.59(m,1H),7.45-7.37(m,1H),7.27(dd,J=9.3,6.2Hz,1H),6.16(d,J=8.1Hz,1H),6.07(d,J=8.1Hz,1H),5.07-4.97(m,1H),4.84-4.82(m,5H),4.65(dd,J=18.0,5.0Hz,1H),4.56-4.43(m,2H),4.33(dd,J=6.1,3.0Hz,1H),3.38(d,J=21.1Hz,6H),3.07(s,2H),3.05(s,1H),2.82-2.63(m,2H),2.34(d,J=1.7Hz,1H)
HRMS(ESI)m/z[M+H]+calcd for C31H34FN7O3 570.26,found 570.27。
化合物3T,4T
(1)中间体合成
将化合物7b(1.5g,8.77mmol)溶于二氧六环(25mL)和H2O(5mL)中,依次加入7a(2.5g,8.09mmol),Pd(dppf)Cl2(640mg,0.877mmol)和K2CO3(2.4g,17.4mmol)。N2保护下110℃反应5h。浓缩,柱层析(PE∶EA=3∶1)后浓缩得淡黄色油状物1.1g。收率:45.6%。LCMS[M+H]+=276.2。
将化合物8b(1.1g,4.0mmol)溶于甲醇(25mL)中,在N2保护下加入50%的Pd/C(700mg),H2氛围下室温搅拌5h。用硅藻土过滤掉固体,甲醇洗涤,滤液浓缩,柱层析(PE∶EA=3∶1)后浓缩得淡黄色油状物620mg。收率:56.4%。LCMS[M+H]+=278.2。
将化合物9b(300mg,1.08mmol)溶于DMF(10mL)中,依次加入9a(230mg,1.08mmol)和DIEA(350mg,2.71mmol)。保持50℃搅拌3h。加水稀释,乙酸乙酯萃取,有机相用饱和食盐水洗涤,干燥,浓缩,柱层析(PE∶EA=2∶1)后浓缩得淡黄色固体210mg。收率:47.3%。LCMS[M+H]+=411.5。
1HNMR(400MHz,CDCl3)7.62(t,1H),7.53(t,1H),7.44(d,1H),7.37(d,1H),6.75(d,1H),6.65(d,1H),5.49(s,1H),4.20(br s,2H),2.81((br s,2H),2.70(tt,1H),1.82(d,2H),1.67(d,2H),1.49(s,9H)
将化合物10b(210mg,0.51mmol)溶于二氯甲烷(6mL)中,加入三氟乙酸(2mL)反应体系在室温下搅拌1h。浓缩,加入乙酸乙酯和饱和碳酸氢钠水溶液,分液,乙酸乙酯萃取,饱和食盐水洗涤,干燥,过滤,浓缩得到蜡状固体130mg。收率:81.8%。LCMS[M+H]+=311.2。
将化合物11b(60mg,0.19mmol)和5a(70mg,0.21mmol)溶于乙腈(5mL)中,加入K2CO3(80mg,0.58mmol)和KI(3.21mg,0.019mmol)。保持50℃搅拌2h。加水稀释,乙酸乙酯萃取,有机相浓缩,柱层析(PE∶EA=1∶2)后浓缩得淡黄色固体80mg。收率:76.7%。LCMS[M+H]+=612.2。
(2)目标化合物合成
将化合物12b(80mg,0.13mmol)溶于二氯甲烷(3mL)中,加入三氟乙酸(3mL)。室温下搅拌1h。浓缩,反相C-18柱色谱分离(甲酸),冻干,得到白色固体25mg。收率:34.2%。
1H NMR(400MHz,MeOD)δ8.30(d,J=0.9Hz,1H),7.96(dd,J=8.5,1.4Hz,1H),7.68(d,J=8.5Hz,1H),7.50(d,J=7.8Hz,1H),7.47-7.36(m,1H),7.31(dd,J=8.1,7.4Hz,1H),6.43(d,J=7.2Hz,1H),6.35(d,J=8.2Hz,1H),5.21(ddd,J=14.5,7.1,2.5Hz,1H),4.79(d,J=7.0Hz,1H),4.71-4.53(m,3H),4.42(dt,J=9.2,5.9Hz,1H),4.19(dd,J=31.8,14.2Hz,2H),3.23-3.15(m,1H),2.81-2.67(m,1H),2.59-2.58(m,2H),2.48(ddd,J=9.0,4.1,1.8Hz,1H),1.88-1.72(m,3H)
HRMS(ESI)m/z[M+H]+calcd for C31H32FN6O3 555.63,found 555.23。
将化合物3T(15mg,0.027mmol,1.0eq)溶于甲醇(2mL)中,依次加入HCHO水溶液(0.2mL)、氰基硼氢化钠(10mg)。室温下搅拌2h。浓缩,反相C-18柱色谱分离(甲酸)得到白色固体8mg。收率:52.0%。
1H NMR(400MHz,DMSO)δ12.67(s,1H),8.26(t,J=6.0Hz,1H),7.84(dd,J=10.0,1.5Hz,1H),7.80(dd,J=8.4,1.5Hz,1H),7.64(d,J=8.4Hz,1H),7.61(dd,J=7.9,1.5Hz,1H),7.52-7.42(m,1H),7.30(t,J=7.7Hz,1H),6.49(dd,J=8.3,6.6Hz,2H),5.08(dd,J=7.2,2.5Hz,1H),4.90(s,2H),4.78(dd,J=15.2,7.2Hz,1H),4.63(dd,J=15.2,2.7Hz,1H),4.45(dt,J=14.0,7.0Hz,1H),4.37(dt,J=9.0,5.9Hz,1H),3.92(d,J=13.5Hz,1H),3.74(d,J=13.5Hz,1H),3.06(s,3H),2.94(d,J=10.9Hz,1H),2.79(d,J=10.6Hz,1H),2.72-2.59(m,1H),2.46-2.39(m,2H),2.28-2.06(m,2H),1.72-1.56(m,4H)
HRMS(ESI)m/z[M+H]+calcd for C32H34FN6O3 569.65,found 569.26。
化合物5T
(1)中间体合成
将化合物13b(2g,11.42mmol)溶于乙腈(40mL)中,依次加入13a(1.9g,11.1mmol)和TEA(3.48g,34.4mmol)。50℃搅拌4h。浓缩,柱层析(PE∶EA=5∶1)后浓缩得淡黄色固体2.2g。收率:59.9%。LCMS[M+H]+=329.4。
微波管中,将化合物14b(1g,3.07mmol)溶于二氧六环(20mL)中,依次加入14a(0.7g,4.6mmol),xantphos(355mg,0.61mmol),Pd2(dba)3(290mg,0.32mmol)和Cs2CO3(2.5g,7.62mmol)。反应体系用N2吹扫置换,在微波反应仪中加热到130℃,反应2h。旋干,柱层析(PE∶EA=2∶1)后浓缩得到淡黄色油状690mg。收率:56.6%。LCMS[M+H]+=398.2。
将化合物15b(650mg,1.64mmol)溶于四氢呋喃(10mL)中,加入LiOH.H2O(0.5M,10mL)。40℃搅拌12h。加入1.0M HCl调节pH=4~5,用乙酸乙酯萃取,有机相浓缩,反相C-18柱色谱分离(甲酸),冻干,得到白色固体250mg。收率:41.4%。LCMS[M+H]+=370.2。
将化合物16b(100mg,0.27mmol),HATU(113mg,0.3mmol),DIPEA(100mg,0.78mmol)溶于DMF(4mL)中,40℃搅拌1h,然后加入16a(75mg,0.27mmol),反应体系在40℃搅拌3h。加水稀释,乙酸乙酯萃取,有机相用饱和食盐水洗涤,干燥,过滤,浓缩。反相C-18柱色谱分离(甲酸),冻干得到浅黄色固体105mg。收率:61.7%。LCMS[M+H]+=630.2。
将化合物17b(105mg,0.17mmol)溶于HOAc(4mL)中。反应体系在70℃搅拌2h。浓缩,反相C-18柱色谱分离(甲酸),冻干得到黄色固体65mg。收率:63.7%。LCMS[M+H]+=612.2。
(2)目标化合物合成
将化合物18b(30mg,0.05mmol)溶于二氯甲烷(2mL)中,加入三氟乙酸(2mL)。反应体系在室温下搅拌1h。浓缩,反相C-18柱色谱分离(甲酸),冻干,得到白色固体6mg。收率:22.1%。
1H NMR(400MHz,MeOD)δ8.23(d,J=1.0Hz,1H),7.94(dd,J=8.5,1.5Hz,1H),7.62(d,J=8.5Hz,1H),7.59(d,J=7.6Hz,1H),7.54-7.47(m,2H),7.39(t,J=8.0Hz,1H),6.25(d,J=8.1Hz,1H),6.06(d,J=7.8Hz,1H),5.40(s,2H),5.15(dd,J=7.3,2.5Hz,1H),4.70-4.53(m,2H),4.48(dd,J=15.6,2.6Hz,1H),4.41-4.30(m,1H),4.21(d,J=12.9Hz,2H),2.94(dd,J=7.3,1.5Hz,2H),2.81-2.68(m,3H),2.52-2.36(m,1H),2.30-2.17(m,1H),1.72(d,J=11.1Hz,2H),1.30-1.26(m,4H)
HRMS(ESI)m/z[M+H]+calcd for C31H31FN5O4 556.61,found 556.23。
化合物6T
(1)中间体合成
微波管中,将化合物14b(0.8g,2,45mmol)溶于二氧六环(20mL)中,依次加入19a(450mg,3.13mmol),xantphos(290mg,0.5mmol),Pd2(dba)3(230mg,0.25mmol)和Cs2CO3(2.0g,6.1mmol)。反应体系用N2吹扫置换,在微波反应仪中加热至130℃,反应2h。旋干,柱层析(PE∶EA=2∶1)后浓缩得到淡黄色油状物510mg。收率:53.3%。LCMS[M+H]+=391.2。
将化合物19b(510mg,1.31mmol)溶于四氢呋喃(8mL)中,加入LiOH.H2O水溶液(0.5M,8mL)。40℃搅拌12h。加入1.0M HCl调节pH=4~5,用乙酸乙酯萃取,有机相浓缩,反相C-18柱色谱分离(甲酸),冻干,得到白色固体210mg。收率:44.4%。LCMS[M+H]+=363.2。
将化合物20b(100mg,0.28mmol),HATU(115mg,0.30mmol),DIPEA(108mg,0.84mmol)溶于DMF(4mL)中,40℃搅拌1h,然后加入16a(78mg,0.28mmol),40℃搅拌3h。加水稀释,乙酸乙酯萃取,有机相用食盐水洗涤,干燥,过滤,浓缩,反相C-18柱色谱分离(甲酸),冻干,得到浅黄色固体92mg。收率:53.5%。LCMS[M+H]+=623.2。
将化合物21b(92mg,0.15mmol)溶于HOAc(3mL)中。反应体系在70℃搅拌2h。浓缩,反相C-18柱色谱分离(甲酸),冻干,得到白色固体55mg。收率:61.8%。LCMS[M+H]+=605.3。
将化合物22b(55mg,0.05mmol)溶于二氯甲烷(2mL)中,加入三氟乙酸(2mL)。反应体系在室温下搅拌1h。浓缩,反相C-18柱色谱分离(甲酸)得到白色固体33mg。收率:66.1%。LCMS[M+H]+=549.2。
1H NMR(400MHz,MeOD)δ8.24(d,J=1.0Hz,1H),7.94(dd,J=8.5,1.5Hz,1H),7.62(d,J=8.4Hz,1H),7.51-7.41(m,1H),7.37(t,J=8.0Hz,1H),6.90(ddt,J=8.4,6.2,2.9Hz,2H),6.24(d,J=8.1Hz,1H),6.01(d,J=7.8Hz,1H),5.29(s,2H),5.15(dd,J=7.3,2.5Hz,1H),4.68-4.54(m,2H),4.49(dd,J=15.6,2.6Hz,1H),4.37(dt,J=9.2,5.9Hz,1H),4.28(d,J=13.1Hz,2H),2.96(dd,J=7.3,1.9Hz,2H),2.86-2.69(m,3H),2.51-2.40(m,1H),2.26(ddd,J=11.3,7.6,3.7Hz,1H),1.76(d,J=11.5Hz,2H),1.33(ddd,J=24.8,12.4,3.9Hz,2H)
HRMS(ESI)m/z[M+H]+calcd for C30H31F2N4O4 549.59,found 549.23。
化合物7T
(1)中间体合成
微波管中,将化合物23b(500mg,3.4mmol)溶于NMP(10mL)中,依次加入14a(513mg,3.4mmol)和Cs2CO3(1.4g,4.26mmol)。在微波仪中加热到120℃,反应2h。加水稀释,乙酸乙酯萃取,有机相用食盐水洗涤,干燥,过滤,浓缩,柱层析(PE∶EA=5∶1)后浓缩得到淡黄色油状603mg。收率:67.6%。LCMS[M+H]+=266.3。
将化合物24b(600mg,2.28mmoL)溶于二氧六环(10mL)和H2O(2mL)中,依次加入7a(705mg,2.28mmoL),Pd(dppf)Cl2(167mg,0.228mmol)和K2CO3(623mg,4.51mmol)。N2保护下加热到110℃并搅拌5h。浓缩,柱层析(PE∶EA=5∶1)后浓缩得淡棕色油状560mg。收率:59.9%。LCMS[M+H]+=411.2。
将化合物25b(560mg,1.37mmol)溶于乙酸乙酯(15mL)中,N2保护下加入50%Pd/C(300mg),在H2气氛下室温搅拌2h。用硅藻土过滤掉固体,乙酸乙酯洗涤,滤液浓缩,柱层析(PE∶EA=3∶1)后浓缩得淡黄色油状410mg。收率:73.2%。LCMS[M+H]+=413.2。
将化合物26b(410mg,0.996mmol)溶于二氯甲烷(6mL)中,加入三氟乙酸(2mL),室温下搅拌1h。浓缩,加入乙酸乙酯和饱和碳酸氢钠水溶液,分液,水相用乙酸乙酯萃取,饱和食盐水洗涤,干燥,过滤,浓缩得到蜡状固体200mg。收率:64.1%。LCMS[M+H]+=313.2。
将化合物27b(60mg,0.19mmol)和5a(70mg,0.21mmol)溶于乙腈(5mL)中,加入K2CO3(80mg,0.58mmol)和KI(3.21mg,0.019mmol)。反应体系在50℃下搅拌2h。加水稀释,用乙酸乙酯萃取,有机相浓缩,柱层析(PE∶EA=1∶2)后浓缩得淡黄色固体80mg。收率:68.3%。LCMS[M+H]+=612.2。
将化合物28b(50mg,0.08mmol)溶于二氯甲烷(3mL)中,加入三氟乙酸(2mL)。反应体系在室温下搅拌1h。浓缩,反相C-18柱色谱分离(甲酸)得到白色固体23mg。收率:51.1%。
1H NMR(400MHz,MeOD)δ8.31(d,J=0.8Hz,1H),8.08(d,J=13.8Hz,2H),7.95(dd,J=8.5,1.5Hz,1H),7.67(dd,J=11.6,7.9Hz,2H),7.56(ddd,J=9.4,8.8,1.4Hz,2H),5.54(s,2H),5.25(dd,J=7.3,2.5Hz,1H),4.91-4.85(m,1H),4.71(dd,J=15.3,2.7Hz,1H),4.66-4.56(m,1H),4.46-4.44(m,1H),4.09-3.95(m,2H),3.17-3.05(m,1H),3.00(d,J=11.6Hz,1H),2.83-2.75(m,2H),2.57-2.44(m,1H),2.44-2.26(m,2H),1.92-1.78(m,3H)
HRMS(ESI)m/z[M+H]+calcd for C30H30FN6O4 557.60,found 557.23。
化合物8T
(1)中间体合成
微波管中,将化合物29b(2g,13.6mmol)溶于NMP(25mL)中,依次加入14a(2.05g,13.6mmol)和Cs2CO3(4.77g,14.5mmol)。反应体系在微波仪中加热到120℃,反应2h。加水稀释,乙酸乙酯萃取,有机相用食盐水洗涤,干燥,过滤,浓缩,柱层析(PE∶EA=5∶1)后浓缩得到淡黄色油状物2.4g。收率:67.0%。LCMS[M+H]+=266.3。
将化合物30b(2g,7.6mmol)溶于二氧六环(25mL)和H2O(5mL)中,依次加入7a(2.5g,8.1mmol),Pd(dppf)Cl2(555mg,0.759mmol)和K2CO3(2.1g,15.2mmol)。反应体系在N2保护下加热到110℃并搅拌5h。浓缩,柱层析(PE∶EA=5∶1)后浓缩得淡棕色油状物1.8g。收率:57.7%。LCMS[M+H]+=411.3。
将化合物31b(1.8g,4.4mmol)溶于乙酸乙酯(60mL)中,在N2保护下加入50%的Pd/C(1.2g),反应体系在H2气氛下,室温搅拌6h。用硅藻土过滤掉固体,乙酸乙酯洗涤,滤液浓缩,柱层析(PE∶EA=3∶1)后浓缩得淡黄色油状1.4g。收率:77.8%。LCMS[M+H]+=413.3。
将化合物32b(1.4g,3.4mmol)溶于二氯甲烷(20mL)中,加入三氟乙酸(15mL)反应体系在室温下搅拌1h。浓缩,加入乙酸乙酯和饱和碳酸氢钠水溶液,分液,水相用乙酸乙酯萃取,有机相用食盐水洗涤,干燥,过滤,浓缩得到浅黄色固体690mg。收率:65.1%。LCMS[M+H]+=313.1。
将化合物33b(200mg,0.64mmol)和5a(235mg,0.70mmol)溶于乙腈(8mL)中,加入K2CO3(220mg,1.59mmol)和KI(10.6mg,0.064mmol)。反应体系在50℃下搅拌3h。加水稀释,用乙酸乙酯萃取,有机相浓缩,柱层析(PE∶EA=1∶2)后浓缩得淡黄色固体250mg。收率:63.9%。LCMS[M+H]+=612.3。
(2)目标化合物合成
将化合物34b(150mg,0.245mmol)溶于二氯甲烷(5mL)中,加入三氟乙酸(5mL)。反应体系在室温下搅拌1h。浓缩,反相C-18柱色谱分离(甲酸),冻干,得到白色固体70mg。收率:51.0%。
1H NMR(400MHz,MeOD)δ8.39(d,J=5.9Hz,1H),8.31(d,J=1.0Hz,1H),7.95(dd,J=8.5,1.5Hz,1H),7.71-7.63(m,2H),7.57(ddd,J=9.4,8.8,1.4Hz,2H),6.77(d,J=5.9Hz,1H),5.58(s,2H),5.24(dd,J=7.4,2.5Hz,1H),4.88-4.86(m,1H),4.70(dd,J=15.4,2.6Hz,1H),4.62(td,J=7.9,6.0Hz,1H),4.45(dt,J=9.2,5.9Hz,1H),4.15-4.02(m,2H),3.16(d,J=11.6Hz,1H),3.06(d,J=11.4Hz,1H),2.91-2.71(m,2H),2.58-2.39(m,3H),2.05-1.85(m,4H)
HRMS(ESI)m/z[M+H]+calcd for C30H30FN6O4 557.60,found 557.23。
化合物9T
将化合物8T(22mg,0.040mmol)溶于DMF(3.0mL)中,加入HATU(16.6mg,0.043mmol),DIPEA(15mg,0.116mmol)。室温搅拌10min,接着加入NH3/DMF(1M,0.12mL,0.12mmol),室温搅拌1h。加水稀释,乙酸乙酯萃取,有机相用食盐水洗涤,干燥,过滤,浓缩,反相C-18柱色谱分离(甲酸)得到白色固体12mg。收率:54.8%。
1H NMR(400MHz,DMSO)δ8.49(d,J=5.8Hz,1H),8.20(s,1H),7.92(d,J=10.0Hz,2H),7.80-7.68(m,3H),7.60(d,J=8.4Hz,1H),7.30(s,1H),6.86(d,J=5.8Hz,1H),5.55(s,2H),5.13(dd,J=7.1,3.0Hz,1H),4.79(dd,J=15.1,7.2Hz,1H),4.64(dd,J=15.1,3.2Hz,1H),4.56-4.46(m,1H),4.42(dt,J=9.0,6.0Hz,1H),3.95(d,J=13.5Hz,1H),3.78(d,J=13.4Hz,1H),3.31(s,3H),2.96(d,J=11.2Hz,1H),2.84(d,J=11.2Hz,1H),2.79-2.64(m,2H),2.49-2.39(m,1H),2.32-2.10(m,2H),1.89(t,J=11.6Hz,2H),1.84-1.61(m,2H)
HRMS(ESI)m/z[M+H]+calcd for C30H31FN7O3 556.61,found 556.27。
化合物10T
将化合物8T(35mg,0.063mmol)溶于DMF(3.0mL)中,加入HATU(26mg,0.068mmol),DIPEA(25mg,0.194mmol)。室温搅拌10min,接着加入甘氨酸叔丁酯(16.5mg,0.126mmol),室温搅拌1h。加水稀释,乙酸乙酯萃取,有机相用食盐水洗涤,干燥,过滤,浓缩,反相C-18柱色谱分离(甲酸)得到白色固体27mg。收率:64.3%。LCMS[M+H]+=669.3。
将化合物35b(27mg,0.04mmol)溶于二氯甲烷(2mL)中,加入三氟乙酸(2mL)。反应体系在室温下搅拌1h。浓缩得白色固体28mg。反相C-18柱色谱分离(甲酸)得到白色固体16mg。收率:64.8%。
1H NMR(400MHz,DMSO)δ12.25(s,1H),8.78(t,J=5.8Hz,1H),8.50(d,J=5.8Hz,1H),8.20(s,1H),7.92(d,J=10.2Hz,1H),7.74(dd,J=5.7,3.2Hz,2H),7.65(d,J=8.4Hz,1H),6.87(d,J=5.7Hz,1H),5.55(s,2H),5.14(dd,J=7.1,2.9Hz,1H),4.80(dd,J=15.2,7.2Hz,1H),4.65(dd,J=15.1,3.0Hz,1H),4.56-4.47(m,1H),4.47-4.37(m,1H),3.97(d,J=5.7Hz,2H),3.79(d,J=5.0Hz,1H),3.31(s,4H),3.00(s,2H),2.79-2.63(m,2H),2.26(s,2H),1.92(s,2H),1.78(s,2H)
HRMS(ESI)m/z[M+H]+calcd for C32H33FN7O5 614.65,found 614.25。
化合物11T
将化合物33b(35mg,0.112mmol)和33a(43mg,0.123mmol)溶于乙腈(4mL)中,加入K2CO3(38mg,0.275mmol)和KI(1.9mg,0.011mmol)。反应体系在50℃下搅拌2h。加水稀释,用乙酸乙酯萃取,有机相浓缩,柱层析(PE∶EA=1∶2)后浓缩得淡黄色油状物36mg。收率:51.4%。LCMS[M+H]+=626.3。
将化合物36b(35mg,0.056mmol)溶于二氯甲烷(2mL)中,加入三氟乙酸(2mL)。反应体系在室温下搅拌1h。浓缩,反相C-18柱色谱分离(甲酸)得到白色固体19mg。收率:59.7%。
1H NMR(400MHz,DMSO)δ12.65(s,1H),8.49(d,J=5.8Hz,1H),8.23(d,J=1.0Hz,1H),7.92(d,J=10.2Hz,1H),7.80(dd,J=8.4,1.5Hz,1H),7.77-7.67(m,2H),7.64(d,J=8.4Hz,1H),6.86(d,J=5.8Hz,1H),5.54(s,2H),4.57(dd,J=14.8,3.1Hz,1H),4.48(dd,J=14.8,8.1Hz,1H),4.26(dd,J=7.6,2.9Hz,1H),3.99(d,J=13.4Hz,1H),3.82(dd,J=14.8,6.9Hz,1H),3.73(d,J=13.3Hz,1H),3.64(td,J=7.7,6.2Hz,1H),2.98(d,J=10.0Hz,1H),2.82(d,J=9.9Hz,1H),2.73(t,J=11.4Hz,1H),2.23(d,J=37.2Hz,2H),2.13-1.96(m,1H),1.93-1.77(m,5H),1.75-1.57(m,2H)
HRMS(ESI)m/z[M+H]+calcd for C31H32FN6O4 571.63,found 571.24。
化合物12T
(1)中间体合成
将三甲基碘化亚砜(22g,100mmol)溶于叔丁醇(250mL)中,在N2保护下加入叔丁醇钾(11.2g,100mmol),搅拌30min后加入1c(8.1g,50mmol)反应体系在60℃搅拌6h。加水稀释,萃取,柱层析,得到7.3g无色液体,收率:90%。
将化合物2c(4g,22.47mmol)溶于乙酸乙酯(60mL)中,在N2保护下加入10%的Pd/C(1.2g),反应体系在H2气氛围下,室温搅拌6h。用硅藻土过滤掉固体,乙酸乙酯洗涤,滤液浓缩,柱层析(PE∶EA=20∶1)后浓缩得淡黄色油状物1.7g。收率:86.3%。
将化合物3c(1.7g,19.3mmol)溶于四氢呋喃(50mL)中,在0℃下依次加入TEA(5.85g,57.9mmo)、Ms2O(3.7g,21.3mmol)。室温搅拌3h。浓缩,柱层析(PE∶EA=20∶1)后浓缩得淡黄色油状1.8g。收率:56.3%。
将化合物5c(1g,4.5mmol)溶于DMF(15mL)中,依次加入4c(0.82g,4.9mmol),Cs2CO3(1.8g,5.5mmol)和KI(75mg,0.45mmol)。60℃搅拌17h。加水稀释,用乙酸乙酯萃取,饱和食盐水洗涤,干燥,过滤,浓缩,柱层析(PE∶EA=10∶1)后浓缩得淡黄色油状物910mg。收率:68.9%。
微波管中,将化合物6c(1.5g,5mmol)溶于二氧六环(10mL)中,依次加入甲酸苯酯(1.32g,10mmol),xantphos(620mg,1mmol),Pd(AcO)2(390mg,0.5mmo)和三乙胺(1mL)。反应体系用N2吹扫置换,在微波反应仪中加热到130℃,反应2h。旋干,柱层析(PE∶EA=4∶1)后浓缩得到淡黄色固体1.5g。收率:70.1%。
1H NMR(400MHz,CDCl3):δ9.58(s,1H),8.01(d,J=7.0Hz,1H),7.88(s,1H),7.80(d,J=7.0Hz,1H),7.66-7.40(m,3H),7.38-7.31(m,2H),5.11-5.03(m,1H)4.71-4.54(m,2H),4.51-4.44(m,1H),4.37-4.29(m,1H),2.3-2.64(m,1H),2.39-2.29(m,1H)
微波管中,将化合物1b(60mg,0.202mmol)溶于二氧六环(3mL)中,依次加入14a(45mg,0.298mmol),xantphos(24mg,0.041mmol),Pd2(dba)3(19mg,0.021mmol)和Cs2CO3(166mg,0.506mmol)。反应体系用N2吹扫置换,在微波反应仪中加热到130℃,反应2h。旋干,柱层析(PE∶EA=2∶1)后浓缩得到淡黄色油状50mg。收率:60.1%。LCMS[M+H]+=413.2。
将化合物37b(100mg,0.243mmol)溶于二氯甲烷(4mL)中,加入三氟乙酸(4mL)。反应体系在室温下搅拌1h。浓缩,柱层析(PE∶EA=1∶2)后浓缩得到无色油状物47mg。收率:62.1%。LCMS[M+H]+=413.1。
将化合物38b(45mg,0.15mmol)和化合物7c(78mg,0.286mmol)溶于二氯乙烷(5mL)中,反应体系在室温下搅拌20min。然后加入醋酸硼氢化钠(36mg,0.573mmol)。反应体系加热至30℃并搅拌24h。加入0.1MHCl调节pH=4~5,搅拌5min。二氯甲烷萃取,浓缩,柱层析(PE∶EA=1∶2)后浓缩得到无色油状物17mg。收率:20.7%。LCMS[M+H]+=632.3。
将化合物39b(15mg,0.026mmol)溶于四氢呋喃(2mL)中,加入LiOH.H2O水溶液(0.1M,1mL)。40℃搅拌12h.加入0.2MHCl调节pH=4~5,用乙酸乙酯萃取,浓缩,反相C-18柱色谱分离(甲酸),冻干,得到白色固体8mg。收率:54.8%。
1H NMR(400MHz,DMSO)δ12.37(s,1H),8.17(s,1H),7.88(dd,J=10.0,1.1Hz,1H),7.70(dd,J=7.9,1.3Hz,1H),7.66(d,J=7.3Hz,1H),7.63(dd,J=8.2,1.4Hz,1H),7.55(d,J=8.3Hz,1H),7.48(t,J=8.0Hz,1H),6.50(s,1H),6.34(d,J=8.2Hz,1H),6.13(d,J=7.8Hz,1H),5.40(s,2H),5.05(dd,J=7.2,2.6Hz,1H),4.72(dd,J=15.3,7.1Hz,1H),4.56(dd,J=15.4,2.5Hz,1H),4.47(dd,J=10.5,5.0Hz,1H),4.36(dt,J=9.0,5.8Hz,1H),3.84(d,J=13.7Hz,1H),3.66(d,J=13.7Hz,1H),3.42(s,3H),3.31(s,3H),2.77-2.60(m,2H),2.47-2.43(m,3H),2.41-2.33(m,1H)
HRMS(ESI)m/z[M+H]+calcd for C31H31FN5O4 556.61,found 556.23。
化合物13T
将化合物36(45mg,0.15mmol)和化合物7c(78mg,0.286mmol)溶于二氯乙烷(5mL)中,反应体系在室温下搅拌20min。加入醋酸硼氢化钠(36mg,0.573mmol)。反应体系加热至30℃并搅拌24h。加入0.1M HCl调节pH=4~5,搅拌5min,用二氯甲烷萃取,浓缩,柱层析(PE∶EA=1∶2)后浓缩得到无色油状物27mg。收率:33%。LCMS[M+H]+=631.3。
将化合物40b(27mg,0.042mmol)溶于四氢呋喃(2mL)中,加入LiOH.H2O水溶液(0.1M,1mL)。40℃搅拌12h。加入0.2M HCl调节pH=4~5,用乙酸乙酯萃取,浓缩,反相C-18柱色谱分离(甲酸),冻干,得到白色固体8mg。收率:38%。LCMS[M+H]+=555.2。
1H NMR(400MHz,DMSO)δ12.42(s,1H),8.17(s,1H),7.89(d,J=10.1Hz,1H),7.70(d,J=3.0Hz,2H),7.64(dd,J=16.9,8.8Hz,2H),7.54(d,J=8.3Hz,1H),6.89(d,J=7.3Hz,1H),6.73(d,J=8.2Hz,1H),6.48(s,1H),5.48(s,2H),5.12-5.01(m,1H),4.73(dd,J=15.3,7.0Hz,1H),4.58(dd,J=15.2,2.3Hz,1H),4.47(dd,J=13.6,7.6Hz,1H),4.36(dt,J=9.0,5.8Hz,1H),3.82(d,J=13.7Hz,1H),3.64(d,J=13.6Hz,1H),3.31(s,3H),2.99(d,J=10.8Hz,1H),2.88(d,J=10.9Hz,1H),2.75-2.65(m,1H),2.62-2.56(m,1H),2.48-2.35(m,1H),2.15-2.04(m,2H),1.85-1.58(m,4H)
HRMS(ESI)m/z[M+H]+calcd for C32H32FN4O4 555.62,found 555.24。
化合物14T
将化合物33b(62mg,0.20mmol)和化合物7c(78mg,0.286mmol)溶于二氯乙烷(5mL)中,室温搅拌20min.然后加入醋酸硼氢化钠(36mg,0.573mmol)。加热至30℃搅拌24h。加入0.1MHCl调节pH=4~5,搅拌5min。二氯甲烷萃取,浓缩,柱层析(PE∶EA=1∶2)后浓缩得到无色油状物36mg。收率:30.7%。LCMS[M+H]+=632.3。
将化合物41b(26.5mg,0.042mmol)溶于四氢呋喃(2mL)中,加入LiOH.H2O水溶液(0.1M,1mL)。40℃搅拌12h。加入0.2MHCl调节pH=4~5,用乙酸乙酯萃取,浓缩,反相C-18柱色谱分离(甲酸),冻干,得到白色固体6.6mg。收率:28.3%。
1H NMR(400MHz,DMSO)δ8.49(d,J=5.8Hz,1H),8.16(s,1H),7.92(d,J=10.1Hz,1H),7.77-7.70(m,2H),7.63(d,J=8.2Hz,1H),7.52(d,J=8.2Hz,1H),6.86(d,J=5.8Hz,1H),6.46(s,1H),5.55(s,2H),5.06(t,J=6.9,4.2Hz,1H),4.72(dd,J=15.3,7.0Hz,1H),4.57(dd,J=15.3,2.5Hz,1H),4.47(dt,J=13.6,7.0Hz,1H),4.36(dt,J=9.0,5.9Hz,1H),3.82(d,J=13.7Hz,1H),3.63(d,J=13.7Hz,1H),2.96(d,J=11.1Hz,1H),2.86(d,J=10.9Hz,1H),2.78-2.59(m,2H),2.47-2.36(m,1H),2.19-2.07(m,2H),2.05-1.94(m,1H),1.89(t,J=11.1Hz,2H),1.83-1.66(m,2H)
HRMS(ESI)m/z[M+H]+calcd for C31H31FN5O4 556.61,found 556.23。
二、生物活性评价
本发明提供了调节胰高血糖素样肽-1(GLP-1)受体的新化合物,其合成方法,及其制药用途。所提供的新化合物对于GLP-1受体具有明显的激动作用,其EC50值达到nm水平。而且,活性化合物对于hERG没有明显的结合作用,表明具有较低的心脏毒性风险。本发明化合物可以作为糖尿病治疗药物单独使用,或者与利拉鲁肽等多肽类GLP-1受体激动剂联合使用,或者与其他机制的治疗II型糖尿病的药物联合使用。
1、GLP-1受体激动体外活性评价
通过高表达GLP-1受体的HEK293细胞cAMP含量的变化,表征化合物对GLP-1受体的激动活性。使用cAMP检测试剂盒(Cisbio Cat#62AM4PEJ),测试原理可参见Cisbio CAMP-GSDYNAMIC KIT说明书。
准备化合物:使用Bravo液体处理平台,DMSO为溶剂,待测化合物从100μm起始浓度,对照化合物从0.5μm起始浓度,分别4倍梯度稀释,各取10个数据点。将100nL化合物转移到OptiPlate-384孔板,2000rpm混匀60sec。
制备细胞悬液:37℃水浴快速解冻细胞,将细胞悬液转移到10mL HBSS中,并置于15mL的锥形管中,1000rpm室温离心5min;吸取上清液,轻弹使细胞团块松散,将细胞重悬于10mLHBSS中;计算细胞浓度,并测定细胞存活率;以2.0x105/mL浓度将细胞重悬于缓冲液中。
激动剂的HTRF cAMP测定:使用电子多通道移液器将10μL细胞悬液加入到测试板中,1000rpm混匀60sec,在室温下孵育30min后,每孔加入5μL检测试剂;用封板膜覆盖,室温孵育60min;移除封板膜,使用EnVision(PerkinElmer)读数,计算EC50值,其中+++++表示1-2nm之间,++++表示2-5nm之间,+++表示5-20nm之间,++表示20-1000nm之间,+表示1-10μM。如表1所示。
表1示例性化合物对GLP-1激动活性EC50值(nm)
2、hERG结合作用体外活性评价
human Ether-a-go-go Related Gene(hERG基因)编码心肌延迟整流钾通道电流,研究发现,部分药物对hERG钾通道产生抑制作用,导致心脏QT间期延长,诱发心律失常。通过检测化合物对bERG的结合力可以初步评估化合物的潜在心脏毒性风险。
通过在高表达hERG基因的CHO细胞上检测化合物与[3H]Dofetilide对bERG的竞争性结合,评价化合物对于hERG的结合作用。
待测化合物从2mM起始浓度,对照化合物从0.2mM起始浓度,DMSO为溶剂,分别4倍梯度稀释,各取8个数据点。将1μL化合物转移到试验板,加入100μL hERG/CHO细胞,加入100μL[3H]Dofetilide,封板,室温孵育1h。每孔使用0.5%BSA 50μL在室温下至少浸泡0.5h。结合试验完成后,过滤反应混合物,洗涤,将测试板在50℃干燥1小时。随后,密封滤板孔底部,加入50μL Perkin Elmer Microscint 20 cocktail,再密封滤板孔顶部。使用PerkinElmer MicroBeta2阅读器计数3H,计算IC50值,如表2所示。
表2示例性化合物对hERG的结合作用IC50值(nm)
注:PF指的是化合物PF-06882961,恩格指恩格列净,达格指达格列净
3、心血管获益作用体内评价
实验动物:8周龄雄性Wistar大鼠,实验前先饲养一周,以适应环境。
实验用药:本发明化合物、现有技术化合物通过左股静脉注射给药,按1mg/Kg。对照组通过左股静脉注射生理盐用。
实验分组:一周后将大鼠分为四组,每组12只,分别是空白对照组:以生理盐水作用媒介给药;缺血前预给药组:在心肌缺血前15分钟给予本发明化合物;缺血中给药组:在心脏缺血期15分钟时给予本发明化合物;缺血再灌注给药组:在再灌注开始时给予本发明化合物。
缺血再灌注模型:麻醉大鼠,气管造口术之后,用啮齿动物呼吸机的室内空气给大鼠通风,在第四肋间隙行左侧开胸手术,切开心包膜以暴露心脏。结扎在距其起点0.2cm的左冠状动脉前降支(LAD)处进行。II导联心电图上的ST段抬高和心肌组织的颜色变化用于确认成功的缺血,并且缺血持续30分钟。然后,释放绑带以诱导再灌注2h。
功能观察:
心律失常评分:由II导心电图(ECG)评估。
缺血面积:在缺血再灌注结束时,立即切除心脏,以进行心肌梗塞大小的测量和心肌组织的研究。再灌注2小时后,处死大鼠并迅速摘除心脏。重新封堵LAD,并通过1毫升Evan的蓝色染料灌注来评估心脏的LV危险区域(AAR)。将心脏在-20℃下放置过夜,然后以1-2mm的厚度水平切开。之后,将心脏切片浸入磷酸盐缓冲盐溶液中的2,3,5-三苯基四唑氯化物(TTC)中。TTC染色区域表示活组织,其通过红色排列检测到。通过没有被任何染料染色的白色区域来识别梗塞大小。根据Reiss等人的公式计算心肌梗塞面积。
心脏线粒体功能测量:用冷的生理盐水冲洗心脏。从远端和局部缺血的心肌组织中分离并收集心脏线粒体,以确定心脏线粒体的功能。记录的变量包括心脏线粒体活性氧(ROS)水平,心脏线粒体膜电位变化和心脏线粒体肿胀。2′,7′-二氯荧光素荧光强度的增强表明线粒体ROS产生增加,这与氧化应激水平的增加有关。JC-1染料的红色/绿色荧光强度比率降低表明线粒体膜去极化增加。最后,线粒体吸光度在540nm处的衰减意味着线粒体肿胀。就线粒体功能而言,预处理组和缺血组大鼠的活性氧(ROS)产量均显着降低,吸收强度增加,线粒体肿胀较少。
以上心血管获益可以表明能够降低心血管不良事件,不仅可以降低患者心肌梗死的发生率,而且可以降低心血管死亡、降低非致死性心肌梗死、降低卒中发生率,降低心血管死亡风险,以及降低心衰风险的住院率,以及降低因心力衰竭而住院的频率,能够降低患者发生心肌梗死和卒中的风险,能够降低射血分数降低的成人心力衰竭的心血管死亡风险和因心力衰竭住院的风险(NYHA II-IV级)。无论是在射血分数、纽约心功能分级II~IV级的心衰患者中,无论是否合并糖尿病,本发明所指示的化合物均可以降低主要终点事件发生率(CVD导致的死亡或心衰恶化),降低心衰恶化风险、降低心血管死亡风险。
表3-1
表3-2
注:PF指的是化合物PF-06882961,恩格指恩格列净,达格指达格列净
表3-3
表3-4
表3-5
本发明提供的化合物不仅具有糖尿病的治疗用途,而且具有降低心血管不良事件,或者降低2型糖尿病中的心血管不良事件的制药用途。所述的降低心血管不良事件包括能够降低患者心肌梗死的发生率,以及因心力衰竭而住院的频率,能够降低患者发生心肌梗死和卒中的风险,能够降低射血分数降低的成人心力衰竭的心血管死亡风险和因心力衰竭住院的风险(NYHA II-IV级)。
Claims (7)
3.根据权利要求1-2所述的GLP-1受体调节剂,其特征在于:所述化合物具有心血管保护作用,或者降低心血管不良事件,或者降低2型糖尿病中的心血管不良事件的制药用途。
4.根据权利要求3所述的GLP-1受体调节剂,其特征在于:所述的降低心血管不良事件包括能够降低患者心肌梗死的发生率,或者因心力衰竭而住院的频率,或者能够降低患者发生心肌梗死和卒中的风险,或者能够降低射血分数降低的成人心力衰竭的心血管死亡风险和因心力衰竭住院的风险(NYHA II-IV级)。
5.根据权利要求3所述的GLP-1受体调节剂,其特征在于:所述的降低心血管不良事件包括降低心血管死亡、降低非致死性心肌梗死、降低卒中发生率,降低心血管死亡风险,以及降低心衰风险的住院率。
6.根据权利要求1-5任一所的GLP-1受体调节剂,其特征在于:所述化合物与SGTL1和/或SGLT2化物组合使用。
7.根据权利要求6所述的GLP-1受体调节剂,其特征在于:所述的SGTL1和/或SGLT2化合物为恩格列净和达格列净。
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