CN104024243A - 作为酪氨酸激酶抑制剂的新咪唑并吡啶衍生物 - Google Patents
作为酪氨酸激酶抑制剂的新咪唑并吡啶衍生物 Download PDFInfo
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- CN104024243A CN104024243A CN201280064532.0A CN201280064532A CN104024243A CN 104024243 A CN104024243 A CN 104024243A CN 201280064532 A CN201280064532 A CN 201280064532A CN 104024243 A CN104024243 A CN 104024243A
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Classifications
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
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Abstract
本发明提供了具有不可逆的酪氨酸激酶抑制活性的新咪唑并吡啶衍生物,以及包含所述新咪唑并吡啶衍生物的药物组合物,所述药物组合物可用于预防或治疗炎性疾病、自身免疫病、增殖性疾病或过度增殖性疾病、免疫介导的疾病、癌症或肿瘤。
Description
技术领域
本发明涉及具有不可逆的酪氨酸激酶抑制活性的新咪唑并吡啶衍生物,以及包含作为活性成分的所述新咪唑并吡啶衍生物的药物组合物。
背景技术
蛋白激酶是通过借助磷酸化向其他蛋白质上的特定残基上化学地添加磷酸基来修饰所述蛋白质的酶。人类基因组包含约500个蛋白激酶基因,其占全部人基因的约2%。一般来说,可根据其底物将蛋白激酶分成3类:使丝氨酸和/或苏氨酸残基磷酸化的丝氨酸/苏氨酸特异性蛋白激酶、使酪氨酸残基磷酸化的酪氨酸特异性蛋白激酶、以及使酪氨酸和丝氨酸/苏氨酸残基磷酸化的蛋白激酶。蛋白激酶在介导响应于多种细胞外的刺激由细胞表面到细胞核的信号转导中具有关键作用。其调节多种生理和病理的细胞现象,包括细胞分裂、增殖、分化、凋亡、细胞迁移、致有丝分裂等,因此其与多种疾病密切相关。这样的激酶相关疾病的实例是:自身免疫病,例如特应性皮炎、哮喘、类风湿性关节炎、克隆病(Crohn’s disease)、银屑病、克鲁宗综合征(Crouzon syndrome)、软骨发育不全和致死性发育不良;癌症,例如前列腺癌、结直肠癌、乳腺癌、脑癌和喉癌、白血病和淋巴瘤;糖尿病;再狭窄(restenosis);动脉粥样硬化;肾和肝纤维化;骨髓增生性疾病和淋巴增生性疾病;以及眼病。已知这些疾病直接或间接地由激酶调节机制的中断造成,例如激酶的突变、过表达或异常活化,影响上游或下游信号传导的生长因子或细胞因子的过量产生或不足量产生。因此,预期可通过选择性地对激酶的机制进行抑制来预防或治疗这样的疾病,因此在药物和化学领域已经进行了多种尝试来发现有效的蛋白激酶抑制剂。
同时,炎症是诸如类风湿性关节炎等疾病的病因。尽管最近发现了生物学治疗,但仍已经进行了持续的尝试以开发治疗炎症的有效药物。已经发现支持T细胞(或T淋巴细胞)和B细胞(或B淋巴细胞)对炎性疾病、自身免疫病、增殖性疾病或过度增殖性疾病和/或免疫介导的疾病的发作具有重要作用的多个证据。
这样的T细胞通过经由位于细胞表面上的T细胞受体(TCR)接收来自抗原递呈细胞的信号来介导信号转导,这激活多种激酶,例如Janus激酶(JAK),从而将信号传达至效应器。就这一点而言,可通过造血细胞因子和干扰素激活JAK蛋白(如酪氨酸激酶),并且该过程可调节转录调节因子STAT蛋白的激活。基于抑制(或促进)JAK/STAT途径的治疗可能性可在免疫调节领域提供潜在的药物。
在4种JAK蛋白中,认为JAK3与炎症相关,因为其仅在T细胞中表达并被IL-2激活。与参与造血活动和红血球内稳态的JAK2或可在不同种类的组织中表达的JAK1不同,JAK3主要在淋巴细胞中表达,并且通过使用多种细胞因子(包括IL-2、IL-4、IL-7、IL-9、IL-15等)在信号传导中发挥非常重要的作用,因此,JAK3在副作用方面正在受到关注(Flanagan等,Journal of Medicinal Chemistry,53,8468,2010)。根据动物研究,JAK3不仅在B细胞和T细胞的成熟中具有重要作用,而且还在维持T细胞的功能中具有重要作用。因此,JAK抑制剂(特别是JAK3抑制剂)可用于治疗自身免疫病,例如类风湿性关节炎、银屑病、特应性皮炎、狼疮、多发性硬化、I型糖尿病和糖尿病并发症、癌症、哮喘、甲状腺自身免疫病、溃疡性结肠炎、克隆病、阿尔茨海默病(Alzheimer’sdisease)、白血病等,以及需要免疫抑制的多种病症,例如同种异体移植排斥和异种移植(Pesu M,Laurence A,Kishore N,等,Immunol.Rev,223,132,2008.;Kawahara A,Minami Y,Miyazaki T,等,Proc.Natl.Acad.Sci.USA,92,8724,1995;Nosaka T,van Deursen JMA,Tripp RA等,Science,270,800,1995;Papageorgiou AC,Wikman LEK.,等,Trends Pharm.Sci.,25,558,2004)。
同时,酪氨酸蛋白激酶(Bruton’s tyrosine kinase,BTK)是TEC激酶家族的一种,其在B细胞的激活和信号转导中具有重要作用。1993年,发现BTK中的突变与主要B细胞免疫缺陷、X连锁无丙种球蛋白血症(XLA)和小鼠X连锁免疫缺陷(XID)有关。
BTK是B细胞发育、激活、信号传导和生存的关键调节剂(Kurosaki,Curr.Op.Imm.,276-281,2000;Schaeffer and Schwartzberg,Curr.Op.Imm.,282-288,2000)。此外,BTK在许多其它造血细胞信号通路中发挥作用,例如巨噬细胞中由toll样受体(TLR)和细胞因子受体介导的TNF-α产生、肥大细胞中IgE受体(FcepsilonRi)信号传导、B淋巴细胞中Fas/APO-1凋亡信号的抑制以及胶原蛋白刺激的血小板聚集。
BTK参与被多种细胞外配体与其细胞表面受体的结合引发的多种信号转导途径。在B细胞抗原受体(BCR)与抗原结合后,需要通过蛋白质酪氨酸激酶Lyn和Syk的协同作用激活BTK以诱导磷脂酶C-γ2介导的钙动员(Kurosaki,T.,Curr.Opin.Immunol.,9,309-318,1997)。因此,抑制BTK可成为有用的治疗选择,因为其防止B细胞介导的疾病的发展。
例如,已经证实BTK缺陷小鼠抗胶原诱导之关节炎中的疾病临床表现,且已经知道BTK抑制剂剂量依赖地有效抗小鼠中的胶原诱导之关节炎(Jansson和Holmdahl,Clin.Exp.Immunol.,94,459,1993;Pan等,Chem.Med Chem.,2,58,2007)。因此,有效的BTK抑制剂可用于治疗类风湿性关节炎。
此外,抑制BTK激活可用于治疗自身免疫病和/或炎性疾病和/或变应性疾病,例如系统性红斑狼疮(SLE)、类风湿性关节炎、银屑病性关节炎、骨关节炎、幼年型关节炎、糖尿病、重症肌无力、桥本甲状腺炎(Hashimoto’s thyroiditis)、多发性硬化、强直性脊柱炎、血管炎、炎性肠病、银屑病、全身脱毛(alopecia universalis)、特发性血小板减少性紫癜(ITP)、过敏、过敏性结膜炎、过敏性鼻炎、特发性皮炎和哮喘,但不限于此。另外,已知BTK调节细胞的凋亡,因此,抑制BTK激活也可用于治疗B细胞淋巴瘤和白血病。
如上文解释的,Janus激酶(如JAK3和TEC激酶(如BTK))在激活T细胞和/或B细胞中具有重要作用,其与炎性疾病、自身免疫病、增殖性疾病或过度增殖性疾病以及免疫介导的疾病的发展密切相关。因此,开发这样的激酶的有效抑制剂可导致发现用于治疗多种炎性疾病、自身免疫病、增殖性疾病或过度增殖性疾病以及免疫介导的疾病的强效药物。
目前,辉瑞(Pfizer)正在开发Tofacitinib(CP-690550)(作为JAK3的抑制剂的口服药)并且正在进行III期临床试验。作为BTK抑制剂的PCI-32765(Pharmacyclics)处于I期临床试验阶段,但是,已报道所述药物可激活不同的靶标,并伴随有不利的副作用,包括诱发皮疹和痢疾。因此,强烈需要可安全并有效地抑制Janus激酶和TEC激酶的新药。
发明内容
因此,本发明的目的是提供抑制主要在异常激活的淋巴细胞(T淋巴细胞和/或B淋巴细胞)中表达的激酶的新化合物,所述激酶包括Janus激酶(如JAK3)和TEC激酶(如BTK(酪氨酸蛋白激酶,Burton’s tyrosinekinase))、ITK(IL2诱导型T细胞激酶)、BMX(骨髓酪氨酸激酶)、RLK(静息淋巴细胞激酶,resting lymphocyte kinase)等。
本发明另一目的是提供包含本发明化合物的药物组合物,其用于预防或治疗炎性疾病、自身免疫病、增殖性疾病或过度增殖性疾病、免疫介导的疾病、癌症或肿瘤。
本发明又一目的是提供用于通过使用所述化合物来预防和治疗炎性疾病、自身免疫病、增殖性疾病或过度增殖性疾病、免疫介导的疾病、癌症或肿瘤的方法。
根据本发明的一个方面,提供了式(I)化合物或其可药用盐:
其中,
R1是氢、卤素或CN;
X是O、NH、CH2、S、SO或SO2;
Y是苯基或吡啶基;
Z是
n是0至4的整数;
R2各自独立地为氢、C1-6烷氧基或二(C1-6烷基)氨甲基;并且
W是被选自以下的一个或更多个取代基取代的苯基或吡啶基:氢、卤素、羟基、硝基、C1-6烷氧基、C1-6烷氧基羰基、氨基、C1-6烷基氨基、C1-6烷基杂环氨基、氨基甲酰基、C1-6烷基氨基甲酰基、二(C1-6烷基)氨基甲酰基、C1-6烷基杂环氨基甲酰基、C1-6烷基杂环C1-6烷基、氨磺酰基、C1-6烷基硫烷基(C1-6alkylsulfanyl)、C1-6烷基磺酰基、C1-6烷基亚磺酰基、C1-6烷氧基C1-6烷基、C1-6烷氧基C1-6烷氧基、二(C1-6烷基)氨基、二(C1-6烷基)氨基C1-6烷基、二(C1-6烷基)氨基C1-6烷氧基、羧基、杂环、C1-6烷基杂环、羟基杂环、羟基C1-6烷基杂环、C1-6烷氧基C1-6烷基杂环、杂环氧基、杂环C1-6烷基、杂环氨基C1-6烷基、杂环羰基和杂环-C1-6烷基羰基,其中所述杂环独立地为含有独立地选自N、O和S的一个或更多个杂原子的饱和3至8元单环杂环。
根据本发明的另一个方面,提供了药物组合物,其包含式(I)化合物或其可药用盐,所述药物组合物用于预防或治疗炎性疾病、自身免疫病、增殖性疾病或过度增殖性疾病、免疫介导的疾病、癌症或肿瘤。
根据本发明的又一个方面,提供了用于预防或治疗哺乳动物中的炎性疾病、自身免疫病、增殖性疾病或过度增殖性疾病、免疫介导的疾病、癌症或肿瘤的方法,其包括向所述哺乳动物施用有效量的式(I)化合物或其可药用盐的步骤。
根据本发明的新咪唑并吡啶衍生物可选择性地并有效地抑制主要在异常激活的淋巴细胞(T淋巴细胞和/或B淋巴细胞)中表达的激酶,包括Janus激酶(如JAK3)和TEC激酶(如BTK、ITK、BMX和RLK等)。因此,根据本发明作为酪氨酸激酶抑制剂的新咪唑并吡啶衍生物可用于预防或治疗通过异常激活的T淋巴细胞、B淋巴细胞或它们二者介导的疾病,例如炎性疾病、自身免疫病、增殖性疾病或过度增殖性疾病、免疫介导的疾病、癌症或肿瘤。
发明详述
在式(I)中,取代基W的具体实例可选自W1至W30,但不限于此。
根据本发明的化合物的实例如下:
N-(3-(6-氯-2-(4-(4-甲基哌嗪-1-基)苯基)-3H-咪唑并[4,5-b]吡啶-7-基氧基)苯基)丙烯酰胺;
N-(3-(6-氯-2-(4-(4-羟基哌啶-1-基)苯基)-3H-咪唑并[4,5-b]吡啶-7-基氧基)苯基)丙烯酰胺;
N-(3-(6-氯-2-(4-(4-甲基哌嗪-1-羰基)苯基)-3H-咪唑并[4,5-b]吡啶-7-基氧基)苯基)丙烯酰胺;
N-(3-(6-氯-2-(4-(吗啉-4-羰基)苯基)-3H-咪唑并[4,5-b]吡啶-7-基氧基)苯基)丙烯酰胺;
N-(3-(6-氯-2-(4-(1-甲基哌啶-4-基氨基)苯基)-3H-咪唑并[4,5-b]吡啶-7-基氧基)苯基)丙烯酰胺;
N-(3-(6-氯-2-(4-(二甲基氨基)苯基)-3H-咪唑并[4,5-b]吡啶-7-基氧基)苯基)丙烯酰胺;
N-(3-(6-氯-2-(4-(甲基亚磺酰基)苯基)-3H-咪唑并[4,5-b]吡啶-7-基氧基)苯基)丙烯酰胺;
4-(7-(3-丙烯酰氨基苯氧基)-6-氯-3H-咪唑并[4,5-b]吡啶-2-基)-N,N-二甲基苯甲酰胺;
4-(7-(3-丙烯酰氨基苯氧基)-6-氯-3H-咪唑并[4,5-b]吡啶-2-基)-苯甲酸;
4-(7-(3-丙烯酰氨基苯氧基)-6-氯-3H-咪唑并[4,5-b]吡啶-2-基)-N-(1-甲基哌啶-4-基)苯甲酰胺;
N-(3-(6-氯-2-(4-((二甲基氨基)甲基)苯基)-3H-咪唑并[4,5-b]吡啶-7-基氧基)苯基)丙烯酰胺;
N-(3-(6-氯-2-(4-((二乙基氨基)甲基)苯基)-3H-咪唑并[4,5-b]吡啶-7-基氧基)苯基)丙烯酰胺;
N-(3-(6-氯-2-(4-((乙基(甲基)氨基)甲基)苯基)-3H-咪唑并[4,5-b]吡啶-7-基氧基)苯基)丙烯酰胺;
N-(3-(6-氯-2-(4-(吡咯烷-1-基甲基)苯基)-3H-咪唑并[4,5-b]吡啶-7-基氧基)苯基)丙烯酰胺;
N-(3-(6-氯-2-(4-(哌啶-1-基甲基)苯基)-3H-咪唑并[4,5-b]吡啶-7-基氧基)苯基)丙烯酰胺;
N-(3-(6-氯-2-(4-(吗啉代甲基)苯基)-3H-咪唑并[4,5-b]吡啶-7-基氧基)苯基)丙烯酰胺;
N-(3-(6-氯-2-(4-((4-甲基哌嗪-1-基)甲基)苯基)-3H-咪唑并[4,5-b]吡啶-7-基氧基)苯基)丙烯酰胺;
N-(3-(6-氯-2-(4-甲氧基苯基)-3H-咪唑并[4,5-b]吡啶-7-基氧基)苯基)丙烯酰胺;
N-(3-(6-氯-2-(吡啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-基氧基)苯基)丙烯酰胺;以及
N-(3-(2-(4-(4-甲基哌嗪-1-基)苯基)-3H-咪唑并[4,5-b]吡啶-7-基氧基)苯基)丙烯酰胺。
本发明的式(I)化合物可通过下文所示反应方案I中示出的方法制备:
<反应方案I>
其中,X、Y、Z、W以及R1、R2与上文定义相同。
在以下的逐步反应中对该反应过程进行举例说明。
使式(VII)化合物在例如吡啶条件下与三甲基乙酰氯进行缩合反应,得到式(VI)化合物。
随后,使式(VI)化合物在室温下与有机溶剂(如乙腈)中的例如N-氯代丁二酰亚胺反应,得到式(V)的氯代化合物,接着于65℃至75℃下在硫酸和硝酸下搅拌,得到含有硝基的式(IV)化合物。
接下来,使以上获得的式(IV)化合物于30℃至40℃下在溶剂(如N,N-二甲基甲酰胺)和无机碱(如碳酸铯)下与具有丙烯酰胺基团的化合物(如N-(3-羟基苯基)丙烯酰胺)反应,得到含有丙烯酰胺基团的式(III)化合物。
可通过使式(III)化合物进行铁介导的还原反应或使用钯/碳作为催化剂进行加氢反应来将所述化合物的硝基转变为氨基,得到式(II)苯胺化合物,使其于115℃至125℃下在氯化铁的存在下在溶剂(如二甲基甲酰胺)中与多种Z取代的醛进行进一步反应,得到式(I)的目标化合物。
本发明的式(I)化合物也可形成可药用的有机或无机酸加成盐。这样的盐的实例是由例如以下的酸形成的酸加成盐:盐酸、氢溴酸、硫酸、磷酸、硝酸、乙酸、羟基乙酸、乳酸、丙酮酸、丙二酸、琥珀酸、戊二酸、富马酸、苹果酸、扁桃酸、酒石酸、柠檬酸、抗坏血酸、棕榈酸、马来酸、羟基马来酸、苯甲酸、羟基苯甲酸、苯乙酸、肉桂酸、水杨酸、甲磺酸、苯磺酸和甲苯磺酸。
具体地,根据本发明的可药用盐可通过将式(I)化合物溶解在水溶性有机溶剂中随后添加有机或无机酸并过滤沉淀的晶体来制备,所述水溶性有机溶剂例如丙酮、甲醇、乙醇或乙腈。此外,其可通过在减压下从具有添加的酸的反应混合物中除去溶剂或过量的酸,随后干燥残余物,或者使用不同的有机溶剂进行离析(eduction)接着过滤沉淀的盐来制备。
根据本发明的式(I)化合物或其可药用盐可以是溶剂合物或水合物的形式,并且这些化合物也涵盖在本发明的范围内。
根据本发明的式(I)化合物或其可药用盐可选择性地并有效地抑制蛋白激酶。在一个实施方案中,这些化合物可选择性地并有效地抑制主要在异常激活的淋巴细胞(T淋巴细胞和/或B淋巴细胞)中表达的激酶,包括Janus激酶3(JAK3)、酪氨酸蛋白激酶(BTK)、IL2诱导型T细胞激酶(ITK)、静息淋巴细胞激酶(RLK)和骨髓酪氨酸激酶(BMX),因此,可用于预防或治疗通过异常激活的T淋巴细胞、B淋巴细胞或它们二者介导的疾病,例如炎性疾病、自身免疫病、增殖性疾病或过度增殖性疾病、免疫介导的疾病、癌症或肿瘤。因此,本发明提供了药物组合物,其包含作为活性成分的式(I)化合物或其可药用盐,所述药物组合物用于预防或治疗炎性疾病、自身免疫病、增殖性疾病或过度增殖性疾病、免疫介导的疾病、癌症或肿瘤。
所述炎性疾病、自身免疫病、增殖性疾病或过度增殖性疾病或免疫介导的疾病可选自关节炎、类风湿性关节炎、脊柱关节病、痛风性关节炎、骨关节炎、幼年型关节炎、其他关节病症、狼疮、系统性红斑狼疮(SLE)、皮肤相关疾病、银屑病、湿疹、皮炎、特应性皮炎、疼痛、肺疾病、肺炎、成人呼吸窘迫综合征(ARDS)、肺结节病、慢性肺部炎性疾病、慢性阻塞性肺病(COPD)、心血管疾病、动脉粥样硬化、心肌梗死、充血性心力衰竭、心肌缺血再灌注损伤(cardiac reperfusion iniury)、炎性肠病、克隆病、溃疡性结肠炎、肠应激综合征、哮喘、舍格伦综合征(Sjogren’ssyndrome)、自身免疫性甲状腺疾病、荨麻疹、多发性硬化、硬皮病、同种异体移植排斥、异种移植、特发性血小板减少性紫癜(ITP)、帕金森病、阿尔茨海默病、糖尿病相关疾病、炎症、盆腔炎、过敏性鼻炎、过敏性支气管炎、过敏性鼻窦炎、白血病、淋巴瘤、B细胞淋巴瘤、T细胞淋巴瘤、骨髓瘤、急性淋巴细胞白血病(ALL)、慢性淋巴细胞白血病(CLL)、急性骨髓性白血病(AML)、慢性骨髓性白血病(CML)、多毛细胞白血病、霍奇金病、非霍奇金淋巴瘤、多发性骨髓瘤、骨髓增生异常综合征(MDS)、骨髓增生性肿瘤(MPN)、弥散性大B细胞淋巴瘤和滤泡型淋巴瘤,但不限于此。
另外,所述癌症和肿瘤的实例可选自:肝癌、肝细胞癌、甲状腺癌、结肠癌、睾丸癌、骨癌、口腔癌、基底细胞癌、卵巢癌、脑肿瘤、胆囊癌、胆道癌、头颈癌、膀胱癌、舌癌、食道癌、神经胶质癌、胶质母细胞瘤、肾癌、恶性黑素瘤、胃癌、乳腺癌、肉瘤、咽癌(pharynx carcinoma)、子宫癌、宫颈癌、前列腺癌、直肠癌、胰脏癌、肺癌、皮肤癌和其他实体瘤,但是不限于此。
本发明的式(I)化合物或其可药用盐可与其他药物组合使用以增强在治疗炎性疾病、自身免疫病、增殖性疾病或过度增殖性疾病或者免疫介导的疾病中的效力。
可与本发明化合物或其可药用盐组合用于治疗炎性疾病、自身免疫病、增殖性疾病或过度增殖性疾病或者免疫介导的疾病的药物的实例是选自以下的一种或更多种药物:类固醇(强的松(prednisone)、强的松龙(prednisolone)、甲基强的松龙(methylprednisolone)、可的松(cortisone)、羟基可的松(hydroxycortisone)、倍他米松(betamethasone)、地塞米松(dexamethasone)等)、氨甲喋呤(methotrexate)、来氟米特(lefluonomide)、抗TNF-α剂(依那西普(etanercept)、因福利美(infliximab)、阿达木单抗(adalimumab)等)、钙调磷酸酶抑制剂(他克莫司(tacrolimus)、吡美莫司(pimecrolimus)等)和抗组胺剂(苯海拉明(diphenhydramine)、羟嗪(hydroxyzine)、氯雷他定(loratadine)、依巴斯汀(ebastine)、酮替芬(ketotifen)、西替利嗪(cetirizine)、左旋西替利嗪(levocetirizine)、非索非那定(fexofenadine)等),但不限于此。
可与本发明化合物或其可药用盐组合用于治疗癌症或肿瘤之药物的实例包括选自以下的一种或更多种:细胞信号传导抑制剂(格列卫(glivec)、易瑞沙(iressa)、特罗凯(tarceva)等)、有丝分裂抑制剂(长春新碱(vincristine)、长春碱(vinblastine)等)、烷基化剂(环磷酰胺(cyclophosphamide)、塞替派(thiotepa)、白消安(busulfan)等)、抗代谢物(替加氟(tagafur)、氨甲喋呤、吉西他滨(gemcitabine)等)、嵌入剂(intercalating agent)(原黄素(proflavin)、溴化乙锭(ethidiumbromide)、放线菌素D(actinomycin D)等)、拓扑异构酶抑制剂(伊立替康(irinotecan)、拓扑替康(topotecan)、安吖啶(amsacrine)、依托泊苷(etoposide)、替尼泊苷(teniposide)等)、免疫治疗剂(干扰素α、β、γ、白细胞介素(interleukin)等)以及抗激素剂(他莫昔芬(tamoxifen)、亮丙瑞林(leuprorelin)、阿那曲唑(anastrozole)等),但不限于此。
式(I)化合物或其可药用盐用于向人(约70kg体重)施用的推荐日剂量可以为0.1mg/天至2,000mg/天,优选1mg/天至1,000mg/天,每天1至4次或者依照/脱离时间表经口或肠胃外施用。本发明化合物可以每天以单剂量或分剂量施用。应理解的是,应根据多种相关因素确定日剂量,这些相关因素包括待治疗对象的病情、年龄、体重和性别、施用途径和疾病严重程度,因此,不应将上述建议剂量解释为以任何方式限制本发明的范围。
本发明的药物组合物通常可包含可药用添加剂、载体或赋形剂。本发明的药物组合物可根据常规方法配制,并且可制备成口服制剂或肠胃外制剂的形式,所述口服制剂例如片剂、丸剂、散剂、胶囊剂、糖浆剂、乳剂、微乳剂等,所述肠胃外制剂例如肌内、静脉内或皮下施用。
对于口服制剂,可使用例如以下的载体或添加剂:纤维素、硅酸钙、玉米淀粉、乳糖、蔗糖、葡萄糖、磷酸钙、硬脂酸、硬脂酸镁、硬脂酸钙、明胶、滑石、表面活性剂、助悬剂、乳化剂、稀释剂等。对于可注射制剂,可使用例如以下的载体或添加剂:水、盐水、葡萄糖溶液、葡萄糖溶液类似物、醇、二醇、醚(例如,聚乙二醇400)、油、脂肪酸、脂肪酸酯、甘油酯、表面活性剂、助悬剂、乳化剂等。
另外,本发明提供了用于预防或治疗哺乳动物中的炎性疾病、自身免疫病、增殖性疾病或过度增殖性疾病、免疫介导的疾病的方法,其包括向所述哺乳动物施用有效量的式(I)化合物或其可药用盐的步骤。
本发明式(I)化合物可用于研究激酶的生物学和病理学现象,研究由激酶介导的细胞内信号通路以及对新激酶抑制剂的比较评价。
实施例
提供了以下实施例以说明本发明的优选实施方案,但是他们不限制本发明的范围。
实施例1:N-(3-(6-氯-2-(4-(4-甲基哌嗪-1-基)苯基)-3H-咪唑并[4,5-b]吡啶-7-基氧基)苯基)丙烯酰胺的制备
步骤1)4-氯-2-三甲基乙酰氨基吡啶的制备
将吡啶(40mL)添加到2-氨基-4-氯吡啶(10.0g,0.077mol)和三甲基乙酰氯(10.4mL,0.116mol)中,然后在室温下搅拌5小时。在减压下蒸馏反应溶液,添加乙酸乙酯并用饱和碳酸氢钠水溶液洗涤。分离出有机层,经无水硫酸钠干燥、过滤并在减压下蒸馏。将所得固体在减压下干燥,得到标题化合物(11.5g,产率:70%)。
1H-NMR(300MHz,DMSO-d6)δ1.24(s,9H),7.25(dd,1H),8.17(d,1H),8.34(d,1H),10.09(s,1H)
步骤2)4,5-二氯-2-三甲基乙酰氨基吡啶的制备
将乙腈(200mL)添加到在步骤1中获得的化合物(11.0g,0.051mol)和N-氯代丁二酰亚胺(34.0g,0.255mol)中,然后在100℃下搅拌5小时。在减压下蒸馏反应溶液,添加乙酸乙酯并用饱和碳酸氢钠水溶液洗涤。分离出有机层,经无水硫酸钠干燥、过滤并在减压下蒸馏。将所得固体在减压下干燥,得到标题化合物(6.3g,产率:50%)。
1H-NMR(300MHz,DMSO-d6)δ1.21(s,9H),8.33(s,1H),8.54(s,1H),10.30(s,1H)
步骤3)2-氨基-4,5-二氯-3-硝基吡啶的制备
将在步骤2中获得的化合物(6.3g,0.025mol)溶解在100℃的浓硫酸(100mL)中,滴加60~62%硝酸(2.4mL),然后在65~70℃下搅拌1小时。将反应溶液冷却到0℃,并使用2N氯化钠水溶液将pH值调节到7.0以获得固体,然后将其搅拌2小时。在减压下过滤出所得固体,用蒸馏水洗涤并干燥,得到标题化合物(2.08g,产率:40%)。
1H-NMR(300MHz,DMSO-d6)δ7.35(s,2H),8.37(s,1H)
步骤4)N-(3-羟基苯基)丙烯酰胺的制备
将四氢呋喃(100mL)和水(30mL)添加到3-氨基苯基(5.0g,0.045mol)中,向其中添加碳酸氢钠(5.6g,0.067mol),并滴加丙烯酰氯(3.6mL,0.045mol)。将反应溶液在室温下搅拌3.5小时,添加二氯甲烷,并用氯化铵水溶液洗涤。分离出有机层,经硫酸钠干燥、过滤并在减压下蒸馏。将所得残余物用二氯甲烷和醚蒸馏,得到标题化合物(2.9g,产率:40%)。
1H-NMR(300MHz,DMSO-d6)δ5.73(dd,1H),6.24(dd,1H),6.42(m,2H),7.04(m,2H),7.24(s,1H),9.39(s,1H),9.97(s,1H)
步骤5)N-(3-((2-氨基-5-氯-3-硝基吡啶-4-基)氧基)苯基)丙烯酰胺的制备
将N,N-二甲基甲酰胺(40mL)添加到在步骤3中获得的化合物(2.0g,0.010mol)和碳酸铯(4.7g,0.001mol),然后在室温下搅拌30分钟。向其中缓慢添加在步骤4中获得的化合物(2.28g,0.001mol),然后在35℃下搅拌5小时。向反应溶液中添加乙酸乙酯,并用水洗涤数次。分离出有机层,经无水硫酸钠干燥、过滤并在减压下蒸馏。将所得残余物通过柱色谱(氯仿∶甲醇=20∶1(v∶v))分离,得到标题化合物(2.0g,产率:65%)。
1H-NMR(300MHz,DMSO-d6)δ5.72(dd,1H),6.35(dd,1H),6.41(m,2H),6.69(d,1H),7.03(m,2H),7.32(s,1H),7.50(s,1H),8.46(s,1H),10.25(s,1H)
步骤6)N-(3-((2,3-二氨基-5-氯吡啶-4-基)氧基)苯基)丙烯酰胺的制备
将铁(3.57g,0.063mol)和12N盐酸水溶液(0.64mL)在50%的乙醇水溶液((60mL)中稀释,然后在100℃下搅拌1小时。将在步骤5中获得的化合物(2g,0.006mol)添加到反应溶液中,然后在100℃下搅拌1小时。将反应溶液在减压下经过硅藻土过滤器(Cellite filter)过滤,并在减压下蒸馏。向所得残余物中添加二氯甲烷,然后利用饱和碳酸氢钠水溶液洗涤。分离出有机层,经无水硫酸钠干燥、过滤并在减压下蒸馏。将所得残余物通过柱色谱(二氯甲烷∶甲醇=10∶1(v∶v))分离,得到标题化合物(1.25g,产率:70%)
1H-NMR(300MHz,DMSO-d6)δ4.86(s,2H),5.73(dd,1H),5.92(s,2H),6.32(m,2H),6.59(d,1H),7.14(s,1H),7.26(t,1H),7.45(s,2H),10.35(s,1H)
步骤7)4-(4-(甲基哌嗪-1-基)苯甲醛的制备
将水(30mL)添加到4-氟苯甲醛(3.0g,0.024mol)和碳酸钠(3.83g,0.036mol)中。向其中缓慢滴加1-甲基哌嗪(4.11g,0.041mol),然后在0℃下搅拌12小时。将二氯甲烷添加到反应溶液中,并用饱和碳酸氢钠水溶液洗涤。分离出有机层,经无水硫酸钠干燥、过滤并在减压下蒸馏,将所得残余物用正己烷结晶,得到标题化合物(2.9g,产率:40%)。
1H-NMR(300MHz,DMSO-d6)δ2.21(s,3H),2.42(m,4H),3.35(m,4H),7.02(d,2H),7.69(d,2H),9.71(s,1H)
步骤8)N-(3-(6-氯-2-(4-(4-甲基哌嗪-1-基)苯基)-3H-咪唑并[4,5-b]吡啶-7-
基氧基)苯基)丙烯酰胺的制备
将N,N-二甲基甲酰胺(30mL)添加到在步骤6中获得的N-(3-((2,3-二氨基-5-氯吡啶-4-基)氧基)苯基)丙烯酰胺(1.25g,0.004mol)和在步骤7中获得的4-(4-甲基哌嗪-1-基)苯甲醛(0.83g,0.004mol)中。向所述混合物中添加氯化铁(0.033g,0.123mmol),然后在120℃下搅拌6小时。向反应溶液中添加二氯甲烷,并用水洗涤数次。分离出有机层,经无水硫酸钠干燥、过滤并在减压下蒸馏。将所得残余物通过柱色谱(氯仿∶甲醇=20∶1(v∶v))分离,得到标题化合物(0.8g,产率:40%)。
1H-NMR(300MHz,DMSO-d6)δ2.18(s,2H),2.38(m,4H),3.33(m,4H),5.73(dd,1H),6.32(m,2H),6.55(d,1H),7.05(d,2H),7.14(s,1H),7.22(t,1H),7.41(s,2H),7.69(d,2H),10.35(s,1H),13.45(s,1H)
MS(ESI+):m/z=489.2[M+H]+
实施例2:N-(3-(6-氯-2-(4-(4-羟基哌啶-1-基)苯基)-3H-咪唑并[4,5-b]吡啶-7-基氧基)苯基)丙烯酰胺的制备
步骤1)4-(4-羟基哌啶-1-基)苯甲醛的制备
将二甲基甲酰胺(15mL)添加到4-氟苯甲醛(1.5g,0.012mol)和碳酸钠(2.5g,0.018mol)中。向其中缓慢滴加哌啶-4-醇(1.47g,0.015mol),然后在70℃至80℃搅拌8小时。向反应溶液中添加二氯甲烷,并将混合物用饱和碳酸氢钠水溶液洗涤。分离出有机层,经无水硫酸钠干燥、过滤并在减压下蒸馏。将所得残余物用正己烷结晶,得到标题化合物(1.5g,产率:52%)。
1H-NMR(300MHz,DMSO-d6)δ1.40(m,2H),1.79(m,2H),3.10(m,2H),3.75(m,3H),4.77(d,1H),7.02(d,2H),7.68(d,2H),9.67(s,1H)
步骤2)N-(3-(6-氯-2-(4-(4-羟基哌啶-1-基)苯基)-3H-咪唑并[4,5-b]吡啶-7-
基氧基)苯基)丙烯酰胺的制备
重复实施例1的步骤8的程序,不同之处是使用在上述步骤1中获得的4-(4-羟基哌啶-1-基)苯甲醛和在实施例1的步骤6中获得的N-(3-((2,3-二氨基-5-氯吡啶-4-基)氧基)苯基)丙烯酰胺,得到实施例2的化合物。
1H-NMR(300MHz,DMSO-d6)δ1.41(m,2H),1.79(m,2H),2.99(m,2H),3.69(m,3H),4.71(d,1H),5.72(d,1H),6.20(m,1H),6.34(m,1H),6.74(d,1H),7.02(d,2H),7.29(m,2H),7.41(d,1H),7.95(br,1H),8.37(s,1H),10.15(s,1H)
MS(ESI+):m/z=490.2[M+H]+
实施例3至19:
使用与用于制备实施例1的步骤7中获得的4-(4-甲基哌嗪-1-基)苯甲醛或实施例2的步骤1中获得的4-(4-羟基哌啶-1-基)苯甲醛的方法相同或相似的方法制备表示为W-COH(W如上文定义)的多种醛衍生物,然后重复实施例1的步骤8的程序,获得表1所示实施例3至19的化合物。实施例20:N-(3-(2-(4-(4-甲基哌嗪-1-基)苯基)-3H-咪唑并[4,5-b]吡啶-7-基氧基)苯基)丙烯酰胺的制备
重复实施例1的程序,不同之处是使用2-氨基吡啶代替实施例1的步骤1中使用的2-氨基-4-氯吡啶,得到表1所示实施例20的化合物。
[表1]
制剂实施例1:片剂的制备
根据常规方法,通过使用实施例1至20中制备的每一种化合物作为活性成分,使用以下表2中给出的组成配方制备用于经口施用的单片剂。[表2]
组成 | 量 |
活性成分 | 100mg |
玉米淀粉 | 80mg |
乳糖 | 80mg |
硬脂酸镁 | mg |
制剂实施例2:胶囊剂的制备
根据常规方法,通过使用实施例1至20中制备的每一种化合物作为活性成分,使用以下表3中给出的组成配方制备用于经口施用的硬明胶胶囊。
[表3]
组成 | 量 |
活性成分 | 100mg |
玉米淀粉 | 40mg |
乳糖 | 80mg |
结晶纤维素 | 80mg |
硬脂酸镁 | mg |
制剂实施例3:可注射药物制剂的制备
根据常规方法,通过使用实施例1至20中制备的每一种化合物作为活性成分,使用以下表4中给出的组成配方制备可注射药物制剂。但是,当使用式(I)化合物的盐作为活性成分时,不控制pH值。
[表4]
组成 | 量 |
活性成分 | 20mg |
5%葡萄糖溶液 | 10mL |
HCl(1N) | 适于保持pH为4 |
制剂实施例4:可注射药物制剂的制备
根据常规方法,通过使用实施例1至20中制备的每一种化合物作为活性成分,使用以下表5中给出的组成配方制备可注射药物制剂。
[表5]
组成 | 量 |
活性成分 | 20mg |
聚乙二醇400 | 2mL |
无菌水 | 8mL |
测试例1:JAK3和BTK抑制活性的评价
测试在实施例1至20中制备的化合物对于JAK3和BTK的抑制活性。通过使用Z-Lyte激酶分析试剂盒(Invitrogen)测量激酶抑制活性,JAK3和BTK酶购自Invitrogen(PV3855,PV3190)。
具体地,用4%DMSO水溶液稀释实施例1至20的化合物,得到浓度为1~0.0001μM的溶液。将每一种激酶都稀释为1~10ng/测定,并且通过计算近似Kd值将ATP稀释以形成激酶缓冲液(50mM HEPES,pH7.4;10mM MgCl2;1mM EGTA;0.01%BRIJ-35)。在384孔聚苯乙烯平底板上进行测定。将5μL稀释的化合物溶液、具有合适浓度的肽底物、10μL混合的激酶溶液和5μL浓度为5至300μM的ATP溶液添加到样品中,并允许在室温下于混合器中反应60分钟。60分钟后,向每一种混合物中添加10μL荧光标记试剂以允许对肽底物进行荧光标记,然后添加完成溶液(finishing solution)以完成反应。使用具有400nm处的激发滤光片(excitation filter)和520um处的发射滤光片(emission filter)的分子器件(Molecular Device)测量荧光水平。参照试剂盒的方案,相对于对照组(星形孢菌素或每一种激酶抑制剂)以0~100%之间的磷酸化率计算化合物的激酶抑制活性,计算抑制百分比并对浓度(x轴)作图以计算50%抑制浓度(IC50)。通过使用Microsoft Excel获得IC50值,结果在表5中示出,其中A∶IC50≤50nM,B∶IC50=50~100nM,C∶IC50=100~1,000nM,以及D∶IC50≥1,000nM。
[表6]
Claims (10)
1.式(I)化合物或其可药用盐:
其中,
R1是氢、卤素或CN;
X是O、NH、CH2、S、SO或SO2;
Y是苯基或吡啶基;
Z是
n是0至4的整数;
R2各自独立地为氢、C1-6烷氧基或二(C1-6烷基)氨甲基;并且
W是被选自以下的一个或更多个取代基取代的苯基或吡啶基:氢、卤素、羟基、硝基、C1-6烷氧基、C1-6烷氧基羰基、氨基、C1-6烷基氨基、C1-6烷基杂环氨基、氨基甲酰基、C1-6烷基氨基甲酰基、二(C1-6烷基)氨基甲酰基、C1-6烷基杂环氨基甲酰基、C1-6烷基杂环C1-6烷基、氨磺酰基、C1-6烷基硫烷基、C1-6烷基磺酰基、C1-6烷基亚磺酰基、C1-6烷氧基C1-6烷基、C1-6烷氧基C1-6烷氧基、二(C1-6烷基)氨基、二(C1-6烷基)氨基C1-6烷基、二(C1-6烷基)氨基C1-6烷氧基、羧基、杂环、C1-6烷基杂环、羟基杂环、羟基C1-6烷基杂环、C1-6烷氧基C1-6烷基杂环、杂环氧基、杂环C1-6烷基、杂环氨基C1-6烷基、杂环羰基和杂环-C1-6烷基羰基,其中所述杂环独立地为含有独立地选自N、O和S的一个或更多个杂原子的饱和3至8元单环杂环。
2.根据权利要求1所述的式(I)化合物或其可药用盐,其中W可选自:
3.根据权利要求1所述的式(I)化合物或其可药用盐,其中所述化合物选自:
N-(3-(6-氯-2-(4-(4-甲基哌嗪-1-基)苯基)-3H-咪唑并[4,5-b]吡啶-7-基氧基)苯基)丙烯酰胺;
N-(3-(6-氯-2-(4-(4-羟基哌啶-1-基)苯基)-3H-咪唑并[4,5-b]吡啶-7-基氧基)苯基)丙烯酰胺;
N-(3-(6-氯-2-(4-(4-甲基哌嗪-1-羰基)苯基)-3H-咪唑并[4,5-b]吡啶-7-基氧基)苯基)丙烯酰胺;
N-(3-(6-氯-2-(4-(吗啉-4-羰基)苯基)-3H-咪唑并[4,5-b]吡啶-7-基氧基)苯基)丙烯酰胺;
N-(3-(6-氯-2-(4-(1-甲基哌啶-4-基氨基)苯基)-3H-咪唑并[4,5-b]吡啶-7-基氧基)苯基)丙烯酰胺;
N-(3-(6-氯-2-(4-(二甲基氨基)苯基)-3H-咪唑并[4,5-b]吡啶-7-基氧基)苯基)丙烯酰胺;
N-(3-(6-氯-2-(4-(甲基亚磺酰基)苯基)-3H-咪唑并[4,5-b]吡啶-7-基氧基)苯基)丙烯酰胺;
4-(7-(3-丙烯酰氨基苯氧基)-6-氯-3H-咪唑并[4,5-b]吡啶-2-基)-N,N-二甲基苯甲酰胺;
4-(7-(3-丙烯酰氨基苯氧基)-6-氯-3H-咪唑并[4,5-b]吡啶-2-基)-苯甲酸;
4-(7-(3-丙烯酰氨基苯氧基)-6-氯-3H-咪唑并[4,5-b]吡啶-2-基)-N-(1-甲基哌啶-4-基)苯甲酰胺;
N-(3-(6-氯-2-(4-((二甲基氨基)甲基)苯基)-3H-咪唑并[4,5-b]吡啶-7-基氧基)苯基)丙烯酰胺;
N-(3-(6-氯-2-(4-((二乙基氨基)甲基)苯基)-3H-咪唑并[4,5-b]吡啶-7-基氧基)苯基)丙烯酰胺;
N-(3-(6-氯-2-(4-((乙基(甲基)氨基)甲基)苯基)-3H-咪唑并[4,5-b]吡啶-7-基氧基)苯基)丙烯酰胺;
N-(3-(6-氯-2-(4-(吡咯烷-1-基甲基)苯基)-3H-咪唑并[4,5-b]吡啶-7-基氧基)苯基)丙烯酰胺;
N-(3-(6-氯-2-(4-(哌啶-1-基甲基)苯基)-3H-咪唑并[4,5-b]吡啶-7-基氧基)苯基)丙烯酰胺;
N-(3-(6-氯-2-(4-(吗啉代甲基)苯基)-3H-咪唑并[4,5-b]吡啶-7-基氧基)苯基)丙烯酰胺;
N-(3-(6-氯-2-(4-((4-甲基哌嗪-1-基)甲基)苯基)-3H-咪唑并[4,5-b]吡啶-7-基氧基)苯基)丙烯酰胺;
N-(3-(6-氯-2-(4-甲氧基苯基)-3H-咪唑并[4,5-b]吡啶-7-基氧基)苯基)丙烯酰胺;
N-(3-(6-氯-2-(吡啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-基氧基)苯基)丙烯酰胺;以及
N-(3-(2-(4-(4-甲基哌嗪-1-基)苯基)-3H-咪唑并[4,5-b]吡啶-7-基氧基)苯基)丙烯酰胺。
4.药物组合物,其包含作为活性成分的根据权利要求1所述的式(I)化合物或其可药用盐,所述药物组合物用于预防或治疗炎性疾病、自身免疫病、增殖性疾病或过度增殖性疾病、免疫介导的疾病、癌症或肿瘤。
5.根据权利要求4所述的药物组合物,其中所述炎性疾病、自身免疫病、增殖性疾病或过度增殖性疾病、免疫介导的疾病、癌症或肿瘤由选自以下的一种或更多种激酶介导:Janus激酶3(JAK3)、酪氨酸蛋白激酶(BTK)、IL2诱导型T细胞激酶(ITK)、静息淋巴细胞激酶(RLK)和骨髓酪氨酸激酶(BMX)。
6.根据权利要求4所述的药物组合物,其中所述炎性疾病、自身免疫病、增殖性疾病或过度增殖性疾病、免疫介导的疾病、癌症或肿瘤由异常激活的T淋巴细胞、B淋巴细胞或它们二者介导。
7.根据权利要求4所述的药物组合物,其中所述炎性疾病、自身免疫病、增殖性疾病或过度增殖性疾病或免疫介导的疾病选自:关节炎、类风湿性关节炎、脊柱关节病、痛风性关节炎、骨关节炎、幼年型关节炎、其他关节病症、狼疮、系统性红斑狼疮(SLE)、皮肤相关疾病、银屑病、湿疹、皮炎、特应性皮炎、疼痛、肺疾病、肺炎、成人呼吸窘迫综合征(ARDS)、肺结节病、慢性肺部炎性疾病、慢性阻塞性肺病(COPD)、心血管疾病、动脉粥样硬化、心肌梗死、充血性心力衰竭、心肌缺血再灌注损伤、炎性肠病、克隆病、溃疡性结肠炎、肠应激综合征、哮喘、舍格伦综合征、自身免疫性甲状腺疾病、荨麻疹、多发性硬化、硬皮病、同种异体移植排斥、异种移植、特发性血小板减少性紫癜(ITP)、帕金森病、阿尔茨海默病、糖尿病相关疾病、炎症、盆腔炎、过敏性鼻炎、过敏性支气管炎、过敏性鼻窦炎、白血病、淋巴瘤、B细胞淋巴瘤、T细胞淋巴瘤、骨髓瘤、急性淋巴细胞白血病(ALL)、慢性淋巴细胞白血病(CLL)、急性骨髓性白血病(AML)、慢性骨髓性白血病(CML)、多毛细胞白血病、霍奇金病、非霍奇金淋巴瘤、多发性骨髓瘤、骨髓增生异常综合征(MDS)、骨髓增生性肿瘤(MPN)、弥散性大B细胞淋巴瘤和滤泡型淋巴瘤。
8.根据权利要求4所述的药物组合物,其还包含选自以下的任意抗癌剂:细胞信号传导抑制剂、有丝分裂抑制剂、烷基化剂、抗代谢物、嵌入剂、拓扑异构酶抑制剂、免疫治疗剂、抗激素剂及其混合物。
9.根据权利要求4所述的药物组合物,其还包含选自以下的另外的药物:类固醇、氨甲喋呤、来氟米特、抗TNF-α剂、钙调磷酸酶抑制剂、抗组胺剂及其混合物。
10.用于预防或治疗哺乳动物中的炎性疾病、自身免疫病、增殖性疾病或过度增殖性疾病、免疫介导的疾病、癌症或肿瘤的方法,所述方法包括向所述哺乳动物施用有效量的根据权利要求1所述的式(I)化合物或其可药用盐的步骤。
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KR10-2011-0144450 | 2011-12-28 | ||
PCT/KR2012/011570 WO2013100631A1 (en) | 2011-12-28 | 2012-12-27 | Novel imidazopyridine derivatives as a tyrosine kinase inhibitor |
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CN114174294A (zh) * | 2019-05-28 | 2022-03-11 | 人类制药有限公司 | 用于抑制janus激酶1的新化合物 |
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JP6891262B2 (ja) * | 2016-07-11 | 2021-06-18 | カンセラ・アーベー | 哺乳動物のチロシンキナーゼror1活性の阻害剤として有用な2−フェニルイミダゾ[4,5−b]ピリジン−7−アミン誘導体 |
WO2018102785A2 (en) | 2016-12-03 | 2018-06-07 | Juno Therapeutics, Inc. | Methods and compositions for use of therapeutic t cells in combination with kinase inhibitors |
WO2022140246A1 (en) | 2020-12-21 | 2022-06-30 | Hangzhou Jijing Pharmaceutical Technology Limited | Methods and compounds for targeted autophagy |
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RU2014131068A (ru) | 2016-02-20 |
JP2015503552A (ja) | 2015-02-02 |
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AU2012363557A1 (en) | 2014-07-17 |
US20150299185A1 (en) | 2015-10-22 |
BR112014016146A8 (pt) | 2017-07-04 |
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WO2013100631A1 (en) | 2013-07-04 |
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