CN113429427A - 杂环化合物及其制备方法和药物用途 - Google Patents
杂环化合物及其制备方法和药物用途 Download PDFInfo
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- CN113429427A CN113429427A CN202110755352.8A CN202110755352A CN113429427A CN 113429427 A CN113429427 A CN 113429427A CN 202110755352 A CN202110755352 A CN 202110755352A CN 113429427 A CN113429427 A CN 113429427A
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Abstract
本发明涉及了一种具有通式(I)的杂环化合物吡咯并[2,3‑d]嘧啶基和吡咯并[2,3‑d]吡啶基衍生物且具有Janus激酶(JAK)激酶抑制活性,尤其对JAK3激酶具有选择性的、较高的抑制活性、且具有优异的口服吸收性。本发明还涉及包含这样的化合物其制备的方法、包含其的药物组合物及使用其的治疗方法。通过施用本发明的化合物提供一种基于JAK3抑制作用、对JAK3表达异常相关的疾病预防和/或治疗有用的医药。所示结构的JAK3抑制剂、其光学异构体或它们的混合物、其药学上可接受的盐、溶剂合物或前药、其药物组合物、其在制药中的用途、使用其抑制JAK3活性治疗和/或预防哺乳动物(尤其是人)中JAK3表达异常相关的疾病或病症的方法。
Description
技术领域
本发明提供了一种杂环化合物具有吡咯并[2,3-d]嘧啶基和吡咯并[2,3-d]吡啶基衍生物且具有Janus激酶(JAK)激酶抑制活性,尤其对JAK3激酶具有选择性的、较高的抑制活性。本发明还涉及包含这样的化合物的组合物、用于制备这样的化合物的方法,以及用于治疗和预防通过JAK3失调所介导的病况的方法。
背景技术
Janus激酶(JAKs)属于酪氨酸激酶家族,通过它们磷酸化酪氨酸残基的能力来改变含有它们的蛋白质的功能。在受到特异性生长因子、生长激素、趋化因子、细胞因子和多种细胞表面受体刺激后被激活,使其具有酪氨酸激酶活性并成对结合,二聚体JAK能发生自发性磷酸化,与STAT蛋白结合,使STAT转录因子磷酸化并转移到细胞核内,将细胞外信号从细胞表面受体转移到细胞内细胞核,改变DNA的转录和随后的翻译蛋白质。JAK-STAT通路作用于50种以上的下游细胞因子和生长因子,因此,JAK激酶被认为是为免疫系统的中枢沟通节点。Janus激酶(JAKs)有四个家族成员:JAK1、JAK2、JAK3和TYK2。其中,JAK1、JAK2和TYK2广泛存在于体内各种组织和细胞中,JAK3主要存在于骨髓细胞、胸腺细胞、NK细胞及活化的B淋巴细胞、T淋巴细胞中。基于JAK激酶家族中各亚型的功能特点和特殊的组织分布,JAK1已成为免疫、炎症和癌症等疾病领域的新型靶点;JAK2已成为血液系统相关疾病治疗和预防的确切作用靶点;JAK3已成为治疗自身免疫性疾病的热门靶标。每个细胞表面受体都需要通过一对相同的同型二聚体(例如JAK2/)JAK2)或异二聚体(例如JAK1/JAK3)来发出信号,激活下游的STAT蛋白(信号转导器和激活物),调控相应靶基因启动子进而影响DNA的转录和随后的翻译蛋白质。每对JAK都有不同的激活配体和作用的下游效应子(Pharmacological Research,2019,147,104392)。
JAK-STAT信号通路功能广泛,参与细胞的增殖、分化、凋亡以及免疫调节等许多重要的生物学过程。JAK-STAT通路作用于50种以上的下游细胞因子和生长因子,这些因子包括白介素类(IL-2~7、IL-9、IL-10、IL-15、IL-21)、干扰素类(IFN-α、IFN-β、IFN-γ)、促红细胞生成素(EPO)、粒细胞和巨细胞集落刺激因子(GM-CSF)、促生长素(GH)、催乳素(PRL)、促血小板生成素(TPO)等,其在参与免疫细胞和造血干细胞的增殖、免疫调节的生物学过程中起关键作用。不同受体可激活不同亚型的JAK激酶,从而实现差异化的生物学功能。JAK1可与IL-10、IL-19、IL-20、IL-22、IL-26、IL-28、IFN-α、IFN-γ、gp130家族中的IL-6以及含γc的其它受体等结合(Cell,1998,93:373-383)。小鼠模型上的JAK1基因敲除实验表明该酶在调节上述多种细胞因子受体的生物学效应中起着关键作用(Gene,2002,285:1-24)。JAK1是免疫、炎症和癌症等疾病领域的新型靶点。JAK1抑制剂可用于治疗/预防自身免疫性疾病、炎症和肿瘤(Blood,2010,115:3287-3295),如白血病、淋巴瘤、黑色素瘤、关节炎、银屑病、克罗恩病、红斑狼疮、获得性免疫缺陷综合症、白塞病(Hum.Genet.,2013,132:1049-1058)等。JAK2在包括EPO、GH、PRL、IL-3、IFN-γ等多种受体信号调节过程中发挥重要作用(Gene,2002,285:1-24;Nat.Rev.Mol.CellBiol.,2002,3:651-662)。在小鼠模型中敲除JAK2可导致贫血引起的动物死亡(J.Biol.Chem.,2007,282:20059-20063);人体中的JAK2基因上的一个碱基突变JAK2V617F,其与骨髓增生性疾病中的真性红细胞增多症(PV)、特发性血小板增多症(ET)、特发性骨髓纤维化(IMF)、慢性粒细胞白血病(CML)等的发生密切相关(Immunol.Rev.,2009,228:273-287)。因此,JAK2已成为该类疾病的治疗/预防的确切作用靶点。JAK3通过与IL-2、IL-4、IL-7、IL-9、IL-15、IL-21等细胞因子受体复合物中的γ共链(γc)相结合,调节细胞信号传导。JAK3或γc突变都可导致重症联合免疫缺陷(SCID)(Blood,1996,88:817-823)。JAK3活性异常表现为T细胞和NK细胞大量减少、B细胞功能丧失,严重影响免疫系统等的正常生物学功能。基于其功能特点和特殊的组织分布,JAK3成为针对免疫系统相关疾病极具吸引力的药物靶点,其抑制剂在类风湿性关节炎(RA)、克罗恩病和溃疡性结肠炎、系统性红斑狼疮、多发性硬化症、Ⅰ型糖尿病、银屑病、过敏性疾病、哮喘、慢性阻塞性肺病、白血病、淋巴瘤、器官移植和其它等疾病的治疗/预防方面具有重要的临床应用价值(Trends Pharm.Sci.,2004,25:558-562)。TYK2是JAK家族中的第一个成员,其可被IFNs、IL-10、IL-6、IL-12、IL-23、IL-27等多种受体激活。在小鼠中,TYK2功能缺失会引起多种细胞因子受体的信号通路发生缺陷,进而导致病毒感染、抗菌免疫功能下降并增加了肺部感染的可能性等(Gene,2002,285:1-24)。
早期获批的JAK抑制剂都属于非选择性的JAK抑制剂,2011年,首个由美国Incyte公司开发的JAK抑制剂鲁索利替尼(Ruxolitinib)在美国批准上市,是第一款专门用于治疗骨髓纤维化的药物。2012年,随着托法替布(Tofacitinib)被FDA批准用于治疗类风湿关节炎(RA)后,2017年,由Incyte和Eli Lilly合作开发的Baricitinib首先在欧洲获得上市许可,但其在FDA的上市申请遭到拒绝;在完善相关临床试验后,2018年1月Baricitinib最终获得了FDA的许可。但目前这几个pan-JAKs抑制剂都带有黑框警告:严重感染、恶性肿瘤、血栓形成的风险。pan-JAKs抑制剂Tofacitinib具有包括引起红细胞与白细胞数量下降、胆固醇水平上升等副作用,这或许与其具有高JAK2抑制活性相关(J.Med.Chem.,2012,55:6176-6193)。
目前,制药公司等机构都将目光聚焦于选择性JAK抑制剂(特别是JAK3)的研究与发现上。JAK3是包含JAKl、JAK2、JAK3和TYK2的Janus家族蛋白激酶的成员,并且在所有组织中以不同水平表达。许多细胞因子受体通过下列组合的JAK激酶对传递信号:JAKl/JAK2、JAKl/JAK3、JAK1/TYK2、JAK2/TYK2或JAK2/JAK2。动物研究表明在免疫系统的发育、功能和稳态中牵涉JAK3通过抑制JAK3激酶活性来调节免疫活性可证明在治疗多种免疫病症中的用途(J.lmmunol.,178,2623—2629(2007);Gene,285,1—24(2002);Cell,109,(suppl.)Sl21—S131(2002)),同时避免JAK2依赖性红细胞生成素(EPO)和血小板生成素(TPO)信号传导(Cell,93(3),397—409(1998);Cell,93(3),385—95(1998))。
发明内容
本发明涉及新型化合物,它们是可用于治疗与JAK3调节异常相关的疾病的选择性JAK3调节剂。本发明还提供包含这样的JAK3调节剂的药物组合物以及治疗和/或预防这样的疾病的方法。因此,本发明提供式(I)所示化合物,其光学异构体或它们的混合物、其药学上可接受的盐、溶剂合物、其N-氧化物或它们的前药,其具有以下结构:
其中Y1独立地选自N或CR1,其中所述R1进一步任选自:氢、氘、卤素、氰基、氨基羰基、(C1-C6线性或支链烷基)氨基羰基、C1-C4烷基、C6-C10芳基、包含5-和/或6-元环的单环或双环杂芳基、(芳基)C1-C6线性或支链烷基、(杂芳基)C1-C6线性或支链烷基、(杂环基)C1-C6线性或支链烷基、(C1-C6线性或支链烷基)芳基、(C1-C6线性或支链烷基)杂芳基或(C1-C6线性或支链烷基)杂环基,其中所述烷基进一步任选地被选自下列的一个或多个取代基取代:卤素、羟基、甲氧基、氨基、CF3和C3-C6环烷基;
R0独立地选自氢、氘、氟、氯、氰基、C1-C8炔基、C1-C8卤代炔基、C1-C6线性或支链烷基、C1-C6线性或支链烷氧基亚甲基、卤代C1-C6线性或支链烷氧基亚甲基、C1-C6线性或支链烷氧基二氟亚甲基、卤代C1-C6线性或支链烷氧基二氟亚甲基、C1-C6线性或支链烷氧基氟代亚甲基、卤代C1-C6线性或支链烷氧基氟代亚甲基、C3-C6环烷基、C3-C6烷基取代环烷基、C3-C6卤素取代环烷基、C6-C10芳基、包含5-和/或6-元环的单环或双环杂芳基、(芳基)C1-C6线性或支链烷基、(杂芳基)C1-C6线性或支链烷基、(杂环基)C1-C6线性或支链烷基、(C1-C6线性或支链烷基)芳基、(C1-C6线性或支链烷基)杂芳基、(C1-C6线性或支链烷基)杂环基、C1-C6线性或支链全氟烷基、C1-C6线性或支链烷氧基、C1-C6线性或支链全氟烷氧基、异丙基羰基、叔丁基羰基、氨基、羧基、氨基羰基、(C1-C6线性或支链烷基)氨基羰基氨基、(C1-C6线性或支链烷基)氨基羰基、乙氧基羰基、异丙氧基羰基、异丁氧基羰基;其中所述烷基、芳基和杂芳基独立任选地被选自下列的一个或多个取代基取代:烷基、卤素、羟基、甲氧基、氨基、氰基、烷基氨基、二烷基氨基、CF3、氨基羰基、(C1-C6线性或支链烷基)氨基羰基和C3-C6环烷基;
其中,R1独立地选自下面结构的一种:
R2,R3和R4各自独立地选自氢、氘、C1-C3烷基、C1-C3卤代烷基、环丙基、C1-C3烷氧基、氟原子、C1-C3卤代烷氧基;
X1和X2独立地选自N或CH;
当X1选自CH,X2选自N时,优选结构具有如下式(II)所示结构:
其中Y1独立地选自N或CR1,其中所述R1进一步任选自:氢、氘、卤素、氰基、氨基羰基、(C1-C6线性或支链烷基)氨基羰基、C1-C4烷基、C6-C10芳基、包含5-和/或6-元环的单环或双环杂芳基、(芳基)C1-C6线性或支链烷基、(杂芳基)C1-C6线性或支链烷基、(杂环基)C1-C6线性或支链烷基、(C1-C6线性或支链烷基)芳基、(C1-C6线性或支链烷基)杂芳基或(C1-C6线性或支链烷基)杂环基,其中所述烷基进一步任选地被选自下列的一个或多个取代基取代:卤素、羟基、甲氧基、氨基、CF3和C3-C6环烷基;
R0独立地选自氢、氘、氟、氯、氰基、C1-C8炔基、C1-C8卤代炔基、C1-C6线性或支链烷基、C1-C6线性或支链烷氧基亚甲基、卤代C1-C6线性或支链烷氧基亚甲基、C1-C6线性或支链烷氧基二氟亚甲基、卤代C1-C6线性或支链烷氧基二氟亚甲基、C1-C6线性或支链烷氧基氟代亚甲基、卤代C1-C6线性或支链烷氧基氟代亚甲基、C3-C6环烷基、C3-C6烷基取代环烷基、C3-C6卤素取代环烷基、C6-C10芳基、包含5-和/或6-元环的单环或双环杂芳基、(芳基)C1-C6线性或支链烷基、(杂芳基)C1-C6线性或支链烷基、(杂环基)C1-C6线性或支链烷基、(C1-C6线性或支链烷基)芳基、(C1-C6线性或支链烷基)杂芳基、(C1-C6线性或支链烷基)杂环基、C1-C6线性或支链全氟烷基、C1-C6线性或支链烷氧基、C1-C6线性或支链全氟烷氧基、异丙基羰基、叔丁基羰基、氨基、羧基、氨基羰基、(C1-C6线性或支链烷基)氨基羰基氨基、(C1-C6线性或支链烷基)氨基羰基、乙氧基羰基、异丙氧基羰基、异丁氧基羰基;其中所述烷基、芳基和杂芳基独立任选地被选自下列的一个或多个取代基取代:烷基、卤素、羟基、甲氧基、氨基、氰基、烷基氨基、二烷基氨基、CF3、氨基羰基、(C1-C6线性或支链烷基)氨基羰基和C3-C6环烷基;
其中,R1独立地选自下面结构的一种:
R2,R3和R4各自独立地选自氢、氘、C1-C3烷基、C1-C3卤代烷基、环丙基、C1-C3烷氧基、氟原子、C1-C3卤代烷氧基;
当X1选自N,X2选自N时,优选结构具有如下式(III)所示结构:
其中Y1独立地选自N或CR1,其中所述R1进一步任选自:氢、氘、卤素、氰基、氨基羰基、(C1-C6线性或支链烷基)氨基羰基、C1-C4烷基、C6-C10芳基、包含5-和/或6-元环的单环或双环杂芳基、(芳基)C1-C6线性或支链烷基、(杂芳基)C1-C6线性或支链烷基、(杂环基)C1-C6线性或支链烷基、(C1-C6线性或支链烷基)芳基、(C1-C6线性或支链烷基)杂芳基或(C1-C6线性或支链烷基)杂环基,其中所述烷基进一步任选地被选自下列的一个或多个取代基取代:卤素、羟基、甲氧基、氨基、CF3和C3-C6环烷基;
R0独立地选自氢、氘、氟、氯、氰基、C1-C8炔基、C1-C8卤代炔基、C1-C6线性或支链烷基、C1-C6线性或支链烷氧基亚甲基、卤代C1-C6线性或支链烷氧基亚甲基、C1-C6线性或支链烷氧基二氟亚甲基、卤代C1-C6线性或支链烷氧基二氟亚甲基、C1-C6线性或支链烷氧基氟代亚甲基、卤代C1-C6线性或支链烷氧基氟代亚甲基、C3-C6环烷基、C3-C6烷基取代环烷基、C3-C6卤素取代环烷基、C6-C10芳基、包含5-和/或6-元环的单环或双环杂芳基、(芳基)C1-C6线性或支链烷基、(杂芳基)C1-C6线性或支链烷基、(杂环基)C1-C6线性或支链烷基、(C1-C6线性或支链烷基)芳基、(C1-C6线性或支链烷基)杂芳基、(C1-C6线性或支链烷基)杂环基、C1-C6线性或支链全氟烷基、C1-C6线性或支链烷氧基、C1-C6线性或支链全氟烷氧基、异丙基羰基、叔丁基羰基、氨基、羧基、氨基羰基、(C1-C6线性或支链烷基)氨基羰基氨基、(C1-C6线性或支链烷基)氨基羰基、乙氧基羰基、异丙氧基羰基、异丁氧基羰基;其中所述烷基、芳基和杂芳基独立任选地被选自下列的一个或多个取代基取代:烷基、卤素、羟基、甲氧基、氨基、氰基、烷基氨基、二烷基氨基、CF3、氨基羰基、(C1-C6线性或支链烷基)氨基羰基和C3-C6环烷基;
其中,R1独立地选自下面结构的一种:
R2,R3和R4各自独立地选自氢、氘、C1-C3烷基、C1-C3卤代烷基、环丙基、C1-C3烷氧基、氟原子、C1-C3卤代烷氧基;
当X1选自CH,X2选自N时,优选结构具有如下式(IV)所示结构:
其中Y1独立地选自N或CR1,其中所述R1进一步任选自:氢、氘、卤素、氰基、氨基羰基、(C1-C6线性或支链烷基)氨基羰基、C1-C4烷基、C6-C10芳基、包含5-和/或6-元环的单环或双环杂芳基、(芳基)C1-C6线性或支链烷基、(杂芳基)C1-C6线性或支链烷基、(杂环基)C1-C6线性或支链烷基、(C1-C6线性或支链烷基)芳基、(C1-C6线性或支链烷基)杂芳基或(C1-C6线性或支链烷基)杂环基,其中所述烷基进一步任选地被选自下列的一个或多个取代基取代:卤素、羟基、甲氧基、氨基、CF3和C3-C6环烷基;
R0独立地选自氢、氘、氟、氯、氰基、C1-C8炔基、C1-C8卤代炔基、C1-C6线性或支链烷基、C1-C6线性或支链烷氧基亚甲基、卤代C1-C6线性或支链烷氧基亚甲基、C1-C6线性或支链烷氧基二氟亚甲基、卤代C1-C6线性或支链烷氧基二氟亚甲基、C1-C6线性或支链烷氧基氟代亚甲基、卤代C1-C6线性或支链烷氧基氟代亚甲基、C3-C6环烷基、C3-C6烷基取代环烷基、C3-C6卤素取代环烷基、C6-C10芳基、包含5-和/或6-元环的单环或双环杂芳基、(芳基)C1-C6线性或支链烷基、(杂芳基)C1-C6线性或支链烷基、(杂环基)C1-C6线性或支链烷基、(C1-C6线性或支链烷基)芳基、(C1-C6线性或支链烷基)杂芳基、(C1-C6线性或支链烷基)杂环基、C1-C6线性或支链全氟烷基、C1-C6线性或支链烷氧基、C1-C6线性或支链全氟烷氧基、异丙基羰基、叔丁基羰基、氨基、羧基、氨基羰基、(C1-C6线性或支链烷基)氨基羰基氨基、(C1-C6线性或支链烷基)氨基羰基、乙氧基羰基、异丙氧基羰基、异丁氧基羰基;其中所述烷基、芳基和杂芳基独立任选地被选自下列的一个或多个取代基取代:烷基、卤素、羟基、甲氧基、氨基、氰基、烷基氨基、二烷基氨基、CF3、氨基羰基、(C1-C6线性或支链烷基)氨基羰基和C3-C6环烷基;
其中,R1独立地选自下面结构的一种:
R2,R3和R4各自独立地选自氢、氘、C1-C3烷基、C1-C3卤代烷基、环丙基、C1-C3烷氧基、氟原子、C1-C3卤代烷氧基;
在其它方面中,本发明还提供:
药物组合物,其包含药学上可接受的载体和本发明的化合物;
治疗或预防病症或病况的方法,所述病症或病况选自类风湿性关节炎、克罗恩氏病和溃疡性结肠炎的炎性肠病、直肠炎、嗜酸细胞性胃肠炎或肥大细胞增多症、肌炎、血管炎、天疤疮、阿尔茨海默病、狼疮、肾炎、系统性红斑狼疮、银屑病、湿疹皮炎、瘙痒症或其它瘙痒病况、白瘢风、脱发、自身免疫性甲状腺病、多发性硬化、重性抑郁症、哮喘、干燥病、系统性硬化病、结节性多动脉炎、干眼综合征、自身免疫性溶血性贫血、恶性贫血的自身免疫性萎缩性胃炎、自身免疫性脑脊髓炎、自身免疫性睾丸炎、自身免疫性血小板减少症、交感性眼炎、重症肌无力、原发性胆汁性肝硬变、慢性活动性肝炎、膜性肾小球病、器官移植排斥、移植物抗宿主病、诸如骨髓、软骨、角膜、心脏、椎间盘、胰岛、肾、四肢、肝、肺、肌肉、成肌细胞、神经、胰、皮肤、小肠或气管的器官和细胞移植排斥或者异种移植,包括强直性脊柱炎、自身免疫性脱发、慢性阻塞性肺病、急性呼吸道疾病、恶病质、和自身抗体介导的脑病的神经精神性病症相关的慢性神经炎症、眼疾病、病症或病况(包括眼的自身免疫疾病、角膜结膜炎、春季结膜炎、包括与贝切特氏病相关的葡萄膜炎和晶状体诱发性葡萄膜炎的葡萄膜炎、角膜炎、疤疹性角膜炎、圆锥形角膜炎、角膜上皮营养障碍、角膜白斑、虹膜炎、干燥性角膜结膜炎(干眼症)、小疤、虹膜睫状体炎、结节病、内分泌性眼病、交感性眼炎、变应性结膜炎和眼新生血管形成),所述方法包括向个体给药有效量的包含本文中所述的化合物或其药学上可接受的盐的组合物的步骤。所述方法通过向有需要的哺乳动物给药治疗有效量的本发明的化合物或其药学上可接受的盐。
治疗病况或病症的方法,所述病况或病症包括特应性皮炎、湿疹、银屑病、硬皮症、狼疮、瘙痒症、其它瘙痒病况、、夏季湿疹、炎症性气道疾病、复发性气道梗阻、气道高反应和慢性阻塞性肺病,所述方法通过向有需要的哺乳动物给药治疗有效量的本发明的化合物或其药学上可接受的盐进行;以及制备本发明的化合物的方法。通过以下说明(仅作为实例给出),会进一步理解本发明。本发明涉及一类吡咯并[2,3-d]嘧啶基和吡咯并[2,3-d]吡啶衍生物及其类似物。特别地,本发明涉及可用作JAK(特别是JAK3)的抑制剂的化合物,其包括吡咯并[2,3-d]嘧啶基和吡咯并[2,3-d]吡啶衍生物及其类似物。尽管本发明并不如此受限,但通过下列讨论和实施例会获得对本发明各方面的了解。
本发明的化合物可以药学上可接受的形式单独给药或与一种或多种调节哺乳动物免疫系统的额外药剂或与抗炎剂联合给药。这些药剂可包括但不限于环孢菌素A(例如山地明TM或新体睦TM)、雷帕霉素、FK-506(他克莫司)、来氟米特、脱氧精胍菌素、霉酚酸酯(例如骁悉TM)、硫唑嘌呤(例如依木兰TM)、达克珠单抗(例如赛尼哌TM)、OKT3(例如OrthocoloneTM)、AtGamTM、阿司匹林、醋氨酚、布洛芬、萘普生、吡罗昔康和抗炎甾体(例如Deflazacort、泼尼松龙或地塞米松)、IFN-β、特立氟胺、拉喹莫德、格拉默醋酸盐、富马酸二甲酯(dimethylf umerate)、利妥昔单抗、芬戈莫德、那他珠单抗、阿仑珠单抗、米托蒽醌、柳氮磺吡啶(Azulfidine)、美沙拉秦(Apriso、安萨科、Lialda等)、巴柳氮(巴柳氮二钠(Colazal))和奥沙拉秦(奥柳氮钠(Dipentum))以及巯嘌呤(巯基嘌呤(Purinethol))、抗生素(抗分支杆菌药,例如甲硝唑、环丙沙星)、乌司奴单抗和维多珠单抗。这些药剂可根据本领域技术人员已知的标准药学操作,以相同或分开的剂型的一部分,通过相同或不同的给药途径,并且按相同或不同的给药时间表给药。
本发明还提供了一种JAK3选择性抑制剂组合物,其光学异构体或它们的混合物、包括本发明化合物、其药学上可接受的盐、溶剂合物或前药。本发明中,如果没有特殊说明,应包括所有异构体。例如,双键,环中的集合异构体(E型,Z型,顺式的(cis),反式的(trans)),烷基包括直链烷基和支链烷基,由存在不对称碳原子等而产生的光学异构体(R,S型,)及它们任意比例的混合物,外消旋混合物,以及所有的由互变异构体产生的异构体均包括在本发明中。
通式I表示的化合物可以通过公知的方法转化为相应的盐。盐优选为水溶性的药学上可接受的无毒酸加成盐的实例为氨基与无机酸(如盐酸、氢溴酸、磷酸、硫酸以及高氯酸)或与有机酸(如乙酸、草酸、顺丁烯二酸、酒石酸、柠檬酸、琥珀酸或丙二酸)形成的盐,或通过使用本领域中已知的其他方法(例如离子交换法)形成的盐。其他药学上可接受的盐包括己二酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、硫酸氢盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、环戊烷丙酸盐、二葡糖酸盐、十二烷基硫酸盐、乙烷磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐、甘油磷酸盐、葡糖酸盐、半硫酸盐、庚酸盐、己酸盐、氢碘化物、2-羟基-乙烷磺酸盐、乳糖酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲烷磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对-甲苯磺酸盐、十一烷酸盐、戊酸盐等。衍生自适当碱的盐包括碱金属盐、碱土金属盐、铵盐以及N+(C1-4烷基)4盐。代表性碱金属或碱土金属盐包括钠盐、锂盐、钾盐、钙盐、镁盐等。适当时,另外的药学上可接受的盐包括使用如卤离子、氢氧根、羧酸根、硫酸根、磷酸根、硝酸根、低级烷基磺酸根以及芳基磺酸根等平衡离子形成的无毒铵、季铵以及胺阳离子。
除非另外说明,本文中术语“JAK3抑制剂”中提供包括具有式(Ⅰ)、式(Ⅱ)、式(Ⅲ)、式(Ⅳ)分子式每种化合物均包括具有相同分子式的不同立体异构体,其中的立体异构体还包括对映异构体和非对映异构体,对映异构体即为光学异构体,非对映异构体为不成手性对映的立体异构体,与本发明化合物具有相同分子式的不同异构体也在本发明的保护范围内。
除非另外说明,本文中的术语“溶剂合物”也可以称为“溶剂化合物”、“溶剂化物”指的是含有溶剂的化合物,其中溶剂分子可以以包括配位键、共价键、范德华力、离子键、氢键等其他方式与化合物分子相结合。
除非另外说明,本文中的术语“药学上可接受的盐”是指本发明的化合物和/或所形成的盐,在化学上或物理上与构成某药物剂型的其它成分相兼容,并在生理上与受体相兼容。“药学上可接受的盐”可以为与无机和/或有机酸和碱形成的酸式和/或碱式盐,也包括两性离子盐(内盐),还包括季铵盐,例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。也可以是通过将本发明的化合物或其立体异构体或溶剂合物,与一定数量的酸或碱适当混合而得到的。这些盐可能在溶液中形成沉淀而以过滤方法收集,或在溶剂蒸发后回收而得到,或在水介质中反应后冷却干燥制得。
除非另外说明,本文中的术语“烷基”是指具有具有1至4个碳原子(“C1-4烷基”)。在一些实施例中,烷基基团具有1至3个碳原子(“C1-3烷基”)。在一些实施例中,烷基基团具有1至2个碳原子(“C1-2烷基”)。在一些实施例中,烷基基团具有1个碳原子(“C1烷基”)。,烷基基团的每个实例是独立地任选取代地,即,未取代的(“未取代的烷基”)或被一个或两个取代基取代的(“取代的烷基”)。
除非另外说明,本文中的术语“5-元杂芳基”除非另外说明,包含一个杂原子的示例性5-元杂芳基基团包括但不限于,吡咯基、呋喃基以及苯硫基。包含两个杂原子的示例性5-元杂芳基基团包括但不限于,咪唑基、吡唑基、噁唑啉基、异噁唑啉基、噻唑基以及异噻唑基。包含三个杂原子的示例性5-元杂芳基基团包括但不限于,噻唑基、噁二唑基以及噻二唑基。包含四个杂原子的示例性5-元杂芳基基团包括但不限于四唑基。
除非另外说明,本文中的术语“杂环烷基”指的是非芳香环的一个或多个构成环的原子是杂原子,所述的杂原子包括而不限于氮原子、氧原子和硫原子等,其余为碳组成的稳定的3-10元饱和杂环系统的基团。除非本说明书中另外特别指明,否则杂环烷基基团可以是单环的(“单环的杂环烷基”),或者是双环、三环或更多环的环体系,其可包括并环的(稠合的)、桥联的(桥环的)或螺的环系统(例如二环系统(“二环的杂环烷基”)。杂环烷基二环的环系统可以在一个或两个环中包括一个或多个杂原子;并且是饱和的。示例性3-元杂环基基团包括但不限于,氮杂环丙基、环氧乙烷基以及硫杂环丙烷基,或者其立体异构体;示例性4-元杂环基基团包括但不限于,氮杂环丁烷基,环氧丙烷基,硫杂环丁烷基,或者其同分异构体和立体异构体;示例性5-元杂环基基团包括但不限于,四氢呋喃基,四氢噻吩基,吡咯烷基,噻唑烷基,异噻唑烷基,噁唑烷基,异噁唑烷基,咪唑烷基,吡唑烷基,二氧戊环基,氧杂硫呋喃基,二硫呋喃基,或者其同分异构体和立体异构体。示例性6-元杂环基基团包括但不限于,哌啶基,四氢吡喃基,硫化环戊烷基,吗啉基,硫代吗啉基,二噻烷基,二噁烷基,哌嗪基,三嗪烷基,或者其同分异构体和立体异构体;示例性7-元杂环基基团包括但不限于,氮杂环庚烷基,氧杂环庚烷基,硫杂环庚烷基,以及二氮杂环庚基,或者其同分异构体和立体异构体。在某一方案中,典型的含1个或多个独立选自N、O和S的杂原子的5-6元单环杂环基。方案中,“杂环烷基”为4-6元杂环烷基,其中杂原子选自N、O和S中的一种或多种,杂原子数为1、2或3个。
术语“杂芳基”是指含有杂原子的芳香基团,可为单环或稠合环,优选含有1-4个独立选自N、O和S的5-12元杂芳基,包括但不限于吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、异噁唑基、吡唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、喹啉基、异喹啉基、三唑基、四氢吡咯基。在某一方案中,典型地含1个或多个独立选自N、O和S的杂原子的5-6元单环杂芳基。
当所列举的基团中没有明确指明其具有取代基时,这种基团仅指未被取代。例如当“C1~C4烷基”前没有“取代或未取代的”的限定时,仅指“C1~C4烷基”本身或“未取代的C1~C4烷基”。
在本发明的各部分,描述了连接取代基。当该结构清楚地需要连接基团时,针对该基团所列举的马库什变量应理解为连接基团。例如,如果该结构需要连接基团并且针对该变量的马库什基团定义列举了“烷基”或“芳基”,则应该理解,该“烷基”或“芳基”分别代表连接的亚烷基基团或亚芳基基团。
在一些具体的结构中,当烷基基团清楚地表示为连接基团时,则该烷基基团代表连接的亚烷基基团,例如,基团“卤代-C1-C6烷基”中的C1-C6烷基应当理解为C1-C6亚烷基。
术语“卤素”(halo和halogen)是指氟(F)、氯(Cl)、溴(Br)或碘(I)。
术语“哺乳动物”是指人、家畜或猫和狗。
除非另有规定,本文使用的所有技术术语和科学术语具有要求保护主题所属领域的标准含义。倘若对于某术语存在多个定义,则以本文定义为准。应该理解,在本发明中使用的单数形式,如“一种”,包括复数指代,除非另有规定。
此外,术语“包括”是开放性限定并非封闭式,即包括本发明所指明的内容,但并不排除其他方面的内容。
除非另有说明,本发明采用质谱、核磁等传统方法鉴定化合物,各步骤和条件可参照本领域常规的操作步骤和条件。
除非另有指明,本发明采用分析化学、有机合成化学和光学的标准命名及标准实验室步骤和技术。在某些情况下,标准技术被用于化学合成、化学分析、发光器件性能检测。
另外,需要说明的是,除非以其他方式明确指出,在本发明中所采用的描述方式“…独立地选自”应做广义理解,是指所描述的各个个体之间彼此独立地被选择。因此,各取代基与其它取代基可以相同或不相同。更详细地,描述方式“…独立地选自”既可以是指在不同基团中,相同符号之间所表达的具体选项之间互相不影响;也可以表示在相同的基团中,相同符号之间所表达的具体选项之间互相不影响。
本领域技术人员可以理解,根据本领域中使用的惯例,本申请描述基团的结构式中所使用的是指,相应的基团通过该位点与化合物中的其它片段、基团进行连接。在不违背本领域常识的基础上,上述各优选条件,可任意组合,即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
在本发明某些实施方式中,本发明的化合物、或其立体异构体或前药,或所述化合物的立体异构体或前药的一种可药用盐可以以药物组合物的形式,其中包含可药用载体、运载剂或稀释剂。它们也可用于制备与用于治疗与JAK3激酶活性异常相关疾病的药物。
具体实施方式
下面通过实施例的方式进一步说明本发明,提供本申请中所述的合成实施例和生物学实施例以说明本文所提供的化合物、药物组合物、以及方法。以下实施例仅用于对本发明进行示例性说明,但不用于限制本发明,在本发明保护范围内所做的修改、改变、变型等都在本发明的保护范围内。
本文所提供的化合物可以使用下文所阐述的特定合成方案的将为本领域技术人员公知的操作方案,由容易获得的起始物质来制备。下列实施例中未注明具体条件的实验方法,按照常规方法和条件,可以由本领域技术人员通过常规的优化程序来确定。
下述实施例中,缩写解释:
Boc2O:二叔丁基二碳酸酯;
DIEA:N,N-二异丙基乙胺
Xantphos:4,5-双(二苯基膦)-9,9-二甲基氧杂蒽
dppf Pd G3:(甲磺酸(1,1'-双(二苯基膦)二茂铁)(2'-氨基-1,1'-联苯-2-基)钯(II)
Pd(PPh3)4:四(三苯基膦)钯
Pd(Pd(PPh3)2Cl2:双苯基磷二氯钯
Pd(dppf)Cl2:[1,1'-双(二苯基磷)二茂铁]二氯化钯
Pd2(dba)3:三(二亚苄基丙酮)二钯
Pd/C:钯碳催化剂
KOtBu:叔丁醇钾
NaOtBu:叔丁醇钠
SEMCl:2-(三甲硅烷基)乙氧甲基氯
NIS:N-碘代琥珀酰胺
TEA:三乙胺
TMSOTf:三氟甲磺酸三甲基硅烷酯
TFA:三氟乙酸
TFAA:三氟乙酸酐
TMS:三甲基硅烷基
PE:石油醚;
EA:乙酸乙酯;
DMF:N,N-二甲基甲酰胺;
DCM:二氯甲烷;
THF:四氢呋喃
MeOH:甲醇
Na2CO3:碳酸钠
Prep-HPLC:高压制备液相色谱
Rf:比移值;
g;克
mg:毫克
h:小时
rt:室温
mol:摩尔
mmol:毫摩尔
mL:毫升
M:摩尔/升
实施例1:4-(5-丙烯酰-4,5,6,7-四氢吡唑[1,5-a]哌嗪-3-基)-7H-吡咯[2,3-d]嘧啶化合物1的制备
参照下面的步骤合成化合物1:
步骤1:在{3-溴-4H,6H,7H-吡咯[1,5-a]哌嗪-5-基}羧酸叔丁酯1a(1.50g,4.90mmol)DMF(20.0mL)的混合液中加入二硼酸频呐醇酯(1.49g,5.80mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(0.36g,0.4mmol)和醋酸钾(1.44g,14.70mmol),然后反应液在氮气氛围下100℃搅拌12h。LCMS监控反应结束,冷却至室温,反应混合物中加入50mL食盐水,用乙酸乙酯(100mL)萃取,萃取后的有机相用Na2SO4干燥过滤后减压浓缩后得到的粗产品通过柱层析(SiO2,石油醚:乙酸乙酯=1:9)分离纯化得到黄色固体化合物1b(0.875g,40.82%)。MS(ESI)m/z 350.22[M+H]+.
步骤2:在圆底烧瓶的1,4-二氧六环/水=10:1(10mL)的混合溶液中加入4-氯-7氢-吡咯[2,3-d]嘧啶1c(250mg,1.63mmol),3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-6,7-二氢吡唑[1,5-a]哌嗪-5(4H)-羧酸叔丁酯1b(682.22mg,1.9534mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(119mg,0.16mmol)和Na2CO3(345mg,3.26mmol),得到的混合物在100℃搅拌12h。LCMS监控反应结束,冷却至室温,反应混合物中加入200mL食盐水,用乙酸乙酯(200mL)萃取,萃取后的有机相用Na2SO4干燥过滤后减压浓缩后得到的粗产品通过柱层析(SiO2,石油醚:乙酸乙酯=1:1)分离纯化得到白色固体化合物(4-{7H-吡咯[2,3-d]嘧啶-4-y基}-4H,6H,7H-吡唑[1,5-a]哌嗪-5-基)羧酸叔丁酯1e(120mg,17.14%)MS(ESI)m/z341.18[M+H]+.
步骤3:在圆底烧瓶中加入(4-{7H-吡咯[2,3-d]嘧啶-4-y基}-4H,6H,7H-吡唑[1,5-a]哌嗪-5-基)羧酸叔丁酯1e(120mg,0.33mmol)和HCl的1,4-二氧六环溶液(1mol/L,10mL)的0℃搅拌2h,LCMS监控反应结束。减压浓缩后得到的粗产品通过柱层析(SiO2,石油醚:乙酸乙酯=1:9)分离纯化得到白色固体化合物4-(4,5,6,7-四氢吡唑[1,5-a]哌嗪-3-基)-7H-吡咯[2,3-d]嘧啶1f(86mg,yield:96.59%)。MS(ESI)m/z 241.15[M+H]+.
步骤4:用二氯甲烷(5mL)将化合物4-(4,5,6,7-四氢吡唑[1,5-a]哌嗪-3-基)-7H-吡咯[2,3-d]嘧啶1f(71.00mg,0.5494mmol,1.00eq)溶解到反应瓶中,往反应体系中加入二异丙基乙胺(71.00mg,0.5494mmol)冷却到-78℃,滴加丙烯酰氯(24.86mg,0.2747mmol)。物料加完后,体系在-78℃下搅拌1小时。LCMS监控反应结束。反应混合物中加入20mL饱和NaHCO3,用乙酸乙酯(50mLX3)萃取,萃取后的有机相用Na2SO4干燥过滤后减压浓缩后得到的粗产品减压浓缩后得到的粗产品通过薄层层析板制备(乙酸乙酯)纯化得到白色固体化合物4-(5-丙烯酰-4,5,6,7-四氢吡唑[1,5-a]哌嗪-3-基)-7H-吡咯[2,3-d]嘧啶化合物1(11.46mg,收率14.02%)MS(ESI)m/z 295[M+H]+.
1H NMR(400MHz,DMSO-d6)δ12.13(s,1H),8.75(s,1H),8.44(s,1H),7.57(s,1H),7.01(s,2H),6.21(d,J=15.6Hz,1H),5.79(s,1H),5.31(d,J=31.6Hz,2H),4.22(d,J=62.6Hz,4H).
实施例2:4-(5-丙烯酰-4,5,6,7-四氢吡唑[1,5-a]哌嗪-3-基)-7H-吡咯[2,3-d]吡啶化合物2的制备
参照下面的步骤合成化合物2:
步骤1:在圆底烧瓶的1,4-二氧六环/水=10:1(10mL)的混合溶液中加入4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-7氢-吡咯[2,3-d]吡啶2b(96.94mg,0.397mmol),3-溴-6,7-二氢吡唑[1,5-a]哌嗪-5(4H)-羧酸叔丁酯2a(100mg,0.331mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(24.21mg,0.033mmol)和Na2CO3(70.16mg,0.662mmol),得到的混合物在100℃搅拌15h。LCMS监控反应结束,冷却至室温,反应混合物中加入100mL食盐水,用乙酸乙酯(2X100 mL)萃取,萃取后的有机相用Na2SO4干燥过滤后减压浓缩后达到的粗产品通过柱层析(SiO2,石油醚:乙酸乙酯=1:1)分离纯化得到白色固体化合物(4-{7H-吡咯[2,3-d]嘧啶吡啶-4-基}-4H,6H,7H-吡唑[1,5-a]哌嗪-5-基)羧酸叔丁酯2c(50mg,收率44.51%)MS(ESI)/z 340.18[M+H]+.
步骤2:在圆底烧瓶中加入(4-{7H-吡咯[2,3-d]吡啶-4-y基}-4H,6H,7H-吡唑[1,5-a]哌嗪-5-基)羧酸叔丁酯2c(50mg,0.147mmol)和HCl的1,4-二氧六环溶液(1mol/L,10mL)的0℃搅拌1h,LCMS监控反应结束。减压浓缩后达到的粗产品在乙酸乙酯中析出白色固体化合物4-(4,5,6,7-四氢吡唑[1,5-a]哌嗪-3-基)-7H-吡咯[2,3-d]吡啶2d(39mg,收率96.06%)。MS(ESI)m/z 240.22[M+H]+.
步骤3:用二氯甲烷(15mL)将化合物4-(4,5,6,7-四氢吡唑[1,5-a]哌嗪-3-基)-7H-吡咯[2,3-d]吡啶2d(39mg,0.1414mmol)溶解到反应瓶中,往反应体系中加入二异丙基乙胺(54.73mg,0.4243mmol)冷却到-40℃,滴加丙烯酰氯(12.80mg,0.1414mmol)。物料加完后,体系在-40℃下搅拌1小时。LCMS监控反应结束。反应混合物中加入20mL饱和NaHCO3,用乙酸乙酯(50mLX3)萃取,萃取后的有机相用Na2SO4干燥过滤后减压浓缩后达到的粗产品减压浓缩后达到的粗产品通过薄层层析板制备(乙酸乙酯)纯化得到白色固体化合物4-(5-丙烯酰-4,5,6,7-四氢吡唑[1,5-a]哌嗪-3-基)-7H-吡咯[2,3-d]吡啶化合物2(14.90mg,收率31.16%)
MS(ESI)m/z=294.21[M+H]+.
1H NMR(400MHz,DMSO-d6)δ=12.83(s,1H),9.19–9.14(m,2H),9.12(s,1H),8.86(s,1H),8.41(s,1H),8.24(s,1H),5.98(s,1H),5.55(s,1H),4.03(t,J=6.8,2H),2.95(t,J=6.7,2H),1.49(s,9H).
实施例3:4-(5-丙烯酰-4,5,6,7-四氢吡唑[1,5-a]哌嗪-3-基)-7H-吡咯[2,3-d]嘧啶-5-羧酸乙酯化合物3的制备
参照下面的步骤合成和化合物3:
步骤1:在圆底烧瓶的1,4-二氧六环/水=10:1(11mL)的混合溶液中加入4-氯-7氢-吡咯[2,3-d]嘧啶-5-羧酸乙酯3a(300mg,1.33mmol),3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-6,7-二氢吡唑[1,5-a]哌嗪-5(4H)-酸叔丁酯3b(557mg,1.60mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(119mg,0.16mmol)和Na2CO3(285mg,2.69mmol),得到的混合物在100℃搅拌12h。LCMS监控反应结束,冷却至室温,反应混合物中加入200mL食盐水,用乙酸乙酯(200mL)萃取,萃取后的有机相用Na2SO4干燥过滤后减压浓缩后得到的粗产品通过柱层析(SiO2,石油醚:乙酸乙酯=1:1)分离纯化得到白色固体化合物(4-{7H-吡咯[2,3-d]嘧啶-5-羧酸乙酯-4基}-4H,6H,7H-吡唑[1,5-a]哌嗪-5基)碳酸叔丁酯3c(110mg,收率20.42%)。LCMS(ESI)m/z 413.2[M+H]+.
步骤2:在圆底烧瓶中加入(4-{7H-吡咯[2,3-d]嘧啶-4-y基-5-羧酸乙酯}-4H,6H,7H-吡唑[1,5-a]哌嗪-5-基)碳酸叔丁酯3c(110mg,0.27mmol)和HCl的1,4-二氧六环溶液(1mol/L,10mL)的0℃搅拌2h,LCMS监控反应结束。减压浓缩后得到的粗产品通过柱层析(SiO2,石油醚:乙酸乙酯=1:9)分离纯化得到白色固体化合物4-(4,5,6,7-四氢吡唑[1,5-a]哌嗪-3-基)-7H-吡咯[2,3-d]嘧啶-5-羧酸乙酯3d(64mg,收率76.83%)。
LCMS(ESI)m/z=313.1[M+H]+.
步骤3:用二氯甲烷(15mL)将化合物4-(4,5,6,7-四氢吡唑[1,5-a]哌嗪-3-基)-7H-吡咯[2,3-d]嘧啶-5-羧酸乙酯3d(64mg,0.20mmol)溶解到反应瓶中,往反应体系中加入二异丙基乙胺(52mg,0.40mmol)冷却到-78℃,滴加丙烯酰氯(20mg,0.22mmol)。物料加完后,体系在-78℃下搅拌1小时。LCMS监控反应结束。反应混合物中加入20mL饱和NaHCO3,用乙酸乙酯(50mLX3)萃取,萃取后的有机相用Na2SO4干燥过滤后减压浓缩后得到的粗产品减压浓缩后得到的粗产品通过薄层层析板制备(乙酸乙酯)纯化得到白色固体化合物4-(5-丙烯酰-4,5,6,7-四氢吡唑[1,5-a]哌嗪-3-基)-7H-吡咯[2,3-d]嘧啶-5-羧酸乙酯化合物3(7mg,收率9.32%)。
LCMS(ESI)m/z 367.4[M+H]+.
1H NMR(400MHz,DMSO-d6)δ=12.83(s,1H),9.19–9.14(m,2H),9.12(s,1H),8.86(s,1H),8.41(s,1H),8.24(s,1H),5.98(s,1H),5.55(s,1H),4.03(t,J=6.8,2H),2.95(t,J=6.7,2H),1.49(s,9H).
实施例4:4-(5-丙烯酰-4,5,6,7-四氢吡唑[1,5-a]哌嗪-3-基)-7H-吡咯[2,3-d]嘧啶-5-(2,2-二氟环丙基)化合物4的制备参照下面的步骤合成和化合物4:
步骤1:将4-氯-7H-吡咯并[2,3-d]嘧啶-5-甲醛4a(3.5g,45.82mmol)溶于N,N-二甲基甲酰胺(40mL)中,并在冰浴条件下加入氢化钠(0.56g,0.024mol),然后缓慢加入2-(三甲基硅基)乙氧基甲基氯(4.83g,0.029mol)。反应液于25℃反应2小时。LCMS检测反应完成,向反应液中加入水,用乙酸乙酯萃取。有机相合并,饱和食盐水洗涤,无水硫酸钠干燥并浓缩。将得到的残留物用硅胶柱[石油醚/乙酸乙酯=3/1]纯化后得到4-氯-7-((2-(三甲基硅基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-5-氨基甲醛4b(3.0g,黄色固体),收率:45%。LCMS(ESI)[M+H]+m/z 312.
步骤2:将甲基三苯基溴化膦(1145mg,3.21mmol)溶于甲苯(15mL),然后在冰浴条件下加入叔丁醇钾(359mg,3.21mmol),氮气保护下,接着在0℃搅拌30分钟。再次将4-氯-7-((2-(三甲基硅基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-5-氨基甲醛4b(500mg,1.6mmol)加到反应体系中并搅拌2小时。LCMS检测反应完成,将溶剂旋干,再向反应液中加入水,用二氯甲烷萃取。有机相合并,饱和食盐水洗涤,无水硫酸钠干燥并浓缩。将得到的残留物用硅胶柱[石油醚/乙酸乙酯=4/1]纯化后得到4-氯-5-乙烯基-7-{[2-(三甲基硅基)乙氧基]甲基}吡咯[2,3-d]嘧啶4c(150mg,白色固体),收率:27%。LCMS(ESI)[M+H]+m/z 310.
步骤3:将4-氯-5-乙烯基-7-{[2-(三甲基硅基)乙氧基]甲基}吡咯[2,3-d]嘧啶4c(500mg,1.6mmol)溶于乙腈(10mL),然后加入碘化钠(723mg,4.8mmol)和三氟甲基三甲基硅烷(686mg,4.8mmol)。氮气保护下,110℃搅拌1小时。LCMS检测反应完成,将溶剂旋干,再向反应液中加入水,用二氯甲烷萃取。有机相合并,饱和食盐水洗涤,无水硫酸钠干燥并浓缩。将得到的残留物用硅胶柱[石油醚/乙酸乙酯=4/1]纯化后得到4-氯-5-(2,2-二氟环丙基)-7-((2-(三甲基硅基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶4d(400mg,黄色固体),收率:62%。LCMS(ESI)[M+H]+m/z 360.
步骤4:将4-氯-5-(2,2-二氟环丙基)-7-((2-(三甲基硅基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶4d(300mg,0.83mmol)溶于(10mL)1.4-二氧六环跟水4:1混合溶剂中,然后加入二(二苯基膦)二茂铁二氯化钯(121mg,0.16mmol),碳酸钾(172mg,1.25mmol)和叔丁基[3-(4,4,5,5-四甲基-1,3,2-二氧代苯并呋喃-2-基)-4H,6H,7H-吡唑并[1,5-a]吡嗪-5-基]甲酸酯4f(320mg,0.91mmol)。氮气保护下,110℃搅拌8小时。LCMS检测反应完成,将溶剂旋干,再向反应液中加入水,用乙酸乙酯萃取。有机相合并,饱和食盐水洗涤,无水硫酸钠干燥并浓缩。将得到的残留物用硅胶柱[石油醚/乙酸乙酯=1/1]纯化后得到叔丁基3-(5-(2,2-二氟环丙基)-7-((2-(三甲基硅基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)-6,7-二氢吡唑并[1,5-a]吡嗪-5(4H)-羧酸盐4g(150mg,黄色固体),收率:30%。LCMS(ESI)[M+H]+m/z 547.
步骤5:将叔丁基3-(5-(2,2-二氟环丙基)-7-((2-(三甲基硅基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)-6,7-二氢吡唑并[1,5-a]吡嗪-5(4H)-羧酸盐4g(150mg,0.27mmol)溶于(4mL)二氯甲烷,然后滴加(1mL)三氟乙酸,室温下搅拌2小时。反应结束后,将溶剂旋干得到粗产品,将粗产品溶于(1mL)甲醇,然后滴加(1mL)氨水溶液。室温下搅拌30分钟。LCMS检测反应完成,将溶剂旋干得到粗产品5-(2,2-二氟环丙基)-4-(4,5,6,7-四氢吡唑并[1,5-a]吡嗪-3-基)-7H-吡咯并[2,3-d]嘧啶4h(70mg,黄色固体),收率:48%。LCMS(ESI)[M+H]+m/z 317.
步骤6:将5-(2,2-二氟环丙基)-4-(4,5,6,7-四氢吡唑并[1,5-a]吡嗪-3-基)-7H-吡咯并[2,3-d]嘧啶4h(70mg,0.22mmol)溶于(4mL)二氯甲烷,并在-78℃下加入N、N-二异丙基乙胺(42.9mg,0.33mmol)。然后将丙烯酰氯(20mg,0.22mmol)缓慢加入。氮气保护下,-78℃搅拌30分钟。LCMS检测反应完成,将溶剂旋干得到粗产品,将得到的残留物用反相柱[45%乙腈/水(0.05%甲酸)]纯化得到化合物4 1-{3-[5-(2,2-二氟环丙基)-7H-吡咯并[2,3-d]嘧啶-4-基]-4H,6H,7H-吡唑并[1,5-a]吡嗪-5-基]丙-2-烯-1-酮(10.56mg,白色固体),收率:12%。LCMS(ESI)[M+H]+m/z 371.1H NMR(400MHz,DMSO-d6)δ12.19(s,1H),8.73(s,1H),7.97(s,1H),7.53(s,1H),6.99–6.78(m,1H),6.18(d,J=16.8Hz,1H),5.78(d,J=10.4Hz,1H),5.20–5.04(m,2H),4.40–4.09(m,4H),3.06–2.94(m,1H),1.89–1.77(m,2H).HPLC:214nm(93.2%),254nm(93.2%).
实施例5:2-氟-1-(3-(5-(氧杂环丁烷-3-乙炔基)-7H-吡咯并[2,3-d]嘧啶-4-基)-6,7-二氢吡唑并[1,5-a]吡嗪-5(4H)-基)丙-2-烯-1-酮化合物5的制备
参照下面的步骤合成和化合物5:
步骤1:在氮气气氛下,将4-{5-[(叔丁氧基)羰基]-4H,6H,7H-吡唑并[1,5-a]吡嗪-3-基}-5-碘吡咯并[2,3-d]嘧啶-7-羧酸叔丁酯5a(200mg,0.35mmol)溶于四氢呋喃(4mL)中,依次加入dppf Pd G3(200mg,0.35mmol),碘化亚铜(13mg,0.07mmol),dppf(20mg,0.035mmol),3-乙炔基氧杂环丁烷5b(116mg,1.41mmol)和三乙胺(1mL),反应液在25℃下搅拌3小时。将溶剂旋干,浓缩得到的残留物用硅胶柱(石油醚/乙酸乙酯=1/1)纯化得到标题产物4-(5-(叔丁氧羰基)-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-3-基)-5-(氧杂环丁烷-3-乙炔基)-7H-吡咯并[2,3-d]嘧啶-7-羧酸叔丁酯5c(50mg,收率:26%),白色固体。LCMS(ESI)[M+H]+m/z 521.
步骤2:将4-(5-(叔丁氧羰基)-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-3-基)-5-(氧杂环丁烷-3-乙炔基)-7H-吡咯并[2,3-d]嘧啶-7-羧酸叔丁酯5c(50mg,0.1mmol)溶于二氯甲烷(1mL)中,在冰水浴下加入三氟乙酸(0.5mL)。反应液在0℃下搅拌2小时。将溶剂旋干得到标题产物5-(氧杂环丁烷-3-乙炔基)-4-{4H,5H,6H,7H-吡唑并[1,5-a]吡嗪-3-基}-7H-吡咯并[2,3-d]嘧啶5d(30mg,收率:88%),白色固体。LCMS(ESI)[M+H]+m/z 321.
步骤3:在氮气气氛下,将5-(氧杂环丁烷-3-乙炔基)-4-{4H,5H,6H,7H-吡唑并[1,5-a]吡嗪-3-基}-7H-吡咯并[2,3-d]嘧啶5d(30mg,0.1mmol)溶于DMF(3mL)中,依次加入N-(3-二甲氨基丙基)-N’-乙基碳化二亚胺盐酸盐(20mg,0.1mmol),1-羟基苯并三唑(14mg,0.1mmol),N、N-二异丙基乙胺(48mg,0.4mmol)和二氟丙烯酸(8mg,0.1mmol),25℃条件下,搅拌16小时。。将溶剂旋干,浓缩得到的残留物用反相柱(乙腈/水=2/3,0.1%甲酸)纯化得到产物5 2-氟-1-(3-(5-(氧杂环丁烷-3-乙炔基)-7H-吡咯并[2,3-d]嘧啶-4-基)-6,7-二氢吡唑并[1,5-a]吡嗪-5(4H)-基)丙-2-烯-1-酮化合物5(5.03mg,收率:12.29%),白色固体。LCMS(ESI)[M+H]+m/z 393.
参照上述合成方法合成下面表1中的化合物。
表1.
实施例6:激酶抑制活性的测定
将四种LanthaScreen JAK生物化学分析的组(JAK1、2、3和Tyk2)载于常见激酶反应缓冲液(50mM HEPES,pH 7.5,0.01%Brij-35,10mM MgCl2,和1mM EGTA)中。重组GST标记
的JAK酶和GFP标记的STAT1肽底物获自Life Technologies。
使连续稀释的化合物与四种JAK酶中的每一者和底物在白色384孔微量培养板(Corning)中一起在环境温度下预培育1小时。随后添加总体积为10μL、具有1%DMSO的ATP以引发激酶反应。JAK1、2、3和Tyk2的最终酶浓度分别是1nM、0.1nM、0.1nM和0.25nM;所用的相应Km ATP浓度是25μM、3μM、1.6μM和10μM;而用于所有四个分析的底物浓度均是200nM。在环境温度下使激酶反应进行1小时,之后加入EDTA(10mM最终浓度)和Tb抗pSTAT1(pTyr701)抗体(Life Technologies,2nM最终浓度)于TRFRET稀释缓冲液(Life Technologies)中的10μL制剂。在环境温度下将培养板培育1小时,之后在EnVision读取器(Perkin Elmer)上读取。记录且使用发射比信号(520nm/495nm),以基于DMSO和背景对照计算抑制百分比值。
对于剂量反应分析,相较于化合物浓度绘制抑制百分比数据,且用Prism软件(GraphPad Software)、利用4参数稳固拟合模型测定IC50值。在测试化合物滴定并导致肽产物形成抑制的情况下,这些数据拟合产生最佳拟合IC50值。
化合物抑制率(%inh)=(阴性对照平均值-化合物)/(阴性对照平均值-阳性对照平均值)*100%阴性对照:空白DMSO
阳性对照:托法替尼(JAK1,2,3);BMS-986165(TYK2)
b)利用以下非线性拟合公式来得到化合物的IC50(半数抑制浓度):
Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))
X:化合物浓度log值
Y:化合物抑制率(%inh)
这些测定的结果如下表1所示,其中“A”代表计算的IC50小于1nM;“B”表示计算的IC50为1nM至小于100nM;“C”表示计算的IC50为100nM至小于1μM;“D”表示计算的IC50大于或等于1μM,“NT”表示未在指定的测定中测试指定的化合物。
表2..本发明选择的化合物对JAK1、JAK2、JAK3和TYK2的抑制活性
以上的结果表明本发明的化合物对JAK3具有良好的选择性抑制作用。
Claims (9)
1.一种具有式I所示结构的化合物、其对映异构体或非对映异构体或其混合物、其药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物、结晶形式或前药,
其中,Y1独立地选自N或CR1,其中所述R1进一步任选自:氢、氘、卤素、氰基、氨基羰基、(C1-C6线性或支链烷基)氨基羰基、C1-C4烷基、C6-C10芳基、包含5-和/或6-元环的单环或双环杂芳基、(芳基)C1-C6线性或支链烷基、(杂芳基)C1-C6线性或支链烷基、(杂环基)C1-C6线性或支链烷基、(C1-C6线性或支链烷基)芳基、(C1-C6线性或支链烷基)杂芳基或(C1-C6线性或支链烷基)杂环基,其中所述烷基进一步任选地被选自下列的一个或多个取代基取代:卤素、羟基、甲氧基、氨基、CF3和C3-C6环烷基;
R0独立地选自氢、氘、氟、氯、氰基、C1-C8炔基、C1-C8卤代炔基、C1-C6线性或支链烷基、C1-C6线性或支链烷氧基亚甲基、卤代C1-C6线性或支链烷氧基亚甲基、C1-C6线性或支链烷氧基二氟亚甲基、卤代C1-C6线性或支链烷氧基二氟亚甲基、C1-C6线性或支链烷氧基氟代亚甲基、卤代C1-C6线性或支链烷氧基氟代亚甲基、C3-C6环烷基、C3-C6烷基取代环烷基、C3-C6卤素取代环烷基、C6-C10芳基、包含5-和/或6-元环的单环或双环杂芳基、(芳基)C1-C6线性或支链烷基、(杂芳基)C1-C6线性或支链烷基、(杂环基)C1-C6线性或支链烷基、(C1-C6线性或支链烷基)芳基、(C1-C6线性或支链烷基)杂芳基、(C1-C6线性或支链烷基)杂环基、C1-C6线性或支链全氟烷基、C1-C6线性或支链烷氧基、C1-C6线性或支链全氟烷氧基、异丙基羰基、叔丁基羰基、氨基、羧基、氨基羰基、(C1-C6线性或支链烷基)氨基羰基氨基、(C1-C6线性或支链烷基)氨基羰基、乙氧基羰基、异丙氧基羰基、异丁氧基羰基;其中所述烷基、芳基和杂芳基独立任选地被选自下列的一个或多个取代基取代:烷基、卤素、羟基、甲氧基、氨基、氰基、烷基氨基、二烷基氨基、CF3、氨基羰基、(C1-C6线性或支链烷基)氨基羰基和C3-C6环烷基;其中,R1独立地选自下面结构的一种:
R2,R3和R4各自独立地选自氢、氘、C1-C3烷基、C1-C3卤代烷基、环丙基、C1-C3烷氧基、氟原子、C1-C3卤代烷氧基;
X1和X2独立地选自N或CH。
2.根据权利要求1所述的化合物、其对映异构体或非对映异构体或其混合物、其药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物、结晶形式或前药,其特征在于:当X1为CH,X2为N时,具有如下式II所示结构:
其中Y1独立地选自N或CR1,其中所述R1进一步任选自:氢、氘、卤素、氰基、氨基羰基、(C1-C6线性或支链烷基)氨基羰基、C1-C4烷基、C6-C10芳基、包含5-和/或6-元环的单环或双环杂芳基、(芳基)C1-C6线性或支链烷基、(杂芳基)C1-C6线性或支链烷基、(杂环基)C1-C6线性或支链烷基、(C1-C6线性或支链烷基)芳基、(C1-C6线性或支链烷基)杂芳基或(C1-C6线性或支链烷基)杂环基,其中所述烷基进一步任选地被选自下列的一个或多个取代基取代:卤素、羟基、甲氧基、氨基、CF3和C3-C6环烷基;
R0独立地选自氢、氘、氟、氯、氰基、C1-C8炔基、C1-C8卤代炔基、C1-C6线性或支链烷基、C1-C6线性或支链烷氧基亚甲基、卤代C1-C6线性或支链烷氧基亚甲基、C1-C6线性或支链烷氧基二氟亚甲基、卤代C1-C6线性或支链烷氧基二氟亚甲基、C1-C6线性或支链烷氧基氟代亚甲基、卤代C1-C6线性或支链烷氧基氟代亚甲基、C3-C6环烷基、C3-C6烷基取代环烷基、C3-C6卤素取代环烷基、C6-C10芳基、包含5-和/或6-元环的单环或双环杂芳基、(芳基)C1-C6线性或支链烷基、(杂芳基)C1-C6线性或支链烷基、(杂环基)C1-C6线性或支链烷基、(C1-C6线性或支链烷基)芳基、(C1-C6线性或支链烷基)杂芳基、(C1-C6线性或支链烷基)杂环基、C1-C6线性或支链全氟烷基、C1-C6线性或支链烷氧基、C1-C6线性或支链全氟烷氧基、异丙基羰基、叔丁基羰基、氨基、羧基、氨基羰基、(C1-C6线性或支链烷基)氨基羰基氨基、(C1-C6线性或支链烷基)氨基羰基、乙氧基羰基、异丙氧基羰基、异丁氧基羰基;其中所述烷基、芳基和杂芳基独立任选地被选自下列的一个或多个取代基取代:烷基、卤素、羟基、甲氧基、氨基、氰基、烷基氨基、二烷基氨基、CF3、氨基羰基、(C1-C6线性或支链烷基)氨基羰基和C3-C6环烷基;
其中,R1独立地选自下面结构的一种:
R2,R3和R4各自独立地选自氢、氘、C1-C3烷基、C1-C3卤代烷基、环丙基、C1-C3烷氧基、氟原子、C1-C3卤代烷氧基。
3.根据权利要求1所述的化合物、其对映异构体或非对映异构体或其混合物、其药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物、结晶形式或前药,其特征在于:当X1和X2均为N时,具有如下式III所示结构:
其中Y1独立地选自N或CR1,其中所述R1进一步任选自:氢、氘、卤素、氰基、氨基羰基、(C1-C6线性或支链烷基)氨基羰基、C1-C4烷基、C6-C10芳基、包含5-和/或6-元环的单环或双环杂芳基、(芳基)C1-C6线性或支链烷基、(杂芳基)C1-C6线性或支链烷基、(杂环基)C1-C6线性或支链烷基、(C1-C6线性或支链烷基)芳基、(C1-C6线性或支链烷基)杂芳基或(C1-C6线性或支链烷基)杂环基,其中所述烷基进一步任选地被选自下列的一个或多个取代基取代:卤素、羟基、甲氧基、氨基、CF3和C3-C6环烷基;
R0独立地选自氢、氘、氟、氯、氰基、C1-C8炔基、C1-C8卤代炔基、C1-C6线性或支链烷基、C1-C6线性或支链烷氧基亚甲基、卤代C1-C6线性或支链烷氧基亚甲基、C1-C6线性或支链烷氧基二氟亚甲基、卤代C1-C6线性或支链烷氧基二氟亚甲基、C1-C6线性或支链烷氧基氟代亚甲基、卤代C1-C6线性或支链烷氧基氟代亚甲基、C3-C6环烷基、C3-C6烷基取代环烷基、C3-C6卤素取代环烷基、C6-C10芳基、包含5-和/或6-元环的单环或双环杂芳基、(芳基)C1-C6线性或支链烷基、(杂芳基)C1-C6线性或支链烷基、(杂环基)C1-C6线性或支链烷基、(C1-C6线性或支链烷基)芳基、(C1-C6线性或支链烷基)杂芳基、(C1-C6线性或支链烷基)杂环基、C1-C6线性或支链全氟烷基、C1-C6线性或支链烷氧基、C1-C6线性或支链全氟烷氧基、异丙基羰基、叔丁基羰基、氨基、羧基、氨基羰基、(C1-C6线性或支链烷基)氨基羰基氨基、(C1-C6线性或支链烷基)氨基羰基、乙氧基羰基、异丙氧基羰基、异丁氧基羰基;其中所述烷基、芳基和杂芳基独立任选地被选自下列的一个或多个取代基取代:烷基、卤素、羟基、甲氧基、氨基、氰基、烷基氨基、二烷基氨基、CF3、氨基羰基、(C1-C6线性或支链烷基)氨基羰基和C3-C6环烷基;
其中,R1独立地选自下面结构的一种:
R2,R3和R4各自独立地选自氢、氘、C1-C3烷基、C1-C3卤代烷基、环丙基、C1-C3烷氧基、氟原子、C1-C3卤代烷氧基。
4.根据权利要求1所述的化合物,其特征在于:当X1选自CH,X2选自N时,所述化合物具有如下式IV所示结构:
其中Y1独立地选自N或CR1,其中所述R1进一步任选自:氢、氘、卤素、氰基、氨基羰基、(C1-C6线性或支链烷基)氨基羰基、C1-C4烷基、C6-C10芳基、包含5-和/或6-元环的单环或双环杂芳基、(芳基)C1-C6线性或支链烷基、(杂芳基)C1-C6线性或支链烷基、(杂环基)C1-C6线性或支链烷基、(C1-C6线性或支链烷基)芳基、(C1-C6线性或支链烷基)杂芳基或(C1-C6线性或支链烷基)杂环基,其中所述烷基进一步任选地被选自下列的一个或多个取代基取代:卤素、羟基、甲氧基、氨基、CF3和C3-C6环烷基;
R0独立地选自氢、氘、氟、氯、氰基、C1-C8炔基、C1-C8卤代炔基、C1-C6线性或支链烷基、C1-C6线性或支链烷氧基亚甲基、卤代C1-C6线性或支链烷氧基亚甲基、C1-C6线性或支链烷氧基二氟亚甲基、卤代C1-C6线性或支链烷氧基二氟亚甲基、C1-C6线性或支链烷氧基氟代亚甲基、卤代C1-C6线性或支链烷氧基氟代亚甲基、C3-C6环烷基、C3-C6烷基取代环烷基、C3-C6卤素取代环烷基、C6-C10芳基、包含5-和/或6-元环的单环或双环杂芳基、(芳基)C1-C6线性或支链烷基、(杂芳基)C1-C6线性或支链烷基、(杂环基)C1-C6线性或支链烷基、(C1-C6线性或支链烷基)芳基、(C1-C6线性或支链烷基)杂芳基、(C1-C6线性或支链烷基)杂环基、C1-C6线性或支链全氟烷基、C1-C6线性或支链烷氧基、C1-C6线性或支链全氟烷氧基、异丙基羰基、叔丁基羰基、氨基、羧基、氨基羰基、(C1-C6线性或支链烷基)氨基羰基氨基、(C1-C6线性或支链烷基)氨基羰基、乙氧基羰基、异丙氧基羰基、异丁氧基羰基;其中所述烷基、芳基和杂芳基独立任选地被选自下列的一个或多个取代基取代:烷基、卤素、羟基、甲氧基、氨基、氰基、烷基氨基、二烷基氨基、CF3、氨基羰基、(C1-C6线性或支链烷基)氨基羰基和C3-C6环烷基;
其中,R1独立地选自下面结构的一种:
R2,R3和R4各自独立地选自氢、氘、C1-C3烷基、C1-C3卤代烷基、环丙基、C1-C3烷氧基、氟原子、C1-C3卤代烷氧基。
6.一种药物组合物,其特征在于:所述药物组合物包含如权利要求1至5中任一项所述的化合物、其对映异构体或非对映异构体或其混合物、其药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物、结晶形式或前药,以及药学上可接受的辅料、稀释剂或载体。
7.根据权利要求1-5中任意一项所述的化合物、其对映异构体或非对映异构体或其混合物、其药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物、结晶形式或前药或者根据权利要求6所述的药物组合物在制备用于治疗或预防病症或病况的药物中的用途,所述病症或病况选自炎性肠病、直肠炎、嗜酸细胞性胃肠炎或肥大细胞增多症、类风湿性关节炎、肌炎、血管炎、天疱疮、大疱性类天疱疮、狼疮、肾炎、系统性红斑狼疮、银屑病、湿疹皮炎、瘙痒症或其它瘙痒病况、白癜风、脱发、自身免疫性甲状腺病、多发性硬化、哮喘、干燥病、系统性硬化病、结节性多动脉炎、干眼综合征、交感性眼炎、器官移植排斥、移植物抗宿主病、自身免疫性脱发慢性阻塞性肺病、急性呼吸道疾病和眼疾病、病症或病况。
8.根据权利要求7所述的用途,其特征在于:所述炎性肠病为克罗恩氏病或溃疡性结肠炎。
9.根据权利要求7所述的用途,其特征在于:所述眼疾病、病症或病况为眼的自身免疫疾病、角膜结膜炎、春季结膜炎、与贝切特氏病相关的葡萄膜炎和晶状体诱发性葡萄膜炎、角膜炎、疱疹性角膜炎、圆锥形角膜炎、角膜白斑、眼天疱疮、干燥性角膜结膜炎、虹膜睫状体炎、结节病、内分泌性眼病、交感性眼炎或变应性结膜炎。
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