CN114907350A - 一类含氮稠环类化合物、制备方法和用途 - Google Patents
一类含氮稠环类化合物、制备方法和用途 Download PDFInfo
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- CN114907350A CN114907350A CN202210074753.1A CN202210074753A CN114907350A CN 114907350 A CN114907350 A CN 114907350A CN 202210074753 A CN202210074753 A CN 202210074753A CN 114907350 A CN114907350 A CN 114907350A
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- alkyl
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- heterocycloalkyl
- halogen
- membered
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Abstract
本发明公开了一种如通式I所示含氮稠环类化合物、或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药、其制备方法及在药学上的应用,其中各基团的定义如说明书中所述。
Description
技术领域
本发明属于药物化学领域,具体地,涉及一类含氮稠环类IRE1a抑制剂化合物、制备方法和医药领域的用途。
背景技术
内质网是真核细胞中蛋白质折叠加工与分泌的细胞器。当细胞内出现未折叠和错误折叠的蛋白质时,细胞会对其应答,包括增强蛋白质折叠能力、停滞大多数蛋白质翻译和加速蛋白质降解等,这些反应被称为未折叠蛋白质应答(unfolded protein response,UPR)。当内质网不能承担蛋白折叠加工高负荷时,引发内质网应激(ER Stress)。ER stress激活UPR。IRE1α(Inositol-requiring enzyme 1α,肌醇需求激酶1α)介导的信号通路,是UPR通路中最保守的一支。IRE1α具有核酸内切酶的活性。当细胞发生内质网应激时,IRE1α激活并特异性剪切XBP1(X-box binding protein 1)mRNA,剪切后mRNA的翻译产物为具有转录活性的XBP1s(X-box binding protein 1spliced)。XBP1s可激活多种基因的转录表达进而增强内质网的蛋白折叠能力,保持细胞的稳态。内质网应激普遍存在于肿瘤细胞中。内质网应激状态下,UPR的激活可以使肿瘤细胞保持稳态,应对胞内胞外的各种环境,有益于肿瘤细胞的生长、生存和转移,在肿瘤生长和应对不利环境过程中发挥重要作用。近期的研究表明,内质网应激和UPR具有促进肿瘤细胞抗药的作用。
大量研究表明,1)、IRE1α抑制剂可以降低耐药肿瘤细胞中耐药基因MDR1表达,与抗癌药物联用可以克服肿瘤耐药,从而大大提高疗效;2)、IRE1a-XBP1通路在肿瘤微环境中也很重要,肿瘤通过旁分泌的方式在树突状细胞,T细胞中激活IRE1-XBP1通路,并抑制他们的功能。特异的在免疫细胞中抑制IRE1,可以大大激活他们的抗肿瘤功效(Cell.2015Jun18;161(7):1527-38.,Nature.2018Oct;562(7727):423-428.);3)、白细胞中的IRE1-XBP1通路可以调控前列腺素的表达,抑制IRE1可以减轻炎症反应中前列腺素引起的疼痛(Science.2019Jul 19;365(6450);4)、内质网应激是脂毒性亚致死应激的重要表现。脂毒性内质网应激激活肌醇所需的酶1a(IRE1a),其方式不同于错误折叠蛋白对IRE1a的传统激活。不管IRE1a是如何激活的,IRE1a的核糖核酸内切酶活性均会切割XBP1(X-box结合蛋白1)mRNA。产生剪接的变体XBP1s mRNA编码的蛋白质通常称为XBP1,起着转录因子的作用。多项研究已将IRE1a-XBP1信号与胰岛素抵抗、血脂异常、肝脂肪变性和NAFLD中的炎症联系起来。肝细胞中IRE1a的药理学小分子抑制剂或基因缺失可以减轻IRE1a刺激的EV释放和NASH中伴随的炎症。IRE1a刺激的EVs将促炎性单核细胞衍生的巨噬细胞吸引到肝脏中。IRE1a上调了从头神经酰胺的生物合成,导致了肝细胞源EVs的释放;这些途径在人NASH中上调,并且可能适合治疗性靶向;5)、阿尔茨海默病(Alzheimer’s disease,AD)中内质网应激的持续性激活和自噬功能障碍,导致ERS与自噬之间的交互作用由适应性、保护性,逐渐转变为持续性、破坏性,是推动AD病程进展的关键因素,由此成为AD防治的重要靶标。UPR相关信号通路在ERS与自噬交互推动AD进展中发挥核心作用。大量研究证明,ERS是AD的核心病变。在AD患者大脑中,ERS标志物GRP78水平明显增高,并且与AD患者的Braak分期呈正相关;UPR中关键蛋白,包括磷酸化的PERK、真核翻译启始因子2α(eucaryotic translationinitiation factor 2α,eIF2α)、IRE1α等水平,在AD患者脑中均明显增加。研究表明,UPR发生在AD早期阶段,随着病情加重,内质网稳态持续失衡,适应性、保护性ERS逐渐转变为持续性、损伤性ERS,造成神经元凋亡和突触缺失,损害认知和学习记忆能力。Marcora等发现,伴随着AD模型果蝇的衰老,UPR的保护作用减弱,而PERK持续磷酸化导致的神经变性损伤明显增强,ERS由适应性、保护性向持续性、损伤性转变。AD患者及模型小鼠脑中,eIF2α持续磷酸化导致的持续性ERS,可抑制突触蛋白的合成,降低神经突触可塑性,加重记忆功能障碍。
目前尚未有IRE1a抑制剂批准上市,目前只有尚处于早期临床阶段的化合物MKC8866正在研究。因此,发现和寻找具有更高活性、更好成药性的IRE1a抑制剂具有广阔的应用前景。
发明内容
本发明需要解决的技术问题之一是提供一种新型的特异性IRE1a抑制剂,用于制备肿瘤、免疫、退行性疾病、疼痛、代谢性疾病等的治疗药物。
解决上述技术问题的方案如下:
具有式I所示的化合物,或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药,
式中:
R1a独立地选自氢、C1-C12烷基、3-12元环烷基或杂环烷基、C1-C12烷氧基、C1-C12烷基氨基烷基、C1-C12烷氧基烷基、C1-C12烯基、C1-C12炔基等;R1b独立地选自氢、C1-C12烷基、3-12元环烷基或杂环烷基、C1-C12烷氧基、C1-C12烷基氨基烷基、C1-C12烷氧基烷基、C1-C12烯基、C1-C12炔基等;并且R1a和R1b可以通过碳链或杂原子形成饱和或部分不饱和或芳香环系;上述R1a和R1b基团上的一个或多个氢可以被选自下组的任意基团所取代:氘、卤素、羟基、氨基、单烷基氨基、双烷基氨基、烷氧基、酰胺、磺酰胺、氰基、砜基、亚砜基、C1-C12烷基、3-12元环烷基或杂环烷基等;
L选自化学键、-CO-、-SO2-、-SONH-、-CONH-、-COCH2-、-SO2CH2-、-COO-等;
R2选自C1-C12烷基、3-12元环烷基或杂环烷基、5-12元芳基或杂芳基、5-12元芳基或杂芳基取代的C1-C6烷基,上述基团中的一个或多个氢可以被选自下组的基团所取代:氘、卤素、C1-C6烷基、C1-C6卤代烷基等;
R3选自氢、卤素、C1-C12烷基、3-12元环烷基或杂环烷基;
R4选自氢、卤素、C1-C12烷基、3-12元环烷基或杂环烷基;
Cy选自3-12元的环烷基或杂环烷基、5-12元的单环或并环的芳基或杂芳基环系;
M选自N或CR5;R5独立地选自氢、氘、卤素、氰基、羟基、氨基、烷基氨基、C1-C6烷基、C1-C6烷氧基、C1-C6烯基、C1-C6炔基、C1-C6烷基酰基、C1-C6烷基磺酰基、5-12元的芳基或杂芳基、3-10元的环烷基或杂环烷基等;
W选自N或CR5;Y和Z分别独立地选自N、-NH-、-CO-、-CR6,R6选自氢、氘、卤素、氰基、羟基、氨基、烷基氨基、C1-C6烷基、C1-C6烷氧基、C1-C6烯基、C1-C6炔基、C1-C6烷基酰基、C1-C6烷基磺酰基、5-12元的芳基或杂芳基、3-10元的环烷基或杂环烷基等;
上述的任一基团上的一个或多个氢原子可以被选自下组的取代基取代:包括但不限于氘、卤素、C1-C3烷基;其中,所述的杂芳基包含1-3个选自下组的杂原子:N、O、P或S,所述的杂环烷基包含1-3个选自下组的杂原子:N、O、P或S。
在一些优选的实施方式中,R1a、R1b独立地选自氢、C1-C6烷基、4-8元环烷基或杂环烷基、C1-C6烷氧基、C1-C6烷基氨基C1-C6烷基、C1-C6烷氧基C1-C6烷基、C2-C6烯基、C2-C6炔基、或者R1a和R1b通过碳链或杂原子形成4-8元环烷基、4-8元杂环烷基;R1a、R1b上的一个或多个氢原子任选地被R11取代,R11独立地选自:卤素、羟基、氨基、单C1-C6烷基氨基、双C1-C6烷基氨基、C1-C6烷基、3-6元环烷基或杂环烷基;
在一些优选的实施方式中,W优选为N;
在一些优选的实施方式中,Y、Z优选为CR6,R6优选为甲基、H、异丙基;
在一些优选的实施方式中,M为N或CH;
在一些优选的实施方式中,Cy为5-8元环烷基或杂环烷基、5-10元杂芳基或6-10元芳基;优选为苯基、吡啶基、萘基、喹啉环、吡唑环;Cy任选地进一步被一个或多个独立地选自如下基团的取代基取代:卤素、C1-C3烷基;
在一些优选实施方式中,R3、R4选自氢、卤素、C1-C6烷基;优选为H、F、Cl、甲基。
在一些优选的实施方式中,R2优选为C1-C6烷基、3-8元环烷基或杂环烷基、6-10元芳基、5-8元杂芳基、6-10元芳基取代的C1-C3烷基、5-8元杂芳基取代的C1-C3烷基,上述基团中的一个或多个氢可以被R21取代,R21优选自:氘、卤素、C1-C3烷基、C1-C3卤代烷基等;
在另一些优选的实施方式中,R2更优选为:丙基、苯基、吡啶基、苄基;R21更优选为卤素、甲基;所述卤素为F、Cl;
在一些优选的实施方式中,式(I)所示的化合物,或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药,其特征在于如下通式(II)化合物,
(II),其它基团的定义如上文所示。
在一些优选的实施方式中,式(I)、(II)所示的化合物,其特征在于,W优选自N,Y和Z独立地优选自CR6;
在一些优选的实施方式中,式(I)、(II)所示的化合物,其特征在于,W优选自N,Y优选自CR6,Z优选自N;
在一些优选的实施方式中,式(I)、(II)所示的化合物,其特征在于,W优选自N,Y优选自N,Z优选自CR6;
在一些优选的实施方式中,式(I)、(II)所示的化合物,其特征在于,Cy优选自苯环、吡啶环、萘环、喹啉环、吡唑环等;R2优选自C3-C5的烷基或卤代烷基、苯基、吡啶基等;R1a优选自氢;R1b优选自5-7元的环烷基或杂环烷基;
一种制备式I化合物的方法,其特征在于,所述方法包括步骤a-d:
a)将通式(A)化合物在酸、或碱或者过渡金属催化剂存在的反应条件下进行取代反应或偶联反应,得到通式(B)化合物;和
b)将通式(B)化合物在钯催化剂催化下,与硼酸、硼酸酯或者金属试剂偶联得到通式(C)硝基化合物;或将通式(B)化合物在钯催化剂催化下,与硼酸/硼酸酯原料(E)发生交叉偶联得到通式(I)化合物;和
c)将通式(C)化合物在金属还原剂或者氢气、硫代硫酸钠等还原剂条件下反应得到通式化合物(D);和
d)将通式化合物(D)与酸或者酰氯或者磺酰氯类化合物在碱催化或者缩合试剂存在条件下发生缩合反应制备得到通式(I)化合物。
各式中,LG代表离去基团,如卤素、砜基、亚砜基、磺酸酯基等,其他各基团的定义如上所述;
优选地,所述步骤a)、b)、c)、d)各自在溶剂中进行,且所述溶剂选自下组:水、甲醇、乙醇、异丙醇、丁醇、乙二醇、乙二醇甲醚、N-甲基吡咯烷酮、二甲基亚砜,四氢呋喃、甲苯、二氯甲烷、1,2-二氯乙烷、乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二氧六环,或其组合物。
优选地,所述过渡金属催化剂选自下组:三(二亚苄基丙酮)二钯(Pd2(dba)3)、四(三苯基膦)钯(Pd(PPh3)4)、醋酸钯、氯化钯、二氯二(三苯基膦)钯、三氟醋酸钯、三苯基膦醋酸钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、双(三邻苯甲基膦)二氯化钯、1,2-二(二苯基膦基)乙烷二氯化钯,或其组合物;所述催化剂配体选自下组:三叔丁基膦、四氟硼酸三叔丁基膦、三正丁基膦、三苯基膦、三对苯甲基膦、三环己基膦、三邻苯甲基膦,或其组合物。
优选地,所述缩合试剂选自下组:二环己基碳二亚胺DCC、二异丙基碳二亚胺DIC、碳基二咪唑CDI、1-乙基-3(3-二甲基丙胺)碳二亚胺EDCI、N-羟基-7-偶氮苯并三氮唑HOAt、1-羟基苯并三氮唑HOBt、卡特试剂BOP、六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷PyBOP、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯HATU、O-(1H-苯并三唑-1-基)-N,N,N’,N’-四甲基异脲四氟化硼TBTU等,或其组合物。
优选地,所述无机碱选自下组:氢化钠、氢氧化钾、醋酸钠、醋酸钾、叔丁醇钾、叔丁醇钠、氟化钾、氟化铯、磷酸钾、碳酸钾、碳酸氢钾、碳酸钠、碳酸氢钠,或其组合物;所述有机碱选自下组:吡啶,三乙胺,N,N-二异丙基乙胺、1,8-二氮杂二环[5.4.0]十一碳-7-烯(DBU)、六甲基二硅基锂、六甲基二硅基钠、二甲基吡啶,或其组合物。
优选地,所述酸选自下组:盐酸、硫酸、磷酸、甲磺酸、甲苯磺酸、三氟乙酸、甲酸、乙酸,三氟甲磺酸或其组合物。
优选地,所述还原剂选自下组:铁粉、锌粉、氯化亚锡、硫代硫酸钠、亚硫酸钠、氢气等。
本发明提供的一类通式(I)优选化合物,包括但不限于以下结构:
本发明的另一目的是提供一种治疗或预防肿瘤、免疫性疾病、退行性疾病、疼痛、代谢性疾病的药物及其组合物。实现上述目的的技术方案如下:
一种由上述通式(I)所示的含氮稠环类化合物,或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药与药学上可接受的载体组成。
本发明的另一目的是提供一种上述化合物的用途。实现上述目的的技术方案如下:
所述通式(I)所示的含氮稠环类化合物,或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药在制备预防或治疗肿瘤、免疫性疾病、退行性疾病、疼痛、代谢性疾病中的应用。
所述的肿瘤独立地选自肺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、胃癌、肠癌、胆管癌、脑癌、白血病、淋巴癌、鼻咽癌、胰腺癌、肾癌、骨癌、甲状腺癌、肉瘤、神经内分泌瘤等;所述的炎性或免疫性疾病独立地选自移植器官的排斥反应、痛风、鼻炎、脱发、阑尾炎、哮喘、关节炎、过敏性皮炎、贝切特氏病、大疱性皮肤病、胆囊炎、慢性特发性血小板减少性紫癜、慢性阻塞性肺病、皮肤炎、皮肌炎、湿疹、肠炎、脑炎、胃炎、肾炎、桥本氏甲状腺炎、肝炎、垂体炎、炎性肠病、肠易激综合征、川崎病、脑脊膜炎、多发性硬化、心肌炎、蕈样真菌病、肌炎、肾炎、骨髓炎、胰腺炎、心包炎、恶性贫血、肺炎、原发性胆汁性硬化性胆管炎、结节性多动脉炎、银屑病、纤维化、红斑狼疮、组织移植排斥、甲状腺炎、尿道炎、葡萄膜炎、血管炎、白癜风、瓦尔登斯特伦氏巨球蛋白血症等;所述的退行性疾病独立地选自阿尔茨海默氏病、退行性关节病、重症肌无力、帕金森病等;所述的代谢性疾病独立地选自动脉粥样硬化、脂肪肝、肝硬化、糖尿病等;所述的疼痛疾病独立地选自神经性疼痛、癌性疼痛、术后疼痛、炎性疼痛等。
本发明涉及具有通式(I)结构特征的含氮稠环类化合物,可以抑制IRE1a酶活性,是一类具有全新作用机制的治疗药物。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合、从而构成新的或优选的技术方案。限于篇幅在此不再一一累述。
具体实施方式
本发明人经过长期而深入的研究,制备了一类具有式I所示结构新颖的化合物,并发现其具有较好的IRE1a酶抑制活性,且所述的化合物在极低浓度(可低至≤10nmol/L)下,即对IRE1a酶产生特异性抑制作用,抑制活性相当优异,因而可以用于治疗与IRE1a酶活性或表达异常引起的相关疾病如肿瘤、免疫性疾病、退行性疾病、疼痛、代谢性疾病。基于上述发现,发明人完成了本发明。
术语
除非另有定义,否则本文所有科技术语具有的涵义与权利要求主题所属领域技术人员通常理解的涵义相同。除非另有说明,本文全文引用的所有专利、专利申请、公开材料通过引用方式整体并入本文。
应理解,上述简述和下文的详述为示例性且仅用于解释,而不对本发明主题作任何限制。在本申请中,除非另有具体说明,否则使用单数时也包括复数。必须注意,除非文中另有清楚的说明,否则在本说明书和权利要求书中所用的单数形式包括所指事物的复数形式。还应注意,除非另有说明,否则所用“或”、“或者”表示“和/或”。此外,所用术语“包括”以及其它形式,例如“包含”、“含”和“含有”并非限制性。
可在参考文献(包括Carey and Sundberg"ADVANCED ORGANIC CHEMISTRY 4THED."Vols.A(2000)and B(2001),Plenum Press,New York)中找到对标准化学术语的定义。除非另有说明,否则采用本领域技术范围内的常规方法,如质谱、NMR、IR和UV/VIS光谱法和药理学方法。除非提出具体定义,否则本文在分析化学、有机合成化学以及药物和药物化学的有关描述中采用的术语是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送,以及对患者的治疗中使用标准技术。例如,可利用厂商对试剂盒的使用说明,或者按照本领域公知的方式或本发明的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述,按照本领域熟知的常规方法实施上述技术和方法。在本说明书中,可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。
当通过从左向右书写的常规化学式描述取代基时,该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言,-CH2O-等同于-OCH2-。
本文所用的章节标题仅用于组织文章的目的,而不应被解释为对所述主题的限制。本申请中引用的所有文献或文献部分包括但不限于专利、专利申请、文章、书籍、操作手册和论文,均通过引用方式整体并入本文。
在本文中定义的某些化学基团前面通过简化符号来表示该基团中存在的碳原子总数。例如,C1-6烷基是指具有总共1至6个碳原子的如下文所定义的烷基。简化符号中的碳原子总数不包括可能存在于所述基团的取代基中的碳。
除前述以外,当用于本申请的说明书及权利要求书中时,除非另外特别指明,否则以下术语具有如下所示的含义。
在本申请中,术语“卤素”是指氟、氯、溴或碘;“羟基”是指-OH基团;“羟基烷基”是指被羟基(-OH)取代的如下文所定义的烷基;“羰基”是指-C(=O)-基团;“硝基”是指-NO2;“氰基”是指-CN;“氨基”是指-NH2;“取代的氨基”是指被一个或两个如下文所定义的烷基、烷基羰基、芳烷基、杂芳烷基取代的氨基,例如,单烷基氨基、二烷基氨基、烷基酰氨基、芳烷基氨基、杂芳烷基氨基;“羧基”是指-COOH。
在本申请中,作为基团或是其它基团的一部分(例如用在卤素取代的烷基等基团中),术语“烷基”意指仅由碳原子和氢原子组成、不含不饱和键、具有例如1至12个(优选为1至8个,更优选为1至6个)碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团。烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、2-甲基丁基、2,2-二甲基丙基、正己基、庚基、2-甲基己基、3-甲基己基、辛基、壬基和癸基等。
在本申请中,作为基团或是其它基团的一部分,术语“烯基”意指仅由碳原子和氢原子组成、含有至少一个双键、具有例如2至14个(优选为2至10个,更优选为2至6个)碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团,例如但不限于乙烯基、丙烯基、烯丙基、丁-1-烯基、丁-2-烯基、戊-1-烯基、戊-1,4-二烯基等。
在本申请中,作为基团或是其它基团的一部分,术语“炔基”意指仅由碳原子和氢原子组成、含有至少一个三键和任选的一个或多个双键、具有例如2至14个(优选为2至10个,更优选为2至6个)碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团,例如但不限于乙炔基、丙-1-炔基、丁-1-炔基、戊-1-烯-4-炔基等。
在本申请中,作为基团或是其它基团的一部分,术语“环烷基”意指仅由碳原子和氢原子组成的稳定的非芳香族单环或多环烃基,其可包括稠合环体系、桥环体系或螺环体系,具有3至15个碳原子,优选具有3至10个碳原子,更优选具有3至8个碳原子,且其为饱和或不饱和并可经由任何适宜的碳原子通过单键与分子的其余部分连接。除非本说明书中另外特别指明,环烷基中的碳原子可以任选地被氧化。环烷基的实例包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环辛基、1H-茚基、2,3-二氢化茚基、1,2,3,4-四氢-萘基、5,6,7,8-四氢-萘基、8,9-二氢-7H-苯并环庚烯-6-基、6,7,8,9-四氢-5H-苯并环庚烯基、5,6,7,8,9,10-六氢-苯并环辛烯基、芴基、二环[2.2.1]庚基、7,7-二甲基-二环[2.2.1]庚基、二环[2.2.1]庚烯基、二环[2.2.2]辛基、二环[3.1.1]庚基、二环[3.2.1]辛基、二环[2.2.2]辛烯基、二环[3.2.1]辛烯基、金刚烷基、八氢-4,7-亚甲基-1H-茚基和八氢-2,5-亚甲基-并环戊二烯基等。
在本申请中,作为基团或是其它基团的一部分,术语“杂环基”意指由2至14个碳原子以及1至6个选自氮、磷、氧和硫的杂原子组成的稳定的3元至20元非芳香族环状基团。除非本说明书中另外特别指明,否则杂环基可以为单环、双环、三环或更多环的环体系,其可包括稠合环体系、桥环体系或螺环体系;其杂环基中的氮、碳或硫原子可任选地被氧化;氮原子可任选地被季铵化;且杂环基可为部分或完全饱和。杂环基可以经由碳原子或者杂原子并通过单键与分子其余部分连接。在包含稠环的杂环基中,一个或多个环可以是下文所定义的芳基或杂芳基,条件是与分子其余部分的连接点为非芳香族环原子。就本发明的目的而言,杂环基优选为包含1至3个选自氮、氧和硫的杂原子的稳定的4元至11元非芳香性单环、双环、桥环或螺环基团,更优选为包含1至3个选自氮、氧和硫的杂原子的稳定的4元至8元非芳香性单环、双环、桥环或螺环基团。杂环基的实例包括但不限于:吡咯烷基、吗啉基、哌嗪基、高哌嗪基、哌啶基、硫代吗啉基、2,7-二氮杂-螺[3.5]壬烷-7-基、2-氧杂-6-氮杂-螺[3.3]庚烷-6-基、2,5-二氮杂-双环[2.2.1]庚烷-2-基、氮杂环丁烷基、吡喃基、四氢吡喃基、噻喃基、四氢呋喃基、噁嗪基、二氧环戊基、四氢异喹啉基、十氢异喹啉基、咪唑啉基、咪唑烷基、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、二氢吲哚基、八氢吲哚基、八氢异吲哚基、吡咯烷基、吡唑烷基、邻苯二甲酰亚氨基等。
在本申请中,作为基团或是其它基团的一部分,术语“芳基”意指具有6至18个碳原子(优选具有6至10个碳原子)的共轭烃环体系基团。就本发明的目的而言,芳基可以为单环、双环、三环或更多环的环体系,还可以与上文所定义的环烷基或杂环基稠合,条件是芳基经由芳香环上的原子通过单键与分子的其余部分连接。芳基的实例包括但不限于苯基、萘基、蒽基、菲基、芴基、2,3-二氢-1H-异吲哚基、2-苯并噁唑啉酮、2H-1,4-苯并噁嗪-3(4H)-酮-7-基等。
在本申请中,术语“芳基烷基”是指被上文所定义的芳基所取代的上文所定义的烷基。
在本申请中,作为基团或是其它基团的一部分,术语“杂芳基”意指环内具有1至15个碳原子(优选具有1至10个碳原子)和1至6个选自氮、氧和硫的杂原子的5元至16元共轭环系基团。除非本说明书中另外特别指明,否则杂芳基可为单环、双环、三环或更多环的环体系,还可以与上文所定义的环烷基或杂环基稠合,条件是杂芳基经由芳香环上的原子通过单键与分子的其余部分连接。杂芳基中的氮、碳或硫原子可任选地被氧化;氮原子可任选地被季铵化。就本发明的目的而言,杂芳基优选为包含1至5个选自氮、氧和硫的杂原子的稳定的5元至12元芳香性基团,更优选为包含1至4个选自氮、氧和硫的杂原子的稳定的5元至10元芳香性基团或者包含1至3个选自氮、氧和硫的杂原子的5元至6元芳香性基团。杂芳基的实例包括但不限于噻吩基、咪唑基、吡唑基、噻唑基、噁唑基、噁二唑基、异噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、苯并咪唑基、苯并吡唑基、吲哚基、呋喃基、吡咯基、三唑基、四唑基、三嗪基、吲嗪基、异吲哚基、吲唑基、异吲唑基、嘌呤基、喹啉基、异喹啉基、二氮萘基、萘啶基、喹噁啉基、蝶啶基、咔唑基、咔啉基、菲啶基、菲咯啉基、吖啶基、吩嗪基、异噻唑基、苯并噻唑基、苯并噻吩基、噁三唑基、噌啉基、喹唑啉基、苯硫基、中氮茚基、邻二氮杂菲基、异噁唑基、吩噁嗪基、吩噻嗪基、4,5,6,7-四氢苯并[b]噻吩基、萘并吡啶基、[1,2,4]三唑并[4,3-b]哒嗪、[1,2,4]三唑并[4,3-a]吡嗪、[1,2,4]三唑并[4,3-c]嘧啶、[1,2,4]三唑并[4,3-a]吡啶、咪唑并[1,2-a]吡啶、咪唑并[1,2-b]哒嗪、咪唑并[1,2-a]吡嗪等。
在本申请中,术语“杂芳基烷基”是指被上文所定义的杂芳基所取代的上文所定义的烷基。
在本申请中,“任选的”或“任选地”表示随后描述的事件或状况可能发生也可能不发生,且该描述同时包括该事件或状况发生和不发生的情况。例如,“任选地被取代的芳基”表示芳基被取代或未被取代,且该描述同时包括被取代的芳基与未被取代的芳基。
本文所用术语“部分”、“结构部分”、“化学部分”、“基团”、“化学基团”是指分子中的特定片段或官能团。化学部分通常被认为是嵌入或附加到分子上的化学实体。
“立体异构体”是指由相同原子组成,通过相同的键键合,但具有不同三维结构的化合物。本发明将涵盖各种立体异构体及其混合物。
当本发明的化合物中含有烯双键时,除非另有说明,否则本发明的化合物旨在包含E-和Z-几何异构体。
“互变异构体”是指质子从分子的一个原子转移至相同分子的另一个原子而形成的异构体。本发明的化合物的所有互变异构形式也将包含在本发明的范围内。
本发明的化合物或其药学上可接受的盐可能含有一个或多个手性碳原子,且因此可产生对映异构体、非对映异构体及其它立体异构形式。每个手性碳原子可以基于立体化学而被定义为(R)-或(S)-。本发明旨在包括所有可能的异构体,以及其外消旋体和光学纯形式。本发明的化合物的制备可以选择外消旋体、非对映异构体或对映异构体作为原料或中间体。光学活性的异构体可以使用手性合成子或手性试剂来制备,或者使用常规技术进行拆分,例如采用结晶以及手性色谱等方法。
制备/分离个别异构体的常规技术包括由合适的光学纯前体的手性合成,或者使用例如手性高效液相色谱法拆分外消旋体(或盐或衍生物的外消旋体),例如可参见GeraldGübitz and Martin G.Schmid(Eds.),Chiral Separations,Methods and Protocols,Methods in Molecular Biology,Vol.243,2004;A.M.Stalcup,Chiral Separations,Annu.Rev.Anal.Chem.3:341-63,2010;Fumiss et al.(eds.),VOGEL'S ENCYCLOPEDIA OFPRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED.,Longman Scientific and TechnicalLtd.,Essex,1991,809-816;Heller,Acc.Chem.Res.1990,23,128。
在本申请中,术语“药学上可接受的盐”包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。
“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其它副作用的,与无机酸或有机酸所形成的盐。无机酸盐包括但不限于盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐等;有机酸盐包括但不限于甲酸盐、乙酸盐、2,2-二氯乙酸盐、三氟乙酸盐、丙酸盐、己酸盐、辛酸盐、癸酸盐、十一碳烯酸盐、乙醇酸盐、葡糖酸盐、乳酸盐、癸二酸盐、己二酸盐、戊二酸盐、丙二酸盐、草酸盐、马来酸盐、琥珀酸盐、富马酸盐、酒石酸盐、柠檬酸盐、棕榈酸盐、硬脂酸盐、油酸盐、肉桂酸盐、月桂酸盐、苹果酸盐、谷氨酸盐、焦谷氨酸盐、天冬氨酸盐、苯甲酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、海藻酸盐、抗坏血酸盐、水杨酸盐、4-氨基水杨酸盐、萘二磺酸盐等。这些盐可通过本专业已知的方法制备。
“药学上可接受的碱加成盐”是指能够保持游离酸的生物有效性而无其它副作用的、与无机碱或有机碱所形成的盐。衍生自无机碱的盐包括但不限于钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等。优选的无机盐为铵盐、钠盐、钾盐、钙盐及镁盐。衍生自有机碱的盐包括但不限于以下的盐:伯胺类、仲胺类及叔胺类,被取代的胺类,包括天然的被取代胺类、环状胺类及碱性离子交换树脂,例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、二乙醇胺、三乙醇胺、二甲基乙醇胺、2-二甲氨基乙醇、2-二乙氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、胆碱、甜菜碱、乙二胺、葡萄糖胺、甲基葡萄糖胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。优选的有机碱包括异丙胺、二乙胺、乙醇胺、三甲胺、二环己基胺、胆碱及咖啡因。这些盐可通过本专业已知的方法制备。
“多晶型物”是指本发明的某些化合物在固体状态下由于存在两种或两种以上不同分子排列而产生的不同固体结晶相。本发明的某些化合物可以存在多于一种晶型,本发明旨在包括各种晶型及其混合物。
通常,结晶化作用会产生本发明化合物的溶剂化物。本发明中使用的术语“溶剂化物”是指包含一个或多个本发明化合物分子与一个或多个溶剂分子的聚集体。溶剂可以是水,该情况下的溶剂化物为水合物。或者,溶剂可以是有机溶剂。因此,本发明的化合物可以以水合物存在,包括单水合物、二水合物、半水合物、倍半水合物、三水合物、四水合物等,以及相应的溶剂化形式。本发明化合物可形成真实的溶剂化物,但在某些情况下,也可以仅保留不定的水或者水加上部分不定溶剂的混合物。本发明的化合物可以在溶剂中反应或者从溶剂中沉淀析出或结晶出来。本发明化合物的溶剂化物也包含在本发明的范围之内。
本发明还包括上述化合物的前药。在本申请中,术语“前药”表示可在生理学条件下或通过溶剂分解而被转化成本发明的生物活性化合物的化合物。因此,术语“前药”是指本发明的化合物的药学上可接受的代谢前体。当被给予有需要的个体时,前药可以不具有活性,但在体内被转化成本发明的活性化合物。前药通常在体内迅速转化,而产生本发明的母体化合物,例如通过在血液中水解来实现。前药化合物通常在哺乳动物生物体内提供溶解度、组织相容性或缓释的优点。前药包括已知的氨基保护基和羧基保护基。具体的前药制备方法可参照Saulnier,M.G.,et al.,Bioorg.Med.Chem.Lett.1994,4,1985-1990;Greenwald,R.B.,et al.,J.Med.Chem.2000,43,475。
在本申请中,“药物组合物”是指本发明化合物与本领域通常接受的用于将生物活性化合物输送至哺乳动物(例如人)的介质的制剂。该介质包括药学上可接受的载体。药物组合物的目的是促进生物体的给药,利于活性成分的吸收进而发挥生物活性。
本文所用术语“药学上可接受的”是指不影响本发明化合物的生物活性或性质的物质(如载体或稀释剂),并且相对无毒,即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。
在本申请中,“药学上可接受的载体”包括但不限于任何被相关的政府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
本发明所述“肿瘤”,“细胞增殖异常相关疾病”等包括但不限于白血病、胃肠间质瘤、组织细胞性淋巴瘤、非小细胞肺癌、小细胞肺癌、胰腺癌、肺鳞癌、肺腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、宫颈癌、卵巢癌、肠癌、鼻咽癌、脑癌、骨癌、食道癌、黑色素瘤、肾癌、口腔癌等疾病。
本发明所述炎性或免疫性疾病包括但不限于移植器官的排斥反应、痛风、鼻炎、脱发、阑尾炎、哮喘、关节炎、过敏性皮炎、贝切特氏病、大疱性皮肤病、胆囊炎、慢性特发性血小板减少性紫癜、慢性阻塞性肺病、皮肤炎、皮肌炎、湿疹、肠炎、脑炎、胃炎、肾炎、桥本氏甲状腺炎、肝炎、垂体炎、炎性肠病、肠易激综合征、川崎病、脑脊膜炎、多发性硬化、心肌炎、蕈样真菌病、肌炎、肾炎、骨髓炎、胰腺炎、心包炎、恶性贫血、肺炎、原发性胆汁性硬化性胆管炎、结节性多动脉炎、银屑病、纤维化、红斑狼疮、组织移植排斥、甲状腺炎、尿道炎、葡萄膜炎、血管炎、白癜风、瓦尔登斯特伦氏巨球蛋白血症等疾病。
所述的退行性疾病包括但不限于阿尔茨海默氏病、退行性关节病、重症肌无力、帕金森病等疾病。
所述的代谢性疾病包括但不限于动脉粥样硬化、脂肪肝、肝硬化、糖尿病等;所述的疼痛疾病独立地选自神经性疼痛、癌性疼痛、术后疼痛、炎性疼痛等疾病。
本文所用术语“预防的”、“预防”和“防止”包括使病患减少疾病或病症的发生或恶化的可能性。
本文所用的术语“治疗”和其它类似的同义词包括以下含义:
(i)预防疾病或病症在哺乳动物中出现,特别是当这类哺乳动物易患有该疾病或病症,但尚未被诊断为已患有该疾病或病症时;
(ii)抑制疾病或病症,即遏制其发展;
(iii)缓解疾病或病症,即,使该疾病或病症的状态消退;或者
(iv)减轻该疾病或病症所造成的症状。
本文所使用术语“有效量”、“治疗有效量”或“药学有效量”是指服用后足以在某种程度上缓解所治疗的疾病或病症的一个或多个症状的至少一种药剂或化合物的量。其结果可以为迹象、症状或病因的消减和/或缓解,或生物系统的任何其它所需变化。例如,用于治疗的“有效量”是在临床上提供显著的病症缓解效果所需的包含本文公开化合物的组合物的量。可使用诸如剂量递增试验的技术测定适合于任意个体病例中的有效量。
本文所用术语“服用”、“施用”、“给药”等是指能够将化合物或组合物递送到进行生物作用的所需位点的方法。这些方法包括但不限于口服途径、经十二指肠途径、胃肠外注射(包括静脉内、皮下、腹膜内、肌内、动脉内注射或输注)、局部给药和经直肠给药。本领域技术人员熟知可用于本文所述化合物和方法的施用技术,例如在Goodman and Gilman,ThePharmacological Basis of Therapeutics,current ed.;Pergamon;and Remington's,Pharmaceutical Sciences(current edition),Mack Publishing Co.,Easton,Pa中讨论的那些。在优选的实施方案中,本文讨论的化合物和组合物通过口服施用。
本文所使用术语“药物组合”、“药物联用”、“联合用药”、“施用其它治疗”、“施用其它治疗剂”等是指通过混合或组合不止一种活性成分而获得的药物治疗,其包括活性成分的固定和不固定组合。术语“固定组合”是指以单个实体或单个剂型的形式向患者同时施用至少一种本文所述的化合物和至少一种协同药剂。术语“不固定组合”是指以单独实体的形式向患者同时施用、合用或以可变的间隔时间顺次施用至少一种本文所述的化合物和至少一种协同制剂。这些也应用到鸡尾酒疗法中,例如施用三种或更多种活性成分。
本领域技术人员还应当理解,在下文所述的方法中,中间体化合物官能团可能需要由适当的保护基保护。这样的官能团包括羟基、氨基、巯基及羧酸。合适的羟基保护基包括三烷基甲硅烷基或二芳基烷基甲硅烷基(例如叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基或三甲基甲硅烷基)、四氢吡喃基、苄基等。合适的氨基、脒基及胍基的保护基包括叔丁氧羰基、苄氧羰基等。合适的巯基保护基包括-C(O)-R”(其中R”为烷基、芳基或芳烷基)、对甲氧基苄基、三苯甲基等。合适的羧基保护基包括烷基、芳基或芳烷基酯类。
保护基可根据本领域技术人员已知的和如本文所述的标准技术来引入和除去。保护基的使用详述于Greene,T.W.与P.G.M.Wuts,Protective Groups in OrganiSynthesis,(1999),4th Ed.,Wiley中。保护基还可为聚合物树脂。
下面结合具体实施例、进一步阐述本发明。应理解、这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法、通常按照常规条件、或按照制造厂商所建议的条件。除非另外说明、否则百分比和份数是重量百分比和重量份数。
实施例制备
实施例1:N-(4-(5-氯-8-甲基-2-(哌啶-3-氨基基氨基)咪唑并[1',2':1,6]吡啶并[2,3-d]嘧啶-6-基)-2-氟苯基氟苯基)苯甲酰胺
第一步:将2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)苯胺(47.4mg,0.2mmol)、四三苯基膦钯(Pd(PPh3)4)(11.5mg,0.01mmol)、碳酸钾(K2CO3)(110.3mg,0.8mmol)放入两口瓶中,氮气N2保护下注入6-溴-8-甲基-2-(甲硫基)咪唑并[1',2':1,6]吡啶并[2,3-d]嘧啶(61.8mg,0.2mmol)的四氢呋喃(THF)(5mL)溶液,搅拌下再注入水和甲醇(H2O/MeOH)(1.5mL/1.5mL),油浴80℃回流,薄层色谱(TLC)监测。反应完全后,过柱,得2-氟-4-(8-甲基-2-(甲硫基)咪唑并[1',2':1,6]吡啶并[2,3-d]嘧啶-6-基)苯胺(60mg,黄色固体)。MS(ESI):m/z=340.2[M+H];1H-NMR(400MHz,DMSO-d6)δ9.21(s,1H),8.07(d,J=13.6Hz,1H),7.85(d,J=8.4Hz,1H),6.92-6.85(m,1H),5.54(s,2H),2.69(s,3H),2.44(s,3H)。
第二步:将2-氟-4-(8-甲基-2-(甲硫基)咪唑并[1',2':1,6]吡啶并[2,3-d]嘧啶-6-基)苯胺(400mg,1.8mmol)和四氢呋喃(THF)(18mL)放入反应瓶中,滴加苯甲酰氯(379mg,2.7mmol),有白色固体析出,直接抽滤,烘干得N-(2-氟-4-(8-甲基-2-(甲硫基)咪唑并[1',2':1,6]吡啶并[2,3-d]嘧啶-6-基)苯基)苯甲酰胺盐酸盐产物(88mg,黄色固体)。MS(ESI):m/z=444.1[M+H];
第三步:0℃下,将N-(2-氟-4-(8-甲基-2-(甲硫基)咪唑并[1',2':1,6]吡啶并[2,3-d]嘧啶-6-基)苯基)苯甲酰胺盐酸盐(88mg,0.2mmol)溶于二氯甲烷(DCM)(2mL)中,滴加间氯过氧苯甲酸(m-CPBA)(103mg,0.6mmol),滴加完毕后室温搅拌。TLC检测,反应结束后加入亚硫酸钠溶液(Na2SO3)(1M,50mL)溶液搅拌10分钟,DCM和水萃取,收集有机相,无水硫酸钠干燥。过柱得产物N-(4-(5-氯-8-甲基-2-(甲砜基)咪唑并[1',2':1,6]吡啶并[2,3-d]嘧啶-6-基)-2-氟苯基)苯甲酰胺。MS(ESI):m/z=510.1[M+H];1H-NMR(400MHz,DMSO-d6)δ10.32(s,1H),9.73(s,1H),8.26(s,1H),8.14(d,J=12.0Hz,1H),7.98-8.03(m,3H),7.85-7.87(m,1H),7.62-7.66(m,1H),7.52-7.56(m,2H),3.58(s,3H),2.46(s,3H)。
第四步:将N-(4-(5-氯-8-甲基-2-(甲砜基)咪唑并[1',2':1,6]吡啶并[2,3-d]嘧啶-6-基)-2-氟苯基)苯甲酰胺(47.5mg,0.09mmol)溶于甲苯,加入叔-丁基3-氨基哌啶-1-羧酸酯(24mg,0.18mmol),反应过夜后加入N,N-二异丙基乙胺(DIPEA)(36mg,0.27mmol),继续搅拌至反应结束。用乙酸乙酯(EA)和水萃取,有机相旋干,过柱纯化得叔-丁基3-((6-(4-苯甲酰胺-3-氟苯基)-5-氯-8-甲基咪唑并[1',2':1,6]吡啶并[2,3-d]嘧啶-2-基)氨基)哌啶-1-羧酸酯(40mg,白色固体)。MS(ESI):m/z=630.2[M+H]。
第五步:将叔-丁基3-((6-(4-苯甲酰胺-3-氟苯基)-5-氯-8-甲基咪唑并[1',2':1,6]吡啶并[2,3-d]嘧啶-2-基)氨基)哌啶-1-羧酸酯(40mg,0.06mmol)溶于DCM(1mL),冰浴下滴加三氟乙酸(TFA)(1mL),滴加完毕室温搅拌,TLC监测。反应完成后用碳酸氢钠洗涤,DCM萃取,有机相旋干过柱纯化,得N-(4-(5-氯-8-甲基-2-(哌啶-3-基氨基)咪唑并[1',2':1,6]吡啶并[2,3-d]嘧啶-6-基)-2-氟苯基)苯甲酰胺(22mg,白色固体)。MS(ESI):m/z=530.6[M+H];1H-NMR(400MHz,DMSO-d6)δ10.26(s,1H),9.07(s,1H),8.84(bs,2H),8.25(d,J=6.8Hz,1H),7.95-8.04(m,3H),7.90(d,J=3.6Hz,1H),7.88(d,J=9.6Hz,1H),7.74-7.76(m,1H),7.56-7.64(m,3H),4.18-4.20(m,1H),3.53-3.55(m,1H),3.25-3.45(m,2H),2.94(bs,2H),2.38(s,3H),1.95-2.11(m,3H),1.57-1.68(m,2H),1.22-1.25(m,1H)。
实施例2:N-(2-氟-4-(8-甲基-2-(哌啶-3-基氨基)咪唑并[1',2':1,6]吡啶并[2,3-d]嘧啶-6-基)苯基)-4-甲基苯磺酰胺
第一步:将6-溴-8-甲基-2-(甲硫基)咪唑并[1',2':1,6]吡啶并[2,3-d]嘧啶(309mg,1mmol)溶于DCM(5mL),冰浴下分批加入m-CPBA(507mg,2.5mmol),滴加完毕,室温反应。反应完成后,加入亚硫酸钠溶液(1M,50mL),搅拌20min,加水,DCM萃取,旋干,直接投下一步,得砜和亚砜的混合物(黄色固体,309mg)。MS(ESI):m/z=324.1/340.1[M+H]。
第二步:将上步所得产物(309mg,0.95mmol)放入封管中,加入N,N-二甲基甲酰胺(DMF)(10mL),搅拌下滴加DIPEA(367.6mg,2.85mmol)和叔-丁基3-氨基哌啶-1-羧酸酯(380mg,1.95mmol),80℃油浴。反应完成后,EA和水萃取三次,点板检测,旋干有机相,柱层析分离得到叔-丁基3-((6-溴-8-甲基咪唑并[1',2':1,6]吡啶并[2,3-d]嘧啶-2-基)氨基)哌啶-1-羧酸酯(280mg,淡黄色固体)。MS(ESI):m/z=4610.1[M+H];1H-NMR(400MHz,CDCl3)δ8.71(s,1H),7.97(s,1H),7.56(s,1H),5.65(bs,1H),4.08-4.12(m,1H),3.57-3.61(m,1H),3.25-3.30(m,2H),2.50(s,3H),1.78-2.08(m,5H),1.46(s,9H)。
第三步:将叔-丁基3-((6-溴-8-甲基咪唑并[1',2':1,6]吡啶并[2,3-d]嘧啶-2-基)氨基)哌啶-1-羧酸酯(46mg,0.1mmol)、Pd(PPh3)4(5.7mg,0.05eq.)、K2CO3(55mg,0.4mmol)放入两口瓶中,N2保护下注入N-(2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)苯基)-4-甲基苯磺酰胺(39mg,0.1mmol)的THF(2.5mL)溶液,搅拌下再注入水(0.8mL)和甲醇(0.8mL),油浴80℃回流,TLC监测。反应完后,旋干,粗产物用EA和H2O萃取,合并有机层,无水硫酸钠干燥,旋干,柱层析得到黄色固体(47mg)。MS(ESI):m/z=645.7[M+H];1H-NMR(400MHz,CDCl3)δ8.78(s,1H),7.88-7.90(m,2H),7.67-7.74(m,5H),7.46-7.54(m,2H),7.36(s,1H),4.86-4.88(m,1H),3.96-4.10(m,2H),3.62-3.64(m,1H),3.26-3.27(m,1H),2.49(s,3H),2.40(s,3H),2.00-2.06(m,2H),1.69-1.71(m,2H),1.44(s,9H)。
第四步:将上步所得固体(47mg)溶于DCM(1mL),滴加TFA(1mL),滴加完毕室温搅拌,TLC监测。反应完全后,用碳酸氢钠溶液洗涤,DCM萃取,得目标产物(黄色固体,32mg)。MS(ESI):m/z=546.7[M+H]。1H-NMR(400MHz,DMSO-d6)δ8.90(d,J=17.6Hz,1H),8.09(s,1H),7.80(d,J=14.4Hz,2H),7.69-7.52(m,4H),7.47(d,J=8.4Hz,1H),7.16(m,3H),4.33(s,1H),3.90(s,2H),3.21-2.93(m,1H),2.71(s,2H),2.38(s,3H),2.28(s,3H),1.96(s,1H),1.63(s,1H),1.50(s,2H),1.22(s,1H)。
实施例3:N-(2-氟-4-(8-甲基-2-(哌啶-3-基氨基)咪唑并[1',2':1,6]吡啶并[2,3-d]嘧啶-6-基)苯基)丙烷-1-磺酰胺
第一步:将叔-丁基3-((6-溴-8-甲基咪唑并[1',2':1,6]吡啶并[2,3-d]嘧啶-2-基)氨基)哌啶-1-羧酸酯(69mg,0.15mmol)、Pd(PPh3)4(9mg,0.075mmol)、K2CO3(83mg,0.6mmol放入两口瓶中,N2保护下注入N-(2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)苯基)丙烷-1-磺酰胺(52mg,0.15mmol)的THF(4mL)溶液,搅拌下再注入水(1mL)和甲醇(1mL),油浴80℃回流,TLC监测。反应完后,旋干,粗产物用EA和H2O萃取,合并有机层,无水硫酸钠干燥,旋干,柱层析得到叔-丁基3-((6-(3-氟-4-(丙磺酰胺)苯基)-8-甲基咪唑并[1',2':1,6]吡啶并[2,3-d]嘧啶-2-基)氨基)哌啶-1-羧酸酯(黄色固体,61mg)。MS(ESI):m/z=498.2[M+H]。
第二步:将叔-丁基3-((6-(3-氟-4-(丙磺酰胺)苯基)-8-甲基咪唑并[1',2':1,6]吡啶并[2,3-d]嘧啶-2-基)氨基)哌啶-1-羧酸酯(60mg)溶于DCM(3mL),冰浴下加入TFA(1.5mL),搅拌。反应完全后,用碳酸氢钠淬灭,DCM萃取,得实施例3(28mg,黄色固体)。MS(ESI):m/z=498.7[M+H]。1H-NMR(400MHz,DMSO-d6)δ8.97(s,1H),8.13(s,1H),8.09(s,1H),7.96(m,1H),7.88(d,J=8.4Hz,1H),7.81(s,1H),7.50(t,J=8.4Hz,1H),3.23-3.25(m,3H),2.92-3.09(s,1H),2.41(s,3H),1.89-1.91(s,1H),1.76-1.78(m,4H),1.50-1.56(m,2H),1.20-1.23(m,4H),0.99(t,J=7.2Hz,3H)。
实施例4:N-(2-氟-4-(8-甲基-2-(哌啶-3-基氨基)咪唑并[1',2':1,6]吡啶并[2,3-d]嘧啶-6-基)苯基)苯甲酰胺
第一步:将2-氟-4-(8-甲基-2-(甲硫基)咪唑并[1',2':1,6]吡啶并[2,3-d]嘧啶-6-基)苯胺(400mg,1.8mmol)和THF(15mL)放入反应瓶中,滴加苯甲酰氯(379mg,2.7mmol),有白色固体析出,过滤,滤饼溶于乙酸乙酯,用碳酸氢钠洗涤,蒸干,过柱得游离碱N-(2-氟-4-(8-甲基-2-(甲硫基)咪唑并[1',2':1,6]吡啶并[2,3-d]嘧啶-6-基)苯基)苯甲酰胺(90mg,黄色固体)。MS(ESI):m/z=444.1[M+H]。
第二步:0℃下,将N-(2-氟-4-(8-甲基-2-(甲硫基)咪唑并[1',2':1,6]吡啶并[2,3-d]嘧啶-6-基)苯基)苯甲酰胺(90mg,0.2mmol)溶于DCM(2mL)中,滴加m-CPBA(87mg,0.61mmol),滴加完毕后rt搅拌。TLC检测,反应结束后加入亚硫酸钠溶液(1M,50mL),搅拌10min。DCM和水萃取,收集有机相,无水硫酸钠干燥。旋干即得产物N-(2-氟-4-(8-甲基-2-(甲砜基)咪唑并[1',2':1,6]吡啶并[2,3-d]嘧啶-6-基)苯基)苯甲酰胺(78mg,黄色固体),直接投下一步。MS(ESI):m/z=476.1[M+H]。
第三步:封管中,将N-(2-氟-4-(8-甲基-2-(甲砜基)咪唑并[1',2':1,6]吡啶并[2,3-d]嘧啶-6-基)苯基)苯甲酰胺(220mg,0.46mmol)溶于N-甲基吡咯烷酮(NMP)(5mL),加入DIPEA(178mg,1.38mmol),加入叔-丁基3-氨基哌啶-1-羧酸酯(184mg,0.92mmol),80℃油浴,TLC监测。反应完成后,萃取,蒸干,得到产物叔-丁基3-((6-(4-苯甲酰胺-3-氟苯基)-8-甲基咪唑并[1',2':1,6]吡啶并[2,3-d]嘧啶-2-基)氨基)哌啶-1-羧酸酯(80mg,白色固体),直接投下一步。MS(ESI):m/z=495.1[M+H]。
第四步:将叔-丁基3-((6-(4-苯甲酰胺-3-氟苯基)-8-甲基咪唑并[1',2':1,6]吡啶并[2,3-d]嘧啶-2-基)氨基)哌啶-1-羧酸酯(78mg,0.13mmol)溶于DCM(1.5mL),冰浴下滴加TFA(1.5mL),滴加完毕室温搅拌,TLC监测。反应完成后用碳酸氢钠洗涤,DCM萃取,有机相旋干过柱纯化,得目标化合物(白色固体,40mg)。MS(ESI):m/z=495.8[M+H]。1H-NMR(400MHz,DMSO-d6)δ10.26(s,1H),9.06(s,1H),8.78(s,1H),8.23(d,J=14.8Hz,2H),8.01(m,3H),7.95(s,1H),7.77(d,J=7.8Hz,1H),7.63(d,J=5.6Hz,1H),7.57(s,2H),4.31(s,1H),3.55(d,J=8.8Hz,1H),3.03-2.76(m,2H),2.45(s,3H),2.04(s,1H),1.94(m,1H),1.87-1.64(m,2H),1.23(s,2H)。
实施例5:N-(4-(5,8-二甲基-2-(哌啶-3-氨基基氨基)咪唑[1',2':1,6]吡啶并[2,3-d]嘧啶-6-基)-2-氟苯基)苯甲酰胺
将叔丁基3-((6-(4-苯甲酰胺-3-氟苯基)-5-氯-8-甲基咪唑[1',2':1,6]吡啶并[2,3-d]嘧啶-2-基)氨基)哌啶-1-羧酸酯(63mg,0.1mmol)、Pd(PPh3)4(9mg,0.075mmol)、K2CO3(83mg,0.6mmol放入两口瓶中,N2保护下注入甲基硼酸(10mg,1.5mmol)的THF(4mL)溶液,搅拌下再注入水(1mL)和甲醇(1mL),油浴120℃回流,TLC监测。反应完后,旋干,粗产物用EA和H2O萃取,合并有机层,无水硫酸钠干燥,旋干,柱层析得到(18mg白色固体)。
将上述白色固体(18mg)溶于DCM(1.5mL),冰浴下滴加TFA(1.5mL),滴加完毕室温搅拌,TLC监测。反应完成后用碳酸氢钠洗涤,DCM萃取,有机相旋干过柱纯化,得目标化合物(白色固体,4.5mg)。MS(ESI):m/z=510.3[M+H];1H-NMR(400MHz,CDCl3)δ10.21(s,1H),8.97(s,1H),8.13(d,J=6.8Hz,1H),7.88-8.01(m,3H),7.71-7.73(m,1H),7.55-7.64(m,3H),4.18-4.20(m,1H),3.53-3.55(m,1H),3.25-3.45(m,2H),2.94(bs,2H),2.41(s,3H),2.34(s,3H),1.92-2.07(m,3H),1.55-1.63(m,2H),1.22-1.25(m,1H)。
实施例6:3-氯-N-(2-氟-4-(8-甲基-2-(哌啶-3-氨基基氨基)咪唑[1',2':1,6]吡啶并[2,3-d]嘧啶-6-基)苯基)-4-甲基苯磺酰胺
采用实施例2相同的方法合成得到实施例6(黄色固体,20.4mg)。MS(ESI):m/z=580.2[M+H];1H-NMR(400MHz,CD3OD)δ9.21(s,1H),8.80(s,1H),8.10(s,1H),7.82(s,1H),7.74-7.64(m,2H),7.54-7.41(m,3H),4.62(bs,1H),3.72-3.79(m,1H),3.66-3.59(m,1H),2.98-3.05(m,2H),2.58(s,3H),2.41(s,3H),2.19-2.22(m,3H),1.82-1.84(m,1H)。
实施例7:3-氯-N-(2-氟-4-(8-甲基-2-(哌啶-3-氨基基氨基)咪唑[1',2':1,6]吡啶并[2,3-d]嘧啶-6-基)苯基)苯甲酰胺
采用实施例4相同的方法合成得到实施例7(白色固体,13mg)。MS(ESI):m/z=530.1[M+H];1H-NMR(400MHz,DMSO-d6)δ10.39(s,1H),9.02(d,J=20.8Hz,1H),8.22(d,J=12.4Hz,1H),8.15(s,1H),8.07(s,1H),7.99-7.97(m,3H),7.91(s,1H),7.73(dd,J=16.8,8.4Hz,2H),7.60(t,J=7.8Hz,1H),4.62(bs,1H),3.25-3.55(m,2H),3.18-3.20(m,2H),2.88-2.91(m,1H),2.44(s,3H),1.97-1.99(m,1H),1.68-1.71(m,1H)。
实施例8:4-氯-N-(2-氟-4-(8-甲基-2-(哌啶-3-基氨基)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-6-基)苯基)苯甲酰胺
采用实施例4相同的方法合成得到实施例8(黄色固体,21mg)。MS(ESI):m/z=530.2[M+H];1H-NMR(400MHz,DMSO-d6)δ8.79(s,1H),8.55(t,J=8.4Hz,1H),8.19-7.99(m,2H),7.86(d,J=8.4Hz,2H),7.75(d,J=8.4Hz,1H),7.49(d,J=8.4Hz,2H),7.40(s,1H),5.87(d,J=6.0Hz,1H),3.30(s,1H),2.92(s,1H),2.82-2.68(m,2H),2.51(s,3H),2.01(d,J=4.4Hz,1H),1.82(d,J=6.4Hz,1H),1.74-1.58(m,3H),1.38-1.29(m,1H)。
实施例9:4-氟-N-(2-氟-4-(8-甲基-2-(哌啶-3-基氨基)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-6-基)苯基)苯甲酰胺
采用实施例4相同的方法合成得到实施例9(黄色固体,21mg)。MS(ESI):m/z=514.5[M+H];1H-NMR(400MHz,氘代丙酮)δ8.75(s,1H),8.53(t,J=8.4Hz,1H),8.06(d,J=6.0Hz,1H),8.02(s,1H),7.95-7.87(m,2H),7.72(d,J=8.4Hz,1H),7.37(s,1H),7.17(t,J=8.4Hz,2H),5.84(s,1H),3.33(d,J=40Hz,1H),2.89(s,1H),2.81-2.65(m,2H),2.48(s,3H),2.00(d,J=13.2Hz,1H),1.78(s,1H),1.63(s,2H)。
实施例10:N-(2-氟-4-(8-甲基-2-(4-甲基哌嗪-1-基)咪唑[1',2':1,6]吡啶并[2,3-d]嘧啶-6-基)苯基)-4-甲基苯磺酰胺
第一步:将6-溴-8-甲基-2-(甲基砜基)咪唑[1',2':1,6]吡啶并[2,3-d]嘧啶(170mg,0.5mmol)溶于DMF(5mL),搅拌下加入DIPEA(194mg,1.5mmol),加入4-甲基哌嗪(100mg,1mmol),滴加完毕,70℃油浴加热搅拌,TLC监测。反应完成后,用乙酸乙酯和水萃取,收集有机相,旋干,柱层析(二氯甲烷:甲醇体积比20:1)纯化得白色固体(160mg)。MS(ESI):m/z=361.2[M+H]。1H-NMR(400MHz,DMSO-d6)δ8.64(s,1H),7.93(s,1H),7.48(s,1H),3.95(bs,4H),2.44(bs,7H),2.30(s,3H)。
第二步:以上步所得化合物(36mg,0.1mmol)和N-(2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)苯基)-4-甲基苯磺酰胺(39mg,0.1mmol)为原料,采用实施例2第三步相同的方法合成,得到实施例化合物(黄色固体,42mg)。MS(ESI):m/z=546.2[M+H]。
1H-NMR(400MHz,CDCl3)δ8.80(s,1H),8.03(s,1H),7.90(d,J=11.8Hz,1H),7.69-7.74(m,4H),7.35(s,1H),7.24-7.26(m,2H),4.09(bs,4H),2.62(bs,4H),2.62(s,3H),2.48(s,3H),2.05(s,3H)。
实施例11:4-氯-N-(2-氟-4-(8-甲基-2-(4-甲基哌嗪-1-基)咪唑[1',2':1,6]吡啶并[2,3-d]嘧啶-6-基)苯基)苯甲酰胺
采用实施例10相同的方法合成得到实施例11(黄色固体,18mg)。MS(ESI):m/z=530.2[M+H];1H-NMR(400MHz,CDCl3)δ8.82(s,1H),8.55(t,J=8.0Hz,1H),8.10-8.13(m,1H),8.06(s,1H),7.85-7.87(m,2H),7.76(d,J=0.8Hz,1H),7.50-7.48(d,J=0.8Hz,2H),7.40(s,1H),4.09(bs,4H),2.61(bs,4H),2.51(s,3H),2.43(s,3H)。
实施例12:4-氟-N-(2-氟-4-(8-甲基-2-(4-甲基哌嗪-1-基)咪唑[1',2':1,6]吡啶并[2,3-d]嘧啶-6-基)苯基)苯甲酰胺
采用实施例10相同的方法合成得到实施例12(黄色固体,17.3mg)。MS(ESI):m/z=514.5[M+H];1H-NMR(400MHz,CDCl3)δ8.85(s,1H),8.59(t,J=8.4Hz,1H),8.11(d,J=10.8Hz,2H),8.04(s,1H),7.96-7.98(m,2H),7.44(s,1H),7.21-7.25(m,2H),4.13(bs,4H),2.65(bs,4H),2.54(s,3H),2.46(s,3H)。
实施例13:3-氯-N-(2-氟-4-(8-甲基-2-(4-甲基哌嗪-1-基)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-6-基)苯基)-4-甲基苯磺酰胺
采用实施例10相同的方法合成得到实施例13(黄色固体,39mg)。MS(ESI):m/z=580.1[M+H];1H-NMR(400MHz,CDCl3)δ8.79(s,1H),7.90(d,J=11.8Hz,1H),7.84(s,1H),7.72-7.63(m,2H),7.60(d,J=7.8Hz,1H),7.32-7.28(m,1H),4.08(s,4H),2.55(s,4H),2.48(s,3H),2.40(s,3H),2.38(s,3H)。
实施例14:N-(2-氟-4-(8-甲基-2-(4-甲基哌嗪-1-基)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-6-基)苯基)丙-1-磺酰胺
采用实施例10相同的方法合成得到实施例14(黄色固体,26mg)。MS(ESI):m/z=498.2[M+H];1H-NMR(400MHz,CDCl3)δ8.82(s,1H),8.00(d,J=13.6Hz,2H),7.79-7.68(m,2H),7.38(s,1H),4.09(s,4H),3.12(d,J=7.2Hz,2H),2.61(s,4H),2.51(s,3H),2.43(s,3H),1.90(dd,J=15.2,7.2Hz,2H),1.07(t,J=7.2Hz,3H)。
实施例15:N-(2-氟-4-(8-甲基-2-(4-甲基哌嗪-1-基)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-6-基)苯基)苯甲酰胺
采用实施例10相同的方法合成得到实施例15(黄色固体,7.8mg)。MS(ESI):m/z=495.8[M+H];1H-NMR(400MHz,CDCl3)δ8.82(s,1H),8.61(t,J=8.4Hz,1H),8.17(s,1H),8.08(d,J=12.8Hz,1H),8.01(s,1H),7.93(d,J=7.2Hz,2H),7.76(d,J=8.4Hz,1H),7.58(q,J=6.4Hz,1H),7.53(t,J=7.2Hz,2H),7.41(s,1H),4.05(s,4H),2.53(d,J=11.2Hz,4H),2.51(s,3H),2.38(s,3H)。
实施例16:N-(4-(2-(4,4-二氟哌啶-1-基)-8-甲基咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-6-基)-2-氟苯基)-4-甲基苯磺酰胺
将4,4-二氟哌啶替换实施例10中的N-甲基哌嗪,采用实施例10相同的方法合成得到实施例16(黄色固体,19.2mg)。MS(ESI):m/z=567.2[M+H];1H-NMR(400MHz,CDCl3)δ8.82(s,1H),8.00(s,1H),7.89(d,J=12Hz,1H),7.74(d,J=8.0Hz,2H),7.69(s,2H),7.36(s,1H),7.25-7.23(m,1H),6.83(s,1H),4.16(d,J=5.2Hz,4H),2.48(s,3H),2.39(s,3H),2.10(dd,J=12.5,6.7Hz,4H)。
实施例17:N-(4-(2-(4,4-二氟哌啶-1-基)-8-甲基咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-6-基)-2-氟苯基)丙-1-磺酰胺
采用实施例16相同的方法合成得到实施例17(黄色固体,9.2mg)。MS(ESI):m/z=519.1[M+H];1H-NMR(400MHz,CDCl3)δ8.85(s,1H),8.08-7.90(m,2H),7.80-7.60(m,2H),7.39(s,1H),6.62(s,1H),4.17(s,4H),3.22-3.06(m,2H),2.52(s,3H),2.17-2.05(m,4H),1.90(dd,J=15.2,7.5Hz,2H),1.07(t,J=7.4Hz,3H)。
实施例18:4-氯-N-(4-(2-(4,4-二氟哌啶-1-基)-8-甲基咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-6-基)-2-氟苯基)苯甲酰胺
采用实施例16相同的方法合成得到实施例18(黄色固体,6.0mg)。MS(ESI):m/z=550.8[M+H];1H-NMR(400MHz,CDCl3)δ8.85(s,1H),8.57(t,J=8.4Hz,1H),8.15-8.04(m,2H),8.03(s,1H),7.87(d,J=8.0Hz,2H),7.77(d,J=8.4Hz,1H),7.51(d,J=8.0Hz,2H),7.43(s,1H),4.17(s,4H),2.52(s,3H),2.18-2.04(m,4H)。
实施例19:N-(4-(2-(4,4-二氟哌啶-1-基)-8-甲基咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-6-基)-2-氟苯基)-2-氟苯甲酰胺
采用实施例16相同的方法合成得到实施例19(黄色固体,18.6mg)。MS(ESI):m/z=535.2[M+H];1H-NMR(400MHz,CDCl3)δ8.92(d,J=16.4Hz,1H),8.85(s,1H),8.65(t,J=8.4Hz,1H),8.22(t,J=7.6Hz,1H),8.06(d,J=12.6Hz,1H),8.02(s,1H),7.77(d,J=8.4Hz,1H),7.62-7.53(m,1H),7.43(s,1H),7.35(t,J=7.6Hz,1H),7.25-7.16(m,1H),4.16(d,J=5.2Hz,4H),2.52(s,3H),2.16-2.04(m,4H)。
实施例20:N-(4-(2-(4,4-二氟哌啶-1-基)-8-甲基咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-6-基)-2-氟苯基)-2,6-二氟苯甲酰胺
采用实施例16相同的方法合成得到实施例20(黄色固体,12.1mg)。MS(ESI):m/z=553.1[M+H];1H-NMR(400MHz,CDCl3)δ8.85(s,1H),8.60(t,J=8.4Hz,1H),8.06(dd,J=12.4,1.6Hz,2H),8.01(s,1H),7.75(d,J=8.4Hz,1H),7.49-7.40(m,2H),7.02(t,J=8.4Hz,2H),4.21-4.14(m,4H),2.51(s,3H),2.10(ddd,J=19.6,13.2,5.6Hz,4H)。
实施例21:3-氯-N-(4-(2-(4,4-二氟哌啶-1-基)-8-甲基咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-6-基)-2-氟苯基)-4-甲基苯磺酰胺
采用实施例16相同的方法合成得到实施例21(黄色固体,26.0mg)。MS(ESI):m/z=601.1[M+H];1H-NMR(400MHz,CDCl3)δ8.82(s,1H),8.00(s,1H),7.91(dd,J=12.4,1.6Hz,2H),7.84(s,1H),7.71-7.66(m,3H),7.62(s,1H),7.32(s,1H),7.37(s,1H),6.90(s,1H),4.15-4.18(m,4H),2.49(s,3H),2.41(s,3H),2.10(ddd,J=19.6,13.2,5.6Hz,4H)。
实施例22:N-(4-(2-((4-(二甲基氨基)环己基)氨基)-8-甲基咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-6-基)-2-氟苯基)-2-氟苯甲酰胺
第一步:将6-溴-8-甲基-2-(甲基砜基)咪唑[1',2':1,6]吡啶并[2,3-d]嘧啶(170mg,0.5mmol)溶于DMF(5mL),搅拌下加入DIPEA(194mg,1.5mmol),加入4-二甲基氨基环己胺(142mg,1mmol),滴加完毕,70℃油浴加热搅拌,TLC监测。反应完成后,用乙酸乙酯和水萃取,收集有机相,旋干,柱层析(二氯甲烷:甲醇体积比20:1)纯化得白色固体(138mg)。MS(ESI):m/z=403.1[M+H];1H-NMR(400MHz,CDCl3)δ8.68(s,1H),8.00(s,1H),7.55(s,1H),5.74(bs,0.5H),5.45(bs,0.5H),2.51(s,3H),2.38(s,3H),2.34(s,3H),2.20-2.28(m,3H),1.72-2.02(m,3H),1.28-1.48(m,4H)。
第二步:将硼酸酯(36mg,0.1mmol)、Pd(PPh3)4(6mg,0,05eq.),K2CO3(55mg,0.4mmol)置于双口瓶中,氮气保护下注入N1-(6-溴-8-甲基咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)-N,N-二甲基环己烷-1,4-二胺的THF溶液(40mg白色固体溶于2.5mL的THF),搅拌下再注入水和甲醇的混合溶液(1mL/1mL),80度加热过夜,TLC监测反应。反应结束后,乙酸乙酯萃取,无水硫酸钠干燥,减压浓缩,柱层析分离得到实施例22(39mg,黄色固体)。MS(ESI):m/z=556.1[M+H];1H-NMR(400MHz,CDCl3)δ8.90(d,J=1.6Hz,1H),8.79(s,1H),8.64(t,J=0.8Hz,1H),8.21(t,J=0.8Hz,1H),8.00-8.06(m,2H),7.76(d,J=0.8Hz,1H),7.56(d,J=0.8Hz,1H),7.40(s,1H),7.32-7.34(m,1H),7.19-7.22(m,1H),5.81(bs,0.5H),5.45(bs,0.5H),4.30(bs,0.5H),3.95(bs,0.5H),3.61(bs,0.5H),2.51(s,3H),2.48(s,3H),2.44(s,3H),2.11-2.35(m,3H),1.58-1.79(m,4H),1.05-1.37(m,4H)。
以市售试剂为原料,采用实施例2和实施例4相同的方法制备合成得到以下实施例化合物:
实施例31:N-(3-氟-4-(8-甲基-2-(哌啶-3-基氨基)咪唑[1',2':1,6]吡啶并[2,3-d]嘧啶-6-基)苯基)-4-甲基苯磺酰胺
实施例32:2-氯-N-(5-(8-甲基-2-(哌啶-3-基氨基)咪唑[1',2':1,6]吡啶并[2,3-d]嘧啶-6-基)吡啶-2-基)苯磺酰胺
实施例33:2-氯-N-(4-(2-((4-(二甲基氨基)环己基)氨基)-8-甲基咪唑[1',2':1,6]吡啶并[2,3-d]嘧啶-6-基)-2-氟苯基)苯磺酰胺
实施例34:2-氯-N-(5-(2-(4-(二甲基氨基)哌啶-1-基)-8-甲基咪唑[1',2':1,6]吡啶并[2,3-d]嘧啶-6-基)吡啶-2-基)苯磺酰胺
实施例35:2-氯-N-(3-氟-4-(8-甲基-2-(哌啶-3-基氨基)咪唑[1',2':1,6]吡啶并[2,3-d]嘧啶-6-基)苯基)苯磺酰胺
实施例36:2-氯-N-(3,5-二氟-4-(8-甲基-2-(哌啶-3-基氨基)咪唑[1',2':1,6]吡啶并[2,3-d]嘧啶-6-基)苯基)苯磺酰胺
实施例37:2-氯-N-(4-(2-((4-(二甲基氨基)环己基)氨基)-8-甲基咪唑[1',2':1,6]吡啶并[2,3-d]嘧啶-6-基)-3-氟苯基)苯磺酰胺
实施例38:2-氯-N-(4-(2-((4-(二甲基氨基)环己基)氨基)-8-甲基咪唑[1',2':1,6]吡啶并[2,3-d]嘧啶-6-基)-3,5-二氟苯基)苯磺酰胺
采用实施例17相同的方法制备合成得到以下实施例39-44。
采用实施例17的方法制备合成得到以下实施例45-50。
采用实施例2和实施例4相同的方法制备得到以下实施例51-73、114。
实施例74:3-氯-4-甲基-N-(5-(8-甲基-2-(4-甲基哌嗪-1-基)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-6-基)萘-1-基)苯磺酰胺
第一步:将溴代萘胺(444mg,2mmol)、二茂铁二氯化钯Pd[dppf]2Cl2(73mg)、醋酸钾(KOAc)(784mg,6mmol)、双片哪醇酯(1016mg,4mmol)放入两口瓶中,N2保护下注入二氧六环(10mL),油浴85℃加热反应,TLC监测。反应完全后,加水,乙酸乙酯萃取,干燥,减压浓缩,硅胶柱层析分离得到5-(4,4,5,5-四甲基-1,3,2-二氧代硼烷-2-基)萘-1-胺(480mg,白色固体)。1H-NMR(400MHz,CDCl3)δ8.26(d,J=8.5Hz,1H),8.07(d,J=6.8Hz,1H),7.96(d,J=8.5Hz,1H),7.45(dd,J=8.4,7.0Hz,1H),7.35(t,J=7.9Hz,1H),6.80(d,J=7.3Hz,1H),4.28–3.79(s,4H),1.43(s,12H)。
第二步:将上步所得产物(269mg,1mmol)溶于DCM(10mL),滴加吡啶(316mg,4mmol),冰浴下滴加磺酰氯(270mg,1.6mmol),滴加完毕,室温搅拌,TLC监测。反应完全后DCM萃取,稀盐酸洗涤,有机相干燥浓缩,柱层析纯化得3-氯-4-甲基-N-(5-(4,4,5,5-四甲基-1,3,2-二氧代硼烷-2-基)萘-1-基)苯磺酰胺(267mg,黄色固体)。1H-NMR(400MHz,CDCl3)δ8.68(d,J=8.4Hz,1H),8.04(d,J=6.5Hz,1H),7.97(d,J=8.5Hz,1H),7.75(s,1H),7.46–7.38(m,3H),7.33(d,J=7.1Hz,1H),7.16(d,J=8.0Hz,1H),6.95(s,1H),2.35(s,3H),1.41(s,12H)。
第三步:以实施例10相同的方法制备得到实施例化合物(32mg,黄色固体)。1H-NMR(400MHz,CD3OD)δ8.90(s,1H),8.10(s,2H),7.57(m,9H),4.08(s,4H),2.60(s,4H),2.38(s,6H),2.30(s,3H)。MS(ESI):m/z=612.2[M+H]。
采用不同的嘧啶并稠环咪唑中间体和不同的萘基硼酸酯为原料,采用实施例74相同的方法制备得到以下实施例75-90。
实施例91:3-氯-N-(4-(2-((4-(二甲基氨基)环己基)氨基)咪唑[1',2':1,6]吡啶并[2,3-d]嘧啶-6-基)-3-氟苯基)-4-甲基苯磺酰胺
第一步:将6-溴-2-(甲硫基)吡啶并[2,3-d]嘧啶-7-胺(1.35g,5mmol)溶于25mLDMF,滴加对甲苯磺酸(430mg,2.5mmol),滴加1,2-二氯乙氧基乙烷(858mg,6mmol),80℃油浴,TLC监测。反应完成后用碳酸氢钠洗涤,DCM萃取,有机相旋干,过柱纯化,得化合物6-溴-2-(甲硫基)咪唑[1',2':1,6]吡啶并[2,3-d]嘧啶(黄色固体,876mg),直接用于下步反应。MS(ESI):m/z=295.1[M+H];
第二步:将上步所得黄色固体(590mg,2mmol)溶于10mL DCM,冰浴下滴加m-CPBA(1014mg,5mmol),滴加完毕后室温搅拌,TLC监测。反应完成后用碳酸氢钠洗涤,DCM萃取,收集有机相,旋干得化合物6-溴-2-(甲砜基)咪唑[1',2':1,6]吡啶并[2,3-d]嘧啶(黄色固体,631mg),直接投下一步。MS(ESI):m/z=327.2[M+H];
第三步:将上步所得化合物(280mg,0.86mmol)溶于4mL DMF,加入DIPEA(332.8mg,2.58mmol),滴加N,N-二甲基-1,4-环己烷二胺(146.5mg,1.03mmol),80℃油浴,TLC监测。反应完成后,加水搅拌30min,有黄色固体析出,抽滤得N1-(6-溴咪唑[1',2':1,6]吡啶并[2,3-d]嘧啶-2-基)-N4,N4-二甲基环己烷-1,4-二胺(186mg,黄色固体),直接投下一步。MS(ESI):m/z=389.2[M+H];
第四步:将上步化合物(39mg,0.1mmol),3-氯-N-(3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)苯基)-4-甲基苯磺酰胺(42.6mg,0.1mmol),K2CO3(55.4mg,0.4mmol),Pd(PPh3)4(5.7mg,0.005%)放入两口瓶中,氮气保护后注入2.5mL THF、0.8mL MeOH、0.8mLH2O,80℃油浴,TLC监测。反应完全后,用二氯甲烷和水萃取,收集有机相,旋干过柱得3-氯-N-(4-(2-((4-(二甲基氨基)环己基)氨基)咪唑[1',2':1,6]吡啶并[2,3-d]嘧啶-6-基)-3-氟苯基)-4-甲基苯磺酰胺(黄色固体,26mg)。1H-NMR(400MHz,CD3OD)δ8.90(s,1H),8.32(d,J=1.5Hz,1H),7.85(d,J=1.8Hz,1H),7.69(dd,J=8.0,1.9Hz,1H),7.56-7.43(m,4H),7.05(ddd,J=10.5,10.0,2.1Hz,2H),4.32(s,1H),2.88(s,1H),2.63(d,J=4.5Hz,6H),2.41(s,3H),2.19(s,2H),1.94-1.77(m,5H),1.45(s,1H),1.33(d,J=25.9Hz,1H).MS(ESI):m/z=608.3[M+H];
采用实施例91相同的方法制备得到实施例92-97。
实施例98:2-氯-N-(3-氟-4-(8-异丙基-2-(哌啶-3-基氨基)咪唑[1',2':1,6]吡啶并[2,3-d]嘧啶-6-基)苯基)苯磺酰胺
第一步:将6-溴-2-(甲硫基)吡啶并[2,3-d]嘧啶-7-胺(1.35g,5mmol)溶于25mLDMF,滴加溴代酮(1.66g,10mmol),80℃油浴,TLC监测。反应完成后用碳酸氢钠洗涤,DCM萃取,有机相旋干,过柱纯化,得化合物6-溴-8-异丙基-2-(甲硫基)咪唑[1',2':1,6]吡啶并[2,3-d]嘧啶(524mg)。MS(ESI):m/z=337.1[M+H];
第二步:将上步所得化合物(524mg,1.55mmol)溶于8mL DCM,冰浴下滴加m-CPBA(835mg,3.87mmol),滴加完毕后室温搅拌,TLC监测。反应完成后用碳酸氢钠洗涤,DCM萃取,收集有机相,旋干得化合物6-溴-8-异丙基-2-(甲砜基)咪唑[1',2':1,6]吡啶并[2,3-d]嘧啶(500mg),直接投下一步。MS(ESI):m/z=368.9[M+H];
第三步:将上步所得化合物(369mg,1mmol)溶于5mL DMF,加入DIPEA(387mg,3mmol),滴加3-氨基-1-Boc-哌啶(240.3mg,1.2mmol),80℃油浴,TLC监测。反应完成后,加水搅拌30min,有黄色固体析出,抽滤得叔丁基3-((6-溴-8-异丙基咪唑[1',2':1,6]吡啶并[2,3-d]嘧啶-2-yl)氨基)哌啶-1-甲酸酯(350mg),直接投下一步。MS(ESI):m/z=489.1[M+H];
第四步:将上步化合物(49mg,0.1mmol),2-氯-N-(3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)苯基)苯磺酰胺(41.2mg,0.1mmol),K2CO3(55.4mg,0.4mmol),Pd(PPh3)4(5.7mg,0.005%)放入两口瓶中,氮气保护后注入2.5mL THF、0.8mL MeOH、0.8mL H2O,80℃油浴,TLC监测。反应完全后,用二氯甲烷和水萃取,收集有机相,减压浓缩,直接用于下一步反应。MS(ESI):m/z=694.1[M+H];
第五步:将上步浓缩物溶于1mL DCM,冰浴下滴加1mL TFA,滴加完毕室温搅拌,TLC监测。反应完全后,旋干,用碳酸氢钠洗涤,DCM萃取收集有机相,旋干,过柱得目标产物(黄色固体,33mg)。1H-NMR(400MHz,CDCl3)δ8.69(s,1H),8.13(d,J=7.5Hz,1H),7.93(dd,J=17.9,9.9Hz,2H),7.52(s,2H),7.40(s,1H),7.31(s,1H),7.08(d,J=11.6Hz,1H),6.95(d,J=8.3Hz,1H),5.98(s,1H),4.28(s,1H),3.33(s,2H),3.11-2.94(m,3H),2.86(d,J=12.8Hz,2H),1.99(d,J=14.3Hz,1H),1.88(s,1H),1.70(s,2H),1.35(s,3H),1.34(s,3H)。MS(ESI):m/z=594.1[M+H];
采用实施例98相同的方法制备得到实施例99-101。
实施例102:1-(4-(8-((4-(二甲基氨基)环几基)氨基)-2-甲基咪唑基[1,2-a][1,6]萘啶-4-基)-3-氟苯基)-3-(对甲苯)脲
第一步:将3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-yl)苯胺(94.8mg,0.4mmol)溶于2mL DCM,搅拌下滴加N-甲吗啉(121.2mg,1.2mmol),滴加对甲苯异氰酸酯(106.5mg,0.8mmol),TLC监测。反应完全后,用DCM和水萃取,收集有机相旋干,过柱得产物1-(3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)苯基)-3-(对甲苯基)脲(90mg,黄色固体)。
第二步:将N1-(6-溴-8-环甲基咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)-N4,N4-二甲基环己烷-1,4-二胺(40.3mg,0.1mmol),1-(3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)苯基)-3-(对甲苯基)脲(37.0mg,0.1mmol),K2CO3(55.4mg,0.4mmol),PdPPh3)4(5.7mg,0.005%)放入两口瓶中,氮气保护后注入2.5mL THF、0.8mL MeOH、0.8mL H2O,80℃油浴,TLC监测。反应完全后,用二氯甲烷和水萃取,收集有机相,旋干过柱得实施例化合物(24mg)。MS(ESI):m/z=566.3[M+H];1HNMR(400MHz,CDCl3)δ9.20(s,1H),8.73(d,J=11.9Hz,1H),8.04(s,1H),7.91(d,J=11.9Hz,1H),7.39(d,J=10.7Hz,1H),7.29(d,J=10.7Hz,2H),7.19(d,J=6.7Hz,2H),7.02(d,J=7.3Hz,2H),6.86(s,1H),5.66(dd,J=130.0,81.3Hz,1H),4.32(s,1H),3.92(s,1H),2.50(s,3H),2.46(s,6H),2.26(s,3H),2.11(s,2H),2.05(s,1H),1.88(s,1H),1.76(d,J=8.5Hz,2H),1.58(d,J=11.4Hz,1H),1.30(dd,J=17.7,10.0Hz,2H)。
采用实施例102相同的方法合成得到实施例化合物103-113。
测试例本发明化合物对IRE1-α核酸酶抑制活性的测定
1、试验方法:a)、设计一个5’端FAM、3’端BHQ标记的XBP1单链茎-环底物,底物序列为5’-FAM-CAUGUCAGGCAUG-3’BHQ,以该小片段XBP-1茎-环RNA作为IREl-α核酸酶底物,该寡核苷酸链完整时,FAM荧光信号被BHQ淬灭,若IRE1-α核酸酶作用下该寡核苷酸链被切割裂解后,荧光不再淬灭,通过荧光强度量化IREl-α核酸酶活性,反应受试化合物与酶共孵育体系化合物对IRE1α核酸酶活性的影响,进而,高通量筛选IREl-α核酸酶抑制剂。b)、人IRElα酶(ERN1亚型1,O75460-1)的胞质结构域(pro465-leu977)与N末端融合多组氨酸标记N末端的GST标签序列由杆状病毒昆虫细胞表达(购自Sino biological公司,11905-H20B)。所有试剂的制备和操作均在无核糖核酸酶的条件下进行。c)、受试化合物、酶、底物的核酸酶分析缓冲液体系为20mM HEPES,pH 7.5,50mM KAc,l mM MgAc,l mM DTT和0.05%Triton X-100,按照20μL反应体积加入384孔白色板(ProxiPlate,Perkin Elmer 6008280)。孵育结束后,将孔板置于Flexstation 3仪器(Molecular Devices)中,以2分钟的间隔(Ex 485,Em535)进行动态荧光读数。使用前50分钟反应速度,计算核糖核酸酶活性及受试化合物对核酸酶的抑制作用。d)、样品的抑制率通过下列公式求得:抑制率(%)=(OD阴性对照孔-OD给药孔)/OD阴性对照孔×100%。结果分析,IC50值采用酶标仪随机附带软件以四参数法回归求得。
2.结果:本发明的绝大部分实施例化合物对IRE1-α核酸酶具有明显的抑制作用,IC50均小于1uM,大部分实施例化合物的IC50小于100nM。具体活性数据如下表所示。(A表示IC50≤20nM,B表示20<IC50<100nM,C表示IC50≥100nM)。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (9)
1.一种如通式I所示的含氮稠环类化合物,或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药,
式中:
R1a独立地选自氢、C1-C12烷基、3-12元环烷基或杂环烷基、C1-C12烷氧基、C1-C12烷基氨基烷基、C1-C12烷氧基烷基、C1-C12烯基、C1-C12炔基等;R1b独立地选自氢、C1-C12烷基、3-12元环烷基或杂环烷基、C1-C12烷氧基、C1-C12烷基氨基烷基、C1-C12烷氧基烷基、C1-C12烯基、C1-C12炔基等;并且R1a和R1b可以通过碳链或杂原子形成饱和或部分不饱和或芳香环系;上述R1a和R1b基团上的一个或多个氢可以被选自下组的任意基团所取代:氘、卤素、羟基、氨基、单烷基氨基、双烷基氨基、烷氧基、酰胺、磺酰胺、氰基、砜基、亚砜基、C1-C12烷基、3-12元环烷基或杂环烷基等;
L选自化学键、-CO-、-SO2-、-SONH-、-CONH-、-COCH2-、-SO2CH2-、-COO-等;
R2选自C1-C12烷基、3-12元环烷基或杂环烷基、5-12元芳基或杂芳基、5-12元芳基或杂芳基取代的C1-C6烷基,上述基团中的一个或多个氢可以被选自下组的基团所取代:氘、卤素、C1-C6烷基、C1-C6卤代烷基等;
R3选自氢、卤素、C1-C12烷基、3-12元环烷基或杂环烷基;
R4选自氢、卤素、C1-C12烷基、3-12元环烷基或杂环烷基;
Cy选自3-12元的环烷基或杂环烷基、5-12元的单环或并环的芳基或杂芳基环系;
M选自N或CR5;R5独立地选自氢、氘、卤素、氰基、羟基、氨基、烷基氨基、C1-C6烷基、C1-C6烷氧基、C1-C6烯基、C1-C6炔基、C1-C6烷基酰基、C1-C6烷基磺酰基、5-12元的芳基或杂芳基、3-10元的环烷基或杂环烷基等;
W选自N或CR5;Y和Z分别独立地选自N、-NH-、-CO-、-CR6,R6选自氢、氘、卤素、氰基、羟基、氨基、烷基氨基、C1-C6烷基、C1-C6烷氧基、C1-C6烯基、C1-C6炔基、C1-C6烷基酰基、C1-C6烷基磺酰基、5-12元的芳基或杂芳基、3-10元的环烷基或杂环烷基等;
上述的任一基团上的一个或多个氢原子可以被选自下组的取代基取代:包括但不限于氘、卤素、C1-C3烷基;其中,所述的杂芳基包含1-3个选自下组的杂原子:N、O、P或S,所述的杂环烷基包含1-3个选自下组的杂原子:N、O、P或S。
2.如权利要求1所述的化合物,或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药,其特征在于:
R1a、R1b独立地选自氢、C1-C6烷基、4-8元环烷基或杂环烷基、C1-C6烷氧基、C1-C6烷基氨基C1-C6烷基、C1-C6烷氧基C1-C6烷基、C2-C6烯基、C2-C6炔基、或者R1a和R1b通过碳链或杂原子形成4-8元环烷基、4-8元杂环烷基;R1a、R1b上的一个或多个氢原子任选地被R11取代,R11独立地选自:卤素、羟基、氨基、单C1-C6烷基氨基、双C1-C6烷基氨基、C1-C6烷基、3-6元环烷基或杂环烷基;
或者,W为N;
或者,Y、Z优选为CR6,R6优选为甲基、H、异丙基;
或者,M为N或CH;
或者,Cy为5-8元环烷基或杂环烷基、5-10元杂芳基或6-10元芳基;Cy任选地进一步被一个或多个独立地选自如下基团的取代基取代:卤素、C1-C3烷基;
或者,R2为C1-C6烷基、3-8元环烷基或杂环烷基、6-10元芳基、5-8元杂芳基、6-10元芳基取代的C1-C3烷基、5-8元杂芳基取代的C1-C3烷基,上述基团中的一个或多个氢可以被R21取代,R21优选自:氘、卤素、C1-C3烷基、C1-C3卤代烷基;
或者,R3、R4独立地选自氢、卤素、C1-C6烷基;优选为F、Cl、甲基。
3.如权利要求1所述的化合物,或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药,其特征在于:
R2为:丙基、苯基、吡啶基、苄基;R21为卤素、甲基;所述卤素为F、Cl;
或者,Cy为苯基、吡啶基、萘基、喹啉基、吡唑基;Cy任选地进一步被一个或多个独立地选自如下基团的取代基取代:卤素、C1-C3烷基;
或者,W选自N,Y和Z独立地选自CR6;
或者,W选自N,Y选自CR6,Z选自N;
或者,W选自N,Y选自N,Z选自CR6。
5.如权利要求1-4中任一项所述的化合物,或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药,其特征在于,
Cy优选自苯环、吡啶环、萘环;
或者,R2优选自C3-C5的烷基或卤代烷基、苯基、吡啶基;
或者,R1a选自氢;R1b选自5-7元的环烷基或杂环烷基。
7.如权利要求1-6中任一项所述的式I化合物或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药的用途,其特征在于,用于制备治疗与IRE1a-XBP1酶活性或表达相关的疾病的药物。
8.如权利要求7所述的用途,其特征在于,所述疾病为肿瘤、炎性或免疫性疾病、退行性疾病、疼痛、代谢性疾病;所述的肿瘤独立地选自肺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、胃癌、肠癌、胆管癌、脑癌、白血病、淋巴癌、鼻咽癌、胰腺癌、肾癌、骨癌、甲状腺癌、肉瘤、神经内分泌瘤等;所述的炎性或免疫性疾病独立地选自移植器官的排斥反应、痛风、鼻炎、脱发、阑尾炎、哮喘、关节炎、过敏性皮炎、贝切特氏病、大疱性皮肤病、胆囊炎、慢性特发性血小板减少性紫癜、慢性阻塞性肺病、皮肤炎、皮肌炎、湿疹、肠炎、脑炎、胃炎、肾炎、桥本氏甲状腺炎、肝炎、垂体炎、炎性肠病、肠易激综合征、川崎病、脑脊膜炎、多发性硬化、心肌炎、蕈样真菌病、肌炎、肾炎、骨髓炎、胰腺炎、心包炎、恶性贫血、肺炎、原发性胆汁性硬化性胆管炎、结节性多动脉炎、银屑病、纤维化、红斑狼疮、组织移植排斥、甲状腺炎、尿道炎、葡萄膜炎、血管炎、白癜风、瓦尔登斯特伦氏巨球蛋白血症等;所述的退行性疾病独立地选自阿尔茨海默氏病、退行性关节病、重症肌无力、帕金森病等;所述的代谢性疾病独立地选自动脉粥样硬化、脂肪肝、肝硬化、糖尿病等;所述的疼痛疾病独立地选自神经性疼痛、癌性疼痛、术后疼痛、炎性疼痛等。
9.包含如权利要求1-6中任一项所述的式I化合物或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药组成的药物组合物,其特征在于,所述的药物组合物包括:
(i)有效量的如权利要求1-6中任一项所述的式I化合物,或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药;和
(ii)药学上可接受的载体。
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