CN117567435A - 谷氨酰胺环化酶抑制剂及其应用 - Google Patents
谷氨酰胺环化酶抑制剂及其应用 Download PDFInfo
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- CN117567435A CN117567435A CN202310062973.7A CN202310062973A CN117567435A CN 117567435 A CN117567435 A CN 117567435A CN 202310062973 A CN202310062973 A CN 202310062973A CN 117567435 A CN117567435 A CN 117567435A
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- Prior art keywords
- triazol
- methyl
- piperidin
- benzonitrile
- compound
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Abstract
本发明公开了具有如式(I)所示结构的化合物,或所述化合物在药学上可接受的盐、溶剂化物、立体异构体或前药,其连接关系为B‑A‑D‑C。本发明的化合物为新型结构的谷氨酰胺环化酶抑制剂,能够抑制、降低或阻断isoQC或QC的活性,可以进一步应用于肿瘤、免疫性疾病或神经性疾病的治疗。
Description
技术领域
本发明属于化学医药领域,具体涉及谷氨酰胺环化酶抑制剂及其应用。
背景技术
谷氨酰胺酰基环化酶(Glutaminyl cyclase,QC,EC2.3.2.5)是一种可以催化多肽、蛋白等N端谷氨酰胺残基分子内环化反应生成焦谷氨酸(pGlu*)的酶,具有改变蛋白等N端化学结构、调节活性、增强稳定性等重要生物学功能。
QC或isoQC介导的N端谷氨酰胺/谷氨酸的焦谷氨酰化
焦谷氨酰化是一种翻译后修饰,其中谷氨酰胺或谷氨酸氨基酸被转化为焦谷氨酸部分。目前已知人体中有两种基因编码的酶参与催化这个N端焦谷氨酰化反应,包括谷氨酰胺酰基环化酶基因(Glutaminyl-peptide cyclotransferase,QPCT)编码的谷氨酰胺酰基环化酶/蛋白(QC)和谷氨酰胺酰基环化酶样基因(glutaminyl-peptide cyclotransferaselike,QPCTL)编码的谷氨酰胺酰基环化酶样蛋白(isoQC)。
QC催化N端谷氨酰胺残基分子内环化为焦谷氨酸(pGlu*),释放氨。编码QC的基因位于染色体2p22.3。人类QC由361个氨基酸组成,具有N端分泌信号,QC最初由Messer于1963年从热带植物番木瓜(Carica papaya)的胶乳中分离(Messer,M.1963,Nature 4874,1299)。24年后,在动物垂体中发现相应的酶促活性(Busby,W.H.J.等人1987,J Biol Chem262,8532-8536;Fischer,W.H.和Spiess,J.1987,Proc Natl Acad Sci USA84,3628-3632)。对于哺乳动物QC,Gln通过QC转化为pGlu可以由TRH和GnRH的前体证实(Busby,W.H.J.等人1987,J Biol Chem 262,8532-8536;Fischer,W.H.和Spiess,J.1987,ProcNatl Acad Sci USA 84,3628-3632)。此外,QC的最初定位实验显示与其推定的催化产物共定位于牛垂体中,进一步增进所提出的在肽激素合成中的功能(Bockers,T.M.等人1995,JNeuroendocrinol 7,445-453)。据证实,重组人QC及来自脑提取物的QC酶活性均催化N端谷氨酰胺以及谷氨酸氨酸环化。最出人意料的是发现约pH 6.0有利于环化酶催化的Glu-转化,而Gln-转化为pGlu-衍生物发生在约8.0的最佳pH。因为抑制重组人QC和来自猪垂体提取物的QC-活性可以抑制pGlu-Aβ-相关肽的形成,所以酶QC是用于治疗阿尔茨海默病的药物开发的靶标(J Med.Chem.2017,60,2573-2590;Alzheimers Res Ther 2018,10,107)。
谷氨酰胺酰肽环转移酶样蛋白(isoQC)亦催化N端谷氨酰胺残基分子内环化为焦谷氨酸(pGlu*),释放氨。isoQC定位于高尔基复合体中,由染色体19q13.32编码该基因。哺乳动物isoQC于2008年确定,包括人isoQC和鼠isoQC(J.Mol.Biol.2008,379,966-80)。与QC相比,isoQC对几种合成底物的催化活性低2至15倍。此外,QC在神经元组织中的表达较高,而isoQC的表达在不同组织和器官之间没有显着差异(FEBS J.2009,276,6522-36)。在九个不同的小鼠品系中,最高的酶促QC/isoQC活性在大脑腹侧,其次是皮质和海马。QC敲除显着降低了小鼠大脑中的QC活性,尤其是在下丘脑和血浆中,尽管在肝脏和脾脏等外周器官中仍可检测到活性,这可能是isoQC表达的结果(Int.J.Dev.Neurosci.2014,36,64-73)。isoQC蛋白包含382个氨基酸残基,包括活性催化域(Ser53-Leu382)、跨膜域(Leu35-Trp52)、胞外域(Met1-Arg34)(J Biol Chem.286,14199-14208)。研究表明isoQC可以在多种细胞中特异性调控CD47/SIRPα信号轴,且该调控作用依赖于isoQC酶活性(Nat.Med.2019,25,612-619;Cell Res.2019,29,502-505)。此外,在细胞中敲除isoQC或者使用isoQC化学抑制剂,可以有效抑制CD47的N端焦谷氨酸化水平以及CD47/SIRPα的结合,但是对细胞表面CD47的表达无明显影响。isoQC通过催化CD47的第19位谷氨酰胺形成焦谷氨酸,从而调控CD47和SIRPα的结合。此外,体外抗体调理细胞的吞噬作用增加和体内调理肿瘤细胞的清除增加被证明是阻断isoQC活性或产生的影响(Nat.Med.2019,25,612-619)。在QPCTL基因敲除的小鼠中,QPCTL的缺失会促进骨髓中巨噬细胞的发育(Cell Res.2019,29,502-505),以及增强中性粒细胞介导的肿瘤细胞杀伤作用(Nat.Med.2019,25,612-619;Cancer Sci 2021,112,3029-3040)。isoQC是高尔基体定位蛋白,在血红细胞中几乎无表达。因此,通过抑制isoQC蛋白功能阻断CD47/SIRPα通路,有可能减少对正常红细胞CD47功能的影响,从而避免CD47抗体药物引起的严重副作用。综上所述,isoQC是通过CD47/SIRPα通路介导的肿瘤免疫治疗的潜在靶点。
肿瘤是导致人类死亡的重要原因,抗击癌症是人类健康面临的严峻挑战。多年来,化学治疗、放射治疗、手术和免疫疗法肿瘤治疗的常用医学手段。肿瘤免疫疗法是一种通过增强人体自然免疫防御以对抗肿瘤的治疗方法。近年来,该方法的迅速发展为人类治疗肿瘤带来了新的希望。现有的肿瘤免疫治疗药物,主要为靶向PD-1/PD-L1和CTLA-4/B7等免疫检查点的抗体药物,但是该类药物在临床上存在免疫相关毒性、药代动力学性质不佳、肿瘤治疗渗透能力弱以及适用人群窄等问题。同时肿瘤细胞可以通过诱导免疫抑制和降低自身免疫原性来实现免疫逃逸。例如,通过高表达免疫抑制信号分子与免疫细胞相互作用,如PD-L1与PD1、CD47与SIRPα的相互作用等,表达“不要吃我”信号直接抑制免疫应答,促进肿瘤细胞逃避免疫监视。
CD47-SIRPα轴
CD47(Cluster of Differentiation 47)也被称为整合素相关蛋白,属于免疫球蛋白超家族成员,其在多种细胞表面均可以表达,包括正常细胞(如红细胞)以及多种肿瘤细胞。CD47和信号调节蛋白SIRPα(Signal Regulatory Proteinα)相互结合,从而介导细胞凋亡、增殖、免疫反应等一系列级联反应。SIRPα主要表达在单核细胞、组织亚群中的大多数巨噬细胞、粒细胞等细胞中,其在巨噬细胞上的表达比较稳定,不受炎症等因素的影响。SIRPα与CD47的N端结构域相互结合后,SIRPα的免疫受体酪氨酸抑制基序(immunoreceptortyrosine-based Inhibitory motifs,ITIM)上的酪氨酸残基被磷酸化,磷酸酶SHP-1/SHP-2被招募和激活,进而引发下游通路分子进行去磷酸化过程,释放“别吃我”信号,抑制巨噬细胞的吞噬作用。CD47/SIRPα相互结合最终引发一系列的细胞负调控作用,包括抑制巨噬细胞和中性粒细胞的吞噬作用以及细胞毒作用,进而使肿瘤细胞逃避免疫监视。
研究发现,阻断CD47/SIRPα相互作用可以促进巨噬细胞对肿瘤细胞的吞噬,从而发挥抗肿瘤作用。临床数据也表明CD47的表达与癌症病人生存率密切相关,高表达CD47的病人往往伴随着较差的生存率以及预后表现。目前已有多个靶向CD47的抗体药物进入临床研究,在实体瘤和血液肿瘤中CD47抗体能够有效地抑制肿瘤生长,但是这类药物会产生严重不良反应。这是因为CD47在人体正常红细胞中也表达,CD47抗体除了能与肿瘤细胞表面的CD47结合,也能与红细胞表面的CD47结合,从而引起严重的红细胞毒性等副作用。此外,由于CD47表达范围广,抗体药物存在着抗原沉默效应,抗体药物需要较高剂量或者频繁给药才能实现有效治疗。因此,临床上迫切需要寻找新的CD47抑制策略,为肿瘤免疫治疗提供有效手段。
由于酶学特征和底物偏好的重叠,在某些情况下,QC蛋白的谷氨酰胺酰基环化酶活性也可能在SIRPα和CD47之间的相互作用中起作用,因此在CD47/SIRPα信号轴中起作用。除CD47外,QC和isoQC还可将其他蛋白质焦谷氨酸化。例如,已知参与阿尔茨海默病的β淀粉样蛋白会被QC焦谷氨酸化,而C-C基序趋化因子配体2(CCL2)蛋白则被isoQC焦谷氨酸化。然而,由于酶特性和底物偏好的巨大重叠,不排除QC和isoQC在这些目标的焦谷氨酰化过程中存在一定量的功能重叠。
然而QC或isoQC抑制剂研究很少,至今无靶向药物上市。因此,开发新的QC或isoQC抑制剂,为肿瘤治疗提供新的治疗药物与方法具有十分重要的意义。
发明内容
本发明旨在至少解决上述现有技术中存在的技术问题之一。为此,本发明提出一种化合物(谷氨酰胺环化酶抑制剂),为一类小分子多环杂环化合物,能够抑制谷氨酸酰胺肽环转移酶样(isoQC)酶和/或谷氨酰胺酰肽环转移酶(QC),即能够抑制、降低或阻断isoQC或QC的活性。
本发明还提出一种包含上述化合物的药物组合物。
本发明还提出一种上述化合物的应用。
根据本发明的一个方面,提出了具有如式(I)所示结构的化合物,或所述化合物在药学上可接受的盐、溶剂化物、立体异构体或前药;
其连接关系为B-A-D-C;
其中,A选自烷基、杂烷基、烷基氨基、芳基、杂芳基、环烷基、杂环基和亚烷基的基团,其中所述基团可以独立地被烷基取代;
B选自取代或未取代的五元或六元氮杂芳基;
C选自氢原子、芳基、五元杂芳基和六元杂芳基,其中所述芳基、五元杂芳基和六元杂芳基可以独立地被一个或多个取代基取代;
D选自其中XD1、XD2和XD3分别独立地选自碳原子和氮原子,RD1选自氢原子和任意取代基,RD1的邻位连接键与A相连,RD1的间位连接键与C相连。
在本发明中,“A”、“B”、“C”、“D”分别与式(I)结构中标识相对应,式(I)结构用于表示化合物的主要结构框架和连接关系,其结构形式并不作为具体结构限定依据;如其中B为五元环结构,D为六元环结构且A和C分别与其邻位连接,C多为六元环结构但也可以为五元环结构或H。
另外注意的是,“C”独立出现时表示式(I)中的结构砌块,而例如“C1~5”等具有数字下标时应毫无疑意地作为碳原子个数表现形式。在本发明中,XD1、XD2和XD3分别独立地被任意取代基团取代或不取代。优选地,所述XD2被甲氨基或二甲氨基取代。
根据本发明的一种具体的实施方式,至少具有以下有益效果:本发明提供的化合物具有新的结构,其作为谷氨酰胺环化酶抑制剂能够有效抑制、降低或阻断isoQC或QC的活性,相比于已知的抑制剂其效力更佳、选择性更好。同时,通过丰富的实施例数据,可以证明A、B、C、D结构砌块可以有广泛的选择和组合。
在本发明的一些实施方式中,A选自4~8元环烷基、4~8元含1~2个氮原子杂环基、芳基、C1~5烷基和C1~5烷基氨基的基团,其中所述基团可以独立地被C1~5烷基取代;
B选自含1~3个氮原子的五环或六元氮杂芳基,其中所述五环氮杂芳基可以独立地被一个或多个取代基取代;
C中所述五元杂芳基选自含1~3个氧原子和/或氮原子的五元杂芳基,C中所述六元杂芳基选自含1~3个氮原子的六元氮杂芳基;
D中XD1和XD3均为碳原子,XD2选自碳原子和氮原子。
在本发明的一些优选的实施方式中,A选自4~8元环烷基、4~8元含1个氮原子杂环基、芳基、C3~5烷基和C2~4烷基氨基的基团,其中所述基团可以独立地被甲基取代;
和/或,B选自其中XB1和XB2分别独立地选自碳原子和氮原子,RB1和RB1分别独立地选自氢原子和C1~3烷基;
和/或,C选自其中XC1、XC2、XC3和XC4分别独立地选自碳原子和氮原子,RC1、RC2和RC3分别独立地选自氢原子、碳基、烷基、烷氧基、卤素、三氟甲基、氰基、氨基;
和/或,D中RD1选自三氟甲基、酰胺基、硝基、氰基、磺酰基。优选地,所述磺酰基包括磺酰氨基和甲磺酰基。
在本发明的一些更优选的实施方式中,A选自:
和/或,B选自:
和/或,C选自:
H;
和/或,D选自:
在本发明的一些更优选的实施方式中,所述化合物选自:
2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-3-(吡啶-3-基)苯甲腈、
2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-[1,1'-联苯基]-3-甲腈、
2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-3-(1-甲基-6-羰基-1,6-二氢吡啶-3-基)苯甲腈、
2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-3-(2-羰基-1,2-二氢吡啶-4-基)苯甲腈、
2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯甲腈、
2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-3-(吡啶-4-基)苯甲腈、
2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-3-(6-羰基-1,6-二氢吡啶-3-基)苯甲腈、
2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-3-(4-甲基吡啶-3-基)苯甲腈、
3-(6-甲氧基吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯甲腈、
3-(5-氟吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯甲腈、
5-(3-氰基-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯基)氰基吡啶、
5-(3-氰基-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯基)尼古丁腈、
3-(4-氯吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯甲腈、
2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-3-(6-(三氟甲基)吡啶-3-基)苯甲腈、
3-(6-氨基吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯甲腈、
2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-3-(嘧啶-5-基)苯甲腈、
3-(3,5-二甲基异噻唑-4-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯甲腈、
3-(呋喃-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯甲腈、
3-(4-甲氧基吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯甲腈、
3-(1-甲基-2-羰基-1,2-二氢吡啶-4-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯甲腈、
2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-3-(4-(三氟甲基)吡啶-3-基)苯甲腈、
3-(2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-3-(三氟甲基)苯基)吡啶、
2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-3-(吡啶-3-基)苯酰胺、
4-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-[3,3'-联吡啶]-5-甲腈、
3-(2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-3-硝基苯基)吡啶、
N,N-二甲基-4-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-3-(吡啶-3-基)苯胺、
N-甲基-4-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-3-(吡啶-3-基)苯胺、
2-(6-(4-甲基-4H-1,2,4-三唑-3-基)-3-氮杂二环[3.1.0]己烷-3-基)-3-(吡啶-3-基)苯甲腈、
2(-6-(4-甲基-4H-1,2,4-三唑-3-基)-2-氮杂螺[3.3]庚烷-2-基)-3-(吡啶-3-基)苯甲腈、
2-(4-(4-甲基-4H-1,2,4-三唑-3-基)环己基)-3-(吡啶-3-基)苯甲腈、
2-(甲基(3-(4-甲基-4H-1,2,4-三唑-3-基)丙基)氨基)-3-(吡啶-3-基)苯甲腈、
2-(4-(4-甲基-4H-1,2,4-三唑-3-基)吖庚环-1-基)-3-(吡啶-3-基)苯甲腈、
2-(4-(4-甲基-4H-1,2,4-三唑-3-基)吖庚环-1-基)-3-(吡啶-3-基)苯甲腈、
4'-(4-甲基-4H-1,2,4-三唑-3-基)-6-(吡啶-3-基)-[1,1'-联苯]-2-甲腈、
2-(3-(4-甲基-4H-1,2,4-三唑-3-基)吡咯烷-1-基)-3-(吡啶-3-基)苯甲腈、
2-(3-(4-甲基-4H-1,2,4-三唑-3-基)吖丁啶-1-基)-3-(吡啶-3-基)苯甲腈、
2-(4-(1-甲基-1H-咪唑-5-基)哌啶-1-基)-3-(吡啶-3-基)苯甲腈、
2-(4-(1H-吡唑-4-基)哌啶-1-基)-3-(吡啶-3-基)苯甲腈、
2-(4-(1H-咪唑-5-基)哌啶-1-基)-3-(吡啶-3-基)苯甲腈、
2-(4-(1H-1,2,4-三唑-1-基)哌啶-1-基)-3-(吡啶-3-基)苯甲腈3-(2-(4-(4-甲基-4H-1,2,4-三唑-3-yl)哌啶-1-基)-3-(甲磺酰基)苯基)吡啶、
2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-3-(吡啶-3-基)苯磺酰胺、
4-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-[3,3'-联吡啶]-5-甲腈、
3-(6-氟吡啶-3-基)-2-[4-(4-甲基-4氢-1,2,4-三唑-3-基)六氢吡啶-1-基]苯-1-甲腈、
3-(6-氟吡啶-3-基)-2-[4-(1-甲基咪唑-5-基)六氢吡啶-1-基]苯-1-甲腈、
2-[4-(4,5-二甲基-4氢-1,2,4-三唑-3-基)六氢吡啶-1-基]-3-(6-氟吡啶-3-基)苯-1-甲腈、
3-(6-氟吡啶-3-基)-2-{4-[4-(丙-2-基)-4氢-1,2,4-三唑-3-基]六氢吡啶-1-基}苯-1-甲腈、
2-[4-(1H-咪唑-5-基)六氢吡啶-1-基]-3-(6-氟吡啶-3-基)-苯-1-甲腈、
3-氟-5-{2-[4-(4-甲基-4氢-1,2,4-三唑-3-基)六氢吡啶-1-基]-3-硝基苯基}吡啶、
N-[3-(5-氟吡啶-3-基)-2-[4-(4-甲基-4氢-1,2,4-三唑-3-基)六氢吡啶-1-基]苯基]乙酰胺、
3-(5-氟吡啶-3-基)-2-{4-[4-(丙-2-基)-4氢-1,2,4-三唑-3-基]六氢吡啶-1-基}苯-1-甲腈、
2-[4-(4-环丙基-4氢-1,2,4-三唑-3-基)六氢吡啶-1-基]-3-(5-氟吡啶-3-基)苯-1-甲腈、
3-(5-氟吡啶-3-基)-2-[4-(3-甲基咪唑-5-基)六氢吡啶-1-基]苯-1-甲腈、
2-[4-(4,5-二甲基-1,2,4-三唑-3-基)六氢吡啶-1-基]-3-(5-氟吡啶-3-基)苯-1-甲腈、
3-(5-氟吡啶-3-基)-2-[4-(1-甲基咪唑-5-基)六氢吡啶-1-基]苯-1-甲腈、
3-(5-氟吡啶-3-基)-2-[4-(吡啶-3-基)六氢吡啶-1-基]苯-1-甲腈、
2-[4-(咪唑-1-基)六氢吡啶-1-基]-3-(5-氟吡啶-3-基)-苯-1-甲腈、
3-氟-5-(2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-3-甲磺酰基苯基)吡啶、
2-[4-(1H-咪唑-5-基)六氢吡啶-1-基]-3-(5-氟吡啶-3-基)-苯-1-甲腈。
在本发明的一些实施方式中,所述化合物具有如式(II)所示的结构:
其中,为烷基氨基,通过氨基氮原子与其它部分连接,所述烷基氨基选自4~8元环烷基氨基或2~5个碳原子线性烷基氨基;优选地,所述4~8元环烷基氨基包括一元环、二元桥环或螺环烷基烷基氨基;
R1选自取代或未取代的五元氮杂芳基;优选地,R1选自含2~3个氮原子的五环氮杂芳基,其中所述五环氮杂芳基可以独立地被一个或多个取代基取代;更优选地,R1选自其中XB1和XB2分别独立地选自碳原子和氮原子,RB1选自氢原子和C1~5烷基;
R2选自氢原子、芳基、五元杂芳基和六元杂芳基,其中所述芳基、五元杂芳基和六元杂芳基可以独立地被一个或多个取代基取代;优选地,R2中所述五元杂芳基选自含1~3个氧原子和/或氮原子的五元杂芳基,C中所述六元杂芳基选自含1~3个氮原子的六元氮杂芳基;更优选地,R2选自选自其中XC1、XC2、XC3和XC4分别独立地选自碳原子和氮原子,RC1、RC2和RC3分别独立地选自氢原子、碳基、烷基、烷氧基、卤素、三氟甲基、氰基、氨基;
R3选自氢原子和任意取代基;优选地,R3选自三氟甲基、酰胺基、硝基、氰基、磺酰基;更优选地,磺酰基包括磺酰氨基和甲磺酰基;
X1、X2和X3分别独立地被任意取代基团取代或不取代;优选地,X2被甲氨基或二甲氨基取代。
在本发明中,上述实施方式为更优选的实施方式之一,其中,R1与“B”对应,R2与“C”对应,与“A”对应;其结构与前述的实施方式具有对应性。
根据本发明的再一个方面,提出了一种药用组合物,所述药用组合物的活性成分上述化合物或其药学上可接受的盐、水合物、溶剂化物、同位素化合物,以及药用载体或稀释剂。
根据本发明的再一个方面,提出上述化合物在制备治疗肿瘤、免疫性疾病或神经性疾病的药物中的应用。
在本发明的一些实施方式中,所述药物包括上述具有式(I)结构的化合物、立体异构或其药学上可接受的盐、水合物、溶剂化物、同位素化合物;或者,所述药物包括上述具有式(I)结构的化合物、立体异构或其药学上可接受的盐、水合物、溶剂化物、同位素化合物作为活性成分的药物组合物;或者,所述物质包括药物包括上述药物组合物。
在本发明的一些实施方式中,所述肿瘤选自结直肠癌、肺癌、胃癌、黑色素瘤、骨髓瘤、乳腺癌、腺癌、膀胱癌和血液瘤中的至少一种。
在本发明的一些实施方式中,所述免疫性疾病选自湿疹、斑秃、银屑病、白癜风、类风湿性关节炎、红斑狼疮综合征、痤疮和化脓性汗腺炎中的至少一种。
在本发明的一些实施方式中,所述神经性疾病选自阿尔茨海默病、亨廷顿病、唐氏综合征中的神经变性、抑郁症、焦虑症、精神病和多发性硬化症中的至少一种。谷氨酰胺环化酶抑制剂用于神经性疾病的治疗可参见文献Nat.Chem.Biol.2015,11,347-354。
术语及相关解释
本发明所述化合物中,当任何变量(例如R1、RD1和XD1等)在任何组分中出现超过一次,则其每次出现的定义独立于其它每次出现的定义,同时其变量的下标仅表示在描述时能够与结构准确对应的编号。同样,允许取代基及变量的组合,只要这种组合使化合物稳定。自取代基划入环系统的线表示所指的键可连接到任何能取代的环原子上。如果环系统为多环,其意味着这种键仅连接到邻近环的任何适当的碳原子上。要理解本领域普通技术人员可选择本发明化合物的取代基及取代型式而提供化学上稳定的并可通过本领域技术和下列提出的方法自可容易获得的原料容易合成的化合物。如果取代基自身被超过一个基团取代,应理解这些基团可在相同碳原子上或不同碳原子上,只要使结构稳定。短语“任选被一个或多个取代基取代”被认为与短语“任选被至少一个取代基取代”相当且在此情况下优选的实施方案将具有0-3个取代基。本文中代表连接键。
本文所用术语“烷基”意指包括具有特定碳原子数目的支链的和直链的饱和脂肪烃基。例如,“C1~5烷基”中“C1~5”的定义包括以直链或支链排列的具有1、2、3、4、或5个碳原子的基团。例如,“C1-C5烷基”具体包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、戊基。同理,C2~4烷基表示具有2、3或4个碳原子的基团,不再赘述。
术语“环烷基”指具有特定碳原子数目的单环饱和脂肪烃基。例如“环烷基”包括环丙基、甲基-环丙基、2,2-二甲基-环丁基、2-乙基-环戊基、环己基等。
本文中所用术语“杂环”或“杂环基”除非有其它说明,是指含有1-4个选自O、N和S的杂原子的5元-6元芳香性或非芳香性杂环,且包括双环基团。“杂环基”因此包括上面提及的杂芳基,也包括其二氢化及四氢化类似物。“杂环基”进一步的实施例包括但不限于:咪唑基、吲哚基、异噻唑基、异噁唑基、噁二唑基、噁唑基、氧杂环丁烷基、吡喃基、吡嗪基、吡唑基、哒嗪基、吡啶基、嘧啶基、吡咯基、喹噁啉基、四唑基、噻二唑基、噻唑基、噻吩基、三唑基、l,4-二噁烷基、吡咯烷基、二氢咪唑基、二氢异噁唑基、二氢异噻唑基、二氢噁二唑基、二氢噁唑基、二氢吡嗪基、二氢吡唑基、二氢吡啶基、二氢嘧啶基、二氢吡咯基、二氢四唑基、二氢噻二唑基、二氢噻唑基、二氢噻吩基、二氢三唑基、二氢氮杂环丁烷基、四氢呋喃基和四氢噻吩基,及其N-氧化物。杂环取代基的连接可通过碳原子或通过杂原子实现。同时,本文中所用术语“杂芳基”是指含有1-4个选自O、N和S的杂原子的5元-6元芳香性杂环,包括在上述范围内。
正如本领域技术人员所理解的,本文中所用“卤素”意指包括氟、氯、溴和碘。
除非另有定义,烷基、环烷基、芳基和杂环基取代基可为未被取代的或取代的。例如,C1~5烷基可被一个、两个或三个选自OH、卤素、烷基、烷氧基等取代基取代。
本发明包括式(I)化合物的游离形式,也包括其药学上可接受的盐及立体异构体。本文中一些特定的示例性化合物为胺类化合物的质子化了的盐。术语“游离形式”指以非盐形式的胺类化合物。包括在内的药学上可接受盐不仅包括本文所述特定化合物的示例性盐,也包括所有式(I)化合物游离形式的典型的药学上可接受的盐。可使用本领域已知技术分离所述化合物特定盐的游离形式。例如,可通过用适当的碱稀水溶液例如NaOH稀水溶液、碳酸钾稀水溶液、稀氨水及碳酸氢钠稀水溶液处理该盐使游离形式再生。游离形式在某些物理性质例如在极性溶剂中溶解度上与其各自盐形式多少有些区别,但是为发明的目的这种酸盐及碱盐在其它药学方面与其各自游离形式相当。
可通过常规化学方法自含有碱性部分或酸性部分的本发明化合物合成本发明的药学上可接受的盐。通常,通过离子交换色谱或通过游离碱和化学计算量或过量的所需盐形式的无机或有机酸在适当溶剂或多种溶剂的组合中反应制备碱性化合物的盐。类似的,通过和适当的无机或有机碱反应形成酸性化合物的盐。
因此,本发明化合物的药学上可接受的盐包括通过碱性本发明化合物和无机或有机酸反应形成的本发明化合物的常规无毒盐。例如,常规的无毒盐包括得自无机酸例如盐酸、氢溴酸、硫酸、氨基磺酸、磷酸、硝酸等的盐,也包括自有机酸例如乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、扑酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、对氨基苯磺酸、2-乙酰氧基-苯甲酸、富马酸、甲苯磺酸、甲磺酸、乙烷二磺酸、草酸、羟乙基磺酸、三氟乙酸等制备的盐。
如果本发明化合物为酸性的,则适当的“药学上可接受的盐”指通过药学上可接受的无毒碱包括无机碱及有机碱制备的盐.得自无机碱的盐包括铝盐、铵盐、钙盐、铜盐、铁盐、亚铁盐、锂盐、镁盐、锰盐、亚锰盐、钾盐、钠盐、锌盐等。特别优选铵盐、钙盐、镁盐、钾盐和钠盐。得自药学上可接受的有机无毒碱的盐,所述碱包括伯胺、仲胺和叔胺的盐,取代的胺包括天然存在的取代胺、环状胺及碱性离子交换树脂例如精氨酸、甜菜碱、咖啡因、胆碱、N,N'-二苄基乙二胺、二乙胺、2一二乙基氨基乙醇、2一二甲基氨基乙醇、氨基乙醇、乙醇胺、乙二胺、N一乙基吗啉、N一乙基哌啶、葡萄糖胺、氨基葡萄糖、组氨酸、羟钴胺、异丙基胺、赖氨酸、甲基葡萄糖胺、吗啉、哌嗪,哌啶、呱咤、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨基丁三醇等。
Berg等,“Pharmaceutical Salts”J.Pharm.Sci.1977:66:1-19更详细描述了上文所述药学上可接受的盐及其它典型的药学上可接受的盐的制备。
由于在生理条件下化合物中脱质子化的酸性部分例如羧基可为阴离子的,而这种带有的电荷然后可被内部带有阳离子的质子化了的或烷基化的碱性部分例如四价氮原子平衡抵消,所以应注意本发明化合物是潜在的内盐或两性离子。
除在文献中已知的或在实验程序中例证的标准方法外,可采用如下列方案中显示的反应制备本发明化合物。因此,下列说明性方案是为说明的目的而不是局限于所列化合物或任何特定的取代基。方案中显示的取代基数目并不必需符合权利要求中所用的数目,且为清楚起见,显示单取代基连接到在上文中式(I)的定义下允许有多取代基的化合物上。
如本文所用,术语“isoQC/QC活性”定义为在释放氨的情况下,N端谷氨酰胺残基分子环化为焦谷氨酸(pGlu*),或者N端L-高谷氨酰胺或L-β-高谷氨酰胺分子内环化为环焦高谷氨酰胺衍生物。因此,参见路线1和2。
路线1:谷氨酰胺通过isoQC/QC环化
路线2:L-高谷氨酰胺通过isoQC/QC环化
如本文所用,术语“EC”包括QC和QC样酶(isoQC)作为谷氨酸环化酶(EC)的活性,进一步定义为EC活性。
如本文所用,术语“EC活性”定义为N端谷氨酸残基通过QC分子内环化为焦谷氨酸(pGlu*)。因此,参见路线3。
路线3:不带电的谷氨酰肽通过isoQC/QC(EC)的N端环化
术语“QC抑制剂”、“谷氨酰胺酰基环化酶抑制剂”是本领域技术人员公知的,并且表示抑制谷氨酰胺酰基环化酶(QC)的催化活性或其谷氨酰环化酶(EC)活性的酶抑制剂。
术语“isoQC抑制剂”、“谷氨酰胺酰肽环转移酶样蛋白抑制剂”是本领域技术人员公知的,并且表示抑制谷氨酰胺酰肽环转移酶样蛋白(isoQC)的催化活性或其谷氨酰环化酶(EC)活性的酶抑制剂。
本发明中术语“谷氨酰胺环化酶抑制剂”包括QC抑制剂和/或isoQC抑制剂,起到对QC/isoQC的抑制作用,具有相同或相似的药理作用效果。
isoQC抑制的效力:鉴于与isoQC抑制的关系,在优选的实施方案中,isoQC抑制的IC50为10μM或更小,优选1μM或更小,甚至更优选0.1μM或更小或者0.01μM或更小,或者最优选0.001μM或更小的物质。因此,尽管本文为了方便将活性物质描述为“isoQC抑制剂”,但是应当理解这样的命名不是为了将本发明的主题限于特定的作用机制。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案,下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍,显而易见地,下面描述中的附图仅仅是本发明的一些实施例,对于本领域普通技术人员来讲,在不付出创造性劳动性的前提下,还可以根据这些附图获得其它的附图,其中:
图1为本发明实施例61中化合物1(Cmpd1)或/和化合物4(Cmpd4)对A375、A549、HCT116、H929、Raji、DLD1细胞表面N-焦谷氨酸化修饰CD47(pGlu-CD47)的抑制作用,其中,A、B、C、D、E、F分别对应A375、A549、HCT116、H929、Raji、DLD1细胞的实验结果;
图2为本发明实施例61中化合物43和化合物44对293T和Raji细胞总CD47(hCD47-B6H12)、表面N-焦谷氨酸化修饰CD47(hCD47-CC2C6)以及CD47-SIRPα结合(hSIRPα-Fc)的抑制活性实验结果图;
图3为本发明实施例62中化合物1和化合物4对巨噬细胞吞噬DLD1结肠癌细胞能力的影响,其中,A、B、C、D分别对应DMSO、PQ912、化合物1、化合物4的流式细胞图,E为总的百分比柱状图;
图4为本发明实施例62中化合物1和化合物4对巨噬细胞吞噬H929细胞能力的影响,其中,A、B、C、D分别对应DMSO、PQ912、化合物1、化合物4的流式细胞图,E为总的百分比柱状图。
具体实施方式
以下将结合实施例对本发明的构思及产生的技术效果进行清楚、完整地描述,以充分地理解本发明的目的、特征和效果。显然,所描述的实施例只是本发明的一部分实施例,而不是全部实施例,基于本发明的实施例,本领域的技术人员在不付出创造性劳动的前提下所获得的其他实施例,均属于本发明保护的范围。实施例中所使用的试验方法如无特殊说明,均为常规方法;所使用的材料、试剂等,如无特殊说明,均可从商业途径得到的试剂和材料。
实施例1
2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-3-(吡啶-3-基)苯甲腈(化合物1)
2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(pyridin-3-yl)benzonitrile
步骤a、苯甲基4-(5-巯基-4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-羧酸酯(3,benzyl 4-(5-mercapto-4-methyl-4H-1,2,4-triazol-3-yl)piperidine-1-carboxylate)的合成:
将1-[(苄氧基)羰基]哌啶-4-羧酸(1)(10.0g,38.0mmol,1.0eq)溶解于(60mL),然后加入N,N'-羰基二咪唑(6.16g,38.0mmol,1.0eq),50℃加热搅拌2小时。然后4-甲基氨基硫脲(2)(4.40g,41.8mmol,1.1eq)加入反应体系中继续50℃搅拌18小时。TLC鉴定反应结束后,减压旋蒸除去溶剂后,再次加入二氯甲烷和饱和氯化铵水溶液萃取。收集有机相后利用SepaBean machine T200分离纯化,最后获得目的化合物9.8g(产率78%)。1H NMR(400MHz,MeOD-d4)δ7.39-7.32(m,5H),5.15(s,2H),4.24-4.18(m,2H),3.56(s,3H),3.10-3.01(m,3H),2.01-1.97(m,2H),1.74-1.63(m,2H)。
步骤b、苯甲基4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-羧酸酯(4,benzyl 4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidine-1-carboxylate)的合成:
冰浴条件下,将苯甲基4-(5-巯基-4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-羧酸酯(3)(9.8g,29.7mmol,1.0eq)溶解于二氯甲烷中,然后依次加入过氧化氢(30%水溶液,2.0mL,65.3mmol,2.2eq)和醋酸(10mL)。室温继续搅拌18小时,TLC检测反应结束后,向体系中加入15% NaOH溶液调节pH至10,然后加入二氯甲烷萃取。收集有机相后利用SepaBeanmachine T200分离纯化,最后获得目的化合物8.1g(产率91%)。1H NMR(400MHz,CDCl3)δ8.04(s,1H),7.37-7.29(m,5H),5.14(s,2H),4.28(d,J=13.2Hz,1H),3.64(s,3H),3.02(brs,2H),2.92-2.84(m,1H),1.93(brs,4H)。
步骤c和d、3-溴-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯甲腈(6,3-bromo-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile)的合成:
苯甲基4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-羧酸酯(4)(8.1g,26.9mmol,1.0eq)加入到6N盐酸溶液(25mL)中,100℃加热搅拌16小时。TLC监测反应结束后,加入饱和NaHCO3溶液和二氯甲烷萃取,收集水相减压旋蒸获得4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶粗产物6.65g。将4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶(5)(0.15g,1.21mmol,1.0eq)溶解于DMF(4mL)中,然后依次加入3-溴-2-氟苯腈(0.29g,1.45mmol,1.2eq)和无水碳酸钾(0.25g,1.82mmol,1.5eq),100℃加热搅拌16小时。TLC监测反应结束后,加入二氯甲烷和水萃取,再次用饱和食盐水和二氯甲烷萃取,收集有机相,利用SepaBean machine T200分离纯化,最后获得目的化合物0.15g(产率36%)。
步骤e、2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-3-(吡啶-3-基)苯甲腈(化合物1,2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(pyridin-3-yl)benzonitrile)的合成:
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将3-溴-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯甲腈(6)(50mg,0.15mmol,1.0eq)和吡啶-3-硼酸频呐醇酯(45mg,0.22mmol,1.5eq)溶解于甲苯:乙醇:2N碳酸钠溶液(2:1:1.5)。体系用氮气置换两次,然后加入四三苯基膦钯(17.3mg,0.015mmol,0.1eq),再次用氮气置换体系三次,90℃搅拌反应8小时。TLC监测反应结束后,乙酸乙酯和水、饱和食盐水依次萃取,无水硫酸镁干燥后,有机相减压旋蒸,利用SepaBean machineT200分离纯化,最后获得目的化合物48mg(产率90%)。合成方法如实施例1所示,得到化合物1的数据为:1H NMR(400Hz,MeOD-d4)δ9.07(s,1H),8.98(s,1H),8.82(d,J=5.5Hz,1H),8.53(d,J=7.9Hz,1H),8.05(dd,J=8.1,5.6Hz,1H),7.82(dd,J=7.7,1.5Hz,1H),7.69(d,J=7.5Hz,1H),7.43(t,J=7.7Hz,1H),3.85(s,3H),3.26(s,1H),3.15(ttt,J=3.8,3.7,3.8Hz,1H),1.95(d,J=12.3Hz,2H),1.72(s,2H);LC-MS(ESI)calcd for C20H20N6[M+H]+345.2,found 345.3。
实施例2
2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-[1,1'-联苯基]-3-甲腈(化合物2)
2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-[1,1'-biphenyl]-3-carbonitrile
合成方法同实施例1,得到化合物2的数据为:1H NMR(400Hz,MeOD-d4)δ9.11(s,1H),7.65(dd,J=7.6,1.6Hz,1H),7.54-7.43(m,3H),7.40(d,J=6.9Hz,1H),7.36(d,J=7.2Hz,2H),7.24(t,J=7.6Hz,1H),3.85(s,3H),3.28(s,1H),3.15-3.02(m,1H),3.01-2.91(m,2H),1.94-1.87(m,4H);LC-MS(ESI)calcd for C21H21N5[M+H]+344.2,found344.4。
实施例3
2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-3-(1-甲基-6-羰基-1,6-二氢吡啶-3-基)苯甲腈(化合物3)
2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)benzonitrile
合成方法同实施例1,得到化合物3的数据为:1H NMR(400Hz,MeOD-d4)δ9.21(s,1H),7.78(d,J=2.2Hz,1H),7.65(dd,J=7.8,1.4Hz,2H),7.54(dd,J=7.7,1.6Hz,1H),7.29(t,J=7.7Hz,1H),6.65(d,J=9.4Hz,1H),3.90(s,3H),3.65(s,3H),3.37(d,J=10.9Hz,2H),3.28-3.18(m,2H),2.02(d,J=11.3Hz,2H),1.96-1.84(m,2H);LC-MS(ESI)calcd for C21H22N6O[M+H]+375.2,found 375.4。
实施例4
2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-3-(2-羰基-1,2-二氢吡啶-4-基)苯甲腈(化合物4)
2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(2-oxo-1,2-dihydropyridin-4-yl)benzonitrile
合成方法同实施例1,得到化合物4的数据为:1H NMR(400MHz,MeOD-d4)δ9.20(s,1H),7.74(dd,J=7.7,1.2Hz,1H),7.58(d,J=6.7Hz,1H),7.54(d,J=7.7Hz,1H),7.29(t,J=7.7Hz,1H),6.58(s,1H),6.52(d,J=6.7Hz,1H),3.92(s,3H),3.42-3.39(m,2H),3.27-3.21(m,3H),2.05-1.91(m,4H);LC-MS(ESI)calcd for C20H20N6O[M+H]+361.2,found361.2。
实施例5
2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯甲腈(化合物5)
2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile
合成方法同实施例1,得到化合物5的数据为:1H NMR(400Hz,MeOD-d4)δ9.08(s,1H),7.65-7.57(m,2H),7.21(d,J=8.4Hz,1H),7.11(t,J=7.7Hz,1H),3.93(s,3H),3.68(d,J=12.3Hz,2H),3.33-3.26(m,2H),3.08-3.00(m,2H),2.24-2.03(m,4H);LC-MS(ESI)calcd for C15H17N5[M+H]+268.1,found 268.3。
实施例6
2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-3-(吡啶-4-基)苯甲腈(化合物6)
2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(pyridin-4-yl)benzonitrile
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合成方法同实施例1,得到化合物6的数据为:1H NMR(400Hz,MeOD-d4)δ8.97-8.91(m,3H),8.11(d,J=1.8Hz,2H),7.89(dd,J=1.6,7.7Hz,1H),7.72(dd,J=1.7,7.8Hz,1H),7.5(t,J=7.8Hz,1H),3.87(s,3H),3.36-3.35(m,2H),3.35-3.34(m,2H),3.23-3.12(m,1H),2.02-1.94(m,2H),1.92-1.79(m,2H);LC-MS(ESI)calcd for C20H25N6[M+H]+344.4,found 345.1。
实施例7
2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-3-(6-羰基-1,6-二氢吡啶-3-基)苯甲腈(化合物7)
2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(6-oxo-1,6-dihydropyridin-3-yl)benzonitrile
合成方法同实施例1,得到化合物7的数据为:1H NMR(400MHz,MeOD-d4)δ9.12(s,1H),7.72(d,J=8.8Hz,1H),7.67(dd,J=7.7,1.4Hz,1H),7.54-7.52(m,2H),7.29(t,J=7.7Hz,1H),6.65(d,J=9.4Hz,1H),3.89(s,3H),3.39-3.33(m,3H),3.23-3.13(m,1H),2.04-1.90(m,5H);LC-MS calcd for C20H20N6O[M+H]+360.4,found361.1。
实施例8
2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-3-(4-甲基吡啶-3-基)苯甲腈(化合物8)
2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(4-methylpyridin-3-yl)benzonitrile
合成方法同实施例1,得到化合物8的数据为:1H NMR(400Hz,MeOD-d4)δ9.00(s,1H),8.79(s,1H),8.74(d,J=6.0Hz,1H),8.04(d,J=6.0Hz,1H),7.85(dd,J=7.7,1.5Hz,1H),7.60(dd,J=7.6,1.5Hz,1H),7.43(t,J=7.7Hz,1H),3.82(s,3H),3.44-3.33(m,1H),3.24(s,3H),3.10(ttt,J=3.8,3.6,3.6Hz,1H),2.48(s,3H),1.90(t,J=11.2Hz,2H),1.55-1.43(m,2H);LC-MS(ESI)calcd for C21H22N6[M+H]+359.2,found 359.4。
实施例9
3-(6-甲氧基吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯甲腈(化合物9)
3-(6-methoxypyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile
合成方法同实施例1,得到化合物9的数据为:1H NMR(400Hz,MeOD-d4)δ9.19(s,1H),8.17(d,J=1.8Hz,1H),7.78(dd,J=8.6,1.7Hz,1H),7.68(dd,J=7.7,1.2Hz,1H),7.51(dd,J=7.7,1.7Hz,1H),7.29(t,J=7.8Hz,1H),6.96(d,J=8.6Hz,1H),3.97(s,3H),3.89(s,3H),3.28(s,1H),3.22-3.06(m,3H),1.97(d,J=10.8Hz,2H),1.92-1.80(m,2H);LC-MS(ESI)calcd for C21H22N6O[M+H]+375.2,found 375.4。
实施例10
3-(5-氟吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯甲腈(化合物10)
3-(5-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile
合成方法同实施例1,得到化合物10的数据为:1H NMR(400MHz,MeOD-d4)δ9.23(s,1H),8.57-8.52(m,2H),7.81(d,J=9.2Hz,1H),7.75(dd,J=7.7,1.4Hz,1H),7.59(d,J=7.6Hz,1H),7.35(t,J=7.7Hz,1H),3.90(s,3H),3.40-3.32(m,1H),3.31-3.21(m,2H),3.20-3.06(m,2H),2.03-1.93(m,2H),1.91-1.69(m,2H);LC-MS(ESI)calcd for C20H19FN6Na[M+H]+385.2,found 385.3。
实施例11
5-(3-氰基-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯基)氰基吡啶(化合物11)
5-(3-cyano-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)picolinonitrile
合成方法同实施例1,得到化合物11的数据为:1H NMR(400MHz,MeOD-d4)δ9.21(s,1H),8.80(d,J=1.2Hz,1H),8.08(dd,J=8.0,2.0Hz,1H),8.01(d,J=7.5Hz,1H),7.78(dd,J=7.8,1.6Hz,1H),7.61(dd,J=7.7,1.5Hz,1H),7.38(t,J=7.7Hz,1H),3.89(s,3H),3.30-3.25(m,2H),3.25-3.21(m,1H),3.21-3.10(m,2H),2.03-1.90(m,2H),1.87-1.65(m,2H).ESI-MS calcd for C21H19N7[M+Na]+392.2,found:392.4.
实施例12
5-(3-氰基-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯基)尼古丁腈(化合物12)
5-(3-cyano-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)nicotinonitrile
合成方法同实施例1,得到化合物12的数据为:1H NMR(400MHz,MeOD-d4)δ9.21(s,1H),8.97-8.91(m,2H),8.31(s,1H),7.77(d,J=7.7Hz,1H),7.62(d,J=7.6Hz,1H),7.38(t,J=7.7Hz,1H),3.90(s,3H),3.38-3.28(m,2H),3.28-3.20(m,2H),3.20-3.10(m,1H),2.02-1.90(m,2H),1.89-1.52(m,2H);LC-MS(ESI)calcd for C21H19N7[M+H]+345.2,found346.3。
实施例13
3-(4-氯吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯甲腈(化合物13)
3-(4-chloropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile
合成方法同实施例1,得到化合物13的数据为:1H NMR(400MHz,MeOD-d4)δ9.23(s,1H),8.73-8.58(m,2H),7.87(d,J=5.6Hz,1H),7.81(d,J=7.6Hz,1H),7.56(d,J=7.6Hz,1H),7.39(t,J=7.7Hz,1H),3.87(s,3H),3.40-3.30(m,2H),3.27-3.22(m,1H),3.21-3.06(m,2H),2.01-1.87(m,2H),1.79-1.41(m,2H);LC-MS(ESI)calcd for C20H19ClN6[M+H]+378.1,found 379.5。
实施例14
2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-3-(6-(三氟甲基)吡啶-3-基)苯甲腈(化合物14)
2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(6-(trifluoromethyl)pyridin-3-yl)benzonitrile
合成方法同实施例1,得到化合物14的数据为:1H NMR(400MHz,MeOD-d4)δ9.21(s,1H),8.80(d,J=1.2Hz,1H),8.12(dd,J=8.0,1.5Hz,1H),7.96(d,J=8.0Hz,1H),7.77(dd,J=7.7,1.6Hz,1H),7.61(dd,J=7.7,1.6Hz,1H),7.37(t,J=7.7Hz,1H),3.89(s,3H),3.32-3.27(m,2H),3.26-3.21(m,1H),3.20-3.07(m,2H),2.02-1.92(m,2H),1.88-1.68(m,2H);LC-MS(ESI)calcd for C21H19F3N6[M+H]+412.2,found413.4。
实施例15
3-(6-氨基吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯甲腈(化合物15)
3-(6-aminopyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile
合成方法同实施例1,得到化合物15的数据为:1H NMR(400MHz,MeOD-d4)δ9.21(s,1H),8.03(d,J=9.0Hz,1H),7.97-7.89(m,1H),7.72(dd,J=7.7,1.2Hz,1H),7.58(d,J=7.6Hz,1H),7.33(t,J=7.7Hz,1H),7.12(d,J=9.2Hz,1H),3.90(s,3H),3.43-3.32(m,2H),3.32-3.31(m,1H),3.30-3.15(m,2H),2.05-1.99(m,2H),1.97-1.73(m,2H);LC-MS(ESI)calcd for C20H21N7[M+H]+359.2,found 360.3。
实施例16
2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-3-(嘧啶-5-基)苯甲腈(化合物16)
2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(pyrimidin-5-yl)benzonitrile
合成方法同实施例1,得到化合物16的数据为:1H NMR(400MHz,MeOD-d4)δ9.18(d,J=3.0Hz,2H),8.92(s,2H),7.78(dd,J=7.8,1.6Hz,1H),7.66(dd,J=7.7,1.5Hz,1H),7.41(t,J=7.7Hz,1H),3.89(s,3H),3.35-3.30(m,2H),3.29-3.23(m,2H),3.22-3.15(m,1H),2.03-1.92(m,2H),1.90-1.54(m,2H);LC-MS(ESI)calcd for C19H19N7[M+H]+345.2,found 346.3。
实施例17
3-(3,5-二甲基异噻唑-4-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯甲腈(化合物17)
3-(3,5-dimethylisoxazol-4-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile
合成方法同实施例1,得到化合物17的数据为:1H NMR(400MHz,MeOD-d4)δ9.07(s,1H),7.72(dd,J=7.8,1.7Hz,1H),7.42(dd,J=7.6,1.7Hz,1H),7.30(t,J=7.7Hz,1H),3.87(s,3H),3.39-3.37(m,2H),3.27-3.16(m,3H),2.32(s,3H),2.15(s,3H),2.05-1.96(m,2H),1.90-1.71(m,2H);LC-MS(ESI)calcd for C20H22N6O[M+H]+363.3,found 363.3。
实施例18
3-(呋喃-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯甲腈(化合物18)
3-(furan-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile
合成方法同实施例1,得到化合物18的数据为:1H NMR(400MHz,MeOD-d4)δ9.06(s,1H),7.86(s,1H),7.62-7.59(m,3H),7.26(t,J=7.7Hz,1H),6.72(s,1H),3.90(s,3H),3.34-3.32(m,4H),3.23-3.17(m,1H),2.09-2.01(m,4H);LC-MS(ESI)calcd for C19H19N5O[M+H]+392.2,found 334.2。
实施例19
3-(4-甲氧基吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯甲腈(化合物19)
3-(4-methoxypyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile
合成方法同实施例1,得到化合物19的数据为:1H NMR(400MHz,MeOD-d4)δ9.14(s,1H),7.76(d,J=6.9Hz,1H),7.73(dd,J=7.7,1.6Hz,1H),7.52(dd,J=7.7,1.6Hz,1H),7.28(t,J=7.7Hz,1H),6.57(d,J=1.6Hz,1H),6.47(dd,J=6.9,1.9Hz,1H),3.90(s,3H),3.63(s,3H),3.42-3.37(m,2H),3.26-3.19(m,3H),2.03-1.94(m,4H);LC-MS(ESI)calcdfor C21H22N6O[M+H]+375.3,found 375.3。
实施例20
3-(1-甲基-2-羰基-1,2-二氢吡啶-4-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯甲腈(化合物20)
3-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile
合成方法同实施例1,得到化合物20的数据为:1H NMR(400MHz,MeOD-d4)δ9.13(s,1H),8.83(dd,J=7.0,1.2Hz,1H),8.69(d,J=1.2Hz,1H),7.82(dd,J=7.7,1.6Hz,1H),7.78(d,J=7.0Hz,1H),7.58(dd,J=7.7,1.4Hz,1H),7.39(t,J=7.8Hz,1H),4.18(s,3H),3.86(s,3H),3.26-3.12(m,5H),1.99-1.94(m,2H),1.63(s,2H);LC-MS(ESI)calcd forC21H22N6O[M+H]+375.2,found 375.2。
实施例21
2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-3-(4-(三氟甲基)吡啶-3-基)苯甲腈(化合物21)
2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(4-(trifluoromethyl)pyridin-3-yl)benzonitrile
合成方法同实施例1,得到化合物21的数据为:1H NMR(400MHz,MeOD-d4)δ9.14(s,1H),8.86(d,J=5.2Hz,1H),8.68(s,1H),7.88(d,J=5.2Hz,1H),7.81(dd,J=7.8,1.5Hz,1H),7.56(d,J=7.7Hz,1H),7.38(t,J=7.7Hz,1H),3.84(s,3H),3.29-3.20(m,3H),3.14-3.07(m,2H),1.92-1.90(m,2H),1.56-1.54(m,2H);LC-MS(ESI)calcd for C21H19F3N6[M+H]+413.1,found 413.1。
实施例22
N-甲基-4-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-3-(吡啶-3-基)苯胺(化合物22)
N-methyl-4-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(pyridin-3-yl)aniline
合成方法同实施例1,得到化合物22的数据为:1H NMR(400MHz,MeOD-d4)δ9.13(s,1H),8.88(s,1H),8.76(d,J=5.2Hz,1H),8.69(d,J=8.0Hz,1H),8.00(dd,J=7.6,5.6Hz,1H),7.39(d,J=8.8Hz,1H),7.25(dd,J=8.8,2.8Hz,1H),7.19(d,J=2.8Hz,1H),3.83(s,3H),3.16-3.05(m,3H),3.00(s,3H),2.92-2.85(m,2H),1.97-1.94(m,2H),1.81-1.70(m,2H);LC-MS(ESI)calcd for C20H25N6[M+H]+349.2;found 349.4。
实施例23
N,N-二甲基-4-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-3-(吡啶-3-基)苯胺(化合物23)
N,N-dimethyl-4-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(pyridin-3-yl)aniline
合成方法同实施例1,得到化合物23的数据为:1H NMR(400MHz,MeOD-d4)δ9.16(s,1H),8.92(s,1H),8.77-8.74(m,2H),8.06-8.01(m,1H),7.42-7.29(m,3H),3.84(s,3H),3.18-3.07(m,9H),2.92-2.85(m,2H),1.97-1.95(m,2H),1.82-1.71(m,2H);LC-MS(ESI)calcd for C20H25N6[M+H]+363.2,found 363.4。
实施例24
3-(2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-3-(三氟甲基)苯基)吡啶(化合物24)
3-(2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(trifluoromethyl)phenyl)pyridine
合成方法如上所示,对应的步骤a和b,与实施例1中的d和e类似,因此通过如实施例1的方法可合成得到化合物24。
实施例25
2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-3-(吡啶-3-基)苯酰胺(化合物25)
2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(pyridin-3-yl)benzamid
化合物25合成方法如上所示,由化合物1制备得到。
实施例26
4-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-[3,3'-联吡啶]-5-甲腈(化合物26)
4-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-[3,3'-bipyridine]-5-carbonitrile
合成方法如实施例1。
实施例27
3-(2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-3-硝基苯基)吡啶(化合物27)
3-(2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-nitrophenyl)pyridine
化合物27合成方法如上所示。
实施例28
2-(6-(4-甲基-4H-1,2,4-三唑-3-基)-3-氮杂二环[3.1.0]己烷-3-基)-3-(吡啶-3-基)苯甲腈(化合物28)
2-(6-(4-methyl-4H-1,2,4-triazol-3-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-3-(pyridin-3-yl)benzonitrile
化合物28合成方法如上所示。
实施例29
2(-6-(4-甲基-4H-1,2,4-三唑-3-基)-2-氮杂螺[3.3]庚烷-2-基)-3-(吡啶-3-基)苯甲腈(化合物29)
2-(6-(4-methyl-4H-1,2,4-triazol-3-yl)-2-azaspiro[3.3]heptan-2-yl)-3-(pyridin-3-yl)benzonitrile
化合物29合成方法如上所示。
实施例30
2-(4-(4-甲基-4H-1,2,4-三唑-3-基)环己基)-3-(吡啶-3-基)苯甲腈(化合物30)
2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)cyclohexyl)-3-(pyridin-3-yl)benzonitrile
化合物30合成方法如上所示。
实施例31
2-(甲基(3-(4-甲基-4H-1,2,4-三唑-3-基)丙基)氨基)-3-(吡啶-3-基)苯甲腈(化合物31)
2-(methyl(3-(4-methyl-4H-1,2,4-triazol-3-yl)propyl)amino)-3-(pyridin-3-yl)benzonitrile
化合物31合成方法如上所示。
实施例32
2-(4-(4-甲基-4H-1,2,4-三唑-3-基)吖庚环-1-基)-3-(吡啶-3-基)苯甲腈(化合物32)
2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)azepan-1-yl)-3-(pyridin-3-yl)benzonitrile
化合物32合成方法如上所示。
实施例33
4'-(4-甲基-4H-1,2,4-三唑-3-基)-6-(吡啶-3-基)-[1,1'-联苯]-2-甲腈(化合物33)
4'-(4-methyl-4H-1,2,4-triazol-3-yl)-6-(pyridin-3-yl)-[1,1'-biphenyl]-2-carbonitrile
实施例34
2-(3-(4-甲基-4H-1,2,4-三唑-3-基)吡咯烷-1-基)-3-(吡啶-3-基)苯甲腈(化合物34)
2-(3-(4-methyl-4H-1,2,4-triazol-3-yl)pyrrolidin-1-yl)-3-(pyridin-3-yl)benzonitrile
化合物34合成方法如上所示。
实施例35
2-(3-(4-甲基-4H-1,2,4-三唑-3-基)吖丁啶-1-基)-3-(吡啶-3-基)苯甲腈(化合物35)
2-(3-(4-methyl-4H-1,2,4-triazol-3-yl)azetidin-1-yl)-3-(pyridin-3-yl)benzonitrile
化合物35合成方法如上所示。
实施例36
2-(4-(1-甲基-1H-咪唑-5-基)哌啶-1-基)-3-(吡啶-3-基)苯甲腈(化合物36)
2-(4-(1-methyl-1H-imidazol-5-yl)piperidin-1-yl)-3-(pyridin-3-yl)benzonitrile
化合物36合成方法如上所示。
实施例37
2-(4-(1H-吡唑-4-基)哌啶-1-基)-3-(吡啶-3-基)苯甲腈(化合物37)
2-(4-(1H-pyrazol-4-yl)piperidin-1-yl)-3-(pyridin-3-yl)benzonitrile
化合物37合成方法如上所示。
实施例38
2-(4-(1H-咪唑-5-基)哌啶-1-基)-3-(吡啶-3-基)苯甲腈(化合物38)
2-(4-(1H-imidazol-5-yl)piperidin-1-yl)-3-(pyridin-3-yl)benzonitrile
化合物38合成方法如上所示。
实施例39
2-(4-(1H-1,2,4-三唑-1-基)哌啶-1-基)-3-(吡啶-3-基)苯甲腈(化合物39)
2-(4-(1H-1,2,4-triazol-1-yl)piperidin-1-yl)-3-(pyridin-3-yl)benzonitrile
化合物39合成方法如上所示。
实施例40
3-(2-(4-(4-甲基-4H-1,2,4-三唑-3-yl)哌啶-1-基)-3-(甲磺酰基)苯基)吡啶(化合物40)
3-(2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(methylsulfonyl)phenyl)pyridine
化合物40合成方法如上所示。
实施例41
2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-3-(吡啶-3-基)苯磺酰胺(化合物41)
2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(pyridin-3-yl)benzenesulfonamide
化合物41合成方法如上所示。
实施例42
4-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-[3,3'-联吡啶]-5-甲腈(化合物42)
4-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-[3,3'-bipyridine]-5-carbonitrile
合成方法如实施例1所示。
实施例43
3-(6-氟吡啶-3-基)-2-[4-(4-甲基-4氢-1,2,4-三唑-3-基)六氢吡啶-1-基]苯-1-甲腈(化合物43)
3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile
合成方法同实施例1,得到化合物43的数据为:1H NMR(400MHz,MeOD-d4)δ8.98(s,1H),8.28(d,J=2.4Hz,1H),8.05(td,J=8.4,2.4Hz,1H),7.75(dd,J=7.6,1.6Hz,1H),7.58(dd,J=8.0,2.0Hz,1H),7.35(t,J=7.6Hz,1H),7.23(dd,J=8.4,2.4Hz,1H),3.86(s,3H),3.29(brs,2H),3.18-3.09(m,3H),1.98-1.94(m,2H),1.85-1.81(m,2H).LRMS(ESI)[M+H]+,found:363.1。
实施例44
3-(6-氟吡啶-3-基)-2-[4-(1-甲基咪唑-5-基)六氢吡啶-1-基]苯-1-甲腈(化合物44)
3-(6-fluoropyridin-3-yl)-2-(4-(1-methyl-1H-imidazol-5-yl)piperidin-1-yl)benzonitrile
合成方法同实施例36,得到化合物44的数据为:1H NMR(400MHz,MeOD-d4)δ8.80(s,1H),8.30(d,J=2.4Hz,1H),8.05(td,J=8.0,2.4Hz,1H),7.74(dd,J=7.6,1.6Hz,1H),7.58(dd,J=7.6,2.0Hz,1H),7.37-7.34(m,2H),7.23(dd,J=8.4,2.8Hz,1H),3.89(s,3H),3.29-3.25(m,4H),2.92-2.83(m,1H),1.95-1.91(m,2H),1.65-1.61(m,2H).LRMS(ESI)[M+H]+,found:362.2。
实施例45
2-[4-(4,5-二甲基-4氢-1,2,4-三唑-3-基)六氢吡啶-1-基]-3-(6-氟吡啶-3-基)苯-1-甲腈(化合物45)
2-(4-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(6-fluoropyridin-3-yl)benzonitrile
合成方法同实施例1,得到化合物45的数据为:1H NMR(400MHz,MeOD-d4)δ8.28(d,J=2.4Hz,1H),8.04(td,J=8.0,2.8Hz,1H),7.75(dd,J=8.0,2.0Hz,1H),7.58(dd,J=7.6,2.0Hz,1H),7.35(t,J=7.6Hz,1H),7.22(dd,J=8.4,2.8Hz,1H),3.74(s,3H),3.30-3.28(m,2H),3.17-3.07(m,3H),2.62(s,3H),1.97-1.93(m,2H),1.87-1.77(m,2H).LRMS(ESI)[M+H]+,found:377.2。
实施例46
3-(6-氟吡啶-3-基)-2-{4-[4-(丙-2-基)-4氢-1,2,4-三唑-3-基]六氢吡啶-1-基}苯-1-甲腈(化合物46)
3-(6-fluoropyridin-3-yl)-2-(4-(4-isopropyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile
合成方法同实施例1,得到化合物46的数据为:1H NMR(400MHz,MeOD-d4)δ9.34(s,1H),8.29(d,J=2.4Hz,1H),8.05(td,J=8.0,2.4Hz,1H),7.75(dd,J=8.0,1.6Hz,1H),7.58(dd,J=8.0,2.0Hz,1H),7.35(t,J=8.0Hz,1H),7.23(dd,J=8.4,2.4Hz,1H),4.80-4.69(m,1H),3.31-3.28(m,2H),3.22-3.13(m,3H),1.96-1.86(m,4H),1.58(d,J=6.8Hz,6H).LRMS(ESI)[M+H]+,found:391.2。
实施例47
2-[4-(1H-咪唑-5-基)六氢吡啶-1-基]-3-(6-氟吡啶-3-基)-苯-1-甲腈(化合物47)
2-(4-(1H-imidazol-5-yl)piperidin-1-yl)-3-(6-fluoropyridin-3-yl)benzonitrile
合成方法同实施例38,得到化合物47的数据为:1H NMR(400MHz,MeOD-d4)δ8.83(s,1H),8.29(d,J=2.4Hz,1H),8.02(td,J=8.0,2.4Hz,1H),7.74(dd,J=8.0,1.6Hz,1H),7.57(dd,J=7.6,1.6Hz,1H),7.36-7.32(m,2H),7.21(dd,J=8.4,2.4Hz,1H),3.29-3.24(m,2H),3.16-3.11(m,2H),2.88-2.79(m,1H),1.98-1.93(m,2H),1.69-1.65(m,2H).LRMS(ESI)[M+H]+,found:348.2。
实施例48
3-氟-5-{2-[4-(4-甲基-4氢-1,2,4-三唑-3-基)六氢吡啶-1-基]-3-硝基苯基}吡啶(化合物48)
3-fluoro-5-(2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-nitrophenyl)pyridine
合成方法同实施例27,得到化合物48的数据为:1H NMR(400MHz,CDCl3)δ8.50-8.47(m,1H),8.01(s,1H),7.64(dd,J=8.0,1.6Hz,1H),7.58-7.54(m,1H),7.40(dd,J=7.6,1.6Hz,1H),7.26(t,J=8.0Hz,1H),3.60(s,3H),3.06-2.96(m,4H),2.74-2.66(m,1H),1.75-1.68(m,4H)。
实施例49
N-[3-(5-氟吡啶-3-基)-2-[4-(4-甲基-4氢-1,2,4-三唑-3-基)六氢吡啶-1-基]苯基]乙酰胺(化合物49)
N-(3-(5-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)acetamide
得到化合物49的数据为:LRMS(ESI)[M+H]+,found:395.4。
实施例50
3-(5-氟吡啶-3-基)-2-{4-[4-(丙-2-基)-4氢-1,2,4-三唑-3-基]六氢吡啶-1-基}苯-1-甲腈(化合物50)
3-(5-fluoropyridin-3-yl)-2-(4-(4-isopropyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile
得到化合物50的数据为:1H NMR(400MHz,MeOD-d4)δ9.47(s,1H),8.56(d,J=2.8Hz,1H),8.52(s,1H),7.82-7.76(m,2H),7.61(dd,J=7.6,1.6Hz,1H),7.37(t,J=8.0Hz,1H),4.82-4.74(m,1H),3.27-3.19(m,4H),1.99-1.94(m,2H),1.89-1.57(m,2H),1.58(d,J=6.8Hz,6H).LRMS(ESI)[M+H]+,found:391.3。
实施例51
2-[4-(4-环丙基-4氢-1,2,4-三唑-3-基)六氢吡啶-1-基]-3-(5-氟吡啶-3-基)苯-1-甲腈(化合物51)
2-(4-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(5-fluoropyridin-3-yl)benzonitrile
得到化合物51的数据为:1H NMR(400MHz,MeOD-d4)δ9.20(s,1H),8.56-8.52(m,2H),7.82-7.76(m,2H),7.61(d,J=8.0Hz,1H),7.37(t,J=7.6Hz,1H),3.63-3.57(m,1H),3.37(brs,1H),3.31-3.20(m,4H),2.07-2.03(m,2H),1.87-1.83(m,2H),1.31-1.19(m,4H).LRMS(ESI)[M+H]+,found:389.3。
实施例52
3-(5-氟吡啶-3-基)-2-[4-(3-甲基咪唑-5-基)六氢吡啶-1-基]苯-1-甲腈(化合物52)
3-(5-fluoropyridin-3-yl)-2-(4-(1-methyl-1H-imidazol-4-yl)piperidin-1-yl)benzonitrile
得到化合物52的数据为:1H NMR(400MHz,MeOD-d4)δ8.80(s,1H),8.54-8.50(m,2H),7.80-7.75(m,2H),7.61(dd,J=8.0,2.0Hz,1H),7.38-7.34(m,2H),3.91(s,1H),3.30-3.26(m,2H),3.16-3.12(m,2H),2.85-2.76(m,1H),1.96-1.92(m,2H),1.69-1.56(m,2H).LRMS(ESI)[M+H]+,found:362.3。
实施例53
2-[4-(4,5-二甲基-1,2,4-三唑-3-基)六氢吡啶-1-基]-3-(5-氟吡啶-3-基)苯-1-甲腈(化合物53)
2-(4-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(5-fluoropyridin-3-yl)benzonitrile
得到化合物53的数据为:LRMS(ESI)[M+H]+,found:377.4。
实施例54
3-(5-氟吡啶-3-基)-2-[4-(1-甲基咪唑-5-基)六氢吡啶-1-基]苯-1-甲腈(化合物54)
3-(5-fluoropyridin-3-yl)-2-(4-(1-methyl-1H-imidazol-5-yl)piperidin-1-yl)benzonitrile
得到化合物54的数据为:LRMS(ESI)[M+H]+,found:362.3。
实施例55
3-(5-氟吡啶-3-基)-2-[4-(吡啶-3-基)六氢吡啶-1-基]苯-1-甲腈(化合物55)
3-(5-fluoropyridin-3-yl)-2-(4-(pyridin-3-yl)piperidin-1-yl)benzonitrile
得到化合物55的数据为:1H NMR(400MHz,MeOD-d4)δ8.55-8.52(m,2H),8.42-8.37(m,2H),7.83-7.79(m,1H),7.76-7.69(m,1H),7.59(dd,J=8.0,1.6Hz,1H),7.39(dd,J=7.6,4.8Hz,1H),7.33(t,J=8.0Hz,1H),3.30-3.26(m,2H),3.19-3.17(m,2H),2.73-2.65(m,1H),1.78-1.64(m,4H).LRMS(ESI)[M+H]+,found:359.3。
实施例56
2-[4-(咪唑-1-基)六氢吡啶-1-基]-3-(5-氟吡啶-3-基)-苯-1-甲腈(化合物56)
2-(4-(1H-imidazol-1-yl)piperidin-1-yl)-3-(5-fluoropyridin-3-yl)benzonitrile
得到化合物56的数据为:LRMS(ESI)[M+H]+,found:348.3。
实施例57
3-氟-5-(2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-3-甲磺酰基苯基)吡啶(化合物57)
3-fluoro-5-(2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(methylsulfonyl)phenyl)pyridine
得到化合物57的数据为:1H NMR(400MHz,MeOD-d4)δ8.89(s,1H),8.64(d,J=1.6Hz,1H),8.49(s,1H),8.22(d,J=7.2Hz,1H),7.78(d,J=9.2Hz,1H),7.57-7.51(m,2H),3.81(s,3H),3.42-3.38(m,5H),2.93-2.86(m,1H),2.66-2.59(m,2H),2.15-2.04(m,2H),1.93-1.89(m,2H).LRMS(ESI)[M+H]+,found:416.2。
实施例58
2-[4-(1H-咪唑-5-基)六氢吡啶-1-基]-3-(5-氟吡啶-3-基)-苯-1-甲腈(化合物58)
2-(4-(1H-imidazol-5-yl)piperidin-1-yl)-3-(5-fluoropyridin-3-yl)benzonitrile
得到化合物58的数据为:1H NMR(400MHz,MeOD-d4)δ8.83(d,J=2.4Hz,1H),8.29-8.02(m,2H),7.81-7.75(m,2H),7.61(dd,J=8.0,1.6Hz,1H),7.36(t,J=7.6Hz,1H),7.34-7.32(m,1H),3.31-3.26(m,2H),3.18-3.10(m,1H),1.98-1.93(m,2H),1.70-1.60(m,2H),1.70-1.60(m,2H).LRMS(ESI)[M+H]+,found:348.1。
实施例59:化合物的谷氨酰胺环化酶抑制活性
化合物的isoQC酶抑制活性测试方法如下:反应体系由isoQC蛋白酶、荧光底物谷氨酰胺7-氨基-4-甲基香豆素(Gln-AMC)、化合物、焦谷氨酰氨肽酶(pyroglutamylaminopeptidase I,PGPEP I)组成,反应在黑色96孔板或384孔板中进行。首先将12.5μLisoQC蛋白酶(浓度7ng/μL),2.5μL不同浓度的化合物混合,摇床中37℃,100rpm反应10分钟,然后加入10μL荧光底物Gln-AMC(终浓度为200μM),摇床中37℃,100rpm反应20分钟,然后向体系中加入25μL PGPEP I(终浓度为2.87ng/μL),摇床中37℃,100rpm反应30分钟。利用TECAN infinite 200Pro酶标仪在激发/发射波长分别为380/460nm时读取微孔板的荧光强度。所得的荧光信号值经过GraphPad Prism 8.0分析,得到化合物的抑制率和IC50,活性数据如下表1所示:
表1.代表化合物的活性数据
化合物ID | 酶活性IC50(nM) |
化合物1 | 21.1 |
化合物2 | 555.0 |
化合物3 | 244.7 |
化合物4 | 11.7 |
化合物5 | 934.7 |
化合物6 | 923.8 |
化合物7 | 164.1 |
化合物8 | 22.0 |
化合物9 | 315.7 |
化合物10 | 22.7 |
化合物11 | 71.9 |
化合物12 | 36.6 |
化合物13 | 20.0 |
化合物14 | 931.9 |
化合物15 | 192.2 |
化合物16 | 59.9 |
化合物17 | 2583.5 |
化合物18 | 172.0 |
化合物19 | 2084 |
化合物20 | 33.8 |
化合物21 | 53.1 |
化合物43 | 15.0 |
化合物44 | 2.8 |
化合物45 | 94.3 |
化合物46 | >1000 |
化合物47 | >1000 |
化合物48 | 76.1 |
化合物49 | >1000 |
化合物50 | >1000 |
化合物51 | >1000 |
化合物52 | >1000 |
化合物53 | 574.4 |
化合物54 | 153.0 |
化合物55 | >1000 |
化合物56 | >1000 |
化合物57 | >1000 |
化合物58 | >1000 |
根据上述实验结果可知,本发明的化合物具有较好的isoQC酶抑制活性,能够作为谷氨酰胺环化酶抑制剂,并进一步研究其抗肿瘤效果。
实施例60:化合物的细胞活性
化合物对细胞CD47的N端焦谷氨酸化修饰(pGlu-CD47)抑制活性IC50检测方法如下:293T细胞以10000/孔的密度接种在48孔板中,加入不同浓度的化合物处理48小时后,采用流式细胞分析技术(FACS)进行化合物的体外活性测试。用CD47的流式抗体CC2C6检测细胞表面CD47的N端焦谷氨酸化(pGlu-CD47)水平。将化合物处理之后的细胞用PBS清洗后加入100μL FACS Buffer重悬细胞。然后加入1μL细胞流式抗体,在冰上避光孵育30分钟,FACSBuffer洗涤后再加入200μL FACS Buffer重悬细胞。用流式仪将细胞上机检测,检测所获得的平均荧光强度(MFI)利用GraphPad Prism 8.0分析,计算得到化合物的pGlu-CD47 IC50。代表化合物的活性数据如下表2所示:
表2.代表化合物的细胞活性数据
化合物ID | IC50(nM) |
化合物1 | 43.9 |
化合物7 | 1825 |
化合物13 | 231.1 |
化合物43 | 5.6 |
化合物44 | 2.8 |
实验结果表明,化合物对293T细胞表面的CD47的N端焦谷氨酸化修饰具有较好的抑制作用,特别是化合物1、43和44,其IC50值在100nM以内,具有极高的细胞活性。
实施例61:化合物的抗肿瘤活性
化合物对对不同种类癌细胞表面的N-焦谷氨酸化修饰抑制作用的实验方法如下:
A375、A549、HCT116、H929、Raji、DLD1等肿瘤细胞以10000-20000/孔的密度接种在48孔板中,加入不同浓度的化合物处理48小时后,采用流式细胞分析技术(FACS)进行化合物的体外活性测试。用CD47的流式抗体CC2C6检测细胞表面CD47的N端焦谷氨酸化(pGlu-CD47)水平。将化合物处理之后的细胞用PBS清洗后加入100μL FACS Buffer重悬细胞。然后加入1μL细胞流式抗体,在冰上避光孵育30分钟,FACS Buffer洗涤后再加入200μL FACSBuffer重悬细胞。用流式仪将细胞上机检测,检测所获得的平均荧光强度(MFI)利用GraphPad Prism 8.0分析,计算得到化合物的抑制率。结果详见图1。化合物对总CD47的作用的实验方法同前所述。
CD47-SIRPα结合实验的详细方法如下:
293T细胞以10000/孔的密度接种在48孔板中,加入不同浓度的化合物处理48小时。将化合物处理之后的细胞用PBS清洗一次,胰酶消化细胞后用含血清的培养基终止消化,用移液器吹下细胞转移至1.5mL EP管中,在离心机中3000rpm转速离心5min。离心后弃掉上清,每管加入100μL PBS重悬细胞。每管加入1μL PE Labeled Human SIRPα/CD172a(ACRO Biosystems),用移液器混匀细胞,将细胞放在冰上避光孵育1小时。每管加入1mLPBS洗涤三次,3000rpm离心5min,弃掉上清后,每管加入200μL PBS重悬细胞,待细胞流式仪上机检测。
图2为本发明中化合物43和44对293T和Raji细胞总CD47(hCD47-B6H12)、表面N-焦谷氨酸化修饰CD47(hCD47-CC2C6)以及CD47-SIRPα结合(hSIRPα-Fc)的抑制活性。hCD47-B6H12和hCD47-CC2C6实验中化合物的处理浓度为100nM,CD47-SIRPα结合实验中化合物的处理浓度为10μM。
实施例62:化合物对巨噬细胞吞噬肿瘤细胞能力的影响
化合物对巨噬细胞吞噬肿瘤细胞能力的影响检测方法如下:从6-8周野生型C57BL/6小鼠的股骨和胫骨获取细胞,用50ng/mL M-CSF(Macrophage-Colony StimulatingFactor)的连续培养7天诱导细胞分化为成熟的巨噬细胞(BMDM)。共培养实验前一天将1x105个BMDM细胞均匀铺板到48孔板中,培养箱中过夜培养。肿瘤细胞用10μM化合物(化合物1和化合物4)培养48小时后,用2.5μM CFSE在37℃水浴锅中染色10分钟然后将2x 105个肿瘤细胞与提前铺板的BMDM进行共培养。共培养2小时后用胰酶原液消化细胞,PBS清洗后进行流式染色,用F4/80抗体标记巨噬细胞,其中CFSE+F4/80+细胞代表被巨噬细胞吞噬的肿瘤细胞。上述实验所述化合物的活性如图3和4所示。
本实施例主要以化合物1和化合物4为例,对化合物的巨噬细胞吞噬肿瘤细胞能力进行研究。图3示出了化合物1和化合物4对巨噬细胞吞噬DLD1结肠癌细胞能力的影响;图4示出了化合物1和化合物4对巨噬细胞吞噬H929细胞能力的影响。实验结果证明该类结构化合物对于能够提升巨噬细胞吞噬肿瘤细胞能力,具有较好的抗肿瘤活性。
实施例61和实施例62中的PQ912(cas:1276021-65-8)为已知谷氨酰胺酰基环化酶抑制剂中的一种,作为阳性对照药物,证明本发明的化合物具有更好的酶抑制活性和抗肿瘤活性,证明其具有更好的成药潜力。
上面结合附图对本发明实施例作了详细说明,但是本发明不限于上述实施例,在所属技术领域普通技术人员所具备的知识范围内,还可以在不脱离本发明宗旨的前提下作出各种变化。此外,在不冲突的情况下,本发明的实施例及实施例中的特征可以相互组合。
Claims (10)
1.具有如式(I)所示结构的化合物,或所述化合物在药学上可接受的盐、溶剂化物、立体异构体或前药;
其连接关系为B-A-D-C;
其中,A选自烷基、杂烷基、烷基氨基、芳基、杂芳基、环烷基、杂环基和亚烷基的基团,其中所述基团可以独立地被烷基取代;
B选自取代或未取代的五元或六元氮杂芳基;
C选自氢原子、芳基、五元杂芳基和六元杂芳基,其中所述芳基、五元杂芳基和六元杂芳基可以独立地被一个或多个取代基取代;
D选自其中XD1、XD2和XD3分别独立地选自碳原子和氮原子,RD1选自氢原子和任意取代基,RD1的邻位连接键与A相连,RD1的间位连接键与C相连。
2.如权利要求1所述的化合物,其特征在于,A选自4~8元环烷基、4~8元含1~2个氮原子杂环基、芳基、C1~5烷基和C1~5烷基氨基的基团,其中所述基团可以独立地被C1~5烷基取代;
B选自含1~3个氮原子的五环或六元氮杂芳基,其中所述五环氮杂芳基可以独立地被一个或多个取代基取代;
C中所述五元杂芳基选自含1~3个氧原子和/或氮原子的五元杂芳基,C中所述六元杂芳基选自含1~3个氮原子的六元氮杂芳基;
D中XD1和XD3均为碳原子,XD2选自碳原子和氮原子。
3.如权利要求2所述的化合物,其特征在于,A选自4~8元环烷基、4~8元含1个氮原子杂环基、芳基、C3~5烷基和C2~4烷基氨基的基团,其中所述基团可以独立地被甲基取代;
和/或,B选自其中XB1和XB2分别独立地选自碳原子和氮原子,RB1和RB1分别独立地选自氢原子和C1~3烷基;
和/或,C选自其中XC1、XC2、XC3和XC4分别独立地选自碳原子和氮原子,RC1、RC2和RC3分别独立地选自氢原子、碳基、烷基、烷氧基、卤素、三氟甲基、氰基、氨基;
和/或,D中RD1选自三氟甲基、酰胺基、硝基、氰基、磺酰基。
4.如权利要求1至3任一项所述的化合物,其特征在于,A选自:
和/或,B选自:
和/或,C选自:
H;
和/或,D选自:
5.如权利要求1至3任一项所述的化合物,其特征在于,所述化合物选自:
2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-3-(吡啶-3-基)苯甲腈、
2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-[1,1'-联苯基]-3-甲腈、
2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-3-(1-甲基-6-羰基-1,6-二氢吡啶-3-基)苯甲腈、
2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-3-(2-羰基-1,2-二氢吡啶-4-基)苯甲腈、
2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯甲腈、
2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-3-(吡啶-4-基)苯甲腈、
2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-3-(6-羰基-1,6-二氢吡啶-3-基)苯甲腈、
2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-3-(4-甲基吡啶-3-基)苯甲腈、
3-(6-甲氧基吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯甲腈、
3-(5-氟吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯甲腈、
5-(3-氰基-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯基)氰基吡啶、
5-(3-氰基-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯基)尼古丁腈、
3-(4-氯吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯甲腈、
2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-3-(6-(三氟甲基)吡啶-3-基)苯甲腈、
3-(6-氨基吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯甲腈、
2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-3-(嘧啶-5-基)苯甲腈、
3-(3,5-二甲基异噻唑-4-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯甲腈、
3-(呋喃-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯甲腈、
3-(4-甲氧基吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯甲腈、
3-(1-甲基-2-羰基-1,2-二氢吡啶-4-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯甲腈、
2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-3-(4-(三氟甲基)吡啶-3-基)苯甲腈、
3-(2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-3-(三氟甲基)苯基)吡啶、
2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-3-(吡啶-3-基)苯酰胺、
4-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-[3,3'-联吡啶]-5-甲腈、
3-(2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-3-硝基苯基)吡啶、
N,N-二甲基-4-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-3-(吡啶-3-基)苯胺、
N-甲基-4-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-3-(吡啶-3-基)苯胺、
2-(6-(4-甲基-4H-1,2,4-三唑-3-基)-3-氮杂二环[3.1.0]己烷-3-基)-3-(吡啶-3-基)苯甲腈、
2(-6-(4-甲基-4H-1,2,4-三唑-3-基)-2-氮杂螺[3.3]庚烷-2-基)-3-(吡啶-3-基)苯甲腈、
2-(4-(4-甲基-4H-1,2,4-三唑-3-基)环己基)-3-(吡啶-3-基)苯甲腈、
2-(甲基(3-(4-甲基-4H-1,2,4-三唑-3-基)丙基)氨基)-3-(吡啶-3-基)苯甲腈、
2-(4-(4-甲基-4H-1,2,4-三唑-3-基)吖庚环-1-基)-3-(吡啶-3-基)苯甲腈、
2-(4-(4-甲基-4H-1,2,4-三唑-3-基)吖庚环-1-基)-3-(吡啶-3-基)苯甲腈、
4'-(4-甲基-4H-1,2,4-三唑-3-基)-6-(吡啶-3-基)-[1,1'-联苯]-2-甲腈、
2-(3-(4-甲基-4H-1,2,4-三唑-3-基)吡咯烷-1-基)-3-(吡啶-3-基)苯甲腈、
2-(3-(4-甲基-4H-1,2,4-三唑-3-基)吖丁啶-1-基)-3-(吡啶-3-基)苯甲腈、
2-(4-(1-甲基-1H-咪唑-5-基)哌啶-1-基)-3-(吡啶-3-基)苯甲腈、
2-(4-(1H-吡唑-4-基)哌啶-1-基)-3-(吡啶-3-基)苯甲腈、
2-(4-(1H-咪唑-5-基)哌啶-1-基)-3-(吡啶-3-基)苯甲腈、
2-(4-(1H-1,2,4-三唑-1-基)哌啶-1-基)-3-(吡啶-3-基)苯甲腈3-(2-(4-(4-甲基-4H-1,2,4-三唑-3-yl)哌啶-1-基)-3-(甲磺酰基)苯基)吡啶、
2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-3-(吡啶-3-基)苯磺酰胺、
4-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-[3,3'-联吡啶]-5-甲腈、
3-(6-氟吡啶-3-基)-2-[4-(4-甲基-4氢-1,2,4-三唑-3-基)六氢吡啶-1-基]苯-1-甲腈、
3-(6-氟吡啶-3-基)-2-[4-(1-甲基咪唑-5-基)六氢吡啶-1-基]苯-1-甲腈、
2-[4-(4,5-二甲基-4氢-1,2,4-三唑-3-基)六氢吡啶-1-基]-3-(6-氟吡啶-3-基)苯-1-甲腈、
3-(6-氟吡啶-3-基)-2-{4-[4-(丙-2-基)-4氢-1,2,4-三唑-3-基]六氢吡啶-1-基}苯-1-甲腈、
2-[4-(1H-咪唑-5-基)六氢吡啶-1-基]-3-(6-氟吡啶-3-基)-苯-1-甲腈、
3-氟-5-{2-[4-(4-甲基-4氢-1,2,4-三唑-3-基)六氢吡啶-1-基]-3-硝基苯基}吡啶、
N-[3-(5-氟吡啶-3-基)-2-[4-(4-甲基-4氢-1,2,4-三唑-3-基)六氢吡啶-1-基]苯基]乙酰胺、
3-(5-氟吡啶-3-基)-2-{4-[4-(丙-2-基)-4氢-1,2,4-三唑-3-基]六氢吡啶-1-基}苯-1-甲腈、
2-[4-(4-环丙基-4氢-1,2,4-三唑-3-基)六氢吡啶-1-基]-3-(5-氟吡啶-3-基)苯-1-甲腈、
3-(5-氟吡啶-3-基)-2-[4-(3-甲基咪唑-5-基)六氢吡啶-1-基]苯-1-甲腈、
2-[4-(4,5-二甲基-1,2,4-三唑-3-基)六氢吡啶-1-基]-3-(5-氟吡啶-3-基)苯-1-甲腈、
3-(5-氟吡啶-3-基)-2-[4-(1-甲基咪唑-5-基)六氢吡啶-1-基]苯-1-甲腈、
3-(5-氟吡啶-3-基)-2-[4-(吡啶-3-基)六氢吡啶-1-基]苯-1-甲腈、
2-[4-(咪唑-1-基)六氢吡啶-1-基]-3-(5-氟吡啶-3-基)-苯-1-甲腈、
3-氟-5-(2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-3-甲磺酰基苯基)吡啶、
2-[4-(1H-咪唑-5-基)六氢吡啶-1-基]-3-(5-氟吡啶-3-基)-苯-1-甲腈。
6.一种药用组合物,其特征在于,所述药用组合物的活性成分包括如权利要求1至5任一项所述的化合物或其药学上可接受的盐、水合物、溶剂化物、同位素化合物,以及药用载体或稀释剂。
7.权利要求1至5任一项所述的化合物在制备治疗肿瘤、免疫性疾病或神经性疾病的药物中的应用。
8.如权利要求7所述的应用,其特征在于,所述肿瘤选自结直肠癌、肺癌、胃癌、黑色素瘤、骨髓瘤、乳腺癌、腺癌、膀胱癌和血液瘤中的至少一种。
9.如权利要求7所述的应用,其特征在于,所述免疫性疾病选自湿疹、斑秃、银屑病、白癜风、类风湿性关节炎、红斑狼疮综合征、痤疮和化脓性汗腺炎中的至少一种。
10.如权利要求7所述的应用,其特征在于,所述神经性疾病选自阿尔茨海默病、亨廷顿病、唐氏综合征中的神经变性、抑郁症、焦虑症、精神病和多发性硬化症中的至少一种。
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