CN104105697A - 二环哌嗪化合物 - Google Patents
二环哌嗪化合物 Download PDFInfo
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- CN104105697A CN104105697A CN201280065858.5A CN201280065858A CN104105697A CN 104105697 A CN104105697 A CN 104105697A CN 201280065858 A CN201280065858 A CN 201280065858A CN 104105697 A CN104105697 A CN 104105697A
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Abstract
本发明提供式(I)的二环哌嗪化合物,包括其立体异构体、互变异构体和药用盐,其用于抑制Btk激酶,并用于治疗免疫病症例如由Btk激酶介导的炎症。本发明公开使用式I化合物用于体外、原位和体内诊断以及治疗哺乳动物细胞中的所述病症或相关的病理状态的方法。
Description
相关申请的交叉引用
根据37CFR§1.53(b)提交的该非临时申请,根据35USC§119(e)要求于2011年11月3日提交的美国临时申请61/555,396的权益,本申请将其全部内容通过引用的方式并入本申请。
技术领域
本发明大体上涉及用于治疗由Bruton酪氨酸激酶(Btk)介导的病症包括炎症、免疫性病症和癌症的化合物,更具体地涉及抑制Btk活性的化合物。本发明还涉及使用所述化合物引用体外、原位及体内诊断或治疗哺乳动物细胞或相关病理状态的方法。
背景技术
蛋白激酶是最大的人类酶家族,包括超过500种蛋白质。Bruton酪氨酸激酶(Btk)是酪氨酸激酶中的Tec家族的成员,并且是早期B细胞发育及成熟B细胞活化、信号转导和存活的调节剂。
经B细胞受体(BCR)的B细胞信号转导能产生广泛的生物学输出信号,而所述信号转而取决于B细胞的发育阶段。BCR信号的强度和持续时间必须被精确地调节。异常的BCR介导的信号转导能造成失调的B细胞活化和/或形成导致多种自身免疫疾病和/或炎性疾病的致病性自身抗体。人体内Btk的突变导致X连锁无γ球蛋白血症(XLA)。这种疾病与B细胞成熟受损、免疫球蛋白产生减少、不依赖T细胞的免疫应答受损以及在BCR刺激时持续的钙信号的显著减弱有关。Btk在变态反应性疾病和/或自身免疫疾病和/或炎性疾病中起作用的证据已经在Btk-缺陷小鼠模型中得到确定。例如,在系统性红斑狼疮(SLE)的标准鼠类临床前模型中,已经表明Btk缺陷引起疾病进展的明显改善。而且,Btk缺陷小鼠还能抵抗形成胶原诱发性关节炎并能对葡萄球菌诱发性关节炎更不易感。大量的证据支持B细胞和体液免疫系统在自身免疫疾病和/或炎性疾病的发病机制中的作用。已开发的为了耗竭B细胞的基于蛋白质的治疗剂(诸如Rituxan)代表治疗许多自身免疫疾病和/或炎性疾病的方法。由于Btk在B细胞活化中的作用,Btk抑制剂可以被用作B细胞介导的致病性活动(例如产生自身抗体)的抑制剂。Btk也在破骨细胞、肥大细胞和单核细胞中表达,并且显示其对于这些细胞的功能很重要。例如,小鼠Btk缺陷与IgE介导的肥大细胞活化受损(显著减少TNF-α及其它炎性细胞因子的释放)有关,并且人Btk缺陷与由激活的单核细胞产生TNF-α大大减少有关。
因此,抑制Btk活性可以用于治疗变态反应性病症和/或自身免疫疾病和/或炎性疾病,例如:SLE、类风湿性关节炎、多血管炎、特发性血小板减少性紫癜(ITP)、重症肌无力、变应性鼻炎和哮喘(Di Paolo等人(2011)NatureChem.Biol.7(1):41-50;Liu等人(2011)Jour.of Pharm.and Exper.Ther.338(1):154-163)。此外,据报道,Btk在细胞凋亡中起作用;因此,抑制Btk活性可用于癌症以及治疗B细胞淋巴瘤、白血病和其它血液恶性肿瘤。而且,考虑到Btk在破骨细胞功能方面的作用,抑制Btk活性可用于治疗骨病例如骨质疏松。特定Btk抑制剂已被报道(Liu(2011)Drug Metab.and Disposition39(10):1840-1849;US7884108,WO2010/056875;US7405295;US7393848;WO2006/053121;US7947835;US2008/0139557;US7838523;US2008/0125417;US2011/0118233;2011年8月31日提交的PCT/US2011/050034“PYRIDINONES/PYRAZINONES,METHOD OFMAKING,AND METHOD OF USE THEREOF”;2011年8月31日提交的PCT/US2011/050013“PYRIDAZINONES,METHOD OF MAKING,ANDMETHOD OF USE THEREOF”;2011年5月6日提交的US序列号13/102720“PYRIDONE AND AZA-PYRIDONE COMPOUNDS AND METHODS OFUSE”)。
发明内容
本发明大体上涉及具有Bruton酪氨酸激酶(Btk)调节活性的式I的二环哌嗪化合物。
式I化合物具有以下结构:
包括其立体异构体、互变异构体或药用盐。各种取代基的定义如下。
本发明的一方面是药物组合物,其包含式I化合物以及药用载体、助流剂、稀释剂或赋形剂。所述药物组合物可进一步包含第二治疗剂。
本发明的另一方面是制备药物组合物的方法,其包括将式I化合物与药用载体混合。
本发明包括治疗疾病或病症的方法,所述方法包括向患有疾病或病症的患者给药治疗有效量的式I化合物,所述疾病或病症选自免疫病症、癌症、心血管疾病、病毒感染、炎症、代谢/内分泌功能障碍和神经障碍,并由Bruton酪氨酸激酶介导。
本发明包括用于治疗由Bruton酪氨酸激酶介导的病症的试剂盒,其包含:a)包含式I化合物的第一药物组合物;和b)使用说明书。
本发明包括式I化合物,其用作药物并且用于治疗疾病或病症,所述疾病或病症选自免疫病症、癌症、心血管疾病、病毒感染、炎症、代谢/内分泌功能障碍和神经障碍,并由Bruton酪氨酸激酶介导。
本发明包括式I化合物在制备用于治疗免疫病症、癌症、心血管疾病、病毒感染、炎症、代谢/内分泌功能障碍和神经障碍的药物中的用途,并且其中所述药物调节Bruton酪氨酸激酶。
本发明包括制备式I化合物的方法。
附图说明
图1a显示由6-氯-8-溴咪唑并[1,2-a]吡啶101a起始制备2-(5-氟-2-(羟基甲基)-3-(8-(5-(4-甲基哌嗪-1-基)吡啶-2-基氨基)咪唑并[1,2-a]吡啶-6-基)苯基)-3,4,6,7,8,9-六氢吡嗪并[1,2-a]吲哚-1(2H)-酮101。
图1b显示由3,4,6,7,8,9-六氢吡嗪并[1,2-a]吲哚-1(2H)-酮101g和乙酸2,6-二溴-4-氟苄酯101j起始制备乙酸4-氟-2-(1-氧代-3,4,6,7,8,9-六氢吡嗪并[1,2-a]吲哚-2(1H)-基)-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苄酯101l。
图2显示由4-(6-(6-氯咪唑并[1,2-a]吡啶-8-基氨基)吡啶-3-基)哌嗪-1-羧酸叔丁酯102a起始制备2-(5-氟-2-(羟基甲基)-3-(8-(5-(4-(氧杂环丁烷-3-基)哌嗪-1-基)吡啶-2-基氨基)咪唑并[1,2-a]吡啶-6-基)苯基)-3,4,6,7,8,9-六氢-吡嗪并[1,2-a]吲哚-1(2H)-酮102。
图3显示由乙酸2-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-4-氟-6-(1-氧代-3,4,5,6,7,8-六氢苯并噻吩并[2,3-c]吡啶-2(1H)-基)苄酯103g起始制备5-[5-氟-2-(羟基甲基)-3-{(8-(5-(4-甲基哌嗪-1-基)吡啶-2-基氨基)咪唑并[1,2-a]吡啶-6-基)}苯基]-8-硫杂-5-氮杂三环[7.4.0.02,7]十三碳-1(9),2(7)-二烯-6-酮103。
图4显示由8-溴-6-氯咪唑并[1,2-b]哒嗪104a起始制备2-(5-氟-2-(羟基甲基)-3-(8-(5-(4-甲基哌嗪-1-基)吡啶-2-基氨基)咪唑并[1,2-b]哒嗪-6-基)苯基)-3,4,6,7,8,9-六氢吡嗪并[1,2-a]吲哚-1(2H)-酮104。
图5显示由6-氯-N-(5-(4-(氧杂环丁烷-3-基)哌嗪-1-基)吡啶-2-基)咪唑并[1,2-b]哒嗪-8-胺105a起始制备2-(5-氟-2-(羟基甲基)-3-(8-(5-(4-(氧杂环丁烷-3-基)哌嗪-1-基)吡啶-2-基氨基)咪唑并[1,2-b]哒嗪-6-基)苯基)-3,4,6,7,8,9-六氢-吡嗪并[1,2-a]吲哚-1(2H)-酮105。
图6显示由4-(6-(6-溴咪唑并[1,2-a]吡嗪-8-基氨基)吡啶-3-基)哌嗪-1-羧酸叔丁酯106a起始制备2-(5-氟-2-(羟基甲基)-3-(8-(5-(4-甲基哌嗪-1-基)吡啶-2-基氨基)咪唑并[1,2-a]吡嗪-6-基)苯基)-3,4,6,7,8,9-六氢吡嗪并[1,2-a]吲哚-1(2H)-酮106。
图7显示由2-(5-氟-3-(8-(5-(4-(氧杂环丁烷-3-基)哌嗪-1-基)吡啶-2-基氨基)-咪唑并[1,2-a]吡嗪-6-基)-2-(2-氧代丙基)苯基)-3,4,6,7,8,9-六氢吡嗪并[1,2-a]吲哚-1(2H)-酮107a起始制备2-(5-氟-2-(羟基甲基)-3-(8-(5-(4-(氧杂环丁烷-3-基)哌嗪-1-基)吡啶-2-基氨基)咪唑并[1,2-a]吡嗪-6-基)苯基)-3,4,6,7,8,9-六氢-吡嗪并[1,2-a]吲哚-1(2H)-酮107。
图8显示由(E)-N'-(3-溴-5-氯吡啶-2-基)-N,N-二甲基甲脒108a起始制备2-(5-氟-2-(羟基甲基)-3-(8-(5-(4-(氧杂环丁烷-3-基)哌嗪-1-基)吡啶-2-基氨基)-[1,2,4]三唑并[1,5-a]吡啶-6-基)苯基)-3,4,6,7,8,9-六氢吡嗪并[1,2-a]吲哚-1(2H)-酮108。
图9显示由2-溴-4-氯-6-硝基苯胺109a起始制备2-(5-氟-2-(羟基甲基)-3-(3-甲基-7-(5-(4-(氧杂环丁烷-3-基)哌嗪-1-基)吡啶-2-基氨基)-3H-苯并[d]咪唑-5-基)苯基)-3,4,6,7,8,9-六氢吡嗪并[1,2-a]吲哚-1(2H)-酮109。
图10显示由乙酸2-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-4-氟-6-(9-氧代-4,4-二甲基-1,10-二氮杂三环[6.4.0.02,6]-十二碳-2(6),7-二烯-10-基)苄酯110g和6-氯-N-(5-(4-(氧杂环丁烷-3-基)哌嗪-1-基)吡啶-2-基)咪唑并[1,2-a]吡啶-8-胺起始制备10-[5-氟-2-(羟基甲基)-3-(8-(5-(4-(氧杂环丁烷-3-基)哌嗪-1-基)吡啶-2-基氨基)咪唑并[1,2-b]哒嗪-6-基)苯基]-4,4-二甲基-1,10-二氮杂三环[6.4.0.02,6]十二碳-2(6),7-二烯-9-酮110。
图11显示由乙酸(4-氟-2-{6-氧代-8-硫杂-5-氮杂三环[7.4.0.02,7]十三碳-1(9),2(7)-二烯-5-基}-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)甲酯103g和6-氯-N-(5-(4-(氧杂环丁烷-3-基)哌嗪-1-基)吡啶-2-基)咪唑并[1,2-b]哒嗪-8-胺起始制备5-[5-氟-2-(羟基甲基)-3-(8-(5-(4-(氧杂环丁烷-3-基)哌嗪-1-基)吡啶-2-基氨基)咪唑并[1,2-b]哒嗪-6-基)苯基]-8-硫杂-5-氮杂三环[7.4.0.02,7]十三碳-1(9),2(7)-二烯-6-酮111。
图12显示由乙酸(4-氟-2-{6-氧代-8-硫杂-4,5-二氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3-三烯-5-基}-6-(四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)甲酯和6-氯-N-(5-(4-(氧杂环丁烷-3-基)哌嗪-1-基)吡啶-2-基)咪唑并[1,2-b]哒嗪-8-胺起始制备5-[5-氟-2-(羟基甲基)-3-(8-(5-(4-(氧杂环丁烷-3-基)哌嗪-1-基)吡啶-2-基氨基)咪唑并[1,2-b]哒嗪-6-基)苯基]-8-硫杂-4,5-二氮杂三环-[7.4.0.02,7]十三碳-1(9),2(7),3-三烯-6-酮112。
图13显示由乙酸(2-{4,4-二甲基-9-氧代-7-硫杂-10-氮杂三环[6.4.0.02,6]十二碳-1(8),2(6)-二烯-10-基}-4-氟-6-(四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)甲酯113j和6-氯-N-(5-(4-(氧杂环丁烷-3-基)哌嗪-1-基)吡啶-2-基)咪唑并[1,2-a]吡啶-8-胺起始制备10-[5-氟-2-(羟基甲基)-3-(8-(5-(4-(氧杂环丁烷-3-基)哌嗪-1-基)吡啶-2-基氨基)咪唑并[1,2-b]哒嗪-6-基)苯基]-4,4-二甲基-7-硫杂-10-氮杂三环[6.4.0.02,6]十二碳-1(8),2(6)-二烯-9-酮113。
图14显示由乙酸(2-(1-氧代-3,4,6,7,8,9-六氢吡嗪并[1,2-a]吲哚-2(1H)-基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡啶-3-基)甲酯114e和6-氯-N-(5-(4-(氧杂环丁烷-3-基)哌嗪-1-基)吡啶-2-基)咪唑并[1,2-b]哒嗪-8-胺起始制备2-(3-(羟基甲基)-4-(8-(5-(4-(氧杂环丁烷-3-基)哌嗪-1-基)吡啶-2-基氨基)咪唑并[1,2-b]哒嗪-6-基)吡啶-2-基)-3,4,6,7,8,9-六氢吡嗪并[1,2-a]吲哚-1(2H)-酮114。
具体实施方式
现详细描述本发明的某些实施方案,其实例在随附结构和分子式中示例说明。虽然结合列举的实施方案来描述本发明,但是应理解本发明并不限于那些实施方案。相反,本发明意在涵盖可包括在本发明的由权利要求书限定的范围内的所有替代方案、修改和等效。本领域技术人员会认识到,与本申请中所述的那些相似或等同的许多方法和材料可用于实施本发明。本发明绝不限于所述的方法和材料。在所引的文献、专利及相似的材料中的一者或多者与本申请(包括但不限于定义的术语、术语用法、所述的技术等)不同或矛盾的情况下,以本申请为准。除非另外定义,否则本申请使用的所有技术和科学术语具有与本发明所属领域普通技术人员通常理解的相同含义。虽然与本申请所述类似或等效的方法和材料可用于实施或测试本发明,然而下文将描述适当的方法和材料。所有出版物、专利申请、专利以及本申请提及的其它参考文献通过引用的方式将其全部内容并入本申请。除非另外说明,否则本申请中使用的命名法是基于IUPAC系统命名法。
定义
当说明取代基数目时,术语“一个或多个”是指从一个取代基至最多可能取代基数目的范围,即,由取代基置换一个氢至置换全部氢。术语“取代基”表示在母体分子上置换氢原子的原子或原子团。术语“经取代”表示指定基团带有一个或多个取代基。当任何基团可带有多个取代基及提供各种可能取代基时,该取代基是独立选择的且无需相同。术语“未取代”是指指定基团不带有取代基。术语“任选取代”是指指定基团是未取代的或被一个或多个独立选自可能的取代基的取代基取代。当说明取代基数目时,术语“一个或多个”是指从一个取代基至最多可能取代基数目,即,由取代基置换一个氢至置换全部氢。
术语“烷基”用于本申请中是指具有1-12个碳原子(C1-C12)的饱和的直链或支链一价烃基,其中所述烷基可任选地独立地被下述一种或多种取代基取代。在另一个实施方案中,烷基具有1-8个碳原子(C1-C8),或者1-6个碳原子(C1-C6)。烷基的实例包括但不限于:甲基(Me,-CH3)、乙基(Et,-CH2CH3)、1-丙基(n-Pr,正丙基,-CH2CH2CH3)、2-丙基(i-Pr,异丙基,-CH(CH3)2)、1-丁基(n-Bu,正丁基,-CH2CH2CH2CH3)、2-甲基-1-丙基(i-Bu,异丁基,-CH2CH(CH3)2)、2-丁基(s-Bu,仲丁基,-CH(CH3)CH2CH3)、2-甲基-2-丙基(t-Bu,叔丁基,-C(CH3)3)、1-戊基(正戊基,-CH2CH2CH2CH2CH3)、2-戊基(-CH(CH3)CH2CH2CH3)、3-戊基(-CH(CH2CH3)2)、2-甲基-2-丁基(-C(CH3)2CH2CH3)、3-甲基-2-丁基(-CH(CH3)CH(CH3)2)、3-甲基-1-丁基(-CH2CH2CH(CH3)2)、2-甲基-1-丁基(-CH2CH(CH3)CH2CH3)、1-己基(-CH2CH2CH2CH2CH2CH3)、2-己基(-CH(CH3)CH2CH2CH2CH3)、3-己基(-CH(CH2CH3)(CH2CH2CH3))、2-甲基-2-戊基(-C(CH3)2CH2CH2CH3)、3-甲基-2-戊基(-CH(CH3)CH(CH3)CH2CH3)、4-甲基-2-戊基(-CH(CH3)CH2CH(CH3)2)、3-甲基-3-戊基(-C(CH3)(CH2CH3)2)、2-甲基-3-戊基(-CH(CH2CH3)CH(CH3)2)、2,3-二甲基-2-丁基(-C(CH3)2CH(CH3)2)、3,3-二甲基-2-丁基(-CH(CH3)C(CH3)3、1-庚基、1-辛基等。
术语“亚烷基”用于本申请中是指具有1-12个碳原子(C1-C12)的饱和直链或支链二价烃基,其中所述亚烷基可任选地独立地被下述一种或多种取代基取代。在另一个实施方案中,亚烷基具有1-8个碳原子(C1-C8),或者1-6个碳原子(C1-C6)。亚烷基的实例包括但不限于亚甲基(-CH2-)、亚乙基(-CH2CH2-)、亚丙基(-CH2CH2CH2-)等。
术语“烯基”是指具有2-8个碳原子(C2-C8),具有至少一个不饱和位点,即,碳-碳sp2双键的直链或支链一价烃基,其中所述烯基可任选地独立地被本申请所述的一种或多种取代基取代,并包括具有“顺式”和“反式”定向,或“E”和“Z”定向的基团。实例包括但不限于乙烯基(-CH=CH2)、烯丙基(-CH2CH=CH2)等。
术语“亚烯基”是指具有2-8个碳原子(C2-C8),具有至少一个不饱和位点,即,碳-碳sp2双键的直链或支链二价烃基,其中所述亚烯基可任选地独立地被本申请所述的一种或多种取代基取代,并包括具有“顺式”和“反式”定向,或“E”和“Z”定向的基团。实例包括但不限于亚乙烯基(-CH=CH-),烯丙基(-CH2CH=CH-)等。
术语“炔基”是指具有2-8个碳原子(C2-C8),具有至少一个不饱和位点,即,碳-碳sp三键的直链或支链一价烃基,其中所述炔基可任选地独立地被本申请所述的一种或多种取代基取代。实例包括但不限于乙炔基(-C≡CH)、丙炔基(炔丙基,-CH2C≡CH)等。
术语“亚炔基”是指具有2-8个碳原子(C2-C8),具有至少一个不饱和位点,即,碳-碳sp三键的直链或支链二价烃基,其中所述亚炔基可任选地独立地被本申请所述的一种或多种取代基取代。实例包括但不限于亚乙炔基(-C≡C-)、亚丙炔基(亚炔丙基,-CH2C≡C-)等。
术语“碳环(carbocycle)”、“碳环基”、“碳环(carbocyclic ring)”和“环烷基”是指具有3-12个碳原子(C3-C12)的单环形式的、或具有7-12个碳原子的二环形式的一价非芳香性饱和或部分不饱和的环。具有7-12个原子的二环碳环可排列成例如二环[4,5]、[5,5]、[5,6]或[6,6]系统,且具有9或10个环原子的二环碳环可排列成二环[5,6]或[6,6]系统或者可排列成桥环系统,例如二环[2.2.1]庚烷、二环[2.2.2]辛烷和二环[3.2.2]壬烷。螺环部分也包括在此定义的范围内。单环碳环的实例包括但不限于:环丙基、环丁基、环戊基、1-环戊-1-烯基、1-环戊-2-烯基、1-环戊-3-烯基、环己基、1-环己-1-烯基、1-环己-2-烯基、1-环己-3-烯基、环己二烯基、环庚基、环辛基、环壬基、环癸基、环十一烷基、环十二烷基等。碳环基任选地独立地被本申请所述的一种或多种取代基取代。
“芳基”是指通过从母体芳香性环系统的单个碳原子除去一个氢原子而得的具有6-20个碳原子(C6-C20)的一价芳香性烃基。一些芳基在示例结构中表示为“Ar”。芳基包括包含与饱和的、部分不饱和的环或芳香性碳环稠合的芳香环的二环基团。典型的芳基包括但不限于由苯(苯基)、取代苯、萘、蒽、联苯、茚基、茚满基、1,2-二氢萘、1,2,3,4-四氢萘基等得到的基团。芳基任选地独立地被本申请所述的一种或多种取代基取代。
“亚芳基”是指通过从母体芳香性环系统的两个碳原子除去两个氢原子而得的具有6-20个碳原子(C6-C20)的二价芳香性烃基。一些亚芳基在示例结构中表示为“Ar”。亚芳基包括包含与饱和的、部分不饱和的环或芳香性碳环稠合的芳香环的二环基团。典型的亚芳基包括但不限于由苯(亚苯基)、取代苯、萘、蒽、亚联苯、亚茚基、亚茚满基、1,2-二氢萘、1,2,3,4-四氢萘基等得到的基团。亚芳基任选地被本申请所述的一种或多种取代基取代。
术语“杂环(heterocycle)”、“杂环基”和“杂环(heterocyclic ring)”在本申请中可互换使用,并且是指具有3-约20个环原子、其中至少一个环原子是选自氮、氧、磷和硫的杂原子且其余环原子是C的饱和或部分不饱和的(即在环内具有一个或多个双键和/或三键)碳环基团,其中一个或多个环原子任选地独立地被下述一个或多个取代基取代。杂环可以是具有3-7个环成员(2-6个碳原子和1-4个选自N、O、P和S的杂原子)的单环,或者具有7-10个环成员(4-9个碳原子和1-6个选自N、O、P和S的杂原子)的二环,例如:二环[4,5]、[5,5]、[5,6]或[6,6]系统。杂环在Paquette,Leo A.;“Principles of Modern Heterocyclic Chemistry”(W.A.Benjamin,New York,1968),特别是第1、3、4、6、7和9章;“The Chemistry of Heterocyclic化合物,A series of Monographs”(John Wiley&Sons,New York,1950发行),特别是第13、14、16、19和28卷;和J.Am.Chem.Soc.(1960)82:5566中有述。“杂环基”还包括其中杂环基与饱和的、部分不饱和的环或者芳香性碳环或杂环稠合的基团。杂环的实例包括但不限于:吗啉-4-基、哌啶-1-基、哌嗪基、哌嗪-4-基-2-酮、哌嗪-4-基-3-酮、吡咯烷-1-基、硫吗啉-4-基、S-二氧代硫吗啉-4-基、氮杂环辛烷-1-基、氮杂环丁烷-1-基、八氢吡啶并[1,2-a]吡嗪-2-基、[1,4]二氮杂环庚烷-1-基、吡咯烷基、四氢呋喃基、二氢呋喃基、四氢噻吩基、四氢吡喃基、二氢吡喃基、四氢噻喃基、哌啶子基、吗啉代、硫吗啉代、噻噁烷基、哌嗪基、高哌嗪基、氮杂环丁烷基、氧杂环丁烷基、硫杂环丁烷基、高哌啶基、氧杂环庚烷基、硫杂环庚烷基、氧氮杂基、二氮杂基、硫氮杂基、2-吡咯啉基、3-吡咯啉基、吲哚啉基、2H-吡喃基、4H-吡喃基、二噁烷基、1,3-二氧杂环戊基、吡唑啉基、二噻烷基、二硫杂环戊烷基、二氢吡喃基、二氢噻吩基、二氢呋喃基、吡唑烷基、咪唑啉基、咪唑烷基、3-氮杂二环[3.1.0]己基、3-氮杂二环[4.1.0]庚基、氮杂二环[2.2.2]己基、3H-吲哚基、喹嗪基和N-吡啶基脲。螺环部分也包括在此定义的范围内。其中2个环原子被氧代(=O)部分替代的杂环基的实例是嘧啶酮基和1,1-二氧代硫吗啉基。本申请中的杂环基团任选地独立地被本申请所述的一个或多个取代基取代。
术语“杂芳基”是指5元、6元或7元环的一价芳香性基团,还包括具有5-20个原子的稠合环系统(至少其一是芳香性的),所述5元、6元或7元环的一价芳香性基团和所述稠合环系统含有一个或多个独立地选自氮、氧和硫的杂原子。杂芳基的实例是:吡啶基(包括例如2-羟基吡啶基)、咪唑基、咪唑并吡啶基、嘧啶基(包括例如4-羟基嘧啶基)、吡唑基、三唑基、吡嗪基、四唑基、呋喃基、噻吩基、异噁唑基、噻唑基、噁二唑基、噁唑基、异噻唑基、吡咯基、喹啉基、异喹啉基、四氢异喹啉基、吲哚基、苯并咪唑基、苯并呋喃基、噌啉基、吲唑基、吲嗪基、酞嗪基、哒嗪基、三嗪基、异吲哚基、蝶啶基、嘌呤基、噁二唑基、三唑基、噻二唑基、噻二唑基、呋咱基、苯并呋咱基、苯并噻吩基、苯并噻唑基、苯并噁唑基、喹唑啉基、喹喔啉基、萘啶基和呋喃并吡啶基。杂芳基任选地独立地被本申请所述的一种或多种取代基取代。
在可能的情况下,所述杂环或杂芳基可以是碳键合的(碳连接的)或氮键合的(氮连接)。作为示例而非限制,碳键合的杂环或杂芳基是在以下位置成键:吡啶的2、3、4、5或6位,哒嗪的3、4、5或6位,嘧啶的2、4、5或6位,吡嗪的2、3、5或6位,呋喃、四氢呋喃、噻吩(thiofuran)、噻吩(thiophene)、吡咯或四氢吡咯的2、3、4或5位,噁唑、咪唑或噻唑的2、4或5位,异噁唑、吡唑或异噻唑的3、4或5位,氮丙啶的2或3位,氮杂环丁烷的2、3或4位,喹啉的2、3、4、5、6、7或8位,或者异喹啉的1、3、4、5、6、7或8位。
作为示例而非限制,氮键合的杂环或杂芳基是在以下位置成键:氮丙啶、氮杂环丁烷、吡咯、吡咯烷、2-吡咯啉、3-吡咯啉、咪唑、咪唑烷、2-咪唑啉、3-咪唑啉、吡唑、吡唑啉、2-吡唑啉、3-吡唑啉、哌啶、哌嗪、吲哚、吲哚啉、1H-吲唑的1位,异吲哚或异吲哚啉的2位,吗啉的4位,以及咔唑或β-咔啉的9位。
术语“治疗(treat)”和“治疗(treatment)”是指治疗性的处置,其目的是减缓(减轻)不期望的生理学变化或病症,例如关节炎或癌症的形成或扩散。出于本发明的目的,有益或期望的临床结果包括但不限于,缓解症状、缩小疾病的范围、稳定疾病状态(即不恶化)、延迟或减缓疾病进展、改善或缓和疾病状态,以及缓解(无论部分或完全地缓解),无论是可检测的还是不可检测的。“治疗”还可以指与若不接受治疗时的预期存活时间相比延长存活时间。需要治疗的那些包括具有病症或障碍的那些。
短语“治疗有效量”是指(i)治疗本申请所述的特定的疾病、病症或障碍,(ii)减轻、改善或消除所述特定的疾病、病症或障碍的一种或多种症状,或者(iii)预防或延迟所述特定的疾病、病症或障碍的一种或多种症状的发作的本发明的化合物的量。在癌症的情况中,药物的治疗有效量可以减少癌细胞数量;缩小肿瘤尺寸;抑制(即,在一定程度上减缓而且优选终止)癌细胞侵润进入周围器官中;抑制(即,在一定程度上减缓而且优选终止)肿瘤转移;在一定程度上抑制肿瘤生长;和/或在一定程度上缓解与癌症相关的一种或多种症状。只要药物可防止现存的癌细胞生长和/或杀死现存的癌细胞,它就可以是抑制细胞生长的和/或细胞毒性的。对于癌症治疗,可通过例如评估疾病进展的时间(TTP)和/或测定应答率(RR)来量度效力。
“炎性病症”用于本申请中可以是指其中过度或失调的炎性反应造成过度的炎性症状、宿主组织损伤或者组织功能丧失的任何疾病、病症或综合征。“炎性病症”也指由白细胞流入和/或中性白细胞趋化介导的病理学状态。
“炎症”用于本申请中是指由组织的损伤或破坏引发的局部保护性反应,其起到破坏、稀释或屏蔽(隔离)有害物质和受伤组织的作用。炎症明显与白细胞流入和/或中性白细胞趋化相关。炎症可起因于致病生物体和病毒导致的感染,以及诸如外伤或者在心肌梗塞或中风之后再灌注、对外来抗原的免疫反应和自身免疫性反应之类的非感染性途径。因此,顺应式I化合物治疗的炎性病症包括与特异性防御系统的反应以及非特异性防御系统的反应相关的病症。
“特异性防御系统”是指对特异性抗原的存在做出反应的免疫系统的组成部分。由特异性防御系统的应答所致的炎症的实例包括对外来抗原的常规应答、自身免疫疾病和由T细胞介导的迟发型超敏反应。特异性防御系统的炎性反应的其它实例还有慢性炎性疾病、对实体移植的组织和器官例如肾移植和骨髓移植的排斥,以及移植物抗宿主疾病(GVHD)。
术语“非特异性防御系统”用于本申请中是指由不能够免疫记忆的白细胞(例如粒细胞和巨噬细胞)介导的炎性病症。至少部分起因于非特异性防御系统的反应的炎症的实例包括与诸如以下的病症相关的炎症:成人(急性)呼吸窘迫综合征(ARDS)或者多器官损伤综合征;再灌注损伤;急性肾小球肾炎;反应性关节炎;伴有急性炎性部分的皮肤病;急性化脓性脑膜炎或其它中枢神经系统炎性病症例如中风;热损伤;炎性肠病;粒细胞输血相关综合征;和细胞因子引发的中毒。
“自身免疫疾病”用于本申请中是指其中组织损伤与由体液或细胞介导的对身体自身组成部分的反应相关的任一类病症。
“变应性疾病”用于本申请中是指由变态反应产生的任何症状、组织损伤或组织功能丧失。“关节炎性疾病”用于本申请中是指以可归因于各种病因学的关节炎性损伤为特征的任何疾病。“皮炎”用于本申请中是指以可归因于各种病因学的皮肤炎症为特征的一大类疾病中的任一种。“移植排斥”用于本申请中是指以移植的组织和周围组织功能丧失、疼痛、肿胀、白细胞增多和血小板减少为特征的针对移植的组织例如器官或细胞(例如骨髓)的任何免疫反应。本发明的治疗方法包括用于治疗与炎性细胞激活相关的病症的方法。
“炎性细胞激活”是指通过增生性细胞反应的刺激物(包括但不限于细胞因子、抗原或自身抗体)、可溶性介质(包括但不限于细胞因子、氧自由基、酶、前列腺素或血管活性胺)的产生、或者在炎性细胞(包括但不限于单核细胞、巨噬细胞、T淋巴细胞、B淋巴细胞、粒细胞(即多形核白细胞例如中性粒细胞、嗜碱性粒细胞和嗜酸性粒细胞)、肥大细胞、树突细胞、朗氏细胞和内皮细胞)中新的或增量的介质(包括但不限于主要的组织相容性抗原或细胞粘附分子)的细胞表面表达来诱导。本领域技术人员可理解,在这些细胞中的这些表型中的一种或组合的激活可促进炎性病症的引发、永久化或恶化。
术语“NSAID”是“非甾体抗炎药”的首字母缩略词,是具有止痛、退烧(降低身体的高温并且缓解疼痛而不损及知觉)并且在较高剂量具有抗炎效力(减轻炎症)的治疗剂。术语“非甾体”用来将这些药物与具有相似的降低类二十烷酸、抗炎作用(宽范围的其它作用)的甾类相区分。作为镇痛药,NSAID的不寻常之处在于它们是非麻醉性的。NSAID包括阿司匹林、布洛芬和萘普生。NSAID通常指定用于治疗其中伴有疼痛和炎症的急性或慢性病症。NSAID一般指定用于在症状上缓解以下病症:类风湿性关节炎、骨关节炎、炎性关节病(例如强直性脊柱炎、银屑病关节炎、莱特尔综合征、急性痛风、痛经、转移性骨痛、头痛和偏头痛、术后疼痛、因炎症和组织损伤所致的轻度至中度疼痛、发热、肠梗阻和肾绞痛。大多数NSAID用作环氧合酶的非选择性抑制剂,抑制环氧合酶-1(COX-1)和环氧合酶-2(COX-2)同功酶。环氧合酶催化由花生四烯酸(其本身通过磷脂酶A2由细胞磷脂双层而得)形成前列腺素和血栓素。前列腺素尤其在炎症过程中用作信使分子。COX-2抑制剂包括塞来考昔、依托考昔、罗美昔布、帕瑞考昔、罗非考昔、罗非考昔和伐地考昔。
术语“癌症”是指或描述哺乳动物中以细胞生长失调为典型特征的生理状况。“肿瘤”包括一种或多种癌细胞。癌症的实例包括但不限于:癌、淋巴瘤、母细胞瘤、肉瘤和白血病或淋巴恶性肿瘤。所述癌症的更具体的实例包括鳞状细胞癌(例如上皮鳞状细胞癌)、包括小细胞肺癌、非小细胞肺癌(“NSCLC”)、肺腺瘤和肺鳞癌在内的肺癌、腹膜癌、肝细胞癌、包括胃肠癌在内的胃癌、胰腺癌、成胶质细胞瘤、宫颈癌、卵巢癌、肝癌、膀胱癌、肝细胞瘤、乳腺癌、结肠癌、直肠癌、结直肠癌、子宫内膜癌或子宫癌、唾液腺癌、肾癌、前列腺癌、外阴癌、甲状腺癌、肝癌、肛门癌、阴茎癌,以及头颈癌。
“血液恶性肿瘤”(英国拼写“Haematological”(血液学)恶性肿瘤)是影响血液、骨髓和淋巴结的癌症类型。由于它们三个通过免疫系统紧密相连,所以影响三者之一的疾病通常也影响另外两者:虽然淋巴癌是淋巴结的疾病,但其通常蔓延至骨髓,影响血液。血液恶性肿瘤是恶性肿瘤(“癌症”),且其基本上是由血液学和/或肿瘤学专家治疗。在某些中心“血液学/肿瘤学”是内科医学的单独亚学科,而在其它中心,其被视为不同部分(还存在外科及放射肿瘤学家)。血液病并非均为恶性(“癌性”);这些其它血液病症也可由血液学家管理。血液恶性肿瘤可由两个主要血液细胞谱系产生:髓样及淋巴样细胞系。髓样细胞系正常产生粒细胞、红细胞、血小板、巨噬细胞及肥大细胞;淋巴样细胞系产生B、T、NK和浆细胞。淋巴瘤、淋巴细胞性白血病和骨髓瘤是来自淋巴样细胞系,而急性和慢性骨髓性白血病、骨髓增生异常综合征和骨髓增生性疾病是源自髓样细胞。白血病包括急性淋巴细胞白血病(ALL)、急性骨髓性白血病(AML)、慢性淋巴细胞白血病(CLL)、慢性骨髓性白血病(CML)、急性单核细胞白血病(AMOL)和小淋巴细胞淋巴瘤(SLL)。淋巴瘤包括霍奇金氏淋巴瘤(所有四种亚型)和非霍奇金氏淋巴瘤(所有亚型)。
“化疗剂”是用于治疗癌症的化合物,无论作用机制如何。化疗剂的类别包括但不限于:烷化剂、抗代谢物、纺锤体毒素植物生物碱、细胞毒性/抗肿瘤抗生素、拓扑异构酶抑制剂、抗体、光敏剂和激酶抑制剂。化疗剂包括用于“靶向治疗”和常规化疗中的化合物。化疗剂的实例包括:厄洛替尼(Genentech/OSI Pharm.)、多西他赛(Sanofi-Aventis)、5-FU(氟尿嘧啶,5-氟尿嘧啶,CAS号51-21-8)、吉西他滨(Lilly)、PD-0325901(CAS号391210-10-9,Pfizer)、顺铂(顺-二胺,二氯化铂(II),CAS号15663-27-1)、卡铂(CAS号41575-94-4)、紫杉醇(Bristol-Myers Squibb Oncology,Princeton,N.J.)、曲妥单抗(Genentech)、替莫唑胺(4-甲基-5-氧代-2,3,4,6,8-五氮杂二环[4.3.0]壬-2,7,9-三烯-9-甲酰胺,CAS号85622-93-1, Schering Plough)、他莫昔芬((Z)-2-[4-(1,2-二苯基丁-1-烯基)苯氧基]-N,N-二甲基乙胺,)和多柔比星()、Akti-1/2、HPPD和雷帕霉素。
化疗剂的其它实例包括:奥沙利铂(oxaliplatin)(Sanofi)、硼替佐米(bortezomib)Millennium Pharm.)、舒尼替尼(sutent)SU11248,Pfizer)、来曲唑(letrozole)(Novartis)、甲磺酸伊马替尼(imatinib mesylate)(Novartis)、XL-518(MEK抑制剂,Exelixis,WO2007/044515)、ARRY-886(MEK抑制剂,AZD6244,Array BioPharma,Astra Zeneca)、SF-1126(PI3K抑制剂,SemaforePharmaceuticals)、BEZ-235(PI3K抑制剂,Novartis)、XL-147(PI3K抑制剂,Exelixis)、PTK787/ZK222584(Novartis)、氟维司群(fulvestrant)(AstraZeneca)、甲酰四氢叶酸(leucovorin)(亚叶酸)、雷帕霉素(西罗莫司、Wyeth)、拉帕替尼(lapatinib)(GSK572016,GlaxoSmith Kline)、lonafarnib(SARASARTM,SCH66336,Schering Plough)、索拉非尼(sorafenib)BAY43-9006、Bayer Labs)、吉非替尼(gefitinib)(AstraZeneca)、伊立替康(irinotecan)(CPT-11,Pfizer)、tipifarnib(ZARNESTRATM,Johnson&Johnson)、ABRAXANETM(Cremophor-free)、紫杉醇的白蛋白工程化纳米微粒制剂(albumin-engineered nanoparticle formulations of paclitaxel)(AmericanPharmaceutical Partners,Schaumberg,Il)、vandetanib(rINN,ZD6474,AstraZeneca)、chloranmbucil、AG1478、AG1571(SU5271;Sugen)、temsirolimus(Wyeth)、pazopanib(GlaxoSmithKline)、canfosfamide(Telik)、塞替派(thiotepa)和环磷酰胺(cyclosphosphamide)();磺酸烷基酯(alkyl sulfonate)如白消安、英丙舒凡和哌泊舒凡(piposulfan);氮丙啶(aziridine)如benzodopa、卡波醌、meturedopa和uredopa;乙撑亚胺(ethylenimine)和甲基氨基吖啶(methylamelamine),包括六甲蜜胺、三亚胺嗪(triethylenemelamine)、三亚乙基磷酰胺(triethylenephosphoramide)、三亚乙基硫化磷酰胺(triethylenethiophosphoramide)和trimethylomelamine;番荔枝内酯(acetogenin)(尤其是布拉它辛(bullatacin)和布拉它辛酮(bullatacinone));喜树碱(包括合成性类似物托泊替康(topotecan));苔藓抑素(bryostatin);callystatin;CC-1065(包括其阿多来新(adozelesin)、卡折来新(carzelesin)和比折来新(bizelesin)合成性类似物);cryptophycins(特别是cryptophycin1和cryptophycin8);多拉司他汀(dolastatin);duocarmycin(包括合成性类似物KW-2189和CB1-TM1);艾榴塞洛素(eleutherobin);pancratistatin;sarcodictyin;spongistatin;氮芥如苯丁酸氮芥、萘氮芥、氯磷酰胺(chlorophosphamide)、雌莫司汀、异环磷酰胺、双氯乙基甲胺(mechlorethamine)、盐酸氧氮芥(mechlorethamine oxide hydrochloride)、美法仑、新氮芥(novembichin)、苯芥胆甾醇(phenesterine)、泼尼莫司汀(prednimustine)、曲磷胺(trofosfamide)、尿嘧啶氮芥(uracil mustard);硝基脲如卡莫司汀、氯脲菌素(chlorozotocin)、福莫司汀、洛莫司汀、尼莫司汀和雷莫司汀;抗生素如烯二炔(enediyne)抗生素(例如刺孢霉素(calicheamicin),刺孢霉素γ1I、刺孢霉素ωI1(Angew Chem.Intl.Ed.Engl.(1994)33:183-186);蒽环类抗生素(dynemicin),dynemicin A;二膦酸盐(bisphosphonate)如氯膦酸盐(clodronate);埃斯培拉霉素(esperamicin);以及新抑癌蛋白生色团(neocarzinostatin chromophore)和相关色蛋白烯二炔抗生素生色团(enediyne antibiotic chromophore)、aclacinomysin、放线菌素(actinomycin)、authramycin、偶氮丝氨酸(azaserine)、博来霉素、放线菌素C(cactinomycin)、carabicin、去甲柔红霉素(carminomycin)、嗜癌素(carzinophilin)、色霉素(chromomycin)、放线菌素D(dactinomycin)、柔红霉素(daunorubicin)、地托比星(detorubicin)、6-重氮基-5-氧代-L-正亮氨酸(6-diazo-5-oxo-L-norleucine)、吗啉代-多柔比星、氰基吗啉代-多柔比星、2-吡咯啉子基-多柔比星和去氧多柔比星)、表柔比星(epirubicin)、依索比星、伊达比星、奈莫柔比星(nemorubicin)、麻西罗霉素(marcellomycin)、丝裂霉素如丝裂霉素C、麦考酚酸(mycophenolic acid)、诺拉霉素(nogalamycin)、橄榄霉素(olivomycins)、培洛霉素(peplomycin)、泊非霉素(porfiromycin)、嘌罗霉素(puromycin)、三铁阿霉素(quelamycin)、罗多比星(rodorubicin)、链黑霉素(streptonigrin)、链佐星(streptozocin)、杀结核菌素(tubercidin)、乌苯美司(ubenimex)、净司他丁(zinostatin)、佐柔比星;抗代谢物如甲氨喋呤和5-氟尿嘧啶(5-FU);叶酸类似物如二甲叶酸(denopterin)、甲氨喋呤(methotrexate)、喋罗呤(pteropterin)、三甲曲沙(trimetrexate);嘌呤类似物如氟达拉滨(fludarabine)、6-巯嘌呤、硫咪嘌呤(thiamiprine)、硫鸟嘌呤(thioguanine);嘧啶类似物如安西他滨(ancitabine)、阿扎胞苷(azacytidine)、6-氮鸟苷(6-azauridine)、卡莫氟(carmofur)、阿糖胞苷(cytarabine)、二脱氧尿苷(dideoxyuridine)、去氧氟尿苷(doxifluridine)、伊诺他滨(enocitabine)、氟尿苷(floxuridine);雄激素如卡普睾酮(calusterone)、丙酸甲雄烷酮(dromostanolonepropionate)、环硫雄醇(epitiostanol)、美雄烷(mepitiostane)、睾内酯(testolactone);抗肾上腺素(anti-adrenal)如氨鲁米特(aminoglutethimide)、米托坦(mitotane)、曲洛司坦(trilostane);叶酸补充剂(folic acid replenisher)如亚叶酸(frolinic acid);醋葡醛内酯(aceglatone);醛磷酰胺糖苷(aldophosphamideglycoside);氨基乙酰丙酸(aminolevulinic acid);恩尿嘧啶(eniluracil);安吖啶(amsacrine);bestrabucil;比生群(bisantrene);伊达曲杀(edatraxate);地磷酰胺(defofamine);秋水仙胺(demecolcine);地吖醌(diaziquone);elfornithine;依利醋铵(elliptinium acetate);埃坡霉素(epothilone);依托格鲁(etoglucid);硝酸镓(gallium nitrate);羟基脲(hydroxyurea);香菇多糖(lentinan);氯尼达明(lonidainine);美登醇(maytansinoid)如美登素(maytansine)和安丝菌素(ansamitocin);米托胍腙(mitoguazone);米托蒽醌(mitoxantrone);mopidanmol;根瘤菌剂(nitraerine);喷司他丁(pentostatin);蛋氨氮芥(phenamet);吡柔比星(pirarubicin);洛索蒽醌(losoxantrone);鬼臼酸(podophyllinic acid);2-乙基肼;丙卡巴肼(procarbazine);多糖复合物(JHS Natural Products,Eugene,OR);雷佐生(razoxane);根霉素(rhizoxin);西佐喃(sizofiran);锗螺胺(spirogermanium);细交链孢菌酮酸(tenuazonic acid);三亚胺醌(triaziquone);2,2',2"-三氯三乙胺;单端孢菌毒素(trichothecene)(尤其是T-2毒素、verracurinA、杆孢菌素A和anguidine);乌拉坦;长春地辛;达卡巴嗪(dacarbazine);甘露莫司汀(mannomustine);二溴甘露醇(mitobronitol);二溴卫矛醇(mitolactol);哌泊溴烷(pipobroman);gacytosine;阿糖胞苷(arabinoside)(“Ara-C”);环磷酰胺;塞替派;6-硫代鸟嘌呤;巯嘌呤;甲氨喋呤;铂类似物如顺铂和卡铂;长春碱;依托泊苷(VP-16);异环磷酰胺;米托蒽醌;长春新碱;长春瑞滨;诺消灵(novantrone);替尼泊苷(teniposide);伊达曲杀(edatrexate);柔红霉素;氨基喋呤(aminopterin);卡培他滨(capecitabine)(Roche);伊班膦酸盐(ibandronate);CPT-11;拓扑异构酶抑制剂RFS2000;二氟甲基鸟氨酸(difluoromethylornithine、DMFO);类视黄醇(retinoid)如视黄酸(retinoic acid);以及上述任何物质的可药用盐、酸和衍生物。
以下物质也包括在“化疗剂”的定义中:(i)用于调节或抑制激素对肿瘤的作用的抗激素药物,如抗雌激素药物(anti-estrogen)和选择性雌激素受体调节剂(selective estrogen receptor modulator,SERM),包括例如他莫昔芬(包括枸橼酸他莫昔芬)、雷洛昔芬、屈洛昔芬、4-羟基他莫昔芬、曲沃昔芬(trioxifene)、雷洛西芬(keoxifene)、LY117018、奥那司酮(onapristone)和(枸橼酸托米芬(toremifine citrate));(ii)抑制芳香酶(调节肾上腺中雌激素产生)的芳香酶抑制剂,例如4(5)-咪唑、氨鲁米特、(醋酸甲地孕酮(megestrol acetate))、(依西美坦(exemestane);Pfizer)、formestanie、法倔唑(fadrozole)、(伏氯唑(vorozole))、(来曲唑;Novartis)和(阿那曲唑(anastrozole);AstraZeneca);(iii)抗雄激素药物(anti-androgen),如氟他胺(flutamide)、尼鲁米特(nilutamide)、比卡鲁胺(bicalutamide)、醋酸亮丙瑞林(leuprolide)和戈舍瑞林(goserelin)以及曲沙他滨(troxacitabine)(1,3-二氧戊环核苷胞嘧啶类似物);(iv)蛋白激酶抑制剂,例如MEK抑制剂(WO2007/044515);(v)脂质激酶抑制剂;(vi)反义寡核苷酸,特别是抑制异常细胞增殖中所涉及的信号转导途径中的基因表达的那些反义寡核苷酸,例如PKC-α、Raf和H-Ras,如oblimersen(Genta Inc.);(vii)核酶如VEGF表达抑制剂(例如)和HER2表达抑制剂;(viii)疫苗如基因治疗疫苗,例如和IL-2;拓扑异构酶1抑制剂如rmRH;(ix)抗血管生成药物如贝伐单抗(Genentech);以及上述任何物质的药用盐、酸和衍生物。
还包括在“化疗剂”定义中的有治疗性抗体,比如阿仑珠单抗(alemtuzumab,Campath)、贝伐珠单抗(Genentech);西妥昔单抗(Imclone);帕木单抗(panitumumab,Amgen)、利妥昔单抗(Genentech/Biogen Idec)、培妥珠单抗(pertuzumab,2C4,Genentech)、曲妥单抗(Genentech)、托西莫单抗单抗(Bexxar,Corixia)和抗体药物轭合物奥吉妥珠单抗(gemtuzumabozogamicin,Wyeth)。
具有作为化学治疗剂的治疗潜力而与本发明的Btk抑制剂联用的人源化单克隆抗体包括:阿仑珠单抗(alemtuzumab)、阿泊珠单抗(apolizumab)、阿塞珠单抗(aselizumab)、atlizumab、bapineuzumab、贝伐珠单抗(bevacizumab)、莫比伐珠单抗(bivatuzumab mertansine)、莫坎妥珠单抗(cantuzumab mertansine)、西利珠单抗(cedelizumab)、赛妥珠单抗(certolizumabpegol)、cidfusituzumab、cidtuzumab、达克珠单抗(daclizumab)、依库珠单抗(eculizumab)、依法珠单抗(efalizumab)、依帕珠单抗(epratuzumab)、厄利珠单抗(erlizumab)、泛维珠单抗(felvizumab)、芳妥珠单抗(fontolizumab)、奥吉妥珠单抗(gemtuzumab ozogamicin)、奥英妥珠单抗(inotuzumab ozogamicin)、ipilimumab、拉贝珠单抗(labetuzumab)、林妥珠单抗(lintuzumab)、马妥珠单抗(matuzumab)、美泊珠单抗(mepolizumab)、莫维珠单抗(motavizumab)、motovizumab、那他珠单抗(natalizumab)、尼妥珠单抗(nimotuzumab)、nolovizumab、numavizumab、ocrelizumab、奥马珠单抗(omalizumab)、帕利珠单抗(palivizumab)、帕考珠单抗(pascolizumab)、pecfusituzumab、pectuzumab、培妥珠单抗(pertuzumab)、培克珠单抗(pexelizumab)、ralivizumab、雷珠单抗(ranibizumab)、瑞利珠单抗(reslivizumab)、瑞利珠单抗(reslizumab)、resyvizumab、罗维珠单抗(rovelizumab)、卢利珠单抗(ruplizumab)、西罗珠单抗(sibrotuzumab)、西利珠单抗(siplizumab)、索土珠单抗(sontuzumab)、他珠单抗(tacatuzumab tetraxetan)、tadocizumab、他利珠单抗(talizumab)、特非珠单抗(tefibazumab)、托珠单抗(tocilizumab)、托利珠单抗(toralizumab)、曲司珠单抗(trastuzumab)、Tucotuzumab西莫白介素(tucotuzumab celmoleukin)、tucusituzumab、umavizumab、乌珠单抗(urtoxazumab)和维西珠单抗(visilizumab)。
“代谢物”是通过具体化合物或其盐在体内的代谢而产生的产物。可使用本领域已知的常规技术鉴定化合物的代谢物,并使用如本申请所述的试验确定它们的活性。所述产物可起因于例如所给药的化合物的氧化、还原、水解、酰胺化、脱酰胺化、酯化、脱酯化、酶法裂解等。因此,本发明包括本发明化合物的代谢物,包括由以下方法产生的化合物,所述方法包括使本发明式I化合物与哺乳动物接触足以产生其代谢产物的一段时间。
术语“包装说明书”是指通常包括在治疗产品的市售包装中的说明书,其含有关于适应症、用法、剂量、给药、禁忌症和/或注意事项的信息,这些信息涉及上述治疗产品的使用。
术语“手性”是指具有镜像配偶体(mirror image partner)不可重叠性质的分子,而术语“非手性”是指可与其镜像配偶体重叠的分子。
术语“立体异构体”是指具有相同化学组成但原子或基团的取向在空间上的排列不同的化合物。
“非对映异构体”是指具有两个或更多手性中心并且其分子不互为镜像的立体异构体。非对映异构体具有不同的物理性质,如熔点、沸点、光谱性质和反应性。非对映异构体的混合物可通过高分辨分析操作如电泳和色谱来分离。
“对映异构体”是指互为不可重叠镜像的化合物的两种立体异构体。
本申请使用的立体化学定义和常规用语(convention)通常遵循S.P.Parker,Ed.,McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-HillBook Company,New York;and Eliel,E.and Wilen,S.、“Stereochemistry ofOrganic Compounds”,John Wiley&Sons,Inc.,New York,1994。本发明化合物可含有不对称或手性中心,因此以不同立体异构形式存在。预期的是,本发明化合物的所有立体异构形式,包括但不限于非对映异构体、对映异构体和阻转异构体(atropisomers)及它们的混合物如外消旋混合物,形成了本发明的部分。许多有机化合物以光学活性形式存在,即它们具有旋转平面偏振光的平面的能力。在描述有光学活性的化合物时,使用前缀D和L或者R和S来表示分子关于其一个或多个手性中心的绝对构型。前缀d和l或者(+)和(-)用于指定平面偏振光由化合物引起的旋转的符号,其中(-)或l表示化合物是左旋的。前缀为(+)或d的化合物是右旋的。对于给定的化学结构而言,除了这些立体异构体互为镜像外,这些立体异构体是相同的。具体的立体异构体也可称为对映异构体,所述异构体的混合物通常称作对映异构混合物。对映异构体的50:50混合物称为外消旋混合物或外消旋体,当化学反应或方法中没有立体选择性或立体专一性时可出现这种情况。术语“外消旋混合物”和“外消旋体”是指两种对映异构物质的等摩尔混合物,其没有光学活性。对映异构体可通过手性分离方法,例如超临界流体色谱法(SFC)而从外消旋混合物分离。经分离对映异构体中手性中心处的构型排布可为暂定的,并用于说明目的在表1结构中描述,而立体化学确定待定,如x-射线晶体学数据。
术语“互变异构体”或“互变异构形式”是指可通过低能垒(low energybarrier)互相转化的不同能量的结构异构体。例如,质子互变异构体(protontautomer)(也称为质子移变互变异构体(prototropic tautomer))包括通过质子迁移进行的互相转化,如酮-烯醇异构化和亚胺-烯胺异构化。价键互变异构体(valence tautomer)包括通过一些成键电子的重组进行的互相转化。
术语“药用盐”表示并非生物学或其它情况下不期望的盐。药用盐包括酸和碱加成盐。短语“药用的”表明该物质或组合物需与制剂包含的其它成分和/或采用其治疗的哺乳动物在化学和/或毒物学上相容。
术语“药用酸加成盐”表示与以下酸形成的那些药用盐:无机酸,例如盐酸、氢溴酸、硫酸、硝酸、碳酸、磷酸,以及选自脂肪族、环脂族、芳香族、芳脂族、杂环、羧酸和磺酸类的有机酸,例如甲酸、乙酸、丙酸、乙醇酸、葡萄糖酸、乳酸、丙酮酸、草酸、苹果酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸、天冬氨酸、抗坏血酸、谷氨酸、氨茴酸、苯甲酸、肉桂酸、扁桃酸、双羟萘酸、苯乙酸、甲磺酸“甲磺酸”、乙磺酸、对甲苯磺酸和水杨酸。
术语“药用碱加成盐”表示与有机或无机碱形成的那些药用盐。可接受的无机碱的实例包括钠、钾、铵、钙、镁、铁、锌、铜、锰和铝盐。源自药用有机无毒碱的盐包括以下化合物的盐:伯、仲和叔胺,经取代胺,包括天然经取代胺、环胺及碱性离子交换树脂,如异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、2-二乙氨基乙醇、三甲胺、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、哈胺(hydrabamine)、胆碱、甜菜碱、乙二胺、葡萄糖胺、甲基葡糖胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌啶和聚胺树脂。
“溶剂化物”是指一种或多种溶剂分子与本发明化合物的缔合物(association)或络合物(complex)。形成溶剂化物的溶剂的实例包括但不限于水、异丙醇、乙醇、甲醇、DMSO、乙酸乙酯、乙酸和乙醇胺。
术语“EC50”是半数最大有效浓度,并表示在体内获得特定效应的最大值的50%所需的特定化合物的血浆浓度。
术语“Ki”是抑制常数并表示特定抑制剂对受体的绝对亲和力。其测量是使用竞争结合测定,且等于当不存在竞争配体(例如,放射配体)时特定抑制剂占据50%受体时的浓度。Ki值可以对数方式转化为pKi值(-log Ki),其中较高值表示指数较大效力。
术语“IC50”是半数最大抑制浓度并表示在体外获得对生物过程的50%抑制所需的特定化合物浓度。IC50值可以对数方式转化为pIC50值(-log IC50),其中较高值表示指数较大效力。IC50值并非绝对值,而是视实验条件而定,例如所使用的浓度,并可利用Cheng-Prusoff等式转化为绝对抑制常数(Ki)(Biochem.Pharmacol.(1973)22:3099)。可计算其它百分抑制参数,例如IC70、IC90等。
术语“该发明化合物”和“本发明化合物”和“式I化合物”包括式I化合物及其立体异构体、几何异构体、互变异构体、溶剂化物、代谢物和药用盐和前药。
本申请给出的任意式或结构(包括式I化合物)也预期表示所述化合物的水合物、溶剂化物和多晶型物或它们的混合物。
本申请给出的任意式或结构(包括式I化合物)也预期表示所述化合物的未标记形式和同位素标记形式。同位素标记的化合物具有本申请给出的式所描述的结构,不同的是一个或多个原子被具有所选原子质量或质量数的原子替换。可结合到本发明化合物中的同位素的实例包括氢、碳、氮、氧、磷、氟和氯的同位素,例如但不限于2H(氘D)、3H(氚)、11C、13C、14C、15N、18F、31P、32P、35S、36Cl和125I。各种同位素标记的本发明化合物例如其中结合了放射性同位素例如3H、13C和14C的那些化合物。所述同位素标记的化合物可用在代谢研究、反应动力性研究、检测或成像技术例如正电子发射断层扫描(PET)或单光子发射计算机断层成像(SPECT)(包括药物或底物组织分布测定)中,或用在放射活性治疗患者中。氘标记或氘取代的本发明化合物可具有改善的DMPK(药物代谢和药代动力学)性质,涉及分布、代谢和排泄(ADME)。用较重同位素例如氘取代可因较大代谢稳定性而得到一些治疗益处,例如体内半衰期延长或剂量需要量减少。18F标记的化合物可用于PET或SPECT研究。同位素标记的本发明化合物及其前药可大体上通过以下方式用实施例中披露的操作和下面描述的制备方法来制备,所述方式为用容易获得的同位素标记的试剂代替非同位素标记的试剂。此外,用较重同位素特别是氘(即,2H或D)取代可因较大代谢稳定性而得到一些治疗益处,例如体内半衰期延长或剂量需要量减少或治疗指数得到改善。应当理解的是,该上下文中的氘被认为是式化合物(I)中的取代基。所述较重同位素(特别是氘)的浓度可通过同位素富集因子(isotopic enrichment factor)定义。在本发明的化合物中,未被专门指定为特定同位素的原子是表示该原子的任意稳定同位素。除非另有说明,当将一处位置专门指定为"H"或"氢",该位置应被理解为具有天然丰度同位素组成的氢。因此,本在本发明化合物中,被专门指定为氘(D)的任意原子意欲表示氘。
二环哌嗪化合物
本发明提供式I包括式Ia-Ih的二环哌嗪化合物及其药物制剂,其可用于治疗由Btk激酶调节的疾病、病症和/或障碍:
或其立体异构体、互变异构体或药用盐,其中:
实/虚线指示单键或双键;
X1是CR1或N;
X2是CR2或N;
X3是CR3或N;
其中X1、X2和X3中的0个、1个或2个是N;
Y1和Y2独立选自CH和N;
Y3是C或N;
Y4是CR6、N或NH;
其中Y1、Y2、Y3和Y4中的1个或2个是N;
R1、R2和R3独立选自H、F、Cl、-NH2、-NHCH3、-N(CH3)2、-OH、-OCH3、-OCH2CH3、-OCH2CH2OH和任选被F、Cl、CN、-NH2、-NHCH3、-N(CH3)2、-OH、-OCH3、-OCH2CH3和-OCH2CH2OH取代的C1-C3烷基;
R4选自H、F、Cl、CN、-CH2OH、-CH(CH3)OH、-C(CH3)2OH、-CH(CF3)OH、-CH2F、-CHF2、-CH2CHF2、-CF3、-C(O)NH2、-C(O)NHCH3、-C(O)N(CH3)2、-NH2、-NHCH3、-N(CH3)2、-NHC(O)CH3、-OH、-OCH3、-OCH2CH3、-OCH2CH2OH、环丙基、环丙基甲基、1-羟基环丙基、咪唑基、吡唑基、3-羟基-氧杂环丁烷-3-基、氧杂环丁烷-3-基和氮杂环丁烷-1-基;
R5选自-CH3、-CH2CH3、-CH2OH、-CH2F、-CHF2、-CF3、-CN和-CH2CH2OH;
或者两个R5基团形成3-、4-、5-或6-元碳环或杂环;
或者R5基团和R8基团形成3-、4-、5-或6-元碳环或杂环;
n是0、1、2、3或4;
R6选自H、Cl、-CH3、-CH2CH3、-CH2CH2OH、-CH2F、-CHF2、-CF3、-NH2、-NHCH3、-N(CH3)2、-OH、-OCH3、-OCH2CH3和-OCH2CH2OH;
R7选自以下结构:
其中波浪线指示连接点;
R8选自H、-CH3、-S(O)2CH3、环丙基、氮杂环丁烷-3-基、氧杂环丁烷-3-基和吗啉-4-基;
Z是CR9或N;其中R9选自H、F、Cl、-CH3、-CH2CH3、-CH2CH2OH、-NH2、-NHCH3、-N(CH3)2、-OH、-OCH3、-OCH2CH3和-OCH2CH2OH。
式I化合物的示例性实施方案包括式Ia-Ih的化合物:
式I化合物的示例性实施方案包括其中X1是N,X2是CR2且X3是CR3。
式I化合物的示例性实施方案包括其中X1是CR1,X2是N且X3是CR3。
式I化合物的示例性实施方案包括其中X1是CR1,X2是CR2且X3是N。
式I化合物的示例性实施方案选自:X1和X3是N,X1和X2是N,或X2和X3是N。
式I化合物的示例性实施方案包括其中R4是-CH2OH。
式I化合物的示例性实施方案包括其中X2是CR2且R2是F。
式I化合物的示例性实施方案包括其中X1和X3是CH。
式I化合物的示例性实施方案包括其中Y4是CR6且R6是CH3。
本发明的式I化合物可包含不对称中心或手性中心,因而以不同的立体异构体形式存在。本发明化合物的所有立体异构体形式,包括但不限于其非对映异构体、对映异构体和阻转异构体以及它们的混合物例如外消旋混合物,意在构成本发明的一部分。
此外,本发明涵盖所有的非对映异构体,包括顺-反(几何)异构体和构象异构体。例如,若式I化合物包含双键或稠合环,则顺式和反式形式以及其混合物被涵盖在本发明的范围内。
在本申请所示的结构中,若未指明任何具体手性原子的立体化学,则所有的立体异构体被视为并被包含为本发明的化合物。若以表示具体构型的楔形实线或虚线指明立体化学,则如此指明和定义该立体异构体。
本发明的化合物可以未溶剂化的形式、以及用药用溶剂例如水、乙醇等溶剂化的形式存在,并且本发明意在涵盖溶剂化的和未溶剂化的形式。
本发明的化合物还可以不同的互变异构体形式存在,并且所有这样的形式都被涵盖在本发明的范围内。术语“互变异构体”或“互变异构形式”是指通过低能垒可互相转变的能量不同的结构异构体。例如,质子互变异构体(也称为质子转移互变异构体)包括通过质子的迁移互相转化,例如酮-烯醇和亚胺-烯胺异构化。价键互变异构体包括通过一些成键电子的重组互相转化。
生物学评价
可通过测定每种化合物将活性抑制到预定程度时的浓度而后将结果对比来确定式I化合物作为酶活性(或其它生物活性)的抑制剂的相对效力。通常,优选测定的是在生化测定中抑制50%的活性时的浓度,即,50%抑制浓度或“IC50”。可利用本领域已知的常规技术完成IC50值的测定。一般可通过测量特定酶在一系列浓度的待研究的抑制剂存在下的活性来确定IC50。然后以实验获得的酶活性值对所用的抑制剂浓度作图。将显示50%酶活性(与不存在任何抑制剂时的活性相比)时的抑制剂浓度作为IC50值。类似地,可通过适当地测定活性来确定其它的抑制浓度。例如,在一些情况中可能期望确定90%抑制浓度,即IC90等。
通过标准生化Btk激酶测定来测试式I化合物(实施例901)。
可用来测试式I化合物的标准细胞Btk激酶测定的一般方法是Ramos细胞Btk测定(实施例902)。
标准细胞B细胞增殖测定可用来以从Balb/c小鼠脾纯化的B细胞测试式I化合物(实施例903)。
标准T细胞增殖测定可用来以从Balb/c小鼠脾纯化的T细胞测试式I化合物(实施例904)。
针对抑制B细胞活性,可以用从8-16周龄的Balb/c小鼠脾纯化的全小鼠脾细胞对式I化合物进行CD86抑制测定(实施例905)。
为了测量在培养物中存活的B-ALL细胞的数量,可以对式I化合物对进行B-ALL细胞存活测定(实施例906)。
可对式I化合物进行CD69全血测定以测量化合物对由表面IgM与山羊F(ab’)2抗-人类IgM交联所活化的人类全血中的B淋巴细胞产生CD69的抑制能力(实施例907)。CD69是参与淋巴细胞迁移和细胞因子分泌的II型C型凝集素。CD69表达代表白细胞激活的最早可用指示剂之一且其快速诱导通过转录激活发生(Vazquez等人(2009)Jour.of Immunology,2009年10月19日公开,doi:10.4049/jimmunol.0900839)。选择性Btk抑制剂对抗原受体刺激的浓度依赖性抑制诱导淋巴细胞活化标记物CD69的细胞表面表达(Honigberg等人(2010)Proc.Natl.Acad.Sci.107(29):13075-13080)。因此,选择性Btk抑制剂的CD69抑制可与某些B细胞病症的治疗功效相关。示例性的式I化合物的CD69Hu Blood FACS IC70值示于表1和2中。
示例性的式I化合物的细胞毒性或细胞生长抑制活性可如下测量:在细胞培养基中确立增殖哺乳动物肿瘤细胞系,加入式I化合物,培养细胞约6小时至约5天时间;并测量细胞存活力(实施例908)。基于细胞的体外测定用于测量存活力,即增殖(IC50)、细胞毒性(EC50)和诱导细胞凋亡(半胱天冬酶活化)并可用于预测对血液恶性肿瘤和实体瘤的临床功效。
式I化合物与化疗剂的组合的体外功效可如下测量:实施例908的细胞增殖测定;可从Promega Corp.,Madison,WI商购的发光细胞存活力测定。该均质测定法是基于鞘翅目萤光素酶的重组表达(US5583024;US5674713;US5700670)和基于存在的ATP(代谢活性细胞的指示剂)的定量来测量培养物中活细胞数目(Crouch等人(1993)J.Immunol.Meth.160:81-88;US6602677)。测定以96或384孔模式进行,使得可进行自动高通量筛选(HTS)(Cree等人(1995)AntiCancer Drugs6:398-404)。所述均质测定程序包括将单一试剂(试剂)直接加入到补充血清的培养基中培养的细胞中。不需要细胞洗涤、移除培养基和多次移液步骤。在加入试剂并混合后的10分钟内,所述系统以384孔模式检测少至15个细胞/孔。
均质“加入-混合-测量”模式导致细胞溶解并产生与存在的ATP的量成比例的发光信号。ATP的量直接与培养物中存在的细胞数目成比例。测定产生由荧光素酶引起的“辉光型”发光信号,其具有通常大于五小时的半衰期,取决于所使用的细胞类型和培养基。以相对发光单位(RLU)反映活细胞。通过重组萤火虫荧光素酶使底物(甲虫荧光素(Beetle Luciferin))氧化脱羧,伴随着将ATP转化成AMP并产生光子。延长的半衰期消除了对使用试剂注射器的需要并且为多板的连续或分批模式处理提供了灵活性。该细胞增殖测定可用于各种多孔模式,例如96或384孔模式。可通过光度计或CCD相机成像装置记录数据。发光输出(luminescenceoutput)表示为随时间测量的相对光单位(RLU)。
通过测定(实施例908)测量示例性的式I化合物和与化疗剂的组合对某些血液肿瘤细胞系的抗增殖功效。确立测试的化合物和组合的EC50值。
按照本发明的方法制备和表征了表1和2中示例性的式I化合物,并且测试了它们对Btk的抑制,所述示例性的式I化合物具有以下结构和相应的名称(ChemDraw Ultra,9.0.1版,和ChemBioDraw,11.0版,CambridgeSoft Corp.,Cambridge MA)。在多于一种名称与式I化合物或中间体相关的情况中,应以化学结构定义该化合物。
表1.
表2.
式I化合物的给药
本发明化合物可通过适于待治疗的病症的任何途径给药。合适的途径包括口服、肠胃外(包括皮下、肌内、静脉内、动脉内、皮内、鞘内和硬膜外)、经皮、直肠、经鼻、局部(包括口腔和舌下)、阴道、腹膜内、肺内和鼻内。对于局部免疫抑制治疗而言,化合物可通过损伤区给药(包括灌注或在移植前使移植物与抑制剂接触)来给药。应该理解的是优选的途径可随例如受体的条件而变化。当口服给药化合物时,可将其与药用载体或赋形剂配制成丸剂、胶囊剂、片剂等。当化合物肠胃外给药时,可将其与药用肠胃外媒介物一起配制,并且呈如下文详述的单位剂量可注射形式。
治疗人类患者的剂量可为约10毫克至约1000毫克的式I的化合物。典型的剂量可为约100毫克至约300毫克化合物。剂量可每日一次(QID)、每日两次(BID)或更频繁给药,这取决于药物代谢动力学和药效学性质,包括具体化合物的吸收、分布、代谢和排泄。此外,毒性因素可能影响剂量和给药方案。当口服给药时,在指定时间期限内,丸剂、胶囊剂或片剂可每日服用,或以更低的频率服用。所述方案可重复多个治疗周期。
用式I化合物治疗的方法
本发明的式I化合物用于治疗患有起因于与Btk激酶相关的异常的细胞生长、功能或行为的疾病或病症的人或动物患者,所述疾病或病症是例如免疫病症、心血管疾病、病毒感染、炎症、代谢/内分泌障碍或神经障碍,因此可通过包括向其给药如上定义的本发明的化合物的方法来治疗。患有癌症的人或动物患者还可通过包括向其给药如上定义的本发明的化合物的方法来治疗。由此可改进或改善所述患者的病症。
式I化合物可用于体外、原位和体内诊断或治疗哺乳动物细胞、生物体或相关的病理状态,例如系统性和局部性炎症、免疫炎性疾病例如类风湿性关节炎、免疫抑制、器官移植排斥、变态反应、溃疡性结肠炎、克罗恩病、皮炎、哮喘、系统性红斑狼疮、斯耶格伦综合征、多发性硬化、硬皮病/系统性硬化病、特发性血小板减少性紫癜(ITP)、抗中性粒细胞胞质抗体(ANCA)血管炎、慢性阻塞性肺病(COPD)、银屑病,以及总体关节保护效力。
本发明的方法还包括治疗疾病例如:关节疾病例如类风湿性关节炎、单关节炎、骨关节炎、痛风性关节炎、脊椎炎;贝切特病;脓毒症、败血症性休克、内毒素性休克、革兰阴性脓毒症、革兰阳性脓毒症和中毒性休克综合征;败血病继发性多器官损伤综合征、外伤或出血;眼病例如变应性结膜炎、春季结膜炎、葡萄膜炎以及甲状腺相关的眼病;嗜酸性细胞肉芽肿;肺部或呼吸道病症例如哮喘、慢性支气管炎、变应性鼻炎、ARDS、慢性肺部炎性疾病(例如慢性阻塞性肺病)、矽肺、肺结节病、胸膜炎、肺泡炎、血管炎、肺气肿、肺炎、支气管扩张和肺型氧中毒;心肌、脑或肢端的再灌注损伤;纤维化例如囊性纤维化;瘢痕疙瘩形成或疤痕组织形成;动脉粥样硬化;自身免疫疾病例如系统性红斑狼疮(SLE)、自身免疫性甲状腺炎、多发性硬化、糖尿病的一些形式和雷诺综合征;以及移植排斥性病症例如GVHD和同种异体移植物排斥;慢性肾小球肾炎;炎性肠病例如慢性炎性肠病(CIBD)、克罗恩病、溃疡性结肠炎和坏死性小肠结肠炎;炎性皮肤病例如接触性皮炎、特应性皮炎、银屑病或风疹;起因于感染的发烧和肌痛;中枢或周围神经系统炎性病症例如脑膜炎、脑炎以及起因于较轻外伤的脑或脊髓损伤;斯耶格伦综合征;涉及白细胞渗出的疾病;酒精性肝炎;细菌性肺炎;抗原-抗体复合物介导的疾病;低血容量性休克;I型糖尿病;急性和迟发性超敏反应;起因于白细胞恶液质和转移的疾病状态;热损伤;粒细胞输血相关的综合征;以及细胞因子诱导的中毒。
本发明的方法还包括治疗选自以下的癌症:乳腺癌、卵巢癌、宫颈癌、前列腺癌、睾丸癌、生殖泌尿道癌、食道癌、喉癌、成胶质细胞瘤、神经母细胞瘤、胃癌、皮肤癌、角化棘皮瘤、肺癌、表皮样癌、大细胞癌、非小细胞肺癌(NSCLC)、小细胞癌、肺腺癌、骨癌、结肠癌、腺瘤、胰腺癌、腺癌、甲状腺癌、滤泡性癌、未分化癌、乳头状癌、精原细胞瘤、黑素瘤、肉瘤、膀胱癌、肝癌和胆道癌、肾癌、胰腺癌、骨髓病症、淋巴瘤、毛细胞癌、口腔癌、鼻咽癌、咽癌、唇癌、舌癌、口癌、小肠癌、结直肠癌、大肠癌、直肠癌、脑和中枢神经系统癌、何杰金淋巴瘤、白血病、支气管癌、甲状腺癌、肝和肝内胆管癌、肝细胞癌、胃癌、神经胶质瘤/成胶质细胞瘤、子宫内膜癌、黑素瘤、肾和肾盂癌、膀胱癌、子宫体癌、子宫颈癌、多发性骨髓瘤、急性髓性白血病、慢性髓性白血病、淋巴细胞白血病、慢性淋巴细胞白血病(CLL)、髓样白血病、口腔和咽癌、非何杰金淋巴瘤、黑素瘤和结肠绒毛腺瘤。
本发明的方法可用于治疗受到或可能受到再灌注损伤(即,由组织或器官经受一段时间的缺血而后再灌注的情形造成的损伤)的受试者。术语“缺血”是指由阻塞动脉血的流入导致的局部组织贫血。短暂缺血而后再灌注特征性地导致中性粒细胞激活并移形经过受影响区域中的血管的内皮。被激活的中性粒细胞的积累转而导致产生反应性氧代谢物,其损害相关组织或器官的组成部分。“再灌注损伤”的这种现象通常与诸如血管中风(包括全脑缺血和病灶缺血)、出血性休克、心肌缺血或梗死形成、器官移植和脑血管痉挛之类的病症相关。举例说明,再灌注损伤发生在心脏搭桥手术结束时或者发生在心脏停博的过程中(当曾被阻止接受血液的心脏起始再灌注时)。据预期,对Btk活性的抑制可导致在这样的情形中再灌注损伤的量减小。
药物制剂
为了使用本发明化合物用于对哺乳动物(包括人)进行治疗性处置,通常根据标准药学实践将其配制为药物组合物。根据本发明的这一方面,其提供了药物组合物,其包含本发明化合物,以及结合有药用稀释剂或载体。
典型的制剂通过将本发明化合物与载体、稀释剂或赋形剂混合来制备。合适的载体、稀释剂和赋形剂是本领域技术人员公知的,并且包括以下物质,诸如碳水化合物、蜡、水溶性聚合物和/或水可溶胀聚合物(swellablepolymer)、亲水性物质或疏水性物质、明胶、油、溶剂、水等。所用的具体载体、稀释剂或赋形剂将取决于应用本发明化合物的方式和目的。通常基于本领域技术人员认为给予哺乳动物安全的溶剂(GRAS)来选择溶剂。一般而言,安全溶剂为无毒性含水溶剂如水和可在水中溶解或混溶的其它无毒性溶剂。合适的含水溶剂包括水、乙醇、丙二醇、聚乙二醇(例如,PEG400、PEG300)等及其混合物。制剂还可包括以下物质中的一种或多种:缓冲剂、稳定剂、表面活性剂、润湿剂、润滑剂、乳化剂、助悬剂、防腐剂、抗氧化剂、遮光剂(opaquing agent)、助流剂、加工助剂(processing aid)、着色剂、增甜剂、芳香剂、矫味剂和提供药物(即本发明化合物或其药物组合物)的优质外观或辅助制造药物产品(即药物)的其它已知添加剂。
制剂可使用常规溶出和混合操作制备。例如,将大块的药品(即,本发明化合物或化合物的经稳定形式(例如,与环糊精衍生物或其它已知复合剂(complexation agent)的复合物))在一种或多种上述的赋形剂存在下溶于合适的溶剂中。通常将本发明化合物配制成提供容易可控制药物的剂量且使患者能够依从所给出的方案的药物剂型。
取决于用于给药药物的方法,用于施用的药物组合物(或制剂)可按多种方式包装。一般地,用于分配的物品包括容器,容器内存放有适当形式的药物制剂。合适的容器是本领域技术人员公知的,并且包括以下物质,诸如瓶(塑料的和玻璃的)、小袋(sachet)、安瓿、塑料袋、金属圆筒等。容器还可包括防止不慎重取得包装中的内含物的的防干扰装置(tamper-proofassemblage)。此外,在容器上具有描述容器中的内含物的标签。所述标签还可包括适当的注意事项。
可制备本发明化合物的药物制剂用于多种给药途径和类型。例如,具有期望的纯度的式I的化合物可任选与药用稀释剂、载体、赋形剂或稳定剂(Remington's Pharmaceutical Sciences(1980)16th edition,Osol,A.Ed.)以冻干制剂、磨细的粉末剂或水溶液剂形式混合。配制可如下进行:在环境温度在适当的pH以及在适当的纯度与生理学可接受的载体(即在采用的剂量和浓度下对受体是无毒性的载体)混合。制剂的pH主要取决于具体用途和化合物的浓度,但范围可为约3至约8。在乙酸盐缓冲液中pH为5的制剂是合适的实施方案。
化合物通常可储存为固体组合物、冻干制剂或水溶液剂。
本发明的药物组合物将按照与良好医学实践一致的方式(即量、浓度、时间表、过程、媒介物和给药途径)来配制、确定剂量和给药。在此背景下考虑的因素包括所治疗的具体病症、所治疗的具体哺乳动物、个体患者的临床情况、病症的起因、药物的递送位点、给药方法、给药的时间表和医学实践者已知的其它因素。所给药的化合物的“治疗有效量”将由这些考虑因素控制,并且是改善或治疗过度增殖性病症所需的最小量。
作为通常的建议,每剂量肠胃外给药的初始药学有效量的抑制剂为约每日0.01-100毫克/kg,即约0.1至20毫克/kg患者体重,所使用的化合物的典型的最初范围为0.3至15毫克/kg/日。
可接受的稀释剂、载体、赋形剂和稳定性在所用的剂量和浓度下对受体是无毒性的,并且包括缓冲剂诸如磷酸盐、枸橼酸盐和其它有机酸;抗氧化剂,包括抗坏血酸和蛋氨酸(methionine);防腐剂(如十八烷基二甲基苄基氯化铵;氯化六甲双铵(hexamethonium chloride);苯扎氯铵、苄索氯胺;苯酚、丁醇或苄醇;对羟基苯甲酸烷基酯,如对羟基苯甲酸甲酯或对羟基苯甲酸丙酯;儿茶酚;间苯二酚(resorcinol);环己醇;3-戊醇和间甲酚);低分子量(少于约10个残基)多肽;蛋白质,如血清白蛋白、明胶或免疫球蛋白;亲水性聚合物,如聚乙烯吡咯烷酮;氨基酸,如甘氨酸、谷氨酰胺、天冬酰胺、组氨酸、精氨酸或赖氨酸;单糖、二糖和其它碳水化合物,包括葡萄糖、甘露糖或糊精;螯合剂,如EDTA;糖如蔗糖、甘露醇、海藻糖或山梨醇;成盐的抗衡离子,如钠;金属络合物(例如,Zn-蛋白质络合物);和/或非离子型表面活性剂,如TWEENTM、PLURONICSTM或聚乙二醇(PEG)。活性药物成分还可包埋在通过例如凝聚技术或通过界面聚合制备的微胶囊中,例如在胶体药物递送系统(例如脂质体、白蛋白微球、微乳液、纳米颗粒和纳米胶囊(nanocapsules))中或在宏观乳液(macroemulsion)中,分别为羟基甲基纤维素或明胶微胶囊和聚-(甲基丙烯酸甲酯)微胶囊。所述技术披露于Remington'sPharmaceutical Sciences16th edition,Osol,A.Ed.(1980)中。
可制备式I的化合物的缓释制剂。缓释制剂的合适实例包括含有式I的化合物的的固态疏水性聚合物的半渗透性基质,其中基质以成形的物品形式(例如薄膜或微胶囊)存在。缓释基质的实例包括聚酯、水凝胶(例如,聚(甲基丙烯酸2-羟基乙酯)或聚(乙烯醇))、聚交酯(US3,773,919)、L-谷氨酸和γ-乙基-L-谷氨酸的共聚物、非降解性乙烯-乙酸乙烯酯、降解性乳酸-羟乙酸共聚物如LUPRON DEPOTTM(由乳酸-羟乙酸共聚物和醋酸亮丙瑞林组成的可注射微球)和聚-D-(-)-3-羟基丁酸。
所述制剂包括适于本申请详述的给药途径的制剂。制剂可适宜地以单位剂量形式存在并可通过药学领域公知的任何方法制备。技术和制剂通常参见Remington's Pharmaceutical Sciences(Mack Publishing Co.,Easton,PA)。所述方法包括使活性成分与构成一种或多种助剂(accessory ingredient)的载体结合的步骤。通常制剂如下制备:使活性成分与液态载体或微细分散的固态载体或与这两种载体同时均匀和紧密的结合,然后必要时,对产品进行成型。
适于口服给药的式I的化合物的制剂可制备为离散的单位,如各自含有预定量的式I的化合物的丸剂、胶囊剂、扁囊剂或片剂。压制片可如下制备:在合适的机器中对自由流动形式(如粉末或颗粒)的活性成分以及任选混合的粘合剂、润滑剂、惰性稀释剂、防腐剂、表面活性剂或分散剂进行压制。模制片可如下制备:在合适的机器中对用惰性液态稀释剂润湿的粉末状活性成分的混合物进行模制。可任选对片剂进行包衣或刻痕,并任选进行配制以提供活性成分从其中缓慢或控制释放。可制备片剂、含片(troche)、糖锭、水性混悬剂或油性混悬剂、可分散粉末剂或可分散颗粒剂、乳剂、硬胶囊剂或软胶囊剂例如明胶胶囊、糖浆剂或酏剂,以用于口服。预期用于口服的式I的化合物的制剂可根据制备药物组合物的领域已知的任何方法制备,所述组合物可含有一种或多种试剂,包括增甜剂、矫味剂、着色剂和防腐剂,以提供适口的制剂。含有活性成分以及混合有适于制造片剂的无毒性生理学可接受的赋形剂的片剂是可接受的。这些赋形剂可以是,例如,惰性稀释剂,如碳酸钙或碳酸钠、乳糖、磷酸钙或磷酸钠;成粒剂和崩解剂(granulating anddisintegrating agent),如玉米淀粉或海藻酸;粘合剂,如淀粉、明胶或阿拉伯胶;以及润滑剂,如硬脂酸镁、硬脂酸或滑石。片剂可以是未包衣的或可通过已知技术(包括微胶囊化)包衣,以延迟在胃肠道的崩解和吸收,由此在较长的时间提供持续的作用。例如,可采用定时延迟物质,如单独的或与蜡结合的单硬脂酸甘油酯或二硬脂酸甘油酯。
对于治疗眼部或其它外部组织如嘴和皮肤而言,所述制剂优选应用为局部软膏剂(ointment)或乳膏剂(cream),其含有的活性成分的量为例如,0.075至20%w/w。当配制成软膏剂时,活性成分可与石蜡(paraffinic)或可与水混溶的软膏基质一起使用。可供选择地,活性成分可与水包油性乳膏基质一起配制成乳膏。如果期望的话,乳膏基质的水相可包括多元醇,即,具有两个或更多个羟基的醇,如丙二醇、丁-1,3-二醇、甘露醇、山梨醇、甘油和聚乙二醇(包括PEG400)及这些醇的混合物。局部制剂可包括增强活性成分通过皮肤或其它作用区域吸收或渗透的化合物。所述皮肤渗透增强剂的实例包括二甲基亚砜和相关类似物。本发明的乳剂的油相可由已知成分以已知方式构成。当所述相可仅包含乳化剂时,预期其包含至少一种乳化剂与脂肪或油或与脂肪和油两者的混合物。优选地,可包括亲水性乳化剂以及作为稳定剂的亲脂性乳化剂。其还优选同时包括油和脂肪。同时,含有或不含有稳定剂的乳化剂构成了所谓的乳化蜡(emulsifying wax),所述蜡和油和脂肪一起构成了形成软膏制剂的油性分散相的所谓乳化软膏基质。适用于本发明制剂的乳化剂和乳化稳定剂包括60、80、十八醇/十六醇(cetostearylalcohol)、苄醇、肉豆蔻醇、单硬脂酸甘油酯和月桂基硫酸钠。
式I的化合物的水性混悬剂含有活性物质以及混合有适于制备水性混悬剂的赋形剂。所述赋形剂包括助悬剂,如羧甲基纤维素钠、交联羧甲基纤维素、聚维酮、甲基纤维素、羟丙基甲基纤维素、海藻酸钠、聚乙烯吡咯烷酮、西黄蓍胶和阿拉伯胶,以及分散或润湿剂(dispersing or wetting agent),如天然存在的磷脂(例如,卵磷脂)、烯化氧与脂肪酸的缩合产物(例如,聚氧乙烯硬脂酸酯)、环氧乙烷与长链脂肪醇的缩合产物(例如,十七亚乙氧基十六醇(heptadeca ethyleneoxycetanol))、环氧乙烷与衍生自脂肪酸和己糖醇脱水物(hexitol anhydride)的偏酯的缩合产物(例如,聚氧乙烯脱水山梨糖醇单油酸酯(polyoxyethylene sorbitan monooleate))。水性混悬剂还可含有一种或多种防腐剂如对羟基苯甲酸乙酯或对羟基苯甲酸正丙酯、一种或多种着色剂、一种或多种矫味剂和一种或多种增甜剂如蔗糖或糖精。
式I的化合物的药物组合物可呈无菌注射制剂,如无菌注射水性混悬剂或油性悬浮液制剂形式存在。该悬浮液可使用上文已提及的合适的分散剂或润湿剂和助悬剂根据本领域已知方法配制。无菌注射制剂还可以是于无毒性的肠胃外可接受的稀释剂或溶剂中的无菌注射溶液或悬浮液,如于1,3-丁二醇中的溶液,或制备为冻干粉末。可使用的可接受媒介物和溶剂包括水、林格氏溶液(Ringer's solution)和等张氯化钠溶液。此外,无菌不挥发性油(sterilefixed oil)通常可用作溶剂或助悬介质。出于该目的,可采用任何温和的不挥发性油,包括合成性甘油一酯或甘油二酯。此外,脂肪酸如油酸同样可用于制备注射剂。
可与载体物质结合以产生单一剂量形式的活性成分的量将随着所治疗的宿主和具体的给药模式而变化。例如,意在对人类口服给药的定时释放制剂可含有约1至1000毫克活性物质,以及混合有适当和适宜量的载体物质,所述载体其可占总组合物(重量:重量)的约5至约95%。可制备药物组合物以提供给药时容易测量的量。例如,意在用于静脉输注的水溶液每毫升溶液可含有约3至500μg活性成分,从而合适体积的输注以约30毫升/hr的速率出现。
适于肠胃外给药的制剂包括水性和非水性无菌注射溶液剂,其可含有抗氧化剂、缓冲剂、抑菌剂和使得制剂与预期受体的血液等张的溶质;以及水性和非水性无菌混悬剂,其可包括助悬剂和增稠剂。
适于局部给药至眼部的制剂还包括滴眼剂,其中将活性成分溶于或悬浮于合适的载体(尤其是活性成分的含水溶剂)中。在所述制剂中存在的活性成分的浓度优选为约0.5至20%w/w,例如约0.5至10%w/w,例如约1.5%w/w。
适于在口内局部给药的制剂包括糖锭(lozenge),其含有于矫味基质(通常是蔗糖和阿拉伯胶或西黄蓍胶)中的活性成分;锭剂(pastille),其含有于惰性基质(如明胶和甘油,或蔗糖和阿拉伯胶)中的活性成分;以及漱口剂,其包含于液态载体中的活性成分。
适于直肠给药的制剂可呈现为栓剂形式,其具有合适基质(其包含例如可可脂或水杨酸酯)。
适于肺内或经鼻给药的制剂具有例如为0.1至500微米的粒度(包括在0.1和500微米之间,增量为例如0.5、1、30微米、35微米等的粒度),其通过鼻道经快速吸入给药或通过口经吸入给药,以便到达肺泡囊(alveolarsacs)。合适的制剂包括活性成分的水性或油性溶液剂。适于气雾剂或干粉给药的制剂可根据常规方法制备,并可与其它治疗药物(如迄今用于治疗或预防下文所述的病症的化合物)一起递送。
适于阴道给药的制剂可呈现为阴道栓剂、棉塞(tampon)、乳膏剂、凝胶剂、糊剂、泡沫或喷雾制剂,这些制剂除了活性成分外还含有本领域已知为适当的载体。
制剂可包装在单位剂量或多剂量容器例如密封安瓿或小瓶中,并且可在冷冻干燥(冻干)条件下储存,在立即使用前仅需要加入无菌液态载体例如水,用于注射。即时注射溶液剂(Extemporaneous injection solutions and suspension)和混悬剂从前述种类的无菌粉末、颗粒和片剂制备。优选的单位剂量制剂是含有本申请上文所述的日剂量或单位日亚剂量(sub-dose)或其适当分数的活性成分的制剂。
本发明还提供了兽用组合物(veterinary composition),由此其含有上文定义的至少一种活性成分以及兽用载体。兽用载体是用于给药所述组合物目的的物质,并可为固态、液态或气态物质,这些物质在兽医领域要么是惰性的要么是可接受的,并且与活性成分相容。这些兽用组合可经肠胃外、口服或经任何其它期望的途径给药。
组合治疗
式I化合物可单独使用,或者与用于治疗本申请所述的疾病或病症例如炎症或过度增殖性病症(例如癌症)的其它治疗剂组合使用。在一些实施方案中,在药学组合制剂或者作为组合治疗的给药方案中,将式I化合物与具有抗炎性或抗过度增殖性或者用于治疗炎症、免疫反应性病症或过度增殖性病症(例如癌)的另外的第二治疗性化合物组合。另外治疗剂可为抗炎剂、免疫调节剂、化疗剂、细胞凋亡强化剂、神经营养因子、心血管疾病的治疗剂、肝病的治疗剂、抗病毒剂、血液疾病的治疗剂、糖尿病的治疗剂以及免疫缺陷病症的治疗剂。所述第二治疗剂可以是NSAID抗炎药。所述第二治疗剂可以是化疗剂。所述药学组合制剂或给药方法的第二化合物优选地具有与式I化合物互补的活性,从而它们不会不利地相互影响。这样的化合物适合地以对预期目的有效的量组合存在。在一个实施方案中,本发明的组合物包含式I化合物或其立体异构体、互变异构体、溶剂化物、代谢物或药用盐或前药与治疗剂例如NSAID的组合。
组合治疗可作为同时或先后方案给药。当先后给药时,组合物可按两次或多次给药方式给药。联用给药包括使用分开的制剂或单一的药物制剂同时给药,和以任一顺序先后给药,其中优选的是存在两种(或所有)活性药物同时发挥其生物活性的一段时间。
任何上述同时给药药物的合适剂量是目前所用的剂量,并且由于新鉴定的药物和其它治疗剂或治疗的联用作用(协同),所述剂量可降低。
联用治疗可提供“协同(synergy)”及提供“协同作用(synergistic)”,即,当活性成分一起使用时实现的作用大于分别使用这些化合物导致的作用的总和。当活性成分:(1)在组合的单位剂量制剂中同时配制以及同时给药或递送时;(2)作为分开的制剂经交替或平行递送时;或(3)通过一些其它方案给药时,可达到协同作用。当在交替治疗中递送时,当化合物例如通过在分开的注射器中分开注射,通过分开的丸剂或胶囊剂或分开输注而先后给药或递送时,可达到协同作用。一般而言,在交替治疗期间,将有效剂量的各种活性成分先后(即顺次)给药,而在联用治疗中,将有效剂量的两种或多种活性成分一起给药。
在治疗的一个具体的实施方案中,式I的化合物或其立体异构体、互变异构体、溶剂化物、代谢产物或药用盐或前药,可与其它治疗剂、激素药物或抗体药物(例如本申请描述的药物)联用,或与外科治疗和放射治疗联用。根据本发明的联用治疗由此包括给药至少一种式I的化合物或其立体异构体、互变异构体、溶剂化物、代谢产物或药用盐或前药,以及使用至少一种其它癌症治疗方法。将对式I的化合物和其它药学活性的治疗剂的量和相关的给药时限进行选择,以便实现期望的联用治疗作用。
式I化合物的代谢物
本申请描述的式I的体内代谢物也落入本发明的范围内。所述产物可以是由例如所给药的化合物的氧化、还原、水解、酰胺化、脱酰胺化、酯化、脱脂化、酶法裂解等而引起的。因此,本发明包括式I的化合物的代谢物,包括由以下方法产生的化合物,所述方法包括使本发明化合物与哺乳动物接触足以产生其代谢物的一段时间。
代谢物通常如下鉴定:制备本发明化合物的放射标记的(例如,14C或3H)同位素,将其以可检测的剂量(例如,大于约0.5毫克/kg)肠胃外给药至动物,如大鼠、小鼠、豚鼠、猴或给药至人,允许足够发生代谢的时间(通常约30秒至30小时),然后将其转化产物与尿、血样或其它生物试样分离。这些产物容易分离,因为它们进行了标记(其它的通过使用能够与代谢物中存活的抗原表位结合的抗体来分离)。代谢物结构以常规方式,例如通过MS、LC/MS或NMR分析确定。一般而言,代谢物的分析以与本领域技术人员公知的常规药物代谢研究中相同的方式完成。所述代谢物,只要它们不是在体内另外存在的,就用于本发明化合物的治疗剂量的诊断测定。
制品
在本发明的另一实施方案中,其提供了含有用于治疗上文描述的疾病和病症的物质的制品和“试剂盒”。在一个实施方案中,所述试剂盒包含容器,所述容器包含式I的化合物或其立体异构体、互变异构体、溶剂化物、代谢产物或药用盐或前药。所述试剂盒还可包含附在容器上或容器中的标签或包装说明书。术语“包装说明书”用来指通常包括在治疗产品的市售包装中的说明书,其含有关于适应症、用法、剂量、给药、禁忌症和/或注意事项的信息,这些信息涉及所述治疗产品的使用。合适的容器包括,例如,瓶、小瓶、注射器、发泡包装(blister pack)等。容器可从多种材料(如玻璃或塑料)形成。容器可装有有效治疗所述病症的式I的化合物或其制剂,并可具有无菌入口(例如,容器可为静脉注射溶液袋或具有可由皮下注射针头刺穿的塞子的小瓶)。在组合物中至少一种活性药物是式I的化合物。标签或包装说明书指示所述组合物用于治疗选择的病症如癌症。此外,标签或包装说明书可指示待治疗的患者是患有病症如过度增殖性病症、神经变性、心脏肥大、疼痛、偏头痛或神经创伤性疾病或事件的患者。在一个实施方案中,标签或包装说明书指示包含式I的化合物的组合物可用于治疗起因于异常细胞生长的病症。标签或包装说明书还可指示所述组合物可用于治疗其它病症。可供选择地或另外地,所述制品还可包含第二种容器,所述容器包含药用缓冲液,如抑菌性注射用水(BWFI)、磷酸盐缓冲生理盐水、林格氏溶液和葡萄糖溶液。试剂盒还可包括从商业和使用者角度看是期望的其它物质,包括其它缓冲液、稀释剂、滤器、针头和注射器。
试剂盒还可包含给药式I的化合物以及第二种药物制剂(如果存在)的说明。例如,若试剂盒包含第一种组合物(含有式I的化合物)和第二种药物制剂,则试剂盒还可包含将第一种和第二种药物组合物同时、先后或分开给予需要所述制剂的患者的说明。
在另一实施方案中,试剂盒适于递送固态口服形式的式I的化合物,如片剂或胶囊剂。这样的试剂盒优选包括多个单位剂量。所述试剂盒可以包括针对预期用途为目的的剂量卡片。这样的试剂盒的一个实例是“泡罩包装”。泡罩包装在包装工业中是公知的,并且广泛用于包装药物单位剂量形式。如果期望的话,可提供记忆辅助装置(memory aid),其可呈例如数字、字母或其它标记形式,或具有日历插入物,所述记忆辅助装置指定在可对所述剂量进行给药的治疗时间表中的天数。
根据一个实施方案,试剂盒可包含(a)在其中含有式I的化合物的第一个容器;以及任选地(b)在其中含有第二种药物制剂的第二个容器,其中所述第二种药物制剂包含具有抗过度增殖活性的第二种化合物。可供选择地或另外地,所述试剂盒还可包含第三个容器,其包含药用缓冲液,如抑菌性注射用水(BWFI)、磷酸盐缓冲生理盐水、林格氏溶液和葡萄糖溶液。其还可包括从商用和使用者角度来看是期望的其它物质,包括其它缓冲液、稀释剂、滤器、针头和注射器。
在试剂盒包含式I和第二种治疗药物的组合物的某些其它实施方案中,所述试剂盒可包含用于容纳分开的组合物的容器,如分开的瓶或分开的箔包装(foil packet),然而,分开的组合物还可容纳在单一的未分开的容器中。典型地,试剂盒包含给药分开的组分的说明。当分开的组分优选以不同剂量形式(例如口服和肠胃外)给药时,当以不同剂量间隔给药时,或当对联用的单独组分进行滴定对主治医师是期望之时,试剂盒形式是特别有益的。
式I化合物的制备
式I的化合物可通过合成途径来合成,所述合成途径包括与化学领域中公知的方法类似的方法,具体而言是借助本申请所包含的说明书,以及针对所述其它杂环的方法:Comprehensive Heterocyclic Chemistry II,EditorsKatritzky and Rees,Elsevier,1997,e.g.Volume3;Liebigs Annalen der Chemie,(9):1910-16,(1985);Helvetica Chimica Acta,41:1052-60,(1958);Arzneimittel-Forschung,40(12):1328-31,(1990),清楚地将其各自引入作为参考。起始物质通常可从商业来源如Aldrich Chemicals(Milwaukee,WI)得到或者使用本领域的技术人员公知的方法容易地制备(例如,通过Louis F.Fieserand Mary Fieser,Reagents for Organic Synthesis,v.1-23,Wiley,N.Y.(1967-2006ed.),或者Beilsteins Handbuch der organischen Chemie,4,Aufl.ed.Springer-Verlag,Berlin,包括附录(还可通过Beilstein网上数据库得到)中通常所述的方法制备)。
在合成式I化合物中有用的合成化学转化和保护基方法学(保护和脱保护)及必要的试剂和中间体是本领域中已知的并包括,例如,在R.Larock,Comprehensive Organic Transformations,VCH Publishers(1989);T.W.Greeneand P.G.M.Wuts,Protective Groups in Organic Synthesis,3rd Ed.,John Wileyand Sons(1999);and L.Paquette,ed.,Encyclopedia of Reagents for OrganicSynthesis,John Wiley and Sons(1995)及其后续版本中所描述的那些。
式I的化合物可单独制备或作为包含至少2种,例如5至1,000种或10至100种化合物的化合物库来制备。式I的化合物库可通过本领域技术人员已知的操作,使用溶液相或固相化学,通过组合的“分裂和混合(split andmix)”途径来制备,或通过多平行合成(multiple parallel syntheses)来制备。由此根据本发明的另一个方法,其提供了含有至少2种化合物或其药用盐的化合物库。
附图和实施例提供了制备式I化合物的示例性方法。本领域的技术人员应当理解的是,其它合成途径可用于合成式I化合物。虽然在附图和实施例中描述并讨论了具体的起始物质和试剂,但是其它起始物质和试剂可容易地被替换,从而提供多种衍生物和/或反应条件。除此之外,多种通过所述方法制备的示例性化合物可根据本公开使用本领域的技术人员所熟知的常规化学来进一步修饰。
在制备式I的化合物时,对中间体的远距离官能团(例如,伯胺或仲胺)的保护可能是必要的。对所述保护的需要将随着远距离官能团(remotefunctionality)的性质和制备方法的条件而变化。合适的氨基保护基包括乙酰基、三氟乙酰基、叔丁氧基羰基(BOC)、苄基氧基羰基(CBZ)和9-芴基甲氧基羰基(Fmoc)。对所述保护的需要由本领域技术人员容易地确定。对于保护基及其用途的一般描述,参见T.W.Greene,Protective Groups in OrganicSynthesis,John Wiley&Sons,New York,1991。
用于制备式I化合物的实验步骤、中间体和试剂可在2011年5月6日提交的US13/102720,“PYRIDONE AND AZA-PYRIDONE COMPOUNDSAND METHODS OF USE”中找到,将其全部内容通过引用的方式并入本申请。
图1-14描述了式I化合物101-115的示例性实施方案的合成,更全面地描述在实施例101-114中,并可用于制备其它式I化合物。
一般制备方法
一般方法:Suzuki偶联
Suzuki型偶联反应用来形成碳-碳键,以连接式I化合物和中间体例如A-3的环(Suzuki(1991)Pure Appl.Chem.63:419-422;Miyaura和Suzuki(1979)Chem.Reviews95(7):2457-2483;Suzuki(1999)J.Organometal.Chem.576:147-168)。Suzuki偶联是钯介导的杂芳基卤例如B-2或B-4与硼酸例如A-1或A-2的交叉偶联反应。例如,可将B-2与约1.5当量的4,4,4',4',5,5,5',5'-八甲基-2,2'-二(1,3,2-二氧杂硼杂环戊烷)混合,并且溶于约3当量的碳酸钠(1M水溶液)和等体积的乙腈中。加入催化量或更多的低价钯试剂例如二(三苯基膦)二氯化钯(II)。在一些情况中,用乙酸钾替代碳酸钠来调节水层的pH。然后将反应混合物在微波反应器(Biotage AB,Uppsala,Sweden)中,在压力下加热至约140-150℃且保持10-30分钟。用乙酸乙酯或另一种有机溶剂萃取内容物。在蒸发有机层后,可在硅胶上或通过反相HPLC纯化硼酸酯A-1。取代基如所定义的那些,或者是其受保护形式或前体。同样,可将溴化物中间体B-4硼酸酯化得到A-2。
B-2和A-2或者A-1和B-4的Suzuki偶联产生式I化合物或中间体A-3。将硼酸酯(或硼酸)(1.5当量)A-1或A-2和钯催化剂例如二(三苯基膦)二氯化钯(II)(0.05当量)加入到卤代中间体(1当量)B-2或B-4在乙腈和1M碳酸钠水溶液(与乙腈等体积)中的混合物中。将反应混合物在微波中加热至约150℃且保持约15分钟。LC/MS指示何时反应完成。将水加入到混合物中,过滤沉淀的产物,然后通过HPLC纯化得到产物A-3。取代基如所定义的那些,或者其被保护的形式或前体。
在Suzuki偶联步骤中可使用各种钯催化剂。各种低价Pd(II)和Pd(0)催化剂可用于Suzuki偶联反应,包括PdCl2(PPh3)2、Pd(t-Bu)3、PdCl2dppfCH2Cl2、Pd(PPh3)4、Pd(OAc)/PPh3、Cl2Pd[(Pet3)]2、Pd(DIPHOS)2、Cl2Pd(Bipy)、[PdCl(Ph2PCH2PPh2)]2、Cl2Pd[P(o-tol)3]2、Pd2(dba)3/P(o-tol)3、Pd2(dba)/P(furyl)3、Cl2Pd[P(furyl)3]2、Cl2Pd(PMePh2)2、Cl2Pd[P(4-F-Ph)3]2、Cl2Pd[P(C6F6)3]2、Cl2Pd[P(2-COOH-Ph)(Ph)2]2、Cl2Pd[P(4-COOH-Ph)(Ph)2]2,以及包封的催化剂Pd EnCatTM30、Pd EnCatTMTPP30和Pd(II)EnCatTM BINAP30(US2004/0254066)。
一般方法:Buchwald反应
Buchwald反应用于氨化6-溴中间体B-1(Wolf和Buchwald(2004)Org.Synth Coll.Vol.10:423;Paul等人(1994)Jour.Amer.Chem.Soc.116:5969-5970)。向卤代中间体B-1在DMF中的溶液中加入适合的胺R5-NH2(200mol%)、Cs2CO3(50mol%)、Pd2(dba)3(5mol%)和4,5-二(二苯基膦基)-9,9-二甲基呫吨(Xantphos,CAS登记号161265-03-8,10mol%)。将反应混合物在微波反应器(Biotage AB,Uppsala,Sweden)中,在压力下加热至约110℃且保持约30分钟。在真空中浓缩所得的溶液得到B-2。可使用其它钯催化剂和膦配体。
N-杂芳基酰胺中间体B-4也可用环状酰胺中间体(R7)例如3,4,6,7,8,9-六氢吡嗪并[1,2-a]吲哚-1(2H)-酮101g和杂芳基二溴化物B-3在Buchwald条件下进行制备。
分离方法
在制备式I化合物的方法中,将反应产物彼此分离和/或与原料分离可能是有益的。通过本领域常见技术将每步或多步中期望的产物分离和/或纯化为期望的均匀性程度。通常所述分离涉及多相萃取、从溶剂或溶剂混合物中结晶、蒸馏、升华或色谱法。色谱法可涉及任何数目的方法,包括例如:反相和正相;尺寸排阻(size exclusion);离子交换;高、中和低压液相色谱方法和装置;小规模分析;模拟移动床(SMB)和制备性薄层或厚层色谱,以及小规模薄层和快速色谱技术。
另一类分离方法涉及用所选择的试剂处理混合物,从而与期望的产物、未反应的原料、反应副产物等结合或使得期望的产物、未反应的原料、反应副产物等分离。所述试剂包括吸附剂(adsorbent)或吸收剂(absorbent),如活性炭、分子筛、离子交换介质等。可供选择地,所述试剂可以是酸(在碱性物质的情况下),碱(在酸性物质的情况下),结合剂如抗体、结合蛋白,选择性螯合剂如冠醚,液/液离子交换试剂(LIX)等。对适当的分离方法的选择依赖于所涉及的物质的性质。例如,沸点和分子量(在蒸馏和升华中)、存在或不存在极性官能团(在色谱法中)、在酸性和碱性介质中物质的稳定性(在多相萃取中)等等。
可通过本领域技术人员公知的方法(如色谱法和/或分级结晶),基于非对映异构体的物理化学差别,将非对映异构混合物分离为其单独的非对映异构体。对映异构体可通过以下方式分离:通过使对映异构体混合物与适当的光学活性的化合物(例如,手性助剂如手性醇或Mosher's酰氯)反应将其转化为非对映异构混合物,分离非对映异构体,然后将单独的非对映异构体转化(例如,水解)为相应的纯的对映异构体。此外,一些本发明化合物可以是阻转异构体(例如,取代的联芳(biaryl))并视为本发明的部分。对映异构体也可通过使用手性HPLC柱分离。
单一的立体异构体,例如,基本上不含其立体异构体的对映异构体,可通过以下方式获得:使用诸如形成非对映异构体的方法,用光学活性的拆分剂来拆分外消旋混合物(Eliel,E.and Wilen,S."Stereochemistry of OrganicCompounds,"John Wiley&Sons,Inc.,New York,1994;Lochmuller,C.H.,(1975)J.Chromatogr.,113(3):283-302)。本发明的手性化合物的外消旋混合物可通过任何合适的方法分开和离析,所述方法包括:(1)与手性化合物形成离子性非对映异构的盐,然后通过分级结晶或其它方法分离,(2)与手性衍生试剂形成非对映异构的化合物,分离所述非对映异构体,然后转化为纯的立体异构体,(3)在手性条件下直接分离基本上纯的或富含的立体异构体。参见:"Drug Stereochemistry,Analytical Methods and Pharmacology,"Irving W.Wainer,Ed.,Marcel Dekker,Inc.,New York(1993)。
在方法(1)的情况下,非对映异构的盐可通过以下方式形成:使对映异构纯的手性碱如马钱子碱(brucine)、奎宁、麻黄碱、番木鳖碱(strychnine)、α-甲基-β-苯基乙胺(安非他明)等与带有酸性官能团的不对称化合物如羧酸和磺酸反应。可通过分级结晶或离子色谱法诱导非对映异构体的盐分离。对于氨基化合物的光学异构体的分离而言,加入手性羧酸或磺酸如樟脑磺酸、酒石酸、扁桃酸或乳酸可引起非对映异构体的盐的形成。
可供选择地,通过方法(2),使待拆分的底物与手性化合物的一种对映异构体反应,形成非对映异构对(Eliel,E.and Wilen,S."Stereochemistry ofOrganic Compounds",John Wiley&Sons,Inc.,1994,p.322)。非对映异构化合物可通过以下方式形成:使不对称化合物与对映异构纯的手性衍生试剂如薄荷基衍生物反应,接着分离非对映异构体,然后水解得到纯的或富集的对映异构体。确定光学纯度的方法涉及制备外消旋混合物的手性酯,如在碱的存在下制备薄荷基酯例如(-)氯甲酸薄荷基酯,或Mosher酯,乙酸α-甲氧基-α-(三氟甲基)苯基酯(Jacob III.J.Org.Chem.(1982)47:4165),然后就两种阻转异构的对映异构体或非对映异构体的存在而分析1H NMR光谱。阻转异构化合物的稳定的非对映异构体可遵循分离阻转异构的萘基-异喹啉(WO1996/15111)的方法通过正相和反相色谱分开和离析。通过方法(3),两种对映异构体的外消旋混合物可使用手性固定相通过色谱来分离("Chiral LiquidChromatography"(1989)W.J.Lough,Ed.,Chapman and Hall,New York;Okamoto,J.Chromatogr.,(1990)513:375-378)。富集的或纯化的对映异构体可通过用于区分带有不对称碳原子的其它手性分子的方法(如旋光性或圆二色性)来区分。
实施例
实施例101a 6-氯-8-溴咪唑并[1,2-a]吡啶101a
50℃加热3-溴-5-氯吡啶-2-胺(10g,49mmol)和氯乙醛(H2O中50%,12mL,98mmol)在乙醇(100mL)中的混合物过夜。然后冷却至室温并浓缩。往残留物中加入丙酮(30mL)并快速搅拌所得混合物2h。通过过滤收集所得固体并干燥得到黄色固体状的101a(10.0g,89%)。MS:[M+H]+231。1H NMR(500MHz,DMSO)δ9.20(s,1H),8.33(s,1H),8.29(s,1H),8.09(s,1H)
实施例101b 6-氯-N-(5-(4-甲基哌嗪-1-基)吡啶-2-基)咪唑并[1,2-a]吡啶-8-胺101b
氮气下100℃加热101a(2.3g,10mmol)、5-(4-甲基哌嗪-1-基)吡啶-2-胺(1.9g,10mmol)、XantPhos(576mg,1.0mmol)、Pd2(dba)3(915mg,1.0mmol)和Cs2CO3(6.5g,20mmol)在二噁烷(50mL)中的混合物12h。然后过滤并真空蒸发。通过硅胶柱纯化残留物(采用1:1乙酸乙酯/石油醚洗脱)得到绿色固体状的101b(1.5g,44%)。MS:(M+H)+343。
实施例101c 2,2,2-三氯-1-(4,5,6,7-四氢-1H-吲哚-2-基)乙酮101c
用氮气吹扫配有磁力搅拌器、冷凝器和氮气入口的100-mL单颈圆底烧瓶并装入4,5,6,7-四氢-1H-吲哚(3.00g,24.8mmol)、三氯乙酰氯(13.5g,74.4mmol)和1,2-二氯乙烷(50mL)。85℃搅拌该溶液2h。之后,减压浓缩该反应混合物得到100%收率(6.50g)的黑色半固体状的101c:1H NMR(500MHz,DMSO-d6)δ11.94(s,1H),7.05(s,1H),2.62(t,2H,J=6.0Hz),2.47(t,2H,J=6.0Hz),1.80(m,2H),1.65(m,2H);MS(ESI+)m/z266.0(M+H)
实施例101d 4,5,6,7-四氢-1H-吲哚-2-羧酸乙酯101d
用氮气吹扫配有磁力搅拌器和氮气入口的100-mL单颈圆底烧瓶并装入101c(6.50g,24.8mmol)、乙醇钠(17.0mg,0.25mmol)和乙醇(40mL)。室温搅拌该溶液1h。之后,减压浓缩反应混合物。通过柱色谱纯化残留物得到100%收率(4.80g)的棕色固体状的101d:mp70–72℃;1H NMR(300MHz,CDCl3)δ9.08(s,1H),6.75(s,1H),4.25(q,2H,J=7.2Hz),2.65(t,2H,J=6.0Hz),2.56(t,2H,J=6.0Hz),1.85(m,4H),1.28(t,3H,J=7.2Hz);MS(ESI+)m/z194.1(M+H)
实施例101e 1-(氰基甲基)-4,5,6,7-四氢-1H-吲哚-2-羧酸乙酯101e
用氮气吹扫配有磁力搅拌器和氮气入口的125-mL单颈圆底烧瓶并装入101d(5.76g,29.8mmol)和DMF(50mL)。使用冰浴将该溶液冷却至0℃。加入NaH(矿物油中60%分散液,1.43g,35.8mmol)。室温搅拌所得混合物1h。之后加入溴乙腈(1.43g,35.8mmol)。室温搅拌该混合物14h。之后减压浓缩反应混合物并在乙酸乙酯(150mL)和(450mL)间分配残留物。分离有机层,并用乙酸乙酯(3×150mL)萃取水层。用盐水洗涤经合并有机层,经硫酸钠干燥并减压浓缩。通过柱色谱纯化残留物得到55%收率(3.80g)的黄色半固体状的101e:1H NMR(300MHz,CDCl3)δ6.66(s,1H),5.29(s,2H),4.28(q,2H,J=7.2Hz),2.62(t,2H,J=6.3Hz),2.49(t,2H,J=6.3Hz),1.92(m,2H),1.75(m,2H),1.33(t,3H,J=7.2Hz);MS(ESI+)m/z233.1(M+H)
实施例101f 1-(2-氨基乙基)-4,5,6,7-四氢-1H-吲哚-2-羧酸乙酯101f
用氮气吹扫200-mL Parr反应器瓶并装入10%钯/炭(50%湿,1.28g干重)、101e(3.00g,12.9mmol)、12%盐酸(6.5mL,25mmol)、乙酸乙酯(60mL)和乙醇(40mL)。将瓶连接Parr氢化器,抽真空,充入氢气至50psi的压力并振摇6h。此后,抽空氢气,并向瓶中冲入氮气。加入硅藻土过滤剂(521,4.0g),并通过Celite521垫过滤混合物。用乙醇(2×75mL)洗涤滤饼,并减压浓缩合并的滤液至干燥。在乙酸乙酯(150mL)和10%碳酸钾水溶液(100mL)间分配残留物。分离有机层,并用乙酸乙酯(3×75mL)萃取水层。经硫酸钠干燥经合并的有机层并减压浓缩。用乙醇(5mL)研磨残留物得到71%收率(1.71g)的白色固体状的1-(2-氨基乙基)-4,5,6,7-四氢-1H-吲哚-2-羧酸乙酯101f:mp102–104℃;1H NMR(500MHz,DMSO-d6)δ6.61(s,1H),6.22(br,2H),4.15(m,4H),2.77(m,2H),2.59(t,2H,J=6.5Hz),2.42(t,2H,J=6.5Hz),1.70(m,2H),1.62(m,2H),1.23(t,3H,J=7.0Hz);MS(APCI+)m/z237.2(M+H)
实施例101g 3,4,6,7,8,9-六氢吡嗪并[1,2-a]吲哚-1(2H)-酮101g
用氮气吹扫配有磁力搅拌器和氮气入口的100-mL单颈圆底烧瓶并装入101f(1.80g,7.63mmol)、乙醇钠(1.55g,22.8mmol)和乙醇(50mL)。55℃搅拌该混合物5h。之后,减压浓缩反应混合物并在乙酸乙酯(200mL)和水(100mL)间分配残留物。分离有机层,并用乙酸乙酯(2×100mL)萃取水层。用盐水洗涤经合并的有机层,经硫酸钠干燥并减压浓缩。通过柱色谱纯化残留物得到42%收率(605mg)的白色固体状的101g:mp207–209℃;1H NMR(500MHz,DMSO-d6)δ7.41(s,1H),6.36(s,1H),3.84(t,2H,J=6.0Hz),3.42(m,2H),2.51(t,2H,J=6.0Hz),2.42(t,2H,J=6.0Hz),1.76(m,2H),1.65(m,2H);(APCI+)m/z191.3(M+H)
实施例101h 2,6-二溴-4-氟苯甲醛101h
在保持内部温度低于-25℃的情况下经30分钟往-35℃冷却的1,3-二溴-5-氟-2-碘苯(50g,132mmol)在无水甲苯(300mL)中的溶液中加入异丙基氯化镁溶液(84mL,171mmol,Et2O中2.0M)。获得澄清棕色溶液并在-25℃继续搅拌1.5h。然后经30分钟时间加入无水DMF(34mL,436mmol)。经1h将反应混合物温热至10℃(室温)并在此温度搅拌1.5h。然后用3.0M HCl淬灭并接着加入乙酸乙酯。分离有机层并减压蒸发。通过硅胶柱色谱纯化残留物(采用石油醚/乙酸乙酯(50:1至20:1)洗脱)得到白色固体状的101h(20g,54%)。1H NMR(500MHz,CDCl3)δ10.23(s,1H),7.48(d,J=7.5,2H)。
实施例101i (2,6-二溴-4-氟苯基)甲醇101i
往101h(20g,71mmol)在EtOH(500mL)中的溶液中加入NaBH4(10g,284mmol)。室温(10℃)搅拌该混合物4h且TLC显示起始原料消失。通过HCl水溶液(150mL,1M)淬灭反应混合物并真空蒸发直至蒸馏大部分EtOH。通过乙酸乙酯(500mL×3)萃取残留物。合并有机层,用Na2SO4干燥并真空蒸发。通过硅胶柱色谱纯化残留物(采用石油醚/乙酸乙酯(50:1至20:1)洗脱)得到白色固体状的101i(15g,75%)。MS:[M-OH]+267。1H NMR(500MHz,DMSO-d6)δ7.68(d,J=8.5,2H),5.23(s,1H),4.71(s,2H)。
实施例101j 乙酸2,6-二溴-4-氟苄酯101j
往101i(20g,71mmol)在CH2Cl2(500mL)中的0℃溶液中加入吡啶(8.4g,107mmol)和乙酰氯(8.3g,107mmol)。室温搅拌该混合物5h。TLC显示起始原料消失。真空蒸发反应混合物并通过硅胶柱色谱纯化残留物(采用石油醚/乙酸乙酯(50:1至20:1)洗脱)得到白色固体状的101j(20g,87%)。MS:[M-Oac]+267。1H NMR(500MHz,CDCl3)δ7.36(d,J=7.5,2H),5.38(s,2H),2.10(s,3H)。
实施例101k 乙酸2-溴-4-氟-6-(1-氧代-3,4,6,7,8,9-六氢吡嗪并[1,2-a]吲哚-2(1H)-基)苄酯101k
往配有磁力搅拌器的250-mL单颈圆底烧瓶中装入101g(3.8g,20mmol)、101j(20g,60mmol)、XantPhos(1.2g,2mmol)、三(二亚苄基丙酮)二钯(0)(1.8g,2mmol)、Cs2CO3(16g,50mmol)和1,4-二噁烷(120mL)。排空该系统并接着用N2再充满。将回流冷凝器连接至烧瓶,并在100℃加热反应混合物16h。然后将混合物冷却至室温并过滤。减压浓缩滤液并通过快速柱色谱纯化所得残留物(采用5:1石油醚/乙酸乙酯洗脱)得到白色固体状的101k(5.2g,60%)。MS:[M+H]+435。1H NMR(500MHz,DMSO-d6)δ7.70(dd,J=3,1H),7.48(dd,J=3,1H),6.52(s,1H),5.01(m,2H),4.18(m,2H),4.02(m,1H),3.73(m,1H),2.60(m,2H),2.45(m,2H),1.98(s,3H),1.77(m,2H),1.68(m,2H)。
实施例101l 乙酸4-氟-2-(1-氧代-3,4,6,7,8,9-六氢吡嗪并[1,2-a]吲哚-2(1H)-基)-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苄酯101l
往配有磁力搅拌器的250-mL单颈圆底烧瓶中装入101k(3.8g,8.65mmol)、(PinB)2(11g,43.25mmol)、Pd(dppf)Cl2(0.4g,0.5mmol)、KOAc(2.5g,26mmol)和1,4-二噁烷(150mL)。排空该系统并接着用N2再充满。将回流冷凝器连接至烧瓶并在100℃加热反应混合物15h。然后将混合物冷却至室温并过滤。减压浓缩滤液并通过快速柱色谱纯化所得残留物(采用5:1石油醚/乙酸乙酯洗脱)得到黄色固体状的101l(3.2g,77%)。MS:[M+H]+483。
实施例101 2-(5-氟-2-(羟基甲基)-3-(8-(5-(4-甲基哌嗪-1-基)吡啶-2-基氨基)咪唑并[1,2-a]吡啶-6-基)苯基)-3,4,6,7,8,9-六氢吡嗪并[1,2-a]吲哚-1(2H)-酮101
往25mL密封管中装入101b(300mg,0.88mmol)、101l(423mg,0.88mmol)、Cs2CO3(572mg,1.76mmol)、Pd2(dba)3(80mg,0.09mmol)在CH3CN(25mL)和H2O(1mL)中的混悬液。在140℃微波辐射下加热该混合物1小时。然后蒸发并通过硅胶柱纯化残留物(采用10:1二氯甲烷/甲醇洗脱)得到粗产物,通过反相Combi-flash对其进一步纯化(采用1:4水/CH3CN中的0.3%NH4HCO3洗脱)得到黄色固体状的101(150mg,28%)。MS:(M+H)+621。1H NMR(500MHz,DMSO)δ8.94(s,1H),8.27(d,J=1.5,1H),8.16(d,J=1.5,1H),7.96(d,J=1.0,1H),7.91(d,J=2.5,1H),7.58(d,J=1.5,1H),7.33-7.42(m,3H),7.25-7.28(m,1H),6.53(s,1H),4.88(t,J=4.5,1H),4.30(d,J=4.5,2H),4.12-4.20(m,3H),3.90-3.92(m,1H),3.06(t,J=4.5,4H),2.53-2.65(m,2H),2.43-2.48(m,6H),2.21(s,3H),1.76-1.81(m,2H),1.67-1.71(m,2H)
实施例102a 4-(6-(6-氯咪唑并[1,2-a]吡啶-8-基氨基)吡啶-3-基)哌嗪-1-羧酸叔丁酯102a
往配有磁力搅拌器和回流冷凝器的250-mL单颈圆底烧瓶中装入1,4-二噁烷(60mL)、4-(6-氨基吡啶-3-基)哌嗪-1-羧酸叔丁酯(1.5g,5.39mmol)、8-溴-6-氯咪唑并[1,2-a]吡啶101a(3.7g,16.18mmol)和碳酸铯(3.52g,10.79mmol)。加入XantPhos(312mg,0.539mmol)和Pd2(dba)3(494mg,0.539mmol),并在100℃氮气下加热反应混合物5h。此后将反应混合物冷却至室温。过滤混合物并减压浓缩滤液。在快速柱上纯化残留物(采用100:1CH2Cl2/MeOH洗脱)得到102a(1.8g,78%)。MS:[M+H]+429。
实施例102b 6-氯-N-(5-(哌嗪-1-基)吡啶-2-基)咪唑并[1,2-a]吡啶-8-胺102b
将化合物102a(1.75g,4.08mmol)混悬在4.0M HCl/二噁烷(10mL)中并在室温搅拌5h。然后减压浓缩得到102b(1.2g,81%)。MS:[M+H]+329。
实施例102c 6-氯-N-(5-(4-(氧杂环丁烷-3-基)哌嗪-1-基)吡啶-2-基)咪唑并[1,2-a]吡啶-8-胺102c
50~60℃搅拌102b(0.773g,1.75mmol)、氧杂环丁烷-3-酮(0.189g,2.62mmol)、NaBH3CN(0.22g,3.5mmol)和氯化锌/Et2O(3.5ml,3.5mmol)在甲醇(40mL)中的混合物5小时。通过过滤除去固体并减压浓缩滤液。通过柱色谱纯化残留物(采用5:1CH2Cl2/甲醇洗脱)得到102c(200mg,30%)。MS:[M+H]+385。
实施例102 2-(5-氟-2-(羟基甲基)-3-(8-(5-(4-(氧杂环丁烷-3-基)哌嗪-1-基)吡啶-2-基氨基)咪唑并[1,2-a]吡啶-6-基)苯基)-3,4,6,7,8,9-六氢-吡嗪并[1,2-a]吲哚-1(2H)-酮102
往102c(180mg,0.468mol)在二噁烷/H2O(12mL/1mL)中的溶液中加入2-(5-氟–2-(羟基甲基)-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)-3,4,6,7,8,9-六氢吡嗪并[1,2-a]吲哚-1(2H)-酮101l(225mg,0.468mmol)、Pd2(dba)3(43mg,0.0468mmol)、三环己基膦(131mg,0.468mmol)和Cs2CO3(305mg,0.935mmol)。微波中140℃加热此混合物1h。然后,过滤固体并浓缩滤液得到黄色固体,通过反相制备型HPLC进一步纯化其得到白色固体状的102(36mg,11%)。LCMS:[M+H]+663。1H NMR(500MHz,DMSO)δ8.53(d,J=2.5,1H),8.27(s,1H),8.16(s,1H),7.95(s,1H),7.92-7.91(d,J=2.5,1H),7.57(s,1H),7.42-7.36(m,2H),7.36-7.33(m,1H),7.27-7.25(d,J=9,1H),6.53(s,1H),4.88-4.86(t,J=9,1H),4.57-4.54(m,2H),4.47-4.45(m,2H),4.31-4.30(d,J=4.5,2H),4.18-4.13(m,3H),3.92-3.90(m,1H),3.45-3.42(m,1H),3.09-3.10(m,4H),2.64-2.54(m,2H),2.47-2.45(m,2H),2.39-2.38(m,4H),1.79-1.78(m,2H),1.69-1.67(m,2H)
实施例103a N-甲氧基-N-甲基-4,5,6,7-四氢苯并[b]噻吩-2-甲酰胺103a
用氮气吹扫配有磁力搅拌器的250-mL单颈圆底烧瓶,装入4,5,6,7-四氢苯并[b]噻吩-2-羧酸(3.00g,16.5mmol)、二氯甲烷(80mL)和DMF(60mg,0.825mmol)并冷却至0℃。往所得溶液中滴加草酰氯(2.31g,18.2mmol)。此加入完成后将反应混合物温热至室温并搅拌2h。此后,减压浓缩反应混合物至干燥。将所得白色固体溶于二氯甲烷(80mL)中并冷却溶液至0℃。然后加入三乙胺(5.00g,49.5mmol)和N,O-二甲基羟基胺(1.61g,16.5mmol)。此加入完成后,移除冷浴,并在室温搅拌反应混合物16h。此后,在水(100mL)和乙酸乙酯(200mL)间分配反应混合物。分离各层,并用乙酸乙酯(100mL)萃取水相。用水(100mL),然后是盐水(100mL)洗涤经合并的有机萃取物并经硫酸钠干燥。通过过滤除去干燥剂,并减压蒸发溶剂。通过快速柱色谱纯化所得残留物得到88%收率的白色固体状的103a(3.29g):mp36–37℃;1H NMR(500MHz,CDCl3)δ7.79(s,1H),3.76(s,3H),3.34(s,3H),2.78(t,2H,J=6.0Hz),2.62(t,2H,J=6.0Hz),1.82(m,4H);MS(APCI+)m/z226.3(M+H)
实施例103b 3-氯-1-(4,5,6,7-四氢苯并[b]噻吩-2-基)丙-1-酮103b
用氮气吹扫配有磁力搅拌器的100-mL单颈圆底烧瓶并装入103a(2.70g,12.0mmol)和无水THF(45mL),用丙酮/冰浴将溶液冷却至-10℃。滴加1.0M乙烯基溴化镁在THF(13.2mL,13.2mmol)中的溶液,并在0℃搅拌所得反应混合物4h。此后,在乙酸乙酯(100mL)和2M盐酸水溶液(40mL)间分配反应混合物。分离各层,并用乙酸乙酯(40mL)萃取水相。用水(100mL),然后是盐水(100mL)洗涤经合并的有机萃取物,经硫酸钠干燥,过滤并减压浓缩。将所得残留物溶于二氯甲烷(30mL)中并加入2M氯化氢在乙醚(15mL)中的溶液。室温搅拌1h后,减压除去溶液。通过柱色谱纯化所得残留物得到29%收率(804mg)的灰白色固体状的103b:mp57–58℃;1H NMR(500MHz,CDCl3)δ7.41(s,1H),3.89(t,2H,J=7.0Hz),3.30(t,2H,J=7.0Hz),2.81(t,2H,J=6.0Hz),2.64(t,2H,J=6.0Hz),1.83(m,4H);MS(ECI+)m/z229.1(M+H)
实施例103c 5,6,7,8-四氢-1H-苯并[b]环戊二烯并[d]噻吩-3(2H)-酮103c
往配有磁力搅拌器的50-mL单颈圆底烧瓶中装入103b(800mg,3.51mmol)和98%硫酸(8mL)。95℃搅拌16h后,将反应混合物倾入冰(50g)中并用乙酸乙酯(3×50mL)萃取所得混悬液。合并有机萃取物,经硫酸钠干燥,过滤并减压浓缩。通过快速柱色谱纯化所得残留物得到47%收率(320mg)的灰白色固体状的103c:mp75–76℃;1H NMR(500MHz,CDCl3) 2.89(m,2H),2.87–2.83(m,4H),2.56(t,2H,J=6.5Hz),1.84(m,4H)
实施例103d 5,6,7,8-四氢-1H-苯并[b]环戊二烯并[d]噻吩-3(2H)-酮肟103d
往配有机械搅拌器和氮气入口的100-mL单颈圆底烧瓶中装入盐酸羟胺(573mg,8.25mmol)和甲醇(10mL)。使用冰浴将混合物冷却至0℃。加入乙酸钠(677mg,8.25mmol)。0℃搅拌该混合物30分钟。此后,加入103c(319mg,1.65mmol),并在室温搅拌反应混合物16h。此后,浓缩混合物并用水(10mL)研磨所得残留物。收集所得固体并在真空烘箱中45℃干燥得到84%收率(287mg)的灰白色固体状的103d:mp173–174℃;1H NMR(500MHz,DMSO-d6)δ10.38(s,1H),2.97(m,2H),2.77–2.73(m,4H),2.47(m,2H),1.75(m,4H);MS(APCI+)m/z208.3(M+H)
实施例103e 3,4,5,6,7,8-六氢苯并噻吩并[2,3-c]吡啶-1(2H)-酮103e
往配有回流冷凝器、磁力搅拌器和氮气入口的50-mL单颈圆底烧瓶中装入103d(285mg,1.38mmol)和聚磷酸(15g)。80℃搅拌16h后,将反应混合物冷却至室温并加水(30mL)。搅拌所得混合物30分钟并过滤。用水(20mL)洗涤滤饼并在真空烘箱中45℃干燥得到75%收率(215mg)的灰白色固体状的103e:mp203℃dec;1H NMR(500MHz,CDCl3)δ5.62(s,1H),3.59(t,2H,J=7.0Hz),2.81(t,2H,J=6.0Hz),2.72(t,2H,J=7.0Hz),2.48(t,2H,J=6.0Hz),1.84(m,4H)。MS(APCI+)m/z208.3(M+H)
实施例103f 乙酸2-溴-4-氟-6-(1-氧代-3,4,5,6,7,8-六氢苯并噻吩并[2,3-c]吡啶-2(1H)-基)苄酯103f
在氮气下100℃加热103e(3g,14.5mmol)、乙酸2,6-二溴-4-氟苄酯101j(14g,43.5mmol)、Xantphos(839mg,1.45mmol)、Pd2(dba)3(1.33g,1.45mmol)和Cs2CO3(9.4g,29mmol)在二噁烷(200mL)中的溶液15h。过滤后,真空蒸发滤液并通过快速柱纯化(采用乙酸乙酯/石油醚(1:1)洗脱)得到黄色固体状的103f(5g,收率77%)。LCMS:(M+H)+452。1H NMR(500MHz,DMSO)δ7.71(dd,J=2.5,1H),7.51(dd,J=3,1H),5.04(m,1H),4.10(m,1H),3.68(m,1H),2.86(m,2H),2.77(m,2H),2.55(m,3H),1.98(s,3H),1.78(m,4H)
实施例103g 乙酸2-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-4-氟-6-(1-氧代-3,4,5,6,7,8-六氢苯并噻吩并[2,3-c]吡啶-2(1H)-基)苄酯103g
往103f(3g,6.65mmol)、4,4,4',4',5,5,5',5'-八甲基-2,2'-二(1,3,2-二氧杂-硼杂环戊烷)(10g,40mmol)在二噁烷(160mL)中的溶液中加入PdCl2(dppf)(543mg,0.66mmol)和CH3COOK(3.9g,40mmol)。氩气氛下100℃搅拌该混合物15h。过滤混合物并真空蒸发,并通过快速柱纯化(采用乙酸乙酯/石油醚(1:2)洗脱)得到黄色固体状的103g(2.5g,收率76%)。LCMS:(M+H)+500
实施例103 5-[5-氟-2-(羟基甲基)-3-{(8-(5-(4-甲基哌嗪-1-基)吡啶-2-基氨基)咪唑并[1,2-a]吡啶-6-基)}苯基]-8-硫杂-5-氮杂三环[7.4.0.02,7]十三碳-1(9),2(7)-二烯-6-酮103
遵循如制备化合物101所述的步骤,使103g(499mg,1.0mmol)和6-氯-N-(5-(4-甲基哌嗪-1-基)吡啶-2-基)咪唑并[1,2-a]吡啶-8-胺101b(342mg,1.0mmol)反应得到白色固体状的103(220mg,35%)。LCMS:[M+H]+638。1H NMR(500MHz,CDCl3)δ8.22(s,2H),7.96(d,J=2.5,1H),7.83(s,1H),7.63(d,J=1.0,1H),7.57(d,J=1.0,1H),7.30(dd,J=3.0,9.0,1H),7.24(dd,J=2.5,9.0,1H),7.03(dd,J=3.0,9.0,1H),6.92(d,J=8.5,1H),4.57(d,J=11.5,1H),4.35(t,J=8.5,1H),4.21(s,1H),4.09-4.15(m,1H),3.87-3.92(m,1H),3.16(t,J=5.0,4H),2.85-3.02(m,4H),2.60(t,J=5.0,4H),2.51-2.57(m,2H),2.37(s,3H),1.85-1.95(m,4H)
实施例104a 8-溴-6-氯咪唑并[1,2-b]哒嗪104a
回流下加热4-溴-6-氯哒嗪-3-胺(5.0g,24mmol)和2-氯乙醛(12g,75mmol)在乙醇(100mL)中的溶液15h。浓缩反应混合物并用丙酮(75mL)洗涤得到黄色固体状的104a(6.0g,71%)。MS:[M+H]+234。
实施例104b 6-氯-N-(5-(4-甲基哌嗪-1-基)吡啶-2-基)咪唑并[1,2-b]哒嗪-8-胺104b
往配有磁力搅拌器和回流冷凝器的100-mL单颈圆底烧瓶中装入104a(2.0g,4mmol)、5-(4-甲基哌嗪-1-基)吡啶-2-胺(920mg,4.8mmol)、三(二亚苄基丙酮)二钯(0)(366mg,0.4mmol)、XantPhos(688mg,1.2mmol)、Cs2CO3(2.6g,8.0mmol)和1,4-二噁烷(60mL)。真空/氩气冲洗三个循环后,回流下加热该混合物15h。然后冷却至室温并过滤。减压浓缩滤液并通过硅胶柱色谱纯化所得残留物(采用二氯甲烷/甲醇(20:1)洗脱)得到黄色固体状的104b(1.4g,70%)。MS:[M+H]+344。
实施例104 2-(5-氟-2-(羟基甲基)-3-(8-(5-(4-甲基哌嗪-1-基)吡啶-2-基氨基)咪唑并[1,2-b]哒嗪-6-基)苯基)-3,4,6,7,8,9-六氢吡嗪并[1,2-a]吲哚-1(2H)-酮104
往密封管中装入104b(340mg,0.8mmol)、乙酸4-氟-2-(1-氧代-3,4,6,7,8,9-六氢吡嗪并[1,2-a]吲哚-2(1H)-基)-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苄酯101l(400mg,0.8mmol)、Pd2(dba)3(72mg,0.1当量,0.08mmol)、PCy3(68mg,0.3当量,0.24mmol)、碳酸铯(520mg,2当量,1.6mmol)、二噁烷(15mL)和水(1mL)。真空/氩气冲洗三个循环后,130℃加热该混合物14h。然后冷却至室温并过滤。减压浓缩滤液并通过硅胶柱色谱纯化所得残留物(采用二氯甲烷/-甲醇(20:1)洗脱)得到104(100mg,16%)。LCMS:[M+H]+622。1H NMR(500MHz,DMSO)δ9.95(s,1H),8.23(s,1H),8.16(s,1H),8.00(d,J=2.0,1H),7.67(s,1H),7.43-7.46(m,3H),7.34-7.36(m,1H),6.52(s,1H),4.67(t,J=5.0,1H),4.34-4.41(m,2H),4.13-4.18(m,3H),3.87-3.88(m,1H),3.10-3.12(m,4H),2.57-2.61(m,2H),2.43-2.47(m,6H),2.21(s,3H),1.77-1.79(m,2H),1.68-1.69(m,2H)
实施例105a 6-氯-N-(5-(4-(氧杂环丁烷-3-基)哌嗪-1-基)吡啶-2-基)咪唑并[1,2-b]哒嗪-8-胺105a
遵循如制备化合物104b所述的步骤,使8-溴-6-氯咪唑并[1,2-b]哒嗪104a(233mg,1.0mmol)和5-(4-(氧杂环丁烷-3-基)哌嗪-1-基)吡啶-2-胺(234mg,1.0mmol)反应得到白色固体状的105a(296mg,77%)。LCMS:[M+H]+386
实施例105 2-(5-氟-2-(羟基甲基)-3-(8-(5-(4-(氧杂环丁烷-3-基)哌嗪-1-基)吡啶-2-基氨基)咪唑并[1,2-b]哒嗪-6-基)苯基)-3,4,6,7,8,9-六氢-吡嗪并[1,2-a]吲哚-1(2H)-酮105
遵循如制备化合物104所述的步骤,105a(385mg,1.0mmol)和乙酸4-氟-2-(1-氧代-3,4,6,7,8,9-六氢吡嗪并[1,2-a]吲哚-2(1H)-基)-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苄酯101l的Suzuki反应得到黄色固体状的105(60mg,9%)。LCMS:[M+H]+664.1H NMR(500MHz,DMSO)δ10.04(d,J=4.0,1H),8.26(s,1H),8.18(s,1H),8.10-8.13(m,1H),7.70(s,1H),7.44-7.55(m,3H),7.34-7.36(m,1H),6.52(s,1H),4.84(s,1H),4.66-4.72(m,3H),4.33-4.43(m,2H),4.11-4.19(m,3H),3.86-3.89(m,2H),3.49-3.51(m,2H),3.03-3.14(m,4H),2.57-2.63(m,3H),2.45-2.47(m,4H),1.77-1.80(m,2H),1.68-1.69(m,2H)
实施例106a 4-(6-(6-溴咪唑并[1,2-a]吡嗪-8-基氨基)吡啶-3-基)哌嗪-1-羧酸叔丁酯106a
微波辐射下130℃搅拌6,8-二溴咪唑并[1,2-a]吡嗪(1.2g,4.3mmol)、二-异丙基乙胺(1.1g,8mmol)和4-(6-氨基吡啶-3-基)哌嗪-1-羧酸叔丁酯(1g,3.5mmol)在IPA(20mL)中的混合物1.5h。过滤所得混悬液并用水洗涤固体,真空干燥得到粗产物,通过硅胶色谱进一步将其纯化(采用CH2Cl2/MeOH(50:1)洗脱)得到白色固体状的106a(800mg,50%)。MS:[M+H]+474。
实施例106b 6-溴-N-(5-(哌嗪-1-基)吡啶-2-基)咪唑并[1,2-a]吡嗪-8-胺106b
往106a(260mg,0.5mmol)在CH2Cl2(3mL)中的混合物中加入TFA(0.5ml)并在25℃搅拌该反应混合物2h。浓缩反应溶液得到淡黄色液体状的106b,未经纯化用于下一步(210mg,97%)。MS:[M+H]+374。
实施例106c 6-溴-N-(5-(4-甲基哌嗪-1-基)吡啶-2-基)咪唑并[1,2-a]吡嗪-8-胺106c
20℃搅拌106b(210mg,0.52mmol)、甲醛(150mg,5mmol)和NaBH3CN(220mg,3.5mmol)在甲醇(8mL)中的混合物3小时。通过过滤除去固体并减压浓缩滤液。通过柱色谱纯化残留物(采用CH2Cl2/甲醇(20:1)洗脱)得到106c(200mg,90%)。MS:[M+H]+388。
实施例106d 乙酸4-氟-2-(8-(5-(4-甲基哌嗪-1-基)吡啶-2-基氨基)咪唑并[1,2-a]吡嗪-6-基)-6-(1-氧代-3,4,6,7,8,9-六氢吡嗪并[1,2-a]吲哚-2(1H)-基)苄酯106d
往配有磁力搅拌器和回流冷凝器的250-mL单颈圆底烧瓶中装入1,4-二噁烷(60mL)、106c(200mg,0.5mmol)、乙酸4-氟-2-(1-氧代-3,4,6,7,8,9-六氢吡嗪并[1,2-a]吲哚-2(1H)-基)-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苄酯101l(385mg,0.8mmol)和碳酸铯(332mg,1mmol)。加入Xantphos(30mg,0.08mmol)和Pd2(dba)3(55mg,0.08mmol)并在90℃加热反应混合物4h。此后将反应混合物冷却至室温,过滤并减压浓缩滤液。在快速柱上纯化残留物(采用CH2Cl2/MeOH(10:1)洗脱)得到106d(200mg,60%)。MS:[M+H]+664。
实施例106 2-(5-氟-2-(羟基甲基)-3-(8-(5-(4-甲基哌嗪-1-基)吡啶-2-基氨基)咪唑并[1,2-a]吡嗪-6-基)苯基)-3,4,6,7,8,9-六氢吡嗪并[1,2-a]吲哚-1(2H)-酮106
50℃搅拌106d(200mg,0.92mmol)和LiOH(300mg,10mmol)在iPrOH/THF(1:1,3.5mL)和H2O(1mL)中的混合物0.5h。真空干燥混合物并用乙酸乙酯(10mL X2)萃取残留物。减压浓缩经合并的乙酸乙酯萃取物并用反相制备型HPLC纯化残留物得到106(45mg,20%)。LCMS:[M+H]+622。1H NMR(500MHz,DMSO)δ9.04(s,1H),8.41(s,1H),8.13-8.10(m,2H),7.98(s,1H),7.71(s,1H),7.47-7.44(m,2H),7.39-7.37(m,1H),6.53(s,1H),5.38-5.36(m,1H),4.37-4.44(m,2H),4.19-3.98(m,4H),3.12(s,4H),2.60-2.58(m,2H),2.50-2.45(m,6H),2.21(s,3H),1.79-1.68(m,2H),1.69-1.67(m,2H)
实施例107a 2-(5-氟-3-(8-(5-(4-(氧杂环丁烷-3-基)哌嗪-1-基)吡啶-2-基氨基)-咪唑并[1,2-a]吡嗪-6-基)-2-(2-氧代丙基)苯基)-3,4,6,7,8,9-六氢吡嗪并[1,2-a]吲哚-1(2H)-酮107a
往配有磁力搅拌器和回流冷凝器的250-mL单颈圆底烧瓶中装入1,4-二噁烷(60mL)、6-溴-N-(5-(4-(氧杂环丁烷-3-基)哌嗪-1-基)吡啶-2-基)咪唑并[1,2-a]吡嗪-8-胺(130mg,0.3mmol)、乙酸4-氟-2-(1-氧代-3,4,6,7,8,9-六氢吡嗪并[1,2-a]吲哚-2(1H)-基)-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苄酯101l(146mg,0.3mmol)、PdCl2(dppf)(25mg,0.03mmol)、K3PO4(138mg,0.6mmol)以及NaOAc(48mg,0.6mmol)在CH3CN(5mL)和H2O(1.5mL)中的溶液。排空该系统并用N2再充满。100℃加热反应混合物2h。然后冷却至室温并过滤。减压浓缩滤液并通过快速柱色谱纯化所得残留物(采用10:1CH2Cl2/MeOH洗脱)得到棕色固体状的107a(150mg,70%)。MS:[M+H]+706.4。
实施例107 2-(5-氟-2-(羟基甲基)-3-(8-(5-(4-(氧杂环丁烷-3-基)哌嗪-1-基)吡啶-2-基氨基)咪唑并[1,2-a]吡嗪-6-基)苯基)-3,4,6,7,8,9-六氢-吡嗪并[1,2-a]吲哚-1(2H)-酮107
搅拌下往100-mL单颈圆底烧瓶中装入THF/iPA/H2O(5mL/5mL/2mL)中的107a(150mg,0.21mol)和LiOH(85mg,3.5mmol)。50℃搅拌此混合物0.5h。然后加入20mL H2O并用EA(30mL x3)萃取混合物。经Na2SO4干燥经合并的有机层并浓缩得到黄色固体,通过反相制备型HPLC进一步纯化得到白色固体状的107(74mg,52%收率)。LCMS:[M+H]+664.3。1H NMR(500MHz,DMSO)δ9.06(s,1H),8.41(s,1H),8.13-8.10(m,2H),7.98(d,J=2.5,1H),7.71(s,1H),7.48-7.44(m,2H),7.39-7.36(m,1H),6.54(s,1H),5.38(m,1H),4.57-4.35(m,6H),4.18-4.13(m,4H),3.44-3.42(m,1H),3.15(s,4H),2.59(d,J=3.0,2H),2.47-2.40(m,6H),1.79-1.69(m,4H)
实施例108a(E)-N'-(3-溴-5-氯吡啶-2-基)-N,N-二甲基甲脒108a
100℃搅拌3-溴-5-氯吡啶-2-胺(10g,0.05mol)和二甲氧基-N,N-二甲基甲胺(7g,0.06mmol)的混合物1h。将混合物倾入水中并接着用乙酸乙酯(20mL X4)萃取。减压浓缩经合并的有机层并通过硅胶柱色谱纯化残留物(采用乙酸乙酯/PE(1:2)洗脱)得到108a(10g,77%)。LCMS:[M+H]+262。
实施例108b (E)-N'-(3-溴-5-氯吡啶-2-基)-N-羟基甲脒108b
100℃搅拌108a(2g,10mmol)和盐酸羟胺(1.4g,20mmol)在MeOH(10mL)中的混合物0.5h。用乙酸乙酯(20mL X4)萃取该混合物并用水洗涤经合并的有机相。然后减压浓缩得到108b(2g,80%),其未经进一步纯化而用于下一步。LCMS:[M+H]+250。
实施例108c 8-溴-6-氯-[1,2,4]三唑并[1,5-a]吡啶108c
100℃搅拌108b(500mg,2mmol)和PPA(1.4g,20mmol)的混合物4h。然后用乙酸乙酯(20mL X4)萃取该混合物并用水洗涤经合并的有机相。减压浓缩得到108c(250mg,50%),其未经进一步纯化而用于下一步。LCMS:[M+H]+250.
实施例108d 6-氯-N-(5-(4-(氧杂环丁烷-3-基)哌嗪-1-基)吡啶-2-基)-[1,2,4]-三唑并[1,5-a]吡啶-8-胺108d
往配有磁力搅拌器和回流冷凝器的25-mL单颈圆底烧瓶中装入1,4-二噁烷(8mL)、108c(250mg,1.07mmol)、5-(4-(氧杂环丁烷-3-基)哌嗪-1-基)吡啶-2-胺(252mg,1mmol)和碳酸铯(700mg,2mmol)。加入Xantphos(30mg,0.08mmol)和Pd2(dba)3(55mg,0.08mmol),105℃加热该反应混合物3h。此后将反应混合物冷却至室温并过滤。减压浓缩滤液并通过硅胶柱色谱纯化残留物(采用CH2Cl2/MeOH(20:1)洗脱)得到108d(250mg,60%)。MS:[M+H]+386。
实施例108e 乙酸4-氟-2-(8-(5-(4-(氧杂环丁烷-3-基)哌嗪-1-基)吡啶-2-基氨基)-[1,2,4]三唑并[1,5-a]吡啶-6-基)-6-(1-氧代-3,4,6,7,8,9-六氢吡嗪并[1,2-a]吲哚-2(1H)-基)苄酯108e
110℃在密封管中加热乙酸4-氟-2-(1-氧代-3,4,6,7,8,9-六氢吡嗪并[1,2-a]吲哚-2(1H)-基)-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苄酯101l(165mg,0.38mmol)、108d(140mg,0.38mmol)、PdCl2(dppf)(41mg,0.056mmol)、K3PO4(100mg)以及NaOAc(50mg)在MeCN(10mL)和H2O(3mL)中的混合物2h。真空蒸发溶剂并通过硅胶柱色谱纯化残留物得到108e(250mg,60%)。MS:[M+H]+706。
实施例108 2-(5-氟-2-(羟基甲基)-3-(8-(5-(4-(氧杂环丁烷-3-基)哌嗪-1-基)吡啶-2-基氨基)-[1,2,4]三唑并[1,5-a]吡啶-6-基)苯基)-3,4,6,7,8,9-六氢吡嗪并[1,2-a]吲哚-1(2H)-酮108
50℃搅拌108e(250mg,0.35mmol)和LiOH(300mg,10mmol)在iPrOH/THF(1:1,3.5mL)和H2O(1mL)中的混合物0.5h。真空蒸发该混合物并用乙酸乙酯(5mL X2)萃取。减压浓缩经合并的乙酸乙酯萃取物并用反相制备型HPLC纯化残留物得到108(110mg,25%)。LCMS:[M+H]+664。1HNMR(500MHz,DMSO)δ9.33(s,1H),8.67(s,1H),8.55-8.54(m,2H),7.95(d,J=3.0,1H),7.44-7.41(m,2H),7.37-7.33(m,2H),6.53(s,1H),4.98(t,J=5.0,1H),4.55-4.54(m,2H),4.45-4.44(m,2H),4.13-4.32(m,5H),3.91(s,1H),3.43-3.41(m,1H),3.10(s,4H),2.60-2.38(m,8H),1.78-1.76(m,2H),1.69-1.67(m,2H)
实施例109a 2-溴-4-氯-6-硝基苯胺109a
回流下加热4-氯-2-硝基苯胺(5.1g,30mmol)和N-溴-琥珀酰亚胺(6.2g,36mmol)在乙腈(50mL)中的混合物过夜。冷却至室温并用乙酸乙酯(50mL)稀释。用饱和K2CO3水溶液(100mL x2)洗涤该混合物。分离有机相,经Na2SO4干燥,过滤并减压蒸发得到黄色固体状的109a(8.1g,100%)。LCMS:[M+H]+253。1H NMR(500MHz,CDCl3)δ8.17(d,J=2.5Hz,1H),7.71(d,J=2.5Hz,1H),6.64(s,2H)。
实施例109b 3-溴-5-氯苯-1,2-二胺109b
往109a(5.0g,20mmol)在乙酸乙酯(100mL)中的溶液中加入SnCl2.2H2O(22.6g,100mmol)。回流下加热反应混合物2h。冷却至室温后,将反应混合物倾入Na2CO3水溶液(200mL)中并用乙酸乙酯(200mL x3)萃取混合物。经无水Na2SO4干燥经合并的有机相,过滤并减压蒸发得到深红色液体状的109b(4.3g,97%)。LCMS:[M+H]+223。1H NMR(500MHz,CDCl3)δ6.97(d,J=2.5Hz,1H),6.65(d,J=2.5Hz,1H),3.67(bs,4H)。
实施例109c 4-溴-6-氯-1H-苯并[d]咪唑109c
80℃加热109b(4.3g,19.5mmol)在甲酸(10mL)中的混合物1h。冷却至室温后,将反应混合物倾入Na2CO3水溶液(30mL)中并用乙酸乙酯(30mLx3)萃取混合物。经无水Na2SO4干燥经合并的有机相,过滤并减压蒸发得到棕色固体状的109c(3.5g,77%)。LCMS:[M+H]+233。1H NMR(500MHz,CDCl3)δ10.05(bs,1H),8.18(s,1H),7.64(bs,1H),7.50(s,1H)。
实施例109d 4-溴-6-氯-1-甲基-1H-苯并[d]咪唑109d
往109c(3.5g,15mmol)在N,N-二甲基甲酰胺(30mL)中的溶液中加入碳酸钾(4.14g,30mmol)和碘甲烷(1.4mL,22.7mmol)。室温搅拌反应混合物过夜。加水(50mL)以淬灭反应混合物并用乙酸乙酯(5mL x3)萃取所得的混合物。经无水Na2SO4干燥经合并的有机相,过滤并减压蒸发。通过柱色谱纯化残留物(采用石油醚/乙酸乙酯(4:1至1:2)洗脱)得到白色固体状的109d(1.4g,38%)。LCMS:[M+H]+245/247。1H NMR(500MHz,CDCl3)δ7.89(s,1H),7.46(d,J=2.0Hz,1H),7.32(d,J=2.0Hz,1H),3.81(s,3H)。
实施例109e 6-氯-1-甲基-N-(5-(4-(氧杂环丁烷-3-基)哌嗪-1-基)吡啶-2-基)-1H-苯并[d]咪唑-4-胺109e
往配有磁力搅拌器的微波瓶中装入109d(486mg,2.0mmol)、5-(4-(氧杂环丁烷-3-基)哌嗪-1-基)吡啶-2-胺(390mg1.67mmol)、碳酸铯(1.09g,3.34mmol)、三(二亚苄基丙酮)二钯(0)(152mg,0.167mmol)和Xantphos(193mg,0.334mmol)。将氮气鼓泡通过该混悬液5分钟后,120℃加热反应混合物过夜。然后冷却至室温并过滤。减压浓缩滤液并用石油醚/乙酸乙酯混合物(15mL,2:1)洗涤残留物得到黄色固体状的109e(720mg,100%)。LCMS:[M+H]+399.3。1H NMR(500MHz,CDCl3)δ8.20(d,J=2.0,1H),8.04(d,J=2.5,1H),7.72(s,1H),7.61(s,1H),7.28-7.29(m,1H),6.90-6.91(m,2H),4.70-4.71(m,4H),3.77(s,3H),3.70-3.71(m,1H),3.17(t,J=5.0,4H),2.52(t,J=5.0,4H)
实施例109 2-(5-氟-2-(羟基甲基)-3-(3-甲基-7-(5-(4-(氧杂环丁烷-3-基)哌嗪-1-基)吡啶-2-基氨基)-3H-苯并[d]咪唑-5-基)苯基)-3,4,6,7,8,9-六氢吡嗪并[1,2-a]吲哚-1(2H)-酮109
往配有磁力搅拌器的微波瓶中装入109e(300mg,0.75mmol)、乙酸4-氟-2-(1-氧代-3,4,6,7,8,9-六氢吡嗪并[1,2-a]吲哚-2(1H)-基)-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苄酯101l(545mg,1.13mmol)、碳酸钾(414mg,3.0mmol)、三(二亚苄基丙酮)二钯(0)(68mg,0.075mmol)和三环己基膦(210mg,0.75mmol)。将氮气鼓泡通过该混悬液5分钟后,110℃加热反应混合物过夜。然后冷却至室温并过滤。减压浓缩滤液并通过反相制备型HPLC纯化残留物得到白色固体状的109(71mg,14%)。LCMS:[M+H]+677.3。1H NMR(500MHz,DMSO)δ8.64(s,1H),8.23(d,J=1.0,1H),8.18(s,1H),7.88(d,J=2.5,1H),7.38-7.39(m,1H),7.33-7.35(m,1H),7.24(d,J=9.0,1H),7.18-7.19(m,2H),6.52(s,1H),4.85(bs,1H),4.56(t,J=6.0,2H),4.46(t,J=6.0,2H),4.29(s,2H),4.16-4.18(m,3H),3.93-3.94(m,1H),3.84(s,3H),3.44-3.45(m,1H),3.07(t,J=4.0,4H),2.61-2.62(m,2H),2.47(t,J=6.0,2H),2.39(t,J=4.0,4H),1.79-1.80(m,2H),1.70-1.71(m,2H)
实施例110a (E)-3-(2-氯-4,4-二甲基环戊-1-烯基)丙烯酸乙酯110a
以下两步改编自Organic Preparations and Procedures Int.,29(4),471-498。往配有磁力搅拌器和氮气入口的500-mL单颈圆底烧瓶中装入2-氯-4,4-二甲基环戊-1-烯甲醛(38g,240mmol)在苯(240mL)中的溶液。往此溶液中加入乙氧基羰基亚甲基三苯基磷烷(84g,240mmol)。搅拌该混合物14h。之后,蒸发溶剂并用己烷(2L)研磨残留物以将产物萃取与PPh3副产物分离。经硫酸钠干燥有机层并真空浓缩。通过柱色谱使用100%己烷–1:1己烷/乙酸乙酯梯度纯化残留物得到37%收率(20g)的110a。
实施例110b 5,5-二甲基-1,4,5,6-四氢环戊二烯并[b]吡咯-2-羧酸乙酯110b
往配有磁力搅拌器和氮气入口的250-mL单颈圆底烧瓶中装入110a(17g,74mmol)在DMSO(100mL)中的溶液。往溶液中加入叠氮化钠(9.6g,150mmol)。然后加热该混合物至75℃并搅拌8h。冷却至室温后,加入H2O(100mL)和CH2Cl2(200mL)并分离有机层。用CH2Cl2(50mL)萃取水层。用盐水洗涤经合并的有机层,经硫酸钠干燥并真空浓缩。通过柱色谱使用100%己烷–1:1己烷/乙酸乙酯梯度纯化残留物得到37%收率(5.7g)的110b。
实施例110c 1-(氰基甲基)-5,5-二甲基-1,4,5,6-四氢环戊二烯并[b]吡咯-2-羧酸乙酯110c
往配有磁力搅拌器和氮气入口的250-mL单颈圆底烧瓶中装入110b(6.2g,30mmol)在DMF(57mL)中的溶液。往该溶液中加入NaH(矿物油中的80%分散液,1.26g,42.1mmol)。室温搅拌所得混合物90分钟。之后加入溴乙腈(2.94mL,42mmol)。搅拌混合物14h。之后,加入水(100mL)和乙酸乙酯(200mL)并分离有机层。用乙酸乙酯(2X50mL)萃取水层。用盐水洗涤经合并的有机层,经硫酸钠干燥并真空浓缩。通过柱色谱纯化残留物得到95%收率(7g)的110c。
实施例110d 1-(2-氨基乙基)-5,5-二甲基-1,4,5,6-四氢环戊二烯并[b]吡咯-2-羧酸乙酯盐酸盐110d
用氮气吹扫500-mL Parr反应器瓶并装入10%钯/炭(50%湿,2.0g干重)、110c(4.5g,18mmol)、12%盐酸(9.2mL,37mmol)、乙酸乙酯(80mL)和乙醇(52mL)。将瓶连接Parr氢化器,抽真空,充入氢气至50psi的压力并振摇6h。此后,抽空氢气,并向瓶中冲入氮气。加入Celite521(10.0g),并通过Celite521垫过滤混合物。用乙醇(2×50mL)洗涤滤饼,并减压浓缩经合并的滤液至干燥。未经进一步纯化采用粗残留物110d进行下一步。
实施例110e 4,4-二甲基-1,10-二氮杂三环[6.4.0.02,6]十二碳-2(6),7-二烯-9-酮110e
用氮气吹扫配有磁力搅拌器和氮气入口的100-mL单颈圆底烧瓶并装入粗110d(~18mmol)、乙醇钠(6.2g,92mmol)和乙醇(120mL)。55℃搅拌该混合物过夜。之后,减压浓缩反应混合物并在乙酸乙酯(200mL)和水(100mL)间分配残留物。过滤溶液。用乙酸乙酯(15mL)洗涤固体得到850mg希望的产物110e。分离有机层并用乙酸乙酯(2×100mL)萃取水层。经硫酸钠干燥经合并的有机层并减压浓缩至近干。过滤溶液并用乙酸乙酯(15mL)洗涤固体(1.44g)。真空干燥经合并的固体得到61%收率(2.3g)的110e。
实施例110f 乙酸2-溴-4-氟-6-(9-氧代-4,4-二甲基-1,10-二氮杂三环[6.4.0.02,6]-十二碳-2(6),7-二烯-10-基)苄酯110f
密封管配有磁力搅拌器并装入110e(740mg,3.6mmol)、乙酸2,6-二溴-4-氟苄酯101j(2.4g,7.2mmol)和碳酸铯(2.6g,7.9mmol)在1,4-二噁烷(36mL)中的溶液。将氮气鼓泡通过该溶液30分钟后,加入Xantphos(250mg,0.43mmol)和三(二亚苄基丙酮)二钯(0)(260mg,0.29mmol)并将反应混合物加热至100℃且保持16h。此后加入H2O(50mL)和乙酸乙酯(50mL)。分离水层并用乙酸乙酯(2×50mL)萃取。用盐水(100mL)洗涤经合并的有机萃取物并经硫酸钠干燥。通过柱色谱纯化所得残留物(用100%己烷–100%乙酸乙酯梯度洗脱)得到56%收率(910mg)的110f。
实施例110g 乙酸2-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-4-氟-6-(9-氧代-4,4-二甲基-1,10二氮杂三环[6.4.0.02,6]-十二碳-2(6),7-二烯-10-基)苄酯110g
除了使用110f(450mg,1.0mmol)、4,4,4',4',5,5,5',5'-八甲基-2,2'-二(1,3,2-二氧杂硼杂环戊烷)(635mg,2.5mmol)、乙酸钾(393mg,4.0mmol)、二(二苯基膦基)-二茂铁]二氯钯(II)-CH2Cl2复合物(Pd Cl2dppf:CH2Cl2(1:1),66mg,0.08mmol)和1,4-二噁烷(20mL)以外,使用与103g相同的步骤合成110g。100℃加热反应混合物5h。将反应混合物冷却至室温并过滤通过Celite521垫。用乙酸乙酯(2×25mL)洗涤滤饼,并减压浓缩经合并滤液至干燥得到黑色油状的110g(定量收率),其直接被用于下一步。MS(ESI+)m/z497.3(M+H)。
实施例110 10-[5-氟-2-(羟基甲基)-3-(8-(5-(4-(氧杂环丁烷-3-基)哌嗪-1-基)吡啶-2-基氨基)咪唑并[1,2-b]哒嗪-6-基)苯基]-4,4-二甲基-1,10-二氮杂三环[6.4.0.02,6]十二碳-2(6),7-二烯-9-酮110
往6-氯-N-(5-(4-(氧杂环丁烷-3-基)哌嗪-1-基)吡啶-2-基)咪唑并[1,2-a]吡啶-8-胺102c(300mg,0.777mol)在二噁烷/H2O(12mL/1mL)中的混悬液中加入110g(385mg,0.777mmol)、Pd2(dba)3(70mg,0.0777mmol)、三环己基膦(220mg,0.777mmol)和CsCO3(510mg,1.554mmol)。N2下120℃搅拌此混合物15h。然后过滤并浓缩滤液得到黄色固体,通过反相制备型HPLC进一步纯化得到白色固体状的110(70mg,15%收率)。LCMS:[M+H]+678。1H NMR(500MHz,MeOD)δ8.29(s,1H),8.09(d,J=2.5,1H),8.05(s,1H),7.66(s,1H),7.50(dd,J=3.5,9.5,1H),7.41(dd,J=2.0,9.0,1H),7.34(dd,J=2.5,8.5,1H),7.17(d,J=9,1H),6.70(s,1H),4.74(t,J=7,2H),4.65(t,J=6,2H),4.58-4.59(m,2H),4.29-4.30(m,1H),4.24-4.25(m,2H),4.04-4.05(m,1H),3.58-3.59(m,1H),3.26-3.27(m,4H),2.61(s,2H),2.56-2.58(m,4H),2.50(s,2H),1.27(s,6H)
实施例111 5-[5-氟-2-(羟基甲基)-3-(8-(5-(4-(氧杂环丁烷-3-基)哌嗪-1-基)吡啶-2-基氨基)咪唑并[1,2-b]哒嗪-6-基)苯基]-8-硫杂-5-氮杂三环[7.4.0.02,7]十三碳-1(9),2(7)-二烯-6-酮111
往配有磁力搅拌器的密封管中装入乙酸(4-氟-2-{6-氧代-8-硫杂-5-氮杂三环[7.4.0.02,7]十三碳-1(9),2(7)-二烯-5-基}-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)甲酯103g(200mg,0.44mmol)、6-氯-N-(5-(4-(氧杂环丁烷-3-基)哌嗪-1-基)吡啶-2-基)咪唑并[1,2-b]哒嗪-8-胺108a(155mg,0.44mmol)、三环己基膦(112mg,0.4mmol)、Pd2(dba)3(28mg,0.024mmol)、Cs2CO3(261mg,0.8mmol)和二噁烷(25mL)。真空/氩气冲洗三个循环后,110℃加热反应混合物16h。真空蒸发混合物并用乙酸乙酯(10mL X2)萃取残留物。减压浓缩经合并的乙酸乙酯萃取物并用反相制备型HPLC纯化残留物得到111(59mg,22%)。MS:[M+H]+681。1H NMR(500MHz,DMSO)δ9.94(s,1H),8.23(s,1H),8.16(s,1H),8.02(s,1H),7.67(s,1H),7.44-7.46(m,3H),7.34-7.36(m,1H),4.64-4.66(m,1H),4.54-4.57(m,2H),4.42-4.48(m,3H),4.35-4.38(m,1H),3.96-4.10(m,1H),3.79-3.89(m,1H),3.42-3.45(m,1H),3.14-3.16(m,4H),2.54-2.96(m,4H),2.47-2.50(m,2H),2.37-2.41(m,4H),1.79(t,J=4.0,4H)
实施例112 5-[5-氟-2-(羟基甲基)-3-(8-(5-(4-(氧杂环丁烷-3-基)哌嗪-1-基)吡啶-2-基氨基)咪唑并[1,2-b]哒嗪-6-基)苯基]-8-硫杂-4,5-二氮杂三环-[7.4.0.02,7]十三碳-1(9),2(7),3-三烯-6-酮112
往配有磁力搅拌器的密封管中装入乙酸(4-氟-2-{6-氧代-8-硫杂-4,5-二氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3-三烯-5-基}-6-(四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)甲酯(200mg,0.44mmol)、6-氯-N-(5-(4-(氧杂环丁烷-3-基)哌嗪-1-基)吡啶-2-基)咪唑并[1,2-b]哒嗪-8-胺105a(155mg,0.44mmol)、三环己基膦(112mg,0.4mmol)、Pd2(dba)3(28mg,0.024mmol)、Cs2CO3(261mg,0.8mmol)和二噁烷(25mL)。真空/氩气冲洗三个循环后,110℃加热反应混合物16h。真空蒸发混合物并用乙酸乙酯(10mL X2)萃取残留物。减压浓缩经合并的乙酸乙酯萃取物并用反相制备型HPLC纯化残留物得到112(26mg,12%)。MS:[M+H]+680。1H NMR(500MHz,DMSO.)δ9.95(s,1H),8.49(s,1H),8.24(s,1H),8.17(s,1H),8.04(s,1H),7.67(s,1H),7.45-7.53(m,4H),4.54-4.57(m,3H),4.45-4.47(m,2H),4.33(d,J=12.5,2H),3.35-3.46(m,1H),3.13-3.17(m,4H),2.83-2.94(m,4H),2.47-2.50(m,4H),1.82-1.87(m,4H)
实施例113a 3,3-二甲基环戊酮113a
用氮气吹扫配有磁力搅拌器、加料漏斗和氮气入口的1-L三颈圆底烧瓶并装入乙醚(200mL)和碘化亚铜(I)(54.46g,0.286mol)。冷却混合物至0℃,经1.5h将甲基锂(乙醚中1.6M,357.5mL,0.572mol)滴加至反应混合物并在0℃另外搅拌2h。此后经1.5h滴加3-甲基环戊-2-烯酮(25g,0.260mol)在乙醚(150mL)中的溶液。然后在0℃搅拌该反应混合物2h并将其倾入硫酸钠十水合物(300g)。搅拌所得混合物30分钟。此后过滤混合物并用乙醚(1000mL)洗涤。浓缩滤液并减压蒸馏得到70%收率(20.5g)的无色液体状的3,3-二甲基环戊酮113a:bp50–55℃(10mmHg);1H NMR(300MHz,CDCl3)δ2.31(t,2H,J=7.8Hz),2.05(s,2H),1.79(t,2H,J=7.8Hz);MS(ESI+)m/z113.3(M+H)
实施例113b 5,5-二甲基-5,6-二氢-4H-环戊二烯并[b]噻吩-2-羧酸乙酯113b
用氮气吹扫配有磁力搅拌器、回流冷凝器、加料漏斗和氮气入口的500-mL三颈圆底烧瓶并装入DMF(9.49g,0.100mol)和二氯甲烷(100mL)。冷却反应混合物至0℃并经30分钟将磷酰氯(14.1g,0.0920mol)滴加至反应混合物。一旦加入完成,将反应混合物温热至室温并搅拌1h。此后经1h滴加113a(11.2g,0.100mol)在二氯甲烷(100mL)中的溶液。然后在回流下搅拌反应混合物18h。将反应混合物冷却至室温并倾入碎冰(400mL)和乙酸钠(100g,1.22mol)的混合物中。搅拌所得混合物45分钟。此后分离水层并用二氯甲烷(2×500mL)萃取。接着用水(2×200mL),然后是盐水(200mL)洗涤经合并的有机层并经硫酸钠干燥。然后通过过滤除去干燥剂,浓缩滤液得到粗产物2-氯-4,4-二甲基环戊-1-烯甲醛,其被置于配有磁力搅拌器、回流冷凝器和氮气入口的500-mL三颈圆底烧瓶中。然后加入二氯甲烷(200mL)、2-巯基乙酸乙酯(11.0g,0.092mol)和三乙胺(30g,0.207mol)。然后在回流下搅拌反应混合物6h。此后将反应混合物冷却至室温并浓缩为粘稠橙色残留物。加入乙醇(200mL)和三乙胺(30.0g,0.207mol)并在回流下加热反应混合物12h。然后冷却反应混合物至室温并减压浓缩,并用乙醚(600mL)稀释所得残留物。用1M盐酸(150mL)、盐水(100mL)洗涤所得混合物,经硫酸钠干燥,过滤并减压浓缩。通过快速柱色谱纯化所得残留物得到无色液体状的34%收率(7.70g)的113b:1H NMR(300MHz,CDCl3)δ7.48(s,1H),4.33(q,2H,J=7.2Hz),2.72(s,2H),2.56(s,2H),1.38(t,3H,J=1.8Hz),1.17(s,6H);MS(ESI+)m/z225.1
实施例113c 5,5-二甲基-5,6-二氢-4H-环戊二烯并[b]噻吩-2-羧酸113c
在配有磁力搅拌器和回流冷凝器的250-mL单颈圆底烧瓶中将113b(4.00g,17.8mmol)溶于乙醇(50mL)。加入THF(50mL)、水(50mL)和氢氧化锂(854mg,35.6mmol),并在60℃搅拌该混合物4h。此后冷却反应混合物至室温并用2M盐酸酸化至pH1.5,并用乙酸乙酯(2×200mL)萃取。合并有机层,用水(2×100mL),然后是盐水(100ml)洗涤并经硫酸钠干燥。然后通过过滤分离干燥剂。蒸发所得滤液后获得91%收率(3.2g)的白色固体状的113c:mp170–172℃;1H NMR(300MHz,CDCl3)δ12.77(s,1H),7.46(s,1H),2.71(s,2H),2.53(s,2H),1.20(s,6H);MS(ESI–)m/z195.0
实施例113d 5,5-二甲基-5,6-二氢-4H-环戊二烯并[b]噻吩-2-羧酸113d
往配有磁力搅拌器、回流冷凝器和置于冷凝器上的鼓泡器的100-mL单颈圆底烧瓶中装入113c(2.30g,11.6mmol)、甲苯(25mL)、亚硫酰氯(4.09g,34.9mmol)和DMF(1滴)。回流下加热该混合物1h并接着在旋转蒸发器上在45℃减压蒸发。用二氯甲烷(20mL)稀释所得酰基氯。
氮气下在单独的配有磁力搅拌器的250-mL三颈圆底烧瓶中将N,O-二甲基羟胺盐酸盐(2.26g,23.2mmol)和N,N-二异丙基乙胺(2.97g,23.0mmol)溶于无水二氯甲烷(20mL),并在冰/水浴中将溶液冷却至0℃。加入酰基氯溶液,并在室温搅拌反应混合物18h。用水(100mL)、10%柠檬酸水溶液(50mL)和饱和碳酸氢钠水溶液和水的1:1混合物(100mL)萃取反应混合物。经硫酸钠干燥有机层并在旋转蒸发器上减压蒸发得到93%收率(2.60g)的浅黄色固体状的113d:1H NMR(300MHz,CDCl3)δ7.66(s,1H),3.77(s,3H),3.35(s,3H),2.74(s,2H),2.58(s,2H),1.23(s,6H)
实施例113e 3-氯-1-(5,5-二甲基-5,6-二氢-4H-环戊二烯并[b]噻吩-2-基)丙-1-酮113e
用氮气吹扫配有磁力搅拌器的100-mL单颈圆底烧瓶并装入113d(2.41g,10.0mmol)和无水THF(20mL)。将溶液冷却至-70℃,并在保持反应温度低于-60℃的情况下加入1M乙烯基溴化镁在THF中的溶液(11mL,11.0mmol)。在-13至-7℃搅拌反应混合物2h并接着经30分钟温热至室温。将反应混合物再次冷却至-70℃,并加入氯化氢在乙醚(22.5ml,45mmol)中的2M溶液。然后在冷冻箱中-10℃贮存反应混合物过夜。此后在旋转蒸发器上减压蒸发混合物,并在水(100mL)和乙醚(100mL)间分配所得残留物。经硫酸钠干燥乙醚萃取物并在旋转蒸发器上减压蒸发得到约75%纯度(通过NMR)的棕色油状的粗113e(2.86g,118%):1H NMR(300MHz,CDCl3)δ7.45(s,1H),3.89(t,2H,J=6.9Hz),3.30(t,2H,J=6.9Hz),2.75(s,2H),2.59(s,2H),1.24(s,6H)
实施例113f 6,6-二甲基-1,2,6,7-四氢二环戊二烯并[b,d]噻吩-3(5H)-酮113f
往配有磁力搅拌器的100-mL单颈圆底烧瓶中装入粗113e(2.86g,10.0mmol推定定量收率)和98%硫酸。在90℃油浴中加热反应混合物过夜。将反应混合物置于冰/丙酮浴中,并加入一批磷酸氢二钾(105g,0.603mol)在水(300mL)中的冷(5℃)溶液。用乙酸乙酯(300mL)振摇所得混合物并过滤。用乙酸乙酯(100mL)洗涤滤饼。分离滤液的乙酸乙酯层,经硫酸钠干燥并在旋转蒸发仪上减压蒸发。通过快速柱色谱(硅胶,80:20己烷/乙酸乙酯)纯化所得残留物得到两步37%收率(683mg)的无定形棕色固体状的113f:mp60–62℃;1H NMR(500MHz,CDCl3)δ2.92–2.87(m,4H),2.79(s,2H),2.53(s,2H),1.26(s,6H);MS(ESI+)m/z207.0(M+H)
实施例113g 6,6-二甲基-1,2,6,7-四氢二环戊二烯并[b,d]噻吩-3(5H)-酮113g
往配有磁力搅拌器和氮气入口的250-mL单颈圆底烧瓶中装入盐酸羟胺(688mg,9.90mmol)、乙酸钠(812mg,9.90mmol)和甲醇(10mL),且该混合物在室温保持30分钟。此后,室温滴加113f(680mg,3.30mmol)溶液,并在氮气氛下室温搅拌反应混合物14h。由于未反应完全,加入盐酸羟胺(1.15g,16.5mmol)和乙酸钠(1.35g,16.5mmol)并在室温继续搅拌58h。此后,用二氯甲烷(150mL)和水(100mL)稀释混合物,并分离各层。用盐水(50mL)洗涤有机层并经硫酸钠干燥。通过过滤除去干燥剂并浓缩滤液得到定量收率(730mg)的黄色半固体状的粗113g,其未经纯化用于下一步:mp122–124℃;主要异构体的1H NMR(500MHz,CDCl3)δ3.13–3.11(m,2H),2.85–2.83(m,2H),2.77(s,2H),2.49(s,2H),1.24(s,6H);MS(ESI+)m/z222.0(M+H)
实施例113h 6,6-二甲基-3,4,6,7-四氢-5H-环戊二烯并[4,5]噻吩并[2,3-c]吡啶-1(2H)-酮113h
往配有回流冷凝器、机械搅拌器和氮气入口的100-mL三颈圆底烧瓶中装入113g(700mg,3.16mmol)和聚磷酸(25g)。氮气氛下80℃搅拌反应混合物13h。此后,将混合物冷却至0℃并小心滴加水(50mL),保持内部温度介于10–45℃。用90:10二氯甲烷/甲醇(100mL)稀释混合物并分离各层。用90:10二氯甲烷/甲醇(50mL)萃取水层,并用饱和碳酸氢钠水溶液(50mL)、盐水(150mL)洗涤经合并的有机层并经硫酸钠干燥。通过过滤除去干燥剂。减压浓缩滤液,并通过快速柱色谱(硅胶,95:5二氯甲烷/甲醇)纯化所得残留物得到90%收率(630mg)的无定形灰白色固体状的6,6-二甲基-3,4,6,7-四氢-5H-环戊二烯并[4,5]噻吩并[2,3-c]吡啶-1(2H)-酮113h:mp205–207℃;1H NMR(500MHz,CDCl3)δ5.51(s,1H),3.60–3.56(m,2H),2.76–2.73(m,4H),2.49(s,2H),1.26(s,6H);MS(ESI+)m/z222.0(M+H)
实施例113i 乙酸(2-溴-6-{4,4-二甲基-9-氧代-7-硫杂-10-氮杂三环[6.4.0.02,6]十二碳-1(8),2(6)-二烯-10-基}-4-氟苯基)甲酯113i
氮气下100℃加热113h(2g,9.05mmol)、乙酸2,6-二溴-4-氟苄酯(101j)(8.8g,27.15mmol)、XantPhos(524mg,0.9mmol)、Pd2(dba)3(828mg,0.9mmol)和Cs2CO3(5.9g,18mmol)在二噁烷(200mL)中的混合物15h。过滤反应混合物并真空蒸发滤液。通过硅胶柱纯化残留物(采用1:1乙酸乙酯/石油醚洗脱)得到黄色固体状的113i(3g,71%).MS:(M+H)+466。
实施例113j 乙酸(2-{4,4-二甲基-9-氧代-7-硫杂-10-氮杂三环[6.4.0.02,6]十二碳-1(8),2(6)-二烯-10-基}-4-氟-6-(四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)甲酯113j
往113i(3g,6.45mmol)、4,4,4',4',5,5,5',5'-八甲基-2,2'-二(1,3,2-二氧杂硼杂环戊烷)(9.8g,38.7mmol)在二噁烷(160mL)中的溶液中加入PdCl2(dppf)(525mg,0.65mmol)和CH3COOK(3.8g,38.7mmol)。氩气氛下100℃搅拌混合物15h。反应后过滤混合物并真空蒸发,并通过硅胶柱纯化残留物(采用1:2乙酸乙酯/石油醚洗脱)得到黄色固体状的113j(2.5g,76%)。MS:(M+H)+514。
实施例113 10-[5-氟-2-(羟基甲基)-3-(8-(5-(4-(氧杂环丁烷-3-基)哌嗪-1-基)吡啶-2-基氨基)咪唑并[1,2-b]哒嗪-6-基)苯基]-4,4-二甲基-7-硫杂-10-氮杂三环[6.4.0.02,6]十二碳-1(8),2(6)-二烯-9-酮113
在实施例112中步骤之后,使6-氯-N-(5-(4-(氧杂环丁烷-3-基)哌嗪-1-基)吡啶-2-基)咪唑并[1,2-a]吡啶-8-胺和113j反应得到13%收率的113。LCMS:[M+H]+695。1H NMR(500MHz,MeOD)δ8.30(s,1H),8.09(d,J=2.5,1H),8.05(s,1H),7.66(s,1H),7.50(dd,J=3.5,9.0,1H),7.40(dd,J=3,9,1H),7.34(dd,J=2,9,1H),7.16(d,J=9,1H),4.74(t,J=6.5,2H),4.65(t,J=6,2H),4.60-4.61(m,2H),4.16-4.17(m,1H),4.01-4.02(m,1H),3.58-3.59(m,1H),3.25-3.26(m,4H),3.12-3.14(m,1H),2.97-2.98(m,1H),2.81(s,2H),2.60-2.61(m,2H),2.55-2.56(m,4H),1.29(d,J=2.5,6H)
实施例114a 2-溴-4-氯烟碱醛114a
经5分钟时间往-70℃冷却的2-溴-4-氯吡啶(1.6g,8.0mmol)在无水四氢呋喃(40mL)中的溶液中加入二异丙基氨基锂(5.0mL,10.0mmol,2.0M)溶液并在-70℃另外搅拌1h。经3分钟时间引入无水DMF(1.3g)并另外搅拌混合物30分钟。然后用饱和NH4Cl(30mL)淬灭反应混合物并用乙酸乙酯(20mL×3)萃取。经无水Mg2SO4干燥经合并的有机层,过滤并减压蒸发。通过硅胶柱色谱纯化残留物(采用石油醚/乙酸乙酯(20:1)洗脱)得到黄色固体状的114a(900mg,48%)。1H NMR(500MHz,DMSO)δ10.21(s,1H),8.52(d,J=5.5Hz,1H),7.79(d,J=5.0Hz,1H)。
实施例114b 4-氯-2-(1-氧代-3,4,6,7,8,9-六氢吡嗪并[1,2-a]吲哚-2(1H)-基)烟碱醛114b
往配有磁力搅拌器和回流冷凝器的100-mL单颈圆底烧瓶中装入114a(800mg,3.5mmol)、3,4,6,7,8,9-六氢吡嗪并[1,2-a]吲哚-1(2H)-酮101g(665mg,3.5mmol)、三(二亚苄基丙酮)二钯(0)(320mg,0.35mmol)、XantPhos(400mg,0.7mmol)、Cs2CO3(2.3g,7.0mmol)和1,4-二噁烷(20mL)。真空/氩气冲洗三个循环后,90℃加热该混合物5h。然后冷却至室温并过滤。减压浓缩滤液并通过硅胶柱色谱纯化所得残留物(采用二氯甲烷/甲醇(80:1)洗脱)得到黄色固体状的114b(1.2g,50%)。MS:[M+H]+330。
实施例114c 2-(4-氯-3-(羟基甲基)吡啶-2-基)-3,4,6,7,8,9-六氢吡嗪并[1,2-a]吲哚-1(2H)-酮114c
10℃往114b(1.0g,3.0mmol)在甲醇(50mL)中的溶液中加入硼氢化钠(380mg,9.0mmol)并另外搅拌30分钟。然后用水(1mL)淬灭反应混合物并浓缩。将残留物溶于二氯甲烷(50mL)中并用水(10mL)洗涤。经无水Na2SO4干燥有机相,过滤并减压蒸发得到黄色固体状的114c(900mg,90%)。MS:[M+H]+332。
实施例114d 乙酸(4-氯-2-(1-氧代-3,4,6,7,8,9-六氢吡嗪并[1,2-a]吲哚-2(1H)-基)吡啶-3-基)甲酯114d
在室温搅拌下往114c(900mg,2.7mol)和三乙胺(900mg,9.0mol)在二氯甲烷(5mL)中的混合物中滴加乙酰氯(600mg,6.0mol)并另外搅拌1h。浓缩反应混合物并通过硅胶柱色谱纯化(采用二氯甲烷洗脱)得到白色固体状的114d(950mg,94%)。MS:[M+H]+374。
实施例114e 乙酸(2-(1-氧代-3,4,6,7,8,9-六氢吡嗪并[1,2-a]吲哚-2(1H)-基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡啶-3-基)甲酯114e
往配有磁力搅拌器和回流冷凝器的100-mL单颈圆底烧瓶中装入114d(950mg,2.5mmol)、Pin2B2(1.6g,2.0当量,5mmol)、Pd2(dba)3(230mg,0.1当量,0.25mmol)、X-phos(232mg,0.2当量,0.5mmol)、AcOK(735mg,3当量,7.5mmol)和二噁烷(20mL)。真空/氩气冲洗三个循环后,将混合物加热至65℃且保持14h。然后冷却至室温并过滤。减压浓缩滤液并通过PE/EA=3/1(10mL)洗涤所得残留物得到黄色固体状的114e(950mg,87%)。MS:[M+H]+383。
实施例114 2-(3-(羟基甲基)-4-(8-(5-(4-(氧杂环丁烷-3-基)哌嗪-1-基)吡啶-2-基氨基)咪唑并[1,2-b]哒嗪-6-基)吡啶-2-基)-3,4,6,7,8,9-六氢吡嗪并[1,2-a]吲哚-1(2H)-酮114
往密封管中装入6-氯-N-(5-(4-(氧杂环丁烷-3-基)哌嗪-1-基)吡啶-2-基)咪唑并[1,2-b]哒嗪-8-胺105a(200mg,0.5mmol)、114e(200mg,1.0当量,0.5mmol)、Pd2(dba)3(46mg,0.1当量,0.05mmol)、PCy3(40mg,0.2当量,0.1mmol)、碳酸铯(325mg,2当量,1.0mmol)和二噁烷(10mL)。真空/氩气冲洗三个循环后,130℃加热该混合物14h。然后冷却至室温并过滤。减压浓缩滤液。通过硅胶柱色谱纯化所得残留物(采用二氯甲烷/甲醇(40:1)洗脱)并进一步采用反相制备型HPLC纯化得到114(13mg,4%)。LCMS:[M+H]+647。1H NMR(500MHz,DMSO)δ9.96(s,1H),8.56(d,J=5.0,1H),8.24(s,1H),8.18(s,1H),7.99(d,J=2.5,1H),7.68(s,1H),7.45-7.50(m,3H),6.58(s,1H),4.72(t,J=5.0,1H),4.55-4.59(m,3H),4.45-4.47(m,2H),4.37-4.40(m,1H),4.19-4.29(m,2H),4.08-4.10(m,1H),3.91-3.94(m,1H),3.42-3.45(m,1H),3.14-3.16(m,4H),2.52-2.63(m,2H),2.46-2.47(m,2H),2.36-2.40(m,4H),1.76-1.78(m,2H),1.66-1.70(m,2H)
实施例115a 4-(6-硝基吡啶-3-基)哌嗪-1-羧酸叔丁酯115a
往5-溴-2-硝基吡啶(30g,148mmol)在DMSO(1L)中的溶液中加入K2CO3(40g,296mmol)和哌嗪-1-羧酸叔丁酯(28g,148mmol)。65℃搅拌该混合物过夜。冷却下来后,将其倾入水(2L)中。收集沉淀固体并真空干燥。然后通过快速柱进一步纯化(采用20:1石油醚/乙酸乙酯以及然后是二氯甲烷洗脱)得到黄色固体状的115a(17g,37%)。MS:[M+H]+309。
实施例115b 4-(6-氨基吡啶-3-基)哌嗪-1-羧酸叔丁酯115b
用氮气吹扫500-mL瓶并装入115a(3.1g,10mmol)、10%钯/炭(50%湿的,1.0g)和乙醇(100mL)。将其排空,装入氢气,并在室温搅拌16h。然后排空氢气并将氮气装入瓶中。通过过滤经硅藻土垫除去催化剂并减压浓缩滤液得到115b(2.7g,97%)。MS:[M+H]+279
实施例115c (S)-4-(6-(6-氯咪唑并[1,2-b]哒嗪-8-基氨基)吡啶-3-基)-3-甲基哌嗪-1-羧酸叔丁酯115c
遵循用于制备101b的步骤并起始自8-溴-6-氯咪唑并[1,2-b]哒嗪104a(1.44g,6.2mmol)和115b(905mg,3.1mmol),得到黄色固体状的115c(2.2g,80%)。MS-ESI:[M+H]+444.2
实施例115d (S)-6-溴-N-(5-(2-甲基哌嗪-1-基)吡啶-2-基)咪唑并[1,2-b]哒嗪-8-胺氢溴酸盐115d
往高压灭菌器中装入115c(1.60g,3.6mmol)和HBr/AcOH(60mL)。150℃加热18h。减压浓缩反应混合物得到黑色油状物。用甲醇(30mL)/二氯甲烷(30mL)/石油醚(90mL)重结晶该油状物得到黄色固体状的115d(1.1g,65%)。MS-ESI:[M+H]+388.1
实施例115e (S)-6-溴-N-(5-(2-甲基-4-(氧杂环丁烷-3-基)哌嗪-1-基)吡啶-2-基)咪唑并[1,2-b]哒嗪-8-胺115e
往(S)-6-溴-N-(5-(2-甲基哌嗪-1-基)吡啶-2-基)咪唑并[1,2-b]哒嗪-8-胺氢溴酸盐115d(1.05g,2.24mmol)、氧杂环丁烷-3-酮(483mg,6.7mmol)和ZnCl2(914mg,6.7mmol)在甲醇(30mL)中的混合物中加入NaBH3CN(421mg,6.7mmol)。50℃加热该反应混合物14h并减压浓缩。加水(30mL)至该残留物并用二氯甲烷(%X30mL)萃取所得混合物。经无水MgSO4干燥经合并的有机相并过滤。减压蒸发滤液。通过硅胶柱色谱纯化残留物(采用40:1二氯甲烷/甲醇洗脱)得到黄色固体状的115e(220mg,22%)。MS-ESI:[M+H]+444.1
实施例115 (S)-2-(3-(羟基甲基)-4-(8-(5-(2-甲基-4-(氧杂环丁烷-3-基)哌嗪-1-基)吡啶-2-基氨基)咪唑并[1,2-b]哒嗪-6-基)吡啶-2-基)-3,4,6,7,8,9-六氢吡嗪并[1,2-a]吲哚-1(2H)-酮115
往密封管中装入115e(156mg,0.35mmol)、3-(乙酰氧基甲基)-2-(1-氧代-3,4,6,7,8,9-六氢吡嗪并[1,2-a]吲哚-2(1H)-基)吡啶-4-基硼酸114e(134mg,0.35mmol)、Pd2(dba)3(64mg,0.070mmol)、PCy3(40mg,0.14mmol)、碳酸铯(228mg,0.70mmol)、水(1滴)和二噁烷(9mL)。真空/氩气冲洗三个循环后,130℃加热该混合物16h。然后冷却至室温并过滤。减压浓缩滤液并通过硅胶柱色谱纯化所得残留物(采用40:1二氯甲烷/甲醇洗脱)并采用反相制备型HPLC进一步纯化得到115(31mg,13%)。MS-ESI:[M+H]+661.3。1H NMR(500MHz,DMSO-d6)δ9.97(s,1H),8.56(d,J=5.0Hz,1H),8.25(d,J=5.0Hz,1H),8.19(d,J=0.5Hz,1H),7.95(s,1H),7.68(d,J=1.0Hz,1H),7.48-7.44(m,3H),6.58(s,1H),4.76(t,J=5.0Hz,1H),4.58-4.54(m,3H),4.49-4.46(m,1H),4.43-4.36(m,2H),4.30-4.05(m,3H),3.94-3.87(m,2H),3.42-3.37(m,1H),3.24-3.19(m,1H),3.00-2.96(m,1H),2.66-2.57(m,3H),2.47-2.43(m,3H),2.28-2.26(m,1H),2.12-2.09(m,1H),1.79-1.68(m,4H),1.00(d,J=6.5Hz,3H)。
实施例116a 4-溴-6-氯-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-苯并[d]咪唑116a
往4-溴-6-氯-1H-苯并[d]咪唑109c(3.5g,15mmol)在N,N-二甲基甲酰胺(30mL)中的溶液中加入氢化钠(360mg,15mmol)和2-(三甲基甲硅烷基)乙氧基甲基氯(2.7g,16.5mmol)。室温搅拌反应混合物2h。加水(100mL)以淬灭反应。用乙酸乙酯(3X80mL)萃取该混合物。经无水Na2SO4干燥经合并的有机相,过滤并减压蒸发得到棕色固体状的116a(4.2g,77%)。MS-ESI:[M+H]+361.0
实施例116b 6-氯-N-(5-(4-(氧杂环丁烷-3-基)哌嗪-1-基)吡啶-2-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-苯并[d]咪唑-4-胺116b
往配有磁力搅拌器的微波瓶中装入116a(600mg,1.65mmol)、5-(4-(氧杂环丁烷-3-基)哌嗪-1-基)吡啶-2-胺(390mg1.67mmol)、碳酸铯(1.09g,3.34mmol)、三(二亚苄基丙酮)二钯(0)(152mg,0.167mmol)、Xantphos(193mg,0.334mmol)和二噁烷(10mL)。将氮气鼓泡经该混悬液10分钟后,120℃加热该反应混合物过夜。然后冷却至室温并过滤。减压浓缩滤液并用石油醚和乙酸乙酯混合溶剂(15mL,2:1)洗涤残留物得到黄色固体状的116b(720mg,85%)。MS-ESI:[M+H]+515.2
实施例116c 6-氯-N-(5-(4-(氧杂环丁烷-3-基)哌嗪-1-基)吡啶-2-基)-1H-苯并[d]咪唑-4-胺116c
室温搅拌116b(720mg,1.4mmol)在TFA(10mL)中的混合物6h。减压浓缩该混合物并用水(10mL)稀释。通过加氨水调节混合物的pH至7。然后用二氯甲烷(3X20mL)萃取。经无水Na2SO4干燥经合并的有机相,过滤并减压蒸发得到棕色固体状的116c(500mg,93%)。MS-ESI:[M+H]+385.1
实施例116 2-[5-氟-2-(羟基甲基)-3-[7-[[5-[4-(氧杂环丁烷-3-基)哌嗪-1-基]-2-吡啶基]氨基]-3H-苯并咪唑-5-基]苯基]-3,4,6,7,8,9-六氢吡嗪并[1,2-a]吲哚-1-酮116
往配有磁力搅拌器的微波瓶中装入116c(300mg,0.78mmol)、乙酸4-氟-2-(1-氧代-3,4,6,7,8,9-六氢吡嗪并[1,2-a]吲哚-2(1H)-基)-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苄酯101k(545mg,1.13mmol)、碳酸钾(414mg,3.0mmol)、三(二亚苄基丙酮)二钯(0)(68mg,0.075mmol)、三环己基膦(210mg,0.75mmol)、水(0.2mL)和二噁烷(10mL)。将氮气鼓泡经该混悬液10分钟后,110℃加热该密封瓶过夜。然后冷却至室温并过滤。减压浓缩滤液并通过反相制备型HPLC纯化残留物得到白色固体状的116(52mg,10%)。MS-ESI:[M+H]+663.3。1H NMR(500MHz,DMSO)δ8.23(bs,1H),8.11(s,1H),7.88(d,J=4.5Hz,1H),7.35-7.31(m,1H),7.23-7.17(m,2H),7.13-7.09(m,2H),6.52(s,1H),4.57-4.45(m,重叠,4H),4.31(d,J=7.5Hz,2H),4.11-4.01(m,4H),3.51-3.47(m,1H),3.10-3.06(m,4H),2.59-2.41(m,8H),1.81-1.68(m,4H)
实施例117a 6-氯-9-((2-(三甲基甲硅烷基)乙氧基)甲基)-9H-嘌呤-2-胺117a
室温搅拌6-氯-9H-嘌呤-2-胺(5.0g,29.6mmol)和NaH(1.43g,32.5mmol)在DMF(30mL)中的混合物0.5h。加入(2-(氯甲氧基)乙基)三甲基甲硅烷(SEMCl,CAS登记号76513-69-4,4.91g,29.6mmol)并在室温搅拌所得混合物1.0h。然后过滤并真空蒸发滤液。通过硅胶柱色谱纯化残留物(采用3:1石油醚/乙酸乙酯洗脱)得到黄色固体状的117a(5.1g,58%)。MS-ESI:[M+H]+300.1
实施例117b 6-氯-2-碘-9-((2-(三甲基甲硅烷基)乙氧基)甲基)-9H-嘌呤117b
往117a(2.99g,10.0mmol)、CH2I2(4.0ml,51.0mmol)和CuI(1.91g,10.0mmol)在THF中的混合物中加入亚硝酸异戊酯(4.0mL,30.0mmol)。回流下加热该混合物1.0h并冷却至室温。在乙酸乙酯和1N HCl水溶液间分配该反应混合物。用饱和NH4Cl水溶液洗涤有机相,经Na2SO4干燥并减压浓缩。通过硅胶柱色谱纯化残留物(采用3:1石油醚/乙酸乙酯洗脱)得到黄色固体状的117b(2.02g,49%)。MS-ESI:[M+H]+411.0
实施例117c 1-(4-硝基苯基)哌嗪117c
往117b(3.07g,10.0mmol)在二噁烷(50mL)中的溶液中加入4.0M HCl/二噁烷(10mL,40.0mmol)。室温搅拌反应混合物5h。然后减压浓缩该混合物得到黄色固体状的117c(2.4g,99%),其未经进一步纯化而被使用。MS:[M+H]+208。
实施例117d 1-(4-硝基苯基)-4-(氧杂环丁烷-3-基)哌嗪117d
往117c(2.0g,8.23mmol)、氯化锌(2.2g,16.4mmol)、氧杂环丁烷-3-酮(1.18g,16.4mmol)在甲醇(80mL)中的混合物中加入NaBH3CN(1.02g,16.4mmol)。50℃搅拌混合物5小时。然后减压浓缩混合物并用水(100mL)稀释残留物。用二氯甲烷(3X100mL)萃取并减压浓缩经合并的有机层。通过硅胶柱色谱纯化残留物(采用4:1石油醚/乙酸乙酯洗脱)得到黄色固体状的117d(1.65g,76%)。MS:[M+H]+264。
实施例117e 4-(4-(氧杂环丁烷-3-基)哌嗪-1-基)苯胺117e
用氮气吹扫250-mL圆底烧瓶并装入117d(1.5g,5.7mmol)、10%钯/炭(50%湿,750mg)和乙醇(60mL)。排空烧瓶,装入氢气,并在室温搅拌15h。然后排空氢气并将氮气装入烧瓶。通过过滤经硅藻土垫除去催化剂并减压浓缩滤液得到117e(1.2g,90%),其未经进一步纯化而用于下一步。MS:[M+H]+234
实施例117f 2-碘-N-(4-(4-(氧杂环丁烷-3-基)哌嗪-1-基)苯基)-9-((2-(三甲基甲硅烷基)乙氧基)甲基)-9H-嘌呤-6-胺117f
80℃搅拌117b(2.05g,5.0mmol)、117e(1.17g,5.0mmol)和三乙胺(1.01g,10mmol)在异丙醇(30mL)中的混合物4h。然后过滤并真空蒸发滤液。通过硅胶柱色谱纯化残留物(采用30:1二氯甲烷/甲醇洗脱)得到黄色固体状的117f(1.82g,60%)。MS-ESI:[M+H]+608.1
实施例117g 乙酸4-氟-2-(6-(4-(4-(氧杂环丁烷-3-基)哌嗪-1-基)苯基氨基)-9-((2-(三甲基甲硅烷基)乙氧基)甲基)-9H-嘌呤-2-基)-6-(1-氧代-3,4,6,7,8,9-六氢吡嗪并[1,2-a]吲哚-2(1H)-基)苄酯117g
往配有磁力搅拌器和回流冷凝器的50-mL单颈圆底烧瓶中装入117f(607mg,1.0mmol)、乙酸4-氟-2-(1-氧代-3,4,6,7,8,9-六氢吡嗪并[1,2-a]吲哚-2(1H)-基)-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苄酯101k(482mg,1.0mmol)、Pd(dppf)Cl2(82mg,0.10mmol)、K3PO4(424mg,2.0mmol)、乙酸钠(164mg,2.0mmol)、水(0.5mL)和乙腈(20mL)。真空/氩气冲洗三个循环后,回流下加热该混合物2h。然后冷却至室温并过滤。减压浓缩滤液并通过硅胶柱色谱纯化所得残留物(采用30:1二氯甲烷/甲醇洗脱)得到黄色固体状的117g(600mg,72%)。MS-ESI:[M+H]+836.5
实施例117h 乙酸4-氟-2-(6-(4-(4-(氧杂环丁烷-3-基)哌嗪-1-基)苯基氨基)-9H-嘌呤-2-基)-6-(1-氧代-3,4,6,7,8,9-六氢吡嗪并[1,2-a]吲哚-2(1H)-基)苄酯117h
室温搅拌117g(550mg,0.660mmol)和CF3COOH(6mL)的混合物2h。然后减压浓缩得到黄色固体状的粗117h(140mg,30%),其未经进一步纯化而用于下一步。MS-ESI:[M+H]+706.4
实施例117 2-[5-氟-2-(羟基甲基)-3-[6-[4-[4-(氧杂环丁烷-3-基)哌嗪-1-基]苯胺基]-9H-嘌呤-2-基]苯基]-3,4,6,7,8,9-六氢吡嗪并[1,2-a]吲哚-1-酮117
30℃搅拌117h(140mg,0.20mmol)和氢氧化锂(48mg,2.0mmol)在异丙醇/THF(1:1,4mL)和水(1mL)中的混合物1h。真空蒸发该混合物并用水(5mL)稀释残留物。然后用乙酸乙酯(2X10mL)萃取。减压浓缩经合并的乙酸乙酯萃取物并通过反相制备型HPLC纯化残留物得到白色固体状的117(85mg,64%)。MS-ESI:[M+H]+664.4。1H NMR(500MHz,CDCl3)δ12.45(s,1H),8.26(s,1H),7.86(d,J=8.5Hz,2H),7.66(d,J=8.0Hz,2H),7.11(d,J=9.0Hz,1H),6.96(d,J=8.0Hz,2H),6.88(s,1H),4.74-4.68(m,4H),4.66-4.60(m,2H),4.17-4.09(m,3H),3.91-3.90(m,1H),3.59(t,J=6.5Hz,1H),3.25-3.23(m,4H),2.59-2.52(m,8H),1.89-1.80(m,4H)。
实施例118a 6-氯-N-(5-(4-(氧杂环丁烷-3-基)哌嗪-1-基)吡啶-2-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-苯并[d]咪唑-4-胺118a
往配有磁力搅拌器的微波瓶中装入4-溴-6-氯-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-苯并[d]咪唑116a(600mg,1.65mmol)、5-(4-(氧杂环丁烷-3-基)哌嗪-1-基)吡啶-2-胺(390mg1.67mmol)、碳酸铯(1.09g,3.34mmol)、三(二亚苄基丙酮)二钯(0)(152mg,0.167mmol)、Xantphos(193mg,0.334mmol)和二噁烷(10mL)。将氮气鼓泡经该混悬液10分钟后,120℃加热该反应混合物过夜。然后冷却至室温并过滤。减压浓缩滤液并用石油醚和乙酸乙酯混合溶剂(15mL,2:1)洗涤残留物得到黄色固体状的118a(720mg,85%)。MS-ESI:[M+H]+515.2
实施例118b 6-氯-N-(5-(4-(氧杂环丁烷-3-基)哌嗪-1-基)吡啶-2-基)-1H-苯并[d]咪唑-4-胺118b
室温搅拌118a(720mg,1.4mmol)在TFA(10mL)中的混合物6h。减压浓缩该混合物并用水(10mL)稀释。通过加氨水调节混合物的pH至7。然后用二氯甲烷(3X20mL)萃取。经无水Na2SO4干燥经合并的有机相,过滤并减压蒸发得到棕色固体状的118b(500mg,93%)。MS-ESI:[M+H]+385.1
实施例118 2-[3-(羟基甲基)-4-[7-[[5-[4-(氧杂环丁烷-3-基)哌嗪-1-基]-2-吡啶基]氨基]-3H-苯并咪唑-5-基]-2-吡啶基]-3,4,6,7,8,9-六氢吡嗪并[1,2-a]吲哚-1-酮118
往配有磁力搅拌器的微波瓶中装入118b(200mg,0.52mmol)、3-(乙酰氧基甲基)-2-(1-氧代-3,4,6,7,8,9-六氢吡嗪并[1,2-a]吲哚-2(1H)-基)吡啶-4-基硼酸114e(545mg,0.78mmol)、碳酸钾(216mg,1.56mmol)、三(二亚苄基丙酮)二钯(0)(48mg,0.052mmol)、三环己基膦(146mg,0.52mmol)、水(0.2mL)和二噁烷(10mL)。将氮气鼓泡经该混悬液10分钟后,110℃微波下辐射该密封瓶1h。然后冷却至室温并过滤。减压浓缩滤液并通过反相制备型HPLC纯化残留物得到白色固体状的118(50mg,15%)。MS-ESI:[M+H]+646.3。1H NMR(500MHz,DMSO)δ8.69(d,J=2.0Hz,1H),8.49(d,J=5.0Hz,1H),8.32-8.28(m,2H),8.13(s,1H),7.85-7.83(m,1H),7.39-7.33(m,2H),7.36(s,1H),7.29(s,1H),6.59(s,1H),5.89(s,1H),4.56(t,J=6.5Hz,2H),4.46(t,J=6.5Hz,2H),4.23-4.16(m,2H),4.15-4.12(m,4H),3.89-3.53(m,1H),3.13-3.07(m,5H),2.64-2.54(m,2H),2.51-2.43(m,5H),1.79-1.70(m,4H)
实施例119a 乙酸{4-氟-2-[6-({4-[4-(氧杂环丁烷-3-基)哌嗪-1-基]苯基}氨基)-9-{[2-(三甲基甲硅烷基)乙氧基]甲基}嘌呤-2-基]-6-{6-氧代-8-硫杂-5-氮杂三环[7.4.0.02,7]十三碳-1(9),2(7)-二烯-5-基}苯基}甲酯119a
往配有磁力搅拌器和回流冷凝器的50-mL单颈圆底烧瓶中装入乙酸(4-氟-2-{6-氧代-8-硫杂-5-氮杂三环[7.4.0.02,7]十三碳-1(9),2(7)-二烯-5-基}-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)甲酯103g(288mg,0.60mmol)、2-碘-N-(4-(4-(氧杂环丁烷-3-基)哌嗪-1-基)苯基)-9-((2-(三甲基甲硅烷基)乙氧基)甲基)-9H-嘌呤-6-胺117f(364mg,0.60mmol)、Pd(dppf)Cl2(49mg,0.060mmol)、K3PO4(254mg,1.20mmol)、乙酸钠(98mg,1.20mmol)、水(0.5mL)和乙腈(10mL)。真空/氩气冲洗三个循环后,100℃加热该混合物2h。然后冷却至室温并过滤。减压浓缩滤液并通过硅胶柱色谱纯化所得残留物(采用30:1二氯甲烷/甲醇洗脱)得到119a(307mg,60%)。MS-ESI:[M+H]+853.4
实施例119b 乙酸{4-氟-2-[6-({4-[4-(氧杂环丁烷-3-基)哌嗪-1-基]苯基}氨基)-9H-嘌呤-2-基]-6-{6-氧代-8-硫杂-5-氮杂三环[7.4.0.02,7]十三碳-1(9),2(7)-二烯-5-基}苯基}甲酯119b
30℃搅拌119a(307mg,0.360mmol)和CF3COOH(5mL)的混合物2h。真空蒸发该混合物并用水(5mL)稀释残留物。用饱和NaHCO3溶液调节混合物的pH至7并用乙酸乙酯(3X10mL)萃取。经MgSO4干燥经合并的萃取物并蒸发至干得到119b(150mg,60%),其未经进一步纯化而用于下一步。MS-ESI:[M+H]+723.4
实施例119 2-[5-氟-2-(羟基甲基)-3-[6-[4-[4-(氧杂环丁烷-3-基)哌嗪-1-基]苯胺基]-9H-嘌呤-2-基]苯基]-3,4,5,6,7,8-六氢苯并噻吩[2,3-c]吡啶-1-酮119
30℃搅拌119b(150mg,0.210mmol)和氢氧化锂(50mg,2.10mmol)在异丙醇/THF(1:1,4mL)和水(1mL)中的混合物1h。真空蒸发该混合物并用水(5mL)稀释残留物。然后用乙酸乙酯(2X10mL)萃取。减压浓缩经合并的乙酸乙酯萃取物并通过反相制备型HPLC纯化残留物得到黄色固体状的119(85mg,58%)。MS-ESI:[M+H]+681.3。1H NMR(500MHz,CDCl3)δ12.72(s,1H),8.45(s,1H),7.93(d,J=7.5Hz,1H),7.79(s,1H),7.72(d,J=9.0Hz,2H),7.12(d,J=8.0Hz,1H),6.98(d,J=9.0Hz,2H),4.74-4.67(m,6H),4.09-4.04(m,1H),3.78-3.73(m,1H),3.57(t,J=6.5Hz,1H),3.24-3.22(m,4H),2.99-2.93(m,1H),2.88-2.83(m,3H),2.53-2.51(m,6H),1.93-1.81(m,5H)。
实施例120a 5,6,7,8-四氢吲嗪-2-羧酸甲酯120a
用氮气吹扫配有磁力搅拌器和氮气入口的500-mL圆底烧瓶并装入5,6,7,8-四氢吲嗪-2-羧酸(30.4g,184mmol)、DMF(1.00g,13.6mmol)和二氯甲烷(300mL)。使用冰浴将溶液冷却至0℃。滴加草酰氯(28.0g,221mmol),经30分钟将反应混合物温热至室温并搅拌5h。此后,浓缩所得溶液得到棕色固体。将此固体溶于无水甲醇(400mL),并将该溶液冷却至0℃。将三乙胺(57g,552mmol)加至反应混合物,并在室温进一步搅拌2h。此后,减压浓缩反应混合物至干。用二氯甲烷(300mL)稀释残留物并用水(200mL)和饱和碳酸氢钠水溶液(200mL)洗涤。经硫酸钠干燥有机层,过滤并减压浓缩。用己烷(200mL)滴定所得残留物得到58%收率(19.1g)的白色固体状的120a:mp72–74℃;1H NMR(300MHz,DMSO-d6)δ7.13(s,1H),6.23(s,1H),3.93(t,2H,J=6.0Hz),3.77(s,3H),2.75(t,2H,J=6.0Hz),1.93(m,2H),1.80(m,2H);(APCI+)m/z180.1(M+H)
实施例120b 3-(氰基甲基)-5,6,7,8-四氢吲嗪-2-羧酸甲酯120b
往配有加料漏斗、温度计的500-mL三颈圆底烧瓶中装入120a(6.70g,37.4mmol)、碘乙腈(12.5g,74.9mmol)、七水硫酸铁(II)(5.20g,18.7mmol)和二甲基亚砜(250mL)。使用水浴在室温通过注射泵经1h时间往该混合物中滴加过氧化氢(35%,18.2g,187mmol)。将七水硫酸铁(II)(2-3当量)按份加至该反应混合物以保持温度介于25℃-35℃,直至反应混合物颜色为深红色。当TLC显示反应不完全时,以相同方式加入更多的过氧化氢(2-3当量)和更多的七水硫酸铁(II)(1-2当量)直至反应完全。之后,在饱和碳酸氢钠溶液(200mL)和乙酸乙酯(400mL)间分配反应混合物。分离有机层,并用乙酸乙酯(2×100mL)萃取水层。用饱和硫代硫酸钠溶液(50mL)洗涤经合并有机层,经硫酸钠干燥并减压浓缩。通过柱色谱纯化残留物得到78%收率(6.40g)的黄色油状的120b:1H NMR(500MHz,CDCl3)δ6.23(s,1H),4.23(s,2H),3.94(t,2H,J=6.5Hz),3.81(s,3H),2.74(t,2H,J=6.5Hz),2.00(m,2H),1.83(m,2H);(APCI+)m/z219.3(M+H)
实施例120c 3-(2-氨基乙基)-5,6,7,8-四氢吲嗪-2-羧酸甲酯盐酸盐120c
在存在氯化氢的情况下在乙醇和乙酸乙酯中采用氧化铂催化剂在50psi氢气下室温过夜氢化3-(氰基甲基)-5,6,7,8-四氢吲嗪-2-羧酸甲酯120b得到120c(380mg,1.74mmol),将其用于下一步。
实施例120d 3,4,6,7,8,9-六氢吡啶并[3,4-b]吲嗪-1(2H)-酮120d
用氮气吹扫配有磁力搅拌器和氮气入口的100-mL单颈圆底烧瓶并装入120c(以上制备,预估1.74mmol,推定定量收率)、乙醇钠(354mg,5.22mmol)和乙醇(20mL)。55℃搅拌该混合物5h。之后,减压浓缩反应混合物并在乙酸乙酯(200mL)和水(100mL)间分配残留物。分离有机层,并用乙酸乙酯(2×100mL)萃取水层。用盐水洗涤经合并的有机层,经硫酸钠干燥并减压浓缩。通过柱色谱纯化残留物得到67%收率(220mg)的白色固体状的120d:mp195–197℃;1H NMR(500MHz,DMSO-d6)δ6.76(s,1H),5.89(s,1H),3.78(t,2H,J=6.5Hz),3.35(m,2H),2.66(m,4H),1.87(m,2H),1.72(m,2H);(APCI+)m/z191.3(M+H)
实施例120e 乙酸2-溴-4-氟-6-(1-氧代-3,4,6,7,8,9-六氢吡啶并[3,4-b]-吲嗪-2(1H)-基)苄酯120e
往配有磁力搅拌器和回流冷凝器的100-mL单颈圆底烧瓶中装入1,4-二噁烷(60mL)、乙酸2,6-二溴-4-氟苄酯(1.9g,6.0mmol)、120d(400mg,2.0mmol)和碳酸铯(1.3g,4.0mmol)。将氮气鼓泡经过所得混合物30分钟后,加入Xantphos(120mg,0.2mmol)和三(二亚苄基丙酮)二钯(0)(180mg,0.2mmol),并在100℃加热反应混合物12h。此后将反应混合物冷却至室温,在乙酸乙酯(40mL)和水(40mL)间分配,并且过滤。分离水层并用乙酸乙酯(3X70mL)萃取。用盐水(30mL)洗涤经合并的有机层并经硫酸钠干燥。通过过滤除去干燥剂并减压浓缩滤液。在冲洗柱上纯化残留物(采用2:1石油醚/乙酸乙酯洗脱)得到黄色固体状的120e(421mg,46%)。MS:[M+H]+435。1H NMR(500MHz,MeOD)δ7.52-7.50(m,1H),7.23-7.20(m,1H),6.14(s,1H),5.20-5.10(m,2H),4.09-4.06(m,1H),3.95-3.92(m,1H),3.88-3.85(m,1H),3.78-3.75(m,1H),3.07-2.97(m,2H),2.81-2.77(m,2H),2.03-2.00(m,5H),1.87-1.84(m,2H)。
实施例120f 乙酸4-氟-2-(1-氧代-3,4,6,7,8,9-六氢吡啶并[3,4-b]吲嗪-2(1H)-基)-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苄酯120f
往配有磁力搅拌器和回流冷凝器的100-mL单颈圆底烧瓶中装入14-二噁烷(30mL)、120e(1000mg.2.30mmol)、二(频哪醇合)二硼(3.03g,11.5mmol)、Pd(dppf)Cl2(94mg,0.11mmol)和乙酸钾(676mg,6.90mmol)。将氮气鼓泡经过该混合物10分钟后,90℃加热3h。然后过滤并真空蒸发滤液得到黑色油状的120f(1.2g,108%)。MS-ESI:[M+H]+483.2
实施例120g 乙酸4-氟-2-(6-(4-(4-(氧杂环丁烷-3-基)哌嗪-1-基)苯基氨基)-9-((2-(三甲基甲硅烷基)乙氧基)甲基)-9H-嘌呤-2-基)-6-(1-氧代-3,4,6,7,8,9-六氢吡啶并[3,4-b]吲嗪-2(1H)-基)苄酯120g
往配有磁力搅拌器和回流冷凝器的50-mL单颈圆底烧瓶中装入120f(400mg,0.82mmol)、2-碘-N-(4-(4-(氧杂环丁烷-3-基)哌嗪-1-基)苯基)-9-((2-(三甲基甲硅烷基)乙氧基)甲基)-9H-嘌呤-6-胺117f(604mg,0.99mmol)、PdCl2(dppf)(33mg,0.040mmol)、K3PO4(347mg,1.64mmol)和乙酸钠(134mg,1.64mmol)、乙腈(15mL)和水(1mL)。排空该系统并接着用N2再充满。100℃加热反应混合物2h。然后冷却至室温并过滤。减压浓缩滤液并通过硅胶柱色谱纯化所得残留物(采用30:1二氯甲烷/甲醇洗脱)得到绿色固体状的120g(460mg,66%)。MS-ESI:[M+H]+836.4。
实施例120h 乙酸4-氟-2-(6-(4-(4-(氧杂环丁烷-3-基)哌嗪-1-基)苯基氨基)-9H-嘌呤-2-基)-6-氧代-3,4,6,7,8,9-六氢吡啶并[3,4-b]吲嗪-2(1H)-基)苄酯120h
往配有磁力搅拌器和回流冷凝器的50-mL单颈圆底烧瓶中装入120g(350mg,0.42mmol)、TBAF(925mg,2.93mmol)和THF(10mL)。80℃加热反应混合物17h。然后冷却至室温并过滤。减压浓缩滤液并通过硅胶柱色谱纯化所得残留物(采用30:1二氯甲烷/甲醇洗脱)得到黄色固体状的120h(240mg,83%)。MS-ESI:[M+H]+706.3。
实施例120 2-[5-氟-2-(羟基甲基)-3-[6-[4-[4-(氧杂环丁烷-3-基)哌嗪-1-基]苯胺基]-9H-嘌呤-2-基]苯基]-3,4,6,7,8,9-六氢吡啶并[3,4-b]吲嗪-1-酮120
往120h(240mg,0.34mmol)在丙-2-醇(8mL)、四氢呋喃(8mL)和水(1.5mL)中的溶液中加入氢氧化锂(25mg,1.02mmol)。30℃搅拌该混合物1.5h。将其蒸发并通过反相制备型HPLC纯化残留物得到黄色固体状的120(116mg,51%)。MS-ESI:[M+H]+664.3。1H NMR(500MHz,CDCl3)δ8.29(s,1H),7.81(d,J=8.0Hz,1H),7.69(d,J=8.0Hz,2H),7.08(d,J=6.5Hz,1H),6.91(d,J=8.0Hz,2H),6.29(s,1H),4.71-4.57(m,6H),4.05-4.03(m,1H),3.86-3.77(m,3H),3.63-3.61(m,1H),3.23-3.22(m,4H),3.05-3.03(m,1H),3.89-2.79(m,3H),2.54-2.56(m,4H),2.00-1.98(m,2H),1.84-1.82(m,2H)。
实施例121a 6-氯-N-(5-(4-(氧杂环丁烷-3-基)哌嗪-1-基)吡啶-2-基)咪唑并[1,2-a]吡啶-8-胺121a
往配有回流冷凝器的50-mL圆底烧瓶中装入8-溴-6-氯咪唑并[1,2-a]吡啶101a(264mg,1.14mmol)、5-(4-(氧杂环丁烷-3-基)哌嗪-1-基)吡啶-2-胺(328mg,1.14mmol)、Pd2(dba)3(102mg,0.11mmol)、Xantphos(63mg,0.11mmol)、Cs2CO3(3.58g,11.0mmol)、二噁烷(20mL)。真空/氩气冲洗三个循环后,100℃加热该混合物过夜。然后过滤并减压蒸发滤液。通过硅胶柱色谱纯化残留物(采用1:50甲醇/二氯甲烷洗脱)得到橙色固体状的121a(290mg,66%)。MS-ESI:[M+H]+385.1
实施例121 2-[3-(羟基甲基)-4-[8-[[5-[4-(氧杂环丁烷-3-基)哌嗪-1-基]-2-吡啶基]氨基]咪唑并[1,2-a]吡啶-6-基]-2-吡啶基]-3,4,6,7,8,9-六氢吡嗪并[1,2-a]吲哚-1-酮121
往微波瓶中装入121a(100mg,0.26mmol)、3-(乙酰氧基甲基)-2-(1-氧代-3,4,6,7,8,9-六氢吡嗪并[1,2-a]吲哚-2(1H)-基)吡啶-4-基硼酸114e(150mg,0.39mmol)、Pd2(dba)3(23mg,0.025mmol)、P(Cy)3(7mg,0.025mmol)、Cs2CO3(170mg,0.52mmol)、二噁烷(5mL)和水(0.1mL)。真空/氩气冲洗三个循环后,微波辐射下130℃搅拌反应混合物1h。然后过滤并减压蒸发滤液。用反相制备型HPLC纯化残留物得到121(66mg,39%)。MS-ESI:[M+H]+646.3。1H NMR(500MHz,DMSO-d6)δ8.99(s,1H),8.53(d,J=5.0Hz,1H),8.31(d,J=1.5Hz,1H),8.23(d,J=1.5Hz,1H),7.99(d,J=1.0Hz,1H),7.90(d,J=3.0Hz,1H),7.58(d,J=1.5Hz,1H),7.43-7.40(m,2H),7.35(d,J=9.0Hz,1H),6.58(s,1H),4.95(bs,1H),4.56(t,J=6.5Hz,2H),4.46(t,J=6.5Hz,2H),4.42-4.40(m,2H),4.28-4.09(m,3H),3.94-3.87(m,1H),3.45-3.42(m,1H),3.10-3.08(m,4H),2.66-2.56(m,2H),2.50-2.47(m,溶剂峰下,2H),2.40-2.38(m,4H),1.80-1.69(m,4H)。
实施例122a 乙酸(4-(8-(5-(4-(氧杂环丁烷-3-基)哌嗪-1-基)吡啶-2-基氨基)[1,2,4]三唑并[1,5-a]吡啶-6-基)-2-(1-氧代-3,4,6,7,8,9-六氢吡嗪并[1,2-a]吲哚-2(1H)-基)吡啶-3-基)甲酯122a
往密封管中装入6-氯-N-(5-(4-(氧杂环丁烷-3-基)哌嗪-1-基)吡啶-2-基)[1,2,4]三唑并[1,5-a]吡啶-8-胺108d(196mg,0.51mmol)、3-(乙酰氧基甲基)-2-(1-氧代-3,4,6,7,8,9-六氢吡嗪并[1,2-a]吲哚-2(1H)-基)吡啶-4-基硼酸114e(200mg,0.52mmol)、PdCl2(dppf)(24mg,0.030mmol)、K3PO4(212mg,1.0mmol)、乙酸钠(83mg,1.0mmol)、乙腈(10mL)和水(0.2mL)。140℃加热该混合物0.5h。然后冷却至室温并过滤。真空蒸发滤液。通过硅胶柱色谱纯化残留物(采用20:1二氯甲烷/甲醇洗脱)得到白色固体状的122a(200mg,56%)。MS-ESI:[M+H]+689.3。
实施例122 2-[3-(羟基甲基)-4-[8-[[5-[4-(氧杂环丁烷-3-基)哌嗪-1-基]-2-吡啶基]氨基]-[1,2,4]三唑并[1,5-a]吡啶-6-基]-2-吡啶基]-3,4,6,7,8,9-六氢吡嗪并[1,2-a]吲哚-1-酮122
40℃搅拌122a(200mg,0.29mmol)和氢氧化锂(42mg,1.0mmol)在异丙醇/THF(1:1,3.5mL)和水(1mL)中的混合物0.5h。减压蒸发该混合物并用水(5mL)稀释残留物。用乙酸乙酯(2x5mL)萃取。减压浓缩经合并的乙酸乙酯萃取物并通过反相制备型HPLC纯化残留物得到淡黄色固体状的122(70mg,38%)。MS-ESI:[M+H]+647.3.1H NMR(500MHz,DMSO-d6)δ9.36(s,1H),8.69(s,1H),8.61(s,1H),8.57-8.55(m,2H),7.93(d,J=2.5Hz,1H),7.48-7.43(m,2H),7.37-7.35(m,1H),6.59(s,1H),5.05(t,J=5.0Hz,1H),4.57-4.55(m,2H),4.61-4.59(m,2H),4.40-4.39(m,2H),4.26-4.12(m,3H),3.92-3.89(m,1H),3.43(t,J=6.0Hz,1H),3.11-3.09(m,4H),2.63-2.57(m,2H),2.50-2.47(m,2H),2.40-2.39(m,4H),1.79-1.77(m,2H),1.70-1.68(m,2H)。
实施例123a 乙酸(2-{4,4-二甲基-9-氧代-1,10-二氮杂三环[6.4.0.02,6]十二碳-2(6),7-二烯-10-基}-4-氟-6-[6-({4-[4-(氧杂环丁烷-3-基)哌嗪-1-基]苯基}氨基)-9-{[2-(三甲基甲硅烷基)乙氧基]甲基}嘌呤-2-基]苯基)甲酯123a
往配有磁力搅拌器和回流冷凝器的25-mL单颈圆底烧瓶中装入2-碘-N-(4-(4-(氧杂环丁烷-3-基)哌嗪-1-基)苯基)-9-((2-(三甲基甲硅烷基)乙氧基)甲基)-9H-嘌呤-6-胺117f(360mg,0.60mmol)、{2-[(乙酰氧基)甲基]-3-{4,4-二甲基-9-氧代-1,10-二氮杂三环[6.4.0.02,6]十二碳-2(6),7-二烯-10-基}-5-氟苯基}硼酸110g(360mg,0.90mmol)、Pd(dppf)Cl2(30mg,0.030mmol)、K3PO4(270mg,1.2mmol)、乙酸钠(180mg,1.2mmol)、水(0.5mL)和乙腈(10mL)。真空/氩气冲洗三个循环后,100℃加热混合物2h。然后冷却至室温并过滤。减压浓缩滤液并通过硅胶柱色谱纯化所得残留物(采用20:1二氯甲烷/甲醇洗脱)得到黄色固体状的123a(200mg,35%)。MS-ESI:[M+H]+850.4
实施例123b 乙酸(2-{4,4-二甲基-9-氧代-1,10-二氮杂三环[6.4.0.02,6]十二碳-2(6),7-二烯-10-基}-4-氟-6-[6-({4-[4-(氧杂环丁烷-3-基)哌嗪-1-基]苯基}氨基)-9H-嘌呤-2-基]苯基)甲酯123b
室温搅拌123a(200mg,0.25mmol)和CF3COOH(4mL)的混合物2h。然后减压浓缩该混合物得到黄色固体状的粗123b(160mg,90%),其未经进一步纯化而用于下一步。MS-ESI:[M+H]+720.4
实施例123 3-[5-氟-2-(羟基甲基)-3-[6-[4-[4-(氧杂环丁烷-3-基)哌嗪-1-基]苯胺基]-9H-嘌呤-2-基]苯基]-7,7-二甲基-1,2,6,8-四氢环戊二烯并[3,4]吡咯并[3,5-b]吡嗪-4-酮123
30℃搅拌123b(160mg,0.20mmol)和氢氧化锂(48mg,2.0mmol)在THF/异丙醇(5:3,8mL)和水(2mL)中的混合物1h。真空蒸发该混合物并用水(5mL)稀释残留物。然后用乙酸乙酯(2x10mL)萃取。减压浓缩经合并的乙酸乙酯萃取物并通过反相制备型HPLC纯化残留物得到白色固体状的123(40mg,32%)。MS-ESI:[M+H]+678.3。1H NMR(500MHz,CDCl3)δ12.28(s,1H),8.62(s,1H),7.89-7.87(m,1H),7.72-7.67(m,3H),7.13-7.11(m,1H),6.99-6.97(m,2H),6.85(s,1H),4.73-4.65(m,6H),4.25-4.21(m,1H),4.16-4.09(m,2H),3.89-3.87(m,1H),3.59-3.57(m,1H),3.25-3.23(m,4H),2.56-2.51(m,重叠,8H),1.28(s,3H),1.27(s,3H)。
实施例124a (3-硝基-1H-吡唑-5-基)甲醇124a
用氮气吹扫配有机械搅拌器、加料漏斗和氮气入口的3-L三颈圆底烧瓶并装入3-硝基吡唑-5-羧酸(28.0g,178mmol)和THF(420mL)并使用冰/丙酮浴冷却至–5℃。以保持内部反应温度低于5℃的速率加入硼烷-THF复合溶液(1.0M,535mL,535mmol)。完成加入后移除冷却浴并在室温搅拌反应混合物18h。此后使用冰/丙酮浴将反应混合物冷却至–5℃,加入水(70mL)和4N盐酸(70mL)并在回流下搅拌反应混合物1h以破坏吡唑硼烷复合物。将反应混合物冷却至室温并减压浓缩至约30mL体积。加入乙酸乙酯(175mL)并搅拌该混合物15分钟。分离水层并用乙酸乙酯(4×200mL)萃取。用饱和碳酸氢钠水溶液(2×50mL)、盐水(50mL)洗涤经合并的有机层并经硫酸钠干燥,通过过滤除去干燥剂,并减压浓缩滤液得到94%收率(24.0g)的浅黄色固体状的(3-硝基-1H-吡唑-5-基)甲醇124a:1H NMR(300MHz,DMSO-d6)δ13.90(br s,1H),6.87(s,1H),5.58(t,1H,J=5.4Hz),4.53(d,2H,J=5.1Hz);MS(ESI+)m/z144.0(M+H)
实施例124b (1-(2-溴乙基)-3-硝基-1H-吡唑-5-基)甲醇124b
用氮气吹扫配有机械搅拌器和温度调节器的1-L三颈圆底烧瓶并装入124a(25.0g,175mmol)、DMF(250mL)和碳酸铯(70.0g,215mmol),104℃加热5分钟。然后使用冰/丙酮浴将反应混合物冷却至0℃并分批加入二溴乙烷(329g,1.75mol)(无放热)。0℃搅拌反应混合物1h然后室温搅拌4h。此后缓慢加入KH2PO4(40g)在水(400mL)中的溶液。室温搅拌反应混合物30分钟。加入乙酸乙酯(450mL)并分离水层,并用乙酸乙酯(2×100mL)萃取。用水(200mL)、盐水(200mL)洗涤经合并的有机层,经硫酸钠干燥,并通过过滤除去干燥剂。减压浓缩滤液得到86%收率(37.5g)的橙色油状的粗124b:1H NMR(300MHz,CDCl3)δ6.85(s,1H),4.82(d,2H,J=5.4Hz),4.66(t,2H,J=6.3Hz),3.83(t,2H,J=6.3Hz);MS(ESI+)m/z249.9(M+H)。
实施例124c 1-(2-溴乙基)-5-(溴甲基)-3-硝基-1H-吡唑124c
用氮气吹扫配有磁力搅拌器、氮气入口和回流冷凝器的500-mL三颈圆底烧瓶并装入124b(37.0g,148mmol)和氯仿(160mL)。使用冰/丙酮浴将反应混合物冷却至–5℃并分批加入三溴化磷(40.0g,148mmol)。移除冷却浴并在回流下搅拌反应混合物2h。此后,将反应混合物冷却至–5℃并加入饱和碳酸氢钠水溶液(250mL)直至达到pH8.5。用乙酸乙酯(3×150mL)萃取该混合物并用饱和碳酸钠水溶液(2×50mL)、盐水(75mL)洗涤经合并的有机层,经硫酸钠干燥并通过过滤除去干燥剂。减压浓缩滤液得到黄色残留物,采用温和加热将其溶于二氯甲烷(60mL)中。加入己烷(约20mL)且溶液变为浑浊。加热该混合物直至形成固体沉淀物,加入二氯甲烷(9mL)且溶液变为澄清。将溶液留置冷却至室温并在4h后通过真空过滤收集所得晶体。用冰冷的二氯甲烷:己烷1:2混合物(2×20mL)洗涤滤饼得到1-(2-溴乙基)-5-(溴甲基)-3-硝基-1H-吡唑(19.7g)。蒸发经合并滤液并再次进行此步骤得到另外9.70g1-(2-溴乙基)-5-(溴-甲基)-3-硝基-1H-吡唑。合并固体并高真空干燥18h得到57%收率(26.0g)的白色晶体状的1-(2-溴乙基)-5-(溴甲基)-3-硝基-1H-吡唑124c:mp95–97℃;1H NMR(300MHz,CDCl3)δ6.93(s,1H),4.63(t,2H,J=6.0Hz),4.54(s,2H),3.86(t,2H,J=6.0Hz)。
实施例124d 5-甲基-2-硝基-4,5,6,7-四氢吡唑并[1,5-a]吡嗪124d
往配有磁力搅拌器和氮气入口的1-L单颈圆底烧瓶中装入THF(350mL)、124c(10.0g,32.2mmol)、THF中的2M甲胺溶液(113mL,225mmol)并在室温搅拌72h。此后减压浓缩反应混合物至干,并用乙酸乙酯(75mL)和10%碳酸钾水溶液(75mL)混合搅拌所得固体。分离水层并用乙酸乙酯(2×75mL)萃取。用10%碳酸钾水溶液(75mL),然后是盐水(50mL)洗涤经合并的有机萃取物并经硫酸钠干燥。通过过滤除去干燥剂,并减压浓缩滤液得到97%收率(5.70g)的黄色固体状的124d:1H NMR(300MHz,CDCl3)δ6.62(s,1H),4.28(t,2H,J=5.4Hz),3.67(s,2H),2.95(t,2H,J=5.4Hz),2.52(s,3H);MS(ESI+)m/z183.0(M+H)
实施例124e 5-甲基-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-2-胺124e
用氮气吹扫500-mL Parr反应器瓶并装入10%钯/炭(50%湿,800mg干重)和124d(4.00g,2.20mmol)在乙醇(160mL)中的溶液。将瓶连接Parr氢化器,排空,充入氢气至45psi压力的压力并振摇2h。此后,抽空氢气,并向瓶中冲入氮气。加入Celite521(1.0g),并通过Celite521垫过滤混合物。用乙醇(2×75mL)洗涤滤饼,并减压浓缩经合并滤液至干得到99%收率的橙色固体状的124e(3.31g):1H NMR(300MHz,CDCl3)δ5.34(s,1H),3.98(t,2H,J=5.4Hz),3.52(s,3H),2.84(t,2H,J=5.7Hz),2.45(s,3H);MS(ESI+)m/z153.1(M+H)
实施例124f 6-氯-N-(5-甲基-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-2-基)咪唑并[1,2-b]哒嗪-8-胺124f
遵循如实施例104b中所述步骤,并起始自8-溴-6-氯咪唑并[1,2-b]哒嗪104a、1.43g,6.2mmol)和124e(900mg,5.9mmol),得到黄色固体状的124f(800mg,44%)。MS-ESI:[M+H]+304.1
实施例124g 6-溴-N-(5-甲基-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-2-基)咪唑并[1,2-b]哒嗪-8-胺124g
往高压灭菌器中装入124f(800mg,2.6mmol))和HBr/AcOH(60mL)。150℃加热18h。减压浓缩反应混合物得到黑色油状物。从甲醇(30mL)/二氯甲烷(30mL)/石油醚(90mL)重结晶该油状物得到黄色固体状的124g(600mg,66%)。MS-ESI:[M+H]+348.1
实施例124 2-[3-(羟基甲基)-4-[8-[(5-甲基-6,7-二氢-4H-吡唑并[1,5-a]吡嗪-2-基)氨基]咪唑并[1,2-b]哒嗪-6-基]-2-吡啶基]-3,4,6,7,8,9-六氢吡嗪并[1,2-a]吲哚-1-酮124
遵循实施例123中所述步骤,并起始自124g(900mg,2.60mmol)和3-(乙酰氧基甲基)-2-(1-氧代-3,4,6,7,8,9-六氢吡嗪并[1,2-a]吲哚-2(1H)-基)吡啶-4-基硼酸114e(1.01g,2.6mmol),获得白色固体状的124(147mg,10%)。MS-ESI:[M+H]+565.3。1H NMR(500MHz,DMSO-d6)δ10.02(s,1H),8.56(d,J=5.0Hz,1H),8.17(s,1H),7.75(s,1H),7.66(s,1H),7.46(d,J=5.0Hz,1H),6.58(s,1H),6.03(s,1H),4.73(t,J=5.0Hz,1H),4.62-4.58(m,1H),4.40-4.37(m,1H),4.27-4.19(m,2H),4.10-4.08(m,1H),4.00-3.93(m,3H),3.54(s,2H),2.82(t,J=5.0Hz,2H),2.64-2.56(m,2H),2.47-2.46(m,2H),2.37(s,3H),1.79-1.68(m,4H)。
实施例901 Btk生化测定
可用来测试式I化合物的标准生化Btk激酶测定的一般方法如下。制备含有1X细胞信号转导激酶缓冲液(25mM Tris-HCl,pH7.5、5mMβ-磷酸甘油、2mM二硫苏糖醇、0.1mM Na3VO4、10mM MgCl2)、0.5μM Promega PTK生物素化的肽底物2和0.01%BSA的无Btk酶的预混试剂(master mix)。制备含有1X细胞信号转导激酶缓冲液、0.5μM PTK生物素化的肽底物2、0.01%BSA和100ng/孔(0.06mU/孔)Btk酶的含Btk酶的预混试剂。Btk酶的制备如下:使具有C-末端V5和6x His标记的全长人野生型Btk(登记号NM-000061)亚克隆到pFastBac载体中,用于制备携带该表位标记的Btk的杆状病毒。根据Invitrogen在其出版的实验方案“Bac-to-Bac Baculovirus Expression Systems”(Cat.Nos.10359-016和10608-016)中详述的使用说明制备杆状病毒。传代3病毒用于感染Sf9细胞以过量表达重组Btk蛋白。然后使用Ni-NTA柱将Btk蛋白纯化至同质。根据敏感的Sypro-Ruby染色法,最终蛋白制品的纯度大于95%。在水中制备200μM ATP溶液并且用1N NaOH调节至pH7.4。将量为1.25μL的化合物的5%DMSO溶液转移至96孔半区Costar聚苯乙烯板。逐一地并用11点剂量响应曲线(起始浓度是10μM;1:2稀释度)来测试化合物。将量为18.75μL的无酶预混试剂(作为阴性对照)和含酶预混试剂转移至96孔半区Costar聚苯乙烯板中的合适孔。将5μL200μM ATP加入96孔半区Costar聚苯乙烯板中的混合物中,使最终ATP浓度是40μM。使反应混合物在室温培养1小时。用含有30mM EDTA、20nM SA-APC和1nM PT66Ab的Perkin Elmer1X检测缓冲液使反应停止。用使用激发滤光片330nm、发射滤光片665nm和第二发射滤光片615nm的Perkin Elmer Envision,使用时间分辨荧光读板。然后计算IC50值。或者,可以使用Lanthascreen测定,通过定量其磷酸化的肽产物来评价Btk活性。在肽产物上的荧光素和在检测抗体上的铽之间发生的FRET(荧光共振能量跃迁)随着添加降低肽的磷酸化的Btk抑制剂而下降。在25uL的最终反应体积中,使Btk(h)(0.1ng/25ul反应)与50mM Hepes pH7.5、10mM MgCl2、2mM MnCl2、2mM DTT、0.2mM NaVO4、0.01%BSA和0.4uM荧光素聚-GAT一起孵育。通过添加ATP至25uM(ATP的Km)引发反应。在室温孵育60分钟后,通过在室温添加在60mM EDTA中终浓度为2nMTb-PY20的检测抗体持续30分钟,来终止反应。在Perkin Elmer Envision上,使用在340nm激发以及在495nm和520nm发射进行检测。示例性Btk抑制IC70值示于表1和2中。
实施例902 Ramos细胞Btk测定
可用于测试式I化合物的标准细胞Btk激酶测定的另一种一般方法如下。以0.5x107个细胞/ml的密度在测试化合物存在下在37℃培养Ramos细胞1小时。然后通过用10μg/ml抗人IgM F(ab)2在37℃培养5分钟来刺激细胞。使细胞成丸(pelleted)、溶解,并且对澄清溶解液进行蛋白测定。对等蛋白量的各样品进行SDS-PAGE并且用抗磷酸Btk(Tyr223)抗体(CellSignaling Technology#3531;Epitomics,cat.#2207-1)或磷酸Btk(Tyr551)抗体(BD Transduction Labs#558034)进行蛋白质印迹,以评估Btk自磷酸化或者用抗Btk抗体(BD Transduction Labs#611116)来控制各溶解液中Btk的总量。
实施例903 B细胞增殖测定
可用于测试式I化合物的标准细胞B细胞增殖测定的一般方法如下。使用B细胞分离试剂盒(Miltenyi Biotech,Cat#130-090-862)从8-16周龄Balb/c小鼠的脾纯化B细胞。将测试化合物稀释在0.25%DMSO中,与2.5x105纯化的小鼠脾B细胞培养30分钟,然后加入10μg/ml抗小鼠IgM抗体(Southern Biotechnology Associates Cat#1022-01),最终体积是100μl。培养24小时后,加入1μCi3H-胸苷,将板培养另外36小时,然后使用生产商的关于SPA[3H]胸苷吸收测定系统(Amersham Biosciences#RPNQ0130)的实验方案收集。在Microbeta计数器(Wallace Triplex1450,PerkinElmer)中计数基于SPA珠的荧光。
实施例904 T细胞增殖测定
可用于测试式I化合物的标准T细胞增殖测定的一般方法如下。使用全T细胞分离试剂盒(Miltenyi Biotech,Cat#130-090-861)从8-16周龄Balb/c小鼠的脾纯化T细胞。将测试化合物稀释在0.25%DMSO中并且与2.5x105个纯化的小鼠脾T细胞以100μl最终体积在透明平底板中一起培养,所述板用各为10μg/ml的抗CD3(BD#553057)和抗CD28(BD#553294)抗体在37℃预涂覆90分钟。培养24小时后,加入1μCi3H-胸苷,将板培养另外36小时,然后使用生产商的关于SPA[3H]胸苷吸收测定系统(Amersham Biosciences#RPNQ0130)的实验方案收集。在Microbeta计数器(Wallace Triplex1450,Perkin Elmer)中计数基于SPA珠的荧光。
实施例905 CD86抑制测定
可用于测试式I化合物的抑制B细胞活性的标准测定的一般方法如下。通过红细胞裂解(BD Pharmingen#555899),从8-16周龄Balb/c小鼠的脾纯化总小鼠脾细胞。在透明平底板(Falcon353072)中,使测试化合物稀释在0.5%DMSO中并且与1.25x106个脾细胞在200μl最终体积中于37℃培养60分钟。然后加入15μg/ml IgM(Jackson ImmunoResearch115-006-020)来刺激细胞,并且细胞在37℃、5%CO2中培养24小时。培养24小时后,使细胞转移至锥形底透明96孔板并且通过以1200x g x5min离心使细胞成丸。用CD16/CD32(BD Pharmingen#553142)将细胞预封闭(preblock),随后用CD19-FITC(BD Pharmingen#553785)、CD86-PE(BD Pharmingen#553692)和7AAD(BD Pharmingen#51-68981E)进行三重染色。在BDFACSCalibur上将细胞分类并且对CD19+/7AAD-群设门(gated)。测量对应于测试化合物的浓度,设门的群上的CD86表面表达的水平。
实施例906 B-ALL细胞存活测定
以下是标准B-ALL(急性淋巴细胞性白血病)细胞存活研究的方法,其使用XTT读数器来测量活细胞的数量。该测定可以用于测试式I化合物抑制培养物中B-ALL细胞的存活的能力。可以使用的一种人B细胞急性淋巴细胞性白血病系是SUP-B15,其为一种可从ATCC获得的人前B细胞ALL系。
以5x105个细胞/ml的浓度将SUP-B15前B-ALL细胞接种在多个96孔微量滴定板的100μl Iscove培养基+20%FBS中。然后加入测试化合物,使最终浓度是0.4%DMSO。细胞在37℃和5%CO2下培养至多3天。三天后,将细胞按1:3分到含有测试化合物的新鲜96孔板中并允许生长另外3天。每24h的时间段后,向一个复制96孔板加入50ul XTT溶液,并且按照生产商的指示在2、4和20小时采集吸光度读数。然后采集仅用DMSO处理的细胞在本测定的线性范围(0.5-1.5)内的OD读数,并且测量化合物处理的孔中的活细胞相对于仅DMSO处理的细胞的百分率。
实施例907 CD69全血测定
从具有以下限制的健康志愿者获得人血:1周未用药、不抽烟。通过静脉穿刺入含有肝素钠的(Becton,Dickinson and Co.)管收集血液(约20ml以测试8种化合物)。
将式I化合物在DMSO中的10mM溶液以1:10在100%DMSO中稀释,然后为了10点剂量-响应曲线,在100%DMSO中以三倍连续稀释进行稀释。将化合物以1:10在PBS中进一步稀释,然后将5.5μl等分量的各化合物一式两份地加入到2ml96孔板;加入5.5μl的10%DMSO/PBS作为对照和无刺激孔。将人全血-HWB(100μl)加入到各孔。在混合后,将板在37℃、5%CO2、100%湿度培养30分钟。将山羊F(ab’)2抗人IgM(10μl500μg/ml溶液,50μg/ml最终)加入到各孔(除了无刺激孔之外)并且混合,将板再培养20小时。在20小时培养结束时,使样品与荧光标记的抗体在37℃、5%CO2、100%湿度一起培养30分钟。包括诱导的对照、用于补偿调节的未染色的和单染色的、以及初始电压设定。然后按照生产商的说明书用PharM LyseTM(BD Biosciences Pharmingen)溶解样品。而后将样品转移至适合于在LSRII仪上的BD Biosciences HTS96孔系统上工作的96孔板。利用BD Biosciences DIVA软件获得采集的数据和平均荧光强度值。通过FACS分析软件(Flow Jo)初步分析结果。测试化合物的抑制浓度(IC50、IC70、IC90等)定义为使经抗-IgM刺激也呈CD20阳性的CD69阳性细胞降低例如50%时的浓度(在减去无刺激背景的8个孔的平均值后,8个对照孔的平均值)。使用非线性回归曲线拟合,通过Prism第5版计算IC70值,结果示于表1和2中。
实施例908 体外细胞增殖测定
采用下列方案通过细胞增殖测定来测量式I化合物的功效(Mendoza等人(2002)Cancer Res.62:5485-5488)。发光细胞存活力测定(包括试剂和方案)是商购获得的(Promega Corp.,Madison,WI,Technical BulletinTB288)。该测定评估化合物进入细胞和抑制细胞增殖的能力。测定原理是基于通过定量均质测定中存在的ATP来确定存在的活细胞数目,其中加入Cell-Titer Glo试剂导致细胞溶解并通过荧光素酶反应产生发光信号。发光信号与存在的ATP的量成比例。
将一组B细胞淋巴瘤细胞系(BJAB、SUDHL-4、TMD8、OCI-Ly10、OCI-Ly3、WSU-DLCL2)放入到正常生长培养基的384孔板中,并将连续稀释的BTK抑制剂或DMSO单独加入到各孔中。孵育96小时后通过(Promega)评估细胞存活力。数据可以表示为BTK抑制剂处理的细胞相对于DMSO处理的对照细胞的相对细胞存活力。数据点是各剂量水平的重复4次的平均数。误差线表示平均数的SD。
程序:第1天–接种细胞板(来自Falcon#353962的带盖的384孔黑色、透明底(微透明)的TC板),收获细胞,以1000个细胞/54μl/孔接种细胞到384孔细胞板中以进行3天测定。细胞培养基:RPMI或DMEM高葡萄糖、10%胎牛血清、2mM L-谷氨酰胺,P/S。37℃、5%CO2下孵育O/N。
第2天–将药物加入到细胞中,稀释化合物,DMSO板(连续1:2,9个点),在96孔板的第2栏中加入10mM的20μl化合物。对于总共9个点,在整个板中使用Precision进行1:2连续稀释(10μl+20μl100%DMSO)。培养基板为来自Nunc(目录编号249946)的96孔圆锥形底聚丙烯板(1:50稀释)。将147μl培养基加入到所有孔中。使用Rapidplate将来自DMSO板每个孔中的3μl DMSO+化合物转移到培养基板上每个相应孔中。
将药物加入到细胞中,细胞板(1:10稀释),将6μl培养基+化合物直接加入到细胞(在细胞上已有54μl培养基)中。37C、5%CO2下在不经常打开的培养箱中孵育3天。
第5天–孵育板,室温解冻Thaw Cell Titer Glo缓冲液。将细胞板从37℃移出并平衡至室温约30分钟。将Cell Titer Glo缓冲液加入到Cell TiterGlo底物中(瓶对瓶)。将30μl Cell Titer Glo试剂(Promega目录编号G7572)加入到每孔细胞中。在板振荡器上放置约30分钟。在Analyst HT板读数器上读取发光(半秒/孔)。
细胞存活力测定和联合测定:将细胞以1000-2000个细胞/孔接种到384孔板中16h。第二天,在96孔板中在DMSO中进行9次1:2的化合物连续稀释。使用Rapidplate自动设备(Zymark Corp.,Hopkinton,MA)将化合物进一步在生长培养基中稀释。然后将稀释的化合物以一式四份加入到384孔细胞板的孔中并在37℃和5%CO2下孵育。4天后,根据制造商的说明书使用Cell-Titer Glo(Promega)发光来测量活细胞的相对数目并在WallacMultilabel读数器(PerkinElmer,Foster City)上读取。使用4.0软件(GraphPad,San Diego)计算EC50值。在所有测定中同时或相隔4小时(一种在另一种之前)加入式I化合物和化疗剂。
额外示例性体外细胞增殖测定包括下列步骤:
1.将在培养基中含有约104个细胞的100μl细胞培养物的等分试样放入384孔不透明壁板的各孔中。
2.制备含有培养基而不含细胞的对照孔。
3.将化合物加入到实验孔中并孵育3-5天。
4.将板平衡至室温约30分钟。
5.加入与各孔中存在的细胞培养基体积相同的体积的CellTiter-Glo试剂。
6.在定轨振荡器上混合内容物2分钟以诱导细胞溶解。
7.将板在室温孵育10分钟以稳定发光信号。
8.记录发光并在图中报道为RLU=相对发光单位。
尽管已通过示例说明和实施例在一定程度上详细描述了前述发明从而用于理解清晰的目的,但描述和实施例不应理解为限制本发明的范围。因此,可将所有合适修改和等价物视为落入由以下权利要求所限定的本发明的范围内。本申请中引用的所有专利和科学文献的公开内容均通过引用的方式整体明确地并入本申请。
Claims (26)
1.化合物,其选自式I:
或其立体异构体、互变异构体或药用盐,其中:
实/虚线指示单键或双键;
X1是CR1或N;
X2是CR2或N;
X3是CR3或N;
其中X1、X2和X3中的0个、1个或2个是N;
Y1和Y2独立选自CH和N;
Y3是C或N;
Y4是CR6、N或NH;
其中Y1、Y2、Y3和Y4中的1个或2个是N;
R1、R2和R3独立选自H、F、Cl、-NH2、-NHCH3、-N(CH3)2、-OH、-OCH3、-OCH2CH3、-OCH2CH2OH和任选被F、Cl、CN、-NH2、-NHCH3、-N(CH3)2、-OH、-OCH3、-OCH2CH3和-OCH2CH2OH取代的C1-C3烷基;
R4选自H、F、Cl、CN、-CH2OH、-CH(CH3)OH、-C(CH3)2OH、-CH(CF3)OH、-CH2F、-CHF2、-CH2CHF2、-CF3、-C(O)NH2、-C(O)NHCH3、-C(O)N(CH3)2、-NH2、-NHCH3、-N(CH3)2、-NHC(O)CH3、-OH、-OCH3、-OCH2CH3、-OCH2CH2OH、环丙基、环丙基甲基、1-羟基环丙基、咪唑基、吡唑基、3-羟基-氧杂环丁烷-3-基、氧杂环丁烷-3-基和氮杂环丁烷-1-基;
R5选自-CH3、-CH2CH3、-CH2OH、-CH2F、-CHF2、-CF3、-CN和-CH2CH2OH;
或者两个R5基团形成3-、4-、5-或6-元碳环或杂环;
或者R5基团和R8基团形成3-、4-、5-或6-元碳环或杂环;
n是0、1、2、3或4;
R6选自H、Cl、-CH3、-CH2CH3、-CH2CH2OH、-CH2F、-CHF2、-CF3、-NH2、-NHCH3、-N(CH3)2、-OH、-OCH3、-OCH2CH3和-OCH2CH2OH;
R7选自以下结构:
其中波浪线指示连接点;
R8选自H、-CH3、-S(O)2CH3、环丙基、氮杂环丁烷-3-基、氧杂环丁烷-3-基和吗啉-4-基;
Z是CR9或N;其中R9选自H、F、Cl、-CH3、-CH2CH3、-CH2CH2OH、-NH2、-NHCH3、-N(CH3)2、-OH、-OCH3、-OCH2CH3和-OCH2CH2OH。
2.权利要求1的化合物,其具有式Ia的结构:
3.权利要求2的化合物,其具有式Ib的结构;
4.权利要求1的化合物,其选自具有以下结构的式Ic-Ih:
5.权利要求1的化合物,其中X1是N,X2是CR2且X3是CR3。
6.权利要求1的化合物,其中X1是CR1,X2是N且X3是CR3。
7.权利要求1的化合物,其中X1是CR1,X2是CR2且X3是N。
8.权利要求1的化合物,选自:X1和X3是N,X1和X2是N,或X2和X3是N。
9.权利要求1的化合物,其中R4是-CH2OH。
10.权利要求4的化合物,其中X2是CR2,且R2是F。
11.权利要求5的化合物,其中X1和X3是CH。
12.权利要求1的化合物,其中Y4是CR6,且R6是CH3。
13.权利要求1的化合物,其选自表1。
14.权利要求1的化合物,其选自表2。
15.药物组合物,其包含权利要求1-14中任一项的化合物,以及药用载体、助流剂、稀释剂或赋形剂。
16.权利要求15的药物组合物,进一步包含治疗剂。
17.制备药物组合物的方法,其包括将权利要求1-14中任一项的化合物与药用载体混合。
18.治疗疾病或病症的方法,其包括向患有疾病或病症的患者给药治疗有效量的权利要求15的药物组合物,所述疾病或病症选自免疫病症、癌症、心血管疾病、病毒感染、炎症、代谢/内分泌功能障碍和神经障碍,并且所述疾病或病症由Bruton酪氨酸激酶介导。
19.权利要求18的方法,其中所述疾病或病症是免疫病症。
20.权利要求19的方法,其中所述免疫病症是类风湿性关节炎。
21.权利要求18的方法,其中所述疾病或病症是系统性和局部性炎症、关节炎、与免疫抑制相关的炎症、器官移植排斥、变态反应、溃疡性结肠炎、克罗恩病、皮炎、哮喘、系统性红斑狼疮、斯耶格伦综合征、多发性硬化、硬皮病/系统性硬化病、特发性血小板减少性紫癜(ITP)、抗中性粒细胞胞质抗体(ANCA)型血管炎、慢性阻塞性肺病(COPD)、银屑病。
22.权利要求18的方法,其中所述疾病或病症是选自以下的癌症:乳腺癌、卵巢癌、宫颈癌、前列腺癌、睾丸癌、生殖泌尿道癌、食道癌、喉癌、成胶质细胞瘤、神经母细胞瘤、胃癌、皮肤癌、角化棘皮瘤、肺癌、表皮样癌、大细胞癌、非小细胞肺癌(NSCLC)、小细胞癌、肺腺癌、骨癌、结肠癌、腺瘤、胰腺癌、腺癌、甲状腺癌、滤泡性癌、未分化癌、乳头状癌、精原细胞瘤、黑素瘤、肉瘤、膀胱癌、肝癌和胆道癌、肾癌、胰腺癌、骨髓病症、淋巴瘤、毛细胞癌、口腔癌、鼻咽癌、咽癌、唇癌、舌癌、口癌、小肠癌、结直肠癌、大肠癌、直肠癌、脑和中枢神经系统癌、何杰金淋巴瘤、白血病、支气管癌、甲状腺癌、肝和肝内胆管癌、肝细胞癌、胃癌、神经胶质瘤/成胶质细胞瘤、子宫内膜癌、黑素瘤、肾和肾盂癌、膀胱癌、子宫体癌、子宫颈癌、多发性骨髓瘤、急性髓性白血病、慢性髓性白血病、淋巴细胞白血病、慢性淋巴细胞白血病(CLL)、髓样白血病、口腔和咽癌、非何杰金淋巴瘤、黑素瘤和结肠绒毛腺瘤。
23.权利要求18的方法,其进一步包括给药选自以下的另外治疗剂:抗炎剂、免疫调节剂、化疗剂、细胞凋亡强化剂、神经营养因子、心血管疾病的治疗剂、肝病的治疗剂、抗病毒剂、血液疾病的治疗剂、糖尿病的治疗剂以及免疫缺陷病症的治疗剂。
24.用于治疗由Bruton酪氨酸激酶介导的病症的试剂盒,其包含:
a)权利要求15的第一药物组合物;和
b)使用说明书。
25.权利要求15的药物组合物,其用作治疗疾病或病症的药物,所述疾病或病症选自免疫病症、癌症、心血管疾病、病毒感染、炎症、代谢/内分泌功能障碍和神经障碍,并且所述疾病或病症由Bruton酪氨酸激酶介导。
26.权利要求15的药物组合物在制备用于治疗免疫病症、癌症、心血管疾病、病毒感染、炎症、代谢/内分泌功能障碍和神经障碍的药物中的用途;并且其中所述药物调节Bruton酪氨酸激酶。
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Publication number | Priority date | Publication date | Assignee | Title |
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WO2022094172A2 (en) | 2020-10-30 | 2022-05-05 | Newave Pharmaceutical Inc. | Inhibitors of btk |
JP7490548B2 (ja) | 2020-12-14 | 2024-05-27 | 住友化学株式会社 | 高分子化合物の製造方法 |
JP2024503237A (ja) | 2020-12-20 | 2024-01-25 | グアンジョウ・ルペン・ファーマシューティカル・カンパニー・リミテッド | Btk分解誘導薬 |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005014599A1 (en) * | 2003-06-04 | 2005-02-17 | Cellular Genomics, Inc. | Imidazo[1,2-a]pyrazin-8-ylamines and method of inhibition of bruton’s tyrosine kinase by such compounds |
WO2009137596A1 (en) * | 2008-05-06 | 2009-11-12 | Cgi Pharmaceuticals, Inc. | Substituted amides, method of making, and use as btk inhibitors |
WO2010068810A2 (en) * | 2008-12-10 | 2010-06-17 | Cgi Pharmaceuticals, Inc. | Certain substituted amides, method of making, and method of use thereof |
CN101952283A (zh) * | 2007-12-14 | 2011-01-19 | 霍夫曼-拉罗奇有限公司 | 新型咪唑并[1,2-a]吡啶和咪唑并[1,2-b]哒嗪衍生物 |
CN102066377A (zh) * | 2008-07-18 | 2011-05-18 | 霍夫曼-拉罗奇有限公司 | 新型的苯基咪唑并吡嗪类 |
CN102164604A (zh) * | 2008-07-24 | 2011-08-24 | 百时美施贵宝公司 | 用作激酶调节剂的稠合杂环化合物 |
WO2011112995A1 (en) * | 2010-03-11 | 2011-09-15 | Gilead Sciences, Inc. | Imidazopyridines syk inhibitors |
Family Cites Families (31)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3773919A (en) | 1969-10-23 | 1973-11-20 | Du Pont | Polylactide-drug mixtures |
US5583024A (en) | 1985-12-02 | 1996-12-10 | The Regents Of The University Of California | Recombinant expression of Coleoptera luciferase |
DE4224133A1 (de) * | 1992-07-22 | 1994-01-27 | Thomae Gmbh Dr K | Benzimidazole, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung |
US5543523A (en) | 1994-11-15 | 1996-08-06 | Regents Of The University Of Minnesota | Method and intermediates for the synthesis of korupensamines |
JPH08336393A (ja) | 1995-04-13 | 1996-12-24 | Mitsubishi Chem Corp | 光学活性なγ−置換−β−ヒドロキシ酪酸エステルの製造法 |
US6602677B1 (en) | 1997-09-19 | 2003-08-05 | Promega Corporation | Thermostable luciferases and methods of production |
CN100528329C (zh) | 2001-07-12 | 2009-08-19 | 里艾克沙有限公司 | 微囊包封的催化剂,它们的制备方法和使用方法 |
US6514989B1 (en) * | 2001-07-20 | 2003-02-04 | Hoffmann-La Roche Inc. | Aromatic and heteroaromatic substituted 1,2,4-triazolo pyridine derivatives |
WO2005005429A1 (en) | 2003-06-30 | 2005-01-20 | Cellular Genomics, Inc. | Certain heterocyclic substituted imidazo[1,2-a]pyrazin-8-ylamines and methods of inhibition of bruton’s tyrosine kinase by such compounds |
EP1812442A2 (en) | 2004-11-10 | 2007-08-01 | CGI Pharmaceuticals, Inc. | Imidazo[1,2-a]pyrazin-8-ylamines useful as modulators of kinase activity |
MX2007011041A (es) | 2005-03-10 | 2008-02-22 | Cgi Pharmaceuticals Inc | Ciertas amidas sustituidas, metodo de elaboracion y metodo de uso de las mismas. |
NZ567140A (en) | 2005-10-07 | 2011-09-30 | Exelixis Inc | Azetidines as MEK inhibitors for the treatment of proliferative diseases |
AR063946A1 (es) | 2006-09-11 | 2009-03-04 | Cgi Pharmaceuticals Inc | Determinadas pirimidinas sustituidas, el uso de las mismas para el tratamiento de enfermedades mediadas por la inhibicion de la actividad de btk y composiciones farmaceuticas que las comprenden. |
US7838523B2 (en) | 2006-09-11 | 2010-11-23 | Cgi Pharmaceuticals, Inc. | Certain substituted amides, method of making, and method of use thereof |
AR063706A1 (es) | 2006-09-11 | 2009-02-11 | Cgi Pharmaceuticals Inc | Determinadas amidas sustituidas, el uso de las mismas para el tratamiento de enfermedades mediadas por la inhibicion de la actividad de btk y composiciones farmaceuticas que las comprenden. |
CN102887900B (zh) * | 2006-09-22 | 2015-04-29 | 药品循环公司 | 布鲁顿酪氨酸激酶的抑制剂 |
CL2008002793A1 (es) | 2007-09-20 | 2009-09-04 | Cgi Pharmaceuticals Inc | Compuestos derivados de amidas sustituidas, inhibidores de la actividad de btk; composicion farmaceutica que los comprende; utiles en el tratamiento del cancer, trastornos oseos, enfermedades autoinmunes, entre otras |
US8426441B2 (en) | 2007-12-14 | 2013-04-23 | Roche Palo Alto Llc | Inhibitors of bruton's tyrosine kinase |
US7683064B2 (en) | 2008-02-05 | 2010-03-23 | Roche Palo Alto Llc | Inhibitors of Bruton's tyrosine kinase |
EP2297142B1 (en) | 2008-06-24 | 2015-10-14 | F. Hoffmann-La Roche AG | Novel substituted pyridin-2-ones and pyridazin-3-ones |
KR101320763B1 (ko) | 2008-07-02 | 2013-10-21 | 에프. 호프만-라 로슈 아게 | 키나아제 억제제로서의 신규 페닐피라지논 |
EP2307413B1 (en) | 2008-07-15 | 2015-09-09 | F. Hoffmann-La Roche AG | Novel phenyl-imidazopyridines and pyridazines |
US8598174B2 (en) | 2008-11-12 | 2013-12-03 | Genetech, Inc. | Pyridazinones, method of making, and method of use thereof |
US8765754B2 (en) * | 2009-04-29 | 2014-07-01 | Locus Pharmaceuticals, Inc. | Pyrrolotriazine compounds |
CN107011330B (zh) * | 2009-09-04 | 2020-07-03 | 比奥根Ma公司 | 布鲁顿酪氨酸激酶抑制剂 |
CN103038233B (zh) | 2010-05-07 | 2017-06-20 | 吉利德康涅狄格有限公司 | 吡啶酮和氮杂吡啶酮化合物及使用方法 |
AR082590A1 (es) | 2010-08-12 | 2012-12-19 | Hoffmann La Roche | Inhibidores de la tirosina-quinasa de bruton |
CA2809662C (en) | 2010-09-01 | 2019-04-16 | Gilead Connecticut, Inc. | Pyridazinones, method of making, and method of use thereof |
US9249123B2 (en) | 2010-09-01 | 2016-02-02 | Genentech, Inc. | Pyridinones/pyrazinones, method of making, and method of use thereof |
JP5859640B2 (ja) | 2011-05-17 | 2016-02-10 | エフ.ホフマン−ラ ロシュ アーゲーF. Hoffmann−La Roche Aktiengesellschaft | ブルトンチロシンキナーゼ阻害剤 |
CA2841801A1 (en) | 2011-08-17 | 2013-02-21 | F.Hoffmann-La Roche Ag | Inhibitors of bruton's tyrosine kinase |
-
2012
- 2012-11-02 MX MX2014005285A patent/MX2014005285A/es active IP Right Grant
- 2012-11-02 CA CA2852964A patent/CA2852964A1/en not_active Abandoned
- 2012-11-02 EP EP12795138.2A patent/EP2773640B1/en not_active Not-in-force
- 2012-11-02 US US13/667,121 patent/US8722676B2/en active Active
- 2012-11-02 RU RU2014121073A patent/RU2628616C2/ru not_active IP Right Cessation
- 2012-11-02 JP JP2014540110A patent/JP5808869B2/ja not_active Expired - Fee Related
- 2012-11-02 KR KR1020147014768A patent/KR20140096100A/ko not_active Application Discontinuation
- 2012-11-02 BR BR112014010391A patent/BR112014010391A2/pt not_active IP Right Cessation
- 2012-11-02 ES ES12795138.2T patent/ES2552514T3/es active Active
- 2012-11-02 WO PCT/US2012/063171 patent/WO2013067260A1/en active Application Filing
- 2012-11-02 CN CN201280065858.5A patent/CN104105697B/zh not_active Expired - Fee Related
-
2015
- 2015-02-18 HK HK15101808.3A patent/HK1201268A1/zh not_active IP Right Cessation
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005014599A1 (en) * | 2003-06-04 | 2005-02-17 | Cellular Genomics, Inc. | Imidazo[1,2-a]pyrazin-8-ylamines and method of inhibition of bruton’s tyrosine kinase by such compounds |
CN101952283A (zh) * | 2007-12-14 | 2011-01-19 | 霍夫曼-拉罗奇有限公司 | 新型咪唑并[1,2-a]吡啶和咪唑并[1,2-b]哒嗪衍生物 |
WO2009137596A1 (en) * | 2008-05-06 | 2009-11-12 | Cgi Pharmaceuticals, Inc. | Substituted amides, method of making, and use as btk inhibitors |
CN102066377A (zh) * | 2008-07-18 | 2011-05-18 | 霍夫曼-拉罗奇有限公司 | 新型的苯基咪唑并吡嗪类 |
CN102164604A (zh) * | 2008-07-24 | 2011-08-24 | 百时美施贵宝公司 | 用作激酶调节剂的稠合杂环化合物 |
WO2010068810A2 (en) * | 2008-12-10 | 2010-06-17 | Cgi Pharmaceuticals, Inc. | Certain substituted amides, method of making, and method of use thereof |
WO2011112995A1 (en) * | 2010-03-11 | 2011-09-15 | Gilead Sciences, Inc. | Imidazopyridines syk inhibitors |
Non-Patent Citations (2)
Title |
---|
DI PAOLO JA ET AL.: "Specific Btk inhibition suppresses B cell- and myeloid cell-mediated arthritis", 《NATURE CHEMICAL BIOLOGY》, vol. 7, no. 1, 28 November 2010 (2010-11-28), pages 41 - 50, XP055080245, DOI: doi:10.1038/nchembio.481 * |
PAN ZY ET AL.: "Discovery of selective irreversible inhibitors for Bruton´s tyrosine kinase", 《CHEMMEDCHEM》, vol. 2, no. 1, 15 January 2007 (2007-01-15), pages 58 - 61 * |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107108604A (zh) * | 2014-10-27 | 2017-08-29 | 豪夫迈·罗氏有限公司 | 制备三环内酰胺化合物的方法 |
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WO2023143491A1 (zh) * | 2022-01-28 | 2023-08-03 | 和记黄埔医药(上海)有限公司 | 7,8-二氢-2h-环戊二烯并吡咯并吡嗪酮化合物的合成方法 |
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KR20140096100A (ko) | 2014-08-04 |
JP5808869B2 (ja) | 2015-11-10 |
US8722676B2 (en) | 2014-05-13 |
ES2552514T3 (es) | 2015-11-30 |
BR112014010391A2 (pt) | 2017-04-18 |
RU2014121073A (ru) | 2015-12-10 |
RU2628616C2 (ru) | 2017-08-21 |
EP2773640A1 (en) | 2014-09-10 |
MX2014005285A (es) | 2014-05-30 |
EP2773640B1 (en) | 2015-08-19 |
CA2852964A1 (en) | 2013-05-10 |
JP2014532715A (ja) | 2014-12-08 |
HK1201268A1 (zh) | 2015-08-28 |
WO2013067260A1 (en) | 2013-05-10 |
CN104105697B (zh) | 2016-11-09 |
US20130116262A1 (en) | 2013-05-09 |
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