CN111868055A - Trpc6的抑制剂 - Google Patents
Trpc6的抑制剂 Download PDFInfo
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- CN111868055A CN111868055A CN201980017013.0A CN201980017013A CN111868055A CN 111868055 A CN111868055 A CN 111868055A CN 201980017013 A CN201980017013 A CN 201980017013A CN 111868055 A CN111868055 A CN 111868055A
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- pharmaceutically acceptable
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- alkyl
- acceptable salt
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Abstract
本发明涉及式(I)的多环化合物及其药学上可接受的盐,其中R1至R4、R7至R10、Y和A如本文所定义。本发明还涉及包含这些化合物的药物组合物、在治疗多种疾病和病症中使用这些化合物的方法、用于制备这些化合物的方法和可用于这些方法的中间体。
Description
技术领域
本发明涉及用于治疗心脏和呼吸系统病况、肾脏疾病、肝脏疾病、肌肉萎缩症、纤维化病症、疼痛、缺血或缺血再灌注损伤和癌症以及抑制瞬时受体电位C6离子通道(TRPC6)的药物化合物、组合物和方法。
背景技术
存在多种离子通道蛋白来介导跨细胞膜的离子通量。离子通道蛋白的正确表达和功能对于维持细胞功能、细胞内通讯等至关重要。实现细胞稳态的一个重要方面是在发育过程中以及对多种刺激的反应中,维持各种细胞类型中适当的离子浓度。大量不同类型的离子通道通过使离子跨过质膜移入和移出细胞以及在细胞内使离子移动跨过细胞内细胞器(包括例如内质网、肌质网、线粒体和内吞细胞器(包括核内体和溶酶体))的膜,来维持细胞稳态。许多疾病是膜电位调节异常或钙处理异常的结果。考虑到离子通道在调节细胞中的膜电位和离子通量方面的重要性,作为研究工具和可能的治疗剂,鉴定能够促进或抑制特定离子通道的试剂非常重要。
一种此类通道是瞬态受体电位C6(TRPC6)通道。TRPC6属于更大的TRP离子通道家族(参见Desai等人,2005Eur J Physiol 451:11-18;Clapham等人,2001Nat Neurosci 2:387-396;Clapham,2003Nature 426:517-524;Clapham等人,2002IUPHAR Compendium)。TRPC6是钙可渗透通道,具体地是非选择性钙可渗透阳离子通道。除钙离子外,TRPC6通道可渗透其它阳离子,例如钠。因此,TRPC6通道不仅调节细胞内钙的浓度,还通过调节包括钙离子和钠离子的阳离子的通量来调节膜电位。尽管非选择性阳离子通道(例如TRPC6)尤其调节钙离子通量,但它们在机理上与电压门控钙通道不同。通常,电压门控钙通道对跨膜电位差的去极化作出响应,并可打开以允许钙从细胞外介质中流入,并迅速增加细胞内钙水平或浓度。相反,非选择性阳离子通道(例如TRPC6)通常经信号转导门控,持续时间长,并产生较小的离子浓度快速变化。此外,TRPC6可响应压力变化。这些机理差异伴随有电压门控和阳离子可渗透通道之间的结构差异。因此,尽管许多不同的通道起着调节各种细胞类型中的离子通量和膜电位的作用,并且响应于多种刺激,但重要的是,认识到不同类别的离子通道之间的显著的结构、功能和机理差异。
TRPC6功能尤其涉及肌源性张力的调节。TRPC6在平滑肌细胞、血管平滑肌细胞、内皮细胞、心肌细胞、肺动脉、主动脉、心脏、肝脏、脑和肾脏中高度表达。TRPC6的表达连同在基因敲除的小鼠和培养的细胞中进行的实验表明,TRPC6可为治疗高血压和其它心脏和血管疾病、子痫前期、局灶性节段性肾小球硬化症(FSGS)、肾病综合征、微小病变肾病、糖尿病性肾病或其它肾脏疾病、呼吸病况、再狭窄、肝脏疾病、肌肉萎缩症、纤维化疾病、疼痛、缺血和缺血再灌注损伤以及某些形式的癌症提供有用的靶标。
Yue等人研究了TRPC6通道在介导可导致特发性肺动脉高压(IPAH)的肺动脉平滑肌细胞增殖中的作用。由过度肺动脉平滑肌细胞(PASMC)增殖引起的肺血管内侧肥大是IPAH患者肺血管阻力升高的主要原因。作者发现,在来自健康肺组织的PASMC中TRPC6高度表达,而TRPC3最低表达。然而,在IPAH患者的肺组织中,与正常血压患者相比,TRPC3和TRPC6的mRNA和蛋白表达显著升高。此外,用TRPC6 siRNA温育后,源自IPAH患者的PASMC细胞的增殖明显减少。基于这些结果,作者得出结论,TRPC6在介导适当的PASMC增殖中可为重要的,且TRPC6的失调可导致IPAH患者中PASMC增殖增加和肺血管内侧肥大(Yu等人,2004Proc Natl Acad Sci 101(38):13861-6)。以下观察结果提供了进一步支持:与正常受试者相比,在IPAH患者中,增加表达的TRPC6启动子中单核苷酸多态性的频率明显更高(Yue等人,2009Circulation 119:2313-22)。
涉及IPAH中的TRPC6失调的其它证据来自对波生坦(bosentan,一种双重内皮素受体阻滞剂,其已在临床上用于治疗IPAH)的研究。该抑制剂降低PASMC的增殖,但尚不清楚其发生的机理。有趣的是,波生坦既降低IPAH患者肺组织中PASMC的增殖,又降低TRPC6的表达(Kunichika等人,2004Am J Respir Crit Care Med 170(10):1101-7)。
大鼠长期暴露于香烟烟雾(CS)导致远端肺动脉中TRPC6 mRNA和蛋白表达增加,且在体外使用PASMC观察到了类似影响。尼古丁对培养的大鼠PASMC的处理上调了TRPC6的表达并增加了细胞内钙水平,这两者均因TRPC6 siRNA沉默而降低(Wang等人,2014Am JPhysiol Cell Physiol 306:C364-73)。这些结果表明TRPC6在CS诱导的肺损伤中起作用。
证据支持TRPC6在其它肺部疾病中的作用。在患有慢性阻塞性肺疾病(COPD)患者的肺泡巨噬细胞中,发现与对照相比,TRPC6表达升高(Finney-Hayward等人,2010Am JRespir Cell Mol Biol 43:296-304)。在人的囊性纤维化上皮细胞中,TRPC6介导的钙内流异常增加,且可导致粘液分泌过多。siRNA-TRPC6能够减少这种异常的钙内流(Antigny等人2011Am J Resp Cell Mol Biol,44:83–90)。在小鼠肺纤维母细胞中,PDGF的促纤维化活性取决于TRPC6的活化,这表明TRPC6的抑制将减少肺纤维化(Lei等人,2014Biomaterials35:2868-77)。在缺血-再灌注-诱导的水肿和脂多糖-诱导的炎症的小鼠肺模型中证明了TRPC6在肺内皮细胞功能中的作用,其中TRPC6缺陷能够通过保留内皮屏障功能来减少急性肺损伤(Weissmann等人,2011Nat Comm,3:649-58和Tauseef等人,2012J Exp Med 209:1953-68)。
近期研究还涉及TRPC6在其它心脏病况(包括心肌肥大)中的作用。与正常心脏相比,扩张型心肌病患者的心脏的TRPC6 mRNA表达升高(Kuwahara等人,2006J Clin Invest116:3114-26)。在心肌肥大的小鼠模型中,压力超负荷(Kuwahara等人,2006J Clin Invest116:3114-26)、慢性异丙肾上腺素治疗(Xie等人,2012Nat Commun 3:1238)和部分肾切除术引起的尿毒症心肌病(Xie等人,2015J Am Soc Nephrol 26:1150-60)提高TRPC6心脏mRNA水平。此外,在转基因小鼠的心肌中,TPC6的心脏特异性过度表达诱导心肌肥大和过早死亡(Kuwahara等人,2006J Clin Invest 116:3114-26)。
Wu及其同事发现,在神经内分泌激动剂输注或压力超负荷模拟后,以心脏特异性方式表达显性阴性TRPC6的转基因小鼠的心脏肥大响应减弱,这表明TRPC6是通道复合物的组分,所述通道复合物是肥大的必要介质(Wu等人,2010Proc Natl Acad Sci.107:7000-05)。靶向TRPC6的小分子药物最近也开始在治疗心脏病况方面显示出希望。例如,Seo和同事证明了TRPC6和TRPC3拮抗剂(GSK2332255B和GSK833503A)在新生儿和成人心肌细胞中均表现出细胞肥大信号传导的剂量依赖性抑制作用(Seo等人,2014Proc Natl Acad Sci111:1551-1556)。类似地,保护缺乏TRPC6的小鼠免受异丙肾上腺素-诱导的心肌肥大(Xie等人,2012Nat Commun 3:1238)。
降低TRPC6活性可有益于心血管疾病的治疗。在体外,与抗动脉粥样硬化的流动状况相比,动脉粥样硬化易发性剪切应力在人血管内皮细胞(EC)中诱导升高的TRPC6 mRNA水平(Thilo等人,2012Hypertension 59:1232-40)。EC迁移对于动脉损伤后的愈合很重要,且在TRPC6缺陷型小鼠的细胞中在体外防止了溶血磷脂酰胆碱介导的EC迁移的抑制作用。此外,与野生型对照相比,高胆固醇饮食与颈动脉损伤相结合并不会损害TRPC6缺陷型小鼠的愈合(Rosembaum等人,2015J Vasc Surg 62:1040-47和Chaudhuri等人,2008Mol BiolCell 19:3203-11)。类似地,与未扩张的动脉相比,球囊扩张诱导的离体人类乳内动脉的损伤导致TRPC6 mRNA水平升高(Bergdahl等人,2005Am J Physiol Cell Physiol 288:C872-80)。内皮细胞的凋亡参与动脉粥样硬化病变的发生和发展,且证实氧化低密度脂蛋白诱导的人主动脉EC凋亡依赖于TRPC6(Zhang等人,2015Sci Rep 5:9401-10)。在前脑缺血的大鼠模型中,血管SMC中TRPC6 mRNA水平升高,并且与脑血流量降低相关(Johannson等人,2015Acta Physiol 214:376-89)。另外,TRPC6基因缺陷或用TRPC6拮抗剂治疗改善轻度创伤性脑损伤后小鼠的内皮功能(Chen等人,2019,J.Neuroinflamm.16:21)。
Reiser、Winn和的研究鉴定了FSGS患者的TRPC6突变(Reiser等人,2005Nature Genet 37:739-744;Winn等人,2005Science 308:1801-1804;等人,2009Am J Physiol Cell Physiol 296:C558-69)。随后的研究鉴定了与类固醇耐药性肾病综合征相关的其它TRPC6突变(C.Sadowski等人,2014J Am Soc Nephrol 26:1279-89)。进一步的研究表明,TRPC6通过控制钙内流和活化的T细胞活化的核因子在正常的足状突细胞功能中是重要的,其中通过该通道的电流升高与肾损伤和蛋白尿的诱导有关(Moller等人,2007J Am Soc Nephrol 18:29-36和等人,2009Am J PhysiolCell Physiol 296:C558-69)。除获得功能突变外,还显示出TRPC6的表达在包括FSGS、微小病变肾病、膜性肾小球肾炎和糖尿病性肾病在内的人类慢性肾脏疾病(Moller等人,2007JAm Soc Nephrol 18:29-36和Thilo等人,2011Nephrol.Dial.Transplant 27:921-9)以及在足状突细胞损伤的小鼠模型(Moller等人,2007J Am Soc Nephrol 18:29-36)中升高。已证明TRPC6缺陷型小鼠具有减少的血管紧张素II(Ang II)诱导的蛋白尿(Eckel等人,2011JAm Soc Nephrol 22:526-35),而在小鼠中人GoF突变的转基因足状突细胞特异性表达则诱导了蛋白尿和肾小球病变(Krall等人,2010PLoS ONE e12859和Canales等人,2015Brit JMedicine Med Res 5:1198-1212)。因此,抑制TRPC6可用于治疗慢性肾脏疾病。这些发现不仅表明TRPC6正常发挥功能以维持适当的肾脏功能,而且还暗示着TRPC6是至少某些FSGS病例的特定原因。基于TRPC6在肾功能中的可能作用,TRPC6抑制剂化合物可用于治疗或改善(全部或部分)由TRPC6功能障碍引起的慢性肾脏疾病或病况。另外,无论疾病的原因如何,TRPC6抑制剂化合物均可用于治疗或改善肾脏疾病的症状(例如,高血压、蛋白尿等)。
在妊娠期间,TRPC6在子宫肌层和胎盘中表达(Ku等人,2006J Soc GynecolInvestig 13:217-225;Clarson等人,2003J Physiol 550:515-528)。因此,TRPC6可有助于在胎盘中维持适当的肌原性张力和/或在妊娠期间维持适当的胎儿和产妇血压。
最近的证据表明,TRPC6与某些形式的癌症有关。几组研究已证实,在从多形性胶质母细胞瘤(最常见且无法治愈的脑癌类型)患者中提取的细胞中,TRPC6表达升高(Chigurupati等人,2010Cancer Res,70:418-427;Ding等人,2010J Natl CancerInst.102:1052-1068)。同样,Ding等人发现人类胶质瘤细胞中TRPC6水平升高,且在药理学上或用显性阴性突变体对TRPC6的抑制在体外抑制了细胞生长。在两种人类神经胶质瘤异种移植模型中,与对照相比,皮下或颅内植入前肿瘤细胞中显性阴性TRPC6的慢病毒介导的表达降低了肿瘤的体积(Ding等人,J.Natl.Cancer Inst.2010,102,1052-1068)。还发现TRPC6水平升高尤其与宫颈癌(Wan等人,2012Onco Targets Ther 5:171-176)、乳腺癌(Dhennin-Duthille等人,2011Cell Physiol Biochem 28:813-822)、肾细胞癌(Song等人,2013Mol Biol Rep 40:5115-5122)、头颈鳞状细胞癌(de Quiros等人,2013BMC Cancer13:116-127)和食道鳞状细胞癌(Zhang等人,2013Med Oncol 30:607)等有关。在肝癌细胞中,已证明阿霉素、低氧和电离辐射会升高TRPC6 mRNA的表达,且发现在肿瘤组织中TRPC6的水平高于在非相关的组织中的水平。升高的TRPC6与在体外因TRPC6 RNA沉默而降低的耐药性相关。在小鼠皮下异种移植模型中在植入之前,TRPC6特异性短发夹(hairpin)RNA的慢病毒递送到Huh7肿瘤细胞中减少了肿瘤生长并使肿瘤对阿霉素敏感(Wen等人,2016SciRep 6:23269)。这些发现表明,TRPC6可能是有前景的用于癌症治疗的治疗靶标。
可通过降低TRPC6活性来治疗包括非酒精性脂肪性肝炎在内的肝脏疾病。与常氧条件相比,低氧增加了人肝星状细胞系中TRPC6的表达。使用这些细胞,响应于低氧,TRPC6RNA沉默下调α平滑肌肌动蛋白和胶原蛋白1A1(两者均与纤维化相关)的转录物(Iyer等人,2015Exp Cell Res 336:66-75)。
抑制TRPC6可为患有杜兴氏肌肉萎缩症(DMD)的患者带来益处。在使用分离的心肌细胞的DMD的mdx/utrn+/-模型中,与具有野生型TRPC6基因的小鼠相比,TRPC6缺陷使应力激刺激的收缩力和钙的瞬时反应恢复至正常,这表明TRPC6抑制将保护DMD患者的心脏功能(Seo等人,2014Circ Res 114:823-32)。
纤维化病症可用TRPC6抑制剂治疗。TRPC6的过表达诱导肌成纤维细胞活化,而TRPC6的缺失则减少转化生长因子β诱导的肌成纤维细胞的转化。此外,TRPC6缺陷型小鼠表现出减少的真皮和心脏伤口愈合(Davis等人,2012Dev Cell 23:705-15)。TRPC6缺陷型小鼠被保护免受博来霉素诱导的肺纤维化(Hofmann等人,2017Biochim Biophys Acta 1863:560-568)。
TRPC6抑制剂可用于降低ARDS、败血症、严重败血症和败血性休克的死亡率,因为在TRPC6缺陷型小鼠中,全身性败血症的小鼠模型(盲肠结扎穿刺,CLP)的存活率得到了显著提高(80%vs媒剂组的10%)(Tauseef等人,2012J Exp Med 209:1953-1968)。
TRPC6抑制剂可用于治疗疼痛。在临床前疼痛模型中,TRPC6反义寡核苷酸的脊髓递送减少了由机械、低渗和热刺激诱导的痛觉过敏(Alessandri-Haber等人,2009JNeurosci 29:6217-28)。
调节TRPC6的功能提供了调节细胞中钙稳态、钠稳态、细胞内钙水平、膜极化(静止膜电位)和/或阳离子水平的手段。可调节一种或多种TRPC6功能的化合物可用于许多方面,包括但不限于维持钙稳态;维持钠稳态;调节细胞内钙水平;调节膜极化(膜电位);调节阳离子水平;和/或治疗或预防与钙稳态、钠稳态、钙或钠稳态失衡或膜极化/超极化(包括低兴奋性和过度兴奋性)有关的疾病、病症或病况,和/或治疗或预防与TRPC6的表达或功能的调节或失调有关的疾病、病症或病况。
发明内容
本发明提供了新型的调节TRPC6的化合物,因此其可用于治疗可通过调节TRPC6缓解的多种疾病和病症,所述疾病和病症包括高血压、子痫前期、再狭窄、心脏或呼吸系统疾况、肾脏疾病、肝脏疾病、肌肉萎缩症、纤维化病症、疼痛、缺血或缺血再灌注损伤和癌症。本发明还涉及包含这些化合物的药物组合物、在治疗多种疾病和病症中使用这些化合物的方法、用于制备这些化合物的方法和可用于这些方法的中间体。
在其最宽的实施方案(实施方案1)中,本发明涉及式(I)的化合物
其中
Y为CH或N;
A为CH或N;
R1为H、C1-3烷基或OC1-3烷基;
R2为H、C1-3烷基或C3-6环烷基,其中所述R2基团的所述C1-3烷基或C3-6环烷基各自可任选地被OH、卤素或OC1-3烷基取代;
R3为H或C1-3烷基;
R2和R3与其所连接的碳原子一起可任选地连接形成3至6元碳环;
R4表示
C1-6烷基,其可任选地被1至3个基团取代,所述基团独立地选自卤素、C3-6环烷基甲基和C3-6环烷基乙基,其中所述C3-6环烷基甲基和C3-6环烷基乙基的C3-6环烷基可任选地被1至3个基团取代,所述基团独立地选自卤素和甲基、1,2,3-噻二唑基甲基、噻唑基甲基、异噁唑基甲基或下式的基团:
其中n为0或1;
R5选自H、卤素、CF3、OCF3、CN、C1-3烷基、OC1-3烷基、C3-6环烷基;其中所述R5基团的所述C1-3烷基和OC1-3烷基各自可任选地被1至3个基团取代,所述基团各自独立地选自卤素、氧代、NH2、NH(C1-3烷基)和N(C1-3烷基)2;
R6选自H、卤素、C1-3烷基和OC1-3烷基;
其中
R5和R6可连接形成5或6元碳环,其中所述5或6元碳环的1个或2个碳原子可任选地被1个或2个氧原子替代;
R7选自H、卤素、C1-3烷基和OC1-3烷基,其中所述R7基团的所述C1-3烷基可任选地被1至3个选自卤素的取代基取代;
R8选自H和卤素;
R9为H或C1-3烷基;其中
R2和R9可连接形成双环;
R10为H或C1-3烷基;
或其药学上可接受的盐。
在第二实施方案(实施方案2)中,本发明涉及根据实施方案1所述的化合物,其中Y为CH且A为N;
或其药学上可接受的盐。
在第三实施方案(实施方案3)中,本发明涉及根据实施方案1所述的化合物,其中Y为CH且A为CH;
或其药学上可接受的盐。
在第四实施方案(实施方案4)中,本发明涉及根据实施方案1所述的化合物,其中Y为N且A为CH;
或其药学上可接受的盐。
在第五实施方案(实施方案5)中,本发明涉及根据实施方案1所述的化合物,其中Y为N且A为N;
或其药学上可接受的盐。
在第六实施方案(实施方案6)中,本发明涉及根据实施方案1至5中任一项所述的化合物,其中R4表示下式的基团:
或其药学上可接受的盐。
在第七实施方案(实施方案7)中,本发明涉及根据实施方案1-6中任一项所述的化合物,其中
R5选自H、F、Cl、CF3、OCF3、CN、甲基、乙基、异丙基、甲氧基、环丙基、乙酰基和(CH3)2NC(O)-;
R6选自H、F和甲氧基;
其中
R5和R6可连接形成5或6元碳环,所述碳环的2个碳原子被2个氧原子替代;
或其药学上可接受的盐。
在第八实施方案(实施方案8)中,本发明涉及根据实施方案1所述的化合物,其中R4、R5和R6共同表示选自以下的基团:苯基、4-甲基苯基、4-乙基苯基、异丙基苯基、4-甲氧基苯基、4-氟苯基、4-氯苯基、4-三氟甲基苯基、4-三氟甲氧基苯基、4-环丙基苯基、苯甲腈、4-N,N-二甲基苯甲酰胺和4-乙酰基苯基;
或其药学上可接受的盐。
在第九实施方案(实施方案9)中,本发明涉及根据实施方案1所述的化合物,其中R4、R5和R6共同表示苯基;
或其药学上可接受的盐。
在第十实施方案(实施方案10)中,本发明涉及根据实施方案1、8或9中任一项所述的化合物,其中R1至R3和R7至R10各自为H;
或其药学上可接受的盐。
在第十一实施方案(实施方案11)中,本发明涉及根据实施方案1至5中任一项所述的化合物,其中R4为C1-6烷基;
或其药学上可接受的盐。
在第十二实施方案(实施方案12)中,本发明涉及根据实施方案1至5和11中任一项所述的化合物,其中R4选自正丙基和异丙基;
或其药学上可接受的盐。
在第十三实施方案(实施方案13)中,本发明涉及根据实施方案1至5中任一项所述的化合物,其中R4为C3-6环烷基甲基或C3-6环烷基乙基,其中C3-6环烷基甲基和C3-6环烷基乙基的C3-6环烷基可任选地被1至3个基团取代,所述基团独立地选自卤素和甲基;
或其药学上可接受的盐。
在第十四实施方案(实施方案14)中,本发明涉及根据实施方案1至5和13中任一项所述的化合物,其中R4选自环丙基甲基、环丙基乙基、2-甲基环丙基甲基、环丁基甲基、3-甲基环丁基甲基、3,3-二氟环丁基甲基和环己基甲基;
或其药学上可接受的盐。
具体实施方式
表1示出了可通过以下合成实施例部分中所示的合成方案和实施例以及本领域已知方法制备的本发明的化合物。
表1
在实施方案中,本发明涉及上表1中所列的化合物1至54的任一项及其药学上可接受的盐。
除非特别说明,否则在整个说明书和所附权利要求书中,给定的化学式或名称应涵盖互变异构体以及其所有立体、光学和几何异构体(例如对映异构体、非对映异构体、E/Z异构体等)及外消旋物,以及不同比例的单独对映异构体的混合物、非对映异构体的混合物或存在上述异构体和对映异构体时任何前述形式的混合物,以及盐,包括其药学上可接受的盐,及其溶剂合物,例如水合物,包括游离化合物的溶剂合物或化合物盐的溶剂合物。
在下面定义的基团(group)、基团(radical)或部分中,碳原子数通常在基团之前指定,例如,C1-6-烷基是指具有1-6个碳原子的烷基基团。通常,在如HO、H2N、(O)S、(O)2S、NC(氰基)、HOOC、F3C等的基团中,熟练技术人员可以从基团本身的自由价态看到基团与分子的连接点。对于包含两个或更多个亚基团(subgroup)的组合基团,最后一个命名的亚基团为基团的连接点,例如,取代基“芳基-C1-3-烷基”是指与C1-3-烷基键合的芳基基团,该C1-3-烷基键合至核心或取代基所连接的基团。
若以化学名称的形式和以分子式描述本发明的化合物,在有差异的情况下,则以分子式为准。
符号
可在子式中使用以表示与定义的核心分子连接的键,例如,
如本文所用,术语“取代的”是指指定的原子上的一个或多个氢被指定基团的选择所替代,其条件是不超过指定原子的正常价态,并且该取代产生稳定的化合物。
本发明的对映异构体纯化合物或中间体可以通过不对称合成制备,例如通过适合的非对映异构体化合物或中间体的制备和随后的分离,它们可以通过已知方法(例如通过色谱分离或结晶)进行分离,和/或通过使用手性试剂,例如手性起始材料、手性催化剂或手性助剂。
此外,本领域技术人员已知如何由相应的外消旋混合物制备对映异构体纯的化合物,例如通过色谱分离手性固定相上相应的外消旋混合物;或通过使用适当的拆分试剂拆分外消旋混合物,例如通过与旋光活性酸或碱形成外消旋化合物的非对映异构体盐,随后拆分所述盐并从所述盐中释放所需化合物;或通过用旋光活性手性辅助试剂将相应的外消旋化合物衍生化,随后进行非对映异构体分离和除去手性辅助基团;或通过外消旋物的动力学拆分(例如通过酶促拆分);通过在适合的条件下从对映异构体形态的晶体的团块中进行对映体选择性结晶;或通过在存在旋光手性助剂的情况下,从适合的溶剂中(分级)结晶。
本发明包括本发明化合物的化学上可接受的衍生物。“药物上可接受的衍生物”是指任何药学上可接受的盐或酯,或在给药至患者后能够(直接或间接)提供对本发明有用的化合物、或其药理活性代谢物或药理活性残基的任何其它化合物。药理活性代谢物应理解为是指能够通过酶或化学方法代谢的本发明的任何化合物。这包括例如本发明化合物的羟基化或氧化的衍生物。
如本文所用,“药学上可接受的盐”是指所公开化合物的衍生物,其中母体化合物通过制备其酸或碱式盐而被修饰。药学上可接受的盐的实例包括但不限于碱性残基如胺的无机或有机酸盐;酸性残基如羧酸的碱或有机盐等。例如,此类盐包括乙酸盐、抗坏血酸盐、苯磺酸盐(benzenesulphonate)、苯甲酸盐、苯磺酸盐(besylate)、碳酸氢盐、酒石酸氢盐、溴化物/氢溴酸盐、乙二胺四乙酸盐、樟脑磺酸盐(camsylate)、碳酸盐、氯化物/氢氯酸盐、柠檬酸盐、乙二磺酸盐、乙烷二磺酸盐、丙酸酯十二烷基硫酸盐(estolate)乙磺酸盐、延胡索酸盐、葡庚糖酸盐、葡糖酸盐、谷氨酸盐、乙醇酸盐、乙醇酰基对氨基苯胂酸盐(glycollylarsnilate)、己基间苯二酚盐、hydrabamines、羟基马来酸盐(hydroxymaleate)、羟基萘甲酸盐、碘化物、异硫代硫酸盐、乳酸盐、乳糖酸盐、苹果酸盐、顺丁烯二酸盐、扁桃酸盐、甲磺酸盐、甲基溴化物、甲基硝酸盐、甲基硫酸盐、粘酸盐(mucate)、萘磺酸盐、硝酸盐、草酸盐、双羟萘酸盐(pamoate)、泛酸盐(pantothenate)、苯基乙酸盐、磷酸盐/二磷酸盐、聚半乳糖醛酸盐(polygalacturonate)、丙酸盐、水杨酸盐、硬脂酸盐、次乙酸盐(subacetate)、琥珀酸盐、磺酰胺(sulphamide)、硫酸盐、丹宁酸盐(tannate)、酒石酸盐、8-氯茶碱盐(teoclate)、甲苯磺酸盐、三乙基碘化物(triethiodide)、铵、苄星(benzathine)、氯普鲁卡因(chloroprocaine)、胆碱、二乙醇胺、乙二胺、葡甲胺及普鲁卡因。另外的药学上可接受的盐可以与铝、钙、锂、镁、钾、钠、锌等金属的阳离子形成(还参见Pharmaceutical salts,Birge,S.M.等人,J.Pharm.Sci.,(1977),66,1-19)。
本发明的药学上可接受的盐可通过常规化学方法由含有碱性或酸性部分的母体化合物合成。通常,此类盐可以通过将这些化合物的游离酸或碱形式与足量的适当碱或酸在水中或在有机稀释剂(如乙醚、乙酸乙酯、乙醇、异丙醇、或乙腈或其混合物)中反应来制备。
除上述提及的那些以外的其它酸的盐,例如可用于提纯或分离本发明的化合物的盐(例如三氟乙酸盐),也构成本发明的一部分。
另外,使用本发明化合物的前药在本发明范围内。前药包括那些通过简单的化学转化即可被修饰以产生本发明化合物的化合物。简单的化学转化包括水解、氧化和还原。具体地,当将前药给药至患者时,该前药可以转化为上文公开的化合物,从而赋予所需的药理作用。
本发明的化合物还包括其同位素标记的形式。本发明的组合的活性剂的同位素标记形式与所述活性剂相同,但是所述活性剂的一个或多个原子已被原子质量或质量数不同于通常在自然界中发现的所述原子的原子质量或质量数的一个或多个原子取代。可容易商购的并且可根据已良好确立的程序将其掺入本发明组合的活性剂中的同位素的实例包括氢、碳、氮、氧、磷、氟和氯的同位素,例如,其分别为2H、3H、13C、14C、15N、18O、17O、31P、32P、35S、18F和36Cl。包含一种或多种上述同位素和/或其它原子的其它同位素的本发明的组合的活性剂、其前药或其药学上可接受的盐被认为在本发明的范围内。
术语卤素通常表示氟、氯、溴和碘。
术语“C1-n-烷基”,其中n是选自2、3、4、5或6,优选4或6的整数,单独地或与另一个基团组合表示具有1至n个C原子的非环的、饱和的、支链的或直链的烃基,例如,术语C1-5-烷基包含基团H3C-、H3C-CH2-、H3C-CH2-CH2-、H3C-CH(CH3)-、H3C-CH2-CH2-CH2-、H3C-CH2-CH(CH3)-、H3C-CH(CH3)-CH2-、H3C-C(CH3)2-、H3C-CH2-CH-CH2-CH2-、H3C-CH2-CH2-CH(CH3)-、H3C-CH2-CH(CH3)-CH2-、H3C-CH(CH3)-CH2-CH2-、H3C-CH2-C(CH3)2-、H3C-C(CH3)2-CH2-、H3C-CH(CH3)-CH(CH3)-和H3C-CH2-CH(CH2CH3)-。
术语“C3-n-环烷基”,其中n是4至n的整数,单独地或与另一个基团组合表示具有3至n个C原子的环状、饱和的、无支链的烃基。例如,术语C3-6-环烷基包括环丙基、环丁基、环戊基和环己基。
通过在“烷基”、“亚烷基”或“环烷基”基团(饱和或不饱和)上加上术语“卤素”,是这样的烷基或环烷基,其中一个或多个氢原子被选自氟、氯或溴的卤素原子,优选氟和氯,特别优选氟替代。实例包括:H2FC-、HF2C-、F3C-。
单独或与另一个基团组合使用的术语“碳环基”是指由3至9个碳原子和任选的选自N、O和S的杂原子组成的单-、双-或三环结构。术语“碳环基”是指完全饱和的环体系,并且包括稠合、桥接和螺环体系。
上文给出的许多术语可以在式或基团的定义中重复使用,并且在每种情况下都彼此独立地具有上文给出的含义之一。
如本领域技术人员所理解的,本发明的化合物仅仅是那些被认为是“化学稳定的”化合物。例如,具有“不稳定价态(danglingvalency)”或“碳负离子”的化合物不是本文公开的发明方法所考虑的化合物。
对于本申请中本文上文公开的所有化合物,在命名与结构冲突的情况下,应理解该化合物由结构定义。
本申请提供可调节TRPC6功能的化合物。还提供采用这些化合物的方法。某些实施方案提供调节细胞或动物中TRPC6功能的方法,其包括给药有效量的抑制TRPC6功能的化合物,其中所述化合物抑制TRPC6-介导的离子通量。某些实施方案提供调节细胞或动物中TRPC6功能的方法,其包括给药有效量的抑制TRPC6功能的化合物,其中所述化合物抑制TRPC6-介导的钙内流。某些实施方案提供调节细胞或动物中TRPC6功能的方法,其包括给药有效量的抑制TRPC6功能的化合物,其中所述化合物抑制TRPC6-介导的细胞骨架重组或细胞形态改变。某些实施方案提供调节细胞中TRPC6功能的方法,其包括向细胞给药有效量的抑制TRPC6功能的化合物,其中所述化合物抑制由TRPC6介导的外向电流。某些实施方案提供调节细胞中TRPC6功能的方法,其包括向细胞给药有效量的抑制TRPC6功能的化合物,其中所述化合物抑制由TRPC6介导的内向电流。某些实施方案提供调节细胞中TRPC6功能的方法,其包括向细胞给药有效量的抑制TRPC6功能的化合物,其中所述化合物抑制由TRPC6介导的内向电流和外向电流。某些实施方案提供调节细胞中TRPC6功能的方法,其包括向细胞给药有效量的抑制TRPC6功能的化合物,其中所述化合物抑制TRPC6介导的细胞内钙浓度的升高。某些实施方案提供调节细胞中TRPC6功能的方法,其包括向细胞给药有效量的抑制TRPC6功能的化合物,其中所述化合物抑制细胞形态改变。某些实施方案还提供预防或治疗受试者中与TRPC6功能相关的疾病或病况的方法,其包括向受试者给药治疗有效量的抑制TRPC6功能的化合物,其中所述化合物抑制由TRPC6介导的内向电流。某些实施方案提供预防或治疗受试者中与TRPC6功能相关的疾病或病况的方法,其包括向受试者给药治疗有效量的抑制TRPC6功能的化合物,其中所述化合物抑制由TRPC6介导的外向电流。某些实施方案还提供预防或治疗受试者中与TRPC6功能相关的疾病或病况的方法,其包括向受试者给药治疗有效量的抑制TRPC6功能的化合物,其中所述化合物抑制由TRPC6介导的内向电流和外向电流。某些实施方案提供预防或治疗受试者中与TRPC6功能相关的疾病或病况的方法,其包括向受试者给药治疗有效量的抑制TRPC6功能的化合物,其中所述化合物抑制由TRPC6介导的离子通量。应注意的是,对特定电流的抑制是指化合物在体外或体内测定中抑制该电流(例如,向内和/或向外)的能力。在体内或体外测定中抑制特定电流充当特定化合物的特定功能活性的代理。
本发明提供用于治疗受试者中TRPC6介导的病症的方法,所述方法包括给药有效量的本发明的化合物,其中例如,在下面的详细描述中,描述了上述每个变量。
本发明进一步提供用于治疗受试者中TRPC6介导的病症的方法,其中所述方法包括给药包含本发明的化合物以及药学上可接受的赋形剂、稀释剂或载体的组合物。
本发明进一步提供用于治疗受试者中TRPC6介导的病症的方法,其中所述方法包括给药包含本发明的化合物以及药学上可接受的赋形剂、稀释剂或载体的组合物,且所述TRPC6介导的病症选自心肌肥大、缺血、缺血再灌注损伤、高血压、肺动脉高血压、特发性肺动脉高压、再狭窄、慢性阻塞性肺疾病、囊性纤维化、阿尔兹海默氏病、帕金森氏病、亨廷顿病、肌萎缩性脊髓侧索硬化症(ALS)、创伤性脑病症、哮喘、类风湿性关节炎、骨关节炎、炎性肠病、多发性硬化症、肌肉萎缩症、杜兴氏肌肉萎缩症(Duchenne综合征)、子痫前期和妊娠引起的高血压、非酒精性脂肪性肝炎、肾病综合征,包括微小病变肾病、局灶性节段性肾小球硬化症(FSGS)和膜性肾小球肾炎、急进性肾小球肾炎、糖尿病性肾病或糖尿病性肾脏疾病(DKD)、慢性肾脏疾病、高血压肾病、全身性红斑狼疮(SLE)、肾功能不全、终末期肾病、缺血或缺血再灌注损伤、癌症、糖尿病、特发性肺纤维化(IPF)、肺气肿以及急性呼吸道疾病综合征(ARDS)、败血症、严重败血症和败血性休克。
缩写列表
下表显示所用的缩写及其定义。
合成实施例
以下实施例是说明性的,并且如本领域技术人员所公认的,可在不进行过度实验的情况下,根据具体化合物的需要改变特定的试剂或条件。
以下是可商购的中间体的实例。这些实例是为了支持本发明的实施方案,而不应以任何方式解释为限制本发明的范围。
其它中间体可根据以下方法制备:
本发明的化合物可通过以下给出的通用方法和实施例以及本领域普通技术人员已知的方法制备。最佳的反应条件和反应时间可根据所使用的特定反应物而变化。除非另有说明,否则本领域普通技术人员可容易地选择溶剂、温度、压力和其它反应条件。合成实施例部分提供了具体步骤。以下合成中使用的中间体可商购或可通过本领域技术人员已知的方法容易地制备。可通过常规方法例如薄层色谱(TLC)或高压液相色谱-质谱(HPLC-MS)监测反应进程。中间体和产物可通过本领域已知的方法提纯,所述方法包括柱色谱、HPLC、制备型TLC或重结晶。
下文和合成实施例部分中描述的方法可用于制备本发明的化合物。
根据所采用的提纯方法和条件,可获得以下报道的带有碱性或酸性基团的中间体和实施例,其为相应的盐或中性化合物。可通过本领域技术人员已知的标准程序将盐转变成其中性对应物。
通用方法:除非另有说明,否则所有反应均在室温(约25℃)、惰性气氛(例如,氩气、N2)和无水条件下进行。所有化合物均通过以下至少一种方法表征:1H NMR、HPLC、HPLC-MS或熔点。
通常,反应进程通过薄层色谱(TLC)或HPLC-MS进行监控。使用以下至少一种方法提纯中间体和产物:
硅胶快速色谱,重结晶,超临界流体(SFC)手性HPLC,使用3.0x 25.0cm RegisPack柱,用MeOH、异丙基胺以及125bar的超临界二氧化碳的等度混合物洗脱;80mL/min,和/或
超临界流体(SFC)手性HPLC,使用10x 250mm或20x 250mm柱,用含20mM NH3的MeOH、含20mM NH3的EtOH或含20mM NH3的异丙基醇以及150bar的超临界二氧化碳的等度混合物洗脱;60至最高80mL/min,和/或
使用C18半制备型柱的反相HPLC,用以下梯度洗脱:
·ACN+0.1%TFA和H2O+0.1%TFA,
·ACN+0.1%甲酸和H2O+0.1%甲酸,或
·ACN和含2.5mM NH4HCO3的H2O。
·ACN和H2O和0.1%TFA,
·ACN和H2O和0.1%NH3的水溶液
·ACN和H2O+0.1%TFA
·ACN和H2O+0.1%NH3的水溶液
·MeOH和H2O+0.1%TFA
·MeOH和H2O+0.1%NH3的水溶液
通用合成程序
制备
根据本发明的化合物及其中间体可使用本领域技术人员已知并且在有机合成文献中描述的合成方法获得。优选地,类似于下文中更详细解释的制备方法,特别是如实验部分中所述,获得化合物。在某些情况下,实施反应方案所采用的顺序可以改变。也可以使用本领域技术人员已知但在此未详细描述的这些反应的变体。通过研究以下方案,制备根据本发明的化合物的通用方法对于本领域技术人员将变得明显。起始化合物是可商购的,或可通过文献或本文中描述的方法制备,或者可以以类似或相似的方式制备。在进行反应之前,可以使用常规的保护基团保护起始化合物中的任何官能团。可使用技术人员熟悉的并且在文献中描述的例如在“Protecting Groups”,3rd Edition,Philip J.Kocienski,Thieme,2005和“Protective Groups in Organic Synthesis”,4th Edition,PeterG.M.Wuts,Theodora W.Greene,John Wiley&Sons,2006中描述的方法,在反应顺序内的适合阶段再次裂解这些保护基团。
如方案1所示,本发明的通式(I)的化合物可以通过以下来制备:适合的式INT-1的羧酸(作为游离酸或作为与适合的金属阳离子如Li+、Na+、K+等的盐)和通式INT-2的适合胺中间体(作为游离胺或作为盐,例如盐酸盐、氢溴酸盐等)在适合的溶剂(例如N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、1-甲基-2-吡咯烷酮、二氯甲烷、四氢呋喃、1,4-二噁烷等)中、在适合的偶联剂(例如O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲鎓六氟磷酸酯(HATU)、O-(苯并三唑-1-基)-N,N-N′,N′-四甲基-脲鎓四氟硼酸酯(TBTU)、(苯并三唑-1-基氧基)三吡咯烷酮-鏻六氟磷酸酯(PyBOP)、碳二亚胺试剂等)和碱(例如三甲基胺、N,N-二异丙基-乙基胺、吡啶等)的存在下反应,形成酰胺键。方案1中的基团/术语R1至R4、R7至R10、A和Y具有上文和下文所定义的含义。
或者,也可将羧酸INT-1转化为酰氯(例如使用二氯甲烷中的亚硫酰氯或草酰氯),并在适合的碱(例如三甲基胺、N,N-二异丙基-乙基胺、吡啶等)存在下在适当的溶剂中这样与胺INT-2偶联。方案1中的基团/术语R1至R4、R7至R10、A和Y具有上文和下文所定义的含义。或者,羧酸INT-1可被二(咪唑-1-基)甲酮(CDI)活化,并可在适当的碱(例如三甲基胺、N,N-二异丙基-乙基胺等)存在下,在适当的溶剂(例如N,N-二甲基甲酰胺、N,N-二甲基乙酰胺等)中这样与胺INT-2偶联。中间体INT-1和INT-2是本领域已知的,或可通过以下描述的方法或有机化学文献中的方法制备。
方案1:
在Y=CH的情况下,可根据方案2制备方案1中所示的通式INT-2的中间体。方案2中的基团/术语R1至R3和R9至R10、A和Y=CH具有上文和下文所定义的含义。
中间体INT-5可以由硼酸衍生物INT-3和含卤素的杂芳族衍生物INT-4制备。该反应用钯催化剂(例如1,1′-双(二苯基膦基)-二茂铁]-二氯化钯(II)-CH2Cl2-络合物(PdCl2(dppf)*CH2Cl2)或氯(2-二环己基膦基-2′,4′,6′-三异丙基-1,1′-联苯基)[2-(2′-氨基-1,1′-联苯基)]钯(II)(XPhos Pd第二代催化剂)或三(二亚苄基丙酮)-二钯Pd2(dba)3,含额外的XPhos作为配体,等等)、在碱(磷酸钾、碳酸钠等)的存在下、在适当的溶剂(水/四氢呋喃、水/1,4-二噁烷、水/正丁醇、1,4-二噁烷或N,N-二甲基甲酰胺等)、在升高的温度(例如80℃至150℃)进行。该反应可任选地在微波中进行。
若将杂芳族中间体INT-4与一个受保护或掩蔽的氨基(NL2不是NH2)一起使用,则可按照有机化学文献中报道的标准程序,通过裂解保护基,将该基团转化为NH2基团。叔丁基羰基基团(例如Boc保护基团)优选在酸性条件下用例如三氟乙酸或盐酸,在溶剂(例如二氯甲烷、1,4-二噁烷、异丙醇、1,4-二噁烷中的HCl或乙酸乙酯等)中裂解。苄基可通过在过渡金属(例如钯碳)的存在下使用氢气来除去。在酸性条件下(例如用三氟乙酸或盐酸)也可以除去在芳环上带有供电子基团(例如甲氧基)的苄基基团。可在适当的溶剂(如乙醇和水的混合物)中,于优选80至100℃的升高的温度,通过羟基胺盐酸盐和三甲基胺裂解2,5-二甲基吡咯环以释放氨基官能团。
可以用适当的保护基团PG1(例如叔丁基-氧基羰基(Boc)、苄基-氧基羰基(Cbz)、苄基(Bn)等)保护中间体INT-3的哌啶环的氮原子。可通过本领域技术人员已知的方法引入保护基团PG1。如方案2所示的从INT-6中除去保护基团PG1得到其中Y=N的INT-2可通过本领域技术人员已知的方法或如上文和下文所述进行。优选地,叔丁基羰基基团(例如Boc保护基团)可在酸性条件下用例如三氟乙酸或盐酸、在溶剂(例如二氯甲烷、1,4-二噁烷、异丙醇、1,4-二噁烷中的HCl或乙酸乙酯等)中裂解。方案2中的基团/术语R1至R3、R9至R10、A和Y=CH具有上文和下文所定义的含义。
双键在中间体INT-3的哌啶环中的位置可取决于取代基R2、R3和R9。基团/术语R2、R3和R9具有上文和下文所定义的含义。中间体INT-3、INT-5和INT-6的取代基R2可包含也可带有适当保护基团的官能团。特别地,羟基可用适当的含甲硅烷基的保护基团(例如三乙基甲硅烷基、叔丁基-二甲基甲硅烷基等)保护。可以这样的方式选择R2上的官能团的保护基团:可不除去PG1而除去保护基团,以允许在R2上进一步修饰。甲硅烷基保护基团可例如用氟化物源(例如四正丁基氟化铵)、在环境温度或酸性条件下(例如1,4-二噁烷中的盐酸,1,4-二噁烷中的HCl)、在适合的溶剂(例如四氢呋喃)中、在升高的温度裂解。
方案2:
如方案2所示,所得双键在中间体INT-5的哌啶环中的位置可取决于取代基R2、R3和R9。基团/术语R1至R3、R9至R10和A具有上文和下文所定义的含义。可在溶剂(例如甲醇、乙醇、四氢呋喃、1,4-二噁烷、甲醇/乙酸等)中,在过渡金属(优选钯(或Pd(OH)2等))存在下,通过使用氢气来氢化中间体INT-5的哌啶环上的双键,得到INT-6。优选地,以1至5bar的压力施加氢气,且该反应可在室温至最高50℃进行。
取决于反应条件和总体脱保护策略(将保护基团PG1从INT-6除去,并将NL2转化为NH2),可以游离碱或盐形式得到其中Y=CH的中间体INT-2,所述盐为例如盐酸盐、三氟乙酸盐、氢溴酸盐等。可通过本领域技术人员已知的标准程序将中间体INT-2的盐转化为其中性对应物。
若Y=N,则可以根据方案3制备方案1中所示的通式INT-2的化合物。方案3中的基团/术语R1至R3、R9至R10、A和Y=N具有上文和下文所定义的含义。方案3中的中间体INT-2和INT-8的取代基R2可包含也可带有适当保护基团的官能团。特别地,羟基可用适当的含甲硅烷基的保护基团(例如三乙基甲硅烷基、叔丁基-二甲基甲硅烷基等)保护。可以这样的方式选择R2上的官能团的保护基团:可不除去PG1而除去保护基团,以允许在R2上进一步修饰。甲硅烷基保护基团可例如用氟化物源(例如四正丁基氟化铵)、在环境温度或酸性条件下(例如1,4-二噁烷中的盐酸,1,4-二噁烷中的HCl)、在适合的溶剂(例如四氢呋喃)中、在升高的温度裂解。
方案3中的INT-4可直接与含氮杂环INT-7偶联以形成碳-氮键,得到中间体INT-8。方案3中的基团/术语R1至R3、R9至R10、A和Y=N具有上文和下文所定义的含义。该反应优选在钯衍生的催化剂(例如2-(2′-二-叔丁基膦)-联苯基钯(II)乙酸盐,或(2-二环己基-膦基-2',6'-二异丙氧基-1,1'-联苯基)[2-(2'-氨基-1,1'-联苯基)]-钯(II)甲磺酸盐(第三代RuPhos Pd)或CPhos-3G-环钯甲磺酸盐等),在碱(例如叔丁醇钠、碳酸铯等)存在下,在适合的溶剂(例如甲苯、四氢呋喃、1,4-二噁烷等)中、在40至120℃进行。
若杂芳族中间体INT-4与受保护或掩蔽的氨基(NL2不是NH2)一起使用,则然后可通过有机化学文献中报道的标准程序或如上文和下文所述裂解掉保护基,将该基团转化为NH2基团。如方案3所示,取决于整体合成策略和整体保护基团策略,可在其中Y=N的中间体INT2的整体合成内的不同阶段(例如,以提供中间体INT-9或其中Y=N的中间体INT-2)进行向NH2-基团的转化。
INT-8或INT-9的保护基团PG1的除去可如有机化学文献中或上文和下文中所报道的进行。叔丁基羰基基团(Boc)可优选在酸性条件下用例如三氟乙酸或盐酸,在诸如二氯甲烷、1,4-二噁烷、异丙醇或乙酸乙酯的溶剂中裂解。可以在过渡金属例如钯碳的存在下,通过使用氢气来除去苄基(Bn)基团或苄基氧基羰基(Cbz)基团。也可以在酸性条件下(例如用三氟乙酸或盐酸)除去在芳环上带有供电子基团(如甲氧基基团)的苄基基团。
根据反应条件和总体脱保护策略,可以以游离碱形式或以盐的形式获得其中Y=N的中间体INT-2,所述盐为例如盐酸盐、三氟乙酸盐、氢溴酸盐等。可通过本领域技术人员已知的标准程序将盐转变成其中性对应物。取决于整体合成策略和脱保护策略,可以在其中Y=N的中间体INT-2的整体合成过程的各个步骤中进行保护基团PG1的除去(例如,如图3所示,从中间体INT-9除去保护基PG1生成其中Y=N的INT-2,或从中间体INT-8除去保护基PG1生成INT-10)。方案3中的基团/术语R1至R3、R9至R10、A和Y=N具有上文和下文所定义的含义。
方案3:
通式INT-2的中间体可替代地根据方案4制备。方案4中的基团/术语R1至R4、R7至R10和A具有上文和下文所定义的含义,且Y=N。
在中间体INT-12中,NOn表示硝基(n=2)或亚硝基(n=1)。通式INT-12的中间体可通过通式INT-11的带有硝基或亚硝基的缺电子杂芳族衍生物和适合的通式INT-7的哌嗪衍生物进行亲核取代而制备,所述哌嗪衍生物可在适合的溶剂(例如乙醇)中、在适合的碱(例如二异丙基-乙基-胺等)存在下,用保护基PG1进行保护。
或者,方案4中其中Y=N的中间体INT-12可通过适合的式INT-7的哌嗪衍生物与通式INT-11的带有硝基(n=2)的杂芳族衍生物,在催化剂优选钯催化剂(例如三(二亚苄基丙酮)-二钯Pd2(dba)3等)和适合的配体优选XantPhos(4,5-双(二苯基膦基)-9,9-二甲基呫吨)的存在下,在适当的溶剂(例如1,4-二噁烷等)中,并在适当的碱(例如碳酸铯等)的存在下,在升高的温度(例如80-120℃)进行过渡金属催化的偶联反应来制备。
中间体INT-9也可根据方案4合成。方案4中的基团/术语R1至R4、R7至R10、A和Y=N具有上文和下文所定义的含义,且Y=N。可以通过本领域技术人员已知的方法将INT-12的亚硝基(n=1)或硝基(n=2)基团转化为氨基。优选地,INT-12的亚硝基或硝基的还原可以在氢气气氛(例如在1至5bar)中和在过渡金属(优选钯碳)存在下、在溶剂(例如甲醇、乙醇、四氢呋喃、1,4-二噁烷等)中进行。以类似方式,按照方案4,可通过还原亚硝基或硝基由INT-14合成通式(I)的化合物。从中间体INT-9中除去保护基团PG1来生成其中Y=N的中间体INT-2可使用与方案3中所述相同的反应条件进行。从其中Y=N的中间体INT-2至式(I)的化合物的反应可使用如方案1中所述的相同反应条件进行。
式INT-14的中间体可以由化合物INT-13和羧酸INT-1以类似于方案1中对通式(I)的化合物所述的方式制备。还可如方案4所示类似于有机化学文献中报道的方法由INT-14通过亚硝基(n=1)或硝基(n=2)基团向氨基的转化,优选在氢气气氛中、在钯碳存在下、在适合的溶剂(例如甲醇、乙醇等)中合成。方案4中的基团/术语R1至R4、R7至R10和A具有上文和下文所定义的含义,且Y=N。
方案4:
如方案5中所示,基团R4=芳基可以经由起始于各种前体的氧而连接至INT-16的苯基部分。R7至R8和R4=芳基具有上文和下文所定义的含义。两个部分(INT-15的R4和INT-16的苯基部分)可通过以下连接:使用其中一个用羟基装饰(V或W表示OH),另一部分用硼酸衍生物(例如W或V表示B(OH)2、B(OCMe2CMe2O)等)。相应配备的两个构造单元INT-15和INT-16可以在碱(例如,吡啶或三甲基胺)、分子筛、任选的助氧化剂(例如,氧气),在溶剂(例如二氯甲烷)中在0至60℃用铜(乙酸盐)偶联。
或者,INT-15的R4与INT-16的苯基部分之间通过氧的键合是通过偶联带有OH基(V=OH)的芳基部分R4和带有离去基团(W=例如F、Cl)的INT-16的苯基部分形成的。INT-15的OH基团的氧通过亲核取代或过渡金属催化的反应取代离去基团。此过程特别适用于INT-16的缺电子苯基部分,该部分在碱(例如Cs2CO3、K2CO3、KOH、三甲基胺或NaH)存在下,优选在溶剂(例如甲苯、四氢呋喃、1,2-二甲氧基乙烷、1,4-二噁烷、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮、醇、水或其混合物)中,在0至220℃之间,与羟基化的R4-部分偶联。
如方案5中所示,取决于保护基团PG2的性质,式INT-1的羧酸(其中基团/术语R4和R7至R8具有上文和下文所定义的含义)优选通过水解或氢解由通式INT-17的相应酯制备。可在酸如盐酸或硫酸,或碱金属氢氧化物如氢氧化锂、氢氧化钠或氢氧化钾的存在下水解INT-17的酯基以产生羧酸。水解优选在水性溶剂中、在0至120℃进行,所述水性溶剂为例如与四氢呋喃、1,4-二噁烷、醇(例如甲醇、乙醇和异丙醇)或二甲基亚砜组合的水。若INT-17的保护基团PG2表示低级烷基酯(例如乙酯或甲酯),则其优选通过在水和适当的可混溶混合物(例如四氢呋喃、甲醇、乙醇、1,4-二噁烷等,或这些的混合物)的混合物中用氢氧化物碱(例如NaOH、LiOH或KOH)水解来裂解,必要时加热。优选通过在适合的溶剂(例如二氯甲烷、1,4-二噁烷、甲醇、乙醇、四氢呋喃、水或这些的混合物)中在酸性条件(例如盐酸或三氟乙酸)下处理来裂解叔丁酯。优选在适合的溶剂(例如乙醇、甲醇、四氢呋喃、二氯甲烷、乙酸乙酯)中,在过渡金属(优选钯碳等)存在下,在氢气气氛(优选1至5bar)中使用氢气裂解苄基酯。也可在氧化条件下除去苯环上带有供电子基团(例如甲氧基)的苄基酯,例如,硝酸铈铵(CAN)或2,3-二氯-5,6-二氰基醌(DDQ)是这种方法常用的试剂。取决于反应条件,方案5中的酸INT-1可作为与金属阳离子的盐或作为游离酸分离。
方案5:
如方案6中所述,若R4不表示芳基,则可通过使用构造单元INT-21和INT-18来组装通式INT-17的化合物。R4和R7至R8具有上文和下文所定义的含义,并且R4不表示芳基。可使用Mitsunobu反应或其变体的条件以立体选择性的方式组合通式INT-21和INT-18的构造单元(方案6)。该反应通常在-30至100℃用膦和偶氮二羧酸酯或酰胺在四氢呋喃、1,4-二噁烷、乙醚、甲苯、苯、二氯甲烷或其混合物中进行。经常使用的膦是三苯基膦和三丁基膦。它们通常与偶氮二甲酸二甲酯、偶氮二甲酸二乙酯、偶氮二甲酸二异丙酯、偶氮二甲酸二-(4-氯苄基)酯、偶氮二甲酸二苄基酯、偶氮二甲酸二-叔丁酯、偶氮二甲酸双-(二甲基酰胺)、偶氮二甲酸二哌啶或偶氮二甲酸二吗啉组合。
方案6
如方案7中所述,可类似于合成方案1中的通式(I)的化合物所述,通过使通式INT-19的适合羧酸(作为游离酸或作为与适合的金属阳离子例如Li+、Na+等的盐)和适合的胺INT-2(作为游离胺或者作为例如盐酸盐、氢溴酸盐等的盐)经由形成酰胺键而反应、来制备通式INT-20的化合物。方案7中的基团/术语R1至R3、R7至R10、A和Y具有上文和下文所定义的含义。
方案7:
如方案8中所示,若R4不表示芳基,则可以通过使用Mitsunobu反应或其变体的条件将构造单元INT-21和INT-20组合来合成通式(I)的化合物。方案8中的基团/术语R1至R4、R7至R10、A和Y具有上文和下文所定义的含义,且R4不表示芳基。针对方案6中合成INT-17描述了Mitsunobu反应的一般程序。
方案8:
所提出的合成途径可依赖于保护基团的使用。例如,存在的潜在反应性基团,例如羟基、羰基、羧基、氨基、烷基氨基或亚氨基,可在反应过程中被常规的保护基团保护,这些保护基团在反应后被再次裂解。适用于相应官能团及其除去的保护基团是本领域技术人员熟知的,且在有机合成的文献中对其进行了描述。
通式I的化合物可如下所述拆分为其对映异构体和/或非对映异构体。因此,例如,可将顺式/反式混合物拆分成其顺式和反式异构体,并可将外消旋化合物分离成其对映异构体。
顺式/反式混合物可例如通过色谱分离为其顺式和反式异构体。可通过本身已知的方法,将以外消旋物存在的通式I化合物分离成其旋光对映异构体,并且可以利用通式I化合物的不同物理化学性质,使用本身已知的方法,将通式I化合物的非对映异构体混合物拆分为其非对映异构体,所述方法例如色谱法和/或分步结晶法;若此后获得的化合物为外消旋物,则可如下所述将它们拆分为对映异构体。
外消旋物优选通过手性相上的柱色谱或通过从旋光活性溶剂中结晶或通过与旋光活性物质反应而进行拆分,所述旋光活性物质与外消旋化合物形成盐或衍生物,例如酯或酰胺。对于碱性化合物,可以与对映异构体纯的酸形成盐,对于酸性化合物,可以与对映异构体纯的碱形成盐。
非对映异构体衍生物用对映异构体纯的辅助化合物,例如酸及其活化的衍生物或醇形成。如此获得的盐或衍生物的非对映异构混合物的分离可以通过利用它们不同的理化特性,例如溶解度的差异来实现;游离的对映异构体可通过适当的试剂作用从纯非对映异构体盐或衍生物中释放出来。通常用于该目的的旋光活性酸以及可用作辅助残基的旋光活性醇是本领域技术人员已知的。
合成中间体
制备4-(4-环丙基-苯氧基)-苯甲酸(A)
向A-1(700mg,5.22mmol)在DCM(25mL)中的搅拌悬浮液中添加A-2(1.88g,10.4mmol)、吡啶(843μL,10.43mmol)和TEA(1.43mL,10.43mmol)。将所得混合物用氧气鼓泡10分钟。添加乙酸铜(II)(1.90g,10.43mmol)并将反应混合物在环境温度、在氧气气氛下搅拌。3天后,将混合物过滤并将滤液用水(10mL)洗涤,经Na2SO4干燥,过滤并浓缩。将粗制混合物在SiO2上提纯,用己烷中的10%EtOAc洗脱,得到A-3。
在0℃,向A-3(700mg,2.60mmol)在THF(6.5mL)和水(5.0mL)的混合物中的搅拌溶液中添加LiOH·H2O(218mg,5.22mmol)。将混合物温热至环境温度并搅拌12小时。将反应混合物用Et2O(10mL)萃取。分离各相并且将有机层用水(2x 1mL)萃取。将合并的水层冷却至0℃,并用HCl(4N)酸化至pH 4.0。将所得混合物过滤,并将固体用水(3x 1mL)和Et2O(3x3mL)洗涤,并在高真空下干燥,得到标题产物(A)。
制备4-(3-氟-4-三氟甲基-苯氧基)-苯甲酸(B)
根据对于合成中间体(A)所述的程序,标题化合物(B)从3-氟-4-三氟甲基-苯酚(600mg,3.33mmol)和A-2(899mg,5.00mmol)合成。
制备4-(4-氯-苯氧基)-苯甲酸(C)
向C-2(500mg,3.28mmol)在DCM(20mL)中的搅拌悬浮液中添加C-1(2.06g,13.1mmol)、吡啶(530μL,6.57mmol)和TEA(900μL,6.57mmol)。将所得混合物用氧气鼓泡5分钟。添加乙酸铜(II)(1.20g,6.57mmol),并将反应混合物在环境温度搅拌。3天后,将混合物用水(20mL)稀释并用EtOAc(50mL)萃取。分离各相并且将有机层用水(10mL)和盐水(10mL)洗涤,经Na2SO4干燥,过滤并浓缩。将粗制混合物在SiO2上提纯,用己烷中的1%EtOAc洗脱,得到C-3。
在0℃,向C-3(150mg,0.571mmol)在THF和水的混合物(1:1,5mL)中的搅拌溶液中添加LiOH·H2O(109mg,2.60mmol)。将反应混合物在环境温度搅拌5小时,并用Et2O(10mL)萃取。分离各相并且将有机层用水(2x 1mL)萃取。将合并的水层在0℃用HCl(1N)酸化至pH4.0,并将所得混合物用EtOAc(3x 10mL)萃取。将合并的EtOAc层用盐水(10mL)洗涤,经Na2SO4干燥,过滤并浓缩得到标题产物(C)。
制备4-(4-乙基-苯氧基)-苯甲酸(D)
根据对于合成中间体(C)所述的程序,标题化合物(D)从4-乙基苯基硼酸(1.23g,8.22mmol)和C-2(500mg,3.28mmol)合成。
制备4-(4-氰基-苯氧基)-苯甲酸(E)
根据对于合成中间体(C)所述的程序,标题化合物(E)从4-氰基苯基硼酸(2.90g,19.7mmol)和C-2(1.00g,6.57mmol)合成。
制备4-(苯并[1,3]间二氧杂环戊烯-5-基氧基)-苯甲酸(F)
根据对于合成中间体(C)所述的程序,标题化合物(F)从(3,4-亚甲基二氧基苯基)硼酸(1.90g,11.5mmol)和C-2(700mg,4.60mmol)合成。
制备4-(4-二甲基氨基甲酰基-苯氧基)-苯甲酸(G)
根据对于合成中间体(C)所述的程序,标题化合物(G)从4-(N,N-二甲基氨基羰基)苯基硼酸(3.80g,19.7mmol)和C-2(1.00g,6.57mmol)合成。
制备4-(4-乙酰基-苯氧基)-苯甲酸(H)
根据对于合成中间体(C)所述的程序,标题化合物(H)从4-乙酰基苯基硼酸(2.10g,12.8mmol)和C-2(1.30g,8.54mmol)合成。
制备4-(3,4-二氯-苯氧基)-苯甲酸(I)
根据对于合成中间体(C)所述的程序,标题化合物(I)从3,4-二氯苯基硼酸(3.76g,19.7mmol)和C-2(1.00g,6.57mmol)合成。
制备4-(4-甲氧基-苯氧基)-苯甲酸(J)
向J-2(1.50g,9.60mmol)在DMSO(10mL)中的搅拌溶液中添加J-1(1.78g,14.4mmol)和Cs2CO3(9.18g,24.0mmol)。将所得混合物在120℃加热15小时。将混合物通过硅藻土垫过滤,将滤垫用EtOAc(3x 30mL)洗涤并将滤液用水(30mL)萃取。分离各相并且将有机层经Na2SO4干燥,过滤,并浓缩。将粗品在SiO2上提纯,用己烷中的10%EtOAc洗脱,得到J-3。
根据对于从A-3合成中间体(A)所述的程序,标题化合物(J)从J-3(350mg,1.36mmol)合成。
制备4-(4-氟-苯氧基)-苯甲酸(K)
根据对于从J-1和J-2合成中间体J-3所述的程序,使用K2CO3(3.70g,26.8mmol)在DMF(13mL)中、在80℃,中间体K-2从K-1(1.50g,13.4mmol)和J-2(3.09g,20.0mmol)合成。
根据对于从A-3合成中间体(A)所述的程序,标题化合物(K)从K-2(1.00g,4.06mmol)合成。
制备4-对-甲苯基氧基-苯甲酸(L)
根据对于合成中间体(K)所述的程序,标题化合物(L)从4-甲基-苯酚(2.08g,19.2mmol)和J-2(1.50g,9.60mmol)合成。
制备4-(4-三氟甲氧基-苯氧基)-苯甲酸(M)
根据对于合成中间体(K)所述的程序,标题化合物(M)从4-三氟甲氧基-苯酚(2.56g,14.4mmol)和J-2(1.50g,9.60mmol)合成。
制备4-(4-异丙基-苯氧基)-苯甲酸(N)
根据对于合成中间体(K)所述的程序,标题化合物(N)从4-异丙基-苯酚(1.96g,14.4mmol)和J-2(1.50g,9.60mmol)合成。
制备6-哌啶-4-基-哒嗪-3-基胺二盐酸盐(O)
将O-2的THF溶液(20.00ml,0.5M,10.00mmol)分批添加至O-1(500mg,2.87mmol)、三(二亚苄基丙酮)二钯(0)(263mg,0.290mmol)和二-叔丁基新戊基鏻四氟硼酸酯(174mg,0.570mmol)的THF(25mL)溶液中,并将所得混合物在环境温度搅拌24小时。将反应混合物浓缩并重新溶于MeOH(10mL)中,并通过硅藻土垫过滤。将滤垫用MeOH(3x 5mL)洗涤并将滤液浓缩。将残余物用反相HPLC色谱提纯(C-18柱,用含0.1%甲酸的水中的5%至60%乙腈洗脱)。将产物在SiO2上进一步提纯,用DCM中的1-10%MeOH的梯度洗脱,得到O-3。
向O-3(486mg,1.74mmol)的1,2二氯乙烷(15mL)溶液中添加HCl的二噁烷溶液(5.00mL,4M,20.0mmol)。将所得溶液搅拌16小时并浓缩。将残余物用DCM研磨并真空干燥,得到标题产物(O)。
制备6-哌嗪-1-基-哒嗪-3-基胺二盐酸盐(P)
在密封的压力容器中,将P-1(10.0g,77.2mmol)和P-2(43.1g,232mmol)的搅拌混合物在150℃加热15小时。将反应混合物冷却至环境温度,用水(50mL)稀释,并用EtOAc(100mL)萃取。将有机层用水(3x 20mL)洗涤,经Na2SO4干燥,过滤并浓缩。将残余物用乙醚研磨,得到P-3。
根据对于从O-3合成中间体(O)所述的程序,标题化合物(P)从P-3(2.73g,6.86mmol)合成。
制备1',2',3',4',5',6'-六氢-[3,4']联吡啶基-6-基胺二盐酸盐(Q)
根据对于合成中间体(O)所述的程序,标题化合物(Q)从Q-1(346mg,2.00mmol)和O-2(12.0mL,0.5M,在THF中,6.00mmol)合成。
合成式I的化合物
制备5-[1-(4-苯氧基苯甲酰基)哌啶-4-基]吡啶-2-胺(化合物1)
将1-1(40.0mg,0.187mmol)和EDCI(53.6mg,0.280mmol)在DMA(1mL)中的混合物搅拌15分钟,并添加至Q(60.7mg,0.242mmol)和DIPEA(0.130mL,0.746mmol)在DMA(0.5mL)中的混合物中。将所得混合物在环境温度振荡16小时,并在40℃搅拌6小时。将粗制反应混合物过滤,并用反相HPLC提纯(C-18柱,用含2.5mM NH4HCO3的水中的5%至95%乙腈洗脱),得到标题产物(1)。
制备6-(1-{4-[4-(三氟甲基)苯氧基]苯甲酰基}哌啶-4-基)哒嗪-3-胺(化合物2)
将2-1(40.0mg,0.142mmol)和HATU(70.0mg,0.184mmol)的DMA(1mL)溶液搅拌15分钟,并添加至O(36.5mg,0.170mmol)和DIPEA(0.086mL,0.496mmol)在DMA(0.5mL)中的混合物中。将所得混合物在40℃振荡16小时。将粗制反应混合物用水(0.1mL)处理,并用反相HPLC提纯(C-18柱,用含0.1%TFA的水中的5%至95%乙腈洗脱),得到标题产物(2)。
根据对于合成化合物2所述的步骤,使用前面部分所述的适当中间体制备以下化合物:
6-[1-(4-苯氧基苯甲酰基)哌啶-4-基]哒嗪-3-胺(化合物3)
6-(1-{4-[4-(三氟甲氧基)苯氧基]苯甲酰基}哌啶-4-基)哒嗪-3-胺(化合物4)
6-{1-[4-(4-甲基苯氧基)苯甲酰基]哌啶-4-基}哒嗪-3-胺(化合物5)
6-{4-[4-(4-环丙基苯氧基)苯甲酰基]哌嗪-1-基}哒嗪-3-胺(化合物6)
4-{4-[4-(6-氨基哒嗪-3-基)哌嗪-1-羰基]苯氧基}苯甲腈(化合物7)
6-{4-[4-(2H-1,3-苯并间二氧杂环戊烯-5-基氧基)苯甲酰基]哌嗪-1-基}哒嗪-3-胺(化合物8)
6-{1-[4-(4-甲氧基苯氧基)苯甲酰基]哌啶-4-基}哒嗪-3-胺(化合物9)
6-{1-[4-(4-氟苯氧基)苯甲酰基]哌啶-4-基}哒嗪-3-胺(化合物10)
6-{4-[4-(4-氯苯氧基)苯甲酰基]哌嗪-1-基}哒嗪-3-胺(化合物11)
6-{1-[4-(4-环丙基苯氧基)苯甲酰基]哌啶-4-基}哒嗪-3-胺(化合物12)
6-{1-[4-(4-氯苯氧基)苯甲酰基]哌啶-4-基}哒嗪-3-胺(化合物13)
5-{4-[4-(4-乙基苯氧基)苯甲酰基]哌嗪-1-基}吡啶-2-胺(化合物14)
5-[4-(4-苯氧基苯甲酰基)哌嗪-1-基]吡啶-2-胺(化合物15)
1-(4-{4-[4-(6-氨基哒嗪-3-基)哌啶-1-羰基]苯氧基}苯基)乙-1-酮(化合物16)
6-(1-{4-[4-(丙-2-基)苯氧基]苯甲酰基}哌啶-4-基)哒嗪-3-胺(化合物17)
6-(4-{4-[4-(丙-2-基)苯氧基]苯甲酰基}哌嗪-1-基)哒嗪-3-胺(化合物18)
5-(4-{4-[4-(三氟甲基)苯氧基]苯甲酰基}哌嗪-1-基)吡啶-2-胺(化合物19)
6-{4-[4-(4-乙基苯氧基)苯甲酰基]哌嗪-1-基}哒嗪-3-胺(化合物20)
6-(4-{4-[4-(三氟甲氧基)苯氧基]苯甲酰基}哌嗪-1-基)哒嗪-3-胺(化合物21)
6-(4-{4-[3-氟-4-(三氟甲基)苯氧基]苯甲酰基}哌嗪-1-基)哒嗪-3-胺(化合物22)
6-{1-[4-(4-乙基苯氧基)苯甲酰基]哌啶-4-基}哒嗪-3-胺(化合物23)
6-[4-(4-苯氧基苯甲酰基)哌嗪-1-基]哒嗪-3-胺(化合物24)
4-{4-[4-(6-氨基哒嗪-3-基)哌嗪-1-羰基]苯氧基}-N,N-二甲基苯甲酰胺(化合物25)
6-(4-{4-[4-(三氟甲基)苯氧基]苯甲酰基}哌嗪-1-基)哒嗪-3-胺(化合物26)
实施例27
5-{4-[2-氟-4-(4-氟苯氧基)苯甲酰基]-4,7-二氮杂螺[2.5]辛-7-基}-4-甲氧基吡啶-2-胺
2-氟-4-(4-氟苯氧基)苯甲酸甲酯
将2,4-二氟苯甲酸甲酯(1.00g;5.81mmol)、4-氟苯酚(0.72g;6.39mmol)和碳酸钾(1.61g;11.62mmol)在DMF(20mL)中、在90℃搅拌4小时。将反应混合物用水稀释,并用DCM萃取三次。将合并的有机层经MgSO4干燥,过滤并减压浓缩。将残余物通过RP-HPLC提纯(ACN/水+TFA)。
产率:0.45g(29%)ESI-MS:m/z=265[M+H]+Rt(HPLC):1.15min(方法1)
2-氟-4-(4-氟苯氧基)苯甲酸
将2-氟-4-(4-氟苯氧基)苯甲酸甲酯(0.45g;1.70mmol)和NaOH(1mol/L;水溶液;5.11mL;5.11mmol)在MeOH(20mL)中、在50℃搅拌2小时。蒸发有机溶剂,并将剩余反应混合物用HCl(1mol/L;水溶液)酸化。将所得沉淀过滤,用水洗涤并在干燥烘箱中干燥。
产率:0.40g(94%)ESI-MS:m/z=251[M+H]+Rt(HPLC):1.02min(方法1)
5-溴-2-(2,5-二甲基-1H-吡咯-1-基)-4-甲氧基吡啶
使用Dean-Stark装置,将5-溴-4-甲氧基-吡啶-2-基胺(9.50g,46.79mmol)、己烷-2,5-二酮(7.08mL,60.83mmol)和对甲苯磺酸(0.81g,4.68mmol)在甲苯(80mL)中、在120℃搅拌过夜。将反应混合物减压浓缩,溶于DCM中,并通过硅胶色谱提纯(DCM)。
产率:7.60g(58%)ESI-MS:m/z=281和283[M+H]+(Br-同位素模式)Rt(HPLC):1.13min(方法1)
7-[6-(2,5-二甲基-1H-吡咯-1-基)-4-甲氧基吡啶-3-基]-4,7-二氮杂螺[2.5]辛烷-4-甲酸叔丁酯
反应在氩气气氛中进行。将5-溴-2-(2,5-二甲基-1H-吡咯-1-基)-4-甲氧基吡啶(1.55g;5.50mmol)、4,7-二氮杂螺[2.5]辛烷-4-甲酸叔丁酯(1.20g;5.65mmol)、CPhos-Pd-3G催化剂(0.44g;0.55mmol)和碳酸铯(5.38g;16.50mmol)在1,4-二噁烷(40mL)中、在80℃搅拌过夜。将反应混合物过滤,并减压浓缩。将残余物溶于EtOAc并用水洗涤数次。分离有机层,经Na2SO4干燥,过滤并减压浓缩。
产率:定量ESI-MS:m/z=413[M+H]+Rt(HPLC):1.07min(方法1)
7-[6-(2,5-二甲基-1H-吡咯-1-基)-4-甲氧基吡啶-3-基]-4,7-二氮杂螺[2.5]辛烷*三氟乙酸
将7-[6-(2,5-二甲基-1H-吡咯-1-基)-4-甲氧基吡啶-3-基]-4,7-二氮杂螺[2.5]辛烷-4-甲酸叔丁酯(2.30g;5.58mmol)和TFA(2.00mL;25.92mmol)在DCM(50mL)中、在室温搅拌过夜。添加相同量的TFA,并将反应混合物在45℃搅拌4小时。将反应混合物减压浓缩并使用无需进一步提纯。
产率:定量ESI-MS:m/z=313[M+H]+Rt(HPLC):0.70min(方法1)
5-{4,7-二氮杂螺[2.5]辛-7-基}-4-甲氧基吡啶-2-胺
将7-[6-(2,5-二甲基-1H-吡咯-1-基)-4-甲氧基吡啶-3-基]-4,7-二氮杂螺[2.5]辛烷*三氟乙酸(2.00g;4.69mmol)、羟基胺盐酸盐(1.96g;28.14mmol)和TEA(1.30mL;9.26mmol)在EtOH/水(2/1;100mL)中、在90℃搅拌过夜。蒸发有机溶剂并将剩余水层用DCM洗涤数次。将水层减压浓缩并通过RP-HPLC提纯(ACN/水/NH4OH)。将产物在PE中研磨,并过滤。所需产物无需进一步提纯而使用。
产率:定量ESI-MS:m/z=235[M+H]+Rt(HPLC):0.60min(方法3)
5-{4-[2-氟-4-(4-氟苯氧基)苯甲酰基]-4,7-二氮杂螺[2.5]辛-7-基}-4-甲氧基吡啶-2-胺
将2-氟-4-(4-氟苯氧基)苯甲酸(30.0mg;0.12mmol)、HATU(45.6mg;0.12mmol)和DIPEA(69.2μL;0.40mmol)在DMF(2mL)中、在室温搅拌5分钟。添加5-{4,7-二氮杂螺[2.5]辛-7-基}-4-甲氧基吡啶-2-胺(23.4mg;0.10mmol)。搅拌1小时后,将反应混合物通过RP-HPLC提纯(ACN/水/NH4OH)。产率:11.0mg(24%)ESI-MS:m/z=467[M+H]+Rt(HPLC):0.99min(方法3)
实施例28
5-{4-[2,5-二氟-4-(4-氟苯氧基)苯甲酰基]-4,7-二氮杂螺[2.5]辛-7-基}-4-甲氧基吡啶-2-胺
2,5-二氟-4-(4-氟苯氧基)苯甲酸
将2,4,5-三氟苯甲酸乙酯(0.50g;2.45mmol,可商购CAS编号:351354-41-1)、4-氟苯酚(0.30g;2.69mmol)和碳酸钾(0.68g;4.90mmol)在DMF(2mL)中、在80℃搅拌2小时。将反应混合物用水稀释并用DCM萃取三次。将合并的有机层经MgSO4干燥,过滤并减压浓缩。将残余物溶于MeOH(20mL)并添加NaOH(1mol/L;水溶液;7.35mL;7.35mmol)。在50℃搅拌2小时后,蒸发有机溶剂。将剩余水层用HCl(1mol/L;水溶液)酸化。将所得沉淀过滤,用水洗涤并在干燥烘箱中干燥。
产率:0.63g(96%)ESI-MS:m/z=269[M+H]+Rt(HPLC):1.04min(方法1)
5-{4-[2,5-二氟-4-(4-氟苯氧基)苯甲酰基]-4,7-二氮杂螺[2.5]辛-7-基}-4-甲氧基吡啶-2-胺
将2,5-二氟-4-(4-氟苯氧基)苯甲酸(32.2mg;0.12mmol)、HATU(45.6mg;0.12mmol)和DIPEA(69.2μL;0.40mmol)在DMF(2mL)中、在室温搅拌5分钟。添加5-{4,7-二氮杂螺[2.5]辛-7-基}-4-甲氧基吡啶-2-胺(23.4mg;0.10mmol)。搅拌1小时后,将反应混合物通过RP-HPLC提纯(ACN/水/NH4OH)。
产率:14.0mg(29%)ESI-MS:m/z=485[M+H]+Rt(HPLC):1.00min(方法3)
实施例29
5-{1-[2-氟-4-(4-氟苯氧基)-5-甲氧基苯甲酰基]哌啶-4-基}-4-甲氧基吡啶-2-胺2-氟-4-(4-氟苯氧基)-5-甲氧基苯甲酸
将2,4-二氟-5-甲氧基苯甲酸甲酯(0.70g;3.46mmol,可商购CAS编号1804416-21-4))、4-氟苯酚(0.43g;3.81mmol)和碳酸钾(0.96g;6.93mmol)在DMF(20mL)中、在90℃搅拌2小时。将反应混合物过滤并通过RP-HPLC提纯(ACN/水+TFA)。将残余物溶于MeOH(20mL),并添加NaOH(1mol/L;水溶液;6.93mL;6.93mmol)。在45℃搅拌3小时后,将反应混合物减压浓缩。将残余物溶于水并用HCl(1mol/L;水溶液)酸化至pH 5。将所得沉淀过滤并在干燥烘箱中干燥。
产率:0.65g(67%)ESI-MS:m/z=281[M+H]+Rt(HPLC):1.01min(方法1)
6-氨基-4-甲氧基-1’,2’,3’,6’-四氢-[3,4’-联吡啶]-1’-甲酸叔丁酯
反应在氩气气氛中进行。将5-溴-4-甲氧基吡啶-2-胺(7.40g;32.80mmol)、4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1,2,3,6-四氢吡啶-1-甲酸叔丁酯(11.16g;36.08mmol)和碳酸钠(2mol/L;水溶液;65.60mL;131.21mmol)在1,4-二噁烷(300mL)用氩气吹扫。5分钟后添加Xphos第二代催化剂(0.77g;0.98mmol)并将反应混合物在密封小瓶中、在100℃搅拌过夜。将反应混合物减压浓缩。将残余物溶于水并用EtOAc萃取数次。将合并的有机层通过Na2SO4干燥,过滤并减压浓缩。将残余物通过硅胶色谱提纯(DCM/MeOH)。产率:9.69g(97%)ESI-MS:m/z=306[M+H]+Rt(HPLC):0.83min(方法2)
在氢气气氛(Parr装置;50psi)中,将6-氨基-4-甲氧基-1’,2’,3’,6’-四氢-[3,4’-联吡啶]-1’-甲酸叔丁酯(5.11g;16.73mmol)和Pd/C(10%;0.60g)在MeOH(100mL)中、在室温搅拌41.5小时。在此时,添加额外的催化剂两次,并将反应混合物进一步氢化。在过滤除去催化剂后,将母液减压浓缩。产物无需进一步提纯而使用。
产率:4.71g(92%)ESI-MS:m/z=308[M+H]+Rt(HPLC):0.82min(方法2)
4-甲氧基-5-(哌啶-4-基)吡啶-2-胺二盐酸盐
将4-(6-氨基-4-甲氧基吡啶-3-基)-哌啶-1-甲酸叔丁酯(6.90g;22.45mmol)和HCl(4mol/L;在1,4-二噁烷中的溶液;69.00mL;276.0mmol)在DCM(89.70mL)中、在室温搅拌过夜。将反应混合物减压浓缩。将残余物在Et2O中研磨并过滤。所需产物无需进一步提纯而使用。
产率:5.30g(84%)ESI-MS:m/z=208[M+H]+Rt(HPLC):0.66min(方法3)
5-{1-[2-氟-4-(4-氟苯氧基)-5-甲氧基苯甲酰基]哌啶-4-基}-4-甲氧基吡啶-2-胺
将2-氟-4-(4-氟苯氧基)-5-甲氧基苯甲酸(33.6mg;0.12mmol)、HATU(45.6mg;0.12mmol)和DIPEA(69.2μL;0.40mmol)在DMF(2mL)中、在室温搅拌5分钟。添加4-甲氧基-5-(哌啶-4-基)吡啶-2-胺二盐酸盐(28.0mg;0.10mmol)。搅拌1小时后,将反应混合物通过RP-HPLC提纯(ACN/水/NH4OH)。
产率:37.0mg(79%)ESI-MS:m/z=470[M+H]+Rt(HPLC):0.99min(方法3)
实施例30
5-{1-[2,5-二氟-4-(4-氟苯氧基)苯甲酰基]哌啶-4-基}-4-甲氧基吡啶-2-胺
将2,5-二氟-4-(4-氟苯氧基)苯甲酸(32.2mg;0.12mmol)、HATU(45.6mg;0.12mmol)和DIPEA(69.2μL;0.40mmol)在DMF(2mL)中、在室温搅拌5分钟。添加4-甲氧基-5-(哌啶-4-基)吡啶-2-胺二盐酸盐(28.0mg;0.10mmol)。搅拌1小时后,将反应混合物通过RP-HPLC提纯(ACN/水/NH4OH)。产率:29.1mg(64%)ESI-MS:m/z=458[M+H]+Rt(HPLC):0.81min(方法6)
实施例31
5-{1-[2-氟-4-(4-氟苯氧基)苯甲酰基]哌啶-4-基}-4-甲氧基吡啶-2-胺
将2-氟-4-(4-氟苯氧基)苯甲酸(30.0mg;0.12mmol)、HATU(45.6mg;0.12mmol)和DIPEA(69.2μL;0.40mmol)在DMF(2mL)中、在室温搅拌5分钟。添加4-甲氧基-5-(哌啶-4-基)吡啶-2-胺二盐酸盐(28.0mg;0.10mmol)。搅拌1小时后,将反应混合物通过RP-HPLC提纯(ACN/水/NH4OH)。
产率:28.2mg(64%)ESI-MS:m/z=440[M+H]+Rt(HPLC):0.80min(方法6)
实施例32
5-{1-[4-(4-氟苯氧基)苯甲酰基]哌啶-4-基}-4-甲氧基吡啶-2-胺4-甲氧基-5-(哌啶-4-基)吡啶-2-胺双(三氟乙酸)
将4-(6-氨基-4-甲氧基吡啶-3-基)-哌啶-1-甲酸叔丁酯(8.74g;28.43mmol)和TFA(21.94mL;284.33mmol)在DCM(200mL)中、在室温搅拌过夜。将反应混合物减压浓缩。将残余物用乙醚研磨,过滤并在干燥烘箱中干燥。残余物无需进一步提纯而使用。
产率:10.60g(86%)ESI-MS:m/z=208[M+H]+Rt(HPLC):0.68min(方法3)
5-{1-[4-(4-氟苯氧基)苯甲酰基]哌啶-4-基}-4-甲氧基吡啶-2-胺*三氟乙酸
将4-甲氧基-5-(哌啶-4-基)吡啶-2-胺双(三氟乙酸)(46.9mg;0.11mmol)、4-(4-氟苯氧基)苯甲酸(25.0mg;0.11mmol)和DIPEA(76.0μL;0.44mmol)在DMF(2mL)中、在室温搅拌。添加HATU(40.9mg;0.11mmol)。搅拌过夜后,将反应混合物通过RP-HPLC提纯(ACN/水+TFA)。
产率:32.9mg(57%)ESI-MS:m/z=422[M+H]+Rt(HPLC):0.65min(方法11)
实施例33
5-{1-[2-氟-5-甲氧基-4-(2-甲基丙氧基)苯甲酰基]哌啶-4-基}-4-甲氧基吡啶-2-胺
2-氟-4-羟基-5-甲氧基苯甲酸甲酯
在一氧化碳气氛(5bar)中,将4-溴-5-氟-2-甲氧基苯酚(0.31g,1.40mmol)、无水乙酸钠(0.13mg,1.54mmol)、[1,1'-双(二苯基膦基)-二茂铁]-二氯化钯-(II)与二氯甲烷的络合物(1:1)(0.06mg,0.07mmol)在甲醇(25mL)中在100℃搅拌19小时。减压除去溶剂。将残余物溶解在适当体积的DMF中,并通过PL-Thiol柱(体积1mL,用MeOH预先洗涤)过滤。用适当体积的DMF/MeOH(比率9/1)洗脱柱。减压浓缩溶剂,并将残余物通过RP-HPLC提纯(ACN/水+TFA)。
产率:0.18g(64%)ESI-MS:m/z=201[M+H]+Rt(HPLC):0.84min(方法1)
2-氟-4-羟基-5-甲氧基苯甲酸
将2-氟-4-羟基-5-甲氧基苯甲酸甲酯(0.70g,3.50mmol,可商购CAS号1935364-07-0)在20mL THF和2mL甲醇中、在室温搅拌,并添加8mL的1M LiOH水溶液(8.0mmol)。将反应混合物在50℃搅拌过夜。添加额外的2mL的1M LiOH水溶液(2.0mmol)并在60℃搅拌过夜。减压除去有机溶剂,并将水层用4M HCL水溶液酸化。将所得沉淀过滤并在干燥烘箱中在45℃干燥。
产率:0.63g(96%)ESI-MS:m/z=187[M+H]+Rt(HPLC):0.59min(方法2)
4-[4-(6-氨基-4-甲氧基吡啶-3-基)哌啶-1-羰基]-5-氟-2-甲氧基苯酚
将2-氟-4-羟基-5-甲氧基苯甲酸(0.20g;1.06mmol)、4-甲氧基-5-(哌啶-4-基)吡啶-2-胺双(三氟乙酸)(0.46g;1.06mmol)和DIPEA(0.75mL;4.34mmol)在DMF(6mL)中、在室温搅拌。添加HATU(0.40g;1.06mmol)。搅拌过夜后,将反应混合物用水稀释,并用DCM萃取。分离有机层并减压浓缩。将残余物通过硅胶色谱提纯(DCM/MeOH)。
产率:0.12g(30%)ESI-MS:m/z=376[M+H]+Rt(HPLC):0.71min(方法2)
5-{1-[2-氟-5-甲氧基-4-(2-甲基丙氧基)苯甲酰基]哌啶-4-基}-4-甲氧基吡啶-2-胺三氟乙酸
将4-[4-(6-氨基-4-甲氧基吡啶-3-基)哌啶-1-羰基]-5-氟-2-甲氧基苯酚(20.0mg;0.05mmol)、2-甲基丙-1-醇(11.1μL;0.12mmol)、TPP(40.0mg;0.15mmol)和DTAD(30.0mg;0.13mmol)在1,4-二噁烷(3mL)中、在60℃搅拌1小时。将反应混合物通过RP-HPLC提纯(ACN/水+TFA)。
产率:11.6mg(40%)ESI-MS:m/z=432[M+H]+Rt(HPLC):0.79min(方法8)
实施例34
5-(1-{2-氟-5-甲氧基-4-[(3-甲基环丁基)甲氧基]苯甲酰基}哌啶-4-基)-4-甲氧基吡啶-2-胺三氟乙酸
将4-[4-(6-氨基-4-甲氧基吡啶-3-基)哌啶-1-羰基]-5-氟-2-甲氧基苯酚(20.0mg;0.05mmol)、(3-甲基环丁基)甲醇(12.0mg;0.12mmol)、TPP(40.0mg;0.15mmol)和DTAD(30.0mg;0.13mmol)在1,4-二噁烷(3mL)中、在60℃搅拌1小时。将反应混合物通过RP-HPLC提纯(ACN/水+TFA)。
产率:6.8mg(22%)ESI-MS:m/z=458[M+H]+Rt(HPLC):0.87min(方法8)
实施例35
5-{1-[4-(环丙基甲氧基)-2-氟-5-甲氧基苯甲酰基]哌啶-4-基}-4-甲氧基吡啶-2-胺三氟乙酸
将4-[4-(6-氨基-4-甲氧基吡啶-3-基)哌啶-1-羰基]-5-氟-2-甲氧基苯酚(25.0mg;0.07mmol)、环丙基甲醇(16.2μL;0.20mmol)、TPP(34.9mg;0.13mmol)和DTAD(30.7mg;0.13mmol)在1,4-二噁烷(3mL)中、在60℃搅拌2小时。将反应混合物通过RP-HPLC提纯(ACN/水+TFA)。
产率:21.0mg(36%)ESI-MS:m/z=430[M+H]+Rt(HPLC):0.86min(方法3)
实施例36
5-{1-[4-(环丁基甲氧基)-2-氟-5-甲氧基苯甲酰基]哌啶-4-基}-4-甲氧基吡啶-2-胺三氟乙酸
将4-[4-(6-氨基-4-甲氧基吡啶-3-基)哌啶-1-羰基]-5-氟-2-甲氧基苯酚(25.0mg;0.07mmol)、环丁基甲醇(19.3μL;0.20mmol)、TPP(34.9mg;0.13mmol)和DTAD(30.7mg;0.13mmol)在1,4-二噁烷(2mL)中、在60℃搅拌2小时。将反应混合物通过RP-HPLC提纯(ACN/水+TFA)。
产率:23.0mg(62%)ESI-MS:m/z=444[M+H]+Rt(HPLC):0.91min(方法1)
实施例37
5-(1-{4-[(3,3-二氟环丁基)甲氧基]-2-氟-5-甲氧基苯甲酰基}哌啶-4-基)-4-甲氧基吡啶-2-胺三氟乙酸
将4-[4-(6-氨基-4-甲氧基吡啶-3-基)哌啶-1-羰基]-5-氟-2-甲氧基苯酚(20.0mg;0.05mmol)、(3,3-二氟环丁基)甲醇(14.7mg;0.12mmol)、TPP(40.0mg;0.15mmol)和DTAD(30.0mg;0.13mmol)在1,4-二噁烷(3mL)中、在60℃搅拌1小时。将反应混合物通过RP-HPLC提纯(ACN/水+TFA)。产率:11.5mg(36%)ESI-MS:m/z=480[M+H]+Rt(HPLC):0.74min(方法8)
实施例38
5-[1-(2-氟-4-{[反式-2-甲基环丙基]甲氧基}苯甲酰基)哌啶-4-基]-4-甲氧基吡啶-2-胺
4-[4-(6-氨基-4-甲氧基吡啶-3-基)哌啶-1-羰基]-3-氟苯酚
将2-氟-4-羟基苯甲酸(1.25g;8.01mmol)、TBTU(2.57g;8.01mmol)和DIPEA(7.00mL;40.69mmol)在DMF(40mL)中、在室温搅拌5分钟。添加4-甲氧基-5-(哌啶-4-基)吡啶-2-胺二盐酸盐(2.33g;8.33mmol)。在50℃搅拌2小时后,添加额外的2-氟-4-羟基苯甲酸和TBTU,并在50℃搅拌过夜。将反应混合物通过RP-HPLC提纯(ACN/水/NH4OH)以及额外的提纯(ACN/水+TFA),并随后再进行一次提纯(ACN/水/NH4OH)。
产率:1.80g(65%)ESI-MS:m/z=346[M+H]+Rt(HPLC):0.72min(方法1)
5-[1-(2-氟-4-{[反式-2-甲基环丙基]甲氧基}苯甲酰基)哌啶-4-基]-4-甲氧基吡啶-2-胺
将4-[4-(6-氨基-4-甲氧基吡啶-3-基)哌啶-1-羰基]-3-氟苯酚(25.0mg;0.07mmol)、[反式-2-甲基环丙基]甲醇(14.6μL;0.17mmol)、TPP(50.0mg;0.19mmol)和DTAD(40.0mg;0.17mmol)在1,4-二噁烷(3mL)中在60℃搅拌1小时。将反应混合物通过RP-HPLC提纯(ACN/水/NH4OH)。
产率:16.3mg(36%)ESI-MS:m/z=414[M+H]+Rt(HPLC):0.67min(方法6)
实施例39
将4-[4-(6-氨基-4-甲氧基吡啶-3-基)哌啶-1-羰基]-3-氟苯酚(25.0mg;0.07mmol)、丙-1-醇(12.2μL;0.17mmol)、TPP(50.0mg;0.19mmol)和DTAD(40.0mg;0.17mmol)在1,4-二噁烷(3mL)中在60℃搅拌1小时。将反应混合物通过RP-HPLC提纯(ACN/水+TFA)。
产率:25.7mg(71%)ESI-MS:m/z=388[M+H]+Rt(HPLC):0.62min(方法11)
实施例40
5-(1-{2-氟-4-[(1,2,3-噻二唑-4-基)甲氧基]苯甲酰基}哌啶-4-基)-4-甲氧基吡啶-2-胺三氟乙酸
将4-[4-(6-氨基-4-甲氧基吡啶-3-基)哌啶-1-羰基]-3-氟苯酚(25.0mg;0.07mmol)、(1,2,3-噻二唑-4-基)甲醇(19.7mg;0.17mmol)、TPP(50.0mg;0.19mmol)和DTAD(40.0mg;0.17mmol)在1,4-二噁烷(3mL)中、在60℃搅拌1小时。将反应混合物通过RP-HPLC提纯(ACN/水+TFA)。
产率:23.7mg(59%)ESI-MS:m/z=444[M+H]+Rt(HPLC):0.51min(方法11)
实施例41
5-{1-[4-(环己基甲氧基)-2-氟苯甲酰基]哌啶-4-基}-4-甲氧基吡啶-2-胺三氟乙酸
将4-[4-(6-氨基-4-甲氧基吡啶-3-基)哌啶-1-羰基]-3-氟苯酚(25.0mg;0.07mmol)、环己基甲醇(21.1μL;0.17mmol)、TPP(50.0mg;0.19mmol)和DTAD(40.0mg;0.17mmol)在1,4-二噁烷(3mL)中、在60℃搅拌1小时。将反应混合物通过RP-HPLC提纯(ACN/水+TFA)。
产率:27.3mg(68%)ESI-MS:m/z=442.5[M+H]+Rt(HPLC):0.78min(方法11)
实施例42
5-{1-[4-(2-环丙基乙氧基)-2-氟苯甲酰基]哌啶-4-基}-4-甲氧基吡啶-2-胺三氟乙酸
将4-[4-(6-氨基-4-甲氧基吡啶-3-基)哌啶-1-羰基]-3-氟苯酚(25.0mg;0.07mmol)、2-环丙基乙-1-醇(14.6mg;0.17mmol)、TPP(50.0mg;0.19mmol)和DTAD(40.0mg;0.17mmol)在1,4-二噁烷(3mL)中、在60℃搅拌1小时。将反应混合物通过RP-HPLC提纯(ACN/水+TFA)。
产率:27.2mg(71%)ESI-MS:m/z=414[M+H]+Rt(HPLC):0.67min(方法11)
实施例43
将4-[4-(6-氨基-4-甲氧基吡啶-3-基)哌啶-1-羰基]-3-氟苯酚(25.0mg;0.07mmol)、苯基甲醇(17.6μL;0.17mmol)、TPP(50.0mg;0.19mmol)和DTAD(40.0mg;0.17mmol)在1,4-二噁烷(3mL)中在60℃搅拌1小时。将反应混合物通过RP-HPLC提纯(ACN/水+TFA)。
产率:26.5mg(67%)ESI-MS:m/z=436[M+H]+Rt(HPLC):0.66min(方法11)
实施例44
5-{1-[4-(环丁基甲氧基)-3-甲氧基苯甲酰基]哌啶-4-基}-4-甲氧基吡啶-2-胺4-[4-(6-氨基-4-甲氧基吡啶-3-基)哌啶-1-羰基]-2-甲氧基苯酚
将4-羟基-3-甲氧基苯甲酸(0.14g;0.86mmol)、HATU(0.33g;0.86mmol)和DIPEA(0.49mL;2.86mmol)在DMF(5mL)中、在室温搅拌5分钟。添加4-甲氧基-5-(哌啶-4-基)吡啶-2-胺二盐酸盐(0.20g;0.71mmol)。在室温搅拌2小时后,添加NaOH(1mol/L;水溶液;0.5mL)并搅拌3天。将反应混合物用水稀释,过滤并通过RP-HPLC提纯(ACN/水/NH4OH)。
产率:0.1g(39%)ESI-MS:m/z=358[M+H]+Rt(HPLC):0.69min(方法3)
5-{1-[4-(环丁基甲氧基)-3-甲氧基苯甲酰基]哌啶-4-基}-4-甲氧基吡啶-2-胺三氟乙酸
将4-[4-(6-氨基-4-甲氧基吡啶-3-基)哌啶-1-羰基]-2-甲氧基苯酚(25.0mg;0.07mmol)、环丁基甲醇(20.3μL;0.21mmol)、TPP(36.7mg;0.14mmol)和DTAD(32.2mg;0.14mmol)在1,4-二噁烷(2mL)中、在60℃搅拌2小时。将反应混合物通过RP-HPLC提纯(ACN/水+TFA)。
产率:12.1mg(32%)ESI-MS:m/z=426[M+H]+Rt(HPLC):0.64min(方法12)
实施例45
6-{1-[2,5-二氟-4-(4-氟苯氧基)苯甲酰基]哌啶-4-基}哒嗪-3-胺4-(6-氨基哒嗪-3-基)-1,2,3,6-四氢吡啶-1-甲酸叔丁酯
反应在氩气气氛中进行。将6-氯哒嗪-3-胺(5.20g;40.14mmol)、4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1,2,3,6-四氢吡啶-1-甲酸叔丁酯(13.65g;44.15mmol)和碳酸钠(2mol/L;水溶液;80.28mL;160.56mmol)在1,4-二噁烷(350mL)中用氩气吹扫。5分钟后添加Xphos第二代催化剂(0.95g;1.20mmol)并将反应混合物在密封小瓶中、在100℃搅拌过夜。将反应混合物过滤,并减压浓缩。将残余物溶于MeOH,用水沉淀并过滤。在干燥烘箱中、在50℃干燥沉淀物。产物无需进一步提纯而使用。
产率:定量ESI-MS:m/z=277[M+H]+Rt(HPLC):0.78min(方法2)
4-(6-氨基哒嗪-3-基)-哌啶-1-甲酸叔丁酯
在氢气气氛(Parr装置;4bar)中,将4-(6-氨基哒嗪-3-基)-1,2,3,6-四氢吡啶-1-甲酸叔丁酯(4.85g;17.55mmol)和Pd/C(10%;0.50g)在MeOH(100mL)中、在室温搅拌3小时。在过滤除去催化剂后,将母液减压浓缩。产物无需进一步提纯而使用。
产率:定量ESI-MS:m/z=279[M+H]+Rt(HPLC):0.86(方法3)
6-(哌啶-4-基)哒嗪-3-胺二盐酸盐
将4-(6-氨基哒嗪-3-基)哌啶-1-甲酸叔丁酯(100.0mg;0.36mmol)和HCl(4mol/L;在1,4-二噁烷中的溶液;1.00mL;4.00mmol)在1,2-二氯乙烷(3mL)中、在室温搅拌16小时。将反应混合物减压浓缩并无需进一步提纯而使用。产率:82mg(82%)ESI-MS:m/z=179[M+H]+Rt(HPLC):0.28min(方法3)
6-{1-[2,5-二氟-4-(4-氟苯氧基)苯甲酰基]哌啶-4-基}哒嗪-3-胺
将2,5-二氟-4-(4-氟苯氧基)苯甲酸(32.2mg;0.12mmol)、HATU(45.6mg;0.12mmol)和DIPEA(69.2μL;0.40mmol)在DMF(2mL)中、在室温搅拌5分钟。添加6-(哌啶-4-基)哒嗪-3-胺二盐酸盐(25.1mg;0.10mmol)。在室温搅拌1小时后,将反应混合物通过RP-HPLC提纯(ACN/水/NH4OH)。产率:32.6mg(76%)ESI-MS:m/z=429[M+H]+Rt(HPLC):0.72min(方法6)
实施例46
将2-氟-4-(4-氟苯氧基)苯甲酸(30.2mg;0.12mmol)、HATU(45.6mg;0.12mmol)和DIPEA(69.2μL;0.40mmol)在DMF(2mL)中、在室温搅拌5分钟。添加6-(哌啶-4-基)哒嗪-3-胺二盐酸盐(25.1mg;0.10mmol)。在室温搅拌1小时后,将反应混合物通过RP-HPLC提纯(ACN/水/NH4OH)。
产率:28.4mg(64%)ESI-MS:m/z=411[M+H]+Rt(HPLC):0.70min(方法6)
实施例47
将2-氟-4-(4-氟苯氧基)-5-甲氧基苯甲酸(33.6mg;0.12mmol)、HATU(45.6mg;0.12mmol)和DIPEA(69.2μL;0.40mmol)在DMF(2mL)中、在室温搅拌5分钟。添加6-(哌啶-4-基)哒嗪-3-胺二盐酸盐(25.1mg;0.10mmol)。在室温搅拌1小时后,将反应混合物通过RP-HPLC提纯(ACN/水/NH4OH)。产率:35.0mg(80%)ESI-MS:m/z=441[M+H]+Rt(HPLC):0.92min(方法3)
实施例48
6-{1-[3-氟-4-(4-氟苯氧基)苯甲酰基]哌啶-4-基}哒嗪-3-胺
3-氟-4-(4-氟苯氧基)苯甲酸
将3-氟-4-(4-氟苯氧基)苯甲醛(描述于WO2013014185)(0.70g;3.00mmol)和高锰酸钾(0.75g;4.75mmol)在丙酮(10mL)和水(8mL)中、在室温搅拌2小时。添加NaOH(1mol/L;水溶液;3mL)并将反应混合物通过过滤并用水洗涤。蒸发有机溶剂,并将水层用HCl(1mol/L;水溶液;5mL)酸化。将所得沉淀过滤,用水洗涤并干燥。
产率:0.70g(93%)ESI-MS:m/z=249[M-H]-
将3-氟-4-(4-氟苯氧基)苯甲酸(30.0mg;0.12mmol)、6-(哌啶-4-基)哒嗪-3-胺二盐酸盐(48.7mg;0.12mmol)和DIPEA(84.6μL;0.49mmol)在DMF(2mL)中、在室温搅拌。添加HATU(45.6mg;0.12mmol)。在室温搅拌过夜后,将反应混合物通过RP-HPLC提纯(ACN/水+TFA)。
产率:40.2mg(64%)ESI-MS:m/z=411[M+H]+Rt(HPLC):0.62min(方法11)
实施例49
6-{1-[4-苯氧基-3-(三氟甲基)苯甲酰基]哌啶-4-基}哒嗪-3-胺4-苯氧基-3-(三氟甲基)苯甲酸
将4-苯氧基-3-(三氟甲基)苯甲醛(根据WO2007129745合成)(0.67g;2.51mmol)和高锰酸钾(0.70g;4.43mmol)在丙酮(10mL)和水(8mL)中、在室温搅拌2小时。添加NaOH(1mol/L;水溶液;3mL)并将反应混合物通过过滤,并用水洗涤。蒸发有机溶剂,并将水层用HCl(1mol/L;水溶液;5mL)酸化。将所得沉淀过滤,用水洗涤并干燥。
产率:0.58g(81%)ESI-MS:m/z=281[M-H]-
6-(哌啶-4-基)哒嗪-3-胺双(三氟乙酸)
将4-(6-氨基哒嗪-3-基)-哌啶-1-甲酸叔丁酯(9.10g;32.69mmol)和TFA(25.19mL;326.93mmol)在DCM(200mL)中、在室温搅拌过夜。将反应混合物减压浓缩。将残余物用乙醚研磨,过滤并在50℃的干燥烘箱中干燥。产率:定量ESI-MS:m/z=179[M+H]+Rt(HPLC):0.28min(方法3)
6-{1-[4-苯氧基-3-(三氟甲基)苯甲酰基]哌啶-4-基}哒嗪-3-胺三氟乙酸
将6-(哌啶-4-基)哒嗪-3-胺双(三氟乙酸)(43.2mg;0.11mmol)、4-苯氧基-3-(三氟甲基)苯甲酸(30.0mg;0.11mmol)和DIPEA(75.0μL;0.44mmol)在DMF(2mL)中、在室温搅拌。添加HATU(40.4mg;0.11mmol)。将反应混合物在室温搅拌直至反应完成。将反应混合物通过RP-HPLC提纯(ACN/水+TFA)。
产率:34.4mg(58%)ESI-MS:m/z=443[M+H]+Rt(HPLC):0.67min(方法11)
实施例50
6-{1-[4-(4-氟苯氧基)苯甲酰基]哌啶-4-基}-4-甲基哒嗪-3-胺6-氯-N-[(2,4-二甲氧基苯基)甲基]-4-甲基哒嗪-3-胺
将3,6-二氯-4-甲基哒嗪(0.87g;5.34mmol)和(2,4-二甲氧基苄基胺(0.88mL;5.87mmol)在DIPEA(0.93mL;5.34mmol)中、在100℃搅拌过夜。将反应混合物减压浓缩并通过硅胶色谱提纯(DCM/MeOH)。
产率:0.53g(34%)ESI-MS:m/z=294和296[M+H]+Rt(HPLC):0.84min(方法1)
4-(6-{[(2,4-二甲氧基苯基)甲基]氨基}-5-甲基哒嗪-3-基)-1,2,3,6-四氢吡啶-1-
甲酸叔丁酯
反应在氩气气氛中进行。将6-氯-N-[(2,4-二甲氧基-苯基)-甲基]-4-甲基哒嗪-3-胺(0.35g;1.19mmol)、4-(3,3,4,4-四甲基-环戊硼烷-1-基)-1,2,3,6-四氢吡啶-1-甲酸叔丁酯(0.37g;1.19mmol)、Xphos第二代催化剂(0.03g;0.04mmol)和碳酸钠(2mol/L;水溶液;2.38mL;4.77mmol)和1,4-二噁烷(10mL)中、在100℃搅拌过夜。除去溶剂,并将残余物溶于DCM,并用水洗涤。分离有机层,经Na2SO4干燥,过滤并减压浓缩。产物无需进一步提纯而使用。产率:0.48g(91%)ESI-MS:m/z=441[M+H]+Rt(HPLC):0.91min(方法1)
在氢气气氛(Parr装置;3bar)中,4-(6-{[(2,4-二甲氧基-苯基)-甲基]氨基}-5-甲基哒嗪-3-基)-1,2,3,6-四氢吡啶-1-甲酸叔丁酯(0.48g;1.09mmol)和Pd/C(10%;0.05g)在MeOH(20mL)中、在室温搅拌16小时。在过滤除去催化剂后,将母液减压浓缩。产物无需进一步提纯而使用。
产率:0.48g(定量)ESI-MS:m/z=443[M+H]+Rt(HPLC):0.90min(方法1)
4-甲基-6-(哌啶-4-基)哒嗪-3-胺二盐酸盐
4-(6-{[(2,4-二甲氧基苯基)甲基]氨基}-5-甲基哒嗪-3-基)哌啶-1-甲酸叔丁酯(0.42g;0.95mmol)和TFA(30%DCM溶液;5mL)中、在室温搅拌3小时。将反应混合物减压浓缩并通过RP-HPLC提纯(ACN/水+TFA)。将含产物的级分减压浓缩,将残余物溶于HCl(1.5mol/L;MeOH溶液)并再次减压浓缩。产物无需进一步提纯而使用。
产率:0.25g(99%)ESI-MS:m/z=193[M+H]+Rt(HPLC):0.12min(方法1)
6-{1-[4-(4-氟苯氧基)苯甲酰基]哌啶-4-基}-4-甲基哒嗪-3-胺三氟乙酸
将4-(4-氟苯氧基)苯甲酸(35.0mg;0.15mmol)、4-甲基-6-(哌啶-4-基)哒嗪-3-胺二盐酸盐(40.0mg;0.15mmol)和DIPEA(103.3μL;0.60mmol)在DMF(3mL)中、在室温搅拌。添加HATU(63.1mg;0.17mmol)。在室温搅拌过夜后,将反应混合物通过RP-HPLC提纯(ACN/水+TFA)。
产率:20.0mg(26%)ESI-MS:m/z=407[M+H]+Rt(HPLC):0.86min(方法1)
实施例51
反应在氩气气氛中进行。将6-氯-5-甲基哒嗪-3-胺(3.00g;20.90mmol)、4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1,2,3,6-四氢吡啶-1-甲酸叔丁酯(7.11g;22.98mmol)和碳酸钠(2mol/L;水溶液;41.79mL;83.58mmol)在1,4-二噁烷(150mL)中用氩气吹扫。添加Xphos第二代催化剂(0.49g;0.63mmol)并将反应混合物在100℃搅拌过夜。将反应混合物减压浓缩。将残余物溶于水并用EtOAc萃取数次。将合并的有机层用盐水洗涤,经Na2SO4干燥,过滤并减压浓缩。将残余物通过硅胶色谱提纯(DCM/MeOH)。
产率:5.20g(86%)ESI-MS:m/z=291[M+H]+Rt(HPLC):0.79min(方法2)
4-(6-氨基-4-甲基哒嗪-3-基)哌啶-1-甲酸叔丁酯
在氢气气氛(Parr装置;50psi)中,4-(6-氨基-4-甲基哒嗪-3-基)-1,2,3,6-四氢吡啶-1-甲酸叔丁酯(5.20g;17.91mmol)和Pd/C(10%;0.75g)在MeOH(100mL)中、在室温搅拌17小时。在过滤除去催化剂后,将母液减压浓缩。产物无需进一步提纯而使用。
产率:5.00g(96%)ESI-MS:m/z=293[M+H]+Rt(HPLC):0.79min(方法2)
5-甲基-6-(哌啶-4-基)哒嗪-3-胺双(三氟乙酸)
将4-(6-氨基-4-甲基哒嗪-3-基)哌啶-1-甲酸叔丁酯(5.00g;17.10mmol)和TFA(13.19mL;171.01mmol)在DCM(100mL)中、在室温搅拌过夜。将反应混合物减压浓缩。将残余物用乙醚研磨,过滤并在50℃的干燥烘箱中干燥。产率:7.20g(定量)ESI-MS:m/z=193[M+H]+
将2-氟-4-(4-氟苯氧基)-5-甲氧基苯甲酸(33.6mg;0.12mmol)、HATU(45.6mg;0.12mmol)和DIPEA(69.2μL;0.40mmol)在DMF(2mL)中、在室温搅拌5分钟。添加5-甲基-6-(哌啶-4-基)哒嗪-3-胺双(三氟乙酸)(42.0mg;0.10mmol)。在室温搅拌1小时后,将反应混合物通过RP-HPLC提纯(ACN/水/NH4OH)。
产率:25.0mg(55%)ESI-MS:m/z=455[M+H]+Rt(HPLC):0.95min(方法3)
实施例52
[(2S)-4-(6-氨基哒嗪-3-基)-1-[2,5-二氟-4-(4-氟苯氧基)苯甲酰基]哌啶-2-基]甲醇
(8aS)-7-(6-氨基哒嗪-3-基)-六氢-1H-[1,3]噁唑并[3,4-a]吡啶-3-酮
步骤1:
反应在氩气气氛中进行。将6-氯哒嗪-3-胺(0.49g;3.77mmol)、(8aS)-7-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H,3H,5H,8H,8aH-[1,3]噁唑并[3,4-a]吡啶-3-酮(1.00g;3.77mmol)(类似于(8aR)-7-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H,3H,5H,8H,8aH-[1,3]噁唑并[3,4-a]吡啶-3-酮合成,如US20150218165所述)、Xphos第二代催化剂(0.09g;0.11mmol)和碳酸钠(2mol/L;水溶液;7.54mL;15.09mmol)在1,4-二噁烷(20mL)中在100℃搅拌过夜。将反应混合物用水稀释,并用DCM萃取数次。将合并的有机层干燥,过滤并减压浓缩。将残余物通过硅胶色谱提纯(DCM/MeOH)并用于下一步骤。产率:0.71g(81%)ESI-MS:m/z=233[M+H]+Rt(HPLC):0.51min(方法3)
步骤2:
在氢气气氛(Parr装置;50psi)中,将来自之前步骤1的产物(0.71g;3.04mmol)、Pd/C(10%;0.07g)和乙酸(1.00mL;17.15mmol)在THF(14mL)中在50℃搅拌2天。添加额外的催化剂并进一步氢化。在过滤除去催化剂后,将母液减压蒸发。使用残余物无需进一步提纯。
产率:0.71g(定量)ESI-MS:m/z=235[M+H]+Rt(HPLC):0.28min(方法3)
[(2S)-4-(6-氨基哒嗪-3-基)哌啶-2-基]甲醇
将(8aS)-7-(6-氨基哒嗪-3-基)-六氢-1H-[1,3]噁唑并[3,4-a]吡啶-3-酮(0.71g;3.04mmol)和氢氧化钡(3.13g;18.24mmol)在水(16mL)和1,4-二噁烷(25mL)中搅拌回流4小时。将反应混合物减压浓缩,并将残余物溶于MeOH。将不溶材料过滤并弃去。将母液减压浓缩。将残余物溶于MeOH/DCM,将不溶材料过滤并弃去,并将母液减压浓缩。残余物无需进一步提纯而使用。
产率:定量ESI-MS:m/z=209[M+H]+Rt(HPLC):0.19min(方法3)
[(2S,4S)-4-(6-氨基哒嗪-3-基)-1-[2,5-二氟-4-(4-氟苯氧基)苯甲酰基]哌啶-2-基]甲醇(实施例52a)和[(2S,4R)-4-(6-氨基哒嗪-3-基)-1-[2,5-二氟-4-(4-氟苯氧基)苯甲酰基]哌啶-2-基]甲醇(实施例52b)
将[(2S)-4-(6-氨基哒嗪-3-基)哌啶-2-基]甲醇(60.0mg;0.29mmol)和2,5-二氟-4-(4-氟苯氧基)苯甲酸(77.3mg;0.29mmol)和DIPEA(203.2μL;1.18mmol)在DMF(4mL)中、在室温搅拌。添加HATU(109.5mg;0.29mmol)。在室温搅拌过夜后,将反应混合物通过RP-HPLC提纯(ACN/水/NH4OH),得到非对映异构体的混合物。将非对映异构体通过手性RP-HPLC(ChiralAmylose SA;scCO2/IPA,含NH3;40℃)分离。通过NMR确定相对立体化学。
产率(实施例52a):5.0mg(4%)ESI-MS:m/z=459[M+H]+Rt(HPLC):3.14min(方法SFC1)
产率(实施例52b):30.0mg(23%)ESI-MS:m/z=459[M+H]+Rt(HPLC):4.22min(方法SFC1)
实施例53
5-(1-{2-氟-4-[(1,2-噁唑-3-基)甲氧基]苯甲酰基}哌啶-4-基)-4-甲氧基吡啶-2-胺三氟乙酸
将4-[4-(6-氨基-4-甲氧基吡啶-3-基)哌啶-1-羰基]-3-氟苯酚(25.0mg;0.07mmol)、(1,2-噁唑-3-基)甲醇(6.8mg;0.17mmol)、TPP(50.0mg;0.19mmol)和DTAD(40.0mg;0.17mmol)在1,4-二噁烷(3mL)中在60℃搅拌1小时。将反应混合物通过RP-HPLC提纯(ACN/水+TFA)。
产率:20.0mg(39%)ESI-MS:m/z=427[M+H]+Rt(HPLC):0.52min(方法11)
实施例54
5-(1-{2-氟-4-[(1,3-噻唑-2-基)甲氧基]苯甲酰基}哌啶-4-基)-4-甲氧基吡啶-2-胺三氟乙酸
将4-[4-(6-氨基-4-甲氧基吡啶-3-基)哌啶-1-羰基]-3-氟苯酚(25.0mg;0.07mmol)、(1,3-噻唑-2-基)甲醇(19.6mg;0.17mmol)、TPP(50.0mg;0.19mmol)和DTAD(40.0mg;0.17mmol)在1,4-二噁烷(3mL)中在60℃搅拌1小时。将反应混合物通过RP-HPLC提纯(ACN/水+TFA)。
产率:31.1mg(77%)ESI-MS:m/z=443[M+H]+Rt(HPLC):0.53min(方法11)
分析数据
报告的质谱(MS)数据(表3)是针对观测质量(例如[M+H]+)。在表2中描述了用于表征本发明化合物的HPLC方法。在下文中描述了HPLC方法A、1-3、6、8、11和12。(有意省略了HPLC方法4、5、7、9和10。)
表2.HPLC方法
表3中显示了化合物1-26的观测质量和保留时间(方法A)。
表3:分析数据
生物活性评估
高通量筛选测定
该筛选测定法通过添加可商购的DAG配体类似物OAG(1-油酰基-2-乙酰基-sn-甘油)或通过添加TRPC6激动剂1-[1-(4,5,6,7,8-五氢环庚[2,1-d]噻吩-2-基羰基)-4-哌啶基]-3-氢苯并咪唑-2-酮(GSK1702934A)来测量RPC6(瞬时受体电位阳离子通道,亚家族C,成员6)离子通道活化。该测定利用了来自Molecular Devices的FLIPR膜电位(FMP)染料,其为带有荧光猝灭剂的电压敏感指示剂。如在膜去极化过程中由荧光信号增加所测量的膜电势变化提供了对通道活性的测量。
高通量筛选测定方法1:
表达人TRPC6通道(Axxam/PerkinElmer)的可商购的HEK293细胞系批量放大,并在液氮中冷冻。将冷冻的细胞原液融化,然后按照制造商的建议重新悬浮在培养基中,该培养基补充有0.5mg/ml的遗传霉素以促进TRPC6构建体的保留。将细胞以15,000个细胞/孔的密度接种在Greiner 384孔聚-D-赖氨酸包被的黑色透明底板中,并在37℃和5%CO2温育18-20小时。为了开始测定,使用平板洗涤器除去生长培养基,并向每个孔中添加25ul的FMP染料混合物。将来自制造商的4x储备FMP染料用含有36μM BAPTA/AM的测定缓冲液(低钙Tyrode测定缓冲液:130mM NaCl,5mM KCl,0.15mM CaCl2,1mM MgCl2,5mM NaHCO3,20mMHEPES pH 7.4)稀释1倍。将细胞在室温(19-22℃)温育30分钟。对于筛选测定,将5uL稀释的化合物储备液添加到每个孔中,并在室温(19-22℃)温育15分钟。使用Hamamatsu FDSS6000或FDSS7000,添加10uL的1,2二酰基甘油(DAG)、1-油酰基-2-乙酰基-n-甘油(OAG)的合成、膜渗透性类似物,并从50秒至3分钟每秒获取荧光读数。结果是测试化合物的最终浓度为3ug/ml,OAG的最终浓度为60μM,DMSO的最终浓度为3%。对照和空白由暴露于OAG的HEK293TRPC6细胞组成。空白的一部分包括与测试化合物一起添加的参考抑制剂。该抑制剂抑制了TRPC6通道活化。这些对照设定了筛选窗口,且“命中”定义为抑制由OAG引起的膜去极化的至少50%的那些化合物。通过滴定最终起始浓度为30μM的化合物储备液,使用3倍连续稀释,11个点,来确定符合这些标准的化合物的IC50值。通过使用非线性回归将每个数据集拟合为四参数对数方程来生成曲线。
高通量筛选测定方法2:
可商购的HEK293细胞系(ATCC)用在pcDNA3.1(+)(Thermo Fisher)中的人TRPC6基因构建体进行稳定转染,并进行筛选以发现具有TRPC6表达的克隆。将这些细胞维持在制造商推荐的生长培养基中,该培养基补充有400μg/ml G418以促进TRPC6构建体的保留。生长到接近汇合后,将细胞以15,000个细胞/孔的密度接种在透明底黑色壁聚-D-Lys包被的384孔组织培养处理板(TwinHelix,目录号GR 4332CPL)中,该处理板位于缺乏G418的生长培养基中,并使细胞生长24小时。从孔中除去生长培养基,然后在30μM BAPTA-AM(Invitrogen)存在下、在Tyrode测定缓冲液(130mM NaCl,5mM KCl,0.15mM CaCl2,1mM MgCl2,5mMNaHCO3,20mM HEPES,pH 7.4)中,使细胞负载20μL的0.5X膜电位敏感染料(MolecularDevices),并在室温于黑暗中温育60分钟。用FLIPRTETRA(Molecular Devices)将10μL/孔的测试化合物或对照加入孔中,并温育5分钟。在板间重复数据点下,以八种浓度(在Tyrode分析缓冲液和0.5%DMSO中稀释的10、3.16、1、0.316、0.1、0.0316、0.01和0.00316μM,终浓度)测试化合物。随后,通过FLIPRTETRA添加Tyrode分析缓冲液中的15μL/孔的GSK1702934A激动剂至终浓度为3μM,并记录发射的荧光信号(激发:510-545nm,发射:565-625nm)持续3分钟。在每个板上包括阴性和阳性对照。阴性对照孔由暴露于Tyrode分析缓冲液和激动剂溶液的细胞组成,但没有测试化合物。阳性对照由暴露于在Tyrode测定缓冲液和0.5%DMSO终浓度和激动剂溶液中稀释的100mM盐酸维拉帕米(Tocris,目录号0654)的细胞组成。抑制表示为对照的百分比,0%活性是其中测试孔的响应值达到与含维拉帕米加GSK1702934A的孔相同水平的结果,100%活性是其中测试孔的响应值达到与仅包含GSK1702934A的孔相同水平的结果。使用Genedata 14.0.6进行数据分析以拟合IC50曲线。
表4.使用高通量筛选测定方法1,本发明化合物对人TRPC6的拮抗作用(IC50)
表5.使用高通量筛选测定方法2,本发明化合物对人TRPC6的拮抗作用(IC50)
治疗用途的方法
本文公开的化合物有效抑制TRPC6活性。抑制TRPC6是预防和治疗各种因TRPC6活性而加剧的疾病或病况的有吸引力的手段。因此,如背景技术和具体实施方式部分所述,这些化合物可用于治疗疾病和病况,包括以下病况和疾病:
心脏病况(例如,心肌肥大)、高血压(例如,原发性或继发性)、肺动脉高血压(例如,IPAH)、神经退行性疾病或病症(例如,阿尔兹海默氏病(AD)、帕金森氏病、亨廷顿病、肌萎缩性脊髓侧索硬化症(ALS)和由创伤或其它损害(包括衰老)导致的其它脑部病症)、炎性疾病(例如,哮喘、慢性阻塞性肺疾病、类风湿性关节炎、骨关节炎、炎性肠病、多发性硬化症以及免疫系统的病症)、再狭窄、囊性纤维化、肌肉萎缩症、杜兴氏肌肉萎缩症、非酒精性脂肪性肝炎、微小病变肾病、特发性肺纤维化(IPF)、肺气肿和急性呼吸系统综合症(ARDS)、子痫前期和妊娠引起的高血压、肾脏疾病(局灶性节段性肾小球硬化症、肾病综合征、微小病变肾病、膜性肾小球肾炎、急进性肾小球肾炎、高血压肾病、全身性红斑狼疮、糖尿病性肾病、肾功能不全、终末期肾病、糖尿病性肾脏疾病(DKD)或慢性肾脏疾病)、缺血或缺血再灌注损伤、癌症、代谢性疾病,例如糖尿病。预防或治疗任何前述或以下疾病和病况的方法包括治疗与这些疾病或病况有关的任何症状。例如,用于治疗肾脏疾病的方法考虑了治疗症状,这些症状包括但不限于继发性高血压、蛋白尿、脂质尿、高胆固醇血症、高脂血症和凝血异常。
由于钙调节在许多细胞过程(包括细胞活化、细胞骨架重排、基因表达、细胞运输和凋亡性细胞死亡)中起着重要作用,因此钙稳态失衡与许多疾病和病症有关。这些疾病和病症包括神经性和神经退行性疾病和病症;炎性疾病和病症,例如炎性肠病和克罗恩病;肾脏疾病,例如高钙血症、肾结石和多囊性肾病;代谢性疾病和病症,包括肥胖症和糖尿病;肝脏和肾脏疾病和病症;心血管疾病和病症,包括高血压;呼吸系统疾病,包括COPD、IPAH和哮喘,以及癌症,包括脑癌、乳腺癌、肾癌、子宫颈癌、前列腺癌、胃肠道癌、皮肤癌和上皮细胞癌。
这些病症在人类中已得到很好的表征,且在其它哺乳动物中也以类似的病因存在,并且可通过本发明的药物组合物进行治疗。
因此,如本文所述的本发明化合物或其药学上可接受的盐可用于制备用于治疗由TRPC6介导的疾病或病症的药物,包括上文以及背景技术和具体实施方式部分中所述的那些疾病或病症。
对于治疗用途,本发明的化合物可以任何常规方式通过药物组合物以任何常规药物剂型给药。常规剂型通常包括适合所选特定剂型的药学上可接受的载体。给药途径包括但不限于静脉内、肌内、皮下、滑膜内、经输注、舌下、透皮、口服、局部或吸入。优选的给药方式是口服和静脉内。
在某些实施方案中,本发明的化合物可单独给药或与佐剂组合给药,所述佐剂可增强抑制剂的稳定性,促进包含它们的药物组合物的给药,提供增加的溶出或分散,增加抑制活性,提供辅助治疗等,包括其它活性成分。在一个实施方案中,例如,可给药多种本发明的化合物。有利地,这样的组合疗法使用较低剂量的常规治疗剂,因此避免了当那些药剂用作单一疗法时可能产生的毒性和不利的副作用。本发明的化合物可以与常规治疗剂或其它佐剂物理组合成单一药物组合物。有利地,然后可以以单一剂型一起给药这些化合物。在一些实施方案中,包含化合物的此类组合的药物组合物包含至少约5%,但更优选至少约20%的本发明化合物(w/w)或其组合。本发明化合物的最佳百分比(w/w)可变化,且在本领域技术人员的能力范围内。或者,本发明的化合物和常规治疗剂或其它佐剂可以分开给药(连续或并行)。单独的给药方式使给药方案具有更大的灵活性。
如上所述,本发明化合物的剂型可以包括本领域普通技术人员已知并适用于剂型的药学上可接受的载体和佐剂。这些载体和佐剂包括例如离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白、缓冲物质、水、盐或电解质和基于纤维素的物质。优选的剂型包括片剂、胶囊、囊片、液体、溶液、混悬剂、乳剂、锭剂、糖浆、可复水的粉剂、颗粒剂、栓剂和透皮贴剂。制备这种剂型的方法是已知的(参见,例如,H.C.Ansel and N.G.Popovish,Pharmaceutical Dosage Forms and Drug Delivery Systems,第5版,Lea和Febiger(1990))。本发明化合物的剂量水平和要求可以由本领域普通技术人员从适用于特定患者的可用方法和技术中选择。在一些实施方案中,对于70kg的患者,剂量水平为约1-1000mg/剂量。尽管每天一个剂量可为足够的,但每天最多可给予五个剂量。对于口服剂量,可需高达2000mg/天的剂量。如本领域技术人员将理解的,取决于特定因素,可需更低或更高的剂量。例如,具体的剂量和治疗方案将取决于诸如患者的总体健康状况、患者病症的严重性和病程或对其的处置以及治疗医师的判断等因素。
Claims (18)
1.式(I)的化合物
其中
Y为CH或N;
A为CH或N;
R1为H、C1-3烷基或OC1-3烷基;
R2为H、C1-3烷基或C3-6环烷基,其中所述R2基团的所述C1-3烷基或C3-6环烷基各自可任选地被OH、卤素或OC1-3烷基取代;
R3为H或C1-3烷基;
R2和R3与其所连接的碳原子一起可任选地连接形成3至6元碳环;
R4表示
C1-6烷基,其可任选地被1至3个基团取代,所述基团独立地选自卤素、C3-6环烷基甲基和C3-6环烷基乙基,其中所述C3-6环烷基甲基和C3-6环烷基乙基的C3-6环烷基可任选地被1至3个基团取代,所述基团独立地选自卤素和甲基、1,2,3-噻二唑基甲基、噻唑基甲基、异噁唑基甲基或下式的基团:
其中n为0或1;
R5选自H、卤素、CF3、OCF3、CN、C1-3烷基、OC1-3烷基、C3-6环烷基;其中所述R5基团的所述C1-3烷基和OC1-3烷基各自可任选地被1至3个基团取代,所述基团各自独立地选自卤素、氧代、NH2、NH(C1-3烷基)和N(C1-3烷基)2;
R6选自H、卤素、C1-3烷基和OC1-3烷基;
其中
R5和R6可连接形成5或6元碳环,其中所述5或6元碳环的1个或2个碳原子可任选地被1个或2个氧原子替代;
R7选自H、卤素、C1-3烷基和OC1-3烷基,其中所述R7基团的所述C1-3烷基可任选地被1至3个选自卤素的取代基取代;
R8选自H和卤素;
R9为H或C1-3烷基;其中
R2和R9可连接形成双环;
R10为H或C1-3烷基;
或其药学上可接受的盐。
2.根据权利要求1所述的化合物,其中Y为CH且A为N;或其药学上可接受的盐。
3.根据权利要求1所述的化合物,其中Y为CH且A为CH;或其药学上可接受的盐。
4.根据权利要求1所述的化合物,其中Y为N且A为CH;或其药学上可接受的盐。
5.根据权利要求1所述的化合物,其中Y为N且A为N;或其药学上可接受的盐。
7.根据权利要求1至6中任一项所述的化合物,其中
R5选自H、F、Cl、CF3、OCF3、CN、甲基、乙基、异丙基、甲氧基、环丙基、乙酰基和(CH3)2NC(O)-;
R6选自H、F和甲氧基;
其中
R5和R6可连接形成5或6元碳环,所述碳环的2个碳原子被2个氧原子替代;
或其药学上可接受的盐。
8.根据权利要求1所述的化合物,其中R4、R5和R6共同表示选自以下的基团:苯基、4-甲基苯基、4-乙基苯基、异丙基苯基、4-甲氧基苯基、4-氟苯基、4-氯苯基、4-三氟甲基苯基、4-三氟甲氧基苯基、4-环丙基苯基、苯甲腈、4-N,N-二甲基苯甲酰胺和4-乙酰基苯基;
或其药学上可接受的盐。
9.根据权利要求1所述的化合物,其中R4、R5和R6共同表示苯基,或其药学上可接受的盐。
10.根据权利要求1、8或9中任一项所述的化合物,其中R1至R3和R7至R10各自为H;
或其药学上可接受的盐。
11.根据权利要求1至5中任一项所述的化合物,其中R4为C1-6烷基;
或其药学上可接受的盐。
12.根据权利要求1至5和11中任一项所述的化合物,其中R4选自正丙基和异丙基;
或其药学上可接受的盐。
13.根据权利要求1至5中任一项所述的化合物,其中R4为C3-6环烷基甲基或C3-6环烷基乙基,其中所述C3-6环烷基甲基和C3-6环烷基乙基的C3-6环烷基可任选地被1至3个基团取代,所述基团独立地选自卤素和甲基;
或其药学上可接受的盐。
14.根据权利要求1至5和13所述的化合物,其中R4选自环丙基甲基、环丙基乙基、2-甲基环丙基甲基、环丁基甲基、3-甲基环丁基甲基、3,3-二氟环丁基甲基和环己基甲基,
或其药学上可接受的盐。
16.药物组合物,其包含根据权利要求1至15中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赋形剂或载体。
17.治疗疾病或病症的方法,所述疾病或病症可通过TRPC6抑制缓解,其包括向有此需要的病人给药治疗有效量的根据权利要求1至15中任一项所述的化合物或其药学上可接受的盐。
18.根据权利要求17所述的方法,其中所述疾病或病症选自心肌肥大、缺血、缺血再灌注损伤、高血压、肺动脉高血压、特发性肺动脉高压、再狭窄、慢性阻塞性肺疾病、特发性肺纤维化、肺气肿、急性呼吸窘迫综合征、囊性纤维化、阿尔兹海默氏病、帕金森氏病、亨廷顿病、肌萎缩性脊髓侧索硬化症(ALS)、创伤性脑病症、哮喘、类风湿性关节炎、骨关节炎、炎性肠病、多发性硬化症、肌肉萎缩症、杜兴氏肌肉萎缩症、子痫前期和妊娠引起的高血压、非酒精性脂肪性肝炎、局灶性节段性肾小球硬化症、肾病综合征、糖尿病性肾病、微小病变肾病、膜性肾小球肾炎、急进性肾小球肾炎、全身性红斑狼疮、高血压肾病、肾功能不全、终末期肾病、缺血或缺血再灌注损伤、癌症和糖尿病。
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CN115583908A (zh) * | 2021-07-05 | 2023-01-10 | 西北农林科技大学 | 一种吲哚甲酰胺类化合物及其制备方法和用途 |
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SG10202011632RA (en) * | 2017-10-27 | 2021-01-28 | Boehringer Ingelheim Int | Pyridine carbonyl derivatives and therapeutic uses thereof as trpc6 inhibitors |
WO2019158572A1 (en) * | 2018-02-15 | 2019-08-22 | Boehringer Ingelheim International Gmbh | Inhibitors of trpc6 |
US20240140895A1 (en) * | 2018-08-24 | 2024-05-02 | Xeniopro GmbH | Novel aromatic molecules |
WO2021160625A1 (en) | 2020-02-11 | 2021-08-19 | Klinikum Rechts Der Isar | Administration of calcium channel trpc6 inhibitors using balloons, stents or other medical devices |
AR121846A1 (es) | 2020-04-16 | 2022-07-13 | Teijin Pharma Ltd | Derivado de arilo o heteroarilo |
KR20230004650A (ko) | 2020-04-16 | 2023-01-06 | 베링거 인겔하임 인터내셔날 게엠베하 | 호흡기 병태를 치료하기 위한 trpc6의 억제제 |
CN118055765A (zh) | 2021-10-15 | 2024-05-17 | 勃林格殷格翰国际有限公司 | 用于治疗脓毒症的trpc6抑制性化合物 |
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SG10202011632RA (en) * | 2017-10-27 | 2021-01-28 | Boehringer Ingelheim Int | Pyridine carbonyl derivatives and therapeutic uses thereof as trpc6 inhibitors |
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EP1396487A1 (en) * | 2001-06-15 | 2004-03-10 | Yamanouchi Pharmaceutical Co. Ltd. | Phenylpyridine carbonyl piperazine derivative |
WO2005011653A2 (en) * | 2003-07-30 | 2005-02-10 | Xenon Pharmaceuticals Inc. | Pyridazine derivatives and their use as therapeutic agents |
WO2009139576A2 (ko) * | 2008-05-14 | 2009-11-19 | 한국화학연구원 | 신규 벤즈옥사졸로 치환된 피리딘 유도체 또는 이의 약학적으로 허용가능한 염, 이의 제조방법 및 이를 유효성분으로 함유하는 이상세포 성장 질환의 예방 및 치료용 약학적 조성물 |
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CN115583908A (zh) * | 2021-07-05 | 2023-01-10 | 西北农林科技大学 | 一种吲哚甲酰胺类化合物及其制备方法和用途 |
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US20210053935A1 (en) | 2021-02-25 |
WO2019161010A1 (en) | 2019-08-22 |
US11370771B2 (en) | 2022-06-28 |
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